WO2019203176A1 - 心筋細胞の保護用の医薬組成物 - Google Patents
心筋細胞の保護用の医薬組成物 Download PDFInfo
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- 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
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- 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
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Definitions
- cardiomyocytes responsible for the pump function are damaged and eventually degenerate or necrotize. Since cardiomyocytes generally lack the ability to self-renew, protecting the damaged cardiomyocytes to prevent degeneration and necrosis is considered effective in the treatment of these diseases. Not.
- Myocardial infarction is a disease in which blood flow decreases due to occlusion or stenosis of coronary blood vessels, causing the myocardium to become ischemic and necrotic, and is one of the main causes of chronic heart failure.
- the treatment of acute myocardial infarction has been improved by the use of surgical therapy using balloon catheters, stents, etc., or reperfusion techniques that resume blood flow in the coronary arteries by thrombolysis, improving mortality and prognosis due to myocardial infarction. It was done.
- the reperfusion method has a new problem that cardiomyocytes are damaged (reperfusion injury) due to intracellular influx of calcium ions and production of active oxygen during reperfusion. Therefore, suppression of reperfusion injury has been demanded.
- Several drugs that suppress reactive oxygen species have been reported (Non-patent Documents 1 and 2), but none have been clinically applied. Control of reperfusion injury by other mechanisms has not been established.
- Certain 4-amino-naphthalene-1-sulfonic acid derivatives have VCP (valosin-containing protein) ATPase inhibitory activity and are expected to have therapeutic effects on various diseases (Patent Document 1). In particular, it is known to be effective for the treatment or prevention of eye diseases and leptin resistance (Patent Documents 2 to 5).
- the purpose of the present application is to provide a pharmaceutical composition for cardiomyocyte protection.
- VCP inhibitor has a cardiomyocyte protective effect and is effective in the treatment of heart diseases such as myocardial infarction.
- the present application provides a compound of formula (I): [Where, Ra is halo, hydroxy, alkyl, halo substituted alkyl, aryl, halo or alkyl substituted aryl, alkoxy, hydroxy or carboxy substituted alkoxy, aryloxy, halo or alkyl substituted aryloxy, CHO, C (O) -alkyl, C (O ) -Aryl, C (O) -alkyl-carboxyl, C (O) -alkylene-carboxyester and cyano, m is an integer selected from 0 to 4] Or a ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical composition for protecting cardiomyocytes.
- the present application provides a pharmaceutical composition for the treatment of myocardial infarction comprising a compound of formula (I) or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof.
- the present application provides a pharmaceutical composition for protecting cardiomyocytes.
- VCP in each human organ is shown.
- the expression level of VCP in each organ of a mouse is shown.
- the expression level of VCP in cardiomyocytes and fibroblasts isolated from mouse heart is shown.
- the cell number and ATP level of rat cardiomyocytes cultured under ER stress with tunicamycin addition are shown.
- 25, 50, 100, or 200 ⁇ M KUS121 was added to the KUS121 (+) group.
- the results of Western blotting of CHOP and Bip in rat myocardial blast cells cultured under ER stress with tunicamycin addition are shown. 200 ⁇ M KUS121 was added to the KUS121 (+) group.
- FIG. 6 shows the ATP level of the heart when KUS121 is intraperitoneally administered before ischemia in a heart ischemia-reperfusion injury model of A team mouse.
- Schedule of KUS121 administration after reperfusion in a mouse cardiac ischemia-reperfusion injury model (80 mg / kg body weight intravenously + 80 mg / kg body weight in coronary artery immediately after reperfusion, 160 mg / kg body weight intraperitoneally every 24 hours thereafter), and The size of the infarct portion with respect to the left ventricle on the seventh day after surgery is shown.
- Schedule of KUS121 administration after reperfusion in mouse cardiac ischemia / reperfusion injury model Intravenous 25 mg / kg body weight + intracoronary artery 25 mg / kg body weight immediately after reperfusion
- infarct on left ventricle 7 days after operation Indicates the size.
- Schedule of KUS121 administration after reperfusion in mouse cardiac ischemia / reperfusion injury model (intravenous 8 mg / kg body weight + intracoronary artery 8 mg / kg body weight immediately after reperfusion) and 7 days after surgery Indicates the size.
- a Left ventricular ejection fraction
- b End diastolic volume
- c End systolic volume
- d Cardiac output
- e Left ventricular weight.
- the result of the histological evaluation in a porcine cardiac ischemia reperfusion injury model is shown. Left: size of ischemic area relative to left ventricle, right: size of infarcted area relative to ischemic area.
- Intra-coronary KUS121 administration schedule after reperfusion (0.64, 2.5 or 5.0 mg / kg body weight after reperfusion) in the porcine cardiac ischemia-reperfusion injury model, infarct size relative to the left ventricle ( Left), the size of the ischemic area relative to the left ventricle (center), and the size of the infarcted area relative to the ischemic area (right).
- Alkyl means a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Alkyl means, for example, straight-chain and branched-chain hydrocarbyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and neopentyl. It is not limited.
- substituted means that one or more hydrogen atoms of the group are replaced by the same or different designated substituents.
- Alkylene means a divalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Alkylene groups include branched and straight chain hydrocarbyl groups.
- Alkoxy means a group of —O-alkyl where alkyl is defined herein. Alkoxy means for example, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy and n-pentoxy.
- Aryl means a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having one ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthryl). Aryl groups typically include phenyl and naphthyl. “Aryloxy” refers to the group —O-aryl where aryl is defined herein and includes, for example, phenoxy and naphthoxy.
- Cyano refers to the group —CN.
- Carboxyl or “carboxy” means —COOH or a salt thereof.
- Carboxyester means a radical of —C (O) O-alkyl, where alkyl is defined herein.
- Halo means halogen, especially fluoro, chloro, bromo and iodo.
