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WO2018151334A1 - Inhibiteur de xanthine oxydase et son procédé de production - Google Patents

Inhibiteur de xanthine oxydase et son procédé de production Download PDF

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Publication number
WO2018151334A1
WO2018151334A1 PCT/JP2018/006089 JP2018006089W WO2018151334A1 WO 2018151334 A1 WO2018151334 A1 WO 2018151334A1 JP 2018006089 W JP2018006089 W JP 2018006089W WO 2018151334 A1 WO2018151334 A1 WO 2018151334A1
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Prior art keywords
xanthine oxidase
oxidase inhibitor
chamomile
chemical formula
inhibitor according
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Japanese (ja)
Inventor
龍一郎 田中
昌之 山口
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Kureha Corp
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Kureha Corp
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Priority to JP2019500194A priority Critical patent/JP6628204B2/ja
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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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a novel xanthine oxidase inhibitor, which can efficiently extract its active ingredients from familiar plants that are well known to be safe,
  • the present invention relates to a production method, and further relates to a utilization method for pharmaceuticals, foods and the like using the production method.
  • xanthine oxidase Metabolism of purine, which is a nucleobase in vivo, is xanthine oxidase (xanthine oxidase and xanthine dehydrogenase are enzymes that reversibly convert each other, and they are collectively referred to as xanthine oxidoreductase.
  • xanthine oxidase and xanthine dehydrogenase are enzymes that reversibly convert each other, and they are collectively referred to as xanthine oxidoreductase.
  • Uric acid itself functions as an antioxidant when it is present in the blood, and effectively acts to remove active oxygen.
  • it when it is taken into cells, it generates active oxygen inside the cells. It is known that it causes an inflammatory reaction. Therefore, the uric acid concentration in the living body needs to be maintained within a preferable range.
  • uric acid level in the blood continuously exceeds 7 mg / dL due to abnormal metabolic pathway or abnormal excretion of uric acid from the kidney, it is diagnosed as hyperuricemia and manifestation of various pathological conditions It becomes the cause that leads to.
  • the solubility of uric acid greatly depends on pH.For example, the solubility decreases in a weakly acidic state, and in the process of gout development, urate crystals are precipitated in joint fluid, and this is phagocytosed by macrophages and other innate immune mechanisms. It is known to provoke.
  • the NLRP3 inflammasome is activated to produce inflammatory cytokines such as IL-1 ⁇ , which stimulates peripheral synovial cells to produce chemokines and migrate to them. It is known that neutrophils develop gout pathology by damaging joint tissue. Furthermore, excessive production of uric acid and a decrease in excretion are closely correlated with the causes of renal failure, and there is also a correlation between heart failure and hyperuricemia. It is clear that high uric acid levels in blood are closely associated with the development of metabolic syndrome with various symptoms, and maintaining blood uric acid levels in a moderate range is extremely important for maintaining health Has been pointed out.
  • the blood uric acid level is controlled by the xanthine oxidase production of uric acid and the reuptake of uric acid via a transporter such as URAT1 within a concentration range preferable for healthy bodies. Therefore, for hyperuricemia, both the use of a xanthine oxidase inhibitor that suppresses the production of uric acid and the promotion of uric acid excretion by a URAT1 inhibitor are basically available.
  • xanthine oxidase inhibitors such as allopurinol and febuxostat are mainly used for the treatment of hyperuricemia, and benzbromarone and the like are known as URAT1 inhibitors, but the latter increases uric acid production.
  • Xanthine oxidase is remarkably expressed in the liver and small intestine in the body, but is also known to be highly expressed in adipose tissue, blood vessels and the like.
  • Uric acid has an antioxidant effect that deactivates active oxygen, and has a function to prevent cell and tissue damage due to active oxygen generated in various parts of the body, but when the activity of xanthine oxidase is enhanced, for example, Various functions in the body can be maintained normally by moderately inhibiting the action of xanthine oxidase, such as attenuating the action of nitric oxide that relaxes vascular smooth muscle and inducing hypertension.
  • xanthine oxidase inhibitors are known to inhibit xanthine oxidase activity and maintain blood uric acid levels at normal levels. Allopurinol is the first choice especially for the treatment of hyperuricemia Although it dominates the market as a drug, it interferes with the action of enzymes related to nucleic acid metabolism other than xanthine oxidase, causing various side effects, and the burden on renal function is often a problem. Is a problem.
  • Febuxostat is mentioned as a xanthine oxidase inhibitor with another skeleton, and it is expected to be widely applied by reducing the burden on renal function. There is a need for xanthine oxidase inhibitors that can be used with greater peace of mind and safety.
  • xanthine oxidase generates reactive oxygen species in the process of oxidizing hypoxanthine to xanthine in the body and further oxidizing xanthine to uric acid. Therefore, when xanthine oxidase activity is enhanced, the concentration of uric acid only increases in the body. In addition, it becomes a factor causing various obstacles due to the influence of the generated active oxygen. Therefore, various antioxidant substances including polyphenols such as catechins are preferably used in the health supplement field such as supplements for the purpose of deactivating active oxygen.
  • problems such as low bioavailability and difficulty in introducing them into the systemic circulatory system to an effective concentration to show pharmacological action have been pointed out.
  • the use of xanthine oxidase inhibitor since the generation of active oxygen can be reduced by inhibiting the activity of xanthine oxidase, which is greatly involved in the production of active oxygen in the body, the use of xanthine oxidase inhibitor not only reduces the uric acid level but also various Since it also has the effect of reducing the generation of active oxygen, which also causes organ damage, it is also expected to be very effective in preventing the development of metabolic syndrome.
