WO2015026170A1 - 세포괴사 저해제로서의 인돌 화합물 - Google Patents
세포괴사 저해제로서의 인돌 화합물 Download PDFInfo
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- WO2015026170A1 WO2015026170A1 PCT/KR2014/007758 KR2014007758W WO2015026170A1 WO 2015026170 A1 WO2015026170 A1 WO 2015026170A1 KR 2014007758 W KR2014007758 W KR 2014007758W WO 2015026170 A1 WO2015026170 A1 WO 2015026170A1
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- indol
- chloro
- amine
- ethyl
- ylmethyl
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- 0 CC1CCN(*)CC1 Chemical compound CC1CCN(*)CC1 0.000 description 4
- AXSPBRKTBUZVME-UHFFFAOYSA-N OCCc1cc(cc(cc2NC3CCCC3)Cl)c2[nH]1 Chemical compound OCCc1cc(cc(cc2NC3CCCC3)Cl)c2[nH]1 AXSPBRKTBUZVME-UHFFFAOYSA-N 0.000 description 1
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Definitions
- the present invention relates to an indole compound of formula (1), a pharmaceutically acceptable salt or isomer thereof, and a composition and a method for producing the composition for preventing or treating cell necrosis and related diseases, which are contained as an active ingredient. It is about.
- PCD programmed cell death
- Cell necrosis has been known as uncontrolled apoptosis for a long period of time, but recent studies (Proskurykakov SY et al. 2002, Biochemistry) indicate that diseases caused by cell necrosis are ischemic (eg myocardial infarction). , Stroke, nerve color), neurodegenerative, and inflammatory diseases. Cell necrosis is an uncontrolled accidental death in a pathological situation. Since its mechanism of action, molecular targets, and signaling system are hardly studied, cell necrosis treats ischemic, neurodegenerative, and inflammatory diseases causing cell necrosis and It is very urgent to find and develop these cell necrosis inhibitors to identify biological and pathological causes.
- ischemic eg myocardial infarction
- Stroke nerve color
- neurodegenerative neurodegenerative
- inflammatory diseases eg cell necrosis
- Indole derivatives according to the present invention are medicinally useful structures, and there are many published studies on these structures, among which patent WO2006 / 112549, which is reported to be active against glucokinase, as an anti-tumor and cardiovascular inhibitor Patent WO95 / 07276, which is reported to be useful, and WO2004 / 018428, which is reported to be usable as an antibiotic, are representative.
- the present inventors conducted an intensive and extensive study to develop a compound useful for preventing or treating cell necrosis and related diseases, and particularly for preventing or treating liver disease, based on the technical background described above.
- the present invention has been accomplished by discovering that substituted indole derivatives of formula (1) as described below show excellent effects in the prevention and treatment of cell necrosis and related diseases.
- the present invention aims to provide novel indole compounds of the formula (1), pharmaceutically acceptable salts or isomers thereof.
- the invention also provides cell necrosis and related diseases, in particular liver protection, characterized in that it contains a compound of formula (1), a pharmaceutically acceptable salt or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier or diluent. It is an object of the present invention to provide a composition for improving liver function and preventing or treating acute or chronic liver disease.
- the present invention also aims to provide a method for preventing or treating cell necrosis and related diseases, in particular liver protection, liver function improvement and sudden, chronic liver disease using the composition.
- the present invention provides an indole compound represented by the following formula (1), a pharmaceutically acceptable salt or isomer thereof:
- n is a number from 1 to 3
- n is a number from 0 to 2
- R 1 represents hydrogen, C 1 -C 6 -alkyl,-(CH 2 ) n -C 3 -C 6 -cycloalkyl or-(CH 2 ) n -heterocyclyl, wherein heterocyclyl is N, O And 4 to 8 membered ring containing 1 to 3 hetero atoms selected from S,
- R 2 represents C 1 -C 6 -alkyl or-(CH 2 ) n -A-R 6, wherein A represents C 4 -C 8 -cycloalkyl, or 1 to 3 selected from N, O and S, respectively 4-8 membered heterocyclyl or heteroaryl containing 6 heteroatoms, or 6-10 membered aryl, R 6 represents hydrogen, C 1 -C 6 -alkyl, halogen, hydroxy, nitrile, nitro , —C (O) —R 7 or —SO 2 R 7, R 7 represents C 1 -C 6 -alkyl or allyl, 6-6 membered aryl, or 1 to 3 selected from N and S, respectively 4-8 membered heterocyclyl or heteroaryl, including hetero atoms, optionally substituted by oxo,
- R3 represents hydrogen, halogen, hydroxy, -O-R7, -NH-R7 or-(CH 2 ) n -R7,
- R 5 represents hydrogen, hydroxy or C 1 -C 6 -alkoxy, each represents an aryl or ar-C 1 -C 6 -alkyloxy having 6 to 10 membered aryl moieties or selected from N, O and S Or represents 4-9 membered-(CH 2 ) n -heterocyclyl containing 1 to 4 heteroatoms and optionally comprising oxo,
- R4 and R5 may combine with the atoms to which they are attached to form the following structure:
- alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, and the substituents are hydroxy, halogen, nitrile, amino, C 1 -C 6 -alkylamino, di (C 1 -C 6 -alkyl) amino, carboxy, C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkoxy and oxo One or more to be selected.
- alkyl means aliphatic hydrocarbon radicals.
- Alkyl may be “saturated alkyl” that does not include alkenyl or alkynyl moieties, or “unsaturated alkyl” that includes at least one alkenyl or alkynyl moiety.
- Alkenyl refers to a group containing at least one carbon-carbon double bond
- alkynyl refers to a group containing at least one carbon-carbon triple bond.
- Alkyl may be branched or straight chain, respectively, when used alone or in combination, such as alkoxy.
- Alkyl groups may have from 1 to 20 carbon atoms unless otherwise defined.
- the alkyl group may be a medium sized alkyl having 1 to 10 carbon atoms.
- the alkyl group may be lower alkyl having 1 to 6 carbon atoms.
- Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl and the like.
- C 1 -C 4 -alkyl has 1 to 4 carbon atoms in the alkyl chain and consists of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl Is selected from the group.
- alkoxy means alkyloxy having 1 to 10 carbon atoms unless otherwise defined.
- cycloalkyl means a saturated aliphatic 3-10 membered ring unless otherwise defined.
- Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- 'aryl' includes at least one ring having a shared pi electron field and includes, for example, a monocyclic or fused polycyclic (ie, rings that divide adjacent pairs of carbon atoms) groups. . That is, aryl in the present specification means a 4-10 membered, preferably 6-10 membered aromatic monocyclic or multicyclic ring including phenyl, naphthyl and the like unless otherwise defined.
- heteroaryl' unless defined otherwise, comprises from 1 to 3 heteroatoms selected from the group consisting of N, O and S atoms and is an aromatic 3-10 membered group which can be fused with benzo or C 3 -C 8 cycloalkyl , Preferably it is a 4-8 member, More preferably, it means a 5-6 member ring.
- Examples of monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadia Sol, pyridine, pyridazine, pyrimidine, pyrazine and similar groups, but is not limited thereto.
- bicyclic heteroaryl examples include indole, indolin, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine , Furypyridine and similar groups, but are not limited to these.
- heterocycle' includes one to three heteroatoms selected from the group consisting of N, O and S atoms, unless defined otherwise, and can be fused with benzo or C 3 -C 8 -cycloalkyl, saturated or 1 Or a 3 to 10 member, preferably 4 to 8 member, and more preferably a 5 to 6 membered ring containing two double bonds.
- heterocycles include pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, hydrofuran and the like. However, it is not limited only to these.
- n is a number from 1 to 3
- n is a number from 0 to 2
- R 1 represents hydrogen, C 1 -C 6 -alkyl,-(CH 2 ) n -C 3 -C 6 -cycloalkyl or-(CH 2 ) n -heterocyclyl, wherein heterocyclyl is N, O And 4 to 8 membered ring containing 1 to 3 hetero atoms selected from S,
- R 2 represents C 1 -C 6 -alkyl or-(CH 2 ) n -A-R 6, wherein A represents C 4 -C 6 -cycloalkyl, or 1 to 3 selected from N, O and S, respectively 5-6 membered heterocyclyl or heteroaryl containing 6 heteroatoms, or 6-10 membered aryl, R6 represents hydrogen, C 1 -C 6 -alkyl, halogen, hydroxy, -C (O) -R7 or -SO 2 R7, R7 represents C 1 -C 6 -alkyl, or represents a 6 to 10 membered aryl, each containing 1 to 3 heteroatoms selected from N and S and optionally on oxo 5-6 membered heterocyclyl or heteroaryl substituted by
- R3 represents hydrogen, halogen, -O-R7, -NH-R7 or-(CH 2 ) n -R7,
- R 5 represents hydrogen, hydroxy or C 1 -C 6 -alkoxy, each represents an aryl or ar-C 1 -C 6 -alkyloxy having 6 to 10 membered aryl moieties or selected from N, O and S Or represents a halogeno-C 1 -C 6 -alkyl substituted 4-9 membered-(CH 2 ) n -heterocyclyl containing 1 to 4 heteroatoms and optionally comprising oxo,
- R4 and R5 may combine with the atoms to which they are attached to form the following structure:
- R 5 and R 8 are the compounds as defined above.
