Endothelin antagonistic peptide derivatives

A peptide of the formula:

• ##STR183## wherein A.sup.1 is a group of the formula R.sup.12 O--CO-- wherein R.sup.12 is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group or a phenyl group,
• B is an oxygen atom or a group of the formula --NR.sup.2 -- wherein R.sup.2 is a hydrogen atom or a methyl group;
• R.sup.3 is a lower alkyl group having 3 to 5 carbon atoms;
• R.sup.4 is a hydrogen atom or a methyl group;
• R.sup.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.sup.51 --CO--(CH.sub.2).sub.s -- wherein R.sup.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.sup.51 is other than a hydroxyl group, or a group of the formula (R.sup.52 O).sub.2 P(.dbd.O)--(CH.sub.2).sub.t -- wherein R.sup.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.sup.53 O--CO--(CH.sub.2).sub.u -- wherein R.sup.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-3benzothienyl)methyl group, or a (1,1-dioxo-3benzothienyl)methyl group;
• X.sup.2 is an oxygen atom or a sulfur atom;
• A.sup.2 is selected from the group consisting of the following formulas (III) and (IV) ##STR184## wherein Y is (a) a group of the formula --CO.sub.2 R.sup.91 wherein R.sup.91 is a hydrogen atom, a lower alkyl group or a benzyl group, or
• (b) a group of the formula --CONR.sup.92 R.sup.93 wherein R.sup.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.sup.93 is a hydrogen atom or a lower alkyl group, R.sup.61 is a hydrogen atom or a lower alkyl group, or together with R.sup.71 represents a methylene group, R.sup.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 alkylsubstituted 4-imidazolyl)methylthiomethyl group, a 3indolylmethyl group, a carbamoyl lower alkyl group or an N-benzyloxycarbonyl-.omega.-amino lower linear alkyl group, or together with R.sup.61 represents a methylene group, provided that when R.sup.61 is a lower alkyl group R.sup.71 is a group other than a hydrogen atom, R.sup.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.sup.8 represents a single bond, R.sup.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.sup.62 is a group other than a hydrogen atom, R.sup.72 is a hydrogen atom or a lower alkyl group, R.sup.8 is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group, or together with R.sup.62 represents a single bond, or a pharmaceutically acceptable salt thereof.

A peptide of the formula:

• ##STR185## wherein A.sup.1 is a group of the formula R.sup.13 R.sup.14 N--C(.dbd.X.sup.1)-- wherein
• X.sup.1 is an oxygen atom or a sulfur atom,
• R.sup.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.sup.2 --(CH.sub.2).sub.q -- wherein Ar.sup.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.sup.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.sup.3 --(CH.sub.2).sub.r -- wherein Ar.sup.3 is a phenyl group, a furyl group or a thienyl group, and r is 1 or 2,
• B is an oxygen atom or a group of the formula --NR.sup.2 -- wherein R.sup.2 is a hydrogen atom or a methyl group;
• R.sup.3 is a lower alkyl group having 3 to 5 carbon atoms;
• R.sup.4 is a hydrogen atom or a methyl group;
• R.sup.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.sup.51 --CO--(CH.sub.2).sub.s -- wherein R.sup.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.sup.51 is other than a hydroxyl group, or a group of the formula (R.sup.52 O).sub.2 P(.dbd.O)--(CH.sub.2).sub.t -- wherein R.sup.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.sup.53 O--CO--(CH.sub.2).sub.u -- wherein R.sup.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-3benzothienyl)methyl group, or a (1,1-dioxo-3benzothienyl)methyl group;
• X.sup.2 is an oxygen atom or a sulfur atom;
• A.sup.2 is selected from the group consisting of the following formulas (III) and (IV):
• ##STR186## wherein Y is (a) a group of the formula --CO.sub.2 R.sup.91 wherein R.sup.91 is a hydrogen atom, a lower alkyl group or a benzyl group, or
• (b) a group of the formula --CONR.sup.92 R.sup.93 wherein R.sup.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.sup.93 is a hydrogen atom or a lower alkyl group, R.sup.61 is a hydrogen atom or a lower alkyl group, or together with R.sup.71 represents a methylene group, R.sup.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 3indolylmethyl group, a carbamoyl lower alkyl group or an N-benzyloxycarbonyl-.omega.-amino lower linear alkyl group, or together with R.sup.61 represents a methylene group, provided that when R.sup.61 is a lower alkyl group R.sup.71 is a group other than a hydrogen atom, R.sup.62 is a hydrogen atom, a phenyl group, a benzyl group, a carboxy group, a carbamoyl group or an Nphenylcarbamoyl group, or together with R.sup.8 represents a single bond, R.sup.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.sup.62 is a group other than a hydrogen atom, R.sup.72 is a hydrogen atom or a lower alkyl group, R.sup.8 is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group, or together with R.sup.62 represents a single bond, or a pharmaceutically acceptable salt thereof.

