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WO2013157728A1 - Composition pharmaceutique destinée à prévenir ou à traiter la démence, et méthode de préparation de celle-ci - Google Patents

Composition pharmaceutique destinée à prévenir ou à traiter la démence, et méthode de préparation de celle-ci Download PDF

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Publication number
WO2013157728A1
WO2013157728A1 PCT/KR2013/000577 KR2013000577W WO2013157728A1 WO 2013157728 A1 WO2013157728 A1 WO 2013157728A1 KR 2013000577 W KR2013000577 W KR 2013000577W WO 2013157728 A1 WO2013157728 A1 WO 2013157728A1
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Prior art keywords
dementia
formula
disease
compound
pharmaceutically acceptable
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English (en)
Korean (ko)
Inventor
노형준
김금숙
이승은
김영옥
김승유
홍윤표
조재한
엄선영
이강노
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Korea Rural Development Administration
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Korea Rural Development Administration
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating dementia comprising a specific substance extracted from roe deer mushroom as an active ingredient, and more specifically, a pharmaceutical composition and a health functional food comprising a specific compound extracted from roe deer mushroom Etc.
  • Roe deer mushrooms are called 'dudugo' in China because their mushrooms resemble monkey heads. From summer to autumn, each one grows on the stems of broad-leaved trees such as oak and oak trees. Mushroom shade is about 5 ⁇ 20 cm in diameter, mostly ball-shaped or egg-shaped ball, hairs on the upper side and countless needles hang on the side and bottom. The needle is 1-5cm long and 1mm thick and has a sharp tip.
  • dementia comes from the Latin word meaning "to be demented.” The lack of intellectual ability since birth is called mental retardation. On the other hand, dementia suffers from cognitive function that is deteriorated and overall declines in daily life as the brain function is damaged by various causes. Significant obstacles are appearing.
  • cognitive function refers to various intellectual abilities such as memory, language ability, time and space grasping ability, judgment ability and abstract thinking ability, and each cognitive function is closely related to a specific brain region. There are about 70 disorders that cause clinical syndrome called dementia.
  • Alzheimer's disease and vascular dementia are a wide variety of dementia-causing diseases, the most common are Alzheimer's disease and vascular dementia, but other degenerative brain diseases such as Lewy dementia and Parkinson's disease, normal pressure hydrocephalus, head trauma, brain tumors, metabolic diseases, deficiency diseases, Dementia can be caused by a wide variety of causative diseases, such as addictive diseases and infectious diseases.
  • degenerative brain diseases such as Lewy dementia and Parkinson's disease, normal pressure hydrocephalus, head trauma, brain tumors, metabolic diseases, deficiency diseases, Dementia can be caused by a wide variety of causative diseases, such as addictive diseases and infectious diseases.
  • Acetylcholine is present in the nervous system of animals and is a chemical that transmits nerve impulses to muscles. Such acetylcholine is decomposed into choline and acetic acid by acetylcholinesterase. Therefore, when acetylcholinesterase is excessively activated, acetylcholine, which is an important chemical of neurotransmission, is decomposed and there is a problem that the transmission of nerve stimulation is not smoothed. In addition, the problem caused by the activation of acetylcholinesterase causes neurotransmission problems, which may cause dementia.
  • the problem of the prior art is a variety of causes and diseases of dementia, but the prior art has a problem that there is a lack of raw materials and drugs that effectively treat or prevent it.
  • the activation of acetylcholinesterase may be a cause of dementia, there is a problem in that there is a shortage of raw materials and drugs that can effectively cope with dementia by inhibiting its activity.
  • an object of the present invention is to find a compound that is effective in the prevention and treatment of dementia and to provide a raw material and medicament that can effectively cope with dementia, the acetylcholinesterase By inhibiting the activity to block the cause of dementia, in addition to the prevention and treatment of dementia, and to provide a specific compound derived from the locust beetle effective to protect the brain nerve.
  • Acetylcholinesterase activity inhibitors according to a feature of the present invention for solving the above problems include a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound is characterized in that derived from the roe deer mushroom.
  • the inhibitors also include Alzheimer's disease dementia, Vascular dementia, Parkinson's disease dementia, Lewy body dementia, Huntington's disease dementia, and Crutzfeldt- It is characterized in that it acts on any one or more diseases selected from the group consisting of Creutzfeldt-Jacob disease type dementia, Pick's disease type dementia, brain tumors, stroke and cognitive impairment.
