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(12) United States Patent (10) Patent No.: US 8,003,783 B2 Vicker Et Al

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(12) United States Patent (10) Patent No.: US 8,003,783 B2 Vicker Et Al USO08003783B2 (12) United States Patent (10) Patent No.: US 8,003,783 B2 Vicker et al. (45) Date of Patent: Aug. 23, 2011 (54) 17B-HYDROXYSTEROID DEHYDROGENASE OTHER PUBLICATIONS INHIBITORS Martin R. Tremblay, et al "Overview of a Rational Approach to (75) Inventors: Nigel Vicker, Slough (GB); Harshani DesignType I 17 B-Hydroxysteroid Dehydrogenase Inhibitors With Rithma Ruchiranani Lawrence, Slough out Estrogenic Activity: Chemical Synthesis and Biological Evalua (GB); Gillian Margaret Allan, Slough tion” 66(4) J. Steroid Biochem (1998): 179-191. (GB); Christian Bubert, Slough (GB); (Continued) Delphine Sophie Marion Fischer, Slough (GB); Atul Purohit, Slough Primary Examiner — Barbara P. Badio (GB); Michael John Reed, Slough Assistant Examiner — Sara E Townsley (GB); Barry Victor Lloyd Potter, (74) Attorney, Agent, or Firm — Frommer Lawrence & Slough (GB) Haug LLP; Sandra Kuzmich; Russell A. Garman (73) Assignee: Sterix Limited, Slough, Berkshire (GB) (57) ABSTRACT (*) Notice: Subject to any disclaimer, the term of this There is provided a compound of Formula (III) patent is extended or adjusted under 35 U.S.C. 154(b) by 1622 days. 3 Formula (III) (21) Appl. No.: 11/234,868 R (22) Filed: Sep. 23, 2005 RI (65) Prior Publication Data US 2006/OO74060 A1 Apr. 6, 2006 N Related U.S. Application Data 3 yCa (63) Continuation-in-part of application No. R2 PCT/GB2004/001234, filed on Mar. 22, 2004. R4 (51) Int. Cl. wherein A6 IK3I/58 (2006.01) R" is a selected from an alkyloxyalkyl group, a nitrile group, CO7I 71/00 (2006.01) alkylaryl group, alkenylaryl group, alkylheteroaryl group, (52) U.S. Cl. .......................................... 540/49; 514/176 alkenylheteroaryl group, =N-O-alkyl or =N-O H (58) Field of Classification Search .................... 540/49; group, branched alkenylalkyl-alcohol group, amide or 514f176 alkylamide or —CHO so that R together with R provide See application file for complete search history. the enol tautomer or R together with R form a pyrazole, wherein(a)R’ is =N O-alkylor=N-O-H group, (b) (56) References Cited the pyrazole is substituted with one of alkyl-OH group, alkyl ester group, alkyloxyalkyl group, branched alkyl U.S. PATENT DOCUMENTS group, and an amide and/or (c) the 2-position is Substituted with a group selected from —OH and —O-hydrocarbyl or 3,047,568 A T. 1962 Kissman et al. a heteroaryl ring; (Continued) R’ is selected from —OH and a sulphamate group; and R is selected from —OH or =O; wherein the ring system FOREIGN PATENT DOCUMENTS may be further substituted with one or more hydroxyl, DE 1176 131 T 1961 alkyl, alkoxy, alkinyl or halo Substituents. (Continued) 19 Claims, 1 Drawing Sheet SS HOSO ES El E. E. Tyge at al 2. 8 2. res, set r US 8,003,783 B2 Page 2 U.S. PATENT DOCUMENTS Gorski J., et al., Hormones receptors: Studies on the interaction of 3,163,641 A 12, 1964 Christiansen et al. estrogens with uterus, Recent Prog. Horm. Res., 1968, vol. 24, p. 3,398,140 A 8, 1968 Clinton 45-80. 5,585,405 A * 12/1996 Labrie et al. .................. 514,733 Gupta, et al., Synthesis and biological activity of Some D-ring modi 5,880,115 A 3/1999 Li et al. fied oestrone derivative, Ind. J. Chem. 1999, vol. 38B, p. 563-571. 6,046,186 A 4/2000 Tanabe et al. Heer, et al., Uber Steroide, Marrianol-und Doisynoisaure, Uber FOREIGN PATENT DOCUMENTS oestrogene carbonsauren II. Heiv. Chim. Acta. 1945, vol. 28, p. 156-165. GB 1033520 6, 1966 GB 1096732 12/1967 Horiuchi, et al., Regioselective 2-Iodination of Estradiol, Estriol & GB 233.1987 6, 1999 Oestrone, J. Chem. Soc. Chem. Commun., 1982, p. 671-672. WO WO O2, 16392 2, 2002 Holli K., et al. 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