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.

We claim:  
     
         1 . A compound of the formula I  
       
         
           
           
               
               
           
         
         in any stereoisomeric form, or a physiologically acceptable salt thereof, where  
         one of the substituents R 1 , R 2 , R 3  and R 4  is a radical of the formula II  
         
           
             
             
                 
                 
             
           
         
         in which D is —C(O)—, —S(O)— or —S(O) 2 —,  
         R 7  is hydrogen or —(C 1 -C 4 )-alkyl,  
         R 8  is R 9  or the characteristic radical of an amino acid,  
         R 9  is 1. aryl, where aryl is unsubstituted or substituted, 
 2. heteroaryl having 5 to 14 ring members, where heteroaryl is unsubstituted or substituted,  
 3. heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or substituted, or  
 4. —(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 
 4.1 aryl, where aryl is unsubstituted or substituted,  
 4.2 heteroaryl having 5 to 14 ring members, where heteroaryl is unsubstituted or substituted,  
 4.3 heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or substituted,  
 4.4 —O—R 10 ,  
 4.5 ═O,  
 4.6 halogen,  
 4.7 —CN,  
 4.8 —CF 3 ,  
 4.9 —S(O) x —R 10 , where x is the integer zero, 1 or 2,  
 4.10 —C(O)—O—R 10 ,  
 4.11 —C(O)—N(R 10 ) 2 ,  
 4.12 —N(R 10 ) 2 ,  
 4.13 —(C 3 -C 6 )-cycloalkyl,  
 4.14 radical of the formula  
                     
  or  
 4.15 radical of the formula    
 
 
         R 10  is a) hydrogen, 
 b) —(C 1 -C 6 )-alkyl, where alkyl is unsubstituted or mono- to trisubstituted, independently of one another, by 
 1. aryl,  
 2. heteroaryl having 5 to 14 ring members,  
 3. heterocycle having 5 to 12 ring members,  
 4. halogen,  
 5. —N-(C 1 -C 6 ) n -alkyl, where n is the integer zero, 1 or 2 and alkyl is unsubstituted or mono-, di- or trisubstituted, independently of one another, by halogen or by —COOH, or  
 6. —COOH,  
 
 c) aryl,  
 d) heteroaryl having 5 to 14 ring members or  
 e) heterocycle having 5 to 12 ring members and, in the case of (R 10 ) 2  R 10 , independently of one another, has the meaning of a) to e),  
 
         Z is 1. aryl, where aryl is unsubstituted or substituted, 
 2. heteroaryl having 5 to 14 ring members, where heteroaryl is unsubstituted or substituted,  
 3. heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or substituted, or  
 4. —C(O)—R 11 , where  
 
         R 11  is 1. —O—R 10  or 
 2. —N(R 10 ) 2 , or  
 
         R 7  and R 8  form, together with the nitrogen atom and carbon atom to which they are each bonded, a heterocyclic ring of the formula IIa,  
         
           
             
             
                 
                 
             
           
         
         in which D, Z and R are as defined in formula II, 
 A is a nitrogen atom or the radical —CH 2 —,  
 B is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 —,  
 X is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 —,  
 Y is absent or is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 —, or  
 X and Y together form a phenyl, 1,2-diazine, 1,3-diazine or a 1,4-diazine radical,  
 
         where the ring system formed by N, A, X, Y, B and the carbon atom contains not more than one oxygen atom, X is not an oxygen atom, sulfur or nitrogen atom if A is a nitrogen atom, contains not more than one sulfur atom, contains 1, 2, 3 or 4 nitrogen atoms and where an oxygen and sulfur atom do not occur at the same time, where the ring system formed by N, A, X, Y, B and the carbon atom is unsubstituted or mono- to trisubstituted, independently of one another, by —(C 1 -C 8 )-alkyl, unsubstituted or mono- to disubstituted by 
 1.1. —OH,  
 1.2. (C 1 -C 8 )-alkoxy,  
 1.3. halogen,  
 1.4. —NO 2 ,  
 1.5. —NH 2 ,  
 1.6. —CF 3 ,  
 1.7. —OH,  
 1.8 methylenedioxy,  
 1.9 —C(O)—CH 3 ,  
 1.10. —CH(O),  
 1.11. —CN,  
 1.12. —C(O)—OH,  
 1.13. —C(O)—NH 2 ,  
 1.14. (C 1 -C 4 )-alkoxycarbonyl,  
 1.15. phenyl,  
 1.16. phenoxy,  
 1.17. benzyl,  
 1.18. benzyloxy or  
 1.19. tetrazolyl, or  
 