A peptide of the formula:

• ##STR187## wherein A.sup.1 is a group of the formula R.sup.13 R.sup.14 N--C(.dbd.X.sup.1)-- wherein
• X.sup.1 is an oxygen atom or a sulfur atom,
• R.sup.13 and R.sup.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.sup.15 -- wherein R.sup.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-fuzed ring,
• B is an oxygen atom or a group of the-formula --NR.sup.2 -- wherein R.sup.2 is a hydrogen atom or a methyl group;
• R.sup.3 is a lower alkyl group having 3 to 5 carbon atoms;
• R.sup.4 is a hydrogen atom or a methyl group;
• R.sup.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.sup.51 --CO--(CH.sub.2).sub.s -- wherein R.sup.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.sup.51 is other than a hydroxyl group, or a group of the formula (R.sup.52 O).sub.2 P(.dbd.O)--(CH.sub.2).sub.t -- wherein R.sup.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.sup.53 O--CO--(CH.sub.2).sub.u -- wherein R.sup.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-3benzothienyl)methyl group, or a (1,1-dioxo-3benzothienyl)methyl group;
• X.sup.2 is an oxygen atom or a sulfur atom;
• A.sup.2 is selected from the group consisting of the following formulas (III) and (IV) ##STR188## wherein Y is (a) a group of the formula --CO.sub.2 R.sup.91 wherein R.sup.91 is a hydrogen atom, a lower alkyl group. or a benzyl group, or
• (b) a group of the formula --CONR.sup.92 R.sup.93 wherein R.sup.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.sup.93 is a hydrogen atom or a lower alkyl group, R.sup.61 is a hydrogen atom or a lower alkyl group, or together with R.sup.71 represents a methylene group, R.sup.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 alkylsubstituted 4-imidazolyl)methylthiomethyl group, a 3indolylmethyl group, a carbamoyl lower alkyl group or an N-benzyloxycarbonyl-.omega.-amino lower linear alkyl group, or together with R.sup.61 represents a methylene group, provided that when R.sup.61 is a lower alkyl group R.sup.71 is a group other than a hydrogen atom, R.sup.62 is a hydrogen atom, a phenyl group, a benzyl group, a carboxy group, a carbamoyl group or an Nphenylcarbamoyl group, or together with R.sup.8 represents a single bond, R.sup.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.sup.62 is a group other than a hydrogen atom, R.sup.72 is a hydrogen atom or a lower alkyl group, R.sup.8 is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group, or together with R.sup.62 represents a single bond, or a pharmaceutically acceptable salt thereof.

A peptide of the formula:

• ##STR189## wherein A.sup.1 is a group of the formula R.sup.13 R.sup.14 N--C(.dbd.X.sup.1)-- wherein
• X.sup.1 is an oxygen atom;
• R.sup.13 and R.sup.14 together with B represents a group of the following formula (II):
• ##STR190## wherein R.sup.16 is a hydrogen atom, a lower alkyl group or a cycloalkyl group, and each of R.sup.17 and R.sup.18, which are independent from each other, is a hydrogen atom or a lower alkyl group;
• R.sup.3 is a lower alkyl group having 3 to 5 carbon atoms;
• R.sup.4 is a hydrogen atom or a methyl group;
• R.sup.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.sup.51 --CO--(CH.sub.2).sub.s -- wherein R.sup.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.sup.51 is other than a hydroxyl group, or a group of the formula (R.sup.52 O).sub.2 P(.dbd.O)--(CH.sub.2).sub.t -- wherein R.sup.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.sup.53 O--CO--(CH.sub.2).sub.u -- wherein R.sup.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-3benzothienyl)methyl group;
• X.sup.2 is an oxygen atom or a sulfur atom;
• A.sup.2 is selected from the group consisting of the following formulas (III) and (IIV) ##STR191## wherein Y is (a) a group of the formula --CO.sub.2 R.sup.91 wherein R.sup.91 is a hydrogen atom, a lower alkyl group or a benzyl group, or
• (b) a group of the formula --CONR.sup.92 R.sup.93 -- wherein R.sup.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.sup.93 is a hydrogen atom or a lower alkyl group, R.sup.61 is a hydrogen atom or a lower alkyl group, or together with R.sup.71 represents a methylene group, R.sup.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 alkylsubstituted 4-imidazolyl)methylthiomethyl group, a 3indolylmethyl group, a carbamoyl lower alkyl group or an N-benzyloxycarbonyl-.omega.-amino lower linear alkyl group, or together with R.sup.61 represents a methylene group, provided that when R.sup.61 is a lower alkyl group R.sup.71 is a group other than a hydrogen atom, R.sup.62 is a hydrogen atom, a phenyl group, a benzyl group, a carboxy group, a carbamoyl group or an Nphenylcarbamoyl group, or together with R.sup.8 represents a single bond, R.sup.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.sup.62 is a group other than a hydrogen atom, R.sup.72 is a hydrogen atom or a lower alkyl group, R.sup.8 is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group, or together with R.sup.62 represents a single bond, or a pharmaceutically acceptable salt thereof.