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Details for Patent: 4,710,495

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Details for Patent: 4,710,495

Title: Soft steroids having anti-inflammatory activity
Abstract:Novel soft steroid anti-inflammatory agents, said agents being esters or thioesters of 17.alpha.-alkoxy-11.beta.-hydroxyandrost-4-en-3-one-17.beta.-carboxylic acids, pharmaceutical compositions containing said agents, novel chemical intermediates useful in the preparation of said agents and methods of administering same to mammals in the treatment of inflammation. Preferred compounds are the haloalkyl esters of 17.alpha.-alkoxy-11.beta.-hydroxyandrost-4-en-3-one-17.beta.-carboxylic acids.
Inventor(s): Bodor; Nicholas S. (Gainesville, FL)
Assignee: Otsuka Pharmaceutical Co., Ltd. (Tokyo, JP)
Filing Date:Apr 08, 1985
Application Number:06/721,282
Claims:1. A compound selected from the group consisting of:

(a) a compound of the formula ##STR78## wherein: R.sub.1 is C.sub.1 -C.sub.10 alkyl; C.sub.2 -C.sub.10 (monohydroxy or polyhydroxy) alkyl; C.sub.1 -C.sub.10 (monohalo or polyhalo)alkyl; or --CH.sub.2 COOR.sub.6 wherein R.sub.6 is unsubstituted or substituted C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkenyl or C.sub.2 -C.sub.10 alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, ##STR79## or R.sub.6 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl; or R.sub.1 is --CH.sub.2 CONR.sub.7 R.sub.8 wherein R.sub.7 and R.sub.8, which can be the same or different, are each hydrogen, lower alkyl, C.sub.3 -C.sub.8 cycloalkyl, phenyl or benzyl, or R.sub.7 and R.sub.8 are combined such that --NR.sub.7 R.sub.8 represents the residue of a saturated monocyclic secondary amine; or R.sub.1 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group of phenyl and benzyl substituents defined hereinabove with respect to R.sub.6 ; or R.sub.1 is ##STR80## (lower alkyl) wherein Y is --S--, --SO--, --SO.sub.2 -- or --O-- and R.sub.9 is hydrogen, lower alkyl or phenyl, or R.sub.9 and the lower alkyl group adjacent to Y are combined so that R.sub.1 is a cyclic system of the type ##STR81## wherein Y is defined as above and the alkylene group contains 3 to 10 carbon atoms, of which at least 3 and no more than 6 are ring atoms; or R.sub.1 is R1 ? ##STR82## wherein R.sub.6 is defined as hereinabove and R.sub.10 is hydrogen, lower alkyl, phenyl or halophenyl;

R.sub.2 is unsubstituted or substituted C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkenyl or C.sub.2 -C.sub.10 alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, ##STR83## or R.sub.2 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl;

R.sub.3 is hydrogen, .alpha.-hydroxy, .beta.-hydroxy, .alpha.-methyl, .beta.-methyl, .dbd.CH.sub.2, or .alpha.- or .beta.-OR.sub.2 wherein R.sub.2 is identical to R.sub.2 as defined hereinabove;

R.sub.4 is hydrogen, fluoro or chloro;

R.sub.5 is hydrogen, fluoro, chloro or methyl;

X is --O-- or --S--;

and the dotted line in ring A indicates that the 1,2 linkage is saturated or unsaturated;

(b) a quaternary ammonium salt of a compound of formula (I) wherein at least one of R.sub.1 and R.sub.2 is a hal.alpha.-substituted alkyl group;

(c) a compound of the formula ##STR84## wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5, and the dotted line is ring A are as defined in (a) above, Z is carbonyl or .beta.-hydroxymethylene and R.sub.3 is hydrogen, .alpha.-methyl, .beta.-methyl, .dbd.CH.sub.2 or .alpha.- or .beta.-OR.sub.2 wherein R.sub.2 is identical to R.sub.2 above;

(d) a compound of the formula ##STR85## wherein R.sub.2, R.sub.4, R.sub.5, and the dotted line in ring A are as defined in (a) above, Z is carbonyl or .beta.-hydroxymethylene and R.sub.3 is hydrogen, .alpha.-methyl, .beta.-methyl, .dbd.CH.sub.2 or .alpha.- or .beta.-OR.sub.2 wherein R.sub.2 is identical to R.sub.2 above;

