WO2002069952A1 - Agents anti-inflammatoires contenant de nouveaux composes ou leurs derives - Google Patents

Agents anti-inflammatoires contenant de nouveaux composes ou leurs derives Download PDF

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Publication number
WO2002069952A1
WO2002069952A1 PCT/JP2002/001823 JP0201823W WO02069952A1 WO 2002069952 A1 WO2002069952 A1 WO 2002069952A1 JP 0201823 W JP0201823 W JP 0201823W WO 02069952 A1 WO02069952 A1 WO 02069952A1
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group
hydroxyl group
compound represented
general formula
optionally
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PCT/JP2002/001823
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English (en)
Japanese (ja)
Inventor
Ikuko Kimura
Masayuki Yoshikawa
Shinjiro Kobayashi
Hisashi Matsuda
Yoshitaka Sugihara
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M's Science Corporation
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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
    • C07C35/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings
    • C07C35/36—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system being a (4.4.0) system, e.g. naphols

Definitions

  • the present invention relates to balsamodendron mukul or komi phora mukul (hereinafter referred to as guggule). ] Pharmaceuticals, especially anti-inflammatory agents, containing these compounds (milhanol A or milhanone A) extracted from a rubber resin obtained from the above, or derivatives of these compounds having these compounds as a basic structure, and these compounds and derivatives thereof It relates to the manufacturing method of the. Background art
  • Gagul rubber resin is directly mixed with powder or extract of other whole crude drugs to produce antiobesity and antibacterial agents. It is used as an anticoagulant and an atherosclerotic agent.
  • the whole herbal medicines of Gagul and Milha are called Balsamodendron (or Comadora), mukul Hook. And Balsamodendron (or Comifora), respectively.
  • Commiphora Myrrha Nees is a natural rubber resin secreted from the genus Bursera (or Commiphora) of the family Burseraceae (or Kanran). Gagul produces milky white sap of these trees (15-20 years old) by drying for one year.
  • Gadarsterone a compound isolated from Gagol, activates lipolytic enzymes, inhibits cholesterol biosynthesis in the liver, and reduces levels of total serum lipids and total cholesterol.
  • Milha was used to embalm corpses. Used by the Egyptians and by the Jews as holy oil.
  • Furanoeudesma a sesquiterpene component isolated from Mill Eight
  • Balsamodendron Mukuru or Comifora * Mukuru is a plant belonging to the family Orchidaceae native to India, and is a small tree or shrub with a height of about 1.2 to 1.8 m. If a cut is made in the stem of this plant, rubbery resin can be collected.
  • the lipophilic extract obtained from such a resin, especially the steroid fraction obtained from the extract, especially the ketosteroids named gagulsterone should be a pharmaceutical composition having anti-inflammatory, immunomodulatory and anti-androgenic activities. (Japanese Unexamined Patent Publication No. Hei 5-178755). However, in this case, a lipophilic component is only extracted by using ethyl acetate or the like as a solvent, and a compound having a pharmacological action such as an anti-inflammatory action is isolated by further purification. Not.
  • the present invention provides higher anti-inflammatory properties than whole crude drugs that have been conventionally used as folk medicines, specifically, compared to lipophilic components extracted from rubbery resins of Milwaga and Gaguru.
  • An object of the present invention is to provide a compound having a symptomatic effect and a medicine containing the compound, particularly an anti-inflammatory agent.
  • the present inventors have conducted various studies to achieve the above object, and found a triterpene component containing a novel compound from an extract obtained by extracting a resin of balsamodendron-mukuru or Comifora-mukul with methanol, and the component was a mouse.
  • a triterpene component containing a novel compound from an extract obtained by extracting a resin of balsamodendron-mukuru or Comifora-mukul with methanol, and the component was a mouse.
  • the compounds of the present invention may also exhibit a greater anti-inflammatory effect than a mere 50% by volume aqueous methanol extract of hydrocortinzone or gagul, which is conventionally known as a compound having an anti-inflammatory effect. I learned.
  • one of X and Y represents a hydrogen atom and the other represents a hydroxyl group which may be protected, or X and Y may be taken together to form a carbonyl group which may be protected.
