Patent EP-0460679-A3 (EP)
Title: Endothelin antagonistic peptide derivatives
IPC: C07K5/06
Filed: 1991-06-06
Abstract: 1. A peptide derivative of the formula: <CHEM> wherein A<1> is a group of the formula R<1><1>-CO- {wherein R<1><1> is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a group of the formula Ar<1>-(CH2)p-(wherein Ar<1> is a phenyl group, a furyl group or a thienyl group, and p is 0, 1 or 2), a 1,3-dithiol-2-ylidenemethyl group, or a 1,3-dithiol-2-ylidene(lower alkoxycarbonyl)methyl group), a group of the formula R<1><2>O-CO- (wherein R<1><2> is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group or a phenyl group}, or a group of the formula R<1><3>R<1><4>N-C(=X<1>)- {wherein X<1> is an oxygen atom or a sulfur atom, R<1><3> is a lower alkyl group which may be substituted by a lower alkoxycarbonyl group, a cycloalkyl group, a lower alkynyl group, a 1-adamantyl group, a pyrrolidino group, a piperidino group, a perhydroazepin-1-yl group, a perhydroazocin-1-yl group, a perhydroazonin-1-yl group, or a group of the formula Ar<2>-(CH2)q- (wherein Ar<2> is a phenyl group wherein one or two optional hydrogen atoms on the benzene ring may independently be replaced by a halogen atom, a lower alkyl group or a lower alkoxy group, a furyl group, or a thienyl group, and q is 0,1 or 2), A<1><4> is a hydrogen atom, a lower alkyl group which may be substituted by a hydroxyl group, a cycloalkyl group, or a group of the formula Ar<3>-(CH2)r- (wherein Ar<3> is a phenyl group, a furyl group or a thienyl group, and r is 1 or 2), or R<1><3> and R<1><4> form, together with the adjacent nitrogen atom, a 5- to 9- membered nitrogen-containing saturated heterocyclic ring having 4 to 8 carbon atoms {wherein among methylene groups forming the ring, one optional methylene group not adjacent to the above nitrogen atom may be replaced by an oxy group, a thio group or a group of the formula -NR<1><5>- (wherein R<1><5> is a lower alkyl group), and one to four optional hydrogen atoms on the carbon atoms of the heterocyclic ring may independently be replaced by a hydroxyl group or a lower alkyl group which may be substituted by a hydroxyl group, and further two adjacent carbon atoms in the heterocyclic ring may form a double bond or a benzo-fused ring}, or together with B represents a group of the following formula(II) <CHEM> wherein R<1><6> is a hydrogen atom, a lower alkyl group or a cycloalkyl group, and each of R<1><7> and R<1><8>, which are independent from each other, is a hydrogen atom or a lower alkyl group; B is an oxygen atom or a group of the formula -NR<2>- (wherein R<2> is a hydrogen atom or a methyl group), or together with A<1> represents a group of the above formula (II); R<3> is a lower alkyl group having 3 to 5 carbon atoms; R<4> is a hydrogen atom or a methyl group; R<5> is a 3-indolylmethyl group, a (2,3-dihydro-2-oxo-3-indolyl)methyl group, a 3-indolylmethyl group wherein the indole ring is substituted at the 1-position by a group of the formula R<5><1>-CO-(CH2)s- (wherein R<5><1> is a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a benzyloxy group, an amino group or a mono lower alkylamino group, s is an integer of from 0 to 6, provided that when s = 0, R<5><1> is other than a hydroxyl group) or a group of the formula (R<5><2>O)2P(=O)-(CH2)t- (wherein R<5><2> is a hydrogen atom, a lower alkyl group or a benzyl group, and t is an integer of from 0 to 6), a benzyl group wherein an optional hydrogen atom on the benzene ring may be replaced by a group of the formula R<5><3>O-CO-(CH2)u- (wherein R<5><3> is a hydrogen atom or a lower alkyl group, and u is an integer of from 0 to 6), a benzyl group wherein one or two optional hydrogen atoms on the benzene ring are replaced by a hydroxyl group(s), or two optional hydrogen atoms on the benzene ring are replaced by a hydroxyl group and a sulfo group, a 3-benzothienylmethyl group, a (1-oxo-3-benzothienyl)methyl group, or a (1,1-dioxo-3-benzothienyl)methyl group; X<2> is an oxygen atom or a sulfur atom; A<2> is an optional group selected from the class consisting of groups of the following formulas (III),(IV),(V),(VI),(VII) and (VIII): <CHEM> wherein Y is a sulfo group, a phosphono group, a group of the formula -CO2R<9><1> (wherein R<9><1> is a hydrogen atom, a lower alkyl group or a benzyl group), or a group of the formula -CONR<9><2>R<9><3> (wherein R<9><3> is a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a phenylsulphonyl group wherein one to five optional hydrogen atoms on the benzene ring may independently be replaced by a lower alkyl group or a halogen atom, or a carboxymethyl group, and R<9><3> is a hydrogen atom or a lower alkyl group), R<6><1> is a hydrogen atom or a lower alkyl group, or together with R<7><1> represents a methylene group, R<7><1> is a hydrogen atom, a lower alkyl group which may be substituted by a hydroxyl group, a phenyl group, a thienyl group, a phenyl lower alkyl group wherein an optional hydrogen atom on the benzene ring may be replaced by a hydroxyl group or a benzyloxy group, a thienyl lower alkyl group, a thiazolyl lower alkyl group, a 4-imidazolylmethyl group, a (lower alkyl-substituted 4-imidazolyl)methylthiomethyl group, a 3-indolylmethyl group, a carbamoyl lower alkyl group or an N-benzyloxycarbonyl- omega -amino lower liner alkyl group, or together with R<6><1> represents a methylene group, provided that when R<6><1> is a lower alkyl group, R<7><1> is a group other than a hydrogen atom, R<6><2> is a hydrogen atom, a phenyl group, a benzyl group, a carboxy group, a carbamoyl group or an N-phenylcarbamoyl group, or together with R<8> represents a single bond, R<7><2> is a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group, a 3-indolylmethyl group, a carbamoyl group or an N-phenylcarbamoyl group, provided that when R<6><2> is a group other than a hydrogen atom, R<7><2> is a hydrogen atom or a lower alkyl group, R<8> is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group, or together with R<6><2> represents a single bond, v is 3, 4 or 5, R<6><3> is a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a group of the formula Ar<4>-(CH2)w-(wherein Ar<4> is a phenyl group, a furyl group or a thienyl group, and w is 1 or 2), Z is CH or N, and x is 1,2 or 3; or a pharmaceutically acceptable salt thereof.