WO2023226614A1 - N-(吡啶-2-基)吡啶-2-硫代酰胺或其盐在制备抗缺氧药物中的用途 - Google Patents

N-(吡啶-2-基)吡啶-2-硫代酰胺或其盐在制备抗缺氧药物中的用途 Download PDF

Info

Publication number
WO2023226614A1
WO2023226614A1 PCT/CN2023/088254 CN2023088254W WO2023226614A1 WO 2023226614 A1 WO2023226614 A1 WO 2023226614A1 CN 2023088254 W CN2023088254 W CN 2023088254W WO 2023226614 A1 WO2023226614 A1 WO 2023226614A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
pyridin
thioamide
hypoxia
pyridine
Prior art date
Application number
PCT/CN2023/088254
Other languages
English (en)
French (fr)
Inventor
何新华
周涛
陈媛
李爱玲
李磊
李西恒
邹晓翠
陈亮
何昆
张学敏
Original Assignee
中国人民解放军军事科学院军事医学研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国人民解放军军事科学院军事医学研究院 filed Critical 中国人民解放军军事科学院军事医学研究院
Publication of WO2023226614A1 publication Critical patent/WO2023226614A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention belongs to the field of medical technology, and specifically relates to the use of N-(pyridin-2-yl)pyridine-2-thioamide or its pharmaceutically acceptable salt in the preparation of anti-hypoxic drugs.
  • the oxidation reaction between oxygen and energy substances such as sugar, fat and amino acids is the basis for generating energy and sustaining 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. In particular, it can cause lung damage, myocardial damage, brain function decline, and severe hypoxia.
  • life-threatening For example, in daily life, the increase in social competition and the acceleration of the pace of life have put modern people under increasing pressure, and the burden of mental work is also increasing. More oxygen is needed to ensure the smooth work of the brain.
  • Hypoxia will cause Causes changes in brain function and causes related diseases; in some jobs, when people enter plateaus, high altitudes, dive and other operations, due to insufficient oxygen content in the environment, the body cannot obtain enough oxygen through normal breathing, causing energy metabolism disorders.
  • 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 suffer from tissue hypoxia, worsening the condition or causing
  • anti-hypoxia drugs are mainly chemical drugs and traditional Chinese medicine.
  • 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 approximately 74% within 24 hours (Gudbjartsson T , NASAdsson E, Gottfredsson M, et al. Laeknabladid, 2019, 105(11):499-507.).
  • its adverse reactions are also relatively common, mainly including numbness of limbs, fatigue, drowsiness, acute kidney disease, kidney stones, etc.
  • anti-hypoxic drugs include traditional Chinese medicine that promotes blood circulation and replenishes qi.
  • Acanthopanax is used to expand blood vessels, inhibit thrombosis, and increase oxygen utilization to adapt the body to a hypoxic environment; Rhodiola rosea can improve hypoxia.
  • N-(Pyridin-2-yl)pyridin-2-thioamide is an ATG4B inhibitor that can significantly weaken autophagic activity and promote tumor cell apoptosis by inhibiting ATG4B. Therefore, the existing technology uses this drug Most of the research focuses on the field of anti-tumor (Autophagy 2014, 10 (11), 2021-2035; Autophagy 2019, 15 (2), 295-311;). In addition, there are also literature reports that this compound has a gastric mucosal protective effect (Journal of Medicinal Chemistry 1990, 33(1), 327-36), antibacterial effect (Chemical & Pharmaceutical Bulletin (1959), 7, 349-56); indications related to anti-hypoxia have not been explored.
  • the present invention uses the currently widely used anti-hypoxic drug acetazolamide as a comparison, and through animal experiments and in vitro cell experiments under hypoxic conditions, discovers the anti-oxidation effects of N-(pyridin-2-yl)pyridine-2-thioamide. Hypoxic effect, and its anti-hypoxic effect is significantly better than existing drugs.
  • the first object of the present invention is to provide the N-(pyridin-2-yl)pyridine-2-thioamide shown in formula (I) or its pharmaceutically acceptable salt in the preparation of anti-hypoxic drugs. use:
  • the pharmaceutically acceptable salt of N-(pyridin-2-yl)pyridine-2-thioamide is a monomer formed by N-(pyridin-2-yl)pyridine-2-thioamide and an organic acid or an inorganic acid.
  • Acid, diacid or polyacid the structure is shown in the following formula (II):
  • acid A is one, two or more organic acids or inorganic acids.
  • the acid A is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid Acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, parapeptic acid, hydroxymaleic acid, Phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid or isethionic acid, etc.
  • acid A is selected from the group consisting of 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, and L-tartaric acid. , glutamic acid, aspartic acid, benzoic acid wait.
  • 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, etc.
  • the second object of the present invention is to provide the use of a composition comprising N-(pyridin-2-yl)pyridin-2-thioamide or a pharmaceutically acceptable salt thereof in the preparation of anti-hypoxic drugs, said combination
  • the substance includes an effective amount of N-(pyridin-2-yl)pyridin-2-thioamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • compositions comprising N-(pyridin-2-yl)pyridin-2-thioamide or a pharmaceutically acceptable salt thereof in the preparation of an anti-hypoxia medicament, wherein the composition also includes other Active drugs, including but not limited to anti-inflammatory agents, antiemetics, diuretics, calcium antagonists, and bronchodilators.
  • Active drugs including but not limited to anti-inflammatory agents, antiemetics, diuretics, calcium antagonists, and bronchodilators.
  • the auxiliary materials include but are not limited to , Solvent, propellant, solubilizer, co-solvent, emulsifier, colorant, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, glidant, flavoring agent , preservatives, suspending agents, coating materials, fragrances, anti-adhesive agents, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoaming agents, Thickener, inclusion agent, humectant, absorbent, diluent, flocculant and deflocculant, filter aid, release retardant.
  • the dosage form of the anti-hypoxia drug involved in the present invention is selected from tablets, capsules, injections, sprays, aerosols, nose drops, powder sprays, suppositories, patches, gels, etc.
  • 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 the group consisting of Self-hard capsules and soft capsules;
  • the injections are selected from sterile or bacteriostatic-containing aqueous injections, oily injections, freeze-dried powder injections, and microspheres for injection;
  • the sprays are selected from oral sprays, nasal sprays, topical sprays, Skin spray;
  • the aerosol is selected from aerosols for pulmonary inhalation and topical skin aerosols;
  • the nasal drops are selected from solutions for nasal drops and gels for nasal drops;
  • the powder aerosols are selected from air Powder spray for cavity use, powder spray for nasal cavity, and powder spray for local skin use.
  • the anti-hypoxic drugs involved in the present invention can be used to treat or prevent diseases or conditions caused by hypoxia, including but not limited to the treatment and prevention of acute mountain sickness, acute mountain sickness, high altitude cerebral edema, pulmonary edema, and chronic mountain sickness.
  • the chronic mountain diseases include high altitude polycythemia, high altitude hypertension, high altitude heart disease, portal hypertension, and myocardial hypertrophy.
  • N-(pyridin-2-yl)pyridine-2-thioamide and its pharmaceutically acceptable salts of the present invention have the effect of increasing cell viability.
  • the present invention has confirmed its anti-deficiency effect at the cellular level and in animal experiments. oxygen effect.
  • N-(pyridin-2-yl)pyridine-2-thioamide can significantly improve the survival status of mice under hypoxic conditions and prolong the survival of mice.
  • the survival time of mice is significantly improved, and its anti-hypoxic effect is significantly better than existing drugs, showing a very powerful anti-hypoxic ability.
  • Figure 1 shows the test results of N-(pyridin-2-yl)pyridin-2-thioamide against cellular hypoxia in Test Example 1.
  • Figure 2 shows the test results of the effect of N-(pyridin-2-yl)pyridin-2-thioamide and its salts on cell viability in Test Example 2.
  • Figure 3 is a graph showing the results of the closed hypoxia test in Test Example 3.
  • Figure 4 is a graph showing the experimental results of the simulated plateau hypoxia test in Test Example 4.
  • the compound N-(pyridin-2-yl)pyridin-2-thioamide contains relatively basic functional groups and is obtained by contacting its neutral form with a sufficient amount of acid in pure solution or a suitable inert solvent.
  • Add salt may exist in the form of their hydrates, solvates or prodrugs. Therefore, hydrates, solvates or prodrugs of the compounds of the present invention or pharmaceutically acceptable salts thereof are also included within the scope of the present invention.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipients 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, projectiles Agents, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, Suspending agents, coating materials, fragrances, anti-adhesive agents, integrating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoaming agents, thickeners, Inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, etc.
  • solvents include solvents, projectiles Agents
  • a typical formulation of the composition of the present invention is 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, for example, carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents , water and other substances.
  • solvents are generally selected based on those considered safe and effective for administration to mammals by those skilled in the art.