- Hydroxy refers to the group —OH.
- substituents not explicitly defined in this specification is performed by naming the terminal portion of the functional group and then naming the adjacent functional group toward the point of attachment.
- substituent “arylalkyloxycarbonyl” refers to (aryl)-(alkyl) -O—C (O) —.
- an enantiomer or a diastereomer may exist depending on a substitution pattern.
- the compound of formula (I) may be a racemate or may be separated into stereoisomerically pure components by known methods. Certain compounds can be tautomeric.
- Ester means an ester that can be hydrolyzed in vivo and includes those that are readily degraded in the human body to release the parent compound or a salt thereof. Suitable ester groups are, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanoic acids, alkenoic acids, cycloalkanoic acids and alkanedioic acids, where each alkyl or alkenyl group is for example 6 Having no more than carbon atoms). Examples of specific esters include formic acid esters, acetic acid esters, propionic acid esters, butyric acid esters, acrylic acid esters and ethyl succinic acid esters. “Oxide” means that the nitrogen ring atom of a heteroaryl group is oxidized to form an N-oxide.
- Prodrugs are within reasonable medical judgment and have a reasonable benefit / suitable for use in contact with human or animal tissue without undue toxicity, irritation, allergic response, etc. Means a prodrug of a compound that is balanced in risk ratio and effective for its intended use. Prodrugs are compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. General explanations are T. Higuchi and V. Stella, Pro drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, Americanocimoneu , 1987, all of which are hereby incorporated by reference.
- “Pharmaceutically acceptable salt” may be a salt of a compound of formula (I) with an inorganic or organic acid.
- Preferred salts are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or organic carboxylic acids or sulfonic acids such as acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, It is a salt with malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or naphthalenedisulfonic acid.
- salts include salts with conventional bases such as alkali metal salts (eg sodium or potassium salts), alkaline earth metal salts (eg calcium or magnesium salts), or ammonia or organic amines ( For example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, methylpiperidine, L-arginine, creatine, choline, L-lysine, ethylenediamine, benzathine, ethanolamine, meglumine or tromethamine ), And in particular sodium salts.
- alkali metal salts eg sodium or potassium salts
- alkaline earth metal salts eg calcium or magnesium salts
- ammonia or organic amines for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorph
- Solidvate means a compound of formula (I) which forms a complex by coordination with solvent molecules in a solid or liquid state.
- the preferred solvate is a hydrate.
- references herein to “compounds of formula (I)” are intended to include their esters, oxides, prodrugs, pharmaceutically acceptable salts and solvates, unless otherwise appropriate in the context. To do.
- each Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl and alkoxy. In certain embodiments, in Formula (I), each Ra is independently selected from the group consisting of halo and alkyl. In one embodiment, in Formula (I), there are two Ra, one is halo and the other is alkyl.
- the compound of formula (I) is selected from the compounds in Table 1 below:
- the active ingredient of the pharmaceutical composition has the formula: 4-amino-3- [6- (4-fluoro-2-methylphenyl) pyridin-3-ylazo] naphthalene-1-sulfonic acid, or an ester, oxide, prodrug thereof, pharmaceutically acceptable Preferred are salts or solvates, especially sodium salts.
- the compound of formula (I) can protect cardiomyocytes.
- a pharmaceutical composition for protecting cardiomyocytes comprising a compound of formula (I) is provided.
- “protect cardiomyocytes” or “cardiomyocyte protection” refers to inhibiting cardiomyocyte cell death and / or cardiomyocyte ischemic injury and / or ischemia resuscitation. Means to inhibit perfusion injury or its progression.
- cardiomyocytes can be protected to maintain cardiac function and / or suppress decline in cardiac function, eg, myocardial infarction, chronic heart failure, hypertensive heart failure or dilated myocardium May treat or prevent heart disease associated with cardiomyocyte death, such as symptom.
- a pharmaceutical composition for the treatment of myocardial infarction comprising a compound of formula (I) is provided.
- administering reduces the amount of necrotic myocardium in patients with myocardial infarction and reduces the risk of heart failure, so that the compound of formula (I) is suitable for heart failure caused by myocardial infarction or It can also be used to treat or prevent heart failure after myocardial infarction, particularly chronic heart failure.
- treating is to reduce or eliminate the cause of a disease, delay or stop its progression in a subject suffering from the disease, and / or Means to reduce, alleviate, ameliorate or eliminate the symptoms.
- preventing or “prevention” is to prevent a disease from occurring in a subject, particularly in a subject who is likely to have a disease but has not yet been affected. Or it means reducing the chance of getting a disease.
- Subjects who may have heart disease but are not yet affected include, for example, aging, family history of coronary artery disease, smoking, hypertension, obesity, impaired glucose tolerance, hypercholesterolemia, hypertriglyceridemia, Subjects with risk factors such as low HDL cholesterolemia, metabolic syndrome, stress, sleep deprivation are included.
- Subjects who may have myocardial infarction but have not yet suffered include, for example, smoking, hypercholesterolemia, diabetes, hypertension, family history of angina / myocardial infarction, aging, stress, obesity, gout , Subjects with risk factors such as hyperuricemia, hemodialysis, hyperhomocysteinemia, periodontal disease.
- Subjects who may have chronic heart failure but are not yet affected include, for example, subjects suffering from coronary artery disease, cardiomyopathy, valvular disease, hypertension, etc., especially those suffering from myocardial infarction It is.
- Subjects who may suffer from hypertensive heart failure but have not yet suffered include, for example, subjects suffering from hypertension.
- Subjects who may have dilated cardiomyopathy but have not yet suffered include, for example, subjects with a genetic predisposition to dilated cardiomyopathy.
- targets for treatment or prevention of diseases include animals, typically mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.), particularly humans.
- mammals eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.
