CA1054441A - Flavour modification - Google Patents

Abstract

Abstract The flavour of flavour-containing ingestible prepara-tions and tobacco is modified by incorporating therein a trace amount of a bicyclic compound selected from [3.1.1]
bicycloheptanes and heptenes, [2.2.1] bicycloheptances and heptenes and [2.2.2] bicyclooctanes and octenes having at least one alkyl substituent in the ring system and a hydrophilic substituent selected from methylol, acid, ester, amide and substituted amide, substituted at a 2-position in the ring.

1.

Description

- ~OS~i44~
Field o~ Invention This invention relates to compounds having the - property of altering the response of the taste receptors of the nervous system to taste sti~uli, thereby to modify the perceived flavour o~ flavoured compositions.

Back~round of the Invention and Prior Art - . . .
Menthol is well known ~or 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 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.
'' It is well established that the 'cooling' effect of ` menthol is a physiological effect due to the direct action of menthol on the nerve endîngs of the human body responsible 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 physio-logical coo:Lantitfiuse, in some compositions, is circum- -scribed by its strong minty odour and its relative

2.

~L05~4~
volatility.

:
A few other compounds have been reported in the technical literature as having an odour or flavour similar to menthol and from time to time have been proposëd as flavourants or odourants in a variety of topical and ingestible compositions. ~or example, Japanese Patent Publication No. 39-19627 reports that 3-hydroxymethyl p-menthane (menthyl carbinol) has a flavour closely resembling that of l-menthol and suggests its use as a flavourant in confectionery, chewing gum, and tobacco.
In Swiss Patent No. 484l032 certain saccharide esters of menthol are proposed as additives to tobacco. In French Patent Specification No. 1,572,332 N,N-dimethyl 2-ethyl-butanamide is reported as having a minty odour and refreshing effect, and the minty odour of N,N-diethyl 2,2-dimethylpropanamide is also referred to. A similar effect is reported for N,N-diethyl 2-ethylbutanamide in Berichte 39, 1223, (1906). A minty odour has also been -~
reported for 2,4,6-trimethylheptan-4-ol and 2,4,6-tri- -methylhept-2-en-4-ol in Parfums-Cosmetiques-Savons, May 1956, pp. 17-20. The cooling effect of menthol and other related terpene alcohols and their derivatives has ~-also been studied and reported in Xoryo, 95, (1970) pp. 39-43. 2,3-p-Menthane diol has also been reported as having a sharp cooling taste (Beilstein, Handbuch der Organischen ~hemie, 4th Ed. (1923) ~ol. 6, p.744).
Still other substituted p-menthanes having a physiological cooling effect are disclosed in German Offenlegungsschrift 1~5444~
Nos. P 22 02 535, P 22 03 947, P 22 03 273 and P 22 05 255.
Yet other compounds having physiological cooling activity are disclosed in German OLS Nos. P 23 16 999, P 23 17 000, P 23 17 5~8, P 23 17 539, P 24 13 639, P 23 36 495, P 23 34 985, P 23 45 156 and P 24 39 770.

More recently it has also been found that compounds having the property of stimu:Lating the cold receptors of the nervous system of the hwnan body act also on the taste receptors of the nervous system to modify their re~ponse ; 10 to taste stimuli even at concentrations below that at '~r which coolin~ activity is noticeable and that such -compounds are therefore ùseful in very small concentrations as flavour modifiers in flavoured preparationsJ see German OLS No. P 25 03 555.
. . .
In this connection , it is well known to the flavour technologist that very small amounts of certain compounds, such as monosodium glutamate and other compounds such as disodium 5'-inosinate, disodium 5'-guanylate, cyclamic acid, N,N'-di-o-tolylethylenediamine, dioctyl sodium sulfosuccinate and 3-hydroxy-2-methyl-4-pyrone (Maltol), have a substantial effect on the flavour of compositions to which they are added, such sffect being far in excess of the change in flavour which might be attributable 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 t~e art as "flavour modifiers", 'Iflavour enhancers" or "flavour potentiators". See, for example, Handbook of Food Additives, 2nd Edition ~1972), CRC Press, pages 513-521; Flavour Chemistry, 1966, American Chemical Society, pages 261-27~; Flavour Research, Edited by Teranishi, Hornstein, Issenberg and Wick, publi~hed by Academic Press, pages 5-12. The precise mode of action of these compounds is unknown. Some appear to act by increasing the perception of a given flavour, i.e. ~y "flavour potentiation" in a strict sense of the phrase, whilst others appear to act by suppressing the perception of undesirable flavour components and bringing other more desirable flavour components into prominence. ~-In this specification the term "flavour modification"
will be used in a generic sense to cover any change in flavour brought about by the additive and which cannot be atrributed to the flavour of the additive itself, either by virtue of its tasteless nature or by virtue of the minute concentration used.

Obiects of the Invention An object of the invention is to provide further compounds having physiological action on the ~ody and useful as flavour modifiers in flavoured ingestible preparations or in tobacco.

A furth~r object is to provide a method of modifying the flavour of flavour-containing orally ingestible prepar~ions, including tobacco and tobacco-containing 5.

. .

. . .

~OS4~

preparations.

- A yet ~urther object is to provide flavoured ingestible preparaions, including tobacco, whose flavour is modified by the incorporation therein of a small amount of a flavour mocLifying agent.

These and other aspects will be apparent from the following detailed description of the invention.

