Bis piperidine derivatives with platelet receptor fibrinogen fixation inhibiting activity, useful in cardiac intervention surgery and for preventing thrombosis

摘要

Bispiperidine derivatives (I) are new. Bispiperidine derivatives of formula (I) or their acid addition salts are new. either R2 = H; and R1 = 1-4C alkyl, mono- or bi-cyclic 3-12C cycloalkyl, 2-4C alkenyl or alkynyl (all optionally substituted by halo or OH), or 6-14C mono-, bi- or tri-cyclic aryl, heteroaryl, phenyl-1-4C alkyl, naphthyl-1-4C alkyl (all optionally substituted on the aryl ring), -CO-NR4R'4,-CO-NH-(CH2)m-R5; or R1 = H; and R2 = -NHCOR6 or -NHSO2R7; R3 = H, 1-4C alkyl or phenyl 1-4C alkyl; R4 = 1-8C alkyl, 3-12C mono- or poly cyclic cycloalkyl (all optionally substituted by halo or OH); R'4 = 1-8C alkyl, 3-12C mono- or polycyclic cycloalkyl (all optionally substituted by halo or OH) or H; or R4 + R'4 = tetramethylene or pentamethylene group (optionally substituted by 6-14C aryl or 6-14C aryl-1-4C alkyl); R5 = phenyl, methoxy phenyl, indolyl, benzodioxolyl, benzodioxanyl, benzothienyl or benzofuranyl; m = 1-4; R6 = 1-4C alkoxy, 3-7C cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl, or benzodioxanyl; R7 = 1-5C alkyl (optionally substituted by halo, OH or trifluoromethyl), 2-5C alkenyl, mono- or bicyclic 3-12C cycloalkyl, 6-14C mono-, bi-, or tricyclic aryl, heteroaryl, phenyl-1-4C alkyl, naphthyl-1-4C alkyl or a bicyclic group of the formula (i); n = 1-3; B1 = -CH2-, -O-, -S- or -NH- A = -NH-CHR10, -NH-CH-R10-CH2- or a group (ii); p = 1 or 2; R10 = H, 1-4C alkyl or 6-14C aryl; Z1, Z2 = H or a group protecting the amine function; heteroaryl = pyridyl, furyl, thienyl, quinolyl, benzodioxanyl, benzodioxolyl, isoxazolyl, benzodioxinyl, benzothienyl, thiazolyl, pyrazolyl, benzofuryl, or benzothiazolyl; substituted aryl and heteroaryl = halo, 1-4C alkyl, 3-7C cycloalkyl, CF3, 1-4C alkylthio, 1-4C alkyloxy, 1-4C alkylsulfonyl, NO2, di-1-4C alkylamino, -COOR, -CH2COOR, or -O-CH2-COOR; and R = 1-4C alkyl, phenyl, naphthyl, thienyl, furyl, or pyridyl. Independent claims are also included for: (1) the intermediates of formula (II) and (IV); and (2) the preparation of (I). R8, R9 = protecting groups.