Anticholinergics, processes for preparing them and pharmaceutical composition containing them

• US 7,652,138 B2
• Filed: 10/21/2004
• Issued: 01/26/2010
• Est. Priority Date: 10/14/2000
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Pieper, Michael Paul, Meissner, Helmut, Speck, Georg, Pohl, Gerald, Morschhaeuser, Gerd, Reichl, Richard
• Primary Examiner(s): Andres; Janet L.
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US10/970,240
• Publication Number:
  US 20050054664A1
• Time in Patent Office: 1,923 Days
• Field of Search: 546/130, 546/131, 546/129, 546/91
• US Class Current: 546/91
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/06 Anti-spasmodics
• CPC Class Codes: C07D 451/10 acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
• CPC Class Codes: C07D 451/14 containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof

Abstract

A compound of formula 1

wherein:

• A is a group selected from

• X⁻ is an anion with a single negative charge;
• R¹ and R² are each independently a C₁-C₄-alkyl optionally substituted with hydroxy or halogen; and
• R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF₃, CN, NO₂, or halogen,
  with the proviso that at least one of the groups R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is not hydrogen, processes for preparing these compounds, pharmaceutical compositions containing these compounds, and their use as pharmaceutical compositions.

Claims

1. A compound of formula 1

2. The compound of formula 1 according to claim 1, wherein:

X⁻

is an anion selected from the group consisting of chloride, bromide, methylsulfate, 4-toluenesulfonate, and methanesulfonate;

R¹ and R² are each independently a group selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl, each optionally substituted by hydroxy or fluorine;

R³ and R⁵ are each independently methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃, or NO₂; and

R⁴,R⁶,R⁷, and R⁸ are each independently hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃, or NO₂.

3. The compound of formula 1 according to claim 1, wherein:

X⁻

is bromide;

R¹ and R² are each independently methyl or ethyl;

R³ and R⁵ are each independently methyl, methyloxy, fluorine, chlorine, or bromine; and

R⁴, R⁶, R⁷, and R⁸ are each independently hydrogen, methyl, methyloxy, fluorine, chlorine, or bromine.

4. The compound of formula 1 according to claim 3, wherein:

R³ and R⁵ are each independently fluorine, chlorine, or bromine; and

R⁴, R⁶, R⁷, and R⁸ are each independently hydrogen, fluorine, chlorine, or bromine.

5. The compound of formula 1 according to claim 4, wherein:

A is

11. A composition comprising a compound of formula 1 according to claim 1 and a pharmaceutically acceptable excipient and/or carrier.

12. The compound according to claim 1 that is Tropenol 3,3′

,4,4′

-tetrafluorobenzilate methobromide.

13. The compound according to claim 1 that is Scopine 3,3′

,4,4′

-tetrafluorobenzilate methobromide.

14. The compound according to claim 1 that is Tropenol 4,4′

-dichlorobenzilate methobromide.

15. The compound according to claim 1 that is Tropenol 2,2′

-dichlorobenzilate methobromide.

16. The compound according to claim 1 that is Tropenol 4,4′

-difluorobenzilate methobromide.

17. The compound according to claim 1 that is Tropenol 2,2′

,4,4′

-tetrafluorobenzilate methobromide.

18. The compound according to claim 1 that is Scopine 4,4′

-dichlorobenzilate methobromide.

19. The compound according to claim 1 that is Scopine 4,4′

-difluorobenzilate methobromide.

20. The compound according to claim 1 that is Tropenol 2,2′

,4,4′

-tetrafluorobenzilate methobromide.

21. The compound according to claim 1 that is Tropenol 4,4′

-dimethylbenzilate methobromide.

22. The compound according to claim 1 that is Scopine 4,4′

-dimethylbenzilate methobromide.

23. The compound according to claim 1 that is Tropine 3,3′

,4,4′

-tetrafluorobenzilate methobromide.

24. The compound according to claim 1 that is Tropenol 3,3′

,4,4′

-tetramethoxybenzilate methobromide.

25. The compound according to claim 1 that is Tropenol 4,4′

-dimethoxybenzilate methobromide.

