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1H-indazole-3-aminobiphenyl compound as well as preparation method and application thereof

An aminobiphenyl and compound technology, applied in the field of biomedicine, can solve the problems of decreased drug efficacy, affecting the quality of life and lifespan of patients, etc., and achieve the effects of good inhibitory activity, good application prospect and scientific research value, and mild reaction conditions.

Inactive Publication Date: 2015-06-10
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the problem of drug resistance in the accelerated phase and the blast phase is mainly due to the mutation of the Bcr-Abl kinase domain, which reduces the efficacy of the drug and affects the quality of life and longevity of patients.

Method used

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  • 1H-indazole-3-aminobiphenyl compound as well as preparation method and application thereof
  • 1H-indazole-3-aminobiphenyl compound as well as preparation method and application thereof
  • 1H-indazole-3-aminobiphenyl compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] In the structural formula of this compound, R 1 Is piperazinyl, R is trifluoromethyl, in the meta position, prepared by the following steps (see figure 1 ):

[0041] 1) Hydrazine hydrate and 2-fluoro-6-iodobenzonitrile (compound 1) were refluxed in an alkaline environment to prepare 4-iodo-1H-indazol-3-amine (compound 2);

[0042] Weigh 5g (20.2mmol) of 2-fluoro-6-iodobenzonitrile (compound 1), 2.6g (31mmol) of sodium bicarbonate, and 5g (99.9mmol) of hydrazine hydrate and dissolve it in 25ml of absolute ethanol. The reaction was monitored after heating to reflux for 8 h. After the reaction was complete, cool to room temperature, add 50 ml of water, stir at room temperature for 2 h, filter with suction, and dry the filter cake to obtain 4.8 g of crude product of 4-iodo-1H-indazol-3-amine (compound 2), with a yield of 92%;

[0043] 2) Prepare p-carboxyphenylboronic acid (compound 6) from p-bromotoluene (compound 3) through Grignard reaction, esterification, hydrolysis...

Embodiment 2

[0057] In the structural formula of this compound, R 1 Is piperazinyl, R is a disubstituted chlorine atom, in the ortho and para positions, prepared by the following steps (see figure 1 ):

[0058] Steps 1) to 2) are the same as steps 1) to 2) in Example 1, that is, 4-iodo-1H-indazol-3-amine (compound 1) is prepared from 2-fluoro-6-iodobenzonitrile (compound 1) 2), preparing p-carboxyphenylboronic acid (compound 6) from p-bromotoluene (compound 3);

[0059] 3) Preparation of 1-(2,4-dichlorobenzoyl)piperazine (compound 9) through condensation reaction of 2,4-dichlorobenzoic acid (compound 7) and piperazine (compound 8);

[0060] 100 g of concentrated hydrochloric acid (12 mol / L) was placed in a 250 ml round bottom flask, and 40 g of anhydrous piperazine (compound 8) was slowly added in an ice bath. After the addition, remove the ice bath, react at room temperature overnight, filter with suction, and dry the filter cake in an oven. The obtained white solid is piperazine dihyd...

Embodiment 3

[0070] In the structural formula of this compound, R 1 Is ethylenediamine, R is a methyl group, in the ortho position, prepared by the following steps (see figure 1 ):

[0071] Steps 1) to 2) are the same as steps 1) to 2) in Example 1, that is, 4-iodo-1H-indazol-3-amine (compound 1) is prepared from 2-fluoro-6-iodobenzonitrile (compound 1) 2), preparing p-carboxyphenylboronic acid (compound 6) from p-bromotoluene (compound 3);

[0072] 3) Preparation of N-(2-aminoethyl)-2-methylbenzamide (compound 9') through condensation reaction between o-toluic acid (compound 7) and ethylenediamine (compound 8');

[0073]60g of concentrated hydrochloric acid (12mol / L) was placed in a 250ml round-bottomed flask, and under ice-bath conditions, 40g of anhydrous ethylenediamine (compound 8') was slowly added. After the addition, remove the ice bath, react at room temperature overnight, filter with suction, and dry the filter cake in an oven. The obtained white solid is ethylenediamine dihyd...

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Abstract

The invention provides a 1H-indazole-3-aminobiphenyl compound as well as a preparation method and an application thereof. the 1H-indazole-3-aminobiphenyl compound takes 1H-indazole-3-aminobiphenyl as a skeleton and has a structural formula as shown in the specification, wherein single substitution or bis substitution is carried out on a benzene ring, R is halogen, alkyl or alkoxy, and R1 is chain or cyclic aliphatic diamino. The 1H-indazole-3-aminobiphenyl compound is prepared by organic synthesis reaction with five steps, has the advantages of simpleness in operation of reaction process, easiness in raw material acquisition, mild reaction conditions, cheap used reagent and the like, is suitable for mass production of pharmaceutical enterprises, has very good inhibition activity to Bcr-Abl kinase, is capable of inhibiting proliferative activity of tumor cells, can be used for preparing antitumor drugs and drugs for inhibiting the activity of the Bcr-Abl kinase and has good application prospect and scientific value.

Description

technical field [0001] The invention relates to the technical field of biomedicine, relates to an anti-leukemia compound, in particular to a 1H-indazole-3-aminobiphenyl compound with Bcr-Abl inhibitory activity and its preparation method and application. Background technique [0002] Chronic myelogenous leukemia is a kind of hematological malignancy with a relatively high incidence, accounting for 20% of adult leukemia. The clinical application of the first-generation small molecule targeted kinase inhibitor Imatinib has made a breakthrough in the treatment of chronic myelogenous leukemia. However, the problem of drug resistance in the accelerated phase and the blast phase is mainly due to the mutation of the Bcr-Abl kinase domain, which reduces the efficacy of the drug and affects the quality of life and longevity of patients. [0003] To develop new drugs to overcome the problem of drug resistance mutations, especially T315 mutation, which is more common in clinical pract...

Claims

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Application Information

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IPC IPC(8): C07D231/56A61P35/00A61P35/02
CPCC07D231/56
Inventor 贺浪冲张杰董金云潘晓艳张涛卢闻王嗣岑
Owner XI AN JIAOTONG UNIV
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