CN106265673B - application of a compound - Google Patents

Abstract

The invention relates to a compound, the application of the compound represented by the structural formula (I) of 2-aminopurine (2-Aminopurine, 2-AP) in the treatment of pulmonary arterial hypertension. The 2-aminopurine can be used as the only active ingredient to prepare a drug for treating pulmonary hypertension. The present invention discovers the effect of 2-aminopurine on inhibiting pulmonary hypertension through experimental research, and is especially suitable for treating pulmonary hypertension caused by hypoxemia. New breakthroughs have been made in the study of the pathogenic molecular mechanism of 2-aminopurine and pulmonary hypertension, providing theoretical basis and targets for the screening of new drugs and clinical treatment of secondary pulmonary hypertension.

Description

application of a compound

technical field

The present invention relates to the use of a compound.

Background technique

Pulmonary arterial hypertension (PAH) has complex etiology and is caused by a variety of heart, lung or pulmonary vascular diseases. The pathological features of pulmonary arteriole vascular remodeling and pulmonary artery smooth muscle proliferation. It is manifested by increased pulmonary circulation pressure and resistance, increased right ventricular load, right ventricular insufficiency, and reduced pulmonary blood flow, which can cause a series of clinical manifestations. Pulmonary hypertension often develops progressively during the course of the disease. Increased pulmonary artery vascular tone leads to right heart failure, a disease that seriously threatens human life and health. In particular, patients with idiopathic arterial PAH can only be diagnosed about 2 years after the onset of symptoms, and the natural course of the disease after diagnosis is 2.5-3.4 years. PAH is divided into two types: "primary" and "secondary". Characteristics Classify pulmonary hypertension, which was revised by the American College of Chest Physicians (ACCP) and the European Society of Cardiology (ESC) in 2004. This classification method has guiding significance for the treatment of patients with pulmonary arterial hypertension.

Traditional treatment methods include oxygen inhalation, cardiotonic, diuretic, calcium channel blockers and anticoagulant adjuvant therapeutic agents, etc., which mainly play a role in relieving symptoms. In recent years, the development and promotion of targeted therapy drugs (mainly including prostacyclin drugs, phosphodiesterase-5 inhibitors, endothelin receptor antagonists and newly explored agonists of soluble guanylate cyclase, 5 Treatment methods such as serotonin transporter inhibitors, growth factor inhibitors, Rho kinase inhibitors, etc.) and living donor lung transplantation have greatly improved the prognosis of patients. These drugs can alleviate the symptoms of PAH to a certain extent. The median survival time of patients under treatment is only 2.7 years. Currently, there is still no effective cure for pulmonary hypertension. Therefore, it is particularly important to find new specific therapeutic drugs.

Contents of the invention

In order to solve the problems in the prior art, the object of the present invention is to provide a drug for treating pulmonary hypertension with definite therapeutic effect and low treatment cost.

In order to realize the object of the invention, the technical scheme of the present invention is as follows:

In a first aspect, the present invention provides the application of 2-aminopurine in the preparation of a drug for treating pulmonary hypertension, and the drug for treating pulmonary hypertension is prepared with 2-aminopurine as an active ingredient.

Further, the application uses 2-aminopurine as the only active ingredient to prepare a drug for treating pulmonary hypertension.

Further, the 2-aminopurine is a compound represented by structural formula (I):

It should be noted that the compound 2-aminopurine can be purchased from commercial sources or synthesized by conventional compound synthesis methods in the prior art using commercially available raw materials. After synthesis, it can be further purified by column chromatography, high performance liquid chromatography or crystallization.

Preferably, the drug is an oral preparation. The present invention finds through tests that oral gavage of the drug prepared by the compound represented by the 2-aminopurine structural formula (I) has obvious therapeutic effect on rats suffering from pulmonary hypertension.

The present invention finds through experimental research that the 2-aminopurine and the above compounds have obvious therapeutic effects on animal models of pulmonary hypertension induced by hypoxia and drug induction.

However, it should be noted that the pulmonary hypertension described in the present invention covers pulmonary hypertension caused by known multiple pathogenic mechanisms, such as arterial pulmonary hypertension (including idiopathic, hereditary, caused by drugs and poisons, and neonatal persistent ), pulmonary hypertension associated with left heart disease (including systolic insufficiency, diastolic insufficiency and valvular disease), pulmonary hypertension caused by pulmonary disease or hypoxemia (including chronic obstructive pulmonary disease, pulmonary interstitial disease, Sleep apnea syndrome, chronic altitude sickness), chronic thromboembolic pulmonary hypertension, and pulmonary hypertension caused by other unknown factors, among which, the application effect on pulmonary hypertension caused by hypoxemia is more significant.

