Novel Selective and Partial Agonists of 5-HT₃Receptors. Part 1. Synthesis and Biological Evaluation of Piperazinopyrrolothienopyrazines

Abstract

A series of piperazinopyrrolo[1,2-a]thieno[3,2-e]- and -[2,3-e]pyrazine derivatives were prepared and evaluated in order to determine the necessary requirements for high affinity on the 5-HT3 receptors and high selectivity versus other 5-HT receptor subtypes. Various substitutions on the piperazine and the thiophene ring of the pyrrolothienopyrazine moieties were systematically explored as well as replacement of the piperazine by other cyclic amines. The best compounds are in the nanomolar range of affinity of 5-HT3 receptors with high to very high selectivity (up to 10,000 for 14b). These high-affinity compounds have in common a benzyl- or allylpiperazine substituent with no substitutions on the thiophene ring. Five of these compounds (1a, 4b, 13a,b, and 14b) have been evaluated on the Von Bezold-Jarisch reflex and were characterized as partial agonists. One of them, 13a, has shown in vivo at very low dose a potent anxiolytic-like activity in the light/dark test.

SNAr and Palladium‐Catalyzed Reactions of Deactivated Thiophene: Application to the Synthesis of Protein Farnesyltransferase Inhibitors

“…[13,14] Amine 18 was then alkylated with iodoethane to provide 5-diethylamine 23 or reacted with 2,5-dimethoxytetrahydrofuran to give pyrrole 28 in excellent yield (Scheme 4). [15] Azide 26 was also converted to 1,2,3-triazole analogue 32 by a [2+3] Huisgen cycloaddition with (trimethylsilyl)-acetylene. [16] Without solvent or catalyst, this reaction proceeded in a very efficient way and gave, after removal of the trimethylsilyl group with HF·Et 3 N, free 1,2,3-triazole derivative 33.…”

Synthesis of aminopyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives as serotoninergic 5-HT7 ligands

“…Flash chromatography was performed using silica gel Merck 40-70 µm (230-400 mesh). Preparations of compounds 1 26 , 2 25 , 3a 27 , 3b 28 , 3c 28 and 3d 20 have been previously described. …”

“…[20][21][22] We found that two of them (5-MeO-DPAC and S 20244) displayed significant affinity for 5-HT 7 R. Subsequently, we planned This lack of selectivity has led us to translate the knowledge acquired in the benzopyran series, to aminopyrrolothienopyrazine series, which has been described recently as being the possible support of new 5-HT ligands. 7 24 So, in this paper, we report the synthesis of a series of tricyclic aminopyrrolothienopyrazine 25 analogues of benzopyran having the structure key elements previously mentioned. …”

Novel Selective 5-HT3 Receptor Ligands: Facile Generation Methods for 2-Amino- and 4-Aminopyrido[4’,3’:4,5]thieno[2,3-d]pyrimidines

“…The present work reports on the synthesis of 2-amino-and 4-aminothieno [2,3-d]pyrimidine derivatives which can be regarded or might behave prospectively as analogues to 5-HT 3 receptor ligands [22]. These compounds possess the three key pharmacophoric elements (an aromatic moiety, a hydrogen-bond acceptor and a basic amino group) required for interaction with the 5-HT 3 receptor [23] and are structurally related to quipazine, a potent ligand for the 5-HT 3 receptor [24].…”