Isoxazolylpyrrolidinylpiperazine Ligands, a New Class for Dopamine D3and D4Receptor Antagonists

Abstract

Since the dopamine receptor system plays an important role in the development of neurological disorders like schizophrenia, extensive efforts have been made to explore potent and selective ligands for dopamine receptors for the discovery of antipsychotic drugs. In connection with search for potent ligands for dopamine receptors, we have studied the construction and biological activities of libraries of arylpiperazine derivatives with isoxazole rings. Recently we reported the design and synthesis of isoxazolylpiperidinylpiperazine derivatives having 6-membered nitrogen heterocycle, piperidine in between piperazine and isoxazole. To investigate the structure-activity relationship, the new isoxazolylpyrrolidinylpiperazine derivatives, which possess 5membered ring system, pyrrolidine in between piperazine and isoxazole, were designed and synthesized. In this paper, we report the construction of a small focused library of isoxazolylpyrrolidinylpiperazines and their binding affinities for dopamine D3 and D4 receptors. The synthesis of isoxazolylpyrrolidinylpiperazine derivatives is shown in Schemes 1, 2 and 3. The key synthetic strategy to these compounds involved coupling between two building blocks 2 and 3 using reductive amination reaction. Preparation of building block 2 is described in Scheme 2. Protection of the amino group of pyrrolidin-2-ylmethanol 4 with (t-Boc)2O in dichloromethane at rt for 1 h provided compound 5 in 90% yield. Oxidation of 5 with PCC and SiO2 in dichloromethane at rt for 3 h gave aldehyde 6 in 71% yield. Reductive amination of the aldehyde 6 with piperazine derivatives 7 using NaBH(OAc)3 in presence of 4 A molecular sieve over 6 h afforded compounds 8 in 60-92% yields. Deprotection of 8 with CF3CO2H in dichloromethane at rt furnished building block 2 in 87-99% yields. Synthesis of building block 3 is shown in Scheme 3. Treatment of aldehydes 9 with hydroxylamine hydrochloride and Na2CO3 at 60 C for 1-6 h gave oximes 10 in 99% yields. Isoxazole ring system was then installed by two-step sequence of nitrile oxide cycloaddition reaction which