LEY, Jakob (Schubertstrasse 5a, Holzminden, 37603, DE)
| Claims:
1. A compound or mixture of compounds selected from the group consisting of compounds of the formulae (I) and (ent-l)
(I) (ent-l)
wherein in the formulae (I) and (ent-l)
R 1 means hydrogen or a linear, branched or cyclic, saturated or unsaturated hydrocarbon residue having 1 to 10 carbon atoms,
R 2 means a linear, branched or cyclic, saturated or unsaturated hydrocarbon residue having 1 to 10 carbon atoms
and
Q means a linear or branched, saturated, unsubstituted or substituted, alkylene group, which, including optionally present substituents, comprises a total of 1 to 12 carbon atoms.
2. The compound or mixture of compounds as claimed in claim 1 , wherein the compound or at least one of the compounds in the mixture is selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein
R 1 means hydrogen or a linear, branched or cyclic, saturated or unsaturated hydrocarbon residue having 1 to 6 carbon atoms
and/or
R 2 means a linear, branched or cyclic, saturated or unsaturated hydrocarbon residue having 1 to 6 carbon atoms.
3. The compound or mixture of compounds as claimed in either of the preceding claims, wherein the compound or at least one of the compounds in the mixture is selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein
R 1 means hydrogen or a methyl, ethyl, propyl, cyclopropyl, 2-propyl, 2- propenyl, 1-propenyl, 2-methylpropyl, methyl-2-propenyl, cyclobutyl, 1- butyl, 2-butyl, tert. -butyl, 2-methylbutyl, 1-pentyl, 2-pentyl, 3-pentyl, 1- hexyl, 2-hexyl, cyclopentyl or cyclohexyl residue
and
R 2 means a methyl, ethyl, propyl, cyclopropyl, 2-propyl, 2-propenyl, 1- propenyl, 2-methylpropyl, methyl-2-propenyl, cyclobutyl, 1-butyl, 2-butyl, tert. -butyl, 2-methylbutyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, cyclopentyl or cyclohexyl residue.
4. The compound or mixture of compounds as claimed in any one of the preceding claims, wherein the compound or at least one of the compounds in the mixture is selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein Q (a) is a linear or branched, saturated, substituted alkylene group having, including the substituents, a total of 1 to 12 carbon atoms, and which
(i) comprises one, two or three alkoxy groups having in each case 1 to 8 C atoms as substituents,
and/or
(ii) comprises one, two or three hydroxyl groups as substituents
or
(b) is a linear or branched, saturated, unsubstituted alkylene group having 1 to 10 carbon atoms.
5. The compound or mixture of compounds as claimed in any one of the preceding claims, wherein the compound or at least one of the compounds in the mixture is selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein
Q is a linear or branched, saturated, unsubstituted alkylene group having a total of 1 to 5 carbon atoms.
6. The compound or mixture of compounds as claimed in any one of the preceding claims, wherein the compound or at least one of the compounds in the mixture is selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein
Q means methylene, ethylene, 1 ,2-propylene, 1 ,3-propylene, 1 ,2-butylene, 1 ,3-butylene, 1 ,4-butylene, 1 ,2-pentylene, 1 ,3-pentylene, 1 ,4-pentylene or 1 ,5- pentylene.
7. The compound or mixture of compounds as claimed in any one of the preceding claims 4 to 6, wherein the compound or at least one of the compounds in the mixture is selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein
R 1 means hydrogen,
R 2 means a preferably linear or branched alkyl residue having 1 to 5 carbon atoms, preferably methyl, ethyl, propyl, cyclopropyl, 2-propyl, 2-propenyl, 1- propenyl, 2-methylpropyl, methyl-2-propenyl, 1 -butyl, 2-butyl, tert.-butyl, 2- methylbutyl, 1-pentyl, 2-pentyl or 3-pentyl.
