Use of N-(pyridin-2-yl)pyridine-2-thioamide or its salt in the preparation of anti-hypoxia drugs

Abstract

The present invention discloses the use of N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof as shown in the following formula (I) in the preparation of an anti-hypoxic drug for treating or preventing a disease caused by hypoxia. Through animal experiments and in vitro cell experiments under hypoxic conditions, and using the currently widely used anti-hypoxic drug acetazolamide as a control, it is verified that N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof has an anti-hypoxic effect that is significantly superior to existing drugs.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to the use of N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof in the preparation of an anti-hypoxia drug. Background Art

[0002] The oxidation reaction between oxygen and energy substances such as sugar, fat and amino acids is the basis for generating energy and maintaining life activities. Hypoxia can cause a series of physiological compensatory reactions in the body, such as increased heart rate, hemodynamic changes, pulmonary hypertension, energy metabolism disorders, etc., especially it can cause lung damage, myocardial damage, decreased brain function, and in severe cases, it is life-threatening. For example, in daily life, the increase in social competition and the accelerated pace of life have put more and more pressure on modern people, and the burden of mental work has also been increasing. More oxygen is needed to ensure the smooth operation of the brain. Hypoxia will cause changes in brain function and cause related diseases. In some jobs, when people enter plateaus, high altitudes, diving and other operations, the body cannot obtain enough oxygen through normal breathing due to insufficient oxygen content in the environment, causing energy metabolism disorders, leading to acute mountain reaction, acute mountain sickness, high-altitude cerebral edema, high-altitude pulmonary edema, etc. When suffering from certain diseases, such as myocardial ischemia, angina pectoris, chronic obstructive pulmonary disease, asthma, apnea syndrome, cerebral infarction, myocardial infarction, ischemia and hypoxia caused by brain trauma, emphysema, anemia, stroke, and tissue hypoxia caused by degenerative diseases, the body will also have tissue hypoxia, which will worsen the condition or cause more serious diseases. Therefore, actively looking for new anti-hypoxia drugs to improve the body's oxygen supply and energy status is of great significance to improving the body's quality of life and activity under hypoxic conditions, as well as the treatment and prevention of related diseases.

[0003] At present, anti-hypoxia drugs are mainly chemical drugs and traditional Chinese medicine. Among chemical drugs, acetazolamide is the only drug approved by the FDA for the treatment and prevention of acute mountain sickness caused by hypoxia. Studies have shown that it can reduce the severity of acute mountain sickness by about 74% within 24 hours (Gudbjartsson T, Sigurdsson E, Gottfredsson M, et al. Laeknabladid, 2019, 105 (11): 499-507.). However, its adverse reactions are also common, mainly including numbness of the limbs, fatigue, drowsiness, acute kidney disease, kidney stones, etc. (Chen Maoling, Liang Guangjiang, Ma Shumei, Analysis of literature on adverse reactions of acetazolamide, China Practical Medicine, 2010, 5 (27): 162-164). In addition, commonly used anti-hypoxia drugs include Chinese medicines that promote blood circulation and replenish qi. For example, Acanthopanax senticosus is used to dilate blood vessels, inhibit thrombosis, increase oxygen utilization and adapt the body to a low oxygen environment; Rhodiola rosea can increase arterial oxygen partial pressure and blood oxygen saturation under hypoxic conditions, enhance the excitability of the brainstem reticular system, improve brain function and certain neurotransmitter disorders, and has anti-hypoxia, anti-fatigue and immune enhancement effects, and can reduce the body's oxygen consumption and bidirectionally regulate the central nervous system; Compound Danshen Drop Pills, Musk Heart Pills, Shenling Baizhu Powder, Compound Codonopsis Capsules, etc. can improve coronary blood flow, reduce myocardial oxygen consumption, and thus improve the body's ability to resist hypoxia. However, the current anti-hypoxia drugs have unstable efficacy and some adverse reactions, and cannot be used more effectively and widely. Research on safe and effective anti-hypoxia drugs is still of great significance and practical need.

[0004] N-(Pyridin-2-yl)pyridine-2-thioamide is an ATG4B inhibitor that can significantly reduce autophagic activity and promote tumor cell apoptosis by inhibiting ATG4B. Therefore, the existing research on this drug is mostly focused on the anti-tumor field (Autophagy 2014, 10(11), 2021-2035; Autophagy 2019, 15(2), 295-311;). In addition, there are also literature reports that this compound has gastric mucosal protective effects (Journal of Medicinal Chemistry 1990, 33(1), 327-36) and antibacterial effects (Chemical & Pharmaceutical Bulletin (1959), 7, 349-56); but no exploration has been conducted on indications related to anti-hypoxia. Summary of the invention

[0005] The present invention uses acetazolamide, a widely used anti-hypoxia drug, as a control, and through animal experiments under hypoxic conditions and in vitro cell experiments, finds the anti-hypoxia effect of N-(pyridin-2-yl)pyridine-2-thioamide, and its anti-hypoxia effect is significantly better than that of existing drugs.

