WO2013080830A1 - 冷感剤及びｔｒｐｍ８活性化剤 - Google Patents

冷感剤及びｔｒｐｍ８活性化剤 Download PDF

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WO2013080830A1
WO2013080830A1 PCT/JP2012/079979 JP2012079979W WO2013080830A1 WO 2013080830 A1 WO2013080830 A1 WO 2013080830A1 JP 2012079979 W JP2012079979 W JP 2012079979W WO 2013080830 A1 WO2013080830 A1 WO 2013080830A1
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carbon atoms
group
hydrogen atom
total
alkoxy group
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French (fr)
Japanese (ja)
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智大 白井
楠奥　比呂志
充好 逆井
堅太郎 組橋
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Kao Corp
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Kao Corp
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Priority to US14/354,260 priority Critical patent/US9340478B2/en
Priority to CN201280058568.8A priority patent/CN103958636B/zh
Priority to EP12853310.6A priority patent/EP2787051B1/en
Publication of WO2013080830A1 publication Critical patent/WO2013080830A1/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
    • A61K2800/24—Thermal properties
    • A61K2800/244—Endothermic; Cooling; Cooling sensation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/02—Preparations for cleaning the hair

Definitions

  • the present invention relates to a cooling sensation agent, a TRPM8 activator, a cooling sensation imparting method, and a novel compound useful for imparting a cooling sensation.
  • a cooling sensation substance is often blended in various products such as cosmetics, hair care products, toiletry products, bathing agents, and pharmaceuticals.
  • menthol it is widely used. It is thought that menthol imparts a cooling sensation by direct action of menthol on sensory nerve endings present in the skin and mucous membrane tissues, and studies have been conducted on mechanisms for imparting a sensation of cooling.
  • Non-Patent Document 1 This discovery revealed that the sensation of cooling by menthol was caused by an inward calcium current.
  • CMR-1 cold and menthol sensitive receptor
  • TRPM8 Non-Patent Document 3
  • this receptor which is an excitable ion channel belonging to the TRP ion channel family, is considered to cause the aforementioned calcium current.
  • the present invention is the following formula (1)
  • R 1 represents a hydrogen atom
  • R 2 represents a hydrogen atom, a hydroxy group or an alkoxy group having 1 to 3 carbon atoms
  • R 3 represents a hydrogen atom or a hydroxy group
  • R 4 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms
  • R 5 represents a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms.
  • R 6 represents a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms in total, a cycloalkoxy group having 3 to 12 carbon atoms, or an aryl having 6 to 12 carbon atoms An oxy group, an aralkyloxy group having 7 to 14 carbon atoms in total, or an alkanoyloxy group having 2 to 12 carbon atoms in total.
  • the cooling sensation agent which uses as an active ingredient the compound (henceforth a compound (1)) represented by these is provided.
  • the present invention also provides a TRPM8 activator comprising compound (1) as an active ingredient. Furthermore, this invention provides the cooling feeling provision method using a compound (1). Furthermore, this invention provides the TRPM8 activation method using a compound (1). Furthermore, the present invention provides the use of compound (1) for producing a cooling sensation agent. Furthermore, the present invention provides the use of compound (1) for producing a TRPM8 activator. Furthermore, the present invention provides compound (1) for use in imparting cooling sensation. Furthermore, the present invention provides compound (1) for use in TRPM8 activation.
  • R 7 is an alkoxy group having 3 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms, a cycloalkoxy group having 3 to 12 carbon atoms, or an aryloxy group having 6 to 12 carbon atoms. Or an aralkyloxy group having 7 to 14 carbon atoms in total, and R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • compound (2) hereinafter also referred to as compound (2)).
  • the present invention relates to a cooling sensation agent excellent in TRPM8 activation action, a TRPM8 activator, a cooling sensation imparting method, and a novel compound useful for imparting a cooling sensation.
  • Non-Patent Document 4 linalool, geraniol, hydroxycitronellal and the like are also known to activate TRPM8 (Non-Patent Document 4), but in recent years, a strong refreshing feeling and its sustainability tend to be required. Therefore, the TRPM8 activation action by the compounds described in menthol and Non-Patent Document 4 cannot sufficiently satisfy such a requirement.
  • the present inventors have found that a specific compound having an 8,4′-oxyneolignan skeleton has an excellent TRPM8 activation action, and have completed the present invention.
  • Compound (1) has an excellent TRPM8 activating action, can impart a cooling sensation, and has excellent cooling sensation sustainability. Accordingly, the cooling sensation agent, TRPM8 activator and cooling sensation imparting method of the present invention are excellent in TRPM8 activating action, and according to these, a cooling sensation can be imparted continuously.
