CA1041506A

CA1041506A - Compounds having a physiological cooling effect and compositions containing them

Info

Publication number: CA1041506A
Application number: CA194,833A
Authority: CA
Inventors: David G. Rowsell
Original assignee: Wilkinson Sword Ltd
Current assignee: Wilkinson Sword Ltd
Priority date: 1973-03-22
Filing date: 1974-03-13
Publication date: 1978-10-31
Also published as: JPS5029753A; DE2413639A1; NL7403797A; GB1422998A

Abstract

Abstract of the Disclosure A novel group of compounds are described having a physiological cooling effect on the skin and mucous membranes of the body but lacking the strong odour of menthol. The compounds are trialkyl-substituted cyclohex?necarboxamides of the formula

Description

Field of the Invention 1~41~
This invention relates to compounds having a physiological cooling effect on the skin and on the mucous membranes of the body, particularly the nose, mouth, throat and gastrointestinal tract, and compositions containing them.
Background of the invention and Prior Art.
Menthol is well known for its physiological cooling effect on the skin and mucous membranes of the mouth and has been extensively used as a flavouring agent (menthol being a 10 major constituent of oil of peppermint) in foodstuffs, beverages, dentifrices, mouthwashes, etc. and as a component in a wide range of toiletries, liniments, and lotions for topical applica-tions. Menthol is also a well known tobacco additive for producing a "cool" sensation in the mouth when smoking.
Carvomenthol has also been reported as having a physiological cooling effect and so also have N,N-dimethyl-2-ethyl butanamide and N,N-diethyl-2-ethyl butanamide, see French Pateht No.
- 1,572,332. Still further compounds having a physiological cooling effect are disclosed in DAS Nos. 2202535.0, 2203273.1, 20 2203947.0 and 2205255.7.
It is well established that the "cooling" effect of menthol is a physiological effect due to the direct action of menthol on the nerve endings of the human body responsible for the detection of hot or cold and is not due to latent heat of evaporation. It is be~ieved that the menthol acts as a direct stimulus on the cold receptors at the nerve endings which in turn stimulate the central nervous system.
Although menthol is well established as a physiological coolant its use, in some compositions, is circumscribed by its strong minty odour and its relative volatility.
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Objects of the lnv~ntion .
It is an object of the invention to provide other eompounds having a physiologleal cooling effeet.
- It is a further object of the invention to provide eompositions and artieles for use by or applieation to the human body, such compositions and artieles eontaining a compound which, when brought into contact with the skin or mucous membranes of the body by use of the article or composition, impart to the body a physiological cooling effect.
Summary of the invention - The present invention is based on the diseovery that eertain other organie eompounds have a physiologieal eooling effeet similar to that obtained with menthol, but do not have the strong minty odour. In many eases the eompounds have little or no odour at all. Sueh eompounds therefore find utility as additives in a wide range of ingestible and topieal eompositions.
The compounds having a physiological cooling effect and provided in aceordanee with the present invention are trialkyl-substituted eyelohexaneearboxamides of the formula CONRlR2 R'v ~ R'' V ~ .
where three of R', R'', R''' and R'v are Cl-C5 alkyl and one is hydrogen, R', R'', R' " and R'v together providing a total of from 3-8 earbon atoms; Rl and R2, when taken separately, are eaeh hydrogen, Cl-C5 alkyl or Cl-C8 hydroxyalkyl or Cl-C8 alkoxyalkyl and together provide a total of no more than 8 earbon atoms, with the proviso that when Rl is hydrogen, R2 may also be alkylearboxyalkyl of up to 6 earbon atoms, and Rl and R2, 104~S0~; 1 when taken together with the nitrogen to which they are attached represent a pyrrolidino, piperidino or morpholino group.
The inv~ntion also provides compositions, in particular ingestible compositions and compositions for topical application, capable of stimulating the cold receptors of the nervous system of the human body comprising an effective amount of a cold receptor stimulant and a carrier therefor, the stimulant com-10 prising one or more of the above defined N-trialkyl- -~
- substituted cyclohexan ecarboxamides.
Particular compositions provided within the scope of this invention are:
1) Comestible compositions comprising an edible base, a flavourant or colourant, and a cold re-ceptor stimulant as defined above.

2) Beverages comprising a potable base, a flavourant or colourant, and a cold receptor stimulant as defined above. -~

3) Lotions comprising an aqueous alcoholic or aqueous-alcoholic carrier, an adjuvant selected from the following: a colourant, an antiseptic or an odourant, and a cold receptor stimulant as defined above.

