IL41995A

Compositions for stimulating the cold receptors of the nervous system,containing alkanoyl or cyclohexyl amides

Abstract

This record has no abstract on file.

IL41995A, drawing sheet 1 — Sheet 1 of 3

Term

No projected expiry on record.

12 claims: 6 independent, 6 dependent

1
41995/2 WHAT WE CLAIM IS:1. A manufactured product for application to or consumption by the human body comprising a physiologically active ingredient capable of stimulating the cold receptors of the nervous system of the body and a carrier therefor, said carrier constituting or providing a vehicle by means of which said ingredient may be brought into contact with the skin or other surface tissue of the body upon use of the said product, said carrier comprising a manufactured article or preparation into which the said ingredient is incorporated by admixture or impregnation and being other than a liquid or mixture of liquids which serve merely to solve for the said ingredient and which contain no other Ingredient, wherein said physiologically active ingredient is a carboxamide of the formula R I 1 /C0nr 4 r 5 R ,v R R״ C*____CONR.Rr or I I | R 3 where R 4 and R 5 , when taken separately, are each hydrogen, or Cj-C 5 alkyl or hydroxyalkyl and together provide a total of no more than 8 carbon atoms, with the proviso that when R 4 is hydrogen Rg may also be alkoxycarboxylalkyl of up to 6 carbon atoms;R 4 and Rg, when taken together, represent an alkylene group of up to 6 carbon atoms, the opposite ends of which group are attached to the amide nitrogen atom thereby to form a nitrogen heterocycle, the carbon atom chain of which may optionally be interrupted by oxygen;Rp R', R, R' and R' v are each hydrogen or ^-Cg al kyl;and Rg and R^ are each 0ן -Cg al kyl;wi th the provisos that 1) R,, R״ and R- together provide a total of at least 5 carbon atoms I £ 0 . II) when 11ן Is hydrogen, R 2 is C 2 ־C 5 alkyl and R 3 1s C 3 -C 5 alkyl and at least one of R 2 and R 3 1s branched: III) R', R, R' and R' v together provide a total of from 1-8 carbon atoms;and iv) at least two of R', R“, and R' and R ,v are hydrogen and that, when R' and R' v are both hydrogen, and R' 1s methyl, then R 1s selected from methyl, ethyl, n_-propyl and straight and branched chain butyl and amyl.
7
A product according to any one of claims 1-6, wherein said earlier is an edible preparation containing an edible base material and a flavourant or colourant.
9
A product according to any one of claims 1-6, wherein said carrier is an orally or topically administrable pharmaceutical preparation, comprising an orally or topically acceptable carrier and an orally or topically administrable pharmaceutically active ingredient. '
10
A product according to any one of claims 1-6, wherein said carrier is a beverage containing a potable base material and a flavourant or colourant.
11
A product according to any one of claims 1-6, wherein said carrier is a dentifrice.
12
A product according to any one of claims 1-6, wherein said carrier is a mouthwash comprising an aqueous or aqueous/alcoholic solution of an orally acceptable antiseptic.

Independent claims6

453 paragraphs in 26 sections, as filed

/ν'Ut f ן —./

<td></td><td> This invention relates to ingestible, topics! and other compositions having a physiological cooling effect on the skin and on the mucous membranes of the body, particu- larly the mucous membranes of the nose and bronchial tract. -</td>

<td> 5</td><td> Menthol is vzell 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 major constituent of oil of peppermint) in foodstuffs, beverages, dentifrices, mouthwashes, etc. and as a component in</td>

<td> 10</td><td> a wide range of toiletries, liniments and lotions for topical application. 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 Nj.j_dimethyl-2-et.hyl butan-</td>

<td> 15</td><td> amide and N,N-diethyl-2-ethyl butanamide, see French Patent Number 1572332. It is well established that the 1booling effect of menthol is a physiological effect due to the direct action of menthol on the nerve endings of the human body responsible</td>

<td> 20</td><td> . for the detection of hot or cold and is not due to latent heat of evaporation. It is believed 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</td>

<td> 25</td><td> coolant its use, in some compositions, is circumscribed by</td>

The present invention is based on the discovery that its strong minty odour.

certain other organic compounds, vzhich can be readily synthesised, have a physiological cooling effect similar to that obtained with menthol, but do not have the strong minty odour. In many cases the compounds have little or no odour at all. Such compounds therefore find utility as additives in a wide range of ingestible and topical compositions. More particularly they find utility as components in compositions for nasal application and in vapour rubs and liniments.

The compounds having a physiological cooling effect and utilisable in accordance with the present invention are amides of the formulae

where and R^, when taken separately, are each hydrogen,

C^-C^ or c!“c8 hydroxyalkyl and provide a total of no more than 8 carbon atoms, with the proviso that alkoxycarbonylalkyl when R^ is hydrogen may also be alkyicarbcccylalky'L of up to 6 carbon atoms;

R^ and R^, when taken together, represent an alkylene group of up to 6 carbon atoms, the opposite ends of which group are attached to the amide nitrogen atom thereby to form a nitrogen heterocycle, the carbon atom chain of which may optionally be interrupted by oxygen;

Rp R’, R”, R’” and R’v are each hydrogen or C^-C^ alkyl; and and are each C-^-C^ alkyl;

with the provisos that

i) Rp R2 and R^ together provide a total of at least 5 carbon atoms, preferably from 5-10 carbon atoms;

ii) when R^ is hydrogen, R2 is C2-C^ alkyl and is C^-C^ alkyl and at least one of R2 and is branched, preferably in an alpha or beta position relative to the carbon atom marked (k) in the formula (1);

iii) R', R, R”' and R’v together provide a total of from 1-3 carbon atoms; and iv) at least two of R1, R” and R’ and R'v are hydrogen and that, when R’ and R,v are both hydrogen and R’ is methyl, then R is selected from methyl, ethyl, n-propyl and straight and branched chain butyl and amyl.

