Shinya Nagashima

New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation

The syntheses and biological evaluation of a series of novel indeno[1,2-d]thiazole derivatives are described. Several groups reported 5-HT(3) receptor agonists which were mainly evaluated for their activities on the von Bezold-Jarisch reflex (B-J reflex). We discovered that tetrahydrothiazolopyridine derivative 1b had a contractile effect on the isolated guinea pig colon with weak B-J reflex. Our efforts to find a new type of 5-HT(3) receptor agonists on the isolated guinea pig colon focused on the synthesis of a fused thiazole derivative 1d modified from 1b and reverse-fused thiazole derivatives (7-10). In this series, 10f (YM-31636) showed high affinity and selectivity for the cloned human 5-HT(3) receptor; furthermore, it showed potent and selective 5-HT(3) receptor agonistic activity. YM-31636 was examined for its effects on defecation in animals, thus evaluating the compound as an agent against constipation.

Chiral spirocyclic (Z)-5-arylmethylene-1,3-oxazine-4,6-diones, new chiral heterodienes

Abstract A series of (Z)-5-arylmethylene-1,3-oxazine-4,6-diones was synthesized in enantiomerically pure form and found to serve as the attractive alternatives of 6-arylmethylene-1,4-oxazepane-5,7-diones.

The effect of para-substituents on the conformational behavior of 2,2-diaryl-1,3-oxazine-4,6-diones: evidence from a crystal structure determination ☆

Abstract The crystal structure of 2,3-bis(4-methoxyphenyl)-2-(4-nitrophenyl)-1,3-oxazine-4,6-dione (9) was elucidated by X-ray structure analysis. This analysis has revealed two interesting characteristics: 1) The molecule is in a boat conformation with C(2) and C(5) pointing upward with angles of 41.9° and 26.0°, respectively and 2) The 4-nitrophenyl group takes a quasi-axial conformation. The second characteristic can be interpreted in terms of stabilizing interaction between the lone pairs on N(3) and/or O(1) and the σ*-orbital on the axial C(2)-aryl bond. The similar interaction of the lone pairs to π-orbitals of C(4 and 6)=O is also considered to account for the first characteristic.