(e) a compound of the formula ##STR86## wherein M is alkali metal, thallium, alkaline earth metal/2 or NH.sub.4 and R.sub.2, R.sub.3, R.sub.4, R.sub.5, Z and the dotted line in ring A are as defined in (a) and (d) above;

(f) a compound of the formula ##STR87## wherein R.sub.3 is hydrogen, .alpha.-methyl, .beta.-methyl, ##STR88## or .beta.-OR.sub.2, and R.sub.1, R.sub.4 and R.sub.5 are as defined in (a) above;

(g) a compound of the formula ##STR89## wherein R.sub.3 is hydrogen, .alpha.-methyl, .beta.-methyl, ##STR90## or .beta.-OR.sub.2, and R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are as defined in (a) above;

(h) a compound of the formula ##STR91## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X and the dotted line in ring A are as defined in (g) above.

2. A compound selected from the group consisting of:

(a) a compound of the formula ##STR92## wherein: R.sub.1 is C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl; --CH.sub.2 COOR.sub.6 wherein R.sub.6 is C.sub.1 -C.sub.6 alkyl; --CH.sub.2 --Y--(C.sub.1 -C.sub.6 alkyl) wherein Y is --S--, --SO--, --SO.sub.2 -- or --O--; or ##STR93## wherein R.sub.6 ' is C.sub.1 -C.sub.6 alkyl or phenyl; R.sub.2 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, phenyl, benzyl or C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl;

R.sub.3 is hydrogen, .alpha.-hydroxy, .alpha.-methyl, .beta.-methyl or ##STR94## wherein R.sub.2 is identical to R.sub.2 as defined hereinabove; R.sub.4 is hydrogen or fluoro;

R.sub.5 is hydrogen or fluoro;

X is --O-- or --S--;

and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated;

(b) a quaternary ammonium salt of a compound of formula (I) wherein at least one of R.sub.1 and R.sub.2 is a hal.alpha.-substituted alkyl group;

(c) a compound of the formula ##STR95## wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5, and the dotted line is ring A are as defined in (a) above, Z is carbonyl or .beta.-hydroxymethylene and R.sub.3 is hydrogen, .alpha.-methyl, .beta.-methyl, .dbd.CH.sub.2 or .alpha.- or .beta.-OR.sub.2 wherein R.sub.2 is identical to R.sub.2 above;

(d) a compound of the formula ##STR96## wherein R.sub.2, R.sub.4, R.sub.5, and the dotted line in ring A are as defined in (a) above, Z is carbonyl or .beta.-hydroxymethylene and R.sub.3 is hydrogen, .alpha.-methyl, .beta.-methyl, .dbd.CH.sub.2 or .alpha.- or .beta.-OR.sub.2 wherein R.sub.2 is identical to R.sub.2 above;

(e) a compound of the formula ##STR97## wherein M is alkali metal, thallium, alkaline earth metal/2 or NH.sub.4 and R.sub.2, R.sub.3, R.sub.4, R.sub.5, Z and the dotted line in ring A are as defined in (a) and (d) above;

(f) a compound of the formula ##STR98## wherein R.sub.3 is hydrogen, .alpha.-methyl, .beta.-methyl, .alpha.-OR.sub.2 or .beta.-OR.sub.2, and R.sub.1, R.sub.4 and R.sub.5 are as defined in (a) above;

(g) a compound of the formula ##STR99## wherein R.sub.3 is hydrogen, .alpha.-methyl, .beta.-methyl, .alpha.-OR.sub.2 or .beta.-OR.sub.2, and R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are as defined in (a) above;

(h) a compound of the formula ##STR100## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X and the dotted line in ring A are as defined in (g) above.

3. A compound of claim 1 or 2, said compound having the structural formula (I).

4. A compound of claim 1 or 2, said compound being a quaternary ammonium salt of a compound of formula (I) wherein at least one of R.sub.1 and R.sub.2 is a hal.alpha.-substituted alkyl group.

5. A compound of claim 1 or 2, said compound having the structural formula (III).

6. A compound of claim 1 or 2, said compound having the structural formula (IV).

7. A compound of claim 1 or 2, said compound having the structural formula (V).

8. A compound of claim 1 or 2, said compound having the structural formula (VII).

9. A compound of claim 1 or 2, said compound having the structural formula (VIII).

10. A compound of claim 1 or 2, said compound having the structural formula (IX).

11. A compound of claim 1, said compound having the structural formula (I) wherein R.sub.3 is hydrogen, .alpha.-methyl, .beta.-methyl, .dbd.CH.sub.2, .alpha.-OR.sub.2 or .beta.-OR.sub.2.

