Pyrazolone compound and application

A technology of pyrazolones and compounds, applied in the field of biomedical applications of pyrazolone compounds and their applications, potent inhibitors, which can solve the problems of affecting bioavailability, not relieving delayed diarrhea, reducing drug dosage, etc. problems, achieve high inhibitory activity, simple synthesis process, and high yield

Inactive Publication Date: 2015-08-26
ANYANG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the inhibitory effect of pyrazolone compounds on human intestinal carboxylesterase has not been reported, nor has there been any report on the use of pyrazolone compounds to relieve CPT-11-induced delayed diarrhea
In addition, many oral drugs containing carboxylate bonds are often metabolized by carboxylesterases distributed in the gastrointestinal tract, and are easily hydrolyzed into water-soluble active drugs before being absorbed into the blood, thereby reducing their absorption into the blood. The amount of drug that affects bioavailability

Method used

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  • Pyrazolone compound and application
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  • Pyrazolone compound and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Synthesis of 1-phenyl-3-(4-bromobenzyl)-4-benzyl-5-pyrazolone

[0030] The synthetic route of 1-phenyl-3-(4-bromobenzyl)-4-benzyl-5-pyrazolone is:

[0031]

[0032] Specifically through the following methods:

[0033] 1) Synthesis of compound 1 (methyl p-bromobenzoylacetate)

[0034]At room temperature, NaH (8.4g, 210mmol), dimethyl carbonate (17.6mL, 210mmol), and 30mL toluene were added to a 250mL three-necked flask, the temperature was raised to 120°C and refluxed, and p-bromoacetophenone (16.5g, 83mmol) in 30mL toluene solution. The reaction was monitored by thin-plate chromatography (TLC). After 30 minutes, the reaction of benzene-to-bromoethanone was complete, cooled to room temperature, added 100 mL of ice water, and 6N HCl solution to adjust the pH to 6-7. Separate the organic phase, extract the aqueous phase with ethyl acetate three times (100 mL×1, 50 mL×2), combine the organic phases, wash once with water (50 mL×1), wash once with saturated b...

Embodiment 2

[0041] Example 2 Quantitative evaluation of formula I pyrazolone compounds on carboxylesterase 2 inhibitory ability

[0042] Using the hydrolytic metabolism of fluorescein diacetate as a probe reaction, the IC of inhibition of carboxylesterase 2 by pyrazolone compounds was determined by means of human liver microsome in vitro incubation system 50 :

[0043] 1) In 200 microliters of in vitro metabolic reaction system, containing phosphate buffer solution with a pH of 7.4, the concentration of human liver microsomal protein is 2 μg / ml, and the final concentration of inhibitors is in the range of 0.01 μM-100 μM. Shake pre-incubation at 37°C 10 minutes;

[0044] 2) Add the substrate (final concentration 10 μM) to the reaction system to initiate the reaction; after reacting at 37°C for 30 minutes, add 200 μl of acetonitrile, shake vigorously, and terminate the reaction;

[0045] 3) Using a high-speed refrigerated centrifuge, under the condition of 20,000×g, centrifuge the above s...

Embodiment 3

[0051] Example 3 1-Phenyl-3-(4-bromobenzyl)-4-benzyl-5-pyrazolone on slowing down irinotecan-induced diarrhea in mice

[0052] Twenty-one Balb / c mice were randomly divided into 3 groups: normal control group, irinotecan diarrhea model group and 1-phenyl-3-(4-bromobenzyl)-4-benzyl-5-pyrazoline Ketone + irinotecan diarrhea model group (referred to as pyrazolone group), 7 rats in each group. The diarrhea status of the mice in the normal control group, the diarrhea model group and the pyrazolone group were observed respectively, and the intestinal tissues of the mice were examined by histological section. The diarrhea model group followed the Trifan method (Cancer Res 2002; 62:5778-84.), and the diarrhea model was injected with irinotecan (100mg / kg / d) for 3 consecutive days (d). It appeared every day, and it was the most serious on the 4th day. Pyrazolone was started 3 days before CPT-11 injection, once a day, 100 mg / kg was administered by intragastric administration, and the ot...

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Abstract

The invention provides a pyrazolone compound and application thereof and belongs to the technical field of biotechnology medicine. The inhibitor is of a 1-phenyl-3,4-di-substituted-5-pyrazolone frame structure and can potently inhibit the activity of human intestinal carboxylesterase subtype 2 to further improve the bioavailability of oral ester prodrugs. In addition, the inhibitor can also relieve delayed diarrhea caused by an anti-cancer drug irinotecan. According to the in vitro activity assay, the compound can inhibit IC50 of human carboxylesterase 2 to 6.01 micromole. Furthermore, the pyrazolone compound has the advantages of being simple in preparation process, high in yield and the like and has good application prospect.

Description

technical field [0001] The invention belongs to the technical field of biomedicine and relates to a pyrazolone compound and its application, in particular to the biomedical application as a potent inhibitor of human intestinal carboxylate. Background technique [0002] Carboxylesterases (CEs, E.C.3.1.1.1) are important metabolic enzymes in the human body, widely distributed in the endoplasmic reticulum of various tissues in the human body, and their active centers contain serine residues, which can effectively catalyze ester-containing bonds. , The hydrolysis of endogenous and exogenous substances of amide bonds and thioester bonds, and the joint action of other metabolic enzymes or carriers play an important role in the metabolism and clearance of ester drugs in vivo. CEs can hydrolyze a variety of drugs or ester prodrugs containing ester bonds, such as angiotensin-converting enzyme inhibitors (temopril, cilazapril, quinapril), antineoplastic drugs (irinotecan and betabine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/06C07D409/04C07D231/22A61K31/4155A61K31/4152A61P1/12A61P43/00
CPCC07D231/22C07D409/04C07D409/06
Inventor 刘林夏宁
Owner ANYANG NORMAL UNIV
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