  • safe solvents are nontoxic aqueous solvents such as water, and other nontoxic solvents that are soluble 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, Coloring agents, sweetening agents, flavoring agents, flavoring agents or other additives known to render the drug in an acceptable form for its manufacture or use.
  • the term "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect.
  • the "effective amount” of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • the two or more drugs can be used separately or in combination, preferably in a pharmaceutical form. administered in the form of a composition.
  • active drugs can be anti-inflammatory agents, antiemetics, diuretics, calcium antagonists, bronchodilators, etc. that can improve hypoxic symptoms under certain circumstances.
  • the anti-inflammatory agent can be selected from the group consisting of salicylates, anilines, indoles, arylacetic acids, arylpropionic acids, enolic acids, alkanones, and isobufenac drugs.
  • sexual cyclooxygenase inhibitors including diarylpyrazoles, diarylfuranones, selective cyclooxygenase-2 inhibitors, and glucocorticoids.
  • aspirin for example, 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, etc.
  • Antiemetics include, but are not limited to, chlorpromazine, hydrochlorothiazide, diphenhydramine, cetirizine hydrochloride, chlorpheniramine, metoclopramide, and domperidone.
  • Diuretics include but are not limited to furosemide, torsemide, bumetanide, triamterene, amiloride, spironolactone, eplerenone, hydrochlorothiazide, indapamide, etc.
  • Calcium antagonists include, but are not limited to, amlodipine, lacidipine, benidipine, diltiazem Verapamil et al.
  • Bronchodilators include, but are not limited to, ipratropium bromide, tiotropium bromide, albuterol, terbutaline, salmeterol, formoterol, bricanid, clenbuterol, theophylline, etc.
  • the compounds of formula (I) or pharmaceutical compositions of the present invention can be administered separately or together in any known oral, intravenous, rectal, vaginal, transdermal absorption, or other local or systemic administration forms.
  • the drug is delivered to the subject.
  • compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids agents, coloring agents, sweetening agents, flavoring agents, flavoring agents or other known additives to render the pharmaceutical composition in an acceptable form for manufacture or use.
  • the medicament of the present invention is preferably administered via oral administration.
  • Solid dosage forms for oral administration may include capsules, tablets, powders or granular formulations.
  • a compound or pharmaceutical composition of the 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 carboxymethylcellulose, alginic acid Salt, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; wetting agents such as glycerol, etc.; disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; Solution retardants such as paraffin, etc.; absorption accelerators such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate.
  • binders such as carboxymethylcellulose, algin
  • the dosage form may also include buffering agents.
  • Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using lactose and high molecular weight polyethylene glycols as excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, acetic acid Ethyl ester, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc. ); glycerin; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or mixtures of several of these substances, etc.
  • inert diluents commonly used in the art, such as water or other solvents
  • compositions may also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring and perfuming agents.
  • excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring and perfuming agents.
  • suspensions in addition to the compounds or combinations of the invention, they may further contain carriers such as suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, or mixtures of several of these substances.
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, or mixtures of several of these substances.
  • 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.
  • the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents. in suitable sterile equipment for injection or infusion.
  • the unit dose of the preparation formula contains 0.5-200 mg of the compound of formula (I).
  • the unit dose of the preparation formula contains 5 mg-100 mg of the compound of formula (I).
  • 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 optimal 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 the individual will depend on the specific treatment. Usually, you start with a small dose and gradually increase the dose until you find the most suitable dose.
  • the experimental methods in the following examples are all conventional methods unless otherwise specified.
  • Human astrocyte NHA cells were seeded into two 96-well plates at a density of 8x10 3 cells/well, and N-(pyridin-2-yl)pyridin-2-thioamide was added for treatment.
  • the drug concentration was set. is 0, 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, 12.8uM; after 24 hours, ultrasonic deoxygenate the culture medium, change the medium, change the medium of plate A, add medicine again, and then place it in a hypoxic incubator (oxygen content 0.3%, which is the CC90 condition of NHA cells (hypoxia causes 90% cell death).
  • Plate B was replaced with the medium and added the medicine again and then placed in a normoxic incubator (oxygen content of 21%) as a parallel control. Incubate for 48 hours, and detect cell viability using MTT assay.
  • N-(pyridin-2-yl)pyridin-2-thioamide Treatment with N-(pyridin-2-yl)pyridin-2-thioamide can significantly enhance cell viability, and treatment with N-(pyridin-2-yl)pyridin-2-thioamide at concentrations of 6.4uM and 12.8uM is more effective It can completely resist cell death caused by hypoxia, confirming the anti-hypoxic effect of N-(pyridin-2-yl)pyridine-2-thioamide.
  • the MMT method was used to detect the effect of the example compounds and their medicinal salts on the cell viability of mouse embryonic fibroblast MEF cells. Each compound and its pharmaceutical salts were tested at 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 20 ⁇ M, 30 ⁇ M, 40 ⁇ M, and 50 ⁇ M. seven concentrations. MEF cells were seeded into a 96-well plate at a density of 1x10 4 cells/well, with a total volume of 100 ⁇ L/well. After the cells are completely attached (about 12 hours to 24 hours) and the cell density is 80%, the compounds of the examples are added to the well plate according to the concentration gradient set by the experiment, and 6 duplicate wells are set for each concentration.
  • MTS and cell culture medium were diluted according to a volume ratio of 1:5, and then added to a 96-well plate. After 1 to 4 hours, the 96-well plate was placed in a microplate reader and the absorbance value at a wavelength of 490nM was detected. The data exported from the microplate reader were processed and analyzed through Excel and Graphad Prism 8.0 software. Cell viability is calculated according to the following formula:
  • Cell activity (%) absorbance value of sample well/absorbance value of negative control well x 100%.
  • hypoxia is a response and adaptive change of cells to low oxygen conditions.
  • cells become Chronic mild hypoxia is dominated by mitochondrial energy metabolism disorders, and chronic mild hypoxia is dominated by compensatory regulation of oxygen receptors.
  • Cell viability reflects the status of cellular energy supply, and therefore can reflect the effect of compounds on cellular resistance to hypoxia.
  • the experimental results are shown in Figure 2, indicating that the example compound N-(pyridin-2-yl)pyridine-2-thioamide and its different medicinal salts have different effects on cell viability.
  • Some compounds have different effects at low concentrations. It can promote cell proliferation at low concentrations, especially dihydrochloride, phosphate, etc. at low concentrations, showing a significant effect in promoting cell proliferation, which further proves the excellent anti-hypoxic properties of the above compounds and their salts.
  • mice purchased from Viton Lever
  • mice were randomly divided into groups according to body weight, with 10 mice in each group.
  • Set up a blank control group N-(pyridin-2-yl)pyridine-2-thioamide high-dose group (100mg/kg), medium-dose group (75mg/kg), low-dose group (50mg/kg), acetazole Amine control group.
  • Animals in each group were dosed continuously for 3 days, and the blank control group was given an equal volume of vehicle.
  • the mice were placed into a wide-mouth bottle with a volume of about 320 mL, and 10 g of soda lime was built in.
  • a closed hypoxia experiment was performed, and the survival time of the mice was recorded.
  • the results showed that N-(pyridin-2-yl)pyridin-2-thioamide significantly extended the survival time of mice in closed hypoxia and had strong anti-hypoxia ability, see Figure 3.
  • BALBc mice purchased from Viton Lever were randomly divided into groups according to body weight, with 8 mice in each group. Set up a blank control group, N-(pyridin-2-yl)pyridine-2-thioamide high-dose group (100 mg/kg), low-dose group (75 mg/kg), and acetazolamide control group. Animals in each group were dosed continuously for 3 days, and the blank control group was given an equal volume of vehicle. Three hours after administration on the third day, put the mouse in a hypobaric oxygen chamber with 10g of soda lime per mouse to increase the pressure. The altitude rising speed is 15 meters/second. The altitude is raised to 5000 meters. The mice adapt for 5 minutes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Toxicology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

