Fused tricyclic compounds as inhibitors of 17.beta.-hydroxysteroid dehydrogenase 3 Number:7,417,040 from the United States Patent and Trademark Office (PTO) owispatent Disclosed are fused tricyclic compounds of the following formula I, ##STR00001## or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof. The disclosed compounds are useful as inhibitors of 17.beta.-hydroxysteriod dehydrogenase 3 (17.beta.HSD3). Also disclosed are methods of using such compounds in the treatment of hormone sensitive diseases such as prostate cancer and pharmaceutical compositions comprising such compounds.<H hydroxysteroid, dehydrogenase, Fused, tricyclic, 7417040.html, Patent, pto, 7417040

Title: Fused tricyclic compounds as inhibitors of 17.beta.-hydroxysteroid dehydrogenase 3

Abstract: Disclosed are fused tricyclic compounds of the following formula I, ##STR00001## or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof. The disclosed compounds are useful as inhibitors of 17.beta.-hydroxysteriod dehydrogenase 3 (17.beta.HSD3). Also disclosed are methods of using such compounds in the treatment of hormone sensitive diseases such as prostate cancer and pharmaceutical compositions comprising such compounds.

Patent Number: 7,417,040 Issued on 08/26/2008 to Fink, et al.

Inventors: Fink; Brian E. (West Windsor, NJ), Gavai; Ashvinikumar V. (Princeton Junction, NJ), Vite; Gregory D. (Titusville, NJ), Han; Wen-Ching (Newtown, PA), Misra; Raj N. (Hopewell, NJ), Xiao; Hai-Yun (Belle Mead, NJ), Norris; Derek J. (Pennington, NJ), Tokarski; John S. (Princeton, NJ)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)

Appl. No.: 11/066,373

Filed: February 25, 2005

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
60548851	Mar., 2004

Current U.S. Class: 514/183 ; 540/466

Current International Class: A61K 31/33 (20060101); A01N 43/00 (20060101); C07D 225/04 (20060101); C07D 267/22 (20060101); C07D 281/18 (20060101); C07D 291/00 (20060101); C07D 337/16 (20060101)

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Primary Examiner: Wilson; James
Assistant Examiner: Jarrell; Noble
Attorney, Agent or Firm: Greenblatt; Gary D.

Parent Case Text

RELATED APPLICATION

This application claims priority benefit under Title 35 .sctn. 119(e) of U.S. provisional Application No. 60/548,851, filed on Mar. 1, 2004, the contents of which are herein incorporated by reference.

Claims

What is claimed is:

1. A compound of formula I: ##STR00709## or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: Y is --C(.dbd.O)-- or --S(.dbd.O).sub.2--; X.sub.1X.sub.2 is --CR.sub.1.dbd.CR.sub.3--, --CR.sub.1R.sub.2--CR.sub.3R.sub.4--, --C(.dbd.O)--CR.sub.3R.sub.4--, or --CR.sub.1R.sub.2--C(.dbd.O)--; R.sub.2, R.sub.4, R.sub.6 and R.sub.10 are each independently hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2OR.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, or NR.sub.bC(.dbd.O)R.sub.a, wherein: R.sub.2 and R.sub.4 together may optionally form a 3-7 membered optionally substituted carbocyclic ring or 3-7 membered optionally substituted heterocyclic ring; R.sub.a is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl; R.sub.b, R.sub.c and R.sub.d are independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, or aryl or substituted aryl, or said R.sub.b and R.sub.c together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle; R.sub.e is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl; R.sub.1 and R.sub.3 are each independently hydrogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)R.sub.a, NR.sub.bC(.dbd.O)OR.sub.e, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, or OC(.dbd.O)NR.sub.bR.sub.c, wherein R.sub.1 and R.sub.3 together may optionally form a 3-7 membered optionally substituted carbocyclic ring or 3-7 membered optionally substituted heterocyclic ring; R.sub.9 is H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.e, or NR.sub.bR.sub.c; m is 1-4; and n is 1-4; provided that: at least one of R.sub.6 and R.sub.10 is not H; and when X.sub.1X.sub.2 is --CH.sub.2--CH.sub.2--, R.sub.9 is not H, aryl or substituted aryl, or heteroaryl or substituted heteroaryl.