  • Non-Patent Documents 1 and 2 reports that xanthine oxidase inhibitory activity is observed in the phenol component contained in licorice.
  • Non-Patent Document 2 reports that three types of rosemary, clove, and sage contain a phenolic component that exhibits xanthine oxidase inhibitory activity.
  • the ratio of the inhibitory component contained in the plant is small, and the inhibitory activity is insufficient unless the active ingredient is extracted and concentrated using a large amount of raw materials, and it is extremely difficult to use this practically. Met.
  • a pharmaceutical in addition to its use as a pharmaceutical as a xanthine oxidase inhibitor, it can be used to prevent daily hyperuricemia and prevent metabolic syndrome related to it by using daily supplements, health foods, health drinks, etc. Be expected.
  • a xanthine oxidase inhibitor in addition to the effect as a xanthine oxidase inhibitor, there is little burden on the accumulation and metabolism in the body and the liver function, kidney function, etc. due to daily intake, There is a need for materials that are free of various safety concerns, such as lack of drug interactions.
  • Herbs and various medicinal plants contain various physiologically active ingredients in addition to active ingredients, so it is important to be able to extract highly safe ingredients including these effects efficiently and with high purity. In addition, even if other components are mixed, it is preferable that the component has no problem with respect to safety to the living body.
  • Patent Document 1 discloses a xanthine oxidase inhibitor containing a plant or a propolis such as pearl millet, cinnamon, cedron, and grape.
  • Patent Document 2 discloses a xanthine oxidase inhibitor extracted from wolfberry, broom, lemon balm, rosemary, spearmint, peppermint, and the like.
  • Patent Document 3 discloses a xanthine oxidase inhibitor, which is an extract from kahakuzansho, koryang, cumin, and rose.
  • Patent Document 4 further discloses a xanthine oxidase inhibitor extracted from pimenta, marjoram, guava, and the like. It is shown.
  • extraction is performed at a temperature around room temperature using an aqueous solution containing an organic solvent such as hot water or alcohols.
  • an organic solvent such as hot water or alcohols.
  • Patent Document 5 shows the results of high-performance liquid chromatography (HPLC) analysis of various active ingredients that act as xanthine oxidase inhibitors extracted from black turmeric. Therefore, it is not easy to verify the effectiveness, side effects, and safety of each of these components, and there is a problem in actually using them.
  • HPLC high-performance liquid chromatography
  • Patent Document 6 shows that quercetin glycosides and Patent Document 7 show that isoquercetin glycosides have high activities comparable to allopurinol as xanthine oxidase inhibitors, respectively.
  • quercetin glycosides are a kind of flavonoids abundantly contained in vegetables and fruits, and it has been reported that the average intake of quercetin by Japanese is about 10 to 35 mg per day regardless of gender age.
  • this level of quercetin glycoside has already been ingested on a daily basis, it is not expected that the effect can be exerted even if a similar amount of the same compound is ingested again. Furthermore, overdose is dangerous because quercetin has been reported to be lethal to mice at 160 mg. In addition, it needs to be used with care because it interacts with certain antibiotics and diminishes its action. Therefore, as a xanthine oxidase inhibitor, in addition to a method of using as a pharmaceutical, a method of using that can be enjoyed through health foods, health drinks and supplements that can be taken on a daily basis is preferable. For that purpose, a xanthine oxidase inhibitor that can be easily and inexpensively extracted from familiar plants well known to be safe is preferable.
  • An object of the present invention is to provide a safe and effective xanthine oxidase inhibitor and a method for producing the same.
  • the xanthine oxidase inhibitor of the present invention is produced, for example, by extracting from the above-ground part of chamomile (Matricaria recutita).
  • chamomile Motricaria recutita
  • a safe and highly effective xanthine oxidase inhibitor can be obtained by using chamomile of a familiar plant that is known to be safe and uses flower parts and whole above-ground plants including them as herbs.
  • Conventionally, chamomile flower parts have been widely used as herbs, but the current situation is that stems and leaves are hardly used.
  • the present inventors have obtained knowledge that, in addition to the flower part, an active ingredient that acts effectively as a xanthine oxidase inhibitor is contained in the stem part and the leaf part, and further, the active ingredient in the future They have found a production method that efficiently extracts the.
  • an active ingredient that effectively acts as a xanthine oxidase inhibitor can be efficiently extracted from German chamomile (Matricaria chamomilla L.).
  • the active ingredient which has the xanthine oxidase inhibitory activity extracted from the above-ground part of a Roman chamomile may be contained in the xanthine oxidase inhibitor derived from a German chamomile.
  • An active ingredient derived from German chamomile and an active ingredient derived from Roman chamomile have common medicinal effects and can be used as xanthine oxidase inhibitors.
  • chamomile flower parts are widely used as herbs, but chamomile stems and leaves are rarely used, but chamomile stems and leaves act effectively as xanthine oxidase inhibitors.
  • the compound to be included is contained in a high concentration.
  • the xanthine oxidase inhibitor of the present invention comprises (E) -2- ⁇ -D-glucopyranosyloxy-4-methoxycinnamic acid ((E) -2- ⁇ -D-glucopyranosyloxy) represented by the following chemical formula (1): -3-methoxycinnamic acid) as an active ingredient.
