Application of chalcone compound in preparation of medicine for treating pulmonary arterial hypertension

Abstract

The invention provides application of a chalcone compound in preparation of a medicine for treating or preventing pulmonary arterial hypertension. The medicine can effectively improve hypertrophy of a right ventricle of a pulmonary arterial hypertension animal model, functional damage of the right ventricle and hemodynamic parameters.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical technology of pharmaceutical compounds, and particularly relates to the use of a chalcone compound in the preparation of a drug for treating pulmonary hypertension. Background Art

[0002] Chalcone compounds are a subclass of flavonoid compounds. They are common yellow pigments in flowers and are also widely distributed in different parts (roots, rhizomes, buds, leaves, flowers and seeds) of plants belonging to Angelica, Sophora flavescens, Glycyrrhiza glabra, Carrot, Scutellaria baicalensis, Ficus carica, Ficus carica, Morus alba, Atractylodes lancea, etc. Chalcones have a wide range of biological activities, including anti-tumor, anti-mutation, anti-inflammatory, antioxidant, anti-fungal, anti-bacterial, anti-protozoal, analgesic and gastroprotective effects. In terms of anti-tumor activity, chalcone compounds have multiple effects such as anti-initiation, induction of apoptosis, anti-proliferation, anti-tumor metastasis, anti-angiogenesis, etc.

[0003] Pulmonary hypertension (PAH) is a rare, chronic and progressive disease, which refers to the abnormal elevation of pulmonary artery pressure beyond the normal range. The main symptoms of pulmonary hypertension include dyspnea after activity, chest pain, dizziness or syncope, lower limb edema, dry cough, hoarseness, cyanosis and clubbing fingers. It is difficult to diagnose pulmonary hypertension in the early stage, the treatment is rather difficult, and the prognosis is poor. Usually, the treatment of pulmonary hypertension depends on the cause or classification of pulmonary hypertension. Current therapies cannot cure pulmonary hypertension and do not directly treat the underlying vascular remodeling and vascular myofibroblast proliferation observed in many patients with pulmonary hypertension. Therefore, there is a high and unmet need for effective therapies for treating pulmonary hypertension. Summary of the Invention

[0004] The present invention provides the use of a compound of formula I its stereoisomers, pharmaceutically acceptable salts or solvates thereof in the preparation of a drug for treating pulmonary hypertension, wherein R1 is C 1-4 alkyl, such as selected from -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3.

[0005] The present invention also provides a method for treating pulmonary hypertension by using a compound of formula I its stereoisomers, pharmaceutically acceptable salts or solvates thereof, characterized in that a therapeutically effective amount of the compound of formula I, its stereoisomers, pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing the compound of formula I, its stereoisomers, pharmaceutically acceptable salts or solvates thereof is administered to a patient in need, wherein R1 is C1-4 An alkyl group, for example, selected from -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3.

[0006] In some embodiments of the present invention, the compound of formula I is selected from compounds having the following structures:

[0007]

[0008] The compound of formula I of the present invention, its stereoisomers, pharmaceutically acceptable salts or solvates thereof can be prepared by referring to the method in Chinese Patent ZL202311595446.9.

[0009] The present invention also provides a pharmaceutical composition for treating or preventing pulmonary hypertension, which comprises the compound of formula I of the present invention Its stereoisomers, pharmaceutically acceptable salts or solvates thereof as active ingredients, and optionally further contains one or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carriers are various excipients commonly used or known in the pharmaceutical field, including but not limited to: diluents, binders, antioxidants, pH regulators, preservatives, lubricants, disintegrants, etc. The definition of the compound of formula I is as described above.

[0010] The pharmaceutical composition can be administered in combination with other therapeutic agents or supportive therapies, or formulated into a combined drug, or the pharmaceutical composition can further contain other therapeutic agents. The other therapeutic agents are other drugs for treating pulmonary hypertension, etc.

[0011] The present invention also provides the use of the compound of formula I Its stereoisomers, pharmaceutically acceptable salts or solvates and other drugs for treating pulmonary hypertension in the preparation of a drug for treating pulmonary hypertension. The definition of the compound of formula I is as described above.