Summary of Invention The present invention is based on the discovery of a group o~ bicyclic acids, amides, esters and substituted methanols having the property o~ stimulating the cold receptors of the nervous system o~ the body and use~ul, there~ore, as flavour modifi~rs in a wide variety of flavoured ingestible prepara~ions and in tobacco and tobacco-containing preparations. This group of bicyclic acids, esters, amides and substituted methanols is represented by compounds of the general formula RX where R is a saturated or monoethyleDically unsaturated alkyl-substituted bicyclic hydrocarbon radical containing a total of from 8-12 carbon atoms and selected from /3.1.1 7bicycloheptanes, ~ .2.1 bicyclshep~anes and hept-5-enes and /~.2.2 7 bicyclooc~anes and oct-5-e~es containing from 1-3 C1-C5 alkyl substitue~ts;
X is a CH20H, COOH, COOR1 or CONR2R3 group attached to said bicyclic radical at a 2-position, and where .

.. .
. . '~' . ' . ' i - ~ ~ 5 ~41 R1 is a hydroxyalkyl or hydroxyalkoxyalkyl radical of from 2-4 carbon atoms;
R2, when taken separately, is H or C1-C5 alkyl;
R3, when taken separate:ly, is H, C~-C5 alkyl, C1-C5 hydroxyalkyl or C3-C6 a:lkoxycarbonylalkyl with the proviso that when R is H, then R2 may also be C3-C6 cycloalkyl, pheny:l or phenyl containing up to 2 hydroxy, methyl or me-thoxy sub~tituents; and : ~2 and R~, when taken together, represent a C4-C5 - -~
alkylene group, the carbon atom chain of which may optionally contain an ether oxygen atom, and forming with the nitrogen to which they are attached a - - pip~ridino-, pyrollidino or morpholino group. : -Statement of Invention In accordance with the pre~ent invention, therefore, there is provided a method of modifying the flavour o~
~lavour-containing ingestible preparations, including tobacco, which comprises incorporating into the flavour-containing preparation a compound of the formula RX, where R and X are as defined above, ~uch compound being incorporated into the preparation in an amount below the threshold of practical cooling activity as hereina~ter .
defined.
;'. ' : Also provided in accordance with this inve~ion are ingestible preparations, including tobacco, containing a .
flavouring agent and a ~lavour modifier being a compound of the for~lla hereinbefore de~ined, and being present in .

105~4~1 the preparation in an amount below the threshold of practical cooling activity.

Detailed Description As already indicated, the compounds useful as physiological flavour modifers in accordance with this invention are acid, amide, esters and hydroxymethyl derivatives of certain bicyclic hydrocarbons, namely alkyl-substituted ~3.1.1 7bicycloheptanes, ~ .2.1 7 bicycloheptanes and hept-5-enes and ~ .2.2 7bicyclooctanes and oct-5-enes containing from 1-3 C1-C5 alkyl substituents and a total of from 8-12 carbon atoms. In the case of bicycloheptanes and heptenes, therefore, the substituent alkyl group(s) provides a total of no more than 5 carbon atoms, and in the case of the bicyclooctanes and bicyclooctenes no more than 4. Preferably at least one of the substituent alkyl groups is in an alpha or beta position relative to the acid, ester, amide or hydroxy~
methyl grouping, which as indicatéd, is itself attached to the bicyclic group at a 2-position. By reasonof cost, availability and activity compounds of the /~.2.1 7 bicycloheptane and hept-5-ene series are preferred.

- Typical bicyclic compounds used in this invention are ~ /3.1.1 7bicycloheptane derivatives of the formula .
~L X

, , ,, ; ~ , .;

1(~54441 where X is as above defined; illustrative examples of such derivatives being 6,6-dimethylbicyclo/3.1.1 7heptane 2-carboxylic acid, N-ethyl-6,6-dimethylbicyclo~3.1.17hep-tane 2-carboxamide and ` 5 6,6-dimethylbicyclo/3.1.17hept-2-yl methanol;
more preferred are /2.2.17bicycloheptane and heptene derivatives of the formula ~6 ~ X
where B is a bridging group selected from -CH2- and -e ~CII3)2-;
the broken line represents an optional et~ylenically unsaturated valency bond;
R4 is H or CH3;
R5 is H or CH3;
R6 is H or C1-~5 alkyl;
R7 is H or C1-C5 alkyl;
X is as above defined;
it being provided i) that when B is -CH2- then at least one, but no more than 3 of R4-R7, is alkyl, R4-R7 together providing a total of from 1-5 carbon atoms;
and ii) that when B is -C(CH3)2- then R4 is -CH3 and R5-R7 are all H;
illustrative examples of such compounds being M-ethyl-1,7,7--trimethylbicyclo/~.2.17heptane-2-carboxamide, N-~,7,7-trimethylbicyclo/~.2.17heptane-2-carbony~7glycine - ethyl ester, 2-isopropylbicyclo/2.2.17heptane-2-carboxylic acid~ ~-methyl-2-isopropylbicyclo¦~.2.17heptane-2-:' ': :

, . - . . . .

1~5~4~L

carboxamide, N-ethyl-1~3,3-trimethylbicyclo~2.2.1 7 heptane-2-carboxamide, N-(3'-Aydroxy-n-propyl)-2-iso-pentylbicyclo~.2.1 7heptane-2-carboxamide, 3,3-dimethyl-bicyclo/~.2.1 7heptane-2-carboxylic acid 2'-hydroxyethyl ester, N-ethyl-2,3-dimethylbicycloL~.2.1 7hept-5-ene-2-carboxamide, N,3-diisopropylbicyclo~.2.1 7hept-5-ene-2-carboxamide, and N,N,3-trimethylbicyclo~.2.1 7hept-5-ene-2-carboxamide; and ~.2.2 7bicyclooctane and oct-5-ene derivatives of the formula:
R

where B is -CH2CH2-; the broken line represents an optional ethylenically unsaturated valency bond; one of R8 and Rg is methyl and the other hydrogen; and X is as defined above;
illustrative bicyclooctane and bicyclooctene derivatives being N-isopropyl-3-methylbicyclo/~.2.2 70ct-5-ene-2-carboxamide, N-(1'-ethyl-2'-hydroxyethyl)-2-methylbicyclo /~.2.2 70ct-5-ene-2-carboxamide, N-/~-methylbicyclo-/2.2.2 70ct-5-ene-2-carbonyl7glycine ethyl ester, and N-isopropyl-2 methylbicyclo/~.2.2 70ctane-2-carboxamide.

