Patent EA-001401-B1 (EA)
Title: Lactone derivatives of 17.beta-carboxy, carbothio and amide androstane derivatives
Inventor: BIGGADIKE KEITH
IPC: C07J3/00
Filed: 1996-12-19
Abstract: 1. A compound of formula (1)    and solvates thereof, in which R1 represents O, S or NH; R2 individually represents OC(=O)C1-6 alkyl; R3 individually represents hydrogen, methyl (which may be in either the .alpha. or .beta. configuration) or methylene; or R2 and R3 together represent    wherein R6 and R7 are the same or different and each represents hydrogen or C1-6 alkyl; R4 and R5 are the same or different and each represents hydrogen or halogen.. 2. A compound according to claim 1 in which R1 represents O or S. 3. A compound according to claim 2 in which R1 represents S. 4. A compound according to any of claims 1 to 3 in which R1 is bonded to the alpha carbon atom of the lactone moiety. 5. A compound according to any of claims 1 to 4 in which R2 individually represents OC(=O) C1-3 alkyl. 6. A compound according to claim 5 in which R2 represents OC(=O) ethyl. 7. A compound according to any of claims 5 or 6 in which R3 is methyl. 8. A compound according to any of claims 1 to 4 in which R2 and R3 together represent    wherein R6 and R7 are the same or different and each represents hydrogen or C1-6 alkyl. 9. A compound according to claim 8 in which R6 and R7 are the same or different and each represents hydrogen or C1-3 alkyl. 10. A compound according to claim 8 or 9 in which R6 and R7 are the same or different and each represents hydrogen, methyl or n-propyl. 11. A compound according to any of claims 8 to 10 in which R6 and R7 are both methyl. 12. A compound according to any of claims 8 to 10 in which R6 and R7 are different and each represents hydrogen or n-propyl. 13. A compound according to any of claims 1 to 12 in which R4 and R5 are the same or different and each represents hydrogen, fluorine or chlorine. 14. A compound according to any of claims 1 to 13 in which R6 and R7 both fluorine. 15. A compound according to claim 1 in which R1 is S; R2 is OC(=O) C1-6 alkyl; R3 is methyl; R4 and R5 are the same or different and each represents hydrogen or fluorine. 16. A compound according to claim 15 in which R2 is OC(=O)ethyl and R4 and R5 are each fluorine. 17. A compound according to claim 1 in which R1 is S; R2 and R3 together represent    wherein R6 and R7 are the same or different and each represents hydrogen or C1-6alkyl; R4 and R5 which can be the same or different each represents hydrogen or fluorine. 18. A compound according to claim 17 in which R6 and R7 are the same or different and each represents hydrogen, methyl or n-propyl; and R4 and R5 are each fluorine. 19. S-(2-oxo-tetrahydro-furan-3-yl)ester 17.alpha.-Butyryloxy-6.alpha.,9.alpha.-difluoro11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic acid; S-(2-oxo-tetrahydro-furan-3-yl)ester 17.alpha.-Acetyloxy-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic acid; S-(2-oxo-tetrahydro-furan-3-yl)ester 9.alpha.-Fluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxo-17.alpha.-propionyloxy-androsta-1,4-diene-17.beta.-carbothioic acid; S-(5-oxo-tetrahydro-furan-2-yl) ester 6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha-propionyloxy-androsta- 1,4-diene-17.beta.-carbothioic acid; S-(2-oxo-tetrahydro-furan-4-yl)ester.6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17a-propionyl oxy-androsta- 1,4-diene-17.beta.-carbothioic acid; (2-oxo-tetrahydro-furan-3-yl)ester 6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha-propionyloxy-androsta- 1,4-diene-17.beta.-carboxylic acid; (2-oxo-tetrahydro-furan-5-yl)ester 6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-propylidenedioxy-3-oxo-androsta-1,4-diene-17.beta.-carboxylic acid; S-(2-oxo-tetrahydro-furan-5-yl)ester 6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-3-oxo-androsta-1.4-ene-17.beta.-carbothioic acid; S-(2-oxo-tetrahydro-furan-3-yl)ester 6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprolpylidenedioxy-3-oxo-androsta- 4-ene-17.beta.-carbthiolic acid; N-(2-oxo-tetrahydro-furan-3-yl)amide 6.alpha,9.alpa-Difluoro-11.beta.-hydroxy-16.alpha,17.alpha-isopropyiidenedioxy-3-oxo-androsta-1,4-diene-17.beta.-carboxylic acid; (2-oxo-tetrahydro-furan-3-yl)ester 6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.,17 alpha.- isopropylidenedi oxy 3-oxo-androsta-1,4-diene-17 .beta.-carboxylic acid; S-(2-oxo-tetrahydro-furan-3-yl)ester 16.alpha.,17.alpha.-Butylidenedioxy-11.beta.