  • a pharmaceutical composition for preventing or treating dementia according to another feature of the present invention includes a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound is characterized in that derived from the roe deer mushroom.
  • the dementia may include Alzheimer's disease dementia, Vascular dementia, Parkinson's disease dementia, Lewy body dementia, Huntington's disease dementia, and Crutzfeldt- It is characterized in that any one or more dementia selected from the group consisting of Creutzfeldt-Jacob disease type dementia and Pick's disease type dementia.
  • Neuroprotective agent according to another feature of the present invention comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound is characterized in that derived from the roe deer mushroom.
  • the neuroprotective agent is characterized in that it acts on any one or more diseases selected from the group consisting of cerebral infarction, stroke, ischemic stroke, cerebral hemorrhage, cerebral edema and cerebrovascular dementia.
  • a method for preparing an acetylcholinesterase inhibitor wherein the step of pulverizing a locust mushroom and adding an alcohol after the pulverization to obtain an extract and concentrating under reduced pressure and organically extracting the concentrated extract under reduced pressure Obtaining a primary fraction through a solvent, obtaining a secondary fraction through chromatography of the primary fraction, and separating and purifying the compound of Formula 1 from the secondary fraction.
  • Health functional food according to another feature of the present invention comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • an acetylcholinesterase activity inhibitor including the novel compound and an acceptable salt thereof according to the present invention effectively inhibits the activity of acetylcholinesterase, one of the causes of dementia, thereby effectively preventing and treating dementia.
  • a pharmaceutical composition capable of protecting the brain nerve and to provide a dietary supplement.
  • FIG. 2 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 1 in Experimental Example 1.
  • FIG. 2 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 1 in Experimental Example 1.
  • Figure 4 is a graph showing the IR spectrum analysis results of the spectroscopic analysis of Compound 1 in Experimental Example 1.
  • Figure 5 is a graph showing the 1 HNMR spectrum analysis results of the spectroscopic analysis of the compound 2 in Experimental Example 1.
  • FIG. 6 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 2 in Experimental Example 1.
  • FIG. 6 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 2 in Experimental Example 1.
  • FIG. 10 is a graph showing the activity inhibitory effect on the acetylcholinesterase of Compound 2 and Comparative Examples 2 to 4 according to the present invention.
  • the present inventors have made a thorough research to develop a pharmaceutical composition for preventing or treating dementia, and as a result, have found a specific compound extracted from the roe deer mushroom according to the present invention to complete the present invention.
  • Acetylcholinesterase is an enzyme that decomposes acetylcholine. If the acetylcholinesterase is activated, acetylcholine may be degraded to interfere with neurotransmission, which may be a cause of dementia.
  • the activity inhibitor of acetylcholinesterase according to the present invention may include the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of Formula 1 may be preferably extracted from the roe deer mushroom.
  • the inhibitor is preferably Alzheimer's disease dementia, Vascular dementia, Parkinson's disease dementia, Lewy body dementia, Huntington's disease dementia, crew It may act on any one or more diseases selected from the group consisting of Creutzfeldt-Jacob disease type dementia, Pick's disease type dementia, brain tumors, stroke and cognitive impairment.
  • the pharmaceutically acceptable salts thereof may include the compound of Formula 1 as an active ingredient.
  • the present invention may also include such agents or salts thereof that are lyophilized and can be reconstituted to form pharmaceutically acceptable formulations for administration, such as by intravenous, intramuscular or subcutaneous injection.
  • the compounds of formula (1) and pharmaceutically acceptable salts thereof described herein can also be administered orally or as inhalations as solids, or intramuscularly or intravenously as solutions, suspensions or emulsions. More preferably, it may be administered as a liposome suspension by inhalation, intravenous or intramuscularly. Also more preferably, a pharmaceutical formulation suitable for administration by inhalation as an aerosol can be provided.
  • the dosage of the activity inhibitor of acetylcholinesterase may be appropriately selected and used depending on symptoms, age, dosage form, etc., preferably, 0.01 to 100 mg per day may be administered once or several times. More preferably, 1 to 100 mg may be administered once or in divided portions.
