New pyrimidinyloxy-propionic acid derivatives useful as endothelin receptor antagonists in treatment of e.g. cardiac insufficiency, restenosis, hypertension, kidney failure, asthma and prostate cancer

摘要

Pyrimidinyloxy-propionic acid derivatives (I) are new. Also new are combinations of (I) with inhibitors of the renin-angiotensin system, beta -blockers, diuretics, calcium antagonists and VEGF blockers. (Pyrimidin-2-yloxy)-propionic acid derivatives of formula (I) and their salts are new: R1 = tetrazolyl or C(O)R; R = OR7, N-bonded heteroaryl optionally substituted with halo, alkyl or alkoxy, -O-(CH2)p-S(O)k-R8 or -NH-SO2-R9; R7 = H, an alkali or alkaline earth cation, NH4+, an organic ammonium ion, cycloalkyl, alkyl, optionally substituted benzyl, optionally halogenated alkenyl or alkynyl or optionally substituted phenyl; R8 = alkyl, cycloalkyl, alkenyl, alkynyl or optionally substituted phenyl; k = 0-2; p = 1-4; R9 = optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl or phenyl; R2 = H, OH, NH2, NH(alkyl), N(alkyl)2, halo, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio or morpholinyl; X = halo, haloalkyl or OH; R3 = H, OH, NH2, NH(alkyl), N(alkyl)2, halo, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -NH-O-alkyl or alkylthio; R4, R5 = optionally substituted phenyl or naphthyl; phenyl or naphthyl ortho-linked with one another via a bond, methylene, ethylene, ethenylene, O, S, SO2, NH or N(alkyl); optionally substituted heteroaryl; or cycloalkyl; Z' = S, O, or a single bond; and R6 = H (when Z = S or O), optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl or heteroaryl. The full definitions are given in the DEFINITIONS (Full Definitions) Field. An Independent claim is also included for combinations of (I) with inhibitors of the renin-angiotensin system, beta -blockers, diuretics, calcium antagonists and VEGF blockers.