Anticholinergics which may be used as medicaments as well as processes for preparing them

• US 6,706,726 B2
• Filed: 10/11/2001
• Issued: 03/16/2004
• 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, Banholzer, Rolf, Speck, Georg, Pohl, Gerald, Morschhaeuser, Gerd, Reichl, Richard
• Primary Examiner(s): Huang, Evelyn Mei
• Application Number:
  US09/976,950
• Publication Number:
  US 20020115680A1
• Time in Patent Office: 887 Days
• Field of Search: 546/91, 546/130, 546/129, 546/131, 514/291, 514/304
• US Class Current: 514/291
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 451/10 acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Abstract

The present invention relates to new anticholinergics of general formula 1:

wherein A, X⁻ and the groups R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ may have the meanings given in the claims and in the specification, processes for preparing them and their use as pharamaceutical compositions.

Claims

1. A compound of formula 1:

wherein;

A is a group selected from

X⁻

is an anion with a single negative charge;

R¹ and R², which are identical or different, are each C₁-C₄-alkyl, which are optionally substituted by hydroxy or halogen;

R³, R⁴, R⁵, and R⁶, which are identical or different, are each hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF₃, CN, NO₂, or halogen;

R⁷ is C₁-C₄-alkyl, C₁-C₄-alkyloxy, C₁-C₄-alkylene-halogen, halogen-C₁-C₄-alkyloxy, C₁-C₄-alkylene-OH, CF₃, —

C₁-C₄-alkylene-C₁-C₄-alkyloxy, —

O—

COC₁-C₄-alkyl, —

O—

COC₁-C₄-alkyl-halogen, —

O—

COCF₃, or halogen.

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

X⁻

is an anion with a single negative charge selected from chloride, bromide, methylsulphate, 4-toluenesulphonate, and methanesulphonate;

R¹ and R², which are identical or different, are each a group selected from methyl, ethyl, n-propyl, and isopropyl, which are optionally substituted by hydroxy or fluorine;

R³, R⁴, R⁵, and R⁶, which are identical or different, are each hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃, or NO₂; and

R⁷ is methyl, ethyl, methyloxy, ethyloxy, —

CH₂—

F, —

CH₂-CH₂—

F, —

O—

CH—

F, —

O—

CH₂—

CH₂—

F, —

CH₂—

OH, —

CH₂—

CH₂—

OH, CF₃, —

CH₂—

OMe, —

CH₂—

CH₂—

OMe, —

CH₂—

OEt, —

CH₂—

CH₂—

OEt, —

O—

COMe, —

O—

COEt, —

O—

COCF₃, —

O—

COCF₃, fluorine, chlorine, or bromine.

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

X⁻

is an anion with a single negative charge selected from chloride, bromide, and methanesulphonate;

R¹ and R², which are identical or different, are each methyl or ethyl, which are optionally substituted by hydroxy or fluorine;

R³, R⁴, R⁵, and R⁶, which are identical or different, are each hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, or bromine; and

R⁷ is methyl, ethyl, methyloxy, ethyloxy, CF₃, or fluorine.

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

X⁻

is bromide;

R¹ and R², which are identical or different, are each methyl or ethyl;

R³, R⁴, R⁵, and R⁶, which are identical or different, are each hydrogen, methyl, methyloxy, chlorine, or fluorine; and

R⁷ methyl or fluorine.

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

X⁻

is bromide;

R¹ and R², which are identical or different, are each methyl or ethyl;

R³, R⁴, R⁵, and R⁶, which are identical or different, denote hydrogen or fluorine; and

R⁷ is methyl or fluorine.

6. A method of treating a disease that is responsive to anticholinergic activity, comprising administering to a host in need thereof an effective amount of a compound of formula 1 according to any one of claims 1 to 5.

7. A method according to claim 6, wherein the disease is selected from asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, and menstrual disorders.

8. A pharmaceutical composition comprising one or more compounds of formula 1 according to any one of claims 1 to 5, or a physiologically acceptable salt thereof, optionally together with one or more conventional excipients and/or carriers.

9. A pharmaceutical composition according to claim 8, further comprising at least one additional active substance selected from the group consisting of:

betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists, and steroids.

10. A process for preparing a compound of formula 1 according to claim 1:

wherein A, X⁻

and R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ have the meanings given in claim 1, characterised in that a compound of formula 3;

wherein R³, R⁴, R⁵, R⁶, and R⁷ have the meanings given in claim 1, and R is chlorine or a C₁-C₄-alkyloxy, is reacted with a compound of formula 2;

wherein A and R¹ have the meanings given in claim 1, to obtain a compound of formula 4;

wherein A and R¹, R³, R⁴, R⁵, R⁶, and R⁷ have the meanings given in claim 1, and the compound of formula 4 is then quaternized by reacting it with a compound R²—

X, wherein R² and X have the meanings given in claim 1, to obtain a compound of formula 1.

11. Scopine 2,2-diphenylpropionate methobromide.

21. A method of treating a disease that is responsive to anticholinergic activity, comprising administering to a host in need thereof an effective amount of a compound according to any one of claims 11 to 20.

22. A method according to claim 21, wherein the disease is selected from asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorder spasms in the gastrointestinal tract, spasms in the urinary tract, and menstrual disorders.

23. A pharmaceutical composition comprising a compound a according to any one of claims 11 to 20 and one or more conventional excipients and/or carriers.

24. A pharmaceutical composition according to claim 23, further comprising at least one additional active substance selected from the group consisting of:

betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists, and steroids.

12. Scopine 2-fluoro-2,2-diphenylacetate methobromide.

13. Tropenol 2,2-diphenylpropionate methobromide.

14. Tropenol 2-fluoro-2,2-bis(3,4-difluorophenyl)acetate methobromide.

15. Scopine 2,2-diphenylpropionate ethylbromide.

16. Scopine 2-fluoro-2,2-bis(3,4-difluorophenyl)acetate methobromide.

17. Tropenol 2-fluoro-2,2-bis(4-fluorophenyl)acetate methobromide.

18. Scopine 2-fluoro-2,2-bis(4-fluorophenyl)acetate methobromide.

19. Tropenol 2-fluoro-2,2-diphenylacetate methobromide.

20. Tropenol 2-fluoro-2,2-(3-chlorophenyl)acetate methobromide.