Trehalose compound, method for producing same, and pharmaceutical product containing the compound

Abstract

A trehalose compound having high immunopotentiating activity and low toxicity is represented by formula (1). (In the formula, X and X′ each represents a phenyl, a naphthyl, R 1 —CHR 1 — (wherein R 1 and R 2 each represents a C 7 -C 21 alkyl group or the like) or the like; and n and n′ each independently represents an integer of 0-3). The compound exhibits a high activating effect on macrophages and neutrophils.

What is claimed is: 
     
         1 . A method for
 immunostimulating;   activating a macrophage;   activating a neutrophil;   activating the phagocytosis of phagocytic cells;   neutralizing a bacterial toxin; or   preventing or treating infectious disease or cancer   in a mammal, comprising administering a therapeutically effective amount of a compound represented by the following formula (1) to the mammal:   
       
         
           
           
               
               
           
         
         
           wherein X represents phenyl, naphthyl, or a group represented by R 1 —CHR 2 —, and X′ represents phenyl, naphthyl, or a group represented by R 1 ′—CHR 2 ′—, 
           wherein R 1 , R 1 ′, R 2  and R 2 ′ independently represent a hydrogen atom or a C 1 -C 21  alkyl group, and with regard to R 1 , R 1 ′, R 2  and R 2 ′, a hydrogen atom in each alkyl group may be replaced by an alkoxy group, all or some of alkyl groups may form a 4- to 8-membered ring, and R 1  and R 2 , and R 1 ′ and R 2 ′ may bind to each other to form a 4- to 8-membered ring, and 
           wherein n and n′ independently represent an integer of 0 to 3, 
           with the proviso that the compound is not the following compounds: 
         
         (1) a compound, in which X represents R 1 —CHR 2 —, X′ represents R 1 ′—CHR 2 ′—, R 1 , R 1 ′, R 2  and R 2 ′ independently represent a hydrogen atom or an unsubstituted linear C 1 -C 6  alkyl group, and n and n′ represent 0; 
         (2) a compound, in which X represents R 1 —CHR 2 —, X′ represents R 1 ′—CHR 2 ′—, any one of R 1 , R 1 ′, R 2  and R 2 ′ represent a C 14  linear alkyl group, and n and n′ represent 0; 
         (3) a compound, in which X represents R 1 —CHR 2 —, X′ represents R 1 ′—CHR 2 ′—, all of R 1 , R 1 ′, R 2  and R 2 ′ represent a hydrogen atom, and n and n′ independently represent 0 to 3; 
         (4) a compound, in which X represents R 1 —CHR 2 —, X′ represents R 1 ′—CHR 2 ′—, any three of R 1 , R 1 ′, R 2  and R 2 ′, represent a hydrogen atom, the remaining one of R 1 , R 1 ′, R 2  and R 2 ′ represents a C 1 -C 21  linear alkyl group, and n and n′ independently represent 0 to 3; 
         (5) a compound, in which X represents R 1 —CHR 2 —, X′ represents R 1 ′—CHR 2 ′—, any one of R 1  and R 2  represents a hydrogen atom, any one of R 1 ′ and R 2 ′ represents a hydrogen atom, and both the remaining one of R 1  and R 2  and the remaining one of R 1 ′ and R 2 ′ independently represent a C 1 -C 21  linear alkyl group, and n and n′ independently represent 0 to 3; and 
         (6) a compound, in which X represents phenyl, X′ represents phenyl, and n and n′ represent 0. 
       
     
     
         2 . The method according to  claim 1 , wherein X represents R 1 —CHR 2 — and X′ represents R 1 —CHR 2 ′—. 
     
     
         3 . The method according to  claim 2 , wherein R 1 , R 1 ′, R 2  and R 2 ′ independently represent a linear C 7 -C 21  alkyl group, and n and n′ independently represent 0 or 1. 
     
     
         4 . The method according to  claim 2 , wherein R 1 , R 1 ′, R 2  and R 2 ′ independently represent a linear C 8 -C 16  alkyl group, and n and n′ independently represent 0. 
     
     
         5 . The method according to  claim 2 , wherein R 1 , R 1 ′, R 2  and R 2 ′ independently represent a linear C 9 -C 14  alkyl group, and n and n′ independently represent 1. 
     
     
         6 . The method according to  claim 1 , wherein R 1  is identical to R 1 ′, R 2  is identical to R 2 ′, and n is identical to n′. 
     
     
         7 . The method according to  claim 1 , wherein the compound is selected from the group consisting of:
 6,6′-bis-O-(2-octyldecanoyl)-α,α′-trehalose,   6,6′-bis-O-(2-nonylundecanoyl)-α,α′-trehalose,   6,6′-bis-O-(2-decyldodecanoyl)-α,α′-trehalose,   6,6′-bis-O-(2-undecyltridecanoyl)-α,α′-trehalose,   6,6′-bis-O-(2-dodecyltetradecanoyl)-α,α′-trehalose,   6,6′-bis-O-(2-tridecylpentadecanoyl)-α,α′-trehalose,   6,6′-bis-O-(2-pentadecylheptadecanoyl)-α,α′-trehalose, and   6,6′-bis-O-(2-hexadecyloctadecanoyl)-α,α′-trehalose.   
     