  • the cooling sensation agent and TRPM8 activator of the present invention comprise the compound (1) as an active ingredient.
  • TRPM8 activation means that a ligand binds to the TRPM8 receptor, thereby increasing the inflow amount of extracellular cation.
  • Cool feeling means that TRPM8 is activated. This means that the temperature sense threshold temperature rises and feels cold despite no actual temperature drop.
  • R 1 represents a hydrogen atom.
  • R 2 represents a hydrogen atom, a hydroxy group or an alkoxy group having 1 to 3 carbon atoms, preferably a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms, more preferably a hydrogen atom.
  • the alkoxy group may be linear or branched, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group.
  • R 3 represents a hydrogen atom or a hydroxy group, preferably a hydrogen atom.
  • R 4 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, preferably a hydrogen atom or an alkenyl group having 2 to 6 carbon atoms. From the viewpoint of activating TRPM8, an alkenyl group having 2 to 6 carbon atoms is more preferable.
  • the number of carbon atoms in the alkyl group is preferably 1 to 3.
  • the carbon number of the alkenyl group is preferably 2 to 4, more preferably 2 or 3, and further preferably 3.
  • the alkyl group, alkenyl group and alkoxy group represented by R 4 may be linear or branched.
  • Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group.
  • alkenyl group examples include a vinyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-methyl-1-butenyl group, 1-pentenyl group, Examples include 1-hexenyl group.
  • alkenyl groups an alkenyl group having a terminal double bond is preferred from the viewpoint of TRPM8 activation.
  • alkoxy group include those exemplified as the alkoxy group represented by R 2 .
  • R 5 represents a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms is preferable from the viewpoint of activating TRPM8.
  • Examples of such an alkoxy group include the same groups as those represented by R 2 , and a methoxy group is preferable.
  • R 6 is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms in total, a cycloalkoxy group having 3 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, An aralkyloxy group having a total carbon number of 7 to 14 or an alkanoyloxy group having a total carbon number of 2 to 12 is shown.
  • More preferred are an aralkyloxy group having 7 to 14 carbon atoms, an alkanoyloxy group having 2 to 12 carbon atoms in total, an alkoxy group having 1 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms in total, and a cycloalkoxy having 3 to 12 carbon atoms.
  • an aralkyloxy group having 7 to 14 carbon atoms and an alkanoyloxy group having 2 to 12 carbon atoms Terms, an alkoxy group having 1 to 14 carbon atoms, alkoxyalkoxy group having a total carbon number of 2 to 12, cycloalkoxy group, total aralkyloxy group having 7 to 14 carbon atoms having 3 to 12 carbon atoms more preferable.
  • the number of carbon atoms of the alkoxy group represented by R 6 is preferably 2 to 14, more preferably 3 to 14, still more preferably 3 to 12, and still more preferably 3 to 10, from the viewpoint of TRPM8 activating action.
  • the alkoxy group may be linear or branched, and in addition to those exemplified as the alkoxy group represented by R 2 , n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n-pentoxy group, Examples include n-hexyloxy group, n-heptyloxy group, n-octyloxy group, n-nonyloxy group, n-decanyloxy group and the like.
  • the total number of carbon atoms of the alkoxyalkoxy group represented by R 6 is preferably 3 to 10, more preferably 4 to 8, still more preferably 5 to 7, and still more preferably 6 or 7.
  • the alkoxyalkoxy group may be linear or branched, and is a methoxymethoxy group, methoxyethoxy group, ethoxymethoxy group, ethoxyethoxy group, methoxypropoxy group, propoxymethoxy group, methoxyisopropoxy group, isopropoxymethoxy group, methoxy Examples include butoxy, butoxymethoxy, ethoxypropoxy, propoxyethoxy, methoxypentoxy, pentoxymethoxy, ethoxybutoxy, butoxyethoxy, and propoxypropoxy. Among these, C 2-4 alkoxy C 2-4 alkoxy groups are preferred.
  • the number of carbon atoms of the cycloalkoxy group represented by R 6 is preferably 5 to 10, and more preferably 6 to 8.
  • a cyclohexyloxy group, a cycloheptyloxy group, a cyclooctyloxy group, etc. are mentioned.
  • the number of carbon atoms of the aryloxy group represented by R 6 is preferably 6 to 8, and more preferably 6.
  • a phenyloxy group etc. are mentioned.
  • the total number of carbon atoms of the aralkyloxy group represented by R 6 is preferably 7 to 12, more preferably 7 to 10, and still more preferably 7 or 8.
