Factor Xa inhibitors

A compound that specifically inhibits the activity of factor Xa, having the general formula A1-A2-(A3).sub.m -B, wherein m is 0 or 1;

• wherein A1 is R.sub.1 --R.sub.2 --R.sub.3 ;
• A2 is R.sub.4 --R.sub.5 --R.sub.6 ;
• A3 is R.sub.7 --R.sub.8 --R.sub.9 ;
• wherein R.sub.1 is selected from the group consisting of:
• i)1 to 20 amino acids;
• ii) ##STR8## and iii) ##STR9## wherein X is selected from the group consisting of N, CH and NC.dbd.O, and wherein R'.sub.1 and R".sub.1 independently are selected from the group consisting of H, alkyl, acyl, aryl, arylalkyl and an amino-protecting group, and
• wherein R.sub.1 can be substituted by a substituent;
• R.sub.2 is --CR.sub.99 R.sub.100 --, wherein R.sub.99 and R.sub.100 independently are selected from the group consisting of an H;
• alkyl, arylalkyl, heteroarylalkyl and heteroaryl, and wherein R.sub.99 and R.sub.100 independently can be substituted with a substituent;
• R.sub.3 is selected from the group consisting of --C(O)--, --CH.sub.2 --, --CHR.sub.99 --C(O)-- and --C(O)--NR.sub.35 --CH.sub.2 --C(O)--, wherein R.sub.35 is the CHR.sub.55 group of the bridging group --C(O)--CR.sub.55 --;
• R.sub.4 is selected from the group consisting of --CH.sub.2 -- and --NR.sub.50 --, wherein R.sub.50 is selected from the group consisting of H, alkyl, arylalkyl and heterocyclic;
• R.sub.5 is --CR.sub.201 R.sub.202 --, wherein R.sub.201 and R.sub.202 independently are selected from the group consisting of H, alkyl, aryl and arylalkyl, and wherein R.sub.201 and R.sub.202 independently can be substituted with a substituent;
• R.sub.6 is selected from the group consisting of --C(O)--, --CH.sub.2 -- and --CHR.sub.99 --C(O)--;
• R.sub.7 is selected from the group consisting of --CH.sub.2 -- and --NR.sub.51 --, wherein R.sub.51 is H, alkyl, arylalkyl, heteroalkyl and heteroarylalkyl, and any of these moieties substituted by a substituent selected from the group consisting of Q and --(CH.sub.2).sub.n --Q, wherein n is 1 to 5 and wherein Q is selected from the group consisting of an amino, amidino, imidazole and guanidino group, which can be substituted with a substituent, and a mono-, di-, tri- or tetra-alkylammonium of a pharmaceutically acceptable salt, isoureide or isothioureide thereof;
• R.sub.8 is --CR.sub.210 R.sub.211 --, wherein R.sub.210 and R.sub.211 independently are selected from the group consisting of H, alkyl, alkylaryl and heterocyclic, and any of these moieties substituted by a substituent selected from the group consisting of Q and --(CH.sub.2).sub.n --Q, wherein n is 1 to 5 and wherein Q is selected from the group consisting of amino, amidino, imidazole and guanidino group, which can be substituted with a substituent, and a mono-, di-, tri- or tetra-alkylammonium of a pharmaceutically acceptable salt, isoureide or isothioureide thereof;
• R.sub.9 is selected from the group consisting of --C(O)--, --CH.sub.2 -- and --CHR.sub.99 --C(O)--;
• and
• wherein, when m is 1, B is selected from the group consisting of 1 to 20 amino acids, --NHR.sub.52, --NR.sub.60 R.sub.61, --OR.sub.70 and --CHR.sub.60 R.sub.61,
• wherein R.sub.52 is selected from the group consisting of H, alkyl, arylalkyl, heteroarylalkyl and heteroaryl;
• wherein R.sub.60 and R.sub.61 independently are selected from the group consisting of H, alkyl, arylalkyl, aryl, heteroarylalkyl and heteroaryl, and
• wherein R.sub.70 is selected from the group consisting of H, acyl, alkyl, arylalkyl and heteroarylalkyl,
• and wherein when m is 0, B is selected from the group consisting of 1 to 20 amino acids, --OR.sub.70, --NHR.sub.52 and --NR.sub.60 R.sub.61, which is joined to R.sub.6 by an amide bond or an ester bond;
• wherein B can be substituted with a substituent,
• provided that when R.sub.3 is --CH.sub.2 -- or --CHR.sub.99 --C(O)--, R.sub.4 is NR.sub.50 ;
• when R.sub.4 is --CH.sub.2 --, R.sub.3 is --C(O)-- or --CHR.sub.99 --C(O)--;
• when R.sub.4 is --CH.sub.2 --, R.sub.3 is --C(O)-- or --CHR.sub.99 --C(O)--;
• when R.sub.6 is --CH.sub.2 --, R.sub.7 is --NHR.sub.51 --;
• when R.sub.7 is CH.sub.2, R.sub.6 is --C(O)-- or --CHR.sub.99 --C(O)--;
• when R.sub.4 is --NR.sub.50 -- and R.sub.1 is ##STR10## R.sub.50 and R'.sub.1 are taken together to form a bridging group having the formula:
• --C(O)--CHR.sub.55 --,
• wherein CHR.sub.55 represents R.sub.50 and the carbonyl group represents R'.sub.1, and
• R".sub.1 and R.sub.55 independently are H, C.sub.1 to C.sub.6 alkyl or arylalkyl;
• and
• when R.sub.3 is --C(O)--NR.sub.35 --CH.sub.2 --C(O)--, then R.sub.4 is --NR.sub.50 --, R.sub.1 is ##STR11## R.sub.35 and R'.sub.1 are taken together to form a bridging group having the formula --C(O)CHR.sub.55 --,
• wherein C(O) represents R'.sub.1 and CHR.sub.55 represents R.sub.35 ;
• R".sub.1 and R.sub.55 independently are H or a C.sub.1 to C.sub.6 alkyl.