Methylmenthol derivative and cool-sensation imparter composition containing same

Abstract

The present invention addresses the problem of providing a novel methylmenthol derivative usable as a cool-sensation imparter or sense-stimulating agent which has none of an undesirable irritating feeling, a peculiar odor, bitterness, and the like and is excellent in terms of the retention of a refreshing sensation or cool sensation. The cool-sensation imparter composition of the present invention contains a methylmenthol derivative represented by general formula (1). [In formula (1), symbol* indicates an asymmetric carbon atom, X represents a hydrogen atom or a substituent, and Y is an optionally substituted C 6-20 aryl group.]

Description

Methyl menthol derivatives and cooling agent compositions containing the same

[0001] The present invention relates to a novel methyl menthol derivative and a cooling agent composition containing the methyl menthol derivative. Furthermore, the present invention relates to a sensory stimulant composition containing the cooling agent composition, and to flavor or fragrance compositions and products containing the sensory stimulant composition.

[0002] Traditionally, cooling agents that provide a refreshing or cool sensation to human skin, mouth, nose, and throat have been used in toothpaste, confectionery (e.g., chewing gum, candy, etc.), tobacco, poultices, and cosmetics. Currently, l-menthol is widely used as a fragrance substance that provides these refreshing or cool sensations, but its cooling effect lacks persistence, and while increasing the amount used enhances the cooling effect, it can also be accompanied by a bitter taste.

[0003] In addition to l-menthol, numerous other compounds have been proposed and used as compounds that have a cooling effect. Examples of conventionally proposed compounds other than l-menthol that have a cooling effect include, for example, 3-substituted-p-menthane (see, for example, Patent Document 1), N-substituted-p-menthane-3-carboxamide (see, for example, Patent Documents 2 and 3), l-menthyl glucoside (see, for example, Patent Document 4), 3-(l-menthoxy)propane-1,2-diol (see, for example, Patent Document 5), 1-menthyl-3-hydroxybutyrate (see, for example, Patent Document 6), 1-alkoxy-3-(l-menthoxy)propane-2-ol (see, for example, Patent Document 7), esters of 3-hydroxymethyl-p-menthane (see, for example, Patent Document 8), N-acetylglycinementhane methyl ester (see, for example, Patent Document 9), l-isoplegol ( For example, see Patent Document 10.), (2S)-3-{(1R,2S,5R)-[5-methyl-2-(1-methylethyl)cyclohexyl]oxy}-1,2-propanediol (for example, see Patent Document 11.), 2-hydroxymethylmenthol (for example, see Patent Document 12.), menthoxyalkane-1-ol (for example, see Patent Document 13.), (l-menthyloxyalkoxy)alkanol (for example, see Patent Document 14.), N-substituted p-menthanecarboxamides (for example, see Patent Documents 15 and 16.), Nα-(menthanecarbonyl)amino acid amides (for example, see Patent Document 17.), isopulegol derivatives (for example, see Patent Document 18.), methylmenthol derivatives (for example, see Patent Document 19.), and so on.

[0004] Japanese Unexamined Patent Publication No. 47-16647 Japanese Unexamined Patent Publication No. 16648 Japanese Unexamined Japanese Patent Publication No. 2007-530689 Unexamined Japanese Patent Application No. 48-33069 Unexamined Japanese Patent Application No. 58-8833 Publication No. 4 Japanese Patent Application Publication No. 61-194049 Publication of Japanese Patent Application Publication No. 2-290827 Publication of Japanese Patent Application Publication No. 5-255186 Publication of Japanese Patent Application Publication No. 5-255217 Publication of Japanese Patent Application Publication No. 6-650 Japanese Patent Publication No. 23, Japanese Patent Publication No. Hei 7-82200, Japanese Patent Publication No. Hei 7-118119, Japanese Patent Publication No. 2001-294546, Japanese Patent Publication No. 2005-343915, Japanese Patent Publication No. 2007-511546, Japanese Patent Publication No. 2011-530608, Japanese Patent Publication No. 2008-115181, International Publication No. 2013 / 033501, International Publication No. 2016 / 153011

[0005] However, while the conventionally proposed cooling agents mentioned above provide a certain degree of cooling effect, they are still not entirely satisfactory in terms of the duration of that cooling effect. Furthermore, improvements are needed in terms of sensory stimulation effects as well.

[0006] Accordingly, the object of the present invention is to provide a novel methyl menthol derivative that can be used as a cooling agent or sensory stimulant that is free from undesirable irritation, peculiar odor, bitterness, etc., and has excellent sustained cooling and refreshing sensations. The object of the present invention is also to provide a cooling agent composition containing the novel methyl menthol derivative, and a sensory stimulant composition containing the cooling agent composition. Furthermore, the object of the present invention is to provide a flavor composition or fragrance composition containing the sensory stimulant composition, and products containing the sensory stimulant composition or the flavor composition or fragrance composition.

[0007] As a result of diligent research to solve the above problems, the present inventors have discovered that a novel methyl menthol derivative having a specific organic group at position 1 of the methyl menthol skeleton has a strong cooling effect, excellent persistence, and is free from bitterness, making it useful as a cooling substance and even a sensory stimulant, thus completing the present invention.

[0008] In other words, the present invention relates to the following [1] to

[19] . [1] The following general formula (1):

[0009]

[0010] A cooling agent composition containing a methyl menthol derivative represented by formula (1), in which * represents an asymmetric carbon atom, X represents a hydrogen atom or a substituent, and Y is an aryl group having 6 to 20 carbon atoms which may have substituents. [2] The cooling agent composition according to [1], wherein in the general formula (1), X is a hydrogen atom, a hydroxyl group, an acetoxy group, an oxo group or a methyl group, and Y is an aryl group which may have substituents. [3] The cooling agent composition according to [1] or [2], wherein the general formula (1) is represented by the following structural formula (2).

[0011]

[0012] [In formula (2), the * indicates an asymmetric carbon atom.] [4] A cooling agent composition according to any one of [1] to [3], further comprising at least one cooling substance other than the methyl menthol derivative. [5] The cooling substance other than the methyl menthol derivative is menthol, menthone, camphor, plegol, isopuregol, cineole, cubenol, menthyl acetate, pregyl acetate, isopuregyl acetate, menthyl salicylate, pregyl salicylate, isopuregyl salicylate, 3-(l-menthoxy)propane-1,2-diol, 2-methyl-3-(l-menthoxy)propane-1,2-diol, 2-(l-menthoxy)ethane-1-ol, 3-(l-menthoxy)propane-1-ol, 4-(l-menthoxy)butane-1 -ol, 3-hydroxybutanoate menthyl, glyoxylate menthyl, p-menthane-3,8-diol, 1-(2-hydroxy-4-methylcyclohexyl)ethanone, lactate menthyl, menthyl glycerin ketal, menthyl-2-pyrrolidone-5-carboxylate, monomentyl succinate, alkali metal salts of monomentyl succinate, alkaline earth metal salts of monomentyl succinate, monomentyl glutarate, alkali metal salts of monomentyl glutarate, Alkaline earth metal salt of monomentyl glutarate, N-{[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl}glycine, p-menthane-3-carboxylic acid glycerol ester, menthol propylene glycol carbonate, menthol ethylene glycol carbonate, p-menthane-2,3-diol, 2-isopropyl-N,2,3-trimethylbutanamide, N-ethyl-p-menthane-3-carboxamide, 3-(p-menthane-3-carbox Thamide) Ethyl acetate, N-(4-methoxyphenyl)-p-menthanecarboxamide, N-ethyl-2,2-diisopropylbutanamide, N-cyclopropyl-p-menthanecarboxamide, N-(4-cyanomethylphenyl)-p-menthanecarboxamide, N-(2-pyridine-2-yl)-3-p-menthanecarboxamide, N-(2-hydroxyethyl)-2-isopropyl-2,3-dimethylbutanamide, N-(1,1-dimethyl-2-hydroxyethyl)-2,2-Diethylbutanamide, Cyclopropanecarboxylic acid (2-Isopropyl-5-methylcyclohexyl)amide, N-Ethyl-2,2-Diisopropylbutanamide, N-[4-(2-amino-2-oxoethyl)phenyl]-p-menthanecarboxamide, 2-[(2-p-menthoxy)ethoxy]ethanol, 2,6-Diethyl-5-isopropyl-2-methyltetrahydropyran, Trans-4-tert-butylcyclohexanol, N-[4-(cyanomethyl)phenyl]-2-isopropyl-5,5-dimethylcyclohexylcarboxamide, and N-[3-Hydroxy-4-methoxyphenyl]-2-isopropyl-5,A cooling agent composition according to [4], wherein the cooling agent is at least one cooling substance selected from the group consisting of: one or more compounds selected from 5-dimethylcyclohexylcarboxamide; one or more sugar alcohols selected from xylitol, erythritol, dextrose, and sorbitol; and one or more natural products selected from Japanese peppermint oil, peppermint oil, spearmint oil, and eucalyptus oil. [6] A sensory stimulant composition containing the cooling agent composition according to any one of [1] to [5]. [7] A sensory stimulant composition according to [6], further containing at least one warming substance. [8] The warming substance is Vanillyl methyl ether, vanillyl ethyl ether, vanillyl propyl ether, vanillyl isopropyl ether, vanillyl butyl ether, vanillyl amyl ether, vanillyl isoamyl ether, vanillyl hexyl ether, isovanillyl methyl ether, isovanillyl ethyl ether, isovanillyl propyl ether, isovanillyl isopropyl ether, isovanillyl butyl ether, isovanillyl amyl ether, isovanillyl isoamyl ether, isovanillyl hexyl ether, ethyl vanillyl methyl ether, ethyl vanillyl ethyl ether, ethyl vanillyl propyl ether, ethyl vanillyl isopropyl ether, ethyl vanillyl butyl ether, ethyl vanillyl Amyl ether, ethyl vanillyl isoamyl ether, ethyl vanillyl hexyl ether, vanillin propylene glycol acetal, isovanillin propylene glycol acetal, ethyl vanillin propylene glycol acetal, vanillyl butyl ether acetate, isovanillyl butyl ether acetate, ethyl vanillyl butyl ether acetate, 4-(l-menthoxymethyl)-2-(3'-methoxy-4'-hydroxyphenyl)-1,3-dioxolane, 4-(l-menthoxymethyl)-2-(3'-hydroxy-4'-methoxyphenyl)-1,3-dioxolane, 4-(l-menthoxymethyl)-2-(3'-ethoxy-4'-hydroxyphenyl)-1,3-Dioxolane, Capsaicin, Dihydrocapsaicin, Nordihydrocapsaicin, Homodihydrocapsaicin, Homocapsaicin, Biscapsaicin, Trishomocapsaicin, Nornorcapsaicin, Norcapsaicin, Capsaicinol, Vanillylcaprylamide (Octyl vanillylamide), Vanillylperillagonamide (Nonyl vanillylamide), Vanillylcaproamide (Decylic vanillylamide), Vanillylundecaneamide (Undecyl (Vanillyl acid amide), N-trans-feruloyltyramine, N-5-(4-hydroxy-3-methoxyphenyl)-2E,4E-pentadienoylpiperidine, N-trans-feruloylpiperidine, N-5-(4-hydroxy-3-methoxyphenyl)-2E-pentenoylpiperidine, N-5-(4-hydroxyphenyl)-2E,4E-pentadienoylpiperidine, piperine, isopiperine, chavicine, isochavicine, piperamine, pipereti Piperolein B, Retrofructamide A, Piperaside, Guinenside, Piperrine, Piperamide C5:1 (2E), Piperamide C7:1 (6E), Piperamide C7:2 (2E, 6E), Piperamide C9:1 (8E), Piperamide C9:2 (2E, 8E), Piperamide C9:3 (2E, 4E, 8E), Fagalamide, Sanshool-I, Sanshool-II, Hydroxysanshool, Sanshoamide, Gingerol, Shogaol, Zingero The sensory stimulant composition according to [7] above, comprising at least one warming substance selected from the group consisting of: one or more compounds selected from methyl gingerol, paradol, spiranthol, cabicin, polygodial (tadeonal), isopolygodial, dihydropolygodial, and tadeon; and one or more natural products selected from capsicum oil, capsicum oleoresin, ginger oleoresin, jambu oleoresin (spicy water pepper extract), sansho pepper extract, sansho amide, black pepper extract, white pepper extract, and knotweed extract.

