Polymer conjugate of bioactive substance having hydroxy group

摘要

A polymer conjugate of a physiologically active substance, which enables drug release independent of a biological enzyme and can be expected to have a high therapeutic effect, is demanded.;Provided is a polymer conjugate of a physiologically active substance, comprising a block copolymer of a polyethylene glycol moiety and a polymer having two or more carboxy groups, in which a substituent represented by general formula (I) or general formula (II) is linked to at least one of the side-chain carboxy groups of the block copolymer via an amide bond [in the formula, R8 and R9 each independently are hydrogen atom or (C1-C6)alkyl which may have a substituent, R10 is hydrogen atom, (C1-C40)alkyl which may have a substituent, (C1-C40) aralkyl group which may have a substituent, an aromatic group which may have a substituent, an amino acid residue having a protected carboxy group, or a sugar residue which may have a substituent, CX—CY represents CH—CH or C═C (double bond), and A represents a residue obtained by removing, from a physiologically active substance having one or more hydroxy groups, one of the one or more hydroxy groups].;

主权项

1. A polymer conjugate of a physiologically active substance, comprising a block copolymer of a polyethylene glycol moiety and a polyglutamic acid moiety, in which a substituent bound to the physiologically active substance is linked to at least one of the side-chain carboxy groups of the block copolymer via an amide bond, and the physiologically active substance is directly bonded to the side-chain carboxy groups of the block copolymer,
wherein the polymer conjugate is a compound represented by general formula (III)wherein
R1 represents hydrogen atom or (C1-C6)alkyl group, R2 represents a linking group, R3 represents hydrogen atom or (C1-C6)acyl group, R4 represents a substituent represented by general formula(I) or general formula (II) in which R8 and R9 each independently represent a hydrogen atom or (C1-C6)alkyl group which may optionally have a substituent, R10 represents hydrogen atom, (C1-C40)alkyl group which may optionally have a substituent, (C1-C40)aralkyl group which may optionally have a substituent, an aromatic group which may optionally have a substituent, an amino acid residue having a protected carboxy group, or a sugar residue which may optionally have a substituent, CX—CY represents CH—CH or C═C (double bond), and A represents a residue obtained by removing, from the physiologically active substance having one or more hydroxy groups, one of the one or more hydroxy groups, R5 represents a substituent represented by general formula (IV) or general formula (V) in which R8, R9, R10, and CX—CY have the same meanings as above, R11 represents one or more substituents selected from a group consisting of hydroxy group, an aromatic amino group which may optionally have a substituent, (C1-C30)alkoxy group which may optionally have a substituent, (C1-C30)aralkyloxy group which may optionally have a substituent, (C1-C30)alkylamino group which may optionally have a substituent, di(C1-C30)alkylamino group which may optionally have a substituent, an amino acid having a protected carboxy group, and NR12CONHR13,
wherein R12 and R13, which may be the same or different from each other, represent (C3-C6)cyclic alkyl group, or (C1-C5)alkyl group which may optionally be substituted with a tertiary amino group, R6 represents a substituent represented by general formula (VI) in which R8, R9, R10, and CX—CY have the same meanings as above, R7 represents a substituent selected from a group consisting of (C1-C30)alkoxy group, (C1-C30)aralkyloxy group, (C1-C30)alkylamino group, di(C1-C30)alkylamino group, an amino acid having a protected carboxy group, and NR 12CONHR13, wherein R12 and R13, which may be the same or different from each other, represent (C3-C6)cyclic alkyl group, or (C1-C5)alkyl group which may optionally be substituted with a tertiary amino group, b is an integer from 5 to 11,500, i is an integer from 1 to 200, j, k, m, and n each represent an integer from 0 to 200 with the proviso that i+j+k+m+n represents an integer from 2 to 200.