USOO8426465B2
(12) United States Patent (10) Patent No.: US 8.426,465 B2 Dalton et al. (45) Date of Patent: Apr. 23, 2013
(54) SUBSTITUTEDACYLANILIDES AND 5,547.933 A 8, 1996 Lin et al. METHODS OF USE THEREOF 5,609,849 A 3/1997 Kung 5,612,359 A 3/1997 Murugesan et al. 5,618,698 A 4/1997 Lin et al. (75) Inventors: James T. Dalton, Lakeland, TN (US); 5,621,080 A 4/1997 Lin et al. Duane D. Miller, Germantown, TN (US) 5,656,651 A 8, 1997 Sovak et al. 6,019,957 A 2/2000 Miller et al. (73) Assignee: University of Tennesse Research 6,022,137 A 2/2000 White et al. 6,043,265 A 3/2000 Murugesan et al. Foundation, Knoxville, TN (US) 6,071,957 A 6/2000 Miller et al. 6, 160,011 A 12/2000 Miller et al. (*) Notice: Subject to any disclaimer, the term of this 6,482,861 B2 11/2002 Miller et al. patent is extended or adjusted under 35 6,492,554 B2 12/2002 Dalton et al. U.S.C. 154(b) by 0 days. 6,548,529 B1 4/2003 Roblet al. 6,569,892 B2 5/2003 Nagano et al. 6,569,896 B2 5/2003 Dalton et al. (21) Appl. No.: 13/302.988 6,777.446 B2 8, 2004 Houze et al. 6,780,625 B2 8/2004 Eldar-Finkelman (22) Filed: Nov. 22, 2011 6,838,484 B2 1/2005 Steiner et al. 6,995,284 B2 2/2006 Dalton et al. (65) Prior Publication Data 6,998,500 B2 2/2006 Dalton et al. 7,026,500 B2 4/2006 Dalton et al. US 2012/O136052 A1 May 31, 2012 7,041,844 B2 5, 2006 Miller et al. 7,157,422 B2 1/2007 Eldar-Finkelman 7,344,700 B2 3/2008 Dalton et al. Related U.S. Application Data 7,547,728 B2 6/2009 Steiner et al. (62) Division of application No. 1 1/892.595, filed on Aug. 7,776,921 B2 8, 2010 Steiner et al. 24, 2007, now Pat. No. 8,080, 682. (Continued) (60) Provisional application No. 60/839,665, filed on Aug. FOREIGN PATENT DOCUMENTS 24, 2006, provisional application No. 60/907,749, O 040932 12/1981 filed on Apr. 16, 2007. EP O 100 172 2, 1984 (51) Int. Cl. (Continued) A 6LX3L/275 (2006.01) (52) U.S. Cl. OTHER PUBLICATIONS USPC ...... 514/522:558/414 Sullivan et al., “Does Androgen Insufficiency Cause Lacrimal Gland (58) Field of Classification Search ...... 558/414: Inflammation and Aqueous Tear Deficiency?', IOVS, May 1999, vol. 514/522 40, No. 6, pp. 1261-1265. See application file for complete search history. Matsumoto, “Hormonal therapy of male hypogonadism'. Endocrinol. Met. Clin. N. Am. 23:857-75 (1994). (56) References Cited Zhou, et al., “Specificity of ligand-dependent androgen receptor sta bilization: receptor domain interactions influce ligand dissociation U.S. PATENT DOCUMENTS and receptor stability”, Molec. Endocrinol. 9:208-18 (1995). 3,239,345 A 3/1966 Hodge et al. Sundaram et al., “7 Alpha-Methyl-Nortestosterone (MENT): The 3,256,096 A 6, 1966 Tucker et al. Optimal Androgen for Male Contraception.” Ann. Med., 25:199-205 3,865,801 A 2f1975 Chiba et al. (1993). 3,875,229 A 4, 1975 Gold Steinberger et al., Effect of Chronic Administration of Testosterone 3,946,109 A 3, 1976 Kolb et al. 3,949,085 A 4, 1976 Feuer et al. Enanthate on Sperm Production and Plasma Testosterone, Follicle 3,991,750 A 1 1/1976 Vickery et al. Stimulating Hormone, and Luteinizing Hormone Levels: A Prelimi 4,036.979 A 7, 1977 Asato et al. nary Evaluation of a Possible Male Contraceptive, Fertility and Ste 4,139,638 A 2f1979 Neri et al. rility 28:1320-28 (1977). 4,191,775 A 3, 1980 Glen 4,211,781 A 7, 1980 Chapman et al. (Continued) 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. Primary Examiner — Shailendra Kumar 4411,890 A 10/1983 Momany et al. (74) Attorney, Agent, or Firm — Pearl Cohen Zedek Latzer, 4,447,421 A 5, 1984 Klothen et al. 4,465,507 A 8, 1984 Konno et al. LLP. Mark S. Cohen 4,636,505 A * 1/1987 Tucker ...... 514,256 4,670.249 A 6/1987 Ivy et al. 4,837,004 A 6, 1989 Wu et al. (57) ABSTRACT 4,849,447 A 7, 1989 Jacobs et al. 4,880,839 A 11, 1989 Tucker This invention provides SARM compounds and uses thereof 4,904.473 A 2f1990 Schricker et al. in treating a variety of diseases or conditions in a Subject, 4,977,288 A 12/1990 Kassis et al. 5,030,657 A 7, 1991 Burtle et al. including, interalia, a muscle wasting disease and/or disorder 5,162,504 A 11/1992 Horoszewicz or a bone-related disease and/or disorder. 5,179,080 A 1/1993 Rothkopfet al. 5,288496 A 2f1994 Lewis et al. 5,441,868 A 8, 1995 Lin 11 Claims, 15 Drawing Sheets US 8,426.465 B2 Page 2
U.S. PATENT DOCUMENTS Sefton, “Implantable Pumps”. CRC Crit. Ref. Biomed. Eng. 14:201 7,855,229 B2 12/2010 Dalton et al. 240 (1987). 2001/0012839 A1 8, 2001 Miller et al. Buchwald et al., “Long-term, continuous intravenous heparin admin 2002/0173495 A1 11, 2002 Dalton et al. istration by an implantable infusion pump in ambulatory patients 2003/0232792 A1 12, 2003 Dalton et al. with recurrent venous thrombosis' Surgery 88:607 (1980). 2004/0087810 A1 5, 2004 Dalton et al. Saudek et al., “A preliminary trial of the programmable implantable 2004/O147489 A1 7/2004 Dalton et al. medication system for insulin delivery'. N. Engl. J. Med. 321:674 2004/0214790 A1 10/2004 Borgens et al. 2005, OO3811.0 A1 2/2005 Steiner et al. (1989). 2006, O183931 A1 8, 2006 Dalton et al. Goodson, “Dental Applications” in Medical Applications of Con 2007.0043029 A1 2/2007 Sakaki et al. trolled Release, Supra, vol. 2, pp. 116-138 (1984). 2007/OO78168 A1 4/2007 Caulkett et al. Abuchowski et al., “Immunosuppresive properties and circulating 2007/0O88O17 A1 4/2007 Gaillard et al. life of achromobacter glutaminase-asparaginase covalently attached 2007/00999.16 A1 5, 2007 Dehmlow et al. to polyethylene glycol in man' Cancert Treat. Rep. 65:1077-1081, 2007/0099930 A1 5, 2007 Dudash et al. 1981. 2007/0099936 A1 5, 2007 Bian et al. 2007/01 17805 A1 5, 2007 Dow et al. Katre et al., “Chemical modification of recombinant interleukin 2 by 2007/O161578 A1 7/2007 Hwa et al. polyethylene glycol increases its potency in the murine Meth A sarcoma model” 1987, Proc. Natl. Acad. Sci., vol. 84, pp. 1487-1491. FOREIGN PATENT DOCUMENTS Heitzman et al., “The effectiveness of anabolic agents in increasing EP OOO 2892 2, 1985 rate of growth in farm animals; report on experiments in cattle'. EP O 188396 T 1986 Environ Qual Saf Suppl. 1976:(5):89-98. EP O253503 12/1991 Singh et al., “Androgens Stimulate Myogenic Differentiation and EP 668351 8, 1995 Inhibit Adipogenesis in C3H10T1/2 Pluripotent Cells through an EP O 683 172 11, 1995 EP O 903 146 3, 1999 Androgen Receptor-Mediated Pathway”. Endocrinology, 2003, EP 1398O29 3, 2004 144(11): 5081-5088. GB 1360001 3, 1970 Tucker et al., “Resolution of the Nonsteroidal Antiandrogen 4'- JP 52-128329 1Of 1977 Cyano-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methyl-3'- JP 54-63047 12, 1980 (trifluoromethyl)-propionanilide and the Determination of the Abso WO WO 89/07110 8, 1989 lute Configuration of the Active Enantiomer'J. MedChem. 1988, 31. WO WO 89/07111 8, 1989 WO WO91,05867 5, 1991 pp. 885-887. WO WO93/04081 3, 1993 Mckillop, et al., “Enantioselective metabolism and pharmacokinetics WO WO95/1977O 7, 1995 of Casodex in the male rat', Xenobiotica, 1995, vol. 25, No. 6, WO WO 98 05962 2, 1998 623-634. WO WO 98.27986 7, 1998 Kirkovsky, et al., “I’I-Radionated Bicalutamide Analogs as Poten WO WO 98.53826 * 12/1998 tial Imaging Agents for Prostate Cancer', Poster Presentation MEDI WO WO98,55153 12/1998 155,214th ACS National Meeting, Las Vegas, NV. Sep. 7-11, 1997, WO WOOOf 38721 T 2000 WO WOOO58293 10, 2000 Department of Pharmaceutical Sciences, University of Tennessee, WO WOO127622 4/2001 Memphis, TN38163. WO WOO128990 4/2001 Baird et al., “Hormonal Contraception—Drug Therapy'. The New WO WOO1 34.563 5, 2001 England Journal of Medicine, May 27, 1993, pp. 1543-1549. WO WOO1? 44216 6, 2001 Wu, “Male Contraception: Current Status and Future Prospects', WO WOO2 OO617 1, 2002 Clinical Endocrinology, (1988), 29, pp. 443-465. WO WO O2, 16310 2, 2002 Francisco, et al., “Long-acting contraceptive agents: testosterone WO WOO3,OOO262 1, 2003 esters of unsaturated acids', Steroids, Jan. 1990, vol. 55, But WO WOO3,OOO267 1, 2003 terworths. WO WOO3 O11302 2, 2003 WO WOO3,O15774 2, 2003 Hoberman et al., “The History of Synthetic Testosterone”, Scientific WO WO 03/049675 6, 2003 American, Feb. 1995, pp. 76-81. WO WOO3,065983 8, 2003 Kirkovsky, et al., “Approaches to Irreversible non-steroidal chiral WO WOO3,065992 8, 2003 antiandrogens'. Department of Pharmaceutical Sciences, University WO WOO3,O74471 9, 2003 of Tennessee, 47th Southeast/51st Southwest Joint Regional Meeting WO WOO3/1042O7 12/2003 of the American Chemical Society, Memphis, TN, Nov. 29-Dec. 1, WO WO 2004/064747 8, 2004 1995. WO WO 2005/0372O1 4/2005 Handelsman, “Bridging the gender gap in contraception: another WO WO 2005/120483 12/2005 hurdle cleared” The Medical Journal of Australia, vol. 154, Feb. 18, WO WO, 2006/O19741 2, 2006 1996, pp. 230-233. WO WO 2007/027582 3, 2007 Zhi et al., Switching androgen receptor antagonists to agonists by OTHER PUBLICATIONS modifying C-ring Substituents on piperidino3.2-gquinolone. Bioorg. Med. Chem. Lett., 9; 1009, 1999. World Health Organization Task Force on Methods and Regulation of Higuchi et al. 4-Alkyl- and 3,4-diaklyl-1,2,3,4-tetrahydro-8- Male Fertility, “Contraceptive Efficacy of Testosterone-Induced pyridono5,6-glguinolines: potent, nonsteroidal androgen receptor AZoospermia and Oligospermia in Normal Men.” Fertility and Ste agonists. Bioorg. Med. Chem. Lett., 9:1335, 1999. rility 65:821-29 (1996). Wu, “Effects of Testosterone Enanthate in Normal Men: Experience Rosen et al. Intracellular receptors and signal transducers and acti From a Multicenter Contraceptive Efficacy Study.” Fertility and Ste vators of transcription Superfamilies: novel targets for Small-mol rility 65:626-36 (1996). ecule drug discovery. J. Med. Chem., 38: 4855, 1995. Langer, “New Methods of Drug Delivery”, Science 249:1627-1633 Dalton et al. Discovery of Nonsteroidal Androgens. Biochem. (1990). Biophys. Res. Commun., 244(1): 1-4, 1998. Treat et al., in Liposomes in the Therapy of Infectious Disease and Edwards et al. . New nonsteroidal androgen receptor modulators Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 363 based on 4-(trifluoromethyl)-2-(1H)-Pyrololidino.3.2-gquinolone. 366 (1989). Bioorg. Med. Chem. Lett., 8: 745, 1998. Lopez-Berestein, "Treatment of systematic fungal infections with Dalton JT, etal "Pharmacokinetics of Aminolevulinic Acid after Oral liposomal-amphotericin B. Liposomes in the Therapy of Infectious and Intravenous Dosing in Dogs.” Drug Metabolism and Disposition, Disease and Cancer, pp. 317-327, 1989. 27 (4):432-435, 1999. US 8,426.465 B2 Page 3
Yin D, et al “Key Structural Features of Nonsteroidal Ligands for Bohl CE, et al "Structural Basis for Antagonism and Resistance of Binding and Activation of the Androgen Receptor.” Molecular Phar Bicalutamide in Prostate Cancer.” Proc Natl AcadSci USA. 102(17): macology, 63:211-223, 2003. 6201-6206, 2005. Eliason et al., “High Throughput Fluorescence Polarization-Based Edwards.JP. Higuchi RI, Winn DT. Pooley CLF, Caferro TR, Hamann LG, Zhi L. Marschke KB, Goldman Me, and Jones TK. Nonsteroidal Screening Assays for the Identification of Novel Nuclear Receptor androgen receptor agonists based on 4-(trifluoromethyl)-2H-pyrano Ligands.” Abstracts of Papers, 223rd ACS National Meeting, 3, 2-gguinolin-2-one. Bioorg. Med. Chem. Lett., 9; 1003, 1999. Orlando, FL, United States, (2002), Apr. 7, 2002. Hamann LG. Mani NS, Davis RL. Wang XN, Marschke KB, and Berger et al., “Concepts and limitations in the application of Jones TK. Discovery of a potent, orally active nonsteroidal androgen radiolabeled antiandrogens, estrogens, or androgens as isotropic receptor agonist: 4-ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8- scanning agents for the prostate'. Invest. Urol, (1975), 1391, 10-16. pyridono.5,6-g-quinoline (LG 121071). J. Med. Chem., 42: 210, Yin D, et al "Pharmacology, Pharmacokinetics and Metabolism of 1999. Acetothiolutamide, A Novel Nonsteroidal Agonist for the Androgen Kim, Juhyun et al., “The para substituent of S-3-(phenoxy)-2- Receptor.” Journal of Pharmacology and Experimental Therapeutics, hydroxy-2-methyl-N-(4-nitro-3- trifluoromethyl-phenyl)- 304(3): 1323-1333, 2003. propionamides is a major structural determinant of in vivo disposi Yin D, et al "Pharmacodynamics of Selective Androgen Receptor tion and activity of selective androgen receptor modulators'. J. of Modulators.” Journal of Pharmacology and Experimental Therapeu Pharmacology and Experimental Therapeutics, 315(1), 230-239 tics, 304(3): 1334-1340, 2003. (2005). Gao, W., etal"Comparison of the Pharmacological Effects of a Novel Mohler et al., “Nonsteroidal tissue selective androgen receptor Selective Androgen Receptor Modulator (SARM), the 5 (alpha}- modulators: a promising class of clinical Candidates'. Expert Opin. Reductase Inhibitor Finasteride, and the Antiandrogen Ther Patents (2005) 15( 11), pp. 1-21. Hydroxyflutamide in Intact Rats: New Approach for Benign Prostate Segal et al., “Therapeutic potential of the SARMs: revisiting the Hyperplasia (BPH).” Endocrinology, 145(12): 5420-5428, 2004. androgen receptor for drug discovery'. Expert Opin. Investig. Drugs Chen J. etal"A Selective Androgen Receptor Modulator (SARM) for (2006) 15(4):377-387. Hormonal Male Contraception.” Journal of Pharmacology and Experimental Therapeutics, 312(2): 546-553, 2005. * cited by examiner U.S. Patent Apr. 23, 2013 Sheet 1 of 15 US 8.426,465 B2
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US 8,426,465 B2 1. 2 SUBSTITUTEDACYLANILDES AND still often bear the brunt of contraceptive choice. Women have METHODS OF USE THEREOF a number of choices, from temporary mechanical devices Such as sponges and diaphragms to temporary chemical CROSS REFERENCE TO RELATED devices such as spermicides. Women also have at their dis APPLICATIONS posal more permanent options, such as physical devices including IUDs and cervical caps as well as more permanent This application is a Divisional Application from U.S. chemical treatments such as birth control pills and Subcuta application Ser. No. 1 1/892,595 filed Aug. 24, 2007, now U.S. neous implants. However, to date, the only options available Pat. No. 8,080,682, which claims priority from U.S. Provi for men include the use of condoms and vasectomy. Condom sional Application Ser. No. 60/839,665, filed Aug. 24, 2006, 10 use, however is not favored by many men because of the and U.S. Provisional Application Ser. No. 60/907,749, filed reduced sexual sensitivity, the interruption in sexual sponta Apr. 16, 2007; and claims priority of U.S. patent application neity, and the significant possibility of pregnancy caused by Ser. No. 11/510,844, filed Aug. 28, 2006, all of which are breakage or misuse. Vasectomies are also not favored. If more hereby incorporated by reference in their entirety. convenient methods of birth control were available to men, 15 particularly long-term methods which require no preparative FIELD OF THE INVENTION activity immediately prior to a sexual act, Such methods could significantly increase the likelihood that men would take This invention provides Substituted acylanilide compounds more responsibility for contraception. and uses thereof in treating a variety of diseases or conditions Administration of the male sex steroids (e.g., testosterone in a Subject, including, inter alia, a muscle wasting disease and its derivatives) has shown particular promise in this and/or disorder or a bone-related disease and/or disorder regard due to the combined gonadotropin-suppressing and 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 25 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 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 30 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 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 35 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 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 40 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 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 45 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 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, (Sundaram et al., “7 Alpha-Methyl-Nortestosterone 50 “Effects of Testosterone Enanthate in Normal Men: Experi (MENT): The Optimal Androgen For Male Contraception.” ence From a Multicenter Contraceptive Efficacy Study.” Fer Ann Med., 25:199-205 (1993) (“Sundaram”). Because the tility and Sterility 65:626-36 (1996)). AR is involved in male sexual development and function, the Bone mineral density (BMD) decreases with age in both AR is a likely target for effecting male contraception or other males and females. Decreased amounts of bone mineral con forms of hormone replacement therapy. 55 tent (BMC) and BMD correlate with decreased bone strength Worldwide population growth and social awareness of and predispose patients to fracture. family planning have stimulated a great deal of research in Osteoporosis is a systemic skeletal disease, characterized contraception. Contraception is a difficult Subject under any by low bone mass and deterioration of bone tissue, with a circumstance. It is fraught with cultural and Social Stigma, consequent increase in bone fragility and Susceptibility to religious implications, and, most certainly, significant health 60 fracture. In the U.S., the condition affects more than 25 mil concerns. This situation is only exacerbated when the Subject lion people and causes more than 1.3 million fractures each focuses on male contraception. Despite the availability of year, including 500,000 spine, 250,000 hip and 240,000 wrist Suitable contraceptive devices, historically, Society has fractures annually. Hip fractures are the most serious conse looked to women to be responsible for contraceptive deci quence of osteoporosis, with 5-20% of patients dying within sions and their consequences. Although concern over sexu 65 one year, and over 50% of survivors being incapacitated. The ally transmitted diseases has made men more aware of the elderly are at greatest risk of osteoporosis, and the problem is need to develop safe and responsible sexual habits, women therefore predicted to increase significantly with the aging of US 8,426,465 B2 3 4 the population. Worldwide fracture incidence is forecasted to Muscle wasting, if left unabated, can have dire health con increase three-fold over the next 60 years, and one study sequences. For example, the changes that occur during estimated that there will be 4.5 million hip fractures world muscle wasting can lead to a weakened physical state that is wide in 2050. detrimental to an individuals health, resulting in increased Women are at greater risk of osteoporosis than men. Susceptibility to infraction and poor performance status. In Women experience a sharp acceleration of bone loss during addition, muscle wasting is a strong predictor of morbidity the five years following menopause. Other factors that and mortality in patients suffering from cachexia and AIDS. increase the risk include Smoking, alcohol abuse, a sedentary New innovative approaches are urgently needed at both the lifestyle and low calcium intake. However, osteoporosis also basic science and clinical levels to develop compounds which 10 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 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 15 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 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 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 25 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 A wide variety of diseases and/or conditions contribute males who have been castrated. tofare affected by hypogonadism, and catabolic effects, Muscle wasting refers to the progressive loss of muscle including kidney disease, central nervous system injuries, mass and/or to the progressive weakening and degeneration 30 burns and chronic wounds. of muscles, including the skeletal or Voluntary muscles, In the United States (US), there is a rising incidence and which control movement, cardiac muscles, which control the prevalence of kidney failure. The number of patients enrolled heart (cardiomyopathies), and Smooth muscles. Chronic in end-stage renal disease (ESRD) Medicare-funded pro muscle wasting is a chronic condition (i.e. persisting over a grams has increased from approximately 10,000 beneficiaries long period of time) characterized by progressive loss of 35 in 1973 to 86,354 in 1983, and to 431,284 as of Dec. 31, 2002. muscle mass, weakening and degeneration of muscle. In 2002 alone, 100,359 patients entered the US ESRD pro The loss of muscle mass that occurs during muscle wasting gram. Chronic kidney disease (CKD) is a precursor to ESRD can be characterized by muscle protein degradation by and occurs when the kidneys are not able to adequately catabolism. Protein catabolism occurs because of an unusu remove wastes from the body. CKD is a slowly progressing ally high rate of protein degradation, an unusually low rate of 40 disease, in which diabetes, hypertension and anemia may be protein synthesis, or a combination of both. Muscle protein co-morbid conditions. catabolism, whether caused by a high degree of protein deg CKD is diagnosed using a staging system that demon radation or a low degree of protein synthesis, leads to a strates the amount of kidney function available (stage 1-nor decrease in muscle mass and to muscle wasting. mal kidney function) and patients often do not present symp Muscle wasting is associated with chronic, neurological, 45 toms in the early stages. Stage 5 of CKD is ESRD, which is a genetic or infectious pathologies, diseases, illnesses or con complete or near complete failure of the kidneys and usually ditions. These include muscular dystrophies such as duch occurs when kidney function is less than 10% of baseline. enne muscular dystrophy and myotonic dystrophy; muscle Accompanying symptoms associated with ESRD include atrophies such as post-polio muscle atrophy (PPMA): hypogonadism, involuntary weight loss, fatigue and others. cachexias Such as cardiac cachexia, AIDS cachexia and can 50 Burns result in a testosterone reduction, nitrogen level cer cachexia, malnutrition, leprosy, diabetes, renal disease, reduction and a reduction in bone mineral density (BMD), chronic obstructive pulmonary disease (COPD), cancer, end which may persist even as long one year following the injury stage renal failure, sarcopenia, emphysema, osteomalacia, and is associated with impaired wound healing, increased HIV infection, AIDS, and cardiomyopathy. infection risks, erosion of lean body mass, hampered reha In addition, other circumstances and conditions are linked 55 bilitation, and delayed reintegration of burn survivors into to and can cause muscle wasting. These include chronic lower society. Catabolic effects initiated as a result of the burn lead back pain, advanced age, central nervous system (CNS) to significant involuntary weight loss, further compounding injury, peripheral nerve injury, spinal cord injury, chemical the problem. injury, central nervous system (CNS) damage, peripheral Spinal cord injuries (SCI) may result in the alteration cen nerve damage, spinal cord damage, chemical damage, burns, 60 tral neurotransmitter secretion or production, which in turn disuse deconditioning that occurs when a limb is immobi may cause a hypothalamus-pituitary-adrenal axis dysfunc lized, long term hospitalization due to illness or injury, and tion, leading to decreases in testosterone and other hormone alcoholism. levels. SCI or other acute illness or trauma characteristically An intact androgen receptor (AR) signaling pathway is includes heightened catabolism in conjunction with the low crucial for appropriate development of skeletal muscles. Fur 65 ered anabolic activity resulting in a condition that is prone to thermore, an intact AR-signaling pathway increases lean loss of lean body tissue. As long as the catabolic process goes muscle mass, muscle strength and muscle protein synthesis. uninterrupted, disturbed nutrient utilization will continue. US 8,426,465 B2 5 6 The effects of the loss of lean body mass include the devel agent treating neuromuscular transmission, a nervous system opment of wounds and impaired healing mechanisms. stimulant, a sedative agent, neurodegenerative disorder medi Because of poor nutrition and protein combined with immo cation, antiepileptic agent, antipsychotic agent, anti-addic bilization, patients with spinal cord injury are at high risk for tion agent, an anti-arrhythmic agent, an anti-anginal agent, a bed sores. vasoactive agent, a calcium channel blocker, an antihyperten Chronic wounds may be caused by any number of condi sive agent, a diuretic agent, an anticoagulant or fibrinolytic tions, including diabetes, circulatory problems, immobiliza agent, a hypocholesterolemic agent, an opioid, 5-HT3 recep tion and others. Compounding the problem, for example in tor antagonist, adsorbent agent, bulking agent, a stool soften diabetes, is the presence of neuropathy, which increases the ing or laxative agent, cathartic agent, an antiemetic agent, an risk of foot ulceration. 10 emetic agent, an antacid agent, an H2-receptor antagonist, a While there are many treatments and therapies for these proton pump inhibitor, a 5-aminosalicylate agent, a prostag conditions, none are ideal. Since the androgen receptor (AR) landin, a glucocorticosteroid, a retinoid, photochemothera signaling pathway has been shown to increase lean muscle peutic agent, a photodynamic agent, aminolevulinic acid, mass, muscle strength and muscle protein synthesis, and dapsone, pyrethrin, pyrethroid, thalidomide, an antimalarial 15 agent, an antimicrobial agent, an antifungal agent, an antiviral since hypogonadism accompanies these conditions, mol agent, a Sulfonamide, a trimethoprim agent, a quinolone ecules targeting the AR signaling pathway may be useful in agent, an oxazolidinone agent, an antiseptic agent, a beta treating these diseases and/or conditions. lactam agent, an aminoglycoside agent, a tetracycline agent, SUMMARY OF THE INVENTION a chloramphenicol agent, a macrollide agent, a lincosamide agent, a bacitracin agent, a glycopeptide agent, a polymyxin In one embodiment, the present invention provides, a com agent, an antiprotozoal agent, an anthelmintic agent, a corti pound represented by the structure of formula (I) Sone, a colchicine, a methotrexate, a ursodeoxycholic acid, a penicillamine, a vitamin, glucosidase alpha, Sodium bicar bonate, bisphosphonate, biotin, allopurinol, levodopa, diaz 25 epam, phenobarbital, haloperidol, folic acid, haptoglobin, NC CN carnitine, a steroid, cannabinoid metoclopramide, cisapride, medroxyprogesterone acetate, megestrol acetate, cyprohep tadine, hydrazine Sulfate, pentoxifylline, thalidomide, anticy FC NH O F tokine antibodies, cytokine inhibitors, eicosapentaenoic acid, 30 indomethacin, ibuprofen, melatonin, insulin, growth hor Hd OH mone, clenbuterol, pancreas extract, cabergoline, bromocrip tine, thyroxine, gonadotropin, glucocorticoid, glucocorticoid or its isomer, pharmaceutically acceptable salt, pharma analogue, corticotrophin, metyrapone, aminoglutethimide, ceutical product, crystal, N-oxide, hydrate or any com mitotane, ketoconazole, mifepristone, dexamethasone, bination thereof. 35 Somatostatin analogue, gonadotropin-releasing hormone In one embodiment, the present invention provides a com analogue, leuprolide, goserelin, antidiuretic hormone, antidi position comprising the compound of formula (I) and/or its uretic hormone analogue, oxytocin, estrogen, progestin, derivative, isomer, pharmaceutically acceptable salt, pharma selective estrogen receptor modulator (SERM), uterine, ceutical product, crystal, hydrate, N-oxide or any combina stimulant, uterine relaxant, androgen, antiandrogen, prostag tion thereof. 40 landin, dopamine receptor agonist, alpha-adrenoreceptor In one embodiment, the compound is a selective androgen blocker, anabolic steroid, an antianxiety agent, an antipsy receptor modulator (SARM). In one embodiment, the SARM chotic agent, an antidepressant, beta-2 agonist, anticholin is a partial agonist. In one embodiment, the SARM is a tissue ergic bronchodilator, theophylline, aminophylline, nedocro selective agonist, or in some embodiments, a tissue-selective mil Sodium, sodium cromoglycate, leukotriene receptor antagonist. 45 antagonist, corticosteroid, expectorant, mucolytic agent, In one embodiment, the compositions of this invention antihistamine, pseudoephedrine, or a neuraminidase inhibi further comprise a therapeutic agent, which in one embodi tor, betagan, betimol, timoptic, betoptic, ocupress, optipra ment is an anti-cancer agent, an immunomodulating agent, an nolol. Xalatan, alphagan, azopt, trusopt, cosopt, pilocar, pila agent treating diabetes, an agent treating the nervous system, gan, propine, opticrom, acular, livostin, alomide, emadine, an agent treating the cardiovascular system, an agent treating 50 patanol, alrex, dexacidin, maxitrol, tobradex, blephamide, the gastrointestinal system, an agent treating a dermatologi ocufen, Voltaren, profenal, pred forte, econpred plus, eflone, cal disease, or condition, an anti-infective agent, an agent flarex, inflamase forte, inflamase mild, lotemax, Vexol, poly treating the liver, an agent treating the kidney, an agent treat trim, ilotycin, ciloxan, ocuflox, tobrex, or garamycin, or any ing a metabolic disease, an agent treating a wasting disease, a combination thereof. gene therapy agent, an agent treating the endocrine system, a 55 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 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 selective androgen receptor ophthalmic disease, or any combination thereof. modulator compound of formula (I) or its isomer, pharma In one embodiment, the therapeutic agent is an anti-andro 60 ceutically acceptable salt, pharmaceutical product, poly gen, an antiestrogen, a monoclonal antibody, a chemothera morph, crystal, hydrate, N-oxide or any combination thereof, peutic agent, an immunosuppressive or anti-inflammatory or a composition comprising the same, in an amount effective agent, an immunostimulatory agent, a Sulfonylurea, meglit to bind the selective androgen receptor modulator compound nide, insulin, biguanide, thiazolidinedione, or alpha-glucosi to the androgen receptor. dase inhibitor, an adrenomimetic agent, adrenoceptor antago 65 In one embodiment, this invention provides a method of nist, cholinomimetic agent, a muscarinic blocker, a Suppressing spermatogenesis in a subject comprising con ganglionic blocker, an anesthetic agent, an analgesic agent, an tacting an androgen receptor of the Subject with the selective US 8,426,465 B2 7 8 androgen receptor modulator compound of formula (I) or its or condition. In one embodiment, the pathology, illness, dis isomer, pharmaceutically acceptable salt, pharmaceutical ease or condition is neurological, infectious, chronic or product, crystal, hydrate, N-oxide or any combination genetic. In one embodiment, the pathology, illness, disease or thereof, or a composition comprising the same, in an amount condition is a muscular dystrophy, a muscular atrophy, effective to Suppress sperm production. X-linked spinal-bulbar muscular atrophy (SBMA), a In one embodiment, this invention provides a method of cachexia, malnutrition, leprosy, diabetes, renal disease, contraception in a male Subject, comprising the step of chronic obstructive pulmonary disease (COPD), cancer, end administering to the Subject the selective androgen receptor stage renal failure, sarcopenia, emphysema, osteomalacia, modulator compound of formula (I) or its isomer, pharma HIV infection, AIDS, or cardiomyopathy. ceutically acceptable salt, pharmaceutical product, crystal, 10 In one embodiment, the muscle wasting disorder is an hydrate, N-oxide or any combination thereof, or a composi age-associated muscle wasting disorder; a disuse decondi tion comprising the same, in an amount effective to suppress tioning-associated muscle wasting disorder; or the muscle sperm production in the Subject, thereby effecting contracep wasting disorder is due to chronic lower back pain; burns; tion in the Subject. central nervous system (CNS) injury or damage; peripheral In one embodiment, this invention provides a method of 15 nerve injury or damage; spinal cord injury or damage; chemi hormonetherapy comprising the step of contacting an andro cal injury or damage; or alcoholism. gen receptor of a subject with the selective androgen receptor In one embodiment, this invention provides a method of modulator compound of formula (I) or its isomer, pharma treating, reducing the severity of reducing the incidence of ceutically acceptable salt, pharmaceutical product, crystal, delaying the onset of, or reducing pathogenesis of diabetes in hydrate, N-oxide or any combination thereof, or a composi a human Subject, comprising administering an effective tion comprising the same, in an amount effective to effect a amount of a compound of formula (I) or its isomer, pharma change in an androgen-dependent condition. ceutically acceptable salt, pharmaceutical product, crystal, In one embodiment, this invention provides a method of N-oxide, hydrate or any combination thereof, to said subject. treating a Subject Suffering from prostate cancer, comprising In one embodiment, this invention provides, a method of the step of administering to said Subject the selective andro 25 treating, reducing the severity of reducing the incidence of gen receptor modulator compound of formula (I), or its iso delaying the onset of, or reducing pathogenesis of glucose mer, pharmaceutically acceptable salt, pharmaceutical prod intolerance in a human Subject, comprising the step of admin uct, crystal, hydrate, N-oxide or any combination thereof, or istering an effective amount of a compound of formula (I) or a composition comprising the same in an amount effective to its isomer, pharmaceutically acceptable salt, pharmaceutical treat prostate cancer in the Subject. 