Derivatives of menthol and uses thereof

Abstract

A compound comprising a glycine menthol ester. The glycine menthol ester includes menthol linked to glycine or a glycine derivative through an ester bond. Groups on the N atom are designated R1 and R2, R1 and R2 are independently selected from the group consisting of: H, alkyl, and R1 and R2 together with the N atom to which they are attached form a 4 to 8 membered ring. R1 and R2 each contain up to 20 carbon atoms.

Description

Background Technology

[0001] Natural menthol is known as an agent that provides a cooling sensation (“cooling agent”) and has been used for many years as an ingredient in various consumer products such as candies and chewing gum, toothpaste, mouthwash, shaving cream, and skin cream. Menthol’s ability to chemically trigger the cold-sensitive TRPM8 receptor is what causes its well-known cooling sensation when inhaled, ingested, or applied to the skin. TRPM8 is an ion channel that, upon activation, allows sodium… + and Ca 2+ Ions enter cells, leading to depolarization and the generation of action potentials. Application of menthol to the skin or mucous membranes directly causes membrane depolarization, followed by calcium influx via voltage-dependent calcium channels. This provides evidence for the role of TRPM8 and other TRP receptors in mediating our sensory interactions with the environment in response to cold, similar to their response to menthol. In a taste dilution test, the cooling threshold of (-)-menthol was 0.8 ppm.

[0002] (-)-Menthol chemical structure

[0003]

[0004] For decades, there has been interest in developing organic compounds that can rival or surpass menthol in their perceived cooling sensation. Most notably, a series of Wilkinson Sword (WS) compounds have been developed, some of which are already used in consumer products. Since these developments began in the 1970s, numerous other cooling agents have been proposed and developed—some of which exceed menthol's cooling potential by >200 times. Several cooling agents are known to have a carboxyl group linked to menthol, such as WS-3, WS-5, WS-12, Frescolat ML, and compound 1 (expected to be approximately 1000 times cooler than menthol).

[0005]

[0006] Chinese patent application (CN 1915966) describes the use of menthol derivatives N,N-dimethylglycine menthol ester, N,N-diethylglycine menthol ester, and N,N-dihydroxyethylglycine menthol ester as transdermal agents to promote subcutaneous absorption of transdermal formulations. This Chinese application describes the use of these menthol derivatives in ointments, creams, patches, pharmaceuticals, and cosmetics. Summary of the Invention

[0007] In a first aspect, this application describes compounds of formula (I):

[0008]

[0009] wherein R1and R2are independently selected from the group consisting of H, alkyl, and R1and R2together with the N atom to which they are attached form a 4 to 8 membered ring. R1and R2each contain up to 20 carbon atoms, and the compound is not N,N-dimethylglycine menthol ester, N,N-diethylglycine menthol ester, or N,N-dihydroxyethylglycine menthol ester.

[0010] In a second aspect, the present application describes a method of providing a cooling sensation in the oral cavity comprising: orally administering a cooling agent, wherein the cooling agent is of formula (I).

[0011]

[0012] wherein R1and R2are independently selected from the group consisting of H, alkyl, and R1and R2together with the N atom to which they are attached form a 4 to 8 membered ring, and R1and R2each contain up to 20 carbon atoms.

[0013] In a third aspect, the present application describes a method of making a glycine menthol ester. The method comprises reacting menthol with bromoacetyl bromide or chloroacetyl chloride to form an ester, isolating the ester, and reacting the ester with an amine to form the glycine menthol ester.

[0014] In a fourth aspect, the present application describes an oral hygiene product or an edible product comprising: a compound of formula (I).

[0015]

[0016] and a solvent or carrier, wherein R1and R2are independently selected from the group consisting of H, alkyl, and R1and R2together with the N atom to which they are attached form a 4 to 8 membered ring, and R1and R2each contain up to 20 carbon atoms.

[0017] In a fifth aspect, the present application describes an insect repellent comprising: a compound of formula (I).

[0018]

[0019] and a carrier. R1and R2are independently selected from the group consisting of H, alkyl, and R1and R2together with the N atom to which they are attached form a 4 to 8 membered ring, and R1and R2each contain up to 20 carbon atoms.

[0020] In a sixth aspect, the present application includes a compound comprising: formula (II),

[0021]

[0022] or formula (III).

[0023]

[0024] wherein R1and R2are independently selected from the group consisting of H, alkyl, and R1and R2together with the N atom to which they are attached form a 4 to 8 membered ring, and R1and R2each contain up to 20 carbon atoms, and L is alkylene, arylene, -(CH2) X -(OCH2CH2) n O-(CH2) X -(wherein x and n are independently 1 to 10, and x + n is up to 10) or (wherein R1and R2are each independently selected from the group consisting of H and OH, and a and b are independently 0, 1, 2, or 3), wherein the L group has up to 20 carbon atoms.

[0025] Definitions

[0026] Aromatic ring or aryl means a monovalent aromatic carbocyclic or heteroaryl group, preferably having 3 to 10 carbon atoms. The aromatic ring or aryl group can be monocyclic (e.g., phenyl (or Ph)) or polycyclic (e.g., naphthyl), and can be unsubstituted or substituted. Preferred aryl groups include phenyl, naphthyl, furanyl, thienyl, pyridyl, indolyl, quinolyl, or isoquinolyl.

[0027] Alkyl (or alk-yl- or alk-) means a monovalent, substituted or unsubstituted, saturated or unsaturated, straight chain, branched, or cyclic hydrocarbon chain, preferably containing 1 to 20 carbon atoms. More preferred alkyl groups are alkyl groups containing 7 to 16 carbon atoms. Preferred cycloalkyl groups have 3 to 10 (preferably 3 to 6) carbon atoms in their ring structure. Suitable examples of unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, sec-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl. Alkylaryl groups and alkylheterocyclyl groups are alkyl groups covalently bonded to an aryl or heterocyclyl group, respectively. Unsaturated alkyl means an alkyl group containing one or more double and / or triple bonds.

[0028] “Substituted” means that the moiety contains at least one (preferably 1-3) substituents. Suitable substituents include hydroxyl (-OH), amino (-NH2), oxyl (-O-), carbonyl (-CO-), thiol, alkyl, alkoxy, halogen, nitrile, nitro, aryl, and heterocyclyl groups. These substituents can optionally be further substituted with 1-3 substituents. Examples of substituted substituents include carboxamide, alkylthiol, alkylsulfonyl, alkylamino, dialkylamino, carboxylate, alkoxycarbonyl, alkylaryl, aralkyl, alkylheterocycle, etc.

[0029] An arylene group refers to a divalent aromatic carbocyclic or heteroaromatic group, preferably having 3 to 10 carbon atoms. The arylene group can be monocyclic (e.g., phenylene (or Ph)) or polycyclic (e.g., naphthylene), and can be unsubstituted or substituted. Preferred arylene groups include phenylene, naphthylene, furanylene, thiopheneylene, pyridylene, indoleylene, quinolinylene, or isoquinolinylene.

[0030] Alkylene refers to a divalent, substituted or unsubstituted, saturated or unsaturated, straight-chain, branched or cyclic hydrocarbon chain, preferably containing 1 to 20 carbon atoms. More preferably, alkylene groups are alkylene groups containing 7 to 16 carbon atoms. Preferred cycloalkylene groups have 3 to 10 (preferably 3 to 6) carbon atoms in their ring structure. Suitable examples of unsubstituted alkylene include methylene, ethylene, propylene, isopropylene, cyclopropylene, butylene, isobutylene, tert-butylene, sec-butylene, cyclobutylene, pentylene, cyclopentylene, hexylene, and cyclohexylene. Attached Figure Description

[0031] Figure 1 This is a graph showing the average area ratio (Comp. / IS) of XI-1-60 and menthol in ethanol measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0032] Figure 2 This is a graph showing the average area ratio (Comp. / IS) of XI-1-60 and menthol in propylene glycol (PG) measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0033] Figure 3 The graph shows the average area ratio (Comp. / IS) of XI-1-60 and menthol in water measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0034] Figure 4 This is a graph showing the average area ratio (Comp. / IS) of XI-1-50 and menthol in ethanol measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0035] Figure 5 This is a graph showing the average area ratio (Comp. / IS) of XI-1-50 and menthol in PG measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0036] Figure 6is a graph showing the average area ratio (Comp. / IS) of RK-2-10 and menthol in PG measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0037] Figure 7 is a graph showing the average area ratio (Comp. / IS) of RK-2-10 and menthol in PG measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0038] Figure 8 is a graph showing the average area ratio (Comp. / IS) of RK-2-10 and menthol in PG measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0039] Figure 9 is a graph showing the average area ratio (Comp. / IS) of RK-2-10 and menthol in PG measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0040] Figure 10 is a graph showing the average area ratio (Comp. / IS) of RK-2-10 and menthol in PG measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0041] Figure 11 is a graph showing the time and intensity of the cooling sensation of menthol and various glycine menthol esters in a lozenge.

[0042] Figure 12 is a graph showing the time and intensity of the cooling sensation of menthol and various glycine menthol esters in a beverage model system.

