Novel galactoside inhibitors of galectins

Abstract

Compounds having an effect as i.a. galectin inhibitors, to the use of said compounds as a medicament, as well as for the manufacture of a medicament for treatment of disorders relating to the binding of galectin to receptors in a mammal, wherein the galectin is preferably a galectin-3. The novel compounds are defined by the general formula:

1 - 31 . (canceled) 
     
     
         32 . A method for treatment of a galectin protein disorder in a mammal, wherein said disorder is selected from the group consisting of inflammation, fibrosis, septic shock, cancer, autoimmune diseases, rheumatoid arthritis and multiple sclerosis, the method comprising administering to said mammal a therapeutically effective amount of a compound of the general formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 the configuration of the pyranose ring is D-galacto; 
 X is selected from the group consisting of O, S, and SO; 
 Y and Z are independently selected from being CONH or a 1H-1,2,3-triazole ring; 
 R 1  and R 2  are independently selected from the group consisting of:
 a) an alkyl group of at least 4 carbons, an alkenyl group of at least 4 carbons, an alkynyl group of at least 4 carbons; 
 b) a carbamoyl group, a carbamoyl group substituted with an alkyl group, a carbamoyl group substituted with an alkenyl group, a carbamoyl group substituted with an alkynyl group, a carbamoyl group substituted with an aryl group, a carbamoyl group substituted with a substituted alkyl group, and a carbamoyl group substituted with a substituted aryl group; 
 c) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkyl group, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one trifluoromethyl group, a phenyl group substituted with at least one trifluoromethoxy group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group, and a phenyl group substituted with at least one substituted carbonyl group; 
 d) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkyl group, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group, and a naphthyl group substituted with at least one substituted carbonyl group; 
 e) a heteroaryl group, a heteroaryl group substituted with at least one carboxy group, a heteroaryl group substituted with at least one halogen, a heteroaryl group substituted with at least one alkoxy group, a heteroaryl group substituted with at least one sulfo group, a heteroaryl group substituted with at least one arylamino group, a heteroaryl group substituted with at least one hydroxy group, a heteroaryl group substituted with at least one halogen, a heteroaryl group substituted with at least one carbonyl group, and a heteroaryl group substituted with at least one substituted carbonyl group; and 
 f) a thienyl group, a thienyl group substituted with at least one carboxy group, a thienyl group substituted with at least one halogen, a thienyl thienyl group substituted with at least one alkoxy group, a thienyl group substituted with at least one sulfo group, a thienyl group substituted with at least one arylamino group, a thienyl group substituted with at least one hydroxy group, a thienyl group substituted with at least one halogen, a thienyl group substituted with at least one carbonyl group, and a thienyl group substituted with at least one substituted carbonyl group. 
 
 
     
     
         33 . The method according to  claim 32 , Y is selected from CONH and a 1H-1,2,3-triazole ring. 
     
     
         34 . The method according to  claim 33 , wherein the CONH group is linked via the N atom to the pyranose ring. 
     
     
         35 . The method according to  claim 33 , the 1H-1,2,3-triazole ring is linked via the N1 atom to the pyranose ring. 
     
     
         36 . The method according to  claim 32 , wherein Z is selected from CONH and a 1H-1,2,3-triazole ring. 
     
     
         37 . The method according to  claim 36 , wherein the CONH group is linked via the N atom to the pyranose ring. 
     
     
         38 . The method according to  claim 36 , wherein the 1H-1,2,3-triazole ring is linked via the N1 atom to the pyranose ring. 
     
     
         39 . The method according to  claim 32 , wherein R 1  is linked to the C4 atom of the 1H-1,2,3-triazole ring. 
     
     
         40 . The method according to  claim 32 , R 2  is linked to the C4 atom of the 1H-1,2,3-triazole ring. 
     
     
         41 . The method according to  claim 32 , wherein R 1  and R 2  are independently selected from the group consisting of a carbamoyl group, an alkylated carbamoyl group, an alkenylated carbamoyl group, an arylated carbamoyl group, a phenyl group, a substituted phenyl group, a halogenated phenyl group, a fluorinated phenyl group, a chlorinated phenyl group, a brominated phenyl group, an alkylated phenyl group, an alkenylated phenyl group, a trifluoromethylated phenyl group, a methoxylated phenyl group, a trifluoromethoxylated phenyl group, a naphthyl group, a substituted naphthyl group, a heteroaryl group, a substituted heteroaryl group, a thienyl group, and a substituted thienyl group. 
     
     
         42 . The method according to  claim 32 , wherein) R 1  is an alkylated carbamoyl group, a fluorinated phenyl group, or a thienyl group. 
     
     
         43 . The method according to  claim 32 , wherein R 2  is an alkylated carbamoyl group, a fluorinated phenyl group, or a thienyl group. 
     
     
         44 . The method according to  claim 32 , X is O or S. 
     
     
         45 . The method according to  claim 32 , wherein said compound is selected from the group consisting of:
 ((1R,2R,3 S)-2-hydroxy-3-(4-(N-(1-propyl)-carbamoyl)-1H-1,2,3-triazol-1-yl)cyclohexyl) 3-deoxy-β-(4-(N-(1-propyl)-carbamoyl)-1H-1,2,3-triazol-1-yl))-β-D-galactopyranoside,   ((1R,2R,3 S)-2-hydroxy-3-(4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl)-cyclohexyl) 3-deoxy-3-(4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl)-1-thio-β-D-galactopyranoside,   ((1R,2R,3 S)-2-hydroxy-3-(4-β-fluorophenyl)-1H-1,2,3-triazol-1-yl)-cyclohexyl) 3-deoxy-3-(4-β-fluorophenyl)-1H-1,2,3-triazol-1-yl)-1-thio-β-D-galactopyranoside,   ((1R,2R,3 S)-2-hydroxy-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)-cyclohexyl) 3-deoxy-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)-1-thio-β-D-galactopyranoside,   (1R,2R,3 S)-2-hydroxy-3-(4-(3-thienyl)-1H-1,2,3-triazol-1-yl)-cyclohexyl) 3-deoxy-3-(4-(3-thienyl)-1H-1,2,3-triazol-1-yl)-1-thio-β-D-galactopyranoside,   (1R,2R,3S)-2-hydroxy-3-(4-(N-(1-propyl)-carbamoyl)-1H-1,2,3-triazol-1-yl)-cyclohexyl) 3-deoxy-3-(4-(N-(1-propyl)-carbamoyl)-1H-1,2,3-triazol-1-yl)-1-thio-β-D-galactopyranoside, and   (1R,2R,3S)-2-hydroxy-3-(4-chlorobenzamido)-cyclohexyl) 3-deoxy-3-(4-chlorobenzamido)-1-thio-β-D-galactopyranoside.   
     
     
         46 . The method according to  claim 32 , wherein the compound of the general formula (I) is adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract. 
     
     
         47 . The method according to  claim 46 , wherein the compound of the general formula (I) is in the form of a tablet, a capsule, a powder, a solution, a transdermal patch or a suppository.