30 product, crystal, N-oxide, hydrate or any combination thereof In one embodiment, this invention provides a method of to said subject. delaying the progression of prostate cancer in a subject suf In one embodiment, this invention provides a method of fering from prostate cancer, comprising the step of adminis treating, reducing the severity of reducing the incidence of tering to said Subject the selective androgen receptor modu delaying the onset of, or reducing pathogenesis of hyperin lator compound of formula (I) or its isomer, pharmaceutically 35 Sulinemia in a human Subject, comprising the step of admin acceptable salt, pharmaceutical product, crystal, N-oxide, istering an effective amount of a compound of formula (I) or hydrate, or any combination thereof, or a composition com its isomer, pharmaceutically acceptable salt, pharmaceutical prising the same in an amount effective to delay the progres product, crystal, N-oxide, hydrate or any combination thereof sion of prostate cancer in the Subject. to said subject. In one embodiment, this invention provides a method of 40 In one embodiment, this invention provides a method of treating a bone-related disorder in a Subject, or increasing a treating, reducing the severity of reducing the incidence of bone mass in a Subject, promoting bone formation in a Sub delaying the onset of or reducing pathogenesis of insulin ject, administering an effective amount of a compound of resistance in a human Subject, comprising the step of admin formula (I) or its isomer, pharmaceutically acceptable salt, istering an effective amount of a compound of formula (I) or pharmaceutical product, crystal, hydrate, N-oxide or any 45 its isomer, pharmaceutically acceptable salt, pharmaceutical combination thereof, or a composition comprising the same, product, crystal, N-oxide, hydrate or any combination thereof in an amount effective to treat said bone-related disorder. to said subject. According to this aspect, and in one embodiment, the Sub In one embodiment, this invention provides a method of ject Suffers from osteoporosis, osteopenia, increased bone treating, reducing the severity of reducing the incidence of resorption, bone fracture, bone frailty, loss of bone mineral 50 delaying the onset of, or reducing pathogenesis of diseases density (BMD), or any combination thereof. In one embodi associated with diabetes comprising the step of administering ment, the method increases the strength of a bone of said an effective amount of a compound of formula (I) or its Subject. In one embodiment, the compound stimulates or isomer, pharmaceutically acceptable salt, pharmaceutical enhances osteoblastogenesis, or in another embodiment the product, crystal, N-oxide, hydrate or any combination thereof compound inhibits osteoclast proliferation. 55 to said subject. In one embodiment, this invention provides a method of In one embodiment, this invention provides a method of treating, reducing the incidence of delaying progression of treating, reducing the severity of reducing the incidence of reducing the severity of or alleviating symptoms associated delaying the onset of, or reducing pathogenesis of fatty liver with a muscle wasting disorder in a Subject, comprising the conditions in a human Subject, comprising the step of admin step of administering to said Subject the selective androgen 60 istering an effective amount of a compound of formula (I) or receptor modulator compound of formula (I) or its isomer, its isomer, pharmaceutically acceptable salt, pharmaceutical pharmaceutically acceptable salt, pharmaceutical product, product, crystal, N-oxide, hydrate or any combination thereof crystal, hydrate, N-oxide or any combination thereof, or a to said subject. composition comprising the same, in an amount effective to In one embodiment, this invention provides a method of treat the muscle wasting disorder in said Subject. 65 treating, reducing the severity of reducing the incidence of According to this aspect, and in one embodiment, the delaying the onset of, or reducing the pathogenesis of cardio muscle wasting disorder is due to a pathology, illness, disease vascular disease in a human Subject, comprising the step of US 8,426,465 B2 9 10 administering an effective amount of a compound of formula FIG.1: Synthetic schemes for the preparation of compound (I) or its isomer, pharmaceutically acceptable salt, pharma of formula I. FIG. 1A is a synthetic scheme for the preparation ceutical product, crystal, N-oxide, hydrate or any combina of an (S) enantiomer of a compound of formula I (S-I). FIG. tion thereof to said subject. 1B is a synthetic scheme for the preparation of an (R) enan In one embodiment, this invention provides a method of 5 treating reducing the severity of reducing the incidence of tiomer of a compound of formula I (R-I). FIG. 1C is a syn delaying the onset of, or reducing the pathogenesis of thetic scheme for the preparation of an (S) enantiomer of a cachexia in a Subject, comprising the step of administering an compound of formula I (S-I) including an oxirane intermedi effective amount of a compound of this invention or its iso ate. FIG. 1D is a synthetic scheme for the preparation of an mer, pharmaceutically acceptable salt, pharmaceutical prod (R) enantiomer of a compound of formula I (R-I) including an uct, crystal, N-oxide, hydrate or any combination thereof to 10 oxirane intermediate. FIG. 1E is a synthetic scheme for the said Subject. preparation of an (S) enantiomer of a compound of formula I In one embodiment, this invention provides a method of (S-I) involving B-ring addition prior to A-ring addition. FIG. treating a disease or condition of the eye of a Subject, com 1F is a synthetic scheme for the preparation of an (R) enan prising the step of administering an effective amount of a tiomer of a compound of formula I (R-I) involving B-ring compound of formula (I) or its isomer, pharmaceutically 15 addition prior to A-ring addition. FIG. 1G is a synthetic acceptable salt, pharmaceutical product, crystal, N-oxide, scheme for the preparation of an (S) enantiomer of a com hydrate or any combination thereof to the subject. In one pound of formula I (S-I) using 2-tribromomethyl-1,3diox embodiment, the disease or condition of the eye comprises olan-4-one intermediate and involving B-ring addition prior Sjogren's syndrome, or Xerophthalmia. to A-ring addition. FIG. 1H is a synthetic scheme for the In one embodiment, the present invention provides a preparation of an (R) enantiomer of a compound of formula I method of reducing a fat mass in a Subject comprising the step (R-I) using 2-tribromomethyl-1,3dioxolan-4-one interme of administering an effective amount of a compound of for diate and involving B-ring addition prior to A-ring addition. mula (I) or its isomer, pharmaceutically acceptable salt, phar FIG. 1I is a synthetic scheme for preparation of a racemic maceutical product, crystal, N-oxide, hydrate or any combi mixture of a compound of formula I, involving oxazolidinedi nation thereof to the subject. 25 In one embodiment, the present invention provides a one intermediate and Bring addition prior to A ring. FIG. 1J method of increasing a lean mass in a Subject comprising the is a synthetic scheme for preparation of a racemic mixture of step of administering an effective amount of a compound of a compound of formula I, involving an oxirane intermediate formula (I) or its isomer, pharmaceutically acceptable salt, and A ring addition prior to Bring. FIG. 1K is a synthetic pharmaceutical product, crystal, N-oxide, hydrate or any scheme for preparation of a large scale of an (5) enantiomer of combination thereof to the subject. 30 a compound of formula I (S-I). FIG.1L is a synthetic scheme In another embodiment, this invention provides a method for preparation of a large scale of an (5) enantiomer of a of Suppressing spermatogenesis; contraception in a male; compound of formula I (S-I), including an oxirane interme hormone therapy; treating prostate cancer, delaying the pro diate. gression of prostate cancer, treating a bone-related disorderin FIG. 2: Pharmacology of Compound S-I in intact rats. a subject, or increasing a bone mass in a Subject and/or pro 35 Asterisks represent statistically significant differences moting bone formation in a Subject; treating, reducing the between the weight of the organ in the indicated group and incidence of delaying progression of reducing the severity that observed in intact animals treated with vehicle (P<0.05). of oralleviating symptoms associated with a muscle wasting FIG. 3: Organ weights from castrated, Compound S-1- disorder; treating, reducing the severity of reducing the inci treated rats presented as a percentage of intact control. dence of delaying the onset of, or reducing pathogenesis of 40 *P-value <0.05 versus intact controls. diabetes; treating, reducing the severity of reducing the inci FIG. 4: Organ weight maintenance dose-response curves dence of delaying the onset of, or reducing pathogenesis of for Compound S-I and seminal vesicles (closed squares) were glucose intolerance; treating, reducing the severity of reduc obtained by nonlinear regression analysis using the sigmoid ing the incidence of delaying the onset of, or reducing patho genesis of hyperinsulinemia; treating, reducing the severity Emax model in WinNonlin R. of reducing the incidence of delaying the onset of, or reduc 45 ing pathogenesis of insulin resistance; treating, reducing the DETAILED DESCRIPTION OF THE PRESENT severity of reducing the incidence of delaying the onset of INVENTION or reducing pathogenesis of diseases associated with diabe tes; treating, reducing the severity of reducing the incidence In the following detailed description, numerous specific of delaying the onset of, or reducing pathogenesis of fatty 50 details are set forth in order to provide a thorough understand liver conditions; treating, reducing the severity of reducing ing of the invention. However, it will be understood by those the incidence of delaying the onset of or reducing pathogen skilled in the art that the present invention may be practiced esis of cardiovascular disease; treating reducing the severity without these specific details. In other instances, well-known of reducing the incidence of delaying the onset of, or reduc methods, procedures, and components have not been ing pathogenesis of cachexia; treating a disease or condition 55 described in detailso as not to obscure the present invention. of the eye; reducing a fat mass; or increasing a lean mass in a This invention provides, in one embodiment, a substituted Subject, comprising the step of administering an effective acylanilide characterized by the structure of Formula I. In one amount of a compound of formula (I) or its isomer, pharma embodiment, the compound is a SARM. In one embodiment, ceutically acceptable salt, pharmaceutical product, crystal, the compound is useful in treating a variety of conditions or N-oxide, hydrate or any combination thereof to the subject as 60 diseases, including, inter alia, oral testosterone replacement herein described. therapy, male contraception, maintaining sexual desire in women, osteoporosis, treating prostate cancer and/or imaging BRIEF DESCRIPTION OF THE DRAWINGS prostate cancer. In some embodiments, the compounds of this invention are nonsteroidal ligands for the AR and exhibit The present invention will be understood and appreciated 65 androgenic and/or anabolic activity. In some embodiments, more fully from the following detailed description taken in the compounds are partial agonists or partial antagonists in a conjunction with the appended drawings in which: tissue selective manner. In some embodiments, the com US 8,426,465 B2 11 12 pounds are full agonists or full antagonists in a tissue selective pounds of the present invention contain at least one chiral manner, which in Some embodiments, allows for tissue-se center. Accordingly, the compounds used in the methods of lective androgenic and/or anabolic effects. These agents may the present invention may exist in, and be isolated in, opti be active alone or in combination with progestins or estro cally-active or racemic forms. Some compounds may also gens, or other agents, as herein described. In other embodi- 5 exhibit polymorphism. It is to be understood that the present ments, the agents are agonists, antagonists, partial agonists or invention encompasses any racemic, optically-active, poly partial antagonists. morphic, or stereroisomeric form, or mixtures thereof, which In some embodiments, this invention provides compounds, form possesses properties useful in the treatment of andro which are useful in androgen replacement therapy (ART), gen-related conditions described herein. In one embodiment, useful ina) improving body composition; b) increasing bone 10 the compounds are the pure (R)-isomers. In another embodi mineral density (BMD); c) increasing bone mass; d) increas ment, the compounds are the pure (S)-isomers. In another ing bone strength; e) improving bone function: f) decreasing embodiment, the SARMs are a mixture of the (R) and the (S) fracture risk; g) increasing muscle strength; h) increasing isomers. In another embodiment, the SARMs are a racemic muscle function: i) improving exercise tolerance; j) enhanc mixture comprising an equal amount of the (R) and the (S) ing libido, k) improving sexual performance; and/or 1) 15 isomers. It is well known in the art how to prepare optically improving mood and/or m) improving cognition. active forms (for example, by resolution of the racemic form In some embodiments, this invention provides synthetic by recrystallization techniques, by synthesis from optically processes of preparation of the SARM compounds of this active starting materials, by chiral synthesis, or by chromato invention. In some embodiments, the invention provides graphic separation using a chiral stationary phase). compositions comprising the selective androgen modulator In one embodiment, the compounds of this invention are compounds or use of the same for binding an AR, modulating SARMs. In one embodiment, the compounds of this inven spermatogenesis, bone formation and/or resorption, treating tion bind a nuclear hormone receptor, such as, for example, muscle wasting or diseases associated with muscle wasting, the estrogen receptor, the progesterone receptor, or the glu treating prostate cancer, and/or providing hormonal therapy cocorticoid receptor. for androgen-dependent conditions. 25 In one embodiment, this invention encompasses the use of In one embodiment, the present invention provides, a various optical isomers of the SARM compound. It will be SARM compound represented by the structure of formula (I): appreciated by those skilled in the art that the compounds of the present invention contain at least one chiral center. Accordingly, the compounds used in the methods of the I 30 present invention may exist in, and be isolated in, optically NC CN active or racemic forms. Some compounds may also exhibit polymorphism. It is to be understood that the present inven tion encompasses any racemic, optically-active, polymor FC NH O F phic, or stereroisomeric form, or mixtures thereof, which 2 35 form possesses properties useful in the treatment of andro H3C OH gen-related conditions described herein. In one embodiment, the compounds are the pure (R)-isomers. In another embodi or its isomer, derivative, pharmaceutically acceptable salt, ment, the compounds are the pure (S)-isomers. In another pharmaceutical product, polymorph, crystal, impurity, N-OX embodiment, the compounds are a mixture of the (R) and the ide, hydrate or any combination thereof. 40 (S) isomers. In another embodiment, the compounds are a In one embodiment, this invention provides an analog of racemic mixture comprising an equal amount of the (R) and the compound of formula (I). In another embodiment, this the (S) isomers. It is well known in the art how to prepare invention provides a derivative of the compound of formula optically-active forms (for example, by resolution of the race (I). In another embodiment, this invention provides a metabo mic form by recrystallization techniques, by synthesis from lite of the compound of formula (I). In another embodiment, 45 optically-active starting materials, by chiral synthesis, or by this invention provides a pharmaceutically acceptable salt of chromatographic separation using a chiral stationary phase). the compound of formula (I). In another embodiment, this The invention includes “pharmaceutically acceptable invention provides a pharmaceutical product of the com salts' of the compounds of this invention, which may be pound of formula (I). In another embodiment, this invention produced, by reaction of a compound of this invention with an provides a hydrate of the compound of formula (I). In another 50 acid or base. embodiment, this invention provides an N-oxide of the com Suitable pharmaceutically-acceptable salts of amines of pound of formula (I). In another embodiment, this invention Formula I may be prepared from an inorganic acid or from an provides a polymorph of the compound of formula (I). In organic acid. In one embodiment, examples of inorganic salts another embodiment, this invention provides a crystal of the of amines are bisulfates, borates, bromides, chlorides, compound of formula (I). In another embodiment, this inven- 55 hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyeth tion provides an impurity of the compound of formula (I). In ylsulfonates (hydroxyethanesulfonates), iodates, iodides, another embodiment, this invention provides a combination isothionates, nitrate, persulfates, phosphate, Sulfates, Sulfa of any of an analog, derivative, metabolite, isomer, pharma mates, Sulfanilates, Sulfonic acids (alkylsulfonates, arylsul ceutically acceptable salt, pharmaceutical product, poly fonates, halogen Substituted alkylsulfonates, halogen Substi morph, crystal, impurity, hydrate, N-oxide of the compound 60 tuted arylsulfonates), Sulfonates and thiocyanates. of formula (I). In one embodiment, examples of organic salts of amines In some embodiments, the term "isomer' includes, but is comprise aliphatic, cycloaliphatic, aromatic, araliphatic, het not limited to, optical isomers and analogs, structural isomers erocyclic, carboxylic and Sulfonic classes of organic acids, and analogs, conformational isomers and analogs, and the examples of which are acetates, arginines, aspartates, ascor like. In one embodiment, the term "isomer is meant to 65 bates, adipates, anthranilate, algenate, alkane carboxylates, encompass optical isomers of the described compounds. It Substituted alkane carboxylates, alginates, benzene will be appreciated by those skilled in the art that the com Sulfonates, benzoates, bisulfates, butyrates, bicarbonates, US 8,426,465 B2 13 14 bitartrates, carboxilates, citrates, camphorates, camphorsul An “alkenyl group refers, in another embodiment, to an fonates, cyclohexylsulfamates, cyclopentanepropionates, unsaturated hydrocarbon, including straight chain, branched calcium edetates, camsylates, carbonates, clavulanates, cin chain and cyclic groups having one or more double bond. The namates, dicarboxylates, digluconates, dodecylsulfonates, alkenyl group may have one double bond, two double bonds, dihydrochlorides, decanoates, enanthuates, ethanesulfonates, three double bonds etc. Examples of alkenyl groups are ethe edetates, edisylates, estolates, esylates, fumarates, formates, nyl, propenyl, butenyl, cyclohexenyl etc. In one embodiment, fluorides, galacturonates, gluconates, glutamates, glycolates, the alkylene group has 1-12 carbons. In another embodiment, glucorate, glucoheptanoates, glycerophosphates, glu the alkylene group has 1-7 carbons. In another embodiment, ceptates, glycolylarsanilates, glutarates, glutamate, hep the alkylene group has 1-6 carbons. In another embodiment, tanoates, hexanoates, hydroxymaleates, hydroxycarboxlic 10 acids, hexylresorcinates, hydroxybenzoates, hydroxynaph the alkylene group has 1-4 carbons. The alkenyl group may be thoate, hydrofluorate, lactates, lactobionates, laurates, unsubstituted or Substituted by one or more groups selected malates, maleates, methylenebis(beta-oxynaphthoate), mal from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, onates, mandelates, mesylates, methane Sulfonates, methyl dialkylamido, nitro, amino, alkylamino, dialkylamino, car bromides, methylnitrates, methylsulfonates, monopotassium 15 boxyl, thio and thioalkyl. maleates, mucates, monocarboxylates, mitrates, naphthale A "haloalkyl group refers to an alkyl group as defined nesulfonates, 2-naphthalenesulfonates, nicotinates, napsy above, which is Substituted by one or more halogen atoms, in lates, N-methylglucamines, oxalates, octanoates, oleates, one embodiment by F, in another embodiment by Cl, in pamoates, phenylacetates, picrates, phenylbenzoates, piv another embodiment by Br, in another embodiment by I. alates, propionates, phthalates, phenylacetate, pectinates, An “aryl group refers to an aromatic group having at least phenylpropionates, palmitates, pantothenates, polygalactur one carbocyclic aromatic group or heterocyclic aromatic ates, pyruvates, quinates, Salicylates. Succinates, Stearates, group, which may be unsubstituted or substituted by one or Sulfanilate, Subacetates, tartarates, theophyllineacetates, more groups selected from halogen, haloalkyl, hydroxy, p-toluenesulfonates (tosylates), trifluoroacetates, terephtha alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, lates, tannates, teoclates, trihaloacetates, triethiodide, tricar 25 amino, alkylamino, dialkylamino, carboxy or thio or thio boxylates, undecanoates or Valerates. alkyl. Nonlimiting examples of aryl rings are phenyl, naph In one embodiment, examples of inorganic salts of car thyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, boxylic acids or phenols comprise ammonium, alkali metals pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isox to include lithium, Sodium, potassium, cesium; alkaline earth azolyl, and the like. In one embodiment, the aryl group is a 4-8 metals to include calcium, magnesium, aluminium, zinc, 30 membered ring. In another embodiment, the aryl group is a barium, cholines or quaternary ammoniums. 4-12 membered ring(s). In another embodiment, the aryl In another embodiment, examples of organic salts of car group is a 6 membered ring. In another embodiment, the aryl boxylic acids orphenols comprise arginine, organic amines to group is a 5 membered ring. In another embodiment, the aryl include aliphatic organic amines, alicyclic organic amines, group is 2-4 fused ring system. aromatic organic amines, benzathines, t-butylamines, 35 A “hydroxyl group refers to an OH group. It is understood benethamines (N-benzylphenethylamine), dicyclohexy by a person skilled in the art that when T is OR, R is not OH. lamines, dimethylamines, diethanolamines, ethanolamines, In one embodiment, the term “halogen refers to in one ethylenediamines, hydrabamines, imidazoles, lysines, embodiment to F, in another embodiment to Cl, in another methylamines, meglamines, N-methyl-D-glucamines, N,N'- embodiment to Br, in another embodiment to I. dibenzylethylenediamines, nicotinamides, organic amines, 40 An “arylalkyl group refers, in another embodiment, to an ornithines, pyridines, picolinates, piperazines, procain, tris alkyl bound to an aryl, wherein alkyl and aryl are as defined (hydroxymethyl)methylamines, triethylamines, triethanola above. An example of an arylalkyl group is a benzyl group. mines, trimethylamines, tromethamines or ureas. In one embodiment, this invention provides a compound of In one embodiment, the salts may be formed by conven formula I and/or, analog, derivative, isomer, metabolite, phar tional means, such as by reacting the free base or free acid 45 maceutically acceptable salt, pharmaceutical product, form of the product with one or more equivalents of the hydrate, N-oxide, prodrug, polymorph, impurity or crystal or appropriate acid or base in a solvent or medium in which the combinations thereof. In one embodiment, this invention pro salt is insoluble or in a solvent such as water, which is vides an analog of the compound. In another embodiment, removed in vacuo or by freeze drying or by exchanging the this invention provides a derivative of the compound. In ions of a existing salt for another ion or Suitable ion-exchange 50 another embodiment, this invention provides an isomer of the resin. compound. In another embodiment, this invention provides a In one embodiment, the invention also includes N-oxides metabolite of the compound. In another embodiment, this of the amino substituents of the compounds described herein. invention provides a pharmaceutically acceptable salt of the Also, esters of the phenolic compounds can be made with compound. In another embodiment, this invention provides a aliphatic and aromatic carboxylic acids, for example, acetic 55 pharmaceutical product of the compound. In another embodi acid and benzoic acid esters. ment, this invention provides a hydrate of the compound. In An “alkyl group refers, in one embodiment, to a saturated another embodiment, this invention provides an N-oxide of aliphatic hydrocarbon, including straight-chain, branched the compound. In another embodiment, this invention pro chain and cyclic alkyl groups. In one embodiment, the alkyl vides a prodrug of the compound. In another embodiment, group has 1-12 carbons. In another embodiment, the alkyl 60 this invention provides a polymorph of the compound. In group has 1-7 carbons. In another embodiment, the alkyl another embodiment, this invention provides a crystal of the group has 1-6 carbons. In another embodiment, the alkyl compound. In another embodiment, this invention provides group has 1-4 carbons. The alkyl group may be unsubstituted an impurity of the compound. In another embodiment, this or Substituted by one or more groups selected from halogen, invention provides composition comprising a compound, as hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, 65 described herein, or, in another embodiment, a combination nitro, amino, alkylamino, dialkylamino, carboxyl, thio and of an analog, derivative, isomer, metabolite, pharmaceuti thioalkyl. In one embodiment, the alkyl group is CHs. cally acceptable salt, pharmaceutical product, hydrate, N-ox US 8,426,465 B2 15 16 ide, prodrug, polymorph, impurity or crystal of the com said process comprising the steps of pounds of the present invention. a) coupling an amine of formula 17: The invention also includes N-oxides of the amino sub stituents of the compounds described herein. This invention provides derivatives of the compounds. In 17 one embodiment, "derivatives' includes but is not limited to NH2 ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like. In another embodiment, this inven NC tion further includes hydrates of the compounds. 10 In one embodiment, “hydrate' includes but is not limited to CF hemihydrate, monohydrate, dihydrate, trihydrate and the like. This invention provides, in other embodiments, metabo lites of the compounds. In one embodiment, “metabolite' 15 means any Substance produced from another Substance by with the carboxylic acid of formula R-18 metabolism or a metabolic process. This invention provides, in other embodiments, pharma R-18 ceutical products of the compounds. The term “pharmaceu O tical product” refers, in other embodiments, to a composition Suitable for pharmaceutical use (pharmaceutical composi HO e Br tion), for example, as described herein. Hd OH In another embodiment, the present invention provides a process for preparing a selective androgen modulator com 25 pound represented by the structure of formula I, as depicted in FIG. 1 and Example 1: in the presence of a coupling reagent, to produce an amide of formula R-19
NC 30 R-19 Ol O NC FC sis. -- HC OH 35 FC NH Br; C oH
CN K2CO3 He 40 2-propanol and HO F b) reacting the amide of formula R-19 with a compound of formula 20:
NC CN 45 2O Ol O O CN FC sis F HO F Hd oH 50
In another embodiment, the present invention provides a process for preparing an (S) enantiomer of SARM compound to produce a compound of formula S-I. represented by the structure of formula I: 55 In one embodiment, compound R-18 of step (a) is reacted with a coupling agent prior to addition of compound of for mula 17. FIG. 1A and Example 1 provide one embodiment of a process for the preparation of a compound of formula S-I. NC CN 60 In another embodiment, the conditions of step (b) of the process outlined hereinabove may comprise potassium car bonate, Sodium carbonate, or cesium carbonate, or another base appropriate for this reaction, using 2-propanol, THF or 65 methylethylketone as a solvent, optionally with a transition catalyst, BTBAC (benzyltributylammonium chloride) or other Suitable agent. US 8,426,465 B2 17 18 In another embodiment, the present invention provides a bonate, Sodium carbonate, or cesium carbonate, or another process for preparing an (R) enantiomer of SARM compound base appropriate for this reaction, using 2-propanol, THF or represented by the structure of formula R-I: methylethylketone as a solvent, optionally with a transition catalyst, BTBAC (benzyltributylammonium chloride) or 5 other suitable agent. R-I In another embodiment, the present invention provides a NC CN: process for preparing an (S) enantiomer of a SARM com O pound represented by the structure of formula S-I: 10 FC N e O F H 2. S-I HO CH, NC CN O said process comprising the steps of 15 to a) coupling an amine of formula 17: FC NH O F He oH S-18 O ' said process comprising the steps of: HO Br a) coupling an amine of formula 17: H6 a. 17 with the carboxylic acid of formula S-18 25 NH2
17 NC NH2 30 CF
NC with the carboxylic acid of formula R-18 CF 35 R-18
in the presence of a coupling reagent, to produce an amide of formula S-19 HO Br 40 2. S-19 HC OH NC
in the presence of a coupling reagent, to produce an amide of formula R-19 FC 45
R-19 NC and O b) reacting the amide of formula S-19 with a compound of so formula 20 FC NH Br; C oH 2O CN b) reacting the amide of formula R-19, with a base to forman oxirane S-21 HO F
S-21
to produce a compound of R-I. 60 NC In one embodiment, compound S-18 of step (a) is reacted with a coupling agent prior to addition of compound of for mula 17. FC FIG. 1B depicts one embodiment of such a process for the preparation of compound of formula R-I. 65 In another embodiment, the conditions of step (b) of the process outlined hereinabove may comprise potassium car US 8,426,465 B2 19 20 and b) reacting the amide of formula S-19, with a base to forman c) reacting the oxirane of formula S-21 with a compound of oxirane R-21 formula 20:
5 R-21 NC 2O CN O FC S HO F 10 CH3s Yo:
to produce a compound of S-I. and In one embodiment, whereby compound R-18 of step (a) is reacted with a coupling agent prior addition of compound of c) reacting the oxirane of formula R-21 with a compound of formula 17. 15 formula 20: FIG. 1C depicts an embodiment of such a process for the preparation of compound of formula S-I. 2O In another embodiment, the present invention provides a CN process for preparing an (R) enantiomer of SARM compound 20 represented by the structure of formula R-I: HO F
R-I to produce a compound of R-I. NC O CN 25 In one embodiment, compound S-18 of step (a) is reacted with a coupling agent prior to addition of compound of for mula 17. FC3 NH % O F FIG. 1D preparation of compound of formula R-I. HO CH In another embodiment, the present invention provides a process for preparing an (S) enantiomer of a SARM com said process comprising the steps of pound represented by the structure of formula S-I a) coupling an amine of formula 17: 35 S-I
17 NC CN
40 FC NH O F NC 2. H3C OH CF said process comprising the steps of with the carboxylic acid of formula S-18 45 a) reacting a ring of formula S-22
S-18 S-22 O H 50 O HO Br N HO CH wO O . Br in the presence of a coupling reagent, to produce an amide HC of formula S-19 with a compound of 20 S-19 NC 60
FC HO rF 65 US 8,426,465 B2 21 22 to produce a compound of formula R-23: said process comprising the steps of a) reacting a ring of formula R-22
R-23 5 R-22 H O N
O 10 -> Br H3C
15 with a compound of 20 CN:
2O CN b) ring opening of compound of formula R-23 to produce a compound of formula S-24 HO F
S-24 to produce a compound of formula R-23:
CN: 25
R-23
30 and coupling the carboxylic acid of compound of formula S-24 in the presence of a coupling agent with the amine of formula HC 1-O 17 35
17 CN NH2 F 40 b) ring opening of compound of formula R-23 to produce a NC compound of formula R-24: CF
45 R-24
to produce the compound of formula S-I CN: In one embodiment, compound S-24 of step (b) is reacted with a coupling agent prior to addition of compound of for F mula 17. 50 FIG. 1E depicts an embodiment of such a process for the preparation of compound of formula S-I. and In another embodiment, the present invention provides a coupling the carboxylic acid of compound of formula R-24 process for preparing an (R) enantiomer of a SARM com 55 in the presence of a coupling agent with the amine of formula pound represented by the structure of formula R-I: 17
R-I 17 NC CN 60 NH2
NC
CF 65 3 US 8,426,465 B2 23 24 to produce the compound of formula S-I to produce a compound of formula R-26; In one embodiment, compound R-24 of step (b) is reacted with a coupling agent prior to addition of compound of for mula 17. R-26 FIG. 1F depicts an embodiment of such a process for the preparation of compound of formula S-I. Q O In another embodiment, the present invention provides a process for preparing an (S) enantiomer of a SARM com pound represented by the structure of formula S-I 10 O CH, O CN:
S-I 15 NC CN b) ring opening of compound of formula R-26 to produce a compound of formula S-24 FC F
S-24
CN:
25 said process comprising the steps of a) reacting the carboxylic acid of formula R-18
30 and
R-18 coupling the carboxylic acid of compound of formula S-24 in the presence of a coupling agent with the amine of formula 17: 35
17 NH2
40 NC with tribromoacetaldehyde to produce a compound of for mula R-25: CF
45 R-25 to produce the compound of formula S-I In one embodiment, compound S-24 of step (b) is reacted with a coupling agent prior to addition of compound of for 50 mula 17. FIG. 1G depicts an embodiment of such a process for the preparation of compound of formula S-I. In another embodiment, the present invention provides a reacting the dioxalane derivative R-25 with a compound of 55 process for preparing an (R) enantiomer of a SARM com formula 20 pound represented by the structure of formula R-I.
60 NC CN
FC HO F 65 US 8,426,465 B2 25 26 said process comprising the steps of and b) coupling the carboxylic acid of compound of formula R-32 a) reacting the carboxylic acid of formula S-18 in the presence of a coupling agent with the amine of formula 17:
17 S-18 NH2
NC 10 CF
to produce the compound of formula R-I. with tribromoacetaldehyde to produce a compound of for In one embodiment, compound R-32 of step (b) is reacted mula S-25: 15 with a coupling agent prior to addition of compound of for mula 17. FIG. 1H depicts an embodiment of such a process for the S-25 preparation of compound of formula R-I. H CBr In another embodiment, the present invention provides a process for preparing a racemic mixture of a SARM com X 2O pound represented by the structure of formula I
NC CN O HC Br 25 FC O sixO CC F CH, OH reacting the dioxalane derivative S-25 with a compound of formula 30: 30 said process comprising the steps of a) reacting a compound of formula 24
2O CN 24 35 CN HO F O CC to produce a compound of formula S-33; 40 CH, OH with a compound of formula 27 S-33 H CBr X 45 27 O O
y - NC HC O CN: 50 CF
F wherein P is selected from isocyanate (NCO) or isothiocyan ate (NCS) to produce a compound of formula 28a or 28b. ring opening of compound of formula S-33 to produce a respectively compound of formula R-32
28a.
