CA1055772A - Flavour modifiers - Google Patents

Abstract

ABSTRACT
A method of modifying the flavour characteristics of flavoured ingestible preparations is disclosed which comprises incorpora-ting into the preparation a flavour modifying amount of a compound having the capability of stimulating the cold receptors of the nervous system of the human body.

Description

s~

Field of Invention This invention relates to ~lavour modification ~ in foodstuffs and other orally ingested compositions such as mouthwashes, dentifrices and chewing gum, i.e.
compositions taken into the mouth, but not necessarily `
swallowed, and not necessarily having any nutritional value. The invention also relates to flavour modificatiQn of other flavoured substances, e.g. tobacco.
Background of Invention It is well known to the flavour technologist that very small amounts of certain compounds, such as monosodium glutamate, have a substantial effect on the flavour of compositions to which they are added, such effect being far in excess of the change in flavour which might be attribu-table to the flavour of the additive itself. Indeed, in most cases, the amount of additive used is well below the taste threshold of the compound used, and quite often is as little as 1 or 2 parts per million or even less. Such additives are known in the art as "flavour modifiers", "flavour enhancers" or ~ -"flavour potentiators". The precise mode of action - of these compounds is unknown. Some appear to act by increasing the perception of a given flavour, i.e. by "flavour potentiation" in a strict sense oE the phase, whilst others appear to act by suppressing the perception of undesirable Elavour components and bringing other more - desirable flavour components into prominence. In this specification the term "flavour modification" will be used in a gener:ic sense to cover any change in flavour brought about by the additive and which cannot be attributed to the flavour of the additive itself, either by virtue

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.. . , ~ , . . .. . .. . .
., . .. , ... . ~ , ..... . . . . ..
.. . . . . .. . . .

1~55772 of its tasteless nature or by virtue of the minute con-centration used.
Other compounds known and used as flavour mod~
ifiers are, for example,5'-nucleotides such as disodium 5'-inosinate and di-sodium 5'-guanylate, cyclamic acid, N,N'-di-o-tolylethylenediamine, dioctyl sodium sulfosuc-cinate and 3-hydroxy-2-methyl-~-pyrone (Maltol). See, for example, Handbook of Food Additives, 2nd Edition (1972), CRC Press, pages 513-521; Flavour Chemistry, 1966, American Chemical Society, pa~es 261-273; Flavour Research, Edited by Teranishi, Hornstein, Issenberg and Wick, published by Academic Press, pages 5-12.
The precise mode of action of these known flavour modifiers is not fully understood. A number of studies have been made of the influence of various unrelated compounds on the taste receptors in man, such as for example, acetylcholine and menthol, see Skouby A.P. and Zil-storff-Pedersèn, Acta Physiologica Scand. 19550 34, 251-258 and Hellekant G., Acta Physiologica Scand.
1969, 76. 361-368, but so far as the inventors are aware no attemp~ has so far been made to correlate a general structure with either sensitization or desensitization of the taste receptors in man, or with the presence or absence of fla~our modifying activity.
- In a somewhat different field of physiological activity, there has recently been disclosed an extensive range of compounds having a physiological cooling activity on the nervous system of the body, similar to that obtained with menthol. Such disclosures include, for example, .
the following published German patent applications~

-3-355~

OLS P 22 02 535.0 OLS P 22 02 255.7 - OLS P 22 03 273.1 OLS P 22 03 947.0 OLS P 23 16 999.5 OL~ P 23 17 000.5 OLS P 23 17 538.4 OLS P 23 17 539.4 OLS P 23 34 985.1 OLS P 23 36 495.6 OLS P 23 45 156.1 OLS P 24 13 639.~
OLS P 24 39 7i0.4 Objects oE Invention ~!r. ,.,, - . , Although, as previously indicated, a number of compounds are already used extensively in the food industry as flavour modifiers, the number is relatively small and there is a need for further compounds active :-as flavour modifiers, particularly compounds which can be readily synthesised, partly to increase the choice available - :
to the flavour technologist, but also to overcome dis-advantages of known compounds, such as, in the case of monosodium glutamate, the need to use a relatively large amount with the accompanying risk of undesirable side effects. Also there is a need for flavour modifiers in specific areas, such as, for example, to reduce the bitter after-taste of some artificial sweeteners, or to improve or modify the relatively unpalatable flavours ~ ~.
of potentially valuable protein foodstuffs of natural, -.
synthetic or semi-synthetic origin.

-4 ' .' ' . . .

~S57~2 Statement or Invention The present invention seeks to fulfill these ~ needs and is based on the discovery that, generally speaking, compounds having a physiological cooling activity, as described, for example, in the above-mentioned published German patent applications, also have flavour modifying activity when added to flavoured ingestible preparations and tobacco in amounts below that required to effect a noticeable stimulation of the cold receptors of the 1 n nervous system in the mucosae of the mouth and/or gastrointestinal tract when the preparations are ingested, or in the case of tobacco, smoked.

-4a- ~-` 3L~5~77~

According to the invention there is providPd -a method of modifying the flavour of flavour-containing ingestible preparations, including tobacco, which comprises incorporating into the p:reparation a compound, being a compound capable of stimulating the cold receptors of the nervous system of the body when brought into contact therewith, but being incorporated into the preparation in an amount below the threshold of practical physiological cooling activity, said compound being a compound of the formula Rll IR4 IRll . 10 I R2--C -X II R5 -P - or III R12--N Y

where, in formula I, Rl is H or C2--C6 alkyl;
R2 and R3, when taken separately, are each alkyl or cycloalkyl of up to 6 carbon atoms, or up to 7 when X is OH or CH2H;
R2 and R3, when taken together, represent a C4 -C
straight or branched chain alkylene group, it being provided that:
i) when Rl is H then the alkylene group is branched at a carbon atom in a beta or gamma position relative to the group 20 X; :
ii) that when X is OH or CH2OH, tnen said alkylene group may contain an OH substituent; and iii) that when Rl is H and X is OH, then the cyclic group represented by ;

,2 ,3 lS other than p-menth-3-yl-group; . .
- Rl, R2 and R3 together provide a total of from 6 18 :
carbon atoms;

- 5 -.

:~5S7~

X is OH, CH20H--COOR7, CONRgRg, SOxNR8R~ or SOxRlo;
_ R7 is H, an alkali or alkaline earth metal, ammonium, alkyl- or hydroxyalkyl-substituted ammonium, or a hydroxyalkyl, hydroxyalkoxyalkyl, carboxyalkyl or alkoxycarbonylalkyl group of up to 12 carbon atoms;
R8 and Rg, when taken separat~ly, are each H or alkyl, hydroxyalkyl, carboxylalkyl or alkoxycarbonylalkyl of up to 12 carbon atoms, with the proviso that when R8 is H, Rg may also be cycloalkyl of up to 8 carbon atoms, phenyl or benzyl, or substituted phenyl or benzyl containing hydroxy, Cl--C4 alkyl or Cl -C4 alkoxy substituents; R8 and Rg, when taken together represent an alkylene group of up to 12 carbon atoms, the carbon atom chain of which may optionally be interrupted by oxygen or an - NH - group;
Rio is alkyl, hydroxyalkyl, carboxyalkyl or alkoxy-caxbonylalkyl of up to 12 carbon atoms; and x is 1 or 2; :~
and where in formula II
R4 is C3 -C20 alkyl;
R5 is C3--C8 alkyl or cycloalkyl;
R6 is Cl - C8 alkyl or C3--C8 cycloalkyl or alkyl-cycloalkyl; it being provided that at least one of R4, R5 and R6 is branched at a carbon atom-in an ~,~ or y position relative to the phosphorus atom, and that R4, R5 and R6 together provide a total of from 10 -24 carbon atoms;
and where in formula III
Rll whlen taken separately, is E~, Cl - C6 alkyl or C3-C6 cycloalkyl;
R12 when takeh separatelyj is C3-C10 alkyl or C3--C10 alkylcycloalkyl, cycloalkyl, or cycloalkylalkyl, with the proviso that R12 is branched at an ~- or ~-carbon atom ' r 5~7~
relative to the N atom, this condition to be satisfied, in the case of cyclic groups, when the carbon atom ~- or ~- to the N
atom is part of the cycle;
Rll and R12, when taken together, represent a branched chain alkylene group having 3 -7 carbon atoms and branching at an a- or ~- carbon atom relative to the N atom, and the chain optionally containing an ether (--O--) oxygen atom;
Rll and R12 when separate groups and when taken together provide a total of at least 5 carbon atoms;

13 ~ R14S2 or R15R16NC----;
Rl 3 lS H, Cl--C6 alkyl or alkenyl, C3--C6 cycloalkyl, Cl--Clo hydroxyalkyl, C2 - C10 carboxyalkyl, C3--C10 alkoxy-carbonylalkyl, phenyl or phenyl containing Cl--C4 alkyl, alkoxy, OH, COOH or NO2 substituents, with the proviso that when R13 is C6 alkyl it is primary in structure;

R14 is Cl - C6 alkyl or C3 - C6 cycloalkyl, with the proviso that when R14 is C5 or C6 alkyl it is primary in structure;
R15 and R16, when taken separately, are each Hj Cl--C6 alkyl, C3--C6 alkylcycloalkyl, cycloalkyl, or cycloalkylalkyl, ~1--C10 hydroxyalkyl, C2--C10 carboxyalkyl or C3--C10 alkoxy- :-carbonylalkyl; or together represent a straight or branched chain C3--C10 alkylene group optionally substituted with oxygen or an oxygen-containing group or containing an ether oxygen a~om; and Rll, R12 and Y provide a total of from 7 -16 carbo~
atoms.

1~55772 Detailed Description As has already been indicated, the flavour - modifiers used in accordance with this invention are compounds having a physiological cooling action on the body. That is to say, when brought into contact with the cold receptors of the nervous system they provoke a physiological response perceived as a feeling of coolness in the area of the body to which the comopound has been applied. The compounds are, however, used in this invention in amounts below that required to effect a noticeable cooling effect in the mouth when the flavour-containing preparations are ingested, such amounts being defined herein as below the threshold of practical `~
physiological cooling activity.
The compounds used in accordance with the present invention as flavour modifiers differ widely in their cooling activity, i.e. the amount required to bring about a noticeable cooling effect when the compound is applied to the body. Not only that, but the perception of the cooling effect may be affected by other omponents of the flavour-containing preparation, and~ moreover, sensitivity to these compounds varies from person to person. Therefore -it is not possible to put any absolute value on the amount of compound required to bring about a noticèable cooling effect in the mouth when the flavour-containing preparations are ingested. However, for the purposes of the present disclosure the threshold of practical physiological cooling activity for any given compound in any given preparation is determined by the following test procedure.
'rest Procedure Since, as already indicated, sensitivity to the cooling activity of the compounds used in this invention varies not only from compound to compound and ~rom preparation to preparation, but also from one individual to another the testing must be done on a statistical basis.
Tests of this nature are commonly used in the testing of the organoleptic properties, e.g. taste, smell etc.
of organic and inorganic compounds, see Kirk-Othmer, Encyclopedia of Chemical- Technology, 2nd Ed. (1967) Vol 14, pages 336-344.
In the following test procedure the tests are carried out on a selected panel of 6 people of average oral sensitivity to l-menthol.
To select this panel of average sensitivity known quantities of l-menthol in solution in petroleum ether (bp. 40-60)- are placed on 5 mm squares of filter paper, whereafter the solvent is allowed to evaporate thereby to leave the squares impregnated with known quantities of l-menthol. A panel of observers is enrolled and asked to place one impregnated square at a time on the tongue and to report on the presence or absence of a cooling effect. The quantity of l-menthol on each impregnated square is gradually reduced from a valuè
substantially above 0.25 ~g. per square to substantially below 0.25 ~g, the precise range being immaterial. Conven-iently, one starts with squares containing 2.0 ~g 1- i menthol, the amount on each successive square being half that of the preceding square, i.e. the second test square will contain 1.0 ~g, the third 0.5 ~g,and so on. Each quantity is tested on the tongue at least 10 times. In this way, the thresholds to cold receptor stimulus by l-menthol are determined for each individual of the pane`l, the threshold for~each individual being that amount of l-menthol for which, in a series of not less than 10 _g_ :

-.