[0043] Figure 13 is a graph showing the time and intensity of the cooling sensation of menthol and various glycine menthol esters in a mouthwash. DETAILED DESCRIPTION

[0044] The present application describes glycine menthol esters, their use as cooling agents, and methods of making glycine menthol esters. A large body of experimental data in the present application is published in Klumpp, DA, et al., “Synthesis of Menthol Glycinates and Their Potential as Cooling Agents.” ACS Omega, vol. 5, no. 8, pp. 4043-4049 (2020). Preferably, the glycine menthol ester is an ester comprising a menthol group linked to a glycine or a glycine derivative through an ester linkage. These glycine menthol esters are well suited to provide a long-lasting cooling effect and are useful as flavoring agents in food products. The ester hydrolyzes in an aqueous environment at a slow rate, providing a slow release of menthol and glycine or glycine derivative. As the hydrolysis reaction proceeds, more menthol is available to act on the TRPM8 receptor, providing a cooling effect over a longer period of time. These compounds can also provide a delay in the onset of the cooling sensation. Taste tests indicate that these glycine menthol esters provide a long-lasting cooling effect at the lowest concentrations, far exceeding menthol itself. In addition, glycine provides a sweet taste and acts as a flavor enhancer, and it is believed that glycine can enhance the cooling sensation of menthol. The amine functionality of glycine can impart good solubility properties to the glycine menthol esters, making these compounds easier to incorporate in a variety of food products. The glycine menthol esters have the following formulas (I), (II), and (III).

[0045]

[0046] Formula (I) comprises a menthol group linked to a glycine derivative through an ester linkage. The glycine menthol ester can also be referred to as a menthol glycinate. Formulas (II) and (III) illustrate a glycine menthol ester comprising two menthol groups. R1and R2may independently be hydrogen or an alkyl group. R1and R2each comprise up to 20 carbon atoms. R1and R2may be different or the same. R1and R2may also form a ring with the nitrogen as part of the ring. The ring can be, for example, a 4-, 5-, 6-, 7-, or 8-membered ring.

[0047] Examples of R1and R2include methyl, ethyl, propyl, butyl, cyclopropyl, ethyl methyl ether, isoamyl, benzyl, isopropyl, isobutyl, t-butyl, and ethyl pyridine. Examples where R1and R2form a ring comprising a nitrogen atom include a pyrrolidine ring and a piperidine ring.

[0048] The L group in Formula (III) is an alkylene, arylene, -(CH2) X -(OCH2CH2) n O-(CH2) X -(where x and n are independently 1 to 10, and x + n is up to 10) or

[0049]

[0050] (wherein R1and R2are each independently selected from H and OH, and a and b are independently 0, 1, 2, or 3), wherein the L group has up to 20 carbon atoms. Examples of L include (CH2) X wherein X = 1 to 20, such as methylene, (CH2)2,

[0051] (CH2)3, (CH2)4, (CH2)(CH)(CH3), and (CH2)(CH2))(CH)(CH3).

[0052] The process to produce the desired glycine menthol ester includes first reacting menthol with bromoacetyl bromide or a similar acid bromide, and then reacting the product with an amine to form the compound of interest. The bromide can be readily displaced by a variety of amines, including ammonia. Chloroacetyl chloride can also be used to react with menthol to produce an ester of chloroacetic acid. The substituents on the amino group can be prepared by simple displacement chemistry. Scheme 1 below illustrates the first step, the reaction of menthol with bromoacetyl bromide to form product 2. Product 2 can then be reacted with a variety of amines to produce the desired product.

[0053] Scheme 1

[0054]

[0055] A variety of glycine menthol esters can be prepared from the ester of bromoacetic acid and an amine. Secondary amines have been found to generally give the desired substituted product in good yield. If a slight excess of the amine is used, most of the conversion will reach 100%.

[0056] Glycine menthol esters have the same or similar uses as menthol and provide similar cooling. Glycine menthol esters can be included in toothpaste, mouthwash, candy, chewing gum, mints, skin cream, aftershave products, smoking products, insect repellents, and flavorings and perfumes. Glycine menthol esters can be used to provide a cooling sensation, to provide a flavoring, to relieve mild sore throat or mild mouth or throat irritation, to reduce skin itch, to relieve mild pain and distress, to treat sunburn, to treat bad breath, and as a perfume that highlights floral notes.

[0057] Glycine menthol ester can be included in formulations containing solvents or carriers to dissolve, dilute, carry, disperse, or deliver the glycine menthol ester. Such solvents or carriers include water, castor oil, citric acid esters of mono- and di-glycerides, ethyl acetate, glycerol (glycerin), glycerol diacetate, isopropyl alcohol, mono- and di-glycerides, and propylene glycol mono- and di-esters of fatty acids. For example, a chewing gum including glycine menthol ester can also contain gum base, sugar, plasticizer, flavoring agent, colorant, and / or polyol. The insect repellent can include water, glyceryl stearate, beeswax, vegetable glycerin, xanthan gum, potassium sorbate, and / or citric acid.

[0058] Effective concentrations of the glycine menthol esters described herein can be determined by routine experimentation. For example, a concentration ladder can be used to determine the concentration needed to achieve the intended result. Different uses can require different concentrations to achieve the intended effect. When the glycine menthol ester is used as a flavoring agent, the concentration can be, for example, 1000 ppm to 0.1 ppm. Preferred concentrations are 100 to 0.5 ppm, including 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, and 0.6 ppm.

[0059] Examples

[0060] Chemical and Material Synthesis

[0061] Bromoacetate (Compound 2 below) was prepared from menthol and bromoacetyl bromide in quantitative yield, optionally using sodium carbonate as a base. Dichloromethane can be used as a solvent, however, other solvents can also be used. Isolation of the product included simple filtration of the solution to remove sodium bicarbonate and evaporation of the solvent under reduced pressure (Scheme 1). Compound 2 is well suited for further synthetic elaboration as the bromomethyl group is reactive to substitution.

[0062] Scheme 1

[0063]

[0064] A series of glycine menthol esters have been prepared from the bromoacetate (see Scheme 2 and Scheme 3). Primary and secondary amines have been found to generally give the desired substitution product in good yield. Optimized procedures using diethylamine provided a 95% conversion to compound 3 with a small amount of unreacted bromide 2. NMR and GC-FID indicated compound 3 to be a minimum of 99% pure. Other secondary amines provided the expected substitution products (compounds 4, 5, and 6). If a slight excess of amine is used, most conversions will reach 100%. A primary amine (isopropylamine) was used to provide compound 7 (DK-2-39 and DK-1-60 are alternate compound names for compound 7 in the study record references). The chemical reaction can also be accomplished using dichloromethane or diethyl ether as the solvent and sodium carbonate or sodium hydroxide as the base.

[0065] Scheme 2

[0066]

[0067] Scheme 3

[0068]

[0069] A synthetic method has been developed that produces compound 4 in high yield with only filtration and solvent removal used in the reaction work-up. Product purification is accomplished using vacuum distillation. Distillation of compound 4 effectively removes any unreacted starting material dimethylamine and the bromoester (compound 2). The ease of distillation will facilitate large scale synthesis of the purified aminoester product.

[0070] A variety of secondary amines provided the corresponding glycine menthol ester. This includes dialkyl amines to give products 3, 6, 9, 10, 15, and 16 (see Table 1 below). Heterocyclic systems, such as pyrrolidine and piperidine, were also found to give the substitution product in good yield (11 and 5, respectively). Primary amines also gave the expected substitution products 7, 12, 14, and 17. The synthetic method is amenable to incorporating structural components such as cycloalkyl groups, benzyl groups, ethers, and heterocycles. In the case of pyridyl derivative 18, the compound was modeled after the known cooling agent amide 19 (FEMA 4549) which is expected to be about 100 times more cooling than menthol.

[0071]

[0072] Table 1: Products and yields of the substitution reaction of compound 1 with amines or ammonia.

[0073]

[0074] In addition to mono-substitution, products can also be prepared by di-substitution reactions. When excess compound 2 is used, isopropylamine reacts twice and the product 20 is isolated. Similarly, N,N'-dimethylethylenediamine reacts twice with compound 2 to give product 21. Both 20 and 21 are purified by distilling off excess compound 2 and then using silica gel chromatography.

[0075] Table 2: Di-substitution products

[0076]

[0077] For most of the substitution reactions described above, optimized procedures involve the use of excess amine nucleophile. The pure glycine menthol ester product is isolated by removing the ethyl acetate solvent and excess amine under reduced pressure. The glycine menthol ester product is then typically distilled at 150-220 °C, 1 mm Hg. Optimization studies indicate that excess amine enables the substitution chemistry to be completed in relatively short times. For example, dibutylamine reacts with product 2 of Scheme 1 to provide product 10, and the substitution reaction is only 79% complete after 3 hours with 1.1 equivalents of amine. If the amount of dibutylamine is increased to 1.6 equivalents (0.13 M in ethyl acetate), the substitution reaction is 100% complete in less than 3 hours.

[0078] Preparation of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-2-bromoacetate (compound 2).