R-32 NC CN: 60 O CH FC F O CN; or 65 O O F US 8,426,465 B2 28 -continued c) oxidizing an amide of formula 29, to produce the oxirane of formula 21 28b NC 5 21 O NC CH3 O FC O CN FC NH O O; 10 CH
and b) ring opening of the oxazolidinedione or 2-thioXooxazolid d) reacting the oxirane of formula 21 with a compound of 4-one ring of formula 28a or 28b in a presence of a base to formula 20 produce a compound of formula I. 15 FIG. 1I depicts an embodiment of such a process for the preparation of racemic compound of formula I. In another embodiment, the present invention provides a process for preparing a racemic mixture of a SARM com pound represented by the structure of formula I: HO F to produce the compound of formula I. I In another embodiment, the oxidizing an amide of formula NC CN 25 29 of step (c) comprises oZone. In another embodiment, the oxidizing agent is a peroxyacid, for example, peracetic acid, (CHCOOOH). In another embodiment, the oxidizing agent meta-chloroperbenzoic acid (m-CPBA). In another embodi FC six F ment, the oxidizing agent is Magnesium MonoPeroxyPthalic CH, OH 30 Acid (MMPP). In another embodiment, the oxidizing agent is hydrogen peroxide together with catalytic amounts (1.0-0.1 mol%) of manganese (2) salts. said process comprising the steps of FIG. 1J depicts an embodiment of a process for the prepa a) chlorinating methacrylic acid ration of racemic compound of formula I. 35 In one embodiment, this invention provides a process for preparing pure enantiomers of compounds of this invention, O O comprising the steps of a) preparing a racemic mixture of a compound of this invention; and b) separating the pure com pound of this invention from its racemic mixture. 40 In one embodiment, separation of the optically-active (R) -- -> Cl 1. isomer or (S) enantiomer, from the racemic mixture of the CH3 CH3 compounds of this invention comprises crystallization tech niques. In another embodiment, the crystallization tech niques include differential crystallization of enantiomers. In another embodiment, the crystallization techniques include b) coupling an 3-cyano 4-trifluoromethyl aniline of formula 45 differential crystallization of diastereomeric salts (e.g. tar 17 with methacryloyl chloride: taric salts or quinine salts). In another embodiment, the crys tallization techniques include differential crystallization of chiral auxiliary derivatives (menthol esters, etc). In another embodiment, separation of the optically-active (R) isomer or 17 50 NC NH2 (S) enantiomer, from the racemic mixtures of the compounds of this invention comprises reacting the racemate mixture with another chiral group, forming of a diastereomeric mix ture followed by separation of the diastereomers and remov FC ing the additional chiral group to obtain pure enantiomers. In 55 another embodiment, separation of the optically-active (R) isomer or (S) enantiomer, from the racemic mixtures of the to produce the amide of formula 29: compounds of this invention comprises chiral synthesis. In another embodiment, separation of the optically-active (R) 29 isomer or (S) enantiomer, from the racemic mixtures of the NC 60 compounds of this invention comprises biological resolution. In another embodiment, separation of the optically-active (R) isomer or (S) enantiomer, from the racemic mixtures of the Ol O compounds of this invention comprises enzymatic resolution. FC s In another embodiment, separation of the optically-active (R) CH 65 isomer or (S) enantiomer, from the racemic mixtures of the compounds of this invention comprises chromatographic separation using a chiral stationary phase. In another embodi US 8,426,465 B2 29 30 ment, separation of the optically-active (R) isomer or (S) The coupling reagent defined hereinabove is a reagent enantiomer, from the racemic mixtures of the compounds of capable of turning the carboxylic acid/thiocarboxylic acid of this invention comprises affinity chromatography. In another formula 24 or 18 into a reactive derivative thereof, thus embodiment, separation of the optically-active (R) isomer or enabling coupling with the respective amine to form an (S) enantiomer, from the racemic mixtures of the compounds 5 amide/thioamide bond. A suitable reactive derivative of a of this invention comprises capillary electrophoresis. In carboxylic acid/thiocarboxylic acid is, for example, an acyl another embodiment, separation of the optically-active (R) halide/thioacyl halide, for example an acyl/thioacyl chloride isomer or (S) enantiomer, from the racemic mixtures of the formed by the reaction of the acid/thioacid and an inorganic compounds of this invention comprises forming an ester acid chloride, for example thionyl chloride; a mixed anhy group of the hydroxyl group of the chiral carbon with an 10 dride, for example an anhydride formed by the reaction of the optically-active acid, for example (-)-camphanic acid, sepa acid and a chloroformate Such as isobutyl chloroformate; an rating the diastereomers esters, thus obtained, by fractional active ester/thioester, for example an ester formed by the crystallization or preferably, by flash-chromatography, and reaction of the acid and a phenol Such as pentafluorophenol, then hydrolyzing each separate ester to the alcohol. an ester Such as pentafluorophenyl trifluoroacetate oran alco In another embodiment, the purity, and selectivity of an 15 hol Such as methanol, ethanol, isopropanol, butanol or N-hy enantiomer obtained to by the process of this invention, or by droxybenzotriazole; an acyl/thioacyl azide, for example an chiral separation of a racemic mixture of this invention can be azide formed by the reaction of the acid/thioacid and azide determined by HPLC analysis. Such as diphenylphosphoryl azide; an acyl cyanide/thioacyl In another embodiment, the process further comprises the cyanide, for example a cyanide formed by the reaction of an step of converting the SARM compound to its analog, isomer, acid and a cyanide Such as diethylphosphorylcyanide; or the metabolite, derivative, pharmaceutically acceptable salt, product of the reaction of the acid/thioacid and a carbodiim pharmaceutical product, N-oxide, hydrate or any combina ide such as dicyclohexylcarbodiimide. tion thereof. It is to be understood that the process may comprise any According to this aspect of the invention, and in one embodiment described herein, as will be appropriate to pro embodiment, the reagent used for reacting the amide deriva 25 duce a compound of a corresponding formula, as will be tive, for example compound of formula 19 and the phenol appreciated by one skilled in the art. derivative such as for example 20, are carried out in the In one embodiment, the process for preparing a compound presence of a base. Any suitable base that will deprotonate the of this invention may involve ring opening in the presence of hydrogen of the —XH moiety (for example, a phenol moiety less acidic conditions, which in another embodiment, dimin when X is O) and allow the coupling may be used. Nonlim 30 ish the likelihood of obtaining the compound mixtures, and iting examples of bases are carbonates Such as alkali carbon provide higher yield and purity of a compound of interest. In ates, for example sodium carbonate (NaCO), potassium one embodiment, the ring opening of a process as described carbonate (KCO) and cesium carbonate (CsCO); bicar herein, to produce a carboxylic acid of formula 13, is carried bonates Such as alkali metal bicarbonates, for example out in the presence of HBr, which, in one embodiment, is at a sodium bicarbonate (NaHCO), potassium bicarbonate 35 concentration of up to 30%, or in another embodiment, of up (KHCO), alkali metal hydrides such as sodium hydride to 40%, or in another embodiment, is of up to 25%, or in (NaH), potassium hydride (KH) and lithium hydride (LiH), another embodiment, of up to 23%, or in another embodi and the like. ment, of up to between 20-25%. In one embodiment, the The leaving group L. according to this aspect, and in one compounds of this invention may be produced via large-scale embodiment, may comprise any removable group customar 40 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) 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, 45 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 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, 50 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 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, 55 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 alia, promoting matic amines Such as pyridine; aliphatic and aromatic hydro erythropoiesis, osteogenesis, muscle growth, glucose uptake, carbons such as benzene, toluene, and Xylene; dimethylsul 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 60 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 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 65 embodiment, is an androgen receptor, or in another embodi one skilled in the art, for example, in the range, of -20 to 120° ment, is an estrogen receptor, or in another embodiment, is a C., or for example at or near ambient temperature. progesterone receptor, or in another embodiment, is a gluco US 8,426,465 B2 31 32 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 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. 5 thus formulated in a form suitable for topical administration. Pharmaceutical Compositions Suitable topical formulations include gels, ointments, In some embodiments, this invention provides methods of creams, lotions, drops and the like. For topical administration, use which comprise administering a composition comprising the compounds of this invention or their physiologically tol the described compounds. As used herein, “pharmaceutical erated derivatives such as salts, esters, N-oxides, and the like 10 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 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 15 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. 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 25 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, As used herein “pharmaceutically acceptable carriers or intradermally, Subcutaneously, Sublingually, intraperito diluents' are well knownto those skilled in theart. The carrier neally, intraventricularly, intracranially, intravaginally, by 30 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 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 35 (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 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 40 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 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 45 some embodiments is referred to as “a compound of this positions of the present invention comprise in addition to a invention'. compound of this invention and the inert carrier or diluent, a Suitable excipients and carriers may be, according to hard gelatin capsule. embodiments of the invention, solid or liquid and the type is In one embodiment, the micronized capsules comprise par generally chosen based on the type of administration being ticles containing a compound of this invention, wherein the 50 used. Liposomes may also be used to deliver the composition. term “micronized' used herein refers to particles having a Examples of Suitable solid carriers include lactose, Sucrose, particle size is of less than 100 microns, or in another embodi gelatin and agar. Oral dosage forms may contain Suitable ment, less than 60 microns, or in another embodiment, less binders, lubricants, diluents, disintegrating agents, coloring than 36 microns, or in another embodiment, less than 16 agents, flavoring agents, flow-inducing agents, and melting microns, or in another embodiment, less than 10 microns, or 55 agents. Liquid dosage forms may contain, for example, Suit in another embodiment, less than 6 microns. able solvents, preservatives, emulsifying agents, Suspending Further, in another embodiment, the pharmaceutical com agents, diluents, Sweeteners, thickeners, and melting agents. positions are administered by intravenous, intraarterial, or Parenteral and intravenous forms should also include miner intramuscular injection of a liquid preparation. Suitable liq als and other materials to make them compatible with the type uid formulations include solutions, Suspensions, dispersions, 60 of injection or delivery system chosen. Of course, other emulsions, oils and the like. In one embodiment, the pharma excipients may also be used. ceutical compositions are administered intravenously, and are For liquid formulations, pharmaceutically acceptable car thus formulated in a form suitable for intravenous adminis riers may be aqueous or non-aqueous Solutions, Suspensions, tration. In another embodiment, the pharmaceutical compo emulsions or oils. Examples of non-aqueous solvents are sitions are administered intraarterially, and are thus formu 65 propylene glycol, polyethylene glycol, and injectable organic lated in a form suitable for intraarterial administration. In esters such as ethyl oleate. Aqueous carriers include water, another embodiment, the pharmaceutical compositions are alcoholic/aqueous solutions, cyclodextrins, emulsions or Sus US 8,426,465 B2 33 34 pensions, including saline and buffered media. Examples of 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 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 10 spheroplasts.) Such compositions will influence the physical are sterile liquids such as water and oils, with or without the 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, 15 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, col and polypropylene glycol, carboxymethyl cellulose, dex guar gum, hydroxypropyl cellulose, hydroxypropyl methyl tran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline. cellulose, povidone), disintegrating agents (e.g. cornstarch, The modified compounds are known to exhibit substantially potato starch, alginic acid, silicon dioxide, croscarmelose longer half-lives in blood following intravenous injection Sodium, crospovidone, guar gum, Sodium starch glycolate), 25 than do the corresponding unmodified compounds (Abu buffers (e.g., Tris-HCl, acetate, phosphate) of various pH and chowski et al., 1981; Newmarket al., 1982; and Katre et al., ionic strength, additives such as albuminor gelatin to prevent 1987). Such modifications may also increase the compounds absorption to Surfaces, detergents (e.g., Tween 20, Tween 80, solubility in aqueous solution, eliminate aggregation, Pluronic F68, bile acid salts), protease inhibitors, surfactants enhance the physical and chemical stability of the compound, (e.g. sodium lauryl Sulfate), permeation enhancers, solubiliz 30 and greatly reduce the immunogenicity and reactivity of the ing agents (e.g., cremophor, glycerol, polyethylene glycerol, compound. As a result, the desired in vivo biological activity benzlkonium chloride, benzyl benzoate, cyclodextrins, sobi may be achieved by the administration of such polymer tan esters, Stearic acids), anti-oxidants (e.g., ascorbic acid, compound abducts less frequently or in lower doses than with sodium metabisulfite, butylated hydroxyanisole), stabilizers the unmodified compound. (e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellu 35 The preparation of pharmaceutical compositions which lose), viscosity increasing agents (e.g. carbomer, colloidal contain an active component is well understood in the art, for silicon dioxide, ethyl cellulose, guar gum), Sweetners (e.g. example by mixing, granulating, or tablet-forming processes. aspartame, citric acid), preservatives (e.g., Thimerosal, ben The active therapeutic ingredient is often mixed with excipi Zyl alcohol, parabens), coloring agents, lubricants (e.g. ents which are pharmaceutically acceptable and compatible Stearic acid, magnesium Stearate, polyethylene glycol, 40 with the active ingredient. For oral administration, the com Sodium lauryl Sulfate), flow-aids (e.g. colloidal silicon diox pounds of this invention or their physiologically tolerated ide), plasticizers (e.g. diethyl phthalate, triethyl citrate), derivatives such as salts, esters, N-oxides, and the like are emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium mixed with additives customary for this purpose. Such as lauryl Sulfate), polymer coatings (e.g., poloxamers or poloX vehicles, stabilizers, or inert diluents, and converted by cus amines), coating and film forming agents (e.g. ethylcellulose, 45 tomary methods into Suitable forms for administration, Such acrylates, polymethacrylates), and/or adjuvants. as tablets, coated tablets, hard or soft gelatin capsules, aque In one embodiment, the pharmaceutical compositions pro ous, alcoholic or oily solutions. For parenteral administration, vided herein are controlled release compositions, i.e. compo the compounds of this invention or their physiologically tol sitions in which the compound of this invention is released erated derivatives such as salts, esters, N-oxides, and the like over a period of time after administration. Controlled or sus 50 are converted into a solution, Suspension, or emulsion, if tained release compositions include formulation in lipophilic desired with the substances customary and suitable for this depots (e.g. fatty acids, waxes, oils). In another embodiment, purpose, for example, solubilizers or other. the composition is an immediate release composition, i.e. a An active component can be formulated into the composi composition in which all of the compound is released imme tion as neutralized pharmaceutically acceptable salt forms. diately after administration. 55 Pharmaceutically acceptable salts include the acid addition In yet another embodiment, the pharmaceutical composi salts (formed with the free amino groups of the polypeptide or tion can be delivered in a controlled release system. For antibody molecule), which are formed with inorganic acids example, the agent may be administered using intravenous Such as, for example, hydrochloric or phosphoric acids, or infusion, an implantable osmotic pump, a transdermal patch, Such organic acids as acetic, oxalic, tartaric, mandelic, and the liposomes, or other modes of administration. In one embodi 60 like. Salts formed from the free carboxyl groups can also be ment, a pump may be used (see Langer, Supra; Sefton, CRC derived from inorganic bases Such as, for example, Sodium, Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., potassium, ammonium, calcium, or ferric hydroxides, and Surgery 88:607 (1980); Saudek et al., N. Engl. J. Med. 321: Such organic bases as isopropylamine, trimethylamine, 674 (1989). In another embodiment, polymeric materials can 2-ethylamino ethanol, histidine, procaine, and the like. be used. In yet another embodiment, a controlled release 65 For use in medicine, the salts of the compound will be system can be placed in proximity to the therapeutic target, pharmaceutically acceptable salts. Other salts may, however, i.e., the brain, thus requiring only a fraction of the systemic be useful in the preparation of the compounds according to US 8,426,465 B2 35 36 the invention or of their pharmaceutically acceptable salts. including an analog, isomer, metabolite, derivative, pharma Suitable pharmaceutically acceptable salts of the compounds ceutically acceptable salt, pharmaceutical product, N-oxide, of this invention include acid addition salts which may, for hydrate thereofor any combination thereof; b) lactose mono example, be formed by mixing a solution of the compound hydrate; c) microcrystalline cellulose; d) magnesium Stear according to the invention with a solution of a pharmaceuti ate; and e) colloidal silicon dioxide. cally acceptable acid such as hydrochloric acid, Sulphuric In some embodiments, the methods of this invention make acid, methaneSulphonic acid, fumaric acid, maleic acid, suc use of compositions comprising compounds of this invention, cinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, which offer the advantage that the compounds are nonsteroi tartaric acid, carbonic acid or phosphoric acid. dal ligands for the androgen receptor, and exhibit anabolic In one embodiment, this invention provides pharmaceuti 10 activity in vivo. According to this aspect, such compounds are cal compositions comprising a compound of this invention. In unaccompanied by serious side effects, provide convenient one embodiment, Such compositions are useful for oral test modes of administration, and lower production costs and are osterone replacement therapy. orally bioavailable, lack significant cross-reactivity with In one embodiment, this invention also provides a compo other undesired steroid receptors, and may possess long bio sition comprising two or more compounds of this invention, 15 logical half-lives. or polymorphs, isomers, hydrates, salts, N-oxides, etc., For administration to mammals, and particularly humans, thereof. The present invention also relates to compositions it is expected that the physician will determine the actual and a pharmaceutical compositions which comprises a com dosage and duration of treatment, which will be most suitable pound of this invention alone or in combination with a proges for an individual and can vary with the age, weight and tin or estrogen, or in another embodiment, chemotherapeutic response of the particular individual. compound, osteogenic or myogenic compound, or other In one embodiment, the compositions for administration agents Suitable for the applications as herein described. In one may be sterile solutions, or in other embodiments, aqueous or embodiment, the compositions of this invention will com non-aqueous, Suspensions or emulsions. In one embodiment, prise a suitable carrier, diluent or salt. the compositions may comprise propylene glycol, polyethyl In one embodiment, the methods of this invention may 25 ene glycol, injectable organic esters, for example ethyl oleate, comprise administration of a compound of formula I of this or cyclodextrins. In another embodiment, compositions may invention at various dosages. In one embodiment, the com also comprise wetting, emulsifying and/or dispersing agents. pound of this invention is administered at a dosage of 0.1-200 In another embodiment, the compositions may also comprise mg per day. In one embodiment, the compound of this inven sterile water or any other sterile injectable medium. tion is administered at a dose of 0.1-10 mg. or in another 30 In one embodiment, the invention provides compounds embodiment, 0.1-26 mg, or in another embodiment, 0.1-60 and compositions, including any embodiment described mg, or in another embodiment, 0.3-16 mg, or in another herein, for use in any of the methods of this invention, as embodiment, 0.3-30 mg. or in another embodiment, 0.6-26 described herein. In one embodiment, use of a compound of mg, or in another embodiment, 0.6-60 mg, or in another this invention or a composition comprising the same, will embodiment, 0.76-16 mg, or in another embodiment, 0.76-60 35 have utility in inhibiting, Suppressing, enhancing or stimulat mg, or in another embodiment, 1-6 mg, or in another embodi ing a desired response in a subject, as will be understood by ment, 1-20 mg. or in another embodiment, 3-16 mg, or in one skilled in the art. In another embodiment, the composi another embodiment, 30-60 mg. or in another embodiment, tions may further comprise additional active ingredients, 30-76 mg, or in another embodiment, 100-2000 mg. whose activity is useful for the particular application for In one embodiment, the methods of this invention may 40 which the compound of this invention is being administered. comprise administration of a compound of formula I of this In some embodiments, the methods of this invention make invention at various dosages. In one embodiment, the com use of compositions comprising compounds of this invention, pound of this invention is administered at a dosage of 1 mg. In which offer the advantage that the compounds are nonsteroi another embodiment the compound of this invention is dal ligands for the androgen receptor, and exhibit anabolic administered at a dosage of 6 mg, 10 mg, 16 mg, 20 mg, 26 45 activity in vivo. According to this aspect, such compounds are mg, 30 mg, 36 mg, 40 mg., 46 mg, 50 mg, 56 mg, 60 mg, 66 unaccompanied by serious side effects, provide convenient mg, 70 mg, 76 mg, 80 mg, 86 mg, 90 mg, 96 mg or 100 mg. modes of administration, and lower production costs and are In one embodiment, the present invention provides meth orally bioavailable, lack significant cross-reactivity with ods of use comprising the administration of a pharmaceutical other undesired steroid receptors, and may possess long bio composition comprising a) any embodiment of a compound 50 logical half-lives. as described herein; and b) a pharmaceutically acceptable For administration to mammals, and particularly humans, carrier or diluent; which is to be understood to include an it is expected that the physician will determine the actual analog, isomer, metabolite, derivative, pharmaceutically dosage and duration of treatment, which will be most suitable acceptable salt, N-oxide, hydrate or any combination thereof for an individual and can vary with the age, weight and of a compound as herein described, and may comprise com 55 response of the particular individual. pounds of formula I. In one embodiment, the compositions for administration In some embodiments, the present invention provides may be sterile solutions, or in other embodiments, aqueous or methods of use of a pharmaceutical composition comprising non-aqueous, Suspensions or emulsions. In one embodiment, a) any embodiment of the compounds as described herein, the compositions may comprise propylene glycol, polyethyl including an analog, isomer, metabolite, derivative, pharma 60 ene glycol, injectable organic esters, for example ethyl oleate, ceutically acceptable salt, pharmaceutical product, N-oxide, or cyclodextrins. In another embodiment, compositions may hydrate thereof or any combination thereof; b) a pharmaceu also comprise wetting, emulsifying and/or dispersing agents. tically acceptable carrier or diluent; c) a flow-aid; and d) a In another embodiment, the compositions may also comprise lubricant. sterile water or any other sterile injectable medium. In another embodiment, the present invention provides 65 In one embodiment, the invention provides compounds methods of use of a pharmaceutical composition comprising and compositions, including any embodiment described a) any embodiment of the compounds as described herein, herein, for use in any of the methods of this invention. In one US 8,426,465 B2 37 38 embodiment, use of a compound of this invention or a com mide, hydroxysteroid dehydrogenase inhibitors, PPARC. position comprising the same, will have utility in inhibiting, ligand such as bezafibrate, fenofibrate, gemfibrozil; PPARY Suppressing, enhancing or stimulating a desired response in a ligands such as darglitaZone, pioglitaZone, rosiglitaZone, isa subject, as will be understood by one skilled in the art. In glitaZone, rivoglitaZone, netoglitaZone, Dual acting PPAR another embodiment, the compositions may further comprise ligands, such as naVeglitazar, fargilitazar, tesaglitazar, ragagli additional active ingredients, whose activity is useful for the tazar, oxeglitazar, PN-2034, PPAR 8; a 17-ketoreductase particular application for which the compound of this inven inhibitors, 3 B-DHA4.6-isomerase inhibitors, 3f-DHA4.5- tion is being administered. isomerase inhibitors, 17.20 desmolase inhibitors, p450c17 In some embodiments, the compositions will further com inhibitors, p450ssc inhibitors, 17.20-lyase inhibitors, or com prise a 5alpha-Reductase Inhibitors (5AR1), a SARM or 10 binations thereof. SARMs, a selective estrogen receptor modulator (SERM), an In some embodiments, the compositions will further com aromatase inhibitor, such as but not limited to anastrazole, prise Ghrelin receptor ligand or growth hormone analogues exemestane, or letrozole; a GnRH agonist or antagonist, a and secretagogues, IGF-1, IGF-1 analogues and secreta steroidal or nonsteroidal GR ligand, a steroidal or nonsteroi gogues, myostatin analogues, proteasome inhibitors, andro dal PR ligand, a steroidal or nonsteroidal AR antagonist, a 15 genic/anabolic steroid, Enbrel, melanocortin 4 receptor ago 17-aldoketoreductase inhibitor or 17 B-hydroxysteroid dehy nist, insulins, or combinations thereof. Such compositions drogenase inhibitor. Such compositions may be used, in some may be used, in some embodiments, for treating sarcopenia or embodiments, for treating a hormone dependent condition, a musculoskeletal condition. Such as, for example, infertility, neoplasia of a hormone In some embodiments, the composition will comprise the responsive cancer, for example, a gonadal cancer, or a uro compounds as described herein, as well as another therapeu genital cancer. tic compound, including interalia, ghrelin receptor ligand or In some embodiments, the composition will comprise the growth hormone analogues and secretagogues, such as, pral compounds as described herein, as well as another therapeu morelin, examorelin, tabimorelin, capimorelin, capromore tic compound, including inter alia, a 5AR1 such as finas lin, ipamorelin, EP-01572, EP-1572, JMV-1843, an andro teride, dutasteride, izonsteride; other SARMs, such as, 25 genic/anabolic steroid such as testosterone/oxandrolone; a RU-58642, RU-56279, WS9761 A and B, RU-59063, melanocortin 4 receptor agonist, Such as bremelanotide, a RU-58841, bexlosteride, LG-2293, L-245976, LG-121071, ghrelin or analogue thereof. Such as human ghrelin, CYT LG-121091, LG-121104, LGD-2226, LGD-2941, LGD 009-GhrOb, L-692429, GHRP-6, SK&F-1 10679, 3303, YM-92088, YM-175735, LGD-1331, BMS-357597, U-75799E), leptin (metreleptin, pegylated leptin: a leptin BMS-391197, S-40503, BMS-482404, EM-4283, EM-4977, 30 receptor agonist, such as LEP (116-130), OB3, D-Leu-4- BMS-564929, BMS-391197, BMS-434588, BMS-487745, OB3, ra AV-leptin, AAV-hCB, ra AVhCB; an insulin (short BMS-501949, GSK971086, GSK2420A, SA-766, intermediate-, and long acting formulations; a cortisol or YM-92088, YM-580, LG-123303, LG-123129, PMCol, corticosteroid, or a combination thereof. YM-175735, BMS-591305, BMS-591309, BMS-665139, The invention contemplates, in Some embodiments, BMS-665539, CE-590, 116BG33, 154BG31, arcarine, ACP 35 administration of compositions comprising the individual 105: SERMs, such as tamoxifene, 4-hydroxytamoxifene, agents, administered separately and by similar or alternative idoxifene, toremifene, ospennifene, droloxifene, raloxifene, routes, formulated as appropriately for the route of adminis arzoxifene, baZedoxifene, PPT (1,3,5-Tris(4-hydroxyphe tration. The invention contemplates, in Some embodiments, nyl)-4-propyl-1H-pyrazole), diarylpropionitrile (DPN), laso administration of compositions comprising the individual foxifene, pipendoxifene, EM-800, EM-652, nafoxidine, Zin 40 agents, administered in the same formulation. The invention doxifene, tesmilifene, miproxifene phosphate, RU 58,688, contemplates, in some embodiments, staggered administra EM 139, ICI 164,384, ICI 182,780, clomiphene, MER-25, tion, concurrent administration, of administration of the Vari diethylstibestrol, coumestrol, genistein, GW5638, ous agents over a course of time, however, their effects are LY353581, Zuclomiphene, enclomiphene, delmadinone synergistic in the Subject. acetate, DPPE, (N,N-diethyl-2-4-(phenylmethyl)- 45 It is to be understood that any of the above means, timings, phenoxyethanamine), TSE-424, WAY-070, WAY-292, routes, or combinations thereof, of administration of two or WAY-818, cyclocommunol, prinaberel, ERB-041, WAY-397, more agents is to be considered as being encompassed by the WAY-244, ERB-196, WAY-169122, MF-101, ERb-002, phrase “administered in combination', as described herein. ERB-037, ERB-017, BE-1060, BE-380, BE-381, WAY-358, In one embodiment, the compound of this invention is 18FFEDNP, LSN-500307, AA-102, Ban Zhilian, CT-101, 50 administered in combination with an anti-cancer agent. In one CT-102, VG-101; GnRH agonists or antagonists, such as, embodiment, the anti-cancer agent is a monoclonal antibody. leuprolide, goserelin, triptorelin, alfaprostol, histrelin, detire In some embodiments, the monoclonal antibodies are used lix, ganirelix, antide iturelix, cetrorelix, ramorelix, ganirelix, for diagnosis, monitoring, or treatment of cancer. In one antarelix, teverelix, abarelix, Ozarelix, Sufugolix, praZarelix, embodiment, monoclonal antibodies react against specific degarelix, NBI-56418, TAK-810, acyline: FSH agonist/an 55 antigens on cancer cells. In one embodiment, the monoclonal tagonist, LH agonist/antagonists, aromatase inhibitors, such antibody acts as a cancer cell receptor antagonist. In one as, letrozole, anastraZole, atamestane, fadrozole, minames embodiment, monoclonal antibodies enhance the patients tane, exemestane, plomestane, liarozole, NKS-01, Vorozole, immune response. In one embodiment, monoclonal antibod YM-511, finrozole, 4-hydroxyandrostenedione, aminoglue ies act against cell growth factors, thus blocking cancer cell thimide, rogletimide: Steroidal or nonsteroidal glucocorti 60 growth. In one embodiment, anti-cancer monoclonal antibod coid receptor ligands, such as, ZK-216348, ZK-243149, ies are conjugated or linked to anti-cancer drugs, radioiso ZK-243185, LGD-5552, mifepristone, RPR-106541, ORG topes, other biologic response modifiers, other toxins, or a 34517, GW-215864X, Sesquicillin, CP-472555, CP-394531, combination thereof. In one embodiment, anti-cancer mono A-222977, AL-438, A-216054, A-276575, CP-394531, clonal antibodies are conjugated or linked to a SARM com CP-409069, UGR-07: Steroidal or nonsteroidal progesterone 65 pound as described hereinabove. receptor ligands; Steroidal or nonsteroidal AR antagonists In another embodiment, the present invention includes Such as flutamide, hydroxyflutamide, bicalutamide, niluta compounds and compositions in which a compound of the US 8,426,465 B2 39 40 invention is either combined with, or covalently bound to, an In one embodiment, the compound is administered in com agent bound to a targeting agent, such as a monoclonal anti bination with a Bax activity modulator such as allisol B body (e.g., a murine or humanized monoclonal antibody). In acetate. In one embodiment, the compound is administered in one embodiment, the agent bound to a targeting agent is a combination with an angiotensin II receptor blocker Such as cytotoxic agent. It will be appreciated that the latter combi losartan. In one embodiment, the compound is administered nation may allow the introduction of cytotoxic agents into for in combination with selenium, green tea cachecins, saw pal example cancer cells with greater specificity. Thus, the active metto, lycopene, Vitamin D, dietary Soy, genistein or isofla form of the cytotoxic agent (i.e., the free form) will be present WO. only in cells targeted by the antibody. Of course, the com In one embodiment, the compound is administered in com pounds of the invention may also be combined with mono 10 bination with antineoplastic agents, such as alkylating agents, clonal antibodies that have therapeutic activity against can antibiotics, hormonal antineoplastics and antimetabolites. C. Examples of useful alkylating agents include alkyl Sulfonates In one embodiment, the compound is administered in com Such as buSulfan, improSulfan and piposulfan, aziridines, bination with a selective tyrosine kinase inhibitor. In some Such as a benzodizepa, carboquone, meturedepa and uredepa; embodiments, the selective tyrosine kinase inhibitor inhibits 15 ethylenimines and methylmelamines such as altretamine, tri catalytic sites of cancer promoting receptors thereby inhibit ethylenemelamine, triethylenephosphoramide, triethyleneth ing tumor growth. In one embodiment, a selective tyrosine iophos-phoramide and trimethylolmelamine; nitrogen mus kinase inhibitor modulates growth factor signaling. In some tards Such aS chlorambucil, chlomaphazine, embodiments, the selective tyrosine kinase inhibitor targets cyclophosphamide, estramustine, iphosphamide, mechlore EGFR (ERBB/HER) family members. In one embodiment, thamine, mechlorethamine oxide hydrochloride, melphalan, the selective tyrosine kinase inhibitor is a BCR-ABL tyrosine novembichine, phenesterine, prednimustine, trofosfamide, kinase inhibitor. In one embodiment, the selective tyrosine and uracil mustard; nitroso ureas, Such as carmustine, chlo kinase inhibitor is an epidermal growth factor receptor rozotocin, fotemustine, lomustine, nimustine, ranimustine, tyrosine kinase inhibitor. In one embodiment, the selective dacarbazine, mannomustine, mitobronitol, mitolactol and tyrosine kinase inhibitor is a vascular endothelial growth 25 pipobroman. More such agents will be known to those having factor tyrosine kinase inhibitor. In one embodiment, the skill in the medicinal chemistry and oncology arts. selective tyrosine kinase inhibitor is a Platelet Derived In some embodiments, other agents suitable for combina Growth Factor (PDGF) inhibitor. tion with the compounds of this invention include protein In one embodiment, the compound is administered in com synthesis inhibitors such as abrin, aurintricarboxylic acid, bination with a to cancer Vaccine. In one embodiment, the 30 chloramphenicol, colicin E3, cycloheximide, diphtheria cancer vaccine is a therapeutic vaccine thus, treating an exist toxin, edeine A, emetine, erythromycin, ethionine, fluoride, ing cancer. In some embodiments, the cancer vaccine is a 5-fluorotryptophan, fusidic acid, guanylyl methylene diphos prophylactic vaccine thus, preventing the development of phonate and guanylyl imidodiphosphate, kanamycin, cancer. In one embodiment, both types of vaccines have the kasugamycin, kirromycin, and O-methyl threonine, modec potential to reduce the burden of cancer. In one embodiment, 35 cin, neomycin, norvaline, pactamycin, paromomycine, puro treatment or therapeutic vaccines are administered to cancer mycin, ricin, C.