8. The compound or mixture of compounds as claimed in any one of the preceding claims, wherein the compound or at least one of the compounds in the mixture is selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein
R 1 means hydrogen,
R 2 means a methyl residue and
Q means a methylene, 1 ,2-ethylene or 1 ,3-propylene residue.
9. The compound or mixture of compounds according to any one of the preceding claims, wherein the compound or at least one of the compounds in the mixture is selected from the group consisting of the following compounds of the formulae (I) and (ent-l):
L-menthane carboxylic acid N-(2-methylthioethyl)amide
and
L-menthane carboxylic acid N-(3-methylthiopropyl)amide.
10. A blend consisting of or comprising
(a) a compound or a mixture of compounds according to any one of the preceding claims
and
(b) a compound or a mixture of compounds of the formulae (Ma), (Mb), (Mc), (ent-Ma), (ent-Mb), (ent-Mc):
(Ma) (ent-Ma)
(Mb) (ent-Mb)
(lie) (ent-llc)
wherein, in the formulae (Na), (Mb), (lie), (ent-lla), (ent-llb) and (ent-llc), R 1 , R 2 and Q in each case mutually independently have one of the meanings stated for the formulae (I) and (ent-l) in the preceding claims, wherein the meanings of R 1 , R 2 and Q for the compounds of the formulae (I), (ent-l), (Ma), (Mb), (Mc), (ent-lla), (ent-llb) and (ent-llc) present in the blend are mutually independent.
11. The blend as claimed in claim 10, comprising as or in constituent (b) a compound or a mixture of compounds of the formulae (Ma), (Mb) and/or (Mc).
12. The blend as claimed in claim 10 or claim 11 , wherein the weight ratio of (a) the entirety of compounds of the formula (I) and (ent-l) to (b) the entirety of compounds of the formulae (Ma), (Mb), (Mc), (ent-lla), (ent-llb) and (ent-llc) is in the range from 200:1 to 4:1 , preferably in the range from 100:1 to 10:1 , particularly preferably in the range from 100:1 to 20:1.
13. A blend consisting of or comprising
(a) a compound or a mixture of compounds as claimed in any one of claims 1-
9 and (c) one or more further substances having a physiological cooling action, wherein the further substance or one, several or all of the further substances (i) cause(s) a flavor effect or (ii) cause(s) no flavor effect, and/or (d) one or more aroma substances without a physiological cooling action and/or
(e) one or more substances without a physiological cooling action which have a trigeminal or salivatory action and optionally a constituent (b) as defined in claims 10 to 12.
14. A preparation consumed for nutrition or for pleasure or used for oral hygiene or a pharmaceutical or cosmetic preparation comprising a sufficient quantity for achieving a physiological cooling action on the skin and/or mucous membranes
(a) of a compound or of a mixture as claimed in any one of preceding claims 1 to 9 or
(b) of a blend as claimed in any one of claims 10 to 13.
15. Use
(i) of a compound or of a mixture as claimed in any one of claims 1 to 9, (ii) of a blend as claimed in any one of claims 10 to 12 or
(iii) of a preparation as claimed in claim 14
(a) as a cooling substance for non-therapeutic purposes or
(b) for the production of a medicament.
16. A therapeutic or non-therapeutic method for achieving a physiological cooling action on the skin and/or mucous membranes comprising the following step: application of a quantity sufficient for achieving a physiological cooling action of a compound or of a mixture as claimed in any one of claims 1 to 9, of a blend as claimed in any one of claims 10 to 12 or of a preparation as claimed in claim 14, onto the skin and/or mucous membranes. |
Menthane carboxylic acid N-(alkylthioalkyl)amides and use thereof as physiologically active cooling active ingredients
The invention primarily relates to specific compounds, in particular menthane carboxylic acid N-(alkylthioalkyl)amides, of the formulae (I) and/or (ent-l) stated further below, and to corresponding mixtures, furthermore to blends with compounds of the formulae (Ma), (Mb), (lie), (ent-lla), (ent-llb), (ent-llc) stated further below, to corresponding preparations which comprise a sufficient quantity of a compound according to the invention, of a mixture according to the invention or of a blend according to the invention to achieve a physiological cooling action on the skin and/or mucous membranes, to corresponding uses as a cooling substance or for the production of a medicament and to corresponding methods for achieving a physiological cooling action on the skin and/or mucous membranes.