[0079] Dissolve (L)-menthol (7.2 g, 0.046 mmol) in 100 mL CH2Cl2and add anhydrous Na2CO3. Cool the resulting solution to 0 °C and the flask is fitted with a CaCl2drying tube. Then add bromoacetyl bromide (4.0 mL, 0.046 mol) and remove the cooling bath and stir the solution for at least four hours. After the reaction period, filter the solution through glass wool and remove the solvent by vacuum. The product is isolated as a clear colorless oil (12.2 g, 0.044 mol, 96%). Analysis of the crude product by GC-FID and NMR indicates that the product is very pure, however, the oil can be further purified by distillation (ca. 120 °C, 2 mm). The yield of the crude product varies between 95-100% by repeating the procedure. 1H NMR (300 MHz, CDC13) δ, 0.78 (d, 3H, J = 6.9 Hz), 0.84-0.96 (m, 7H), 0.96-1.14 (m, 2H), 1.40-1.58 (m, 2H), 1.64-1.74 (m, 2H), 1.88-1.97 (m, 1H), 1.98-2.07 (m, 1H), 3.80-3.82 (m, 2H), 4.70-4.79 (m, 1H).13C NMR (75 MHz, CDC13) δ, 16.2, 20.7, 22.0, 23.3, 26.1, 26.3, 31.4, 34.1, 40.5, 46.9, 76.5, 166.9. Low resolution MS (electron impact): 197 (M-80), 141, 139, 138 (100), 123, 109.

[0080] General procedure for synthesis of menthyl glycinate (1° amine).

[0081] The amine (0.02 mmol) was dissolved in 25 mL EtOAc, followed by the addition of NaOH (0.6 g, 15 mmol) and anhydrous sodium sulfate (0.5 g, 3.5 mmol). To this solution was slowly added (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-bromoacetate (compound 2, 1.68 g, 6.06 mmol). The mixture was stirred for 6 hours or until GC-FID analysis showed no remaining bromoester (2). The solution was then filtered through a glass wool plug and the solvent removed under reduced pressure. For low boiling point amines, the excess amine was removed in this step. For non-volatile amines, fractional distillation can be required. Final purification of the menthyl glycinate was achieved by vacuum distillation.

[0082] General procedure for synthesis of menthyl glycinate (2° amine).

[0083] (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-bromoacetate (compound 2, 1.68 g, 6.06 mmol) was dissolved in 25 mL EtOAc. To this solution was added the amine (9 mmol), followed by the addition of NaOH (0.6 g, 15 mmol) and anhydrous sodium sulfate (0.5 g, 3.5 mmol). The mixture was stirred for 6 hours or until GC-FID analysis showed no remaining bromoester (2). The solution was then filtered through a glass wool plug and the solvent removed under reduced pressure. For low boiling point amines, the excess amine was removed in this step. For non-volatile amines, fractional distillation can be required. Final purification of the menthyl glycinate was achieved by vacuum distillation.

[0084] Product 4-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(dimethylamino)acetate

[0085] Using the general procedure with 2° amine, (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with dimethylamine (2.0 M in THF) to provide the glycine menthol ester 4 as a clear oil (about 140 °C at 1 mm boiling point) in 86% yield. 1 H NMR (300 MHz, CDC13) δ, 0.36-0.42 (m, 2H), 0.42-0.48 (m, 2H), 0.78 (d, 3H, J = 7.0 Hz), 0.85-0.90 (m, 6H), 0.96-1.13 (m, 2H), 1.34-1.44 (m, 1H), 1.46-1.57 (m, 1H), 1.67-1.73 (m, 2H), 1.82-1.90 (m, 1H), 1.97-2.04 (m, 1H), 2.20-2.26 (m, 1H), 2.40 (bs, 1H), 3.34-3.42 (m, 2H), 4.71-4.76 (m, 1H). 13 C NMR (75 MHz, CDC13) δ, 16.2, 20.7, 22.0, 23.3, 26.3, 31.4, 34.2, 40.9, 45.1, 46.9, 60.5, 74.6, 169.9. Low resolution MS (electron impact ionization): 241 (M+), 226, 138, 123, 102.

[0086] Product 8-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-aminoacetate

[0087] In a deep three necked flask, about 1.5 mL (0.064 mol) of anhydrous ammonia was condensed at -78 °C, then 7 mL of EtOAc was added. To this solution was added NaOH (0.6 g, 15 mmol), then a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) in EtOAc (1.51 g, 5.5 mmol in 7 mL EtOAc) was added dropwise. The solution was stirred at -60 °C for 2 hours, then warmed to room temperature, and the excess ammonia was distilled off. The resulting solution was then filtered through glass wool, and the solvent was removed under reduced pressure to give the crude product 8 as an oil. Spectral data were consistent with previously published data.

[0088] Product 8 can be prepared by the optional procedure described below. Ammonia is condensed in a cooled (-78°C) round bottom flask and NaOH (0.5 g, 12.5 mmol) is added to the flask. An addition funnel is attached to the flask. Bromomethyl phenylacetate (compound 2, 1.4 g, 5.0 mmol) is dissolved in 10 mL of ethyl acetate and the solution is placed in the addition funnel. The solution of 2 is then slowly added to the liquid ammonia. The resulting mixture is stirred at -30°C and monitored by periodic sampling and GCMS analysis of the samples. The conversion is usually complete in 6 hours. If it is only partially complete, additional ammonia is condensed into the cooled flask. After the reaction is complete, the mixture is warmed to room temperature and the excess ammonia is evaporated. Anhydrous sodium sulfate is added to the reaction mixture and the mixture is filtered through a plug of silica gel. The reaction flask is rinsed with 10 mL of ethyl acetate and the solution is passed through the silica gel. The solvent is removed in vacuo to give a clear oil. Further purification is achieved by vacuum distillation.

[0089] Product 3-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(diethylamino)acetate

[0090] The general procedure using a 2° amine is used to react (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) with diethylamine to give glycine menthol ester 3 in 92% yield as a clear oil (about 160°C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ, 0.73 (d, 3H, J = 7.0 Hz), 0.82-0.91 (m, 7H), 0.92-1.2 (m, IH), 1.05 (t, 6H, J = 7.2 Hz), 1.31-1.40 (m, IH), 1.40-1.54 (m, IH), 1.60-1.73 (m, 2H), 1.79-1.89 (m, IH), 1.94-2.04 (m, IH), 2.66 (q, 4H, J = 7.2 Hz), 3.30 (s, 2H), 4.67-4.76 (m, IH). 13 C NMR (75 MHz, CDC13) δ, 9.1, 11.2, 16.0, 20.7, 21.8, 23.1, 26.1, 31.4, 33.8, 40.4, 42.6, 46.5, 56.9, 58.4, 77.8, 164.4. Low resolution MS (electron impact ionization): 269 (M+), 132, 130, 116, 102.

[0091] Product 9-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(dipropylamino)acetate

[0092] The general procedure using a 2° amine was used to react (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) with dipropylamine to give the glycine menthol ester 9 in 81% yield as a clear oil (about 170°C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ, 0.73 (d, 3H, J = 7.0 Hz), 0.80-0.89 (m, 13H), 0.90-1.08 (m, IH), 1.30-1.51 (m, 6H), 1.60-1.67 (m, 2H), 1.79-1.88 (m, IH), 1.92-2.03 (m, IH), 2.48-2.55 (m, 4H), 3.29 (s, 2H), 4.65-4.74 (m, IH). 13 C NMR (75 MHz, CDC13) δ, 11.7, 16.2, 20.6, 20.7, 22.0, 23.3, 26.2, 31.3, 34.2, 40.9, 46.9, 55.2, 56.3, 74.1, 171.1. Low resolution MS (electron impact ionization): 297 (M+), 268, 158, 130, 114, 102.

[0093] Product 10-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(dibutylamino)acetate

[0094] The general procedure using a 2° amine was used to react (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) with dibutylamine to give the glycine menthol ester 10 in 79% yield as a clear oil (about 180°C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ, 0.72 (d, 3H, J = 7.0), 0.83-0.90 (m, 13H), 0.90-1.10 (m, 3H), 1.19-1.53 (m, 9H), 1.61-1.69 (m, 2H), 1.76-1.90 (m, IH), 1.91-2.01 (m, IH), 2.54 (t, 4H, J = 7.2), 3.27 (s, 2H), 4.65-4.74 (m, IH). 13 C NMR (75 MHz, CDC13) δ, 14.0, 16.2, 20.7, 22.0, 23.3, 26.2, 29.6, 31.3, 34.2, 40.9, 47.0, 54.2, 55.2, 74.1, 171.2. Low resolution MS (electron impact ionization): 325 (M+), 282, 144, 143, 142, 102, 100.

[0095] Product 11-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(pyrrolidin-1- yl)acetate

[0096] Using the general procedure for 2° amines, (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with pyrrolidine to provide the glycine menthol ester 11 in 81% yield as a clear oil (about 160°C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ, 0.75 (d, 3H, J = 7.0), 0.82-0.93 (m, 7H), 0.95-1.11 (m, 2H), 1.33-1.40 (m, 1H), 1.41-1.56 (m, 1H), 1.64-1.72 (m, 2H), 1.76-1.92 (m, 5H), 1.95-2.07 (m, 1H), 2.60-2.70 (m, 4H), 3.25-3.38 (m, 2H), 4.71-4.80 (m, 1H). 13 C NMR (75 MHz, CDC13) δ, 16.3, 20.7, 22.0, 23.4, 23.8, 26.3, 31.4, 34.2, 40.9, 46.9, 53.9, 57.1, 74.3, 170.4. Low resolution MS (electron impact ionization): 267 (M+), 224, 130, 128, 100.

