(12) United States Patent (10) Patent No.: US 7,772.433 B2 Dalton Et Al

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(12) United States Patent (10) Patent No.: US 7,772.433 B2 Dalton et al. (45) Date of Patent: Aug. 10, 2010

(54) SARMS AND METHOD OF USE THEREOF 5,609,849 A 3/1997 Kung 5,612,359 A 3/1997 Murugesan et al. (75) Inventors: James T. Dalton, Upper Arlington, OH 5,656,651 A 8, 1997 Sovak et al. (US): Duane D. Miller, Germantown, 6,019,957 A 2/2000 Miller et al. TN (US) 6,043,265 A 3/2000 Murugesan et al. (73) Assignee: University of Tennessee Research 6,071,957 A 6/2000 Miller et al. Foundation, Knoxville, TN (US) 6, 160,011 A 12/2000 Miller et al. 6,482,861 B2 11/2002 Miller et al. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 6,492,554 B2 12/2002 Dalton et al. U.S.C. 154(b) by 550 days. 6,548,529 B1 4/2003 Roblet al. 6,569,896 B2 5/2003 Dalton et al. (21) Appl. No.: 11/785,250 6,777.427 B2 8/2004 Miyakawa et al. 6,838,484 B2 1/2005 Steiner et al. (22) Filed: Apr. 16, 2007 6,960,474 B2 11/2005 Salvati et al. (65) Prior Publication Data 7,026,500 B2 4/2006 Dalton et al. 2001/0012839 A1 8, 2001 Miller et al. US 2008/OO57O68A1 Mar. 6, 2008 2002/0173445 A1 11/2002 Salvati et al. Related U.S. Application Data 2004/0214790 A1 10/2004 Borgens et al. (60) Continuation-in-part of application No. 10/861.905, filed on Jun. 7, 2004, which is a continuation-in-part of application No. 10/371,155, filed on Feb. 24, 2003, FOREIGN PATENT DOCUMENTS application No. 1 1/785,250, which is a continuation in-part of application No. 1 1/723,957, filed on Mar. 22, EP O 040932 12/1981 2007, now abandoned, which is a division of applica EP O 100 172 2, 1984 tion No. 10/683,125, filed on Oct. 14, 2003, now Pat. EP OOO 2892 2, 1985 No. 7,214,693, application No. 1 1/785,250, which is a EP O 253 503 1, 1988 continuation-in-part of application No. 1 1/510,844, EP 1221439 T 2002 filed on Aug. 28, 2006. GB 1360001 3, 1970 (60) Provisional application No. 60/453,736, filed on Feb. JP 52-128329 1Of 1977 28, 2002, provisional application No. 60/423.381, JP 54-63047 12, 1980 filed on Nov. 4, 2002, provisional application No. WO WO 89/07110 8, 1989 60/418,173, filed on Oct. 15, 2002, provisional appli WO WO 89/07111 8, 1989 cation No. 60/712,390, filed on Aug. 31, 2005, provi WO WO93/04081 3, 1993 sional application No. 60/839,665, filed on Aug. 24, WO WO95/1977O 7, 1995 2006. WO WO9805962 2, 1998 (51) Int. Cl. C07C 23.3/05 (2006.01) A6 IK3I/I65 (2006.01) (52) U.S. Cl...... 564/175; 558/414: 514/522; (Continued) 514f617 OTHER PUBLICATIONS (58) Field of Classification Search ...... 564/175; 558/414: 514/522,617 U.S. Appl. No. 09/644,970, filed Aug. 2, 2000, Dalton et al. See application file for complete search history. (Continued) (56) References Cited Primary Examiner Shailendra Kumar U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm—Mark S. Cohen: Pearl Cohen Zedek Latzer, LLP 3,875,229 A 4, 1975 Gold 4,139,638 A 2f1979 Neri et al. (57) ABSTRACT 4,191,775 A 3, 1980 Glen 4,239,776 A 12/1980 Glen et al. 4,282,218 A 8, 1981 Glen et al. 4,386,080 A 5/1983 Crossley et al. This invention provides SARM compounds and uses thereof 4411,890 A 10/1983 Momany et al. in treating a variety of diseases or conditions in a Subject, 4,465,507 A 8, 1984 Konno et al. including, inter-alia, muscle wasting diseases and/or disor 4,636,505 A 1, 1987 Tucker ders, bone-related diseases and/or disorders, diabetes, cardio 4,880,839 A 11, 1989 Tucker vascular disease, renal disease and others. 5,162,504 A 11/1992 Horoszewicz 5,179,080 A 1/1993 Rothkopfet al. 7 Claims, 15 Drawing Sheets US 7,772.433 B2 Page 2

FOREIGN PATENT DOCUMENTS pyridono5,6-glguinolines: potent, nonsteroidal androgen receptor agonists. Bioorg. Med. Chem. Lett., 9:1335, 1999. WO WO 98.53826 12/1998 Hamann LG. Mani NS, Davis RL. Wang XN, Marschke KB, and WO WO98,55153 12/1998 Jones TK. Discovery of a potent, orally active nonsteroidal androgen WO WO/O1/27086 4/2001 receptor agonists: 4-ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8- WO WOO127622 4/2001 pyridono.5,6-g-quinoline (LG 121071). J. Med. Chem., 42: 210, WO WOO128990 4/2001 1999. WO WOO1 34.563 5, 2001 Rosen J. Day A. Jones TK, Jones ET, Nadzan AM, and Stein RB. WO WOO168603 9, 2001 Intracellular receptors and signal transducers and activators of tran WO WOO2 OO617 1, 2002 Scription Superfamilies: novel targets for Small-molecule drug dis WO WO O2, 16310 2, 2002 covery. J. Med. Chem., 38: 4855, 1995. WO WO?O2.22585 3, 2002 Dalton JT. Mukherjee A. Zhu Z, Kirkovsky L, and Miller DD. Dis WO WOf O3,O77919 9, 2003 covery of Nonsteroidal Androgens. Biochem. Biophys. Res. Com OTHER PUBLICATIONS mun.,244(1): 1-4, 1998. Edwards JP, West SJ, Pooley CLF, Marschke KB, Farmer LJ, and U.S. Appl. No. 09/935,044, filed Aug. 23, 2001, Dalton et al. Jones TK. New nonsteroidal androgen receptor modulators based on U.S. Appl. No. 09/935,045, filed Aug. 23, 2001, Dalton et al. 4-(trifluoromethyl)-2-(III)-Pyrololidino.3.2-gquinolone. Bioorg. U.S. Appl. No. 10/298,229, filed Nov. 28, 2002, Miller et al. Med. Chem. Lett., 8: 745, 1998. U.S. Appl. No. 10/270.232, filed Oct. 15, 2002, Dalton et al. Eliason et al., “High Throughput Fluorescence Polarization-Based U.S. Appl. No. 10/277.108, filed Oct. 23, 2002, Dalton et al. Screening Assays for the Identification of Novel Nuclear Receptor U.S. Appl. No. 10/270,233, filed Oct. 15, 2002, Dalton et al. Ligands.” Abstracts of Papers, 223rd ACS National Meeting, U.S. Appl. No. 10/270.732, filed Oct. 15, 2002, Dalton et al. Orlando, FL, United States, (2002), Apr. 7, 2002. U.S. Appl. No. 10/310,150, filed Dec. 5, 2002, Steiner et al. Berger et al., “Concepts and limitations in the application of Howard Tucker and Glynne J. Chesterson, J. Med Chem, 1988, 31. radiolabeled antiandrogens, estrogens, or androgens as isotropic pp. 885-887. “Resolution of the Nonsteroidal Antiandrogen -4'- scanning agents for the prostate'. Invest. Urol. (1975), 1391, 10-16. Cyano-3-(4-fluorophenyl)-sulfonyl-2-hydroxy-2-methyl-3'- Wahner, et al (1984) “Assesment of Bone Mineral Part I” J. Nucl. (trifluoromethyl)-propionanilide and the Determination of the Abso Medicine, 1134-1141. lute Configuration of the Active Enantiomer'. Wahner, et al (1985) “Bone Mineral Density of the Radius' J. Nucl D. McKillop, et al., “Enantioselective metabolism and Medicine 26 13-39. pharmacokinetics of Casodex in the male rat', Xenobiotica, 1995, vol. 25, No. 6, 623-634. Faulkner KG, etal (1991) “Noninvasive measurements of bone mass, Leonid Kirkovsky, et al., “I''Il-Radionated Bicalutamide Analogs structure, and strength: current methods and experimental tech as Potential Imaging Agents for Prostate Cancer', Poster Presenta niques.” Am J Rosentgenology 157: 1229-1237. tion MEDI 155, 214th ACS National Meeting, Las Vegas, NV. Sep. Hanada, K., et al (2003) “Bone anabolic effects of S-40503, a novel 7-11, 1997. Department of Pharmaceutical Sciences, University of nonsteroidal selective androgen receptor modulator (SARM), in rat Tennessee, Memphis, TN38163. models of osteoperosis.” Biol. Pharm. Bull. 26:1563-1569. David T. Baird and Anna F. Glasier, "Hormonal Kalu, DN. (1991) “The ovariectomized rat model of postmenopausal Contraception—Drug Therapy'. The New England Journal of Medi bone loss. Bone Miner 15, 175-91. cine, May 27, 1993, pp. 1543-1549. Langer (1990) “New methods of drug delivery.” Science 249:1527 F.C. W. Wu, “Male Contraception: Current Status and Future Pros 1533. pects”. Clinical Endocrinology, (1988), 29, pp. 443-465. Negro-Vilar, A. (1999) “Selective androgen receptor modulators Carl Djerassi and S.P. Leibo, "A new look at male contraception'. (SARMs): a novel approach to androgen therapy for the new illen Nature, vol. 370, pp. 11-12. nium. J. Clin. Endocrin Metabol. 84:3459-3462. World Health Organisation Task Force on Methods for the Regulation Koski GK, Kariko K, Xu S, Weissman D, Cohen PA, Czerniecki B.J. of Male Fertility, “Contraceptive efficacy of testosterone-induced Cutting edge: innate immune system discriminates between RNA azoospermia in normal men'. The Lancet, vol. 336, Oct. 20, 1990, pp. containing bacterial versus eukaryotic structural features that prime 955-959and 1517-1518. for high-level 11-12 secretion by dendritic cells. J Immunol. Apr. 1, C. G. Francisco, et al., “Long-acting contraceptive agents: 2004: 172(7):3989-93. testosterone esters of unsaturated acids', Steroids, Jan. 1990, vol. 55, Heil F. Hemmi II, Hochrein II, Ampenberger F. Kirschning C, Akiru Butterworths. S. Lipford G. Wagner II, Bauer S. Species-specific recognition of John M. Hoberman and Charles E. Yesalis, “The History of Synthetic single-stranded RNA via toll-like receptor 7 and 8. Science. Mar. 5, Testosterone”, Scientific American, Feb. 1995, pp. 76-81. 2004:303(5663): 1526-9. Leonid Kirkovsky, et al., “Approaches to Irreversible non-steroidal Diebold SS, Kaisho T, Hemmi II, Akiru S, Reis e Sousa C. Innate chiral antiandrogens'. Department of Pharmaceutical Sciences, Uni antiviral responses by means of TLR7-mediated recognition of versity of Tennessee, 47th Southeast/51st Southwest Joint Regional single-stranded RNA. Science. Mar. 5, 2004:303(5663): 1529-31. Meeting of the American Chemical Society, Memphis, TN, Nov. Campfield et al., 1995, “Recombinant mouse OB protein: evidence 29-Dec. 1, 1995. for a peripheral signal linking adiposity and central neural networks' David J. Handelsman, “Bridging the gender gap in contraception: Science 269:546-549. another hurdle cleared” The Medical Journal of Australia, vol. 154, Considine et al., 1995, “Evidence against either a premature stop Feb. 18, 1996, pp. 230-233. endon or the absence of obese gene mRNA in human obesity.” J. Clin. Edwards.JP. Higuchi RI, Winn DT. Pooley CLF, Caferro TR, Hamann Invest. 95:2986-2988. LG, Zhi L. Marschke KB, Goldman ME, and Jones TK. Nonsteroidal androgen receptor agonists based on 4-(trifluoromethyl)-2II Grundy, 1990, Disease-a-Month 36:645-696. pyrano.3.2-gquinolin-2-one. Bioorg. Med. Chem. Lett., 9; 1003, Halaas et al., 1995, “Weight-Reducing effects of the plasma protein 1999. encoded by the obese gene.” Science 269:543-546. Zhi L. Tegley CM, Marschke KB, and Jones TK. Switching androgen Hamilton et al., 1995, <

Singh et al., 2003, 'Androgens stimulate myogenic differentiation Yepuru, etal "AN Androgen Receptor-b Specific Selective Estrogen and inhibit adipogenesis in C3H IOTI/2 pluripotent cells through an Receptor Modulator (SERM) Inhibits the Growth of the Prostate androgen receptor-mediated pathway.” Endocringology, Cancer Cells and Stromal-Epithilial Tumor Xenograft”. The Endo 144(11):5081-8. crine Society Programs and Abstracts 89" Annual Meeting Paper Sefton, 1987. “Implantable pumps.” CRC Cric. Ref. Biomed. Eng. OR6-3. 14:2O1. Dalton, et al "Therapeutic Promise of Selective Androgen Receptor Narayanan, et all “Steroidal Androgens and Nonsteroidal, Tissue Modulators (SARSs): Preclinical and Clinical Proof-of-Concept Selective Androgen Receptor Modulators (SARM) Regulate Andro Studies.”The Endocrine Society Programs and Abstracts 89" gen Receptor Function Through Distinct Genomic and Non Annual Meeting Paper S41-2. Genomic Signaling Pathways.” The Endocrine Society—Programs Edwards, J. P. et al., Bio. Med. Chem. Let., 9, 1003-1008 (1999). and Abstracts 89" Annual Meeting Paper P1-595. Hamann, L. G. et al., J. Med. Chem, 42, 210-212 (1999).

U.S. Patent Aug. 10, 2010 Sheet 3 of 15 US 7,772.433 B2

E. Synthetic Scierge for (S- oxirane intern ediate Cospot: i:

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U.S. Patent Aug. 10, 2010 Sheet 7 Of 15 US 7,772.433 B2

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Figure U.S. Patent Aug. 10, 2010 Sheet 10 of 15 US 7,772.433 B2

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U.S. Patent Aug. 10, 2010 Sheet 13 of 15 US 7,772.433 B2

U.S. Patent Aug. 10, 2010 Sheet 14 of 15 US 7,772.433 B2

U.S. Patent Aug. 10, 2010 Sheet 15 Of 15 US 7,772.433 B2

US 7,772,433 B2 1. 2 SARMS AND METHOD OF USE THEREOF (Sundaram et al., “7 Alpha-Methyl-Nortestosterone (MENT): The Optimal Androgen For Male Contraception.” CROSS REFERENCE TO RELATED Ann. Med., 25:199-205 (1993) (“Sundaram'). Because the APPLICATIONS AR is involved in male sexual development and function, the 5 AR is a likely target for effecting male contraception or other This application is a Continuation-In-Part Application of forms of hormone replacement therapy. U.S. patent application Ser. No. 10/861,905 filed Jun. 7, 2004, Worldwide population growth and social awareness of which is a Continuation-In-Part Application of U.S. patent family planning have stimulated a great deal of research in application Ser. No. 10/371,155 filed Feb. 24, 2003, which contraception. Contraception is a difficult Subject under any claims the benefit of U.S. Provisional Patent Application Ser. 10 circumstance. It is fraught with cultural and Social Stigma, No. 60/453,736 filed Feb. 28, 2002 and U.S. Provisional religious implications, and, most certainly, significant health Patent Application Ser. No. 60/423.381, filed Nov. 4, 2002: concerns. This situation is only exacerbated when the Subject and this Application is a Continuation-In-Part Application of focuses on male contraception. Despite the availability of U.S. patent application Ser. No. 1 1/723,957, filed on Mar. 22, Suitable contraceptive devices, historically, Society has 2007, now abandoned which is a Divisional Application of 15 looked to women to be responsible for contraceptive deci U.S. patent application Ser. No. 10/683,125, filed on Oct. 14, sions and their consequences. Although concern over sexu 2003, now U.S. Pat. No. 7,214,693 which claims the benefit ally transmitted diseases has made men more aware of the of U.S. Provisional Patent Application Ser. No. 60/418,173, need to develop safe and responsible sexual habits, women filed Oct. 15, 2002; and this Application is a Continuation still often bear the brunt of contraceptive choice. Women have In-Part Application of U.S. patent application Ser. No. a number of choices, from temporary mechanical devices 11/510,844, filed on Aug. 28, 2006, which claims the benefit Such as sponges and diaphragms to temporary chemical of U.S. Provisional Patent Application No. 60/712,390, filed devices such as spermicides. Women also have at their dis Aug. 31, 2005; and this Application claims the benefit of U.S. posal more permanent options, such as physical devices Provisional Application Ser. No. 60/839,665, filed Aug. 24. including IUDs and cervical caps as well as more permanent 2006, all of which are hereby incorporated by reference in 25 chemical treatments such as birth control pills and Subcuta their entirety. neous implants. However, to date, the only options available for men include the use of condoms and vasectomy. Condom GOVERNMENT INTEREST STATEMENT use, however is not favored by many men because of the reduced sexual sensitivity, the interruption in sexual sponta This invention was made in whole or in part with govern 30 neity, and the significant possibility of pregnancy caused by ment support under grant number R01 DK598006, awarded breakage or misuse. Vasectomies are also not favored. If more by the National Institute of Health; under grant number R29 convenient methods of birth control were available to men, CA068096 awarded by the National Cancer Institute, particularly long-term methods which require no preparative National Institute of Health; under grant number R15 activity immediately prior to a sexual act, Such methods could HD35329, awarded by the National Institute of Child Health 35 significantly increase the likelihood that men would take and Human Development, National Institute of Health and more responsibility for contraception. under grant number R01 DK598.00, awarded by the National Administration of the male sex steroids (e.g., testosterone Institute of Health. The government may have certain rights and its derivatives) has shown particular promise in this in the invention. regard due to the combined gonadotropin-suppressing and 40 androgen-Substituting properties of these compounds (Stein BACKGROUND OF THE INVENTION berger et al., “Effect of Chronic Administration of Testoster one Enanthate on Sperm Production and Plasma Testoster The androgen receptor (“AR”) is a ligand-activated tran one. Follicle Stimulating Hormone, and Luteinizing Scriptional regulatory protein that mediates induction of male Hormone Levels: A Preliminary Evaluation of a Possible sexual development and function through its activity with 45 Male Contraceptive, Fertility and Sterility 28:1320-28 endogenous androgens. Androgens are generally known as (1977)). Chronic administration of high doses of testosterone the male sex hormones. The androgenic hormones are ste completely abolishes sperm production (aZoospermia) or roids which are produced in the body by the testes and the reduces it to a very low level (oligospermia). The degree of cortex of the adrenal gland or can be synthesized in the spermatogenic Suppression necessary to produce infertility is laboratory. Androgenic steroids play an important role in 50 not precisely known. However, a recent report by the World many physiologic processes, including the development and Health Organization showed that weekly intramuscular injec maintenance of male sexual characteristics Such as muscle tions oftestosterone enanthate resultinaZoospermia or severe and bone mass, prostate growth, spermatogenesis, and the oligospermia (i.e., less than 3 million sperm per ml) and male hair pattern (Matsumoto, Endocrinol. Met. Clin. N. Am. infertility in 98% of men receiving therapy (World Health 23:857-75 (1994)). The endogenous steroidal androgens 55 Organization Task Force on Methods And Regulation of Male include testosterone and dihydrotestosterone (“DHT). Test Fertility, “Contraceptive Efficacy of Testosterone-Induced osterone is the principal steroid secreted by the testes and is AZoospermia and Oligospermia in Normal Men.' Fertility the primary circulating androgen found in the plasma of and Sterility 65:821-29 (1996)). males. Testosterone is converted to DHT by the enzyme 5 A variety of testosterone esters have been developed which alpha-reductase in many peripheral tissues. DHT is thus 60 are more slowly absorbed after intramuscular injection and thought to serve as the intracellular mediator for most andro thus result in greater androgenic effect. Testosterone enan gen actions (Zhou, et al., Molec. Endocrinol. 9:208-18 thate is the most widely used of these esters. While testoster (1995)). Other steroidal androgens include esters of testoster one enanthate has been valuable in terms of establishing the one. Such as the cypionate, propionate, phenylpropionate, feasibility of hormonal agents for male contraception, it has cyclopentylpropionate, isocarporate, enanthate, and 65 several drawbacks, including the need for weekly injections decanoate esters, and other synthetic androgens such as and the presence of Supraphysiologic peak levels of testoster 7-Methyl-Nortestosterone (“MENT) and its acetate ester one immediately following intramuscular injection (Wu, US 7,772,433 B2 3 4 “Effects of Testosterone Enanthate in Normal Men: Experi Cancer Cachexia, malnutrition, Leprosy, Diabetes, Renal ence From a Multicenter Contraceptive Efficacy Study.” Fer Disease, Chronic Obstructive Pulmonary Disease (COPD), tility and Sterility 65:626-36 (1996)). Cancer, end stage Renal failure, Sarcopenia, Emphysema, Bone mineral density (BMD) decreases with age in both Osteomalacia, HIV Infection, AIDS, and Cardiomyopathy. males and females. Decreased amounts of bone mineral con 5 In addition, other circumstances and conditions are linked tent (BMC) and BMD correlate with decreased bone strength to and can cause muscle wasting. These include chronic lower and predispose patients to fracture. back pain, advanced age, central nervous system (CNS) Osteoporosis is a systemic skeletal disease, characterized injury, peripheral nerve injury, spinal cord injury, chemical by low bone mass and deterioration of bone tissue, with a injury, central nervous system (CNS) damage, peripheral consequent increase in bone fragility and Susceptibility to 10 nerve damage, spinal cord damage, chemical damage, burns, fracture. In the U.S., the condition affects more than 25 mil disuse deconditioning that occurs when a limb is immobi lion people and causes more than 1.3 million fractures each lized, long term hospitalization due to illness or injury, and year, including 500,000 spine, 250,000 hip and 240,000 wrist alcoholism. fractures annually. Hip fractures are the most serious conse An intact androgen receptor (AR) signaling pathway is quence of osteoporosis, with 5-20% of patients dying within 15 crucial for appropriate development of skeletal muscles. Fur one year, and over 50% of survivors being incapacitated. The thermore, an intact AR-signaling pathway increases lean elderly are at greatest risk of osteoporosis, and the problem is muscle mass, muscle strength and muscle protein synthesis. therefore predicted to increase significantly with the aging of Muscle wasting, if left unabated, can have dire health con the population. Worldwide fracture incidence is forecasted to sequences. For example, the changes that occur during increase three-fold over the next 60 years, and one study muscle wasting can lead to a weakened physical state that is estimated that there will be 4.5 million hip fractures world detrimental to an individuals health, resulting in increased wide in 2050. Susceptibility to infraction and poor performance status. In Women are at greater risk of osteoporosis than men. addition, muscle wasting is a strong predictor of morbidity Women experience a sharp acceleration of bone loss during and mortality in patients suffering from cachexia and AIDS. the five years following menopause. Other factors that 25 New innovative approaches are urgently needed at both the increase the risk include Smoking, alcohol abuse, a sedentary basic science and clinical levels to develop compounds which lifestyle and low calcium intake. However, osteoporosis also are useful for a) male contraception; b) treatment of a variety occurs frequently in males. It is well established that the bone of hormone-related conditions, for example conditions asso mineral density of males decrease with age. Decreased ciated with Androgen Decline in Aging Male (ADAM), such amounts of bone mineral content and density correlates with 30 as fatigue, depression, decreased libido, sexual dysfunction, decreased bone strength, and predisposes to fracture. The erectile dysfunction, hypogonadism, osteoporosis, hair loss, molecular mechanisms underlying the pleiotropic effects of anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign sex-hormones in non-reproductive tissues are only beginning prostate hyperplasia, alterations in mood and cognition and to be understood, but it is clear that physiologic concentra prostate cancer; c) treatment of conditions associated with tions of androgens and estrogens play an important role in 35 ADIF, such as sexual dysfunction, decreased sexual libido, maintaining bone homeostasis throughout the life-cycle. hypogonadism, sarcopenia, osteopenia, osteoporosis, alter Consequently, when androgen or estrogen deprivation occurs ations in cognition and mood, depression, anemia, hair loss, there is a resultant increase in the rate of bone remodeling that obesity, endometriosis, breast cancer, uterine cancer and ova tilts the balance of resorption and formation to the favor of rian cancer; d) treatment and/or prevention of chronic mus resorption that contributes to the overall loss of bone mass. In 40 cular wasting; e) decreasing the incidence of halting or caus males, the natural decline in sex-hormones at maturity (direct ing a regression of prostate cancer, f) oral androgen decline in androgens as well as lower levels of estrogens replacement and/or other clinical therapeutic and/or diagnos derived from peripheral aromatization of androgens) is asso tic areas. ciated with the frailty of bones. This effect is also observed in males who have been castrated. 45 A wide variety of diseases and/or conditions are affected Muscle wasting refers to the progressive loss of muscle by hypogonadism, and catabolic effects, including kidney mass and/or to the progressive weakening and degeneration disease, central nervous system injuries, burns and chronic of muscles, including the skeletal or Voluntary muscles, wounds. which control movement, cardiac muscles, which control the In the United States (US), there is a rising incidence and heart (cardiomyopathics), and Smooth muscles. Chronic 50 prevalence of kidney failure. The number of patients enrolled muscle wasting is a chronic condition (i.e. persisting over a in end-stage renal disease (ESRD) Medicare-funded pro long period of time) characterized by progressive loss of grams has increased from approximately 10,000 beneficiaries muscle mass, weakening and degeneration of muscle. in 1973 to 86,354 in 1983, and to 431,284 as of Dec. 31, 2002. The loss of muscle mass that occurs during muscle wasting In 2002 alone, 100,359 patients entered the US ESRD pro can be characterized by muscle protein degradation by 55 gram. Chronic kidney disease (CKD) is a precursor to ESRD catabolism. Protein catabolism occurs because of an unusu and occurs when the kidneys are not able to adequately ally high rate of protein degradation, an unusually low rate of remove wastes from the body. CKD is a slowly progressing protein synthesis, or a combination of both. Muscle protein disease, in which diabetes, hypertension and anemia may be catabolism, whether caused by a high degree of protein deg co-morbid conditions. radation or a low degree of protein synthesis, leads to a 60 CKD is diagnosed using a staging system that demon decrease in muscle mass and to muscle wasting. strates the amount of kidney function available (stage 1-nor Muscle wasting is associated with chronic, neurological, mal kidney function) and patients often do not present symp genetic or infectious pathologies, diseases, illnesses or con toms in the early stages. Stage 5 of CKD is ESRD, which is a ditions. These include Muscular Dystrophies such as Duch complete or near complete failure of the kidneys and usually enne Muscular Dystrophy and Myotonic Dystrophy; Muscle 65 occurs when kidney function is less than 10% of baseline. Atrophies such as Post-Polio Muscle Atrophy (PPMA): Accompanying symptoms associated with ESRD include Cachexias such as Cardiac Cachexia, AIDS Cachexia and hypogonadism, involuntary weight loss, fatigue and others. US 7,772,433 B2 5 6 Burns result in a testosterone reduction, nitrogen level In one embodiment, the present invention provides, a com reduction and a reduction in bone mineral density (BMD), pound represented by the structure of formula II: which may persist even as long one year following the injury and is associated with impaired wound healing, increased II infection risks, erosion of lean body mass, hampered reha NC C bilitation, and delayed reintegration of burn survivors into society. Catabolic effects initiated as a result of the burn lead to significant involuntary weight loss, further compounding FC NH the problem. 10 Hd oH Spinal cord injuries may result in the alteration central neurotransmitter secretion or production, which in turn may cause a hypothalamus-pituitary-adrenal axis dysfunction, or its isomer, pharmaceutically acceptable salt, pharma leading to decreases intestosterone and otherhormone levels. ceutical product, N-oxide, hydrate or any combination SCI or other acute illness or trauma characteristically 15 thereof. includes heightened catabolism in conjunction with the low In one embodiment, the present invention provides, a com ered anabolic activity resulting in a condition that is prone to pound represented by the structure of formula III: loss of lean body tissue. As long as the catabolic process goes uninterrupted, disturbed nutrient utilization will continue. III The effects of the loss of lean body mass include the devel m(R3) opment of wounds and impaired healing mechanisms. Because of poor nutrition and protein combined with immo bilization, patients with spinal cord injury are at high risk for bed sores. 25 Chronic wounds may be caused by any number of condi tions, including diabetes, circulatory problems, immobiliza tion and others. Compounding the problem, for example in wherein X is a bond, O, CH, NH, Se, PR, NO or NR; diabetes, is the presence of neuropathy, which increases the 30 risk of foot ulceration. G is O or S: While there are many treatments and therapies for these T is OH, OR, NHCOCH, or NHCOR; conditions, none are ideal. Since the androgen receptor (AR) R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl or signaling pathway has been shown to increase lean muscle 35 mass, muscle strength and muscle protein synthesis, and OH: since hypogonadism accompanies these conditions, mol R is CH, CHF, CHF, CF, CHCH, or CFCF: ecules targeting the AR signaling pathway may be useful in R is H, F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, treating these diseases and/or conditions. NHCOCF, NHCOR, alkyl, arylalkyl, OR, NH, NHR, 40 N(R), SR; SUMMARY OF THE INVENTION R is H, F, Cl, Br, I, CN, NO, COR, COOH,CONHR, CF, Sn(R), or In one embodiment, the present invention provides, a com R together with the benzene ring to which it is attached pound represented by the structure of formula (I): 45 forms a fused ring system represented by the structure:

(I)

55 Z is NO, CN, C1, F, Br, I, H, COR, COOH, or CONHR: wherein Q, is alkyl, F, Cl, Br, I, CF, CN, C(R), Sn(R), Y is CF, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, formyl, H, F, Br, Cl, I, CN, or Sn(R): NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, 60 NHCSRNHSOCH, NHSOR, OR, COR, OCOR, OSOR, Q is H, alkyl, halogen, CF, CN CR, Sn(R), N(R), NHCOCH NHCOCF, NHCOR, NHCONHR, SOR, SR; and NHCOOR, OCONHR, CONHR, NHCSCH, NHC R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF. SCF, NHCSR NHSOCH, NHSOR, OH, OR, COR, CF, CFCF, aryl, phenyl, F, Cl, Br, I, alkenyl or OH: 65 OCOR, OSOR, SOR, SR: or Q together with the ben or its isomer, pharmaceutically acceptable salt, pharmaceuti Zene ring to which it is attached is a fused ring system cal product, N-oxide, hydrate or any combination thereof. represented by structure A, B or C: US 7,772,433 B2 7 8 In one embodiment, the therapeutic agent is an anti-andro gen, an antiestrogen, a monoclonal antibody, a chemothera peutic agent, an immunosuppressive or anti-inflammatory 21 NH O A agent, an immunostimulatory agent, a Sulfonylurea, meglit nide, insulin, biguanide, thiazolidinedione, or alpha-glucosi dase inhibitor, an adrenomimetic agent, adrenoceptor antago Ás nist, cholinomimetic agent, a muscarinic blocker, a ganglionic blocker, an anesthetic agent, an analgesic agent, an 21 NH O B agent treating neuromuscular transmission, a nervous system 10 stimulant, a sedative agent, neurodegenerative disorder medi cation, antiepileptic agent, antipsychotic agent, anti-addic Ás 2 tion agent, an anti-arrhythmic agent, an anti-anginal agent, a vasocative agent, a calcium channel blocker, an antihyperten 21 NH C sive agent, a diuretic agent, an anticoagulant or fibrinolytic 15 agent, a hypocholesterolemic agent, an opioid, 5-HT3 recep yul/ tor antagonist, adsorbent agent, bulking agent, a stool soften ing or laxative agent, cathartic agent, an antiemetic agent, an emetic agent, an antacid agent, an H2-receptor antagonist, a n is an integer of 1-4; and proton pump inhibitor, a 5-aminosalicylate agent, a prostag landin, a glucocorticosteroid, a retinoid, photochemothera m is an integer of 1-3: peutic agent, a photodynamic agent, aminolevulinic acid, or its isomer, pharmaceutically acceptable salt, pharma dapsone, pyrethrin, pyrethroid, thalidomide, an antimalarial ceutical product, N-oxide, hydrate or any combination agent, an antimicrobial agent, an antifungal agent, an antiviral thereof. agent, a Sulfonamide, a trimethoprim agent, a quinolone In one embodiment, Z, Y and Q are not H. In one embodi 25 agent, an oxazolidinone agent, an antiseptic agent, a beta ment, Z.Y. Q and R are not H, if R is H. In one embodiment, lactam agent, an aminoglycoside agent, a tetracycline agent, Z. Y. Q and Rs are not H, if R is H. a chloramphenicol agent, a macrollide agent, a lincosamide In one embodiment, Z is NO, CN, Cl, F, Br, I, COR, agent, a bacitracin agent, a glycopeptide agent, a polymyxin COOH, or CONHR: Y is CF, alkoxy, alkyl, hydroxyalkyl, agent, an antiprotozoal agent, an antithelmintic agent, a cor alkylaldehyde, formyl, F, Br, Cl, I, CN, or Sn(R); andR is H. 30 tisone, a colchicine, a methotrexate, a ursodeoxycholic acid, F, Cl, Br, I, CN, NO, COR, COOH, CONHR, CF, Sn(R). a penicillamine, a vitamin, glucosidase alpha, Sodium bicar According to this aspect, and in one embodiment, neither R bonate, bisphosphonate, biotin, allopurinol, levodopa, diaz nor Q is H. epam, phenobarbital, haloperidol, folic acid, haptoglobin, In one embodiment, the present invention provides a com carnitine, a steroid, cannabinoid metoclopramid, cisapride, pound characterized by the structure of formula IV: 35 medroxyprogesterone acetate, megestrol acetate, cyprohep tadine, hydrazine Sulfate, pentoxifylline, thalidomide, anticy tokine antibodies, cytokine inhibitors, eicosapentaenoic acid,

IV indomethacin, ibuprofen, melatonin, insulin, growth hor mone, clenbuterol, pancreas extract, cabergoline, bromocrip 40 tine, thyroXine, gonadotropin, glucocorticoid, glucocorticoid analogue, corticotrophin, metyrapone, aminoglutethimide, mitotane, ketoconazole, mifepristone, dexamethasone Soma to statin analogue, gonadotropin-releasing hormone ana logue, leuprolide, goserelin, antidiuretic hormone, antidi 45 uretic hormone analogue, oxytocin, estrogen, progestin, specific estrogen receptor modulator (SERM), uterine, stimu In one embodiment, the present invention provides a com lant, uterine relaxant, androgen, antiandrogen, prostaglandin, position comprising the compound of formula (I), (II), (III) or dopamine receptor agonist, alpha-adrenoreceptor blocker, (IV) and/or its derivative, isomer, pharmaceutically accept anabolic steroid, an antianxiety agent, an antipsychotic agent, able salt, pharmaceutical product, crystal, hydrate, N-oxide 50 an antidepressant, beta-2 agonist, anticholinergic bronchodi or any combination thereof. lator, theophylline, aminophylline, nedocromil Sodium, In one embodiment, the compounds of this invention are Sodium cromoglycate, leukotriene receptor antagonist, corti selective androgen receptor modulators. costeroid, expectorant, mucolytic agent, antihistamine, pseu In one embodiment, the compositions of this invention doephedrine, or a neuraminidase inhibitor, betagan, betimol, further comprise a therapeutic agent, which in one embodi 55 timoptic, betoptic, betoptic, ocupress, optipranolol. Xalatan, ment is an anti-cancer agent, an immunomodulating agent, an alphagan, azopt, trusopt, cospot, pilocar, pilagan, propine, agent treating diabetes, an agent treating the nervous system, opticrom, acular, livostin, alomide, emadine, patanol, alrex, an agent treating the cardiovascular system, an agent treating dexacidin, maxitrol, tobradex, blephamide, ocufen, Voltaren, the gastrointestinal system, an agent treating a dermatologi profenal, pred forte, econpred plus, eflone, flarex, inflamase cal disease, or condition, an anti-infective agent, an agent 60 forte, inflamase mild, lotemax, Vexol, polytrim, illotycin, cil treating the liver, an agent treating the kidney, an agent treat oxan, ocuflox, tobrex, or garamycin, or any combination ing a metabolic disease, an agent treating a wasting disease, a thereof. gene therapy agent, an agent treating the endocrine system, a In one embodiment, this invention provides a method of Vitamin, a stomatognathic agent, a urogenital agent, behav binding a selective androgen receptor modulator compound ior-modulating agent, an agent treating the respiratory sys 65 to an androgen receptor, comprising the step of contacting the tem, an agent treating the hemic System, an agent treating an androgen receptor with the compound of this invention or its ophthalmic disease, or any combination thereof. isomer, pharmaceutically acceptable salt, pharmaceutical US 7,772,433 B2 10 product, polymorph, crystal, hydrate, N-oxide or any combi thereof, or a composition comprising the same, in an amount nation thereof, or a composition comprising the same, in an effective to treat the muscle wasting disorder in said subject. amount effective to bind the selective androgen receptor According to this aspect, and in one embodiment, the modulator compound to the androgen receptor. muscle wasting disorder is due to a pathology, illness, disease In one embodiment, this invention provides a method of Suppressing spermatogenesis in a subject comprising con or condition. In one embodiment, the pathology, illness, dis tacting an androgen receptor of the Subject with the com ease or condition is neurological, infectious, chronic or pound of this invention or its isomer, pharmaceutically genetic. In one embodiment, the pathology, illness, disease or acceptable salt, pharmaceutical product, crystal, hydrate, condition is a Muscular Dystrophy, a Muscular Atrophy, N-oxide or any combination thereof, or a composition com 10 X-linked spinal-bulbar Muscular Atrophy (SBMA), a prising the same, in an amount effective to Suppress sperm Cachexia, malnutrition, Leprosy, Diabetes, Renal Disease, production. Chronic Obstructive Pulmonary Disease (COPD), Cancer, In one embodiment, this invention provides a method of end stage Renal failure, Sarcopenia, Emphysema, Osteoma contraception in a male Subject, comprising the step of lacia, HIV Infection, AIDS, or Cardiomyopathy. administering to the Subject a compound of this invention or 15 In one embodiment, the muscle wasting disorder is an its isomer, pharmaceutically acceptable salt, pharmaceutical age-associated muscle wasting disorder; a disuse decondi product, crystal, hydrate, N-oxide or any combination tioning-associated muscle wasting disorder; or the muscle thereof, or a composition comprising the same, in an amount wasting disorder is due to chronic lower back pain; burns; effective to Suppress sperm production in the Subject, thereby central nervous system (CNS) injury or damage; peripheral effecting contraception in the Subject. nerve injury or damage; spinal cord injury or damage; chemi In one embodiment, this invention provides a method of cal injury or damage; or alcoholism. hormonetherapy comprising the step of contacting an andro In one embodiment, this invention provides a method of gen receptor of a Subject a compound of this invention or its treating, reducing the severity of reducing the incidence of isomer, pharmaceutically acceptable salt, pharmaceutical delaying the onset of, or reducing pathogenesis of diabetes in product, crystal, hydrate, N-oxide or any combination 25 a human Subject, comprising administering an effective thereof, or a composition comprising the same, in an amount amount of a compound of this invention or its isomer, phar effective to effect a change in an androgen-dependent condi maceutically acceptable salt, pharmaceutical product, crys tion. tal, N-oxide, hydrate or any combination thereof, to said In one embodiment, this invention provides a method of Subject. treating a Subject Suffering from prostate cancer, comprising 30 In one embodiment, this invention provides, a method of the step of administering to said Subject a compound of this treating, reducing the severity of reducing the incidence of invention, or its isomer, pharmaceutically acceptable salt, delaying the onset of or reducing pathogenesis of glucose pharmaceutical product, crystal, hydrate, N-oxide or any intolerance in a human Subject, comprising the step of admin combination thereof, or a composition comprising the same istering an effective amount of a compound of this invention in an amount effective to treat prostate cancer in the Subject. 35 or its isomer, pharmaceutically acceptable salt, pharmaceuti In one embodiment, this invention provides a method of cal product, crystal, N-oxide, hydrate or any combination delaying the progression of prostate cancer in a Subject Suf thereof to said subject. fering from prostate cancer, comprising the step of adminis In one embodiment, this invention provides a method of tering to said Subject a compound of this invention or its treating, reducing the severity of reducing the incidence of isomer, pharmaceutically acceptable salt, pharmaceutical 40 delaying the onset of, or reducing pathogenesis of hyperin product, crystal, N-oxide, hydrate, or any combination Sulinemia in a human Subject, comprising the step of admin thereof, or a composition comprising the same in an amount istering an effective amount of a compound of this invention effective to delay the progression of prostate cancer in the or its isomer, pharmaceutically acceptable salt, pharmaceuti Subject. cal product, crystal, N-oxide, hydrate or any combination In one embodiment, this invention provides a method of 45 treating a bone-related disorder in a Subject, or increasing a thereof to said subject. bone mass in a Subject, promoting bone formation in a Sub In one embodiment, this invention provides a method of ject, administering an effective amount of a compound of this treating, reducing the severity of reducing the incidence of invention or its isomer, pharmaceutically acceptable salt, delaying the onset of or reducing pathogenesis of insulin pharmaceutical product, crystal, hydrate, N-oxide or any 50 resistance in a human Subject, comprising the step of admin combination thereof, or a composition comprising the same, istering an effective amount of a compound of this invention in an amount effective to treat said bone-related disorder. or its isomer, pharmaceutically acceptable salt, pharmaceuti According to this aspect, and in one embodiment, the Sub cal product, crystal, N-oxide, hydrate or any combination ject Suffers from osteoporosis, osteopenia, increased bone thereof to said subject. resorption, bone fracture, bone frailty, loss of bone mineral 55 In one embodiment, this invention provides a method of density (BMD), or any combination thereof. In one embodi treating, reducing the severity of reducing the incidence of ment, the method increases the strength of a bone of said delaying the onset of, or reducing pathogenesis of diseases Subject. In one embodiment, the compound stimulates or associated with diabetes comprising the step of administering enhances osteoblastogenesis, or in another embodiment the an effective amount of a compound of this invention or its compound inhibits osteoclast proliferation. 60 isomer, pharmaceutically acceptable salt, pharmaceutical In one embodiment, this invention provides a method of product, crystal, N-oxide, hydrate or any combination thereof treating, reducing the incidence of delaying progression of to said subject. reducing the severity of or alleviating symptoms associated In one embodiment, this invention provides a method of with a muscle wasting disorder in a Subject, comprising the treating, reducing the severity of reducing the incidence of step of administering to said a compound of this invention or 65 delaying the onset of, or reducing pathogenesis of fatty liver its isomer, pharmaceutically acceptable salt, pharmaceutical conditions in a human Subject, comprising the step of admin product, crystal, hydrate, N-oxide or any combination istering an effective amount of a compound of this invention US 7,772,433 B2 11 12 or its isomer, pharmaceutically acceptable salt, pharmaceuti amount of a compound of this invention or its isomer, phar cal product, crystal, N-oxide, hydrate or any combination maceutically acceptable salt, pharmaceutical product, crys thereof to said subject. tal, N-oxide, hydrate or any combination thereof to the sub In one embodiment, this invention provides a method of ject as herein described. treating, reducing the severity of reducing the incidence of 5 delaying the onset of, or reducing the pathogenesis of cardio BRIEF DESCRIPTION OF THE DRAWINGS vascular disease in a human Subject, comprising the step of administering an effective amount of a compound of this The present invention will be understood and appreciated invention or its isomer, pharmaceutically acceptable salt, more fully from the following detailed description taken in pharmaceutical product, crystal, N-oxide, hydrate or any 10 conjunction with the appended drawings in which: combination thereof to said subject. FIG.1: Synthetic schemes for the preparation of compound In one embodiment, this invention provides a method of of formula II. FIG. 1A is a synthetic scheme for the prepara treating reducing the severity of reducing the incidence of tion of an (S) enantiomer of a compound of formula II (S-II). delaying the onset of, or reducing the pathogenesis of FIG. 1B is a synthetic scheme for the preparation of an (R) cachexia in a Subject, comprising the step of administering an 15 enantiomer of a compound of formula II (R-II). FIG. 1C is a effective amount of a compound of this invention or its iso synthetic scheme for the preparation of an (S) enantiomer of mer, pharmaceutically acceptable salt, pharmaceutical prod a compound of formula II (S-II) including an oxirane inter uct, crystal, N-oxide, hydrate or any combination thereof to mediate. FIG.1D is a synthetic scheme for the preparation of said Subject. an (R) enantiomer of a compound of formula II (R-II) includ In one embodiment, this invention provides a method of ing an oxirane intermediate. FIG.1E is a synthetic scheme for treating a disease or condition of the eye of a Subject, com the preparation of an (S) enantiomer of a compound of for prising the step of administering an effective amount of a mula II (S-II) involving B-ring addition prior to A-ring addi compound of this invention or its isomer, pharmaceutically tion. FIG. 1F is a synthetic scheme for the preparation of an acceptable salt, pharmaceutical product, crystal, N-oxide, (R) enantiomer of a compound of formula II (R-II) involving hydrate or any combination thereof to the subject. In one 25 B-ring addition prior to A-ring addition. FIG. 1G is a syn embodiment, the disease or condition of the eye comprises thetic scheme for the preparation of an (S) enantiomer of a Sjogren's syndrome, or Xerophthalmia. compound of formula II (S-II) using 2-tribromomethyl-1,3 In one embodiment, the present invention provides a dioxolan-4-one intermediate and involving B-ring addition method of reducing a fat mass in a Subject comprising the step prior to A-ring addition. FIG. 1H is a synthetic scheme for the of administering an effective amount of a compound of this 30 preparation of an (R) enantiomer of a compound of formula II invention or its isomer, pharmaceutically acceptable salt, (R-II) using 2-tribromomethyl-1,3dioxolan-4-one interme pharmaceutical product, crystal, N-oxide, hydrate or any diate and involving B-ring addition prior to A-ring addition. combination thereof to the subject. FIG. 1I is a synthetic scheme for preparation of a racemic In one embodiment, the present invention provides a mixture of a compound of formula II, involving oxazo method of increasing a lean mass in a Subject comprising the 35 lidinedione intermediate and Bring addition prior to A ring. step of administering an effective amount of a compound of FIG. 1J is a synthetic scheme for preparation of a racemic this invention or its isomer, pharmaceutically acceptable salt, mixture of a compound of formula II, involving an oxirane pharmaceutical product, crystal, N-oxide, hydrate or any intermediate and A ring addition prior to Bring. FIG. 1K is a combination thereof to the subject. synthetic scheme for preparation of a large scale of an (S) In another embodiment, this invention provides a method 40 enantiomer of a compound of formula II (S-II). FIG. 1L is a of Suppressing spermatogenesis; contraception in a male; synthetic scheme for preparation of a large scale of an (S) hormone therapy; treating prostate cancer, delaying the pro enantiomer of a compound of formula II (S-II), including an gression of prostate cancer, treating a bone-related disorderin oxirane intermediate. a subject, or increasing a bone mass in a Subject and/or pro FIG. 2: Anabolic and androgenic pharmacology of Com moting bone formation in a Subject; treating, reducing the 45 pound II. incidence of delaying progression of reducing the severity FIG.3: Levator ani weight in castrated rats. of oralleviating symptoms associated with a muscle wasting FIG. 4: Prostate weight in castrated rats. disorder; treating, reducing the severity of reducing the inci dence of delaying the onset of, or reducing pathogenesis of DETAILED DESCRIPTION OF THE PRESENT diabetes; treating, reducing the severity of reducing the inci 50 INVENTION dence of delaying the onset of, or reducing pathogenesis of glucose intolerance; treating, reducing the severity of reduc In the following detailed description, numerous specific ing the incidence of delaying the onset of, or reducing patho details are set forth in order to provide a thorough understand genesis of hyperinsulinemia; treating, reducing the severity ing of the invention. However, it will be understood by those of reducing the incidence of delaying the onset of, or reduc 55 skilled in the art that the present invention may be practiced ing pathogenesis of insulin resistance; treating, reducing the without these specific details. In other instances, well-known severity of reducing the incidence of delaying the onset of methods, procedures, and components have not been or reducing pathogenesis of diseases associated with diabe described in detailso as not to obscure the present invention. tes; treating, reducing the severity of reducing the incidence This invention provides, in one embodiment, a substituted of delaying the onset of, or reducing pathogenesis of fatty 60 acylanilide characterized by the structure of Formula I. In one liver conditions; treating, reducing the severity of reducing embodiment, the compound is a SARM.INone embodiment, the incidence of delaying the onset of or reducing pathogen the compound is useful in treating a variety of conditions or esis of cardiovascular disease; treating reducing the severity diseases, including, inter alia, oral testosterone replacement of reducing the incidence of delaying the onset of, or reduc therapy, male contraception, maintaining sexual desire in ing pathogenesis of cachexia; treating a disease or condition 65 women, osteoporosis, treating prostate cancer and/or imaging of the eye; reducing a fat mass; or increasing a lean mass in a prostate cancer. In some embodiments, the compounds of this Subject, comprising the step of administering an effective invention are nonsteroidal ligands for the AR and exhibit US 7,772,433 B2 13 14 androgenic and/or anabolic activity. In some embodiments, In one embodiment, the present invention provides, a com the compounds are partial agonists or partial antagonists in a pound represented by the structure of formula III: tissue selective manner. In some embodiments, the com pounds are full agonists or full antagonists in a tissue selective III manner, which in Some embodiments, allows for tissue-se lective androgenic and/or anabolic effects. These agents may be active alone or in combination with progestins or estro gens, or other agents, as herein described. In other embodi ments, the agents are agonists, antagonists, partial agonists or partial antagonists. 10 In some embodiments, this invention provides compounds, which are useful in androgen replacement therapy (ART), useful ina) improving body composition; b) increasing bone wherein X is a bond, O, CH, NH, Se, PR, NO or NR; mineral density (BMD); c) increasing bone mass; d) increas 15 G is O or S: ing bone strength; e) improving bone function: f) decreasing T is OH, OR, NHCOCH or NHCOR; fracture risk; g) increasing muscle strength; h) increasing R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, muscle function: i) improving exercise tolerance; j) enhanc CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl or ing libido, k) improving sexual performance; and/or 1) OH: improving mood and/or m) improving cognition. R is CH, CHF, CHF, CF, CHCH, or CFCF: In some embodiments, this invention provides synthetic R is H, F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, processes of preparation of the SARM compounds of this NHCOCF, NHCOR, alkyl, arylalkyl, OR, NH, NHR, invention. In some embodiments, the invention provides N(R), SR; compositions comprising the selective androgen modulator R is H, F, Cl, Br, I, CN, NO, COR, COOH,CONHR, CF, compounds or use of the same for binding an AR, modulating 25 Sn(R), or spermatogenesis, bone formation and/or resorption, treating R together with the benzene ring to which it is attached muscle wasting or diseases associated with muscle wasting, forms a fused ring system represented by the structure: treating prostate cancer, and/or providing hormonal therapy for androgen-dependent conditions. 30 In one embodiment, the present invention provides, a com pound represented by the structure of formula (I):

