Synthesis, and analgesic and antiparkinsonian activities of thiopyrimidine, pyrane, pyrazoline, and thiazolopyrimidine derivatives from 2-chloro-6-ethoxy-4-acetylpyridine

A series of substituted pyridine derivatives were prepared from 2-chloro-6-ethoxy-4-acetylpyridine, which was prepared from the corresponding citrazinic acid as starting material. Reaction of acetylpyridine with thiophene-2-carboxaldehyde afforded the 2-chloro-6-ethoxy-4-beta-(2-thienyl)acryloylpyridine, which was reacted with malononitrile in refluxing ethanol in the presence of piperidine as a catalyst to afford the cyanoaminopyrane derivative. Acryloylpyridine was treated with urea or guanidine hydrochloride in refluxing ethanolic potassium hydroxide to give the corresponding pyrimidinone and aminopyrimidine derivatives. The latter was condensed with hydrazine hydrate or phenyl hydrazine to give pyrazoline and N-phenylpyrazoline derivatives. Finally, cycloaddition reaction of acryloylpyridine with thiourea yielded thioxopyrimidine, which was treated with 2-bromopropionic acid, 3-bromopropionic acid, or bromoacetic acid to yield methylthiazolo-, thiazino-, and thiazolopyrimidine derivatives. The arylmethylene derivative was prepared by reacting thiazolopyrimidine with benzaldehyde or by reacting thioxopyrimidine with benzaldehyde and bromoacetic acid in one step. The pharmacological screening showed that many of these compounds have good analgesic and antiparkinsonian activities comparable to Valdecoxib (R) and Benzatropine (R) as reference drugs.