The design of rigid cyclic analogues derived from cinnamamide 1, (E)-N-cyclopropyl-3-(3-fluorophenyl)prop-2-enamide, and beta-methylcinnamamide 2, (E)-N-cyclopropyl-3-(3-fluorophenyl)but-2-enamide, has led to the discovery of the potent, centrally acting muscle relaxant (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 17. Compound 17 also possesses potent antiinflammatory and analgesic activity. This paper describes the synthesis and the muscle relaxant, antiinflammatory, and analgesic structure-activity relationships of 17 and 67 of its analogues. Compound 17 has been taken into phase I clinical trials.
A number of pyrimidine acyclic nucleosides were synthesized and tested for activity against herpes simplex virus type 1. Synthesis of 1-[(2-hydroxyethoxy)methyl]cytosine (8) and 1-[(2-hydroxyethoxy)methyl]uracil (14) was accomplished in two or three steps from 2,4-diethoxypyrimidine and 2-(benzoyloxy)ethoxymethyl chloride. The 5-methyl (20), 5-(trifluoromethyl) (21), and 5-fluoro (22) analogues of 14 were available in two steps form the appropriate bis(trimethylsilyl)ated 5-substituted uracil and 2-(acetoxymethoxy)ethyl acetate or 2-(benzoyloxy)ethoxymethyl chloride. Bromination of 8 and 14 or iodination of 14 gave the 5-halogeno-1-[(2-hydroxyethoxy)methyl]pyrimidines 9, 23, and 24. These pyrimidine acyclic nucleosides exhibited little or no activity against herpes simplex virus type 1 or against a range of other DNA and RNA viruses. This is compatible with their lack of substrate properties toward herpes simplex virus induced thymidine kinase.
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