Use of compound in preparing drug for preventing and / or treating mountain sickness

Abstract

Use of a compound and a pharmaceutical composition thereof in preparing a drug for preventing and / or treating mountain sickness. The compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine.

Description

Use of compound in preparing medicine for preventing and / or treating altitude sickness Technical Field

[0001] The present invention belongs to the field of medical application technology 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]triazolo[1,5-a]pyridine-8-carbonyl]glycine. Background Art

[0002] The low-pressure, low-oxygen environment at altitudes above 3,000 meters can have a significant impact on human health. This is especially true for those who have not undergone acclimatization and are rapidly transported from the plains to the plateau. Acute mountain sickness (AMS), also known as acute altitude sickness, is highly susceptible. If untreated, it can lead to life-threatening conditions such as high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema (HACE). Currently, there is a lack of effective oral medications for these conditions.

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

[0004] , used to treat anemia. Summary of the Invention

[0005] 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 medicament 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).

[0006] The N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine is a compound having the following structure:

[0007] Specifically, the present invention provides a 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.

[0008] 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]triazolo[1,5-a]pyridine-8-carbonyl]glycine, and the pharmaceutical composition contains one or more excipients.

[0009] As a preferred technical solution of the present invention, it includes application in medicine for treating altitude sickness caused by angioedema.

[0010] As a preferred technical solution of the present invention, the altitude sickness includes acute altitude sickness.

[0011] As a preferred technical solution of the present invention, the altitude sickness includes high altitude pulmonary edema.

[0012] As a preferred technical solution of the present invention, the altitude sickness includes high altitude cerebral edema.

[0013] As a preferred technical solution of the present invention, the medicine contains additional active ingredients for preventing and / or treating altitude sickness caused by hypobaric hypoxia.

[0014] As a preferred technical solution of the present invention, the daily dose is about 1 mg to about 30 mg, including:

[0015] 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.

[0016] As an implementation technical solution of the present invention, the preparation of the compound is introduced into the present invention by the technical solution described in CN201780072928.2;

[0017] The crystal form and preparation used in the pharmaceutical composition are introduced into the present invention by the technical solution described in US20200017492A1.

[0018] The composition further comprises other active drugs (including additional active ingredients), including but not limited to anti-inflammatory agents, antiemetics, diuretics, calcium antagonists, bronchodilators, antipyretics, vasodilators, and adrenocortical hormones.

[0019] The pharmaceutical composition of the present invention contains one or more excipients (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, defoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, etc.

[0020] 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.

[0021] 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; and the powder sprays are selected from powder sprays for cavity use, powder sprays for nasal use, and powder sprays for local skin use.

[0022] The use of the pharmaceutical composition of the present invention in preventing and / or treating altitude sickness includes, but is not limited to, treating and / or preventing acute altitude sickness, including: high altitude cerebral edema, pulmonary edema, myocardial ischemia, angina pectoris, cerebral ischemia, chronic obstructive pulmonary disease, sleep apnea syndrome, cerebral infarction, myocardial infarction, degenerative diseases, and decreased ability to work in confined spaces at high altitudes, deep water, or underground, etc. caused by hypoxia.

[0023] The beneficial effects of the present invention over the prior art include but are not limited to:

[0024] (1) The application 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.

[0025] (2) Under the same dosage and frequency, the compound of the present invention is more effective than rosuvastatin in hypoxic environment.

[0026] (3) The compounds of the present invention have good effects in both prevention and treatment under hypoxic conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG1 is a schematic diagram of the survival time of mice in each group in Example 1 of the present invention.

[0028] FIG2 is a schematic diagram showing the improvement of RBC and HCT in each group of mice in Example 1 of the present invention.

[0029] Note: In Figures 1 and 2, **P<0.01 compared with the vehicle group.

[0030] FIG3 shows the 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).

[0031] Figure 4 shows the effect of drug administration before hypoxia induction on plasma EPO levels in Example 3 of the present invention;

[0032] FIG5 shows the effect of drug administration before hypoxia induction in Example 3 of the present invention on left ventricular function in mice.

[0033] Figure 6 shows the effect of hypoxia-induced and simultaneous drug administration on plasma EPO levels in Example 4 of the present invention;

[0034] FIG7 shows the effects of hypoxia-induced simultaneous drug administration on left ventricular function in mice according to Example 4 of the present invention.

[0035] Note: In Figures 4 to 7, *P<0.05, ****P<0.0001. DETAILED DESCRIPTION

[0036] The present invention will be further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0037] Example 1 Evaluation of atmospheric pressure airtight hypoxia resistance test

[0038] Experimental Methods: Male BALB / c mice were randomly divided into a vehicle control group, a low-dose (50 mg / kg) and high-dose (100 mg / kg) Compound A group, and a low-dose (50 mg / kg) and high-dose (100 mg / kg) roxadustat group, with 12 animals per group. Vehicle or drug were administered by gavage once daily for 7 consecutive days. Blood was collected on the fourth day of administration for red blood cell count (RBC) and hematocrit (HCT). Hypoxia tolerance was tested 1 hour after the last dose.

