Phthalazinone derivative and its preparation method and use in medicine

A compound, heterocyclic group technology, applied in the field of polymerase inhibitors, can solve problems such as inability to perform repair process

Inactive Publication Date: 2012-03-14
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PARP without poly(ADP-ribosylation) modification cannot dissociate from the DNA damage site, which will cause other proteins involved in repair to enter the damage site, and then cannot perform the repair process

Method used

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  • Phthalazinone derivative and its preparation method and use in medicine
  • Phthalazinone derivative and its preparation method and use in medicine
  • Phthalazinone derivative and its preparation method and use in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0190] 4-[(7-bromo-2,3-dihydrobenzofuran-5-yl)methyl]-2H-phthalazin-1-one

[0191]

[0192] first step

[0193] 2,3-Dihydrobenzofuran-5-carbaldehyde

[0194] 2,3-Dihydrobenzofuran 1a (2g, 16mmol) was dissolved in N,N-dimethylformamide (2.60g, 35.20mmol) under stirring, and phosphorus oxychloride (5.20 g, 52mmol), reacted at 90°C for 7 hours, cooled to room temperature, poured into 20mL of ice water, and stirred for 12 hours. Extract with toluene (15mL×3), combine the organic phases, wash with saturated sodium bicarbonate solution (20mL) and saturated sodium chloride solution (20mL) successively, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use a silica gel column The resulting residue was purified by chromatography with eluent system B to give the title product 2,3-dihydrobenzofuran-5-carbaldehyde 1b (1.70 g, colorless oil), yield: 70.8%.

[0195] MS m / z(ESI): 149.1[M+1]

[0196] second step

[0197] 7-bromo-2,3-dihydr...

Embodiment 2

[0210] 4-(2,3-Dihydrobenzofuran-5-ylmethyl)-2H-phthalazin-1-one

[0211]

[0212]Dissolve 4-[(7-bromo-2,3-dihydrobenzofuran-5-yl)methyl]-2H-phthalazin-1-one 1 (177mg, 0.50mmol) in 5mL tetrahydrofuran with stirring, Tetramethylethylenediamine (116mg, 1mmol) was added, cooled to -78°C, 0.6mL of 1.6M n-butyl lithium in n-hexane was added dropwise, and kept at -78°C for 3 hours. Add 5 mL of water, extract with ethyl acetate (15 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title product 4-(2,3-dihydrobenzofuran-5 -ylmethyl)-2H-phthalazin-1-one 2 (85 mg, white solid), yield: 61.6%.

[0213] MS m / z(ESI): 279.1[M+1]

[0214] 1 H NMR (400MHz, CDCl 3 ): δ10.50(s, 1H), 8.46-8.48(m, 1H), 7.74-7.80(m, 3H), 7.04-7.10(m, 2H), 6.71-6.73(m, 1H), 4.54(t , 2H), 4.23(s, 2H), 3.16(t, 2H)

Embodiment 3

[0216] 4-[[7-(4-methylpiperazine-1-carbonyl)-2,3-dihydrobenzofuran-5-yl]methyl]-2H-phthalazin-1-one

[0217]

[0218] first step

[0219] 5-[(4-Oxo-3H-phthalazin-1-yl)methyl]-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester

[0220] 4-[(7-bromo-2,3-dihydrobenzofuran-5-yl)methyl]-2H-phthalazin-1-one 1 (480mg, 1.34mmol), palladium acetate (30mg, 0.13mmol ) and 1,3-bis(diphenylphosphine)propane (55mg, 0.13mmol) were placed in a dry reaction flask, sealed and passed into carbon monoxide, and 10mL containing triethylamine (0.41g, 4mmol) and methanol (0.13 g, 4 mmol) of dimethyl sulfoxide, reacted at 75°C for 24 hours. Add 15 mL of water, extract with dichloromethane (20 mL×5), combine the organic phases, wash with water (30 mL) and saturated sodium chloride solution (30 mL×2) successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The title product 5-[(4-oxo-3H-phthalazin-1-yl)methyl]-2,3-dihydrobenzofuran-7-carboxylic...

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PUM

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Abstract

The invention relates to a phthalazinone derivative and its preparation method and use in medicine, and specifically, relates to a novel phthalazinone derivative shown in the general formula I, a preparation method of the novel phthalazinone derivative, a novel phthalazinone derivative-containing pharmaceutical composition, and a use of the novel phthalazinone derivative-containing pharmaceutical composition utilized as a treatment agent and especially utilized as a poly(ADP-ribose)polymerase(PAPR) inhibitor.

Description

technical field [0001] The present invention relates to a new phthalazinone derivative represented by the general formula (I), its preparation method and pharmaceutical composition containing the derivative, and its therapeutic agent as poly(ADP-ribose) polymerase (PARP ) uses of 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 proliferative rates while exhibiting defective signaling of cell cycle regulatory loci. Therefore, it can be inferred that there is a specific DNA rep...

Claims

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Application Information

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IPC IPC(8): C07D405/06C07D405/14C07D487/04C07D471/04C07D498/04A61K31/502A61K31/541A61K31/551A61K31/5377A61K31/5383A61P35/00
CPCA61P35/00C07D405/06C07D405/14C07D471/04C07D487/04C07D498/04
Inventor 邓炳初张学军李晓涛朱耀平杨斌斌
Owner JIANGSU HENGRUI MEDICINE CO LTD
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