Novel substituted amides, their preparation and use

Abstract

An amide of the formula I and its tautomeric forms, possible enantiomeric and diastereomeric forms, E and Z forms, and possible physiologically tolerated salts, in which the variables have the following meanings: A —(CH 2 ) p —R 1 , where R 1 can be pyrrolidine, morpholine, piperidine, —NR 5 R 6 and and R 5 , R 6 and R 7 can, independently of one another, be hydrogen, C 1 -C 4 -alkyl, CH 2 Ph, Ph, CH 2 CH 2 Ph, it also being possible for the phenyl rings to be substituted by R 6 , and p can be 1 and 2, and B can be phenyl, pyridyl, pyrimidyl and pyridazyl, it also being possible for the rings to be substituted by up to 2 R 8 radicals, and D can be a bond, —(CH 2 ) m —, —CH═CH—, —C═C—, and R 2 is chlorine, bromine, fluorine, C 1 -C 6 -alkyl, NHCO—C 1 -C 4 -alkyl, NHSO 2 —C 1 -C 4 -alkyl, NO 2 , —O—C 1 -C 4 -alkyl and NH 2 , and R 3 is —C 1 -C 6 -alkyl, branched or unbranched, and which may also carry a phenyl ring, indolyl ring or cyclohexyl ring which is in turn substituted by a maximum of two R 8 radicals, where R 8 is hydrogen, C 1 -C 4 -alkyl, branched or unbranched, —O—C 1 -C 4 -alkyl, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO—C 1 -C 4 -alkyl, NHCO—C 1 -C 4 -alkyl, —NHSO 2 —C 1 -C 4 -alkyl and —SO 2 —C 1 -C 4 -alkyl; and Y is phenyl, pyridine, pyrimidine and pyrazine and R 4 is hydrogen, COOR 9 and CO—Z in which Z is NR 10 R 11 and R 9 is hydrogen, C 1 -C 6 -alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which may itself also be substituted by one or two R 12 radicals, and R 10 is hydrogen, C 1 -C 6 -alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which itself may also be substituted by one or two R 12 radicals, and R 11 is hydrogen, C 1 -C 6 -alkyl, branched or unbranched, which may also be and substituted by a phenyl ring which may also carry an R9 radical, and R 12 can be hydrogen, C 1 -C 4 -alkyl, branched or unbranched, —O—C 1 -C 4 -alkyl, OH, Cl, F, Br, J, CF 3 , NO 2 , NH 2 , CN, COOH, COO—C 1 -C 4 -alkyl, —NHCO—C 1 -C 4 -alkyl, —NHCO-phenyl, —NHSO 2 —C 1 -C 4 -alkyl, NHSO 2 -phenyl, —SO 2 —C 1 -C 4 -alkyl and —SO 2 -phenyl, R 13 is hydrogen, C 1 -C 6 -alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which may itself also be substituted by one or two R 12 radicals, and R 14 is hydrogen, C 1 -C 6 -alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which may itself also be substituted by one or two R 12 radicals, and n is a number 0, 1 or 2, and m,q are, independently of one another, a number 0, 1, 2, 3 or 4.

1 . An amide of the formula I 
       
         
           
           
               
               
           
         
       
       and its tautomeric forms, possible enantiomeric and diastereomeric forms, E and Z forms, and possible physiologically tolerated salts, in which the variables have the following meanings:
 A —(CH 2 ) p —R 1 , where R 1  can be pyrrolidine, morpholine, hexahydroazepine, piperidine, —NR 5 R 6  and 
 
       
         
           
           
               
               
           
         
         
           it also being possible for the cyclic amines to be substituted by one or two R 15  radicals, and R 15  are hydrogen, C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl and phenyl, 
           and R 5 , R 6  and R 7  can be, independently of one another, hydrogen, C 1 -C 4 -alkyl, cyclohexyl, cyclopentyl, CH 2 Ph, Ph, CH 2 CH 2 Ph, it also being possible for the phenyl rings to be substituted by R 6 , and p can be 1 and 2, and 
         
         B can be phenyl, pyridyl, pyrazyl, pyrimidyl and pyridazyl, it also being possible for the rings to be substituted by up to 2 R 8  radicals, and 
         A and B together can also be 
       
       
         
           
           
               
               
           
         
         
           and R 16  is hydrogen, C 1 -C 6 -alkyl and (CH 2 ) 1-4 -phenyl, it also being possible for the phenyl ring to be substituted by a maximum of 2 R 6  radicals, and 
         
         D can be a bond, —(CH 2 ) 0-2 —O—(CH 2 ) 0-2 , —(CH 2 ) m —, —CH═CH—, —C═C—, and 
         R 2  is chlorine, bromine, fluorine, C 1 -C 6 -alkyl, NHCO—C 1 -C 4 -alkyl, NHSO 2 —C 1 -C 4 -alkyl, NO 2 , —O—C 1 -C 4 -alkyl and NH 2 , and 
         R 3  is —C 1 -C 6 -alkyl, branched or unbranched, and which may also carry a SCH 3  radical, a phenyl ring, imidazolyl ring, indolyl ring and cyclopentyl, cycloheptyl or cyclohexyl ring which is in turn substituted by a maximum of two R 8  radicals, where R 8  is hydrogen, C 1 -C 4 -alkyl, branched or unbranched, —O—C 1 -C 4 -alkyl, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO—C 1 -C 4 -alkyl, —NHSO 2 —C 1 -C 4 -alkyl and —SO 2 —C 1 -C 4 -alkyl; and 
         Y is phenyl, pyridine, pyridazine, pyrimidine and pyrazine and 
         R 4  is hydrogen, COOR 9  and CO—Z in which Z is NR 10 R 11  and 
       
