3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as medicament

Abstract

Ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in the crystalline modifications I and II and as the hemihydrate and the use thereof as a pharmaceutical composition.

1 . The compound ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in crystalline form, wherein the compound has a melting point of T mp =180° C.±3° C. determined by DSC, evaluation by peak maximum, at a heating rate of 10° C./min.  
     
     
         2 . The compound ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in crystalline form, wherein the compound has a melting point of T mp =190° C.±3° C. (hemihydrate), determined by DSC, evaluation by peak maximum, at a heating rate of 10° C./min.  
     
     
         3 . The compound ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in crystalline form, wherein the compound has a melting point of T mp =120° C.±5° C. (hemihydrate), determined by DSC, evaluation by peak maximum, at a heating rate of 10° C./min).  
     
     
         4 . A pharmaceutical composition comprising: 
 (a) ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate according to  claim 1;  and    (b) one or more inert carriers and/or diluents.    
     
     
         5 . A pharmaceutical composition comprising: 
 (a) ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate according to  claim 2;  and    (b) one or more inert carriers and/or diluents.    
     
     
         6 . A pharmaceutical composition comprising: 
 (a) ethyl 3-[(2-{[4-(hexyloxycarbonylaminoinminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate according to  claim 3;  and    (b) one or more inert carriers and/or diluents.    
     
     
         7 . A method for the post-operative prophylaxis of deep vein thrombosis or the prevention of stroke in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 1 .  
     
     
         8 . A method for the post-operative prophylaxis of deep vein thrombosis or the prevention of stroke in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 2 .  
     
     
         9 . A method for the post-operative prophylaxis of deep vein thrombosis or the prevention of stroke in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 3 .  
     
     
         10 . A process for preparing a polymorph of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in crystalline form, the process comprising: 
 (a) slowly adding a solution of a slight deficiency of methanesulfonic acid in acetone to a solution of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate base in acetone at a temperature of approximately 30° C. to 36° C.;    (b) stirring the mixture of step (a) for about 1 hour at a temperature of approximately 26° C. to 33° C.;    (c) cooling the mixture of step (b) to about 17° C. to 23° C. and stirring the mixture for a further 40 to 80 minutes at this temperature to precipitate crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate;    (d) suction filtering the precipitated crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate; and    (e) drying the precipitated crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate thus obtained in vacuo for at least 4 hours at a maximum of 50° C. to obtain the polymorph of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in crystalline form.    
     
     
         11 . A process for preparing a polymorph of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in crystalline form, the process comprising: 
 (a) slowly adding a solution of a slight deficiency of methanesulfonic acid in acetone to a solution of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate base in acetone at a temperature of approximately 40° C. to 46° C.;    (b) optionally inoculating the mixture of step (a) with BIBR 1048 polymorph II crystals;    (c) stirring the mixture of the previous step for about 1 hour at a temperature of approximately 40° C. to 46° C.;    (d) cooling the mixture of step (c) to approximately 17° C. to 23° C. and stirring the mixture for a further 40 to 80 minutes at this temperature to precipitate crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate;    (e) suction filtering the precipitated crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate; and    (f) drying the precipitated crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in vacuo for at least 4 hours at a maximum of 50° C. to obtain the polymorph of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in crystalline form.    
     
     
         12 . A process for preparing a polymorph of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in crystalline form, the process comprising: 
 (a) heating with stirring a suspension of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate polymorph I in acetone to 45° C. to 50° C. for approximately 4 hours;    (b) optionally (i) inoculating the mixture of step (a) with ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate (polymorph II) crystals, or (ii) inoculating the mixture of step (a) with ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate (polymorph II) crystals and additionally adding a small amount of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate base;    (c) cooling the mixture of the previous step to approximately 15° C. to precipitate crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate (polymorph II);    (d) suction filtering the precipitated crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate (polymorph II); and    (e) drying the precipitated crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate (polymorph II) thus obtained in vacuo for at least 4 hours at a maximum of 50° C.    
     
     
         13 . A process for preparing a polymorph of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate in crystalline form, the process comprising: 
 (a) ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate (polymorph I) is placed in acetone;    (b) optionally (i) inoculating the mixture of step (a) with a small amount of crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate (polymorph II), or (ii) inoculating the mixture of step (a) with crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate (polymorph II) and additionally a small amount of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate base is added;    (c) heating the mixture of the previous step to 40° C. to 46° C. for at least one hour with stirring;    (d) cooling the mixture of step (c) to approximately 17° C. to 23° C. and stirring for a further 40 to 80 minutes at this temperature;    (e) separating the precipitated crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate (polymorph II); and    (f) drying the precipitated crystals of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate (polymorph II) thus obtained in vacuo for at least 4 hours at a maximum of 50° C.    
     
     
         14 . A process for preparing a polymorph of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate hemihydrate in crystalline form, the process comprising: 
 (a) slowly adding a solution of one equivalent of methanesulfonic acid in ethyl acetate to a solution of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate base in a mixture of 90% aqueous ethanol and ethyl acetate in a ratio by volume of approximately 2:5 at a temperature of approximately 35° C. to 40° C.;    (b) optionally adding further ethyl acetate for dilution as the product begins to crystallize out;    (c) stirring the mixture of the previous step for about another 30 minutes at approximately 35° C. to 40° C.;    (d) stirring the mixture of step (c) for a further 30 minutes at ambient room temperature;    (e) suction filtering the precipitate of ethyl 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate methanesulfonate hemihydrate; and    (f) dried at approximately 40° C. in the circulating air drying cupboard.    
     
     
         15 . The product of the process of  claim 10 .  
     
     
         16 . The product of the process of  claim 11 .  
     
     
         17 . The product of the process of  claim 12 .  
     
     
         18 . The product of the process of  claim 14 .  
     
     
         19 . The product of the process of  claim 15.