  • the compound of the chemical formula (1) may be artificially synthesized, but it is preferably derived from the above-mentioned extract of the above-mentioned chamomile (Matricaria recutita) from the viewpoint of ensuring safety.
  • the active ingredient of the above chemical formula (1) represents an E-form in which both are in the trans position with respect to the relative arrangement of the carboxyl group and the phenyl group bonded to the double bond of the cinnamic acid skeleton, and both are in the cis position. Differentiated from the body.
  • the effect of the present invention as a xanthine oxidase inhibitor is remarkably exhibited in the E form, whereas the effect of the Z form is much inferior to that of the E form.
  • the xanthine oxidase inhibitor of the present invention is a case where at least the E-form represented by the chemical formula (1) is contained, and may further contain a Z-form together with the E-form.
  • the pharmaceutical and food of the present invention contain the above xanthine oxidase inhibitor of the present invention.
  • the method for producing a xanthine oxidase inhibitor of the present invention comprises a step of extracting from the above-ground part of chamomile (Matricaria recutita).
  • the method for producing a xanthine oxidase inhibitor of the present invention comprises the following steps 1) to 3). 1) A step of extracting the above-ground portion of chamomile (Matricaria recutita) with water, a hydrophilic organic solvent or a mixed solvent thereof. 2) A step of separating an aqueous layer from the extracted extract and eluting with a mixed solvent of water and a hydrophilic organic solvent. 3) A step of concentrating and crystallizing the eluted fraction.
  • hydrophilic organic solvent lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol and isobutanol are preferable, and methanol or ethanol and a mixed solvent with water containing these are particularly preferable.
  • the separated aqueous layer of 2) is subjected to gel separation, and after elution with water, it is eluted with a mixed solvent of water-alcohol-organic solvent.
  • the obtained eluate may be separated and purified by a gel filtration carrier.
  • the above extraction is performed under mild conditions of 10 to 40 ° C. This is because when extraction is performed at a temperature below 10 ° C., it takes a very long time to extract the components, and a sufficient yield cannot be obtained. On the other hand, when extraction is performed at a temperature exceeding 40 ° C., This is because xanthine oxidase inhibitory activity is lost due to heat denaturation.
  • (E) -2- ⁇ -D-glucopyranosyloxy-4-methoxycinnamic acid ((E) -2- (2)) represented by the above chemical formula (1) is used.
  • a xanthine oxidase inhibitor containing ⁇ -D-glucopyranosyloxy-3-methoxycinnamic acid) as an active ingredient is obtained.
  • a safe and effective xanthine oxidase inhibitor can be obtained by extracting the above-ground parts of familiar chamomile that are well known to be safe, and to pharmaceuticals and foods using the same. There is an effect that can be used.
  • the present invention provides a familiar plant with chamomile (Matricaria recutita), in addition to the flower part normally used as a herb, the stem part and the leaf part, which have been rarely used so far, are newly added. Was found to contain a high concentration of compounds that act effectively as xanthine oxidase inhibitors.
  • the chamomile that can be used in the present invention is so-called German chamomile (Matricaria chamomilla L .; Japanese name chamomile), but similar components are also found in the above-ground parts of roman chamomile (Chamaemelum nobile) of different strains. It is known to be included, and since its medicinal properties are common, it can also be used in combination with German chamomile.
  • Chamomile is an annual herb belonging to the family Asteraceae native to Southern and Eastern Europe. Its distribution is spread all over the world and is widely distributed in Europe, Asia, North Africa, South America, North America, Australia and New Zealand. Hungary is the main production area, and flower parts are exported to Germany, where essential oils and other components are extracted and distributed.
  • the optimum temperature for growth is preferably around 10 to 20 ° C., and it is known that growth is possible even at lower temperatures.
  • soil for growth it is possible to grow even in soil with relatively little nutrient, and it is possible to grow well even in alkaline soil, so that their cultivation is relatively easy.
  • Chamomile has long been known to contain compounds that exhibit various pharmacological effects on the flower parts of the above-ground parts. Typical components include (1) essential oil components, (2) phenolic components, and (3) coumarins.
  • the essential oil component of (1) includes azulenes such as ⁇ -bisabolol, cis-spiroether, chamazulene, their oxides, and various volatile components, which can be used as essential oils. Representative.
  • the scent is known to exhibit mental depression and sedation, and is used in aromatherapy and cosmetics. Furthermore, it is used as an anti-inflammatory agent, disinfectant, disinfectant, digestive system diseases and inflammation, or It is used for anti-inflammatory action against various allergic symptoms.
  • Chamomile tea in which a dried product of the chamomile flower part is immersed in hot water to extract the essential oil component, and an oil component obtained by concentrating the essential oil component by a method such as steam distillation have a sedative effect and an anti-inflammatory effect.
  • Such essential oil components are mainly contained in the flower part, and are produced from the whole above-ground part or only the flower part using a method such as steam distillation.
  • the xanthine oxidase inhibitor of the present invention is obtained by extraction from chamomile, when such an essential oil component is contained, the compound of the above formula (1), which is an active ingredient as a xanthine oxidase inhibitor, is extracted from the extract.
  • the xanthine oxidase inhibitor of the present invention preferably contains no essential oil component.
  • phenolic components include apigenin, quercetin, patuletin, luteolin, and their glycosides, and their pharmacological effects include relief of flatulence, anxiety disorder, insomnia, etc. The effect is mentioned.
  • quercetin is known to have a xanthine oxidase inhibitory action, but the xanthine oxidase inhibitor of the present invention does not contain these phenolic components.