Physiological cooling active ingredients are often used to bring about a sensation of coolness on the skin or mucous membranes, for example on the mucous membranes in the oral, nasal and/or pharyngeal cavities, but without any physical cooling, such as occurs for example on solvent evaporation, actually occurring. Both individual components and mixtures may be used as physiological cooling active ingredients.
The best known cooling active ingredient is L-menthol, but this exhibits various disadvantages, for example a strong odor impression, elevated volatility and, at relatively high concentrations, a bitter and/or spicy hot intrinsic flavor. In certain
aroma compositions, in particular those which do not tend towards a (pepper)mint aroma, the use of L-menthol may thus be undesirable.
Investigations have already been carried out which were directed towards strong cooling active ingredients without an aroma effect. DE 2 608 226 has accordingly described, for example, lactic acid esters of menthol(s) and DE 4 226 043 has described mixed carbonates with menthol(s) and polyols, which, while having a strong cooling action, on hydrolysis in aqueous media, may however give rise to the strong smelling menthol. Menthone ketals according to EP 0 507 190 B1 are strong cooling active ingredients, which, in acidic media, may however liberate menthone and due to the latter's aromatic action (strong intrinsic flavor and low threshold value) cannot be widely used.
While menthyl monoesters of diacids according to US 5,725,865 and US 5,843,466 are indeed interesting naturally occurring alternatives, in sensory testing they cannot achieve the strength of previously described cooling active ingredients. Moreover, being esters, they are likewise susceptible to hydrolysis.
While menthol polyol ethers, for example from EP 1 398 306, are indeed more resistant to hydrolysis, they provide a somewhat weaker cooling impression.
H. R. Watson, R. Hems, D. G. Rowsell and D.J. Spring, J. Soc. Cosmet. Chem. 1978, 29, 185-200 present the results of a study of approx. 1200 compounds, in which the compounds L-menthane carboxylic acid λ/-ethylamide ("WS3") and in particular /^-(L-menthanecarbonylJglycine ethyl ester ("WS5") were found to be the most strongly cooling active ingredients. The latter, while having a strong action, has the disadvantage of being susceptible to hydrolysis and, as a result, forming the corresponding free acid /^-(L-menthanecarbonylJglycine, which itself retains only a very weak cooling action. Despite the exhaustive investigations which have been described, a systematic prediction of the properties of potential cooling active ingredients, in particular regarding the bitterness thereof and/or the other trigeminal effects thereof, is not possible and has also not been described. Accordingly, while many molecules falling within the class of menthane
carboxamides are indeed strongly cooling, they frequently simultaneously exhibit marked bitter notes (for example the menthane carboxylic acid N- (alkyloxyalkyl)amides according to JP 2004059474) or are additionally strongly irritant (WS5: N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycine ethyl ester, US 2005/0222256).
/^-(Menthanecarbonyl) alkyloxyalkylamides have been described in JP 2004059474. These have at strong cooling action and elevated resistance to hydrolysis, but suffer the disadvantage of being strongly bitter and thus being unusable in foodstuffs and also in cosmetic products for facial care.
The primary object of the present invention was therefore to provide novel compounds or mixtures of compounds which have a strong physiological cooling action, stability (resistance to hydrolysis) which is good and improved in comparison with known cooling active ingredients and which may be used as cooling substances (cooling active ingredients) in foodstuffs and/or products consumed for pleasure and/or oral care products and/or oral pharmaceutical preparations. The compounds or mixtures of compounds to be provided should preferably exhibit the weakest possible intrinsic flavor, in particular should taste only slightly or not at all bitter and exhibit the slightest possible irritancy.
