Core 2 GlcNAc-T inhibitors

Abstract

A method of treating a subject in need of therapy for a condition involving detrimental activity of the enzyme core 2 GlcNAc-T is provided, comprising administration of a therapeutically effective amount of an inhibitor of core 2 GlcNAc-T of formula I to a patient in need thereof wherein: R 1 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 -alkoxy-C 1-6 -alkyl; R 2 is H, —OH or C 1-6 alkoxy; S 1 and S 2 are independently selected saccharide moieties; and Z is a steroid moiety; or a pharmaceutically acceptable salt, ether or ester thereof.

1 . A method of treating a subject in need of therapy for a condition involving detrimental activity of the enzyme core 2 GlcNAc-T comprising administration of a therapeutically effective amount of an inhibitor of core 2 GlcNAc-T of formula I to a patient in need thereof  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is H, C 1-6  alkyl, C 1-6  hydroxyalkyl, C 1-6  alkoxy or C 1-6 -alkoxy-C 1-6 -alkyl;  
 R 2  is H, —OH or C 1-6  alkoxy;  
 Sac 1  and Sac 2  are independently selected saccharide moieties; and  
 Z is a steroid moiety;  
 or a pharmaceutically acceptable salt, ether or ester thereof.  
 
     
     
         2 . A method according to claims  1  in which R 1  is —H, —CH 3  or —CH 2 OH.  
     
     
         3 . A method according to  claim 1  in which R 1  is —CH 2 OH.  
     
     
         4 . A method according to  claim 1  in which R 1  is —CH 2 OH and the ring is a glucose moiety.  
     
     
         5 . A method according to  claim 1  in which R 2  is —OH.  
     
     
         6 . A method according to  claim 1  in which Sac 1  and Sac 2  are monosaccharides.  
     
     
         7 . A method according to  claim 1  in which Sac 1  is a pentose or an aldohexose  
     
     
         8 . A method according to  claim 1  in which Sac 1  is an aldohexose  
     
     
         9 . A method according to  claim 1  in which Sac 1  is glucose.  
     
     
         10 . A method according to  claim 1  in which Sac 2  is selected from the group consisting of a tetrose a pentose and a hexose moiety.  
     
     
         11 . A method according to claims  1  in which Sac 2  is rhamnose.  
     
     
         12 . A method according to  claim 1  in which the compound of the formula I is  
       
         
           
           
               
               
           
         
       
     
     
         13 . A method according to claims  1  in which the steroid moiety Z is a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 3 , R 10  and R 18  are independently selected from H and —OH;  
 R 4  and R 25  are independently selected from C 1-6  alkyl;  
 R 5 , R 7  and R 12  are independently selected from H and C 1-6 alkyl;  
 R 6  is H or —OH or the H normally also present is absent and R 6  is ═O;  
 R 8  is H, —OH or C 1-6  acyl or a group selected from VII a or VII b.  
                     
 R 9  is H.  
 R 11  is H, C 1-6  alkyl or —OH or R 9  and R 11  taken together form a —CH 2 —CH 2 -group;  
 R 13  is H, C 1-6  alkyl or C 1-6  hydroxyalkyl; preferably R 13  is H, —CH 2 OH, or —CH 3 .  
 R 26  is C 1-6  hydroxyalkyl;  
 R 27  is C 1-6  alkyl, C 1-6  hydroxyalkyl or C 1-6  alkyl substituted by S 4 .  
 R 28  is C 1-8  alkyl, C 2-8  alkenyl or C 2-8  alkynyl;  
 Sac 4  is a saccharide; and  
    Represents either a single bond or a double bond.  
 