- the administration method of the pharmaceutical composition is not particularly limited, but can be administered through general administration routes such as oral administration, parenteral administration, injection, infusion and the like, and the composition can be in a dosage form suitable for each administration route. .
- the pharmaceutical composition is administered intracoronary.
- Examples of the dosage form for oral administration include granules, fine granules, powders, coated tablets, tablets, suppositories, powders, capsules, microcapsules, chewables, solutions, suspensions, emulsions and the like.
- general dosage forms for pharmaceutical preparations such as intracoronary administration, intravenous injection, infusion administration, preparations that prolong the release of active substances, and the like can be adopted.
- Dosage forms for intracoronary administration, intravenous injection or infusion administration include aqueous and non-aqueous injection solutions (may include antioxidants, buffers, bacteriostatic agents, isotonic agents, etc.); and aqueous And non-aqueous injection suspensions (which may include suspensions, thickeners, etc.).
- Dosage forms for injection may be provided in sealed ampoules or vials, or may be provided as a lyophilizate that requires only the addition of a sterile liquid (eg, water for injection) immediately prior to use.
- Injection solutions or suspensions may be prepared from powders, granules or tablets.
- dosage forms are manufactured by formulating in a conventional manner. Further, various pharmaceutically acceptable pharmaceutical substances can be blended as required in the preparation.
- the substance for formulation can be appropriately selected depending on the dosage form of the formulation, for example, buffering agent, surfactant, stabilizer, preservative, excipient, diluent, additive, disintegrant, binder, Examples include a coating agent, a lubricant, a lubricant, a flavoring agent, a sweetening agent, and a solubilizing agent.
- the dosage and frequency of administration of the pharmaceutical composition is such that the effective species of the compound of formula (I) is administered to the subject, the animal species to be administered, the health condition of the subject, age, body weight, route of administration, dosage form
- a person skilled in the art can set as appropriate according to the above. Effective amounts for a given situation can be readily determined by routine experimentation and are within the skill and judgment of the ordinary clinician.
- the pharmaceutical composition is administered one or more times, especially once, during reperfusion following myocardial infarction.
- the pharmaceutical composition is administered once into the coronary artery during reperfusion following myocardial infarction.
- the compound of formula (I) can be used alone or in combination with one or more additional active ingredients, in particular active ingredients for the treatment or prevention of heart diseases such as myocardial infarction.
- a pharmaceutical composition may contain one or more additional active ingredients in addition to the compound of formula (I).
- “Combination” of the ingredients not only involves the use of dosage forms containing all ingredients and the combination of dosage forms containing each ingredient separately, but they also protect cardiomyocytes or prevent heart disease and It also means that as long as it is used for treatment, each component is administered at the same time, or any component is delayed. It is also possible to use two or more additional active ingredients in combination. Active ingredients suitable for use in combination include, for example, anti-inflammatory agents, vasodilators, thrombolytic agents, antiplatelet agents, anticoagulants, statin drugs and the like.
- a therapeutic method other than drug therapy can also be performed.
- Suitable therapies include, for example, coronary artery intervention (PCI) using balloon catheters, stents or drug eluting stents (DES), and surgical procedures such as thrombus aspiration, gene therapy, regenerative medicine, and the like.
- a method for protecting cardiomyocytes comprising administering a compound of formula (I) to a subject in need of cardiomyocyte protection.
- a compound of formula (I) for cardiomyocyte protection is provided.
- the use of a compound of formula (I) for protecting cardiomyocytes is provided.
- a method for treating myocardial infarction comprising administering a compound of formula (I) to a subject in need of treatment for myocardial infarction.
- a compound of formula (I) for the treatment of myocardial infarction is provided.
- use of a compound of formula (I) for treating myocardial infarction is provided.
- use of a compound of formula (I) in the manufacture of a pharmaceutical composition for the treatment of myocardial infarction is provided.
- the pharmaceutical composition according to item 1 wherein the cardiomyocyte protection comprises suppression of cardiomyocyte death.
- the pharmaceutical composition according to item 1 or 2 for the treatment of myocardial infarction, chronic heart failure, hypertensive heart failure or dilated cardiomyopathy.
- the pharmaceutical composition according to any of paragraphs 13 to 15 for administering about 0.01 to about 100 mg / kg body weight of the compound of formula (I).
- the pharmaceutical composition according to any one of items 13 to 16 for administering about 1 to about 10 mg / kg body weight of the compound of formula (I).
- KUS121 4-amino-3- [6- (4-fluoro-2-methylphenyl) pyridin-3-ylazo] naphthalene-1-sulfonic acid sodium salt
- Patent Document 1 4-amino-3- [6- (4-fluoro-2-methylphenyl) pyridin-3-ylazo] naphthalene-1-sulfonic acid sodium salt
- VCP expression in human organs VCP expression in human organs was quantitatively evaluated by qPCR using human Total RNA Master Panel II (Clonthech) and total RNA: human adipose (Biochain). First, 1 ⁇ g of RNA was reverse-transcribed into cDNA using Verso cDNA Synthesis Kit (Thermo Fisher Scientific). QPCR was performed from the cDNA using Step One Plus (Thermo Fisher Scientific) and THUNDERBIRD qPCR Mix (TOYOBO), and the expression level of VCP was measured. The results are shown in FIG. VCP expression in the human heart was relatively high and comparable to that of the central nervous system.
- Test 2 VCP expression in mouse organs Each organ was excised from 8-week-old C57BL / 6J mice (Japan SLC), and RNA was extracted using TriPure Isolation Reagent (Roche) according to the manufacturer's protocol. . 1 ⁇ g of RNA was reverse transcribed into cDNA using Verso cDNA Synthesis Kit. QPCR was performed from the cDNA using Step One Plus and THUNDERBIRD qPCR Mix, and the expression level of VCP was measured. The results are shown in FIG. VCP expression in the mouse heart was relatively high.