This primary object has been achieved according to the invention by a compound or a mixture of compounds selected from the group consisting of
(I) (ent-l) wherein in the formulae (I) and (ent-l)
- A -
R 1 means hydrogen or a linear, branched or cyclic, saturated or unsaturated hydrocarbon residue (residue solely comprising C and H atoms) having 1 to 10 carbon atoms,
R 2 means a linear, branched or cyclic, saturated or unsaturated hydrocarbon residue having 1 to 10 carbon atoms
and
Q means a linear or branched, saturated, unsubstituted or substituted, alkylene group, which, including optionally present substituents, comprises a total of 1 to 12 carbon atoms.
The compounds of the formulae (I) and (ent-l) are hereinafter also designated as menthane carboxylic acid N-(alkylthioalkyl)amides according to the invention.
The compound according to the invention or at least one of the compounds in the mixture according to the invention is preferably selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein
R 1 means hydrogen or a linear, branched or cyclic, saturated or unsaturated hydrocarbon residue having 1 to 6 carbon atoms
and/or
R 2 means a linear, branched or cyclic, saturated or unsaturated hydrocarbon residue having 1 to 6 carbon atoms.
A particularly preferred compound according to the invention or mixture of compounds according to the invention is one wherein the compound or at least one of the compounds in the mixture is selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein
R 1 means hydrogen or a methyl, ethyl, propyl, cyclopropyl, 2-propyl, 2- propenyl, 1-propenyl, 2-methylpropyl, methyl-2-propenyl, cyclobutyl, 1- butyl, 2-butyl, tert. -butyl, 2-methylbutyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, cyclopentyl or cyclohexyl residue
and
R 2 means a methyl, ethyl, propyl, cyclopropyl, 2-propyl, 2-propenyl, 1- propenyl, 2-methylpropyl, methyl-2-propenyl, cyclobutyl, 1 -butyl, 2-butyl, tert. -butyl, 2-methylbutyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, cyclopentyl or cyclohexyl residue.
R 1 is here preferably hydrogen, wherein R 2 simultaneously means a preferably linear or branched, preferably saturated alkyl residue having 1 to 5 carbon atoms, preferably methyl, ethyl, propyl, cyclopropyl, 2-propyl, 2-propenyl, 1-propenyl, 2- methylpropyl, methyl-2-propenyl, 1 -butyl, 2-butyl, tert. -butyl, 2-methylbutyl, 1- pentyl, 2-pentyl or 3-pentyl. R 2 very particularly preferably means methyl.
Preferred compounds or mixtures of compounds according to the invention are those wherein the compound or at least one of the compounds in the mixture is selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein
Q (a) is a linear or branched, saturated, substituted alkylene group having, including the substituents, a total of 1 to 12 carbon atoms, which
(i) comprises one, two or three alkoxy groups having in each case 1 to 8 C atoms as substituents,
and/or
(ii) comprises one, two or three hydroxyl groups as substituents
or
(b) is a linear or branched, saturated, unsubstituted alkylene group having 1 to 10 carbon atoms.
Preferred compounds of the formulae (I) and (ent-l) are those wherein
Q (a) is a linear or branched, saturated, substituted alkylene group having, including the substituents, a total of 1 to 8 carbon atoms, and which
(i) comprises one, two or three alkoxy groups having in each case 1 to 5 C atoms as substituents,
and/or
(ii) comprises one, two or three hydroxyl groups as substituents
or
(b) is a linear or branched, saturated, unsubstituted alkylene group having 1 to 5 carbon atoms.
While the preferred meanings of group Q generally apply independently of the meaning of groups R 1 and R 2 , a compound according to the invention is, however, preferably selected such that R 1 , R 2 and Q in each case have a preferred meaning.