- R4 when R4 is XR8R9, the substituents R4 and R5 may or may not be cyclized, and may have the following structures as shown in Formulas (1a) and (1b).
- X, m, n, R1, R2, R3, R5, R8 and R9 are as defined above.
- ring of formula 1b can represent within the definition of m and n is cyclohexyl, pyrrolidine or piperidine.
- Substituent R1 more preferably represents hydrogen or C 1 -C 6 -alkyl or represents a 5-6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, and R 1 is most preferred
- R 1 is most preferred
- Substituent R2 more preferably represents C 1 -C 6 -alkyl or-(CH 2 ) n -A-R 6, wherein n is a number from 0 to 2 and A represents C 4 -C 6 -cycloalkyl Or a 5-6 membered heterocyclyl comprising 1 to 2 heteroatoms selected from N and O, or represents phenyl, R6 represents hydrogen, -C (O) -R7 or -SO 2 R7 , R7 represents C 1 -C 3 -alkyl.
- R2 is most preferably isopentyl, cyclopentyl, benzyl, tetrahydropyran, tetrahydropyran-4-ylmethyl, 1-acetyl-piperidine, tetrahydropyran-2-ylmethyl or piperidine-4- Ilmethyl is shown.
- the substituent R 3 more preferably represents hydrogen, halogen or — (CH 2 ) n —R 7, wherein n is a number from 0 to 2 and R 7 represents C 1 -C 6 -alkyl or is selected from N and S A 5-6 membered heterocyclyl containing 1 to 2 heteroatoms and optionally substituted by oxo, most preferably R 3 is hydrogen, methyl, chloro or 1,1-dioxothiomorpholin-4-yl Methyl is indicated.
- Substituent R 5 more preferably represents hydrogen, hydroxy or C 1 -C 6 -alkoxy, each represents aryl or ar-C 1 -C 3 -alkyloxy wherein the aryl moiety is a 6-10 membered ring, or N, 1-4 heteroatoms selected from O and S, optionally containing oxo and optionally halogeno-C 1 -C 3 -alkyl substituted 4-9 membered- (CH 2 ) n -heterocyclyl, wherein N is a number from 0 to 2.
- R5 is most preferably hydrogen, hydroxy, benzyloxy, 1,1-dioxothiomorpholine, 2-oxopiperazine, 3-trifluoromethyl-5,6,7,8-tetrahydro- [1 , 2,4] triazolo [4,3-a] pyrazin-1-yl, morpholine or phenyl.
- Representative compounds of formula (1) according to the present invention include the following compounds:
- the compounds of formula (1) according to the invention may also form pharmaceutically acceptable salts.
- Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like; Organic carbon acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, and the like; Acid addition salts formed by sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like.
- alkali or alkaline earth metal salts formed by pharmaceutically acceptable base addition salts such as lithium, sodium, potassium, calcium, magnesium, and the like; Amino acid salts such as lysine, arginine and guanidine; Organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline, triethylamine and the like.
- the compound of formula (1) according to the present invention can be converted to its salt by conventional methods, and the preparation of the salt can be easily carried out by those skilled in the art based on the structure of formula (1) without further explanation. have.
- the compounds according to the invention may have asymmetric carbon center (s) and therefore may exist as R or S isomers, racemic compounds, diastereomeric mixtures and individual diastereomers, all of these isomers being within the scope of the invention. Included in
- the present invention also provides a process for preparing the compound of formula (1).
- a method for preparing a compound of formula (1) will be described based on exemplary reaction schemes to aid in understanding the present invention, but those skilled in the art to which the present invention pertains will be based on the structure of formula (1).
- Compounds of formula (1) may be prepared by various methods, all of which should be construed as being included in the scope of the present invention. That is, the compounds of formula (1) may be prepared by arbitrarily combining various synthesis methods described herein or disclosed in the prior art, which is understood to fall within the scope of the present invention, and the process for preparing the compound of formula (1) It is not limited to what is described.
- the compound of formula (1) is prepared by reducing the nitro group of compound (2) according to the method of Scheme (1) to prepare an amine compound (3), and then reducing amination with compound (4) for the formed amine group.
- the reaction can be carried out to synthesize.
- n, m, R2, R3, R4 and R5 are as defined above.
- Compound (3) can be prepared by reducing Compound (2).
- the reduction reaction can be carried out using an acid catalyst and a metal, or using a metal catalyst in the presence of hydrogen gas.
- Acids which can be used in the reduction reaction using an acid catalyst and a metal are, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like, organic carbonic acids such as acetic acid and trifluoroacetic acid, amine salts such as ammonium chloride, and the like. Is hydrochloric acid, acetic acid or ammonium chloride and the like.
- the use amount of acid is conventionally 0.01-10 equivalents, preferably 0.1-5 equivalents to 1 equivalent of Compound (2).
- Metals which can be used are, for example, iron, zinc, lithium, sodium, tin (typically, tin chloride) and the like, and particularly preferably iron, zinc, tin chloride and the like.
- the use amount of metal is conventionally 1-20 equivalents, preferably 1-10 equivalents to 1 equivalent of Compound (2).
- the metal reaction in the presence of an acid catalyst can proceed in an inert solvent.
- inert solvents include alkyl alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and diethyl ether, alkyl esters such as ethyl acetate, and the like, and preferably methanol, ethanol, tetrahydrofuran and ethyl acetate. to be.
- the reaction temperature is usually -10 to 200 degrees, preferably 25 to 120 degrees
- the reaction time is usually 10 minutes to 60 hours, preferably 10 minutes to 12 hours.
- Metal catalysts that can be used in a reduction reaction using a metal catalyst in the presence of hydrogen gas are palladium, nickel, platinum, ruthenium, rhodium, and the like, and particularly preferably palladium, nickel and the like.
- the use amount of metal catalyst is conventionally 0.001-2 equivalents, preferably 0.01-1 equivalent to 1 equivalent of Compound (2).
- the pressure of the hydrogen gas is usually 1 to 10 atmospheres, preferably 1 to 3 atmospheres.
- the reaction may be performed in an inert solvent such as alkyl alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and diethyl ether, alkyl acetates such as methyl acetate and ethyl acetate, and the like.
- the reaction proceeds in methanol, ethanol, ethyl acetate and the like.
- the temperature of the reaction using the metal catalyst is usually -10 to 200 degrees, preferably 25 to 50 degrees, the reaction time is usually 10 minutes to 60 hours, preferably 10 minutes to 12 hours.
- Compound (4) can be prepared through reductive amination (RA) reaction with respect to the amine group of compound (3).
- the reductive amination reaction can be carried out by reaction with an aldehyde or ketone using a reducing agent and an acid catalyst can be used if necessary.
- the amount of aldehyde or ketone is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (3).
- Reducing agents that can be used are sodium borohydride, sodium cyanoborohydride (NaBH 3 CN), sodium triacetoxy-borohydride ⁇ NaBH (OAc) 3 ⁇ , and the like.
- the use amount of reducing agent is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (3).
- Acid catalysts that can be used are, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like, organic carbon acids such as acetic acid and trifluoroacetic acid, amine salts such as ammonium chloride, and the like, and particularly preferably hydrochloric acid, acetic acid to be.
- the use amount of acid is conventionally 0.1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (3).
- the reaction can be carried out in an inert solvent such as ether such as tetrahydrofuran, diethyl ether, chloroalkane such as dichloromethane, chloroform, dichloroethane, and the like, preferably dichloroethane, chloroform and the like.
- ether such as tetrahydrofuran
- diethyl ether chloroalkane
- chloroalkane such as dichloromethane, chloroform, dichloroethane, and the like, preferably dichloroethane, chloroform and the like.
- the reaction temperature is usually -10 to 100 degrees, preferably -10 to 50 degrees
- the reaction time is usually 10 minutes to 60 hours, preferably 10 minutes to 12 hours.
- Compound (2) can be obtained by cyclizing the acetylene compound (7) obtained by linking and reacting the acetylene compound of compound (5) with compound (6) as in the following scheme (2).
- n, m, R3, R4 and R5 are as defined above,
- Q represents iodine or bromine.
- Preparation of the acetylene compound (7) can be carried out by the addition of a base in the presence of a metal catalyst, wherein the metal catalyst is used as Pd (II), Cu (I) and the like and Et 3 N, Et 2 N ( iPr), DBU, N-methyl-morpholine, methyl-pyrrolidine, K 2 CO 3 and the like.