[0006] Therefore, the first object of the present invention is to provide the use of N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof represented by formula (I) in the preparation of an anti-hypoxic drug:

[0007]

[0008] The pharmaceutically acceptable salt of N-(pyridin-2-yl)pyridine-2-thioamide is a monoacid salt, a diacid salt or a polyacid salt formed by N-(pyridin-2-yl)pyridine-2-thioamide and an organic acid or an inorganic acid, and the structure is shown in the following formula (II):

[0009]

[0010] Wherein, acid A is one, two or more organic acids or inorganic acids.

[0011] The acid A is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid or isethionic acid, etc. Preferably, the acid A is selected from hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, citric acid, oxalic acid, D-tartaric acid, malic acid, fumaric acid, maleic acid, lactic acid, methanesulfonic acid, benzenesulfonic acid, L-tartaric acid, glutamic acid, aspartic acid, benzoic acid, etc.

[0012] More preferably, acid A is selected from hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, citric acid, oxalic acid, D-tartaric acid, malic acid, fumaric acid, maleic acid, methanesulfonic acid or L-tartaric acid.

[0013] The second object of the present invention is to provide a composition comprising N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof for use in the preparation of an anti-hypoxic drug, wherein the composition comprises an effective amount of N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0014] Preferably, according to the use of a composition comprising N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof in the preparation of an anti-hypoxic drug, wherein the composition further comprises other active drugs, the active drugs including but not limited to anti-inflammatory agents, antiemetics, diuretics, calcium antagonists, bronchodilators.

[0015] Preferably, according to the use of the composition comprising N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof in the preparation of an anti-hypoxic drug, the excipients include, but are 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, and release retardants.

[0016] The dosage form of the anti-hypoxia drug involved in the present invention is selected from tablets, capsules, injections, sprays, aerosols, nasal drops, powder sprays, suppositories, patches, gels and the like.

[0017] 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.

[0018] The anti-hypoxia drug involved in the present invention can be used to treat or prevent diseases or symptoms caused by hypoxia, including but not limited to the treatment and prevention of acute mountain reaction, acute mountain sickness, high-altitude cerebral edema, pulmonary edema, chronic mountain sickness, myocardial ischemia, angina pectoris, cerebral insufficiency, chronic obstructive pulmonary disease, sleep apnea syndrome, cerebral infarction, myocardial infarction, ischemia and hypoxia caused by brain trauma, hypoxia caused by chest trauma, asthma, allergic laryngeal edema spasm, foreign body obstruction, anesthesia accident and other reasons leading to respiratory dysfunction, emphysema, anemia, stroke, acute hypoxic encephalopathy, neonatal hypoxic-ischemic encephalopathy, memory loss caused by hypoxia, vertigo caused by hypoxia, body numbness caused by tissue hypoxia caused by degenerative diseases, and decreased working ability caused by hypoxia in confined spaces at high altitudes, deep water or underground.

[0019] Among them, the chronic altitude sickness includes high-altitude polycythemia, high-altitude hypertension and high-altitude heart disease, portal hypertension and myocardial hypertrophy.

[0020] Beneficial Effects

[0021] The compound N-(pyridin-2-yl)pyridine-2-thioamide of the present invention and its pharmaceutically acceptable salt have the effect of increasing cell viability, and the present invention has confirmed its anti-hypoxia effect at the cell level and in animal experiments. In particular, in the closed hypoxia experiment of mice and the simulated plateau hypoxia experiment, N-(pyridin-2-yl)pyridine-2-thioamide can significantly improve the survival state of mice under hypoxic conditions, prolong the survival time of mice, and its anti-hypoxia effect is significantly better than that of existing drugs, showing a very strong anti-hypoxia ability. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the test result of the anti-cell hypoxia effect of N-(pyridin-2-yl)pyridine-2-thioamide in Test Example 1.

[0023] Figure 2 This is the test result of the effect of N-(pyridin-2-yl)pyridine-2-thioamide and its salts on cell viability in Test Example 2.

[0024] Figure 3 This is a diagram showing the results of the closed hypoxia test experiment in Test Example 3.

[0025] Figure 4 This is a graph showing the experimental results of the simulated plateau hypoxia test in Test Example 4. DETAILED DESCRIPTION

[0026] Hereinafter, the present invention will be described in detail. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as being limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that the inventor is allowed to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are only preferred examples for illustrative purposes and are not intended to limit the scope of the present invention, so that it should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0027] The compound N-(pyridin-2-yl)pyridine-2-thioamide contains a relatively basic functional group, and an acid addition salt is obtained by contacting its neutral form with a sufficient amount of acid in a pure solution or a suitable inert solvent. The compound of the present invention or its pharmaceutically acceptable salt may exist in the form of a hydrate, solvate or prodrug. Therefore, the hydrate, solvate or prodrug of the compound of the present invention or its pharmaceutically acceptable salt is also included in the scope of the present invention. The term "pharmaceutically acceptable" used here refers to those compounds, materials, compositions and / or dosage forms, which are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0028] The term "pharmaceutically acceptable excipient" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative excipients include 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. For other information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0029] The composition of the present invention is typically prepared by mixing the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, and a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art, and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and the like.

