Cooling sensation composition

Abstract

A composition comprising at least one cooling compound and a solvent, and the use of said composition in a flavor or fragrance composition.

Description

[Technical Field]

[0001] Technical field The present invention relates to compositions, and more particularly to solutions comprising at least one cooling compound and a solvent as further defined herein, and to the use of said compositions in flavor or fragrance compositions. [Background technology]

[0002] background Compounds that provide a cooling sensation have long played a crucial role in the flavor and fragrance industry by creating associations with freshness and cleanliness. Cooling compounds are widely used in various products, such as food ingredients, tobacco products, beverages, toothpaste, mouthwash, and toiletries. The cooling sensation they provide contributes to the appeal and acceptance of consumer products. In particular, oral care products, such as toothpaste and mouthwash, incorporate cooling agents to provide a refreshing effect on breathing and a feeling of cleanliness, coolness, and freshness in the mouth.

[0003] While the most recent synthetic cooling compounds are highly effective at low concentrations, unfortunately, many of them are crystalline solids at room temperature, posing problems for their use. Firstly, mixing solids with consumer products that may be in liquid or paste form is not always convenient or easy. Secondly, powdered components must be handled in a manner that avoids the associated dust hazards. Consequently, there remains a need to provide a cooled compound that is in a form that is easy to use in further formulation operations and that remains stable in that form for extended storage. [Overview of the project]

[0004] Summary of the present invention According to a first aspect of the present invention, a composition is: (a) Equation (I) [ka] During the ceremony, R is a C3-C7 branched alkyl or alkenyl that optionally contains one S atom; and R 1 is a phenyl molecule, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of Me, F, and Cl; and optionally substituted with one further substituent selected from the group consisting of Et, vinyl, CN, NO2, methoxy, and CF3. Compounds represented by; and (b) at least one solvent selected from the group consisting of butyl lactate, ethanol, ethyl lactate, isopropyl alcohol, isopropylideneglycerol, and lactic acid, or mixtures thereof. A composition comprising the above is provided. In one aspect, the solvent is lactic acid.

[0005] In accordance with a second aspect of the present invention, a fragrance composition or flavor composition is provided which comprises the composition of the first aspect of the present invention, and at least one activator selected from the group consisting of flavors and fragrances, and optionally a sweetener.

[0006] In one embodiment, at least one flavor / fragrance is selected from a list of ingredients that provide an additional cooling effect to the skin and / or mucous membranes, comprising menthol, peppermint oil, N-ethyl-p-menthane-3-carboxamide (WS-3), N-(4-(cyanomethyl)phenyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Evercool 180), 2-isopropyl-5-methyl-N-(2-(pyridine-2-yl)ethyl)cyclohexane-1-carboxamide (Evercool 190), and menthyl lactate.

[0007] In accordance with a third aspect of the present invention, a fragranced or flavored product is provided, comprising a composition of the first aspect of the present invention or a composition of the second aspect of the present invention, and a product base. In one embodiment, the products are selected from consumer products that come into contact with human skin and / or mucous membranes, including food products, beverages, chewing gum, tobacco and tobacco substitutes, dental care products, lip care products, and personal care products, including sexual health and inner care products.

[0008] In one embodiment, the product is selected from air care products, such as air fresheners, or “ready-to-use” powdered air fresheners that can be used in home spaces (rooms, refrigerators, cupboards, shoes, or cars) and / or in public spaces (halls, hotels, malls, etc.). Since cooling compounds are primarily used in the flavor and fragrance industry, particularly in consumer products that come into contact with human skin and / or mucous membranes, solvents approved for use in such products are specifically preferred.

[0009] Details, examples, and preferences relating to one or more specific aspects of the present invention are further described herein and will apply equally to all aspects of the invention. In all possible modifications, any combination of the embodiments, examples, and preferences described herein is exhaustive unless otherwise indicated herein or clearly contradicted by the context.

[0010] Detailed description The present invention relates at least in part to formula (I) [ka] During the ceremony, R is a C3-C7 branched alkyl or alkenyl that optionally contains one S atom; and R 1 is a phenyl molecule, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of CH3, F, and Cl; and optionally substituted with one further substituent selected from the group consisting of Et, vinyl, CN, NO2, methoxy, and CF3. It is based on the surprising finding that the cooling compound represented by dissolves in a greater amount in a solvent selected from the group consisting of butyl lactate, ethanol, ethyl lactate, isopropyl alcohol, isopropylidene glycerol, and lactic acid, or a mixture thereof.

[0011] A non-limiting example is a compound represented by formula (I), wherein R 1 is optionally substituted at the para position by one substituent selected from the group consisting of CH3, F and Cl; and is optionally substituted by one further substituent selected from the group consisting of Et, vinyl, CN, NO2, methoxy and CF3, and is phenyl.

[0012] In one specific embodiment, the compound represented by formula (I) is of formula (II)

Chemical formula

[0013] The compound represented by formula (I) as defined herein has been developed by the applicant as a novel cooling compound (which is described in more detail in the applicant's patent application PCT / CN2019 / 111690 - the contents of which are incorporated herein by reference). The compound can activate the TRPM8 (transient receptor potential melastatin member 8, also known as Trp-p8 or MCR1) ion channel, which induces a sensation of cold.

[0014] The compounds represented by formula (I) as defined herein are crystalline solids at room temperature and are relatively insoluble in common solvents suitable for use in the flavor and fragrance industries. Applicants have surprisingly found that synthetic cooling compounds, especially cooling compounds as defined by formula (I), are specifically sufficiently soluble in solvents selected from butyl lactate, ethanol, ethyl lactate, isopropyl alcohol, isopropylidene glycerol, and lactic acid, or mixtures thereof.

[0015] "Specifically sufficiently soluble" means, in the context of the present invention, that a stable solution containing up to 50% by weight of the compound represented by formula (I) can be prepared. The advantage of such highly concentrated solutions is that the contribution of the inherent odor of the solvent used can be minimized. This is specifically important when such cooling compounds are used in combination with flavor and fragrance formulations. It is also worth noting that miscibility with a liquid, for example a flavor / fragrance formulation, can be considered more sustainable than mixing a solid which would require more energy. "Stable" means, in the context of the present invention, that no precipitation is observed when stored at a temperature of at least room temperature (i.e., about 22 °C) for up to 4 weeks.

