Deuterated 1, 4-benzodiazepine-2, 5-diketone compound and application thereof

A compound and deuterium technology, which is applied in the field of deuterated 1,4-benzodiazepine-2,5-dione compounds, can solve the problems of short half-life and achieve extended half-life, good inhibitory activity, and extended The effect of degradation

Pending Publication Date: 2022-05-17
NINGBO COMBIREG PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to provide a deuterated 1,4-dione compound for the short half-life of 1,4-benzodiazepine-2,5-dione compounds in the prior art. Benzodiazepine-2,5-dione compounds and their applications

Method used

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  • Deuterated 1, 4-benzodiazepine-2, 5-diketone compound and application thereof
  • Deuterated 1, 4-benzodiazepine-2, 5-diketone compound and application thereof
  • Deuterated 1, 4-benzodiazepine-2, 5-diketone compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0300] Example 1 (S)-2-Chloro-N-[3-[2-(diethylamino)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5- Dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-yl]-3,4,5-tris(trideuteromethoxy base) benzamide (compound 1)

[0301] Preparation of 5-chloro-2,4-dinitrobenzoic acid (intermediate 42): Dissolve 3-chlorobenzoic acid (63.9 mmol) in 120 mL of concentrated sulfuric acid with stirring at room temperature, and add potassium nitrate (163.2 mmol). The reaction solution was reacted at 80° C. for 30 minutes, 110° C. for 2 hours, and 120° C. for 2 hours. The reaction solution was poured into 660 g of ice water, filtered, and the resulting white solid was recrystallized with a mixed solvent of ethanol and water to obtain 8.08 g of light yellow crystals, with a yield of 51.3%. 1 H NMR (400MHz, DMSO-d 6 )δ14.21(brs,1H),8.85(s,1H),8.28(s,1H). 13 C NMR (100MHz, DMSO-d 6 )δ163.78, 147.95, 145.70, 132.86, 132.06, 130.52, 122.05.

[0302]Preparation of 5-(3,5-dimethylphenoxy)-2,4-dinitrob...

Embodiment 2

[0308] Example 2 (S)-2-Chloro-N-[3-[2-(diethylamino)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5- Dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-yl]-3,5-dimethoxy-4-(tri deuterated methoxy) benzamide (compound 2)

[0309] Preparation of 2-chloro-3,5-dimethoxy-4-(trideuteromethoxy)benzoic acid (Intermediate 48): Syringic acid (2.52 mmol), potassium carbonate (10.10 mmol) were dissolved in 5 mL Add deuteroiodomethane (5.05 mmol) to DMF, and react overnight at 35°C. It was detected that a small amount of substrate was not completely reacted, and deuterated methyl iodide (5.05 mmol) was added, and the reaction was continued for 9 h, and the reaction was completed. The reaction solution was evaporated to dryness, dissolved in DCM, washed three times with water, the organic phase was collected, dried and concentrated to obtain 544 mg of intermediate product with a yield of 93.0%. The above intermediate (2.34 mmol) and NCS (2.81 mmol) were dissolved in 5 mL DMF, and reacted ov...

Embodiment 3

[0311] Example 3 (S)-2-Chloro-N-[3-[2-(diethylamino)-2-oxoethyl]-7-(3,5-dimethylphenoxy)-2,5- Dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-yl]-3,5-dimethoxy-4-(tri Deuterated methyl) benzamide (compound 3)

[0312] Preparation of 2-chloro-3,5-dimethoxy-4-(trideuteromethyl)benzoic acid (intermediate 49): Dissolve potassium tert-butoxide (4.38 mmol) in 10 mL of anhydrous THF, stir, 10 mL of anhydrous THF solution dissolved in 3,5-dimethylbenzoic acid (1.10 mmol) was added under the protection of argon at -78°C. Add butyllithium (4.38mmol, 2.5M in hexanes), and react at -78°C for 40min. Deuteroiodomethane (2.20 mmol) was added, and the reaction was continued for 1 h at -78°C. The reaction solution was raised to room temperature, quenched by adding 6 mL of saturated ammonium chloride solution, washed twice with 10 mL of ether, and the water phase was separated, and the pH of the water phase was adjusted to acidic with 2M hydrochloric acid, and a white precipitate was ...

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Abstract

The invention discloses a deuterated 1, 4-benzodiazepine-2, 5-diketone compound and an application of the deuterated 1, 4-benzodiazepine-2, 5-diketone compound. The invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof. The 1, 4-benzodiazepine-2, 5-diketone active compound keeps the activity of inhibiting tumor cells and tumor stem cells, the degradation effect of in-vitro human liver microsome on the compound is prolonged, the half-life period is obviously prolonged, and a safer and more reliable candidate is provided for developing novel anti-tumor drugs.

Description

technical field [0001] The present invention relates to a class of deuterated 1,4-benzodiazepine-2,5-dione compounds and their use in treating proliferative diseases, especially cancer. Background technique [0002] Isotopes are different atoms of the same chemical element that have different masses due to the presence of different numbers of neutrons in the nucleus. Based on their physical properties, isotopes can be divided into radioactive and stable forms. There are three isotopes of hydrogen in nature: protium (1H, H), deuterium (2H, D), tritium (3H, T). Among them, deuterium is a stable non-radioactive isotope with a content of 0.015% in nature. There are two main ways to introduce deuterium into compounds: one is through proton exchange with hydrogen, and the other is synthesis using deuterated raw materials. Currently the second method is more commonly used. Since the deuterium content in the synthesized deuterated compound is much higher than the content of 0.01...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/08A61P35/00A61P35/02A61K31/551
CPCC07D243/08A61P35/00A61P35/02C07B2200/05A61K31/551A61K31/5513C07D243/14C07B59/002
Inventor 刘刚马瑶于文俊
Owner NINGBO COMBIREG PHARMA TECH CO LTD
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