Patent DE-19858779-A1 (DE)
Title: New 3-acylamino-propionic acid and 3-sulfonylamino-propionic acid derivatives useful as endothelin receptor antagonists in treatment of e.g. cardiovascular and renal disorders, migraine and cancer
Inventor: AMBERG WILHELM
IPC: C07D491/048
Filed: 1998-12-18
Abstract: 3-(Acylamino or sulfonylamino)-2-heteroaryloxy-propionic acid derivatives are new. The 3-(acylamino or sulfonylamino)-2-heteroaryloxy-propionic acid derivatives are compounds of formula (I) and their enantiomers, diastereoisomers and salts, excluding the compounds 2-(6-ethyl-2-methyl-pyrimidin-4-yloxy)-3-(4-methoxybenzoylamino)-3,3-d iphenylpropionic acid; 2-(2,6-dimethyl-pyrimidin-4-yloxy)-3-(4-methoxybenzoylamino)-3,3-diphe nylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(6-methoxy-2-methyl-pyrimidin-4-yloxy)-3, 3-diphenylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(6-methoxy-5-methyl-pyrazin-2-yloxy)--3,3 -diphenylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(5-methoxy-6-methyl-(1,2,4)triazin-3-ylox y)-3,3-diphenylpropionic acid; 2-(4-ethyl-6-methyl-(1,3,5)triazin-2-yloxy)-3-(4-methoxy-benzoylamino) -3,3-diphenylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(5-methoxy-6-methyl-pyridazin-3-yloxy)--3 ,3-diphenylpropionic acid; 2-(4,6-dimethyl-(1,3,5)triazin-2-yloxy)-3-(4-methoxy-benzoylamino)--3, 3-diphenylpropionic acid; 3-(4-methoxy-benzoyl amino)-2-(4-methoxy-6-methyl-(1,3,5)triazin-2-yloxy)-3,3-diphenylpropi onic acid; 3-(4-methoxy-benzoylamino)-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrim idin-2-yloxy)-3,3-diphenylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(4-methoxy-5,6-dihydrofuro(2,3-d)pyrimidi n-2-yloxy)--3,3-diphenylpropionic acid; 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-(4-methoxy-benzoylamino)-3,3-dip henylpropionic acid; 2-(4-ethyl-6-methyl-pyrimidin-2-yloxy)-3-(4-methoxy-benzoylamino)-3,3- diphenylpropionic acid; 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(4-methoxy-benzoylamino)-3,3-diph enylpropionic acid; 3-(4-methoxy-benzoylamino)-2-(4-methoxy-6-methyl-pyrimidin-2-yloxy)-3, 3-diphenylpropionic acid; 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(4-hydroxy-benzoylamino)--3,3-dip henylpropionic acid; 2-(4-methoxy-6-methyl-pyrimidin-2-yloxy)-3-(4-methylsulfanyl-benzoylam ino)--3,3-diphenylpropionic acid; 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(4-nitro-benzoylamino)-3,3-diphen ylpropionic acid; 3-(4-chloro-benzoylamino)-2-(4-ethyl-6-methyl-pyrimidin-2-yloxy)-3,3-d iphenylpropionic acid; 3-(4-ethyl-benzoylamino)-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimid in-2-yloxy)-3,3-diphenylpropionic acid; 3,3-bis(4-fluorophenyl)-3-(4-methoxy-benzoylamino)-2-(4-methoxy-5,6-di hydrofuro(2,3-d)pyrimidin-2-yloxy)-3,3-diphenylpropionic acid; 3-(4-chloro-benzoylamino)--2-(4,6-dimethyl-(1,3,5)triazin-2-yloxy)--3, 3-diphenylpropionic acid; 3-(3,4-dimethoxy-benzoylamino)-2-(4-methoxy-6-methyl-(1,3,5)triazin-2- yloxy)-3,3-diphenylpropionic