[0016] Thus, in a further aspect of the present invention, a liquid comprising: (a) formula (I)

Chemical formula

[0017] An example of a non-limiting compound is a compound represented by formula (I), where R 1 It is a phenyl molecule that is optionally substituted at the para position with one substituent selected from the group consisting of CH3, F, and Cl; and optionally substituted with one further substituent selected from the group consisting of Et, vinyl, CN, NO2, methoxy, and CF3.

[0018] In a specific embodiment of 1, the compound represented by formula (I) is represented by formula (II) [ka] In the formula, R is a C3-C7 branched alkyl or alkenyl molecule that optionally contains one sulfur atom. This is shown by.

[0019] In a specific embodiment of 1, the liquid contains at least 3% by weight (for example, 3 to 50% by weight (for example, 4 to 45, 5 to 40, 15 to 35, or about 20% by weight) of a compound represented by formula (I) (covering the compounds represented by formula (II)). In a further specific embodiment, a liquid composition is provided comprising (a) a compound represented by formula (I) (covering the compounds represented by formula (II)) and (b) a solvent selected from butyl lactate, ethanol, ethyl lactate, isopropyl alcohol, isopropylideneglycerol, and lactic acid, or mixtures thereof, wherein the weight ratio of component (a) to solvent (b) is 1:20 to 1:1 (including 1:18 to 1:2, e.g., 1:4, 1:3, or 1:5).

[0020] In a specific embodiment of 1, lactic acid (2-hydroxypropanoic acid) is used as the sole solvent. Lactic acid is a chiral compound consisting of two enantiomers: one is l-(+)-lactic acid or (S)-lactic acid, and the other is its enantiomer, d-(-)-lactic acid or (R)-lactic acid. A mixture of the two in equal amounts is called dl-lactic acid, or racemic lactic acid. dl-lactic acid is miscible with water and miscible with ethanol above its melting point, which is approximately 17°C. Lactic acid is hygroscopic and is therefore used fairly frequently in the food and beverage industry at a purity of about 85-90 wt%. L-lactic acid is supplemented in foods and beverages (E270) and is widely used as a non-volatile acidulant. The use of the term “lactic acid” in this description encompasses not only the individual enantiomers and racemic compounds in their pure forms, but also the commercially available forms of lactic acid, which are generally 85-90 wt% pure.

[0021] While 50% by weight or more of the compound represented by formula (I) (including the compound represented by formula (II)) as defined above herein is soluble in lactic acid, compositions containing lower concentrations (e.g., less than 30% by weight, e.g., 25-15% by weight) are preferred due to the viscosity of the resulting mixture. The more viscous the liquid, the more difficult it is to administer. Instead of reducing the concentration of the compound represented by formula (I) (including the compound represented by formula (II)), healable mixing facilities may be used. The lactic acid used is commercially available, such as from Biochem BV (The Netherlands) and Prinova Europe LTD.

[0022] In another specific embodiment, a lactate (e.g., butyl lactate or ethyl lactate, or a mixture thereof) is used as the solvent. In another specific embodiment, solvent (b) is selected from butyl lactate, isopropyl alcohol, and isopropylideneglycerol, or a mixture thereof.

[0023] Compounds represented by formula (I) (including those represented by formula (II)) contain several chiral centers and thus exist as a mixture of stereoisomers, or they can be decomposed into isomerically pure forms. The decomposing stereoisomers increase the complexity of the preparation and purification of these compounds, and it is preferable to use the compounds as a mixture of their stereoisomers simply for economic reasons. However, if it is desired to prepare individual stereoisomers, this can be achieved by methods known in the art, e.g., preparative HPLC and GC, crystallization, or stereoselective synthesis. Compounds as defined by formula (I) (including those represented by formula (II)) may exist in their tautomer form, 1H-imidazole-3H-imidazole form. Consequently, the chemical structures depicted herein encompass all viable stereoisomers and tautomers of the exemplified compounds.

[0024] In a specific embodiment of 1, a liquid composition is provided comprising or consisting of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one (including (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one) and at least one solvent selected from butyl lactate, ethanol, ethyl lactate, isopropyl alcohol, isopropylideneglycerol, and lactic acid, or a mixture thereof.

[0025] In a further embodiment, a liquid composition is provided comprising or consisting of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one (including (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one) and one solvent selected from butyl lactate, ethanol, ethyl lactate, isopropyl alcohol, isopropylideneglycerol, and lactic acid, or a mixture thereof.

[0026] In another specific embodiment, a composition is provided comprising or consisting of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one (including (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one) and lactic acid.

[0027] The compositions as defined above in this specification may be added to any product in which a cooling effect on the skin or mucous membranes is desired. They may be incorporated into the product simply by directly mixing the composition with the product, or, in an earlier step, by encapsulating them in a suitable incorporation material. Alternatively, the compositions as defined above in this specification may be mixed with other activators, such as flavors, fragrances, and sweeteners, and mixtures thereof, before being incorporated into the product.

[0028] Therefore, in a further embodiment, a flavor or fragrance formulation, the following: (a) Equation (I) [ka] R is a C3-C7 branched alkyl or alkenyl that optionally contains one S atom, and R 1is a phenyl molecule, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of Me, F, and Cl; and optionally substituted with one further substituent selected from the group consisting of Et, vinyl, CN, NO2, methoxy, and CF3. Compounds represented by; and (b) at least one solvent selected from butyl lactate, ethanol, ethyl lactate, isopropyl alcohol, isopropylideneglycerol, lactic acid, and peppermint oil, or mixtures thereof; and (c) at least one activator selected from the group consisting of flavors and fragrances, A flavor or fragrance formulation is provided which includes, and optionally includes, a sweetener.

