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Pyrimidoimidazole compound and pharmaceutical composition and preparation method and use thereof

A compound, imidazole technology, applied in the field of poly (ADP-ribose) polymerase (PARP) inhibitors, can solve problems affecting ATP levels, NAD levels, etc.

Active Publication Date: 2014-11-12
上海壹典医药科技开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In addition, NAD, which is consumed as a PARP catalytic substrate, is essential for the synthesis of ATP in cells. Therefore, under high PARP activity levels, the intracellular NAD level will decrease significantly, thereby affecting the intracellular ATP level.

Method used

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  • Pyrimidoimidazole compound and pharmaceutical composition and preparation method and use thereof
  • Pyrimidoimidazole compound and pharmaceutical composition and preparation method and use thereof
  • Pyrimidoimidazole compound and pharmaceutical composition and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Compound (1): 2-(4-(2-oxo-2,3-dihydro-1hydro-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)-1 The preparation of hydrogen-benzimidazole-4-carboxamide, concrete reaction formula is as follows:

[0099]

[0100] Step 1: Preparation of 2-oxo-2,3-dihydro-1hydro-benzimidazole-4-carboxylic acid methyl ester

[0101] Add carbonyldiimidazole (1.56g, 9.6mmol) to an anhydrous tetrahydrofuran solution (20mL) dissolved with methyl 2,3-diaminobenzoate (0.8g, 4.8mmol), heat up to reflux, and react for 8 hours After cooling, the solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain light yellow solid compound a: 2-oxo-2,3-dihydro-1 hydrogen- Benzimidazole-4-carboxylic acid methyl ester (0.3 g, yield 33%). MS (ESI) m / z: [M+H]+=193.

[0102] Step 2: Preparation of 2-chloro-1hydro-benzimidazole-4-carboxylic acid methyl ester

[0103] Compound a (1.1g, 5.7mmol) was added to phosphorus ox...

Embodiment 2

[0115] Compound (2): 2-(4-(8-oxo-8,9-dihydro-7hydro-purin-6-yl)piperazin-1-yl)-1hydro-benzimidazole-4-methanol The preparation of amides, concrete reaction formula is as follows:

[0116]

[0117] Step 1: Preparation of 2-(4-(6-amino-5-nitropyrimidin-4-yl)piperazin-1-yl)-1-hydro-benzimidazole-4-carboxylic acid methyl ester

[0118] Using the method similar to that of Example 1 to prepare compound d, compound g was obtained by nucleophilic substitution reaction between compound c and 6-chloro-5-nitro-4-aminopyrimidine: 2-(4-(6-amino-5- Nitropyrimidin-4-yl)piperazin-1-yl)-1-hydro-benzimidazole-4-carboxylic acid methyl ester (150 mg, yield 93%). MS (ESI) m / z: [M+H]+=399.

[0119] Step 2: Preparation of 2-(4-(5,6-diaminopyrimidin-4-yl)piperazin-1-yl)-1-hydro-benzimidazole-4-carboxylic acid methyl ester

[0120] Using a method similar to that of Example 1 to prepare compound e, compound h was obtained by catalytic hydrogenation of compound g with palladium carbon: 2-(4-(5,6-d...

Embodiment 3

[0126] Compound (3): 2-(4-(2-oxo-2,3-dihydro-1hydro-imidazo[4,5-c]pyridin-4-yl)piperazin-1-yl)-1 The preparation of hydrogen-benzimidazole-4-carboxamide, concrete reaction formula is as follows:

[0127]

[0128] Step 1: Preparation of 2-(4-(6-amino-5-nitropyridin-4-yl)piperazin-1-yl)-1-hydro-benzimidazole-4-carboxylic acid methyl ester

[0129] Using the method similar to the preparation of compound d in Example 1, compound j was obtained by nucleophilic substitution reaction between compound c and 2-chloro-3-nitro-4-aminopyrimidine: 2-(4-(6-amino-5- Nitropyridin-4-yl)piperazin-1-yl)-1-hydro-benzimidazole-4-carboxylic acid methyl ester (150 mg, yield 92%). MS (ESI) m / z: [M+H]+=398.

[0130] Step 2: Preparation of 2-(4-(3,4-diaminopyridin-2-yl)piperazin-1-yl)-1-hydro-benzimidazole-4-carboxylic acid methyl ester

[0131] Using a method similar to that of Example 1 to prepare compound e, compound k was obtained by catalytic hydrogenation of compound j with palladium on carbo...

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Abstract

The invention relates to a pyrimidoimidazole derivative, a preparation method and medical use thereof, and particularly relates to a new pyrimidoimidazole derivative as shown in a general formula (I) or formula (II), a preparation method thereof, a pharmaceutical composition containing the new pyrimidoimidazole derivative, and use thereof as a therapeutic agent in particular as a poly (ADP(adenosine diphosphate)-ribose) polymerase (PARP) inhibitor.

Description

technical field [0001] The present invention relates to pyrimidoimidazole derivatives, their preparation method, pharmaceutical composition containing the derivatives, and their use as therapeutic agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Background technique [0002] Chemotherapy drugs and ionizing radiation therapy are two common ways to treat cancer. Both of these treatments induce cytotoxicity by inducing single- and / or double-strand breaks in DNA, and target tumor cells die due to chromosomal damage. An important consequence of the response to DNA damage signals is the activation of cell cycle regulatory site signaling, the purpose of which is to protect cells from mitosis in the event of DNA damage and thus avoid cell damage. In most cases, tumor cells exhibit high rates of proliferation while exhibiting defective signaling of cell cycle regulatory loci. Therefore, it can be inferred that there is a specific DNA repair mechanism in tumor cells, which ...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D471/04A61K31/496A61K31/519A61P35/00A61P9/10A61P29/00A61P25/28A61P25/16A61P25/14A61P43/00
CPCC07D471/04C07D487/04
Inventor 樊兴秦继红
Owner 上海壹典医药科技开发有限公司
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