  • Z represents an optionally protected hydroxyl group
  • R represents CHsR 1 (R 1 represents an optionally protected hydroxyl group) or an optionally protected carboxyl group
  • R 11 , R 12 , R 13 , R 14 , R 15 , R 16 may be the same or different
  • n represents an integer of 0 to 4.
  • R ' may be CH 2 R 2 (R 2 represents a hydroxyl group which may be etherified or esterified), C ⁇ OH, COOM 1 (M 1 represents an alkali metal or a quaternary ammonium) , COOM 5 (M 2 represents an alkaline earth metal) or COOR 3 (R 3 represents an optionally substituted alkyl group having 1 to 6 carbon atoms),
  • an anti-inflammatory agent comprising a compound represented by the general formula (II),
  • an anti-inflammatory agent comprising a compound represented by the general formula (III),
  • a X and a Y each represent a hydrogen atom, the other represents an optionally protected hydroxyl group, Z represents an optionally protected hydroxyl group, and R represents CHsR 1 (R 1 represents a protected group) Or a carboxyl group which may be protected, wherein R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are the same or different and may be substituted
  • R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are the same or different and may be substituted
  • aX 'and aY' each represent a hydrogen atom and the other represents a hydroxyl group which may be etherified or esterified, and R 'is CH 2 R 2 (R 2 is etherified or esterified. are also representative of the hydroxy group optionally have), COOH, COOM 1 (M 1 represents Al force Li metal or a quaternary Anmoniumu), COOM 2 0. 5 ( M 2 represents an alkaline earth metal) or COOR 3 ( R 3 represents an optionally substituted alkyl group having 1 to 6 carbon atoms),
  • Balsamondendron mukul or Commiphora mukul resin is extracted with an organic solvent, and the extract is subjected to at least one purification step.
  • (i) a reaction of introducing a protecting group into a carbonyl group (ii) a reaction of converting a carbonyl group to a salt, and (g) a reduction reaction of a double bond.
  • one of X and Y represents a hydrogen atom and the other represents a hydroxyl group which may be protected, or X and Y may be combined together to form an optionally protected hydroxyl group.
  • Z represents an optionally protected hydroxyl group
  • R represents CH ⁇ R 1 (R 1 represents an optionally protected hydroxyl group) or an optionally protected hydroxyl group
  • R 11 R 12 , R 13 , R 14 , R 15 , and R 16 are the same or different and each represent an optionally substituted alkyl group having 1 to 6 carbon atoms (when n is an integer of 2 to 4) the even R 15 are each isoprene unit identical or different.)
  • n represents an integer of 0 to 4. ].
  • FIG. 1 is a diagram showing the correlation of the compound of the present invention, Milhanol A, in the H—HCO S Y spectrum, the HMB C spectrum, and the phase detection NO E S Y spectrum.
  • FIG. 2 is a diagram for explaining the process of determining the absolute structure of the compound of the present invention, Milhanol A, by applying the improved Mosher method.
  • FIG. 3 is a diagram comparing the anti-inflammatory effects of the compounds of the present invention, milhanol A (filled circles) and milhanone A (filled triangles), with those of hydrocortisone (open circles).
  • FIG. 4 is a diagram comparing the anti-inflammatory effect of a 50% by volume aqueous methanol extract of a compound of the present invention, Milhanol 8, Gagol rubber resin, with that of Hidmouth cortisone.
  • FIG. 5 is a graph showing the anti-inflammatory effect of an extract of gagoul rubber resin extracted with 50% by volume aqueous methanol (solid circles) and 100% by volume methanol (solid triangles).
  • FIG. 6 is a graph showing the inflammatory action of the Millha rubber resin extract extracted with 50% by volume aqueous methanol (solid circles) and 100% by volume methanol (solid triangles).
  • the present invention provides a drug, preferably an anti-inflammatory agent, containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof.
  • one of X and Y represents a hydrogen atom and the other represents a hydroxyl group which may be protected, or X and Y may be taken together to form an optionally protected hydroxyl group.
