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N,6 diphenylpyrimidine-4-amine Bcr-Abl inhibitors as well as preparation method and application thereof

A technology of diphenylpyrimidine and bcr-abl, which is applied in the field of biomedicine, can solve problems such as drug resistance and mutation resistance, and achieve the effect of cheap reagents, easy-to-obtain raw materials, and mild reaction conditions

Active Publication Date: 2015-01-07
XIAN HONGHUI HOSPITAL
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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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  • N,6 diphenylpyrimidine-4-amine Bcr-Abl inhibitors as well as preparation method and application thereof
  • N,6 diphenylpyrimidine-4-amine Bcr-Abl inhibitors as well as preparation method and application thereof
  • N,6 diphenylpyrimidine-4-amine Bcr-Abl inhibitors as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] In the structural formula of the inhibitor, the R group is m-trifluoromethyl, which is prepared by the following steps:

[0042] 1) Preparation of p-carboxyphenylboronic acid (compound 4)

[0043] 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-toluene (compound 1, 60mmol) with a syringe under heating conditions. After the reaction is triggered, it is in a reflux state, and the remaining solution is continued to be added. After the addition, the reaction is refluxed for 5 hours to obtain p-bromotoluene. Grignard reagent (compound 2), after cooling to room temperature, transfer the reaction device to a low-temperature reactor, adjust the temperature to -20°C, add trimethyl borate (9.36g, 90mmol) anhydrous THF solution with a syringe after 5 minutes , reacted at room temperature for 3 hours after the addition was completed, ...

Embodiment 2

[0059] In the structural formula of the inhibitor, wherein the R group is o-chloro, prepared by the following steps

[0060] Steps 1) to 3) are the same as steps 1) to 3) in Example 1, that is, p-carboxyphenylboronic acid (compound 4), 4,6-dichloropyrimidine and p-methoxy Aniline undergoes an electrophilic substitution reaction to give 6-chloro-N-(4-methoxyphenyl)pyrimidine 4-amine (compound 7), 6-chloro-N-(4-methoxyphenyl)pyrimidine 4-amine (Compound 7) and p-carboxyphenylboronic acid (Compound 4) were coupled by SUZUKI to obtain 4-{6-[(4-methoxyphenyl)amino]pyrimidin4-yl}benzoic acid (Compound 8).

[0061] 4) Condensation of o-chlorobenzoic acid (compound 9) and ethylenediamine by CDI to give N-(2-aminoethyl)-2-chlorobenzamide (compound 11)

[0062] Add o-chlorobenzoic acid (compound 9, 10mmol) and N,N'-carbonyldiimidazole (1.94g, 12mmol) into a 100ml beaker, and mechanically stir until the reaction system forms a viscous substance, that is, an active intermediate (compound...

Embodiment 3

[0071] In the structural formula of the inhibitor, the R group is a p-tert-butyl group, which is prepared by the following steps

[0072] Steps 1) to 3) are the same as steps 1) to 3) in Example 1, that is, p-carboxyphenylboronic acid (compound 4), 4,6-dichloropyrimidine and p-methoxy Aniline undergoes an electrophilic substitution reaction to give 6-chloro-N-(4-methoxyphenyl)pyrimidine 4-amine (compound 7), 6-chloro-N-(4-methoxyphenyl)pyrimidine 4-amine (Compound 7) and p-carboxyphenylboronic acid (Compound 4) were coupled by SUZUKI to obtain 4-{6-[(4-methoxyphenyl)amino]pyrimidin4-yl}benzoic acid (Compound 8).

[0073] 4) Condensation of p-tert-butylbenzoic acid (compound 9) and ethylenediamine by CDI gives N-(2-aminoethyl)-4-tert-butylbenzamide (compound 11)

[0074] Add p-tert-butylbenzoic acid (compound 9, 10mmol), N,N'-carbonyldiimidazole (1.94g, 12mmol) into a 100ml beaker, and mechanically stir until the reaction system forms a viscous substance, that is, an active in...

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Abstract

The invention discloses N,6 diphenylpyrimidine-4-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, R is a mono-substituent or a di-substituent, and the substituent is alkyl, halogen or tertiary amino. The series of inhibitors have a certain inhibiting effect on ABL1 kinase in vitro, can inhibit tumor cell proliferation and can be used for preparing antitumor drugs, especially CML (chronic myelocytic leukemia) drugs. The preparation method of the N,6 diphenylpyrimidine-4-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 anti-tumor compound, in particular to an N,6 diphenylpyrimidin-4-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 ...

Claims

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Application Information

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IPC IPC(8): C07D239/42A61K31/505A61P35/00A61P35/02
CPCC07D239/42
Inventor 张杰贺怀贞潘晓艳贺浪冲卢闻张涛王嗣岑
Owner XIAN HONGHUI HOSPITAL
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