N-6 substituted-5'-(N-substituted carboxamido)adenosines as cardiac vasodilators and antihypertensive agents

Abstract

Compounds of the formulaare disclosed, wherein R1, represents secondary alkyl; aralkyl; cycloalkyl; heteroaryl substituted alkyl; norbornyl; and substituted secondary alkyl, aralkyl, cycloalkyl, heteroaryl substituted alkyl, norbornyl; and para-substituted phenyl groups; and R2 and R3 are hydrogen or pharmacologically acceptable acyl groups. The compounds of the invention are useful as cardiovascular vasodilator or anti-hypertensive agents. The therapeutically useful compounds of the invention as well as similar 5-N and N-6 substituted adenosine 5-uronamides are prepared, in accordance with a novel process, from isopropylidene (or otherwise suitably blocked) inosine-5'-uronic acid. Isopropylideneinosine-5'-uronic acid is reacted with a suitable inorganic acid halide, such as thionyl chloride, to yield 6-halogeno-9-[2',3'-O-isopropylidene-beta-D-ribofuranosyl-5-uronic acid halide]-9H-purine. This intermediate is reacted with an amine of the general formula R4R5NH to give a 6-halogeno substituted, substituted uronic acid amide of the formulawherein X is halogen. Reaction of the latter intermediate with an amine of the formula R1-NH2, and removal of the isopropylidene (or other) blocking groups yields the compounds of the invention.

Description

2. Field of the InventionThe present invention is directed to certain N-6 and 5'-N substituted carboxamidoadenosine derivatives which have beneficial cardiovascular and antihypertensive activity in mammals, including humans and domestic animals. The present invention is also directed to a process for making said compounds.3. Brief Description of the Prior ArtAdenosine has been known for a long time to possess certain cardiovascular activity and particularly coronary dilatory activity. In an effort to obtain adenosine analogs of greater potency, or longer duration of activity, or both, many analogs of this naturally occurring nucleoside have been synthesized and tested.Moreover, numerous studies have been conducted in order to elucidate the biochemical mechanism of action of adenosine and its analogs, and several theories and hypotheses have been proposed regarding biochemical pathways and receptor sites.For discussion of current theories regarding the foregoing, reference is made to...

AI Technical Summary

Benefits of technology

It is an object of the present invention to provide adenosine analogs which have potent and prolonged cardiovascular activity in mammals and humans, coupled with relatively low toxicity and minimal side effects.

It is still another object of the present invention to provide a relatively efficient synthetic process for the preparation of the adenosine derivatives which meet the above-noted objectives.

Problems solved by technology

In the cardiovascular and anti-hypertensive field, however, the therapeutic utility of the natural nucleoside adenosine and many of its analogs is limited because the desired beneficial effect is often of relatively short duration.

Some known adenosine analogs, however, cannot be phosphorylated in the 5' position because the 5' position is effectively blocked.

Many of the known adenosine derivatives, including the above-noted N-6 substituted and the 5'-carboxamide derivatives are less than satisfactory as cardiovascular or antihypertensive drugs for animal and human use.

This is either because of low activity, short duration of the desired activity, undue toxicity or undesirable side effects.

Undesirable side effects of cardiovascularly active adenosine analogs often include cardiac depression.

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