Hydrophilic polymer derivative having cyclic benzylidene acetal linker

Abstract

A hydrophilic polymer derivative having a cyclic benzylidene acetal linker represented by the following formula (1): wherein 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; X 1 is a chemically reactive functional group; P is a hydrophilic polymer, s is 1 or 2, t is 0 or 1, and s+t is 1 or 2; w is an integer of 1 to 8; and Z 1 and Z 2 are each independently a selected divalent spacer.

1 . A hydrophilic polymer derivative having a cyclic benzylidene acetal linker represented by formula (1): 
       
         
           
           
               
               
           
         
       
       wherein 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; X 1  is a chemically reactive functional group; P is a hydrophilic polymer, s is 1 or 2, t is 0 or 1, and s+t is 1 or 2; m is an integer of 1 to 8; and Z 1  and Z 2  are each independently a selected divalent spacer. 
     
     
         2 . The hydrophilic polymer 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—Z 1  satisfies −0.30≦Σσ≦1.05. 
     
     
         3 . The hydrophilic polymer 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, and a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and P—Z 1  satisfies −1.71≦Σσ≦0.88. 
     
     
         4 . The hydrophilic polymer 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—Z 1  satisfies −0.19≦Σσ≦0.57. 
     
     
         5 . The hydrophilic polymer 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, and a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and P—Z 1  satisfies −0.98≦Σσ≦0.48. 
     
     
         6 . The hydrophilic polymer 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. 
     
     
         7 . The hydrophilic polymer derivative as claimed in  claim 1 , wherein X 1  is selected from the group consisting of formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m) and formula (n): 
       
         
           
           
               
               
           
         
       
       wherein R 7  is a hydrogen atom or a sulfo group; R 8  and R 11  are each independently a hydrogen atom or a hydrocarbon group having from 1 to 5 carbon atoms; R 9  is a hydrocarbon group having from 1 to 10 carbon atoms which may contain a halogen atom; and R 10  is a halogen atom selected from a chlorine atom, a bromine atom and an iodine atom. 
     
     
         8 . The hydrophilic polymer derivative as claimed in  claim 1 , wherein Z 1  and Z 2  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, and in a case where at least one of Z 1  and Z 2  is an ether bond, an ester bond, a carbonate bond, a urethane bond, an amide bond, a secondary amino group or an alkylene group containing any of these bonds and group and a plurality of identical structural units are connected, a number of the structural units is 2 or less. 
     
     
         9 . The hydrophilic polymer derivative as claimed in  claim 1 , wherein P is a linear polyethylene glycol having a hydrocarbon group or a chemically reactive functional group at its terminal. 
     
     
         10 . The hydrophilic polymer derivative as claimed in  claim 9 , wherein w is 1, and P is represented by formula (2):
   Y—(OCH 2 CH 2 ) n —  (2)
   
       wherein Y is a hydrocarbon group having from 1 to 24 carbon atoms; and n is an integer of 3 to 2,000. 
     
     
         11 . The hydrophilic polymer derivative as claimed in  claim 9 , wherein w is 1, and P is represented by formula (3):
   X 2 —Z 3 —(OCH 2 CH 2 ) n —  (3)
   
       wherein X 2  is a chemically reactive functional group different from X 1 ; Z 3  is a divalent spacer, and n is an integer of 3 to 2,000. 
     
     
         12 . The hydrophilic polymer derivative as claimed in  claim 1 , wherein P is a branched polyethylene glycol having a hydrocarbon group or a chemically reactive functional group different from X 1  at its terminal. 
     
     
         13 . The hydrophilic polymer derivative as claimed in  claim 12 , wherein w is 1, and P is represented by formula (4): 
       
         
           
           
               
               
           
         
       
       wherein Y is a hydrocarbon group having from 1 to 24 carbon atoms; n is an integer of 3 to 1,000; and v is 0 or 2. 
     
     
         14 . The hydrophilic polymer derivative as claimed in  claim 12 , wherein w is 1, and P is represented by formula (5): 
       
         
           
           
               
               
           
         
       
       wherein X 2  is a chemically reactive functional group different from X 1 ; Z 3  is a divalent spacer, n is an integer of 3 to 1,000; and v is 0 or 2. 
     
     
         15 . The hydrophilic polymer derivative as claimed in  claim 12 , wherein w is v+2, and P is represented by formula (6): 
       
         
           
           
               
               
           
         
       
       wherein X 2  is a chemically reactive functional group different from X 1 ; Z 3  is a divalent spacer, n is an integer of 3 to 1,000; and v is 0 or 2. 
     
     
         16 . The hydrophilic polymer derivative as claimed in  claim 11 , 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. 
     
     
         17 . The hydrophilic polymer derivative as claimed in  claim 11 , wherein X 2  is selected from the group consisting of formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m) and formula (n): 
       
         
           
           
               
               
           
         
       
       wherein R 7  is a hydrogen atom or a sulfo group; R 8  and R 11  are each independently a hydrogen atom or a hydrocarbon group having from 1 to 5 carbon atoms; R 9  is a hydrocarbon group having from 1 to 10 carbon atoms which may contain a halogen atom; and R 10  is a halogen atom selected from a chlorine atom, a bromine atom and an iodine atom. 
     
     
         18 . The hydrophilic polymer derivative as claimed in  claim 11 , wherein Z 3  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, and in a case where Z 3  is an ether bond, an ester bond, a carbonate bond, a urethane bond, an amide bond, a secondary amino group or an alkylene group containing any of these bonds and group and a plurality of identical structural units are connected, a number of the structural units is 2 or less. 
     