  • Dementia can be caused by a variety of causes, and inhibiting the activity of acetylcholinesterase, which can be one of the causative agents, can be effective in preventing or treating dementia.
  • another feature of the present invention may be a pharmaceutical composition for preventing or treating dementia comprising the compound of Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of Chemical Formula 1 may be preferably extracted from scab mushroom.
  • the dementia is preferably Alzheimer's disease dementia, Vascular dementia, Parkinson's disease dementia, Lewy body dementia, Huntington's disease dementia, crew At least one selected from the group consisting of Creutzfeldt-Jacob disease dementia and Pick's disease dementia.
  • the Alzheimer's disease dementia is a very slow onset and gradually progresses as a specific dementia. Initially, a problem in the memory of recent days is shown, and the progression is progressed, as well as other cognitive declines such as language function and judgment. Symptoms of mental behavior, such as nervousness, depression, delusions, hallucinations, increased aggression, and sleep disorders, are often accompanied by neurological disorders such as stiffness and abnormal gait or physical complications such as stool incontinence, infection, and pressure sores. . In addition, the vascular dementia is a case in which brain tissue is damaged by cerebrovascular disease and dementia occurs.
  • the vascular dementia is at least one selected from the group consisting of acute onset vascular dementia, multiple infarct dementia, and subcortical vascular dementia.
  • Parkinson's disease dementia is a progressive neurodegenerative disorder characterized by Parkinson's symptoms such as slow movement, trembling at rest, muscle stiffness, dragging and walking and bending posture.
  • the Lewy dementia is a memory disorder is not as severe as Alzheimer's disease, judgment judgment, confusion of consciousness is often present and show vision.
  • the chorea dementia is a dementia that occurs as part of extensive degeneration of the brain, and is transmitted by a dominant gene of a single autosomal chromosome. Symptoms are typical of thirty-four teenagers.
  • the Creutzfeldt-Jakob disease dementia is a progressive dementia that is presumed to be caused by a spreadable pathogen and is accompanied by a wide range of neurological signs caused by specific neuropathological changes. The course can be subacute and die within a year.
  • the Pix's disease dementia is a progressive dementia that begins in middle age and is characterized by slowly progressive personality changes and social degeneration, and has disorders of intelligence, memory, and language function accompanied by apathy, morbid pleasure, and sometimes extracorporeal phenomena.
  • the pharmaceutically acceptable salts thereof may include the compound of Formula 1 as an active ingredient.
  • the present invention may also include such agents or salts thereof that are lyophilized and can be reconstituted to form pharmaceutically acceptable formulations for administration, such as by intravenous, intramuscular or subcutaneous injection.
  • the compounds of formula (1) and pharmaceutically acceptable salts thereof described herein can also be administered orally or as inhalations as solids, or intramuscularly or intravenously as solutions, suspensions or emulsions. More preferably, it may be administered as a liposome suspension by inhalation, intravenous or intramuscularly. Also more preferably, a pharmaceutical formulation suitable for administration by inhalation as an aerosol can be provided.
  • the dosage of the pharmaceutical composition for preventing or treating dementia may be appropriately selected and used depending on symptoms, age, dosage form, and the like, and preferably, 0.01 to 100 mg per day may be divided once or several times. More preferably, 1 to 100 mg may be administered once or in divided portions.
  • the cranial nerve refers to 12 pairs of motor nerves, sensory nerves, or a mixture of motor and sensory nerves.
  • the first brain nerve corresponds to the sensory nerve as a posterior nerve with respect to smell.
  • the second cranial nerve is also the nerve for seeing as the sensory nerve.
  • the third cranial nerve is a motor nerve and is related to eye movement and pupil contraction.
  • the fourth cranial nerve is the motor nerve, which governs the superior muscle that is involved in eye movement.
  • the fifth cranial nerve is a mixed nerve of the senses and the movement, the motor nerve dominates chewing, the sensory nerve is responsible for the perception of the face, head, ears and the like.
  • the sixth cranial nerve is the motor nerve, which governs the extraocular muscles (external rectus muscles) of the eye between the school and training.
  • the seventh cranial nerve is a mixed nerve of motor and sensory nerves that transmits the taste in the anterior two-thirds of the tongue through facial expression movements that dominate the facial muscles, and the hard nerves, one of the facial nerves. Dominate.