[0097] Product 5-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(piperidin-1- yl)acetate

[0098] Using the general procedure for 2° amines, (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with piperidine to provide the glycine menthol ester 5 in 61% yield as a clear oil (about 180°C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ, 0.70 (d, 3H, J = 4.2 Hz), 0.72-0.80 (m, 1H), 0.84 (d, 3H, J = 3.6 Hz), 0.86 (d, 3H, J = 3.0 Hz), 0.87-1.0 (m, 3H), 1.34-1.42 (m, 3H), 1.54-1.65 (m, 6H), 1.72-1.86 (m, 1H), 1.90-1.96 (m, 1H), 2.37-2.57 (m, 4H), 3.07 and 3.14 (ABq, 2H, J = 16.5 Hz), 4.61-4.75 (m, 1H). 13C NMR (75 MHz, CDC13) δ, 16.3, 20.7, 22.0, 23.4, 26.3, 31.4, 34.2, 41.0, 42.2, 46.9, 53.9, 58.2, 74.6, 170.0. Low resolution MS (electron impact ionization): 281 (M+), 266, 144, 142.

[0099] Product 12-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(cyclopropylamino)acetate

[0100] Using the general procedure for 1° amines, (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with cyclopropylamine to provide the glycine menthol ester 12 in 74% yield as a clear oil (about 140°C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ, 0.36-0.42 (m, 2H), 0.42-0.48 (m, 2H), 0.78 (d, 3H, J = 7.0 Hz), 0.85-0.90 (m, 6H), 0.96-1.13 (m, 2H), 1.34-1.44 (m, 1H), 1.46-1.57 (m, 1H), 1.67-1.73 (m, 2H), 1.82-1.90 (m, 1H), 1.97-2.04 (m, 1H), 2.20-2.26 (m, 1H), 2.40 (bs, 1H), 3.34-3.42 (m, 2H), 4.71-4.76 (m, 1H). 13 C NMR (75 MHz, CDC13) δ, 6.2, 6.3, 16.4, 20.7, 22.0, 23.5, 26.3, 29.9, 31.4, 34.2, 40.9, 47.0, 50.8, 74.7, 172.2. Low resolution MS (electron impact ionization): 253 (M+), 224, 138, 116, 102.

[0101] Product 13-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(bis(2-methoxyethyl)amino)acetate

[0102] Using the general procedure for 2° amines, (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with bis(2-methoxyethyl)amine to provide the glycine menthol ester 13 in 68% yield as a clear oil (about 200°C at 1 mm boiling point). 1H NMR (300 MHz, CDC13) δ, 0.69 (d, 3H, J = 7.0), 0.75-0.86 (m, 7H), 0.88-1.07 (m, 2H), 1.25-1.35 (m, IH), 1.35-1.48 (m, IH), 1.54-1.66 (m, 2H), 1.73-1.85 (m, IH), 1.87-1.96 (m, IH), 2.83-2.90 (m, 4H), 3.24-3.28 (m, 6H), 3.37-3.45 (m, 6H), 4.59-4.71 (m, IH).

[0103] 13 C NMR (75 MHz, CDC13) δ, 16.3, 20.7, 21.9, 22.6, 23.4, 26.0, 26.3, 31.4, 34.2, 38.9, 40.9, 47.0, 47.7, 51.1, 74.7, 171.9. Low resolution MS (electron impact ionization): 283 (M+), 226, 145, 138, 123, 100.

[0104] Product 14-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(isopentylamino)acetate

[0105] Using the general procedure with the 1° amine, (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with isopentylamine to provide the menthyl glycinate 14 in 90% yield as a clear oil (about 180°C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ, 0.75 (d, 3H, J = 7.0 Hz), 0.87-0.92 (m, 13H), 0.95-1.01 (m, IH), 1.03-1.13 (m, IH), 1.35-1.43 (m, 3H), 1.43-1.59 (m, IH), 1.61-1.74 (m, 3H), 1.77-1.89 (m, IH), 1.95-2.03 (m, IH), 2.10 (s, IH), 2.59-2.64 (m, 2H), 3.38 (s, 2H), 4.70-4.79 (m, IH). 13 C NMR (75 MHz, CDC13) δ, 16.3, 20.7, 21.9, 22.6, 23.4, 26.0, 26.3, 31.4, 34.2, 38.9, 40.9, 47.0, 47.7, 51.1, 74.7, 171.9. Low resolution MS (electron impact ionization): 283 (M+), 226, 145, 138, 123, 100.

[0106] Product 15-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(benzyl(methyl)amino)acetate

[0107] Using the general procedure for 1° amines, (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with N-methylbenzylamine to provide the glycine menthol ester 15 in 90% yield as a clear oil (about 210°C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ, 0.78 (d, 3H, J = 7.0 Hz), 0.89 (d, 3H, J = 7.0 Hz), 0.91 (d, 3H, J = 7.0 Hz), 0.96-1.14 (m, 2H), 1.34-1.43 (m, 1H), 1.44-1.57 (m, 1H), 1.64-1.72 (m, 2H), 1.82-1.92 (m, 1H), 1.99-2.05 (m, 1H), 2.39 (s, 3H), 3.24 (s, 2H), 3.69 (s, 2H), 4.73-4.82 (m, 1H). 13 C NMR (75 MHz, CDC13) δ, 16.3, 20.7, 22.0, 23.4, 26.3, 31.4, 34.2, 41.0, 47.0, 57.7, 74.2, 127.1, 128.2, 129.1, 138.4, 170.5. Low resolution MS (electron impact ionization): 317 (M+), 180, 178, 135, 134, 120.

[0108] Product 7-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(isopropylamino)acetate

[0109] Using the general procedure for 1° amines, (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with isopropylamine to provide the glycine menthol ester 7 in 88% yield as a clear oil (about 140°C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ, 0.78 (d, 3H, J = 7.0 Hz), 0.89 (d, 3H, J = 7.0 Hz), 0.91 (d, 3H, J = 7.0 Hz), 0.96-1.14 (m, 2H), 1.34-1.43 (m, 1H), 1.44-1.57 (m, 1H), 1.64-1.72 (m, 2H), 1.82-1.92 (m, 1H), 1.99-2.05 (m, 1H), 2.39 (s, 3H), 3.24 (s, 2H), 3.69 (s, 2H), 4.73-4.82 (m, 1H).13 C NMR (125 MHz, CDC13) δ, 16.3, 20.7, 22.0, 22.6, 23.4, 26.3, 31.3, 34.2, 40.9, 47.0, 48.3, 48.8, 48.8, 74.7, 172.2. Low resolution MS (electron impact ionization): 255 (M+), 240, 138, 116, 102.

[0110] Product 16-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(isopropyl(methyl)amino)acetate

[0111] Using the general procedure for 2° amines, (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with methyl-isopropylamine to provide the glycine menthol ester 16 in 88% yield as a clear oil (about 160 °C at 1 mm boiling point). 13 C NMR (75 MHz, CDC13) δ, 16.2, 18.4, 18.4, 20.7, 22.0, 23.4, 26.3, 31.3, 34.2, 38.3, 40.9, 46.9, 53.4, 55.1, 74.3, 171.0. Low resolution MS (electron impact ionization): 269 (M+), 254, 138, 132, 130, 116.

[0112] Product 6-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(diisobutylamino)acetate

[0113] Using the general procedure for 2° amines, (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with methyl-isopropylamine to provide the glycine menthol ester 16 in 88% yield as a clear oil (about 160 °C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ, 0.74 (d, 3H, J = 7.0), 0.82-0.91 (m, 19H), 0.92-1.11 (m, 2H), 1.30-1.38 (m, 1H), 1.40-1.54 (m, 1H), 1.60-1.71 (m, 4H), 1.81-1.91 (m, 1H), 1.94-2.01 (m, 1H), 2.31 (d, 4H, J = 7.3), 3.26 (s, 2H), 4.65-4.74 (m, 1H). 13C NMR (75 MHz, CDC13) δ 16.2, 20.6, 20.7, 22.0, 23.3, 26.2, 26.7, 31.4, 34.2, 41.0, 47.0, 56.0, 63.4, 73.9, 171.6. Low resolution MS (electron impact ionization): 325 (M+), 283, 282, 144, 142, 100.

[0114] Product 17-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-(tert-Butylamino)acetate

[0115] Using the general procedure with the 1° amine, (1R,2S,5R)-2-Isopropyl-5- methylcyclohexyl 2-bromoacetate (2) was reacted with tert-butylamine to provide the glycine menthol ester 17 in 78% yield as a clear oil (about 180°C at 1 mm boiling point). 1 H NMR (300 MHz, CDC13) δ 0.73 (d, 3H, J = 7.0 Hz), 0.86-0.90 (m, 7H), 0.90-1.04 (m, 1H), 1.09 (s, 9H), 1.29-1.37 (m, 1H), 1.38-1.54 (m, 1H), 1.57-1.72 (m, 3H), 1.79-1.92 (m, 1H), 1.94-2.07 (m, 1H), 3.35 (s, 2H), 4.68-4.77 (m, 1H). 13 C NMR (75 MHz, CDC13) δ 16.3, 20.7, 21.9, 23.4, 26.2, 28.7, 31.3, 34.2, 40.8, 44.9, 47.0, 50.2, 74.6, 172.7. Low resolution MS (electron impact ionization): 269 (M+), 254, 130, 116.

