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6-phenylpyridine-2-amine Bcr-Abl inhibitors as well as preparation method and application thereof

A technology of bcr-abl and phenylpyridine, which can be used in pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., can solve problems such as drug resistance and mutation resistance, and achieve cheap reagents and easy availability of raw materials. , the effect of mild reaction conditions

Inactive Publication Date: 2015-01-07
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, a variety of small molecule inhibitors targeting BCR-ABL have emerged, but all of them have drug resistance problems. Therefore, Bcr-Abl mutation drug resistance is a major problem in this research field. The research and development of pharmaceutical agents has become one of the hot spots in the field of pharmacy

Method used

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  • 6-phenylpyridine-2-amine Bcr-Abl inhibitors as well as preparation method and application thereof
  • 6-phenylpyridine-2-amine Bcr-Abl inhibitors as well as preparation method and application thereof
  • 6-phenylpyridine-2-amine Bcr-Abl inhibitors as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] In the structural formula of the inhibitor, R 1 is an acetylated group, R 2 For m-trifluoromethyl, prepared by the following steps:

[0043] 1) Preparation of p-carboxyphenylboronic acid (compound 4)

[0044] Add treated Mg strips (2.15g, 90mmol), 2 capsules of iodine into a 250ml double-necked bottle, protect with nitrogen, and vacuumize 3 times. Slowly add the anhydrous THF solution of the compound p-methylbromobenzene (compound 1, 60mmol) with a syringe under heating conditions. After the reaction is initiated, it is in a reflux state. Continue to add the remaining solution. After the addition, reflux for 5 hours to obtain the format of p-bromotoluene Reagent (compound 2), after cooling to room temperature, the reaction device was transferred to a low-temperature reactor, and the temperature was adjusted to -20 ° C. After 5 minutes, anhydrous THF solution of trimethyl borate (9.36 g, 90 mmol) was added with a syringe, After the addition, react at room temperature ...

Embodiment 2

[0060] In the structural formula of the inhibitor, R 1 is a mesylation group, R 2 is 4-chloro-3-trifluoromethyl, prepared by the following steps:

[0061] Step 1) is the same as Step 1) in Example 1, that is, p-carboxyphenylboronic acid (compound 4) is prepared from p-bromotoluene (compound 1).

[0062] 2) Preparation of N-(6-bromopyridin-2-yl)methanesulfonamide (compound 6)

[0063] 2-Amino-6-bromopyridine (compound 5, 5.19 g, 30 mmol) was dissolved in 100 ml of anhydrous dichloromethane, 20 ml of anhydrous triethylamine was added, and stirred in an ice bath for 30 minutes. A solution of methanesulfonyl chloride (60mmol, 4.64ml) in anhydrous dichloromethane (40ml) was added dropwise in an ice bath. After the dropwise addition, the ice bath was removed, and the mixture was raised to room temperature to react overnight. After the reaction, dilute with dichloromethane, wash with water (30ml×3), wash with sodium bicarbonate solution (30ml×3), wash with saturated sodium chlori...

Embodiment 3

[0077] In the structural formula of the inhibitor, R 1 is a pivaloyl group, R 2 For p-tert-butyl, prepared by the following steps:

[0078] Step 1) is the same as Step 1) in Example 1, that is, p-carboxyphenylboronic acid (compound 4) is prepared from p-bromotoluene (compound 1).

[0079] 2) Preparation of N-(6-bromopyridin-2-yl)-2,2-dimethylpropionamide (compound 6)

[0080] 2-Amino-6-bromopyridine (compound 5, 5.19 g, 30 mmol) was dissolved in 100 ml of anhydrous dichloromethane, 20 ml of anhydrous triethylamine was added, and stirred in an ice bath for 30 minutes. A solution of pivaloyl chloride (60mmol, 7.39ml) in anhydrous dichloromethane (40ml) was added dropwise under ice-cooling conditions. After the dropwise addition, the ice bath was removed, and the mixture was raised to room temperature to react overnight. After the reaction, dilute with dichloromethane, wash with water (30ml×3), wash with sodium bicarbonate solution (30ml×3), wash with saturated sodium chlorid...

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Abstract

The invention discloses 6-phenylpyridine-2-amine Bcr-Abl inhibitors as well as a preparation method and application thereof. A structural formula of the inhibitors is shown in the specification, wherein in the structural formula, R1 is acetyl, methylsulfonyl or pivaloyl; R2 is a mono-substituent or a di-substituent, and the substituent is alkyl or halogen. The series of inhibitors have a certain inhibiting effect on ABL1 kinase in vitro, can inhibit proliferation of a tumor cell K562 and can be used for preparing antitumor drugs, especially CML (chronic myelocytic leukemia) drugs. The preparation method of the 6-phenylpyridine-2-amine Bcr-Abl inhibitors, which is provided by the invention, has the advantages of easiness in obtainment of raw materials, mild reaction conditions, simplicity in operation of reaction processes and cheap used reagents.

Description

technical field [0001] The invention belongs to the technical field of biomedicine and relates to an antitumor compound, in particular to a 6-phenylpyridin-2-amine Bcr-Abl inhibitor and its preparation method and application. Background technique [0002] Chronic myelogenous leukemia (CML) is a hematological systemic clonal proliferative disease occurring in hematopoietic stem cells, and it is also the most common type of leukemia. In western countries, CML accounts for about 15-20% of adult leukemias, and can occur in all age groups, with middle-aged and elderly cases being the most common. CML is caused by the overexpressed Bcr-Abl protein of the breakpoint cluster region-Abelsonian leukemia virus (BCR-ABL) fusion gene formed by t(9;22)(q34;q11) chromosome translocation. At present, a variety of small-molecule inhibitors targeting BCR-ABL have emerged, but all of them have drug resistance problems. Therefore, Bcr-Abl mutation drug resistance is a major problem in this res...

Claims

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Application Information

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IPC IPC(8): C07D213/75C07D213/76A61K31/496A61P35/00A61P35/02
CPCC07D213/75C07D213/76
Inventor 贺浪冲张杰潘晓艳卢闻张涛董金云王嗣岑贺怀贞
Owner XI AN JIAOTONG UNIV
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