EP-4734997-A1 - USE OF COMPOUND 1 IN TREATMENT OR PREVENTION OF DISEASES SUCH AS PULMONARY FIBROSIS OR LUNG DISEASES WITH FIBROSIS

Abstract

Use of N-(3-chloro-5-(trifluoromethyl)phenyl)-3-((6-(4-hydroxypiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-2-methylbenzamide (also referred to herein as compound 1) or a pharmaceutically acceptable salt thereof in the treatment or prevention of diseases such as pulmonary fibrosis or lung diseases with fibrosis.

Inventors

• HE, XUN
• JIN, FENG
• GUO, Yuhan
• ZHANG, TIANYUAN
• HUANG, Liye

Assignees

• Shenzhen Newdel Biotech Co., Ltd.

Dates

Publication Date

20260506

Application Date

20240628

Claims (4)

1. Use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing pulmonary fibrosis or lung diseases with fibrosis, wherein compound 1 has the following structure:
2. Use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease mediated by DDR1 or that can be controlled by inhibiting DDR1, wherein compound 1 has the following structure:
3. Use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease mediated by DDR2 or that can be controlled by inhibiting DDR2, wherein compound 1 has the following structure:
4. Use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease mediated by CSF1R or that can be controlled by inhibiting CSF1R, wherein compound 1 has the following structure:

Description

USE OF COMPOUND 1 IN TREATMENT OR PREVENTION OF DISEASES SUCH AS PULMONARY FIBROSIS OR LUNG DISEASES WITH FIBROSIS TECHNICAL FIELD The present invention relates to use of N- (3-chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4-hydroxypiperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (also referred to herein as compound 1) or a pharmaceutically acceptable salt thereof in the treatment or prevention of diseases such as pulmonary fibrosis or lung diseases with fibrosis. BACKGROUND Pulmonary fibrosis is the ultimate outcome of the development, evolution, and scarring of many lung diseases. It is a disease process characterized by alveolar epithelial cell injury, aggregation and proliferation of inflammatory cells, activation of fibroblasts and myofibroblasts, transformation of extracellular matrix (ECM) components, and activation of signaling pathways and gene expression. The ultimate result of this process is the loss of lung elasticity and the loss of alveolar surface area, resulting in impairment of gas exchange efficiency and lung function. Pulmonary fibrosis has various etiologies; for example, acute severe viral pneumonia, post-healed pulmonary tuberculosis, and pneumoconiosis late stage cause secondary pulmonary fibrosis. However, some have unknown etiologies, such as idiopathic pulmonary fibrosis (IPF) ; IPF develops in a chronic and progressive manner with a complicated pathogenesis and a pathological manifestation of usual interstitial pneumonia (UIP) , and the average survival time after diagnosis is about 3 years, with a 5-year survival rate of 30-50%, indicating an extremely poor prognosis. Currently, pirfenidone and nintedanib are clinically used for treatment to relieve disease progression. However, for progressive pulmonary fibrosis, pirfenidone treatment does not significantly improve mortality, DLCO (diffusing capacity of the lung for carbon monoxide) , and respiratory symptoms; in addition, the risk of gastrointestinal discomfort is increased by 1.8 times, the risk of photosensitivity is increased by 4.9 times, and the overall risk of adverse events is increased by 1.2 times. Nintedanib treatment can reduce the annual decline in FVC (forced vital capacity) in CTD-ILD (connective tissue disease-associated interstitial lung disease) , fibrotic NSIP (nonspecific interstitial pneumonia) , and fibrotic occupational lung disease. However, it has no significant effect on fibrotic HP (hypersensitivity pneumonitis) , sarcoidosis, and unclassified ILD (interstitial lung disease) , and does not significantly improve mortality; in addition, the overall risk of adverse events is increased by 1.1 times, the adverse events mainly including gastrointestinal tract issues, elevated liver transferases,  and the like. Therefore, there is still an urgent need to develop effective and safe pulmonary fibrosis drugs. DDR1/2 inhibitor drugs have not yet entered the clinical trial stage for pulmonary fibrosis. Two marketed TRK inhibitor drugs (larotrectinib and entrectinib) are both targeted at tumor patients with NTRK gene mutations. There are no marketed drugs for pulmonary fibrosis indications, nor clinical trials and preclinical studies for pulmonary fibrosis indications. For the PDGFR target and CSF1R target, only one marketed multi-target inhibitor, nintedanib, is used for anti-pulmonary fibrosis treatment. The bleomycin (BLM) -induced pulmonary fibrosis model is the most commonly used experimental pulmonary fibrosis model. BLM induces DNA strand breakage, generates free radicals, induces oxidative stress responses, causes cell apoptosis or necrosis, and induces inflammatory responses and fibrosis. This model is employed in the present invention to test the therapeutic effect of the compound on pulmonary fibrosis. It is known in the art that the bleomycin-induced pulmonary fibrosis model is the most commonly used experimental pulmonary fibrosis model, as the histopathological changes of bleomycin-induced pulmonary fibrosis are very similar to those of human pulmonary fibrosis. CN113831344B discloses N- (3-chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4-hydroxypiperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide. SUMMARY OF THE INVENTION The present invention relates to use of N- (3-chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4-hydroxypiperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (also referred to herein as compound 1) or a pharmaceutically acceptable salt thereof in the treatment of pulmonary fibrosis or lung diseases with fibrosis. In the present invention, the pulmonary fibrosis or lung diseases with fibrosis include idiopathic pulmonary fibrosis (IPF) , non-idiopathic pulmonary fibrosis, and progressive pulmonary fibrosis. For example, in the present invention, the pulmonary fibrosis or lung diseases with fibrosis include idiopathic pulmonary fibrosis, giant cell interstitial pneumonia, sarcoidosis, cystic fibrosis,