Where the compounds used in this invention have an asymmetric carbon atom either optical isomer may be used in pure form but generally a mixture of optical isomers will be used. In some cases the degree of cooling produced by the compounds on the skin will differ as between optical isomer, in which case on© or other isomer may be preferred. Likewise, the compounds of formula II exhibit geometric isomerism and will usually be employed as a mixture of isomers. However, in some cases one or other geometric isomer may be preferred.

The preferred acyclic amides of formula I used in this invention are the tertiary compounds, i.e. those where each of Rp R? and R^ is alkyl, especially those where is methyl, ethyl or n-propyl and at least one of R2 and. R^ is a branched chain group having branching in an alpha or beta position relative, to the C atom marked, (k) in. the formula. Also preferred, are mono-substituted amides, i.e. where is H, and disubstituted amides where Rz, and are methyl or ethyl. A further preferred group consists of amides of formula I where R^ is hydrogen and at least one of R2 and. R^ is branched in an alpha position relative to the carbon atom marked » in the formula.

II

The preferred cyclohexanamides of formula Z7 used in this invention are cyclohexanamides having either one or two nuclear alkyl substituents with the nuclear alkyl substituent in the case of the mono-nuclear substituted compounds being either in the 1- or the 2- position and the second being either in the 5- or the 6- position. Especially preferred are tertiary compounds, i.e. where R’ is alkyl. Generally it is preferred that one alkyl group, preferably־ R’, is a branched chain group with branching in an alpha or beta position relative to the ring. Again, the monosubstituted cyclic amides, i.e. where one of R^ and R^ is ־5hydrogen, and. disubstituted cyclic amides where R/4 and Rg are methyl or ethyl are preferred.

The amides may. readily be prepared by conventional techniques, for example, by reaction of an acid chloride of the formula R^i^R-^COCl or

R’ COCI

with an.amine of the formula HNR^Rg in the presence of a hydrogen chloride acceptor. Such reactions are entirely conventional and the procedures involved will readily be understood by persons skilled in the art.

Typical amides of Formula I usable in the compositions of this invention are listed below in Table I together with an indication of their cooling activity; the more stars the greater the activity, i.e. the greater the degree of cooling produced by a given quantity of the compound.

<td rowspan="2"> h</td><td rowspan="2"> r2</td><td colspan="2"> TABLE I</td><td rowspan="2"> *5</td><td rowspan="2"> Activity</td>

<td></td><td>R1</td><td> r2</td><td>R3</td><td>R4</td><td>R5</td><td> Activity</td>

<td></td><td> ch3</td><td> iso-C^Hy-</td><td> 2.S 0—C^Hy—</td><td> H-</td><td> C0HcOOCCH9-</td><td> ****</td>

<td></td><td> H-</td><td> iso-C^Hg</td><td> If</td><td> h-</td><td> C2H5OOCCH2-</td><td> ****</td>

<td></td><td> It</td><td> lSO-C^Hg-</td><td> זז</td><td> H-</td><td> C2H5OOCCH2-</td><td> ****</td>

<td> 25</td><td> It</td><td> 1 S O~C</td><td> iso-C^Hy-</td><td> h-'</td><td> CoHnOOCCHo- 2 ל c~</td><td> ***</td>

TABLE I (continued) R1 R2 R3 r4 r5

Typical cyclic amides of formula II usable according to the invention are indicated in the following Table II.

<td colspan="2" rowspan="2"> •</td><td colspan="4"> TABLE 11</td><td colspan="2" rowspan="3"> Rg Activity</td>

TABLE IT (continued)

<td> R*</td><td> R”</td><td> R'</td><td> R׳v</td><td>ra</td><td>R5</td><td> Activit</td>

<td> H</td><td> n-C4Hg-</td><td> tt</td><td> u</td><td> II</td><td> CoHf-OOCCH-״ 2 לס</td><td> *</td>

W The compounds of th*e 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 ג

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, e.g. 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.

י/'-

-?1-

<td></td><td> 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.</td>

<td> ל</td><td> The compositions of this invention will contain an amount of the active cooling compound sufficient to stimulate the cold, receptors in. the areas of the skin or mucous membrane . with which the compositions come into contact and thereby promote the desired cold sensation. As the degree and</td>

<td> 10</td><td> 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</td>

<td> 15</td><td> 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. 5.0% by weight or more of the active</td>

<td> 20</td><td> 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</td>

<td> ל2</td><td> the active cooling compound will usually be incorporated</td>

into a carrier which may 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 hydrocarbon 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 alcohol! 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, /3 face creams, hand creams, sunburn lotions, cleansing tissues, dentifrices, 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 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 jellies and in chewing gum. The formulation of such confections

<td></td><td> will be by ord.in.ary 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</td>

<td> 5</td><td> 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% by weight based on</td>

<td> 10</td><td> the total composition will be found suitable. Similar considerations apply to the formulation of beverages. Generally speaking the compounds will find most utility in soft drinks e.g. fruit squashes, lemonade, cola etc., but may also be used in alcoholic beverages. The</td>

<td> 15</td><td> 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</td>

<td> 20</td><td> 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</td>

<td> 25</td><td> alcoholic or aqueous alcoholic solution, such solutions</td>

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.

Another field of ut.ili.t3z 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 emollients, 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 the formulation of such compositions, apart from the incorporation of the cooling compound, usually in an amount of from 0.05 to 10% by weight, is conventional.