4) Dentifrices comprising an abrasive, a detergent or foaming agent and a cold receptor stimulant.
S) Toilet preparations, e.g. soaps and creams, comprising an oleaginous or surfactant base and a cold receptor stimulant as above defined.
. 6) Pharmaceutical preparations comprising an antacid and a cold receptor stimulant as above defined.
7) Toilet articles, e.g. cleansing tissues, and toothpicks, comprising a carrier impregnated or coated with a cold receptor stimulant as defined.

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8) Tobacco impregnated with a cold receptor stimulant as defined above.
9) Tobacco filters comprising a fibrous or porous filter impregnated with a cold receptor stimulant as defined.
Detailed Description The trialkyl-substituted cyclohexanecarboxamides of the invention may be prepared by conventional methods, such as by the reaction of the corresponding acid ahloride with ammonia or the appropriate mono or di-substituted amine. The reaction will usually be carried out in solution in the presence of a hydrogen chloride acceptor e.g. sodium hydroxide.
The substituted cyclohexanecarboxamides of the above formulae exhibit both geometric and optical isomerism and the present invention contemplates using the compounds in an iso-merically pure state i.e. consisting of one geometric or optical isomer, as well as in isomer mixtures. In most cases the compounds will be used as an isomer mixture but with certain compounds there may be a difference in cooling effect as between isomers, for example, as between d- and l-forms, and in such cases one - or other isomeric form may be preferred.
The preferred compounds provided according to this inven-tion are compounds were R' is alkyl. Especially preferred are the 3-alkyl-p-menthane-3-carboxamides, i.e. compounds where R' is Cl-C5 alkyl, R'' is isopropyl; R' " is methyl and R'v is hydrogen.
Also preferred are the mono-N-Substituted amides, i.e.
where one of Rl and R2 is hydrogen, and the di-N-substituted amides ; where Rl and R2 are each methyl or ethyl.
Typical amides prepared and usable according to the invention are listed in the following Table together with an indication of their relative activities. These were obtained by a panel of observers who were asked to assess the degree of cooling produced by application of sample quantities of the :. - . ,, .. -compounds according to an arbitrary scale, the greater the cooling effect produced by a given quantity of the compound, the higher the star rating.
TABLE
_R'' R''' R v Rl R2 C. Activity C2H5H CH3- CH - CH - CH - bp.81-87 *****
/0.45mm.
- " iso-c3H7- ~ H H C2H5- bp.96-104 *****
/0.3mm.
n ~ H bp.90-95 *****
/0.02mm.
" " .. " CH - CH - bp.88-91 *****
/0.2mm.
H CH3 H HOCH2C(CH3)2- bp.l33-40 ****
/0.5 mm.
" " " " " C H bp.105-110 ****
/0.5 mm.
iso-c8H7- " H ~ HOCH2CH2 mp. 101-4 ****
n-C4Hg~ H 3 3 CH3 H bp.104-8 ****
/0.01 mm.
2 2CH2CH2 bp.107-112 ****
/0.01 mm.
" " " " H H bp.l24-128 ****
/0.35 mm.
2 5 3 3 2H5 *** `
H " 3 2H5 /0 55 mm.

" -cH2cH2ocH2cH2- bp 106-12 *** -v H CH3 ~ H C2H5OCOCH2- mp. 83-91 ***
C5Hll H " ~ C2H5- bp.l26-30 ***
/0.3 mm. -CH3ocH2cH2- bp.146-50 **
/0.75mm.
C5Hll H .. HO(CH2)3- H bp.l68-174 **
/0.3 mm.
5Hll H CH3 CH3 CH2cH2ocH2cH2- /0 8 mm.
2H5H " " H n-c4H9- bp.126-31 *
C H /0.55 mm.

5 11 " HOCH2CH2- CH3 bp.151-6 *
/0.3 mm.
" iso-C3H7- H bp.117-22 *
/0.3 mm.
H CH3 CH3 CH3 HO(CH2)5 bp.l60-70 *

