Application of compound in preparation of medicine for preventing and / or treating altitude sickness

Abstract

The invention relates to application of a compound and a pharmaceutical composition thereof in preparation of medicines for preventing and / or treating altitude sickness, and the compound is N-[7-hydroxy-5-(2-phenethyl) [1, 2, 4] triazole [1, 5-a] pyridine-8-carbonyl] glycine.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical applications, and relates to the use of a compound and a pharmaceutical composition thereof in the preparation of a drug for preventing and / or treating altitude sickness, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazole[1,5-a]pyridine-8-carbonyl]glycine. Background Art

[0002] The low-pressure and low-oxygen environment at plateaus above 3,000 meters above sea level has a great impact on human health, especially when people who have not undergone acclimatization training quickly enter the plateau from the plains, they are very likely to suffer from acute mountain sickness (AMS, also known as acute altitude sickness). If not treated in time, high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE) may endanger life. Currently, there is a lack of effective oral drugs for such patients.

[0003] CN102471337B discloses triazolopyridine compounds having prolyl hydroxylase inhibitory effects and erythropoietin production induction capabilities, specifically including compounds having the following structure:

[0004] Chemical name: N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine

[0005] , used to treat anemia. Summary of the invention

[0007] In view of the problems existing in the prior art, the present invention first provides the use of a compound in the preparation of a drug for preventing and / or treating altitude sickness, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine (Compound A).

[0008] The N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazole[1,5-a]pyridine-8-carbonyl]glycine is a compound having the following structure:

[0009] Chemical name: N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine

[0010]

[0011] Specifically, the present invention provides an application of a compound in the preparation of a drug for preventing and / or treating altitude sickness, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazole[1,5-a]pyridine-8-carbonyl]glycine.

[0012] In addition, the present invention provides a use of a pharmaceutical composition containing a compound in the preparation of a drug for preventing and / or treating altitude sickness, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazole[1,5-a]pyridine-8-carbonyl]glycine, and the pharmaceutical composition contains one or more excipients.

[0013] As a preferred technical solution of the present invention, the invention includes application in medicine for treating altitude sickness caused by angioedema.

[0014] As a preferred technical solution of the present invention, the altitude sickness includes acute altitude sickness.

[0015] As a preferred technical solution of the present invention, the altitude sickness includes high altitude pulmonary edema.

[0016] As a preferred technical solution of the present invention, the altitude sickness includes high altitude cerebral edema.

[0017] As a preferred technical solution of the present invention, the drug contains additional active ingredients for preventing and / or treating altitude sickness caused by hypobaric hypoxia.

[0018] As a preferred technical solution of the present invention, the daily dose is about 1 mg to about 30 mg, including:

[0019] 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9; 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9; 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9; 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9; 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9; 6, 6.1, 6.2, 6.3 9 , 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9; 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30mg.

[0020] As an implementation technical scheme of the present invention, the preparation of the compound is introduced into the present invention by the technical scheme recorded in CN201780072928.2;

[0021] The crystal form and preparation used in the pharmaceutical composition are introduced into the present invention by the technical solution described in US20200017492A1.

[0022] The composition further comprises other active drugs (including additional active ingredients), and the active drugs include but are not limited to anti-inflammatory agents, antiemetics, diuretics, calcium antagonists, bronchodilators, antipyretics, vasodilators, and adrenocortical hormones.

[0023] The pharmaceutical composition of the present invention contains one or more auxiliary materials (excipients), including but not limited to solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesive agents, integrities, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, etc.

[0024] The dosage form of the pharmaceutical composition of the present invention is selected from tablets, capsules, injections, sprays, aerosols, nasal drops, powder sprays, suppositories, patches, gels, etc.

[0025] Preferably, the tablets are selected from ordinary tablets, immediate-release tablets, sustained-release tablets, controlled-release tablets, film-coated tablets, sugar-coated tablets, buccal tablets, sublingual tablets, and bioadhesive tablets; the capsules are selected from hard capsules and soft capsules; the injections are selected from sterile or antibacterial-containing aqueous injections, oily injections, freeze-dried powder injections, and microspheres for injection; the sprays are selected from oral sprays, nasal sprays, and local skin sprays; the aerosols are selected from aerosols for pulmonary inhalation and local skin aerosols; the nasal drops are selected from nasal solutions and nasal gels; the powder sprays are selected from powder sprays for cavities, powder sprays for nasal cavities, and powder sprays for local skin.