55~72 test applications, a cooling effect is reported 50~ of the time. Six panel members are now selected whose threshold - to l-menthol is in the range 0.1 ~,g to 10 ~g and whose average threshold is approximately 0.25 ~g, this select panel being regarded as the test panel of average sensitivity.
To obtain the threshold of practical physiological activity of compounds used as flavour modifiers according to this invention, the 6 selected panel members are asked to taste samples of the flavour-containing preparation containing increasing amounts of the flavour modifier, each sample being tasted at least 10 times~ and to report on the presence of absence of a cooling effect in the mouth. The threshold of practical physiological cooling activity for any given compound in any given preparation for each panel member is then taken as that amount for which a cooling efEect is reported 50~ of the time, that is to say, in the case of each sample being tasted 10 times a cooling effect is reported on at least 5 occas:ions by each panel member. The individual values thus obtained are then averaged to give the average threshold of practical cooling activity for the whole panel.
Although this procedure establishes the upper limit of the amount of flavour modifier which may be used in accordance wi-th this invention, flavour modifying effects wlll be obtained when using amounts of modifier substantially below the threshold for physiological cooling activity. Generally speaking the amount of modifier ;
used will be from 0.01 to 100 parts per million of the flavour-containing preparation on an as consumed basis, i.e. as ingested. Concentrates, such as fruit squashes, intended for dilution before consumption will contain -10- ' ~L~5S772 larger amounts of the flavour modifier, such that on dilution the modifier concentration will be in the stated range. The amount of modifier used will in fact vary widely from co~pound to compound and Erom preparation to preparation, but amounts within the above range generally being satisfactory and with amounts in the range of 0.1 - 10 ppm being generally preferred. In accordance with this invention it has also been found that, in general, there is an increase in flavour modifying activity with increasing concentration of the modifier upto a certain maximum, after which the flavour modifying effects become less noticeable. Thus, for any given compound there will be an optimum concentration range for obtaining maximum flavour modification, such range being different from compound to compound, and also from composition to composition, and above and below which range the flavour modifying effects diminish.
Because of individual variations no generally applicable limits can be put on this optimum concentration range, but these limits can readily be obtained for any given icompound in any given composition by a series of routine tests similar to those referred to above.
The above described test procedure may also be used to identify and define compounds having physiological activity and useful as flavour modifiers in accordance with this invention. Compounds having a physiological cooling activity and useful in accordance with this invention may be defined as those which, when tested by the selected panel according to the procedure used in the selection of the panel, i.e. by placing squares of filter paper impregnated with increasing ~S5772 amounts of the compound, have an actual threshold activity of 100 ~g. or less.
It will be appreciated, therefore, that the phrase "threshold of practical physiological cooling activity" as used herein refers to the activity of the compounds when formulated in the ingestible preparation, whereas "actual threshold of physiological cooling activity"
refers to the activity of the compounds when applied substantially directly to the tongue in an inert, tasteless medium, i.e. the square of filter paper.
In a practical demonstration of the above described test procedures 6 panel members having individual thresholds to l-menthol in the range 0.1 to 10.0 ~g and an average threshold of approximately 0~25 ~g were selected by the described procedure.
The 6 panel members were then used in a first test to establish the actual threshold of physiological cooling activity of two named compounds. For this test each panel member was asked to place filter paper squares each impregnated with a kno~n quantity of the named compound on the tongue in accordance with the above-described procedure and to report on the presence or absence of the cooling effect. Thé answers of each panel member were recorded and the lowest quantity giving rise to positive answers on at least 50% of the occasions ; on which that quantity was tested was taken as the actual threshold value. The individual thresholds were then averaged to give the average for the panel.
The 6 panel members were then used in a second test to establish the threshold of practical physiological cooling activity of the two compounds in an aqueous orange -.

, . .
.. .... .

.. . ~ . ..... .. . ~ . , , drink. For this purpose the 6 panel members were asked to taste a series of 25 ml. aliquots of a commercial = orange squash diluted with water and containing 2,4,6,8, 10 and 12 ~g/ml. (i.e. ppm) of the two selected compounds.
The samples were presented in random order with a five minute gap between each sample. Each panel member was asked to report on the presence or absence of a cooling effect in the mouth. In this part of the procedure each sample was tasted only once in order to shorten the duration of the test. A preliminary figure was thus obtained for the threshold of physiological cooling activity of each compound for each individual panel member.
Fresh dilute orange squash solutions were then prepared and into three separate 25 ml. aliquots of each solution for each individual were added amounts of the test compound just above, just below and equal, respectively, to the preliminary threshold figure obtained in the first part of the procedure. Each of the three 25 ml. aliquots was then presented to the respective panel member for tasting on a total of 10 occasions at five minute intervals and in random order. Again the panel member was asked to report on the presence or absence of cooling and the minimum quantity of compound that gave rise to positive answers or at least 5 out of 10 occasions was taken as the threshold of practical physiological cooling activity. These individual values were then averaged over the whole panel.
The results obtained were as follows :

10~772 . _ _ Compound A* C~rpr~

Threshold _ _ _ __ _ ____________ Panel to Practical Practical Member menthol Actual Threshold Actual Threshold No. ~g Threshold in Orange Threshold in Orange ~g drink ~g drink _ _ _ _ ~g/ml. ~g/ml 1 0.3 0.3 8 1.0 8 2 0.l 0.05 7 0.3 2 3 0.3 0.3 6 2.0 8 4 0.3 0.1 6 2.0 8 0.2 0.5 2 3.0 4

6 0.4 0.5 10 3-0 12 _ _,_ . ... ~ ::, Average 0.27 0.29 5.5 1.9 7 ~ -_ ~
*Compound A = N-ethyl-p-menthane-3-carboxamide " B = 2-hydroxyethyl p-menthane-3-carboxylate In a further test the same 6 panel members were asked to taste and report on the flavour of the same orange drink containing amounts of compounds A and B below the average value of the threshold of practical physiolog-ical cooling activity given above and to compare the flavour with that of a control sample containing no added compound.
The following reports were obtained :

Amount Compound ~g/ml.(ppm) Flavour Modification__ A 0.2 Increased sweetness and total flavour A 0.8 Increased sweetness, ~ut only slight effect on total flavour B 0.2 Increased sweetness, dry mouth after~aste B 0.8 Increase sweetness and orange flavour. Dry mouth feel B 1.5 Very little effect. Some ~ ;
dry mouth feel ~ .

-~577~
These results demonstrate the flavour modification effects of the compounds of the invention when used in edible preparations in amounts be:Low that required to bring about a noticeable cooling effect. They also show the decrease in flavour modifying activity which occurs above a certain concentration level.
The compounds used in accordance with the present invention as flavour modifiers may ~e used in a wide range of flavour-containing ingestible preparations including a wide variety of foodstuffs and beverages, and a wide variety of flavoured ingestible preparations of other types, e.g. flavour-containing orally administered medical preparations and preparations for oral hygiene.
Typical ingestible compositions into which they may be incorporated include flavoured foodstuffs such as chocolate, chocolate puddings and other milk puddings, jellies, conserves, confectionery, bread, starch foods, meat products, beverages such as coffee, tea, cocoa, drinking chocolate, soft drinks, squashes, cola, beer and other alcoholic beverages, chewing gum, flavoured mouthwashes, toothpaste, throat lozenges, orally administered pharmaceuticals etc. In many cases the low volatility of the flavour modifiers used in accordance with this invention will recomment their use in cooked foodstuffs to which they can be added during preparation and before cooking.
As well as incorporation directly into foodstuffs, the flavour modifiers of this invention may be added to flavouring additives e.g. spices, flavour essences etc.
which are themselves added to or used in t~e manufacture or preparation of foodstuffs.

' ~5577Z

Mixtures of two or more compounds may be used in accordance with this invention, as well as mixtures of the flavour modifiers of this invention with known flavour modifiers such as monosodium glutama-te.
Also, as already indicated, the flavour modifiers used in accordance with this invention may also be used as flavour modifiers in tobacco and tobacco-containing preparations e.g. cigarettes, cigars, pipe tobacco and chewing tobacco.
The flavour modifiers used in accordance with the present invention may be incorporated into the ingestible preparations at any suitable time during manufacture or immediately before ingestion e.g. as a condiment or sweetner. They may be added as such or in a suitable liquid or solid carrier to aid dispersion.
The compounds used as flavour modifiers according to this invention will now be discussed in more detail.
Cyclic Amides Amongst the most useful compounds used as flavour modifiers in accordance with this invention are cyclic amides of the formula IV

~ ''':
(CH2)n ~ 28 29 /
IV
where n is 0 or an integer of from 1~6 inclusive;
R is Cl-C5 alkyl;
y is an integer of from 1-~ inclusive, with the proviso that at least one R group is in a 1-, 2- or 3-position in the ring;

~ -15a-~55772 R28, when taken separa-tely, is hydrogen, or an alkyl or hydroxyalkyl group of up to 12 carbon atoms;
R29, when taken separately, is hydrogen, an alkyl, hydroxyalkyl, carboxyalkyl or alkylcarboxyalkyl group of up to 12 carbon atoms; wlth the proviso that when R28 is H, R29 may also be cycloalkyl of up to 8 carbon atoms, phenyl, benzyl or phenyl -lSb- :

577~
~ or benzyl containing hydroxy~ Cl-C4 31kyl or Cl-C4 alkoxy ~ub~tituent~ and a maximum of 12 carbon atoms; and R28 and R29, when taken together represent an alkylene group of up to 12 carbon atom~ optionally co~taining an oxygen hetero atom.

These smides may be prepared in a conventional manner by reaçtion of the corre~ponding acid chloride with an appropriate ami~e.

- ~any of the cyclic ~mides (and-other oompounds u~ed as fla~onr modifier~ i~ accordance with thls invention) e~hibit eithsr geometrio or optical isomeri~m or both and, depenaing on tha ~tarting m~teri~ls and the methods used in thair preparation the oompounds may be lsomerically pure, i.e. consi~ting of one geometric or optical i~omer, or they m~y be isomeric mi~tures, both in the geometric and optical ~en~e. Generally, ,~he compounds will be u~ed as isomerio mixture~, but i~ some cases the flavour modi~ying effeot ma~ differ as between geometrio or optical i80-mers, and therefore one or othar isomer may be preferred.
;
Amides of formula IV h~ving a~secondary aIkyl group e.g. an ``~
isoprop~l or ~eo. butyl group, in a 1 or 2 position of the ring are of ~ -eQpecial interest as flaYour modifiers i~ aooordance ~ith ~his invention ~lth p-mentha~e-3-carboxamiaes of the formula V being espeoially prefe~red~ -.

~here ~28 and R29 are as herei~before defined. `
, . ~ - ' ,` ' :
16.