  • ⁇ represents an optionally protected hydroxyl group
  • R represents CHsR 1 (R 1 represents an optionally protected hydroxyl group) or an optionally protected hydroxyl group
  • R 11 R 12 , R 13 , R 14 , R 15 and R 16 are the same or different and each represents an optionally substituted alkyl group having 1 to 6 carbon atoms (when n is an integer of 2 to 4, isoprene R 15 may be the same or different for each unit.)
  • n represents an integer of 0 to 4.
  • examples of the hydroxyl-protecting group include lower alkyl groups (preferably having 1 to 6 carbon atoms) such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a tert-butyl group;
  • lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group (preferably having 3 to 9 carbon atoms); lower alkoxymethyl groups such as methoxymethyl group and 2-methoxyethoxymethyl group (preferably having 2 carbon atoms) 6); for example, a tetrahydropyranyl group; for example, a trimethylsilylethoxymethyl group; for example, a benzyl group, a p-methoxybenzyl group, a 2,3-dimethoxybenzyl group, an o-nitrobenzoyl group, and a ⁇ -nitro group Aralkyl groups such as a methyl group, an ethy
  • examples of the protecting group for the carbonyl group include acetal such as ethylene ketal, trimethylene ketal and dimethyl ketal, and ketal.
  • examples of the protective group for the carbonyl group include lower alkyl groups (preferably having 1 to 6 carbon atoms) such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group.
  • a lower haloalkyl group such as a 2,2,2-trichloroethyl group; a lower alkenyl group (preferably having 2 to 6 carbon atoms) such as a 2-propenyl group; And aralkyl groups (preferably having 7 to 12 carbon atoms) such as benzyl group, P-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group and trityl group.
  • lower alkyl groups such as propyl group, isopropyl group and tert-butyl group.
  • the alkyl group having 1 to 6 carbon atoms may be linear or branched, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Examples include an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a tert-pentyl group or a hexyl group.
  • Examples of the substituent for the alkyl group having 1 to 6 carbon atoms include, but are not limited to, (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine), and (ii) an alkylenedioxy group (eg, methylenedioxy). , Echirenjiokishi etc.) (preferably 1 to 3 carbon atoms), (iii) nitro group, (iv) Shiano group, (v) a halogen atom, Ji Bok 3 Alkylenedioxy, nitro, cyano, optionally halogenated — a cycloalkyl group (preferably having 3 to 6 carbon atoms) which may be substituted by 6 alkyl or the like;
  • an amino group which may be substituted for example, an amino group which may be substituted with a monovalent or divalent substituent of an amino group known per se such as a dimethylamino group
  • a X and a Y each represent a hydrogen atom, the other represents an optionally protected hydroxyl group, Z represents an optionally protected hydroxyl group, and R represents CHsR 1 (R 1 represents a protected group) Represents an optionally protected hydroxyl group.
  • R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are the same or different and are substituted
  • Examples of the salt of the compound represented by formula (I) or (aI) include compounds in which a carboxyl group forms a salt. More specifically, examples of the salt of the carboxyl group include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; for example, trimethylamine salt, triethylamine salt, and the like.
  • Organic salts such as dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, proforce salt, and N, N'-dibenzylethylenediamine salt, among which sodium salt and potassium Preferred are alkali metal salts such as salts; alkaline earth metal salts such as potassium and magnesium salts; and ammonium salts.
  • a preferred embodiment of the compound represented by the above-mentioned compound (I) or a salt thereof includes a compound represented by the following general formula ( ⁇ ).
  • R may be CH 2 R 2 (R 2 represents a hydroxyl group which may be etherified or esterified), COOH, COOM 1 (M 1 represents an alkali metal or quaternary ammonium), COOM 2 0.5 a (M 2 represents an alkaline earth metal) or COOR 3 (R 3 is optionally substituted carbon atoms may have an alkyl group having from 1 to 6 Represents), represents
  • examples of the alkali metal include sodium, potassium, and lithium, and examples of the alkaline earth metal include calcium and magnesium.
  • the etherified hydroxyl group is, for example, a lower alkyl group (preferably having 1 to 6 carbon atoms) such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a tert-butyl group.
