Coumarins NEDD8 activating enzyme inhibitor

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

Active Publication Date: 2016-10-12
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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  • Coumarins NEDD8 activating enzyme inhibitor
  • Coumarins NEDD8 activating enzyme inhibitor
  • Coumarins NEDD8 activating enzyme inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Example 1 7-(4-(phenethylamino)piperidine-1-substituted)-4-phenyl-coumarin (I-1)

[0128] Steps:

[0129] (1) Synthesis of methyl 1-(4-bromo-2-hydroxy-phenyl)pyruvate (1)

[0130] 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. The product 60.41 g was purified...

Embodiment 2

[0143] Example 2 7-(4-phenethylaminopiperidine-1-substituted)-4-(3-fluoro-4-methylbenzene-1-substituted)coumarin (I-2)

[0144] The synthesis method is as in Example 1, except that the raw materials used in step (7) are 0.147g intermediate 7, 0.042g 3-fluoro-4-methylphenylboronic acid, 0.014g tetrakis(triphenylphosphine) palladium and 0.061g Sodium carbonate, 74.6 mg was obtained, the yield was 81.2%, and the purity was 99.0%.

[0145] HNMR(300MHz,DMSO-d6)δ:7.45(t,J=7.6Hz,H),7.23-7.38(m,8H),6.95(d,2H),6.09(s,H),4.05(d,J =12.8Hz,2H),3.40(s,H),3.23(s,2.65),2.90(m,4H),2.33(s,3H),2.08(d,J=10.7Hz,2H),1.51(q ,J=11.8Hz,2H).CNMR(500MHz,DMSO-d6)δ:161.93,160.74,159.99,156.39,154.27,152.96,137.52,135.27,135.20,132.52,132.48,129.09,129.06,1227.82 ,126.22,124.71,115.54,115.36,111.93,109.81,109.09,101.15.

Embodiment 3

[0146] Example 3 7-(4-phenethylaminopiperidine-1-substituted)-4-(3-methyl-4-fluorobenzene-1-substituted)coumarin (I-3)

[0147] The synthesis method is as in Example 1, except that the raw materials used in step (7) are 0.16g intermediate 7, 0.045g 3-methyl-4-fluorophenylboronic acid, 0.015g tetrakis(triphenylphosphine) palladium and 0.067g Sodium carbonate, 64.9 mg was obtained, the yield was 56.5%, and the purity was 97.5%.

[0148] HNMR(300MHz,DMSO-d6)δ:7.44(d,J=7.3Hz,H),7.23-7.38(m,8H),6.96(d,2H),6.06(s,H),4.05(d,J =13.3Hz,2H),3.39(H),3.22(s,2H),2.90(m,4H),2.31(s,3H),2.08(d,J=11.0Hz,2H),1.51(q,J =11.6Hz,2H).CNMR(500MHz,DMSO-d6)δ:162.74,160.78,156.37,154.79,152.92,137.50,132.21,131.79,129.10,129.06,128.39,128.33,125.98,1121.25,2 ,115.76,111.92,109.69,109.27,101.13,54.66,45.87,45.19,32.22,27.51,14.58.

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Abstract

The invention discloses two kinds of coumarins NEDD8 activating enzyme inhibitors different in general formula as well as salts, solvates, polymorphic substances, tautomers, metabolites and prodrugs of the coumarins NEDD8 activating enzyme inhibitors. The invention further discloses application of the coumarins NEDD8 activating enzyme inhibitors to preparation of antitumor drugs. Pharmacological results show that the compounds, namely the coumarins NEDD8 activating enzyme inhibitors, have remarkable effects on NEDD8 inhibitory activity, anti-tumor cell proliferation and tumor cell apoptosis promotion and therefore can be used for preparing the drugs for treating the tumors clinically.

Description

technical field [0001] The invention belongs to the field of biochemistry, and in particular relates to a coumarin-based NEDD8 activating enzyme inhibitor. 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 attracted much attention. [0003] In eukaryotic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04C07D405/14A61K31/453A61K31/4709A61K31/454A61K31/506A61P35/00A61P35/02
CPCC07D405/04C07D405/14
Inventor 王玉斌陆鹏袁新睿
Owner NANJING UNIV OF TECH
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