As will be apparent from the above formulae some of the compounds used as flavour modi~ers in accordance with this invention exhibit either geometric or optical lsomerism or both, and, depending on the startirlg materials . .
,.
10.

544~Li i~nd the methods used in their preparation the compounds may be isomerically pure, i.e. consisting of one - gesmetric or optical isomer, or they may be isomeric mixtures, both in the geometric and optical sense.
Generally, the compounds will be used as isomeric mixtures, but in some cases the flavour modifying effect may differ as between geometric or optical isomers, and therefore o~ or other isomer may be - preferred.

The bicyclic compounds useful in this invention are, in most cases, partiolarly the /~.2.1 7bicycloheptanes and heptenes, synthesisable from readily available, low cost, naturally occuring starting materials by conven tional techniques as hereinafter described. The bicyclic compounds are characterised by the ease with which they crystallise~ even when present as isomer mixtures. This leads in general to easy recovery and purification procedures which in turn provide low cost compounds of high purity.

Broadly s~eaking the bicyclic compounds o~ this invention can be prepared by standard procedures for the preparation of bicyclic compounds, the following procedures being 1llustrative:

:.
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., 11.

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

~05~

> ~ (ii) CO2 a-pinene see 'The Terpenes', Vo.. II, by J. Simonsen, (2nd Edition), pp.
156, 343.

R~r 0~CW ~CCOOH

e.g. see W.R. Boehme et al. J.A.C.S. ~1958), 80, 5488-5495.

(iii) ~ + ~b~ 1 reflùx ) ¢~

COCl e.g. see J.C;. Martin et al., Chem. P~ev. (1961~, 537.
'Diels-Alder Reactions', by A. Wadderman.

(iv1 ~ +~/autoclav~ i OH

~ H ~

COOH COOC ~H5 COCl `! ~ ~

COCl COr~RlP~2 C~ iR2 ..

.

~ ~05444~

)H202/OH ~ ~ ,J

e.g. see 'Hydroboration', by H.C.Brown, p.15, 'Reagents for Organic Synthesis', Vol. I, by L.F.
and M.Fieser, p. 143.

-: 5 As already indicated the compounds used in ~his invention as flavour modifers in flavour-containing ingestible preparations and tobacco are incorporated into the preparation in amounts below that required to effect a noticeable cooling effect in the mouth when the flavour-containing preparations are consumed, 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 ~heir 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 components of the flavour-containing preparation3 and,moreover, . .
sensitivity to these compounds varies from person to ; person. Therefore i~ is not possible to put any absolute value on the amount of compound required to bring about a noticeable cooling effect in the mouth .~' ,. :~

.. ~ ' . . . . . . . . . . . .. . .

105~4~

when the flavour-containing preparations are consumed.
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.

Test Procedure .
The following test procedure is aimed at determinin~
the minimum quantity of the test compound required to produce a noticeable cooling effect in a person of average sensitivity, this minimum quantity being termed the threshold for that particular compound. The tests are carried out on a selected panel of 6 people of median sensitivity to l-menthol.

Panel Selection To select a test panel of average sensiti~ity the following procedure is used. 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. 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 value - substantially above 0.25 ~g. per square to substantially below 0.25 ~g9 the precise range being immaterial.
Conveniently, one starts with squares containing 2.0~g ~ l-menthol, the amount on each successive square being '' , :
~ 14 , :
. :

lOS444~l 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 panel, the threshold for each individual being that amount of l-menthol for which, in a series of not less than 10 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.

Compound Testing To obtain the threshold of practical physiological activity of compounds used as flavour modifiers according to this invention, the 6 selected panel members are then asked to taste (or to smoke) samples of the flavour-containing preparation containing increasing amounts of the flavour modifier, each sample being tested at least -~ 10 times, and to report on the presence or 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 membsr is then - 25 taken as that amount ~or which a cooling effect is reported 50~ of the time, that is to say, in the case of each sample being tested 10 times a cooling effect is reported on at least 5 occasions by each panel member.

: .
:.- 15.

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

31 0544~

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 modi~ier which may be used in r accordance with this aspect of the present invention, flavour modifying effects will 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 larger amounts of the flavour modifier, such that on dilution the modi~er concentration will be in the stated range. The amount of modifier used will in fact vary widely from compound to compound and from preparation to preparation, but amounts within the above range generally being satisfactory and with amounts in ~ 20 the range 0.1 - 10 ppm being ~aerally preferred. In `~ - accordance with this invention it has also been found - that, ingeneral, there is an increase in flavour modifying activity with increasing concentration of the modifier up to a certain maximum, after which the navour 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 .:
.

.
16.

~054441 also from composition to composition, and above and below which range the flavour modifying effects diminish.
Because of individual ~ariations no generally applicable limits can be put on this optimum concentration range, but these limits can readily be obtained for any given compound in any composition by a series of routine tests similar to those referred to above.

From the above it will be appreciated 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 compou~ds when - applied substantially directly to the tongue in an inert, tasteless medium, i~e. the square of filter paper.