26. The compound according to claim 1 that is Tropine 3,3′

,4,4′

-tetramethoxybenzilate methobromide.

27. The compound according to claim 1 that is Scopine 3,3′

,4,4′

-tetramethoxybenzilate methobromide.

28. The compound according to claim 1 that is Tropenol 3,3′

-dimethyl-4,4′

-dimethoxybenzilate methobromide.

29. The compound according to claim 1 that is Scopine 3,3′

-dimethyl-4,4′

-dimethoxybenzilate.

30. The compound according to claim 1 that is Tropenol 3,3′

,4,4′

-tetrafluorobenzilate ethyibromide.

31. The compound according to claim 1 that is Tropenol 3,3′

,5,5′

-tetrafluorobenzilate methobromide.

32. The compound according to claim 1 that is Scopine 2,2′

,4,4′

-tetrafluorobenzilate methobromide.

33. The compound according to claim 1 that is Scopine 3,3′

,5,5′

-tetrafluorobenzilate methobromide.

34. The compound according to claim 1 that is Tropenol 3,3′

-dichlorobenzilate methobromide.

35. The compound according to claim 1 that is Tropenol 4,4′

-di(trifluoromethyl)benzilate methobromide.

36. The compound according to claim 1 that is Tropenol 3,3′

-di(trifluoromethyl)benzilate methobromide.

37. The compound according to claim 1 that is Scopine 4,4′

-di(trifluoromethyl)benzilate methobromide.

38. The compound according to claim 1 that is Scopine 3,3′

-di(trifluoromethyl)benzilate methobromide.

39. The compound according to claim 1 that is Tropenol 4,4′

-difluorobenzilate ethyl bromide.

40. The compound according to claim 1 that is Tropenol 3,3′

-dichloro-4,4′

-difluorobenzilate methobromide.

41. The compound according to claim 1 that is Scopine 3,3′

-dichlorobenzilate methobromide.

42. The compound according to claim 1 that is Tropenol 2′

,5,5′

-tetrafluorobenzilate methobromide.

43. The compound according to claim 1 that is Tropenol 2′

,3,3′

-tetrafluorobenzilate methobromide.

44. The compound according to claim 1 that is Scopine 4,4′

-difluorobenzilate ethyl bromide.

45. The compound according to claim 1 that is Tropenol 3,3′

-difluorobenzilate methobromide.

46. The compound according to claim 1 that is Scopine 3,3′

-difluorobenzilate methobromide.

47. The compound according to claim 1 that is Scopine 3,3′

-dichloro-4,4′

-difluorobenzilate methobromide.

48. The compound according to claim 1 that is Scopine 4,4′

-dichloro-3,3′

-difluorobenzilate methobromide.

49. The compound according to claim 1 that is Tropenol 3,3′

,4,4′

-tetrachlorobenzilate methobromide.

50. The compound according to claim 1 that is Tropenol 4,4′

-dichloro-3,3′

-difluorobenzilate methobromide.

51. The compound according to claim 1 that is Tropenol 3,3′

,4,4′

,5,5′

-tetrafluorobenzilate methobromide.

6. A compound of formula 4

7. The compound of formula 4 according to claim 6, wherein:

R¹ is a group selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl, each optionally substituted by hydroxy or fluorine;

R³ and R⁵ are each independently methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃, or NO₂; and

R⁴, R⁶, R⁷, and R⁸ are each independently hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃, or NO₂.

8. The compound of formula 4 according to claim 6, wherein:

R¹ is methyl or ethyl;

R³ and R⁵ are each independently methyl, methyloxy, fluorine, chlorine, or bromine; and

R⁴, R⁶, R⁷, and R⁸ are each independently hydrogen, methyl, methyloxy, fluorine, chlorine, or bromine.

9. The compound of formula 4 according to claim 8, wherein:

R³ and R⁵ are each independently fluorine, chlorine, or bromine; and

R⁴, R⁶, R⁷, and R⁸ are each independently hydrogen, fluorine, chlorine, or bromine.

10. The compound of formula 4 according to claim 6, wherein:

R³ and R⁵ are each fluorine; and

R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen or fluorine.