本发明公开了如下式(I)所示的N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐在制备抗缺氧药物中的用途，用于治疗或者预防因缺氧所致的疾病。通过缺氧条件下的动物实验以及体外细胞实验，并以目前广泛采用的抗缺氧药物乙酰唑胺为对照，验证了N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐具有显著优于现有药物的抗缺氧效果。

Description

N-(吡啶-2-基)吡啶-2-硫代酰胺或其盐在制备抗缺氧药物中的用途 技术领域
本发明属于医药技术领域，具体涉及N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐在制备抗缺氧药物中的用途。
背景技术
氧气与能量物质如糖、脂肪和氨基酸等的氧化反应是产生能量、维持生命活动的基础。缺氧可引起机体一系列生理代偿反应，如心率增加、血流动力学改变、肺动脉高压、能量代谢障碍等,尤其是其可致肺损伤、心肌受损、脑功能下降，缺氧严重的时候危及生命。比如，在日常生活中，社会竞争的增大和生活节奏的加快使得现代人承担的压力越来越大,脑力劳动的负担也不断增加，需更多的氧气才能保证大脑的顺畅工作，缺氧会导致脑部机能变化，引发相关疾病；在某些工作中，当人们进入高原、高空、潜水等作业，会因为环境中氧气含量不足，机体无法通过正常呼吸获得足够的氧气，引起能量代谢障碍，导致急性高原反应、急性高原病、高原脑水肿、高原肺水肿等；在患某些疾病时,如心肌缺血、心绞痛、慢性阻塞性肺病、哮喘、呼吸暂停综合症、脑梗、心梗、脑外伤所致的缺血缺氧、肺气肿、贫血、中风、以及退行性病变所致组织缺氧等病理条件下，机体也会组织缺氧，促使病情恶化或者引发更严重的疾病。因此积极寻找新的抗缺氧的药物，改善机体供氧和能量状态,对提高机体在缺氧条件下的生活质量和活动能力，以及相关疾病的治疗和预防具有非常重要的意义。
现阶段抗缺氧药物主要是化学药物和中药。化学药物中，乙酰唑胺是FDA唯一批准的用于治疗和预防缺氧引起的急性高原病的药物，有研究表明其在24小时内可以将急性高原病的严重程度降低约74％(Gudbjartsson T，Sigurdsson E，Gottfredsson M，et al.Laeknabladid，2019，105(11):499-507.)。但是，其不良反应也较常见，主要包括四肢麻木、疲劳、困倦、急性肾病、肾结石等(陈茂玲，梁光江，马淑媚，乙酰唑胺的不良反应文献分析，中国实用医药，2010,5(27)：162-164)。此外常用的抗缺氧药物还有活血、补气的中药，比如，刺五加用于扩张血管、抑制血栓形成、增加氧利用度而使机体适应低氧环境；红景天可提高缺氧情况下动脉氧分压和血氧饱和度，增强脑干网状系统兴奋性、改善脑功能和某些神经递质失调，具有抗缺氧、抗疲劳和增强免疫功能等作用，且能降低机体耗氧量，双向调节中枢神经系统；复方丹参滴丸、麝香保心丸、参苓白术散、复方党参胶囊等可改善冠状动脉血流量，降低心肌耗氧量，从而提高机体抗缺氧的能力等。 但是，目前的抗缺氧药物疗效不稳定、且存在一些不良反应,无法更加有效和广泛地应用。研究安全、强效的抗缺氧药物依然具有非常重要的意义和现实的需要。
N-(吡啶-2-基)吡啶-2-硫代酰胺是一种ATG4B抑制剂，可以通过抑制ATG4B从而显著减弱自噬(autophagic)活性，促进肿瘤细胞凋亡，因此现有技术对该药物的研究多集中在抗肿瘤领域(Autophagy 2014,10(11),2021-2035；Autophagy 2019,15(2),295-311；)，此外，也有文献报道该化合物具有胃黏膜保护作用(Journal of Medicinal Chemistry 1990,33(1),327-36)、抗菌作用(Chemical&Pharmaceutical Bulletin(1959),7,349-56)；并未对抗缺氧相关的适应症进行探索。
发明内容
本发明以目前广泛使用的抗缺氧药物乙酰唑胺为对照，通过缺氧条件下的动物实验以及体外细胞实验，发现了N-(吡啶-2-基)吡啶-2-硫代酰胺的抗缺氧作用，且其抗缺氧效果显著优于现有药物。
因此，本发明的第一个目的是提供式(I)所示的N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐在制备抗缺氧药物中的用途：
所述N-(吡啶-2-基)吡啶-2-硫代酰胺药学上可接受的盐为N-(吡啶-2-基)吡啶-2-硫代酰胺与有机酸或无机酸形成的单酸盐、二酸盐或多酸盐，结构如下式(II)所示：
其中，酸A为一个、两个或多个有机酸或无机酸。
所述酸A选自盐酸、氢溴酸、硫酸、硝酸、胺基磺酸、磷酸、柠檬酸、酒石酸、乳酸、丙酮酸、醋酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸或羟乙磺酸等。优选地，酸A选自盐酸、磷酸、硫酸、氢溴酸、柠檬酸、草酸、D-酒石酸、苹果酸、富马酸、马来酸、乳酸、甲磺酸、苯磺酸、L-酒石酸，谷氨酸、天冬氨酸、苯甲酸 等。
进一步优选地，酸A选自盐酸、磷酸、硫酸、氢溴酸、柠檬酸、草酸、D-酒石酸、苹果酸、富马酸、马来酸、、甲磺酸或L-酒石酸等。
本发明的第二个目的是提供包含N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐的组合物在制备抗缺氧药物中的用途，所述组合物中包括有效量的N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐和药学上可接受的载体或辅料。
优选地，根据包含N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐的组合物在制备抗缺氧药物中的用途，其中所述组合物还包括其他活性药物，所述活性药物包括但不限于抗炎剂、止吐剂、利尿剂、钙拮抗剂、支气管扩张剂。
优选地，根据包含N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐的组合物在制备抗缺氧药物中的用途，所述辅料，包括但不限于，溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂。
本发明涉及的抗缺氧药物的剂型选自片剂，胶囊剂，注射剂，喷雾剂，气雾剂，滴鼻剂，粉雾剂，栓剂、贴剂、凝胶剂等。
优选的，所述片剂选自普通片剂、速释片、缓释片、控释片、薄膜衣片、糖衣片、口含片、舌下片、生物粘附片；所述胶囊剂选自硬胶囊、软胶囊；所述注射剂选自无菌或者含抑菌剂的水性注射剂、油性注射剂、冷冻干粉针剂、注射用微球；所述喷雾剂选自口腔喷雾剂、鼻腔喷雾剂、局部皮肤喷雾剂；所述气雾剂选自肺吸入用气雾剂、局部皮肤气雾剂；所述滴鼻剂选自滴鼻用溶液、滴鼻用凝胶；所述粉雾剂选自空腔用粉雾剂、鼻腔用粉雾剂、局部皮肤用粉雾剂。
本发明涉及的抗缺氧药物可以用于治疗或者预防因缺氧所致的疾病或病症，包括但不限于治疗和预防急性高原反应，急性高原病，高原脑水肿，肺水肿，慢性高原病，心肌缺血，心绞痛，脑供血不足，慢性阻塞性肺病，呼吸暂停综合症，脑梗，心梗，脑外伤所致的缺血缺氧，胸部外伤所致缺氧，哮喘，过敏性喉头水肿痉挛，异物阻塞、麻醉意外等多种原因导致呼吸功能障碍，肺气肿，贫血，中风，急性缺氧性脑病，新生儿缺氧缺血性脑病，缺氧所致的记忆力衰退，缺氧所致的眩晕，退行性病变所致的组织缺氧引起的机体 麻木，以及高空、深水或地下的密闭空间缺氧引起的作业能力下降等。
其中，所述慢性高原病包括高原红细胞增多症、高原高血压及高原心脏病、门静脉高压、心肌肥大。
有益效果
本发明的化合物N-(吡啶-2-基)吡啶-2-硫代酰胺及其药学上可接受的盐具有增加细胞活力的作用，本发明在细胞层面以及动物实验中均证实了其抗缺氧效果。特别的，在小鼠密闭缺氧实验和模拟高原缺氧实验中，N-(吡啶-2-基)吡啶-2-硫代酰胺可以显著改善小鼠在缺氧条件下的生存状态，延长小鼠的生存时间，且其抗缺氧效果显著优于现有药物，显示出非常强大的抗缺氧能力。
