WO2014098306A1 - Pharmaceutical composition for preventing or treating dementia - Google Patents

Pharmaceutical composition for preventing or treating dementia Download PDF

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Publication number
WO2014098306A1
WO2014098306A1 PCT/KR2013/000578 KR2013000578W WO2014098306A1 WO 2014098306 A1 WO2014098306 A1 WO 2014098306A1 KR 2013000578 W KR2013000578 W KR 2013000578W WO 2014098306 A1 WO2014098306 A1 WO 2014098306A1
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Prior art keywords
dementia
formula
disease
group
compound
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PCT/KR2013/000578
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French (fr)
Korean (ko)
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노형준
김금숙
이승은
김승유
홍윤표
이지현
이대영
최재훈
김재윤
최수임
김남식
임성빈
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대한민국(농촌진흥청장)
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Publication of WO2014098306A1 publication Critical patent/WO2014098306A1/en

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating dementia comprising a substance extracted from roe deer mushroom as an active ingredient, and more particularly, to a pharmaceutical composition and health functional food including the substance extracted from roe deer mushroom will be.
  • 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 characterized by various dementia-causing diseases, but 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, as well as effective in the prevention and treatment of dementia, to provide a substance derived from the locust beetle effective to protect the brain nerve.
  • Acetylcholinesterase activity inhibitor according to a feature of the present invention for solving the above problems comprises at least one compound selected from the group consisting of Formula 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • the formula 1 to Formula 4 may be derived from the roe deer mushroom.
  • the inhibitor may include Alzheimer's disease dementia, Vascular dementia, Parkinson's disease dementia, Lewy body dementia, Huntington's disease dementia, and Crutzfeldt. 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 present invention provides a pharmaceutical composition for preventing or treating dementia comprising at least one compound selected from the group consisting of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a neuroprotective agent comprising at least one compound selected from the group consisting of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof.
  • the health functional food according to another feature of the present invention includes at least one compound selected from the group consisting of Formulas 1 to 4 or a food acceptable salt thereof.
  • Preparation of an acetylcholinesterase activity inhibitor including the compound according to the present invention and an acceptable salt thereof may inhibit the activity of acetylcholinesterase, which is one of the causes of dementia, to effectively cope with the prevention and treatment of dementia. And, it is possible to provide a pharmaceutical composition and health functional food that can protect the brain nerve.
  • FIG. 2 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 1 of Experimental Example 1.
  • Figure 4 is a graph showing the IR spectrum analysis results of the spectroscopic analysis of the compound 1 of Experimental Example 1.
  • FIG. 6 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 2 of Experimental Example 1.
  • FIG. 10 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 3 of Experimental Example 1.
  • FIG. 10 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 3 of Experimental Example 1.
  • FIG. 14 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 4 of Experimental Example 1.
  • FIG. 14 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 4 of Experimental Example 1.
  • 17 is a graph showing the activity inhibitory effect on the acetylcholinesterase of Compounds 1 to 4 and Comparative Example 1 according to 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 at least one compound selected from the group consisting of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof.
  • the compounds of Formulas 1 to 4 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 dementia, Pick's disease dementia, brain tumors, stroke and cognitive impairment.
  • the pharmaceutically acceptable salt thereof may include one or more compounds selected from the group consisting of Chemical Formulas 1 to 4.
  • the 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.
  • at least one compound selected from the group consisting of Formulas 1 to 4 and pharmaceutically acceptable salts thereof described herein can be administered orally or as inhalation as a solid, or intramuscularly as a solution, suspension or emulsion. Or intravenously. More preferably, it may be administered as a liposome suspension by inhalation, intravenous or intramuscularly.
  • 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 80 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 at least one compound selected from the group consisting of Chemical Formulas 1 to 4 and a pharmaceutically acceptable salt thereof.
  • the compound of Chemical Formulas 1 to 4 may be extracted from a 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 very slowly developed and gradually progresses as a specific dementia.
  • the problem mainly occurs in memory of recent days, and progresses as well as other cognitive declines such as language function and judgment, as well as changes in personality.
  • Psychobehavioral symptoms such as anxiety, depression, delusions, hallucinations, increased aggression, and sleep disorders are often accompanied, and neurological disorders such as stiffness and gait abnormalities or physical complications such as stool incontinence, infection, and pressure sores appear.
  • 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 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.
  • 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 single autosomal dominant gene. Symptoms are typical of thirty-four teenagers. Progression is slow and usually dies within 10 to 15 years after onset.
  • 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 salt thereof may include one or more compounds selected from the group consisting of Chemical Formulas 1 to 4.
  • the 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.
  • one or more compounds selected from the group consisting of Formulas 1-4 and pharmaceutically acceptable salts thereof described herein can be administered orally or as inhalations as a solid, or as a solution, suspension or emulsion It can be administered intravenously or intravenously. More preferably, it may be administered as a liposome suspension by inhalation, intravenous or intramuscularly.
  • 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 80 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 compounds of Formulas 1 to 4 may be preferably extracted from the 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 salt thereof may include one or more compounds selected from the group consisting of Chemical Formulas 1 to 4.
  • the 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.
  • at least one compound selected from the group consisting of Formulas 1 to 4 and pharmaceutically acceptable salts thereof described herein can be administered orally or as inhalation as a solid, or intramuscularly as a solution, suspension or emulsion. Or intravenously. More preferably, it may be administered as a liposome suspension by inhalation, intravenous or intramuscularly.
  • 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 80 mg may be administered once or in divided portions.
  • the health functional food of the present invention may include at least one compound selected from the group consisting of Chemical Formulas 1 to 4 or a food acceptable salt thereof, and there is no particular limitation on the type of the health functional food.
  • the health functional foods are dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, various soups, beverages, tea, drink, alcoholic beverages and vitamins. And the like, and may be used in the form of pills, powders, granules, acupuncture, tablets, capsules, or beverages, and include all health functional foods in the conventional sense.
  • the health beverage composition of the present invention is not particularly limited to the liquid component except for containing at least one compound selected from the group consisting of Chemical Formulas 1 to 4 or a food acceptable salt thereof, and various flavoring agents as in general beverages.
  • natural carbohydrate or the like as an additional component.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; Polysaccharides such as dextrin, cyclodextrin; Conventional sugars such as and the like and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have.
  • the health functional food of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid And salts thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • the health functional foods of the present invention may contain pulp for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components can be used independently or in combination.
  • 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 concentration 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 to HEH6 9 muskeleton methylene chloride fractions
  • HEM1 to HEE5 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.
  • the molecular weight and molecular formula of the compounds 1 to 4 isolated in Examples 1-4 were determined using LC / MS spectroscopy (manufacturer: Thermo finnigan LCQ decaplus), and through a nuclear magnetic resonance (NMR) analyzer (Verian 500 MHz) 1 H NMR and 13 C NMR spectra were obtained to determine the molecular structure.
  • NMR data were very similar to hericenone J and its spectroscopic results are shown in FIGS. 9-12.
  • 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.
  • PBS-A 12.5M sodium phosphate buffer pH 7.0, 400 mM NaCl
  • Acetylcholinesterase inhibitory ability was calculated by the following equation.
  • tacrine, Comparative Example 1 exhibited 23% inhibitory activity against acetylcholinesterase, but Compounds 1 to 4 of the present invention exhibited higher inhibitory activity than Comparative Example 1, thereby degenerative brain disease. It can be usefully used as a therapeutic substance for phosphorus dementia.
  • Compounds 1 to 4 which are the extracts of the Roestock fungus, according to the present invention, have a high inhibitory effect on acetylcholinesterase activity, and thus inhibit acetylcholinesterase activity, pharmaceutical compositions for preventing or treating dementia, and health functional foods. It is obvious that the material is highly applicable in many fields such as
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
  • composition ratio of the above-mentioned vitamin and mineral mixture is a composition suitable for a relatively healthy food in a preferred manufacturing example, but the composition ratio may be arbitrarily modified, and the above ingredients are mixed according to a general health food manufacturing method.
  • the granules may be prepared and used for preparing a health food composition according to a conventional method.
  • composition ratio is a composition suitable for a preferred beverage in a preferred manufacturing example
  • the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

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Abstract

The present invention relates to an acetylcholinesterase activity inhibitor, a pharmaceutical composition for preventing and/or treating dementia, and/or a cerebral nerve protective agent containing a compound derived from Hericium erinaceus or a salt thereof, and/or preparation methods therefor.

Description

치매 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating dementia
본 발명은 노루궁뎅이 버섯에서 추출된 물질을 유효성분으로 포함하는 치매 예방 또는 치료용 약제학적 조성물에 관한 것으로서, 보다 구체적으로는 노루궁뎅이 버섯에서 추출된 물질을 포함한 약학적 조성물 및 건강기능식품 등에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating dementia comprising a substance extracted from roe deer mushroom as an active ingredient, and more particularly, to a pharmaceutical composition and health functional food including the substance extracted from roe deer mushroom will be.
노루궁뎅이버섯은 버섯의 모양이 원숭이 머리와 비슷하다고 해서 중국에서는 ‘후두고’라고 한다. 여름에서 가을까지 졸참나무, 떡갈나무 등 활엽수의 줄기에 한 개씩 자란다. 버섯갓은 지름 약 5 ~ 20 ㎝로 대부분 공 모양 또는 달걀형 공 모양이며 윗면에는 털이 있고 옆면과 아랫면에는 무수한 바늘이 늘어져 있다. 바늘은 길이 1 ~ 5 ㎝, 굵기 1㎜정도로 끝이 뾰족하다.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 ㎝ 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.
치매라는 말은 라틴어에서 유래된 말로서 ‘정신이 없어진 것’이라는 의미를 지니고 있다. 태어날 때부터 지적 능력이 모자라는 경우를 ‘정신 지체’라고 부르는 반면, 치매는 정상적으로 생활해오던 사람이 다양한 원인에 의해 뇌기능이 손상되면서 이전에 비해 인지 기능이 지속적이고 전반적으로 저하되어 일상생활에 상당한 지장이 나타나고 있는 상태이다. 여기서 인지 기능이란 기억력, 언어능력, 시공간 파악 능력, 판단력 및 추상적 사고력 등 다양한 지적 능력을 가리키는 것으로서 각 인지기능은 특정 뇌 부위와 밀접한 관련이 있다. 치매라는 임상증후군을 유발하는 원인 질환은 이를 각각 세분화할 경우 약 70여 가지에 이른다. 다양한 치매 원인 질환들 중에서 가장 많은 것은 ‘알츠하이머병’과 ‘혈관성 치매’이지만, 그 밖에도 루이체 치매, 파킨슨씨병 등의 퇴행성 뇌질환들과 정상압뇌 수두증, 두부외상, 뇌종양, 대사성 질환, 결핍성 질환, 중독성 질환, 감염성 질환 등 매우 다양한 원인 질환에 의해 치매가 발생할 수 있다.The word 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. Here, 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. Among the various 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.