- a metal catalyst is used as Pd (II), Cu (I) and the like and Et 3 N, Et 2 N ( iPr), DBU, N-methyl-morpholine, methyl-pyrrolidine, K 2 CO 3 and the like.
- the acetylene compound (5) is commercially available or can be synthesized from aldehyde by the method of the following scheme (3).
- n, m, R4 and R5 are as defined above.
- Compound (6) can be synthesized from the commercially available aniline compound (9) by the method of Scheme (4) below.
- R3 is as defined above
- Q represents iodine or bromine.
- Halogenated materials for preparing compound (6) can be selected from iodine, bromine, iodine monobromide and iodine monochloride, and include silver ions such as silver nitrate (AgNO 3 ), silver carbonate (AgCO 3 ), Silver sulfate (Ag 2 SO 4 ) and the like can be used together.
- silver ions such as silver nitrate (AgNO 3 ), silver carbonate (AgCO 3 ), Silver sulfate (Ag 2 SO 4 ) and the like can be used together.
- acetylation and nitration reactions can be used to obtain compound (10) from compound (9).
- the nitration reaction can be carried out at low temperature (-15 to 0 ° C.) using nitric acid as it is, or can be used with various solvents such as dichloromethane, dichloroethane, toluene and the like.
- Compound (11) can be synthesized by the method of Scheme (2), and reductive amination reaction can be carried out by the same method as in Scheme (1).
- DCC dicyclohexylcarbodiimide
- EDC 1- (3
- the use amount of binder is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (12).
- the use amount of HOBT or HOAT to be used is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (12).
- hydrochloride salts of amines are used in the coupling reaction, the acid must be removed using a base.
- the base used at this time is an organic base such as triethylamine and diisopropylethylamine.
- the use amount of base is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (12).
- the coupling reaction can be carried out in an inert solvent tetrahydrofuran, diethyl ether, N, N-dimethylformamide, or the like.
- the reaction temperature is usually -10 to 200 degrees, preferably 25 to 120 degrees
- the reaction time is usually 10 minutes to 60 hours, preferably 10 minutes to 12 hours.
- the present invention also relates to cell necrosis and related diseases, characterized by containing a therapeutically effective amount of a compound of formula (1), a pharmaceutically acceptable salt or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier or diluent It provides a composition for preventing or treating.
- the present invention also provides a method for preventing or treating cell necrosis and related diseases using the composition.
- Cell necrosis and related diseases that can be treated and / or prevented according to the invention include acute / chronic liver disease (eg hepatitis, liver fibrosis, cirrhosis), neurodegenerative diseases (eg dementia, Parkinson's disease, Huntington's disease) , Ischemic heart disease, reperfusion injury, ischemic stroke or ischemic injury, pancreatitis, bacterial / viral sepsis, diabetes or diabetic complications, diabetic vascular disease [these diabetes are due, in particular, to pancreatic cell destruction substances, Mediated by high blood sugar, fatty acids, diets, toxins, streptozotocin, etc.], necrotizing procolitis, cystic fibrosis, rheumatoid arthritis, degenerative arthritis, nephropathy, bacterial infections, viral infections (eg For example, HIV), multiple sclerosis, leukemia, lymphoma, neonatal respiratory distress syndrome, suffocation, tuberculosis, endometriosis, ang
- Cell necrosis and related diseases caused by drugs and toxic substances include alcoholism and ***e, drugs (e.g. paracetamol, antibiotics, anticancer agents, adriamycin, puromycin, bleomycin) Exposure to and / or administration of NSAIDs, cyclosporine, chemical toxins (eg carbon tetrachloride, cyanide, methanol, ethylene glycol), poison gases, pesticides, heavy metals (eg lead, mercury, cadmium) and / or Or necrosis associated with self-administration, damage by exposure to radiation / UV, and associated cell necrosis.
- drugs e.g. paracetamol, antibiotics, anticancer agents, adriamycin, puromycin, bleomycin
- NSAIDs e.g. paracetamol, antibiotics, anticancer agents, adriamycin, puromycin, bleomycin
- NSAIDs e.g. paracetamol, antibiotics, antican
- the composition according to the present invention not only shows the effect of protecting the liver and improving the function of the liver, but also prevents or treats the effects of preventing or treating chronic liver disease such as chronic liver disease such as fatty liver, liver fibrosis and cirrhosis, hepatitis caused by viruses or drugs. Indicates.
- chronic liver disease such as fatty liver, liver fibrosis and cirrhosis, hepatitis caused by viruses or drugs.
- the pharmaceutical composition according to the present invention is also effective for the treatment or prevention of liver diseases selected from liver transplantation, alcoholic or non-alcoholic fatty liver, hepatic fibrosis, cirrhosis, virus or hepatitis due to the drug, Effective for chronic liver disease
- composition according to the present invention is effective for the treatment or prevention of fatty liver derived from fatty acids or acute, chronic liver disease derived from fatty liver.
- treatment means stopping or delaying the progression of the disease when used in a subject exhibiting symptoms of onset
- preventing means stopping or showing signs of development when used in a subject who is not at risk of developing the disease. Means to delay.
- the "pharmaceutical composition” may include a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof as needed with the compound of the present invention.
- the pharmaceutical composition facilitates the administration of the compound into the organism.
- techniques for administering compounds including but not limited to oral, injection, aerosol, parenteral and topical administration, and the like.
- carrier refers to a substance that facilitates the addition of a compound into a cell or tissue.
- DMSO dimethylsulfoxide
- carrier commonly used to facilitate the incorporation of many organic compounds into cells or tissues of an organism.
- diluent is defined as a substance that not only stabilizes the biologically active form of a compound of interest, but also is diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, which mimics the salt form of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.
- pharmaceutically acceptable means a property that does not impair the biological activity and physical properties of the compound.
- the compounds of the present invention can be formulated in a variety of pharmaceutical dosage forms as desired.
- various pharmaceutically acceptable compounds which can be selected according to the active ingredient, in particular the compound of the formula (1), a pharmaceutically acceptable salt or isomer thereof, may be selected according to the dosage form. Is mixed with a carrier.
- the pharmaceutical compositions according to the invention may be formulated as injectable preparations, oral preparations and the like as desired.
- the compounds of the present invention can be formulated in a known manner using known pharmaceutical carriers and excipients and incorporated into unit dose forms or in multidose containers.
- the form of the preparation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium and may contain conventional dispersing agents, suspending agents or stabilizers. In addition, for example, it may be in the form of a dry powder used by dissolving in sterile, pyrogen-free water before use.
- the compounds of the present invention may also be formulated in suppository forms using conventional suppository bases such as cocoa butter or other glycerides.
- Solid dosage forms for oral administration may be capsules, tablets, pills, powders, and granules, and capsules and tablets are particularly useful.
- Tablets and pills are preferably prepared with enteric agents.
- Solid dosage forms can be prepared by mixing the compounds of the present invention with one or more inert diluents such as sucrose, lactose, starch and the like and with carriers such as lubricants, disintegrants, binders and the like, such as magnesium stearate.
- the compounds according to the invention or pharmaceutical compositions containing them are useful for other active agents, for example, cell protective agents with different kinds of mechanisms of action, in particular for liver protection, improving liver function and preventing or treating liver disease. It may be administered in combination with existing agents used, such as hepatocyte regeneration accelerators, liver function aids, antiviral agents, immunosuppressants, and fibrosis inhibitors.
- the compounds according to the invention or pharmaceutical compositions containing them can be administered in combination with agents for the prophylaxis or treatment of all drug-induced cell necrosis and related diseases.
- agents for the prophylaxis or treatment of all drug-induced cell necrosis and related diseases include antibiotics, anticancer agents, antiviral agents, anti-infective agents, anti-inflammatory agents, anticoagulants, lipid improving agents, cell death inhibitors, antihypertensives, diabetes / obesity agents, cardiovascular agents, neurodegenerative agents, anti-aging agents, and metabolic diseases. Includes drugs from all disease groups, including therapeutics.
- the compound according to the present invention or a pharmaceutical composition containing the same may be used to prevent cell damage induced by various causes such as toxins, and thus cell necrosis and related diseases, which are caused by reactive oxygen species (ROS).
- ROS reactive oxygen species
- reactive oxygen species heavy metals, alcohols, food, supplements, radiation, diets, and the like.
- the dosage of the compound of formula (1) depends on the doctor's prescription depending on factors such as the patient's weight, sex, age, health condition, diet, the specific nature of the disease, the time of administration of the drug, the method of administration, the drug mixture and the severity of the disease.
- dosages required for adult treatment typically range from about 1.0 mg to 2,000 mg per day, depending on the frequency and intensity of administration.
