WO2015002095A1 - 刺激感緩和剤 - Google Patents

刺激感緩和剤 Download PDF

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Publication number
WO2015002095A1
WO2015002095A1 PCT/JP2014/067213 JP2014067213W WO2015002095A1 WO 2015002095 A1 WO2015002095 A1 WO 2015002095A1 JP 2014067213 W JP2014067213 W JP 2014067213W WO 2015002095 A1 WO2015002095 A1 WO 2015002095A1
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hydrogen atom
alkyl group
carbon atoms
formula
irritation
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PCT/JP2014/067213
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English (en)
French (fr)
Japanese (ja)
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和樹 木下
智大 白井
堅太郎 組橋
麻紀子 室井
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花王株式会社
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    • 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
    • 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
    • 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
    • A61K8/37—Esters of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/75—Anti-irritant

Definitions

  • the present invention relates to a TRPA1 activity inhibitor and an irritation sensation reducing agent.
  • TRPA1 is a non-selective cation channel belonging to the superfamily of transient receptor potential (TRP) ion channels, and was found as a cold receptor (17 ° C.) in nociceptive neurons (Non-patent Document 1). . After that, TRPA1 is a chemical receptor that reacts with mustard oil and allyl isothiocyanate (AITC), cinnamon, garlic, methyl salicylate, eugenol, alcohols, etc. contained in it, as well as low temperature and mechanical stimulation, It has been reported to be a pain receptor that responds to stimuli (Non-Patent Documents 2, 3, 4, and 5).
  • AITC mustard oil and allyl isothiocyanate
  • TRPA1 is a nociceptor of skin and mucous membranes and is activated by various stimuli
  • suppressing TRPA1 activity is considered to be effective in reducing pain caused by stimuli.
  • the test substance and AITC are brought into contact with a cell expressing TRPA1, and the change in intracellular calcium ion concentration caused by TRPA1 by AITC is measured, so that a search (evaluation of a stimulus (pain) inhibitory substance is performed. Has been found, and a stimulus-suppressing substance has been found (Non-patent Document 6).
  • Patent Document 1 JP 2008-79528 A
  • Patent Document 2 JP 2009-82053 A
  • Patent Document 3 JP 2011-205975 A
  • Non-Patent Document 1 Story et al. 2003, Cell 112, 819-829
  • Non-Patent Document 2 Yaman et al. 2006, Neuron 50, 277-289
  • Non-Patent Document 3 Journal of Japanese Pharmacology, Vol. 124, pp. 219-227, 2004, published by the Japanese Pharmacological Society
  • Non-Patent Document 4 Fijita et al. 2010, IFSCC Congress 2010
  • Non-Patent Document 5 Komatsu et al. 2012, Eur J Physio 463, 549-559
  • Non-Patent Document 6 Molecular Pain 2008, 4:48
  • the present invention relates to the following 1) to 7).
  • a TRPA1 activity inhibitor comprising a compound represented by the following formula (1) as an active ingredient.
  • a skin or mucous membrane irritation reducing agent comprising a compound represented by the following formula (1) as an active ingredient.
  • Use of a compound represented by the following formula (1) for producing a TRPA1 activity inhibitor comprising using a compound represented by the following formula (1).
  • Use of a compound represented by the following formula (1) for producing a TRPA1 activity inhibitor comprising a compound represented by the following formula (1) for producing a TRPA1 activity inhibitor.
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or a cyclohexane ring together with a carbon chain to which R 1 and R 2 are bonded together.
  • R 3 and R 4 which may be the same or different, each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (provided that R 1 and R 2 are combined to form a carbon to which they are bonded).
  • R 3 and R 4 both represent a hydrogen atom when forming a cyclohexane ring together with the chain),
  • R 5 represents an alkyl group having 1 to 6 carbon atoms,
  • R 6 represents a hydrogen atom or an acyl group, and
  • a dotted line The solid double line is a single bond or a double bond, and R 4 is present only when it is a single bond.