附图说明
图1为测试实施例1中N-(吡啶-2-基)吡啶-2-硫代酰胺抗细胞缺氧测试结果。
图2为测试实施例2中N-(吡啶-2-基)吡啶-2-硫代酰胺及其盐对细胞活力影响测试结果。
图3为测试实施例3中密闭缺氧测试实验结果图。
图4为测试实施例4中模拟高原缺氧测试实验结果图。
具体实施方式
以下，将详细地描述本发明。在进行描述之前，应当理解的是，在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义，而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上，根据与本发明的技术方面相应的含义和概念进行解释。因此，这里提出的描述仅仅是出于举例说明目的的优选实例，并非意图限制本发明的范围，从而应当理解的是，在不偏离本发明的精神和范围的情况下，可以由其获得其他等价方式或改进方式。
化合物N-(吡啶-2-基)吡啶-2-硫代酰胺中含有相对碱性的官能团，通过在纯的溶液或合适的惰性溶剂中用足够量的酸与其中性形式接触的方式获得酸加成盐。本发明化合物或其药学上可接受的盐可以存在为其水合物，溶剂化物或前药的形式。因此，本发明化合物或其药学上可接受的盐的水合物，溶剂化物或前药也包括在本发明的范围内。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的辅料”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质，代表性的辅料有溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂等。关于载体的其他信息，可以参考Remington：The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
本发明中组合物典型的配方是通过混合本发明的式(I)表示的化合物或其药学上可接受的盐，及载体、稀释剂或赋形剂制备而成。适宜的载体、稀释剂或赋形剂是本领域技术人员所熟知的，包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。
所用的特定载体、稀释剂或赋形剂，将根据本发明的化合物的使用方式和目的而定。一般以本领域技术人员认为可安全有效地给药至哺乳类动物的溶剂为基础而选择溶剂。一般而言，安全的溶剂是无毒性含水溶剂诸如水，以及其他可溶于水或与水混溶的无毒性溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中的一种或多种。该配方也可包括一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物以可被接受的形式制造或使用。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本发明所述的如式(I)的化合物或其药学上可接受的盐与至少一种其它活性药物的组合使用时，两种药物或多种药物可以分开使用也可以组合使用，优选以药学组合物的形式给药。
其它活性药物可以为在一定情况下改善缺氧症状的抗炎剂、止吐剂、利尿剂、钙拮抗剂、支气管扩张剂等。
抗炎剂可选自水杨酸类、苯胺类、吲哚类、芳基乙酸类、芳基丙酸类、烯醇酸类、烷酮类药物、异丁芬酸类药物在内的非选择性环氧酶抑制药，包括二芳基吡唑类药物、二芳基呋喃酮类药物在内的选择性环氧酶-2抑制药，以及糖皮质激素类药物。例如阿司匹林、双水杨酯、二氟尼柳、对氨基水杨酸、非那西丁、对乙酰氨基酚、阿西美辛、吲哚美辛、托美丁、双氯芬酸钠、布洛芬、氟比洛芬酯、萘普生、吡罗昔康、美洛昔康、萘丁美酮、舒林酸、塞来昔布、罗非昔布、泼尼松、甲泼尼龙、地塞米松等。
止吐剂包括但不限于氯丙嗪、氢氯噻嗪、苯海拉明、盐酸西替利嗪、扑尔敏、胃复安、吗丁啉。
利尿药包括但不限于呋塞米、托拉塞米、布美他尼、氨苯蝶啶、阿米洛利、螺内酯、依普利酮、氢氯噻嗪、吲达帕胺等。
钙拮抗剂包括但不限于氨氯地平、拉西地平、贝尼地平、地尔硫维拉帕米等。支气管扩张剂包括但不限于溴化异丙托品、噻托溴胺、沙丁胺醇、特布他林、沙美特罗、福莫特罗、博利康尼、克伦特罗、茶碱等。
本发明的如式(I)的化合物或药物组合物能以任一已知的口服、静脉注射、直肠给药、阴道给药、透皮吸收、其它局部或全身给药形式，分开或一起给药至受试者。
这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物组合物以可被接受的形式制造或使用。
本发明药物优选口服给药途径。用于口服给药的固态剂型可包括胶囊、片剂、粉末或颗粒制剂。在固态剂型中，本发明的化合物或药物组合物与至少一种惰性赋形剂、稀释剂或载剂混合。适宜的赋形剂、稀释剂或载剂包括诸如柠檬酸钠或磷酸二钙的物质，或淀粉、乳糖、蔗糖、甘露糖醇、硅酸等；粘合剂如羧甲基纤维素、褐藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等；湿润剂如甘油等；崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、特定的络合硅酸盐、碳酸钠等；溶液阻滞剂如石蜡等；吸收促进剂如季铵化合物等；吸附剂如高岭土、膨润土等；润滑剂如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠等。在胶囊与片剂的情况下，该剂型亦可包括缓冲剂。类似类型的固态组合物亦可作为软式与硬式填充明胶胶囊中的填料，其使用乳糖以及高分子量聚乙二醇等作为赋形剂。
用于口服给药的液态剂型包括药学上可接受的乳化液、溶液、悬浮液、糖浆液与酏剂。 除了本发明的化合物或其组合物之外，该液态剂型可含有本领域中常用的惰性稀释剂，诸如水或其他溶剂；增溶剂及乳化剂诸如乙醇、异丙基醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺；油类(如棉籽油、落花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油等)；甘油；四氢糠基醇；聚乙二醇与脱水山梨糖醇的脂肪酸酯；或这些物质中的几种的混合物等。
除了这些惰性稀释剂之外，该组合物也可包括赋形剂，诸如润湿剂、乳化剂、悬浮剂、增甜剂、调味剂与香料剂中的一种或多种。
就悬浮液而言，除了本发明的化合物或组合之外，可进一步含有载剂诸如悬浮剂，如乙氧基化异硬脂醇、聚氧乙烯山梨醣醇、脱水山梨醣醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄耆胶，或这些物质中几种的混合物等。
本发明化合物或药物组合物可采用其它局部给药剂型给药，包括膏、粉末、喷剂及吸入剂。该药物可在无菌条件下与药学上可接受的赋形剂、稀释剂或载剂以及所需要的任一防腐剂、缓冲剂或推进剂混合。眼用配方、眼用油膏、粉末与溶液，亦意欲涵盖于本发明的范围内。
本发明所提供的化合物和药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中以及适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位剂量中包含0.5-200mg式(I)化合物，优选地，制剂配方的单位剂量中包含5mg-100mg式(I)化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径。最优选为口服。最佳优选日剂量为5-200mg/kg体重，一次性服用，或5-100mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。下述实施例中的实验方法，如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径获得。熔点采用YRT-3熔点仪测定。1H-NMR和13C-NMR采用LSI-IST-005/JNM-ECA400核磁共振仪测定。ESI-MS采用LSI-IST-003/G6230A型质谱仪测定。薄层层析板采用默克GF254型荧光板。紫外线高压汞灯由上海季光特种照明电器厂提供。所用化学试剂均为化学纯或分析纯。
