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

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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 (C.sub.1 -C.sub.4) 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 --CH.sub.2 --CH.sub.2 -- group, a --CH.sub.2 --O--CH.sub.2 -- group, a --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 -- group, and a --CH.sub.2 O--CH.sub.2 --CH.sub.2 --O--CH.sub.2 -- group; wherein R.sub.1 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.sup.- 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 (C.sub.1 -C.sub.4) 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 --CH.sub.2 --CH.sub.2 -- group, a --CH.sub.2 --O--CH.sub.2 -- group, a --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 -- group, and a --CH.sub.2 O--CH.sub.2 --CH.sub.2 --O--CH.sub.2 -- group; wherein R.sub.1 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.sup.- 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.
Other info:

Inventors: Higuchi, Takeru (Lawrence, KS, US)
Bodor, Nicolae S. (Lawrence, KS, US)
Shek, Efraim (Lawrence, KS, US)

Application Number: 603612
Filing Date: 1975-08-11
Publication_date: 1976-06-08
Assignee: Interx Research Corporation (Lawrence, KS)
Primary Class(es): 514/89 514/332
Other Classes:
US Patent Ref:
Other Refs:
Primary Examiner: Friedman, Stanley J.
Assistant Examiner:
Attorney: Blitzer; Charles N.