  • the graph which shows the TRPA1 activity inhibitory effect (dose dependence) of this invention compound The graph which shows the skin sensory irritation reduction effect with respect to the irritation
  • the present invention relates to providing a TRPA1 activity inhibitor capable of alleviating sensory stimulation to skin and mucous membranes, and an agent for reducing irritation to skin or mucous membranes.
  • the compound represented by the following formula (1) suppresses the activity of TRPA1, and alleviates the irritation to the skin and mucous membrane by the substance causing irritation. Found to be effective.
  • the TRPA1 activity inhibitor and the skin or mucous membrane irritation mitigating agent of the present invention have the effect of effectively suppressing the activation of TRPA1. Therefore, the TRPA1 activity inhibitor of the present invention, skin or mucous membrane irritation reducing agent is used together with various compositions containing irritation-causing substances such as preservatives and antiseptics, or before and after use of the composition. Thus, the irritation and pain caused by the irritation causing substance can be alleviated.
  • the alkyl group having 1 to 3 carbon atoms represented by R 1 , R 2 , R 3 , and R 4 may be either linear or branched, specifically a methyl group , An ethyl group, an n-propyl group, and an isopropyl group, and of these, a methyl group is preferable.
  • R 1 and R 2 are both hydrogen atoms, or R 1 is a hydrogen atom and R 2 is an alkyl group having 1 to 3 carbon atoms (preferably a methyl group), or R 1 and R 2 are combined It is preferable to form a cyclohexane ring together with the carbon chain to which they are bound.
  • R 3 and R 4 are preferably both hydrogen atoms, both methyl groups, or either one is a hydrogen atom or a methyl group.
  • the alkyl group having 1 to 6 carbon atoms represented by R 5 may be linear or branched.
  • a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group examples thereof include an n-pentyl group and an n-hexyl group.
  • an alkyl group having 1 to 3 carbon atoms is preferable, and a methyl group, an ethyl group, and an isopropyl group are more preferable.
  • R 1 and R 2 are combined to form a cyclohexane ring together with the carbon chain to which they are bonded (the above formula (1A)
  • R 5 is preferably a methyl group.
  • the acyl group represented by R 6 is preferably a saturated or unsaturated aliphatic carbonyl group having 2 to 6 carbon atoms, and more preferably a saturated aliphatic carbonyl group having 2 to 6 carbon atoms (alkanoyl group). Further, an alkanoyl group having 2 to 4 carbon atoms is more preferable, and an acetyl group and a propionyl group are more preferable.
  • R 6 is preferably a hydrogen atom.
  • the single bond or the double bond indicated by the dotted and solid double lines is a single bond.
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom, a methyl group or an ethyl group
  • R 1 and R 2 are integrated.
  • R 3 and R 4 are both hydrogen atoms, both methyl groups, or either one is a hydrogen atom or a methyl group
  • R 5 is a methyl group, an ethyl group or an isopropyl group
  • R 6 is a hydrogen atom or an acetyl group.
  • the compound represented by the formula (1) of the present invention is chemically synthesized by appropriately combining conventional methods according to known methods (for example, J. Chem. Soc., Perkin Trans. 1, 2001, 1300-1303). be able to.
  • a compound in which R 1 and R 2 are both hydrogen atoms and R 4 is a hydrogen atom can be obtained by the method shown in the following ⁇ Reaction 1>. That is, benzaldehyde (A) is condensed with ⁇ -methylene aldehyde to form aldehyde (B), and then an alkyl group is introduced using an alkylating agent such as a Grignard reagent to obtain compound (C). Can be subjected to a catalytic hydrogenation reaction in the presence of a catalyst such as Pd / C to obtain compound (D).
  • a catalyst such as Pd / C
  • a compound in which R 1 and R 2 are a hydrogen atom or an alkyl group having 1 to 3 carbon atoms can also be obtained by a method as shown in the following ⁇ Reaction 2>. That is, the phenyl-1-propanol derivative (E) is subjected to an oxidation reaction using TEMPO and iodobenzene diacetate to obtain a carbonyl compound (F), and then an alkyl group is introduced using an alkylating agent such as a Grignard reagent. By doing this, the compound (G) can be obtained.