- the present invention also provides a prophylactic or therapeutic agent for cell necrosis and related diseases comprising mixing a compound of formula (1), a pharmaceutically acceptable salt or isomer thereof as an active ingredient with a pharmaceutically acceptable carrier or diluent
- a prophylactic or therapeutic agent for cell necrosis and related diseases comprising mixing a compound of formula (1), a pharmaceutically acceptable salt or isomer thereof as an active ingredient with a pharmaceutically acceptable carrier or diluent
- Liver protection and liver function improvement, class with the pharmaceutical composition according to the invention. It is possible to prevent or treat complications of chronic liver disease and consequent liver disease such as portal hypertention, but is not limited thereto.
- novel compounds according to the present invention not only show the effect of protecting the liver and improving liver function, but also are useful for the prevention or treatment of acute or chronic liver disease such as chronic liver disease such as fatty liver, liver fibrosis, cirrhosis, hepatitis induced by virus or drug. Can be used.
- the compounds of the present invention also showed efficacy in inhibiting cell necrosis in the pancreas, kidney, brain, cartilage and heart cells.
- the compounds of the present invention can be usefully used for the prevention or treatment of cell necrosis and related diseases.
- M means molarity
- N means normal concentration
- DIPEA Diisopropylethylamine
- Step A 4-Amino-3-nitro-benzoic acid ethyl ester
- Step B 4-Amino-3-iodo-5-nitro-benzoic acid ethyl ester
- Step A ((R) -1-Benzyl-2-oxo-ethyl) -carbamic acid t-butyl ester
- Step B ((R) -1-Benzyl-2-prop-2-ynyl) -carbamic acid t-butyl ester
- Tosyl chloride (10 g, 52.4 mmol) was dissolved in acetone (100 mL) and water (100 mL), and sodium azide (3.4 g, 52.4 mmol) was added thereto and stirred at room temperature for 2 hours. After completion of the reaction, acetone was removed under reduced pressure, water was added, and organics were extracted with diethyl ether. Washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. Removal of solvent under reduced pressure yielded tosyl azide (9.8 g, 88%).
- the tosyl azide (2.48 g, 12.6 mmol) obtained above was dissolved in acetonitrile (50 mL), and commercially available dimethyl acetophosphonate (1.94 g, 11.7 mmol) and potassium carbonate (3.23 g, 23.9 mmol) were obtained. Put and stirred at room temperature for 3 hours.
- ((R) -1-benzyl-2-oxo-ethyl) -carbamic acid t-butyl ester (2.66 g, 10.6 mmol) obtained in step A was slowly added to 50 mL of methanol. Potassium carbonate (2.94 g, 21.3 mmol) was added and stirred for 18 hours.
- Step A (S) -2,2-Dimethyl-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester
- Step B (R) -4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid 3-t-butyl ester
- Step C (R) -4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester
- Step A [(R) -3- (2-Amino-5-chloro-3-nitro-phenyl) -1-benzyl-prop-2-ynyl] -carbamic acid t-butyl ester
- Step B [(R) -1- (5-Chloro-7-nitro-1H-indol-2-yl) -2-phenyl-ethyl] -carbamic acid t-butyl ester
- step A [(R) -3- (2-amino-5-chloro-3-nitro-phenyl) -1-benzyl-prop-2-ynyl] -carbamic acid t-butyl ester obtained in step A (1.75 g, 4.21 mmol) was dissolved in N-methyl-pyrrolidinone (15 mL), and potassium thi-butoxide (944 mg, 8.41 mmol) was added thereto and stirred at room temperature for 3 hours. After completion of the reaction, the reaction was diluted with water and the organics were extracted with ethyl acetate. Washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give the title compound (674 mg, 39%).
- Step A (5-Chloro-7-nitro-1 H-indol-2-yl) -methanol
- step A (5-chloro-7-nitro-1H-indol-2-yl) -methanol (155 mg, 0.68 mmol) obtained in step A was dissolved in THF (10 mL), imidazole (140 mg, 2.0 mmol) and Triphenylphosphine (269 g, 1.03 mmol) was added thereto, iodine (261 mg, 1.03 mmol) was added, followed by stirring for 10 minutes. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography to give the title compound (130 mg, 66%).
- Step C 4- (5-Chloro-7-nitro-1 H-indol-2-ylmethyl) -piperazin-2-one
- step B The 5-chloro-2-iodomethyl-7-nitro-1H-indole (130 mg, 0.37 mmol) obtained in step B was dissolved in acetonitrile (10 mL) and piperazin-2-one (111 mg, 1.01). mmol) was added and stirred at 80 ° C. for 18 hours. After completion of the reaction, the solvent was removed under reduced pressure, water (20 mL) was added, the organics were extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give the title compound (89 mg, 78%).
- Step D 4- (7-Amino-5-chloro-1 H-indol-2-ylmethyl) -piperazin-2-one
- step C 4- (5-chloro-7-nitro-1H-indol-2-ylmethyl) -piperazin-2-one (90 mg, 0.29 mmol) obtained in step C was purified by tetrahydrofuran (3 mL), methanol ( 3 mL) and water (3 mL) were added, and ammonium chloride (156 mg, 2.92 mmol) and iron powder (82 mg, 1.47 mmol) were added and stirred at 70 ° C. for 1 hour. After completion of the reaction, the mixture was filtered through celite, washed with tetrahydrofuran (50 mL), and the solvent was removed under reduced pressure.
- Step E 4- (5-Chloro-7-cyclopentylamino-1 H-indol-2-ylmethyl) -piperazin-2- one
- step D 4- (7-amino-5-chloro-1H-indol-2-ylmethyl) -piperazin-2-one (27 mg, 0.10 mmol) obtained in step D was dissolved in dichloroethane (10 mL) and acetic acid (10 mg, 0.17 mmol), cyclopentanone (0.30 mg, 0.35 mmol) and sodium triacetoxyborohydride (30 mg, 0.14 mmol) were added dropwise and stirred at room temperature for 18 hours. After completion of the reaction, the reaction was diluted with water and the organics were extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give the title compound (15 mg, yield 45%).
- Step A 4- ⁇ 5-Chloro-2- [2- (3-oxo-piperazin-1-yl) -ethyl] -1 H-indol-7-ylamino] -piperidine-1-carboxylic acid t- Butyl ester
- Step B 4- ⁇ 2- [5-Chloro-7- (piperidin-4-ylamino) -1 H-indol-2-yl] -ethyl ⁇ -piperazin-2-one
- Step A [(R) -1- (7-cyclopentylamino-5-methyl-1H-indol-2-yl) -2-phenyl-ethyl] -carbamic acid t-butyl ester
- Step B [2- (R) -1-Amino-2-phenyl-ethyl] -5-methyl-1H-indol-7-yl] -cyclopentyl amine
- step A [(R) -1- (7-cyclopentylamino-5-methyl-1H-indol-2-yl) -2-phenyl-ethyl] -carbamic acid t-butyl ester obtained in step A was prepared in Example 2. Reaction according to step B affords the title compound.
- Step A [2-((R) -1-Amino-2-phenyl-ethyl) -5-chloro-1 H-indol-7-yl] -benzyl-amine
- Step B Benzyl- ⁇ 5-chloro-2-[(R) -2-phenyl-1- (pyrrolidin-3-ylamino) -ethyl] -1 H-indol-7-yl ⁇ -amine
- Step A ⁇ [(R) -1- (7-benzylamino-5-chloro-1H-indol-2-yl) -2-phenyl-ethylcarbamoyl] -methyl ⁇ -carbamic acid t-butyl ester
- Step B 2-Amino-N-[(R) -1- (7-benzylamino-5-chloro-1H-indol-2-yl) -2-phenylethyl] -acetamide
- step A The compound obtained in step A was reacted according to step B of Example 2 to obtain the title compound.
- Step A N-[(R) -1- (7-benzylamino-5-chloro-1 H-indol-2-yl) -2-phenyl-ethyl] -N ' , N "-diBOC-guanidine
- Step B N-[(R) -1- (7-benzylamino-5-chloro-1H-indol-2-yl) -2-phenyl-ethyl] -guanidine
- Step A [5-Chloro-2-((S) -2,2-dimethyl-oxazolidin-4-yl) -1 H-indol-7-yl] -cyclopentyl-amine
- Step B (S) -2-Amino-2- (5-chloro-7-cyclopentylamino-1 H-indol-2-yl) -ethanol
- Step A ((S) -2- ⁇ 7- [Bis- (3-methyl-butyl) -amino] -5-chloro-1 H-indol-2-yl ⁇ -pyrrolidin-1-yl) -acetic acid Methyl ester
- Step B ((S) -2- ⁇ 7- [Bis- (3-methyl-butyl) -amino] -5-chloro-1 H-indol-2-yl ⁇ -pyrrolidin-1-yl) -acetic acid
- Step C N- [2-((S) -2- ⁇ 7- [Bis- (3-methyl-butyl) -amino] -5-chloro-1 H-indol-2-yl ⁇ -pyrrolidine-1 -Yl) -acetyl] -guanidine
- Step A 2- (1-t-butoxycarbonyl-piperidin-4-yl) -7-nitro-1H-indole-5-carboxylic acid
- Step B 4- (5-hydroxymethyl-7-nitro-1H-indol-2-yl) -piperidine-1-carboxylic acid t-butyl ester
- Step C 4- [5- (1,1-Dioxo-thiomorpholin-4-ylmethyl) -7-nitro-1H-indol-2-yl) -piperidine-1-carboxylic acid t-butyl ester
- step B 4- (5-hydroxymethyl-7-nitro-1H-indol-2-yl) -piperidine-1-carboxylic acid t-butyl ester (85 mg, 0.22 mmol) obtained in step B was diluted with THF (10 mL). ), 1,1-dioxo-thiomorpholine (90 mg, 0.67 mmol) and triphenylphosphine (119 mg, 0.45 mmol) were added and iodine (115 mg, 0.45 mmol) was added, followed by 2 hours. Stirred. After the reaction was completed, sodium bicarbonate solution was added and the organics were extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The filtrate was filtered off the solvent under reduced pressure and the residue was separated by column chromatography to give the title compound (49 mg, yield 44%).