[0026] The use of the pharmaceutical composition of the present invention in the prevention and / or treatment of altitude sickness includes, but is not limited to, the treatment and / or prevention of acute altitude sickness, including: high altitude cerebral edema, pulmonary edema, myocardial ischemia, angina pectoris, cerebral ischemia, chronic obstructive pulmonary disease, apnea syndrome, cerebral infarction, myocardial infarction, degenerative lesions, and decreased working ability in confined spaces at high altitudes, deep water or underground, etc. caused by hypoxia.

[0027] The beneficial effects of the present invention compared with the prior art include but are not limited to:

[0028] (1) The use of the compound of the present invention in the preparation of drugs for treating altitude sickness is characterized by small dosage and lower adverse reactions.

[0029] (2) Under the same dosage and frequency, the compound of the present invention is more effective than roxadustat in hypoxic environment.

[0030] (3) The compounds of the present invention have good effects in both prevention and treatment under hypoxic conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 , a schematic diagram of the survival time of each group of mice in Example 1 of the present invention.

[0032] Figure 2 , a schematic diagram of the improvement of RBC and HCT of each group of mice in Example 1 of the present invention.

[0033] Note: Figure 1 and Figure 2 **P<0.01 compared with the vehicle group.

[0034] Figure 3 , Survival time of mice in the sodium nitrite poisoning experiment in Example 2 of the present invention, (mean ± SEM, ***p<0.001 vs vehicle group, ##p<0.01 vs rosuvastatin group).

[0035] Figure 4 , the effect of administration before hypoxia induction on plasma EPO levels in Example 3 of the present invention;

[0036] Figure 5 , Example 3 of the present invention shows the effect of administration before hypoxia induction on left ventricular function in mice.

[0037] Figure 6 , the effect of hypoxia-induced simultaneous administration on plasma EPO levels in Example 4 of the present invention;

[0038] Figure 7 , Example 4 of the present invention shows the effect of hypoxia-induced simultaneous administration on left ventricular function in mice.

[0039] Note: Figures 4 to 7 In the table, *P<0.05, ****P<0.0001. DETAILED DESCRIPTION

[0040] The present invention is further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0041] Example 1 Evaluation of atmospheric pressure airtight hypoxia resistance test

[0042] Experimental methods: Male BALB / c mice were randomly divided into vehicle control group, compound A low-dose group (50 mg / kg), high-dose group (100 mg / kg), and roxadustat low-dose group (50 mg / kg), high-dose group (100 mg / kg) according to body weight after the adaptation period, with 12 animals in each group. The vehicle or drug was administered by gavage once a day for 7 consecutive days. On the 4th day of administration, blood was collected to detect red blood cell count (RBC) and hematocrit (HCT), and hypoxia tolerance test was performed 1 hour after the last administration.

[0043] Test index for hypoxia tolerance: At room temperature, mice were placed in 250 ml wide-mouth bottles containing 5 g of soda lime (wrapped in double gauze), and vaseline was applied to the bottle stopper and bottle mouth to prevent air leakage. After the animals were placed in, the bottle stopper was tightened and the timing was started. The death index was taken as the cessation of breathing and the end of leg twitching, and the survival time of mice in each group was recorded. The experimental data were expressed as mean ± standard deviation and statistical analysis was performed.

[0044] Experimental results: Compared with the vehicle control group, the survival time of mice in each compound A treatment group was significantly prolonged in a dose-dependent manner, and the survival time was significantly improved at high doses. However, rosuvastatin had no such effect at the same dose. Figure 1 shown.

[0045] At the same time, compound A could significantly increase the red blood cell count (RBC) and hematocrit (HCT) in both the low and high dose groups, and was superior to the improvement of rosuvastatin. Figure 2 shown.

[0046] In summary, at the same dosage and frequency of administration, compound A has better effects in promoting erythropoiesis and improving hypoxia tolerance than rosuvastatin.

[0047] Example 2 Sodium nitrite toxicity hypoxia experiment in mice

[0048] Experimental method: Male Balb / c mice were used. After the quarantine and adaptation period, they were randomly divided into a vehicle group (0.5% CMC-Na), a compound A administration group (100 mg / kg / day), and a roxadustat administration group (100 mg / kg / day) according to their body weight. Each group had 10 animals, and the vehicle or drug was administered by gavage once a day for 7 consecutive days. Before the fourth administration, 100 μL of whole blood was collected from the eye frame and placed in an EDTA-K2 anticoagulant tube. The red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Hct) were detected by a complete blood cell analyzer; 1 hour after the last gavage, each group of animals was intraperitoneally injected with 200 mg / kg of sodium nitrite, and the time was immediately counted. The last respiratory arrest of the mouse (the mouse suddenly collapsed after struggling and convulsing, and the chest no longer rose and fell) was taken as the death indication, and the time from the administration of sodium nitrite to the complete cessation of breathing (i.e., survival time) was recorded.

