17β-carbothioate 17α-arylcarbonyloxyloxy androstane derivative as anti-inflammatory agents

• US 7,498,321 B2
• Filed: 08/03/2001
• Issued: 03/03/2009
• Est. Priority Date: 08/05/2000
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline Intellectual Property Management Limited (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Jones, Paul, Payne, Jeremy John, Biggadike, Keith
• Primary Examiner(s): Badio; Barbara P
• Application Number:
  US10/343,842
• Publication Number:
  US 20040028615A1
• Time in Patent Office: 2,769 Days
• Field of Search: 552/610, 540/114, 540/107, 540/120, 514/172, 514/180
• US Class Current: 514/172
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/44 Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
• CPC Class Codes: C07J 31/006 not covered by C07J31/003

Abstract

There are provided according to the invention compounds of formula (I) wherein R₁ represents C_1-6 alkyl or C_1-6 haloalkyl; R₂ represents —C(═O)-aryl or —C(═O)-heteroaryl; R₃ represents hydrogen, methyl (which may be in either the α or β configuration) or methylene; R₄ and R₅ are the same or different and each represents hydrogen or halogen; and——represents a single or a double bond; and salts and solvates thereof. There are also provided processes for preparing compounds of formula (I) and use of the compounds in therapy especially in the treatment of inflammatory and allergic conditions.

Claims

1. A compound of formula (I)

2. A compound according to claim 1 in which R₁ represents fluoromethyl, chloromethyl, bromomethyl or 2′

-fluoroethyl.

3. A compound according to claim 2 in which R₁ represents fluoromethyl.

4. A compound according to claim 1 in which R₂ represents —

C(═

O)-heteroaryl, wherein said heteroaryl is a 5 member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N and S, or a 5 member heterocyclic aromatic ring containing 2-3 hetero atoms selected from N, O and S, or a 6 member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N, O and S.

5. A compound according to claim 4 wherein heteroaryl represents a 5-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms selected from N and S which may optionally be substituted.

6. A compound according to claim 5 wherein the heterocyclic ring is substituted with one or more substituents selected from C_1-6alkyl, C_1-6alkoxy and halogen.

7. A compound according to claim 5 in which the heterocyclic ring is pyrrolyl or thiophenyl.

8. A compound according to claim 7 in which the heterocyclic ring is thiophenyl.

9. A compound according to claim 5 in which the 5-membered heterocyclic ring contains 2 heteroatoms selected from N and S.

10. A compound according to claim 9 wherein the heterocyclic ring is selected from thiazolyl, isothiazolyl, pyrazolyl and imidazolyl.

11. A compound according to claim 5 in which the 5-membered heterocyclic ring contains 3 heteroatoms selected from N and S.

12. A compound according to claim 11 wherein the heterocycle is thiadiazolyl.

13. A compound according to claim 5 wherein the heterocyclic ring is substituted with one or more substituents selected from C_1-6alkyl and halogen.

14. A compound according to claim 1 in which R₃ is methyl.

15. A compound according to claim 1 in which R₄ and R₅ are the same or different and each represents hydrogen, fluorine or chlorine.

16. A compound according to claim 1 in which R₄ and R₅ are the same or different and each represents hydrogen or fluorine.

17. A compound according to claim 1 in which both R₄ and R₅ are fluorine.

18. A compound according to claim 1 in which represents a double bond.

19. A compound according to claim 1 which is:

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17α

-[(2-thienylcarbonyl)oxy]-androsta -1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17α

-[(3-thienylcarbonyl)oxy]-androsta -1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

17β

-(Benzoyl)oxy-6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene -17β

-carbothioic acid S-fluoromethyl ester;

or a salt or solvate of any one thereof.