2. The compound of claim 1, wherein: R.sub.2, R.sub.4, R.sub.6 and R.sub.10 are each independently hydrogen, halogen, cyano, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2OR.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, or NR.sub.bC(.dbd.O)R.sub.a, wherein: R.sub.2 and R.sub.4 together may optionally form a 3-7 membered carbocyclic ring or 3-7 membered heterocyclic ring; R.sub.1 and R.sub.3 are each independently hydrogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, or OC(.dbd.O)NR.sub.bR.sub.c, wherein R.sub.1 and R.sub.3 together may optionally form a 3-7 membered optionally substituted carbocyclic ring or 3-7 membered optionally substituted heterocyclic ring; and R.sub.9 is H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, or NR.sub.bR.sub.c.

3. The compound of claim 1, wherein: R.sub.6 and R.sub.10 are each independently hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2OR.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, or NR.sub.bC(.dbd.O)R.sub.a; R.sub.2 and R.sub.4 are each independently hydrogen, cyano, nitor, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, or NR.sub.bC(.dbd.O)R.sub.a, wherein R.sub.2 and R.sub.4 together may optionally form a 3-6 membered optionally substituted carbocyclic ring or 3-6 membered optionally substituted heterocyclic ring; R.sub.1 and R.sub.3 are each independently hydrogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, or OC(.dbd.O)NR.sub.bR.sub.c, wherein R.sub.1 and R.sub.3 together may optionally form a 3-6 membered optionally substituted carbocyclic ring or 3-6 membered optionally substituted heterocyclic ring; and R.sub.9 is H, C.sub.1-C.sub.4 alkyl or substituted C.sub.1-C.sub.4 alkyl, cycloalkyl or substituted cycloalkyl, or NR.sub.bR.sub.c.

4. The compound of claim 1 having the following structure Ia, ##STR00710## wherein: X.sub.1X.sub.2 is --CR.sub.1.dbd.CR.sub.3--, --CR.sub.1R.sub.2--CR.sub.3R.sub.4--, or --C(.dbd.O)--CR.sub.3R.sub.4--; R.sub.6, R.sub.7, R.sub.8, R.sub.10, R.sub.11, and R.sub.12 are each independently hydrogen, halogen, cyano, nitor, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2OR.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, or NR.sub.bC(.dbd.O)R.sub.a, wherein R.sub.a is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl; R.sub.2 and R.sub.4 are each independently hydrogen, cyano, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, or NR.sub.bC(.dbd.O)R.sub.a, wherein R.sub.2 and R.sub.4 together may optionally form a 3-6 membered optionally substituted carbocyclic ring or 3-6 membered optionally substituted heterocyclic ring; R.sub.1 and R.sub.3 are each independently hydrogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, or OC(.dbd.O)NR.sub.bR.sub.c, wherein R.sub.1 and R.sub.3 together may optionally form a 3-6 membered optionally substituted carbocyclic ring or 3-6 membered optionally substituted heterocyclic ring; and R.sub.9 is H, C.sub.1-C.sub.4 alkyl or substituted C.sub.1-C.sub.4 alkyl, cycloalkyl or substituted cycloalkyl, or NR.sub.bR.sub.c.