[0116] Product 18-(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-(Methyl(pyridin-2- yl)ethyl)amino)acetate

[0117] (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2, 1.3 g, 4.69 mmol) was dissolved in 25 mL EtOAc and to this solution was added NaOH (1.2 g, 0.03 mol) and anhydrous Na2SO4(0.5 g). To this solution was added 2-(2-methylaminoethyl)pyridine (1.0 mL, 7.22 mmol) and the mixture was stirred at room temperature for 4 hours or until GC-FID analysis showed no remaining bromoester 2. The solution was then filtered through glass wool and the solvent removed under reduced pressure. The resulting oil was vacuum distilled (at 1 mm, 120 °C for 2 h) to remove excess 2-(2-methylaminoethyl)pyridine. The residual oil was taken up in 20 mL EtOAc and passed through a plug of SiO2. After removal of the solvent, an oil was obtained which was primarily glycine menthol ester 18 (1.54 g, 4.63 mmol, 99%). The product was further purified by distillation (boiling point ~ 230 °C at 1 mm) to provide pure glycine menthol ester 18 as a clear oil in 75% yield. 1 H NMR (300 MHz, CDC13) δ, 0.73 (d, 3H, J = 7.0 Hz), 0.80-0.92 (m, 7H), 0.89-1.10 (m, 2H), 1.31-1.43 (m, 1H), 1.43-1.54 (m, 1H), 1.61-1.70 (m, 2H), 1.77-1.89 (m, 1H), 1.94-2.05 (m, 1H), 2.44 (s, 3H), 2.89-3.01 (m, 4H), 3.29 (s, 2H), 4.69-4.78 (m, 1H), 7.06-7.11 (m, 1H), 7.18 (d, 1H, J = 7.8 Hz), 7.54-7.60 (m, 1H), 8.49-8.51 (m, 1H)). 13 C NMR (75 MHz, CDC13) δ, 16.2, 20.7, 22.0, 23.4, 26.3, 31.4, 34.2, 36.3, 41.0, 46.9, 56.8, 58.7, 74.4, 121.1, 123.1, 136.3, 149.2, 160.2, 170.5.

[0118] Product 20-bis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 2,2'-(isopropylimino)diacetate

[0119] (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2, 2.33 g, 8.4 mmol) was dissolved in 25 mL EtOAc and to this solution was added NaOH (1.2 g, 0.03 mol) and anhydrous Na2SO4(0.5 g). Isopropylamine (0.25 mL, 2.9 mmol) was added to the solution and the mixture was stirred at room temperature for 5 hours or until GC-FID analysis showed no remaining bromoester 2. The solution was then filtered through glass wool and the solvent was removed under reduced pressure. The resulting oil was vacuum distilled (at 1 mm, 160 °C for 20 min) to remove excess bromoester 2. The distillate was a clear oil (about 0.5 g) which was identified as a mixture of bromoester 2 and the desired product 20. The residual oil was added to 20 mL EtOAc and passed through a plug of SiO2. After removal of the solvent, a clear oil was obtained which was glycine menthol ester 20 (0.425 g, 0.94 mmol, 32%). 1 H NMR (300 MHz, CDC13) δ, 0.76 (d, 6H, J = 6.9 Hz), 0.85-0.95 (m, 14H), 0.94-1.04 (m, 2H), 1.04-1.10 (m, 4H), 1.33-1.42 (m, 2H), 1.42-1.55 (m, 2h), 1.64-1.73 (m, 4H), 1.80-1.93 (m, 2H), 1.96-2.04 (m, 2H), 3.04-3.13 (sep, 1H, J = 6.5 Hz), 3.54 (s, 4H), 4.68-4.77 (m, 2H). 13 C NMR (75 MHz, CDC13) δ, 16.3, 20.3, 20.7, 22.0, 23.4, 26.3, 31.4, 34.3, 40.9, 47.0, 52.7, 74.2, 171.8.

[0120] Product 21 - bis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 2,2'-(ethane-1,2-diylbis(methylimino))diacetate

[0121] (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2, 2.13 g, 7.7 mmol) was dissolved in 50 mL EtOAc and to this solution was added NaOH (1.2 g, 0.03 mol) and anhydrous Na2SO4(0.5 g). To this solution was added N,N-dimethylethylenediamine (0.3 mL, 2.79 mmol) and the mixture was stirred at room temperature for 5 hours or until GC-FID analysis showed no remaining bromoester 2. The solution was then filtered through glass wool and the solvent removed under reduced pressure. The resulting oil was vacuum distilled (at 1 mm, 170-190 °C for 30 min) to remove excess bromoester 2. The residual yellow oil was taken up in 20 mL EtOAc and passed through a plug of SiO2. After removal of the solvent, a clear oil was obtained which was the glycinol menthol ester 21 (0.84 g, 1.75 mmol, 43%). 1 H NMR (500 MHz, CDC13) δ, 0.78 (d, 6H, J = 6.7 Hz), 0.82-0.95 (m, 14H), 0.96-1.13 (m, 4H), 1.37-1.42 (m, 2H), 1.43-1.55 (bs, 2H), 1.70 (d, 4H, J = 2.4 Hz), 1.80-1.90 (m, 2H), 2.00 (d, 2H, J = 6.9 Hz), 2.48 (s, 6H), 2.82 (s, 4H), 3.42 (s, 4H), 4.74-4.78 (m, 2H). 13 C NMR (125 MHz, CDC13) δ, 16.3, 20.7, 22.0, 23.4, 26.3, 31.4, 34.2, 41.0, 42.2, 46.9, 53.9, 58.2, 74.6, 170.0.

[0122] Example 1: Toxicology Investigation of Menthol Derivatives

[0123] The recommended“sip and spit” concentrations of the compounds referred to by the product numbers used in Table 1 were investigated and preliminary safety was assessed. Products 3, 5-7, 9-11, 13, 15, 16, 18, and (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-2-(dibenzylamino)acetate were investigated. These compounds, as well as potential breakdown compounds, were investigated using a toxicology prediction database. It was determined that samples containing 100 ppm of the menthol derivative could be safely tested using the“sip and spit” method.

[0124] Example 2: Preliminary Sensory Evaluation

[0125] Solutions were prepared for sensory testing using the "suck and spit" method. A 100 ppm menthol derivative solution was prepared by adding 0.025 g of the menthol derivative to a 250 mL volumetric flask with a q.s. amount of deionized water (DI) at 20 °C. The solution was dispersed by agitation before tasting. The tasting was performed by a panel of six participants. The compounds evaluated were: XI-1-48 (Product 9), DK-1-36 (Product 5), XI-1-50 (Product 16), DK-1-34 (Product 6), RK-1-10 (Product 15), DK-2-44 (Product 11), RK-2-10 (Product 10), DK-1-44 (Product 13), dimethylamino glycinate (Product 4), and RK-2-10 (Product 7). The tasting results revealed the unique properties of this class of compounds. Overall, the 100 ppm materials exhibited a delayed onset of cooling from 20 seconds to 40 seconds. These compounds exhibited very different cooling onset compared to menthol which provides an immediate cooling sensation.

[0126] The sensory properties of the menthol derivatives in water are listed below by compound:

[0127] • XI-1-48 (Product 9): slight ester / fruit aroma with a latent onset of cooling.

[0128] • DK-1-36 (Product 5): no cooling present for the compound.

[0129] • XI-1-50 (Product 16): no off-note, cooling onset at 20 seconds, strong cooling at 1 minute.

[0130] • DK-1-34 (Product 6): sweet metallic, no pungent taste, delayed cooling after 20 seconds.

[0131] • RK-1-10 (Product 15): dry mouth feel, very slight cooling, but delayed after 30 seconds.

[0132] • DK-2-44 (Product 11): smells like chlorine, with a swimming pool water taste.

[0133] • RK-2-10 (Product 10): delayed cooling onset over 20 seconds; very strong cooling curve extending to 2 minutes.

[0134] • DK-1-44 (Product 13): bitter, tongue numbing, slight cooling, cooler after continuous water rinse.

[0135] • Product 4: minty cooling, very faint, early cooling.

[0136] • DK-2-39 (Product 7): significantly delayed cooling over 30 seconds, long cooling lasting to 2 minutes.

[0137] Example 3: Sensory evaluation of menthol derivatives in ethanol (EtOH), propylene glycol (PG) and water.

[0138] Prepare stock solutions of each solution to a final concentration of 100 ppm as follows.

[0139] Prepare with aqueous ethanol solution:

[0140] Stock solution

[0141] a. Prepare stock solution of 2.5% ethanol solution by adding 25 mg of menthol analog (mix well) to 1 gram of ethanol.

[0142] b. Add q.s. (quantity sufficient) deionized water to a total weight of 250 grams.

[0143] C. Mix well to achieve a final concentration of 100 ppm.

[0144] Prepare with aqueous PG solution:

[0145] Stock solution

[0146] a. Prepare stock solution of 2.5% PG solution by adding 25 mg of menthol analog (mix well) to 1 gram of PG.

[0147] b. Add q.s. (quantity sufficient) deionized water to a total weight of 250 grams.

[0148] c. Mix well to achieve a final concentration of 100 ppm.

[0149] Prepare with water:

[0150] Stock solution

[0151] a. Add 25 mg of menthol derivative and q.s. (quantity sufficient) deionized water to a total weight of 250 grams to achieve a final concentration of 100 ppm.

[0152] The sensory profiles of the menthol derivatives in ethanol, propylene glycol and water are listed below:

[0153] • RK-2-10 (product 10) exhibits a delayed onset of cooling and a pre-bitter taste from PG.

[0154] • XI-1-60 (product 7) sample exhibits a delayed onset of cooling after about 10 seconds and a very strong cooling environment after about 40 seconds.

