モルホリンおよびオキサゾリジン環を基本骨格に有する新規タキキニン受容体拮抗薬の合成研究
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概要
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Tachykinin actions are mediated by at least three distinct receptors designated as NK<SUB>1</SUB>, NK<SUB>2</SUB> and NK<SUB>3</SUB>. The endogeneous tachykinin ligands interact with all tachykinin receptors, although there is a defined agonist rank order of potency such that substance P (SP), neurokinin A (NKA), and neu-rokinin B (NKB) have the highest affinities for the NK<SUB>1</SUB>, NK<SUB>2</SUB> and NK<SUB>3</SUB> receptors, respectively. SP, NKA, and NKB have all been linked to numerous chronic diseases, including asthma and chronic obstructive pulmonary disease. Speculating that a combined tachykinin receptor antagonist may be of greater benefit than a selective antagonist in the treatment of pulmonary diseases, we designed a series of novel morpholine and oxazolidine analogues (I and II). We report herein the synthesis and structure-activity relationships of novel morpholine- and oxazolidine-based ana-logues with regards to NK<SUB>1</SUB>, NK<SUB>2</SUB> and NK<SUB>3</SUB> tachykinin receptor binding affinity. Efficient and practi-cal synthetic methods for the preparation of enantiomerically pure 2- [(2<I>R</I>) -arylmorpholin-2-yl] ethanols 8a-d and 2- [(5<I>R</I>) -aryloxazolidin-5-yl] ethanols 23a-d, key intermediates of I and II are described. Among these analogues, the compounds that possess properties such as spiro [benzo [<I>c</I>] thiophene-1 (3<I>H</I>), 4-piperidine] - (2<I>S</I>) -oxide (<I>S</I>) -29 and spiro [((2S) -hydroxy) indane-1, 4-piperidine] (<I>S</I>) -41 moiety had strong binding affinities to the tachykinin receptor. This report also describes efficient and practical synthetic methods for the preparation of enan-tiomerically pure (<I>S</I>) -29 and (<I>S</I>) -41. One of the enantiomers, (<I>S</I>, <I>R</I>) -42 HCl salt (R-113281), exhib-ited high binding affinities for NK<SUB>1</SUB>, NK<SUB>2</SUB> and NK<SUB>3</SUB> receptors in humans and guinea pigs. In vivo, R-113281 exerted highly potent antagonism toward SP-induced tracheal vascular hyperpermeabili-ty and NKA-, NKB- and capsaicin-induced bronchoconstriction in guinea pigs.
- 社団法人 有機合成化学協会の論文
- 2002-07-01
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