(I)

Z is NO, CN, C1, F, Br, I, H, COR, COOH, or CONHR: 40 Y is CF, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, formyl, H, F, Br, Cl, I, CN, or Sn(R): Q is H, alkyl, halogen, CF, CN CR, Sn(R), N(R), wherein Q is alkyl, F, Cl, Br, I, CF, CN, C(R) Sn(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, 45 NHCOOR, OCONHR, CONHR, NHCSCH, NHC NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, SCF, NHCSR NHSOCH, NHSOR, OH, OR, COR, NHCSRNHSOCH, NHSOR, OR, COR, OCOR, OSOR, OCOR, OSOR, SOR, SR: or Q together with the ben SOR, SR; and Zene ring to which it is attached is a fused ring system R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF represented by structure A, B or C: CF, CFCF, aryl, phenyl, F, Cl, Br, I, alkenyl or OH: 50 or its isomer, pharmaceutically acceptable salt, pharmaceuti A cal product, N-oxide, hydrate or any combination thereof. 21 NH O In one embodiment, the present invention provides, a com pound represented by the structure of formula II: 55 Ás B II NC C 21 NH O

60 Ás 21 NH C Hd OH 21 NH

or its isomer, pharmaceutically acceptable salt, pharma 65 ceutical product, N-oxide, hydrate or any combination thereof. US 7,772,433 B2 15 16 n is an integer of 1-4; and X is bond, O, CH, NH, S, SO, SO, Se, PR, NO or NR; m is an integer of 1-3: Z is NO, CN, COR, COOH, or CONHR: wherein if R is H, then none of Z or Y or R or Q are H: Y is CF, alkoxy, hydroxyalkyl, alkylaldehyde, formyl, F, or an isomer, pharmaceutically acceptable salt, pharma Br, Cl, I, CN, alkyl or Sn(R): ceutical product, N-oxide, hydrate thereof or any com Q is H, alkyl, halogen, CF, CN, C(R), Sn(R), N(R), bination thereof. NHCOCH, NHCOCF, NHCOR, NHCONHR, In one embodiment, the present invention provides a com NHCOOR, OCONHR, CONHR, NHCSCH, NHC pound of formula II wherein X is O. In another embodiment, SCF, NHCSR, NHSOCH, NHSOR, OH, OR, COR, the present invention provides a compound of formula II OCOR, OSOR, SOR, SR; wherein T is OH. In another embodiment, the present inven 10 R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, tion provides a compound of formula II wherein R is CH. In CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, another embodiment, the present invention provides a com alkynyl, haloalkenyl, haloalkynyl, perhaloalkyl, or OH: pound of formula II wherein Z is CN. In another embodiment, RCH, CHF, CHF, CF, CHCH, or CFCF: the present invention provides a compound of formula II R is F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, wherein Z is F. In another embodiment, the present invention 15 NHCOCF, NHCOR, alkyl, arylalkyl, allyl, alkenyl, provides a compound of formula II wherein Z is NO. In alkynyl, OR, NH, NHR, N(R), SR; another embodiment, the present invention provides a com R is H, F, Cl, Br, I, CN, NO, COR, COOH,CONHR, CF, pound of formula II, wherein Y is CH. In another embodi alkyl, arylalkyl, allyl, alkenyl, alkynyl, Sn(R): ment, the present invention provides a compound of formula C, D, E and Fareindependently a bond, alkyl (C-C), alkenyl II, wherein Y is H. In another embodiment, the present inven (C-C), alkynyl (C-C), alkoxy (C-C), alkylester (C- tion provides a compound of formula II wherein Y is CF. In Cs), alkylether (C-C), alkylamide (C-C), alkylcarbam another embodiment, the present invention provides a com ate (C-C), alkyl amine (C-Cs), alkyl ketone (C-C), pound of formula II, whereinY is C1. In another embodiment, alkyl-COOH(C-C); the present invention provides a compound of formula II M is substituted or unsubstituted amide, substituted or unsub wherein R is H and none ofY, Z, Q or R are H. In another 25 stituted thioamide substituted or unsubstituted reverse embodiment, the present invention provides a compound of amide, substituted or unsubstituted reversethioamide, Sub formula II wherein R is CN. In another embodiment, the stituted or unsubstituted amine, substituted or unsubsti present invention provides a compound of formula II wherein tuted carbamate, substituted or unsubstituted urea, substi R is Cl. In another embodiment, the present invention pro tuted or unsubstituted thiourea substituted or unsubstituted vides a compound of formula II wherein R is F. In another 30 ester, substituted or unsubstituted reverse ester, or substi embodiment, the present invention provides a compound of tuted or unsubstituted ether; n is 1-3; and formula II wherein Q is CN. In another embodiment, the m is 1-4. present invention provides a compound of formula II wherein In another embodiment, the present invention provides a Q is F. In another embodiment, the present invention provides compound represented by the structure of formula V: a compound of formula II wherein Q is C1. 35 In one embodiment, the present invention provides a com pound characterized by the structure of formula IV: V (R2)m (R3)n 40 IV T E-X-F Q Z C-M(amide)-D R Y 45 wherein A and Brings are independently carbocyclic, heterocyclic, wherein R, m and n are as described for the structure of aryl, heteroaryl, bicyclic, polycyclic, or spiro rings. formula III. 50 T is OH, OR, NHCOCH, or NHCOR; In one embodiment, the present invention provides a com X is bond, O, CH, NH, S, SO, SO, Se, PR, NO or NR; pound characterized by the structure of formula V: Z is NO, CN, COR, COOH, or CONHR: Y is CF, alkoxy, hydroxyalkyl, alkylaldehyde, formyl, F, Br, Cl, I, CN, alkyl or Sn(R): V 55 Q is H, alkyl, halogen, CF, CN, C(R), Sn(R), N(R), (R2)m NHCOCH, NHCOCF, NHCOR, NHCONHR, (R3)n NHCOOR, OCONHR, CONHR, NHCSCH, NHC T E-X-F Q SCF, NHCSR, NHSOCH, NHSOR, OH, OR, COR, Z C-M(amide)-D OCOR, OSOR, SOR, SR; 60 R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, R CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, Y alkynyl, haloalkenyl, haloalkynyl, perhaloalkyl, or OH: RCH, CHF, CHF, CF, CHCH, or CFCF; wherein R is F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, A and Brings are independently carbocyclic, heterocyclic, 65 NHCOCF, NHCOR, alkyl, arylalkyl, allyl, alkenyl, aryl, heteroaryl, bicyclic, polycyclic, or spiro rings. alkynyl, OR, NH, NHR, N(R), SR; T is OH, OR, NHCOCH or NHCOR; R is hydrogen; US 7,772,433 B2 17 18 C, D, E and Fare independently a bond, alkyl (C-C), alkenyl In another embodiment, the present invention provides a (C-C), alkynyl (C-C), alkoxy (C-C), alkylester (C- compound represented by the structure of formula VI: Cs), alkylether (C-C), alkylamide (C-C), alkylcarbam ate (C-C), alkyl amine (C-C), alkyl ketone (C-C), VI alkyl-COOH(C-C); (R2) M is substituted or unsubstituted amide, substituted or unsub (R3), stituted thioamide substituted or unsubstituted reverse T D-X-E Q amide, substituted or unsubstituted reversethioamide, Sub Z C stituted or unsubstituted amine, substituted or unsubsti 10 tuted carbamate, substituted or unsubstituted urea, substi R tuted or unsubstituted thiourea substituted or unsubstituted Y ester, substituted or unsubstituted reverse ester, or substi tuted or unsubstituted ether; wherein R is hydrogen, A and Brings, Y, Z, Q, R., C, D, E, n is 1-3; and 15 T. R., Xn, and mare as defined in compound of formula m is 1-4. V. In another embodiment, preferred examples of ring A of In one embodiment, the present invention provides a com formula V include carbazoles, norharmans, saccharins, isat pound represented by the structure of formula 15A: ins, purines, isatoic anhydrides, benzisoxazoles, benzisthia Zoles, quinolines, quinolinones, tetrahydroquinolines, iso quinolines, tetrahydroisoquinolines, aZulenes, 1-aza aZulenes, and 1,3-diaza-aZulenes. T In one embodiment, preferred examples of ring B, of for mula V, include pyridines, pyrazines, pyrimidines, 25 z-(E)-c-k D-(E)- pyridazines, thiophenes, pyrroles, furans, triazines, tetra R Zines, isothiazoles, thiazoles, isoxazoles, oxazoles, furazans, Y imidazoles, pyrazoles, thiadiazoles, triazoles, and tetrazoles. In another embodiment, less preferred examples of ringSA wherein A and Brings, Y, Z, Q, R. R. C. D. E. T. R. X., n, and B include the following: aromatics such as benzene, 30 thiophenes, pyrroles, furans, isothiazoles, thiazoles, isox and m are as defined in compound of formula V. azoles, oxazoles, furazans, imidazoles, pyrazoles, thiadiaz In another embodiment, the present invention provides a oles, 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles, pyridines, compound represented by the structure of formula 15A: pyrazines, pyrimidines, pyridazines, 1,3,5-triazines, tetra Zines, bicyclics Such as indolines, isoindolines, indenes, pen 35 talenes, isoindoles, indolenines, idolizines, indazoles, oxin doles, isatins, saccharins, quinolizidines, pyrrolizidines, T tetrahydroquinolines, tetrahydroisoquinolines, decahydro quinolines, decahydroisoquinolines, heterocyclics and car 40 z-(E)-c-l-D-(E)- bocyclics such as 1,2,4-oxadiazoles, aziridines, aZetidines, R pyrrolidines, pyrrolidinones, piperidines, piperidinones, pip Y erazines, 2,5-dioxopiperazines, A2- and A3-thiazolines, oxiranes, oxetans, tetrahydrofurans, tetrahydropyrians, thi irans, thietans, thiolans, tetrahydrothiopyrians, azepines, wherein R is hydrogen, A and Brings, Y, Z, Q, R., C, D, E, oxepines, Sultones, isoxazolidines, Sultams, 5-oxazolones, 45 T. R., Xn, and m are as defined in compound of formula V. oxazolidines, succinimides, ethylene, ureas, imidazolines, In another embodiment, preferred examples of ring A of thioimidazolidines, hydantoins, thiohydantoins, oxazo formula VI and VIA include carbazoles, norharmans, saccha lidinediones, 1,4-dihydropyridines, cyclopentadieneones, rins, indoles, isoindoles, indene, benzothiophene, benzofu cyclopentadienes, 1.3-oxathioles, 1.3-oxazinan-2-ones, full ran, C. and B naphthenes, dihydronaphthenes, tetrahy venes, fulvalenes, pyrans, 1,4-thiazines, 4-pyridthiones, 50 dronaphthylenes, azepines, diazepines, isatins, purines, 4-pyrones, 2-pyrimidones, uracils, barbituric acids, and isatoic anhydrides, benzisoxazoles, benzisthiazoles, benzox 3-pyrazolidones. azole, benzthiazoles, quinolines, quinolinones, tetrahydro In one embodiment, the present invention provides a com quinolines, isoquinolines, tetrahydroisoquinolines, aZulenes, pound represented by the structure of formula VI: 55 1-aza-aZulenes, and 1,3-diaza-aZulenes. In one embodiment, the present invention provides a com VI pound represented by the structure of formula VII:

VII 60 (R3), O Z ()-es-leis 1 - (R2) in H 65 Y (E)- wherein A and Brings, Y, Z, Q, R. R. C. D. E.T. R. X., n, and m are as defined in compound of formula V. US 7,772,433 B2 19 20 wherein In another embodiment, the present invention provides a A and Brings are independently carbocyclic, heterocyclic, compound represented by the structure of formula VIII: aryl, heteroaryl, bicyclic, polycyclic, or spiro rings. VIII X is bond, O, CH, NH, S, SO, SO, Se, PR, NO or NR; (R3), (R2) Z is NO, CN, COR, COOH, or CONHR: Y is CF, alkoxy, hydroxyalkyl, alkylaldehyde, formyl, F, Z T (E)- Br, C1, I, CN, alkyl or Sn(R): - Dys-O-H Q is H, alkyl, halogen, CF, CN, C(R) Sn(R), N(R), ()---is, Y R NHCOCH, NHCOCF, NHCOR, NHCONHR, 10 NHCOOR, OCONHR, CONHR, NHCSCH, NHC wherein R is hydrogen, A and Brings, Y, Z, Q, R. D. T. R. SCF, NHCSR, NHSOCH, NHSOR, OH, OR, COR, X, in and m are as defined in compound of formula V. OCOR, OSOR, SOR, SR; In one embodiment, the present invention provides a com R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, pound represented by the structure of formula IX: CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl, 15 DX alkynyl, haloalkenyl, haloalkynyl, perhaloalkyl, or OH: (R3), RCH, CHF, CHF, CF, CHCH, or CFCF: R is F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, Z () O T D E (R2) in NHCOCF, NHCOR, alkyl, arylalkyl, allyl, alkenyl, n1 alkynyl, OR, NH, NHR, N(R), SR; R is H, F, Cl, Br, I, CN, NO, COR, COOH, CONHR, CF, Y R alkyl, arylalkyl, allyl, alkenyl, alkynyl, Sn(R): wherein A and B rings, Y, Z, Q, R. R. D. ET. R. X., n and C, D, E and Fareindependently a bond, alkyl (C-C), alkenyl m are as defined in compound of formula V. (C-C), alkynyl (C-Cs), alkoxy (C-C), alkylester (C- 25 In another embodiment, the present invention provides a Cs), alkylether (C-C), alkylamide (C-C), alkylcarbam compound represented by the structure of formula IX: ate (C-C), alkyl amine (C-C), alkyl ketone (C-C), alkyl-COOH(C-C); n is 1-3; and (R3), m is 1-4; wherein 30 if C and E are bonds, X is CH or a bond than ring B is not a 5 membered ring comprising one sulfur atom and one Z () O T D E (R2) in nitrogen atom; and n1 if each of C, D, E and F is a bond, and each of A and B is a Y R phenyl ring, and R is H, then none of Z. Y. Q or R are H. 35 In another embodiment, the present invention provides a compound represented by the structure of formula VII: wherein R is hydrogen, A and Brings, Y, Z, Q, R. D. ET. R. X, in and m are as defined in compound of formula V. In one embodiment, the present invention provides a com VII 40 pound represented by the structure of formula X: (R3), O (R2) n Y N X 45 Y wherein R is hydrogen, A and Brings, Y, Z, Q, R. C. E. X, n, and mare as defined hereinabove. 50 In another embodiment, the thiazine may include thiazoli dine, thiazolidinone, or thiazole. wherein A and B rings, Y, Z, Q, R. R. C. D. T. R., n and m In one embodiment, the present invention provides a com are as defined in compound of formula V. pound represented by the structure of formula VIII: In another embodiment, the present invention provides a 55 compound represented by the structure of formula X:

VIII

65 wherein A and B rings, Y, Z, Q, R. R. D. T. R. X., n and m wherein R is hydrogen, A and B rings, Y, Z, Q, R. C. D. T. are as defined in compound of formula V. R., n and mare as defined in compound of formula V. US 7,772,433 B2 21 22 In one embodiment, the present invention provides a com wherein A and B rings, Y, Z, Q, R. R. D. E. T. R., n and m pound represented by the structure of formula XI: are as defined in compound of formula V; and XI (R3), wherein ring C is benzene, phenyl, benzyl, thiophenes, pyr O (R2) roles, furans, isothiazoles, thiazoles, isoxazoles, oxazoles, T furazans, imidazoles, pyrazoles, thiadiazoles, 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles, pyridines, pyrazines, pyrimidines, pyridazines, 1,3,5-triazines, tetrazines, hydantoin, thiohy Y N R R2r"(E)- dantoin, oxazolidinedione, cyclopentadieneone, cyclopenta diene, 1.3-oxathiole, fulvene, thiophene, pyrrole, furan, isox 10 azole, pyrazole, isothiazole, thiazole, oxazole, imidazole, wherein A and B rings, Y, Z, Q, R. R. D. E. T. R., n and m imidazoline, pyridazine, pyrazine, pyrimidine, pyridine, full are as defined in compound of formula V. Valene, quinazoline, phthalazine, cinnoline, quinoxaline, In another embodiment, the present invention provides a quinoline, isoquinoline, quinolinone, isoquinolinone, chro compound represented by the structure of formula XI: 15 man, chromene, coumarin, isocoumarin. XI In another embodiment, the present invention provides a (R3), compound represented by the structure of formula XIII: O (R2) T XIII -"Y"(E)- (R3), Y R R (R2) wherein R is hydrogen and A and Brings, Y, Z, Q, R. D. E. T. R., n and mare as defined in compound of formula V. 25 In one embodiment, the present invention provides a com pound represented by the structure of formula XII: XII 30 Wherein R is hydrogen, A and Brings, Y, Z, Q, R. D. E. T. R., n and mare as defined in compound of formula V; and wherein ring C is benzene, phenyl, benzyl, thiophenes, pyr roles, furans, isothiazoles, thiazoles, isoxazoles, oxazoles, 35 furazans, imidazoles, pyrazoles, thiadiazoles, 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles, pyridines, pyrazines, pyrimidines, wherein A and B rings, Y, Z, Q, R. R. D. E. T. R., n and m pyridazines, 1,3,5-triazines, tetrazines, hydantoin, thiohy are as defined in compound of formula V. dantoin, oxazolidinedione, cyclopentadieneone, cyclopenta In another embodiment, the present invention provides a diene, 1.3-oxathiole, fulvene, thiophene, pyrrole, furan, isox compound represented by the structure of formula XII: 40 azole, pyrazole, isothiazole, thiazole, oxazole, imidazole, imidazoline, pyridazine, pyrazine, pyrimidine, pyridine, full Valene, quinazoline, phthalazine, cinnoline, quinoxaline, XII quinoline, isoquinoline, quinolinone, isoquinolinone, chro man, chromene, coumarin, isocoumarin. 45 In one embodiment, the present invention provides a com pound represented by the structure of formula XIV:

XIV 50 (R3), (R2) wherein A and B rings, Y, Z, Q, R. R. D. E. T. R., n and m X are as defined in compound of formula V. In one embodiment, the present invention provides a com Y pound represented by the structure of formula XIII: 55

XIII wherein A and B rings, Y, Z, Q, R. R. D. E. X., n and mare (R3), as defined in compound of formula V; and (R2) in 60 wherein (E) is hydantoin, thiohydantoin, oxazolidinedione, cyclopentadieneone, cyclopentadiene, 1.3-oxathiole, full Vene, thiophene, pyrrole, furan, isoxazole, pyrazole, isothia Zole, thiazole, oxazole, imidazole, imidazoline, pyridazine, pyrazine, pyrimidine, pyridine, fulvalene, quinazoline, 65 phthalazine, cinnoline, quinoxaline, quinoline, isoquinoline, quinolinone, isoquinolinone, chroman, chromene, coumarin, isocoumarin. US 7,772,433 B2 23 24 In another embodiment, the present invention provides a In another embodiment, the present invention provides a compound represented by the structure of formula XIV: compound represented by the structure of formula XVI:

XIV 5 XVI (R3), (R2) in

Y 10 wherein R is hydrogen, and A and Brings, Y, Z, Q, R. R. D. E.X., n and m are as defined in compound of formula V; and wherein (E) is hydantoin, thiohydantoin, oxazolidinedione, wherein R is hydrogen, and A and Brings, Y, Z, Q, R, D, E, cyclopentadieneone, cyclopentadiene, 1.3-oxathiole, full X, in and m are as defined in compound of formula V. Vene, thiophene, pyrrole, furan, isoxazole, pyrazole, isothia In one embodiment, the present invention provides a com Zole, thiazole, oxazole, imidazole, imidazoline, pyridazine, pound represented by the structure of formula XVII: pyrazine, pyrimidine, pyridine, fulvalene, quinazoline, 2O phthalazine, cinnoline, quinoxaline, quinoline, isoquinoline, quinolinone, isoquinolinone, chroman, chromene, coumarin, isocoumarin. In one embodiment, the present invention provides a com XVII pound represented by the structure of formula XV: 25 (R3)n (R2)m Z () i-DirN X Y(Ep (E) Q N H 30 Y

35 wherein A and B rings, Y, Z, Q, R. R. D. E. X., n and mare as defined in compound of formula XVII. wherein A and B rings, Y, Z, Q, R. R. D. E. X., n and mare In another embodiment, the present invention provides a as defined in compound of formula V. compound represented by the structure of formula XVII: In another embodiment, the present invention provides a compound represented by the structure of formula XV: 40 XVII XV R iii. (R2) (R3), (R2) (R3), X N D1 NE

N 45 -)-( H Q Y Y wherein R is hydrogen, and A and Brings, Y, Z, Q, R. D. E. wherein R is hydrogen and A and Brings, Y, Z, Q, R., D, E, X, in and m are as defined in compound of formula V. In one embodiment, the present invention provides a com X, in and m are as defined in compound of formula V. pound represented by the structure of formula XVI: In one embodiment, the present invention provides a com pound represented by the structure of formula XVIII: 55 XVI XVIII (R3), (R)R iii. X N 1 n

N H Y

65 wherein A and B rings, Y, Z, Q, R. R. D. E. X., n and mare wherein A and B rings, Y, Z, Q, R. R. D. E. X., n and mare as defined in compound of formula V. as defined in compound of formula V. US 7,772,433 B2 25 26 In another embodiment, the present invention provides a In another embodiment, the present invention provides a compound represented by the structure of formula XVIII: compound represented by the structure of formula XX:

XVIII 5 XX (R3), (R)R iii. (R3), (R2)R iii. X X N D1 NE N D1 NE

z-(S)-(CN Q 10 Z O 5 Q H Y Y wherein R is hydrogen and A and Brings, Y, Z, Q, R., D, E, is wherein R is hydrogen and A and B rings, Y, Z, Q, R., D, E, X, in and m are as defined in compound of formula V. X, in and m are as defined in compound of formula V. In one embodiment, the present invention provides a com- In one embodiment, the present invention provides a com pound represented by the structure of formula XIX: pound represented by the structure of formula XXI:

2O XIX XXI (R2) (R2) (R3), (R3), X -X N. 7 D1NE Q z-(S)-(CYNHD E Q 25 Z - 1 Y

30 wherein A and B rings, Y, Z, Q, R. R. D. E. X., n and mare wherein A and B rings, Y, Z, Q, R. R. D, E, X, n and mare as defined in compound of formula V. as defined in compound of formula V. In another embodiment, the present invention provides a In another embodiment, the present invention provides a compound represented by the structure of formula XXI: selective androgen receptor modulator (SARM) compound 35 represented by the structure of formula XIX: XXI (R2) in (R3), XIX 40 X / N D1 NE Q (R3), (R2) Z - Y Y 2 45 Y wherein R is hydrogen, A and Brings, Y, Z, Q, R. D. E. X, in and m are as defined in compound of formula V. In one embodiment, the present invention provides a com wherein R is hydrogen and A and Brings, Y, Z, Q, R. D, E, 50 pound represented by the structure of formula XXII: X, in and m are as defined in compound of formula V. In one embodiment, the present invention provides a com pound represented by the structure of formula XX: 55 XXII R2). (R2) XX (R3), (R2) 2it (R3), O -X N Z () iPN - n E Q 60 ,-(S)-(32. ( ) - Y Y

65 wherein A and B rings, Y, Z, Q, R. R. D. E. X., n and mare wherein A and B rings, Y, Z, Q, R. R. D. E. X., n and mare as defined in compound of formula V. as defined in compound of formula V. US 7,772,433 B2 27 28 In another embodiment, the present invention provides a compound represented by the structure of formula XXII: -continued (R4)q (R)n (R4)q XXII (R3), HN, 2 : FN-y-e -X N tetrahydroisoquinoline tetrahydroisoquinoline (R3)n (R3)n (5 or2. -(D- 10 Y COCY------wherein R is hydrogen and A and Brings, Y, Z, Q, R., D, E, is benzoxazole quinolinone X, n, and mare as defined in compound of formula V. (R3)n (R4)q (R3)n (R4)q In other specific non-limiting embodiments, ring A and its 2é Sé pe sa% Substituents include the following schematic structures: Z y-S-4 Ns-y-x 2O Y Z Y (R3)n isoquinoline isoquinoline

Z-H As *f, ^? . S S4 NS y- %2 %2 25 s R3 s pyridine thiazole imidazole C. S. (R3)n N (R3)n N O aS (R3)n benzthiazole carbazole z-f y z- s O 30

Yyu Yye Y-y-eY Z pyrimidine pyridazine R isatin 35 (R3)n (R4)4 (R3)n (R4)q 7- XN1^ CXN1. l, 7. 21 N A-X 40 tetrahydroquinoline tetrahydroquinoline

O (R3)n (R3)n N A-Xals 3 O y } 45 R benzisoxazole R isatonic anhydride 50 (R3)n (R4)q (R)n (R4)q e sas e sas ( R 3-4 \ | Y, y-N4 S4-y-e N, 2 Y Y Z Y 55 Z-S\=l= quinoline quinoline Y norharman (R), (R) (R4)q / y \ ^ 60 wherein & J. lu RandR are independently H, F, Cl, Br, I, CN, NO, COR, A2. Y COOH, CONHR, CF, alkyl, arylalkyl, allyl, alkenyl, R O 65 alkynyl, Sn(R), benzisothiazole isoquinolinone in and q are independently 1-3, and R, Z and Y are as defined for structure V.

US 7,772,433 B2 31 32 sulfur atoms; wherein R is alkyl, haloalkyl, dihaloalkyl, tri -continued haloalkyl, CHF, CHF, CF, CFCF: aryl, phenyl, halogen, (R5)p alkenyl, alkynyl, haloalkenyl, haloalkynyl, alkoxy, perha (R2)m Y loalkyl, or OH. In one embodiment, the present invention provides a com KA Qu I 21 pound of any of formulas I-XXII wherein R is F. In another embodiment, the present invention provides a compound of Q any of formulas I-XXII wherein R is C1. In another embodi carbazole ment, the present invention provides a compound of any of 10

H R formulas I-XXII wherein R is Br. In another embodiment, (R2)m N (R5)p the present invention provides a compound of any of formulas I-XXII wherein R is I. In another embodiment, the present invention provides a compound of any of formulas I-XXII wherein R is CH. In another embodiment, the present inven 15 tion provides a compound of any of formulas I-XXII wherein carbazole R is OH. In another embodiment, the present invention pro vides a compound of any of formulas I-XXII wherein R is CF. In another embodiment, the present invention provides a wherein compound of any of formulas I-XXII wherein R is CN. In RandRs are independently H, F, Cl, Br, I, CN, NO, COR, another embodiment, the present invention provides a com COOH, CONHR, CF, alkyl, arylalkyl, allyl, alkenyl, pound of any of formulas I-XXII wherein R is NO. In alkynyl, Sn(R): another embodiment, the present invention provides a com m and pare independently 1-3; and pound of any of formulas I-XXII wherein R is NHCOCH. R and Q are as defined for structure V. In another embodiment, the present invention provides a In other non-limiting embodiments amide M include the 25 compound of any of formulas I-XXII wherein R is following schematic structures: NHCOCF. In another embodiment, the present invention provides a compound of any of formulas I-XXII wherein R is NHCOR In another embodiment, the present invention provides a compound of any of formulas I-XXII wherein R 30 is alkyl. In another embodiment, the present invention pro vides a compound of any of formulas I-XXII wherein R is phy arylalkyl. In another embodiment, the present invention pro amine amide reverse amide vides a compound of any of formulas I-XXII wherein R is O O alkenyl. In another embodiment, the present invention pro 35 vides a compound of any of formulas I-XXII wherein R is alkynyl. In another embodiment, the present invention pro 1. vides a compound of any of formulas I-XXII wherein R is 8 O OR. In another embodiment, the present invention provides a 2-oxoacetamide compound of any of formulas I-XXII wherein R is NH2. In 40 another embodiment, the present invention provides a com pound of any of formulas I-XXII wherein R is NHR. In another embodiment, the present invention provides a com pound of any of formulas I-XXII wherein R is N(R). In another embodiment, the present invention provides a com 'il 45 pound of any of formulas I-XXII wherein R is SR. 2-aminoacet In one embodiment, the present invention provides a com aldehyde pound of any of formulas I-XXII wherein R is F. In another embodiment, the present invention provides a compound of any of formulas I-XXII wherein R is Cl. In another embodi 50 ment, the present invention provides a compound of any of formulas I-XXII wherein R is Br. In another embodiment, reverse1 carbamate ester rewerse ester the present invention provides a compound of any of formulas I-XXII wherein R is I. In another embodiment, the present invention provides a compound of any of formulas I-XXII 55 wherein R is CN. In another embodiment, the present inven tion provides a compound of any of formulas I-XXII wherein hy/34 R is NO. In another embodiment, the present invention provides a compound of any of formulas I-XXII wherein R O is H. In another embodiment, the present invention provides a 60 compound of any of formulas I-XXII wherein R is COR. In N another embodiment, the present invention provides a com pound of any of formulas I-XXII wherein R is COOH. In 1. another embodiment, the present invention provides a com pound of any of formulas I-XXII wherein R is CONHR. In 65 another embodiment, the present invention provides a com wherein each NH or NH groups can be optionally substituted pound of any of formulas I-XXII R is CF. In another with an R group, and oxygenatoms may be also replaced with embodiment, the present invention provides a compound of US 7,772,433 B2 33 34 any of formulas I-XXII wherein R is Sn(R). In another embodiment, the invention relates to the use of a hydrate of embodiment, the present invention provides a compound of the SARM compound. In another embodiment, the invention any of formulas I-XXII wherein R together with the benzene relates to the use of an N-oxide of the SARM compound. In ring to which it is attached forms a compound represented by another embodiment, the invention relates to the use of a the structure: 5 polymorph of the SARM compound. In another embodiment, the invention relates to the use of a crystal of the SARM compound. In another embodiment, the invention relates to the use of an impurity of the SARM compound. As defined herein, the term "isomer' includes, but is not 10 limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like. In Z ( ) or Z. one embodiment, the term "isomer' is meant to encompass optical isomers of the SARM compound. It will be appreci Y Y ated by those skilled in the art that the SARMs of the present 15 invention contain at least one chiral center. Accordingly, the SARMs used in the methods of the present invention may In one embodiment, the present invention provides a com existin, and be isolated in, optically-active or racemic forms. pound of any of formulas I-XXII wherein m is 1. In another Some compounds may also exhibit polymorphism. It is to be embodiment, the present invention provides a compound of understood that the present invention encompasses any race any of formulas I-XXII wherein m is 2. In another embodi mic, optically-active, polymorphic, or stereroisomeric form, ment, the present invention provides a compound of any of or mixtures thereof, which form possesses properties useful formulas I-XXII wherein m is 3. In another embodiment, the in the treatment of androgen-related conditions described present invention provides a compound of any of formulas herein. In one embodiment, the SARMs are the pure (R)- I-XXII wherein n is 1. In another embodiment, the present isomers. In another embodiment, the SARMs are the pure invention provides a compound of any of formulas I-XXII 25 (S)-isomers. In another embodiment, the SARMs are a mix wherein n is 2. In another embodiment, the present invention ture of the (R) and the (S) isomers. In another embodiment, provides a compound of any of formulas I-XXII wherein n is the SARMs are a racemic mixture comprising an equal 3. In another embodiment, the present invention provides a amount of the (R) and the (S) isomers. It is well known in the compound of any of formulas I-XXII wherein n is 4. art how to prepare optically-active forms (for example, by In one embodiment, this invention provides an analog of 30 resolution of the racemic form by recrystallization tech the compound of formula I-XXII. In another embodiment, niques, by synthesis from optically-active starting materials, this invention provides a derivative of the compound of for by chiral synthesis, or by chromatographic separation using a mula I-XXII. In another embodiment, this invention provides chiral stationary phase). a prodrug of the compound of formula I-XXII. In another In one embodiment, this invention encompasses the use of embodiment, this invention provides a metabolite of the com 35 various optical isomers of the SARM compound. It will be pound of formula I-XXII. In another embodiment, this inven appreciated by those skilled in the art that the SARMs of the tion provides a pharmaceutically acceptable salt of the com present invention contain at least one chiral center. Accord pound of formula I-XXII. In another embodiment, this ingly, the SARMs used in the methods of the present inven invention provides a pharmaceutical product of the com tion may exist in, and be isolated in, optically-active or race pound of formula I-XXII. In another embodiment, this inven 40 mic forms. Some compounds may also exhibit tion provides a hydrate of the compound of formula I-XXII. polymorphism. It is to be understood that the present inven In another embodiment, this invention provides an N-oxide of tion encompasses any racemic, optically-active, polymor the compound of formula I-XXII. In another embodiment, phic, or stereroisomeric form, or mixtures thereof, which this invention provides a polymorph of the compound of form possesses properties useful in the treatment of andro formula I-XXII. In another embodiment, this invention pro 45 gen-related conditions described herein. In one embodiment, vides a crystal of the compound of formula I-XXII. In another the SARMs are the pure (R)-isomers. In another embodiment, embodiment, this invention provides an impurity of the com the SARMs are the pure (S)-isomers. In another embodiment, pound of formula I-XXII. In another embodiment, this inven the SARMs are a mixture of the (R) and the (S) isomers. In tion provides a combination of any of an analog, derivative, another embodiment, the SARMs area racemic mixture com metabolite, isomer, prodrug, pharmaceutically acceptable 50 prising an equal amount of the (R) and the (S) isomers. It is salt, pharmaceutical product, polymorph, crystal, impurity, well known in the art how to prepare optically-active forms hydrate, N-oxide of the compound of formula I-XXII. (for example, by resolution of the racemic form by recrystal As contemplated herein, the present invention relates to the lization techniques, by synthesis from optically-active start use of a SARM compound and/or its analog, derivative, iso ing materials, by chiral synthesis, or by chromatographic mer, metabolite, pharmaceutically acceptable salt, pharma 55 separation using a chiral stationary phase). ceutical product, hydrate, N-oxide, polymorph, crystal, The invention includes “pharmaceutically acceptable impurity or combinations thereof. In one embodiment, the salts' of the compounds of this invention, which may be invention relates to the use of an analog of the SARM com produced, by reaction of a compound of this invention with an pound. In another embodiment, the invention relates to the acid or base. use of a derivative of the SARM compound. In another 60 Suitable pharmaceutically-acceptable salts of amines of embodiment, the invention relates to the use of an isomer of Formula I-V may be prepared from an inorganic acid or from the SARM compound. In another embodiment, the invention an organic acid. In one embodiment, examples of inorganic relates to the use of a metabolite of the SARM compound. In salts of amines are bisulfates, borates, bromides, chlorides, another embodiment, the invention relates to the use of a hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyeth pharmaceutically acceptable salt of the SARM compound. In 65 ylsulfonates (hydroxyethanesulfonates), iodates, iodides, another embodiment, the invention relates to the use of a isothionates, nitrate, persulfates, phosphate, Sulfates, Sulfa pharmaceutical product of the SARM compound. In another mates, Sulfanilates, Sulfonic acids (alkylsulfonates, arylsul US 7,772,433 B2 35 36 fonates, halogen Substituted alkylsulfonates, halogen Substi This invention provides derivatives of the SARM com tuted arylsulfonates), Sulfonates and thiocyanates. pounds. In one embodiment, “derivatives” includes but is not In one embodiment, examples of organic salts of amines limited to ether derivatives, acid derivatives, amide deriva may be selected from aliphatic, cycloaliphatic, aromatic, tives, ester derivatives and the like. In another embodiment, araliphatic, heterocyclic, carboxylic and Sulfonic classes of 5 this invention further includes hydrates of the SARM com organic acids, examples of which are acetates, arginines, pounds. aspartates, ascorbates, adipates, anthranilate, algenate, In one embodiment, “hydrate' includes but is not limited to alkane carboxylates, Substituted alkane carboxylates, algi hemihydrate, monohydrate, dihydrate, trihydrate and the like. nates, benzenesulfonates, benzoates, bisulfates, butyrates, This invention provides, in other embodiments, metabo bicarbonates, bitartrates, carboxilate, citrates, camphorates, 10 lites of the SARM compounds. In one embodiment, “metabo camphorsulfonates, cyclohexylsulfamates, cyclopentanepro lite” means any Substance produced from another Substance pionates, calcium edetates, camsylates, carbonates, clavulan by metabolism or a metabolic process. ates, cinnamates, dicarboxylates, digluconates, dodecylsul This invention provides, in other embodiments, pharma fonates, dihydrochlorides, decanoates, enanthuates, ceutical products of the SARM compounds. The term “phar ethanesulfonates, edetates, edisylates, estolates, esylates, 15 maceutical product” refers, in other embodiments, to a com fumarates, formates, fluorides, galacturonate gluconates, position Suitable for pharmaceutical use (pharmaceutical glutamates, glycolates, glucorate, glucoheptanoates, glycero composition), for example, as described herein. phosphates, gluceptates, glycolylarsanilates, glutarates, An “alkyl group refers, in one embodiment, to a saturated glutamate, heptanoates, hexanoates, hydroxymaleates, aliphatic hydrocarbon, including straight-chain, branched hydroxycarboxlic acids, hexylresorcinates, hydroxyben chain and cyclic alkyl groups. In one embodiment, the alkyl Zoates, hydroxynaphthoate, hydrofluorate, lactates, lacto group has 1-12 carbons. In another embodiment, the alkyl bionates, laurates, malates, maleates, methylenebis(beta-OX group has 1-7 carbons. In another embodiment, the alkyl ynaphthoate), malonates, mandelates, mesylates, methane group has 1-6 carbons. In another embodiment, the alkyl Sulfonates, methylbromides, methylnitrates, methylsul group has 1-4 carbons. The alkyl group may be unsubstituted fonates, monopotassium maleates, mucates, monocarboxy 25 or Substituted by one or more groups selected from halogen, lates, mitrates, naphthalenesulfonates, 2-naphthalene hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, Sulfonates, nicotinates, napsylates, N-methylglucamines, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, thioalkyl. In one embodiment, the alkyl group is CHs. phenylacetate, pectinates, phenylpropionates, palmitates, 30 An “alkenyl group refers, in another embodiment, to an pantothenates, polygalacturates, pyruvates, quinates, salicy unsaturated hydrocarbon, including straight chain, branched chain and cyclic groups having one or more double bond. The lates, succinates, stearates, sulfanilate, subacetates, tart alkenyl group may have one double bond, two double bonds, arates, theophyllineacetates, p-toluenesulfonates (tosylates), three double bonds etc. Examples of alkenyl groups are ethe trifluoroacetates, terephthalates, tannates, teoclates, trihalo nyl, propenyl, butenyl, cyclohexenyl etc. In one embodiment, acetates, triethiodide, tricarboxylates, undecanoates and Val 35 the alkylene group has 1-12 carbons. In another embodiment, erates. the alkylene group has 1-7 carbons. In another embodiment, In one embodiment, examples of inorganic salts of car the alkylene group has 1-6 carbons. In another embodiment, boxylic acids or phenols may be selected from ammonium, the alkylene group has 1-4 carbons. The alkenyl group may be alkali metals to include lithium, Sodium, potassium, cesium; unsubstituted or Substituted by one or more groups selected alkaline earch metals to include calcium, magnesium, alu 40 from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, minium; Zinc, barium, cholines, quaternary ammoniums. In another embodiment, examples of organic salts of car dialkylamido, nitro, amino, alkylamino, dialkylamino, car boxylic acids or phenols may be selected from arginine, boxyl, thio and thioalkyl. organic amines to include aliphatic organic amines, alicyclic A "haloalkyl group refers to an alkyl group as defined organic amines, aromatic organic amines, benzathines, t-bu 45 above, which is Substituted by one or more halogen atoms, in tylamines, benethamines (N-benzylphenethylamine), dicy one embodiment by F, in another embodiment by Cl, in clohexylamines, dimethylamines, diethanolamines, ethano another embodiment by Br, in another embodiment by I. lamines, ethylenediamines, hydrabamines, imidazoles, An “aryl group refers to an aromatic group having at least lysines, methylamines, meglamines, N-methyl-D-glucam one carbocyclic aromatic group or heterocyclic aromatic ines, N,N'-dibenzylethylenediamines, nicotinamides, 50 group, which may be unsubstituted or substituted by one or organic amines, ornithines, pyridines, picolies, piperazines, more groups selected from halogen, haloalkyl, hydroxy, procain, tris(hydroxymethyl)methylamines, triethylamines, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, triethanolamines, trimethylamines, tromethamines and amino, alkylamino, dialkylamino, carboxy or thio or thio leaS. alkyl. Nonlimiting examples of aryl rings are phenyl, naph In one embodiment, the salts may be formed by conven 55 thyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, tional means, such as by reacting the free base or free acid pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isox form of the product with one or more equivalents of the azolyl, and the like. In one embodiment, the aryl group is a 4-8 appropriate acid or base in a solvent or medium in which the membered ring. In another embodiment, the aryl group is a salt is insoluble or in a solvent such as water, which is 4-12 membered ring(s). In another embodiment, the aryl removed in vacuo or by freeze drying or by exchanging the 60 group is a 6 membered ring. In another embodiment, the aryl ions of a existing salt for another ion or Suitable ion-exchange group is a 5 membered ring. In another embodiment, the aryl resin. group is 2-4 fused ring system. In one embodiment, the invention also includes N-oxides A “hydroxyl group refers to an OH group. It is understood of the amino substituents of the compounds described herein. by a person skilled in the art that when T is OR, R is not OH. Also, esters of the phenolic compounds can be made with 65 In one embodiment, the term “halogen refers to in one aliphatic and aromatic carboxylic acids, for example, acetic embodiment to F, in another embodiment to Cl, in another acid and benzoic acid esters. embodiment to Br, in another embodiment to I. US 7,772,433 B2 37 38 An “arylalkyl group refers, in another embodiment, to an (C-Cs), aryl (C-C) group, phenyl, carbocyclic (C-Cs) alkyl bound to an aryl, wherein alkyl and aryl are as defined group, heterocyclic(C-C) group, acyl, alkyl (C-Cs) halide, above. An example of an arylalkyl group is a benzyl group. alkenyl (C-C) group. In one embodiment, the term "amide' refers to carbonyl group attached to an amine group. In another embodiment the In one embodiment, the term "carbamate” refers to an ester amide group has the following schematic structure: of a carbamic acid (NHCOOH). In another embodiment the carbamate group has the following schematic structure: vX 10 wry In another embodiment, the amide group is unsubstituted or 15 Substituted via the nitrogen atom by alkyl (C-C), aryl (C- In another embodiment, the carbamate group is unsubstituted Cs) group, phenyl, carbocyclic (C-C) group, heterocyclic or Substituted via the nitrogen atom by alkyl (C-Cs), aryl (C-C) group, acyl, alkyl (C-Cs) halide, alkenyl (C-Cs) (C-C) group, phenyl, carbocyclic (C-C) group, heterocy group. In one embodiment, the term “thioamide' refers to C=S clic(C-C) group, acyl, alkyl (C-C) halide, alkenyl (C-C) group attached to an amine group. In another embodiment the group. thioamide group has the following schematic structure: In one embodiment, the term “urea' refers to carbonyl diamide group. In another embodiment the urea group has the following schematic structure: vX 25 30 v'ry In another embodiment, the thioamide group is unsubstituted or substituted via the nitrogen atom by alkyl (C-C), aryl (C-C) group, phenyl, carbocyclic (C-C) group, heterocy clic(C-C) group, acyl, alkyl (C-C) halide, alkenyl (C-C) In another embodiment, the urea group is unsubstituted or group. 35 substituted, independently via each or both of the nitrogen In one embodiment, the term “reverse amide' refers to atoms by alkyl (C-Cs), aryl (C-C) group, phenyl, carbocy amine group attached to a carbonyl group. In another embodi clic (C-C) group, heterocyclic(C-C) group, acyl, alkyl ment the reverse amide group has the following schematic (C-Cs) halide, alkenyl (C-C) group. Structure: 40 In one embodiment, the term “thiourea' refers to an C=S- diamide group. In another embodiment the urea group has the following schematic structure: 45 v'ry In another embodiment, the reverse amide group is unsubsti tuted or Substituted via the nitrogen atom by alkyl (C-C), aryl (C-C) group, phenyl, carbocyclic (C-C) group, het 50 erocyclic(C-C) group, acyl, alkyl (C-C) halide, alkenyl (C-C) group. In another embodiment, the thiourea group is unsubstituted or In one embodiment, the term “reverse thioamide' refers to substituted, independently via each or both of the nitrogen amine group attached to a C=S group. In another embodi 55 atoms by alkyl (C-Cs), aryl (C-C) group, phenyl, carbocy ment the reverse thioamide group has the following sche clic (C-C) group, heterocyclic(C-C) group, acyl, alkyl matic structure: (C-Cs) halide, alkenyl (C-C) group. In one embodiment, the term “ester refers to carboxylate (—CO O—), phosphonate (PO (OR)—O ) or to 60 thioesters (—SO—O—) groups. In one embodiment, the term “reverse ester refers to the reverse of the ester groups for example: —O CO . In another embodiment, the present invention provides 65 process for preparing a selective androgen receptor modula In another embodiment, the reverse thioamide group is tor (SARM) compound represented by the structure of for unsubstituted or substituted via the nitrogen atom by alkyl mula III: US 7,772,433 B2 39 40 the process comprising the step of coupling a compound of formula (10): III (R3)m 2. Y 7 10 ls Sás N 10 (R3)m 2, wherein X is a bond, O, CH, NH, Se, PR, NO or NR; G is O or S: wherein Z. Y. G. R. T. R. and mare as defined above and T is OH, OR, NHCOCH, or NHCOR; L is a leaving group, with a compound of formula 11: R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, 15 CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl or OH: 11 s R R is CH, CHF, CHF, CF, CHCH, or CFCF: HX 21 y 2) R is H, F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, h NHCOCF, NHCOR, alkyl, arylalkyl, OR, NH, NHR. ' N R is H, F, Cl, Br, I, CN, NO, COR, COOH,CONHR, CF, Sn(R), or wherein Q, X, R and n are as defined above. R, together with the benzene ring to which it is attached as In one embodiment, the coupling step is carried out in the forms a fused ring system represented by the structure: presence of a base. In another embodiment, the leaving group L is Br. In another embodiment, the compound of formula 10 is prepared by: 30 a) preparing a compound of formula 13 by ring opening of a cyclic compound of formula 12:

M or K. Z-S\- / Z-S\- / H Y Y 35 N Z is NO, CN, C1, F, Br, I, H, COR, COOH, or CONHR: G T Y is CF, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, R formyl, H, F, Br, Cl, I, CN, or Sn(R): 40 12 13 Q is H, alkyl, halogen, CF, CN CR, Sn(R), N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHC- wherein L, R, G and T are as defined above, and T is O or SCF, NHCSR NHSOCH, NHSOR, OH, OR, COR, NH; and OCOR, OSOR, SOR, SR: or Q together with the ben- as b) reacting an amine of formula 14: Zene ring to which it is attached is a fused ring system represented by structure A, B or C: 14

A e NH2 NH O 50 ".2 21 Z-l Sás Ás Y B 55 wherein Z. Y. R. and m are as defined above, with the 21 NH O compound of formula 13, in the presence of a coupling reagent, to produce the compound of formula 10. Ás 21 C 10 21 NH 60 Z

Ás / ly2

65 n is an integer of 1-4; and m is an integer of 1-3: US 7,772,433 B2 41 42 It is understood to a person skilled in the art that when T is for preparing a compound of formula III wherein Q is F. In O or NH, T in compound 13 is O or NH. Thus, when T in another embodiment, the present invention provides a process compound 13 is OR, the reaction will involve a further step of for preparing a compound of formula III wherein Q is C1. converting the OH to OR by a reaction with, for example, an In another embodiment, the present invention provides a alkyl halide R X. When T in compound 13 is NHCOR, 5 process for preparing a selective androgen modulator com NHCOCH, the reaction will involve a further step of con verting the NH, to NHCOR or NHCOCH, by a reaction with, pound represented by the structure of formula I: for example, the corresponding acyl chloride CICOR or CICOCH, (I) In one embodiment, step (a) is carried out in the presence of 10 HBr. In one embodiment, whereby compound 13 of step (a) is reacted with a coupling agent prior to step (b). In one embodiment, the coupling step is carried out in the presence of a base. In another embodiment, the leaving group 15 L is Br. In another embodiment, the process further comprises the step of converting the selective androgen receptor modulator wherein Q is hydrogen, alkyl, F, Cl, Br, I, CF, CN, C(R), (SARM) compound to its analog, isomer, metabolite, deriva Sn(R), N(R), NHCOCH, NHCOCF, NHCOR, tive, pharmaceutically acceptable salt, pharmaceutical prod 2O NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, uct, polymorph, crystal, impurity, N-oxide, hydrate or any NHCSCF, NHCSR NHSOCH, NHSOR, OR, COR, combination thereof. OCOR, OSOR, SOR, SR; and In another embodiment, this invention provides a large R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF scale process for the preparation of compound of formula III, 25 CF, CFCF, aryl, phenyl, F, Cl, Br, I, alkenyl or OH: wherein the process comprises the same steps as described In another embodiment, the present invention provides a herein above, wherein compound of formula 12 is prepared process for preparing a selective androgen modulator com according to the following scheme, in the presence of 4N pound represented by the structure of formula II, as depicted NaOH: in FIG. 1 and Example 1: 30 C NC -- aCOH 4NNaOH O <10°C., 2 hrs N H MtBE H 35 FC H CO2H O N N H NBSDMF HsRT 'O 40 C O & Br K2CO3 O He H3C 2-propanol HO F 12

45 NC C FIGS. 1K and 1L provide one embodiment of a large scale process for the preparation of a large scale synthesis of com pounds of formulas S-II. In one embodiment, the present invention provides a pro FC cess for preparing a compound of formula III wherein is X is 50 O. In another embodiment, the present invention provides a process for preparing a compound of formula III wherein is T is OH. In another embodiment, the present invention provides a process for preparing a compound of formula III wherein is In another embodiment, the present invention provides a R is CH. In another embodiment, the present invention 55 process for preparing an (S) enantiomer of SARM compound provides a process for preparing a compound of formula III represented by the structure of formula II: wherein Z is CN, and/or Cland/or F. In another embodiment, the present invention provides a process for preparing a com pound of formula III, wherein Z is CN. In another embodi S-II ment, the present invention provides a process for preparing a 60 NC C compound of formula III whereinY is CF and/or CH, and/or H and/or Cl. In another embodiment, the present invention provides a process for preparing a compound of formula III wherein R is H, and/or CN, and/or C1 and/or F. In another FC embodiment, the present invention provides a process for 65 preparing a compound of formula III wherein Q is CN. In another embodiment, the present invention provides a process US 7,772,433 B2 43 44 said process comprising the steps of a) coupling an amine of formula 17: R-II NC Cl; O 17 NH2 FC NH O F

NC H6 H, 10 CF said process comprising the steps of a) coupling an amine of formula 17: with the carboxylic acid of formula R-18 15 17 NH2 R-18

NC HO Br Hd OH CF with the carboxylic acid of formula S-18 in the presence of a coupling reagent, to produce an amide 25 of formula R-19 S-18

R-19 NC 30 HO Br CH, NH Br; and C oH in the presence of a coupling reagent, to produce an amide 35 of formula S-19 b) reacting the amide of formula R-19 with a compound of formula 20: S-19 NC

40 2O C FC NH

HO F 45 b) reacting the amide of formula S-19 with a compound of formula 20 wherein Q is C1 or CN: to produce a compound of formula S-II. 50 In one embodiment, whereby compound R-18 of step (a) is reacted with a coupling agent prior to addition of compound of formula 17. FIG. 1A and Example 1 provide one embodiment of a HO F process for the preparation of a compound of formula S-II. 55 In another embodiment, the conditions of step (b) of the to produce a compound of R-II. process outlined hereinabove may comprise potassium car In one embodiment, whereby compound S-18 of step (a) is bonate, Sodium carbonate, or cesium carbonate, or another reacted with a coupling agent prior to addition of compound base appropriate for this reaction, using 2-propanol, THF or 60 of formula 17 methylethylketone as a solvent, optionally with a transition FIG. 1B depicts one embodiment of such a process for the catalyst, BTBAC (benzyltributylammonium chloride) or preparation of compound of formula R-II. other Suitable agent. In another embodiment, the conditions of step (b) of the In another embodiment, the present invention provides a 65 process outlined hereinabove may comprise potassium car process for preparing an (R) enantiomer of SARM compound bonate, Sodium carbonate, or cesium carbonate, or another represented by the structure of formula R-II: base appropriate for this reaction, using 2-propanol, THF or US 7,772,433 B2 45 46 methylethylketone as a solvent, optionally with a transition c) reacting the oxirane of formula S-21 with a compound of catalyst, BTBAC (benzyltributylammonium chloride) or formula 20: other Suitable agent.

