Synthetic anticonvulsants, antihypoxics, and liver monooxygenase system inducers based on amides and urea. IV. Antihypoxic activity of benzhydrylurea and its haloid derivatives

Abstract

We have previously observed high levels of anticonvulsive activity among the benzhydrylureas, and have demonstrated a quantitative relationship between changes in their anticonvulsive properties and structural and other parameters. The relationship between the antihypoxic activity of benzhydrylureas and chemical structure has not yet been described. This, along with the lack of highly effective antihypoxic preparations has provided considerable impetus to the search for new substances able to correct acid insufficiency elicited by a variety of extreme conditions. The aim of the present work was to study the antihypoxic properties of benzhydrylureas, and to assess qualitative and quantitative relationships between changes in their antihypoxic activities and structures. Benzhydrylureas I-XVI were synthesized as described in [2, 3], where their physicochemical properties are also described. R R 'C~H3 (R2CGH4) CH NHCON H2 I--XVI R=Ri=R2=H(I); RI=R~=H, R=o-F(II),m-F(III),P~F(IV), o-CI(V), m-CI(VI),P-CI(VII), o-Br(Vlll), m-Br (IX),P~Br(X) o-l(Xl),m-l(Xll); R2=H, R=o-Cb RI=p~I(XIII); R~=H, R=~-CI, R'=p~I(XIV); R=H, R'=R2=p-CI(XV); Rl=lI, R=o-CI, RT=p-CI (XVI). Antihypoxic activity of benzhydrylureas I-XVI was determined using the following models: acute hemic hypoxia (sodium nitrite, 300 mg/kg), acute histotoxic hypoxia (sodium nitroprusside, 25 mg/kg), and hypoxic hypoxia with hypercapnia (in a hermetic chamber); activity was assessed in terms of survival rates. Data were analyzed statistically and are presented in Table I. Overall, the vast majority of these compounds had antihypoxic activity in all three models of acute hypoxia. More detailed consideration of the antihypoxic activity of compounds I-XVI using separate screening tests reveals a number of qualitative relationships (see Table