[0029] In a specific embodiment of 1, a flavor or fragrance formulation, the following: (a) Equation (I) [ka] R is a C3-C7 branched alkyl or alkenyl that optionally contains one S atom, and R 1 It is a phenyl molecule substituted at the para position with one substituent independently selected from the group consisting of CH3, F, and Cl; and optionally substituted with one further substituent selected from the group consisting of Et, vinyl, CN, NO2, methoxy, and CF3. Compounds represented by; and (b) at least one solvent selected from butyl lactate, ethanol, ethyl lactate, isopropyl alcohol, isopropylideneglycerol, lactic acid, and peppermint oil, or mixtures thereof; and (c) at least one activator selected from the group consisting of flavors and fragrances, A flavor or fragrance formulation is provided which includes, and optionally includes, a sweetener.

[0030] In a more specific embodiment, the compound represented by formula (I) is represented by formula (II) [ka] In the formula, R is a C3-C7 branched alkyl or alkenyl molecule that optionally contains one sulfur atom. A flavor or fragrance formulation is provided, represented by a compound shown by [the formula shown].

[0031] Examples of flavor components include natural flavors, artificial flavors, spices, seasonings, etc. Exemplary flavor components include synthetic flavor oils and flavor fragrances and / or oils, oleopolymers, essential oils, and distillates, as well as combinations containing at least one of the above. Flavoring oils include spearmint oil, cinnamon oil, wintergreen oil (methyl salicylate), peppermint oil, mint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, thuja oil, nutmeg oil, allspice, sage oil, mace, bitter tonsil oil, and cassia oil; useful flavoring agents include artificial, natural, and synthetic fruit flavors, such as vanilla, and citrus oils including lemon, orange, lime, grapefruit, yuzu, and sudachi; fruit extracts including apple, pear, peach, grape, raspberry, blackberry, currant, blueberry, strawberry, cherry, plum, prune, raisin, cola, guarana, neroli, pineapple, apricot, banana, melon, apricot, cherry, tropical fruit, mango, mangosteen, pomegranate, papaya, and more.

[0032] Additional example flavors imparted by the flavoring agent composition include milk flavor, butter flavor, cheese flavor, cream flavor, and yogurt flavor; vanilla flavor; tea or coffee flavor, e.g., green tea flavor, oolong tea flavor, tea flavor, cocoa flavor, chocolate flavor, and coffee flavor; mint flavor, e.g., peppermint flavor, spearmint flavor, and mint flavor; spicy flavor, e.g., agi flavor, ajwain flavor, anise flavor, angelica flavor, fennel flavor, allspice flavor, cinnamon flavor, chamomile flavor, mustard flavor, cardamom flavor, caraway flavor, cumin flavor, clove flavor, pepper flavor, coriander flavor, sassafras flavor, savory flavor, and zanthoxyli Fructus flavor, perilla flavor, juniper berry flavor, ginger flavor, star anise flavor, horseradish flavor, thyme flavor, tarragon flavor, dill flavor, chili pepper flavor, nutmeg flavor, basil flavor, marjoram flavor, rosemary flavor, bay leaf flavor, and wasabi flavor, etc.

[0033] This includes nutty flavors such as almond, hazelnut, macadamia nut, peanut, pecan, pistachio, and walnut; alcoholic flavors such as wine, whiskey, brandy, rum, gin, and liqueur; floral flavors; and vegetable flavors such as onion, garlic, cabbage, carrot, celery, mushroom, and tomato.

[0034] In general, any flavoring agent or food additive (including food colorings), such as those described in “Essential guide to food additives,” Third edition 2008, pages 101-321 (ISBN: 978-1-905224-50-0) by Leatherhead Food International Ltd., may be used. Publications are incorporated herein by reference.

[0035] In a specific embodiment of 1, at least one activator (C) is anethole, menthol laevo, or carbon laevo. You may choose from laevo), ethyl maltol, vanillin, eucalyptol, eugenol, menthol racemic, cis-3-hexenol, linalool, mint oil (e.g., peppermint arvensis oil, peppermint piperita oil, spearmint native oil, spearmint scotch oil), corylone, ethyl butyrate, cis-3-hexenyl acetate, citral, eucalyptus oil, ethyl vanillin, methyl salicylate, 2'-hydroxypropiophenone, ethyl acetate, methyl dihydrojasmonate, geraniol, lemon oil, isoamyl acetate, thymol, ionone beta, linalyl acetate, decanal, cis-jasmone, ethyl hexanoate, melonal (2,6-dimethylhepta-5-enal), citronellol, ethyl acetoethyl acetate, nutmeg oil and clove oil, or mixtures thereof.

[0036] In another specific embodiment, at least one activator (C) is menthol (e.g., in the form of peppermint oil), menthone, p-menthanecarboxamide, N-2,3-trimethyl-2-isopropyl-butanamide (WS-23), menthyl lactate (Frescolat® ML), menthong glycerol acetal (Frescolat® MGA), 3-(1-menthoxy)-propane-1,2-diol (TK-10), p-menthane-3,8-diol (also known as Coolact 38D), isopuregol (Coolact Also known as P), monomentyl succinate (Physcool®), monomentyl glutarate, o-menthylglycerol, menthyl N,N-dimethyl succinate, 2-(sec-butyl)cyclohexane-1-one (Freskomenthe), N-(pyrazole-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-toluyloxy)acetamide, 2-(4-ethylphenoxy)-N-(pyrazole-3-yl)-N-(thiophen-2-ylmethyl)acetamide, 3-(benzo[d][1,3]dioxol-5-yl)-N,N-diphenylacrylamide, 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-ethoxypropyl)-2-methoxyphenol,

[0037] 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-((2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol (including 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-(((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol) and 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-(((1R,2S,5R)-2- The following may be selected: sopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol), N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexane-1-carboxamide, N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide, and N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide.

[0038] Examples of p-methanecarboxamides include, for example, N-ethyl-p-menthane-3-carboxamide (commercially known as WS-3), N-ethoxycarbonylmethyl-p-menthane-3-carboxamide (WS-5), N-(4-methoxyphenyl)-p-menthane-3-carboxamide (WS-12), and N-tert-butyl-p-menthane-3-carboxamide (WS-14), N-(4-(cyanomethyl)phenyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (commercially also known as Evercool 180), and 2-isopropyl-5-methyl-N-(2-(pyridine-2-yl)ethyl)cyclohexane-1-carboxamide (commercially known as Evercool 180). This includes compounds such as (190, also known as 190) and (1R,2S,5R)-N-((S)-2-((R)-2-aminopropanamide)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide.

