17.beta.-carbothioate 17.alpha.-arylcarbonyloxyloxy androstane derivative as anti-inflammatory agents

• US 20040028615A1
• Filed: 09/02/2003
• Published: 02/12/2004
• Est. Priority Date: 08/05/2000
• Status: Active Grant

• Current Assignee: GlaxoSmithKline Intellectual Property Management Limited (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Payne, Jeremy, Jones, Paul, Biggadike, Keith
• Granted Patent: US 7,498,321 B2
• Time in Patent Office: Days
• US Class Current: 424/45
• 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 R₂ represents fluoromethyl.

4. A compound according to any one of claims 1 to 3 in which R₂ represents —

C(═

O)-heteroaryl.

5. A compound according to claim 4 wherein heteroaryl represents a 5-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms selected from O, 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 or claim 6 in which the heterocyclic ring is furanyl, pyrrolyl or thiophenyl.

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

9. A compound according to claim 5 or claim 6 in which the 5-membered heterocyclic ring contains 2 heteroatoms selected from O, 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 or claim 6 in which the 5-membered heterocyclic ring contains 3 heteroatoms selected from O, N and S.

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

13. A compound according to any one of claims 5 to 12 wherein the heterocyclic ring is substituted with one or more substituents selected from C_1-6alkyl and halogen.

14. A compound according to any one of claims 1 to 13 in which R₃ is methyl.

15. A compound according to any of claims 1 to 14 in which R₄ and R₅ are the same or different and each represents hydrogen, fluorine or chlorine.

16. A compound according to any one of claims 1 to 15 in which R₄ and R₅ are the same or different and each represents hydrogen or fluorine.

17. A compound according to any of claims 1 to 16 in which both R₄ and R₅ are fluorine.

18. A compound according to claim 1 in which R₁ is fluoromethyl;

R₂ is —

C(═

O)-2-furanyl;

R₃ is methyl;

R₄ and R₅ are the same or different and each represents hydrogen or fluorine; and

represents a single or a double bond.

19. A compound according to claim 18 in which R₄ and R₅ are each fluorine.

20. A compound according to any one of claims 1 to 19 in which represents a double bond.

21. A compound according to claim 1 which is:

6α

,9α

-Difluoro-17α

-[(3-furanylcarbonyl)oxy]-11 β

-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

-[(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;

17α

-(Benzoyl)oxy-6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

9α

-Fluoro-17α

-[(2-furanylcarbonyl)oxy]-11β

-hydroxy-16β

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-17α

-[(2-furanylcarbonyl)oxy]-11β

-hydroxy-16α

-methyl-3-oxo-androst-4-ene-17β

-carbothioic acid S-fluoromethyl ester;

or a salt or solvate of any one thereof.

22. 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-fluoromethyl 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

-[(5-Bromofuran-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

-[(2,5-dimethylfuran-3-carbonyl)oxy]-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

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

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-17α

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

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-17α

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

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester;

6α

,9α

-Difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17 α

-[(1,2,3-thiadiazole-4-carbonyl)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-1-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-17,β

-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-17α

-[(2-furanylcarbonyl)oxy]-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-methyl 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 S-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.

23. A compound of formula (I) as defined in any of claims 1 to 22 or a physiologically acceptable salt or solvate thereof for use in veterinary or human medicine.

24. Use of a compound of formula (I) as defined in any of claims 1 to 22 or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of inflammatory and/or allergic conditions.

25. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 22 or a physiologically acceptable salt or solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.

26. A pharmaceutical aerosol formulation comprising a compound of formula (I) as defined in any of claims 1 to 22 or a physiologically acceptable salt or solvate thereof, and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and or a cosolvent.

27. A pharmaceutical composition according to claim 25 which further comprises another therapeutically active agent.

28. A pharmaceutical composition according to claim 27 in which said another therapeutically active agent is a β

₂-adrenoreceptor agonist.

29. A pharmaceutical composition comprising a combination of a compound of formula (I) according to any one of claims 1 to 22 or a physiologically acceptable salt or solvate thereof together with a PDE4 inhibitor.

30. 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 salt or solvate thereof.

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

32. A process according to claim 31 wherein alkylation is performed by reacting the compound of formula (II) with an appropriate alkyl or haloalkyl halide.

33. A compound of formula (II)

34. A process for preparing a compound of formula (I) as defined in claim 1 wherein R₄ represents fluorine or a salt or solvate thereof which comprises reacting a compound of formula (VI)

35. A process for preparing a compound of formula (I) as defined in claim 1 or a salt or solvate thereof which comprises deprotecting or unmasking a compound of formula (I) in which the 11-β

-hydroxy group is protected or masked.

36. A process according to claim 35 in which the 11-β

-hydroxy group is protected which comprises deprotecting a compound of formula (XV)

37. A process according to claim 35 in which the 11β

-hydroxy group is masked as a carbonyl group which comprises reduction of a compound of formula (XVI)

38. A compound of formula (VI)

39. A compound of formula (XV)

40. A compound of formula (XVI)

41. A compound of formula (VII)

42. A compound of formula (X)

43. A compound of formula (VIII)