Pyrrole formamide derivative, and preparation method and application thereof

Abstract

The present invention relates to compounds with a structure shown as a formula I or pharmaceutically acceptable salts thereof. R1, R2, R3, R4, R5 and R6 are defined as in the specification. The invention also provides a preparation method of the compounds with a structure shown as the formula I or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds and pharmaceutically acceptable salts thereof, and application of betulinic acid analogues or solvates thereof as active ingredients to preparation of antineoplastic medicaments for treating lung cancer, prostate cancer, colon cancer, leukemia, breast cancer, liver cancer, gastric cancer, pancreatic cancer, human malignant glioma and brain tumor.

Description

technical field

[0001] The invention belongs to the technical field of medicine, more specifically, relates to a class of compounds with anti-tumor effect and their preparation method and application. Background technique

[0002] Cancer has become a major chronic disease that seriously endangers human health. According to statistics, there are 9 million people who suffer from cancer every year in the world, and 6 million patients die from cancer. Almost one cancer patient dies every second. The annual incidence of cancer in my country is about 1.2 million, the number of cancer deaths is as high as more than 900,000, and the number of patients waiting for treatment exceeds 1.5 million, and there is an increasing trend year by year. Therefore, cancer has become the second largest killer after cardiovascular disease. Clinically, tumors are treated in three major ways: surgery, radiotherapy, and chemotherapy. Although the chemotherapy method is quicker, the cure rate is very...

Examples

Embodiment 1

[0057] Example 1: Intermediate III-1

[0058]

[0059] Add 22.1g (0.1mol) 4-acetyl-1-cyclopropane-2,5-dimethyl-1H-pyrrole-3-carboxylic acid into the reaction flask equipped with stirring, condenser and thermometer, and use 200ml di It was dissolved in thionyl chloride, stirred, and refluxed for 4h (the plate showed that the reaction was complete). Thionyl chloride was evaporated to dryness to obtain a white solid (HPLC: 99.7%). HRMS(m / z)[M+H] + : 241.0684.

Embodiment 2

[0060] Example 2: 4-acetyl-N, N-bis(2-chloroethyl)-1-cyclopropyl-2,5-dimethyl-1H-pyrrole-3-amide (compound I-1)

[0061]

[0062] Add 23.9g (0.1mol) intermediate III-1, 21.4g (0.12mol) bis(2-chloroethyl)ammonia hydrochloride, 20.2g triethylamine in the reaction flask equipped with stirring, thermometer and condenser and 200ml of DMF, stirred, refluxed for 5h, TLC showed that the reaction was complete, washed with saturated brine (50ml×3), dried the dichloromethane layer with anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure to obtain a light yellow solid. Column separation [mobile phase: v (petroleum ether): v (ethyl acetate) = 1: 1] to obtain a white solid (HPLC: 99.5%). HRMS(m / z)[M+H] + : 293.1279.

[0063] Referring to the method of Example 1, compounds I-2 to I-5 can be synthesized.

[0064]

Embodiment 3

[0065] Example 3: 4-acetyl-1-cyclopropyl-N, N-bis(2-nitrate ethyl)-2,5-dimethyl-1H-pyrrole-3-carboxamide (compound I- 6)

[0066]

[0067] Add compound I-1 (2.9g, 0.01mol) in the reaction flask equipped with stirring, condenser, thermometer, anhydrous acetonitrile (30ml) dissolves, add the anhydrous acetonitrile solution of silver nitrate (2.0g, 0.012mol) ( 10ml), and refluxed for 5 hours under stirring in the dark. TLC showed that the reaction was complete, then cooled to room temperature, and evaporated the solvent under reduced pressure. Dichloromethane (20ml) was added to the residue, stirred for 10min, filtered, and the filtrate was evaporated to dryness under reduced pressure. Add absolute ethanol (30ml), decolorize with activated carbon, evaporate to dryness under reduced pressure, and dry under reduced pressure at room temperature overnight to obtain yellow transparent oil I-6 (3.6g, yield 90%), purity 99.2% (HPLC method). HRMS(m / z)[M+H] + : 339.1471.

technical field

[0001] The invention belongs to the technical field of medicine, more specifically, relates to a class of compounds with anti-tumor effect and their preparation method and application. Background technique

[0002] Cancer has become a major chronic disease that seriously endangers human health. According to statistics, there are 9 million people who suffer from cancer every year in the world, and 6 million patients die from cancer. Almost one cancer patient dies every second. The annual incidence of cancer in my country is about 1.2 million, the number of cancer deaths is as high as more than 900,000, and the number of patients waiting for treatment exceeds 1.5 million, and there is an increasing trend year by year. Therefore, cancer has become the second largest killer after cardiovascular disease. Clinically, tumors are treated in three major ways: surgery, radiotherapy, and chemotherapy. Although the chemotherapy method is quicker, the cure rate is very...

Examples

Embodiment 1

[0057] Example 1: Intermediate III-1

[0058]

[0059] Add 22.1g (0.1mol) 4-acetyl-1-cyclopropane-2,5-dimethyl-1H-pyrrole-3-carboxylic acid into the reaction flask equipped with stirring, condenser and thermometer, and use 200ml di It was dissolved in thionyl chloride, stirred, and refluxed for 4h (the plate showed that the reaction was complete). Thionyl chloride was evaporated to dryness to obtain a white solid (HPLC: 99.7%). HRMS(m / z)[M+H] + : 241.0684.

Embodiment 2

[0060] Example 2: 4-acetyl-N, N-bis(2-chloroethyl)-1-cyclopropyl-2,5-dimethyl-1H-pyrrole-3-amide (compound I-1)

[0061]

[0062] Add 23.9g (0.1mol) intermediate III-1, 21.4g (0.12mol) bis(2-chloroethyl)ammonia hydrochloride, 20.2g triethylamine in the reaction flask equipped with stirring, thermometer and condenser and 200ml of DMF, stirred, refluxed for 5h, TLC showed that the reaction was complete, washed with saturated brine (50ml×3), dried the dichloromethane layer with anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure to obtain a light yellow solid. Column separation [mobile phase: v (petroleum ether): v (ethyl acetate) = 1: 1] to obtain a white solid (HPLC: 99.5%). HRMS(m / z)[M+H] + : 293.1279.

[0063] Referring to the method of Example 1, compounds I-2 to I-5 can be synthesized.

[0064]

Embodiment 3

[0065] Example 3: 4-acetyl-1-cyclopropyl-N, N-bis(2-nitrate ethyl)-2,5-dimethyl-1H-pyrrole-3-carboxamide (compound I- 6)

[0066]

[0067] Add compound I-1 (2.9g, 0.01mol) in the reaction flask equipped with stirring, condenser, thermometer, anhydrous acetonitrile (30ml) dissolves, add the anhydrous acetonitrile solution of silver nitrate (2.0g, 0.012mol) ( 10ml), and refluxed for 5 hours under stirring in the dark. TLC showed that the reaction was complete, then cooled to room temperature, and evaporated the solvent under reduced pressure. Dichloromethane (20ml) was added to the residue, stirred for 10min, filtered, and the filtrate was evaporated to dryness under reduced pressure. Add absolute ethanol (30ml), decolorize with activated carbon, evaporate to dryness under reduced pressure, and dry under reduced pressure at room temperature overnight to obtain yellow transparent oil I-6 (3.6g, yield 90%), purity 99.2% (HPLC method). HRMS(m / z)[M+H] + : 339.1471.

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