[0039] In a particular embodiment of 1, at least one activator (C) is selected from menthol, mint oil, N-ethyl-p-menthane-3-carboxamide (WS-3), N-(4-(cyanomethyl)phenyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (Evercool 180), 2-isopropyl-5-methyl-N-(2-(pyridine-2-yl)ethyl)cyclohexane-1-carboxamide (Evercool 190), and menthyl lactate.

[0040] Examples of sweeteners include, but are not limited to, sucrose, fructose, glucose, high-fructose corn syrup, corn syrup, xylose, arabinose, rhamnose, erythritol, xylitol, mannitol, sorbitol, inositol, acesulfame potassium, aspartame, neotame, sucralose, and saccharin, and mixtures thereof; trilobatin, hesperetine dihydrochalcone glucoside, naringin dihydrochalcone, mogroside V, and monk fruit (Luo Han) Guo) extract, rubusoside, raspberry extract, glycifylin, isomogroside V, mogroside IV, siamenoside I, neomogroside, muclodiodioside IIb, (+)-hernandulcin, 4β-hydroxyhernandulcin, bayunoside, flomisoside I, briodulcoside, brioside brionoside, abrusoside AE, cyclocarioside A, cyclocarioside I, albidiasaponin AE, glycyrrhizin,

[0041] This includes alaboglycyrrhizin, periandrin IV, pterocariosides A and B, osradin, polypodosides A and B, telesmosides A8-18, phyllodulcin, huangqioside E, neoastilbin, monatin, 3-acetoxy-5,7-dihydroxy-4'-methoxyflavanone, 2R,3R-(+)-3-acetoxy-5,7,4'-trihydroxyflavanone, (2R,3R)-dihydroquercetin 3-O-acetate, dihydroquercetin 3-O-acetate 4'-methyl ether, blazein, curculin, mavinrin, monerin, neocrine, pentazin, thaumatin, and combinations thereof. Some of the compounds listed above are known as sweetness enhancers and sweeteners. When used as sweetness enhancers, they are typically used below their sweetness detection threshold.

[0042] In a further aspect, flavored or scented products are provided, including flavor or fragrance compositions and product bases, such as orally acceptable carriers for products taken orally and skin-acceptable carriers for products that come into contact with the skin. In some respects, the product base may include salts (e.g., sodium bicarbonate, sodium carbonate, calcium carbonate, trisodium phosphate, and / or disodium hydrogen phosphate) that can act as buffers for imidazole cooling compounds represented by formula (I) (covering the compounds represented by formula (II)) when lactic acid is used as the solvent.

[0043] In some respects, orally acceptable carriers may contain one or more compatible solid or liquid excipients or diluents suitable for topical oral administration. “Compatible” means, when used herein, that the components of the composition can be mixed without interactions that would substantially reduce stability and / or efficacy. Carriers include common and conventional components of toothpastes, non-abrasive gels, subgingival gels, mouthwashes or rinses, mouth sprays, chewing gums, lozenges, and breath mints. The choice of carrier used is essentially determined by the way the composition is introduced into the oral cavity.

[0044] Carrier materials for toothpaste, toothpaste gel, or similar products typically include, for example, abrasives, sudsing agents, binders, humectants, flavoring agents, and sweeteners, etc., as disclosed in Benedict's U.S. Patent No. 3,988,433. Carrier materials for two-phase toothpaste formulations are disclosed in Lukacovic et al.'s U.S. Patents No. 5,213,790; No. 5,145,666 and No. 5,281,410, and Schaeffer et al.'s U.S. Patents No. 4,849,213 and No. 4,528,180. Carrier materials for mouthwash, rinse, or mouth spray typically include, for example, water, flavoring agents, and sweeteners, etc., as disclosed in Benedict's U.S. Patent No. 3,988,433.

[0045] Troche carrier materials include a candy base; chewing gum carrier materials include a rubber base, flavoring agent, and sweetener, as shown, for example, in U.S. Patent No. 4,083,955 by Grabenstetter et al. Sachet carrier materials typically include a sachet bag, flavoring agent, and sweetener. For subgingival gels used for delivery of activators into or near-periodontal pockets, “subgingival gel carriers” are selected, as shown, for example, in U.S. Patents No. 5,198,220 and 5,242,910 by Damani. Carriers suitable for the preparation of the compositions of this disclosure are well known in the art. Their selection will depend on secondary considerations such as taste, cost, and storability.

[0046] Further preferred types of orally acceptable carrier materials or excipients are listed in WO2010 / 059289, particularly on pages 17-31, which are incorporated by reference.

[0047] The compositions of the present invention are added to and incorporated into product bases by known methods. A sufficient amount may be added to provide a cooling effect. The percentage required to provide such an effect will naturally depend on the desired cooling effect, but a typical weight percentage is 0.01 to 0.5%. For example, in oral applications of the compounds of the present invention, such as toothpaste, floss, chewing gum, or white strips, the level of use may be about 0.00001% (0.01 ppm) to about 0.1% (1000 ppm); about 0.00005% (0.5 ppm) to about 0.1% (1000 ppm); about 0.0001% (1 ppm) to about 0.05% (500 ppm); about 0.005% (50 ppm) to about 0.03% (300 ppm); or about 0.001% (10 ppm) to about 0.01% (100 ppm) relative to the weight of the composition. When the compound of the present invention is used in a mouthwash, the level of use may be about 0.000001% (10 ppb) to about 0.01% (100 ppm) or about 0.0001% (1 ppm) to about 0.001% (10 ppm) relative to the weight of the composition. When the compound of the present invention is delivered topically, for example, in a shampoo and lotion, the level may be about 0.001% (10 ppm) to about 0.5% (5000 ppm) or about 0.01% (100 ppm) to about 0.4% (4000 ppm) relative to the weight of the composition. These are general guidelines, not strict boundaries, and inventors exploring specific effects may find other levels possible or even more desirable.

[0048] Compositions and methods are now described further with reference to the following non-limiting examples that describe specific embodiments.

