Anticholinergics, processes for preparing them and pharmaceutical composition containing them

• US 20050054664A1
• Filed: 10/21/2004
• Published: 03/10/2005
• Est. Priority Date: 10/14/2000
• Status: Active Grant

• 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: Pohl, Gerald, Pieper, Michael Paul, Meissner, Helmut, Speck, Georg, Morschhaeuser, Gerd, Reichl, Richard
• Granted Patent: US 7,652,138 B2
• Time in Patent Office: Days
• US Class Current: 514/291
• 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

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

R¹ and R² are each methyl;

R³ and R⁵ are each fluorine; and

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

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

8. A pharmaceutical composition comprising a compound of formula 1 according to claim 2 and a pharmaceutically acceptable excipient and/or carrier.

9. A pharmaceutical composition comprising a compound of formula 1 according to claim 3 and a pharmaceutically acceptable excipient and/or carrier.

10. A pharmaceutical composition comprising a compound of formula 1 according to claim 4 and a pharmaceutically acceptable excipient and/or carrier.

11. A pharmaceutical composition comprising a compound of formula 1 according to claim 5 and a pharmaceutically acceptable excipient and/or carrier.

12. A pharmaceutical composition comprising a compound of formula 1 according to claim 6 and a pharmaceutically acceptable excipient and/or carrier.

13. The pharmaceutical composition according to claim 7, further comprising an additional active substance selected from the group consisting of betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists, and steroids.

14. The pharmaceutical composition according to claim 8, further comprising an additional active substance selected from the group consisting of betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists, and steroids.

15. The pharmaceutical composition according to claim 9, further comprising an additional active substance selected from the group consisting of betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists, and steroids.

16. The pharmaceutical composition according to claim 10, further comprising an additional active substance selected from the group consisting of betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists, and steroids.

17. The pharmaceutical composition according to claim 1, further comprising an additional active substance selected from the group consisting of betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists, and steroids.

18. The pharmaceutical composition according to claim 12, further comprising an additional active substance selected from the group consisting of betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists, and steroids.

19. A method of treating asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, or menstrual disorders, comprising administering to a host in need of such treatment a compound of formula 1 according to claim 1.

20. A method of treating asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, or menstrual disorders, comprising administering to a host in need of such treatment a compound of formula 1 according to claim 2.

21. A method of treating asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, or menstrual disorders, comprising administering to a host in need of such treatment a compound of formula 1 according to claim 3.

22. A method of treating asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, or menstrual disorders, comprising administering to a host in need of such treatment a compound of formula 1 according to claim 4.

23. A method of treating asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, or menstrual disorders, comprising administering to a host in need of such treatment a compound of formula 1 according to claim 5.

24. A method of treating asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, or menstrual disorders, comprising administering to a host in need of such treatment a compound of formula 1 according to claim 6.

25. A compound of formula 4

26. The compound of formula 4 according to claim 25, 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.

27. The compound of formula 4 according to claim 25, 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.

28. The compound of formula 4 according to claim 27, 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.

29. The compound of formula 4 according to claim 25, wherein:

R³ and R⁵ are each fluorine; and

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

30. A compound of formula 3

31. The compound of formula 3 according to claim 30, wherein:

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.

32. The compound of formula 3 according to claim 30, wherein:

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.

33. The compound of formula 3 according to claim 30, 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.

34. The compound of formula 3 according to claim 30, wherein:

R³ and R⁵ are each fluorine; and

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