4-,6- or 7-hydroxyindoles with N-oxide groups and the use thereof as therapeutic agents

Abstract

The invention relates to substituted 4-, 6- or 7-hydroxyindoles with N-oxide groups, process for their preparation, pharmaceutical preparations which comprise these compounds, and the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 4, as active ingredients for the treatment of disorders which can be influenced by inhibition of phosphodiesterase 4 activity in particular in immunocompetent cells (e.g. macrophages and lymphocytes) by the compounds of the invention.

1 - 16 . (canceled)  
   
   
       17 . A method of treating a disorder for which inhibition of phosphodiesterase 4 is therapeutically beneficial comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula 1  
     
       
         
         
             
             
         
       
       wherein  
       R 1  is —C 1-10 -alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted by mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3-14 ring members, wherein the carbocyclic substituents in turn are substituted one or more times by —NO 2  and may optionally be substituted one or more times by —C 1-6 -alkyl, —OH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, —SO 3 H, —SO 2 C 1-6 -alkyl, —OSO 2 C 1-6 -alkyl, —COOH, —(CO)C 1-5 -alkyl, —COO—C 1-5 -alkyl or/and —O(CO)C 1-5 -alkyl, and wherein the alkyl groups on the carbocyclic substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H or/and —COOH;  
       R 2  is hydrogen or —C 1-3 -alkyl;  
       R 3 , R 4  and R 5  are hydrogen or a hydroxyl group, wherein at least one of these substituents must be a hydroxyl group;  
       R 6  and R 7  may be identical or different and are hydrogen, —C 1-6 -alkyl, —OH, —SH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —SO 3 H, —SO 3 —C 1-6 -alkyl, —COOH, —COO—C 1-6 -alkyl, —O(CO)—C 1-5 -alkyl, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, -phenyl or -pyridyl, wherein the phenyl or pyridyl substituents in turn may optionally be substituted one or more times by —C 1-3 -alkyl, —OH, —SH, —NH 2 , —NHC 1-3 -alkyl, —N(C 1-3 -alkyl) 2 , —NO 2 , —CN, —SO 3 H, —SO 3 C 1-3 -alkyl, —COOH, —COOC 1-3 -alkyl, —F, —Cl, —Br, —I, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl, or/and —O(CO)C 1-3 -alkyl, and wherein the alkyl substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H, —SO 3 C 1-3 -alkyl, —COOH, —COOC 1-3 -alkyl, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl or/and —O(CO)—C 1-3 -alkyl;  
       or a salt thereof.  
     
   
   
       18 . A method of treating disorders associated with the effect of eosinophils comprising administering a therapeutically effective amount of a compound of formula 1  
     
       
         
         
             
             
         
       
       wherein  
       R 1  is —C 1-10 -alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted by mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3-14 ring members, wherein the carbocyclic substituents in turn are substituted one or more times by —NO 2  and may optionally be substituted one or more times by —C 1-6 -alkyl, —OH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, —SO 3 H, —SO 2 C 1-6 -alkyl, —OSO 2 C 1-6 -alkyl, —COOH, —(CO)C 1-5 -alkyl, —COO—C 1-5 -alkyl or/and —O(CO)C 1-5 -alkyl, and wherein the alkyl groups on the carbocyclic substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H or/and —COOH;  
       R 2  is hydrogen or —C 1-3 -alkyl;  
       R 3 , R 4  and R 5  are hydrogen or a hydroxyl group, wherein at least one of these substituents must be a hydroxyl group;  
       R 6  and R 7  may be identical or different and are hydrogen, —C 1-6 -alkyl, —OH, —SH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —SO 3 H, —SO 3 —C 1-6 -alkyl, —COOH, —COO—C 1-6 -alkyl, —O(CO)—C 1-5 -alkyl, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, -phenyl or -pyridyl, wherein the phenyl or pyridyl substituents in turn may optionally be substituted one or more times by —C 1-3 -alkyl, —OH, —SH, —NH 2 , —NHC 1-3 -alkyl, —N(C 1-3 -alkyl) 2 , —NO 2 , —CN, —SO 3 H, —SO 3 C 1-3 -alkyl, —COOH, —COOC 1-3 -alkyl —Cl, —Br, —I, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl, or/and —O(CO)C 1-3 -alkyl, and wherein the alkyl substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H, —SO 3 C 1-3 -alkyl, —COOH, —COOC 1-3 -alkyl, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl or/and —O(CO)—C 1-3 -alkyl; or a salt thereof to a patient in need thereof.  
     
   
   
       19 . A method of treating disorders associated with the effect of neutrophils comprising administering a therapeutically effective amount of a compound of formula 1  
     
       
         
         
             
             
         