[0049] example Example 1: 2-(methylthio)-1-(2-(5-(p-tolyl)imidazole-2-yl)piperidine-1-yl)propan-1-one Example 1a: tert-Butyl 2-(1H-imidazol-2-yl)piperidine-1-carboxylate: A solution of tert-butyl 2-formylpiperidine-1-carboxylate (9.5 g, 35.6 mmol) and glyoxal solution (40% in water, 25.9 g, 178 mmol) in methanol (100 mL) was added dropwise with ammonia solution (25% in water, 17.0 g, 249 mmol) at 0 °C. The solution was warmed to rt. (room temperature) and stirred at rt. for 16 h. Then, the solution was concentrated under reduced pressure and the resulting residue was extracted with ethyl acetate (100 mL * 3). Any precipitate was removed by filtration and the organic phase was washed with saturated aqueous NaHCO3 solution (100 mL) and brine (100 mL). Then, by concentrating the solution under reduced pressure, tert-butyl 2-(1H-imidazol-2-yl)piperidine-1-carboxylate (5.2 g, yield: 58%) was obtained as a white solid. GC / MS (EI): m / z (%): 251 (3) [M + , 195 (4), 178 (10), 150 (20), 134 (13), 122 (5), 95 (100), 82 (10), 57 (21).

[0050] Example 1b:tert-butyl-2-(4,5-dibromo-1H-imidazole-2-yl)piperidine-1-carboxylate:N-bromosuccinimide (7.4 g, 41.8 mmol) was added dropwise to a solution of tert-butyl-2-(1H-imidazole-2-yl)piperidine-1-carboxylate (5.0 g, 19.9 mmol) in dichloromethane (100 mL) at 0°C for more than 10 min. The mixture was stirred for a further 2 h at 0°C and then concentrated using a rotary evaporator. The residue was dissolved in ethyl acetate (250 mL), washed with water (100 mL x 2) and brine (100 mL), dried over MgSO4, and concentrated to obtain a very brown residue. The residue was recrystallized with dichloromethane / hexane (1:1) to obtain tert-butyl-2-(4,5-dibromo-1H-imidazole-2-yl)piperidine-1-carboxylate (6.0 g, yield: 74%) as a white solid. GC / MS (EI): m / z (%): 411 (2) [M+], 409 (4) [M+], 407 (2) [M+], 355 (6), 353 (12), 351 (6), 311 (11), 309 (22), 307 (11), 294 (11), 292 (22), 290 (11), 255 (50), 253 (100), 251 (50), 242 (12), 240 (24), 238 (12), 148 (9), 57 (50).

[0051] Example 1c :tert-butyl-2-(5-bromo-1H-imidazole-2-yl)piperidine-1-carboxylate (34.0 g, 90%, 74.8 mmol) and a suspension of Na2SO3 (94 g, 748 mmol) and water in ethanol (300 mL) were refluxed overnight. The mixture was then cooled and concentrated. The residue was separated between CH2Cl2 (200 mL) and H2O (200 mL). The aqueous layer was extracted with ethyl acetate (200 mL). *3) The combined organic layers were washed with brine (200 mL), dried with Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel to obtain tert-butyl-2-(5-bromo-1H-imidazole-2-yl)piperidine-1-carboxylate (23.0 g, yield: 93%) as a white solid. GC / MS (EI): m / z (%): 329 (3) [M+], 331 (3) [M+], 275 (10), 273 (10), 258 (9), 256 (9), 230 (20), 228 (20), 214 (26), 212 (26), 175 (100), 173 (100), 162 (9), 160 (9), 93 (8), 57 (44).

[0052] Example 1d:tert-butyl 2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-carboxylate: A pressure vessel was filled with tert-butyl 2-(5-bromoimidazole-2-yl)piperidine-1-carboxylate (400 mg, 1.211 mmol), p-tolylboronic acid (181 mg, 1.332 mmol, 1.1 equiv.), sodium carbonate (257 mg, 2.42 mmol, 2 equiv.), 1,1'-bis(diphenylphosphino)-ferrocene-palladium(II) dichloride dichloromethane complex (49 mg, 0.061 mmol, 0.05 equiv.), tetrahydrofuran (5 mL), and water (1 mL). The mixture was degassed by purging with nitrogen, and the vessel was sealed. The mixture was stirred and heated overnight to 100°C. The resulting mixture was cooled to 0°C, the tank was opened, and the contents were poured into aq.sat.NaHCO3 solution (50 mL). Extraction was performed with ethyl acetate (2 x 50 mL), washed with water (50 mL) and brine (50 mL), dried on MgSO4, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography using a gradient of ethyl acetate in heptane to obtain tert-butyl 2-(5-(p-tolyl)imidazole-2-yl)piperidine-1-carboxylate (314 mg, 0.920 mmol, 76% yield) as a white solid.

[0053] MS (EI, 70 eV): 341 (4, [M]+·), 285 (11), 268 (3), 240 (30), 185 (100), 172 (16), 91 (6), 57 (99). 1H NMR (DMSO-d6, 400MHz, mixture of alternating and non-alternating phases): δ 11.66-12.09 (m, 1H), 7.49-7.70 (m, 2H), 7.20-7.48 (m, 1H), 7.08-7.23 (m, 2H), 5.34 - 5.23 (m, 1H), 3.89 (br d, J=12.1 Hz, 1H), 3.05 (br t, J=10.9 Hz, 1H), 2.28 (s, 3H), 2.18-2.25 (m, 1H), 1.65-1.78 (m, 1H), 1.22-1.63 (m, 13H) ppm. 13C NMR (75 MHz, DMSO, mixture of tautomers) δ 155.1 (q), 147.5 (q), 140.2 (q), 135.3 (q), 132.7 (q), 129.4 (t), 124.6 (t), 112.5 (t), 79.3 (q), 63.3 (d), 49.7 (t), 41.2 (d), 28.5 (s), 28.4 (d), 26.8 (d), 25.3 (d), 21.2 (s), 19.9 (d) ppm.