5. The compound of claim 1 having the following structure Ib, ##STR00711## wherein: X.sub.1X.sub.2 is --CR.sub.1.dbd.CR.sub.3--, --CR.sub.1R.sub.2--CR.sub.3R.sub.4--, or --C(.dbd.O)--CR.sub.3R.sub.4--; R.sub.7, R.sub.8, R.sub.10 and R.sub.11 are each independently hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2OR.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, or NR.sub.bC(.dbd.O)R.sub.a; R.sub.2 and R.sub.4 are each independently hydrogen, cyano, nitro, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, or NR.sub.bC(.dbd.O)R.sub.a, wherein R.sub.2 and R.sub.4 together may optionally form a 3-6 membered optionally substituted carbocyclic ring or 3-6 membered optionally substituted heterocyclic ring; R.sub.1 and R.sub.3 are each independently hydrogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, or OC(.dbd.O)NR.sub.bR.sub.c, wherein R.sub.1 and R.sub.3 together may optionally form a 3-6 membered optionally substituted carbocyclic ring or 3-6 membered optionally substituted heterocyclic ring; and R.sub.9 is H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, or NR.sub.bR.sub.c; provided that: at least one of R.sub.7, R.sub.8, R.sub.10 and R.sub.11 is not H.

6. The compound of claim 5, wherein R.sub.9 is H, methyl, trifluoromethyl, ethyl, isopropyl, cyclopropyl, or NH.sub.2, or ##STR00712##

7. The compound of claim 6, wherein R.sub.7 and R.sub.8 are each independently hydrogen, halogen, cyano, nitro, SMe, S(.dbd.O).sub.2Me, or OMe, and wherein at least one of R.sub.7 and R.sub.8 is not hydrogen.

8. The compound of claim 7, wherein Y is --C(.dbd.O)--.

9. The compound of claim 8, wherein X.sub.1X.sub.2 is --CH.dbd.CH--, --CH.sub.2--CH.sub.2--, or ##STR00713##

10. The compound of claim 9, wherein R.sub.9 is methyl; R.sub.10 and R.sub.11 are each independently hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.c, S(.dbd.O).sub.2R.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.e, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, NR.sub.bC(.dbd.O)OR.sub.e, or NR.sub.bC(.dbd.O)R.sub.a.

11. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically-acceptable carrier or diluent.

12. A method for treating a condition or disorder comprising administering to a mammalian species in need thereof a therapeutically effective amount of at least one compound according to claim 1, wherein said condition or disorder is selected from the group consisting of benign prostate hypertrophia, benign prostatic hyperplasia, adenomas and neoplasies of the prostate, prostate cancer, hirsutism, and polycystic ovary syndrome.

13. The method of claim 12, wherein said condition or disorder is prostate cancer.

Description

FIELD OF THE INVENTION

The present invention relates to fused tricyclic compounds, to methods of using such compounds in the treatment of hormone sensitive diseases such as prostate cancer, and to pharmaceutical compositions containing such compounds.

BACKGROUND OF THE INVENTION

17.beta.-hydroxysteroid dehydrogenase 3 (17.beta.-HSD3) is an essential enzyme in the biosynthesis of testosterone. It catalyzes the reduction of androstenedione, a weakly active androgen produced by the adrenal glands, to testosterone. Inano et al., Steroids, 48, 1-26, (1986) and Luu-The et al., J. Steroid Biochem. Mol. Biol., 55, 581-587 (1995). 17.beta.-HSD3 is expressed predominately in the adult testes and to a lesser extent in seminal vesicles and prostate tissue, an expression pattern consistent with an enzyme involved in both gonadal and peripheral target tissue androgen biosynthesis. 17.beta.-HSD3 is responsible for the synthesis of about 60% of all active androgens in men. Labrie, Mol. Cell. Endocrinol. 78, C113-C118 (1991). The development and progression of hormone sensitive diseases, e.g., prostate cancer, is stimulated by androgens such as testosterone. Inhibition of 17.beta.-HSD3 therefore provides a novel means to disrupt testosterone biosynthesis for the treatment of androgen-associated diseases. Van Weerden et al., J. Steroid Biochem. Mol. Biol., 20, 903-907 (1990) and Liu et al., J. Clin. Endocrinol., 77, 1472-1478 (1993).