Very particularly preferably, in the formulae (I) and (ent-l),
Q is a linear or branched, saturated, unsubstituted alkylene group having a total of 1 to 5 carbon atoms.
In the formulae (I) and (ent-l), Q very particularly preferably means methylene, ethylene, 1 ,2-propylene, 1 ,3-propylene, 1 ,2-butylene, 1 ,3-butylene, 1 ,4-butylene, 1 ,2-pentylene, 1 ,3-pentylene, 1 ,4-pentylene or 1 ,5-pentylene.
It has already been pointed out that the preferred meanings of groups R 1 , R 2 and Q are preferably present in combination with one another and the corresponding compounds according to the invention are particularly preferred.
The compound according to the invention or at least one of the compounds in the mixture according to the invention is very particularly preferably selected from the group consisting of compounds of the formulae (I) and (ent-l), wherein
R 1 means hydrogen,
R 2 means a preferably linear or branched alkyl residue having 1 to 5 carbon atoms, preferably methyl, ethyl, propyl, cyclopropyl, 2-propyl, 2-propenyl, 1- propenyl, 2-methylpropyl, methyl-2-propenyl, 1 -butyl, 2-butyl, tert.-butyl, 2- methylbutyl, 1-pentyl, 2-pentyl or 3-pentyl, wherein the alkyl residue is preferably saturated.
Q here has one the meanings which are stated above to be preferred.
Preferably
R 1 means hydrogen,
R 2 means a methyl residue and
Q means a methylene, 1 ,2-ethylene or 1 ,3-propylene residue.
Very particularly preferred individual compounds of the formula (I) or (ent-l) are:
L-menthane carboxylic acid N-(2-methylthioethyl)amide (see Example 1 )
(R 1 = H, R 2 = CH 3 , Q = CH 2 -CH 2 )
L-menthane carboxylic acid N-(3-methylthiopropyl)amide (see Example 3)
(R 1 = H, R 2 = CH 3 , Q = CH 2 -CH 2 -CH 2 )
Both of the stated individual compounds alternatively assume the configuration according to formula (I) or (ent-l).
With regard to mixtures according to the invention of compounds (according to the invention), it should be noted that said mixtures comprise two, three or more compounds according to the invention. The presence of enantiomeric pairs, i.e. the presence a compound of the formula (I) in addition to a compound of the formula (ent-l), wherein the meaning of groups R 1 , R 2 and Q is identical in the particular formulae (I) or (ent-l), is in many cases particularly preferred. It is moreover particularly preferred if a mixture according to the invention contains not just one compound which is stated above to be particularly preferred (i.e. a compound which comprises one, several or all particularly preferred groups R 1 , R 2 and Q), but instead a mixture according to the invention comprises two or more particularly preferred compounds according to the invention. It has already been explained that, in a mixture of compounds according to the invention, at least one of the compounds in the mixture is selected from a preferred group, but preferably two, three or all the compounds in the mixture according to the invention are from the preferred group.
A further aspect of the present invention relates to a blend consisting of or comprising
(a) a compound or a mixture of compounds of the present invention, as defined above
and
(b) a compound or a mixture of compounds of the formulae (Ma), (Mb), (Mc), (ent-lla), (ent-Mb), (ent-Mc):
(Ma) (ent-Ma)
(Mb) (ent-Mb)
(Mc) (ent-Mc)
wherein, in the formulae (Na), (Mb), (lie), (ent-lla), (ent-Mb) and (ent-Mc), R 1 , R 2 and Q in each case mutually independently have one of the meanings stated above for the formulae (I) and (ent-l), wherein the meaning of R 1 , R 2 and Q for
the compounds of the formulae (I), (ent-l), (Na), (lib), (lie), (ent-lla), (ent-llb) and (ent-llc) present in the blend are in each case mutually independent.