[0012] The present invention also provides the use of the compound of formula I Its stereoisomers, pharmaceutically acceptable salts or solvates in the preparation of a drug for treating pulmonary hypertension in combination with other drugs for treating pulmonary hypertension. The definition of the compound of formula I is as described above.

[0013] The dosage form of the pharmaceutical composition can be in the form of an oral preparation, such as tablets, capsules, pills, powders, granules, suspensions, syrups, etc.; or it can also be a dosage form for injection, such as injection solutions, powder for injection, etc., and is administered by injection through intravenous, intraperitoneal, subcutaneous or intramuscular routes. All the dosage form forms used are well-known to those of ordinary skill in the pharmaceutical field.

[0014] The administration routes of the pharmaceutical composition include, but are not limited to: oral; buccal; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous; by implantation of a depot or reservoir.

[0015] According to the present invention, other drugs or supportive therapies for treating pulmonary hypertension include, but are not limited to: prostacyclin and its derivatives (e.g., epoprostenol, treprostinil, and iloprost); prostacyclin receptor agonists (e.g., selexipag); endothelin receptor antagonists (e.g., sitaxentan (thelin), ambrisentan, macitentan, and bosentan); calcium channel blockers (e.g., amlodipine, diltiazem, and nifedipine); anticoagulants (e.g., warfarin); diuretics; oxygen therapy; atrial septostomy; pulmonary thromboendarterectomy; phosphodiesterase-5 inhibitors (e.g., sildenafil and tadalafil); activators of soluble guanylate cyclase (e.g., cinaciguat and riociguat); ASK-1 inhibitors (e.g., CIIA; SCH79797; GS-4997; MSC2032964A; 3H-naphtho[1,2,3-de]quinoline-2,7-dione, NQDI-1; 2-thioxo-thiazolidine, 5-bromo-3-(4-oxo-2-thioxo-thiazolidin-5-ylidene)-1,3-dihydro-indol-2-one); NF-κB antagonists (e.g., dh404, CDDO-epoxide; 2.2-difluoropropionamide; C28 imidazole (CDDO-Im); 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO); 3-acetyl oleanolic acid; 3-trifluoroacetyl oleanolic acid; 28-methyl-3-acetyl oleanane; 28-methyl-3-trifluoroacetyl oleanane; 28-methoxy oleanolic acid; SZC014; SCZ015; SZC017; derivatives of oleanolic acid with polyethylene glycol added; 3-O-(β-D-glucopyranosyl) oleanolic acid; 3-O-[β-D-glucopyranosyl-(1-->3)-β-D-glucopyranosyl] oleanolic acid; 3-O-[β-D-glucopyranosyl-(1-->2)-β-D-glucopyranosyl] oleanolic acid; 3-O-[β-D-glucopyranosyl-(1-->3)-β-D-glucopyranosyl] oleanolic acid 28-O-β-D-glucopyranosyl ester; 3-O-[β-D-glucopyranosyl-(1-->2)-β-D-glucopyranosyl] oleanolic acid 28-O-β-D-glucopyranosyl ester; 3-O-[α-L-rhamnopyranosyl-(1-->3)-β-D-glucuronopyranosyl] oleanolic acid; 3-O-[α-L-rhamnopyranosyl-(1-->3)-β-D-glucuronopyranosyl] oleanolic acid 28-O-β-D-glucopyranosyl ester; 28-O-β-D-glucopyranosyl-oleanolic acid; 3-O-β-D-glucopyranosyl(1→3)-β-D-glucuronide (CS1); oleanolic acid 3-O-β-D-glucopyranosyl(1→3)-β-D-glucuronide (CS2); methyl 3,11-dioxoolean-12-ene-28-oate (DIOXOL); ZCVI4-2; 3-dehydroxy-1,2,5-diazolo[3',4':2,3] oleanolic acid benzyl ester); lung and / or heart transplantation.

[0016] In certain aspects according to the present invention, the treatment of pulmonary arterial hypertension refers to treating, preventing or reducing the progression rate and / or severity of pulmonary arterial hypertension (e.g., treating, preventing or reducing the progression rate and / or severity of one or more complications of pulmonary arterial hypertension).

