WO2021187679A1 - Composition, comprising sea cucumber-derived saponin compound, for preventing, alleviating, or treating neuropathy - Google Patents
Composition, comprising sea cucumber-derived saponin compound, for preventing, alleviating, or treating neuropathy Download PDFInfo
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- WO2021187679A1 WO2021187679A1 PCT/KR2020/009363 KR2020009363W WO2021187679A1 WO 2021187679 A1 WO2021187679 A1 WO 2021187679A1 KR 2020009363 W KR2020009363 W KR 2020009363W WO 2021187679 A1 WO2021187679 A1 WO 2021187679A1
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- neuropathy
- compound
- alleviating
- preventing
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Images
Classifications
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/616—Echinodermata, e.g. starfish, sea cucumbers or sea urchins
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- 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
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- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/20—Natural extracts
- A23V2250/204—Animal extracts
- A23V2250/2042—Marine animal, fish extracts
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
Definitions
- the present invention relates to a composition for preventing, alleviating or treating neuropathy comprising a sea cucumber-derived saponin compound.
- TRP channels Transient receptor potential channels are ion channels that exist in animal cell membranes and are involved in the transmission of sensory signals related to temperature, taste, pain, pressure, and visual field by mediating intracellular/extracellular movement of potassium, sodium, and magnesium.
- the TRP channel is divided into various subgroups according to the amino acid sequence constituting the protein, structure, function, distribution, etc.
- TRPA1 TRP ankyrin 1
- TRPA1 TRP ankyrin 1
- TRP ankyrin 1 has 14 to 18 ankyrin protein sequences in the protein, has been shown to mediate ion transport for the formation of sensations associated with TRPA1 is expressed in various primary sensory neurons constituting the nervous system as well as various cells forming glial cells, and is widely involved in the expression and control of pain-related pathological symptoms.
- TRPA1 pathological symptoms related to TRPA1 that have been identified so far include cold hypersensitivity, pain caused by irritant compounds or tissue damage, pain caused by bacterial infection or inflammation, migraine or visceral pain, as well as neuropathy. Included.
- Neuropathy is pain caused by damage or disease of peripheral nerves, and includes allodynia, in which severe pain is felt even with minute symptoms, or hyperalgesia, which is a state in which pain sensitivity to stimuli is increased.
- Neuropathies caused by various causes include diabetic neuropathy, chemotherapy-induced painful neuropathy, traumatic neuropathy, and inflammatory neuropathy. neuropathy), etc.
- antidepressants As neuropathy treatments, but antidepressants and anticonvulsants have been reported to have an analgesic effect of 50% in less than 30% of patients. There is a need to develop a treatment for neuropathy with high efficacy and fewer side effects even after long-term use.
- TRPA1 agonists such as methylglyoxal and 4-hydroxynonenal to increase nerve endings. It has been reported to induce disease.
- chemotherapy-induced neuropathy the efficacy of TRPA antagonists has been demonstrated in animal experiments.
- allodynia caused by anticancer drugs paclitaxel, bortezomib, oxaliplatin, etc. is controlled by TRPA1 antagonists. that has been confirmed
- the function of TRPA1 is also linked to the signaling mechanism of the bradykinin B2 receptor, so it has been reported that it is highly related to cold pain caused by tissue damage or inflammation. Accordingly, the potential for development of TRPA1 antagonists as a treatment for neuropathy is highly evaluated.
- TRPA1 antagonists include synthetic organic compounds in the form of xanthine, oxime, and sulfonamide. It has been confirmed, and the related efficacy was also confirmed in Shiho ( Bupleuri Radix ) extract and psychosaponin D isolated therefrom. Clinical trials have been conducted on TRPA1 antagonists synthesized in the US and Europe as a treatment for pain, but TRPA1 antagonists that have been approved as pharmaceuticals have not been reported at home or abroad.
- An object of the present invention is to provide a preventive, alleviating or therapeutic use of a saponin compound derived from sea cucumber having an inhibitory ability of TRPA1 (TRP ankyrin 1) for neuropathy.
- the present invention provides a pharmaceutical composition for preventing, alleviating or treating neuropathy, comprising a compound of Formula 1 below:
- R 1 is , , or represents,
- R 2 and R 3 each independently represents hydrogen or hydroxy, or R 2 and R 3 form a carbon-oxygen double bond between the carbon and oxygen atoms to which they are attached,
- R 4 represents a sugar
- the present invention also provides the use of the compound of formula (1) above for the manufacture of a medicament for the prevention, alleviation or treatment of neuropathy.
- the present invention provides a method for treating neuropathy comprising administering to a subject in need thereof an effective amount of the compound of Formula 1 above.
- the present invention also provides a food composition for preventing, alleviating or improving neuropathy comprising the compound of Formula 1 above.
- the present invention also provides the use of the compound of formula 1 for the manufacture of a food for preventing, alleviating or ameliorating neuropathy.
- the present invention also provides a compound represented by the formula (5):
- the sea cucumber-derived saponin compound according to the present invention lowers the function of the TRPA1 protein, which mediates the transmission of pain signals through the movement of calcium ions, so that it can be usefully used as an active ingredient in medicine, food, etc. for the prevention, alleviation or treatment of neuropathy.
- Figure 1a shows the TRPA1 inhibition rate of a fraction obtained from a methanol 90% mobile phase in a fraction of a sea cucumber ( Bohadschia vitiensis ) extract at five concentrations (10 -1.0 , 10 -0.5 , 10 0.0 , 10 0.5 , 10 1.0 , 10 1.5 ⁇ g/mL ) is the result of checking.
- Figure 1b shows the TRPA1 inhibition rate of the fraction obtained from the methanol 100% mobile phase in the fraction of the sea cucumber ( Bohadschia vitiensis ) extract at five concentrations (10 -1.0 , 10 -0.5 , 10 0.0 , 10 0.5 , 10 1.0 , 10 1.5 ⁇ g/mL ) is the result of checking.
- Figures 2a to 2f show the TRPA1 inhibition rate of 6 saponin compounds (compounds 1, 2, 3, 4, 5 and 6) isolated from the active fraction of the sea cucumber ( Bohadschia vitiensis ) extract at 5 concentrations (10 -1.0 , 10 ) -0.5 , 10 0.0 , 10 0.5 , 10 1.0 , 10 1.5 ⁇ g/mL).
- the present invention relates to a pharmaceutical composition for preventing, alleviating or treating neuropathy, comprising a compound of formula (1):
- R 1 is , , or represents,
- R 2 and R 3 each independently represents hydrogen or hydroxy, or R 2 and R 3 form a carbon-oxygen double bond between the carbon and oxygen atoms to which they are attached,
- R 4 represents a sugar
- the present invention also provides the use of the compound of formula (1) above for the manufacture of a medicament for the prevention, alleviation or treatment of neuropathy.
- the compound of Formula 1 may specifically include compounds of Formulas 2 to 7:
- the compound of Formula 1 of the present invention is characterized in that it is derived from a sea cucumber ( Bohadschia vitiensis ) extract.
- extract refers to a preparation obtained by extracting a crude drug with an appropriate extraction solvent and evaporating the extraction solvent to concentrate, an extract obtained by extraction treatment, a diluted or concentrated liquid of the extract, a dried product obtained by drying the extract, and a crude product thereof Or it may be a purified product.
- the sea cucumber extract may be prepared using a general extraction method known in the art, for example, hot water extraction, hot water extraction, cold extraction, reflux cooling extraction, or ultrasonic extraction may be used.
- a crude extract can be obtained by lyophilizing the sea cucumber individual after cutting, extracting it cold with alcohol and filtering it.
- the compound of Formula 1 is a saponin compound having a saponin matrix structure, and has TRPA1 (Transient receptor potential cation channel, subfamily A, member 1) inhibitory activity that mediates the transmission of a pain signal through the movement of calcium ions. It can be used for prevention, alleviation or treatment.
- TRPA1 Transient receptor potential cation channel, subfamily A, member 1
- the compounds of Formulas 2 to 7 have TRPA1 inhibitory ability calculated as IC 50 values, respectively, 0.6 ⁇ M, 1.07 ⁇ M, 1.26 ⁇ M, 2.26 ⁇ M, 1.36 ⁇ M, and 1.33 ⁇ M, respectively, representing TRPA1 as a control. Compared to 0.80 ⁇ M of the antagonist A-967970, it exhibited superior or similar TRPA1 inhibitory ability.