[0054] Example 1eA solution of tert-butyl 2-(5-(p-tolyl)imidazole-2-yl)piperidine-1-carboxylate (304 mg, 0.890 mmol) in dichloromethane (3 mL) was titrated with trifluoroacetic acid (0.549 mL, 7.12 mmol, 8 equiv.) at 5°C. The resulting mixture was stirred at room temperature for 2 hours or until the starting materials were completely consumed. The mixture was poured into ice water (30 mL) and the pH was made basic by adding aqueous 1 M NaOH solution. The mixture was then extracted with dichloromethane (3 x 20 mL), dried over MgSO4, and concentrated under reduced pressure to obtain 2-(5-(p-tolyl)imidazole-2-yl)piperidine (160 mg, 0.664 mmol, 74% yield) as a pale yellow oil, which was used in the next step without further purification. MS (EI, 70 eV): 241 (6, [M]+·), 185 (100), 172 (13), 158 (8), 91 (3), 84 (4). 1H NMR (chloroform-d, 400MHz): δ 8.67-8.89 (br s, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 7.13 (s, 1H), 4.14 (dd, J=12.3, 3.1 Hz, 1H), 3.30 (br d, J=12.7 Hz, 1H), 2.71-2.84 (m, 1H), 2.37 (s, 3H), 2.15-2.27 (m, 1H), 2.01 (br dd, J=14.4, 3.2 Hz, 1H), 1.90 (br d, J=13.4 Hz, 1H), 1.67-1.77 (m, 2H), 1.32-1.46 ppm (m, 1H).

[0055] Example 1f:2-(methylthio)-1-(2-(5-(p-tolyl)imidazole-2-yl)piperidine-1-yl)propan-1-one:To a solution of 2-(5-(p-tolyl)imidazole-2-yl)piperidine (0.88 mmol) in dichloromethane (DCM) (2 mL), hydroxybenzotriazole (HOBt) (1.056 mmol, 1.2 equiv.) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (EDCI) (1.056 mmol, 1.2 equiv.) were added at 0-5°C, and the mixture was stirred for 0.5 hours at room temperature. Next, the mixture was treated with (methylthio)propanoic acid (0.968 mmol, 1.1 equiv.) and N,N-diisopropylethylamine (DIPEA) (0.88 mmol, 1 equiv.), and the resulting mixture was stirred at rt. for 16 h. The mixture was filtered to remove the solvent, and the crude product was purified by silica gel chromatography (SiO gradient in heptane) to obtain 2-(methylthio)-1-(2-(5-(p-tolyl)imidazole-2-yl)piperidine-1-yl)propan-1-one as a white solid.

[0056] MS (EI, 70 eV): 343 (2, [M]+·), 241 (17), 240 (100), 213 (13), 185 (18), 184 (9), 75 (55), 56 (11), 55 (9), 47 (10), 41 (11). 1H NMR (400 MHz, DMSO-d6, a mixture of stereoisotopes and interphases) δ 12.07, 11.99, 11.95, 11.76 (brs, 1H), 7.72 - 7.60 (m, 2H), 7.59 - 7.42 (m, 1H), 7.26 - 7.08 (m, 2H), 5.75 - 5.39 (m, 1H), 4.49 - 3.00 (m, 3H), 2.71 - 2.15 (m, 1H), 2.30 (s, 3H), 2.07 - 1.96 (m, 3H), 1.94 - 1.48 (m, 5H), 1.43 - 1.34 (m, 3H) ppm. 13C NMR (101 MHz, DMSO-d6, mixture of stereoisotropic isomers) δ 170.2 (q), 170.2 (q), 170.0 (q), 147.0 (q), 146.8 (q), 146.7 (q), 140.4 (q), 140.3 (q), 139.9 (q), 135.3 (q), 135.2 (q), 135.1 (q), 132.7 (q), 132.6 (q), 132.6 (q), 129.7 (t), 129.3 (t), 124.6 (t), 113.0 (t), 112.6 (t), 112.5 (t), 51.5 (t), 47.3 (t), 47.0 (t), 43.1 (d), 43.0 (d), 38.8 (d), 38.0 (t), 37.6 (t), 37.3 (t), 28.8 (d), 28.6 (d), 28.1 (d), 27.9 (d), 26.1 (d), 25.7 (d), 25.4 (d), 21.2 (s), 20.3 (d), 20.1 (d), 18.3 (s), 18.0 (s), 17.8 (s), 11.9 (s), 11.7 (s), 11.6 (s) ppm.

[0057] Example 2: 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)buta-3-en-1-one Example 1fFollowing the general procedure described above, the product described in the title was reacted with 2,2-dimethylbuta-3-enonic acid (170 mg, 1.492 mmol), HOBt (228 mg, 1.492 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (232 mg, 1.492 mmol), 2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine (300 mg, 1.243 mmol), and DIPEA (0.391 ml, 2.238 mmol) in dichloromethane (30 mL) to obtain the product described in the title as a white solid (255 mg, yield: 68%).

[0058] GC / MS (EI): m / z (%): 337 (1) [M+], 322 (3), 268 (10), 240 (89), 213 (6), 197 (6), 172 (100), 117(8), 69 (8). 1H NMR (300 MHz, DMSO-d6, mixture of tautomers) δ 12.04 - 11.70 (m, 1H), 7.83 - 7.51 (m, 2H), 7.51 - 7.37 (m, 1H), 7.32 - 7.00 (m, 2H), 6.23 - 6.10 (m, 1H), 5.81 - 5.34 (m, 1H), 5.27 - 4.80 (m, 2H), 4.60 - 2.96 (m, 2H), 2.43 - 2.17 (m, 4H), 1.87 - 1.43 (m, 5H), 1.40 - 1.19 (m, 6H). 13C NMR (75 MHz, DMSO-d6, mixture of tautomers) δ 174.1 (q), 147.0 (q), 144.4 (t), 139.9 (q), 135.2 (q), 132.7 (q), 129.7 (t), 129.3 (t), 124.5 (t), 112.9 (t), 112.5 (d), 52.7 (t), 47.6 (t), 45.1 (s), 43.9 (d), 28.0 (d), 27.4 (s), 27.1 (s), 25.3 (d), 21.2 (s), 20.2 (d) ppm.