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Utility 1~41~
The compounds of the above formulae find utility in a wide variety of compositions for consumption by or application to the human body. Broadly speaking, these compositions can be divided into comestible and topical compositions, both terms being taken in their broadest possible sense. Thus comestible is to be taken as including not only foodstuffs and beverages taken into the mouth and swallowed, but also other orally ingested compositions taken for reasons other than their nutritional value, e.g. indigestion tablets, antacid preparations, laxatives, etc.
Comestible compositions are also to be taken to include edible compositions taken by mouth, but not necessarily swallowed, eg.
chewing gum. Topical compositions are to be taken as including not only compositions such as perfumes, powders and other toiletries, lotions, liniments, oils and ointments applied to the external surfaces of the human body, whether for medical or other reasons, but also compositions applied to, or which, in normal usage, come in contact with, internal mucous membranes of the body, such as those of the nose, mouth, or throat, whether by direct or indirect application or inhalation, and thus include nasal and throat sprays, dentifrice, mouthwash and gargle compositions. Also included within the present invention are toilet articles such as cleansing tissues and toothpicks impregnated or coated with the active cooling compound.
A further class of compositions included within the scope of this invention are tobacco and associated articles e.g. pipe and cigarette filters, especially filter tips for cigarettes.
. The compositions of this invention will contain an amount of the active cooling compound sufficient to stimulate 4150~
the cold rcceptors in the areas of the skin or mucous mcmbrane with which the compositions come into contact and there~y promote the desired cold sensation. As the degree and longevity of cooling sensation varies from compound to compound the quantity of stimulant used in each composition will vary widely.
As a guide, it may be said that, with the more active compounds, ~ -a significant cooling sensation, which, in some cases, may persist for several hours, is achieved upon application to the skin of as little as 0.05 ml. of a 1.0% weight percent solution of the active ingredient in ethanol. For the less active compounds a significant cooling effect is achieved only with more concentrated solutions, e.g. 5% by weight or more of the active ingredient, It must also be admitted that such skin tests are somewhat subjective, some individuals experiencing a greater or lesser cooling sensation than others when subjected to the same test.
In formulating the compositions of this invention the active cooling compound will usually be incorporated into a carrier which may be completely inert or which may be or contain other active ingredients. A wide variety of carriers will be suitable, depending upon the end use of the composition, such carriers including solids, liquids, emulsions, foams and gels. Typical carriers for the active cooling compound include aqueous or alcoholic solutions; oils and fats such as hydro- ~ -carbon oils, fatty acid esters, long chain alcohols and silicone oils; finely divided solids such as starch or talc;
cellulosic materials such as paper tissue; tobacco; low-boiling hydrocarbons and halohydrocarbons used as aerosol propellents;
gums and natural or synthetic resins.
In most compositions according to the invention the carrier will be or contain as an adjuvant one or more of the ~, . . . '. ,-. - . . . .
. . . -- ~ - , . ' ; ,.'. - , following: an antacid, antiseptic or analgesic, a flavourant, colourant, or odourant, or a surfactant.
The following illustrate the range of compositions into which the active cooling compounds can be incorporated:
1. Edible or potable compositions including alcoholic and non-alcoholic beverages, confectionery, chewing gum, cachous, ice cream; jellies;
2. Toiletries including after shave lotions, shaving soaps, creams and foams, toilet water, deodorants and antiperspirants, "solid colognes", toilet soaps, bath oils and salts, shampoos, hair oils, talcum powders, face creams, hand creams, sunburn lotions, cleansing tissues, dentrifrices, toothpicks, mouthwashes, hair tonics, eyedrops.
- 3. Medicaments including antiseptic ointments, pile ointments, liniments, lotions, decongestants, counter-irritants, cough mixtures, throat lozenges, antacid and indigestion preparations, oral analgesics;
4. Tobacco preparations including cigars, cigarettes, pipe tobacco, chewing tobacco and snuff; tobacco filters, especially filter tips for cigarettes.
5. Miscellaneous compositions such as water soluble adhesive compositions for envelopes, postage stamps, adhesive labels etc.
Particular preparations according to the invention are discussed in more detail below.
Edible and Potable Compositions The edible and potable compositions of this invention will contain the active cooling compound in combination with an edible carrier and usually a flavouring or colouring agent.
The particular effect of the cooling compounds is to create a 1041S0~
cool or fresh sensation in the mouth, and in some cases, even in the stomach, and therefore the compounds find particular utility in sugar-based confectionery such as chocolate, boiled sweets and candy, in ice cream and jellles and in chewing gum.
The formulation of such confections will be by ordinary techniques and according to conventional recipes and as such forms no part of this invention. The active compound will be added to the recipe at a convenient point and in amount sufficient to produce the desired cooling effect in the final product. As already indicated, the amount will vary depending upon the particular compound, the degree of cooling effect desired and the strength of other flavourants in the recipe. For general guidance, however, amounts in the range 0.1 to 5.0~ by weight based on the total composition will be found suitable.
Similar considerations apply for the formulation of beverages. Generally speaking the compounds will find most utility in soft drinks e.g. fruit squashes, lemondade, cola etc., but may also be used in alcoholic beverages. The amount of compound used will generally be in the range 0.1 to 2.5% by weight based on the total composition.
Toiletries Because of the cooling sensation imparted to the skin, a major utility of the cooling compounds will be in a wide range of toilet preparations and toilet articles. The particular preparations discussed -below are to be taken as exemplary.
A major utility will be in after shave lotions, toilet water etc., where the compound will be used in alcoholic or -aqueous alcoholic solution, such solutions usually also containing a perfume or mild antiseptic or both. The amount of compound added to the formulation will usually be in the range 0.1 to 10% by weight based on the total composition.

