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(10) Patent No.: US 8080682 B2 US008080682B2 (12) United States Patent (10) Patent No.: US 8,080,682 B2 Dalton et al. (45) Date of Patent: Dec. 20, 2011 (54) SUBSTITUTEDACYLANILIDES AND E. 9:2: 3. 3. METHODS OF USE THEREOF GB 1360001 3, 1970 JP 52-128329 1Of 1977 (75) Inventors: James T. Dalton, Lakeland, TN (US); JP 54-63047 12, 1980 Duane D. Miller, Germantown, TN (US) WO WO95/1977O 7, 1995 WO WO9805962 2, 1998 (73) Assignee: University of Tennessee Research W W g 3. 3. 2. Foundation, Knoxville, TN (US) WO WOO127622 4/2001 - WO WOO128990 4/2001 (*) Notice: Subject to any disclaimer, the term of this WO WOO1 34.563 5, 2001 patent is extended or adjusted under 35 WO WOO2 OO617 1, 2002 U.S.C. 154(b) by 647 days. WO WO O2, 16310 2, 2002 WO WOO3 O11302 2, 2003 WO WO 03/049675 6, 2003 (21) Appl. No.: 11/892,595 WO WOO3,065992 8, 2003 WO WOO3,O74471 9, 2003 (22) Filed: Aug. 24, 2007 WO WO 2004/064747 8, 2004 WO WO 2005/0372O1 4/2005 (65) Prior Publication Data WO WO 2005/120483 12/2005 WO WO 2007/027582 3, 2007 US 2008/OO76829 A1 Mar. 27, 2008 OTHER PUBLICATIONS Related U.S. Application Data Byrnet al. Solid-State Chemistry of Drugs, 2d, Chapter 11 Hydrates (60) Provisional application No. 60/839,665, filed on Aug. and Solvates, 233-247.* 24, 2006, provisional application No. 60/907,749, Morissette et al. Adv. Drug Delivery Rev. 2004, 56, 275-300.* filed on Apr. 16, 2007. I A.M. Rouhi, Chem. & Eng. News, Feb. 24, 2003, 81 (8), 32-35.* Carter et al., Chemotherapy of Cancer, second edition, John Wiley & (51) Int. Cl. Sons, N.Y., N.Y., 1981, pp. 362-365.* C07C 255/50 (2006.01) Kim, Juhyun et al., “The para substituent of S-3-(phenoxy)-2- A6K3I/275 (2006.01) hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)- propionamides is a major structural determinant of in vivo disposi (52) U.S. Cl. ........................................ 558/414: 514/522 tion and activity of selective androgen receptor modulators'. J. of (58) Field of Classification Search .................. 558/414: Pharmacology and Experimental Therapeutics, 315(1), 230-239 514/522 (2005). See application file for complete search history. .S. Appl. No. 09/935,044, filed Aug. 23, 2001, Dalton et al. Appl. No. 09/935,045, filed Aug. 23, 2001, Dalton et al. (56) References Cited . Appl. No. 09/644,970, filed Aug. 2, 2000, Dalton et al. Appl. No. 10/298,229, filed Nov. 28, 2002, Miller et al. U.S. PATENT DOCUMENTS . Appl. No. 10/270,232, filed Oct. 15, 2002, Dalton et al. 3,875,229 A 4, 1975 Gold . Appl. No. 10/277,108, filed Oct. 23, 2002, Dalton et al. 4,139,638 A 2f1979 Neri et al. Appl. No. 10/270,233, filed Oct. 15, 2002, Dalton et al. 4,191,775 A 3, 1980 Glen 4,239,776 A 12/1980 Glen et al. Appl. No. 10/270,732, filed Oct. 15, 2002, Dalton et al. 4,282,218 A 8, 1981 Glen et al. Appl. No. 10/371,213, filed Feb. 24, 2003, Dalton et al. 4,386,080 A 5/1983 Crossley et al. Appl. No. 10/371.209, filed Feb. 24, 2003, Dalton et al. 4,465,507 A 8, 1984 Konno et al. Appl. No. 10/371,211, filed Feb. 24, 2003, Dalton et al. 4,636,505 A 1, 1987 Tucker . Appl. No. 10/371,210, filed Feb. 24, 2003, Dalton et al. 4,880,839 A 11, 1989 Tucker . Appl. No. 10/359,270, filed Feb. 6, 2003, Steiner et al. 4,977,288 A 12/1990 Kassis et al. Appl. No. 10/310,150, filed Dec. 5, 2002, Steiner et al. 5,162,504 A 11/1992 Horoszewicz Howard Tucker and Glynne J. Chesterson, J. Med Chem. 1988, 31. 