     
         8 . The method according to  claim 1 , wherein the compound is selected from the group consisting of:
 6,6′-bis-O-(3-nonyldodecanoyl)-α,α′-trehalose,   6,6′-bis-O-(3-decyltridecanoyl)-α,α′-trehalose,   6,6′-bis-O-(3-undecyltetradecanoyl)-α,α′-trehalose,   6,6′-bis-O-(3-dodecylpentadecanoyl)-α,α′-trehalose,   6,6′-bis-O-(3-tridecylhexadecanoyl)-α,α′-trehalose, and   6,6′-bis-O-(3-tetradecylheptadecanoyl)-α,α′-trehalose.   
     
     
         9 . The method according to  claim 1 , wherein the compound is selected from the group consisting of:
 6,6′-bis-O-(2-decyldodecanoyl)-α,α′-trehalose,   6,6′-bis-O-(3-nonyldodecanoyl)-α,α′-trehalose,   6,6′-bis-O-(3-tridecylhexadecanoyl)-α,α′-trehalose, and   6,6′-bis-O-(3-tetradecylheptadecanoyl)-α,α′-trehalose.   
     
     
         10 . A method for
 inducing a cytokine, wherein the cytokine is selected from the group consisting of IL-8, TNF-α, and IFN-γ;   activating a neutrophil;   activating the phagocytosis of phagocytic cells;   neutralizing a bacterial toxin;   preventing or treating bacterial infectious disease, wherein the bacterium is selected from the group consisting of Welch  bacillus, Pseudomonas aeruginosa , and enteropathogenic  Escherichia coli ; or   preventing or treating cancer, wherein the cancer is infiltrative cancer in a mammal, comprising administering a therapeutically effective amount of a compound represented by the following formula (2) to the mammal:   
       
         
           
           
               
               
           
         
         
           wherein X represents phenyl, naphthyl, or a group represented by R 1 —CHR 2 —, and X′ represents phenyl, naphthyl, or a group represented by R 1 ′—CHR 2 ′—, 
         
         wherein R 1 , R 1 ′, R 2  and R 2 ′ independently represent a hydrogen atom or a C 1 -C 21  alkyl group, and with regard to R 1 , R 1 ′, R 2  and R 2 ′, a hydrogen atom in each alkyl group may be replaced by a hydroxyl group or an alkoxy group, all or some of alkyl groups may form a 4- to 8-membered ring, and R 1  and R 2 , and R 1 ′ and R 2 ′ may bind to each other to form a 4- to 8-membered ring, and 
         wherein n and n′ independently represent an integer of 0 to 3, with the proviso that the compound is not the following compounds:
 (1) a compound, in which X represents R 1 —CHR 2 —, X′ represents R 1 ′—CHR 2 ′—, R 1 , R 1 ′, R 2  and R 2 ′ independently represent a hydrogen atom or an unsubstituted linear C 1 -C 6  alkyl group, and n and n′ represent 0; and 
 (2) a compound, in which X represents R 1 —CHR 2 —, X′ represents R 1 ′—CHR 2 ′—, R 1 , R 1 ′, R 2  and R 2 ′ represent a C 14  linear alkyl group, and n and n′ represent 0. 
 
       
     
     
         11 . The method according to  claim 10 , wherein the method is characterized for
 inducing a cytokine, wherein the cytokine is selected from the group consisting of IL-8, TNF-α, and IFN-γ;   activating a neutrophil; or   neutralizing a bacterial toxin in a mammal.   
     
     
         12 . A method for neutralizing a bacterial toxin in a mammal, comprising administering a therapeutically effective amount of a compound represented by the following formula (3) to the mammal: 
       
         
           
           
               
               
           
         
         wherein X represents phenyl, naphthyl, or a group represented by R 1 —CHR 2 —, and X′ represents phenyl, naphthyl, or a group represented by R 1 ′—CHR 2 ′—, 
         wherein R 1 , R 1 ′, R 2  and R 2 ′ independently represent a hydrogen atom or a C 1 -C 21  alkyl group, and with regard to R 1 , R 1 ′, R 2  and R 2 ′, a hydrogen atom in each alkyl group may be replaced by a hydroxyl group or an alkoxy group, all or some of alkyl groups may form a 4- to 8-membered ring, and R 1  and R 2 , and R 1 ′ and R 2 ′ may bind to each other to form a 4- to 8-membered ring, and 
         wherein n and n′ independently represent an integer of 0 to 3. 
       
     
     
         13 . The method according to  claim 12 , wherein the compound is selected from the group consisting of:
 6,6′-bis-O-(2-decyldodecanoyl)-α,α′-trehalose,   6,6′-bis-O-(2-tetradecylhexadecanoyl)-α,α′-trehalose,   6,6′-his-O-(3-nonyldodecanoyl)-α,α′-trehalose,   6,6′-bis-O-(3-tridecylhexadecanoyl)-α,α′-trehalose, and   6,6′-bis-O-(3-tetradecylheptadecanoyl)-α,α′-trehalose.