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~ noth~r ~ield o~ utility will be in soaps, shampoos, bath oils, etc. where the compound will be used in combination with an oil or fat or a natural or synthetic surfactant e.g.
a fatty acid salt or a lauroylsulphate salt, the composition usually also containing an essential oil or perfume. The range of soap compositions will include soaps of all kinds e.g. toilet soaps, shaving soaps, shaving foams etc. Usually the compound will be added to the formulation in amount of from 0.1 to 10%
by weight.
A further class of toilet compositions into which the compounds may be incorporated includes cosmetic creams and emoillents, such creams and emollients usually comprising a base emulsion and optionally a range of ingredients such as wax, preservative, perfume, antiseptics, astringents, pigments, etc. Also included within this class are lipstick compositions such compositions usually comprising an oil and wax base into which the compound can be incorporated along with the conventional ingredients i.e. pigments, perfumes etc. Once again in formulation of such compositions, apart from the incorporation of the cooling compound, usually in an a unt of from 0.05 to 10% by weight is conventional.
Compositions for oral hygiene containing the cooling compounds include mouthwash, gargle and dentifrice compositions.
The first two may be considered together and will usually comprise an aqueous, a~coholic, or aqueous-alcoholic solution of an antiseptic often coloured or flavoured for palatability, to which the coolant is added in an amount of from 0.1 to 1.0%
by weight.
Dentifrice compositions may be of the solid block, powder, paste or liquid type and will usually comprise a finely divided abrasive or polishing material, e.g. precipitated chalk, ' .

silica, magnesium silicate, aluminiu~ hydroxide or other similar materials well known in the art, and a detergent or foaming agent. Optional ingredients which may also be ineluded are flavouring agents and eolourants, antisepties, lubrieants, thickeners, emulsifiers or plasticizers. The amount of coolant added in such composition will generally be from 0.1 to 5.0%
by weight based on the total composition.
Medieaments Because of their cooling effect on the skin and on the mucous membranes of the mouth, throat and nose and of the gastrointestinal traet the eooling eompounds may be used in a variety of oral medieines, nasal and throat sprays, and topieal eompositions, partieularly where a eounter-irritant is required. In particular the eoolants may be formulated into antacid and indigestion remedies, in particular those based on sodium bicarbonate, magnesium oxide, calcium or magnesium carbonate, aluminium or magnesium hydroxide or magnesium trisilicate. In sueh eompositions the eoolant will usually be added in an amount of from 0.1 to 2.0% by weight.
The eoolants may also be ineluded in oral analgesie eompositions e.g. with acetylsalicylic aeid or its salts, and in nasal deeongestants e.g. those eontaining ephedrine.
Tobaceo Preparations The eoolants of this invention may be incorporated direetly into tobacco ~o give a cool effeet when smoking but without the attendant strong and eharaeteristie odour which is assoeiated with mentholated tobaeeo and eigarettes. Sueh eompositions also have eonsiderable storage stability, whieh is in eontrast with mentholated produets. However, a more advantageous utilisation o~ the eoolants of this invention is in pipe or eigarette filters, in partieular, filter tipped ,-.
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' ' ''' '." ~, -- 1()41~0~i cigarettes. The pad of filter material, which may be of any of the well known types, e.g. cellulose acetate, paper, cotton ~-cellulose or asbestos fiber, is simply impregnated with an alcohol~c solution of the coolant and dried to deposit the coolant in the filter pad. The effect is to give a pleasant cool sensation in the mouth when the cigarette is smoked. As little as 0.1 mg. of the coolant is effective.
Compositions of this invention are illustrated by the following Examples.

After Shave Lotion An after shave lotion was prepared according to the following recipe by dissolution of the ingredients in the liquid and cooling and filtering:
Denatured Ethanol. 75%
Diethylphthalate 1.0%
Propylene Glycol 1.0%
Lactic Acid 1.0%
Perfume 3.0 Water to lO0~
Into the base lotion was added l.0~ by weight based on the total composition of N,N-2,3-tetramethyl-l-ethyl cyclohexane-carboxamide.
When the final lotion is applied to the face a clearly noticeable cooling effect becomes apparent after a short interval of time.

