Inhibitors for the blood-clotting factor Xa
The invention relates to derivatives of amidino-benzylamine, especially derivatives of 4-amidino-benzylamine, with two bonded amino acids. These derivatives represent a novel group of highly active and very selective F Xa-inhibitors for treating cardiovascular diseases and thrombotic events.
1. Inhibitors for the coagulation factor Xa of the formula:
in which the substituent Y occurs in the 3- or 4-position and is an amidino group
in which R 5 is selected from the group consisting of H, OH, —CO—R 7 and —COO—R 7 , where R 7 is selected from a branched or unbranched alkyl having 1-16 C atoms, a substituted or unsubstituted aryl or heteroaryl group and a substituted or unsubstituted aralkyl or heteroaralkyl group,
X is CH or N,
R 1 is H or a branched or unbranched alkyl having 1-8 C atoms or (CH 2 ) n —OH where n=1-5,
R 2 is H or a branched or unbranched alkyl having 1-8 C atoms,
R 3 is a branched or unbranched alkyl having 1-8 C atoms or (CH 2 ) n —O—R 6 , where N=1-5 and R 6 is a branched or unbranched alkyl having 1-6 C atoms, a substituted or unsubstituted aryl or heteroaryl group or a substituted or an unsubstituted aralkyl or heteroaralkyl group and
R 4 is selected from the group consisting of —SO 2 —R 8 , —CO—R 8 , —COO—R 8 and H, where R 8 is a branched or unbranched alkyl having 1-16 C atoms, a substituted or an unsubstituted aryl or heteroaryl group, a substituted or unsubstituted aralkyl or heteroaralkyl group, an adamantyl group, a camphoryl group or a cyclohexylmethyl group.
2. Inhibitors according to claim 1 , wherein Y is in the 4-position, X is CH, R 1 and R 2 are H, R 3 is (CH 2 ) n —O—R 6 , where n is 1 and R 6 is t-butyl, wherein R 3 is in the D configuration, and R 4 is —SO 2 —R 8 , wherein R 8 is a substituted or unsubstituted aryl or aralkyl group.
3. A method of preventing or treating thromboembolic diseases comprising administering to a patient a factor Xa inhibitor of claim 1 .
4. The method of claim 3 , wherein the factor Xa inhibitor is in the form of a tablet, coated tablet, capsule, pellet, suppository, solution or patch.
5. Inhibitors for the coagulation factor Xa of the formula:
in which the substituent Y occurs in the 3- or 4-position and is an amidino group
in which R 5 is selected from the group consisting of H, OH, —CO—R 7 and —COO—R 7 , where R 7 is selected from a branched or unbranched alkyl having 1-16 C atoms, a substituted or unsubstituted aryl or heteroaryl group and a substituted or unsubstituted aralkyl or heteroaralkyl group,
X is CH or N,
R 1 is H or a branched or unbranched alkyl having 1-8 C atoms or (CH 2 ) n —OH where n=1-5,
R 2 is H or a branched or unbranched alkyl having 1-8 C atoms,
R 3 is (CH 2 ) n —S—R 6 or (CH 2 ) n —NH—R 6 where n=1-5 and R 6 is a branched or unbranched alkyl having 1-16 C atoms, a substituted or unsubstituted aryl or heteroaryl group or a substituted or an unsubstituted aralkyl or heteroaralkyl group and
R 4 is selected from the group consisting of —SO 2 —R 8 , —CO—R 8 , —COO—R 8 and H, where R 8 is a branched or unbranched alkyl having 1-16 C atoms, a substituted or an unsubstituted aryl or heteroaryl group, a substituted or unsubstituted aralkyl or heteroaralkyl group, an adamantyl group, a camphoryl group or a cyclohexylmethyl group.
6. A method of preventing or treating thromboembolic diseases comprising administering to a patient a factor Xa inhibitor of claim 5 .
7. The method of claim 6 , wherein the factor Xa inhibitor is in the form of a tablet, coated tablet, capsule, pellet, suppository, solution or patch.