Sulfonated sugar compounds, pharmaceutical compositions which contain the same, and methods of treating tumors with the same

Abstract

Sulfoquinovosylacyl propanediol compounds represented by formula (I): wherein R 1 is an acyl residue of a fatty acid, Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y and pharmaceutically acceptable salts thereof are effective for treating tumors.

1 . A sulfoquinovosylacyl propanediol compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is an acyl residue of a fatty acid, Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y, 
         or pharmaceutically acceptable salt thereof. 
       
     
     
         2 . An anion represented by formula (I′): 
       
         
           
           
               
               
           
         
       
       wherein R 1  is an acyl residue of a fatty acid. 
     
     
         3 . A pharmaceutical composition, comprising at least one sulfoquinovosylacyl propanediol compound or pharmaceutically acceptable salt thereof according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         4 . A pharmaceutical composition according to  claim 3 , which is a radiosensitizer. 
     
     
         5 . The pharmaceutical composition according to  claim 3 , which is an antineoplastic or antitumor agent. 
     
     
         6 . The sulfoquinovosylacyl propanediol compound according to  claim 1 , wherein the acyl residue has 26, or less and 1 or more carbon atoms. 
     
     
         7 . The sulfoquinovosylacyl propanediol compound according to  claim 1 , wherein the acyl residue has 22 or less and 1 or more carbon atoms. 
     
     
         8 . The sulfoquinovosylacyl propanediol compound according to  claim 1 , wherein M is a hydrogen atom. 
     
     
         9 . The sulfoquinovosylacyl propanediol compound according to  claim 1 , wherein M is selected from the group consisting of sodium, potassium, calcium and magnesium. 
     
     
         10 . The sulfoquinovosylacyl propanediol compound according to  claim 1 , wherein the compound is selected from the group consisting of
 3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-stearoyl-propane-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-stearoyl-propane-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-decanoyl-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-decanoyl-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-myristoyl-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-myristoyl-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-behenoyl-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-behenoyl-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-hexanoyl-propane-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-hexanoyl-propane-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-acetyl-propane-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-acetyl-propane-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-formyloxy-propane-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-formyloxy-propane-1,3-diol calcium salt;   3-O-(6-sulfo-β-D-quinovopyranosyl)-1-O-oleoyl-propane-1,3-diol sodium salt; and   3-O-(6-sulfo-β-D-quinovopyranosyl)-1-O-oleoyl-propane-1,3-diol calcium salt.   3-O-(6-sulfo-β-D-quinovopyranosyl)-1-O-stearoyl-propane-1,3-diol sodium salt.   3-O-(6-sulfo-β-D-quinovopyranosyl)-1-O-stearoyl-propane-1,3-diol calcium salt.   
     
     
         11 . A process for making a compound or pharmaceutically acceptable salt thereof according to  claim 1 , which comprises:
 deprotecting a compound of formula (IX):   
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, R 1  is an acyl residue of a fatty acid, Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y, to obtain said compound or pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         12 . A process according to  claim 11 , wherein said compound of formula (IX) is prepared by a process comprising:
 oxidizing a compound of formula (VIII):   
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, SAc is an acetylthio group, and R 1  is an acyl residue of a fatty acid, to obtain said compound of formula (IX). 
     
     
         13 . A process according to  claim 12 , wherein said compound of formula (VIII) is prepared by a process comprising:
 reacting a compound of formula (VII):   
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, and SAc is an acetylthio group, with a compound of formula R 1 C(═O)L, wherein R 1  is an acyl residue of a fatty acid and L is a leaving group, to obtain said compound of formula (VIII). 
     
     
         14 . A process according to  claim 11 , wherein said compound of formula (IX) is prepared by a process comprising:
 reacting a compound of formula (X′):   
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y, with a compound of formula R 1 C(═O)L, wherein R 1  is an acyl residue of a fatty acid and L is a leaving group, to obtain said compound of formula (IX). 
     