Eye Lotion An eye lotion was prepared containing the following ingredients:

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" 1~)4:~SO~i ~itch h~zel 12.95%
Boric Acid 2,00%
Sodium Borate 0.50%
Allantoin 0.05%
Salicylic Acid 0.025%
- Chlorobutol 0.02%
Zinc Sulphate 0.004%
Water to 100%
To the formulation was added 0.01%, based on the total composition, of N,N,l-triethyl-2,3-dimethylcyclohexanecarboxamide. When used to bathe the eyes a cool fresh sensation is apparent on the eyeball and eyelids.
EXP~PLE 3 -- Toothpaste The following ingredients were mixed in a blender: -~
Dicalcium Phosphate 48.0%
- Sodium lauryl sulphate 2.5%
Glycerol 24.8%
Sodium carboxymethyl cellulose 2.0%
Citrus flavourant1.0~
Sodium saccharin0.5%
Water to 100~
- Shortly before completion of the blending operation 1% by weight of N,l-diethyl-2,3-dimethylcyclohexanecar~oxamide was added to the blender.
When applied as a toothpaste, a cooling effect is noticed in the mouth.

Aerosol Shaving Soap An aerosol shaving soap composition was formulated ; according to the following recipe: ;

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Stearic acid 6.3%
Lauric acid 2.7%
Triethanolamine 4.6%
Sodium carboxymethyl cellulose 0.1%
Sorbitol 5.0%
Perfume 0-4%
Water to 100%
The composition was prepared by fusing the acids in water, adding the triethanolamine, cooling and adding the other constituents.
To the mixture was then added 2.0%, based on the total composition of N-(l,l-dimethyl-2-hydroxyethyl)-1-ethyl-2,3-dimethylcyclo-hexanecarboxamide. The composition was then packaged in an aerosol dispenser under pressure of a butane propellant.
When used in shaving a fresh cool sensation was distinctly noticeable on the face.

Toilet Water A toilet water was prepared according to the following recipe:
Denatured ethanol 75%
Perfume 5.0%
Water to 100%
To the recipe was added 3.0%, based on the total composition, of ~-_-butyl-l-ethyl-2,3-dimethylcyclohexanecarboxamide.
As with the after shave lotion, a cooling effect was clearly noticeable on the skin well after the termination of any cooling effect attributable to the evaporation of the alcoholic carrier.
EXAMæ~E 6 Cleansing Tissue A cleansing liquid was prepared having the formulation:

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1()41S06 Triethanolamine Lauryl 1,0 sulphate Glycerol 2.0%
Perfume .95%
Water to 100%
To this liquid was added 3.0% of N,l-diethyl p-menthane- -3-carboxamide. A paper tissue was then soaked in the liquid.
When the impregnated tissue was used to wipe the skin a fresh cool sensation developed on the skin after a short interval.

Cigarette Tobacco -A proprietary brand of cigarette tobacco was sprayed with an ethanolic solution of N,3-diethyl-p-menthane-3-carboxamide and was rolled into cigarettes each containing approximately .05 mg. of active compound. Smoking the impregnated cigarettes produced a cool effect in the mouth characteristic of mentholated cigarettes but without any attendant odour other than that normally associated with tobacco.
Impregnation of the filter tip of a proprietary brand - of tipped cigarette with 0.01 mg. of l-ethyl p-menthane-3--~ carboxamide produced a similar effect.
EXAMPLE
Deodorant Composition A deodorant composition suitable for formulation and dispensing as an aerosol under pressure of a suitable propellant was formulated according to the following recipe~
Denatured ethanol 96.9%
Hexachlorophene2.0%
Isopropyl myristate 1.0%
Perfume 0.1%

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To thc composition w~s added 4~ by wei~ht of N,N-dimethyl-3-ethyl-p-menthane-3-carboxamide. Application of the final compositlon gave rise to a definite cooling sensation on the skin.

Hair Shampoo Sodium lauryl ether sulphate, lOg., was dispersed in 90g. water in a high speed mill. ~o the dispersion was added 4.5% by weight of N,N,2,3-tetramethyl-1-ethylcyclohexanecarboxamide.
When the hair is washed using the shampoo a fresh, cool sensation is noticed on the scalp.