  • a protected hydroxyl group refers to a protected hydroxyl group.
  • the esterified hydroxyl group means a hydroxyl group protected by a lower alkoxymethyl group (preferably having 2 to 6 carbon atoms) such as a methoxymethyl group and a 2-methoxyethoxymethyl group.
  • the compound represented by the following general formula (aI ′) is a novel compound.
  • aX 'and aY' each represent a hydrogen atom and the other represents a hydroxyl group which may be etherified or esterified, and R 'is CH 2 R 2 (R 2 is etherified or esterified. Represents an optionally substituted hydroxyl group), COOH, COOM 1 (M 1 Alkali metal or an quaternary Anmoniumu), COOM 2 0 is. 5 (M 2 represents an alkaline earth metal) or C_ ⁇ _ ⁇ _R 3 (R 3 is an alkyl carbon atoms optionally substituted 1 to 6 Represents a group),
  • more preferable embodiments of the compound represented by the above compound (I) include compounds represented by the following formulas (II) and (III). Among them, the compound represented by the formula (II) is a novel compound.
  • the resin of Balsamondendron 'Mukuru (Balsamondendron mukul) or Comifora' Mukuru (Cosole iphora mukul) is extracted with an organic solvent (preferably methanol), and the extract is subjected to at least one purification step.
  • an organic solvent preferably methanol
  • the compounds represented by the above formulas (II) and (III) can be isolated. So followsed by (a) alkyl chain extension reaction of a methyl group, (b) chain shortening or chain extension reaction of an isoprene chain with the compounds represented by the formulas ( ⁇ ) and (III) obtained as desired.
  • a reaction for introducing a protecting group into a hydroxyl group for example, etherification or esterification of a hydroxyl group, or a reaction for introducing a protecting group into a hydroxyl group, for example, acetalization of a carbonyl group.
  • a reaction to introduce a protecting group into a group a reaction to oxidize a hydroxymethyl group to convert it to a carboxyl group, a reaction to introduce a protecting group into a carboxyl group by, for example,
  • the reaction for converting to a salt with a metal, an alkaline earth metal or an amine has been well established in the chemical and pharmaceutical fields, and therefore, in the present invention, these known reaction means may be used.
  • a methyl group is subjected to an alkyl chain extension reaction to convert the methyl group into another alkyl group (preferably having a carbon number of
  • the isoprene chain comprising a plurality of isoprene units may be shortened or extended.
  • all or a part of the double bond may be subjected to a reduction reaction to be converted to a single bond.
  • reduction Means are well-established in the past, for example, catalytic reduction, and may be in accordance with the known means in the present invention.
  • a methyl group or an alkyl group obtained by subjecting the methyl group to an alkyl chain extension reaction may be added to a compound according to a method known per se, for example, a halogen atom Substituents commonly used in the pharmaceutical field such as (eg, fluorine, chlorine, bromine, iodine) may be introduced.
  • Balsamondendron mukul or Commiphora mukul Hook Used in the present invention is a small tree of the family Orchidaceae, as described above, and originates from the Indian Peninsula and Bengal.
  • the resin of pulsamodendron 'Mukuru (Balsamondendron mukul) or Commiphora mukul (Commiphora mukul) used in the present invention is usually collected by damaging the tree trunk.
  • the resin is a yellow rubbery exudate that quickly solidifies into stalactites. Since the resin is commercially available after being dried and ground, the commercially available resin may be used in the present invention.
  • the above resin preferably further pulverized, is extracted with an organic solvent.
  • a polar solvent, a low-polar solvent, and the like are preferable, and a polar alcohol, for example, an alcohol having 1 to 6 carbon atoms, specifically, methanol, ethanol, n-propanol, Isopropanol and the like are particularly preferred, and methanol is particularly preferred, and 50% by volume aqueous methanol is most preferred.
  • the extract contains many compounds such as lignans, terpenes, and gagosterones.
  • the extraction conditions may be in accordance with a method known per se.
  • the extraction solvent is 100% by volume methanol, it may take about 1 to 96 hours under reflux. It is preferable to carry out.
