New amido-substituted (hetero)aryloxy-alkanoic acid derivative endothelin receptor antagonists for treating e.g. cardiovascular disorders

摘要

Amido-substituted (hetero)aryloxy-alkanoic acid derivatives (I) are new. Carboxylic acid derivatives of formula (I), and their salts and pure enantiomers or diastereomers, are new: R1 = tetrazole or -CO-R; R = OR9, N-bonded 5-membered heteroaryl, -O(CH2)p-S(O)k-R10 or -NHSO2R11; R9 = H; alkali metal, alkaline earth metal or organic ammonium cation; cycloalkyl; alkyl; or (all optionally substituted) benzyl, 3-6C alkenyl, 3-6C alkynyl or phenyl; k = 0-2; p = 1-4; R10 = A, cycloalkyl, 3-6C alkenyl, 3-6C alkynyl or optionally substituted phenyl; A = 1-4C alkyl; R11 = A, 3-6C alkenyl, 3-6C alkynyl or cycloalkyl (all optionally substituted by OA, SA and/or phenyl); or optionally substituted phenyl; R2, R3 = H, OH, NH2, NHA, N(A)2, halo, A', 2-4C alkenyl, 2-4C alkynyl, OA' or SA; A' = A or 1-4C haloalkyl; X, Y = CH or N; Z' = N or CR12; R12 = H, halo or A; or R2+R12 or R3+R12 = alkylene or alkenylene (both optionally substituted and optionally having one or more CH2 replaced by O, S, NH or NA), completing a 5- or 6-membered ring; R4, R5 = phenyl, naphthyl or cycloalkyl (all optionally substituted); or phenyl or naphthyl bonded together in the ortho-position via a direct bond, CH2, CH2CH2, CH=CH, O, S, SO2, NH or N-alkyl (C number not given); R6 = -CO-NR13R14 or -CR21R20-NR18R19; R13, R14 = H (but not both H) or (all optionally substituted) alkyl, cycloalkyl, alkenyl, alkynyl, benzyl, phenyl or naphthyl; or R13+R14 = optionally substituted 3-7C alkylene (optionally with one CH2 replaced by O, S or N or carrying an optionally substituted fused benzene ring); or optionally substituted 3-7C alkenylene carrying an optionally substituted fused benzene ring; R7, R8, R21 = H or A; R18 = H or (all optionally substituted) alkyl, cycloalkyl, alkenyl, alkynyl, phenyl or naphthyl; R19 = alkylcarbonyl, (2-8C) alkenylcarbonyl, (2-8C) alkynylcarbonyl, benzyloxycarbonyl, cycloalkylcarbonyl, benzoyl, naphthoyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, phenylsulfonyl or naphthylsulfonyl (all optionally substituted); or cycloalkylsulfonyl; R20 = H or A (optionally substituted); W = O or S; alkyl moieties = 1-8C and alkenyl, alkynyl or cycloalkyl moieties = 3-8C unless specified otherwise. Independent claims are included for: (i) the use of alcohols of formula (V) as starting materials for the synthesis of endothelin (ET) receptor antagonists; (ii) structural fragments of formula (II); (iii) the use of (II) as a structural component of ET receptor antagonists; (iv) ET receptor antagonists consisting of a fragment of formula (III) covalently bonded with a group having molecular weight at least 30 or a fragment of formula (IV) covalently bonded via N to a group of molecular weight at least 58; and (v) new amines of formula (I'). N.B. The additional CO groups attached to R6 in (V) and (II) have been omitted in the disclosure.