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Pyridazinone derivative, and preparation method and medical application thereof

A derivative, the technology of phthalazinone, which is applied in drug combination, antineoplastic drugs, organic chemistry, etc., can solve the problems of lack of homologous recombination repair function in cells and increase the risk of breast cancer, etc., and achieve good antitumor activity and good inhibition The effect of activity and mild reaction conditions

Inactive Publication Date: 2019-09-24
WUHAN UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Breast cancer susceptibility gene (BRCA) is a tumor suppressor gene that maintains normal DNA function. However, harmful mutations in BRCA1 / 2 will cause cells to lose homologous recombination repair function, which greatly increases the risk of breast cancer and / or ovarian cancer. and other cancer risks

Method used

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  • Pyridazinone derivative, and preparation method and medical application thereof
  • Pyridazinone derivative, and preparation method and medical application thereof
  • Pyridazinone derivative, and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 (E)-4-{3-[4-[3-(furan-2-yl)acryloyl]piperazine-1-carbonyl]-4-fluorobenzyl}-2H-phthalazine-1- Ketone (X 1 ) preparation

[0027]

[0028] Step 1: Preparation of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (IV)

[0029] Add 2.00 g (0.015 mol) of o-aldehyde benzoic acid and 4.00 g (0.036 mol) of dimethyl phosphite in sequence in a 100 mL round-bottomed flask equipped with a condenser, heat the oil bath to 100 ° C, reflux for 8 h, and thin layer The reaction was monitored by chromatography (TLC) until the starting point disappeared. Stop the reaction, let it stand to cool to room temperature, pour the reaction liquid into 20 mL ice water, extract with 30 mL×3 dichloromethane, and combine the organic phases. Use a rotary evaporator to distill off excess solvent to obtain a colorless transparent oil, which is allowed to stand overnight to precipitate a colorless solid. The resulting solid was recrystallized from ethanol to obtain 1.58 g ...

Embodiment 2

[0038] Example 2 (E)-4-{3-[4-(3-phenylacryloyl)piperazine-1-carbonyl]-4-fluorobenzyl}-2H-phthalazin-1-ketone (X 2 ) preparation

[0039]

[0040] Step 1: The preparation of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (IV) was prepared according to the method described in Example 1.

[0041] Step 2: phenylacryloylpiperazine (IX 2 ) preparation

[0042] Add 2.54g (0.024mol) of benzaldehyde, 4.90g (0.047mol) of malonic acid, 0.18g (0.023mol) of ammonium acetate, and 16mL of pyridine into a 50mL round-bottomed flask with a reflux condenser, and place on an oil bath Heated to 85°C and refluxed for 5 hours in the dark. Stop the reaction, let it cool down to room temperature and pour it into 50 mL of ice water, adjust the pH to about 2 with dilute hydrochloric acid, a large amount of solid precipitates, filter with suction, and wash the solid with water until there is no pyridine smell. After drying, a solid product was obtained. Recrystallized from abso...

Embodiment 3

[0048] Example 3 (E)-4-{3-[4-[3-(3,4-dimethoxyphenyl)acryloyl]piperazine-1-carbonyl]-4-fluorobenzyl}-2H-phthalein Azin-1-one (X 3 ) preparation

[0049]

[0050] Step 1: The preparation of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (IV) was prepared according to the method described in Example 1.

[0051] Step 2: 3,4-dimethoxyphenylacryloylpiperazine (IX 3 ) preparation

[0052] Add 3,4-dimethoxybenzaldehyde 3.98g (0.024mol) successively in the 50mL round bottom flask that has reflux condenser, malonic acid 4.90g (0.047mol), ammonium acetate 0.18g (0.023mol), Pyridine 16mL was placed on an oil bath and heated to 85°C, and refluxed for 5 hours in the dark. Stop the reaction, let it cool down to room temperature and pour it into 50 mL of ice water, adjust the pH to about 2 with dilute hydrochloric acid, a large amount of solid precipitates, filter with suction, and wash the solid with water until there is no pyridine smell. After drying, a solid pr...

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Abstract

The invention provides a pyridazinone derivative, and a preparation method and a medical application thereof. O-formylbenzoic acid used as a raw material reacts with dimethyl phosphite to obtain dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate, the dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate reacts with 3-cyano-4-fluorobenzaldehyde in the presence of triethylamine to prepare (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile, and the (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile is reduced by hydrazine hydrate to prepare 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid; and benzaldehyde or substituted aromatic formaldehyde or furfural used as a raw material and malonic acid undergo a Knoevenagel reaction to obtain cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid, the cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid and 1-tert-butoxycarbonylpiperazine undergo an amidation reaction, a tert-butoxycarbonyl group is removed from the obtained amidation product in the presence of trifluoroacetic acid, and the obtained product and the 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid undergo the amidation reaction to obtain a series of (E)-4-{3-[4-[(3-substituted aryl)acryloyl]piperazin-1-carbonyl]-4-fluorobenzyl}-2H-pyridazin-1-one derivatives. Results of preliminary pharmacological activity screening show that the compound represented by a general formula shown in the present invention has a certain in-vitro PARP-1 inhibition ability and a certain in-vitro tumor cell proliferation resisting activity. The structural general formula of compound is shown in the description; and in the general formula, Ar is selected from two formulas also shown in the description, and R1, R2, R3, R3, R4 and R5 can be the hydrogen atom, the fluorine atom, the chlorine atom, the bromine atom, a methyl group, a methoxy group, a tetrafluoromethyl group and a nitro group.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a class of phthalazinone derivatives, its preparation method and its use as an antitumor drug. Background technique [0002] Poly(adenosine diphosphate(ADP)-ribose) polymerases (PARPs) is a family of ribozyme superproteins widely present in eukaryotic cells. The most important function of PARPs is to participate in DNA Repair of single-strand damage and maintain DNA integrity. Breast cancer susceptibility gene (BRCA) is a tumor suppressor gene that maintains normal DNA function. However, harmful mutations in BRCA1 / 2 will cause cells to lose homologous recombination repair function, which greatly increases the risk of breast cancer and / or ovarian cancer. and other cancer risks. It has been reported in the literature that BRCA1 / 2-deficient cells are highly sensitive to PARP inhibitors or PARP gene knockout. PARP inhibitors have a targeted killing effect on tumor cells carrying BRCA ge...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D237/32A61P35/00
CPCC07D237/32C07D405/12
Inventor 闵真立董伟胡霞敏
Owner WUHAN UNIV OF SCI & TECH
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