Cyclic thienouracil-carboxamides and use thereof

Abstract

The present application relates to novel 2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxamide derivatives (“thienouracil”-carboxamides), to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases and to their use for the preparation of medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of pulmonary and cardiovascular disorders.

1 - 12 . (canceled) 
     
     
         13 . A method of making the compound of formula (I), 
       
         
           
           
               
               
           
         
         in which 
         R 1  represents hydrogen, methyl or ethyl, where methyl and ethyl may be substituted up to three times by fluorine, 
         R 2  represents methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, 2,2-difluorovinyl, 3,3-difluoroallyl or propargyl or represents a group of the formula 
       
       
         
           
           
               
               
           
         
         in which * denotes the point of attachment to the CH 2  group, 
         Ar represents phenyl or 5- or 6-membered heteroaryl having up to two ring nitrogen atoms,
 where phenyl and heteroaryl may be mono- or disubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and trifluoromethoxy, 
 
         R 4A  represents hydrogen, fluorine or methyl, 
         R 4B  represents hydrogen, fluorine, methyl, trifluoromethyl, hydroxy or methoxy, 
         or 
         R 4A  and R 4B  are attached to one another and together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, 
         R 8  represents methyl or trifluoromethyl, and 
         R 9A  and R 9B  independently of one another represent hydrogen, methyl or trifluoromethyl, 
         R 3  represents (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 7 )-cycloalkyl or [(C3-CT)-cycloalkyl]methyl, 
         where alkyl and alkenyl may be substituted up to three times and cycloalkyl may be substituted up to two times by fluorine and 
         where in alkyl and cycloalkyl up to two CH 2  groups may be replaced by —O— or —S—, with the proviso that there are at least two carbon atoms between such heteroatoms including the uracil N 1 -atom, and 
         the ring A represents a mono- or bicyclic aza heterocycle of the formula 
       
       
         
           
           
               
               
           
         
         in which ** denotes the point of attachment to the carbonyl group, 
         R 5  represents hydrogen, methyl, trifluoromethyl, hydroxymethyl or ethyl, 
         R 6A  and R 6B  each independently of one another represent hydrogen, methyl or ethyl, 
         R 10A  represents methyl, ethyl, hydroxy or methoxy, and 
         R 10B  represents hydrogen, methyl or ethyl, and 
         their salts, solvates and solvates of the salts; 
         characterized in that either 
         [A-1] a compound of the formula (II) 
       
       
         
           
           
               
               
           
         
         
           in which R 1  and R 2  have the meanings given above and 
           T 1  represents (C 1 -C 4 )-alkyl or benzyl is alkylated in the presence of a base with a compound of the formula (III) 
         
       
       
         
           
           
               
               
           
         
         
           
             in which R 3  has the meaning given above and 
             X 1  represents a leaving group, for example chlorine, bromine, iodine, mesylate, triflate or tosylate, 
           
           to give a compound of the formula (IV) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 2 , R 3  and T 1  have the meanings given above, 
           then the ester radical T 1  is cleaved off and the carboxylic acid of the formula (V) obtained in this manner 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 2  and R 3  have the meanings given above 
           is then coupled with activation of the carboxyl function with an amine of the formula (VI) 
         
       
       
         
           
           
               
               
           
         
         
           in which the ring A has the meaning given above, 
         
         or 
         [A-2] the compound of the formula (II) 
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 2  and T 1  have the meanings given above 
           is initially converted by cleavage of the ester radical T 1  into the carboxylic acid of the formula (VII) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1  and R 2  have the meanings given above, 
           then coupled with activation of the carboxyl function with an amine of the formula (VI) 
         
       
       
         
           
           
               
               
           
         
         
           in which the ring A has the meaning given above 
           to give a compound of the formula (VIII) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 2  and the ring A have the meanings given above and this is then alkylated in the presence of a base with a compound of the formula (III) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 3  and X 1  have the meanings given above 
         
         or 
         [B] initially an N 3  protected compound of the formula (IX) 
       
       
         
           
           
               
               