~55~

Another group of cyclic amides of particular interest are cycloheptanecarboxamides and cyclooctane-carboxamides of the formula VI R23 ~ R24 VI (CH2) ~ 28 29 where m is 2 or 3, at least one of R23 and R24 is Cl-C5 alkyl especially a secondary alkyl group and the other is H or Cl-C5 alkyl, and R28 and R29 are as hereinbefore defined.
Generally speaking, preferred amides are those where R28 is H and R29 is H, Cl-C5 hydroxyalkyl, alkyl-earboxyalkyl of up to 6 carbon atoms, C5-C6 cycloalkyl, phenyl, or phenyl containing hydroxy, methyl or methoxy substituents, and disubstituted amides where R28, and R29 .
are each Cl-C5 alkyl or Cl-C5 hydroxyalkyl.
Typical compounds according to formula IV and usable as flavour modifiers in accordance with this invention are listed in Table I.
TA~LE I
N-ethyl-l-isopropyleycloheptaneearboxamide N,l-diisopropyl-2-methylcyclopentaneearboxamide N-(l',l'-dimethyl-2-hydroxyethyl)-l-sec butylcycloheptanecarboxamide N,N-dimethyl-l-ethyleyelooctanecarboxamide N-(2'-isopropylcycloheptanecarbonyl)glycine ethyl ester N-(l'-ethyl-2'-methyleyeloheptaneearbonyl)morpho-line -~
N-p-methoxyphenyl-lO-ethyl-2-methyleyeloheptane-earboxamide ~-. :.:

~57~Z

TABL~ I (con't) N-ethyl-l-sec. butylcyclohexanecarboxamide N-n-bu-tyl-l-n-propylcyclohexanecarboxamide ~ N-ethyl-2,5-dimethylcyclohexanecarboxamide N,N,2,3,6-pentamethylcyclohexanecarboxamide N-(2'-hydroxyethyl)-1-ethyl-3-methyl-6-isopropyl-cyclohexanecarboxamide N,N2,3-tetramethyl-1-ethylcyclohexanecarboxamide l-ethyl-2-isopropyl-2-methylcyclohexanecarboxamide p-methane-3-carboxamide N-ethyl-p-menthane-3-carboxamide ;
N-(p-menth-3-oyl)glycine N-benzyl-p-menthane-3-carboxamide N-p-hydroxyphenyl-p-methane-3-carboxamide .
N-isopropyl-p-menthane-3-carboxamide N-(6'-hydroxy-n-hexyl)-p-menthane-3-carboxamide N (p~menth-3-oyl)morpholine N-methyl-N-(p-menth-3-oyl)glycine ethyl ester N-(p-tolyl)-p-menthane-3-carboxamide N-(l',l'-dimethyl-2'-hydroxyethyl)-1,2-diethylcyclohexanecarboxamide N-(l',l'-dimethyl-2'-hydroxyethyl)-p-menthane-3-carboxamide N-t-butyl-p-menthane-3-carboxamide N-(p-menth-3-oyl) glycine n-propyl ester N-ethyl-l-isopropylcyclohexanecarboxamide N-cyclopentyl-l-isopropylcycloheptanecarboxamide `
N-n-octvl-l-isopropylcycloheptanecarboxamide N-methyl-l-ethylcycloundecanecarboxamide N-(l'-ethyl-2'-methylcycloheptanecarbonyl)pyrroli-dine TABLE I (con't) N-(p-menth-3-oyl)glycine n-propyl ester N,N-dimethyl-p-menthane-3-carboxamide N-(carboxymethyl)-p-menthane-3-carboxamide N-(p-menth-3-oyl)piperidine :~
N-(p-menth-3-oyl)piperazine N-(p-methoxyphenyl)-p-menthane-3-carboxamide N-n-decyl-p-menthane-3-carboxamide N-cyclopropyl-p-mçnthane-3-carboxamide N-cycloheptyl-p-menthane-3-carboxamide N-cycloheptylmèthyl-p-menthane-3-carboxamide .
N,N-(1',4'-dimethyl-3'-~thyltetramethylene)-p-methane-3-carboxamide N~(3'-hydroxy-4'-methylphenyl)-p-menthane-3-carboxamide N-phenyl-p-menthane-3-carboxamide ~
N-(2'-n-butylcyclohexanecarbonyl)glycine ethyl ester N-(l'-n-propylcyclohexanecarbonyl)morpholine N-(5'-hydroxy-n-pentyl)-1-isopropyl-2-methyl-cyclopentanecarboxamide N-ethyl-l-isopentylcyclopentanecarboxamide~ ~:
N-~ isopropylcyclopentanecarbonyl)glycine e~hyl ~:
ester N,1,4~4~tetramethylcycloheptanecarboxamide N-(3'--4'-dimethylphenyl)-1-isopropylcycloheptané-carboxamidè
N-(3',3',7'-trimethylcycloheptanecarbonyl)glycine ethyl ester ~
N-methyl-2-ethylcycloheptanecarboxamide -~ N-(l',l'-dimethyl-2'-hydroxyethyl)-1-ethylcyclo-octanecarboxamide N,2-diethyIcyclooctanecarboxamide ~ .

.~ 19 . ...

TABLE I ( con't) N-(l',l'-dimethyl-2'-hydroxyethyl)-1-ethylcyclo~
undecanecarboxamide N,N-dimethyl-l-ethylcycloundecanecarboxamide.
Numerous other cyclic amides having physiological cooling activity and useful in accordance with this inven-tion as flavour modifiers are disclosed in published German patent applications OLS Nos. P 22 03 535.0, P 22 02 255.7, P 23 17 539,5, P 24 13 639.8 and P 24 58 562.4.
Acyclic secondary and tertia~ amides ~ . second group of lamides useful in this invention is constituted by acyclic secondary or tertiary amides of the formula VII

IRl where Rl is H or Cl-C5 alkyl;
R2 and R3 are each Cl-C5 alXyl;
Rl, R2 and R3 together provide a total of from 5-15 carbon atom~; and R28 and R29 are as defined above;
Acyclic amides of formula VII having physiologi-cal cooling activity and useful as flavour modifiers in accordance with this invention are described in detail in German patent application OLS No. P 23 17 538.4.
Generally, spea~ing they may be prepared by conventional methods for the preparation of amides, for example by the reaction of the appropriate acid chloride with ammonia or appropriate amine.

Preferred acyclic amides of formula VII ~or use ;~
as flavour modifiers are those where at least one of . ' ,.. ~ . .. .. .. .. . . . ..... . , .,, . ... ,; . . . . .

1055'77Z

Rl~ R2 and R3 is a branched chain alkyl group, preferably having branching in an alpha or beta-position relative to the carbon atom to which is attached the CONR28R29 group. Preferred values for R28 and R29 are as listed above for the cyclic amides.
Typical acyclic amides of formula VII are listed in Table II.
TABLE II
N,N2-triethyl-3-methyl pentanamide N,2,3-trimethyl-2-isopropyl butanamide N-ethyl-2,3-dimethyl-2-isopropyl butanamide N,2,2-triethyl-3-methyl butanamide N-(2-isopropyl-2,3-dimethylbutanoyl)glycine ethyl ester N,N,2-trimethyl-2-isopropylhexanamide - 2,3-dimethyl-2-sec. butyl pentanamide (2,4-dimethyl-2-isobutylpentanoyl)piperidine N,2-diisopropyl-3-methyl butanamide N-ethyl-2,4-dimethyl-2-isopropylpentanamide N,2-diethyl-5-methylhexanamide N,2-disec. butyl-3-methylpentanamide N-ethyl-2-isobutyl-4-methylpentanamide N-ethyl-2,3-dimethyl-2-sec. butylpentanamide N-(l',l'-dimethyl-2'-hydroxyethyl)-2,2-diethyl butanamide N-ethyl-2,4-dimethyl-2-isobutylpentanamide N,N,2,2,4-pentamethylpentanamide N-(2'-isobutyl-3'-methylbutanoyl)glycine ethyl ester -20a-: ' ' .. ,. , ... ,. , , , , .: :

~S577~
N,~,3-trimet~vl-2-e-thylpentanamide ~-ethyl-2-isopropyl-4-methylpentanamide -trimethyl-2-ethylbutanamLde ~clic carbo~ylic acids, salts and ester ~180 of con~iderable interest as fla~our modifier3 in accordance ~ith this invention are cyclic secondaxy and tertiary carboxylic acids, ealts thereof and esters of the formula YIII

(C~2 ~ COOhj whe~e~~ n, y, R and ~ ae defi~ed above;

~he cyclîc acids of formula ~III may be prepared by con~en~ional methods for the-preparation of carbo~ylic acids a~d these ca~ then resaily be co~erted into their alkali metal, alk~line ea~th metal~
nmmonium, ~Ikylamine ana alkanolamine ~alts and into their corresponding hydro~yaIkyl ester~. Prefer,re~ o~clio carbo~ylic acids, e~ter~ and qalts are p-menth~ne-3-oarbo~y;ic and derivatives of the formula I

~ COOR~

~here ~ ie ae def~ned above, preferably H or a C2-C5 hydro2yaIkyl~group~ . ~
, o of par~icular intereat are c~cloheptane and c~¢looctane , oarboxylic a¢id~ of the formNla X

~ / ~ 3 (CE2 ~ 24 . COOR7 where m~ R23p R24and R7 are a~ abo .

21.

., . , . - . . . , ~ , . , , .. . . ; , ~55~72 Typical compounds of formula VIII ar~ listed iIl ~able III.

~BLE III
p-menthane-3~carboxylic acid triethyla~monium p-menthane-3-carboxylate sodium p-menthane-3-carbo ylate ammoniu~ p-menthane-3-c~rboxylate hydroxyethyla~monium p-menthan.e-3-carboxylate 2-hydroxyethyl p-menthane-3-oarbox~late `l-sec. butylcycloheptanec~rboxylio acid 2-isopropylcyclohepta~ecarboxylic acid l-isopIopyl-2-methylcyclohepta~ecarboxylic acid ~~ l-ethylcyclooctanecarboxylic acid 2',3'-dihydroxy-n-propyl p-me~tha~é-3-carboxylate 2n-(2'-hydroxyethoxy hthyl p-menthane-3-carboxylate ' l'-carboxy-l'-methylethyl p-menthane-3-carboxylate l'-ethoxycarbonylethyl p-menthane-3-carboxylate ~.
l-isopropyl-2-methylcyc10pentanecarboxylic acid .~
2-ethylcyolooctanecarboxylic acid - ~ :.
2'-~ydroxyethyl l-isopropylcycloheptanecarboxylate 2'-hydroxyethyl 1-isopropyl-2-methylcyclopentanec rboxylate 2'-hydroxyethyl 2-ethylpyoloootanecarboxylate l'-methyl-2'-hydroxypropyl p_menthane-3-carboxylate . -l-sec. butylcycloheptanecarboxylic acid :
- 2-isopIopylcyclohsptanecarbox~lio acia . 1-ethyl-2-methylcyclohepta~ecarboxylic acid 1,4,4-trimethylcycloheptanecarboxylic acid l-ethylcyclooctanecarboxylio~ acid ~ ;
l-i~ope~1;yl-2-methylcyclopentane carboxylic acid - 2'-hydro?~yl-~-propyl l-i60pentylcyclopentanecarboxylat0 ~0 2'-hydro?~ethyl 1-isopropyl-2-methylcyclopentanecarboxyIate - 2'-h~dlo~Lyethyl 1~ethyl-2 _ thylcycloheptanecarbo~ylate : :
- .

2~

1 ~557~Z

Other cyclic carboxylic acids, salts and esters having physiological cooling activity and useful in this - invention are listed in German patent applications OLS
Nos. P 22 0~ 535.0 and P 24 58 562.4 referred to previously.
Cyclic Sulphonamides and Sulphinamides Also having flavour mod:ifying properties in accordance with this invention are cyclic sulphinamides and sulphonamides of the formula XI:

XI y ~ SOx~R28R~9 where R, y, R28 and R29 are as defined above and x is 1 or 2;
These cyclic sulphonamides and sulphinamides are disclosed in detail in German OLS No. P 23 36 945.6.
The sulphonamides and sulphinamides may readily be prepared by reaction of the corresponding acid chlorides with ammonia or with the appropriate mono or disubstituted amine.
Preferred sulphonamides and sulphinamides for use in this invention are p-menthane-3-sulphinamides and sulphonamides of the formula XII

XII ~ x 28 29 ~ . .' .
where x, R28 and R29 are as defined above. Preferably R28 and R29 are each H or Cl-C12 alkyl or hydroxyalkyl, and are such that R28 and R29 together contribute a total of no more than 12 Icarbon atoms.