  • a benzyloxy group etc. are mentioned.
  • the total number of carbon atoms of the alkanoyloxy group represented by R 6 is preferably 2 to 8, more preferably 2 to 4, and still more preferably 2.
  • an acetoxy group, a propionyloxy group, etc. are mentioned.
  • R 1 to R 6 are hydrogen atoms
  • R 4 is a hydrogen atom or an alkenyl group having 2 to 6 carbon atoms from the viewpoint of TRPM8 activation action
  • R 5 Is a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms
  • R 6 is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms in total, or an alkyl group having 3 to 12 carbon atoms
  • R 1 to R 3 are hydrogen atoms
  • R 4 is 2 to 6 carbon atoms.
  • R 5 is an alkoxy group having 1 to 3 carbon atoms
  • R 6 is a hydrogen atom, an alkoxy group having 1 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms in total, 12 cycloalkoxy Total aralkyloxy group having 7 to 14 carbon atoms, more preferably a combination is the total alkanoyloxy group having a carbon number of 2 ⁇ 12,
  • R 1 ⁇ R 3 is a hydrogen atom
  • R 4 is alkenyl having 2 to 6 carbon atoms
  • R 5 is an alkoxy group having 1 to 3 carbon atoms
  • R 6 is an alkoxy group having 1 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms in total, a cycloalkoxy group having 3 to 12 carbon atoms
  • a combination of an aralkyloxy group having 7 to 14 carbon atoms and an alkanoyloxy group having 2 to 12 carbon atoms is more
  • R 5 is an alkoxy group having 1 to 3 carbon atoms
  • R 6 is an alkoxy group having 1 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms in total, a cycloalkoxy group having 3 to 12 carbon atoms , Total carbon number More preferably a combination is an aralkyl group having to 14.
  • the compound (1) has at least two asymmetric carbon atoms, and derived from such asymmetric carbon atoms, the compound (1) has the following formula (1) -1) to (1-4)
  • Compound (1) may be any of these stereoisomers or a mixture of these isomers, but from the viewpoint of TRPM8 activating action, it is represented by formula (1-1) or formula (1-2). Or a mixture thereof, and a stereoisomer represented by the formula (1-1) is more preferable.
  • R 7 is an alkoxy group having 3 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms, a cycloalkoxy group having 3 to 12 carbon atoms, or an aryloxy group having 6 to 12 carbon atoms. Or an aralkyloxy group having 7 to 14 carbon atoms in total, and R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • an alkoxy group having 3 to 14 carbon atoms represented by R 7 an alkoxyalkoxy group having 2 to 12 carbon atoms in total, a cycloalkoxy group having 3 to 12 carbon atoms, and an aryl having 6 to 12 carbon atoms
  • Examples of the oxy group and the aralkyloxy group having 7 to 14 carbon atoms are the same as those represented by R 6 .
  • R 7 an alkoxy group having 3 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms, a cycloalkoxy group having 3 to 12 carbon atoms, and an aralkyloxy group having 7 to 14 carbon atoms are preferable. .
  • Compound (1) is a compound described in K. Konya, Zs. Valga & S. It can be synthesized by combining conventional methods according to the method described in Antus, Phytomedicine, 2001, 8 (6), 454-459.
  • A. Isogai, S .; Murakoshi, A .; Suzuki & S. Tamura, Agr. Biol. Chem. , 1973, 37 (4), 889-895, etc. a group —OH isolated from a natural product or bonded to the 7-position carbon of neolignans isolated from a natural product is converted into a group —R It can also be prepared by converting to 6 .
  • Examples of such a method include the following synthesis methods. In such a method, the steps (i) to (vi) described later may be appropriately combined with a protection reaction, a deprotection reaction, and an optical resolution as necessary.
  • Step (i) is a step of reacting the raw material compound (a) with the Grignard reagent (b) to obtain an intermediate (c).
  • the raw material compound (a) include vanillin, 5-hydroxyvanillin, syringaldehyde and the like.
  • the Grignard reagent (b) include ethyl magnesium bromide.
  • Step (ii) is a step of obtaining the intermediate (d) by converting the group —OH of the intermediate (c) to the group ⁇ O using an oxidizing agent.
  • the oxidizing agent include manganese dioxide.
  • Step (iii) is a step in which intermediate (d) is ⁇ -brominated to obtain intermediate (e).
  • Step (iv) is a step of obtaining intermediate (g) by reacting intermediate (e) with compound (f) in the presence of a base.
