A class of oral gsnor inhibitors and their pharmaceutical use

A technology of inhibitors and drugs, applied in the direction of drug combinations, antineoplastic drugs, pharmaceutical formulations, etc., can solve the problem of reduced activity, achieve the effects of increased permeability, promotion of angiogenesis and blood flow recovery, and long half-life

Active Publication Date: 2022-05-17
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The applicant modified the structure of N6022 and found that the activity of the amide derivative N6022-1 of N6022 and the ester derivative N6022-2 of N6022 were significantly reduced in vitro studies

Method used

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  • A class of oral gsnor inhibitors and their pharmaceutical use
  • A class of oral gsnor inhibitors and their pharmaceutical use
  • A class of oral gsnor inhibitors and their pharmaceutical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: 4-(2-(4-(1H-imidazol-1-yl)phenyl)-5-(3-oxo-3-(2-oxothiazolidin-3-yl)propyl)- Synthesis of 1H-pyrrol-1-yl)-3-methylbenzamide (target compound 1), as figure 1 shown.

[0025] Experimental operation:

[0026] In a 250 ml single-necked flask, successively put 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrole -2-yl)propionic acid (N6022, 500mg, 1.21mmol), 2-chloro-1-picoline iodide (CMPI, 370mg, 1.45mmol), dimethylaminopyridine (DMAP, 10mg, 0.06mmol), thiazole Add alkanone (250mg, 2.41mmol), triethylamine (TEA, 490.2mg, 4.84mmol), add dichloromethane (15ml), and react at room temperature for 8 hours. Suction filtration, take the filtrate, adjust the pH to 7 with dilute hydrochloric acid, add dichloromethane (15ml) and water (15ml) for extraction, combine the organic phases, spin-steam to make sand, and separate by column chromatography (dichloromethane:methanol=25:1 ) to obtain 400 mg of a beige crude product, and recrystallized from ...

Embodiment 2

[0028] Example 2: In vitro activity research of target compound 1 on asthma and cystic fibrosis (with N6022, N6022-1, N6022-2 as controls)

[0029]GSNOR plays a key regulatory role in asthma and cystic fibrosis; the activity of GSNOR in the lungs of asthmatic patients increases significantly, and GSNOR allele mutations lead to a significant increase in the probability of children suffering from asthma; at the same time; the respiratory tract of cystic fibrosis patients The activity of GSNOR increased significantly, and the level of its catalytic product GSNO decreased significantly; therefore, in order to explore the protective effect of target compound 1 in asthma and cystic fibrosis, we tested the effect of target compound 1, N6022, N6022-1 and N6022-2 in vitro Inhibitory effect of GSNOR activity. Such as figure 2 As shown, the in vitro activity study of the target compound 1 on asthma and cystic fibrosis. Human umbilical vein endothelial cells (HUVECs) were treated with ...

Embodiment 3

[0031] Example 3: Study on the In Vitro Activity of Target Compound 1 on Diabetic Vascular Complications (with N6022, N6022-1, and N6022-2 as Controls)

[0032] It is known that in diabetic vascular complications, decreased angiogenesis and increased permeability of vascular endothelial cells are one of the risk factors for local edema, ischemia followed by ulcer and amputation. In order to study the therapeutic effect of target compound 1 on diabetic vascular complications, we administered high glucose (30mM) stimulation to human umbilical vein endothelial cells (HUVECs) at the cellular level, and simultaneously administered target compound 1, N6022, N6022-1 and N6022-2 (10nM) for 24 hours, and the angiogenesis ability of endothelial cells was detected by endothelial cell tube formation assay. Such as image 3 As shown, the in vitro activity study of the target compound 1 on diabetic vascular complications. Human umbilical vein endothelial cells (HUVECs) were given high glu...

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PUM

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Abstract

A class of oral GSNOR inhibitors and pharmaceutical applications thereof, the invention has good oral bioavailability and longer half-life. In vitro experiments, the compound of the present invention can improve the reduction of migration ability and tube-forming ability of human umbilical vein endothelial cells caused by high glucose, and the increase of permeability; Neogenesis and blood flow recovery suggest that the compound of the present invention can be used for treating diseases related to diabetic vascular complications. The compound of the present invention can improve the smooth muscle cell phenotype conversion caused by angiotensin II, and the compound of the present invention can obviously improve the incidence and mortality of aortic aneurysm / dissection, suggesting that the compound of the present invention can be used for the treatment of diseases related to aortic aneurysm / dissection . The compound of the present invention can effectively inhibit the activity of GSNOR, suggesting that the compound of the present invention can be used for treating diseases related to asthma and cystic fibrosis.

Description

technical field [0001] The present invention relates to thiazolone derivatives of nitrosoglutathione reductase (GSNOR) inhibitor N6022 and their pharmaceutical application, especially to their preparation and improvement in the treatment of asthma, cystic fibrosis, diabetic vascular complications, aortic aneurysm / dissection-related disease drug application. Background technique [0002] N6022 is a specific reversible nitrosoglutathione reductase (GSNOR) inhibitor. Studies have shown that N6022 can effectively improve asthma and allergic airway inflammation. N6022 is used as a first-stage treatment for chronic asthma and cystic fibrosis. , Phase II clinical trials have been completed. [0003] Diabetes is a serious health problem worldwide. 70% of the deaths of diabetic patients are caused by various cardiovascular complications. Diabetic vascular complications are also the main reasons that affect the quality of life of diabetic patients and cause death and disability, in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/14A61P11/06A61P3/10A61P35/00A61P43/00
CPCC07D417/14A61P11/06A61P3/10A61P35/00A61P43/00A61P9/10A61P11/12A61K31/427C07D403/10A61K31/4178A61P9/00C07D277/02
Inventor 季勇谢利平赵爽宋天宇韩艺
Owner NANJING MEDICAL UNIV
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