实施例1 N-(吡啶-2-基)吡啶-2-硫代酰胺(制备方法一)
将以2-氨基吡啶(9.3g，0.1mol)和2-甲基吡啶(9.4g，0.1mol)加入到100mL的圆底瓶中，加入单质硫(6.4g，0.2mol)，在氩气保护下，加热至160-165℃，保温反应24小时，反应液倒入冰水中，用稀盐酸调节溶液pH为1-2，抽滤除未反应的单质硫，然后用氢氧化钠溶液调节溶液pH为7-8，静止2小时，抽滤，得到N-(吡啶-2-基)吡啶-2-硫代酰胺粗品，用异丙醇重结晶，除去色素，再酸碱除微量的硫，然后再甲醇重结晶，得到纯度在99.5％以上的精制品，9.6g，收率45％。1H 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,1H),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]+.
实施例2 N-(吡啶-2-基)吡啶-2-硫代酰胺(制备方法二)
将吡啶-2-甲酸(12.3g，0.1mol)和2-氨基吡啶(9.3g，0.1mol)加入到无水二甲基甲酰胺(100mL)中，加入N,N’-二环己基碳二亚胺(DCC，26.4g,0.12mol)和催化量的HOBt，氮气保护，室温搅拌30分钟，然后加热50-55℃，保温反应24小时。降温至室温，滴加饱和氯化铵(2mL)，搅拌30分钟，减压除去溶剂，残余物溶解于乙酸乙酯(50mL)，抽滤，滤液浓缩，柱层析，得到白色固体16.5g，Yield:83％。1H 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]+.
将上步所得白色固体(10g，0.05mol)和lawesson试剂(20g，0.05mol)的甲苯溶液(175mL)加入到反应瓶中，回流反应12小时。将反应液减压除去溶剂，过快速硅胶色谱柱纯化(石油醚：乙酸乙酯＝1：3)，得到目标产物N-(吡啶-2-基)吡啶-2-硫代酰胺(16.7g)，收率78％。MP 81-83℃。1H 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,1H),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]+.
实施例3 N-(吡啶-2-基)吡啶-2-硫代酰胺二盐酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(30mL)，滴加1N的盐酸乙酸乙酯(21mL，21mmol)，搅拌，冰浴析晶充分，抽滤，得到橙红色固体(2.47g)，收率90％。MP 165-167℃。MS(ESI,m/z):216.3[M+H]+.(为N-(吡啶-2-基)吡啶-2-硫代酰胺结构片段信号)。1H 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＝1.3Hz,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).
实施例4 N-(吡啶-2-基)吡啶-2-硫代酰胺单盐酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(30mL)，滴加1N的盐酸乙酸乙酯(10mL，10mmol)，搅拌，冰浴析晶充分，抽滤，得到橙红色固体(2.47g)，收率90％。MP 164-166℃。MS(ESI,m/z):216.3[M+H]+(为N-(吡啶-2-基)吡啶-2-硫代酰胺结构片段信号)。1H 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).
实施例5 N-(吡啶-2-基)吡啶-2-硫代酰胺硫酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于二氯甲烷(30mL)，滴加浓硫酸(10mmol)，搅拌，冰浴析晶充分，抽滤，得到红色固体(2.97g)，收率95％。MP 112-114℃。MS(ESI,m/z):216.3[M+H]+(为N-(吡啶-2-基)吡啶-2-硫代酰胺结构片段信号)。1H 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).
实施例6 N-(吡啶-2-基)吡啶-2-硫代酰胺磷酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于二氯甲烷(30mL)，滴加1磷酸(10mmoL)，搅拌，冰浴析晶充分，抽滤，得到红色固体(2.90g)，收率93％。MS (ESI,m/z):216.3[M+H]+(为N-(吡啶-2-基)吡啶-2-硫代酰胺结构信号)。1H 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).
实施例7 N-(吡啶-2-基)吡啶-2-硫代酰胺氢溴酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于二氯甲烷(30mL)；低温下加入1N氢溴酸(10mL,10mmol)，搅拌，冰浴析晶充分，抽滤，得到红色固体(2.90g)，收率93％。MP 194-196℃。MS(ESI,m/z):216.3[M+H]+(为N-(吡啶-2-基)吡啶-2-硫代酰胺结构信号)。1H 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).
实施例8 N-(吡啶-2-基)吡啶-2-硫代酰胺草酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(30mL)加入到圆底瓶中；再加入将草酸(0.9g，10mmol)溶于无水乙醇(2mL)得到的溶液，回流30分钟，冷却析晶充分，抽滤，得到红色固体(2.90g)，收率95％。MP 161-162℃。1H 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(ddd,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).
实施例9 N-(吡啶-2-基)吡啶-2-硫代酰胺醋酸盐(未成功)
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(10mL)；加入冰醋酸(0.65g，10mmol)搅拌，冰浴析晶充分，抽滤，得到红色固体，MP 79-81℃，与游离碱相同，核磁未见醋酸甲基氢信号，未得到N-(吡啶-2-基)吡啶-2-硫代酰胺醋酸盐。
实施例10 N-(吡啶-2-基)吡啶-2-硫代酰胺苹果酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(30mL)加入到圆底瓶中；再加入将苹果酸(1.34g，10mmol)溶于无水乙醇(5mL)得到的溶液，回流30分钟，冷却析晶充分，抽滤，得到红色固体(3.11g)，收率89％。MP 67-69℃。1H 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(ddd,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＝7.4,4.8,1.0Hz,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).
