WO2022080576A1 - Composition comprenant un inhibiteur de pmca pour le traitement d'une infection à coronavirus ou de maladies infectieuses - Google Patents
Composition comprenant un inhibiteur de pmca pour le traitement d'une infection à coronavirus ou de maladies infectieuses Download PDFInfo
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- WO2022080576A1 WO2022080576A1 PCT/KR2020/016934 KR2020016934W WO2022080576A1 WO 2022080576 A1 WO2022080576 A1 WO 2022080576A1 KR 2020016934 W KR2020016934 W KR 2020016934W WO 2022080576 A1 WO2022080576 A1 WO 2022080576A1
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- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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- A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- A—HUMAN NECESSITIES
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Definitions
- the present invention relates to a composition for various uses that can effectively ameliorate or treat a coronavirus infection or a disease caused by the infection, including a PMCA inhibitor.
- Coronavirus is a representative virus that causes lethal infectious diseases in modern civilization.
- Severe Acute Respiratory Syndrome also known as SARS
- MERS Middle East Respiratory Syndrome
- COVID-19 coronavirus
- SARS Severe acute respiratory syndrome coronavirus 2
- -CoV-2 Severe acute respiratory syndrome coronavirus 2
- Coronavirus Infectious Disease-19 is transmitted when droplets (saliva) of an infected person penetrate the respiratory tract or the mucous membranes of the eyes, nose, and mouth. After infection, after an incubation period of about 2 to 14 days (estimated), the main symptoms are fever (37.5 degrees), respiratory symptoms such as cough or shortness of breath, and pneumonia. reach
- One object of the present invention is to provide a composition for various uses that can improve or treat infection by coronavirus or various diseases caused by the infection.
- N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) represented by the following formula (1) Ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H) )-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazin-6-yl) represented by Formula 2 below -N-(3-methoxyphenethyl)piperazine-1-carboxamide(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide ) at least one
- N- (2- (2-butyl-2,3-dihydrobenzo [f] [1,4] oxazepine-4 (5H) - yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide
- N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4) (5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide
- it relates to a method of improving or treating
- the present invention in principle provides an intermediate, for example in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof
- an intermediate for example in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof
- salts of the compounds according to the invention which are not themselves pharmaceutically acceptable.
- Said salts include water-insoluble salts, particularly water-soluble salts.
- a particular compound according to the invention or a physiologically functional derivative thereof is capable of forming salts, ie whether said compound according to the invention or a physiologically functional derivative thereof is, for example, For example, it can be easily determined whether or not a group has a chargeable group such as an amino group, a carboxylic acid group, and the like.
- Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceuticals, which are water-insoluble or particularly water-soluble acid addition salts. is salt Depending on the substituents of the compounds of the present invention, salts with bases may also be suitable.
- Acid addition salts can be prepared, for example, by combining a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. It can be formed by mixing.
- pharmaceutically acceptable base addition salts include alkali metal salts (eg, sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (eg, ammonium, quaternary ammonium and amines formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations) may be included.
- alkali metal salts eg, sodium or potassium salts
- alkaline earth metal salts eg, calcium or magnesium salts
- suitable organic ligands eg, ammonium, quaternary ammonium and amines formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates
- Illustrative examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, Bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulphate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide , 2-hydroxy-ethanesulfonate, hydroxynaphthoate
- Salts which are not pharmaceutically acceptable in the present invention and which, for example, can be obtained as process products during the preparation of the compounds according to the invention on an industrial scale, are also included in the invention and, if desired, are known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt by a method.
- the virus may be an RNA virus.
- the “RNA virus” refers to any virus using RNA as a genetic material.
