Celastrol derivative and preparation method thereof and application of celastrol derivative to preparation of antitumor medicine

Abstract

The invention relates to celastrol, a celastrol derivative, a method for preparing the celastrol derivative, biogenetic salt prepared from the celastrol derivative serving as a raw material, and application of the celastrol derivative to the preparation of an antitumor medicine. The celastrol derivative has a structure shown as a formula I, wherein R1 is H, C1-C6 straight-chain or branched-chain alkyl, benzyl and benzyl with a substituent group on a benzene ring; and R2 or R3 are independent C5-C6 cyclic hydroxyl, C1-C6 chain alkyl, phenyl and substituted phenyl respectively, or R2 and R3 are cyclized with N, and the cycle is hexahydric cyclic heterocycle containing N or O. The celastrol derivative has high antitumor activity, stability and water solubility. The celastrol derivative can be salified with one of medically acceptable inorganic acids (such as hydrochloric acid, sulfuric acid and phosphoric acid) or organic acids (citric acid, cinnamic acid, succinic acid and the like); and the salt has high water solubility.

Description

(1) Technical field

[0001] The present invention relates to the preparation method of tripterygne and its derivatives and tripteryne derivatives, also relates to the biological salt prepared from tripteryne derivatives as raw materials, and tripteryne derivatives in the preparation of anti-tumor drugs in the application. (2) Background technology

[0002] Malignant tumors seriously endanger people's health. According to WHO statistics, among the more than 5 billion people in the world, 6.9 million people die from malignant tumors every year on average, and 8.7 million new cases occur, and the number is still increasing year by year. Antineoplastic drug therapy is one of the main methods of cancer treatment. Natural products are a treasure trove for discovering new antineoplastic drugs. The lead compounds of many antineoplastic drugs are obtained from nature, such as vinblastine, vincristine, camptothecin, Paclitaxel, etc., but these natural compounds often require structura...

Examples

Embodiment 1

[0032] Example 1: Synthesis of tripterine derivative CLS-1 (synthesis route as shown in Figure 1)

[0033] Dissolve 72.8 mg of triphosgene (BTC) (0.24 mmol) in 2 mL of dichloromethane (DCM), add dropwise 1 mL of 0.35 mol / L morpholine (0.35 mmol) dichloromethane solution and 100 μL of triethyl Amine (0.99mmol), stirred at room temperature for 1h, then added dropwise 1mL tripterine (0.2mmol) dichloromethane solution with a concentration of 0.2mol / L, continued to stir for 24h, stopped the reaction, added 15mL deionized water, ethyl acetate Extract 4mL*3 times, combine the organic layers, wash with saturated NaCl solution 4mL*3 times, anhydrous NaCl 2 SO 4 Drying, suction filtration, the filtrate was concentrated to obtain a dark red oily crude product, and then the crude extract was eluted by flash column chromatography with a mixed solvent of n-hexane:acetone volume ratio of 3:1 as the eluent, and spot plate Detect (developing agent petroleum ether: acetone=2: 1; Rf value 0.38...

Embodiment 2

[0038] Synthesis of embodiment 2 tripterine derivatives CLS-2 (synthetic route diagram as shown in Figure 1)

[0039] Dissolve 72.8 mg of BTC (0.24 mmol) in 2 mL of dichloromethane (DCM), add 1 mL of 0.35 mol / L N-methylpiperazine (0.35 mmol) dichloromethane solution and 100 μL of triethyl ether dropwise under ice cooling Amine (0.99mmol), stirred at room temperature for 1h, then added 1mL tripterine (0.2mmol) dichloromethane solution with a concentration of 0.2mol / L, continued to stir for 24h, then stopped the reaction, added 15mL deionized water, extracted with ethyl acetate 4mL*3 times, combined organic layer, washed with saturated NaCl solution 4mL*3 times, anhydrous NaCl 2 SO 4 Drying, suction filtration, and concentration to obtain a dark red oily crude product, then the crude extract was eluted by flash column chromatography with a mixed solvent of n-hexane: acetone volume ratio of 3: 1 as eluent, and spot plate detection ( Developing agent sherwood oil: acetone=2: 1; ...

Embodiment 3

[0040] Example 3 Synthesis of tripterine derivatives CLS-3 (synthesis route as shown in Figure 1)

[0041] Dissolve 72.8 mg of triphosgene BTC (0.24 mmol) in 2 mL of dichloromethane (DCM), add dropwise 1 mL of 0.35 mol / L N-ethylpiperazine (0.35 mmol) in dichloromethane solution and 100 μL of Triethylamine, stirred at room temperature for 1h, then added dropwise 1mL of tripterine (0.2mmol) dichloromethane solution with a concentration of 0.2mol / L, continued to stir for 24h, then stopped the reaction, added 15mL of deionized water, and extracted 4mL with ethyl acetate *3 times, combine the organic layers, wash with 4mL of saturated NaCl solution*3 times, anhydrous NaCl 2 SO 4Drying, suction filtration, and concentration to obtain a dark red oily crude product, then the crude extract was eluted by flash column chromatography with a mixed solvent of n-hexane: acetone volume ratio of 3: 1 as eluent, and spot plate detection ( Developing agent sherwood oil: acetone=2: 1; Rf value ...