- neuropathy refers to pain caused by damage or disease of the peripheral nerves, and includes allodynia, in which severe pain is felt even with minute symptoms, or hyperalgesia, which is a state in which pain sensitivity to stimuli is increased.
- Neuropathies caused by various causes include diabetic neuropathy, chemotherapy-induced painful neuropathy, traumatic neuropathy, and inflammation-induced neuropathy (Inflammatory). neuropathy), etc.
- treatment refers to any action in which symptoms of neuropathy are improved or cured by administration of the composition according to the present invention.
- prevention refers to any action that suppresses or delays the symptoms of neuropathy by administration of the composition according to the present invention.
- the content of the compound of Formula 1 in the pharmaceutical composition according to the present invention can be appropriately adjusted according to the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, and the like. For example, it may be contained in an amount of 0.0001 to 99.9 wt%, 0.1 to 90 wt%, 1 to 80 wt%, 1 to 70 wt%, 1 to 60 wt%, or 1 to 50 wt% based on the total weight of the composition.
- the pharmaceutical composition of the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions.
- Carriers, excipients and diluents that may be contained in the composition include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil, but is not limited thereto.
- the pharmaceutical composition of the present invention may be an oral dosage form.
- the pharmaceutical composition according to the present invention may be formulated into a suitable dosage form for topical administration using techniques well known to those skilled in the art, and the topical dosage form may include external preparations, effervescent tablets, suppositories, and the like.
- the pharmaceutical composition of the present invention may be formulated for external use by mixing the compound of Formula 1 with a base well known and commonly used in the art.
- the external preparations may include emulsions, gels, ointments, creams, patches, linens, powders, aerosols, sprays, lotions, serums, pastes, foams, drops, suspensions, and/or tinctures.
- the pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as pills, powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods.
- oral dosage forms such as pills, powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods.
- a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc.
- Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc.
- various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included.
- Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories.
- the pharmaceutical composition of the present invention is administered to a subject in a pharmaceutically effective amount.
- pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment for medical treatment, and the effective dose level is determined by the type and severity of the subject, age, It can be determined according to factors including sex, drug activity, drug sensitivity, administration time, administration route and excretion rate, duration of treatment, co-administered drugs, and other factors well known in the medical field.
- the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. and may be administered single or multiple. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art.
- the pharmaceutical composition of the present invention may vary depending on the age, sex, and weight of the patient, and specifically, 0.1 to 100 mg/kg of the composition of the present invention is administered once a day according to the degree of pain of the patient suffering from neuropathy. It can be administered several times.
- the dosage may be increased or decreased depending on the route of administration, the degree of pain, sex, weight, age, in particular the pain level of the patient. Accordingly, the above dosage does not limit the scope of the present invention in any way.
- the present invention also relates to a method of treating neuropathy comprising administering to a subject in need thereof an effective amount of the compound of formula 1 above.
- the types of neuropathy are as described above.
- the subject may be a mammal such as a human, a pig, a gorilla, a monkey, a dog, a cat, and a mouse, but is not limited thereto.
- the present invention also relates to a food composition for preventing, alleviating or improving neuropathy comprising the compound of Formula 1 above.
- the present invention also provides the use of the compound of formula 1 for the manufacture of a food for preventing, alleviating or ameliorating neuropathy.
- the compound of Formula 1 and the neuropathy are the same as those mentioned in the pharmaceutical composition, respectively, unless otherwise specified.
- improvement refers to any action in which the degree of neuropathy is at least reduced, ameliorated or beneficial by administration of the composition according to the present invention.
- the food may be a health functional food.
- health functional food refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients useful for the human body.
- functionality refers to obtaining useful effects for health purposes, such as regulating nutrients or physiological actions with respect to the structure and function of the human body.
- the food composition according to the present invention can be prepared by a method commonly used in the art, and during the preparation, it can be prepared by adding raw materials and components commonly added in the art.
- the food composition of the present invention is used for enhancing or improving the neuropathy treatment effect. It can be taken as a supplement.
- the amount of the compound of Formula 1 as an active ingredient of the food composition according to the present invention may be appropriately determined depending on the purpose of use (prevention, improvement or therapeutic treatment).
- the compound of Formula 1 may be included in an amount of 0.001 to 20% by weight, 0.001 to 15% by weight, or 0.001 to 10% by weight of the raw material composition.
- 0.01 to 2 g, specifically 0.02 to 2 g, more specifically 0.3 to 1 g, based on 100 mL may be added.
- the above amount may be used below the above range.
- the content of the compound of Formula 1 added to the food composition in the process of preparing the food composition of the present invention may be appropriately increased or decreased as necessary.
- the food composition may be in any one formulation selected from the group consisting of pills, tablets, granules, powders, capsules, and liquid solutions.
- the type of the food is not particularly limited.
- foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages, vitamin complexes, and the like, and includes all foods in a conventional sense.
- the food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional food.
- the above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
- a natural sweetener such as taumatin or stevia extract, or a synthetic sweetener such as saccharin or aspartame may be used.
- the food composition of the present invention is a beverage composition
- the liquid component except for containing the extract in the indicated ratio as an essential component, and it may contain various flavoring agents or natural carbohydrates as an additional component like a conventional beverage.
- the present invention also provides a compound represented by the formula (5):
- the HEK-293 cell line expressing TRPA1 was aliquoted on a 384 black clear plate (1.5 ⁇ 10 4 cells/20 ⁇ l/well), 20 ⁇ l FLIRP Calcium 6 assay reagent was added, and incubated for 2 hours. After adding the extract obtained in Example 1 and the control drug (A-967079) to each cell and leaving it for 10 minutes, the change in the intracellular calcium concentration was measured by the change in fluorescence intensity that appeared after 5 ⁇ M AITC was added.
- the TRPA1 function inhibition rate of the extract was measured at a concentration of 10 ⁇ g/mL by setting the value treated with AITC 5 ⁇ M as 0% inhibition and setting the value not treated with AITC 5 ⁇ M as 100% inhibition. A value of 97% was obtained (Table 1).
- TRPA1 function inhibition rate was measured in the same manner as in Example 2 at 5 concentrations (10 -1.0 , 10 -0.5 , 10 0.0 , 10 0.5 , 10 1.0 , 10 1.5 ⁇ g/mL) with respect to the fraction obtained in Example 3 to calculate the IC 50 value.
- the compounds of Formulas 6, 2, 3, 4 and 5 were sequentially separated by performing HPLC from the 90% fraction of methanol obtained in Example 3, and the compound of Formula 7 was purified by performing HPLC from the 100% methanol fraction. did.
- a semi-preparative ODS column (YMC-Pack Pro C18 (YMC, Kyoto, Japan)) was used for the stationary phase, and a mixed solvent of water and methanol was used for the mobile phase.
- the TRPA1 function inhibition rate was measured in the same manner as in Example 4 to confirm the TRPA1 inhibitory activity of each compound.
- the present invention can be usefully used as an active ingredient in medicine, food, etc. for the prevention, alleviation or treatment of neuropathy.
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Abstract
The present invention relates to a composition, comprising a sea cucumber-derived saponin compound, for preventing, alleviating, or treating neuropathy. More specifically, the sea cucumber-derived saponin compound of the present invention decreases the function of TRPA1 protein that mediates the transmission of a pain signal through the migration of calcium ions and, as such, can be advantageously used as an active ingredient for a medicine, a food, etc. for preventing, alleviating, or treating neuropathy.
Description
본 발명은 해삼 유래 사포닌 화합물을 포함하는 신경병증의 예방, 완화 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, alleviating or treating neuropathy comprising a sea cucumber-derived saponin compound.
Transient receptor potential(TRP) 채널은 동물 세포막에 존재하는 이온 채널로 칼륨, 나트륨, 마그네슘의 세포 내/외 이동을 매개함으로써 온도, 맛, 통증, 압력, 시야 등과 관련한 감각 신호의 전달에 관여하다. TRP 채널은 단백질을 구성하는 아미노산 서열과 구조, 기능, 분포 등에 따라 다양한 서브그룹으로 나누어지는데, 이 중 TRPA1(TRP ankyrin 1)은 단백질 내에 14개에서 18개에 달하는 ankyrin 단백질 서열을 가지고 있으며, 통증과 관련한 감각의 형성을 위한 이온 이동을 매개하는 것으로 밝혀졌다. TRPA1은 신경계를 구성하는 다양한 일차 감각 뉴런(primary sensory neuron) 뿐만 아니라 신경 아교를 형성하는 다양한 세포들에서 발현되어 통증과 관련한 병리학적 증상의 발현, 조절에 광범위하게 관여한다. Transient receptor potential (TRP) channels are ion channels that exist in animal cell membranes and are involved in the transmission of sensory signals related to temperature, taste, pain, pressure, and visual field by mediating intracellular/extracellular movement of potassium, sodium, and magnesium. The TRP channel is divided into various subgroups according to the amino acid sequence constituting the protein, structure, function, distribution, etc. Among them, TRPA1 (TRP ankyrin 1) has 14 to 18 ankyrin protein sequences in the protein, has been shown to mediate ion transport for the formation of sensations associated with TRPA1 is expressed in various primary sensory neurons constituting the nervous system as well as various cells forming glial cells, and is widely involved in the expression and control of pain-related pathological symptoms.