[0030] The specific carrier, diluent or excipient used will be determined according to the mode of use and purpose of the compound of the present invention. Solvents are generally selected based on solvents that are considered safe and effective for administration to mammals by those skilled in the art. Generally speaking, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives to make the drug in an acceptable form for manufacture or use.

[0031] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0032] When the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present invention is used in combination with at least one other active drug, the two or more drugs may be used separately or in combination, preferably in the form of a pharmaceutical composition.

[0033] Other active drugs may be anti-inflammatory agents, antiemetics, diuretics, calcium antagonists, bronchodilators, etc., which improve the symptoms of hypoxia under certain circumstances.

[0034] The anti-inflammatory agent can be selected from non-selective cyclooxygenase inhibitors including salicylates, anilines, indoles, arylacetic acids, arylpropionic acids, enolic acids, alkanones, ibufenac drugs, selective cyclooxygenase-2 inhibitors including diarylpyrazoles and diarylfuranones, and glucocorticoids, such as aspirin, salsalate, diflunisal, para-aminosalicylic acid, phenacetin, acetaminophen, acemetacin, indomethacin, tolmetin, diclofenac sodium, ibuprofen, flurbiprofen axetil, naproxen, piroxicam, meloxicam, nabumetone, sulindac, celecoxib, rofecoxib, prednisone, methylprednisolone, dexamethasone, and the like.

[0035] Antiemetics include, but are not limited to, chlorpromazine, hydrochlorothiazide, diphenhydramine, cetirizine hydrochloride, chlorpheniramine, metoclopramide, and metoclopramide.

[0036] Diuretics include but are not limited to furosemide, torsemide, bumetanide, triamterene, amiloride, spironolactone, eplerenone, hydrochlorothiazide, indapamide, etc.

[0037] Calcium antagonists include but are not limited to amlodipine, lacidipine, benidipine, diltiazem Verapamil, etc. Bronchodilators include but are not limited to ipratropium bromide, tiotropium bromide, salbutamol, terbutaline, salmeterol, formoterol, bricanil, clenbuterol, theophylline, etc.

[0038] The compound or pharmaceutical composition of formula (I) of the present invention can be administered to a subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other local or systemic administration forms.

[0039] These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

[0040] The drug of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders or granular preparations. In the solid dosage form, the compound or pharmaceutical composition of the present invention is mixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; wetting agents such as glycerol, etc.; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; solution retardants such as paraffin, etc.; absorption promoters such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the dosage form may also include a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or other excipients such as high molecular weight polyethylene glycols.

[0041] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compound of the present invention or its composition, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and dehydrated sorbitan; or a mixture of several of these substances, etc.

[0042] In addition to these inert diluents, the composition may also include excipients such as one or more of wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfuming agents.

[0043] In the case of suspensions, in addition to the compound or combination of the present invention, it may further contain a carrier such as a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or a mixture of several of these substances.

[0044] The compounds or pharmaceutical compositions of the present invention may be administered in other topical dosage forms, including creams, powders, sprays and inhalants. The drug may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier and any desired preservative, buffer or propellant. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.

[0045] The compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and may be present in suitable solid or liquid carriers or diluents and in suitable sterile devices for injection or infusion.

[0046] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dose of the preparation formula contains 0.5-200 mg of the compound of formula (I), preferably, the unit dose of the preparation formula contains 5 mg-100 mg of the compound of formula (I).

[0047] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered through the oral, nasal, skin, lung, or gastrointestinal tract. Oral administration is most preferred. The best daily dose is 5-200 mg / kg body weight, taken at one time, or 5-100 mg / kg body weight taken in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Usually, it is started with a small dose and the dose is gradually increased until the most suitable dose is found. The experimental methods in the following examples are conventional methods unless otherwise specified.

[0048] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources. Melting points were determined using a YRT-3 melting point apparatus. 1 H-NMR and 13 C-NMR was measured by LSI-IST-005 / JNM-ECA400 nuclear magnetic resonance instrument. ESI-MS was measured by LSI-IST-003 / G6230A mass spectrometer. The thin layer chromatography plate used Merck GF254 fluorescent plate. The ultraviolet high pressure mercury lamp was provided by Shanghai Jiguang Special Lighting Appliance Factory. All chemical reagents used were chemically pure or analytically pure.

[0049] Example 1 N-(pyridin-2-yl)pyridine-2-thioamide (Preparation Method 1)

[0050] 2-Aminopyridine (9.3 g, 0.1 mol) and 2-methylpyridine (9.4 g, 0.1 mol) were added to a 100 mL round-bottom bottle, elemental sulfur (6.4 g, 0.2 mol) was added, and the mixture was heated to 160-165° C. under argon protection, and the reaction was kept warm for 24 hours. The reaction solution was poured into ice water, and the pH of the solution was adjusted to 1-2 with dilute hydrochloric acid. The unreacted elemental sulfur was removed by suction, and then the pH of the solution was adjusted to 7-8 with sodium hydroxide solution. The solution was left to stand for 2 hours and then filtered to obtain a crude product of N-(pyridin-2-yl)pyridine-2-thioamide. The crude product was recrystallized from isopropanol to remove the pigment, and then the trace amount of sulfur was removed by acid and alkali. The crude product was recrystallized from methanol to obtain a refined product with a purity of more than 99.5%, 9.6 g, and a yield of 45%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.53 (s, 1H), 9.31 (d, J = 8.3Hz, 1H), 8.72 (d, J = 7.9Hz, 1H), 8.53 (d, J = 4.5Hz, 1 H),8.45(d,J=4.9Hz,1H),7.85-7.75(m,2H),7.44-7.40(m,1H),7.17-7.13(m,1H).MS(ESI,m / z):216.3[M+H] + .