- Step D [5- (1,1-Dioxo-thiomorpholin-4-ylmethyl) -2-piperidin-4-yl-1H-indol-7-yl]-(tetrahydropyran-4- Yl) -amine
- Example 56 1- ⁇ 4- [5- (1,1-dioxo-thiomorpholin-4-ylmethyl) -7- (tetrahydropyran-4-ylamino) -1H-indol-2-yl ] -Piperidin-1-yl ⁇ -ethanone
- Steps D and E of Example 1 were carried out using 2-cyclohexyl-5-methyl-7-nitro-1H-indole and cyclopentanone obtained in Preparation Example 22 to obtain the title compound.
- apoptosis mechanisms are largely activated in two forms: apoptosis or necrosis.
- Current experiments use these cell death mechanisms to treat primary hepatocytes isolated from rats with drugs or other chemicals that induce cell death known to have serious side effects of hepatotoxicity in the clinic. And after 24 to 48 hours the liver cell protective effect of the compounds synthesized in the Example was measured.
- Hepatic cell death inducing substances include CCl 4 , ActD, H 2 O 2 , doxorubicin, anti-Fas antibody / actinomycin D, acetoaminophen, EtOH, CdCl 2 , palmitate, stearate, cyclophosphamide, terfenadine, diclofenac, simvastatin, adefovir were used. Isolation of primary liver cells was performed using the method of Seglen PO (Experimental Cell Research 74 (1972) pp450-454).
- hepatocytes are isolated according to a two-step collagenase perfusion method and then percoll gradient; Kreamer BL etc, In Vitro Cellular & Developmental Biology 22 (1986). dead cells were removed by centrifugation at low speed (500 rpm) for 10 minutes using pp201-211). The viability of the cells was maintained at 90% or more. The number of cells was counted by applying to HepatoZYME media (Gibco BRL). 100 ⁇ l of 1.5 ⁇ 10 4 cells were placed in a collagen-coated 96-well plate (BD biocoat) to attach the cells to the bottom for 3 to 4 hours.
- BD biocoat collagen-coated 96-well plate
- the attached cells were pretreated with the example compound for 30 minutes to confirm the liver cell protective effect.
- the concentration of the compound of Example 5 was used by serial dilution of two or three times from 30 uM, 10 uM or 1 uM according to the experiment and the final DMSO concentration was 0.2%.
- hepatic cell death-inducing substances or hepatotoxic drugs were treated at the concentrations indicated in Table 1 and after 24 or 48 hours, the survival of the cells was measured to evaluate the effect of liver cell protection.
- Cell viability was measured at 440 nm of absorbance by WST-1 (MK-400, Takeda) method.
- the hepatocellular protective effect of the example compound was expressed as “EC 50 ” calculated from the measured values. This refers to the concentration of a compound that represents 50% of the maximum protective effect seen in the “EC 50 ” experiment.
- the preferred EC 50 of the example compounds is 30 uM or less, more preferably 10 uM or less, particularly preferably 1 uM or less.
- EC 50 for doxorubicin treatment of representative example compounds is shown in Table 1.
- Hepatocellular separation was performed in the same manner as described in Experiment 1, and hepatocytes were plated on the plate by bouilloning with DMEM (Gibco + 10% FBS + 1X antibiotics) medium. 24 hours after planting the liver cells were pretreated for 30 minutes by serial dilution three times so that the final concentration of the compound is 30, 10, 3, 1, 0.3, 0.1 uM. tBHP was treated to a final concentration of 300 uM and the protective effect was measured after 1 hour. After treatment with WST-1 (Takeda, 10uL) for 1 hour 30 minutes as in Experimental Example 1, the EC 50 value was calculated by measuring the absorbance at 440nm using SpectraMax (Molecular Device).
- Linm5F cells one of beta cells, were first divided into 2 ⁇ 10 4 cells in 96-well plates and incubated for 24 hours. EXAMPLES Three times dilutions were made so that the final concentration of compound was 30, 10, 3, 1, 0.3, 0.1 uM, and the wells were treated for 1 hour. tBHP was treated to a final concentration of 400 uM and further incubated for 5 hours. Protective effect was measured using the SRB (Sulforhodamine B Protein) method, which stains the total protein amount of cells.
- SRB Sulforhodamine B Protein
- the cells were incubated for 5 hours, and then fixed by adding 50 uL of 4% formaldehyde solution to each well and stored at room temperature for about 30 minutes. The medium was discarded and each well was washed 2-3 times with distilled water and the plates were dried in a 50 ° C. oven. 50 uL of each SRB solution was added to each well and left at room temperature for 30 minutes. After removing the SRB solution, the plates were washed 2-3 times with 1% acetic acid solution. The plate was dried in an oven at 50 ° C., and then 100 ⁇ L of 10 mM Tris was used to elute SRB staining intracellular proteins. SpectMax was used to measure the absorbance at 590 nm and 650 nm, and then the EC 50 value was calculated by subtracting the absorbance value of 650 nm from the absorbance at 590 nm.
- H9C2 cells were aliquoted into 1.5 ⁇ 10 4 and cultured for 24 hours. EXAMPLES Three-fold serial dilutions were made to ensure that the final concentration of compound was 30, 10, 3, 1, 0.3, 0.1 uM, treated in each well and incubated for 45 minutes. tBHP was treated to a final concentration of 400 uM and incubated for 2 hours. The protective effect of each compound was measured by the same SRB method as in Linm5F above.
- Example Compounds were treated to a final concentration of 30, 10, 3, 1, 0.3, 0.1 uM and incubated for 30 minutes. 400 uM tBHP was treated and further incubated for 6 hours.
- the protective effect of each compound was measured by the same SRB method as in Linm5F above.
- chondrocytes were first isolated from two hind limbs of 16-week-old SD rats (weight: 450-460 g). The separation method is as follows. Cartilage was removed from the knees of the rats' hind legs and transferred to a 100 pie plate containing PBS (+ 1X antibiotics). PBS was placed in an ice bath to maintain 4 °C. Exchange with fresh PBS and centrifuged at 1000 rpm. PBS was removed and treated for 15 minutes by adding 3 mL of 1 ⁇ trypsin (Gibco) at 37 ° C. After centrifugation, the supernatant was discarded and washed again with PBS. Centrifuge and discard supernatant.
- PBS 1 ⁇ trypsin
- DMEM medium Gibco, 10% FBS
- Example Treatment was carried out for 1 hour by diluting serially three times so that the final concentration of the compound was 30, 10, 3, 1, 0.3, 0.1 uM.
- tBHP was treated to a final concentration of 400 uM and incubated for 6 hours.
- 50 uL of medium was taken from each well for LDH assay (Promega). In LDH assay (Promega), 50 uL of the medium was mixed with 50 uL of the assay solution and reacted at room temperature for 30 minutes, and the absorbance was measured at 490 nm using SpectraMax (Molecular Device).
- the novel compounds according to the present invention not only show the effect of protecting the liver and improving liver function, but also acute and chronic liver such as chronic liver disease such as fatty liver, liver fibrosis, cirrhosis, hepatitis induced by virus or drugs It can be usefully used for the prevention or treatment of diseases.
- the compounds of the present invention also showed efficacy in inhibiting cell necrosis in the pancreas, kidney, brain, cartilage and heart cells.
- the compounds of the present invention can be usefully used for the prevention or treatment of cell necrosis and related diseases.
