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Five-membered urea ring-coumarin derivative or pharmaceutical salt and application thereof

A technology of medicinal salt and halogen, which is applied in the field of chemical medicine and can solve problems such as large side effects

Inactive Publication Date: 2013-08-21
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional first-line drugs generally have the problem of large side effects and no selectivity for normal cells and tumor cells

Method used

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  • Five-membered urea ring-coumarin derivative or pharmaceutical salt and application thereof
  • Five-membered urea ring-coumarin derivative or pharmaceutical salt and application thereof
  • Five-membered urea ring-coumarin derivative or pharmaceutical salt and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1 Compound Ia: 2-methyl-2-[4-[2-oxo-8-bromo-2,3-dihydroimidazo[4,5-c]coumarin-1-yl]benzene Base] the preparation of propionitrile

[0062]

[0063] Intermediates involved:

[0064] The synthetic method of this intermediate is as follows:

[0065]

[0066] 1, the preparation of 4-bromophenyl acetate:

[0067] Add 4-bromophenol (97.87g, 0.566mol) into 80mL of acetic anhydride (86.6g, 0.849mol), add 91mL of pyridine (89.43g, 1.132mol), heat the reaction solution to 100°C, stir for 4 hours, and use Adjust dilute hydrochloric acid to slightly acidic, and then extract 3 times with ethyl acetate, adjust the organic layer to weak alkaline with saturated sodium bicarbonate solution, wash 3 times with water, anhydrous MgSO 4 After drying and concentrating, 122 g of the product was obtained, and the yield was 100%.

[0068] The preparation of 4-bromophenylacetate is also commercially available.

[0069] 2. Preparation of 2-hydroxyl-5-bromoacetophenone:

[007...

Embodiment 2

[0099] Example 2 Compound Ib: 2-methyl-2-[4-[2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]coumarin Preparation of prime-1-yl]phenyl]propionitrile

[0100]

[0101] 2-Methyl-2-[4-(2-oxo-8-bromo-2,3-dihydroimidazo[4,5-c]coumarin-1-yl)phenyl]propionitrile ( 214 mg, 0.51 mmol) and quinoline-3-boronic acid (100 mg, 0.56 mmol) were mixed in 40 mL of dioxane: water = 3:1 solution, and then potassium carbonate (210 mg, 1.52 mmol) and PdCl were added 2 (dppf) (20mg, 0.02mmol), under nitrogen protection, react at 65°C. After 4 hours, the reaction solution was filtered, the filtrate was concentrated, and the product was separated by column chromatography (115 mg, yield 48%).

[0102] 1 H-NMR (DMSO-d 6 , 400MHz): 2.65 (s, 6H), 6.82 (d, J=1.6Hz, 1H), 7.65 (t, J=7.4Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 7.78 (t , J=7.8Hz, 1H), 7.86 (d, J=8.4Hz, 2H), 7.98 (m, 5H), 8.28 (s, 1H), 8.71 (d, J=2.0Hz, 1H) ppm.

Embodiment 3

[0103] Example 3 Compound IIa: Preparation of 2-[4-(2-oxo-8-bromo-2,3-dihydroimidazo[4,5-c]coumarin-1-yl)phenyl]acetonitrile

[0104]

[0105] 1. Preparation of 2-[4-N-(3-nitro-6-bromocoumarin-4-yl)phenyl]acetonitrile

[0106] Method with reference to embodiment 1.

[0107] 1 H-NMR (CDCl 3 , 400MHz): 4.03 (s, 2H), 5.30 (s, 1H), 7.30 (d, J=8.8Hz, 1H), 7.71 (dd, J=2.4Hz, 9.6Hz, 1H), 7.88 (dd, J =2.0Hz, 9.2Hz, 1H), 8.05 (s, 1H), 8.30 (d, J=8.8Hz, 1H), 8.91 (d, J=2.4Hz, 1H), 9.23 (s, 1H) ppm.

[0108] 2. Preparation of 2-[4-N-(3-amino-6-bromocoumarin-4-yl)phenyl]acetonitrile

[0109] Method with reference to embodiment 1.

[0110] 1 H-NMR (CDCl 3 , 400MHz): 3.19 (s, 2H), 4.23 (br, s, 2H), 5.44 (s, 1H), 6.71 (d, J=8.4Hz, 2H), 7.25 (m, 3H), 7.43 (dd, J=2.2Hz, 8.6Hz, 1H), 7.53 (d, J=2.4Hz, 1H) ppm.

[0111] 3. Preparation of 2-[4-(2-oxo-8-bromo-2,3-dihydroimidazo[4,5-c]coumarin-1-yl)phenyl]acetonitrile

[0112] Method with reference to embodiment 1.

[0113] 1 H-NMR (D...

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Abstract

The invention relates to a small molecule medicament based on PI3K (Phosphatidyl Inositol 3-kinase) / mTOR (Mammalian Target of Rapamycin) double targets, belongs to the technical field of chemical medicines, and in particular relates to a five-membered urea ring-coumarin derivative or a pharmaceutical salt and an application thereof. A compound claimed by the invention has a structure shown as formula I described in the specification, and pharmacological experiments show that the compound has excellent inhibitory activity in a plurality of tumor cell strains.

Description

technical field [0001] The invention relates to a small-molecule drug based on PI3K / mTOR dual targets, belongs to the technical field of chemistry and medicine, and particularly relates to a five-membered urea cyclocoumarin derivative or a pharmaceutically acceptable salt thereof and its application. Background technique [0002] Cancer is a major disease that endangers human health. It is one of the three major causes of death in all countries in the world today. Judging from the current incidence trend of cancer, the next few years will be years with high incidence of cancer. According to the World Health Organization, there were 7.4 million cancer deaths in 2004 (approximately 13% of all deaths). It is estimated that the incidence of cancer will increase by 50% in 2020, and there will be 15 million new cancer cases in the world every year. An estimated 12 million people will die from cancer in 2030. [0003] At present, the main means of treating cancer are surgery, r...

Claims

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Application Information

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IPC IPC(8): C07D491/052A61K31/4188A61K31/4709A61K31/4439A61P35/00A61P35/02
Inventor 李锐魏于全
Owner SICHUAN UNIV
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