<td></td><td> 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, alcoholic, or aqueous-alcoholic</td>

<td> 5</td><td> solution of an antiseptic often coloured or flavoured for palatability, to which the coolant is added in an amount of from 0,1 tn 1.0% by weight. Dentifrice compositions may be of the solid block, powder, paste or liquid type and. will usually comprise a</td>

<td> 10</td><td> finely 'divided abrasive or polishing material, e.g. precipitated. chalk, silica, magnesium.silicate, aluminium hydroxide or other similar materials well known in the art, and a detergent .or foaming agent. Optional ingredients which may also be included are flavouring agents and colourants,</td>

<td> 15</td><td> antiseptics, lubricants, thickeners, emulsifiers or plasticizers. The amount of coolant added in such compositions will generally be from 0.1 to 5.0% by weight based on the total composition. Medicaments</td>

<td> 20</td><td> Because of their cooling effect on the skin and on the mucous membranes of the mouth, throat and nose and of the gastrointestinal tract the cooling compounds may be used in a variety of oral medicines, nasal and throat sprays, and topical compositions, particularly where a</td>

<td> 25</td><td> counter-irritant is required. In particular the coolants may be formulated into antacid and indigestion remedies, in</td>

<td></td><td> particular those based on sodium bicarbonate, magnesium oxide, calcium or magnesium carbonate, aluminium or magnesium hydroxide or magnesium trisilicate. In such compositions the coolant will usually be added in an amount</td>

<td> 5</td><td> of from 0.01 to 2.0% by weight. The coolants may also be included in oral analgesic compositions e.g. with acetylsalicylic acid or its salts, and in nasal decongestants e.g. those containing ephedrine. Tobacco Preparations</td>

<td> 10</td><td> The coolants of this invention may be incorporated directly into tobacco to give a cool effect when smoking but without the attendant strong and characteristic odour which is associated, with mentholated, tobacco and. cigarettes However, a more advantageous utilisation of the coolants</td>

<td> 15</td><td> of this invention is in pipe or cigarette filters, in particular, filter tipped 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 fibre, is simply impregnated, with an alcoholic solution of.</td>

<td> 20</td><td> 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</td>

<td> 25</td><td> the following Examples.</td>

After Shave Lotion

An after shave lotion was prepared according to the following recipe by dissolution of the ingredients in the

<td> liquid and cooling and filtering:</td><td></td>

<td> Denatured Ethanol</td><td> 75%</td>

<td> Di e thy!phthalate</td><td> 1.0%</td>

<td> Propylene Glycol</td><td> 1.0%</td>

<td> Lactic Acid</td><td> 1.0%</td>

<td> Perfume</td><td> 3.0%</td>

<td> Water</td><td> to 100%'</td>

Into the base lotion vias added 0.5% by weight based on the total composition of N,2,3“trimethyl-2-isopropylbutanamide. When the final lotion is applied to the face a clearly noticeable cooling effect becomes apparent after a short interval of time.

EXAMPLE

Eye Lotion

An eye lotion was prepared containing the following ingredients:

<td> Witch Hazel</td><td> 12.95%</td>

<td> Boric Acid</td><td> 2.00%</td>

<td> Sodium Borate</td><td> 0.50%</td>

<td> Allantoin</td><td> 0.05%</td>

<td> Salicylic Acid</td><td> 0.025%</td>

<td> Chlorobutol</td><td> 0.02%</td>

Zinc Sulphate

0.004' later to 100׳;

To the formulation was added 0.01%, based on the total composition of N-(2־־isopropyl~2,3-dime thy !butanoyl )glycine ethyl ester. When used to bathe the eyes a cool fresh sensation is apparent on the eyeball and eyelids.

EXAMPLE HI

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%

Water to 100%

Shortly before completion of the blending operation 1.0% . by weight N,N,2,3-tetramethyl-2-isopropylbutanamide was added to the blender. When applied as a toothpaste, a cooling effect is noticed in the mouth.

EXAMPLE

Soft. Sweet

Water vzas added to icing sugar at 40% to form a stiff paste. 0.5% of M-ethyl 2^2-diisopropylbutanamide vzas then stirred into the paste and the mixture allowed to iweet.mass resulted having the characterist cooling effect in the mouth of peppermint but without the set minty flavour or odour.

EXAMPLE V

Cigarette Tobacco

I 1——rw—יוו י I ι.ι,.ιτι

A proprietary brand of cigarette tobacco was impregnated with an alcoholic solution of N-ethyl 2-isopropy1-2,5״ dimethylbutanamide, dried and rolled into cigarettes each containing approximately 0.00025 gm. of active compound. Smoking the impregnated cigarettes produced a cool effect in the mouth characteristic of mentholated cigarettes.

A similar effect is noticed when smoking a proprietary brand of tipped cigarette, the coolant being used to impregnate the filter tip rather than the tobacco.

EXAMPLE

Antiseptic Ointment

An ointment was prepared according to the following formulation:

Cetyltrimethyl ammonium bromide 4,0%

Cetyl Alcohol 6.0%

Stearyl Alcohol 6,0%

White Paraffin 14.0%

Mineral Oil 21.0%

Water to 100%

The ingredients were mixed, warmed to 40°C and emulsified.

in a high speed blender. Added to the mixture during blending was 1.5% of M,N, 2-trimethyl-2-isopropylhexanamide.

The final ointment when applied to the skin gave rise to a marked cooling effect.

EXAMPLE

Aerosol Shaving Soar

An aerosol shaving soap composition was formulated according to the following recipe:

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 0.5% based on the total composition of N,2,2-triethyl-3-methylbutanamide. The composition was then packaged in an aerosol dispenser under pressure of a butane propellent.

When used in shaving a fresh cool sensation was distinctly noticeable on the face.

EXAMPLE

Toilet Water

A toilet water w׳as prepared according to the following recipe:

Denatured ethanol.

75.0%

Perfume

0%־5

Water to 100%

To the recipe ?vas added 2.0%, based on the total composition, of N-ethyl 2-sec-butyl-2,3-dimethylpentanamid.e.

As with the after shave lotion, a cooling effect was clearly noticeable on the skin well after !he termination of any cooling effect attributable to the evaporation of the alcoholic carrier.

EXAMPLE.