Solid Cologne A solid cologne was formulated according to the following recipe:-Denatured ethanol 74.5%
Propylene Glycol 3.0%
Sodium Stearate 5.0%
Perfume 5-0%
Water to 100%
The sodium stearate was dissolved by stirring in a ` warm mixture of the ethanol, propylene glycol and water. To the solution was added the perfume and 4% of n,l-diethyl-2,5-dimethyl cyclohexanecarboxamide and the mixture then allowed to solidify into a waxy cake.
When applied to the forehead a distinct cooling effect is noticeable.
- EX~MPLE 11 Mouthwash A concentrated mouthwash composition was prepared according to the following recipe:

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~thanol 3.0%
Borax 2.0~
Sodium Bicarbonate 1.0%
Glycerol 10.0%
Flavourant 0.4%
Thymol 0.03%
Water to 100% ~ -To the composition was added 0.2% of N-(2'-hydroxy-ethyl)-3-ethyl-p-menthane-3-carboxamide.
When diluted with approximately 10 times its own volume of water and used to rinse the mouth a cooling effect is obtained in the mouth.

Soft Drink A soft drink concentrate was prepared from the following recipe:-Pure orange juice 60%
Sucrose 10%
Saccharin 0.2%
Orange Flavouring 0.1%
Citric acid 0.2%
Sulphur dioxide trace amount - Water to 100%
To the concentrate was added 0.05% of N,3-diethyl-p-menthane-3-carboxamide.~
The concentrate was diluted with water and tasted.
An orange flavour having a pleasantly cool after-effect was ; obtained.

Boiled Sweet 99.5% sucrose and 0.5% citric acid were carefully -- . . ' ~ : ' ' ': ~, :' 1()41S~
fused together i~ the presence of a tr~ce of water, Just before casting the melt onto a chilled plate 0.3% of N,l-diethyl-2,5-dimethylcyclohexanecarboxamide was rapidly stirred in. The melt was then cast. A boiled sweet resulted having a marked cooling effect in the mouth.

Hydrophilic Ointment A hydrophilic ointment was prepared having the following formulation:-Propylene Glycol 12~
l-Octadecanol 25%
White Soft Paraffin 25~
Sodium Lauryl Sulphate 1%
Water to 100% -The sodium lauryl sulphate was added to the water and heated to 60C. The paraffin was melted by heating to ;
60C and was then added to the sodium lauryl sulphate mixture with stirring. Propylene glycol and l-octadecanol were then added to this mixture.
To the resultant mixture was added 5% of N-morpholino-l-ethyl-2,3-dimethylcyclohexanecarboxamide. The final ointment when applied to the skin gave rise to a marked cooling effect.
EXAMæLE 15 Toothpick The tip of a wooden toothpick was impregnated with an ~ ~ -alcoholic solution containing N,3-diethyl-p-menthane-3-.carboxamide in an amount sufficient to deposit on the toothpick 0.05 mg. of the compound. The toothpick was then dried.

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When placed against the tongue a cool sensation is noticed after a short period of time.

_ - Aerosol Shaving Soap : An aerosol shaving soap composition was formulated according to the following recipe:
Stearic Acid 6.3%
Lauric Acid 2.7 Triethanolamine 4.6 : 10 Sodium Carboxymethyl Cellulose 0.1%
Sorbitol 5.0 Water to 100 Perfume 0.5%
- The composition was prepared by fusing the acids in water, adding the triethanolamine, cooling and adding the other constituents. To the mixture was then added 0.5% of 3-ethyl-p-menthane-3-carboxamide. The composition was then . packaged in an aerosol dispenser under pressure of a butane propellant.

Toothpaste . The following ingredients were mixed in a blender:
Dicalcium phosphate 48.0%
Sodium lauryl sulphate 2.5%
Glycerol 24.8%
Sodium carboxymethyl cellulose 2.0%
Citrus flavourant 1.0~
Sodium saccharin 0.5%
30 . Water to 100%
Shortly before completion of the blending operation lV41S~
0.5% by weic3ht of N,N-dimethyl-3-ethyl-p-menthane-3-carboxamide was added to the blender.
When applied as a toothpaste a pleasant cooling effect is noticed in the mouth.
In each of the above Examples the specified active ingredient may be replaced by one or more of the other compounds according to this invention and listed hereinbefore Table with equivalent results. However, in some cases a large amount of the active ingredient may be necessary to compensate for the lower activity.
The preparation of the compounds of this invention is illustrated by the following Examples.