-hydroxy-3-oxo-androsta-1,4-diene-17 .beta.-carbothioic acid; S-(2-oxo-tetrahydro-furan-3-yl)ester 16.alpha.,17.alpha.-(R-Butylidenedioxy)-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-3-oxo-androsta-1,4-diene-17.beta.-carbothioic acid; (2-oxo-tetrahydro-furan-3-yl)ester 16.alpha.,17.alpha.-Butylidenedioxy-11.beta.-hydroxy-3-oxo-androsta- 1.4-diene-17.beta.-carboxylic acid; N-(2-oxo-tetrahydro-furan-3-yl)amide 16.alpha.,17.alpha.-(R-Butylidenedioxy)-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-3-oxo-androsta-4-ene-17.beta.-carboxylic acid; N-(2-oxo-tetrahydro-furan-4-yl)amide 6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.,17.alpha- isopropyiidenedioxy-3-oxo-androsta-1,4-diene-17.beta.-carboxylic acid; S-(2-oxo-tetrahydro-furan-3-yl)ester 6.alpha.,9.alpha.-Diffouro-11.beta-hydroxy-16.alpha-methyl-3-oxo-17.alpha- propionyloxy-androsta-4-ene-17.beta.-carbothioic acid; (5-oxo-tetrahydro-furan-2-yl)ester 16.alpha,17.alpha-(R-Butylidenedioxy)-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-3-oxo-androsta-4-ene-17.beta.-carbothioic acid; and solvates thereof. 20. S-(2-oxo-tetrahydro-furan-3-yl)ester 6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alph a.-propionyloxy-androsta-1,4-diene-17.beta.-carbothioic acid; and solvates thereof. 21. S-(2-oxo-tetrahydro-furan-3-yl)ester 6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.,17.alpha- isopropyiidenedioxy-3-oxo-androsta-1,4-diene-17.beta.-carbothioic acid; and solvates thereof. 22. S-(2-oxo-tetrahydro-furan-3-yl)ester 16.alpha.,17.alpha.-(R-Butylidenedioxy)-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-3-oxo-androsta-4-ene-17.beta.-carbothioic acid; and solvates thereof 23. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 22 or a physioligically acceptable solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers. 24. A pharmaceutical aerosol formulation comprising a compound of formula (I) as defined in any of claims 1 to 22 or a physiologically acceptable solvate thereof, and a fluorocarbon or hydrogen-containing chlorofluoro carbon as propellant, optionally in combination with a surfactant and or a cosolvent. 25. A combiantion comprising a compound of formula (1) as defined in any of claims 1 to 22 or a physiologically acceptable solvate thereof together with another therapeutically active agent. 26. A combination according to claim 25 in which said another therapeutically active agent is a .beta.2-adrenoreceptor agonist. 27. A method for the treatment of a human or animal subject with an anti-inflammatory and/or allergic condition which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) as defined in any of claims 1 to 22 or a physiologically acceptable solvate thereof. 28. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises treating a compound of formula (II)   in which R2, R3, R4 R5 and -----  are as defined hereinbefore for compounds of formula (I) and X represents OH or an activated derivative thereof with a compound of formula (Ill)   and salts thereof in which Z represents OH NH2 or SH;and further, if necessary or desirable followed by (i) solvate formation or (ii) preparation of an individual isomer of a compound of formula (I). 29. A process for the preparation of a compound of formula (I) as defined in claim 1 in which for compounds of formula (I) wherein R1 represents O or S treating a compound of formula (II) in which R2, R3, R4, R5 are as defined hereinbefore for compounds of formula (I) and X represents OH or  SH or their corresponding salts, with a compound of formula (VI) or formula (VII)   in which Q represents a suitable leaving group (such as Cl, Br, OSO2A wherein A is, for example CH3, CF3, p-CH3C6H4); and further, if necessary or desirable followed by (1) solvate formation or (2) preparation of an individual isomer of a compound of formula (I). 30. A process for the preparation of a compound of formula (I) as defined in claims 28 and 29 in which a compound of formula (I) is converted to a different compound of formula (I) and further if necessary or desirable followed by (1) solvate formation or (2) preparation of an individual isomer of a compound of formula (I). 31. A process for the preparation of a compound of formula (I) as defined in claims 28 and 29 in which deprotecting a protected derivative of a compound of formula (I), and further, if necessary or desirable followed by (1) solvate formation or (2) preparation of an individual isomer of a compound of formula (I).