- Test 3 Expression of VCP in the mouse heart
- a heart was extracted from a newborn C57BL / 6J mouse on the first day of life, treated with collagenase, and cells were isolated.
- Mito Tracker GreenFM M7514, Thermo Fisher Scientific
- Thy1.2-APC Thy1.2-APC
- Test 4 Effect of KUS121 on rat cardiomyocytes 0.1 mg / mL tunicamycin (Sigma Aldrich) induces endoplasmic reticulum stress in Dulbecco's modified Eagle's medium (DMEM) supplemented with 5% fetal bovine serum. And 24 hours in the presence of 25, 50, 100 or 200 ⁇ M KUS121. The number of cells was measured with Countess II (Thermo Fisher Scientific). Intracellular ATP levels were measured using a “cellular” ATP measurement reagent (Toyo B-Net). The luciferase activity showing ATP level was measured with ARVO X3 (PerkinElmer). The results are shown in FIG. The cell number increased with the dose of KUS121. Addition of tunicamycin reduced ATP levels, but improved with the dose of KUS121.
- DMEM Dulbecco's modified Eagle's medium
- ARVO X3 PerkinElmer
- the above cultured cells were subjected to Western blot.
- proteins were extracted from cultured cells, and the protein concentration was measured with a BCA protein assay kit (Bio-Rad, 5000006JA).
- CHOP sc575, Snata Cruz
- Bip sc575, Snata Cruz
- GAPDH GAPDH
- ⁇ -actin Sigma Aldrich
- the cells were cultured in a medium not containing glucose, and the same experiment was performed. The results are shown in FIGS.
- the cell number increased with the dose of KUS121. Under no glucose, ATP levels decreased but improved with the dose of KUS121. In the presence of KUS121, the expression of endoplasmic reticulum stress markers CHOP and Bip was suppressed.
- KUS121 suppresses ATP consumption in cardiomyocytes and cardiac myoblasts under endoplasmic reticulum stress, suppresses endoplasmic reticulum stress, and suppresses cell death.
- Test 5 Mouse cardiac ischemia / reperfusion injury model (KUS administration before ischemia) Anesthesia was performed by intraperitoneal administration of 64.8 mg / kg of pentobarbital. After anesthesia was introduced, an endotracheal tube was inserted and positive pressure ventilation was performed. Eight-week-old C57BL / 6J mice were fixed in the right lateral recumbent position, and thoracotomy was performed between the left third intercostals to expose the heart. The pericardium was peeled off slightly, and the left anterior descending coronary artery was ligated with 7-0 proline together with PE10 tube at a site near the apex of the heart, 1 mm from the lower edge of the left atrium.
- FIG. 8 shows a schematic diagram of the administration schedule.
- 160 mg / kg of KUS121 was intraperitoneally administered 2 hours before reperfusion (about 1 hour before the start of ischemia).
- 160 mg / kg of KUS121 was intraperitoneally administered every 24 hours until the first to sixth days after the operation.
- cardiac ultrasound examination (Vevo (registered trademark) 2100, VISUALSONICS) was performed for cardiac function evaluation. The test was performed under 2% isoflurane inhalation anesthesia, the left ventricular diameter shortening rate and the left ventricular ejection fraction were measured in the parasternal short-axis image, and the left ventricular contractility was evaluated. The results are shown in FIG. In the KUS121 administration group, the left ventricular contractility was better maintained compared to the control group, which was comparable to the sham operation group.
- Test 6 Mouse cardiac ischemia / reperfusion injury model (ATP visualization mouse) ATP visualization mouse (A team mouse) developed by Mr. Masamichi Yamamoto, Department of Nephrology, graduate School of Medicine, Kyoto University was used.
- FRET fluorescence resonance energy transfer
- a team mouse fluorescence resonance energy transfer (FRET) from GFP to OFP occurs according to the amount of intracellular ATP, and the OFP / GFP ratio is proportional to the amount of ATP.
- a team mice were anesthetized with 4% isoflurane and maintained at 2% during surgery. After anesthesia was introduced, an endotracheal tube was inserted and positive pressure ventilation was performed. An incision was made in the bilateral chest and bilateral lower ribs, the chest cavity was opened, and the heart was exposed.
- the anterior descending coronary artery of the left coronary artery was ligated with 7-0 proline together with a PE10 tube at a site near the apex of 1 mm from the left atrial lower edge. After 45 minutes of ischemia, the PE10 tube was removed and reperfusion was obtained. KUS121 was administered intraperitoneally 160 mg / kg 2 hours before reperfusion.
- excitation was performed at 470/40
- GFP was detected at 515/30
- OFP was detected at 575/40
- an image was taken.
- the OFP / GFP ratio was analyzed using MetaMorph (Molecular Devices). The results are shown in FIG. In the control group, ATP levels decreased during ischemia, but were maintained in the KUS121 administration group.
- Test 7 Mouse cardiac ischemia / reperfusion injury model (KUS administration after reperfusion) A mouse myocardial infarction model was prepared in the same manner as in Test 5.
- 160 mg / kg In the first administration, 80 mg / kg intravenous administration and 80 mg / kg intraperitoneal administration of KUS121 were performed immediately after reperfusion. Thereafter, 160 mg / kg of KUS121 was intraperitoneally administered every 24 hours until the first to fourth days after the operation.
- histological evaluation was performed in the same manner as in Test 5 to determine the area of the infarct region.
- a schematic diagram and results of the administration schedule are shown in FIG. In the KUS121 administration group, the infarct area was small compared to the control group.
- Test 8 Porcine cardiac ischemia / reperfusion injury model (intravenous and intracoronary KUS administration) A catheter was inserted into Yorkshire pigs under general anesthesia, and the left coronary artery was occluded with a balloon to create a myocardial infarction model. An intravenous drip in which 4 mg / kg KUS121 was dissolved in 250 mL of glucose solution was intravenously administered by continuous infusion over 3 hours from 45 minutes after coronary artery occlusion. The balloon was released 60 minutes after the occlusion, and 10 mL of the infusion solution was injected into the coronary artery. A schematic diagram of the administration schedule is shown in FIG.