- the RNA virus is Coronaviridae, Amalgaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae ( Endornaviridae), Hypoviridae, Megabirnaviridae, Partitiviridae, Picobirnaviridae, Reoviridae, Totiviridae, Quadriviridae, Arteriviridae, Mesoniviridae, Roniviridae, Dicistroviridae, Iflaviridae, Marnaviridae Marnaviridae, Picornaviridae, Secoviridae, Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae, Tymoviridae ), Bornaviridae, Filoviridae, Paramyx
- the "coronavirus (Coronavirus)” has four genera (alpha, beta, gamma, delta) in the coronavirus subfamily (Coronavirinae) of the coronaviridae, and is an RNA virus with a gene size of 27 to 32 kb. It is known to cause respiratory and digestive system infections in animals. It is easily transmitted mainly through mucosal transmission and droplet transmission. Humans usually cause mild respiratory infections, but rarely fatal infections. Diarrhea in cattle and pigs, and respiratory diseases in chickens. Among coronaviruses, coronaviruses that have humans as hosts are divided into classifications in Table 1 below (Centers for Disease Control and Prevention, 2020). Among the four genera, alpha and beta infect humans and animals, and gamma and delta are reported to infect only animals.
- Virus name Genus host Symptom HCoV-229E Alpha Human mild respiratory symptoms HCoV-NL63 Alpha Human mild respiratory symptoms SARS-CoV Beta Human severe respiratory symptoms MERS-CoV Beta Human severe respiratory symptoms HCoV-OC43 Beta Human mild respiratory symptoms HCoV-HKU1 Beta Human Pneumonia symptoms SARS-CoV-2 Beta Human Mild respiratory symptoms Severe cases can cause shortness of breath
- beta coronavirus corresponds to a zoonotic infection as one of four genera of coronaviruses in the subfamily Coronavirus.
- beta coronaviruses include Severe Acute Respiratory Syndrome virus (SARS; SARS-CoV), Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2), Middle East Respiratory Syndrome virus (SARS-CoV) Middle East Respiratory Syndrome virus (MERS; MERS-CoV), human coronavirus OC43 (HCoV-OC43), or human coronavirus HKU1 (HCoV-HKU1) are known to exist.
- nucleocapsid protein includes N1, N2 and N3 fragments.
- the coronavirus includes naturally or artificially mutated variants.
- the infectious disease caused by the coronavirus is coronavirus enteritis, coronavirus diarrhea, severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome (MERS), or their It may be a combination, but may be included without limitation as long as it is a disease that can be caused by the coronavirus infection.
- coronavirus enteritis coronavirus diarrhea
- severe acute respiratory syndrome coronavirus SARS
- MERS Middle East respiratory syndrome
- the infectious disease may be a respiratory disease, hepatitis, gastroenteritis or encephalitis caused by the viral infection.
- the respiratory disease may be one that causes Severe Acute Respiratory Syndrome (SARS).
- SARS Severe Acute Respiratory Syndrome
- the severe acute respiratory syndrome is a disease that can cause infection of the upper or lower respiratory tract, which can cause sudden fever, cough, and shortness of breath, and can progress to pneumonia and even lead to death.
- composition of the present invention may be used alone or in combination with conventional antiviral agents, or may be used in combination with biological agents such as antiserum.
- composition of the present invention may be used as a pharmaceutical composition, a food composition, a food additive composition, a feed composition, or a feed additive composition, but is not particularly limited.
- treatment and “improvement” refer to any action that improves or beneficially changes viral infection by inhibiting virus infection or proliferation by administering the composition of the present invention.
- the compound or pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or drinks, and the pharmaceutical composition may be characterized in that it is targeted to humans.
- the pharmaceutical composition of the present invention is not limited thereto, but each can be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods.
- the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, fragrances, etc., in the case of oral administration, and in the case of injections, buffers, preservatives, pain relief A topical agent, solubilizer, isotonic agent, stabilizer, etc.
- the dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
- a pharmaceutically acceptable carrier as described above.
- it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. there is.
- it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
- suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
- it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
- the route of administration of the compound or pharmaceutical composition according to the present invention is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal , topical, sublingual or rectal. Oral or parenteral administration is preferred.
- parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
- the compound or pharmaceutical composition of the present invention may be determined by several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
- the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and from 0.0001 to 0.0001 per day It may be administered at 50 mg/kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
- the pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
- the "individual” means a subject who has or is suspected of having a virus infection, and needs improvement or treatment for virus infection or a disease caused by the infection by suppressing virus activity, etc., which is already infected or infected with the virus means any animal, including human beings, who can become
- a specific pharmaceutically effective amount for a target subject includes the type and extent of the reaction to be achieved, the specific composition comprising the active ingredient, including whether other agents are used in some cases, the age of the patient, Body weight, general health status, sex and diet, administration time, administration route and secretion rate of a composition containing the active ingredient, treatment period, various factors including drugs used or used together with a specific composition and well-known in the pharmaceutical field It is preferable to apply differently depending on similar factors.
- the amount may be added in a proportion of 0.1 to 50% of the total weight.
- the food composition is prepared in the form of a beverage, there is no particular limitation other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. That is, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, and common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol are included. can do.
- the food composition or food composition additive of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
- These components may be used independently or in combination.
- the proportion of these additives is not so important, but is generally selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention.
- the composition may be 20 to 90% highly concentrated or may be prepared in powder or granular form.
- the feed additive is an organic acid such as citric acid, humic acid, adipic acid, lactic acid, malic acid, or phosphate such as sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate (polyphosphate), polyphenol, catechin, alpha-tocopherol, rosemary Extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, any one or more of natural antioxidants such as phytic acid may be further included.
- organic acid such as citric acid, humic acid, adipic acid, lactic acid, malic acid, or phosphate such as sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate (polyphosphate), polyphenol, catechin, alpha-tocopherol, rosemary Extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, any one or
- the composition when the compound represented by Formula 1 or 2 is used as feed, the composition may be formulated in a conventional feed form, and may include common feed ingredients together.
- the feed additive and feed include grains such as milled or crushed wheat, oats, barley, corn and rice; plant protein feeds, for example feeds based on rape, soybean and sunflower; animal protein feeds such as blood meal, meat meal, bone meal and fish meal; Sugar and dairy products, for example, may further include dry ingredients made of various types of milk powder and whey powder, and in addition, may further include nutritional supplements, digestion and absorption enhancers, growth promoters, and the like.
- the compound represented by Formula 1 or 2 when used as the feed additive, it may be administered to an animal alone or in combination with other feed additives in an edible carrier.
- the feed additives can be easily administered to the animal as a top dressing, directly mixing them into the animal feed, or in an oral formulation separate from the feed.
- a pharmaceutically acceptable edible carrier as well known in the art to prepare an immediate release or sustained release formulation.
- Such edible carriers may be solid or liquid, for example corn starch, lactose, sucrose, soy flakes, peanut oil, olive oil, sesame oil and propylene glycol.
- composition provided in the present invention has a coronavirus inhibitory activity, and can effectively improve or treat an infection caused by a coronavirus or a disease caused by the infection.
- Figure 3 shows the results of confirming the change in the expression level of ACE2 after treating Vero cells with the compound of Formula 2 in Experimental Example 3.
- N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) represented by the following formula (1) Ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H) )-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazin-6-yl) represented by Formula 2 below -N-(3-methoxyphenethyl)piperazine-1-carboxamide(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide ) at least one
- N- (2- (2-butyl-2,3-dihydrobenzo [f] [1,4] oxazepine-4 (5H) - yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide
- N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4) (5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide
- it relates to a method of improving or treating
- RT-25] (IVD approved) kit was used to quantitatively detect N1, N2 and N3 fragments derived from the nucleocapsid (N) gene, which plays an important role in the proliferation of Sars-CoV-2 virus, through real-time RT assay. .
- the assay was performed at 25° C. for 2 minutes; 15 min at 50 °C; 2 min at 95 °C; 3 seconds at 95 °C; 45 cycles were performed at 55° C. for 30 seconds, and a BioRad CFX96 instrument was used.
- N1, N2 and N3 obtained by amplifying the RNA sample obtained from the Sars-CoV-2 infected Vero cells pretreated with the compound represented by Formula 2 with the obtained kit were analyzed.