In another embodiment, the present invention provides a 2O process for preparing an (S) enantiomer of a SARM com C pound represented by the structure of formula S-II

HO F S-II 10 NC C to produce a compound of S-II. In one embodiment, whereby compound R-18 of step (a) is FC NH 15 reacted with a coupling agent prior addition of compound of C oH formula 17 FIG. 1C depicts an embodiment of such a process for the preparation of compound of formula S-II. said process comprising the steps of In another embodiment, the present invention provides a a) coupling an amine of formula 17: process for preparing an (R) enantiomer of SARM compound represented by the structure of formula R-II:

17 NH2 R-II 25 NC C O NC

CF FC NH O F 30 H6 H, with the carboxylic acid of formula R-18 said process comprising the steps of

R-18 35 a) coupling an amine of formula 17:

17 HO Br NH2 Hd OH 40 NC in the presence of a coupling reagent, to produce an amide of formula R-19 CF

45 with the carboxylic acid of formula S-18 R-19 NC

S-18

50 Br; C oH HO Br H6 ah, b) reacting the amide of formula R-19, with a base to forman 55 oxirane S-21 in the presence of a coupling reagent, to produce an amide of formula S-19

S-21 NC S-19 60 NC

FC FC 65 US 7,772,433 B2 47 48 b) reacting the amide of formula S-19, with a base to forman to produce a compound of formula R-23: oxirane R-21 R-23

NH CH 10 c) reacting the oxirane of formula R-21 with a compound of Cl; F formula 20: 15 a) ring opening of compound of formula R-23 to produce a compound of formula S-24 2O C S-24 Cl; and 2O O

HO F HO O F H3C oH to produce a compound of R-II. 25 In one embodiment, whereby compound S-18 of step (a) is coupling the carboxylic acid of compound of formula S-24 reacted with a coupling agent prior to addition of compound with the amine of formula 17 of formula 17. FIG. 1D preparation of compound of formula R-II. 30 17 In another embodiment, the present invention provides a NH2 process for preparing an (S) enantiomer of a SARM com pound represented by the structure of formula S-II. NC 35 CF S-II NC C to produce the compound of formula S-II. FIG. 1E depicts an embodiment of such a process for the Ol O 40 preparation of compound of formula S-II. FC NH O F In another embodiment, the present invention provides a C, OH process for preparing an (R) enantiomer of a SARM com pound represented by the structure of formula R-II: said process comprising the steps of 45 a) reacting a ring of formula S-22 R-II NC C O S-22 H 50 FC NH O F O N H6 H, wO O w Br 55 said process comprising the steps of H3C a) reacting a ring of formula R-22

with a compound of 20 R-22 60 H O N

O B 2 -'1 r HO .F 65 HC1 " US 7,772,433 B2 49 50 with a compound of 20 said process comprising the steps of 2O a) reacting the carboxylic acid of formula R-18 C R-18 O

HO F HO Br to produce a compound of formula S-23; with tribromoacetaldehyde to produce a compound of for S-23 mula R-25: R-25

reacting the dioxalane derivative R-25 with a compound of formula 20 Cl

2O C b) ring opening of compound of formula S-23 to produce a 25 compound of formula R-24 HO F

R-24 to produce a compound of formula R-26; Cl; and 30

R-26 H CBr HO

CH, 35 O O coupling the carboxylic acid of compound of formula R-24 with the amine of formula 17 40

17 NH2 b) ring opening of compound of formula R-26 to produce a 45 compound of formula S-24 NC S-24 CF Cl; and

to produce the compound of formula S-III. HO FIG. 1F depicts an embodiment of such a process for the preparation of compound of formula S-II. C oH In another embodiment, the present invention provides a process for preparing an (S) enantiomer of a SARM com 55 coupling the carboxylic acid of compound of formula S-24 pound represented by the structure of formula S-II with the amine of formula 17:

S-II 17 60 NH2 NC C

NC FC CF 65 to produce the compound of formula S-II. US 7,772,433 B2 51 52 FIG. 1G depicts an embodiment of such a process for the ring opening of compound of formula S-26 to produce a preparation of compound of formula S-II. compound of formula R-24 In another embodiment, the present invention provides a process for preparing an (R) enantiomer of a SARM com- 5 R-24 pound represented by the structure of formula R-II Cl; and

R-II F NC C 10 O

FC NH O F coupling the carboxylic acid of compound of formula R-24 H6 aH, 15 with the amine of formula 17:

said process comprising the steps of NH2 17 a) reacting the carboxylic acid of formula S-18 2O NC S-18

HO Br 25 to produce the compound of formula R-III. H6 a. FIG. 1H depicts an embodiment of such a process for the preparation of compound of formula R-II. In another embodiment, the present invention provides a with tribromoacetaldehyde to produce a compound of for process for preparing a racemic mixture of a SARM com mula S-25: 3 pound represented by the structure of formula II

S-25 II H CBr NC C -X 35 Ol O O FC sixCH, OH F H3 Br 40 said process comprising the steps of reacting the dioxalane derivative S-25 with a compound of a) reacting a compound of formula 24 formula 20

45 24 C 2O O OC

HO 50 -->CH, OH F

to produce a compound of formula S-26; with a compound of formula 27 55 S-26 27 P