  • the extraction solvent is 50% by volume aqueous methanol, it is preferably carried out under reflux for about 2 to 150 hours.
  • Purification means include, for example, fractionation by column chromatography using silica gel or alumina, countercurrent distribution between alcohols and aliphatic hydrocarbons, or selective reagents for the isolation of keto compounds, Girard Examples include treatment using a reagent.
  • purification may be performed by a series of fractional distillation by high performance liquid chromatography. Specifically, the above extract was further partitioned with a mixed solvent of ethyl acetate-water, and the ethyl acetate-soluble component was subjected to normal-phase and reverse-phase silica gel column chromatography. A purification step of subjecting to HPLC) is preferred. In this way, the compounds represented by the above formulas (II) and (III) can be obtained.
  • such an embodiment is a preferred embodiment of the present invention, and the extraction / purification step is not limited to this.
  • the medicament according to the present invention contains the above compound obtained as described above or a pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable salts include, for example, inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.), organic acids (eg, carbonic acid, bicarbonate, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.), Inorganic bases (eg, alkali metal such as sodium or magnesium, alkaline earth metals such as calcium or magnesium) and organic base compounds (eg, organic amines such as triethylamine, basic amino acids such as arginine) )).
  • inorganic acids eg, hydrochloric acid, sulfuric acid, nitric acid, etc.
  • organic acids eg, carbonic acid, bicarbonate, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.
  • Inorganic bases eg, alkali metal such as sodium or
  • the compound represented by the formula (1), (a1), ( ⁇ ) or (al ′) has an asymmetric carbon, two optical isomers are generated for each asymmetric carbon. Can exist. Therefore, the medicament in the present invention may contain only one of the optical isomers, or may contain a racemic or diastereomer.
  • the compounds of the present invention may be used in adjuvant-induced air pouch granuloma Shows an anti-inflammatory effect. Therefore, the medicament of the present invention containing the compound can be suitably used particularly as an anti-inflammatory agent by utilizing this effect.
  • Inflammatory diseases that can be applied in this case include, but are not limited to, skin diseases (for example, inflammation due to various causes such as atopic dermatitis, psoriasis, or erythema caused by ultraviolet irradiation or radiation therapy).
  • the above compound or a pharmacologically acceptable salt thereof may be directly administered as a medicament according to the present invention.
  • the content of the compound of the present invention in the medicament according to the present invention is about 0.001 to 1% by weight, preferably about 0.01 to 0.1% by weight.
  • Such a pharmaceutical composition can be produced according to a method known or used per se in the field of pharmaceuticals.
  • liquid preparations suitable for oral administration for example, sugars such as water, sucrose, sorbitol, fructose; dalicols such as polyethylene glycol and propylene glycol; oils such as sesame oil, olive oil and soybean oil; Pharmaceutical additives such as preservatives such as hydroxybenzoates can be used.
  • preparations such as capsules, tablets, powders or granules
  • excipients such as lactose, glucose, sucrose and mannitol
  • disintegrants such as starch and sodium alginate
  • magnesium stearate And talc binders such as polyvinyl alcohol, hydroxypropylcellulose and gelatin
  • surfactants such as fatty acid esters
  • plasticizers such as glycerin.
  • preparations suitable for parenteral administration preparations for intravascular administration such as injections and drops can be prepared preferably using an aqueous medium isotonic with a body fluid.
  • the injection can be prepared as a solution, suspension or dispersion using an aqueous medium selected from a salt solution, a glucose solution or a mixture of a salt solution and a glucose solution together with a suitable auxiliary according to a conventional method. it can.
  • eye drops can be prepared using a water-soluble solvent such as sterilized purified water or physiological saline, or a water-insoluble solvent such as vegetable oil.
  • a water-soluble solvent such as sterilized purified water or physiological saline
  • a water-insoluble solvent such as vegetable oil
  • Suppositories for enteral administration can be prepared using carriers such as, for example, cocoa butter, hydrogenated fats or hydrogenated rugonic acid.
  • Sprays can be prepared using a carrier which does not irritate the oral and respiratory tract mucosa and which can promote absorption by dispersing the compound of the present invention as an active ingredient as fine particles.
