Application of compound in preparation of medicine for preventing and / or treating pulmonary arterial hypertension
The inhibition of PDE4B activity by compound formula I and combining with other pharmaceutical compositions, the problem of the lack of cure regimens for the treatment of pulmonary hypertension and adverse reactions of PDE4 inhibitors has been solved, effectively treating and preventing pulmonary hypertension and reducing relevant indicators.
Patent Information
- Application Number
- CN202510410167.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-02
- Publication Date
- 2025-07-04
AI Technical Summary
The existing drugs for treating pulmonary hypertension are mainly vasodilators, and there is a lack of cure plans. PDE4 inhibitors have adverse gastrointestinal reactions, resulting in narrowing of the treatment window and limiting their clinical application.
Compound formula I and its pharmaceutically acceptable salts are provided, which prevent the hydrolysis of cAMP by inhibiting PDE4B activity, and are used to prepare drugs for preventing and treating pulmonary hypertension, combined with compositions such as PDE5 inhibitors, endothelin receptor antagonists, prostacyclin drugs, and the like, and are preferred in the form of controlled release formulations.
Effectively reduce the acceleration time of the pulmonary artery systolic period, right ventricular systolic pressure, right heart hypertrophy index, pulmonary vascular media thickness and right ventricular anterior wall thickness, improve the symptoms of pulmonary artery hypertension, and reduce adverse reactions.
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Figure CN120241680A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceutical technology, and particularly to the use of a compound in the preparation of a drug for preventing and / or treating pulmonary arterial hypertension. Background Art
[0002] Pulmonary arterial hypertension (PAH) is a pathophysiological state in which the pulmonary artery pressure is abnormally elevated due to various known or unknown reasons. At present, the drugs for treating PAH mainly target the prostacyclin pathway, the endothelin pathway, and the nitric oxide (NO) pathway. Although these drugs have improved the prognosis and slowed down the progression of PAH, they are vasodilators and do not provide a cure.
[0003] Phosphodiesterases (PDEs) have the function of hydrolyzing intracellular second messengers [cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP)], degrading intracellular cAMP or cGMP, and thus terminating the biochemical effects transmitted by these second messengers. Among them, PDE4 inhibitors such as Rolipram, Denbufylline, CDP840, CP80633, Ro20 1724, etc. may become new anti-inflammatory drugs. The development of selective PDE4 subtype inhibitors will probably enhance the efficacy and reduce the adverse reactions. A series of derivatives of the new and potent PDE4 inhibitor 1-pyridy|naph—thalene show good pharmacodynamic effects and few adverse reactions in vomiting and cardiovascular aspects. PDE4 inhibitors have been reported to have the potential to be used in the treatment of adult class I PAH, idiopathic PAH (IPAH), and CTD-PAH, improve exercise ability, and delay clinical deterioration by inhibiting the migration of smooth muscle cells and reversing pulmonary vascular remodeling. When PDE4 is inhibited, the concentration of cAMP is up-regulated, which will lead to the nuclear translocation of NF-xB and the down-regulation of the levels of intracellular inflammatory factors (such as TNF-4, IL-1β, and IL-6, etc.), and then relieve inflammation and reduce apoptosis. It has been used in the research of various diseases, such as asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, pulmonary arterial hypertension, psoriasis, Alzheimer's disease, schizophrenia, Parkinson's syndrome, depression, etc. Clinical studies have found that PDE4 inhibitors show good therapeutic potential in many disease fields such as cognitive and emotional disorders, autoimmune diseases, respiratory diseases, and cancer. However, due to their common gastrointestinal adverse reactions, the treatment window is narrow, resulting in limited clinical development. Therefore, the research on the development of specific subtype inhibitors for the adverse reactions caused by PDE4 inhibitors has important clinical and scientific significance. Summary of the Invention
[0004] The present invention aims to solve at least one of the above-mentioned technical problems in the prior art. To this end, the object of the present invention is to provide the use of a compound in the preparation of a medicament for preventing and / or treating pulmonary hypertension.
[0005] To achieve the above object, the technical solution adopted by the present invention is as follows:
[0006] In the first aspect of the present invention, there is provided the use of a compound of formula I, or its deuterated compound, or its pharmaceutically acceptable salt in the preparation of a medicament for preventing and / or treating pulmonary hypertension:
[0007] wherein, R is isopropyl or cyclopentyl.