  • herniarin and umbelliferone are known as typical components. These coumarin compounds are converted to cinnamic acid by the action of the enzyme PAL (phenylalanine ammonia lyase) in the metabolic pathways of plants, and further oxidized to p-coumaric acid by the action of oxidase, and then as an intermediate. It is known that it is cyclized via 2-glucopyranosyloxy-p-coumaric acid and converted to umbelliferone which is a coumarin compound. It is also known that hernialin is biosynthesized from p-coumaric acid via 2-glucopyranosyloxy-4-methoxycinnamic acid (GMCA).
  • GMCA 2-glucopyranosyloxy-4-methoxycinnamic acid
  • the xanthine oxidase inhibitor of the present invention does not contain these coumarin compounds.
  • GMCA is produced in the flower part and leaf part of chamomile, and hernialin is produced from GMCA under the influence of various stresses (Repcak M et al, Journal of Plant Physiology, Volume 158, Issue 8). , 2001, Pages 1085-1087).
  • these coumarins have been conventionally used as a herbal component of chamomile, they do not have an action as a xanthine oxidase inhibitor as in the present invention. Therefore, it is preferable to suppress the formation of coumarins in chamomile and increase the content of the active ingredient of chemical formula (1).
  • Essential oil extracted from the flower part of chamomile is the most used ingredient at present, but research on various ingredients contained in these parts has also been reported for the above-ground part and root other than the flower part. It is known that essential oil components also exist in the above-ground parts and roots other than the flower parts, but unlike the ingredients contained in the flower parts, these have been extracted and used as ingredients. It was never discarded, and was partly disposed of except for being used as a bath salt. Moreover, it has been analytically known that coumarins and precursors thereof, such as GMCA, exist in the leaf part in addition to the flower part, but there exists an active ingredient having xanthine oxidase inhibitory action in these. Was not known at all.
  • the inventors of the present invention have conducted research on the useful components contained in a wide variety of resource plants and their actions for many years, and the chamomile above-ground part that has not been studied in detail in the course of the research,
  • the ground stem part and leaf part were found to contain extremely high concentrations of xanthine oxidase inhibitory activity, and as a method for producing xanthine oxidase inhibitor, the extraction and purification method of the ingredient was examined.
  • the present invention has been achieved.
  • the ingredient extracted from this is the ingredient having the xanthine oxidase inhibitory effect of the present invention.
  • the stem part and the leaf part which are the above-ground part, are used as raw materials, and an extraction medium is added to this to extract under mild conditions with a high yield. It was found that the obtained extract component exhibits a remarkable xanthine oxidase inhibitory activity.
  • 2-glucopyranosyloxy-4-methoxycinnamic acid ((E) -2- ⁇ -D-glucopyranosyloxy-4-methoxycinnamic acid) having the structure represented by the chemical formula (1) is highly concentrated in the extracted component. It was found that this has a remarkable effect as a xanthine oxidase inhibitor.
  • the compound represented by the chemical formula (1) represents an E-form in which both the carboxyl group and phenyl group bonded to the double bond of the cinnamic acid skeleton are in the trans position, and both are in the cis position. It is distinguished from a certain Z body.
  • the effect of the present invention as a xanthine oxidase inhibitor is remarkably exhibited in the E form, whereas the effect of the Z form is much inferior to that of the E form.
  • the xanthine oxidase inhibitor of the present invention is a case where at least the E-form represented by the chemical formula (1) is contained, and may further contain a Z-form together with the E-form.
  • Cinnamic acid and its derivatives are known to cause isomerization between E-form and Z-form by the action of light irradiation or catalyst.
  • E-form is more stable than Z-form, but in various plants such as chamomile, it is isomerized from E-form to Z-form by exposure to sunlight, which is further cyclized to hernia as a coumarin derivative
  • a Z isomer which is a geometric isomer thereof may be contained.
  • the E-form which is the compound of the chemical formula (1) is contained at a ratio of at least 1% by mass, and even if the Z-form and other types of components are contained, It is preferable that the ratio of the E isomer in the sum of is at least 1% by mass or more.
  • the compound of the chemical formula (1) is changed to a Z form by light irradiation, and when the compound of the chemical formula (1) is used or stored in a state exposed to light, the Z form is gradually increased. Is included in this.
  • the Z form has no effect as a xanthine oxidase inhibitor or is extremely weak, but there is no adverse effect when used together with the compound of the chemical formula (1), but both are included. Therefore, an equilibrium state is established between the E body and the Z body, and the ratio between the two is maintained in a stable state, which can be used very preferably.
  • the raw material that can be used for the purpose of producing the xanthine oxidase inhibitor of the present invention includes German chamomile (Matricaria chamomilla L .; Japanese name chamomile) as a chamomile, excluding the flower part, or together with the flower part Leaves and stems that are above-ground parts can be used as raw materials. By allowing the following extraction medium to act on these, an extract that effectively acts as a xanthine oxidase inhibitor can be efficiently obtained.
  • the flower part is used together with the leaf and stem as the above-mentioned part of the above chamomile, and the extract extracted therefrom can be used as the xanthine oxidase inhibitor.
  • the essential oil component mainly contained in the flower part together with the compound represented by the chemical formula (1) and the apigenin derivative is contained together with the compound of the chemical formula (1) in the extract, so that separation of them becomes extremely difficult.
  • Addition of effects (aroma and taste) other than the xanthine oxidase inhibitory activity targeted by the present invention may cause problems when applied to foods and pharmaceuticals as usage forms.
