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Coumarin NEDD8 activating enzyme inhibitor as well as preparation method and application thereof

A technology of coumarins and activating enzymes, applied in the field of biochemistry, can solve problems such as the lack of similar products

Active Publication Date: 2016-05-04
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to provide a coumarin-based NEDD8 activating enzyme inhibitor to solve the problem of lack of similar products in the prior art

Method used

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  • Coumarin NEDD8 activating enzyme inhibitor as well as preparation method and application thereof
  • Coumarin NEDD8 activating enzyme inhibitor as well as preparation method and application thereof
  • Coumarin NEDD8 activating enzyme inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Preparation of Example 17-(4-(phenethylamino)piperidine-1-substituted)-4-benzylamino-coumarin (I-1)

[0105] Steps:

[0106] (1) Synthesis of ethyl 1-(4-bromo-2-hydroxy-phenyl)pyruvate (1)

[0107] Add 1000mL of anhydrous toluene and 31g of NaH into a 2L four-neck round bottom flask, and stir in an ice bath for 5min under nitrogen protection. 400 mL of a toluene solution dissolved with 60 g of 4-bromo-2-hydroxyacetophenone was added dropwise under ice-bath conditions. After the dropwise addition, continue to stir in an ice bath for 20 min. Then 67 g of diethyl carbonate were added dropwise. After the dropwise addition was completed, it was heated to reflux and stirred overnight. After the reaction was detected by TLC, the temperature was cooled in an ice bath, and the pH was adjusted to acidity with concentrated hydrochloric acid. After filtration, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to the crude product. Purified by colu...

Embodiment 2

[0121] Example 2 (R)-7-(4-(phenethylamino)piperidine-1-substituted)-4-(1-phenethyl-1-substituted)amino-coumarin (I-2)

[0122] The preparation method is the same as in Example 1, except that in step (7), the raw materials used are 0.215g of intermediate 7, 0.044g of (R)-α-methylbenzylamine and 0.036g of triethylamine to obtain the product 90.1 mg, yield 50.3%, purity 98.1%.

[0123] HNMR (500MHz, DMSO-d6) δ: 8.11 (d, J = 9.5Hz, H), 7.64 (d, J = 6.5Hz, H), 7.22-7.39 (m, 10H), 6.70 (d, J = 9Hz ,H)4.71(m,2H),4.03(d,J=13Hz,2H),3.35(s,1H),3.22(s,2H),2.87(m,4H),2.06(d,J=11Hz, 2H),1.54(m,5H).CNMR(500MHz,DMSO-d6)δ:162.41,155.42,153.31,152.83,144.52,137.54,129.09,129.06,128.99,127.36,127.25,126.15,124.28,1105. 101.23,81.29,54.77,52.41,46.11,46.07,15.22,32.23,27.52,24.01.MS(ESI)(m / z):467.9[M+1] +

Embodiment 3

[0124] Example 3 (S)-7-(4-(phenethylamino)piperidine-1-substituted)-4-(phenethyl-2-substituted)amino-coumarin (I-3)

[0125] The preparation method is the same as in Example 1, except that in step (7), the raw materials used are 0.215g of intermediate 7, 0.044g of (S)-α-methylbenzylamine and 0.036g of triethylamine to obtain product 83.0 mg, yield 46.4%, purity 96.1%.

[0126] HNMR (300MHz, DMSO-d6) δ: 8.10 (d, J = 9.1Hz, 1H), 7.61 (d, J = 6.4Hz, 2H), 7.21-7.39 (m, 10H), 6.98 (d, J = 8.0 Hz,1H),6.74(s,1H),4.70(d,2H),4.01(d,J=12.8Hz,2H),3.34(s,1H),3.22(s,2H),2.85(m,4H ), 2.06(d, J=10.8Hz, 2H), 1.54(m, 5H). ,127.26,126.14,124.26,111.10,105.18,101.23,81.27,54.75,52.39,46.09,46.05,45.21,32.23,27.51,24.05.MS(ESI)(m / z):467.8[M+1] + .

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Abstract

The invention discloses a coumarin NEDD8 activating enzyme inhibitor in the general formula I as well as pharmaceutically acceptable salts, solvate, polymorphic substances, tautomers, metabolites and prodrugs of the coumarin NEDD8 activating enzyme inhibitor. The invention further discloses an application of the coumarin NEDD8 activating enzyme inhibitor to preparation of anti-tumor drugs and a preparation method of the coumarin NEDD8 activating enzyme inhibitor. Pharmacological results show that the compound has a good effect of resisting tumor cell proliferation and is clinically applicable to preparation of drugs for treating tumors.

Description

technical field [0001] The invention belongs to the field of biochemistry, and in particular relates to a coumarin-based NEDD8 activating enzyme inhibitor and a preparation method and application thereof. Background technique [0002] Malignant tumors are a large class of common multiple diseases that seriously endanger human health, with a high fatality rate, second only to cardiovascular and cerebrovascular diseases. According to the statistics of the World Health Organization, about 8.2 million people died of cancer in the world in 2012, and it is estimated that the number of deaths due to cancer will exceed 11 million in 2030. China is a country with a high incidence and mortality rate of cancer, which causes economic losses of hundreds of billions of yuan every year, and with the aging of the population, the deterioration of the ecological and living environment, this trend is more likely to intensify. Therefore, finding effective drugs for the treatment of tumors has ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04C07D405/14A61P35/00
CPCC07D405/04C07D405/14
Inventor 王玉斌陆鹏袁新睿
Owner NANJING UNIV OF TECH
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