[0013] [9] A flavor or fragrance composition containing the sensory stimulant composition described in any one of [6] to [8] above.

[10] The flavor or fragrance composition described in [9] above, wherein the content of the sensory stimulant composition is 0.00001 to 90% by mass.

[11] A product selected from the group consisting of beverages, food, cosmetics, toiletries, air care products, daily necessities and general merchandise, oral compositions, hair care products, skin care products, body care products, laundry detergents, fabric softeners, tobacco, quasi-drugs and pharmaceuticals, which contains the sensory stimulant composition described in any one of [6] to [8] above.

[12] The product described in

[11] above, wherein the content of the sensory stimulant composition is 0.00001 to 50% by mass.

[13] A product selected from the group consisting of beverages, food, cosmetics, toiletries, air care products, daily necessities and general merchandise, oral compositions, hair care products, skin care products, body care products, laundry detergents, fabric softeners, tobacco, quasi-drugs, and pharmaceuticals, which contains the flavor or fragrance composition described in [9] or

[10] above.

[14] The product described in

[13] above, wherein the content of the flavor or fragrance composition is 0.00001 to 50% by mass.

[15] A method for producing a product selected from the group consisting of beverages, food, cosmetics, toiletries, air care products, daily necessities and general merchandise, oral compositions, hair care products, skin care products, body care products, laundry detergents, fabric softeners, tobacco, quasi-drugs, and pharmaceuticals, the method for producing a product which contains the sensory stimulant composition described in any one of [6] to [8] above.

[16] A method for producing any product selected from the group consisting of beverages, food products, cosmetics, toiletries, air care products, daily necessities and general merchandise, oral compositions, hair care products, skin care products, body care products, laundry detergents, fabric softeners, tobacco, quasi-drugs, and pharmaceuticals, wherein the product is formulated with the flavor or fragrance composition described in [9] or

[10] above.

[0014]

[17] The following general formula (1):

[0015]

[0016] [In formula (1), the * mark represents an asymmetric carbon atom, X represents a hydrogen atom or a substituent, and Y represents an aryl group having 6 to 20 carbon atoms which may have a substituent.] A methyl menthol derivative represented by the formula.

[18] In the general formula (1), the methyl menthol derivative according to

[17] above, wherein X is a hydrogen atom, a hydroxyl group, an acetoxy group, an oxo group or a methyl group, and Y is a phenyl group which may have a substituent.

[19] The methyl menthol derivative according to

[17] or

[18] above, wherein the general formula (1) is represented by the following structural formula (2).

[0017]

[0018] [In formula (2), the * mark represents an asymmetric carbon atom.]

[0019] The cooling sensation agent composition containing the methyl menthol derivative of the present invention has a strong cooling sensation intensity, has a clear cooling sensation, is excellent in its persistence, and has little bitterness. Therefore, by blending the cooling sensation agent composition of the present invention into various products, it is possible to impart a cooling sensation and a cool feeling with excellent persistence to these products.

[0020] Hereinafter, the present invention will be described in detail. However, the present invention is not limited to the following embodiments, and can be arbitrarily modified and implemented without departing from the gist of the present invention. In this specification, "the compound represented by formula (X)" may be simply referred to as "compound (X)". In this specification, "weight %" and "mass %" are synonymous. Also, when the unit "ppm" is described, it indicates "weight ppm". Further, "~" indicating a numerical range is used in the sense of including the numerical values described before and after it as the lower limit value and the upper limit value.

[0021] The cooling sensation agent composition of the present invention is characterized by containing a methyl menthol derivative represented by the following general formula (1) as a cooling sensation substance.

[0022] <第

[0023] [In formula (1), the * mark represents an asymmetric carbon atom, X represents a hydrogen atom or a substituent, and Y represents an aryl group having 6 to 20 carbon atoms which may have a substituent.]

[0024] Specifically, methyl menthol derivatives represented by general formula (1) have a cyclohexane ring structure and chiral carbons at positions 1 and 2, and therefore there are four diastereomers shown in the following formulas (1-a) to (1-d).

[0025]

[0026] The methyl menthol derivative represented by general formula (1) is preferably the trans isomer.

[0027] In general formula (1), X represents a hydrogen atom or a substituent. Examples of substituents include hydroxyl groups, acetoxy groups, oxo groups, C1-C10 alkyl groups, hydroxymethyl groups, hydroxyethyl groups, methoxy groups, ethoxy groups, and phenoxy groups. Examples of C1-C10 alkyl groups include methyl groups, ethyl groups, n-propyl groups, isopropyl groups, isobutyl groups, sec-butyl groups, tert-butyl groups, pentyl groups, hexyl groups, heptyl groups, octyl groups, nonyl groups, and decyl groups. Among these, from the viewpoint of sustained cooling sensation, cooling intensity, low bitterness, and ease of manufacture, it is preferable that X is a hydrogen atom, a hydroxyl group, an acetoxy group, an oxo group, or a methyl group.

[0028] In general formula (1), Y is an aryl group having 6 to 20 carbon atoms, which may have substituents. Examples of aryl groups having 6 to 20 carbon atoms include aromatic monocyclic groups, aromatic polycyclic groups, or aromatic fused cyclic groups having 6 to 20 carbon atoms. Specifically, examples include phenyl groups, naphthyl groups, anthryl groups, phenanthryl groups, indenyl groups, and the like.

[0029] Substituents that a C6-C20 aryl group may have include, for example, a hydroxyl group; a C1-C4 hydroxyalkyl group such as a hydroxymethyl group, a hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, and a 1-hydroxybutyl group; a methoxy group, an ethoxy group, an n-propoxyl group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a methylenedioxy group, an ethylenedioxy group, a tert-butoxy group, and a phenoxy group. C1-C6 alkoxy groups such as steroids; mercapto groups; C1-C4 thioalkoxy groups such as thiomethoxy, thioethoxy, n-thiopropoxy, thioisopropoxy, n-thiobutoxy, thioisobutoxy, sec-thiobutoxy, methylenedithio, and tert-thiobutoxy; C1-C6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl; Cycloalkyl groups with 5 to 8 carbon atoms, such as cyclopentyl, cyclohexyl, and cycloheptyl groups; halogen atoms, such as fluorine, chlorine, bromine, and iodine atoms; phenyl groups; aralkyl groups with 7 to 12 carbon atoms, such as benzyl, phenylethyl, and naphthylmethyl groups; carboxyl groups; alkoxycarbonyl groups with 2 to 8 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl groups; and groups with 1 to 7 carbon atoms, such as formyl, acetyl, propionyl, and benzoyl groups. Acyl groups; carboxamide groups; C2-C8 dialkylamino groups such as dimethylamino, diethylamino, and dibutylamino groups; nitrile groups; cyanoalkyl (C1-C4 alkyl group) groups such as cyanomethyl, cyanoethyl, cyanopropyl, and cyanobutyl groups; aliphatic heterocyclic groups such as oxyranyl, aziridinyl, 2-oxopyropidyl, piperidyl, piperazinyl, morpholino, tetrahydrofuryl, tetrahydropyranyl, and tetrahydrothienyl groups;Examples of aromatic heterocyclic groups include tetradinyl, furyl, thienyl, pyridyl, pyridinyl, pyrazinyl, pyradadinyl, imidazoyl, oxazoyl, thiazoyl, benzofuryl, benzothienyl, quinolyl, isoquinolyl, quinoxanoyl, phthalazinyl, quinazolinyl, naphthyldinyl, synnolinyl, benzimidazoline, benzoxazolyl, and benzothiazolyl groups.

[0030] In the present invention, Y is preferably a phenyl group which may have substituents, from the viewpoint of the persistence of the cooling sensation, the intensity of the cooling sensation, the low bitterness, and the ease of manufacture.

[0031] The methyl menthol derivative (1) of the present invention can be synthesized, for example, by the methods shown in the following schemes 1 to 5. However, the synthesis method is not limited to the methods shown in schemes 1 to 5 below.

[0032] The methyl menthol derivative (1) of the present invention is synthesized from a ketone compound represented by the following formula (3) (hereinafter also referred to as ketone compound (3)) or an alcohol compound represented by the following formula (4) (hereinafter also referred to as alcohol compound (4)) according to the method described in International Publication No. 2016 / 153011. In formulas (3) and (4) below, the asterisk (*) indicates a chiral carbon atom.

[0033]

[0034] The ketone compound (3) and the alcohol compound (4) are synthesized according to the method shown in Scheme 1 below.

[0035]

[0036] (In Scheme 1 above, the asterisk (*) represents a chiral carbon atom.)

[0037] Steps [A], [B], and [D] can be carried out by the same method as described in Tetrahedron 1986, Vol. 42, No. 8, p2230. Specifically, step [A] can be carried out by a conjugate addition (1,4-addition) reaction, step [B] can be carried out by an intramolecular Prince reaction, and step [D] can be carried out by a conjugate addition (1,4-addition) reaction. Step [C] can be carried out by hydrogenation using a commonly used metal catalyst such as nickel or palladium. Step [E] can be carried out by the same method as described in J. Mol. Cat. A (1996), No. 109, pp. 201-208, i.e., by a hydrogenation reaction.

[0038] Next, a carboxylic acid compound represented by the following general formula (11) (hereinafter also referred to as "carboxylic acid compound (11)") is synthesized from a ketone compound (3) or an alcohol compound (4), for example, according to the method shown in Scheme 2 below. On the other hand, an aldehyde compound represented by the general formula (13) (hereinafter also referred to as "aldehyde compound (13)") is synthesized from a ketone compound (3), for example, according to the method shown in Scheme 2 below.

[0039]

[0040] (In scheme 2 above, the asterisk (*) represents a chiral carbon atom, R １ and R ２ (wherein is a linear or branched alkyl group having 1 to 10 carbon atoms, which may have substituents; V is a halogen atom; and Ph is a phenyl group.)

[0041] The halogenation reaction in step [F] can be carried out, for example, by reacting alcohol compound (4) with phosphorus pentachloride to synthesize halide (9) (V=Cl). Alternatively, it can be carried out by a similar method as described in J. Chem. Soc. Perkin Trans., (1990): pp. 1275-1277. Steps [G] and [H] can be carried out by a similar method as described in British Patent Application Publication No. 1392907. Steps [I], [J] and [K] can be carried out by a similar method as described in German Patent Application Publication No. 102012202885. Steps [L] and [M] can be carried out by J. Am. Chem. Soc. (2004), Vol. 126, No. 41, pp. This can be done by the same method as described in 13312-13319.

[0042] The compound represented by general formula (1) of the present invention can be synthesized from the carboxylic acid compound (11) obtained by the above method, for example, according to the method shown in scheme 3 below.

[0043]

[0044] (In scheme 3 above, the asterisk, X, and Y have the same meaning as described above.)

[0045] When synthesis is carried out according to Scheme 3, step [N] can be performed by a method similar to that described in International Publication No. 2013 / 033501.