Abstract
Description
Claims (32)
- 하기 화학식 (1)의 인돌 화합물, 약제학적으로 허용되는 그의 염 또는 이성체:[화학식 1]상기 식에서,m은 1 내지 3의 수이고,n은 0 내지 2의 수이며,R1은 수소, C1-C6-알킬, -(CH2)n-C3-C6-사이클로알킬 또는 -(CH2)n-헤테로사이클릴을 나타내고, 여기에서 헤테로사이클릴은 N, O 및 S 중에서 선택된 1 내지 3개의 헤테로 원자를 포함하는 4~8원환이며,R2는 C1-C6-알킬 또는 -(CH2)n-A-R6를 나타내고, 여기에서 A는 C4-C8-사이클로알킬을 나타내거나, 각각 N, O 및 S 중에서 선택된 1 내지 3개의 헤테로 원자를 포함하는 4~8원 헤테로사이클릴 또는 헤테로아릴을 나타내거나, 6~10원 아릴을 나타내며, R6는 수소, C1-C6-알킬, 할로겐, 하이드록시, 나이트릴, 나이트로, -C(O)-R7 또는 -SO2R7을 나타내고, R7은 C1-C6-알킬 또는 알릴을 나타내거나, 6~10원 아릴을 나타내거나, 각각 N 및 S 중에서 선택된 1 내지 3개의 헤테로 원자를 포함하며 임의로 옥소에 의해 치환된 4~8원 헤테로사이클릴 또는 헤테로아릴을 나타내고,R3는 수소, 할로겐, 하이드록시, -O-R7, -NH-R7 또는 -(CH2)n-R7을 나타내며,R4는 수소 또는 XR8R9을 나타내고, 여기에서 X는 CH 또는 N을 나타내며, R8 및 R9은 각각 독립적으로 수소 또는 Z-R10을 나타내고, Z는 -(CH2)n-, -C(O)-, -C(O)(CH2)n- 또는 -(CH2)nC(O)- 를 나타내며, R10은 수소, 아미노, C3-C6-사이클로알킬 또는 -(NH)rC(=NH)NH2 을 나타내거나, 각각 N, O 및 S 중에서 선택된 1 내지 3개의 헤테로 원자를 포함하는 4~8원 헤테로아릴 또는 헤테로사이클릴을 나타내고, r은 0 또는 1의 수이며,R5는 수소, 하이드록시 또는 C1-C6-알콕시를 나타내거나, 각각 아릴 부분이 6~10원환인 아릴 또는 아르-C1-C6-알킬옥시를 나타내거나, N, O 및 S 중에서 선택된 1 내지 4개의 헤테로 원자를 포함하고 임의로 옥소를 포함하는 4~9원 -(CH2)n-헤테로사이클릴을 나타내거나,R4 및 R5는 이들이 부착된 원자들과 함께 결합하여 하기 구조를 형성할 수 있으며:여기에서 R5 및 R8은 앞에서 정의한 바와 같고,상기에서, 알킬, 알콕시, 아릴, 사이클로알킬, 헤테로사이클 및 헤테로아릴은 임의로 치환될 수 있으며, 치환체는 하이드록시, 할로겐, 니트릴, 아미노, C1-C6-알킬아미노, 디(C1-C6-알킬)아미노, 카복시, C1-C6-알킬, 할로게노-C1-C6-알킬, C1-C6-알콕시, 아릴-C1-C6-알콕시 및 옥소로 이루어진 그룹에서 선택되는 하나 이상이다.
- 제1항에 있어서,m은 1 내지 3의 수이고,n은 0 내지 2의 수이며,R1은 수소, C1-C6-알킬, -(CH2)n-C3-C6-사이클로알킬 또는 -(CH2)n-헤테로사이클릴을 나타내고, 여기에서 헤테로사이클릴은 N, O 및 S 중에서 선택된 1 내지 3개의 헤테로 원자를 포함하는 4~8원환이며,R2는 C1-C6-알킬 또는 -(CH2)n-A-R6를 나타내고, 여기에서 A는 C4-C6-사이클로알킬을 나타내거나, 각각 N, O 및 S 중에서 선택된 1 내지 3개의 헤테로 원자를 포함하는 5~6원 헤테로사이클릴 또는 헤테로아릴을 나타내거나, 6~10원 아릴을 나타내며, R6는 수소, C1-C6-알킬, 할로겐, 하이드록시, -C(O)-R7 또는 -SO2R7을 나타내고, R7은 C1-C6-알킬을 나타내거나, 6~10원 아릴을 나타내거나, 각각 N 및 S 중에서 선택된 1 내지 3개의 헤테로 원자를 포함하며 임의로 옥소에 의해 치환된 5~6원 헤테로사이클릴 또는 헤테로아릴을 나타내고,R3는 수소, 할로겐, -O-R7, -NH-R7 또는 -(CH2)n-R7을 나타내며,R4는 수소 또는 XR8R9을 나타내고, 여기에서 X는 CH 또는 N을 나타내며, R8 및 R9은 각각 독립적으로 수소 또는 Z-R10을 나타내고, Z는 -(CH2)n-, -C(O)-, -C(O)(CH2)n- 또는 -(CH2)nC(O)- 를 나타내며, R10은 수소, 아미노, C3-C6-사이클로알킬 또는 -(NH)rC(=NH)NH2 를 나타내거나, 각각 N, O 및 S 중에서 선택된 1 내지 3개의 헤테로 원자를 포함하며 임의로 아미노 치환된 4~8원 헤테로아릴 또는 헤테로사이클릴을 나타내며, r은 0 또는 1의 수이고,R5는 수소, 하이드록시 또는 C1-C6-알콕시를 나타내거나, 각각 아릴 부분이 6~10원환인 아릴 또는 아르-C1-C6-알킬옥시를 나타내거나, N, O 및 S 중에서 선택된 1 내지 4개의 헤테로 원자를 포함하며 임의로 옥소를 포함하고 임의로 할로게노-C1-C6-알킬 치환된 4~9원 -(CH2)n-헤테로사이클릴을 나타내거나,R4 및 R5는 이들이 부착된 원자들과 함께 결합하여 하기 구조를 형성할 수 있으며:여기에서 R5 및 R8은 앞에서 정의한 바와 같은 화합물.
- 제3항에 있어서, m 및 n의 정의 범위 내에서 화학식 1b의 환이 사이클로헥실, 피롤리딘 또는 피페리딘을 나타내는 화합물.
- 제1항에 있어서, R1이 수소 또는 C1-C6-알킬을 나타내거나, N, O 및 S 중에서 선택된 1 내지 3개의 헤테로 원자를 포함하는 5~6원 헤테로사이클릴을 나타내는 화합물.
- 제5항에 있어서, R1이 수소, 이소펜틸 또는 테트라하이드로피란을 나타내는 화합물.
- 제1항에 있어서, R2가 C1-C6-알킬 또는 -(CH2)n-A-R6를 나타내고, 여기에서 n은 0 내지 2의 수이며, A는 C4-C6-사이클로알킬을 나타내거나, N 및 O 중에서 선택된 1 내지 2개의 헤테로 원자를 포함하는 5~6원 헤테로사이클릴을 나타내거나, 페닐을 나타내고, R6는 수소, -C(O)-R7 또는 -SO2R7을 나타내며, R7은 C1-C3-알킬을 나타내는 화합물.
- 제7항에 있어서, R2가 이소펜틸, 사이클로펜틸, 벤질, 테트라하이드로피란, 테트라하이드로피란-4-일메틸, 1-아세틸-피페리딘, 테트라하이드로피란-2-일메틸 또는 피페리딘-4-일메틸을 나타내는 화합물.
- 제1항에 있어서, R3가 수소, 할로겐 또는 -(CH2)n-R7을 나타내며, 여기에서 n은 0 내지 2의 수이고, R7은 C1-C6-알킬을 나타내거나 N 및 S 중에서 선택된 1 내지 2개의 헤테로 원자를 포함하고 임의로 옥소에 의해 치환된 5~6원 헤테로사이클릴을 나타내는 화합물.
- 제9항에 있어서, R3가 수소, 메틸, 클로로 또는 1,1-디옥소티오몰포린-4-일메틸을 나타내는 화합물.
- 제1항에 있어서, R5가 수소, 하이드록시 또는 C1-C6-알콕시를 나타내거나, 각각 아릴 부분이 6~10원환인 아릴 또는 아르-C1-C3-알킬옥시를 나타내거나, N, O 및 S 중에서 선택된 1 내지 4개의 헤테로 원자를 포함하며 임의로 옥소를 포함하고 임의로 할로게노-C1-C3-알킬 치환된 4~9원 -(CH2)n-헤테로사이클릴을 나타내며, 여기에서 n은 0 내지 2의 수인 화합물.
- 제11항에 있어서, R5가 수소, 하이드록시, 벤질옥시, 1,1-디옥소티오몰포린, 2-옥소피페라진, 3-트리플루오로메틸-5,6,7,8-테트라하이드로-[1,2,4]트리아졸로[4,3-a]피라진-1-일, 몰포린 또는 페닐을 나타내는 화합물.