[0155] • XI-1-50 (product 16) exhibits a slightly delayed onset of cooling after 20 seconds with some pre-bitter taste from PG. A very strong cooling is produced after 50 seconds.

[0156] • XI-1-50 (product 16) PG: initial bitterness from the PG, cooling at 30 seconds, and lasting until 1.5 minutes later.

[0157] • XI-1-50 (product 16) EtOH: initial alcoholic burn, delayed cooling at 20 seconds, and deep cooling at 60 seconds.

[0158] • XI-1-60 (product 7) PG: early cooling at 10 seconds, stronger cooling at 20 seconds, much stronger cooling than XI-1-50.

[0159] • XI-1-60 (product 7) EtOH: cooling starts at 20 seconds, with a slight alcoholic burn, cooling curve very strong from 20 seconds to 2 minutes.

[0160] • RK-2-10 (product 10) PG: very low intensity cooling develops slowly, with a skin tingling sensation. At taste threshold, can be a good candidate for taste modification applications and bitterness masking.

[0161] • RK-2-10 (product 10) EtOH: delayed onset of mild cooling (after 20 seconds), with a slight tingling sensation and sweetness, lasting over 1 minute.

[0162] The sensory profile of menthol in simple solutions of PG and water or ethanol was evaluated, and it was found that menthol provides a very strong immediate cooling effect.

[0163] Example 4: Hydrolysis study

[0164] Gas chromatography (GC) was used to evaluate the hydrolysis of menthol derivatives (also referred to as menthol analogs) over time. The average area ratio of menthol analog and menthol (area of the component of interest divided by the area of the internal standard) was measured at initial, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

[0165] Stock solutions of each menthol derivative in ethanol, PG, or water were prepared to a final concentration of 200 ppm as follows. 5 mL of the 200 ppm stock solution was mixed with 1 mL of internal standard (IS) and added to 10.00 mL of chloroform. The organic layer was transferred to the respective GC vial and run. Each GC was run in duplicate. All stock solutions were stored at room temperature in the dark. All stock solutions were stored at room temperature in the dark.

[0166] Prepared with an aqueous ethanol solution:

[0167] Stock solutions

[0168] a. Prepare a stock solution of 5% ethanol solution by adding 50 mg of the menthol analog to 1 gram of ethanol (mix well).

[0169] b. Add Q.S. (quantity sufficient) deionized water to a total weight of 250 grams.

[0170] c. Mix well to achieve a final concentration of 200 ppm.

[0171] Prepare in water:

[0172] Stock solution

[0173] a. Prepare a stock solution of 5% PG solution by adding 50 mg of the menthol analog to 1 gram of PG (mix well).

[0174] b. Add Q.S. (quantity sufficient) deionized water to a total weight of 250 grams.

[0175] c. Mix well to achieve a final concentration of 200 ppm.

[0176] Prepare in water:

[0177] Stock solution

[0178] a. Prepare a stock solution of 5% solution by adding 50 mg of the menthol analog to deionized water.

[0179] b. Add Q.S. (quantity sufficient) deionized water to a total weight of 250 grams.

[0180] c. Mix well to achieve a final concentration of 200 ppm.

[0181] Figures 1-9 The average area ratio of the menthol analog and menthol over time is illustrated. As the menthol analog is hydrolyzed, more menthol is present in the solution. Figure 10 The average area ratio of menthol in ethanol is illustrated.

[0182] Example 5: Solubility Analysis

[0183] The Hansen Solubility Parameters of the menthol derivatives were calculated using Hansen Solubility Parameters in Practice (HSPiP). The calculations were performed using HSPiP Version 5.1.02 licensed to: FONA INTERNATIONAL. The data from the Hansen Solubility Parameters for various menthol derivatives and target solvents is listed in Table 3, shown below.

[0184] Table 3: Hansen Solubility Parameters

[0185]

[0186]

[0187] Example 7: Electronic Tongue Test Example (Predictive)

[0188] The target compounds were tested using an instrument called an electronic tongue for the measurement and analysis of flavor profiles. The target compounds were tested and the results were compared to known coolants. The electronic tongue has seven sensors that can detect the same dissolved organic and inorganic compounds as human taste receptors. Like human receptors, each sensor has a distinct set of responses. The information provided by each sensor is complementary, and the combination of all sensor results generates a unique fingerprint for the analyzed compound.

[0189] Example 8: Measurement of Menthol and Glycol Menthol Ester Time-Intensity in Lozenge, Beverage Model System, and Mouthwash

[0190] In this example, the experimental compound names correspond to the products shown in Table 1. RK-2-10 corresponds to product 10 in Table 1. DK-1-50 corresponds to product 16 in Table 1. XI-1-60 corresponds to product 7 in Table 1. XI-1-65 corresponds to product 12 in Table 1. XI-2-73 corresponds to product 15 in Table 1.

[0191] To evaluate the potential use of glycol menthol ester as a sensate in different food, beverage, and oral hygiene products, the selected compounds were incorporated into different application systems. Beverage model systems, lozenges, and mouthwash applications were created and time-intensity analysis was performed using a trained panel of discriminant analysts.

[0192] Time-Intensity (TI) is a time-based sensory method. During TI evaluation, the evaluator is asked to score the intensity of the perception of a single attribute of the product use. In contrast to single-point measurements, TI analysis can characterize the onset, decay, and rate of a specific sensory attribute. This analysis can represent a rich information of the intensity of an attribute over time and identify differences in perception over time between samples that can greatly affect the overall profile of a product. For each sample evaluation, a time curve was generated based on the repetition case. The time curves of each panelist were combined to generate a combined curve for each evaluated product. The following different parameters were calculated:

[0193] I max : Peak intensity or maximum observed intensity over the curve;

[0194] T start : Time point at which the response to the stimulus was first perceived on the curve;

[0195] T max : time position of the peak intensity on the curve;

[0196] T plateau : prolongation of the maximum intensity or duration of the maximum intensity;

[0197] T ext : time point of the disappearance of the perception of the stimulus, defined as the time position of the disappearance of the intensity (or end of the evaluation window) measured after the peak intensity;

[0198] I ext : intensity at the time of the disappearance or at the end of the evaluation;

[0199] R increase : slope or rate of the increase in intensity between T start and T max ;

[0200] R decrease : slope or rate of the decrease in intensity between T start and T max ; and

[0201] Area: total area under the time-intensity curve.

[0202] Details and results of the evaluation of the selected glycine menthol esters in application are shown below.

[0203] Lozenge application

[0204] Lozenge applications were created with the formulations detailed in Table 4 to evaluate the target glycine menthol esters using time-intensity analysis.

[0205] Table 4. Lozenge formulations, 100 g of raw material per batch

[0206]

[0207] * The following test compounds were evaluated: RK-2-10, menthol, DK-1-50, XI-1-60, and XI-1-65.

[0208] Sensory evaluation of lozenge applications

[0209] For the time-intensity (T-I) evaluation of the lozenge coolness intensity, 9 panelists (3 males, 6 females) were recruited. The panelists were trained in basic taste descriptive analysis. A sweetness reference series (intensity range 2-12) was provided as a cross-modality reference to help assess the intensity of the cooling attribute present in the lozenge samples. Panelists evaluated samples in duplicate, all samples were presented in a randomized order using a blind method and using 3-digit codes. Panelists were instructed to provide coolness intensity at predetermined time points throughout the 4 minute evaluation window. Samples were pre- weighed (2 g) and panelists were instructed to evaluate the full amount of sample to ensure consistency between panelists and repeated evaluations. At least 4 hours were allowed between evaluations to ensure no carry over.

[0210] R STUDIO was used for data analysis for generating T-I statistics and ANOVA analysis for determining significant differences between samples.

[0211] Results for lozenge application

[0212] All relevant T-I parameters for lozenge are presented in Table 5. The maximum coolness intensity (I max ) values for all samples indicate that all test compounds evaluated have strong cooling potential (cooling range of approximately 9-11.5). ANOVA analysis indicates that the maximum coolness intensity of glycine menthol esters XI-1-60 and XI-1-65 are not significantly different from the maximum coolness intensity of menthol, which supports their strong cooling potential. Although the maximum coolness intensity of glycine menthol esters RK-2-10 and DK-1-50 are significantly different from the overall maximum coolness intensity of menthol, their cooling potential is still strong according to the panelists’ ratings. For some of the samples evaluated, significant differences in the T start indicate significant differences in the time course and onset of cooling. More specifically, glycine menthol esters RK-2-10 and DK-1-50 exhibit a significantly delayed onset of cooling compared to menthol. The onset of glycine menthol ester XI-1-65 is nearly identical to menthol. XI-1-60 exhibits a delayed onset trend, but is not significantly different from menthol. Although not all glycine menthol esters exhibit a significant difference in the onset of cooling compared to menthol, all glycine menthol esters tested have a significantly delayed T maxThis shows a significantly different cooling time profile. The rate of increase and decrease in cooling intensity also indicates a significant difference between menthol and the glycine menthol esters. All of the glycine menthol esters trend lower than menthol, with RK-2-10 and DK-1-50 having significantly lower rates of increase and decrease, while XI-1-60 has a significantly lower rate of decrease, indicating a potentially longer lasting cooling sensation.