  • the xanthine oxidase inhibitor of the present invention it is preferable to use an extract obtained from these by using chamomile leaves and stems as raw materials, without using flower parts, and after removing essential oil components Extracting from the leaves and stems of chamomile is preferred. From a commercial point of view, it is possible to extract and use the compound of the above chemical formula (1) from the residue left after the extraction of essential oil components or the steam distillation process that has been used industrially. Since it can do, it leads to the effective utilization of the conventional waste, and is very preferable.
  • the extraction medium that can be used in the present invention is water or a hydrophilic organic solvent, or a mixed solvent thereof.
  • the hydrophilic organic solvent include lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and isobutanol.
  • a mixed solvent of methanol or ethanol and water containing these can be most preferably used.
  • the conditions for extracting chamomile from above-ground stems and leaves using these extraction solvents are preferably mild, and the temperature is preferably in the range of 10 to 40 ° C.
  • the above-ground portion of chamomile that can be used in the present invention can be used for extraction as it is after being collected without being dried.
  • nitrogen fertilizer in soil used for the cultivation of chamomile the proportion of the compound of chemical formula (1) contained in the above-ground part of chamomile increases when the nitrogen content is deficient or relatively small.
  • the content of the compound of the chemical formula (1) is relatively high when collected in the state of young leaves.
  • the ratio of the Z form produced by isomerization may change during the drying process, and the extract obtained from the above-ground part in a fresh state without drying does not contain the E form. Is relatively high.
  • the above-ground portion of chamomile can be used after being collected, but it is not preferable to dry at a temperature exceeding 90 ° C. when drying, when drying at a temperature of 90 ° C. or lower. Can be preferably used as in the case of undried.
  • the above-described extraction medium may be added to the above-ground part, and the extraction may be performed in a standing state, or the time required for extraction may be obtained by finely cutting or finely pulverizing and extracting with a mixer or a homogenizer. It is also preferable to shorten the length. As described above, it is known that the compound of the chemical formula (1) isomerizes to the Z form upon exposure to light.
  • the compound of the chemical formula (1) isomerizes into a Z form due to the influence of sunlight during the daytime, and the rate at which this is further cyclized to hernialin increases. Therefore, when cultivating and harvesting chamomile, it is preferable to avoid sunlight during the day, and after cutting, store it in a cool and dark place away from direct sunlight, and handle it so that it is not exposed to light as much as possible even when extracting from there. Is preferred.
  • the extract obtained by the extraction solvent is further added with a solvent in which three kinds of solvents of chloroform / methanol / water are mixed in a preferable ratio, so that an upper hydrophilic layer and a lower hydrophobic layer are added.
  • the compound of the chemical formula (1) can be effectively separated from other components other than the active component by being selectively contained in the upper hydrophilic layer.
  • a preferred ratio of the above three solvents of chloroform / methanol / water it is most preferable that each ratio is included in this order at 4: 2: 3.
  • each ratio is included in this order at 4: 2: 3.
  • the fraction separated as a hydrophilic layer using the above mixed solvent of chloroform / methanol / water is further purified by adsorbing and separating the compound of the formula (1) on the surface using an adsorption carrier.
  • an adsorption carrier Can be increased.
  • activated carbon or various silica gels can be used as the adsorption carrier, but the adsorption carrier having the best adsorption ability for organic substances having fine pores composed of crosslinked polymer beads as the synthetic adsorbent is the most. It can be preferably used.
  • Examples of synthetic adsorbents that can be used for such purposes include Diaion HP20 or HP21 (manufactured by Mitsubishi Chemical), which is a styrene-divinylbenzene synthetic adsorbent having large pores.
  • the compound of the chemical formula (1) can be preferably used for adsorption purification.
  • the compound of the chemical formula (1) adsorbed and supported on the adsorption carrier is further subjected to a washing operation with water and alcohol to separate and purify extract components other than the chemical formula (1), which are components, It can be separated and eluted from the adsorption carrier with an alcohol mixed solvent.
  • an alcohol mixed solvent that can be used in this case, a mixed solvent in which water and methanol are mixed in equal amounts can be preferably used.
  • the solution containing the compound of the chemical formula (1) eluted from the adsorption carrier with the above mixed solvent can be further purified by gel filtration chromatography.
  • a carrier for gel filtration chromatography that can be preferably used, Sephadex (made by GE Healthcare Japan) can be mentioned.
  • the fraction purified by the above gel filtration chromatography can be obtained as high-purity colorless crystals by evaporating the alcohol to precipitate the compound of the formula (1) as crystals.
  • the compound of the chemical formula (1) which is a high-purity component thus purified, was previously shown by structural analysis using a mass spectrometer, NMR, FT-IR, etc., as shown in the examples described later. It was revealed that it was (E) -2- ⁇ -D-glucopyranosyloxy-4-methoxycinnamic acid having the structure of chemical formula (1).
  • the final yield is between 0.02 and 0.04% by weight with respect to the above-ground portion of the undried chamomile, which is the raw material used first, from about 1 kilogram of undried raw material to about
  • the compound of formula (1) was obtained in high purity with a yield of 0.2 to 0.4 grams.
  • the chemical formula (1) obtained by concentrating from the fraction obtained in the intermediate step without necessarily passing through all the above steps. It is also possible to use it in the state of a mixture containing the compound.
