Claims for Patent: 5,998,427

Summary for Patent: 5,998,427

Title:	Androstenones
Abstract:	The present invention relates to compounds of formula (I), wherein carbons 1 and 2 are joined by either a single or a double bond; R1 is hydrogen or methyl; R2 is hydrogen or methyl; R3 is (B) wherein X, R6, R7 and R8 are various groups, and pharmaceutically acceptable solvates thereof and their use in the treatment of androgen responsive and mediated diseases. ##STR1##
Inventor(s):	Kenneth William Batchelor, Stephen Vernon Frye
Assignee:	SmithKline Beecham Corp
Application Number:	US09/078,468
Patent Claims:	1. A compound of formula (I) ##STR17## wherein carbons 1 and 2 are joined by either a single or a double bond; R1 is hydrogen or methyl;R2 is hydrogen or methyl; R3 is (B) ##STR18## wherein R6 is trifluoromethyl, phenyl optionally substituted with one or more halogens or branched (C4-7) alkyl groups, or branched (C4-7) alkyl; either of R7 or R8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens or branched (C4-7)alkyl groups, or branched (C4-7)alkyl, while the other is hydrogen or halogen; and X is hydrogen or halogen,or a pharmaceutically acceptable solvate thereof. 2. A compound as claimed in claim 1 wherein X is hydrogen. 3. A compound as claimed in claim 1 wherein R2 is hydrogen. 4. A compound as claimed in claim 1 wherein R6 is trifluoromethyl, phenyl optionally substituted with one or more halogens, or branched (C4-7) alkyl; and either of R7 or R8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens, or branched (C4-7) alkyl, while the other is hydrogen or halogen. 5. A compound as claimed in claim 1 wherein carbons 1 and 2 are joined by a double bond. 6. A compound as claimed in claim 1 of formula (IB); ##STR19## wherein carbons 1 and 2 are joined by either a single or a double bond; R1 is hydrogen or methyl;R6 is trifluoromethyl, phenyl optionally substituted with one or more halogens, or branched (C4-7) alkyl; either of R7 or R8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens, or branched (C4-7) alkyl, while the other is hydrogen or halogen; and X is hydrogen or halogen. 7. A compound as claimed in claim 6 wherein when R7 or R8 is branched (C4-7) alkyl and X is hydrogen, R6 is trifluoromethyl or phenyl optionally substituted with one or more halogens. 8. A compound as claimed in claim 6 wherein R6 is trifluoromethyl or branched (C4-7) alkyl; and either of R7 or R8 is trifluoromethyl, halogen, or phenyl substituted with one or more halogens, while the other is hydrogen or halogen. 9. A compound as claimed in claim 8 wherein R6 is trifluoromethyl or branched (C4-7) alkyl; either of R7 or R8 is trifluoromethyl while the other is hydrogen; and X is hydrogen. 10. A compound as claimed in claim 6 wherein R6 and R8 are independently trifluoromethyl or t-butyl, while R7 and X are hydrogen. 11. A pharmaceutical formulation comprising an effective amount of a compound as claimed in claim 1 a pharmaceutically acceptable carrier thereof. 12. A process for preparing a compound as claimed in claim 1 which comprises:(A) for compounds of formula (I) wherein carbons 1 and 2 are joined by a single bond, hydrogenating a compound of formula (IVa) ##STR20## (B) for compounds of formula (I) wherein carbons 1 and 2 are joined by a double bond, reacting a compound of formula (V) ##STR21## with a compound of formula (IIa) H.sub.2 NR.sup.3 (IIa) and if necessary and/or desired, subjecting the compound thus obtained to one or more further reactions comprising:(i) interconversion to another compound of formula (I); (ii) removing any protecting group or groups; and/or (iii) converting the compound of formula (I) or a solvate thereof into a pharmaceutically acceptable solvate thereof. 13. A process as claimed in claim 12 wherein in process (B) the compound of formula (V) is treated with a halogenating agent in the presence of a base prior to reaction with a compound of formula (IIa). 14. A process as claimed in claim 12 wherein in step (i) a compound of formula (I) wherein there is a double bond between carbons 1 and 2 and wherein R2 is hydrogen is prepared by dehydrogenating a compound of formula (Ia). ##STR22## 15. A method of inhibiting 5α-testosterone reductase enzyme comprising contacting said enzyme with an effective 5α-testosterone inhibitory amount of a compound as claimed in claim 1. 16. A method of treating an androgen responsive or mediated disease in a mammal suffering from said disease comprising administering to said mammal, an effective androgen responsive or mediated disease amount of a compound as claimed in claim 1. 17. A method of claim 16 wherein the androgen responsive or mediated disease is benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness and hirsutism. 18. A compound of formula (IVa) wherein R1 and R2 are independently hydrogen or methyl and R3 is as defined in claim 1, or a solvate thereof. 19. The compound of claim 1 wherein said compound is selected from the group consisting of: 17β-N-(2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-aza-5α-androstan-3-one, 17β-N-(2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-methyl-4-aza-5.alpha.-androstan-3-one, 17β-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-aza-5α-androst-1-en-3-one, 17β-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-aza-5α-androstan-3-one, 17β-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-methyl-4-aza-5.alpha.-androstan-3-one, 17β-N-(2,5-Di-t-butyl)phenylcarbamoyl-4-aza-5α-androst-1-en-3-one, 17β-N-(2,5-Di-t-butyl)phenylcarbamoyl-4-aza-5α-androstan-3-one, 17β-N-(2,5-Di-t-butyl)phenylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, 17β-N-(2,5-bis(Trifluoromethyl)phenylcarbamoyl-4-aza-7β-methyl-5α-androst-1-en-3-one, and 17β-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-aza-7β-methyl-5α-androst-1-en-3-one.