The above-mentioned test procedure may also be used ` as a means to identify compounds having a physiological cooling activity and useful in accordance with the present invention as flavour modifiers. Typical compounds and their respective thresholds of physiological cooling activity as determined by the above described test proced-ure are listed in Table I. In this Table the bicyclic hydrocarbo~ radical, R, is identified by a reference letter, these being further identified in Table II, which lists the basic bicyclic hydrocarbon from which the radical K is obtained by the removal of a hydrogen atom at the 2-position.
. ' ' .
,:' 17.
,~
:,;;' :;:
. . .. . .. . ,- . . , . . ., , ~ ~
.. . . : . ,. . , ~, . - , . ~ ~ . . . ; .

. - . . .

1~59~44~iL

TABLE I
Compound b~po or m.p. Act ~ity No. R X C
1 K -CONHC2H5 104-5(mp) 0.5 2 K -CONCH(CH3)2 110-11(mp) 0.7 t

3 C -CONHC2H5 100-2(mp) 0.7

4 B -CONHC2H5 go (mp) B -CON(CH3)2 45 47(mp) 6 J -CONHC2H5 115-8JO.01mm. 1 7 J -CONHcH2coocH3 145/0.01mm.
K -CONHCH~CH(CH3)2 117-9/0.03mm.
9 K -CONHCH2COOC2H5 99-101(mp) 0 -CONH(o-CH3,p-CH30C6H4) 104-6 (mp) 11 P -CONH(o-CH30,p-CH30C~H4) 85-7(mp) : 15 12 P -CONHC~CH332CH2oH 102 4(mp) 1 :
- 13 A -CONHC2H5 120-4/0.5mm 1.5 14 S -CONHCH3 116 8(mp) 1.5 ~ :
. 15 A -CONHC(CH3)2CH20H 104-5(mp) 2 16 A -CONHCH(CH3)2 . 109-11(mp) 2 17 B -CH20H 55lO.005mm 2 ~ :
18 E -CONHC2H5 97-8/0.1mm 2 :
19 K -COOCH2CH20H 94-8/0.02mm 2 - -:
L -CONHC2H5 90-1/0.005mm 2 ~:.
21 S -CONHC2H5 14g-50tmp) 2 .
22 E -CH2H 74-8/0.05mm 2.5 -- 23 B -coNHc~cH3)2cH2oH 130 /0.005mm 3 -. 24 E -COOCH2CH20H 78-80~0.005mm 3 :: , . 25 F -CONHC2H5 88-92/0.01mm 3 26 F -CONHCH(CH3)C2Hs 96-98(mp) 3 '.

. :
.,.' .
.18. -; ~ .

S4~41 . . .

TABLE I Continued 27 F -CONHCH2C~2CH3 84/0.01~ 3 28 J -CONHCH3 82(mp) 3 29 J -coNHc(cH3)2cH2oH 69-70tmp) 3 J -COOCH2CH20H 120-2¦0.3mm 3 31 N -CONHC2H5 90-1 (mp) 3 32 0 -CONHC2H5 110/0.02mm 3 33 P -CON ~ 67-8(mp) 3 34 B -CON ~ 83-5(mp) 4 D -CONHCH3 110-2(mp) 4 36 G -CONHC2H5 97-103/0.01mm 4 ! 37 G -CONHCH2CH2CH3 74 /0~01mm 4 38 H -coNHcH(cH3)c2H5 123 4(mp) 4 39 J -CON ~ 127-30/0.01mm 4 0 -CONHcycloC5H9 102-4(mp) 4 41 P -CONH(~-CH30C6H5) 138-40(mp) 4 42 S -CONHCH(CH3)2 122-4(mp) 4 43 A -CON(CH3)(CH2CH20H) 125-30/0.02mm 4 44 T -CONHCH(CH3~2 135-6~mp) 4 B -CO~HCH2COOC2H5 112-3(mp) 5 46 B -CON ~ o 77-9 (mp) 5 47 B -COOH 112 /0.2mm 5 48 B -COOCH2CH20H 110/0~2mm 5 49 D -CONH cyolo C3H5 135-7(mp) 5 D -CH20H 83/0.02 mm 5 51 E -CONHCH(CH3~2 114-5(mp) 5 52 M -CONHCH(CH3)~ 133(mp) 5 53 0 -CONH(m-OH, p-CH~C6H4) 116-8(mp) 5 ' i 19 .

- ., - 1~544~
Table I Continued 54 0 -CONHCH2COOC2H5 139/0.02mm 5 P -CONHCH3 77-8(mp) 5 56 A -CONHCH2COOC2H5 104-6(mp) 6 57 A -COOCH2CH20H 116-8/O.~mm 6 58 B -CONHCH~ 139-41(mp) 6 59 D -CONHC2H5 110-2(mp) 6 G -coNHcH`~cH3)c2~s 70 /0.005mm 6 61 K -CON(t-C4~ )(CH2CH20H~ 98-102/0.01mm 6 62 N -CONHCH(CH3)2 118-9(mp) 6 63 0 -COOCH(CH3)CH(OH)CH3 110/0.05mm 6 64 D ~CONHCH2CHOHCH3 59-60(mp) 7 - 65 J -CONH cyclo C5H9 80-82(mp) 7 ~ '66 N -CONHCH(C2H5)CH20H 142-7/0.02mm ?
67 A -CON(C2H5)2 95 /0.02mm 7 68 A -CONH~p-CH30C6H5) 123-5(mp) 8 69 A -COOCH2CH20CH2CH20H 145/0.5mm 8 H -CONHC2H5 75 6(mp) 8 71 I -CONHC(CH3)2C2H5 128(mp) 8 72 M -CONC(CH3)3 115-8(mp) 8 73 P -CONH(m-OH, p-CH3C6H4) 72 4(mp) 8 74 A -CON(iso-C3H7)(CH2CH20H) 127/0~02mm 8 A -CON(iso-C4~ )(C ~5) 100/0.02m~ 8 - 76 A -CON ~ 110/0.02mm 8 77 E -CONHCH(CH3)CH20H 12~-30/0.005mm 9 78 F -CONHCH2CH2CH2QH 135/0.005mm 9 79 N -CONHCH2COOC2H5 126-32/0~02mm 9 A -CONH cyclo C6H11 141-3(mp) g 81 A -CONHCH2CH2COOC2H5 145/0.04mm 9 82 A -CH20H 76-8 (mp) 10 ' .: ' .

