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Gemcitabine amide derivates, and preparation method and application thereof

A technology of amides and derivatives is applied in the field of preparing antitumor drugs and gemcitabine amide derivatives, which can solve the problems of poor oral bioavailability and intestinal damage of gemcitabine, and achieve the effect of good antitumor activity.

Inactive Publication Date: 2012-05-02
宋云龙 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Studies have shown that gemcitabine has poor oral bioavailability due to first-pass metabolism
In addition, oral administration can cause dose-limiting intestinal damage

Method used

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  • Gemcitabine amide derivates, and preparation method and application thereof
  • Gemcitabine amide derivates, and preparation method and application thereof
  • Gemcitabine amide derivates, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: N 4 - Synthesis of n-butyryl gemcitabine (SYN-140)

[0029] 0.44 g (1.67 mmol) of gemcitabine, 5 mL of anhydrous pyridine, and 1.1 mL of triethylchlorosilane were sequentially added into a 50 mL round bottom flask, and stirred at room temperature for 1.5 hours. Obtain solution A; at the same time, dissolve 0.16g (1.81mmol) of n-butyric acid in 4mL of acetonitrile, add 0.33g (2.03mmol) of carbonyldiimidazole, stir at room temperature for 0.5 hours, drop this solution into solution A, and keep warm at 60°C Stir overnight, remove the solvent from the reaction solution under reduced pressure, dissolve the residue in 5 mL of methanol, add 1 mL of trifluoroacetic acid dropwise, stir for 0.5 hours, pour 50 mL of ethyl acetate, collect the precipitated solid, wash the solution with saturated brine 15 mL×2, Wash once with water, dry the organic phase with anhydrous sodium sulfate, reclaim the solvent, combine the residue and the previously precipitated solid to obtai...

Embodiment 2

[0031] Example 2: N 4 -Synthesis of phenylbutyryl gemcitabine (SYN-141)

[0032] Prepare with reference to the method of Example 1.

[0033] MP: 111°C, 1 H NMR (DMSO-d6) δ: 11.0 (1H, s), 8.22 (1H, d, J = 7.8Hz), 7.27 (3H, m), 7.18 (3H, m), 6.29 (1H, d, J = 6.6Hz), 6.16(1H, t, J=7.2Hz), 5.28(1H, brs), 4.18(1H, m), 3.88(1H, m), 3.80(1H, m), 3.65(1H, m) , 2.58(2H, t, J=7.2Hz), 2.45(2H, m), 1.87(3H, t, J=7.2Hz), ESIMS m / z(relintensity): 410(M+H + , 100).

Embodiment 3

[0034] Example 3: N 4 -Synthesis of n-valeryl gemcitabine (SYN-147)

[0035] Prepare with reference to the method of Example 1.

[0036]MP: 184°C, 1 H NMR (DMSO-d6) δ: 10.96 (1H, s), 8.22 (1H, d, J = 7.8Hz), 7.27 (1H, d, J = 7.8Hz), 6.29 (1H, brs), 6.16 (1H , t, J=7.2Hz), 5.28(1H, brs), 4.18(1H, m), 3.88(1H, m), 3.79(1H, m), 3.63(1H, m), 2.40(2H, t, J=7.2Hz), 1.52(2H, m), 1.28(2H, m), 0.86(3H, t, J=7.2Hz), ESIMSm / z(relintensity): 348(M+H + , 100).

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Abstract

The invention relates to the technical field of medicines, in particular to gemcitabine amide derivates having a structure which is shown in a formula (I) (the specific definitions of each group are shown in the specification). The derivates have good activity in various kinds of tumor cells of lung cancer, colon cancer, breast cancer, liver cancer and the like. The invention also relates to a composite of the derivates, a preparation method of the derivates, and application of the derivates in the preparation of antineoplastic drugs.

Description

technical field [0001] The present invention relates to the technical field of medicine, more specifically, the present invention relates to a class of gemcitabine amide derivatives, and the present invention also relates to the composition, preparation method and use of the compound in the preparation of antineoplastic drugs. Background technique [0002] Gemcitabine hydrochloride (2', 2'-difluoro-2'-deoxycytidine hydrochloride, trade name Gemze) is an antineoplastic drug listed by Eli Lilly and Company of the United States, and its medicinal form is a freeze-dried powder preparation. It has been approved for the treatment of pancreatic cancer, breast cancer and non-small cell lung cancer. In addition, gemcitabine hydrochloride also has antiviral activity. The oral bioavailability of gemcitabine is poor, therefore, the clinical administration mode is about 1000 to 1250 mg / m within 30 minutes 2 The dose is given as an intravenous infusion once a week for up to 7 weeks, fol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00A61K31/7068A61P35/00
CPCC07H19/073A61K31/7068C07H1/00C07H19/06A61P31/12A61P35/00
Inventor 邵志宇宋云龙
Owner 宋云龙
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