60 NC CF Cl;

65 wherein P is selected from isocyanate (NCO) or isothiocyan ate (NCS) to produce a compound of formula 28a or 28b. respectively US 7,772,433 B2 53 54 28a. c) oxidizing an amide of formula 29, to produce the oxirane of formula 21 NC O 21 CH 5 FC NC O Cl; or O O FC NH F 28b 10 CH, O NC O d) reacting the oxirane of formula 21 with a compound of formula 20 CH3 FC 15 O C S O F b) ring opening of the oxazolidinedione or 2-thioXooxazolid HO F 4-one ring of formula 28a or 28b in a presence of a base to produce a compound of formula III. FIG. 1I depicts an embodiment of such a process for the to produce the compound. preparation of racemic compound of formula II. In another embodiment, the oxidizing an amide of formula In another embodiment, the present invention provides a 25 29 of step (c) comprises oZone. In another embodiment, the process for preparing a racemic mixture of a SARM com oxidizing agent is a peroxyacid, for example, peracetic acid, pound represented by the structure of formula II: (CHCOOOH). In another embodiment, the oxidizing agent meta-chloroperbenzoic acid (m-CPBA). In another embodi II NC C ment, the oxidizing agent is Magnesium MonoPeroxyPthalic 30 Acid (MMPP). In another embodiment, the oxidizing agent is hydrogen peroxide together with catalytic amounts (1.0-0.1 Ol O ICC mol%) of manganese (2') salts. FC six F FIG. 1J depicts an embodiment of a process for the prepa CH OH ration of racemic compound of formula II. 35 In one embodiment, this invention provides a process for said process comprising the steps of preparing pure enantiomers of SARMs compounds of this a) chlorinating methacrylic acid invention, comprising the steps of a) preparing a racemic SARM compound of this invention; and b) separating pure O O SARM compound of this invention from its racemic mixture. 40 In one embodiment, separation of the optically-active (R) He isomer or (S) enantiomer, from the racemic SARM com HO C pounds of this invention comprises crystallization tech niques. In another embodiment, the crystallization tech CH CH niques include differential crystallization of enantiomers. In 45 another embodiment, the crystallization techniques include b) coupling an 3-cyano 4-trifluoromethyl aniline of formula differential crystallization of diasteriomeric salts (tartaric 17 with methacryloyl chloride: salts or quinine salts). In another embodiment, the crystalli zation techniques include differential crystallization of chiral auxiliary derivatives (mentholesters, etc). In another embodi 17 50 ment, separation of the optically-active (R) isomer or (S) NC NH2 enantiomer, from the racemic SARM compounds of this invention comprises reacting the racemate mixture with another chiral group, forming of a diasteriomeric mixture FC followed by separation of the diasteriomers and removing the 55 additional chiral group to obtain pure enantiomers. In another embodiment, separation of the optically-active (R) isomer or to produce the amide of formula 29. (S) enantiomer, from the racemic SARM compounds of this invention comprises chiral synthesis. In another embodiment, 29 separation of the optically-active (R) isomer or (S) enanti NC 60 omer, from the racemic SARM compounds of this invention comprises biological resolution. In another embodiment, separation of the optically-active (R) isomer or (S) enanti Ol O omer, from the racemic SARM compounds of this invention FC -- comprises enzymatic resolution. In another embodiment, CH3 65 separation of the optically-active (R) isomer or (S) enanti omer, from the racemic SARM compounds of this invention comprises chromatographic separation using a chiral station US 7,772,433 B2 55 56 ary phase. In another embodiment, separation of the opti one skilled in the art, for example, in the range, of -20 to 120° cally-active (R) isomer or (S) enantiomer, from the racemic C., or for example at or near ambient temperature. SARM compounds of this invention comprises affinity chro The coupling reagent defined hereinabove is a reagent matography. In another embodiment, separation of the opti capable of turning the carboxylic acid/thiocarboxylic acid of cally-active (R) isomer or (S) enantiomer, from the racemic formula 24 or 18 into a reactive derivative thereof, thus SARM compounds of this invention comprises capillary elec enabling coupling with the respective amine to form an trophoresis. In another embodiment, separation of the opti amide/thioamide bond. A suitable reactive derivative of a cally-active (R) isomer or (S) enantiomer, from the racemic carboxylic acid/thiocarboxylic acid is, for example, an acyl SARM compounds of this invention comprises forming an halide/thioacyl halide, for example an acyl/thioacyl chloride ester group of the hydroxyl group of the chiral carbon with an 10 formed by the reaction of the acid/thioacid and an inorganic optically-active acid, for example (-)-camphanic acid, sepa acid chloride, for example thionyl chloride; a mixed anhy rating the diastereomers esters, thus obtained, by fractional dride, for example an anhydride formed by the reaction of the crystallization or preferably, by flash-chromatography, and acid and a chloroformate Such as isobutyl chloroformate; an then hydrolyzing each separate ester to the alcohol. active ester/thioester, for example an ester formed by the In another embodiment, the purity, and selectivity of an 15 reaction of the acid and a phenol Such as pentafluorophenol, enantiomer obtained by the process of this invention, or by an ester Such as pentafluorophenyl trifluoroacetate oran alco chiral separation of a racemic mixture of this invention can be hol Such as methanol, ethanol, isopropanol, butanol or N-hy determined by HPLC analysis. droxybenzotriazole; an acyl/thioacyl azide, for example an In another embodiment, the process further comprises the azide formed by the reaction of the acid/thioacid and azide step of converting the SARM compound to its analog, isomer, Such as diphenylphosphoryl azide; an acyl cyanide/thioacyl metabolite, derivative, pharmaceutically acceptable salt, cyanide, for example a cyanide formed by the reaction of an pharmaceutical product, N-oxide, hydrate or any combina acid and a cyanide Such as diethylphosphorylcyanide; or the tion thereof. product of the reaction of the acid/thioacid and a carbodiim According to this aspect of the invention, and in one ide such as dicyclohexylcarbodiimide. embodiment, the reagent used for reacting the amide deriva 25 It is to be understood that the process may comprise any tive, for example compound of formula 19 and the phenol embodiment described herein, as will be appropriate to pro derivative such as for example 20, or the compound of for duce a SARM of a corresponding formula, as will be appre mula 19 with the phenol of formula 30, or the compound of ciated by one skilled in the art. formula 37 together with the compound of formula 38 are In one embodiment, the process for preparing a SARM of carried out in the presence of a base. Any suitable base that 30 this invention may involvering opening in the presence of less will deprotonate the hydrogen of the XH moiety (for acidic conditions, which in another embodiment, diminish example, a phenol moiety when X is O) and allow the cou the likelihood of obtaining SARM compound mixtures, and pling may be used. Nonlimiting examples of bases are car provide higher yield and purity of a SARM of interest. In one bonates such as alkali carbonates, for example Sodium car embodiment, the ring opening of a process as described bonate (NaCO), potassium carbonate (KCO) and cesium 35 herein, to produce a carboxylic acid of formula 13, is carried carbonate (CSCO); bicarbonates such as alkali metal bicar out in the presence of HBr, which, in one embodiment, is at a bonates, for example sodium bicarbonate (NaHCO), potas concentration of up to 30%, or in another embodiment, of up sium bicarbonate (KHCO), alkali metal hydrides such as to 40%, or in another embodiment, is of up to 25%, or in sodium hydride (NaH), potassium hydride (KH) and lithium another embodiment, of up to 23%, or in another embodi hydride (LiH), and the like. 40 ment, of up to between 20-25%. In one embodiment, the The leaving group L. according to this aspect, and in one SARMs of this invention may be produced via large-scale embodiment, may comprise any removable group customar synthesis, providing highly pure products in high yields. ily considered for chemical reactions, as will be known to the In one embodiment, the reaction may be carried out in a person skilled in the art. Suitable leaving groups are halogens, suitable inert solvent or diluent as described hereinabove, for example F, Cl, Brand I: alkylsulfonate esters (—OSOR) 45 Suitably in the presence of a base such as triethylamine, and at wherein R is an alkyl group, for example methanesulfonate a temperature in the range, as described above. (mesylate), trifluoromethanesulfonate, ethanesulfonate, 2.2, In some embodiments, the compounds as described herein 2-trifluoroethanesulfonate, perfluoro butanesulfonate: aryl are useful in preventing and treating muscle wasting disor sulfonate esters ( OSOAr) wherein Aris an aryl group, for ders, bone related disorders, and diabetes related disorders. example p-toluoylsulfonate (tosylate), benzenesulphonate 50 In some embodiments, the compounds as described herein which may be unsubstituted or substituted by methyl, chlo are useful, either alone or as a composition, in males and rine, bromine, nitro and the like: NONO or sulfate, sulfite, females for the treatment of a variety of hormone-related phosphate, phosphite, carboxylate, imino ester, N or car conditions, such as hypogonadism, sarcopenia, erectile dys bamate. function, lack of libido, osteoporosis and fertility. In some According to this aspect of the invention and in one 55 embodiments, the compounds as described herein are useful embodiment, the reaction is carried out in a suitable inert in stimulating or promoting or restoring function to various Solvent or diluent such as, for example, tetrahydrofuran, processes, which in turn result in the treatment of the condi diethyl ether, acetone, methyl ethyl ketone, 2-propanol, aro tions as herein described, including, inter aila, promoting matic amines Such as pyridine; aliphatic and aromatic hydro erythropoiesis, osteogenesis, muscle growth, glucose uptake, carbons such as benzene, toluene, and Xylene; dimethylsul 60 insulin secretion, and/or preventing lipidogenesis, clotting, foxide (DMSO), dimethylformamide (DMF), and insulin resistance, atherosclerosis, osteoclast activity, and dimethylacetamide (DMAC). In one embodiment, the reac others. tion may be carried out in a suitable inert solvent or diluent as In one embodiment, the methods of this invention make use described hereinabove, suitably in the presence of a base such of the described compound contacting or binding a receptor, as triethylamine, and at a temperature in the range, as 65 and thereby mediating the described effects. In some embodi described above. In one embodiment, the reaction may be ments, the receptor is a nuclear receptor, which in one carried out at an appropriate temperature, as will be known to embodiment, is an androgen receptor, or in another embodi US 7,772,433 B2 57 58 ment, is an estrogen receptor, or in another embodiment, is a lated in a form suitable for intraarterial administration. In progesterone receptor, or in another embodiment, is a gluco another embodiment, the pharmaceutical compositions are corticoid receptor. In some embodiments, the multitude of administered intramuscularly, and are thus formulated in a effects may occur simultaneously, as a function of binding to form suitable for intramuscular administration. multiple receptors in the Subject. In some embodiments, the 5 Further, in another embodiment, the pharmaceutical com tissue selective effects of the compounds as described herein positions are administered topically to body Surfaces, and are provide for simultaneous action on different target organs. thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, Pharmaceutical Compositions creams, lotions, drops and the like. For topical administration, In some embodiments, this invention provides methods of 10 the compounds of this invention or their physiologically tol use which comprise administering a composition comprising erated derivatives such as salts, esters, N-oxides, and the like the described compounds. As used herein, “pharmaceutical are prepared and applied as Solutions, Suspensions, or emul composition” means a “therapeutically effective amount of sions in a physiologically acceptable diluent with or without the active ingredient, i.e. the compound of Formula I, together a pharmaceutical carrier. with a pharmaceutically acceptable carrier or diluent. A 15 Further, in another embodiment, the pharmaceutical com “therapeutically effective amount’ as used herein refers to positions are administered as a Suppository, for example a that amount which provides a therapeutic effect for a given rectal Suppository or a urethral Suppository. Further, in condition and administration regimen. another embodiment, the pharmaceutical compositions are As used herein, the term “administering refers to bringing administered by Subcutaneous implantation of a pellet. In a a subject in contact with a compound of the present invention. further embodiment, the pellet provides for controlled release As used herein, administration can be accomplished in vitro, of a compound as herein described over a period of time. In a i.e. in a test tube, or in Vivo, i.e. in cells or tissues of living further embodiment, the pharmaceutical compositions are organisms, for example humans. In one embodiment, the administered intravaginally. present invention encompasses administering the compounds In another embodiment, the active compound can be deliv of the present invention to a subject. 25 ered in a vesicle, in particular a liposome (see Langer, Science The pharmaceutical compositions containing the com 249:1627-1633 (1990); Treat et al., in Liposomes in the pounds of this invention can be administered to a subject by Therapy of Infectious Disease and Cancer, Lopez-Berestein any method known to a person skilled in the art. Such as orally, and Fidler (eds.), Liss, New York, pp. 363-366 (1989); Lopez parenterally, intravascularly, paracancerally, transmucosally, Berestein, ibid., pp. 317-327; see generally ibid). transdermally, intramuscularly, intranasally, intravenously, 30 As used herein “pharmaceutically acceptable carriers or intradermally, Subcutaneously, Sublingually, intraperito diluents' are well knownto those skilled in theart. The carrier nealy, intraventricularly, intracranially, intravaginally, by or diluent may be a solid carrier or diluent for solid formula inhalation, rectally, intratumorally, or by any means in which tions, a liquid carrier or diluent for liquid formulations, or the recombinant virus/composition can be delivered to tissue mixtures thereof. (e.g., needle or catheter). Alternatively, topical administration 35 Solid carriers/diluents include, but are not limited to, a may be desired for application to mucosal cells, for skin or gum, a starch (e.g. corn starch, pregeletanized starch), a Sugar ocular application. Another method of administration is via (e.g., lactose, mannitol. Sucrose, dextrose), a cellulosic mate aspiration or aerosol formulation. rial (e.g. microcrystalline cellulose), an acrylate (e.g. polym In one embodiment, the pharmaceutical compositions are ethylacrylate), calcium carbonate, magnesium oxide, talc, or administered orally, and are thus formulated in a form Suit 40 mixtures thereof. able for oral administration, i.e. as a solid or a liquid prepa In one embodiment, the compositions of this invention ration. Suitable solid oral formulations include tablets, cap may include, a compound of this invention or any combina Sules, pills, granules, pellets, powders, and the like. Suitable tion thereof, together with one or more pharmaceutically liquid oral formulations include Solutions, Suspensions, dis acceptable excipients. persions, emulsions, oils and the like. In one embodiment of 45 It is to be understood that this invention encompasses any the present invention, the SARM compounds are formulated embodiment of a compound as described herein, which in in a capsule. In accordance with this embodiment, the com some embodiments is referred to as “a compound of this positions of the present invention comprise in addition to a invention'. Such reference will include any compound, compound of this invention and the inert carrier or diluent, a which is characterized by a structure of the formulae I-XXII, hard gelatin capsule. 50 or any embodiment thereof, as described herein. In one embodiment, the micronized capsules comprise par Suitable excipients and carriers may be, according to ticles containing a compound of this invention, wherein the embodiments of the invention, solid or liquid and the type is term “micronized' used herein refers to particles having a generally chosen based on the type of administration being particle size is of less than 100 microns, or in another embodi used. Liposomes may also be used to deliver the composition. ment, less than 60 microns, or in another embodiment, less 55 Examples of Suitable solid carriers include lactose, Sucrose, than 36 microns, or in another embodiment, less than 16 gelatin and agar. Oral dosage forms may contain Suitable microns, or in another embodiment, less than 10 microns, or binders, lubricants, diluents, disintegrating agents, coloring in another embodiment, less than 6 microns. agents, flavoring agents, flow-inducing agents, and melting Further, in another embodiment, the pharmaceutical com agents. Liquid dosage forms may contain, for example, Suit positions are administered by intravenous, intraarterial, or 60 able solvents, preservatives, emulsifying agents, Suspending intramuscular injection of a liquid preparation. Suitable liq agents, diluents, Sweeteners, thickeners, and melting agents. uid formulations include solutions, Suspensions, dispersions, Parenteral and intravenous forms should also include miner emulsions, oils and the like. In one embodiment, the pharma als and other materials to make them compatible with the type ceutical compositions are administered intravenously, and are of injection or delivery system chosen. Of course, other thus formulated in a form suitable for intravenous adminis 65 excipients may also be used. tration. In another embodiment, the pharmaceutical compo For liquid formulations, pharmaceutically acceptable car sitions are administered intraarterially, and are thus formu riers may be aqueous or non-aqueous Solutions, Suspensions, US 7,772,433 B2 59 60 emulsions or oils. Examples of non-aqueous solvents are 674 (1989). In another embodiment, polymeric materials can propylene glycol, polyethylene glycol, and injectable organic be used. In yet another embodiment, a controlled release esters such as ethyl oleate. Aqueous carriers include water, system can be placed in proximity to the therapeutic target, alcoholic/aqueous solutions, cyclodextrins, emulsions or Sus i.e., the brain, thus requiring only a fraction of the systemic pensions, including saline and buffered media. Examples of 5 dose (see, e.g., Goodson, in Medical Applications of Con oils are those of petroleum, animal, vegetable, or synthetic trolled Release, supra, Vol. 2, pp. 116-138 (1984). Other origin, for example, peanut oil, soybean oil, mineral oil, olive controlled release systems are discussed in the review by oil, sunflower oil, and fish-liver oil. Langer (Science 249:1627-1633 (1990). Parenteral vehicles (for Subcutaneous, intravenous, intraar The compositions may also include incorporation of the terial, or intramuscular injection) include Sodium chloride 10 active material into or onto particulate preparations of poly Solution, Ringer's dextrose, dextrose and Sodium chloride, meric compounds such as polylactic acid, polglycolic acid, lactated Ringer's and fixed oils. Intravenous vehicles include hydrogels, etc, or onto liposomes, microemulsions, micelles, fluid and nutrient replenishers, electrolyte replenishers such unilamellar or multilamellar vesicles, erythrocyte ghosts, or as those based on Ringer's dextrose, and the like. Examples spheroplasts.) Such compositions will influence the physical are sterile liquids such as water and oils, with or without the 15 state, solubility, stability, rate of in vivo release, and rate of in addition of a Surfactant and other pharmaceutically accept Vivo clearance. able adjuvants. In general, water, saline, aqueous dextrose Also comprehended by the invention are particulate com and related Sugar Solutions, and glycols such as propylene positions coated with polymers (e.g. poloxamers or poloxam glycols or polyethylene glycol are preferred liquid carriers, ines) and the compound coupled to antibodies directed particularly for injectable solutions. Examples of oils are against tissue-specific receptors, ligands or antigens or those of petroleum, animal, vegetable, or synthetic origin, for coupled to ligands of tissue-specific receptors. example, peanut oil, soybean oil, mineral oil, olive oil, Sun Also comprehended by the invention are compounds modi flower oil, and fish-liver oil. fied by the covalent attachment of water-soluble polymers In addition, the compositions may further comprise bind Such as polyethylene glycol, copolymers of polyethylene gly ers (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, 25 guar gum, hydroxypropyl cellulose, hydroxypropyl methyl col and polypropylene glycol, carboxymethyl cellulose, dex cellulose, povidone), disintegrating agents (e.g. cornstarch, tran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline. potato starch, alginic acid, silicon dioxide, croscarmelose The modified compounds are known to exhibit substantially Sodium, crospovidone, guar gum, Sodium starch glycolate), longer half-lives in blood following intravenous injection buffers (e.g., Tris-HCl, acetate, phosphate) of various pH and 30 than do the corresponding unmodified compounds (Abu ionic strength, additives such as albuminor gelatin to prevent chowski et al., 1981; Newmarket al., 1982; and Katre et al., absorption to surfaces, detergents (e.g., Tween 20, Tween 80, 1987). Such modifications may also increase the compound's Pluronic F68, bile acid salts), protease inhibitors, surfactants solubility in aqueous solution, eliminate aggregation, (e.g. sodium lauryl Sulfate), permeation enhancers, solubiliz enhance the physical and chemical stability of the compound, ing agents (e.g., cremophor, glycerol, polyethylene glycerol, 35 and greatly reduce the immunogenicity and reactivity of the benzlkonium chloride, benzyl benzoate, cyclodextrins, sobi compound. As a result, the desired in vivo biological activity tan esters, Stearic acids), anti-oxidants (e.g., ascorbic acid, may be achieved by the administration of such polymer sodium metabisulfite, butylated hydroxyanisole), stabilizers compound abducts less frequently or in lower doses than with (e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellu the unmodified compound. lose), viscosity increasing agents (e.g. carbomer, colloidal 40 The preparation of pharmaceutical compositions which silicon dioxide, ethyl cellulose, guar gum), Sweetners (e.g. contain an active component is well understood in the art, for aspartame, citric acid), preservatives (e.g., Thimerosal, ben example by mixing, granulating, or tablet-forming processes. Zyl alcohol, parabens), coloring agents, lubricants (e.g. The active therapeutic ingredient is often mixed with excipi Stearic acid, magnesium Stearate, polyethylene glycol, ents which are pharmaceutically acceptable and compatible Sodium lauryl Sulfate), flow-aids (e.g. colloidal silicon diox 45 with the active ingredient. For oral administration, the com ide), plasticizers (e.g. diethyl phthalate, triethyl citrate), pounds of this invention or their physiologically tolerated emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium derivatives such as salts, esters, N-oxides, and the like are lauryl Sulfate), polymer coatings (e.g., poloxamers or poloX mixed with additives customary for this purpose. Such as amines), coating and film forming agents (e.g. ethylcellulose, vehicles, stabilizers, or inert diluents, and converted by cus acrylates, polymethacrylates), and/or adjuvants. 50 tomary methods into Suitable forms for administration, Such In one embodiment, the pharmaceutical compositions pro as tablets, coated tablets, hard or soft gelatin capsules, aque vided herein are controlled release compositions, i.e. compo ous, alcoholic or oily solutions. For parenteral administration, sitions in which the compound of this invention is released the compounds of this invention or their physiologically tol over a period of time after administration. Controlled or sus erated derivatives such as salts, esters, N-oxides, and the like tained release compositions include formulation in lipophilic 55 are converted into a solution, Suspension, or emulsion, if depots (e.g. fatty acids, waxes, oils). In another embodiment, desired with the substances customary and suitable for this the composition is an immediate release composition, i.e. a purpose, for example, solubilizers or other. composition in which all of the compound is released imme An active component can be formulated into the composi diately after administration. tion as neutralized pharmaceutically acceptable salt forms. In yet another embodiment, the pharmaceutical composi 60 Pharmaceutically acceptable salts include the acid addition tion can be delivered in a controlled release system. For salts (formed with the free amino groups of the polypeptide or example, the agent may be administered using intravenous antibody molecule), which are formed with inorganic acids infusion, an implantable osmotic pump, a transdermal patch, Such as, for example, hydrochloric or phosphoric acids, or liposomes, or other modes of administration. In one embodi Such organic acids as acetic, oxalic, tartaric, mandelic, and the ment, a pump may be used (see Langer, Supra; Sefton, CRC 65 like. Salts formed from the free carboxyl groups can also be Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., derived from inorganic bases Such as, for example, Sodium, Surgery 88:607 (1980); Saudek et al., N. Engl. J. Med. 321: potassium, ammonium, calcium, or ferric hydroxides, and US 7,772,433 B2 61 62 Such organic bases as isopropylamine, trimethylamine, In some embodiments, the present invention provides 2-ethylamino ethanol, histidine, procaine, and the like. methods of use of a pharmaceutical composition comprising For use in medicine, the salts of the compound will be a) any embodiment of the compounds as described herein, pharmaceutically acceptable salts. Other salts may, however, including an analog, isomer, metabolite, derivative, pharma be useful in the preparation of the compounds according to ceutically acceptable salt, pharmaceutical product, N-oxide, the invention or of their pharmaceutically acceptable salts. hydrate thereof or any combination thereof; b) a pharmaceu Suitable pharmaceutically acceptable salts of the compounds tically acceptable carrier or diluent; c) a flow-aid; and d) a of this invention include acid addition salts which may, for lubricant. example, be formed by mixing a solution of the compound In another embodiment, the present invention provides according to the invention with a solution of a pharmaceuti 10 methods of use of a pharmaceutical composition comprising cally acceptable acid such as hydrochloric acid, Sulphuric a) any embodiment of the compounds as described herein, acid, methaneSulphonic acid, fumaric acid, maleic acid, suc including an analog, isomer, metabolite, derivative, pharma cinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, ceutically acceptable salt, pharmaceutical product, N-oxide, tartaric acid, carbonic acid or phosphoric acid. hydrate thereofor any combination thereof; b) lactose mono In one embodiment, this invention provides pharmaceuti 15 hydrate; c) microcrystalline cellulose; d) magnesium Stear cal compositions comprising a compound of this invention. In ate; and e) colloidal silicon dioxide. one embodiment, Such compositions are useful for oral test In some embodiments, the methods of this invention make osterone replacement therapy. use of compositions comprising compounds of this invention, In one embodiment, this invention also provides a compo which offer the advantage that the compounds are nonsteroi sition comprising two or more compounds of this invention, dal ligands for the androgen receptor, and exhibit anabolic or polymorphs, isomers, hydrates, salts, N-oxides, etc., activity in vivo. According to this aspect, such compounds are thereof. The present invention also relates to compositions unaccompanied by serious side effects, provide convenient and a pharmaceutical compositions which comprises a com modes of administration, and lower production costs and are pound of this invention alone or in combination with a proges orally bioavailable, lack significant cross-reactivity with tin or estrogen, or in another embodiment, chemotherapeutic 25 other undesired steroid receptors, and may possess long bio compound, osteogenic or myogenic compound, or other logical half-lives. agents Suitable for the applications as herein described. In one For administration to mammals, and particularly humans, embodiment, the compositions of this invention will com it is expected that the physician will determine the actual prise a suitable carrier, diluent or salt. dosage and duration of treatment, which will be most suitable In one embodiment, the methods of this invention may 30 for an individual and can vary with the age, weight and comprise administration of a compound of this invention at response of the particular individual. various dosages. In another embodiment, the methods of this In one embodiment, the compositions for administration invention may comprise administration of a compound of may be sterile solutions, or in other embodiments, aqueous or formula II of this invention at various dosages. In one embodi non-aqueous, Suspensions or emulsions. In one embodiment, ment, the compound of this invention is administered at a 35 the compositions may comprise propylene glycol, polyethyl dosage of 0.1-200 mg per day. In one embodiment, the com ene glycol, injectable organic esters, for example ethyl oleate, pound of this invention is administered at a dose of 0.1-10 mg. or cyclodextrins. In another embodiment, compositions may or in another embodiment, 0.1-26 mg, or in another embodi also comprise wetting, emulsifying and/or dispersing agents. ment, 0.1-60 mg, or in another embodiment, 0.3-16 mg, or in In another embodiment, the compositions may also comprise another embodiment, 0.3-30 mg. or in another embodiment, 40 sterile water or any other sterile injectable medium. 0.6-26 mg, or in another embodiment, 0.6-60 mg, or in In one embodiment, the invention provides compounds another embodiment, 0.76-16 mg, or in another embodiment, and compositions, including any embodiment described 0.76-60 mg. or in another embodiment, 1-6 mg, or in another herein, for use in any of the methods of this invention, as embodiment, 1-20 mg. or in another embodiment, 3-16 mg, 45 described herein. In one embodiment, use of a compound of or in another embodiment, 30-60 mg. or in another embodi this invention or a composition comprising the same, will ment, 30-76 mg, or in another embodiment, 100-2000 mg. have utility in inhibiting, Suppressing, enhancing or stimulat In one embodiment, the methods of this invention may ing a desired response in a subject, as will be understood by comprise administration of a compound of this invention at one skilled in the art. In another embodiment, the composi various dosages. In another embodiment, the methods of this 50 tions may further comprise additional active ingredients, invention may comprise administration of a compound of whose activity is useful for the particular application for formula II of this invention at various dosages. In one embodi which the compound of this invention is being administered. ment, the compound of this invention is administered at a In some embodiments, the methods of this invention make dosage of 1 mg. In another embodiment the compound of this use of compositions comprising compounds of this invention, invention is administered at a dosage of 6 mg, 10 mg, 16 mg, 55 which offer the advantage that the compounds are nonsteroi 20 mg, 26 mg, 30 mg, 36 mg, 40 mg., 46 mg, 60 mg. 66 mg, 60 dal ligands for the androgen receptor, and exhibit anabolic mg, 66 mg, 70 mg, 76 mg, 80 mg, 86 mg, 90 mg., 96 mg or 100 activity in vivo. According to this aspect, such compounds are ng. unaccompanied by serious side effects, provide convenient In one embodiment, the present invention provides meth modes of administration, and lower production costs and are ods of use comprising the administration of a pharmaceutical 60 orally bioavailable, lack significant cross-reactivity with composition comprising a) any embodiment of a compound other undesired steroid receptors, and may possess long bio as described herein; and b) a pharmaceutically acceptable logical half-lives. carrier or diluent; which is to be understood to include an For administration to mammals, and particularly humans, analog, isomer, metabolite, derivative, pharmaceutically it is expected that the physician will determine the actual acceptable salt, N-oxide, hydrate or any combination thereof 65 dosage and duration of treatment, which will be most suitable of a compound as herein described, and may comprise com for an individual and can vary with the age, weight and pounds of formula II. response of the particular individual. US 7,772,433 B2 63 64 In one embodiment, the compositions for administration tane, liarozole, NKS-01, Vorozole, YM-511, finrozole, 4-hy may be sterile solutions, or in other embodiments, aqueous or droxyandrostenedione, aminogluethimide, rogletimide; Ste non-aqueous, Suspensions or emulsions. In one embodiment, roidal or nonsteroidal glucocorticoid receptor ligands. Such the compositions may comprise propylene glycol, polyethyl as, ZK-216348, ZK-243149, ZK-243185, LGD-5552, mife ene glycol, injectable organic esters, for example ethyl oleate, pristone, RPR-106541, ORG-34517, GW-215864X, Sesqui or cyclodextrins. In another embodiment, compositions may cillin, CP-472555, CP-394531, A-222977, AL-438, also comprise wetting, emulsifying and/or dispersing agents. A-216054, A-276575, CP-394531, CP-409069, UGR-07; In another embodiment, the compositions may also comprise Steroidal or nonsterodial progesterone receptor ligands; Ste sterile water or any other sterile injectable medium. roidal or nonsteroidal AR antagonists Such as flutamide, In one embodiment, the invention provides compounds 10 hydroxyflutamide, bicalutamide, nilutamide, hydroxysteroid and compositions, including any embodiment described dehydrogenase inhibitors, PPARö ligand such as bezafibrate, herein, for use in any of the methods of this invention. In one fenofibrate, gemfibrozil; PPARY ligands such as dargilitazone, embodiment, use of a compound of this invention or a com pioglitaZone, rosiglitaZone, isaglitaZone, rivoglitaZone, position comprising the same, will have utility in inhibiting, netoglitaZone; Dual acting PPAR ligands, such as navegli Suppressing, enhancing or stimulating a desired response in a 15 tazar, fargilitazar, tesaglitazar, ragaglitazar, Oxeglitazar, subject, as will be understood by one skilled in the art. In PN-2034, PPAR 8; a 17-ketoreductase inhibitors, 3 B-DHA4, another embodiment, the compositions may further comprise 6-isomerase inhibitors, 3 f-DHA4.5-isomerase inhibitors, additional active ingredients, whose activity is useful for the 17.20 desmolase inhibitors, p450c17 inhibitors, p450ssc particular application for which the compound of this inven inhibitors, 17.20-lyase inhibitors, or combinations thereof. tion is being administered. In some embodiments, the compositions will further com In some embodiments, the compositions will further com prise Ghrelin receptor ligand or growth hormone analogues prise a 5a-Reductase Inhibitors, a SARM or SARMs, a selec and secretagogues, IGF-1, IGF-1 analogues and secreta tive estrogen receptor modulator (SERM), an aromatase gogues, Myostatin Analogues, Proteasome Inhibitors, Andro inhibitor, Such as but not limited to anastraZole, exemestane, genic/Anabolic Steroid, EnbrelMelanocortin 4 Receptor or letrozole; a GnRH agonist or antagonist, a steroidal or 25 Agonist, Insulins, or combinations thereof. Such composi nonsteroidal GR ligand, a steroidal or nonsterodial PR ligand, tions may be used, in Some embodiments, for treating Sar a steroidal or nonsteroidal AR antagonist, a 17-aldoketore copenia or a musculoskeletal condition. ductase inhibitor or 17b-hydroxysteroid dehydrogenase In some embodiments, the composition will comprise the inhibitor. Such compositions may be used, in Some embodi copounds as described herein, as well as another therapeutic ments, for treating a hormone dependent condition, such as, 30 compound, including inter alia, Ghrelin receptor ligand or for example, infertility, neoplasia of a hormone-responsive growth hormone analogues and secretagogues, such as, pral cancer, for example, a gonadal cancer, or a urogenital cancer. morelin, examorelin, tabimorelin, capimorelin, capromore In some embodiments, the composition will comprise the lin, ipamorelin, EP-01572, EP-1572, JMV-1843, an andro compounds as described herein, as well as another therapeu genic/Anabolic Steroid such as Testosterone/Oxandrolone; a tic compound, including interalia, a 5ARI Such as finasteride, 35 melanocortin 4 receptor agonist, such as Bremelanotide, a dutasteride, izonsteride; other SARMs, such as, RU-58642, Ghrelin or analogue thereof, such as human ghrelin, CYT RU-56279, WS9761A and B, RU-59063, RU-58841, bexlos 009-GhrOb, L-692429, GHRP-6, SK&F-1 10679, teride, LG-2293, L-245976, LG-121071, LG-121091, U-75799E), leptin (metreleptin, pegylated leptin: a leptin LG-121 104, LGD-2226, LGD-2941, YM-92088, receptor agonist, such as LEP (116-130), OB3, D-Leu-4- YM-175735, LGD-1331, BMS-357597, BMS-391197, 40 OB3, ra AV-leptin, AAV-hCB, ra AVhCB; an insulin (short S-40503, BMS-482404, EM-4283, EM-4977, BMS-564929, intermediate-, and long acting formulations; a cortisol or BMS-391197, BMS-434588, BMS-487745, BMS-501949, corticosteroid, or a combination thereof. SA-766, YM-92088, YM-580, LG-123303, LG-123129, The invention contemplates, in Some embodiments, PMCol, YM-175735, BMS-591305, BMS-591309, BMS administration of compositions comprising the individual 665139, BMS-665539, CE-590, 116BG33, 154BG31, arcar 45 agents, administered separately and by similar or alternative ine, ACP-105: SERMs, such as tamoxifene, 4-hydroxyta routes, formulated as appropriately for the route of adminis moxifene, idoxifene, toremifene, ospennifene, droloxifene, tration. The invention contemplates, in Some embodiments, raloxifene, arzoxifene, baZedoxifene, PPT (1,3,5-Tris(4-hy administration of compositions comprising the individual droxyphenyl)-4-propyl-1H-pyrazole), DPN, lasofoxifene, agents, administered in the same formulation. The invention pipendoxifene, EM-800, EM-652, nafoxidine, Zindoxifene, 50 contemplates, in some embodiments, staggered administra tesmilifene, miproxifene phosphate, RU 58,688, EM 139, ICI tion, concurrent administration, of administration of the Vari 164,384, ICI 182,780, clomiphene, MER-25, diethyl ous agents over a course of time, however, their effects are stibestrol, coumestrol, genistein, GW5638, LY353581, synergistic in the Subject. Zuclomiphene, enclomiphene, delmadinone acetate, DPPE, It is to be understood that any of the above means, timings, (N,N-diethyl-2-4-(phenylmethyl)-phenoxyethanamine), 55 routes, or combinations thereof, of administration of two or TSE-424, WAY-070, WAY-292, WAY-818, cyclocommunol, more agents is to be considered as being encompassed by the prinaberel, ERB-041, WAY-397, WAY-244, ERB-196, WAY phrase “administered in combination', as described herein. 169122, MF-101, ERB-002, ERB-037, ERB-017, BE-1060, In one embodiment, the compound of this invention is BE-380, BE-381, WAY-358, 18FIFEDNP, LSN-500307, administered in combination with an anti-cancer agent. In one AA-102, Ban Zhilian, CT-101, CT-102, VG-101; GnRHago 60 embodiment, the anti-cancer agent is a monoclonal antibody. nists orantagonists, such as, leuprolide, goserelin, triptorelin, In some embodiments, the monoclonal antibodies are used alfaprostol, histrelin, detirelix, ganirelix, antide iturelix, for diagnosis, monitoring, or treatment of cancer. In one cetrorelix, ramorelix, ganirelix, antarelix, teverelix, abarelix, embodiment, monoclonal antibodies react against specific ozarelix, Sufugolix, prazarelix, degarelix, NBI-56418, TAK antigens on cancer cells. In one embodiment, the monoclonal 810, acyline; FSH agonist/antagonist, LH agonist/antago 65 antibody acts as a cancer cell receptor antagonist. In one nists, aromatase inhibitors, such as, letrozole, anastrazole, embodiment, monoclonal antibodies enhance the patients atameStane, fadrozole, minamestane, exemestane, plomes immune response. In one embodiment, monoclonal antibod US 7,772,433 B2 65 66 ies act against cell growth factors, thus blocking cancer cell to methotrexate. In one embodiment, the anti-cancer chemo growth. In one embodiment, anti-cancer monoclonal antibod therapeutic agent is a Vinca alkaloid, such as but not limited to ies are conjugated or linked to anti-cancer drugs, radioiso vindesine. In some embodiments, the anti-cancer chemo topes, other biologic response modifiers, other toxins, or a therapeutic agents include platinum compounds such as but combination thereof. In one embodiment, anti-cancer mono not limited to carboplatin, and taxanes Such as docetaxel. In clonal antibodies are conjugated or linked to a SARM com one embodiment, the anti-cancer chemotherapeutic agent is pound as described hereinabove. an aromatase inhibitor Such as but not limited to anastraZole, In another embodiment, the present invention includes exemestane, or letrozole. compounds and compositions in which a compound of the In one embodiment, the compound is administered in com invention is either combined with, or covalently bound to, an 10 bination with a Bax activity modulator such as allisol B agent bound to a targeting agent, such as a monoclonal anti acetate. In one embodiment, the compound is administered in body (e.g., a murine or humanized monoclonal antibody). In combination with an angiotensin II receptor blocker Such as one embodiment, the agent bound to a targeting agent is a losartan. In one embodiment, the compound is administered cytotoxic agent. It will be appreciated that the latter combi in combination with selenium, green tea cachecins, saw pal nation may allow the introduction of cytotoxic agents into for 15 metto, lycopene, Vitamin D, dietary Soy, genistein or isofla example cancer cells with greater specificity. Thus, the active WO. form of the cytotoxic agent (i.e., the free form) will be present In one embodiment, the compound is administered in com only in cells targeted by the antibody. Of course, the com bination with antineoplastic agents, such as alkylating agents, pounds of the invention may also be combined with mono antibiotics, hormonal antineoplastics and antimetabolites. clonal antibodies that have therapeutic activity against can Examples of useful alkylating agents include alkyl Sulfonates C. Such as buSulfan, improSulfan and piposulfan, aziridines, In one embodiment, the compound is administered in com Such as a benzodizepa, carboquone, meturedepa and uredepa; bination with a selective tyrosine kinase inhibitor. In some ethylenimines and methylmelamines such as altretamine, tri embodiments, the selective tyrosine kinase inhibitor inhibits ethylenemelamine, triethylenephosphoramide, triethyleneth catalytic sites of cancer promoting receptors thereby inhibit 25 iophos-phoramide and trimethylolmelamine; nitrogen mus ing tumor growth. In one embodiment, a selective tyrosine tards Such aS chlorambucil, chlomaphazine, kinase inhibitor modulates growth factor signaling. In some cyclophosphamide, estramustine, iphosphamide, mechlore embodiments, the selective tyrosine kinase inhibitor targets thamine, mechlorethamine oxide hydrochloride, melphalan, EGFR (ERBB/HER) family members. In one embodiment, novembichine, phenesterine, prednimustine, trofosfamide, the selective tyrosine kinase inhibitor is a BCR-ABL tyrosine 30 and uracil mustard; nitroso ureas, Such as carmustine, chlo kinase inhibitor. In one embodiment, the selective tyrosine rozotocin, fotemustine, lomustine, nimustine, ranimustine, kinase inhibitor is an epidermal growth factor receptor dacarbazine, mannomustine, mitobronitol, mitolactol and tyrosine kinase inhibitor. In one embodiment, the selective pipobroman. More such agents will be known to those having tyrosine kinase inhibitor is a vascular endothelial growth skill in the medicinal chemistry and oncology arts. factor tyrosine kinase inhibitor. In one embodiment, the 35 In some embodiments, other agents suitable for combina selective tyrosine kinase inhibitor is a Platelet Derived tion with the compounds of this invention include protein Growth Factor (PDGF) inhibitor. synthesis inhibitors such as abrin, aurintricarboxylic acid, In one embodiment, the compound is administered in com chloramphenicol, colicin E3, cycloheximide, diphtheria bination with a cancer vaccine. In one embodiment, the can toxin, edeine A, emetine, erythromycin, ethionine, fluoride, cer vaccine is a therapeutic Vaccine thus, treating an existing 40 5-fluorotryptophan, fusidic acid, guanylyl methylene diphos cancer. In some embodiments, the cancer vaccine is a pro phonate and guanylyl imidodiphosphate, kanamycin, phylactic vaccine thus, preventing the development of cancer. kasugamycin, kirromycin, and O-methyl threonine, modec In one embodiment, both types of vaccines have the potential cin, neomycin, norvaline, pactamycin, paromomycine, puro to reduce the burden of cancer. In one embodiment, treatment mycin, ricin, C.-sarcin, shiga toxin, showdomycin, sparsomy or therapeutic vaccines are administered to cancer patients 45 cin, spectinomycin, streptomycin, tetracycline, thiostrepton and are designed to strengthen the body's natural defenses and trimethoprim. Inhibitors of DNA synthesis, including against cancers that have already developed. In one embodi alkylating agents such as dimethyl Sulfate, mitomycin C, ment, therapeutic vaccines may prevent additional growth of nitrogen and sulfur mustards, MNNG and NMS: intercalating existing cancers, prevent the recurrence of treated cancers, or agents such as acridine dyes, actinomycins, adriamycin, eliminate cancer cells not killed by prior treatments. In some 50 anthracenes, benzopyrene, ethidium bromide, propidium embodiments, prevention or prophylactic vaccines are diiodide-intertwining, and agents such as distamycin and administered to healthy individuals and are designed to target netropsin, can also be combined with compounds of the cancer in individuals who present high risk for the disease. In present invention in pharmaceutical compositions. DNA base one embodiment, the cancer vaccine is an antigen/adjuvant analogs such as acyclovir, adenine, B-1-D-arabinoside, ame vaccine. In one embodiment, the cancer vaccine is a whole 55 thopterin, aminopterin, 2-aminopurine, aphidicolin, 8-aza cell tumor vaccine. In one embodiment, the cancer vaccine is guanine, azaserine, 6-azauracil, 2’-azido-2'-deoxynuclio a dendritic cell vaccine. In one embodiment, the cancer vac sides, 5-bromodeoxycytidine, cytosine, B-1-D-arabinoside, cine comprises viral vectors and/or DNA vaccines. In one diazooxynorleucine, dideoxynucleosides, 5-fluorodeoxycy embodiment, the cancer vaccine is an idiotype vaccine. tidine, 5-fluorodeoxyuridine, 5-fluorouracil, hydroxyurea In one embodiment, the compound is administered in com 60 and 6-mercaptopurine also can be used in combination thera bination with an anti-cancer chemotherapeutic agent. In one pies with the compounds of the invention. Topoisomerase embodiment, the anti-cancer chemotherapeutic agent is an inhibitors, such as coumermycin, nalidixic acid, novobiocin alkylating agent, such as but not limited to cyclophospha and oxolinic acid, inhibitors of cell division, including colce mide. In one embodiment, the anti-cancer chemotherapeutic mide, colchicine, vinblastine and Vincristine; and RNA syn agent is a cytotoxic antibiotic Such as but not limited to 65 thesis inhibitors including actinomycin D. C.-amanitine and doxorubicin. In one embodiment, the anti-cancer chemo other fungal amatoxins, cordycepin (3'-deoxyadenosine), therapeutic agent is an antimetabolite, such as but not limited dichlororibofuranosyl benzimidazole, rifampicine, strepto US 7,772,433 B2 67 68 Varicin and streptolydigin also can be combined with the invention in a Subject with prostate cancer undergoing or compounds of the invention to provide pharmaceutical com having undergone androgen deprivation therapy (ADT). positions. It is to be understood that reference to “a compound of this In one embodiment, the compound is administered in com invention’, or a use thereof is to be considered to encompass bination with a vaccine for prostate cancer, Alisol B acetate, use of any compound as herein described, including any angiotensin II receptor blocker, or others known in the art. In embodiment thereof. It is to be considered to encompass all of one embodiment, the compound is administered in combina compounds which may be characterized by the structure of tion with an agent to decrease prostate (benign or malignant) Formulae I-XXII. hypertrophy, such as, for example, Selenium, green tea In one embodiment, the skeletal-related events treated cachecins, saw palmetto, lycopene, Vitamin D, dietary Soy, 10 using the methods provided herein and/or utilizing the com genistein and isoflavone food product and others. positions provided herein, are fractures, which in one In one embodiment, the compound is administered in com embodiment, are pathological fractures, non-traumatic frac bination with an immunomodulating agent. In one embodi tures, vertebral fracture, non-vertebral fractures, morphomet ment, the immunomodulating agent is an immunosuppressive ric fractures, or a combination thereof. In some embodiments, agent. In one embodiment, immunosuppressive agents com 15 fractures may be simple, compound, transverse, greenstick, prise corticosteroids, cyclosporine, azathioprine, methotrex or comminuted fractures. In one embodiment, fractures may ate, cyclophosphamide, tacrolimus —FK-506, anti-thy be to any bone in the body, which in one embodiment, is a mocyte globulin, mycophenylate moeftil, or a combination fracture in any one or more bones of the arm, wrist, hand, thereof. In one embodiment, the corticosteroid is a glucocor finger, leg, ankle, foot, toe, hip, collarbone, or a combination ticoid. thereof. In one embodiment, the immunomodulating agent is an In another embodiment, the methods and/or compositions immunostimulatory agent. In one embodiment, the immuno provided herein, are effective in treatment, prevention, Sup stimulatory agent is a specific immunostimulator thus, pro pression, inhibition or reduction of the risk of skeletal-related vides antigenic specificity during an immune response. Such events such as pathologic fractures, spinal cord compression, as a vaccine or any antigen. In one embodiment, the immu 25 hypercalcemia, bone-related pain, or their combination. nostimulatory agent is a non-specific immunostimulator thus, In another embodiment, the skeletal-related events sought acting irrespective of antigenic specificity to augment to be treated using the methods provided herein and/or utiliz immune response of otherantigen or stimulate components of ing the compositions provided herein, comprise the necessity the immune system without antigenic specificity. In one for bone Surgery and/or bone radiation, which in some embodiment, the non-specific immunostimulator is Freund's 30 embodiments, is for the treatment of pain resulting in one complete adjuvant. In one embodiment, the non-specific embodiment from bone damage, or nerve compression. In immunostimulator is Freund's incomplete adjuvant. In one another embodiment, the skeletal-related events sought to be embodiment, the non-specific immunostimulator is a mon treated using the methods provided herein and/or utilizing the tanide ISA adjuvant. In one embodiment, the non-specific compositions provided herein, comprise spinal cord com immunostimulator is a Ribis adjuvant. In one embodiment, 35 pression, or the necessity for changes in antineoplastic the non-specific immunostimulator is a Hunter's TiterMax. In therapy, including changes in hormonal therapy, in a Subject. one embodiment, the non-specific immunostimulator is an In some embodiments, skeletal-related events sought to be aluminum salt adjuvant. In one embodiment, the non-specific treated using the methods provided herein and/or utilizing the immunostimulator is a nitrocellulose-adsorbed protein. In compositions provided herein, comprise treating, Suppress one embodiment, the non-specific immunostimulator is a 40 ing, preventing, reducing the incidence of, or delaying pro Gerbu Adjuvant. gression or severity of bone metastases, or bone loss. In one In one embodiment, the compound is administered in com embodiment, bone loss may comprise osteoporosis, osteope bination with an agent, which treats bone diseases, disorders nia, or a combination thereof. In one embodiment, skeletal or conditions, such as osteoporosis, bone fractures, etc., and related events may comprise any combination of the embodi this invention comprises methods of treating the same, by 45 ments listed herein. administering the compounds as herein described, alone or in In one embodiment, the methods provided herein and/or combination with other agents. utilizing the compositions provided herein, are effective in In one embodiment, bone turnover markers have been reducing metastases to the bone, such as in terms of number demonstrated as an effective, validated tool for the clinical of foci, the size of foci, or a combination thereof. According Scientist to monitor bone activity. In another embodiment, 50 to this aspect of the invention and in one embodiment, pro urinary hydroxyproline, serumalkaline phosphatase, tartrate vided herein is a method of preventing or inhibiting cancer resistant acid phosphatase, and osteocalcin levels, along with metastasis to bone in a subject, comprising the step of admin the urinary calcium-creatinine ratio are used as bone turnover istering to the Subject a composition comprising toremifene, markers. In another embodiment osteocalcin levels is used as raloxifene, tamoxifen or an analogue, functional derivative, a bone formation marker. In another embodiment c-telopep 55 metabolite or a combination thereof, or a pharmaceutically tide is used as a bone resorption marker. acceptable salt thereof. In one embodiment, such metabolites In one embodiment, this invention provides for the treat may comprise ospennifene, fispennifene or their combination. ment, prevention, Suppression or inhibition of, or the reduc In one embodiment, the cancer is prostate cancer. tion of the risk of developing a skeletal-related event (SRE), A person skilled in the art would readily recognize that Such as bone fractures, Surgery of the bone, radiation of the 60 changes in the antineoplastic therapy according to the meth bone, spinal cord compression, new bone metastasis, bone ods provided herein, utilizing the compositions provided loss, or a combination thereof in a Subject with cancer, com herein may be conducted as a function of, or adjusted or prising administering to the a compound as herein described varied as a function of inter-alia, the severity of the underly and/or its analog, derivative, isomer, metabolite, pharmaceu ing disease, the source of the underlying disease, the extent of tically acceptable salt, pharmaceutical product, hydrate, 65 the patients’ pain and Source of the patients’ pain, as well as N-oxide, or any combination thereof. The invention relates, the stage of the disease. The therapeutic changes may include inter alia to treatment of an SRE with the compound of this in certain embodiments, changes in the route of administra US 7,772,433 B2 69 70 tion (e.g. intracavitarily, intraartiarly, intratumoraly etc.), In one embodiment, the immunomodulating agent is an forms of the compositions administered (e.g. tablets, elixirs, anti-rheumatic agent. In one embodiment, the anti-rheumatic Suspensions etc.), changes in dosage and the like. Each of agent is a non-steroidal anti-inflammatory agent. In one these changes are well recognized in the art and are encom embodiment, the anti-rheumatic agent is a corticosteroid. In passed by the embodiments provided herein. one embodiment, the corticosteroid is prednisone or dexam In one embodiment, the skeletal-related events area result ethasone. In one embodiment, the anti-rheumatic agent is a of cancer therapy. In one embodiment, the skeletal-related disease modifying anti-rheumatic drug. In one embodiment, events are a result of hormone deprivation therapy, while in the disease modifying anti-rheumatic drug is a slow-acting another embodiment, they are a product of androgen depri anti-rheumatic drug. In one embodiment, the disease modi vation therapy (ADT). 10 fying anti-rheumatic drug is an antimalarial agent. In one In one embodiment, the compounds of this invention are embodiment, disease modifying anti-rheumatic drugs useful in prevention or reversal of androgen-deprivation include but are not limited to chloroquine, hydroxychloro therapy (ADT) induced side effects such as reduced muscle quine, methotrexate, Sulfasalazine, cyclosporine, azathio mass, reduced muscle strength, frailty, hypogonadism, 15 prine, cyclophosphamide, azathioprine, SulfaSalazine, peni osteoporosis, osteopenia, decreased BMD and/or decreased cillamine, aurothioglucose, gold sodium thiomalate, or bone mass. auranofin. In one embodiment, the anti-rheumatic agent is an In males, while the natural decline in sex-hormones at immunosuppressive cytotoxic drug. In one embodiment, maturity (direct decline in androgens as well as lower levels immunosuppressive cytotoxic drugs include but are not lim of estrogens derived from peripheral aromatization of andro ited to methotrexate, mechlorethamine, cyclophosphamide, gens) is associated with the frailty of bones, this effect is more pronounced in males who have undergone androgen depriva chlorambucil, or azathioprine. tion therapy. In one embodiment, the compound is administered in com bination with an antidiabetic agent. In one embodiment, the Such agents for combined use may comprise a SERM, as antidiabetic agent is a Sulfonylurea. In one embodiment, Sul herein described, a bisphosphonate, for example, alendr 25 onate, tiludroate, clodroniate, pamidronate, etidronate, allen fonylureas include but are not limited to tolbutamide, aceto dronate, Zolendronate, cimadronate, neridronate, minodronic hexamide, tolaZamide, chlorpropamide, glipizide, glyburide, acid, ibandronate, risedronate, homoresidronate, a calcitonin, glimepiride, or gliclazide. In one embodiment, the antidia for example, salmon, Elcatonin, SUN-8577, TJN-135; a Vita betic agent is a meglitinide. In one embodiment, meglitinides min D or derivative (ZK-156979); a Vitamin D receptor 30 include but are not limited to prandin or nateglinide. In one ligand or analogues thereof. Such as calcitriol, topitriol, embodiment, the antidiabetic agent is a biguanide. In one ZK-150.123, TEI-9647, BXL-628, Ro-26-9228, BAL-2299, embodiment, biguanides include but are not limited to met Ro-65-2299, DP-035, an estrogen, estrogen derivative, or formin. In one embodiment, the antidiabetic agent is a thia conjugated estrogen; an antiestrogen, progestin, Synthetic Zolidinedione. In one embodiment, thiazolidinediones estrogen/progestin; a RANK ligand mAb, for example, deno 35 include but are not limited to rosiglitaZone, pioglitaZone, or sumab or AMG162 (Amgen); an Ov3 integrin receptor troglitaZone. In one embodiment, the antidiabetic agent is an antagonist; an osteoclast vacuolar ATPase inhibitor; an alpha glucosidase inhibitor. In one embodiment, alpha glu antagonist of VEGF binding to osteoclast receptors; a cal cosidase inhibitors include but are not limited to miglitol or cium receptor antagonist; PTh (parathyroid hormone) orana acarbose. In one embodiment, the antidiabetic agent is logues thereof, PTHrP analogues (parathyroid hormone-re 40 PPARO/Y ligand, dipeptidylpeptidase 4 (DPP-4) inhibitor, lated peptide), Cathepsin K inhibitors (AAE581); Strontium SGLT (sodium-dependent glucose transporter 1) inhibitor, or ranelate; Tibolone: HCT-1026, PSK3471; Gallium maltolate: FBPase (fructose 1,6-bisphosphatase) inhibitor. In one Nutropin AQ: Prostaglandins, p38 protein kinase inhibitor; a embodiment, the antidiabetic agent is insulin. In one embodi bone morphogenetic protein; an inhibitor of BMP antago ment, the insulin is rapid-acting insulin. In one embodiment, nism, an. HMG-CoA reductase inhibitor, a Vitamin K or 45 the insulin is short-acting insulin. In one embodiment, the derivative, an antiresorptive, an Ipriflavone, a fluoride salt, insulin is intermediate-acting insulin. In one embodiment, the dietary calcium Supplement, Osteoprotegerin, or any combi insulin is intermediate- and short-acting insulin mixtures. In nation thereof. In one embodiment, the combined adminis one embodiment, the insulin is long-acting insulin. In one tration of a SARM as herein described, Osteoprotegerin and embodiment, the antidiabetic agents are inhibitors of fatty parathyroid hormone is contemplated for treating any dis 50 acid binding protein (aP2) such as those disclosed in U.S. Ser. ease, disorder or condition of the bone. No. 09/519,079 filed Mar. 6, 2000, glucagon-like peptide-1 In one embodiment, the immunomodulating agent is an (GLP-1), and dipeptidyl peptidase IV (DPP4) inhibitors such anti-inflammatory agent. In one embodiment, the anti-in as those disclosed in WOO168603, which are incorporated by flammatory agent is a non-steroidal anti-inflammatory agent. reference. In one embodiment, the non-steroidal anti-inflammatory 55 In one embodiment, the compound is administered in com agent is a cox-1 inhibitor. In one embodiment, the non-ste bination with an agent treating the nervous system. In one roidal anti-inflammatory agent is a cox-2 inhibitor. In one embodiment, the agent treating the nervous system is an agent embodiment, the non-steroidal anti-inflammatory agent is a treating the autonomic nervous system. In one embodiment, coX-1 and cox-2 inhibitor. In some embodiments, non-steroi the agent treating the autonomic nervous system is an dal anti-inflammatory agents include but are not limited to 60 adrenomimetic drug. In one embodiment, the adrenomimetic aspirin, Salsalate, diflunisal, ibuprofen, fenoprofen, flubipro drug is a beta-adrenoceptoragonist, alpha-adrenoceptorago fen, fenamate, ketoprofen, nabumetone, piroxicam, nist, or a combination thereof. In one embodiment, the naproxen, diclofenac, indomethacin, Sulindac, tolmetin, adrenomimetic drug is a catecholamine. In one embodiment, etodolac, ketorolac, oxaprozin, or celecoxib. In one embodi adrenomimetic drugs include but are not limited to isoprot ment, the anti-inflammatory agent is a steroidal anti-inflam 65 erenol, norepinephrine, epinephrine, amphetamine, ephe matory agent. In one embodiment, the steroidal anti-inflam drine, or dopamine. In one embodiment, the adrenomimetic matory agent is a corticosteroid. drug is a directly acting adrenomimetic drug. In some US 7,772,433 B2 71 72 embodiments, directly acting adrenomimetic drugs include cyclobenzaprine, dantrolene, metaxalone, orphenadrine, but are not limited to phenylephrine, metaraminol, or meth amyl nitrite, pancuronium, tizanidine, clonidine, orgabapen oxamine. tin. In one embodiment, vasoconstrictor agents include but In one embodiment, the agent treating the autonomic ner are not limited to antihistamines, adrenalin dimethylarginine, Vous system is an adrenoceptor antagonist. In one embodi caffeine, cannabis, catecholamines, decongestants, pseu ment, the adrenoceptor antagonist is a haloalkylamine, imi doephedrinse, norepinephrines, tetrahydrozoline, or throm dazoline, or quinazoline. In one embodiment, boxane. haloalkylamines include but are not limited to phenoxyben In one embodiment, the agent treating the central nervous Zamine. In one embodiment, imidazolines include but are not system is an antiemetic drug. In one embodiment, the anti limited to phentolamine or tolaZoline. In one embodiment, 10 emetic drug is a 5-HT3 receptor antagonist Such as dolas quinazolines include but are not limited to praZosine, tera etron, granisetron, ondansetron, or tropisetron. In one Zosin, doxazosin, or trimaZosin. In one embodiment, the embodiment, the antiemetic drug is a dopamine antagonist adrenoceptor antagonist has a combined alpha and beta Such as domperidone droperidol, haloperidol, chlorprom blocking activity. In one embodiment, the combined alpha azine, promethazine, or metoclopramide. In one embodi and beta blocking agent is labetalol, bucindolol, carvedilol, or 15 ment, the antiemetic drug is an antihistamine Such as cycliz medroxalol ine, diphenhydramine, dimenhydrinate, or meclizine. In one In one embodiment, the agent treating the autonomic ner embodiment, the antiemetic drug is a cannabinoid such as Vous system is a cholinomimetic agent. In one embodiment, cannabis or marinol. the cholinomimetic agent is a direct-acting parasympathomi In one embodiment, the agent treating the central nervous metic drug. In one embodiment, direct-acting parasympatho system is a sedative agent. In one embodiment, the sedative mimetic drugs include but are not limited to methacholine, agent is an antidepressant agent such as mirtazapine or traZ pilocarpine, carbachol, or bethanechol. odone. In one embodiment, the sedative agent is a barbiturate In one embodiment, the agent treating the autonomic ner such as secobarbital, pentobarbital, or amobarbital. In one Vous system is a cholinesterase inhibitor. In one embodiment, embodiment, the sedative agent is a benzodiazepine Such as the cholinesterase inhibitor is a quaternary ammonium agent. 25 diazepam, clonazepam, alprazolam, temazepam, chlordiaz In one embodiment, quaternary ammonium agents include epoxide, flunitrazepam, lorazepam, or cloraZepate. In one but are not limited to edrophonium or ambenonium. In one embodiment, the sedative agent is an imidazopyridines Such embodiment, the cholinesterase inhibitor is a carbamate such as Zolpidem or alpidem. In one embodiment, the sedative as physostigmine, pyridostigmine, neostigmine, or rivastig agent is a Pyrazolopyrimidine such as Zaleplon. In one mine. In one embodiment, the cholinesterase inhibitor is an 30 embodiment, the sedative agent is an antihistamine Such as organophosphate agent. In one embodiment, the inhibitor diphenhydramine, dimenhydrinate, or doxylamine. In one targets acetylcholine in the central nervous system such as embodiment, the sedative agent is an antipsychotic agent tacrine, donepezil, or galanthamine. Such as Ziprasidone, risperidone, quetiapine, clozapine, In one embodiment, the agent treating the autonomic ner prochlorperazine, perphenazine, loxapine, trifluoperazine, Vous system is a muscarinic blocking agent. In one embodi 35 thiothixene, haloperidol, or fluphenazine. In one embodi ment, the muscarinic blocking agent is a belladonna alkaloid ment, the sedative agent is an herbal sedative such as Valerian Such as atropine or Scopolamine. plant mandrake, or kava. In some embodiments, the sedative In one embodiment, the agent treating the autonomic ner agent is esZopiclone, ramelteon, methaqualone, ethchlor Vous system is a gangilionic blocking agent. In one embodi Vynol, chloral hydrate, meprobamate, glutethimide, meth ment, gangilionic blocking agents include but are not limited 40 yprylon, gamma-hydroxybutyrate, ethyl alcohol, methyl to nicotine, trimethaphan, or mecamylamine. trichloride, Zopiclone, or diethyl ether. In one embodiment, the agent treating the nervous system In one embodiment, the agent treating the central nervous is an agent treating the central nervous system. In one system is a neurodegenerative disorder medication. In one embodiment, the agent treating the central nervous system is embodiment, the neurodegenerative disorder medication is a local anesthetic agent. In one embodiment, local anesthetic 45 an acetylcholinesterase inhibitor Such as tacrine, donepezil, agents include but are not limited to benzocaine, chlorop galanthamine, or rivastigmine. In one embodiment, the neu rocaine, cocaine, procaine, bupivacaine, levobupivacaine, rodegenerative disorder medication is an N-methyl-D-aspar lidocaine, mepivacaine, prilocalne, or ropivacaine. In one tate (NMDA) antagonist Such as memantine. In one embodi embodiment, the agent treating the central nervous system is ment, the neurodegenerative disorder medication reduces a general anaesthetic agent. In one embodiment, general 50 damage to motor neurons such as riluzole. In one embodi anesthetic agents include but are not limited to esflurane, ment, the neurodegenerative disorder medication silences the sevoflurane, isoflurane, halothane, enflurane, methoxyflu gene that causes the progression of the disease. In one rane, Xenon, propofol, etomidate, methohexital, midazolam, embodiment, the agent treating the central nervous system is diazepamor, ketamine, thiopentone/thiopental, or lidocaine/ an antiepileptic drug (AED). In some embodiments, antiepi prilocalne. 55 leptic agents include Sodium channel blockers, GABA recep In one embodiment, the agent treating the central nervous toragonists, GABA reuptake inhibitors, GABA transaminase system is an analgesic agent. In some embodiments, analge inhibitor, AEDs with a potential GABA mechanism of action, sic agents include but are not limited to paracetamol or non glutamate blockers, or AEDs with other mechanisms of steroidal anti-inflammatory agent. In some embodiments, action. In some embodiments, antiepileptic agents include analgesic agents include opiates or morphinomimetics Such 60 but are not limited to carbamazepine, fosphenyloin, oXcarba as morphine, pethidine, oxycodone, hydrocodone, diamor Zepine, lamotrigine, Zonisamide, clobazam, clonazepam, phine, tramadol, or buprenorphine. In some embodiments, a phenobarbital, primidone, tiagabine, vigabatrin, gabapentin, combination of two or more analgesics is desired. valproate, felbamate, topiramate, levetiracetam, or pregaba In one embodiment, the agent treating the central nervous lin. system is a muscle relaxant or vasoconstrictor agent. In one 65 In one embodiment, the agent treating the central nervous embodiment, muscle relaxants include but are not limited to system is an anti-addiction drug. In one embodiment, the methocarbamol, baclofen, carisoprodol, chlorZoxaZone, anti-addiction is an anti-alcoholism drug Such as disulfuram. US 7,772,433 B2 73 74 In one embodiment, the anti-addiction drug is a serotonin mide, or flecamide. In one embodiment, beta-adrenergic uptake inhibitor, dopaminergic agonist, or opioid antagonist. blockers include but are not limited to propranolol, acebu In one embodiment, the agent treating the central nervous tolol, esmolol, or Sotalol. In one embodiment, agents that system is an agent treating Alzheimer disease. In some prolong repolarization include but are not limited to Sotalolor embodiments, agents treating Alzheimer's disease include amiodarone. In one embodiment, calcium channel blockers but are not limited to a cholinesterase inhibitor, gamma secre include but are not limited to Verapamil, diltiazem, nife atse inhibitor, or a beta lowering drug. dipine, or mebefradil. In one embodiment, the anti-arrhyth In one embodiment, the agent treating the central nervous mic agent is adenosine or digoxin. system is an agent treating mild cognitive impairment. In In one embodiment, the agent treating the cardiovascular Some embodiments, agents treating mild cognitive impair 10 system is an anti-anginal agent. In one embodiment, the anti ment include but are not limited to an AMPA regulator. anginal agent is an antiplatelet agent, adrenoceptor antago In one embodiment, the agent treating the central nervous nist, calcium channel blocker, or a vasodilator. In some system is an agent treating Parkinson's disease. In some embodiments, the adrenoceptor antagonists and calcium embodiments, agents treating Parkinson's disease includebut channel blockers comprise agents as described hereinabove. are not limited to a dopaminergic drugs, amantadine, benz 15 In one embodiment, the antiplatelet agent is a cyclooxyge tropine, biperiden, bromocriptine, entacapone, carbidopa/ nase inhibitor, ADP inhibitor, phosphodiesterase (I) inhibitor, levodopa, selegiline/deprenyl, iphenhydramine, pergolide, glycoprotein IIb/IIIa inhibitor, or an adenosine reuptake procyclidine, selegiline, or trihexyphenidyl. inhibitor. In one embodiment, cyclooxygenase inhibitors In one embodiment, the compound is administered with an include but are not limited to acetylsalicylic acid or an ace agent, which treats Alzheimer's disease, such as cholinest tylsalicylic acid in combination with dipyridimole. In one erase inhibitors, gamma secreatse inhibitors, A-beta lowering embodiment, ADP inhibitors include but are not limited to drugs; or an agent, which treats mild cognitive impairment clopidogrel, CS-747, or ticlopdipine. In one embodiment, (MCI)—such as AMPA regulators, or an agent, which treats phosphodiesterase III inhibitors include but are not limited to Parkinson's Disease. Such as dopaminergic drugs, or an cilostazol. In one embodiment, glycoprotein IIb/IIIa inhibi agent, which treats Major Depression, such as SSRIs, 25 tors include but are not limited to abciximab, rheopro, eptifi SNRIs, for example, dulloxetine, or an agent, which treats batide, integrilin, tirofiban, or aggrastat. In one embodiment, sexual dysfunction, such as PDE5 inhibitors. adenosine reuptake inhibitors include but are not limited to In one embodiment, the compound is administered in com dipyridimole. In one embodiment, vasodilator agents include bination with an agent treating the cardiovascular system. In but are not limited to isosorbide dinitrate, isosorbide mono one embodiment, the agent treating the cardiovascular system 30 nitrate, or nitroglycerine. In one embodiment, cardiac glyco is treating a congestive heart failure. In one embodiment, the sides such as digitalis or ouabain may be used in combination agent treating congestive heart failure is an angiotensin con with a SARM compound. Verting enzyme (ACE) inhibitor Such as benazepril, captopril, In one embodiment, the agent treating the cardiovascular cilaZapril, enalapril, fosinopril, lisinopril, moexipril, perin system is a vasocative agent or an inotrope. In one embodi dopril, quinapril, ramipril, trandolapril, or enalaprilat. In one 35 ment, vasocative agents or inotropes include but are not lim embodiment, the agent treating congestive heart failure is a ited to digoxin, dopamine, dobutamine, hydralazine, pra beta-blocker such as acebutolol, atenolol, betaxolol hydro Zosin, carvedilol, nitroprusside, nitroglycerin, captopril, chloride, bisoprolol fumarate, carteolol hydrochloride, lisinopril, nifedipine, diltiazem, hydrochlorothiazide, furo carvedilol, celiprolol hydrochloride, esmolol hydrochloride, semide, spironolactone, AT-1 receptor antagonists (e.g., losa labetalol hydrochloride, levobunolol, metoprolol tartrate, 40 rtan, irbesartan, Valsartan). ET receptor antagonists (e.g., metipranolol, nadolol, nebivolol, Oxprenolol hydrochloride, sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. pindolol, propranolol hydrochloride, Sotalol hydrochloride, Nos. 5,612.359 and 6,043,265), Dual ET/AII antagonist (e.g., or timolol maleate. In one embodiment, the agent treating compounds disclosed in WO 00/01389), neutral endopepti congestive heart failure is digoxin. In one embodiment, the dase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP agent treating congestive heart failure is a diuretic Such as 45 ACE inhibitors) (e.g., omapatrilat and gemopatrilat), or thiazide diuretic, loop diuretic, potassium-sparing diuretic, or nitrates. a combination thereof. In some embodiments, thiazide diuret In one embodiment, the agent treating the cardiovascular ics include but are not limited to bendrofluazide, bendroflu system is an anticoagulant agent. In one embodiment, the methiazide, benzthiazide, chlorothiazide, chlorthalidone, anticoagulantagent is a coumarin derivative oran unfraction cyclopenthiazide, Diucardin R, Diuril R. Enduron R, Esid 50 ated heparin. In one embodiment, coumarin derivatives rix R, Exna R., HCTZ, Hydrochlorothiazide, HydroDI include but are not limited to warfarin. URIL(R), HYDROFLUMETHLAZIDE, Hydromox(R), In one embodiment, the agent treating the cardiovascular Hygroton R, indapamide, LoZol R, methyclothiazide, metola system is a fibrinolytic agent Such as Streptokinase, uroki Zone, MykroxR), NaquaR), Naturetin R, Oretic(R), polythiaz nase, alteplase, anistreplase, prourokinase, reteplase, tenect ide, quinethaZone, Renese(R), trichlormethiazide, Xipamide, 55 eplase, lanoteplase, staphylokinase, vampire, or alfimeprase. or Zaroxolyn R. In some embodiments, loop diuretics include In one embodiment, the agent treating the cardiovascular but are not limited to furosemide/frusemide, bumetanide, or system is a hypercholesterolemic agent Such as niacin-lovas torasemide. In some embodiments, potassium-sparing diuret tatin, colestipol HCl, fluvastatin Sodium, atorvastatin cal ics include but are not limited to amiloride, triamterene, cium, simvastatin, gemfibrozil, lovastatin, pravastatin aldosterone antagonists, or spironolactone. 60 Sodium, cholestyramine, cholestyramine light, fenofibrate, In one embodiment, the agent treating the cardiovascular colesevelam HCl, or ezetimibe. system is an anti-arrhythmic agent. In one embodiment, the In one embodiment, the SARM compound is administered anti-arrhythmic agent is a sodium channel blocker, beta-adr in combination with an agent treating the gastrointestinal energic blocker, calcium channel blocker, or an agent that system. In one embodiment, the agent treating the gas prolong repolarization. In one embodiment, sodium channel 65 trointestinal (GI) system is enhancing GI motility. In one blockers include but are not limited to quinidine, procaina embodiment, the agent enhancing GI motility is a prokinetic mide, disopyramidei, lidocaine, tocamide, mexiletine, enca agent Such as metoclopramide, cisapride, tegaserod, or eryth US 7,772,433 B2 75 76 romycin. In one embodiment, the agent treating the GI system glucagon-like peptide-1 analogues (exenatide, liraglutide), is decreasing GI motility. In one embodiment, the agent amylin analogues (pramlintide), statins (atorvastatin, simv decreasing GI motility is an opioid Such as morphine, diphe astatin, rosuvastatin, pravastatin, fluvastatin, lovastatin, noxylate, loperamide hydrochloride, or opium. pitavastatin), cholesterol absorption inhibitors (ezetimibe), In one embodiment, the agent treating the GI system is an 5 nicotinic acid derivatives (immediate release and controlled adsorbent or a bulking agent. In one embodiment, the adsor release niacins, niaslo, etc.), antidyslipidemic fixed combina bent is kaolin or other hydrated aluminum silicate clays. In tions (simvastatin/ezetimibe, lovastatin/nicotinic acid, atorV one embodiment, the hydrated aluminum silicate clay is fur astatin/amlodipine, atorvastatin/torcetrapib, simvastatin/ ther combined with pectin. In one embodiment, adsorbents or nicotinic acid (ER)). ACE inhibitors (ramipril, captopril, bulking agents comprise bismuth Subsalicylate, methylcellu 10 lisinopril), AT-II receptorantagonists (Valsartan, telmisartan), lose, psyllium derivative, or calcium polycarbophil. cannabinoid receptor antagonists (rimonabant), cholesteryl In one embodiment, the agent treating the GI system is a ester transfer protein or CETP Inhibitors (JTT-705, CET1-1), stool softener. In one embodiment, stool softeners includebut beta3 adrenergic agonists, PPARa ligands, or combinations are not limited to mineral oil, docusate dioctyl Sodium sulfo thereof. Succinate, dioctyl calcium Sulfo Succinate, or dioctyl potas 15 In one embodiment, the compound is administered in com sium sulfoSuccinate. bination with an agent treating a dermatological disorder. In In one embodiment, the agent treating the GI system is a one embodiment, the agent treating a dermatological disorder laxative. In one embodiment, the agent treating the GI system is a corticosteroid or glucocorticosteroid Such as betametha is a bulk forming laxative as described hereinabove. In one Sone dipropionate, clobetasol, diflorasone, amcinonide, des embodiment, the laxative is an osmotic laxative such as lactu Oximetasone, fluocinonide, aclometaSone, desonide triamci lose, Sorbitol, or polyethylene glycol. In one embodiment, the nolone, fluticasone, halobetasol, mometasone, or laxative is a saline laxative such as milk of magnesia, mag hydrocortisone. In one embodiment, the agent treating a der nesium citrate, sodium phosphate, docusate potassium, Sor matological disorder is a retinoid such as isotretinoin, acitre bitol, Sodium phosphate-biphosphate, or visicoli. tin, tretinoin, adapalene, tazarotene, bexarotene, alitretinoin, In one embodiment, the agent treating the GI system is a 25 or beta-carotene. cathartic stimulant. In one embodiment, the cathartic stimu In one embodiment, the agent treating a dermatological lant is an anthraquinone dervative Such as cascara, aloe, disorder is photochemotherapy agent. In one embodiment, Senna, or rhubarb. In one embodiment, the cathartic stimulant the photochemotherapy agent is PUVA or psoralen such as is phenolphthalein, castor oil, or bisacodyl. oXSoralen. In one embodiment, the agent treating a dermato In one embodiment, the agent treating the GI system is an 30 logical disorder is a photodynamic agent such as porphyrin. emetic agent. In one embodiment, the emetic agent is ipecac In one embodiment, the agent treating a dermatological or apomorphine. In one embodiment, the agent treating the GI disorder is daspone, thalidomide, anti-malarial agent, antimi system is an anti-emetic agent Such as antihistamine, anti crobial agent, or antifungal agent. In one embodiment, the cholinergic agent, benzodiazepine, cannabinoid, dopamine anti-malarial agent is chloroquine or hydroxychloroquine. antagonist, phenothiazine derivative, or 5-HT3 antagonist 35 Such as ondansetron or granisetron. In one embodiment, the agent treating a dermatological In one embodiment, the agent treating the GI system is an disorder is an antibiotic. In one embodiment, the antibiotic is antacid. In one embodiment the antacid pharmaceutical a systemic antibiotic Such as griseofulvin, ketoconazole, flu preparation comprises buffering agents such as Sodium bicar conazole, itraconazole, terbinafine, or potassium iodide. In bonate, calcium carbonate, magnesium hydroxide, or alumi 40 one embodiment, the antibiotic is a topical antifungal agent. num hydroxide. In some embodiment, topical antifungal agents include but In one embodiment, the agent treating the GI system is an are not limited to ciclopirox, clotrimazole, econazole, keto H2-receptor antagonist. In some embodiments, the H2-recep conazole, miconazole, naftifine, oxiconazole, terbinafine, or tor antagonist is cimetidine, ranitidine, famotidine, or nizati tolnaftate. dine. 45 In one embodiment, the agent treating a dermatological In one embodiment, the agent treating the GI system is a disorder is an antiviral agent such as interferon alpha. In one proton pump inhibitor. In some embodiments, the proton embodiment, the agent treating a dermatological disorder is pump inhibitor is omeprazole, lansoprazole, pantoprazole, an antiscabies agent Such as pyrethrin or pyrethroid. In one rebeprazole, or esomeprazole. embodiment, the agent treating a dermatological disorder is In one embodiment, the agent treating the GI system is an 50 an immunosuppressive agent Such as mycophenolate motefil agent treating inflammation. In one embodiment, the agent or 6-thioguanine. In one embodiment, the agent treating a treating inflammation is 5-amino-Salicylate, corticosteroid, dermatological disorder is a topical immunosuppressive metronidazole, ciprofloxacin, infiximab, budesonide, oranti agent Such as tacrolimus, pimecrolimus, imiquimod, 5-fluo TNF alpha antibody. rouracil, or mechlorethamine. In one embodiment, the agent In one embodiment, the compound is administered in com 55 treating a dermatological disorder is an antihistamine such as bination with an agent treating a metabolic disease, disorder doxepin. In one embodiment, the agent treating a dermato or condition, which in some embodiments refers to metabolic logical disorder is treating pigmentation Such as hydro syndrome. In some embodiments, such agents comprise, inter quinone or monobenzone. In one embodiment, the agent alia, pancreatic lipase inhibitors, such as for example, orlistat, treating a dermatological disorder is a protein or a recombi cetilistat, serotonin and norepinephrine reuptake inhibitors, 60 nant protein Such as becaplermin, etanercept, denileukin Such as sibutramine, insulin-sensitizers such as biguanides diftitox, or botulinum toxin. In one embodiment, the agent (metformin) or PPAR agonists, dual-acting PPAR agonists treating a dermatological disorder is capsaicin, anthralin, (muraglitazar, tesaglitazar, naveglitazar), PPAR-delta ago benzoyl peroxide, or calcipotriene. nists (GW-501516), DPP-IV Inhibitors (vildagliptin, sita In one embodiment, the agent treating a dermatological gliptin), alpha glucosidase inhibitors (acarbose), anti-dia 65 disorder is a keratolytic agent. In one embodiment, the agent betic combinations (ActoPlus Met, AvandaMet, metformin/ treating a dermatological disorder is selenium sulfide. In one pioglitaZone, metformin/rosiglitaZone, Glucovance, etc.), embodiment, the agent treating or preventing a dermatologi US 7,772,433 B2 77 78 cal disorder is a Sunscreen. In one embodiment, the Sunscreen but are not limited to ethambutol, rifabutin, isoniazid, absorbs UVB, UVA, or a combination thereof. rifampicin, pyrazinamide, or rifampin In one embodiment, the agent treating a dermatological In one embodiment, the antibiotic is an antifungal agent. In disorder may be a growth factor Such as epidermal growth one embodiment, antifungal agents include but are not lim factor (EGF), transforming growth factor-O. (TGF-C.), platelet ited to terbinafine, flucytosine, fluconazole, itraconazole, derived growth factor (PDGF), fibroblast growth factors ketoconazole, ravuconazole, posaconazole, Voriconazole, (FGFs) including acidic fibroblast growth factor (C.-FGF) and caspofungin, micafungin, V-echinocandin, amphotericin B, basic fibroblast growth factor (B-FGF), transforming growth amphotericin B lipid complex (ABLC), amphotericin B col factor-B (TGF-B) and insulin like growth factors (IGF-1 and loidal dispersion (ABCD), liposomal amphotericin b IGF-2), or any combination thereof. 10 (1-Amb), liposomal nystatin, or griseofulvin. In one embodiment, the compound is administered in com In one embodiment, the antibiotic is an antiprotozoal bination with an anti-infective agent. In one embodiment, the agent. In one embodiment the antiprotozoal agent is an anti anti-infective agent is an antibiotic agent. In one embodiment malarial agent. In one embodiment, antimalarial agents the antibiotic is a beta-lactam antibiotic. In one embodiment include but are not limited to chloroquine, mefloquine, beta-lactamantibiotics include but are not limited to penicil 15 proguanil, pyrimethamine with dapsone, pyrimethamine with lin, benzathine penicillin, benzylpenicillin, amoxicillin, Sulfadoxine, quinine, or primaquine. In one embodiment, the procaine penicillin, dicloxacillin, amoxicillin, flucloxacillin, antiprotozoal agent is an amoebicide. In one embodiment, ampicillin, methicillin, aziocillin, carbenicillin, ticarcillin, amoebicides include but are not limited to metronidazole, meZlocillin, piperacillin, phenoxymethylpenicillin, timidazole, or diloxanide furoate. In one embodiment, the co-amoxiclav, cephalosporin, cefalexin, cephalothin, cefazo antiprotozoal agent is an antigiadial agent. In one embodi lin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ment, antigiadial agents include but are not limited to met ceftriaxone, cefotaxime, ceftazidime, cefepime, ce?pirome, ronidazole, timidazole, or mepacrine. In one embodiment, the imipenem, meropenem, ertapenem, faropenem, monobac antiprotozoal agent is a leishmanicide. In one embodiment, tam, aztreonam, or carbapenem. leishmanicides include but are not limited to sodium stibo In one embodiment the antibiotic is a tetracycline antibi 25 gluconate. In one embodiment, the antibiotic is an antithel otic. In one embodiment tetracycline antibiotics include but mintic agent. are not limited to tetracycline, chlortetracycline, demeclocy In one embodiment, the antibiotic is an antiviral agent. In cline, doxycycline, lymecycline, minocycline, or oxytetracy one embodiment, antiviral agents include but are not limited cline. to abacavir, acyclovir, amantadine, didanosine, emitricitabine, In one embodiment the antibiotic is a macrollide antibiotic. 30 enfuVirtide, entecavir, lamivudine, nevirapine, oseltamivir, In one embodiment macrollide antibiotics include but are not ribavirin, rimantadine, stavudine, Valaciclovir, Vidarabine, limited to erythromycin, azithromycin, oxithromycin, Zalcitabine, or zidovudine. In one embodiment, the antiviral dirithromycin, clarithromycin, josamycin, oleandomycin, agent is a nucleotide analog reverse transcriptase inhibitor. In kitasamycin, spiramycin, tylosin/tylocine, troleandomycin, one embodiment, nucleotide analog reverse transcriptase carbomycin, cethromycin, or tellithromycin. 35 inhibitors include but are not limited totenofovir or adefovir. In one embodiment the antibiotic is an aminoglycoside In one embodiment, the antiviral agent is a protease inhibitor. antibiotic. In one embodiment, aminoglycoside antibiotics In one embodiment, protease inhibitors include but are not include but are not limited to gentamicin, tobramycin, faro limited to saquinavir, ritonavir, indinavir, nelfinavir, penem, imipenem, kanamycin, neomycin, ertapenem, apra amprenavir, lopinavir, foSamprenavir, or tipranavir. In one mycin, paromomycin Sulfate, streptomycin, or amikacin. 40 embodiment, the antiviral agent is a fusion inhibitor Such as In one embodiment the antibiotic is a quinolone antibiotic. enfuvirtide. In one embodiment, a combination of antiviral or In one embodiment quinolone antibiotics include but are not antiretroviral agents is desired. In one embodiment, antiviral limited to ciprofloxacin, norfloxacin, lomefloxacin, enoxa orantiretroviral agents or a combination thereof, further com cin, ofloxacin, ciprofloxacin, levofloxacin, Sparfloxacin, gati prise hydroxyurea, resveratrol, grapefruit, ritonavir, lefluno floxacin, moxifloxacin, trovafloxacin, or alatrofloxacin. 45 mide, or a combination thereof. In one embodiment the antibiotic is a cyclic peptide anti In one embodiment, the compound is administered in com biotic. In one embodiment cyclic peptide antibiotics include bination with an agent treating the liver. In one embodiment, but are not limited to Vancomycin, Streptogramins, Microcin the compound is administered in combination with a statin. In Some embodiment, statins include but are not limited to ator J25, Bacteriocin AS-48, RTD-1, or polymyxins. 