[0051] Example 2 N-(Pyridin-2-yl)pyridine-2-thioamide (Preparation Method 2)

[0052] Pyridine-2-carboxylic acid (12.3 g, 0.1 mol) and 2-aminopyridine (9.3 g, 0.1 mol) were added to anhydrous dimethylformamide (100 mL), and N, N'-dicyclohexylcarbodiimide (DCC, 26.4 g, 0.12 mol) and a catalytic amount of HOBt were added. The mixture was stirred at room temperature for 30 minutes under nitrogen protection, and then heated to 50-55°C and kept warm for 24 hours. The mixture was cooled to room temperature, saturated ammonium chloride (2 mL) was added dropwise, and stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL), filtered, and the filtrate was concentrated and subjected to column chromatography to obtain 16.5 g of a white solid with a yield of 83%. 1 H NMR (CDCl3, 400MHz): δ (ppm) 10.45 (s, 1H, ANH), 8.56 (d, 1H, H6, J = 5.2), 8.45 (d, 1H, H3, J = 5.2), 8.40 (t, 1H, H4, J = 4.4), 8.32 (d, 1H, H60, J = 6. 4),7.93(t,1H,H5,J=7.6),7.79(t,1H,H40,J=8),7.51(dt,1H,H50,J= 1.6,J=4.8),7.11(dd,1H,H30,J=6.4,J=12).MS(ESI,m / z):202.2[M+H] + .

[0053] The white solid (10 g, 0.05 mol) obtained in the previous step and a toluene solution (175 mL) of Lawesson's reagent (20 g, 0.05 mol) were added to a reaction flask and refluxed for 12 hours. The reaction solution was decompressed to remove the solvent and purified by a rapid silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain the target product N-(pyridin-2-yl)pyridine-2-thioamide (16.7 g) with a yield of 78%. MP 81-83°C. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.53 (s, 1H), 9.31 (d, J = 8.3Hz, 1H), 8.72 (d, J = 7.9Hz, 1H), 8.53 (d, J = 4.5Hz, 1 H),8.45(d,J=4.9Hz,1H),7.85-7.75(m,2H),7.44-7.40(m,1H),7.17-7.13(m,1H).MS(ESI,m / z):216.3[M+H] + .

[0054] Example 3 N-(Pyridin-2-yl)pyridine-2-thioamide dihydrochloride

[0055] Dissolve N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) in ethyl acetate (30 mL), add 1N hydrochloric acid ethyl acetate (21 mL, 21 mmol) dropwise, stir, ice bath crystallize fully, filter to obtain an orange-red solid (2.47 g), yield 90%. MP 165-167 ° C. MS (ESI, m / z): 216.3 [M+H] + .(Signal of the structural fragment of N-(pyridin-2-yl)pyridine-2-thioamide). 1 H NMR(400MHz, DMSO-d6)δ(ppm):12.52(brs,2H),9.97(dt,J=6.7,1.0Hz,1H),8.88(dt,J=4.8,1.3Hz,1H),8.75–8.73(m,1H),8.61(t,J=1.3H z,1H),8.42(dt,J=7.8,1.2Hz,1H),8.28(td,J=7.7,1.6Hz,1H),8.07–8.04(m,1H),7.90(ddd,J=7.8,4.8,1.2Hz,1H),6.95–7.72(brs,2H).

[0056] Example 4 N-(Pyridin-2-yl)pyridine-2-thioamide monohydrochloride

[0057] N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in ethyl acetate (30 mL), and 1N hydrochloric acid ethyl acetate (10 mL, 10 mmol) was added dropwise, stirred, ice-bathed for sufficient crystallization, and filtered to obtain an orange-red solid (2.47 g) with a yield of 90%. MP 164-166°C. MS (ESI, m / z): 216.3 [M+H] + (N-(pyridin-2-yl)pyridine-2-thioamide structural fragment signal). 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.52 (brs, 1H), 9.01 (d, J = 8.3Hz, 1H), 8.73–8.71 (m, 1H), 8.66–8.60 (m, 1H), 8.58–8.54 (m, 1H), 8.13 (td,J=7.8,1.7Hz,1H),8.05–8.00(m,1H),7.75(ddd,J=7.6,4.7,1.2Hz,1H),7.40(ddd,J=7.4,4.8,0.9Hz,1H),6.95–7.72(brs,1H).

