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(12) United States Patent (10) Patent No.: US 9,096,639 B2 Klar Et Al

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(12) United States Patent (10) Patent No.: US 9,096,639 B2 Klar Et Al USOO9096639B2 (12) United States Patent (10) Patent No.: US 9,096,639 B2 Klar et al. (45) Date of Patent: Aug. 4, 2015 (54) 17-HYDROXY-17-PENTAFLUORETHYL- (56) References Cited ESTRA-4.9(10)-DIEN-11 ACYLOXYALKYLENE PHENYL U.S. PATENT DOCUMENTS DERIVATIVES, METHODS FOR THE 4,386,085 A 5/1983 Teutsch et al. PRODUCTION THEREOF AND USE 4,519,946 A 5, 1985 Teutsch et al. THEREOF FORTREATING DSEASES 4,609,651 A 9, 1986 Rohde et al. 4,634,695 A 1/1987 Torelli et al. 4,900,725 A 2f1990 Nioue et al. (75) Inventors: Ulrich Klar, Berlin (DE); Wolfgang 4,921,846 A 5/1990 Nedelec et al. Schwede, Glienicke (DE); Carsten 4.954,490 A 9, 1990 Cook et al. Moller, Berlin (DE); Andrea Rotgeri, 5,073,548 A 12/1991 Cook et al. 5,108,996 A 4, 1992 Claussner et al. Berlin (DE); Ursula Krenz, Leichlingen 5,272,140 A 12/1993 Loozen (DE) 5,407,928 A 4/1995 Kasch et al. 5,576,310 A 11/1996 Schubert et al. 5,693,628 A 12/1997 Schubert et al. (73) Assignee: Bayer Intellectual Property GmbH, 5,712.264 A 1/1998 Hamersma et al. Monheim (DE) 5,739,125 A 4/1998 Kasch et al. 5,986,115 A 11/1999 Bohlmann et al. 6,020,328 A 2/2000 Cook et al. (*) Notice: Subject to any disclaimer, the term of this 6,043,234. A 3/2000 Stöckemann et al. patent is extended or adjusted under 35 6,225,298 B1 5/2001 Spicer et al. U.S.C. 154(b) by 623 days. 6,316,432 B1 1 1/2001 Schwede et al. 6,476,079 B1 1 1/2002 Jukarainen et al. 6,503,895 B2 1/2003 Schwede et al. (21) Appl. No.: 13/384,332 6,806,263 B2 10/2004 Schwede et al. 6.825, 182 B2 11/2004 Ring et al. 6,861.415 B2 3/2005 Kim et al. (22) PCT Filed: Jul. 7, 2010 7,087,591 B2 8, 2006 Kim et al. 7,148,213 B2 12/2006 Schwede et al. 7,192,942 B2 3/2007 Grawe et al. (86). PCT No.: PCT/EP201 O/OO4148 7.550.451 B2 6/2009 Hillisch et al. S371 (c)(1), (Continued) (2), (4) Date: Jun. 4, 2012 FOREIGN PATENT DOCUMENTS (87) PCT Pub. No.: WO2011/009530 CA 2280041 C 8, 1998 PCT Pub. Date: Jan. 27, 2011 EP OO571 15 A2 4f1982 (Continued) (65) Prior Publication Data OTHER PUBLICATIONS US 2012/O232042 A1 Sep. 13, 2012 Fuhrmann etal. “Synthesis and Biological Activity of a Novel, highly Potent Progesterone Receptor Antiagonist.” J. Med. Chem... vol. 43. (30) Foreign Application Priority Data pp. 5010-5016 (2000). (Continued) Jul. 20, 2009 (DE) ......................... 10 2009 O34 368 Primary Examiner — Barbara P Badio (51) Int. Cl. (74) Attorney, Agent, or Firm — Karen B. King; Thomas C. A6 IK3I/56 (2006.01) Blankinship A6 IK3I/58 (2006.01) C07, II/00 (2006.01) C07. 