아세틸콜린은 동물의 신경조직에 존재하며, 신경의 자극을 근육에 전달하는 화학물질이다. 이러한 아세틸콜린은 아세틸콜린에스터라제에 의해 콜린과 아세트산으로 분해되게 된다. 그러므로 아세틸콜린에스터라제가 지나치게 활성화되게 되면 신경 전달의 중요한 화학물질인 아세틸콜린이 분해되어 신경 자극의 전달이 원활해 지지 못하는 문제가 있다. 또한 이렇게 아세틸콜린에스터라제의 활성화에 따르는 문제는 신경 전달에 문제를 일으키는 것으로서 치매의 원인이 될 수 있다.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.
이러한 종래 기술의 문제점은 치매의 원인 및 질환은 다양하지만 종래기술은 이를 효과적으로 치료하거나 예방하는 원료 및 약제가 부족한 문제가 있다. 또한 아세틸콜린에스터라제의 활성화가 치매의 한 원인이 될 수 있음에도 이의 활성을 저해하여 치매에 효과적으로 대처할 수 있는 원료 및 약제가 부족한 문제가 있다.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. In addition, although 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.
본 발명은 상술한 문제점을 해결하기 위해 안출된 것으로, 본 발명의 목적은 치매의 예방 및 치료에 효과적인 화합물을 발견하여 치매에 효과적으로 대처할 수 있는 원료 및 약제를 제공하고자 하며, 아세틸콜린에스터라제의 활성을 억제하여 치매의 원인을 차단하고, 더불어 치매의 예방과 치료에 효과적이며, 뇌신경을 보호하는데 효과적인 노루궁뎅이 버섯에서 유래한 물질을 제공하는 것이다.The present invention has been made to solve the above problems, 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, as well as effective in the prevention and treatment of dementia, to provide a substance derived from the locust beetle effective to protect the brain nerve.
위와 같은 과제를 해결하기 위한 본 발명의 한 특징에 따른 아세틸콜린에스터라제 활성 억제제는 하기 화학식 1 내지 4로 구성되는 군에서 선택된 1종 이상의 화합물 또는 약학적으로 허용 가능한 그의 염을 유효성분으로 포함한다.Acetylcholinesterase activity inhibitor according to a feature of the present invention for solving the above problems comprises at least one compound selected from the group consisting of Formula 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient. do.
화학식 1
Figure PCTKR2013000578-appb-C000001
 Formula 1
Figure PCTKR2013000578-appb-C000001
화학식 2
Figure PCTKR2013000578-appb-C000002
 Formula 2
Figure PCTKR2013000578-appb-C000002
화학식 3
Figure PCTKR2013000578-appb-C000003
 Formula 3
Figure PCTKR2013000578-appb-C000003
화학식 4
Figure PCTKR2013000578-appb-C000004
 Formula 4
Figure PCTKR2013000578-appb-C000004
본 발명의 바람직한 일실시예에 따르면, 상기 화합식 1 내지 화학식 4는 노루궁뎅이버섯에서 유래된 것일 수 있다.According to a preferred embodiment of the present invention, the formula 1 to Formula 4 may be derived from the roe deer mushroom.
또한, 상기 억제제는 알츠하이머병(Alzheimer's disease)형 치매, 혈관성 치매(Vascular dementia), 파킨슨씨 병(Parkinson's disease)형 치매, 루이체 치매(Lewy body dementia), 무도병(Huntington's disease)형 치매, 크루츠펠트-야콥병(Creutzfeldt-Jacob disease)형 치매, 픽스씨 병(Pick's disease)형 치매, 뇌종양, 뇌졸증 및 인지장애로 이루어지는 군 중에서 선택된 어느 하나 이상의 질병에 작용할 수 있다.In addition, the inhibitor may include Alzheimer's disease dementia, Vascular dementia, Parkinson's disease dementia, Lewy body dementia, Huntington's disease dementia, and Crutzfeldt. 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.
또한, 본 발명은 상기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 또는 약학적으로 허용 가능한 그의 염을 포함하는 치매 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating dementia comprising at least one compound selected from the group consisting of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 또는 약학적으로 허용 가능한 그의 염을 포함하는 뇌신경보호제를 제공한다.The present invention also provides a neuroprotective agent comprising at least one compound selected from the group consisting of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 특징에 따른 건강기능성식품은 상기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 또는 식품학적으로 허용 가능한 그의 염을 포함한다.The health functional food according to another feature of the present invention includes at least one compound selected from the group consisting of Formulas 1 to 4 or a food acceptable salt thereof.
본 발명에 따른 화합물 및 허용 가능한 그의 염을 포함하는 아세틸콜린에스터라제 활성 억제제 등을 제조하게 되면, 치매의 원인 중 하나인 아세틸콜린에스터라제의 활성을 저해하여 치매의 예방 및 치료에 효과적으로 대응할 수 있으며, 뇌신경의 보호가 가능한 약학적 조성물 및 건강기능식품의 제공이 가능하다.Preparation of an acetylcholinesterase activity inhibitor including the compound according to the present invention and an acceptable salt thereof may inhibit the activity of acetylcholinesterase, which is one of the causes of dementia, to effectively cope with the prevention and treatment of dementia. And, it is possible to provide a pharmaceutical composition and health functional food that can protect the brain nerve.
도 1은 실험예 1의 화합물 1에 대한 분광학적 분석결과 중 1HNMR 스펙트럼 분석결과를 나타낸 그래프이다.1 is a graph showing the 1 HNMR spectrum analysis results of the spectroscopic analysis of the compound 1 of Experimental Example 1.
도 2는 실험예 1의 화합물 1에 대한 분광학적 분석결과 중 13CNMR 스펙트럼 분석결과를 나타낸 그래프이다.2 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 1 of Experimental Example 1. FIG.
도 3은 실험예 1의 화합물 1에 대한 분광학적 분석결과 중 ESI-MS 스펙트럼 분석 결과를 나타낸 그래프이다.3 is a graph showing the ESI-MS spectrum analysis results of the spectroscopic analysis of the compound 1 of Experimental Example 1.
도 4는 실험예 1의 화합물 1에 대한 분광학적 분석결과 중 IR 스펙트럼 분석 결과를 나타낸 그래프이다.Figure 4 is a graph showing the IR spectrum analysis results of the spectroscopic analysis of the compound 1 of Experimental Example 1.
도 5는 실험예 1의 화합물 2에 대한 분광학적 분석결과 중 1HNMR 스펙트럼 분석결과를 나타낸 그래프이다.5 is a graph showing the 1 HNMR spectrum analysis results of the spectroscopic analysis of the compound 2 of Experimental Example 1.
도 6은 실험예 1의 화합물 2에 대한 분광학적 분석결과 중 13CNMR 스펙트럼 분석결과를 나타낸 그래프이다.FIG. 6 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 2 of Experimental Example 1.
도 7은 실험예 1의 화합물 2에 대한 분광학적 분석결과 중 ESI-MS 스펙트럼 분석 결과를 나타낸 그래프이다.7 is a graph showing the ESI-MS spectrum analysis results of the spectroscopic analysis of the compound 2 of Experimental Example 1.
도 8은 실험예 1의 화합물 2에 대한 분광학적 분석결과 중 IR 스펙트럼 분석 결과를 나타낸 그래프이다.8 is a graph showing the results of IR spectrum analysis of the spectroscopic analysis of the compound 2 of Experimental Example 1.
도 9은 실험예 1의 화합물 3에 대한 분광학적 분석결과 중 1HNMR 스펙트럼 분석결과를 나타낸 그래프이다.9 is a graph showing the 1 HNMR spectrum analysis results of the spectroscopic analysis of the compound 3 of Experimental Example 1.
도 10는 실험예 1의 화합물 3에 대한 분광학적 분석결과 중 13CNMR 스펙트럼 분석결과를 나타낸 그래프이다.10 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 3 of Experimental Example 1. FIG.
도 11은 실험예 1의 화합물 3에 대한 분광학적 분석결과 중 ESI-MS 스펙트럼 분석 결과를 나타낸 그래프이다.11 is a graph showing the ESI-MS spectrum analysis results of the spectroscopic analysis of the compound 3 of Experimental Example 1.
도 12는 실험예 1의 화합물 3에 대한 분광학적 분석결과 중 IR 스펙트럼 분석 결과를 나타낸 그래프이다.12 is a graph showing the results of IR spectrum analysis of the spectroscopic analysis of the compound 3 of Experimental Example 1.
도 13는 실험예 1의 화합물 4에 대한 분광학적 분석결과 중 1HNMR 스펙트럼 분석결과를 나타낸 그래프이다.13 is a graph showing the 1 HNMR spectrum analysis results of the spectroscopic analysis of the compound 4 of Experimental Example 1.
도 14은 실험예 1의 화합물 4에 대한 분광학적 분석결과 중 13CNMR 스펙트럼 분석결과를 나타낸 그래프이다.14 is a graph showing 13 CNMR spectrum analysis results of spectroscopic analysis of Compound 4 of Experimental Example 1. FIG.
도 15은 실험예 1의 화합물 4에 대한 분광학적 분석결과 중 ESI-MS 스펙트럼 분석 결과를 나타낸 그래프이다.15 is a graph showing the ESI-MS spectrum analysis results of the spectroscopic analysis of the compound 4 of Experimental Example 1.
도 16은 실험예 1의 화합물 4에 대한 분광학적 분석결과 중 IR 스펙트럼 분석 결과를 나타낸 그래프이다.16 is a graph showing the results of IR spectrum analysis of the spectroscopic analysis of the compound 4 of Experimental Example 1.
도 17은 본 발명에 따른 화합물 1 내지 4와 비교예 1 의 아세틸콜린에스터라제에 대한 활성 억제 효과를 측정하여 나타낸 그래프이다.17 is a graph showing the activity inhibitory effect on the acetylcholinesterase of Compounds 1 to 4 and Comparative Example 1 according to the present invention.
아세틸콜린에스터라제는 아세틸콜린을 분해하는 효소로서, 상기 아세틸콜린에스터라제가 활성화된다면 다수의 아세틸콜린이 분해되어 신경 전달에 방해를 줄 수 있고, 이는 치매의 한 원인이 될 수 있다. 구체적으로 본 발명에 따른 아세틸콜린에스터라제의 활성 억제제는 하기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 또는 약학적으로 허용 가능한 그의 염을 포함할 수 있다.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. Specifically, the activity inhibitor of acetylcholinesterase according to the present invention may include at least one compound selected from the group consisting of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2013000578-appb-I000001
Figure PCTKR2013000578-appb-I000001
[화학식 2][Formula 2]
Figure PCTKR2013000578-appb-I000002
Figure PCTKR2013000578-appb-I000002
[화학식 3][Formula 3]
Figure PCTKR2013000578-appb-I000003
Figure PCTKR2013000578-appb-I000003
[화학식 4][Formula 4]
Figure PCTKR2013000578-appb-I000004
Figure PCTKR2013000578-appb-I000004
또한 상기 화학식 1 내지 4의 화합물은 바람직하게는 노루궁뎅이 버섯에서 추출될 수 있다. 또한 상기 억제제는 바람직하게는 알츠하이머병(Alzheimer's disease)형 치매, 혈관성 치매(Vascular dementia), 파킨슨씨 병(Parkinson's disease)형 치매, 루이체 치매(Lewy body dementia), 무도병(Huntington's disease)형 치매, 크루츠펠트-야콥병(Creutzfeldt-Jacob disease)형 치매, 픽스씨병(Pick's disease)형 치매, 뇌종양, 뇌졸증 및 인지장애로 이루어지는 군 중에서 선택된 어느 하나 이상의 질병에 작용할 수 있다.In addition, the compounds of Formulas 1 to 4 may be preferably extracted from the roe deer mushroom. In addition, 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 dementia, Pick's disease dementia, brain tumors, stroke and cognitive impairment.