- FIG. 16 shows the area of the infarct region per left ventricle. Further, left ventricular ejection fraction, end-diastolic volume, end-systolic volume, cardiac output, and left ventricular weight were measured by MRI to evaluate cardiac function. The results are shown in FIG. A tendency to improve left ventricular contractility was recognized by administration of KUS121.
- the left graph shows the size of the ischemic area with respect to the left ventricle
- the right graph shows the size of the infarct portion with respect to the ischemic area.
- Test 9 Porcine cardiac ischemia / reperfusion injury model (KUS administration after reperfusion) As in Test 8, a porcine myocardial infarction model was created. The balloon was released 60 minutes after the occlusion, and immediately after that 0.64, 2.5, or 5.0 mg / kg body weight of KUS121 was injected into the coronary artery for 3 minutes. On the seventh day after the operation, the infarct size was evaluated by MRI as in Test 8, and the area of the infarct region was determined by histological evaluation. The administration schedule and results are shown in FIG. The ratio of infarct area / left ventricle (LV) area as assessed by MRI decreased in a dose-dependent manner in the KUS121 treatment group.
- KUS administration after reperfusion As in Test 8, a porcine myocardial infarction model was created. The balloon was released 60 minutes after the occlusion, and immediately after that 0.64, 2.5, or 5.0 mg / kg body weight of KUS121 was injected into the coronary artery for
- the ratio of ischemic area / left ventricular area in the KUS121-treated group was equivalent to that in the control group, and the infarct area / ischemic area (AAR) ratio of the KUS121-treated group decreased in a dose-dependent manner. Furthermore, it was confirmed that the appearance of the infarct region by Masson trichrome staining was the same as that evaluated by TTC staining.
- Tests 1-9 suggest that the compounds of formula (I) can protect cardiomyocytes and suppress cell death during ischemia-reperfusion and are therefore useful in the treatment of myocardial infarction. .
- This application provides a method for protecting cardiomyocytes and can be used in the medical field. For example, it is expected to be used for the treatment and prevention of diseases associated with cardiomyocyte death, particularly for the treatment of myocardial infarction.
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Abstract
Description
本願は、心筋細胞の保護用の医薬組成物に関する。
Raはハロ、ヒドロキシ、アルキル、ハロ置換アルキル、アリール、ハロまたはアルキル置換アリール、アルコキシ、ヒドロキシまたはカルボキシ置換アルコキシ、アリールオキシ、ハロまたはアルキル置換アリールオキシ、CHO、C(O)-アルキル、C(O)-アリール、C(O)-アルキル-カルボキシル、C(O)-アルキレン-カルボキシエステルおよびシアノから成る群から選択され、
mは0~4から選択される整数である〕
の化合物またはそのエステル、オキシド、プロドラッグ、薬学的に許容される塩もしくは溶媒和物を含む、心筋細胞保護用の医薬組成物を提供する。
「アリールオキシ」は、-O-アリール(ここで、アリールは本明細書に定義されている)の基を意味し、例えばフェノキシおよびナフトキシを含む。
「カルボキシル」または「カルボキシ」は-COOHまたはその塩を意味する。
「カルボキシエステル」は、-C(O)O-アルキル(ここで、アルキルは本明細書に定義されている)の基を意味する。
「ハロ」は、ハロゲン、特に、フルオロ、クロロ、ブロモおよびヨードを意味する。
「ヒドロキシ」は-OHの基を意味する。
「オキシド」は、ヘテロアリール基の窒素環原子が酸化され、N-オキシドを形成しているものを意味する。
ある実施態様では、式(I)中、Raは、それぞれ独立して、ハロおよびアルキルから成る群から選択される。
ある実施態様では、式(I)中、Raは2個存在し、一方がハロであり、他方がアルキルである。
ある態様では、心筋細胞保護用の式(I)の化合物が提供される。
ある態様では、心筋細胞を保護するための式(I)の化合物の使用が提供される。
ある態様では、心筋細胞保護用の医薬組成物の製造における、式(I)の化合物の使用が提供される。
ある態様では、心筋梗塞の処置用の式(I)の化合物が提供される。
ある態様では、心筋梗塞を処置するための式(I)の化合物の使用が提供される。
ある態様では、心筋梗塞の処置用の医薬組成物の製造における、式(I)の化合物の使用が提供される。