[0017] In some embodiments of the present invention, the pulmonary arterial hypertension is arterial pulmonary hypertension, including idiopathic, hereditary, drug- and toxin-induced pulmonary arterial hypertension, disease-related pulmonary arterial hypertension (including connective tissue disease-related PAH, portal hypertension-related PAH, HIV-related PAH, etc.), PAH with pulmonary vein or capillary involvement, persistent pulmonary hypertension of the newborn.

[0018] In some embodiments of the present invention, the pulmonary hypertension is pulmonary hypertension caused by left heart diseases: the left heart diseases include left ventricular systolic or diastolic dysfunction, valvular heart disease, congenital heart disease, etc.

[0019] In some embodiments of the present invention, the pulmonary hypertension is pulmonary hypertension caused by hypoxia and / or lung diseases: for example, caused by chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep disordered breathing, long-term residence in high altitude environment, etc.

[0020] In some embodiments of the present invention, the pulmonary hypertension is pulmonary hypertension caused by chronic thromboembolic pulmonary hypertension and other pulmonary obstructive diseases: for example, pulmonary hypertension caused by intravascular tumors, arteritis, etc.

[0021] In some embodiments of the present invention, the pulmonary hypertension is pulmonary hypertension of unknown and / or multifactorial origin: for example, caused by hematological diseases (chronic hemolytic anemia, myelodysplastic syndrome, etc.), systemic diseases (sarcoidosis, etc.), metabolic diseases.

[0022] According to the present invention, in certain aspects of the present invention, treating, preventing or reducing the progression rate and / or severity of pulmonary hypertension (for example, treating, preventing or reducing the progression rate and / or severity of one or more complications of pulmonary hypertension), wherein the patient has a resting pulmonary artery pressure (PAP) of at least 25 mmHg (for example, 25, 30, 35, 40, 45 or 50 mmHg).

[0023] In some embodiments, the treating, preventing or reducing the progression rate and / or severity of pulmonary hypertension (for example, treating, preventing or reducing the progression rate and / or severity of one or more complications of pulmonary hypertension) is to adjust one or more hemodynamic parameters of a patient with pulmonary hypertension to a more normal level (for example, normal compared to healthy people of similar age and gender).

[0024] In some embodiments, adjusting the hemodynamic parameters to a more normal level means reducing the PAP, for example, reducing the patient's PAP by at least 3 mmHg, at least 4 mmHg, at least 5 mmHg, at least 6 mmHg, at least 7 mmHg, at least 8 mmHg, at least 9 mmHg, at least 10 mmHg, at least 12 mmHg, at least 15 mmHg, at least 20 mmHg, at least 25 mmHg, etc.

[0025] In some embodiments, adjusting the hemodynamic parameters to a more normal level means reducing the pulmonary vascular resistance (PVR).

[0026] In some embodiments, adjusting the hemodynamic parameter to a more normal level refers to increasing the pulmonary capillary wedge pressure (PCWP).

[0027] In some embodiments, adjusting the hemodynamic parameter to a more normal level refers to increasing the left ventricular end-diastolic pressure (LVEDP).

[0028] In some embodiments, adjusting the hemodynamic parameter to a more normal level refers to increasing the pulmonary acceleration time (PAT).

[0029] In some embodiments, adjusting the hemodynamic parameter to a more normal level refers to increasing the ratio of the pulmonary acceleration time (PAT) to the pulmonary ejection time (PET).

[0030] In some embodiments, treating, preventing, or reducing the rate of progression and / or severity of pulmonary hypertension (e.g., treating, preventing, or reducing the rate of progression and / or severity of one or more complications of pulmonary hypertension) is treating, preventing, or reducing the rate of progression and / or severity of cell proliferation in the pulmonary arteries of a patient with pulmonary hypertension. In some embodiments, the rate of progression and / or severity of cell proliferation in the pulmonary arteries is the rate of progression and / or severity of smooth muscle and / or endothelial cell proliferation in the pulmonary arteries. In some embodiments, the rate of progression and / or severity of cell proliferation in the pulmonary arteries is the rate of progression and / or severity of angiogenesis in the pulmonary arteries.