또한 상기 약학적으로 허용 가능한 그의 염은 상기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물을 포함할 수 있다. 또한 본 발명은 동결건조되어 있고, 정맥내, 근육내 또는 피하 주사에 의해서와 같이 투여를 위한 약제학상 허용되는 제제를 형성하도록 재구성될 수 있는 그러한 약제 또는 그의 염이 포함될 수 있다. 또한 본 발명에서 기술된 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 및 약학적으로 허용 가능한 그의 염은 고체로서 경구로 또는 흡입을 통해 투여될 수 있거나, 용액, 현탄액 또는 에멀젼으로서 근육내 또는 정맥내로 투여될 수 있다. 또한 더욱 바람직하게는 리포좀 현탁액으로서 흡액, 정맥내 또는 근육내로 투여될 수 있다. 또한 더욱 바람직하게는 에어로졸로서 흡입에 의해 투여하기 적당한 약제학적 제제가 제공될 수 있다. 또한 상기 아세틸콜린에스터라제의 활성 억제제의 투여량은 증상, 연령, 제형 등에 따라 적절하게 선택하여 사용할 있으나, 바람직하게는 통상 1일당 0.01 ~ 100 ㎎을 1회 또는 수회에 나누어 투여할 수 있다. 또한 더욱 바람직하게는 1 ~ 80 ㎎을 1회 또는 수회에 나누어 투여할 수 있다.In addition, the pharmaceutically acceptable salt thereof may include one or more compounds selected from the group consisting of Chemical Formulas 1 to 4. The 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. In addition, at least one compound selected from the group consisting of Formulas 1 to 4 and pharmaceutically acceptable salts thereof described herein can be administered orally or as inhalation as a solid, or intramuscularly as a solution, suspension or emulsion. Or intravenously. 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. In addition, 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 80 mg may be administered once or in divided portions.
치매는 다양한 원인에 의해 발생할 수 있으며, 이 중 하나의 원인 물질이 될 수 있는 아세틸콜린에스터라제의 활성을 억제하게 되면 치매의 예방 또는 치료에 효과적일 수 있다. 그리하여 본 발명의 또 다른 특징은 상기 화학식 1 내지 4로 구성된 군에서 선택되는 1종 이상의 화합물 및 약학적으로 허용 가능한 그의 염을 포함하는 치매 예방 또는 치료용 약학적 조성물 일 수 있다. 상기 치매 예방 또는 치료용 약학적 조성물에서의 상기 화학식 1 내지 4의 화합물은 바람직하게는 노루궁뎅이 버섯에서 추출될 수 있다. 또한 상기 치매는 바람직하게는 알츠하이머병(Alzheimer's disease)형 치매, 혈관성 치매(Vascular dementia), 파킨슨씨 병(Parkinson's disease)형 치매, 루이체 치매(Lewy body dementia), 무도병(Huntington's disease)형 치매, 크루츠펠트-야콥병(Creutzfeldt-Jacob disease)형 치매 및 픽스씨 병(Pick's disease)형 치매로 이루어진 군 중에서 선택된 어느 하나 이상일 수 있다. 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. Thus, another feature of the present invention may be a pharmaceutical composition for preventing or treating dementia comprising at least one compound selected from the group consisting of Chemical Formulas 1 to 4 and a pharmaceutically acceptable salt thereof. In the pharmaceutical composition for preventing or treating dementia, the compound of Chemical Formulas 1 to 4 may be extracted from a scab mushroom. In addition, 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.
상기 알츠하이머병형 치매는 매우 서서히 발병하여 점진적으로 진행되는 경과가 특이적인 치매로서, 초기에는 주로 최근 일에 대한 기억력에서 문제를 보이다가 진행하면서 언어기능이나 판단력 등 다른 여러 인지기능 저하뿐만 아니라 성격변화, 초조행동, 우울증, 망상, 환각, 공격성 증가, 수면 장애 등의 정신행동 증상이 흔히 동반되며 말기에 이르면 경직, 보행 이상 등의 신경학적 장애 또는 대소변 실금, 감염, 욕창 등 신체적인 합병증까지 나타나게 된다. 또한 상기 혈관성 치매는 뇌혈관 질환에 의해 뇌조직이 손상을 입어 치매가 발생하는 경우로서 바람직하게는 급성 발병의 혈관성 치매, 다발경색 치매, 피질하 혈관성 치매로 이루어지는 중에서 선택된 어느 하나 이상이다. 또한 상기 파킨스씨병형 치매는 느린 운동, 정지시 떨림, 근육 강직, 질질 끌며 걷기, 굽은 자세와 같은 파킨슨 증상들을 특징으로 하는 진행형 신경 퇴행성 질환이다. 또한 상기 루이체 치매는 기억력 장애가 알쯔하이머병처럼 심하지 않으면서도 판단력 장애, 의식의 혼동이 존재하며 환시를 보이는 경우가 흔하다. 또한 상기 무도병형 치매는 뇌의 광범위한 변성의일부로 발생하는 치매로서, 단일 상염색체의 우성 유전자에 의해 전파된다. 증상은 삼사십대에 전형적으로 나타난다. 진행은 느리며, 발병 후 10년 내지 15년 내에 보통 사망한다. 상기 크루츠펠트-야콥병형 치매는 전파 가능한 병원체에 의해 발생한다고 추정되며 특이적 신경병리학적 변화에 의한 광범위한 신경학적 징후를 동반하는 진행성 치매로서, 발병은 보통 중년 또는 그 이후이지만 어느 성인 연령에서도 발생할 수 있고 경과는 아급성으로 일년 이내에 사망한다. 상기 픽스씨병형 치매는 중년에 시작되는 진행성 치매로서 초기에 서서히 진행되는 성격의 변화와 사회성 퇴화로 특징지워지며, 무감정과 병적 쾌감 및 때때로 추체외로 현상을 동반한 지능, 기억 및 언어기능의 장애가 뒤따른다.The Alzheimer's disease dementia is very slowly developed and gradually progresses as a specific dementia. In the early stages, the problem mainly occurs in memory of recent days, and progresses as well as other cognitive declines such as language function and judgment, as well as changes in personality. Psychobehavioral symptoms such as anxiety, depression, delusions, hallucinations, increased aggression, and sleep disorders are often accompanied, and neurological disorders such as stiffness and gait abnormalities or physical complications such as stool incontinence, infection, and pressure sores appear. In addition, the vascular dementia is a case in which brain tissue is damaged by cerebrovascular disease and dementia occurs. Preferably, the vascular dementia is at least one selected from 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. In addition, 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. In addition, the chorea dementia is a dementia that occurs as part of extensive degeneration of the brain, and is transmitted by a single autosomal dominant gene. Symptoms are typical of thirty-four teenagers. Progression is slow and usually dies within 10 to 15 years after onset. 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. Follows.
또한 상기 약학적으로 허용 가능한 그의 염은 상기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물을 포함할 수 있다. 또한 본 발명은 동결건조 되어 있고, 정맥내, 근육내 또는 피하 주사에 의해서와 같이 투여를 위한 약학상 허용되는 제제를 형성하도록 재구성될 수 있는 그러한 약제 또는 그의 염이 포함될 수 있다. 또한 본 발명에서 기술된 화학식 1 내지 4로 구성된 군에서 선택되는 1종 이상의 화합물 및 약제학적으로 허용 가능한 그의 염은 고체로서 경구로 또는 흡입을 통해 투여될 수 있거나, 용액, 현탄액 또는 에멀젼으로서 근육내 또는 정맥내로 투여될 수 있다. 또한 더욱 바람직하게는 리포좀 현탁액으로서 흡액, 정맥내 또는 근육내로 투여될 수 있다. 또한 더욱 바람직하게는 에어로졸로서 흡입에 의해 투여하기 적당한 약제학적 제제가 제공될 수 있다. 또한 상기 치매 예방 또는 치료용 약제학적 조성물의 투여량은 증상, 연령, 제형 등에 따라 적절하게 선택하여 사용할 있으나, 바람직하게는 통상 1일당 0.01 ~ 100 ㎎을 1회 또는 수회에 나누어 투여할 수 있다. 또한 더욱 바람직하게는 1 ~ 80 ㎎을 1회 또는 수회에 나누어 투여될 수 있다.In addition, the pharmaceutically acceptable salt thereof may include one or more compounds selected from the group consisting of Chemical Formulas 1 to 4. The 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. Also one or more compounds selected from the group consisting of Formulas 1-4 and pharmaceutically acceptable salts thereof described herein can be administered orally or as inhalations as a solid, or as a solution, suspension or emulsion It can be administered intravenously or intravenously. 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. In addition, 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 80 mg may be administered once or in divided portions.
