Core 2 GlcNAc-T inhibitors III

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 the formula I to a patient in need thereof wherein R 1 is H, —OH, C 1-6 alkoxy, —NR 5 R 6 , or Sac 1; R 2 is H, —OH, C 1-6 alkoxy or Sac 2; R 3 is H, —OH, C 1-6 alkoxy or Sac 3; R 4 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl; R 5 is H, C 1-6 alkyl or C 1-6 acyl; R 6 is H, C 1-6 alkyl or C 1-6 acyl; Sac 1 Sac 2 and Sac 3 are independently selected saccharide moieties; and Z is a steroid moiety; or a pharmaceutically acceptable salt, ether or ester form thereof

1 - 27 . (canceled) 
   
   
       28 . A food or beverage product into which has been incorporated a compound of the formula (I) isolated to at least 1% purity 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is H, —OH, C 1-6  alkoxy, —NR 5 R 6 , or Sac 1; 
       R 2  is H, —OH, C 1-6  alkoxy or Sac 2; 
       R 3  is H, —OH, C 1-6  alkoxy or Sac 3; 
       R 4  is H, C 1-6  alkyl, C 1-6  hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl; 
       R 5  is H, C 1-6  alkyl or C 1-6  acyl; 
       R 6  is H, C 1-6  alkyl or C 1-6  acyl; 
       Sac 1 Sac 2 and Sac 3 are independently selected saccharide moieties; and 
       Z is a steroid moiety; 
       or a pharmaceutically acceptable salt, ether or ester form thereof. 
     
   
   
       29 . A food or beverage product according to  claim 28  in which R 1  is —OH, or Sac 1. 
   
   
       30 . A food or beverage product according to  claim 28  in which Sac 1 is selected from a pentose, a deoxy-aldohexose and an aldohexose. 
   
   
       31 . A food or beverage product according to  claim 28  in which R 2  is —OH. 
   
   
       32 . A food or beverage product according to  claim 28  in which R 3  is Sac 3. 
   
   
       33 . A food or beverage product according to  claim 28  in which Sac 3 is selected from a pentose, a deoxy-aldohexose and an aldohexose. 
   
   
       34 . A food or beverage product according to  claim 28  in which Sac 3 is selected from a pentose, and an aldohexose. 
   
   
       35 . A food or beverage product according to  claim 28  in which Sac 3 is an aldohexose. 
   
   
       36 . A food or beverage product according to  claim 28  in which Sac 3 is glucose. 
   
   
       37 . A food or beverage product according to  claim 28  in which R 1  is —OH, C 1-6  alkoxy, —NR 5 R 6 ; R 2  is Sac 2 and R 3  is —OH. 
   
   
       38 . A food or beverage product according to  claim 37  in which R 1  —NR 5 R 6 . 
   
   
       39 . A food or beverage product according to  claim 28  in which R 4  is H, —CH 2 OH or —CH 3 . 
   
   
       40 . A food or beverage product according to  claim 28  in which R 5  is H or —CH 3 . 
   
   
       41 . A food or beverage product according to  claim 28  in which R 6  is H or —COCH 3 . 
   
   
       42 . A food or beverage product according to  claim 28  in which the steroid group, Z, is of the formula IV: 
     
       
         
         
             
             
         
       
       wherein: 
       R 7  and R 14  are independently selected from H and —OH; 
       R 8  is C 1-6  alkyl; 
       R 9 , R 11 , R 16  are independently selected from H and C 1-6  alkyl; 
       R 10  is H or —OH or the H normally also present is absent and R 10  is ═O; 
       R 12  is H, —OH or C 1-6 acyl or a group selected from VII a or VII b; 
     
     
       
         
         
             
             
         
       
       R 13  is H; 
       R 15  is H, —OH or C 1-6  alkyl or R 13  and R 15  taken together form a —CH 2 —CH 2 — group; 
       R 17  is H, C 1-6  alkyl or C 1-6  hydroxyalkyl; 
       R 22  is H or —OH; 
       R 29  is C 1-6  alkyl; 
       R 30  is C 1-6  hydroxyalkyl; 
       R 31  is C 1-6  alkyl, C 1-6  hydroxyalkyl or C 1-6  alkyl substituted by Sac 5; 
       R 32  is C 1-8  alkyl, C 2-8  alkenyl or C 2-8  alkynyl; and 
          represents a bond that is either double or single. 
     
   
   
       43 . A food or beverage product according to  claim 42  in which the steroid moiety Z incorporates a further group selected from the groups consisting of groups VI (a) to VI (e): 
     
       
         
         
             
             
         
       
       wherein: 
       R 18 , R 23 , R 27  and R 33  are independently selected from C 1-6  alkyl; 
       R 19  and R 24  are independently selected from H and —OH; 
       R 20  is H, —OH or C 1-6  alkoxy or R 19  and R 20  taken together represent the second bond of a double bond joining adjacent carbon atoms; 
       R 21  is C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or a C 1-6  alkyl or C 2-6  alkenyl group substituted by one or more groups selected from the group consisting of —OH, C 1-6  alkoxy and Sac 4; 
       R 25  is C 1-6  alkyl, C 1-6  hydroxyalkyl or ═CH 2 ; 
       R 26  is —OH; 
       R 28  is C 1-6  alkyl, C 2-6  alkenyl or C 2-6  alkynyl; 
       R 34  is C 1-6  hydroxyalkyl or C 1-6  alkyl substituted by Sac 6; 
       R 35  is C 1-6  alkyl; 
       Sac 4, Sac 5 and Sac 6 are independently selected saccharides; 
       X is either O or NH. 
     
   
   
       44 . A food or beverage product according to  claim 43  in which R 21  is C 1-6  alkyl, C 2-6  alkenyl, C 1-6  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 4. 
   
   
       45 . A food or beverage product according to  claim 43  in which R 21  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, C 1-6  alkoxy and Sac 4. 
   
   
       46 . A method according to  claim 42  in which R 21  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 4. 
   
   
       47 . A food or beverage product according to  claim 42  in which Sac 4 is glucose. 
   
   
       48 . A food or beverage product according to  claim 42  in which R 31  is —CH 3  or —CH 2 -Sac 5. 
   
   
       49 . A food or beverage product according to  claim 42  in which Sac 5 is glucose. 
   
   
       50 . A food or beverage product according to  claim 42  in which R 34  is —CH 2 -Sac-6. 
   
   
       51 . A food or beverage product according to  claim 42  in which Sac 6 is glucose. 
   
   
       52 . A food or beverage product according to  claim 42  in which X is O. 
   
   
       53 . A method of treating a subject in need of therapy for a condition involving detrimental activity of the enzyme core 2 GlcNAc-T comprising administering to the subject a food or beverage product into which has been incorporated an isolated compound of the formula (I) according to  claim 28 . 
   
   
       54 . A method according to  claim 53  in which the condition to be treated is selected from the group consisting of vascular diseases, autoimmune and inflammatory conditions. 
   
   
       55 . A method according to  claim 54  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.