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5-phenylnicotinamide bcr-abl inhibitors as well as preparation method and application thereof

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

Active 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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  • 5-phenylnicotinamide bcr-abl inhibitors as well as preparation method and application thereof
  • 5-phenylnicotinamide bcr-abl inhibitors as well as preparation method and application thereof
  • 5-phenylnicotinamide 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 5-phenylnicotinamide Bcr-Abl inhibitors, R 1 is morpholinyl, 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...

Embodiment 2

[0062] In the structural formula of the inhibitor, R 1 is cyclopropylamino, R 2 is 3,4-difluoro, prepared by the following steps:

[0063] Step 1) is the same as in Example 1, that is, p-carboxyphenylboronic acid (compound 4) is prepared from p-bromotoluene (compound 1).

[0064] 2) Preparation of 5-bromo-N-cyclopropylnicotinamide (compound 7)

[0065] Under the protection of nitrogen, 20ml of thionyl chloride was added dropwise to 5-bromonicotinic acid (compound 5, 5.0g, 24.7mmol). After the dropwise addition, reflux to clarification and react for 2 hours. After the reaction was completed, the pressure was reduced. Thionyl chloride was spin-off to obtain 5-bromonicotinoyl chloride (compound 6);

[0066] 5-Bromonicotinoyl chloride (compound 6) was dissolved in anhydrous dichloromethane (30ml), and the acid chloride solution was added dropwise to cyclopropylamine (3.77ml, 54.4mmol) in anhydrous dichloromethane ( 50ml) solution, after the dropwise addition, remove the ice ba...

Embodiment 3

[0080] In the structural formula of the inhibitor, R 1 is diisopropylamino, R 2 For m-dimethylamino, prepared by the following steps:

[0081] 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).

[0082] 2) Preparation of 5-bromo-N,N-diisopropylnicotinamide (compound 7)

[0083] Under the protection of nitrogen, 20ml of thionyl chloride was added dropwise to 5-bromonicotinic acid (compound 5, 5.0g, 24.7mmol). After the dropwise addition, reflux to clarification and react for 2 hours. After the reaction was completed, the pressure was reduced. Thionyl chloride was spin-off to obtain 5-bromonicotinoyl chloride (compound 6);

[0084] 5-Bromonicotinoyl chloride (compound 6) was dissolved in anhydrous dichloromethane (30ml), and the acid chloride solution was added dropwise to diisopropylamine (7.66ml, 54.4mmol) in anhydrous dichloromethane (30ml) in an ice bath. Chloromethane (50ml) soluti...

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Abstract

The invention discloses 5-phenylnicotinamide Bcr-Abl inhibitors as well as a preparation method and application thereof. A structural formula of the compounds is shown in the specification, wherein in the structural formula, R1 is morpholinyl, cyclopropylamino, diisopropylamino, diethylin, isopropylamino or an N,N-dimethylethylenediamine group; R2 is a mono-substituent or a di-substituent, and the substituent is tertiary amine 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 5-phenylnicotinamide 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 5-phenylnicotinamide Bcr-Abl inhibitor and a preparation method and application thereof. 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82A61K31/496A61K31/5377A61P35/00A61P35/02
CPCC07D213/82
Inventor 张杰贺浪冲潘晓艳卢闻张涛王嗣岑董金云苏萍
Owner XI AN JIAOTONG UNIV
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