[0049] The results are as follows Figure 3 and Table 1:

[0050] Table 1 Hematological parameters of mice on the 4th day after administration

[0051]

[0052] Compared with the vehicle control group, compound A (100 mg / kg / day) can significantly prolong the survival time of mice after sodium nitrite poisoning. Hematological test results show that after four days of continuous administration of compound A and rosuvastatin, RBC, Hb, Hct and other indicators have improved compared with the vehicle group, and the improvement effect of animals in the compound A administration group is more obvious.

[0053] This indicates that under the same dosage and frequency of administration, compound A is more effective in promoting erythropoiesis and improving the hypoxia tolerance of mice to sodium nitrite poisoning.

[0054] Example 3 Effect of administration before hypoxia induction on mice (preventive administration)

[0055] Experimental method: Male C57 mice were used. After 3 days of adaptation, they were divided into normoxic control group, hypoxic control group, rosuvastatin (60 mg / kg) + hypoxic group, low-dose compound A (15 mg / kg) + hypoxic group, medium-dose compound A (30 mg / kg) + hypoxic group, and high-dose compound A (60 mg / kg) + hypoxic group according to body weight. All groups were placed in a normoxic environment for the first three days of the experiment, and the solvent or drug was administered once a day. From the fourth day, except for the normoxic control group, all animals in the hypoxic group were placed in a hypobaric hypoxic chamber simulating an altitude of 5000m, and then continued to be administered until the 10th day. The mice were weighed every day during the experiment, and a cardiac ultrasound examination was performed one day before the end of the experiment. Blood gas analysis and hematological tests were performed at the end of the experiment.

[0056] Experimental results: Figure 4 As shown, the EPO test results showed that 24 hours after the last administration, the EPO levels in the medium and high dose groups of compound A were still maintained at a relatively high level, which was superior to rosuvastatin at the same dose.

[0057] like Figure 5 As shown in the figure, cardiac ultrasound examination showed that the left ventricular ejection fraction (LVEF) of mice in the hypoxia group tended to decrease compared with the normal control group, suggesting that left ventricular function may be impaired. Compared with the hypoxia group, compound A increased LVEF in a dose-dependent manner, and was superior to roxadustat at the same dose.

[0058] Example 4 Effects of Compound A on Mice During Hypoxia Induction

[0059] Experimental method: Male C57 mice were used. After 3-7 days of adaptation, they were randomly divided into normoxic control group, hypoxic control group, rosuvastatin (100 mg / kg) + hypoxic group, and high-dose compound A (100 mg / kg) + hypoxic group according to body weight. From the first day of the experiment, the mice in the hypoxic group were placed in a hypobaric hypoxic chamber simulating an altitude of 5000m, and the mice in the normoxic control group were kept in a normoxic environment and given the drug once a day for 7 consecutive days. The mice were weighed every day during the experiment, and hematology and cardiac ultrasound examinations were performed at the end of the experiment.

[0060] Results: Figure 6 As shown, the results of plasma EPO detection showed that compound A was superior to rosuvastatin in increasing EPO concentration at the same dose.

[0061] like Figure 7 As shown, the results of cardiac ultrasound examination showed that compared with the hypoxia group, the left ventricular ejection fraction (LVEF) of the animals in the compound A administration group was significantly improved, which was better than that of rosuvastatin.

[0062] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. Use of a compound in the preparation of a drug for preventing and / or treating altitude sickness, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine.

2. Use of a pharmaceutical composition containing a compound in the preparation of a drug for preventing and / or treating altitude sickness, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine, and the pharmaceutical composition contains one or more excipients.

3. The use according to claim 1 or 2, characterized in that: Use of medications for altitude sickness, including angioedema.

4. The use according to claim 1 or 2, wherein the altitude sickness comprises acute mountain sickness.

5. The use according to claim 1 or 2, wherein the altitude sickness comprises high altitude pulmonary edema.

6. The use according to claim 1 or 2, wherein the altitude sickness comprises high altitude cerebral edema.

7. The use according to claim 1 or 2, wherein the medicine comprises additional active ingredients for preventing and / or treating altitude sickness caused by hypobaric hypoxia.

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