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Tegafur derivatives and their preparation methods and uses

A derivative, tegafur technology, applied in the field of tegafur derivatives and its preparation, can solve the problems of high toxicity and low bioavailability of derivatives, achieve good tumor cell apoptosis induction effect, alleviate toxicity, improve selective effect

Active Publication Date: 2020-09-08
INST OF PHARMACY SHANDONG PROV ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to provide a tegafur derivative to solve the problems of high toxicity and low bioavailability of tegafur and its derivatives

Method used

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  • Tegafur derivatives and their preparation methods and uses
  • Tegafur derivatives and their preparation methods and uses
  • Tegafur derivatives and their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the preparation of compound 5a

[0052]

[0053] Take 3 (1.00mmol, 258.00mg, 1.00eq), 1-hydroxybenzotriazole (1.11mmol, 150.00mg, 1.11eq), EDC·HCl (1.11mmol, 213.00mg, 1.11eq), DIPEA (3.05mmol, 532.00mg, 3.05eq), DMF (7.5mL), glycine methyl ester hydrochloride (1.00mmol, 125.55mg, 1.00eq), stirred at room temperature for 16h. After the reaction, add a small amount of water and saturated NaHCO 3 solution, extracted 3 times with ethyl acetate, and the ester layer was washed 2 times with saturated NaCl solution. Anhydrous sodium sulfate was added to dry for 0.5 h, and spin-dried to obtain a white solid 5n.

[0054] 1 H NMR (400MHz, DMSO) δ8.64 (t, J = 5.8Hz, 1H), 8.02 (d, J = 6.7Hz, 1H), 5.99–5.90 (m, 1H), 4.46 (s, 2H), 4.32 –4.24(m,1H),3.88(d,J=5.8Hz,2H),3.83(dd,J=15.0,7.3Hz,1H)3.64(s,3H),2.31–2.21(m,1H),2.06 – 1.89(m,3H). 13 C NMR(101MHz,DMSO)δ170.6,167.1,156.8(d,J=26.1Hz),149.1,139.8(d,J=228.3Hz), 124.5(d,J=33.8Hz),87.8,70.1,52.23,43.4 ,41.3,32.1...

Embodiment 2

[0056] Embodiment 2: the preparation of compound 5b

[0057]

[0058] Take 3 (1.00mmol, 258.00mg, 1.00eq), 1-hydroxybenzotriazole (1.11mmol, 150.00mg, 1.11eq), EDC·HCl (1.11mmol, 213.00mg, 1.11eq), DIPEA (3.05mmol, 532.00mg, 3.05eq), DMF (7.5mL), L-alanine methyl ester hydrochloride (1.00mmol, 139.60mg, 1.00eq). The reaction was stirred at room temperature for 16h. After the reaction, add a small amount of water and saturated NaHCO 3 solution, extracted three times with ethyl acetate, and the ester layer was washed twice with saturated NaCl solution. Anhydrous sodium sulfate was added to dry for 0.5 h, and spin-dried to obtain light yellow solid 5a.

[0059] 1 H NMR (400MHz, DMSO) δ8.64 (d, J = 7.0Hz, 1H), 8.02 (d, J = 6.7Hz, 1H), 5.99–5.92 (m, 1H), 4.44 (q, J = 16.0Hz ,2H),4.33–4.23(m,2H),3.82(q,J=7.4Hz,1H),3.63(s,3H),2.33–2.18(m,1H),2.05–1.88(m, 3H), 1.28(d,J=7.2Hz,3H). 13 C NMR (100MHz, DMSO) δ173.3, 166.3, 156.8(d, J=26.1Hz), 149.1, 139.8(d, J=228.2Hz), 124.5(d, ...

Embodiment 3

[0061] Embodiment 3: the preparation of compound 5c

[0062]

[0063] Take 3 (1.00mmol, 258.00mg, 1.00eq), 1-hydroxybenzotriazole (1.11mmol, 150.00mg, 1.11eq), EDC·HCl (1.11mmol, 213.00mg, 1.11eq), DIPEA (3.05mmol, 532.00mg, 3.05eq), DMF (7.50mL), L-valine methyl ester hydrochloride (1.00mmol, 167.63mg, 1.00eq). The reaction was stirred at room temperature for 16h. After the reaction, add a small amount of water and saturated NaHCO 3 solution, extracted 3 times with ethyl acetate, and the ester layer was washed 2 times with saturated NaCl solution. Anhydrous sodium sulfate was added to dry for 0.5 h, and spin-dried to obtain light yellow solid 5e.

[0064] 1 H NMR (400MHz, DMSO) δ8.56 (d, J = 8.3Hz, 1H), 8.02 (d, J = 6.6Hz, 1H), 5.96 (m, 1H), 4.56-4.42 (m, 2H), 4.27 (dd, J=13.0, 6.3Hz, 1H), 4.21(dd, J=11.9, 7.0Hz, 1H), 3.82(q, J=7.3Hz, 1H), 3.65(s, 3H), 2.32– 2.20(m ,1H),2.12–1.84(m,4H),0.92–0.84(m,6H). 13 C NMR (101MHz, DMSO) δ172.3, 166.7, 156.7 (d, J = 26.2Hz), 14...

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Abstract

The invention relates to a drug for treating tumors, and belongs to the field of drugs. A tegafur derivative or a pharmaceutically acceptable salt thereof are provided. Essential amino acid groups forhuman health are introduced in pharmaceutical molecules, the selectivity to tumor cells is improved, the solubility and drug penetrability of the drug are improved, and the toxicity of the drug to cells is reduced; metabolism is lowered, compared with tegafur pharmaceutical molecules, the tegafur derivative shows slow release performance, and due to the safety performance of the amino acid, the safety problem of a prodrug modified by the amino acid of the tegafur derivative is controllable.

Description

technical field [0001] The present invention relates to medicinal compounds, in particular to a tegafur derivative and its preparation method and use. Background technique [0002] Malignant tumor is a serious disease that threatens human health. Since the second half of the 20th century, the incidence and mortality of cancer worldwide have been increasing year by year. According to the statistics of the "Annual Report of Tumor Registration in 2015", there were 3.12 million new cancer cases in the country. 6 people are diagnosed with cancer every minute. Not only is the incidence of cancer gradually increasing, but the age of onset is also tending to be younger. The World Health Organization predicts that cancer will be the "number one killer" of human beings in the 21st century. Tumor is a worldwide disease and one of the most vicious killers of human health. Many researchers at home and abroad have conducted various researches on the early diagnosis and treatment of tumo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/062C07K1/02C07D405/04A61K38/05A61K31/513A61P35/00
CPCA61K38/00A61P35/00C07D405/04C07K5/06026
Inventor 刘爱芹白著双许士琪郝超朱礼岩于胜海庞靖祥王风玲初海平王丹丹袁晔
Owner INST OF PHARMACY SHANDONG PROV ACAD OF MEDICAL SCI