[0213] Figure 11 A time-intensity plot of the cooling sensation is illustrated. The total area under the T-I curve (AUC) was also analyzed, which correlates to the total perceived cooling intensity over the evaluation time window. Glycine menthol esters XI-1-60 and XI-1-65 were not significantly different from menthol, while RK-2-10 and DK-1-50 were significantly lower.

[0214] Overall, the glycine menthol esters in the lozenge exhibit interesting time profiles, which suggest their potential use in sensory blends to achieve a more prolonged / sustained cooling effect. Blending customization can lead to optimized products due to lower cooling increase and decrease rates and strong cooling potential.

[0215] Table 5. Time-intensity analysis statistics. Results were obtained from the evaluation of lozenges by 9 trained panelists. Lozenges containing the following cooling test compounds were evaluated: RK-2-10, menthol, DK-1-50, XI-1-60, and XI-1-65. Each sample was evaluated in duplicate within a 4 minute time window.

[0216] I max ]] [CAT start ]]> [CAT max ]]> [R Inc ]]> [R Dec ]]> AUC RK-2-10 9.06 a ]]> 8.74 a ]] 210.00 a ]]> 0.038 ac ]]> 0.038 a ]] 1669.06 a ]]> Menthol 11.53 bc ]]> 5.00 b ]]> 180.00 b ]]> 0.053 b ]]> 0.056 b ]] 2064.83 b ]]> DK-1-50 9.41 a ]] 7.85 ac ]] 204.71 a ]] 0.039 ac ]] 0.032 a ]]> 1698.24 a ]]> XI-1-60 9.88 ac ]]> 6.55 bc ]]> 210.00 a ]]> 0.041 ab ]]> 0.021 c ]] 1750.31 ab ]]> XI-1-65 10.31 c ]]> 5.31 b ]]> 206.25 a ]]> 0.042 ab ]] 0.042 ab ]]> 1945.31 bc ]]>

[0217] Different superscript letters in each column indicate statistical significance (ANOVA a = 0.5, p < 0.05). For variables with the same letter, the difference is not statistically significant. In addition, for variables with different letters, the difference is statistically significant.

[0218] Beverage model system

[0219] A simple beverage model system was created using the formulas detailed in Table 6 to evaluate the target glycine menthol esters using time-intensity analysis.

[0220] Table 6. Beverage model system recipe, 100 g of raw material per batch

[0221] Raw Material Amount (g) Water 97.99 Propylene Glycol 2 Test Compound 0.01

[0222] *The following test compounds were evaluated: RK-2-10, menthol, DK-1-50, XI-1-60.

[0223] Sensory evaluation of the beverage model system

[0224] For time-intensity (T-I) evaluation of the cooling attribute of the model beverage system, 8 panelists (2 males, 6 females) were recruited. Panelists were trained in basic taste descriptive analysis. A sweetness reference series (intensity range 2-12) was provided as a cross-modal reference to help rate the intensity of the cooling attribute present in the model beverage samples. Panelists evaluated samples in duplicate, all samples were presented in a randomized order using a 3-digit code in a blind fashion. Panelists were instructed to hold the sample in their mouth for 30 seconds, then spit out. During the hold period, panelists were instructed to note the onset and intensity of the cooling sensation. After spitting out, panelists continued to report the intensity of the cooling sensation at predetermined time points throughout the 2 minute evaluation window. Samples were pre- weighed and panelists were instructed to evaluate the full amount of sample to ensure consistency between panelists and replicate evaluations. At least 4 hours were allowed between evaluations to ensure no carryover.

[0225] Data analysis for generating T-I statistics and ANOVA analysis for determining significant differences between samples were performed using R STUDIO.

[0226] Results for the model beverage system

[0227] All relevant T-I parameters for the model beverage system are shown in Table 7. The maximum cooling intensity (I max ) values for all samples indicate that all test compounds evaluated have strong cooling potential, especially considering the low level of incorporation (100 ppm) in the model beverage system. ANOVA analysis showed that the maximum cooling intensity of glycine menthol ester XI-1-60 was not significantly different from menthol, which supports the strong cooling potential of this compound. Overall, while the maximum cooling intensity of glycine menthol esters RK-2-10 and DK-1-50 were significantly different from menthol, their cooling potential was still strong according to the panelists’ ratings. The T startSignificant differences, indicating a significant difference in the time profile and onset of cooling sensation for all evaluated new compounds compared to menthol. The time to reach maximum cooling intensity was also evaluated, although all glycine menthol esters exhibited a trend towards higher maximum onset compared to menthol, only DK-1-50 was significantly different. This observed trend further supports the ability of these glycine menthol esters to deliver a different time profile. This evaluation also additionally examined the plateau time, although menthol was not significantly different from DK-1-50, the plateau time for glycine menthol esters RK-2-10 and XI-1-60 was significantly higher than menthol, indicating the potential to maintain peak intensity for longer. The rate of increase in cooling intensity also indicated a significant difference between menthol and the glycine menthol esters. All glycine menthol esters were found to have a significantly lower rate than menthol, indicating the potential for a more prolonged and sustained cooling sensation.

[0228] Figure 12 Time-intensity plots of the cooling effect in a beverage model system are illustrated. The total area under the T-I curve was also analyzed, which correlates to the total perceived cooling intensity over the evaluation time window. Glycine menthol ester XI-1-60 was not significantly different from menthol, while RK-2-10 and DK-1-50 were significantly lower.

[0229] Overall, the glycine menthol esters in a beverage model system exhibited interesting time profiles, which indicate their potential use in a sensory blend to achieve a more prolonged / sustained cooling effect. With lower rates of cooling increase, longer onset times of cooling, times to reach maximum intensity, and strong cooling potential, a blend custom can lead to an optimized beverage product.

[0230] Table 7. Time-intensity analysis statistics. Results obtained from the evaluation of a beverage model system by 9 trained panelists. The following cooling test compounds were used to test the beverage system: RK-2-10, menthol, DK-1-50, XI-1-60 were evaluated. Each sample was evaluated in duplicate over a 2 minute time window.

[0231] I max ]] [CAT start ]]> [CAT max ]]> [CAT plateau ]]> [R Inc ]]> [R Dec ]]> AUC Menthol 5 a ]] 10 a ]] 50.2 a ]]> 23.3 a ]]> 0.12 a ]] 0.03 a ]] 429.1 a ]]> RK-2-10 2.5 b ]]> 6.1 b ]]> 58.9 ab ]]> 39.6 b ]]> 0.04 b ]] 0.06 a ]] 260.1 b ]]> DK-1-50 3.7 b ]]> 16 c ]] 71.6 b ]]> 21.8 a ]]> 0.05 b ]] 0.02 a ]] 319.6 bc ]] XI-1-60 4.2 ab ]]> 16 c ]] 60.5 ab ]]> 37.2 b ]]> 0.06 b ]]> 0.02 a ]] 355 ac ]]>

[0232] Different superscript letters in each column indicate statistical significance (ANOVA a = 0.5, p < 0.05).

[0233] Mouthwash application

[0234] A mouthwash product was created using the formulations shown in Table 8 to evaluate the target glycine menthol esters using time-intensity analysis.

[0235] Table 8: Mouthwash application formulations

[0236]

[0237]

[0238] The following test compounds were evaluated: menthol, XI-I-60, RK-2-10, XI-I-65, DK-1-50 and XI-2-73.

[0239] Sensory evaluation of mouthwash application

[0240] For the time-intensity (T-I) evaluation of the cooling attribute of the mouthwash product, 8 panelists (2 males, 6 females) were recruited. The panelists were trained in basic taste descriptive analysis. A sweetness reference series (intensity range 2-12) was provided as a cross-modal reference to help rate the intensity of the cooling attribute present in the mouthwash samples. The panelists evaluated the samples in duplicate, all samples were presented in a randomized order using a blind procedure and using 3-digit codes. The panelists evaluated 15 ml of mouthwash at a time and were instructed to rinse for 30 seconds before spitting out. The panelists were instructed to provide a cooling intensity rating before and after spitting out. For the pre-spit time, the evaluation started at the time of pouring the sample and was evaluated every 10 seconds thereafter. After spitting out, the evaluation continued for 15 minutes and the panelists provided a cooling intensity rating at predetermined times. Due to the unique nature of the product and the interest in the length of time of the cooling attribute after extended consumption, an additional parameter was evaluated in the samples by ANOVA ext . This parameter was the cooling intensity at the time of cooling disappearance, or in our case the cooling intensity at the end of the evaluation.

[0241] R STUDIO was used for the data analysis for generating the T-I statistics and for the ANOVA analysis for determining significant differences between samples.

[0242] Results of mouthwash application

[0243] All relevant T-I parameters for the mouthwash application are shown in Tables 9a, 9b and 10. The maximum cooling intensity (I max ) values for all samples indicate that all glycine menthol ester compounds evaluated have a strong cooling potential.

[0244] The time-intensity analysis data for the mouthwash samples evaluated during the 30 second rinse phase (Table 9a) indicates that all new glycine esters have a similar maximum cooling intensity as menthol, with the glycine esters XI-I-65, DK-1-50 and XI-2-73 showing a higher trend, but not statistically significant. During this rinse phase, the initial perception time (T start ), the time to maximum intensity (T max) and the total area under the curve also did not show significant differences, further supporting the cooling potential of the new glycinate esters given the widespread use of menthol in oral hygiene applications. The slope or rate of intensity decrease between T max and T ext ) showed significant differences. The R decrease for glycinate menthol esters XI-I-60, RK-2-10, XI-I-65, DK-1-50, and XI-2-73 was significantly lower, some approaching zero. This indicates that all of the glycinate menthol esters maintained their maximum cooling intensity throughout the rinse phase, while menthol began to decrease before the swallow.

