Weigl Manuela, Wünsch Bernhard
Institut für Pharmazeutische und Medizinische Chemie, Hittorfstrasse 58-62, 48149 Münster, Germany.
Eur J Med Chem. 2007 Oct;42(10):1247-62. doi: 10.1016/j.ejmech.2007.02.005. Epub 2007 Feb 25.
Bridged piperazines 4 were designed as conformationally restricted piperazine sigma receptor ligands. The chiral pool synthesis started from (S)-glutamate, which was transformed in five reaction steps into the piperazinediones 5 bearing a propionic acid ester side chain. A two-step Dieckmann analogous cyclization provided the bicyclic ketones 7 as key intermediates. The alcohols 8 were prepared by LiAlH4 reduction of the ketones 7. NaBH4 reduction, Williamson ether synthesis and LiAlH4 reduction led to the methyl and benzyl ethers 12 and 13. High sigma1 affinity is attained when one large substituent is introduced either at N-8 or O-2. The most potent sigma1 ligand in this series of compounds is the methyl ether 12b with the N-butyl substituent (K(i)=13.2 nM, selectivity sigma2:sigma1 = 16). Moreover, the N-methyl derivatives 13a (sigma2: K(i)=30.4 nM) and 12a (sigma2 preference) represent promising starting points for the development of potent and selective sigma2 ligands.
桥连哌嗪4被设计为构象受限的哌嗪σ受体配体。手性池合成从(S)-谷氨酸开始，经过五步反应将其转化为带有丙酸酯侧链的哌嗪二酮5。两步类似迪克曼反应的环化反应提供了双环酮7作为关键中间体。通过用LiAlH4还原酮7制备醇8。用NaBH4还原、威廉姆森醚合成法和LiAlH4还原反应得到甲基醚和苄基醚12和13。当在N-8或O-2处引入一个大的取代基时，可获得高的σ1亲和力。该系列化合物中最有效的σ1配体是带有N-丁基取代基的甲基醚12b（K(i)=13.2 nM，σ2:σ1选择性 = 16）。此外，N-甲基衍生物13a（σ2：K(i)=30.4 nM）和12a（σ2偏好性）是开发强效和选择性σ2配体的有前景的起始点。