:
:

-`` 1~55~

Typical cyclic sulphonamides and sulphinamides usable in this invention are listed in Table IV. Others are listed in German OLS P 23 36 495.6 TABLE IV
N-(2'-hydroxyethyl)-p-menthane-3-sulphinamide N-(p-menthane-3-sulphonyl)morpholine N-ethyl-2,5-dimethylcyc:Lohexanesulphonamide N-(2',5'-dimethylcyclohexane sulphonyl)glycine ethyl ester N-n-butyl-2-methylcyclohexanesulphinamide N,N-dimethyl-p-menthane-3-sulphonamide N,N-diethyl-l-methylcyclohexanesulphinamide N-n-butyl-p-menthane-3-sulphinamide -~
p-menthane-3-sulphonamide N-ethyl-2,5-dimethylcyclohexanesulphinamide N-ni-hèxyl-l-methylcyclohexanesulphinamide .:.
N-n-butyl-3-methylcyclohexanesulphonamide Acyclic sulphonamides and sulphinamides Other sulphonamides and sulphinamides useful in this invention are acyclic sulphinamides and sulphonamides of the formula XIII
R~
XIII R2 --- ~ C x 28R29 1~ R2, R3, R28' R29 are as defined above in ---connection with formula VII and x is 1 or 2.
Such compounds are also disclosed in German OLS No. P 23 36 495.6.
Again, the acyclic compounds may be readily prepared from the corresponding acid chloride and ammonia or substituted amine.
- , - .

~5~ Z

Preferred acyclic sulphonamides and sulphinamides for use in this invention are of formula XIII, where Rl, R2 and R3 together provide a total of from 6 - 11 carbon atoms and R28 and R29 have the preferred values indicated hereinabove for the cyclic sulphonamides and sulphinamides.
Typical acyclic sulphonamides and sulphinamides of formula XIII are listed in Table V.
TABLE V
N,N-diethyl-3-methylpent-3-ylsulphinamide N-n-octylpent-3-ylsulphinamide N-~2'-hydroxyethyl)-N-methyl-2,8-dimethylnon-5- .
ylsulphinamide N-n-hexyl-3-methylpent-3-ylsulphinamide N,N-diisopropyl-2-methylpent-4-ylsulphinamide N-isopropyl-hex-3-ylsulphinamide N,N~diethyl-3-methylpent-3-ylsulphonamide N-(2-methylhept-4-ylsulphinyl)piperidine N-n-hexyl-2-methylpent-3-ylsulphonamide N,N-dimethyl-2-methyloct-3-ylsulphinamide N-(2-methyloct-3-yl)sulphinylmorpholine N-n-octylhex-3-ylsulphonamide Other suitable compounds of formula XIII are listed in German OLS P 23 36 495.6. -Cyclic and acyclic sulphoxides and sulphones Other compounds havin~ flavour modifyin~ properties in accordance with this invention are cyclic sulphoxides and sulphones of the formula XIV:
XIV ~ -Y V--SxRl O
where R,x,y and Rlo are as defined above; and ~SS7~Z
, aoyolio Dulphoxid~s and sulphonea of the formula XVs Rl ~ ' ,. .
R2 C----SOyR10 ~ here ~ , R2, R3 are as defined above in conneotion with fD~mNl~ VII, . and ~ 0 and x are as defined in conneotion with for~ula I.

~he oyolio and aoyolio oompounda of ~o~mulae XIY ~nd XV having ~ , .
physio10gical oooling aotivity and useful as flavour modifiers in thi~
invention are described in detail in Ge~man ~LS ~o. P 23 34 985.1.
,.They may be prepared by the oxida~io~ of the oorresponding sulph~de.
. ^ ~ .: . .
Preferred oyclio sulphoxidea and ~ulphone~ zre of fo~mNla XIV
where y is 1 or 2, and ~ 0 i~ C iC5 alkyl or hydroxyalkyl~ or aIkyloarboxyalkyl of up to 6 oarbon atoms.

; I .
- I P.raferred aoyclic compounds of formnla XV are those where ~ , and ~ together pro~ide a total of 6-15.carbon atoma and ~ 0 has the ~referred value~ given above for the cyclic sulphoxidea and ~ulphones.

..
Typioal compounds of fo~mDla XIV sre 11sted~in Tablà ~I. -' ..
.
- ~-hexyl 1,2-diethylcyclohexyl sulphone isopropy:L 2,5-dimethylcyc}ohe~yl 3ulphone ~-hexyl :L-isobutylcyclohexyl s~Lphoxide ~-menth-~-yl n but~l sulphoxiae - : (; ., ` p-me~th-3-yl ethylcarboxymethyl ~ulphoxide .
.~ t-butyl 3,3,5-trimethylcyclohexyl sulphone - .
p-menth-3-yl oarboxymeth;yl sulphoxide i .
. .
methyl 2,6-dimethylGyclohexyl ~Jlphone msthJ~1 2,6-dlmethylcyclohexy1 ~iLphoxlde p-menth-3-yl 2-bydro.w ethyl ~ulphoxide - n~bu~yl l~ti~op~ntylayolohex~l ~ulpho~da ; . - " ' :

26.

1~5~77;~

n-hexyl 2-n-butylcyclohexyl sulphoxide p-menth-3-yl methyl sulphone - isopropyl 2-methylcyclohexyl sulphoxide ~ isopropyl 3-methylcyclohexyl sulphoxide methyl 2,5-dimethylcyclohexyl sulphoxide methyl 2,5-dimethylcyclohexyl sulphone n-octyl 2-methylcyclohexyl sulphoxide n-butyl l-isopentylcyclohexyl sulphone Typical acyclic sulphones and sulphoxides of formula XV are listed in Table VII.
TABLE VII
3-methylpent-3-yl l-ethylbutyl sulphoxide 2-methylnon-3-yl n-propyl sulphoxide 3-methylhex-3-yl n-octyl sulphoxide 2,6-dimethylhept-4-yl 2-hydroxyethyl sulphoxide 2,3-dimethylbut-4-yl n-hexyl sulphoxide 3-ethylpent-3-yl n-butyl sulphoxide 2-methylhept-3-yl n-hexyl sulphoxide 2,6-dimethylhept-4-yl sec.butyl sulphoxide 2-methylbut-3-yl sec.butyl sulphoxide 3,4,5-trimethylhex-4-yl n-butyl sulphoxide ~-~
2,3-dimethylbuty-2-yl sec.butyl sulphoxide 3-methylhept-4-yl n-butyl sulphoxide 2-methylhex-3-yl n-butyl sulphoxide 4-n-propylhept-4-yl n-propyl sulphoxide 2,4-dimethylhept-4-yl n-propyl sulphoxide 2,5-dimethyloct-5-yl _-propyl sulphoxide `
3-methylpent-3-yl 2'-ethoxycarbonylethyl sulphoxide 3-methylpent-3-yl 2'-hydroxyethyl sulphoxide hex-3 yl methyl sulphoxide -3-methylhept-5-yl sec.butyl sulphoxide .. :
.

~5577z 3-methylhex-3-yl isopentyl sulphoxide 3-methylhept-4-yl n-butyl sulphone 3-ethylpent-3-yl n-butyl sulphone 3-methylpent-3-yl _-hexyl sulphone 2-methylhex-3-yl n-butyl sulphone ~-2-methylnon-3-yl n-propyl sulphone Other suitable compounds of formulae XIV and XV are listed in German OLS ~ 23 34 985Ol.
Phosphine Oxides The phosphine oxides useful as flavour modifiers in accordance with this invention are of formula II which, it will be noted contains the requirement that at least one of R4, R5 and R6 shall have branching in an ~
or ~ position rela-tive to the phosphorus atom. For the avoidance of doubt, branching in this context is to be taken to include cyclic structures, as well as branched chain acyclic groups, i.e. this condition will be met by compounds in which either of R5 and R6 is cycloalkyl, the carbon atom of R5 or R6, as the case may be, in the alpha position relative to the phosphorus atom being part of the ring and therefore being considered as "branched".
Preferably R4r R5 and R6 are such that any two, when taken together present a total of at least 6 carbon atoms.
Compounds of highest activity and especially preferred `
in accordance with this invention are those where R4 is a straight chain alkyl group of from 4-8 carbon atoms r more especially 5-8 carbon atoms, R5 is a branched chain alkyl group of from 3-5 carbon atoms, and especially isopropyl r sec.-butyl r isobutyl or isopentyl, and R6 is an alkyl group, preferably a branched chain alkyl group, of from 3-6 carbon atoms, preferably 4 or 5 carbon ', .

..

.', , ~, ~355772 atoms, or a cyclopentyl group, R4, R5 and R6 providing a total of from 12-18 carbon atoms.
The phosphine oxides used in this invention may be readily prepared by conventional routes. If two alkyl groups are the same, then dialkylphosphinyl chlorides, R2P0Cl, may be prepared by the action of thionyl chloride on tetraalkyldiphosphine disulphides, or preferably by the action of chlorine on secondary phosphine oxides ~repared from Grignard reagents and diethyl phosphite).
These dialkylphosphinyl chlorides will react with Gri~nard reagents to form the desired tertiary phosphine oxides.
If all three alkyl groups of a tertiary phosphine oxide are different then the following route is satisfactory.
Reaction between a Grignard reagent, RMgX, and diethyl chlorphosphite gives ethyl alkyl-phosphinite. This latter compound, when allowed to react with a Grignard reagent, R'MgX, will give the unsymmetrical secondary phosphine oxide, RR'P(O~H. Tertiary phosphine oxides can be prepared from these secondary phosphin~ oxides as described previously.
Representative phosphine oxides of formula II
which may be used in the present invention are listed in Tab~e VIII. Others are listed in German OI,S P 23 45 156.1.
TABLE VIII
t-butyl n-hexyl isopentyl phosphine oxide diisobutyl n-hexyl~phosphine oxide n-hexyl cyclopentyl isopropyl pnosphine oxide isobutyl sec.-butyl n-heptyl phosphine oxide sec.butyl isopropyl n-heptyl phosphine oxide n-hexyl diisopentyl phosphine oxide n-butyl n-heptyl l-methylbutyl phosphine oxide n-pentyl dicyclopentyl phosphine oxide diisobutyl n-nonyl phosphine oxide p-menth-3-yl di-n-propyl phosphine oxide sec.butyl isopropyl n-octyl phosphine oxide diisobutyl l-methyl-n-heptyl'phosphine oxide n-butyl isopropyl 2-ethyl-n-hexyl phosphine oxide ; :
di-n-butyl.cycloheptyl phosphine oxide tri-(2-methylbutyl~) phosphine oxide triisopentyl phosphine oxide n-heptyl isopropyl isopentyl phosphine oxide.
Acyclic secondary and tertlary _lcohols Where X is OH in formula I, a preferred group of flavour modifiers is represented by acyclic secondary and tertiary alcohols of the formula XVI:

,Rlll where Rlll is H or Cl-C5 alkyl;
R112 and R113 are each C2-C5 alkyl, with the provisos that ij when Rlll is H at least one R112 and .
R113 is a branched chain group, and ii) Rlll, R112 and R113 together provide a total of from 7-12 carbon atoms.
Secondary and tertiary alcohols of formula XVI
having physiological cooling a¢tivity and useful in this invention as flavour modifiers are disclosed in detail in German OLS P 23 16 999.5.
Prefexred acyclic alcohols are secondary alcohols : ~ -w ere Rlll is H, R112 and RI13 together contribute from 7-3 30 - carbon atoms and at least one of R112 and R113 has ' .
-30~
,. . .