实施例11 N-(吡啶-2-基)吡啶-2-硫代酰胺柠檬酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(30mL)加入到圆底瓶中；再加入将柠檬酸(1.92g，10mmol)溶于无水乙醇(5mL)得到的溶液，回流30分钟，冷却析晶充分，抽滤，得到红色固体(3.74g)，收率92％。MP 97-99℃。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).
实施例12 N-(吡啶-2-基)吡啶-2-硫代酰胺富马酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(30mL)加入到圆底瓶中；再加入将富马酸(1.16g，10mmol)溶于无水乙醇(5mL)得到的溶液，回流30分钟，冷却析晶充分，抽滤，得到红色固体(3.01g)，收率91％。MP108-109℃。1H 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).
实施例13 N-(吡啶-2-基)吡啶-2-硫代酰胺马来酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(30mL)加入到圆底瓶中；再加入将苹果酸(1.16g，10mmol)溶于无水乙醇(5mL)得到的溶液，回流30分钟，冷却析晶充分，抽滤，得到红色固体(3.18g)，收率96％。MP 107-109℃。1H 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(ddd,J＝7.5,4.7,1.1Hz,1H),7.38(ddd,J＝7.4,4.8,0.9Hz,1H),6.28(s,2H).
实施例14 N-(吡啶-2-基)吡啶-2-硫代酰胺二甲磺酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(30mL)加入到圆底瓶中；再加入将甲磺酸(1.92g，20mmol)，回流30分钟，除去溶剂，得到糖浆状物(3.99g)，收率98％。1H 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).
实施例15 N-(吡啶-2-基)吡啶-2-硫代酰胺-D-酒石酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(30mL)加入到圆底瓶中；再加入将D-酒石酸(1.50g，10mmol)溶于无水乙醇(5mL)得到的溶液，回流30分钟，冷却析晶充分，抽滤，得到红色固体(3.36g)，收率92％。MP 116-119℃。1H NMR(600MHz,DMSO-d6)δ(ppm):13.10-12.15(brs,2H),12.46(s,1H),9.03(d,J＝8.2Hz,1H),8.73(dt,J＝4.7,1.2Hz,1H),8.62(dt,J＝8.0,1.0Hz,1H),8.55(dd,J＝4.9,1.8Hz,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).
实施例16 N-(吡啶-2-基)吡啶-2-硫代酰胺-L-酒石酸盐
将N-(吡啶-2-基)吡啶-2-硫代酰胺(2.15g，10mmol)溶于乙酸乙酯(30mL)加入到圆底瓶中；再加入将L-酒石酸(1.50g，10mmol)溶于无水乙醇(5mL)得到的溶液，回流30分钟，冷却析晶充分，抽滤，得到红色固体(3.50g)，收率96％。MP 112-114℃。 1H 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).
测试实施例1 N-(吡啶-2-基)吡啶-2-硫代酰胺抗细胞缺氧测试
将人星形胶质细胞NHA细胞按照8x103cells/well的密度种到2块96孔板中，分别加N-(吡啶-2-基)吡啶-2-硫代酰胺进行处理，药物浓度设置为0，0.2，0.4，0.8，1.6，3.2，6.4，12.8uM；24小时后，将培养基超声除氧、换液，A板换液再次加药后放入低氧孵箱(含氧量为0.3％，为NHA细胞CC90(缺氧导致细胞死亡90％)条件)，B板换液再次加药后放入常氧孵箱(含氧量为21％)作为平行对照。孵育48小时，用MTT法检测细胞活力。
结果见附图1，药物处理后，常氧条件下，不同实验浓度N-(吡啶-2-基)吡啶-2-硫代酰胺处理的NHA细胞增殖活力均增强；低氧条件下，高浓度的N-(吡啶-2-基)吡啶-2-硫代酰胺处理可显著增强细胞活力，6.4uM和12.8uM浓度下的N-(吡啶-2-基)吡啶-2-硫代酰胺处理更可以完全抵抗低氧所致的细胞死亡，证实了N-(吡啶-2-基)吡啶-2-硫代酰胺的抗缺氧作用。
测试实施例2 N-(吡啶-2-基)吡啶-2-硫代酰胺及其盐对细胞活力影响测试
利用MMT法检测实施例化合物及其药用盐对小鼠胚胎成纤维细胞MEF细胞的细胞活力的影响，每个化合物及其药用盐检测1μM、5μM、10μM、20μM、30μM、40μM、50μM，七个浓度。将MEF细胞按照1x104cells/well的密度种至96孔板，总体积为100μL/孔。待细胞贴壁完全后(约12小时～24小时)，细胞密度80％时，将实施例化合物按照实验设定的浓度梯度分别加入孔板中，每种浓度设置6个复孔。加药24小时后，吸弃原培养基。将MTS和细胞培养基按照1:5的体积比进行稀释，随后加入96孔板中，1小时～4小时后，将96孔板置于酶标仪中，检测490nM波长处的吸光度值。从酶标仪中导出的数据，通过Excel、Graphad Prism 8.0软件进行数据处理分析。细胞活度按照以下公式计算：
细胞活度(％)＝样品孔的吸光度值/阴性对照孔吸光度值x 100％。
缺氧的本质是细胞对低氧状态的一种反应和适应性改变。当急性严重缺氧时细胞变 化以线粒体能量代谢障碍为主，慢性轻度缺氧细胞以氧感受器的代偿性调节为主。细胞活力反映细胞能量供给的状态，因此可以从侧面反映化合物对细胞抗缺氧的影响。实验结果如附图2所示，提示实施例化合物N-(吡啶-2-基)吡啶-2-硫代酰胺及其不同的药用盐对细胞活力的影响各不相同，部分化合物在低浓度下可以促进细胞增殖，尤其是低浓度下的二盐酸盐、磷酸盐等，显示出显著的促进细胞增殖效果，进而佐证上述化合物及其盐优异的抗缺氧性能。
测试实施例3密闭缺氧测试实验
将BALBc小鼠(购自维通利华)按照体重随机分组，每组10只。设置空白对照组、N-(吡啶-2-基)吡啶-2-硫代酰胺高剂量组(100mg/kg)、中剂量组(75mg/kg)、低剂量组(50mg/kg)、乙酰唑胺对照组。各组动物连续给药3天，空白对照组给与等体积的溶媒。第三天给药3小时后，将小鼠分别放入体积为约320mL的广口瓶中，内置钠石灰10g，进行密闭缺氧实验，记录小鼠存活的时间。结果显示，N-(吡啶-2-基)吡啶-2-硫代酰胺显著延长小鼠密闭缺氧的生存时间，具有强效的抗缺氧能力，见附图3。
测试实施例4模拟高原缺氧测试实验
将BALBc小鼠(购自维通利华)按照体重随机分组，每组8只。设置空白对照组、N-(吡啶-2-基)吡啶-2-硫代酰胺高剂量组(100mg/kg)、低剂量组(75mg/kg)、乙酰唑胺对照组。各组动物连续给药3天，空白对照组给与等体积的溶媒。第三天给药3小时后，将小鼠低压氧舱，内置钠石灰10g/只小鼠，进行升压，海拔上升速度为15米/秒，海拔升至5000米，小鼠适应5分钟，然后再升高海拔至8000米，小鼠适应5分钟，最后升高海拔至10000米，记录小鼠存活的时间。结果显示，N-(吡啶-2-基)吡啶-2-硫代酰胺显著延长小鼠在10000米海拔模拟条件下的缺氧的生存时间，具有显著的抗缺氧能力，见附图4。