[0058] Example 5 N-(Pyridin-2-yl)pyridine-2-thioamide sulfate

[0059] Dissolve N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) in dichloromethane (30 mL), add concentrated sulfuric acid (10 mmol), stir, ice-bath crystallize fully, filter, and obtain a red solid (2.97 g), yield 95%. MP 112-114 ° C. MS (ESI, m / z): 216.3 [M+H] + (Signal of the structural fragment of N-(pyridin-2-yl)pyridine-2-thioamide). 1 H NMR(400MHz, DMSO-d6)δ(ppm):9.01(d,J=8.3Hz,1H),9.88-7.56(brs,3H),8.77(d,1H),8.62(d,J=8.0Hz,1H),8.59–8.52(m,1H),8 .13(td,J=7.8,1.7Hz,1H), 8.03(ddd,J=8.3,7.5,1.9Hz,1H), 7.75(ddd,J=7.6,4.7,1.2Hz,1H), 7.40(ddd,J=7.4,4.8,1.0Hz,1H).

[0060] Example 6 N-(Pyridin-2-yl)pyridine-2-thioamide phosphate

[0061] N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in dichloromethane (30 mL), 1 phosphoric acid (10 mmol) was added dropwise, stirred, ice-bathed for crystallization, and filtered to obtain a red solid (2.90 g) with a yield of 93%. MS (ESI, m / z): 216.3 [M+H] + (N-(pyridin-2-yl)pyridine-2-thioamide structure signal). 1 H NMR(600MHz,DMSO-d6)δ(ppm):12.46(s,1H),9.03(dd,J=8.3,1.0Hz,1H),11.20-8.01(brs,3H),8.73(dt,J=4.8,1.3Hz,1H),8.62(dt,J=8.0 ,1.1Hz,1H),8.55(ddd,1H),8.12(td,J=7.8,1.7Hz,1H),8.01(ddd,1H),7.74(ddd,J=7.5,4.7,1.2Hz,1H),7.38(ddd,J=7.3,4.8,1.0Hz,1H).

[0062] Example 7 N-(Pyridin-2-yl)pyridine-2-thioamide hydrobromide

[0063] Dissolve N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) in dichloromethane (30 mL); add 1N hydrobromic acid (10 mL, 10 mmol) at low temperature, stir, ice-bath crystallize fully, filter and obtain a red solid (2.90 g), yield 93%. MP 194-196°C. MS (ESI, m / z): 216.3 [M+H] + (N-(pyridin-2-yl)pyridine-2-thioamide structure signal). 1 H NMR(600MHz, DMSO-d6)δ(ppm):12.55(s,1H),9.00(d,J=8.4Hz,1H),8.73(dt,J=4.7,1.2Hz,1H),8.64–8.60(m,1H),9.25-8.30(brs,1H),8.56 (dd,1H),8.14(td,J=7.8,1.7Hz,1H),8.04(ddd,J=8.3,7.4,1.9Hz,1H),7.76(ddd,J=7.6,4.7,1.2Hz,1H),7.41(ddd,J=7.4,4.9,1.0Hz,1H).

[0064] Example 8 N-(Pyridin-2-yl)pyridine-2-thioamide oxalate

[0065] N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in ethyl acetate (30 mL) and added to a round-bottomed bottle; then a solution obtained by dissolving oxalic acid (0.9 g, 10 mmol) in anhydrous ethanol (2 mL) was added, refluxed for 30 minutes, cooled and crystallized fully, and filtered to obtain a red solid (2.90 g), with a yield of 95%. MP 161-162°C. 1 H NMR (600MHz, DMSO-d6) δ (ppm): 14.10 (s, 2H), 12.46 (s, 1H), 9.03 (dt, J = 8.3, 1. 0Hz,1H),8.73(ddd,J=4.8,1.7,0.9Hz,1H),8.62(dt,J=8.0,1.1Hz,1H),8.55(d dd,J=4.8,1.9,0.9Hz,1H),8.12(td,J=7.8,1.7Hz,1H),8.01(ddd,J=8.3,7.4,1 .9Hz,1H),7.74(ddd,J=7.6,4.7,1.1Hz,1H),7.38(ddd,J=7.5,4.8,1.0Hz,1H).

[0066] Example 9 N-(Pyridin-2-yl)pyridine-2-thioamide acetate (unsuccessful)

[0067] N-(Pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in ethyl acetate (10 mL); glacial acetic acid (0.65 g, 10 mmol) was added and stirred, ice-bathed for sufficient crystallization, and filtered to obtain a red solid with MP 79-81°C, which was the same as the free base. No acetate methyl hydrogen signal was observed by NMR, and N-(pyridin-2-yl)pyridine-2-thioamide acetate was not obtained.