(1) Technical field

[0001] The present invention relates to the preparation method of tripterygne and its derivatives and tripteryne derivatives, also relates to the biological salt prepared from tripteryne derivatives as raw materials, and tripteryne derivatives in the preparation of anti-tumor drugs in the application. (2) Background technology

[0002] Malignant tumors seriously endanger people's health. According to WHO statistics, among the more than 5 billion people in the world, 6.9 million people die from malignant tumors every year on average, and 8.7 million new cases occur, and the number is still increasing year by year. Antineoplastic drug therapy is one of the main methods of cancer treatment. Natural products are a treasure trove for discovering new antineoplastic drugs. The lead compounds of many antineoplastic drugs are obtained from nature, such as vinblastine, vincristine, camptothecin, Paclitaxel, etc., but these natural compounds often require structura...

Examples

Embodiment 1

[0032] Example 1: Synthesis of tripterine derivative CLS-1 (synthesis route as shown in Figure 1)

[0033] Dissolve 72.8 mg of triphosgene (BTC) (0.24 mmol) in 2 mL of dichloromethane (DCM), add dropwise 1 mL of 0.35 mol / L morpholine (0.35 mmol) dichloromethane solution and 100 μL of triethyl Amine (0.99mmol), stirred at room temperature for 1h, then added dropwise 1mL tripterine (0.2mmol) dichloromethane solution with a concentration of 0.2mol / L, continued to stir for 24h, stopped the reaction, added 15mL deionized water, ethyl acetate Extract 4mL*3 times, combine the organic layers, wash with saturated NaCl solution 4mL*3 times, anhydrous NaCl 2 SO 4 Drying, suction filtration, the filtrate was concentrated to obtain a dark red oily crude product, and then the crude extract was eluted by flash column chromatography with a mixed solvent of n-hexane:acetone volume ratio of 3:1 as the eluent, and spot plate Detect (developing agent petroleum ether: acetone=2: 1; Rf value 0.38...

Embodiment 2

[0038] Synthesis of embodiment 2 tripterine derivatives CLS-2 (synthetic route diagram as shown in Figure 1)

[0039] Dissolve 72.8 mg of BTC (0.24 mmol) in 2 mL of dichloromethane (DCM), add 1 mL of 0.35 mol / L N-methylpiperazine (0.35 mmol) dichloromethane solution and 100 μL of triethyl ether dropwise under ice cooling Amine (0.99mmol), stirred at room temperature for 1h, then added 1mL tripterine (0.2mmol) dichloromethane solution with a concentration of 0.2mol / L, continued to stir for 24h, then stopped the reaction, added 15mL deionized water, extracted with ethyl acetate 4mL*3 times, combined organic layer, washed with saturated NaCl solution 4mL*3 times, anhydrous NaCl 2 SO 4 Drying, suction filtration, and concentration to obtain a dark red oily crude product, then the crude extract was eluted by flash column chromatography with a mixed solvent of n-hexane: acetone volume ratio of 3: 1 as eluent, and spot plate detection ( Developing agent sherwood oil: acetone=2: 1; ...

Embodiment 3

[0040] Example 3 Synthesis of tripterine derivatives CLS-3 (synthesis route as shown in Figure 1)

[0041] Dissolve 72.8 mg of triphosgene BTC (0.24 mmol) in 2 mL of dichloromethane (DCM), add dropwise 1 mL of 0.35 mol / L N-ethylpiperazine (0.35 mmol) in dichloromethane solution and 100 μL of Triethylamine, stirred at room temperature for 1h, then added dropwise 1mL of tripterine (0.2mmol) dichloromethane solution with a concentration of 0.2mol / L, continued to stir for 24h, then stopped the reaction, added 15mL of deionized water, and extracted 4mL with ethyl acetate *3 times, combine the organic layers, wash with 4mL of saturated NaCl solution*3 times, anhydrous NaCl 2 SO 4Drying, suction filtration, and concentration to obtain a dark red oily crude product, then the crude extract was eluted by flash column chromatography with a mixed solvent of n-hexane: acetone volume ratio of 3: 1 as eluent, and spot plate detection ( Developing agent sherwood oil: acetone=2: 1; Rf value ...

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