Current pharmacological treatments to prevent androgen action in androgen-associated diseases such as prostate cancer are centered on the combined use of luteinizing hormone releasing hormone (LHRH) analogues with androgen receptor antagonists ("anti-androgens"). Labrie et al., Endocr.-Relat. Cancer, 3, 243-278 (1996); Gheiler et al., World J. Urol., 18, 190-193 (2000); and Simard, et al., J. Urol., 49, 580-586 (1997). LHRH analogues interfere with central nervous system feedback mechanisms to suppress testosterone biosynthesis in the testes to produce chemical castration. However, it is estimated that up to 50% of testosterone levels remain within prostate tissue following chemical or surgical castration indicating the existence of alternate routes of testosterone biosynthesis independent of the testes. Anti-androgens are used to block the action of this remaining testosterone in prostate cancer cells by antagonizing hormone function at the level of receptor binding. Although the combined use of LHRH analogues with anti-androgens has shown success in the management of prostate cancer, these responses are largely restricted to advanced metastatic disease. Further, patients receiving these treatments ultimately become refractory and progress to a more aggressive, hormone-independent state for which there is no effective therapy.

Inhibitors of 17.beta.-HSD3 have been described in the art. See, e.g., Pittaway, Contraception, 27, 431 (1983); Labrie et al., WO99/46279; Maltais et al., J. Med. Chem., 45, 640-653 (2002); and Guzi et al., WO03/022835. There remains a need for potent, selective inhibitors of 17.beta.-HSD3 with improved pharmacological properties, physical properties and side effect profiles.

The compounds of the present invention are inhibitors of 17.beta.-HSD3, and therefore have therapeutic use as anti-cancer agents, as well as other therapeutic agents, for example, as anti-fertility agents as described following.

SUMMARY OF THE INVENTION

The present invention provides a fused tricyclic compound of the following formula I, or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt or solvate thereof, which compounds are especially useful as inhibitors of 17.beta.-hydroxysteroid dehydrogenase 3 (17.beta.-HSD3):

##STR00002##

As used in formula I, and throughout the specification, the symbols have the following meanings unless otherwise indicated, and are, for each occurrence, independently selected: Y is --C(.dbd.O)--, or --S(.dbd.O).sub.2--; X.sub.1X.sub.2 is --CR.sub.1.dbd.CR.sub.3--, --CR.sub.1R.sub.2--CR.sub.3R.sub.4--, --C(.dbd.O)--CR.sub.3R.sub.4--, --S--CR.sub.3R.sub.4--, --S(.dbd.O).sub.2--CR.sub.3R.sub.4--, --O--CR.sub.3R.sub.4--, --NR.sub.5--CR.sub.3R.sub.4--, --CR.sub.1R.sub.2--S--, --CR.sub.1R.sub.2--S(.dbd.O)--, --CR.sub.1R.sub.2--S(.dbd.O).sub.2--, --CR.sub.1R.sub.2--C(.dbd.O)--, --CR.sub.1R.sub.2--O--, or CR.sub.1R.sub.2--NR.sub.5--; R.sub.2, R.sub.4, R.sub.6 and R.sub.10 are each independently hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl (including CF.sub.3), alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, P(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2OR.sub.e, P(.dbd.O).sub.2OR.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, NR.sub.bP(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, P(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, NR.sub.dP(.dbd.O).sub.2NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)R.sub.a, or NR.sub.bP(.dbd.O).sub.2R.sub.e, wherein: R.sub.2 and R.sub.4 together may optionally form a 3-7 membered optionally substituted carbocyclic ring or 3-7 membered optionally substituted heterocyclic ring; R.sub.a is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl; R.sub.b, R.sub.c and R.sub.d are independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, or aryl or substituted aryl, or said R.sub.b and R.sub.c together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle; R.sub.e is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl; R.sub.1 and R.sub.3 are each independently hydrogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)R.sub.a, NR.sub.bC(.dbd.O)OR.sub.e, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, or OC(.dbd.O)NR.sub.bR.sub.c, wherein R.sub.1 and R.sub.3 together may optionally form a 3-7 membered optionally substituted carbocyclic ring or 3-7 membered optionally substituted heterocyclic ring; R.sub.5 is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, S(.dbd.O).sub.2R.sub.e, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, or C(.dbd.O)NR.sub.bR.sub.c; R.sub.9 is H, alkyl or substituted alkyl (including CF.sub.3), cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.e, or NR.sub.bR.sub.c; m is 1-4; and n is 1-4; provided that: at least one of R.sub.6 and R.sub.10 is not H; and when X.sub.1X.sub.2X.sub.1X.sub.2 is --CH.sub.2--CH.sub.2--, R.sub.9 is not aryl or substituted aryl, or heteroaryl or substituted heteroaryl; when X.sub.1X.sub.2 is --S--CR.sub.3R.sub.4--, each R.sub.10 is H, and m=1, R.sub.6 at the C-3 position is not H, methyl, halogen, OMe, CF.sub.3, or SCF.sub.3; when X.sub.1X.sub.2 is --NR.sub.5--CR.sub.3R.sub.4--, m=1, R.sub.6 at the C-3 position is not H or halogen or R.sub.6 at the C-2 position is not H, halogen, CF.sub.3 or OMe; and when X.sub.1X.sub.2 is --CR.sub.1R.sub.2--NR.sub.5--, m=1 and n=1, R.sub.6 at the C-2 position is not H, halogen, methyl, or OMe and R.sub.10 at the C-8 position is not H, halogen or methyl, wherein the C-2, C-3 and C-8 positions are as designated in formula I.