[0031] In some embodiments, treating, preventing, or reducing the rate of progression and / or severity of pulmonary hypertension (e.g., treating, preventing, or reducing the rate of progression and / or severity of one or more complications of pulmonary hypertension) is increasing the physical activity of a patient with pulmonary hypertension.

[0032] The improvement in physical activity can be measured using any suitable measure of exercise capacity. For example, exercise capacity in the 6-minute walk test (6MWT), which measures how far a subject can walk in 6 minutes, i.e., the 6-minute walk distance (6MWD), is often used to assess the severity of pulmonary hypertension and disease progression. The Borg dyspnea index (BDI) is a numerical scale used to assess perceived dyspnea (breathing discomfort). It measures the degree of dyspnea, e.g., after completion of the 6MWT, where a BDI of 0 indicates no shortness of breath and a BDI of 10 indicates maximal shortness of breath.

[0033] In some embodiments, increasing the physical activity of a patient with pulmonary hypertension is increasing their 6MWD by at least 10 meters, at least 15 meters, at least 20 meters, at least 30 meters, at least 40 meters, at least 50 meters, at least 60 meters, at least 70 meters, at least 80 meters, at least 90 meters, at least 100 meters, and the like.

[0034] In some embodiments, increasing the physical activity of a patient with pulmonary hypertension is decreasing their BDI by at least 0.5 index points, at least 1 index point, at least 1.5 index points, at least 2 index points, at least 2.5 index points, at least 3 index points, at least 3.5 index points, at least 4 index points, at least 4.5 index points, at least 5 index points, at least 5.5 index points, at least 6 index points, at least 6.5 index points, at least 7 index points, at least 7.5 index points, at least 8 index points, at least 8.5 index points, at least 9 index points, at least 9.5 index points, and the like.

[0035] In some embodiments, treating, preventing, or reducing the rate of progression and / or severity of pulmonary hypertension (e.g., treating, preventing, or reducing the rate of progression and / or severity of one or more complications of pulmonary hypertension) is treating, preventing, or reducing the rate of progression and / or severity of dyspnea in a patient with pulmonary hypertension.

[0036] In some embodiments, treating, preventing, or reducing the rate of progression and / or severity of pulmonary hypertension (e.g., treating, preventing, or reducing the rate of progression and / or severity of one or more complications of pulmonary hypertension) is treating, preventing, or reducing the rate of progression and / or severity of chest pain in a patient with pulmonary hypertension.

[0037] In some embodiments, treating, preventing, or reducing the rate of progression and / or severity of pulmonary hypertension (e.g., treating, preventing, or reducing the rate of progression and / or severity of one or more complications of pulmonary hypertension) is treating, preventing, or reducing the rate of progression and / or severity of fatigue in a patient with pulmonary hypertension.

[0038] In some embodiments, treating, preventing, or reducing the rate of progression and / or severity of pulmonary hypertension (e.g., treating, preventing, or reducing the rate of progression and / or severity of one or more complications of pulmonary hypertension) is treating, preventing, or reducing the rate of progression and / or severity of pulmonary fibrosis in a patient with pulmonary hypertension.

[0039] In some embodiments, the treating, preventing or reducing the rate of progression and / or severity of pulmonary arterial hypertension (e.g., treating, preventing or reducing the rate of progression and / or severity of one or more complications of pulmonary arterial hypertension) is treating, preventing or reducing the rate of progression and / or severity of pulmonary vascular remodeling in a patient with pulmonary arterial hypertension.

[0040] In some embodiments, the treating, preventing or reducing the rate of progression and / or severity of pulmonary arterial hypertension (e.g., treating, preventing or reducing the rate of progression and / or severity of one or more complications of pulmonary arterial hypertension) is treating, preventing or reducing the rate of progression and / or severity of right ventricular hypertrophy in a patient with pulmonary arterial hypertension. In some embodiments, treating, preventing or reducing the rate of progression and / or severity of right ventricular hypertrophy in a patient with pulmonary arterial hypertension is reducing the right ventricular free wall thickness (RVFWT).

