Novel1,2-diphenylethene derivatives for treatment of immune diseases

Abstract

The invention provides novel 1,2-diphenylethene derivatives and pharmaceutically acceptable salts thereof, the process for production of these compounds and their pharmaceutical composition and the use of these compounds as modulators of T-cells, neutrophils, macrophages and their associated cytokines as agents for treating immune, inflammatory and auto-immune diseases.

1 . A compound of formula I, or salt thereof  
       
         
           
           
               
               
           
         
         wherein R 1  is selected from 
 a). H,  
 b). Unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl,  
 c). Halo,  
 d). CN,  
 e). COOR 6 ,  
 f). NR 7 R 8 ′ 
 g). S(O) 2 N R 7 R 8 ,  
 h). COR 9 ,  
 i). OR 10 ,  
 j). S(O) n R 11 , n=0-2,  
 k). Substituted or unsubstituted cyclic or heterocyclic group;  
 
         R 2  and R 3  are independently selected from a group consisting of 
 a). H,  
 b). Unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl,  
 c). Halo,  
 d). CN,  
 e). COOR 6 ,  
 f). NR 7 R 8 ,  
 g). S(O) 2 N R 7 R 8 ,  
 h). COR 9 ,  
 i). OR 10 ,  
 j). S(O) n R 11 , n=0-2,  
 k). Substituted or unsubstituted cyclic or heterocyclic group;  
 
         R 4  and R 5  are independently each selected from the group consisting of 
 a). H,  
 b). Unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl,  
 c). Acyl;  
 
         R 6  is selected from 
 a). H,  
 b). Unsubstituted or subustituted alkyl, cycloalkyl, aryl or aralkyl;  
 
         R 7  and R 8  are independently selected from a group consisting of 
 a). H,  
 b). Unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl;  
 
         R 9  is selected from 
 a). H,  
 b). Unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl,  
 c). NR 7 R 8 ;  
 
         R 10  is selected from 
 a). H,  
 b). Unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl,  
 c). Acyl;  
 
         R 11  is selected from 
 a). H,  
 b). Unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl;  
 
         Ar is selected from 
 a). Unsubstituted, mono or multi-substituted phenyl with the proviso that R 2  and R 3  cannot be H simultaneously.  
 b). Unsubstituted, mono or multi-substituted five-member heterocyclic ring containing O, S and/or N,  
 c). Unsubstituted, mono or multi-substituted six-member heterocyclic ring containing O, S and/or N;  
 
         The configuration of the double bond is Z or E.  
       
     
     
         2 . A compound of  claim 1  wherein R 1  is selected from unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl;  
     
     
         3 . A compound of  claim 1  wherein R 2  and R 3  are independently selected from a group consisting of: a). H, b). Unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl;  
     
     
         4 . A compound of  claim 3  wherein R 1  is selected from unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl;  
     
     
         5 . A compound of  claim 1  wherein R 2  and R 3  are independently selected from a group consisting of: a). CN, b). COOR 6 , c). COR 9 ,  
     
     
         6 . A compound of  claim 5  wherein R 1  is selected from unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl;  
     
     
         7 . A compound of  claim 2 ,  4 , or  6  wherein R 1  is selected from unsubstituted or substituted alkyl,  
     
     
         8 . A compound of  claim 7  wherein R 1  is isopropyl;  
     
     
         9 . A compound of  claim 1  wherein Ar is selected from a). unsubstituted, mono or multi-substituted five-member heterocyclic ring containing O, S and/or N, b). unsubstituted, mono or multi-substituted six-member heterocyclic ring containing O, S and/or N.  
     
     
         10 . A compound of  claim 13  wherein Ar is thiophene or furan.  
     
     
         11 . A compound of formula I selected from: 
 5-(1-Benzyl-2-phenylethenyl)-2-i-propyl-1 ,3-benzenediol;    5-[1-(4-Methylbenzyl)-2-(4-methylphenyl)ethenyl]-2-i-propyl-1,3-benzenediol;    5-[1-(3-Fluorobenzyl)-2-(3-fluorophenyl)ethenyl]-2-i-propyl-1,3-benzenediol;    5-[1-(3,5-Difluorobenzyl)-2-(3,5-difluorophenyl)ethenyl]-2-i-propyl-1,3-20-benzenediol;    5-(1-Methyl-2-phenylethenyl)-2-i-propyl-1,3-benzenediol;    2-(3,5-Dimethoxy-4-i-propylphenyl)-3-phenylpropenylnitrile;    2-(3,5-Dihydroxy-4-i-propylphenyl)-3-phenylpropenylnitrile;    5-(2,2-Diphenylethenyl)-2-i-propyl-1,3-benzenediol;    3-(3,5-Dimethoxy-4-i-propylphenyl)-2-phenylpropenylnitrile;    3-(3,5-Dihydroxy-4-i-propylphenyl)-2-phenylpropenylnitrile;    1-(3,5-Dimethoxy-4-i-propylphenyl)-2-phenylpropene;    5-(2-Methyl-2-phenylethenyl)-2-i-propyl-1,3-benzenediol;    2-[2-(3,5-Dimethoxy-4-i-propylphenyl)ethenyl]pyridine;    2-[2-(3,5-Dihydroxy-4-i-propylphenyl)ethenyl]pyridine hydrochloride;    2-[2-(3,5-Dimethoxy-4-i-propylphenyl)ethenyl]thiophene;    2-i-Propyl-5-(2-thiophene-2-ylethenyl)-1 ,3-benzenediol;    2-[2-(3.5-Dimethoxy-4-i-propylphenyl)ethenyl]furan;    5-(2-Methyl-2-phenylethenyl)-2-i-propyl-1,3-benzenediol diacetate;    2-(3,5-Dihydroxy4-i-propylphenyl)-3-phenylpropenoic acid;    3-(3,5-Dihydroxy-4-i-propylphenyl)-2-phenylpropenoic acid.    
     
     
         12 . A pharmaceutical composition comprising a compound of formula I as defined in  claim 1  or salt thereof and a pharmaceutically acceptable carrier or excipient  
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 11  or salt thereof and a pharmaceutically acceptable carrier or excipient  
     
     
         14 . A compound of formula I as defined in  claim 1  for use in therapy.  
     
     
         15 . A compound of  claim 11  for use in therapy.  
     
     
         16 . The use of a compound of formula I of  claim 1  or  claim 11  in the manufacture of a medicament for treatment of a disorder comprising modulation of T-cells, neutrophils, macrophages and the associated cytokines.  
     
     
         17 . The use of  claim 16  for treatment of a disorder comprising, immune, inflammatory and auto-immune conditions.  
     
     
         18 . The method for treating immune, inflammatory and auto-immune conditions in mammals comprising administering to a mammal so afflicted an effective amount of a compound of formula I of  claim 1  or  claim 11  or a salt thereof.