  • a carrier for example, lactose or dalyserin can be used.
  • it can be prepared as a preparation in the form of aerosol / dry powder.
  • parenteral preparations for example, one or more selected from diluents, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. Can be used.
  • the medicament according to the present invention can also be made into an ointment by mixing the above compound with a suitable base material.
  • a suitable base material examples include oil-based bases such as petrolatum, liquid paraffin, silicon, and vegetable oil; bases such as hydrophilic base and emulsion bases such as purified lanolin; and water-soluble bases such as macrogol.
  • the ointment may contain an emulsifier such as an anionic or nonionic surfactant and a preservative such as paraoxybenzoate.
  • the medicament according to the present invention may be, for example, transdermal such as patches, cataplasms, creams, plasters, tapes, lotions, solutions, suspensions, emulsions, and sprays. It can also be a preparation for administration.
  • transdermal such as patches, cataplasms, creams, plasters, tapes, lotions, solutions, suspensions, emulsions, and sprays. It can also be a preparation for administration.
  • the form of the medicament of the present invention and the method for producing the same are not limited to those specifically described above.
  • the administration route, dose and frequency of administration of the medicament according to the present invention are not particularly limited, and are appropriately determined according to various conditions such as the type of the disease to be treated, the age and weight of the patient, and the severity of the symptoms and diseases. It is possible to choose. More specifically, the therapeutic dose as an anti-inflammatory agent is about 1 to 100 Omg / day, preferably about 10 to about 15 OmgZ days for oral administration.
  • the therapeutic dose as an anti-inflammatory agent is about 1 to 100 Omg / day, preferably about 10 to about 15 OmgZ days for oral administration.
  • the compound represented by the formula (II) may be referred to as "Milhanol A” and the compound represented by the formula (III) may be referred to as "Milhanone A”.
  • Miruhanoru A is positive optical rotation [shed] White showing D 2 7 + 12. 2 ° a (MeOH) Obtained as the color powder, and this revealed a compound having a fast atom bombardment-mass spectrometry (FAB- MS) and high resolution FAB- MS molecular formula C 3Q H 52 0 3 from.
  • FAB- MS fast atom bombardment-mass spectrometry
  • IR infrared absorption
  • Milhanol A Revealed the relative stereostructure of Milhanol A. Furthermore, the absolute structure of Milhanol A was determined by applying the modified Mo sher method. That is, as shown in FIG. 2, in the 1 H-NMR spectrum of the 3- (S) -MTPA ester form of miruhanol A (lb in FIG. 2), the signals of the 1, 2, and 25-position hydrogens are 3- (R) It was observed on the high magnetic field side compared to that of one MTPA ester (la in Fig. 2) ( ⁇ : one). On the other hand, in the 1 H-NMR spectrum of the 3_ (S) - ⁇ ester (1b in Fig. 2), 23 and 24 The signal of the hydrogen atom was observed on the lower magnetic field side than that of the 3- (R) -MTPA ester (la in Fig. 2) ( ⁇ : tens).
  • the absolute tertiary structure of miruhanol ⁇ is (3S, 5S, 8R, 9R, 10S)-3, 8, 30-trihydroxypolypoder 13E, 17E, 21E— Trien was determined to be.
  • Milhanone A was obtained as a white powder exhibiting positive optical rotation [H] D 28 + l1.9 ° (Me OH), and was found to have hydroxyl groups (3453, 1080 cm- x and liponyl groups (1650 cm)) in the IR spectrum. 1 ), and FAB-MS and high-resolution FAB-MS revealed that the compounds had the molecular formulas C 3, H 5, and ⁇ 3. — and 13 C—NMR (No. mill in table 1) spectrum, 3-position Miruhanoru a (compound (II) with the exception of the signal near) was very similar to signaling Internacional.
  • Hydrocortisone acetate was purchased from Nakarai Tesque (Kyoto, Japan). Milganol A, Milhanon A, Gagul extract with 50% by volume aqueous methanol and Milha extract with 100% by volume methanol are uniformly dissolved in physiological saline containing 1% Av ice 1 (Asahi Kasei Kogyo, Tokyo, Japan). Or suspended, FC A (Freund's complete adjuvant) was injected intraperitoneally 2 hours after injection and then once a day for 4 days once a day.