  • the compound (f) include 6-methoxyeugenol, 4- (1-propenyl) syringol, eugenol, isoeugenol and the like.
  • potassium carbonate etc. are mentioned as a base.
  • a strong reducing agent such as lithium aluminum hydride
  • an erythro isomer of intermediate (h) is obtained, while in the presence of a weak reducing agent such as sodium borohydride and crown ether. If it carries out, the threo body of an intermediate body (h) will be obtained.
  • Step (vi) using the C 1 ⁇ 4 alkyl iodide or C 1 ⁇ 14 alcohol, to convert the group -OH attached to the 7-position carbons of intermediate (h) to group -R 6,
  • compound (1) is obtained.
  • the C 1-4 alkyl iodide used in this reaction include methyl iodide, ethyl iodide, propyl iodide, butyl iodide and the like.
  • isolation of each reaction product may be performed by usual filtration, washing, drying, recrystallization, reprecipitation, centrifugation, extraction with various solvents, neutralization, chromatography, etc., if necessary.
  • the means may be combined appropriately.
  • the compound (1) obtained as described above has an excellent TRPM8 activating action and can impart a cooling sensation, as shown in the examples below, and is excellent in the sensation of cooling sensation. Therefore, the compound (1) can be used as it is as a cooling sensation agent and a TRPM8 activator (hereinafter also referred to as a cooling sensation agent), and can be used as a raw material for producing the cooling sensation agent and the like. it can. Moreover, a cool feeling can be provided by using a compound (1). In addition, even if it does not use menthol, the said effect can be acquired.
  • non-therapeutic means a concept that does not include medical practice, that is, a concept that does not include a method for operating, treating, or diagnosing humans. It is a concept that does not include a method for performing surgery, treatment, or diagnosis on a patient. Such non-therapeutic use includes treatment by estheticians.
  • the said cooling sensation agent etc. can be used as a pharmaceutical for humans or animals, cosmetics, food / beverage products, compositions for oral cavity, pet food, other luxury goods (such as tobacco) and the like.
  • the cooling agent or the like When the cooling agent or the like is used as a pharmaceutical, it can be administered in any dosage form.
  • the administration forms are roughly classified into parenteral administration such as transmucosal and transdermal and oral administration.
  • the dosage form of the said pharmaceutical is not specifically limited.
  • pharmaceutical dosage forms for parenteral administration include, for example, external preparations for skin such as solutions, gels, creams, ointments, poultices, aerosols, lotions, foundations, eye drops, nasal drops, etc. Is mentioned.
  • pharmaceutical dosage forms for oral administration include, for example, tablets, capsules, granules, powders, powders, pills, dragees, liquids for internal use, suspensions, syrups and the like.
  • the said pharmaceutical may contain 1 type (s) or 2 or more types of other medicinal components, such as an anti-inflammatory analgesic, a bactericidal disinfectant, an astringent, and antibiotics.
  • the form is not specifically limited.
  • it can be used as an external preparation for skin (insect repellent spray, etc.), detergent, lotion, emulsion, skin cream, foundation, lipstick, scalp cosmetic, hair cosmetic (shampoo, hair tonic, etc.), bath preparation, etc.
  • the cosmetics include oils, ceramides, pseudoceramides, sterols, humectants, antioxidants, ultraviolet absorbers, whitening agents, alcohols, chelating agents, pH adjusters.
  • One or two or more kinds of preservatives may be included.
  • the form is not specifically limited. Examples include candy, gum, tablet, capsule, and drinking water.
  • the form is not specifically limited, For example, a dentifrice, a mouthwash, a gingival massage cream etc. are mentioned.
  • the content of the compound (1) contained in the cooling sensation agent and the like is not particularly limited, but in the case of a pharmaceutical, food or drink, oral composition or pet food for oral administration, a viewpoint of TRPM8 activation action Therefore, the lower limit is preferably 0.1 ppm or more, more preferably 1 ppm or more, further preferably 10 ppm or more, and further preferably 50 ppm or more.
  • the upper limit is preferably 10,000 ppm or less, more preferably 1000 ppm or less, and further preferably 750 ppm or less, from the same viewpoint as the lower limit.
  • the lower limit is preferably 0.001% by mass or more and more preferably 0.01% by mass or more from the viewpoint of TRPM8 activation.
  • the upper limit is preferably 10% by mass or less from the same viewpoint as the lower limit.
  • 0.001% by mass or more is preferable, and 0.01 to 10% by mass is more preferable.
  • it is a person who requires it as administration person of the said cooling sensation agent or ingestion, it will not specifically limit.
  • cooling sensation imparting method and TRPM8 activation method of the present invention will be described.
