Coordination complex of diaminocyclohexaneplatinum(II) with block copolymer containing poly(carboxylic acid) segment and antitumor agent comprising the same

A coordinate complex in the form of a polymer micelle, said polymer micelle comprises a complex of diaminocyclohexane platinum (II) and a block copolymer comprising a structure of the general formula (I-a) or (2-a):

• wherein
• R1 represents a hydrogen atom or an unsubstituted or substituted linear or branched C1-12 alkyl group;
• L1 represents —(CH2)b—NH— wherein b represents an integer of 1 to 5;
• L2 represents —(CH2)c—CO— wherein c represents an integer of 1 to 5;
• R3 respectively and independently represents an atom or a group selected from the group consisting of a hydrogen atom, a benzyl oxycarbonyl group, a t-butyl oxycarbonyl group, an acetyl group, a trifluoroacetyl group, a benzyl carbonyl group, a benzhydryl carbonyl group, an acryloyl group and a methacryloyl group;
• R4 respectively and independently represents a group selected from the group consisting of a hydroxyl group, a benzyloxy group, a t-butyloxy group, a methoxy group, a benzhydryloxy group, an allyloxy group and a vinyl phenyl methoxy group;
• R5 respectively and independently represents a hydrogen atom, an alkali metal ion, a group selected from the group consisting of a benzyl group, a benzhydryl group and a C1-6 alkyl group;
• m represents an integer of 5 to 20,000;
• n represents an integer of 2 to 5,000, with the proviso that hydrogen atoms or alkali metal ions account for 50% or more of R5's the number of which is n;
• wherein diaminocyclohexane platinum (II) is immobilized with the block copolymer via bonding between carboxyl anion of the block copolymer represented by the general formula (I-a) or (2-a) and the platinum, and the equivalent ratio of platinum (Pt) of diaminocyclohexane platinum (II) to a carboxyl group of the block copolymer (Pt/COO−) is from 0.3 to 1.

An anti-tumor composition comprising an anti-tumor effective amount of a coordinate complex in the form of a micelle and a pharmaceutically acceptable carrier, said coordinate complex comprising diaminocyclohexane platinum (II) and the block copolymer having the structure represented by the general formula (A):

• PEG-block-poly(carbo) (A)
• wherein PEG represents a poly(ethylene glycol) chain segment and poly(carbo) represents a polymer chain segment having a carboxyl group and selected from the group consisting of poly(glutamic acid) chain segment and poly(aspartic acid) chain segment,
• wherein diaminocyclohexane platinum (II) is immobilized with the block copolymer via binding between carboxyl anion of poly(carbo) and the platinum, and
• wherein the block copolymer is represented by the following general formula (1) or (2), or salt thereof:
• wherein
• R1 represents a hydrogen atom or an unsubstituted or substituted liner or branched C1-12 alkyl group;
• L1 represents —(CH2)b—NH— wherein b represents an integer of 1 to 5;
• L2 represents —(CH2)c—CO— wherein c represents an integer of 1 to 5;
• R2 represents a methylene group or ethylene group;
• R3 respectively and independently represents an atom or a group selected from the group consisting of a hydrogen atom, a benzyl oxycarbonyl group, a t-butyl oxycarbonyl group, an acetyl group, a trifluoroacetyl group, a benzyl carbonyl group, a benzhydryl carbonyl group, an acryloyl group and methacryloyl group;
• R4 respectively and independently represents a group selected from the group consisting of a hydroxyl group, a benzyloxy group, a t-butyloxy group, a methoxy group, a benzhydryloxy group, an allyloxy group and a vinyl phenyloxy group;
• R5 respectively and independently represents an atom or a group selected from the group consisting of a hydrogen atom, an alkali metal ion, a benzyl group, a benzhydryl group and a C1-6 alkyl group;
• m represents an integer of 5 to 20,000;
• n represents an integer of 2 to 5,000;
• and
• x represents an integer of 0 to 5,000 with the proviso that x is not larger than n, and that hydrogen atoms or alkali metal ions account for 50% or more of R5's the number of which is the sum of n-x and x wherein the equivalent ratio of platinum (Pt) of diaminocyclohexane platinum (II) to a carboxyl group of the block copolymer (Pt/COO−) is from 0.3 to 1.