Preparation of N,3-diethyl-p-menthane-3-carboxamide Part A A mixture of p-menth-3-yl cyanide (66 g., prepared ~ -by dehydration of p-menthane-3-carboxamide) and ethyl bromide (80g.) was added dropwise to a stirred suspension of sodium amide (from 16.6g of sodium) in liquid ammonia. The ammonia was allowed to evaporate over a period of 20 hours. Water was cautiously added and the product was isolated by ether extraction to give 3-ethyl-p-menth-3-yl cyanide, bp. 80-4/0.5 mm.
A solution of the cyanide (58g.) in dry ether (600 ml.) was added dropwise to a stirred suspension of lithium aluminium hydride (lOg.) in ether (200 ml.). The mixture was then heated under reflux for 7 hours. Wet ether and then water was cautiously added to the mixture. The ether solution was filtered, dried (NgS04), concentrated and distilled to give 3-ethyl-p-menth-3-yl methylamine, bp. 79-81/0.7 mm.
Analysis: Found C, 79.0; H, 14.3; N,7.3 30 Calc. C, 79.2; H, 13.7; N,7.1%
A solution of the above amine (14g.) and magnesium - : . : :.

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~1)41S(~i sulphate (15g.) in aqueous acetone (250 ml. acetone/62 ml. water) was stirred at room temperature for 2 hours. During this time potassium permanganate (95g.) was slowly added. The mixture was stirred for a further 5 hours and then left at room temperature for 5 days. Hydrochloric acid (4N) was then slowly added until a clear solution was obtained. The solution was extracted with ether and the ether extracts were washed with aqueous sodium hydroxide (2N). The basic extracts were acidified and then extracted with ether to give 3-ethyl-p-. 10 menth-3-yl carboxylic acid (3.1 g., 20~) bp. 115-122/0.05 mm.
This acid was converted to the corresponding chloride by reaction with thionyl chloride. The acid chloride had bp.
78-81 /0.35 mm.
Part B
A solution of 3-ethyl-p-menth-3-oyl chloride (l.Og. prepared as in Part A) in ether (25ml.) was added dropwise to a stirred solution of ethylamine (3ml. of a 70%
aqueous solution) in ether (30ml.). After 2 hours the ethereal solution was washed with dilute hydrochloric acid and water, 2~ dried (MgS04) and concentrated to give a colourless syrup.
Distillation of this residue gave N,3-diethyl-p-menthane-3-carboxamide bp. 96-104/0.3mm., which slowly crystallized, mp. 54-7 Analysis: Found C, 75.5; H, 12.2; N, 5.8 Calc. C, 75.4; H, 12.1; N, 5.9 Preparation of N,N-dimethyl-3-ethYl p-menthane-3-carboxamide The procedure of Part B of Example 18 was repeated but using aqueous dimethylamine in place of ethylamine.
.N,N-dimethyl-3-ethyl p-menthane-3-carboxamide was obtained as a colourless liquid, bp. 88-91/0.2mm.

. ~ .....
, . . .

- 1C)41~
Analysis: Found C, 75.4; H, 12.5; N, 6.0 Calc. C, 75.4; H, 12.1: N, 5.9%

Preparation of N-(2-Hydroxyethyl)-3-ethyl-p-menthane-3-carboxamide The procedure of Part B of Example 18 was repeated but using ethanolamine in place of ethylamine. The white solid product was recrystallised from petroleum ether ;
(bp. 60-80) to give N-(2-hydroxyethyl)-3-ethyl-p-menthane-3-carboxamide, mp. 101-4.
Analysis: Found C, 70.8; H, 11.6; N, 5.5 Calc. C, 70.7; H, 11.4; N, 5.5%

Preparation of N-(l,l-dimethYl-2-hYdroxYethYl)-l-ethyl-2~3 - dimethyl-cyclohexanecarboxamide Triethylcarbinyl 2,3-dimethylcyclohexane carboxylate (25.4g., bp. 98-105/l.Omm, prepared by reaction between 2,3-dimethylcyclohexanoyl chloride and the sodium salt of triethyl-carbinol in ether) was added to a stirred solution of -potassium amide (from 4.lg., of potassium) in liquid ammonia.
After 30 minutes, ethyl bromide (15.0g) in dry ether ~lO.Oml.) was added, and the ammonia allowed to evaporate over a period of 16 hours. Water was cautiously added and the product was isolated by ether extraction to give triethylcarbinyl 1-ethyl-2,3-dimethylcyclohexane-carboxylate ~bp. 122-7/1.5mm).
A solution of this ester ~17.0g) in dioxan ~35 ml.) ~
and concentrated hydrochloric acid (25ml.) was heated under -reflux for 16 hours. Most of the solvent was then removed by distillation under reduced pressure, and the product isolated via the sodium salt in the normal way to give 1-ethyl-2,3-dimethylcyclohexane carboxylic acid. This was converted to :,:

- . ~
" . , , ' . ' ~. ' "''~ ' ' . .

