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Farnesyl thiosalicylic acid-nucleoside conjugate as well as preparation method and medical application thereof

A technology of farnesylthiosalicylic acid and nucleoside conjugates, applied in the field of biomedicine, can solve the problems of increased side effects and increased burden, and achieve the effects of preventing degradation, reducing drug resistance, and promoting apoptosis

Active Publication Date: 2013-12-18
JIANGSU FANGSHIYUANLVE SCI & TECH CONSULTING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the combination of drugs increases the side effects suffered by patients and increases the burden of taking multiple drugs for multiple drugs

Method used

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  • Farnesyl thiosalicylic acid-nucleoside conjugate as well as preparation method and medical application thereof
  • Farnesyl thiosalicylic acid-nucleoside conjugate as well as preparation method and medical application thereof
  • Farnesyl thiosalicylic acid-nucleoside conjugate as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Example 1N-(1-((2R,4S,5R)-3,3-difluoro-4-hydroxyl-5-hydroxymethyltetrahydrofuran-2-yl)-2-one-1,2-dihydropyrimidine -4-yl)-farnesylthiosalicylic acid amide (I 1 ) preparation

[0102] 4-amino-1-((2R,4S,5R)-3,3-difluoro-4-(tert-butyldimethylsilyloxy)-5-(tert-butyldimethylsilyloxymethyl ) Tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (2a) preparation

[0103] Dissolve gemcitabine (1a) (108 mg, 0.41 mmol) in 20 mL of dry DMF solution, add TBDMS-Cl (247 mg, 1.64 mmol) and 112 mg of imidazole, stir at room temperature for 10 h, evaporate the solvent under reduced pressure, and pass the crude product through silica gel column chromatography Purification (mobile phase AE:PE=1:2-2:1) gave 181mg, yield 90%.

[0104] Preparation of farnesylthiosalicylic acid chloride

[0105] Dissolve 0.54 g (1.50 mmol) of FTA in 10 mL of anhydrous CH 2 Cl 2 0.60 mL (8.27 mmol) of thionyl chloride was added thereto, stirred at 55°C for 1 h, and concentrated to obtain farnesylthiosalicylic acid ch...

Embodiment 2

[0110] Example 2N-(1-((2R,3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-2-one-1,2-dihydropyrimidine-4 -yl)-farnesylthiosalicylic acid amide (I 2 ) preparation

[0111] 4-Amino-1-((2R,3R,4R,5R)-3,4-bis(tert-butyldimethylsilyloxy)-5-(tert-butyldimethylsilyloxymethyl)tetrahydrofuran Preparation of -2-yl)-1H-pyrimidin-2-one (2b)

[0112] Referring to the preparation method of compound (2a) in Example 1, the pale yellow oily substance (2b) was prepared by reacting TBDMS-Cl with cytarabine (1b) instead of gemcitabine in the method, with a yield of 72%.

[0113] N-(1-((2R,3R,4R,5R)-3,4-bis(tert-butyldimethylsilyloxy)-5-(tert-butyldimethylsilyloxymethyl)tetrahydrofuran- Preparation of 2-yl)-2-keto-1,2-dihydropyrimidin-4-yl)-farnesylthiosalicylic acid amide (3b)

[0114] With reference to the preparation method of compound (3a) in Example 1, the compound (2a) in the alternative method of compound (2b) reacts with farnesyl thiosalicylic acid chloride to obtain light y...

Embodiment 3

[0117] Example 3 N-(1-((2R, 3R, 4R, 5R)-3-cyano-4-hydroxyl-5-hydroxymethyltetrahydrofuran-2-yl)-2-one-1,2-dihydropyrimidine -4-yl)-farnesylthiosalicylic acid amide (I 3 ) preparation

[0118] 4-amino-1-((2R,3R,4R,5R)-3-cyano-4-(tert-butyloxycarbonyloxy)-5-(tert-butyloxycarbonyloxymethyl)tetrahydrofuran-2 Preparation of -yl)-1H-pyrimidin-2-one (2c)

[0119] 4-amino-1-((2R,3R,4R,5R)-3-cyano-4-hydroxyl-5-hydroxymethyltetrahydrofuran-2-yl)-1H-pyrimidin-2-one (1c) (103mg, 0.41mmol) was dissolved in 10mL of 1,4-dioxane and 15ml of 1N potassium hydroxide aqueous solution, and Boc anhydride (1.48g, 6.8mmol) was slowly added dropwise in 10mL of 1,4-dioxane solution, return to room temperature and stir for 10 h after dropping, evaporate the solvent under reduced pressure after spot plate reaction, add 25ml of water, extract the water layer with 20ml of ethyl acetate three times, combine the organic layers and wash with saturated saline, dry and concentrate under reduced pressure The...

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Abstract

The invention provides a farnesyl thiosalicylic acid-nucleoside conjugate and pharmaceutically acceptable salts thereof. The farnesyl thiosalicylic acid-nucleoside conjugate and the pharmaceutically acceptable salts thereof have the structure as shown in a general formula I, wherein in the general formula I, X is H, F, Cl or Br; R1 represents H, OH, OAc, SH, -OP(O)(OH)2, -OPO3HNa, -OP(O)(ONA)2, -OPO3HK or -OP(O)(OK)2; R2 represents H, OH, OAc or OCH; R3 represents H, OH, F, CN, OAc or OCH3; R4 represents H, OH, F, CN, OAc or OCH3. The invention also provides a preparation method of the farnesyl thiosalicylic acid-nucleoside conjugate and the pharmaceutically acceptable salts thereof and a pharmaceutical composition containing the derivatives as well as medical applications thereof, especially application in preparation of antitumor drug medicines.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to a class of farnesylthiosalicylic acid-nucleoside conjugates and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these derivatives and their The medical application, especially the application in the preparation of antineoplastic drugs. Background technique [0002] All-trans farnesyl thiosalicylic acid (abbreviation: FTA, trade name: Salirasib) is the first farnesyl-based Ras protein inhibitor, which can competitively replace F-Ras and F-Ras muteins with half Lectin binds and inhibits Ras-induced downstream signaling pathways (including Raf and P13K signaling pathways) and mTOR (a stimulator of tumorigenesis, which can rely on or independently open P13K signaling pathways), thereby promoting tumor cell apoptosis and inhibiting tumors cell growth. However, although FTA has been in Phase II clinical research, it is no...

Claims

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Application Information

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IPC IPC(8): C07H19/067C07H19/073C07H19/10C07H1/00A61K31/7068A61P35/00
Inventor 凌勇杨宇民王新杨王志强丰楠楠郭益冰王雪敏颜森森
Owner JIANGSU FANGSHIYUANLVE SCI & TECH CONSULTING CO LTD
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