현재까지 밝혀진 TRPA1과 관련된 병리학적 증상에는 냉과민증(cold hypersensitivity), 자극성 화합물이나 조직 손상으로 인한 통증, 세균 감염이나 염증으로 인한 통증, 편두통(migraine) 이나 내장통(visceral pain) 뿐만 아니라 신경병증이 포함된다. The pathological symptoms related to TRPA1 that have been identified so far include cold hypersensitivity, pain caused by irritant compounds or tissue damage, pain caused by bacterial infection or inflammation, migraine or visceral pain, as well as neuropathy. Included.
신경병증은 말초신경의 손상 또는 질병으로 인해 나타나는 통증으로, 미세한 증상에도 심한 통증을 느끼는 이질통(allodynia)이나 자극에 대해 통증 민감도가 높아진 상태인 통각과민(hyperalgesia) 등이 이에 해당한다. 다양한 원인에 의해 유발되는 신경병증에는 당뇨성 신경병증(diabetic neuropathy), 항암 화학요법으로 인한 신경병증(chemotherapy-induced painful neuropathy), 외상으로 인한 신경병증(traumatic neuropathy), 염증으로 인한 신경병증(inflammatory neuropathy) 등이 있다. Neuropathy is pain caused by damage or disease of peripheral nerves, and includes allodynia, in which severe pain is felt even with minute symptoms, or hyperalgesia, which is a state in which pain sensitivity to stimuli is increased. Neuropathies caused by various causes include diabetic neuropathy, chemotherapy-induced painful neuropathy, traumatic neuropathy, and inflammatory neuropathy. neuropathy), etc.
현재 신경병증 치료제로 항우울제, 항경련제, 마약성 진통제 등이 사용되고 있으나, 항우울제와 항경련제는 30% 이하의 환자에 대해 50% 정도의 진통 효과가 있는 것으로 보고되었고, 마약성 진통제는 오남용과 부작용의 문제가 있어 효능이 높고 장기 복용에도 부작용이 적은 신경병증 치료제 개발이 필요하다. Currently, antidepressants, anticonvulsants, and narcotic analgesics are used as neuropathy treatments, but antidepressants and anticonvulsants have been reported to have an analgesic effect of 50% in less than 30% of patients. There is a need to develop a treatment for neuropathy with high efficacy and fewer side effects even after long-term use.
당뇨는 세포에 있어 소포체 스트레스(endoplasmic reticulum stress)를 증가시키며 장기적으로는 메틸글리옥살(methylglyoxal), 4-하이드록시노넨알(4-hydroxynonenal) 등의 TRPA1 항진제(agonist)의 혈중 농도를 상승시켜 신경병증을 유도하는 것으로 보고되어 있다. 화학요법으로 인한 신경병증에 있어서는 TRPA 길항제의 효능이 동물실험으로 입증되고 있는데, 현재까지 항암제 파클리탁셀(paclitaxel), 보르테조밉(bortezomib), 옥살리플라틴(oxaliplatin) 등에 의해 유발되는 이질통이 TRPA1 길항제에 의해 조절되는 것이 확인되었다. 또한 TRPA1의 기능은 브라디키닌 B2(bradykinin B2) 수용체의 신호 기작과도 연결되어 있어 조직 손상이나 염증으로 인한 냉감성 통증과도 관련성이 높은 것으로 보고되어 있다. 이에 TRPA1 길항제의 신경병증 치료제로서의 개발 가능성이 높게 평가되고 있다. Diabetes increases endoplasmic reticulum stress in cells, and in the long term, it increases the blood concentration of TRPA1 agonists such as methylglyoxal and 4-hydroxynonenal to increase nerve endings. It has been reported to induce disease. In chemotherapy-induced neuropathy, the efficacy of TRPA antagonists has been demonstrated in animal experiments. To date, allodynia caused by anticancer drugs paclitaxel, bortezomib, oxaliplatin, etc. is controlled by TRPA1 antagonists. that has been confirmed In addition, the function of TRPA1 is also linked to the signaling mechanism of the bradykinin B2 receptor, so it has been reported that it is highly related to cold pain caused by tissue damage or inflammation. Accordingly, the potential for development of TRPA1 antagonists as a treatment for neuropathy is highly evaluated.
보고된 TRPA1 길항제는 잔틴(xanthine)이나 옥심(oxime), 설폰아미드(sulfonamide) 형태의 합성 유기 화합물이 있으며, 천연물의 경우 보르네올(borneol) 계열의 모노테르펜(monoterpene) 화합물 등에서 인간 TRPA1 길항 효과가 확인된 바가 있으며, 시호(
Bupleuri Radix) 추출물과 이로부터 분리된 사이코사포닌 D에서도 관련 효능이 확인 되었다. 미국과 유럽에서 합성된 TRPA1 길항제에 대한 통증 치료제로서의 임상시험이 진행된 바 있으나, 의약품으로서의 승인을 받은 TRPA1 길항제는 국, 내외에 보고된 바가 없다.Reported TRPA1 antagonists include synthetic organic compounds in the form of xanthine, oxime, and sulfonamide. It has been confirmed, and the related efficacy was also confirmed in Shiho ( Bupleuri Radix ) extract and psychosaponin D isolated therefrom. Clinical trials have been conducted on TRPA1 antagonists synthesized in the US and Europe as a treatment for pain, but TRPA1 antagonists that have been approved as pharmaceuticals have not been reported at home or abroad.
본 발명의 목적은 TRPA1(TRP ankyrin 1) 억제능이 있는 해삼 유래 사포닌 화합물의 신경병증의 예방, 완화 또는 치료적 용도를 제공하는 것이다.An object of the present invention is to provide a preventive, alleviating or therapeutic use of a saponin compound derived from sea cucumber having an inhibitory ability of TRPA1 (TRP ankyrin 1) for neuropathy.
상기 목적을 달성하기 위해, 본 발명은 하기 화학식 1의 화합물을 포함하는 신경병증의 예방, 완화 또는 치료용 약학적 조성물을 제공한다:In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing, alleviating or treating neuropathy, comprising a compound of Formula 1 below:
[화학식 1][Formula 1]
상기 식에서,In the above formula,
R
1은
,
, 또는
를 나타내고,R 1 is , , or represents,
R
2 및 R
3는 각각 독립적으로 수소 또는 하이드록시를 나타내거나, R
2 및 R
3는 이들이 결합된 탄소와 산소 원자 사이에 탄소-산소 이중결합을 형성하며, R 2 and R 3 each independently represents hydrogen or hydroxy, or R 2 and R 3 form a carbon-oxygen double bond between the carbon and oxygen atoms to which they are attached,
R
4는 당을 나타낸다.R 4 represents a sugar.
본 발명은 또한 신경병증의 예방, 완화 또는 치료용 의약을 제조하기 위한 상기 화학식 1의 화합물의 용도를 제공한다.The present invention also provides the use of the compound of formula (1) above for the manufacture of a medicament for the prevention, alleviation or treatment of neuropathy.
본 발명은 유효량의 상기 화학식 1의 화합물을 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는 신경병증의 치료 방법을 제공한다. The present invention provides a method for treating neuropathy comprising administering to a subject in need thereof an effective amount of the compound of Formula 1 above.
본 발명은 또한 상기 화학식 1의 화합물을 포함하는 신경병증의 예방, 완화 또는 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for preventing, alleviating or improving neuropathy comprising the compound of Formula 1 above.
본 발명은 또한 신경병증의 예방, 완화 또는 개선용 식품을 제조하기 위한 상기 화학식 1의 화합물의 용도를 제공한다.The present invention also provides the use of the compound of formula 1 for the manufacture of a food for preventing, alleviating or ameliorating neuropathy.
