ABSTRACT
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.
Subject(s)
Acetamides/chemical synthesis , Analgesics/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Indans/chemical synthesis , Muscle Relaxants, Central/chemical synthesis , Acetamides/chemistry , Acetamides/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Hypnotics and Sedatives/chemical synthesis , Hypnotics and Sedatives/chemistry , Hypnotics and Sedatives/pharmacology , Indans/chemistry , Indans/pharmacology , Mice , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Muscle Relaxants, Central/chemistry , Muscle Relaxants, Central/pharmacology , Rats , Rats, Inbred Lew , Rats, Wistar , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Extension of the structure-activity relationship studies that led to the discovery of the nonsedating potent muscle relaxant, antiinflammatory, and analgesic agent (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 1, has given rise to (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-methylacetamide, 2. Compound 2 is a potent antiinflammatory and analgesic agent without centrally acting muscle relaxant activity.