Deodorant Composit.i.on

A deodorant composition suitable for formulation and dispensing as an aerosol under pressure of a suitable propellent was formulated according to the following recipe:

Denatured ethanol 969%־

Hexachlorophene 2.0% ' Isopropyl, myristate 1.0%

Perfume 0.1%

To the composition was added 2% by weight of N,N,2,2tetraethyl-3~methyl~butanamide. Application of the final composition gave rise to a definite cooling sensation on the skin.־

EXAMPLE

Hair Shampoo

Sodium lauryl ether sulphate, 10 g., was dispersed

<td> •</td><td> in 90 g. water in a high speed mill. To the dispersion was added 2% by weight of N~(1,1-dimethy1-2-hydroxyethyl)-2isopropyl-2,3־־d.imethylbutanam.ide. When the hair is vzashed using the shampoo a fresh, cool sensation is noticed on the</td>

<td> '5</td><td> scalp. EXAMPLS Solid Cologne A solid cologne.was formulated according to.the following recipe:</td>

<td> 10</td><td> Denatured ethanol 74.5% Propylene glycol 3»0% Sodium stearate 5.0% Perfume 5.0% Water to 100%</td>

<td> 15</td><td> 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 2% of N,N,2-dimethyl2-isopropylhexanamide and/the mixture then allowed to solidify into a waxy cake.</td>

<td> 20</td><td> When applied to the forehead a distinct cooling effec is noticeable. EXAMPLE Mouthwash A concentrated mouthwash composition was prepared</td>

<td> 25</td><td> according to the following recipe:</td>

<td></td><td> Ethanol 3.0% Borax 2.0% Sodium bicarbonate 1.0% Glycerol 10.0%</td>

<td> 5</td><td> Flavour ant 0.4/$ Thymol 0.03% Water to 100% To the composition was added 0.1% of N-(l,l-dimethyl-2hydroxyethyl)-2,2-diethylbutanamide.</td>

<td> 10</td><td> 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. EXAMPLE Toothnicks</td>

<td> 15</td><td> The tip of a wooden toothpick was impregnated with an alcoholic solution containing N-ethyl 2,2-diisopropylbutanamide in sufficient amount to deposit on the toothpick 0.05 mg. of the compound. The impregnated toothpick was then dried. When placed on the tongue there is no</td>

<td> ?.0</td><td> detectable taste, however, a distinct cooling effect is noticeable after a short period of time. EXAMPLE Soft Brink A soft drink concentrate was prepared from the</td>

<td> 25</td><td> following recipe:</td>

*2 J׳

<td></td><td> Pure orange juice 60% Sucrose 10% Saccharin 0.2% Orange flavouring 0.1%</td>

<td> 5</td><td> Citric acid 0,2% Sulphur dioxide trace amount Water to 100% To the concentrate was added 0,10% of N,2,3“trimethyl-2״isopropylbutanamide.</td>

<td> 10</td><td> The concentrate was diluted Tvith water and tested. An orange flavour having a pleasantly cool after-effect was obtained. EXAMPLE Boiled Sweet</td>

<td> 15</td><td> 99.5% sucrose and 0.5% citric acid were carefully fused together in the presence of a trace of water. . Just before casting the melt onto a chilled plate 0.5% of N-ethyl 2~methyl-2-isoprppylhexanamide was rapidly stirred, in. The melt was then cast, A boiled sweet resulted</td>

<td> 20</td><td> having a marked cooling effect on the mouth. EXAMPLE Indigestion. Tablet The following ingredients were ground together: Magnesium carbonate 4-9.5%</td>

<td> 25</td><td> Sorbitol 49.4% Saccharin. 0.1% Talc 1.0%</td>

<td></td><td> Added to the mixture during grinding was 0.10% of N~ethyl 2-isobutyl-2,4-dimethylpentanaraide. After mixing the mixture was pressed into 0.5 g tablets. Taken by mouth and swallowed the, tablets produced</td>

<td> c J</td><td> after a short interval of time a noticeable cooling effect in the stomach. EXAMPLE XVII Cleansing Tissue A cleansing tissue was prepared having the</td>

<td> 10</td><td> formulation: Triethanolamine Lauryl sulphate 1.0% Glycerol 2.0% Perfume 0.95% Water to 100%</td>

<td> 15 20</td><td> To this liquid was added 1.0% of N-ethyl 2-isopropyl-2,3dimethylbutanamide. 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. EXAMPLE After Shave Lotion An after shave lotion was prepared according to the־ following recipe by dissolution of the ingredients in the</td>

<td> 25</td><td> liquid and cooling and filtering:</td>

<td> Denatured Ethanol</td><td> 7RQ<</td>

<td></td><td> Di ethylphthalate</td><td> 1.0%</td>

<td></td><td> Propylene Glycol</td><td> 1.0%</td>

<td></td><td> Lactice Acid</td><td> 1.0%</td>

<td> 5</td><td> Perfume</td><td> 3*0% '</td>

<td></td><td> Water</td><td> to 100%</td>

Into the base lotion was added 0.5% by weight based on the total composition of N,2-di-sec.butyl-3-methylpentanamide. When the final lotion.is applied to the face a clearly noticeable cooling effect becomes apparent after a short interval of time.

EXAMPLE

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%

Sodium carboxymethyl cellulose 0.1%

Sorbitol 50%־

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 0.5% based on the total composition of ^-ethyl-2-sec.butyl-4-methylpentanamide. The composition was then packaged in an aerosol dispenser under pressure of a butane propellent.

When used in shaving a fresh cool sensation was

<td> 5</td><td colspan="2"> distinctly noticeable on the face. FYfU.TPTT? γγ</td>

<td> 10</td><td colspan="2"> 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%</td>

<td> *</td><td> Lactic Acid</td><td> 1.0%</td>

<td> 15</td><td> Perfume Water</td><td> 3.0% to 100%</td>

Into the base lotion was added 1.0% by weight based on the total composition of N-ethyl-2-methyl-l-isopropylcyclohexan-־ amide.

When the final lotion is applied to the face a clearly noticeable cooling effect becomes apparent after a short interval of time.