[0046] Alternatively, the compound represented by general formula (1) of the present invention can also be synthesized from a carboxylic acid compound (11) according to the method shown in scheme 4 below, for example.

[0047]

[0048] (In scheme 4 above, the asterisk, X, and Y are equivalent to those described above.)

[0049] When synthesis is carried out according to Scheme 4, step [O] can be performed by a method similar to that described in Japanese Patent Publication No. 47-16648 or International Publication No. 2013 / 033501.

[0050] Furthermore, the compound represented by the general formula (1) of the present invention can also be synthesized from a carboxylic acid compound (11) according to the method shown in scheme 5 below, for example.

[0051]

[0052] (In scheme 5 above, the asterisk, X, and Y are equivalent to those described above.)

[0053] When synthesized according to Scheme 5, step [P] can be carried out by mesyling the carboxylic acid compound (11) to convert it into an active acyl intermediate, and then reacting it with an amine.

[0054] Preferred specific examples of the methyl menthol derivative of the present invention represented by formula (1) include, but are not limited to, the following compounds. In the following compounds, Me represents a methyl group, Et represents an ethyl group, and Ac represents an acetyl group.

[0055]

[0056]

[0057] The methyl menthol derivative represented by general formula (1) of the present invention obtained in this manner has a strong, persistent cooling effect and can be used as a cooling agent or sensory stimulant on its own.

[0058] The methyl menthol derivative of the present invention needs to have its application range and method appropriately changed depending on the type of product and intended use, but typically it is applied in an amount of 1.0 × 10⁻¹⁶ relative to the total composition of the product. －８ ~50% by mass, preferably 1.0 × 10 －７ ~20% by mass, particularly preferably 1.0 × 10 －６ It is preferable to use it at a concentration of ~5% by mass.

[0059] When preparing a cooling agent composition, the content of methyl menthol derivatives needs to be appropriately adjusted in terms of its application range and method depending on the type of product and intended use. However, it is usually 0.00001 to 100% by mass, preferably 0.0001 to 50% by mass, and particularly preferably 0.001 to 30% by mass, based on the total mass of the cooling agent composition.

[0060] In the cooling agent composition containing the methyl menthol derivative according to the present invention, a cooling agent composition with even greater cooling intensity can be obtained by using at least one cooling substance selected from other cooling substances in combination with the methyl menthol derivative of the present invention. Furthermore, a sensory stimulant composition containing the cooling agent composition with enhanced cooling intensity can be prepared.

[0061] Examples of cooling substances not included in the methyl menthol derivatives of the present invention include: menthol, menthone, camphor, plegol, isopuregol, cineole, cubenol, menthyl acetate, plegyl acetate, isopuregyl acetate, menthyl salicylate, plegyl salicylate, isopuregyl salicylate, 3-(l-menthoxy)propane-1,2-diol, 2-methyl-3-(l-menthoxy)propane-1,2-diol, 2-(l-menthoxy)ethane-1-ol, 3-(l-menthoxy)propane-1-ol, 4-(l-menthoxy)butan-1-ol, and 3-hydroxybutanoic acid menthyl Menthyl glyoxylate, p-menthane-3,8-diol, 1-(2-hydroxy-4-methylcyclohexyl)ethanone, menthyl lactate, menthyl glycerin ketal, menthyl-2-pyrrolidone-5-carboxylate, monomentyl succinate, alkali metal salt of monomentyl succinate, alkaline earth metal salt of monomentyl succinate, monomentyl glutarate, alkali metal salt of monomentyl glutarate, alkaline earth metal salt of monomentyl glutarate, N-{[5-methyl-2-(1- [Methylethyl)cyclohexyl]carbonyl}glycine, p-menthane-3-carboxylic acid glycerol ester, menthol propylene glycol carbonate, menthol ethylene glycol carbonate, p-menthane-2,3-diol, 2-isopropyl-N,2,3-trimethylbutanamide, N-ethyl-p-menthane-3-carboxamide, 3-(p-menthane-3-carboxamide)ethyl acetate, N-(4-methoxyphenyl)-p-menthanecarboxamide, N-ethyl-2,2-diisopropyl Tanamide, N-cyclopropyl-p-menthanecarboxamide, N-(4-cyanomethylphenyl)-p-menthanecarboxamide, N-(2-pyridine-2-yl)-3-p-menthanecarboxamide, N-(2-hydroxyethyl)-2-isopropyl-2,3-dimethylbutanamide, N-(1,1-dimethyl-2-hydroxyethyl)-2,2-diethylbutanamide, cyclopropanecarboxylic acid (2-isopropyl-5-methylcyclohexyl)amide, N-ethyl-2,2-diisopropylbutanamide,Compounds such as N-[4-(2-amino-2-oxoethyl)phenyl]-p-menthanecarboxamide, 2-[(2-p-menthoxy)ethoxy]ethanol, 2,6-diethyl-5-isopropyl-2-methyltetrahydropyran, trans-4-tert-butylcyclohexanol, N-[4-(cyanomethyl)phenyl]-2-isopropyl-5,5-dimethylcyclohexylcarboxamide, and N-[3-hydroxy-4-methoxyphenyl]-2-isopropyl-5,5-dimethylcyclohexylcarboxamide (α), as well as their racemic and optically active forms; sugar alcohols such as xylitol, erythritol, dextrose, and sorbitol (β); natural products such as Japanese peppermint oil, peppermint oil, spearmint oil, and eucalyptus oil (γ); Japanese Patent Publication No. 2001-294546, Japanese Patent Publication No. 2005-343915, Japanese Patent Publication No. 2007-002005, Japanese Patent Publication No. 2009-263664, Japanese Patent Publication No. 2010-254621, Japanese Patent Publication No. 2010-254622, Japanese Patent Publication No. 2011-079953, U.S. Patent No. 4,136163, U.S. Patent U.S. Patent No. 4150052, U.S. Patent No. 4178459, U.S. Patent No. 4190643, U.S. Patent No. 4193936, U.S. Patent No. 4226988, U.S. Patent No. 4230688, U.S. Patent No. 4032661, U.S. Patent No. 4153679, U.S. Patent No. 4296255, U.S. Patent No. 445942 U.S. Patent No. 5, U.S. Patent No. 5,009893, U.S. Patent No. 5,266592, U.S. Patent No. 5,698181, U.S. Patent No. 5,725865, U.S. Patent No. 5,843466, U.S. Patent No. 6,231900, U.S. Patent No. 6,277385, U.S. Patent No. 6,280762, U.S. Patent No. 6,306429, U.S. Patent No. 6,432441, U.S. Patent No. 6,455080, U.S. Patent No. 6,627233, U.S. Patent No. 7,078066, U.S. Patent No. 6,783783, U.S. Patent No. 6,884906, U.S. Patent No. 7,030273, U.S. Patent No. 7,090832, U.S. Patent Application Publication No. 2004 / 0175489,Examples include the compounds (δ) described in U.S. Patent Publication No. 2004 / 0191402, U.S. Patent Publication No. 2005 / 0019445, U.S. Patent Publication No. 2005 / 0222256, U.S. Patent Publication No. 2005 / 0265930, U.S. Patent Publication No. 2006 / 015819, U.S. Patent Publication No. 2006 / 0249167, European Patent Publication No. 1689256, International Publication No. 2005 / 082154, International Publication No. 2005 / 099473, International Publication No. 2006 / 058600, International Publication No. 2006 / 092076, International Publication No. 2006 / 125334, and International Publication No. 2016 / 153011. These can be used by combining one or more of them as appropriate. In particular, it is preferable to include at least one cooling substance selected from the group consisting of compounds (α), sugar alcohols (β), and natural products (γ).

[0062] The methyl menthol derivative of the present invention and the cooling substance not contained herein can be used in any ratio as long as the effects of the present invention are not impaired. However, the preferred ratio of the methyl menthol derivative to the cooling substance not contained herein is preferably in the range of 1:99 to 90:10 by mass ratio.

[0063] The cooling agent composition of the present invention can be incorporated into products such as flavor compositions or fragrance compositions (hereinafter also referred to as flavor or fragrance compositions), beverages, foods, cosmetics, toiletries, air care products, daily necessities and general merchandise, oral compositions, hair care products, skin care products, body care products, laundry detergents, fabric softeners, tobacco, quasi-drugs, and pharmaceuticals.

[0064] Furthermore, since the cooling agent composition containing the methyl menthol derivative of the present invention has a strong and sustained cooling effect, a sensory stimulant composition having a cooling effect can be prepared by incorporating this cooling agent composition. When preparing a sensory stimulant composition, the amount of the cooling agent composition to be blended needs to be appropriately changed depending on the type of product, the intended use, etc., but it is generally preferable to use it at a concentration of 0.00001 to 50% by mass, preferably 0.0001 to 20% by mass, and particularly preferably 0.001 to 4% by mass, relative to the total composition of the sensory stimulant composition. The sensory stimulant composition of the present invention is a composition that provides a sensory stimulating effect. The sensory stimulating effect includes a cooling effect and / or a warming effect, and therefore, in the present invention, the sensory stimulant composition is used as a concept that also includes a cooling agent composition and / or a warming agent composition.

[0065] In the cooling agent composition of the present invention, the stimulating effect of the sensory stimulant composition can be adjusted by using a warming substance in combination. Examples of warming substances include: Vanillyl methyl ether, vanillyl ethyl ether, vanillyl propyl ether, vanillyl isopropyl ether, vanillyl butyl ether, vanillyl amyl ether, vanillyl isoamyl ether, vanillyl hexyl ether, isovanillyl methyl ether, isovanillyl ethyl ether, isovanillyl propyl ether, isovanillyl isopropyl ether, isovanillyl butyl ether, isovanillyl amyl ether, isovanillyl isoamyl ether, isovanillyl hexyl ether, ethyl vanillyl methyl ether, ethyl vanillyl ethyl ether, ethyl vanillyl propyl ether, ethyl vanillyl isopropyl ether, ethyl vanillyl butyl ether, ethyl vanillyl amyl ether, ethyl vanillyl isoamyl ether, ethyl vanillyl hexyl ether, vanillin propylene glycol acetal, isovanillin propylene glycol acetal, ethyl vanillin propylene glycol acetal, vanillyl butyl ether acetate, isovanillyl Tyl ether acetate, ethyl vanillyl butyl ether acetate, 4-(l-menthoxymethyl)-2-(3'-methoxy-4'-hydroxyphenyl)-1,3-dioxolane, 4-(l-menthoxymethyl)-2-(3'-hydroxy-4'-methoxyphenyl)-1,3-dioxolane, 4-(l-menthoxymethyl)-2-(3'-ethoxy-4'-hydroxyphenyl)-1,3-dioxolane, capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homo Dihydrocapsaicin, homocapsaicin, biscapsaicin, trishomocapsaicin, nororcapsaicin, norcapsaicin, capsaicinol, vanillylcaprylamide (octylic acid vanillylamide), vanillylperillagonamide (nonyl acid vanillylamide), vanillylcaproamide (decylic acid vanillylamide), vanillylundecanamide (undecylic acid vanillylamide), N-transferuloyltyramine, N-5-(4-hydroxy-3-methoxyphenyl)-2E,4E-pentadienolpiperidine, N-trans-feruloylpiperidine, N-5-(4-hydroxy-3-methoxyphenyl)-2E-pentenoylpiperidine, N-5-(4-hydroxyphenyl)-2E, 4E-pentadienolpiperidine, piperine, isopiperine, chavicine, isochavicine, piperamine, piperetin, piperolein B, retrofructamide A, piperaside, gwinenside, piperine, piperamide C5:1 (2E), piperamide C7:1 (6E), piperamide C7:2 Compounds such as (2E, 6E), piperamide C9:1 (8E), piperamide C9:2 (2E, 8E), piperamide C9:3 (2E, 4E, 8E), fagalamide, sanshool-I, sanshool-II, hydroxysanshool, sanshoamide, gingerol, shogaol, zingerone, methylgingerol, paradol, spirantol, cabicin, polygodial (tadeonal), isopolygodial, dihydropolygodial, tadeone, etc. (ε) and their racemic and optically active forms; natural products such as capsicum oil, capsicum oleoresin, ginger oleoresin, jambu oleoresin (Acmella vulgaris extract), sansho extract, sanshoamide, black pepper extract, white pepper extract, and knotweed extract (ζ); Examples include the compound (η) described in Japanese Patent Publication No. 8-225564, Japanese Patent Publication No. 2007-015953, Japanese Patent Publication No. 2007-510634, Japanese Patent Publication No. 2008-505868, International Publication No. 2007 / 013811, International Publication No. 2003 / 106404, European Patent Application Publication No. 1323356, German Patent Application Publication No. 10351422, US Patent Application Publication No. 2005 / 0181022, and US Patent Application Publication No. 2008 / 0038386. These can be used in combination of one or more as appropriate. In particular, it is preferable to include at least one temperature-sensing substance selected from the group consisting of compound (ε) and natural product (ζ).