본 발명은 또한 하기 화학식 5로 표현되는 화합물을 제공한다:The present invention also provides a compound represented by the formula (5):
[화학식 5][Formula 5]
본 발명에 따른 해삼 유래 사포닌 화합물은 칼슘 이온의 이동을 통해 통증 신호의 전달을 매개하는 TRPA1 단백질의 기능을 저하시키므로 신경병증의 예방, 완화 또는 치료를 위한 의약, 식품 등의 유효성분으로 유용하게 사용될 수 있다. The sea cucumber-derived saponin compound according to the present invention lowers the function of the TRPA1 protein, which mediates the transmission of pain signals through the movement of calcium ions, so that it can be usefully used as an active ingredient in medicine, food, etc. for the prevention, alleviation or treatment of neuropathy. can
도 1a은 해삼(
Bohadschia vitiensis) 추출물의 분획물 중 메탄올 90% 이동상으로부터 획득된 분획의 TRPA1 억제율을 5개의 농도(10
-1.0, 10
-0.5, 10
0.0, 10
0.5, 10
1.0, 10
1.5 ㎍/mL)에서 확인한 결과이다. Figure 1a shows the TRPA1 inhibition rate of a fraction obtained from a methanol 90% mobile phase in a fraction of a sea cucumber ( Bohadschia vitiensis ) extract at five concentrations (10 -1.0 , 10 -0.5 , 10 0.0 , 10 0.5 , 10 1.0 , 10 1.5 μg/mL ) is the result of checking.
도 1b는 해삼(
Bohadschia vitiensis) 추출물의 분획물 중 메탄올 100% 이동상으로부터 획득된 분획의 TRPA1 억제율을 5개의 농도(10
-1.0, 10
-0.5, 10
0.0, 10
0.5, 10
1.0, 10
1.5 ㎍/mL)에서 확인한 결과이다. Figure 1b shows the TRPA1 inhibition rate of the fraction obtained from the methanol 100% mobile phase in the fraction of the sea cucumber ( Bohadschia vitiensis ) extract at five concentrations (10 -1.0 , 10 -0.5 , 10 0.0 , 10 0.5 , 10 1.0 , 10 1.5 μg/mL ) is the result of checking.
도 2a 내지 도 2f는 해삼(
Bohadschia vitiensis) 추출물의 활성 분획으로부터 분리된 사포닌계 화합물 6종(compound 1, 2, 3, 4, 5 및 6)의 TRPA1 억제율을 5개 농도(10
-1.0, 10
-0.5, 10
0.0, 10
0.5, 10
1.0, 10
1.5 ㎍/mL)에서 확인한 결과이다. Figures 2a to 2f show the TRPA1 inhibition rate of 6 saponin compounds ( compounds 1, 2, 3, 4, 5 and 6) isolated from the active fraction of the sea cucumber ( Bohadschia vitiensis ) extract at 5 concentrations (10 -1.0 , 10 ) -0.5 , 10 0.0 , 10 0.5 , 10 1.0 , 10 1.5 μg/mL).
이하, 본 발명의 구성을 구체적으로 설명한다.Hereinafter, the configuration of the present invention will be described in detail.
본 발명은 하기 화학식 1의 화합물을 포함하는 신경병증의 예방, 완화 또는 치료용 약학적 조성물에 관한 것이다:The present invention relates to a pharmaceutical composition for preventing, alleviating or treating neuropathy, comprising a compound of formula (1):
[화학식 1][Formula 1]
상기 식에서,In the above formula,
R
1은
,
, 또는
를 나타내고,R 1 is , , or represents,
R
2 및 R
3는 각각 독립적으로 수소 또는 하이드록시를 나타내거나, R
2 및 R
3는 이들이 결합된 탄소와 산소 원자 사이에 탄소-산소 이중결합을 형성하며, R 2 and R 3 each independently represents hydrogen or hydroxy, or R 2 and R 3 form a carbon-oxygen double bond between the carbon and oxygen atoms to which they are attached,
R
4는 당을 나타낸다.R 4 represents a sugar.
본 발명은 또한 신경병증의 예방, 완화 또는 치료용 의약을 제조하기 위한 상기 화학식 1의 화합물의 용도를 제공한다.The present invention also provides the use of the compound of formula (1) above for the manufacture of a medicament for the prevention, alleviation or treatment of neuropathy.
상기 화학식 1의 화합물은 구체적으로 화학식 2 내지 7의 화합물을 포함할 수 있다:The compound of Formula 1 may specifically include compounds of Formulas 2 to 7:
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
[화학식 6][Formula 6]
[화학식 7][Formula 7]
본 발명의 화학식 1의 화합물은 해삼(
Bohadschia vitiensis) 추출물에서 유래된 것을 특징으로 한다.The compound of Formula 1 of the present invention is characterized in that it is derived from a sea cucumber ( Bohadschia vitiensis ) extract.
용어 "추출물"은 생약을 적절한 추출용매로 추출하고 추출용매를 증발시켜 농축한 제제를 의미하는 것으로, 추출처리에 의해 얻어지는 추출액, 추출액의 희석액 또는 농축액, 추출액을 건조하여 얻어지는 건조물, 이들의 조정제물 또는 정제물일 수 있다. 상기 해삼 추출물은 당업계에 공지된 일반적인 추출방법을 이용하여 제조할 수 있으며, 예를 들어 열탕 추출, 열수 추출, 냉침 추출, 환류 냉각 추출 또는 초음파 추출 등의 방법을 사용할 수 있다. 본 발명의 일 구체예에 따르면, 해삼 개체를 절단 후 동결건조하고, 알코올로 냉침 추출한 뒤 여과하여 조추출물을 얻을 수 있다.The term "extract" refers to a preparation obtained by extracting a crude drug with an appropriate extraction solvent and evaporating the extraction solvent to concentrate, an extract obtained by extraction treatment, a diluted or concentrated liquid of the extract, a dried product obtained by drying the extract, and a crude product thereof Or it may be a purified product. The sea cucumber extract may be prepared using a general extraction method known in the art, for example, hot water extraction, hot water extraction, cold extraction, reflux cooling extraction, or ultrasonic extraction may be used. According to one embodiment of the present invention, a crude extract can be obtained by lyophilizing the sea cucumber individual after cutting, extracting it cold with alcohol and filtering it.
상기의 해삼 추출물을 감압 건조한 후 물과 노르말부탄올로 분배하고, 노르말부탄올층을 감압 건조한다. 이 후 물과 메탄올의 혼합 용매와 노르말헥산으로 분배하고, 물과 메탄올의 혼합 용매층을 감압 건조한 후 물과 메탄올의 혼합 용매를 이용한 농도 구배 역상 컬럼 크로마토그래피를 수행하여 5종의 메탄올 분획(메탄올 %=30, 50, 70, 90, 100)으로 나누고 90% 메탄올 분획으로부터 HPLC를 수행하여 화학식 6, 2, 3, 4 및 5의 화합물을 순차적으로 분리하였고, 메탄올 100% 분획으로부터 HPLC를 수행하여 화학식 7의 화합물을 획득한다.After drying the sea cucumber extract under reduced pressure, it is distributed between water and n-butanol, and the n-butanol layer is dried under reduced pressure. Thereafter, the mixture was divided into a mixed solvent of water and methanol and n-hexane, and the mixed solvent layer of water and methanol was dried under reduced pressure, and then concentration gradient reversed-phase column chromatography using a mixed solvent of water and methanol was performed to fractionate 5 types of methanol (methanol). % = 30, 50, 70, 90, 100) and performing HPLC from a 90% methanol fraction to sequentially separate the compounds of Formulas 6, 2, 3, 4 and 5, and performing HPLC from a 100% methanol fraction A compound of formula (7) is obtained.
상기 화학식 1의 화합물은 사포닌 모핵 구조를 가지는 사포닌 화합물로, 칼슘 이온의 이동을 통해 통증 신호의 전달을 매개하는 TRPA1(Transient receptor potential cation channel, subfamily A, member 1) 억제 활성을 가지고 있어 신경병증의 예방, 완화 또는 치료에 사용할 수 있다.The compound of Formula 1 is a saponin compound having a saponin matrix structure, and has TRPA1 (Transient receptor potential cation channel, subfamily A, member 1) inhibitory activity that mediates the transmission of a pain signal through the movement of calcium ions. It can be used for prevention, alleviation or treatment.