           
         
         
           in which R 1  and T 1  have the meanings given above and 
           R 7A  and R 7B  independently of one another represent hydrogen or methoxy is alkylated in the presence of a base with a compound of the formula (III) 
         
       
       
         
           
           
               
               
           
         
         
           
             in which R 3  and X 1  have the meanings given above 
             to give a compound of the formula (X) 
           
         
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 3 , R 7A , R 7B  and T 1  have the meanings given above, 
           the N 3 -benzyl group and the ester radical T 1  are then cleaved off simultaneously by treatment with a strong Lewis acid such as aluminium trichloride, the carboxylic acid of the formula (XI) obtained in this manner 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1  and R 3  have the meanings given above, 
           is then coupled with activation of the carboxyl function with an amine of the formula (VI) 
         
       
       
         
           
           
               
               
           
         
         
           in which the ring A has the meaning given above 
           to give a compound of the formula (XII) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 3  and the ring A have the meanings given above 
           and the latter is then either reacted (a) in the presence of a base with a compound of the formula (XIII) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 2  has the meaning given above and 
         
         X 2  represents a leaving group, for example chlorine, bromine, iodine, mesylate, triflate or tosylate,
 or (b) in the presence of a suitable phosphine and an azodicarboxylate with a compound of the formula (XIV) 
 
       
       
         
           
           
               
               
           
         
         
           in which R 2  has the meaning given above, and 
         
         the compounds of the formula (I) prepared in this manner are optionally converted with the appropriate (i) solvents and/or (ii) acids into their solvates, salts and/or solvates of the salts. 
       
     
     
         14 . A method of making the compound of the formula (II-C) 
       
         
           
           
               
               
           
         
         in which R 2  has the meaning given in  claim 13   
         R 1F  represents difluoromethyl or trifluoromethyl and 
         T 1  represents (C 1 -C 4 )-alkyl or benzyl, 
         characterized in that a compound of the formula (XIX) 
       
       
         
           
           
               
               
           
         
         
           in which R 2  has the meaning given above, 
           is converted with phosphorus oxychloride into a compound of the formula (XXIV) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 2  has the meaning given above, 
           then in the presence of excess pyridine is reacted with an anhydride of the formula (XXV) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1F  has the meaning given above 
           to give a betaine compound of the formula (XXVI) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1F  and R 2  have the meanings given above and 
           these are then condensed in the presence of a base with an α-mercaptoacetic ester of the formula (XXI) 
         
       
       
         
           
           
               
               
           
         
         
           in which T 1  has the meaning given above 
           to give the compound (II-C). 
         
       
     
     
         15 . A method for treatment and/or prevention of diseases using the compound of  claim 13 . 
     
     
         16 . A method for the treatment and/or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, Bronchiolitis obliterans syndrome, chronic-obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure and sickle cell anemia using the compound of  claim 13 . 
     
     
         17 . A method of making a medicament for the treatment and/or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, Bronchiolitis obliterans syndrome, chronic-obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure and sickle cell anemia using the compound of  claim 13 . 
     
     
         18 . A medicament comprising the compound of  claim 13  in combination with one or more inert, nontoxic, pharmaceutically suitable excipients. 
     
     
         19 . A medicament comprising the compound of  claim 13  in combination with one or more further active compounds selected from the group of PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, endothelin antagonists, antifibrotic agents, the antiinflammatory, immunomodulating, immunosuppressive agents, cytotoxic agents, and signal transduction cascade-inhibiting compounds. 
     
     
         20 . A method for the treatment and/or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, Bronchiolitis obliterans syndrome, chronic-obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure and sickle cell anemia using the medicament of  claim 18 . 
     
     
         21 . A method for the treatment and/or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, Bronchiolitis obliterans syndrome, chronic-obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure and sickle cell anemia in humans and animals by administration of an effective amount of the compound of  claim 13 . 
     
     
         22 . A method for the treatment and/or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, Bronchiolitis obliterans syndrome, chronic-obstructive pulmonary disease, asthma, cystic fibrosis, myocardial infarction, heart failure and sickle cell anemia in humans and animals by administration of an effective amount of the medicament of  claim 18 .