20. A compound of formula (I) according to claim 1 which is:

6α

,9α

-Difluoro-11β

-hydroxy-17α

-[(isoxazole-5-carbonyl)oxy]-16α

-methyl-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyi ester;

17α

-[(5-Chlorothiophene-2-carbonyl)oxy]-6α

,9α

-difluoro-11β

-hydroxy-16α

-methyl-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-17α

-[(3,5-dimethylisoxazole-4-carbonyl)oxy]-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

17α

-[(5-Chloro-4-methoxy-thiophene-3-carbonyl)oxy]-6α

, 9α

-difluoro-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(4-methyl-1,2,3-thiadiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

17α

-[(3-Bromothiophene-2-carbonyl)oxy]-6α

,9α

-difluoro-11β

-hydroxy-16α

-methyl-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

17α

-[(2,5-Dichlorothiophene-3-carbonyl)oxy]-6α

,9α

-difluoro-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

17α

-[(3-Chlorothiophene-2-carbonyl)oxy]-6α

,9α

-difluoro-11β

-hydroxy-16α

-methyl-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(5-methylisoxazole-4-carbonyl)oxy]-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(1-methyl-1H-pyrrole-2-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17α

-[(1,3-thiazoie-4-carbonyl)oxy]-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-17α

-[(2,4-dimethyl-1,3-thiazole-5-carbonyl)oxy]-11β

-hydroxy-16α

-methyl -3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(5-methylisoxazole-3-carbonyl)oxy]-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(3-methylisoxazole-5-carbonyl)oxy]-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-17α

-[(1,3-dimethyl-1H-pyrazole-5-carbonyi)oxy]-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-17α

-[(isoxazole-3-carbonyl)oxy]-16α

-methyl-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-17α

-[(4-methoxy-thiophene-3-carbonyi)oxy]-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(2-methyl-1,3-thiazole-4-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-17α

-[(3-ethoxy-thiophene-2-carbonyl)oxy]-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothicic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17α

-[(1,2,3-thiadiazole-4-carbonyt)oxy]-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17α

-[(1H-pyrrole-2-carbonyl)oxy]-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17α

-[(1,3-thiazole-5-carbonyl)oxy]-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17α

-[(1,2,5-thiadiazole-3-carbonyl)oxy]-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-17α

-[(isothiazole-3-carbonyl)oxy]-16α

-methyl-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-17α

-[(isothiazole-5-carbonyl)oxy]-16α

-methyl-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(5-methylthiophene-2-carbonyl)oxy]-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(3-methylthiophene-2-carbonyl)oxy]-3-oxo -androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

17α

-[(1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl)oxy]-6α

, 9α

-difluoro-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid 5-fluoromethyl ester;

6α

,9α

-Difluoro-17α

-[(1-methyl-1H-imidazole-5-carbonyl)oxy]-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17α

-[(1,2,3-thiadiazole-5-carbonyl)oxy]-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

or a salt or solvate of any one thereof.

21. A compound of claim 1 wherein when R₁ is a C₁ fluoroalkyl, and R₃ is methyl, and R₄ and R₅ are both fluorine, R₂ represents —

C(═

O)-aryl or —

C(═

O)-heteroaryl, wherein heteroaryl is a 5 member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N and S, or a 5 member heterocyclic aromatic ring containing 2-3 heteroatoms selected from N, O and S, or a 6 member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N, O and S.

22. A compound according to claim 1 which is 6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester.

23. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers.

24. A method for the treatment of a human or animal subject with an 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 claim 1 or a physiologically acceptable salt or solvate thereof.

25. A process for preparing a compound of formula (I) according to claim 1 which comprises alkylation of a compound of formula (II)

26. A process according to claim 25 wherein alkylation is performed by reacting the compound of formula (II) with an alkyl or haloalkyl halide.

27. A compound of formula (II)

28. A compound of formula (XV)

29. A compound of formula (XVI)

30. A compound of formula (I)

31. The compound according to claim 30, wherein:

R₃ represents methyl (which may be in either the α

or β

configuration);

R₄ and R₅ are the same or different and each represents halogen; and

represents a single or a double bond; and

or a salt or a solvate thereof.

32. The compound according to claim 30, wherein is methyl.

33. The compound according to claim 30, wherein R₄ and R₅ are the same or different and each represents hydrogen, fluorine or chlorine.

34. The compound according to claim 30, wherein R₄ and R₅ are the same or different and each represents hydrogen or fluorine.