The preparation form of the pharmaceutical composition can be any pharmaceutically acceptable dosage form, and these dosage forms include: tablet, sugar-coated tablet, film-coated tablet, enteric-coated tablet, capsule, hard capsule, soft capsule, Oral liquids, buccal preparations, granules, granules, pills, powders, ointments, elixirs, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches agent; preferred oral dosage forms, such as: capsules, tablets, oral liquids, granules, pills, powders, elixirs, ointments, etc. The oral dosage form can contain common excipients, such as binders, fillers, diluents, compressing agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and tablets can be added if necessary. Perform coating. Suitable fillers include cellulose, mannitol, lactose and other similar fillers; suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate; suitable lubricants include, for example, starch Magnesium fatty acid. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

The therapeutically effective dose of the pharmaceutical composition of the present invention is between 0.1-200 mg/kg body weight/day. The preferred effective dosage of the pharmaceutical composition of the present invention is between 1～100mg/kg body weight/day; more preferably between 10～50mg/Kg body weight/day, it is suggested that the preferred dosage of the pharmaceutical composition used in human body The effective dosage is between 0.15-15 mg/kg body weight/day; more preferably 1.5-8 mg/Kg body weight/day. The "therapeutically effective dosage" can be used for single drug or combined drug treatment of related diseases.

The preferred method of using the pharmaceutical composition (medicine) for treating pulmonary hypertension is oral administration, and the preferred dose is 10-50 mg/Kg per day, administered once a day at a fixed time.

The beneficial effects of the present invention are:

The present invention has discovered the effect of 2-aminopurine on inhibiting pulmonary hypertension through experimental research, and has made a new breakthrough in the research on the pathogenic molecular mechanism of 2-aminopurine and pulmonary hypertension, and screened new drugs for preventing and treating secondary pulmonary hypertension. Provide theoretical basis and targets for clinical treatment.

The present invention further confirms the therapeutic effect of the compound represented by the structural formula (I) in 2-aminopurine on pulmonary hypertension, and is especially suitable for treating pulmonary hypertension caused by hypoxemia.

The technical scheme provided by the invention has strong clinical significance and can provide a solid foundation for the optimization of preventive measures and treatment methods for pulmonary hypertension.

Detailed ways

2-Aminopurine (2-Aminopurine, 2-AP) was purchased from Sigma, USA.

Preferred embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that the following examples are given for the purpose of illustration only, and are not intended to limit the scope of the present invention. Those skilled in the art can make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

The experimental methods used in the following examples are conventional methods unless otherwise specified.

The materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

Description of drawings

Fig. 1 is the effect of 2-aminopurine treatment on hypoxia-induced pulmonary hemodynamics and right ventricular hypertrophy in Example 1 of the present invention;

Fig. 2 is the result of the effect of 2-aminopurine treatment on the proportion of the right ventricle of hypoxia-induced rats in Example 1 implemented by the present invention;

Fig. 3 is the result of the effect of 2-aminopurine treatment on hypoxia-induced rat arterial medial wall thickness ratio in Example 1 of the present invention;

Fig. 4 is the result of the effect of 2-aminopurine treatment on the cross-sectional area ratio of the hypoxia-induced rat vessel wall in Example 1 of the present invention.

The influence test of embodiment 2-aminopurine on pulmonary hypertension caused by hypoxia

Male Sprague Dawley (SD) rats were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd., weighing 200 ± 20 g, and randomly divided into 5 groups (10 rats in each group) (common feed was purchased from the Academy of Military Sciences, and mice ate freely. ). The first group of normal oxygen control group, the second group of hypoxia model control group, the third group of hypoxia model dissolution control group, the fourth group of 2-aminopurine low-dose group (10mg/kg/d), the fifth group of 2-aminopurine Purine high dose group (50mg/kg/d). Rats in the normal control group were fed in a normal pressure and oxygen (21% O ₂ ) environment, and the rest of the groups were placed in a normal pressure hypoxic chamber (oxygen concentration 11% O ₂ ) for continuous hypoxia for 6 weeks. The 2-aminopurine treatment groups (the fourth group and the fifth group) were administered intragastrically once a day after 2 weeks from the start of modeling, and lasted for 4 weeks. The normoxia control group and the model control group (group 2 and group 3) were intragastrically administered an equal amount of solvent before each hypoxia two weeks after the start of modeling as a control.