[0068] Example 10 N-(Pyridin-2-yl)pyridine-2-thioamide malate

[0069] N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in ethyl acetate (30 mL) and added to a round-bottomed bottle; then a solution obtained by dissolving malic acid (1.34 g, 10 mmol) in anhydrous ethanol (5 mL) was added, refluxed for 30 minutes, cooled and crystallized fully, and filtered to obtain a red solid (3.11 g), with a yield of 89%. MP 67-69°C. 1 H NMR (600MHz, DMSO-d6) δ (ppm): 12.62-12.20 (brs, 2H), 12.46 (s, 1H), 9.03 (dt, J = 8.4, 1.0Hz, 1H), 8.73 (dd d,J=4.7,1.6,0.9Hz,1H),8.62(dt,J=8.0,1.1Hz,1H),8.55(ddd,J=4.8,1.9,0.9Hz,1H),8.11(td,J=7.8,1 .7Hz,1H),8.01(ddd,J=8.2,7.4,1.9Hz,1H),7.74(ddd,J=7.5,4.7,1.1Hz,1H),7.38(ddd,J=7.4,4.8,1.0 Hz,1H),5.62-5.35(brs,1H),4.27(dd,J=7.9,4.8Hz,1H),2.62(dd,J=15.7,4.7Hz,1H),2.48–2.41(m,1H).

[0070] Example 11 N-(Pyridin-2-yl)pyridine-2-thioamide citrate

[0071] N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in ethyl acetate (30 mL) and added to a round-bottomed bottle; then a solution of citric acid (1.92 g, 10 mmol) in anhydrous ethanol (5 mL) was added, refluxed for 30 minutes, cooled and crystallized thoroughly, and filtered to obtain a red solid (3.74 g) with a yield of 92%. MP 97-99°C. 1H NMR (600MHz, DMSO-d6) δ (ppm): 2.99-11.98 (brs, 3H) 12.46 (s, 1H), 9.03 (dt, J = 8.3, 1. 0Hz, 1H), 8.73 (ddd, J=4.8, 1.7, 0.9Hz, 1H), 8.62 (dt, J=8.1, 1.1Hz, 1H), 8.55 (ddd, J= 4.9,1.9,0.9Hz,1H),8.11(td,J=7.8,1.7Hz,1H),8.04–7.98(brs,1H),7.74(ddd,J=7 .6,4.7,1.1Hz,1H),7.38(ddd,J=7.4,4.8,1.0Hz,1H),5.18(s,1H),2.80–2.61(m,4H).

[0072] Example 12 N-(Pyridin-2-yl)pyridine-2-thioamide fumarate

[0073] N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in ethyl acetate (30 mL) and added to a round-bottomed bottle; then a solution obtained by dissolving fumaric acid (1.16 g, 10 mmol) in anhydrous ethanol (5 mL) was added, refluxed for 30 minutes, cooled and crystallized fully, and filtered to obtain a red solid (3.01 g), with a yield of 91%. MP108-109°C. 1 H NMR (600MHz, DMSO-d6) δ (ppm): 13.13 (s, 1H), 12.46 (s, 1H), 9.03 (d, J = 8.2Hz, 1H), 8.73 (dd, J = 4.8, 1.6Hz, 1H), 8.62 (d, J = 7.9Hz, 1H), 8.55 (dd, J =5.0,1.7Hz,1H),8.12(td,J=7.8,1.6Hz,1H),8.01(td,J=7.8,1.8Hz,1H),7.74(dd,J=7.5,4.7Hz,1H),7.38(dd,J=7.4,4.8Hz,1H),6.63(s,1H).

[0074] Example 13 N-(Pyridin-2-yl)pyridine-2-thioamide maleate

[0075] N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in ethyl acetate (30 mL) and added to a round-bottomed bottle; then a solution obtained by dissolving malic acid (1.16 g, 10 mmol) in anhydrous ethanol (5 mL) was added, refluxed for 30 minutes, cooled and crystallized fully, and filtered to obtain a red solid (3.18 g), with a yield of 96%. MP 107-109°C.1 H NMR (600MHz, DMSO-d6) δ (ppm): 12.05-11.01 (brs, 2H), 12.46 (s, 1H), 9.03 (d, J = 8.3Hz, 1H), 8.73 (dt, J = 4.5, 1.3Hz, 1H), 8.62 (dd, J = 8.0, 1.1Hz, 1H), 8.57–8.51(m,1H),8.11(td,J=7.7,1.7Hz,1H),8.05–7.97(m,1H),7.74(d dd,J=7.5,4.7,1.1Hz,1H),7.38(ddd,J=7.4,4.8,0.9Hz,1H),6.28(s,2H).

[0076] Example 14 N-(Pyridin-2-yl)pyridine-2-thioamide dimethanesulfonate

[0077] N-(Pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in ethyl acetate (30 mL) and added to a round-bottom flask; methanesulfonic acid (1.92 g, 20 mmol) was then added and refluxed for 30 minutes. The solvent was removed to obtain a syrup (3.99 g) with a yield of 98%. 1 H NMR (600MHz, DMSO-d6) δ9.50-8.75(brs,2H),8.96(d,J=7.3Hz,1H),8.74(ddd,J=4.9,1.7,0.9Hz,1H),8.62(d,J=8.0Hz,1H),8.60–8.53( m,1H),8.16(td,J=7.8,1.7Hz,1H),8.08(ddd,J=8.3,7.4,1.9Hz,1H),7.78(ddd,J=7.6,4.8,1.2Hz,1H),7.47–7.39(m,1H),2.48(s,6H).