[0066] When the purpose is to achieve a cooling effect, the mixing ratio of the warming substance to the cooling substance should be within a range where the addition of the warming substance does not impart a warming effect. Typically, the amount of the warming substance is 0.001 to 0.95 times, preferably 0.01 to 0.5 times, relative to the total mass of the cooling agent composition. In the sensory stimulant composition containing the methyl menthol derivative of the present invention, the addition of the warming substance to the cooling agent composition in the above proportions further improves the cooling effect and increases the cooling effect. Furthermore, when the purpose is to achieve a warming effect, the amount of the cooling agent composition should be within a range where the addition of the cooling agent composition does not impart a cooling effect. Typically, the amount of the cooling agent composition is 0.001 to 0.95 times, preferably 0.01 to 0.5 times, relative to the total mass of the warming substance.

[0067] Fragrance components that can be included with the cooling agent composition or sensory stimulant composition of the present invention include various synthetic fragrances, natural essential oils, synthetic essential oils, citrus oils, animal fragrances, etc. For example, a wide range of fragrance components as described in "Collection of Known and Conventional Technologies (Fragrances) Part I" (published by the Japan Patent Office on January 29, 1999) can be used. Representative examples among these include α-pinene, limonene, cis-3-hexenol, phenylethyl alcohol, styraryl acetate, eugenol, rose oxide, linalool, benzaldehyde, muscone, Musk T (trade name, manufactured by Takasago International Corporation), Tesalon (trade name, manufactured by Takasago International Corporation).

[0068] The content of the cooling agent composition or sensory stimulant composition in a flavor or fragrance composition containing the cooling agent composition or sensory stimulant composition of the present invention and the above-mentioned fragrance component can be adjusted depending on the type of fragrance and other components blended together, the intended use of the flavor or fragrance composition, and so on. For example, in a fragrance composition for cosmetics, the content of the cooling agent composition or sensory stimulant composition is generally 0.00001 to 90% by mass, preferably 0.001 to 50% by mass, and particularly preferably 0.01 to 20% by mass, relative to the total mass of the flavor or fragrance composition.

[0069] Furthermore, in flavor compositions for beverages and food products, the content of the cooling agent composition or sensory stimulant composition is generally 0.00001 to 90% by mass, preferably 0.0001 to 50% by mass, and particularly preferably 0.001 to 30% by mass, relative to the total mass of the flavor or fragrance composition.

[0070] A flavor or fragrance composition containing a cooling agent composition, or a flavor or fragrance composition containing a sensory stimulant composition, may optionally contain one or more other fragrance fixatives commonly used in flavor or fragrance compositions. Examples of these other fragrance fixatives include ethylene glycol, propylene glycol, dipropylene glycol, glycerin, hexyl glycol, benzyl benzoate, triethyl citrate, diethyl phthalate, Harcolin, medium-chain triglyceride, and medium-chain diglyceride, and one or more of these may be included.

[0071] As described above, the cooling agent composition or sensory stimulant composition of the present invention can be used to impart a cooling sensation or sensory stimulation to various products, either alone or as a cooling agent composition-containing flavor or fragrance composition or a sensory stimulant composition-containing flavor or fragrance composition.

[0072] Products that are provided with a cooling sensation or sensory stimulation by the cooling agent composition or sensory stimulant composition of the present invention, or by a cooling agent composition-containing flavor or fragrance composition or a sensory stimulant composition-containing flavor or fragrance composition, are not particularly limited, but include, for example, beverages; food; toiletries such as detergents, dish soaps, and bleaches; air care products such as deodorizers and air fresheners; oral compositions; cosmetics such as fragrance products, basic cosmetics, finishing cosmetics, hair cosmetics, sunscreens, and medicated cosmetics; hair care products; skin care products such as soaps; body care products such as body washes; bath additives; laundry detergents; fabric softeners; aerosols; daily necessities and miscellaneous goods; tobacco; quasi-drugs or pharmaceuticals.

[0073] The beverages include fruit juices, fruit wines, dairy beverages, carbonated drinks, soft drinks, energy drinks, and alcoholic beverages (beer, beer-flavored drinks, highballs, chuhai, etc.); tea beverages or beverages such as green tea, oolong tea, black tea, persimmon leaf tea, chamomile tea, bamboo grass tea, mulberry tea, houttuynia cordata tea, pu-erh tea, mate tea, rooibos tea, gymnema tea, guava tea, coffee, and cocoa; soups such as Japanese-style soup, Western-style soup, and Chinese soup; and various instant beverages; the food products include frozen desserts such as ice cream, sherbet, and ice pops; desserts such as jelly and pudding; Western-style confectionery such as cakes, cookies, chocolate, and chewing gum; Japanese-style confectionery such as manju, yokan, and uiro; jams; candies; breads; flavorings; various instant foods; and various snack foods. The oral compositions include toothpaste, mouthwash, mouthwash, lozenges, chewing gum, etc.; the fragrance products include perfume, eau de parfum, eau de toilette, eau de cologne, etc.; the basic cosmetics include facial cleansing cream, vanishing cream, cleansing cream, cold cream, massage cream, lotion, toner, serum, mask, makeup remover, etc.; the finishing cosmetics include foundation, loose powder, solid powder, talcum powder, lipstick, lip balm, blush, eyeliner, mascara, eyeshadow, eyebrow pencil, eye mask, nail polish, nail polish remover, etc.; the hair cosmetics include pomade, brillanthin, setting lotion, hair stick, hair solid, hair oil, hair treatment, hair cream, hair tonic, hair liquid, hair spray, bandolin, hair tonic, hair dye, etc.; the sunscreen cosmetics include suntan products, sunscreen products, etc. The aforementioned medicated cosmetics include antiperspirants, aftershave lotions and gels, permanent wave agents, medicated soaps, medicated shampoos, medicated skin cosmetics, etc.; the aforementioned hair care products include shampoos, rinses, rinse-in shampoos, conditioners, treatments, hair packs, etc.; the aforementioned soaps include cosmetic soaps, bath soaps, perfumed soaps, clear soaps, synthetic soaps, etc.;The body cleansing agents include body soap, body shampoo, hand soap, face cream, etc.; the bath additives include bath salts (bath salts, bath tablets, bath liquids, etc.), foam baths (bubble baths, etc.), bath oils (bath perfumes, bath capsules, etc.), milk baths, bath jellies, bath cubes, etc.; the detergents include heavy laundry detergents, light laundry detergents, liquid detergents, laundry soaps, compact detergents, powder soaps, etc.; the fabric softeners include softeners, furniture care products, etc.; the cleaning agents include cleansers, house cleaners, toilet cleaners, bathroom cleaners, glass cleaners, mold removers, drain cleaners, etc.; the kitchen detergents include kitchen soaps, synthetic kitchen soaps, dish soaps, etc.; the bleaches include oxidizing bleaches (chlorine-based bleaches, oxygen-based bleaches, etc.), reducing bleaches (sulfur-based bleaches, etc.), optical bleaches, etc.; the aerosols include spray types, powder sprays, etc. Examples of deodorizers and air fresheners include solid, gel, and liquid types (water-based and oil-based); daily necessities and general merchandise include tissue paper and toilet paper; tobacco products include cigarettes, cigars, pipes, kiseru, hookahs, smokeless tobacco, heated tobacco products, and e-cigarettes; quasi-drugs include liquid bath additives, mouthwashes, and repellents, with repellents including mist spray and water-based liquid types; and pharmaceuticals include medicated cosmetics and medicated lotions; these are just a few examples of the various forms that can be cited.

[0074] The methyl menthol derivative of the present invention can take the form of a mixture. Other dosage forms include, for example, a liquid dissolved in alcohols, polyhydric alcohols such as propylene glycol, glycerin, and dipropylene glycol, and esters such as triethyl citrate, benzyl benzoate, and diethyl phthalate; natural gums such as gum arabic and tragacanth gum; an emulsified form emulsified with emulsifiers such as glycerin fatty acid esters and sucrose fatty acid esters; a powder coated with natural gums such as gum arabic, gelatin, and dextrin as excipients; a solubilized or dispersed form solubilized or dispersed using surfactants such as nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants; and microcapsules obtained by treatment with an encapsulating agent. Various dosage forms can be listed, and any form can be selected and used depending on the purpose.

[0075] As a method for imparting a cooling sensation or sensory stimulation to the various products described above using the cooling agent composition or sensory stimulant composition of the present invention, or a cooling agent composition-containing flavor or fragrance composition or sensory stimulant composition-containing flavor or fragrance composition containing the same, for example, depending on the type of product to which the cooling sensation or sensory stimulation is to be imparted and the final form of the product (e.g., liquid, solid, powder, gel, mist, aerosol, etc.), the cooling agent composition or sensory stimulant composition, or a cooling agent composition-containing flavor or fragrance composition or sensory stimulant composition-containing flavor or fragrance composition containing the same, may be directly added to or imparted to the product; or the cooling agent composition or sensory stimulant composition, or a cooling agent composition-containing flavor or fragrance composition or sensory stimulant composition-containing flavor or fragrance composition containing the same may be dissolved in polyhydric alcohols such as alcohols, propylene glycol, or glycerin to make it liquid and then added or imparted; The product may be added or applied in a solubilized or dispersed form by solubilizing or emulsifying it with natural gums such as gum arabic and tragacanth gum, or with surfactants (e.g., nonionic surfactants such as glycerin fatty acid esters and sucrose fatty acid esters, anionic surfactants, cationic surfactants, amphoteric surfactants, etc.); it may be added or applied in a powder form coated with natural gums such as gum arabic, gelatin, dextrin, or other excipients; or it may be added or applied in microcapsules formed by treatment with an encapsulating agent. Furthermore, it may be encapsulated with an inclusion agent such as cyclodextrin to stabilize and sustainably release the cooling agent composition or sensory stimulant composition, or a cooling agent composition-containing flavor or fragrance composition containing them.

[0076] The amount of cooling agent composition or sensory stimulant composition added to a product when providing a cooling sensation or sensory stimulation can be adjusted according to the type and form of the product, and the desired cooling or sensory stimulation effect and action. Generally, the amount of cooling agent composition or sensory stimulant composition added or applied is 0.00001 to 50% by mass, preferably 0.0001 to 20% by mass, and particularly preferably 0.001 to 5% by mass, relative to the mass of the product. The amount of flavor or fragrance composition added or applied to a product when providing a cooling sensation or sensory stimulation can also be adjusted as appropriate. Generally, the amount of flavor or fragrance composition added or applied is 0.00001 to 50% by mass, preferably 0.0001 to 20% by mass, and particularly preferably 0.001 to 5% by mass, relative to the mass of the product.