2~.
;' , :
.' , 1054~
TABLE I Continued 83 S -CON(CH3)2 95/0.2mm 10 84 S -COOCH2CH20H 122 /0.2mm 10 A -CON(CH2CH2CH~)2 100 jO.02mm 10 86 A -CON(iso C4Hg)(iso C3~ ) 104/0.02mm 10 87 Q -GONHC(CH3)2C2H5 138-40(mp) 10 88 A -CONHCH2COOCH~ 103-5(mp) 10 89 I -COI~HC2H5 98-102/0.01mm 12 I -CON(CH~)2 75/0.25mm 12 - 10 91 A CONH2 128-30(mp) 12 92 I -COOCH(CH3)CHOHCH3 100-3/0.01mm 14 ;
93 D -CONHCH2CH2CH20H 116-8(mp) 94 L -CH20H 75/0.3mm 15 ~95 S -CONHC(CH3)2CH20H 153-5 ~P) 96 S -CONH(p-CH30C6H5) 175-7(mp) i5 97 A -CON(iS-csH11)2 1~5/0.02mm 15 98 A -COOCH(CH3)CH(OH)CH3 105/0.01mm 15 99 A -CONHCH(CH3)COOCH2CH2CH3 141/0.005mm 15 100 I -CON~CH3)(CH2CH20H) 122-7/0.01~m 18 101 D -CONHCH2CH2CH3 125 (mp) 20 102 D -COOH 125/0. mm 20 103 D -COOCH2CH(OH)CH3 ~ 114/0.25mm 20*
104 D -coocH(cH3)cH2oH 5 n 105 E CONH(2',5'-dimethylphenyl)116.5-117.5(mp) 20 106 E ~CONH(p-CH30C6H5)111-29(~p) 20 ; 107 E -coNHcH2coocH3109-10/0.0025m~ 20 -~ 108 E -COOH 92-3~/0.5m~ 20 109 L ~COOH 79~/O.aO~mm 20 110 D --coMHcH(cH3)c~Hs 149-51(mp) 30 , :.
; ~ .

~ .2~.

:, , 105g~4~

TABLE I Continued 111 D -CO~-ICH2CH2CH2CH3 112-4(mp) 30 112 L -CONHC(CH3)3 8g-90/0.005mm 5 * tested in isomeric mixture. ~ -., . '' ',' '',"', ' ''.

:.
22.
'.

~5d~4431 - T~BLE II
`~ Reference - etter Hydrocarbon A 1,7,7-trimethylbicyclo/~.2.1 7heptane B 2-isopropylbicyclo/~.2.1 7heptane C 1,3,3-trimethylbicyclo/~.2.1.7heptane ;
~ D 2-isopentylbicyclo/~.2.1.7heptane E 3,3-dimethylbicyclo~.2.1 7heptane F 2,3-dimethylbicyclo~ .2.1.7hept-5-ene G 3,3-dimethylbicyclo~.2.1.7hept-5-ene H 2-methylbicyclo/~.2.1 7hept-5-ene I 3-methylbicyclo~.2.1 7hept-5-ene J 3-n-propylbicyclo~ .2.1.7hept-5-ene K 3-isopropylbicyclo/2.2.1.7hept-5-ene L 6,6-dimethylbicyclo~3.1.1 7heptane M 3-methylbicyclo~.2.2.70ct-5-ene N 2-methylbicyclo/~.2.2 70ct-5-ene O 3-n-butylbicyclo/~.2.1 7hept-5-ene P 3-isobutylbicyclo~ .2.1 7hept-5-ene Q 3-methylbicyclo~.2.1 7heptane -;
R 2-methylbicyclo~.2.1 7heptane S 3-isopropylbicyclo~.2.1 7heptane T 2-methylb~cyclo~2.2.2 70cte~e.

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The compounds used in accordance with the present invention as flavour modifiers may be 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 incor-` porated 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 recommend their use in cooked foodstuffs to ~ which they can be added during preparation and before cooking.
As well as incorporated 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 the manufacture or prparation of foodstuffs.
Mixtures of two or more compounds may be used in accordance with this invention, as well as mixtures of the , ~ . . ~ . . ~ . . . . ... . . . . .

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flavour modifiers of this invention with known flavour modifiers such as monosodium glutamate.

Also, as already indicated, t~ 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 manufa~cture or immediately before ingestion e.g. as a condiment or sweetener. They may be added as such or in a suitable liquid or solid carrier to aid dispersion. ;~

The preparation of compounds accor~ing to the present invention is illustrated in the following Examples 1-13.

