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Quinazolinone derivatives and their preparation and application

A technology for quinazolinone and derivatives, applied in the fields of quinazolinone derivatives and their preparation and application, can solve problems such as being difficult to become drug candidate compounds, and achieve the effects of good pharmacokinetic properties and druggability

Inactive Publication Date: 2011-12-28
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The research on PTP1B selective inhibitors has made some progress, but most of them are limited to some peptides or peptidoids, such as the inhibitor EEDE(F2PMP)M (Ki=7.2nM) designed based on the substrate sequence of PTP1B dephosphorylation , Glu-F 2 PMP-F 2 PMP (IC 50 =40nM), although these peptide inhibitors have strong inhibitory activity and high selectivity, the fact that they are peptide phosphate compounds makes them difficult to be drug candidates

Method used

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  • Quinazolinone derivatives and their preparation and application
  • Quinazolinone derivatives and their preparation and application
  • Quinazolinone derivatives and their preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: Preparation of WB-409

[0026]

[0027] In the first step, 8.6g of 2-amino-5-iodobenzoic acid and 10.4g of 2-methoxyphenylthioisocyanate were dissolved in 50mL of absolute ethanol, refluxed for 10 hours, cooled to room temperature, filtered, and the filter cake was washed with 10mL Petroleum ether rinse, 10mL saturated sodium bicarbonate solution rinse, 10mL anhydrous EtOH rinse, dry to obtain the quinazolinone intermediate crude product, 200-300 mesh silica gel column chromatography purification, eluent is dichloromethane and The mixed solvent of methyl alcohol, mixed solvent ratio is dichloromethane: methyl alcohol=100: 1, gets 5.4g quinazolinone intermediate, productive rate 30%, the compound 1 H NMR (DMSO, 500MHz): δ = 13.11 (brs, 1H), 8.18 (d, J = 2.0Hz, 1H), 8.05 (dd, J = 2.0, 4.2Hz, 1H), 7.39-7.42 (m, 1H ), 7.23(m, J=9.0Hz, 1H), 7.21(dd, J=1.5, 7.5Hz, 1H), 7.14(d, J=8.0Hz, 1H), 7.02(t, J=8.0Hz, 1H ), 3.71(s, 3H);

[0028] In the second step, the ...

Embodiment 2

[0029] Example 2: Preparation of WLH-535

[0030]

[0031] In the first step, 16.6g of anthranilic acid and 10.4g of 2-methoxyphenyl thioisocyanate were dissolved in 50mL of absolute ethanol, refluxed for 10 hours, cooled to room temperature, filtered, and the filter cake was rinsed with 10mL of petroleum ether , 10mL saturated sodium bicarbonate solution rinse, 10mL anhydrous EtOH rinse, dry to obtain the quinazolinone intermediate crude product, 200-300 mesh silica gel column chromatography purification, eluent is a mixed solvent of dichloromethane and methanol , the mixed solvent ratio is dichloromethane: methyl alcohol=100: 1, obtains 6.7g quinazolinone intermediate, productive rate 26%, the compound 1 H NMR (DMSO, 500MHz): δ = 13.11 (brs, 1H), 8.18 (d, J = 2.0Hz, 1H), 8.05 (dd, J = 2.0, 4.2Hz, 1H), 7.39-7.42 (m, 1H ), 7.23(d, J=9.0, 1H), 7.21(dd, J=1.5, 7.5Hz, 1H), 7.14(d, J=8.0Hz, 1H), 7.02(t, J=7.5Hz, 1H) , 3.71(s, 3H);

[0032] In the second step, the quinazolino...

Embodiment 3

[0034] Example Three: Preparation of WLH-424

[0035] In the second step, the halogenating reagent is Add-on is 0.14g, productive rate is 65%, the derivative 1 H NMR (CDCl 3 , 500MHz): δ=11.52(brs, 1H), 8.27(d, J=5.0Hz, 1H), 7.82(d, J=5.0Hz, 2H), 7.54(t, J=10.0Hz, 1H), 7.47 (t, J=15.0Hz, 1H), 7.43(m, 1H), 7.25(s, 1H), 7.09(t, J=10.0Hz, 1H), 6.98-6.97(s, 1H), 4.02(d, J=15Hz, 1H), 3.89(d, J=15.0Hz, 1H), 3.82(s, 3H).

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Abstract

A class of quinazolinone derivatives and their preparation and application, the application refers to as a protein tyrosine phosphatase 1B (abbreviated PTP1B) inhibitor, belongs to the technical field of medicine and its preparation and application, with 2-amino-5 - Iodobenzoic acid or anthranilic acid as raw materials react with 2-methoxyphenylthioisocyanate to form a ring, and then undergo substitution reactions with various halogenated reagents to obtain a class of quinazolinone derivatives. The compound has significant PTP1B inhibitory activity, and is particularly suitable as a potential antidiabetic drug.

Description

technical field [0001] The invention relates to a class of quinazolinone derivatives and their preparation and application. The application refers to the protein tyrosine phosphatase 1B (abbreviated as PTP1B) inhibitor, which belongs to the technical field of medicine and its preparation and application. Background technique [0002] Diabetes is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is a chronic disease that occurs when the pancreas does not produce enough insulin or the body cannot effectively use the insulin produced. Diabetes and its complications have become a worldwide public health problem that seriously threatens human health. [0003] Currently, diabetes is generally divided into two types, type I diabetes (insulin-dependent diabetes mellitus, IDDM) and type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). 90% of diabetics around the world are type 2 diabetes. Type 2 diabetes, formerly known as ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61P3/10C07D403/12C07D239/95A61K31/517C07D417/12
Inventor 杨帆汤杰仇文卫王利华赵丽华穆秋超
Owner EAST CHINA NORMAL UNIV
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