  • application and administration of the compound (1) can be mentioned.
  • the present invention further discloses the following cooling sensation agent and the like.
  • a cooling sensation agent comprising a compound represented by the above formula (1) as an active ingredient.
  • a TRPM8 activator comprising a compound represented by the above formula (1) as an active ingredient.
  • ⁇ 3> A cooling sensation imparting method using the compound represented by the formula (1).
  • ⁇ 4> A cooling sensation imparting method in which the compound represented by the formula (1) is administered or ingested.
  • ⁇ 5> A TRPM8 activation method using the compound represented by the above formula (1).
  • ⁇ 6> A method for activating TRPM8, which comprises administering or ingesting a compound represented by the above formula (1).
  • R 2 is preferably a hydrogen atom or an alkoxy group having 1 to 3 carbon atoms, and more preferably a hydrogen atom.
  • R 3 is preferably a hydrogen atom.
  • R 4 is preferably a hydrogen atom, an alkenyl group having 2 to 6 carbon atoms, more preferably an alkenyl group having 2 to 6 carbon atoms, and more preferably a terminal 2 An alkenyl group having 2 to 6 carbon atoms having a heavy bond.
  • R 5 is preferably an alkoxy group having 1 to 3 carbon atoms, and more preferably a methoxy group.
  • R 6 is preferably a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms in total, or 3 to 12 carbon atoms.
  • R 7 is preferably an alkoxy group having 3 to 14 carbon atoms, an alkoxyalkoxy group having 2 to 12 carbon atoms, a cycloalkoxy group having 3 to 12 carbon atoms, or a 7 to 7 carbon atom. 14 aralkyloxy groups.
  • ⁇ NMR spectrum> The 1 H-NMR spectrum was measured by Bruker Avance-600 using CHCl 3 (7.24) as an internal standard substance.
  • the 13 C-NMR spectrum was measured by Bruker Avance-600 using CHCl 3 (77.0) as an internal standard substance.
  • Vanillin (3) (7.61 g) was dissolved in N, N-dimethylformamide (100 mL), and imidazole (9.02 g) and tert-butyldimethylchlorosilane (4.43 g) were added. Stir for 5 hours. Water and ethyl acetate were added to the reaction solution, and the ethyl acetate layer was dried under reduced pressure and purified by silica gel chromatography to obtain TBS protected product (5) (12.6 g).
  • de-TBS product (8) (7.20 g).
  • the obtained de-TBS product (8) was dissolved in dichloromethane (60 mL), diisopropylethylamine (6.29 mL) and chloromethyl methyl ether (2.53 mL) were added, and the mixture was stirred at room temperature / nitrogen atmosphere for 2 hr.
  • MOM-protected product (9) 6.23 g
  • 711 mg of the obtained MOM protector (9) was dissolved in acetone (20 mL), 6-methoxyeugenol (10) (0.46 mL) and potassium carbonate (1.62 g) were added, and room temperature under a nitrogen atmosphere. Stir for 2 days and filter the reaction. The filtrate was dried under reduced pressure and purified by silica gel chromatography to obtain a condensate (4) (691 mg).
  • Example 1 According to the following synthesis route, erythro- ⁇ 8′-7-ethoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8-O-4′-neolignan (hereinafter also referred to as erythro isomer (1)) is synthesized. did.
  • erythro-hydroxy compound (11) 122 mg was dissolved in tetrahydrofuran (3 mL), sodium hydride (purity 55%, 63.6 mg) and ethyl iodide (0.075 mL) were added, and 0 ° C. was added. Stir for 5 hours at room temperature for 12 hours under nitrogen atmosphere. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the ethyl acetate layer was dried under reduced pressure and purified by silica gel chromatography to obtain an erythro-ethoxy compound (12) (99.8 mg).
  • erythro-ethoxy compound (12) 28.0 mg was dissolved in tetrahydrofuran (1 mL), 6N HCl (0.1 mL) was added, and the mixture was stirred at room temperature / nitrogen atmosphere for 20 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the ethyl acetate layer was dried under reduced pressure and purified by silica gel chromatography to obtain erythro isomer (1) (15.4 mg) as a racemate.
  • Example 2 According to the following synthesis route, threo- ⁇ 8′-7-ethoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8-O-4′-neolignan (hereinafter also referred to as threo form (2)) was synthesized. did.
