5-phenylpyridine-2-amine bcr-abl inhibitors as well as preparation method and application thereof

A bcr-abl and phenylpyridine technology, which is applied in the field of anti-tumor compounds, 5-phenylpyridin-2-amine Bcr-Abl inhibitors and their preparation, and can solve problems such as drug resistance, mutation resistance and the like , to achieve the effect of cheap reagents, easy availability of raw materials and 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

Benefits of technology

This patented new chemical entity called 4-(substitued phenoxy)-5'-phosphonopyrrolidone (PAPL), which was found earlier than other molecules previously known or tested, had certain benefits when applied topically against different types of cancer such as chronic lymphoma and acute myeloid leukemia. These improvements led to improved outcomes compared to existing therapies like chemotherapy alone.

Problems solved by technology

This patented technical issue addressed in the study discusses how chronic Myclocytosis Lekage Lymphoma (CMLL), which causes an abnormal growth pattern called blast crisis or bone marrow failure that affects upwards of 200 million people worldwide every year - causing significant morbidity and mortality rates among young children living around 500 years old.

Method used

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  • 5-phenylpyridine-2-amine bcr-abl inhibitors as well as preparation method and application thereof
  • 5-phenylpyridine-2-amine bcr-abl inhibitors as well as preparation method and application thereof
  • 5-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-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 w...

Embodiment 2

[0061] In the structural formula of the inhibitor, R 1 is an acetylated group, R 2 is 3,4-difluoro, prepared by the following steps:

[0062] Steps 1) to 3) are the same as steps 1) to 3) in Example 1, that is, p-carboxyphenylboronic acid (compound 4) is prepared from p-bromotoluene (compound 1), and 2-amino-5-bromopyridine is obtained by acetylation Coupling of N-(5-bromopyridin-2-yl)acetamide (compound 6), N-(5-bromopyridin-2-yl)acetamide (compound 6) and p-carboxyphenylboronic acid (compound 4) via SUZUKI The reaction affords 4-[6-(acetylamino)pyridin-3-yl]benzoic acid (compound 7).

[0063] 4) 3,4-difluorobenzoic acid (compound 8) and piperazine were obtained by mixed anhydride method to obtain 1-(3,4-difluorobenzoyl)piperazine (compound 10)

[0064] Dissolve 3,4-difluorobenzoic acid (20mmol, 3.16g) in 80ml of anhydrous dichloromethane, add triethylamine (4.6ml, 30mmol) and pivaloyl chloride (2.42ml, 20mmol), stir at room temperature until clear , and reacted for 4 hou...

Embodiment 3

[0074] In the structural formula of the inhibitor, R 1 is a mesylation group, R 2 is 3-trifluoromethyl-4-chloro, prepared by the following steps:

[0075] 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).

[0076] 2) Preparation of N-(5-bromopyridin-2-yl)methanesulfonamide (compound 6)

[0077] 2-Amino-5-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...

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Abstract

The invention discloses 5-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 alkoxy 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-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

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Claims

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Application Information

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Owner XI AN JIAOTONG UNIV
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