-sarcin, shiga toxin, showdomycin, sparsomy patients and are designed to strengthen the body's natural cin, spectinomycin, streptomycin, tetracycline, thiostrepton defenses against cancers that have already developed. In one and trimethoprim Inhibitors of DNA synthesis, including embodiment, therapeutic vaccines may prevent additional alkylating agents such as dimethyl Sulfate, mitomycin C, growth of existing cancers, prevent the recurrence of treated 40 nitrogen and sulfur mustards, MNNG and NMS: intercalating cancers, or eliminate cancer cells not killed by prior treat agents such as acridine dyes, actinomycins, adriamycin, ments. In some embodiments, prevention or prophylactic anthracenes, benzopyrene, ethidium bromide, propidium vaccines are administered to healthy individuals and are diiodide-intertwining, and agents such as distamycin and designed to target cancer in individuals who present high risk netropsin, can also be combined with compounds of the for the disease. In one embodiment, the cancer vaccine is an 45 present invention in pharmaceutical compositions. DNA base antigen/adjuvant vaccine. In one embodiment, the cancer analogs such as acyclovir, adenine, B-1-D-arabinoside, ame vaccine is a whole cell tumor vaccine. In one embodiment, the thopterin, aminopterin, 2-aminopurine, aphidicolin, 8-aza cancer vaccine is a dendritic cell vaccine. In one embodiment, guanine, azaserine, 6-azauracil, 2’-azido-2'-deoxynuclio the cancer vaccine comprises viral vectors and/or DNA vac sides, 5-bromodeoxycytidine, cytosine, B-1-D-arabinoside, cines. In one embodiment, the cancer vaccine is an idiotype 50 diazooxynorleucine, dideoxynucleosides, 5-fluorodeoxycy vaccine. tidine, 5-fluorodeoxyuridine, 5-fluorouracil, hydroxyurea In one embodiment, the compound is administered in com 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 55 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 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 to methotrexate. In one embodiment, the anti-cancer chemo 60 Varicin and streptolydigin also can be combined with the therapeutic agent is a Vinca alkaloid, such as but not limited to compounds of the invention to provide pharmaceutical com vindesine. In some embodiments, the anti-cancer chemo positions. therapeutic agents include platinum compounds such as but In one embodiment, the compound is administered in com not limited to carboplatin, and taxanes Such as docetaxel. In bination with a vaccine for prostate cancer, allisol B acetate, one embodiment, the anti-cancer chemotherapeutic agent is 65 angiotensin II receptor blocker, or others known in the art. In an aromatase inhibitor Such as but not limited to anastrazole, one embodiment, the compound is administered in combina exemestane, or letrozole. tion with an agent to decrease prostate (benign or malignant) US 8,426,465 B2 41 42 hypertrophy, Such as, for example, selenium, green tea fractures may be simple, compound, transverse, greenstick, cachecins, saw palmetto, lycopene, Vitamin D, dietary Soy, or comminuted fractures. In one embodiment, fractures may genistein and isoflavone food product and others. be to any bone in the body, which in one embodiment, is a In one embodiment, the compound is administered in com fracture in any one or more bones of the arm, wrist, hand, bination with an immunomodulating agent. In one embodi finger, leg, ankle, foot, toe, hip, collarbone, or a combination ment, the immunomodulating agent is an immunosuppressive thereof. agent. In one embodiment, immunosuppressive agents com In another embodiment, the methods and/or compositions prise corticosteroids, cyclosporine, azathioprine, methotrex provided herein, are effective in treatment, prevention, Sup ate, cyclophosphamide, tacrolimus—FK-506, anti-thy pression, inhibition or reduction of the risk of skeletal-related mocyte globulin, mycophenylate moeftil, or a combination 10 events such as pathologic fractures, spinal cord compression, thereof. In one embodiment, the corticosteroid is a glucocor ticoid. hypercalcemia, bone-related pain, or their combination. In one embodiment, the immunomodulating agent is an In another embodiment, the skeletal-related events sought immunostimulatory agent. In one embodiment, the immuno to be treated using the methods provided herein and/or utiliz stimulatory agent is a specific immunostimulator thus, pro 15 ing the compositions provided herein, comprise the necessity vides antigenic specificity during an immune response. Such for bone Surgery and/or bone radiation, which in some as a vaccine or any antigen. In one embodiment, the immu embodiments, is for the treatment of pain resulting in one nostimulatory agent is a non-specific immunostimulator thus, embodiment from bone damage, or nerve compression. In acting irrespective of antigenic specificity to augment another embodiment, the skeletal-related events sought to be immune response of otherantigen or stimulate components of treated using the methods provided herein and/or utilizing the the immune system without antigenic specificity. In one compositions provided herein, comprise spinal cord com embodiment, the non-specific immunostimulator is Freund's pression, or the necessity for changes in antineoplastic complete adjuvant. In one embodiment, the non-specific therapy, including changes in hormonal therapy, in a Subject. immunostimulator is Freund's incomplete adjuvant. In one In some embodiments, skeletal-related events sought to be embodiment, the non-specific immunostimulator is a mon 25 treated using the methods provided herein and/or utilizing the tanide ISA adjuvant. In one embodiment, the non-specific compositions provided herein, comprise treating, Suppress immunostimulator is a Ribis adjuvant. In one embodiment, ing, preventing, reducing the incidence of, or delaying pro the non-specific immunostimulator is a Hunter's TiterMax. In gression or severity of bone metastases, or bone loss. In one one embodiment, the non-specific immunostimulator is an embodiment, bone loss may comprise osteoporosis, osteope aluminum salt adjuvant. In one embodiment, the non-specific 30 nia, or a combination thereof. In one embodiment, skeletal immunostimulator is a nitrocellulose-adsorbed protein. In related events may comprise any combination of the embodi one embodiment, the non-specific immunostimulator is a ments listed herein. Gerbu Adjuvant. In one embodiment, the methods provided herein and/or In one embodiment, the compound is administered in com utilizing the compositions provided herein, are effective in bination with an agent, which treats bone diseases, disorders 35 reducing metastases to the bone, such as in terms of number or conditions, such as osteoporosis, bone fractures, etc., and of foci, the size of foci, or a combination thereof. According this invention comprises methods of treating the same, by to this aspect of the invention and in one embodiment, pro administering the compounds as herein described, alone or in vided herein is a method of preventing or inhibiting cancer combination with other agents. metastasis to bone in a subject, comprising the step of admin In one embodiment, bone turnover markers have been 40 istering to the Subject a composition comprising toremifene, demonstrated as an effective, validated tool for the clinical raloxifene, tamoxifen or an analogue, functional derivative, Scientist to monitor bone activity. In another embodiment, metabolite or a combination thereof, or a pharmaceutically urinary hydroxyproline, serumalkaline phosphatase, tartrate acceptable salt thereof. In one embodiment, such metabolites resistant acid phosphatase, and osteocalcin levels, along with may comprise ospennifene, fispennifene or their combination. the urinary calcium-creatinine ratio are used as bone turnover 45 In one embodiment, the cancer is prostate cancer. markers. In another embodiment osteocalcin levels is used as A person skilled in the art would readily recognize that a bone formation marker. In another embodiment c-telopep changes in the antineoplastic therapy according to the meth tide is used as a bone resorption marker. ods provided herein, utilizing the compositions provided In one embodiment, this invention provides for the treat herein may be conducted as a function of, or adjusted or ment, prevention, Suppression or inhibition of, or the reduc 50 varied as a function of interalia, the severity of the underly tion of the risk of developing a skeletal-related event (SRE), ing disease, the source of the underlying disease, the extent of Such as bone fractures, Surgery of the bone, radiation of the the patients’ pain and Source of the patients’ pain, as well as bone, spinal cord compression, new bone metastasis, bone the stage of the disease. The therapeutic changes may include loss, or a combination thereof in a Subject with cancer, com in certain embodiments, changes in the route of administra prising administering to the a compound as herein described 55 tion (e.g. intracavitarily, intraarterially, intratumorally etc.), and/or its analog, derivative, isomer, metabolite, pharmaceu forms of the compositions administered (e.g. tablets, elixirs, tically acceptable salt, pharmaceutical product, hydrate, Suspensions etc.), changes in dosage and the like. Each of N-oxide, or any combination thereof. The invention relates, these changes are well recognized in the art and are encom inter alia to treatment of an SRE with the compound of for passed by the embodiments provided herein. mula (I) in a subject with prostate cancer undergoing or 60 In one embodiment, the skeletal-related events are a result having undergone androgen deprivation therapy (ADT). of cancer therapy. In one embodiment, the skeletal-related In one embodiment, the skeletal-related events treated events are a result of hormone deprivation therapy, while in using the methods provided herein and/or utilizing the com another embodiment, they are a product of androgen depri positions provided herein, are fractures, which in one vation therapy (ADT). embodiment, are pathological fractures, non-traumatic frac 65 In one embodiment, the compounds of this invention are tures, vertebral fracture, non-vertebral fractures, morphomet useful in prevention or reversal of androgen-deprivation ric fractures, or a combination thereof. In some embodiments, therapy (ADT) induced side effects such as reduced muscle US 8,426,465 B2 43 44 mass, reduced muscle strength, frailty, hypogonadism, cillamine, aurothioglucose, gold sodium thiomalate, or osteoporosis, osteopenia, decreased BMD and/or decreased auranofin. In one embodiment, the anti-rheumatic agent is an bone mass. immunosuppressive cytotoxic drug. In one embodiment, In males, while the natural decline in sex-hormones at immunosuppressive cytotoxic drugs include but are not lim maturity (direct decline in androgens as well as lower levels ited to methotrexate, mechlorethamine, cyclophosphamide, of estrogens derived from peripheral aromatization of andro chlorambucil, or azathioprine. gens) is associated with the frailty of bones, this effect is more In one embodiment, the compound is administered in com pronounced in males who have undergone androgen depriva bination with an antidiabetic agent. In one embodiment, the tion therapy. antidiabetic agent is a Sulfonylurea. In one embodiment, Sul Such agents for combined use may comprise a SERM, as 10 fonylureas include but are not limited to tolbutamide, aceto herein described, a bisphosphonate, for example, alendr hexamide, tolaZamide, chlorpropamide, glipizide, glyburide, onate, tiludroate, clodroniate, pamidronate, etidronate, Zolen glimepiride, or gliclazide. In one embodiment, the antidia dronate, cimadronate, neridronate, minodronic acid ibandr betic agent is a meglitinide. In one embodiment, meglitinides onate, risedronate, homoresidronate, a calcitonin, for include but are not limited to prandin or nateglinide. In one example, salmon, Elcatonin, SUN-8577, TJN-135; a Vitamin 15 embodiment, the antidiabetic agent is a biguanide. In one D or derivative (ZK-156979); a Vitamin D receptor ligand or embodiment, biguanides include but are not limited to met analogues thereof, such as calcitriol, topitriol, ZK-150123, formin. In one embodiment, the antidiabetic agent is a thia TEI-9647, BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299, Zolidinedione. In one embodiment, thiazolidinediones DP-035, an estrogen, estrogen derivative, or conjugated include but are not limited to rosiglitaZone, pioglitaZone, or estrogen; an antiestrogen, progestin, synthetic estrogen/ troglitaZone. In one embodiment, the antidiabetic agent is an progestin; a RANK ligand mAb, for example, denosumab or alpha glucosidase inhibitor. In one embodiment, alpha glu AMG 162 (Amgen); an CVB3 integrin receptor antagonist; an cosidase inhibitors include but are not limited to miglitol or osteoclast vacuolar ATPase inhibitor; an antagonist of VEGF acarbose. In one embodiment, the antidiabetic agent is binding to osteoclast receptors; a calcium receptor antago PPARO/Y ligand, dipeptidylpeptidase 4 (DPP-4) inhibitor, nist; PTh (parathyroid hormone) or analogues thereof. PTHrP 25 SGLT (sodium-dependent glucose transporter 1) inhibitor, or analogues (parathyroid hormone-related peptide), cathepsin FBPase (fructose 1,6-bisphosphatase) inhibitor. In one K inhibitors (AAE581); strontium ranelate; tibolone: HCT embodiment, the antidiabetic agent is insulin. In one embodi 1026, PSK3471; gallium maltolate: Nutropin AQ: prostag ment, the insulin is rapid-acting insulin. In one embodiment, landins, p38 protein kinase inhibitor, a bone morphogenetic the insulin is short-acting insulin. In one embodiment, the protein; an inhibitor of BMP antagonism, an HMG-CoA 30 insulin is intermediate-acting insulin. In one embodiment, the reductase inhibitor, a Vitamin K or derivative, an antiresorp insulin is intermediate- and short-acting insulin mixtures. In tive, an Ipriflavone, a fluoride salt, dietary calcium supple one embodiment, the insulin is long-acting insulin. In one ment, osteoprotegerin, or any combination thereof. In one embodiment, the antidiabetic agents are inhibitors of fatty embodiment, the combined administration of a SARM as acid binding protein (aP2) such as those disclosed in U.S. Ser. herein described, osteoprotegerin and parathyroid hormone is 35 No. 09/519,079 filed Mar. 6, 2000, glucagon-like peptide-1 contemplated for treating any disease, disorder or condition (GLP-1), and dipeptidyl peptidase IV (DPP4) inhibitors such of the bone. as those disclosed in WOO168603, which are incorporated by In one embodiment, the immunomodulating agent is an reference. anti-inflammatory agent. In one embodiment, the anti-in In one embodiment, the antidiabetic agent is a GRantago flammatory agent is a non-steroidal anti-inflammatory agent. 40 nist, for example, as described in United States Patent Appli In one embodiment, the non-steroidal anti-inflammatory cation Publication Number 200701 17805, European Patent agent is a cox-1 inhibitor. In one embodiment, the non-ste Application, Publication No. 0 188396, European Patent roidal anti-inflammatory agent is a cox-2 inhibitor. In one Application 0 683 172, International Patent Application Pub embodiment, the non-steroidal anti-inflammatory agent is a lication No. WO 98/27986, European Patent Application 0 coX-1 and cox-2 inhibitor. In some embodiments, non-steroi 45 903 146, a glucokinase activator, for example, as described in dal anti-inflammatory agents include but are not limited to United States Patent Application Publication Number aspirin, Salsalate, diflunisal, ibuprofen, fenoprofen, flubipro 20070099930, 20070078168, 20070099936, World Intellec fen, fenamate, ketoprofen, nabumetone, piroxicam, tual Property Organization Publication Number WO0058293 naproxen, diclofenac, indomethacin, Sulindac, tolmetin, and WO01/44216, WO03/015774, WO03/000262, WO03/ etodolac, ketorolac, oxaprozin, or celecoxib. In one embodi 50 000267, which are fully incorporated herein by reference, a ment, the anti-inflammatory agent is a steroidal anti-inflam glycogen phosphorylase inhibitor, Such as, for example, matory agent. In one embodiment, the steroidal anti-inflam CP-368,296, CP-316,819, or BAYR3401, a beta-3 adrenergic matory agent is a corticosteroid. receptoragonist, such as the beta.3 adrenergic agonists BMS In one embodiment, the immunomodulating agent is an 194449, 196085, 201620 (BMS), GW427353 or SB418790, a anti-rheumatic agent. In one embodiment, the anti-rheumatic 55 gluconeogenesis inhibitor, such as CS-917 (Sankyo/Metaba agent is a non-steroidal anti-inflammatory agent. In one sis), a CETP inhibitor, for example, as described in PCT embodiment, the anti-rheumatic agent is a corticosteroid. In Patent Application No. WO 00/38721, U.S. Pat. No. 6,147, one embodiment, the corticosteroid is prednisone or dexam 090, which are incorporated herein by reference, a GPR40 ethasone. In one embodiment, the anti-rheumatic agent is a inhibitor, a liver X receptor (LXR) modulator, for example, as disease modifying anti-rheumatic drug. In one embodiment, 60 described herein in United States Patent Application Publi the disease modifying anti-rheumatic drug is a slow-acting cation Number 20070099916, 20070161578, 20070088017, anti-rheumatic drug. In one embodiment, the disease modi which are incorporated herein by reference, a farnesoid X fying anti-rheumatic drug is an antimalarial agent. In one receptor (FXR) modulator, for example, as described in U.S. embodiment, disease modifying anti-rheumatic drugs Pat. No. 6,777,446 fully United States Patent Application include but are not limited to chloroquine, hydroxychloro 65 Publication Number 20070043029, which are fully incorpo quine, methotrexate, SulfaSalazine, cyclosporine, azathio rated herein by reference, an estrogen-related receptor alpha prine, cyclophosphamide, azathioprine, SulfaSalazine, peni modulator, for example as described in World Intellectual US 8,426,465 B2 45 46 Property Organization Publication Number WO/2006/ ment, the muscarinic blocking agent is a belladonna alkaloid 019741, European Published Patent Application 1398.029, Such as atropine or Scopolamine. which are incorporated herein by reference, a protein tyrosine In one embodiment, the agent treating the autonomic ner phosphatase-1B (PTP-1B) inhibitor, such as, for example Vous system is a ganglionic blocking agent. In one embodi A-401,674, KR 61639, OC-060062, OC-83839, OC-297962, ment, ganglionic blocking agents include but are not limited MC52445, and MC52453, or pharmaceutically acceptable to nicotine, trimethaphan, or mecamylamine. salts and esters thereof, an AMP kinase inhibitor, a glycogen In one embodiment, the agent treating the nervous system synthase kinase 3-beta inhibitor, for example, as described in is an agent treating the central nervous system. In one U.S. Pat. No. 7,157,422, or U.S. Pat. No. 6,780,625, which embodiment, the agent treating the central nervous system is are incorporated herein by reference, an 11-beta-hydroxys 10 a local anesthetic agent. In one embodiment, local anesthetic teroid dehydrogenase type 1 inhibitor, such as, but not limited agents include but are not limited to benzocaine, chlorop to an agent as described in International Patent Application rocaine, cocaine, procaine, bupivacaine, levobupivacaine, Nos. WO03/065983; WO03/104,207, which are incorporated lidocaine, mepivacaine, prilocalne, or ropivacaine. In one herein by reference, or any combination of agents thereof. It embodiment, the agent treating the central nervous system is is to be understood that many compounds which fit the above 15 a general anaesthetic agent. In one embodiment, general classifications are known in the art and the above are to be anesthetic agents include but are not limited to esflurane, considered as examples of agents which are appropriate for sevoflurane, isoflurane, halothane, enflurane, methoxyflu the indicated classes, and are not to be considered as limiting rane, Xenon, propofol, etomidate, methohexital, midazolam, the agents for use in any way. diazepamor, ketamine, thiopentone/thiopental, or lidocaine/ In one embodiment, the compound is administered in com prilocalne. bination with an agent treating the nervous system. In one In one embodiment, the agent treating the central nervous embodiment, the agent treating the nervous system is an agent system is an analgesic agent. In some embodiments, analge treating the autonomic nervous system. In one embodiment, sic agents include but are not limited to paracetamol or non the agent treating the autonomic nervous system is an steroidal anti-inflammatory agent. In some embodiments, adrenomimetic drug. In one embodiment, the adrenomimetic 25 analgesic agents include opiates or morphinomimetics Such drug is a beta-adrenoceptoragonist, alpha-adrenoceptorago as morphine, pethidine, oxycodone, hydrocodone, diamor nist, or a combination thereof. In one embodiment, the phine, tramadol, or buprenorphine. In some embodiments, a adrenomimetic drug is a catecholamine. In one embodiment, combination of two or more analgesics is desired. adrenomimetic drugs include but are not limited to isoprot In one embodiment, the agent treating the central nervous erenol, norepinephrine, epinephrine, amphetamine, ephe 30 system is a muscle relaxant or vasoconstrictor agent. In one drine, or dopamine. In one embodiment, the adrenomimetic embodiment, muscle relaxants include but are not limited to drug is a directly acting adrenomimetic drug. In some methocarbamol, baclofen, carisoprodol, chlorZoxazone, 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. 35 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 40 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, 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 45 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 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, 50 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 55 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. 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 to embodiment, the cholinesterase inhibitor is a carbamate such 60 Such as Zolpidem or alpidem. In one embodiment, the seda as physostigmine, pyridostigmine, neostigmine, or rivastig tive agent is a pyrazolopyrimidine Such as Zaleplon. In one mine. In one embodiment, the cholinesterase inhibitor is an 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. 65 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 thiothixene, haloperidol, or fluphenazine. In one embodi US 8,426,465 B2 47 48 ment, the sedative agent is an herbal sedative Such as Valerian embodiment, the agent treating congestive heart failure is a plant mandrake, or kava. In some embodiments, the sedative beta-blocker such as acebutolol, atenolol, betaxolol hydro agent is esZopiclone, ramelteon, methaqualone, ethchlor chloride, bisoprolol fumarate, carteolol hydrochloride, Vynol, chloral hydrate, meprobamate, glutethimide, meth carvedilol, celiprolol hydrochloride, esmolol hydrochloride, yprylon, gamma-hydroxybutyrate, ethyl alcohol, methyl labetalol hydrochloride, levobunolol, metoprolol tartrate, trichloride, Zopiclone, or diethyl ether. metipranolol, nadolol, nebivolol, oxprenolol hydrochloride, In one embodiment, the agent treating the central nervous pindolol, propranolol hydrochloride, so talol hydrochloride, system is a neurodegenerative disorder medication. In one or timolol maleate. In one embodiment, the agent treating embodiment, the neurodegenerative disorder medication is congestive heart failure is digoxin. In one embodiment, the an acetylcholinesterase inhibitor Such as tacrine, donepezil, 10 agent treating congestive heart failure is a diuretic Such as galanthamine, or rivastigmine. In one embodiment, the neu thiazide diuretic, loop diuretic, potassium-sparing diuretic, or rodegenerative disorder medication is an N-methyl-D-aspar a combination thereof. In some embodiments, thiazide diuret tate (NMDA) antagonist Such as memantine. In one embodi ics include but are not limited to bendrofluazide, bendroflu ment, the neurodegenerative disorder medication reduces methiazide, benzthiazide, chlorothiazide, chlorthalidone, damage to motor neurons such as riluzole. In one embodi 15 cyclopenthiazide, Diucardin R, Diuril R. Enduron(R), Esid ment, the neurodegenerative disorder medication silences the rix R, Exna R., HCTZ, Hydrochlorothiazide, HydroDI gene that causes the progression of the disease. In one URIL(R), HYDROFLUMETHIAZIDE, Hydromox(R), Hygro embodiment, the agent treating the central nervous system is ton(R), indapamide, LoZol R, methyclothiazide, metolaZone, an antiepileptic drug (AED). In some embodiments, antiepi Mykrox R, Naqua R, Naturetin R, Oretic(R), polythiazide, leptic agents include Sodium channel blockers, GABA recep quinethaZone, Renese(R), trichlormethiazide, Xipamide, or toragonists, GABA reuptake inhibitors, GABA transaminase ZaroXolyn R. In some embodiments, loop diuretics include inhibitor, AEDs with a potential GABA mechanism of action, but are not limited to furosemide, bumetanide, or torasemide. glutamate blockers, or AEDs with other mechanisms of In some embodiments, potassium-sparing diuretics include action. In some embodiments, antiepileptic agents include but are not limited to amiloride, triamterene, aldosterone but are not limited to carbamazepine, fosphenyloin, oXcarba 25 antagonists, or spironolactone. Zepine, lamotrigine, Zonisamide, clobazam, clonazepam, In one embodiment, the agent treating the cardiovascular phenobarbital, primidone, tiagabine, vigabatrin, gabapentin, system is an anti-arrhythmic agent. In one embodiment, the valproate, felbamate, topiramate, levetiracetam, or pregaba anti-arrhythmic agent is a sodium channel blocker, beta-adr lin. energic blocker, calcium channel blocker, or an agent that In one embodiment, the agent treating the central nervous 30 prolong repolarization. In one embodiment, sodium channel system is an anti-addiction drug. In one embodiment, the blockers include but are not limited to quinidine, procaina anti-addiction is an anti-alcoholism drug such as disulfuram. mide, disopyramide, lidocaine, tocamide, mexiletine, enca 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 35 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 40 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 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 45 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 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. 50 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 55 phosphodiesterase III inhibitors include but are not limited to Parkinson's Disease. Such as dopaminergic drugs, or an cilostazol. In one embodiment, glycoprotein inhibitors agent, which treats major depression, such as SSRIs, 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 60 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 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, 65 In one embodiment, the agent treating the cardiovascular cilaZapril, enalapril, fosinopril, lisinopril, moexipril, perin system is a vasoactive agent or an inotrope. In one embodi dopril, quinapril, ramipril, trandolapril, or enalaprilat. In one ment, vasoactive agents or inotropes include but are not lim US 8,426,465 B2 49 50 ited to digoxin, dopamine, dobutamine, hydralazine, pra antagonist, phenothiazine derivative, or 5-HT3 antagonist Zosin, carvedilol, nitroprusside, nitroglycerin, captopril, Such as ondansetron or granisetron. lisinopril, nifedipine, diltiazem, hydrochlorothiazide, furo In one embodiment, the agent treating the GI system is an semide, spironolactone, AT-1 receptor antagonists (e.g., losa antacid. In one embodiment the antacid pharmaceutical rtan, irbesartan, Valsartan). ET receptor antagonists (e.g., preparation comprises buffering agents such as Sodium bicar sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. bonate, calcium carbonate, magnesium hydroxide, or alumi Nos. 5,612.359 and 6,043,265), Dual ET/AII antagonist (e.g., num hydroxide. compounds disclosed in WO 00/01389), neutral endopepti In one embodiment, the agent treating the GI system is an dase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP H2-receptor antagonist. In some embodiments, the H2-recep ACE inhibitors) (e.g., omapatrilat and gemopatrilat), or 10 tor antagonist is cimetidine, ranitidine, famotidine, or nizati nitrates. dine. In one embodiment, the agent treating the cardiovascular In one embodiment, the agent treating the GI system is a system is an anticoagulant agent. In one embodiment, the proton pump inhibitor. In some embodiments, the proton anticoagulantagent is a coumarin derivative oran unfraction 15 pump inhibitor is omeprazole, lansoprazole, pantoprazole, ated heparin. In one embodiment, coumarin derivatives rebeprazole, or esomeprazole include but are not limited to warfarin. In one embodiment, the agent treating the GI system is an In one embodiment, the agent treating the cardiovascular agent treating inflammation. In one embodiment, the agent system is a fibrinolytic agent such as Streptokinase, uroki treating inflammation is 5-amino-Salicylate, corticosteroid, nase, alteplase, anistreplase, prourokinase, reteplase, tenect metronidazole, ciprofloxacin, infiximab, budesonide, oranti eplase, lanoteplase, staphylokinase, vampire, or alfimeprase. TNF alpha antibody. In one embodiment, the agent treating the cardiovascular In one embodiment, the compound is administered in com system is a hypercholesterolemic agent Such as niacin-lovas bination with an agent treating a metabolic disease, disorder tatin, colestipol HCl, fluvastatin Sodium, atorvastatin cal or condition, which in some embodiments refers to metabolic cium, simvastatin, gemfibrozil, lovastatin, pravastatin 25 syndrome. In some embodiments, such agents comprise, inter Sodium, cholestyramine, cholestyramine light, fenofibrate, alia, pancreatic lipase inhibitors, such as for example, orlistat, colesevelam HCl, or ezetimibe. cetilistat, serotonin and norepinephrine reuptake inhibitors, In one embodiment, the SARM compound is administered Such as sibutramine, insulin-sensitizers such as biguanides in combination with an agent treating the gastrointestinal (metformin) or PPAR agonists, dual-acting PPAR agonists system. In one embodiment, the agent treating the gas 30 (muraglitazar, tesaglitazar, naveglitazar). PPAR-delta ago trointestinal (GI) system is enhancing GI motility. In one nists (GW-501516), DPP-IV inhibitors (vildagliptin, sitaglip embodiment, the agent enhancing GI motility is a prokinetic tin), alpha glucosidase inhibitors (acarbose), anti-diabetic agent such as metoclopramide, cisapride, tegaserod, or eryth combinations (ActoPlusMet, AvandaMet, metformin/piogli romycin. In one embodiment, the agent treating the GI system taZone, metformin/rosiglitaZone, Glucovance, etc.), gluca is decreasing GI motility. In one embodiment, the agent 35 gon-like peptide-1 analogues (exenatide, liraglutide), amylin decreasing GI motility is an opioid Such as morphine, diphe analogues (pramlintide), statins (atorvastatin, simvastatin, noxylate, loperamide hydrochloride, or opium. rosuvastatin, pravastatin, fluvastatin, lovastatin, pitavastatin), In one embodiment, the agent treating the GI system is an cholesterol absorption inhibitors (ezetimibe), nicotinic acid adsorbent or a bulking agent. In one embodiment, the adsor derivatives (immediate release and controlled release niacins, bent is kaolin or other hydrated aluminum silicate clays. In 40 niaslo, etc.), antidyslipidemic fixed combinations (simvasta one embodiment, the hydrated aluminum silicate clay is fur tin/eZetimibe, lovastatin/nicotinic acid, atorvastatin/amlo ther combined with pectin. In one embodiment, adsorbents or dipine, atorvastatin/torcetrapib, simvastatin/nicotinic acid a bulking agents comprise bismuth Subsalicylate, methylcel (ER)). ACE inhibitors (ramipril, captopril, lisinopril), AT-II lulose, psyllium derivative, or calcium polycarbophil. receptor antagonists (Valsartan, telmisartan), cannabinoid In one embodiment, the agent treating the GI system is a 45 receptor antagonists (rimonabant), cholesteryl ester transfer stool softener. In one embodiment, stool softeners includebut protein or CETP Inhibitors (JTT-705, CETi-1), beta3 adren are not limited to mineral oil, docusate dioctyl Sodium sulfo ergic agonists, PPARa ligands, or combinations thereof. Succinate, dioctyl calcium Sulfo Succinate, or dioctyl potas 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 50 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 55 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 visicol. tin, tretinoin, adapalene, tazarotene, bexarotene, alitretinoin, In one embodiment, the agent treating the GI system is a or beta-carotene. cathartic stimulant. In one embodiment, the cathartic stimu In one embodiment, the agent treating a dermatological lant is an anthraquinone derivative such as cascara, aloe, 60 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 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 orapomorphine. In one embodiment, the agent treating the GI 65 disorder is dapsone, 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. US 8,426,465 B2 51 52 In one embodiment, the agent treating a dermatological In one embodiment the antibiotic is an aminoglycoside disorder is an antibiotic. In one embodiment, the antibiotic is antibiotic. In one embodiment, aminoglycoside antibiotics a systemic antibiotic Such as griseofulvin, ketoconazole, flu include but are not limited to gentamicin, tobramycin, faro conazole, itraconazole, terbinafine, or potassium iodide. In penem, imipenem, kanamycin, neomycin, ertapenem, apra one embodiment, the antibiotic is a topical antifungal agent. mycin, paromomycin Sulfate, streptomycin, or amikacin. In some embodiment, topical antifungal agents include but In one embodiment the antibiotic is a quinolone antibiotic. are not limited to ciclopiroX, clotrimazole, econazole, keto In one embodiment quinolone antibiotics include but are not conazole, miconazole, naftifine, oxiconazole, terbinafine, or limited to ciprofloxacin, norfloxacin, lomefloxacin, enoxa tolnaftate. cin, ofloxacin, ciprofloxacin, levofloxacin, Sparfloxacin, gati In one embodiment, the agent treating a dermatological 10 floxacin, moxifloxacin, trovafloxacin, or alatrofloxacin. disorder is an antiviral agent Such as interferon alpha. In one In one embodiment the antibiotic is a cyclic peptide anti embodiment, the agent treating a dermatological disorder is biotic. In one embodiment cyclic peptide antibiotics include an antiscabies agent Such as pyrethrin or pyrethroid. In one but are not limited to Vancomycin, Streptogramins, Microcin embodiment, the agent treating a dermatological disorder is J25, Bacteriocin AS-48, RTD-1, or polymyxins. an immunosuppressive agent such as mycophenolate motefil 15 In one embodiment the antibiotic is a lincosamide antibi or 6-thioguanine. In one embodiment, the agent treating a otic. In one embodiment lincosamide antibiotics include but dermatological disorder is a topical immunosuppressive are not limited to clindamycin. agent such as tacrolimus, pimecrolimus, imiquimod, 5-fluo In one embodiment, the antibiotic is an oxazolidinone anti rouracil, or mechlorethamine. In one embodiment, the agent biotic. In one embodiment oxazolidinone antibiotics include treating a dermatological disorder is an antihistamine such as but are not limited to linezolid, U-100592, DA-7867, doxepin. In one embodiment, the agent treating a dermato AZD2563, or U-100766. logical disorder is treating pigmentation Such as hydro In one embodiment, the antibiotic is a sulfa antibiotic. In quinone or monobenzone. In one embodiment, the agent one embodiment, sulfa antibiotics include but are not limited treating a dermatological disorder is a protein or a recombi to Sulfisoxazole. nant protein Such as becaplermin, etanercept, denileukin 25 In one embodiment, the antibiotic is an antiseptic agent. In diftitox, or botulinum toxin. In one embodiment, the agent one embodiment, antiseptic agents include but are not limited treating a dermatological disorder is capsaicin, anthralin, to alcohols, chlorhexidine, chlorine, hexachlorophene, benzoyl peroxide, or calcipotriene. iodophors, chloroxylenol (PCMX), quaternary ammonium In one embodiment, the agent treating a dermatological compounds, or triclosan. disorder is a keratolytic agent. In one embodiment, the agent 30 In one embodiment, the antibiotic is an anti-tuberculosis treating a dermatological disorder is selenium Sulfide. In one agent. In one embodiment an anti-tuberculosis agents include embodiment, the agent treating or preventing a dermatologi but are not limited to ethambutol, rifabutin, isoniazid, cal disorder is a Sunscreen. In one embodiment, the Sunscreen rifampicin, pyrazinamide, or rifampin absorbs UVB, UVA, or a combination thereof. In one embodiment, the antibiotic is an antifungal agent. In In one embodiment, the agent treating a dermatological 35 one embodiment, antifungal agents include but are not lim disorder may be a growth factor Such as epidermal growth ited to terbinafine, flucytosine, fluconazole, itraconazole, factor (EGF), transforming growth factor-O. (TGF-C.), platelet ketoconazole, ravuconazole, posaconazole, Voriconazole, derived growth factor (PDGF), fibroblast growth factors caspofungin, micafungin, V-echinocandin, amphotericin B, (FGFs) including acidic fibroblast growth factor (C.-FGF) and amphotericin B lipid complex (ABLC), amphotericin B col basic fibroblast growth factor (B-FGF), transforming growth 40 loidal dispersion (ABCD), liposomal amphotericin B factor-B (TGF-B) and insulin like growth factors (IGF-1 and (1-Amb), liposomal nyStatin, or griseofulvin. IGF-2), or any combination thereof. In one embodiment, the antibiotic is an antiprotozoal In one embodiment, the compound is administered in com agent. In one embodiment the antiprotozoal agent is an anti bination with an anti-infective agent. In one embodiment, the malarial agent. In one embodiment, antimalarial agents anti-infective agent is an antibiotic agent. In one embodiment 45 include but are not limited to chloroquine, mefloquine, the antibiotic is a beta-lactam antibiotic. In one embodiment proguanil, pyrimethamine with dapsone, pyrimethamine with beta-lactamantibiotics include but are not limited to penicil Sulfadoxine, quinine, or primaquine. In one embodiment, the lin, benzathine penicillin, benzylpenicillin, amoxicillin, antiprotozoal agent is an amoebicide. In one embodiment, procaine penicillin, dicloxacillin, amoxicillin, flucloxacillin, amoebicides include but are not limited to metronidazole, ampicillin, methicillin, azlocillin, carbenicillin, ticarcillin, 50 timidazole, or diloxanide furoate. In one embodiment, the meZlocillin, piperacillin, phenoxymethylpenicillin, antiprotozoal agent is an antigiardial agent. In one embodi co-amoxiclav, cephalosporin, cefalexin, cephalothin, cefazo ment, antigiardial agents include but are not limited to met lin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ronidazole, timidazole, or mepacrine. In one embodiment, the ceftriaxone, cefotaxime, ceftazidime, cefepime, ce?pirome, antiprotozoal agent is a leishmanicide. In one embodiment, imipenem, meropenem, ertapenem, faropenem, monobac 55 leishmanicides include but are not limited to sodium stibo tam, aztreonam, or carbapenem. gluconate. In one embodiment, the antibiotic is an antithel In one embodiment the antibiotic is a tetracycline antibi mintic agent. otic. In one embodiment tetracycline antibiotics include but In one embodiment, the antibiotic is an antiviral agent. In are not limited to tetracycline, chlortetracycline, demeclocy one embodiment, antiviral agents include but are not limited cline, doxycycline, lymecycline, minocycline, or oxytetracy 60 to abacavir, acyclovir, amantadine, didanosine, emitricitabine, cline. enfuVirtide, entecavir, lamivudine, nevirapine, oseltamivir, In one embodiment the antibiotic is a macrollide antibiotic. ribavirin, rimantadine, stavudine, Valaciclovir, Vidarabine, In one embodiment macrollide antibiotics include but are not Zalcitabine, or zidovudine. In one embodiment, the antiviral limited to erythromycin, azithromycin, OXithromycin, agent is a nucleotide analog reverse transcriptase inhibitor. In dirithromycin, clarithromycin, josamycin, oleandomycin, 65 one embodiment, nucleotide analog reverse transcriptase kitasamycin, spiramycin, tylosin/tylocine, troleandomycin, inhibitors include but are not limited totenofovir or adefovir. carbomycin, cethromycin, or tellithromycin. In one embodiment, the antiviral agent is a protease inhibitor. US 8,426,465 B2 53 54 In one embodiment, protease inhibitors include but are not embodiments, agents treating a metabolic disease include but limited to saquinavir, ritonavir, indinavir, nelfinavir, are not limited to a vitamin, Coenzyme Q10, glucosidase alfa, amprenavir, lopinavir, fosamprenavir, or tipranavir. In one Sodium bicarbonate, bisphosphonate, biotin, allopurinol, embodiment, the antiviral agent is a fusion inhibitor Such as levodopa, diazepam, phenobarbital, haloperidol, folic acid, enfuvirtide. In one embodiment, a combination of antiviral or 5 antioxidants, activators of cation channels haptoglobin, or antiretroviral agents is desired. In one embodiment, antiviral carnitine. orantiretroviral agents or a combination thereof, further com In one embodiment, the agent treating a metabolic disease prise hydroxyurea, resveratrol, grapefruit, ritonavir, lefluno is a pancreatic lipase inhibitor Such as orlistat or cetilistat, mide, or a combination thereof. serotonin or norepinephrine reuptake inhibitor Such as In one embodiment, the compound is administered in com 10 sibutramine, insulin-sensitizers such as biguanide, PPAR bination with an agent treating the liver. In one embodiment, agonist, dual-acting PPAR agonist Such as muraglitazar, tesa the compound is administered in combination with a statin. In glitazar, or naveglitazar, PPAR-delta agonist Such as Some embodiment, statins include but are not limited to ator GW-501516, DPP-IV inhibitor such as vildagliptin or sita vastatin, fluvastatin, lovastatin, pravastatin, simvastatin, or gliptin, alpha glucosidase inhibitor Such as acarbose, anti rosuvastatin. 15 diabetic combination such as ActoPlus Met, AvandaMet, met In one embodiment, the compound is administered in com formin/pioglitaZone, metformin/rosiglitaZone, O bination with a bile acid sequestrant. In some embodiment, Glucovance, Glucagon-like peptide-1 analogue Such as bile acid sequestrants include but are not limited to exenatide or liraglutide, amylin analogue Such as pramlintide, cholestyramine, colestipol, or colesevelam. statin Such as atorvastatin, simvastatin, rosuvastatin, pravas In one embodiment, the compound is administered in com tatin, fluvastatin, lovastatin, or pitavastatin, cholesterol bination with a cholesterol absorption inhibitor. In some absorption inhibitor Such as eZetimibe, nicotinic acid deriva embodiment, cholesterol absorption inhibitors include but tive such as niacin or niaslo, antidyslipidemic fixed combi are not limited to ezetimibe. nation Such as simvastatin/eZetimibe, lovastatin/nicotinic In one embodiment, the compound is administered in com acid, atorvastatin/amlodipine, or atorvastatin/torcetrapib, bination with a nicotinic acid agent. In some embodiments, 25 simvastatin/nicotinic acid, ACE inhibitor Such as ramipril, nicotinic acid agents include but are not limited to niacin, captopril, or lisinopril, AT-II receptor antagonist Such as Val niacor, or slo-niacin. Sartan or telmisartan, cannabinoid receptorantagonist Such as In one embodiment, the compound is administered in com rimonabant, cholesteryl ester transfer protein or CETP bination with a fibrate. In some embodiments, fibrates include Inhibitor such as JTT-705, CETi-1, or beta-3 adrenergicago but are not limited to gemfibrozil, or fenofibrate. 30 nist. 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 35 mide, 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, furosemide, humetanide, piretanide, muZolimine, chlo insulin, growth hormone, clenbuterol, porcine pancreas rothiazide and thiazide, phthalimidine, chlorthalidone, clor 40 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, In one embodiment, the agent treating a wasting disease is potassium-sparing compound, aldosterone antagonist, 45 a ghrelin receptor ligand, growth hormone analogue, or a spironolactone and canrenoate, pteridines, pyrazine, car secretagogue. In some embodiments, ghrelin receptor boxamide-triamterene, oramiloride. In one embodiment, the ligands, growth hormone analogues, or secretagogues agent treating 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 50 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 55 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 60 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)). 65 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 US 8,426,465 B2 55 56 which inhibit somatostatin or its release, Such as physostig EM 139, ICI 164,384, ICI 182,780, clomiphene, MER-25, mine and pyridostigmine. In some embodiments, agents diethylstibestrol, coumestrol, genistein, GW5638, treating a wasting disease may comprise parathyroid hor LY353581, Zuclomiphene, enclomiphene, delmadinone mone, PTH (1-34) or bisphosphonates, such as MK-217 (al acetate, DPPE, (N,N-diethyl-2-4-(phenylmethyl)- endronate). In other embodiments, agents treating wasting 5 phenoxyethanamine), TSE-424, WAY-070, WAY-292, disease may further comprise estrogen, a selective estrogen WAY-818, cyclocommunol, prinaberel, ERB-041, WAY-397, receptor modulator, Such as tamoxifene or raloxifene, or other WAY-244, ERB-196, WAY-169122, MF-101, ERb-002, androgen receptor modulators, such as those disclosed in ERB-037, ERB-017, BE-1060, BE-380, BE-381, WAY-358, Edwards, J. P. et. al., Bio. Med. Chem. Let., 9, 1003-1008 18FFEDNP. LSN-500307, AA-102, Ban Zhilian, CT-101, (1999) and Hamann, L. G. et. al., J.Med. Chem., 42. 210-212 10 (1999). In some embodiments, agents treating a wasting dis CT-102, or VG-101. ease may further comprise a progesterone receptor agonists In one embodiment, the agent treating the endocrine sys (“PRA), such as levonorgestrel, medroxyprogesterone tem is a gonadotropin-releasing hormone agonist or antago acetate (MPA). In some embodiments, agents treating a wast nist. In some embodiments, gonadotropin-releasing hormone ing disease may include nutritional Supplements, such as 15 agonists or antagonists include but are not limited to leupro those described in U.S. Pat. No. 5,179,080, which, in other lide, goserelin, triptorelin, alfaprostol, histrelin, detirelix, embodiments are in combination with whey protein or casein, ganirelix, antide iturelix, cetrorelix, ramorelix, ganirelix, amino acids (such as leucine, branched amino acids and antarelix, teverelix, abarelix, Ozarelix, Sufugolix, praZarelix, hydroxymethylbutyrate), triglycerides, vitamins (e.g., A, B6. degarelix, NBI-56418, TAK-810, or acyline. B 12, folate, C, D and E), minerals (e.g., selenium, magne In one embodiment, the agent treating the endocrine sys sium, Zinc, chromium, calcium and potassium), carnitine, tem is a luteinizing hormone agonist or antagonist. In some lipoic acid, creatinine, B-hyroxy-B-methylbutyriate (Juven) embodiments, luteinizing hormone agonists or antagonists and coenzyme Q. In one embodiment, agents treating a wast include but are not limited to letrozole, anastraZole, atames ing disease may further comprise antiresorptive agents, Vita tane, fadrozole, minamestane, exemestane, plomestane, min D analogues, elemental calcium and calcium Supple 25 liarozole, NKS-01, Vorozole, YM-511, finrozole, 4-hy ments, cathepsin K inhibitors, MMP inhibitors, vitronectin droxyandrostenedione, aminogluethimide, or rogletimide. In receptor antagonists, Src SH2 antagonists, vacular-H-AT one embodiment, the agent treating the endocrine system is a Pase inhibitors, ipriflavone, fluoride, tibolone, prostanoids, follicle stimulating hormone agonist or antagonist. In one 17-beta hydroxysteroid dehydrogenase inhibitors and Src embodiment, the agent treating the endocrine system is a kinase inhibitors. 