- the Cq values of these virus targets (N1, N2, N3) were normalized to an internal control (Delta Ct), and the multiples of the virus targets (N1, N2, N3) were calculated for the vehicle CTR-treated cells, and the result was calculated 1 is shown.
- cells not infected with the Sars-CoV-2 virus and cells treated with the vehicle were used as controls.
- the assay was performed at 25° C. for 2 minutes; 15 min at 50 °C; 2 min at 95 °C; 3 seconds at 95 °C; 45 cycles were performed at 55° C. for 30 seconds, and a BioRad CFX96 instrument was used.
- the amplification plots of N1, N2 and N3 obtained by amplifying the RNA sample obtained from the Sars-CoV-2 infected Vero cells pretreated with the compound represented by Formula 2 with the obtained kit were analyzed.
- the Cq values of these viral targets are shown in Table 3 below, which were normalized to an internal control (Delta Ct), and the viral targets (N1, N2, N3) with respect to vehicle CTR-treated cells Calculate the multiple of , and the results are shown in FIG. 2 . However, cells not infected with the Sars-CoV-2 virus and cells treated with the vehicle were used as controls.
- Vero cells 5.0 X 10 5 cells were treated with 1 mM of the compound represented by Formula 2 for 15 hours, and the expression level of ACE2 was measured by immunoblot analysis using an anti-ACE antibody (Ab15348) for total protein lysate. did The results are shown in FIG. 3 . However, valproic acid was used as a control here.
- the present invention relates to a composition for various uses that can effectively ameliorate or treat a coronavirus infection or a disease caused by the infection.
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Abstract
Par l'utilisation du composé représenté par la formule chimique 1 ou 2, la présente invention peut permettre d'atténuer ou de traiter efficacement une infection à coronavirus ou des maladies provoquées par l'infection par l'activité inhibitrice des composés contre le coronavirus.
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WO2014039714A2 (fr) * | 2012-09-06 | 2014-03-13 | Plexxikon Inc. | Composés et procédés pour la modulation des kinases, et leurs indications |
KR20140138865A (ko) * | 2012-03-09 | 2014-12-04 | 렉시컨 파마슈티컬스 인코퍼레이티드 | 이미다조[1,2-b]피리다진계 화합물, 그를 포함하는 조성물 및 그의 용도 |
JP2015513557A (ja) * | 2012-03-09 | 2015-05-14 | レクシコン ファーマシューティカルズ インコーポレイテッド | 疼痛の治療に対するアダプター関連キナーゼ1の阻害 |
KR20170009276A (ko) * | 2015-07-16 | 2017-01-25 | 일양약품주식회사 | 호흡기 바이러스성 질환 치료를 위한 라도티닙의 용도 |
KR20180018683A (ko) * | 2015-06-15 | 2018-02-21 | 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 | Nrf2 조절제 |
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KR102260675B1 (ko) * | 2019-07-30 | 2021-06-07 | 주식회사 하임바이오 | 신규한 항암용 화합물, 및 이를 유효성분으로 포함하는 약학조성물 |
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KR20140138865A (ko) * | 2012-03-09 | 2014-12-04 | 렉시컨 파마슈티컬스 인코퍼레이티드 | 이미다조[1,2-b]피리다진계 화합물, 그를 포함하는 조성물 및 그의 용도 |
JP2015513557A (ja) * | 2012-03-09 | 2015-05-14 | レクシコン ファーマシューティカルズ インコーポレイテッド | 疼痛の治療に対するアダプター関連キナーゼ1の阻害 |
WO2014039714A2 (fr) * | 2012-09-06 | 2014-03-13 | Plexxikon Inc. | Composés et procédés pour la modulation des kinases, et leurs indications |
KR20180018683A (ko) * | 2015-06-15 | 2018-02-21 | 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 | Nrf2 조절제 |
KR20170009276A (ko) * | 2015-07-16 | 2017-01-25 | 일양약품주식회사 | 호흡기 바이러스성 질환 치료를 위한 라도티닙의 용도 |
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