  • the compound of the chemical formula (1) in the xanthine oxidase inhibitor of the present invention is extremely stable against heat. That is, it was confirmed that even when an aqueous solution in which the compound of the chemical formula (1) was dissolved was heated at a temperature of 90 ° C., for example, the properties of the components did not change and the composition was extremely stable against heat. However, when long-term storage is required, it is preferable to store the compound of the chemical formula (1) alone, foods and raw materials containing the compound alone in a cool and dark place.
  • the xanthine oxidase inhibitory action of the compound of the chemical formula (1) and the extract containing the compound obtained as described above can be evaluated as follows. That is, a sample solution having a constant concentration was added to a phosphate buffer solution in which xanthine was dissolved, preincubated for 15 minutes at 37 ° C., and a predetermined amount thereof was taken and added to a phosphate buffer solution in which xanthine oxidase was dissolved.
  • the inhibitory effect can be quantitatively estimated from the ratio of the change in xanthine concentration due to the addition of the sample solution containing the xanthine oxidase inhibitor to the change in xanthine concentration when the sample solution is not added. Is possible.
  • the inhibitory effect of the compound of the chemical formula (1) thus determined was confirmed to increase in action in a dose-dependent manner, and showed an action equivalent to or higher than that of the comparative allopurinol in the state of the crude extract. became. Details will be described in an embodiment described later.
  • the compound of the chemical formula (1) is characterized in that it is absorbed into the body very efficiently in the process of being orally administered and reaches the digestive tract, and exhibits high bioavailability in the flow of the systemic circulation. is there.
  • the compound of formula (1) may undergo chemical changes due to the action of various enzymes during the absorption process, but after oral administration, approximately 70 to 80% or more of the whole is not subject to chemical changes. It rides in the systemic circulation as it is, acts on xanthine oxidase existing on the surface of endothelial cells of blood vessels and various organs in the body, and effectively inhibits this to lower the excessive uric acid concentration in the body.
  • the effect is moderately moderated.
  • the uric acid concentration in the blood is significantly lower than the normal range.
  • a xanthine oxidase inhibitor containing the compound of formula (1) when administered, the effect is not excessively expressed and the blood uric acid concentration is avoided to fall below the normal range. it can. It is known that uric acid exhibits a remarkable reducing action in the body and prevents various damages caused by active oxygen in the body by maintaining the blood concentration within an appropriate concentration range.
  • a drug that exhibits a strong uric acid level-lowering action such as allopurinol, particularly when the blood uric acid level is in the normal range.
  • the xanthine oxidase inhibitor of the present invention since its pharmacological action is limited, it does not cause blood uric acid levels below normal values in normal use, so it can be used safely. it can.
  • the compound of the chemical formula (1) can be efficiently extracted from the above-ground part of chamomile using a relatively simple method as described above. It has been clarified by the present inventors for the first time that it exhibits an oxidase inhibitory action.
  • As an object of the present invention it is possible to efficiently extract an active ingredient from familiar plants well known to be safe, and to find a xanthine oxidase inhibitor excellent in effect and a method for producing the same. From this point of view, chamomile is a very familiar plant and can be easily cultivated.
  • the novel xanthine oxidase represented by the structure of the compound of the chemical formula (1) clarified in the present invention It becomes clear that an inhibitor can be efficiently extracted from the above-ground portion of chamomile by a simple method, and it can be said that the utility value of the present invention is high in that resources that have not been used can be effectively used.
  • the above-described extract of chamomile obtained from the present invention is used as a xanthine oxidase inhibitor for humans, it is preferably used by oral administration, and the dose is generally one. It is preferably used in an amount of 0.01 to 50 mg / kg of body weight per day, preferably once or several times a day. When an amount below this range is used, the target xanthine oxidase inhibitory effect of the present invention may not be observed. In addition, when an amount exceeding the above range is used, the bioavailability may decrease due to an increase in the ratio of excretion without being absorbed into the body.
  • the extract using the above-ground portion of chamomile obtained in the present invention can be used as a medicine containing this as a xanthine oxidase inhibitor.
  • the dosage form can be used as a solid agent such as a tablet, granule, powder or capsule, or as a liquid agent such as a solution, suspension, emulsion, syrup or spray.
  • pharmaceutical carriers that can be used in the preparation include glucose, sucrose, lactose, starch, mannitol, dextrin, gelatin, collagen, hyaluronic acid, albumin, polyethylene glycol, amino acid, water, and physiological saline. I can do it.
  • the extract using the above-ground portion of chamomile obtained in the present invention can be used as a food containing this as a xanthine oxidase inhibitor.
  • the food form can be used as an additive in various foods usually eaten.
  • it when used as a food in the form of a beverage, it can be used by adding in the range of 0.01 mg to 100 mg per liter to various beverages that are normally distributed.
  • drinking it is possible to heat and drink, but preferably it is stored at a temperature of room temperature or lower and supplied for drinking.
  • it can be added to milk, carbonated drinks, semi-solid foods such as yogurt, and the like, and can be provided as a beverage having a preventive effect on hyperuricemia.
  • the food containing the xanthine oxidase inhibitor obtained in the present invention is particularly preferably used as a beverage.
  • the xanthine oxidase inhibitor in the body in a preferable amount range, it is possible to suppress the production of uric acid due to the metabolism of purine to an appropriate range and prevent the development of hyperuricemia.
  • Hyperuricemia is characteristically observed in adult males, and in addition, the uric acid level is often high in the layer that prefers alcoholic beverages, more than 20% of adult men, especially more than 30% of men in their 30s and 40s Has been reported to show hyperuricemia.