30 luteinizing hormone releasing hormone (LHRH) or a LHRH In one embodiment, the compound is administered in with analog. an agent treating the endocrine system. In some embodi In one embodiment, the agent treating the endocrine sys ments, agents treating the endocrine system include but are tem is a steroidal or nonsteroidal glucocorticoid receptor not limited to radioactive iodine, antithyroid agent, thyroid ligand. In some embodiments, nonsteroidal glucocorticoid hormone Supplement, growth hormone, cabergoline, bro 35 receptor ligands include but are not limited to ZK-216348, mocriptine, thyroxine, gonadotropin, glucocorticoid, gluco ZK-243149, ZK-243185, LGD-5552, mifepristone, RPR corticoid analogue, corticotrophin, metyrapone, aminoglute 106541, ORG-34517, GW-215864X, sesquicillin, thimide, mitotane, ketoconazole, mifepristone, CP-472555, CP-39.4531, A-222977, AL-438, A-216054, dexamethasone somatostatin analogue, gonadotropin-releas A-276575, CP-39.4531, CP-409069, or UGR-07. ing hormone analogue, leuprolide, goserelin, antidiuretic 40 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 5-alpha-reductase inhibitors include but are not limited to 45 androgen receptor antagonists include but are not limited to finasteride, dutasteride, orizonsteride. flutamide, hydroxyflutamide, bicalutamide, nilutamide, or In one embodiment, the agent treating the endocrine sys hydroxysteroid dehydrogenase inhibitor. 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, 50 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, LGD-3303, YM-92088, YM-175735, brate, gemfibrozil, dargilitaZone, pioglitaZone, rosiglitaZone, LGD-1331, BMS-357597, BMS-391197, S-40503, BMS isaglitaZone, rivoglitaZone, netoglitaZone, naveglitazar, far 482404, GSK-971086, GSK-2420A, EM-4283, EM-4977, glitazar, tesaglitazar, ragaglitazar, Oxeglitazar, or PN-2034. BMS-564929, BMS-391197, BMS-434588, BMS-487745, 55 In one embodiment, an agent treating the endocrine system BMS-501949, SA-766, YM-92088, YM-580, LG-123303, is a human growth hormone. In some embodiments, human LG-123129, PMCol, YM-175735, BMS-591305, BMS growth hormones include but are not limited to Somatotropin 591309, BMS-665139, BMS-665539, CE-590, 116BG33, or analogues. 154BG31, arcarine, or ACP-105. In one embodiment, the agent treating the endocrine sys In one embodiment, the additional agent treating the endo 60 tem is a ghrelin. In some embodiments, ghrelins include but crine system is a SERM compound. In some embodiments, are not limited to human ghrelin, CYT-009-GhrOb. SERMs include but are not limited to tamoxifene, 4-hydrox L-692429, GHRP-6, SK&F-110679, or U-75799E. ytamoxifene, idoxifene, toremifene, ospennifene, drolox In one embodiment, the agent treating the endocrine sys ifene, raloxifene, arzoxifene, baZedoxifene, PPT (1,3,5-tris tem is a leptin. In some embodiments, leptins include but are (4-hydroxyphenyl)-4-propyl-1H-pyrazole), DPN, 65 not limited to metreleptin or pegylated leptin. In one embodi lasofoxifene, pipendoxifene, EM-800, EM-652, nafoxidine, ment, an agent treating the endocrine system is a leptin recep Zindoxifene, tesmilifene, miproxifene phosphate, RU 58,688, tor agonist. In some embodiments, leptin receptor agonists US 8,426,465 B2 57 58 includebut are not limited to LEP (116-130), OB3, D-Leu-4- Sodium, Sodium cromoglycate, leukotriene receptor antago OB3, ra AV-leptin, AAV-hCB, or raAVhOB. nist, corticosteroid, expectorant, mucolytic agent, antihista In one embodiment, the SARM compound is administered mine, pseudoephedrine, methylphenidate, amphetamine, with an inhibitor of an enzyme involved in the androgen buspirone, benzodiazepine, dextroamphetamine, tricyclic biosynthetic pathway. In some embodiments, inhibitors of 5 antidepressant, serotonin reuptake inhibitor, phenothiazines, enzymes involved in the androgen biosynthetic pathway benztropine, bupropion, propranolol, lithium, Venlafaxine, include but are not limited to 17-ketoreductase inhibitor, haloperidol, buspirone, or a neuraminidase inhibitor. 3-AH4.6-isomerase inhibitor, 3-A4.5-isomerase inhibitor, In one embodiment, the behavior-modulating agent is a 17.20 desmolase inhibitor, p450c17 inhibitor, p450ssc inhibi benzodiazepine. In one embodiment, benzodiazepines com tor, or 17.20-lyase inhibitor. 10 prise alprazolam, chlordiazepoxide, diazepam, flurazepam, In one embodiment, the SARM compound is administered lorazepam, oxazepam, temazepam, or triazolam. with an agent treating osteoporosis. In some embodiments, In one embodiment, the behavior-modulating agent is a osteoporosis is induced by alcohol and/or Smoking. In some phenothiazine. In one embodiment, phenothiazines comprise embodiments, agents treating osteoporosis includebut are not fluphenazine, perphenazine, thioridazine, or trifluoperazine. limited to SERMs, calcitonin, vitamin D, vitamin D deriva 15 In one embodiment, the behavior-modulating agent is a tives, vitamin D receptor ligand, Vitamin D receptor ligand tricyclic antidepressant or a serotonin reuptake inhibitor. In analogue, estrogen, estrogen derivative, conjugated estrogen, one embodiment, tricyclic antidepressants or serotonin antiestrogen, progestin, synthetic estrogen, synthetic proges reuptake inhibitors comprise phenothiazine, protriptyline, tin, RANK ligand monoclonal antibody, integrin receptor fluoxetine, paroxetine, or Sertraline. antagonist, osteoclast vacuolar ATPase inhibitor, antagonist In one embodiment, the compound of this invention is of VEGF binding to osteoclast receptors, calcium receptor administered with an agent treating a connective tissue. In antagonist, parathyroid hormone, parathyroid hormone ana Some embodiments, agents treating a connective tissue logue, parathyroid hormone-related peptide, cathepsin K include but are not limited to an anti-malaria agent, a cyto inhibitor, strontium ranelate, tibolone, HCT-1026, PSK3471, toxic agent, a steroid, corticosteroid, lupus medication, imu gallium maltolate, nutropin AQ, prostaglandin, p38 protein 25 ran, cytoxan, anti-rheumatic agent, corticosteroid, nifedipine, kinase inhibitor, bone morphogenetic protein (BMP), inhibi aspirin, colchicine, captopril, penicillamine, azathioprine, tor of BMP antagonism, HMG-CoA reductase inhibitor, vita methotrexate, cyclophosphamide, prednisone, nicardipine, min K. vitamin K derivative, ipriflavone, fluoride salts, or a non-steroidal anti-inflammatory agent. dietary calcium Supplement, or osteoprotegerin. In one embodiment, the compound of this invention is In one embodiment, the agent treating osteoporosis is a 30 administered with an agent treating an ophthalmic disease. In calcitonin. In some embodiments, calcitonins include but are Some embodiments, agents treating an ophthalmic disease not limited to salmon, elcatonin, SUN-8577, or TJN-135. include but are not limited to betagan, betimol, timoptic, In one embodiment, the agent treating osteoporosis is a betoptic, betoptic, ocupress, optipranolol. Xalatan, alphagan, Vitamin D receptor ligand or analogue. In some embodi aZopt, trusopt, cosopt, pilocar, pilagan, propine, opticrom, ments, vitamin D receptor ligands or analogues include but 35 acular, livostin, alomide, emadine, patanol, alrex, poly-pred. are not limited to calcitriol, topitriol, ZK-150123, TEI-9647, pred-g, dexacidin, erythromycin, maxitrol, tobradex, blepha BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299, or DP-035. mide, FML, ocufen, voltaren, profenal, pred forte, econpred In one embodiment, the SARM compound is administered plus, eflone, flarex, inflamase forte, betadine, gramicidin, with an agent treating or inducing pharmacotherapy induced prednisolone, betaxolol, humorsol, proparacaine, betoptic, hypogonadal and/or osteopenic and/or sarcopenic State. In 40 hylartin, inflamase mild, lotemax, flurbiprofen, chloram Some embodiments, agents treating pharmacotherapy phenicol, methazolamide, timolol, ciloxan, terramycin, induced hypogonadal and/or osteopenic and/or sarcopenic ciprofloxacin, miostat, triamcinolone, miconazole, tobramy states include but are not limited to opioids, narcotics, opi cin, physostimine, gentamicin, pilocarpine, bacitracin, ates, opioids, methadone, Kadian, D2 dopamine receptor goniosol, polymyxin, oxytetracycline, Viroptic, Vexol. Supro antagonist, Zotepine, haloperidol, amisulpride, risperidone, 45 fen, celluvisc, polytrim, illotycin, ciloxan, ocuflox, brinZola anti-epileptic agent, valproic acid, carbamazepine, oXcar mide, cefazolin, tobrex, latanoprost, indocycanine, trifluri bamazepine, chemotherapeutic agent, methotrexate, cyclo dine, phenylephrine, demecarium, neomycin, tropicamide, phosphamide, ifosfamide, adriamycin, doxorubicin, gluco dexamethasone, neptazane, diplivefrin, ocuflox, Vidarabine, corticoids, cyclosporine, L-thyroxine, SERMs, aromatase dorzolamide, ofloxacin, epinephrine, acyclovir, carbonic inhibitor (AI), fulvestrant, gonadotropin-releasing hormone 50 anhydrase inhibitor, antihistamine vitaminA, Vitamin C, Vita agent, androgen depravation agent, prolactinemia-inducing min E. Zinc, copper, atropine, or garamycin. agent, serotonergic antidepressant, selective serotonin In one embodiment, the compound of this invention is reuptake inhibitor, monoamine oxidase inhibitor, tricyclic administered in with a gene therapy agent. In some embodi antidepressant, antihypertensive agents, methyldopa, reser ments, gene therapy agents include but are not limited to an pine, clonidine, Verapamil, antidopaminergic agent, anti 55 antisense agent, or a replacement gene. emetic agent, metoclopramide, H2 receptor antagonist, cime In some embodiments, any of the compositions of this tidine, ranitidine, estrogen, or amphetamine. invention will comprise a compound of formula I, in any form In one embodiment, the compound of this invention is or embodiment as described herein. In some embodiments, administered with a vitamin. In some embodiments, vitamins any of the compositions of this invention will consist of a includebutare not limited to vitamin D, vitamin E, vitamin K, 60 compound of formula I, in any form or embodiment as vitamin B, Vitamin C, or a combination thereof. described herein. In some embodiments, of the compositions In one embodiment, the compound of this invention is of this invention will consist essentially of a compound of administered with a behavior-modulating agent. In some formula I, in any form or embodiment as described herein. In embodiments, behavior-modulating agents include but are some embodiments, the term “comprise' refers to the inclu not limited to an anti-anxiety agent, anti-psychotic agent, 65 sion of the indicated active agent, such as the compound of anti-depressant, beta-blocker, beta-2 agonist, anticholinergic formula I, as well as inclusion of other active agents, and bronchodilator, theophylline, aminophylline, nedocromil pharmaceutically acceptable carriers, excipients, emollients, US 8,426,465 B2 59 60 stabilizers, etc., as are known in the pharmaceutical industry. treatment of diabetic neuropathy; n) treatment of diabetic In some embodiments, the term "consisting essentially of retinopathy; o) treatment offatty liver condition; p) treatment refers to a composition, whose only active ingredient is the of cachexia; q) oral androgen replacement and/or other clini indicated active ingredient, however, other compounds may cal therapeutic and/or diagnostic areas, including any be included which are for stabilizing, preserving, etc. the embodiment of what is encompassed by the term “treating as formulation, but are not involved directly in the therapeutic described herein. effect of the indicated active ingredient. In some embodi In some embodiments, the compounds of this invention ments, the term “consisting essentially of may refer to com possess in Vivo tissue selective androgenic and anabolic activ ponents which facilitate the release of the active ingredient. In ity, which is accordingly utilized for particular applications, Some embodiments, the term "consisting refers to a compo 10 as will be appreciated by one skilled in the art. sition, which contains the active ingredient and a pharmaceu In one embodiment, this invention provides: a) a method of tically acceptable carrier or excipient. treating a subject having a muscle wasting disorder; b) a In one embodiment, the present invention provides com method of treating a subject Suffering from malnutrition; c) a bined preparations. In one embodiment, the term "a com method of treating a bone-related disorder in a subject; d) a bined preparation' defines especially a “kit of parts” in the 15 method of increasing a bone mass in a subject; e) a method of sense that the combination partners as defined above can be improving the lipid profile in a Subject, f) a method of treating dosed independently or by use of different fixed combinations atherosclerosis and its associated diseases; g) a method of with distinguished amounts of the combination partners i.e., improving dexterity and movement in a Subject; h) a method simultaneously, concurrently, separately or sequentially. In of treating a Subject having dwarfism: i) a method of treating Some embodiments, the parts of the kit of parts can then, e.g., a Subject having dysmenorrhea, j) a method of treating a be administered simultaneously or chronologically stag Subject having dysparunia; k) a method of treating a subject gered, that is at different time points and with equal or differ having dysspermtogenic sterility; comprising the step of ent time intervals for any part of the kit of parts. The ratio of administering to said Subject a compound of formula I and/or the total amounts of the combination partners, in some an analog, derivative, isomer, metabolite, pharmaceutically embodiments, can be administered in the combined prepara 25 acceptable salt, pharmaceutical product, hydrate, N-oxide, tion. In one embodiment, the combined preparation can be prodrug, polymorph, impurity or crystal of said compound, or varied, e.g., in order to cope with the needs of a patient any combination thereof. subpopulation to be treated or the needs of the single patient In some embodiments, the compounds as described herein which different needs can be due to a particular disease, and/or compositions comprising the same may be used for severity of a disease, age, sex, or body weight as can be 30 applications and treating diseases in which the improvement readily made by a person skilled in the art. of cognition, reduction or treatment of depression, or other It is to be understood that this invention is directed to neuroprotective effects are desired. compositions and combined therapies as described herein, for In one embodiment, “Cognition” refers to the process of any disease, disorder or condition, as appropriate, as will be knowing, specifically the process of being aware, knowing, appreciated by one skilled in the art. Certain applications of 35 thinking, learning and judging. Cognition is related to the Such compositions and combined therapies have been fields of psychology, linguistics, computer Science, neuro described hereinabove, for specific diseases, disorders and Science, mathematics, ethology and philosophy. In one conditions, representing embodiments of this invention, and embodiment, “mood refers to a temper or state of the mind methods of treating Such diseases, disorders and conditions in As contemplated herein, alterations mean any change for the a Subject by administering a compound as herein described, 40 positive or negative, in cognition and/or mood. alone or as part of the combined therapy or using the compo In one embodiment, “depression” refers to an illness that sitions of this invention represent additional embodiments of involves the body, mood and thoughts that affects the way a this invention. person eats, sleeps and the way one feels about oneself, and Biological Activity of Selective Androgen Modulator Com thinks about things. The signs and symptoms of depression pounds 45 include loss of interest in activities, loss of appetite or over The compounds of this invention may be useful, in some eating, loss of emotional expression, an empty mood, feelings embodiments, for oral testosterone replacement therapy. In of hopelessness, pessimism, guilt or helplessness, Social other embodiments, appropriately Substituted compounds are withdrawal, fatigue, sleep disturbances, trouble concentrat useful for a) male contraception; b) treatment of a variety of ing, remembering, or making decisions, restlessness, irrita hormone-related conditions, for example conditions associ 50 bility, headaches, digestive disorders or chronic pain. ated with ADAM, Such as fatigue, depression, decreased In one embodiment, the methods of this invention are use libido, sexual dysfunction, erectile dysfunction, hypogo ful a subject, which is a human. In another embodiment, the nadism, osteoporosis, hair loss, obesity, sarcopenia, osteope Subject is a mammal. In another embodiment the Subject is an nia, benign prostate hyperplasia, and alterations in mood and animal. In another embodiment the subject is an invertebrate. cognition; c) treatment of conditions associated with ADIF, 55 In another embodiment the subject is a vertebrate. Such as sexual dysfunction, decreased sexual libido, hypogo In one embodiment, the subject is male. In another embodi nadism, sarcopenia, osteopenia, osteoporosis, alterations in ment, the subject is female. In some embodiments, while the cognition and mood, depression, anemia, hair loss, obesity, methods as described herein may be useful for treating either endometriosis, breast cancer, uterine cancer and ovarian can males or females, females may respond more advantageously cer; d) treatment and/or prevention of chronic muscular wast 60 to administration of certain compounds, for certain methods, ing; e) treatment of prostate cancer, imaging of prostate can as described and exemplified herein. cer, decreasing the incidence of halting or causing a In some embodiments, while the methods as described regression of prostate cancer, f) treatment of diabetes type I; herein may be useful for treating either males or females, g) treatment of diabetes type II; h) Suppressing or inhibiting or males may respond more advantageously to administration of reducing the incidence of diabetes i) treatment of glucose 65 certain compounds, for certain methods, as described herein. intolerance;) treatment of hyperinsulinemia; k) treatment of In some embodiments, the compounds as described herein insulin resistance 1) treatment of diabetic nephropathy; m) and/or compositions comprising the same may be used for US 8,426,465 B2 61 62 applications in or treating hair loss, alopecia, androgenic Androgen-dependent conditions which may be treated alopecia, alopecia areata, alopecia secondary to chemo with the compounds and/or compositions as herein described, therapy, alopecia secondary to radiation therapy, alopecia and comprising a method of the invention, may comprise induced by Scarring or alopecia induced by stress. In one conditions characterized by elevated androgen or estrogen embodiment, “hair loss’, or “alopecia', refers to baldness as levels, including hirsutism, infertility, polycystic ovarian Syn in the very common type of male-pattern baldness. Baldness drome, endometrial carcinoma, breast cancer, male pattern typically begins with patch hair loss on the Scalp and some baldness, prostate cancer, testicular cancer, and others, as will times progresses to complete baldness and even loss of body be known to one skilled in the art. For such conditions, the hair. Hair loss affects both males and females. Subject may be administered a compound as herein described, In some embodiments, the compounds as described herein 10 alone or in combination with another therapeutic agent, as and/or compositions comprising the same may be used for will be appreciated by one skilled in the art. applications in, or treating diseases or conditions associated In one embodiment, this invention provides methods for with a subject having anemia. In one embodiment, 'anemia the treatment of a cancer in a subject, reduction of incidence refers to the condition of having less than the normal number or severity or pathogenesis of a cancer in a Subject, delaying of red blood cells or less than the normal quantity of hemo 15 progression, prolonging remission or delaying onset of can globin in the blood, reduced hematocrit or reduced mean cer in a Subject, comprising the step of administering to the corpuscular Volume, or reduced corpuscular size. The oxy Subject a compound as herein described and/or its analog, gen-carrying capacity of the blood is decreased in anemia. In derivative, isomer, metabolite, pharmaceutically acceptable Some embodiments, treating anemia may also refer herein to salt, pharmaceutical product, polymorph, crystal, impurity, treating underlying factors resulting in anemia, Such as for hydrate, N-oxide or any combination thereof. In some example: a) hemorrhage (bleeding); b) hemolysis (excessive embodiments, such cancers are hormone-dependent or destruction of red blood cells); c) underproduction of red androgen receptor dependent tumors (malignant or benign) blood cells; and d) not enough normal hemoglobin. In some associated with reproductive tissue in males or females. Such embodiments, treating anemia in this invention refers to treat as cancer of the prostate, ovary, breast, uterus, testicle, or ing any form thereof, including aplastic anemia, benzene 25 others. 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. 30 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 35 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. 40 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 45 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 50 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/ 55 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. 60 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, 65 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 US 8,426,465 B2 63 64 maceutical product, polymorph, crystal, impurity, hydrate, cer comprises androgen AR dependent tumors (malignant or N-oxide or any combination thereof, in an amount effective to benign) Such as prostate cancer, breast cancer (male or treat BPH in the subject. female, operable or inoperable). In another embodiment the In some embodiments, this invention provides for the use SARM compounds adjunct to ADT for treating prostate can of a compound as herein described, or its prodrug, analog, cer; bladder cancers; brain cancers; bone tumors, colon can isomer, metabolite, derivative, pharmaceutically acceptable cer, endometrial cancer, liver cancer, lung cancer, lymphatic salt, pharmaceutical product, polymorph, crystal, impurity, cancer, kidney cancer, osteosarcoma cancer, ovarian cancer, N-oxide, hydrate or any combination thereof, for treating pancreas cancer, penis cancer, skin cancer, thyroid cancer, reducing the severity of reducing the incidence of or reduc and/or hormone-dependent cancers. ing pathogenesis of cachexia and/or cachexia associated with 10 In one embodiment, this invention provides for the use of a cancer in a Subject. In another embodiment, the cancer com compound as herein described, or its prodrug, analog, isomer, prise adrenocortical carcinoma, anal cancer, bladder cancer, metabolite, derivative, pharmaceutically acceptable salt, brain tumor, brain stem glioma, brain tumor, cerebellar astro pharmaceutical product, polymorph, crystal, impurity, N-OX cytoma, cerebral astrocytoma, ependymoma, medulloblas ide, hydrate or any combination thereof, fora) treating a bone toma, Supratentorial primitive neuroectodermal, pineal 15 related disorder; b) preventing a bone related disorder; c) tumors, hypothalamic glioma, breast cancer, carcinoid tumor, Suppressing a bone related disorder; d) inhibiting a bone carcinoma, cervical cancer, colon cancer, endometrial cancer, related disorder; e) increasing a strength of a bone of a Sub esophageal cancer, extrahepatic bile duct cancer, ewings fam ject, f) increasing a bone mass in a subject, g) use for osteo ily of tumors (Pnet), extracranial germ cell tumor, eye cancer, clastogenesis inhibition. intraocular melanoma, gallbladder cancer, gastric cancer, In one embodiment, this invention provides for the use of a germ cell tumor, extragonadal, gestational trophoblastic compound as herein described, or its prodrug, analog, isomer, tumor, head and neck cancer, hypopharyngeal cancer, islet metabolite, derivative, pharmaceutically acceptable salt, cell carcinoma, laryngeal cancer, leukemia, acute lympho pharmaceutical product, polymorph, crystal, impurity, N-OX blastic, leukemia, oral cavity cancer, liver cancer, lung cancer, ide, hydrate or any combination thereof, for a) accelerating non Small cell lung cancer, Small cell, lymphoma, AIDS 25 bone repair; b) treating bone disorders; c) treating bone den 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 30 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 35 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, 40 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 45 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, 50 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, 55 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. 60 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 65 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 US 8,426,465 B2 65 66 fracture. The fracture can be, in one embodiment, either in the Zuclomiphene, enclomiphene, delmadinone acetate, DPPE, form of cracking (as in a hip fracture) or collapsing (as in a (N,N-diethyl-2-4-(phenylmethyl)-phenoxyethanamine), compression fracture of the spine). The spine, hips, and wrists TSE-424, WAY-070, WAY-292, WAY-818, cyclocommunol, are common areas of osteoporosis-induced bone fractures, prinaberel, ERB-041, WAY-397, WAY-244, ERB-196, WAY although fractures can also occur in other skeletal areas. 169122, MF-101, ERb-002, ERB-037, ERB-017, BE-1060, Unchecked osteoporosis can lead, in another embodiment, to BE-380, BE-381, WAY-358, 18FIFEDNP, LSN-500307, changes in posture, physical abnormality, and decreased AA-102, Ban Zhilian, CT-101, CT-102, or VG-101. mobility. In another embodiment, the methods of the present inven In one embodiment, the osteoporosis results from andro tion comprise administering the SARM compound, in com gen deprivation. In another embodiment, the osteoporosis 10 bination with bisphosphonates such as alendronate, follows androgen deprivation. In another embodiment, the tiludroate, clodroniate, pamidronate, etidronate, alendronate, osteoporosis is primary osteoporosis. In another embodi Zolendronate, cimadronate, neridronate, minodronic acid, ment, the osteoporosis is secondary osteoporosis. In another ibandronate, risedronate, or homoresidronate for treating embodiment, the osteoporosis is postmenopausal osteoporo osteoporosis. sis. In another embodiment, the osteoporosis is juvenile 15 In another embodiment, the methods of the present inven osteoporosis. In another embodiment, the osteoporosis is tion comprise administering the compound, in combination idiopathic osteoporosis. In another embodiment, the with Calcitonin such as salmon, Elcatonin, SUN-8577 or osteoporosis is senile osteoporosis. TJN-135 for treating osteoporosis. In another embodiment, the primary osteoporosis is Type I In another embodiment, the methods of treating osteoporo primary osteoporosis. In another embodiment, the primary sis of the present invention comprise administering the osteoporosis is Type II primary osteoporosis. Each type of SARM compound, in combination with a) vitamin D or osteoporosis represents a separate embodiment of the present derivative such as ZK-156979; b) vitamin D receptor ligand invention. and analogues such as calcitriol, topitriol, ZK-150123, TEI According to this aspect of the invention and in one 9647, BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299 or embodiment, the bone-related disorder is treated with a com 25 DP-035; c) estrogen, estrogen derivative, or conjugated estro 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) CVB3 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 30 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, PTHrPanalogues (parathyroid hormone-related comprise a bone morphogenetic protein (BMP), a growth peptide); k) Cathepsin K inhibitors (AAE581, 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 35 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 40 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 45 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 50 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 55 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 60 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 65 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. US 8,426,465 B2 67 68 In another embodiment the invention is directed to treating mass and to muscle wasting. The term “catabolism” has its sarcopenia or cachexia, and associated conditions related commonly known meaning in the art, specifically an energy thereto, for example diseases or disorders of the bone. burning form of metabolism. In one embodiment, this invention provides for the use of a Muscle wasting can occur as a result of a pathology, dis compound as herein described, or its prodrug, analog, isomer, ease, condition or disorder. In one embodiment, the pathol metabolite, derivative, pharmaceutically acceptable salt, ogy, illness, disease or condition is chronic. In another pharmaceutical product, polymorph, crystal, impurity, N-OX embodiment, the pathology, illness, disease or condition is ide, hydrate or any combination thereof, for 1) treating a genetic. In another embodiment, the pathology, illness, dis muscle wasting disorder; 2) preventing a muscle wasting ease or condition is neurological. In another embodiment, the disorder; 3) treating, preventing, Suppressing, inhibiting or 10 pathology, illness, disease or condition is infectious. As reducing muscle loss due to a muscle wasting disorder; 4) described herein, the pathologies, diseases, conditions or dis treating, preventing, inhibiting, reducing or Suppressing orders for which the compounds and compositions of the muscle wasting due to a muscle wasting disorder, and/or 5) present invention are administered are those that directly or treating, preventing, inhibiting, reducing or Suppressing indirectly produce a wasting (i.e. loss) of muscle mass, that is muscle protein catabolism due to a muscle wasting disorder; 15 a muscle wasting disorder. and/or treating, preventing, inhibiting, reducing or Suppress In one embodiment, muscle wasting in a subject is a result ing end stage renal disease; and/or 6) treating, preventing, of the Subject having a muscular dystrophie; muscle atrophy; inhibiting, reducing or Suppressing fraility. X-linked spinal-bulbar muscular atrophy (SBMA). In another embodiment, the use of a compound for treating The muscular dystrophies are genetic diseases character a subject having a muscle wasting disorder, or any of the ized by progressive weakness and degeneration of the skeletal disorders described herein, includes administering a pharma or Voluntary muscles that control movement. The muscles of ceutical composition including a compound as herein the heart and some other involuntary muscles are also affected described. In another embodiment, the administering step in Some forms of muscular dystrophy. The major forms of includes intravenously, intraarterially, or intramuscularly muscular dystrophy (MD) are: duchenne muscular dystro injecting to said Subject said pharmaceutical composition in 25 phy, myotonic dystrophy, duchenne muscular dystrophy, 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. 30 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 35 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, 40 weakness, muscle fatigue, and pain. Another type of MA is for example, cancer, or an infection, or it can be due to a X-linked spinal-bulbar muscular atrophy (SBMA also physiologic or metabolic state, such as disuse deconditioning known as Kennedy's Disease). This disease arises from a that can occur, for example, due to prolonged bed restor when defect in the androgen receptor gene on the X chromosome, a limb is immobilized. Such as in a cast. A wasting condition affects only males, and its onset is in adulthood. Because the can also be age associated. The loss of body mass that occurs 45 primary disease cause is an androgen receptor mutation, during a wasting condition can be characterized by a loss of androgen replacement is not a current therapeutic strategy. total body weight, or a loss of organ weight Such as a loss of There are some investigational studies where exogenous tes bone or muscle mass due to a decrease in tissue protein. tosterone propionate is being given to boost the levels of In one embodiment, "muscle wasting or “muscular wast androgen with hopes of overcoming androgen insensitivity ing, used herein interchangeably, refer to the progressive 50 and perhaps provide an anabolic effect. Still, use of Supra loss of muscle mass and/or to the progressive weakening and physiological levels of testosterone for Supplementation will degeneration of muscles, including the skeletal or Voluntary have limitations and other potentially serious complications. muscles which control movement, cardiac muscles which Sarcopenia is a debilitating disease that afflicts the elderly control the heart, and Smooth muscles. In one embodiment, and chronically ill patients and is characterized by loss of the muscle wasting condition or disorder is a chronic muscle 55 muscle mass and function. Further, increased lean body mass wasting condition or disorder. "Chronic muscle wasting is is associated with decreased morbidity and mortality for cer defined hereinas the chronic (i.e. persisting overalong period tain muscle-wasting disorders. In addition, other circum of time) progressive loss of muscle mass and/or to the chronic stances and conditions are linked to, and can cause muscle progressive weakening and degeneration of muscle. wasting disorders. For example, studies have shown that in The loss of muscle mass that occurs during muscle wasting 60 severe cases of chronic lower back pain, there is paraspinal can be characterized by a muscle protein breakdown or deg muscle wasting. radation, by muscle protein catabolism. Protein catabolism Muscle wasting and other tissue wasting is also associated occurs because of an unusually high rate of protein degrada with advanced age. It is believed that general weakness in old tion, an unusually low rate of protein synthesis, or a combi age is due to muscle wasting. As the body ages, an increasing nation of both. Protein catabolism or depletion, whether 65 proportion of skeletal muscle is replaced by fibrous tissue. caused by a high degree of protein degradation or a low The result is a significant reduction in muscle power, perfor degree of protein synthesis, leads to a decrease in muscle mance and endurance. US 8,426,465 B2 69 70 Long term hospitalization due to illness or injury, or disuse ment, the method comprises administering to a subject a deconditioning that occurs, for example, when a limb is composition comprising a compound and an immunomodu immobilized, can also lead to muscle wasting, or wasting of lating agent, an anti-infective agent, a gene therapy agent, or other tissue. Studies have shown that in patients suffering a combination thereof. In some embodiments, infections injuries, chronic illnesses, burns, trauma or cancer, who are comprise actinomycosis, anaplasmosis, anthrax, aspergillo hospitalized for long periods of time, there is a long-lasting sis, bacteremia, bacterial mycoses, bartonella infections, unilateral muscle wasting, and a decrease in body mass. botulism, brucellosis, burkholderia infections, campylo Injuries or damage to the central nervous system (CNS) are bacter infections, candidiasis, cat-scratch disease, chlamydia also associated with muscle wasting and other wasting disor infections, cholera, clostridium infections, coccidioidomyco ders. Injuries or damage to the CNS can be, for example, 10 sis, cross infection, cryptococcosis, dermatomycoses, diph caused by diseases, trauma or chemicals. Examples are cen theria, ehrlichiosis, Escherichia coli infections, fasciitis, tral nerve injury or damage, peripheral nerve injury or dam necrotizing, Fusobacterium infections, gas gangrene, gram age and spinal cord injury or damage. In one embodiment negative bacterial infections, gram-positive bacterial infec CNS damage or injury comprise Alzheimer's disease (AD): tions, histoplasmosis, impetigo, Klebsiella infections, legion anger (mood); anorexia, anorexia nervosa, anorexia associ 15 ellosis, leprosy, leptospirosis, Listeria infections, lyme ated with aging and/or assertiveness (mood). disease, maduromycosis, melioidosis, mycobacterium infec In another embodiment, muscle wasting or other tissue tions, mycoplasma infections, mycoses, nocardia infections, wasting may be a result of alcoholism, and may be treated onychomycosis, plague, pneumococcal infections, with the compounds and compositions of the invention, rep pseudomonas infections, psittacosis, q fever, rat-bite fever, resenting embodiments thereof. relapsing fever, rheumatic fever, Rickettsia infections, rocky In one embodiment, the invention provides a use of SARM mountain spotted fever, salmonella infections, Scarlet fever, compound as described herein or its prodrug, analog, isomer, scrub typhus, sepsis, sexually transmitted diseases, Staphy metabolite, derivative, pharmaceutically acceptable salt, lococcal infections, Streptococcal infections, tetanus, tick pharmaceutical product, polymorph, crystal, impurity, N-OX borne diseases, tuberculosis, tularemia, typhoid fever, ide, hydrate or any combination thereof for the treatment of a 25 typhus, louse-borne, Vibrio infections, yaws, yersinia infec wasting disease, disorder or condition in a Subject. tions, Zoonoses, Zygomycosis, acquired immunodeficiency In one embodiment, the wasting disease, disorder or con syndrome, adenoviridae infections, alphavirus infections, dition being treated is associated with chronic illness arbovirus infections, borna disease, bunyaviridae infections, This invention is directed to treating, in some embodi caliciviridae infections, chickenpox, coronaviridae infec ments, any wasting disorder, which may be reflected in 30 tions, coxsackievirus infections, cytomegalovirus infections, muscle wasting, weight loss, malnutrition, starvation, or any dengue, DNA virus infections, eethyma, contagious, wasting or loss of functioning due to a loss of tissue mass. encephalitis, arbovirus, Epstein-ban virus infections, In some embodiments, wasting diseases or disorders, such erythema infectiosum, hantavirus infections, hemorrhagic as cachexia; malnutrition, tuberculosis, leprosy, diabetes, fevers, viral hepatitis, viral human herpes simplex, herpes renal disease, chronic obstructive pulmonary disease 35 Zoster, herpes Zosteroticus, herpesviridae infections, infec (COPD), cancer, end stage renal failure, sarcopenia, emphy tious mononucleosis, human-lassa fever, measles, mollus sema, osteomalacia, or cardiomyopathy, may be treated by cum, contagiosum, mumps, paramyxoviridae infections, the methods of this invention, via the administration of a phlebotomus fever, polyomavirus infections, rabies, respira SARM compound as herein described, compositions com tory syncytial virus infections, rift valley fever, RNA virus prising the same, with or without additional drugs, com 40 infections, rubella, slow virus diseases, Smallpox, Subacute pounds, or agents, which provide a therapeutic effect for the Sclerosing panencephalitis, tumor virus infections, warts, condition being treated. west nile fever, virus diseases, yellow fever, amebiasis, In some embodiments, wasting is due to infection with anisakiasis, ascariasis, babesiosis, blastocystis hominis infec enterovirus, Epstein-Ban virus, herpes Zoster, HIV, trypano tions, bug bite, cestode infections, chagas disease, cryptospo Somes, influenze, coxsackie, rickettsia, trichinella, Schisto 45 ridiosis, cyclosporiasis, cysticercosis, dientamoebiasis, Soma or mycobacteria, and this invention, in Some embodi diphyllobothriasis, dracunculiasis, echinococcosis, ectopara ments, provides methods of treatment thereof. sitic infestations, filariasis, giardiasis, helminthiasis, hook Cachexia is weakness and a loss of weight caused by a worm infections, larva migrans, leishmaniasis, lice infesta disease or as a side effect of illness. Cardiac cachexia, i.e. a tions, loiasis, malaria, mite infestations, myiasis, muscle protein wasting of both the cardiac and skeletal 50 onchocerciasis, protozoan infections, Scabies, Schistosomia muscle, is a characteristic of congestive heart failure. Cancer sis, skin diseases, parasitic, strongyloidiasis, taeniasis, toXo cachexia is a syndrome that occurs in patients with Solid cariasis, toxoplasmosis, trichinosis, trichomonas infections, tumors and hematological malignancies and is manifested by trypanosomiasis, trypanosomiasis, african, or whipworm weight loss with massive depletion of both adipose tissue and infections. lean muscle mass. 55 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 In one embodiment, the method comprises administering to a with HIV-associated myopathy or muscle weakness or wast 60 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 ease, a gene therapy agent, an agent treating the endocrine method for treating, reducing the incidence, delaying the 65 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, US 8,426,465 B2 71 72 arthritis, arthrogryposis, arthropathy, neurogenic bursitis, combination thereof. In some embodiments, stomatognathic cartilage diseases, cleidocranial dysplasia, clubfoot, com diseases comprise ankyloglossia, bruxism, burning mouth partment syndromes, craniofacial dysostosis, craniosynos syndrome, cheilitis, cherubism, cleft lip, dentigerous cyst, toses, dermatomyositis, Dupuytren’s contracture, dwarfism, gingivitis, glossitis, benign migratory, herpes labialis, Lud Ellis Van Creveld syndrome, enchondromatosis, eosino wigs angina, macroglossia, Melkersson-Rosenthal Syn philia-myalgia syndrome, exostoses, fasciitis, fatigue syn drome, periodontal diseases, Pierre Robin syndrome, prog drome, fibromyalgia, fibrous dysplasia of bone, fibrous dys nathism, salivary gland diseases, sialorrhea, stomatitis, plasia, polyostotic, flatfoot, foot deformities, Freiberg's aphthous, temporomandibular joint disorders, temporoman disease, funnel chest, Goldenhar syndrome, gout, hallux Val dibular joint dysfunction syndrome, or Xerostomia. gus, hip dislocation, hyperostosis, intervertebral disk dis 10 In some embodiments, the present invention provides a placement, kabuki make-up syndrome, Klippel-Feil Syn method for treating, reducing the incidence, delaying the drome, Langer-Giedion syndrome, Legg-Perthes disease, onset or progression, or reducing and/or abrogating the Symp lordosis, mandibulofacial dysostosis, melorheostosis, mito toms associated with a respiratory tract disease in a Subject. In chondrial myopathies, muscle cramp, muscle spasticity, mus one embodiment, the method comprises administering to a cular dystrophies, musculoskeletal abnormalities, muscu 15 Subject a composition comprising a compound and an anti loskeletal diseases, myositis, myositis ossificans, myotubular cancer agent, an immunomodulating agent, an agent treating myopathy, osteitis deformans, osteoarthritis, osteochondritis, the central nervous system, an agent treating the cardiovas osteogenesis imperfecta, osteomyelitis, osteonecrosis, osteo cular system, an anti-infective agent, an agent treating a wast petrosis, osteoporosis, poland syndrome, polychondritis (re ing disease, a gene therapy agent, an agent treating the endo lapsing), polymyalgia rheumatica, polymyositis, rhabdomy crine system, vitamins, or a combination thereof. In some olysis, rheumatic diseases, Russell silver syndrome, embodiments, respiratory tract diseases comprise airway Scheuermann's disease, scoliosis, Sever's disease/calcaneal obstruction, apnea, asbestosis, asthma, asthma-induced apophysitis, spinal diseases, spinal osteophytosis, spinal muscle weakness or bone weakness, atelectasis, berylliosis, Stenosis, spondylitis (ankylosing), spondylolisthesis, Spren bronchial diseases, bronchiectasis, bronchiolitis, bronchioli gel's deformity, synovitis, tendinopathy, tennis elbow, teno 25 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. 