- 제1항에 있어서, R8가 수소 또는 Z-R10을 나타내며, 여기에서 Z는 -(CH2)n-, -C(O)-, -C(O)(CH2)n- 또는 -(CH2)nC(O)- 을 나타내고, n은 0 내지 2의 수이며, R10은 수소, 아미노, C4-C6-사이클로알킬 또는 -(NH)rC(=NH)NH2 를 나타내거나, 각각 N 및 S 중에서 선택된 1 내지 3개의 헤테로 원자를 포함하고 임의로 아미노 치환된 5~6원 헤테로아릴 또는 헤테로사이클릴을 나타내며, r은 0 또는 1의 수인 화합물.
- 제13항에 있어서, R8가 수소, 사이클로헥실-에틸, 2-아미노-피리딘-3-일메틸, 피롤리딘, 3-아미노-트리아졸-5-카보닐, 아미노메틸-카보닐, NH2(NH=)C-, NH2(NH=)C-NH-CH2-C(O)-, 2-아미노-티아졸-4-일메틸, 사이클로펜틸-메틸, NH2(NH=)C-NH-C(O)-CH2- 또는 아세틸을 나타내는 화합물.
- 제1항에 있어서, 하기 그룹으로부터 선택되는 화합물:4-(5-클로로-7-사이클로펜틸아미노-1H-인돌-2-일메틸)-피페라진-2-온;4-{2-[5-클로로-7-(피페리딘-4-일아미노)-1H-인돌-2-일]-에틸}-피페라진-2-온;4-{2-[7-(1-아세틸-피페리딘-4-일아미노)-5-클로로-1H-인돌-2-일]-에틸}-피페라진-2-온;(5-클로로-7-사이클로펜틸아미노-1H-인돌-2-일)메탄올;2-(5-클로로-7-사이클로펜틸아미노-1H-인돌-2-일)-에탄올;4-{5-메틸-7-[(피페리딘-4-일메틸)-아미노]-1H-인돌-2-일메틸}-피페라진-2-온;[2-(1,1-디옥소티오몰포린-4-일메틸)-5-메틸-1H-인돌-7-일]-(테트라하이드로피란-4-일메틸)-아민;사이클로펜틸-[2-(1,1-디옥소티오몰포린-4-일메틸)-5-메틸-1H-인돌-7-일]-아민;4-[5-메틸-7-(테트라하이드로피란-4-일메틸아미노)-1H-인돌-2-일메틸)-피페라진-2-온;{5-클로로-2-[2-(3-트리플루오로메틸-5,6,7,8-테트라하이드로-[1,2,4]트리아졸로[4,3-a]피라진-1-일)-에틸]-1H-인돌-7-일}-(테트라하이드로퓨란-2-일메틸)-아민;{5-클로로-2-[2-(3-트리플루오로메틸-5,6,7,8-테트라하이드로-[1,2,4]트리아졸로[4,3-a]피라진-1-일)-에틸]-1H-인돌-7-일}-(테트라하이드로피란-2-일메틸)-아민;{5-클로로-2-[2-(3-트리플루오로메틸-5,6,7,8-테트라하이드로-[1,2,4]트리아졸로[4,3-a]피라진-1-일)-에틸]-1H-인돌-7-일}-(1-메탄설포닐-피페리딘-4-일)-아민;1-(4-{5-클로로-2-[2-(3-트리플루오로메틸-5,6,7,8-테트라하이드로-[1,2,4]트리아졸로[4,3-a]피라진-1-일)-에틸]-1H-인돌-7-일}-피페리딘-1-일)-에탄온;4-[2-(7-벤질아미노-5-클로로-1H-인돌-2-일)-에틸]-피페라진-2-온;4-(2-{5-클로로-7-[(테트라하이드로퓨란-2-일메틸)-아미노]-1H-인돌-2-일)-에틸]-피페라진-2-온;4-(2-{5-클로로-7-[(테트라하이드로피란-2-일메틸)-아미노]-1H-인돌-2-일)-에틸]-피페라진-2-온;4-{5-클로로-7-[(테트라하이드로피란-4-일메틸)-아미노]-1H-인돌-2-일메틸}-피페라진-2-온;{5-클로로-2-[2-(1,1-디옥소티오몰포린-4-일)-에틸]-1H-인돌-7-일}-(테트라하이드로피란-4-일)-아민;{5-클로로-2-[2-(1,1-디옥소티오몰포린-4-일)-에틸]-1H-인돌-7-일}-사이클로펜틸-아민;{5-클로로-2-[2-(3-트리플루오로메틸-5,6,7,8-테트라하이드로-[1,2,4]트리아졸로[4,3-a]피라진-1-일)-에틸]-1H-인돌-7-일}-사이클로펜틸-아민;{5-클로로-2-[2-(1,1-디옥소티오몰포린-4-일)-에틸]-1H-인돌-7-일}-(테트라하이드로피란-4-일메틸)-아민;4-(2-{5-클로로-7-[(테트라하이드로피란-4-일메틸)-아미노]-1H-인돌-2-일}-에틸)-피페라진-2-온;{5-클로로-2-[2-(3-트리플루오로메틸-5,6,7,8-테트라하이드로-[1,2,4]트리아졸로[4,3-a]피라진-1-일)-에틸]-1H-인돌-7-일}-(테트라하이드로피란-4-일메틸)-아민;[5-클로로-2-(2-몰포린-4-일-에틸)-1H-인돌-7-일-(테트라하이드로피란-4-일메틸)-아민;사이클로펜틸-(5-메틸-2-몰포린-4-일메틸-1H-인돌-7-일)-아민;(2-사이클로헥실-5-메틸-1H-인돌-7-일)-사이클로펜틸-아민;[2-(R)-1-아미노-2-페닐-에틸]-5-메틸-1H-인돌-7-일]-사이클로펜틸아민;{2-[(R)-1-(2-사이클로헥실-에틸아미노)-2-페닐-에틸]-5-메틸-1H-인돌-7-일}-사이클로펜틸-아민;벤질-{5-클로로-2-[(R)-2-페닐-1-(피롤리딘-3-일아미노)-에틸]-1H-인돌-7-일}-아민;2-아미노-N-[(R)-1-(7-벤질아미노-5-클로로-1H-인돌-2-일)-2-페닐에틸]-아세타미드;N-[(R)-1-(7-벤질아미노-5-클로로-1H-인돌-2-일)-2-페닐-에틸]-구아니딘;{2-[(R)-1-(사이클로헥실메틸-아미노)-2-페닐-에틸]-5-메틸-1H-인돌-7-일}-사이클로펜틸-아민;(2-{(S)-1-[(2-아미노-피리딘-3-일메틸)-아미노]-2-페닐-에틸}-5-클로로-1H-인돌-7-일)-(3-메틸-부틸)-아민;3-아미노-4H-[1,2,4]트리아졸-4-카복실산 [(S)-1-(7-벤질아미노-5-클로로-1H-인돌-2-일)-2-페닐-에틸]-아미드;2-아미노-N-{(S)-1-[5-클로로-7-(3-메틸-부틸아미노)-1H-인돌-2-일]-2-페닐-에틸}-아세타미드;N-[(R)-1-(7-벤질아미노-5-클로로-1H-인돌-2-일)-2-페닐-에틸]-2-구아니디노-아세타미드;(S)-2-아미노-2-(5-클로로-7-사이클로펜틸아미노-1H-인돌-2-일)-에탄올;((S)-5-클로로-2-피롤리딘-2-일-1H-인돌-7-일)-비스-(3-메틸-부틸)-아민;(2S,4R)-4-벤질옥시-2-(5-클로로-7-사이클로펜틸아미노-1H-인돌-2-일)-피롤리딘-1-카복사미딘;(S)-2-{7-[비스-(3-메틸-부틸)-아미노]-5-클로로-1H-인돌-2-일)-피롤리딘-1-카복사미딘;(S)-2-(5-클로로-7-사이클로펜틸아미노-1H-인돌-2-일)-피롤리딘-1-카복사미딘;[2-((2S,4R)-4-벤질옥시-[1,3']비피롤리딘-2-일)-5-클로로-1H-인돌-7-일)-사이클로펜틸-아민;((S)-[1,3']비피롤리딘-2-일-5-클로로-1H-인돌-7-일)-사이클로펜틸-아민;{2-[(S)-1-(2-아미노-티아졸-4-일메틸)-피롤리딘-2-일]-5-클로로-1H-인돌-7-일)-사이클로펜틸-아민;[5-클로로-2-((S)-1-사이클로펜틸메틸-피롤리딘-2-일)-1H-인돌-7-일]-비스-(3-메틸-부틸)-아민;((S)-[1,3']비피롤리딘-2-일-5-클로로-1H-인돌-7-일)-비스-(3-메틸-부틸)-아민;N-[2-((S)-2-{7-[비스-(3-메틸-부틸)-아미노]-5-클로로-1H-인돌-2-일}-피롤리딘-1-일)-아세틸]-구아니딘;(5-클로로-2-피페리딘-4-일-1H-인돌-7-일)-사이클로펜틸-아민;(5-클로로-2-피페리딘-4-일-1H-인돌-7-일)-(테트라하이드로피란-4-일)-아민;사이클로펜틸-(5-메틸-2-피페리딘-4-일-1H-인돌-7-일)-아민;1-[4-(7-사이클로펜틸아미노-5-메틸-1H-인돌-2-일)-피페리딘-1-일]-에탄온;(5-메틸-2-피페리딘-4-일-1H-인돌-7-일)-(테트라하이드로피란-4-일)-아민;(5-메틸-2-피페리딘-4-일-1H-인돌-7-일)-비스-(테트라하이드로피란-4-일)-아민;1-{4-[5-메틸-7-(테트라하이드로피란-4-일아미노)-1H-인돌-2-일]-피페리딘-1-일]-에탄온;(2-사이클로헥실-5-메틸-1H-인돌-7-일)-사이클로펜틸-아민;[5-(1,1-디옥소-티오몰포린-4-일메틸)-2-피페리딘-4-일-1H-인돌-7-일]-(테트라하이드로피란-4-일)-아민; 및1-{4-[5-(1,1-디옥소-티오몰포린-4-일메틸)-7-(테트라하이드로피란-4-일아미노)-1H-인돌-2-일]-피페리딘-1-일}-에탄온.