  • threo-hydroxy compound (13) 125 mg was dissolved in tetrahydrofuran (3 mL), and sodium hydride (purity 55%, 65.1 mg) and ethyl iodide (0.077 mL) were added. Stir for 5 hours at room temperature for 12 hours under nitrogen atmosphere. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the ethyl acetate layer was dried under reduced pressure and purified by silica gel chromatography to obtain a threo-ethoxy compound (14) (85.8 mg).
  • threo-ethoxy compound (14) 29.0 mg was dissolved in tetrahydrofuran (1 mL), 6N HCl (0.1 mL) was added, and the mixture was stirred at room temperature / nitrogen atmosphere for 20 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was dried under reduced pressure and purified by silica gel chromatography to obtain the threo form (2) (18.8 mg) as a racemic form.
  • Example 3 The erythro isomer (1) obtained in Example 1 was optically resolved by a chiral column (CHIRALPAK IC 10 ⁇ 250 mm manufactured by Daicel), and (7R, 8S) - ⁇ 8′-7-ethoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8-O-4′-neolignan (hereinafter also referred to as 7R8S isomer (1a)) (5.1 mg) and (7S, 8R) - ⁇ 8′-7-ethoxy-4-hydroxy-3,3 ', 5'-trimethoxy-8-O-4'-neolignan (hereinafter also referred to as 7S8R isomer (1b)) (4.4 mg) was obtained.
  • the threo isomer (2) obtained in Example 2 was optically resolved under the same conditions, and (7R, 8R) - ⁇ 8′-7-ethoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8 was obtained.
  • Example 4 The erythro isomer (1) obtained in Example 1 and the threo isomer (2) obtained in Example 2 were mixed at a ratio of 1: 1, and ⁇ 8′-7-ethoxy-4-hydroxy-3,3 ′, A mixture of four isomers of 5′-trimethoxy-8-O-4′-neolignan (hereinafter also referred to as mixture (15)) was obtained.
  • Example 5 The condensate (4) was converted to erythro- ⁇ 8′-4-hydroxy-3,3 ′, 5 ′, 7-tetramethoxy-8-O in the same manner as in Example 1 except that ethyl iodide was replaced with methyl iodide.
  • -4′-Neolignan (hereinafter also referred to as erythro isomer (16)) was synthesized.
  • the condensate (4) was converted from threo- ⁇ 8′-4-hydroxy-3,3 ′, 5 ′, 7-tetramethoxy-8 in the same manner as in Example 2 except that ethyl iodide was replaced with methyl iodide.
  • -O-4'-neolignan (hereinafter also referred to as threo form (17)) was synthesized.
  • the erythro isomer (16) and the threo isomer (17) obtained as described above were mixed at a ratio of 60:40, and ⁇ 8′-4-hydroxy-3,3 ′, 5 ′, 7-tetramethoxy-8 was mixed.
  • a mixture of four isomers of —O-4′-neolignan (hereinafter also referred to as a mixture (18)) was obtained.
  • the chemical structure of the obtained mixture (18) is shown below.
  • Example 6 Except that ethyl iodide was replaced with butyl iodide, the erythro- ⁇ 8'-7-butoxy-4-hydroxy-3,3 ', 5'-trimethoxy-8- was converted from the condensate (4) in the same manner as in Example 1.
  • O-4′-neolignan hereinafter also referred to as erythro isomer (19)
  • the NMR spectrum and chemical structure of the obtained erythro isomer (19) are shown below.
  • Example 7 Except that ethyl iodide was replaced with butyl iodide, threo- ⁇ 8′-7-butoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8- O-4′-neolignan (hereinafter also referred to as threo form (20)) was synthesized.
  • Example 8 (Isolation Example 1) According to the following isolation scheme, erythro- ⁇ 8′-4,7-dihydroxy-3,3 ′, 5′-trimethoxy-8-O-4′-neolignan (hereinafter also referred to as erythro isomer (21)), erythro- ⁇ 8′-4,7-dihydroxy-3,3′-dimethoxy-8-O-4′-neolignan (hereinafter also referred to as erythro (22)), and erythro- ⁇ 8′-7-acetyl-4-hydroxy- 3,3 ′, 5′-trimethoxy-8-O-4′-neolignan (hereinafter also referred to as erythro isomer (23)) was isolated from Nikuzu.
  • erythro isomer (21) erythro- ⁇ 8′-4,7-dihydroxy-3,3′-dimethoxy-8-O-4′-neolignan
  • erythro erythro- ⁇ 8′-7-acetyl-4-hydroxy- 3,
  • Example 9 The erythro isomer (21) (5.9 mg) obtained in Isolation Example 1 was dissolved in isopropyl alcohol (0.2 mL), concentrated hydrochloric acid (2 ⁇ L) was added, and the mixture was reacted at 60 ° C. for 5 hours. After cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the ethyl acetate layer was concentrated under reduced pressure and purified by silica gel chromatography to obtain ⁇ 8′-7-isopropoxy-4-hydroxy-3,3 ′, 5′-trimethoxy. -8-O-4'-neolignan (hereinafter also referred to as mixture (24)) (4.4 mg) was obtained in a diastereomeric ratio of 60:40.