Claims (9)

  1. 式(I)所示的N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐在制备抗缺氧药物中的用途：
  2. 根据权利要求1所述的用途，其特征在于，所述N-(吡啶-2-基)吡啶-2-硫代酰胺药学上可接受的盐为N-(吡啶-2-基)吡啶-2-硫代酰胺与有机酸或无机酸形成的单酸盐、二酸盐或多酸盐，结构如下式(II)所示：
    其中，酸A为一个、两个或多个有机酸或无机酸。
  3. 根据权利要求2所述的用途，其特征在于，所述酸A选自盐酸、氢溴酸、硫酸、硝酸、胺基磺酸、磷酸、柠檬酸、酒石酸、乳酸、丙酮酸、醋酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸或羟乙磺酸；
    优选的，所述酸A选自盐酸、磷酸、硫酸、氢溴酸、柠檬酸、草酸、D-酒石酸、苹果酸、富马酸、马来酸、乳酸、甲磺酸、苯磺酸或L-酒石酸、谷氨酸、天冬氨酸、苯甲酸；
    更优选的，所述酸A选自盐酸、磷酸、硫酸、氢溴酸、柠檬酸、草酸、D-酒石酸、苹果酸、富马酸、马来酸、甲磺酸或L-酒石酸。
  4. 包含N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐的组合物在制备抗缺氧药物中的用途，所述组合物中包括有效量的根据权利要求1至3中任意一项所述N-(吡啶-2-基)吡啶-2-硫代酰胺或其药学上可接受的盐和药学上可接受的载体或辅料。
  5. 根据权利要求4所述用途，所述组合物还包括其他活性药物，所述活性药物包括抗炎剂、止吐剂、利尿剂、钙拮抗剂、支气管扩张剂。
  6. 根据权利要求4所述的用途，其特征在于，所述辅料包括溶剂、抛射剂、增溶剂、 助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂。
  7. 根据权利要求1至6中任意一项所述的用途，其特征在于，所述抗缺氧药物的剂型选自片剂，胶囊剂，注射剂，喷雾剂，气雾剂，滴鼻剂，粉雾剂，栓剂、贴剂、凝胶剂；
    优选的，所述片剂选自普通片剂、速释片、缓释片、控释片、薄膜衣片、糖衣片、口含片、舌下片、生物粘附片；所述胶囊剂选自硬胶囊、软胶囊；所述注射剂选自无菌或者含抑菌剂的水性注射剂、油性注射剂、冷冻干粉针剂、注射用微球；所述喷雾剂选自口腔喷雾剂、鼻腔喷雾剂、局部皮肤喷雾剂；所述气雾剂选自肺吸入用气雾剂、局部皮肤气雾剂；所述滴鼻剂选自滴鼻用溶液、滴鼻用凝胶；所述粉雾剂选自空腔用粉雾剂、鼻腔用粉雾剂、局部皮肤用粉雾剂。
  8. 根据权利要求1至6中任意一项所述的用途，其特征在于，所述抗缺氧药物用于治疗或预防因缺氧所致的疾病，包括如下疾病或病症：急性高原反应，急性高原病，高原脑水肿，肺水肿，慢性高原病，心肌缺血，心绞痛，脑供血不足，慢性阻塞性肺病，呼吸暂停综合症，脑梗，心梗，脑外伤所致的缺血缺氧，胸部外伤所致缺氧，哮喘，过敏性喉头水肿痉挛，异物阻塞、麻醉意外导致的呼吸功能障碍，肺气肿，贫血，中风，急性缺氧性脑病，新生儿缺氧缺血性脑病，缺氧所致的记忆力衰退，缺氧所致的眩晕，退行性病变所致的组织缺氧引起的机体麻木，以及高空、深水或地下的密闭空间缺氧引起的作业能力下降。
  9. 根据权利要求8所述的用途，其特征在于，所述慢性高原病包括高原红细胞增多症、高原高血压及高原心脏病、门静脉高压、心肌肥大。
PCT/CN2023/088254 2022-05-24 2023-04-14 N-(吡啶-2-基)吡啶-2-硫代酰胺或其盐在制备抗缺氧药物中的用途 WO2023226614A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210571369.2 2022-05-24
CN202210571369.2A CN117137914A (zh) 2022-05-24 2022-05-24 N-(吡啶-2-基)吡啶-2-硫代酰胺或其盐在制备抗缺氧药物中的用途