12. A compound of claim 1 or 2, said compound having the structural formula (I) wherein R.sub.1 is C.sub.1 -C.sub.6 alkyl.

13. A compound of claim 12 wherein R.sub.2 is C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 monohaloalkyl.

14. A compound of claim 12 wherein R.sub.2 is C.sub.3 -C.sub.8 cycloalkyl, phenyl, benzyl or C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl.

15. A compound of claim 1 or 2, said compound having the structural formula (I) wherein R.sub.1 is C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl.

16. A compound of claim 15 wherein C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl is C.sub.1 -C.sub.6 monohaloalkyl.

17. A compound of claim 16 wherein X is --O--.

18. A compound of claim 17 wherein R.sub.4 and R.sub.5 are hydrogen.

19. A compound of claim 17 wherein at least one of R.sub.4 and R.sub.5 is fluoro.

20. A compound of claim 17 wherein R.sub.4 is fluoro and R.sub.5 is hydrogen.

21. A compound of claim 16, wherein C.sub.1 -C.sub.6 monohaloalkyl is C.sub.1 -C.sub.6 monochloroalkyl.

22. A compound of claim 21 wherein R.sub.2 is C.sub.1 -C.sub.6 alkyl.

23. A compound of claim 21 wherein R.sub.2 is C.sub.3 -C.sub.8 cycloalkyl, phenyl, benzyl or C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl.

24. A compound of claim 21 wherein X is --O--.

25. A compound of claim 24 wherein R.sub.4 and R.sub.5 are hydrogen.

26. A compound of claim 24 wherein at least one of R.sub.4 and R.sub.5 is fluoro.

27. A compound of claim 26 wherein R.sub.3 is .alpha.-methyl or .beta.-methyl.

28. A compound of claim 24 wherein R.sub.4 is fluoro and R.sub.5 is hydrogen.

29. A compound of claim 28 wherein R.sub.3 is .alpha.-methyl or .beta.-methyl.

30. A compound of claim 16 wherein R.sub.2 is C.sub.1 -C.sub.6 alkyl.

31. A compound of claim 16 wherein R.sub.2 is C.sub.3 -C.sub.8 cycloalkyl, phenyl, benzyl or C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl.

32. A compound of claim 15 wherein C.sub.1 -C.sub.6 monochloroalkyl is chloromethyl.

33. A compound of claim 32 wherein R.sub.2 is C.sub.1 -C.sub.6 alkyl.

34. A compound of claim 32 wherein R.sub.2 is C.sub.3 -C.sub.8 cycloalkyl, phenyl, benzyl or C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl.

35. A compound of claim 15 wherein R.sub.2 is C.sub.1 -C.sub.6 alkyl.

36. A compound of claim 15 wherein R.sub.2 is C.sub.3 -C.sub.8 cycloalkyl, phenyl, benzyl or C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl.

37. A compound of claim 15 wherein X is --O--.

38. A compound of claim 37 wherein at least one of R.sub.4 and R.sub.5 is fluoro.

39. A compound of claim 38 wherein R.sub.3 is .alpha.-methyl or .beta.-methyl.

40. A compound of claim 37 wherein R.sub.4 and R.sub.5 are hydrogen.

41. A compound of claim 37 wherein R.sub.4 is fluoro and R.sub.5 is hydrogen.

42. A compound of claim 41 wherein R.sub.3 is .alpha.-methyl or .beta.-methyl.

43. A compound of claim 1 or 2, said compound having the structural formula (I) wherein X is --O--.

44. A compound of claim 43 wherein R.sub.4 and R.sub.5 are hydrogen.

45. A compound of claim 43 wherein at least one of R.sub.4 and R.sub.5 is fluoro.

46. A compound of claim 43 wherein R.sub.4 is fluoro and R.sub.5 is hydrogen.

47. A compound of claim 1, said compound having the structural formula (I) wherein R.sub.1 is --CH.sub.2 CONR.sub.7 R.sub.8.

48. A compound of claim 47 wherein at least one of R.sub.7 and R.sub.8 is hydrogen or C.sub.1 -C.sub.6 alkyl.

49. A compound of claim 47 wherein R.sub.7 and R.sub.8 are combined so that --NR.sub.7 R.sub.8 represents the residue of a saturated monocyclic secondary amine containing 5 to 7 carbon atoms.

