Collect. Czech. Chem. Commun. 1994, 59, 2343-2350

Some 4-Substituted 1-(3-Pyridylmethyl)piperazines with Antihistamine Activity

Vojtěch Kmoníčeka, Martin Valchářb and Zdeněk Polívkaa

a Research Institute for Pharmacy and Biochemistry, 130 60 Prague 3, Czech Republic
b State Institute for the Drug Control, 110 00 Prague 10, Czech Republic


Several compounds derived from nicotinic acid were prepared within a more extensive programme aiming at the synthesis of new substances with expected antihistamine and antidepressant activity. Some of these compounds display certain structural resemblance with the antidepressant agent piberaline (EGYT 475, Trelibet®, I) and its analogues. The products were used as intermediates for the synthesis of further compounds and most of them were subjected to pharmacological testing. Substituted nicotinic acid piperazides IIa - IId and IVa - IVe were obtained by reactions of nicotinoyl chloride (prepared in situ) with the correspondingly substituted piperazines. Reduction of the piperazides IIa - IId and IVa - IVd with diborane in situ in tetrahydrofuran afforded corresponding 1-substituted 4-(3-pyridylmethyl)piperazines IIIa - IIId and Va - Vd. Whereas the alkylation of 1-(2-pyrimidinyl)piperazine with 2-(chloromethyl)pyridine in ethanol in the presence of triethylamine resulted in compounds Ve, compound Vf was obtained by the addition reaction of 1-(3-pyridylmethyl)piperazine to acrylamide. The piperazides VIe and VIf were prepared by reactions of 2-(3-pyridyl)acetic acid with 1-(2-pyrimidinyl)piperazine or 3-(1-piperazinyl)propionamide in N,N-dimethylformamide in the presence 1,1'-carbonyldiimidazole. A similar procedure starting from nicotinic acid afforded the piperazide IVf. Compounds Vc and Vd showed significant affinity for the histamine H1-receptors (inhibition of binding of 2 nmol/l [3H]mepyramine in membranes from the rat brain: Vc, IC50 = 28 nmol/l; Vd, IC50 = 148 nmol/l). They also proved active in test of histamine aerosol in guinea pigs (PD50 = 4.1 mg/kg p.o. for compound Vc and 2.4 for compound Vd). Results of a more detailed pharmacological testing of these compounds will be published elsewhere.