[0245] Time-intensity analysis for evaluating the cooling potential of the new glycinate menthol esters in mouthwash applications after the swallow (Table 9b) indicates that all of the new glycinate esters have similar maximum cooling intensity to menthol, with all of the glycinate esters trending higher compared to menthol. Although there were no significant differences in the initial perception time (T start ) and the time of maximum intensity (T max ) among the compounds tested, interesting differences in the values of R increase and R decrease were observed. The R increase (the slope or rate of intensity increase between T start and T max ) for glycinate menthol esters XI-I-65, RK-2-10, and XI-2-73 was positive and significantly higher than menthol, indicating that the cooling intensity was still rising even after the swallow, while no such trend was observed for menthol. This indicates that these glycinate esters have great cooling potential and the ability to affect the temporal cooling profile in a mouthwash application. In addition, the R decrease (the slope or rate of intensity decrease between T max and T ext ) for the menthol glycinate esters was significantly lower compared to menthol, indicating that the glycinate menthol esters were able to maintain a stronger and more prolonged cooling sensation after the rinse phase. Figure 13 The time-intensity plot of the cooling sensation of the mouthwash is illustrated. The total area under the curve for T-I also indicates a trend for all of the glycinate menthol esters to be higher when compared to menthol, with DK-1-50 being significantly higher.

[0246] Due to the unique nature of mouthwash products and the interest in prolonging the cooling attributes after the swallow, the I extAn assessment was made to compare the cooling intensity of the samples at the time of cooling loss or in our case at the end of the evaluation. The results (Table 10) indicate that glycine menthol esters XI-1-65 and DK-1-50 have significantly higher cooling intensity at the end of our evaluation window when compared to menthol. This observation further supports the potential of these new sensates to expand the cooling profile in oral hygiene applications. The unique blend of these compounds has the potential to further modify the time profile of the cooling profile and thus has great potential in a variety of flavor applications.

[0247] Tables 9a-9b: Time-Intensity Analysis Statistics. Results obtained from the evaluation of mouthwash products by 8 trained panelists. The mouthwash products included the following cooling test compounds: menthol, XI-I-60, RK-2-10, XI-I-65, DK-1-50, and XI-2-73. Each sample was evaluated in duplicate in 2 different time windows: during the rinse phase lasting 30 seconds (Table 9a) and 15 minutes after spitting (Table 9b).

[0248] Table 9a

[0249] Product I max ]] [CAT start ]]> [CAT max ]]> [R inc ]]> [R dec ]]> AUC Menthol 12.56 a ]]> 10.88 a ]] 16.18 a ]]> 0.21 a ]] -0.09 a ]]> 168.97 a ]]> XI-I-60 12.43 a ]]> 11.00 a ]]> 16.33 a ]]> 0.20 a ]] -0.02 b ]]> 170.50 a <!-- 25 -->]]> RK-2-10 12.82 a ]] 10.91 a ]] 15.00 a ]]> 0.18 b ]] -0.01 b ]]> 182.05 a ]]> XI-I-65 13.50 a ]]> 10.00 a ]]> 17.08 a ]]> 0.23 a ]] 0.00 b ]] 186.88 a ]]> DK-1-50 13.09 a ]]> 10.00 a ]]> 17.27 a ]]> 0.23 a ]] 0.00 b ]]> 180.91 a ]]> XI-2-73 13.00 a ]] 10.00 a ]]> 17.50 a ]]> 0.21 a ]] 0.00 b ]]> 179.79 a ]]>

[0250] Different superscript letters in each column indicate statistical significance (ANOVA a = 0.5, p < 0.05).

[0251] Table 9b

[0252] Product I max ]]> [CAT start ]]> [CAT max ]]> [R inc ]]> [R dec ]]> AUC Menthol 12.01 a ]] 30.00 a ]] 33.53 a ]]> 0.00 a ]] -0.03 a ]]> 3608.38 a ]]> XI-I-60 12.33 ab ]]> 30.00 a ]]> 36.00 a ]]> 0.00 a ]] -0.01 b ]]> 4344.50 ac ]]> RK-2-10 12.65 ab ]]> 30.00 a ]]> 30.00 a ]]> 0.00 a ]]> -0.01 b ]]> 4105.91 ac ]]> XI-I-65 13.20 ab ]]> 30.00 a ]]> 32.50 a ]]> 0.03 b ]] -0.01 b ]]> 5211.25 bc ]]> DK-1-50 13.37 ab ]]> 30.00 a ]] 32.73 a ]] 0.03 b ]] -0.01 b ]]> 5565.00 b ]]> XI-2-73 13.50 ab ]] 30.00 a ]] 32.50 a ]]> 0.03 b ]] -0.01 b ]]> 4082.50 ac ]]>

[0253] Different superscript letters in each column indicate statistical significance (ANOVA a = 0.5, p < 0.05).

[0254] Table 10. Cooling intensity at cooling loss or end of evaluation. Mouthwash products evaluated the following cooling test compounds: menthol, XI-I-60, RK-2-10, XI-I-65, DK-1-50, and XI-2-73. Each sample was evaluated in duplicate with the parameter of focus being the cooling intensity reported 15 minutes after spitting.

[0255] Product I ext ]]> Menthol 1 a ]] XI-I-60 1.23 a ]]> RK-2-10 0.9 a ]] XI-I-65 2.18 b ]]> DK-1-50 2.33 b ]]> XI-2-73 0.67 a ]]

[0256] Different superscript letters in each column indicate statistical significance (ANOVA a = 0.5, p < 0.05).

[0257] References

[0258] (1) Eccles, R. (1994). "Menthol and Related Cooling Compounds". J. Pharm. Pharmacol. 46(8): 618-630.

[0259] (2) "Update on Menthol Production & Use." http: / / www.leffingwell.com / menthol1 / menthol1.htm; downloaded 12 / 31 / 18.

[0260] (3) "Cool without Menthol & Cooler than Menthol and Cooling Compounds as Insect Repellents." Leffingwell, J. C., http: / / www.leffingwell.com / cooler_than_menthol.htm; 12 / 31 / 18.

[0261] (4) "Common Fragrance and Flavor Materials: Preparation, Properties and Uses 4th Ed." Bauer, K.; Garbe, D.; Surburg, H., Wiley-VHC, Weinheim, Germany, 2001.

[0262] (5) Hettstedt, C.; Betzl, W.; Karaghiosoff, K. Zeits. Anorg. Allgem. Chemie 2012, 638, 377. For alternative routes leading to compound 2, see:

[0263] (6) Shankar, S. P.; Jagodzinska, M.; Malpezzi, L.; Lazzari, P.; Manca, I.; Greig, I. R.; Sani, M.; Zanda, M. Org. Biomol. Chem. 2013, 11, 2273.

[0264] (7) Singh, R.; Ghosh, S. K. Tetrahedron: Asymmetry, 2014, 25, 57. d. Streinz, L.; Koutek, B.; Saman, D. Synlett, 2001, 809.

[0265] (8) Dentel, H.; Chataigner, I.; Lohier, J.-F.; Gulea, M. Tetrahedron, 2012, 68, 2326.

[0266] (9) Yin, Y.; Wu, M.; Zubcevic, L.; Borschel, W. F.; Lander, G. C.; Lee, S.-Y. Science, 2018, 359, 237.

[0267] (10) Shirai, T.; Kumihashi, K.; Sakasai, M. Kusuoku, H.; Shibuya, Y.; Ohuchi, A. ACS Med. Chem. Lett. 2017, 8, 715.

[0268] (11) Kweka, E. J., et al., Protective efficacy of menthol propylene glycol carbonate compared to N,N-diethyl-methylbenzamide against mosquito bites in Northern Tanzania, Parasites & Vectors, 5:189 (2012)

[0269] (12) Hansen Solubility Parameters in Practice, available at https: / / www.hansen-solubility.com / HSPiP / .

[0270] (13) “Synthesis of Menthol Glycinates and Their Potential as Cooling Agents.” Klumpp, D. A.; Sobel, R. M.; Osei-Badu, B.; Liveras, Z.; Klumpp, R. A.; Kokkinidou, S. G.; Stentzel, M. R. ACS Omega, 2020, 5, 4043-4049 (doi.org / 10.1021 / acsomega.9b03624).

Claims

1. An oral hygiene product or comestible product comprising: a compound of formula (I): ###0001### wherein the product is selected from the group consisting of toothpaste, mouthwash, candy, and lozenge.

2. The oral hygiene product or comestible product of claim 1, wherein the candy is selected from the group consisting of chewing gum and peppermint.

3. An oral hygiene product or comestible product comprising: a compound of formula (I): ###0002### wherein the product further comprises water and at least one compound selected from the group consisting of castor oil, citric acid esters of mono- and di-glycerides, ethyl acetate, glycerol, glycerol diacetate, isopropyl alcohol, mono-glycerides, di-glycerides, fatty acid propylene glycol monoesters, fatty acid propylene glycol diesters, and mixtures thereof.

4. The oral hygiene product or comestible product of claim 2, wherein the product is chewing gum.

5. The oral hygiene product or comestible product of claim 1, wherein the product is toothpaste. ​ ​

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