[1]式(I):
Raはハロ、ヒドロキシ、アルキル、ハロ置換アルキル、アリール、ハロまたはアルキル置換アリール、アルコキシ、ヒドロキシまたはカルボキシ置換アルコキシ、アリールオキシ、ハロまたはアルキル置換アリールオキシ、CHO、C(O)-アルキル、C(O)-アリール、C(O)-アルキル-カルボキシル、C(O)-アルキレン-カルボキシエステルおよびシアノから成る群から選択され、
mは0~4から選択される整数である〕
の化合物またはそのエステル、オキシド、薬学的に許容される塩もしくは溶媒和物を含む、心筋細胞保護用の医薬組成物。
[2]心筋細胞保護が心筋細胞死の抑制を含む、第1項に記載の医薬組成物。
[3]心筋梗塞、慢性心不全、高血圧性心不全または拡張型心筋症の処置用の、第1項または第2項に記載の医薬組成物。
[4]心筋梗塞の処置用の、第1項~第3項のいずれかに記載の医薬組成物。
[5]式(I):
Raはハロ、ヒドロキシ、アルキル、ハロ置換アルキル、アリール、ハロまたはアルキル置換アリール、アルコキシ、ヒドロキシまたはカルボキシ置換アルコキシ、アリールオキシ、ハロまたはアルキル置換アリールオキシ、CHO、C(O)-アルキル、C(O)-アリール、C(O)-アルキル-カルボキシル、C(O)-アルキレン-カルボキシエステルおよびシアノから成る群から選択され、
mは0~4から選択される整数である〕
の化合物またはそのエステル、オキシド、薬学的に許容される塩もしくは溶媒和物を含む、心筋梗塞の処置用の医薬組成物。
[6]さらに心不全を処置または予防するための、第5項に記載の医薬組成物。
[7]さらに慢性心不全を処置または予防するための、第5項または第6項に記載の医薬組成物。
[8]Raが、それぞれ独立して、ハロ、ヒドロキシ、アルキル、ハロ置換アルキルおよびアルコキシから成る群から選択される、第1項~第7項のいずれかに記載の医薬組成物。
[9]Raが、それぞれ独立して、ハロおよびアルキルから成る群から選択される、第1項~第8項のいずれかに記載の医薬組成物。
[10]Raが2個存在し、一方がハロであり、他方がアルキルである、第1項~第9項のいずれかに記載の医薬組成物。
[11]式(I)の化合物が表1に記載の化合物から選択される、第1項~第10項のいずれかに記載の医薬組成物。
[12]式(I)の化合物が、4-アミノ-3-[6-(4-フルオロ-2-メチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸である、第1項~第11項のいずれかに記載の医薬組成物。
[13]冠動脈内に投与される、第1項~第12項のいずれかに記載の医薬組成物。
[14]心筋梗塞後の再灌流時に投与される、第1項~第13項のいずれかに記載の医薬組成物。
[15]心筋梗塞後の再灌流時に単回投与される、第1項~第14項のいずれかに記載の医薬組成物。
[16]約0.01~約100mg/kg体重の式(I)の化合物を投与するための、第13項~第15項のいずれかに記載の医薬組成物。
[17]約1~約10mg/kg体重の式(I)の化合物を投与するための、第13項~第16項のいずれかに記載の医薬組成物。
[18]約2~約10mg/kg体重の式(I)の化合物を投与するための、第13項~第17項のいずれかに記載の医薬組成物。
以下、実施例にて、本発明をさらに詳細に説明するが、本発明はこの実施例に限定されない。また、上記の説明は、すべて非限定的なものであり、本発明は添付の特許請求の範囲において定義され、その技術的思想を逸脱しない範囲で種々の変更が可能である。
KUS121:4-アミノ-3-[6-(4-フルオロ-2-メチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸ナトリウム塩
KUS121は、国際公開第2012/014994号(特許文献1)に記載の方法により製造した。
human Total RNA Master Panel II (Clonthech社)、total RNA: human adipose (Biochain社) を用いて、ヒト臓器でのVCPの発現をqPCRで定量評価した。まずRNA1μgをVerso cDNA Synthesis Kit (Thermo Fisher Scientific社) を用いてcDNAに逆転写した。そのcDNAから Step One Plus (Thermo Fisher Scientific社)、THUNDERBIRD qPCR Mix (TOYOBO社) を用いてqPCRを行い、VCPの発現量を測定した。結果を図1に示す。ヒトの心臓におけるVCPの発現は比較的高く、中枢神経系と同程度であった。
8週齢C57BL/6Jマウス(日本SLC社)から各臓器を摘出し、TriPure Isolation Reagent(Roche社)を用いて、製造業者のプロトコールに沿ってRNAを抽出した。RNA1μgを Verso cDNA Synthesis Kit を用いてcDNAに逆転写した。そのcDNAから Step One Plus、THUNDERBIRD qPCR Mix を用いてqPCRを行い、VCPの発現量を測定した。結果を図2に示す。マウスの心臓におけるVCPの発現は比較的高かった。
生後1日目の新生児C57BL/6Jマウスより心臓を摘出し、コラゲナーゼ処理を行い、細胞を単離した。Mito Tracker GreenFM (M7514、Thermo Fisher Scientific)、Thy1.2-APC (eBioscience社) を用いて、FACSで心筋細胞と線維芽細胞に分離した。試験2と同様の手順でqPCRを行い、VCPの発現量を定量評価した。結果を図3に示す。マウスの心臓において、VCPは心筋細胞で多く発現していた。
H9C2(ラット心筋芽細胞)を、5%ウシ胎児血清添加 Dulbecco’s modified Eagle’s medium (DMEM) 中、小胞体ストレスを誘導する0.1μg/mLツニカマイシン (Sigma Aldrich社) および、25、50、100または200μMのKUS121の存在下で24時間培養した。細胞数を Countess II (Thermo Fisher Scientific社) で測定した。「細胞の」ATP測定試薬(東洋ビーネット社)を用いて細胞内のATPレベルを測定した。ATPレベルを示すルシフェラーゼ活性を、ARVO X3 (PerkinElmer社) で測定した。結果を図4に示す。細胞数はKUS121の用量に伴って増加した。ツニカマイシンの添加によりATPレベルが低下したが、KUS121の用量に伴って改善された。
ペントバルビタール64.8mg/kgの腹腔内投与で麻酔を行った。麻酔導入後に気管内チューブを挿入し、陽圧換気を行った。
8週齢C57BL/6Jマウスを右半側臥位に固定し、左第三肋間で開胸し、心臓を露出させた。心膜を少し剥離し、左房下縁から1、2mm心尖部寄りの部位でPE10チューブとともに7-0プロリンで左冠動脈前下行枝を結紮した。心筋の色調が変化するのを観察して、冠動脈血流が遮断できているのを確認した。45分間の虚血の後にPE10チューブを抜去し、再灌流を得た。再灌流は心筋の色調が回復することをもって確認した。その後、胸郭を7-0プロリン、皮膚を4-0シルクで縫合した。マウスが覚醒したのを確認して、気管内チューブを抜去した。
生理食塩水に溶解したKUS121を虚血前投与した。図8に投与スケジュールの模式図を示す。初回投与は、再灌流の2時間前(虚血開始の約1時間前)にKUS121の160mg/kg腹腔内投与を行った。その後は術後1~6日目まで24時間毎にKUS121の160mg/kg腹腔内投与を行った。
