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Dihydrothiazolone compounds containing sulfamide and pharmaceutical compositions and use thereof

A dihydrothiazolone and sulfonamide-containing technology, which can be used in drug combinations, medical preparations containing active ingredients, organic chemistry, etc., and can solve problems such as interference

Inactive Publication Date: 2016-04-13
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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  • Dihydrothiazolone compounds containing sulfamide and pharmaceutical compositions and use thereof
  • Dihydrothiazolone compounds containing sulfamide and pharmaceutical compositions and use thereof
  • Dihydrothiazolone compounds containing sulfamide and pharmaceutical compositions and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116]

[0117] The synthetic route is:

[0118]

[0119] Reagents and conditions: a) sodium nitrite, cuprous chloride, concentrated hydrochloric acid, glacial acetic acid, water, saturated sulfur dioxide solution of glacial acetic acid, -15°C to room temperature; b) cyclopentylamine, pyridine, dichloromethane, room temperature; c) copper bromide, ethyl acetate, 80°C; d) potassium thiocyanate, acetone, room temperature; e) 50% sulfuric acid, glacial acetic acid, 100°C

[0120] a) 3-Aminoacetophenone (1g, 7.4mmol) was dissolved in 5mL of glacial acetic acid and 5mL of concentrated hydrochloric acid, sodium nitrite (0.613g, 8.88mmol) was dissolved in 2mL of water, and slowly added to the reaction solution at -15°C, Control the temperature not to be higher than -5°C, stir for 30 minutes; dissolve cuprous chloride (0.22g, 2.22mmol) in 10mL of saturated sulfur dioxide solution of glacial acetic acid, stir at 0°C for 30 minutes, the solution changes from dark green to blue-gre...

Embodiment 15

[0130]

[0131] The synthetic route is:

[0132]

[0133] Reagents and conditions: a) reduced iron powder, ammonium chloride, ethanol, water, 80°C; b) sodium nitrite, cuprous chloride, concentrated hydrochloric acid, glacial acetic acid, water, saturated sulfur dioxide solution of glacial acetic acid, -15°C to room temperature; c) cyclopentylamine, pyridine, dichloromethane, room temperature; d) copper bromide, ethyl acetate, 80 ° C; e) potassium thiocyanate, acetone, room temperature; f) 50% sulfuric acid, glacial acetic acid, 100°C

[0134] a) 3-nitro-4-methylacetophenone (3g, 16.74mmol) was dissolved in 20mL ethanol, ammonium chloride (3.58g, 67mmol) was dissolved in 5mL water and added to the reaction solution, and then reduced iron powder ( 3.74g, 67mmol), the reaction solution was heated to 80°C and stirred for 30 minutes, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure...

Embodiment 43

[0139]

[0140] The synthetic route is:

[0141]

[0142] Reagents and conditions: a) reduced iron powder, ammonium chloride, ethanol, water, 80°C; b) sodium nitrite, cuprous chloride, concentrated hydrochloric acid, glacial acetic acid, water, saturated sulfur dioxide solution of glacial acetic acid, -15°C to room temperature; c) cyclopentylamine, pyridine, dichloromethane, room temperature; d) copper bromide, ethyl acetate, 80 ° C; e) potassium thiocyanate, acetone, room temperature; f) 50% sulfuric acid, glacial acetic acid, 100°C; g) ethyl 2-bromoacetate, potassium carbonate, potassium iodide, N,N-dimethylformamide, 100°C

[0143] Steps a, b, c, d, e, f were carried out in a similar manner to Preparation Example 15 to obtain Intermediate G. MS(ES):m / z339.10[M+H] + ; 1 HNMR(400MHz,DMSO)δ11.97(s,1H),8.09(s,1H),7.79–7.70(m,2H),7.45(d,J=7.8Hz,1H),6.86(s,1H), 3.44(dd,J=14.0,6.8Hz,1H),2.58(s,3H),1.53(m,4H),1.39–1.22(m,4H).

[0144] g) Intermediate G (150mg, 0.443mmol)...

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Abstract

The invention provides dihydrothiazolone compounds containing sulfamide, represented by a formula (I), pharmaceutical compositions and use thereof. The compounds can be combined with proteins with bromodomain structural domains so as to adjust a downstream signal channel and exert a special function, and can be used for treating many diseases associated with bromodomain structural domains. The compounds can interfere combination of Brd4 with the bromodomain structural domain and an acetylized histone so as to down-regulate transcription of a cancer gene c-myc and associated target genes thereof, so that the compounds can become effective therapeutic drugs for treating tumors.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular, the invention relates to a class of sulfonamide-containing 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 AD...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/34C07D417/12A61K31/426A61K31/427A61K31/5377A61K31/496A61P35/00A61P35/02
Inventor 沈竞康熊兵赵乐乐曹丹燕王迎庆缪泽鸿王昕许叶春何建华
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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