Adamantylpyridines and their biological activities

Abstract

A wide range of pharmacological activities, including anti-anginal and hypertensive [13, 14], vasodilator [15, 16], antioxidant, and psychotropic activities [3-6, 12] are found in compounds belonging to the class of substituted pyridines. Adamantane derivatives such as the psychotropic and antidepressant compounds gludantan [6] and adapramine [2], and immunotropic compounds of the adamantyl-phenothiazine and -aniline series also possess a variety of pharmacological properties. Adamantane derivatives are also known to exhibit positive inotropic action resulting from blockage of the calcium channels [17]. The wide spectrum of biological activities exhibited by these classes of compounds provides a perspective for investigations in the synthesis and study of the pharmacological activities in the adamantylpyridine series. With the goal of studying the effects of introducing the pyridine group on the pharmacological spectrum of adamantane derivatives, the directed syntheses of several adamantylpyridines were undertaken. Using the Leuckart reaction, adamantan-2-one and aminopyridines were condensed to yield 3-(adamant-2-ylamino)pyridine (I) and 4(adamant-2-ylamino)pyridine (II) [8]. For comparative pharmacological studies on the effects of esterification of primary, secondary and tertiary alcohol derivatives of adamantane, adamantyl esters of nicotinic and 5-bromonicotinic acids (III-VI) were synthesized. N-acylation of 1and 2-aminoadamantanes with the acid chloride of 5-bromonicotinic acid yielded the amides VIIIX. Condensation of the ethyl ester of 5-aminonicotinic acid with the acid chloride of 1-adamantancarboxylic acid yielded amide X. In carrying out the acylation of 4-amino-3-hydroxy-2-ethyl-6-methylpyridine with 1-adamantanecarboxychloride in toluene in the presence of triethylamine at 35-40~ a mixture of Nand O-acylated compounds was obtained (XI-XII). Under more stringent conditions such as reflux the reaction yielded a single product 4adamantoylamino-3-adamantoyloxy-6-methyl-2-ethylpyridine (XII). Under mild conditions such as conducting the reaction at 0~ with an equimolar quantity of the acid chloride only the N-acyl compound was obtained (XI). In the alkylation of l-(N-methylamino)adamantane with 4-bromomethyl-3-hydroxy-2-ethyl-6methylpyridine (XIII) under reflux in toluene in the presence of an HBr acceptor the compound XIV was obtained. The starting material XIII was obtained from the action of hydrobromic acid on 4-acetoxylmethyl-2-ethyl-6-methyl3-acetoxypyridine. The psychotropie properties of the substituted adamantylpyridines were studied. We examined the effects in mice of the compounds on spontaneous activity, prevention of development of triftazine catalepsy, and on physical working efficiency (swimming with weights of up to 10% of body weight). The acute toxicities of the compounds were determined. A significant positive effect on spontaneous motor activity was shown by compounds I, III, and V. Statistically significant increases in the duration of swimming by weighted mice was shown by compounds V, VII, and VIII. It is interesting to note that an increase in the working efficiency was brought about, as a rule, by compounds containing a bromine atom in the pyridine ring.