Aromatic sulfonamides as peroxynitrite-rearrangement catalysts

Abstract

The invention relates to the use of aromatics sulfonamides of the general formula I as peroxynitrite rearrangement catalysts, to the preparation thereof and to the use thereof as medicament for the treatment of various disorders.

1 . A compound of formula I  
     
       
         
         
             
             
         
       
     
     in which 
 A)  
 R 1  is a C 5 -C 6 -alkylene-containing ring which may optionally be substituted one or more times by C 1 -C 6 -alkyl and which ring may optionally be interrupted by one or more nitrogen, sulfur or oxygen atoms and/or may contain one or more possible double bonds in the ring, or is a C 3 -C 7 -aryl or C 3 -C 12 -heteroaryl, which may optionally be substituted one or more times, identically or differently, by halogen, hydroxyl, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy,  
 R 2  and R 3  are each, independently of one another, C 2 -C 6 -alkyl or C 1 -C 6 -alkoxy, or  
 R 2  and R 3  form a C 5 -C 6 -alkylene-containing ring together with the nitrogen atom, which may optionally be substituted by C 1 -C 4 -alkyl, and  
 R 4  is hydrogen, hydroxyl, nitro, halogen, C 1 -C 6 -alkyl, COOH, CF 3  or C 1 -C 6 -alkoxy,  
 or an the isomer, diastereomer, enantiomer thereof, or a salt thereof,  
 wherein the compound of formula I is not  
                     
 or  
 B)  
 R 1  is a C 5 -C 6 -alkylene-containing ring which may optionally be substituted one or more times by C 1 -C 6 -alkyl and which ring may optionally be interrupted by one or more nitrogen, sulfur or oxygen atoms and/or may contain one or more possible double bonds in the ring, or is a C 3 -C 7 -aryl or C 3 -C 12 -heteroaryl, which may optionally be substituted one or more times, identically or differently by halogen, hydroxyl, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, wherein R 1  is not  
                     
 R 2  and R 3  are each, independently of one another. C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or  
 R 2  and R 3  form a C 5 -C 6 -alkylene-containing ring together with the nitrogen atom, which may optionally be substituted by C 1 -C 4 -alkyl, and  
 R 4  is hydrogen, hydroxyl, nitro, halogen, C 1 -C 6 -akyl, COOH, CF 3  or C 1 -C 6 -alkoxy. or an the isomer, diastereomer, enantiomer thereof, or a salt thereof, or  
 C)  
 R 1  is a C 5 -C 6 -alkylene-containing ring which may optionally be substituted one or more times by C 1 -C 6 -alkyl and which ring may optionally be interrupted by one or more nitrogen, sulfur or oxygen atoms and/or may contain one or more possible double bonds in the ring, or is a C 3 -C 7 -aryl or C 3 -C 12 -heteroaryl, which may optionally be substituted one or more times, identically or differently, by halogen, hydroxyl, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy,  
 R 2  and R 3  are each, independently of one another, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or  
 R 2  and R 3  form a C 5 -alkylene-containing ring together with the nitrogen atom, which may optionally be interrupted by a further nitrogen atom in the ring, and which may optionally be substituted by C 1 -C 4 -alkyl, and  
 R 4  is hydrogen, hydroxyl, nitro, halogen, C 1 -C 6 -alkyl, COOH, CF 3  or C 1 -C 6 -alkoxy, or an the isomer, diastereomer, enantiomer thereof, or a salt thereof; or  
 D)  
 R 1  is  
                     
 R 2  and R 3  are each, independently of one another, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or  
 R 2  and R 3  form a C 5 -C 6 -alkylene-containing ring together with the nitrogen atom, which may optionally be interrupted by a further nitrogen atom in the ring, and which may optionally be substituted by C 1 -C 4 -alkyl, and  
 R 4  is hydrogen, hydroxyl, nitro, halogen, C 1 -C 6 -alkyl, COOH, CF 3  or C 1 -C 6 -alkoxy, or an the isomer, diastereomer, enantiomer thereof, or a salt thereof.  
 
