Quaternary ammonium antiarrhythmic drugs

• US 4,289,787 A
• Filed: 12/10/1979
• Issued: 09/15/1981
• Est. Priority Date: 12/19/1977
• Status: Expired due to Term

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Steinberg, Mitchell I., Molloy, Bryan B.
• Primary Examiner(s): Robinson, Douglas W.
• Application Number:
  US06/102,043
• Time in Patent Office: 645 Days
• Field of Search: 424/329, 260/567.6 M, 56/282, 56/284, 56/287, 56/289
• US Class Current: 514/643
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/33 Heterocyclic compounds

Abstract

Quaternary ammonium salts of certain phenylbutylamines are useful antiarrhythmic drugs. A method for treating arrhythmia and prolonging the action potential of cardiac tissue is provided. Pharmaceutical formulations containing such quaternary ammonium salts are disclosed.

Claims

1. A compound having the general formula ##STR3## wherein:

R¹ is hydrogen or C₁ -C₂ alkyl;

R² is hydrogen or C₁ -C₃ alkyl;

R³ is C₁ -C₄ alkyl or phenyl C₁ -C₄ alkyl;

R⁴ is C₁ -C₈ alkyl;

R⁵ is C₆ -C₁₀ alkyl;

R⁶ is hydrogen, hydroxy, halogen, nitro, C₁ -C₃ alkoxy, or C₁ -C₃ alkyl; and

X is a therapeutically acceptable anion.

2. The compound of claim 1 wherein R³ is C₁ -C₄ alkyl and R⁶ is halogen, nitro, C₁ -C₃ alkoxy, or C₁ -C₃ alkyl.

3. The compound according to claim 1, said compound being N,N-diethyl-N-n-heptyl-4-phenylbutylammonium bromide.

4. The compound according to claim 1, said compound being N,N-dimethyl-N-n-octyl-4-phenylbutylammonium bromide.

5. The compound according to claim 1, said compound being N,N-dimethyl-N-n-hexyl-4-phenylbutylammonium bromide.

6. The compound according to claim 1, said compound being N,N-dimethyl-N-n-heptyl-1-methyl-4-phenylbutylammonium bromide.

7. The compound according to claim 1, said compound being N,N-dimethyl-N-sec-octyl-4-phenylbutylammonium bromide.

8. The compound of claim 1 wherein R⁶ is halogen or nitro.

9. The compound according to claim 8, said compound being N,N-diethyl-N-n-heptyl-4-(4-chlorophenyl)butylammonium bromide.

10. The compound according to claim 8, said compound being N,N-diethyl-N-n-heptyl-4-(4-(4-nitrophenyl)butylammonium bromide.

11. The compound according to claim 8, said compound being N,N-diethyl-N-n-heptyl-4-(4-chlorophenyl)butylammonium phosphate.

12. The compound of claim 1 wherein R³ and R⁴ both are C₁ -C₂ alkyl.

13. The compound of claim 1 wherein R³ and R⁴ both are methyl and R⁵ is n-hexyl or n-heptyl.

14. The compound of claim 1 wherein R³ and R⁴ both are ethyl and R⁵ is n-hexyl or n-heptyl.

15. The compound of claim 1 wherein R³ is C₁ -C₂ alkyl and R⁴ is C₄ -C₅ alkyl.

16. The compound of claim 1 wherein R¹ is C₁ -C₂ alkyl and R² is hydrogen.

17. The compound of claim 1 wherein R¹ is methyl, R² is hydrogen, R³ and R⁴ are C₁ -C₂ alkyl, R⁵ is C₆ -C₇ alkyl and R⁶ is other than hydrogen.

18. The compound of claim 1 wherein R¹ and R² are hydrogen, R³ and R⁴ independently are C₁ -C₂ alkyl, R⁶ is halogen or nitro, and X^- is phosphate.

19. A method of treating re-entrant arrhythmias comprising administering to a subject in need thereof an antiarrhythmically effective dose of a compound of claim 1.

20. The method according to claim 19 employing the compound wherein R³ is C₁ -C₄ alkyl and R⁶ is hydrogen, halogen, nitro, C₁ -C₃ alkoxy, or C₁ -C₃ alkyl.

21. The method according to claim 19 employing the compound wherein R¹ is hydrogen or methyl, R² is hydrogen, R³ is C₁ -C₂ alkyl, R⁴ is C₁ -C₂ alkyl, and R⁶ is other than hydrogen.

22. The method according to claim 19 wherein the compound administered is N,N-diethyl-N-n-heptyl-4-(4-chlorophenyl)butylammonium bromide.

23. The method according to claim 19 wherein the compound administered is N,N-diethyl-N-n-heptyl-4-(4-chlorophenyl)butylammonium phosphate.

24. A pharmaceutical formulation useful in the treatment of re-entrant arrhythmias in humans comprising as active ingredient an antiarrhythmic amount of a quaternary ammonium salt defined in claim 1 in combination with one or more pharmaceutically acceptable diluents or carriers thereof.

25. The formulation of claim 24 employing the active ingredient wherein R³ is C₁ -C₄ alkyl, and R⁶ is hydrogen, halogen, nitro, C₁ -C₃ alkoxy or C₁ -C₃ alkyl.

26. The formulation according to claim 25 employing the active ingredient of the formula

R¹ is hydrogen or methyl;

R² is hydrogen;

R³ is C₁ -C₂ alkyl;

R⁴ is C₁ -C₂ alkyl;

R⁶ is hydrogen, C₁ -C₃ alkoxy, C₁ -C₃ alkyl or nitro, and

X is a therapeutically acceptable anion.

27. The formulation according to claim 25 wherein the active ingredient is N,N-diethyl-N-n-heptyl-4-(4-chlorophenyl)butylammonium bromide.

28. The formulation according to claim 25 wherein the active ingredient is N,N-diethyl-N-n-heptyl-4-(4-chlorophenyl)butylammonium phosphate.