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 - 28 . (canceled) 
   
   
       29 . 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, 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. 
     
   
   
       30 . A food or beverage product according to  claim 29  in which R 1  is —H, —CH 3  or —CH 2 OH. 
   
   
       31 . A food or beverage product according to  claim 29  in which R 1  is —CH 2 OH. 
   
   
       32 . A food or beverage product according to  claim 29  in which R 1  is —CH 2 OH and the ring is a glucose moiety. 
   
   
       33 . A food or beverage product according to  claim 29  in which R 2  is —OH. 
   
   
       34 . A food or beverage product according to  claim 29  in which Sac 1  and Sac 2  are monosaccharides. 
   
   
       35 . A food or beverage product according to  claim 29  in which Sac 1  is a pentose or an aldohexose. 
   
   
       36 . A food or beverage product according to  claim 29  in which Sac 1  is an aldohexose. 
   
   
       37 . A food or beverage product according to  claim 29  in which Sac 1  is glucose. 
   
   
       38 . A food or beverage product according to  claim 29  in which Sac 2  is selected from the group consisting of a tetrose a pentose and a hexose moiety. 
   
   
       39 . A food or beverage product according to  claim 29  in which Sac 2  is rhamnose. 
   
   
       40 . A food or beverage product according to  claim 29  in which the compound of the formula I is 
     
       
         
         
             
             
         
       
     
   
   
       41 . A food or beverage product according to  claim 29  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. 
     
   
   
       42 . A food or beverage product according to  claim 41  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 19 , 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. 
     
   
   
       43 . A food or beverage product according to  claims 42  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 3 . 
   
   
       44 . A food or beverage product according to  claim 42  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 . 
   
   
       45 . A food or beverage product according to  claim 42  in which R 21  is —CH 3 , —CH 2 OH or ═CH 2 . 
   
   
       46 . A food or beverage product according to  claim 42  in which R 24  is C 2-6  alkenyl. 
   
   
       47 . A food or beverage product according to  claims 42  in which R 27  is —CH 3  or —CH 2 -Sac 4 . 
   
   
       48 . A food or beverage product according to  claim 42  in which S 4  is glucose. 
   
   
       49 . A food or beverage product according to  claim 42  in which R 28  is C 1-8  alkyl or C 2-8  alkenyl. 
   
   
       50 . A food or beverage product according to  claim 42  in which R 28  is 3-ethyl-4-methyl-pentanyl or 5-methyl-hex-4-enyl. 
   
   
       51 . A food or beverage product according to  claim 42  in which R 30  is —CH 2 -Sac 5 . 
   
   
       52 . A food or beverage product according to  claim 42  in which Sac 5  is glucose. 
   
   
       53 . A food or beverage product according to  claim 42  in which X is O. 
   
   
       54 . A food or beverage product according to  claim 29  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.   
   
   
       55 . 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 29 . 
   
   
       56 . A method according to  claim 55  in which the condition to be treated is selected from the group consisting of vascular diseases, autoimmune and inflammatory conditions. 
   
   
       57 . A method according to  claim 55  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.