50 In one embodiment the antibiotic is a lincosamide antibi vastatin, fluvastatin, lovastatin, pravastatin, simvastatin, or otic. In one embodiment lincosamide antibiotics include but rosuvastatin. are not limited to clindamycin. In one embodiment, the compound is administered in com In one embodiment, the antibiotic is an oxazolidinone anti bination with a bile acid sequestrant. In some embodiment, biotic. In one embodiment oxazolidinone antibiotics include 55 bile acid sequestrants include but are not limited to but are not limited to linezolid, U-100592, DA-7867, cholestyramine, colestipol, or colesevelam. AZD2563, or U-100766. In one embodiment, the compound is administered in com In one embodiment, the antibiotic is a sulfa antibiotic. In bination with a cholesterol absorption inhibitor. In some one embodiment, sulfa antibiotics include but are not limited embodiment, cholesterol absorption inhibitors include but to Sulfisoxazole. 60 are not limited to ezetimibe. In one embodiment, the antibiotic is an antiseptic agent. In In one embodiment, the compound is administered in com one embodiment, antiseptic agents include but are not limited bination with a nicotinic acid agent. In some embodiments, to alcohols, chlorhexidine, chlorine, hexachlorophene, nicotinic acid agents include but are not limited to niacin, iodophors, chloroxylenol (PCMX), quaternary ammonium niacor, or Sloniacin. compounds, or triclosan. 65 In one embodiment, the compound is administered in com In one embodiment, the antibiotic is an anti-tuberculosis bination with a fibrate. In some embodiments, fibrates include agent. In one embodiment an anti-tuberculosis agents include but are not limited to gemfibrozil, or fenofibrate. US 7,772,433 B2 79 80 In one embodiment, the agent treating the liver is cortisone, In one embodiment, the compound is administered with an cortisol or corticosterone. In some embodiments, the agent agent treating a wasting disease. In some embodiments, treating the liver is colchicine, methotrexate, urSodeoxy agents treating a wasting disease include but are not limited to cholic acid, or penicillamine. corticosteroids, anabolic steroids, cannabinoids, metoclopra In one embodiment, the compound is administered in with 5 mid, cisapride, medroxyprogesterone acetate, megestrol an agent treating the kidney. In one embodiment, the agent acetate, cyproheptadine, hydrazine Sulfate, pentoxifylline, treating the kidney is a diuretic. In some embodiments, diuret thalidomide, anticytokine antibodies, cytokine inhibitors, ics include but are not limited to organomercurial, ethacrynic eicosapentaenoic acid, indomethacin, ibuprofen, melatonin, acid, frusemide, humetanide, piretanide, muZolimine, chlo insulin, growth hormone, clenbuterol, porcine pancreas rothiazide and thiazide, phthalimidine, chlorthalidone, clor 10 extract, IGF-1, IGF-1 analogue and secretagogue, myostatin exolone, quinazolinone, quinethaZone, metolaZone ilenzene analogue, proteasome inhibitor, testosterone, Oxandrolone, Sulphonamide, mefruside, chlorobenzamide, enbrel, melanocortin 4 receptor agonist, or a combination clopamidesalicylamide, Xipamide, Xanthine, aminophylline, thereof. carbonic anhydrase inhibitor, acetazolamide mannitol, potas In one embodiment, the agent treating a wasting disease is sium-sparing compound, aldosterone antagonist, spironolac 15 a ghrelin receptor ligand, growth hormone analogue, or a tone and canrenoate, pteridines, pyrazine, carboxamide-tri secretagogue. In some embodiments, ghrelin receptor amterene, oramiloride. In one embodiment, the agent treating ligands, growth hormone analogues, or secretagogues the kidney is a steroid. include but are not limited to prailmorelin, examorelin, tabi In one embodiment, the agent treating the kidney is eryth morelin, capimorelin, capromorelin, ipamorelin, EP-01572, ropoietin. In one embodiment, erythropoietin is obtained by EP-1572, or JMV-1843. natural sources (e.g., urinary erythropoietin: See U.S. Pat. In one embodiment, growth promoting agents such as but No. 3,865,801), or is a recombinantly produced protein and not limited to TRH. diethylstilbesterol, theophylline, analogs thereof, for example, as described in U.S. Pat. Nos. enkephalins, E series prostaglandins, compounds disclosed in 5,441,868, 5,547,933, 5,618,698 and 5,621,080 as well as U.S. Pat. No. 3.239,345, e.g., Zeranol, and compounds dis human erythropoietin analogs with increased glycosylation 25 closed in U.S. Pat. No. 4,036.979, e.g., sulbenox or peptides and/or changes in the amino acid sequence as those described disclosed in U.S. Pat. No. 4,411,890 are utilized as agents in European Patent Publication No. EP 668351 and the hyper treating a wasting disease. glycosylated analogs having 1-14 sialic acid groups and In other embodiments, agents treating a wasting disease changes in the amino acid sequence described in PCT Publi may comprise growth hormone secretagogues such as cation No. WO 91/05867. In one embodiment, erythropoi 30 GHRP-6, GHRP-1 (as described in U.S. Pat. No. 4,411,890 etin-like polypeptides are administered in combination with and publications WO 89/07110 and WO 89/07111), GHRP-2 the compounds of this invention. In some embodiments, (as described in WO 93/04081), NN703 (Novo Nordisk), erythropoietin-like polypeptides comprise darbepoietin LY444711 (Lilly), MK-677 (Merck), CP424391 (Pfizer) and (from Amgen; also known as Aranesp and novel erthyropoie B-HT920, or, in other embodiments, with growth hormone sis stimulating protein (NESP)). 35 releasing factor and its analogs or growth hormone and its In one embodiment, the SARM compound is administered analogs, or with alpha-adrenergic agonists, such as clonidine in with an agent treating a metabolic disease. In some or serotinin 5-HTDagonists, such as Sumatriptan, or agents embodiments, agents treating a metabolic disease include but which inhibit somatostatin or its release, Such as physostig are not limited to a vitamin, Coenzyme Q10, glucosidase alfa, mine and pyridostigmine. In some embodiments, agents Sodium bicarbonate, bisphosphonate, biotin, allopurinol, 40 treating a wasting disease may comprise parathyroid hor levodopa, diazepam, phenobarbital, haloperidol, folic acid, mone, PTH (1-34) or bisphosphonates, such as MK-217 (al antioxidants, activators of cation channels haptoglobin, or endronate). In other embodiments, agents treating wasting carnitine. disease may further comprise estrogen, a selective estrogen In one embodiment, the agent treating a metabolic disease receptor modulator, Such as tamoxifene or raloxifene, or other is a pancreatic lipase inhibitor Such as orlistat or cetilistat, 45 androgen receptor modulators, such as those disclosed in Serotonin or norepinephrine reuptake inhibitor Such as Edwards, J. P. et. al., Bio. Med. Chem. Let., 9, 1003-1008 sibutramine, insulin-sensitizers such as biguanide, PPAR (1999) and Hamann, L. G. et. al., J.Med. Chem., 42, 210-212 agonist, Dual-acting PPAR agonist Such as muraglitazar, (1999). In some embodiments, agents treating a wasting dis tesaglitazar, or naveglitazar, PPAR-delta agonist Such as ease may further comprise a progesterone receptor agonists GW-501516, DPP-IV Inhibitor such as vildagliptin or sita 50 (“PRA), such as levonorgestrel, medroxyprogesterone gliptin, alpha glucosidase inhibitor Such as acarbose, anti acetate (MPA). In some embodiments, agents treating a wast diabetic combination such as ActoPlus Met, AvandaMet, met ing disease may include nutritional Supplements, such as formin/pioglitaZone, metformin/rosiglitaZone, O those described in U.S. Pat. No. 5,179,080, which, in other Glucovance, Glucagon-like peptide-1 analogue Such as embodiments are in combination with whey protein or casein, exenatide or liraglutide, Amylin analogue Such as pramlint 55 amino acids (such as leucine, branched amino acids and ide, statin Such as atorvastatin, simvastatin, rosuvastatin, hydroxymethylbutyrate), triglycerides, vitamins (e.g., A, B6. pravastatin, fluvastatin, lovastatin, or pitavastatin, Choles B 12, folate, C, D and E), minerals (e.g., selenium, magne terol absorption inhibitor such as eZetimibe, Nicotinic acid sium, Zinc, chromium, calcium and potassium), camitine, derivative Such as niacin or niaslo, antidyslipidemic fixed lipoic acid, creatinine, B-hyroxy-B-methylbutyriate (Juven) combination Such as simvastatin/ezetimibe, lovastatin/nico 60 and coenzyme Q. In one embodiment, agents treating a wast tinic acid, atorvastatin/amlodipine, or atorvastatin/torce ing disease may further comprise antiresorptive agents, Vita trapib, simvastatin/nicotinic acid, ACE inhibitor such as min D analogues, elemental calcium and calcium Supple ramipril, captopril, or lisinopril, AT-II receptor antagonist ments, cathepsin K inhibitors, MMP inhibitors, vitronectin Such as Valsartan or telmisartan, cannabinoid receptorantago receptor antagonists, Src SH2 antagonists, Vacular-H+-AT nist Such as rimonabant, cholesteryl ester transfer protein or 65 Pase inhibitors, ipriflavone, fluoride, fibolone, prostanoids, CETP Inhibitor such as JTT-705, CETi-1, or beta-3 adrener 17-beta hydroxysteroid dehydrogenase inhibitors and Src gic agonist. kinase inhibitors. US 7,772,433 B2 81 82 In one embodiment, the compound is administered in with In one embodiment, the agent treating the endocrine sys an agent treating the endocrine system. In some embodi tem is a steroidal or nonsteroidal glucocorticoid receptor ments, agents treating the endocrine system include but are ligand. In some embodiments, nonsteroidal glucocorticoid not limited to radioactive iodine, antithyroid agent, thyroid receptor ligands include but are not limited to ZK-216348, hormone Supplement, growth hormone, cabergoline, bro ZK-243149, ZK-243185, LGD-5552, mifepristone, RPR mocriptine, thyroxine, gonadotropin, glucocorticoid, gluco 106541, ORG-34517, GW-215864x, Sesquicillin, corticoid analogue, corticotrophin, metyrapone, aminoglute CP-472555, CP-39.4531, A-222977, AL-438, A-216054, thimide, mitotane, ketoconazole, mifepristone, dexamethasone somatostatin analogue, gonadotropin-releas A-276575, CP-39.4531, CP-409069, or UGR-07. ing hormone analogue, leuprolide, goserelin, antidiuretic 10 In one embodiment, the agent treating the endocrine sys hormone, antidiuretic hormone analogue, oxytocin, calcium tem is a steroidal or non-steroidal progesterone receptor Supplement, vitamin D, or a combination thereof. ligand. In one embodiment, the agent treating the endocrine In one embodiment, the agent treating the endocrine sys system is a steroidal or nonsteroidal androgen receptor tem is a 5-alpha-reductase inhibitor. In some embodiments, antagonist. In some embodiments, steroidal or nonsteroidal 15 androgen receptor antagonists include but are not limited to 5-alpha-reductase inhibitors include but are not limited to flutamide, hydroxyflutamide, bicalutamide, nilutamide, or finasteride, dutasteride, orizonsteride. hydroxysteroid dehydrogenase inhibitor. In one embodiment, the agent treating the endocrine sys tem is a SARM compound. In some embodiments, SARMs In one embodiment, the agent treating the endocrine sys includebut are not limited to RU-58642, RU-56279, WS9761 tem is a peroxisome proliferator-activated receptor ligand. In A and B, RU-59063, RU-58841, bexlosteride, LG-2293, Some embodiments, peroxisome proliferator-activated recep L-245976, LG-121071, LG-121091, LG-121104, LGD tor ligands include but are not limited to bezafibrate, fenofi 2226, LGD-2941, YM-92088, YM-175735, LGD-1331, brate, gemfibrozil, dargilitaZone, pioglitaZone, rosiglitaZone, BMS-357597, BMS-391197, S-40503, BMS-482-404, isaglitaZone, rivoglitaZone, netoglitaZone, naveglitazar, far EM-4283, EM-4977, BMS-564929, BMS-391197, BMS glitazar, tesaglitazar, ragaglitazar, Oxeglitazar, or PN-2034. 43.4588, BMS-487745, BMS-501949, SA-766, YM-92088, 25 In one embodiment, an agent treating the endocrine system YM-580, LG-123303, LG-123129, PMCol, YM-175735, is a human growth hormone. In some embodiments, human BMS-591305, BMS-591309, BMS-665139, BMS-665539, growth hormones include but are not limited to Somatotropin CE-590, 116BG33, 154BG31, arcarine, or ACP-105. or analogues. In one embodiment, the additional agent treating the endo In one embodiment, the agent treating the endocrine sys crine system is a SERM compound. In some embodiments, 30 tem is a ghrelin. In some embodiments, ghrelins include but SERMs include but are not limited to tamoxifene, 4-hydrox are not limited to human ghrelin, CYT-009-GhrOb. ytamoxifene, idoxifene, toremifene, ospennifene, drolox L-692429, GHRP-6, SK&F-110679, or U-75799E. ifene, raloxifene, arzoxifene, baZedoxifene, PPT (1,3,5-Tris In one embodiment, the agent treating the endocrine sys (4-hydroxyphenyl)-4-propyl-1H-pyrazole), DPN, tem is a leptin. In some embodiments, leptins include but are lasofoxifene, pipendoxifene, EM-800, EM-652, nafoxidine, 35 not limited to metreleptin or pegylated leptin. In one embodi Zindoxifene, tesmilifene, miproxifene phosphate, RU 58,688, ment, an agent treating the endocrine system is a leptin recep EM 139, ICI 164,384, ICI 182,780, clomiphene, MER-25, tor agonist. In some embodiments, leptin receptor agonists diethylstibestrol, coumestrol, genistein, GW5638, includebut are not limited to LEP (116-130), OB3, D-Leu-4- LY353581, Zuclomiphene, enclomiphene, delmadinone 40 OB3, ra AV-leptin, AAV-hCB, or raAVhOB. acetate, DPPE, (N,N-diethyl-2-4-(phenylmethyl)- In one embodiment, the SARM compound is administered phenoxyethanamine), TSE-424, WAY-070, WAY-292, with an inhibitor of an enzyme involved in the androgen WAY-818, cyclocommunol, prinaberel, ERB-041, WAY-397, biosynthetic pathway. In some embodiments, inhibitors of WAY-244, ERB-196, WAY-169122, MF-101, ERb-002, enzymes involved in the androgen biosynthetic pathway ERB-037, ERB-017, BE-1060, BE-380, BE-381, WAY-358, 45 include but are not limited to 17-ketoreductase inhibitor, 18FFEDNP, LSN-500307, AA-102, Ban Zhilian, CT-10, 3-DH4,6-isomerase inhibitor, 3-DH4.5-isomerase inhibitor, CT-102, or VG-101. 17.20 desmolase inhibitor, p450c17 inhibitor, p450ssc inhibi In one embodiment, the agent treating the endocrine sys tor, or 17.20-lyase inhibitor. tem is a gonadotropin-releasing hormone agonist or antago In one embodiment, the SARM compound is administered nist. In some embodiments, gonadotropin-releasing hormone 50 with an agent treating osteoporosis. In some embodiments, agonists or antagonists include but are not limited to leupro osteoporosis is induced by alcohol and/or Smoking. In some lide, goserelin, triptorelin, alfaprostol, histrelin, detirelix, embodiments, agents treating osteoporosis includebut are not ganirelix, antide iturelix, cetrorelix, ramorelix, ganirelix, limited to SERMs, calcitonin, vitamin D, vitamin D deriva antarelix, teverelix, abarelix, Ozarelix, Sufugolix, praZarelix, tives, vitamin D receptor ligand, Vitamin D receptor ligand degarelix, NBI-56418, TAK-810, or acyline. 55 analogue, estrogen, estrogen derivative, conjugated estrogen, In one embodiment, the agent treating the endocrine sys antiestrogen, progestin, synthetic estrogen, synthetic proges tem is a luteinizing hormone agonist or antagonist. In some tin, RANK ligand monoclonal antibody, integrin receptor embodiments, luteinizing hormone agonists or antagonists antagonist, osteoclast vacuolar ATPase inhibitor, antagonist include but are not limited to letrozole, anastraZole, atames of VEGF binding to osteoclast receptors, calcium receptor tane, fadrozole, minamestane, exemestane, plomestane, 60 antagonist, parathyroid hormone, parathyroid hormone ana liarozole, NKS-01, Vorozole, YM-511, finrozole, 4-hy logue, parathyroid hormone-related peptide, cathepsin K droxyandrostenedione, aminogluethimide, or rogletimide. In inhibitor, strontium ranelate, tibolone, HCT-1026, PSK3471, one embodiment, the agent treating the endocrine system is a gallium maltolate, nutropin AQ, prostaglandin, p38 protein follicle stimulating hormone agonist or antagonist. In one kinase inhibitor, bone morphogenetic protein (BMP), inhibi embodiment, the agent treating the endocrine system is a 65 tor of BMP antagonism, HMG-CoA reductase inhibitor, vita luteinizing hormone releasing hormone (LHRH) or a LHRH min K. vitamin K derivative, ipriflavone, fluoride salts, analog. dietary calcium Supplement, or osteoprotegerin. US 7,772,433 B2 83 84 In one embodiment, the agent treating osteoporosis is a In one embodiment, the compound of this invention is calcitonin. In some embodiments, calcitonins include but are administered with an agent treating an ophthalmic disease. In not limited to salmon, elcatonin, SUN-8577, or TJN-135. Some embodiments, agents treating an ophthalmic disease In one embodiment, the agent treating osteoporosis is a include but are not limited to betagan, betimol, timoptic, Vitamin D receptor ligand or analogue. In some embodi betoptic, betoptic, ocupress, optipranolol. Xalatan, alphagan, ments, vitamin D receptor ligands or analogues include but aZopt, trusopt, cospot, pilocar, pilagan, propine, opticrom, are not limited to calcitriol, topitriol, ZK-150123, TEI-9647, acular, livostin, alomide, emadine, patanol, alrex, poly-pred. BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299, or DP-035. pred-g, dexacidin, erythromycin, maxitrol, tobradex, blepha In one embodiment, the SARM compound is administered mide, FML, ocufen, voltaren, profenal, pred forte, econpred with an agent treating pharmacotherapy induced hypogo 10 plus, eflone, flarex, inflamase forte, betadine, gramicidin, nadal and/or osteopenic and/or sarcopenic state. In some prednisolone, betaxolol, humorsol, proparacaine, betoptic, embodiments, agents treating pharmacotherapy induced hylartin, inflamase mild, lotemax, flurbiprofen, chloram hypogonadal and/or osteopenic and/or sarcopenic states phenicol, methazolamide, timolol, ciloxan, terramycin, include but are not limited to opioids, narcotics, opiates, ciprofloxacin, miostat, triamcinolone, miconazole, tobramy opioids, methadone, kadian, D2 dopamine receptor antago 15 cin, physostimine, gentamicin, pilocarpine, bacitracin, nist, Zotepine, haloperidol, amisulpride, risperidone, anti-epi goniosol, polymyxin, oxytetracycline, Viroptic, Vexol. Supro leptic agent, Valproic acid, carbamazepine, oXcarbam fen, celluvisc, polytrim, illotycin, ciloxan, ocuflox, brinZola aZepine, chemotherapeutic agent, methotrexate, mide, cefazolin, tobrex, latanoprost, indocycanine, trifluri cyclophosphamide, ifosfamide, adriamycin, doxorubicin, dine, phenylephrine, demecarium, neomycin, tropicamide, glucocorticoids, cyclosporine, L-thyroxine, SERMs, AI, full dexamethasone, neptazane, diplivefrin, ocuflox, Vidarabine, Vestrant, gonadotropin-releasing hormone agent, androgen dorzolamide, ofloxacin, epinephrine, acyclovir, carbonic depravation agent, prolactinemia-inducing agent, serotoner anhydrase inhibitor, antihistamine vitaminA, Vitamin C, Vita gic antidepressant, selective serotonin reuptake inhibitor, min E. Zinc, copper, atropine, or garamycin. monoamine oxidase inhibitor, tricyclic antidepressant, anti In one embodiment, the compound of this invention is hypertensive agents, methyldopa, reserpine, clonidine, Vera 25 administered in with a gene therapy agent. In some embodi pamil, antidopaminergic agent, anti-emetic agent, metoclo ments, gene therapy agents include but are not limited to an pramide, H2 receptor antagonist, cimetidine, ranitidine, antisense agent, or a replacement gene. estrogen, or amphetamine. In some embodiments, any of the compositions of this In one embodiment, the compound of this invention is invention will comprise a compound of formula I, in any form administered with a vitamin. In some embodiments, vitamins 30 or embodiment as described herein. In some embodiments, includebutare not limited to vitamin D, vitamin E, vitamin K, any of the compositions of this invention will consist of a vitamin B, Vitamin C, or a combination thereof. compound of formula I, in any form or embodiment as In one embodiment, the compound of this invention is described herein. In some embodiments, of the compositions administered with a behavior-modulating agent. In some of this invention will consistessentially of a compound of I, in embodiments, behavior-modulating agents include but are 35 any form or embodiment as described herein. In some not limited to an anti-anxiety agent, anti-psychotic agent, embodiments, the term “comprise' refers to the inclusion of anti-depressant, beta-blocker, beta-2 agonist, anticholinergic the indicated active agent. Such as the compound of formula bronchodilator, theophylline, aminophylline, nedocromil I, as well as inclusion of other active agents, and pharmaceu Sodium, Sodium cromoglycate, leukotriene receptor antago tically acceptable carriers, excipients, emollients, stabilizers, nist, corticosteroid, expectorant, mucolytic agent, antihista 40 etc., as are known in the pharmaceutical industry. In some mine, pseudoephedrine, methylphenidate, amphetamine, embodiments, the term “consisting essentially of refers to a buspirone, benzodiazepine, dextroamphetamine, tricyclic composition, whose only active ingredient is the indicated antidepressant, serotonin reuptake inhibitor, phenothiazines, active ingredient, however, other compounds may be benztropine, bupropion, propranolol, lithium, Venlafaxine, included which are for stabilizing, preserving, etc. the formu haloperidol, buspirone, or a neuraminidase inhibitor. 45 lation, but are not involved directly in the therapeutic effect of In one embodiment, the behavior-modulating agent is a the indicated active ingredient. In some embodiments, the benzodiazepine. In one embodiment, benzodiazepines com term “consisting essentially of may refer to components prise alprazolam, chlordiazepoxide, diazepam, flurazepam, which facilitate the release of the active ingredient. In some lorazepam, oxazepam, temazepam, or triazolam. embodiments, the term “consisting refers to a composition, 50 which contains the active ingredient and a pharmaceutically In one embodiment, the behavior-modulating agent is a acceptable carrier or excipient. phenothiazine. In one embodiment, phenothiazines comprise In one embodiment, the present invention provides com fluiphenazine, perphenazine, thioridazine, or trifluoperazine. bined preparations. In one embodiment, the term "a com In one embodiment, the behavior-modulating agent is a bined preparation' defines especially a “kit of parts” in the tricyclic antidepressant or a serotonin reuptake inhibitor. In 55 sense that the combination partners as defined above can be one embodiment, tricyclic antidepressants or serotonin dosed independently or by use of different fixed combinations reuptake inhibitors comprise phenothiazine, protriptyline, with distinguished amounts of the combination partners i.e., fluoxetine, paroxetine, or Sertraline. simultaneously, concurrently, separately or sequentially. In In one embodiment, the compound of this invention is Some embodiments, the parts of the kit of parts can then, e.g., administered with an agent treating a connective tissue. In 60 be administered simultaneously or chronologically stag Some embodiments, agents treating a connective tissue gered, that is at different time points and with equal or differ include but are not limited to an anti-malaria agent, a cyto ent time intervals for any part of the kit of parts. The ratio of toxic agent, a steroid, corticosteroid, lupus medication, imu the total amounts of the combination partners, in some ran, cytoxan, anti-rheumatic agent, corticosteroid, nifedipine, embodiments, can be administered in the combined prepara aspirin, coichicine, captopril, penicillamine, azathioprine, 65 tion. In one embodiment, the combined preparation can be methotrexate, cyclophosphamide, prednisone, nicardipine, varied, e.g., in order to cope with the needs of a patient or a non-steroidal anti-inflammatory agent. subpopulation to be treated or the needs of the single patient US 7,772,433 B2 85 86 which different needs can be due to a particular disease, the compound may be characterized by the structure of for severity of a disease, age, sex, or body weight as can be mula I-XXII, or any embodiment thereof, as herein described. readily made by a person skilled in the art. In some embodiments, the compounds as described herein It is to be understood that this invention is directed to and/or compositions comprising the same may be used for compositions and combined therapies as described herein, for applications and treating diseases in which the improvement any disease, disorder or condition, as appropriate, as will be of cognition, reduction or treatment of depression, or other appreciated by one skilled in the art. Certain applications of neuroportective effects are desired. Such compositions and combined therapies have been In one embodiment, “Cognition” refers to the process of described hereinabove, for specific diseases, disorders and knowing, specifically the process of being aware, knowing, conditions, representing embodiments of this invention, and 10 thinking, learning and judging. Cognition is related to the methods of treating Such diseases, disorders and conditions in fields of psychology, linguistics, computer Science, neuro a Subject by administering a compound as herein described, Science, mathematics, ethology and philosophy. In one alone or as part of the combined therapy or using the compo embodiment, “mood refers to a temperor state of the mind. sitions of this invention represent additional embodiments of As contemplated herein, alterations mean any change for the this invention. 15 positive or negative, in cognition and/or mood. In one embodiment, “depression” refers to an illness that Biological Activity of Selective Androgen Modulator Com involves the body, mood and thoughts that affects the way a pounds person eats, sleeps and the way one feels about oneself, and The compounds of this invention may be useful, in some thinks about things. The signs and symptoms of depression embodiments, for oral testosterone replacement therapy. In include loss of interest in activities, loss of appetite or over other embodiments, appropriately Substituted compounds are eating, loss of emotional expression, an empty mood, feelings useful for a) male contraception; b) treatment of a variety of of hopelessness, pessimism, guilt or helplessness, Social hormone-related conditions, for example conditions associ withdrawal, fatigue, sleep disturbances, trouble concentrat ated with ADAM, Such as fatigue, depression, decreased ing, remembering, or making decisions, restlessness, irrita libido, sexual dysfunction, erectile dysfunction, hypogo 25 bility, headaches, digestive disorders or chronic pain. nadism, osteoporosis, hair loss, obesity, sarcopenia, osteope In one embodiment, the methods of this invention are use nia, benign prostate hyperplasia, and alterations in mood and ful a subject, which is a human. In another embodiment, the cognition; c) treatment of conditions associated with ADIF, Subject is a mammal. In another embodiment the Subject is an Such as sexual dysfunction, decreased sexual libido, hypogo animal. In another embodiment the subject is an invertebrate. nadism, sarcopenia, osteopenia, osteoporosis, alterations in 30 In another embodiment the subject is a vertebrate. cognition and mood, depression, anemia, hair loss, obesity, In one embodiment, the subject is male. In another embodi endometriosis, breast cancer, uterine cancer and ovarian can ment, the subject is female. In some embodiments, while the cer; d) treatment and/or prevention of chronic muscular wast methods as described herein may be useful for treating either ing; e) treatment of prostate cancer, imaging of prostate can males or females, females may respond more advantageously cer, decreasing the incidence of halting or causing a 35 to administration of certain compounds, for certain methods, regression of prostate cancer, f) treatment of diabetes type I; as described and exemplified herein. g) treatment of diabetes type II; h) Suppressing or inhibiting or In some embodiments, while the methods as described reducing the incidence of diabetes i) treatment of glucose herein may be useful for treating either males or females, intolerance;) treatment of hyperinsulinemia; k) treatment of males may respond more advantageously to administration of insulin resistance 1) treatment of diabetic nephropathy; m) 40 certain compounds, for certain methods, as described herein. treatment of diabetic neuropathy; n) treatment of diabetic In some embodiments, the compounds as described herein retinopathy; o) treatment offatty liver condition; p) treatment and/or compositions comprising the same may be used for of cachexia; q) oral androgen replacement and/or other clini applications in or treating hair loss, alopecia, androgenic cal therapeutic and/or diagnostic areas, including any alopecia, alopecia areata, alopecia secondary to chemo embodiment of what is encompassed by the term “treating as 45 therapy, alopecia secondary to radiation therapy, alopecia described herein. induced by Scarring or alopecia induced by stress. In one In some embodiments, the compounds of this invention embodiment, “hair loss’, or “alopecia', refers to baldness as possess in Vivo tissue selective androgenic and anabolic activ in the very common type of male-pattern baldness. Baldness ity, which is accordingly utilized for particular applications, typically begins with patch hair loss on the Scalp and some as will be appreciated by one skilled in the art. 50 times progresses to complete baldness and even loss of body In one embodiment, this invention provides: a) a method of hair. Hair loss affects both males and females. treating a subject having a muscle wasting disorder; b) a In some embodiments, the compounds as described herein method of treating a subject Suffering from malnutrition; c) a and/or compositions comprising the same may be used for method of treating a bone-related disorder in a subject; d) a applications in, or treating diseases or conditions associated method of increasing a bone mass in a subject; e) a method of 55 with a subject having anemia. In one embodiment, 'anemia improving the lipid profile in a subject, f) a method of treating refers to the condition of having less than the normal number atherosclerosis and its associated diseases; g) a method of of red blood cells or less than the normal quantity of hemo improving dexterity and movement in a Subject; h) a method globin in the blood, reduced hematocrit or reduced mean of treating a subject having dwarfism: i) a method of treating corpuscular Volume, or reduced corpuscular size. The oxy a Subject having dysmenorrhea, j) a method of treating a 60 gen-carrying capacity of the blood is decreased in anemia. In Subject having dysparunia; k) a method of treating a subject Some embodiments, treating anemia may also refer herein to having dysspermtogenic sterility; comprising the step of treating underlying factors resulting in anemia, Such as for administering to said subject a compound of this invention example: a) hemorrhage (bleeding); b) hemolysis (excessive and/or an analog, derivative, isomer, metabolite, pharmaceu destruction of red blood cells); c) underproduction of red tically acceptable salt, pharmaceutical product, hydrate, 65 blood cells; and d) not enough normal hemoglobin. In some N-oxide, prodrug, polymorph, impurity or crystal of said embodiments, treating anemia in this invention refers to treat compound, or any combination thereof. In one embodiment, ing any form thereof, including aplastic anemia, benzene US 7,772,433 B2 87 88 poisoning, Fanconi anemia, hemolytic disease of the new In some embodiments, this invention provides methods for born, hereditary spherocytosis, iron deficiency anemia, the treatment of a precancerous precursor or lesion in a Sub osteoporosis, pernicious anemia, aplastic anemia, hemolytic ject, reduction of incidence of precancerous precursors or anemia, sickle cell anemia, renal anemia, thalassemia, myelo lesions in a Subject, comprising the step of administering to dysplastic syndrome, and a variety of bone marrow diseases. the Subject a compound as herein described and/or its analog, In some embodiments, the compounds as described herein derivative, isomer, metabolite, pharmaceutically acceptable and/or compositions comprising the same may be used for salt, pharmaceutical product, polymorph, crystal, impurity, applications in and/or treating diseases and/or conditions hydrate, N-oxide or any combination thereof. In some associated with problems with a subject’s libido, or erectile embodiments, such precancerous precursors are androgen dysfunction in a subject. In one embodiment, “libido’, may 10 receptor dependent tumors found in hormone-responsive tis refer to sexual desire. Sue or are associated with reproductive tissue in males or In one embodiment, the term "erectile” refers to the ability females, such as in the prostate, ovary, breast, uterus, testicle, to be erect or upright. An erectile tissue is a tissue, which is or others. In some embodiments, such precancerous precur capable of being greatly dilated and made rigid by the disten sors comprise any local intraepithelial neoplasia, for sion of the numerous blood vessels, which it contains. 15 example, of the prostate, the cervix, etc. In some embodi In another embodiment of the present invention, a method ments, such methods are useful in treating neoplasia or pre is provided for hormonal therapy in a patient (i.e., one suffer neoplasia, dysplasia or hyperplasia in a tissue, such as in ing from an androgen-dependent condition) which includes reproductive tissue in males or females. contactinganandrogen receptor of a patient with a compound In one embodiment, this invention provides compounds, and/or a non steroidal agonist of the present invention and/or compositions and/or methods of use thereof in treating its analog, derivative, isomer, metabolite, pharmaceutically benign prostate hyperplasia (BPH). “BPH (benign prostate acceptable salt, pharmaceutical product, polymorph, crystal, hyperplasia) is a nonmalignant enlargement of the prostate impurity, hydrate, N-oxide or any combination thereof, in an gland, and is the most common non-malignant proliferative amount effective to bind the compound to the androgen abnormality found in any internal organ and the major cause receptor and effect a change in an androgen-dependent con 25 of morbidity in the adult male. BPH occurs in over 75% of dition. men over 50 years of age, reaching 88% prevalence by the In one embodiment of this invention, a method is provided ninth decade. BPH frequently results in a gradual Squeezing for hormone replacement therapy in a patient (i.e., one Suf of the portion of the urethra which traverses the prostate fering from an androgen-dependent condition) which (prostatic urethra). This causes patients to experience a fre includes administering a compound as herein described and/ 30 quent urge to urinate because of incomplete emptying of the or its analog, derivative, isomer, metabolite, pharmaceuti bladder and urgency of urination. The obstruction of urinary cally acceptable salt, pharmaceutical product, polymorph, flow can also lead to a general lack of control over urination, crystal, impurity, hydrate, N-oxide or any combination including difficulty initiating urination when desired, as well thereof, to a subject, in an amount Sufficient to effect a change as difficulty in preventing urinary flow because of the inabil in a hormone-dependent condition in the Subject. 35 ity to empty urine from the bladder, a condition known as Androgen-dependent conditions which may be treated overflow urinary incontinence, which can lead to urinary with the compounds and/or compositions as herein described, obstruction and to urinary failure. comprising the methods of the present invention include In another embodiment of the present invention, the those conditions which are associated with aging, hypogo method for treating benign prostate hyperplasia (BPH) in a nadism, sarcopenia, diminished erythropoiesis, osteoporosis, 40 Subject, comprises the step of administering to the Subject a and any other conditions dependent upon low androgen (e.g., compound as herein described and/or its analog, derivative, testosterone) or estrogen levels. isomer, metabolite, pharmaceutically acceptable salt, phar Androgen-dependent conditions which may be treated maceutical product, polymorph, crystal, impurity, hydrate, with the compounds and/or compositions as herein described, N-oxide or any combination thereof, in an amount effective to and comprising a method of the invention, may comprise 45 treat BPH in the subject. conditions characterized by elevated androgen or estrogen In some embodiments, this invention provides for the use levels, including hirsutism, infertility, polycystic ovarian Syn of a compound as herein described, or its prodrug, analog, drome, endometrial carcinoma, breast cancer, male pattern isomer, metabolite, derivative, pharmaceutically acceptable baldness, prostate cancer, testicular cancer, and others, as will salt, pharmaceutical product, polymorph, crystal, impurity, be known to one skilled in the art. For such conditions, the 50 N-oxide, hydrate or any combination thereof, for treating Subject may be administered a compound as herein described, reducing the severity of reducing the incidence of or reduc alone or in combination with another therapeutic agent, as ing pathogenesis of cachexia and/or cachexia associated with will be appreciated by one skilled in the art. cancer in a Subject. In another embodiment, the cancer com In one embodiment, this invention provides methods for prise adrenocortical carcinoma, anal cancer, bladder cancer, the treatment of a cancer in a subject, reduction of incidence 55 brain tumor, brain stem glioma, brain tumor, cerebellar astro or severity or pathogenesis of a cancer in a subject, delaying cytoma, cerebral astrocytoma, ependymoma, medulloblas progression, prolonging remission or delaying onset of can toma, Supratentorial primitive neuroectodermal, pineal cer in a Subject, comprising the step of administering to the tumors, hypothalamic glioma, breast cancer, carcinoid tumor, Subject a compound as herein described and/or its analog, carcinoma, cervical cancer, colon cancer, endometrial cancer, derivative, isomer, metabolite, pharmaceutically acceptable 60 esophageal cancer, extrahepatic bile duct cancer, ewings fam salt, pharmaceutical product, polymorph, crystal, impurity, ily of tumors (Pnet), extracranial germ cell tumor, eye cancer, hydrate, N-oxide or any combination thereof. In some intraocular melanoma, gallbladder cancer, gastric cancer, embodiments, such cancers are hormone-dependent or germ cell tumor, extragonadal, gestational trophoblastic androgen receptor dependent tumors (malignant or benign) tumor, head and neck cancer, hypopharyngeal cancer, islet associated with reproductive tissue in males or females. Such 65 cell carcinoma, laryngeal cancer, leukemia, acute lympho as cancer of the prostate, ovary, breast, uterus, testicle, or blastic, leukemia, oral cavity cancer, liver cancer, lung cancer, others. non Small cell lung cancer, Small cell, lymphoma, AIDS US 7,772,433 B2 89 90 related lymphoma, central nervous system (primary), lym sity loss; d) treating low bone mineral density (BMD); e) phoma, cutaneous T-cell, lymphoma, Hodgkin’s disease, treating reduced bone mass: f) treating metabolic bone dis non-Hodgkin’s disease, malignant mesothelioma, mela ease; g) promoting bone growth or regrowth; h) promoting noma, Merkel cell carcinoma, metasatic squamous carci bone restoration: i) promoting bone fracture repair, j) promot noma, multiple myeloma, plasma cell neoplasms, mycosis ing bone remodeling, k) treating bone damage following fungoides, myelodysplastic syndrome, myeloproliferative reconstructive Surgery including of the face, hip, or joints; 1) disorders, nasopharyngeal cancer, neuroblastoma, oropha enhancing of bone strength and function; m) increasing cor ryngeal cancer, osteosarcoma, ovarian epithelial cancer, ova tical bone mass; n) increasing trabecular connectivity. rian germ cell tumor, ovarian low malignant potential tumor, In one embodiment, the bone related disorder is a genetic pancreatic cancer, exocrine, pancreatic cancer, islet cell car 10 disorder, or in another embodiment, is induced as a result of cinoma, paranasal sinus and nasal cavity cancer, parathyroid a treatment regimen for a given disease. For example, and in cancer, penile cancer, pheochromocytoma cancer, pituitary one embodiment, the compounds as herein described are cancer, plasma cell neoplasm, prostate cancer, rhabdomyosa useful in treating a bone-related disorder that arises as a result rcoma, rectal cancer, renal cell cancer, salivary gland cancer, of cancer metastasis to bone, or in another embodiment, as a Sezary syndrome, skin cancer, cutaneous T-cell lymphoma, 15 result of androgen-deprivation therapy, for example, given in skin cancer, Kaposi's sarcoma, skin cancer, melanoma, Small response to prostate carcinogenesis in the Subject. intestine cancer, soft tissue sarcoma, Soft tissue sarcoma, In one embodiment, the bone-related disorder is testicular cancer, thymoma, malignant, thyroid cancer, ure osteoporosis. In another embodiment, the bone-related disor thral cancer, uterine cancer, sarcoma, unusual cancer of child der is osteopenia. In another embodiment, the bone-related hood, vaginal cancer, Vulvar cancer, Wilms tumor, or any disorder is increased bone resorption. In another embodi combination thereof. ment, the bone-related disorder is bone fracture. In another In another embodiment, this invention provides for the use embodiment, the bone-related disorder is bone frailty. of a compound as herein described, or its prodrug, analog, In another embodiment, the bone-related disorder is a loss isomer, metabolite, derivative, pharmaceutically acceptable of bone mineral density (BMD). In another embodiment, the salt, pharmaceutical product, polymorph, crystal, impurity, 25 bone-related disorder is any combination of osteoporosis, N-oxide, hydrate or any combination thereof, for treating osteopenia, increased bone resorption, bone fracture, bone reducing the severity of reducing the incidence of delaying frailty and loss of BMD. Each disorder represents a separate the onset of lung cancer. embodiment of the present invention. In another embodiment, this invention provides for the use “Osteoporosis' refers, in one embodiment, to a thinning of of a compound as herein described, or its prodrug, analog, 30 the bones with reduction in bone mass due to depletion of isomer, metabolite, derivative, pharmaceutically acceptable calcium and bone protein. In another embodiment, salt, pharmaceutical product, polymorph, crystal, impurity, osteoporosis is a systemic skeletal disease, characterized by N-oxide, hydrate or any combination thereof, for treating low bone mass and deterioration of bone tissue, with a con reducing the severity of reducing the incidence of delaying sequent increase in bone fragility and Susceptibility to frac the onset of non Small cell lung cancer. 35 ture. In osteoporotic patients, bone strength is abnormal, in In some embodiments, this invention provides for the use one embodiment, with a resulting increase in the risk of of a compound as herein described, or its prodrug, analog, fracture. In another embodiment, osteoporosis depletes both isomer, metabolite, derivative, pharmaceutically acceptable the calcium and the protein collagen normally found in the salt, pharmaceutical product, polymorph, crystal, impurity, bone, in one embodiment, resulting in either abnormal bone N-oxide, hydrate or any combination thereof, for treating 40 quality or decreased bone density. In another embodiment, reducing the severity of reducing the incidence of or reduc bones that are affected by osteoporosis can fracture with only ing pathogenesis of cancer. In another embodiment, the can a minor fall or injury that normally would not cause a bone cer comprises androgen AR dependent tumors (malignant or fracture. The fracture can be, in one embodiment, either in the benign) such as prostate cancer, breast cancer (male or form of cracking (as in a hip fracture) or collapsing (as in a female, operable or inoperable). In another embodiment the 45 compression fracture of the spine). The spine, hips, and wrists SARM compounds adjunct to ADT for treating prostate can are common areas of osteoporosis-induced bone fractures, cer; bladder cancers; brain cancers; bone tumors, colon can although fractures can also occur in other skeletal areas. cer, endometrial cancer, liver cancer, lung cancer, lymphatic Unchecked osteoporosis can lead, in another embodiment, to cancer, kidney cancer, osteosarcoma cancer, ovarian cancer, changes in posture, physical abnormality, and decreased pancreas cancer, penis cancer, skin cancer, thyroid cancer, 50 mobility. and/or hormone-dependent cancers. In one embodiment, the osteoporosis results from andro In one embodiment, this invention provides for the use of a gen deprivation. In another embodiment, the osteoporosis compound as herein described, or its prodrug, analog, isomer, follows androgen deprivation. In another embodiment, the metabolite, derivative, pharmaceutically acceptable salt, osteoporosis is primary osteoporosis. In another embodi pharmaceutical product, polymorph, crystal, impurity, N-OX 55 ment, the osteoporosis is secondary osteoporosis. In another ide, hydrate or any combination thereof, fora) treating a bone embodiment, the osteoporosis is postmenopausal osteoporo related disorder; b) preventing a bone related disorder; c) sis. In another embodiment, the osteoporosis is juvenile Suppressing a bone related disorder; d) inhibiting a bone osteoporosis. In another embodiment, the osteoporosis is related disorder; e) increasing a strength of a bone of a Sub idiopathic osteoporosis. In another embodiment, the ject, f) increasing a bone mass in a subject, g) use for osteo 60 osteoporosis is senile osteoporosis. clastogenesis inhibition. In another embodiment, the primary osteoporosis is Type I In one embodiment, this invention provides for the use of a primary osteoporosis. In another embodiment, the primary compound as herein described, or its prodrug, analog, isomer, osteoporosis is Type II primary osteoporosis. Each type of metabolite, derivative, pharmaceutically acceptable salt, osteoporosis represents a separate embodiment of the present pharmaceutical product, polymorph, crystal, impurity, N-OX 65 invention. ide, hydrate or any combination thereof, for a) Accelerate According to this aspect of the invention and in one bone repair; b) treating bone disorders; c) treating bone den embodiment, the bone-related disorder is treated with a com US 7,772,433 B2 91 92 pound as herein described, or a combination thereof. In gens; d) antiestrogen, progestins, or synthetic estrogen/ another embodiment, other bone-stimulating compounds can progestins; e) RANK ligand mAb Such as denosumab for be provided to the subject, prior to, concurrent with or fol merly AMG162 (Amgen); f) Ov3 Integrin receptor lowing administration of a compound or compounds as herein antagonist; g) osteoclast vacuolar ATPase inhibitor; h) described. In one embodiment. Such a bone stimulating com antagonist of VEGF binding to osteoclast receptors: i) cal pound may comprise natural or synthetic materials. cium receptor antagonist, j) PTh (parathyroid hormone) and In one embodiment, the bone stimulating compound may analogues, PTHrP analogues (parathyroid hormone-related comprise a bone morphogenetic protein (BMP), a growth peptide); k) Cathepsin K inhibitors (ME581, etc.); 1) stron factor, such as epidermal growth factor (EGF), a fibroblast tium ranelate; m) tibolone; n) HCT-1026, PSK3471; o) gal growth factor (FGF), a transforming growth factor (TGF, an 10 lium maltolate; p) nutropinAO; q) prostaglandins (for osteo); insulin growth factor (IGF), a platelet-derived growth factor r) p38 protein kinase inhibitor, s) bone morphogenetic pro (PDGF) hedgehog proteins such as Sonic, indian and desert tein; t) inhibitor of BMP antagonism; u) HMG-CoA reduc hedgehog, a hormone Such as follicle stimulating hormone, tase inhibitor; v) vitamin K or derivative: w) ipriflavone: X) parathyroid hormone, parathyroid hormone related peptide, fluoride salts:y) dietary calcium Supplement, and Z) osteopro activins, inhibins, follistatin, frizzled, frzb or frazzled pro 15 tegerin. teins, BMP binding proteins such as chordin and fetuin, a In one embodiment, the methods of this invention are use cytokine such as IL-3, IL-7, GM-CSF, a chemokine, such as ful in treating diseases or disorders caused by, or associated eotaxin, a collagen, osteocalcin, osteonectin and others, as with a hormonal disorder, disruption or imbalance. In one will be appreciated by one skilled in the art. embodiment, the hormonal disorder, disruption or imbalance In another embodiment, the compositions for use in treat comprises an excess of a hormone. In another embodiment, ing a bone disorder of this invention may comprise a com the hormonal disorder, disruption or imbalance comprises a pound or compounds as herein described, an additional bone deficiency of a hormone. In one embodiment, the hormone is stimulating compound, or compounds, and osteogenic cells. a steroid hormone. In another embodiment, the hormone is an In one embodiment, an osteogenic cell may be a stem cell or estrogen. In another embodiment, the hormone is an andro progenitor cell, which may be induced to differentiate into an 25 gen. In another embodiment, the hormone is a glucocorticoid. osteoblast. In another embodiment, the cell may be an osteo In another embodiment, the hormone is a cortico-steroid. In blast. In another embodiment, nucleic acids which encode another embodiment, the hormone is Luteinizing Hormone bone-stimulating compounds may be administered to the Sub (LH). In another embodiment, the hormone is Follicle Stimu ject, which is to be considered as part of this invention. lating Hormone (FSH). In another embodiment, the hormone In one embodiment, the methods of the present invention 30 is any other hormone known in the art. In another embodi comprise administering the compound for treating ment, the hormonal disorder, disruption or imbalance is asso osteoporosis. In another embodiment, the methods of this ciated with menopause. In another embodiment, the hor invention comprise administering a compound in combina monal disorder, disruption or imbalance is associated with tion with SERMs for treating osteoporosis. In another andropause, andropausal vasomotor symptoms, andropausal embodiment, the SERMs are tamoxifene, 4-hydroxytamox 35 gynecomastia, muscle strength and/or function, bone ifene, idoxifene, toremifene, ospemifene, droloxifene, ralox strength and/or function and anger. In another embodiment, ifene, arzoxifene, baZedoxifene, PPT (1,3,5-Tris(4-hydrox hormone deficiency is a result of specific manipulation, as a yphenyl)-4-propyl-1H-pyrazole), DPN, lasofoxifene, byproduct of treating a disease or disorder in the subject. For pipendoxifene, EM-800, EM-652, nafoxidine, Zindoxifene, example, the hormone deficiency may be a result of androgen tesmilifene, miproxifene phosphate, RU 58,688, EM 139, ICI 40 depletion in a subject, as a therapy for prostate cancer in the 164,384, ICI 182,780, clomiphene, MER-25, diethyl Subject. Each possibility represents a separate embodiment of stibestrol, coumestrol, genistein, GW5638, LY353581, the present invention. Zuclomiphene, enclomiphene, delmadinone acetate, DPPE, In another embodiment the invention is directed to treating (N,N-diethyl-2-4-(phenylmethyl)-phenoxyethanamine), sarcopenia or cachexia, and associated conditions related TSE-424, WAY-070, WAY-292, WAY-818, cyclocommunol, 45 thereto, for example diseases or disorders of the bone. prinaberel, ERB-041, WAY-397, WAY-244, ERB-196, WAY In one embodiment, this invention provides for the use of a 169122, MF-101, ERb-002, ERB-037, ERB-017, BE-1060, compound as herein described, or its prodrug, analog, isomer, BE-380, BE-381, WAY-358, 18FIFEDNP, LSN-500307, metabolite, derivative, pharmaceutically acceptable salt, AA-102, Ban Zhilian, CT-101, CT-102, or VG-101. pharmaceutical product, polymorph, crystal, impurity, N-OX In another embodiment, the methods of the present inven 50 ide, hydrate or any combination thereof, for 1) treating a tion comprise administering the SARM compound, in com muscle wasting disorder; 2) preventing a muscle wasting bination with bisphosphonates such as alendronate, disorder; 3) treating, preventing, Suppressing, inhibiting or tiludroate, clodroniate, pamidronate, etidronate, alendronate, reducing muscle loss due to a muscle wasting disorder; 4) Zolendronate, cimadronate, neridronate, minodronic acid, treating, preventing, inhibiting, reducing or Suppressing ibandronate, risedronate, or homoresidronate for treating 55 muscle wasting due to a muscle wasting disorder, and/or 5) osteoporosis. treating, preventing, inhibiting, reducing or Suppressing In another embodiment, the methods of the present inven muscle protein catabolism due to a muscle wasting disorder; tion comprise administering the compound, in combination and/or treating, preventing, inhibiting, reducing or Suppress with Calcitonin such as salmon, Elcatonin, SUN-8577 or ing end stage renal disease; and/or 6) treating, preventing, TJN-135 for treating osteoporosis. 60 inhibiting, reducing or Suppressing frailty. In another embodiment, the methods of treating osteoporo In another embodiment, the use of a compound for treating sis of the present invention comprise administering the a Subject having a muscle wasting disorder, or any of the SARM compound, in combination with a) vitamin D or disorders described herein, includes administering a pharma derivative such as ZK-156979; b) vitamin D receptor ligand ceutical composition including a compound as herein and analogues such as calcitriol, topitriol, ZK-150123, TEI 65 described. In another embodiment, the administering step 9647, BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299 or includes intravenously, intraarterially, or intramuscularly DP-035; c) estrogen, estrogen derivative, or conjugated estro injecting to said Subject said pharmaceutical composition in US 7,772,433 B2 93 94 liquid form; Subcutaneously implanting in said subject a pel becker muscular dystrophy, limb-girdle muscular dystrophy, let containing said pharmaceutical composition; orally facioscapulhumeral muscular dystrophy, congenital muscu administering to said Subject said pharmaceutical composi lar dystrophy, oculopharyngeal muscular dystrophy, distal tion in a liquid or Solid form; or topically applying to the skin muscular dystrophy and emery-dreifuss muscular dystrophy. Surface of said subject said pharmaceutical composition. Muscular dystrophy can affect people of all ages. Although A muscle is a tissue of the body that primarily functions as Some forms first become apparent in infancy or childhood, a source of power. There are three types of muscles in the others may not appear until middle age or later. Duchenne body: a) skeletal muscle—the muscle responsible for moving MD is the most common form, typically affecting children. extremities and external areas of the bodies; b) cardiac Myotonic dystrophy is the most common of these diseases in muscle—the heart muscle; and c) Smooth muscle—the 10 adults. muscle that is in the walls of arteries and bowel. Muscle atrophy (MA) is characterized by wasting away or A wasting condition or disorder is defined herein as a diminution of muscle and a decrease in muscle mass. For condition or disorder that is characterized, at least in part, by example, Post-Polio MA is a muscle wasting that occurs as an abnormal, progressive loss of body, organ or tissue mass. A part of the post-polio syndrome (PPS). Theatrophy includes wasting condition can occuras a result of a pathology Such as, 15 weakness, muscle fatigue, and pain. for example, cancer, or an infection, or it can be due to a Another type of MA is X-linked spinal-bulbar muscular physiologic or metabolic state, such as disuse deconditioning atrophy (SBMA also known as Kennedy's Disease). This that can occur, for example, due to prolonged bed restor when disease arises from a defect in the androgen receptor gene on a limb is immobilized. Such as in a cast. A wasting condition the X chromosome, affects only males, and its onset is in can also be age associated. The loss of body mass that occurs adulthood. Because the primary disease cause is an androgen during a wasting condition can be characterized by a loss of receptor mutation, androgen replacement is not a current total body weight, or a loss of organ weight Such as a loss of therapeutic strategy. There are some investigational studies bone or muscle mass due to a decrease in tissue protein. where exogenous testosterone propionate is being given to In one embodiment, "muscle wasting or “muscular wast boost the levels of androgen with hopes of overcoming andro ing, used herein interchangeably, refer to the progressive 25 gen insensitivity and perhaps provide an anabolic effect. Still, loss of muscle mass and/or to the progressive weakening and use of Supraphysiological levels of testosterone for Supple degeneration of muscles, including the skeletal or Voluntary mentation will have limitations and other potentially serious muscles which control movement, cardiac muscles which complications. control the heart, and Smooth muscles. In one embodiment, Sarcopenia is a debilitating disease that afflicts the elderly the muscle wasting condition or disorder is a chronic muscle 30 and chronically ill patients and is characterized by loss of wasting condition or disorder. "Chronic muscle wasting is muscle mass and function. Further, increased lean body mass defined hereinas the chronic (i.e. persisting over along period is associated with decreased morbidity and mortality for cer of time) progressive loss of muscle mass and/or to the chronic tain muscle-wasting disorders. In addition, other circum progressive weakening and degeneration of muscle. stances and conditions are linked to, and can cause muscle The loss of muscle mass that occurs during muscle wasting 35 wasting disorders. For example, studies have shown that in can be characterized by a muscle protein breakdown or deg severe cases of chronic lower back pain, there is paraspinal radation, by muscle protein catabolism. Protein catabolism muscle wasting. occurs because of an unusually high rate of protein degrada Muscle wasting and other tissue wasting is also associated tion, an unusually low rate of protein synthesis, or a combi with advanced age. It is believed that general weakness in old nation of both. Protein catabolism or depletion, whether 40 age is due to muscle wasting. As the body ages, an increasing caused by a high degree of protein degradation or a low proportion of skeletal muscle is replaced by fibrous tissue. degree of protein synthesis, leads to a decrease in muscle The result is a significant reduction in muscle power, perfor mass and to muscle wasting. The term “catabolism” has its mance and endurance. commonly known meaning in the art, specifically an energy Long term hospitalization due to illness or injury, or disuse burning form of metabolism. 45 deconditioning that occurs, for example, when a limb is Muscle wasting can occur as a result of a pathology, dis immobilized, can also lead to muscle wasting, or wasting of ease, condition or disorder. In one embodiment, the pathol other tissue. Studies have shown that in patients suffering ogy, illness, disease or condition is chronic. In another injuries, chronic illnesses, burns, trauma or cancer, who are embodiment, the pathology, illness, disease or condition is hospitalized for long periods of time, there is a long-lasting genetic. In another embodiment, the pathology, illness, dis 50 unilateral muscle wasting, and a decrease in body mass. ease or condition is neurological. In another embodiment, the Injuries or damage to the central nervous system (CNS) are pathology, illness, disease or condition is infectious. As also associated with muscle wasting and other wasting disor described herein, the pathologies, diseases, conditions or dis ders. Injuries or damage to the CNS can be, for example, orders for which the compounds and compositions of the caused by diseases, trauma or chemicals. Examples are cen present invention are administered are those that directly or 55 tral nerve injury or damage, peripheral nerve injury or dam indirectly produce a wasting (i.e. loss) of muscle mass, that is age and spinal cord injury or damage. In one embodiment a muscle wasting disorder. CNS damage or injury comprise Alzheimer's diseases (AD): In one embodiment, muscle wasting in a subject is a result anger (mood); anorexia, anorexia nervosa, anorexia associ of the Subject having a muscular dystrophie; muscle atrophy; ated with aging and/or assertiveness (mood). X-linked spinal-bulbar muscular atrophy (SBMA). 60 In another embodiment, muscle wasting or other tissue The muscular dystrophies are genetic diseases character wasting may be a result of alcoholism, and may be treated ized by progressive weakness and degeneration of the skeletal with the compounds and compositions of the invention, rep or Voluntary muscles that control movement. The muscles of resenting embodiments thereof. the heart and some other involuntary muscles are also affected In one embodiment, the invention provides a use of SARM in some forms of muscular dystrophy. The major forms of 65 compound as described herein or its prodrug, analog, isomer, muscular dystrophy (MD) are: duchenne muscular dystro metabolite, derivative, pharmaceutically acceptable salt, phy, myotonic dystrophy, duchenne muscular dystrophy, pharmaceutical product, polymorph, crystal, impurity, N-OX US 7,772,433 B2 95 96 ide, hydrate or any combination thereof for the treatment of a louse-bome, vibrio infections, yaws, versinia infections, wasting disease, disorder or condition in a Subject. Zoonoses, Zygomycosis, acquired immunodeficiency syn In one embodiment, the wasting disease, disorder or con drome, adenoviridae infections, alphavirus infections, arbo dition being treated is associated with chronic illness virus infections, borna disease, bunyaviridae infections, cali This invention is directed to treating, in some embodi civiridae infections, chickenpox, coronaviridae infections, ments, any wasting disorder, which may be reflected in coxsackievirus infections, cytomegalovirus infections, den muscle wasting, weight loss, malnutrition, starvation, or any gue, DNA virus infections, eethyma, contagious, encephali wasting or loss of functioning due to a loss of tissue mass. tis, arbovirus, Epstein-barr virus infections, erythema infec In some embodiments, wasting diseases or disorders, such tiosum, hantavirus infections, hemorrhagic fevers, viral as cachexia; malnutrition, tuberculosis, leprosy, diabetes, 10 hepatitis, viral human herpes simplex, herpes Zoster, herpes renal disease, chronic obstructive pulmonary disease (COPD), cancer, end stage renal failure, sarcopenia, emphy Zoster oticus, herpesviridae infections, infectious mono sema, osteomalacia, or cardiomyopathy, may be treated by nucleosis, human-lassa fever, measles, molluscum, contagio the methods of this invention, via the administration of a Sum, mumps, paramyxoviridae infections, phlebotomus SARM compound as herein described, compositions com 15 fever, polyomavirus infections, rabies, respiratory syncytial prising the same, with or without additional drugs, com virus infections, rift valley fever, RNA virus infections, pounds, or agents, which provide a therapeutic effect for the rubella, slow virus diseases, Smallpox, Subacute Sclerosing condition being treated. panencephalitis, tumor virus infections, warts, west nile In some embodiments, wasting is due to infection with fever, virus diseases, yellow fever, amebiasis, anisakiasis, enterovirus, Epstein-Barr virus, herpes Zoster, HIV, trypano ascariasis, babesiosis, blastocystis hominis infections, bug Somes, influenze, coxsackie, rickettsia, trichinella, schisto bite, cestode infections, chagas disease, cryptosporidiosis, Soma or mycobacteria, and this invention, in Some embodi cyclosporiasis, cysticercosis, dientamoebiasis, diphylloboth ments, provides methods of treatment thereof. riasis, dracunculiasis, echinococcosis, ectoparasitic infesta Cachexia is weakness and a loss of weight caused by a tions, filariasis, giardiasis, helminthiasis, hookworm infec disease or as a side effect of illness. Cardiac cachexia, i.e. a 25 tions, larva migrans, leishmaniasis, lice infestations, loiasis, muscle protein wasting of both the cardiac and skeletal malaria, mite infestations, myiasis, onchocerciasis, proto muscle, is a characteristic of congestive heart failure. Cancer Zoan infections, Scabies, Schistosomiasis, skin diseases, para cachexia is a syndrome that occurs in patients with Solid sitic, strongyloidiasis, taeniasis, toxocariasis, toxoplasmosis, tumors and hematological malignancies and is manifested by trichinosis, trichomonas infections, trypanosomiasis, trypa weight loss with massive depletion of both adipose tissue and 30 nosomiasis, african, or whipworm infections. lean muscle mass. In some embodiments, the present invention provides a Cachexia is also seen in acquired immunodeficiency syn method for treating, reducing the incidence, delaying the drome (AIDS), human immunodeficiency virus (HIV)-asso onset or progression, or reducing and/or abrogating the Symp ciated myopathy and/or muscle weakness/wasting is a rela toms associated with a musculoskeletal disease in a Subject. tively common clinical manifestation of AIDS. Individuals 35 In one embodiment, the method comprises administering to a with HIV-associated myopathy or muscle weakness or wast Subject a composition comprising a compound and an anti ing typically experience significant weight loss, generalized cancer agent, an immunomodulating agent, an antidiabetic or proximal muscle weakness, tenderness, and muscle atro agent, an agent treating the central nervous system, an agent phy. treating a metabolic disease, an agent treating a wasting dis In some embodiments, the present invention provides a 40 ease, a gene therapy agent, an agent treating the endocrine method for treating, reducing the incidence, delaying the system, Vitamins, or a combination thereof. In some embodi onset or progression, or reducing and/or abrogating the Symp ments, musculoskeletal diseases comprise achondroplasia, toms associated with an infection in a subject. In one embodi acquired hyperostosis syndrome, acrocephaloSyndactylia, ment, the method comprises administering to a subject a arthritis, arthrogryposis, arthropathy, neurogenic bursitis, composition comprising a compound and an immunomodu 45 cartilage diseases, cleidocranial dysplasia, clubfoot, com lating agent, an anti-infective agent, a gene therapy agent, or partment syndromes, craniofacial dysostosis, craniosynos a combination thereof. In some embodiments, infections toses, dermatomyositis, Dupuytren’s contracture, dwarfism, comprise actinomycosis, anaplasmosis, anthrax, aspergillo Ellis Van Creveld syndrome, enchondromatosis, eosino sis, bacteremia, bacterial mycoses, bartonella infections, philia-myalgia syndrome, exostoses, fasciitis, fatigue syn botulism, brucellosis, burkholderia infections, campylo 50 drome, fibromyalgia, fibrous dysplasia of bone, fibrous dys bacter infections, candidiasis, cat-scratch disease, chlamydia plasia, polyostotic, flatfoot, foot deformities, Freiberg's infections, cholera, clostridium infections, coccidioidomyco disease, funnel chest, Goldenhar syndrome, gout, hallux Val sis, cross infection, cryptococcosis, dermatomycoses, diph gus, hip dislocation, hyperostosis, intervertebral disk dis theria, ehrlichiosis, Escherichia coli infections, fasciitis, placement, kabuki make-up syndrome, Klippel-Feil Syn necrotizing, Fusobacterium infections, gas gangrene, gram 55 drome, Langer-Giedion syndrome, Legg-Perthes disease, negative bacterial infections, gram-positive bacterial infec lordosis, mandibulofacial dysostosis, melorheostosis, mito tions, histoplasmosis, impetigo, Klebsiella infections, legion chondrial myopathies, muscle cramp, muscle spasticity, mus ellosis, leprosy, leptospirosis, Listeria infections, lyme cular dystrophies, musculoskeletal abnormalities, muscu disease, maduromycosis, melioidosis, mycobacterium infec loskeletal diseases, myositis, myositis ossificans, myotubular tions, mycoplasma infections, mycoses, nocardia infections, 60 myopathy, osteitis deformans, osteoarthritis, osteochondritis, onychomycosis, plague, pneumococcal infections, osteogenesis imperfecta, osteomyelitis, osteonecrosis, osteo pseudomonas infections, psittacosis, q fever, rat-bite fever, petrosis, osteoporosis, poland syndrome, polychondritis, relapsing fever, rheumatic fever, Rickettsia infections, rocky relapsing, polymyalgia rheumatica, polymyositis, rhab mountain spotted fever, salmonella infections, Scarlet fever, domyolysis, rheumatic diseases, Russell silver syndrome, scrub typhus, sepsis, sexually transmitted diseases, Staphy 65 Scheuermann's disease, Scoliosis, Sever's disease/calceneal lococcal infections, Streptococcal infections, tetanus, tick apophysitis, spinal diseases, spinal osteophytosis, spinal bome diseases, tuberculosis, tularemia, typhoid fever, typhus, Stenosis, spondylitis, ankylosing, spondylolisthesis, Spren US 7,772,433 B2 97 98 gel's deformity, synovitis, tendinopathy, tennis elbow, teno tis obliterans organizing pneumonia, bronchitis, bronchopul synovitis, thanatophoric dysplasia, or Tietze's syndrome. monary dysplasia, chronic obstructive pulmonary disease In some embodiments, the present invention provides a (COPD), common cold, cough, empyema, pleural, epiglotti method for treating, reducing the incidence, delaying the tis, glucocorticoid (GC)-induced myopathy or osteopenia onset or progression, or reducing and/or abrogating the Symp hemoptysis, hypertension, pulmonary, hyperventilation, toms associated with a digestive system disease in a subject. kartagener syndrome, lung abscess, lung diseases, meconium In one embodiment, the method comprises administering to a aspiration syndrome, pleural effusion, pleurisy, pneumonia, Subject a composition comprising a compound and an anti pneumothorax, pulmonary alveolar proteinosis, pulmonary cancer agent, an immunomodulating agent, an antidiabetic disease, chronic obstructive, pulmonary edema, pulmonary agent, an agent treating the central nervous system, an agent 10 embolism, pulmonary emphysema, pulmonary fibrosis, res treating the gastrointestinal system, an anti-infective agent, piratory distress syndrome, newborn-respiratory hypersensi an agent treating a metabolic disease, a genetherapy agent, an tivity, respiratory tract infections, rhinoscleroma, Scimitar agent treating the endocrine system, Vitamins, or a combina syndrome, severe acute respiratory syndrome, silicosis, sleep tion thereof. In some embodiments, gastrointestinal diseases apnea, central stridor, tracheal Stenosis, decreased muscle comprise adenomatous polyposis coli, Alagile syndrome, 15 mass or bone mass due to asthma, wasting in chronic obstruc anus diseases, appendicitis, barrett esophagus, biliary atresia, tive pulmonary disease (COPD), Wegener's granulomatosis, biliary tract diseases, Caroli disease, celiac disease, cholan or whooping cough. gitis, cholecystitis, cholelithiasis, colitis, ulcerative, Crohn's In some embodiments, the present invention provides a disease, deglutition disorders, duodenal ulcer, dysentery, method for treating, reducing the incidence, delaying the enterocolitis, pseudomembranous, esophageal achalasia, onset or progression, or reducing and/or abrogating the Symp esophageal atresia, esophagitis, exocrine pancreatic insuffi toms associated with an otorhinolaryngologic disease in a ciency, fatty liver, fecal incontinence, gastritis, gastritis, Subject. In one embodiment, the method comprises adminis hypertrophic, gastroenteritis, gastroesophageal reflux, gas tering to a subject a composition comprising a compound and troparesis, hemorrhoids, hepatic vein thrombosis, hepatitis, an anti-cancer agent, an immunomodulating agent, an anti hepatitis, chronic, hernia, diaphragmatic, hernia, hiatal, Hir 25 infective agent, an agent treating a wasting disease, a gene schsprung disease, hypertension (HTN), portal, inflamma therapy agent, an agent treating the endocrine system, Vita tory bowel diseases, intestinal diseases, intestinal neoplasms, mins, or a combination thereof. In some embodiments, intestinal neuronal dysplasia, intestinal obstruction, irritable otorhinolaryngologic diseases comprise cholesteatoma, bowel syndrome, lactose intolerance, liver cirrhosis, liver middle ear, croup, deafness, epistaxis, hearing loss, hypera diseases, meckel diverticulum, pancreatic diseases, pancre 30 cusis, labyrinthitis, laryngitis, laryngomalacia, laryngosteno atic neoplasms, pancreatitis, peptic ulcer, Peutz-Jeghers Syn sis, mastoiditis, Meniere's disease, nasal obstruction, nasal drome, proctitis, rectal diseases, rectal prolapse, short bowel polyps, otitis, otorhinolaryngologic diseases, otoScierosis, syndrome, tracheoesophageal fistula, whipple disease, or pharyngitis, presbycusis, retropharyngeal abscess, rhinitis, Zollinger-Ellison syndrome. sinusitis, tinnitus, tonsillitis, tympanic membrane perfora In some embodiments, the present invention provides a 35 tion, Vestibular neuronitis, Vocal cord paralysis, or Voice dis method for treating, reducing the incidence, delaying the orders. onset or progression, or reducing and/or abrogating the Symp In some embodiments, the present invention provides a toms associated with a stomatognathic disease in a subject. In method for treating, reducing the incidence, delaying the one embodiment, the method comprises administering to a onset or progression, or reducing and/or abrogating the Symp Subject a composition comprising a compound and an anti 40 toms associated with a nervous system disease in a Subject. In cancer agent, an immunomodulating agent, an anti-infective one embodiment, the method comprises administering to a agent, an agent treating a wasting disease, a gene therapy Subject a composition comprising a compound and an anti agent, an agent treating the endocrine system, Vitamins, or a cancer agent, an immunomodulating agent, an agent treating combination thereof. In some embodiments, stomatognathic the central nervous system, an anti-infective agent, an agent diseases comprise ankyloglossia, bruxism, burning mouth 45 treating a metabolic disease, an agent treating a wasting dis syndrome, cheilitis, cherubism, cleft lip, dentigerous cyst, ease, a gene therapy agent, an agent treating the endocrine gingivitis, glossitis, benign migratory, herpes labialis, Lud system, Vitamins, or a combination thereof. In some embodi wigs angina, macroglossia, Melkersson-Rosenthal Syn ments, nervous system diseases comprise autonomic nervous drome, periodontal diseases, Pierre Robin syndrome, prog system diseases, central nervous system diseases, cranial nathism, salivary gland diseases, sialorrhea, stomatitis, 50 nerve diseases, demyelinating diseases, nervous system mal aphthous, temporomandibular joint disorders, temporoman formations, neurologic manifestations, or neuromuscular dis dibular joint dysfunction syndrome, or Xerostomia. CaSCS. In some embodiments, the present invention provides a In Some embodiments, autonomic nervous system diseases method for treating, reducing the incidence, delaying the comprise causalgia, or reflex sympathetic dystrophy. onset or progression, or reducing and/or abrogating the Symp 55 In some embodiments, central nervous system diseases toms associated with a respiratory tract disease in a Subject. In comprise Alzheimer's disease, arachnoiditis, brain abscess, one embodiment, the method comprises administering to a brain ischemia, central nervous system infections, cerebral Subject a composition comprising a compound and an anti palsy, cerebrovascular disorders, corticobasal ganglionic cancer agent, an immunomodulating agent, an agent treating degeneration (CBGD), Creutzfeldt-Jakob syndrome, Dandy the central nervous system, an agent treating the cardiovas 60 Walker syndrome, dementia, encephalitis, encephalomyeli cular system, an anti-infective agent, an agent treating a wast tis, epilepsy, epilepsy induced hypogonadal and/or hyper ing disease, a gene therapy agent, an agent treating the endo metabolic state, essential tremor, Friedreich ataxia, crine system, vitamins, or a combination thereof. In some Gerstmann-Straussler-Scheinker disease, Hallervorden embodiments, respiratory tract diseases comprise airway Spatz syndrome, Huntington disease, hydrocephalus, obstruction, apnea, asbestosis, asthma, asthma-induced 65 hypoxia, insomnia, ischemic attack, kuru, Landau-Kleffner muscle weakness or bone weakness, atelectasis, berylliosis, syndrome, Lewy Body disease, Machado-Joseph disease, bronchial diseases, bronchiectasis, bronchiolitis, bronchioli meige syndrome, meningitis, bacterial meningitis, viral, US 7,772,433 B2 99 100 migraine disorders, movement disorders, multiple system cord injury, may be accompanied by treatment of the Subject atrophy, myelitis, olivopontocerebellar atrophies, Parkin with electrical stimulation of the injured site and the admin son's disease, parkinsonian disorders, poliomyelitis, postpo istration of a purine nucleoside, or analog thereof, for liomyelitis syndrome, prion diseases, pseudotumor cerebri, example as described in United States Patent Application Shy-Drager syndrome, spasms, infantile, spinal cord dis Publication Number 20040214790A1. eases, Supranuclear palsy, Syringomyelia, thalamic diseases, In some embodiments, demyelinating diseases comprise tic disorders, tourette syndrome, or uveomeningoencephal adrenoleukodystrophy, alexander disease, canavan disease, itic syndrome. In some embodiments, the central nervous demyelinating disease, diffuse cerebral sclerosis of Schilder, system disease is cystic fibrosis induced hypogonadal state. leukodystrophy-globoid cell, leukodystrophy-metachro In some embodiments, cranial nerve diseases comprise bell 10 matic, multiple Sclerosis, or neuromyelitis optica. palsy, cranial nerve diseases, facial hemiatrophy, facial neu In some embodiments, nervous system malformations ralgia, glossopharyngeal nerve diseases, Moebius syndrome, comprise Arnold-Chiari malformation, Charcot-Marie-Tooth or trigeminal neuralgia. disease, encephalocele, hereditary motor and sensory neuro In some embodiments, central nervous system diseases pathies, septo-optic dysplasia, spina bifida occulta, or spinal comprise injuries or damage to the central nervous system 15 dySraphism. (CNS). In some embodiments, injuries or damage to the CNS In some embodiments, neurologic manifestations com may be associated with muscle wasting disorders. Injuries or prise agnosia, amnesia, anomia, aphasia, apraxias, back pain, damage to the CNS can be, for example, caused by diseases, Brown-Sequard syndrome, cerebellar ataxia, chorea, com trauma or chemicals. Examples are central nerve injury or munication disorders, confusion, dizziness, dyslexia, dysto damage, peripheral nerve injury or damage and spinal cord nia, facial paralysis, fasciculation, gait disorders, neurologic injury or damage. headache, hemiplegia, memory disorders, mental retardation, Studies involving patients with spinal cord injuries (SCI) mutism, myoclonus, neck pain, nonverbal learning disorder, have shown that central neurotransmitters may be altered olfaction disorders, pain, paralysis, phantom limb, prosopag after SCI causing hypothalamus-pituitary-adrenal axis dys nosia, quadriplegia, seizures, spasm, speech disorders, Syn function, whose disruption led to a significant decrease in 25 esthesia tardive dyskinesia, taste disorders, torticollis, tremor, testosterone and other hormone levels. SCI or other acute trismus, unconsciousness, or vertigo. illness or trauma characteristically includes heightened In some embodiments, neuromuscular diseases comprise. catabolism in conjunction with the lowered anabolic activity amyotrophic lateral Sclerosis, brachial plexus neuritis, bra resulting in a condition that is prone to loss of lean body chial plexus neuropathies, bulbar palsy, carpal tunnel Syn tissue, which is often accompanied by disturbed nutrient uti 30 drome, cubital tunnel syndrome, diabetic neuropathies, dys lization. The effects of the loss of lean body mass include the autonomia, guillain, barre Syndrome, hereditary sensory and development of wounds and impaired healing mechanisms, autonomic neuropathies, miller fisher syndrome, motor neu further compounding the problem. Because of poor nutrition ron disease, muscular atrophy, spinal, myasthenia gravis, and protein combined with immobilization, patients with spi myopathies, structural, congenital, nerve compression syn nal cord injury are at high risk for bed Sores. 35 dromes, neuralgia, neuromuscular diseases, paralyses, famil In one embodiment, a wide variety of injuries of the CNS ial periodic, peripheral nervous system diseases, poems Syn may be treated by the methods of the present invention. CNS drome, polyneuropathies, polyradiculopathy, refsum disease, injury may refer, in one embodiment, to a breakdown of the sciatica, spinal muscular atrophies of childhood, stiff-person membrane of a nerve cell, or, in another embodiment, to the syndrome, thoracic outlet syndrome, or ulnar nerve compres inability of the nerve to produce and propagate nerve 40 sion syndromes. impulses, or in another embodiment, to the death of the cell. In one embodiment, methods of treating a Subject with a An injury includes damage that directly or indirectly affects nervous system disease encompass treating any secondary the normal functioning of the CNS. The injury may be a conditions in the subject, which arise due to the subject hav structural, physical, or mechanical impairment and may be ing a nervous system disease, some of which are described caused by physical impact, as in the case of a crushing, 45 herein. compression, or stretching of nerve fibers. Alternatively, the In some embodiments, the present invention provides a cell membrane may be destroyed by or degraded by an illness, method for treating, reducing the incidence, delaying the a chemical imbalance, or a physiological malfunction Such as onset or progression, or reducing and/or abrogating the Symp anoxia (e.g., stroke), aneurysm, or reperfusion. A CNS injury toms associated with an ophthalmic disease in a subject. In includes, for example and without limitation, damage to reti 50 one embodiment, the method comprises administering to a nal ganglion cells, a traumatic brain injury, a stroke-related Subject a composition comprising a compound and an anti injury, a cerebral aneurism-related injury, a spinal cord injury, cancer agent, an immunomodulating agent, an agent treating including monoplegia, diplegia, paraplegia, hemiplegia and the cardiovascular system, an anti-infective agent, an agent quadriplegia, a neuroproliferative disorder, or neuropathic treating a wasting disease, a gene therapy agent, an agent pain syndrome. 55 treating the endocrine system, vitamins, or a combination With injury to the spinal cord of a mammal, connections thereof. In some embodiments ophthalmic disease comprise between nerves in the spinal cord are broken. Such injuries acute Zonal occult outer retinopathy, Adie syndrome, albi block the flow of nerve impulses for the nerve tracts affected nism, ocular-amaurosis, fugax, amblyopia, aniridia, anisoco by the injury, with a resulting impairment to both sensory and ria, anopthalmos, aphakia, astigmatism, blepharitis, ble motor function. Injuries to the spinal cord may arise from 60 pharoptosis, blepharospasm, blindness, cataract, chalazion, compression or other contusion of the spinal cord, or a crush chorioretinitis, choroideremia, coloboma, color vision ing or severing of the spinal cord. A severing of the spinal defects, conjunctivitis, corneal diseases, corneal dystrophies, cord, also referred to herein as a “transection.” may be a corneal edema, corneal ulcer, diabetic retinopathy, diplopia, complete severing or, may be an incomplete severing of the distichiasis, dry eye syndromes, Duane retraction syndrome, spinal cord. 65 ectropion, entropion, esotropia, exfoliation syndrome, In some embodiments, the methods of treating a subject exotropia, eye hemorrhage, eye neoplasms, eyelid diseases, suffering form a CNS injury or, in other embodiments, spinal floaters, general fibrosis syndrome, glaucoma, gyrate atro US 7,772,433 B2 101 102 phy, hemianopsia, Henmanski-Pudlak syndrome, eczema, epidermolysis bullosa, erysipelas, erythroderma, hordeolum, Horner syndrome, hyperopia, hyphema, iritis, friction blister, genital wart, hidradenitis, Suppurativa, hives, Kearns-Sayer syndrome, keratitis, keratoconus, lacrimal hyperhidrosis, ichthyosis, impetigo, jock itch, Kaposi’s Sar apparatus diseases, lacrimal duct obstruction, lens diseases, coma, keloid, keratoacanthoma, keratosis pilaris, lice infec macular degeneration, micropthalmos, myopia, nystagmus, tion, lichen planus, lichen simplex chronicus, lipoma, lym pathologic, ocular motility disorders, oculomotor nerve dis phadenitis, malignant melanoma, melasma, miliaria, eases, opthalmoplegia, optic atrophies, optic nerve diseases, molluscum contagiosum, nummular dermatitis, paget’s dis optic neuritis, optic neuropathy, orbital cellulitis, papille ease of the nipple, pediculosis, pemphigus, perioral dermati dema, peter's anomaly, presbyopia, pterygium, pupil disor tis, photoallergy, photosensitivity, pityriasis rosea, pityriasis ders, refractive errors, retinal detachment, retinal diseases, 10 rubra pilaris, psoriasis, raynaud's disease, ring worm, rosa retinal vein occlusion, retinitis pigmentosa, retinopathy of cea, scabies, Scleroderma, sebaceous cyst, Seborrheic kerato prematurity, retinoschisis, Scleritis, Scotoma, Strabismus, sis, Seborrhoeic dermatitis, shingles, skin cancer, skin tags, Thygeson's Superficial punctate keratitis, trachoma, uveitis, spider veins, squamous cell carcinoma, stasis dermatitis, tick white dot syndrome, vision disorders, or vitreous disorders bite, tinea barbae, tinea capitis, tinea corporis, tinea cruris, In some embodiments, the present invention provides a 15 tinea pedis, tinea unguium, tinea versicolor, tinea, tungiasis, method for treating, reducing the incidence, delaying the vitiligo, or warts. onset or progression, or reducing and/or abrogating the Symp In one embodiment, the dermatological disorder is a toms associated with an urologic and/or male genital disease wound or a burn. In some embodiments, wounds and/or in a subject. In one embodiment, the method comprises ulcers are found protruding from the skin or on a mucosal administering to a Subject a composition comprising a com Surface or as a result of an infarction in an organ. A wound pound and an anti-cancer agent, an immunomodulating may be a result of a soft tissue defect or a lesion or of an agent, an antidiabetic agent, an agent treating the gastrointes underlying condition. In one embodiment, the term “wound tinal system, an anti-infective agent, an agent treating the denotes a bodily injury with disruption of the normal integrity kidney, an agent treating a metabolic disease, an agent treat of tissue structures. The term is also intended to encompass ing a wasting disease, a gene therapy agent, an agent treating 25 the terms "sore”, “lesion”, “necrosis' and “ulcer. In one the endocrine system, vitamins, or a combination thereof. In embodiment, the term "sore refers to any lesion of the skin or Some embodiments, an urologic and/or male genital diseases mucous membranes and the term “ulcer refers to a local comprise anti-glomerular basement membrane disease, bal defect, or excavation, of the Surface of an organ or tissue, anitis, bladder exstrophy, bladder neoplasms, cryptorchid which is produced by the sloughing of necrotic tissue. Lesion ism, cystitis, interstitial, diabetes insipidus, nephrogenic, epi 30 generally relates to any tissue defect. Necrosis is related to didymitis, fournier gangrene, glomerulonephritis, dead tissue resulting from infection, injury, inflammation or Goodpasture syndrome, hematospermia, hematuria, infarctions. All of these are encompassed by the term hemolytic-uremic syndrome, hydronephrosis, hypospadias, “wound', which denotes any wound at any particular stage in impotence, infertility, kidney calculi, kidney failure, acute, the healing process including the stage before any healing has kidney failure, chronic, kidney tubular necrosis, acute, med 35 initiated or even before a specific wound like a Surgical inci ullary sponge kidney, multicystic dysplastic kidney, nephri sion is made (prophylactic treatment). tis, hereditary, nephrosis, nephrotic syndrome, nocturia, olig Examples of wounds which can be prevented and/or uria, penile diseases, penile induration, penile neoplasms, treated in accordance with the present invention are, e.g., phimosis, priapism, prostatic diseases, benign prostate hyper aseptic wounds, contused wounds, incised wounds, lacerated plasia, prostatic neoplasms, proteinuria, pyelonephritis, 40 wounds, non-penetrating wounds (i.e. wounds in which there Reiter disease, renal artery obstruction, spermatic cord tor is no disruption of the skin but there is injury to underlying Sion, testicular diseases, urethral stricture, urethritis, urinary structures), open wounds, penetrating wounds, perforating retention, urinary tract infections, urination disorders, uro wounds, puncture wounds, septic wounds, Subcutaneous logic and male genital diseases, urologic diseases, varicocele, wounds, etc. Examples of Sores are bed Sores, canker Sores, vesico, or urethral reflux. 