Thiazoline compounds and pharmaceutical composition and application thereof

A technology of dihydrothiazolone and compounds, which is applied in the field of drug synthesis and can solve problems such as interference

Inactive Publication Date: 2014-06-04
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, if small molecules are designed to interfere with the binding of Brd4 to acetylated histones, it will be possible to inhibit the transcription of c-myc

Method used

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  • Thiazoline compounds and pharmaceutical composition and application thereof
  • Thiazoline compounds and pharmaceutical composition and application thereof
  • Thiazoline compounds and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073]

[0074] The synthetic route is:

[0075]

[0076] Reagents and conditions: a) copper bromide, ethyl acetate, 80°C; b) potassium thiocyanate, acetone, room temperature; 50% sulfuric acid, glacial acetic acid, 100°C

[0077] a) 3-Chloroacetophenone (0.2g, 1.294mmol) and copper bromide (0.347g, 1.552mmol) were successively dissolved in ethyl acetate (30mL), heated to 80°C and stirred overnight, and the reaction solution was cooled to room temperature, Add 30 mL of ethyl acetate, extract with 100 mL of water and 100 mL of saturated sodium chloride solution successively, separate the ethyl acetate layer, dry with anhydrous sodium sulfate, evaporate the organic solvent under reduced pressure, and purify the residue by flash silica gel column chromatography. Elute with petroleum ether / ethyl acetate (V / V=10:1) to obtain 220 mg of 2-bromo-1-(3-chlorophenyl)ethanone as a white solid with a yield of 72.8%. 1 H NMR (400MHz, CDCl3) δ7.94 (td, J=5.8, 3.0Hz, 1H), 7.88–7.83(m, ...

Embodiment 5

[0082]

[0083] The synthetic route is:

[0084]

[0085]Steps a and b were carried out in the same manner as in Preparation Example 1. The specific steps of step c are: 4-(3-nitrophenyl)thiazol-2(3H)-one (1.05g, 4.73mmol) was dissolved in 20mL ethanol, ammonium chloride (1.264g, 23.66mmol) was dissolved in Add 5mL of water to the reaction solution, then add reduced iron powder (1.319g, 23.66mmol), heat the reaction solution to 80°C and stir for 30 minutes, dilute the reaction solution with ethyl acetate, filter through diatomaceous earth, and concentrate the filtrate under reduced pressure to leave The product was purified by flash silica gel column chromatography, eluting with dichloromethane / methanol (V / V=20:1), to obtain 700 mg of the title compound as a pale yellow solid, with a yield of 77%. MS(ES):m / z 193.1[M+H] + ; 1 H NMR(400MHz,DMSO)δ11.62(s,1H),7.05(t,J=7.7Hz,1H),6.78–6.73(m,2H),6.57(ddd,J=8.0,2.2,1.0Hz, 1H),6.53(d,J=1.6Hz,1H),5.21(s,2H).

[0086] The fol...

Embodiment 9

[0089]

[0090] The synthetic route is:

[0091]

[0092] The specific steps of step a are: dissolve 2-hydroxyacetophenone (11.3g, 83mmol) in 100mL glacial acetic acid, add fuming nitric acid (5.57mL, 125mmol) dropwise within 30 minutes under ice bath, and continue under ice bath Stir for 1 hour, warm to room temperature and stir for 16 hours. The reaction solution was poured into ice water, the precipitated solid was filtered, washed with water, and dried. The solid was purified by flash silica gel column chromatography and eluted with petroleum ether / ethyl acetate (V / V=5:1) to obtain 1-(2-hydroxyl -5.3 g of 5-nitrophenyl) ethyl ketone, which is a pale yellow solid, with a yield of 35.2%. 1 H NMR (400MHz, DMSO) δ6.65(t, J=5.3Hz, 2H), 6.51(s, 1H), 6.47(dd, J=8.5, 2.7Hz, 1H), 4.56(s, 2H).

[0093] Steps b, c and d are carried out in the same manner as steps a, b and c of Preparation Example 5 to obtain the title compound of Example 9, 1 H NMR (400MHz, DMSO) δ6.65(t, J=...

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Abstract

The invention provides thiazoline compounds as shown in a general formula (I) and a pharmaceutical composition and application of the thiazoline compounds. The thiazoline compounds provided by the invention can be used for regulating the downstream signal passage and exerting the specific function after being bonded with a protein with a bromodomain structural domain and thus can be used for treating multiple diseases related to the protein with the bromodomain structural domain. The thiazoline compounds provided by the invention can be used for down regulating the transcription of a cancer gene c-myc and a related target gene by disturbing the bond of Brd4 with the bromodomain structural domain and an acetylated histone, thereby becoming the effective therapeutic drug of tumors.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular, the invention relates to a class of dihydrothiazolone compounds and their pharmaceutical composition and use. Background technique [0002] Epigenetic variation refers to heritable changes in gene function without changes in the DNA sequence of the gene, which eventually lead to phenotypic changes. Chromatin is composed of DNA, histones and non-histones. The nucleosome is the basic repeating unit of chromatin, an octamer composed of histones H3, H4, H2A, and H2B, as well as histone H1 located outside the nucleosome and a 146-base pair wound around it. DNA makeup. The state of chromatin plays an important role in regulating gene transcription. Epigenetics involves DNA methylation, histone modification, chromosome remodeling and non-coding RNA regulation, etc. Histone modification includes histone acetylation, phosphorylation, methylation, ubiquitination and ADP ribose These diverse...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/34C07D417/12C07D417/14A61K31/426A61K31/4709A61K31/427A61K31/4439A61P35/00A61P35/02
CPCC07D277/34C07D417/12C07D417/14
Inventor 沈竞康赵乐乐熊兵缪泽鸿许叶春何建华曹丹燕王昕陈麟王迎庆李艳莲陈五妍王炜
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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