[0059] Example 3: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one Example 3a:2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)buta-3-en-1-one: To a solution of 2-methylbuta-3-enonic acid (0.597 g, 5.97 mmol) in 100 mL of dichloromethane, HOBt (0.914 g, 5.97 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (0.926 g, 5.97 mmol) were added at 0-5°C, and the mixture was stirred for 0.5 hours at room temperature. Next, 2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine (1.2 g, 4.97 mmol) and DIPEA (1.563 ml, 8.95 mmol) were added, and the mixture was stirred at rt. for 16 h. The suspension was filtered to remove the solvent, and the crude product was purified by silica gel chromatography (hexane:MTBE=3:1) to obtain 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)buta-3-en-1-one (808 mg, yield: 50%) as a white solid.

[0060] GC / MS (EI, mixture of stereoisopeptides, ratio 1:2): Isopeptide 1: m / z (%): 323 (2) [M+], 268 (5), 240 (100), 172 (95), 117 (7), 84 (3), 55 (11). Isopeptide 2: m / z (%): 323 (2) [M+], 268 (5), 240 (100), 211 (6), 172 (81), 117 (7), 84 (2), 55 (10). 1H NMR (300 MHz, DMSO-d6, a mixture of stereoisotopes and inter-stereoisotopes) δ 12.06, 11.81 (brs, 1H), 7.69 - 7.62 (m, 2H), 7.49 (s, 1H), 7.15 (d, J = 7.3 Hz, 2H), 6.12 - 5.70 (m, 2H), 5.47 - 4.81 (m, 2H), 4.63 - 2.90 (m, 3H), 2.81 - 2.35 (m, 1H), 2.29 (s, 3H), 1.78 - 1.29 (m, 5H), 1.17 (t, J = 5.6 Hz, 3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisotropic isomers) δ 172.7 (q), 172.5 (q), 172.3 (q), 147.1 (q), 146.7 (q), 140.3 (q), 139.8 (q), 139.6 (t), 139.1 (t), 135.3 (q), 132.7 (q), 129.4 (t), 124.6 (t), 115.4 (d), 115.3 (d), 113.0 (t), 112.6 (t), 51.7 (t), 51.3 (t), 47.0 (t), 46.8 (t), 42.8 (d), 42.6 (d), 40.2 (t), 39.3 (t), 38.6 (d), 28.4 (d), 28.1 (d), 26.1 (d), 25.8 (d), 25.3 (d), 21.2 (s), 20.3 (d), 20.1 (d), 18.4 (s), 18.2 (s), 18.0 (s) ppm.

[0061] Example 3b2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one (350 mg, 1.082 mmol) was hydrogenated and catalytically reacted with 10% Pd / C (216 mg, 0.216 mmol) in ethyl acetate (20 ml) under a hydrogen atmosphere overnight. The mixture was then purged with nitrogen, filtered on Celite, and evaporated to obtain the crude material, which was purified by flash column chromatography (hexane:MTBE=3:1) to give the title product (290 mg, yield: 82%) as a white solid.

[0062] GC / MS (EI): m / z (%): 325 (10) [M+], 268 (2), 240 (100), 224 (3), 185 (10), 159(2), 142 (1), 84 (2), 57 (4). 1H NMR (300 MHz, DMSO-d6, a mixture of stereoisos and interstices) δ 12.05 - 11.72 (m, 1H), 7.73 - 7.53 (m, 2H), 7.51 - 7.40 (m, 1H), 7.27 - 7.03 (m, 2H), 5.81 - 5.28 (m, 1H), 4.61 - 3.16 (m, 2H), 2.87 - 2.58 (m, 1H), 2.38 - 2.19 (m, 4H), 1.86 - 1.49 (m, 5H), 1.46 - 1.23 (m, 2H), 1.09 - 0.95 (m, 3H), 0.94 - 0.80 (m, 3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisotropic isomers) δ 175.4 (q), 175.2 (q), 147.3 (q), 147.2 (q), 140.5 (q), 140.1 (q), 135.2 (q), 132.7 (q), 129.7 (t), 129.3 (t), 124.6 (t), 112.9 (t), 112.6 (t), 51.5 (t), 46.9 (t), 46.8 (t), 42.6 (d), 38.6 (d), 36.8 (t), 36.5 (t), 36.1 (t), 29.2 (d), 28.9 (d), 28.4 (d), 27.2 (d), 26.9 (d), 26.2 (d), 25.4 (d), 25.2 (d), 21.2 (s), 20.3 (d), 18.4 (s), 17.7 (s), 17.3 (s), 12.2 (s), 12.0 (s), 11.9 (s) ppm.

[0063] Example 4: 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)propan-1-one Example 1fFollowing the general procedure described: 2-methyl-2-(methylthio)propanoic acid (0.267 g, 1.989 mmol), HOBt (305 mg, 1.989 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (309 mg, 1.989 mmol), 2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine (400 mg, 1.657 mmol), and DIPEA (0.521 ml, 2.980 mmol) in dichloromethane (30 mL) were reacted to obtain the title product (287 mg, yield: 48%) as a white solid.

[0064] GC / MS (EI): m / z (%): 357 (5) [M+], 342(7), 268 (11), 240 (100), 185 (11), 159 (5), 117 (4), 89 (10). 1H NMR (300 MHz, DMSO-d6, mixture of tautomers) δ 12.06, 11.82 (brs, 1H), 7.80 - 7.54 (m, 2H), 7.50 (s, 1H), 7.33 - 7.08 (m, 2H), 6.15 - 5.89 (m, 1H), 4.92 - 2.73 (m, 2H), 2.47 - 2.23 (m, 4H), 2.19 - 2.03 (m, 3H), 1.86 - 1.35 (m, 11H). 13C NMR (75 MHz, DMSO-d6, mixture of tautomers) δ 171.1 (q), 170.8 (q), 148.3 (q), 146.8 (q), 140.1 (q), 136.1 (q), 135.2 (q), 132.6 (q), 131.6 (q), 129.7 (t), 129.7 (t), 129.3 (t), 124.6 (t), 112.8 (t), 53.5 (t), 48.4 (t), 47.6 (q), 44.4 (d), 29.3 (d), 28.6 (d), 27.6 (s), 25.8 (d), 21.2 (s), 20.2 (d), 12.9 (s) ppm.