E~XA~T~
Preparation of 1.7?7-Trimeth~ylbic~clo ~.2.1,_?he~ne-2-carboxylic acid A Grignard r~agent was prepare~ f~o~ endo-2-chloro-1,7,7-trimethylbicyclo~.2.1_7heptane (bornyl chloride , , .
23.0g.J 0.13 moles~, magnesium (3.1g., Q.13 ~oles) and THF
(100 ml.). The mix~ure wa9 carb~ate~ by bu~bling through C2 gas overnight. The ~ixt~re wa~ th-n ~idifi~d, and extrac~ted wi-th ether. The ether extraet~ ~re separabe~
and washed with excess 2N NaOH. The ~u~ou~ ~tracts 25.

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105444:~L
~ere acidified and the precipi-tated acid extracted into ether and dried ~MgS04). Removal of the solven-t yielded a white solid (21g.).
... ~.

Preparation of N-EthY1-1,7~7-trimethylbicycloL~.2.1_7 hepta e-2-carboxamide The product of Example 1 was treated with excess thionyl chloride and then distilled to yield 1,7,7-tri- i methylbicyclo~.2.1 7heptane-2-carbonyl chloride as a colourless liquid, b.p. 55-60/0.2 mm. An ether solution of 3.8g (0.02 mole) of the acid chloride was treated with excess ethylamine (as a 70yo solution in wate.). When - reaction was complete, the ether layer was washed with dilute HCl, then with NaHC03 solution and dried (MgS04).
Removal of the solvent left an oil (4.3 g) which was distilled to yield N-ethyl-1,7,7-trimethylbicyclo/~.2.1 7 heptane-2-carboxamide, b.p. 120-4/0.5 mm as a colourless liquid which rapidly solidifies.
Analysis: C, 74.1; H, 11.0; N, 6.7.
Calc.: C, 74.6; H, 11.0; N, 5.7~.
- . . .

Preparation of N-(1',1'-Dimethyl-2'-hydroxyethvl)-1,7l7- -trimethylbicyclo/~.2.1 7heptane-2-carboxamide ; This was prepared, as in Example 2, from the acid chloride (308g) and excess t-butanolamine in ether solution. The crude product was a white solid which was recrystallised from petroleum ether /chloroform to yield 26.

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white crystals, m.p. 104-5.

Preparation of 2-Isopropylbicyclo~ . 2 .1 7heptane-2-carboxYlic acid Sodium (5.1g., 0.22 mole) was dissolved in liquid NH3 (300 ml.) in the presence of a catalytic amount of ferric nitrate. A mixture of isopropyl bromide (26.1g., 0.22 molç) and bicyclo~.2.1 7heptyl-2-cYanide (25g, 0.20 mole) was added slowly, and the ammonia left to evaporate over-night. Benzene and water were added, and the organic ~- layer separated and dried (MgS04). Removal of the solvent - left an oil which was distilled to yield 2-isopropylbicyclo-/~.2.1 7heptyl-2-cyanide (25g), b.p. 108-110/10mm. Th.is was stirred at 120 with 50 mls. of 75~ H2S04 and then NaN02(23.1g, 0.35 mole) was added, When the reaction had subsided, water, ether and excess 2N NaOH were added.
The ether layer was separated, the aqueous layer was acidified and the precipitated acid extracted into ether and dried (MgS04). Removal of the solvent and distilla~
- 20 tion of the crude product yielded 2-isopropylbicyclo-/-2.2.1 7hept~ne-2-carboxYlic acid as a low melting solid, b.p. 112/0.2mm.

EXAMPL~ 5 Preparation of N-(2-isopropylbicyclo/2.2.1 7heptane-2-carbon~l)~lYcine ethYl ester.
me product of Example 4 was converted, by the method of Example 2, to the acid chloride, b.p. 70-73/0.1mm.

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To a solution o~ NaHC03(0.64g, 7.5 mmoles) in water (50mls.) were added ether (50 mls.), glycine ethyl ester hydrochloride ~0.53g, 3.75 mmole~ and the acid chloride : (0.75g, 3.75 mmoles). When reaction had ceased the ether layer was separated and dried (MgS04). Removal of the solvent left a white solid which was recrystallised from 40-60 petroleum to yield N-(2-isopropylbicyclo/~.2. 1 7 heptane-2-carbonyl)glycine ethyl ester, m.p. 112-3.
Analysis: C, 68.0; H, 9.5; N, 5.3.
Calc.: C, 67.4; H, 9.4, N, 5.2~.

N-(2-isoPropylbicyclo~.2.1~ hePtane-2-carbon~l)morpholine The acid chloride (1.25g) was reacted with excess - morpholine in ether. When reaction had ceased the ether solution was washed with dilute acid, NaHC03 solution and then dried (MgS04). Removal of the solvent left a white solid which was recrystallised from 40-60 petroleum to yield N-(2-isopropylbicyclo/~.2.1 7heptane-2-carbonyl)-morpholine as white crystals, m.p. 77-79.
Analysis: C, 71.7; H, 9.9; N, 5.6.
Calc.: C, 71.7; H, 1000; N, 5.6%.

~reparation of 3-Isopropylbicyclo~.2.1 7hept-5-ene-2- -carbonyl chloride 4-Methylpent-2-enoic acid was prepared by a Knoe~enagl condensation between isobutyraldehyde and malonic acid in pyridine (see 'Organic ~nctional Group ~ .

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~544~
Preparations', Vol. I, by Sandler and ~aro, p.291-220).
This was then converted to 4-methylpent-2-enoyl chloride, b.p. 65/15 mm, with thionyl chloride.

A mixture o~ freshly distilled cyclopentadiene (27ml), 4-methylpent-2-enoyl chloride (24g, 0.18 mole) and toluene (120ml) was refluxed for 17 hours. The toluene was removed on a rotary evaporator and the residual oil distilled to yield 3-isopropylbicyclol~.2.1 7hept-5-ene-2-carbonyl chloride (26g, 73~), b.p. 56-60/0.5 mm.