[0008] In some embodiments of the present invention, the compound of formula I is selected from the compound of formula I-1 and the compound of formula I-2:
[0009]
[0010] In the present invention, the chemical name of the compound of formula I-1 is 1-(3-(ethylamino)-4-methoxyphenyl)-3-methylbutan-1-one (denoted as P9J1), and the chemical name of the compound of formula I-2 is cyclopentyl(3-(ethylamino)-4-methoxyphenyl)methanone (denoted as P9J2).
[0011] In some embodiments of the present invention, the medicament reduces the activity of PDE4B in the body cells and / or prevents the binding of the PDE4B molecule to its specific catalytic substrate cAMP.
[0012] In some embodiments of the present invention, the PDE4B activity includes the ability of PDE4B to catalyze the chemical reaction of hydrolyzing cAMP.
[0013] In some embodiments of the present invention, the effective dosage of the compound of formula I, or its deuterated compound, or its pharmaceutically acceptable salt in the medicament is 0.005 - 0.5 mg / kg / d, such as 0.01 - 0.4 mg / kg / d, 0.05 - 0.3 mg / kg / d, 0.08 - 0.25 mg / kg / d, 0.1 - 0.2 mg / kg / d, 0.12 - 0.18 mg / kg / d, 0.15 mg / kg / d. The preferred effective dosage for the human body in the present invention is 0.15 mg / kg / d calculated according to the body weight of 70 kg for a human.
[0014] In some embodiments of the present invention, the pulmonary hypertension is primary pulmonary hypertension or secondary pulmonary hypertension.
[0015] In some embodiments of the present invention, the pulmonary hypertension includes arterial pulmonary hypertension (such as idiopathic pulmonary hypertension, heritable pulmonary hypertension, pulmonary hypertension caused by drugs and poisons, or persistent pulmonary hypertension of the newborn), pulmonary hypertension caused by left heart diseases (such as pulmonary hypertension caused by systolic heart insufficiency, diastolic heart insufficiency, or valvular heart disease), pulmonary hypertension caused by lung diseases (such as pulmonary hypertension caused by chronic obstructive pulmonary disease, pulmonary hypertension caused by emphysema, or pulmonary hypertension caused by interstitial lung disease), pulmonary hypertension caused by hypoxia (such as pulmonary hypertension caused by sleep apnea syndrome, pulmonary hypertension caused by chronic mountain sickness such as high altitude heart disease), chronic thromboembolic pulmonary hypertension, obstructive pulmonary hypertension, or pulmonary hypertension of unknown multiple factors.
[0016] In some embodiments of the present invention, the prevention and / or treatment of pulmonary hypertension includes one or more of 1) to 6):
[0017] 1) Increasing the pulmonary artery systolic acceleration time / pulmonary artery systolic ejection time;
[0018] 2) Decreasing the right ventricular systolic pressure;
[0019] 3) Decreasing the right ventricular hypertrophy index;
[0020] 4) Decreasing the pulmonary vascular medial thickness;
[0021] 5) Decreasing the right ventricular anterior wall thickness;
[0022] 6) Decreasing the right ventricular internal diameter.
[0023] In a second aspect of the present invention, there is provided a composition for preventing and / or treating pulmonary hypertension, comprising a first component and a second component; the first component comprises a compound of formula I, or a deuterated compound thereof, a pharmaceutically acceptable salt thereof; the second component comprises one or more of a PDE5 inhibitor, an endothelin receptor antagonist, a prostacyclin drug, a prostacyclin receptor agonist, and a guanylate cyclase agonist.
[0024] In some embodiments of the present invention, the PDE5 inhibitor includes at least one of Sildenafil, Vardenafil, Tadalafil, or Avanafil.
[0025] In some embodiments of the present invention, the prostacyclin drug includes at least one of Benapnost, Treprostinil, iloprost, or Ventavis.
[0026] In some embodiments of the present invention, the endothelin receptor antagonist is bosentan.
[0027] In some embodiments of the present invention, the drug further comprises a pharmaceutically acceptable excipient.