  • the compound in which both R 1 and R 2 are hydrogen atoms can also be obtained by the method shown in the following ⁇ Reaction 3>. That is, a benzyl halide is reacted with a ketone body (H) in the presence of a base to obtain a carbonyl compound (I), which is subjected to a reduction reaction using LiAlH 4 or the like to obtain a compound (J). Can do.
  • a compound when R 1 and R 2 are united to form a cyclohexane ring together with the carbon chain to which they are bonded, a compound can be obtained, for example, by the method shown in the following ⁇ Reaction 4>. It can. That is, 2-cyclohexen-1-one (K) is reacted with phenylmagnesium bromide in the presence of a copper salt such as copper (I) iodide to give 2-cyclohexen-1-one (L).
  • the compound (M) can be obtained by introducing an alkyl group using an alkylating agent such as a Grignard reagent.
  • R 1a and R 2a may be the same or different and each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, X represents a halogen atom, R 1 , R 2 , R 3 , R 4 , R 5 represents the same as described above. ]
  • a compound in which R 6 is an acyl group can be obtained by acylating a hydroxyl group using an acylating agent such as acetic anhydride or acetyl chloride.
  • the compound represented by the formula (1) of the present invention depends on a stimulating substance when it is brought into contact with various TRPA1-stimulating substances and cells (TRPA1-expressing cells) transduced with TRPA1. It has a TRPA1 activity inhibitory action of suppressing the inflow of cation amount in cells (Example 1).
  • TRPA1 activity inhibitory action of suppressing the inflow of cation amount in cells (Example 1).
  • the compound represented by the formula (1) of the present invention is applied to the skin in advance and then a TRPA1 activator is applied, it exerts an effect of reducing sensory irritation to the TRPA1 activator (implementation) Example 2). Therefore, the compound represented by the formula (1) of the present invention is a TRPA1 activity inhibitor, and a skin or mucous membrane irritation reducing agent that is effective for the stimulation of skin and mucous membranes and pain caused by TRPA1. obtain.
  • TRPA1 activity means that the activity of TRPA1 which is a receptor is suppressed, specifically, the activity expressed by binding of TRPA1 stimulating substance (agonist) to TRPA1, for example, ion flux It refers to suppressing or inhibiting regulatory ability (eg, ability to transport cations such as calcium ions and sodium ions from the outside of the cell into the cell) and membrane potential regulation ability (eg, ability to generate current).
  • regulatory ability eg, ability to transport cations such as calcium ions and sodium ions from the outside of the cell into the cell
  • membrane potential regulation ability eg, ability to generate current
  • the TRPA1 stimulating substance for example, allyl isothiocyanate (AITC), ammonia, bradykinin, cinnamaldehyde, 4-hydroxynonenal, allicin, acrolein, menthol, methyl salicylate, eugenol, parabens, phenoxyethanol, butylcarbamine
  • AITC allyl isothiocyanate
  • IPBC propynyl oxyiodide
  • triclosan triclosan
  • benzyl alcohol for example, allyl isothiocyanate (AITC), ammonia, bradykinin, cinnamaldehyde, 4-hydroxynonenal, allicin, acrolein, menthol, methyl salicylate, eugenol, parabens, phenoxyethanol, butylcarbamine
  • IPBC propynyl oxyiodide
  • triclosan triclosan
  • the inhibitory effect of the TRPA1 activity by the compound represented by the formula (1) of the present invention is, for example, using a TRPA1-expressing cell, and in the presence of the compound represented by the formula (1), a TRPA1 stimulating substance (for example, AITC)
  • a TRPA1 stimulating substance for example, AITC
  • the difference between the calcium ion concentration in the TRPA1-expressing cell brought into contact with) and the calcium ion concentration in the TRPA1-expressing cell contacted with the TRPA1-stimulating substance in the absence of the compound represented by the formula (1) It can be evaluated by things.
