WO2009062332A2

WO2009062332A2 - Cooling compounds

Info

Publication number: WO2009062332A2
Application number: PCT/CH2008/000480
Authority: WO
Inventors: David C. Bom
Original assignee: Givaudan Sa
Priority date: 2007-11-16
Filing date: 2008-11-13
Publication date: 2009-05-22
Also published as: WO2009062332A3

Abstract

A method of providing a cooling sensation to the skin or the mucous membranes of the body, comprising the application thereto of at least one compound of the Formula (I) in which R1 is selected from H and OMe, R2 is selected from OH, OMe and OEt and R3 is selected from H and OH. Some of the compounds provide simultaneously cooling and sweetening effects.

Description

COOLING COMPOUNDS

Provided are chemical compounds having a cooling effect.

Chemical compounds that have a cooling effect on the skin, mouth and mucous membranes are well known and widely used. Among the most successful of these are various carboxamide derivatives. Typical examples of such materials that have been successfully marketed are those sold under the trade names WS-3 and WS-23. However, despite the considerable commercial success of these materials, there has been continued searching for other compounds with cooling properties and additional advantages.

It has now been found that a particular class of compounds has cooling properties, and in addition, some members of the class exhibit additional desirable properties. There is therefore provided a method of providing a cooling sensation to the skin, the mouth or the mucous membranes of the body, comprising the application thereto of at least one compound of the Formula I

in which R is selected from H and OMe, R is selected from OH, OMe and OEt and R³ is selected from H and OH.

By "OMe" is meant methoxy and by "OEt" is meant ethoxy.

The compounds of formula I give rise to R- and S-enantiomers. These may be resolved if desired, but this adds to the expense of the process, often without gaining any advantage, and for the most part, the compounds may be used as racemates (racemic mixture). An illustrative cooling compound is 4-(4H-benzo[d][l,3]dithiin-2-yl)benzonitrile. In a particular embodiment, there can be simultaneously supplied cooling and sweetening. Therefore, there is also provided a method of providing simultaneously to the mouth cooling and sweetening effects, comprising the application to the mouth of a compound selected from the group consisting of 5-(4H-benzo[d][l,3]dithiin-2-yl)-2-ethoxyphenol; 5-(4H-benzo[d][l,3]dithiin-2-yl)-2-methoxyphenol; and 4-(4H-benzo[d][l,3]dithiin-2- yl)phenol.

Some of the compounds useful in the abovementioned method are novel compounds. There is therefore also provided the following novel compounds:

5-(4H-benzo[d][ 1 ,3]dithiin-2-yl)-2-ethoxyphenol, 4-(4H-benzo[d] [ 1 ,3]dithiin-2-yl)phenol, 4-(4H-benzo[d][l,3]dithiin-2-yl)benzonitrile, 5-(4H-benzo[d][l,3]dithiin-2-yl)-2,3-dimethoxyphenol.

In use, the compounds may be simply blended into an application in a proportion sufficient to provide the desired cooling or cooling/sweetening effect. A suitable level may be determined in every case by simple experimentation, but as a general guide the level is from 1 ppm to 100 ppm, particularly from 1 ppm to 50 ppm.

By "application" is meant any practical use of the compounds in which cooling or cooling/sweetening is desired. Typical (and non-limiting) applications include all kinds of foodstuffs, beverages, confectionery, medicaments, oral care products such as toothpastes and mouthwashes, and personal care products such as cosmetics, creams and salves.

In the formulation of any such products, all of the normal materials of the art may be used in art-recognised proportions. A non-limiting list includes surfactants and emulsifiers, gelling agents, pigments, dyestuffs and other colouring matters, agents against deterioration and degradation, such as light stabilisers, antimicrobial agents, antifungal agents, fillers and extenders, abrasive materials and liposomes.

The compounds may also be used in conjunction with known cooling and sweetening agents. Non-limiting examples of known cooling agents include menthol, menthone, isopulegol, N-ethyl p-menthanecarboxamide (WS-3), N,2,3-trimethyl-2-isopropyl- butanamide (WS-23), menthyl lactate, menthone glycerine acetal (Frescolat® MGA), mono-menthyl succinate (Physcool®), mono-menthyl glutarate, O-menthyl glycerine (CoolAct® 10) and 2-sec-butylcyclohexanone (Freskomenthe®), ethyl 2-(2-isopropyl-5- methylcyclohexanecarboxamido)acetate (WS-5) and the menthyl pyrrolidone carboxylic acid compounds sold under the commercial name "Questice". Non-limiting examples of known sweetening agents include cyclamate, nutrasweet (aspartame), sucrose, fructose, sucralose, neohesperidin dihydrochalcone, rebaudioside, stevioside, neotame, mannitol, erithrytol, xylose, rhamnose, Luo Han Guo extract, mogriside (V), stevia extract, and thaumatin.