[0028] In some embodiments of the present invention, the pharmaceutically acceptable excipient comprises at least one of a filler, a disintegrant, a diluent, a lubricant, a binder, a wetting agent, a flavoring agent, a suspending agent, a solvent, a sustained-release agent, an emulsifier, a vegetable oil, an absorption enhancer, a surfactant or a preservative.
[0029] In some embodiments of the present invention, the filler is selected from starch, sucrose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose or glucose, etc.; the binder is selected from cellulose derivatives, alginates, starch, water, dextrin, gelatin, hydroxypropyl cellulose, methyl cellulose or polyvinylpyrrolidone, etc.; the diluent is selected from at least one of lactose, sucrose, mannitol, corn starch, potato starch, calcium phosphate, calcium citrate and crystalline cellulose; the disintegrant is selected from at least one of corn starch, potato starch, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, calcium carboxymethyl cellulose and alginic acid; the lubricant is selected from at least one of stearic acid, polyethylene glycol, calcium carbonate, sodium bicarbonate, colloidal silica, talc, anhydrous silica and magnesium stearate: the suspending agent is selected from at least one of colloidal silica, beeswax, cellulose, sodium carboxymethyl cellulose and solid polyethylene glycol: the wetting agent is selected from at least one of glycerol, Tween-80, oxyhydrogenated castor oil, sodium dodecyl sulfate and lecithin: the solvent is selected from at least one of water, ethanol, liquid polyethylene glycol, isopropanol, Tween-80, glycerol, propylene glycol and vegetable oil, and the vegetable oil is selected from rapeseed oil, beeswax, soybean oil, castor oil, peanut oil, blended oil, etc.: the surfactant is selected from at least one of sodium dodecylbenzenesulfonate, stearic acid, polyoxyethylene-polyoxypropylene copolymer, sorbitan fatty acid ester and polysorbate (Tween): the flavoring agent is selected from at least one of aspartame, sucralose, essence, steviol glycoside, acesulfame potassium, citric acid and sodium saccharin; the preservative is selected from at least one of methyl paraben or propyl paraben.
[0030] In some embodiments of the present invention, the dosage form of the drug includes any one of decoction, tablet, capsule, granule, pill, oral liquid, powder, plaster or injection.
[0031] The oral preparation of the present invention is preferably used in the form of a controlled-release preparation. The injection of the present invention is preferably formulated in a form suitable for parenteral administration, more preferably formulated in the form of a sterile solution suitable for intravenous or intramuscular administration.
[0032] There is no special limitation on the preparation method of the oral preparation or injection of the drug of the present invention, and conventional preparation methods can be adopted. The present invention preferably prepares the drug by using the methods disclosed in Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams and Wilkins).
[0033] The present invention provides a method for preventing and / or treating pulmonary arterial hypertension in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a deuterated compound thereof, a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound of formula I, or a deuterated compound thereof, a pharmaceutically acceptable salt thereof.
[0034] As used herein, the term "prevention" means administering a compound of formula I of the present invention, or a deuterated compound thereof, a pharmaceutically acceptable salt thereof, before a subject exhibits one or more symptoms of a related disease to prevent the occurrence of the disease or symptoms, or to alleviate the disease or symptoms, or to slow the progression of the disease or symptoms.
[0035] As used herein, the term "treatment" means administering a compound of formula I of the present invention, or a deuterated compound thereof, a pharmaceutically acceptable salt thereof, when a subject exhibits one or more symptoms of a related disease to (i) inhibit the disease or symptoms; (ii) alleviate the disease or symptoms; (iii) slow the progression of the disease or symptoms; and / or (iv) cause the disease or symptoms to subside.
[0036] The beneficial effects of the present invention are:
[0037] The compound of formula I in the present invention can improve indexes such as pulmonary artery systolic acceleration time / pulmonary artery systolic ejection time, right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary vascular media thickness, right ventricular anterior wall thickness (RVAW), right ventricular internal diameter (RVID) of pulmonary arterial hypertension. Detailed Description of the Invention
[0038] The content of the present invention will be further described in detail below through specific examples. The raw materials, reagents or devices used in the examples and comparative examples can be obtained from conventional commercial channels or can be obtained by methods of the prior art without special description. Unless otherwise specified, the test or testing methods are conventional methods in the art.