[0077] The following synthesis examples and product measurements were performed using the following instruments and equipment: Nuclear magnetic resonance spectrum: １ H-NMR: AM-500 (500 MHz) (Brooker) Internal standard: Tetramethylsilane gas chromatograph (GC): GC-2010AF (Shimadzu Corporation) Columns: DB-WAX (30 m x 0.32 mm x 0.5 μm) (Hewlett-Packard), IC-1 (30 m x 0.25 mm x 0.25 μm) (Hewlett-Packard), Rtx-1 (30 m x 0.25 mm x 0.25 μm) (Restek) Chiral column (optical purity measurement): Beta DEX ＴＭ 225 (30m x 0.25mm x 0.25μm), Beta DEX ＴＭ 325 (30m x 0.25mm x 0.25μm) (manufactured by Spelco) High-resolution mass spectrum (HRMS): JMS-T100GCV (manufactured by JEOL Ltd.), LCMS-IT-TOF (manufactured by Shimadzu Corporation) Optical rotation: JASCO P-1020 (manufactured by JASCO Corporation) Melting point: Melting point measuring device (serial number: 2678) (manufactured by Yanagimoto Seisakusho Co., Ltd.)

[0078] Incidentally, the exemplified compounds (1-1) to (1-13) prepared in the following examples are mainly composed of a mixture of trans isomers having the structures of the above formulas (1-b) and (1-d). In addition, in the exemplified compounds and comparative compounds shown below, Me represents a methyl group and Ac represents an acetyl group.

[0079] [Example 1] Synthesis of Exemplified Compound (1-1) (N-(2-Hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide)

[0080]

[0081] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (25 g, 126 mmol) obtained according to the method of International Publication No. 2016 / 153011, thionyl chloride (10.2 mL, 1.12 eq.), toluene (50 mL), and a few drops of dimethyl sulfoxide (DMF) were added, and the mixture was stirred at room temperature for 3 hours. Then, the temperature inside the system was cooled to 10°C or lower, and a mixed solution of (±)-2-amino-1-phenylethanol (19.0 g, 1.1 eq.), toluene (75 mL), and triethylamine (22.8 mL) was slowly added. After reacting for 2.5 hours, the reaction solution was transferred to a separatory funnel and washed by adding tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid and once with saturated brine, and then dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and recrystallized with heptane / ethyl acetate to obtain N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide as white crystals (29.2 g, yield 73%).

[0082] Melting point: 105-110°C HRMS: Mass 318.2428 ([M+H] ＋ ) Measured value 318.2436 １ H-NMR (500 MHz, CDCl ３): δ0.75 (dd, 3H, J=10.8, 7.0Hz), 0.84-0.92 (m, 9H), 1.10-1.28 (m, 3H), 1.37-1.52 (m, 4H), 1.60-1.72 (m, 1H), 2.08-2 .17 (m, 1H), 3.29-3.46 (m, 1H), 3.53-3.84 (m, 2H), 4.87-4.91 (m, 1H), 5.79 (br, 1H), 7.26-7.37 (m, 5H) (diastereomer mixture).

[0083] [Example 2] Synthesis of Exemplary Compounds (1-2) (N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide)

[0084]

[0085] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (1.31 g, 6.63 mmol), thionyl chloride (0.58 mL, 1.2 eq.), toluene (10 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and the mixture was stirred at room temperature for 3 hours. The temperature in the system was then cooled to below 10°C, and (S)-2-amino-1-phenylethanol (1.00 g, 1.1 eq.) and triethylamine (1.2 mL) were slowly added. After reacting for 2.5 hours, the reaction solution was transferred to a separatory funnel and washed with tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain N-((S)-2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide as white crystals (0.71 g, yield 34%).

[0086] Melting point 90-94°C HRMS: Mass 318.2428 ([M+H] ＋ ) Measured value: 318.2430 １ H-NMR (500MHz, CDCl ３): δ 0.75 (dd, 3H, J=10.8, 6.9 Hz), 0.85–0.92 (m, 9H), 1.10–1.28 (m, 3H), 1.37–1.52 (m, 4H), 1.60–1.72 (m, 1H), 2.08–2.17 (m, 1H), 3.29–3.45 (m, 1H), 3.54 (d, 1H, J=3.9 Hz (diastereomer)), 3.68 (d, 1H, J=3.3 Hz (diastereomer)), 3.65–3.84 (m, 1H), 4.87–4.91 (m, 1H), 5.79 (br, 1H), 7.26–7.37 (m, 5H) (diastereomer mixture).

[0087] [Example 3] Synthesis of Exemplary Compounds (1-3) (N-((R)-2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide)

[0088]

[0089] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (1.31 g, 6.63 mmol), thionyl chloride (0.58 mL, 1.2 eq.), toluene (10 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and the mixture was stirred at room temperature for 3 hours. The temperature in the system was then cooled to below 10°C, and (R)-2-amino-1-phenylethanol (1.00 g, 1.1 eq.) and triethylamine (1.2 mL) were slowly added. After reacting for 2.5 hours, the reaction solution was transferred to a separatory funnel and washed with tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain N-((R)-2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide as white crystals (0.49 g, yield 23%).

[0090] Melting point 89-94°C HRMS: Mass 318.2428 ([M+H] ＋ ) Measured value: 318.2433 １ H-NMR (500MHz, CDCl３ ): δ0.75 (dd, 3H, J=10.8, 6.9Hz), 0.85-0.94 (m, 9H), 1.10-1.28 (m, 3H), 1.37-1.52 (m, 4H), 1.60-1.72 (m, 1H), 2.08-2 .17 (m, 1H), 3.29-3.45 (m, 1H), 3.54-3.84 (m, 2H), 4.87-4.91 (m, 1H), 5.79 (br, 1H), 7.25-7.37 (m, 5H) (diastereomer mixture).

[0091] [Example 4] Synthesis of Exemplary Compounds (1-4) (2-(2-isopropyl-5,5-dimethylcyclohexanecarboxamide)-1-phenylethyl acetate)

[0092]

[0093] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, the exemplary compound (1-1) obtained in Example 1 (620 mg, 1.95 mmol), acetyl chloride (0.15 mL, 1.1 eq.), triethylamine (0.81 mL), and toluene (10 mL) were added and the mixture was stirred at room temperature for 2 hours. The reaction solution was then transferred to a separatory funnel and washed with tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid and then once with saturated brine, and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain 2-(2-isopropyl-5,5-dimethylcyclohexanecarboxamide)-1-phenylethyl acetate as an amorphous solid (275 mg, yield 39%).

[0094] HRMS: Mass 359.2460, Measured value 359.2431 １ H-NMR (500MHz, CDCl ３): δ0.76 (dd, 3H, J=13.8, 6.9Hz), 0.83-0.94 (m, 9H), 1.10-1.28 (m, 2H), 1.33-1.51 (m, 4H), 1.55-1.69 (m, 2H), 2.03- 2.09 (m, 1H), 2.10 (d, 3H, J=4.8Hz), 3.41-3.88 (m, 2H), 5.54 (br, 1H), 5.86 (m, 1H), 7.29-7.38 (m, 5H) (diastereomer mixture).

[0095] [Example 5] Synthesis of Exemplary Compounds (1-5) (2-isopropyl-5,5-dimethyl-N-(2-oxo-2-phenylethyl)cyclohexanecarboxamide)

[0096]

[0097] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (963 mg, 4.86 mmol), thionyl chloride (0.42 mL, 1.2 eq.), toluene (10 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and stirred at room temperature for 3 hours. Then, the temperature in the system was cooled to below 10°C, and 2-aminoacetophenone hydrochloride (1.00 g, 1.2 eq.) and triethylamine (1.5 mL) were slowly added. The mixture was heated and stirred at 40°C for 2.5 hours. After the reaction, the reaction solution was transferred to a separatory funnel and washed with tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain 2-isopropyl-5,5-dimethyl-N-(2-oxo-2-phenylethyl)cyclohexanecarboxamide as white crystals (632 mg, yield 77%).

[0098] Melting point 85-88°C HRMS: Mass 315.2198 Measured value 315.2190 １ H-NMR (500MHz, CDCl ３): δ0.84 (d, 3H, J = 6.9Hz), 0.89-0.94 (m, 9H), 1.17-1.30 (m, 2H), 1.41-1.60 (m, 5H), 1.67-1.73 (m, 1H), 2.33 (td, 1H, J = 11.1, 5.0Hz), 4.78 (d, 2H, J = 4.3Hz), 6.52 (br, 1H), 7.51 (t, 2H, J = 7.8Hz), 7.63 (t, 1H, J = 7.5Hz), 7.99 (d, 1H, J = 7.5Hz).

[0099] [Example 6] Synthesis of Exemplary Compounds (1-6) (2-isopropyl-5,5-dimethyl-N-(2-phenylpropyl)cyclohexanecarboxamide)

[0100]

[0101] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (963 mg, 4.86 mmol), thionyl chloride (0.42 mL, 1.2 eq.), toluene (10 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and the mixture was stirred at room temperature for 3 hours. The temperature in the system was then cooled to below 10°C, and (±)-1-methyl-1-phenylethylamine (722 mg, 1.1 eq.) and triethylamine (0.81 mL) were slowly added. The mixture was heated and stirred at 40°C for 2.5 hours. After the reaction, the reaction solution was transferred to a separatory funnel and washed with tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain 2-isopropyl-5,5-dimethyl-N-(2-phenylpropyl)cyclohexanecarboxamide as a white to pale yellow solid (1.05 g, yield 68%).

[0102] Melting point 80-85°C HRMS: Mass 315.2562 Measured value 315.2567 １ H-NMR (500MHz, CDCl ３): δ0.66 (dd, 3H, J = 17.1, 6.9Hz), 0.79-0.92 (m, 9H), 1.05-1.21 (m, 2H), 1.26 (d, 3H, J = 7.0Hz), 1.28-1.47 (m, 5H), 1.48-1.69 (m, 1 H), 1.91-2.00 (m, 1H), 2.89-3.02 (m, 1H), 3.11-3.39 (m, 1H), 3.46-3.76 (m, 1H), 5.23 (br, 1H), 7.15-7.36 (m, 5H) (diastereomer mixture).

[0103] [Example 7] Synthesis of Exemplary Compounds (1-7) (2-isopropyl-5,5-dimethyl-N-((S)-2-phenylpropyl)cyclohexanecarboxamide)

[0104]

[0105] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (1.00 g, 5.04 mmol), thionyl chloride (0.40 mL, 1.1 eq.), toluene (10 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and the mixture was stirred at room temperature for 3 hours. The temperature in the system was then cooled to below 10°C, and (S)-1-methyl-1-phenylethylamine (0.79 mL, 1.1 eq.) and triethylamine (0.84 mL) were slowly added. The mixture was heated and stirred at 40°C for 2.5 hours. After the reaction, the reaction solution was transferred to a separatory funnel and washed with tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain 2-isopropyl-5,5-dimethyl-N-((S)-2-phenylpropyl)cyclohexanecarboxamide as a colorless amorphous solid (1.26 g, yield 80%).

[0106] Melting point 125-133°C HRMS: Mass 316.2635 ([M+H] ＋ ) Measured value: 316.2635 １ H-NMR (500MHz, CDCl ３): δ0.67 (dd, 3H, J = 17.1, 7.0Hz), 0.79-0.92 (m, 9H), 1.05-1.21 (m, 2H), 1.26 (d, 3H, J = 7.0Hz), 1.28-1.47 (m, 5H), 1.48-1.69 (m, 1 H), 1.91-2.01 (m, 1H), 2.89-3.02 (m, 1H), 3.11-3.39 (m, 1H), 3.46-3.76 (m, 1H), 5.22 (br, 1H), 7.17-7.36 (m, 5H) (diastereomer mixture).