45 chrome Sores, cold Sores, pressure Sores etc. Examples of In some embodiments, the present invention provides a ulcers are, e.g., peptic ulcer, duodenal ulcer, gastric ulcer, method for treating, reducing the incidence, delaying the gouty ulcer, diabetic ulcer, hypertensive ischemic ulcer, Stasis onset or progression, or reducing and/or abrogating the Symp ulcer, ulcus cruris (venous ulcer). Sublingual ulcer, Submu toms associated with a dermatological disorder in a subject. cous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer, In one embodiment, the method comprises administering to a 50 Veneral ulcer, e.g. caused by gonorrhoea (including urethritis, Subject a composition comprising a compound and anti-can endocerviciitis and proctitis). Conditions related to wounds or cer agent, an immunomodulating agent, an agent treating a Sores which may be successfully treated according to the dermatological disorder, an anti-infective agent, a gene invention are burns, anthrax, tetanus, gas gangrene, Scalatina, therapy agent, an agent treating the endocrine system, Vita erysipelas, Sycosis barbae, folliculitis, impetigo contagiosa, mins, or a combination thereof. In some embodiments, der 55 or impetigo bullosa, etc. There is often a certain overlap matological disorders comprise acne, actinic keratosis, alope between the use of the terms “wound' and “ulcer and cia, androgenic alopecia, alopecia greata, alopecia secondary “wound' and "sore' and, furthermore, the terms are often to chemotherapy, alopecia secondary to radiation therapy, used at random. Therefore as mentioned above, in the present alopecia induced by Scarring, alopecia induced by stress, context the term “wounds’ encompasses the term “ulcer, angioma, athlete's foot, aquagenic pruritus, atopic dermatitis, 60 “lesion', 'sore' and “infarction', and the terms are indis baldness, premature baldness, male pattern baldness, andro criminately used unless otherwise indicated. genic baldness, basal cell carcinoma, burns, bed sore, Beh The kinds of wounds to be treated according to the inven cet’s disease, blepharitis, boil, Bowen's disease, bullous pem tion include also i) general wounds such as, e.g., Surgical, phigoid, canker Sore, carbuncles, cellulitis, chloracne, traumatic, infectious, ischemic, thermal, chemical and chronic dermatitis of the hands and feet, dyshidrosis, cold 65 bullous wounds; ii) wounds specific for the oral cavity such Sores, contact dermatitis, creeping eruption, dandruff, derma as, e.g., post-extraction wounds, endodontic wounds espe titis, dermatitis herpetiformis, dermatofibroma, diaper rash, cially in connection with treatment of cysts and abscesses, US 7,772,433 B2 103 104 ulcers and lesions of bacterial, viral or autoimmunological The term “skin' is used in a very broad sense embracing the origin, mechanical, chemical, thermal, infectious and epidermal layer of the skin and in those cases where the skin lichenoid wounds; herpes ulcers, stomatitis aphthosa, acute surface is more or less injured also the dermal layer of the necrotising ulcerative gingivitis and burning mouth Syn skin. Apart from the stratum corneum, the epidermal layer of drome are specific examples; and iii) wounds on the skin Such 5 the skin is the outer (epithelial) layer and the deeper connec as, e.g., neoplasm, burns (e.g. chemical, thermal), lesions tive tissue layer of the skin is called the dermis. (bacterial, viral, autoimmunological), bites and Surgical inci In some embodiments, burns are associated with reduced sions. Another way of classifying wounds is as i) Small tissue testosterone levels, and hypgonadism is associated with loss due to Surgical incisions, minor abrasions and minor delayed wound healing. In one embodiment, the methods of bites, or as ii) significant tissue loss. The latter group includes 10 this invention, provide for treating a Subject suffering from a ischemic ulcers, pressure Sores, fistulae, lacerations, severe wound or a burn. bites, thermal burns and donor site wounds (in soft and hard In some embodiments, the present invention provides a tissues) and infarctions. method for prooting healing of anterior cruciate ligament In other aspects of the invention, the wound to be prevented (ACL) or medial cruciate ligament (MCL) injuries, or accel and/or treated is selected from the group consisting of aseptic 15 erating recovery after ACL or MCL surgery. wounds, infarctions, contused wounds, incised wounds, lac In some embodiments, the present invention provides a erated wounds, non-penetrating wounds, open wounds, pen method for treating, reducing the incidence, delaying the etrating wounds, perforating wounds, puncture wounds, sep onset or progression, or reducing and/or abrogating the Symp tic wounds and Subcutaneous wounds. toms associated with an endocrine disorder in a Subject. In one embodiment, the method comprises administering to a Other wounds which are of importance in connection with Subject a composition comprising a compound and anti-can the present invention are wounds like ischemic ulcers, pres cer agent, an immunomodulating agent, an antidiabetic agent, Sure Sores, fistulae, severe bites, thermal burns and donor site an agent treating the cardiovascular system, an agent treating wounds. the gastrointestinal system, an agent treating a dermatologi In one embodiment, the compound as described herein is 25 cal disorder, an agent treating the central nervous system, an useful in wound healing as an adjunct to physical therapy/ anti-infective agent, an agent treating the liver, an agent treat rehabilitation, as an anabolic agent. In another embodiment, ing the kidney, an agent treating a metabolic disease, an agent the compound as described herein is useful in promoting treating a wasting disease, a gene therapy agent, an agent healing of anterior cruciate ligament (ACL) or medial cruci ate ligament (MCL) injuries, or accelerating recovery after treating the endocrine system, vitamins, or a combination 30 thereof. In some embodiments, endocrine disorders comprise ACL or MCL surgery. In another embodiment, the compound acromegaly, Addison disease, adrenal gland diseases, adrenal as described herein is useful in enhancing athletic perfor hyperplasia, congenital, androgen-insensitivity Syndrome, mance. In another embodiment, the compound as described congenital hypothyroidism, Cushing syndrome, diabetes herein is useful in treating burns. In another embodiment, the insipidus, diabetes mellitus, diabetes mellitus-type 1, diabe compound as described herein is useful in Stimulating carti 35 tes mellitus-type 2, diabetic, ketoacidosis, empty Sella syn lage regrowth. In another embodiment, the compound as drome, endocrine gland neoplasms, endocrine system dis described herein is useful in preventing, treating, or reversing eases, gigantism, gonadal disorders, graves disease, of catabolism associated with prolonged critical illness, pull hermaphroditism, hyperaldosteronism, hyperglycemic monary dysfunction, ventilator dependency, aging, AIDS, hyperosmolar nonketotic coma, hyperpituitarism, hyperpro trauma, Surgery, congestive heart failure, cardiac myopathy, 40 lactinemia, hyperthyroidism, hypogonadism, hypopituitar burns, cancer, COPD. In another embodiment, the compound ism, hypothyroidism, Kallmann syndrome, Nelson Syn as described herein is useful in preventing or reversing protein drome, parathyroid diseases, pituitary diseases, catabolism due to trauma. In another embodiment, the com polyendocrinopathies, autoimmune, puberty, delayed, pound as described herein is useful as a) adjunct to cauteriza puberty, precocious, renal osteodystrophy, thyroid diseases, tion therapy (laser or radio) as is used in Surgery to promote 45 thyroid hormone resistance syndrome, thyroid neoplasms, wound healing, b) adjunct to cryotherapy to promote wound thyroid nodule, thyroiditis, thyroiditis, autoimmune, thy healing, c) adjunct to chemotherapy to prevent side effects roiditis, subacute, or Wolfram syndrome. Such as alopecia, hypogonadism, muscle wasting, osteopenia, In one embodiment, "Hypogonadism’ is a condition osteoporosis, sarcopenia, increased LDL, TG or total choles resulting from or characterised by abnormally decreased terol, decreased HDL. In another embodiment, the compound 50 functional activity of the gonads, with retardation of growth as described herein is useful in chronic catabolic state (coma, and sexual development. wasting conditions, starvation, eating disorders); concomi In some embodiments, the present invention provides a tant bone fracture and muscle damage; critical illness in method for treating, reducing the incidence, delaying the which muscle or bone wasting are apparent; and/or connec onset or progression, or reducing and/or abrogating the Symp tive tissue diseases and disorders. 55 toms associated with urogenital disease and/or fertility in a Ischemic ulcers and pressure Sores are wounds, which nor Subject. In one embodiment, the method comprises adminis mally only heal very slowly and especially in Such cases an tering to a Subject a composition comprising a compound of improved and more rapid healing is of course of great impor this invention and anti-cancer agent, an immunomodulating tance for the patient. Furthermore, the costs involved in the agent, an anti-infective agent, an agent treating the kidney, treatment of patients suffering from Such wounds are mark 60 gene therapy agent, an agent treating the endocrine system, edly reduced when the healing is improved and takes place Vitamins, or a combination thereof. In some embodiments, more rapidly. urogenital diseases and/or fertility diseases comprise abor Donor site wounds are wounds which e.g. occur in connec tion, spontaneous-adhesions-pelvic, candidiasis, Vulvovagi tion with removal of hard tissue from one part of the body to nal, depression-postpartum, diabetes, gestational, dyspareu another part of the body e.g. in connection with transplanta 65 nia, dystocia, eclampsia, endometriosis, fetal death, fetal tion. The wounds resulting from Such operations are very growth retardation, fetal membranes, premature rupture, painful and an improved healing is therefore most valuable. genital diseases, female, genital neoplasms, female, hydatidi US 7,772,433 B2 105 106 form mole, hyperemesis gravidarum, infertility, ovarian nevus syndrome. Beckwith-Wiedemann syndrome, bloom cysts, ovarian torsion, pelvic inflammatory disease, placenta syndrome, branchio-oto-renal syndrome, cat eye syndrome, diseases, placental insufficiency, polycystic ovary syndrome, cerebral gigantism-charge syndrome, chromosome 16 abnor polyhydramnios, postpartum hemorrhage, pregnancy com malities, chromosome 18 abnormalities, chromosome 20 plications, pregnancy, ectopic, pruritus Vulvae, puerperal dis abnormalities, chromosome 22 abnormalities, Costello Syn orders, puerperal infection, Salpingitis, trophoblastic neo drome, cri-du-chat syndrome, Currarino syndrome, cystic plasms, uterine cervix incompetence, uterine inversion, fibrosis, de-Lange syndrome, distal trisomy 10q, down Syn uterine prolapse, vaginal diseases, Vulvar diseases, Vulvar drome, ectodermal dysplasia, fetal alcohol syndrome, fetal lichen Sclerosis. diseases, fetofetal transfusion, fragile X syndrome, Freeman In some embodiments, the present invention provides a 10 Sheldon syndrome, gastroschisis, genetic diseases, inborn, method for treating, reducing the incidence, delaying the hernia, umbilical, holoprosencephaly, incontinentia pig onset or progression, or reducing and/or abrogating the Symp menti, Ivemark syndrome, Jacobsen syndrome, jaundice, toms associated with hemic and/or lymphatic disease in a Klinefelter syndrome, Larsen syndrome, Laurence-moon Subject. In one embodiment, the method comprises adminis syndrome, lissencephaly, microcephaly, monosomy 9p, nail tering to a Subject a composition comprising a compound of 15 patella syndrome, neurofibromatoses, neuronal ceroid-lipo this invention and an anti-cancer agent, an immunomodulat fuscinosis, Noonan syndrome, ochoa syndrome (urofacial ing agent, an antidiabetic agent, an agent treating the cardio syndrome, hydronephrosis with peculiar facial expression), vascular system, an anti-infective agent, an agent treating the oculocerebrorenal syndrome, Pallister-Killian syndrome, liver, an agent treating the kidney, an agent treating a meta Prader-Willi syndrome, proteus syndrome, prune belly syn bolic disease, a gene therapy agent, an agent treating the drome, Rett syndrome, Robinow syndrome, Rubinstein endocrine system, vitamins, or a combination thereof. In Taybi syndrome, Schizencephaly, situs inversus, Smith Some embodiments, hemic and/or lymphatic diseases com Lemli-Opitz syndrome, Smith-Magenis Syndrome, Sturge prise afibrinogenemia, anemia, aplastic anemia, hemolytic Weber syndrome, syphilis, congenital, trichothiodystrophy, anemia, congenital nonspherocytic anemia, megaloblastic triple-X females, trisomy 13 (Patau syndrome), trisomy 9, anemia, pernicious anemia, sickle cell anemia, renal anemia, 25 turner syndrome, twins, conjoined, Usher syndrome, angiolymphoid hyperplasia with eosinophilia, antithrombin Waardenburg's syndrome, Werner syndrome, or Wolf-Hir III deficiency, Bernard-Soulier syndrome, blood coagulation schhorn syndrome. disorders, blood platelet disorders, blue rubber bleb nevus In some embodiments, the present invention provides a syndrome, Chediak-Higashi syndrome, cryoglobulinemia, method for treating, reducing the incidence, delaying the disseminated intravascular coagulation, eosinophilia, Erd 30 onset or progression, or reducing and/or abrogating the Symp heim-Chester disease, erythroblastosis, fetal, evans Syn toms associated with a connective tissue disease in a Subject. drome, factor V deficiency, factor VII deficiency, factor X In one embodiment, the method comprises administering to a deficiency, factor XI deficiency, factor XII deficiency, fanconi Subject a composition comprising a compound of this inven anemia, giantlymph node hyperplasia, hematologic diseases, tion and anti-cancer agent, an immunomodulating agent, an hemoglobinopathies, hemoglobinuria, paroxysmal, hemo 35 agent treating a dermatological disorder, an anti-infective philia a, hemophiliab, hemorrhagic disease of newborn, his agent, an agent treating a metabolic disease, an agent treating tiocytosis, histiocytosis, langerhans-cell, histiocytosis, non a wasting disease, a gene therapy agent, an agent treating the langerhans-cell, jobs syndrome, leukopenia, lymphadenitis, endocrine system, Vitamins, or a combination thereof. In lymphangioleiomyomatosis, lymphedema, methemoglobin Some embodiments, connective tissue diseases comprise emia, myelodysplastic syndromes, myelofibrosis, myeloid 40 ankylosing spondylitis, Ehlers-Danlos Syndrome, Henoch metaplasia, myeloproliferative disorders, neutropenia, para Schonlein purpura, Kawasaki disease, Marfan syndrome, proteinemias, platelet storage pool deficiency, polycythemia polyarteritis nodosa, polymyositis, psoriatic arthritis, reac Vera, protein c deficiency, protein S deficiency, purpura, tive arthritis, rheumatoid arthritis, Scleroderma, Sjogren's thrombocytopenic, purpura, thrombotic thrombocytopenic, syndrome, Xerophthalmia, Still's disease, systemic lupus RH-isoimmunization, sarcoidosis, sarcoidosis, spherocyto 45 erythematosus, Takayasu disease, or Wegener's granuloma sis, splenic rupture, thalassemia, thrombasthenia, thromb tosis. ocytopenia, Waldenstrom macroglobulinemia, or Von Will In some embodiments, the present invention provides a ebrand disease. method for treating, reducing the incidence, delaying the In some embodiments, the present invention provides a onset or progression, or reducing and/or abrogating the Symp method for treating, reducing the incidence, delaying the 50 toms associated with a metabolic disease in a subject. In one onset or progression, or reducing and/or abrogating the Symp embodiment, the method comprises administering to a Sub toms associated with a congenital, hereditary, or neonatal ject a composition comprising a compound of this invention disease in a Subject. In one embodiment, the method com and antidiabetic agent, an agent treating the gastrointestinal prises administering to a subject a composition comprising a system, an agent treating a dermatological disorder, an agent compound of this invention and anti-cancer agent, an immu 55 treating the central nervous system, an anti-infective agent, an nomodulating agent, an antidiabetic agent, an agent treating agent treating the liver, an agent treating the kidney, an agent the cardiovascular system, an agent treating the gastrointes treating a metabolic disease, an agent treating a wasting dis tinal system, an agent treating a dermatological disorder, an ease, a gene therapy agent, an agent treating the endocrine agent treating the central nervous system, an anti-infective system, Vitamins, or a combination thereof. In some embodi agent, an agent treating the liver, an agent treating the kidney, 60 ments, metabolic diseases comprise acid-base imbalance, an agent treating a metabolic disease, an agent treating a acidosis, alkalosis, alkaptonuria, alpha-mannosidosis, amino wasting disease, a gene therapy agent, an agent treating the acid metabolism inborn errors, amyloidosis, iron-deficiency endocrine system, vitamins, or a combination thereof. In anemia, ascorbic acid deficiency, avitaminosis, beriberi, bio Some embodiments, congenital, hereditary, and neonatal dis tinidase deficiency, carbohydrate-deficient glycoprotein Syn eases comprise Aicardi syndrome, amniotic band syndrome, 65 drome, carnitine disorders, cystinosis, cystinuria, dehydra anencephaly, Angelman syndrome, ataxia telangiectasiai, tion, fabry disease, fatty acid oxidation disorders, Bannayan-Zonana syndrome, Barth syndrome, basal cell fucosidosis, galactosemias, Gaucher disease, Gilbert disease, US 7,772,433 B2 107 108 glucosephosphate dehydrogenase deficiency, glutaric aci tal disorders comprise Asperger syndrome, attention deficit demia, glycogen storage disease, Hartnup disease, hemo disorder with hyperactivity, autistic disorder, bipolar disor chromatosis, hemosiderosis, hepatolenticular degeneration, der, borderline personality disorder, capgras Syndrome, child histidinemia, homocystinuria, hyperbilirubinemia, hypercal behavior disorders, combat disorders, cyclothymic disorder, cemia, hyperinsulinism, hyperkalemia, hyperlipidemia, dependent personality disorder, depressive disorder, disso hyperoxaluria, hypervitaminosis A, hypocalcemia, hypogly ciative disorders, dysthymic disorder, eating disorders, fire cemia, hypokalemia, hyponatremia, hypophosphatasia, insu setting behavior, hypochondriasis, impulse control disorders, lin resistance, iodine deficiency, iron overload, jaundice, Kleine-Levin Syndrome, mental disorders, mental disorders chronic idiopathic, leigh disease, lesch-nyhan syndrome, leu diagnosed in childhood, multiple personality disorder, Mun cine metabolism disorders, lysosomal storage diseases, mag 10 chausen syndrome, Munchhausen syndrome, narcissistic per nesium deficiency, maple syrup urine disease, Melas Syn Sonality disorder, narcolepsy, obsessive-compulsive disorder, drome, Menkes kinky hair syndrome, metabolic diseases, paraphilias, phobic disorders, psychotic disorders, restless metabolic syndrome X, metabolism, inborn errors, mitochon legs Syndrome, Schizophrenia, seasonal affective disorder, drial diseases, mucolipidoses, mucopolysaccharidoses, sexual and gender disorders, sexual dysfunctions, psycho Niemann-Pick diseases, obesity, ornithine carbamoyltrans 15 logical, sleep disorders, Somatoform disorders, stress disor ferase deficiency disease, osteomalacia, pellagra, peroxiso ders, post-traumatic, Substance-related disorders, Suicidal mal disorders, phenylketonurias, porphyria, erythropoietic, behavior, or trichotillomania. porphyrias, progeria, pseudo, gaucher disease, refsum dis In one embodiment, “depression” refers to an illness that ease, Reye syndrome, rickets, Sandhoff disease, starvation, involves the body, mood and thoughts that affects the way a tangier disease, Tay-Sachs disease, tetrahydrobiopterin defi person eats, sleeps and the way one feels about oneself, and ciency, trimethylaminuria, tyrosinemias, urea cycle disor thinks about things. The signs and symptoms of depression ders, water-electrolyte imbalance, Wernicke encephalopathy, include loss of interest in activities, loss of appetite or over vitaminA deficiency, vitamin B12 deficiency, vitamin B defi eating, loss of emotional expression, an empty mood, feelings ciency, Wolman disease, or Zellweger syndrome. of hopelessness, pessimism, guilt or helplessness, Social In some embodiments, the present invention provides a 25 withdrawal, fatigue, sleep disturbances, trouble concentrat method for treating, reducing the incidence, delaying the ing, remembering, or making decisions, restlessness, irrita onset or progression, or reducing and/or abrogating the Symp bility, headaches, digestive disorders or chronic pain. toms associated with a disorder of environmental origin in a In one embodiment, “cognition” refers to the process of Subject. In one embodiment, the method comprises adminis knowing, specifically the process of being aware, knowing, tering to a Subject a composition comprising a compound of 30 thinking, learning and judging. Cognition is related to the this invention and anti-cancer agent, an immunomodulating fields of psychology, linguistics, computer Science, neuro agent, an antidiabetic agent, an agent treating the cardiovas science, mathematics, ethology and philosophy. In one cular system, an agent treating the gastrointestinal system, an embodiment, “mood refers to a temperor state of the mind. agent treating a dermatological disorder, an agent treating the As contemplated herein, alterations mean any change for the central nervous system, an anti-infective agent, an agent treat 35 positive or negative, in cognition and/or mood. ing the liver, an agent treating the kidney, an agent treating a In some embodiments, the present invention provides a metabolic disease, an agent treating a wasting disease, a gene method for treating, reducing the incidence, delaying the therapy agent, an agent treating the endocrine system, Vita onset or progression, or reducing and/or abrogating the Symp mins, or a combination thereof. In some embodiments, dis toms associated with a liver disease in a subject. In one orders of environmental origin comprise barotrauma, bites 40 embodiment, the method comprises administering to a Sub and stings, brain concussion, burns, central cord syndrome, ject a composition comprising a compound of this invention craniocerebral trauma, electric injuries, fractures, bone, frost and anti-cancer agent, an immunomodulating agent, an agent bite, heat stress disorders, motion sickness, occupational dis treating the gastrointestinal system, an anti-infective agent, eases, poisoning, shaken baby Syndrome, shoulder injuries, an agent treating the liver, an agent treating a metabolic dis space motion sickness, spinal cord injuries, tick paralysis, or 45 ease, an agent treating a wasting disease, a gene therapy wounds (penetrating and non-penetrating). agent, an agent treating the endocrine system, Vitamins, or a In some embodiments, the present invention provides a combination thereof. In some embodiments, liver diseases method for treating, reducing the incidence, delaying the comprise liver cancer, primary biliary cirrhosis, autoimmune onset or progression, or reducing and/or abrogating the Symp hepatitis, chronic liver disease, cirrhosis of the liver, hepatitis, toms associated with a behavior mechanism in a subject. In 50 viral hepatitis (hepatitis a, hepatitis b, chronic hepatitis b, one embodiment, the method comprises administering to a hepatitis c, chronic hepatitis c, hepatitis d, hepatitis e, hepa Subject a composition comprising a compound of this inven titis X), liver failure, jaundice, neonatal jaundice, hepatoma, tion and an agent treating the cardiovascular system, an agent liver cancer, liver abscess, alcoholic liver disease, hemochro treating the central nervous system, a gene therapy agent, an matosis, Wilson's disease, portal hypertension, primary scle agent treating the endocrine system, Vitamins, or a combina 55 rosing cholangitis, sarcoidosis, tapeworms, alveolar hydatid tion thereof. In some embodiments, behavior mechanisms disease, fascioliasis, Schistosomiasis, gaucher disease, Zell comprise aggression, attitude to death, codependency, self weger syndrome, alcoholism, food poisoning, pneumococcal injurious behavior, sexual behavior, or social behavior. pneumonia' or vibrio Vulnificus. In some embodiments, the present invention provides a In some embodiments, the present invention provides a method for treating, reducing the incidence, delaying the 60 method for treating, reducing the incidence, delaying the onset or progression, or reducing and/or abrogating the Symp onset or progression, or reducing and/or abrogating the Symp toms associated with a mental disorder in a subject. In one toms associated with a kidney disease in a subject. In one embodiment, the method comprises administering to a Sub embodiment, the method comprises administering to a Sub ject a composition comprising a compound of this invention ject a composition comprising a compound of this invention and an agent treating the central nervous system, a gene 65 and anti-cancer agent, an immunomodulating agent, an therapy agent, an agent treating the endocrine system, Vita antidiabetic agent, an agent treating the gastrointestinal sys mins, or a combination thereof. In some embodiments, men tem, an anti-infective agent, an agent treating the kidney, an US 7,772,433 B2 109 110 agent treating a metabolic disease, a gene therapy agent, an the present invention may comprise concomitant treatment agent treating the endocrine system, Vitamins, or a combina with a compound of this invention and an agent which treats tion thereof. In some embodiments, kidney diseases comprise hypertension. acromegaly, acute renal failure (ARF) amyloidosis, autoso In some embodiments, the present invention provides a mal dominant polycystic kidney disease, kidney Stones, kid method for treating, reducing the incidence, delaying the ney cysts, autosomal recessive polycystic kidney disease, onset or progression, or reducing and/or abrogating the Symp chronic renal failure (CRF), chronic renal disease, coffin Lowry syndrome, corpulmonale, cryoglobulinemia, diabetic toms associated with a wasting disease in a subject. In one nephropathy, dyslipidemia, Gaucher disease, glomerulone embodiment, the method comprises administering to a Sub phritis, goodpasture syndrome, hemolytic uremic syndrome, 10 ject a composition comprising a compound of this invention hepatitis, kidney cancer, kidney Stones, leukemia, lipopro and anti-cancer agent, an immunomodulating agent, an teinemia, lupus, multiple myeloma, nephritis, polyartekidney antidiabetic agent, an agent treating the cardiovascular sys cysts, post streptococcal glomerulonephritis, glomerulone tem, an agent treating the gastrointestinal system, an agent phritis, kidney pain, preeclampsia, renal tuberculosis, pyelo treating the central nervous system, an agent treating a meta nephritis, renal tubular acidosis kidney disease, streptococcal 15 bolic disease, an agent treating a wasting disease, a gene toxic shock syndrome, thromboembolism, toxoplasmosis, therapy agent, an agent treating the endocrine system, Vita urinary tract infections, vesicoureteral reflux, or williams mins, or a combination thereof. In some embodiments, wast syndrome. ing diseases comprise muscle injury, bed rest, immobility, In one embodiment, the kidney disease or disorder is acute, nerve injury, neuropathy, diabetic neuropathy, alcoholic neu or in another embodiment, chronic. In one embodiment, clini ropathy, Subacute combined degeneration of the spinal cord, cal indications of a kidney disease or disorder, wherein the diabetes, rheumatoid arthritis, motor neurone diseases, Duch methods of treatment may be useful include urinary casts, enne muscular dystrophy, carpal tunnel syndrome, chronic measured GFR, or other markers of renal function. infection, tuberculosis, Addison's disease, adult Sma, limb In one embodiment, the methods of this invention are use muscle atrophy, alcoholic neuropathy, anorexia, anorexia ful in Subjects predisposed to kidney diseases or disorders. In 25 nervosa, anorexia associated with cachexia, anorexia associ one embodiment, the phrase "predisposed to a kidney disease ated with aging, back tumour, dermatomyositis, hip cancer, or disorder with respect to a subject is synonymous with the inclusion body myositis, incontinentia pigmenti, intercostal phrase “subject at risk', and includes a Subject at risk of acute neuralgia, juvenile rheumatoid arthritis, Legg-Calve-Perthes or chronic renal failure, or at risk of the need for renal replace disease, muscle atrophy, multifocal motor neuropathy, neph ment therapy, if the subject is reasonably expected to suffer a 30 rotic syndrome, osteogenesis imperfecta, post-polio Syn progressive loss of renal function associated with progressive drome, rib tumor, spinal muscularatrophy, reflex sympathetic loss of functioning nephron units. Whether a particular sub dystrophy syndrome, or Tay-Sachs. ject is at risk is a determination which may routinely be made A wasting condition or disorder is defined herein as a by one of ordinary skill in the relevant medical or veterinary condition or disorder that is characterized, at least in part, by art. 35 an abnormal, progressive loss of body, organ or tissue mass. A In one embodiment, Subjects with kidney disease, in par wasting condition can occuras a result of a pathology Such as, ticular male subjects with end-stage renal disease (ESRD) for example, cancer, or it can be due to a physiologic or Suffer from hypogonadism, with some having concomitant metabolic State, such as disuse deconditioning that can occur, moderate to severe protein-energy malnutrition (PEM), 40 for example, due to prolonged bed rest or when a limb is which leads to higher required doses of EPO, lower QOL immobilized, such as in a cast, or with the occurrence of scores, and higher mortality. Many have other symptoms multiple wounds, including, for example, amputation, as associated with hypogonadism, including fatigue, lack of occurs in diabetics, and other conditions, as will be appreci apetite, muscle weakness, etc. In some embodiments, the ated by one skilled in the art. A wasting condition can also be treatment methods of this invention are useful in treating age associated. The loss of body mass that occurs during a symptoms associated with hypogonadism, brought about in 45 wasting condition can be characterized by a loss of total body the subject by androgen deficiency in a female (ADIF); weight, or a loss of organ weight Such as a loss of bone or androgen deficiency in aging male (ADAM) to include muscle mass due to a decrease in tissue protein. fatigue, depression, decreased libido, erectile dysfunction, In one embodiment, the terms “muscle wasting or “mus decreased cognition, decreased mood; androgen insuffi 50 cular wasting, refer to the progressive loss of muscle mass ciency (male or female), androgen deficiency (male or and/or to the progressive weakening and degeneration of female). muscles, including the skeletal or Voluntary muscles which In one embodiment, diabetic nephropathy is a complica control movement, cardiac muscles which control the heart, tion of diabetes that evolves early, typically before clinical and Smooth muscles. In one embodiment, the muscle wasting diagnosis of diabetes is made. The earliest clinical evidence 55 condition or disorder is a chronic muscle wasting condition or of nephropathy is the appearance of low but abnormal levels disorder. “Chronic muscle wasting is defined herein as the (>30 mg/day or 20 ug/min) of albumin in the urine (microal chronic (i.e. persisting over along period of time) progressive buminuria), followed by albuminuria (>300 mg/24 h or 200 loss of muscle mass and/or to the chronic progressive weak ug/min) that develops over a period of 10-15 years. In patients ening and degeneration of muscle. with type 1 diabetes, diabetic hypertension typically becomes 60 The loss of muscle mass that occurs during muscle wasting manifest early on, by the time that patients develop microal can be characterized by a muscle protein breakdown or deg buminuria. Once overt nephropathy occurs, the glomerular radation, by muscle protein catabolism. Protein catabolism filtration rate (GFR) falls over a course of times, which may occurs because of an unusually high rate of protein degrada be several years, resulting in End Stage Renal Disease tion, an unusually low rate of protein synthesis, or a combi (ESRD) in diabetic individuals. 65 nation of both. Protein catabolism or depletion, whether Hypertension is another comorbid factor for renal disease. caused by a high degree of protein degradation or a low In some embodiments, treatment of renal disease according to degree of protein synthesis, leads to a decrease in muscle US 7,772,433 B2 111 112 mass and to muscle wasting. The term “catabolism” has its embodiment, the present invention provides a method for commonly known meaning in the art, specifically an energy treating, reducing the incidence, delaying the onset or pro burning form of metabolism. gression, or reducing and/or abrogating the symptoms asso Muscle wasting can occur as a result of pathology, disease, ciated with a pharmacotherapy induced hypogonadal state in condition or disorders, including disorders for treatment via a subject. In some embodiments, hypogonadism is caused by the methods of this invention, Such as, for example, end stage treatments which alter the secretion of hormones from the sex renal failure. glands in both women and men. In some embodiments, In some embodiments, the present invention provides a hypogonadism may be "primary or “central'. In primary method for prevention of statin induced rhabdomyolysis. In hypogonadism, the ovaries or testes themselves do not func Some embodiments, the present invention provides a method 10 tion properly. In some embodiments, hypogonadism may be for prevention of Statin induced rhabdomyolysis, organ fail induced by Surgery, radiation, genetic and developmental ure or insufficiency. In some embodiments, the present inven disorders, liver and kidney disease, infection, or certain tion provides a method for prevention of statin induced kid autoimmune disorders. In some embodiments, menopause is ney or liver failure or insufficiency. In one embodiment, the a form of hypogonadism. Menopause may cause, in some method comprises administering to a subject a composition 15 embodiments, amenorrhea, hot flashes, vaginal dryness, or comprising a compound of this invention and a statin. irritability due to woman's estrogen levels fall. In one In one embodiment, the wasting disease is cachexia or embodiment, the method comprises administering to a Sub involuntary weight loss in a subject. In another embodiment, ject a composition comprising a compound of this invention the present invention provides a method of treating, prevent and an anti-cancer agent, an immunomodulating agent, an ing, inhibiting, reducing or suppressing muscle wasting in a antidiabetic agent, an agent treating the cardiovascular sys Subject Suffering from a kidney disease. In one embodiment, tem, an agent treating the gastrointestinal system, an agent the present invention provides a method of treating, prevent treating the central nervous system, an agent treating a meta ing, inhibiting, reducing or Suppressing protein catabolism in bolic disease, an agent treating a wasting disease, a gene a subject Suffering from a kidney disease or disorder, therapy agent, an agent treating the endocrine system, an Cachexia is weakness and a loss of weight caused by a 25 agent treating a dermatological disorder, an anti-infective disease or as a side effect of illness. Long term hospitalization agent, an agent treating the liver, an agent treating the kidney, due to illness or injury, or disuse deconditioning that occurs, Vitamins, or a combination thereof. for example, when a limb is immobilized, can also lead to In some embodiments, the present invention provides a muscle wasting. Studies have shown that in patients suffering method for treating, reducing the incidence, delaying the injuries, chronic illnesses, burns, trauma or cancer, who are 30 onset or progression, or reducing and/or abrogating the Symp hospitalized for long periods of time, there is a long-lasting toms associated with osteopenic state in a Subject. In one unilateral muscle wasting, with a consequent decrease in embodiment, the present invention provides a method for body mass. Nervous system injury, for example, spinal cord treating, reducing the incidence, delaying the onset or pro injury, as described further herein, may be a contributory gression, or reducing and/or abrogating the symptoms asso factor, as well. 35 ciated with a pharmacotherapy induced osteopenic state in a In some embodiments, the present invention provides a Subject. In some embodiments, osteopenia is a mild thinning method for treating, reducing the incidence, delaying the of the bone mass. In some embodiments, osteopenia is a onset or progression, or reducing and/or abrogating the Symp precursor to osteoporosis. In some embodiments osteopenia toms associated with a wasting diseases or disorders in a is defined as a bone density between one standard deviation Subject. In another embodiment, the wasting diseases and 40 (SD) and 2.5 SD below the bone density of a normal young disorders include inter-alia: a) acquired immunodeficiency adult. In one embodiment, the method comprises administer syndrome (AIDS) wasting; b) wasting associated with bed ing to a subject a composition comprising a compound of this rest; c) bulimia, and/or wasting associated with bulimia; c) invention and an anti-cancer agent, an immunomodulating cachexia; d) cancer cachexia; e) HIV wasting: f) reduce agent, an antidiabetic agent, an agent treating the cardiovas cachexia and protein loss due to prolonged critical illness, 45 cular system, an agent treating the gastrointestinal system, an pulmonary dysfunction, ventilator dependency, aging, AIDS, agent treating the central nervous system, an agent treating a trauma, Surgery, congestive heart failure, cardiac myopathy, metabolic disease, an agent treating a wasting disease, a gene burns, cancer, chronic obstructive pulmonary disease therapy agent, an agent treating the endocrine system, an (COPD), eating disorders such bulimia, anorexia nervosa, agent treating a dermatological disorder, an anti-infective loss of appetite, starvation, and/or depression. 50 agent, an agent treating the liver, an agent treating the kidney, In some embodiments, the present invention provides a Vitamins, or a combination thereof. method for treating, reducing the incidence, delaying the In some embodiments, the present invention provides a onset or progression, or reducing and/or abrogating the Symp method for treating, reducing the incidence, delaying the toms associated with invalid states in a subject. In one onset or progression, or reducing and/or abrogating the Symp embodiment, the invalid state is post-polio syndrome. In one 55 toms associated with a sarcopenic state in a Subject. In one embodiment, the method comprises administering to a Sub embodiment, the present invention provides a method for ject a composition comprising a compound of this invention treating, reducing the incidence, delaying the onset or pro and an immunomodulating agent, an antidiabetic agent, an gression, or reducing and/or abrogating the symptoms asso agent treating the cardiovascular system, an agent treating the ciated with a pharmacotherapy induced sarcopenic state in a gastrointestinal system, an agent treating the central nervous 60 Subject. In some embodiments, sarcopenia is a significant loss system, an agent treating a metabolic disease, an agent treat of muscle mass. In one embodiment, sarcopenia definition is ing a wasting disease, a gene therapy agent, an agent treating having a lean body mass less than two standard deviation the endocrine system, vitamins, or a combination thereof. below the mean for normal young adults. In some embodi In some embodiments, the present invention provides a ments, sarcopenia is caused by genetic factors, altered circu method for treating, reducing the incidence, delaying the 65 lation, decrease in the capillary:muscle fiber ratio, altered onset or progression, or reducing and/or abrogating the Symp motor neurons, denervation, deterioration of motor end toms associated with a hypogonadal state in a Subject. In one plates, selective reinnervation of Type I fibers, inflammatory US 7,772,433 B2 113 114 responses causing muscle damage, reduced exercise, malnu In another embodiment, this invention provides methods of trition, low dietary protein intake, Vitamin D deficiency, age treatment of cystic fibrosis and induced hypogonadal states as related decline in Vitamin D, oxidative stress, muscle mito a result of the same, epilepsy and induced hypogonadal and/ chondrial mutations, changes in specific types of muscle or hypermetabolic states as a result of the same, hereditary fibers, decline in muscle protein, disabling disease, strokes, angioedema, lupus erythematosus and decreased BMD as a Alzheimer's disease, Parkinson's disease, osteoporsis, ath result of the same, alcohol and Smoking induced osteoporo erosclerosis, diabetes mellitus, hyperinsulimemia, renal fail sis, in a Subject the methods comprising administering a ure, or hypogonadism. In one embodiment, the method com SARM as herein described to the subject. prises administering to a subject a composition comprising a In another embodiment, this invention provides methods of SARM compound and an anti-cancer agent, an immuno 10 treatment of polio and post-polio syndrome and other invalid modulating agent, an antidiabetic agent, an agent treating the states, statin induced rhabdomyolysis, statin-induced muscle cardiovascular system, an agent treating the gastrointestinal weakness, statin-induced organ failure or insufficiency, in a system, an agent treating the central nervous system, an agent Subject, the methods comprising the administration of a com treating a metabolic disease, an agent treating a wasting dis pound as herein described, optionally with a statin, as appro ease, a gene therapy agent, an agent treating the endocrine 15 priate, as will be appreciated by one skilled in the art, and/or system, an agent treating a dermatological disorder, an anti with any therapeutic agent. infective agent, an agent treating the liver, an agent treating In another embodiment, this invention provides a method the kidney, vitamins, or a combination thereof. of treating Opioid Induced Androgen Deficiency (OPIAD), In some embodiments, the present invention provides a the method comprising administering to the Subject a com method for treating, reducing the incidence, delaying the pound as herein described, and optionally opiates, opioids, onset or progression, or reducing and/or abrogating the Symp narcotics, etc. methadone, long-acting opiates/opioids Such toms associated with a combination of diseases and/or disor as Kadian, extended release morphines, all opiates/opioids/ ders in a subject as described hereinabove. In one embodi narcotics agents approved by FDA, opiates/opioids used in ment, the method comprises administering to a subject a treatment of heroin addiction, opiates/opioids used in the composition comprising a compound of this invention and an 25 treatment of chronic pain of malignancy, opiates/opioids used anti-cancer agent, an immunomodulating agent, an antidia in the treatment non-malignant of chronic pain syndromes. betic agent, an agent treating the cardiovascular system, an In another embodiment, this invention provides a method agent treating the gastrointestinal system, an agent treating of treating a nervous system disease, disorder or condition, the central nervous system, an agent treating a metabolic the method comprising administering to the Subject a com disease, an agent treating a wasting disease, a gene therapy 30 pound as herein described, and optionally anti-psychotics, agent, an agent treating the endocrine system, an agent treat Such as, for example, Zotepine, haloperidol, amisulpride, ris ing a dermatological disorder, an anti-infective agent, an peridone, other D2 dopamine receptor antagonists; anti-epi agent treating the liver, an agent treating the kidney, Vitamins, leptics, such as valproic acid, carbamazepine, oXcarbam or a combination thereof. azepine, etc. or combinations thereof. It is to be understood that any method of this invention, as 35 In another embodiment, this invention provides a method herein described, encompasses the administration of a com of treating a hormone dependent disease, disorder or condi pound as herein described, or a composition comprising the tion, the method comprising administering to the Subject a same, to the Subject, in order to treat the indicated disease, compound as herein described, and optionally chemothera disorder or condition. The methods as herein described each peutics agents and therapies (methotrexate, cyclophospha and/or all may further comprise administration of an addi 40 mide, ifosfamide, adriamycin, doxorubicin, glucocorticoids, tional therapeutic agent as herein described, and as will be cyclosporine, L-thyroxine, SERMs, AI, fulvestrant, GnRH appreciated by one skilled in the art. agents, ADT discontinuation of hormone replacement In some embodiments, the present invention provides a therapy, cranial irradiation, peripheral irradiation, etc.; pro method for enhanced production Such as milk, sperm, or egg. lactinemia-inducing pharmacotherapeutics (serotonergic In some embodiments, the present invention provides a 45 antidepressants acting through 5HT2 receptors, selective method for enhanced production of lean meats or eggs. In serotonin reuptake inhibitors, monoamine oxidase inhibitors, Some embodiments, the present invention provides a method tricyclic antidepressants, antihypertensives such as methyl for increased productivity of feeds or stud livestock, for dopa, reserpine, clonidine, and Verapamil; antidopaminergic example, increased sperm count, improved morphology of anti-emetics such as metoclopramide, H2 receptor antago sperm, etc. In some embodiments, the present invention pro 50 nists Such as cimetidine and ranitidine, estrogens, amphet vides a method for expanding the productive life of farm amines, AR partial antagonists (ketoconazole, spironolac animals, for example, egg-laying hens, milk-producing cows, tone, eplerenone) etc., and/or enhanced herd health, for example, improved In another embodiment, the compounds of this invention immune clearance, stronger animals. and compositions as described herein are useful in promoting In one embodiment, the method comprises administering 55 or speeding recovery following a Surgical procedure. to a Subject a composition comprising a compound of this In one embodiment, the present invention provides a use of invention and an anti-cancer agent, an immunomodulating a compound as described herein for reducing a fat mass in a agent, an antidiabetic agent, an agent treating the cardiovas subject. In another embodiment the invention provides such cular system, an agent treating the gastrointestinal system, an methods for use of the compound as described herein or its agent treating the central nervous system, an agent treating a 60 prodrug, analog, isomer, metabolite, derivative, pharmaceu metabolic disease, an agent treating a wasting disease, a gene tically acceptable salt, pharmaceutical product, polymorph, therapy agent, an agent treating the endocrine system, an crystal, impurity, N-oxide, hydrate or any combination agent treating a dermatological disorder, an anti-infective thereof, or a composition comprising the same. agent, an agent treating the liver, an agent treating the kidney, In another embodiment, this invention provides for the use Vitamins, nutritional additives, hormones, each and/or all as 65 of a compound as described herein or its prodrug, analog, herein described, or any other therapeutic agent as herein isomer, metabolite, derivative, pharmaceutically acceptable described, or a combination thereof. salt, pharmaceutical product, polymorph, crystal, impurity, US 7,772,433 B2 115 116 N-oxide, hydrate or any combination thereof, or a composi Cholesterol, triacylglycerol and other lipids are trans tion comprising the same, in treating abdominal fat accumu ported in body fluids by lipoproteins which may be classified lation; improving body composition; lowering body fat con according to their density, for example, the very low density tent; lowering fat mass; improving blood lipid profile, lipoproteins (VLDL), intermediate density lipoproteins increasing muscle mass/strength/function; increasing bone (HDL), low density lipoproteins (LDL) and high density lipo mass/BMD/strength/function; lowering body fat; congenital proteins (HDL). hyperinsulinemia; cushing's disease (hypercortisolemia); It has been shown that high levels of LDL-Cholesterol in obesity or diabetes associated with a metabolic syndrome in a the blood correlate with atherosclerosis which is a progres Subject. sive disease characterized in part by sedimentation of lipids in In another embodiment, the Subject has a hormonal imbal 10 inner walls of arteries, particularly of coronary arteries. It has ance, disorder, or disease. In another embodiment the Subject also been shown that a high blood level of LDL-Cholesterol has menopause. correlates with coronary heart disease. Also, a negative cor In one embodiment, the present invention provides a use of relation exists between blood levels of HDL cholesterol and a compound as described herein for increasing a lean mass in coronary heart disease. a subject. In another embodiment Such use comprises admin 15 The level of total cholesterol in blood, which is the sum of istration of a compound as described herein or its prodrug, HDL-Cholesterol, LDL-Cholesterol, VLDL-Cholesterol and analog, isomer, metabolite, derivative, pharmaceutically chylomicron-Cholesterol, is not necessarily predictive of the acceptable salt, pharmaceutical product, polymorph, crystal, risk of coronary heart disease and atherosclerosis. impurity, N-oxide, hydrate or any combination thereof. The correlation between atherosclerosis and LDL choles In one embodiment the Subject has a hormonal imbalance, terol levels, however, is much higher than a similar correla disorder, or disease. In another embodiment the Subject has tion between atherosclerosis and total serum cholesterol lev menopause. els. Example 4 demonstrates that a compound of formula (II) is In one embodiment, this invention provides methods ofuse anabolic yet minimally androgenic, thus Such compounds of the compounds as herein described for improving the lipid may be useful in treating patient groups in which androgens 25 profile and/or reducing the circulating lipid levels in a Subject. were contraindicated in the past. Compound of formula (II) In some embodiments, according to this aspect of the inven was shown to stimulate muscle growth, whether in the pres tion, the subject suffers from one or more conditions selected ence or absence of testosterone while exerting anti-prolifera from the group consisting of atherosclerosis and its associ tive effects on the prostate, thus, in one embodiment, the ated diseases, premature aging, Alzheimer's disease, stroke, methods of this invention provide for restoring lost muscle 30 toxic hepatitis, viral hepatitis, peripheral vascular insuffi mass in patients with sarcopenia or cachexia. ciency, renal disease, and hyperglycemia, and the invention In one embodiment, the compounds as herein described provides for the administration of a compound or composi alter the levels of leptin in a subject. In another embodiment, tion comprising the same, as herein described, which in some the compounds as herein described decrease the levels of embodiments positively affects a lipid profile in the subject, leptin. In another embodiment, the compounds as herein 35 which is one means by which the method is useful in treating described increase the levels of leptin in a subject. Leptin is the indicated diseases, disorders and conditions. known to have an effect on appetite on weight loss in obese In one embodiment the invention provides for the treat mice, and thus has been implicated in obesity. ment ofatherosclerosis and its associated diseases, such as for The compounds as herein described, in one embodiment, example, cardiovascular disorders, cerebrovascular disor affect circulating, or in another embodiment, tissue levels of 40 ders, peripheral vascular disorders, intestinal vascular disor leptin. In one embodiment, the term level/s of leptin refers to ders, or combinations thereof. the serum level of leptin. As contemplated herein, the com In one embodiment cardiovascular disorders comprise of pounds of the present invention have an effect on leptin in hypertention (HTN), coronary artery disease (CAD) or myo vitro and in-vivo. Leptin levels can be measured by methods cardial perfusion. In another embodiment this invention pro known to one skilled in the art, for example by commercially 45 vides methods of use of the SARM compounds as herein available ELISA kits. In addition, Leptin levels may be deter described for promoting aortic Smooth muscle cell prolifera mined in in-vitro assays, or in in-vivo assays, by any method tion. In another embodiment this invention provides methods known to a person skilled in the art. of use of the compounds as herein described for treating Since leptin is implicated in controlling appetite, weight arteriosclerosis. In another embodiment this invention pro loss, food intake, and energy expenditure, modulating and/or 50 vides methods of use of the compounds as herein described controlling the levels of leptin is a useful therapeutic for lowering blood pressure. In another embodiment this approach in treating preventing, inhibiting or reducing the invention provides methods of use of the compounds as incidence of obesity in subjects suffering from obesity. herein described for treating cardiac diseases and disorders Modulating the level of leptin can result in a loss of appetite, comprising cardiomyopathy, cardiac dysfunctions such as, a reduction of food intake, and an increase in energy expen 55 myocardial infarction, cardiac hypertrophy and cognitive diture in the subject, and thus may contribute to the control heart failure. In another embodiment this invention provides and treatment of obesity. methods of use of the compounds as herein described for The term “obesity' is defined, in one embodiment, as an cardioprotection comprising cardioprotection in insulin increase in body weight beyond the limitation of skeletal and resistance; treating diabetes type I and II, metabolic Syn physical requirement, as the result of excessive accumulation 60 drome, syndrome X and/or high blood pressure. offat in the body. In one embodiment, the invention provides a method of The term “obesity-associated metabolic disorder” refers, treating, preventing, reducing the risk of mortality from car in one embodiment, to a disorder which results from, is a diovascular and/or cerebrovascular disease in a Subject, com consequence of, is exacerbated by or is secondary to obesity. prising administering a compound of this invention or its Non-limiting examples of Such a disorder are osteoarthritis, 65 prodrug, ester, analog, isomer, metabolite, derivative, phar Type II diabetes mellitus, increased blood pressure, stroke, maceutically acceptable salt, pharmaceutical product, poly and heart disease. morph, crystal, impurity, N-oxide, hydrate or any combina US 7,772,433 B2 117 118 tion thereof, or a pharmaceutical composition comprising the blood pressure can cause blood vessel changes in the back of same. In one embodiment, the compound is characterized by the eye, thickening of the heart muscle, kidney failure, and the structure of formula (II). brain damage. In one embodiment, compounds of this invention reduce The term “stroke” refers, in other embodiments, to damage LDL and total cholesterol levels. In another embodiment the to nerve cells in the brain due to insufficient blood supply compound of formula (II) reduces LDL and total cholesterol often caused by a bursting blood vessel or a blood clot. The levels in a Subject. In one embodiment, the compound is term “heart disease', in other embodiments, refers to a mal characterized by the structure of the formula I-XXII, or any function in the heart normal function and activity, including embodiment thereof, as herein described. heart failure. In another embodiment, compounds of formulae I are co 10 In addition, androgens have recently been shown to be administered with HDL-elevating agents. In another embodi involved in commitment of mesenchymal pluripotent cells ment, a compound of this invention is co-administered with into myogenic lineage and to block differentiation into adi an HDL-elevating agents. In another embodiment, HDL-el pogenic lineage (Singh et al., Endocrinology, 2003, Jul. 24). evating agents include niacin. In another embodiment the Accordingly, the compounds can be useful in methods of HDL-elevating agents include fibrates including gemfibrozil 15 blocking adipogenesis, and/or altering stem cell differentia (Lopid), thiourea based gemfibrozil analogues, and fenofi tion, as described herein. brate (TriCor). In another embodiment, HDL-elevating In another embodiment, this invention relates to a method agents include statins. In another embodiment, HDL-elevat of promoting, increasing or facilitating weight loss in a Sub ing agents include 1-hydroxyalkyl-3-phenylthiourea, and ject, comprising the step of administering to the Subject a analogs thereof. compound as herein described and/or its analog, derivative, In one embodiment, this invention provides a method of isomer, metabolite, pharmaceutically acceptable salt, phar reducing circulating lipid levels in a Subject, said method maceutical product, hydrate, N-oxide, prodrug, polymorph, comprising administering a compound of this invention or its crystal, or any combination thereof, in an amount effective to pharmaceutically acceptable salt, hydrate, N-oxide, or any promote, increase or facilitate weight loss in the Subject. combination thereof, or a composition comprising the same. 25 In another embodiment, this invention relates to a method In one embodiment, the subject suffers from atherosclerosis of decreasing, Suppressing, inhibiting or reducing appetite of and its associated diseases, premature aging, Alzheimer's a Subject, comprising the step of administering to the Subject disease, stroke, toxic hepatitis, viral hepatitis, peripheral vas a compound as herein described and/or its analog, derivative, cular insufficiency, renal disease, hyperglycemia, or any com isomer, metabolite, pharmaceutically acceptable salt, phar bination thereof. In one embodiment, the compound is char 30 maceutical product, hydrate, N-oxide, prodrug, polymorph, acterized by the structure of the formula I-XXII, or any crystal, or any combination thereof, in an amount effective to embodiment thereof, as herein described. decrease, suppress, inhibit or reduce the appetite of the sub In one embodiment, this invention provides a method of ject. treating atherosclerosis and its associated diseases, such as, In another embodiment, this invention relates to a method for example, cardiovascular disorders, cerebrovascular disor 35 of altering the body composition of a subject, comprising the ders, peripheral vascular disorders, or intestinal vascular dis step of administering to the Subject a compound as herein orders in a Subject, the method comprising the step of admin described and/or its analog, derivative, isomer, metabolite, istering to the Subject compound of this invention or its pharmaceutically acceptable salt, pharmaceutical product, pharmaceutically acceptable salt, hydrate, N-oxide, or any hydrate, N-oxide, prodrug, polymorph, crystal, or any com combination thereof, or a composition comprising the same. 40 bination thereof, in an amount effective to alter the body In one embodiment, the compound is characterized by the composition of the Subject. In one embodiment, altering the structure of the formula I-XXII, or any embodiment thereof, body composition comprises altering the lean body mass, the as herein described. fat free body mass of the subject, or a combination thereof. The method may further comprise co-administration, Sub In another embodiment, this invention relates to a method sequent or prior administration with an agentoragents, which 45 of altering lean body mass or fat free body mass of a Subject, are known to be useful in treating cardiovascular disorders, comprising the step of administering to the Subject a com cerebrovascular disorders, peripheral vascular disorders, or pound as herein described and/or its analog, derivative, iso intestinal vascular disorders. mer, metabolite, pharmaceutically acceptable salt, pharma In one embodiment, this invention provides a method of ceutical product, hydrate, N-oxide, prodrug, polymorph, improving the dexterity and movement in a Subject, for 50 crystal, or any combination thereof, in an amount effective to example, by treating arthritis in the Subject. alter the lean body mass or fat free body mass of the subject. The term “arthritis' refers, in another embodiment, to a In another embodiment, this invention relates to a method non-inflammatory degenerative joint disease occurring of converting fat to lean muscle in a subject, comprising the chiefly in older people, characterized by degeneration of the step of administering to the Subject a compound as herein articular cartilage, hypertrophy of bones and the margins, 55 described and/or its analog, derivative, isomer, metabolite, changes in the synovial membrane, etc. It is accompanied, in pharmaceutically acceptable salt, pharmaceutical product, other embodiments, by pain and stiffness, particularly after hydrate, N-oxide, prodrug, polymorph, crystal, or any com prolonged activity. bination thereof, in an amount effective to convert fat to lean The term "diabetes', in one embodiment, refers to a rela muscle in the Subject. tive or absolute lack of insulin leading to uncontrolled carbo 60 In another embodiment, this invention relates to a method hydrate metabolism. Most patients can be clinically classified of treating an obesity-associated metabolic disorder in a Sub as having either insulin-dependent diabetes mellitus (IDDM ject, comprising the step of administering to the Subject a or Type-I diabetes) or non-insulin-dependent diabetes melli compound as herein described and/or its analog, derivative, tus (NIDDM or Type-II diabetes). isomer, metabolite, pharmaceutically acceptable salt, phar The term “increased blood pressure' or “hypertension” 65 maceutical product, hydrate, N-oxide, prodrug, polymorph, refers, in other embodiments, to a repeatedly high blood crystal, or any combination thereof, in an amount effective to pressure above 140 over 90 mmHg. Chronically-elevated treat the obesity-associated metabolic disorder in the subject. US 7,772,433 B2 119 120 In another embodiment, this invention relates to a method In one embodiment this invention provides a method of of preventing, Suppressing, inhibiting or reducing an obesity treating, Suppressing, inhibiting or reducing the incidence of associated metabolic disorder in a Subject, comprising the (a) diabetes type I; (b) diabetes type II; (c) glucose intoler step of administering to the Subject a compound as herein ance; (d) hyperinsulinemia; (e) insulin resistance (f) nephr described and/or its analog, derivative, isomer, metabolite, opathy; (g) diabetic neuropathy: (h) diabetic retinopathy (i) pharmaceutically acceptable salt, pharmaceutical product, fatty liver conditions () MODY and (k) cardiovascular dis hydrate, N-oxide, prodrug, polymorph, crystal, or any com ease in a human Subject, comprising the step of administering bination thereof, in an amount effective to prevent, Suppress, to said subject a compound of this invention. In one embodi inhibit or reduce the obesity-associated metabolic disorder in ment, the compound is characterized by the structure of the the subject. 10 formula I-XXII, or any embodiment thereof, as herein In one embodiment, the obesity-associated metabolic dis described. order is hypertension. In another embodiment, the disorder is In some embodiments, the compounds as herein described osteoarthritis. In another embodiment, the disorder is Type II and/or compositions comprising the same may be used for diabetes mellitus. In another embodiment, the disorder is applications in, or treating diseases or conditions associated increased blood pressure. In another embodiment, the disor 15 with a Subject having diabetes. In one embodiment, the Sub der is stroke. In another embodiment, the disorder is heart ject for whom treatment is sought via the methods of this disease. invention is one with diabetic I. Type I diabetes is character In another embodiment, this invention relates to a method ized by autoimmune destruction of pancreatic beta-cells. of decreasing, Suppressing, inhibiting or reducing adipogen Markers of immune destruction of the beta-cell are present at esis in a subject, comprising the step of administering to the the time of diagnosis in 90% of individuals and include anti Subject a compound as herein described and/or its analog, bodies to the islet cell (ICAS), to glutamic acid decarboxylase derivative, isomer, metabolite, pharmaceutically acceptable (GAD), and to insulin (IAAS). While this form of diabetes salt, pharmaceutical product, hydrate, N-oxide, prodrug, usually occurs in children and adolescents, it can occurat any polymorph, crystal, or any combination thereof. age. Younger individuals typically have a rapid rate of beta 25 cell destruction and present with ketoacidosis, while adults In another embodiment, this invention relates to a method often maintain Sufficient insulin secretion to prevent ketoaci of altering stem cell differentiation in a subject, comprising dosis for many years. Eventually, all type I diabetic patients the step of administering to the Subject a compound as herein require insulin therapy to maintain normglycemia. described and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, In one embodiment, this invention provides a method of 30 treating diabetes type II. Type II diabetes is characterized by hydrate, N-oxide, prodrug, polymorph, crystal, or any com insulin resistance and at Some stage in pathogenesis of the bination thereof, in an amount effective to alter stem cell disease, a relative deficiency of insulin secretion. In absolute differentiation in the subject. terms, the plasma insulin concentration (both fasting and In one embodiment, the compounds as herein described are meal-stimulated) usually is increased, although “relative' to useful in a) treating, preventing, Suppressing, inhibiting, or 35 the severity of insulin resistance, the plasma insulin concen reducing obesity; b) promoting, increasing or facilitating tration is insufficient to maintain normal glucose homeosta weight loss; c) decreasing, Suppressing, inhibiting or reduc sis. With time, however, there is progressive beta cell failure ing appetite; d) altering the body composition; e) altering lean and absolute insulin deficiency ensues. Most individuals with body mass or fat free body mass: f) converting fat to lean type II diabetes exhibit intra abdominal (visceral) obesity, muscle; g) treating, preventing, Suppressing, inhibiting, or 40 fatty liver, which is closely related to the presence of insulin reducing an obesity-associated metabolic disorder, for resistance. The patient's liver becomes insulin resistant and example hypertension, osteoarthritis, diabetes mellitus, glycogen breakdown is uncontrolled and the result is MODY, increased blood pressure, stroke, or heart disease; h) increased and unphysiological glucose delivery to the blood decreasing, Suppressing, inhibiting or reducing adipogenesis; stream. The liver generated cholesterol and VLDL particles is i) altering stem cell differentiation; and/orj) altering the level 45 also uncontrolled. In addition, hypertension, dyslipidemia of leptin. (high triglyceride and low HDL-cholesterol levels; postpran In one embodiment, the compounds as herein described dial hyperlipemia), and elevated PAI-1 levels often are find utility in treating or halting the progression of, or treating present in these individuals. This clustering of abnormalities symptoms of diabetes. In another embodiment, the com is referred to as the “insulin resistance syndrome', or the pounds as herein described are useful in treating co-morbidi 50 “metabolic syndrome' or obesity related disorders. Because ties related to diabetes. These conditions include: hyperten of these abnormalities, patients with type II diabetes are at sion (HTN), cerebrovascular disease, atherosclerotic increased risk of developing macrovascular complications coronary artery disease, macular degeneration, diabetic ret Such as myocardial infarction and stroke. inopathy (eye disease) and blindness, cataracts—systemic In one embodiment, this invention provides a method of inflammation (characterized by elevation of inflammatory 55 treating diabetic nephropathy. Diabetic nephropathy is a com markers such as erythrocyte sedimentation rate or C-reactive plication of diabetes that evolves early, typically before clini protein), birth defects, pregnancy related diabetes, pre-ec cal diagnosis of diabetes is made. The earliest clinical evi clampsia and hypertension in pregnancy, kidney disease (re dence of nephropathy is the appearance of low but abnormal nal insufficiency, renal failure etc.), nerve disease (diabetic levels (>30 mg/day or 20 lug/min) of albumin in the urine neuropathy), Superficial and systemic fungal infections, con 60 (microalbuminuria), followed by albuminuria (>300 mg/24h gestive heart failure, gout/hyperuricemia, obesity, hypertrig or 200 ug/min) that develops over a period of 10-15 years. In lyceridemia, hypercholesterolemia, fatty liver disease (non patients with type 1 diabetes, diabetic hypertension typically alcoholic steatohepatitis, or NASH), and diabetes-related becomes manifest early on, by the time that patients develop skin diseases such as Necrobiosis Lipoidica Diabeticorum microalbuminuria. Once overt nephropathy occurs, the glom (NLD), Blisters of diabetes (Bullosis Diabeticorum), Erup 65 erular filtration rate (GFR) falls over a course of times, which tive Xanthomatosis, Digital Sclerosis, Disseminated Granu may be several years, resulting in End Stage Renal Disease loma Annulare, and Acanthosis Nigricans. (ESRD) in diabetic individuals. US 7,772,433 B2 121 122 In one embodiment, this invention provides a method of liver and hepatic insulin resistance is a major driving force treating diabetic neuropathy. Diabetic neuropathy is a family behind hyperglycemia and type II diabetes. of nerve disorders caused by diabetes. Diabetic neuropathies In one embodiment, this invention provides methods that cause numbness and sometimes pain and weakness in the inhibit (improve) the fatty liver, resulting in that the insulin hands, arms, feet, and legs. Neurologic problems in diabetes resistance in the liver is inhibited (improved) and thereby may occur in every organ system, including the digestive solving the basic problem in type II diabetes. tract, heart, and genitalia. Diabetic neuropathies are classified In another embodiment, the diabetes is a type I diabetes. In as peripheral, autonomic, proximal, and focal. Peripheral another embodiment, the diabetes is a type II diabetes. neuropathy causes pain or loss offeeling in the toes, feet, legs, In one embodiment, this invention provides a method of hands, and arms. Autonomic neuropathy causes changes in 10 treating Suppressing, inhibiting or reducing the incidence of digestion, bowel and bladder function, sexual response, and diabetes is a human Subject, comprising the step of adminis perspiration and can also affect the nerves that serve the heart tering to said Subject a compound of this invention or its and control blood pressure. Proximal neuropathy causes pain isomer, pharmaceutically acceptable salt, pharmaceutical in the thighs, hips, or buttocks and leads to weakness in the product, hydrate, N-oxide, or any combination thereof. In one legs. Focal neuropathy results in the Sudden weakness of one 15 embodiment, the compound is characterized by the structure nerve, or a group of nerves, causing muscle weakness or pain. of the formula I-XXII, or any embodiment thereof, as herein Any nerve in the body may be affected. described. In one embodiment, this invention provides a method of In another embodiment, the diabetes is a Type I diabetes. In treating diabetic retinopathy. The effect of diabetes on the eye another embodiment, the diabetes is a type II diabetes. is called diabetic retinopathy. Patients with diabetes are more In one embodiment, this invention provides a method of likely to develop eye problems such as cataracts and glau treating a human Subject having glucose intolerance, com coma. The affect of diabetic retinopathy on vision varies prising the step of administering to said subject compound of widely, depending on the stage of the disease. Some common this invention or its isomer, pharmaceutically acceptable salt, symptoms of diabetic retinopathy are blurred vision (this is pharmaceutical product, hydrate, N-oxide, or any combina often linked to blood sugar levels), floaters and flashes and 25 tion thereof. In one embodiment, the compound is character Sudden loss of vision. ized by the structure of the formula I-XXII, or any embodi In one embodiment, the subject for whom treatment is ment thereof, as herein described. sought via the methods of this invention is one with glucose In one embodiment, this invention provides a method of intolerance. Glucose intolerance is a pre-diabetic state in treating hyperinsulinemia in a human Subject, comprising the which the blood glucose is higher than normal but not high 30 step of administering to said Subject a compound of this enough to warrant the diagnosis of diabetes. invention or its isomer, pharmaceutically acceptable salt, In one embodiment, the subject for whom treatment is pharmaceutical product, hydrate, N-oxide, or any combina sought via the methods of this invention is one with hyperin tion thereof. Sulinemia. Hyperinsulinemia is a sign of an underlying prob In one embodiment, the compound is characterized by the lem that is causing the pancreas to secrete excessive amounts 35 structure of the formula I-XXII, or any embodiment thereof, of insulin. The most common cause of hyperinsulinemia is as herein described. insulin resistance, a condition in which your body is resistant In one embodiment, this invention provides a method of to the effects of insulin and the pancreas tries to compensate treating insulin resistance in a human Subject, comprising the by making more insulin. hyperinsulinemia is associated with step of administering to said Subject the compound of this type II diabetes 40 invention or its isomer, pharmaceutically acceptable salt, In one embodiment, the subject for whom treatment is pharmaceutical product, hydrate, N-oxide, or any combina sought via the methods of this invention is one with insulin tion thereof. In one embodiment, the compound is character resistance. Insulin resistance is a condition in which normal ized by the structure of the formula I-XXII, or any embodi amounts of insulin are inadequate to produce a normal insulin ment thereof, as herein described. response from fat, muscle and liver cells. Insulin resistance in 45 In one embodiment, this invention provides a method of fat cells results in hydrolysis of stored triglycerides, which treating diabetic nephropathy in a human Subject, comprising elevates free fatty acids in the blood plasma. Insulin resis the step of administering to said subject a selective androgen tance in muscle reduces glucose uptake whereas insulin resis receptor modulator compound of this invention or its isomer, tance in liver reduces glucose storage, with both effects Serv pharmaceutically acceptable salt, pharmaceutical product, ing to elevate blood glucose. High plasma levels of insulin 50 hydrate, N-oxide, or any combination thereof. In one embodi and glucose due to insulin resistance often leads to the meta ment, the compound is characterized by the structure of the bolic syndrome and type It diabetes. formula I-XXII, or any embodiment thereof, as herein Diabetes and the liver obesity is typically associated with described. elevated levels of free fatty acid (FFAs) that promote lipid In one embodiment, this invention provides a method of accumulation and insulin resistance in target tissues, i.e. 55 treating diabetic neuropathy in a human Subject, comprising reduced action of insulin primarily in skeletal muscle and the step of administering to said subject compound of this liver. A prominent role of insulin is to reduce glucose output invention or its isomer, pharmaceutically acceptable salt, from the liver. FFAs stimulate hepatic gluconeogenesis which pharmaceutical product, hydrate, N-oxide, or any combina per se does not lead to increased hepatic glucose output as tion thereof. In one embodiment, the compound is character long as it is paralleled by a decrease in hepatic glycogenoly 60 ized by the structure of the formula I-XXII, or any embodi sis, a compensatory process referred to as “hepatic autoregu ment thereof, as herein described. lation’. FFAs stimulate insulin secretion and insulin blocks In one embodiment, this invention provides a method of glycogenolysis in part by inhibiting secretion of glucagon, an treating diabetic retinopathy in a human Subject, comprising inducer of glycogenolysis. However, long-term elevated lev the step of administering to said Subject a compound of this els of FFAs leads to hepatic insulin resistance and thus break 65 invention or its isomer, pharmaceutically acceptable salt, down of hepatic autoregulation, resulting in increased hepatic pharmaceutical product, hydrate, N-oxide, or any combina glucose production and development of type II diabetes. Fatty tion thereof. In one embodiment, the compound is character US 7,772,433 B2 123 124 ized by the structure of the formula I-XXII, or any embodi which leads to higher required doses of EPO, lower QOL ment thereof, as herein described. scores, and higher mortality. Many have other symptoms In one embodiment, this invention provides a method of associated with hypogonadism, including fatigue, lack of treating fatty liver conditions in a human Subject, comprising apetite, muscle weakness, etc. In some embodiments, the the step of administering to said subject a selective androgen 5 treatment methods of this invention are useful in treating receptor modulator compound of this invention or its isomer, symptoms associated with hypogonadism, brought about in pharmaceutically acceptable salt, pharmaceutical product, the subject by the kidney disease or disorder. hydrate, N-oxide, or any combination thereof. In one embodi In one embodiment, diabetic nephropathy is a complica ment, the compound is characterized by the structure of the tion of diabetes that evolves early, typically before clinical formula I-XXII, or any embodiment thereof, as herein 10 diagnosis of diabetes is made. The earliest clinical evidence described. of nephropathy is the appearance of low but abnormal levels In one embodiment, this invention provides a method of (>30 mg/day or 20 ug/min) of albumin in the urine (microal treating ovascular disease in a human Subject, comprising the buminuria), followed by albuminuria (>300 mg/24 h or 200 step of administering to said Subject a compound of this ug/min) that develops over a period of 10-15 years. In patients invention or its isomer, pharmaceutically acceptable salt, 15 with type 1 diabetes, diabetic hypertension typically becomes pharmaceutical product, hydrate, N-oxide, or any combina manifest early on, by the time that patients develop microal tion thereof. buminuria. Once overt nephropathy occurs, the glomerular In one embodiment, the compound is characterized by the filtration rate (GFR) falls over a course of times, which may structure of the formula I-XXII, or any embodiment thereof, be several years, resulting in End Stage Renal Disease as herein described. (ESRD) in diabetic individuals. In one embodiment this invention provides a method fora) Hypertension is another comorbid factor for renal disease. treating, preventing, Suppressing inhibiting atherosclerosis b) In some embodiments, treatment of renal disease according to treating, preventing, Suppressing inhibiting liver damage due the present invention may comprise concomitant treatment to fat deposits comprising the step of administering to the with a compound of this invention and an agent which treats Subject a compound as described herein and/or its analog, 25 hypertension. derivative, isomer, metabolite, pharmaceutically acceptable Androgen-dependent conditions which may be treated salt, pharmaceutical product, hydrate, N-oxide, prodrug, with the compounds and/or compositions as herein described, polymorph, crystal, or any combination thereof, or a compo comprising the methods of the present invention include sition comprising the same, in an amount effective to treat, those conditions which are associated with aging. In one prevent or inhibit atherosclerosis and liver damage due to fat 30 embodiment, the compound as described herein is useful ina) deposit. Age-related functional decline (ARFD); b) reversal or pre In one embodiment, the compound as described herein is vention of ARFD; c) reversal or prevention of ARFD in eld useful in a) treating, preventing, Suppressing, inhibiting, or erly d) reversal or prevention of ARFD-induced sarcopenia or reducing atherosclerosis; b) treating, preventing, Suppressing osteopenia; e) Andropause, andropausal vasomotor Symp inhibiting liver damage due to fat deposits. 35 toms, f) andropausal gynecomastia, muscle strength/func In one embodiment atherosclerosis refers to a slow, com tion, g) bone strength/function; h) Anger, i) Asthenia; ) plex disease that may begin with damage to the innermost Chronic fatigue syndrome; k) Cognitive impairment; and/or layer of the artery. In another embodiment the causes of l) improving cognitive function. damage to the arterial wall may includea) elevated levels of cholesterol and in the blood; b) high blood pressure; c) 40 In one embodiment, the compound as described herein is tobacco Smoked) diabetes. In another embodiment, the con useful in treating inflammation and related disorders such dition is treatable in a smoker, despite the fact that tobacco as: a) prevention, treatment, or reversal of arthritis; b) preven Smoke may greatly worsen atherosclerosis and speed its tion, treatment, or reveral of an arthritic condition Such as Behcet’s disease (autoimmune vasculitis), bursitis, calcium growth in the coronary arteries, the aorta and arteries in the pyrophosphate dihydrate crystal (CPPD), deposition disease legs. Similarly, in another embodiment, the methods of this 45 invention may be useful in treating Subjects with a family (or pseudogout), carpal tunnel syndrome, connective tissue history of premature cardiovascular disease who have an disorders, Crohn's disease, Ehlers-Danlos syndrome (EDS), increased risk of atherosclerosis. fibromyalgia, gout, infectious arthritis, inflammatory bowel In one embodiment, liver damage due to fat deposits refer disease (IBD), juvenile arthritis, systemic lupus erythemato to the build-up of fat in the liver cells forming a Fatty Liver 50 SuS (SLE), Lyme’s disease, Marfan syndrome, myositis, which may be associated with or may lead to inflammation of osteoarthritis, polyarteritis nodosa, polymyalgia rheumatica, the liver. This can cause Scarring and hardening of the liver. psoriasis, psoriatic arthritis, Raynaud's phenomenon, reflex When scarring becomes extensive, it is called cirrhosis. sympathetic dystrophy syndrome, Reiter's syndrome, rheu In another embodiment the fat accumulates in the liver as matoid arthritis, Scleroderma, Sjögrens syndrome, tendonitis obesity. In another embodiment fatty liver is also associated 55 or ulcerative colitis; c) preventing, treatment, or reversing an with diabetes mellitus, high blood triglycerides, and the autoimmune disease. heavy use of alcohol. In another embodiment fatty Liver may In one embodiment, the compound as described herein is occur with certain illnesses such as tuberculosis and malnu useful in prevention of iatrogenic effects comprising acute trition, intestinal bypass Surgery for obesity, excess vitamin A fatigue syndrome (post-Surgical) or androgen-deprivation in the body, or the use of certain drugs such as valproic acid 60 therapy (ADT) induced side effects such as reduced muscle (trade names: Depakene/Depakote) and corticosteroids (cor mass, reduced muscle strength, frailty, hypogonadism, tisone, prednisone). Sometimes fatty liver occurs as a com osteoporosis, osteopenia, decreased BMD and/or decreased plication of pregnancy. bone mass. In one embodiment, Subjects with kidney disease, in par In one embodiment, the compounds and/or compositions ticular male subjects with end-stage renal disease (ESRD) 65 and/or methods of use thereofare for the treatment of human Suffer from hypogonadism, with some having concomitant Subjects, wherein, in one embodiment, the Subject is male, or moderate to severe protein-energy malnutrition (PEM), in another embodiment, the subject is female. US 7,772,433 B2 125 126 In one embodiment, the methods of the present invention readily determined by a person skilled in the art. In some comprise administering a compound of this invention as the embodiments, the methods of the present invention comprise sole active ingredient. However, also encompassed within the personalized medicine methods which treat the needs of a scope of the present invention are methods for diabetes and single patient. In one embodiment, different needs can be due related disorders, hormone therapy, dry eye, obesity, treating to the particular disease, severity of the disease, the overall prostate cancer, delaying the progression of prostate cancer, medical state of a patient, or the age of the patient. In some and for preventing and/or treating the recurrence of prostate embodiments, personalized medicine is the application of cancer, male contraception; treatment of osteoporosis, treat genomic data to better target the delivery of medical interven ment of conditions associated with ADIF and for treatment tions. Methods of personalized medicine, in some embodi and/or prevention of chronic muscular wasting which com 10 ments, serve as a tool in the discovery and clinical testing of prise administering the compounds in combination with one new products of the present invention. In one embodiment, or more therapeutic agents. These agents include, but are not personalized medicine involves the application of clinically limited to: LHRH analogs, reversible antiandrogens, anties useful diagnostic tools that may help determine a patients trogens, anticancer drugs, 5-alpha reductase inhibitors, aro predisposition to a particular disease or condition. In some matase inhibitors, progestins, agents acting through other 15 embodiments, personalized medicine is a comprehensive nuclear hormone receptors, selective estrogen receptor approach utilizing molecular analysis of both patients and modulators (SERM), progesterone, estrogen, PDE5 inhibi healthy individuals to guide decisions throughout all stages of tors, apomorphine, bisphosphonate, and one or more addi the discovery and development of pharmaceuticals and diag tional SARMs. nostics; and applying this knowledge in clinical practice for a Thus, in one embodiment, the methods of the present more efficient delivery of accurate and quality healthcare invention comprise administering the compound of this through improved prevention, diagnosis, treatment, and invention in combination with diabetes drug such as Trogli monitoring methods. taZone, RosiglitaZone, and PioglitaZone. In another embodi It is to be understood that any use of any of the compounds ment, the methods of the present invention comprise admin as herein described may be used in the treatment of any istering the compound in combination with an LHRH analog. 25 disease, disorder or condition as described herein, and repre In another embodiment, the methods of the present invention sents an embodiment of this invention. comprise administering the compound, in combination with a The following examples are presented in order to more reversible antiandrogen. In another embodiment, the methods fully illustrate the preferred embodiments of the invention. of the present invention comprise administering the com They should in no way, however, be construed as limiting the pound, in combination with an antiestrogen. In another 30 broad scope of the invention. embodiment, the methods of the present invention comprise administering the compound, incombination with an antican EXAMPLES cer drug. In another embodiment, the methods of the present invention comprise administering the compound, in combi Example 1 nation with a 5-alpha reductase inhibitor. In another embodi 35 ment, the methods of the present invention comprise admin Synthesis of (S) Enantiomer of Compound of istering the compound, in combination with an aromatase Formula II inhibitor. In another embodiment, the methods of the present invention comprise administering the compound, in combi nation with a progestin. In another embodiment, the methods 40 of the present invention comprise administering the com C pound, in combination with an agent acting through other -- Cy" He2NNaOHacetone nuclear hormone receptors. In another embodiment, the O N H O-5°C. RT3 hrs methods of the present invention comprise administering the H compound, in combination with a selective estrogen receptor 45 modulators (SERM). In another embodiment, the methods of the present invention comprise administering the compound, in combination with a progesterone. In another embodiment, N H the methods of the present invention comprise administering the compound, in combination with an estrogen. In another 50 embodiment, the methods of the present invention comprise administering the compound, in combination with a PDE5 inhibitor. In another embodiment, the methods of the present invention comprise administering the compound, in combi (2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid. D-Pro nation with apomorphine. In another embodiment, the meth 55 line, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2N NaOH ods of the present invention comprise administering the com and cooled in an ice bath; the resulting alkaline solution was pound, in combination with a bisphosphonate. In another diluted with acetone (71 mL). An acetone solution (71 mL) of embodiment, the methods of the present invention comprise metacryloly chloride (13.56 g., 0.13 mol) and 2N NaOH solu administering the compound, in combination with one or tion (71 mL) were simultaneously added over 40 minto the more additional SARMs. In some embodiments, the methods 60 aqueous solution of D-proline in an ice bath. The pH of the of the present invention comprise combined preparations mixture was kept at 10-11° C. during the addition of the comprising the compound and an agent as described herein metacryloly chloride. After stirring (3h, room temperature), above. In some embodiments, the combined preparations can the mixture was evaporated in vacuo at a temperature at be varied, e.g., in order to cope with the needs of a patient 35-45° C. to remove acetone. The resulting solution was subpopulation to be treated or the needs of the single patient 65 washed with ethyl ether and was acidified to pH 2 with con which different needs can be due to the particular disease, centrated HC1. The acidic mixture was saturated with NaCl severity of the disease, age, sex, or body weight as can be and was extracted with EtOAc (100 mLX3). The combined US 7,772,433 B2 127 128 extracts were dried over NaSO, filtered through Celite, and acetate (100 mLx4). The combined extracts were washed evaporated in vacuo to give the crude product as a colorless with saturated NaHCO (100 mLx4). The aqueous solution oil. Recrystallization of the oil from ethyl ether and hexanes was acidified with concentrated HCl to pH=1, which, in turn, afforded 16.2 (68%) of the desired compound as colorless was extracted with ethyl acetate (100 mLx4). The combined crystals: mp 102-103°C. (lit. 214 mp 102.5-103.5°C.); the organic Solution was dried over Na2SO4, filtered through NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. "H NMR (300 MHz, Celite, and evaporated in vacuo to dryness. Recrystallization DMSO-d) & 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) from toluene afforded 10.2 g (86%) of the desired compound and 5.03 (s) for the second rotamer (totally 2H for both as colorless crystals: mp 107-109° C. (lit. 214 mp 109-113° rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24 10 C. for the S-isomer); H NMR (300 MHz, DMSO-d) & 3.63 4.20 (m) for the second rotamer (totally 1H for both rotamers, (d. J=10.1 Hz, 1H, CHH), 3.52 (d. J=10.1 Hz, 1H, CHH), CH at the chiral canter), 3.57-3.38 (m, 2H, CH), 2.27-2.12 1.35 (s.3H, Me); IR (KBr)3434 (OH), 3300-2500 (COOH), (1H, CH), 1.97-1.72 (m, 6H, CH, CH, Me); C NMR (75 1730 (C=O), 1449, 1421, 1380, 1292, 1193, 1085 cm; MHz, DMSO-d) 8 for major rotamer 173.3, 169.1, 140.9, C+10.5° (c=2.6, MeOH); Anal. Calcd. for CH, BrO: C 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 15 26.25, H 3.86. Found: C 26.28, H 3.75. 170.0, 1416, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7: IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508,

