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Uracil compounds and their antitumor applications

A compound and representative technology, applied in the field of medicinal chemistry, can solve the problems of short plasma half-life, poor patient compliance, and poor tumor selectivity

Active Publication Date: 2022-04-29
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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  • Uracil compounds and their antitumor applications
  • Uracil compounds and their antitumor applications
  • Uracil compounds and their antitumor applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 , (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl n-hexyloxyformate

[0055]

[0056] 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.

[0057] 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

[0060] Embodiment 2, (5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl n-decyloxyformate

[0061] 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.

[0062] 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).

[0063] MS-ESI(m / z):345(M+H) + .

Embodiment 3

[0064] Embodiment 3, (5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl n-tetradecyloxycarboxylate

[0065] 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.

[0066] 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).

[0067] MS-ESI(m / z):401(M+H) + .

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Abstract

The invention relates to uracil compounds and their antitumor application. Specifically, the present invention relates to a group of novel uracil compounds with anti-tumor activity, their preparation methods, and their anti-tumor applications. The compound of the present invention has the chemical structure shown in the following formula (I), wherein each substituent is as described in the description. The compound prepared by the invention has excellent antitumor effect on various tumors.

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. 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 (5-FdUrd) under the action of thymidine phosphorylase (TP), which can convert The folate cofactor N5-10-methylenetetrahydrofolate covalently binds to thymine synthase (TS) to form a polymer that inhibits the conversion of uracil to thymine, thereby interfe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/553A61P35/00
CPCC07D239/553A61P35/00
Inventor 刘明亮夏桂民汪阿鹏
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI