JP-2026514526-A - Combination therapy of dacomitinib and nintedanib for the prevention or treatment of pulmonary fibrosis

Abstract

This invention relates to a combination therapy of dacomitinib and nintedanib for the prevention or treatment of pulmonary fibrosis. [Selection Diagram] Figure 1

Inventors

• イ、ユン－ジン
• ナム、ジェ ギョン
• キム、ジヒ

Assignees

• コリア インスティテュート オブ ラジオロジカル アンド メディカル サイエンシズ

Dates

Publication Date

20260511

Application Date

20240426

Priority Date

20230428

Claims (5)

1. A pharmaceutical composition for the prevention or treatment of pulmonary fibrosis, comprising a pharmaceutically effective amount of dacomitinib or a pharmaceutically acceptable salt or solvate thereof, The aforementioned pharmaceutical composition is characterized by being administered in combination with nintedanib or a pharmaceutically acceptable salt or solvate thereof. Pharmaceutical composition.
2. The aforementioned dacomitinib is a compound represented by the following chemical formula 1. The pharmaceutical composition according to claim 1.
3. The aforementioned nintedanib is a compound represented by the following chemical formula 2. The pharmaceutical composition according to claim 1.
4. The composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent. The pharmaceutical composition according to claim 1.
5. The aforementioned dacomitinib or a pharmaceutically acceptable salt or solvate thereof is administered in combination with nintedanib or a pharmaceutically acceptable salt or solvate thereof, either simultaneously, sequentially, or in reverse order. The pharmaceutical composition according to claim 1.

Description

This invention relates to a combination therapy of dacomitinib and nintedanib for the prevention or treatment of pulmonary fibrosis. Pulmonary fibrosis refers to a condition in which fibrous connective tissue proliferates in the lungs, destroying normal lung structure and causing hardening and deterioration of the lung tissue. In particular, idiopathic pulmonary fibrosis is a disease in which chronic inflammatory cells invade the alveolar walls, causing various changes and hardening of the lungs, leading to serious structural changes in lung tissue and progressive deterioration of lung function. To date, there is no effective treatment. Furthermore, while radiotherapy is frequently used for NSCLC tumor patients who cannot undergo surgical resection, it often causes radiation-induced pulmonary fibrosis (RIPF). To date, Ofev, a compound containing nintedanib as its active ingredient manufactured by Boehringer Ingelheim, is known to have some effect in slowing the decline of lung function. However, there is a growing need to develop a more effective drug. This figure shows the effect of suppressing radiation-induced pulmonary fibrosis in mice that were administered nintedanib, dacomitinib, or a combination of nintedanib and dacomitinib, as confirmed by micro-CT imaging.This graph shows the degree of inflammation and fibrosis confirmed by H&E and Masson's Trichrome staining in mice in which pulmonary fibrosis was induced by radiation, and who were administered nintedanib, dacomitinib, or a combination of nintedanib and dacomitinib. These will be explained in detail below. Note that each description and embodiment disclosed in this invention applies to other descriptions and embodiments. That is, any combination of the various elements disclosed in this invention is included. Furthermore, this invention is not limited to the following specific descriptions. Furthermore, a person with ordinary skill in the art would be able to recognize and confirm many equivalents of the specific embodiments of the present invention described herein using only ordinary experiments. Moreover, these equivalents are also intended to be included in the present invention. Furthermore, numerous papers and patent documents are referenced throughout this specification, and their citations are indicated. The disclosures of the cited papers and patent documents are incorporated in their entirety as references within this specification, thereby more clearly explaining the level of the art to which the present invention pertains and the content of the present invention. One aspect of the present invention is a therapy for the prevention, improvement, or treatment of pulmonary fibrosis, comprising the combined use of dacomitinib or a pharmaceutically acceptable salt or solvate thereof with nintedanib or a pharmaceutically acceptable salt or solvate thereof. Another aspect of the present invention is a pharmaceutical composition for the prevention or treatment of pulmonary fibrosis, comprising dacomitinib or a pharmaceutically acceptable salt or solvate thereof, characterized in that the pharmaceutical composition is administered in combination with nintedanib or a pharmaceutically acceptable salt or solvate thereof. A further aspect of the present invention is a pharmaceutical composition for the prevention or treatment of pulmonary fibrosis, comprising nintedanib or a pharmaceutically acceptable salt or solvate thereof, characterized in that the pharmaceutical composition is administered in combination with dacomitinib or a pharmaceutically acceptable salt or solvate thereof. The dacomitinib of the present invention, also known as PF-00299804 or Vizimpro (trade name), is a commercially available compound and has the structure of Chemical Formula 1. The IUPAC name for the aforementioned dacomitinib is (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide. Dacomitinib is a human (pan-human) epidermal growth factor receptor (EGFR/HER1, HER2, HER4) inhibitor and is known to be used for mutant EGFRs with exon 19 deletion or exon 21 L858R substitution. The nintedanib of this invention is also known as BIBF 1120, Vargatef, Ofev (trade name), etc., and is a commercially available compound having the structure of chemical formula 2. The IUPAC name for the aforementioned nintedanib is Methyl(3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate. Furthermore, the term "compound of the present invention" includes not only compounds having a specific structural formula, but also their clathrates, hydrates, solvates, or polymorphs. Also, unless a pharmaceutically acceptable salt of the compound is specifically mentioned, the term "compound of the present invention" includes pharmaceutically acceptable salts of the compound. In one example, the compound of the present invention exists as a stereoisomerically pure compound (for exampl