S77;~:
branching in an alpha or beta position rela~ive to the carbon atom to which is attached the OH group, and tertiary alcohols where Rlll is Cl-C5 alkyl, Rlll, R112 and R113 together provide from 9-12 carbon atoms and at f R112 and R113 has branching in an alpha or beta position relative to the carbon atom to which is attached the OH group.
The acyclic a~cohols of formula XVI can readily be prepared by conventional methods such as by reduction of the corresponding ketone.
Typical alcohols of formula XVI are listed in Table IX.
TABLE IX
3-ethyl-4-methyl-3-hexanol 2-methyl-3-isopropyl-3-hexanol`
4-1 propyl-4-heptanol 2,4-dimethyl-3-ethyl-3-pentanol 2-methyl-3-n-propyl-3-hexanol 2,4-dimethyl-4-heptanol 2,5-dimethyl-3-hexanol 3-ethyl-4-methyl-3-hexanol 3,3,4,5-tetramethyl-4-heptanol 2,2,4-trimethyl-4-heptanol 2,6-dimethyl-4-heptanol 2-methyl-4-heptanol 2,4-dimethyl-3-hexanol -2-methyl-3-isopropyl-3-pentanol 2,5-dimethyl-3-isopropyl-3-pentanol 2,4-dimethyl-3-ethyl-3-hexanol 2,5-dimethyl-3-isopropyl-3-hexanol 4-ethyl-2-methyl-4-octànol , ~SS7~2 3-methyl-4-heptanol 2-methyl-5-heptanol 2,2,3-trimethyl-3-hexanol 3,4,5-trimethyl-4-heptanol Other acyclic alcohols suitable for use in this invention are listed in OLS 23 16 999.5.
Cyclic Alcohols Another group of preferred compounds useful in accordance with this invention are cyclic alcohols of the formula XVII:

~ .
(CH2)p ~ OH

where p is 0 or an integer of from 1--5 inclusive and R and y are as above defined, it being provided that the values of p, R and y are such that the compound contains from 10-14 carbon atoms and that when p is 1 and y is 2 and one of the two R groups is an isopropyl group in a 2-position in the ring relative to the OH group and the other R group is methyl, then said methyl group is in a 1, 2, 3, 4 or 6 position in the ring relative to the OH group;
Cyclic alcohols of formula XVII having physiolog~
ical cooling activity and useful as flavour modifiers in this invention are disclosed in German OLS P 23 17000.5, P 22 03 947.0 and P 24 58 562.4.
Preferred cyclic alcohols are those having alkyl substituents in a 1-, or 2-position in the ring, -and especially a secondary group such as isopropyl or sec.butyl. Preferably p has a value of 1, 2 or 3.
Examples of suitable cyclic alcohols for use in this invention are listed in Table X.

-32- ~

.

~ [35~77;~

TAsLE X
2,5-dilsopropylcyclohexanol 2-t-butylcyclohexanol 2-ethyl-1-1sopropylcyclohexanol l-lsopentylcyclohexanol l-sec.butyl-2-methylcyclohexanol l-ethyl-2,6-dimethylcyclohexanol 1,5-dimethyl-2-isopropylcyclohexanol (3-methyl menthol) 1-ethyl-5-methyl-2-1sopropylcyclohexanol ~3-ethyl menthol) l-n-propyl-2-methylcyclohexanol 1,2-diethylcyclohexanol l-methyl-2-isopropylcyclohexanol l-n-butylcyclohexanol 2-n-propylcyclohexanol :
2-isobutyl-5-methylcyclohexanol l-n-propyl-3-methylcyclohexanol ~ -l-lsopropylcycloheptanol -: :
2-ethylcyclooctanol l-ethyl-3-methylcycloheptanol l-methyl-2-isopropylcyclooctanol : :
2-sec.butylcyclopentanol l-isopentylcycloheptanol ;
2-n-propylcycloheptanol 1,2-diethylcyclooctanol ~
2,6,6-trimethylcycloheptanol ~ :
1,2,6,6-tetramethylcycloheptanol l-ethylcyclodecanol 2,4,4-trimethylcyclopentanol l-sec.butyl cycloheptanol .

~SS'7~2 1-(2'-ethylbutyl)cycloheptanol 2-1sopropylcyclooctanol 3,3,5,5-tetramethylcyclohexanol Methylol Compounds -Methylol compounds (alternatively called substituted methanols) having physiological cooling activity and useful as flavour modifiers in this invention are disclosed in German OLS Nos. P 22 03 947.0 and P 24 39 770.4 to which reference should be made. They may readily be prepared, for example, by reduction of the corresponding carboxylic acid or ester.
Preferred methylol compounds for use in this invention are o~ the formula XVIII:

XVIII Rll C-- - CH2OH

where R114 is H or Cl-C6 alkyl;
R115 and R116, taken separately, each represent Cl-C6 alkyl, and, when taken together~ represent alkylene optionally containing a hydroxy substituent;
R114, R115 and R116 together providing a total of from 6-14 carbon atoms.
Preferred compounds of formula XVIII for use in this invention are those where R114, R115 116 each alkyl, especially with at least one of them having a -secondary or tertiary structure, and those where R114 is alkyl and R115 and R116 are joined together to form an alkylene group.
Suitable methylol compounds for use in this inven-i -tion are listed in Table XI.
.

1055~7~

TAsLE XI
p-menth-3-yl methanol (3-hydroxymethyl p-menthane) 2,4-dimethylpent-3-yl methanol 3-ethyl-2-methylpent-3-yl methanol 3-ethyl-2,4-dimethylpent-3-yl methanol tl- _ propylcyclohexyl) methanol (l-isopropyl-2-methylcyclopentyl)methanol (2-hydroxy-p-menth-3-yl~ methanol (3-hydroxy-p-menth-2-yl) methanol (alternatively: 2-hydroxymethylmenthol) 2,4,6-trimethylhept-4-yl methanol 2-sec.butyl-3-methylpent-2-yl methanol (l-sec.butylcycloheptyl) methanol (2,2,6-trimethylcyclohexyl) methanol :
n-hept-3-yl methanol 3,4,5-trimethylhept-4-yl methanol (l-lsopropylcycloheptyl) methanol (2,2,6~trimethylcyclohexyl) methanol (l-n-butyl-2,3-diethylcyclohexyl) methanol Substituted Ureas : - .
Within formula III, three types of compound are identifiable, namely the substituted ureas where Y is R15R16NCO, substltuted amides where Y is R13CO, and -substituted sulphonamides where Y is R14SO2. Of these three, particularly effective as flavour modifiers are substituted ureas of the formula XIX:

XIX 117 ~ / 119 N - ~ C ~ ~ N
R118 ~

;577Z
where R1~7 when taken separately is H, Cl-C6 alkyl or C3-C6 cycloalkyl;
R118 when taken separately is C3-C10 alkyl or C3-C10 alkylcycloalkyl, cycloalky}., or cycloalkylalkyl, with the proviso that R118 is branched at an alpha or beta carbon atom relative to the N atom, this condition to be satisfied, in the case of cyclic groups, when the carbon atom alpha or beta to the N atom is part of the cycle;
R117 and R118, when taken together, represent a branched chain alkylene group having 3-7 carbon atoms and branching at an alpha or beta carbon atom relative to the N atom, and the chain optionally containing an ether (-0-) oxygen atom;
R117 and R118 when separate groups and when taken together provide a total of at least 5 carbon atoms;~ :
Rllg and R120 when taken separately are each H, ~
Cl-C6 alkyl, C3-C6 alkylcycloalkyl, cycloalkyl, or cycloalkyl~ : :
alkyl, Cl-C10 hydroxyalkyl~ C2-C10 carbox~alky1 or C3-C10 alkylcarboxyalkyl; or together represent a straight or branched chain C3-C10 alkylene group optionally substituted with oxygen or an oxygen-containing group and/or containing an ether oxygen atom; and R117, Rll~, Rllg and R120 together provide a total of from 6-15 carbon atoms;
- Typical substituted ureas of formula XIX useful in this invention are listed in Table XII:
TABLE XII
N,N-di-sec. butyl-n'-ethylurea-N-cyclohexyl-N-isopropyl-N'N'-dimethylurea N,N-diisobutyl--N',N'-dimethylurea~
N,N-(1,5-dimethylpentamethylene)-N'-ethylurea :~L0557~2 ethyl-N-(N',N'-disec.butylaminocarbonyl) glycinate N,N-di-sec.butyl-N'-(2-hydroxyethyl)urea N,N-heptamethylene-N'-isopropylurea N-sec.butyl-N-(cyclohexylmethyl)-N'-ethylurea N-cyclopentyl-N-sec.pentyl-N'-N-propylurea Amides Also within formula III are amides of the formula XX NCOR

where R117 and R118 are as defined above; and R121 is H, Cl-C6 alkyl or alkenyl, C3-C6 cycloalkyl, Cl-C10 hydroxyalkyl, C2-C10 carboxyalkyl, or C3-C10 alkylcarboxyalkyl, phenyl or phenyl containing Cl-C4 alkyL, alkoxy, OH, COOH or NO2 substituents, with the proviso that when R121 is C6 ~lkyl it is primary in structure. -The acyclic amides of formula XX useful as flavour modifiers in this invention differ from those of formula~
VII. Whereas the amides of formula VII are amides of secondary and tertiàry alkanoic acids containing from

7-20 carbon atoms, the amides of formula XX include amides of straight chaln alkanoic acids containing up to 7 carbon atoms, amides o~ branched chain alkanoic acids containing up to 6 carbon atoms and amides of cycloalkanoic acids and subs~ituted alkanoic acids none of which are covered by formula VII. The amides of formula XX may, however, gen- -erally be prepared by the same methods as those of formu~à VII.
Typical amides of formula XX useful in this in~ention are listed in Table XIII.

I

5~77~

TABLE XIII
N-sec.butyl-N-cycloheptylpropionamide N,N-di.sec-butyl-3-methylbut-2-enamide N-(diisopropylmethyl)-2-methylpropionamide N,N-di-sec.butylacetamicie N-cyclohexyl-N-isopropylbutanamide N-(2,4,4-trimethylpent-2-yl)pentanamide N-propionyl-2,6-dimethylpiperidine N-acetyl-4-methyl-7-isopropylhexahydroazepin lQ N,N-(1',5'-dimethylpentamethylene)propionamide ' :' ~5~'77~
isopropyl-N~n-pentylpropionamide N-(l,1,3 9 3-tetramethylbutyl)~ormamide j ~-(diisopropylmethyl)cyclopropane carboxamid~
i ~-sec.butyl-~-cyclopro~ylmethylpropionamide N,N(1,5-dimethylpentamethylene)cyclobutane carboxamide N-isopropyl-I~-isobutylcyclope:nta~ecarboxamide ~ disec.butylcyclohe2aneca~bo2amide N-isopropyl-N-(cycloheptylmethyl)propionamide ~-t.octylcyclohe~anecarboxamide N-isobutyl-~ 1,2-dimeth~lprop~l)-p-nitrobe~zamide ~,N-diisopropylbenzamide -di.sec.butyl-p-methoxybenzamide ¦ Sulphonamides j ~lso within formNla III are sulphonam~des of the formula XXI:

'~ /~S2~122 ` ~

whero ~17 and ~ 18 are a~ above de$ined; and -~
22 is Cl-C6 alkyl or C3-C~ cyoloaIkyl, with the pi~viso that when ~ 22 i9 C5 or C6 alkyl it is primary in structure;

- - ~he sulphonamides of formula XXI differ-~rom those Of formul~a -~III in the ~ame~way~as the amides of formNla XX di~$er from the amides -of fon~-a VII. In other wôrds~ the ~ulphonamides of formula XIII are derivatives of second æy and tertiary alka~e Fulphonic acids ha~ing from 6-19 carbon atom~, whilst those of formula X~I ~re derivatives of primary alkane sulphonic acids and branched chain suiphonic acids of up to 5 carbon atom~3 and al80 of cyoloalkane sulphonic acids. ~he ~ulphonamides of formula XXI may readily be prepared from the co~re~pondl~g acid ohloride , --,, ~ ~ 3~- ~

Typicai sulphonamides of formula XXI are listed in Table XIV.
TABLE XIV
- N,N-di-sec.butylmethane sulphonamide N,N-diisopropylethanesulphonamide N,Ntl,5-dimethylpentanemethylene)ethane sulphonamide N-isopropyl-N-cyclohexylethanesulphonamide N-(1,1,3-trimethylbutyl)ethane sulphonamide N-isopropyl-N-isobutyl-n-propanesulphonamide p-Menthane diols When, in Formula I, X is OH or CH2OH, then R2 and R3 may jointly represent an alkylene group carrying an `-OH substituent. Where this is the case a preferred group of flavour modifiers in accordance with this invention is represented by p-menthane diols of the formula XXII:

XXII

where X is OH, it being provided that the two OH substituents are on different carbon atoms and at`least one is in the ; -2-or 3-position. `
p-Menthane diols of formula XXII having physiological cooling activity are disclosed in German OLS P 22 03 273.1, to which reference should be made.