- llJ41SU~
l-ethyl-2,3-dimethylcyclohexane ca~bonyl chloride (bp. 102-112/16 Omm.) by refluxing with thlonyl chloride.

A solution of l-ethyl~2,3-dimethylcyclohexanecarbonyl chloride (l.Og.) in ether (20ml) was added to a stirred solution of l,l-dimethyl-2-hydroxyethylamine (2.0g.) in ether - (40ml.). After heating the reaction mixture under reflux for 2 hours, the ether solution was washed with dilute hydrochloric acid and water, dried (MgS04), and concentrated to give N-(l,l-dimethyl-2-hydroxyethyl)-1-ethyl-2,3-dimethyl-cyclo-hexanecarboxamide (bp. 133-40/0.5mm.) as a colourless syrup.
Analysis: Found C : 70.1; H : 11.4; N : 5.6 Calculated C : 70.6; H : 11.4; N : 5.5%

Preparation of l-n-but~1-2,3-dimethylcyclohexanecarboxamide The alkylation of triethylcarbinyl 2,3-dimethyl-cyclohexanoate described in Example 20 (Part 1) was repeated -using n-butyl bromide in place of ethyl bromide. The product, triethylcarbinyl l-n-butyl-2,3-dimethylcyclohexane carboxylate (pb. 114-6/0.3mm) was hydrolysed with HCl/dioxan to give l-n-butyl-2,3-dimethylcyclohexanoic acid (bp. 118-20/0.6mm.).
Treatment of the acid with thionyl chloride gave l-n-butyl-2,3-dimethylcyclohexanecarbonyl chloride (bp. 84-7/0.6mm.).
A solution of l-n-butyl-2,3-dimethylcyclohexanecarbonyl chloride (l.Og.) in ether (lOml.) was added dropwise to a saturated solution of ammonia in ether (lOOml.). After 1 hour, the reaction - mixture was washed with water, dried (MgS04), and concentrated to give l-n-butyl-2,3-dimethylcyclohexanecarboxamide (bp. 124-8 /0.35mm.).
.Analysis: Found C: 74.3; H : 11.8i N : 6.2 Calculated C: 74.0; H : 11.85;N : 6.6~

`: :

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1~)41S~
EX~MPLE 23 Preparation of N-methyl-l-n-butyl-2,3-dimethYlcyclohexane~
carboxamide The procedure of Example 22 was repeated using a solution of methylamine in place of ammonia. Distillation of the product gave N-methyl-l n-butyl-2,3-dimethylcyclohexanecarbox-amide (bp. 104-8/O.Olmm.).
Analysis: Found C : 74.8; H : 12.1; N : 6.0 ~ -Calculated C : 74.7i H : 12.0; M : 6.2%

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:

Claims

The embodiments of the invention in which an exclusive property or privilege is cliamed are defined as follows:

1. Compounds of the formula:

where three of R', R" and R''' and R'v are C1-C5 alkyl groups and the other is hydrogen, R', R", R''' and R'v together providing a total of from 3-8 carbon atoms;
R1 and R2 , when taken separately are each selected from hydrogen, C1-C5 alkyl, C1-C8 hydroxyalkyl and C1-C8 alkoxyalkyl, and together provide a total of no more than 8 carbon atoms, with the proviso that when R1 is hydrogen R2 has one of the above meanings or alkylcarboxy-alkyl of up to 6 carbon atoms; or R1 and R2 when taken to-gether with the nitrogen to which they are attached re-present a pyrrolidino, piperidino or morpholino group.

2. Compounds according to claim 1, where R' is C1-C5 alkyl, R" is isopropyl, R''' is methyl and R'v is hydrogen.

3. A compound according to claim 1, namely N, N, 2,3-tetramethyl-1-ethylcyclohexanecarboxamide.

4. A compound according to claim 1, namely N,3-diethyl-p-menthane-3-carboxamide.

5. A compound according to claim 1, namely 3-ethyl-p-menthane-3-carboxamide.

6. A compound according to claim 1, namely N,N-dimethyl-3-ethyl-p-menthane-3-carboxamide.

7. A compound according to claim 1, namely N-(2'-hydroxy-ethyl)-3-ethyl-p-menthane-3-carboxamide.