Synthesis and Serotonin 2 (5-HT2) Receptor Antagonist Activity of 5-Aminoalkyl-Substituted Pyrrolo[3,2-c]azepines and Related Compounds.

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Abstract
A series of 5-aminoalkylpyrrolo[3, 2-c]azepine derivatives was synthesized and their serotonin 2 (5-HT2) receptor antagonist and antiplatelet aggregation activities were evaluated. 5-HT2 receptor antagonist activity was largely determined by the nature of the substituent at the 8-position as well as 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-methyl-1, 4, 5, 6, 7, 8, -hexahydropyrrolo[3, 2-c]azepin-4-one, was recognized as having potent 5-HT2 receptor antagonist activity with weak α1 adrenoceptor blocking activity and no significant D2 receptor binding affinity, while the corresponding isomeric pyrrolo[3, 4-c]azepine derivative (22) displayed only weak 5-HT2 receptor antagonist activity. After racemic 18a was resolved directly via diastereomeric salt formation, each enantiomer was evaluated precisely. The 5-HT2 receptor antagonist activity of 18a was found to reside primarily in (-)-18a (which was about 14-fold more potent than (+)-18a in isolated guinea pig arteries). Consequently, (S)-(-)-18a (SUN C5174) displayed the overall best profile with potent 5-HT2 receptor antagonist activity (pA2=8.98±0.06) and high selectivity versus other receptors.SUN C5174 showed a marked inhibitory effect on the platelet aggregation induced by serotonin in combination with collagen and adenosine diphosphate (ADP) in canine or human platelet-rich plasma (IC50=6.5 to 16 nM). Moreover, this compound significantly inhibited the mortality rate in mouse acute pulmonary thromboembolitic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or higher.

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