. . , -39- ~

~5S77~
Typlcal p-menthane diols useful in this invention as flavour modifiers are :
2,3-p-menthane diol - 2,6-p-menthane diol 2,5-p-menthane diol 3,5-p-menthane diol 3,9-p-menthane diol Acyclic Carboxylic Acids, Salts and Esters A last group of compounds having flavour modifying activity is represented by the formula XXIII

Rl .:
XXIII 2 C*.

where Rl is H or Cl-C6 alkyl, preferably H or Cl-C5 alkyl;
R2 and R3 are each Cl-C6 alkyl, preferably Cl-C5 .
alkyl;
Rl, R2, R3 together providing a total of from 6-18 carbon atoms, and R7 is as defined above, both with respect to i~s broad :~
and preferred meanings.
Preferred acyclic acids where at least one of ~ :
Rl, R2 and R3 is a branched chain alkyl group, preferably -: -having branching in an alpha or beta position relative to :
: the carbon atom marked 1*)-Typical acids and esters according to formula XXIII are listed in Table XV. They may be prepared by methods readily available in the art, for example, by -. .
carbonation of the corresponding Grignard reagent~
, .

~ .

~55772 TAsLE XV
3-hydroxypropyl 3-methyl-2-isopropylpentanoate 2'-hydroxyethyl 2,2-diethylbutanoate 2-ethyl-3-methylpentanoic acid 2'-hydroxyethyl 2-isopropyl-3-methylbutanoate 2'-hydroxyethyl 2-ethyl-2-isopropyl-3-methyl butanoate 2-ethyl-2-methylbutanoic acid 3-methyl-2-isopropyl pentanoic acid 2-ethyl-2-isopropyl butanoic acid 2-sec-butyl-2,3-dimethyl-pentanoic acid -3-methyl-2-isopropyl-butanoic acid 2-sec-bu-tyl-3-methyl-pentanoic acid 2-iso-butyl-4-methyl-pentanoic acid The use of -the compounds in accordance with this invention as flavour modifiers is illustrated by the follow-inq Examples. The Examples give the results reported by panels of tas-ters, who in each test tasted a comparative control substance, and a substance similar to the control except in that it contained a flavour modifier according to this invention, in the concentration stated. Aqueous solutions of the flavour modifier in the concentrations used in these Examples had no flavour.
EXAMPLE 1 `
Into separate samples of an infusion of ground coffee were added 1 ppm each of N (p-methoxyphenyl)-p-menthane-3-carboxamide (sample A), and N-(l,l-dimethyl-2-hydroxyethyl)-p-menthane-3-carboxamide (sample B).
Both samples were tasted and compared with a~
control. The taste reports were~as follows:

.
.

: ~' ..., ~

~ ~55~7Z

Sample A Sample B
Less burnt Less bitter Less bitter Less burnt More blended Less sour Less drying 1 ppm. of N-(p-methoxyphenyl)-p-menthane-3-carboxamide was added to an infusion of instant coffee~
powder and compared for taste with a control infusion.
The test samplé showed an increased blend, an incr'eased coffee flavour and decreased bitterness.

N-(l',l'-dimethyl-2'-hydroxyethyl)-p-menthane-3-carboxamide was added to milk at room temperature in an amount of 4 ppm. Compared with a control the treated sample showed, in flavour testing, decreased waxiness and sourness, an increase in flavour amplitude and an increased creaminess.

N-(p-methoxyphenyl)-p-menthane-3-carboxamide (1 ppm) was a`dded to an infusion of instant tea with sugar and lemon and compared with a control infusion. The treated sample showed an increased sweetness, a better blend and sharper lemon flavour.

2-Hydroxyethyl p-menthane-3-carboxylate was added to a proprietary chewing gum in an amount of 16 ppm. Compared with a control, the treated sample showed an increased sweet-- ness and mintiness. Similar results were obtained with the same quantity of N-(l',l'-dimethyl-2'-hydroxyethyl)-p-menthane carboxamide.

- ' '. ' 1~5~i~72 4 ppm of N-(l',l'-dimethyl-2'-hydroxyethyl)-p-- menthane-3-carboxamide were added to a proprietary chocolate milk pudding. Compared with a control sample the treated sample showed a significant increase in chocolate flavour and increased sweetness together with reduced sourness and bitterness and a less milky caseinate flavour.

A powdered drinking chocolate composition was prepared using low fat cocoa and non-fat milk solids. To the dry powder was added a mixture of N-(l',l'-dimethyl-2'-hydroxyethyl)-p-menthane-3-carboxamide and 2-hydroxethyl p-menthane-3-carboxylate. The dry powder was mixed with water to obtain a chocolate beverage containing 3 ppm of the former compound, and 1 ppm of the latter. Compared with a control, the test sample showed an increased resinous chocolate identity with less perception of the dry-milk solids and a less chalky drying mouthfeel.

4 ppm. of 2-hydroxyethyl p-menthane-3-carboxylate were added to a coating chocolate low in chocolate liquor.
The resultant product showed an increased resinous chocolate identity, a creamy mouthfeel and a total flavour comparable with that obtained with a high chocolate liquor.

3 ppm. of N-(l',l'-dimethyl-2'-hydroxyethyl)-p-menthane-3-carboxamide and 1 ppm. of 2-hydroxyethyl p-menthane-3-carboxylate were added to a proprietary packaged vanilla pudding. Compared with a control the ~
treated pudding was fuller and more blended, sweeter, -more custardy and less starchy.

, ~C~557'7Z
.'.

An aqueous white taste medium, i.e. containin~
all four basic tastes, viz.: sweet, sour, bitter and salt, - was made up as follows:
sodium chloride 0.928 gms.
Sucrose 6.800 gms.
Citric acid (anhydrous) 0.252 gms.
Caffeine (anhydrous) 0.112 gms.
Water q.s. 1000 ml.
1 ppm. of various compounds was added to samples of the taste medium and the change in flavour assessed against a control. The following flavour changes were -noted.
Compound Change/Flavour p-menthane-3-carboxylic acid Increased sweetness, delayed sourness. -N-ethyl-p-menthane-3-carboxamide Increased sweetness.
2-Hydroxyethyl p-menthane-3- Increased sweetness carboxylate decreased sourness.
N-(p-menth-3-oyl) glycine ethyl Increased sweetness ester increased bitterness N-(l',l'-dimethyl-2'-hydroxyethyl) Increased saltiness -p-menthane-3-carboxamide and bite N-t-butyl-p-menthane-3-carboxamide Increased saltiness and bitterness N-(p-menth-3-oyl) glycine n-propyl Increased sourness ester and bitterness N,2,3-trimethyl--2-isopropylbutana- Increased sweetness mide sour aftertaste ~-ethyl-2,3-dimethyl-2-isopropyl- Sour aftertaste and butanamide tannin mouthfeel.
N-ethyl-l isopropylcyclohexane- Increased sourness -carboxamide and saltiness -N-isopropyl-p-menthane-3-carboxamide Suppression and late flavour .

:

1al55~2 Compound Change/Flavour N-(p-Menth-3-oyl)morpholine Increased sweetness N-(p-Menthane-3-sulphonyl~morpholine More blended, increased amplitude, yeasty flavour - N-ethyl-p-menthane-3-carboxamide Increased saltiness (dl-axial) and bitterness Isopropyl-2,5-dimethylcyclohexyl Increased sweetness sulphone n-hexyl cyclopen-tyl isopropyl Decreased bitterness phosphine oxide increased fruitiness Isobutyl sec. butyl n-heptyl Sweet aftertaste phosphine oxide N,N,2-triethyl-3-methylpentanamide Oily or butterlike flavour N(l'-l'-dimethyl-21-hydroxyethyl)-l, Metallic flavour 2-diethyl cyclohexanecarboxamide Sec. butyl isopropyl n-heptyl Lingering fruitiness phosphine oxide N,N-diethyl 3-methylpent-3-yl sul- Fruitiness phinamide N-(4-Hydroxy-3-methoxyphenyl)-p- Lingering bitter menthane-3-carboxamide N-(2~-acetoxy-1',1'-dimethylethyl)- Sour aftertaste p-menthane 3-carboxamide N,N-diethyl-p-menthane-3-carboxamide Decreased sour, peppery N-cyclohexyl-p-menthane-3-carboxamide Increased sour, salty N-n-Decyl-p-menthane-3-carboxamide Increased sweet, salty, sour aftertaste N,l-diisopropyl-2-methyl-cyclo- Increased sour pentanecarboxamide ~-N-(l-ethyl-2-methylcycloheptane- Increased salty, carbonyl)-glycine ethyl ester Tannin Mouthfeel N-(tert-butyl)-2-isopropylcyclo- Increased sour.
heptane carboxamide Sour aftertaste ~-Triisopentylphosphine oxide Increased sweet (syrupy). Tannin mouthfeel Isobutyl-n-heptylcyclopentyl- Lingering sour ; phosphine oxide ~ -S~'72 Compound Chan~e/Flavour Isobutyl-sec-butyl-n-pentylphosphine Increased sour, sal-ty oxide n-Heptylcyclopentyl-isopropylphos- Increased sweet, tannin phine oxlde mouthfeel N-(3,4-dimethoxyphenyl)-p-menthane-3- Increased sweet (syrupy~
carboxamide N-(3,4-dimethylphenyl)-p-menthane-3- Increased sweet, sour, carboxamide salty. Saline mouthfeel N-(4-methylphenyl)-p-menthane-3- Increased sour, carboxamide astringent N-(3-hydroxy-4-methylphenyl)-p- Increased sour (sharp) ~
menthane 3-carboxamide N-(p-menthane-3-carbonyl)-glutamic Increased bitter acid diethyl ester 2-(2'-hydroxyethoxy)et~yl p-menthane Increased sweet, bitter -3-carboxylate 3-Hydroxypropyl p-menthane-3-carboxy- Increased salty, late astringent p-Menth-3-yldi-n-propylphosphine Increased bitter oxide Diisobutyl-n-nonylphosphine oxide Increased salty.
Saline mouthfeel Diisobutyl-n-heptylphosphine oxide Increased bitter, astringent An infusion of instant coffee was prepared using a commercially available brand of instant coffee powder.
Separate`portions of the infusion were sweetened'with saccharin and to one sweetened portion was added 1 part per million of N-(l',l'-dimethyl-2'-hydroxyethyl)-p-menthane-3-carboxamide. When tasted, this latter portion tasted pleasantly sweet and without any bitter after-taste.
The control sample possessed the bitter after taste commonly associated with saccharin when used as an artificial sweetener.

- . - ~ - .. - .. . ,, .. ~, ... , ~.... , - . .. . . ..