1459, 1369, 1348, 1178 cm; C+80.8° (c=1, MeOH): Anal. Calcd. for CHNO: C, 59.00; H, 7.15; N, 7.65. Found: C, 59.13; H, 7.19; N, 7.61. Br

(R)-3-bromo-2-hydroxy CO H 2-methylpropanoic acid N 25 R-18 N H NBSDMF Her FC NH2 RT O O w Br EtN/RT O -- Her H3C NC NC (3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo O 2.1-c. 14 oxazine-1,4-dione. A solution of NBS (23.5 g. FC N e Br 0.132 mol) in 100 mL of DMF was added dropwise to a stirred H a. 35 2. solution of the (methyl-acryloyl)-pyrrolidine (16.1 g, 88 O mmol) in 70 mL of DMF under argon at room temperature, and the resulting mixture was stirred 3 days. The solvent was removed in vacuo, and a yellow solid was precipitated. The Solid was suspended in water, stirred overnight at room tem Synthesis of (2R)-3-Bromo-N-4-cyano-3-(trifluorom perature, filtered, and dried to give 18.6 (81%) (smaller 40 ethyl)phenyl-2-hydroxy-2-methylpropanamide. Thionyl weight when dried ~34%) of the title compound as a yellow solid: mp 152-154° C. (lit. 214 mp 107-109° C. for the chloride (46.02 g, 0.39 mol) was added dropwise to a cooled S-isomer); H NMR (300 MHz, DMSO-d) & 4.69 (dd, J=9.6 solution (less than 4°C.) of R-18 (51.13 g, 0.28 mol) in 300 HZ, J=6.7 Hz, 1H, CH at the chiral center), 4.02 (d. J=11.4 Hz, mL of THF under an argon atmosphere. The resulting mixture 1H, CHH), 3.86 (d. J=11.4 Hz, 1H, CHH), 3.53-3.24 (m, 45 was stirred for 3 h under the same condition. To this was 4H, CH), 2.30-2.20 (m, 1H, CH), 2.04-1.72 (m,3H, CH, and added EtN (39.14g, 0.39 mol) and stirred for 20 min under CH), 1.56 (s. 2H, Me); C NMR (75 MHz, DMSO-d) & the same condition. After 20 min, 5-amino-2-cyanobenzotri 167.3, 163.1,83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) fluoride (40.0 g, 0.21 mol), 400 mL of THF were added and 3474, 1745 (C=O), 1687 (C=O), 1448, 1377, 1360, 1308, then the mixture was allowed to stir overnight at room tem 1227, 1159, 1062 cm; C+124.5° (c=1.3, chloroform): 50 perature. The solvent was removed under reduced pressure to Anal. Calcd. for CHBrNO: C, 41.24; H, 4.61; N, 5.34. give a solid which was treated with 300 mL of HO, extracted Found: C 41.46, H 4.64, N 5.32. with EtOAc (2x400 mL). The combined organic extracts were washed with saturated NaHCO solution (2x300 mL)

