Application of compounds in the preparation of drugs for the prevention and / or treatment of altitude sickness

Abstract

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

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical purposes, and relates to application of a compound and a pharmaceutical composition thereof in preparation of a medicine for preventing and / or treating high altitude disease, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine. BACKGROUND

[0002] A low-pressure and low-oxygen environment at an altitude of 3000 m or above has a great impact on human health, especially when people who have not been adapted to the exercise enter the plateau from the plain, acute mountain sickness (AMS, also known as acute high altitude reaction) is prone to occur, and if not treated in time, high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE) and other life-threatening diseases may occur. There is currently a lack of effective oral drugs for such patients.

[0003] CN102471337B discloses a triazolopyridine compound having a prolyl hydroxylase inhibiting effect and an erythropoietin production inducing ability, and specifically includes a compound having the following formula:

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

[0005]

[0006] for anemia treatment. SUMMARY

[0007] In view of the problems in the prior art, the application first provides application of a compound in preparation of a medicine for preventing and / or treating high altitude disease, 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]triazolo[1,5-a]pyridine-8-carbonyl]glycine is a compound having the following formula:

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

[0010]

[0011] In particular, the present application provides use of a compound in the manufacture of a medicament for preventing and / or treating high altitude sickness, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]glycine.

[0012] In addition, the present application provides use of a pharmaceutical composition containing a compound in the manufacture of a medicament for preventing and / or treating high 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.

[0013] As a preferred technical solution of the present application, use of the compound in the manufacture of a medicament for preventing and / or treating high altitude sickness including edema.

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

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

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

[0017] As a preferred technical solution of the present application, the medicament contains additional active ingredients for preventing and / or treating high altitude sickness caused by low pressure hypoxia.

[0018] As a preferred technical solution of the present application, 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, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9; 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9; 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9; 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, 30 mg.

[0020] As an embodiment of the present application, the preparation of the compound is introduced into the present application from the technical solution recorded in CN201780072928.2;

[0021] The crystal form and preparation used in the pharmaceutical composition are introduced into the present application from the technical solution recorded in US20200017492A1.

[0022] The composition further comprises other active drugs (containing additional active ingredients), which include but are not limited to anti-inflammatory agents, antiemetics, diuretics, calcium antagonists, bronchodilators, antipyretic analgesics, vasodilators, and adrenal cortical hormones.

[0023] The pharmaceutical composition of the present application contains one or more excipients (excipients), including but not limited to solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavorings, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integration agents, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickening agents, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, etc.

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

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

[0026] The application of the pharmaceutical composition in the prevention and / or treatment of high altitude sickness drugs, including but not limited to the treatment and / or prevention of acute high altitude reaction, including: high altitude cerebral edema caused by hypoxia, pulmonary edema, myocardial ischemia, angina pectoris, cerebral ischemia, chronic obstructive pulmonary disease, apnea syndrome, cerebral infarction, cardiac infarction, degenerative diseases, and decreased work capacity in high altitude, deep water or underground closed space, etc.

[0027] The beneficial effects of the present application relative to the prior art include but are not limited to:

[0028] (1) The application of the compound in the preparation of drugs for treating high altitude sickness, which has the advantages of small dosage and lower adverse reactions.

[0029] (2) Under the same dosage and frequency of administration, the effect of the compound in hypoxic environment is better than that of Roxadustat.

[0030] (3) The compound has good effects in preventing and treating in hypoxic environment. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 The survival time of mice in each group in Example 1 of the present application is shown in the schematic diagram.

[0032] Figure 2 The RBC and HCT improvement of mice in each group in Example 1 of the present application is shown in the schematic diagram.

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

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

[0035] Figure 4 The effect of pre-administration on plasma EPO level in hypoxia induction in Example 3 of the present application;

[0036] Figure 5 Effect of pre-administration of hypoxia induction on left ventricular function in mice according to Embodiment 3 of the present application.

[0037] Figure 6 Effect of simultaneous administration of hypoxia induction on plasma EPO level according to Embodiment 4 of the present application.

[0038] Figure 7 Effect of simultaneous administration of hypoxia induction on left ventricular function in mice according to Embodiment 4 of the present application.

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

[0040] The present application will be further described in conjunction with the examples below, but the embodiments of the present application are not limited thereto.

[0041] Example 1: Evaluation of normobaric hypoxic tolerance test

[0042] Experimental method: Male BALB / c mice were used, and after the adaptation period, they were randomly divided into vehicle control group, low-dose compound A group (50 mg / kg), high-dose group (100 mg / kg), and low-dose Roxadustat group (50 mg / kg), high-dose group (100 mg / kg), 12 animals in each group. The vehicle or drug was given once a day by gavage, for 7 consecutive days. Blood was collected on the 4th day of administration for detection of red blood cell count (RBC) and hematocrit (HCT), and 1 hour after the last administration, the hypoxic tolerance test was performed.

[0043] Hypoxic tolerance test index: Under room temperature conditions, the mice were placed in 250 ml jars containing 5 g of sodium lime (wrapped with double-layer gauze), and vaseline was applied to the stopper and the mouth of the jar to prevent air leakage. After the animals were placed, the stopper was tightened and the timing started. The death index was the stoppage of breathing and the no longer convulsions of the legs, and the survival time of the 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 the mice in each administration group of compound A was significantly prolonged, and it was dose-dependent, and the survival time was significantly improved at high dose. However, Roxadustat had no such effect at the same dose, as shown in Figure 1

[0045] At the same time, compound A at low and high doses could significantly increase red blood cell count (RBC) and hematocrit (HCT), and the improvement was better than that of Roxadustat, as shown in Figure 2

[0046] ​​In summary, at the same dose and frequency, the erythropoietic effect and the effect of improving hypoxia tolerance of compound A are better than that of Roxadustat.

