METHOD FOR MANUFACTURE OF DIHYDROISOBENZOFURAN DERIVATIVES
The present invention relates to a method for the manufacture of dihydroisobenzofurans of formula I; comprising generation a dianion of formula II, reaction of the dianion with a carbonyl compound of formula III and acidification of the reaction mixture t
-
Page 10-11
(2010/02/06)
Spiro-substituted piperidines as neurokinin receptor antagonists. I. Design and synthesis of (±)-N-[2-(3,4-Dichlorophenyl)-4- (spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl)butyl]-N-methylbenzamide, YM- 35375, as a new lead compound for novel neurokinin receptor antagonists
Analysis of the structural requirements of compound 1 (SR48968), a potent NK2 receptor antagonist, revealed that the 4-phenyl group of the piperidine is essential for binding with the NK2 receptor and occupies an equatorial position. Energy calculation of a variety of substituted 4-phenyl piperidines revealed that spiro[isobenzofuran-1(3H), 4'-piperidine] possesses a conformationally restricted equatorial phenyl group. Our compound 12 (YM- 35375) possessing this spiro-substituted piperidine bound to the NK2 receptor with an IC50 value of 84nM and to the NK1 receptor with an IC50 value of 710nM. It showed more potent inhibitory activity (ID50 41μg/kg (i.v.)) against [β-Ala8]-NKA(4-10)-induced bronchoconstriction in guinea pigs than (±)-SR48968 (ID50 68μg/kg (i.v.)). YM-35375 may be a new lead compound for novel NK2 receptor antagonists or NK1-NK2 dual antagonists.