30 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 embolism, pulmonary emphysema, pulmonary fibrosis, res treating the gastrointestinal system, an anti-infective agent, 35 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, mass or bone mass due to asthma, wasting in chronic obstruc anus diseases, appendicitis, barrett esophagus, biliary atresia, 40 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 45 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 infective agent, an agent treating a wasting disease, a gene schsprung disease, hypertension (HTN), portal, inflamma 50 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 cusis, labyrinthitis, laryngitis, laryngomalacia, laryngosteno atic neoplasms, pancreatitis, peptic ulcer, Peutz-Jeghers Syn 55 sis, mastoiditis, Meniere's disease, nasal obstruction, nasal drome, proctitis, rectal diseases, rectal prolapse, short bowel polyps, otitis, otorhinolaryngologic diseases, otosclerosis, 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 tion, Vestibular neuronitis, Vocal cord paralysis, or Voice dis method for treating, reducing the incidence, delaying the 60 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 toms associated with a nervous system disease in a Subject. In cancer agent, an immunomodulating agent, an anti-infective 65 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 US 8,426,465 B2 73 74 the central nervous system, an anti-infective agent, an agent structural, physical, or mechanical impairment and may be treating a metabolic disease, an agent treating a wasting dis caused by physical impact, as in the case of a crushing, ease, a gene therapy agent, an agent treating the endocrine compression, or stretching of nerve fibers. Alternatively, the system, Vitamins, or a combination thereof. In some embodi cell membrane may be destroyed by or degraded by an illness, ments, nervous system diseases comprise autonomic nervous a chemical imbalance, or a physiological malfunction Such as system diseases, central nervous system diseases, cranial anoxia (e.g., stroke), aneurysm, or reperfusion. A CNS injury nerve diseases, demyelinating diseases, nervous system mal includes, for example and without limitation, damage to reti formations, neurologic manifestations, or neuromuscular dis nal ganglion cells, a traumatic brain injury, a stroke-related CaSCS. injury, a cerebral aneurism-related injury, a spinal cord injury, In some embodiments, autonomic nervous system diseases 10 including monoplegia, diplegia, paraplegia, hemiplegia and comprise causalgia, or reflex sympathetic dystrophy. quadriplegia, a neuroproliferative disorder, or neuropathic In some embodiments, central nervous system diseases comprise Alzheimer's disease, arachnoiditis, brain abscess, pain syndrome. brain ischemia, central nervous system infections, cerebral With injury to the spinal cord of a mammal, connections palsy, cerebrovascular disorders, corticobasal ganglionic 15 between nerves in the spinal cord are broken. Such injuries degeneration (CBGD), Creutzfeldt-Jakob syndrome, Dandy block the flow of nerve impulses for the nerve tracts affected Walker syndrome, dementia, encephalitis, encephalomyeli by the injury, with a resulting impairment to both sensory and tis, epilepsy, epilepsy induced hypogonadal and/or hyper motor function. Injuries to the spinal cord may arise from metabolic state, essential tremor, Friedreich ataxia, compression or other contusion of the spinal cord, or a crush Gerstmann-Straussler-Scheinker disease, Hallervorden ing or severing of the spinal cord. A severing of the spinal Spatz syndrome, Huntington disease, hydrocephalus, cord, also referred to herein as a “transection.” may be a hypoxia, insomnia, ischemic attack, kuru, Landau-Kleffner complete severing or, may be an incomplete severing of the syndrome, Lewy Body disease, Machado-Joseph disease, spinal cord. meige syndrome, meningitis, bacterial meningitis, viral, In some embodiments, the methods of treating a subject migraine disorders, movement disorders, multiple system 25 suffering form a CNS injury or, in other embodiments, spinal atrophy, myelitis, olivopontocerebellar atrophies, Parkin cord injury, may be accompanied by treatment of the Subject son's disease, parkinsonian disorders, poliomyelitis, postpo with electrical stimulation of the injured site and the admin liomyelitis syndrome, prion diseases, pseudotumor cerebri, istration of a purine nucleoside, or analog thereof, for Shy-Drager syndrome, spasms, infantile, spinal cord dis example as described in United States Patent Application eases, Supranuclear palsy, Syringomyelia, thalamic diseases, 30 Publication Number 20040214790A1. tic disorders, tourette syndrome, or uveomeningoencephal In some embodiments, demyelinating diseases comprise itic syndrome. In some embodiments, the central nervous adrenoleukodystrophy, alexander disease, canavan disease, system disease is cystic fibrosis induced hypogonadal state. demyelinating disease, diffuse cerebral sclerosis of Schilder, In some embodiments, cranial nerve diseases comprise bell leukodystrophy-globoid cell, leukodystrophy-metachro palsy, cranial nerve diseases, facial hemiatrophy, facial neu 35 matic, multiple Sclerosis, or neuromyelitis optica. ralgia, glossopharyngeal nerve diseases, Moebius syndrome, In some embodiments, nervous system malformations or trigeminal neuralgia. comprise Arnold-Chiari malformation, Charcot-Marie-Tooth In some embodiments, central nervous system diseases disease, encephalocele, hereditary motor and sensory neuro comprise injuries or damage to the central nervous system pathies, septo-optic dysplasia, spina bifida occulta, or spinal (CNS). In some embodiments, injuries or damage to the CNS 40 dySraphism. may be associated with muscle wasting disorders. Injuries or In some embodiments, neurologic manifestations com damage to the CNS can be, for example, caused by diseases, prise agnosia, amnesia, anomia, aphasia, apraxias, back pain, trauma or chemicals. Examples are central nerve injury or Brown-Sequard syndrome, cerebellar ataxia, chorea, com damage, peripheral nerve injury or damage and spinal cord munication disorders, confusion, dizziness, dyslexia, dysto injury or damage. 45 nia, facial paralysis, fasciculation, gait disorders, neurologic Studies involving patients with spinal cord injuries (SCI) headache, hemiplegia, memory disorders, mental retardation, have shown that central neurotransmitters may be altered mutism, myoclonus, neck pain, nonverbal learning disorder, after SCI causing hypothalamus-pituitary-adrenal axis dys olfaction disorders, pain, paralysis, phantom limb, prosopag function, whose disruption led to a significant decrease in nosia, quadriplegia, seizures, spasm, speech disorders, Syn testosterone and other hormone levels. SCI or other acute 50 esthesia tardive dyskinesia, taste disorders, torticollis, tremor, illness or trauma characteristically includes heightened trismus, unconsciousness, or vertigo. catabolism in conjunction with the lowered anabolic activity In some embodiments, neuromuscular diseases comprise resulting in a condition that is prone to loss of lean body amyotrophic lateral Sclerosis, brachial plexus neuritis, bra tissue, which is often accompanied by disturbed nutrient uti chial plexus neuropathies, bulbar palsy, carpal tunnel Syn lization. The effects of the loss of lean body mass include the 55 drome, cubital tunnel syndrome, diabetic neuropathies, dys development of wounds and impaired healing mechanisms, autonomia, guillain, barre Syndrome, hereditary sensory and further compounding the problem. Because of poor nutrition autonomic neuropathies, miller fisher syndrome, motor neu and protein combined with immobilization, patients with spi ron disease, muscular atrophy, spinal, myasthenia gravis, nal cord injury are at high risk for bed Sores. myopathies, structural, congenital, nerve compression syn In one embodiment, a wide variety of injuries of the CNS 60 dromes, neuralgia, neuromuscular diseases, paralyses, famil may be treated by the methods of the present invention. CNS ial periodic, peripheral nervous system diseases, poems Syn injury may refer, in one embodiment, to a breakdown of the drome, polyneuropathies, polyradiculopathy, refsum disease, membrane of a nerve cell, or, in another embodiment, to the sciatica, spinal muscular atrophies of childhood, stiff-person inability of the nerve to produce and propagate nerve syndrome, thoracic outlet syndrome, or ulnar nerve compres impulses, or in another embodiment, to the death of the cell. 65 sion syndromes. An injury includes damage that directly or indirectly affects In one embodiment, methods of treating a Subject with a the normal functioning of the CNS. The injury may be a nervous system disease encompass treating any secondary US 8,426,465 B2 75 76 conditions in the subject, which arise due to the subject hav retention, urinary tract infections, urination disorders, uro ing a nervous system disease, some of which are described logic and male genital diseases, urologic diseases, varicocele, herein. vesico, or urethral reflux. In some embodiments, the present invention provides a In some embodiments, the present invention provides a method for treating, reducing the incidence, delaying the 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 an ophthalmic disease in a Subject. In toms associated with a dermatological disorder in a Subject. one embodiment, the method comprises administering to a In one embodiment, the method comprises administering to a Subject a composition comprising a compound and an anti Subject a composition comprising a compound and anti-can cancer agent, an immunomodulating agent, an agent treating 10 cer agent, an immunomodulating agent, an agent treating a the cardiovascular system, an anti-infective agent, an agent dermatological disorder, an anti-infective agent, a gene treating a wasting disease, a gene therapy agent, an agent therapy agent, an agent treating the endocrine system, Vita treating the endocrine system, vitamins, or a combination mins, or a combination thereof. In some embodiments, der thereof. In some embodiments ophthalmic disease comprise matological disorders comprise acne, actinic keratosis, alope acute Zonal occult outer retinopathy, Adie syndrome, albi 15 cia, androgenic alopecia, alopecia areata, alopecia secondary nism, ocular-amaurosis, fugax, amblyopia, aniridia, anisoco to chemotherapy, alopecia secondary to radiation therapy, ria, anophthalmos, aphakia, astigmatism, blepharitis, ble alopecia induced by Scarring, alopecia induced by stress, pharoptosis, blepharospasm, blindness, cataract, chalazion, angioma, athlete's foot, aquagenic pruritus, atopic dermatitis, chorioretinitis, choroideremia, coloboma, color vision baldness, premature baldness, male pattern baldness, andro defects, conjunctivitis, corneal diseases, corneal dystrophies, genic baldness, basal cell carcinoma, burns, bed sore, Beh corneal edema, corneal ulcer, diabetic retinopathy, diplopia, cet’s disease, blepharitis, boil, Bowen's disease, bullous pem distichiasis, dry eye syndromes, Duane retraction syndrome, phigoid, canker Sore, carbuncles, cellulitis, chloracne, ectropion, entropion, esotropia, exfoliation syndrome, chronic dermatitis of the hands and feet, dyshidrosis, cold exotropia, eye hemorrhage, eye neoplasms, eyelid diseases, Sores, contact dermatitis, creeping eruption, dandruff, derma floaters, general fibrosis syndrome, glaucoma, gyrate atro 25 titis, dermatitis herpetiformis, dermatofibroma, diaper rash, phy, hemianopsia, Hermanski-Pudlak syndrome, hordeolum, eczema, epidermolysis bullosa, erysipelas, erythroderma, Horner syndrome, hyperopia, hyphema, iritis, Kearns-Sayer friction blister, genital wart, hidradenitis, Suppurativa, hives, syndrome, keratitis, keratoconus, lacrimal apparatus dis hyperhidrosis, ichthyosis, impetigo, jock itch, Kaposi’s Sar eases, lacrimal duct obstruction, lens diseases, macular coma, keloid, keratoacanthoma, keratosis pilaris, lice infec degeneration, microphthalmos, myopia, nystagmus, patho 30 tion, lichen planus, lichen simplex chronicus, lipoma, lym logic, ocular motility disorders, oculomotor nerve diseases, phadenitis, malignant melanoma, melasma, miliaria, ophthalmoplegia, optic atrophies, optic nerve diseases, optic molluscum contagiosum, nummular dermatitis, paget’s dis neuritis, optic neuropathy, orbital cellulitis, papilledema, ease of the nipple, pediculosis, pemphigus, perioral dermati peters anomaly, presbyopia, pterygium, pupil disorders, tis, photoallergy, photosensitivity, pityriasis rosea, pityriasis refractive errors, retinal detachment, retinal diseases, retinal 35 rubra pilaris, psoriasis, raynaud's disease, ring worm, rosa vein occlusion, retinitis pigmentosa, retinopathy of prematu cea, scabies, Scleroderma, sebaceous cyst, Seborrheic kerato rity, retinoschisis, Scleritis, Scotoma, Strabismus, Thygeson's sis, Seborrhoeic dermatitis, shingles, skin cancer, skin tags, Superficial punctate keratitis, trachoma, uveitis, white dot spider veins, squamous cell carcinoma, stasis dermatitis, tick syndrome, vision disorders, or vitreous disorders bite, tinea barbae, tinea capitis, tinea corporis, tinea cruris, In some embodiments, the present invention provides a 40 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 45 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 50 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 55 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 60 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, 65 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 US 8,426,465 B2 77 78 wounds, puncture wounds, septic wounds, Subcutaneous pound as described herein is useful as a) adjunct to cauteriza wounds, etc. Examples of Sores are bed Sores, canker Sores, tion therapy (laser or radio) as is used in Surgery to promote chrome Sores, cold Sores, pressure Sores etc. Examples of wound healing, b) adjunct to cryotherapy to promote wound ulcers are, e.g., peptic ulcer, duodenal ulcer, gastric ulcer, healing, c) adjunct to chemotherapy to prevent side effects gouty ulcer, diabetic ulcer, hypertensive ischemic ulcer, Stasis Such as alopecia, hypogonadism, muscle wasting, osteopenia, ulcer, ulcus cruris (venous ulcer). Sublingual ulcer, Submu osteoporosis, sarcopenia, increased LDL, TG or total choles cous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer, terol, decreased HDL. In another embodiment, the compound Veneral ulcer, e.g. caused by gonorrhoea (including urethritis, as described herein is useful in chronic catabolic state (coma, endocerviciitis and proctitis). Conditions related to wounds or wasting conditions, starvation, eating disorders); concomi Sores which may be successfully treated according to the 10 tant bone fracture and muscle damage; critical illness in invention are burns, anthrax, tetanus, gas gangrene, Scalatina, which muscle or bone wasting are apparent; and/or connec erysipelas, Sycosis barbae, folliculitis, impetigo contagiosa, tive tissue diseases and disorders. or impetigo bullosa, etc. There is often a certain overlap Ischemic ulcers and pressure Sores are wounds, which nor between the use of the terms “wound' and “ulcer and mally only heal very slowly and especially in Such cases an “wound' and "sore' and, furthermore, the terms are often 15 improved and more rapid healing is of course of great impor used at random. Therefore as mentioned above, in the present tance for the patient. Furthermore, the costs involved in the context the term “wounds’ encompasses the term “ulcer, treatment of patients Suffering from Such wounds are mark “lesion', 'sore' and “infarction', and the terms are indis edly reduced when the healing is improved and takes place criminately used unless otherwise indicated. more rapidly. The kinds of wounds to be treated according to the inven Donor site wounds are wounds which e.g. occur in connec tion include also i) general wounds such as, e.g., Surgical, tion with removal of hard tissue from one part of the body to traumatic, infectious, ischemic, thermal, chemical and another part of the body e.g. in connection with transplanta bullous wounds; ii) wounds specific for the oral cavity such tion. The wounds resulting from Such operations are very as, e.g., post-extraction wounds, endodontic wounds espe painful and an improved healing is therefore most valuable. cially in connection with treatment of cysts and abscesses, 25 The term “skin' is used in a very broad sense embracing the ulcers and lesions of bacterial, viral or autoimmunological epidermal layer of the skin and in those cases where the skin origin, mechanical, chemical, thermal, infectious and surface is more or less injured also the dermal layer of the lichenoid wounds; herpes ulcers, stomatitis aphthosa, acute skin. Apart from the stratum corneum, the epidermal layer of necrotising ulcerative gingivitis and burning mouth Syn the skin is the outer (epithelial) layer and the deeper connec drome are specific examples; and iii) wounds on the skin Such 30 tive tissue layer of the skin is called the dermis. as, e.g., neoplasm, burns (e.g. chemical, thermal), lesions In some embodiments, burns are associated with reduced (bacterial, viral, autoimmunological), bites and surgical inci testosterone levels, and hypgonadism is associated with sions. Another way of classifying wounds is as i) Small tissue delayed wound healing. In one embodiment, the methods of loss due to Surgical incisions, minor abrasions and minor this invention, provide for treating a Subject suffering from a bites, or as ii) significant tissue loss. The latter group includes 35 wound or a burn. ischemic ulcers, pressure Sores, fistulae, lacerations, severe In some embodiments, the present invention provides a bites, thermal burns and donor site wounds (in soft and hard method for prooting healing of anterior cruciate ligament tissues) and infarctions. (ACL) or medial cruciate ligament (MCL) injuries, or accel In other aspects of the invention, the wound to be prevented erating recovery after ACL or MCL surgery. and/or treated is selected from the group consisting of aseptic 40 In some embodiments, the present invention provides a wounds, infarctions, contused wounds, incised wounds, lac method for treating, reducing the incidence, delaying the erated wounds, non-penetrating wounds, open wounds, pen onset or progression, or reducing and/or abrogating the Symp etrating wounds, perforating wounds, puncture wounds, sep toms associated with an endocrine disorder in a Subject. In tic wounds and Subcutaneous wounds. one embodiment, the method comprises administering to a Other wounds which are of importance in connection with 45 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 cal disorder, an agent treating the central nervous system, an useful in wound healing as an adjunct to physical therapy/ 50 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 treating the endocrine system, vitamins, or a combination ate ligament (MCL) injuries, or accelerating recovery after thereof. In some embodiments, endocrine disorders comprise ACL or MCL surgery. In another embodiment, the compound 55 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 tes mellitus-type 2, diabetic, ketoacidosis, empty Sella syn lage regrowth. In another embodiment, the compound as 60 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, lactinemia, hyperthyroidism, hypogonadism, hypopituitar burns, cancer, COPD. In another embodiment, the compound 65 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, US 8,426,465 B2 79 80 puberty, precocious, renal osteodystrophy, thyroid diseases, thrombocytopenic, purpura, thrombotic thrombocytopenic, thyroid hormone resistance syndrome, thyroid neoplasms, RH-isoimmunization, sarcoidosis, sarcoidosis, spherocyto thyroid nodule, thyroiditis, thyroiditis, autoimmune, thy sis, splenic rupture, thalassemia, thrombasthenia, thromb roiditis, subacute, or Wolfram syndrome. ocytopenia, Waldenstrom macroglobulinemia, or Von Will In one embodiment, "Hypogonadism’ is a condition 5 ebrand disease. resulting from or characterised by abnormally decreased In some embodiments, the present invention provides a functional activity of the gonads, with retardation of growth method for treating, reducing the incidence, delaying the and sexual development. onset or progression, or reducing and/or abrogating the Symp In some embodiments, the present invention provides a toms associated with a congenital, hereditary, or neonatal method for treating, reducing the incidence, delaying the 10 disease in a Subject. In one embodiment, the method com onset or progression, or reducing and/or abrogating the Symp prises administering to a subject a composition comprising a toms associated with urogenital disease and/or fertility in a compound of this invention and anti-cancer agent, an immu Subject. In one embodiment, the method comprises adminis nomodulating agent, an antidiabetic agent, an agent treating tering to a Subject a composition comprising a compound of the cardiovascular system, an agent treating the gastrointes this invention and anti-cancer agent, an immunomodulating 15 tinal system, an agent treating a dermatological disorder, an agent, an anti-infective agent, an agent treating the kidney, agent treating the central nervous system, an anti-infective gene therapy agent, an agent treating the endocrine system, agent, an agent treating the liver, an agent treating the kidney, Vitamins, or a combination thereof. In some embodiments, an agent treating a metabolic disease, an agent treating a urogenital diseases and/or fertility diseases comprise abor wasting disease, a gene therapy agent, an agent treating the tion, spontaneous-adhesions-pelvic, candidiasis, Vulvovagi endocrine system, Vitamins, or a combination thereof. In nal, depression-postpartum, diabetes, gestational, dyspareu Some embodiments, congenital, hereditary, and neonatal dis nia, dystocia, eclampsia, endometriosis, fetal death, fetal eases comprise Aicardi syndrome, amniotic band syndrome, growth retardation, fetal membranes, premature rupture, anencephaly, Angelman syndrome, ataxia telangiectasia, genital diseases, female, genital neoplasms, female, hydatidi Bannayan-Zonana syndrome, Barth syndrome, basal cell form mole, hyperemesis gravidarum, infertility, ovarian 25 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 30 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 Sheldon syndrome, gastroschisis, genetic diseases, inborn, method for treating, reducing the incidence, delaying the 35 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 patella syndrome, neurofibromatoses, neuronal ceroid-lipo this invention and an anti-cancer agent, an immunomodulat 40 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 45 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, turner syndrome, twins, conjoined, Usher syndrome, angiolymphoid hyperplasia with eosinophilia, antithrombin 50 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 onset or progression, or reducing and/or abrogating the Symp heim-Chester disease, erythroblastosis, fetal, evans Syn 55 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 agent treating a dermatological disorder, an anti-infective philia a, hemophiliab, hemorrhagic disease of newborn, his 60 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 ankylosing spondylitis, Ehlers-Danlos Syndrome, Henoch metaplasia, myeloproliferative disorders, neutropenia, para 65 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 US 8,426,465 B2 81 82 syndrome, Xerophthalmia, Still's disease, systemic lupus eases, poisoning, shaken baby Syndrome, shoulder injuries, erythematosus, Takayasu disease, or Wegener's granuloma space motion sickness, spinal cord injuries, tick paralysis, or tosis. wounds (penetrating and non-penetrating). In some embodiments, the present invention provides a In some embodiments, the present invention provides a method for treating, reducing the incidence, delaying the 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 metabolic disease in a subject. In one toms associated with a behavior mechanism in a subject. In embodiment, the method comprises administering to a Sub one embodiment, the method comprises administering to a ject a composition comprising a compound of this invention Subject a composition comprising a compound of this inven and antidiabetic agent, an agent treating the gastrointestinal 10 tion and an agent treating the cardiovascular system, an agent system, an agent treating a dermatological disorder, an agent treating the central nervous system, a gene therapy agent, an treating the central nervous system, an anti-infective agent, an agent treating the endocrine system, Vitamins, or a combina agent treating the liver, an agent treating the kidney, an agent tion thereof. In some embodiments, behavior mechanisms treating a metabolic disease, an agent treating a wasting dis comprise aggression, attitude to death, codependency, self ease, a gene therapy agent, an agent treating the endocrine 15 injurious behavior, sexual behavior, or social behavior. system, Vitamins, or a combination thereof. In some embodi In some embodiments, the present invention provides a ments, metabolic diseases comprise acid-base imbalance, method for treating, reducing the incidence, delaying the acidosis, alkalosis, alkaptonuria, alpha-mannosidosis, amino onset or progression, or reducing and/or abrogating the Symp acid metabolism inborn errors, amyloidosis, iron-deficiency toms associated with a mental disorder in a subject. In one anemia, ascorbic acid deficiency, avitaminosis, beriberi, embodiment, the method comprises administering to a Sub biotimidase deficiency, carbohydrate-deficient glycoprotein ject a composition comprising a compound of this invention syndrome, carnitine disorders, cystinosis, cystinuria, dehy and an agent treating the central nervous system, a gene dration, fabry disease, fatty acid oxidation disorders, fucosi therapy agent, an agent treating the endocrine system, Vita dosis, galactosemias, Gaucher disease, Gilbert disease, glu mins, or a combination thereof. In some embodiments, men cosephosphate dehydrogenase deficiency, glutaric acidemia, 25 tal disorders comprise Asperger syndrome, attention deficit glycogen storage disease, Hartnup disease, hemochromato disorder with hyperactivity, autistic disorder, bipolar disor sis, hemosiderosis, hepatolenticular degeneration, histidine der, borderline personality disorder, capgras Syndrome, child mia, homocystinuria, hyperbilirubinemia, hypercalcemia, behavior disorders, combat disorders, cyclothymic disorder, hyperinsulinism, hyperkalemia, hyperlipidemia, hyperoX dependent personality disorder, depressive disorder, disso aluria, hypervitaminosis A, hypocalcemia, hypoglycemia, 30 ciative disorders, dysthymic disorder, eating disorders, fire hypokalemia, hyponatremia, hypophosphatasia, insulin setting behavior, hypochondriasis, impulse control disorders, resistance, iodine deficiency, iron overload, jaundice, chronic Kleine-Levin syndrome, mental disorders, mental disorders idiopathic, leigh disease, lesch-nyhan syndrome, leucine diagnosed in childhood, multiple personality disorder, Mun metabolism disorders, lysosomal storage diseases, magne chausen syndrome, Munchhausen syndrome, narcissistic per sium deficiency, maple syrup urine disease, Melas Syndrome, 35 Sonality disorder, narcolepsy, obsessive-compulsive disorder, Menkes kinky hair syndrome, metabolic diseases, metabolic paraphilias, phobic disorders, psychotic disorders, restless syndrome X, metabolism, inborn errors, mitochondrial dis legs Syndrome, Schizophrenia, seasonal affective disorder, eases, mucolipidoses, mucopolysaccharidoses, Niemann sexual and gender disorders, sexual dysfunctions, psycho Pick diseases, obesity, ornithine carbamoyltransferase defi logical, sleep disorders, Somatoform disorders, stress disor ciency disease, osteomalacia, pelagra, peroxisomal 40 ders, post-traumatic, Substance-related disorders, Suicidal disorders, phenylketonurias, porphyria, erythropoietic, por behavior, or trichotillomania. phyrias, progeria, pseudo, gaucher disease, refsum disease, In one embodiment, “depression” refers to an illness that Reye syndrome, rickets, Sandhoff disease, starvation, tangier involves the body, mood and thoughts that affects the way a disease, Tay-Sachs disease, tetrahydrobiopterin deficiency, person eats, sleeps and the way one feels about oneself, and trimethylaminuria, tyrosinemias, urea cycle disorders, water 45 thinks about things. The signs and symptoms of depression electrolyte imbalance, Wernicke encephalopathy, vitamin A include loss of interest in activities, loss of appetite or over deficiency, vitamin B12 deficiency, vitamin B deficiency, eating, loss of emotional expression, an empty mood, feelings Wolman disease, or Zellweger syndrome. of hopelessness, pessimism, guilt or helplessness, Social In some embodiments, the present invention provides a withdrawal, fatigue, sleep disturbances, trouble concentrat method for treating, reducing the incidence, delaying the 50 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 thinking, learning and judging. Cognition is related to the this invention and anti-cancer agent, an immunomodulating 55 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 positive or negative, in cognition and/or mood. ing the liver, an agent treating the kidney, an agent treating a 60 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 embodiment, the method comprises administering to a Sub and stings, brain concussion, burns, central cord syndrome, 65 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, US 8,426,465 B2 83 84 an agent treating the liver, an agent treating a metabolic dis the treatment methods of this invention are useful in treating ease, an agent treating a wasting disease, a gene therapy symptoms associated with hypogonadism, brought about in agent, an agent treating the endocrine system, Vitamins, or a the subject by androgen deficiency in a female (ADIF); combination thereof. In some embodiments, liver diseases androgen deficiency in aging male (ADAM) to include comprise liver cancer, primary biliary cirrhosis, autoimmune fatigue, depression, decreased libido, erectile dysfunction, hepatitis, chronic liver disease, cirrhosis of the liver, hepatitis, decreased cognition, decreased mood; androgen insuffi viral hepatitis (hepatitis a, hepatitis b, chronic hepatitis b, ciency (male or female), androgen deficiency (male or hepatitis c, chronic hepatitis c, hepatitis d, hepatitis e, hepa female). titis X), liver failure, jaundice, neonatal jaundice, hepatoma, In one embodiment, diabetic nephropathy is a complica liver cancer, liver abscess, alcoholic liver disease, hemochro 10 tion of diabetes that evolves early, typically before clinical matosis, Wilson's disease, portal hypertension, primary scle diagnosis of diabetes is made. The earliest clinical evidence rosing cholangitis, sarcoidosis, tapeworms, alveolar hydatid of nephropathy is the appearance of low but abnormal levels disease, fascioliasis, Schistosomiasis, gaucher disease, Zell (>30 mg/day or 20 ug/min) of albumin in the urine (microal weger syndrome, alcoholism, food poisoning, pneumococcal buminuria), followed by albuminuria (>300 mg/24 h or 200 pneumonia or vibrio Vulnificus. 15 ug/min) that develops over a period of 10-15 years. In patients In some embodiments, the present invention provides a with type 1 diabetes, diabetic hypertension typically becomes method for treating, reducing the incidence, delaying the manifest early on, by the time that patients develop microal onset or progression, or reducing and/or abrogating the Symp buminuria. Once overt nephropathy occurs, the glomerular toms associated with a kidney disease in a subject. In one filtration rate (GFR) falls over a course of times, which may embodiment, the method comprises administering to a Sub be several years, resulting in End Stage Renal Disease ject a composition comprising a compound of this invention (ESRD) in diabetic individuals. and anti-cancer agent, an immunomodulating agent, an Hypertension is another comorbid factor for renal disease. antidiabetic agent, an agent treating the gastrointestinal sys In some embodiments, treatment of renal disease according to tem, an anti-infective agent, an agent treating the kidney, an the present invention may comprise concomitant treatment agent treating a metabolic disease, a gene therapy agent, an 25 with a compound of this invention and an agent which treats agent treating the endocrine system, Vitamins, or a combina hypertension. tion thereof. In some embodiments, kidney diseases comprise In some embodiments, the present invention provides a acromegaly, acute renal failure (ARF) amyloidosis, autoso method for treating, reducing the incidence, delaying the mal dominant polycystic kidney disease, kidney Stones, kid onset or progression, or reducing and/or abrogating the Symp ney cysts, autosomal recessive polycystic kidney disease, 30 toms associated with a wasting disease in a subject. In one chronic renal failure (CRF), chronic renal disease, coffin embodiment, the method comprises administering to a Sub Lowry syndrome, corpulmonale, cryoglobulinemia, diabetic ject a composition comprising a compound of this invention nephropathy, dyslipidemia, Gaucher disease, glomerulone and anti-cancer agent, an immunomodulating agent, an phritis, goodpasture syndrome, hemolytic uremic syndrome, antidiabetic agent, an agent treating the cardiovascular sys hepatitis, kidney cancer, kidney Stones, leukemia, lipopro 35 tem, an agent treating the gastrointestinal system, an agent teinemia, lupus, multiple myeloma, nephritis, polyartekidney treating the central nervous system, an agent treating a meta cysts, post streptococcal glomerulonephritis, glomerulone bolic disease, an agent treating a wasting disease, a gene phritis, kidney pain, preeclampsia, renal tuberculosis, pyelo therapy agent, an agent treating the endocrine system, Vita nephritis, renal tubular acidosis kidney disease, streptococcal mins, or a combination thereof. In some embodiments, wast toxic shock syndrome, thromboembolism, toxoplasmosis, 40 ing diseases comprise muscle injury, bed rest, immobility, urinary tract infections, vesicoureteral reflux, or williams nerve injury, neuropathy, diabetic neuropathy, alcoholic neu syndrome. ropathy, Subacute combined degeneration of the spinal cord, In one embodiment, the kidney disease or disorder is acute, diabetes, rheumatoid arthritis, motor neurone diseases, Duch or in another embodiment, chronic. In one embodiment, clini enne muscular dystrophy, carpal tunnel syndrome, chronic cal indications of a kidney disease or disorder, wherein the 45 infection, tuberculosis, Addison's disease, adult Sma, limb methods of treatment may be useful include urinary casts, muscle atrophy, alcoholic neuropathy, anorexia, anorexia measured GFR, or other markers of renal function. nervosa, anorexia associated with cachexia, anorexia associ In one embodiment, the methods of this invention are use ated with aging, back tumour, dermatomyositis, hip cancer, ful in Subjects predisposed to kidney diseases or disorders. In inclusion body myositis, incontinentia pigmenti, intercostal one embodiment, the phrase "predisposed to a kidney disease 50 neuralgia, juvenile rheumatoid arthritis, Legg-Calve-Perthes or disorder with respect to a subject is synonymous with the disease, muscle atrophy, multifocal motor neuropathy, neph phrase “subject at risk', and includes a Subject at risk of acute rotic syndrome, osteogenesis imperfecta, post-polio Syn or chronic renal failure, or at risk of the need for renal replace drome, rib tumor, spinal muscularatrophy, reflex sympathetic ment therapy, if the subject is reasonably expected to suffer a dystrophy syndrome, or Tay-Sachs. progressive loss of renal function associated with progressive 55 A wasting condition or disorder is defined herein as a loss of functioning nephron units. Whether a particular sub condition or disorder that is characterized, at least in part, by ject is at risk is a determination which may routinely be made an abnormal, progressive loss of body, organ or tissue mass. A by one of ordinary skill in the relevant medical or veterinary wasting condition can occuras a result of a pathology Such as, art. for example, cancer, or it can be due to a physiologic or In one embodiment, Subjects with kidney disease, in par 60 metabolic State, such as disuse deconditioning that can occur, ticular male subjects with end-stage renal disease (ESRD) for example, due to prolonged bed rest or when a limb is Suffer from hypogonadism, with some having concomitant immobilized, such as in a cast, or with the occurrence of moderate to severe protein-energy malnutrition (PEM), multiple wounds, including, for example, amputation, as which leads to higher required doses of EPO, lower quality of occurs in diabetics, and other conditions, as will be appreci life (QOL) scores, and higher mortality. Many have other 65 ated by one skilled in the art. A wasting condition can also be symptoms associated with hypogonadism, including fatigue, age associated. The loss of body mass that occurs during a lack of apetite, muscle weakness, etc. In some embodiments, wasting condition can be characterized by a loss of total body US 8,426,465 B2 85 86 weight, or a loss of organ weight Such as a loss of bone or trauma, Surgery, congestive heart failure, cardiac myopathy, muscle mass due to a decrease in tissue protein. burns, cancer, chronic obstructive pulmonary disease In one embodiment, the terms “muscle wasting or “mus (COPD), eating disorders such bulimia, anorexia nervosa, cular wasting, refer to the progressive loss of muscle mass loss of appetite, starvation, and/or depression. and/or to the progressive weakening and degeneration of 5 In some embodiments, the present invention provides a muscles, including the skeletal or Voluntary muscles which method for treating, reducing the incidence, delaying the control movement, cardiac muscles which control the heart, onset or progression, or reducing and/or abrogating the Symp and Smooth muscles. In one embodiment, the muscle wasting toms associated with invalid states in a Subject. In one condition or disorder is a chronic muscle wasting condition or embodiment, the invalid state is post-polio syndrome. In one disorder. “Chronic muscle wasting is defined herein as the 10 embodiment, the method comprises administering to a Sub chronic (i.e. persisting over along period of time) progressive ject a composition comprising a compound of this invention loss of muscle mass and/or to the chronic progressive weak and an immunomodulating agent, an antidiabetic agent, an ening and degeneration of muscle. agent treating the cardiovascular system, an agent treating the The loss of muscle mass that occurs during muscle wasting gastrointestinal system, an agent treating the central nervous can be characterized by a muscle protein breakdown or deg 15 system, an agent treating a metabolic disease, an agent treat radation, by muscle protein catabolism. Protein catabolism ing a wasting disease, a gene therapy agent, an agent treating occurs because of an unusually high rate of protein degrada the endocrine system, vitamins, or a combination thereof. tion, an unusually low rate of protein synthesis, or a combi In some embodiments, the present invention provides a nation of both. Protein catabolism or depletion, whether method for treating, reducing the incidence, delaying the caused by a high degree of protein degradation or a low onset or progression, or reducing and/or abrogating the Symp degree of protein synthesis, leads to a decrease in muscle toms associated with a hypogonadal state in a Subject. In one 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, 25 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 30 hypogonadism, the ovaries or testes themselves do not func Some embodiments, the present invention provides a method 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 35 a form of hypogonadism. Menopause may cause, in some method comprises administering to a subject a composition 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 40 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, 45 therapy agent, an agent treating the endocrine system, an Cachexia is weakness and a loss of weight caused by a 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 50 method for treating, reducing the incidence, delaying the injuries, chronic illnesses, burns, trauma or cancer, who are 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 55 gression, or reducing and/or abrogating the symptoms asso factor, as well. 