50. A compound of claim 49 wherein --NR.sub.7 R.sub.8 represents morpholino, 1-pyrrolidinyl, 4-benzyl-1-piperazinyl, perhydr.alpha.-1, 2,4-oxathiazin-4-yl, 1- or 4-piperazinyl, 4-methyl-1-piperazinyl, piperidino, hexamethyleneimino, 4-phenylpiperidino, 2-methyl-1-pyrazolidinyl, 1- or 2-pyrazolidinyl, 3-methyl-1-imidazolidinyl, 1- or 3-imidazolidinyl, 4-benzylpiperidino or 4-phenyl-1-piperazinyl.

51. A compound of claim 1, said compound having the structural formula (I) wherein R.sub.1 is ##STR101## (lower alkyl) wherein R.sub.9 is hydrogen or methyl, or wherein R.sub.9 and the lower alkyl group adjacent to Y are combined so that R.sub.1 is ##STR102## wherein Y is --S--, --SO--, --SO.sub.2 -- or --O-- and the alkylene group contains 3 to 10 carbon atoms, of which at least 3 and no more than 6 are ring atoms.

52. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a topical inflammatory response, which comprises topically administering thereto an anti-inflammatory effective amount of a composition of claim 1.

53. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a localized inflammatory response, which comprises locally administering thereto an anti-inflammatory effective amount of a composition of claim 1.

54. A compound of claim 1 or 2, said compound having the structural formula (I) wherein R.sub.1 is --CH.sub.2 COOR.sub.6, --CH.sub.2 --Y--(C.sub.1 --C.sub.6 alkyl) or ##STR103##

55. A compound of claim 1 or 2, said compound having the structural formula (III) wherein Z is .beta.-hydroxymethylene and R.sub.2 is C.sub.1 -C.sub.6 alkyl.

56. A compound of claim 1 or 2, said compound having the structural formula (IV) wherein Z is .beta.-hydroxymethylene and R.sub.2 is C.sub.1 -C.sub.6 alkyl.

57. A compound of claim 1 or 2, said compound having the structural formula (VII) wherein Z is .beta.-hydroxymethylene and R.sub.1 is C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 monohaloalkyl.

58. A compound of claim 1 or 2, said compound having the structural formula (VIII) wherein Z is .beta.-hydroxymethylene and R.sub.2 is C.sub.1 -C.sub.6 alkyl.

59. A compound of claim 1 or 2, said compound having the structural formula (IX) wherein R.sub.1 is C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl.

60. A compound of claim 59 wherein C.sub.1 -C.sub.6 (monohalo or polyhalo)alkyl is C.sub.1 -C.sub.6 monohaloalkyl.

61. A compound of claim 60 wherein R.sub.2 is C.sub.1 -C.sub.6 alkyl.

62. A compound of claim 1 or 2, said compound having the structural formula (IX) wherein R.sub.1 is C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 monohaloalkyl, R.sub.2 is C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 monohaloalkyl and X is --0--.

63. A compound of claim 62 wherein R.sub.3 is hydrogen or methyl, R.sub.4 is hydrogen and R.sub.5 is hydrogen or chloro and the 1,2 linkage is saturated or unsaturated.

64. A pharmaceutical composition of matter comprising an anti-inflammatory effective amount of a compound of claim 1 or 2 having the structural formula (I), in combination with a non-toxic pharmaceutically acceptable carrier therefor suitable for topical or other local application.

65. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a topical inflammatory response, which comprises topically administering thereto an anti-inflammatory effective amount of a composition of claim 64.

66. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a localized inflammatory response, which comprises locally administering thereto an anti-inflammatory effective amount of a composition of claim 64.

67. A compound of claim 1 or 2, said compound having the structural formula (I) wherein R.sub.3, R.sub.4 and R.sub.5 are hydrogen and the 1,2 linkage is saturated or unsaturated.

68. A compound of claim 1 or 2, said compound having the structural formula (I) wherein R.sub.3 is selected from hydrogen or methyl, R.sub.4 is fluoro and R.sub.5 is hydrogen and the 1,2 linkage is saturated or unsaturated.

69. A compound of claim 1 or 2, said compound having the structural formula (I) wherein R.sub.3 is hydrogen or methyl, R.sub.4 is hydrogen or fluoro and R.sub.5 is fluoro or methyl and the 1,2 linkage is unsaturated.

70. A compound of claim 1 or 2, said compound having the structural formula (I) wherein R.sub.3 is ##STR104## and wherein R.sub.4 is fluoro and R.sub.5 is hydrogen and the 1,2 linkage is unsaturated.
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