In addition, the compounds may be combined with the cooling compounds described in International Published Applications WO 2005/049553 and WO 2007/019719, in particular with N-(4-cyanomethylphenyl) p-menthanecarboxamide, particularly ( 1 /?,2S,5/?)-N-(4-cyanomethylphenyl) p-menthanecarboxamide, and N-(2-pyridin-2- ylethyl) p-menthane-carboxamide, particularly (IR,2S,5R)- N-(2-pyridin-2-ylethyl) p- menthanecarboxamide .

The compounds may be used in all applications in which it is desirable to impart a cooling sensation to the skin or the mucous membranes of the body. Examples of these include:

Consumable products, including, but not limited to all food products, food additives, nutraceuticals, pharmaceuticals and any product placed in the mouth including chewing gum, oral care products, and oral hygiene products including but not limited to, cereal products, rice products, tapioca products, sago products, baker's products, biscuit products, pastry products, bread products, confectionery products, dessert products, gums, chewing gums, mouthwash, dental floss, flavored or flavor-coated straws, flavor or flavor-coated food/beverage containers, chocolates, ices, honey products, treacle products, yeast products, baking-powder, salt and spice products, savoury products, mustard products, vinegar products, sauces (condiments), tobacco products, cigars, cigarettes, processed foods, cooked fruits and vegetable products, meat and meat products, jellies, jams, fruit sauces, egg products, milk and dairy products, yoghurts, cheese products, butter and butter substitute products, milk substitute products, soy products, edible oils and fat products, medicaments, beverages, carbonated beverages, alcoholic drinks such as beers, wines and spirits, non-alcoholic drinks such as soft drinks, mineral and aerated waters, fruit drinks, fruit juices, coffee, artificial coffee, tea, cocoa, including forms requiring reconstitution including, without limitation, beverage powder, milk based beverage powder, sugar- free beverage powder, beverage syrup, beverage concentrate, instant coffee, instant tea, instant cocoa, and coffee whitener, food extracts, plant extracts, meat extracts, condiments, gelatins, pharmaceutical and non-pharmaceutical gums, tablets, lozenges, drops, emulsions, elixirs, syrups and other preparations for making beverages, and combinations thereof.

Oral care products, as hereinabove mentioned, include any composition applied to the oral cavity for the purposes of cleaning, freshening, healing, deodorising the cavity or any part thereof, may include, but are not limited to, toothpastes, tooth gels, tooth powders, tooth whitening products, mouthwashes, lozenges, dental floss, toothpicks, anti-plaque and anti- gingivitis compositions, throat lozenges, throat drops, inflammatory compositions, compositions for treatment of nasal symptoms, cold symptoms and upper gastrointestinal tract distress, compositions for cold relief, for alleviating discomfort of hot flash, and gargle compositions.

Cosmetic products, such as aftershave lotions, baby products, including lotions, oils, powders, creams and shampoos, basecoats and undercoats, bath preparations, including capsules, oils, tablets, salts, soaps and detergents, beard softeners, blushers, body and hand preparations, bubble baths, cleaning products, colognes and toilet waters, cuticle softeners, dentifrices, deodorants, depilatories, douches, eye lotions, eye makeup preparations including eye makeup removers, eye shadows, eyebrow pencils and eyeliners, face and neck preparations, face powders, feminine hygiene deodorants, foot powders and sprays, foundations, fragrance preparations, hair and scalp preparations including bleaches, colour sprays and other colouring preparations such as dyes and colours, hair lighteners with colour, hair conditioners, hair preparations, hair rinses, hair shampoos, hair sprays, hair straighteners, hair tints, hair tonics, hair wave sets, indoor tanning preparations, leg and body paints, lipsticks, makeup bases, makeup preparations including fixatives, manicuring preparations, mascara, men's talcum, moisturising preparations, nail creams and lotions, nail extenders, nail polish and enamel removers, nail polish and enamels, night skin care preparations, paste masks, perfumes, permanent waves, personal cleanliness products, powders, preshave lotions, rouges, sachets, shampoos, shaving cream, shaving preparations miscellaneous, shaving soap, skin care preparations, including fresheners, suntan preparations including gels, creams and liquids.