FURTHER DESCRIPTION OF THE INVENTION

The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated.

The terms "alkyl" and "alk" refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term "C.sub.1-C.sub.4 alkyl" refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF.sub.3 or an alkyl group bearing Cl.sub.3), cyano, nitro, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR.sub.a, SR.sub.a, S(.dbd.O)R.sub.e, S(.dbd.O).sub.2R.sub.e, P(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2OR.sub.e, P(.dbd.O).sub.2OR.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, NR.sub.bP(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, P(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, NR.sub.dP(.dbd.O).sub.2NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)R.sub.a, or NR.sub.bP(.dbd.O).sub.2R.sub.e, wherein R.sub.a is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R.sub.b, R.sub.c and R.sub.d are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R.sub.b and R.sub.c together with the N to which they are bonded optionally form a heterocycle; and R.sub.e is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.

The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. "Substituted alkenyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substituents.

The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary such groups include ethynyl. "Substituted alkynyl" refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substituents.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. "Substituted cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substituents. Exemplary substituents also include spiro-attached or fused cylic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substitutents can themselves be optionally substituted.

The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to nitro, cyano, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substituents. Exemplary substituents also include spiro-attached or fused cylic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

The term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl and the like). "Substituted aryl" refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substituents. Exemplary substituents also include fused cylic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

The terms "heterocycle" and "heterocyclic" refer to fully saturated, or partially or fully unsaturated, including aromatic (i.e., "heteroaryl") cyclic groups (for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 16 membered tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. (The term "heteroarylium" refers to a heteroaryl group bearing a quaternary nitrogen atom and thus a positive charge.) The heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofurazanyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

"Substituted heterocycle" and "substituted heterocyclic" (such as "substituted heteroaryl") refer to heterocycle or heterocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, nitro, oxo (i.e., =O), cyano, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substituents. Exemplary substituents also include spiro-attached or fused cylic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

The term "quaternary nitrogen" refers to a tetravalent positively charged nitrogen atom including, for example, the positively charged nitrogen in a tetraalkylammonium group (e.g., tetramethylammonium, N-methylpyridinium), the positively charged nitrogen in protonated ammonium species (e.g., trimethyl-hydroammonium, N-hydropyridinium), the positively charged nitrogen in amine N-oxides (e.g., N-methyl-morpholine-N-oxide, pyridine-N-oxide), and the positively charged,nitrogen in an N-amino-ammonium group (e.g., N-aminopyridinium).