~5~77Z

An aqueous sucrose solution was prepared as a standard "sweet" solution. To separate samples of the solution were added increasing quantities of various compounds and the minimum amount of compound required to produce a perceptible increase in sweetness was noted.
The results were as follows:
Compound Amount ~./ml.
t-butyl-n-hexyl isopentyl phosphine oxide diisobutyl-n-hexyl phosphine oxide isopropyl-n-hexyl-cyclopentyl phosphine oxide 8 isobutyl-sec-butyl-n-hexyl phosphine oxide 0.5 . _ A O.OlM aqueous sucrose solution was prepared and tasted and it was found that at this concentration the sweetness was imperceptible. Addition of the following compounds in the amounts stated to separate samples of the sucrose solution produced solutions having a quite perceptible sweet taste:
Compound Amount ~g/ml.

2~-hydroxyethyl 2-isopropyl-3-methyl 2 butanoate 2'-hydroxyethyl 2-ethyl-2-isopropyl-3- 3 methyl butanoate 2-ethyl-2-methyl butanoic acid 5 Aqueous solutions of the three compounds in the concentrations stated had no taste.

The flavour-modifying effect of each of a number of compounds was estimated by comparison of the flavour of a so-called white taste medium, i.e. one containing -substances having all four basic flavours, sweet, sour, . , .

~S~

bitter and salt, with a similar medium containing the compound at a concentration of 1 ppm.
The white taste medium had the following compositions:
Sodium chloride 0.928 g Sucrose 6.800 g Citric acid (anhydrous) 0.252 g Caffein (anhydrous) 0.112 g Water q.s. 1,000 ml.
Modified flavours due to the following compounds were compared with the control by the tasters as follows:
Compound Tests Effect reported . . . _ 2-methyl-3-1sopropyl-3-hexanol Increased sweet and salt taste 2,4-dimethyl-3-ethyl-3-hexanol Increased sweet taste 2,5-dimethyl-3-1 propyl-3- Increased bitter and salt ~ . .
hexanol tastes : -2-methyl-3- _ propyl-3-decanol Increased sour taste 3-ethyl-menthol Syrupy after-taste A test similar to that reported in Example 14 was carried out, except that a basic taste medium contain- .
ing 1.5 x 10 3M citric acid and 2 x 10 5M saccharin (sodium ~:
salt) in aqueous solution was employed in p~ace of the white taste medium, and the following compounds were tested at a level of 1 ppm, with results as given below :
Compound used Effect reported l-sec-butyl-cycloheptanol Increased in sour flavour l-iso-propyl-cycloheptanol Slight increase in sour flavour ~ :

. 4~- .

~55~77Z

EX~PLE 1~
-A solution of 0.01 M sucrose was compared in flavour with solutions of 0.01 M sucrose each also contain-ing one of the undermentioned compounds at a concentration of 1 ppm. The solutions containing the compounds had modified flavours as follows:
Compound used Effect reported 1-(2-ethylbutyl)-cycloheptanol Enhancement of sweet flavour 4~ethyl-2-methyl-4-octanol Slight enhancement of sweet flavour 0 2-methyl-3-1sopropyl-3-decanol Slight enhancement of sweet flavour 6-ethyl-3-decanol " " " "

l-_-butyl-2,3-dimethylcyclo- " " " "
hexyl methanol "

2,2,6-trimethylcyclohexyl " " " "
methanol "

2-sec-butyl-cyclopentanol " " " "
,, p-menthyl-3-methanol Slight enhancement of sweet flavour and a slight syrupy after-taste.

The effect of each of the following compounds at a concentration of 1 ppm on the flavour of a solution ~
containing 2 x 10 5N saccharin was estimated by comparison - `
of a solution containing the compound with a control saccharin solution. Results were as follows:
Compo_nd tested Effect reported l-methyl-2-isopropylcyclo- Reduction in bitter/
octanol ~ metallic after-taste.

2,2,6-trimethylcyclohexyl Slight enhancement of methanol sweet flavour 2,2-diethyl-3-methylbutanol Slight enhancement of sweet flavour.

`` 1C35577~

Additionally, the compound 2-1sopropylcyclooctanol at a concentration of 1 ppm had a very enhancing effect on the sweet flavour of 4 x 10 5M saccharin solution when tested in a similar way.

l-lsopropyl-2-methyloyc:lopentyl methanol was incorporated at a concentration oE 0.5 ppm into a sample of a carbonated ginger ale. Compared with an untreated sample of the beverage, the sample containing the flavour modifier was judged to have a sharper drier after-taste.
2,5-diisopropyl cyclohexanol gave to a similar beyerage a more blended flavour with a sharper ginger after-taste, when added at a concentration of 0.3 ppm.

~ =
0.5 ppm of each of the compounds mentioned below were added to separate samples of a proprietary carbonated -~
cola beverage, and the flavour of each treated sample .
compared with the untreated beverage. Results were as indicated.
Compound used Effect reported 2-methyl-4-heptanol Cola flavour sharper, more tangy, more blended.

2,4-dimethyl-4-heptanol Slight increase of sweet flavour, more tangy.

1- _ propyl-cycloheptanol Citrus-flavour sharper, more tangy; suppression of "off"
after-taste of untreated beverage; increased sweet aftertaste.

A coating chocolate composition was prepared as a number of samples, each containing one of the compounds listed below at the concentration indicated. The flavour of each sample so treated was compared w;th that of a control sample, with the results indicated:

. -~S5'77;~

. Compound ~sed Concentration(ppm) Effect reported 3,3,5,5-tetramethylcyclo- 0.5 Improved chocolate hexanol and creamy flavour;
reduced fatty taste and texture.
l-isopropyl-2-methylcyclo- 0.5 Slightly improved pentylmethanol fuller chocolate flavour.

2,6-dimethyl-4-heptanol 0.5 Slightly increased chocolate flavourO

2-t-butyl-cyclohexanol 0.25 Slightly smoother increased chocolate flavour.

l-isopropylcyclohexyl methanol was added at a concentration of 0.3 ppm to a proprietary lemon and lime cordial. The flavour of the coxdial so treated was smoother, with an enhanced lime flavour and a sharper citrus after-taste, compared with an untreated cordial.

2,4,4-trimethyl-cyclopentanol was added to a sample of milk, at a concentration of 0.2 ppm. The milk so treated had an extended creamy after-taste, compared --with an untreated control sample.

In a test of the flavour-modifying effect of each of a number of compounds when present in a proprietary ' dairy milk chocolate, samples of the chocolate were treated by incorporation of one of the compounds, at a concentration of 0.5 ppm. Flavour comparison of the treated chocolate with untreated samples gave results as follows:

' S7'72 -~~ Compound used Effect reported 2-ethyl-cyelooctanol Stronger ehocolate flavour;
less eloying milkiness.
2,2,4-trimethyl-4-heptanol Increased choeolate flavour;
smoother less cloying textureO
2~4,4-trimethyl-cyclopentanol Faster impaet of ehoeolate flavour; redueed creamy after-taste.

--51 ~--':. ' ::

~55~72 In a similar test, carried out however with a proprietary plain chocolate, l-ethyl-3-methyl cyeloheptanol at a concentration of 0.5 ppm yave the chocolate an improved, less harsh, more rounded, bitter resiny chocolate after-taste, and 3-hydroxy-p-menth-2-yl methanol at a concentra-tion of 0.5 ppm yave the chocolate a smoother, less bitter chocolate flavour, and a less bitter after-taste.

An infusion of instant tea with sugar and lemon was prepared as several samples, to each of whieh one of the undermentioned compounds was added at a concentration of 0.1 ppm. Flavour comparison of the beverage so treated, and untreated control samples, gave the following results:
Compound used Effeet reported .
6-ethyl-3-decanol Increased sweet syrupy flavour;
earlier impaet of sour flavour;
redueed bitter aftex-taste.

l-sec-butyl cyeloheptanol Earlier impaet of flavour;
slight inerease in tannin flavour; reduced bitter/
metallie after-taste.

2-isopropyl eyclooetanol Reduced sour flavour, redueed bitter/metallic after-taste.

Infusions of a proprietary instant coffee powder were prepared, each containing 0.1 ppm of one of the fol-lowing compounds: 2-sec-butyl-2,3-dimethyl-1-pentanol, and 2,2,6-trimethylcyclohexyl methanol. Compared with ~ -a control infusion, an infusion containing either compound gave a quicker impaet and inereased amplitude and duration -of the coffee Elavour, while the flavour and after-taste were less bitter.
': :
,. ~

:. . .. : .: ':

S~7Z

~ 2-ethyl-1-1sopropylcyclohexanol was added at a - concentr~tion of 0.2 ppm to a commercially available powdered ; drinking chocolate preparation macle up in hot milk. Compared with a beverage made similarly but without the additive according to this invention, the treated beverage had a sweeter, creamier and smoother chocolate flavour.
When l-isopropylcycloheptyl methanol was tested ~ -in a similar way, its effect on the beverage at a concen-tration of 0.1 ppm was to give a creamier flavour with an earlier impact.

. _ . .
A commercially available proprietary chocolate and malt drink was made up in hot milk according to the manufacturer's instructions. 0.4 ppm of one of the compounds mentioned below was added to each of several samples of the beverage, and flavour comparison with untreated control samples gave the following results:
Compound used Effect reported . .
0 1,2,6,6-tetramethylcycloheptanol Increased sweetness, slight reduction in chocolate and malt flavour.
2, 4-dimethylpent-3-yl methanol Increased sweetness, increase in malt flavour, smoother chocolate flavour.

:::
Each of the following compounds was tested in the medium indicated and in the amounts specified. The -flavour modification is noted in the fourth column.
'',''''~

-53- .

~S~72 Compound Test Medium Amoun-t of Effects Compound Add_d (ppm?
N-sec-butyl-N- Instant mashed 0.3 Slightly creamier cycloheptyl potato propionamide N,N-disectbutyl- Salad cream 0.5 Slightly sharper 3-methyl-but 2- taste enamide Chocolate dessert 0.3 Increased cho-colate flavour N-(Diisopropyl- Vanilla pudding 0.1 Slightly increased methyl)-2-methyl- vanilla propionamide Cooking choco- 0.8 Improved bitter late after-taste N,N-Disecbutyl- Lime flavoured 0.5 Improved sharper propionamide jelly lime flavour N-(2,4,4-trimethyl- 2 x 10 M 1.0 increased sweet, pent-2-yl)-propi- saccharin im~roved after-onamide taste N,N-Disecbutyl- 2 x 10 ~1 1.0 Slightly increased acetamide saccharin sweet N-Cyclohexyl-N- Instant lemon 0.3 Increased sharp isopropylbutan- tea citrus taste amide N-(2,4,4-tri- Cooking choco- 0.3 Long lasting methylpent-2-yl)- late after-taste pentanamide .
Bottled lager Q.1 Increased bitter after-taste N-Propionyl-2,6- O.OlM sucrose 1.0 Slight increase dimethyl-piperi- in sweet dine N-~2,2-dimethyl- Strawberry 0.5 - Slight increase propionyl)-2,6- flavoured jelly in flavour :
dimethylpiperidine N-Acetyl-4-methyl-Vanilla pudding 0.2 Increased sweet, 7-isopropyl-hexa- particularly hydroazepin after-taste i; :
.

