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Substituted 2,3-phthalazinone compounds and uses thereof

A compound and oxo-generation technology, which is applied to the active ingredients of heterocyclic compounds, medical preparations containing active ingredients, organic chemistry, etc., can solve the problems of weakening the killing effect of radiotherapy on cancer cells and weakening the killing effect of cancer cells

Active Publication Date: 2015-12-09
曹亚
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the DNA damage of cancer cells caused by drugs, the ribozyme PARP is activated in large quantities and promotes DNA repair, thereby weakening the killing effect of drugs on cancer cells
Similarly, radiotherapy can damage the DNA of cancer cells, but the DNA damage of cancer cells caused by radiotherapy leads to a large amount of activation of the ribozyme PARP and promotes DNA repair, thereby weakening the killing effect of radiotherapy on cancer cells

Method used

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  • Substituted 2,3-phthalazinone compounds and uses thereof
  • Substituted 2,3-phthalazinone compounds and uses thereof
  • Substituted 2,3-phthalazinone compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] 2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)-methyl)-N-(2-(2-oxotetrahydropyrrol-1-yl)ethyl Benzamide

Embodiment 1A

[0172] (3-oxo-1,3-dihydroisobenzofuranyl) dimethyl phosphonate

[0173] Add 500 mL of anhydrous methanol to a 1 L pear-shaped flask, slowly add sodium lumps (11.5 g, 0.5 mol) under ice bath conditions, and when it disappears completely, add diethyl phosphite (46 mL, 0.5 mol). After the mixture was stirred for 0.5 hour, o-carboxybenzaldehyde (52.5 g, 0.35 mol) was added, and then the mixture was raised to room temperature and stirred for 1 hour. Then, methanesulfonic acid (36 mL, 0.55 mol) was added to the reactant. After stirring at room temperature for 2 hours, the solvent was evaporated. The residue was dissolved in 400 mL of dichloromethane and 200 mL of water. The organic phase was washed sequentially with saturated sodium carbonate and saturated sodium chloride, and then dried with anhydrous sodium sulfate and filtered. After the solvent was distilled off, the residue was recrystallized with a mixed solvent of dichloromethane and ether to obtain 64.25 g of white solid. Yiel...

Embodiment 1B

[0175] 2-fluoro-5-formyl-benzocyanide

[0176] Place 3-bromo-4-fluoro-benzaldehyde (100g, 0.49mol) in a 1L round-bottom flask, dissolve it with 400ml NMP, then add cuprous cyanide (50.6g, 0.56mol), and heat the reaction to Stir at 170°C overnight. After cooling to room temperature, add appropriate amount of diatomaceous earth, stir, and filter. The filtrate was partitioned with 400 ml of water and 500 ml of ethyl acetate, the organic phase was washed twice with water, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was recrystallized with a mixed solvent of petroleum ether and ethyl acetate to obtain 55.95 g of a pale yellow solid. Yield: 76.1%. MS (ESI): 150 (M+1, 100%).

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PUM

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Abstract

Provided are substituted 2,3-phthalazinone compounds, their isomers, salts, solvates, prodrugs, their preparation and the use for the preparation of medicaments for inhibiting the activity of poly (adenosine diphosphate-ribose) polymerase and the related diseases thereof.

Description

Technical field [0001] The invention relates to substituted phthalazinone compounds and their uses. In particular, the present invention relates to the use of these compounds for inhibiting the activity of poly (ADP-ribose) polymerase (commonly referred to as PARP). Background technique [0002] Poly(ADP-ribose) polymerase [poly(ADP-ribose) polymerase, PARP], also called poly(ADP-ribose) synthase (PARS) or poly(ADPRT), is present in eukaryotic One of the key nuclear enzyme family in the cell. So far, 18 members of the PARP ribozyme family have been confirmed, and the most abundant member, PARP-1, catalyzes more than 90% of the polymerization of ribose diphosphate. [0003] In human body cells, especially in immune cells and germ cells, the content of PARP is quite abundant. Many physiological processes such as chromatin degradation, DNA replication, DNA repair, gene expression, cell division and differentiation, and cell apoptosis are involved in polyadenosine diphosphate (ADP) ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12C07D237/32C07D401/12C07D401/14C07D417/10C07D417/14A61K31/502A61K31/55A61K31/549A61P35/00
CPCC07D237/32A61K31/502A61K31/549A61K31/55C07D401/10C07D401/12C07D401/14C07D403/10C07D403/12C07D417/10C07D417/14A61P35/00
Inventor 李晨曦曹亚沈伟生
Owner 曹亚
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