   
   
       2 . A compound of formula I according to  claim 1 , in which in A) 
 R 1  is a C 5 -C 6 -alkylene-containing ring which may optionally be substituted one or more times by methyl, and which ring may optionally be interrupted by one or more nitrogen, sulfur or oxygen atoms and/or one or more possible double bonds may be present in the ring, or is a C 3 -C 6 -aryl or C 3 -C 12 -heteroaryl,    R 2  and R 3  are each, independently of one another, C 2 -C 6 -alkyl, or    R 2  and R 3  form a C 5 -C 6 -alkylene-containing ring together with the nitrogen atom, which may optionally be substituted by C 1 -C 4 -alkyl, and    R 4  is hydrogen, CF 3 , —O—CH 3  or nitro, or an the isomer, diastereomer, enantiomer thereof, or a salt thereof.    
   
   
       3 . A compound of formula I according to  claim 1 , in which in A) 
 R 1  is                          R 2  and R 3  are each, independently of one another, C 2 -C 6 -alkyl, or    R 2  and R 3  form a C 2 -C 6 -alkylene-containing ring together with the nitrogen atom, which may optionally be substituted by C 1 -C 4 -alkyl, and    R 4  is hydrogen, CF 3 , —O—CH 3  or nitro, or an the isomer, diastereomer. enantiomer thereof, or a salt thereof.    
   
   
       4 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I  
     
       
         
         
             
             
         
       
     
     in which 
 R 1  is a C 1 -C 6 -alkyl,  
 R 2  and R 3  are each, independently of one another, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or  
 R 2  and R 3  form a C 5 -C 6 -alkylene-containing ring together with the nitrogen atom, which may optionally be interrupted by a further nitrogen atom in the ring, and which may optionally be substituted by C 1 -C 4 -alkyl, and  
 R 4  is hydrogen, hydroxyl, nitro, halogen, C 1 -C 6 -alkyl, COOH, CF 3  or C 1 -C 6 -alkoxy,  
 or an the isomer, diastereomer, enantiomer thereof, or a salt thereof.  
 
   
   
       5 . A method for the treatment or prophylaxis of a chronic or acute neurodegenerative disorder, an autoimmune disease, an inflammatory disorder, an infectious disease, cancer, a viral infection, a cardiovascular disorder, or a nephrological disorder comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to  claim 1 .  
   
   
       6 . A method according to  claim 5 , which is for the treatment or prophylaxis of Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, dementia, Alzheimer's disease, HIV dementia, presenile dementia, Korksakoff's disease, epilepsy, schizophrenia, depression, cerebral ischemia, neurotrauma, hypotension, adult respiratory distress syndrome, sepsis, septic shock, rheumatoid arthritis, osteoarthritis, inflammatory disease of the pelvis/bowel, bowel disease, meningitis, multiple sclerosis, alopecia, psoriasis, a disease caused by a unicellular parasite a solid tumor, leukemia, a cytomegalovirus infection, hepatitis, hepatitis B or C, an HIV disorder, ischemic reperfusion disorder, stenoses, arterioscleroses, restenoses, or glomerulonephritis.  
   
   
       7 - 9 . (canceled)  
   
   
       10 . A method for catalyzing peroxynitrite rearrangement comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to  claim 1 .  
   
   
       11 - 12 . (canceled)  
   
   
       13 . A compound of formula I according to  claim 1 , wherein in D) 
 R 1  is                          
   
   
       14 . A compound of formula I according to  claim 1 , wherein in B) 
 R 1  is a C 5 -C 6 -alkylene-containing ring which may optionally be substituted one or more times by methyl, and which ring may optionally be interrupted by one or more nitrogen, sulfur or oxygen atoms and/or one or more possible double bonds may be present in the ring, or is a C 3 -C 6 -aryl or C 3 -C 12 -heteroaryl,    R 2  and R 3  are each, independently of one another, C 1 -C 6 -alkyl, or    R 2  and R 3  form a C 5 -C 6 -alkylene-containing ring together with the nitrogen atom, which may optionally be substituted by C 1 -C 4 -alkyl, and    R 4  is hydrogen, CF 3 , —O—CH 3  or nitro,    or an the isomer, diastereomer, enantiomer thereof, or a salt thereof.    
   
