Cyclized peptides and their use as platelet aggregation inhibitors

A compound of the formula:

• ##STR14## wherein R.sub.1 and R.sub.9 are the same or different and are selected from the group consisting of hydroxy, C.sub.1 -C.sub.8 alkoxy, and C.sub.6 -C.sub.12 aryl-C.sub.1 -C.sub.8 alkoxy;
• R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7, R.sub.8, are the same or different and are selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl which include branched and unsaturated alkyl groups substituted C.sub.1 -C.sub.6 alkyl where the substituent(s) are selected from the group consisting of isothioureido, ureido, amino, C.sub.1 -C.sub.4 alkylamino di-C.sub.1 -C.sub.4 alkylamino, hydroxy, acetamido, benzamido, C.sub.6 -C.sub.12 arylamino, guanidino, mercapto, C.sub.1 -C.sub.8 alkythio, carboxy, carboxamide, carbo-C.sub.1 -C.sub.4 alkoxy, C.sub.6 -C.sub.12 aryl-C.sub.1 -C.sub.8 alkyl, aromatic heterocyclo-C.sub.1 -C.sub.8 alkyl where the heterocyclic groups have 5-10 ring atoms and contain up to two O, N, or S heteroatoms substituted C.sub.6 -C.sub.12 aryl-C.sub.1 -C.sub.8 alkyl, and substituted aromatic heterocyclo-C.sub.1 -C.sub.8 alkyl where the substituent(s) are selected from the group consisting of halo, dihalo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub. 4 alkoxy, amino, guanidino, isothioureido, ureido, amino-C.sub.1 -C.sub.4 alkyl, acetamido, benzamido, di-C.sub.1 -C.sub.4 alkylamino, C.sub.1 -C.sub.4 alkylamino, carboxyl, C.sub.6 -C.sub.12 aroyl, C.sub.1 -C.sub.4 alkanoyl, and the heterocyclic groups are as defined above;
• optionally either R.sub.5 or R.sub.6 is phenyl;
• R.sub.4 is hydrogen or may be joined with R.sub.2 or R.sub.3 to form an alkylene bridge of from two to five carbon atoms or an alkylene bridge of from two to four carbon atoms and one O or S heteroatom;
• R.sub.2 and R.sub.3, R.sub.5 and R.sub.6, or R.sub.7 and R.sub.8 may be joined together to form a ring of three to six carbon atoms or a ring of two to five carbon atoms and one O or S heteroatom or substituted heteroatom NR.sub.12 ;
• R.sub.12 is selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.6 -C.sub.12 -aryl, C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 alkanoyl, and C.sub.6 -C.sub.12 aroyl;
• X is an O or S heteroatom beating one or two O heteroatoms or substituted NR.sub.13 heteroatom or a methylene group;
• R.sub.13 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.6 -C.sub.12 -aryl, C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 alkanoyl, and C.sub.6 -C.sub.12 aroyl;
• R.sub.14 is selected from the group, consisting of hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.6 -C.sub.12 -aryl, and C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl,
• n is an integer from 1 to 6;
• m is 1;
• and the pharmaceutically acceptable salts thereof, provided that the chirality of the carbon atoms bearing the (CH.sub.2).sub.n sidechain and the (CH.sub.2).sub.m sidechain is S.

A compound of the formula:

