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EP-4741374-A1 - TREPROSTINIL DERIVATIVE, AND PREPARATION METHOD THEREFOR AND USE THEREOF

EP4741374A1EP 4741374 A1EP4741374 A1EP 4741374A1EP-4741374-A1

Abstract

The present invention relates to the field of chemistry and medicine. Provided is a treprostinil derivative represented by formula I, or an isomer or a pharmaceutically acceptable salt thereof, wherein each group is as defined in the description. The compound of formula I, or the isomer or the pharmaceutically acceptable salt thereof can remain in the lung for a long time and slowly release treprostinil at an effective concentration after pulmonary administration, and can therefore be used for treating pulmonary hypertension and pulmonary fibrosis. The pulmonary administration of the compound of formula I, or the isomer or the pharmaceutically acceptable salt thereof provided in the present invention can greatly reduce the administration dosage, provide a lower administration frequency and a broader therapeutic window, and reduce systemic side effects and local lung irritation. Therefore, the drug safety and drug tolerance of a patient are greatly improved, and a new treatment choice is provided for a patient with pulmonary hypertension and pulmonary fibrosis.

Inventors

  • XU, LIN
  • LIANG, Bill Wenqing
  • QUAN, Mengxue
  • CHE, Lin
  • ZHANG, LIANG
  • LI, Xiujuan
  • XU, BEIBEI
  • DONG, Jingwei
  • LIU, XIAO
  • TAO, Hongfu

Assignees

  • CF PharmTech HongKong Limited
  • CF Pharmtech Guangzhou Limited
  • CF PharmTech USA, Inc.
  • CF Pharmtech, Inc.

Dates

Publication Date
20260513
Application Date
20240619

Claims (20)

  1. A compound of Formula I, an isomer or a pharmaceutically acceptable salt thereof, wherein, X is each independently selected from the group consisting of O and S; A is a cyclic group, and the cyclic group is selected from the group consisting of phenyl and 5- to 10-membered heteroaryl, wherein the heteroatom in the 5- to 10-membered heteroaryl is selected from one or more of N, O and S; R 1 and R 2 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogen atom, hydroxyl, amino, cyano, nitro and -ONO 2 , or R 1 and R 2 form a cyclic group together with the carbon atom to which R 1 and R 2 are attached, wherein, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 1 -C 6 alkoxy are optionally substituted by one or more substituents selected from the following groups: cycloalkyl, aryl, heteroaryl, -NR 3 R 4 , halogen atom, hydroxyl, cyano, mercapto, nitro or -ONO 2 ; R 3 and R 4 are each independently selected from the group consisting of H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, or R 3 and R 4 form a 5-8 membered heterocyclic ring together with the nitrogen atom to which R 3 and R 4 are attached; Y is each independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, hydroxyl, carboxyl, cyano, mercapto, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino and 3-8 membered cycloalkyl; m is an integer from 4 to 16; n is an integer from 0 to 8; j is an integer from 0 to 2; and k is an integer from 0 to 3.
  2. The compound, the isomer or the pharmaceutically acceptable salt thereof according to claim 1, wherein, A is phenyl.
  3. The compound, the isomer or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X is each independently O.
  4. The compound, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 and R 2 are each independently selected from H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more substituents selected from the following groups: halogen atom, hydroxyl, cyano, amino, nitro, -ONO 2 and mercapto.
  5. The compound, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Y is each independently selected from the group consisting of C 1 -C 6 alkyl, halogen, cyano and C 1 -C 6 alkoxy.
  6. The compound, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Y is each independently chlorine.
  7. The compound, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein m is an integer from 6 to 10.
  8. The compound, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein n is an integer from 4 to 6.
  9. The compound, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein j is an integer from 0 to 1.
  10. The compound, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein k is an integer from 0 to 2.
  11. A compound, an isomer or a pharmaceutically acceptable salt thereof, selected from a group of the following compounds: and
  12. An isotope substitute of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein the isotope substitute is preferably a deuterium atom substitute.
  13. A pharmaceutical composition, comprising the compound of Formula I, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, or the isotope substitute according to claim 12, and a pharmaceutically acceptable excipient.
  14. A use of the compound, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, the isotope substitute according to claim 12, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating pulmonary hypertension.
  15. A use of the compound, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, the isotope substitute according to claim 12, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating pulmonary fibrosis.
  16. The use according to claim 14 or 15, comprising administering an effective dose of the compound, the isomer or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, the isotope substitute according to claim 12, or the pharmaceutical composition according to claim 13 to a patient in need thereof.
  17. The use according to claim 16, wherein the drug adopts pulmonary administration.
  18. The use according to claim 17, wherein the pulmonary administration comprises administrating through a metered dose inhaler, a dry powder inhaler, a nebulizer and a soft mist inhaler.
  19. The use according to claim 17, wherein the pulmonary administration comprises administrating through a metered dose inhaler.
  20. The use according to claim 17, wherein the pulmonary administration comprises administrating through a dry powder inhaler.