4I/00 (2006.01) (57) ABSTRACT C07 L/00 (2006.01) The invention relates to 17-hydroxy-13-methyl-17-pen C07J 7/00 (2006.01) tafluoroethyl-11-acyloxyalkylenephenyl CO7 43/00 (2006.01) dodecahydrocyclopentaalphenanthren-3-one derivatives of A61 K3I/573 (2006.01) the formula I with progesterone-antagonizing action and to (52) U.S. Cl. processes for preparation thereof, to use thereof for treatment CPC .............. C07J I/0081 (2013.01); C07J 7/0085 and/or prophylaxis of disorders and to the use thereof for (2013.01); C07J 4 I/0044 (2013.01); C07J production of medicaments for treatment and/or prophylaxis 4I/0083 (2013.01); C07J 43/003 (2013.01); of disorders, especially of fibroids of the uterus (myomas, A61 K 3 1/573 (2013.01); A61 K 3 1/58 (2013.01) uterine leiomyomas), endometriosis, heavy menstrual bleeds, (58) Field of Classification Search meningiomas, hormone-dependent breast cancers and com CPC ... C07J 7/0085; C07J 41/0083: C07J 43/003; plaints associated with the menopause, or for fertility control A61K31/573; A61K31/58 and emergency contraception. USPC ................... 514/176, 179; 552/517,519,648 See application file for complete search history. 20 Claims, No Drawings US 9,096,639 B2 Page 2 (56) References Cited Kettel et al., “Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU486).”. Am J ObstetGynecol, vol. U.S. PATENT DOCUMENTS 178, No. 6, pp. 1151-1156 (Jun. 1998). Möller et al., “Investigational developments for the treatment of 7,799,770 B2 9, 2010 Grawe et al. progesterone-dependent diseases.” Expert Opin. Investig. Drugs. 7,910,573 B2 3/2011 Beckmann et al. vol. 17, No. 4, pp. 469-479 (2008). 8,053,426 B2 11/2011 Fuhrmann et al. Bagaria et al., Low-dose mifepristone in treatment of uterine 2001 OO16578 A1 8/2001 Spicer et al. leiomyoma: A randomised double-blind placebo-controlled clinical 2002/0045774 A1 4/2002 Schwede et al. trial. The Royal Australian and New Zealand College of Obstetricians 2002.0143000 A1 10/2002 Hegele-Hartung et al. and Gynaecologists, vol. 49, pp. 77-83 (2009). 2003, OO69434 A1 4/2003 Bohlmann et al. Murphy et al., “Regression of Uterine Leiomyomata in Response to 2003,019 1099 A1 10/2003 Bohlmann et al. the Antiprogesterone RU486,” J. Clin. Endocrinol. Metab., vol. 76, 2004.0006241 A1 1/2004 Grawe et al. No. 2, pp. 513-517 (1993). 2004/0048841 A1 3, 2004 Hoffmann et al. Bohl et al., “Molecular mechanics and X-ray crystal structure inves 2004/O157811 A1 8, 2004 Lichtner et al. tigations on conformations of 113 Substituted 4,9-dien-3-one ste 2005, 0080060 A1 4/2005 Schwede et al. roids.” J. Mol. Graphics, vol. 7, pp. 122-153 (Sep. 1989). 2005/0277769 A1 12/2005 Burton et al. Braga et al., “3.3 Crystal Polymorphism: Challenges at the Cross 2007/0105828 A1 5, 2007 Joshi et al. roads of Science and Technology. Making Crystals By Design 2009.0075989 A1 3/2009 Schwede et al. (Dario Braga and Fabrizia Grepioni eds., Wiley-VCHVerlag GmbH 2011 0112057 A1 5/2011 Fuhrmann et al. 2012fO149670 A1 6, 2012 Schwede et al. & Co. KgaA. Weinheim, Germany), pp. 293-314 (2007). 2012fO184515 A1 7, 2012 Klar et al. Cabriet al., “Polymorphisms and Patent, Market, and Legal Battles: 2012fO190660 A1 7, 2012 Klar et al. Cefdinir Case Study.” Organic Process Research & Devel., vol. 11, 2012fO258941 A1 10/2012 Klar et al. No. 1, pp. 64-72 (2007). 