Biodegradable polyethylene glycol derivative having cyclic benzylidene acetal linker

Abstract

A biodegradable polyethylene glycol derivative in which a polyethylene glycol chain is linked by an acetal linker capable of accurately controlling the hydrolysis rate under different pH environments in the living body, and whose division rate into a polyethylene glycol chain of low molecular weight in the living body can be accurately controlled. The biodegradable polyethylene glycol derivative is represented by formula (1) or formula (2) as described.

1 . A biodegradable polyethylene glycol derivative having a cyclic benzylidene acetal linker represented by formula (1) or formula (2): 
       
         
           
           
               
               
           
         
       
       wherein, in the formula (1) and the formula (2), R 1  and R 6  are each independently a hydrogen atom or a hydrocarbon group; R 2 , R 3 , R 4  and R 5  are each independently an electron-withdrawing or electron-donating substituent or a hydrogen atom; s is 1 or 2, t is 0 or 1, and s+t is 1 or 2; P 1  is a straight-chain or branched polyethylene glycol having a number of ethylene glycol units of 3 or more; P 2  is a straight-chain or branched polyethylene glycol having a number of ethylene glycol units of 3 or more; w is an integer of 1 to 8; u is an integer of 1 to 40; v is an integer of 1 to 4; X 1  is a chemically reactive functional group; and Z 1 , Z 2  and Z 3  are each independently a selected divalent spacer. 
     
     
         2 . The biodegradable polyethylene glycol derivative as claimed in  claim 1 , wherein s is 1 and t is 0, R 2  and R 5  are each a hydrogen atom, and a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and P 1 —Z 1  in formula (1) or a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and P 2 —Z 1  in formula (2) satisfies −0.30≦Σσ≦1.05. 
     
     
         3 . The biodegradable polyethylene glycol derivative as claimed in  claim 1 , wherein s is 1 and t is 0, at least one of R 2  and R 5  is the substituent described above, and a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and P 1 —Z 1  in formula (1) or a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and P 2 —Z 1  in formula (2) satisfies −1.71≦Σσ≦0.88. 
     
     
         4 . The biodegradable polyethylene glycol derivative as claimed in  claim 1 , wherein s is 1 and t is 1, or s is 2 and t is 0, R 2  and R 5  are each a hydrogen atom, and a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and P 1 —Z 1  in formula (1) or a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and P 2 —Z 1  in formula (2) satisfies −0.19≦Σσ≦0.57. 
     
     
         5 . The biodegradable polyethylene glycol derivative as claimed in  claim 1 , wherein s is 1 and t is 1, or s is 2 and t is 0, at least one of R 2  and R 5  is the substituent described above, and a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and P 1 —Z 1  in formula (1) or a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and P 2 —Z 1  in formula (2) satisfies −0.98≦Σσ≦0.48. 
     
     
         6 . The biodegradable polyethylene glycol derivative as claimed in  claim 1 , wherein w is 1. 
     
     
         7 . The biodegradable polyethylene glycol derivative as claimed in  claim 6 , wherein P 1  is a straight-chain polyethylene glycol having a hydrocarbon group or a chemically reactive functional group at a terminal thereof. 
     
     
         8 . The biodegradable polyethylene glycol derivative as claimed in  claim 7 , wherein P 1  is represented by formula (3):
   Y—(OCH 2 CH 2 ) n —  (3)
   
       wherein, in the formula (3), Y is a hydrocarbon group having from 1 to 24 carbon atoms; and n is an integer of 3 to 2,000. 
     
     
         9 . The biodegradable polyethylene glycol derivative as claimed in  claim 7 , wherein P 1  is represented by formula (4):
   X 2 —Z 4 —(OCH 2 CH 2 ) n —  (4)
   
       wherein, in the formula (4), X 2  is a chemically reactive functional group different from X 1 ; Z 4  is a divalent spacer; and n is an integer of 3 to 2,000. 
     
     
         10 . The biodegradable polyethylene glycol derivative as claimed in  claim 6 , wherein P 1  is a branched polyethylene glycol having a hydrocarbon group or a chemically reactive functional group different from X 1  at a terminal thereof. 
     
     
         11 . The biodegradable polyethylene glycol derivative as claimed in  claim 10 , wherein P 1  is represented by formula (5): 
       
         
           
           
               
               
           
         
       
       wherein, in the formula (5), Y is a hydrocarbon group having from 1 to 24 carbon atoms; n is an integer of 3 to 1,000; and a is 0 or 2. 
     