• ##STR15## wherein R.sub.1 and R.sub.9 are the same or different and are selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy and C.sub.6 -C.sub.12 aryl-C.sub.1 -C.sub.4 alkoxy:
• R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7, R.sub.8 are the same or different and are selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl which include branched and unsaturated alkyl groups substituted C.sub.1 -C.sub.6 alkyl where the substituent(s) are selected from the group consisting of amino, C.sub.1 -C.sub.4 alkylamino, di-C.sub.1 -C.sub.4 alkylamino, hydroxy, acetamido, benzamido, C.sub.6 -C.sub.12 arylamino, guanidino, mercapto, C.sub.1 -C.sub.8 alkylthio, carboxy, carboxamide, carbo-C.sub.1 -C.sub.4 alkoxy, C.sub.6 -C.sub.12 aryl-C.sub.1 -C.sub.4 alkyl aromatic heterocyclo-C.sub.1 -C.sub.4 where the heterocyclic groups have 5-10 ring atoms and contain up to two O, N, or S heteroatoms, substituted C.sub.6 -C.sub.12 aryl-C.sub.1 -C.sub.4 alkyl and substituted aromatic heterocyclo-C.sub.1 -C.sub.4 alkyl where the substituent(s) are selected from the group consisting of halo, dihalo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, amino, guanidino, amino-C.sub.1 -C.sub.4 alkyl, acetamido, benzamido, di-C.sub.1 -C.sub.4 alkylamino, C.sub.1 -C.sub.4 alkylamino, carboxyl, C.sub.6 -C.sub.12 aroyl, C.sub.1 -C.sub.4 alkanoyl, and the heterocyclic groups are as defined above, optionally either R.sub.5 or R.sub.6 is phenyl;
• R.sub.4 is hydrogen or may be joined with R.sub.2 or R.sub.3 to form an alkylene bridge of from two to five carbon atoms or an alkylene bridge of from two to four carbon atoms and one O or S heteroatom;
• R.sub.2 and R.sub.3, R.sub.5 and R.sub.6, or R.sub.7 and R.sub.8 may be joined together to form a ring of three to six carbon atoms or a ring of two to five carbon atoms and one O or S heteroatom or substituted heteroatom NR.sub.12 ;
• R.sub.12 is selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.6 -C.sub.12 -aryl, C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.1 -C.sub.4 alkanoyl, and C.sub.6 -C.sub.12 aroyl;
• X is an O or S heteroatom or S heteroatom bearing one or two heteroatoms or substituted NR.sub.13 heteroatom or a methylene group;
• R.sub.13 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 alkanoyl, and C.sub.6 -C.sub.12 aroyl;
• R.sub.14 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.6 -C.sub.12 -aryl, and C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
• n is an integer from 2 to 4;
• m is 1;
• and the pharmaceutically acceptable salts thereof provided that the chirality of the carbon atoms bearing the (CH.sub.2).sub.n sidechain and the (CH.sub.2).sub.m sidechain is S and the chirality of the carbon atom bearing substituents R.sub.2 and R.sub.3 corresponds to that of a D amino acid.

A compound of the formula:

• ##STR16## wherein R.sub.1 and R.sub.9 are the same or different and are selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy, and benzyloxy;
• R.sub.2 or R.sub.3 is hydrogen and the remaining substituent is selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups, and substituted C.sub.1 -C.sub.6 alkyl where the substituent are selected from the group consisting of amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl, hydroxyphenyl, indolyl, and imidazolyl;
• R.sub.5 or R.sub.6 is hydrogen and the remaining substituent is selected from the group consisting of hydrogen, phenyl, C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups, and substituted C.sub.1 -C.sub.6 alkyl where the substituents are selected from the group Consisting of amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl, hydroxyphenyl, indolyl, and imidazolyl;
• R.sub.7 or R.sub.8 is hydrogen or C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups and the remaining substituent is selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups, and substituted C.sub.1 -C.sub.6 alkyl where the substituent can be amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl, hydroxyphenyl, indolyl, and imidazolyl;
• R.sub.4 is hydrogen or may be joined with R.sub.2 or R.sub.3 to form an alkylene bridge of three or four carbon atoms or an alkylene bridge of two carbon atoms and one S heteroatom;
• X is an or S heteroatom or an S heteroatom bearing one or two O heteroatoms;
• R.sub.14 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.6 -C.sub.12 -aryl, and C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
• n is 3;
• m is 1;
• and the pharmaceutically acceptable salts thereof, provided that the chirality of the carbon atoms bearing the (CH.sub.2).sub.n sidechain and the (CH.sub.2).sub.m sidechain is S, the chirality of the carbon atom bearing the COR.sub.1 group is R, and the chirality of the carbon atom bearing substituents R.sub.2 and R.sub.3 corresponds to that of a D amino acid.

