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Neutrophil inflammation inhibitor and uses thereof

Active Publication Date: 2020-05-14
CHANG GUNG UNIVERSITY OF SCIENCE AND TECHNOLOGY +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about a new compound that can help treat or prevent inflammatory diseases caused by overactive neutrophils. A therapeutic amount of this compound can be given to patients to reduce the symptoms of these diseases.

Problems solved by technology

Despite their importance in fighting infection, neutrophils themselves can promote tissue damage.
During an abnormal inflammatory response, neutrophils can cause significant tissue damage by releasing toxic substances at the vascular wall or in uninjured tissue.
Alternatively, neutrophils that stick to the capillary wall may produce tissue damage by ischemia.

Method used

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  • Neutrophil inflammation inhibitor and uses thereof
  • Neutrophil inflammation inhibitor and uses thereof
  • Neutrophil inflammation inhibitor and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Production and Characterization of Compound of Formula (I)

[0125]1.1 Production of Compound of Formula (I)

[0126]In general, the compound of formula (I) was synthesized in accordance with the procedures described in Scheme I.

[0127]The Compound of Formula (I)

Compound # andnameXR1R2R3R4R5 3HKI-4961NCH3HHHH 4HKI-4962NCH3HHFH 5HKI-4966NCH3OCH3HHH 6HKI-4965NCH3HOCH3HH 7HKI-4964NCH3HHOCH3H 8HKI-4963NCH3HOCH3OCH3OCH3 9HKI-4967NCH3HHSCH3H10HKI-4968NCH3HH—(C═O)CH3H11HKI-4973NCH3OHHHH12HKI-4972NCH3HOHHH13HKI-4971NCH3HHOHH14HKI-4974NCH3HHCF3H15HKI-4970NCH3HHCOOHH16HKI-4975NCH3SHHHH17TCH-30oNCH3HHClH18TCH-30pNCH3HHCH3H19HKI-4978ONilHHHH20HKI-4979ONilHHFH21HKI-4983ONilOCH3HHH22HKI-4982ONilHOCH3HH23HKI-4981ONilHHOCH3H24HKI-4980ONilHOCH3OCH3OCH325HKI-4984ONilHHSCH3H26HKI-4986ONilH—(C═O)CH3HH27HKI-4987ONilHH—(C═O)CH3H28HKI-4990ONilOHHHH29HKI-4988ONilHHOHH30HKI-4991ONilHHCF3H31HKI-4985ONilHHCOOHH32TCH-30qONilHHClH33TCH-30rONilHHCH3H

[0128]4-Chloro-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-amine (compound 2...

example 2

HKI-4971 Suppresses the Development of Imiquimod-Induced Psoriasis

[0204]In this example, the effect of HKI-4971 (or compound 13) on the development of psoriasis was investigated using the well-established psoriasis animal model, in which imiquimod (IMQ) was used to induce psoriasis-like skin inflammation. Briefly, BALB / c mice are pre-treated by intraperitoneal injection of HKI-4971 (20 mg / kg) for 30 min before 5% IMQ cream was topically administered onto the back of the mice every day for 7 days. Then, skin samples taken from these animals were subjected to microscopy examination and immunohistochemistry staining, while blood samples were subjected to analysis for liver and kidney functions. Results are depicted in FIGS. 1 to 3.

[0205]FIG. 1(A) is a photograph taken from one representative mouse treated with IMQ (left), and IMQ+HKI-4971 (right); while photographs in FIGS. 1(B) and 1(C) respectively illustrating microscopic presentation of the skins taken from the control IMQ-treated ...

example 3

HKI-497 Modulates LPS-Induced ALI

[0208]In this example, the Gram-negative bacterial endotoxin LPS induced ALI in mice was employed to mimic ARDS in human, and the effect of HKI-4971 was evaluated. Briefly, BALB / c mice were pre-treated by intravenous injection of compound HKI-4971 (20 mg / Kg) for 1 hr, and then challenged with intratracheal injection of LPS (2 mg / Kg) for 5 hrs. The level of MPO activity and the markers for neutrophils (Ly6g and MPO) in lung tissues were taken as indications of lung injury. Results are depicted in FIG. 4.

[0209]As FIG. 4(A) depicted, LPS evoked a surge in MPO activity in lung tissues, an indication of inflammatory cells in lung tissue, which was suppressed by the administration of HKI-4971. FIG. 4(B) are representative photographs of lung sections staining by H&E and the markers for neutrophils viewed under light microscopy. It is evident that HKI-4971 significantly alleviated LPS-induced neutrophil infiltration and lung injury.

[0210]Taken together, the...

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PUM

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Abstract

Disclosed herein are compounds of formula (I), and pharmaceutical compositions comprising the same. The compounds of formula (I) are neutrophilic inflammation inhibitors, thus, they are useful for treatment and / or prophylaxis of inflammatory diseases and / or disorders associated with abnormal activation of neutrophils, such as ARDS, ALI, COPD, lung fibrosis, chronic bronchitis, pulmonary emphysema, α-1 anti-trypsin deficiency, cystic fibrosis, idiopathic pulmonary fibrosis, liver injury, steatohepatitis, liver fibrosis, damages caused by ischemia and reperfusion, myocardial infarction, shock, stroke, and organ transplantation, ulcerative cholitis, vasculitis, SLE, sepsis, SIRS, arthritis, psoriasis, atopic dermatitis, and inflammatory skin diseases.

Description

BACKGROUND OF THE INVENTION1. Field of the Invention[0001]The present disclosure in general relates to the field of inhibitors of neutrophilic inflammation, and their uses in the treatment or prophylaxis of neutrophil associated diseases and / or disorders.2. Description of Related Art[0002]Neutrophils are a class of white blood cells (leukocytes) that comprise an essential component of the host defense system against microbial invasion. In response to soluble inflammatory mediators released by cells at the site of injury, neutrophils emigrate into tissue from the bloodstream by crossing the blood vessel wall. At the site of injury, activated neutrophils kill foreign cells by phagocytosis and by the release of cytotoxic compounds, such as oxidants, proteases and cytokines. Despite their importance in fighting infection, neutrophils themselves can promote tissue damage. During an abnormal inflammatory response, neutrophils can cause significant tissue damage by releasing toxic substanc...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61P17/06C07D498/04A61P11/00
CPCC07D471/04A61P11/00C07D498/04A61P17/06
Inventor HWANG, TSONG-LONGCHEN, YEH-LONGTZENG, CHERNG-CHYITSENG, CHIH-HUA
Owner CHANG GUNG UNIVERSITY OF SCIENCE AND TECHNOLOGY
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