[0041] In some embodiments, the treating, preventing or reducing the rate of progression and / or severity of pulmonary arterial hypertension (e.g., treating, preventing or reducing the rate of progression and / or severity of one or more complications of pulmonary arterial hypertension) is improving the right ventricular systolic function in a patient with pulmonary arterial hypertension. In some embodiments, the improving right ventricular systolic function is increasing the tricuspid annular plane systolic excursion (TAPSE).

[0042] According to the present invention, pulmonary arterial hypertension at the treatment baseline can be mild, moderate or severe, as measured, for example, by the World Health Organization (WHO) functional class (which is a measure of disease severity in patients with pulmonary arterial hypertension). The WHO functional system is divided into four functional levels: Class I: Pulmonary arterial hypertension that does not cause limitation of physical activity, and ordinary physical activity does not cause excessive dyspnea or fatigue, chest pain or near syncope; Class II: Pulmonary arterial hypertension that causes mild limitation of physical activity, the patient is comfortable at rest, and ordinary physical activity causes excessive dyspnea or fatigue, chest pain or near syncope; Class III: Pulmonary arterial hypertension that causes significant limitation of physical activity, the patient is comfortable at rest, and less than ordinary activity causes excessive dyspnea or fatigue, chest pain or near syncope; Class IV: Pulmonary arterial hypertension that causes inability to perform any physical activity without symptoms, the patient shows signs of right heart failure, and dyspnea and / or fatigue may even be present at rest, and any physical activity increases discomfort.

[0043] In some aspects, the patients in whom the present invention treats, prevents or reduces the progression rate and / or severity of pulmonary hypertension (e.g., treats, prevents or reduces the progression rate and / or severity of one or more complications of pulmonary hypertension) have pulmonary hypertension of WHO Class I, II, III or IV.

[0044] In some embodiments, the patient is a patient with WHO Class I pulmonary hypertension. In some embodiments, the treating, preventing or reducing the progression rate and / or severity of pulmonary hypertension (e.g., treating, preventing or reducing the progression rate and / or severity of one or more complications of pulmonary hypertension) is preventing or delaying the progression of the patient from Class I pulmonary hypertension to Class II pulmonary hypertension.

[0045] In some embodiments, the patient is a patient with WHO Class II pulmonary hypertension. In some embodiments, it is preventing or delaying the progression of the patient from Class II pulmonary hypertension to Class III pulmonary hypertension. In some embodiments, it is promoting or increasing the regression of the patient from Class II pulmonary hypertension to Class I pulmonary hypertension.

[0046] In some embodiments, the patient is a patient with WHO Class III pulmonary hypertension. In some embodiments, it is preventing or delaying the progression of the patient from Class III pulmonary hypertension to Class IV pulmonary hypertension. In some embodiments, it is promoting or increasing the regression of the patient from Class III pulmonary hypertension to Class II pulmonary hypertension. In some embodiments, it is promoting or increasing the regression of the patient from Class III pulmonary hypertension to Class I pulmonary hypertension.

[0047] In some embodiments, the patient is a patient with WHO Class IV pulmonary hypertension. In some embodiments, it is promoting or increasing the regression of the patient from Class IV pulmonary hypertension to Class III pulmonary hypertension. In some embodiments, it is promoting or increasing the regression of the patient from Class IV pulmonary hypertension to Class II pulmonary hypertension. In some embodiments, it is promoting or increasing the regression of the patient from Class IV pulmonary hypertension to Class I pulmonary hypertension. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1In a mouse model of pulmonary hypertension, the cardiac ultrasound results of the control group (Control), the model group (HYSU), and the drug administration group (FV008) are as follows: Among them, A shows the cardiac ultrasound results of the right ventricular free wall thickness (RVFWT); the cardiac ultrasound results of the tricuspid annular plane systolic excursion (TAPSE); the cardiac ultrasound results of the pulmonary artery acceleration time (PAT) and the pulmonary ejection time (PET); B - E show the quantitative analysis diagrams of the right ventricular free wall thickness (RVFWT), the tricuspid annular plane systolic excursion (TAPSE), the pulmonary artery acceleration time (PAT), and the pulmonary artery acceleration time (PAT) / pulmonary ejection time (PET) (***P < 0.001, ****P < 0.001). Detailed implementation manners

[0049] The technical solutions of the present invention will be further described in detail below in combination with specific embodiments. It should be understood that the following embodiments are only for illustrative and explanatory purposes of the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0050] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products or can be prepared by known methods.