본 발명의 또 다른 특징으로서 상기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 및 약학적으로 허용 가능한 그의 염을 포함하는 뇌신경보호제일 수 있다. 일반적으로 뇌신경이란 뇌로 직접 출입하는 12쌍의 운동신경, 감각신경 또는 운동과 감각의 혼합신경을 말한다. 구체적으로 제 1뇌신경은 냄새에 관한 후신경으로서 감각신경에 해당한다. 제 2뇌신경도 감각신경으로서 보는 것에 관한 신경이다. 또한 제 3뇌신경은 운동신경으로서 눈의 움직임과 동공수축에 관련된 신경이다. 또한 제 4뇌신경은 운동신경으로서 안구의 운동에 관여하는 상사근을 지배한다. 또한 제 5뇌신경은 감각과 운동의 혼합신경으로서 운동신경은 저작을 지배하고, 감각신경은 안면, 두부, 귀 등의 지각을 담당한다. 제 6뇌신경은 운동신경으로서 교와 연수 사이에서 안구의 외전근(외직근)을 지배한다. 제 7뇌신경은 운동신경과 감각신경의 혼합신경으로서 안면근을 지배하는 얼굴의 표정운동, 안면신경 중의 하나인 고삭신경을 통하여 혀의 전방 2/3에서 미각을 전달하며, 자율신경섬유로 타액선과 누선을 지배한다. 제 8뇌신경은 감각신경으로서 와우신경이 청각을 전도하고 전정신경은 위치감각과 평형감각을 전도한다. 제 9뇌신경은 운동신경과 감각신경의 혼합신경으로서 혀와 인두에 분포하며 지각, 운동 및 분비를 일으킨다. 혀의 운동과 연하작용을 하는 근육과 혀의 후방 1/3에 분포하여 미각을 담당한다. 제 10뇌신경은 운동신경과 감각신경의 혼합신경으로서 경부, 흉부 및 복부 내장에 분포하며 그 지각, 운동, 분비를 조절하는 중요한 신경이다. 제 11뇌신경은 운동신경과 감각신경의 혼합신경으로서 후두의 근육을 지배하여 말을 하게 하고, 승모근과 흉쇄유돌근을 지배하여 머리를 움직이게 한다. 제 12뇌신경은 운동신경으로서 혀의 근육을 수축시켜 말을 하게 하고, 저작작용과 연하작용을 하는 순수 운동신경이다. 상기 뇌신경보호제에서 상기 화학식 1 내지 4의 화합물은 바람직하게는 노루궁뎅이 버섯에서 추출되는 것일 수 있다. 또한 상기 뇌신경 보호제는 바람직하게는 뇌경색, 뇌졸중, 허혈성 뇌졸중, 뇌출혈, 뇌부종 및 뇌혈관성치매로 이루어지는 군 중에서 선택된 어느 하나 이상의 질병에 작용할 수 있다. 상기 뇌경색은 뇌의 혈관이 막히고 그 앞의 뇌조직이 괴사하게 되는 질환이다. 또한 상기 뇌졸중은 부분적 또는 전체적으로 급속히 발생한 뇌기능의 장애가 상당 기간 이상 지속되는 것으로서, 뇌혈관의 병 이외에는 다른 원인을 찾을 수 없는 상태를 일컫는다. 또한 상기 허혈성 뇌졸중은 뇌혈관이 막혀서 생기는 뇌졸중이며, 상기 뇌출혈은 뇌혈관이 터져서 생기는 출혈성 뇌졸중의 일종이다. 또한 상기 뇌부종은 뇌 실질 내 수분 함량의 비정상적인 증가로 인해 뇌조직의 용적이 증가한 상태를 말한다. 또한 상기 뇌혈관성치매는 뇌 부위의 혈관이 막히거나 터지면서 일어나는 치매로서, 알츠하이머 병과는 달리 인지 기능이 갑자기 떨어지는 것이 특징이다.Another feature of the present invention may be a neuroprotective agent comprising at least one compound selected from the group consisting of Formulas 1 to 4 and a pharmaceutically acceptable salt thereof. Generally, the cranial nerve refers to 12 pairs of motor nerves, sensory nerves, or a mixture of motor and sensory nerves. Specifically, 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. In addition, the third cranial nerve is a motor nerve and is related to eye movement and pupil contraction. In addition, the fourth cranial nerve is the motor nerve, which governs the superior muscle that is involved in eye movement. In addition, 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. In the neuroprotective agent, the compounds of Formulas 1 to 4 may be preferably extracted from the roe deer mushroom. In addition, 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. In addition, 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. In addition, the ischemic stroke is a stroke caused by clogging a cerebrovascular vessel, and the hemorrhagic stroke is a type of hemorrhagic stroke caused by a bursting cerebrovascular vessel. In addition, 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. In addition, 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.
또한 상기 약학적으로 허용 가능한 그의 염은 상기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물을 포함할 수 있다. 또한 본 발명은 동결건조 되어 있고, 정맥내, 근육내 또는 피하 주사에 의해서와 같이 투여를 위한 약학상 허용되는 제제를 형성하도록 재구성될 수 있는 그러한 약제 또는 그의 염이 포함될 수 있다. 또한 본 발명에서 기술된 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 및 약학적으로 허용 가능한 그의 염은 고체로서 경구로 또는 흡입을 통해 투여될 수 있거나, 용액, 현탄액 또는 에멀젼으로서 근육내 또는 정맥내로 투여될 수 있다. 또한 더욱 바람직하게는 리포좀 현탁액으로서 흡액, 정맥내 또는 근육내로 투여될 수 있다. 또한 더욱 바람직하게는 에어로졸로서 흡입에 의해 투여하기 적당한 약제학적 제제가 제공될 수 있다. 또한 상기 뇌신경보호제의 투여량은 증상, 연령, 제형 등에 따라 적절하게 선택하여 사용할 있으나, 바람직하게는 통상 1일당 0.01 ~ 100 ㎎을 1회 또는 수회에 나누어 투여할 수 있다. 또한 더욱 바람직하게는 1 ~ 80 ㎎을 1회 또는 수회에 나누어 투여할 수 있다.In addition, the pharmaceutically acceptable salt thereof may include one or more compounds selected from the group consisting of Chemical Formulas 1 to 4. The 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. In addition, at least one compound selected from the group consisting of Formulas 1 to 4 and pharmaceutically acceptable salts thereof described herein can be administered orally or as inhalation as a solid, or intramuscularly as a solution, suspension or emulsion. Or intravenously. 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. In addition, 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 80 mg may be administered once or in divided portions.
본 발명의 건강기능식품은 상기 화학식 1 내지 4로 구성되는 군에서 선택된 1종 이상의 화합물 또는 식품학적으로 허용 가능한 그의 염을 포함할 수 있으며, 상기 건강기능식품의 종류에는 특별한 제한은 없다. 상기 건강기능식품의 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료 및 비타민 복합제 등이 있으며, 환제, 분말, 과립, 침제, 정제, 캡슐 또는 음료인 형태로 사용할 수 있고 통상적인 의미에서의 건강 기능성 식품을 모두 포함한다. The health functional food of the present invention may include at least one compound selected from the group consisting of Chemical Formulas 1 to 4 or a food acceptable salt thereof, and there is no particular limitation on the type of the health functional food. Examples of the health functional foods are dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, various soups, beverages, tea, drink, alcoholic beverages and vitamins. And the like, and may be used in the form of pills, powders, granules, acupuncture, tablets, capsules, or beverages, and include all health functional foods in the conventional sense.
본 발명의 건강 음료 조성물은 상기 화학식 1 내지 4로 구성되는 군에서 선택된 1종 이상의 화합물 또는 식품학적으로 허용 가능한 그의 염을 함유하는 외에는 액체성분에는 특별한 제한은 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예로는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린; 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제 (타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등)) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. The health beverage composition of the present invention is not particularly limited to the liquid component except for containing at least one compound selected from the group consisting of Chemical Formulas 1 to 4 or a food acceptable salt thereof, and various flavoring agents as in general beverages. Or natural carbohydrate or the like as an additional component. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; Polysaccharides such as dextrin, cyclodextrin; Conventional sugars such as and the like and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have.
상기 외에 본 발명의 건강 기능성 식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다.In addition to the above, the health functional food of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid And salts thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
그밖에 본 발명의 건강 기능성 식품들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. In addition, the health functional foods of the present invention may contain pulp for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components can be used independently or in combination.
이하, 본 발명을 실시예에 의해 상세히 설명하기로 한다. 그러나 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of examples. However, these examples are intended to illustrate the present invention in more detail, and the scope of the present invention is not limited to these examples.
[실시예]EXAMPLE
실시예 1: 노루궁뎅이 버섯의 추출물로부터 단일 화합물의 분리Example 1 Isolation of a Single Compound from the Extract of Roebuck Mushroom
1-1. 노루궁뎅이 버섯의 추출물 제조1-1. Extract Preparation of Roebuck Mushroom
특별히 부위별로 구별함이 없이 자실체 전체를 가지고 건조된 노루궁뎅이 버섯(구매처: 포천버섯개발) 3㎏을 적당한 크기로 분쇄한 후, 80%메탄올 20ℓ를 가하고, 상온에서 24시간씩 2회 반복 추출하였고, 여과지로 여과하였으며, 이를 감압농축하여 300g의 추출물을 수득하였다.3 kg of dried roe deer mushroom (Purchased in Pocheon mushroom development) with whole fruiting bodies were pulverized to a suitable size, and then 20 liters of 80% methanol was added and extracted twice at room temperature for 24 hours. It was filtered through a filter paper, and concentrated under reduced pressure to obtain an extract of 300g.
1-2. 노루궁뎅이 버섯 추출물로부터 유기 용매 분획물의 제조1-2. Preparation of Organic Solvent Fraction from Roebuck Mushroom Extract
상기 실시예 1-1에서 제조한 노루궁뎅이 버섯의 추출물 300g을 증류수 2ℓ에 현탁하고, 헥산을 2ℓ 추가 현탁한 후 헥산, 메틸렌클로라이드, 에틸아세테이트, 부탄올로 차례로 분배하였고, 각각 분배된 헥산, 메틸렌클로라이드, 에틸아세테이트, 부탄올을 증발 및 농축시켜 헥산, 메틸렌클로라이드, 에틸아세테이트, 부탄올 분획물을 제조하였다.300 g of the extract of the Roe deer mushroom prepared in Example 1-1 was suspended in 2 L of distilled water, and 2 L of the hexane was further suspended, and then partitioned into hexane, methylene chloride, ethyl acetate, butanol, and each of hexane and methylene chloride, which were distributed. Ethyl acetate, butanol was evaporated and concentrated to prepare a hexane, methylene chloride, ethyl acetate, butanol fraction.
1-3. 유기용매 분획물로부터 활성 분획물 및 화합물의 제조1-3. Preparation of Active Fractions and Compounds from Organic Solvent Fractions
상기 실시예 1-2에서 얻어진 헥산, 메틸렌클로라이드, 에틸아세테이트, 부탄올 분획물을 실리카겔 칼럼을 사용한 크로마토그래피를 이용하여 또 다른 분획물을 얻었다. 즉, 헥산-에틸아세테이트 혼합용매(99% : 1%, 50% : 50%), 메틸렌클로라이드-메탄올 혼합용매(98% : 2%, 50% : 50%)로 구성되는 단계별 농도 구배 용매시스템을 적용하여 각각 노루궁뎅이 버섯 헥산 분획물 6개(HEH1 ~ HEH6), 노루궁뎅이버섯 메틸렌클로라이드 분획물 9개(HEM1 ~ HEM9), 노루궁뎅이 버섯 에틸아세테이트 분획물 5개(HEE1 ~ HEE5)의 분획물을 얻었다. 분획물 중 HEH2, HEM2, HEM6, HEM7, HEE3가 아세틸콜린 에스터라아제에 농도 의존적으로 저해활성을 나타냄을 확인하여 활성 분획물을 얻었다.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 concentration 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%) Six hexane fractions (HEH1 to HEH6), 9 muskeleton methylene chloride fractions (HEM1 to HEM9), and 5 fractions of ethyl acetate acetate (HEE1 to HEE5) were obtained. In the fractions, HEH2, HEM2, HEM6, HEM7, HEE3 showed an inhibitory activity concentration-dependently on acetylcholine esterase to obtain an active fraction.