5,609,849 A 3/1997 Kung pp. 885-887, “Resolution of the Nonsteroidal Antiandrogen 4'- 5,656,651 A 8, 1997 Sovak et al. Cyano-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methyl-3'- 6,019,957 A 2/2000 Miller et al. 6,071,957 A 6, 2000 Miller et al. (trifluoromethyl)-propionanilide and the Determination of the Abso 6, 160,011 A 12/2000 Miller et al. lute Configuration of the Active Enantiomer'. 6,482,861 B2 11/2002 Miller et al. 6,492,554 B2 12/2002 Dalton et al. (Continued) 6,569,896 B2 5, 2003 Dalton et al. 6,838,484 B2 1/2005 Steiner et al. Primary Examiner — Shailendra Kumar 6,998,500 B2 2/2006 Dalton et al. (74) Attorney, Agent, or Firm — Mark S. Cohen: Pearl 7,026,500 B2 4/2006 Dalton et al. 7,705, 182 B2* 4/2010 Dalton et al. ................. 564,175 Cohen Zedek Latzer, LLP 2001/0012839 A1 8, 2001 Miller et al. 2002/0173495 A1 11/2002 Dalton et al. (57) ABSTRACT 2005, OO3811.0 A1 2/2005 Steiner et al. 2006/011 1441 A1 5, 2006 Dalton et al. This invention provides SARM compounds and uses thereof 2006, O183931 A1 8, 2006 Dalton et al. in treating a variety of diseases or conditions in a Subject, including, interalia, a muscle wasting disease and/or disorder FOREIGN PATENT DOCUMENTS or a bone-related disease and/or disorder. EP O 040932 12/1981 EP O 100 172 2, 1984 19 Claims, 15 Drawing Sheets US 8,080,682 B2 Page 2 OTHER PUBLICATIONS receptor agonist: 4-ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8- pyridono.5,6-g-quinoline (LG 121071). J. Med. Chem., 42: 210, D. McKillop, et al., "Enantioselective metabolism and 1999. pharmacokinetics of Casodex in the male rat', Xenobiotica, 1995, Rosen J. Day A. Jones TK, Jones ET, Nadzan AM, and Stein RB. vol. 25, No. 6, 623-634. Intracellular receptors and signal transducers and activators of tran Leonid Kirkovsky, et al., “I'I-Radionated Bicalutamide Analogs Scription Superfamilies: novel targets for Small-molecule drug dis as Potential Imaging Agents for Prostate Cancer', Poster Presenta covery. J. Med. Chem., 38: 4855, 1995. tion MEDI 155, 214th ACS National Meeting, Las Vegas, NV. Sep. Dalton JT. Mukherjee A. Zhu Z, Kirkovsky L, and Miller DD. Dis 7-11, 1997. Department of Pharmaceutical Sciences, University of covery of Nonsteroidal Androgens. Biochem. Biophys. Res. Tennessee, Memphis, TN38163. Comniun., 244(1): 1-4, 1998. David T. Baird and Anna F. Glasier, “Hormonal Contraception— Edwards JP, West SJ, Pooley CLF, Marschke KB, Farmer LJ, and Drug Therapy'. The New England Journal of Medicine, May 27, Jones TK. New nonsteroidal androgen receptor modulators based on 1993, pp. 1543-1549. 