[0051] FV008 was prepared according to the method in Chinese invention patent ZL202311595446.9 The NMR data is as follows:

[0052] 1 H NMR(400MHz,CDCl3)δ7.79–7.51(m,4H),7.40(q,J=5.3,4.3Hz,4H),6.91(dd,J=15.9,6.5Hz,1H),6.63(dd,J=10.1,6.0Hz,1H),6.08(d,J=16.2Hz,1H),5.74–5.65(m,1H),3.73(d,J=5.9Hz,3H),3.46(t,J=6.1Hz,2H),2.55(q,J=7.1Hz,2H),1.44(d,J=5.9Hz,6H),1.06(q,J=7.0Hz,3H).

[0053] 1313C NMR (100 MHz, CDCl3) δ 201.23, 190.68, 155.49, 155.27, 144.39, 143.20, 135.16, 131.88, 130.80, 130.55, 130.31, 128.95, 128.48, 126.07, 125.22, 121.75, 116.60, 114.74, 77.24, 63.60, 33.14, 32.61, 28.22, 8.12.

[0054] Experimental Study on the Therapeutic Effect of FV008 in a Mouse Model of Pulmonary Hypertension

[0055] 1.1 Experimental Procedures

[0056] Mouse Model for the Treatment of Pulmonary Hypertension

[0057] Procedure for establishing the mouse model for the treatment of pulmonary hypertension: 30 male inbred C57BL / 6JNifdc mice aged 6 - 8 weeks were randomly divided into three groups, namely the Control group, the HYSU group, and the drug - administration group, with 10 animals in each group. SU5416 was dissolved in DMSO and intraperitoneally injected into the mice in the HYSU group and the drug - administration group once a week (20 mg / kg). At the same time, the mice in the HYSU group and the drug - administration group were placed in a hypoxic chamber (oxygen partial pressure 10%) for continuous hypoxia. The above treatment lasted for 21 days. After the treatment, each mouse in the drug - administration group was intragastrically administered FV008 at a dose of 50 mg / kg per day under normoxia for 7 consecutive days. In the first 3 weeks, when the Control group was injected with SU5416, an equal volume of DMSO was intraperitoneally injected. In the following 7 days, when the drug - administration group was intragastrically administered FV008, the HYSU group and the Control group were intraperitoneally injected with an equal volume of PBS.

[0058] 1.2 Experimental Results

[0059] FV008 Can Effectively Alleviate Right Ventricular Function Injury and Improve Hemodynamic Parameters in a Mouse Model of Pulmonary Hypertension

[0060] The right ventricular free wall thickness (RVFWT) reflects right ventricular hypertrophy in mice, the tricuspid annular plane systolic excursion (TAPSE) reflects the right ventricular systolic function in mice, and the pulmonary acceleration time (PAT), pulmonary acceleration time (PAT) / pulmonary ejection time (PET) reflect the right ventricular afterload function in mice.

[0061] The above indicators of mice were detected using a high-resolution in vivo imaging system (High-Resolution In Vivo Imaging System).

[0062] The experimental results are as Figure 1 shown: Compared with the control group, the right ventricular free wall thickness (RVFWT) of mice in the HYSU group increased significantly, the tricuspid annular plane systolic excursion (TAPSE) decreased significantly, the pulmonary artery acceleration time (PAT) and the ratio of pulmonary artery acceleration time (PAT) / pulmonary ejection time (PET) decreased significantly; compared with the HYSU group, the right ventricular free wall thickness (RVFWT) of the FV008 administration group decreased significantly, the tricuspid annular plane systolic excursion (TAPSE) increased significantly, the pulmonary artery acceleration time (PAT) and the ratio of pulmonary artery acceleration time (PAT) / pulmonary ejection time (PET) increased significantly. The results indicate that FV008 treatment can effectively relieve right ventricular hypertrophy, right ventricular function injury, and hemodynamic parameters in an animal model of pulmonary hypertension.