[0039] Example 1
[0040] In this example, the effect of compound P9J1 on mice with pulmonary hypertension was tested. The specific process was as follows:
[0041] 1 Experimental method
[0042] 1.1 Model establishment, grouping and administration
[0043] Ten C57BL / 6 mice were randomly divided into a normal control group (Control, n = 10), a model group (Hypoxia, n = 10), a P9J1 group (n = 10), a positive drug group (n = 10), and a PDE4B KO group (n = 10) (using the Cre-loxP system combined with the CRISPR / Cas9 technology to construct endothelial conditional knockout mice of Pde4B, that is, KO PDE4B KO mice, and C57BL / 6 mice were used as control gene mice. The model establishment method was the same as that of the model group mice, and they were given the same amount of solvent intervention for 4 weeks). The mice in the model group were exposed to hypoxia (10 v% O2, 90 v% N2) and maintained a 12 h / 12 h dark / light cycle for 4 weeks, and freely obtained water and food to induce pulmonary hypertension (the success of model establishment was indicated by the differences in indicators such as RVSP, RVID, RVAW, and RVHI compared with the Control group). The P9J1 group and the positive drug sildenafil group were respectively given P9J1 and sildenafil under the same hypoxia exposure conditions. P9J1 (0.1 mg·kg -1 ·d -1 ·21 d) and sildenafil (100 mg·kg -1 ·d -1 ·21 d) were administered by gavage for 4 weeks. The Control group and the hypoxia group were kept in a normal oxygen clean environment and given the same amount of solvent intervention for 4 weeks.
[0044] 1.2 Echocardiogram detection method
[0045] Using the 30MHz transducer provided by the small animal ultrasound instrument, transthoracic echocardiography was performed on mice. Each group of mice was successively placed in an anesthesia induction box and anesthetized with 2% isoflurane. The instrument flow rate was adjusted to 1.5L / min. After successful anesthesia, the anesthetic gas flow in the induction box was quickly turned off, the mask ventilation was turned on, and the isoflurane flow rate was adjusted to 1.5L / min for maintenance. The mice were fixed on the mouse carrier board, the face mask was connected, the chest was shaved, conductive paste was applied to the four limbs, and ultrasonic coupling agent was applied to the chest. The MS-400 ultrasonic probe was selected, the probe was fixed on the bracket, and the position was adjusted. The long axis section of the right ventricle was found in the B-M mode, and the M mode was switched to measure the right ventricular free wall thickness (RVEWT). The probe position was adjusted to the short axis section of the left ventricle, the pulmonary artery was found, the Color mode was switched, and after framing the measurement area, the P\W mode was selected to measure the pulmonary artery blood flow acceleration time (PAT) and the pulmonary artery ejection time (PET) respectively. The change in pulmonary artery pressure of each group was evaluated by the ratio of PAT / PET.
[0046] 1.3 Right ventricular pressure measurement
[0047] After the modeling of each group of mice was completed, echocardiography was used to detect relevant indicators. After the detection was completed, thoracotomy was performed to measure the right ventricular systolic pressure (RVSP), and RVSP was used to replace the pulmonary artery pressure. At the same time, the maximum rate of rise of right ventricular pressure (dP / dt(+)max) was measured using the RM6240E multi-channel physiological signal acquisition and processing system. Each group of mice was successively anesthetized with sodium pentobarbital and tracheally intubated. A 22G tracheal intubation catheter was selected. The mice were fixed on a foam board, the light source was aligned with the center of the trachea in the neck of the mice, the oral cavity of the mice was opened with a hemostatic forceps, the tracheal intubation needle was inserted into the airway of the mice, and a cotton ball was used to judge whether the tracheal intubation catheter was in place. The small animal ventilator was connected, the respiratory rate was adjusted to 100 times / min, the respiratory ratio was 1:1, and the tidal volume was 2. The abdominal cavity was opened, the diaphragm was cut, and the heart was exposed by cutting along both sides of the ribs. A 22G needle was connected to the pressure amplifier and the multi-channel physiological acquisition system, inserted into the right ventricle and recorded for 10 minutes. After the recording was completed, the mice were immediately sacrificed by cervical dislocation for tissue sampling and standby.