1-4. 활성 분획물로부터 단일화합물의 분리1-4. Isolation of Single Compounds from Active Fractions
상기 실시예 1-3의 활성 분획물들 중 노루궁뎅이 버섯 헥산 분획물로서 HEH2 및 메틸렌클로라이드 분획물로서 HEM2을 HPLC를 통해 분석하여 화합물 1 내지 4를 분리 정제하였다.Among the active fractions of Examples 1-3, Compounds 1 to 4 were isolated by analyzing HEM2 as a hexane fraction of Roestock mushroom hexane and HEM2 as a methylene chloride fraction through HPLC.
비교예 1.Comparative Example 1.
기존의 치매치료용 조성물로서 시중에서 판매되는 타크린(Tacrine) 300nM을 본 비교예로 하였다.As a conventional composition for treating dementia, commercially available tacrine (Tacrine) 300nM was used as a comparative example.
실험예 1. 화합물 1 내지 4의 구조분석Experimental Example 1. Structural Analysis of Compounds 1 to 4
상기 실시예 1-4에서 분리된 화합물 1 내지 4의 분자량 및 분자식을 LC/MS 분광기(제조사: Thermo finnigan LCQ decaplus)를 사용하여 결정하고, 핵자기공명(NMR) 분석기(Verian 500 MHz)를 통하여 1H NMR, 13C NMR 스펙트럼을 얻어, 분자구조를 결정하였다.The molecular weight and molecular formula of the compounds 1 to 4 isolated in Examples 1-4 were determined using LC / MS spectroscopy (manufacturer: Thermo finnigan LCQ decaplus), and through a nuclear magnetic resonance (NMR) analyzer (Verian 500 MHz) 1 H NMR and 13 C NMR spectra were obtained to determine the molecular structure.
그 결과 화합물 1 내지 4의 하기 화학구조를 결정하였다.As a result, the following chemical structures of the compounds 1 to 4 were determined.
[화학식 1][Formula 1]
Figure PCTKR2013000578-appb-I000005
Figure PCTKR2013000578-appb-I000005
1) 물성: 무색gum (colorless gum)1) Properties: colorless gum
2) 분자량 : 3322) Molecular Weight: 332
3) 분자식 : C19H24O5 3) Molecular formula: C 19 H 24 O 5
4) 1H NMR (500MHz, CD3OD), δ6.92 (1H, s, H-7), 5.54 (1H, m, H-2'), 5.22 (2H, s, H-3), 5.01 (1H, br d, J = 8.5 Hz, H-6'), 4.39 (1H, dt, J = 7.5, 8.5 Hz, H-5'), 3.87 (3H, s, OCH3), 3.45 (1H, dd, J = 13.5, 7.0 Hz, H-1'b), 3.39 (1H, dd, J = 13.5, 7.0 Hz, H-1'a), 2.21 (1H, dd, J = 12.5, 6.0 Hz, H-4'b), 2.03 (1H, dd, J = 12.5, 6.0 Hz, H-4'a), 1.80 (3H, s, H-9'), 1.76 (3H, s, H-8'), 1.58 (3H, s, H-10') 13C NMR (125MHz, CD3OD), δ171.7 (C-1), 160.1 (C-6), 149.7 (C-4), 139.3 (C-3'), 134.2 (C-7'), 127.9 (C-7a), 127.0 (C-6'), 124.8 (C-3a), 124.0 (C-2'), 122.4 (C-5), 97.5 (C-7), 68.4 (C-3), 66.8 (C-5'), 55.2 (OCH3), 47.8 (C-4'), 28.7 (C-8'), 24.5 (C-1'), 16.9 (C-10'), 15.7 (C-9').4) 1 H NMR (500MHz, CD 3 OD), δ6.92 (1H, s, H-7), 5.54 (1H, m, H-2 '), 5.22 (2H, s, H-3), 5.01 (1H, broad doublet, J = 8.5 Hz, H-6 ′), 4.39 (1H, dt, J = 7.5, 8.5 Hz, H-5 ′), 3.87 (3H, s, OCH 3 ), 3.45 (1H, dd, J = 13.5, 7.0 Hz, H-1'b), 3.39 (1H, dd, J = 13.5, 7.0 Hz, H-1'a), 2.21 (1H, dd, J = 12.5, 6.0 Hz, H -4'b), 2.03 (1H, dd, J = 12.5, 6.0 Hz, H-4'a), 1.80 (3H, s, H-9 '), 1.76 (3H, s, H-8'), 1.58 (3H, s, H-10 ') 13 C NMR (125 MHz, CD 3 OD), δ 171.7 (C-1), 160.1 (C-6), 149.7 (C-4), 139.3 (C-3 '), 134.2 (C-7'), 127.9 (C-7a), 127.0 (C-6 '), 124.8 (C-3a), 124.0 (C-2'), 122.4 (C-5), 97.5 ( C-7), 68.4 (C-3), 66.8 (C-5 '), 55.2 (OCH 3 ), 47.8 (C-4'), 28.7 (C-8 '), 24.5 (C-1'), 16.9 (C-10 '), 15.7 (C-9').
5) ESI-MS) data at m/z 331 [M-H]- (calcd. for C19H24O5 : 332)5) ESI-MS) data at m / z 331 [M − H] − (calcd. For C 19 H 24 O 5 : 332)
6) 화합물에 대한 구조분석기술6) Structural analysis technology for compounds
* IR spectrum은 3375 cm-1와 1676 cm-1 에서 hydroxyl 과 carbonyl 작용기를 각각 나타냈다. * The IR spectrum shows hydroxyl and carbonyl functional groups at 3375 cm -1 and 1676 cm -1 , respectively.
* 1H NMR spectrum을 통하여 3개의 methyl groups (δH = 1.80, 1.76 and 1.58), 한 개의 methoxy group (δH = 3.87), 한 개의 aromatic proton (δH = 6.92) 및 4개의 methylene proton signals (δH = 3.45 (dd, J = 13.5, 7.0 Hz), 3.39 (dd, J = 13.5, 7.0 Hz), 2.21 (dd, J = 12.5, 6.0 Hz) and 2.03 (dd, J = 12.5, 6.0 Hz))를 나타내었다. * 1 H NMR spectrum shows three methyl groups (δH = 1.80, 1.76 and 1.58), one methoxy group (δH = 3.87), one aromatic proton (δH = 6.92) and four methylene proton signals (δH = 3.45 (dd, J = 13.5, 7.0 Hz), 3.39 (dd, J = 13.5, 7.0 Hz), 2.21 (dd, J = 12.5, 6.0 Hz) and 2.03 (dd, J = 12.5, 6.0 Hz)). .
* 13C NMR spectrum을 통하여 19개의 탄소 신호를 발견했으며, 한 개의 carbonyl 그룹 (δC = 171.7), 6개의 aromatic carbons (δC = 160.0, 149.7, 127.9, 124.8, 122.4 and 97.5), 3개의 methyl carbons (δC = 28.7, 16.9 and 15.7), 2개의 methylene carbons (δC = 47.8 and 24.5), 한 개의 methoxy group (δC = 55.2) 및 4개의 olefinic carbons (δC = 139.3, 134.2, 127.0 and 124.0). * 13 C NMR spectra revealed 19 carbon signals, one carbonyl group (δC = 171.7), six aromatic carbons (δC = 160.0, 149.7, 127.9, 124.8, 122.4 and 97.5), and three methyl carbons ( δC = 28.7, 16.9 and 15.7), two methylene carbons (δC = 47.8 and 24.5), one methoxy group (δC = 55.2) and four olefinic carbons (δC = 139.3, 134.2, 127.0 and 124.0).
NMR data는 erinacerin B과 매우 비슷했고, 이의 분광학적 결과는 도 1 내지 4에 나타냈다.NMR data were very similar to erinacerin B, whose spectroscopic results are shown in FIGS.
[화학식 2][Formula 2]
Figure PCTKR2013000578-appb-I000006
Figure PCTKR2013000578-appb-I000006
1) 물성: 무색gum (colorless gum)1) Properties: colorless gum
2) 분자량 : 3302) Molecular Weight: 330
3) 분자식 : C19H22O5 3) Molecular formula: C 19 H 22 O 5
4) 1H NMR (500MHz, CD3OD), δ6.68 (1H, s, H-6), 6.38 (1H, br s, H-3'), 5.20 (2H, s, H-7), 3.92 (3H, s, OCH3), 2.86 (1H, d, J = 14.0 Hz, H-1'), 2.72 (1H, d, J = 14.0 Hz, H-1'), 2.66 (1H, m, H-4), 2.27 (1H, m, H-4), 2.02 (3H, s, H-6'), 1.93 (2H, m, H-3), 1.87 (3H, s, H-5'), 1.40 (3H, s, H-2a) 13C NMR (125MHz, CD3OD), δ199.4 (C-2'), 170.5 (C-9), 164.1 (C-5), 156.2 (C-4'), 153.0 (C-9b), 150.3 (C-6a), 125.1 (C-3'), 110.5 (C-4a), 105.4 (C-9a), 95.4 (C-6), 76.8 (C-2), 69.1 (C-7), 55.5 (OCH3), 52.5 (C-1'), 30.1 (C-3), 26.4 (C-5'), 23.4 (C-2a), 19.7 (C-6'), 16.5 (C-4).4) 1 H NMR (500 MHz, CD 3 OD), δ6.68 (1H, s, H-6), 6.38 (1H, br s, H-3 ′), 5.20 (2H, s, H-7), 3.92 (3H, s, OCH 3 ), 2.86 (1H, d, J = 14.0 Hz, H-1 '), 2.72 (1H, d, J = 14.0 Hz, H-1'), 2.66 (1H, m, H-4), 2.27 (1H, m, H-4), 2.02 (3H, s, H-6 '), 1.93 (2H, m, H-3), 1.87 (3H, s, H-5') , 1.40 (3H, s, H-2a) 13 C NMR (125 MHz, CD 3 OD), δ 199.4 (C-2 '), 170.5 (C-9), 164.1 (C-5), 156.2 (C- 4 '), 153.0 (C-9b), 150.3 (C-6a), 125.1 (C-3'), 110.5 (C-4a), 105.4 (C-9a), 95.4 (C-6), 76.8 (C -2), 69.1 (C-7), 55.5 (OCH 3 ), 52.5 (C-1 '), 30.1 (C-3), 26.4 (C-5'), 23.4 (C-2a), 19.7 (C -6 '), 16.5 (C-4).
5) ESI-MS) data at m/z 353 [M+Na]+ (calcd. for C19H22O5 : 330)5) ESI-MS) data at m / z 353 [M + Na] + (calcd. For C 19 H 22 O 5 : 330)
6) 화합물에 대한 구조분석기술6) Structural analysis technology for compounds
* IR spectrum은 3366 cm-1 와 1615 cm-1 에서 hydroxyl 과 carbonyl 작용기를 각각 나타냈다. * The IR spectrum shows hydroxyl and carbonyl groups at 3366 cm -1 and 1615 cm -1 , respectively.
