Antithrombotic, Antihypertensive/PAF-Antagonist: Novel Pyridinium Nitrate Derivaties as PAF Antagonists

Summary

Novelty: 3-Bromo-5-rN-phenyl-N-[2-[[2-(1,2,3,4-tetrahydro-2-isoquinolylcarbonyloxy) ethyl]-carbamoyl]ethyl]carbamoyl]-1-propylpyridinium nitrate, which exhibits excellent PAF antagonism, is disclosed. It is useful in the treatment of circulatory diseases, thrombosis, cerebral apoplexy, myocardial infarction, diseases related to allergic inflammation etc.

Biology: The inhibitory action on PAF-induced rabbit platelet aggregation is assessed. Concentrations of 3 × 10⁻⁶ M and 3 × 10⁻⁷ M gives 100% inhibition and 3 × 10⁻⁸ M gives 71% inhibition. The inhibition of PAF-induced hypotension in rats is described. Inhibition is expressed as the ratio of the PAF-induced decrease in blood pressure before treatment with the test substance to the decrease after treatment. This ratio is then expressed as a percentage. A dose of 0.01 mg/kg iv of the test substance gives 93% inhibition after five minutes which falls to 24% after an eight hour period. A dose of 1 mg/kg po gave 69% inhibition after one hour and this falls to 69% after eight hours. A number of other tests are described.

Chemistry: 3-Bromo-5-[N-phenyl-N-[2-[[2-(1,2,3,4-tetrahydro-2-isoquinolylcarbonyl oxy)ethyl]-carbamoyl]ethyl]carbamoyl]-1-propylpyridinium nitrate is specifically claimed.