         R 8  and Z form, together with the carbon atoms to which they each are bonded, a heterocyclic ring of the formula IIc,  
         
           
             
             
                 
                 
             
           
         
         in which D, R and R are as defined in formula II, 
 T is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 —,  
 W is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 —,  
 V is absent or is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 —, or  
 
         T and V or V and W together form a phenyl, 1,2-diazine, 1,3-diazine or a 1,4-diazine radical, where the ring system formed by N, T, V, W and two carbon atoms contains not more than one oxygen atom, not more than one sulfur atom and 1, 2, 3 or 4 nitrogen atoms, where an oxygen atom and sulfur atom do not occur at the same time, and where the ring system formed by N, T, V, W and two carbon atoms is unsubstituted or mono- to trisubstituted, independently of one another, by the substituents defined above under 1.1. to 1.19., and the respective other substituents R 1 , R 2 , R 3  and R 4  independently of one another are 
 1. hydrogen,  
 2. halogen,  
 3. aryl, where aryl is unsubstituted or substituted,  
 4. heteroaryl having 5 to 14 ring members, where heteroaryl is unsubstituted or substituted,  
 5. heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or substituted,  
 6. —(C 1 -C 6 )-alkyl,  
 7. —CN,  
 8. —O—R 10 ,  
 9. —N(R 10 ) 2 ,  
 10. —S(O) x —R 10 , where x is the integer zero, 1 or 2, or  
 11. —CF 3 ,  
 
         R 5  is 1. hydrogen, 
 2. —OH or  
 3. ═O, and  
 
         R 6  is 1. aryl, where aryl is unsubstituted or substituted, 
 2. heteroaryl having 5 to 14 ring members, where heteroaryl is unsubstituted or mono- to trisubstituted, or  
 3. heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or mono-, di- or trisubstituted.  
 
       
     
     
         2 . A compound as claimed in  claim 1 , wherein 
 one of the substituents R 1 , R 2 , R 3  and R 4  is a radical of the formula II, in which 
 D is —C(O)—,  
 R 7  is hydrogen or —(C 1 -C 4 )-alkyl,  
 R is 1. —(C 1 -C 4 )-alkyl, where alkyl is straight-chain or branched and is mono- or disubstituted, independently of one another, by 
 1.1 heteroaryl having 5 to 14 ring members, where heteroaryl is unsubstituted or substituted,  
 1.2 heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or substituted,  
 1.3 —O—R 10 ,  
 1.4 —S(O) x —R 10 , where x is the integer zero, 1 or 2,  
 1.5 —N(R 10 ) 2 ,  
 1.6 radical of the formula  
                     or    
 1.7 radical of the formula  
 or  
 
 2. is the characteristic radical of an amino acid,  
 
 R 9  is 1. R 8 , 
 2. —(C 1 -C 4 )-alkyl, where alkyl is straight-chain or branched and is, independently of one another, mono-, di- or trisubstituted by  
 2.1 aryl, where aryl is unsubstituted or substituted,  
 2.2 halogen,  
 2.3 —CN or  
 2.4 —CF 3  or  
 3. aryl, where aryl is unsubstituted or substituted,  
 
