Cannabinoid glycoside prodrugs and methods of synthesis

Abstract

The present invention relates to cannabinoid glycoside prodrugs suitable for site- and tissue-specific delivery of cannabinoid molecules. The present invention also relates to methods of forming the cannabinoid glycoside prodrugs through glycosyltransferase mediated glycosylation of cannabinoid molecules.

1 . A cannabinoid glycoside prodrug compound having formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R is H, β-D-glucopyranosyl, or 3-O-β-D-glucopyranosyl-β-D-glucopyranosyl; 
         R′ is H or β-D-glucopyranosyl, or 3-O-β-D-glucopyranosyl-β-D-glucopyranosyl; and 
         A is an aglycone moiety formed through reaction of a hydroxyl group on a cannabinoid compound, an endocannabinoid compound, or a vanilloid compound, 
       
       or a pharmaceutically compatible salt thereof. 
     
     
         2 . A compound according to  claim 1 , wherein A is A′, A″ or A′″;
 wherein A′ is: 
 
       
         
           
           
               
               
           
         
         wherein A″ is: 
       
       
         
           
           
               
               
           
         
         and 
         wherein A′″ is: 
       
       
         
           
           
               
               
           
         
       
       wherein G is H, β-D-glucopyranosyl, 3-O-β-D-glucopyranosyl-β-D-glucopyranosyl, or β-D-glucopyranosyl-(1→3)-3-D-glucopyranosyl-(1→3)-D-glucopyranosyl. 
     
     
         3 . A compound according to  claim 2 , wherein A is A′. 
     
     
         4 .- 11 . (canceled) 
     
     
         12 . A compound according to  claim 2 , wherein A is A″. 
     
     
         13 .- 20 . (canceled) 
     
     
         21 . A compound according to  claim 2 , wherein A is A′″. 
     
     
         22 .- 28 . (canceled) 
     
     
         29 . A pharmaceutical composition comprising a compound as defined in  claim 1  and a pharmaceutically acceptable carrier, diluent, excipient, or adjuvant. 
     
     
         30 . A method for the site-specific delivery of a cannabinoid drug to a subject, comprising the step of administering a cannabinoid glycoside prodrug as defined in  claim 1  to a subject in need thereof. 
     
     
         31 . The method of  claim 30 , wherein the cannabinoid glycoside prodrug is formulated for oral, parenteral, or transdermal administration. 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . A method for the site-specific delivery of a cannabinoid drug to a subject, comprising the step of administering a pharmaceutical composition as defined in  claim 29  to a subject in need thereof. 
     
     
         35 . The method of  claim 34 , wherein the pharmaceutical composition is formulated for oral, parenteral, or transdermal administration. 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . A method for facilitating the transport of a cannabinoid drug across the blood brain barrier of a subject comprising administering a cannabinoid glycoside prodrug as defined in  claim 1  to a subject in need thereof. 
     
     
         39 . An antimicrobial agent comprising an effective amount of a cannabinoid glycoside prodrug as defined in  claim 1 . 
     
     
         40 . (canceled) 
     
     
         41 . A detersive agent comprising an effective amount of a cannabinoid glycoside prodrug as defined in  claim 1 . 
     
     
         42 . (canceled) 
     
     
         43 . A method of producing a cannabinoid glycoside, comprising incubating a cannabinoid aglycone with one or more sugar donors in the presence of one or more glycosyltransferases, wherein the one or more glycosyltransferases is a UGT76G1 or UGT76G1-like glucosyltransferase. 
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 43 , wherein the one or more glycosyltransferases further comprise a Os03g0702000 or Os03g0702000-like glucosyltransferase. 
     
     
         46 . The method of  claim 43 , wherein the one or more sugar donors are selected from the group consisting of UDP-glucose, UDP-glucuronic acid, UDP-mannose, UDP-fructose, UDP-xylose, UDP-rhamnose, UDP-fluoro-deoxyglucose and combinations thereof. 
     
     
         47 .- 52 . (canceled) 
     
     
         53 . The method of  claim 43 , wherein the cannabinoid glycoside produced by the method is a compound of the Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R is H, β-D-glucopyranosyl, or 3-O-β-D-glucopyranosyl-β-D-glucopyranosyl; 
         R′ is H or β-D-glucopyranosyl, or 3-O-β-D-glucopyranosyl-β-D-glucopyranosyl; and 
         A is an aglycone moiety formed through reaction of a hydroxyl group on a cannabinoid compound, an endocannabinoid compound, or a vanilloid compound, 
       
       or a pharmaceutically compatible salt thereof. 
     
     
         54 . A method of producing a cannabinoid glycoside prodrug of  claim 1 , comprising incubating a cannabinoid aglycone with maltodextrin, in the presence of a cyclodextrin glucanotransferase under conditions that allow for glycosylation. 
     
     
         55 . A method of producing a cannabinoid glycoside prodrug of  claim 1 , comprising incubating a cannabinoid aglycone with UDP-glucose and maltodextrin in the presence of a UGT76G1 or UGT76G1-like glucosyltransferase and cyclodextrin glucanotransferase under conditions which allow for glycosylation. 
     
     
         56 .- 59 . (canceled) 
     
     
         60 . A method producing a cannabinoid glycoside prodrug of  claim 1 , comprising expressing one or more of the glycosyltransferases in a cell or plant which produces a cannabinoid aglycone and isolating the cannabinoid glycoside. 
     
     
         61 .- 79 . (canceled)