Гостра токсичність і діуретична активність похідних аміно-3-метилксантинів

Abstract

Проведено експериментальне дослідження гострої токсичності і впливу на видільну функцію нирок лабораторних тварин вперше синтезованих 7-заміщених 8-аміно-3-метилксантинів. Встановлено, що найбільшу діуретичну активність виявила сполука 3-метил-7-(2-гідрокси-3-n-метоксифенокси-)пропіл-8-(фуріл-2)метиламіноксантина, яка збільшувала діурез на 201,3% і за діуретичним ефектом перевищувала ак­тивність гідрохлортіазиду на 111,3%. 7-заміщені 8-амино-3-метилксантинів є перспективною групою органі­чних речовин для подальшого проведення синтезу і дослідження діуре­тичної активності з метою створення на їх основі високоефективних засобів для поліпшення видільної функції нирок.

A vital problem of the contemporary pharmacology lies in creation of safer and more efficient medicinal products. Regulation of sodium balance and water being one of the important homeostatic functions is essential for developing the methods of rational therapy through means of diuretics of renal function of kidneys. This work is aimed to study the dependence of acute toxicity and diuretic activity on chemical structure of the newly synthesized 7-substituted-8-amino-3-methylxanthines in experiments on rats. The acute toxicity of 7-(2-hydroxy-3-p-methoxyphenoxy) propyl-8-substituted theophylline has been studied on the intact white nonlinear mice weighing 20-24 LD50 and has been calculated according to the method of Körber. The study of the diuretic activity of the above-mentioned compounds has been carried out on white rats of Wistar line weighing 180-195g according to the method of Y.B. Berkhina. The gained outcome of research into the acute toxicity of 7-substituted-8-amino-3-methylxanthines (compounds 1-11) has shown that LD50 of the synthesized compounds is in the range from 290 to 835 mg/kg. The most toxic (LD50=290 mg/kg) compound is the 6th one: 3-methyl-7-(2-hydroxy-3-p-methoxyphenoxy-) propyl-8-n-butylaminoethyl. Substitution in the 8th position of the molecule of 7-substituted-8-amino-3-methylxanthines n-butylamine (compound 6) of radical with 4-benzylpiperazine-1-ilne (compound 11), p-ethoxyphenyl-amic (compound 10) N,N-diethylaminoethylamine (compound 4), 4-methylpiperazine-1- ilne (compound 1), N,N-diethylaminoethylamine (compound 3), N-methyl-N-benzylamine (compound 2), (pyrrolidine-1- ilne (compound 7), m-tolylamine (compound 9), β-hydroxyethylepiperazine-1- ilne (compound 8), (furil-2)methylamine (compound 5) causes a reduction of the acute toxicity of the aforesaid substances. Analysis of the diuretic activity research shows that derivatives of 7-substituted-8-amino-3-methylxanthines (compounds 1-11) increases excretion of urine in the range from 25.1% to 201.4% (p<0.05). The most signifying diuretic activity has been shown by the compound 5: 3-methyl-7-(2-hydroxy-3-p-methoxyphenoxy-) propyl-8-(furil-2)methylaminoxanthine, which in the dose of 41.8 mg/kg enhances the water diuresis for 201.4% (p<0.01). Introduction to the 8th position of the molecule of 7-substituted-8-amino-3-metylxanthines instead of furil-2-methylamine (compound 5) radical of m-tolylamine (compound 9), n-butylamine (compound 6) and p-ethoxyphenylamine (compound 10) fragments leads to a reduction in renal excretory function for 143.5%; 131.8% and 111%, accordingly. Hydrochlorothiazide in the dose of 25 mg/kg enhances the water diuresis for 90.1%. Thus, the most signifying diuretic effect is observed in the compound 5, which exceeds the effect of the hydrochlorothiazide for 111.3% (p<0.05) and has been selected for further study of the specific activity.