EXAMPLE

Eye Lotion

An eye lotion \׳zas prepared containing the following ingredients:

<td> •</td><td> Witch Hazel Boric Acid</td><td> 12.95% 2.00%</td>

<td></td><td> Sodium Borate</td><td> 0.50%</td>

<td></td><td> Allantoin</td><td> 0.05%</td>

<td> 5</td><td> Salicylic Acid</td><td> 0.025% '</td>

<td> -</td><td> Chlorobutol</td><td> 0.02%</td>

<td></td><td> Zinc Sulphate</td><td> 0.004%</td>

<td></td><td> To the formulation was added 0.01/%</td><td> based on the total</td>

<td> 10</td><td> composition, of N,2-diethylcyclohex</td><td> :anamide. When used to</td>

bathe the eyes a cool fresh sensation is apparent on the eyeball and eyelids.

EXAMPLE

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%

Water to 100%

Shortly before completion of the blending operation 1% by weight of N,N-dimethyl-l-isopropylcyclohexana111ide was added

2-5 to the blender.

When applied as a toothpaste, a cooling effect is noticed in the mouth.

EXAMPLE

Soft Sweet

Water was added to icing sugar at 40°C to form a stiff paste. 05%־ of N~ethyl-l-״n-propylcyclohexanamide was then stirred into the paste and the mixture allowed to set. A soft sweet mass resulted having the characteristic cooling effect, in the mouth of peppermint but without the minty flavour or odour.

EXAMPLE

Cigarette Tobacco

A proprietary brand of cigarette tobacco was irapregnated with N-ethyl-1-isopropylcyclohexan.amide and was rolled into cigarettes each containing approximately 0.001 gm. 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.

A similar effect is noticed ’׳/hen smoking a proprietary brand of tipped cigarette, the coolant being used to impregnate the filter tip rather than the tobacco. EXAMPLE XXV Anti s eptic 0 i n tm en t ׳

An ointment was prepared, according to the following formulation:

3/ ί

<td> Cetyltrirtiethyl ammonium bromide</td><td> 4.0%</td>

<td> Cetyl Alcohol</td><td> 6.0%</td>

<td> Stearyl Alcohol</td><td> 6.0%</td>

<td> idiite Paraffin</td><td> 14.0%</td>

<td> nineral Oil</td><td> 21.0%</td>

<td> Water</td><td> to 100^</td>

The ingredients were mixed, warmed to 40°C and emulsified in a high speed blender. Added to the mixture during blending was 3.0% M~(l,l-diemthyl~2-hydro>^ethyl)-l-isobutyl~2methylcyclohexanamide.

The final ointment when applied to the skin gave rise to a marked cooling effect.

EXAMPLE

Aerosol Shaving Soap

An aerosol shaving soap composition was formulated according to the following recipe:

Stearic acid 6.3%

Lauric acid 2.7%

Trie than 01amine 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, 2-d.iethyl cyclohexanamide.

The composition was then packaged in an aerosol dispenser under pressure of a butane propellent.

When used in shaving a fresh cool sensation was distinctly noticeable on the face.

EXAMPLE

Toilet, Water

A toilet water was prepared according to the following recipe:

Denatured, ethanol 75.0%

Perfume 5.0%

Water to 100%

To the recipe was added 3.0% based on the total composition, of N,N, 2-trimet.hyl-l-isobutylcyclohexanamide.

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.

EXAMPLE

Deodorant Composition

A deodorant composition suitable for formulation and dispensing as an aerosol under pressure of a suitable propellent was formulated, according to the following recipe: Denatured ethanol 96.9%

Hexachlorophene 2.0%

A Isopropyl, myristate 1.0%

Perfume 0.1%

To the composition was added 2.5% by weight of N--( ?.-hydroxy1,1-dimethyl-ethyl)-l-ethyl-2-methyl cyclohexanamide.

Application of the final composition gave rise to a definite cooling sensation on the skin. EXAMPLE XXIX

Hair Shampoo

Sodium lauryl ether sulphate, 10 g, vzas dispersed “ in 90 g water in a high speed mill. To the dispersion vzas added 3.0% by weight of H-methyl-1,2-diethyl cyclohexanamide. When the hair is washed using the shampoo a fresh, cool sensation is noticed on the scalp. EXAMPLE

Solid Cologne

A solid cologne was formulated according to the

<td></td><td> following recipe:</td><td></td>

<td></td><td> Denatured ethanol</td><td> 74.5%</td>

<td></td><td> Propylene glycol</td><td> 3.0%</td>

<td> 20</td><td> Sodium stearate</td><td> 5.0%</td>

<td></td><td> Perfume</td><td> 5.0%</td>

<td></td><td> Water</td><td> to 100%</td>

The sodium stearate was dissolved by.stirring in a vzarm mixture of the ethanol, propylene glycol and water. To ?5 the solution was added the perfume and 2.0% of N-ethyl-1• . > .

φ sec.butyl cyclohexanamidetand the mixture then allowed to solidify into a waxy cake.

Whan applied to the forehead a distinct cooling effect is noticeable.

EXAMPLE XXXI

Mouthwash

A concentrated mouthwash composition was prepared according to the following recipe: Ethanol 3.0% ״ Borax 2.0%

Sodium bicarbonate 1.0%

Glycerol 10.0%

Flavourant. 0.F

Thymol 0.03% water ' to 100%

To the composition was added 0.1% of N-ethyl-1-isopropyl2-methyl cyclohexanamide,

When diluted with approximately 10'times its own volume of water and used to rinse the mouth a cooling effect

I 20 is obtained in the mouth.

