CN-121991066-A - Riocidine prodrug, preparation method, intermediate, composition and application thereof

Abstract

The invention relates to a riocidine prodrug shown in a formula X or pharmaceutically acceptable salt thereof, a preparation method, an intermediate and a pharmaceutical composition thereof. The prodrug takes amino of riocigua as a modification site, is connected through an ester carrier, utilizes pulmonary amidase to trigger drug release, and realizes pulmonary targeting delivery by adjusting the lipid water distribution coefficient. The pharmacokinetic study shows that the prodrug can obviously improve the lung drug concentration and the total exposure, reduce the systemic blood drug concentration and show excellent lung targeting characteristics. The invention also provides a pharmaceutical composition (preferably an inhalation formulation) comprising the prodrug and its use in the manufacture of a medicament for preventing, treating or alleviating pulmonary hypertension in a patient; 。

Inventors

• HE YUN
• LIN YU
• PEI QI
• WEI QIJUN
• ZHANG SHENGNAN

Assignees

• 贺耘
• 林羽
• 裴奇
• 韦奇君
• 张声南

Dates

Publication Date

20260508

Application Date

20260310

Claims (10)

1. 1. A riocicidine prodrug which is a compound represented by the following formula X: 。
2. 2. A pharmaceutical composition comprising compound X of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.
3. 3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is a solid formulation, a semi-solid formulation, or a liquid formulation.
4. 4. A pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is an inhalation formulation.
5. 5. Use of a compound according to claim 1 or a pharmaceutical composition according to any one of claims 2-4 for the manufacture of a medicament for preventing, treating or alleviating pulmonary arterial hypertension in a patient.
6. 6. The use according to claim 5, wherein the pulmonary arterial hypertension is pulmonary arterial hypertension and/or pulmonary arterial hypertension caused by pulmonary arterial occlusive disease.
7. 7. The use according to claim 6, wherein the pulmonary arterial hypertension caused by pulmonary artery occlusive disease is chronic thromboembolic pulmonary arterial hypertension.
8. 8. An intermediate for preparing a compound X, which is a compound shown as the following formula Y, 。
9. 9. A process for preparing compound Y comprising the steps of: 。
10. 10. a process for preparing compound X comprising the steps of: 。

Description

Riocidine prodrug, preparation method, intermediate, composition and application thereof Technical Field The invention belongs to the technical field of drug synthesis, and particularly relates to a riocidine prodrug, a preparation method, an intermediate, a composition and application thereof. Background Pulmonary arterial hypertension (Pulmonary Hypertension, PH) is a group of diseases characterized by elevated pulmonary arterial pressure, often secondary to chronic obstructive pulmonary disease, left heart dysfunction, or thromboembolic events, and may also be caused by primary pulmonary vascular remodeling. PH causes a sustained increase in pulmonary vascular resistance, eventually leading to right heart failure, with hidden disease and rapid progression. In the absence of effective therapeutic intervention, the patient's mortality is extremely high, the rates of clinical misdiagnosis and missed diagnosis remain high, and once diagnosis is confirmed, the patient usually needs to take medicine for life. PH is classified into five types, namely PH caused by Pulmonary Arterial Hypertension (PAH), left heart disease, respiratory disease and/or PH caused by hypoxia, PH caused by pulmonary artery obstructive disease and PH caused by various factors with unknown mechanisms, according to the characteristics and etiology of blood flow dynamics. Among them, chronic thromboembolic pulmonary hypertension (CTEPH) belongs to PH caused by pulmonary artery obstructive disease, and has potential cure possibilities but is extremely easy to miss. The currently marketed targeted drugs are directed mainly against PAH, including endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostacyclin analogues and soluble guanylate cyclase (sGC) agonists. Among them, riociciquone (riociquone) as sGC agonist is currently the only targeted drug available worldwide for simultaneous treatment of PAH and CTEPH dual indications, showing unique clinical advantages. However, the recommended initial dose of the riocidine oral tablet is 1mg three times a day, and systemic adverse reactions such as hypotension, dizziness, syncope and the like are often accompanied, and fatigue and limb pain also occur in part of patients, so that the clinical use of the riocidine oral tablet is limited. From the pathological localization point of view, vascular lesions of PH patients are concentrated in terminal bronchi, alveolar ducts and surrounding areas of alveoli, and inhaled administration can directly deliver drugs to deep lesions of the lung, so that local high exposure and rapid onset of action are realized. Compared with systemic administration, the dosage required by the inhalation mode is obviously reduced, and the systemic adverse reaction is reduced. Meanwhile, compared with intravenous administration, inhalation administration can also reduce infection risk and improve the administration convenience and long-term compliance of patients. At present, the only inhaled PAH medicine on the market worldwide is Ventavis (iloprost), and the pulmonary retention is prolonged by aerosol inhalation, so that the problem of rapid degradation of the medicine in blood is partially overcome. However, due to the instability of iloprost itself, the product needs to be administered 6 times a day, the burden of patients is heavy, the compliance is poor, and the product is currently released from the market in China. Furthermore, the only inhaled treprostinil available today still requires multiple daily inhalations, limiting its wide clinical application. In order to better meet the clinical demands of patients with PAH and CTEPH which are not fully met, riociquo is used as the only targeting drug for simultaneously treating the double indications of PAH and CTEPH in the global acquisition at present, and shows unique clinical advantages. The medicine is developed into an inhalation preparation, and is expected to effectively reduce systemic adverse reactions brought by an oral route while maintaining the curative effect advantage. However, despite the high absolute bioavailability of riocidine orally, this property suggests good tissue membrane penetration, which may present challenges of shorter pulmonary residence time in the inhaled administration setting, thus increasing the potential need for multiple administrations. In addition, the low water solubility and rapid systemic absorption characteristics of riociguat also present biopharmaceutical and formulation process challenges for developing inhalation formulations. Therefore, development of a riociquo analogue and an inhaled preparation thereof capable of reducing the administration frequency, reducing adverse reactions of the system, enhancing the local curative effect and improving the administration experience of patients has become a key technical problem to be solved in the current PH treatment field. Disclosure of Invention The invention provides a novel riocidine prodrug or pharmaceutical