Antihypertensive pyridylguanidine compounds

Abstract

The invention relates to a series of new compounds, to methods for preparing the compounds, to compositions containing said compounds which are useful in the human and veterinary medical practice, and to methods for treating patients suffering from certain illnesses with said compounds, the new compounds having the general formula I ##STR1## or the tautomeric forms thereof in which the R 1 -substituted cyano-guanidyl radical is placed in the 2-, 3- or 4-position of the pyridine ring, and in which R 1 stands for a straight or branched, saturated or unsaturated, aliphatic hydrocarbon radical having from 1 to 8 carbon atoms, a cycloalkyl or cycloalkenyl radical having from 3 to 7 carbon atoms, an aryl or an aralkyl radical, and R 2 stands for hydrogen, halogen, hydroxy, lower alkyl or alkoxy radicals; and in the case of the present compounds containing one or more asymmetric carbon atoms, also the stereoisomers thereof and racemic mixtures of same; and salts of the compounds of formula I with nontoxic, pharmaceutically acceptable acids. The new compounds of the invention have surprisingly shown to be highly potent hypotensive compounds giving rise to a pronounced reduction of the blood pressure. They have a low toxicity and consequently a high therapeutic ratio.

What we claim is: 
     
       1. A compound of the formula I ##STR9## or the tautomeric forms thereof in which the R 1  -substituted cyano-guanidyl radical is placed in the 2-, 3- or 4-position of the pyridine ring, and in which R 1  stands for aliphatic hydrocarbon having from 1 to 8 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms, phenyl, benzyl or phenethyl, and R 2  stands for hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy radicals, or a salt thereof with a non-toxic, pharmaceutically acceptable acid. 
     
     
       2. A compound according to claim 1 in which the R 1  -substituted cyano-guanidyl radical is placed in the 3-position of the pyridine ring. 
     
     
       3. A compound according to claim 1, in which the R 1  -substituted cyano-guanidyl radical is placed in the 4-position of the pyridine ring. 
     
     
       4. A compound according to claim 1, in which R 1  is selected from the group consisting of isopropyl, isobutyl, sec-butyl, tert-butyl, branched pentyl, branched hexyl and branched heptyl. 
     
     
       5. A compound as defined in claim 1 which is N-tert-butyl-N"-cyano-N'-3-pyridylguanidine; or a non-toxic, pharmaceutically-acceptable acid-addition salt thereof. 
     
     
       6. A compound as defined in claim 1 which is N"-cyano-N-tert-pentyl-N'-3-pyridylguanidine; or a non-toxic, pharmaceutically-acceptable acid-addition salt thereof. 
     
     
       7. A compound as defined in claim 1 which is N"-cyano-N-(1-ethyl-1-methylpropyl)-N'-3-pyridylguanidine; or a non-toxic, pharmaceutically-acceptable acid-addition salt thereof. 
     
     
       8. A compound as defined in claim 1 which is N"-cyano-N-3-pyridyl-N'-1,1,2-trimethylpropylguanidine; or a non-toxic, pharmaceutically-acceptable acid-addition salt thereof. 
     
     
       9. A compound as defined in claim 1 which is N"-cyano-N-(1,1-diethylpropyl)-N'-3-pyridylguanidine; or a non-toxic, pharmaceutically-acceptable acid-addition salt thereof. 
     
     
       10. A compound as defined in claim 1 which is N"-cyano-N-neopentyl-N'-3-pyridylguanidine; or a non-toxic, pharmaceutically-acceptable acid-addition salt thereof. 
     
     
       11. A compound according to claim 1 wherein R 1  is either saturated hydrocarbon or ##STR10## 
     
     
       12. A composition for the treatment of hypertension containing as an active component, an effective amount of at least one compound according to claim 1, together with a carrier therefor. 
     
     
       13. A composition according to claim 12, which contains at least 0.1% of the active compound. 
     
     
       14. A composition according to claim 12 containing at least 0.1% of said compound in combination with another therapeutic compound applied in the treatment of hypertension, together with a pharmaceutical carrier. 
     
     
       15. A composition according to claim 14, which also contains an effective amount of a β-adrenergic blocker, a diuretic, reserpine, or α-methyldopa. 
     
     
       16. A composition according to claim 14, which contains an effective amount of a β-adrenergic blocker. 
     
     
       17. A method of treating a human suffering from hypertension which comprises administering an effective amount of a compound of the formula I ##STR11## or the tautomeric forms thereof in which the R 1  -substituted cyano-guanidyl radical is placed in the 2-, 3- or 4-position of the pyridine ring, and in which R 1  stands for aliphatic hydrocarbon having from 1 to 8 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms, phenyl, benzyl or phenethyl, and R 2  stands for hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy radicals; or a salt thereof with a non-toxic, pharmaceutically acceptable acid. 
     
     
       18. A method as claimed in claim 17, in which the compound is administered to an adult in dosage units containing not less than 0.01 mg and up to 1000 mg. 
     
     
       19. A method as claimed in claim 18 wherein the compound is administered in a dosage unit of from 0.02 to 200 mg. .Iadd. 20. A compound as defined in claim 1 which is N"-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine; or a non-toxic, pharmaceutically acceptable acid addition salt thereof. .Iaddend..Iadd. 21. A composition for the treatment of hypertension containing as an active component, an effective amount of a compound according to claim 20, together with a carrier therefor. .Iaddend..Iadd. 22. A method as claimed in claim 17 in which the compound is N"-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine. .Iaddend.