Antithrombotic agents

A compound having the Formula I

• X--Y--NH--(CH.sub.2).sub.r --G I
• wherein
• X is prolinyl, homoprolinyl, R.sup.m --(CH.sub.2).sub.g --NH--CH.sub.2 --C(O)--, ##STR135## in which R.sup.d is carboxy or methylsulfonyl;
• R.sup.e is NHR.sup.c, NHCOR.sup.c or NHCOOR.sup.c ;
• in which
• R.sup.c is C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.8 cycloalkyl or a (C.sub.3 -C.sub.8) cycloalkyl (C.sub.1 -C.sub.6) alkyl radical of 4-10 carbons;
• T is C.sub.3 -C.sub.8 cycloalkyl, C.sub.1 -C.sub.8 alkyl, ##STR136## a is 0, 1 or 2;
• and Q is --OH, C.sub.1 -C.sub.4 alkoxy, or --NH--A;
• A is hydrogen, C.sub.1 -C.sub.4 alkyl, R"SO.sub.2 --, R"OC(O)--, R"C(O)--, R.sup.n C(O)-- or --(CH.sub.2).sub.g --R.sup.m ;
• g is 1, 2, or 3;
• B is hydrogen or C.sub.1 -C.sub.4 alkyl;
• R' is hydrogen or C.sub.1 -C.sub.4 alkyl;
• R" is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 perfluoroalkyl, --(CH.sub.2).sub.d --R.sup.m, or unsubstituted or substituted aryl, where aryl is phenyl, naphthyl, a 5- or 6-membered unsubstituted or substituted aromatic heterocyclic ring, having one or two heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen, or a 9- or 10-membered unsubstituted or substituted fused bicyclic aromatic heterocyclic group having one or two heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen;
• R.sup.m is --COOR.sup.b, --SO.sub.2 (C.sub.1 -C.sub.4 alkyl), --SO.sub.3 H, --P(O)(OR.sup.b).sub.2 or tetrazol-5-yl;
• R.sup.n is --COOR.sup.b or tetrazol-5-yl;
• each R.sup.b is independently hydrogen or C.sub.1 -C.sub.4 alkyl;
• d is 1, 2, or 3;
• m is 0, 1, or 2;
• n is 0, 1, or 2;
• and
• Z is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, halo or R.sub.a SO.sub.2 NH--, where R.sub.a is C.sub.1 -C.sub.4 alkyl;
• Y is ##STR137## in which R.sup.g is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or --(CH.sub.2).sub.p --L--(CH.sub.2).sub.q --T';
• R.sup.p is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or --(CH.sub.2).sub.p --L--(CH.sub.2).sub.q --T';
• where p is 0, 1, 2, 3, or 4;
• L is a bond, --O--, --S--, or --NH--;
• q is 0, 1, 2 or 3;
• and T' is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 cycloalkyl, --COOH, --CONH.sub.2, or Ar, where Ar is unsubstituted or substituted aryl, where aryl is phenyl, naphthyl, a 5- or 6-membered unsubstituted or substituted aromatic heterocyclic ring, having one or two heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen, or a 9- or 10-membered unsubstituted or substituted fused bicyclic aromatic heterocyclic group having one or two heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen;
• R.sup.y is --CH.sub.2 --, --O--, --S--, or --NH--;
• and
• R.sup.z is a bond or, when taken with R.sup.y and the three adjoining carbon atoms, forms a saturated carbocyclic ring of 5-8 atoms, one atom of which may be --O--, --S--, or --NH--;
• r is 1, 2 or 3;
• and
• G is --(CH.sub.2).sub.s --R, where s is 0-5, --CH.dbd.CH--(CH.sub.2).sub.t --R, where t is 0-3;
• and
• R is ##STR138## or a pharmaceutically acceptable salt thereof;
• or a pharmaceutically acceptable solvate of said compound or salt thereof;
• provided that A is not hydrogen, C.sub.1 -C.sub.4 alkyl, R.sup.n C(O)-- when R.sup.n is --COOR.sup.b, --(CH.sub.2).sub.g --R.sup.m where R.sup.m is COOR.sup.b or t-butyloxycarbonyl when R is --C(NH)NH.sub.2 or --NH--C(NH)NH.sub.2, Y is ##STR139## or unsubstituted prolinyl (R.sup.p is hydrogen), and T is ##STR140## and provided further that R is not amino or guanidino when r=1 and s=0;
• and provided further that A is not hydrogen, C.sub.1 -C.sub.4 alkyl, methylsulfonyl, R.sup.n C(O)-- where R.sup.n is --COOR.sup.b or --(CH.sub.2).sub.g --R.sup.m when G is --(CH.sub.2).sub.s --R in which R is ##STR141## Y is ##STR142## unsubstituted prolinyl (R.sup.p is hydrogen) or 4-hydroxyprolinyl (R.sup.p is OH), R' is hydrogen, T is cyclohexyl and Q is --NH--A;
• and further provided that A is not hydrogen, C.sub.1 -C.sub.4 alkyl, R"SO.sub.2 -- (where R" is C.sub.1 -C.sub.4 alkyl), R.sup.n C(O)-- (where R.sup.n is --COOR.sup.b) or --(CH.sub.2).sub.g --R.sup.m (where R.sup.m is --COOR.sup.b) when T is cyclohexyl or ##STR143## Y is ##STR144## or unsubstituted prolinyl (R.sup.p is hydrogen), and R is --C(NH)NH.sub.2 or --NH--C(NH)NH.sub.2 ;
• and provided further that R"SO.sub.2 is not arylsulfonyl when G is --(CH.sub.2).sub.s --R in which R is ##STR145## Y is unsubstituted prolinyl (R.sup.p is hydrogen) or 4-methylthioprolinyl (R.sup.p is --SCH.sub.3), and Q is --NH--A.