  • FC A Freund's complete adjuvant
  • mice Male ddY mice (6 weeks old, weighing 25.5-35.5 g) were purchased from Kiwa Experimental Animal Laboratory (Wakayama, Japan). Mice should be maintained at a constant temperature (25 ⁇ 1 ° C) and humidity (55 ⁇ 5%) under light conditions from 7 am to 7 pm and on a regular laboratory diet (PML, lab diet). , Japan, SLC Co., Ltd., Shizuoka, Japan).
  • Air pouch granuloma was prepared by FCA injection with 0.1% croton oil as previously reported. 0.1% Croton oil (Nacalai Tesque, Kyoto, Japan), 42.5% liquid paraffin, 7.5% incomplete Freund's adjuvant containing 7.5% mannide monooleate (Nacalai) and 50% saline, heated per mL
  • An FCA emulsion was prepared using 2 mg of the treated Mycobacterium tuberculosis (M. tuberculosis) (H37RA, Dfco, Detroid, Michigan, USA).
  • a standard oval air sac was generated by subcutaneously injecting 3 mL of air into the dorsal side of ether anesthetized mice.
  • FCA emulsion (0.5 mL) was injected into the air pouch under ether anesthesia.
  • a 10% by weight carmine solution (Merck, Darmshut, Germany) containing 5% gelatin (Nacalai 'Tesque), kept at 40 ° C, was injected into the tail vein of the mouse on the 5th day. He was killed by injection. The dead mice were cooled below 4 ° C for several hours.
  • the carmine content of the granuloma tissue was measured as follows. Granuloma tissue was minced, dissolved in 3N NaOH and oxidized with 36% HC1. After the suspension was centrifuged, the supernatant was filtered.
  • the amount of carmine in the filtrate was determined by measuring the optical density at 490 nm.
  • Granuloma tissue was excised and separated from surrounding loose connective tissue and weighed. Inflammatory cells in the capsule were counted using a hemocytometer. Granulocytes, monocytes and macrophages were included in the numbers. On the other hand, dead cells, erythrocytes and platelets stained with trypan blue were excluded. All sac fluids were collected and weighed.
  • Adjuvant induces inhibitory effect (anti-inflammatory effect) on inflammatory processes I (exudative: cystic fluid weight), II (migration: inflammatory cell count), III (angiogenic: carmine volume) and IV (granuloma formation) Air pouch granuloma was used for comparison.
  • the anti-inflammatory effect on inflammatory process I (exudative) is measured by measuring the sac weight
  • the anti-inflammatory effect on inflammatory process II (migratory) is measured by measuring the number of inflammatory cells.
  • the anti-inflammatory effect on inflammatory process IV (granuloma formation) was compared by measuring granuloma weight.
  • Milhanol A (0.6, 1.2 and 2.4 mgZkg), Milhanone A (0.6 mgZkg), crude extract of Gagool with 50% by volume aqueous methanol and crude extract of Milha with 100% by volume methanol (1 2, 6, and 30 mg / kg), and hydrocortisone (3.8, 7.6, and 15 mg Zkg) were injected intraperitoneally into mice as described above.
  • the dose-response curves of miruhanol A and milhavanone A were compared with those of hydrocortisone in all four inflammation parameters (Fig. 3).
  • test compound means miruhanol A, miruhanone A or hydrocortisone.
  • the dose-inhibition response curve of Milhanone A was poorly soluble in water and a homogeneous suspension could not be obtained, so no dose data could be obtained.
  • the 50% inhibition of Milhanol A was 2.80 [imo 1 / kg (95% confidence limit: 2.07-3.79) for carmine and 5.83 jumo 1 / kg (95 for granuloma weight).
  • % Confidence limit: 3.03 to 1 1.2) the sac weight was 1.75 / imo 1 / kg (95% confidence limit: 1.34 to 2.29).
