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Last Updated: April 18, 2024

Claims for Patent: 5,998,427

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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; R.sup.1 is hydrogen or methyl; R.sup.2 is hydrogen or methyl; R.sup.3 is (B) wherein X, R.sup.6, R.sup.7 and R.sup.8 are various groups, and pharmaceutically acceptable solvates thereof and their use in the treatment of androgen responsive and mediated diseases. ##STR1##
Inventor(s):	Batchelor; Kenneth William (Durham, NC), Frye; Stephen Vernon (Durham, NC)
Assignee:	Glaxo Wellcome Inc. (Research Triangle Park, NC)
Application Number:	09/078,468
Patent Claims:	1. A compound of formula (I) ##STR17## wherein carbons 1 and 2 are joined by either a single or a double bond; R.sup.1 is hydrogen or methyl; R.sup.2 is hydrogen or methyl; R.sup.3 is (B) ##STR18## wherein R.sup.6 is trifluoromethyl, phenyl optionally substituted with one or more halogens or branched (C.sub.4-7) alkyl groups, or branched (C.sub.4-7) alkyl; either of R.sup.7 or R.sup.8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens or branched (C.sub.4-7)alkyl groups, or branched (C.sub.4-7)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 R.sup.2 is hydrogen. 4. A compound as claimed in claim 1 wherein R.sup.6 is trifluoromethyl, phenyl optionally substituted with one or more halogens, or branched (C.sub.4-7) alkyl; and either of R.sup.7 or R.sup.8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens, or branched (C.sub.4-7) 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; R.sup.1 is hydrogen or methyl; R.sup.6 is trifluoromethyl, phenyl optionally substituted with one or more halogens, or branched (C.sub.4-7) alkyl; either of R.sup.7 or R.sup.8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens, or branched (C.sub.4-7) alkyl, while the other is hydrogen or halogen; and X is hydrogen or halogen. 7. A compound as claimed in claim 6 wherein when R.sup.7 or R.sup.8 is branched (C.sub.4-7) alkyl and X is hydrogen, R.sup.6 is trifluoromethyl or phenyl optionally substituted with one or more halogens. 8. A compound as claimed in claim 6 wherein R.sup.6 is trifluoromethyl or branched (C.sub.4-7) alkyl; and either of R.sup.7 or R.sup.8 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 R.sup.6 is trifluoromethyl or branched (C.sub.4-7) alkyl; either of R.sup.7 or R.sup.8 is trifluoromethyl while the other is hydrogen; and X is hydrogen. 10. A compound as claimed in claim 6 wherein R.sup.6 and R.sup.8 are independently trifluoromethyl or t-butyl, while R.sup.7 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) 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 R.sup.2 is hydrogen is prepared by dehydrogenating a compound of formula (Ia). ##STR22## 15. A method of inhibiting 5.alpha.-testosterone reductase enzyme comprising contacting said enzyme with an effective 5.alpha.-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 R.sup.1 and R.sup.2 are independently hydrogen or methyl and R.sup.3 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: 17.beta.-N-(2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-aza-5.alpha.-andros tan-3-one, 17.beta.-N-(2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-methyl-4-aza-5.alph a.-androstan-3-one, 17.beta.-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-aza-5.alpha.-and rost-1-en-3-one, 17.beta.-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-aza-5.alpha.-and rostan-3-one, 17.beta.-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-methyl-4-aza-5.a lpha.-androstan-3-one, 17.beta.-N-(2,5-Di-t-butyl)phenylcarbamoyl-4-aza-5.alpha.-androst-1-en-3-o ne, 17.beta.-N-(2,5-Di-t-butyl)phenylcarbamoyl-4-aza-5.alpha.-androstan-3-one, 17.beta.-N-(2,5-Di-t-butyl)phenylcarbamoyl-4-methyl-4-aza-5.alpha.-androst an-3-one, 17.beta.-N-(2,5-bis(Trifluoromethyl)phenylcarbamoyl-4-aza-7.beta.-methyl-5 .alpha.-androst-1-en-3-one, and 17.beta.-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-aza-7.beta.-meth yl-5.alpha.-androst-1-en-3-one.

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