본 발명의 일 구체예에 따르면, 화학식 2 내지 7의 화합물은 TRPA1 억제능을 IC
50 값으로 계산한 결과, 각각 0.6 μM, 1.07 μM, 1.26 μM, 2.26 μM, 1.36 μM, 1.33 μM으로 대조군으로 대표적인 TRPA1 길항제인 A-967970의 0.80 μM과 비교하여 우수하거나 유사한 정도로 TRPA1 억제능을 나타냈다.According to one embodiment of the present invention, the compounds of Formulas 2 to 7 have TRPA1 inhibitory ability calculated as IC 50 values, respectively, 0.6 μM, 1.07 μM, 1.26 μM, 2.26 μM, 1.36 μM, and 1.33 μM, respectively, representing TRPA1 as a control. Compared to 0.80 μM of the antagonist A-967970, it exhibited superior or similar TRPA1 inhibitory ability.
용어 "신경병증"은 말초신경의 손상 또는 질병으로 인해 나타나는 통증으로, 미세한 증상에도 심한 통증을 느끼는 이질통(allodynia)이나 자극에 대해 통증 민감도가 높아진 상태인 통각과민(hyperalgesia) 등이 이에 해당한다. 다양한 원인에 의해 유발되는 신경병증에는 당뇨성 신경병증(Diabetic neuropathy), 항암 화학요법으로 인한 신경병증(Chemotherapy-induced painful neuropathy), 외상으로 인한 신경병증(traumatic neuropathy), 염증으로 인한 신경병증(Inflammatory neuropathy) 등이 있다. The term "neuropathy" refers to pain caused by damage or disease of the peripheral nerves, and includes allodynia, in which severe pain is felt even with minute symptoms, or hyperalgesia, which is a state in which pain sensitivity to stimuli is increased. Neuropathies caused by various causes include diabetic neuropathy, chemotherapy-induced painful neuropathy, traumatic neuropathy, and inflammation-induced neuropathy (Inflammatory). neuropathy), etc.
용어 "치료"는 본 발명에 따른 조성물의 투여로 신경병증의 증상이 호전되거나 완치되는 모든 행위를 의미한다. 또한, 용어 "예방"은 본 발명에 따른 조성물의 투여로 신경병증의 증상을 억제 또는 지연시키는 모든 행위를 의미한다.The term “treatment” refers to any action in which symptoms of neuropathy are improved or cured by administration of the composition according to the present invention. In addition, the term "prevention" refers to any action that suppresses or delays the symptoms of neuropathy by administration of the composition according to the present invention.
본 발명에 따른 약학적 조성물 내의 화학식 1의 화합물의 함량은 질환의 증상, 증상의 진행 정도, 환자의 상태 등에 따라 적절히 조절 가능하다. 예컨대, 전체 조성물 중량을 기준으로 0.0001 내지 99.9 중량%, 0.1 내지 90 중량%, 1 내지 80 중량%, 1 내지 70 중량%, 1 내지 60 중량%, 또는 1 내지 50 중량%로 함유할 수 있다.The content of the compound of Formula 1 in the pharmaceutical composition according to the present invention can be appropriately adjusted according to the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, and the like. For example, it may be contained in an amount of 0.0001 to 99.9 wt%, 0.1 to 90 wt%, 1 to 80 wt%, 1 to 70 wt%, 1 to 60 wt%, or 1 to 50 wt% based on the total weight of the composition.
본 발명의 약학적 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 조성물에 함유될 수 있는 담체, 부형제 및 희석제는 예를 들어 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유일 수 있으나, 이에 제한되지 않는다. The pharmaceutical composition of the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions. Carriers, excipients and diluents that may be contained in the composition include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil, but is not limited thereto.
본 발명의 약학적 조성물은 경구 투여 제형일 수 있다. 또는, 본 발명에 따른 약학적 조성물은 당업자에게 잘 알려진 기술을 이용하여 국소 투여를 위한 적합한 투여 제형으로 제형화될 수 있고, 국소 투여 제형은 외용제, 발포정, 좌제 등을 포함할 수 있다. 일 구체예에서, 본 발명의 약학적 조성물은 상기 화학식 1의 화합물을 당해 기술분야에서 잘 알려지고 일반적으로 사용되는 기재(base)와 혼합하여 외용제로 제형화될 수 있다. 상기 외용제는 에멀젼, 겔, 연고, 크림, 패치, 리니먼트, 파우더, 에어로졸, 스프레이, 로숀, 세럼, 페이스트, 폼, 점적제, 현탁액, 및/또는 팅크를 포함할 수 있다.The pharmaceutical composition of the present invention may be an oral dosage form. Alternatively, the pharmaceutical composition according to the present invention may be formulated into a suitable dosage form for topical administration using techniques well known to those skilled in the art, and the topical dosage form may include external preparations, effervescent tablets, suppositories, and the like. In one embodiment, the pharmaceutical composition of the present invention may be formulated for external use by mixing the compound of Formula 1 with a base well known and commonly used in the art. The external preparations may include emulsions, gels, ointments, creams, patches, linens, powders, aerosols, sprays, lotions, serums, pastes, foams, drops, suspensions, and/or tinctures.
본 발명의 약학적 조성물은 통상의 방법에 따라 환제, 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 추출물에 적어도 하나 이상의 부형제, 예를 들어 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들어 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함될 수 있다.The pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as pills, powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods. can In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc. in the extract. It can be prepared by mixing. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 개체에 투여된다. 본 발명에서 사용된 용어 "약학적으로 유효한 양"은 의학적 치료에 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여되거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered to a subject in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment for medical treatment, and the effective dose level is determined by the type and severity of the subject, age, It can be determined according to factors including sex, drug activity, drug sensitivity, administration time, administration route and excretion rate, duration of treatment, co-administered drugs, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. and may be administered single or multiple. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art.
본 발명의 약학적 조성물은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 구체적으로 신경병증으로 고통 받는 환자가 갖는 통증의 정도에 따라 본 발명의 조성물을 0.1 내지 100 mg/kg을 일일 1회 내지 수회 투여할 수 있다. 또한, 그 투여량은 투여 경로, 통증의 정도, 성별, 체중, 나이, 특히 환자의 통증 정도 등에 따라 증감될 수 있다. 따라서, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The pharmaceutical composition of the present invention may vary depending on the age, sex, and weight of the patient, and specifically, 0.1 to 100 mg/kg of the composition of the present invention is administered once a day according to the degree of pain of the patient suffering from neuropathy. It can be administered several times. In addition, the dosage may be increased or decreased depending on the route of administration, the degree of pain, sex, weight, age, in particular the pain level of the patient. Accordingly, the above dosage does not limit the scope of the present invention in any way.
본 발명은 또한 유효량의 상기 화학식 1의 화합물을 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는 신경병증의 치료 방법에 관한 것이다.The present invention also relates to a method of treating neuropathy comprising administering to a subject in need thereof an effective amount of the compound of formula 1 above.
상기 신경병증의 치료 방법에 사용되는 화합물의 제형 및 투여 방법은 상기에서 기술하였으므로, 이 둘 사이에 공통된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여, 그 기재를 생략한다. Since the formulation and administration method of the compound used in the method for treating neuropathy have been described above, descriptions of common content between the two are omitted to avoid excessive complexity of the present specification.
상기 신경병증의 종류는 상술한 바와 같다.The types of neuropathy are as described above.
상기 대상체는 인간, 돼지, 고릴라, 원숭이, 개, 고양이, 생쥐 등의 포유동물일 수 있으나, 이에 제한하지는 않는다.The subject may be a mammal such as a human, a pig, a gorilla, a monkey, a dog, a cat, and a mouse, but is not limited thereto.
본 발명은 또한 상기 화학식 1의 화합물을 포함하는 신경병증의 예방, 완화 또는 개선용 식품 조성물에 관한 것이다.The present invention also relates to a food composition for preventing, alleviating or improving neuropathy comprising the compound of Formula 1 above.
본 발명은 또한 신경병증의 예방, 완화 또는 개선용 식품을 제조하기 위한 상기 화학식 1의 화합물의 용도를 제공한다.The present invention also provides the use of the compound of formula 1 for the manufacture of a food for preventing, alleviating or ameliorating neuropathy.
본 발명에 따른 식품 조성물에 있어서 상기 화학식 1의 화합물 및 신경병증은 특별한 언급이 없는 한, 각각 상기 약학적 조성물에서 언급한 바와 같다.In the food composition according to the present invention, the compound of Formula 1 and the neuropathy are the same as those mentioned in the pharmaceutical composition, respectively, unless otherwise specified.