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 60 is defined as a bone density between one standard deviation Subject. In another embodiment, the wasting diseases and (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; reduce 65 agent, an antidiabetic agent, an agent treating the cardiovas cachexia and protein loss due to prolonged critical illness, 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 US 8,426,465 B2 87 88 metabolic disease, an agent treating a wasting disease, a gene Some embodiments, the present invention provides a method therapy agent, an agent treating the endocrine system, an for increased productivity of feeds or stud livestock, for agent treating a dermatological disorder, an anti-infective example, increased sperm count, improved morphology of agent, an agent treating the liver, an agent treating the kidney, sperm, etc. In some embodiments, the present invention pro Vitamins, or a combination thereof. vides a method for expanding the productive life of farm In some embodiments, the present invention provides a animals, for example, egg-laying hens, milk-producing cows, method for treating, reducing the incidence, delaying the etc., and/or enhanced herd health, for example, improved onset or progression, or reducing and/or abrogating the Symp immune clearance, stronger animals. toms associated with a sarcopenic state in a subject. In one In some embodiments, the present invention provides com embodiment, the present invention provides a method for 10 pounds, compositions and methods of use thereof for the treating, reducing the incidence, delaying the onset or pro enhanced meat productivity in food animals. In some gression, or reducing and/or abrogating the symptoms asso embodiments, this invention provides compounds, composi ciated with a pharmacotherapy induced sarcopenic state in a tions and methods of use thereof for the modulation of appe Subject. In some embodiments, sarcopenia is a significant loss tite for feedlot animals. In some embodiments, this invention of muscle mass. In one embodiment, sarcopenia definition is 15 provides compounds, compositions and methods of use having a lean body mass less than two standard deviation thereof for improved feed efficiency. In some embodiments, below the mean for normal young adults. In some embodi this invention provides compounds, compositions and meth ments, sarcopenia is caused by genetic factors, altered circu ods of use thereof for decreased time to market for feedlot lation, decrease in the capillary:muscle fiber ratio, altered animals. In some embodiments, this invention provides com motor neurons, denervation, deterioration of motor end pounds, compositions and methods of use thereof for plates, selective reinnervation of Type I fibers, inflammatory increased terminal weight of feedlot animals. In some responses causing muscle damage, reduced exercise, malnu embodiments, this invention provides compounds, composi trition, low dietary protein intake, Vitamin D deficiency, age tions and methods of use thereof for decreased time to termi related decline in Vitamin D, oxidative stress, muscle mito nal weight of feedlot animals. In some embodiments, this chondrial mutations, changes in specific types of muscle 25 invention provides compounds, compositions and methods of fibers, decline in muscle protein, disabling disease, strokes, use thereof for increased lean weight of feedlot animals. In Alzheimer's disease, Parkinson's disease, osteoporsis, ath Some embodiments, this invention provides compounds, erosclerosis, diabetes mellitus, hyperinsulimemia, renal fail compositions and methods of use thereof for decreased fat ure, or hypogonadism. In one embodiment, the method com body weight of feedlot animals. In some embodiments, this prises administering to a subject a composition comprising a 30 invention provides compounds, compositions and methods of SARM compound and an anti-cancer agent, an immuno use thereof for the modulation of meat quality in feedlot modulating agent, an antidiabetic agent, an agent treating the animals. In some embodiments, this invention provides com cardiovascular system, an agent treating the gastrointestinal pounds, compositions and methods of use thereof for system, an agent treating the central nervous system, an agent increased meat production. treating a metabolic disease, an agent treating a wasting dis 35 In some embodiments, the term “feedlot animals' refers to, ease, a gene therapy agent, an agent treating the endocrine interalia, any animal the meat of which is considered edible system, an agent treating a dermatological disorder, an anti in a given culture or country. In some embodiments, such term infective agent, an agent treating the liver, an agent treating may include without limitation Swine (domestic pig, wild the kidney, vitamins, or a combination thereof. boars), bovine (bison, cattle, yaks), cervids (deer, elk, In some embodiments, the present invention provides a 40 moose), Ovine (sheep/lamb), caprine (goats), lagomorphs method for treating, reducing the incidence, delaying the (rabbit, pika), avian (chicken, turkey, duck, game birds, emu/ onset or progression, or reducing and/or abrogating the Symp ostrich), fish (catfish, tilapia, salmon, red drum), shellfish toms associated with a combination of diseases and/or disor (crustaceans such as crab, lobster, shrimp; and mollusks Such ders in a subject as described hereinabove. In one embodi as clams, octopus, squid), roe (caviar), amphibians (frogs, ment, the method comprises administering to a subject a 45 salamanders), reptiles (Snakes, turtle, alligator), canids (dog, composition comprising a compound of this invention and an foX), felines (cat), equines (horse, donkey, Zebras), marsupi anti-cancer agent, an immunomodulating agent, an antidia als (kangaroo, opossum), insects (grasshopper, beetles, lar betic agent, an agent treating the cardiovascular system, an vae), primates (gorilla, monkey), rodents (rat, mouse, Squir agent treating the gastrointestinal system, an agent treating rel, beaver), cetaceans (whale, dolphin), pinnipeds (walrus, the central nervous system, an agent treating a metabolic 50 seal), miscellaneous (bear, raccoon, elephant) or others as disease, an agent treating a wasting disease, a gene therapy will be appreciated by one skilled in the art. agent, an agent treating the endocrine system, an agent treat In one embodiment, the compounds, compositions or ing a dermatological disorder, an anti-infective agent, an methods of use thereofmay find application in increasing the agent treating the liver, an agent treating the kidney, Vitamins, yield of all retail products derived from such feedlot animals. or a combination thereof. 55 For instance, each of the above food animals have different It is to be understood that any method of this invention, as types of tissues and preparations thereof Such as for Swine: herein described, encompasses the administration of a com ham, bacon, sausage, pork bellies, pork chop, ribs, brain, pound as herein described, or a composition comprising the chitterling, tripe, tenderloin, etc. same, to the Subject, in order to treat the indicated disease, Feedlot practices often include castration in order to better disorder or condition. The methods as herein described each 60 control the behavior of feedlot animals and to improve the and/or all may further comprise administration of an addi quality of the meat (more tender, marbled, and colored). This tional therapeutic agent as herein described, and as will be occurs with a loss of productivity which could be offset using appreciated by one skilled in the art. nonsteroidal androgens, representing one embodiment of a In some embodiments, the present invention provides a mechanism whereby the compounds and composition find method for enhanced production Such as milk, sperm, or egg. 65 application therein. In some embodiments, the present invention provides a In some embodiments, enhancing measures of productiv method for enhanced production of lean meats or eggs. In ity in feedlot animals may comprise enhancing the number of US 8,426,465 B2 89 90 animals per litter, litters per breeding animal per year, slaugh In some embodiments, an advantage of the compounds/ ter head count per breeding animal per year, meat product compositions of this invention may comprise the anabolic production (in pounds) per breeding animal per year, average activity of the compound thereby producing larger animals in daily growth in pounds, live weight (in pounds), dressing less time. Factors contributing to the increasing productivity percent (% of live weight), dressed weight in pounds, retail 5 may include, in some embodiments, enhanced mineral (and meat in pounds perhead count, retail meat yield (percent of other nutrient) absorption in the gut, enhanced body protein live weight), or any combination thereof. accretion and metabolism of fat stores resulting in increased In one embodiment, the compounds, compositions or lean growth rates; increasing nitrogen uptake by muscles, methods of use thereof may find application in Stud farm leading to an increase in the rate of protein synthesis and productivity. Androgens (steroidal and nonsteroidal) are 10 muscle/bone growth. known to enhance sex drive in males and females such that, in In some embodiments, the compounds/compositions of Some embodiments, the stud animals are productive in terms this invention promote anabolic processes while limiting of “open mating time or births per mating event. In some androgenic processes; exhibit enhanced potency, efficacy, embodiments, the Support of sex organs and accessory tissues and safety margins, which in some embodiments, represents (and health benefits) of the compounds/compositions of this 15 advantages of this invention. invention may increase productive life of a stud animal, In some embodiments, the compounds/compositions of allowing him to 'stand at Stud' (i.e. meaning available for this invention increase productivity in livestock and compen reproduction) for a longer period of time. Female receptivity sate for productivity losses as a result of castrating feedlot is enhanced, in Some embodiments, in terms of frequency, in animals. In some embodiments, the compounds are hyper response to contact with/administration of a compound/com myoanabolic, accelerating the growth of food animals position of this invention. thereby increasing productivity in terms of average daily In some embodiments, this invention comprises applica growth and feed requirements. In some embodiments, this is tion of any method as herein described for veterinary use, in achieved without inducing aggressive behavior or compro any animal as described herein. In some embodiments, treat mising meat quality in Such animals. In some embodiments, ment of Such conditions or diseases in animals may find 25 Such use of the compounds/compositions of the invention application for pleasure and/or profit animals, may increase have minimal environmental impact, in terms of their pres the size of game animals by Supplementation, etc. as will be ence in lakes and streams due to the effluent from feedlots, in appreciated by one skilled in the art. some embodiments owing to the short half-life of the com In some embodiments, the compounds/compositions may pounds of this invention, allowing for their administration be administered to any animal as herein described, for 30 and biodegradation prior to being excreted. In some embodi example to livestock. Such administration, in some embodi ments, the reduced androgenic effects and inability to be ments, is accomplished via, inter alia, supplementation in aromatized into estrogenic agents lessens the pharmacologic feeds, formulation into feeds, controlled release implants, impact on wildlife of the compounds/compositions of the dissolution in drinking water; rumen-stable formulations to invention. Such compounds could beformulated into the feed include coatings and derivatives, repeated injection, and other 35 of food animals, according to methods known in the art (U.S. means as will be known to the skilled artisan. Pat. No. 4,447,421 and U.S. Pat. No. 4,211,781 which are In some embodiments, dosages as described herein for incorporated by reference), and thus dosed on a daily basis. humans will be adjusted to accommodate the varying size of In some embodiments, the anabolic effects that may animals. Such modification of dosage is well known in the increase livestock productivity may increase absorption of field of veterinary art, and is available in common veterinary 40 minerals and nutrients from food, increase retention of nitro manuals, and may vary on a scale ranging from milligrams to gen and nitrogen uptake in muscles facilitating protein accre grams as a function of Such varying size. tion and muscle growth, and increased metabolism of fat In some embodiments, the compounds/compositions may stores. In some embodiments, these effects allow for be administered to any animal as herein described, in combi increased production of meat (in pounds) per breeding animal nation with any other agent as described herein, befitting the 45 per year, increased average daily growth in pounds, and live particular animal and condition in the animal, which is being weight (in pounds). The enlargement of muscle tissue as a treated. In some embodiments, such combination therapy result of the compounds/compositions of this invention and may comprise administration of the compounds/composi their use thereby may increase dressing percent (% of live tions with high fat diets such as Supplemented with fatty acids weight), dressed weight in pounds, retail meat in pounds per or oils to improve the meat quality; various combinations 50 head count, and retail meat yield (percent of live weight) with androgens, progestins, anti-glucocorticoids, estrogens, while concomitantly decreasing feed requirements and short growth hormone, etc. can be tailored to produce maximum ening time to slaughter. The resulting meat would be leaner weight gain performance in different types of animals (cows and hence should be healthier to consume. vs. pigs; intact vs. castrated) the specifics of which are known In some embodiments, the compounds/compositions of by those skilled in the art (see for example, Environ Qual Saf 55 this invention Support of androgenic processes, e.g. Support Suppl. 1976; (5):89-98). ing sex organs and accessory tissues (and health benefits), In some embodiments, the compounds/compositions may which in turn, in some embodiments, is beneficial in food be administered to any animal as herein described, which is a livestock management by potentially increasing the number food source for humans, and in Some embodiments, the tis of offspring per litter, litters per breeding animal per year, or sue-selectivity and shorter half-lives of the compounds as 60 slaughter head count per breeding animal per year. In some herein described significantly lowers anticipated environ embodiments, additional advantages may comprise increased mental effects. In some embodiments, the risk to human productive life of a stud animal, allowing him to 'stand at consumption thereby, as compared to agricultural use of Ste stud' (i.e. meaning available for reproduction) for a longer roidal androgens such as trenbolone acetate whose half-life is period of time. Female receptivity may also be enhanced. 3 days, is much reduced, and comprises thereofore an 65 These and other benefits of the use of the compounds/com embodiment of an advantage of the compounds of this inven positions of this invention in agriculture can be appreciated tion. by those skilled in the art (see for example, U.S. Pat. Nos. US 8,426,465 B2 91 92 3,949,085, 3,946,109, 3,256,096, 4,670,249 which are incor In another embodiment, this invention provides a method porated by reference in their entirety), and are generally of treating Opioid Induced Androgen Deficiency (OPIAD), applicable to any farmed food animal Such as, without limi the method comprising administering to the Subject a com tation, Swine (domestic pig, wildboars), bovine (bison, cattle, pound as herein described, and optionally opiates, opioids, yaks), cervids (deer, elk, moose), Ovine (sheep/lamb), caprine 5 narcotics, etc. methadone, long-acting opiates/opioids Such (goats), lagomorphs (rabbit, pika), avian (chicken, turkey, as Kadian, extended release morphines, all opiates/opioids/ duck, game birds, emufostrich), fish (catfish, tilapia, Salmon, narcotics agents approved by FDA, opiates/opioids used in red drum), shellfish (crustaceans such as crab, lobster, treatment of heroin addiction, opiates/opioids used in the shrimp; and mollusks such as clams, octopus, squid), roe treatment of chronic pain of malignancy, opiates/opioids used (caviar), amphibians (frogs, Salamanders), reptiles (Snakes, 10 in the treatment non-malignant of chronic pain syndromes. turtle, alligator), canids (dog, fox), felines (cat), equines In another embodiment, this invention provides a method (horse, donkey, Zebras), marsupials (kangaroo, opossum), of treating a nervous system disease, disorder or condition, insects (grasshopper, beetles, larvae), primates (gorilla, mon the method comprising administering to the Subject a com key), rodents (rat, mouse, squirrel, beaver), cetaceans (whale, pound as herein described, and optionally anti-psychotics, dolphin), pinnipeds (walrus, Seal), and miscellaneous (bear, 15 Such as, for example, Zotepine, haloperidol, amisulpride, ris raccoon, elephant). peridone, other D2 dopamine receptor antagonists; anti-epi Depending on the animal in question, a wide variety of leptics, such as valproic acid, carbamazepine, oXcarbam methods of administering the compounds/compositions of azepine, etc., or combinations thereof. this invention are feasible Such as Supplementation in feeds, In another embodiment, this invention provides a method formulation into feeds, controlled release implants, dissolu of treating a hormone dependent disease, disorder or condi tion in drinking water, rumen-stable formulations to include tion, the method comprising administering to the Subject a coatings and derivatives, repeated injection, and other meth compound as herein described, and optionally chemothera ods as would be known to those skilled in the art (see for peutics agents and therapies (methotrexate, cyclophospha example, U.S. Pat. Nos. 3,991,750, 4,837.004, 6,022,137, mide, ifosfamide, adriamycin, doxorubicin, glucocorticoids, 4,849,447, 5,030,657, 4,904,473, which are incorporated by 25 cyclosporine, L-thyroxine, SERMs, AI, fulvestrant, GnRH reference herein in their entirety). The requirements, condi agents, ADT discontinuation of hormone replacement tions for the achievement of maximum weight gain perfor therapy, cranial irradiation, peripheral irradiation, etc.); pro mance may vary as a function of the type of animal and sexual lactinemia-inducing pharmacotherapeutics (serotonergic status (intact vs. castrated). Various combinations of the com antidepressants acting through 5HT2 receptors, selective pounds of this invention with other growth promoting agents 30 serotonin reuptake inhibitors, monoamine oxidase inhibitors, is envisioned, representing an embodiment of this invention, tricyclic antidepressants, antihypertensives such as methyl including, interalia, growth hormone, antibiotics, digestive dopa, reserpine, clonidine, and Verapamil); antidopaminergic enzymes, vitamins, nutritional Supplements, or other hor anti-emetics such as metoclopramide, H2 receptor antago mones such as androgens, progestins, anti-glucocorticoids, nists Such as cimetidine and ranitidine, estrogens, amphet estrogens, etc. can be tailored to optimize the productivity 35 amines, AR partial antagonists (ketoconazole, spironolac and/or quality of any specific marketable product (see for tone, eplerenone) example, Environ Qual Saf Suppl. 1976; (5):89-98: U.S. Pat. In another embodiment, the compounds of this invention No. 5,288,496). and compositions as described herein are useful in promoting In one embodiment, the method comprises administering or speeding recovery following a Surgical procedure. to a Subject a composition comprising a compound of this 40 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 prodrug, analog, isomer, metabolite, derivative, pharmaceu metabolic disease, an agent treating a wasting disease, a gene 45 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 of a compound as described herein or its prodrug, analog, herein described, or any other therapeutic agent as herein 50 isomer, metabolite, derivative, pharmaceutically acceptable described, or a combination thereof. salt, pharmaceutical product, polymorph, crystal, impurity, In another embodiment, this invention provides methods of N-oxide, hydrate or any combination thereof, or a composi treatment of cystic fibrosis and induced hypogonadal states as tion comprising the same, in treating adominal fat accumula a result of the same, epilepsy and induced hypogonadal and/ tion; improving body composition; lowering body fat con or hypermetabolic states as a result of the same, hereditary 55 tent; lowering fat mass; improving blood lipid profile, angioedema, lupus erythematosus and decreased BMD as a increasing muscle mass/strength/function; increasing bone result of the same, alcohol and Smoking induced osteoporo mass/BMD/strength/function; lowering body fat; congenital sis, in a subject the methods comprising administering a hyperinsulinemia; cushing's disease (hypercortisolemia); SARM as herein described to the subject. obesity or diabetes associated with a metabolic syndrome in a In another embodiment, this invention provides methods of 60 Subject. treatment of polio and post-polio syndrome and other invalid In another embodiment, the Subject has a hormonal imbal states, statin induced rhabdomyolysis, statin-induced muscle ance, disorder, or disease. In another embodiment the Subject weakness, statin-induced organ failure or insufficiency, in a has menopause. Subject, the methods comprising the administration of a com In one embodiment, the present invention provides a use of pound as herein described, optionally with a statin, as appro 65 a compound as described herein for increasing a lean mass in priate, as will be appreciated by one skilled in the art, and/or a subject. In another embodiment Such use comprises admin with any therapeutic agent. istration of a compound as described herein or its prodrug, US 8,426,465 B2 93 94 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 (I) 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 profile and/or reducing the circulating lipid levels in a Subject. were contraindicated in the past. Compound of formula (I) 10 was shown to stimulate muscle growth, whether in the pres In some embodiments, according to this aspect of the inven ence or absence of testosterone while exerting anti-prolifera tion, the subject suffers from one or more conditions selected tive effects on the prostate, thus, in one embodiment, the from the group consisting of atherosclerosis and its associ methods of this invention provide for restoring lost muscle ated diseases, premature aging, Alzheimer's disease, stroke, mass in patients with sarcopenia or cachexia. 15 toxic hepatitis, viral hepatitis, peripheral vascular insuffi In one embodiment, the compounds as herein described ciency, renal disease, and hyperglycemia, and the invention alter the levels of leptin in a subject. In another embodiment, provides for the administration of a compound or composi the compounds as herein described decrease the levels of tion comprising the same, as herein described, which in some leptin. In another embodiment, the compounds as herein embodiments positively affects a lipid profile in the subject, described increase the levels of leptin in a subject. Leptin is which is one means by which the method is useful in treating known to have an effect on appetite on weight loss in obese the indicated diseases, disorders and conditions. mice, and thus has been implicated in obesity. In one embodiment the invention provides for the treat The compounds as herein described, in one embodiment, ment ofatherosclerosis and its associated diseases, such as for affect circulating, or in another embodiment, tissue levels of example, cardiovascular disorders, cerebrovascular disor leptin. In one embodiment, the term levels of leptin refers to 25 ders, peripheral vascular disorders, intestinal vascular disor the serum level of leptin. As contemplated herein, the com ders, or combinations thereof. pounds of the present invention have an effect on leptin in In one embodiment cardiovascular disorders comprise of vitro and in vivo. Leptin levels can be measured by methods hypertention (HTN), coronary artery disease (CAD) or myo known to one skilled in the art, for example by commercially cardial perfusion. In another embodiment this invention pro available ELISA kits. In addition, Leptin levels may be deter 30 vides methods of use of the SARM compounds as herein mined in in vitro assays, or in in Vivo assays, by any method described for promoting aortic Smooth muscle cell prolifera known to a person skilled in the art. tion. In another embodiment this invention provides methods Since leptin is implicated in controlling appetite, weight of use of the compounds as herein described for treating loss, food intake, and energy expenditure, modulating and/or arteriosclerosis. In another embodiment this invention pro controlling the levels of leptin is a useful therapeutic 35 vides methods of use of the compounds as herein described approach in treating preventing, inhibiting or reducing the for lowering blood pressure. In another embodiment this incidence of obesity in subjects suffering from obesity. invention provides methods of use of the compounds as Modulating the level of leptin can result in a loss of appetite, herein described for treating cardiac diseases and disorders a reduction of food intake, and an increase in energy expen comprising cardiomyopathy, cardiac dysfunctions such as diture in the subject, and thus may contribute to the control 40 myocardial infarction, cardiac hypertrophy and cognitive and treatment of obesity. heart failure. In another embodiment this invention provides The term “obesity' is defined, in one embodiment, as an methods of use of the compounds as herein described for increase in body weight beyond the limitation of skeletal and cardioprotection comprising cardioprotection in insulin physical requirement, as the result of excessive accumulation resistance; treating diabetes type I and II, metabolic Syn offat in the body. 45 drome, syndrome X and/or high blood pressure. The term “obesity-associated metabolic disorder” refers, In one embodiment, the invention provides a method of in one embodiment, to a disorder which results from, is a treating, preventing, reducing the risk of mortality from car consequence of, is exacerbated by or is secondary to obesity. diovascular and/or cerebrovascular disease in a Subject, com Non-limiting examples of Such a disorder are osteoarthritis, prising administering a compound of formula (I) or its pro Type II diabetes mellitus, increased blood pressure, stroke, 50 drug, ester, analog, isomer, metabolite, derivative, and heart disease. pharmaceutically acceptable salt, pharmaceutical product, Cholesterol, triacylglycerol and other lipids are trans polymorph, crystal, impurity, N-oxide, hydrate or any com ported in body fluids by lipoproteins which may be classified bination thereof, or a pharmaceutical composition compris according to their density, for example, the very low density ing the same. In one embodiment, the compound is charac lipoproteins (VLDL), intermediate density lipoproteins 55 terized by the structure of formula (I). (IDL), low density lipoproteins (LDL) and high density lipo In one embodiment, compounds of formulae I reduce LDL proteins (HDL). and total cholesterol levels. In another embodiment the com It has been shown that high levels of LDL-Cholesterol in pound of formula (I) reduces LDL and total cholesterol levels the blood correlate with atherosclerosis which is a progres in a subject. sive disease characterized in part by sedimentation of lipids in 60 In another embodiment, compounds of formulae I are co inner walls of arteries, particularly of coronary arteries. It has administered with HDL-elevating agents. In another embodi also been shown that a high blood level of LDL-Cholesterol ment, a compound of formula (I) is co-administered with an correlates with coronary heart disease. Also, a negative cor HDL-elevating agents. In another embodiment, HDL-elevat relation exists between blood levels of HDL cholesterol and ing agents include niacin. In another embodiment the HDL coronary heart disease. 65 elevating agents include fibrates including gemfibrozil The level of total cholesterol in blood, which is the sum of (Lopid), thiourea based gemfibrozil analogues, and fenofi HDL-Cholesterol, LDL-Cholesterol, VLDL-Cholesterol and brate (TriCor). In another embodiment, HDL-elevating US 8,426,465 B2 95 96 agents include statins. In another embodiment, HDL-elevat crystal, or any combination thereof, in an amount effective to ing agents include 1-hydroxyalkyl-3-phenylthiourea, and promote, increase or facilitate weight loss in the Subject. analogs thereof. In another embodiment, this invention relates to a method In one embodiment, this invention provides a method of of decreasing, Suppressing, inhibiting or reducing appetite of reducing circulating lipid levels in a Subject, said method 5 a Subject, comprising the step of administering to the Subject comprising administering a compound of formula I or its a compound as herein described and/or its analog, derivative, pharmaceutically acceptable salt, hydrate, N-oxide, or any isomer, metabolite, pharmaceutically acceptable salt, phar combination thereof, or a composition comprising the same. maceutical product, hydrate, N-oxide, prodrug, polymorph, In one embodiment, the subject suffers from atherosclerosis crystal, or any combination thereof, in an amount effective to and its associated diseases, premature aging, Alzheimer's 10 decrease, Suppress, inhibit or reduce the appetite of the Sub disease, stroke, toxic hepatitis, viral hepatitis, peripheral vas ject. cular insufficiency, renal disease, hyperglycemia, or any com In another embodiment, this invention relates to a method bination thereof. of altering the body composition of a subject, comprising the In one embodiment, this invention provides a method of step of administering to the Subject a compound as herein treating atherosclerosis and its associated diseases, such as, 15 described and/or its analog, derivative, isomer, metabolite, for example, cardiovascular disorders, cerebrovascular disor pharmaceutically acceptable salt, pharmaceutical product, ders, peripheral vascular disorders, or intestinal vascular dis hydrate, N-oxide, prodrug, polymorph, crystal, or any com orders in a Subject, the method comprising the step of admin bination thereof, in an amount effective to alter the body istering to the Subject compound of formula I or its composition of the Subject. In one embodiment, altering the pharmaceutically acceptable salt, hydrate, N-oxide, or any body composition comprises altering the lean body mass, the combination thereof, or a composition comprising the same. fat free body mass of the subject, or a combination thereof. The method may further comprise co-administration, Subse In another embodiment, this invention relates to a method quent or prior administration with an agent or agents, which 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 25 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 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 30 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, 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 35 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 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 40 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” 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 45 treat the obesity-associated metabolic disorder in the subject. blood pressure can cause blood vessel changes in the back of In another embodiment, this invention relates to a method the eye, thickening of the heart muscle, kidney failure, and of preventing, Suppressing, inhibiting or reducing an obesity brain damage. associated metabolic disorder in a subject, comprising the The term “stroke refers, in other embodiments, to damage step of administering to the Subject a compound as herein to nerve cells in the brain due to insufficient blood supply 50 described and/or its analog, derivative, isomer, metabolite, often caused by a bursting blood vessel or a blood clot. The pharmaceutically acceptable salt, pharmaceutical product, term “heart disease', in other embodiments, refers to a mal hydrate, N-oxide, prodrug, polymorph, crystal, or any com function in the heart normal function and activity, including bination thereof, in an amount effective to prevent, Suppress, heart failure. inhibit or reduce the obesity-associated metabolic disorder in In addition, androgens have recently been shown to be 55 the subject. involved in commitment of mesenchymal pluripotent cells In one embodiment, the obesity-associated metabolic dis into myogenic lineage and to block differentiation into adi order is hypertension. In another embodiment, the disorder is pogenic lineage (Singh et al., Endocrinology, Jul. 24, 2003). osteoarthritis. In another embodiment, the disorder is Type II Accordingly, the compounds can be useful in methods of diabetes mellitus. In another embodiment, the disorder is blocking adipogenesis, and/or altering stem cell differentia 60 increased blood pressure. In another embodiment, the disor tion, as described herein. der is stroke. In another embodiment, the disorder is heart In another embodiment, this invention relates to a method disease. of promoting, increasing or facilitating weight loss in a Sub In another embodiment, this invention relates to a method ject, comprising the step of administering to the Subject a of decreasing, Suppressing, inhibiting or reducing adipogen compound as herein described and/or its analog, derivative, 65 esis in a subject, comprising the step of administering to the isomer, metabolite, pharmaceutically acceptable salt, phar Subject a compound as herein described and/or its analog, maceutical product, hydrate, N-oxide, prodrug, polymorph, derivative, isomer, metabolite, pharmaceutically acceptable US 8,426,465 B2 97 98 salt, pharmaceutical product, hydrate, N-oxide, prodrug, dosis for many years. Eventually, all type I diabetic patients polymorph, crystal, or any combination thereof. require insulin therapy to maintain normoglycemia. In another embodiment, this invention relates to a method In one embodiment, this invention provides a method of of altering stem cell differentiation in a subject, comprising treating diabetes type II. Type II diabetes is characterized by the step of administering to the Subject a compound as herein insulin resistance and at Some stage in pathogenesis of the described and/or its analog, derivative, isomer, metabolite, disease, a relative deficiency of insulin secretion. In absolute pharmaceutically acceptable salt, pharmaceutical product, terms, the plasma insulin concentration (both fasting and hydrate, N-oxide, prodrug, polymorph, crystal, or any com meal-stimulated) usually is increased, although “relative' to bination thereof, in an amount effective to alter stem cell the severity of insulin resistance, the plasma insulin concen differentiation in the subject. 10 tration is insufficient to maintain normal glucose homeosta In one embodiment, the compounds as herein described are sis. With time, however, there is progressive beta cell failure useful in a) treating, preventing, Suppressing, inhibiting, or and absolute insulin deficiency ensues. Most individuals with reducing obesity; b) promoting, increasing or facilitating type II diabetes exhibit intra abdominal (visceral) obesity, weight loss; c) decreasing, Suppressing, inhibiting or reduc fatty liver, which is closely related to the presence of insulin ing appetite; d) altering the body composition; e) altering lean 15 resistance. The patient's liver becomes insulin resistant and body mass or fat free body mass; converting fat to lean glycogen breakdown is uncontrolled and the result is muscle; g) treating, preventing, Suppressing, inhibiting, or increased and unphysiological glucose delivery to the blood reducing an obesity-associated metabolic disorder, for stream. The liver generated cholesterol and VLDL particles is example hypertension, osteoarthritis, diabetes mellitus, also uncontrolled. In addition, hypertension, dyslipidemia maturity onset diabetes of the young (MODY), increased (high triglyceride and low HDL-cholesterol levels; postpran blood pressure, stroke, or heart disease; h) decreasing, Sup dial hyperlipemia), and elevated PAI-1 levels often are pressing, inhibiting or reducing adipogenesis: i) altering stem present in these individuals. This clustering of abnormalities cell differentiation; and/orj) altering the level of leptin. is referred to as the “insulin resistance syndrome', or the In one embodiment, the compounds as herein described “metabolic syndrome' or obesity related disorders. Because find utility in treating or halting the progression of, or treating 25 of these abnormalities, patients with type II diabetes are at symptoms of diabetes. In another embodiment, the com increased risk of developing macrovascular complications pounds as herein described are useful in treating co-morbidi Such as myocardial infarction and stroke. ties related to diabetes. These conditions include: hyperten In one embodiment, this invention provides a method of sion (HTN), cerebrovascular disease, atherosclerotic treating diabetic nephropathy. Diabetic nephropathy is a com coronary artery disease, macular degeneration, diabetic ret 30 plication of diabetes that evolves early, typically before clini inopathy (eye disease) and blindness, cataracts-systemic cal diagnosis of diabetes is made. The earliest clinical evi inflammation (characterized by elevation of inflammatory dence of nephropathy is the appearance of low but abnormal markers such as erythrocyte sedimentation rate or C-reactive levels (>30 mg/day or 20 lug/min) of albumin in the urine protein), birth defects, pregnancy related diabetes, pre-ec (microalbuminuria), followed by albuminuria (>300 mg/24h clampsia and hypertension in pregnancy, kidney disease (re 35 or 200 ug/min) that develops over a period of 10-15 years. In nal insufficiency, renal failure etc.), nerve disease (diabetic patients with type 1 diabetes, diabetic hypertension typically neuropathy), Superficial and systemic fungal infections, con becomes manifest early on, by the time that patients develop gestive heart failure, gout/hyperuricemia, obesity, hypertrig microalbuminuria. Once overt nephropathy occurs, the glom lyceridemia, hypercholesterolemia, fatty liver disease (non erular filtration rate (GFR) falls over a course of times, which alcoholic steatohepatitis, or NASH), and diabetes-related 40 may be several years, resulting in End Stage Renal Disease skin diseases such as Necrobiosis Lipoidica Diabeticorum (ESRD) in diabetic individuals. (NLD), Blisters of diabetes (Bullosis Diabeticorum), Erup In one embodiment, this invention provides a method of tive Xanthomatosis, Digital Sclerosis, Disseminated Granu treating diabetic neuropathy. Diabetic neuropathy is a family loma Annulare, and Acanthosis Nigricans. of nerve disorders caused by diabetes. Diabetic neuropathies In one embodiment this invention provides a method of 45 cause numbness and sometimes pain and weakness in the treating, Suppressing, inhibiting or reducing the incidence of hands, arms, feet, and legs. Neurologic problems in diabetes (a) diabetes type I; (b) diabetes type (c) glucose intolerance; may occur in every organ system, including the digestive (d) hyperinsulinemia; (e) insulin resistance (f) nephropathy; tract, heart, and genitalia. Diabetic neuropathies are classified (g) diabetic neuropathy: (h) diabetic retinopathy (i) fatty liver as peripheral, autonomic, proximal, and focal. Peripheral conditions () MODY and (k) cardiovascular disease in a 50 neuropathy causes pain or loss offeeling in the toes, feet, legs, human Subject, comprising the step of administering to said hands, and arms. Autonomic neuropathy causes changes in Subject a compound of formula I. digestion, bowel and bladder function, sexual response, and In some embodiments, the compounds as herein described perspiration and can also affect the nerves that serve the heart and/or compositions comprising the same may be used for and control blood pressure. Proximal neuropathy causes pain applications in, or treating diseases or conditions associated 55 in the thighs, hips, or buttocks and leads to weakness in the with a Subject having diabetes. In one embodiment, the Sub legs. Focal neuropathy results in the Sudden weakness of one ject for whom treatment is sought via the methods of this nerve, or a group of nerves, causing muscle weakness or pain. invention is one with diabetes type I. Type I diabetes is char Any nerve in the body may be affected. acterized by autoimmune destruction of pancreatic beta-cells. In one embodiment, this invention provides a method of Markers of immune destruction of the beta-cell are present at 60 treating diabetic retinopathy. The effect of diabetes on the eye the time of diagnosis in 90% of individuals and include anti is called diabetic retinopathy. Patients with diabetes are more bodies to the islet cell (ICAS), to glutamic acid decarboxylase likely to develop eye problems such as cataracts and glau (GAD), and to insulin (IAAS). While this form of diabetes coma. The affect of diabetic retinopathy on vision varies usually occurs in children and adolescents, it can occurat any widely, depending on the stage of the disease. Some common age. Younger individuals typically have a rapid rate of beta 65 symptoms of diabetic retinopathy are blurred vision (this is cell destruction and present with ketoacidosis, while adults often linked to blood sugar levels), floaters and flashes and often maintain Sufficient insulin Secretion to prevent ketoaci Sudden loss of vision. US 8,426,465 B2 99 100 In one embodiment, the subject for whom treatment is I or its isomer, pharmaceutically acceptable salt, pharmaceu sought via the methods of this invention is one with glucose tical product, hydrate, N-oxide, or any combination thereof. intolerance. Glucose intolerance is a pre-diabetic state in In one embodiment, this invention provides a method of which the blood glucose is higher than normal but not high treating insulin resistance in a human Subject, comprising the enough to warrant the diagnosis of diabetes. step of administering to said Subject the compound of formula In one embodiment, the subject for whom treatment is I or its isomer, pharmaceutically acceptable salt, pharmaceu sought via the methods of this invention is one with hyperin tical product, hydrate, N-oxide, or any combination thereof. Sulinemia. Hyperinsulinemia is a condition, which in some In one embodiment, this invention provides a method of embodiments, serves as an indicator for underlying malfunc treating diabetic nephropathy in a human Subject, comprising tion of the pancreas resulting in the secretion of excessive 10 the step of administering to said subject a selective androgen amounts of insulin. One of the most common causes of hyper receptor modulator compound of formula (I) or its isomer, insulinemia is insulin resistance, a condition in which cells in pharmaceutically acceptable salt, pharmaceutical product, the body become resistant to insulin activity resulting in hydrate, N-oxide, or any combination thereof. pancreatic compensation by increased insulin production. In one embodiment, this invention provides a method of Hyperinsulinemia is associated with type II diabetes. 