Polymer conjugate of combretastatin

A technology of combretastatin and high molecular weight, which is applied in the field of preparation of high molecular weight conjugates, can solve problems such as no description of combretastatin conjugates, etc., and achieve the effect of effective therapeutic effect

Inactive Publication Date: 2009-07-22
NIPPON KAYAKU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, Patent Document 4, Patent Document 5 and Patent Document 6 do not describe conjugates of combretastatin

Method used

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  • Polymer conjugate of combretastatin
  • Polymer conjugate of combretastatin
  • Polymer conjugate of combretastatin

Examples

Experimental program
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Effect test

Embodiment 1

[0086] Embodiment 1: the synthesis of compound 1 (combretastatin A-4 and the methoxypolyethylene glycol part of molecular weight 5000 and the polyaspartic acid part of degree of polymerization 30 constitute the block copolymer conjugate: General Formula (I), wherein R1=Me (methyl), R2=1,3-propylene, R3=Ac (acetyl), R4=combretastatin A-4 residue, R5=isopropylaminocarbonyl isopropylamino, d+e+f+g+h+i+j=30, t=113).

[0087] The methoxypolyethylene glycol-polyaspartic acid block copolymer prepared according to the method described in Patent Document 5 (aspartic acid part: a mixture of α-type and β-type, polymerization degree: 30, 2670 mg) and combretastatin A-4 (600 mg) synthesized according to the method described in Non-Patent Document 1 were dissolved in DMF (60 ml), and DMAP (174 mg) and DIPC (2.97 ml) were added thereto. The mixture was stirred at 25°C for 20 hours. Ethyl acetate (180 ml) and diisopropyl ether (720 ml) were added to the reaction liquid, and the mixture was ...

Embodiment 2

[0090] Embodiment 2: the synthesis of compound 2 (combretastatin A-4 and the methoxypolyethylene glycol part of molecular weight 12000 and the polyglutamic acid part of degree of polymerization 23 constitute the block copolymer conjugate: general formula (II), wherein R1 = Me (methyl), R2 = 1,3-propylene, R3 = Ac (acetyl), R4 = combretastatin A-4 residue, R5 = isopropylaminocarbonyliso Propylamino, k+m+n=23, t=273).

[0091]The methoxypolyethylene glycol-polyglutamic acid block copolymer (581 milligrams) prepared according to the method described in Japanese Patent Application Laid-Open No. 5-955 and the Cobb synthesized according to the method described in Non-Patent Document 1 Statin A-4 (100 mg) was dissolved in DMF (4.5 mL), DMAP (16.5 mg) and DIPC (0.283 mL) were added thereto, and stirred at 20° C. for 40 hours. DIPC (0.070 ml) was added to the reaction solution, and the stirring was continued for 1.5 hours after the temperature reached 25°C. To the reaction solution w...

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Abstract

The invention relates to a novel derivative of a combretastatin which has water solubility and is capable of releasing a drug independent of biological enzymes in which individual differences are likely caused and whose effective therapeutic effect can be expected has been demanded. A polymer conjugate of a combretastatin, characterized by having a structure in which a hydroxy group of a combretastatin is linked via an ester bond to a carboxylic acid group of the following polymer moiety in a block copolymer of a polyethylene glycol structure moiety with a polymer moiety having two of more carboxylic acid groups such as polyaspartic acid or polyglutamic acid is provided.

Description

technical field [0001] The present invention relates to high molecular weight conjugates of combretastatin comprising a block copolymer of a polyethylene glycol moiety and a polymer moiety having two or more carboxylic acids, wherein the carboxylic acid groups of the polymer moiety pass through The ester bond is connected to the hydroxyl group of the combretastatin, and the invention also relates to the preparation method and application of the high molecular weight conjugate of the combretastatin. Background technique [0002] Combretastatin was obtained from natural African dwarf willow ( Combretum caffrum) Combretastatin has been confirmed to have tubulin polymerization inhibitory activity. Specifically, the compound has blood flow inhibitory activity by causing morphological changes in vascular endothelial cells. Therefore, the compound is expected to be useful as a therapeutic agent for neovascularization-related diseases, for example, for the treatment of solid can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61P9/00A61P35/00C08G81/00
CPCA61K47/48315A61K47/48215C08G73/1092A61K47/60A61K47/645A61P9/00A61P35/00A61P43/00A61K47/50
Inventor 北川正行石川惠三增田亮高盐一俊
Owner NIPPON KAYAKU CO LTD
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