* 1H NMR spectrum을 통하여 3개의 methyl groups (δH = 2.02, 1.87 and 1.40), 한 개의 methoxy group (δH = 3.92), 한 개의 aromatic proton (δH = 6.68), 5개의 methylene proton signals (δH = 2.86 (d, J = 14.0 Hz), 2.72 (d, J = 14.0 Hz), 2.66, 2.27, and 1.93), 한 개의 oxymethylene proton signal (δH = 5.20) 및 한 개의 olefinic proton (δH = 6.38)을 나타내었다.* 1 H NMR spectrum shows three methyl groups (δH = 2.02, 1.87 and 1.40), one methoxy group (δH = 3.92), one aromatic proton (δH = 6.68), and five methylene proton signals (δH = 2.86 (d, J = 14.0 Hz), 2.72 (d, J = 14.0 Hz), 2.66, 2.27, and 1.93), one oxymethylene proton signal (δH = 5.20) and one olefinic proton (δH = 6.38) .
* 13C NMR spectrum을 통하여 19개의 탄소 신호를 발견했으며, 한 개의 ketone (δC = 199.4), 6개의 aromatic carbons (δC = 164.1, 153.0, 150.3, 110.5, 105.4 and 95.4), 3개의 methyl carbons (δC = 26.4, 23.4 and 19.7), 한 개의 methylene carbon (δC = 52.5), 한 개의 oxymethylene carbon (δC = 69.1), 한 개의 methoxy group (δC = 55.5) 및 2개의 olefinic carbons (δC = 156.2 and 125.1)을 확인하였다. * 13 C NMR spectra revealed 19 carbon signals, one ketone (δC = 199.4), six aromatic carbons (δC = 164.1, 153.0, 150.3, 110.5, 105.4 and 95.4), and three methyl carbons (δC = 26.4, 23.4 and 19.7), one methylene carbon (δC = 52.5), one oxymethylene carbon (δC = 69.1), one methoxy group (δC = 55.5) and two olefinic carbons (δC = 156.2 and 125.1) Confirmed.
NMR data는 3,4-dihydro-5-methoxy-2-methyl-2-(4'-methyl-2'-oxo-3'-pentenyl)-9(7H)-oxo-2H-furo[3,4-h]benzopyran과 매우 비슷했고, 이의 분광학적 결과는 도 5 내지 8에 나타냈다.NMR data were 3,4-dihydro-5-methoxy-2-methyl-2- (4'-methyl-2'-oxo-3'-pentenyl) -9 (7H) -oxo-2H-furo [3,4 Very similar to -h] benzopyran, its spectroscopic results are shown in FIGS.
[화학식 3][Formula 3]
1) 물성: 무색gum (colorless gum)1) Properties: colorless gum
2) 분자량 : 3162) Molecular Weight: 316
3) 분자식 : C19H24O4 3) Molecular formula: C 19 H 24 O 4
4) 1H NMR (500MHz, CD3OD), δ6.70 (1H, s, H-4), 5.25 (2H, s, H-3), 5.16 (1H, t, J = 7.0 Hz, H-2'), 5.04 (1H, t, J = 7.0 Hz, H-6'), 3.90 (3H, s, OCH3), 3.36 (2H, d, J = 7.0 Hz, H-1'), 2.03 (2H, m, H-5'), 1.76 (3H, s, H-10'), 1.59 (3H, s, H-9'), 1.54 (3H, s, H-8') 13C NMR (125MHz, CD3OD), δ172.7 (C-1), 164.9 (C-5), 154.2 (C-7), 147.6 (C-3a), 134.8 (C-3'), 130.8 (C-7'), 124.1 (C-6'), 122.0 (C-2'), 117.0 (C-6), 104.2 (C-7a), 96.3 (C-4), 70.2 (C-3), 55.5 (OCH3), 39.6 (C-4'), 26.4 (C-5'), 24.6 (C-8'), 21.3 (C-1'), 17.6 (C-9'), 16.1 (C-10').4) 1 H NMR (500MHz, CD 3 OD), δ6.70 (1H, s, H-4), 5.25 (2H, s, H-3), 5.16 (1H, t, J = 7.0 Hz, H- 2 '), 5.04 (1H, t, J = 7.0 Hz, H-6'), 3.90 (3H, s, OCH 3 ), 3.36 (2H, d, J = 7.0 Hz, H-1 '), 2.03 ( 2H, m, H-5 '), 1.76 (3H, s, H-10'), 1.59 (3H, s, H-9 '), 1.54 (3H, s, H-8') 13 C NMR (125 MHz , CD 3 OD), δ 172.7 (C-1), 164.9 (C-5), 154.2 (C-7), 147.6 (C-3a), 134.8 (C-3 '), 130.8 (C-7' ), 124.1 (C-6 '), 122.0 (C-2'), 117.0 (C-6), 104.2 (C-7a), 96.3 (C-4), 70.2 (C-3), 55.5 (OCH 3 ), 39.6 (C-4 '), 26.4 (C-5'), 24.6 (C-8 '), 21.3 (C-1'), 17.6 (C-9 '), 16.1 (C-10').
5) ESI-MS) data at m/z 339 [M+Na]+ (calcd. for C19H24O4 : 316)5) ESI-MS) data at m / z 339 [M + Na] + (calcd. For C 19 H 24 O 4 : 316)
6) 화합물에 대한 구조분석기술6) Structural analysis technology for compounds
* IR spectrum은 3356 cm-1 및 1679 cm-1 에서 hydroxyl 과 carbonyl 작용기를 각각 나타냈다.* The IR spectrum shows hydroxyl and carbonyl functional groups at 3356 cm -1 and 1679 cm -1 , respectively.
* 1H NMR spectrum을 통하여 3개의 methyl groups (δH = 1.76, 1.59 and 1.54), 한 개의 methoxy group (δH = 3.90), 한 개의 aromatic proton (δH = 6.70), 2개의 olefinic proton signals (δH = 5.16 (t, J = 7.0 Hz) and 5.04 (t, J = 7.0 Hz)) 및 3개의 methylene proton signals (δH = 3.36 (d, J = 7.0 Hz), 2.03 and 1.93)을 나타내었다.* 1 3 methyl groups via a H NMR spectrum (δH = 1.76, 1.59 and 1.54), one methoxy group (δH = 3.90), one aromatic proton (δH = 6.70), 2 single olefinic proton signals (δH = 5.16 (t, J = 7.0 Hz) and 5.04 (t, J = 7.0 Hz) and three methylene proton signals (δH = 3.36 (d, J = 7.0 Hz), 2.03 and 1.93).
* 13C NMR spectrum을 통하여 19개의 탄소 신호를 발견했으며, 한 개의 carbonyl unit (δC = 172.7), 6개의 aromatic carbons (δC = 164.9, 154.2, 147.6, 117.0, 104.2 and 96.3), 3개의 methyl carbons (δC = 24.6, 17.6 and 16.1), 3개의 methylene carbons (δC = 39.6, 26.4 and 21.3), 한 개의 oxymethylene carbon (δC = 70.2), 한 개의 methoxy group (δC = 55.5) 및 4개의 olefinic carbons (δC = 130.8, 134.8, 124.1 and 122.0)을 확인하였다. * 13 C NMR spectra revealed 19 carbon signals, one carbonyl unit (δC = 172.7), six aromatic carbons (δC = 164.9, 154.2, 147.6, 117.0, 104.2 and 96.3), and three methyl carbons ( δC = 24.6, 17.6 and 16.1), three methylene carbons (δC = 39.6, 26.4 and 21.3), one oxymethylene carbon (δC = 70.2), one methoxy group (δC = 55.5) and four olefinic carbons (δC = 130.8, 134.8, 124.1 and 122.0).
NMR data는 hericenone J와 매우 비슷했고, 이의 분광학적 결과는 도 9 내지 12에 나타내었다.NMR data were very similar to hericenone J and its spectroscopic results are shown in FIGS. 9-12.
[화학식 4][Formula 4]
Figure PCTKR2013000578-appb-I000008
Figure PCTKR2013000578-appb-I000008
1) 물성: 무색gum (colorless gum)1) Properties: colorless gum
2) 분자량 : 4332) Molecular Weight: 433
3) 분자식 : C27H31NO4 3) Molecular formula: C 27 H 31 NO 4
4) 1H NMR (500MHz, CD3OD), δ7.27-7.21 (5H, m, H-4"-H-8"), 6.85 (1H, s, H-7), 6.05 (1H, br s, H-6'), 4.12 (1H, d, J = 16.8 Hz, H-3a), 4.08 (1H, d, J = 16.8 Hz, H-3b), 3.87 (3H, s, OCH3), 3.84 (2H, m, H-1"), 2.97 (2H, t, J = 7.0 Hz, H-2"), 2.77 (1H, d, J = 13.5 Hz, H-4'b), 2.69 (1H, dd, J = 7.0, 7.0 Hz, H-1'b), 2.68 (1H, dd, J = 7.0, 7.0 Hz, H-1'a), 2.64 (1H, d, J = 14.0 Hz, H-4'a), 2.11 (3H, s, H-10'), 2.02 (1H, m, H-2'a), 1.89 (1H, m, H-2'b), 1.85 (3H, s, H-8'), 1.37 (3H, s, H-9') 13C NMR (125MHz, CD3OD), δ199.0 (C-5'), 169.8 (C-1), 158.9 (C-6), 156.0 (C-7'), 148.7 (C-4), 138.9 (C-3"), 131.5 (C-7a), 128.5, 128.4 (C-4", C-5", C-7", C-8"), 126.3 (C-6"), 125.0 (C-6'), 122.4 (C-3a), 114.1 (C-5), 96.2 (C-7), 76.0 (C-3'), 55.1 (OCH3), 51.8 (C-4'), 48.3 (C-3), 44.4 (C-1"), 34.4 (C-2"), 30.6 (C-2'), 26.6 (C-8'), 23.7 (C-9'), 20.8 (C-10'), 17.1 (C-1').4) 1 H NMR (500 MHz, CD 3 OD), δ 7.27-7.21 (5H, m, H-4 "-H-8"), 6.85 (1H, s, H-7), 6.05 (1H, br s, H-6 '), 4.12 (1H, d, J = 16.8 Hz, H-3a), 4.08 (1H, d, J = 16.8 Hz, H-3b), 3.87 (3H, s, OCH 3 ), 3.84 (2H, m, H-1 "), 2.97 (2H, t, J = 7.0 Hz, H-2"), 2.77 (1H, d, J = 13.5 Hz, H-4'b), 2.69 (1H , dd, J = 7.0, 7.0 Hz, H-1'b), 2.68 (1H, dd, J = 7.0, 7.0 Hz, H-1'a), 2.64 (1H, d, J = 14.0 Hz, H- 4'a), 2.11 (3H, s, H-10 '), 2.02 (1H, m, H-2'a), 1.89 (1H, m, H-2'b), 1.85 (3H, s, H -8 '), 1.37 (3H, s, H-9') 13 C NMR (125 MHz, CD 3 OD), δ 199.0 (C-5 '), 169.8 (C-1), 158.9 (C-6) , 156.0 (C-7 '), 148.7 (C-4), 138.9 (C-3 "), 131.5 (C-7a), 128.5, 128.4 (C-4", C-5 ", C-7", C-8 "), 126.3 (C-6"), 125.0 (C-6 '), 122.4 (C-3a), 114.1 (C-5), 96.2 (C-7), 76.0 (C-3') , 55.1 (OCH 3 ), 51.8 (C-4 '), 48.3 (C-3), 44.4 (C-1 "), 34.4 (C-2"), 30.6 (C-2'), 26.6 (C- 8 '), 23.7 (C-9'), 20.8 (C-10 '), 17.1 (C-1').