[0047] Example 2 Mouse sodium nitrite poisoning hypoxia experiment

[0048] Test method: Male Balb / c mice were used, after quarantine and adaptation period, according to the body weight, randomly divided into vehicle group (0.5% CMC-Na), compound A administration group (100 mg / kg / day), Roxadustat administration group (100 mg / kg / day), 10 animals in each group, once a day intragastrically administered with vehicle or drug, continuous administration for 7 days. Before the 4th administration, 100 μL of whole blood was taken from the eye frame and placed in an EDTA-K2 anticoagulant tube, and the red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Hct) were detected by whole blood cell analyzer; 1 h after the last intragastric administration, 200 mg / kg of sodium nitrite was intraperitoneally administered to each group of animals, and immediately timed, with the mouse respiratory arrest (mouse convulsions suddenly flaccid, and the chest no longer fluctuated) as the death indicator, and the time from the administration of sodium nitrite to the complete respiratory arrest of the mouse (i.e. survival time) was recorded.

[0049] Results are shown in Table 1 and Figure 1. Figure 3 and Table 1:

[0050] Table 1 Hematology index of mice on the 4th day of 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. The results of hematology detection show that after continuous administration of compound A and Roxadustat for four days, compared with the vehicle group, the RBC, Hb, Hct and other indicators are improved, and the improvement effect of the compound A administration group is more obvious.

[0053] It is shown that at the same dose and frequency, the erythropoietic effect and the effect of improving the hypoxia tolerance of compound A are better than that of Roxadustat.

[0054] Example 3 Effect of low oxygen induction on mice before administration (prevention administration)

[0055] Test method: Male C57 mice were used, and after 3 days of adaptation, they were divided into normoxic control group, hypoxic control group, Roxadustat (60 mg / kg) + hypoxic group, Compound A low dose (15 mg / kg) + hypoxic group, Compound A medium dose (30 mg / kg) + hypoxic group, Compound A high dose (60 mg / kg) + hypoxic group according to body weight. Three days before the experiment, all groups were placed in a normoxic environment, and the solvent or drug was given once a day. From the fourth day, all hypoxic groups of animals were placed in a low-pressure hypoxic chamber simulating an altitude of 5000 m, and then the drug was continued to be given until the tenth day. The weight was measured every day during the experiment, and the cardiac ultrasound examination was performed one day before the end of the experiment, and the blood gas analysis and hematology detection were performed at the end of the experiment.

[0056] Experimental results: As shown in Table 1, the EPO test results showed that 24 hours after the last administration, the EPO of the Compound A medium and high dose groups remained at a high level, which was better than that of Roxadustat at the same dose. Figure 4

[0057] As shown in Table 2, the cardiac ultrasound detection showed that the left ventricular ejection fraction (LVEF) of the hypoxic group of mice had a decreasing trend compared with the normal control group, suggesting that the left heart function might be impaired. Compared with the hypoxic group, Compound A improved the LVEF in a dose-dependent manner, which was better than Roxadustat at the same dose. Figure 5 Example 4 Effect of Compound A on mice induced by hypoxia

[0058] Test method: Male C57 mice were used, and after 3-7 days of adaptation, they were randomly divided into normoxic control group, hypoxic control group, Roxadustat (100 mg / kg) + hypoxic group, Compound A high dose (100 mg / kg) + hypoxic group according to body weight. From the first day of the experiment, the hypoxic group of mice was placed in a low-pressure hypoxic chamber simulating an altitude of 5000 m, and the normoxic control group of mice was placed in a normoxic environment for feeding, and the drug was given once a day, continuously for 7 days. The weight was measured every day during the experiment, and the hematology and cardiac ultrasound examination were performed at the end of the experiment.

[0059] Results: As shown in Table 3, the plasma EPO detection results showed that Compound A improved the EPO concentration at the same dose, which was better than Roxadustat.

[0060] Figure 6 As shown in Table 4, the cardiac ultrasound detection results showed that compared with the hypoxic group, the left ventricular ejection fraction (LVEF) of the Compound A administration group of animals was significantly improved, which was better than Roxadustat.

[0061] Figure 7

[0062] ​​​​The above embodiments are the preferred embodiments of the present application, but the embodiments of the present application are not limited to the above embodiments, and any changes, modifications, substitutions, combinations, simplifications, etc. made without departing from the spirit and principles of the present application should be equivalent replacement manners and should be included in the protection scope of the present application.

Claims

1. Use of a compound for the manufacture of a medicament for the prophylaxis and / or treatment of high altitude sickness, wherein the compound is N-[7-hydroxy-5-(2- phenylethyl)[l,2,4]triazolo[l,5-a]pyridine-8-carbonyl]glycine.

2. Use of a pharmaceutical composition containing a compound for the manufacture of a medicament for the prophylaxis and / or treatment of high altitude sickness, wherein the compound is N-[7-hydroxy-5-(2-phenylethyl)[l,2,4]triazolo[l,5-a]pyridine-8- carbonyl]glycine, and the pharmaceutical composition contains one or more excipients.

3. Use according to claim 1 or 2, characterized in that, The high altitude sickness is high altitude sickness of vascular edema.

4. Use according to claim 1 or 2, wherein the high altitude sickness is acute mountain sickness.

5. Use according to claim 1 or 2, wherein the high altitude sickness is high altitude pulmonary edema.

6. Use according to claim 1 or 2, wherein the high altitude sickness is high altitude cerebral edema.

7. Use according to claim 1 or 2, wherein the medicament comprises an additional active ingredient for the prophylaxis and / or treatment of high altitude sickness caused by hypobaric hypoxia.

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