acid; 3-(3,4-dimethoxy-benzoylamino)-2-(4-ethyl-6-methyl-(1,3,5)triazin-2-yl oxy)-3,3-diphenylpropionic acid; 3-(4-chloro-benzoylamino)-2-(5-methoxy-6-methyl-pyridazin-3-yloxy)-3,3 -diphenylpropionic acid; 3-(3,4-dichloro-benzoylamino)-2-(6-methoxy-5-methyl-pyrazin-2-yloxy)-3 ,3-diphenylpropionic acid; 3-(4-hydroxy-3-methoxy-benzoylamino)-2-(5-methoxy-6-methyl-(1,2,4)tria zin-3-yloxy)-3,3-diphenylpropionic acid; 3-(3-chloro-benzoylamino)-2-(2,6-dimethyl-pyrimidin-4-yloxy)-3,3-diphe nylpropionic acid; 3-(2-chloro-benzoylamino)-2-(6-methoxy-2-methyl-pyrimidin-4-yloxy)-3,3 -diphenylpropionic acid; and 2-(6-ethyl-2-methyl-pyrimidin-4-yloxy)-3-(4-nitro-benzoylamino)-3,3-di phenylpropionic acid.  R1 = tetrazolyl, or C(O)R;  R = OR6, N-bonded 5-membered heteroaryl; -O-(CH2)p-S(O)k-R7; or -NH-SO2-R8;  R6 = H, or 3-8C cycloalkyl, 1-8C alkyl, benzyl, 3-8C alkenyl, 3-8C alkynyl, or phenyl (all optionally substituted);  k = 0-2;  p = 1-4;  R7 = 1-4C alkyl; 3-8C cycloalkyl; 3-8C alkenyl; 3-8C alkynyl; or optionally substituted phenyl;  R8 = 1-4C alkyl, 3-8C alkenyl, 3-8C alkynyl or 3-8C cycloalkyl (each optionally substituted with 1-4C alkoxy, 1-4C alkylthio and/or phenyl); 1-4C haloalkyl; or optionally substituted phenyl;  X = N or CR9;  Y = N or CR10;  Q = N or CR11 (X = CR9 and Y = CR10 when Q = N);  W and V = N or CH (Q = N when W = V = CH);  R9 and R10 = H, halo, 1-4C alkoxy, 1-4C haloalkoxy, 3-6C alkenyloxy, 3-6C alkynyloxy, 1-4C alkylthio, 1-4C alkylcarbonyl, 1-4C alkoxycarbonyl, OH, NH2, NH(1-4C alkyl), N(1-4C alkyl)2, or 1-4C alkyl, 2-4C alkenyl or 2-4C alkynyl (each optionally substituted); or R9 or R10 together with R11 forms a 5-6 membered alkylene or alkenylene group in which 1 or more CH2 is replaced with O, S, NH or N(1-4 alkyl);  R11 = H, halo, 1-4C alkoxy, 1-4C haloalkoxy, 3-6C alkenyloxy, 3-6C alkynyloxy, 1-4C alkylthio, 1-4C alkylcarbonyl, 1-4C alkoxycarbonyl, NH(1-4C alkyl), N(1-4C alkyl)2, OH, COOH, CN, NH2, SH, or 1-4C alkyl, 2-4C alkenyl or 2-4C alkynyl (each optionally substituted); R2 and R3 = phenyl or naphthyl (both optionally substituted or optionally bonded to one another via a bond, CH2, CH2CH2, CH=CH, O, S, SO2, NH or N-alkyl); or 5-6C cycloalkyl; R4 = C(O)R12 or SO2R13; R12 = phenyl, naphthyl or 5-6 membered heteroaryl containing 1-3 N and/or 1 O or S atom (each optionally substituted); R13 = 1-4C alkyl or 1-4C alkoxy (each optionally substituted with halo), 1-4C alkylthio, or phenyl or phenoxy (each optionally substituted); and R5 = H or 1-4C alkyl. Independent claims are also included for the following: (1) 3-(acylamino or sulfonamido)-2-hydroxy-propionic acid derivatives (II); (2) the use of (I) in combination with a renin angiotensin system inhibitor, e.g. renin inhibitor, angiotensin-II antagonist, especially an ACE inhibitor, mixed ACE/neutral endopeptidase (NEP) inhibitor or  beta -blocker; and (3) a fragment of formula (A) as a structural element in an endothelial receptor antagonist.