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Albumin nanoparticle composition and its preparation method

A technology of albumin nanoparticles and composition, applied in the field of medicinal chemistry, can solve the problems affecting the clinical drug benefit/risk ratio of gemcitabine

Active Publication Date: 2021-09-14
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These adverse reactions will seriously affect the benefit / risk ratio of gemcitabine clinical use

Method used

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  • Albumin nanoparticle composition and its preparation method
  • Albumin nanoparticle composition and its preparation method
  • Albumin nanoparticle composition and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] Example 1. Preparation of 2', 2'-difluoro-2'-deoxycytidine-3', 5'-di-n-decanoate

[0176] The schematic reaction scheme is as follows:

[0177]

[0178] Dissolve commercially available 2',2'-difluoro-2'-deoxycytidine-3',5'-dibenzoate (compound of formula II, 4.7 g, 0.01 mol) in 50 mL of dioxane ring, then add triethylamine (4.0g, 0.04mol), N,N-lutidine (1.8g, 0.01mol) and Boc 2 O (12.9 g, 0.04 mol). The reaction was carried out at 40° C. for 5 hours, and the reaction was monitored by TLC to complete. Post-treatment: Pour the reaction liquid into water, extract with dichloromethane, concentrate the organic phase (to obtain compound III) and proceed to the next reaction directly. The above compound III was dissolved in 20 mL of methanol solution, then solid NaOH (28 mg, 0.7 mmol) was added, stirred at room temperature for 4 hours, and the reaction was monitored by TLC. Post-treatment: Filtrate directly with silica gel, concentrate the filtrate and perform column ...

Embodiment 2

[0183] Example 2, preparation of 2',2'-difluoro-2'-deoxycytidine-3',5'-dilaurate

[0184] The preparation method refers to Example 1. Compound IV is reacted with lauroyl chloride, and the Boc protecting group is removed by trifluoroacetic acid to obtain a white solid as the title compound.

[0185] 1 H NMR (500MHz, CDCl 3 )δ7.55(brs,1H),6.32(brs,1H),6.09(brs,1H),5.29(brs,1H),4.34-4.45(m,3H),2.37-2.40(m,4H),1.60 -1.70(m,4H),1.25-1.29(m,32H),0.92(t,J=6.50Hz,6H).MS-ESI(m / z):628.3(M+H) + .

Embodiment 3

[0186] Example 3, Preparation of 2',2'-difluoro-2'-deoxycytidine-3',5'-dimyristate

[0187] The preparation method refers to Example 1. Compound IV is reacted with myristoyl chloride, and the Boc protecting group is removed by trifluoroacetic acid to obtain a white solid as the title compound.

[0188] Mp:142-144℃; 1 H NMR (500MHz, CDCl 3 )δ7.44(d, J=6.85Hz, 1H), 6.44(d, J=8.85Hz, 1H), 5.74(d, J=7.30Hz, 1H), 5.22(d, J=11,90Hz, 1H ),4.38(brs,2H),4.26(brs,1H),2.41(t,J=7.35Hz,2H),2.36(t,J=7.35Hz,2H),1.60-1.70(m,4H),1.25 -1.29(m,40H),0.87(t,J=6.50Hz,6H).MS-ESI(m / z):684.4(M+H) + .

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Abstract

The present invention relates to an albumin nano particle composition and a preparation method thereof. The composition contains 100 parts by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof and 100-1500 parts by weight of albumin. The albumin is an albumin selected from the following: ovalbumin, bovine blood albumin, human blood albumin, recombinant human albumin, etc., preferably human blood albumin or recombinant human albumin; Optionally contain one or more excipients selected from the following: cholesterol, phospholipids, lecithin, PEGylated phospholipids, phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, glycerophospholipids Acids, synthetic phospholipids and other types of phospholipids. The preparation method and pharmaceutical use of the composition are also provided, and the method of the invention presents excellent technical effects as described in the description.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a method for improving the antitumor activity of gemcitabine, in particular to a group of gemcitabine ester compounds with antitumor activity, a composition thereof, a preparation method, and an antitumor application. The present invention also relates to an albumin nanoparticle preparation composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a preparation method thereof. Background technique [0002] Gemcitabine, English name gemcitabine, Chinese chemical name: 4-amino-1-(3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-1H-pyrimidin-2-one), English Chemical name: 2′-deoxy-2′,2′-difluorocytidine, molecular formula: C 9 h 11 f 2 N 3 o 4 , is a novel fluorinated nucleoside analog, and the chemical structure of gemcitabine is shown in the following formula (J): [0003] [0004] Gemcitabine itself has no pharmacologi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/51A61K31/7068A61K47/42A61K9/19A61P35/00
CPCA61K9/19A61K9/5169A61K31/7068A61P35/00
Inventor 夏桂民刘明亮郭晓茹
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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