[The synthesis, toxicological and comparative cytogenetic characteristics of the anticoagulant warfarin].

Abstract

4-hydroxy-3-(3-oxo-1-phenyl butyl)-2H-1-benzopyran-2-one (warfarin) has been synthesised by an original method. The influence of a phase-transfer catalyst of ammonium type with alkyl substituents containing eight carbon atoms upon the reaction of Michael addition has been investigated. It has been found out that when elongating the hydrocarbon chain of the substituents to the nitrogen atom in the quaternary ammonium salt the yield of the product decreased. The acute (LD50) and subchronic (lasting for 30 days) toxicity was determined when taking warfarin orally. The experimental data show that LD50 is 500 mg/kg for mice and 420 mg/kg body mass for rats. The subchronic toxicity at experiments made with rabbits (each day taking orally respectively 25 and 100 mg/kg) does not reveal any humoral and tissue toxic influence of warfarin. The results from the comparative cytogenetic analysis of warfarin and Niffcumar are the basis of the conclusion cytogenetic analysis of warfarin and Niffcumar are the basis of the conclusion that warfarin damages chromosomes of mice's marrow cells (used as a model) less than Niffcumar. Moreover warfarin has a slight influence on these cells in the first place changing the orientation of chromosomes one towards the other and unlike other drugs it does not damage nuclear chromatin strongly.