[0065] Example A : Solubility of the compound represented by formula (I) 0.4 g of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one (white solid) was added to a 20 ml vial, followed by the addition of 1.6 g of each solvent as indicated in Table 1 below. The vial was heated to approximately 50°C with gentle shaking for 1 hour. If 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one did not dissolve, 2 g of each solvent was added (resulting in a composition containing 10 wt% of the compound represented by formula (I)), and the mixture was gently shaken again at approximately 50°C for an additional time. If 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one still did not dissolve, 4 g of each solvent was added (resulting in a composition containing 5 wt% of the compound represented by formula (I)), and the mixture was gently shaken again at approximately 50°C for an additional time.

[0066] If 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one did not dissolve, the vial was removed from the heat and allowed to cool to room temperature. If no precipitate was observed, the vial was placed in the refrigerator overnight (approximately 4°C). If 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one still did not dissolve, the above procedure was repeated, starting with 0.05 g of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one and 0.95 g of each solvent as indicated in Table 1 below. If it still did not dissolve, 1 g of each solvent was added (resulting in a composition containing 2.5 wt% of the compound represented by formula (I)). If it still did not dissolve, further solvent was added. The results are shown in Table 1 below.

[0067] [Table 1] a) L-lactic acid; Purity: 86.7% by weight b) dl-lactic acid; purity: 88% by weight c) The same results were observed for the solubility of (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one.

[0068] As can be seen from the table above, - At least 20% by weight of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one is soluble in lactic acid or ethanol; - At least 10% by weight (but less than 20% by weight) of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one is soluble in butyl lactate, ethyl lactate, isopropyl alcohol, or isopropylideneglycerol; - 2.5% by weight of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one is soluble in propylene glycol or triethyl citrate (two common solvents suitable for oral care compositions); - 1% by weight of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one is soluble in triacetin.

[0069] Example B Stability of solutions containing the compound represented by formula (I) over time at different temperatures. The compound represented by formula 1 was 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one (hereinafter referred to as "the compound"). The test procedure using numerous different solvents was as follows: 1.6 g of solvent was added to 1.0.4 g of compound. This corresponds to 20% solvent. 2. This mixture was heated to 50°C and shaken for 1 hour. 3. If the compound dissolved, the solution was allowed to cool to room temperature, and if any residue remained, it was stored overnight at 4°C. 4. If crystals grew, an additional 2 g of solvent was added (this immediately corresponds to a 10% solution), and step 2 was repeated. 5. The observations and actions described in Step 3 were carried out. 6. If the 10% combination from step 4 was not a solution, an additional 4g of solvent was added (this immediately corresponds to a 5% solution), and step 2 was performed. 7. The observations and actions of Step 3 were carried out. If crystals grew, all of the solvents were considered unsuitable.

[0070] The following tests were repeated using higher concentrations of any solvent in which the compound did not crystallize in a 20% by weight solution: 1 g of solvent was added to 1.1 g of the compound. This corresponds to a 50% solution. 2. The mixture was heated to 50°C and shaken for 1 hour. 3. If the compound dissolved, the solution was cooled to room temperature, and if any residue remained, it was stored overnight at 4°C. 4. If crystals grew, an additional 0.5 g of solvent was added (this immediately corresponds to a 40% solution), and step 2 was repeated. 5. The observations and actions described in Step 3 were carried out. 6. If the 40% combination in Step 4 was not a solution, an additional 0.83 g of solvent was added (this immediately corresponds to a 30% solution), and Step 2 was performed. 7. The observations and actions described in Step 3 were carried out.

[0071] Table 2 below shows the solvents in which at least 5% by weight of the compound was soluble (see Example A), and the weight percentages and conditions under which they were considered "good" beyond a week at room temperature. [Table 2] d) L-lactic acid; Purity: 86.7% by weight e) dl-lactic acid; purity: 88% by weight The same results were observed regarding the solubility of f)(2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one.

[0072] As can be seen from Table 2, a) A composition containing 50% by weight of the compound represented by formula (I) using lactic acid as the solvent is stable for at least 4 weeks both in a refrigerator and at room temperature (RT); b) A composition containing 30% by weight of the compound represented by formula (I) using ethanol as the solvent is stable in a refrigerator; c) A composition containing 20% ​​by weight of the compound represented by formula (I), using ethanol as the solvent, for at least 4 weeks at room temperature (RT); d) A composition containing 10% by weight of the compound represented by formula (I) using ethyl lactate as the solvent is stable for at least 4 weeks both in a refrigerator and at room temperature (RT).

[0073] Example C: Preparation of Flavor Compounds The flavor agent composition was prepared by mixing the following components: [Table 3]

[0074] [Table 4]

[0075] [Table 5]

[0076] Flavoring compositions can be added to oral care products (e.g., mouthwash) or confectionery (e.g., chewing gum).

Claims

1. A composition, the following: a) Equation (II) 【Chemistry 1】 During the ceremony, R contains any one S atom, C ３ ~C ７ It is a branched alkyl or alkenyl, Compounds represented by; and b) At least one solvent selected from the group consisting of butyl lactate, ethanol, ethyl lactate, isopropyl alcohol, isopropylideneglycerol, and lactic acid, or mixtures thereof. The composition comprising the above.

2. The composition according to claim 1, wherein the cooling compound represented by formula (II) is 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)propan-1-one, 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)propan-1-one, or 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)buta-3-en-1-one, or a mixture thereof.

3. The composition according to claim 1 or 2, wherein solvent (b) is lactic acid.

4. A fragrance or flavor formulation comprising a composition as defined in any one of claims 1 to 3, further comprising at least one activator selected from the group consisting of flavors and fragrances, and optionally comprising a sweetener.

5. A fragranced or flavored product comprising the composition according to claim 1, or the formulation according to claim 4, in proportion to the product base and the proportion that provides a cooling effect.

6. A method for incorporating at least one cooling compound (a) as defined in claim 1 into a fragranced or flavored product, comprising (a) blending at least one cooling compound represented by formula (I) with at least one solvent selected from butyl lactate, ethanol, ethyl lactate, isopropyl alcohol, isopropylideneglycerol, and lactic acid, or a mixture thereof, and adding the resulting composition to the product.

7. A method for providing a product with a cooling sensation to the skin or mucous membrane, comprising adding a proportion of the composition according to any one of claims 1 to 3 to a product base that provides a cooling effect.

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