2012,0316145 A1 12/2012 Klar et al. Caira, “Crystalline Polymorphism of Organic Compounds.” Topics 2013, OOO5697 A1 1/2013 Schwede et al. in Current Chemistry, vol. 198, pp. 164-208 (1998). 2013,007 2464 A1 3/2013 Schwede et al. Davey, "Solvent Effects in Crystallization Processes.” Current Topics in Material Science, vol. 8, pp. 429-479. FOREIGN PATENT DOCUMENTS English Translation of Office Action for European App. No. 06 090 095 dated Jan. 16, 2007 (US 7,910,573 B2). EP O411733 B1 2, 1991 Braja, “Mifepristone (RU-486), the recently developed EP O6762O3 A1 10, 1995 antiprogesterone drug and tisanalogues. J. Indian Inst. Sci., vol. 81, EP 909764 A1 4f1999 pp. 287-298 (May-Jun. 2001). EP O970 103 B1 4/2002 U.S. Appl. No. 13/577,799, 371(c) date Sep. 21, 2012, published as EP 1862468 12/2007 US 2013-0005697. IN 978. MUM/2005 8, 2005 JP H11171774. A 6, 1999 Maibauer et al., “First human data for ZK 230211 (ZK-PRA), a new WO 96.03130 A1 2, 1996 progesterone receptor antagonist: a phase I clinical analysis of safety WO 96.15794 5, 1996 and pharmacokinetics in healthy postmenopausal women.” WO 9623503 A1 8, 1996 Abstracts-Poster Session IV, 29th Annual San Antonio Breast Cancer WO 98,05679 A2 2, 1998 Symposium, Dec. 14-17, 2006. WO 98.07740 2, 1998 Tellekson et al., “Strategies for Attacking and Defending Pharma WO 98.26783 A1 6, 1998 ceutical Patents: A Modern Take on The Art of War.” Int. Property WO 98.34947 A1 8, 1998 & Techn. Law Journal, vol. 17, No. 12, pp. 5-14 (Dec. 2005). WO 99.53924 A1 10, 1998 English Language Translation of EP0411733, 1991. WO 993.3855 7, 1999 English Language Translation of EP0676203, 1995. WO O147490 A1 T 2001 English Language Translation of WO 1998/026783, 1998. WO O2/32429 A2 4/2002 WO O3O45972 A1 6, 2003 English Language Abstract of JP H1 1171774, 1999. WO O3,O93292 11, 2003 Vippagunta et al., “Crystalline Solids.” Adv. Drug Delivery Reviews, WO 2004O14935 A1 2, 2004 vol. 48, pp. 3-26 (2001). WO 2006/010097 A2 1, 2006 Patani et al., "Bioisosterism: A Rational Approach in Drug Design.” WO 2008/O58767 A1 5, 2008 Chem. Rev., vol. 96, pp. 3147-3176 (1996). WO 2009 138186 A2 11/2009 Hazra, et al., “Mifepristone (RU-486), the Recently Developed ZA 97/7482 2, 1998 Antiprogesterone Drug and its Analogues.” J. Indian Inst. Sci, May Jun. 2001, 81:287-298. Van Geerstein et al., “Structure of the n-Butyl Acetate Solvate of OTHER PUBLICATIONS 11B-4-(Dimethylamino)phenyl-17B-hydroxy-17O-(1- Steinauer et al., “Systematic review of mifepristone for the treatment propynyl)estra-4.9-dien-3-one.” Acta Cryst., C42, pp. 1521-1523 ofuterine leiomyomata.” ObstetGynecol, vol. 103, No. 6, pp. 1331 (1986). U.S. Appl. No. 13/578,500 371(c) date Oct. 1, 2012, published as US 1336 (Jun. 2004). 2013-0072464. Chwalisz et al., “A randomized, controlled trial of asoprisnil, a novel U.S. Appl. No. 13/384,765,371(c) date Apr.
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