The terms "halogen" or "halo" refer to chlorine, bromine, fluorine or iodine.

The term "carbocyclic" refers to aromatic or non-aromatic 3 to 7 membered monocyclic and 7 to 11 membered bicyclic groups, in which all atoms of the ring or rings are carbon atoms. "Substituted carbocyclic" refers to a carbocyclic group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, nitro, cyano, OR.sub.a, wherein R.sub.a is as defined hereinabove, as well as those groups recited above as exemplary cycloalkyl substituents.

When a functional group is termed "protected", this means that the group is in modified form to mitigate, especially preclude, undesired side reactions at the protected site. Suitable protecting groups for the methods and compounds described herein include, without limitation, those described in standard textbooks, such as Greene, T. W. et al., Protective Groups in Organic Synthesis, Wiley, N.Y. (1999).

Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

The compounds of formula I form salts which are also within the scope of this invention. Reference to a compound of the formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of formula I contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

The compounds of formula I which contain a basic moiety, such as but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

The compounds of formula I which contain an acidic moiety, such but not limited to a carboxylic acid, may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug" as employed herein denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a salt and/or solvate thereof. Solvates of the compounds of formula I include, for example, hydrates.

Compounds of the formula I, and salts thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

Compounds of the formula I are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% formula I compound ("substantially pure" compound I), which is then used or formulated as described herein. Such "substantially pure" compounds of the formula I are also contemplated herein as part of the present invention.

All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

Throughout the specifications, groups and substituents thereof may be chosen to provide stable moieties and compounds.

Methods of Preparation

The compounds of the present invention may be prepared by methods such as those illustrated in the following schemes. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art.

##STR00003## ##STR00004##

##STR00005##

##STR00006##

As illustrated in Schemes 1, 1a and 1b, compounds of formula I can be made from either 1-1 or 1-2. Y, R.sub.6, R.sub.9, R.sub.b, R.sub.c and m are defined as above (R.sub.6 is preferably not Br); R.sub.10' is hydrogen, halogen (preferably F and Cl), cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR.sub.a, SR.sub.a, S(.dbd.O)F.sub.e, S(.dbd.O).sub.2R.sub.e, P(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2OR.sub.e, P(.dbd.O).sub.2OR.sub.e, NR.sub.bR.sub.c, NR.sub.bS(.dbd.O).sub.2R.sub.e, NR.sub.bP(.dbd.O).sub.2R.sub.e, S(.dbd.O).sub.2NR.sub.bR.sub.c, P(.dbd.O).sub.2NR.sub.bR.sub.c, C(.dbd.O)OR.sub.e, C(.dbd.O)R.sub.a, C(.dbd.O)NR.sub.bR.sub.c, OC(.dbd.O)R.sub.a, OC(.dbd.O)NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)OR.sub.e, NR.sub.dC(.dbd.O)NR.sub.bR.sub.c, NR.sub.dS(.dbd.O).sub.2NR.sub.bR.sub.c, NR.sub.dP(.dbd.O).sub.2NR.sub.bR.sub.c, NR.sub.bC(.dbd.O)R.sub.a, or NR.sub.bP(.dbd.O).sub.2R.sub.e, wherein R.sub.a, R.sub.b, R.sub.c, R.sub.d and R.sub.e are as defined above; q=1-3; and R.sub.10 is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, or aryl or substituted aryl. The definition contained herein also applies to Scheme 2 through Scheme 8, unless otherwise noticed.

Treatment of 1-2 with hydrazine 1-3 yields intermediate 1-4, which gives intermediate 1-5 upon treating with acid. Hydrazine 1-3 is either commercially available or can be prepared by one skilled in the art. Oxidation of 1-5 forms intermediate 1-6, which can be reduced to offer compound 1-7. Treatment of 1-7 with acid affords intermediate 1-8, which generates compound 1-9 through coupling with an acid, an acid chloride, an acid anhydride, or a chloroformate, wherein Y is --(C.dbd.O)--, or with a sulfonyl chloride or a phenyl isocyanatoformate, wherein Y is --S(.dbd.O).sub.2--. Compound 1-10 can be obtained from 1-9 by hydrogenation.

