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Multifunctional H-type polyethylene glycol derivative and preparation method thereof

A technology for polyethylene glycol and derivatives, applied in the field of multifunctional H-type polyethylene glycol derivatives and its preparation, can solve problems such as failure to meet biological safety requirements, disappearance, and decline in drug activity, and achieve structural and The effect of enriching performance, promoting functional groups, and weakening stereoscopic effect

Active Publication Date: 2015-04-22
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Branched polyethylene glycol with two polyethylene glycol arms represented by this traditional V-shaped structure has only a single active group that can react with drug molecules, and the drug loading is low, so the application range is very limited
[0005] In addition, for drug molecules modified by PEGylated derivatives, since the binding site may be connected to the active site or near the active site of the drug, or the steric effect is introduced, the activity of the drug after PEGylation will often result. decline or even disappear
Moreover, in conventional administration methods, such as injection, oral administration, etc., besides acting on the lesion, drug molecules usually also accumulate in normal tissues, causing certain or even serious side effects.
Although the toxicity and side effects can be greatly reduced through PEGylation modification, for some drugs, especially anticancer drugs, the existing PEGylation modification still cannot meet the biological safety requirements

Method used

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  • Multifunctional H-type polyethylene glycol derivative and preparation method thereof
  • Multifunctional H-type polyethylene glycol derivative and preparation method thereof
  • Multifunctional H-type polyethylene glycol derivative and preparation method thereof

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preparation example Construction

[0115] 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.

[0116] 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. E.g,

[0117] represents any ring structure;

[0118] Represents an aliphatic ring structure without any aromatic or heteroaromatic rings, also known as aliphatic rings;

[0119] Represents an aromatic ring structure, containing at least one aromatic ring or heteroaromatic ring, also known as an aromatic ring;

[0120] Indicates the skeleton of sugars or sugar derivatives containing cyclic monosaccharide skeletons, also known as sugar rings;

[0121] Indicates a ring containing amide bonds, ester bonds, imides, acid anhydrides and other c...

Embodiment 1

[1679] Embodiment 1: Preparation of H-type polyethylene glycol terminal hydroxyl derivatives

[1680] Synthesis of Hydroxyl Derivatives H1-H1-1

[1681] In this example, the type H polyethylene glycol compound is selected as F 1 =F 2 =-CH 2 CH 2 Oh, (U 1 , U 2 symmetrical, L 1 =L 2 =L 3 =L 4 =CH 2 , L 5 , L 6 does not exist), j=1, W 0 for -CH 2 CH 2 -, m 1 =0. The total molecular weight is designed to be about 25000, and the molecular weight of the four branched chains is about 4*5000=20000, namely n 1 ≈n 2 ≈n 3 ≈n 4 ≈114, the molecular weight of the main chain is about 5000, m 2 ≈113.

[1682]

[1683] a. In an anhydrous and oxygen-free airtight reaction kettle, sequentially add tetrahydrofuran (250mL), ethylene glycol (2.532mmol) and diphenylmethyl potassium (4.0mmol);

[1684] B, adding the calculated amount of oxirane (570mmol), gradually warming up to a temperature of 60 ° C, reacted for 48 hours;

[1685] c. Add excess diphenylmethyl potass...

Embodiment 2

[1697] Embodiment 2: the preparation of H type polyethylene glycol sulfonate derivative

[1698] Synthesis of Sulfonate Derivatives B1-B1-1

[1699] In this example, the type H polyethylene glycol compound is selected as F 1 =F 2 =Ts(p-toluenesulfonyl), j=1,W 0 for CH 2 CH 2 ,m 1 =0. The total molecular weight is designed to be about 25000, and the molecular weight of the four branched chains is about 4*5000=20000, namely n 1 ≈n 2 ≈n 3 ≈n 4 ≈114, the molecular weight of the main chain is about 5000, m 2 ≈113.

[1700]

[1701] After adding 40g of tetrahydroxyl H-type branched polyethylene glycol (H1-H1-1) with symmetrical bifurcation points in a dry and clean 1L round bottom flask, nitrogen protection, add 500mL of anhydrous anhydrous Oxygen dichloromethane, 20mL pyridine and 5g p-toluenesulfonyl chloride, reacted at room temperature for 24 hours, added 1mol / L hydrochloric acid to neutralize to pH<7, washed the aqueous phase with dichloromethane (3*50mL), comb...

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Abstract

The invention discloses a multifunctional H-type polyethylene glycol derivative and a preparation method thereof. The structure is as shown in formula (1) in the description, wherein a linear main axis LPEG and four PEG branched chains are included, and n1, n2, n3 and n4 are polymerization degrees of the branched chains, respectively; U1 and U2 are trivalent branching groups connecting the main axis LPEG with two PEG branched chains; F1 and F2 contain functional groups or their protected forms R01, and contain or do not contain branching groups G, and correspondingly, the number of R01 is one or more than one; F1 is the same as or different from F2; any linking group in the molecule or linking groups formed with adjacent heteroatom groups are stable or degradable; any PEG chain segment in the molecule independently shows polydispersity or monodispersity. The functionalized polyethylene glycol is diverse in branching structure and branching arm length, is adjustable and easily-controllable in various parameters and performance indexes, and is wide in application.

Description

technical field [0001] The invention relates to the field of polymer synthesis, in particular to a multifunctional H-type polyethylene glycol derivative and a preparation method thereof. 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 drug avoids glomerular filtering biological responses such as ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/336C08G65/334C08G65/333C08G65/337
Inventor 翁文桂刘超闫策吴少锋周纯
Owner XIAMEN SINOPEG BIOTECH
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