  • Suitable TRPA1-stimulating substances are chemical substances that may give a feeling of irritation to the skin and mucous membranes (referred to as “irritant substances”), such as parabens, phenoxyethanol, propynyl iodide butylcarbamate.
  • IPBC antiseptics such as triclosan
  • antiseptics such as benzyl alcohol
  • alcohols such as ammonia, acrolein, menthol, methyl salicylate, eugenol
  • monohydric alcohol for example, linear or branched chain having 2 to 10 carbon atoms such as ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, nonyl alcohol, decyl alcohol, etc.
  • polyhydric alcohols examples include aliphatic alcohols having 2 to 6 carbon atoms such as propylene glycol, dipropylene glycol, 1,3-butylene glycol, pentylene glycol, and hexylene glycol.
  • a dihydric alcohol etc. are mentioned.
  • “mucosa” includes the oral cavity, throat, nasal cavity, ear cavity, conjunctival sac, and the like.
  • the stimulating sensation mitigating effect may be measured by sensory evaluation as shown in Examples below, or can be evaluated by a change in intracellular calcium ion concentration using the above-mentioned TRPA1-expressing cells.
  • the TRPA1 activity inhibitor and the skin or mucosal irritation mitigating agent may be those using the compound represented by the formula (1) of the present invention alone, or oils, pigments, fragrances, preservatives, chelates.
  • those forms are not particularly limited, and can be prepared in any form such as a solution, emulsion, suspension, gel, solid, powder, granule, aerosol, and the like.
  • the compounding amount of the compound represented by the formula (1) in the composition is 0.001% by mass or more, preferably 0.01% by mass or more, and 10% by mass or less, preferably 1% of the total mass of the preparation. It is below mass%. For example, 0.001 to 10% by mass, preferably 0.01 to 1% by mass.
  • the TRPA1 activity inhibitor and the skin or mucous membrane irritation reducing agent of the present invention include, for example, a composition containing the above-mentioned irritation sensation causing substance (skin cleaning agent, hair cleaning agent, makeup agent, bath agent, permanent wave use). Cosmetics, hair dyes, soaps, kitchen detergents, laundry detergents, toothpaste and other cosmetics, quasi-drugs, pharmaceuticals, daily necessities, etc.) or contain substances that cause irritation
  • a composition containing the above-mentioned irritation sensation causing substance skin cleaning agent, hair cleaning agent, makeup agent, bath agent, permanent wave use.
  • Cosmetics, hair dyes, soaps, kitchen detergents, laundry detergents, toothpaste and other cosmetics, quasi-drugs, pharmaceuticals, daily necessities, etc. or contain substances that cause irritation
  • the amount of the TRPA1 activity inhibitor and the skin or mucosal irritation reducing agent used is irritation.
  • the compound represented by the formula (1) of the present invention is preferably 0.01 parts by mass or more, more preferably 0.
  • the ratio can be 1 part by mass or more, preferably 10 parts by mass or less, more preferably 1 part by mass or less.
  • the ratio can be preferably 0.01 to 10 parts by mass, more preferably 0.1 to 1 part by mass with respect to 1 part by mass of the substance that causes irritation.
  • a TRPA1 activity inhibitor comprising a compound represented by the following formula (1) as an active ingredient.
  • a skin or mucous membrane irritation reducing agent comprising a compound represented by the following formula (1) as an active ingredient.
  • ⁇ 7> A method for inhibiting TRPA1 activity, comprising using a compound represented by the following formula (1).
  • ⁇ 8> A method of reducing irritation to skin or mucous membrane, comprising using a compound represented by the following formula (1).
  • the relaxation of sensory irritation is, for example, skin or mucous membrane caused by an irritation-causing substance selected from antiseptics, antiseptics, alcohols and ammonia The relaxation of sensory stimulation.
