Claims for Patent: 4,335,121

Summary for Patent: 4,335,121

Title:	Androstane carbothioates
Abstract:	Compounds of the formula ##STR1## wherein R.sup.1 represents a fluoro-, chloro- or bromo-methyl group or a 2'-fluoroethyl group, R.sup.2 represents a group COR.sup.6 where R.sup.6 is a C.sub.1-3 alkyl group or OR.sup.2 and R.sup.3 together form a 16.alpha.,17.alpha.-isopropylidenedioxy group; R.sup.3 represents a hydrogen atom, a methyl group (which may be in either the .alpha.- or .beta.-configuration) or a methylene group; R.sup.4 represents a hydrogen, chlorine or fluorine atom; R.sup.5 represents a hydrogen or fluorine atom and symbol represents a single or double bond have good anti-inflammatory activity, particularly on topical applications. The compounds of formula I are prepared by esterification, halogenation, reduction, deprotection and reaction at a 9,11-double bond to form a 9.alpha.-halo-11.beta.-hydroxy grouping. Pharmaceutical compositions containing the compounds of formula I and methods for the use of the compounds are described and claimed.
Inventor(s):	Phillipps; Gordon H. (Wembley, GB2), Bain; Brian M. (Chalfont St. Peter, GB2), Steeples; Ian P. (Ruislip Manor, GB2), Williamson; Christopher (Cobham, GB2)
Assignee:	Glaxo Group Limited (London, GB2)
Application Number:	06/234,113
Patent Claims:	1. Compounds of the formula ##STR5## wherein R.sup.1 represents a fluoro-, chloro- or bromo-methyl group or a 2'-fluoroethyl group, R.sup.2 represents a group COR.sup.6 where R.sup.6 is a C.sub.1-3 alkyl group or OR.sup.2 and R.sup.3 together form a 16.alpha.,17.alpha.-isopropylidenedioxy group; R.sup.3 represents a hydrogen atom, a methyl group (which may be in either the .alpha.- or .beta.- configuration) or a methylene group; R.sup.4 represents a hydrogen, chlorine or fluorine atom; R.sup.5 represents a hydrogen or fluorine atom and the symbol represents a single or double bond. 2. Compounds as claimed in claim 1 in which R.sup.1 is a chloromethyl or fluoromethyl group. 3. Compounds as claimed in claim 1 in which R.sup.4 is fluorine. 4. Compounds as claimed in claim 1 which are 1,4-dienes. 5. Compounds as claimed in claim 2 which are 1,4-dienes wherein R.sup.4 and R.sup.5 are fluorine and R.sup.3 is .alpha.- or .beta.-methyl or methylene. 6. Compounds as claimed in claim 5 which are 1,4-dienes wherein R.sup.3 is .alpha.-methyl group. 7. A compound as claimed in claim 1 which is S-chloromethyl 9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propiony loxyandrosta-1,4-diene-17.beta.-carbothioate. 8. S-chloromethyl 6.alpha., 9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propio nyloxyandrosta-1,4-diene-17.beta.-carbothioate. 9. Pharmaceutical compositions for topical use in antiinflammatory therapy, comprising at least one androstane compound of formula I as defined in claim 1, together with one or more pharmaceutical carriers or excipients. 10. A method of treating inflammation which comprises administering, to a subject suffering from inflammation, an effective amount of a compound of formula I as defined in claim 1. 11. A compound as claimed in claim 1 which is S-chloromethyl 9.alpha.-fluoro-11.beta.-hydroxy-16-methylene-3-oxo-17.alpha.-propionyloxy androsta-1,4-diene-17.beta.-carbothioate. 12. A compound as claimed in claim 1 which is S-fluoromethyl 6.alpha., 9.alpha.-difluoro-11.beta.-hydroxy-16.alpha., 17.alpha.-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17.beta.-carbothioat e. 13. A compound as claimed in claim 1 which is S-fluoromethyl 6.alpha., 9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propio nyloxyandrosta-1,4-diene-17.beta.-carbothioate. 14. Compounds as claimed in claim 5 wherein R.sup.2 is acetyl or propionyl. 15. A pharmaceutical composition as claimed in claim 9 wherein the active compound is S-chloromethyl 6.alpha., 9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propio nyloxyandrosta-1,4-diene-17.beta.-carbothioate. 16. A pharmaceutical composition as claimed in claim 9 wherein R.sup.1 is a chloromethyl or fluoromethyl group, R.sup.4 and R.sup.5 are fluorine, R.sup.3 is .alpha.- or .beta.-methyl or methylene and the compound is a 1,4-diene. 17. A method of treating inflammation which comprises administering, to a subject suffering form inflammation, an effective amount of the composition of claim 15. 18. A method of treating inflammation which comprises administering, to a subject suffering from inflammation, an effective amount of the composition of claim 16. 19. A process for the preparation of compounds as claimed in claim 1 in which a compound corresponding to formula I as defined in claim 1 but containing either a free 17.beta.-carbothioic acid group (or salt thereof) or a free 17.alpha.-hydroxy group (R.sup.3 being a hydrogen atom or a methyl or methylene group), any other reactive groups present optionally being in protected form, is subjected to esterification. 20. A process for the preparation of compounds as claimed in claim 1 in which a compound corresponding to formula I as defined in claim 1 but containing a 17.beta.-substituent of formula --COS(CH.sub.2).sub.n Y (wherein Y represents a displaceable substituent and n is 1 or 2) is reacted with a compound serving to replace the group Y by a halogen atom, whereby a compound of formula I as claimed in claim 1 is formed. 21. A process for the preparation of compounds as claimed in claim 1 in which a compound corresponding to formula I as defined in claim 1 but carrying an 11-oxo group is subjected to reduction to form the required 11.beta.-hydroxy androstane. 22. A process for the preparation of compounds as claimed in claim 1 in which a compound corresponding to formula I as defined in claim 1 but carrying a protected 11.beta.-hydroxy group is subjected to deprotection. 23. A process for the preparation of compounds as claimed in claim 1 in which a compound corresponding to formula I as defined in claim 1 but having a 9,11-double bond, and no substituent in the 11-position, is reacted with an N-bromoamide or -imide followed by treatment of the bromohydrin thus obtained with a base to form the corresponding 9,11-epoxide, which epoxide is reacted with hydrogen fluoride or hydrogen chloride whereby a compound of formula I as claimed in claim 1 is formed containing a 9.alpha.-fluoro-11 hydroxy or 9-chloro-11.beta.-hydroxy grouping. 24. A process for the preparation of compounds as claimed in claim 1 in which a compound corresponding to formula I as defined in claim 1 but having a 9,11-double bond and no substituent in the 11-position, is reacted with an N-chloro-amide or -imide whereby a compound as claimed in claim 1 is obtained which contains 9.alpha.-chloro-11.beta.-hydroxy grouping. 25. A process for the preparation of compounds as claimed in claim 1 in which a compound corresponding to formula I as defined in claim 1 in which represents a double bond is subjected to partial reduction to produce a corresponding compound in which represents a single bond.