5) ESI-MS) data at m/z 456 [M+Na]+ (calcd. for C27H31NO4 : 433)5) ESI-MS) data at m / z 456 [M + Na] + (calcd. For C 27 H 31 NO 4 : 433)
6) 화합물에 대한 구조분석기술6) Structural analysis technology for compounds
* IR spectrum은 3375 cm-1 및 1675 cm-1에서 hydroxyl 과 carbonyl 작용기를 각각 나타냈다.* The IR spectrum shows hydroxyl and carbonyl functional groups at 3375 cm -1 and 1675 cm -1 , respectively.
* 1H NMR spectrum을 통하여 3개의 methyl groups (δH = 2.11, 1.85, and 1.37), 한 개의 methoxy group (δH = 3.87), 6개의 aromatic protons (δH = 7.27-7.21 (5H) and 6.85) , 한 개의 olefinic proton (δH = 6.05), 6개의 methylene proton signals (δH = 4.12 (d, J = 16.8 Hz), 4.08 (d, J = 16.8 Hz), 3.84, 2.97 (t, J = 7.0 Hz), 2.77 (d, J = 13.5 Hz) and 2.69 (dd, J = 7.0, 7.0 Hz), 2.68 (dd, J = 7.0, 7.0 Hz), 2.64 (d, J = 14.0 Hz), 2.02 and 1.89)을 확인하였다.* 1 H NMR spectrum shows three methyl groups (δH = 2.11, 1.85, and 1.37), one methoxy group (δH = 3.87), six aromatic protons (δH = 7.27-7.21 (5H) and 6.85), Olefinic protons (δH = 6.05), 6 methylene proton signals (δH = 4.12 (d, J = 16.8 Hz), 4.08 (d, J = 16.8 Hz), 3.84, 2.97 (t, J = 7.0 Hz), 2.77 (d, J = 13.5 Hz) and 2.69 (dd, J = 7.0, 7.0 Hz), 2.68 (dd, J = 7.0, 7.0 Hz), 2.64 (d, J = 14.0 Hz), 2.02 and 1.89) .
* 13C NMR spectrum을 통하여 27개의 탄소 신호를 발견했으며, 한 개의 ketone (δC = 199.0), 한 개의 carbonyl unit (δC = 169.8), 12개의 aromatic carbons (δC = 158.9, 148.7, 138.9, 131.5, 128.5, 128.5, 128.4, 128.4, 126.3, 122.4, 114.1 and 96.2), 3개의 methyl carbons (δC = 26.6, 23.7 and 20.8), 6개의 methylene carbons (δC = 51.8, 48.3, 44.4, 34.4, 30.6 and 17.1), 한 개의 methoxy group (δC = 55.1) 및 2개의 olefinic carbons (δC = 156.0 and 125.0)를 확인하였다. * 27 carbon signals were found through 13 C NMR spectrum, one ketone (δC = 199.0), one carbonyl unit (δC = 169.8), and 12 aromatic carbons (δC = 158.9, 148.7, 138.9, 131.5, 128.5 , 128.5, 128.4, 128.4, 126.3, 122.4, 114.1 and 96.2), three methyl carbons (δC = 26.6, 23.7 and 20.8), six methylene carbons (δC = 51.8, 48.3, 44.4, 34.4, 30.6 and 17.1), One methoxy group (δC = 55.1) and two olefinic carbons (δC = 156.0 and 125.0) were identified.
NMR data는 erinacerin A과 매우 비슷했고, 이의 분광학적 결과는 도 13 내지 16에 나타냈다.NMR data were very similar to erinacerin A, its spectroscopic results are shown in Figures 13-16.
실험예 2. 아세틸콜린에스터라제에 대한 활성 억제 실험Experimental Example 2. Activity Inhibition Experiment on Acetylcholinesterase
상기 실시예에 의해 분리된 화합물 1 내지 4와 비교예 1의 아세틸콜린에스터라제의 활성 억제 능력을 확인하기 위하여 하기와 같이 실험을 수행하였다.In order to confirm the activity inhibitory ability of the compounds 1 to 4 and the acetylcholinesterase of Comparative Example 1 separated by the above Example was performed as follows.
아세틸콜린에스터라제(acetylcholinesterase)의 활성을 측정하는 데 사용한 아세틸콜린에스터라제, 아세틸콜린 요오드화물 (axetylcholine iodide), 5,5-디티오-비스-(2-니트로벤조산), 네오스티그민 브로미드(neostigmine bromide)는 Sigma-Aldrich Chemistry Co.에서 구입하여 사용하였다. 아세틸콜린에스터라제 저해 활성 측정은 엘만(Ellman)법에 따라 행하였다 (Ellman et al., 1961).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).
먼저, 마우스의 뇌를 적출하여 10배 부피의 PBS-A (12.5M sodium phosphate buffer pH 7.0, 400mM NaCl)에 넣고 테플론 글래스 튜브를 이용하여 500 rpm에서 분쇄하고, 이를 1000 X g에서 10분간 원심분리하여 상등액을 얻었다. 이 상등액에 PBS-A와 Triton X-100을 첨가하고 30분 동안 교반한 다음 10000 X g에서 10분간 원심분리하여, 아세트콜린에스터라제가 포함된 효소액을 얻었다. 여기에 각각 화합물 1 내지 4 와 비교예 1의 화합물을 상기 효소액과 함께 녹인 후, 이러한 용액 1.5 ㎖의 시료용액과 완충액 2.6 ㎖, 75 mM 아세트콜린 아이오드 용액(acetylthioholine iodide solution) 20 ㎕, 엘만스(Ellman's) 시약 0.1㎖으로 이루어진 반응용액을 섞어서 25℃에서 30분간 전배양한 후 여기에 효소액을 0.4㎖ 넣고 30초 간격으로 5분 동안 410nm에서 흡광도를 측정하였다.First, the brains of the 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. After dissolving the compounds 1 to 4 and the compounds of Comparative Example 1 together with the enzyme solution, 20 ml of a 1.5 ml sample solution, 2.6 ml of buffer, and 75 mM acetylthioholine iodide solution, Elmans, respectively. (Ellman's) A reaction solution consisting of 0.1 ml of reagent was mixed and preincubated at 25 ° C. for 30 minutes, and 0.4 ml of enzyme solution was added thereto, and absorbance was measured at 410 nm for 5 minutes at 30 second intervals.
아세틸콜린에스터라제 저해능은 하기 수학식 1에 의해 계산되었다.Acetylcholinesterase inhibitory ability was calculated by the following equation.
수학식 1
Figure PCTKR2013000578-appb-M000001
 Equation 1
Figure PCTKR2013000578-appb-M000001
이 결과를 하기 도 17에 나타내었다.This result is shown in FIG. 17.
도 17에 나타난 바와 같이, 비교예 1인 타크린은 아세틸콜린에스터라아제에 대한 23% 억제활성을 나타내었지만, 본 발명의 화합물 1 내지 4는 비교예 1보다 높은 억제활성을 나타내어, 퇴행성 뇌질환인 치매 치료 물질로서 유용하게 사용될 수 있다.As shown in FIG. 17, tacrine, Comparative Example 1, exhibited 23% inhibitory activity against acetylcholinesterase, but Compounds 1 to 4 of the present invention exhibited higher inhibitory activity than Comparative Example 1, thereby degenerative brain disease. It can be usefully used as a therapeutic substance for phosphorus dementia.
상기에서는 본 발명의 바람직한 실시예에 대하여 설명하였지만, 본 발명은 이에 한정되는 것은 아니고, 본 발명의 기술 사상 범위 내에서 여러 가지로 변형하여 실시하는 것이 가능하고, 이 또한 첨부된 특허 청구 범위에 속하는 것은 당연하다.Although the preferred embodiments of the present invention have been described above, the present invention is not limited thereto, and various modifications can be made within the scope of the technical idea of the present invention, which also belong to the appended claims. It is natural.
이와 같이, 본 발명에 따른 노루궁뎅이버섯 유래 물질인 화합물 1 내지 4는 높은 아세틸콜린에스터라제 활성 억제 효과가 있어 추후 아세틸콜린에스터라제 활성 억제제, 치매 예방 또는 치료용 약학적 조성물 및 건강기능성 식품 등의 여러 분야에서 활용가능성이 큰 물질임이 자명하다.As described above, Compounds 1 to 4, which are the extracts of the Roestock fungus, according to the present invention, have a high inhibitory effect on acetylcholinesterase activity, and thus inhibit acetylcholinesterase activity, pharmaceutical compositions for preventing or treating dementia, and health functional foods. It is obvious that the material is highly applicable in many fields such as
[제조예][Production example]
제조예 1 : 약학적 조성물의 제조Preparation Example 1 Preparation of Pharmaceutical Composition
본 발명의 노루궁뎅이버섯 유래 물질인 화합물 1, 화합물 2 또는 화합물 4를 포함하는 약학적 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.The preparation of the pharmaceutical composition comprising Compound 1, Compound 2, or Compound 4, which is a substance derived from the Roestock fungus of the present invention, will be described. However, the present invention is not intended to be limited thereto, but is intended to be described in detail.
제조예 1-1. 산제의 제조Preparation Example 1-1. Manufacture of powder
화합물 1 2 gCompound 1 2 g
유당 1 g1 g lactose
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above ingredients were mixed and filled in airtight cloth to prepare a powder.
제조예 1-2. 정제의 제조Preparation Example 1-2. Manufacture of tablets
화합물 1 100 ㎎Compound 1 100 mg
옥수수전분 100 ㎎ Corn starch 100 mg
유 당 100 ㎎ Lactose 100 mg
스테아린산 마그네 2 ㎎ Stearic Acid Magnesium 2 mg
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
제조예 1-3. 캡슐제의 제조Preparation Example 1-3. Preparation of Capsules
화합물 2 100 ㎎ Compound 2 100 mg
옥수수전분 100 ㎎ Corn starch 100 mg
유 당 100 ㎎ Lactose 100 mg
스테아린산 마그네슘 2 ㎎2 mg magnesium stearate
상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
제조예 1-4. 환의 제조Preparation Example 1-4. Manufacture of rings
화합물 2 1 g Compound 2 1 g
유당 1.5 gLactose 1.5 g
글리세린 1 g1 g of glycerin
자일리톨 0.5 gXylitol 0.5 g
상기의 성분을 혼합한 후, 통상의 방법에 따라 1환 당 4 g이 되도록 제조하였다.After mixing the above components, it was prepared to be 4 g per ring in a conventional manner.