     
         19 . The hydrophilic polymer derivative as claimed in  claim 1 , wherein P is polyethylene glycol having a number of terminals of 2 to 8, all the terminals of the polyethylene glycol constituting P are each connected to Z 1 , and w is equal to the number of terminals of the polyethylene glycol. 
     
     
         20 . The hydrophilic polymer derivative as claimed in  claim 19 , wherein P is selected from the group consisting of formula (r), formula (s), formula (t), formula (u) and formula (v): 
       
         
           
           
               
               
           
         
       
       wherein n is an integer of 3 to 2,000, and w is 2 when P is represented by formula (r), w is 3 when P is represented by formula (s), w is 4 when P is represented by formula (t), w is 4 when P is represented by formula (u), and w is 8 when P is represented by formula (v). 
     
     
         21 . A cyclic benzylidene acetal linker compound represented by formula (55): 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 6  am 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; X 3  and X 4 , which may be the same or different, are each independently a chemically reactive functional group; s is 1 or 2, t is 0 or 1, and s+t is 1 or 2; and Z 1  and Z 2  are each independently a selected divalent spacer. 
     
     
         22 . The cyclic benzylidene acetal linker compound as claimed in  claim 21 , 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 X 3 —Z 1  satisfies −0.30≦Σσ≦1.05. 
     
     
         23 . The cyclic benzylidene acetal linker compound as claimed in  claim 21 , wherein s is 1 and t is 0, at least one of R 2  and R 5  is the substituent, and a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and X 3 —Z 1  satisfies −1.71≦Σσ≦0.88. 
     
     
         24 . The cyclic benzylidene acetal linker compound as claimed in  claim 21 , 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 X 3 —Z 1  is −0.19≦Σσ≦0.57. 
     
     
         25 . The cyclic benzylidene acetal linker compound as claimed in  claim 21 , 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, and a sum (Σσ) of substituent constants (σ) in R 3 , R 4  and X 3 —Z 1  satisfies −0.98≦Σσ≦0.48. 
     
     
         26 . The cyclic benzylidene acetal linker compound as claimed in  claim 21 , wherein X 3  and X 4  are each 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, an azide group and hydroxy group. 
     
     
         27 . The cyclic benzylidene acetal linker compound as claimed in  claim 21 , wherein X 3  and X 4  are each selected from the group consisting of formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n) and formula (o). 
       
         
           
           
               
               
           
         
       
       wherein R 7  is a hydrogen atom or a sulfo group; R 8  and R 11  are each independently a hydrogen atom or a hydrocarbon group having from 1 to 5 carbon atoms; R 9  is a hydrocarbon group having from 1 to 10 carbon atoms which may contain a halogen atom; and R 10  is a halogen atom selected from a chlorine atom, a bromine atom and an iodine atom. 
     
     
         28 . The cyclic benzylidene acetal linker compound as claimed in  claim 21 , wherein Z 1  and Z 2  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, and in a case where at least one of Z 1  and Z 2  is an ether bond, an ester bond, a carbonate bond, a urethane bond, an amide bond, a secondary amino group or an alkylene group containing any of these bonds and group and a plurality of identical structural units are connected, a number of the structural units is 2 or less. 
     
     
         29 . The cyclic benzylidene acetal linker compound as claimed in  claim 21 , wherein the functional group constituting any one of X 3  and X 4  contains a protective group. 
     
     
         30 . The hydrophilic polymer derivative as claimed in  claim 14 , 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. 
     
     
         31 . The hydrophilic polymer derivative as claimed in  claim 14 , wherein X 2  is selected from the group consisting of formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m) and formula (n): 
       
         
           
           
               
               
           
         
       
       wherein R 7  is a hydrogen atom or a sulfo group; R 8  and R 11  are each independently a hydrogen atom or a hydrocarbon group having from 1 to 5 carbon atoms; R 9  is a hydrocarbon group having from 1 to 10 carbon atoms which may contain a halogen atom; and R 10  is a halogen atom selected from a chlorine atom, a bromine atom and an iodine atom. 
     
     
         32 . The hydrophilic polymer derivative as claimed in  claim 14 , wherein Z 3  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, and in a case where Z 3  is an ether bond, an ester bond, a carbonate bond, a urethane bond, an amide bond, a secondary amino group or an alkylene group containing any of these bonds and group and a plurality of identical structural units are connected, a number of the structural units is 2 or less. 
     
     
         33 . The hydrophilic polymer derivative as claimed in  claim 15 , 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. 
     
     
         34 . The hydrophilic polymer derivative as claimed in  claim 15 , wherein X 2  is selected from the group consisting of formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m) and formula (n): 
       
         
           
           
               
               
           
         
       
       wherein R 7  is a hydrogen atom or a sulfo group; R 8  and R 11  are each independently a hydrogen atom or a hydrocarbon group having from 1 to 5 carbon atoms; R 9  is a hydrocarbon group having from 1 to 10 carbon atoms which may contain a halogen atom; and R 10  is a halogen atom selected from a chlorine atom, a bromine atom and an iodine atom. 
     
     
         35 . The hydrophilic polymer derivative as claimed in  claim 15 , wherein Z 3  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, and in a case where Z 3  is an ether bond, an ester bond, a carbonate bond, a urethane bond, an amide bond, a secondary amino group or an alkylene group containing any of these bonds and group and a plurality of identical structural units are connected, a number of the structural units is 2 or less.