術後7日目に、ペントバルビタールで麻酔後に4%パラホルムアルデヒド(PFA)で灌流固定を行い、心臓を摘出した。摘出した心臓は、さらに4%PFAで一晩浸漬固定を行った。その後にパラフィン包埋を行い、切片を作成した。マッソントリクローム染色で梗塞領域の評価を行った。画像は顕微鏡 (BZ-9000, Keyence) で撮影し、Image J (NIH) で梗塞領域の面積を求めた。結果を図9に示す。KUS121投与群では、対照群と比較して、梗塞領域が小さかった。ウェスタンブロットによると、投与群においては、境界領域、非虚血領域において小胞体ストレスマーカーのCHOPの発現が抑制された。
マウス心臓虚血再灌流障害モデルにおいて、心機能評価のため心臓超音波検査 (Vevo(登録商標)2100, VISUALSONICS) を行った。2%イソフルラン吸入麻酔下に行い、傍胸骨短軸像において左室内径短縮率および左室駆出率を測定し、左室収縮能を評価した。結果を図10に示す。KUS121投与群では、対照群と比較して左室収縮能が良好に保たれ、偽手術群と同程度であった。
京都大学医学研究科腎臓内科山本正道氏が開発したATP可視化マウス(A teamマウス)を用いた。A teamマウスでは、細胞内ATP量に応じてGFPからOFPへの蛍光共鳴エネルギー移動(FRET)が起こり、OFP/GFP比がATP量に比例する。
A teamマウスを4%イソフルランで麻酔導入し、術中は2%で維持した。麻酔導入後に気管内チューブを挿入し、陽圧換気を行った。両側側胸部と両側肋骨下縁を切開し、胸腔を開け、心臓を露出した。左房下縁から1、2mm心尖部寄りの部位でPE10チューブとともに7-0プロリンで左冠動脈前下行枝を結紮した。45分間の虚血の後にPE10チューブを抜去し、再灌流を得た。KUS121は再灌流2時間前に160mg/kg腹腔内投与した。ATP測定では、470/40で励起し、515/30でGFPを、575/40でOFPを検出し、画像を撮影した。MetaMorph (Molecular Devices社) を用いて、OFP/GFP比を解析した。結果を図11に示す。対照群では虚血時にATPレベルが低下したが、KUS121投与群では維持された。
試験5と同様にマウス心筋梗塞モデルを作成した。
(1)160mg/kg
初回投与は、再灌流直後にKUS121の80mg/kg静脈内投与、80mg/kg腹腔内投与を行った。その後は術後1~4日目まで24時間毎にKUS121の160mg/kg腹腔内投与を行った。術後7日目に、試験5と同様に組織学的評価を行い、梗塞領域の面積を求めた。投与スケジュールの模式図と結果を図12に示す。KUS121投与群では、対照群と比較して、梗塞領域が小さかった。
再灌流直後にKUS121の25mg/kg静脈内投与、25mg/kg腹腔内投与を行った。その後はKUS121を投与しなかった。術後7日目に、試験5と同様に組織学的評価を行い、梗塞領域の面積を求めた。投与スケジュールの模式図と結果を図13に示す。KUS121投与群では、対照群と比較して、梗塞領域が小さかった。
再灌流直後にKUS121の8mg/kg静脈内投与、8mg/kg腹腔内投与を行った。その後はKUS121を投与しなかった。術後7日目に、試験5と同様に組織学的評価を行い、梗塞領域の面積を求めた。投与スケジュールの模式図と結果を図14に示す。KUS121投与群と対照群の梗塞領域の面積に有意差は見られなかった。
ヨークシャーブタに全身麻酔下でカテーテルを挿入し、バルーンにて左冠動脈を閉塞し、心筋梗塞モデルを作成した。4mg/kgのKUS121を250mLのブドウ糖液に溶解した点滴液を、冠動脈閉塞45分後より3時間にわたり持続点滴により静脈投与した。閉塞60分後にバルーンを解除し、冠動脈内に上記点滴液10mLを注入した。投与スケジュールの模式図を図15に示す。
閉塞の1週間後に、ガドリニウム遅延造影MRIにより、心筋梗塞巣の大きさを評価した。図16は、左室あたりの梗塞領域の面積を示す。また、MRIにより左室駆出率、拡張末期容積、収縮末期容積、心拍出量、左室重量を測定し、心機能を評価した。結果を図17に示す。KUS121の投与により、左室収縮能の改善傾向を認めた。
MRI撮影後に、左冠動脈の閉塞部をバルーンカテーテルで再度閉塞し、左右両冠動脈に1%エバンスブルーを注入した(左冠動脈は60mL、右冠動脈は30mL。非梗塞部が青く染まる)。さらに30mLの1%TTC液を閉塞バルーンのガイドワイヤールーメンを用いて注入した。その後、塩化カリウムの静脈注射にてブタを安楽死させた。心臓を取り出し、房室溝と平行に10mm厚で断片を作成した。さらに37℃で10分間、1%TTC液に浸した(心筋梗塞に陥っていない場所が赤く染まる)。すべてのスライスの重さを測定し、写真を撮影した。10%ホルムアルデヒドで固定し、その後の組織観察に使用した。結果を図18に示す。左のグラフは、左心室に対する虚血域の大きさを示し、右のグラフは、虚血域に対する梗塞部の大きさを示す。虚血域の大きさは偽手術群とKUS投与群では差がなかったが、KUS投与により、虚血域あたりの梗塞部の大きさは減少した。
試験8と同様にブタ心筋梗塞モデルを作成した。閉塞60分後にバルーンを解除し、その直後に冠動脈内に0.64、2.5または5.0mg/kg体重のKUS121を3分間で注入した。術後7日目に、試験8と同様にMRIにより梗塞サイズを評価し、組織学的評価により梗塞領域の面積を求めた。投与スケジュールおよび結果を図19に示す。MRIにより評価した梗塞領域/左心室(LV)領域比は、KUS121処置群で用量依存的に低下した。KUS121処置群の虚血域/左心室領域比は対照群と同等であり、KUS121処置群の梗塞領域/虚血域(AAR)比は用量依存的に低下した。さらに、マッソントリクローム染色による梗塞領域の外見が、TTC染色により評価した場合と同等であることを確認した。これらのデータは、ブタ心筋梗塞モデルにおいて、心臓の損傷後のKUS121の冠動脈内投与が有効であることを示す。
Claims (10)
- 心筋細胞保護が心筋細胞死の抑制を含む、請求項1に記載の医薬組成物。
- 心筋梗塞、慢性心不全、高血圧性心不全または拡張型心筋症の処置用の、請求項1または2に記載の医薬組成物。
- さらに慢性心不全を処置または予防するための、請求項4に記載の医薬組成物。
- Raが、それぞれ独立して、ハロ、ヒドロキシ、アルキル、ハロ置換アルキルおよびアルコキシから成る群から選択される、請求項1~5のいずれかに記載の医薬組成物。
- 式(I)の化合物が、
4-アミノ-3-(6-フェニルピリジン-3-イルアゾ)ナフタレン-1-スルホン酸;
4-アミノ-3-(6-p-トルイルピリジン-3-イルアゾ)ナフタレン-1-スルホン酸;
4-アミノ-3-(6-m-トルイルピリジン-3-イルアゾ)ナフタレン-1-スルホン酸;
4-アミノ-3-(6-o-トルイルピリジン-3-イルアゾ)ナフタレン-1-スルホン酸;
4-アミノ-3-(6-ビフェニル-2-イルピリジン-3-イルアゾ)ナフタレン-1-スルホン酸;
3-[6-(2-アセチルフェニル)ピリジン-3-イルアゾ]-4-アミノナフタレン-1-スルホン酸;
3-[6-(3-アセチルフェニル)ピリジン-3-イルアゾ]-4-アミノナフタレン-1-スルホン酸;
3-[6-(4-アセチルフェニル)ピリジン-3-イルアゾ]-4-アミノナフタレンスルホン酸;
