Substituted 2-oxo-3-phenyl-5-carbonylaminomethyl-1, 3-oxazolines and their use as anticoagulant and antithrombotics

Abstract

The invention relates to the field of blood coagulation, more particularly, to novel compounds of general formula (I), to a method for producing said compounds and to their use as active ingredients in medicaments for the prevention and/or the treatment of diseases.

1 . A compound of the formula (I) 
     
       
         
         
             
             
         
       
       in which 
       R 1  represents (C 6 -C 14 )-aryl, 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S or 5- to 10-membered heterocyclyl having up to three heteroatoms from the group consisting of N, O and S, where the rings may be mono- to trisubstituted, independently of one another, by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, oxo, carboxyl or cyano, 
       R 2  represents a radical —C(O)NR 8 R 9 , —N(R 10 )C(O)R 11  or 
     
     
       
         
         
             
             
         
       
       
         where 
         R 8  represents hydrogen,
 (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, 
 (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, 
 or (C 3 -C 7 )-cycloalkyl, 
 and 
 
         R 9  represents (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano,
 (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, 
 or (C 3 -C 7 )-cycloalkyl, 
 
         or 
         R 8  and R 9  together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, 
         R 10  and R 11 , independently of one another, represent (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano,
 (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, 
 or (C 3 -C 7 )-cycloalkyl, 
 
         or 
         R 10  and R 11  together with the N—C(O) group to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, 
         x represents 0 or 1, 
         R 12  and R 13  together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S and which may be up to disubstituted, independently of one another, by amino, hydroxyl, halogen, trifluoromethyl, cyano, oxo, mono- or di-(C 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkoxy, carboxamido, (C 1 -C 4 )-alkylcarbonyl or (C 3 -C 5 )-cycloalkylcarbonyl, 
       
       R 3 , R 4 , R 5  and R 6 , independently of one another, represent hydrogen, halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, mono- or di-(C 1 -C 6 )-alkylaminocarbonyl, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkanoyl, (C 1 -C 6 )-alkanoylamino, trifluoromethyl, carbamoyl, nitro or cyano, 
       and 
       R 7  represents hydrogen or (C 1 -C 6 )-alkyl, 
       and its salts, hydrates, hydrates of the salts and solvates, 
       but excluding compounds of the general formula (I) in which the radical R 1  is an optionally substituted thiophene radical. 
     
   
   
       2 . A compound of the formula (I) as claimed in  claim 1 ,
 in which   R 1  represents (C 6 -C 14 )-aryl, 5- to 10-membered heteroaryl having one nitrogen or oxygen atom as heteroatom and optionally up to two further heteroatoms from the group consisting of N, O and S or 5- to 10-membered heterocyclyl having up to three heteroatoms from the group consisting of N, O and S, where the rings may be mono- to trisubstituted, independently of one another, by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, oxo, carboxyl or cyano,   R 2  represents a radical —C(O)NR 8 R 9 , —N(R 10 )C(O)R 11  or   
     
       
         
         
             
             
         
       
       
         where 
         R 8  represents hydrogen,
 (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, 
 (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, 
 or (C 3 -C 7 )-cycloalkyl, 
 and 
 
         R 9  represents (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano,
 (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, 
 or (C 3 -C 7 )-cycloalkyl, 
 
         or 
         R 8  and R 9  together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, 
         R 10  and R 11 , independently of one another, represent (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano,
 (C 6 -C 14 )-aryl which for its part may be substituted by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, 
 or (C 3 -C 7 )-cycloalkyl, 
 
         or 
         R 10  and R 11  together with the N—C(O) group to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, 
         x represents 0 or 1, 
         R 12  and R 13  together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S and which may be up to disubstituted, independently of one another, by amino, hydroxyl, halogen, trifluoromethyl, cyano, oxo, mono- or di-(C 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkoxy, carboxamido, (C 1 -C 4 )-alkylcarbonyl or (C 3 -C 5 )-cycloalkylcarbonyl, 
       
       R 3 , R 4 , R 5  and R 6 , independently of one another, represent hydrogen, halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, mono- or di-(C 1 -C 6 )-alkylaminocarbonyl, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkanoyl, (C 1 -C 6 )-alkanoylamino, trifluoromethyl, carbamoyl, nitro or cyano, 
       and 
       R 7  represents hydrogen or (C 1 -C 6 )-alkyl, 
       and its salts, hydrates, hydrates of the salts and solvates. 
     