       
       wherein  
       R 1  is —C 1-10 -alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted by mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3-14 ring members, wherein the carbocyclic substituents in turn are substituted one or more times by —NO 2  and may optionally be substituted one or more times by —C 1-6 -alkyl, —OH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, —SO 3 H, —SO 2 C 1-6 -alkyl, —OSO 2 C 1-6 -alkyl, —COOH, —(CO)C 1-5 -alkyl, —COO—C 1-5 -alkyl or/and —O(CO)C 1-5 -alkyl, and wherein the alkyl groups on the carbocyclic substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H or/and —COOH;  
       R 2  is hydrogen or —C 1-3 -alkyl;  
       R 3 , R 4  and R 5  are hydrogen or a hydroxyl group, wherein at least one of these substituents must be a hydroxyl group;  
       R 6  and R 7  may be identical or different and are hydrogen, —C 1-6 -alkyl, —OH, —SH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —SO 3 H, —SO 3 —C 1-6 -alkyl, —COOH, —COO—C 1-6 -alkyl, —O(CO)—C 1-5 -alkyl, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, -phenyl or -pyridyl, wherein the phenyl or pyridyl substituents in turn may optionally be substituted one or more times by —C 1-3 -alkyl, —OH, —SH, —NH 2 , —NHC 1-3 -alkyl, —N(C 1-3 -alkyl) 2 , —NO 2 , —CN, —SO 3 H, —SO 3 C 1-3 -alkyl, —COOH, —COOC 1-3 -alkyl, —F, —Cl, —Br, —I, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl, or/and —O(CO)C 1-3 -alkyl, and wherein the alkyl substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H, —SO 3 C 1-3 -alkyl, —COOH, —COOC 1-3 -alkyl, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl or/and —O(CO)—C 1-3 -alkyl; or a salt thereof to a patient in need thereof to a patient in need thereof.  
     
   
   
       20 . A method of treating a hyperproliferative disorder comprising administering a therapeutically effective amount of a compound of formula 1  
     
       
         
         
             
             
         
       
       wherein  
       R 1  is —C 1-10 -alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted by mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3-14 ring members, wherein the carbocyclic substituents in turn are substituted one or more times by —NO 2  and may optionally be substituted one or more times by —C 1-6 -alkyl, —OH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, —SO 3 H, —SO 2 C 1-6 -alkyl, —OSO 2 C 1-6 -alkyl, —COOH, —(CO)C 1-5 -alkyl, —COO—C 1-5 -alkyl or/and —O(CO)C 1-5 -alkyl, and wherein the alkyl groups on the carbocyclic substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H or/and —COOH;  
       R 2  is hydrogen or —C 1 3 -alkyl;  
       R 3 , R 4  and R 5  are hydrogen or a hydroxyl group, wherein at least one of these substituents must be a hydroxyl group;  
       R 6  and R 7  may be identical or different and are hydrogen, —C 1-6 -alkyl, —OH, —SH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —NO 2 , —CN, —SO 3 H, —SO 3 —C 1-6 -alkyl, —COOH, —COO—C 1-6 -alkyl, —O(CO)—C 1-5 -alkyl, —F, —Cl, —Br, —I, —O—C 1-6 -alkyl, —S—C 1-6 -alkyl, -phenyl or -pyridyl, wherein the phenyl or pyridyl substituents in turn may optionally be substituted one or more times by —C 1-3 -alkyl, —OH, —SH, —NH 2 , —NHC 1-3 -alkyl, —N(C 1-3 -alkyl) 2 , —NO 2 , —CN, —SO 3 H, —SO 3 C 1-3 -alkyl, —COOH, —COOC 1-3 -alkyl, —F, —Cl, —Br, —I, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl, or/and —O(CO)C 1-3 -alkyl, and wherein the alkyl substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH 2 , —F, —Cl, —Br, —I, —SO 3 H, —SO 3 C 1-3 -alkyl, —COOH, —COOC 1-3 -alkyl, —O—C 1-3 -alkyl, —S—C 1-3 -alkyl or/and —O(CO)—C 1-3 -alkyl; or a salt thereof to a patient in need thereof to a patient in need thereof to treat the hyperproliferative disorder.  
     
   
   
       21 . The method of  claim 17 , wherein said disorder is COPD.  
   
   
       22 . The method of  claim 17 , wherein said disorder is asthma.  
   
   
       23 . The method of  claim 17 , wherein said disorder is a skin disorder.  
   
   
       24 . The method of  claim 17 , wherein said compound is selected from the group consisting of 
 N-(3,5-dichloro-1-oxopyridin-4-yl)-[7-hydroxy-1-(3-nitrobenzyl)-indol-3-yl]glyoxylamide;    N-(3,5-dichloro-1-oxopyridin-4-yl)-[7-hydroxy-1-(2-nitrobenzyl)-indol-3-yl]glyoxylamide;    and physiologically tolerated salts thereof    
   
   
       25 . The method of  claim 17 , wherein said compound is N-(3,5-dichloro-1-oxopyridin-4-yl)-[7-hydroxy-1-(3-nitrobenzyl)-indol-3-yl]glyoxylamide.  
   
   
       26 . The method of  claim 17 , wherein said compound is N-(3,5-dichloro-1-oxopyridin-4-yl)-[7-hydroxy-1-(2-nitrobenzyl)-indol-3-yl]glyoxylamide.  
   
   
       27 . The method of  claim 22 , wherein said compound is selected from the group consisting of 
 N-(3,5-dichloro-1-oxopyridin-4-yl)-[7-hydroxy-1-(3-nitrobenzyl)-indol-3-yl]glyoxylamide;    N-(3,5-dichloro-1-oxopyridin-4-yl)-[7-hydroxy-1-(2-nitrobenzyl)-indol-3-yl]glyoxylamide;    and physiologically tolerated salts thereof    
   
   
       28 . The method of  claim 22 , wherein said compound is 
 N-(3,5-dichloro-1-oxopyridin-4-yl)-[7-hydroxy-1-(3-nitrobenzyl)-indol-3-yl]glyoxylamide.    
   
   
       29 . The method of  claim 22 , wherien said compound is N-(3,5-dichloro-1-oxopyridin-4-yl)-[7-hydroxy-1-(2-nitrobenzyl)-indol-3-yl]glyoxylamide.