Piperidinothieno small-molecular organic compounds and applications thereof

A technology of organic compounds and small molecules, applied in the fields of organic chemistry, organic active ingredients, medical preparations containing active ingredients, etc., can solve problems such as staying

Active Publication Date: 2018-06-22
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] STAT3 has received more and more attention as a new target for tumor therapy. There have been a large number of research reports on STAT3 inhibitors and their anti-tumor activities, including nucleic acid inhibitors such as siRNA, antisense oligonucleotides, G - Quadruplet oligodeoxynucleotides, decoy oligonucleotides and dominant negative plasmids, etc., block cell surface receptors upstream of STAT3 or tyrosine kinase inhibitors such as IL-6 neutralizing antibody, gp130 neutralization Antibodies, JAK kinase inhibitors TG-101348, WP1066, INCB018424, S-Ruxolitinib and EGFR kinase inhibitors gefitinib, erlotinib, afatinib, etc., regulate SOCS, PIAS, SHP and other STAT3 endogenous regulation protein, as well as some STAT3-specific inhibitors such as Stattic and S3I-201 that inhibit STAT3 dimerization, but most of the current research on the anti-tumor effect of STAT3 in

Method used

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  • Piperidinothieno small-molecular organic compounds and applications thereof
  • Piperidinothieno small-molecular organic compounds and applications thereof
  • Piperidinothieno small-molecular organic compounds and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] Embodiment one: the preparation of each compound

Embodiment 1-1

[0147] Example 1-1, N-(2-(6-((5-chloro-2-furyl)methyl)-3-cyano-4,5,6,7-tetrahydrothieno-[2, Synthesis of 3-c]pyridyl))-1-methyl-1H-pyrazole-4-carboxamide (ZZ001)

[0148]

[0149] Dissolve N-tert-butoxycarbonyl-4-piperidone (1.99g, 10mmol) and malononitrile (0.73g, 11mmol) in 30mL of ethanol, add sulfur (363mg, 11mmol) and morpholine (1.74g, 20mmol). The mixture was heated to reflux and stirred for 2h, the solution turned orange and a solid was formed. Cool the reactant to room temperature, filter with suction, wash the filter cake with ice ethanol, and dry to obtain a light yellow solid 2-amino-3-cyano-4,7-dihydrothiophene-[2,3-c]pyridine-6 (5H)-tert-butylcarboxylate (2.50 g, crude yield: 90%).

[0150]

[0151] 2-Amino-3-cyano-4,7-dihydrothiophene-[2,3-c]pyridine-6(5H)-tert-butyl carboxylate (2.50g, 9mmol) and 1-picoline- 4-Carboxylic acid (1.25g, 9.9mmol) was dissolved in 30mL of dichloromethane, 2-chloro-1-picoline iodide (2.53g, 9.9mmol), 4-dimethylaminopyridine...

Embodiment 1-16

[0156] Example 1-16, N-(2-(6-(3-bromobenzyl)-3-cyano-4,5,6,7-tetrahydrothieno-[2,3-c]pyridyl) )-1-methyl-1H-pyrazole-4-carboxamide

[0157]

[0158] Take N-(2-(3-cyano-4,5,6,7-tetrahydrothieno-[2,3-c]pyridyl))-1-methyl-1H-pyrazole-4-methyl Amide (153mg, 0.53mmol) and 3-bromobenzyl bromide (200mg, 0.8mmol) were dissolved in 20ml of acetone, cesium carbonate (518mg, 1.59mmol) was added, and reacted at 0°C. After the reaction was completed, the solvent was removed under reduced pressure and used Dichloromethane and water were extracted three times, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and column chromatography purified to obtain N-(2-(6-(3-bromobenzyl)-3 -cyano-4,5,6,7-tetrahydrothieno-[2,3-c]pyridyl))-1-methyl-1H-pyrazole-4-carboxamide (116 mg, crude yield: 48%). 1 H NMR(500MHz,DMSO)δ11.43(s,1H),8.46(s,1H),8.06(s,1H),7.56(s,1H),7.48(d,J=7.8Hz,1H),7.37 (d,J=7.6Hz,1...

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Abstract

The invention discloses piperidinothieno small-molecular organic compounds, related analogues thereof or pharmaceutically acceptable salts as well as related compounds. The invention also discloses applications of the piperidinothieno small-molecular organic compounds or pharmaceutical composition thereof in preparation of drugs for preventing and/or treating growth, transfer and relapse of malignant tumor and other diseases as well as applications in prevention and/or treatment of STAT3 medicated diseases as an STAT3 inhibitor. The invention also provides a preparation method of the piperidinothieno small-molecular organic compounds and derivatives thereof.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a piperidothiophene small-molecule organic compound and its application. technical background [0002] Cancer is a kind of malignant disease that seriously threatens human health. According to statistics, the total mortality rate is about 23% and has remained high for more than half a century. With the impact of multiple factors such as environmental pollution, aging population and lifestyle changes, China has become the country with the largest number of new cancer cases in the world. According to the statistics of "Cancer Statistics in China, 2015", the incidence of cancer in China is severe, and the incidence and mortality rates are on the rise. There are about 4.292 million new cancer cases and about 2.814 million cancer deaths every year. In the next few decades, the number of cancer patients in China will continue to increase. At the same time, the therapeutic effect of chemot...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/4365A61K31/506A61K31/497A61K31/444A61P35/00A61P35/02
CPCC07D495/04
Inventor 陈益华刘明耀周珍肖洋炯陈煌易正芳杜冰
Owner EAST CHINA NORMAL UNIV
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