2-Mercapto-4,5-Diarylimidazole Derivatives and the use thereof as Cyclooxygenase Inhibitors

Abstract

The invention relates to the 2-mercapto-4,5-diarylimidazole derivatives of formula (I), wherein R 1 , R 2 , R 3 and R 4 are defined as in the description. The inventive compounds have an immunomodulatory and cyclooxygenase-inhibiting activity and are therefore suitable for the treatment of disease that are associated with a disturbed immune system.

1 . A compound of the formula I  
     
       
         
         
             
             
         
       
       in which 
 R 1  is selected from:  
 a) CONR 5 R 6 , in which R 5  and R 6 , together with the nitrogen atom to which they are bonded, form a saturated heterocyclic radical having 5 or 6 ring atoms and one or two heteroatoms which independently of one another are selected from N and O,  
 b) C 1 -C 6 -alkylene-R 7 , where R 7  is an aromatic heterocyclic radical having 5 or 6 ring atoms and one or two heteroatoms, which independently of one another are selected from N, S and O, where the heterocyclic radical can optionally be fused to a benzene ring, or  
 c) C 1 -C 6 -alkylene-NR 10 -CO-R 11 ;  
 R 10  is H or C 1 -C 6 -alkyl;  
 R 11  is  
 a) CH═CH-phenyl, or  
 b) an aromatic, heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms, which independently of one another are selected from N, O or S;  
 R 2  is H, C 1 -C 6 -alkyl or (CH 2 ) o COOH;  
 R 3  and R 4 , which can be identical or different, are H, OH, OC 1 -C 6 -alkyl, halogen or C 1 -C 6 -alkyl which is substituted by 1, 2 or 3 halogen atoms, where at least one of the radicals R 3  and R 4  is OH or OC 1 -C 6 -alkyl;  
 n is 0, 1 or 2; and  
 o is 0, 1, 2, 3 or 4;  
 
       and the optical isomers and physiologically tolerable salts thereof.  
     
   
   
       2 . A compound as claimed in  claim 1 , where R 1  is selected from: 
 a) CONR 5 R 6 , in which R 5  and R 6 , together with the nitrogen atom to which they are bonded, form a saturated heterocyclic radical having 5 or 6 ring atoms and one or two heteroatoms which independently of one another are selected from N and O, or    b) C 1 -C 6 -alkylene-NR 10 -CO-R 11 ;    R 11  is CH═CH-phenyl or an aromatic, heterocyclic radical having 5 ring atoms and 1 or 2 heteroatoms, which independently of one another are selected from N, O or S;    and R 2 , R 3 , R 4 , and R 10  have the meaning as indicated in  claim 1 .    
   
   
       3 . A compound as claimed in  claim 1 , where both radicals R 3  and R 4  are a C 1 -C 6 -alkoxy group.  
   
   
       4 . A compound as claimed in  claim 1 , where RI is CONR 5 R 6  and R 5  and R 6  have the meaning indicated in  claim 1 .  
   
   
       5 . A compound as claimed in  claim 1 , where R 1  is C 1 -C 6 -alkylene-R 7 , in which R 7  is pyridyl, quinolyl, or benzimidazolyl.  
   
   
       6 . A compound as claimed in  claim 5 , in which R 7  is 3-pyridyl or 4-pyridyl.  
   
   
       7 . A compound as claimed in  claim 1 , where R 1  is C 1 -C 6 -alkylene-R 7 , in which R 7  is an aromatic heterocyclic radical having 5 or 6 ring atoms and one or two heteroatoms, which independently of one another are selected from N, S and O.  
   
   
       8 . A compound as claimed in  claim 7 , in which R 2  is (CH 2 ) o COOH and o is 1, 2, 3, or 4.  
   
   
       9 . A compound as claimed in  claim 1 , where R 1  is C 1 -C 6 -alkylene-NR 10 —CO—R 11 , in which R 10  is H or C 1 -C 4 -alkyl and R 11  is —CH═CH-phenyl.  
   
   
       10 . A compound as claimed in  claim 9 , where R 1  is C 1 -, C 2 - or C 3 -alkylene-NR 10 —CO—R 11 , in which R 10  and R 11  have the meanings indicated in  claim 9 .  
   
   
       11 . A compound as claimed in  claim 1 , where R 1  is C 1 -C 6 -alkylene-NR 10 —CO—R 11 , in which R 11  is an aromatic, heterocyclic radical having 5 ring atoms and 1 or 2 heteroatoms, which independently of one another are selected from N, O or S, and R 10  is H or C 1 -C 6 -alkyl.  
   
   
       12 . A compound as claimed in  claim 11 , where R 11  is a furyl or thienyl radical.  
   
   
       13 . A compound as claimed in  claim 1 , where R 1  is C 1 -C 6 -alkylene-R 7 , in which R 7  is 2-pyridyl.  
   
   
       14 . A compound 2-[4-(4-chlorophenyl)-5-(4-methoxyphenyl)-2-(pyridylmethylsulfanyl) -1H-imidazol-1-yl]acetic acid of the following formula  
     
       
         
         
             
             
         
       
     
   
   
       15 . A pharmaceutical or cosmetic composition comprising at least one compound as claimed in  claim 1 , together with one or more pharmaceutically acceptable vehicles or additives.  
   
   
       16 . A method for treating a disease that is connected with an immune system disorder, comprising administering a pharmaceutical composition comprising at least one compound as claimed in  claim 1 .  
   
   
       17 . A method for treating inflammation, comprising topically applying a pharmaceutical composition comprising at least one compound as claimed in  claim 1 .  
   
   
       18 . A procedure for the treatment of diseases which are connected with a disorder of the immune system, where an amount of a compound as claimed in  claim 1  having an immunomodulating or cyclooxygenase-inhibiting action is administered to a person in need of such treatment.  
   
   
       19 . A method for treating a disease that is connected with an immune system disorder, comprising administering a pharmaceutical composition comprising at least one compound as claimed in  claim 1 , wherein said disease is selected from the group consisting of premature labor, colon carcinoma, Alzheimer's disease, rheumatoid arthritis, gout, septic shock, osteoporosis, neuropathic pain, alopecia, psoriasis, acute pancreatitis, rejection reactions in allogenic transplants, allergically caused pneumonia, arteriosclerosis, multiple sclerosis, cachexia, inflammatory bowel disease, adenomatous polyposis, inhibition of angiogenesis in connection with oncoses, contact eczema, and erythema.  
   
   
       20 . A procedure for the treatment of diseases which are connected with a disorder of the immune system, where an amount of a compound as claimed in  claim 1  having an immunomodulating or cyclooxygenase-inhibiting action is administered to a person who need treatment of this type, and wherein said disease is selected from the group consisting of premature labor, colon carcinoma, Alzheimer's disease, rheumatoid arthritis, gout, septic shock, osteoporosis, neuropathic pain, alopecia, psoriasis, acute pancreatitis, rejection reactions in allogenic transplants, allergically caused pneumonia, arteriosclerosis, multiple sclerosis, cachexia, inflammatory bowel disease, adenomatous polyposis, inhibition of angiogenesis in connection with oncoses, contact eczema, and erythema.