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Pyrazole quinazolinone derivative serving as PARP (poly ADP-ribose polymerase) inhibitor and application of pyrazole quinazolinone derivative serving as PARP inhibitor

A technology of pyrazoloquinazolone and derivatives, which is applied in the field of pyrazoloquinazolone derivatives, which can solve problems such as no standard treatment plan, limited drug delivery efficiency, difficult onset of brain tumors, etc., and achieve oral Good bioabsorption, good application prospects, significant selective inhibitory effect

Active Publication Date: 2019-01-25
SHANGHAI JOYU PHARMATECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Triple-negative breast cancer refers to breast cancer that lacks estrogen and progesterone receptors and does not express human epidermal growth factor receptor-2 (HER2). Such patients account for about 15% of all breast cancers. Unresponsive to hormone therapy and human epidermal growth factor receptor-2 (HER2)-targeted therapy, no standard treatment
The blood-brain barrier refers to the barrier between plasma and brain cells formed by brain capillary walls and glial cells, and the barrier between plasma and cerebrospinal fluid formed by the choroid plexus, which can limit the efficiency of drug administration and make it difficult for ordinary drugs to treat brain tumor onset

Method used

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  • Pyrazole quinazolinone derivative serving as PARP (poly ADP-ribose polymerase) inhibitor and application of pyrazole quinazolinone derivative serving as PARP inhibitor
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  • Pyrazole quinazolinone derivative serving as PARP (poly ADP-ribose polymerase) inhibitor and application of pyrazole quinazolinone derivative serving as PARP inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: Synthesis of compound I-1, prepared according to general scheme 1. The specific method is as follows:

[0050]

[0051] Step 1: Prepare SMb1: Add diethyl oxalate d1 (5 g) to a solution of sodium ethoxide (2.55 g, 37.7 mmol) in ethanol (50 ml), stir at 60°C for 0.5 h, and add propionitrile e1 (3 ml) Add to the mixture and heat to reflux for 7 h. The reactant was cooled to room temperature, the solid was collected by filtration, washed with ether, and naturally dried to obtain SMb1, which was directly used in the next reaction.

[0052] Step 2 Preparation c1: It can be prepared by General Method A and General Method B.

[0053] General method A: The raw material SMa1 is dissolved in acetic acid, SMb1 is added, the mixture is reacted in a microwave reactor at 150°C for 5-10 minutes, the precipitate is collected by filtration, washed with ether, and recrystallized with ethyl acetate / ethanol to obtain c1.

[0054] General method B: Suspend the raw materials SMa1 and SMb1...

Embodiment 2

[0058] Example 2: Preparation of I-2.

[0059] Dissolve I-1 (15 mmol) and methyl iodide (15 mmol) in ethanol, add sodium ethoxide, stir at 0℃~40℃ for 6h-10h, recover the solvent and perform silica gel column chromatography (ethyl acetate: petroleum ether 1 : 3) I-2 is separated. MS m / z (ESI): 243.1[M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 10.24 (s, 1H), 7.50-7.52 (m,1H), 7.81 (dd, 1H), 8.04 (d,1H), 8.09 (dd , 1H), 4.18 (s,2H), 3.23 (s,3H), 2.05 (s,3H).

Embodiment 3

[0060] Example 3: Preparation of I-3.

[0061] In the same manner as in Example 2, I-1 (10 mmol) and methyl iodide (30 mmol) were dissolved in ethanol, sodium ethoxide was added, and the mixture was stirred at reflux for 18 h-24 h. The solvent was recovered and subjected to silica gel column chromatography (ethyl acetate : Petroleum ether 1:5) I-3 is isolated. MS m / z(ESI): 257.1 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.51-7.55 (m,1H), 7.86 (dd, 1H), 8.03 (d,1H), 8.14 (dd, 1H), 3.65 (s ,2H), 2.06 (s,3H ), 2.18 (s,6H ).

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Abstract

The invention discloses a pyrazole quinazolinone derivative serving as a PARP (poly ADP-ribose polymerase) inhibitor and application of the pyrazole quinazolinone derivative serving as the PARP inhibitor. The pyrazole quinazolinone derivative serving as the PARP inhibitor refers to a compound in a formula (I) as shown in the specification or pharmaceutically acceptable salts of the compound. The compound can be used as the PARP inhibitor, has great PARP-1 inhibition activity and can serve as a selective inhibitor for prevention and treatment of PARP related diseases. The compound further has agreat characteristic of blood-brain-barrier penetrating and has a promising application prospect in prevention and treatment of brain metastasis of brain tumors and other tumors.

Description

Technical field [0001] The invention relates to the field of biomedicine, in particular to a series of pyrazoloquinazolinone derivatives as PARP inhibitors and their uses. Background technique [0002] Poly ADP-ribose Polymerase (PARP) is found in mammalian cells and most eukaryotic cells. It is a type of ribozyme that catalyzes the poly ADP ribosylation and can recognize DNA single-strand breaks. Repair is an important DNA repair enzyme, which plays a key role in the DNA repair pathway. Among all kinds of DNA damage, DNA single-strand damage occurs most frequently, and the enzyme used in a series of repair pathways is PARP. When DNA damage breaks, it will activate PARP. As a molecular sensor of DNA damage, it has the function of recognizing and binding to the DNA break position, increasing its catalytic activity by 10-500 times, and then activating and catalyzing the poly ADP ribose of the receptor protein. Basication, involved in the DNA repair process. [0003] PARP utilizes ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00A61P9/10A61P9/12A61P29/00A61P3/10
CPCA61P3/10A61P9/10A61P9/12A61P29/00A61P35/00C07D487/04
Inventor 钟燕曹西蓉王永临
Owner SHANGHAI JOYU PHARMATECH LTD
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