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Pyrroloquinolines compound and application thereof

A kind of compound and quinoline technology, applied in the field of pyrazoloquinoline compounds

Inactive Publication Date: 2013-03-20
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Although many histone deacetylase inhibitors have been synthesized and patented (Expert Opinion on Therapeutic Patents, 2009, 19, 1727), judging from the current clinical results, their anti-tumor efficacy remains to be seen. improved, better drug efficacy, less side effects, and better pharmacokinetic properties of compounds still need to be found, clinically also need more alternative histone deacetylase inhibitors, the present invention comes from this

Method used

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  • Pyrroloquinolines compound and application thereof
  • Pyrroloquinolines compound and application thereof
  • Pyrroloquinolines compound and application thereof

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preparation example Construction

[0047] The method for preparing compounds shown in formulas I and II provided by the present invention specifically comprises the following steps:

[0048] (1) In an organic solvent, react 5-bromoindole with oxalyl chloride at -10°C~50°C for 2-8h, and then react with absolute ethanol at -10°C~50°C for 2-8h Obtain ethyl 2-(5-bromo-1H-indol-3-yl)-2-oxoacetate;

[0049] Among them, the molar ratio of 5-bromoindole, oxalyl chloride and ethanol is 1: (0.8~2): (2~5);

[0050] (2) In the presence of an organic solvent and an acid, mix ethyl 2-(5-bromo-1H-indol-3-yl)-2-oxoacetate with R 1 NHNH 2 HCl reacted at 80~120°C for 4~36h; or firstly mixed ethyl 2-(5-bromo-1H-indol-3-yl)-2-oxoacetate with t-BuNHNH 2 HCl was reacted at 80~120°C for 4~36h, and then in the presence of alkali, the obtained product was mixed with different halogenated aromatic hydrocarbons (R 1 X, X is Cl, Br or I) Coupling at 80~120°C to obtain the compound shown in formula III;

[0051] Among them, ethyl 2-(5...

Embodiment 1

[0069] (E)-3-(2-Phenyl-4-(2-diethylaminoethylamine)-2H-pyrazol[3,4-c]quinolin-8-yl)-N-hydroxypropene Amide dihydrochloride (Compound I-1)

[0070] (1) Preparation of ethyl 2-(5-bromo-1H-indol-3-yl)-2-oxoacetate:

[0071] Dissolve 5-bromoindole (5.9g, 30mmol) in anhydrous ether (100mL), slowly add oxalyl chloride (4.3mL, 45mmol) in anhydrous ether solution (20mL) in an ice bath, and react at room temperature 3h, after the reaction was complete, absolute ethanol (10.5mL, 180mmol) was added and reacted at room temperature for 3h. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethanol and petroleum ether, and dried to obtain 8.3 g of a bright yellow solid (the title compound), with a yield of 93.0%.

[0072] 1 H NMR(400MHz,DMSO)δ12.55(s,1H),8.49(d,J=2.1Hz,1H),8.29(s,1H),7.54(d,J=8.6Hz,1H),7.44(dd ,J=8.6,2.1Hz,1H),4.37(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0073] (2) Preparation of 2-phenyl-8-bromo-2H-pyrazol[3,4-c]quinolin-...

Embodiment 2

[0092] (E)-3-(2-Benzyl-4-(2-diethylaminoethylamine)-2H-pyrazol[3,4-c]quinolin-8-yl)-N-hydroxypropene Preparation of Amide Dihydrochloride (Compound I-2)

[0093](1) Preparation of 2-benzyl-8-bromo-2H-pyrazol[3,4-c]quinolin-4(5H)-one (compound Ⅲ-2):

[0094] Referring to the preparation method of compound III-1, except that the raw material phenylhydrazine hydrochloride was replaced by benzylhydrazine hydrochloride, a light yellow solid (compound III-2) was obtained with a yield of 69.1%.

[0095] 1 H NMR(400MHz,DMSO)δ11.49(s,1H),8.84(s,1H),8.16(s,1H),7.48(d,J=8.8Hz,1H),7.41–7.32(m,5H) ,7.25(d,J=8.8Hz,1H),5.61(s,2H).

[0096] 13 C NMR (101MHz, DMSO) δ156.66, 140.19, 136.28, 134.98, 129.81, 128.71, 128.09, 128.01, 126.57, 125.92, 120.49, 117.91, 117.20, 113.88, 56.45.

[0097] (2) (E)-3-(2-Benzyl-4,5-dihydro-4-oxo-2H-pyrazol[3,4-c]quinolin-8-yl)ethyl acrylate ( Compound IV-2) Preparation:

[0098] Referring to the preparation method of compound IV-1, compound III-1 was re...

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Abstract

The invention relates to a pyrroloquinolines compound and an application thereof. A pyrroloquinoline ring is taken as a matrix and is appropriately and chemically modified to obtain a series of pyrroloquinolines compounds. Preliminary in vitro screen discovers that the pyrroloquinolines compound provided by the invention has a different-degree proliferation inhibition function on multiple tumour cell strains including human cervical cancer cell strain (HeLa), human lung cancer cell strain (A549), human colon cancer cell strain (HCT116), human leukemia cell strain (K562), human breast cancer cell strain (MCF-7) and the like; and moreover, the proliferation inhibition function of most compounds in 5 tumour cells is obviously better or is equivalent to a positive control drug SAHA (N-hydroxy-N'-phenyloctanediamide).

Description

technical field [0001] The invention relates to a pyrazoloquinoline compound and its application. Background technique [0002] In eukaryotes, DNA strands wrap around histones to form nucleosomes, which are repeatedly wound to form chromatin and further condensed to form chromosomes. Nucleosomal histones are highly basic and highly conserved, and their ends are rich in specific lysine and arginine residues. They exist in balance in the state of acetylation and deacetylation in the body. This reversible acetylation process is in the regulation of important role in gene expression. After the ε amino acid of a specific lysine residue is acetylated, the positive charge is neutralized, the affinity with the negatively charged DNA is weakened, and the chromosome is in a relaxed state, which is conducive to the proximity of various transcription factors to DNA, thereby activating various Gene expression, including a variety of tumor suppressor genes. This acetylation and deacety...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/4745A61P35/00
Inventor 邓卫平刘建文安娜梁倩男吴迪
Owner EAST CHINA UNIV OF SCI & TECH
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