  • Eighth cranial nerve is sensory nerve, cochlear nerve conducts hearing, vestibular nerve conducts positional sense and equilibrium sense.
  • the ninth cranial nerve is a mixed nerve of motor and sensory nerves, distributed in the tongue and pharynx and causes perception, exercise and secretion. It is distributed in the rear muscles of the tongue and the muscles that work and swallow the tongue, and is responsible for the taste.
  • the 10th cranial nerve is a mixed nerve of motor and sensory nerves, which is distributed in the cervix, thorax and abdominal viscera and is an important nerve that controls perception, movement, and secretion.
  • the eleventh cranial nerve is a mixed nerve of motor and sensory nerves that dominates the muscles of the larynx and speaks, and controls the mitral muscles and thoracic vertebral muscles to move the head.
  • the twelfth cranial nerve is a motor neuron, which contracts the muscles of the tongue to speak, and acts as a pure motor neuron with chewing and swallowing.
  • the compound of Chemical Formula 1 may be preferably extracted from roe deer mushroom.
  • the neuroprotective agent may preferably act on any one or more diseases selected from the group consisting of cerebral infarction, stroke, ischemic stroke, cerebral hemorrhage, cerebral edema and cerebrovascular dementia.
  • the cerebral infarction is a disease in which blood vessels of the brain are blocked and necrotic tissue in front of it is necrotic.
  • the stroke refers to a condition in which partial or totally rapid brain function disorder persists for a considerable period of time, and no cause can be found other than cerebrovascular disease.
  • the ischemic stroke is a stroke caused by clogging a cerebrovascular vessel
  • the hemorrhagic stroke is a type of hemorrhagic stroke caused by a bursting cerebrovascular vessel.
  • the brain edema refers to a state in which the volume of brain tissue is increased due to an abnormal increase in the water content in the brain parenchyma.
  • the cerebrovascular dementia is a dementia caused by clogging or bursting blood vessels in the brain region, and unlike Alzheimer's disease, cognitive function is suddenly dropped.
  • the pharmaceutically acceptable salts thereof may include the compound of Formula 1 as an active ingredient.
  • the present invention may also include such agents or salts thereof that are lyophilized and can be reconstituted to form pharmaceutically acceptable formulations for administration, such as by intravenous, intramuscular or subcutaneous injection.
  • the compounds of formula (1) and pharmaceutically acceptable salts thereof described herein can also be administered orally or as inhalations as solids, or intramuscularly or intravenously as solutions, suspensions or emulsions. More preferably, it may be administered as a liposome suspension by inhalation, intravenous or intramuscularly. Also more preferably, a pharmaceutical formulation suitable for administration by inhalation as an aerosol can be provided.
  • the dosage of the neuroprotective agent may be appropriately selected and used depending on symptoms, age, dosage form, etc., preferably, 0.01 to 100 mg per day may be administered once or several times. More preferably, 1 to 100 mg may be administered once or in divided portions.
  • a method for preparing an activity inhibitor of acetylcholinesterase comprises the steps of pulverizing a locust mushroom and adding an alcohol after crushing to obtain an extract, and then concentrating under reduced pressure and extracting the concentrated extract under reduced pressure.
  • the alcohol may preferably be methanol or ethanol, more preferably methanol.
  • the organic solvent may be preferably hexane, methylene chloride, ethyl acetate or butanol, more preferably methylene chloride.
  • the secondary fraction may be obtained through a stepwise concentration gradient system preferably consisting of a hexane-ethyl acetate mixed solvent and a methylene chloride-methanol mixed solvent.
  • the health functional food according to the present invention may include the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the health functional food may include all of the health functional foods produced by a general method, preferably may be prepared in various forms, such as beverages, food, processed foods.
  • Example 1-1 300 g of the extract of the Roe deer fungus prepared in Example 1-1 was suspended in 2 L of distilled water, and 2 L of hexane was further suspended, and then partitioned into hexane, methylene chloride, ethyl acetate, butanol, and each of hexane and methylene chloride, respectively, distributed. Ethyl acetate, butanol was evaporated and concentrated to prepare a hexane, methylene chloride, ethyl acetate, butanol fraction.