[0107] [Example 8] Synthesis of Exemplary Compounds (1-8) (2-isopropyl-5,5-dimethyl-N-((R)-2-phenylpropyl)cyclohexanecarboxamide)

[0108]

[0109] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (1.00 g, 5.04 mmol), thionyl chloride (0.40 mL, 1.1 eq.), toluene (10 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and the mixture was stirred at room temperature for 3 hours. The temperature in the system was then cooled to below 10°C, and (R)-1-methyl-1-phenylethylamine (0.79 mL, 1.1 eq.) and triethylamine (0.84 mL) were slowly added. The mixture was heated and stirred at 40°C for 2.5 hours. After the reaction, the reaction solution was transferred to a separatory funnel and washed with tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain 2-isopropyl-5,5-dimethyl-N-((R)-2-phenylpropyl)cyclohexanecarboxamide as a white solid (1.21 g, yield 76%).

[0110] Melting point 127-134°C HRMS: Mass 316.2635 ([M+H] ＋ ) Measured value: 316.2636 １ H-NMR (500MHz, CDCl ３): δ0.66 (dd, 3H, J = 17.1, 7.0Hz), 0.79-0.92 (m, 9H), 1.05-1.21 (m, 2H), 1.26 (d, 3H, J = 7.0Hz), 1.28-1.47 (m, 5H), 1.48-1.69 (m, 1 H), 1.91-2.01 (m, 1H), 2.89-3.02 (m, 1H), 3.11-3.39 (m, 1H), 3.46-3.76 (m, 1H), 5.22 (br, 1H), 7.15-7.36 (m, 5H) (diastereomer mixture).

[0111] [Example 9] Synthesis of Exemplary Compounds (1-9) (N-(4-hydroxyphenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide)

[0112]

[0113] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (1.00 g, 5.04 mmol), thionyl chloride (0.40 mL, 1.1 eq.), toluene (10 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and the mixture was stirred at room temperature for 3 hours. The temperature in the system was then cooled to below 10°C, and tyramine (0.83 g, 1.2 eq.) and triethylamine (1.4 mL) were slowly added. The mixture was heated and stirred at 70°C for 4.5 hours. After the reaction, the reaction solution was transferred to a separatory funnel and washed with tap water, chloroform, and THF. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain N-(4-hydroxyphenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide as a pale yellow solid (0.76 g, yield 47%).

[0114] Melting point 183-190°C HRMS: Mass 318.2428 ([M+H] ＋ ) Measured value: 318.2415 １ H-NMR (500MHz, DMSO-D ６): δ0.72 (d, 3H, J = 6.9Hz), 0.80 (d, 3H, J = 6.9Hz), 0.84-0.89 (m, 6H), 1. 03-1.13 (m, 2H), 1.20-1.41 (m, 6H), 1.49 (quid, 1H, J=7.1, 2.2Hz), 2.1 4-2.23 (m, 1H), 2.56 (t, 2H, J=7.2Hz), 3.06-3.14 (m, 1H), 3.21-3.30 (m , 1H), 6.63-6.67 (m, 2H), 6.96 (d, 2H, J=8.4Hz), 7.81 (t, 1H, J=5.6Hz).

[0115] [Example 10] Synthesis of Exemplary Compounds (1-10) (2-isopropyl-N-(4-methoxyphenylethyl)-5,5-dimethylcyclohexanecarboxamide)

[0116]

[0117] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (1.00 g, 5.04 mmol), thionyl chloride (0.40 mL, 1.1 eq.), toluene (10 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and the mixture was stirred at room temperature for 3 hours. The temperature in the system was then cooled to below 10°C, and 2-(4-methoxyphenyl)ethylamine (0.89 mL, 1.2 eq.) and triethylamine (1.4 mL) were slowly added. The mixture was heated and stirred at 40°C for 2.5 hours. After the reaction, the reaction solution was transferred to a separatory funnel and washed with tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain 2-isopropyl-N-(4-methoxyphenylethyl)-5,5-dimethylcyclohexanecarboxamide as a white solid (1.29 g, yield 77%).

[0118] Melting point 86-88℃ HRMS: Mass 332.2584 ([M+H] ＋ ) Measured value: 332.2572 １ H-NMR (500MHz, CDCl ３): δ0.73 (d, 3H, J=6.9Hz), 0.83-0.90 (m, 9H), 1.04-1.24 (m, 2H), 1.35- 1.49 (m, 5H), 1.64 (quid, 1H, J=6.8, 2.5Hz), 2.02 (td, 1H, J=11.4, 4.2Hz ), 2.75 (td, 2H, J=6.8, 1.8Hz), 3.37-3.45 (m, 1H), 3.53-3.61 (m, 1H), 3 .79 (s, 3H), 5.35 (br, 1H), 6.85 (d, 2H, J=8.7Hz), 7.01 (d, 1H, J=8.7Hz).

[0119] [Example 11] Synthesis of Exemplary Compound (1-11) (N-(3,4-dihydroxyphenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide)

[0120]

[0121] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (1.00 g, 5.04 mmol), thionyl chloride (0.40 mL, 1.1 eq.), toluene (10 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and the mixture was stirred at room temperature for 3 hours. The temperature in the system was then cooled to below 10°C, and dopamine hydrochloride (1.05 g, 1.1 eq.) and triethylamine (2.1 mL) were slowly added. The mixture was heated and stirred at 60°C for 4.5 hours. The reaction solution was then transferred to a separatory funnel and washed with tap water, chloroform, and THF. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain N-(3,4-dihydroxyphenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide as a pale orange amorphous solid (0.20 g, yield 12%).

[0122] HRMS: Mass 334.2377 ([M+H] ＋ ) Measured value: 334.2387 １ H-NMR (500MHz, DMSO-D ６): δ0.73 (d, 3H, J = 6.9Hz), 0.80 (d, 3H, J = 6.9Hz), 0.83-0.88 (m, 6H), 1.06-1.14 (m, 2H), 1.23-1.39 (m, 5H), 1.47-1.54 (m, 1H), 2.14-2.21 (m, 1H), 2.46-2.54 (m, 2H), 3.08-3.14 (m, 1H), 3.18-3.26 (m, 1H), 6.41 (dd, 1H, J = 8.0, 2.0Hz), 6.55 (d, 1H, J=2.0Hz), 6.61 (d, 1H, J=7.9Hz), 7.81 (t, 1H, J=5.5Hz), 8.52-8.70 (br, 2H).

[0123] [Example 12] Synthesis of Exemplary Compounds (1-12) (N-(3,4-dimethoxyphenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide)

[0124]

[0125] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (1.00 g, 5.04 mmol), thionyl chloride (0.40 mL, 1.1 eq.), toluene (15 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and the mixture was stirred at room temperature for 3 hours. The temperature in the system was then cooled to below 10°C, and homoveratrillamine (1.16 g, 1.1 eq.) and triethylamine (0.91 mL) were slowly added. The mixture was stirred at room temperature for 2 hours, after which the reaction solution was transferred to a separatory funnel and washed with tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain N-(3,4-dimethoxyphenylethyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide as a white solid (1.49 g, yield 82%).

[0126] Melting point 85-89°C HRMS: Mass 361.2617 Measured value 361.2633 １ H-NMR (500MHz, CDCl ３): δ0.73 (d, 3H, J=6.9Hz), 0.83-0.90 (m, 9H), 1.07-1.25 (m, 2H), 1. 35-1.50 (m, 5H), 1.60-1.68 (m, 1H), 2.02 (td, 1H, J=11.3, 4.3Hz), 2. 70-2.81 (m, 2H), 3.41-3.48 (m, 1H), 3.58 (hex, 1H, J = 6.8Hz), 3.87 (d , 6H, J=3.1Hz), 5.38 (br, 1H), 6.70-6.75 (m, 2H), 6.78-6.84 (m, 1H).

[0127] [Example 13] Synthesis of Exemplary Compound (1-13) (2-isopropyl-5,5-dimethyl-N-phenylethylcyclohexanecarboxamide)

[0128]

[0129] This reaction was carried out under a nitrogen atmosphere. In a 100 mL four-necked flask, 5-methylmenthylcarboxylic acid (1.00 g, 5.04 mmol), thionyl chloride (0.40 mL, 1.1 eq.), toluene (25 mL), and a few drops of DMF, obtained according to the method of International Publication No. 2016 / 153011, were added and the mixture was stirred at room temperature for 3 hours. The temperature in the system was then cooled to below 10°C, and phenethylamine (0.70 mL, 1.1 eq.) and triethylamine (0.91 mL) were slowly added. The mixture was stirred at room temperature for 2 hours, after which the reaction solution was transferred to a separatory funnel and washed with tap water and ethyl acetate. The oil layer was washed twice with dilute hydrochloric acid, then once with saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by column chromatography (heptane / ethyl acetate) to obtain 2-isopropyl-5,5-dimethyl-N-phenylethylcyclohexanecarboxamide as a white solid (1.12 g, yield 73%).

[0130] Melting point 90-93°C HRMS: Mass 302.2478 ([M+H] ＋ ) Measured value: 302.2478 １ H-NMR (500MHz, CDCl ３): δ0.73 (d, 3H, J = 6.9Hz), 0.83-0.92 (m, 9H), 1.06-1.24 (m, 2H), 1.34-1.48 (m, 5H), 1.65 (quid, 1H, J = 6.9, 2.5Hz), 2.02 ( td, 1H, J = 11.3, 4.4Hz), 2.75-2.85 (m, 2H), 3.41-3.49 (m, 1H), 3.61 (hex, 1H, J = 6.8Hz), 5.37 (br, 1H), 7.16-7.34 (m, 5H).

[0131] [Example 14] Sensory evaluation of exemplary compound (1-1)

[0132]

[0133] Sensory evaluation was performed in comparison with conventionally known comparative compounds 1-4. Comparative compounds 1, 3, and 4 were synthesized according to the method described in International Publication No. 2016 / 153011, and comparative compound 2 was synthesized according to the method described in International Publication No. 2005 / 020897. 30 ppm aqueous solutions were prepared for both example compound (1-1) and comparative compounds 1-4, and evaluation was performed using these solutions. The evaluation was conducted by three flavorists. The aqueous solutions were swished in the mouth, rinsed, and then spat out, and the intensity, duration, and quality of the cooling sensation in the oral cavity were evaluated.

[0134] [Sensory Findings] ・Example compound (1-1) had a very strong cooling sensation, clearly stronger than comparative compounds 3 and 4. Furthermore, this cooling sensation lasted for more than 60 minutes. ・Comparative compound 2 had a cooling intensity and duration equivalent to example compound (1-1), and the cooling sensation was considerably strong and persistent. ・Regarding the onset of the cooling sensation, example compound (1-1) was clearly faster than comparative compounds 1-4. The cooling sensation was strongly felt the moment it entered the mouth, and there were fewer off-flavors such as bitterness compared to comparative compounds 2-4. ・Regarding the quality of the cooling sensation, example compound (1-1) was sharper and more refreshing than comparative compounds 1-4. Furthermore, it had less of a burning or tingling sensation than comparative compounds 1-4, and possessed a clearer cooling sensation.

[0135] [Example 15] Sensory evaluation of exemplary compounds (1-2)

[0136]

[0137] A 30 ppm aqueous solution of the example compounds (1-2) was prepared, and the evaluation was performed using this aqueous solution. The evaluation was carried out by three flavorists. The aqueous solution was taken into the mouth, rinsed, and then spat out, and the intensity, duration, and quality of the cooling sensation in the oral cavity were evaluated.