[0048] 1.4 Right ventricular hypertrophy index
[0049] After the right ventricular pressure measurement was completed, the mice were euthanized by cervical dislocation, and the heart and lungs were taken for further examination. The right ventricular hypertrophy index (RVHI) was measured. RVHI = right ventricular free wall mass / (left ventricular + interventricular septum mass). The taken heart was rinsed with PBS to remove residual blood, the left and right atrial appendages were removed, the right ventricular free wall was cut along the edge of the right ventricle with ophthalmic scissors, the right ventricular free wall was completely removed, and the water was blotted dry with filter paper and weighed. The remaining tissue was the left ventricular and interventricular septum mass.
[0050] 1.5 Observation of the degree of pulmonary artery remodeling
[0051] The right middle and lower lobes of the lung were separated and fixed with 4% paraformaldehyde. Routine paraffin embedding, sectioning, adding xylene solution for clearing, dewaxing with ethanol of gradient concentration to water, and staining with hematoxylin for 5 minutes. Rinsing with distilled water, putting into 75% hydrochloric acid ethanol differentiation solution for several seconds, bluing with 0.6% ammonia water, and rinsing with distilled water. Adding 0.5% eosin for counterstaining, dehydrating with ethanol of gradient concentration. Soaking in xylene for clearing, and mounting with neutral gum. Observation was carried out under a fluorescence microscope. Randomly select 10 distal pulmonary arteries with a diameter of 50 - 150 μm for analysis, calculate the ratio of distal pulmonary artery wall thickness (WT%) and the ratio of pulmonary artery wall area (WA%), WT% = [(outer diameter of the tube - inner diameter of the tube) / outer diameter of the tube] x 100%, WA% = (area of the vascular media / total area of the vascular wall) x 100%. The degree of pulmonary artery remodeling was evaluated by WT% and WA%.
[0052] 2. Experimental results
[0053] 2.1 Comparison and evaluation of RVSP levels and right heart function in mice of each group
[0054] Table 1 Comparison of RVSP levels and right heart function in mice of each group (x±s, n = 10)
[0055] Group RVSP (mmHg) RVID (mm) RVAW (mm) RVHI Control group 18.50±1.28 1.95±0.18 0.20±0.01 0.19±0.01 Model group 34.98±1.30* 1.38±0.11* 0.39±0.03* 0.46±0.03* Sildenafil group 30.35±1.89*# 1.57±0.14*# 0.29±0.02*# 0.37±0.03*# P9J1 group 21.90±1.09##ΔΔ 1.82±0.14#Δ 0.22±0.01##Δ 0.25±0.02##Δ <![CDATA[PDE4B KO > 24.90±0.98##ΔΔ 1.61±0.11#Δ 0.27±0.02##Δ 0.31±0.03##Δ
[0056] Note: Compared with the Control group, *, p < 0.05. Compared with the model group, #, p < 0.05; ##, p < 0.01. Compared with the sildenafil group, Δ, p < 0.05; ΔΔ, p < 0.01.
[0057] In this example, compared with the Control group, the right ventricular systolic pressure (RVSP), right ventricular anterior wall thickness (RVAW), and right ventricular hypertrophy index (RVHI) in the model group were significantly increased, and the right ventricular internal diameter (RVID) was significantly decreased, with statistically significant differences (P < 0.01). Compared with the model group, in the drug administration groups, the positive drug sildenafil group and P9J1 significantly improved the RSVP level and heart function-related indicators (P < 0.01), and the results were statistically significant.
[0058] 2.2 Evaluation of pulmonary vascular remodeling in mice of each group
[0059] Compared with the control group, the WT% and WA% of the rats in the model group were significantly increased (P < 0.01). Compared with the model group, the sildenafil group and P9J1 significantly decreased, and P9J1 was superior to the sildenafil group, with statistical significance (P < 0.05, P < 0.01).
