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Substituted 2,3-phthalazinone compounds and application thereof

A compound and solvate technology, applied in the field of inhibiting the activity of poly(ADP-ribose) polymerase, can solve the problems of weakening the killing effect of cancer cells, weakening the killing effect of radiotherapy on cancer cells, etc.

Active Publication Date: 2012-06-06
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 application thereof
  • Substituted 2,3-phthalazinone compounds and application thereof
  • Substituted 2,3-phthalazinone compounds and application 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 base) benzamide

Embodiment 1A

[0172] Dimethyl (3-oxo-1,3-dihydroisobenzofuryl)phosphonate

[0173] Add 500 mL of anhydrous methanol to a 1 L pear-shaped flask, slowly add sodium block (11.5 g, 0.5 mol) under ice-bath conditions, and after it completely disappears, 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, followed by warming to room temperature and stirring for 1 hour. Then methanesulfonic acid (36 mL, 0.55 mol) was added to the reactant, and the solvent was distilled off after stirring at room temperature for 2 hours, and 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, then dried with anhydrous sodium sulfate, and filtered. After distilling off the solvent, the residue was recrystallized with a mixed solvent of dichloromethane and ether to obtain 64.25 g of white solid, yield: 75.8...

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 400 milliliters of NMP, then add cuprous cyanide (50.6g, 0.56mol), and heat the reactant to Stir overnight at 170°C. After cooling to room temperature, add an appropriate amount of diatomaceous earth, stir, and filter. The filtrate was separated 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 distilled off. The residue was recrystallized from a mixed solvent of petroleum ether and ethyl acetate to obtain 55.95 g of a light yellow solid. Yield: 76.1%. MS (ESI): 150 (M+1, 100%).

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PUM

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Abstract

The invention relates to substituted 2,3-phthalazinone compounds, preparation of the compounds and their isomers, salts, solvates, chemical protection forms, prodrugs and the like, and application of the compounds and their isomers, salts, solvates, prodrugs and the like in preparing medicines which are used for inhibiting the activity of poly(ADP-ribose)polymerase (PARP) or are related to inhibition of the activity of PARP, wherein, the medicines include, but not limited to, antitumor drugs.

Description

technical field [0001] The present invention relates to substituted phthalazinone compounds and their use. In particular, the present invention relates to the use of these compounds for inhibiting the activity of poly ADP-ribose polymerase (commonly known as PARP). Background technique [0002] Polyadenosine diphosphate-ribose polymerase [poly(ADP-ribose) polymerase, PARP], also known as polyadenosine diphosphate-ribose synthetase (PARS) or polyadenosine diphosphate transferase (PADPRT), exists in eukaryotic One of the key nucleozyme families in cells. So far, 18 members of the PARP nucleozyme family have been identified, among which PARP-1, the most abundant member, catalyzes more than 90% of the ribose diphosphate polymerization. [0003] In human body cells, especially in immune cells and germ cells, the content of PARP is quite abundant. Polyadenosine diphosphate (ADP) ribosylation is involved in many physiological processes, such as chromatin degradation, DNA replica...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D237/32C07D401/12C07D401/14C07D417/10C07D417/14A61K31/502A61K31/55A61K31/549A61P35/00
CPCC07D401/14C07D401/12C07D417/14C07D403/10C07D403/12A61K31/549A61K31/502C07D401/10C07D237/32C07D417/10A61K31/55A61P35/00
Inventor 李晨曦曹亚沈伟生
Owner 曹亚
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