Compositions for the treatment and prevention of arterial thrombosis and use of an inhibitor of factor Xa alone and/or in combination with an anti-platelet aggregation agent

Abstract

The invention relates to the use of direct or indirect selective inhibitors of factor Xa acting via antithrombin III, alone or in combination with one or more compounds with anti-platelet aggregation activity, for the preparation of medicines intended to prevent and to treat thromboembolic arterial diseases. The subject of the invention is also pharmaceutical compositions containing one or more direct or indirect selective inhibitors of factor Xa which act via antithrombin III in combination with one or more compounds with anti-platelet aggregation activity, and optionally one or more pharmaceutically acceptable vehicles.

1 . Use of direct or indirect selective inhibitors of factor Xa which act via antithrombin III, alone or in combination with one or more compounds with anti-platelet aggregation activity, for the preparation of medicines intended to prevent and to treat thromboembolic arterial diseases.  
     
     
         2 . Use according to  claim 1 , of a direct or indirect selective inhibitor of factor Xa which acts via antithrombin III, alone or in combination with a compound with anti-platelet aggregation activity.  
     
     
         3 . Use according to either of claims  1  and  2 , characterized in that there is used as direct selective inhibitor of factor Xa (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)-propanoic acid of structure (A)  
       
         
           
           
               
               
           
         
       
       or one of its pharmaceutically acceptable salts.  
     
     
         4 . Use according to either of claims  1  and  2 , characterized in that an oligosaccharide is used as indirect inhibitor of factor Xa.  
     
     
         5 . Use according to  claim 4 , characterized in that the indirect inhibitor of factor Xa is methyl O-(2-deoxy-2-sulphoamino-6-O-sulfo-α-D-glucopyranosyl)-(1→4)-O-(β-D-glucopyranosyluronic acid)-(1→4)-O-(2-deoxy-2-sulphoamino-3,6-di-O-sulpho-α-D-glucopyranosyl-(1→4)-O-(2-O-sulpho-α-L-idopyranosyluronic acid)-(1→4)-2-deoxy-2-sulphoamino-6-O-sulpho-α-D-gluco-pyranoside whose anion has the structure (B)  
       
         
           
           
               
               
           
         
       
       or one of its pharmaceutically acceptable salts.  
     
     
         6 . Use according to any one of the preceding claims, for the preparation of medicines intended to prevent and to treat arterial thromboembolic diseases in patients not treated by a revascularization procedure, such as percutaneous angioplasty, characterized in that aspirin is used as anti-platelet aggregation agent.  
     
     
         7 . Use according to one of  claims 1  to  5 , characterized in that ticlopidine or clopidogrel is used as anti-platelet aggregation agent.  
     
     
         8 . Use according to any one of  claims 1  to  5 , characterized in that an antagonist of glycoprotein IIb/IIIa is used as anti-platelet aggregation agent.  
     
     
         9 . Use according to  claim 8 , characterized in that the antagonist of glycoprotein IIb/IlIa is selected from 
 ethyl N-(1-ethoxycarbonylmethylpiperidin-4-yl)-N-{4-(4-{(N-ethoxycarbonylimino)(amino)methyl}phenyl]-thiazol-2-yl}-3-aminopropionate,    N-(1-carboxymethylpiperidin-4-yl)-N-{4-[4-{(amino)-(imino)methyl}phenyl]thiazol-2-yl}-3-aminopropionic acid,    and their pharmaceutically acceptable salts.    
     
     
         10 . Use according to  claim 9 , characterized in that the antagonist of glycoprotein IIb/IIIa is ethyl N-(1-ethoxycarbonylmethylpiperidin-4-yl)-N-(4-[4-{(N-ethoxycarbonylimino)(amino)methyl}phenyl]thiazol-2-yl)-3-aminopropionate or N-(1-carboxymethylpiperidin-4-yl)-N-{4-[4-{(amino)(imino)methyl}phenyl]thiazol-2-yl}-3-aminopropionic acid trihydrochloride.  
     
     
         11 . Pharmaceutical compositions containing one or more direct or indirect selective inhibitors of factor Xa acting via antithrombin III in combination with one or more compounds with anti-platelet aggregation activity, and optionally one or more pharmaceutically acceptable vehicles.  
     
     
         12 . Pharmaceutical compositions according to  claim 11 , comprising an antagonist of glycoprotein IIb/IIIa as anti-platelet aggregation agent and methyl O-(2-deoxy-2-sulphoamino-6-O-sulfo-α-D-glucopyranosyl)-(1→4)-O-(β-D-glucopyranosyluronic acid-(1→4)-O-(2-deoxy-2-sulphoamino-3,6-di-O-sulpho-α-D-glucopyranosyl-(1→4)-O-(2-O-sulpho-α-L-idopyranosyluronic acid)-(1→4)-2-deoxy-2-sulphoamino-6-O-sulpho-α-D-glucopyranoside whose anion has the structure (B)  
       
         
           
           
               
               
           
         
       
       or one of its pharmaceutically acceptable salts, as indirect selective inhibitor of factor Xa.  
     
     
         13 . Pharmacological compositions according to  claim 11 , comprising methyl O-(2-deoxy-2-sulphoamino-6-O-sulfo-α-D-glucopyranosyl)-(1→4)-O-(β-D-gluco-pyranosyluronic acid)-(1→4)-O-(2-deoxy-2-sulphoamino-3,6-di-O-sulpho-α-D-glucopyranosyl-(1→4)-O-(2-O-sulpho-α-L-idopyranosyluronic acid)-(1→4)-2-deoxy-2-sulphoamino-6-O-sulpho-α-D-glucopyranoside whose anion has the structure (B)  
       
         
           
           
               
               
           
         
       
       or one of its pharmaceutically acceptable salts, as indirect selective inhibitor of factor Xa, as anti-platelet aggregation agent.  
     
     
         14 . Use according to  claim 1 , the said mediaments being active for pathological conditions such as disorders of the cardiovascular or cerebrovascular system such as thromboembolic disorders associated with atherosclerosis or with diabetes such as unstable angina, cerebral attack, restenosis following angioplasty, endarterectomy or fitting of metallic endovascular prostheses, or such as thromboembolic disorders associated with rethrombosis following thrombolysis, with infarction, with dementia of ischaemic origin, with peripheral arterial diseases, with haemodialysis, with atrial fibrillations, or during the use of vascular prostheses, of aortocoronary bypasses or for stable or unstable angina, or for patients treated by a revascularization procedure at the risk of thrombosis including percutaneous angioplasties, endovascular prostheses, vascular prostheses, aortocoronary bypasses.