[0138] [Sensory findings] - Exemplary compounds (1-2) produced a very strong cooling sensation, which lasted for more than 90 minutes. - Exemplary compounds (1-2) produced a strong cooling sensation the moment they entered the mouth, and no bitterness was detected. The quality of the cooling sensation was sharp and refreshing, and no burning or tingling sensation was felt.

[0139] [Example 16] Sensory evaluation of exemplary compounds (1-3)

[0140]

[0141] A 30 ppm aqueous solution of the example compounds (1-3) was prepared, and the evaluation was performed using this aqueous solution. The evaluation was carried out by three flavorists. The aqueous solution was taken into the mouth, rinsed, and then spat out, and the intensity, duration, and quality of the cooling sensation in the oral cavity were evaluated.

[0142] [Sensory findings] - Exemplary compounds (1-3) produced a very strong cooling sensation, which lasted for more than 60 minutes. - Exemplary compounds (1-3) produced a strong cooling sensation the moment they entered the mouth, and no bitterness was detected. The quality of the cooling sensation was sharp and refreshing, and no burning or tingling sensation was felt.

[0143] [Example 17] Sensory evaluation of exemplary compounds (1-5)

[0144]

[0145] A 30 ppm aqueous solution of the example compounds (1-5) was prepared, and the evaluation was performed using this aqueous solution. The evaluation was carried out by three flavorists. The aqueous solution was swished in the mouth, rinsed, and then spat out, and the intensity, duration, and quality of the cooling sensation in the oral cavity were evaluated.

[0146] [Sensory findings] • The example compounds (1-5) produced a gradually increasing cooling sensation, which was very strong at its peak, with very little other irritation or tingling. The cooling sensation lasted for more than 60 minutes.

[0147] [Example 18] Evaluation of toothpaste fragrance

[0148]

[0149] Sensory evaluations were conducted on toothpastes flavored with l-menthol and comparative compound 1 or exemplary compound (1-1).

[0150] Toothpastes (A) to (C) were prepared according to the following formulations: (A) Toothpaste base 990g + Toothpaste flavor base 4g + l-menthol 4g + ethyl alcohol (EtOH) 2g (B) Toothpaste base 990g + Toothpaste flavor base 4g + l-menthol 4g + comparative compound 1 (1% in EtOH) 2g (C) Toothpaste base 990g + Toothpaste flavor base 4g + l-menthol 4g + exemplary compound (1-1) (1% in EtOH) 2g

[0151] The prescription for two-paste flavor BASE is as follows:

[0152]

[0153] Furthermore, the prescription for the toothpaste base is as follows:

[0154]

[0155] The evaluation was conducted by three flavorists. Participants applied approximately 1g of toothpaste to a toothbrush and brushed their teeth for about 5 minutes using their normal brushing method. After brushing, they rinsed their mouths, and the intensity, duration, and quality of the cooling sensation in the oral cavity were evaluated.

[0156] [Evaluation Comments] Toothpaste (B) and toothpaste (C) have a stronger cooling effect than toothpaste (A), and toothpaste (C) has a cooling effect equivalent to toothpaste (B). Compared to toothpaste (B), toothpaste (C) exhibits a clearer flavor profile of Toothpaste Flavor BASE and provides a more distinct cooling sensation. Both toothpaste (B) and toothpaste (C) provided a cooling effect that lasted for more than 30 minutes.

[0157] [Example 19] Evaluation of mouthwash fragrance

[0158]

[0159] A sensory evaluation was conducted on mouthwashes flavored with l-menthol and comparative compound 1 or exemplary compound (1-1).

[0160] Mouthwashes (D) to (F) were prepared according to the following formulations: (D) Mouthwash base 999g + Mouthwash flavor base 0.35g + l-Menthol 0.45g + Ethyl alcohol (EtOH) 0.2g (E) Mouthwash base 999g + Mouthwash flavor base 0.35g + l-Menthol 0.45g + Comparative compound 1 (10% in EtOH) 0.2g (F) Mouthwash base 999g + Mouthwash flavor base 0.35g + l-Menthol 0.45g + Exemplary compound (1-1) (10% in EtOH) 0.2g

[0161] The formula for BASE mouthwash flavor is as follows:

[0162]

[0163] Furthermore, the prescription for the mouthwash base is as follows:

[0164]

[0165] The evaluation was conducted by three flavorists. Each participant took 20 mL of mouthwash into their mouth, gargled, and then spat it out. They then evaluated the intensity, duration, and quality of the cooling sensation in the oral cavity.

[0166] [Evaluation Comments] Mouthwash (E) and mouthwash (F) have a stronger cooling effect than mouthwash (D), and mouthwash (F) has a cooling effect equivalent to mouthwash (E). In addition, compared to mouthwash (E), mouthwash (F) exhibits the mint flavor profile of the BASE mouthwash flavor more clearly, and the cooling sensation is also clearer. Both mouthwash (E) and mouthwash (F) provided a cooling effect that lasted for more than 30 minutes.

[0167] [Example 20] Evaluation of chewing gum fragrance

[0168]

[0169] Sensory evaluations were conducted on chewing gum flavored with l-menthol and either a conventionally known comparative compound 5 ("Coolact® 10" manufactured by Takasago International Corporation) or an exemplary compound (1-1).

[0170] Chewing gums (G) to (I) were prepared according to the following formulations: (G) Chewing gum base 990g + Peppermint flavor base 7.3g + l-Menthol 0.7g + Ethyl alcohol (EtOH) 2g (H) Chewing gum base 990g + Peppermint flavor base 7.3g + l-Menthol 0.7g + Comparative compound 5 2g (I) Chewing gum base 990g + Peppermint flavor base 7.3g + l-Menthol 0.7g + Exemplary compound (1-1) (10% in EtOH) 2g

[0171] The prescription for Peppermint Flavor BASE is as follows:

[0172]

[0173] Furthermore, the prescription for the chewing gum base is as follows:

[0174]

[0175] The evaluation was conducted by three flavorists. Each participant placed 1g of chewing gum in their mouth, chewed it for about 5 minutes, and then evaluated the intensity, duration, and quality of the cooling sensation in the oral cavity after spitting it out.

[0176] [Evaluation Comments] Chewing gum (H) and chewing gum (I) have a greater cooling effect than chewing gum (G), and chewing gum (I) has a greater cooling effect than chewing gum (H) despite containing only 1 / 10 the amount of cooling agent. Furthermore, chewing gum (I) exhibits a slightly sharp cooling sensation from the moment you start chewing, and a refreshing cooling sensation spreads throughout the mouth. The cooling effect was also felt for more than 30 minutes after spitting it out.

[0177] [Example 21] Candy fragrance evaluation

[0178]

[0179] Sensory evaluations were conducted on candies flavored with l-menthol and either the conventionally known comparative compound 5 ("Coolact® 10" manufactured by Takasago International Corporation) or the exemplary compound (1-1).

[0180] Candies (J) to (L) were prepared according to the following formulations: (J) Candy base 998g + Herb flavor base 0.9g + l-Menthol 0.9g + Ethyl alcohol (EtOH) 0.2g (K) Candy base 998g + Herb flavor base 0.9g + l-Menthol 0.9g + Comparative compound 5 0.2g (L) Candy base 998g + Herb flavor base 0.9g + l-Menthol 0.9g + Exemplary compound (1-1) (10% in EtOH) 0.2g

[0181] The prescription for Herb Flavor BASE is as follows:

[0182]

[0183] Furthermore, the prescription for the candy base is as follows:

[0184]

[0185] [Candy Making Method] Granulated sugar, corn syrup, and purified water were heated to 150°C. After that, the heat was turned off, the mixture was weighed, flavors were added, and the mixture was poured into molds while maintaining a temperature of 135-140°C and shaped. After cooling, the candies were removed from the molds, and each candy weighed approximately 3g.

[0186] The evaluation was conducted by three flavorists. Each participant placed one candy in their mouth, licked it until it dissolved, and then evaluated the intensity, duration, and quality of the cooling sensation in the mouth after the candy was completely gone.

[0187] [Evaluation Comments] Candy (K) and Candy (L) have a greater cooling effect than Candy (J), and Candy (L) has a greater cooling effect than Candy (K) despite containing 1 / 10 the amount of cooling agent. Furthermore, Candy (L) has a sharp and clear cooling sensation from the start, which becomes a cooling sensation that stimulates the back of the throat after a while. No unpleasant aftertaste is detected. In addition, the cooling effect was felt for more than 30 minutes after spitting it out.

[0188] [Example 22] Evaluation of shampoo fragrance

[0189]

[0190] Sensory evaluations were conducted on shampoos scented with l-menthol and either the conventionally known comparative compound 5 ("Coolact® 10" manufactured by Takasago International Corporation) or the exemplary compound (1-1).

[0191] Shampoos (M) to (O) were prepared according to the following formulations: (M) Body Shampoo BASE 900g + l-menthol 30g + dipropylene glycol (DPG) 70g (N) Body Shampoo BASE 900g + l-menthol 30g + comparative compound 5 10% in DPG 70g (O) Body Shampoo BASE 900g + l-menthol 30g + exemplary compound (1-1) 1% in DPG 70g

[0192] The formula for Body Shampoo BASE is as follows:

[0193]

[0194] The evaluation was conducted by a total of five male and female monitors. Male monitors washed their hair with approximately 3 mL of shampoo, and female monitors washed their hair with approximately 9 mL of shampoo. The intensity and duration of the cooling sensation after rinsing were then evaluated.

[0195] [Evaluation Comments] Shampoo (N) and Shampoo (O) had a greater cooling effect than Shampoo (M), and Shampoo (O), despite containing 1 / 10 the amount of cooling agent as Shampoo (N), had a cooling effect equivalent to or better than Shampoo (N).

[0196] [Example 23] Evaluation of beer-flavored beverage aroma

[0197]

[0198] Beer-flavored beverages (P) to (R) were prepared by flavoring them with l-menthol and either the conventionally known comparative compound 5 ("Coolact® 10" manufactured by Takasago International Corporation) or the exemplary compound (1-1), respectively, and sensory evaluation was performed. The formulations of beer-flavored beverages (P) to (R) are shown below. (P) Non-alcoholic beer-flavored beverage 1000g + l-menthol 1mg (1ppm) (Q) Non-alcoholic beer-flavored beverage 1000g + l-menthol 1mg (1ppm) + comparative compound 5 1mg (1ppm) added (R) Non-alcoholic beer-flavored beverage 1000g + l-menthol 1mg (1ppm) + exemplary compound (1-1) 0.1mg (0.1ppm) added

[0199] The prescription for the non-alcoholic beer-flavored beverage is as follows:

[0200]

[0201] The formula for the beer flavor contained in the above non-alcoholic beer-flavored beverage is as follows:

[0202]

[0203] The evaluation was conducted by five adult monitors. They drank approximately 50 mL of beer-flavored beverage chilled to 2-6°C and evaluated the intensity, duration, and quality of the cooling sensation.

[0204] [Evaluation Comments] Beer-flavored beverage (Q) and beer-flavored beverage (R) had a greater cooling effect than beer-flavored beverage (P). Despite containing only 1 / 10 the amount of cooling agent as beer-flavored beverage (Q), beer-flavored beverage (R) had a cooling effect equivalent to or better than beer-flavored beverage (Q). Furthermore, beer-flavored beverage (R) had a better quality and more pleasant cooling sensation compared to beer-flavored beverage (Q).