EXAMPLE XXXII ! 1 Toothpicks

The tip of a wooden toothpick was impregnated with 1 an alcoholic solution containing N-ethyl-l-methylcyclohexanί 25 amide in sufficient amount to deposit on the toothpick 0.10 mg

<td></td><td> of the compound. The impregnated toothpick was then dried. When placed on the tongue there is no detectable taste, however, a distinct cooling effect is noticeable after a short period of time.</td>

<td> ר» ✓</td><td> EXAMPLE Soft Drink A soft drink concentrate was prepared fromthe following recipe: Pure orange ,־juice 60%</td>

<td> 10</td><td> Sucrose 10% Saccharin 0.2% Orange flavouring 0.1% Citric acid 0.2% Sulphur dioxide trace amount</td>

<td> 15</td><td> Water to 100% To the concentrate was added 0.10% of N-n-butyl-l-n-propyl cyclohexanamide. The concentrate was diluted with water and tasted. An orange flavour having a pleasantly cool after-effect was</td>

<td> 2.0</td><td> obtained. EXAMPLE Boiled Sweet 99.5% sucrose and 0.5% citric acid, were carefully fused, together in the presence of a trace of water. Just</td>

<td> 28 lj.</td><td> before casting the melt onto a chilled plate 0.5% of N-ethy'</td>

I

A) l-isopropyl cyclohexanamitie was rapidly stirred, in. The melt was then cast. A boiled sweet resulted having a marked cooling effect on the mouth. EXAMPLE

Indigestion Tablet

<td></td><td> The follo?ving ingredients ?vere</td><td> ground together:</td>

<td></td><td> Magne s ium c?. rb ona t e</td><td> A 9.5%</td>

<td></td><td> Sorbitol</td><td> 40, /!.%</td>

<td></td><td> Saccharin</td><td> 0.1%</td>

Added to the mixture during grinding was 0.10% of N,N,2trimethyl-l-ethylcyclohexanamide. . After mixing the mixturce was pressed, into 0.5 g tablets.

Taken by mouth and. swallowed, the tablets produced after a short interval of time a noticeable cooling effect in the stomach.

EXAMPLE

Cleansing Tissue

A cleansing liquid was prepared having the formulation: 2.0 Triethanolamine Lauryl sulphate 1.0%

<td> Glycerol</td><td> 2.0%</td>

<td> Perfume</td><td> 0.95%</td>

<td> Water</td><td> to 100%</td>

To this liquid ?vas added 2.0% of M,l,2~triethyl cyclohexan25 amide. A paper tissue was then soaked in the liquid.

When the impregnated tissue x*zas used to wipe ,!.

skin a fresh cool sensation developed on the skin alter a short interval.

The above Examples illustrate the range of compounds and the range of compositions included within the present invention. However, they are not to 00 taken as limiting the scope of the invention in any way. Other compounds within the general formulae will be equally suitable for use in the compositions of Examples I - .XXXVI and. the physiological cooling effect obtained with the compounds of the invention will recommend their use in a vice variety of other compositions where the cooling effect will be of value,

The novel cyclic compounds of this invention are illustrated by the following Examples XXXVII — XLIII. All temperatures are given in degrees Centigrade, The cyclohexanecarboxylic, acids used as starting materials were nrepared either by carbonation of Grignard reagenrs or by hydrolysis of alkylcyclohexyl cyanides according to known techniques. EXAMPLE PREPARATION OF N-ETHYL^l-ISOPROPYLCYCLOHEXANANTDE 1-isopropylcyclohexanoyl chloride was prepared from 1-isopropylcyclohexanoic acid and thionyl chloride. A solution of this acid chloride ,(2.6 g) in ether (25 ml) was

A

P added dropwise ־to a stirred solution of ethyla?nine (5 ml of a 70%) solution in water) in ether (100 ml),. After 2 hours the ethereal solution was washed with dilute hydrochloric acid and water, dried (MgSO^,) and concentrated to give a white solid. This.was recrystallised from petroleum ether (bp. 40-60°) to giv^e I'i-e'chy 1— 1-isopropylcyclohexanamide mp. 101-2°.

Analysis: Found,, C: 77.5: H: 11.9; N:. 7.2

Calculated C: 73.2; H: 117־; N: 7.1%

EXAMPLE XXXVIII

PRE PARATION OF N-n-BUTYL-l-n-PROPYLCYCLOHEXANAMIDE 1-n-propylcyclohexanoyl chloride (bp. 118122°/16״ ram) was prepared in the usual way from 1-n-propylcyclohexanoic acid and thionyl chloride. A solution of this acid chloride 15 (2,0 g) in ether (20 ml) was added dropwise to a stirred solution of n-butylamine (3.0 g) in ether (100 ml)״ After 3 hours the ethereal, solution was washed with dilute hydrocloric acid and water, dried (MgSO;,), and concentrated to 'V give a colourless syrup. Distillation gave N-n-butyl-l-n20 propylcyclohexanamide, bp. 116-S°/lmm.

Analysis: Found C: 7^.8 H: 12.1.; N: 6.3

Calculated C: 74.7; H: 12.0: N: 6.2%

EXAMPLE XXXIX

PREPARATION OF Ν,Ν״ΡΙ^ΤΗΥΙ,-1-η-ΡΡΟΡΥΙ.ΟΥΟΙ,ΟΗΕΧΑΝΑΜΠΙΕ.

2,5 The procedure of Example.XXXVIII was repeated but using dimethylamine in pl^ce of n-butylamine, N,N-dimethyll-n-propylcyclohexanstmide was obtained as a colourless liquid, bp. 6j-66°/0.01 mm.