 R 10  is a) hydrogen, 
 b) —(C 1 -C 6 )-alkyl, where alkyl is unsubstituted or mono- to trisubstituted, independently of one another, by 
 1. aryl,  
 2. heteroaryl having 5 to 14 ring members,  
 3. heterocycle having 5 to 12 ring members,  
 4. halogen,  
 5. —N—(C 1 -C 6 ) n -alkyl, where n is the integer zero, 1 or 2 and alkyl is unsubstituted or mono-, di- or trisubstituted, independently of one another, by halogen or by —C(O)—OH, or  
 6. —C(O)—OH,  
 
 c) aryl,  
 d) heteroaryl having 5 to 14 ring members or  
 e) heterocycle having 5 to 12 ring members and, in the case of (R 10 ) 2 , R 10 , independently of one another, has the meaning of a) to e),  
 
 Z is 1. 1,3,4-oxadiazole, where 1,3,4-oxadiazole is unsubstituted or mono- to trisubstituted by —NH 2 , OH or —(C 1 -C 4 )-alkyl or 
 2. —(O)—R 10 , in which  
 
 R 11  is 1. —O—R 10  or 
 2. —N(R 10 ) 2 , or  
 
 R 7  and R 8  form, together with the nitrogen atom and carbon atom to which they are each bonded, a ring of the formula IIa selected from the group consisting of pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, tetrazole, 1,2,3,5-oxathiadiazole 2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles, which are unsubstituted or substituted by F, —CN, —CF 3  or C(O)—O—(C 1 -C 4 )-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, isoxazoles, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine, pteridine, indole, isoquinoline, tetrahydroquinoline and tetrahydroisoquinoline, or  
 R 8  and Z form, together with the carbon atoms to which they are each bonded, a ring of the formula IIc selected from the group consisting of pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, pyrazoline, phthalazine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, 1,3,4-oxadiazole, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, tetrazole, 1,2,3,5-oxathiadiazole 2-oxides, oxadiazolones, isoxazolones, triazolones, oxadiazolidindiones, triazoles, which are unsubstituted or substituted by F, —CN, —CF 3  or —C(O)—O—(C 1 -C 4 )-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, quinazoline, quinoxaline, purine, indole, pteridine, tetrahydroquinoline, tetrahydroisoquinoline and isoquinoline, and  
   the other substituents R 1 , R 2 , R 3  and R 4  in each case independently of one another are 
 1. hydrogen,  
 2. halogen,  
 3. aryl, where aryl is unsubstituted or substituted,  
 4. heteroaryl having 5 to 14 ring members, where heteroaryl is unsubstituted or substituted,  
 5. heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or substituted, or  
 6. —(C 1 -C 6 )-alkyl  
 7. —CN,  
 8. —CF 3 ,  
 9. —OR 10 ,  
 10. —N(R 10 ) 2  or  
 11. —S(O) x —R 10 , where x is the integer zero, 1 or 2,  
   R 5  is hydrogen and    R 6  is 1. phenyl, mono- or disubstituted, independently of one another, by 
 1.1 —CN,  
 1.2 —CF 3  or  
 1.3 halogen,  
 1.4 —O—R 10 ,  
 1.5 —N(R 10 ) 2 ,  
 1.6 —NH—C(O)—R 11 ,  
 1.7 —S(O) x —R 10 , where x is the integer zero, 1 or 2,  
 1.8 —C(O)—R 11  or  
 1.9 —(C 1 -C 4 )-alkyl-NH 2 ,  
 2. heteroaryl having 5 to 14 ring members, where heteroaryl is unsubstituted or mono-, di- or trisubstituted, independently of one another, by the substituents defined above under 1.1 to 1.9 or  
 3. heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or mono-, di- or trisubstituted, independently of one another, by the substituents defined above under 1.1 to 1.9.  
   
