Endothelin antagonistic peptide derivatives

Claim 1

A peptide derivative of the formula: wherein A 1 is a group of the formula R 11 -CO- {wherein R 11 is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a group of the formula Ar l- (CH 2 )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 12 O-CO- {wherein R 12 is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group or a phenyl group}, or a group of the formula R 13 R 14 N-C(=X 1 )- {wherein X 1 is an oxygen atom or a sulfur atom, R 13 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- (CH 2 )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), R 14 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- (CH 2 ) r - (wherein Ar 3 is a phenyl group, a furyl group or a thienyl group, and r is 1 or 2), or R 13 and R 14 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 15 - (wherein R 15 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) wherein R 16 is a hydrogen atom, a lower alkyl group or a cycloalkyl group, and each of R 17 and R 16 , 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 51 -CO-(CH 2 ) s - (wherein R 51 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 51 is other than a hydroxyl group) or a group of the formula (R520)2P(=O)-(CH2)t- (wherein R 52 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 53 O-CO-(CH 2 ) u - (wherein R 53 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): wherein Y is a sulfo group, a phosphono group, a group of the formula -C0 2 R 91 (wherein R 91 is a hydrogen atom, a lower alkyl group or a benzyl group), or a group of the formula -CONR 92 R 93 (wherein R 92 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 93 is a hydrogen atom or a lower alkyl group), R 61 is a hydrogen atom or a lower alkyl group, or together with R71 represents a methylene group, R 71 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-ω-amino lower liner alkyl group, or together with R 61 represents a methylene group, provided that when R 61 is a lower alkyl group, R71 is a group other than a hydrogen atom, R 62 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 72 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 62 is a group other than a hydrogen atom, R 72 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 62 represents a single bond, v is 3, 4 or 5, R 63 is a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a group of the formula Ar 4 -(CH 2 ) w -(wherein Ar4 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.