     
         12 . The biodegradable polyethylene glycol derivative as claimed in  claim 10 , wherein P 1  is represented by formula (6): 
       
         
           
           
               
               
           
         
       
       wherein, in the formula (6), X 2  is a chemically reactive functional group different from X 1 ; Z 4  is a divalent spacer; n is an integer of 3 to 1,000, and a is 0 or 2. 
     
     
         13 . The biodegradable polyethylene glycol derivative as claimed in  claim 1 , wherein w is 2 to 8. 
     
     
         14 . The biodegradable polyethylene glycol derivative as claimed in  claim 13 , wherein P 1  is represented by formula (7): 
       
         
           
           
               
               
           
         
       
       wherein, in the formula (7), X 2  is a chemically reactive functional group different from X 1 ; Z 4  is a divalent spacer; n is an integer of 3 to 1,000, and a is 0 or 2. 
     
     
         15 . The biodegradable polyethylene glycol derivative as claimed in  claim 13 , wherein P 1  is a straight-chain polyethylene glycol or a branched polyethylene glycol having a number of terminals of 3 to 8, all terminals of the polyethylene glycol constituting P 1  are each connected to Z 1  in formula (1) or Z 2  in formula (2), and w is equal to the number of terminals of the polyethylene glycol. 
     
     
         16 . The biodegradable polyethylene glycol derivative as claimed in  claim 15 , wherein P 1  is selected from the group consisting of formula (r), formula (s), formula (t), formula (u) and formula (v): 
       
         
           
           
               
               
           
         
       
       wherein, in the formulae, n is an integer of 3 to 2,000; and w is 2 in a case where P 1  is represented by formula (r), w is 3 in a case where P 1  is represented by formula (s), w is 4 in a case where P 1  is represented by formula (t), w is 4 in a case where P 1  is represented by formula (u), and w is 8 in a case where P 1  is represented by formula (v). 
     
     
         17 . The biodegradable polyethylene glycol derivative as claimed in  claim 1 , wherein P 2  is represented by formula (8):
   —(OCH 2 CH 2 ) m —  (8)
   
       wherein, in the formula (8), m is an integer of 3 to 2,000; and v in formula (1) or formula (2) is 1. 
     
     
         18 . The biodegradable polyethylene glycol derivative as claimed in  claim 1 , wherein P 2  is represented by formula (9): 
       
         
           
           
               
               
           
         
       
       wherein, in the formula (9), m is an integer of 3 to 1,000, b is 0 or 2; and v in formula (1) or formula (2) is b+2. 
     
     
         19 . The biodegradable polyethylene glycol derivative as claimed in  claim 1 , wherein X 1  is selected from the group consisting of an active ester group, an active carbonate group, an aldehyde group, an isocyanate group, an isothiocyanate group, an epoxy group, a maleimide group, a vinyl sulfone group, an acryl group, a sulfonyloxy group, a carboxy group, a thiol group, a dithiopyridyl group, an α-haloacetyl group, an alkynyl group, an allyl group, a vinyl group, an amino group, an oxyamino group, a hydrazide group and an azide group. 
     
     
         20 . The biodegradable polyethylene glycol derivative as claimed in  claim 1  wherein Z 1 , Z 2  and Z 3  are each independently an ether bond, an ester bond, a carbonate bond, a urethane bond, an amide bond, a secondary amino group, an alkylene group containing any of these bonds and group, a single bond or an alkylene group. 
     
     
         21 . The biodegradable polyethylene glycol derivative as claimed in  claim 9 , wherein X 2  is selected from the group consisting of an active ester group, an active carbonate group, an aldehyde group, an isocyanate group, an isothiocyanate group, an epoxy group, a maleimide group, a vinyl sulfone group, an acryl group, a sulfonyloxy group, a carboxy group, a thiol group, a dithiopyridyl group, an α-haloacetyl group, an alkynyl group, an allyl group, a vinyl group, an amino group, an oxyamino group, a hydrazide group and an azide group. 
     
     
         22 . The biodegradable polyethylene glycol derivative as claimed in  claim 9 , wherein Z 4  is an ether bond, an ester bond, a carbonate bond, a urethane bond, an amide bond, a secondary amino group, an alkylene group containing any of these bonds and group, a single bond or an alkylene group.