  • hyperuricemia If hyperuricemia is left unattended, there is a high possibility of a gout attack, and the number of gout patients exceeds 1 million per year as of 2016. Furthermore, it is said that there are 10 million hyperuricemia patients nationwide as a gout reserve army, and as guidelines for life as an improvement measure against this, restrictions on purine intake and alcohol intake are guidelines. Are listed. However, at present, there are limits to the effects of these intake restrictions, and there is no effective method for lowering uric acid levels other than medical intervention, so it is difficult to respond positively until a doctor diagnoses hyperuricemia. There is a problem.
  • a beverage obtained by adding the compound of the formula (1) according to the present invention to an alcoholic beverage has an effect of lowering the uric acid level in the blood. It is preferably used as a means for preventing the disease. Furthermore, as mentioned above, by inhibiting the action of xanthine oxidase, it suppresses not only uric acid but also the generation of active oxygen, thereby suppressing and preventing various disorders due to the effect of active oxygen in various organs in the body. It is possible.
  • the crude extract was further subjected to a gel separation operation using a polystyrene gel for adsorption (DIAION (registered trademark) HP-20 manufactured by Mitsubishi Chemical Corporation) ( ⁇ 45 mm ⁇ 270 mm), and the eluent was first eluted with water. Subsequently, elution was performed with a mixed solvent of water-methanol (1: 1) (volume ratio), and finally elution was performed with methanol alone. Among these, it was confirmed that the component of the chemical formula (1) was selectively contained in the fraction eluted with a water-methanol (1: 1) mixed solvent.
  • DIAION polystyrene gel for adsorption
  • FIG. 1 represents a flow scheme for extracting the component of the chemical formula (1) from the above-ground stem portion and leaf portion of chamomile.
  • FIG. 2 shows a production flow chart of a xanthine oxidase inhibitor.
  • the xanthine oxidase inhibitor of this invention performs the extraction process by the methanol with respect to the above-ground part of chamomile first (step S01).
  • a separation and purification process is performed on the extract extracted in step 01 with a mixed solvent of chloroform, methanol, and water (step S02).
  • a separation and purification process is performed on the hydrophilic layer separated into the organic layer and the hydrophilic layer (methanol-water layer) in step S02 (step S03).
  • step S04 After performing the gel separation and purification process for the aqueous layer (step S04), the elution process such as elution with water first, elution with water and methanol, and elution with methanol again is performed (step S05). Then, a separation and purification step is performed on the fraction eluted with water and methanol by the gel filtration carrier (step S06), and a concentration step for concentrating and crystallizing the eluted fraction is performed (step S07). Crystallization proceeds by transpiration, and the compound of the chemical formula (1) is produced as a crystalline product of the active compound having the intended effect of inhibiting xanthine oxidase (step S08).
  • FIG. 3 represents a positive ion mode mass spectrometry chart of the sodium salt of the compound represented by the chemical formula (1).
  • FIG. 4 shows a negative ion mode mass spectrometry chart of the compound represented by the chemical formula (1).
  • FIG. 5 shows a 1 H-NMR chart of the compound represented by the chemical formula (1).
  • FIG. 6 shows a 13 C-NMR chart of the compound represented by the chemical formula (1).
  • FIG. 7 shows an FT-IR chart of the compound represented by the chemical formula (1). From the above results, in this example, the compound having the structure represented by the chemical formula (1) can be obtained in high yield as a high-purity compound in the form of crystals from the ground stem part and leaf part excluding the flower part of chamomile. done.
  • xanthine oxidase inhibitory activity of crude extract In the extraction step described above, xanthine oxidase was obtained by using the following method using a part of 22.0 grams of a water-soluble crude extract (MR) separated by a mixed solvent of butanol-water (1: 1) (volume ratio). Inhibitory activity was evaluated.
  • the crude extract used contained 2.3% by mass of the component of the chemical formula (1), further contained 9.5% by mass of Z-form, and other components contained saccharides and amino acids. It was.
  • a commercially available xanthine oxidase was dissolved in a 0.1 molar phosphate buffer (pH 7.8) to prepare a xanthine oxidase buffer (3.2 kg units / mL).
  • a xanthine phosphate buffer (65.7 ⁇ M) in which xanthine was similarly dissolved in phosphate buffer was prepared.
  • allopurinol which is a commercially available xanthine oxidase inhibitor was dissolved in a phosphate buffer to prepare an allopurinol buffer (11.9 ⁇ M).
  • the compound of the chemical formula (1) showed a result of 15% as an inhibition rate, and allopurinol was 55%. From this result, it was revealed that the compound of the chemical formula (1) obtained by the method for producing a xanthine oxidase inhibitor of the present invention exhibits extremely remarkable xanthine oxidase inhibitory activity.
  • a tablet was produced as follows. That is, 23% by mass of the compound of the chemical formula (1), lactose 60%, corn starch 15%, guar gum 1% and magnesium stearate 1% were uniformly mixed to produce tablets according to a conventional method.
  • Alcohol beverage containing xanthine oxidase inhibitor according to the present invention by adding 10 mg of the compound of chemical formula (1) obtained in Example 1 to 100 mL of commercially available sake (Laurel Wreath (registered trademark) “Sugar Zero”) was made. No influence on the taste, fragrance, flavor, etc. due to the addition of the compound of the chemical formula (1) was observed, and no adverse effect on the quality of sake was found.
