Pyridinyl cyclohexanecarboxamide cooling compounds

Abstract

A method of providing a cooling effect to a product includes the incorporation into the product of at least one compound of the formula I ##STR00001##
in which m is a number between 0 and 2, X, Y and Z are selected independently from the group consisting of H, halogen, OH, Me, Et, MeO and EtO, and R.sup.1, R.sup.2 and R.sup.3 together comprise at least 6 carbons, selected such that (a) (i) R.sup.1 is selected from the group consisting of H, Me, Et, isopropyl and C.sub.4-C.sub.5 branched alkyl; and (ii) R.sup.2 and R.sup.3 are independently selected from the group consisting of Me, Et, isopropyl and C.sub.4-branched alkyl; or (b) any two or all of R.sup.1, R.sup.2 and R.sup.3 together form a monocyclic, bicyclic or tricyclic radical having up to 10 carbons. The compounds confer substantial cooling effects on compositions applied to the skin or taken orally, such as toothpastes, mouthwashes, foodstuffs, beverages, confectionery, tobacco products, skin creams and ointments.

Claims

1. A method of providing a cooling effect to a product, comprising the incorporation into the product of a resolved stereoisomer compound (1R,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl) cyclohexane carboxamide.

2. The method according to claim 1 wherein the resolved stereoisomer compound is used in combination with at least one other cooling compound comprising menthol, menthone, isopulegol, N-ethyl p-menthanecarboxamide, N,2,3-trimethyl-2-isopropylbutanamide, menthyl lactate, menthone glycerine acetal, mono-menthyl succinate, mono-menthyl glutarate, o-menthyl glycerine, menthyl-N,N-dimethylsuccinamate, or 2-sec-butyl cyclohexanone.

3. A product adapted to be applied to the skin or taken orally to give a cooling sensation, comprising a resolved stereoisomer compound (1R,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl) cyclohexane carboxamide.

4. The product according to claim 3, wherein the product is used in combination with at least one other cooling compound comprising menthol, menthone, isopulegol, N-ethyl p-menthanecarboxamide, N,2,3-trimethyl-2-isopropylbutanamide, menthyl lactate, menthone glycerine acetal, mono-menthyl succinate, mono-menthyl glutarate, o-menthyl glycerine, menthyl-N,N-dimethylsuccinamate, or 2-sec-butyl cyclohexanone.

Description

EXAMPLE 1

Preparation of N-(4-pyridinyl) p-menthanecarboxamide [(1R,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide]

(1) To a flask are added 4.7 g (50 mmol) of pyridin-4-ylamine, 4.04 mL of pyridine and 100 mL MtBE. To this mixture, 10 g of p-menthanecarboxyl chloride are added dropwise over 5 minutes. The reaction mixture is stirred for 24 hours. To the reaction mixture, 50 mL of water are added. The mixture is separated. The organic layer is washed with 50 mL of water and 50 mL of brine. The organic layer is dried over MgSO.sub.4. The solvent is evaporated in vacuo to afford the crude product, which is recrystallized from hexanes to afford 6.2 g of the desired product with the following spectroscopic properties:

(2) MS: 260 ([M.sup.+.]), 217, 149, 121, 95

(3) .sup.1H NMR (300 MHz; CDCl.sub.3) δ: 8.49 (d, 2H), 7.77 (s, 1H), 7.52 (d, 2H), 2.22 (td, 1H), 1.9 (broad d, 2H), 1.85-1.57 (m, 3H), 1.44-1.22 (m, 2H), 1.16-0.99 (m, 2H), 0.94 (d, 3H), 0.91 (d, 3H), 0.81 (d, 3H)

(4) .sup.13C NMR (75 MHz; CDCl.sub.3) δ: 175.4, 150.5, 145.0, 113.4, 50.7, 44.3, 39.25, 34.3, 32.1, 28.7, 23.7, 22.1, 21.2, 16.1

EXAMPLE 2

Preparation of N-(2-pyridin-2-ylethyl) p-menthanecarboxamide [(1R,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl)cyclohexanecarboxamide]

(5) A preparation similar to that described in example 1 gives the desired product with the following spectroscopic properties:

(6) MS: 288 ([M.sup.+.]), 273, 245, 149, 121, 95

(7) .sup.1H NMR (300 MHz; DMSO) δ: 8.53 (d, 1H), 7.62 (td, 1H), 7.16 (m, 2H), 6.43 (s, 1H), 3.67 (nontuplet, 2H), 3.00 (t, 2H), 1.95 (td, 1H), 1.84-1.53 (m, 4H), 1.47 (broad t, 1H), 1.4-1.1 (m, 2H), 0.87 (d, 3H), 0.84 (d, 3H), 0.66 (d, 3H)

(8) .sup.13C NMR (75 MHz; DMSO) δ: 175.8, 159.7, 148.9, 136.7, 123.6, 121.55, 49.8, 44.3, 39.4, 38.35, 36.9, 34.6, 32.3, 28.55, 23.9, 22.3, 21.3, 15.95

