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Single functional branched polyethylene glycol containing degradable radical, preparation method and biorelevant substance of single functional branched polyethylene glycol

A technology of polyethylene glycol and functionalization, which is applied in the direction of medical preparations and pharmaceutical formulations of non-active ingredients, can solve the problems of activity reduction and disappearance, increase exposure, improve drug activity reduction, and improve drug activity. effective effect

Active Publication Date: 2015-06-24
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to overcome the deficiencies in the prior art, the present invention develops a preparation method and application of a single functionalized branched polyethylene glycol containing degradable groups. Problems with reduced or lost activity after PEGylation

Method used

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  • Single functional branched polyethylene glycol containing degradable radical, preparation method and biorelevant substance of single functional branched polyethylene glycol
  • Single functional branched polyethylene glycol containing degradable radical, preparation method and biorelevant substance of single functional branched polyethylene glycol
  • Single functional branched polyethylene glycol containing degradable radical, preparation method and biorelevant substance of single functional branched polyethylene glycol

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preparation example Construction

[0110] In the preparation method part of the present invention, dotted lines are used in the structural formulas of some skeleton groups to indicate that the skeletons will be directly connected to the groups shown in the structural formulas in the specified compounds.

[0111] In the present invention, the ring structure is represented by a circle, and different labels are given according to the difference of the ring structure. For example,

[0112] represents any ring structure;

[0113] Represents an aliphatic ring structure without any aromatic or heteroaromatic rings, also known as aliphatic rings;

[0114] Represents an aromatic ring structure, containing at least one aromatic ring or heteroaromatic ring, also known as an aromatic ring;

[0115] Indicates the skeleton of sugars or sugar derivatives containing cyclic monosaccharide skeletons, also known as sugar rings;

[0116] Indicates a ring containing amide bonds, ester bonds, imides, acid anhydrides and...

Embodiment 1

[1090] Embodiment 1: the preparation of several key intermediates:

[1091] Preparation of Compound H1-1

[1092] In this example, the H-like compound selects the branched group is a symmetric type, and is a carbon atom branching center, L 1 =CH 2 , L 2 =CH 2 , A 1 =A 2 =CH 3 , R=OH, the protecting group PG=TBS of the hydroxyl group at the end of the symmetry axis of the small molecule initiator. The total molecular weight is designed to be about 10,000, and the molecular weight of the two branched chains is about 2*4500=9000, that is, n 1 ≈n 2 ≈102; the molecular weight of the main chain of the symmetry axis is about 1000, that is, n 3 ≈23.

[1093]

[1094] a. In an anhydrous and oxygen-free airtight reaction kettle, add tetrahydrofuran (250mL), small molecule initiator (2.532mmol) and diphenylmethyl potassium (4.0mmol) successively;

[1095] b. Add calculated amount of ethylene oxide (26.5mL), gradually heat up to a temperature of 60°C, and react for 48 ho...

Embodiment 2

[1122] Embodiment 2: Preparation of F2-1 compound

[1123]

[1124] Preparation of compound F2-1

[1125] In this example, the selected branched group of the class F compound is a symmetrical type, U is a nitrogen atom, and L 1 =CH 2 CH 2 , L 2 =CH 2 CH 2 , L 3 =CH 2 CH 2 ,A 1 =A 2 =CH 3 ,q 1 = 1, The protecting group of the terminal hydroxyl group of the main chain of the small molecule initiator is PG=acetone. The total molecular weight is designed to be about 20,000, and the molecular weight of the two branched chains is about 2*1500=3000, that is, n 1 ≈n 2 ≈34; the molecular weight of the main chain containing active functional groups is about 17000, that is, n 3 ≈396.

[1126]

[1127] a. In an anhydrous and oxygen-free airtight reaction kettle, sequentially add tetrahydrofuran (250mL), small molecule initiator 9-1 (2.532mmol) and diphenylmethyl potassium (2.0mmol);

[1128] b. Add the calculated amount of ethylene oxide (8.8mL), gradually heat up...

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Abstract

The invention discloses single functional branched polyethylene glycol (formula 1 in the specification) containing a degradable radical, a preparation method and a modified biorelevant substance of single functional branched polyethylene glycol (formula 2 in the specification), wherein U is a trivalent branched radical; n1, n2 and n3 are degree of polymerization of PEG chains; three PEG chains are respectively and independently polydisperse or monodisperse; A1 and A2 are C1-20 alkyl; L1, L2, L3 and Z1 are linking radicals; q1 is 0 or 1; R01 is a functional radical or of protected form; D is residue of the biorelevant substance; L4 is a linking group formed after R01 reacts with the biorelevant substance; and the part other than R01 of formula (1) contains at least one radical degradable under the condition of light, heat, enzyme, oxidoreduction, acidity or alkality. The medicine modified by the single functional branched polyethylene glycol containing the degradable radical can be degraded under specified conditions to release highly active medicine molecules, so that the activity and efficacy of the medicine are improved.

Description

technical field [0001] The invention relates to the field of polymer synthesis chemistry, in particular to a single functionalized branched polyethylene glycol containing degradable groups, a preparation method and biological related substances. Background technique [0002] PEGylation is one of the important means of drug modification. Among them, functionalized polyethylene glycol (PEG) can use its active groups to interact with drug molecules (including protein drugs and organic small molecule drugs), peptides, sugars, lipids, oligonucleotides, affinity ligands, etc. Polymers, cofactors, liposomes, and biological materials are coupled through covalent bonds to achieve polyethylene glycol modification of drugs and other biologically related substances. The modified drug molecule will have many excellent properties of polyethylene glycol (such as hydrophilicity, flexibility, anticoagulation, etc.). At the same time, due to the steric repulsion effect, the PEG-modified dru...

Claims

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Application Information

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IPC IPC(8): C08G65/331C08G65/333C08G65/334C08G65/337C08G65/336C08G65/28C08G65/00A61K47/48A61K47/60
Inventor 翁文桂刘超廖金城闫策周纯
Owner XIAMEN SINOPEG BIOTECH
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