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Triazole derivatives of rapamycin and application

A halogen and compound technology, applied in the field of medicine, can solve problems such as low selectivity, easy drug resistance, and large toxic and side effects

Active Publication Date: 2015-02-04
FUJIAN INST OF MICROBIOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2009, WHO clearly pointed out that cancer is becoming the deadliest "killer" of human beings, and more than 90% of malignant tumors have no satisfactory treatment drugs and measures
The traditional anticancer drugs currently used in clinical practice mainly include plant alkaloids, alkylating agents, antibiotics and hormones. significantly affected

Method used

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  • Triazole derivatives of rapamycin and application
  • Triazole derivatives of rapamycin and application
  • Triazole derivatives of rapamycin and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] Example 1: 40-O-(2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)acetyl)oxyrapamycin (X-42) preparation

[0119] (prepared according to synthetic routes A and C)

[0120] Step A: Preparation of 28-oxytrimethylsilyl-rapamycin

[0121] Add rapamycin (5.5mmol, 5.0g) and imidazole (1.5g) into ethyl acetate (80mL) solution respectively, cool to 0-5°C after addition, add trimethylchlorosilane (mmol, 4.3g), heat preservation reaction for 2 hours. When the bissilyl ether protected product was formed, dilute sulfuric acid (15 mL, 1N H 2 SO 4 ), continue to stir and react for about 16h. After the reaction is completed, the reaction solution is washed with saturated sodium bicarbonate and saturated brine respectively. The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness to obtain 5.1 g of a white foamy solid with a yield of 47%. MS(ESI)m / z:1008.5(M+Na) + ..

[0122] Step B: Preparation of 28-oxytrimethylsilyl-43-O-(2-chloroacetyl)-oxrapamycin ...

Embodiment 2

[0133] Example 2: 40-O-(2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin (X-60)

[0134] (prepared according to synthetic routes A and C)

[0135] Step A: Preparation of 28-oxytrimethylsilyl-43-O-(2-bromoisopropionyl)-oxrapamycin

[0136] 28-OTMS-rapamycin (2.5g, 2.5mmol) and anhydrous dichloromethane (40mL) were added to a three-necked flask, triethylamine (3mL) was added, and 2- Isopropionyl chloride (1.1g, 5mmol) was added and reacted at 0-5°C for 8h. After the reaction was completed, the reaction solution was poured into 300 mL of water, extracted with dichloromethane, the extracts were combined, washed with water, and dried over anhydrous sodium sulfate. Evaporate to dryness to obtain 1.9 g of white solid, yield: 77.2% MS (ESI) m / z: 1142.5 (M+Na) + .

[0137] Step B: Preparation of 43-O-(2-bromoisopropionyl)-oxrapamycin

[0138] Add 28-OTMS-43-O-(2-bromoisopropionyl)-oxrapamycin (1.9g, 1.7mmol) into acetone (40mL) solution, cool to 0-5°C afte...

Embodiment 3

[0146] Example 3: 40-O-(2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin (X-51)

[0147] (prepared according to synthetic routes A and B)

[0148] Step A: Preparation of 43-O-(2-bromoethyl)-oxrapamycin

[0149] Add rapamycin (6g, 6.6mmol) and diisopropylethylamine (4.2g, 33mmol) to 50mL of toluene solution, add 2-bromoethylsulfonate side chain (5g, 19.6mmol), After the addition was completed, the temperature was raised to 60°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, respectively, in dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and evaporated to dryness to give a light yellow solid, which was finally separated by column chromatography to obtain 2.9g White solid, yield: 82.6%, 1042.5 (M+Na) + .

[0150] Step B: Preparation of 43-O-(2-azidoethyl)-oxrapamycin

[0151] 43-O-(2-bromoethyl)-oxrapamycin (5.9g, 5.7...

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Abstract

The invention relates to triazole derivatives of rapamycin and application. Concretely, the triazole derivatives of rapamycin comprises compounds of the following formula I, or pharmaceutically acceptable salts, solvates, isomers, esters and prodrugs thereof. In the formula I, n is 1, 2 or 3, X is carbonyl or chemical bonds, R is hydrogen or C1-C4 alkyl, R1 is hydrogen, hydroxyl, hydroxymethyl, halogens, trifluoromethyl, trifluoromethoxyl, amino, carboxyl, cyan, N-(C1-C4)alkylamino, N,N-di(C1-C4)alkylamino, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkoxylethyl, (C1-C4)alkylacyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di(C1-C4)alkylcarbamoyl or (C1-C3)alkylenedioxyl. The compounds have excellent biological activity.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to novel rapamycin derivatives, their optically active bodies and pharmaceutically acceptable salts thereof, in particular to a class of triazole derivatives of rapamycin. The invention also relates to processes for their preparation and pharmaceutical compositions containing said compounds. The present invention also relates to the use of the derivative in the preparation of medicines for treating and / or preventing cancer. technical background [0002] Cancer / malignant tumors seriously endanger human health and have become a global health problem, seriously threatening human life. In 2009, WHO clearly pointed out that cancer is becoming the deadliest "killer" of human beings, and more than 90% of malignant tumors have no satisfactory treatment drugs and measures. At present, there are about 10 million cancer patients in the world every year, and 7.6 million people die. In my count...

Claims

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Application Information

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IPC IPC(8): C07D498/18A61K31/436A61P35/00A61P35/02
CPCC07D498/18
Inventor 程元荣谢立君黄捷李邦良潘福生李夸良余辉应加银杨国新金东伟陈夏琴吕裕斌
Owner FUJIAN INST OF MICROBIOLOGY
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