Preparation of N,3-Diisopropylbicyclo~.2.1 7hept-5-ene-.
2-carboxamide The product of Example 7 (2g) was reacted with excess ` isopropylamine in ether (lOOml). When reaction had ceased,the solution was washed with dilute acid, NaHC03 solution and dried (MgS04). ~emoval o~ the solvent yielded a white solid, which was recrystallised from 40-60 petroleum/CH2Cl2 to yield N,3-diisopropylbicyclo~.2.1 7-hept-5-ene-2-carboxamide as white crystals, m.p. 110-111t Preparation of 3-isopropylbicyclo~.2.1 7hept-5-ene-. ~
2-carboxylic acid 2'-hydroxyeth~l ester.
A mixture of ethylene glycol (6g), triethylamine (2g) and acid chloride ~2g) in acetone (100ml) was stirred at room temperature overnight. Ether and dilute anid were added. The ether layer was separated, washed 544~1 .
wi-th I~aI-ICO~ solution and dried (MgSOI+). Removal of the solvent left an oil which was distilled to yield the 2'-hydroxyethyl ester of 3-isopropylbicyclo/~.2.1 7hept-5-ene-2-carboxylic acid, b.p. 94-~/0.02mm as a colourless liquid.

E~LE 10 .
Preparation of 2-rlethylbicyclo~2.2.2 70ct-5-ene-2-carbonyl _ . . _ . . .. .. _ _ ch].oride - A mixture of ethyl methacrylate (14.3g, 0.13 mole), 1,3-cyclohexadiene (10g, 0.13 mole) and p-hydroquinone (1g) was heated, in a 75 ml,steel autoclave, to 170 for 26 hours. Distillation of the crlde product yielded ethyl 2-methylbicyclo/2.2.2 70ct-5-ene-2-carboxylate (11g, 45,~) as a colourless liquid, bp. 60-70/
0.2mm. This was deesterified by heating with NaOH in diethylene glycol (140, 17 hours) to yield 2-methyl-bicyclo/2.2.2 70ct-5-ene-2-carboxylic acid (9.5g) as a solid which was purified by sublimation at 100/0.02mm.
Treatment with thionyl chloride yielded 2-methylbicyclo-l~.2.2 70ct-5-ene-2-carbonyl chloride, b.p. 56-62/0.2mm, as a colourless liquid.

: EX~LE 11 ~ ~reparation of N-Ethyl-2-methylbicyclo/2.2.2 70ct-5-ene-. ~ .
2-carboxamide Treatment of the acid chloride, prepared in Example 10, with excess ethylamine as in Example 2, yielded N-ethyl-2-methylbicyclo~2.270ct-5-ene-2-carboxamide as 30.

white crystals, mp. 9Q-91(recrystallised from 40-60 petroleum).
Analysis: C, 74.6; H, 10.1; ~, 7.2.
- Calc.: C, 74.6; H, 9.8; N, 7.3%, EX*MPLE 12 Preparation of 6,6-Dimethylbicyclo/3.1.1 7heptane-2-car ~ id Aluminium trichloride (22.4g) was suspended in diglyme ~OOml) and sodium borohydride (19g) was added slowly, ~ollowed by dropwise addition o~ ~-pinene (81.6g).
After 4 hours the mixture was hydrolysed with 2NHCl, extracted with ether and dried (MgS04). Removal of the solYent left an oil, which wa~ treated with a solution of NaOH (16g) in ethanol (400ml), and hydro~en peroxide (1~6g, of 30% solution) was added at such a ràte to maintain a steady reflux. When reaction had ceased, most of the ethanol was removed by evaporation, the residue was extracted with ether and dried (MgS04). Removal o~
the solvent yielded crude 6,6-dimethylbicyclo/3.1.1 7-heptyl-2-methanol.

The crude methanol was dissolved in ether (500ml3 and chromic acid (prepared from 200g Na2Cr207 in 600ml water, to which was added 272g H2S04 and the whole mad~
up to 1 litre3 added dropwi3e, with stirring, at such a rate as to maintain the temperature of the mixture at 20-25C. When the solution turned red, addition of the chromic aoid wa~ stopped. me ether layer was separated, ~i1. ~.

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the aqueous layer extracted with more ether, the combined extracts were washed with saturated NaCl ~olution and dried (MgS04). Removal of the solvent left an oil which was distilled to yield 6,6-dimethylbicyclo/3.1.1 7heptane-2-carboxylic acid t20g), b.p. 79/0.005mm.

N-t-Butyl-6,6-dimethylbicyclo/~.1.1 7heptane-2-carboxamide . . . .
Treatment of the product of Example 12 with thionyl chloride yielded 6,6-dimethylbicyclo/3.1.1 7heptane-2-carbonyl chloride, b.p. 61/0.2 mm. This acid chloride - (1.0g) was reacted with excess t-butylamine in ether asin Example 8, to yield N-t-butyl-6,6-dimethylbicyclo-~3.1.17heptane-2-carboxamide as a viscous liquid, b.p.
89-90/0.005 mm.
'.

The following Examples 14-26 illustrate the use oY
the compounds of this invention as flavour modifiers.

~X~PLE 14 - N,3-diisopropylbicyclo/~.2.1 7hept-5-ene-2-carboxamide was blended into a commercial brand of soft margarine in an amount of 0.5 ppm. Compared with the untreated margarine, the margarine to which the modifier ~-had been added had a reduced oily and greasy taste.
' 0.5 ppm. of N-(1',1'-dimethyl-2'-hydroxyethyl)-1,7,7-trimethylbicyclo/~.2.17heptane-2-carboxamide added 32.
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to a commercial arange drink reduced the ~harp/sour taste and gave a sweeter, more blended flavour.

