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Compound with sulfonyl phenylamine pyrimidine structure and application of compound as antitumor medicine

A technology containing sulfonanilidine and sulfonanilidine, which is applied in the application field of treating malignant tumors and diseases related to differentiation and proliferation, can solve the problems of weak EGFR kinase inhibitory activity and decreased tumor growth rate, and achieves a good choice Inhibitory activity, anti-tumor clinical application prospect, effect of good clinical application prospect

Active Publication Date: 2019-10-29
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly targets MET and VEGFR2 tyrosine kinases related to the growth and spread of prostate cancer, inhibits tumor metastasis and angiogenesis, and has weak inhibitory activity on EGFR kinases
Results of a phase II trial presented at the 2014 ASCO Annual Meeting showed that erlotinib was effective in patients with EGFR-positive non-small cell lung cancer whose disease had progressed on prior erlotinib (EGFR inhibitor) monotherapy. + Cabozantinib combination therapy has anti-tumor activity, and the growth rate of tumors in 85% of patients was significantly reduced
[0009] Strong activity on target enzymes c-Met and VEGFR-2, but only a certain inhibitory activity on EGFR kinase

Method used

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  • Compound with sulfonyl phenylamine pyrimidine structure and application of compound as antitumor medicine
  • Compound with sulfonyl phenylamine pyrimidine structure and application of compound as antitumor medicine
  • Compound with sulfonyl phenylamine pyrimidine structure and application of compound as antitumor medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] N-(3-fluoro-4-((2-((3-sulfonamido)amino)pyrimidine)-4-oxyl)phenyl)-N-(4-fluorophenyl)cyclopropyl-1, Preparation of 1-dicarboxamide (I-1) and its salt

[0074] Prepare according to the synthetic general method, and the specific operation is as follows:

[0075] Preparation of intermediate 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (1-1):

[0076] Dissolve cyclopropane-1,1-dicarboxylic acid (13.01g, 0.10mol) in THF 120mL, under nitrogen protection, slowly add triethylamine (10.12g, 0.10mol) dropwise at 0°C, stir for 15min, then slowly Add SOCl dropwise 2(9.95g, 0.10mol), maintain this temperature and continue to stir for 30min. 60 mL of THF solution dissolved in 4-fluoroaniline (12.22 g, 0.11 mol) was added dropwise, and the reaction was completed under ice bath conditions. The reaction solution was adjusted to pH 9.0 with 10% sodium hydroxide solution, and after stirring for 10 min, the pH was adjusted to 5.0 with 1N HCl to precipitate a solid, which wa...

Embodiment 2

[0092] N-(4-fluorophenyl)-N-(4-((2-((3-sulfonamidophenyl)amino)pyrimidine)-4-oxyl)phenyl)cyclopropyl-1,1- Preparation of Diformamide (I-2) and Its Salts

[0093] According to the general synthesis method, the target compound I-2 was prepared with a yield of 56%, ESI-MS (m / z): 563.15[M+H]+. 1 H NMR (400Hz, DMSO-d 6 )δppm: 10.31(s,1H,NH),10.12(s,1H,NH),9.90(s,1H,NH),8.42(d,1H,J=4.0Hz,ArH),8.04(s,1H, ArH),7.81(m,1H,ArH),7.73(d,1H,J=8.0Hz,ArH),7.65(m,4H,ArH),7.30(m,5H,ArH),7.16(m,2H, NH 2 ), 6.60(d, 1H, J=8.0Hz, ArH), 1.47(d, 4H, J=8.0Hz, CH 2 ).

[0094] The preparation of compound 1-2 hydrobromide:

[0095] Using compound I-2 (2.0 mmol) and 5% hydrobromic acid aqueous solution (2.1 mmol) as raw materials, the preparation method of compound I-1 hydrobromide was used to obtain 0.9 g of white I-2 hydrobromide as a solid.

Embodiment 3

[0097] N-(3-fluoro-4-((2-((3-(methylsulfonamido)phenyl)amino)pyrimidine)-4-oxyl)phenyl)-N-(4-fluorophenyl) Preparation of cyclopropyl-1,1-dicarboxamide (I-3) and its salt

[0098] According to the general method of synthesis, the target compound I-3 was prepared with a yield of 43%, ESI-MS (m / z): 595.11

[0099] [M+H] + . 1 H NMR (400Hz, DMSO-d 6 )δppm: 10.36(s,1H,NH),10.05(s,1H,NH),9.93(s,1H,NH),8.42(d,1H,J=4.0Hz,ArH),8.04(s,1H, ArH),7.81(m,1H,ArH),7.73(d,1H,J=8.0Hz,ArH),7.65(m,2H,ArH),7.46(d,1H,J=8.0Hz,ArH),7.30 (m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J=8.0Hz,ArH),2.93(s,3H,CH 3 ), 1.41 (d, 4H, J=8.0Hz, CH 2 ).

[0100] The preparation of compound 1-3 malate:

[0101] Compound I-1 (0.1 mmol) and malic acid (0.8 mmol) were added to ethanol (10 mL), dissolved under reflux, and a white solid was precipitated by cooling, and filtered to obtain 0.12 g of white I-3 malate solid.

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Abstract

The invention discloses a compound with a sulfonyl phenylamine pyrimidine structure and application of the compound as an antitumor medicine. Pharmacology experiments show that the compound has multi-target inhibition activity, has good multi-target inhibition activity (a grade nM) upon c-Met, VEGFR-2 and EGFR, has a weak inhibition function on normal cells when effectively inhibiting multiple tumor cells, has good selective inhibition activity, has good security low potential cardiotoxicity, good antitumor activity and small toxic and side effects, is capable of overcoming tumor cell drug resistance, can be easily used as an antitumor medicine and can be used for preparing antitumor medicines. The compound has a good treatment effect on diseases such as endocrine disorder, immune system diseases, genetic diseases and nervous system diseases caused by genetic expression abnormity. The compound with the sulfonyl phenylamine pyrimidine structure is a compound of a formula (I) shown in the specification or a pharmaceutically acceptable salt of the compound.

Description

technical field [0001] The invention relates to a class of compounds containing a sulfonylaniline structure and the application of the compounds in treating malignant tumors and diseases related to differentiation and proliferation. Background technique [0002] Malignant tumor cells are characterized by persistent proliferative signals, evasion of growth inhibition, resistance to cell death, continual replication, angiogenesis, activation of invasion, metastasis, restart of energy metabolism, avoidance of immune destruction, and recruitment of the tumor microenvironment. Receptor tyrosine kinases transmit extracellular signals into cells and mediate the control of signaling networks of many fundamental cellular functions. The dysregulation of receptor tyrosine kinase activity is a key factor in the occurrence and development of tumors, which has been confirmed in the research and development of various receptor tyrosine kinase drugs. [0003] More than 50 receptor tyrosine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47C07D401/12A61P35/00A61P35/02A61P25/24A61P5/00A61P37/00A61P25/00A61K31/505A61K31/506A61K31/5377
CPCC07D239/47C07D401/12A61P35/00A61P35/02A61P25/24A61P37/00A61P25/00
Inventor 李建其张庆伟陆冰榴曾景
Owner SHANGHAI INST OF PHARMA IND