The method is now further described with reference to the following non-limiting examples. The compounds used are compounds of the Formula I as follows:

Example 1

Preparation of 5-(4H-benzo[d][ 1 ,3]oxathiin-2-yl)-2-ethoxyphenol.

a.) 4-ethoxy-3-hydroxybenzaldehyde was first prepared as described by Wymann et. al. (Synthetic Comm., 1988, pp. 1379-1384).

The compound was a light yellow solid. ¹H NMR (300 MHz, CDCl₃, ppm) δ 1.49 (t, J= 7 Hz, 3 H); 4.21 (q, J= 7 Hz, 2 H); 5.94 (br s, 1 H); 6.95 (d, J= 8 Hz, 1 H); 7.39-7.45 (m, 2 H); 9.83 (s, 1 H); ¹³C NMR (75 MHz, CDCl₃, ppm) 5 14.8; 65.1; 111.0; 114.2; 124.7; 130.6; 146.4; 151.4; 191.3; MS calculated for C9H10O3+H 167 observed 167.

b.) 5-(4H-benzo[d][ 1 ,3]dithiin-2-yl)-2-ethoxyphenol.

Hydrogen chloride gas was bubbled for three minutes at 22° C through a solution of 4- ethoxy-3-hydroxybenzaldehyde (0.50 g, 3.0 mmol) and 2-(mercaptomethyl)benzenethiol (0.52 g, 3.3 mmol) in dichloromethane (15 ml). After an additional 15 min., the reaction mixture was poured into saturated NaHCO₃ (50 ml) and extracted with dichloromethane (2x75 ml). The combined organic layer was washed with brine (30 ml), dried (Na₂SO₄), filtered and concentrated providing a crude solid. This solid was triturated with hexane and then purified by flash chromatography using a gradient of hexanes (100%) up to hexanes (70%:30%). Concentration of the product containing fractions provided the above subtitle compound (0.65 g, 70%) as a cream colored solid. ¹H NMR (300 MHz, CDCl₃, ppm) δ 1.46 (t, J=7 Hz, 3 H), 3.98 (s, 3 H), 4.13 (q, J=7 Hz, 2 H), 5.44 (s, 1 H), 5.68 (br s, 1 H), 6.80 (d, J=8 Hz, IH), 6.99 (dd, J,=8 Hz, J₂=2 Hz, 1 H), 7.13 (d, J=2 Hz, 1 H), 7.15- 7.35 (m, 4 H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ 15.1, 34.4, 51.2, 64.9, 111.6, 114.6, 120.0, 126.2, 127.7, 128.6, 129.4, 132.2, 135.1, 135.9, 146.0, 146.2; MS calculated for C16H16O2S2-H 303 observed 303.

Example 2

Preparation of 5-(4H-benzo[d][ 1 ,3]dithiin-2-yl)-2,3-dimethoxyphenol

Hydrogen chloride gas was bubbled for three minutes at 22° C through a solution of 3- hydroxy-4,5-dimethoxybenzaldehyde (0.55 g, 3.0 mmol) and 2- (mercaptomethyl)benzenethiol (0.52 g, 3.3 mmol) in dichloromethane (15 ml). After an additional 15 min., the reaction mixture was poured into saturated NaHCO₃ (50 ml) and extracted with dichloromethane (2x75 ml). The combined organic layer was washed with brine (30 ml), dried (Na₂SO₄), filtered and concentrated providing a crude solid. This solid was triturated with hexane and then purified by flash chromatography using a gradient of 5 hexanes (100%) up to hexanes (70%:30%). Concentration of the product containing fractions provided the above subtitle compound (0.76 g, 78%) as a white solid. ¹H NMR (300 MHz, CDCl₃, ppm) δ 3.84 (s, 3 H), 3.90 (s, 3 H), 3.94 (d, J=I 5 Hz, 1 H), 4.00 (d, J=15 Hz, 1 H), 5.42 (s, 1 H), 5.89 (br s, 1 H), 6.63 (d, J=2 Hz, 1 H), 6.78 (d, J=2 Hz, 1 H), 7.15-7.36 (m, 4 H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ 34.3, 51.5, 56.0, 61.0, 104.1, 10 108.2, 126.4, 127.7, 128.5, 129.6, 135.2, 135.3, 135.5, 135.7, 149.4, 152.5; MS calculated for C16H16O3S2-H 319 observed 319.

