Unlock instant, AI-driven research and patent intelligence for your innovation.

Isoxazole sulfonamide compound with BRD4 inhibitory activity as well as preparation method and application of isoxazole sulfonamide compound

A technology of isoxazole sulfonamide and inhibitory activity, which is applied in the field of preparation of isoxazole sulfonamide compounds, can solve the problems of inhibition effect, high risk of toxic and side effects, unclear compound target, etc., and achieves good selectivity, good Protein inhibitory effect, good in vitro inhibitory effect on tumor cells

Pending Publication Date: 2021-11-16
TAIZHOU POLYTECHNIC COLLEGE
View PDF1 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] 1. The selective inhibitory effect on tumor cells is not high, and it may bring potential side effects when targeting a single tumor, that is, while killing specific tumor cells, it may also have an inhibitory effect on other tissue cells
[0012] 2. For the optimal compound of the above existing patents, its binding activity to BRD4 still needs to be further improved
If the activity of the compound at the target level in vitro is not high enough (that is, the binding activity with BRD4 is not high enough), after entering cells with a more complex environment, it can bind to and inhibit the target, and then inhibit related pathways to inhibit tumor growth. decline
In this case, higher doses are required to achieve the same effect, with high doses carrying a high risk of toxic side effects
In addition, if the cytotoxicity screening is carried out without first screening based on the target, the target of the compound is not clear, and the safety risk is greater

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Isoxazole sulfonamide compound with BRD4 inhibitory activity as well as preparation method and application of isoxazole sulfonamide compound
  • Isoxazole sulfonamide compound with BRD4 inhibitory activity as well as preparation method and application of isoxazole sulfonamide compound
  • Isoxazole sulfonamide compound with BRD4 inhibitory activity as well as preparation method and application of isoxazole sulfonamide compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1 N-(3-ethyl-6-methoxybenzo[d]isoxazol-5-yl)ethanesulfonamide (7a)

[0088] Step 1 Preparation of N-(2,4-dimethoxyphenyl)acetamide (2) Add 2,4-dimethoxyaniline (15g, 97.9mmol) and dichloromethane in sequence to a dry 250mL reaction flask (40mL), cooled to 0°C, added acetic anhydride (18.0g, 176.3mmol) with stirring, then slowly added triethylamine (15.9g, 156.7mmol) dropwise, stirred at room temperature for 4h, and TLC detected that the reaction was complete. The solvent was evaporated under reduced pressure, dilute hydrochloric acid was added, suction filtered, the filter cake was washed twice with dilute hydrochloric acid, and dried to obtain 16.5 g of white solid with a yield of 86.3%. 1 H NMR (400MHz, DMSO-d 6 ),δ:8.99(s,1H),7.64(d,J=8.7Hz,1H),6.59(s,1H),6.45(d,J=8.8Hz,1H),3.79(s,3H),3.73 (s,3H), 2.01(s,3H); MS-ESI, m / z: 196.1(M+H) + . .

[0089] Step 2 Preparation of N-(4-hydroxy-2-methoxy-5-propionylphenyl)acetamide (3) Add N-(2,4-dimethoxyphenyl)etha...

Embodiment 2

[0094] Example 2 N-(3-ethyl-6-methoxybenzo[d]isoxazol-5-yl)propane-1-sulfonamide (7b)

[0095] It was prepared according to the method of Example 1, using compound 6 and propylsulfonyl chloride as reactants. White solid; yield: 39.4%; m.p.: 108–109℃; 1 H NMR (400MHz, CDCl 3 )δ7.76(s,1H,7-ArH),7.05(s,1H,4-ArH),6.76(s,1H,SO 2 NH),3.99(s,3H,OCH 3 ), 3.05–2.90 (m, 4H, SO 2 C H 2 ,3-C H 2 CH 3 ), 1.88–1.76 (m,2H,SO 2 CH 2 C H 2 ), 1.41(t, J=7.5Hz, 3H, 3-CH 2 C H 3 ),0.99(t,J=7.4Hz,3H,CH 2 CH 2 C H 3 ); 13 CNMR (101MHz, CDCl 3 )δ161.35, 159.87, 152.40, 123.49, 114.53, 112.75, 92.22, 56.52, 52.94, 18.85, 17.20, 12.92, 12.11; LC-MS (ESI) m / z calcd for C 13 h 18 N 2 o 4 S[M+H] + :299.0987; found: 299.1.

Embodiment 3

[0096] Example 3 N-(3-ethyl-6-methoxybenzo[d]isoxazol-5-yl)butane-1-sulfonamide (7c)

[0097] It was prepared according to the method of Example 1, using compound 6 and 1-butanesulfonyl chloride as reactants. White solid; yield: 48%; m.p.: 100–102℃; 1 H NMR (400MHz, CDCl 3 )δ7.76(s,1H,7-ArH),7.05(s,1H,4-ArH),6.76(s,1H,SO 2 NH),3.99(s,3H,OCH 3 ),3.10–2.85(m,4H,SO 2 C H 2 ,3-C H 2 CH 3 ), 1.85–1.75 (m,2H,SO 2 CH 2 C H 2 ),1.51–1.28(m,5H,3-CH 2 C H 3 , SO 2 CH 2 CH 2 C H 2 ),0.88(t,J=7.0Hz,3H,CH 2 CH 2 C H 3 ); 13 C NMR (101MHz, CDCl 3 )δ161.36, 159.88, 152.39, 123.49, 114.53, 112.79, 92.21, 56.48, 50.94, 25.41, 21.44, 18.85, 13.56, 12.11; LC-MS (ESI) m / z calcd for C 14 h 20 N 2 o 4 S[M+H] + :313.1144; found: 313.1.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides an isoxazole sulfonamide compound with BRD4 inhibitory activity or a pharmaceutically acceptable salt thereof. The compound has a structural formula as shown in a general formula (I). The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of drugs for preventing or treating cancers related to BRD4, wherein the cancers comprise leukemia, lymphoma, myeloma, lung cancer, prostate cancer, pancreatic cancer, colon cancer, breast cancer, liver cancer, gastric cancer and the like. The invention provides a novel BRD4 inhibitor, and experiments prove that the novel compound with a 3-ethylbenzo [d] isoxazole sulfonamide structure has a good BRD4 protein inhibition effect and an in-vitro tumor cell inhibition effect, and especially, the inhibition activity of partial compounds for leukemia cells reaches or is superior to that of a positive control compound. The compound can also effectively inhibit the expression of c-Myc oncogene.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of isoxazole sulfonamide compounds with BRD4 inhibitory effect, compositions containing these compounds and uses thereof. Background technique [0002] Acetylation of histone lysine is one of the important post-translational modifications. Bromodomains are a class of protein domains that can recognize acetylated lysines on histones, thereby opening the chromatin structure, promoting transcriptional activation, and are closely related to the occurrence of diseases such as tumors or inflammation. At present, 61 bromodomains have been found in 46 proteins, which can be divided into eight families. BRD4 is a member of the BET (Bromodomain and Extra-Terminal) family. It contains two bromodomains, BD1 and BD2, which bind to acetylated lysine through BD1 and BD2. [0003] BRD4 can recruit positive transcription elongation factor b (P-TEFb) to promoters and activ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D261/20C07D413/12A61K31/423A61K31/4439A61P35/00A61P35/02
CPCC07D261/20C07D413/12A61P35/00A61P35/02Y02P20/55
Inventor 张茂风
Owner TAIZHOU POLYTECHNIC COLLEGE
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com