용어 "개선"은 본 발명에 따른 조성물의 투여로 신경병증의 정도가 적어도 감소 또는 호전되거나 이롭게 되는 모든 행위를 의미한다.The term “improvement” refers to any action in which the degree of neuropathy is at least reduced, ameliorated or beneficial by administration of the composition according to the present invention.
상기 식품은 건강기능성 식품일 수 있다. 용어 "건강기능성 식품"이란, 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 의미한다. 여기서 "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻는 것을 의미한다.The food may be a health functional food. The term "health functional food" refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients useful for the human body. Herein, the term "functionality" refers to obtaining useful effects for health purposes, such as regulating nutrients or physiological actions with respect to the structure and function of the human body.
본 발명에 따른 식품 조성물은 당업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조 시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나므로, 본 발명의 식품 조성물은 신경병증 치료 효과를 증진 또는 개선시키기 위한 보조제로 섭취가 가능하다.The food composition according to the present invention can be prepared by a method commonly used in the art, and during the preparation, it can be prepared by adding raw materials and components commonly added in the art. In addition, unlike general drugs, there is no side effect that may occur when taking the drug for a long time by using food as a raw material, and since it is excellent in portability, the food composition of the present invention is used for enhancing or improving the neuropathy treatment effect. It can be taken as a supplement.
본 발명에 따른 식품 조성물의 유효성분인 상기 화학식 1의 화합물의 양은 사용 목적(예방, 개선 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품의 제조 시에 상기 화학식 1의 화합물은 원료 조성물 중 0.001 내지 20 중량%, 0.001 내지 15 중량% 또는 0.001 내지 10 중량%의 양으로 포함될 수 있다. 건강음료의 경우 100 mL를 기준으로 0.01 내지 2 g, 구체적으로 0.02 내지 2 g, 보다 구체적으로 0.3 내지 1 g을 가할 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하로도 사용될 수 있다. The amount of the compound of Formula 1 as an active ingredient of the food composition according to the present invention may be appropriately determined depending on the purpose of use (prevention, improvement or therapeutic treatment). In general, in the production of food, the compound of Formula 1 may be included in an amount of 0.001 to 20% by weight, 0.001 to 15% by weight, or 0.001 to 10% by weight of the raw material composition. For health drinks, 0.01 to 2 g, specifically 0.02 to 2 g, more specifically 0.3 to 1 g, based on 100 mL, may be added. However, in the case of long-term intake for health and hygiene purposes or for health control purposes, the above amount may be used below the above range.
본 발명의 식품 조성물을 제조하는 과정에서 식품 조성물에 첨가되는 상기 화학식 1의 화합물은 필요에 따라 그 함량을 적절히 가감할 수 있다.The content of the compound of Formula 1 added to the food composition in the process of preparing the food composition of the present invention may be appropriately increased or decreased as necessary.
상기 식품 조성물은 환제, 정제, 과립, 분말, 캡슐, 액상의 용액으로 이루어진 군으로부터 선택된 어느 하나의 제형일 수 있다.The food composition may be in any one formulation selected from the group consisting of pills, tablets, granules, powders, capsules, and liquid solutions.
또한, 상기 식품의 종류는 특별한 제한되지 않는다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.In addition, the type of the food is not particularly limited. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages, vitamin complexes, and the like, and includes all foods in a conventional sense.
본 발명의 식품 조성물은 통상의 식품과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 단당류, 말토스, 수크로스와 같은 이당류, 및 덱스트린, 사이클로덱스트린과 같은 다당류, 자일리톨, 소르비톨, 에리트리톨 등의 당 알코올이다. 감미제로서는 타우마틴, 스테비아 추출물 등과 같은 천연 감미제, 또는 사카린, 아스파르탐 등과 같은 합성 감미제 등을 사용할 수 있다.The food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional food. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As the sweetener, a natural sweetener such as taumatin or stevia extract, or a synthetic sweetener such as saccharin or aspartame may be used.
본 발명의 식품 조성물이 음료 조성물일 경우 필수 성분으로서 상기 추출물을 지시된 비율로 함유하는 외에는 액체 성분에 특별한 제한점은 없으며, 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.When the food composition of the present invention is a beverage composition, there is no particular limitation on the liquid component except for containing the extract in the indicated ratio as an essential component, and it may contain various flavoring agents or natural carbohydrates as an additional component like a conventional beverage. can
본 발명은 또한 하기 화학식 5로 표현되는 화합물을 제공한다:The present invention also provides a compound represented by the formula (5):
[화학식 5][Formula 5]
상기 화학식 5의 화합물은 해삼(
Bohadschia vitiensis) 추출물에서 유래된 것으로, 해삼 추출물을 감압 건조한 후 물과 노르말부탄올로 분배하고, 노르말부탄올층을 감압 건조한다. 이 후 물과 메탄올의 혼합 용매와 노르말헥산으로 분배하고, 물과 메탄올의 혼합 용매층을 감압 건조한 후 물과 메탄올의 혼합 용매를 이용한 농도 구배 역상 컬럼 크로마토그래피를 수행하여 5종의 메탄올 분획(메탄올 %=30, 50, 70, 90, 100)으로 나누고 90% 메탄올 분획으로부터 HPLC를 수행하여 획득한다.The compound of Formula 5 is derived from a sea cucumber ( Bohadschia vitiensis ) extract, and after drying the sea cucumber extract under reduced pressure, it is distributed between water and n-butanol, and the n-butanol layer is dried under reduced pressure. After that, the mixture was divided into a mixed solvent of water and methanol and n-hexane, and the mixed solvent layer of water and methanol was dried under reduced pressure, and then concentration gradient reversed-phase column chromatography using a mixed solvent of water and methanol was performed to fractionate 5 types of methanol (methanol). % = 30, 50, 70, 90, 100) and obtained by performing HPLC from the 90% methanol fraction.
상기 화학식 5의 화합물의 신경병증 예방, 완화 또는 치료적 용도에 대한 기재는 상술한 화학식 1의 화합물의 설명을 참조한다.For the description of the use of the compound of Formula 5 for preventing, alleviating or treating neuropathy, refer to the description of the compound of Formula 1 above.
이하, 본 발명에 따르는 실시예 통하여 본 발명을 보다 상세히 설명하나, 본 발명의 범위가 하기 제시된 실시예에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail through Examples according to the present invention, but the scope of the present invention is not limited by the Examples presented below.
<실시예 1> 해삼(
Bohadschia vitiensis) 추출물의 제조 <Example 1> Preparation of sea cucumber ( Bohadschia vitiensis ) extract
해삼(
Bohadschia vitiensis)의 한 개체 전체(600 g)를 2 mL 정도 부피의 조각으로 절단한 후 24시간 동안 동결건조하고, 이를 메탄올과 디클로로메탄을 각각 2회와 1회 상온에서 냉침 추출한 뒤 추출액을 여과 후 감압 농축하여 조추출물 21 g을 얻었다. After cutting a whole body (600 g) of sea cucumber ( Bohadschia vitiensis ) into pieces with a volume of about 2 mL, freeze-drying for 24 hours, extracting the extract with methanol and dichloromethane twice and once at room temperature After filtration, the mixture was concentrated under reduced pressure to obtain 21 g of a crude extract.
<실시예 2> 해삼 추출물의 TRPA1 기능 억제율 측정<Example 2> Measurement of TRPA1 function inhibition rate of sea cucumber extract
TRPA1을 발현하는 HEK-293 세포주를 384 black clear plate에 분주한 후(1.5×10
4 cells/20 ㎕/well), 20 ㎕ FLIRP Calcium 6 assay 시약을 넣고 2시간 배양하였다. 실시에 1에서 얻은 추출물과 대조 약물(A-967079)을 각 세포에 넣고 10 분간 방치한 후 5 μM AITC를 가한 후 나타나는 형광 세기 변화로 세포 내 칼슘 농도 변화를 측정하였다. The HEK-293 cell line expressing TRPA1 was aliquoted on a 384 black clear plate (1.5×10 4 cells/20 μl/well), 20 μl FLIRP Calcium 6 assay reagent was added, and incubated for 2 hours. After adding the extract obtained in Example 1 and the control drug (A-967079) to each cell and leaving it for 10 minutes, the change in the intracellular calcium concentration was measured by the change in fluorescence intensity that appeared after 5 μM AITC was added.