Example 3

15 Preparation of 4-(4H-benzo[d] [ 1 ,3]dithiin-2-yl)benzonitrile

Hydrogen chloride gas was bubbled for three minutes at 22° C through a solution of the 20 product from step a) (0.41 g, 3.1 mmol) and 2-(mercaptomethyl)benzenethiol (0.54 g, 3.5 mmol) in dichloromethane (16 ml). After an additional 15 min., the reaction mixture was poured into saturated NaHCO₃ (50 ml) and extracted with dichloromethane (2x75 ml). The combined organic layer was washed with brine (30 ml), dried (Na₂SO₄), filtered and concentrated providing a crude solid. This solid was triturated with hexane and then 25 purified by flash chromatography using a gradient of hexanes (100%) up to hexanes

(70%:30%). Concentration of the product containing fractions provided the above subtitle compound (0.44 g, 52%) as a white solid. ¹H NMR (300 MHz, CDCl₃, ppm) δ 3.92 (d, J-14 Hz, 1 H), 3.97 (d, J=14 Hz, 1 H), 5.51 (s, 1 H), 7.20-7.40 (m, 4 H), 7.50-7.57 (m, 2 H), 7.59-7.70 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ 33.6, 50.4, 112.2, 118.6, 127.3, 128.1, 128.4, 129.0, 130.4, 132.6, 134.2, 136.8, 145.7; MS calculated for C15H11NS2-H 268 observed 268.

Example 4

Preparation of 4-(4H-benzo[d] [ 1 ,3]dithiin-2-yl)phenol

Hydrogen chloride gas was bubbled for three minutes at 22° C through a solution of 4- hydroxybenzaldehyde (0.5 g, 4.1 mmol) and 2-(mercaptomethyl)benzenethiol (0.7 g, 4.5 mmol) in dichloromethane (20 ml). After an additional 15 min., the reaction mixture was poured into saturated NaHCO₃ (50 ml) and extracted with dichloromethane (2x75 ml). The combined organic layer was washed with brine (30 ml), dried (Na₂SO₄), filtered and concentrated providing a crude solid. This solid was triturated with hexane and then purified by flash chromatography using a gradient of hexanes ( 100%) up to hexanes

(70%:30%). Concentration of the product containing fractions provided the above subtitle compound (0.83 g, 78%) as a white solid. ¹H NMR (300 MHz, CDCl₃, ppm) δ 3.96 (d, J=I 5 Hz, 1 H), 4.02 (d, J=I 5 Hz, 1 H), 4.86 (br s, 1 H), 5.49 (s, 1 H), 6.70-6.84 (m, 2 H), 7.15-7.35 (m, 4 H), 7.36-7.45 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ 34.4, 51.0, 115.7, 126.3, 127.7, 128.6, 129.4, 129.8, 131.4, 134.9, 135.9, 155.8; MS calculated for C14H12OS2+H 261 observed 261.

Example 5:

Testing of Example 1 compound.

A 1% w/w solution of the compound of Example 1 in ethanol (0.06 % by weight) was added to de-ionized water to give a concentration of 6ppm and the contents were mixed well. This solution was tasted using de-ionized water as the control. It was found to have both a cooling and sweetening effect. Other flavor properties relative to the control noted were bitter, sulphury, astringent, metallic.

Example 6:

Example 1 compound 2 ppm in key lime pie-flavored carbonated beverage.

A 1% w/w solution of 5-(4H-benzo[d][l,3]dithiin-2-yl)-2-ethoxyphenol in ethanol (0.02 % by weight) was added to the key lime flavored carbonated beverage (key lime pie flavor level was set at 1000 ppm). and the contents were mixed well. This gave a concentration of 5-(4H-benzo[d][l,3]dithiin-2-yl)-2-ethoxyphenol of 2 ppm. This solution was tasted using the unspiked key lime flavored carbonated beverage as the control. Comments on flavor properties relative to the control included: sweeter, tingling, numbing, cooling, creamier, artificial sweetener aftertaste.

Example 7

Example 2 compound 2 ppm in water.

A 1% w/w solution of the compound of Example 2 in ethanol (0.02 % by weight) was added to de-ionized water and the contents were mixed well. This solution was tasted using de-ionized water as the control. Comments on flavor properties relative to the control included: cooling, sweet, sulphury, lingers.

Example 8

Example 2 compound 2 ppm in Coffee-Mate™ Vanilla Caramel Creamer tasted at 0.2 ppm in coffee.