  • Example 1 the components extracted from fresh above-ground portions of chamomile (Matricaria chamomilla L.) using methanol were mixed with an organic layer (chloroform using a mixed solvent of chloroform-methanol-water (4: 2: 3) (volume ratio). -Methanol layer) and a hydrophilic layer, and the hydrophilic layer is further purified with a mixed solvent of butanol-water (1: 1) to obtain a polystyrene gel for adsorption (DIAION (registered trademark) HP-20 manufactured by Mitsubishi Chemical). Gel separation operation using ( ⁇ 45 mm ⁇ 270 mm) was performed to obtain 2.7 g of component CPPG eluted with a water-methanol (1: 1) (volume ratio) mixed solvent. The following tests were performed using this.
  • DIAION registered trademark
  • FIG. 8 shows a 1 H-NMR spectrum chart of the extracted component CPPG used in this example.
  • the compound of the chemical formula (1) has a concentration of about 16% by mass in CPPG.
  • FIG. 9 shows the results of HPLC analysis of samples collected from mice before oral administration under the above conditions.
  • FIG. 9 shows a chart when a sample collected from a mouse before CPPG is orally administered is analyzed by HPLC.
  • FIG. 10 shows a chart when a sample collected from mice after oral administration (60 mg administration group, 60 minutes after administration) is analyzed by HPLC. From this chart, CPPG-derived components contained in mouse blood after oral administration of CPPG mainly have three peaks that appear at elution times of 3.4 minutes, 4.7 minutes, and 5.9 minutes. The component of was not recognized.
  • the peak component with an elution time of 4.7 minutes is contained in a ratio of 70 to 80% with respect to all the three components, and this is not metabolized and is transferred into the blood with the compound of the formula (1)
  • Identification of the retention time given by the crystal obtained in Example 1 and the FAB-MS in both pos- and neg- ⁇ ⁇ ⁇ modes are both Z-forms (hereinafter, the component including both is referred to as CA). (Molecular weight 356), but the other two peak components were small compared to the CA component in blood, and structural analysis was difficult.
  • FIG. 11 shows the results of quantifying the concentration of components derived from CPPG contained in blood from the HPLC chart obtained as described above, and plotting the blood concentration of CA after administration against time.
  • FIG. 11 shows the time change of the blood concentration of CA transferred to the blood after oral administration.
  • Example 1 Comparative evaluation on the xanthine oxidase inhibitory action of Z form on the compound of chemical formula (1)
  • a separation and purification process was performed on the fraction eluted with water and methanol using the carrier for gel filtration (step S06), and a concentration process for concentrating and crystallizing the eluted fraction was performed (step S07). Crystallization progressed to obtain a compound of the chemical formula (1).
  • a solution (comparative example) containing mainly Z form from the supernatant excluding crystals and substantially free of the compound of chemical formula (1) was obtained. Produced.
  • As a result of evaluating the inhibition rate of xanthine oxidase in the same manner as in Example 1 for the produced comparative example it was 0%, and no inhibitory effect was observed.
  • the xanthine oxidase inhibitor of the present invention can be used as pharmaceuticals, foods (including various beverages such as carbonated drinks and alcoholic drinks), supplements and the like for the purpose of preventing or treating hyperuricemia. Furthermore, it can be used as a health food for preventing excessive active oxygen generation in various organs in the body and preventing symptoms such as hypertension, diabetes and obesity.

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Abstract

L'invention concerne un inhibiteur de xanthine oxydase qui est sûr et possède un excellent effet, ainsi qu'un procédé de production de cet inhibiteur de xanthine oxydase. Un nouvel inhibiteur de xanthine oxydase peut être produit par extraction à partir de pousses de camomille (Matricaria recutita). En utilisant la camomille, plante familière connue comme étant sans danger et dont les fleurs sont utilisées comme herbe aromatique, il est possible de produire un inhibiteur de xanthine oxydase qui est sans danger et possède un excellent effet. Le procédé de production d'un inhibiteur de xanthine oxydase consiste à soumettre les pousses de camomille à une extraction à l'aide d'eau, d'un solvant organique hydrophile ou d'un solvant mixte de celui-ci, afin de produire un extrait, et à séparer une couche aqueuse à partir de l'extrait extrait. La couche aqueuse séparée est éluée avec un mélange de solvants composé d'eau et du solvant organique hydrophile. Le composant principal présent dans une fraction d'élution est concentré et cristallisé pour produire l'inhibiteur de xanthine oxydase.
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WO2022075185A1 (fr) 2020-10-05 2022-04-14 花王株式会社 Procédé de production d'une composition d'extrait
CN115236018A (zh) * 2022-06-30 2022-10-25 铜仁学院 功能性茶加工工艺及叶水提物对xod活性抑制研究方法
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JP2021014415A (ja) * 2019-07-10 2021-02-12 味の素株式会社 尿酸値低減作用を有する組成物の製造方法
WO2022075185A1 (fr) 2020-10-05 2022-04-14 花王株式会社 Procédé de production d'une composition d'extrait
CN115236018A (zh) * 2022-06-30 2022-10-25 铜仁学院 功能性茶加工工艺及叶水提物对xod活性抑制研究方法
JP2025115575A (ja) * 2024-01-26 2025-08-07 株式会社Sbs セロトニン合成促進用経口組成物及び機能性食品又はサプリメント
JP7747356B2 (ja) 2024-01-26 2025-10-01 株式会社Sbs Ｔｐｈ２遺伝子発現促進用組成物

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