15 treating diabetic neuropathy in a human Subject, comprising In one embodiment, the subject for whom treatment is the step of administering to said subject compound of formula sought via the methods of this invention is one with insulin (I) or its isomer, pharmaceutically acceptable salt, pharma resistance. Insulin resistance is a condition in which normal ceutical product, hydrate, N-oxide, or any combination amounts of insulin are inadequate to produce a normal insulin thereof. response from fat, muscle and liver cells. Insulin resistance in In one embodiment, this invention provides a method of fat cells results in hydrolysis of stored triglycerides, which treating diabetic retinopathy in a human Subject, comprising elevates free fatty acids in the blood plasma. Insulin resis the step of administering to said Subject a compound of for tance in muscle reduces glucose uptake whereas insulin resis mula (I) or its isomer, pharmaceutically acceptable salt, phar tance in liver reduces glucose storage, with both effects Serv maceutical product, hydrate, N-oxide, or any combination ing to elevate blood glucose. High plasma levels of insulin 25 thereof. and glucose due to insulin resistance often leads to the meta In one embodiment, this invention provides a method of bolic syndrome and type II diabetes. treating fatty liver conditions in a human Subject, comprising Diabetes and the liver obesity is typically associated with the step of administering to said subject a selective androgen elevated levels of free fatty acid (FFAs) that promote lipid receptor modulator compound of formula (I) or its isomer, accumulation and insulin resistance in target tissues, i.e. 30 pharmaceutically acceptable salt, pharmaceutical product, reduced action of insulin primarily in skeletal muscle and hydrate, N-oxide, or any combination thereof. liver. A prominent role of insulin is to reduce glucose output In one embodiment, this invention provides a method of from the liver. FFAs stimulate hepatic gluconeogenesis which treating vascular disease in a human Subject, comprising the per se does not lead to increased hepatic glucose output as step of administering to said Subject a compound of formula long as it is paralleled by a decrease in hepatic glycogenoly 35 (I) or its isomer, pharmaceutically acceptable salt, pharma sis, a compensatory process referred to as “hepatic autoregu ceutical product, hydrate, N-oxide, or any combination lation’. FFAs stimulate insulin secretion and insulin blocks thereof. glycogenolysis in part by inhibiting secretion of glucagon, an In one embodiment this invention provides a method fora) inducer of glycogenolysis. However, long-term elevated lev treating, preventing, Suppressing inhibiting atherosclerosis b) els of FFAs leads to hepatic insulin resistance and thus break 40 treating, preventing, Suppressing inhibiting liver damage due down of hepatic autoregulation, resulting in increased hepatic to fat deposits comprising the step of administering to the glucose production and development of type II diabetes. Fatty Subject a compound as described herein and/or its analog, liver and hepatic insulin resistance is a major driving force derivative, isomer, metabolite, pharmaceutically acceptable behind hyperglycemia and type II diabetes. salt, pharmaceutical product, hydrate, N-oxide, prodrug, In one embodiment, this invention provides methods that 45 polymorph, crystal, or any combination thereof, or a compo inhibit (improve) the fatty liver, resulting in that the insulin sition comprising the same, in an amount effective to treat, resistance in the liver is inhibited (improved) and thereby prevent or inhibit atherosclerosis and liver damage due to fat solving the basic problem in type II diabetes. deposit. In another embodiment, the diabetes is a type I diabetes. In In one embodiment, the compound as described herein is another embodiment, the diabetes is a type II diabetes. 50 useful in a) treating, preventing, Suppressing, inhibiting, or In one embodiment, this invention provides a method of reducing atherosclerosis; b) treating, preventing, Suppressing treating Suppressing, inhibiting or reducing the incidence of inhibiting liver damage due to fat deposits. diabetes is a human Subject, comprising the step of adminis In one embodiment atherosclerosis refers to a slow, com tering to said Subject a compound of formula I or its isomer, plex disease that may begin with damage to the innermost pharmaceutically acceptable salt, pharmaceutical product, 55 layer of the artery. In another embodiment the causes of hydrate, N-oxide, or any combination thereof. damage to the arterial wall may includea) elevated levels of In another embodiment, the diabetes is a Type I diabetes. In cholesterol and in the blood; b) high blood pressure; c) another embodiment, the diabetes is a type II diabetes. tobacco Smoked) diabetes. In another embodiment, the con In one embodiment, this invention provides a method of dition is treatable in a smoker, despite the fact that tobacco treating a human Subject having glucose intolerance, com 60 Smoke may greatly worsen atherosclerosis and speed its prising the step of administering to said subject compound of growth in the coronary arteries, the aorta and arteries in the formula I or its isomer, pharmaceutically acceptable salt, legs. Similarly, in another embodiment, the methods of this pharmaceutical product, hydrate, N-oxide, or any combina invention may be useful in treating Subjects with a family tion thereof. history of premature cardiovascular disease who have an In one embodiment, this invention provides a method of 65 increased risk of atherosclerosis. treating hyperinsulinemia in a human Subject, comprising the In one embodiment, liver damage due to fat deposits refer step of administering to said Subject a compound of formula to the build-up of fat in the liver cells forming a fatty liver US 8,426,465 B2 101 102 which may be associated with or may lead to inflammation of psoriasis, psoriatic arthritis, Raynaud's phenomenon, reflex the liver. This can cause Scarring and hardening of the liver. sympathetic dystrophy syndrome, Reiter's syndrome, rheu When scarring becomes extensive, it is called cirrhosis. matoid arthritis, Scleroderma, Sjögrens syndrome, tendonitis In another embodiment the fat accumulates in the liver as or ulcerative colitis; c) preventing, treatment, or reversing an obesity. In another embodiment fatty liver is also associated autoimmune disease. with diabetes mellitus, high blood triglycerides, and the In one embodiment, the compound as described herein is heavy use of alcohol. In another embodiment fatty liver may useful in prevention of iatrogenic effects comprising acute occur with certain illnesses such as tuberculosis and malnu fatigue syndrome (post-Surgical) or androgen-deprivation trition, intestinal bypass Surgery for obesity, excess vitamin A therapy (ADT) induced side effects such as reduced muscle in the body, or the use of certain drugs such as valproic acid 10 mass, reduced muscle strength, frailty, hypogonadism, (trade names: Depakene/Depakote) and corticosteroids (cor osteoporosis, osteopenia, decreased BMD and/or decreased tisone, prednisone). Sometimes fatty liver occurs as a com bone mass. plication of pregnancy. In one embodiment, the compounds and/or compositions In one embodiment, Subjects with kidney disease, in par and/or methods of use thereofare for the treatment of human ticular male subjects with end-stage renal disease (ESRD) 15 Subjects, wherein, in one embodiment, the Subject is male, or Suffer from hypogonadism, with some having concomitant in another embodiment, the subject is female. moderate to severe protein-energy malnutrition (PEM), In one embodiment, the methods of the present invention which leads to higher required doses of EPO, lower QOL comprise administering a compound of this invention as the scores, and higher mortality. Many have other symptoms sole active ingredient. However, also encompassed within the associated with hypogonadism, including fatigue, lack of scope of the present invention are methods for diabetes and apetite, muscle weakness, etc. In some embodiments, the related disorders, hormone therapy, dry eye, obesity, treating treatment methods of this invention are useful in treating prostate cancer, delaying the progression of prostate cancer, symptoms associated with hypogonadism, brought about in and for preventing and/or treating the recurrence of prostate the subject by the kidney disease or disorder. cancer, male contraception; treatment of osteoporosis, treat In one embodiment, diabetic nephropathy is a complica 25 ment of conditions associated with ADIF and for treatment tion of diabetes that evolves early, typically before clinical and/or prevention of chronic muscular wasting which com diagnosis of diabetes is made. The earliest clinical evidence prise administering the compounds in combination with one of nephropathy is the appearance of low but abnormal levels or more therapeutic agents. These agents include, but are not (>30 mg/day or 20 ng/min) of albumin in the urine (microal limited to: LHRH analogs, reversible antiandrogens, anties buminuria), followed by albuminuria (>300 mg/24 h or 200 30 trogens, anticancer drugs, 5-alpha reductase inhibitors, aro ng/min) that develops over a period of 10-15 years. In patients matase inhibitors, progestins, agents acting through other with type 1 diabetes, diabetic hypertension typically becomes nuclear hormone receptors, selective estrogen receptor manifest early on, by the time that patients develop microal modulators (SERM), progesterone, estrogen, PDE5 inhibi buminuria. Once overt nephropathy occurs, the glomerular tors, apomorphine, bisphosphonate, and one or more addi filtration rate (GFR) falls over a course of times, which may 35 tional SARMs. be several years, resulting in End Stage Renal Disease Thus, in one embodiment, the methods of the present (ESRD) in diabetic individuals. invention comprise administering the compound of this Hypertension is another comorbid factor for renal disease. invention in combination with diabetes drug Such as troglita In some embodiments, treatment of renal disease according to Zone, rosiglitaZone, and pioglitaZone. In another embodi the present invention may comprise concomitant treatment 40 ment, the methods of the present invention comprise admin with a compound of this invention and an agent which treats istering the compound in combination with an LHRH analog. hypertension. In another embodiment, the methods of the present invention Androgen-dependent conditions which may be treated comprise administering the compound, in combination with a with the compounds and/or compositions as herein described, reversible antiandrogen. In another embodiment, the methods comprising the methods of the present invention include 45 of the present invention comprise administering the com those conditions which are associated with aging. In one pound, in combination with an antiestrogen. In another embodiment, the compound as described herein is useful ina) embodiment, the methods of the present invention comprise Age-related functional decline (ARFD); b) reversal or pre administering the compound, incombination with an antican vention of ARFD; c) reversal or prevention of ARFD in eld cer drug. In another embodiment, the methods of the present erly d) reversal or prevention of ARFD-induced sarcopenia or 50 invention comprise administering the compound, in combi osteopenia; e) Andropause, andropausal vasomotor Symp nation with a 5-alpha reductase inhibitor. In another embodi toms, f) andropausal gynecomastia, muscle strength/func ment, the methods of the present invention comprise admin tion, g) bone strength/function; h) Anger: i) Asthenia; ) istering the compound, in combination with an aromatase Chronic fatigue syndrome; k) Cognitive impairment; and/or inhibitor. In another embodiment, the methods of the present l) improving cognitive function. 55 invention comprise administering the compound, in combi In one embodiment, the compound as described herein is nation with a progestin. In another embodiment, the methods useful in treating inflammation and related disorders such as: of the present invention comprise administering the com a) prevention, treatment, or reversal of arthritis; b) prevention, pound, in combination with an agent acting through other treatment, or reveral of an arthritic condition such as Behcet’s nuclear hormone receptors. In another embodiment, the disease (autoimmune vasculitis), bursitis, calcium pyrophos 60 methods of the present invention comprise administering the phate dihydrate crystal (CPPD), deposition disease (or compound, in combination with a selective estrogen receptor pseudogout), carpal tunnel syndrome, connective tissue dis modulators (SERM). In another embodiment, the methods of orders, Crohn's dieases, Ehlers-Danlos syndrome (EDS), the present invention comprise administering the compound, fibromyalgia, gout, infectious arthritis, inflammatory bowel in combination with a progesterone. In another embodiment, disease (IBD), juvenile arthritis, systemic lupus erythemato 65 the methods of the present invention comprise administering SuS (SLE), Lyme’s disease, Marfan syndrome, myositis, the compound, in combination with an estrogen. In another osteoarthritis, polyarteritis nodosa, polymyalgia rheumatica, embodiment, the methods of the present invention comprise US 8,426,465 B2 103 104 administering the compound, in combination with a PDE5 -continued inhibitor. In another embodiment, the methods of the present invention comprise administering the compound, in combi nation with apomorphine. In another embodiment, the meth N H ods of the present invention comprise administering the com pound, in combination with a bisphosphonate. In another embodiment, the methods of the present invention comprise administering the compound, in combination with one or more additional SARMs. In some embodiments, the methods of the present invention comprise combined preparations 10 comprising the compound and an agent as described herein (2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid above. In some embodiments, the combined preparations can be varied, e.g., in order to cope with the needs of a patient D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline subpopulation to be treated or the needs of the single patient 15 which different needs can be due to the particular disease, solution was diluted with acetone (71 mL). An acetone solu severity of the disease, age, sex, or body weight as can be tion (71 mL) of metacrylolyl chloride (13.56 g., 0.13 mol) and readily determined by a person skilled in the art. In some 2N NaOH solution (71 mL) were simultaneously added over embodiments, the methods of the present invention comprise 40 minto the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11° C. during the addition of personalized medicine methods which treat the needs of a the metacrylolyl chloride. After stirring (3h, room tempera single patient. In one embodiment, different needs can be due ture), the mixture was evaporated in vacuo at a temperature at to the particular disease, severity of the disease, the overall 35-45° C. to remove acetone. The resulting solution was medical state of a patient, or the age of the patient. In some washed with ethyl ether and was acidified to pH 2 with con embodiments, personalized medicine is the application of centrated HC1. The acidic mixture was saturated with NaCl genomic data to better target the delivery of medical interven 25 and was extracted with EtOAc (100 mLX3). The combined tions. Methods of personalized medicine, in some embodi extracts were dried over NaSO filtered through Celite, and ments, serve as a tool in the discovery and clinical testing of evaporated in vacuo to give the crude product as a colorless new products of the present invention. In one embodiment, oil. Recrystallization of the oil from ethyl ether and hexanes personalized medicine involves the application of clinically afforded 16.2 (68%) of the desired compound as colorless useful diagnostic tools that may help determine a patients 30 crystals: mp 102-103°C. (lit. 214 mp 102.5-103.5°C.); the predisposition to a particular disease or condition. In some NMR spectrum of this compound demonstrated the existence embodiments, personalized medicine is a comprehensive of two rotamers of the title compound. "H NMR (300 MHz, approach utilizing molecular analysis of both patients and DMSO-d) & 5.28(s) and 5.15 (s) for the first rotamer, 5.15 (s) healthy individuals to guide decisions throughout all stages of and 5.03 (s) for the second rotamer (totally 2H for both the discovery and development of pharmaceuticals and diag 35 rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24 nostics; and applying this knowledge in clinical practice for a 4.20 (m) for the second rotamer (totally 1H for both rotamers, more efficient delivery of accurate and quality healthcare CH at the chiral center), 3.57-3.38 (m, 2H, CH), 2.27-2.12 through improved prevention, diagnosis, treatment, and (1H, CH), 1.97-1.72 (m, 6H, CH, CH, Me); C NMR (75 monitoring methods. 40 MHz, DMSO-d) & for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, It is to be understood that any use of any of the compounds 170.0, 1416, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7: IR (KBr) as herein described may be used in the treatment of any 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, disease, disorder or condition as described herein, and repre 1459, 1369, 1348, 1178 cm; C+80° (c=1, MeOH): sents an embodiment of this invention. Anal. Calcd. for CHNO: C, 59.00; H, 7.15; N, 7.65. The following examples are presented in order to more 45 Found: C, 59.13; H, 7.19; N, 7.61. fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention. 50 EXPERIMENTAL SECTION
Example 1 55 Synthesis of (S) Enantiomer of Compound of Formula I (FIGS. 1A-1L) (3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyr rolo2.1-c1.4oxazine-1,4-dione 60 A solution of NBS (23.5g, 0.132 mol) in 100 mL of DMF C was added dropwise to a stirred solution of the (methyl acryloyl)-pyrrolidine (16.1 g, 88 mmol) in 70 mL of DMF -- Cy"X -e-2NNaOHA acetone O N H O-5°C. RT3 hrs under argon at room temperature, and the resulting mixture H 65 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 temperature, filtered, and US 8,426,465 B2 105 106 dried to give 18.6 (81%) (smaller weight when dried -34%) Synthesis of (2R)-3-Bromo-N-4-cyano-3-(trifluo of the title compound as a yellow solid: mp 152-154°C. (lit. romethyl)phenyl-2-hydroxy-2-methylpropanamide 214 mp 107-109° C. for the S-isomer); H NMR (300 MHz, DMSO-d) & 4.69 (dd, J–9.6 Hz, J=6.7 Hz, 1H, CH at the Thionyl chloride (46.02 g, 0.39 mol) was added dropwise chiral center), 4.02 (d.J=11.4 Hz, 1H, CHH), 3.86 (d. J=11.4 to a cooled solution (less than 4°C.) of R-18 (51.13 g, 0.28 HZ, 1H, CHH), 3.53-3.24 (m, 4H, CH), 2.30-2.20 (m. 1H, mol) in 300 mL of THF under an argon atmosphere. The CH), 2.04-1.72 (m, 3H, CH, and CH), 1.56 (s. 2H, Me); 'C resulting mixture was stirred for 3 hunder the same condition. NMR (75 MHz, DMSO-d) & 167.3, 163.1, 83.9, 57.2, 45.4, To this was added EtN (39.14g, 0.39 mol) and stirred for 20 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474, 1745 (C=O), 1687 min under the same condition. After 20 min, 5-amino-2- (C=O), 1448, 1377, 1360, 1308, 1227, 1159, 1062 cm; 10 cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF C+124.5° (c=1.3, chloroform); Anal. Calcd. for were added and then the mixture was allowed to stir overnight CHBrNO: C, 41.24; H, 4.61; N, 5.34. Found: C, 41.46; H, at room temperature. The solvent was removed under reduced 4.64; N, 5.32. pressure to give a solid which was treated with 300 mL of 15 HO, extracted with EtOAc (2x400 mL). The combined
organic extracts were washed with saturated NaHCO solu tion (2x300 mL) and brine (300 mL). The organic layer was dried over MgSO and concentrated under reduced pressure to give a solid which was purified from column chromatog raphy using CH.Cl/EtOAc (80:20) to give a solid. This solid was recrystallized from CHCl2/hexane to give 55.8 g. (R)-3-bromo-2-hydroxy (73.9%) of (2R)-3-bromo-N-4-cyano-3-(trifluoromethyl) 2-methylpropanoic acid phenyl-2-hydroxy-2-methylpropanamide (R-18) as a light yellow solid. 25 H NMR (CDC1/TMS) & 1.66 (s.3H, CH), 3.11 (s, 1H, (2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid OH), 3.63 (d. J=10.8 Hz, 1H, CH,), 4.05 (d. J=10.8 Hz, 1H, CH), 7.85 (d. J=8.4 Hz, 1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, A mixture of bromolactone (18.5g, 71 mmol) in 300 mL of 1H, ArH), 8.12 (d. J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH). 24% HBr was heated at reflux for 1 h. The resulting solution Calculated Mass: 349.99, M-H 349.0. M.p.: 124-126° C. was diluted with brine (200 mL), and was extracted with ethyl 30 acetate (100 mLx4). The combined extracts were washed NC with saturated NaHCO, (100 mLX4). The aqueous solution was acidified with concentrated HCl to pH=1, which, in turn, was extracted with ethyl acetate (100 mLx4). The combined FC -- organic Solution was dried over Na2SO4, filtered through 35 Celite, and evaporated in vacuo to dryness. Recrystallization from toluene afforded 10.2 g (86%) of the desired compound R-19 as colorless crystals: mp 107-109° C. (lit. 214 mp 109-113° CN K2CO3 C. for the S-isomer); H NMR (300 MHz, DMSO-d) & 3.63 -e- (d. J=10.1 Hz, 1H, CHH), 3.52 (d. J=10.1 Hz, 1H, CHH), 40 2-propanol 1.35 (s.3H, Me); IR (KBr)3434 (OH), 3300-2500 (COOH), HO F 1730 (C=O), 1449, 1421, 1380, 1292, 1193, 1085 cm; NC CN C+10.5° (c=2.6, MeOH); Anal. Calcd. for CHBrO: C, O 26.25; H, 3.86. Found: C, 26.28; H, 3.75.
45 FC NH O F
Hd OH SOCI THF/O-59 C. Br -> Cl 50 Synthesis of (S)-N-(4-cyano-3-(trifluoromethyl)phe HC nyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2- (R)-3-bromo-2-hydroxy methylpropanamide 2-methylpropanoic acid R-18 A mixture of bromoamide (2R)-3-bromo-N-4-cyano-3- FC NH2 55 (trifluoromethyl)phenyl-2-hydroxy-2-methylpropanamide, EtN/RT R-19 (2.0 g, 5.70 mmol), anhydrous KCO (2.4 g, 17.1 -- -e- mmol) in 50 mL of acetone was heated to reflux for 2 hand NC then concentrated under reduced pressure to give a solid. The NC resulting solid was treated with 2-fluoro-4-hydroxybenzoni 60 trile (1.2g, 8.5 mmol) and anhydrous KCO (1.6 g., 11.4 mmol) in 50 mL of 2-propanol was heated to reflux for 3 hand then concentrated under reduced pressure to give a solid. The FC residue was treated with 100 mL of HO and then extracted with EtOAc (2x100 mL). The combined EtOAc extracts were 65 washed with 10% NaOH (4x100 mL) and brine, successively. The organic layer was dried over MgSO and then concen trated under reduced pressure to give an oil which was crys US 8,426,465 B2 107 108 tallized from CHCl2/hexane to give 0.5 g (23%) of (S)-N- (CLint) were calculated from 0-60 minutes based on first (4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3- order decay kinetics as a function of microsomal protein fluorophenoxy)-2-hydroxy-2-methylpropanamide aS a concentration. colorless solid. Permeability across Human, Intestinal Epithelial Monolay "H NMR (CDC1/TMS) & 1.63 (s, 3H, CH), 3.34 (bs, CS 1H-OH), 4.08 (d. J=9.17 Hz, 1H, CH), 4.50 (d. J=9.17 Hz, Permeability was measured in the Apical (pH 6.6) to Baso 1H, CH), 6.74-6.82 (m, 2H, ArH), 7.50-7.55 (m, 1H, ArH), lateral (pH 7.4) and Basolateral (pH 7.4) to Apical (pH 6.6) 7.81 (d. J=8.50 Hz, 1H, ArH), 7.97 (q, J=2.03, 8.50 Hz, 1H, directions across polarized, Caco-2 epithelial monolayers. ArH), 8.11 (d. J–2.03 Hz, 1H, ArH), 9.12 (s, 1H, NH). Cal Compound stocks (10 mM acetonitrile) were tested in the 10 study at a final concentration of 10 uM. The concentration of culated Mass: 407.1, M+Na"430.0. Mp: 124-125° C. drug in the receiver well was measured by LC/MS/MS using FIG. 1 schematically depicts some embodiments of syn a standard curve. The apparent permeability (Papp) for each thetic processes to obtain Compounds of formula I. compound was calculated, and values (A-B) were classified Example 2 as: Poor (Papp: <1), Low (Papp 1-2), Medium (Papp 2-10) or 15 High (Papp >10). Metabolic Stability of the Compounds of this Papp(x10 cm/sec)=Amount transported/ Invention (Area. Initial concentration*Time) Metabolic stability assays were performed in order to assess the in vitro half-life of compounds of formula I 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) Ci-initial concentration of drug (uM) was transformed to determine intrinsic clearance values, Cf-final concentration of drug (uM) which was then used to rank-order these compounds. In a Tassay time (seconds) separate experiment, permeability across human, intestinal 25 epithelial monolayers (Caco-2 cells) was used as a measure of Analytical Methods: intestinal permeability as well as an indicator of efflux poten All samples were analyzed on the MDS/Sciex API4000 Q tial. Caco-2 cells are often used as an early Screening Surro Trap system with electrospray ionization (ESI) in the positive gate for oral bioavailability. Microsomal half-life can be con or negative SIM mode, depending on the compounds. The Verted to in vitro clearance values as a means to predict 30 mobile phases were isocratic at 30% A (0.1% formic acid in hepatic intrinsic clearance. Intrinsic clearance is defined as water) and 70% B (0.1% formic acid in acetonitrile) with a the functional ability of the liver to metabolize a drug or other flow rate of 0.4 mL/min A Phenomenex Luna Phenyl-Hexyl compound. column (60x2.0 mm ID, 6L) was used. The injection volume Materials and Methods: was 10 ul. The total run time per sample was 1.6 to 3.0 minutes. Tamoxifen and diclofenac were used as internal Metabolic Stability Measured in Human Liver Microsomes: 35 standards for the positive and negative mode, respectively. Compounds of formula I in this study were incubated at a The percentage of parent drug compound remaining after final concentration of 0.6 uM. Microsome reactions were each time point was determined relative to the initial mea performed under either Phase I or “Phase I and II' conditions, Sured concentration at the beginning of the reaction (To min). where indicated. Compound stocks (10 mMACN) were ini Data Analysis: tially diluted to a concentration of 60 uM (in 60% ACN/HO) 40 resulting in a “working stock” solution of 100x. Human liver For half-life determination, data was fitted using GraphPad microsomes were utilized at a final concentration of 0.6 Prism, v 4.03 with the non-linear regression equation “one mg/ml. Duplicate wells were used for each time point (0, 6, phase exponential decay” defined as: 10, 30, and 60 minutes). Reactions were carried out at 37°C. Y-Spanexp(-KX)+Plateau(decays to Plateau with a in a shaking water bath, and the final concentration of solvent 45 first-order rate constant, K). was kept constant at 0.6%. The final volume for each reaction “-K is the slope of the curve. The halflife (minutes), T =ln was 600 ul, comprised of 368 ul of 100 mMKPO, buffer, (pH 0.6/-K and is therefore defined as -0.693/-K, or 0.693/K, 7.4); 12.6 ul of HLM (from a 20 mg/ml stock); 6 Jul of 100x a/k/a -0.693/slope). Intrinsic Clearance (ul/min/mg protein) “working stock' drug compound, and 126 ul of NRS “master is defined as: CL=0.693*(1/T2)*(ml incubation/mg pro mix' solution. At each time point, 100 ul of reaction was 50 tein)*1000; This equation can also be expressed as (K*1000)/ removed and added to a sample well containing 100 ul of microSome conc. ice-cold, 100% ACN (plus internal standards), to stop the Results: reaction. The NRS “master mix' is a solution of glucose 6-phosphate dehydrogenase, NADP", MgCl, and glucose TABLE 1 6-phosphate, prepared per manufacturers instructions (BD 55 Biosciences, Waltham, Mass.). Each 6.0 ml stock of NRS Metabolic Stability Measured in Human Liver Microsomes: “master mix' solution contains 3.8 ml H.O. 1.0 ml solution Compound HalfLife CLint HalfLife CL in “A” (Cat. #461220), and 0.2 ml solution “B” (Cat. #461200). having (minutes) (limin/mg) (minutes) (liminimg) Human liver microsomes (lot #0610279, Xenotech Corp.) formula Phase I only Phase I only Phase I+II Phase I+II represented a pool of 60 donors. 60 Samples were centrifuged at 3,000 rpm for 10 minutes at 4 I Stable <1 Stable <1 C. to remove debris and precipitated protein. Approximately 160 ul of Supernatant was Subsequently transferred to a new The results had shown that in vitro half-life as determined sample block for analysis. The concentration of parent drug from the microsomal assays demonstrated that compound of remaining in each well (expressed as percent remaining ver 65 formula (I) under both phase I and phase I/II metabolic con sus Time 0, at the beginning of the reaction) was measured ditions. As shown in Table 1, the compound did not exhibit an by LC/MS, as detailed below. The intrinsic clearance rates intrinsic clearance (CL) value greater than 10 ul/min/mg. It US 8,426,465 B2 109 110 is generally accepted that an in vitro CL value of less than Materials and Methods: 10 ul/min/mg protein represents favorable metabolic stability Male Sprague-Dawley rats weighing approximately 200 g of the test compound. Compound of formula I exhibited low were purchased from Harlan Bioproducts for Science (India clearance in human liver microsomes. Thus, Compound I napolis, Ind.). The animals were maintained on a 12-hlight/ exhibited a favorable metabolic stability profile. 5 dark cycle with food (7012C LM-485 Mouse/Rat Sterilizable Example 3 Diet, Harlan Teklad, Madison, Wis.) and water available ad libitum. The animal protocol was reviewed and approved by Androgen Receptor Binding Affinity of SARMs the Institutional Animal Care and Use Committee of the Uni versity of Tennessee. Materials and Methods: 10 The testarticle for this study was weighed and dissolved in The androgen receptor (AR) binding affinity of SARMs 10% DMSO (Fisher) diluted with PEG 300 (Acros Organics, was determined by using an in vitro competitive radioligand NJ) for preparation of the appropriate dosage concentrations. binding assay with 17C.-methyl-H-Mibolerone (HMIB, The animals were housed in groups of 2 to 3 animals percage. PerkinElmer), a high affinity AR ligand. Recombinant andro Animals were randomly assigned to one of seven groups gen receptor ligand binding domain (AR LBD) was com 15 bined with HIMIB in buffer A (10 mM Tris, pH 7.4, 1.6 mM consisting of 4 to 5 animals per group. Control groups (intact disodium EDTA, 0.26 M sucrose, 10 mM sodium molybdate, and ORX) were administered vehicle daily. Compound of 1 mM PMSF) to determine the equilibrium dissociation con formula (I) was administered via oral gavage at doses of 0.01, stant(K) of HIMIB. Protein was incubated with increasing 0.03, 0.1, 0.3, 0.75, and 1 mg/day to both intact and ORX concentrations of HIMIB with and without a high concen groups. Where appropriate, animals were castrated on day tration of unlabeled MIB in order to determine total and one of the study. Treatment with compound of formula (I) non-specific binding. Non-specific binding was then Sub began nine days post ORX and was administered daily via tracted from total binding to determine specific binding and oral gavage for fourteen days. graphed using SigmaPlot and non-linear regression for ligand The animals were sacrificed under anesthesia (ketamine? binding curve with one site Saturation to determine the K, of as Xyalzine, 87: 13 mg/kg) and body weights were recorded. In MIB (1.84 nM). In addition, the concentration of HIMIB addition, Ventral prostate, seminal vesicles, and levator ani required to saturate ARLBD was determined to be 4 nM. muscle were removed, individually weighed, normalized to Compound of formula (I) was tested in a range of concen body weight, and expressed as a percentage of intact control. trations from 10' to 10 Musing the conditions described Students T-test was used to compare individual dose groups above. Following incubation, plates were harvested with 30 to the intact control group. Significance was defined a priori GF/B filters on the Unifilter-96 Harvester (PerkinElmer) and washed three times with ice-cold buffer B (60 mM Tris, pH as a P-value <0.05. Ventral prostate and seminal vesicle 7.2). The filter plates were dried at RT, then 36 ul Micros weights were evaluated as a measure of androgenic activity, cint-O cocktail was added to each well and sealed with whereas levator ani muscle weight was evaluated as a mea TopSeal-A. The receptor bound radioligand was then deter sure of anabolic activity. Blood was collected from the mined with the TopCount(R) NXT Microplate Scintillation 35 abdominal aorta, centrifuged, and sera were frozen at-80°C. Counter (PerkinElmer). prior to determination of serum hormone levels. Serum The specific binding of HIMIB at each concentration of luteinizing hormone (LH) and follicle stimulating hormone SARM was determined by subtracting the nonspecific bind (FSH) concentrations were determined. ing of HIMIB (determined by incubating with 10 Munla Results: beled MIB), and expressed as a percentage of the specific 40 A series of dose-response studies in intact and castrated binding in the absence of each SARM. The concentration of rats in order to evaluate the potency and efficacy of compound SARM required to decrease the HIMIB binding by 60%, of formula (I) in both androgenic (prostate and seminal IC value, was determined by computer-fitting the data with vesicles) and anabolic (levator ani muscle) tissue was con SigmaPlot and non-linear regression with the standard curve ducted. In intact animals, compound of formula (I) treatment four parameter logistic curve. The equilibrium binding con 45 resulted in decreases in the weight of both prostate and semi stant (K) of each compound was then determined with the nal vesicles while the levator ani muscle weight was signifi following equation: cantly increased. Levator ani muscle weight following Com pound I treatment were 116%+7%, 134%+8%, 134%+21%, 134%+11%, 142%-10%, and 147%+10% of intact controls, where K is the equilibrium dissociation constant of HIMIB 50 following treatment with 0.01, 0.03, 0.1, 0.3, 0.75, and 1.0 (1.84 nM), and L is the concentration of HIMIB (4 nM). mg/day dose groups, respectively. The prostate weights were Results: 98%+21%, 99%-8%, 85%+18%, 98%+22%, 126%-17%, The binding affinity for Compound S-I was tested in the and 126%-17% of intact controls, following treatment with radioligand binding assay with ARLBD as the receptor with 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg/day, respectively. Simila K (nM)=3.05. Compound S-I had demonstrably enhanced 55 lry seminal vesicle weight was 115%+12%, 109%+17%, binding as compared to testosterone (3.05 nM, as compared 106%-13%, 121%.11%, 157%-5%, and 136%+3% of to 14.6 nM, respectively). intact controls following treatment with 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg/day, respectively. The results are graphically Example 4 presented in FIG. 2. These results are significant since current 60 androgen therapies are contraindicated in Some patient popu Preclinical Anabolic and Androgenic Pharmacology lations due to the proliferative androgenic effects in prostate of Compounds (I) in Intact and Castrate Male Rats and breast tissues. However, many patients in these popula tions could benefit from the anabolic actions of androgens in Anabolic and androgenic efficacy of Compound of formula muscle and bone. Since compound of formula (I) exhibited (I) administered by daily oral gavage were tested. The S-iso 65 tissue selective anabolic effects, it may be possible to treat mer of compound (I) was synthesized and tested as described patient groups in which androgens were contraindicated in herein the past. US 8,426,465 B2 111 112 In castrated, ORX animals, prostate weights following Results: Compound I treatment were 24%+4%,37%+9%, 50%+11%, The in vitro Screening results for potential drug-drug inter 88%+16%, 132%+16%, and 118-12% of intact controls fol actions (DDI) of SARM compound of formula I is presented lowing doses of 0, 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg/day, in Table 2: respectively. Similarly, seminal vesicle weights were 15%-2%, 25%.9%, 67%-20%, 113%6%, 155%.16%, TABLE 2 and 1.60%+7% of intact controls, following doses of 0, 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg/day, respectively. Significant CYP (P450) Inhibition. ICsa (LIM) increases were seen in levator ani muscle weights of in all Compound 3A4 2D6 2C19 2C9 1A2 dose groups, when compared to intact controls. The levator 10 animuscle weights were 71%+4%, 1.01%+15%, 125%+20%. I >2O >2O 1.9 1.1 >2O 126%+14%, 151.9%, and 143-17% of intact controls corre sponding to 0, 0.01, 0.03, 0.1, 0.3, 0.75, and 1.0 mg/day dose groups, respectively. The results are graphically presented in 15 Example 6 FIG. 3. One unexpected finding was that administration of only Pharmacokinetics of Compound (I) in Dogs 0.03 mg/day was able to fully restore levator ani muscle weight. In order to determine the pharmacokinetics of Compound Comparable administration of Testosterone propionate I, the compound was administered to beagle dogs perorally, (TP) and S-3-(4-Acetylaminophenoxy)-2-hydroxy-2-me and circulating plasma levels, terminal elimination half-life thyl-N-(4-nitro-3-trifluoromethylphenyl) propionamide, (t), total body clearance (CL), terminal Volume distribution maximally stimulated the levator ani muscle weight to 104% (VZ) and absolute bioavailability (F%) (Table 3) were deter and 10.1%, respectively, indicating the significantly enhanced mined Compound of formula I was rapidly and completely efficacy and potency of Compound S-I. Taken together, these 25 absorbed. data show that Compound I restores lost muscle mass, which in some embodiments, finds valuable application in patients TABLE 3 with sarcopenia or cachexia, or other wasting diseases or Compound I disorders. Additionally, the antiproliferative effects of com pound of formula (I) on the prostate may allow some patient 30 T12 (hr) 8.75 1.9S CL (mL/min kg) 1.85 OO6 populations, in which androgens are currently contraindi VZ (mL/kg) 1457 - 368 cated, access to anabolic agents. Emax values were obtained F 9% 109% and were 147%+10%, 188%-135%, and 147%+10% for prostate, seminal vesicles, and levator ani, respectively. The 35 EDs in prostate, seminal vesicles, and levator ani was 0.21+0.04, 0.2+0.04, and 0.03+0.01 mg/day, respectively. Example 7 These results are graphically depicted in FIG. 4. Serum Hormone Modulation by Compound (I) Example 5 40 In order to determine serumhormone modulation effects of In Vitro CYP Inhibition Assay Compound S-I, the compound was administered to animals as described in Example 4, and serum hormone levels were Materials and Methods: assessed by RIA. P450 enzyme inhibition was measured using human 45 Statisitically significant decreases in serum LH of intact cDNA-expressed CYP3A4, 2D6, 2C19, 2C9, and 1A2 animals were observed at doses of 0.3 mg/d or higher, with recombinant enzymes and fluorogenic Substrates (coumarin LH levels below the limit of quantitation (0.04 ng/mL) at the analogues) that are converted to fluorescent products. The two highest doses. A similar trend was observed in castrated analogues utilized for each isoenzyme are as follows: 7-Ben animals, with the first significant difference observed at a Zyloxy-trifluoromethylcoumarin, (BFC) for 3A4; 3-2-(N.N- 50 dose of 0.1 mg/d. No effects on FSH levels were observed in diethyl-N-methyl amino)ethyl 7-methoxy-4-methylcou intact animals. In ORX animals, a dose-dependent decrease marin, (AMMC) for 2D6: 3-Cyano-7-Ethoxycoumarin, in FSH levels to the level of intact controls was observed (CEC) for 2C19 and 1A2; and 7-Methoxy-4-trifluoro-meth (Table 4). ylcoumarin, (MFC) for 2C9. These substrates were utilized at a single concentration (either 50 uM or 75uM) at or near the 55 TABLE 4 apparent K, for each substrate. Fluorescence intensity was Serum LH and FSH levels from intact and castrated animals. measured using a Wallac 1420 Victor Multi-label Counter Follicle Model (Perkin-Elmer, Wellesley, Mass.), with an excitation Compound Luteinizing Hormone Stimulating Hormone wavelength filter of 405 nm, and an emission filter of 460 nm 60 (535 nm for the 3A4 and 2C9 substrates). Compound stocks S-I Intact ORX Intact ORX (10 mM in a 4:1 ratio of acetonitrile:DMSO) were tested in (mg/day) (ngi ml) (ng/ml) (ng/ml) (ngi ml) this study using an 8-point dose response curve in duplicate Vehicle 0.483 + 0.27 19.8 +4.27 5.40 + 1.00 64.1 + 12.7 O.O1 0.632 + 0.204 15.01 + 2.59° 5.48 + 1.15° 58.4 + 12.5° (ranging from 0.15uM-20.0LM). The concentration of aceto O.O3 0.401 + 0.187 11.9 + 2.05 - 5.30 + 0.48° 46.1 + 15.0° nitrile was kept constant at 0.4%, and the reaction was carried 65 O.1 0.458 + 0.373 3.3 + 1.13. 6.57 + 1.38 28.5 + 6.8. out at 37° C. for 30 minutes. Averages (minus background) O.3 0.173 + 0.121- 0.04 + 0.006: 7.13 + 1.50 10.3 + 1.3: and ICso values were calculated. US 8,426,465 B2 113 114 TABLE 4-continued step of administering an effective amount of the compound represented by the structure of formula (I): Serum LH and FSH levels from intact and castrated animals.
Follicle Compound Luteinizing Hormone Stimulating Hormone 5 I NC CN S-I Intact ORX Intact ORX O (mg/day) (ngi ml) (ng ml) (ng/ml) (ng ml) 0.75 What is claimed is: NC O CN 1. A pharmaceutical composition for contraception in a male Subject, comprising the compound represented by the 25 structure of formula (I): FC NH O F He at NC CN I O 30 or its isomer or pharmaceutically acceptable salt, to said Subject. FC NH O F 6. A method of treating, reducing the severity of reducing H3C oH the incidence of delaying the onset of or reducing pathogen esis of insulin resistance in a human Subject, comprising the or its isomer or pharmaceutically acceptable salt. 35 step of administering an effective amount of the compound 2. A method of hormone therapy comprising the step of represented by the structure of formula (I): contacting an androgen receptor of a subject with compound represented by the structure of formula (I): I 40 NC CN NC CN O O FC NH s O F FC NH s O F 2. 2 45 HC OH H3C OH or its isomer or pharmaceutically acceptable salt. or its isomer or pharmaceutically acceptable salt, to said 3. A method of treating, reducing the severity of reducing Subject. the incidence of delaying the onset of or reducing pathogen- 7. A method of treating, reducing the severity of reducing esis of diabetes in a human subject, comprising the step of 50 the incidence of delaying the onset of, or reducing pathogen administering an effective amount of the compound repre- esis of diseases associated with diabetes comprising the step sented by the structure of formula (I): of administering an effective amount of the compound repre sented by the structure of formula (I): I 55 NC CN I O NC CN O FC NH O F Hd OH 60 FC NH 2. O F HC OH or its isomer or pharmaceutically acceptable salt, to said Subject. or its isomer or pharmaceutically acceptable salt, to said 4. A method of treating, reducing the severity of reducing 65 Subject. the incidence of delaying the onset of or reducing pathogen- 8. A method of treating, reducing the severity of reducing esis of glucose intolerance in a human Subject, comprising the the incidence of delaying the onset of or reducing pathogen US 8,426,465 B2 115 116 esis of fatty liver conditions in a human Subject, comprising or its isomer or pharmaceutically acceptable salt, to the step of administering an effective amount of the com said subject. pound represented by the structure of formula (I): I 10. A method of treating a disease or condition of the eye of NC CN a Subject, comprising the step of administering an effective O 5 amount of a compound represented by the structure of for mula (I): FC NH O F Hd OH or its isomer or pharmaceutically acceptable salt, to said 10 NC CN Subject. O 9. A method of treating, reducing the severity of reducing the incidence of delaying the onset of or reducing pathogen FC NH e O F esis of cardiovascular disease in a human Subject, comprising 15 He at the step of administering an effective amount of the com pound represented by the structure of formula (I): I NC CN or its isomer or pharmaceutically acceptable salt, to said O Subject. 20 11. The method of claim 10, wherein the disease or condi FC tion is selected from the group consisting of Sjogren's Syn HC OH drome, or Xerophthalmia. k k k k k