- 활성 성분으로서 치료학적 유효량의 제1항에 따른 화학식 (1)의 화합물, 약제학적으로 허용되는 그의 염 또는 이성체를 약제학적으로 허용되는 담체 또는 희석제와 함께 함유함을 특징으로 하는 세포괴사 및 관련 질환을 예방 또는 치료하기 위한 조성물.
- 제16항에 있어서, 세포괴사 및 관련 질환이 급성/만성 간 질환, 신경퇴행성 질환, 허혈성 질환, 당뇨병, 췌장염, 박테리아성/바이러스성 패혈증, 괴사성 프로콜리티스 (necrotizing procolitis), 낭포성 섬유증, 류마티스성 관절염, 퇴행성 관절염, 신증, 박테리아 감염, 바이러스 감염, 다발성 경화증, 백혈병, 림프종, 신생아 호흡곤란증후군, 질식, 결핵, 자궁내막증, 혈관무력증, 건선, 동상, 스테로이드처리 합병증, 회저병, 압통, 혈색소뇨증, 화상, 고열증, 크론씨병, 셀리악병, 구획증후군, 나상맥 손상, 사구체신염, 근이양증, 대사성 유전질환, 마이코플라즈마 질환, 탄저병, 앤더슨병, 선천성 마이토콘드리아병, 페닐케톤뇨증, 태반경색, 매독 및 무균성 괴사로 구성된 그룹에서 선택되는 조성물.
- 제16항에 있어서, 세포괴사 및 관련 질환이 약물 및 독성 물질에 의한 질환으로서 알코올 중독 및 코카인, 약물, 항생제, 항암제, 아드리아마이신 (adriamycin), 퓨로마이신 (puromycin), 블레오마이신 (bleomycin), NSAID, 사이클로스포린 (cyclosporine), 화학독소, 독가스, 농약, 중금속에의 노출 또는 이들의 투여 또는 자가투여와 관련된 괴사, 방사능/UV에의 노출에 의한 손상 및 이와 관련된 세포괴사로 구성된 그룹에서 선택되는 조성물.
- 제16항에 있어서, 간 보호, 간 기능 개선 및 간 질환을 예방 또는 치료하기 위한 조성물.
- 제19항에 있어서, 간 질환이 간이식, 알콜성 또는 비알콜성 지방간, 간섬유증, 간경변, 바이러스 또는 약물로 인한 간염으로 구성된 그룹에서 선택되는 조성물.
- 제19항에 있어서, 간 질환이 알콜성 급, 만성 간질환인 조성물.
- 제19항에 있어서, 간 질환이 지방산으로부터 유래된 지방간 또는 지방간으로부터 유래된 급, 만성 간 질환인 조성물.
- 제19항에 있어서, 간 질환이 활성 산소종 (ROS; reactive oxygen species)에 의해 매개됨을 특징으로 하는 조성물.
- 제19항에 있어서, 간 질환이 중금속에 의해 매개됨을 특징으로 하는 조성물.
- 제16항에 있어서, 약물-유도성 세포괴사 및 관련 질환의 예방 또는 치료제와 병용 투여됨을 특징으로 하는 조성물.
- 제25항에 있어서, 약물-유도성 세포괴사 및 관련 질환의 예방 또는 치료제가 항생제, 항암제, 항 바이러스제, 항감염제, 항염증제, 항응혈제, 지질 개선제, 세포사 억제제, 항고혈압제, 당뇨/비만 치료제, 심혈관 질환 치료제, 퇴행성 신경질환 치료제, 항노화제, 및 대사성 질환 치료제로 구성된 그룹에서 선택되는 조성물.
- 제19항에 있어서, 간세포 재생 촉진제, 간기능 보조제, 항 바이러스제, 면역 억제제, 및 섬유화 억제제로 구성된 그룹에서 선택된 약제와 병용 투여됨을 특징으로 하는 조성물.
- 제17항에 있어서, 신경퇴행성 질환이 치매, 파킨슨병 또는 헌팅톤병인 조성물.
- 제17항에 있어서, 허혈성 질환이 심장질환, 재관류 손상, 허혈성 뇌졸중 또는 허혈성 손상인 조성물.
- 제17항에 있어서, 당뇨병이 췌장세포 파괴 물질에 기인한 당뇨병, 당뇨병성 합병증 또는 당뇨병성 혈관 질환인 조성물.
- 제30항에 있어서, 당뇨병이 바이러스, 고혈당, 지방산, 다이어트, 독소 또는 스트렙토조토신 (streptozotocin)에 의해 매개된 것임을 특징으로 하는 조성물.
- 활성 성분으로서 제1항에 따른 화학식 (1)의 화합물, 약제학적으로 허용되는 그의 염 또는 이성체를 약제학적으로 허용되는 담체와 함께 혼합하는 단계를 포함함을 특징으로 하는, 세포괴사 및 관련 질환의 예방 또는 치료제 조성물의 제조 방법.
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EP14837897.9A EP3037418B1 (en) | 2013-08-22 | 2014-08-21 | Indole compound as inhibitor of necrosis |
US14/913,132 US10927097B2 (en) | 2013-08-22 | 2014-08-21 | Indole compound as inhibitor of necrosis |
JP2016536036A JP6315853B2 (ja) | 2013-08-22 | 2014-08-21 | 細胞壊死阻害剤としてのインドール化合物 |
CN201480056286.3A CN105636956B (zh) | 2013-08-22 | 2014-08-21 | 作为细胞坏死阻碍剂的吲哚化合物 |
ES14837897T ES2753324T3 (es) | 2013-08-22 | 2014-08-21 | Compuesto de indol como inhibidor de necrosis |
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JP (1) | JP6315853B2 (ko) |
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CN114080386A (zh) * | 2019-06-19 | 2022-02-22 | 株式会社Lg化学 | 制备吲哚或吲唑化合物的方法 |
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WO2006112549A1 (ja) | 2005-04-20 | 2006-10-26 | Takeda Pharmaceutical Company Limited | 縮合複素環化合物 |
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KR20130087283A (ko) * | 2012-01-27 | 2013-08-06 | 재단법인 의약바이오컨버젼스연구단 | 인돌 및 인다졸 유도체를 유효성분으로 포함하는 암 전이 억제용 조성물 |
-
2014
- 2014-08-21 CN CN201480056286.3A patent/CN105636956B/zh active Active
- 2014-08-21 EP EP14837897.9A patent/EP3037418B1/en active Active
- 2014-08-21 ES ES14837897T patent/ES2753324T3/es active Active
- 2014-08-21 JP JP2016536036A patent/JP6315853B2/ja active Active
- 2014-08-21 WO PCT/KR2014/007758 patent/WO2015026170A1/ko active Application Filing
- 2014-08-21 US US14/913,132 patent/US10927097B2/en active Active
- 2014-08-21 KR KR1020140108965A patent/KR101986580B1/ko active IP Right Grant
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Also Published As
Publication number | Publication date |
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CN105636956B (zh) | 2019-07-09 |
EP3037418B1 (en) | 2019-10-02 |
JP6315853B2 (ja) | 2018-04-25 |
EP3037418A1 (en) | 2016-06-29 |
JP2016528281A (ja) | 2016-09-15 |
KR101986580B1 (ko) | 2019-06-10 |
US10927097B2 (en) | 2021-02-23 |
ES2753324T3 (es) | 2020-04-08 |
KR20150022706A (ko) | 2015-03-04 |
EP3037418A4 (en) | 2017-01-18 |
US20160200709A1 (en) | 2016-07-14 |
CN105636956A (zh) | 2016-06-01 |
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