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Pure PEG-lipid conjugates

A technology of conjugates and lipids, applied in the field of PEG-lipid conjugates of PEG chains, which can solve problems such as expensive

Inactive Publication Date: 2012-09-12
UKRAINIAN INDEPENDENT INFORMATION AGENCY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these PEG chains are extremely expensive and require additional synthetic steps to incorporate them into pharmaceutical and / or cosmetic formulations

Method used

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Examples

Experimental program
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Embodiment 1

[0195] Embodiment 1.3-oleoyl-1, the synthesis of 2-two (methoxyhexaethylene glycol) glycerol

[0196] Part 1A: 3-Benzyl-1,2-di(methoxyhexaethylene glycol)glycerol

[0197] (±)-3-Benzyloxy-1,2-propanediol (1.2 g, 6 mmol), NaH (0.96 g, 40 mmol) and dry THF (150 mL) were added into a three-necked flask. A dry THF solution (50 mL) of monomethoxyhexaethylene glycol tosylate (5.4 g, 12 mmol) was then added dropwise to the mixture at room temperature. The mixture was refluxed for 24 hours and cooled to room temperature. Ice-cold methanol was added to the reaction mixture to quench excess NaH. Evaporate the solvent and wash with 5% HCl (w / v) and CH 2 Cl 2 The crude product was extracted. The solvent was evaporated and further purified by gel permeation chromatography to give 85% colorless liquid.

[0198] Part 1B: 3-Hydroxy-1,2-bis(methoxyhexaethylene glycol)glycerol

[0199] 5 drops of acetic acid and 0.6 g of palladium black were added to a solution of 5 g of 3-benzyl-1,2-di(...

Embodiment 21

[0204] Example 2.1,2-dioleoyl-racemic-3-monomethoxy dodecaethylene glycol (mPEG-12)-glycerol

[0205] The general steps used for this synthesis are shown schematically in Reaction Scheme 8.

[0206]

[0207] Reaction Scheme 8: Synthesis of 1,2-isopropylidene-glycerol-3-monomethoxydodecyl glycol ester

[0208] 1 mole of hexaethylene glycol is mixed with 0.15 mole of pyridine and heated to 45-50°C, and 0.1 mole of trityl chloride is added. The reaction was carried out overnight (approximately 16 hours) with continuous stirring, then cooled to room temperature and extracted with toluene. The extract was washed with water, then extracted with hexane, and washed with MgSO 4 dry. The solvent was removed in vacuo to give trityl-hexaethylene glycol as a pale yellow oil (70-85% yield).

[0209] 0.1 mole of trityl-hexaethylene glycol and 0.101 mole of p-toluenesulfonyl chloride were mixed in 100 mL of dichloromethane. The homogeneous mixture was cooled to 0 °C in a dry ice aceto...

Embodiment 31

[0220] Example 3.1,2-Dioleoyl-racemic-3-monomethoxydodecaethylene glycol (mPEG-12) glycerol

[0221] The general steps used for this synthesis are illustrated in the following scheme (Scheme 9):

[0222]

[0223] Reaction Scheme 9: Synthesis of 1,3-dioleoyl-2-glyceride

[0224] 0.033 molar dihydroxyacetone was stirred continuously in 150 mL of chloroform under nitrogen. 0.06 mol of oleoyl chloride was dissolved in 150 mL of chloroform and added to this heterogeneous mixture of dihydroxyacetone, followed by 10 mL of anhydrous pyridine. The reaction was carried out at room temperature for 30 minutes with continuous stirring. The mixture became homogeneous and the reaction was complete when no oleoyl chloride was detectable in the mixture. The bulk solvent was removed under vacuum. The residue was washed with water, then extracted with ethyl acetate. The aqueous phase was repeatedly extracted with ethyl acetate, the combined organic layers were washed again with water, dr...

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Abstract

Syntheses of polyethyleneglycol (PEG)-lipid conjugates are disclosed. Such syntheses involve stepwise addition of small PEG oligomers to a glycerol backbone until the desired chain size is attained. Polymers resulting from the syntheses are highly monodisperse. The present invention provides several advantages such as simplified synthesis, high product yield and low cost for starting materials. The present synthesis method is suitable for preparing a wide range of conjugates. In another aspect, the invention comprises PEG lipid conjugates having a glycerol backbone covalently attached to one or two monodisperse PEG chains and one or two lipids. These conjugates are especially useful for pharmaceutical formulations.

Description

field of invention [0001] The present invention relates to the synthesis of polyethylene glycol (PEG)-lipid conjugates. More specifically, the present invention relates to convenient and economical synthetic methods and compositions for the preparation of PEG-lipid conjugates with substantially monodisperse PEG chains. [0002] priority claim [0003] This application claims U.S. Provisional Patent Application No. 61 / 217,627, entitled "PURE PEG-LIPID CONJUGATES" and filed June 2, 2009; and entitled "PURE PEG -LIPID CONJUGATES (pure PEG-lipid conjugates)" and the priority of U.S. Provisional Patent Application No. 61 / 284,065 filed on December 12, 2009. Background of the invention [0004] When used as a delivery vehicle, PEG-lipid conjugates have the ability to improve the pharmacology profile and solubility of lipophilic drugs. It also offers other potential advantages, such as minimizing side effects and toxicity associated with therapeutic treatment. [0005] The narro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127
CPCC08G65/329C08L2203/02A61K47/60A61K47/6911A61K31/77C08L63/10
Inventor 念·吴布莱恩·查尔斯·凯勒
Owner UKRAINIAN INDEPENDENT INFORMATION AGENCY
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