   
       15 . A compound of formula I according to  claim 1 , wherein in B) 
 R 1  is                          R 2  and R 3  are each, independently of one another, C 1 -C 6 -alkyl, or    R 2  and R 3  form a C 5 -C 6 -alkylene-containing ring together with the nitrogen atom, which may optionally be substituted by C 1 -C 4 -alkyl, and    R 4  is hydrogen, CF 3 , —O—CH 3  or nitro,    or an the isomer, diastereomer, enantiomer thereof, or a salt thereof.    
   
   
       16 . A compound of formula I according to  claim 1 , wherein in C) 
 R 1  is a C 5 -C 6 -alkylene-containing ring which may optionally be substituted one or more times by methyl, and which ring may optionally be interrupted by one or more nitrogen, sulfur or oxygen atoms and/or one or more possible double bonds may be present in the ring, or is a C 3 -C 6 -aryl or C 3 -C 12 -heteroaryl,    R 2  and R 3  are each, independently of one another, C 2 -C 6 -alkyl, or    R 2  and R 3  form a C 5 -alkylene-containing ring together with the nitrogen atom, which may optionally be interrupted by a further nitrogen atom in the ring, and which may optionally be substituted by C 1 -C 4 -alkyl, and    R 4  is hydrogen, CF 3 , —O—CH 3  or nitro,    or an the isomer, diastereomer, enantiomer thereof, or a salt thereof.    
   
   
       17 . A compound of formula I according to  claim 1 , wherein in C) 
 R 1  is                          R 2  and R 3  are each, independently of one another, C 2 -C 6 -alkyl, or    R 2  and R 3  form a C 5 -alkylene-containing ring together with the nitrogen atom, which may optionally be interrupted by a further nitrogen atom in the ring, and which may optionally be substituted by C 1 -C 4 -alkyl, and    R 4  is hydrogen, CF 3 , —O—CH 3  or nitro, or an the isomer, diastereomer, enantiomer thereof, or a salt thereof    
   
   
       18 . A compound of formula I according to  claim 1 , wherein in D) 
 R 2  and R 3  are each, independently of one another, C 1 -C 6 -alkyl, or    R 2  and R 3  form a C 5 -C 6 -alkylene-containing ring together with the nitrogen atom, which may optionally be interrupted by a further nitrogen atom in the ring, which may optionally be substituted by C 1 -C 4 -alkyl, and    R 4  is hydrogen, CF 3 , —O—CH 3  or nitro,    or an the isomer, diastereomer, enantiomer thereof, or a salt thereof.    
   
   
       19 . A compound of formula I according to  claim 1 , wherein in D) 
 R 2  and R 3  are each, independently of one another, C 1 -C 6 -alkyl, or    R 2  and R 3  form a C 5 -C 6 -alkylene-containing ring together with the nitrogen atom, which may optionally be interrupted by a further nitrogen atom in the ring, which may optionally be substituted by C 1 -C 4 -alkyl, and    R 4  is hydrogen, CF 3 , —O—CH 3  or nitro,    or an the isomer, diastereomer, enantiomer thereof, or a salt thereof.    
   
   
       20 . A compound of formula I according to  claim 15 , which is thiophene-2-sulfonic acid 4-dimethylamino-2-nitrophenylamide; or 3,5-dimethylisoxazole-4-sulfonic acid 4-dimethylamino-2-nitrophenylamide.  
   
   
       21 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 .  
   
   
       22 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 20.