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(12) United States Patent (10) Patent No.: US 9.271,961 B2 Penning Et Al

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(12) United States Patent (10) Patent No.: US 9.271,961 B2 Penning Et Al US00927 1961 B2 (12) United States Patent (10) Patent No.: US 9.271,961 B2 Penning et al. (45) Date of Patent: Mar. 1, 2016 (54) BFUNCTIONAL AKR1C3 (56) References Cited INHIBITORS/ANDROGEN RECEPTOR MODULATORS AND METHODS OF USE U.S. PATENT DOCUMENTS THEREOF 2006/0235035 A1 10/2006 Hogberg et al. 2007/0129.433 A1 6/2007 Lardy et al. (71) Applicant: THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, FOREIGN PATENT DOCUMENTS Philadelphia, PA (US) FR 28.62964 B1 12/2006 (72) Inventors: Trevor M. Penning, Springfield, PA (US); Adegoke O. Adeniji, Drexel Hill, OTHER PUBLICATIONS PA (US); Michael C. Burns, Definition of prevent, Princeton University "About WordNet.” Philadelphia, PA (US); Jeffrey Winkler, WordNet. Princeton University. 2010. <http://wordnet.princeton. Wynnewood, PA (US); Barry Twenter, edud, accessed Sep. 18, 2012.* Philadelphia, PA (US) Flanders Prostate 1984, 5 (6), 621-629.* Dunning et al. Cancer Epidemiology, Biomarkers and Prevention (73) Assignee: The Trustees of the University of 1999, 8,843-854.* Pennsylvania, Philadelphia, PA (US) Day et al. Endocrine-Related Cancer 2008, 15, 665-692.* Loriotetal. Invest. New Drugs 2014, published on-line Apr. 27, 2014, (*) Notice: Subject to any disclaimer, the term of this pp. 1-10.* patent is extended or adjusted under 35 Khanim et al. British Journal of Cancer 2014, 110, 1506-1516. U.S.C. 154(b) by 0 days. Yin et al. Frontiers in Oncology 2014, vol. 4, article 159, 1-12.* Lovering et al. Cancer Research 2004, 64, 1802-1810.* Medivation Press Release Nov. 6, 2007. http://www. (21) Appl. No.: 14/050,937 medicalnewstoday.com/releases/87762.php, accessed Jul. 23, 2015.* (22) Filed: Oct. 10, 2013 Adeniji, et al., “Discovery of substituted 3-(phenylamino)benzoic acids as potent and selective inhibitors of type 517B-hydroxysteroid (65) Prior Publication Data dehydrogenase (AKR1C3).” Bioorganic & Medicinal Chemistry US 2014/O1 O7085A1 Apr. 17, 2014 Letters, 2011, 21: 1464-1468. Burczynski, et al., “Expression and Characterization of Four Recom Related U.S. Application Data binant Human Dihydrodiol Dehydrogenase Isoforms: Oxidation of trans-7,8-Dihrdroxy-7,8-dihydrobenzoapyrene to Activated (63) Continuation-in-part of application No. o-Quinone Metabolite Benzoa pyrene-7,8-dione”, Biochemistry, PCT/US2012/033199, filed on Apr. 12, 2012. 