N,N-Disecbutyl- Instant mashed 2.0 Improved methane-sulphon- potato aftertaste amide N-Cyclohexyl-N- Chocolate 0.5 Sliyhtly increased isopropyl N',N'- drink sweet and choco-dimethylurea late N,N-Diisobutyl-N',O.OlM sucrose 1.0 Slight increased N'-dimethylurea in sweet -54a-~SS77Z
-N-Ethyl-N'-isobu-tyl- Vanilla des~ert 0.1 Slightly in-N'-(2,3-dimethylpropyl) crease sweet urea after-taste The following compounds were added -to the media indicated and the flavour and compared with a control sample.
N-(2,3-dimethyl-2-isopropylbutanoyl)glycine ethyl ester 0.5ppm in instant lemon drink gave slightly increased sweet and increased "peel" character.
N-Ethyl-3,3-dimethyl-2-isopropylbutanamide 0.2ppm in instant orange drink gave à more natural orange flavour.
N-Pentyl-3-methyl-2-isopropylbutanamide 0.5ppm in instant lemon tea gave a much improved overall flavour with increased tea flavour and greater natural lemon character.
3-Hydroxypropyl 3-methyl-2-isopropylpentanoate 0.3ppm in a prcprietary oxtail soup increased meat and herb flavours and decreased salt and vegetable flavours.
2-Hydroxyethyl ?, 2-dl hylbutanoate 0.2ppm in beer gave a prolonged bitter aftertaste with very little effect on main flavour. -2-Ethyl-_-methylpentanoic acid 0.5ppm in instant lemon tea reduced lemon flavour and increased sweet.
N-Secbutyl-N-isobutyl-N'-isopropylurea 0.4ppm in lemon drink slightly increased sour and increased overall lemon flavour.
N-(2,4~Dimethyl-2-isopropylpentanoyl)pyrrolidine -0.4ppm in orange drink gave increased sweet and orange flavour.
N-Isobutyl-N-(2-ethyl-n-propyl)-N'-cyclopropylurea ..__ 0.2ppm in instant lemon tea gave increased tannin flavour. ~

__ . . :
~1) O.lppm of N-(p-methoxyphenyl)-p-menthane-3-carboxamide +
- 0.5ppm of 2-hydroxyethyl p-menthane-3-carboxylate in orange squash gave an increased orange flavour. ~ --~ -55-. - , l~lS577Z

(2) 0.5ppm of N,2,3-trimethyl-2-isopropylbutanamide +
0.5ppm 2~hydroxyethyl p-menthane-3-carboxylate in orange squash gave an improved flavour and an increased sweet aftertaste.
, (3) 5ug of N,2,3-trimethyl-2-isopropylbutanamide in a cigarette gave a stronger tobacco flavour.
(4) 5~1g of N-tert-butyl-p-menthane-3-carboxamide in a cigarette produced a milder, less harsh taste.
(5) 5~g of N,2,3-trimethyl-2-isopropylbutanamide in lg. of pipe tobacco gave a milder flavour.
(6) Sug of 2-hydroxyethyl p-menthane-3-carboxylate in lg.
of pipe tobacco gave a more fragrant smoke - the flavour was less harsh.
0 (~) 2ug of di-sec-butyl-n-heptyl-phosphine oxide in a cigarette produced a slightly milder, improved flavourO

(8) 2~1g of l-isopropyl-cycloheptanol in a cigarette produced a slightly stronger flavour.

(9) 2ug of N,N-di-sec-butyl-acetamide in lg. of pipe tobacco gave a mellower and milder flavour.

(10) 5ug of N,N-di-sec-butyl-acetamide in lg. of pipe tobacco gave an increased flavour.

(11) 51lg of 2,4-dimethyl-3-ethyl-hexan-3-ol in lg. of pipe tobacco gave a molder and improved flavour.
Similar flavour modifying effects may be obtained using any of the compounds hereinbefore described, being compounds capable of stimulating the cold receptors of the nervous system of the human body.

-55a-

Claims (12)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method of modifying the flavour of flavour-containing ingestible preparations, including tobacco, which comprises incorporating into the preparation a compound, being a compound capable of stimulating the cold receptors of the nervous system of the body when brought into contact therewith, but being incorporated into the preparation in an amount below the threshold of practical physiological cooling activity, said compound being a compound of the formula II II or III where, in formula I, R1 is H or C2-C6 alkyl;
R2 and R3, when taken separately, are each alkyl or cycloalkyl of up to 6 carbon atoms, or up to 7 when X is OH or CH2OH;
R2 and R3, when taken together, represent a C4-C11 straight or branched chain alkylene group, it being provided that:

i) when R1 is H then the alkylene group is branched at a carbon atom in a beta or gamma position relative to the group X;
ii) that when X is OH or CH2OH, then said alkylene group may contain an OH substituent; and iii) that when R1 is H and X is OH, then the cyclic group represented by is other than p-menth-3-yl-group;
R1, R2 and R3 together provide a total of from 6-18 carbon atoms;

X is OH, CH2OH-COOR7, CONR8R9, SOXNR8R9 or SOXR10;
R7 is H, an alkali or alkaline earth metal, ammonium, alkyl- or hydroxyalkyl-substituted ammonium, or a hydroxyalkyl, hydroxyalkoxyalkyl, carboxyalkyl or alkoxycarboxylalkyl group of up to 12 carbon atoms;
R8 and R9, when taken separately, are each H or alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl of up to 12 carbon atoms, with the proviso that when R8 is H, R9 may also be cycloalkyl of up to 8 carbon atoms, phenyl or benzyl or substituted phenyl or benzyl containing hydroxy, C1-C4 alkyl or C1-C4 alkoxy substituents; R8 and R9, when taken together represent an alkylene group of up to 12 carbon atoms, the carbon atom chain of which may optionally be interrupted by oxygen or an -NH- group;
R10 is alkyl, hydroxyalkyl, carboxyalkyl or alkoxy-carbonylalkyl of up to 12 carbon atoms: and x is 1 or 2;
and where in formula II
R4 is C3-C20 alkyl;
R5 is C3-C8 alkyl or cycloalkyl;
R6 is C1-C8 alkyl or C3-C8 cycloalkyl or alkyl-cycloalkyl; it being provided that at least one of R4, R5 and R6 is branched at a carbon atom in an .alpha., .beta. or .gamma. position relative to the phosphorus atom, and that R4, R5 and R6 together provide a total of from 10-24 carbon atoms;
and where in formula III
R11 when taken separately, is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R12 when taken separately, is C3-C10 alkyl or C3-C10 alkylcycloalkyl, cycloalkyl, or cycloalkylalkyl, with the proviso that R12 is branched at an .alpha.- or .beta.-carbon atom relative to the N atom, this condition to be satisfied, in the case of cyclic groups, when the carbon atom .alpha.- or .beta.- to the N
atom is part of the cycle;
R11 and R12, when taken together, represent a branched chain alkylene group having 3-7 carbon atoms and branching at an .alpha.- or .beta.- carbon atom relative to the N atom, and the chain optionally containing an ether (-O-) oxygen atom;
R11 and R12 when separate groups and when taken together provide a total of at least 5 carbon atoms;
Y represents R13CO-, R14SO2- or R15R16NCO-;
R13 is H, C1-C6 alkyl or alkenyl, C3-C6 cycloalkyl, C1-C10 hydroxyalkyl, C2-C10 carboxyalkyl, C3-C10 alkoxy-carbonylalkyl, phenyl or phenyl containing C1-C4 alkyl, alkoxy, OH, COOH or NO2 substituents, with the proviso that when R13 is C6 alkyl it is primary in structure;

R14 is C1-C6 alkyl or C3-C6 cycloalkyl, with the proviso that when R14 is C5 or C6 alkyl it is primary in structure;
R15 and R16, when taken separately, are each H, C1-C6 alkyl, C3-C6 alkylcycloalkyl, cycloalkyl, or cycloalkylalkyl, C1-C10 hydroxyalkyl, C2-C10 carboxyalkyl or C3-C10 alkoxy-carbonylalkyl; or together represent a straight or branched chain C3-C10 alkylene group optionally substituted with oxygen or an oxygen-containing group or containing an ether oxygen atom; and R11, R12 and Y provide a total of from 7-16 carbon atoms.

2. A method according to claim 1, wherein said compound, being a compound of formula I, is of the formula where n is 0 or an integer of from 1 - 6 inclusive;
R is C1-C5 alkyl;
y is an integer of from 1-4 inclusive, with the proviso that at least one R group is in a 1-, 2- or 3-position in the ring;
R28, when taken separately, is hydrogen, or an alkyl or hydroxyalkyl group of up to 12 carbon atoms;

R29, when taken separately, is hydrogen, an alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl group of up to 12 carbon atoms; with the proviso that when R28 is H, R29 may also be cycloalkyl of up to 8 carbon atoms, phenyl, benzyl or phenyl or benzyl containing hydroxy, C1-C4 alkyl or C1-C4 alkoxy substituents and a maximum of 12 carbon atoms; and R28 and R29, when taken together represent an alkylene group of up to 12 carbon atoms optionally containing an oxygen hetero atom.

3. A method according to claim 1, wherein said compound, being a compound of formula I, is of the formula where R28 and R29 are as defined in claim 2.

4. A method according to claim 1, wherein said compound, being a compound of formula I, is of the formula where m is 2 or 3, at least one of R23 and R24 is C1-C5 alkyl and the other is H or C1-C5 alkyl, and R28 and R29 are as defined in claim 2.

5. A method according to claim 1, wherein said compound, being a compound of formula I, is of the formula where R1 is H or C1-C5 alkyl;
R2 and R3 are each C1-C5 alkyl;
R1, R2 and R3 together provide a total of from 5-15 carbon atoms; and R28 and R29 are as defined in claim 2.

6. A method according to claim 1, wherein said compound, being a compound of formula I, is of the formula where n, y and R are as defined in claim 2; and R7 is H, an alkali metal or an alkaline earth metal atom, an ammonium or alkyl- or hydroxyalkylammonium radical, or a hydroxyalkyl, hydroxyalkoxyalkyl, carboxyalkyl, or alkoxycarbonylalkyl group of up to 12 carbon atoms.

7. A method according to claim 1, wherein said compound, being a compound of formula I, is of the formula where R7 is H or C2-C5 hydroxyalkyl, m is 2 or 3 and at least one of R23 and R24 is C1-5 alkyl and the other is H or C1-5 alkyl.

8. A method according to claim 1, wherein said compound is of formula II where R4 is C4-C8 straight chain alkyl;
R5 is C3-C5 branched chain alkyl; and R6 is C3-C6 alkyl or cyclopentyl; it being provided that R4, R5 and R6 together provide a total of 12-18 carbon atoms, and that at least one of R5 and R6 is branched at a carbon atom in an alpha, beta or gamma position relative to the phosphorus atom.

9. A method according to claim 1, wherein said compound, being a compound of formula III, is of the formula where R117 when taken separately is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R118, when taken separately, is C3-C10 alkyl or C3-C10 alkylcycloalkyl, cycloalkyl, or cycloalkylalkyl, with the proviso that R118 is branched at an alpha or beta carbon atom relative to the N atom, this condition to be satisfied, in the case of cyclic groups, when the carbon atom alpha or beta to the N atom is part of the cycle;
R117 and R118, when taken together, represent a branched chain alkylene group having 3-7 carbon atoms and branching at an alpha or beta carbon atom relative to the N
atom, and the chain optionally containing an ether (-O-) oxygen atom;
R117 and R118 when separate groups and when taken together provide a total of at least 5 carbon atoms;
R119 and R120 when taken separately are each H, C1-C6 alkyl, C3-C6 alkylcycloalkyl, carboxyalkyl, or C3-C10 alkoxycarbonylalkyl; or together represent a straight or branched chain C3-C10 alkylene group optionally substituted with oxygen or an oxygen-containing group or containing an ether oxygen atom; and R117, R118, R119 and R120 together provide a total from 6-15 carbon atoms.

10. A method according to claim 1, wherein said compound, being a compound of formula III, is of the formula where R117 and R118 are as defined in claim 9; and R121 is H, C1-C6 alkyl or alkenyl, C3-C6 cycloalkyl, C1-C10 hydroxyalkyl, C2-C10 carboxyalkyl, or C3-C10 alkoxy-carbonylalkyl, phenyl or phenyl containing C1-C4 alkyl, alkoxy, OH, COOH or NO2 substituents, with the proviso that when R121 is C6 alkyl it is primary in structure.

11. A method according to claim 1, wherein the flavour modifier is added in an amount of from 0.1 to 100 ppm. based on the total preparation.

12. A method according to claim 11, wherein said amount is from 0.1 to 10 ppm.