Description

TECHNICAL FIELD The present invention relates to the field of chemical medicine, and particularly to a treprostinil derivative as shown in Formula I, a preparation method therefor and a use thereof. BACKGROUND Pulmonary hypertension (PH) is a clinical and pathophysiological syndrome defined by a mean pulmonary arterial pressure ≥25 mmHg at rest, as measured by right heart catheterization at sea level. The disease is characterized by pulmonary vascular disease and remodeling, arterial luminal narrowing and impaired vasodilation. These pathological changes lead to increased pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), which in turn limits the capacity of the right ventricle to pump blood to lungs through pulmonary arteries, resulting in shortness of breath and eventually leading to right heart failure and death. PH has diverse etiologies and complex pathogenesis. It is clinically classified into 5 groups: (1) Pulmonary arterial hypertension (PAH); (2) PH due to left heart diseases (PH-LHD); (3) PH due to lung diseases and/or hypoxia; (4) Chronic thromboembolic pulmonary hypertension (CTEPH) and (or) PH due to pulmonary arterial obstructive diseases; and (5) PH with unclear and (or) multifactorial mechanism. According to statistics, the prevalence rate of the PH is approximately 1% in general population, but increased to 10% in people over 65 years old. Among various types of PH, PH due to left heart diseases and PH due to lung diseases and/or hypoxia are the most common types in clinical practice. For PH due to lung diseases and/or hypoxia, chronic obstructive pulmonary disease (COPD), interstitial lung disease, and pulmonary fibrosis are the most common causes. The causes of idiopathic pulmonary arterial hypertension (IPAH) are currently unknown. Although the incidence of PAH is low, it is often referred to as "cancer of the cardiovascular system". Epidemiological data indicate that the 5-year survival rate of patients with idiopathic and heritable PAH is only 20.8% following conventional treatment. Furthermore, due to a lack of professional disease management capacity and effective patient-physician communication mode, disease remains suboptimal in most PAH patients even after discharge. At present, the treatment of PAH still primarily targets three signaling pathways: prostacyclin (PGI2), endothelin-1 (ET-1) and nitric oxide (NO). Among these, the PGI2 signaling pathway is the most important and represents the only class of targeted drugs among the three that can reduce mortality in patients with PAH. The PGI2 is a potent vasodilator, which binds to prostaglandin receptors (IP receptor,EP receptor), activates adenylate cyclase, and increases the intracellular concentration of cAMP, thereby inducing vasodilation. In addition, PGI2 also has antiplatelet, antiproliferative, and anti-inflammatory effects. In patients with PAH, the synthesis of PGI2 and the expression of the IP receptor are decreased. PGI2 analogues function by mimicking the binding of PGI2 to the IP receptor. Currently marketed prostacyclin drugs, which primarily include epoprostenol, iloprost, beraprost and treprostinil, are mostly expensive and plagued by problems such as a short half-life, poor chemical stability, and significant side effects, and often need to be administered by continuous intravenous or subcutaneous infusion, which can lead to severe injection site pain and infection. Moreover, if the intravenous infusion is abruptly interrupted, patients may also face the risk of fatal rebound pulmonary hypertension. Although an inhaled form of treprostinil (trade name: Tyvaso) has been approved for the treatment of the PAH and its efficacy has been established in clinical studies for patients with idiopathic pulmonary interstitial pneumonia (IIP), including idiopathic pulmonary fibrosis (IPF) and combined pulmonary fibrosis and emphysema (CPFE), the short half-life (about 30 minutes) necessitates frequent administration of inhaled treprostinil to maintain pulmonary vasodilation. In addition, the inhalation of the treprostinil is associated with local and systemic adverse events, including cough, headache, throat irritation, and the like, thereby affecting the tolerance and the curative effect, and complicating the clinical application. To overcome these shortcomings, researchers have evaluated numerous alternative therapeutic strategies, including liposomal encapsulation, novel drug delivery devices, particle engineering using modern technologies, and prodrug modification of treprostinil. Insmed has developed treprostinil palmitate (C16-TR), an ester prodrug of treprostinil that undergoes slow hydrolysis to provide sustained release of treprostinil over an extended period. The structural formulas of treprostinil and C16-TR are shown below. C16-TR, a sustained-release prodrug designed for inhalation administration, aims to improve patient compliance and reduce side effects of systemic administration. Clinica