     
         15 . A process according to  claim 14 , wherein said compound of formula (X′) is prepared by a process comprising:
 converting a compound of formula (IX′):   
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, and Ts is a tosyl group, to said compound of formula (X′). 
     
     
         16 . A compound represented by formula (VIII): 
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, SAc is an acetylthio group, and R 1  is an acyl residue of a fatty acid. 
     
     
         17 . A compound represented by formula (IX): 
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, R 1  is an acyl residue of a fatty acid, Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y. 
     
     
         18 . A compound represented by formula (X′): 
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y. 
     
     
         19 . A compound represented by formula (IX′): 
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, and Ts is a tosyl group. 
     
     
         20 . A process for making a compound or pharmaceutically acceptable salt thereof according to  claim 1 , which comprises:
 reacting a compound of formula (IX″):   
       
         
           
           
               
               
           
         
       
       wherein Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y, with a compound of formula R 1 C(═O)L, wherein R 1  is an acyl residue of a fatty acid and L is a leaving group, to obtain said compound or pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         21 . A process according to  claim 20 , wherein said compound of formula (IX″) is prepared by a process comprising:
 deprotecting a compound of formula (VIII″):   
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y, to obtain said compound of formula (IX″). 
     
     
         22 . A process according to  claim 21 , wherein said compound of formula (VIII″) is prepared by a process comprising:
 oxidizing a compound of formula (VII):   
       
         
           
           
               
               
           
         
         wherein P 1 , P 2 , and P 3  are each independently a protecting group and SAc is an acetylthio group, to obtain said compound of formula (VIII″). 
       
     
     
         23 . A compound represented by formula (VIII″): 
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are each independently a protecting group, Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y. 
     
     
         24 . A compound represented by formula (IX″): 
       
         
           
           
               
               
           
         
       
       wherein Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y. 
     
     
         25 . A method of treating a tumor, comprising administering an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof to a subject in need thereof. 
     
     
         26 . The method according to  claim 25 , wherein the compound is selected from the group consisting of
 3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-stearoyl-propane-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-stearoyl-propane-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-decanoyl-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-decanoyl-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-myristoyl-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-myristoyl-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-behenoyl-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-behenoyl-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-hexanoyl-propane-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-hexanoyl-propane-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-acetyl-propane-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-acetyl-propane-1,3-diol calcium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-formyloxy-propane-1,3-diol sodium salt;   3-O-(6-sulfo-α-D-quinovopyranosyl)-1-O-formyloxy-propane-1,3-diol calcium salt;   3-O-(6-sulfo-β-D-quinovopyranosyl)-1-O-oleoyl-propane-1,3-diol sodium salt; and   3-O-(6-sulfo-β-D-quinovopyranosyl)-1-O-oleoyl-propane-1,3-diol calcium salt.   3-O-(6-sulfo-β-D-quinovopyranosyl)-1-O-stearoyl-propane-1,3-diol sodium salt.   3-O-(6-sulfo-β-D-quinovopyranosyl)-1-O-stearoyl-propane-1,3-diol calcium salt.   
     
     
         27 . The method of  claim 25 , wherein said compound of  claim 1  or pharmaceutically acceptable salt thereof is administered concurrently with radiation therapy. 
     
     
         28 . The method of  claim 25 , wherein said compound of  claim 1  or pharmaceutically acceptable salt thereof is administered prior to radiation therapy. 
     
     
         29 . The method of  claim 25 , wherein said compound of  claim 1  or pharmaceutically acceptable salt thereof is administered after radiation therapy. 
     
     
         30 . A method for treating a malignant neoplasm comprising administering to a human in need thereof an antineoplastic effective amount of at least one compound according to  claim 1 . 
     
     
         31 . A method for treating a malignant neoplasm comprising administering to a human in need thereof radiosensitizing amount of the compound according to  claim 1  and exposing said human to an effective dose of radiation.