Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo [3,2-c]azepines and related compounds

A series of 5-aminoalkylpyrrolo[3,2-c] azepine derivatives was synthesized and their serotonin 2 (5-MT2) receptor antagonist and antiplatelet aggregat ion activities were evaluated, 5-HT2 receptor antagonist activity was large ly determined by the nature of the substituent at the 8-position as well as the aminoalkyl group at the 5-position of the pyrrolo[3,2-c]azepine ring. Compound 18a, 5-[3-[4(-4-fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-me thyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, was recognized as hav ing potent 5-MT2 receptor antagonist activity with weak cc, adrenoceptor bl ocking activity and no significant D-2 receptor binding affinity, while the corresponding isomeric pyrrolo[3,4-c]azepine derivative (22) displayed onl y weak 5-HT2 receptor antagonist activity. After racemic 18a was resolved d irectly via diastereomeric salt formation, each enantiomer was evaluated pr ecisely. The 5-MT2 receptor antagonist activity of 18a was found to reside primarily in (-)-18a (which was about 14-fold more potent than (+)-18a in i solated guinea pig arteries). Consequently, (S)-(-)-18a (SUN C5174) display ed the overall best profile with potent 5-HT2 receptor antagonist activity (pA(2)=8.98+/-0.06) and high selectivity versus other receptors. SUN C5174 showed a marked inhibitory effect on the platelet aggregation ind uced by serotonin in combination with collagen and adenosine diphosphate (A DP) in canine or human platelet-rich plasma (IC50=6.5 to 16 nM), Moreover, this compound significantly inhibited the mortality rate in mouse acute pul monary thromboembolitic death induced by collagen and serotonin at oral dos es of 0.3 mg/kg or higher. SUN C5174 is currently undergoing clinical evaluation.