O.3 ppm of the same compound added to a blackcurrant jelly gave an improved flavour with an incre~sed sour taste.

O.4 ppm. of N~ methyl-2'-hydroxyethyl) 3l3-dimethylbicyclo/~.2.1 7heptane-2-carboxamide added to a commercial blackcurrant drink gave a fuller, more natural red fruit flavour with increased body.

0.3 ppm. of N-ethyl-1,7,7-trimethylbicyclo~.2.1 7-heptane-2-carboxamide added to a sparkling orange drink gave an improved natural f~our.

0.5 ppm. of N-ethyl-3,3-dimethylbicyclo~.2.1 7-heptane-2-carbox~ide added to an infusion of in~tant lemon tea gave an increased tea flavour with increased tannin.

0.5 ppm. of N-tert.butyl-6,6-dimethylbi~yclo~.1.1 7-heptane-2-carboxa~i~e added to a commer~ial ~ranæ~ drink gave a slightly increased flavour and more body.
' t 33.

105~49L~

0.25 ppm. of N-ethyl-6,6-dimethylbicyclo/3.1.1 7-heptane-2-carboxamide added t;o a commercial oxtail soup gave increased saltiness and a more spicy flavour. - - -.

0.5 ppm. of N-(3,3-dimethylbicyclo~.2.1 7heptane-- 2-carbonyl)glycine methyl ester added to a commercial grapefruit drink gave an enhanced bitter grape~ruit after-taste.
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0.3 ppm. of N-ethyl-2-isop~opylbicyclo~ .2.1 7heptane-2-carboxamide added to a chocolate milk drink enhanced the chocolate after-taste.

0.4 ppm. of the same compound added to oxtail soup gave increased saltiness. ~ -.

O.2 ppm. of N-(3-isopropylbicyclo~.2.1 7hept-5-ene-2-carbonyl)glycine ethyl ester added to dry red wine reduced off notes and sour flavour.

0.4 ppm. of N-isopropylb~cyclo~ .2.2 7Oct-5-ene-2-; carboxamide added to a sweet white wine reduced the sugary sweetness and gave a smoother, more syrupy and more blended flavour.
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EXAMPLE 2~
0.6 ppm. of N-ethyl-3,3-dimethylbicyclo~.2.1 7hept-

5-ene-2-carboxamide added to a commercial cream of tomato soup increased the tomato flavour.

0.4 ppm. of the same compound in an instant lemon drink reduced the sweetness with increased sharpness and more blend.

0.3 ppm. of N-(1,7,7-trimethylbicyclo/~.2.1 7heptane-2-carbonyl)glycine ethyl ester added to a sweet white wine reduced sweetness with increased sour and blend.

0.3 ppm. of the same compound in a sparkling bitter lemon drink gave increased bitterness.

Similar flavour modifying ef~ects may be noted with any of the bicyclic acids, amides, esters and substituted methanols hereinbefore described.

35.

Claims (8)

The embodiments of the invention in which an exclusive privilege or property 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 RX where R is a saturated or monoethylenically unsaturated alkyl-substituted bicyclic hydrocarbon radical containing a total of from 8-12 carbon atoms and selected from [3.1.1] bicycloheptanes, [2.2.1]-bicycloheptanes and hept-5-enes and [2.2.2]bicyclo-octanes and oct-5-enes containing from 1-3 C1-C5 alkyl substituents;
X is a CH2OH, COOH, COOR1 or CONR2R3 group attached to said bicyclic radical at a 2-position, and where R1 is a hydroxyalkyl or hydroxyalkoxyalkyl radical of from 2-4 carbon atoms;
R2, when taken separately, is H or C1-C5 alkyl;
R3, when taken separately, is H, C1-C5 alkyl, C1-C5 hydroxyalkyl or C3-C6 alkoxycarbonylalkyl with the proviso that when R1 is H, then R2 may also be 36.

C3-C6 cycloalkyl, phenyl or phenyl containing up to 2 hydroxy, methyl or methoxy substituents; and R2 and R3, when taken together, represent a C4-C5 alkylene group, the carbon atom chain of which may optionally contain an ether oxygen atom, and forming with the nitrogen to which they are attached a piperidino-, pyrollidino or morpholino group.

2. A method according to claim 1, wherein said compound is of the formula where B is a bridging group selected from -CH2- and -C(CH3)2-;
the broken line represents an optional ethylenically unsaturated valency bond;
R4 is H or CH3;
R5 is H or CH3;
R6 is H or C1-C5 alkyl;
R7 is H or C1-C5 alkyl, X is as defined in claim 1;
it being provided i) that when B is -CH2- then at least one, but no more than 3 of R4-R7 is alkyl, R4-together providing a total of from 1-5 carbon atoms;
and ii) that when B is -C(CH3)2- then R4 is -CH3 and R5-R7 are all H.

37.

3. 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.

4. A method according to claim 3, wherein said amount is from 0.1 to 10 ppm.

5. A flavour-containing ingestible preparation, including tobacco, having incorporated therein, as a flavour modifier, a compound being a compound capable of stimulating the cold receptors of the nervous system of the body, but being incorporated into the preparation in an amount below the threshold of practical physio-logical cooling activity and being a compound of the formula defined in claim 1.

6. A preparation according to claim 5, wherein said modifier is a compound as required by claim 2.

7. A preparation according to claim 5, wherein said modifier is present in an amount of from 0.1 to 100 ppm.

8. A preparation according to claim 7, wherein said amount is from 0.1 to 10 ppm.

38.