       
         
           
           
               
               
           
         
         R 9  is hydrogen, C 1 -C 6 -alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which may itself also be substituted by one or two R 12  radicals, and 
         R 10  is hydrogen, C 1 -C 6 -alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which itself may also be substituted by one or two R 12  radicals, and 
       
       
         
           
           
               
               
           
         
         R 11  is hydrogen, C 1 -C 6 -alkyl, branched or unbranched, which may also be and substituted by a phenyl ring which may also carry an R 9  radical, and 
         R 12  can be hydrogen, C 1 -C 4 -alkyl, branched or unbranched, —O—C 1 -C 4 -alkyl, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO—C 1 -C 4 -alkyl, —NHCO—C 1 -C 4 -alkyl, —NHCO-phenyl, —NESO 2 —C 1 -C 4 -alkyl, NHSO 2 -phenyl, —SO 2 —C 1 -C 4 -alkyl and —SO 2 -phenyl, 
         R 13  is hydrogen, C 1 -C 6 -alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which may itself also be substituted by one or two R 12  radicals, and 
         R 14  is hydrogen, C 1 -C 6 -alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which may itself also be substituted by one or two R 12  radicals, and 
         n is a number 0, 1 or 2, and 
         m,q are, independently of one another, a number 0, 1, 2, 3 or 4. 
       
     
     
         2 . An amide of the formula I as claimed in  claim 1 , where
 A —CH 2 —R 1      B phenyl   D —CH═CH—   R 2  hydrogen   R 3  benzyl, CH 2 —CH 3 , CH 2 —CH 2 —CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 2 CH 3  and   Y phenyl and   R 4 CO—NH 2  and   all the remaining variables have the same meaning as in  claim 1 .   
     
     
         3 . An amide of the formula I as claimed in  claim 1 , where
 A —CH 2 —R 1      B phenyl   D —CH═CH—   R 2  hydrogen   R 3  benzyl, CH 2 —CH 3 , CH 2 —CH 2 —CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 2 CH 3  and   Y phenyl and   R 4  hydrogen and   all the remaining variables have the same meaning as in  claim 1 .   
     
     
         4 . An amide of the formula I as claimed in  claim 1 , where
 A —CH 2 —R 1      B phenyl   D —CH═CH—   R 2  hydrogen   R 3  benzyl, CH 2 —CH 3 , CH 2 —CH 2 —CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 2 CH 3  and   Y pyridine and   R 4  hydrogen and   all the remaining variables have the same meaning as in  claim 1 .   
     
     
         5 . An amide of the formula I as claimed in  claim 1 , where
 A —CH 2 —R 1      B phenyl   D —CH═CH—   R 2  hydrogen   R 3  benzyl, CH 2 —CH 3 , CH 2 —CH 2 —CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 2 CH 3  and   Y pyridine and   R 4 CO—NH 2  and   all the remaining variables have the same meaning as in  claim 1 .   
     
     
         6 . The use of amides of the formula I as claimed in  claim 1 - 5  for treating diseases. 
     
     
         7 . The use of amides of the formula I as claimed in  claim 1 - 5  as inhibitors of cysteine proteases. 
     
     
         8 . The use as claimed in  claim 6  as inhibitors of cysteine proteases such as calpains and cathepsins, in particular calpains I and II and cathepsins B and L. 
     
     
         9 . The use of amides of the formula I as claimed in  claim 1 - 5  for production as pharmaceuticals for treating diseases in which elevated calpain activities occur. 
     
     
         10 . The use of amides of the formula I as claimed in  claim 1 - 5  for producing pharmaceuticals for treating neurodegenerative disorders and neuronal damage. 
     
     
         11 . The use as claimed in  claim 9  for treating neurodegenerative disorders and neuronal damage induced by ischemia, trauma or massive bleeding. 
     
     
         12 . The use as claimed in  claim 10  for treating stroke and craniocerebral trauma. 
     
     
         13 . The use as claimed in  claim 10  for treating Alzheimer's disease and Huntington's disease. 
     
     
         14 . The use as claimed in  claim 10  for treating epilepsies. 
     
     
         15 . The use of compounds of the formula I as claimed in  claim 1 - 5  for producing pharmaceuticals and treating damage to the heart after cardiac ischemias, damage due to reperfusion after vascular occlusions, damage to the kidneys after renal ischemias, skeletal muscle damage, muscular dystrophies, damage produced by proliferation of smooth muscle cells, coronary vasospasm, cerebral vasospasm, cataracts of the eyes and restenosis of blood vessels after angioplasty. 
     
     
         16 . The use of amides of the formula I as claimed in  claim 1 - 5  for producing pharmaceuticals for treating tumors and metastasis thereof. 
     
     
         17 . The use of amides of the formula I as claimed in  claim 1 - 5  for producing pharmaceuticals for treating disorders in which elevated interleukin-1 levels occur. 
     
     
         18 . The use of amides as claimed in  claim 1 - 5  for treating immunological disorders such as inflammations and rheumatic disorders. 
     
     
         19 . A pharmaceutical preparation for oral, parenteral or intraperitonal use, comprising at least one amide I as claimed in  claim 1 - 5  per single dose, besides conventional pharmaceutical ancillary substances.