[0060] Table 2 WT% and WA% of distal pulmonary arteries in mice of each group (x±s, n = 10)
[0061] Group WT% WA% Control group 22.15±2.31 19.92±2.73 Model group 44.98±3.27* 48.54±3.92* Sildenafil group 35.87±3.19*## 36.05±4.23*# P9J1 group 25.07±2.98##ΔΔ 22.41±3.27##ΔΔ <![CDATA[PDE4B ko > 30.21±2.03## 31.64±2.85##
[0062] Note: Compared with the Control group, *, p < 0.05. Compared with the model group, #, p < 0.05; ##, p < 0.01. Compared with the sildenafil group, Δ, p < 0.05; ΔΔ, p < 0.01.
[0063] This example shows that compound P9J1 can improve pulmonary arterial hypertension in mice.
[0064] Example 2
[0065] The specific process of this example is as follows:
[0066] 1 Experimental method
[0067] 1.1 Model establishment, grouping and administration
[0068] Thirty 6-week-old male SPF-grade SD rats weighing approximately 180 g were randomly divided into a normal control group (Control, n = 10), a model group 1 (n = 10), a P9J2 group (n = 10), a positive drug sildenafil group (n = 10), and a PDE4B group (treated with siRNA, dose 250 nmol / kg body weight, injected once every 3 days, and the siRNA sequences are as follows:
[0069] S: 5'-UUCACCAUCCACAACAACAGUCUUG-3 (SEQ ID NO: 1)
[0070] A: 5'-AAGUGGUAGGUGUUGUUGUCAGAA-3' (SEQ ID NO: 2).
[0071] Thirty 6-week-old male SPF-grade SD rats weighing approximately 180 g were used to establish a PAH model by injecting monocrotaline. The specific process of model establishment was as follows: Monocrotaline (MCT) was dissolved in a 2:8 mixture of absolute ethanol and normal saline to prepare a solution with a concentration of 30 mg / mL. Forty male SD rats were randomly divided into a control group (n = 10), a pulmonary arterial hypertension model group (n = 10), a positive drug sildenafil treatment group (n = 10), and a P9J2 group; a PAH model was constructed by single intraperitoneal injection of MCT (65 mg / kg), and the control group was injected with an equal volume of 0.9% sodium chloride solution (60 mg / kg) by single intraperitoneal injection. Compared with the control group, the modeled animals showed cyanosis of the lips and claws, rapid breathing, reduced food intake, increased pulmonary artery pressure, increased RV / (LV + S), and pulmonary vascular remodeling, indicating successful establishment of the PAH model. From the second day, the control group and the model group were intraperitoneally injected with 0.9% sodium chloride every day, the positive drug group was intragastrically administered sildenafil (50 mg·kg -1 ·d -1 ·21d); the P9J2 group was intragastrically administered (0.08 mg·kg-1 ·d -1 ·21d). Measure the body weight of rats in each group daily.
[0072] 1.2 Hemodynamic detection
[0073] On the 28th day after modeling, use echocardiography to detect the pulmonary artery acceleration time (PAAT), right ventricular internal diameter (RVID), and tricuspid annular plane systolic excursion (TAPSE) of rats in each group; after the ultrasonic detection, use a cardiac catheter to measure the right ventricular systolic pressure (RVSP).
[0074] 1.3 Measurement of right ventricular hypertrophy index and detection of lung tissue
[0075] After the pressure measurement, sacrifice the rats in each group, anatomically separate the right ventricle (RV) of the rats from the left ventricle and interventricular septum (LV+S), weigh and calculate the right ventricular hypertrophy index, namely RV / (LV+S). Embed the large lung tissue in paraffin, section it with a thickness of 5 μm, dewax the paraffin sections, stain with HE, and seal with neutral gum. Observe the morphological changes of the small pulmonary arteries under the microscope, including vascular thickness and muscleization.