   
   
       3 . A compound of the formula (I) as claimed in  claim 1 ,
 in which   R 1  represents phenyl, naphthyl, 5- to 8-membered heteroaryl having one nitrogen or oxygen atom as heteroatom and optionally up to two further heteroatoms from the group consisting of N, O and S or 5- to 8-membered heterocyclyl having up to three heteroatoms from the group consisting of N, O and S, where the rings may be mono- to trisubstituted, independently of one another, by halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, cyano, trifluoromethyl, trifluoromethoxy or trifluoromethylthio,   R 2  represents a radical —C(O)NR 8 R 9 , —N(R 10 )C(O)R 11  or,   
     
       
         
         
             
             
         
       
       
         where 
         R 8  represents hydrogen, (C 1 -C 4 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 4 )-alkylamino, hydroxyl, oxo, (C 1 -C 4 )-alkoxy, trifluoromethyl or cyano or (C 3 -C 7 )-cycloalkyl,
 and 
 
         R 9  represents (C 1 -C 4 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 4 )-alkylamino, hydroxyl, oxo, (C 1 -C 4 )-alkoxy, trifluoromethyl or cyano, or (C 3 -C 7 )-cycloalkyl, 
         or 
         R 8  and R 9  together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, 
         R 10  and R 11 , independently of one another, represent (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, or (C 3 -C 7 )-cycloalkyl, 
         or 
         R 10  and R 11  together with the N—C(O) group to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, 
         x represents 0 or 1, 
         R 12  and R 13  together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S and which may be monosubstituted by amino, hydroxyl, halogen, trifluoromethyl, cyano, oxo, mono- or di-(C 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkoxy, carboxamido, (C 1 -C 4 )-alkylcarbonyl or (C 3 -C 5 )-cycloalkylcarbonyl, 
       
       R 3  and R 6 , independently of one another, represent hydrogen, halogen, (C 1 -C 6 )-alkyl, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkanoylamino, cyano, trifluoromethyl or nitro, 
       R 4  and R 5  represent hydrogen, 
       and 
       R 7  represents hydrogen or (C 1 -C 4 )-alkyl, 
       and its salts, hydrates, hydrates of the salts and solvates. 
     
   
   
       4 . A compound of the formula (I) as claimed in  claim 1 ,
 in which   R 1  represents phenyl, furyl, dihydrothienyl, thiazolyl, pyrrolyl or pyridyl, where the rings may be mono- to trisubstituted, independently of one another, by fluorine, chlorine, bromine, (C 1 -C 4 )-alkyl, trifluoromethyl, trifluoromethoxy or trifluoromethylthio,   R 2  represents a radical —C(O)NR 8 R 9 , —N(R 10 )C(O)R 11  or   
     
       
         
         
             
             
         
       
       
         where 
         R 8  and R 9 , independently of one another, represent (C 1 -C 4 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 4 )-alkylamino, hydroxyl, oxo, (C 1 -C 4 )-alkoxy, trifluoromethyl or cyano, or (C 3 -C 7 )-cycloalkyl, 
         or 
         R 8  and R 9  together with the nitrogen atom to which they are attached represent morpholinyl, pyrrolidinyl, thiomorpholinyl or piperidinyl, where the rings may be mono- or disubstituted by (C 1 -C 4 )-alkyl and/or oxo, 
         R 10  and R 11 , independently of one another, represent (C 1 -C 6 )-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C 1 -C 6 )-alkylamino, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, trifluoromethyl or cyano, or (C 3 -C 7 )-cycloalkyl, 
         or 
         R 10  and R 11  together with the N—C(O) group to which they are attached represent morpholinonyl, pyrrolidinonyl, thiomorpholinonyl or piperidinonyl, where the rings may be mono- or disubstituted by (C 1 -C 4 )-alkyl, 
         x represents 0 or 1, 
       
       R 12  and R 13  together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocycle which may contain a further oxygen atom in the ring and which may be monosubstituted by amino or hydroxyl, 
       R 3  represents hydrogen, fluorine, chlorine, bromine, (C 1 -C 4 )-alkyl, amino, mono- or di-(C 1 -C 3 )-alkylamino, cyano or nitro, 
       R 4 , R 5  and R 6  represent hydrogen, 
       and 
       R 7  represents hydrogen, 
       and its salts, hydrates, hydrates of the salts and solvates. 
     
   
   
       5 . A process for preparing compounds of the formula (I) as claimed in  claim 1 , characterized in that
 compounds of the formula (II)   
     
       
         
         
             
             
         
       
       in which R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are as defined above 
       are reacted with carboxylic acids of the formula (III) 
     
     
       
         
         
             
             
         
       
       in which R 1  is as defined above, 
       or else with the corresponding carbonyl halides or else with the corresponding symmetric or mixed carboxylic anhydrides of the carboxylic acids of the formula (III) defined above. 
     
   
   
       6 . A compound of the formula (I) as claimed in  claim 1  for the prevention and/or treatment of disorders. 
   
   
       7 . A medicament comprising at least one compound of the formula (I) as claimed in  claim 1  and at least one further auxiliary. 
   
   
       8 . The use of compounds of the formula (I) for preparing a medicament for the prevention and/or treatment of thromboembolic disorders, in particular myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, cerebro vascular accident, transitory ischemic attacks, peripheral occlusive diseases, pulmonary embolisms or deep vein thromboses. 
   
   
       9 . The use of compounds of the formula (I) as claimed in  claim 1  for preparing a medicament for the prevention and/or treatment of disseminated intravasal coagulation (DIC). 
   
   
       10 . The use of compounds of the formula (I) as claimed in  claim 1  for preparing a medicament for the prevention and/or treatment of disorders such as atherosclerosis; arthritis; Alzheimer's disease or cancer. 
   
   
       11 . A process for preventing the coagulation of blood in vitro, in particular in banked blood or biological samples containing factor Xa, characterized in that compounds of the general formula (I) as claimed in  claim 1  are added.