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Anti-tumour uracil compound and lipid composition thereof

A lipid composition and compound technology, applied in the field of medicinal chemistry, can solve problems such as poor patient compliance, high incidence of adverse reactions, and short plasma half-life

Pending Publication Date: 2021-04-09
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

However, due to the poor selectivity of this product to tumors, the incidence of adverse reactions to myelosuppression, gastrointestinal tract, central nervous system and skin is very high.
In addition, the plasma half-life of this product is short (t1 / 2: 5-20min), requiring continuous intravenous administration (oral absorption is incomplete and difficult to predict), so the patient's compliance is poor (Shimma N, et al. Bioorganic & Medicinal Chemistry 8 (2000) 1697 -1706)

Method used

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  • Anti-tumour uracil compound and lipid composition thereof
  • Anti-tumour uracil compound and lipid composition thereof
  • Anti-tumour uracil compound and lipid composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1 , (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl n-hexyloxyformate

[0087]

[0088] Commercially available 5-fluorouracil (compound of formula II, 1.3 g, 0.01 mol) was dissolved in 15 mL of 37% formaldehyde solution, stirred at 50° C. for 3 hours, and the reaction was detected by TLC. The reaction solution was concentrated to dryness under reduced pressure to obtain compound III, which was used in the next reaction.

[0089] Dissolve 0.01 mol of compound III obtained above in 20 mL of dichloromethane, add triethylamine (2.02 g, 0.02 mol), then add hexyloxychloroformate (III', 1.97 g, 0.012 mol) in batches, and stir at room temperature for 2 hours , TLC monitored the end of the reaction. The reaction solution was washed successively with saturated brine and saturated sodium bicarbonate solution, the organic phase was concentrated, and the residue was subjected to silica gel column chromatography (eluent V 石油醚 :V 乙酸乙酯 =5: 1) Separation and puri...

Embodiment 2

[0092] Embodiment 2, (5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl n-decyloxyformate

[0093] Referring to the method of Example 1, compound III was reacted with n-decyloxyformyl chloride to obtain the title compound as a white solid, which can be referred to as compound 2 in the present invention.

[0094] 1 H NMR (500MHz, CDCl 3 )δ8.59(s,1H),7.65(d,J=5.36Hz,1H),5.67(s,2H),4.20(t,J=6.88Hz,2H),1.33-1.25(m,16H), 0.87(t,J=6.89Hz,3H).

[0095] MS-ESI(m / z):345(M+H) + .

Embodiment 3

[0096] Embodiment 3, (5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl n-tetradecyloxycarboxylate

[0097] Referring to the method of Example 1, compound III was reacted with n-tetradecyloxycarbonyl chloride to obtain the title compound as a white solid, which may be referred to as compound 3 in the present invention.

[0098] 1 H NMR (500MHz, CDCl 3 )δ8.63(s,1H),7.62(d,J=5.36Hz,1H),5.66(s,2H),4.19(t,J=6.86Hz,2H),1.34-1.25(m,24H), 0.87(t,J=6.99Hz,3H).

[0099] MS-ESI(m / z):401(M+H) + .

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Abstract

The invention relates to an anti-tumour uracil compound and a lipid composition thereof. The invention provides a lipid composition comprising a compound shown in the formula (I), phospholipid, pegylated phospholipid, cholesterol and an excipient. The compound shown in the formula (I) is shown in the specification, wherein various substituent groups are shown in the specification. The invention also provides a method for preparing the lipid composition, a method for preparing the lipid composition from the compound shown in the formula (I) so as to improve the anti-tumour activity of an anti-tumour drug, and application of the lipid composition as an anti-tumour drug; for example, the lipid composition is used for colorectal cancer, prostate cancer, breast cancer, gastric cancer, ovarian cancer, chorionic epithelial cancer, malignant grape embryo, head and neck squamous cell carcinoma, skin cancer, liver cancer, bladder cancer, lung cancer, cervical cancer, liver cancer, biliary tract system tumour, pancreatic cancer and the like. The method and the lipid composition provided by the invention can effectively improve the anti-tumour activity of the drug; and the lipid composition prepared by the method provided by the invention shows excellent pharmaceutical properties.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a method for improving the antitumor activity of 5-fluorouracil, in particular to a group of 5-fluorouracil prodrugs with antitumor activity, a preparation method thereof, and an antitumor application. In addition, the present invention also provides the lipid composition of the above-mentioned 5-fluorouracil prodrug and the preparation method of the lipid composition. The lipid composition of the present invention exhibits excellent technical effects. Background technique [0002] Fluorouracil, Fluorouracil, also known as 5-fluorouracil, chemical name is 5-fluoro-2,4(1H,3H)-pyrimidinedione, CAS number 51-21-8, molecular formula C4H3FN2O2, molecular weight 130.08, its chemical structure is as follows As shown in (II): [0003] [0004] 5-Fluorouracil is the first pyrimidine anti-metabolite synthesized according to a certain idea, which is converted into 5-fluorodeoxyuridine ...

Claims

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Application Information

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IPC IPC(8): A61K31/513A61K47/24A61K47/28A61K9/10A61K9/127A61K9/14A61K9/19A61P35/00
CPCA61K9/10A61K9/1277A61K9/146A61K9/19A61K31/513A61K47/24A61K47/28A61P35/00
Inventor 夏桂民刘明亮王雪蕾
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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