Novel pro-drug derivatives of pyridinium aldoxime type cholinesterase reactivators and method of using same

• US 3,962,447 A
• Filed: 08/11/1975
• Issued: 06/08/1976
• Est. Priority Date: 12/26/1973
• Status: Expired due to Term

• Current Assignee: Interx Research Corporation
• Original Assignee: Interx Research Corporation
• Inventors: Higuchi, Takeru, Bodor, Nicolae S., Shek, Efraim
• Primary Examiner(s): Friedman, Stanley J.
• Application Number:
  US05/603,612
• Time in Patent Office: 302 Days
• Field of Search: 424/263, 424/267
• US Class Current: 514/89
• CPC Class Codes: C07D 211/82 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

There is provided, novel pro-drug forms of pyridinium aldoxime type cholinesterase reactivators, namely, dihydropyridinium aldoximes, having the formula: ##SPC1##

Wherein R represents a member selected from the group consisting of an alkyl (C₁ -C₄) group, a ##SPC2##

Group, a ##SPC3##

Group, ##SPC4##

Group, and a ##SPC5##

Wherein Z represents a member selected from the group consisting of a --CH₂ --CH₂ -- group, a --CH₂ --O--CH₂ -- group, a --CH₂ CH₂ OCH₂ CH₂ -- group, and a --CH₂ O--CH₂ --CH₂ --O--CH₂ -- group; wherein R₁ represents a member selected from the group consisting of a hydrogen atom, a methyl group, an acyl group and a ##EQU1## group; and wherein X^- represents an anion derived from a pharmaceutically acceptable acid addition salt.

These compounds are useful in reactivating cholinesterase, inhibited following exposure to and/or ingestion of conventional anti-cholinesterase agents, especially in the brain.

Claims

1. A pharmaceutical composition for reactivating blocked cholinesterase in a warm-blooded animal and suitable for oral administration and absorption through the small intestine of said warm-blooded animal, comprising an effective cholinesterase reactivating amount of a pro-drug compound of the pyridine aldoxime-(hydroxyiminomethyl pyridinium) type capable of reactivating blocked cholinesterase having the formula:

##SPC17##

wherein R represents a member selected from the group consisting of an alkyl (C₁ -C₄) group, a ##SPC18##

group, a ##SPC19##

group, ##SPC20##

group, and a ##SPC21##

group, wherein Z represents a member selected from the group consisting of a --CH₂ --CH₂ -- group, a --CH₂ --O--CH₂ -- group, a --CH₂ CH₂ OCH₂ CH₂ -- group, and a --CH₂ O--CH₂ --CH₂ --O--CH₂ -- group;

wherein R₁ represents a member selected from the group consisting of a hydrogen atom, a methyl group, an acyl group and a ##EQU3## group; and

wherein X^- represents an anion derived from a pharmaceutically acceptable acid addition salt in combination with a pharmaceutically acceptable enteric carrier.

2. The composition of claim 1, wherein said compound is:

1-Methyl-1,6-dihydropyridine-2-aldoxime and its HX salts, wherein X represents a pharmaceutically acceptable anion.

3. The composition of claim 1, wherein said compound is:

Trimethylene-bis-[1-(dihydropyridine-4-carbaldoxime)] and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

4. The composition of claim 3, wherein said compound is:

Trimethylene-bis-[1-(1,4-dihydropyridine-4-carbaldoxime] and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

5. The composition of claim 3, wherein said compound is:

Trimethylene-bis-[(1,6-dihydropyridine-4-carbaldoxime] and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

6. The composition of claim 1, wherein said compound is:

Bis-(4-hydroxyiminomethyl-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

7. The composition of claim 6, wherein said compound is:

Bis-(4-hydroxyiminomethyl-1,4-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

8. The composition of claim 6, wherein said compound is:

Bis-(4-hydroxyiminomethyl-1,6-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

9. The composition of claim 1, wherein said compound is:

Bis-(2-hydroxyiminomethyl-1,6-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

10. The composition of claim 1, wherein said compound is:

Bis-[2-(4-hydroxyiminomethyl-dihydropyridino)ethyl] ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