AITC 5 μM 을 처리한 값을 0% 억제율로 설정하고 AITC 5 μM 을 처리하지 않은 값을 100% 억제율로 설정하여 추출물의 TRPA1 기능 억제율을 10 ㎍/mL 농도에서 측정한 결과, 두 번의 실험에서 모두 97%의 값을 얻었다(표 1). The TRPA1 function inhibition rate of the extract was measured at a concentration of 10 μg/mL by setting the value treated with AITC 5 μM as 0% inhibition and setting the value not treated with AITC 5 μM as 100% inhibition. A value of 97% was obtained (Table 1).
| 추출물 번호extract number | %Inhibition-1%Inhibition-1 | %Inhibition-2%Inhibition-2 | %Inhibition-Avg%Inhibition-Avg | SDSD |
| 151KO-610(B)151KO-610(B) | 97.08 97.08 | 96.99 96.99 | 97.03 97.03 | 0.06 0.06 |
<실시예 3> 해삼 추출물의 분획상기 실시에 1에서 획득된 물과 메탄올의 혼합 용매층을 감압 건조한 후, 이것을 물과 노르말부탄올로 분배한 후, 노르말부탄올층을 감압 건조하였고, 이것을 다시 물과 메탄올(15:85 (v:v))의 혼합 용매와 노르말헥산으로 분배하였다. 물과 메탄올의 혼합 용매층을 취하여 감압 건조한 후 물과 메탄올의 혼합 용매를 이용한 농도 구배 역상 컬럼 크로마토그래피를 수행하여 5개 분획(메탄올 % = 30, 50, 70, 90, 100)으로 나누었다.<Example 3> Fractionation of sea cucumber extract After drying the mixed solvent layer of water and methanol obtained in Example 1 under reduced pressure, this was distributed with water and n-butanol, the n-butanol layer was dried under reduced pressure, and this was again mixed with water and It was partitioned into a mixed solvent of methanol (15:85 (v:v)) and n-hexane. A mixed solvent layer of water and methanol was dried under reduced pressure, and then concentration gradient reversed-phase column chromatography using a mixed solvent of water and methanol was performed to divide it into 5 fractions (methanol % = 30, 50, 70, 90, 100).
<실시예 4> 해삼 분획물의 TRPA1 기능 억제 활성 측정<Example 4> Measurement of TRPA1 function inhibitory activity of sea cucumber fraction
상기 실시예 3에서 획득된 분획에 대하여 5개의 농도(10
-1.0, 10
-0.5, 10
0.0, 10
0.5, 10
1.0, 10
1.5 ㎍/mL)에서 실시예 2와 동일한 과정으로 TRPA1 기능 억제율을 측정하여 IC
50 값을 산출하였다. TRPA1 function inhibition rate was measured in the same manner as in Example 2 at 5 concentrations (10 -1.0 , 10 -0.5 , 10 0.0 , 10 0.5 , 10 1.0 , 10 1.5 μg/mL) with respect to the fraction obtained in Example 3 to calculate the IC 50 value.
5개의 분획 중 메탄올 90%(도 1a)와 메탄올 100%(도 1b) 이동상으로부터 획득된 분획이 TRPA1 기능 억제 활성을 나타내는 것을 확인할 수 있었으며, 각 분획의 IC
50 값은 각각 0.43 ㎍/mL 과 0.62 ㎍/mL로 계산되었다.Among the five fractions, it was confirmed that the fractions obtained from the mobile phase of 90% methanol (Fig. 1a) and 100% methanol (Fig. 1b) exhibited TRPA1 function inhibitory activity, and the IC 50 values of each fraction were 0.43 μg/mL and 0.62, respectively. Calculated in μg/mL.
<실시예 5> 활성 분획으로부터 사포닌계 화합물의 분리<Example 5> Separation of saponin-based compounds from the active fraction
상기 실시예 3에서 획득된 메탄올 90%의 분획으로부터 HPLC를 수행하여 화학식 6, 2, 3, 4 및 5의 화합물을 순차적으로 분리하였고, 메탄올 100% 분획으로부터 HPLC를 수행하여 화학식 7의 화합물을 정제하였다. 고정상은 semi-preparative ODS column (YMC-Pack Pro C18 (YMC, Kyoto, Japan)), 이동상은 물과 메탄올의 혼합 용매를 사용하였다. The compounds of Formulas 6, 2, 3, 4 and 5 were sequentially separated by performing HPLC from the 90% fraction of methanol obtained in Example 3, and the compound of Formula 7 was purified by performing HPLC from the 100% methanol fraction. did. A semi-preparative ODS column (YMC-Pack Pro C18 (YMC, Kyoto, Japan)) was used for the stationary phase, and a mixed solvent of water and methanol was used for the mobile phase.
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
[화학식 6][Formula 6]
[화학식 7][Formula 7]
<실시예 6> 분리된 사포닌계 화합물의 TRPA1 기능 억제 효능 확인 <Example 6> Confirmation of the TRPA1 function inhibitory effect of the isolated saponin-based compound
상기 실시예 5에서 획득된 사포닌계 화합물에 대하여 실시예 4와 동일한 과정으로 TRPA1 기능 억제율을 측정하여 개별 화합물의 TRPA1 억제 활성을 확인하였다. For the saponin-based compound obtained in Example 5, the TRPA1 function inhibition rate was measured in the same manner as in Example 4 to confirm the TRPA1 inhibitory activity of each compound.
도 2a 내지 도 2f에 나타난 바와 같이, 모두 10 μM 이하의 농도에서 TRPA1의 기능을 99% 이상 차단하는 것으로 확인하였으며, 표 2는 사포닌계 화합물의 TRPA1 억제능을 IC
50 값으로 계산한 결과이다As shown in FIGS. 2a to 2f, it was confirmed that all of them blocked 99% or more of the function of TRPA1 at a concentration of 10 μM or less, and Table 2 shows the results of calculating the TRPA1 inhibitory ability of the saponin-based compound as an IC 50 value.
| 화합물 번호compound number | IC 50 (㎍/mL)IC 50 (μg/mL) | IC 50 (μM)IC 50 (μM) |
| #1(화학식 2의 화합물)#1 (Compound of Formula 2) | 0.850.85 | 0.600.60 |
| #2(화학식 3의 화합물)#2 (Compound of Formula 3) | 1.551.55 | 1.071.07 |
| #3(화학식 4의 화합물)#3 (Compound of Formula 4) | 1.801.80 | 1.261.26 |
| #4(화학식 5의 화합물)#4 (Compound of Formula 5) | 3.223.22 | 2.262.26 |
| #5(화학식 6의 화합물)#5 (Compound of Formula 6) | 1.921.92 | 1.361.36 |
| #6(화학식 7의 화합물)#6 (Compound of Formula 7) | 1.941.94 | 1.331.33 |
| A-967970A-967970 | 0.800.80 |
본 발명은 신경병증의 예방, 완화 또는 치료를 위한 의약, 식품 등의 유효성분으로 유용하게 사용될 수 있다. The present invention can be usefully used as an active ingredient in medicine, food, etc. for the prevention, alleviation or treatment of neuropathy.
Claims (13)
- 하기 화학식 1의 화합물을 포함하는 신경병증의 예방, 완화 또는 치료용 약학적 조성물:A pharmaceutical composition for preventing, alleviating or treating neuropathy comprising a compound of Formula 1 below:[화학식 1][Formula 1]
상기 식에서,In the above formula,R 1은,
, 또는
를 나타내고,R 1 is
,, orrepresents,R 2 및 R 3는 각각 독립적으로 수소 또는 하이드록시를 나타내거나, R 2 및 R 3는 이들이 결합된 탄소와 산소 원자 사이에 탄소-산소 이중결합을 형성하며, R 2 and R 3 each independently represents hydrogen or hydroxy, or R 2 and R 3 form a carbon-oxygen double bond between the carbon and oxygen atoms to which they are attached,R 4는 당을 나타낸다.R 4 represents a sugar. - 제1항에 있어서,According to claim 1,화학식 1의 화합물은 화학식 2 내지 7의 화합물을 포함하는, 신경병증의 예방, 완화 또는 치료용 약학적 조성물:The compound of Formula 1 is a pharmaceutical composition for preventing, alleviating or treating neuropathy, comprising the compounds of Formulas 2 to 7:[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
[화학식 6][Formula 6]
[화학식 7][Formula 7]
- 제1항에 있어서,According to claim 1,상기 화학식 1의 화합물은 TRPA1(transient receptor potential cation channel, subfamily A, member 1) 억제 활성을 가지는 것인, 신경병증의 예방, 완화 또는 치료용 약학적 조성물.The compound of Formula 1 is TRPA1 (transient receptor potential cation channel, subfamily A, member 1) having inhibitory activity, the prevention, alleviation or treatment of neuropathy pharmaceutical composition.