Analysis: Found C: 73.7: H: 11.7; N: 7.3

Calculated C: 730־: H: 11.7; M: 7.1%

EXAMPLE

PREPARATION OF NM(1-n-.pR0PYLCYCL0mXAHCYL):i0RPH0LIHE

The procedure of Example XXXVIII was repeated but using morpholine in place of n-butylamine. N-(1-n-propylcyclohexanoyl)morpholine was obtained, as a colourless syrup, bp. 105-llA°/0.01 mm. Analysis: Found C: 70.1;: H: 10.9: N: 5.7

Calculated C: ?0.5: H: 10.5; N: 5.9% EXAMPLE PREPARATION OF N- (1, Ί -ΡΙΙ-ΙίΤΙ-ΐΥΕ-Ρ-ΗΥΏΡΟΧΥΕΤΙΓΙΕ)-l-ETHYL-2METHYLCYCLOHEWAMIDE l-e.thyl-2-methylcyclohexanoyl chloride (bp, 108-114° /15 mm) was prepared in the usual v,ray. A solution of this acid chloride (1.0 g) in ether' (20 ml) was added to a stirred, solution of 2.״amino-2-methylpropan-l-ol (1.0 g) in ether (100 ml). After 17 hours the product was isolated, as in Example XXXVII. Distillation-gave N-(l,l-dimethyl-2.~ hydroxyethyl)-l-ethyl-2-methylcyclohexanaraide, bp. 136-143° /1,0 mm, as a colourless liquid which slowly solidified. Analysis: Found C: 69.1; H: 11.3; N: 5.7

Calculated C: 69.7; H: 11.2: N: 5.8%

<td></td><td> EXAMPLE PREPARATION OF N t ?.gyi;T1rrLCYCLOHE.W,?AMIDE 2~ethylcyclohexanoyl chloride was prepared in.the usual way. The acid chloride was allowed to react with</td>

<td> 5</td><td> an excess of ethylamine in ether solution and th© product was worked up as in Example XXXVII to give N,2-diethylcyclohexanami.de as a colourless liquid, bp. 84-94°/0.01 mm. The following Examples XLIV-L illustrate the preparation of the novel compounds of this invention. All</td>

<td> 10</td><td> temperatures are in degrees Centigrade. The tertiary carboxylic acid starting materials were obtained by alkalation of nitriles by known techniques followed by hydrolysis. EXAMPLE XLTV PREPARATION OF N-ETHYL-213-DIr'Er?RYT-2-IS0PR0PYLEUTANAMIDE</td>

<td> 15</td><td> 2,3-dn?ne thy l-2~is opr opylbutanoic acid. (22 g) was heated under reflux with thionyl chloride (50 ml) for 60 minutes, . The excess of thionyl chloride was removed under reduced pressure and the 2,3~din1pt.hyl-2-isopropylbutanoyl chloride was distilled, bp. 7.3-5°/15 mm.</td>

<td> 20</td><td> Λ portion (2 g) of the acid chloride in ether (20 ml) was added dropwise to a. stirred solution of ethylamine (5 ml of a 70% solution in water) in ether (100 ml). The mixture was stirred for 1 hour. The ether layer was then washed with water, dilute hydroc^oric acid and water. The dried</td>

<td> 25</td><td> (MgSO^) ether solution was concentrated, and the residue</td>

distilled to give N-ethyl-2,3-dimethyl-2-isonropylbutanamide, bp. 93-5°/1.5 mm, as a colourless liquid which.

rapidly solidified to a colourless solid nip 38-40°.

<td></td><td> EXAMPLE</td>

<td> 5</td><td> PREPARATION OF N, 2,?-TRI^THgT^P-ISOPROPYLBUTAPW-IIDE Th© procedure of Example XLIV was repeated using methylamine in place of ethylamine. N,2,3~trimethyl-2isopropylbutanamide was obtained as a colourless solid, mp 53-61°־, bp. 83-5°/0.35 mm.</td>

<td> 10</td><td> EXAMPLE PREPARATION OF N-(2, 3-DIMETHYL.»?.־ISOPROPYLBUTANOYL)-GLYCINE ETHYL ESTER ־' Sodium bicarbonate (1.7 g, 0.02 mole) and glycine ethyl ester hydrochlor5.de (1.4 g, 0,01 mole) were dissolves.</td>

<td> 15</td><td> in water (10 ml) and a solution of 2,3-diraethyl-2-isopropylbutanoyl chloride (1.6 g, 0.009 mole) in. ether (10 ml) was added. The mixture was stirred vigorously at room temperature for 2 hours. After 16 hours at room temperature the ether layer was separated and dried (MgSO^). Removal of</td>

<td> 20</td><td> the solvent left a white solid which was recrystallised from ether/petroleum ether to give N-(2,3-dimethyl-2-isopropylbutanoyl)glycine ethyl ester, mp. 74.5-755°־. Analysis: Found C: 64.0; H: 10.3; Νί 59־ Calculated C: 64.2; H: 10.3; N: 5.8%</td>

B EXAMPLE XLVII t

PREPARATION OF N- (1, l~DII-ETIIYll-HYDR0XYETHYL )-2,2-DIETHYL' BUTANAMIDE

2,2-diethylbutanoyl chloride was prepared from 2,25 diethylbutanoic acid and thionyl chloride in the usual way.

A solution of this acid chloride (1.2 g) in ether (30 ml) was added to a stirred solution of 2-amino-2-methylpropan-l-ol (4.0 g) in ether (90 ml). After 4 hours the ethereal solution was washed with dilute hydrochloric acid 10 *־ and water, dried (MgSO^), and concentrated. The residue was distilled to give N-(l,l-dimethyl-2-hydroxyethyl)-2,2diethylbutanamide, bp. 113-5°/0.9 mm, mp. 578°״. Analysis: Found C: 67.5; H: 12.0; N: 6.6

Calculated C: 67.0; H: 11.6; N; 6.5%

EXAMPLE XLVIII

PREPARATION OF N-ETHYL-2-IS0BUTYL-2,4-DBSTHYLPENTANAMIDE 2-isobutyi-2,4-dimethylpentanoyl chloride (bp. 97-100° /16 mm) was prepared in the usual way from 2-isobutyl-2,4dimethylpentanoic acid (prepared by the alkylation of ethyl 20 cyanide with 2 equivalents of isobutyl bromide, followed by hydrolysis) and thionyl chloride. A solution of the acid chloride' (1.5 g) in ether (20 ml) was added with stirring to a solution of ethylamine (5 ml of a 70% solution in water) in ether (100 ml). After stirring for 2 hours the 25 ethereal layer was washed with dilute hydrochloric acid and 'h ׳ ן water. The dried (MgSO^ ether solution was concentrated and the residue was recrystallised from petroleum ether (bp. 40-60°) to give N-ethyl-2-isobutyl-2,4-dimethylpentanamide, mp. 71.5-72.5°״