[0205] [Example 24] Evaluation of Cold Sensation Intensity (Evaluation of TRPM8 Activity) Generally, compounds that have a cooling effect, such as menthol, are known to induce a cooling sensation by activating TRPM8 (melastatin transient receptor potential channel 8), which is a cold stimulus receptor (see, for example, J. Neurobiol. (2004), Vol. 61, pp. 3-12). Therefore, in order to evaluate the cold sensation intensity, the following procedure was followed to evaluate the EC in the TRPM8 activation effect of each exemplary compound obtained in the example. ５０ The value was measured.

[0206] (1) Preparation of a stable human TRPM8-expressing cell line The full-length human TRPM8 gene was amplified using the PCR method from plasmid RC220615 (Origine). The obtained PCR product was subcloned into pcDNA5 / FRT / TO (Thermo Fisher Scientific), and then introduced into Flp-In293293 cells (Thermo Fisher Scientific) using the Flp-InT-REx system (Thermo Fisher Scientific) to prepare a stable human TRPM8-expressing cell line.

[0207] (2) Evaluation of Human TRPM8 Activity: Cultured human TRPM8-stable expressing cells were seeded at a rate of 50,000 cells / well in a poly-D-lysine coated 96-well microplate (Corning), 1 μg / mL doxycycline (Takara Bio Inc.) was added, and human TRPM8 expression was induced by incubation at 37°C overnight. After replacing the culture medium with buffer, a fluorescent calcium indicator (Fluo4-AM: Dojin Chemical Laboratory Inc.) was added, and the cells were incubated at 37°C for 30 minutes before being transferred to a fluorescence microplate reader (FlexStation3: Molecular Devices Inc.). Exemplary compounds were added in a final concentration range of 0.1 μM to 1000 μM, and the change in fluorescence at a wavelength of 525 nm was measured when excited at a wavelength of 485 nm at an in-instrument temperature of 32°C. ５０ The value was calculated.

[0208] EC in the TRPM8 activating effect of each example compound ５０ The values ​​were as shown in the table below.

[0209]

[0210] From the results in Table 12, all of the example compounds (1-1) to (1-13) are EC ５０ The low value suggests that it has a high cooling effect.

[0211] Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. This application is based on Japanese Patent Application No. 2017-001852, filed on January 10, 2017, the contents of which are incorporated herein by reference.

Claims

1. The following general formula (1): [In formula (1), the * mark represents an asymmetric carbon atom, X represents a hydrogen atom or a substituent, and Y represents an aryl group having 6 to 20 carbon atoms which may have a substituent.] A cooling sensation agent composition containing a methyl menthol derivative represented by the formula.

2. The cooling sensation agent composition according to claim 1, wherein in the general formula (1), X is a hydrogen atom, a hydroxyl group, an acetoxy group, an oxo group or a methyl group, and Y is a phenyl group which may have a substituent.

3. The cooling sensation agent composition according to claim 1 or 2, wherein the general formula (1) is represented by the following structural formula (2). [In formula (2), the * mark represents an asymmetric carbon atom.] 4. The cooling sensation agent composition according to any one of claims 1 to 3, further containing at least one kind of cooling sensation substance other than the methyl menthol derivative.

5. The cooling substances other than the methyl menthol derivative are menthol, menthone, camphor, pregol, isopregol, cineol, cubenol, methyl acetate, pregil acetate, isopregil acetate, methyl salicylate, pregil salicylate, isopregil salicylate, 3-(l-menthoxy)propane-1,2-diol, 2-methyl-3-(l-menthoxy)propane-1,2-diol, 2-(l-menthoxy)ethan-1-ol, 3-(l-menthoxy)propan-1-ol, 4-(l-menthoxy)butan-1-ol, menthyl 3-hydroxybutyrate, menthyl glyoxylate, p-menthane-3,8-diol, 1-(2-hydroxy-4-methylcyclohexyl)ethanone, menthyl lactate, menthone glycerol ketal, menthyl 2-pyrrolidone-5-carboxylate, monomethyl succinate, alkali metal salts of monomethyl succinate, alkaline earth metal salts of monomethyl succinate, monomethyl glutarate, alkali metal salts of monomethyl glutarate, alkaline earth metal salts of monomethyl glutarate, N-{[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl}glycine, glycerol ester of p-menthane-3-carboxylic acid, menthol propylene glycol carbonate, menthol ethylene glycol carbonate, p-menthane-2,3-diol, 2-isopropyl-N,2,3-trimethylbutanamide, N-ethyl-p-menthane-3-carboxamide, ethyl 3-(p-menthane-3-carboxamide)acetate, N-(4-methoxyphenyl)-p-menthane carboxamide, N-ethyl-2,2-diisopropylbutanamide, N-cyclopropyl-p-menthane carboxamide, N-(4-cyanomethylphenyl)-p-menthane carboxamide, N-(2-pyridin-2-yl)-3-p-menthane carboxamide, N-(2-hydroxyethyl)-2-isopropyl-2,3-dimethylbutanamide, N-(1,1-dimethyl-2-hydroxyethyl)-2,2-diethylbutanamide, (2-isopropyl-5-methylcyclohexyl)amide of cyclopropanecarboxylic acid, N-ethyl-2,One or more compounds selected from 2 - diisopropylbutanamide, N - [4 - (2 - amino - 2 - oxoethyl)phenyl] - p - menthane carboxamide, 2 - [(2 - p - menthoxy)ethoxy]ethanol, 2,6 - diethyl - 5 - isopropyl - 2 - methyltetrahydropyran, trans - 4 - tert - butylcyclohexanol, N - [4 - (cyanomethyl)phenyl] - 2 - isopropyl - 5,5 - dimethylcyclohexylcarboxamide, and N - [3 - hydroxy - 4 - methoxyphenyl] - 2 - isopropyl - 5,5 - dimethylcyclohexylcarboxamide; one or more sugar alcohols selected from xylitol, erythritol, dextrose, and sorbitol; and one or more natural products selected from Japanese mint oil, peppermint oil, spearmint oil, and eucalyptus oil; The cooling agent composition according to claim 4, which is at least one cooling substance selected from the group consisting of., 6. A sensory stimulant composition containing the cooling agent composition according to any one of claims 1 to 5.

7. The sensory stimulant composition according to claim 6, further containing at least one warm - feeling substance.

8. The thermosensitive substance is vanillyl methyl ether, vanillyl ethyl ether, vanillyl propyl ether, vanillyl isopropyl ether, vanillyl butyl ether, vanillyl amyl ether, vanillyl isoamyl ether, vanillyl hexyl ether, isovanillyl methyl ether, isovanillyl ethyl ether, isovanillyl propyl ether, isovanillyl isopropyl ether, isovanillyl butyl ether, isovanillyl amyl ether, isovanillyl isoamyl ether, isovanillyl hexyl ether, ethyl vanillyl methyl ether, ethyl vanillyl ethyl ether, ethyl vanillyl propyl ether, ethyl vanillyl isopropyl ether, ethyl vanillyl butyl ether, ethyl vanillyl amyl ether, ethyl vanillyl isoamyl ether, ethyl vanillyl hexyl ether, vanillin propylene glycol acetal, isovanillin propylene glycol acetal, ethyl vanillin propylene glycol acetal, vanillyl butyl ether acetate, isovanillyl butyl ether acetate, ethyl vanillyl butyl ether acetate, 4-(l-mentoxymethyl)-2-(3'-methoxy-4'-hydroxyphenyl)-1,3-dioxolane, 4-(l-mentoxymethyl)-2-(3'-hydroxy-4'-methoxyphenyl)-1,3-dioxolane, 4-(l-mentoxymethyl)-2-(3'-ethoxy-4'-hydroxyphenyl)-1,3-dioxolane, capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, biscapsaicin, trishomocapsaicin, nor-nor-capsaicin, norcapsaicin, capsicinol, vanillyl caprylamide (vanillyl octylate), vanillyl pelargonate (vanillyl nonylate), vanillyl caproamide (vanillyl decylate), vanillyl undecanamide (vanillyl undecylate), N-trans-feruloyltyramine, N-5-(4-hydroxy-3-methoxyphenyl)-2E,4E-pentadienoyl piperidine, N-trans-feruloyl piperidine, N-5-(4-hydroxy-3-methoxyphenyl)-2E-pentenoyl piperidine, N-5-(4-hydroxyphenyl)-2E,One or more compounds selected from 4E-pentadienoylpiperidine, piperine, isopiperine, chavicine, isochavicine, piperamine, piperettine, piperolein B, retrofractamide A, piperoside, guinenoside, piperillin, piperamide C5:1(2E), piperamide C7:1(6E), piperamide C7:2(2E,6E), piperamide C9:1(8E), piperamide C9:2(2E,8E), piperamide C9:3(2E,4E,8E), fagaramide, sanshool-I, sanshool-II, hydroxysanshool, sanshoamide, gingerol, shogaol, gingerone, methyldingerol, paradol, spirantol, kavicin, polygodial (tadeonal), isopolygodial, dihydropolgodial, and tadeon; and one or more natural products selected from capsicum oil, capsicum oleoresin, ginger oleoresin, jambu oleoresin (extract of Zanthoxylum piperitum), sansho extract, sanshoamide, black pepper extract, white pepper extract, and tade extract; The sensory stimulant composition according to claim 7, which is at least one warm-sensitive substance selected from the group consisting of., 9. A flavor or fragrance composition containing the sensory stimulant composition according to any one of claims 6 to 8.

10. The flavor or fragrance composition according to claim 9, wherein the content of the sensory stimulant composition is 0.00001 to 90% by mass.

11. Any product selected from the group consisting of beverages, foods, cosmetics, toiletries, air care products, daily necessities and sundries, oral compositions, hair care products, skin care products, body care products, laundry detergents, fabric softeners, tobacco, quasi-drugs, and pharmaceuticals, which contains the sensory stimulant composition according to any one of claims 6 to 8.

12. The product according to claim 11, wherein the content of the sensory stimulant composition is 0.00001 to 50% by mass.

13. A product selected from the group consisting of beverages, foods, cosmetics, toiletries, air care products, daily necessities and sundries, oral compositions, hair care products, skin care products, body care products, laundry detergents, fabric softeners, tobacco, quasi-drugs and pharmaceuticals, which contains the flavor or fragrance composition according to claim 9 or 10.

14. The product according to claim 13, wherein the content of the flavor or fragrance composition is 0.00001 to 50% by mass.

15. A method for manufacturing a product selected from the group consisting of beverages, foods, cosmetics, toiletries, air care products, daily necessities and sundries, oral compositions, hair care products, skin care products, body care products, laundry detergents, fabric softeners, tobacco, quasi-drugs and pharmaceuticals, which comprises blending the sensory stimulant composition according to any one of claims 6 to 8.

16. A method for manufacturing a product selected from the group consisting of beverages, foods, cosmetics, toiletries, air care products, daily necessities and sundries, oral compositions, hair care products, skin care products, body care products, laundry detergents, fabric softeners, tobacco, quasi-drugs and pharmaceuticals, which comprises blending the flavor or fragrance composition according to claim 9 or 10.

17. The following general formula (1): [In formula (1), the * mark represents an asymmetric carbon atom, X represents a hydrogen atom or a substituent, and Y represents an aryl group having 6 to 20 carbon atoms which may have a substituent.] A methyl menthol derivative represented by the formula.

18. The methyl menthol derivative according to claim 17, wherein in the general formula (1), X is a hydrogen atom, a hydroxyl group, an acetoxy group, an oxo group or a methyl group, and Y is a phenyl group which may have a substituent.

19. The methyl menthol derivative according to claim 17 or 18, wherein the general formula (1) is represented by the following structural formula (2). [In formula (2), the * mark represents an asymmetric carbon atom.]