A 1% w/w solution of 5-(4H-benzo[d][l,3]dithiin-2-yl)-2-methoxyphenol in ethanol (0.02 % by weight) was added to Coffee-Mate™ Vanilla Caramel Creamer and the contents were mixed well. The spiked creamer was added to hot coffee, thereby, diluting 5-(4H- benzo[d][l,3]dithiin-2-yl)-2-methoxyphenol to 0.2 ppm. This solution was tasted using the unspiked Coffee-Mate™ Vanilla Caramel Creamer in hot coffee as the control. Comments on flavor properties relative to the control included: creamier, less bitter, sweet, cooling, artificial sweetener taste on back of tongue, brown, nutty, smooths and balances flavor.

Example 9

Testing of Example 4 compound 30 ppm in water.

A 1 % w/w solution of 4-(4H-benzo[d] [ 1 ,3]dithiin-2-yl)phenol in ethanol (0.3 % by weight) was added to de-ionized water and the contents were mixed well. This solution was tasted using de-ionized water as the control. Comments on flavor properties relative to the control included: sulphury, rubbery, delayed cooling, skunky, medicinal, alliaceous, oniony, tropical fruit, sweet, dried herb, mothball aroma.

Example 10

Testing of 4-(4H-benzo[d][l,3]dithiin-2-yl)phenol (Example 4) 30 ppm in Peach Passion Fruit Frusion Smoothie.

A 1% w/w solution of 4-(4H-benzo[d][l,3]dithiin-2-yl)phenol in ethanol (0.3 % by weight) was added to a Peach Passion Fruit Frusion Smoothie (passion fruit flavor level was set at 25 ppm) and the contents were mixed well. This solution was tasted using the unspiked Peach Passion Fruit Frusion Smoothie as the control. Comments on flavor properties relative to the control included: sweeter, creamier, less sour, fruitier, cooling, juicier, more dairy-like.

Example 11

Testing of 4-(4H-benzo[d][l,3]dithiin-2-yl)benzonitrile (Example 3) at 10 ppm and 1 ppm in water. A 1% w/w solution of 4-(4H-benzo[d][l,3]dithiin-2-yl)benzonitrile was diluted into water generating 10 ppm and 1 ppm solutions. The taste results were as follows: 10 ppm- cooling, astringent, celery and 1 ppm- vegetable, astringent.

It will be understood that the embodiments described herein are merely exemplary and 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.

Claims

Claims:

1. A method of providing a cooling sensation to the skin or the mucous membranes of the body, comprising the application thereto of at least one compound of Formula I

in which R¹ is selected from H and OMe, R² is selected from OH, OMe, OEt and CN, and R³ is selected from H and OH.

2. A method according to claim 1, in which the compound of Formula I comprises at least one of 5-(4H-benzo[d][l,3]dithiin-2-yl)-2-ethoxyphenol; 5-(4H- benzo[d][l,3]dithiin-2-yl)-2-methoxyphenol; 4-(4H-benzo[d][l,3]dithiin-2- yl)phenol; or 4-(4H-benzo[d][l,3]dithiin-2-yl)benzonitrile.

3. A method of providing simultaneously to the mouth cooling and sweetening effects, comprising applying to the mouth a compound comprising at least one of 5 -(4H- benzo[d] [ 1 ,3]dithiin-2-yl)-2-ethoxyphenol; 5-(4H-benzo[d] [ 1 ,3]dithiin-2-yl)-2- methoxyphenol; or 4-(4H-benzo[d][l,3]dithiin-2-yl) phenol.

4. The compound 5-(4H-benzo[d][l,3]dithiin-2-yl)-2-ethoxyphenol.

5. The compound 4-(4H-benzo[d] [ 1 ,3]dithiin-2-yl)phenol.

6. The compound 4-(4H-benzo[d][l,3]dithiin-2-yl)benzonitrile.

7. The compound 5-(4H-benzo[d][l,3]dithiin-2-yl)-2,3-dimethoxyphenol. A product having a cooling effect on the skin and mucous membranes of the body, comprising a compound of the formula I

A product having both cooling and sweetening effects on the mouth, comprising at least one compound selected from the group consisting of 5-(4H- benzo[d][l,3]dithiin-2-yl)-2-ethoxyphenol; 5-(4H-benzo[d][l,3]dithiin-2-yl)-2- methoxyphenol; and 4-(4H-benzo[d][l,3]dithiin-2-yl) phenol.