As shown in Scheme 1a, compound 1-12 can be synthesized from 1-9 or 1-10 by preparing intermediate 1-11 though a coupling with a borane reagent, such as bis(pinacolato)borane, followed by a palladium coupling with a bromo-substititued compound (Br--R.sub.10) or a triflate substituted compound (TfO--R.sub.10). The said Br--R.sub.10 or TfO--R.sub.10 is either commercially available or can be prepared by one skilled in the art. According to Scheme 1b, compound 1-12 can also be prepared by reacting 1-9 or 1-10 with R.sub.10--B(OH).sub.2 using a palladium catalyst. R.sub.10--B(OH).sub.2 is commercially available or readily prepared by one skilled in the art. Compound 1-13 can be obtained from 1-9 or 1-10 through a palladium coupling with HNR.sub.bR.sub.c. The alkene portion (--CH.dbd.CH--) of the center ring in compounds 1-12 and 1-13 can also be converted to alkane (--CH.sub.2--CH.sub.2--) through hydrogenation.

##STR00007##

##STR00008##

##STR00009##

Alternatively, a compound of formula I can be prepared according to Scheme 2. Coupling of 2-1 with agents such as an acid, an acid chloride, an acid anhydride, a chloroformate, a sulfonyl chloride or a phenyl isocyanatoformate, affords intermediate 2-2, which can be subsequently converted to compound 2-3 via a tin coupling. A nuclear substitution of compound 2-4 with intermediate 2-3 gives intermediate 2-5, which can be transformed to compound 2-6 by a palladium coupling reaction. Hydrogenation of compound 2-6 yields compound 2-7. Additionally, compound 2-9 and 2-10 can be prepared according to Schemes 2a and 2b.

##STR00010##

According to Scheme 3, compound 3-2 can also be prepared from 3-1 via hydrogenation. Compound 3-3 can be prepared from 3-1 through oxidation by using agents such as mCPBA.

##STR00011##

As shown in Scheme 4, a compound of formula I can also be prepared from 1-7. Oxidization of 1-7 gives intermediate 4-1, which can be converted to 4-2 via a coupling as described above. Additional analogues can be synthesized from 4-2 through palladium coupling as illustrated in Schemes la and lb. Substituted esters 5-1 and amides 5-3 can be prepared according to Scheme 5, wherein R.sub.b and R.sub.c are defined as above and R' is C.sub.1-C.sub.4 alkyl such as methyl, ethyl, propyl, 2-methyl-propyl, or n-butyl.

##STR00012##

##STR00013##

Substituted heterocycles, such as compounds 6-1, 6-3 and 6-4, wherein R'' is H, alkyl (such as methyl or ethyl) or substituted alkyl, or aryl (such as phenyl) or substituted aryl, can be synthesized according to Scheme 6.

##STR00014##

As shown in Scheme 7, compound of formula I wherein X.sub.1X.sub.2 is --O--CH.sub.2--, can be prepared from starting material 7-1. Bromination of compound 7-1 gives intermediate 7-2, which can be coupled with 7-3 to afford intermediate 7-4. Compound 7-3 is commercially available or can be readily made by one skilled in the art. Reduction of compound 7-4 gives intermediate 7-5, which can be cyclized via an internal palladium coupling. Compound 7-7 can be obtained via a coupling as described above. Additional analogues can be prepared from compound 7-7 as illustrated in Schemes 1a and 1b. Similarly, compound of formula I wherein X.sub.1X.sub.2 is --CH.sub.2--O--, can be prepared according to Scheme 8.

##STR00015##

Preferred Compounds

A preferred subgenus of the compounds of the present invention includes compounds of the formula I or salts thereof where