  • the compound represented by the following formula (1) is used by blending with a composition containing a substance that causes irritation, or separate from the composition It is prepared as a composition and is used simultaneously with the composition or before and after use of the composition.
  • the compound represented by the following formula (1) is preferably 0.01 parts by mass or more, more preferably 0.1 parts by mass or more, with respect to 1 part by mass of the irritation sensation causing substance And it is preferably used at a ratio of 10 parts by mass or less, more preferably 1 part by mass or less.
  • the compound represented by the formula (1) is 2,2,4-trimethyl-1-phenyl-3-pentanol or t-1-methyl-3-phenyl Cyclohexanol.
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or a cyclohexane ring together with a carbon chain to which R 1 and R 2 are bonded together.
  • R 3 and R 4 which may be the same or different, each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (provided that R 1 and R 2 are combined to form a carbon to which they are bonded).
  • R 3 and R 4 both represent a hydrogen atom when forming a cyclohexane ring together with the chain),
  • R 5 represents an alkyl group having 1 to 6 carbon atoms,
  • R 6 represents a hydrogen atom or an acyl group, and
  • a dotted line The solid double line is a single bond or a double bond, and R 4 is present only when it is a single bond.
  • Table 1 below shows an example of the compound of the present invention.
  • the compound of the present invention can be chemically synthesized by a known method, or a commercially available product can be used.
  • Examples of commercially available products include Compound 1 (3-methyl-4-phenyl-2-butanol) from IFF Corporation, Compound 2 (3-methyl-1-phenyl-3-pentanol) and Compound 3 (2-methyl- 4-phenyl-2-butanol) was obtained from Tokyo Chemical Industry Co., Ltd. with Compound 4 (1.1-dimethyl-3-phenyl-propyl acetate) and Compound 5 (2-methyl-4-phenyl-3-buten-2-ol). ) Is available from SIGMA-AlDRICH.
  • the production examples of the compounds of the present invention (compounds 6 to 11) shown in Table 1 are shown below.
  • the 1 H-NMR spectrum was measured by Bruker Avance-600 using CHCl 3 (7.24) as an internal standard substance, and the 13 C NMR spectrum was measured using CHCl 3 (77.0) as an internal standard substance. Then, measurement was performed using an Avance-600 manufactured by Bruker.
  • TRPA1 activity inhibitory action (1) Production of stable expression strain of human TRPA1
  • the human TRPA1 gene was purchased from Open Biosystems in a state where it was inserted into pENTR223.1.
  • the TRPA1 gene was subcloned into the expression vector pcDNA3.2-V5 / DEST (Invitrogen) from the purchased entry vector and transduced into HEK293 cells with Lipofectamine 2000 (Invitrogen). Transduced cells were selected by growing in DMEM medium containing G-418 (450 ⁇ g / ml; Promega). Since HEK293 cells do not express endogenous TRPA1, they can be used as a control (control) for the TRPA1 transduced strain.
  • a fluorescence image was detected with a CCD camera at a detection wavelength of 520 nm when excited at an excitation wavelength of 480 nm with the apparatus internal temperature set at 24 ° C. Measurement is performed for 4 minutes every second, and 15 seconds after the start of measurement, TRPA1 stimulating substance allyl isothiocyanate and the compound of the present invention are added at final concentrations of 5.0 ⁇ M and 0.01%, respectively, using a dispenser with a built-in FDSS 3000. TRPA1 activity was evaluated by the change in fluorescence intensity thereafter.
  • the TRPA1 activity was expressed as a fluorescence intensity ratio (Ratio; F peak / F 0 ) obtained by dividing the fluorescence intensity peak (F peak ) after addition of the stimulating substance by the fluorescence intensity (F 0 ) before adding the stimulating substance.
  • a fluorescence intensity ratio (Ratio; F peak / F 0 ) obtained by dividing the fluorescence intensity peak (F peak ) after addition of the stimulating substance by the fluorescence intensity (F 0 ) before adding the stimulating substance.
