1-Substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 1

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Abstract
The preparation and analgesic activities of a series of the entitled compounds and the optical isomers of the 1-cyclohexyl derivative are described. Reactions of N,N-bis(2-chloroethyl)-1,12-diphenylethylamine with ammonia and primary amines gave N-(1,2-diphenylethyl)piperazine and N1-substituted derivatives, respectively. The alkylation of N-(1,2-diphenylethyl)piperazine afforded 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives. Several 1-substituted 4-(1,2-diphenylethyl)piperazines were also obtained by the reactions of 1,2-diphenylethylamine and N-substituted 2,2''-dichlorodiethylamine. d,l-1-Cyclohexyl-4-(1,2-diphenylethyl)piperazine (5) was resolved with (+)- or (-)-2''-nitrotartranilic acid into its optical isomers [(+)-5 and (-)-5], and the absolute configuration of (+)-5 was determined to be S by the synthesis and optical rotatory dispersion measurements. The most active members in this series of compounds were 5 and 2 other compounds which were approximately as potent as (-)-morphine. In the case of 5, the more potent enantiomer (S)-(+)-5 has the opposite configuration to that of (-)-N,N-dimethyl-1,2-diphenylethylamine (Spa) or (-)-morphine with respect to the (C-9) asymmetric center and belongs to a new series of compounds having potent analgesic activity.