- 제1항에 있어서,According to claim 1,신경병증은 당뇨성 신경병증(diabetic neuropathy), 항암 화학요법으로 인한 신경병증(chemotherapy-induced painful neuropathy), 외상으로 인한 신경병증(traumatic neuropathy) 및 염증으로 인한 신경병증(inflammatory neuropathy)을 포함하는, 신경병증의 예방, 완화 또는 치료용 약학적 조성물.Neuropathy includes diabetic neuropathy, chemotherapy-induced painful neuropathy, traumatic neuropathy and inflammatory neuropathy. A pharmaceutical composition for preventing, alleviating or treating neuropathy.
- 하기 화학식 1의 화합물을 포함하는 신경병증의 예방, 완화 또는 개선용 식품 조성물:A food composition for preventing, alleviating or improving neuropathy comprising a compound of Formula 1 below:[화학식 1][Formula 1]
상기 식에서,In the above formula,R 1은,
, 또는
를 나타내고,R 1 is
,, orrepresents,R 2 및 R 3는 각각 독립적으로 수소 또는 하이드록시를 나타내거나, R 2 및 R 3는 이들이 결합된 탄소와 산소 원자 사이에 탄소-산소 이중결합을 형성하며, R 2 and R 3 each independently represents hydrogen or hydroxy, or R 2 and R 3 form a carbon-oxygen double bond between the carbon and oxygen atoms to which they are attached,R 4는 당을 나타낸다.R 4 represents a sugar. - 제5항에 있어서,6. The method of claim 5,화학식 1의 화합물은 화학식 2 내지 7의 화합물을 포함하는, 신경병증의 예방, 완화 또는 개선용 식품 조성물:The compound of Formula 1 is a food composition for preventing, alleviating or ameliorating neuropathy, comprising the compounds of Formulas 2 to 7:[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
[화학식 6][Formula 6]
[화학식 7][Formula 7]
- 제5항에 있어서,6. The method of claim 5,신경병증은 당뇨성 신경병증(diabetic neuropathy), 항암 화학요법으로 인한 신경병증(chemotherapy-induced painful neuropathy), 외상으로 인한 신경병증(traumatic neuropathy) 및 염증으로 인한 신경병증(inflammatory neuropathy)을 포함하는, 신경병증의 예방, 완화 또는 개선용 식품 조성물.Neuropathy includes diabetic neuropathy, chemotherapy-induced painful neuropathy, traumatic neuropathy and inflammatory neuropathy. A food composition for preventing, alleviating or ameliorating neuropathy.
- 유효량의 하기 화학식 1의 화합물을 이를 필요로 하는 대상체에게 투여하는 단계를 포함하는 신경병증의 치료 방법:A method of treating neuropathy comprising administering to a subject in need thereof an effective amount of a compound of formula (1):[화학식 1][Formula 1]
상기 식에서,In the above formula,R 1은,
, 또는
를 나타내고,R 1 is
,, orrepresents,R 2 및 R 3는 각각 독립적으로 수소 또는 하이드록시를 나타내거나, R 2 및 R 3는 이들이 결합된 탄소와 산소 원자 사이에 탄소-산소 이중결합을 형성하며, R 2 and R 3 each independently represents hydrogen or hydroxy, or R 2 and R 3 form a carbon-oxygen double bond between the carbon and oxygen atoms to which they are attached,R 4는 당을 나타낸다.R 4 represents a sugar. - 제8항에 있어서,9. The method of claim 8,화학식 1의 화합물은 화학식 2 내지 7의 화합물을 포함하는, 신경병증의 치료 방법:A method for treating neuropathy, wherein the compound of formula 1 comprises the compounds of formulas 2-7:[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
[화학식 6][Formula 6]
[화학식 7][Formula 7]
- 제8항에 있어서,9. The method of claim 8,신경병증은 당뇨성 신경병증(diabetic neuropathy), 항암 화학요법으로 인한 신경병증(chemotherapy-induced painful neuropathy), 외상으로 인한 신경병증(traumatic neuropathy) 및 염증으로 인한 신경병증(inflammatory neuropathy)을 포함하는, 신경병증의 치료 방법.Neuropathy includes diabetic neuropathy, chemotherapy-induced painful neuropathy, traumatic neuropathy and inflammatory neuropathy. Methods of treatment of neuropathy.
- 신경병증의 예방, 완화 또는 치료용 의약을 제조하기 위한 하기 화학식 1의 화합물의 용도:Use of a compound of formula (1) for the manufacture of a medicament for the prevention, alleviation or treatment of neuropathy:[화학식 1][Formula 1]
상기 식에서,In the above formula,R 1은,
, 또는
를 나타내고,R 1 is
,, orrepresents,R 2 및 R 3는 각각 독립적으로 수소 또는 하이드록시를 나타내거나, R 2 및 R 3는 이들이 결합된 탄소와 산소 원자 사이에 탄소-산소 이중결합을 형성하며, R 2 and R 3 each independently represents hydrogen or hydroxy, or R 2 and R 3 form a carbon-oxygen double bond between the carbon and oxygen atoms to which they are attached,R 4는 당을 나타낸다.R 4 represents a sugar. - 신경병증의 예방, 완화 또는 개선용 식품을 제조하기 위한 하기 화학식 1의 화합물의 용도:Use of a compound of the formula (1) for the preparation of a food for preventing, alleviating or ameliorating neuropathy:[화학식 1][Formula 1]
상기 식에서,In the above formula,R 1은,
, 또는
를 나타내고,R 1 is
,, orrepresents,R 2 및 R 3는 각각 독립적으로 수소 또는 하이드록시를 나타내거나, R 2 및 R 3는 이들이 결합된 탄소와 산소 원자 사이에 탄소-산소 이중결합을 형성하며, R 2 and R 3 each independently represents hydrogen or hydroxy, or R 2 and R 3 form a carbon-oxygen double bond between the carbon and oxygen atoms to which they are attached,R 4는 당을 나타낸다.R 4 represents a sugar. - 하기 화학식 5로 표현되는 화합물:A compound represented by the following formula (5):[화학식 5][Formula 5]
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| KR1020200033900A KR20210117552A (en) | 2020-03-19 | 2020-03-19 | Composition for preventing, alleviate or treating neuropathy comprising saponins derived from sea cucumber |
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| US20090269415A1 (en) * | 2005-08-31 | 2009-10-29 | Imex Japan Co., Ltd. | Novel therapeutic agent derived from marine organism |
| KR20130104930A (en) * | 2012-03-16 | 2013-09-25 | 합자회사 에스에이치해양수산개발 | Preparation method of cosmetic composition comprising saponin from sea slug and the cosmetic composition thereby |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090269415A1 (en) * | 2005-08-31 | 2009-10-29 | Imex Japan Co., Ltd. | Novel therapeutic agent derived from marine organism |
| KR20130104930A (en) * | 2012-03-16 | 2013-09-25 | 합자회사 에스에이치해양수산개발 | Preparation method of cosmetic composition comprising saponin from sea slug and the cosmetic composition thereby |
Non-Patent Citations (3)
| Title |
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| CHOI HANSOL, OH CHULHONG, HYUN JEONGMI, YANG JEUNGEUN, SONG MYUNG JIN, LEE HYI-SEUNG, LEE YEON-JU: "Triterpene Glycosides Isolated from the Edible Sea Cucumber Bohadschia vitiensis and Their Antagonistic Activity against Transient Receptor Potential Ankyrin 1", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 68, no. 19, 13 May 2020 (2020-05-13), US, pages 5349 - 5355, XP055852221, ISSN: 0021-8561, DOI: 10.1021/acs.jafc.0c00847 * |
| KITAGAWA I, ET AL.: "STRUCTURES OF FOUR NEW TRITERPENOIDAL OLIGOGLYCOSIDES, BIVITTOSIDE A, B, C, AND D, FROM THE SEA CUCUMBER BOHADSCHIA BIVITTATA MITSUKURI", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 29, no. 01, 1 January 1981 (1981-01-01), JP, pages 282 - 285, XP001182694, ISSN: 0009-2363 * |
| ZHAO YING-CAI, XUE CHANG-HU, ZHANG TIAN-TIAN, WANG YU-MING: "Saponins from Sea Cucumber and Their Biological Activities", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 66, no. 28, 18 July 2018 (2018-07-18), US, pages 7222 - 7237, XP055852214, ISSN: 0021-8561, DOI: 10.1021/acs.jafc.8b01770 * |
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