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula:

• ##STR17## wherein R.sub.1 and R.sub.9 are the same or different and are selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy and benzyloxy;
• R.sub.2 or R.sub.3 is hydrogen and the remaining substituent is selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups, and substituted C.sub.1 -C.sub.6 alkyl where the substituent are selected from the group consisting of amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl, hydroxyphenyl, indolyl, and imidazolyl;
• R.sub.5 or R.sub.6 is hydrogen and the remaining substituent is selected from the group consisting of hydrogen, phenyl, C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups, and substituted C.sub.1 -C.sub.6 alkyl where the substituents are selected from the Soup consisting of amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl, hydroxyphenyl, indolyl, and imidazolyl;
• R.sub.7 or R.sub.8 is hydrogen or C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups and the remaining substituent is selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups, and substituted C.sub.1 -C.sub.6 alkyl where the substituent is selected from the group consisting of amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl, hydroxyphenyl, indolyl, and imidazolyl;
• R.sub.4 is hydrogen or may be joined with R.sub.2 or R.sub.3 to form an alkylene bridge of three or four carbon atoms or an alkylene bridge of two carbon atoms and one S heteroatom;
• X is an O or S heteroatom or an S heteroatom bearing one or two O heteroatoms;
• R.sub.14 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.6 -C.sub.12 -aryl, and C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
• n is 3;
• m is 1;
• and the pharmaceutically acceptable salts thereof, provided that the chirality of the carbon atoms bearing the (CH.sub.2).sub.n sidechain and the (CH.sub.2).sub.m sidechain is S, the chirality of the carbon atom bearing the COR.sub.1 group is R, and the chirality of the carbon atom bearing substituents R.sub.2 and R.sub.3 corresponds to that of a D amino acid.

A method for inhibiting platelet aggregation which method comprises administering a platelet aggregation inhibiting amount of a compound of the formula:

• ##STR18## wherein R.sub.1 and R.sub.9 are the same or different and are selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy and benzyloxy;
• R.sub.2 or R.sub.3 is hydrogen and the remaining substituent is selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups, and substituted C.sub.1 -C.sub.6 alkyl where the substituent are selected from the group consisting of amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl or hydroxyphenyl, indolyl, and imidazolyl;
• R.sub.5 or R.sub.6 is hydrogen and the remaining substituent is selected from the group consisting of hydrogen, phenyl, C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups, and substituted C.sub.1 -C.sub.6 alkyl where the substituents are selected from the group consisting of amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl, hydroxphenyl, indolyl, and imidazolyl;
• R.sub.7 or R.sub.8 is hydrogen or C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups and the remaining substituent is selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl which includes branched alkyl groups, and substituted C.sub.1 -C.sub.6 alkyl where the substituent is selected from the group consisting of amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl, hydroxyphenyl, indolyl, and imidazolyl;
• R.sub.4 is hydrogen or may be joined with R.sub.2 or R.sub.3 to form an alkylene bridge of three or four carbon atoms or an alkylene bridge of two carbon atoms and one S heteroatom;
• X is an O or S heteroatom or an S heteroatom bearing one or two O heteroatoms;
• R.sub.14 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.6 -C.sub.12 -aryl, and C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
• n is 3;
• m is 1;
• and
• the pharmaceutically acceptable salts thereof;
• provided that the chirality of the carbon atoms bearing the (CH.sub.2).sub.n sidechain and the (CH.sub.2).sub.m l sidechain is S, the chirality of the carbon atom bearing the COR.sub.1 group is R, and the chirality of the carbon atom bearing substituents R.sub.2 and R.sub.3 corresponds to that of a D amino acid.