Tyrosine protein kinase inhibitor and preparation method thereof

A kinase inhibitor, tyrosine protein technology, applied in pharmaceutical formulations, medical preparations containing active ingredients, organic chemistry, etc., can solve the problems of poor water solubility, large toxic and side effects of cytotoxic drugs, etc. Good inhibitory activity and high selectivity

Inactive Publication Date: 2014-06-18
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to overcome the defects that the existing tyrosine protein kinase inhibitor system does not contain a series capable of coordinating with cytotoxic organometallic complexes, and the cytotoxic drugs have relatively large toxic and side effects and poor water solubility, and provide A tyrosine protein kinase inhibitor capable of coordinating with cytotoxic organometallic ruthenium complexes, having less toxic and side effects of cytotoxic drugs, and good water solubility

Method used

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  • Tyrosine protein kinase inhibitor and preparation method thereof
  • Tyrosine protein kinase inhibitor and preparation method thereof
  • Tyrosine protein kinase inhibitor and preparation method thereof

Examples

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preparation example Construction

[0048] For example, the preparation method of the compound represented by general formula (26)-(27) may include:

[0049] (1) One of nitro-substituted 1,2-diaminobenzene and a saturated fatty acid with 1-3 carbon atoms, 2-pyridyl formic acid and 2-pyridyl acetic acid in hydrochloric acid aqueous solution, phosphoric acid and polymer In one or several solutions of phosphoric acid, under reflux conditions, reflux for 3-5 hours, cool, and adjust the pH of the reaction mixture to 9-10, filter, wash and recrystallize to obtain nitro-substituted benzene and imidazole; the 1,2-diaminobenzene substituted with nitro and the molar ratio of one of saturated fatty acid, 2-pyridyl formic acid and 2-pyridyl acetic acid with carbon number of 1-3 can be 1:1 -1:3, based on the amount of 1 gram of nitro-substituted 1,2-diaminobenzene, the volume of the acid or acid aqueous solution is 8-20 milliliters, and the concentration of the aqueous hydrochloric acid solution is generally 5 mol / liter of h...

Embodiment 1

[0066] This example is used to illustrate the preparation of the tyrosine protein kinase inhibitor provided by the present invention.

[0067]

[0068] The first reactant (1) (purchased from Shanghai Fude Chemical Co., Ltd.) and the second reactant (2) (purchased from Sigma Company) in the above reaction formula are heated to reflux in isobutanol, and the first reaction The product is 4-chloro-6,7-dimethoxyquinazoline, and the second reactant is respectively The molar ratio of the first reactant and the second reactant is 1:1, based on the total amount of the first reactant and the second reactant being 100 mg, the consumption of isobutanol is 15 milliliters; The conditions of heating to reflux include a reflux temperature of 80°C and a reflux time of 4 hours to obtain compounds LQ1001, LQ1002, LQ1003, LQ1004, LQ1005, LQ1006, LQ1007, LQ1008, LQ1009, and LQ10010.

[0069] The compounds prepared above were characterized by nuclear magnetic resonance and mass spectrometry ...

Embodiment 2

[0092] This example is used to illustrate the preparation of the tyrosine protein kinase inhibitor provided by the present invention.

[0093]

[0094] Be the first reactant (1) 4-chloro-6,7-dimethoxyquinazoline and the second reactant (3) 5-aminophenanthroline ( purchased by Sigma Company), in the catalyst Pd 2 (dba) 3 、t(Bu) 3 In the presence of P and t-BuONa (the catalyst Pd 2 (dba) 3 、t(Bu) 3 The molar ratio of P and t-BuONa to the first reactant (1) is 0.0125:0.075:3:1), heated to reflux in toluene for 28 hours, cooled to room temperature, filtered, washed with toluene and ether until the unreacted The raw material was removed and recrystallized in ethanol to obtain a pale yellow solid. The target product LS1001 was characterized by NMR and mass spectrometry.

[0095] LS1001: C 22 h 17 N 5 o 2 Calc.MW=383.3, ESI-MS (m / z): [M+H] + 384.1.

[0096] 1 H NMR: (deuterated DMSO) δ (ppm): 10.1197 (s, 1H), 9.1047 (d, 1H), 9.0564 (s, 1H), 8.4577 (m, 2H), 8.1917 (s...

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Abstract

The invention relates to a tyrosine protein kinase inhibitor. The tyrosine protein kinase inhibitor is a compound represented by a general formula (1), wherein R is one or more of aryl amino, hexahydric aryl heterocycle amino, pentatomic heterocycle amino and thick heterocycle amino, which have a substituent group having the functions of coordination. The tyrosine protein kinase inhibitor has the advantages of high selectivity, fewer toxic and side effects and stronger water solubility. In addition, the tyrosine protein kinase inhibitor can be used for substituting one or more ligands in cytotoxicity organic metal ruthenium coordination compounds. The prepared coordination compound can act on protein kinase (or protein phosphatase) and can act on multiple target point-combined molecule anti-tumor compounds of DNA. The tyrosine protein kinase inhibitor is also favorable for reducing possibility that tumor cells generate medicinal resistance to medicaments.

Description

technical field [0001] The invention relates to a tyrosine protein kinase inhibitor and a preparation method thereof. Background technique [0002] Clinically used anti-tumor chemical drugs include two categories: cytotoxic drugs and molecular targeted drugs. Cytotoxic antineoplastic drugs (such as cisplatin, etc.) are non-specific. While inhibiting and killing abnormally proliferating tumor cells, they also inhibit and kill other rapidly proliferating normal cells. The resulting Toxic side effects and innate or acquired resistance of tumor cells to drugs have always been the bottleneck restricting the clinical application of cytotoxic chemotherapy drugs. [0003] In the past ten years, the design and synthesis of highly selective molecular targeted therapy drugs for the specific proliferation, differentiation and apoptosis mechanisms of tumor cells have been developed rapidly. Tyrosine protein kinase inhibitor (TKI) imatinib (Gleevec TM ), gefitinib (Iressa TM ) and erl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61K31/517A61K31/53C07D239/94C07D401/12C07D471/04C07D403/14C07D403/12A61P35/00
Inventor 汪福意罗群吕爽纪丽云胡文兵吴魁韩玉苗
Owner INST OF CHEM CHINESE ACAD OF SCI
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