Series of 1,4-disubstituted piperazine and of N,N-disubstituted ethylenediamine having the 2,3-diphenyl-1H-indole-5-carbonyl group as one of the two substituents were prepared. Compounds 3, 4, 11, 15 -17, and 20 -22 were tested for analgesic activity. After ip administration all compounds induced significant visceral antinociceptive activities where acetic acid-induced writhing was significantly reduced by all compounds.Arylpiperazine derivatives are known to display analgesic action with the efficiency of morphine but without the side effects, especially drug dependency [1 -6]. Our goal in this paper is to develop new analgesic and antidepressant agents by synthesizing analogues to trazodone (Fig. 1), which was reported as an antidepressant and possessing antinociceptive effects [7 -12]. As the indole moiety is common in many analgesic drugs, e.g. pravadoline [13 -15] and clometacin [16 -21], we have investigated the replacement of the aryl group in trazodone by a heteroaryl group such as 2,3-diphenylindole-5-carbonyl group and introducing different substituents in the 1-position of piperazine. We have also replaced the piperazine nucleus in our synthesized molecules by the 1,2-diaminoethyl group to observe the effect of this replacement on activity. We have successfully prepared potent analgesic compounds containing 1,4-disubstituted piperazines and N,N-disubstituted ethylene diamines. We deduced that the piperazine moiety could be replaced by the 1,2-diaminoethyl group offering comparable analgesic activity. All the tested compounds did not show any antidepressant activity.Compound 1 was prepared from 5-carboxyphenylhydrazine with deoxybenzoin according to the Fischer method [22] and converted to the acid chloride 2 by thionyl chloride. Compound 2 was reacted with piperazine or ethylenediamine in dimethylformamide and triethylamine to obtain the amide 3 or 4, respectively. The desired disubstituted piperazine derivatives 5 -17 and disubstituted ethylenediamine derivatives 18 -22 were obtained according to the procedures described in schemes 1 and 2, respectively.
Structure-activity RelationshipWe deduce from Tables 1 -3 that among the series 3, 4, 11, and 15 -17, compound 17 was found to be the most active which emphasizes the presence of the free 4-amino group in the phenyl ring to increase the activity, as compound 17 is more active than 16 carrying the NHCOCH 3 group in the 4-position. Compounds 11 and 15 having no NH protons at the 4-position are not active.For the series 20 -22, the presence of 2-OH group in the phenyl ring is important for activity, as compound 22 is the most active one.Comparing both series compounds 11, 15 -17, and 20 -21, it is noticed that the latter has comparable analgesic activity to the piperazine series, indicating that disubstituted ethylenediamines can replace disubstituted piperazine to obtain potent analgesic compounds.Conclusion: We have successfully prepared 1,4-disubstituted piperazines and N,N-disubstituted ethylenediamines, both containing a 1,2-diphenyl-5-carbonyl moi...