Analysis; Found C: 72.9; H: 12.3: N: 6.9

Calculated C: 73.3; H: 12.8: N: 6.6%

EXAMPLE

PREPARATION OF LT^IS0PR0PYL-2~S5C־BUTYL-2, 3~PPETHYLPBNTANAMIDE . 2-sec-butyl-2,3-dimethylpentanoyl chloride (bp. 10810 110°/17 mm) was prepared in the usual way from 2-sec-butyl2,3-dimethylpentanoic acid and thionyl chloride. A solution of this acid chloride (2.0 g) in ether (30 ml) was added with stirring to a solution of isopropylamine (2.0 g) in ether (100 ml). After 16 hours the ethereal solution was washed with dilute hydrochloric acid, and water, dried (MgSO^), and concentrated to give a white solid. This solid was recrystallised from petroleum ether (Bp. 40-60°) to give N-isopropyl-2-sec-butyl-2,3-dimethylpentanamide, mp. 7^6°־. Analysis: Found C: 74.3: H: 13.1; N: 6.2

Calculated C: 7^.0; H: 12.8; N: 6.2%

EXAMPLE PREPARATION OF N-(2-HYDR0XYETHYL)-2-SEC-BUTYL-2.3-P^IETHYL.PENTANAMIDE .

A solution of 2-sec-hutyl-2,3-dimethylpentanoyl chloride (2.0 g) in benzene (10. ml) 1?as added, to a stirred solution of ethanolamine (,2.0 g) in benzene (100 ml).

After 16 hours the benzene solution was washed with dilute hydrochloric acid and water, dried (MgSO^) and concentrated to give a pale yellow syrup. Distillation of this syrup gave N-(2-hydroxyethyl)-2-sec-butyl-2,3-dimethylpentanamide bp. 125~10.03/ס0ע mm which slowly solidified on standing.

Analysis: Found C: 68.6; H: 11.6; N: 6.3

Calculated C: 63.2; H: 11.8; N: 6.1%

52 members in 27 offices

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Document	Office	Kind	Date
1791472	United Kingdom	A	1972-04-18
1791472	United Kingdom	A	1972-04-18
1791672	United Kingdom	A	1972-04-18
1791672	United Kingdom	A	1972-04-18
17914	–	–	–
17916	–	–	–
GB19720017914	–	–	–
GB19720017916	–	–	–

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IL41995A0	Israel	A0	1973-06-29
LU67436A1	Luxembourg	A1	1973-07-05
BE798312A	Belgium	A	1973-10-17
IE38028L	Ireland	L	1973-10-18
NL7305508A	Netherlands (Kingdom of the)	A	1973-10-22
NL7305509A	Netherlands (Kingdom of the)	A	1973-10-22
DE2317538A1	Germany	A1	1973-10-31
DE2317539A1	Germany	A1	1973-10-31
FR2180942A1	France	A1	1973-11-30
FR2180943A1	France	A1	1973-11-30
DD104026A5	German Democratic Republic (until 1990)	A5	1974-02-20
JPS4919043A	Japan	A	1974-02-20
JPS4919044A	Japan	A	1974-02-20
ZA732515B	South Africa	B	1974-02-27
BR7302825D0	Brazil	D0	1974-07-18
AU5442973A	Australia	A	1974-10-17
CH564914A5	Switzerland	A5	1975-08-15
ATA348073A	Austria	A	1975-10-15
GB1411786A	United Kingdom	A	1975-10-29
HU167887B	Hungary	B	1975-12-25
AU468442B2	Australia	B2	1976-01-15
GB1421743A	United Kingdom	A	1976-01-21
CA984745A	Canada	A	1976-03-02
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AT330963B	Austria	B	1976-07-26
IL41995AThis record	Israel	A	1976-07-30
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EG11313A	Egypt	A	1977-12-31
FR2180942B1	France	B1	1978-01-13
FR2180943B1	France	B1	1978-01-13
DK137915B	Denmark	B	1978-06-05
DK137915C	Denmark	C	1978-11-06
FI55440B	Finland	B	1979-04-30
US4153679A	United States of America	A	1979-05-08
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FI55440C	Finland	C	1979-08-10
RO67320A	Romania	A	1980-03-15
US4230688A	United States of America	A	1980-10-28
PH14013A	Philippines	A	1980-12-08
SE418453B	Sweden	B	1981-06-09
US4296255A	United States of America	A	1981-10-20
DE2366423A1	Germany	A1	1982-09-23
DE2317538C2	Germany	C2	1983-02-03
NO148699B	Norway	B	1983-08-22
NO148699C	Norway	C	1983-11-30
DE2366423C2	Germany	C2	1984-01-19
JPS597744B2	Japan	B2	1984-02-20
JPS5935940B2	Japan	B2	1984-08-31
DE2317539C2	Germany	C2	1985-03-07
NL181164B	Netherlands (Kingdom of the)	B	1987-02-02
NL181164C	Netherlands (Kingdom of the)	C	1987-07-01

Compositions for stimulating the cold receptors of the nervous system,containing alkanoyl or cyclohexyl amides

Abstract

Term

II

EXAMPLE

EXAMPLE HI

EXAMPLE

EXAMPLE V

EXAMPLE

EXAMPLE

EXAMPLE

EXAMPLE

EXAMPLE

EXAMPLE

EXAMPLE

EXAMPLE

EXAMPLE

EXAMPLE

EXAMPLE

EXAMPLE

EXAMPLE XXXI

I

EXAMPLE

A

EXAMPLE XXXVIII

EXAMPLE XXXIX

EXAMPLE

EXAMPLE XLVIII

EXAMPLE

Priority claims8

Members52

Numbers

Titles

Classification