  • the same substance was added to HEK293 cells not transduced with TRPA1, the fluorescence intensity ratio (Ratio 293 ) was calculated, and it was confirmed that the peak of activity due to the stimulating substance was derived from TRPA1 activation. .
  • the inhibitory action (activity inhibition rate;%) of each compound with respect to was evaluated.
  • the TRPA1 activity inhibitory action by mixing and adding allyl isothiocyanate (stimulant) (5.0 ⁇ M) and compound (0.01%) was calculated by the following formula.
  • TRPA1 activity inhibition rate (%) (1 ⁇ ((Stimulus substance + Ratio by addition of compound) ⁇ (Stimulation substance + Ratio by addition of compound 293 ))) / ((Stimulation substance + Ratio by addition of ethanol) ⁇ (Stimulation substance + Ethanol) Ratio 293 by addition))) x 100
  • TRPA1 activity of the following compounds of the present invention and comparative compounds each 100 ⁇ M) and d-camphor (100 ⁇ M, 500 ⁇ M, 1000 ⁇ M) against TRPA1 activation by 5.0 ⁇ M allyl isothiocyanate
  • the inhibition effect (activity inhibition rate) was evaluated (Table 2).
  • TRPA1 activity inhibitory action (2) The dose dependence of the TRPA1 activity inhibitory effect of 2,2,4-trimethyl-1-phenyl-3-pentanol (Compound 10) and t-1-methyl-3-phenylcyclohexanol (Compound 11) was examined. The effect of each compound on TRPA1 activation by 10 ⁇ M allyl isothiocyanate was measured (FIG. 1), and the IC 50 value of each compound is shown in Table 3. As a result, volume dependency was observed in the TRPA1 activity inhibitory effect of each compound.
  • Example 2 Effect of reducing human skin sensory irritation (1) Evaluation of sensory irritation to stimulating substances After washing the face, acclimation for 10 minutes was performed, and about 350 ⁇ l of 0.02% aqueous solution of the present compound (compound 10 and compound 11) was included. A 3 cm square filter paper was applied to the cheek for 3 minutes. Thereafter, the filter paper was removed, and acclimation was performed for 1 minute in a state where moisture on the cheek was sufficiently removed. Thereafter, a filter paper having a diameter of 2 centimeters containing about 200 ⁇ l of a 0.4 mM allyl isothiocyanate solution was placed on the area to which the filter paper containing 0.02% aqueous solution of the present invention was attached, and measurement was started. After the start of measurement, the degree of pain (intensity) reported according to the following pain standard value was recorded after 15, 30, 60, 90, 120, 150, 180 seconds.
  • FIG. 2 shows that an increase in the sense of discomfort (pain) caused by allyl isothiocyanate is reduced by the present invention.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022058946A1 (fr) 2020-09-18 2022-03-24 Université Grenoble Alpes Inhibition du canal trpa1 astrocytaire comme nouvelle cible therapeutique neuroprotectrice dans les phases prodromales de la maladie d'alzheimer

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JPS6456635A (en) * 1987-08-25 1989-03-03 Kao Corp 2,2,4-trimethyl-1-phenyl-3-pentanol and perfume composition containing said compound
WO1997030689A1 (en) * 1996-02-26 1997-08-28 The Procter & Gamble Company Personal treatment compositions and/or cosmetic compositions containing enduring perfume
JP2002121152A (ja) * 2000-10-13 2002-04-23 Chugai Pharmaceut Co Ltd 外用消炎鎮痛剤
WO2005004601A1 (de) * 2003-07-08 2005-01-20 Symrise Gmbh & Co. Kg Sekundäre alkohole als antimikrobielle wirkstoffe
JP2012511614A (ja) * 2008-12-16 2012-05-24 ザ プロクター アンド ギャンブル カンパニー 香料系
US20130315843A1 (en) * 2012-05-25 2013-11-28 The Procter & Gamble Company Composition for reduction of trpa1 and trpv1 sensations

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