Theophylline acetic acid derivative with antitumor activity and preparation method thereof

A technology of theophylline acetic acid and its derivatives, which is applied in the fields of antineoplastic drugs, organic chemistry, drug combinations, etc., can solve the problems of large adverse reactions and easy drug resistance, and achieve novel molecular structure, low toxicity of normal cells, and good The effect of inhibition

Active Publication Date: 2022-06-21
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Chemotherapy is the most widely used method for tumor treatment, but it has the disadvantages of large adverse reactions and easy drug resistance, so designing a safe, effective and small side effect tumor drug has a good application prospect

Method used

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  • Theophylline acetic acid derivative with antitumor activity and preparation method thereof
  • Theophylline acetic acid derivative with antitumor activity and preparation method thereof
  • Theophylline acetic acid derivative with antitumor activity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030]

[0031] At room temperature, theophyllineacetic acid (compound 1 (5 g, 0.02 mol)), 3-aminophenylacetylene (3.69 g, 0.03 mol), HATU (12.96 g, 0.03 mol) and DIPEA (8.13 g, 0.06 mol) and Solvent DMF250mL was added to a 500mL reaction flask together, and stirred for 24 hours under nitrogen protection. Using thin layer chromatography (TLC) monitoring, after 24 hours, the reaction was complete, and the reaction solution was light brown. Concentrate under reduced pressure to remove DMF, add dichloromethane to extract the reaction solution (150 mL×3), combine all organic phases, wash with saturated sodium chloride (150 mL×2) to pH=7, and concentrate to obtain a very viscous brown-yellow product. Under ultrasonic vibration, methanol was slowly added dropwise, and a solid was precipitated. Then stand, suction filtration, and drying to obtain the condensation intermediate of theophylline acetic acid and 3-aminophenylacetylene (compound 2, 3.64 g). LC-MS m / z (%): 337 [M+H] +...

Embodiment 2

[0033]

[0034] In the reaction flask, add compound 2 (1 g), 1 g of 3-chloro-4-fluorobenzyl azide, 70 mL of tert-butanol, 70 mL of water, 70 mL of tetrahydrofuran, 0.5 g of anhydrous copper sulfate and 1 g of sodium ascorbate in sequence. The reaction was carried out under the condition of ℃ for 6 hours, the raw materials were completely reacted, 100 mL of dichloromethane was added, and the reaction solution was filtered to obtain a yellow liquid. The organic phase was separated, and the aqueous phase was extracted twice with 50 mL of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate. , concentrated under reduced pressure to obtain a solid, which was separated by chromatography to obtain compound J1 (1.03 g). 1 H NMR (400MHz, DMSO-d 6 )δ10.55(s, 1H), 8.64(s, 1H), 8.18(s, 1H), 8.09(s, 1H), 7.67(d, J=9.0, 1H), 7.52(d, J=7.5, 2H), 7.47–7.37(m, 3H), 5.65(s, 2H), 5.23(s, 2H), 3.46(s, 3H), 3.20(s, 3H).

Embodiment 3

[0036]

[0037] In the reaction flask, add compound 2 (1 g), 1 g of 2-trifluoromethylbenzyl azide, 70 mL of tert-butanol, 70 mL of water, 70 mL of tetrahydrofuran, 0.5 g of anhydrous copper sulfate and 1 g of sodium ascorbate in sequence. The reaction was carried out under the conditions for 6 h, the raw materials were completely reacted, 100 mL of dichloromethane was added, the reaction solution was filtered to obtain a yellow liquid, the organic phase was separated, the aqueous phase was extracted twice with 50 mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate, Concentration under reduced pressure gave a solid, which was separated by column chromatography to give compound J2 (0.96 g). 1H NMR (400MHz, DMSO-d6)δ10.55(s,1H), 8.61(s,1H), 8.18(s,1H), 8.09(s,1H), 7.83(d,J=7.7,1H), 7.70 (d, J=15.1, 1H), 7.57 (d, J=32.7, 3H), 7.40 (d, J=15.8, 1H), 7.24 (d, J=7.7, 1H), 5.84 (s, 2H) , 5.23(s, 2H), 3.46(s, 3H), 3.20(s, 3H).

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Abstract

A theophylline acetic acid derivative with antitumor activity and its preparation method. The theophylline acetic acid derivative has the structural formula shown in formula (J). Its preparation comprises the following steps: (1) taking theophylline acetic acid as a raw material, under the action of a condensation reagent, condensation reaction occurs with 3-aminophenylacetylene to obtain N-3-alkynylphenyl-theophylline acetamide; (2) N ‑3‑alkynylphenyl‑theophylline acetamide reacts with azide compounds of different substituent groups to obtain the target compound. The theophylline acetic acid derivatives have good inhibitory effects on various tumor cells. The preparation method of such derivatives is simple and the raw materials are easy to obtain, and the discovery of anti-tumor active compounds is of great significance.

Description

technical field [0001] The invention belongs to the technical field of antitumor drug preparation. Specifically, it relates to a theophylline acetic acid derivative with antitumor activity and a preparation method thereof. Background technique [0002] Malignant tumors seriously endanger human health. According to the latest global cancer data released by the World Health Organization's International Agency for Research on Cancer (IARC), there will be 19.29 million new cancer cases and 9.96 million deaths worldwide in 2020. Almost 1 in 5 people will develop cancer in their lifetime, and 1 in 8 men and 1 in 11 women will die from cancer. Cancer treatment is a worldwide problem, and the current treatment methods are mainly surgery, chemotherapy and radiotherapy. Chemotherapy is the most widely used method for tumor treatment, but it has disadvantages such as large adverse reactions and easy generation of drug resistance. Therefore, designing a safe, effective tumor drug with...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/08A61P35/00A61K31/522
CPCC07D473/08A61P35/00
Inventor 汪贞贞吴琼毛龙飞李月明王欣
Owner NANKAI UNIV
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