     
     
         3 . A compound as claimed in  claim 1 , wherein 
 one of the substituents R 1 , R 2 , R 3  and R 4  is a radical of the formula II, in which 
 D is —C(O)—,  
 R 7  is hydrogen,  
 Z is —C(O)—OH or —C(O)—NH 2 , 
 R 8  is 1. —(C 1 -C 4 )-alkyl, where alkyl is straight-chain or branched and is mono- or disubstituted, independently of one another, by  
 1.1 —S(O)—R 10 , where R 10  is as defined below,  
 1.2 —N(R 10 ) 2 , where R 10  is as defined below, or  
 1.3 pyrrole or  
 
  2. is the characteristic radical of an amino acid,  
 R 10  is a) hydrogen, 
 b) —(C 1 -C 6 )-alkyl, where alkyl is unsubstituted or mono- to trisubstituted, independently of one another, by halogen,  
 c) phenyl, where phenyl is unsubstituted or mono- to trisubstituted, independently of one another, by halogen or —(C 1 -C 4 )-alkyl,  
 
 the other substituents R 1 , R 2 , R 3  and R 4  in each case are hydrogen, 
 R 5  is hydrogen,  
 R 6  is phenyl or pyridine, and  
 R 7  is 1. hydrogen, 
 2. —(C 1 -C 4 )-alkyl, where alkyl is straight-chain or branched and, independently of one another, mono-, di- or trisubstituted by —C(O)—OH, —OH or —C(O)—NH 2 , or  
 3. phenyl, where phenyl is unsubstituted or mono- to trisubstituted, independently of one another, by halogen or —(C 1 -C 4 )-alkyl.  
 
 
   
     
     
         4 . A process for preparing a compound as claimed in  claim 1 , which comprises 
 a) reacting a compound of the formula IV,                        in which Pg is a suitable protective group, an amide group or a hydroxyl group and Z, R 7  and R 8  are as defined in formula I, with an acyl chloride or an activated ester of the compound of the formula III,                          where D1 is —COOH or sulfonyl halogen and R 5 , R 6  and R 9  are as defined in formula I, in the presence of a base or, if appropriate, of a dehydrating agent in solution and, after removal of the protective group, converting into a compound of the formula I, or      b) coupling a compound of the formula IVa,                        in which R and R are as defined in formula I and E is an N-amino protective group, through its carbonyl group and via an intermediate chain L to a polymeric resin of the formula PS, to result in a compound of the formula V,                          selectively removing the protective group E from the compound of formula V, and reacting the unprotected compound with a compound of the formula III, where R 5 , R 6  and R 9  are as defined in formula I, in the presence of a base or, if appropriate, of a dehydrating agent to give a compound of the formula VI                          and converting the compound of the formula VI, after cleavage from the support material, into a compound of the formula I, or      c) converting a compound of the formula I into a physiologically acceptable salt.    
     
     
         5 . A pharmaceutical composition comprising an efficacious amount of at least one compound as claimed in  claim 1  together with a pharmaceutically suitable and physiologically acceptable excipient.  
     
     
         6 . A method for the prophylaxis or therapy of a disorder in the course of which an increased activity of NFκB is involved, which comprises administering to a host in need of the prophylaxis or therapy an effective amount of a compound as claimed in  claim 1 .  
     
     
         7 . A method as claimed in  claim 6 , wherein the disorder is joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, osteoarthritis, acute synovitis, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, endotoxaemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, gout, toxic shock syndrome, chronic pulmonary inflammatory diseases including asthma and adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft versus host reaction, allograft rejection, leprosy, infections for example viral infections, for example HIV, cytomegalovirus, influenza, adenovirus and the Herpes group of viruses, parasitic infections, for example malaria such as cerebral malaria, and yeast and fungal infections, for example fungal meningitis; fever and myalgias due to infection; acquired immune deficiency syndrome (AIDS); AIDS related complex; cachexia secondary to infection or malignancy; cachexia secondary to acquired immune deficiency syndrome or to cancer; keloid and scar tissue formation; pyresis; diabetes; and inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; diseases of or injury to the brain in which over-expression of TNFα has been implicated such as multiple sclerosis, and head trauma; or psoriasis, Alzheimer's disease, carcinomatous disorders (potentiation of cytotoxic therapies), cardiac infarct, chronic obstructive pulmonary disease and acute respiratory distress syndrome.  
     
     
         8 . A process as claimed in  claim 4 , wherein Pg is a methyl ester.