  • mixture (24) 4.4 mg
  • Example 10 The erythro compound (21) was converted to ⁇ 8′-7-isobutoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8-O-4 in the same manner as in Example 9 except that isopropyl alcohol was replaced with isobutyl alcohol.
  • '-Neolignan (hereinafter also referred to as mixture (25)) was obtained in a diastereomeric ratio of 60:40.
  • Example 11 The erythro compound (21) was converted to ⁇ 8′-7-hexoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8-O— in the same manner as in Example 9 except that isopropyl alcohol was changed to 1-hexanol. 4′-Neolignan (hereinafter also referred to as mixture (26)) was obtained in a diastereomeric ratio of 60:40.
  • Example 12 The erythro isomer (21) was converted to ⁇ 8′-7-octoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8-O— in the same manner as in Example 9 except that isopropyl alcohol was replaced with 1-octanol. 4′-Neolignan (hereinafter also referred to as the mixture (27)) was obtained in a diastereomeric ratio of 60:40.
  • Example 13 The erythro compound (21) was converted to ⁇ 8′-7-decoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8-O— in the same manner as in Example 9 except that isopropyl alcohol was replaced with 1-decanol. 4′-Neolignan (hereinafter also referred to as mixture (28)) was obtained in a diastereomeric ratio of 60:40.
  • Example 14 The erythro compound (21) was converted to ⁇ 8′-7-cyclohexoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8-O— in the same manner as in Example 9 except that isopropyl alcohol was replaced with cyclohexanol. 4′-Neolignan (hereinafter also referred to as the mixture (29)) was obtained in a diastereomeric ratio of 60:40.
  • Example 15 The erythro isomer (21) was converted into ⁇ 8′-7-benzyloxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8-O-4 in the same manner as in Example 9 except that isopropyl alcohol was replaced with benzyl alcohol.
  • '-Neolignan (hereinafter also referred to as mixture (30)) was obtained in a diastereomeric ratio of 60:40.
  • Example 16 The erythro isomer (21) was converted to ⁇ 8′-7-t-butoxy-4-hydroxy-3,3 ′, 5′-trimethoxy-8-like in the same manner as in Example 9 except that isopropyl alcohol was changed to t-butanol.
  • O-4′-neolignan (hereinafter also referred to as mixture (31)) was obtained in a diastereomeric ratio of 50:50.
  • Example 17 The erythro compound (21) was converted to ⁇ 8′-7-oxybutoxyethyl-4-hydroxy-3,3 ′, 5′-trimethoxy-8 in the same manner as in Example 9 except that isopropyl alcohol was replaced with 2-butoxyethanol.
  • —O-4′-Neolignan (hereinafter also referred to as mixture (32)) was obtained in a diastereomeric ratio of 60:40.
  • Example 18 The erythro isomer (22) (5.0 mg) obtained in Isolation Example 1 was dissolved in ethanol (0.2 mL), concentrated hydrochloric acid (2 ⁇ L) was added, and the mixture was reacted at 60 ° C. for 5 hours. After cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the ethyl acetate layer was concentrated under reduced pressure and purified by silica gel chromatography, and erythro- ⁇ 8′-7-ethoxy-4-hydroxy-3,3′-dimethoxy-8 was obtained. -O-4'-neolignan (hereinafter also referred to as erythro isomer (33)) (4.0 mg) was obtained.
  • Example 19 ⁇ 8′-4-hydroxy-3,3′-dimethoxy-8-O-4′-neolignan (manufactured by Analycon, NP-016261) (hereinafter also referred to as compound (34)) was diluted with a solvent as it was and tested 1 was used.
  • the chemical structure of compound (34) is shown below.
  • Example 20 ⁇ 8′-4-hydroxy-3,3′-dimethoxy-1′-propenyl-8-O-4′-neolignan (manufactured by Analycon, NP-000262) (hereinafter also referred to as compound (35)) (4.8 mg ) was dissolved in ethanol (0.2 mL), concentrated hydrochloric acid (2 ⁇ L) was added, and the mixture was reacted at 60 ° C. for 3 hours.
