Compound and application thereof

A compound and solvate technology, which is applied in the treatment of proliferative diseases, especially in the field of cancer, can solve the problems of high inhibitory activity and achieve the effect of inhibiting regeneration and strongly inhibiting the proliferation of tumor cells

Active Publication Date: 2016-06-22
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The present invention aims to solve at least one of the problems in the research and development of anti-tumor drugs existing in the prior art, such as high inhibitory activity on CSCs

Method used

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  • Compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] Example 1 (S)-2-[7-(3,5-Dimethylphenoxy)-2,5-dioxo-8-(3,4,5-trimethoxybenzamido)-2, Methyl 3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetate (compound 1)

[0193] Preparation of 5-chloro-2,4-dinitrobenzoic acid (Intermediate 188): Dissolve 3-chlorobenzoic acid (10.0 g, 63.9 mmol) in 120 mL of concentrated sulfuric acid with stirring at room temperature, and add nitric acid in batches within 15 min Potassium (16.5 g, 163.2 mmol). The reaction solution was reacted at 80°C for 30min, 110°C for 2h, and 120°C for 2h. 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 HNMR (400MHz, DMSO-d 6 )δ14.21(brs,1H),8.85(s,1H),8.28(s,1H). 13 CNMR (100MHz, DMSO-d 6 )δ163.78, 147.95, 145.70, 132.86, 132.06, 130.52, 122.05.

[0194] Preparation of 5-(3,5-dimethylphenoxy)-2,4-dinitrobenzoic acid (Interme...

Embodiment 2

[0198] Example 2 (S)-2-[8-(3,5-dimethoxybenzamido)-7-(3,5-dimethylphenoxy)-2,5-dioxo-2,3 ,4,5-Tetrahydro-1H-benzo[e][1,4]diazepine-3-yl]acetic acid methyl ester (compound 2)

[0199] According to the method described in Example 1, the title compound (2) was prepared using intermediate 191 (191.7 mg, 0.5 mmol) and 3,5-dimethoxybenzoyl chloride (200 mg, 1.0 mmol). Mp137–139°C. 1 HNMR (300MHz, DMSO-d 6 )δ10.54(s,1H),9.87(s,1H),8.60(d,J=5.1Hz,1H),7.71(s,1H),7.22(s,1H),6.94(d,J=2.2 Hz,2H),6.80(s,1H),6.73–6.66(m,3H),4.14(dt,J=8.7,5.6Hz,1H),3.78(s,6H),3.60(s,3H),2.90 (dd,J=17.0,8.7Hz,1H),2.74(dd,J=17.0,5.8Hz,1H),2.24(s,6H). 13 CNMR (100MHz, DMSO-d 6 )δ170.61,170.56,166.85,165.29,160.48,156.19,145.59,139.54,136.18,132.97,132.43,125.58,123.19,119.62,117.31,116.23,105.71,103.79,55.52,51.65,48.68,32.53,20.91.HRMScalcd.forC 29 h 30 N 3 o 8 (M+H + )548.2033; found548.2027

Embodiment 3

[0200] Example 3(S)-2-[7-(3,5-Dimethylphenoxy)-2,5-dioxo-8-(2,3,4-trimethoxybenzamido)-2, 3,4,5-Tetrahydro-1H-benzo[e][1,4]diazepin-3-yl]acetic acid methyl ester (compound 3)

[0201] According to the method described in Example 1, the title compound (3) was prepared using intermediate 191 (191.7 mg, 0.5 mmol) and 2,3,4-trimethoxybenzoyl chloride (230.6 mg, 1.0 mmol). Mp136–138°C. 1 HNMR (300MHz, DMSO-d 6 )δ10.96(s,1H),10.53(s,1H),8.55(d,J=5.1Hz,1H),8.49(s,1H),7.86(d,J=9.0Hz,1H),7.10( s,1H),7.05(d,J=9.2Hz,1H),6.90(s,1H),6.85(s,2H),4.10(dt,J=8.7,5.5Hz,1H),3.89(s,3H ),3.87(s,3H),3.77(s,3H),3.59(s,3H),2.89(dd,J=17.0,8.8Hz,1H),2.72(dd,J=17.0,5.8Hz,1H) ,2.30(s,6H). 13 CNMR (100MHz, DMSO-d 6 )δ170.63,170.47,166.83,162.29,157.24,155.65,151.89,142.93,141.34,139.98,133.24,132.67,126.45,126.34,120.91,117.52,117.39,116.83,112.34,108.54,61.97,60.61,56.19,51.60,48.62 ,32.50,20.93.HRMScalcd.forC 30 h 32 N 3 o 9 (M+H + )578.2139; found578.2116.

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Abstract

The invention discloses a compound and application thereof. The compound is the compound shown in the formula (I) or a stereoisomer or a pharmaceutical acceptable salt or solvate or a prodrug of the compound shown in the formula (I). The compound can restrain tumor cell proliferation through the effect RRM2, and restrain tumor stem cell regeneration, thereby being effectively used for preparing medicine for preventing or treating proliferative diseases and particularly anti-cancer medicine.

Description

technical field [0001] The present invention relates to a class of 1,4-benzodiazepine-2,5-dione compounds, a preparation method thereof, and their use in treating proliferative diseases, especially cancer. Background technique [0002] In recent years, more and more studies have shown that in the same tumor tissue, tumor cells are heterogeneous in tumorigenesis ability, differentiation degree and metastasis ability, and only a small number of cells have the ability to initiate tumors. Such cells are called tumor stem cells (Cancer stem cells, CSCs) or tumorigenic cancer cells (Tumorigenic cancer cells). [0003] At present, the main reasons why malignant tumors are difficult to cure are metastasis and recurrence. Recently, some scholars have suggested that CSCs may be the root cause of tumor metastasis, and put forward the view that CSCs are the "seed" cells of tumor metastasis. CSCs have strong proliferative potential, and they can rapidly undergo clonal proliferation onc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/14C07D405/04C07D409/12C07D403/12C07D401/06C07D413/06C07F9/645A61K31/5513A61K31/662C07C59/265C07C57/13C07C57/145C07C55/08C07C51/41A61P35/00
CPCC07D243/14C07D401/06C07D403/12C07D405/04C07D409/12C07D413/06C07F9/645
Inventor 刘刚解希雷于文俊郭伟张艳梅
Owner TSINGHUA UNIV
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