1998, 37; 6781-6790. Byrns, et al., “Type 5 17B-hydroxysteroid dehydrogenase? (60) Provisional application No. 61/475,091, filed on Apr. prostaglandin F synthase (AKR1C3): Role in breast cancer and inhi 13, 2011. bition by non-steroidal anti-inflammatory drug analogs.” Chem Biol Interact. Mar. 16, 2009, 178(1-3): 221-227 (Abstract). (51) Int. C. International Search Report and Written Opinion for PCT/US2012/ A6 IK3I/96 (2006.01) 033199 dated Sep. 21, 2012. CD7C 229/60 (2006.01) A6IP35/00 (2006.01) * cited by examiner A6 IK3I/405 (2006.01) A 6LX3L/95 (2006.01) Primary Examiner — Shengjun Wang A6 IK3I/205 (2006.01) Assistant Examiner — Irina Neagu A6 IK 45/06 (2006.01) (74) Attorney, Agent, or Firm — Saul Ewing LLP. Kathryn C07C 229/58 (2006.01) Doyle; Domingos J. Silva (52) U.S. C. CPC ............. A6 IK3I/405 (2013.01); A61 K3I/195 (57) ABSTRACT (2013.01); A61 K31/196 (2013.01); A61 K The invention includes compositions comprising selective 3 1/205 (2013.01); A61K 45/06 (2013.01); AKR1C3 inhibitors. The invention also includes composi C07C 229/58 (2013.01); C07C 229/60 tions comprising bifunctional AKR1C3 inhibitors and selec (2013.01) tive androgen receptor modulators. The invention further (58) Field of Classification Search includes methods of treatment using the compositions of the CPC ... C07C 229/58; C07C 229/60; A61 K31/196 invention. USPC ........... 514/567; 562/458, 454, 456, 457, 435 See application file for complete search history. 12 Claims, 42 Drawing Sheets U.S. Patent Mar. 1, 2016 Sheet 1 of 42 US 9.271,961 B2 Fig. 1 SIMS HSDs t-s Steroid (AKRs and SDRs) Steroic St. o St (inactive)s s Hormone N Structural Gene \ N NUCLEUS N 1. N- e - - - or - 11S U.S. Patent Mar. 1, 2016 Sheet 2 of 42 US 9.271,961 B2 Fig. 2 STEROD HORMONES O OH O O A- Androstenedione Testosterone O OH c AKR1c3 HO HO Estrone 17B-Estradiol O AOH AKR1C3 s' O O Progesterone 20o-Hydroxyprogesterone PROSTAGLANDINS sySN 1 Y1COOH AKR1c3 HO %-sy=1 N1) cooH SCN-- - S. oil S OH HO OH PGH2 PGF2, OH2 SN-1N1N HO2. SY-1N1N O 6H HOS-a--- ÖH PGD2 90,11 B-PGF2 U.S. Patent Mar. 1, 2016 Sheet 3 of 42 US 9.271,961 B2 Fig. 3 Progesterone -> DHP - allopregnanolone HSD3B2 SRDSA AKR1C2 DHEA -> A-AD see Actione me Androsterone Y HSD3B2 SRD5A AKR1C2 k A-AD .... Testosterone- DHT --> 3o-androstanedio U.S. Patent Mar. 1, 2016 Sheet 5 of 42 US 9.271,961 B2 HoH H 117 O o, HoH NADP Y55 OS U.S. Patent Mar. 1, 2016 Sheet 6 of 42 US 9.271,961 B2 9-51A U.S. Patent Mar. 1, 2016 Sheet 7 of 42 US 9.271,961 B2 U.S. Patent Mar. 1, 2016 Sheet 8 of 42 US 9.271,961 B2 fr| frae : ". V8(54H tae $ s U.S. Patent Mar. 1, 2016 Sheet 9 of 42 US 9.271,961 B2 5:5ae ){ ! : Tae, 88(51H. : x. !1 U.S. Patent Mar. 1, 2016 Sheet 10 of 42 US 9.271,961 B2 i U.S. Patent Mar. 1, 2016 Sheet 11 of 42 US 9.271,961 B2 