[0063] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

Use of a compound of formula I, its stereoisomers, pharmaceutically acceptable salts or solvates in the preparation of a medicament for the treatment of pulmonary hypertension: Among them, R1 is C 1-4 alkyl group.

2. The use according to claim 1, wherein the compound of formula I is selected from compounds having the following structures:

3. The use according to claim 1 or 2, characterized in that: The pulmonary hypertension is arterial pulmonary hypertension, pulmonary hypertension caused by left heart disease, pulmonary hypertension caused by hypoxia and / or lung diseases, chronic thromboembolic pulmonary hypertension and pulmonary hypertension caused by other pulmonary obstructive diseases, pulmonary hypertension of unknown and / or multifactorial origin.

4. The use according to claim 1 or 2, characterized in that: The treatment of pulmonary hypertension means treating, preventing or reducing the progression rate and / or severity of pulmonary hypertension; Preferably, the treatment of pulmonary hypertension is to adjust one or more hemodynamic parameters of a patient with pulmonary hypertension to a more normal level; preferably, adjusting the hemodynamic parameters to a more normal level means increasing the pulmonary acceleration time (PAT); preferably, adjusting the hemodynamic parameters to a more normal level means increasing the ratio of pulmonary acceleration time (PAT) / pulmonary ejection time (PET); Preferably, the treatment of pulmonary hypertension is to treat, prevent or reduce the progression rate and / or severity of dyspnea in patients with pulmonary hypertension; Preferably, the treatment of pulmonary hypertension is to treat, prevent or reduce the progression rate and / or severity of chest pain in patients with pulmonary hypertension; Preferably, the treatment of pulmonary hypertension is to treat, prevent or reduce the progression rate and / or severity of fatigue in patients with pulmonary hypertension; Preferably, the treatment of pulmonary hypertension is to treat, prevent or reduce the progression rate and / or severity of right ventricular hypertrophy in patients with pulmonary hypertension; preferably, reducing the right ventricular free wall thickness (RVFWT) of the patient; Preferably, the treatment of pulmonary hypertension is to improve the right ventricular systolic function of patients with pulmonary hypertension; preferably, the improvement of right ventricular systolic function is to increase the tricuspid annular plane systolic excursion (TAPSE).

5. The use according to any one of claims 1 or 2, characterized in that, Patients with pulmonary hypertension have grade I, II, III or IV pulmonary hypertension recognized by WHO; Preferably, the patient is a patient with grade I pulmonary hypertension recognized by WHO; preferably, the treatment of pulmonary hypertension is to prevent or delay the progression of the patient from grade I pulmonary hypertension to grade II pulmonary hypertension; Alternatively, preferably, the patient is a patient with grade II pulmonary hypertension recognized by WHO; preferably, the treatment of pulmonary hypertension is to prevent or delay the progression of the patient from grade II pulmonary hypertension to grade III pulmonary hypertension; preferably, the treatment of pulmonary hypertension is to promote or increase the regression of the patient from grade II pulmonary hypertension to grade I pulmonary hypertension; Alternatively, preferably, the patient is a patient with WHO - recognized grade III pulmonary hypertension; preferably, the treatment of pulmonary hypertension is to prevent or delay the progression of the patient from grade III pulmonary hypertension to grade IV pulmonary hypertension; preferably, the treatment of pulmonary hypertension is to promote or increase the regression of the patient from grade III pulmonary hypertension to grade II pulmonary hypertension; preferably, the treatment of pulmonary hypertension is to promote or increase the regression of the patient from grade III pulmonary hypertension to grade I pulmonary hypertension. Alternatively, preferably, the patient is a patient with WHO - recognized grade IV pulmonary hypertension; preferably, the treatment of pulmonary hypertension is to promote or increase the regression of the patient from grade IV pulmonary hypertension to grade III pulmonary hypertension; preferably, the treatment of pulmonary hypertension is to promote or increase the regression of the patient from grade IV pulmonary hypertension to grade II pulmonary hypertension; preferably, the treatment of pulmonary hypertension is to promote or increase the regression of the patient from grade IV pulmonary hypertension to grade I pulmonary hypertension.

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