Enantiomerically pure basic arylcycloalkylhydroxycarboxylic esters, processes for their preparation and their use in medicaments

• US 20020173536A1
• Filed: 07/09/2001
• Published: 11/21/2002
• Est. Priority Date: 11/11/1996
• Status: Active Grant

• Current Assignee: MEDA Pharma GmbH & Co. KG (Mylan N.V.)
• Original Assignee: Christian NOE and Ernst Mutschler
• Inventors: Noe, Christian, Czeche, Sittah, Mutschler, Ernst, Waelbroeck, Magali, Elgert, Ruth Irene, Lambrecht, Gunter, Elgert, Michael
• Granted Patent: US 6,613,795 B2
• Time in Patent Office: Days
• US Class Current: 514/424
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

Disclosed are enantiomerically pure cyclic aminoalcohol esters of arylcycloalkylhydroxycarboxylic acids with at least 90% enantiomeric excess of the (3R,2′R), (3S,2′R), (3R,2′S), or (3S,2′S) configured enantiomer.

Claims

1. A method of treatment of obstructive respiratory diseases by inhalative administration of a pharmaceutically suitable salt of the enantiomerically enriched ester (3R,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium in an effective amount to a patient in need thereof.

2. The method according to claim 1, wherein the pharmaceutically suitable salt is selected from the group consisting of fluoride, chloride, bromide and iodide.

3. The method according to claim 1, wherein the (3R,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 96% enantiomeric excess.

4. The method according to claim 1, wherein the (3R,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 97% enantiomeric excess.

5. The method according to claim 1, wherein the (3R,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 98% enantiomeric excess.

6. The method according to claim 1, wherein the (3R,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of an aerosol formulation.

7. The method according to claim 1, wherein the (3R,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of a dry powder formulation.

8. The method according to claim 1, wherein the obstructive respiratory disease is selected from the group consisting of bronchial asthma and chronic bronchitis.

9. The method according to claim 2, wherein the (3R,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the fort of an aerosol formulation.

10. The method according to claim 2, wherein the (3R,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of a dry powder formulation.

11. The method according to claim 2, wherein the obstructive respiratory disease is selected from the group consisting of bronchial asthma and chronic bronchitis.

13. The method according to claim 12, wherein the pharmaceutically suitable salt is selected from the group consisting of fluoride, chloride, bromide and iodide.

14. The method according to claim 12, wherein the (3R,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 96% enantiomeric excess.

15. The method according to claim 12, wherein the (3R,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 97% enantiomeric excess.

16. The method according to claim 12, wherein the (3R,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 98% enantiomeric excess.

17. The method according to claim 12, wherein the (3R,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of an aerosol formulation.

18. The method according to claim 12, wherein the (3R,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of a dry powder formulation.

19. The method according to claim 12, wherein the obstructive respiratory disease is selected from the group consisting of bronchial asthma and chronic bronchitis.

20. The method according to claim 13, wherein the (3R,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of an aerosol formulation.

21. The method according to claim 13, wherein the (3R,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of a dry powder formulation.

22. The method according to claim 13, wherein the obstructive respiratory disease is selected from the group consisting of bronchial asthma and chronic bronchitis.

24. The method according to claim 23, wherein the pharmaceutically suitable salt is selected from the group consisting of fluoride, chloride, bromide and iodide.

25. The method according to claim 23, wherein the (3S,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 96% enantiomeric excess.

26. The method according to claim 23, wherein the (3S,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 97% enantiomeric excess.

27. The method according to claim 23, wherein the (3S,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 98% enantiomeric excess.

28. The method according to claim 23, wherein the (3S,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of an aerosol formulation.

29. The method according to claim 23, wherein the (3S,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of a dry powder formulation.

30. The method according to claim 23, wherein the obstructive respiratory disease is selected from the group consisting of bronchial asthma and chronic bronchitis.

31. The method according to claim 24, wherein the (3S,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of an aerosol formulation.

32. The method according to claim 24, wherein the (3S,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of a dry powder formulation.

33. The method according to claim 24, wherein the obstructive respiratory disease is selected from the group consisting of bronchial asthma and chronic bronchitis.

35. The method according to claim 34, wherein the pharmaceutically suitable salt is selected from the group consisting of fluoride, chloride, bromide and iodide.

36. The method according to claim 34, wherein the (3S,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 96% enantiomeric excess.

37. The method according to claim 34, wherein the (3S,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 97% enantiomeric excess.

38. The method according to claim 34, wherein the (3S,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium has an enantiomeric purity of minimum 98% enantiomeric excess.

39. The method according to claim 34, wherein the (3S,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of an aerosol formulation.

40. The method according to claim 34, wherein the (3S,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of a dry powder formulation.

41. The method according to claim 34, wherein the obstructive respiratory disease is selected from the group consisting of bronchial asthma and chronic bronchitis.

42. The method according to claim 35, wherein the (3S,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of an aerosol formulation.

43. The method according to claim 35, wherein the (3S,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium salt is administered in the form of a dry powder formulation.

44. The method according to claim 35, wherein the obstructive respiratory disease is selected from the group consisting of bronchial asthma and chronic bronchitis.

46. The method according to claim 45, wherein the pharmaceutically suitable salt is selected from the group consisting of fluoride, chloride, bromide and iodide.

47. The method according to claim 45, wherein said ester has an enantiomeric purity of minimum 96% enantiomeric excess.

48. The method according to claim 45, wherein said ester has an enantiomeric purity of minimum 97% enantiomeric excess.

49. The method according to claim 45, wherein said ester has an enantiomeric purity of minimum 98% enantiomeric excess.

50. The method according to claim 45, wherein said ester is (3R,2 R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium.

51. The method according to claim 45, wherein said ester is (3S,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium.

52. The method according to claim 45, wherein said ester is (3R,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium.

53. The method according to claim 45, wherein said ester is (3S,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium.

54. The method according to claim 45, wherein said salt is administered by inhalation.

55. The method according to claim 45, wherein said salt is administered by inhalation of an aerosol formulation.

56. The method according to claim 45, wherein said salt is administered by inhalation of a dry powder formulation.

57. The method according to claim 46, wherein said salt is administered by inhalation of an aerosol formulation.

58. The method according to claim 46, wherein said salt is administered by inhalation of a dry powder formulation.

12. A method of treatment of obstructive respiratory diseases by inhalative administration of a pharmaceutically suitable salt of the enantiomerically enriched ester (3R,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium in an effective amount to a patient in need thereof.

23. A method of treatment of obstructive respiratory diseases by inhalative administration of a pharmaceutically suitable salt of the enantiomerically enriched ester (3S,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium in an effective amount to a patient in need thereof.

34. A method of treatment of obstructive respiratory diseases by inhalative administration of a pharmaceutically suitable salt of the enantiomerically enriched ester (3S,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium in an effective amount to a patient in need thereof.

45. A method of treatment of spasms of smooth muscles by administration of a pharmaceutically suitable salt of an enantiomerically enriched ester selected from the group consisting of

(3R,2′

R)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium, ((3S,2′

R)-)-3-[cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium, (3R,2′

R)-3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium, and (3S,2′

R)--3-[cyclohexylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium in an effective amount to a patient in need thereof.