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Application of pyrimidazole-type STAT3 inhibitor in preparation of medicine capable of delaying or reversing acquired resistance to TKIs

A pyridoimidazole and inhibitor technology, applied in the field of medicine, can solve the problems of high phosphorylation expression, short survival period, poor prognosis, etc., and achieve the effects of enhancing sensitivity, improving curative effect, and overcoming easy drug resistance

Active Publication Date: 2020-08-14
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patients with acquired EGFR-TKIs resistance, their STAT3 phosphorylation expression is higher, the survival time is shorter, and the prognosis is poorer

Method used

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  • Application of pyrimidazole-type STAT3 inhibitor in preparation of medicine capable of delaying or reversing acquired resistance to TKIs
  • Application of pyrimidazole-type STAT3 inhibitor in preparation of medicine capable of delaying or reversing acquired resistance to TKIs
  • Application of pyrimidazole-type STAT3 inhibitor in preparation of medicine capable of delaying or reversing acquired resistance to TKIs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of W2014

[0045]

[0046] Weigh compound 1, iron powder (3 equivalents) and ammonium chloride (4 equivalents) and dissolve them in 20ml of ethanol, heat at 80°C, cool to room temperature after the reaction is complete, filter the reaction solution through diatomaceous earth and rinse the silicon with an appropriate amount of ethyl acetate. alginate, the organic phase was dried with anhydrous sodium sulfate, and spin-dried to obtain a purple solid compound 2 with a yield of 78%. 1 H NMR (500MHz, CDCl 3 )δ6.85(d, J=7.8Hz, 1H), 6.60(d, J=7.8Hz, 1H), 4.45(s, 2H), 3.28(s, 2H).ESI-MS: 145.0[M+H ]+;

[0047] Weigh compound 3, p-hydroxybenzaldehyde (1.1 equivalents), and potassium carbonate (2 equivalents) and dissolve them in 40ml of acetonitrile, stir at room temperature overnight for reaction, filter after the reaction is complete, spin the organic phase to dry column chromatography and purify to obtain compound 4, the yield 90%, 1 H NMR (400MHz, CDCl 3 ...

Embodiment 2

[0050] Embodiment 2: Preparation of W2014R

[0051]

[0052] Weighed triphenylphosphine (1.8 equivalents) and dissolved it in 80 ml of tetrahydrofuran, under nitrogen protection, slowly added DIAD (1.8 equivalents) to the reaction under ice bath conditions, and after 20 minutes, kept ice bath conditions, successively added compound 6 (1 equivalent) and p-Hydroxybenzaldehyde (1 equivalent) were dissolved in 20 ml of tetrahydrofuran and added to the reaction respectively, stirred at room temperature for the reaction, and the reaction was complete after 10 hours. The organic phase was spin-dried and concentrated, and the residue was purified by column chromatography to obtain compound 7 , with a yield of 44%, 1 H NMR (400MHz, CDCl 3 )δ9.84(s,1H),7.78–7.74(m,2H),7.39–7.36(m,4H),7.32–7.28(m,1H),6.99(d,J=8.7Hz,2H),5.44 (q, J=6.4Hz, 1H), 1.70 (d, J=6.4Hz, 3H).ESI-MS: 227.2[M+H]+;

[0053] Weigh intermediate compound 2 and compound 7 (1.1 equivalent) and dissolve in 10ml methano...

Embodiment 3

[0055] Embodiment 3: Preparation of W2014S

[0056]

[0057]Weighed triphenylphosphine (1.8 equivalents) and dissolved it in 80 ml of tetrahydrofuran, under nitrogen protection, slowly added DIAD (1.8 equivalents) to the reaction under ice bath conditions, and after 20 minutes, maintained ice bath conditions, successively added compound 9 (1 equivalent) and p-Hydroxybenzaldehyde (1 equivalent) were dissolved in 20 milliliters of tetrahydrofuran and added to the reaction respectively, stirred at room temperature, and the reaction was complete after 10 hours. The organic phase was spin-dried and concentrated, and the residue was purified by column chromatography to obtain compound 10 , with a yield of 48%, 1 H NMR (400MHz, CDCl 3 )δ9.84(s,1H),7.79–7.74(m,2H),7.40–7.35(m,4H),7.32–7.28(m,1H),6.99(d,J=8.7Hz,2H),5.44 (q, J=6.4Hz, 1H), 1.70 (d, J=6.4Hz, 3H).ESI-MS: 227.2[M+H]+;

[0058] Weigh intermediate compound 2, compound 10 (1.1 equivalent) and dissolve in 10ml methanol, h...

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PUM

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Abstract

The invention discloses application of a pyrimidazole-type STAT3 inhibitor in preparation of a medicine capable of delaying or reversing acquired resistance to TKIs, wherein the pyrimidazole-type STAT3 inhibitor is a substituted pyrimidazole compound with a structure as follows (including chiral isomers R and S). As a small-molecule compound, the pyrimidazole-type STAT3 inhibitor disclosed by theinvention is capable of delaying or reversing occurrence of acquired drug resistance in EGFR-TKIs cancer treatment, as well as inhibiting the acquired resistance to the EGFR-TKIs in NSCLC patients soas to enhance sensitivity of the cancer to the EGFR-TKIs, thereby overcoming the disadvantage of liable occurrence of resistance of the EGFR-TKIs and improving curative effects of the EGFR-TKIs; and thus, the pyrimidazole-type STAT3 inhibitor has good application prospects.

Description

technical field [0001] The invention relates to the technical field of medicine, and more specifically, relates to the application of a pyridoimidazole STAT3 inhibitor in the preparation of drugs for delaying or reversing TKI acquired drug resistance. [0002] technical background [0003] Epidermal growth factor receptor (EGFR) is a tyrosine kinase involved in the regulation of cell homeostasis. After binding with the ligand to form a dimer, phosphorylated EGFR activates downstream signaling pathways, such as PI3K / AKT, STATs, and MAPK signaling pathways, and ultimately promotes cell proliferation, migration, and survival, and is also involved in angiogenesis, tumorigenesis, and many other complex physiological process. [0004] In non-small cell lung cancer, EGFR mutation is a common oncogene. According to statistics, about 17% of patients with non-small cell lung cancer have EGFR mutation, and in Chinese patients, the mutation rate exceeds 30%. EGFR sensitive mutations m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4545A61P35/00A61P35/04
CPCA61K31/4545A61P35/00A61P35/04
Inventor 张小雷王元相刘培庆郑琪瑶张毅
Owner SUN YAT SEN UNIV
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