PARP inhibitor containing phthalazine-1 -(2H)-ketone structure as well as preparation method and medical application of PARP inhibitor

A pharmacy and drug technology, applied in the field of PARP inhibitors, can solve the problems of lack of specificity of the target, normal cell canceration, etc.

Active Publication Date: 2021-02-19
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, at the same time, a large number of experiments have shown that most PARP-1 inhibitors lack specificity to the target and are prone to drug resistance, which has caused the current clinical compounds to fail to show a good chemotherapy sensitization effect
In addition, PARP-1 inhibitors have non-negligible cytotoxicity, and because they inhibit DNA damage repair, they are more likely to cause cancer in normal cells

Method used

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  • PARP inhibitor containing phthalazine-1 -(2H)-ketone structure as well as preparation method and medical application of PARP inhibitor
  • PARP inhibitor containing phthalazine-1 -(2H)-ketone structure as well as preparation method and medical application of PARP inhibitor
  • PARP inhibitor containing phthalazine-1 -(2H)-ketone structure as well as preparation method and medical application of PARP inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Synthesis of 4-(3-(4-(cyclopropylcarbonyl)-3-methylpiperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (I-1)

[0034] 3-Methylpiperazine-1-carboxylic acid tert-butyl ester (Ⅲ-1)

[0035] (1.0g, 9.8mmol) 2-methylpiperazine (II-1) was dissolved in 20mL of dichloromethane (DCM), and (2.2g, 10.0mmol) Boc dissolved in DCM was added dropwise 2 O, the reaction was stirred at room temperature for 5h. TLC monitors that the reaction of the raw materials is complete, spin out the solvent under reduced pressure, add 40mL of water, extract with EA (3×20mL), combine the organic phases, wash the organic phases with saturated brine (3×50mL), dry over anhydrous sodium sulfate, filter, The filtrate was concentrated to give 1.7 g of a colorless oil. The crude product was purified by column chromatography (eluent, DCM:EA=1:1) to obtain 1.2 g of a colorless oil. Yield 60.0%. 1 H-NMR (300MHz, CDCl 3 )δ(ppm):3.95(brs,2H,-NC H 2 CH-,-C H CH 3 ), 2.96 (d, J=7.9Hz, 1H, -NC H 2 ...

Embodiment 2

[0042] 4-(4-fluoro-3-(3-methyl-4-(2-oxo-2-phenylethyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one ( I-2) Synthesis

[0043] 3-Methyl-4-(2-oxo-2-phenylethyl)piperazine-1-carboxylic acid tert-butyl ester (Ⅳ-2)

[0044] Dissolve (250mg, 1.2mmol) tert-butyl 3-methylpiperazine-1-carboxylate (Ⅲ-1) in 10mL of acetonitrile, then add (248mg, 1.2mmol) 2-bromoacetophenone and (862mg, 6.2mmol) K 2 CO 3 , the temperature was raised to 80°C, and the reaction was stirred for 5h. TLC monitored the complete reaction of the raw materials, cooled to room temperature, filtered, washed the filter cake with EA, and concentrated the filtrate to obtain 400 mg of oil. The crude product was purified by column chromatography (eluent, PE:EA=9:1) to obtain 250 mg of a colorless oil. The yield was 63.0%. 1 H-NMR (300MHz, CDCl 3 )δ (ppm): 8.03 (d, J = 7.4Hz, 2H, Ar H ), 7.61(t, J=7.3Hz, 1H, Ar H ), 7.49(t, J=7.5Hz, 2H, Ar H ), 4.18 (d, J=16.3Hz, 1H, -NC H 2 CHN-),3.97–3.60(m,3H,-COC H 2 ...

Embodiment 3

[0048] 4-(3-(4-(2-(benzofuran-3-yl)-2-oxoethyl)-3-methylpiperazine-1-carbonyl)-4-fluorobenzyl)phthalazine- 1(2H)-Kone(I-3)

[0049] Synthesis

[0050] tert-butyl 4-(2-(benzofuran-3-yl)-2-oxoethyl)-3-methylpiperazine-1-carboxylate (IV-3)

[0051] Dissolve (200mg, 1.0mmol) tert-butyl 3-methylpiperazine-1-carboxylate (Ⅲ-1) in 10mL DMF, and then add (239mg, 1.0mmol) 1-(benzofuran-3-yl )-2-Bromoethanone and (303mg, 3.0mmol) Et 3 N, the reaction was stirred at room temperature for 12 h, and the reaction of the raw materials was monitored by TLC to complete. Pour the reaction solution into 50 mL saturated NH 4 Cl solution, extracted with EA (3×15 mL), combined organic phases, washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 320 mg of yellow oil. The crude product was purified by column chromatography (eluent, PE:EA=9:1) to obtain 200 mg of light yellow oil. 1 H-NMR (300MHz, CDCl 3 )δ(ppm):8.81(s,1...

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Abstract

The invention discloses a PARP inhibitor containing a phthalazine-1(2H)-ketone structure as well as a preparation method and medical application of the PARP inhibitor. A compound as shown in a generalformula (I) or a pharmaceutically acceptable salt thereof are described in the specification. The invention provides novel PARP inhibitors containing phthalazine-1(2H)-ketone structures, and the PARPinhibitors can be used as single therapeutic agents for tumors or combined with other anti-tumor drugs, so that the effects of improving the curative effect of the existing anti-tumor drugs and reducing the dosage and toxicity are achieved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a PARP inhibitor containing a phthalazin-1(2H)-one structure, its preparation method and medical application. Background technique [0002] Poly ADP-ribose polymerase (PARP) is a kind of protein post-translational modification enzyme widely present in most eukaryotic cells. Current studies have found that there are at least 18 subtypes of the PARP family, which can be divided into 3 groups according to the degree of homology: PARP-1 group (including PARP-1~PARP-4, PARP-6, PARP-8, PARP-16) ), Tankyrase group (including PARP-5a~PARP-5c) and III group (including PARP-7, PARP-9~PARP-15). Among them, PARP-1 accounts for the largest proportion, which can recognize and bind to the gap where DNA damage occurs, and quickly catalyze NAD + It is decomposed into nicotinamide and ADP-ribose, and then ADP-ribose is used as a substrate to make nuclear receptor protein and ADP-ribose form a ...

Claims

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Application Information

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IPC IPC(8): C07D403/10C07D405/14A61K31/502A61P35/00
CPCC07D403/10C07D405/14A61P35/00
Inventor 朱启华张广霞吴尧尧孙进进张宏波徐云根
Owner CHINA PHARM UNIV
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