Publications (1)

Publication Number Publication Date
WO2023226614A1 true WO2023226614A1 (zh) 2023-11-30

Family

ID=88899396

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/088254 WO2023226614A1 (zh) 2022-05-24 2023-04-14 N-(吡啶-2-基)吡啶-2-硫代酰胺或其盐在制备抗缺氧药物中的用途

Country Status (2)

Country Link
CN (1) CN117137914A (zh)
WO (1) WO2023226614A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06298733A (ja) * 1993-04-13 1994-10-25 Mitsubishi Kasei Corp ３−オキソ−３−（ピリジン）プロパンチオアミド誘導体
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
US20210069202A1 (en) * 2019-09-10 2021-03-11 Northwestern University Methods for enhancing cytotoxic cancer therapy through inhibition of atg4b

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06298733A (ja) * 1993-04-13 1994-10-25 Mitsubishi Kasei Corp ３−オキソ−３−（ピリジン）プロパンチオアミド誘導体
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
US20210069202A1 (en) * 2019-09-10 2021-03-11 Northwestern University Methods for enhancing cytotoxic cancer therapy through inhibition of atg4b

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
SUN SHENGMING, WU YING, FU HONGTUO, GE XIANPING, YOU HONGZHENG, WU XUGAN: "Identification and Characterization of Four Autophagy-Related Genes That Are Expressed in Response to Hypoxia in the Brain of the Oriental River Prawn (Macrobrachium nipponense)", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL (MDPI), BASEL, CH, vol. 20, no. 8, Basel, CH , pages 1856, XP093112416, ISSN: 1422-0067, DOI: 10.3390/ijms20081856 *
WAN, BAOLAN ET AL.: "Research on Mechanism of Nuclear Respiratory Factor 1 Affecting neuronal autophagy in Neonatal Rat Hypoxic Ischemic Encephalophathy by Regulating ATG4", 2020 NATIONAL ACADEMIC ONLINE CONFERENCE ABSTRACT COLLECTION OF THE CHINESE SOCIETY OF BIOCHEMISTRY AND MOLECULAR BIOLOGY, 22 October 2020 (2020-10-22) *
YANG, GAOXIA ET AL.: "Targeting Atg4B for Cancer Therapy: Chemical Mediators", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 209, 11 October 2020 (2020-10-11), XP086407130, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2020.112917 *

Also Published As

Publication number Publication date
CN117137914A (zh) 2023-12-01

Similar Documents

Publication Publication Date Title
KR101502957B1 (ko) (아자)인돌 유도체 및 그 의약 용도
KR102488479B1 (ko) 인플루엔자 바이러스 감염에 사용하기 위한 인돌
JP5203214B2 (ja) プリン化合物およびその使用方法
CN102985402B (zh) 反苯环丙胺衍生物作为组蛋白去甲基酶lsd1和/或lsd2的抑制剂
US20070219239A1 (en) Nitrogen-containing heterocycle derivatives, pharmaceutical compositions, and methods of use thereof as antiviral agents
US9139583B2 (en) Selective HDAC3 inhibitors
JP2017128605A (ja) 抗ウイルス化合物の固体形態
JP2002529503A (ja) ニトロソ化及びニトロシル化ｈ２リセプターアンタゴニスト化合物及び組成物並びにその利用方法
US20210347773A1 (en) Activator of trek (twik related k+ channels) channels
JP2005519907A (ja) Ｈｉｖインテグラーゼ阻害薬として有用なヒドロキシナフチリジノンカルボキサミド類
JP2013139483A (ja) インフルエンザ治療剤
WO2006030739A1 (ja) 光学活性アミン誘導体の製造方法
TW201213329A (en) Pyrazine derivatives as ENaC blockers
EA009941B1 (ru) Имидазопиридинзамещённые тропановые производные, обладающие активностью антагониста ccr5 рецептора, для лечения вируса иммунодефицита человека (вич) и воспаления
CN111410661A (zh) 帽依赖性内切核酸酶抑制剂及其用途
ES2314446T3 (es) Derivados de tetrahidrocarbazol y su uso farmaceutico.
US9464051B2 (en) Compositions and methods for the treatment of inflammation and pain
JP2013515766A (ja) イマチニブジクロロ酢酸塩及びそれを含む抗癌剤組成物
WO2014091384A2 (en) Compositions and methods for the treatment of mucositis
JP2008520673A (ja) Ｈｃｖ阻害剤
UA120856C2 (uk) Способи та композиції для лікування розладів, пов'язаних з віл
JP2022507117A (ja) 呼吸器疾患の処理のための新規な化合物
US20120058085A1 (en) Deuterium Modified Benzimidazoles
ES2327416T3 (es) Derivados de tetraidrocarbazol y su uso farmaceutico.
WO2023226614A1 (zh) N-(吡啶-2-基)吡啶-2-硫代酰胺或其盐在制备抗缺氧药物中的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23810688

Country of ref document: EP

Kind code of ref document: A1