  • the 50% inhibition of hydrocortisone is 22. lmol Zkg (95% confidence limit: 18.0-27.1) for potency and 29.2 ⁇ 1 / kg (95% for granuloma weight).
  • the relative properties of the anti-inflammatory response are plotted on a graph of the 50% aqueous methanol extract of miruhanol A, gagul rubber resin and 50% inhibition (g / kg) of hydrocortisone (Fig. 4). ).
  • Milhanol A was more potent than the 50% by volume aqueous methanol extract of gagul-rubber resin in both carmine and granuloma weight.
  • the efficacy of Milhanol A on 50% by volume aqueous methanol extract of Gaddar rubber resin was 23-fold and 34-fold, respectively.
  • 2 shows the anti-inflammatory effect in adjuvant-induced air pouch granuloma of the indicated mice. Force, granuloma weight, migrating inflammatory cell count, and exudative fluid weight For, the effect is plotted. In each graph, the mean soil standard deviation (SEM) of the relative amount% calculated from the following formula is shown against the intraperitoneal dose (g / kg).
  • SEM soil standard deviation
  • Relative amount% (value when test compound was administered / value when test compound was not administered) x 100
  • test compound is referred to as a crude extract of gagul with 50% by volume aqueous methanol and 100% by volume methanol.
  • the anti-inflammatory effect of the gagul extract by the polar solvent tended to be stronger than that by the less polar solvent, especially in the amount of carmine and the sac weight.
  • the exudate of the crude extract of Milha with a less polar solvent rather tended to enhance inflammation (Fig. 6).
  • Relative% (value when test compound is administered Z value when test compound is not administered) X 100
  • test compound is a crude extract of Mirha with 50% by volume aqueous methanol and 100% by volume methanol.
  • the compounds identified and isolated from Gagul gum resin, milhanol A and minohanone A can be potent anti-inflammatory agents.
  • Milhanol A is a nonsteroidal and hydrophilic compound, and therefore has the advantage of having fewer side effects than hydrocortisone, which has been conventionally used as an anti-inflammatory agent.

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Abstract

L'invention porte sur des composés représentés par la formule générale suivante (II) ou leurs sels et sur les agents anti-inflammatoires contenant ces composés ou leurs sels pharmaceutiquement acceptables. Ces agents anti-inflammatoires ont une action anti-inflammatoire supérieure à celle des drogues utilisées à ce jour dans des médicaments à base de plantes, notamment des composants lipophiles extraits de résines de caoutchouc, dont la myrrhe et le guggulu.
PCT/JP2002/001823 2001-03-01 2002-02-27 Agents anti-inflammatoires contenant de nouveaux composes ou leurs derives WO2002069952A1 (fr)

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WO1997010196A1 (fr) * 1995-09-13 1997-03-20 Parfums Christian Dior Produits extraits d'une plante du genre commiphora, en particulier de la plante commiphora mukul, et extraits en contenant et leurs applications notamment en cosmetique

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Publication number Priority date Publication date Assignee Title
WO1997010196A1 (fr) * 1995-09-13 1997-03-20 Parfums Christian Dior Produits extraits d'une plante du genre commiphora, en particulier de la plante commiphora mukul, et extraits en contenant et leurs applications notamment en cosmetique

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Title
DATABASE CAPLUS [online] AMERICAN CHEMICAL SOCIETY (ACS), (COLUMBUS, OH, USA); accession no. STN Database accession no. 116:190977 *
DATABASE CAPLUS [online] AMERICAN CHEMICAL SOCIETY (ACS), (COLUMBUS, OH, USA); accession no. STN Database accession no. 135:116812 *
KIMURA, I. ET AL.: "New triterpenes, myrrhanol A and myrrhanone A, from guggul-gum resins and their potent anti-inflammatory effect on adjubant-induced air-pouch granuloma of mice", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 11, no. 8, 23 April 2001 (2001-04-23), pages 985 - 989, XP002953126 *
MARNER, F.J. ET AL.: "Triterpenoids from gum mastic, the resin of Pistacia lentiscus", PHYTOCHEMISTRY, vol. 30, no. 11, 1991, pages 3709 - 3712, XP002953125 *

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