U.S. Patent Mar. 1, 2016 Sheet 12 of 42 US 9.271,961 B2 II(51,1 uºquun.N?IDAD Shun duo Solon U.S. Patent Mar. 1, 2016 Sheet 13 of 42 US 9.271,961 B2 C O : e U.S. Patent Mar. 1, 2016 Sheet 14 of 42 US 9.271,961 B2 U.S. Patent Mar. 1, 2016 Sheet 15 of 42 US 9.271,961 B2 anlewOSOIWITH OI< U.S. Patent Mar. 1, 2016 Sheet 18 of 42 US 9.271,961 B2 LI'54) U.S. Patent Mar. 1, 2016 Sheet 19 of 42 US 9.271,961 B2 sq?VSN–||colaxv sqIVSN—FITZIL-xoo U.S. Patent Mar. 1, 2016 Sheet 20 of 42 US 9.271,961 B2 0001,001, | |-XOO- Z-XOOV |'0||0'0 O O O O 0 00|| CO O r CN fuuleue. AAIoW % U.S. Patent US 9.271,961 B2 U.S. Patent Mar. 1, 2016 Sheet 22 of 42 US 9.271,961 B2 zz(51H. U.S. Patent Mar. 1, 2016 Sheet 23 of 42 US 9.271,961 B2 V O ven 1. |Ng O O O O 3 OO O r CN fuuleue MAOW 96 U.S. Patent US 9.271,961 B2 U.S. Patent Mar. 1, 2016 Sheet 25 of 42 US 9.271,961 B2 £Ipunoduopjosuo?eu?u00uop ync~*~wnco–wnu–º– wnov~wn…~~~~ynw0–D– (up to Ric) (A) U.S. Patent Mar. 1, 2016 Sheet 26 of 42 US 9.271,961 B2 3 AIAW euAZu% U.S. Patent Mar. 1, 2016 Sheet 28 of 42 US 9.271,961 B2 (udo)AApeople-o 3. 3. O SN O r (udo)AAoeople-oil U.S. Patent Mar. 1, 2016 Sheet 29 of 42 US 9.271,961 B2 wS. + 2 > 2 H. O. P. on a S riII c O O itS (5is Of Y sexe f s T l T l l 6ugueue MW3W AW 96 U.S. Patent Mar. 1, 2016 Sheet 30 of 42 US 9.271,961 B2 s AA3Weseleyan 9, U.S. Patent Mar. 1, 2016 Sheet 31 of 42 US 9.271,961 B2 20101|10 (wn)Ipunoduuoo] |2.01±01-0.1901 fu put 99eds 9%, U.S. Patent Mar. 1, 2016 Sheet 32 of 42 US 9.271,961 B2 6Z(51) o06 U.S. Patent Mar. 1, 2016 Sheet 33 of 42 US 9.271,961 B2 Fig. 30 ICso Values (uM) Compds (R) 1C3 1C1 1 C2 1C4 1B1 1B10 C.CO2H an-j-R Compound 5 0.03 6.74 3.38 32.7 > 50 46.0 -NO 204) (101 (988) Compound 6 0.05 15.6 19.5 25.7 38.6 37.1 (p-Ac) (292) (364) (477) Compound 7 0.06 22.7 5.4 62.7 > 50 > 50 (p-CFs) (368) (249) (1015) Compound 8 0.14 30.2 19.1 48.7 ND ND (p-Cl) (222) (140) (357) Compound 9 0.13 31.3 18.1 91.4 > 50 > 50 -Br 250) (145) 728) Compound 10 0.28 35.6 3. 39. > 50 15 (p-t-Bu) (126) (110) (139) BMT 3-224 30.5 6.4 28.7 (R: o-COH, 0.04 27.7 16.2 p-Ac) (787) (165) (739) R. s' 0.03 4.35 5.50 50 ND p-CF)u v V2, (132)132 (136)136 (172)172 BMT 4-90 6.32 5.56 20.4 (R: o-NO, 0.04 42.7 39.3 p-OMe) (173) (139) (560) Compound 13 11.0 11.7 8.17 '' (138) (156) (102) ND >30 U.S. Patent Mar. 1, 2016 Sheet 34 of 42 US 9.271,961 B2 Fig. 31 Cmpds (R) COX-1 ICs (uM) COX-2 ICso (uM) C.COH 2 N. N --R FLU 2.23 O.06 Compound 5 30.76 O.74 (p-NO) Compound 6 > 00 > 00 -Ac) Compound 7 > 100 > 100 (p-CFs) Compound 8 > 00 ND (p-Cl) Compound 9 > 00 > 00 (p-Br) Compound 10 > 100 > 100 (p-t-Bu) BMT 3-224 > 00 > 00 (R: O-CO2H.
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