[0078] Example 15 N-(Pyridin-2-yl)pyridine-2-thioamide-D-tartrate

[0079] N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in ethyl acetate (30 mL) and added to a round-bottomed bottle; then a solution obtained by dissolving D-tartaric acid (1.50 g, 10 mmol) in anhydrous ethanol (5 mL) was added, refluxed for 30 minutes, cooled and crystallized fully, and filtered to obtain a red solid (3.36 g), with a yield of 92%. MP 116-119°C. 1H NMR (600MHz, DMSO-d6) δ (ppm): 13.10-12.15 (brs, 2H), 12.46 (s, 1H), 9.03 (d, J = 8.2H z,1H),8.73(dt,J=4.7,1.2Hz,1H),8.62(dt,J=8.0,1.0Hz,1H),8.55(dd,J=4.9,1.8 Hz,1H),8.12(td,J=7.8,1.8Hz,1H),8.01(td,J=7.9,1.9Hz,1H),7.74(ddd,J=7.5,4 .7,1.1Hz,1H),7.38(ddd,J=7.4,4.8,0.9Hz,1H),5.40–4.71(brs,2H),4.32(s,2H).

[0080] Example 16 N-(Pyridin-2-yl)pyridine-2-thioamide-L-tartrate

[0081] N-(pyridin-2-yl)pyridine-2-thioamide (2.15 g, 10 mmol) was dissolved in ethyl acetate (30 mL) and added to a round-bottomed bottle; then a solution obtained by dissolving L-tartaric acid (1.50 g, 10 mmol) in anhydrous ethanol (5 mL) was added, refluxed for 30 minutes, cooled and crystallized fully, and filtered to obtain a red solid (3.50 g), with a yield of 96%. MP 112-114°C. 1 H NMR(600MHz,DMSO-d6)δ13.60-12.01(brs,2H),12.46(s,1H),9.03(dt,J=8.2,0.9Hz,1H ),8.72(ddd,J=4.9,1.7,0.9Hz,1H),8.62(dt,J=7.9,1.0Hz,1H),8.55(ddd,J=4.9,2.0,0 .9Hz,1H),8.11(td,J=7.8,1.8Hz,1H),8.01(ddd,J=8.2,7.4,1.9Hz,1H),7.74(ddd,J=7 .5,4.7,1.1Hz,1H),7.38(ddd,J=7.4,4.8,1.0Hz,1H),5.87–4.58(brs,2H),4.33(s,2H).

[0082] Test Example 1 N-(pyridin-2-yl)pyridine-2-thioamide anti-cell hypoxia test

[0083] Human astrocyte NHA cells were cultured at 8x10 3The cells / well were seeded into two 96-well plates, and N-(pyridin-2-yl)pyridine-2-thioamide was added for treatment. The drug concentrations were set to 0, 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, and 12.8 uM. After 24 hours, the culture medium was ultrasonically deoxygenated and the medium was changed. Plate A was changed and the drug was added again and then placed in a hypoxic incubator (oxygen content was 0.3%, which is the condition of NHA cell CC90 (hypoxia causes cell death 90%)), and plate B was changed and the drug was added again and then placed in a normoxic incubator (oxygen content was 21%) as a parallel control. After incubation for 48 hours, the cell viability was detected by MTT method.

[0084] See attached for the results Figure 1 After drug treatment, under normoxic conditions, the proliferation activity of NHA cells treated with different experimental concentrations of N-(pyridin-2-yl)pyridine-2-thioamide was enhanced; under hypoxic conditions, high concentrations of N-(pyridin-2-yl)pyridine-2-thioamide treatment could significantly enhance cell viability, and N-(pyridin-2-yl)pyridine-2-thioamide treatment at concentrations of 6.4uM and 12.8uM could completely resist cell death caused by hypoxia, confirming the anti-hypoxic effect of N-(pyridin-2-yl)pyridine-2-thioamide.

[0085] Test Example 2 Test on the effect of N-(pyridin-2-yl)pyridine-2-thioamide and its salts on cell viability

[0086] The MMT method was used to detect the effects of the example compounds and their pharmaceutical salts on the cell viability of mouse embryonic fibroblasts MEF cells. Each compound and its pharmaceutical salt was tested at seven concentrations: 1 μM, 5 μM, 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM. MEF cells were cultured at 1x10 4 The density of cells / well was seeded into a 96-well plate with a total volume of 100 μL / well. After the cells were completely attached (about 12 hours to 24 hours), when the cell density was 80%, the example compounds were added to the well plate according to the concentration gradient set in the experiment, and 6 replicate wells were set for each concentration. 24 hours after the addition of the drug, the original culture medium was discarded. MTS and cell culture medium were diluted in a volume ratio of 1:5, and then added to the 96-well plate. After 1 hour to 4 hours, the 96-well plate was placed in a microplate reader to detect the absorbance value at a wavelength of 490 nM. The data exported from the microplate reader were processed and analyzed using Excel and Graphad Prism 8.0 software. Cell activity was calculated according to the following formula:

[0087] Cell activity (%) = absorbance value of sample well / absorbance value of negative control well x 100%.