55 and brine (300 mL). The organic layer was dried over MgSO H and concentrated under reduced pressure to give a solid, which was purified from column chromatography using 24% HBir HO Her CHC1/EtOAc (80:20) to give a solid. This solid was recrys O Reflux OH tallized from CHCl2/hexane to give 55.8 g. (73.9%) of (2R)- O Br (R)-3-bromo-2-hydroxy 60 3-Bromo-N-4-cyano-3-(trifluoromethyl)phenyl-2-hy H3N C 2-methylpropanoic acid droxy-2-methylpropanamide (R-32a) as a light-yellow solid. H NMR (CDC1/TMS) & 1.66 (s.3H, CH), 3.11 (s, 1H, (2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid. A OH), 3.63 (d. J=10.8 Hz, 1H, CH,), 4.05 (d. J=10.8 Hz, 1H, mixture of bromolactone (18.5g, 71 mmol) in 300 mL of 24% 65 CH), 7.85 (d. J=8.4 Hz, 1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, HBr was heated at reflux for 1 h. The resulting solution was 1H, ArH), 8.12 (d. J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH). diluted with brine (200 mL), and was extracted with ethyl Calculated Mass: 349.99, M-H 349.0. M.p.: 124-126° C., US 7,772,433 B2 129 130 Materials and Methods: Metabolic Stability Measured in Human Liver Microsomes: NC Compounds of formula II in this study were incubated at a final concentration of 0.6 uM. Microsome reactions were performed under either Phase I or “Phase I and II' conditions, NH where indicated. Compound stocks (10 mMACN) were ini tially diluted to a concentration of 60LM (in 60% ACN/HO) R-19 resulting in a “working stock” solution of 100x. Human liver C microsomes were utilized at a final concentration of 0.6 10 K2CO3 mg/ml. Duplicate wells were used for each time point (0, 6, He2-propanol 10, 30, and 60 minutes). Reactions were carried out at 37°C. HO F in a shaking water bath, and the final concentration of solvent NC C was kept constant at 0.6%. The final volume for each reaction O was 600 ul, comprised of 368 ul of 100 mMKPO, buffer, (pH 15 7.4); 12.6 ul of HLM (from a 20 mg/ml stock); 6 Jul of

FC NH O F 100x"working stock' drug compound, and 126 ul of NRS “master mix' solution. At each time point, 100 ul of reaction OH was removed and added to a sample well containing 100 ul of ice-cold, 100% ACN (plus internal standards), to stop the reaction. The NRS “master mix' is a solution of glucose Synthesis of (S)-3-(4-chloro-3-fluorophenoxy)-N-(4-cy 6-phosphate dehydrogenase, NADP, MgCl, and glucose ano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpro 6-phosphate, prepared per manufacturers instructions (BD panamide. A mixture of bromoamide (2R)-3-bromo-N-4- Biosciences, Waltham, Mass.). Each 6.0 ml stock of NRS cyano-3-(trifluoromethyl)phenyl-2-hydroxy-2- “master mix' solution contains 3.8 ml H.O. 1.0 ml solution methylpropanamide, (R-19) 2.0 g, 5.70 mmol), anhydrous 25 “A” (Cat. #461220), and 0.2 ml solution “B” (Cat. #461200). KCO (2.4g, 17.1 mmol) was heated to reflux for 2 hand Human liver microsomes (lot #0610279, Xenotech Corp.) then concentrated under reduced pressure to give a solid. The represented a pool of 60 donors. resulting solid was treated with 4-chloro-3-fluorophenol (1.3 Samples were centrifuged at 3,000 rpm for 10 minutes at 4 g, 8.5 mmol) and anhydrous KCO (1.6 g., 11.4 mmol) in 50 C. to remove debris and precipitated protein. Approximately mL of 2-propanol was heated to reflux for 3 h and then 30 160 ul of Supernatant was Subsequently transferred to a new concentrated under reduced pressure to give a solid. The sample block for analysis. The concentration of parent drug residue was treated with 100 mL of HO and then extracted remaining in each well (expressed as percent remaining ver with EtOAc (2x100 mL). The combined EtOAc extracts were sus Time 0, at the beginning of the reaction) was measured washed with 10% NaOH (4x100 mL) and brine, successively. by LC/MS, as detailed below. The intrinsic clearance rates The organic layer was dried over MgSO and then concen 35 (CLint) were calculated from 0-60 minutes based on first trated under reduced pressure to give an oil which was puri order decay kinetics as a function of microsomal protein fied by column chromatography using EtOAc/hexane (50:50) concentration. to give a solid which was recrystallized from CH2Cl2/hexane to give 1.7 g (70.5%) of (S)-3-(4-chloro-3-fluorophenoxy)- Permeability across Human, Intestinal Epithelial Monolay 40 CS N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-meth Permeability was measured in the Apical (pH 6.6) to Baso ylpropanamide as a colorless Solid. lateral (pH 7.4) and Basolateral (pH 7.4) to Apical (pH 6.6) "H NMR (CDC1/TMS) & 1.60 (s.3H, CH,), 3.28 (s, 1H, directions across polarized, Caco-2 epithelial monolayers. OH), 3.98 (d. J=9.05 Hz, 1H, CH), 6.64-6.76 (m, 2H, ArH), Compound stocks (10 mM acetonitrile) were tested in the 7.30 (d. J=8.67 Hz, 1H, Arm), 7.81 (d. J=8.52 Hz, 1H, ArH), 45 study at a final concentration of 10 uM. The concentration of 7.96 (q, J=2.07, 8.52 Hz, 1H, ArH), 8.10 (d. J=2.07 Hz, 1H, drug in the receiver well was measured by LC/MS/MS using ArH), 9.10 (s, 1H, NH). Calculated Mass: M-H-414.9. Mp: a standard curve. The apparent permeability (Papp) for each 132-1349 C. compound was calculated, and values (A-B) were classified aS Example 2 50 Poor (Papp: <1), Low (Papp 1-2), Medium (Papp 2-10) or High (Papp. 10). Metabolic Stability of the Compounds of this Invention Papp(x10 cm/sec)=Amount transported/ (Area. Initial concentration*Time)

Metabolic stability assays were performed in order to 55 assess the in vitro half-life of compounds of formula II when V-volume of the receptor chamber (ml, or cm) incubated with human liver microsomes. The data generated A=area of the membrane insert (cm) was transformed to determine intrinsic clearance values. In a Ci-initial concentration of drug (uM) separate experiment, permeability across human, intestinal Cf-final concentration of drug (uM) epithelial monolayers (Caco-2 cells) was used as a measure of 60 intestinal permeability as well as an indicator of efflux poten Tassay time (seconds) tial. Caco-2 cells are often used as an early Screening Surro Analytical Methods: gate for oral bioavailability. Microsomal half-life can be con All samples were analyzed on the MDS/Sciex API4000 Q Verted to in vitro clearance values as a means to predict Trap system with electrospray ionization (ESI) in the positive hepatic intrinsic clearance. Intrinsic clearance is defined as 65 or negative SIM mode, depending on the compounds. The the functional ability of the liver to metabolize a drug or other mobile phases were isocratic at 30% A (0.1% formic acid in compound. water) and 70% B (0.1% formic acid in acetonitrile) with a US 7,772,433 B2 131 132 flow rate of 0.4 m/min. A Phenomenex Luna Phenyl-Hexyl MIB (1.84 nM). In addition, the concentration of HMIB column (60x2.0 mm ID, 6L) was used. The injection volume required to saturate ARLBD was determined to be 4 nM. was 10 uL. The total run time per sample was 1.6 to 3.0 Compound of formula (II) was tested in a range of concen minutes. Tamoxifen and diclofenac were used as internal trations from 10' to 10 Musing the conditions described standards for the positive and negative mode, respectively. 5 above. Following incubation, plates were harvested with The percentage of parent drug compound remaining after GF/B filters on the Unifilter-96 Harvester (PerkinElmer) and each time point was determined relative to the initial mea washed three times with ice-cold buffer B (60 mM Tris, pH Sured concentration at the beginning of the reaction (To min). 7.2). The filter plates were dried at RT, then 36 ul Micros Data Analysis: cint-O cocktail was added to each well and sealed with 10 TopSeal-A. The receptor bound radioligand was then deter For half-life determination, data was fitted using GraphPad mined with the TopCount(R) NXT Microplate Scintillation Prism, v 4.03 with the non-linear regression equation “one Counter (PerkinElmer). phase exponential decay defined as: The specific binding of HIMIB at each concentration of Y=Spanexp(-KX)+Plateau (decays to Plateau with a SARM was determined by subtracting the nonspecific bind first-order rate constant, K). 15 ing of HIMIB (determined by incubating with 10 Munla “-K is the slope of the curve. The half life (minutes), T, beled MIB), and expressed as a percentage of the specific =ln 0.6/-K and is therefore defined as -0.693/-K, or 0.693/ binding in the absence of each SARM. The concentration of K, a?k/a -0.693/slope). Intrinsic Clearance (ul/min/mg SARM required to decrease the HIMIB binding by 60%, protein) is defined as: CLint=0.693*(1/T)*(ml incuba IC value, was determined by computer-fitting the data with tion/mg protein)*1000; This equation can also be 2 SigmaPlot and non-linear regression with the standard curve expressed as (K* 1000)/microsome conc. four parameter logistic curve. The equilibrium binding con stant (K) of each compound was then determined with the Results: following equation:

TABLE 1. 25 Metabolic Stability Measured in Human Liver Microsomes: where K is the equilibrium dissociation constant of HIMIB (1.84 nM), and L is the concentration of HIMIB (4 nM). HalfLife CL in Compound (minutes) (ulmin/mg) HalfLife CLint Results: having Phase I Phase I (minutes) (ul/min/mg) 30 formula only only Phase I+II Phase I+II The binding affinity for compound of formula (II) was tested in the radioligand binding assay with ARLBD as the receptor II Stable <1 Stable <1 with K, (nM)=8.1 The results had shown that in vitro half-life as determined Example 4 from the microsomal assays demonstrated that compound of 35 formula (II) under both phase I and phase I/II metabolic Preclinical Anabolic and Androgenic Pharmacology conditions. As shown in Table 1, the compound didn't exhibit of Compound (II) in Intact and Castrate Male Rats an intrinsic clearance (CLint) value greater than 10 ul/min/ mg. It is generally accepted that an in vitro CLint value of less Anabolic and androgenic efficacy of Compound (II) than 10 ul/min/mg protein represents favorable metabolic 40 administered by daily oral gavage were tested. The S-isomer stability of the test compound. Compound of formula II of Compound (II) was synthesized and tested as described exhibited low clearance in human liver microsomes. In con herein clusion, based on the data reported herein, compound of Materials and Methods: formula (II) exhibited favorable metabolic stability profiles in 45 Male Sprague-Dawley rats weighing approximately 200 g vivo studies. were purchased from Harlan Bioproducts for Science (India Example 3 napolis, Ind.). The animals were maintained on a 12-hlight/ dark cycle with food (7012C LM-485 Mouse/Rat Sterilizable Diet, Harlan Teklad, Madison, Wis.) and water available ad Androgen Receptor Binding Affinity of SARMs 50 libitum. The animal protocol was reviewed and approved by the Institutional Animal Care and Use Committee of the Uni Materials and Methods: versity of Tennessee. The anabolic and androgenic activity of The androgen receptor (AR) binding affinity of SARMs Compound (II) in intact animals, acutely orchidectomized was determined by using an in vitro competitive radioligand (ORX) animals and chronically (9 days) ORX rats. binding assay with 17o-methyl-H-Mibolerone (HMIB, 55 The testarticle for this study was weighed and dissolved in PerkinElmer), a high affinity AR ligand. Recombinant andro 10% DMSO (Fisher) diluted with PEG 300 (Acros Organics, gen receptor ligand binding domain (AR LBD) was com NJ) for preparation of the appropriate dosage concentrations. bined with HIMIB in buffer A (10 mM Tris, pH 7.4, 1.6 mM The animals were housed in groups of 2 to 3 animals percage. disodium EDTA, 0.26 M sucrose, 10 mM sodium molybdate, Animals were randomly assigned to one of seven groups 1 mM PMSF) to determine the equilibrium dissociation con 60 consisting of 4 to 5 animals per group. Control groups (intact stant(K) of HIMIB. Protein was incubated with increasing and ORX) were administered vehicle daily. Compound (II) concentrations of HIMIB with and without a high concen was administered via oral gavage at doses of 0.01, 0.03, 0.1, tration of unlabeled MIB in order to determine total and 0.3, 0.75, and 1 mg/day to both intact and ORX groups. non-specific binding. Non-specific binding was then Sub Where appropriate, animals were castrated on day one of the tracted from total binding to determine specific binding and 65 study. Treatment with Compound (II) began nine days post graphed using SigmaPlot and non-linear regression for ligand ORX and was administered daily via oral gavage for fourteen binding curve with one site Saturation to determine the K of days. US 7,772,433 B2 133 134 The animals were sacrificed under anesthesia (ketamine? patient populations, in which androgens are currently con Xyalzine, 87:13 mg/kg) and body weights were recorded. In traindicated, access to anabolic agents. addition, Ventral prostate, seminal vesicles, and levator ani Compound II exhibited anabolic muscle/prostate ratio in muscle were removed, individually weighed, normalized to castrated rats of 4.10, 2.39, 2.28, 1.97, 1.53, 1.05 following body weight, and expressed as a percentage of intact control. doses of 0.01, 0.03, 0.1, 0.3, 0.75 and 1 mg/day, respectively. Students T-test was used to compare individual dose groups Pharmacology results following 1 mg/day of compound II to the intact control group. Significance was defined a priori exhibited that prostate weight was 110%+14% of intact con as a P-value <0.05. Ventral prostate and seminal vesicle trol and levator ani muscle weight was 129%+10% of intact weights were evaluated as a measure of androgenic activity, control. Compound II maintained prostate weight following whereas levator ani muscle weight was evaluated as a mea 10 orchidectomy at 123+22% of intact controls and levator ani sure of anabolic activity. Blood was collected from the muscle weight at 129-14% of intact controls. A range of abdominal aorta, centrifuged, and sera were frozen at-80°C. between 0.1 mg/day to 0.3 mg/day of Compound II restored 100% of levator animuscle weight, while between 39 to 60% prior to determination of serum hormone levels. Serum prostate weight was restored. luteinizing hormone (LH) and follicle stimulating hormone 15 (FSH) concentrations were determined. Example 5 Results: A series of dose-response studies in intact and castrated In Vitro CYP Inhibition Assay rats in order to evaluate the potency and efficacy of Com pound (II) in both androgenic (prostate and seminal vesicles) Materials and Methods: and anabolic (levator ani muscle) tissue was conducted. In P450 enzyme inhibition was measured using human intact animals, Compound (II) treatment resulted in decreases cDNA-expressed CYP3A4, 2D6, 2019, 209, and 1A2 in the weight of both prostate and seminal vesicles while the recombinant enzymes and fluorogenic Substrates (coumarin levator ani muscle weight was significantly increased. Leva 25 analogues) that are converted to fluorescent products. The torani muscle weight following Compound II treatment were analogues utilized for each isoenzyme are as follows: 7-Ben 100%-10%, 98%+7%, 110%-5%, 110%-5%, 125%+10%, Zyloxy-trifluoromethylcoumarin, (BFC) for 3A4; 3-2-(N.N- and 129%+10% of intact controls following doses of 0.01, diethyl-N-methyl amino)ethyl 7-methoxy-4-methylcou 0.03, 0.1, 0.3, 0.75, and 1 mg/day, respectively. The prostate marin, (AMMC) for 2D6: 3-Cyano-7-Ethoxycoumarin, weights were 117%+20%, 98%+15%, 82%+20%. 62%+5%, 30 (CEC) for 2C19 and 1A2; and 7-Methoxy-4-trifluoro-meth 107%+30%, and 110%+14% of intact controls following ylcoumarin, (MFC) for 2C9. These substrates were utilized at doses of 0.01, 0.03, 0.1.0.3, 0.75, and 1 mg/day, respectively. a single concentration (either 50 LM or 75uM) at or near the These results are significant since current androgen therapies apparent Km for each Substrate. Fluorescence intensity was are contraindicated in some patient populations due to the measured using a Wallac 1420 Victor Multi-label Counter proliferative androgenic effects in prostate and breast tissues. 35 Model (Perkin-Elmer, Wellesley, Mass.), with an excitation However, many patients in these populations could benefit wavelength filter of 405 nm, and an emission filter of 460 nm from the anabolic actions of androgens in muscle and bone. (535 nm for the 3A4 and 2C9 substrates). Compound stocks Since Compound (II) exhibited tissue selective anabolic (10 mM in a 4:1 ratio of acetonitrile. DMSO) were tested in effects, it may be possible to treat patient groups in which this study using an 8-point dose response curve in duplicate androgens were contraindicated in the past. 40 (ranging from 0.15uM-20.0 uM). The concentration of aceto In castrated, ORX animals, prostate weights following nitrile was kept constant at 0.4%, and the reaction was carried Compound II treatment were 10%+3%, 12%+3%, 26%+7%, out at 37° C. for 30 minutes. Averages (minus background) 39%+6%. 60%-14%, 88%–16%, and 123%22% of intact and ICso values were calculated. controls following doses of 0, 0.01, 0.03, 0.1, 0.3, 0.75, and 1 Results: mg/day, respectively (FIG. 2). Similarly, seminal vesicle 45 weights were 11%+1%, 11%+1%, 11%+1%, 27%+14%, The in-vitro Screening results for potential drug-drug inter 58%+18%, 86%+12%, and 100%-8% of intact controls fol actions (DD1) of SARM compound of formula II is presented lowing doses of 0, 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg/day, in Table 2: respectively (FIG. 2). Significant increases were seen in leva torani muscle weights of in all dose groups, when compared 50 TABLE 2 to intact controls. The levator ani muscle weights were 48%-8%, 50%-5%, 62%.6%, 89%+10%, 118%+6%, CYP (P450) Inhibition. IC50 (IM) 134%-8% and 129%+14% of intact controls corresponding Compound 3A4 2D6 2C19 2C9 1A2 to 0, 0.01, 0.03, 0.1, 0.3, 0.75, and 1.0 mg/day dose groups, II >2O 17.7 2.4 1.3 >2O respectively (FIG. 2). 55 Testosterone propionate (TP) and S-3-(4-Acetylami nophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluorom ethylphenyl) propionamide (S-4), maximally stimulated the Example 6 levator ani muscle weight to 104% and 10.1%, respectively. These data show that Compound (II) exhibited significantly 60 Pharmacokinetics of Compound (II) in Dogs greater efficacy and potency than eitherTP or S-4. As a whole, these data show that Compound II is able to stimulate muscle In order to determine the pharmacokinetics of Compound growth in the presence or absence of testosterone while exert II, the compound was administered to beagle dogs perorally, ing anti-proliferative effects on the prostate. These data show and circulating plasma levels, terminal elimination half-life that Compound (II) restore lost muscle mass in patients with 65 (t/2), total body clearance (CL), terminal volume distribution sarcopenia or cachexia. Additionally, the antiproliferative (VZ) and absolute bioavailability (F%) (Table 3) were deter effects of Compound (II) on the prostate may allow some mined. Compound I was rapidly and completely. US 7,772,433 B2 136 shown and described hereinabove. Rather, the scope of the TABLE 3 invention is defined by the claims that follow: What is claimed is: Compound II 1. A compound represented by the structure of formula (I): T/3 (hr) 37 - 26.8 CL (mL/min kg) O.36 O.12 VZ (mL/kg) 1266,352 (I) F9% 72.5%

10 Example 7 Anabolic and Androgenic Activity of SARM Compounds in Intact and Castrated Male Rats 15 wherein Q is alkyl, F, Cl, Br, I, CF, CN, C(R), Sn(R), The in vivo pharmacological activity of each synthetic AR N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHC ligand (listed in Table 4, below) was examined in five male SCF, NHCSR NHSOCH, NHSOR, OR, COR, Sprague-Dawley rats weighing approximately 200 g. Ani OCOR, OSOR, SOR, SR; and mals were castrated via a scrotal incision under anesthesia 24 R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, h before drug treatments and received daily Sc injections of CHF, CF, CFCF, aryl, phenyl, F, Cl, Br, I, alkenyl or the compound of interest at a dose rate of 1 mg/d for 14 d. All OH: compounds of interest were freshly dissolved in vehicle con or its isomer, pharmaceutically acceptable salt or any com taining dimethylsulfoxide (5%, vol/vol) in polyethylene gly bination thereof. col300 before dose administration. An additional two groups 25 2. The compound of claim 1, wherein said compound is of animals with or without castration received vehicle only and served as castrated or intact control groups, respectively. represented by the structure of formula II: Animals were killed at the end of the treatment. Plasma samples were collected and stored at -80C for future use. The II Ventral prostate, seminal vesicles, and levator ani muscle 30 NC C were removed, cleared of extraneous tissue, and weighed. All

organ weights were normalized to body weight and com pared. The weights of prostate and seminal vesicles were used FC NH to evaluate androgenic activity, whereas the levator ani muscle weight was used as a measure of anabolic activity. The 35 results are summarized in FIGS. 2 and 3. or its isomer, or pharmaceutically acceptable salt, or any TABLE 4 combination thereof. 3. A composition comprising a compound of claim 1, and 40 a pharmaceutically acceptable carrier, diluent, salt or a com bination thereof. ON 4. A method of hormone therapy comprising the step of contacting an androgen receptor of a Subject with a com pound of claim 1 or its isomer, pharmaceutically acceptable FC 45 salt or any combination thereof, in an amount effective to effect a change in an androgen-dependent condition. 5. A method of treating a subject wherein said subject Suffers from osteoporosis, osteopenia, increased bone resorp Compound Rs tion, bone fracture, bone frailty, loss of bone mineral density S-1 50 (BMD), or any combination thereof, comprising the step of C-1 administering to said Subject a compound of claim 1, or its C-2 H 3 C-3 isomer, pharmaceutically acceptable salt or any combination C-4 thereof, in an amount effective to treat osteoporosis, increase C-6 bone resorption, bone fracture, bone frailty, or loss of bone C-8 55 mineral density (BMD) in said subject. C-10 C-11 6. A method of treating, reducing the incidence of delaying C-12 progression of reducing the severity of, or alleviating Symp C-13 toms associated with a muscle wasting disorder in a Subject, C-14 comprising the step of administering to said Subject a com C-17 C-18 60 pound of claim 1 or its isomer, pharmaceutically acceptable C-22 salt or any combination thereof, in an amount effective to treat C-23 said muscle wasting disorder in said subject. 7. The method of claim 6, wherein said muscle wasting disorder is due to a pathology, illness, disease or condition. It will be appreciated by a person skilled in the art that the present invention is not limited by what has been particularly k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,772,433 B2 Page 1 of 4 APPLICATIONNO. : 11/785250 DATED : April 16, 2007 INVENTOR(S) : James T. Dalton et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

In Figure 1A the title should be: --I. Synthetic Scheme for (S)-II Compound:-- And not --I. Synthetic Scheme for (S)-III II Compound:--

In Figure 1B the title should be: --II. Synthetic Scheme for (R)-II Compound:-- And not --II. Synthetic Scheme for (R)-III II Compound:--

In Figure 1C the title should be: --III. Synthetic Scheme for (S)-II (oxirane intermediate) Compound:-- And not --III. Synthetic Scheme for (S)-III II (oxirane intermediate) Compound:--

In Figure 1D the title should be: --IV. Synthetic Scheme for (R)-II (oxirane intermediate) Compound:-- And not --IV. Synthetic Scheme for (R)-III II (oxirane intermediate) Compound:--

Signed and Sealed this Seventh Day of December, 2010

David J. Kappos Director of the United States Patent and Trademark Office CERTIFICATE OF CORRECTION (continued) Page 2 of 4 U.S. Pat. No. 7,772,433 B2

In Figure 1E the title should be: --V. Synthetic Scheme for (S)-II involving B-ring addition prior to A-ring addition:-- And not --V. Synthetic Scheme for (S)-III II involving B-ring addition prior to A-ring addition:--

In Figure 1F the title should be: --VI. Synthetic Scheme of (R)-II involving B-ring addition prior to A-ring addition:-- And not --VI. Synthetic Scheme of (R)-III II involving B-ring addition prior to A-ring addition:--

In Figure 1G the title should be: --VII. Synthetic Scheme of (S)-II Using Chiral Intermediate and Involving B-ring Addition prior to A-ring Addition:-- And not --VII. Synthetic Scheme of (S)-III II Using Chiral Intermediate and Involving B-ring Addition prior to A-ring Addition:--

In Figure 1H the title should be: --VIII. Synthetic Scheme for (R)-II Using Chiral Intermediate and Involving B-ring Addition prior to A-ring Addition:-- And not --VIII. Synthetic Scheme for (R)-III II Using Chiral Intermediate and Involving B-ring Addition prior to A-ring Addition:--

In Figure 1 I the title should be: --IX. Synthetic Scheme for Racemic Compound II Involving Oxazolidinedione Intermediate:-- And not --IX. Synthetic Scheme for Racemic Compound III II Involving Oxazolidinedione Intermediate:--

In Figure 1J the title should be: --X. Racemic Synthetic Scheme for Compound II:-- And not --X. Racemic Synthetic Scheme for Compound III II:-- CERTIFICATE OF CORRECTION (continued) Page 3 of 4 U.S. Pat. No. 7,772,433 B2

In Figure 1 K the title should be: --XI. Large-scale Synthetic Scheme for (S)- II:-- And not --XI. Large-scale Synthetic Scheme for (S)- III II:--

In Figure 1L the title should be: --XII. Large-scale Synthetic Scheme for (SR)-II:-- And not --XII. Large-scale Synthetic Scheme for (S)- III II:--

In column 135, lines 40-45 the represented structure should be:

R ON O Rs R - C Sixso R2 HC OH R

And not

1R4 ONc C -0.O Rs R HC OH R1

In column 136, lines 47-55: Claim 5 should read: --5. A method of treating a subject wherein said subject suffers from osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of bone mineral density (BMD), or any combination thereof, comprising the step of administering to said Subject a compound of claim 1, or its isomer, pharmaceutically acceptable Salt or any combination thereof, in an amount effective to treat osteoporosis, increased bone resorption, bone fracture, bone frailty, or loss of bone mineral density (BMD) in said subject.-- CERTIFICATE OF CORRECTION (continued) Page 4 of 4 U.S. Pat. No. 7,772,433 B2

And not --5. A method of treating a subject wherein said subject suffers from osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of bone mineral density (BMD), or any combination thereof, comprising the step of administering to said Subject a compound of claim 1, or its isomer, pharmaceutically acceptable Salt or any combination thereof, in an amount effective to treat osteoporosis, increase bone resorption, bone fracture, bone frailty, or loss of bone mineral density (BMD) in said subject.--