11. The composition of claim 10, wherein said compound is:

Bis-[2-(4-hydroxyiminomethyl-1,4-dihydropyridino) ethyl] ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

12. The composition of claim 10, wherein said compound is:

Bis-[2-(4-hydroxyiminomethyl-1,6-dihydropyridino) ethyl] ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

13. The composition of claim 1, wherein said compound is:

Ethylene glycol-bis-(4-hydroxyiminomethyl-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

14. The composition of claim 13, wherein said compound is:

Ethylene glycol-bis-(4-hydroxyiminomethyl-1,4-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

15. The composition of claim 13, wherein said compound is:

Ethylene glycol-bis-(4-hydroxyiminomethyl-1,6-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

16. A method for reactivating blocked cholinesterase in a warm-blooded animal as a result of anticholinesterase compound poisoning, which comprises:

administering thereto, an effective cholinesterase reactivating amount of a pro-drug compound of the pyridine aldoxime (hydroxyiminomethyl pyridinium) type capable of reactivating blocked cholinesterase having the formula;

##SPC22##

wherein R represents a member selected from the group consisting of an alkyl (C₁ -C₄) group, a ##SPC23##

group, a ##SPC24##

group, ##SPC25##

group and a ##SPC26##

group, wherein Z represents a member selected from the group consisting of a --CH₂ --CH₂ -- group, a --CH₂ --O--CH₂ -- group, a --CH₂ CH₂ OCH₂ CH₂ -- group, and a --CH₂ O--CH₂ --CH₂ --O--CH₂ -- group;

wherein R₁ represents a member selected from the group consisting of a hydrogen atom, a methyl group, an acyl group and a ##EQU4## group; and

wherein X^- represents an anion derived from a pharmaceutically acceptable acid addition salt.

17. The method of claim 16, wherein said compound is:

1-Methyl-1,6-dihydropyridine-2-aldoxime and its HX salts, wherein X represents a pharmaceutically acceptable anion.

18. The method of claim 16, wherein said compound is:

Trimethylene-bis-[1-(dihydropyridine-4-carbaldoxime)] and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

19. The method of claim 18, wherein said compound is:

Trimethylene-bis-[1-(1,4-dihydropyridine-4-carbaldoxime] and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

20. The method of claim 18, wherein said compound is:

Trimethylene-bis-[(1,6-dihydropyridine-4-carbaldoxime] and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

21. Th method of claim 16, wherein said compound is:

Bis-(4-hydroxyiminomethyl-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

22. The method of claim 21, wherein said compound is:

Bis-(4-hydroxyiminomethyl-1,4-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptble anion.

23. The method of claim 21, wherein said compound is:

Bis-(4-hydroxyiminomethyl-1,6-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

24. The method of claim 16, wherein said compound is:

Bis-(2-hydroxyiminomethyl-1,6-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

25. The method of claim 16, wherein said compound is:

Bis-[2-(4-hydroxyiminomethyl-dihydropyridino) ethyl] ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

26. The method of claim 25, wherein said compound is:

Bis-[2-(4-hydroxyiminomethyl-1,4-dihydropyridino) ethyl] ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

27. The method of claim 25, wherein said compound is:

Bis-[2-(4-hydroxyiminomethyl-1,6-dihydropyridino) ethyl ] ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

28. The method of claim 16, wherein said compound is:

Ethylene glycol-bis-(4-hydroxyiminomethyl-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

29. The method of claim 28, wherein said compound is:

Ethylene glycol-bis-(4-hydroxyiminomethyl-1,4-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

30. The method of claim 28, wherein said compound is:

Ethylene glycol-bis-(4-hydroxyiminomethyl-1,6-dihydropyridine-1-methyl) ether and its di-HX salts, wherein X represents a pharmaceutically acceptable anion.

31. The method of claim 16, wherein said compound is maintained in combination with a pharmaceutically acceptable enteric carrier.

32. The method of claim 16, wherein said compound is maintained in combination with a pharmaceutically acceptable parenteral vehicle.