[0076] 2. Experimental results
[0077] 2.1 Hemodynamics and right ventricular hypertrophy index
[0078] Table 3 Comparison of echocardiogram and hemodynamic indexes of rats in each group
[0079] Group PAAT / ms RVID (mm) TAPSE / mm RVSP (mmHg) RV / (LV+S) Control group 23.80±1.05 2.45±0.12 2.65±0.15 19.50±0.70 0.28±0.012 Model group 16.85±0.88* 3.45±0.22* 2.18±0.17* 46.20±1.10* 0.60±0.025* Sildenafil group 18.30±1.00# 2.85±0.12# 2.35±0.13# 35.30±0.90## 0.39±0.015# P9J2 group 22.70±0.87##Δ 2.48±0.09#Δ 2.64±0.14# 25.80±0.76##ΔΔ 0.30±0.011##Δ <![CDATA[PDE4B ko > 20.15±0.97# 2.73±0.11# 2.45±0.18# 30.37±0.89# 0.38±0.014#
[0080] Note: Compared with the Control group, *, p < 0.05. Compared with the model group, #, p < 0.05; ##, p < 0.01. Compared with the sildenafil group, Δ, p < 0.05; ΔΔ, p < 0.01.
[0081] 2.2 Evaluation of intimal thickening
[0082] Table 4 Results of intimal thickness evaluation
[0083] Group Media thickness Control group 104.85±1.70 Model group 408.20±13.95*** Sildenafil group 255.30±19.10### P9J2 group 138.15±21.00ΔΔ <![CDATA[PDE4B ko > 185.76±22.48##
[0084] Note: Compared with the Control group, ***, p < 0.001. Compared with the model group, ##, p < 0.01; , p < 0.001. Compared with the sildenafil group, Δ, p < 0.05; ΔΔ, p < 0.01.
[0085] In this example, compared with the Control group, the RVID, RVSP, and right ventricular hypertrophy index in the model group were significantly increased, while the PAAT and TAPSE were significantly decreased, and the differences were statistically significant (P<0.01). Compared with the model group, in the drug administration group, the positive drug sildenafil group and P9J2 significantly improved the related indicators such as pulmonary hypertension (P<0.01), and the results were statistically significant.
[0086] The above embodiments are the preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.
Claims
1. Use of a compound of formula I, or its deuterated compound, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing and / or treating pulmonary hypertension: Among them, R is isopropyl or cyclopentyl.
2. The application according to claim 1, characterized in that: The compound of formula I is selected from the compound of formula I-1 and the compound of formula I-2:
3. The application according to claim 1, characterized in that: The medicament reduces the activity of PDE4B in body cells and / or prevents the binding of the PDE4B molecule to its specific catalytic substrate cAMP.
4. The application according to claim 1, wherein: The effective dosage of the compound of formula I, or its deuterated compound, or a pharmaceutically acceptable salt thereof, in the medicament is 0.005 - 0.5 mg / kg / d.
5. The application according to claim 1, characterized in that: The pulmonary hypertension is primary pulmonary hypertension or secondary pulmonary hypertension.
6. The application according to claim 1, characterized in that: The pulmonary hypertension includes arterial pulmonary hypertension, pulmonary hypertension caused by left heart diseases, pulmonary hypertension caused by lung diseases, pulmonary hypertension caused by hypoxia, chronic thromboembolic pulmonary hypertension, obstructive pulmonary hypertension or pulmonary hypertension of unknown multiple factors.
7. The application according to claim 1, characterized in that: The prevention and / or treatment of pulmonary hypertension includes one or more of 1) - 6): 1) Increasing the pulmonary artery systolic acceleration time / pulmonary artery systolic ejection time; 2) Reducing the right ventricular systolic pressure; 3) Reducing the right ventricular hypertrophy index; 4) Reducing the pulmonary vascular medial thickness; 5) Reducing the right ventricular anterior wall thickness; 6) Reducing the right ventricular internal diameter.
8. The application according to claim 1, wherein: The medicament further includes pharmaceutically acceptable excipients.
9. A composition for preventing and / or treating pulmonary hypertension, characterized in that: It includes a first component and a second component; the first component includes a compound of formula I, or its deuterated compound, or a pharmaceutically acceptable salt thereof; the second component includes one or more of a PDE5 inhibitor, an endothelin receptor antagonist, a prostacyclin drug, a prostacyclin receptor agonist and a guanylate cyclase agonist.
10. The composition for preventing and / or treating pulmonary hypertension according to claim 9, characterized in that: The PDE5 inhibitor preferably includes, but is not limited to, at least one of sildenafil, vardenafil, tadalafil or avanafil; and / or, the prostacyclin drug includes at least one of beraprost, treprostinil, iloprost or ventavis; and / or, the endothelin receptor antagonist is bosentan.