1. Determination of hemodynamic indicators: insert a polyethylene plastic microcatheter filled with heparin solution (0.9% sodium chloride solution + heparin 10U/m1) from the right external jugular vein of the rat, and connect the other end of the catheter with a miniature pressure sensor Continuously monitor pressure changes. Under the guidance of the pressure waveform, the catheter enters the right atrium, tricuspid valve orifice, right ventricle (RV) through the superior vena cava, and finally enters the pulmonary artery trunk to measure the mean pulmonary arterial pressure (mPAP) and the end-systolic pressure of the right ventricle. (RVSP) etc. After stabilizing for 30 minutes, use the POWERLAB multi-channel intelligent physiological signal acquisition system to collect, record and analyze various indicators.

2. Determination of right ventricular (RV) hypertrophy index: after the experiment, the heart of the mouse was taken out by thoracotomy, and the atrial tissue was cut off. The RV, left ventricle (LV) and interventricular septum (S) were separated along the edge of the interventricular septum, and the weight of the RV, LV and S was weighed after blotted dry with filter paper, and the ratio of RV/(LV+S) was used to reflect the degree of RV hypertrophy ( figure 2).

3. Pulmonary blood vessel pathology detection: Tissue blocks were taken from the same part of the lower lobe of the right lung, and fixed in 10% neutral formaldehyde (pH7.4) for 2 days. Routine paraffin embedding, serial sections, hematoxylin-eosin staining and elastic fiber staining (Hart's modified method for elastic fiber staining, Van Gieson counterstaining), and observation of morphological changes of pulmonary arterioles under a light microscope. The outer diameter (ED), arterial medial wall thickness (MT) and pulmonary medial cross-sectional area of pulmonary arterioles (diameter less than 100 μm) accompanied by respiratory bronchioles and alveolar ducts were measured with an image analyzer. (MA), vascular lumen cross-sectional area (VA) and total vessel cross-sectional area (TAA), and then calculate the percentage of vessel wall media thickness in the outer diameter (MT%) (Fig. 3), vessel wall media cross-sectional area The percentage of the total cross-sectional area of blood vessels (MA%) (Figure 4), reflects the degree of wall thickening of small pulmonary vessels. The above indexes of 6-10 pulmonary arterioles were measured in lung slices of each rat, and the mean value was calculated as the blood vessel indexes of the rat for statistical analysis. Effects of pulmonary vascular pathological indicators and right ventricular hypertrophy in rats in each group

According to the test results in Figure-4 (*P<0.05, **P<0.01), it can be seen that the right ventricle in the normal control group has no thickening, and the right ventricle in the hypoxic control group has obvious hypertrophy, and the right ventricular hypertrophy index RV/(LV+ S) significantly increased. Pathological examination found that hypertrophic cardiomyocytes were seen in the right ventricle of the hypoxic control group, the wall of pulmonary arteriole was thickened, and the lumen was narrowed. However, both dose groups of 2-aminopurine can improve the pathological remodeling of pulmonary artery, including reducing the ratio of arterial-media wall thickness, wall-media cross-sectional area ratio and reducing right ventricular hypertrophy in a dose-dependent manner.

Claims (7)

1.2- adenine phosphate preparation treatment pulmonary hypertension drug in application, which is characterized in that using 2-aminopurine as The drug of active constituent preparation treatment pulmonary hypertension, it is structural formula (I) compound represented to the 2-aminopurine,

2. application according to claim 1, which is characterized in that prepare treatment using 2-aminopurine as sole active agent The drug of pulmonary hypertension.

3. according to claim 1 to 2 described in any item applications, which is characterized in that the effective dose of the drug be 0.1~ 200mg/kg rat body weight/day；The effective dose of affiliated drug is 0.15~15mg/kg body weight/day.

4. described in any item applications according to claim 1~2, which is characterized in that the drug is oral preparation.

5. described in any item applications according to claim 1~2, which is characterized in that the pulmonary hypertension be low-oxygen environment and Pulmonary hypertension caused by drug-induced.

6. application according to claims 1 to 2, which is characterized in that the drug is powder, tablet, granule, capsule Agent, suspension, emulsion or injection.

7. described in any item applications according to claim 1~2, which is characterized in that the drug is changed as shown in structural formula (I) Available auxiliary material in object and pharmacy is closed to be prepared.