제조예 1-5. 과립의 제조Preparation Example 1-5. Preparation of Granules
화합물 4 150 ㎎ Compound 4 150 mg
대두추출물 50 ㎎Soy extract 50 mg
포도당 200 ㎎ Glucose 200 mg
전분 600 ㎎ Starch 600 mg
상기의 성분을 혼합한 후, 30% 에탄올 100 ㎎을 첨가하여 섭씨 60 ℃에서 건조하여 과립을 형성한 후 포에 충진하였다.After mixing the above components, 100 mg of 30% ethanol was added, dried at 60 ° C. to form granules, and then filled into fabrics.
제조예 2 : 건강 기능성 식품의 제조.Preparation Example 2 Preparation of Health Functional Food.
제조예 2-1. 건강 기능성 식품의 제조Preparation Example 2-1. Preparation of health functional food
화합물 3 3000 ㎎ Compound 3 3000 mg
비타민 A 아세테이트 70 ㎍70 μg of Vitamin A Acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎Vitamin B1 0.13 mg
비타민 B2 0.15 ㎎Vitamin B2 0.15 mg
비타민 C 10 ㎎ Vitamin C 10 mg
비오틴 10 ㎍10 μg biotin
엽산 50 ㎍ Folate 50 ㎍
판토텐산 칼슘 0.5 ㎎Calcium Pantothenate 0.5mg
황산제1철 1.75 ㎎Ferrous Sulfate 1.75 mg
산화아연 0.82 ㎎Zinc Oxide 0.82 mg
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎Potassium monophosphate 15 mg
구연산칼륨 90 ㎎ Potassium Citrate 90 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 제조예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.The composition ratio of the above-mentioned vitamin and mineral mixture is a composition suitable for a relatively healthy food in a preferred manufacturing example, but the composition ratio may be arbitrarily modified, and the above ingredients are mixed according to a general health food manufacturing method. The granules may be prepared and used for preparing a health food composition according to a conventional method.
제조예 2-2. 건강 음료의 제조Preparation Example 2-2. Manufacture of healthy drinks
화합물 3 3 g Compound 3 3 g
구연산 1000 ㎎ Citric acid 1000 mg
올리고당 100 g100 g oligosaccharides
매실농축액 2 gPlum concentrate 2 g
타우린 1 g1 g of taurine
정제수를 가하여 전체 900 ㎖Add 900 ml of purified water
통상의 건강 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강 기능성 음료 조성물 제조에 사용한다.After mixing the above components in accordance with a conventional method for preparing a healthy beverage, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed sterilized and then refrigerated and stored in the present invention For the preparation of health functional beverage compositions.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 제조예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is a composition suitable for a preferred beverage in a preferred manufacturing example, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

Claims (11)

  1. 하기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 또는 약학적으로 허용 가능한 그의 염을 포함하는 것을 특징으로 하는 아세틸콜린에스터라제 활성 억제제:An acetylcholinesterase activity inhibitor comprising at least one compound selected from the group consisting of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2013000578-appb-I000009
    Figure PCTKR2013000578-appb-I000009
    [화학식 2][Formula 2]
    Figure PCTKR2013000578-appb-I000010
    Figure PCTKR2013000578-appb-I000010
    [화학식 3][Formula 3]
    Figure PCTKR2013000578-appb-I000011
    Figure PCTKR2013000578-appb-I000011
    [화학식 4][Formula 4]
    Figure PCTKR2013000578-appb-I000012
    Figure PCTKR2013000578-appb-I000012
  2. 제 1항에 있어서, 상기 화합물은 노루궁뎅이 버섯에서 유래된 것을 특징으로 하는 아세틸콜린에스터라제 활성 억제제.The acetylcholinesterase activity inhibitor according to claim 1, wherein the compound is derived from a locust mushroom.
  3. 제 1항에 있어서, 상기 억제제는 알츠하이머병(Alzheimer's disease)형 치매, 혈관성 치매(Vascular dementia), 파킨슨씨 병(Parkinson's disease)형 치매, 루이체 치매(Lewy body dementia), 무도병(Huntington's disease)형 치매, 크루츠펠트-야콥병(Creutzfeldt-Jacob disease)형 치매, 픽스씨 병(Pick's disease)형 치매, 뇌종양, 뇌졸증 및 인지장애로 이루어지는 군 중에서 선택된 어느 하나 이상의 질병에 작용하는 것을 특징으로 하는 아세틸콜린에스터라제 활성 억제제.The method of claim 1, wherein the inhibitor is Alzheimer's disease dementia, Vascular dementia, Parkinson's disease dementia, Lewy body dementia, Huntington's disease dementia. Acetylcholine, 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 Terase activity inhibitors.
  4. 하기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 또는 약학적으로 허용 가능한 그의 염을 포함하는 것을 특징으로 하는 치매 예방 또는 치료용 약학적 조성물:A pharmaceutical composition for preventing or treating dementia comprising at least one compound selected from the group consisting of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2013000578-appb-I000013
    Figure PCTKR2013000578-appb-I000013
    [화학식 2][Formula 2]
    Figure PCTKR2013000578-appb-I000014
    Figure PCTKR2013000578-appb-I000014
    [화학식 3][Formula 3]
    Figure PCTKR2013000578-appb-I000015
    Figure PCTKR2013000578-appb-I000015
    [화학식 4][Formula 4]
    Figure PCTKR2013000578-appb-I000016
    Figure PCTKR2013000578-appb-I000016
  5. 제 4항에 있어서, 상기 화합물은 노루궁뎅이 버섯에서 유래되는 것을 특징으로 하는 치매 예방 또는 치료용 약학적 조성물.The method of claim 4, wherein the compound is a pharmaceutical composition for the prevention or treatment of dementia, characterized in that derived from the locust mushroom.
  6. 제 4항에 있어서, 상기 치매는 알츠하이머병(Alzheimer's disease)형 치매, 혈관성 치매(Vascular dementia), 파킨슨씨 병(Parkinson's disease)형 치매, 루이체 치매(Lewy body dementia), 무도병(Huntington's disease)형 치매, 크루츠펠트-야콥병(Creutzfeldt-Jacob disease)형 치매 및 픽스씨 병(Pick's disease)형 치매로 이루어진 군 중에서 선택된 어느 하나 이상의 치매인 것을 특징으로 하는 치매 예방 또는 치료용 약제학적 조성물.The method of claim 4, wherein the dementia is Alzheimer's disease dementia, Vascular dementia, Parkinson's disease dementia, Lewy body dementia, Huntington's disease dementia. Crutzfeldt-Jacob disease (Creutzfeldt-Jacob disease) type dementia and Pix's disease type dementia selected from the group consisting of any one or more dementia, characterized in that the pharmaceutical composition for preventing or treating dementia.
  7. 하기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 또는 약학적으로 허용 가능한 그의 염을 포함하는 것을 특징으로 하는 뇌신경보호제:A neuroprotective agent comprising at least one compound selected from the group consisting of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2013000578-appb-I000017
    Figure PCTKR2013000578-appb-I000017
    [화학식 2][Formula 2]
    Figure PCTKR2013000578-appb-I000018
    Figure PCTKR2013000578-appb-I000018
    [화학식 3][Formula 3]
    Figure PCTKR2013000578-appb-I000019
    Figure PCTKR2013000578-appb-I000019
    [화학식 4][Formula 4]
    Figure PCTKR2013000578-appb-I000020
    Figure PCTKR2013000578-appb-I000020
  8. 제 7항에 있어서, 상기 화합물은 노루궁뎅이 버섯에서 유래되는 것을 특징으로 하는 뇌신경보호제.8. The neuroprotective agent according to claim 7, wherein the compound is derived from a locust mushroom.
  9. 제 7항에 있어서, 상기 뇌신경보호제는 뇌경색, 뇌졸중, 허혈성 뇌졸중, 뇌출혈, 뇌부종 및 뇌혈관성치매로 이루어지는 군 중에서 선택된 어느 하나 이상의 질병에 작용하는 것을 특징으로 하는 뇌신경보호제.8. The neuroprotective agent of claim 7, wherein the neuroprotective agent 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.
  10. 하기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 또는 식품학적으로 허용 가능한 그의 염을 포함하는 것을 특징으로 하는 건강기능성식품:A health functional food comprising at least one compound selected from the group consisting of Chemical Formulas 1 to 4, or a food acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2013000578-appb-I000021
    Figure PCTKR2013000578-appb-I000021
    [화학식 2][Formula 2]
    Figure PCTKR2013000578-appb-I000022
    Figure PCTKR2013000578-appb-I000022
    [화학식 3][Formula 3]
    Figure PCTKR2013000578-appb-I000023
    Figure PCTKR2013000578-appb-I000023
    [화학식 4][Formula 4]
    Figure PCTKR2013000578-appb-I000024
    Figure PCTKR2013000578-appb-I000024
  11. 하기 화학식 1 내지 4로 구성된 군에서 선택된 1종 이상의 화합물 또는 그의 염을 포유동물에게 유효량으로 투여하는 것을 포함하는 포유동물 치매의 치료방법:A method of treating mammalian dementia comprising administering to a mammal an effective amount of at least one compound or salt thereof selected from the group consisting of Formulas 1-4:
    [화학식 1][Formula 1]
    Figure PCTKR2013000578-appb-I000025
    Figure PCTKR2013000578-appb-I000025
    [화학식 2][Formula 2]
    Figure PCTKR2013000578-appb-I000026
    Figure PCTKR2013000578-appb-I000026
    [화학식 3][Formula 3]
    Figure PCTKR2013000578-appb-I000027
    Figure PCTKR2013000578-appb-I000027
    [화학식 4][Formula 4]
    Figure PCTKR2013000578-appb-I000028
    Figure PCTKR2013000578-appb-I000028
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CN108912136A (en) * 2018-08-07 2018-11-30 云南中烟工业有限责任公司 A kind of benzisoxa Furanones compound, preparation method and the usage for having effects that drop thorn and promoting the production of body fluid
CN108912136B (en) * 2018-08-07 2020-04-24 云南中烟工业有限责任公司 Benzoisothiafuranone compound with effects of reducing thorns and promoting production of body fluid, and preparation method and application thereof
JP2023506419A (en) * 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 Method for preparing isoindolinone derivative, novel intermediate used therefor, and method for preparing same
CN115836059A (en) * 2019-12-03 2023-03-21 忠北大学校产学协力团 Process for the preparation of isoindolinone derivatives, novel intermediates used therein and process for the preparation thereof
JP7326623B2 (en) 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 Method for preparing isoindolinone derivative, novel intermediate used therefor, and method for preparing same

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