  • the hexane, methylene chloride, ethyl acetate, butanol fractions obtained in Example 1-2 were obtained by chromatography using a silica gel column. That is, a stepwise gradient solvent system consisting of a hexane-ethyl acetate mixed solvent (99%: 1%, 50%: 50%) and a methylene chloride-methanol mixed solvent (98%: 2%, 50%: 50%)
  • HEH1 ⁇ HEH6 9 muskeleton methylene chloride fractions
  • HEM1 ⁇ HEM5 5 fractions of ethyl acetate acetate
  • tacrine As a conventional composition for treating dementia, commercially available tacrine (Tacrine) 300nM was used as a comparative example.
  • IR spectra show hydroxyl and carbonyl functionalities at 3357 and 1662 cm -1 , respectively.
  • Acetylcholinesterase, acetylcholine iodide, 5,5-dithio-bis- (2-nitrobenzoic acid), neostigmine bromine used to measure the activity of acetylcholinesterase Meade (neostigmine bromide) was purchased from Sigma-Aldrich Chemistry Co. and used. Acetylcholinesterase inhibitory activity was measured according to the Elman method (Ellman et al., 1961).
  • mice were extracted and placed in a 10-fold volume of PBS-A (12.5M sodium phosphate buffer pH 7.0, 400 mM NaCl) and pulverized at 500 rpm using a Teflon glass tube, which was centrifuged at 1000 X g for 10 minutes. The supernatant was obtained. PBS-A and Triton X-100 were added to the supernatant, stirred for 30 minutes, and centrifuged at 10000 X g for 10 minutes to obtain an enzyme solution containing acetcholine esterase.
  • Compounds 1 and 2 and Comparative Example were dissolved together with the enzyme solution.
  • Acetylcholinesterase inhibitory ability was calculated by the following equation.
  • tacrine of Comparative Example 1 exhibited 23% inhibitory activity against acetylcholinesterase, but Compound 1 of the present invention exhibited higher inhibitory activity than Comparative Example 1, which is a degenerative brain disease. It can be usefully used as a therapeutic substance.
  • Comparative Example 2 Comparative Example 3 and Comparative Example 4, which is known to have the ability to inhibit the activity of the existing acetylcholinesterase, isolated by Example according to the present invention It was confirmed that the activity inhibitory ability against acetylcholinesterase in comparison to the excellent.

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PCT/KR2013/000577 2012-04-19 2013-01-24 Composition pharmaceutique destinée à prévenir ou à traiter la démence, et méthode de préparation de celle-ci Ceased WO2013157728A1 (fr)

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KR1020120041087A KR101349113B1 (ko) 2012-04-19 2012-04-19 노루궁뎅이 버섯에서 추출된 특정물질을 유효성분으로 포함하는 치매 예방 또는 치료용 약제학적 조성물 및 그 제조방법
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Cited By (2)

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CN104164370A (zh) * 2014-08-12 2014-11-26 中国科学院微生物研究所 一株猴头菌及其应用
JP2023506419A (ja) * 2019-12-03 2023-02-16 チュンブク ナショナル ユニバ―シティ インダストリー アカデミック コーオペレーション ファウンデーション イソインドリノン誘導体の調製方法、それに用いられる新規な中間体、及びその調製方法

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KR102676255B1 (ko) 2023-10-06 2024-06-18 장현수 노루궁뎅이 버섯의 열수 추출방법

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104164370A (zh) * 2014-08-12 2014-11-26 中国科学院微生物研究所 一株猴头菌及其应用
JP2023506419A (ja) * 2019-12-03 2023-02-16 チュンブク ナショナル ユニバ―シティ インダストリー アカデミック コーオペレーション ファウンデーション イソインドリノン誘導体の調製方法、それに用いられる新規な中間体、及びその調製方法
CN115836059A (zh) * 2019-12-03 2023-03-21 忠北大学校产学协力团 异吲哚啉酮衍生物的制备方法、该方法所使用的新型中间体及其制备方法
JP7326623B2 (ja) 2019-12-03 2023-08-15 シーエヌジー バイオ カンパニー リミテッド イソインドリノン誘導体の調製方法、それに用いられる新規な中間体、及びその調製方法
CN115836059B (zh) * 2019-12-03 2024-11-08 希恩巨生物有限公司 异吲哚啉酮衍生物的制备方法、该方法所使用的新型中间体及其制备方法

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