[0039] Hypoxia tolerance test: At room temperature, mice were placed in 250ml wide-mouth bottles containing 5g of soda lime (wrapped in double gauze). Vaseline was applied to the stopper and mouth of the bottle to prevent air leakage. After the animals were placed, the stopper was tightened and timing began. Cessation of breathing and cessation of leg twitching were considered death indicators. Survival time was recorded for each group. Data were expressed as mean ± standard deviation and statistical analysis was performed.

[0040] Experimental results: Compared with the vehicle control group, the survival time of mice in each Compound A-treated group was significantly prolonged in a dose-dependent manner, with significant improvement at high doses. Roxadustat had no such effect at the same dose, as shown in Figure 1.

[0041] 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 achieved by rosuvastatin, as shown in Figure 2.

[0042] In summary, at the same dosage and frequency, compound A has better effects on promoting erythropoiesis and improving hypoxia tolerance than rosuvastatin.

[0043] Example 2 Sodium nitrite toxicity hypoxia experiment in mice

[0044] Experimental Methods: Male Balb / c mice were randomly divided into a vehicle group (0.5% CMC-Na), a compound A group (100 mg / kg / day), or a roxadustat group (100 mg / kg / day) according to body weight after the quarantine and acclimation period. Each group consisted of 10 animals. Vehicle or drug was administered orally once daily for 7 consecutive days. Before the fourth administration, 100 μL of whole blood was collected from the eye socket and placed in an EDTA-K2 anticoagulant tube. Red blood cell count (RBC), hemoglobin (Hb), and hematocrit (Hct) were measured using a complete blood cell analyzer. One hour after the last oral administration, each group was intraperitoneally injected with 200 mg / kg of sodium nitrite. Immediately, the mice were timed to death by the last respiratory arrest (the mice suddenly collapsed after struggling and twitching, and the chest stopped rising and falling). The time from sodium nitrite administration to complete respiratory arrest (i.e., survival time) was recorded.

[0045] The results are shown in Figure 3 and Table 1:

[0046] Table 1 Hematological parameters of mice on the 4th day after administration

[0047] Compared to the vehicle control group, Compound A (100 mg / kg / day) significantly prolonged the survival of mice after sodium nitrite poisoning. Hematological tests showed that after four days of continuous administration of Compound A and roxadustat, RBC, Hb, and Hct levels all increased compared to the vehicle group, with the Compound A group showing a more pronounced improvement.

[0048] 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.

[0049] Example 3 Effects of Administration Before Hypoxia Induction on Mice (Preventive Administration)

[0050] Experimental method: Male C57 mice were used. After acclimation for 3 days, 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. For the first three days of the experiment, all groups were placed in a normoxic environment and administered with vehicle or drug once a day. Starting from the 4th 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 drug administration was continued until the 10th day. The mice were weighed every day during the experiment, and a cardiac ultrasound examination was performed the day before the end of the experiment. Blood gas analysis and hematological tests were performed at the end of the experiment.

[0051] Experimental results: As shown in Figure 4, the EPO test results showed that 24 hours after the last administration, the EPO levels of the medium and high dose groups of Compound A still maintained at a high level, which was better than roxadustat at the same dose.

[0052] As shown in Figure 5, cardiac ultrasound examination revealed a decreased left ventricular ejection fraction (LVEF) in the hypoxic group compared to the normal control group, suggesting possible impaired left ventricular function. Compound A increased LVEF in a dose-dependent manner compared to the hypoxic group, and was superior to roxadustat at the same dose.

[0053] Example 4 Effects of Hypoxia Induction and Simultaneous Administration of Compound A on Mice

[0054] Experimental Methods: Male C57 mice were acclimated for 3-7 days and then randomly divided according to body weight into a normoxic control group, a hypoxic control group, a rosuvastatin (100 mg / kg) + hypoxic group, and a high-dose Compound A (100 mg / kg) + hypoxic group. Starting on the first day of the experiment, mice in the hypoxic group were placed in a hypobaric hypoxic chamber simulating an altitude of 5000m, while mice in the normoxic control group were housed in a normoxic environment. Dosing was performed once daily for 7 consecutive days. Daily weight was measured during the experimental period, and hematological and cardiac ultrasound examinations were performed at the end of the experiment.

[0055] Results: As shown in Figure 6, the results of plasma EPO detection showed that compound A was better than roxadustat in increasing EPO concentration at the same dose.

[0056] As shown in FIG7 , the cardiac ultrasound test results showed that compared with the hypoxia group, the left ventricular ejection fraction (LVEF) of the animals in the Compound A-administered group was significantly improved, which was better than that of the animals in the Roxadustat group.

[0057] 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 considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. Use of a compound in the preparation of a medicament 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 medicament 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 an additional active ingredient for preventing and / or treating altitude sickness caused by hypobaric hypoxia.

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