Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 1.

The preparation and analgesic activities of a series of the entitled compounds (5-22) and the optical isomers of the 1-cyclohexyl derivative 5 are described. Reactions of N,N-bis(2-chloroethyl)-1,2-diphenylethylamine (3) with ammonia and primary amines gave N-(1,2-diphenylethyl)piperazine (4) and N1-substituted derivatives (5-20, 22), respectively. The alkylation of 4 afforded 12-21. Compounds 5-18 and 22 were also obtained by the reactions of 1,2-diphenylethylamine (23) and N-substituted 2,2'-dichlorodiethylamine. Racemate 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 configuration by the synthesis and optical rotatory dispersion measurements. The most active members in this series of compounds were 5-7, 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.

Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 2. Structure-activity relationships of 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines.

Forty-six 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines were synthesized. The influence of substituents on phenyl groups of 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines 4a-c on the analgesic activity was investigated in experimental animals. The most active compounds, 5a-c, in this series had a m-hydroxyl group on the 2-phenyl group of 4a-c, while morphine has a phenolic hydroxyl group para to th- aminoethyl moiety. Their activities were 23-56 and 23-38 times those of their original compounds 4a-c and morphine, respectively, tested by the D'Amour-Smith method after subcutaneous administration.

Synthesis and structure-activity relationships of 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives having narcotic agonist and antagonist activity.

Racemates and enantiomers of 1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives (3-18) were synthesized, and their analgesic and other pharmacological activities and structure-activity relationships were investigated. The S-(+) enantiomers of 2a, 5, 7, 9, 10, and 15-18 had a stronger analgesic activity than their R-(-) enantiomers; analgesic activity of the strongest one [(S)-(+)-10] was 105 times as potent as that of morphine. The S-(+) enantiomers of these compounds had the opposite configuration to that of morphine with respect to its (C-9) asymmetric center but the same configuration to that of the tyrosine residue of Met5-enkephalin. The R-(-) enantiomers of 16 and 18 showed narcotic antagonist activity, but the S-(+) enantiomers did not. (R)-(-)-18 had analgesic and narcotic antagonist activities comparable to pentazocine but showed no significant physical dependence liability. From these results, it is suggested that these compounds show an uncommon enantioselectivity in comparison with morphine and its surrogates, and belong to a new series of compounds having a potent analgesic activity.

Analgesic and other pharmacological activities of a new narcotic antagonist analgesic (-)-1-(3-methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazine and its enantiomorph in experimental animals.

Of 1-chclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine (I) and its 1-(3-methyl-2-butenyl) derivative (II), the S(+)-isomers were analgesically more active than either their +(-)-isomers or their racemates, having 15 to 44 times the potency of morphine in mice and rats. R(-)-I had comparable analgesic activity to morphine R(-)-II to pentazocine in mice, rats and dogs and they were nearly equipotent with pentazocine in reversing some actions of morphine. The S(+)-isomers and racemates lacked this action. R(-)-II required about 10 times more naloxone to reverse its analgesic activity than was needed to antagonise the S(+)-isomers, morphine and pentazocine. The S(+)-isomers and racemates produce a typical Straub tail reaction and increased spontaneous locomotor activity in mice, but the R(-)-isomers did not. R(-)-II had no significant physical dependence liability in mice, rats and monkeys. From these results, it is suggested that the compounds show an uncommon steroselectivity in comparison with morphine and its surrogates, and that R(-)-II is worth investigating further as a narcotic antagonist analgesic.

Roles of two basic nitrogen atoms in 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives in production of opioid agonist and antagonist activities.

To ascertain roles of the two basic nitrogen atoms in 1-substituted 4-[2,(3-hydroxyphenyl)-1-phenylethyl]-piperazine derivatives (1) in the expression of opioid agonist and antagonist activities, a methine group (CH) was isosterically substituted for nitrogen atom at the 1-position (N-1) in compound 1 to obtain 4-substituted 1-[2-(3-hydroxyphenyl)-1-phenylethyl]piperidine derivatives (2). Their analgesic action and ability to produce physical dependence (jump-producing activity) as the mu-opioid receptor specific in vivo actions, and narcotic antagonist action in mice were compared with those of compound 1. Results of this study showed that, in cases of the racemate and the (S)-(+) enantiomer, opioid agonist activities (analgesic and jump-producing activities) were not greatly affected by the methine-substitution for N-1 in compound 1, but that the narcotic antagonist activity of the (R)-(-) enatiomer was abolished by this substitution. It thus appears that N-1 in compound 1 contributes to the expression of narcotic antagonist activity, whereas the nitrogen atom at the 4-position corresponds to the tyramine moiety necessary for the expression of mu-opioid agonist activity.