Substituted indoles

Abstract

Compounds of the formula I are suitable for preparing pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of NFκB is involved.

1 - 8 . (Canceled)  
     
     
         9 . A compound of the formula I  
       
         
           
           
               
               
           
         
       
       in any stereoisomeric form, or a physiologically acceptable salt thereof, where R 1 , R 2  and R 4  are, independently, hydrogen, halogen, or aryl; 
 R 5  is hydrogen;  
 R 3  is a radical of formula II  
                     
  in which 
 D is —C(O)—;  
 R 7  is hydrogen;  
 R 8  is —(C 1 -C 6 )-alkyl, where alkyl is straight-chain or branched and is unsubstituted or mono-, di- or trisubstituted, independently of one another, by —N(R 10 ) 2 , where each R 10  is, independently, hydrogen, —(C 1 -C 4 )-alkyl, aryl, or a heterocycle having 5 to 12 ring members; and  
 Z is —CONH 2  or —COO—R 10  or 
 a monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring which is partly saturated or completely saturated, wherein said heterocycle is unsubstituted or monosubstituted, disubstituted, trisubstituted or tetrasubstituted on carbon atoms by identical or different radicals from the group consisting of (C 1 -C 8 )-alkyl, phenyl-(C 1 -C 4 )-alkoxy, hydroxyl, oxo, halogen, nitro, amino or trifluoromethyl;  
 
 
 R 9  is, independently, any substituent identified above for R 8 ; and  
 R 6  is a heterocycle having 5 to 12 ring members, which is unsubstituted or substituted by —CN, —CF 3 , halogen, —O—R 10 , —N(R 10 ) 2 , —NH—C(O)—R 11 , —S(O) x —R 10 , where x is the integer zero, 1 or 2, —C(O)—R 11  or —(C 1 -C 4 )-alkyl-NH 2 , and where R 10  is as defined above and R 11  is —O—R 10 or —N(R 10 ) 2 .  
 
     
     
         10 . A compound as claimed in  claim 9 , wherein Z is pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole 2-oxide, triazolone, oxadiazolone, isoxazolone, oxadiazolidinedione, triazole, 3-hydroxypyrrole-2,4-dione, 5-oxo-1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline or a benzo-fused or cyclopenta-, cyclohexa- or cyclohepta-fused derivative of any of the above heterocycles, 
 which is unsubstituted or substituted by (C 1 -C 4 )-alkyl, methoxy, benzyloxy, hydroxyl, oxo, halogen, nitro, amino or trifluoromethyl.    
     
     
         11 . A compound as claimed in  claim 9 , wherein Z is oxazole, isoxazole, 1,2,3,5-oxathiadiazole 2-oxide, oxadiazolone, isoxazolone, oxadiazolidinedione, 3-hydroxypyrrole-2,4-dione, 5-oxo-1,2,4-thiadiazole or 1,3,4-oxadiazole, 
 which is unsubstituted or substituted by (C 1 -C 4 )-alkyl, methoxy, benzyloxy, hydroxyl, oxo, halogen, nitro, amino or trifluoromethyl.    
     
     
         12 . A compound as claimed in  claim 9 , wherein R 8  is —CH 2 —N(phenyl) 2 .  
     
     
         13 . A compound as claimed in  claim 9 , wherein R 6  is pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole 2-oxide, triazolone, oxadiazolone, isoxazolone, oxadiazolidinedione, triazole, 3-hydroxypyrrole-2,4-dione, 5-oxo-1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline or a benzo-fused or cyclopenta-, cyclohexa- or cyclohepta-fused derivative of any of the above heterocycles, which is unsubstituted or substituted by —N(R 10)   2 , wherein R 10  is —(C 1 -C 4 )-alkyl.  
     
     
         14 . A compound as claimed in  claim 9 , wherein R 6  is unsubstituted or substituted pyrrole, pyrazole, pyridine, pyrazine or pyrimidine.  
     
     
         15 . A compound as claimed in  claim 9 , wherein R 1 , R 2  and R 4  are hydrogen.  
     
     
         16 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is joint inflammation.  
     
     
         17 . A method as claimed in  claim 16 , wherein the joint inflammation is arthritis, rheumatoid arthritis or other arthritic condition.  
     
     
         18 . A method as claimed in  claim 17 , wherein the other arthritic condition is rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, or osteoarthritis.  
     
     
         19 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is acute synovitis, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, endotoxaemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, gout, or toxic shock syndrome.  
     
     
         20 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is chronic pulmonary inflammatory disease.  
     
     
         21 . A method as claimed in  claim 20 , wherein the chronic pulmonary inflammatory disease is asthma or adult respiratory distress syndrome.  
     
     
         22 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft versus host reaction, allograft rejection or leprosy.  
     
     
         23 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is a viral infection.  
     
     
         24 . A method as claimed in  claim 23 , wherein the viral infection is HIV, cytomegalovirus, influenza, adenovirus, or a Herpes virus.  
     
     
         25 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is a parasitic infection.  
     
     
         26 . A method as claimed in  claim 25 , wherein the parasitic infection is malaria.  
     
     
         27 . A method as claimed in  claim 26 , wherein the malaria is cerebral malaria.  
     
     
         28 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is a yeast or fungal infection.  
     
     
         29 . A method as claimed in  claim 28 , wherein the infection is fungal meningitis.  
     
     
         30 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is fever or myalgia due to infection.  
     
     
         31 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is acquired immune deficiency syndrome (AIDS) or AIDS related complex.  
     
     
         32 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is keloid or scar tissue formation.  
     
     
         33 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is pyresis or diabetes.  
     
     
         34 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is inflammatory bowel disease.  
     
     
         35 . A method as claimed in  claim 34 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.  
     
     
         36 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is multiple sclerosis or head trauma.  
     
     
         37 . A method for the treatment of a disorder in the course of which an increased activity of NFKB is involved, which comprises administering to a host in need of the treatment an effective amount of a compound as claimed in  claim 9 , wherein the disorder is psoriasis, Alzheimer's disease, a carcinomatous disorder, cardiac infarct, chronic obstructive pulmonary disease or acute respiratory distress syndrome.