[0088] The essence of hypoxia is a cell's response and adaptive change to low oxygen. In acute severe hypoxia, the cell changes are mainly mitochondrial energy metabolism disorders, while in chronic mild hypoxia, the cells are mainly compensated by oxygen receptors. Cell viability reflects the state of cell energy supply, so it can indirectly reflect the effect of compounds on cell resistance to hypoxia. The experimental results are shown in the attached Figure 2 As shown, it is suggested that the effects of the example compound N-(pyridin-2-yl)pyridine-2-thioamide and its different pharmaceutical salts on cell viability are different. Some compounds can promote cell proliferation at low concentrations, especially the dihydrochloride and phosphate salts at low concentrations, which show a significant effect of promoting cell proliferation, thereby confirming the excellent anti-hypoxia performance of the above compounds and their salts.

[0089] Test Example 3: Sealed Hypoxia Test Experiment

[0090] BALBc mice (purchased from Vital River) were randomly divided into groups according to their body weight, with 10 mice in each group. A blank control group, a high-dose group (100 mg / kg) of N-(pyridin-2-yl)pyridine-2-thioamide, a medium-dose group (75 mg / kg), a low-dose group (50 mg / kg), and an acetazolamide control group were set up. Each group of animals was given the drug for 3 consecutive days, and the blank control group was given an equal volume of solvent. Three hours after the drug administration on the third day, the mice were placed in wide-mouth bottles with a volume of about 320 mL, with 10 g of soda lime built in, and a closed hypoxia experiment was carried out, and the survival time of the mice was recorded. The results showed that N-(pyridin-2-yl)pyridine-2-thioamide significantly prolonged the survival time of mice in closed hypoxia, and had a strong anti-hypoxia ability, see attached. Figure 3 .

[0091] Test Example 4 Simulated Plateau Hypoxia Test Experiment

[0092] BALBc mice (purchased from Vital River) were randomly divided into groups according to body weight, with 8 mice in each group. A blank control group, a high-dose group (100 mg / kg) of N-(pyridin-2-yl)pyridine-2-thioamide, a low-dose group (75 mg / kg), and an acetazolamide control group were set up. Each group of animals was given the drug for 3 consecutive days, and the blank control group was given an equal volume of solvent. Three hours after the drug administration on the third day, the mice were placed in a hypobaric oxygen chamber with 10 g of soda lime per mouse for pressurization. The altitude was increased at a rate of 15 meters per second. The altitude was raised to 5,000 meters, and the mice adapted for 5 minutes. The altitude was then raised to 8,000 meters, and the mice adapted for 5 minutes. Finally, the altitude was raised to 10,000 meters, and the survival time of the mice was recorded. The results showed that N-(pyridin-2-yl)pyridine-2-thioamide significantly prolonged the survival time of mice under hypoxia-induced conditions at an altitude of 10,000 meters, and had significant anti-hypoxia ability, see attached. Figure 4 .

Claims

1. Use of N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof represented by formula (I) in the preparation of an anti-hypoxic drug:

2. The use according to claim 1, characterized in that The pharmaceutically acceptable salt of N-(pyridin-2-yl)pyridine-2-thioamide is a monoacid salt, a diacid salt or a polyacid salt formed by N-(pyridin-2-yl)pyridine-2-thioamide and an organic acid or an inorganic acid, and the structure is shown in the following formula (II): Wherein, acid A is one, two or more organic acids or inorganic acids.

3. The use according to claim 2, characterized in that: The acid A is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid or isethionic acid.

4. The use according to claim 2, characterized in that: The acid A is selected from hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, citric acid, oxalic acid, D-tartaric acid, malic acid, fumaric acid, maleic acid, lactic acid, methanesulfonic acid, benzenesulfonic acid or L-tartaric acid, glutamic acid, aspartic acid, benzoic acid.

5. The use according to claim 4, characterized in that The acid A is selected from hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, citric acid, oxalic acid, D-tartaric acid, malic acid, fumaric acid, maleic acid, methanesulfonic acid or L-tartaric acid.

6. Use of a composition comprising N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof in the preparation of an anti-hypoxic drug, wherein the composition comprises an effective amount of N-(pyridin-2-yl)pyridine-2-thioamide or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier or excipient.

7. The use according to claim 6, characterized in that The excipients include 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-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, and release retardants.

8. The use according to any one of claims 1 to 7, characterized in that The dosage form of the anti-hypoxia drug is selected from tablets, capsules, injections, sprays, aerosols, nasal drops, powder sprays, suppositories, patches, and gels.

9. The use according to claim 8, characterized in that 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 solution and nasal gel; the powder sprays are selected from powder sprays for cavity, powder sprays for nasal cavity, and powder sprays for local skin.

10. The use according to any one of claims 1 to 7, characterized in that The anti-hypoxia drug is used to treat or prevent diseases caused by hypoxia, including the following diseases or symptoms: acute mountain sickness, acute mountain sickness, chronic mountain sickness, chronic obstructive pulmonary disease, ischemia and hypoxia caused by brain trauma, hypoxia caused by chest trauma, and decreased work capacity caused by hypoxia in confined spaces at high altitudes, deep water or underground.

11. The use according to claim 10, characterized in that The chronic mountain sickness includes high altitude polycythemia.

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