4-アミノ-3-[6-(2,4-ジクロロフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-トリフルオロメチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4-トリフルオロメチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-クロロフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(3-クロロフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4-クロロフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-メトキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4-メトキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-イソプロポキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4-イソプロポキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-フェノキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(3-メトキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2,3-ジメチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2,5-ジメチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(3,5-ジメチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(3-トリフルオロメチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-{4-[5-(1-アミノ-4-スルホナフタレン-2-イルアゾ)ピリジン-2-イル]フェニル}-4-オキソブチル酸;
4-アミノ-3-(6-ビフェニル-3-イルピリジン-3-イルアゾ)ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(3-シアノフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4-シアノフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(3,5-ビストリフルオロメチルフェニル)ピリジン-3-イルアゾ]ナフタレンスルホン酸;
4-アミノ-3-[6-(4-ベンゾイルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-プロポキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4-フルオロ-2-メチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(5-フルオロ-2-プロポキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-フルオロ-6-プロポキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4-フルオロ-2-プロポキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(5-フルオロ-2-メチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-フルオロ-5-メチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-ブトキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-ヘキシルオキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4-ブチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-ヒドロキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-{6-[2-(6-ヒドロキシヘキシルオキシ)フェニル]ピリジン-3-イルアゾ}ナフタレン-1-スルホン酸;
4-{2-[5-(1-アミノ-4-スルホナフタレン-2-イルアゾ)ピリジン-2-イル]フェノキシ}ブチル酸;
4-アミノ-3-{6-[2-(3-ヒドロキシプロポキシ)フェニル]ピリジン-3-イルアゾ}ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2-イソブトキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(5-クロロ-2-ヒドロキシフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4-メチルビフェニル-2-イル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4’-クロロ-4-メチルビフェニル-2-イル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(4,3’,5’-トリメチルビフェニル-2-イル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(3’-クロロ-4-メチルビフェニル-2-イル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(2,6-ジメチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
4-アミノ-3-[6-(3-ホルミル-2-イソプロポキシ-5-メチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;および、
4-アミノ-3-[6-(3-ホルミル-2-ブトキシ-5-メチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸;
からなる群から選択される、請求項1~5のいずれかに記載の医薬組成物。 - 式(I)の化合物が、4-アミノ-3-[6-(4-フルオロ-2-メチルフェニル)ピリジン-3-イルアゾ]ナフタレン-1-スルホン酸である、請求項1~7のいずれかに記載の医薬組成物。
- 冠動脈内に投与される、請求項1~8のいずれかに記載の医薬組成物。
- 心筋梗塞後の再灌流時に投与される、請求項1~9のいずれかに記載の医薬組成物。
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WO2023120704A1 (ja) * | 2021-12-24 | 2023-06-29 | 国立大学法人京都大学 | 心機能を改善するための組成物 |
WO2023140242A1 (ja) * | 2022-01-18 | 2023-07-27 | 国立大学法人京都大学 | 生体から分離された組織を保護するための組成物 |
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JP7369454B2 (ja) | 2023-10-26 |
US20210145808A1 (en) | 2021-05-20 |
EP3782623A1 (en) | 2021-02-24 |
KR20200143441A (ko) | 2020-12-23 |
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