Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 4. Central nervous system depressants

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Abstract
The synthesis of 1''-[3-(4-fluorobenzoyl)propyl]-3-phenylspiro[isobenzofuran-1(3H),4''-piperidine] (2a) and 8 halo and methoxy analogs was described. The compounds were generally more potent per os (oral administration) than chlorpromazine in the Sidman avoidance paradigm in rats and less potent than haloperidol. 1''-[3-(4-Fluorobenzoyl)propyl]-3-(4-fluorophenyl)spiro[isobenzofuran-1(3H),4''-piperidine] (2e) approached the per os potency of haloperidol in this test and was active in inhibiting monkey avoidance also. Compound 2e was much less active than haloperidol in antagonizing apomorphine-induced emesis in dogs, apomorphine-induced stereotypy in rats, and amphetamine-induced circling in lesioned rats. This lack of nonselective, dopamine-receptor blocking effects makes 2e attractive as a potential neuroleptic.