Pharmacologically active guanidine compounds

• US 3,950,333 A
• Filed: 03/14/1974
• Issued: 04/13/1976
• Est. Priority Date: 03/09/1971
• Status: Expired due to Term

• Current Assignee: Smith Kline & French Laboratories Limited (GlaxoSmithKline PLC)
• Original Assignee: Smith Kline & French Laboratories Limited (GlaxoSmithKline PLC)
• Inventors: Ganellin, Charon Robin, Emmett, John Colin, Durant, Graham John
• Primary Examiner(s): Randolph, John D.
• Assistant Examiner(s): Jaisle, C. M. S.
• Application Number:
  US05/450,957
• Time in Patent Office: 761 Days
• Field of Search: 260/309, 260/310 R, 260/256.4 N, 260/256.4 R, 260/250 BN, 260/250 A
• US Class Current: 544/224
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 213/32 Sulfur atoms
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/65 attached in position 3 or 5
• CPC Class Codes: C07D 213/70 Sulfur atoms
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/84 Sulfur atoms
• CPC Class Codes: C07D 233/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 235/06 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 249/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 263/46 Sulfur atoms
• CPC Class Codes: C07D 275/02 not condensed with other rings
• CPC Class Codes: C07D 275/03 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/26 Radicals substituted by sulfur atoms
• CPC Class Codes: C07D 285/135 Nitrogen atoms
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The compounds are substituted thioalkyl-, aminoalkyl- and oxyalkyl-guanidines which are inhibitors of histamine activity.

Claims

1. A compound of the formula:

##SPC10##

wherein A is such that there is formed together with the carbon atom shown an unsaturated heterocyclic nucleus, said unsaturated heterocyclic nucleus being an imidazole, pyrazole, pyrimidine, pyrazine or pyridazine ring;

X₁ is hydrogen, lower alkyl, hydroxy, trifluoromethyl, benzyl, halogen, amino or ##EQU6## in which E'"'"' is NH or N-cyano;

X₂ is hydrogen or when X₁ is lower alkyl, lower alkyl or halogen;

k is 0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4;

Y is oxygen, sulphur or NH;

E is NR₂ ;

R₁ is hydrogen, lower alkyl or di-lower alkylamino-lower alkyl; and

R₂ is hydrogen, nitro or cyano, or a pharmaceutically acceptable addition salt thereof with the proviso that X₁ is ##EQU7## only when E is NH or N-cyano.

2. A compound of claim 1 wherein Y is oxygen or sulphur.

3. A compound of claim 1 wherein Y is NH.

4. A compound of claim 1 wherein said unsaturated heterocyclic nucleus is imidazole, pyrazole, pyrimidine pyrazine or pyridazine and R₂ is hydrogen or nitro.

5. A compound of claim 4 wherein k is 1 and m is 2.

6. A compound of claim 1 wherein said unsaturated heterocyclic nucleus is imidazole.

7. A compound of claim 6 wherein X₁ is hydrogen, methyl, bromo, hydroxyl or amino and X₂ is hydrogen;

Y is sulphur and R₁ is methyl.

8. A compound of claim 1, said compound being N-cyano-N'"'"'-methyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine.

9. A compound of claim 1, said compound being 2-(4-imidazolylmethylthio)ethyleneguanidine sulphate.

10. A compound of claim 1, said compound being N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'"'"'-nitroguanidine.

11. A compound of claim 1, said compound being N-cyano-N'"'"'-ethyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine

12. A compound of claim 1, said compound being N-[2-((4-bromo-5-imidazolyl)methylthio)ethyl]-N'"'"'-cyano-N"-methylguanidine.

13. A compound of claim 1, said compound being N-cyano-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine.

14. A compound of claim 1, said compound being N-cyano-N'"'"'-[2-(4-imidazolylmethylthio)ethyl]-N"-methylguanidine.

15. A compound of claim 1, said compound being N-cyano-N'"'"'-[2-((4-methyl-5-imidazolyl)methylthio)-ethyl]-N"-propylguanidine.

16. A compound of claim 1, said compound being N-cyano-N'"'"'-methyl-N"-[2-((1-methyl-2-imidazolyl)-methylthio)ethyl]guanidine.

17. A compound of claim 1, said compound being N-cyano-N'"'"'-[2-(2-imidazolylmethylthio)ethyl]-N"-methylguanidine.

18. A compound of claim 1, said compound being N-cyano-N'"'"'-methyl-N"-[2-((5-trifluoromethyl-4-imidazolyl)methylthio)ethyl]guanidine.

19. A compound of claim 1, said compound being N-cyano-N'"'"'-[2-(4-imidazolylmethoxy)ethyl]-N"-methylguanidine.

20. A compound of claim 1 said compound being N-cyano-N'"'"'-methyl-N"-[2-(3-pyrazolylmethylthio)-ethyl]guanidine.

21. A compound of claim 1, said compound being N-cyano-N'"'"'-methyl-N"-[2-(2-pyrazinylmethylthio)ethyl]guanidine.

22. A compound of claim 1, said compound being N-cyano-N'"'"'-methyl-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.