  • Example 21 4- [1-hydroxy-2- (2-methoxyphenoxy) propyl] -2-methoxyphenol (manufactured by Pharmeks, P2000N-11879) (hereinafter also referred to as compound (37)) (5.1 mg) was added to ethanol (0 2 mL), concentrated hydrochloric acid (2 ⁇ L) was added, and the mixture was reacted at 60 ° C. for 3 hours. After cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the ethyl acetate layer was concentrated under reduced pressure and purified by silica gel chromatography to give 4- [1-ethoxy-2- (2-methoxyphenoxy) propyl] -2-methoxy. Phenol (hereinafter also referred to as mixture (38)) (5.4 mg) was obtained in a diastereomeric ratio of 50:50.
  • mixture (38) mixture (38)
  • Test example 1 The following procedure was measured and EC 50 values in the TRPM8 activating effect of the test sample.
  • (1) Production of human TRPM8 stable expression strain To produce the human TRPM8 stable expression HEK293 cell line, the human TRPM8 gene was cloned. The full-length human TRPM8 gene was amplified from human prostate tissue total RNA (COSMOBIO) using the RT-PCR method. The obtained PCR product was cloned into the entry vector pENTR-D / TOPO (Invitrogen), then subcloned into pCDNA3.2-V5 / DEST (Invitrogen), and HEK293 using Lipofectamine 2000 (Invitrogen). Cells were transduced.
  • COSMOBIO human prostate tissue total RNA
  • Transduced cells were selected by growing in DMEM medium containing 450 ⁇ g / mL G-418 (Promega). Since HEK293 cells do not express endogenous TRPM8, they can be used as a control for TRPM8 transduced strains.
  • (2) Calcium imaging TRPM8 activity transduced into HEK293 cells was measured by the fluorescent calcium imaging method. First, cultured TRPM8-expressing cells were seeded (30,000 cells / well) in a 96-well plate (manufactured by BD Falcon) coated with poly-D-lysine, incubated at 37 ° C. overnight, and then the culture solution was removed.
  • Fluo4-AM solution (manufactured by Dojindo; calcium kit II) was added and incubated at 37 ° C. for 30-60 minutes. Thereafter, the 96-well plate was set in a fluorescent plate reader (FDSS3000; manufactured by Hamamatsu Photonics), and the fluorescence image by Fluo4 when excited at an excitation wavelength of 480 nm with the temperature inside the apparatus being set at 32 ° C. was captured at a detection wavelength of 520 nm. Measurement is performed every second for a total of 4 minutes. After 15 seconds from the start of measurement, a test sample (each compound shown in Table 1 below is dissolved in ethanol) is added from a dispenser built in FDSS 3000, and the fluorescence intensity is measured. TRPM8 activity was evaluated by changes.
  • FDSS3000 fluorescent plate reader
  • TRPM8 activation TRPM8 activity was obtained by subtracting the autofluorescence component from the following formula in order to eliminate the influence of autofluorescence by the test sample.
  • Fluorescence intensity minus autofluorescence (F sub ) (Fluorescence intensity of TRPM8 expressing cells at each time point)- ⁇ (Fluorescence intensity of HEK293 cells at each time point)-(Fluorescence intensity of HEK293 cells at the start of measurement) ⁇
  • the TRPM8 activation action by each sample was evaluated using the peak of the fluorescence intensity ratio after addition of the test sample.
  • TRPM8 activation action was evaluated in the final concentration range from 1 nM to 100 ⁇ M, and a capacity dependence curve approximated to Hill's equation was determined by the least square method.
  • the EC 50 values in the TRPM8 activation action of each test sample calculated from this curve are as shown in Table 1 below.
  • each compound obtained in the examples has an excellent TRPM8 activation action.
  • Test example 2 The test sample (mouth wash) shown in Table 2 was prepared, and the coolness induction effect was evaluated according to the following procedures and standards. The evaluation results are shown in FIG.
  • Example 22 was the mouthwash of Comparative Example 1 (containing the same concentration of l-menthol instead of the mixture (15)). Compared with, it shows a long lasting cool feeling.

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MX389514B (es) * 2015-10-01 2025-03-20 Firmenich Incorporated Compuestos útiles como moduladores de canal receptor 8 de potencial transitorio de melastatina (trpm8).
WO2022088026A1 (zh) * 2020-10-30 2022-05-05 江苏君澜纺织品有限公司 一种口罩面料制备方法及口罩

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WO2014010657A1 (ja) * 2012-07-12 2014-01-16 花王株式会社 ニクズク加工処理物及びその製造方法
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WO2019121660A1 (en) 2017-12-20 2019-06-27 Firmenich Sa Oral care compositions

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