     
     
         14 . A method according to  claim 13  in which the steroid moiety Z incorporates a further group selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       Wherein: 
 R 20  is H or —OH;  
 R 14 , R 14 , R 23  and R 29  are independently selected from C 1-6  alkyl;  
 R 15  is H or —OH;  
 R 16  is H, —OH or C 1-6  alkoxy or R 15  and R 16  taken together represent the second bond of a double bond joining adjacent carbon atoms;  
 R 17  is C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or a C 1-6  alkyl group substituted by one or more groups selected from the group consisting of —OH, C 1-6  alkoxy and Sac 3 ;  
 R 21  is C 1-6  alkyl, C 1-6  hydroxyalkyl or ═CH 2 ;  
 R 22  is —OH;  
 R 24  is C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl;  
 R 30  is C 1-6  hydroxyalkyl or C 1-6  alkyl substituted by Sac 5 ;  
 R 31  is C 1-6  alkyl;  
 Sac 3  and Sac 5  are independently selected saccharide moieties; and  
 X is either O or NH.  
 
     
     
         15 . A method according to claims  14  in which R 17  is C 2-6  alkenyl or a C 1-6  alkyl group substituted by one or more groups selected from the group consisting of —OH, —OCH 3  and Sac.  
     
     
         16 . A method according to  claim 14  in which R 17  is selected from the group comprising 3-methyl but-2-eneyl, 2-methyl-prop-2-enyl, 3-methylbutanyl substituted at the 4-position by Sac 3 , 1-hydroxy-3-methylbutanyl substituted at the 4-position by Sac 3  or 1-methoxy-3-methylbutanyl substituted at the 4-position by Sac 3 ;  
     
     
         17 . A method according to  claim 14  in which R 21  is —CH 3 , —CH 2 OH or ═CH 2 .  
     
     
         18 . A method according to  claim 14  in which R 24  is C 2-6  alkenyl.  
     
     
         19 . A method according to claims  14  in which R 27  is —CH 3  or —CH 2 -Sac 4 .  
     
     
         20 . A method according to  claim 14  in which S 4  is glucose.  
     
     
         21 . A method according to  claim 14  in which R 28  is C 1-8  alkyl or C 2-8  alkenyl.  
     
     
         22 . A method according to  claim 14  in which R 28  is 3-ethyl-4-methyl-pentanyl or 5-methyl-hex-4-enyl;.  
     
     
         23 . A method according to  claim 14  in which R 30  is —CH 2 -Sac 5 .  
     
     
         24 . A method according to  claim 14  in which Sac 5  is glucose.  
     
     
         25 . A method according to  claim 14  in which X is O.  
     
     
         26 . A method according to  claim 1  in which the compound is selected from the group consisting of: 
 Protogracillin protoneogracillin methylprotogracillin methylprotoneogracillin, pseudoprotogracillin, dracenoside Q, dioscoreside E dracenoside P tuberoside C, icogenin, gracillin, collettiside IV, 17-OH gracillin, dracaenoside H dracaenoside L, dracaenoside I, lilioglycoside H, lilioglycoside I, dracaenoside D, neoalsoside A, neoalsoside C, hoduloside V, Lotoside II, compound 17, compound 21 and compound 25.    
     
     
         27 . A method according to  claim 1  in which the condition to be treated is selected form the group consisting of vascular diseases, autoimmune and inflammatory conditions.  
     
     
         28 . A method according to  claim 1  in which the condition to be treated is selected from the group consisting of: 
 multiple sclerosis, myopathy, retinopathy, nephropathy, atherosclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, transplant rejection, ischemia reperfusion injury, restenosis, ileitis, Crohn's disease, thrombosis, cholitis, lupus, frost bite injury, acute leukocyte mediated lung injury, traumatic shock, septic shock, nephritis, psoriasis, cholicytitis, cirrhosis, diverticulitis, fulminant hepatitis, gastritis, gastric and duodenal ulcers, hepatorenal syndrome, irritable bowel syndrome, jaundice, pancreatitis, ulcerative cholitis, Wiskott-Aldrich syndrome T-cell activation, AIDS, infection with viruses, bacteria, protozoa and parasites adapted to use core 2 derived glycans, cancer and cancer metastasis.