EXAMPLE 3

Preparation of 2-isopropyl-2,3-dimethyl-N-(2-(pyridin-2-yl)ethyl)butanamide

(9) A preparation similar to that described in example 1, using 2-isopropyl-2,3-dimethylbutanoyl chloride, gives the desired product with the following spectroscopic properties:

(10) MS: 262 ([M+]), 220, 205, 149, 121, 106, 93

(11) .sup.1H NMR (300 MHz; CDCl3) 8.53 (d, 1H), 7.63 (t, 1H), 7.16 (m, 2H), 6.69 (s, 1H), 3.67 (dd, 2H), 2.99 (t, 2H), 1.96 (m, 2H), 0.96 (s, 3H), 0.85 (d, 6H), 0.79 (d, 6H)

(12) 13C (75 MHz; CDCL3) 175.6, 160.0, 149.1, 136.6, 123.4, 121.5, 51.4, 38.4, 36.9, 32.6, 18.1, 17.4, 14.1

EXAMPLE 4

Assessment of Cooling Effect

(13) A small group of panelists is asked to taste various aqueous solutions of cooling compounds and indicate which solutions had a cooling intensity similar or slightly higher than that of a solution of menthol at 2 ppm. The same panel is asked to taste these solutions at the chosen concentrations and to record the cooling intensity at regular time intervals until no cooling could be sensed in the mouth. The results are shown in Table 2.

(14) TABLE-US-00002 TABLE 2 Experiments on cooling intensity and longevity. Chemical Concentration Longevity 1-Menthol  2.0 ppm 35 minutes N-ethyl p-menthanecarboxamide (WS-3)  1.5 ppm 57 minutes Formula I, m = 0, X = Y = Z = R1 = H,  0.5 ppm 50 minutes R2 + R3 = p-menthyl (compound of Example 1) Formula I, m = 2, X = Y = Z = R1 = H, 0.02 ppm 60 minutes R2 + R3 = p-menthyl (compound of example 2) Formula I, m = 2, X = Y = Z = H,  0.4 ppm R1 = methyl, R2 = R3 = isopropyl (compound of example 3)

(15) From Table 2, it can be seen that the compounds of Formula I are up to 100 times stronger and last longer than menthol, the reference cooling compound. Compounds of Formula I are also much stronger than WS-3, the best cooling compound of the prior art.

(16) In a second experiment, the same panel is asked to taste various solutions of compounds having various concentrations and to indicate which of these solutions had a cooling intensity similar to or slightly higher than that of a solution of menthol at 2 ppm. This is the “isointensive concentration”. The results are shown in Table 3.

(17) TABLE-US-00003 TABLE 3 Intensity of compounds where R.sup.2 + R.sup.3 = p-menthane and R.sup.1 = X = Y = Z = H Value of m Position of main Isointensive (Chain length) moiety on ring concentration 0 2 or 6  0.2 ppm 0 3 or 5  0.4 ppm 0 4  0.5 ppm 1* 2 or 6*  0.67 ppm 1 3 or 5  0.25 ppm 1 4  0.2 ppm 2 2 or 6  0.02 ppm 2 3 or 5 0.004 ppm 2** 4**  0.05 ppm *compound of Example 1 **compound of Example 2

(18) From Table 2 and 3, it can be seen that compounds of Formula I with various chain lengths and substitution patterns all have lower usage levels than the reference cooling chemicals, menthol and WS-3.

EXAMPLE 5

Application in Mouthwash

(19) TABLE-US-00004 Alcohol 95%   177 mL Sorbitol 70%   250 g Compound of example 1 as a   50 mL 1% solution in alcohol Peppermint oil, Terpeneless 0.300 g Methyl salicylate 0.640 g Eucalyptol 0.922 g Thymol 0.639 g Benzoic acid 1.500 g Pluronic ™ F127 nonionic surfactant 5.000 g Sodium Saccharin 0.600 g Sodium Citrate 0.300 g Citric Acid 0.100 g Water q.s. 1 liter

(20) All the ingredients are mixed. 30 mL of obtained solution is put in the mouth, swished around, gargled and spit out. An icy-cool sensation is felt in every area of the mouth as well as lips.

EXAMPLE 6

Application in Toothpaste

(21) TABLE-US-00005 Opaque toothgel 97.000 g Compound of example 2 as a 2% solution  2.500 g in propylene glycol Peppermint oil, Terpeneless  0.500 g

(22) The chemicals are mixed in the toothgel, a piece of toothgel is put on a toothbrush and a panelist's teeth are brushed. The mouth is rinsed with water and the water is spit out. An intense cooling sensation is felt by the panelist in all areas of the mouth.

EXAMPLE 7

Application in Beverages

(23) 1.5 mg of the compound of example 2 is dissolved in a 355 mL (12 fl oz.) can of clear lemon/lime soda. A panelist experiences an agreeable delayed cooling sensation in the mouth with no throat burning. No unpleasant after-taste is observed.

(24) Although the invention has been described in detail through the above detailed description and the preceding examples, these examples are for the purpose of illustration only and it is understood that variations and modifications can be made by one skilled in the art without departing from the spirit and the scope of the invention. It should be understood that the embodiments described above are not only in the alternative, but can be combined.