4-(trifluoromethyl)-2-(1H)-Pyrololidino.3.2-gquinolone. Bioorg. F.C. W. Wu, “Male Contraception: Current Status and Future Pros Med. Chem. Lett., 8: 745, 1998. pects”. Clinical Endocrinology, (1988), 29, pp. 443-465. Dalton JT, etal "Pharmacokinetics of Aminolevulinic Acid after Oral World Health Organisation Task Force on Methods for the Regulation and Intravenous Dosing in Dogs.” Drug Metabolism and Disposition, of Male Fertility, “Contraceptive efficacy of testosterone-induced 27 (4):432-435, 1999. azoospermia in normal men'. The Lancet, vol. 336, Oct. 20, 1990, pp. Yin D, et al “Key Structural Features of Nonsteroidal Ligands for 955-959and 1517-1518. Binding and Activation of the Androgen Receptor.” Molecular Phar C. G. Francisco, et al., “Long-acting contraceptive agents: macology, 63:211-223, 2003. testosterone esters of unsaturated acids', Steroids, Jan. 1990, vol. 55, Eliason et al., “High Throughput Fluorescence Polarization-Based Butterworths. Screening Assays for the Identification of Novel Nuclear Receptor John M. Hoberman and Charles E. Yesalis, “The History of Synthetic Ligands.” Abstracts of Papers, 223rd ACS National Meeting, Testosterone”, Scientific American, Feb. 1995, pp. 76-81. Orlando, FL, United States, (2002), Apr. 7, 2002. Leonid Kirkovsky, et al., “Approaches to Irreversible non-steroidal Berger et al., “Concepts and limitations in the application of chiral antiandrogens'. Department of Pharmaceutical Sciences, Uni radiolabeled antiandrogens, estrogens, or androgens as isotropic versity of Tennessee, 47th Southeast/51st Southwest Joint Regional scanning agents for the prostate'. Invest. Urol, (1975), 1391, 10-16. Meeting of the American Chemical Society, Memphis, TN, Nov. Yin D, et al "Pharmacology, Pharmacokinetics and Metabolism of 29-Dec. 1, 1995. Acetothiolutamide, A Novel Nonsteroidal Agonist for the Androgen David J. Handelsman, “Bridging the gender gap in contraception: Receptor.” Journal of Pharmacology and Experimental Therapeutics, another hurdle cleared” The Medical Journal of Australia, vol. 154, 304(3): 1323-1333, 2003. Feb. 18, 1996, pp. 230-233. Yin D, et al "Pharmacodynamics of Selective Androgen Receptor Edwards.JP. Higuchi RI, Winn DT. Pooley CLF, Caferro TR, Hamann Modulators.” Journal of Pharmacology and Experimental Therapeu LG, Zhi L. Marschke KB, Goldman ME, and Jones TK. Nonsteroidal tics, 304(3): 1334-1340, 2003. androgen receptor agonists based on 4-(trifluoromethyl)-2H-pyrano Gao, W., etal"Comparison of the Pharmacological Effects of a Novel 3, 2-gguinolin-2-one. Bioorg. Med. Chem. Lett., 9; 1003, 1999. Selective Androgen Receptor Modulator (SARM), the 5 (alpha}- Zhi L. Tegley CM, Marschke KB, and Jones TK. Switching androgen Reductase Inhibitor Finasteride, and the Antiandrogen receptor antagonists to agonists by modifying C-ring Substituents on Hydroxyflutamide in Intact Rats: New Approach for Benign Prostate piperidino.3.2-gquinolone. Bioorg. Med. Chem. Lett., 9; 1009, Hyperplasia (BPH).” Endocrinology, 145(12): 5420-5428, 2004. 1999. Chen J. etal"A Selective Androgen Receptor Modulator (SARM) for Higuchi RI, Edwards JP Caferro TR. Ringgenberg JD, Kong JW. Hormonal Male Contraception.” Journal of Pharmacology and Hamann LG, Arienti KL, Marschke KB, Davis RL, Farmer LJ, and Experimental Therapeutics, 312(2): 546-553, 2005.
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