35. The compound according to claim 30, wherein both R₄ and R₅ are fluorine.

36. The compound according to claim 30, wherein represents a double bond.

37. A method for the treatment of at least one condition selected from the group consisting of inflammatory and allergic conditions in a human or animal subject, which comprises administering an effective amount of the compound of formula (I) or a physiologically acceptable salt or solvate thereof as defined in claim 30 to said human or animal subject in need thereof for the treatment of said at least one condition.

38. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 30 or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers.

39. A process for preparing a compound of formula (I) according to claim 30 which comprises alkylation of a compound of formula (II)

40. The process according to claim 39, wherein alkylation is performed by reacting the compound of formula (II) with an alkyl halide.

41. A compound of formula (II)

42. A compound of formula (XV)

43. A compound of formula (XVI)

44. A compound of formula (I)

45. The compound according to claim 44, wherein:

R₃ represents methyl (which may be in either the α

or β

configuration);

R₄ and R₅ are the same or different and each represents halogen; and

represents a single or a double bond;

or a salt or a solvate thereof.

46. The compound according to claim 44, wherein R₁ represents fluoromethyl, chloromethyl, bromomethyl or 2′

-fluoroethyl.

47. The compound according to claim 44, wherein R₁ represents fluoromethyl.

48. The compound according to claim 44, wherein the heteroaryl of R₂ represents a 5-member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N and S, or a 5 member heterocyclic aromatic ring containing 2-3 hetero atoms selected from N, O and S which may optionally be substituted.

49. The compound according to claim 48, wherein the 5-membered heterocyclic aromatic ring is substituted with one or more substituents selected from the group consisting of C_1-6alkyl, C_1-6alkoxy and halogen.

50. The compound according to claim 49, wherein the 5-membered heterocyclic aromatic ring is selected from the group consisting of pyrrolyl and thiophenyl.

51. The compound according to claim 50, wherein the 5-membered heterocyclic ring is thiophenyl.

52. The compound according to claim 48, wherein the 5-membered heterocyclic ring contains 2 heteroatoms and each of said 2 heteroatoms is independently selected from the group consisting of O, N and S.

53. The compound according to claim 48, wherein the 5-membered heterocyclic ring is selected from the group consisting of thiazolyl, isothiazolyl, pyrazolyl and imidazolyl.

54. The compound according to claim 48, wherein the 5-membered heterocyclic ring contains 3 heteroatoms and each of said 3 heteroatoms is independently selected from the group consisting of O, N and S.

55. The compound according to claim 48, wherein the heterocycle of the 5-membered heterocyclic ring is thiadiazolyl.

56. The compound according to claim 48, wherein the 5-membered heterocyclic ring is substituted with one or more substituents selected from the group consisting of C_1-6alkyl and halogen.

57. The compound according to claim 44, wherein R₃ is methyl.

58. The compound according to claim 44, wherein R₄ and R₅ are the same or different and each represents hydrogen, fluorine or chlorine.

59. The compound according to claim 44, wherein R₄ and R₅ are the same or different and each represents hydrogen or fluorine.

60. The compound according to claim 44, wherein both R₄ and R₅ are fluorine.

61. The compound according to claim 44, wherein represents a double bond.

62. A method for the treatment of at least one condition selected from the group consisting of inflammatory and allergic conditions in a human or animal subject, which comprises administering an effective amount of the compound of formula (I) or a physiologically acceptable salt or solvate thereof as defined in claim 44 to said human or animal subject in need thereof for the treatment of said at least one condition.

63. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 44 or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers.

64. A process for preparing a compound of formula (I) according to claim 44 which comprises alkylation of a compound of formula (II)

65. The process according to claim 64, wherein alkylation is performed by reacting the compound of formula (II) with a haloalkyl halide.

66. A compound of formula (II)

67. A compound of formula (XV)

68. A compound of formula (XVI)

69. 6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

-[(4-methyl-1,3-thiazole- 5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester or a salt or solvate thereof.

70. A method for the treatment of at least one condition selected from the group consisting of inflammatory and allergic conditions in a human or animal subject, which comprises administering an effective amount of the compound of claim 69 or a physiologically acceptable salt or solvate thereof to said human or animal subject in need thereof for the treatment of said at least one condition.

71. A pharmaceutical composition comprising the compound of claim 69 or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers.