Novel pro-drug derivatives of pyridinium aldoxime type cholinesterase reactivators and process for preparing same

• US 3,929,813 A
• Filed: 12/26/1973
• Issued: 12/30/1975
• Est. Priority Date: 12/26/1973
• Status: Expired due to Term

• Current Assignee: Efraim Shek, Nicolae S. Bodor, Takeru Higuchi
• Original Assignee: Efraim Shek, Nicolae S. Bodor, Takeru Higuchi
• Inventors: Shek, Efraim, Higuchi, Takeru, Bodor, Nicolae S.
• Primary Examiner(s): Randolph, John D.
• Application Number:
  US05/428,215
• Time in Patent Office: 734 Days
• Field of Search: 260/296M
• US Class Current: 546/261
• CPC Class Codes: C07D 211/78 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• 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:
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.

WHEREIN R represents a member selected from the group consisting of an alkyl (C1-C4) group, a
WHEREIN Z represents a member selected from the group consisting of a -CH2-CH2- group, a -CH2-O-CH2- group, a -CH2CH2OCH2CH2group, and a -CH2O-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

GROUP, AND A

GROUP,

GROUP, A

Claims

1. A PRO-DRUG COMPOUND OF THE PYRIDINE ALDOXIME (HYDROXYIMINOMETHYL PYRIDINIUM) TYPE CAPABLE OF REACTIVATING BLOCKED CHOLINESTERASE HAVING THE FORMULA:

2. Preparing the HX salt of the above obtained tetrahydropyridinium compound of step (1) by introducing said compound into an ether type solvent, saturated with anhydrous HX;

3. The compound of claim 1:

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

4. Separating the objective compound from the reaction mixture, said overall reaction being conducted at standard temperature and pressure.

5. The compound of claim 3:

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

6. The compound of claim 1:

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

7. The compound of claim 6:

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

8. The compound of claim 6:

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

9. The compound of claim 1:

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

10. The compound of claim 1:

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

11. The compound of claim 10:

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

12. The compound of claim 10:

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

13. The compound of claim 1:

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

14. The compound of claim 13:

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 compound of claim 13:

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 preparing a pro-drug compound of the pyridine aldoxime (hydroxyiminomethyl pyridinium) type having the formula:

17. The process of claim 16, wherein in step (3) thereof, said C1-C3 aliphatic alcohol is methanol.

18. The process of claim 16, wherein in step (1) thereof, the reducing agent is NaBH4.

19. The process of claim 16, wherein in step (1) thereof, the heterogeneous reaction mixture is an ether/water mixture.

20. The process of claim 16, wherein in step (2) thereof, the ether type solvent is tetrahydrofuran.

21. The process of claim 16, wherein in step (2) thereof, HX is HCl.

22. The process of claim 16, wherein in step (3) thereof, HY is HCN.