The compounds of the formulae (Ma), (Mb), (Mc), (ent-lla), (ent-llb) and (ent-llc), like the compounds of the formulae (I) and (Ia), fall within the general formula (III):
A blend according to the invention preferably comprises a compound or a mixture of compounds of the formulae (Ma), (Mb) and/or (Mc) as or in constituent (b).
Also with regard to blends according to the invention comprising constituents (a) and (b), it is preferably the case that, in all the compounds used which fall within the general formula (III), the groups R 1 , R 2 and Q have a meaning which is stated above to be preferred (for the compounds of the formulae (I) and (ent-l)).
In blends according to the invention, in particular in blends according to the invention which as or in constituent (b) comprise a compound or a mixture of compounds of the formulae (Ma), (Mb) and/or (Mc), and furthermore in particular in blends according to the invention in which all the compounds which fall within the general formula (III) comprise groups R 1 , R 2 and Q which have been designated above to be preferred, the weight ratio of (a) the entirety of compounds of the formula (I) and (ent-l) to (b) the entirety of compounds of the formulae (Na), (Mb), (Mc), (ent-lla), (ent-llb) and (ent-llc) is in the range from 200:1 to 4:1 , preferably in
the range from 100:1 to 10:1 , particularly preferably in the range from 100:1 to 20:1.
The compounds of the formulae (I) and (ent-l) and (Ma), (lib), (lie), (ent-lla), (ent- Mb) and (ent-llc), i.e. all those compounds which fall within the general formula (III), are novel. The invention is based on the surprising recognition that these novel compounds, in particular the menthane carboxylic acid N- (alkylthioalkyl)amides of the formulae (I) and (ent-l) according to the invention and mixtures thereof, but in particular the compound of the formula (I), cause a strong and long-lasting sensation of coldness on the skin or mucous membranes, in particular on the mucous membranes of the oral, nasal and pharyngeal cavities. Said compounds here exhibit no other trigeminal effects such as spiciness, tingling or numbing and are bitter to only a very subordinate extent, if at all. At the same time, within the bounds of conventional formulations and conditions of preparation, the compounds according to the invention are resistant to hydrolysis in the range from pH 1 to pH 12, in particular in the range from pH 4 to pH 9, in relation to preparations containing water, such that the compounds and mixtures according to the invention have a long storage life in preparations and the particular preparation itself in turn has a long storage life.
Individual compounds of the formulae (Ma), (Mb), (Mc), (ent-lla), (ent-llb) and (ent- Mc), in particular those of the formula (Ma), exhibit, in comparison with the compounds of the formulae (I) and (ent-l), a distinctly weaker cooling action and/or unwanted flavor notes. The compounds of the formulae (Ma-Pr) and (Ma- Et), for example, exhibit a weak cooling action and a herbaceous, strongly bitter flavor which is desired or acceptable in only individual cases.
(Na-Pr) (Ma-Et)
In order to obtain the strongest possible cooling action simultaneously combined with the lowest possible bitterness, in mixtures (i.e. in combinations with compounds of the formulae (ent-l)) or blends (i.e. in combinations with compounds of the formulae (Ma), (Mb), (Mc), (ent-Ma), (ent-Mb) and (ent-Mc)) according to the invention, the proportion of compounds of the formula (I) is selected as high as possible, i.e. preferably greater than or equal to 90 wt.%, preferably greater than or equal to 95 wt.%, relative to the total weight of all the compounds of the formulae (I), (ent-l), (Na), (Mb), (lie), (ent-lla), (ent-Mb) and (entile) (compounds of the general formula (III)) contained in the mixture or blend.
The invention furthermore also relates to blends consisting of or comprising
(a) a compound according to the invention or a mixture of compounds according to the invention as described above (in particular in one of the preferred developments)
and
(c) one or more further substances having a physiological cooling action, wherein the further substance or one, several or all of the further substances (i) cause(s) a flavor effect or (ii) cause(s) no flavor effect,
and/or
(d) one or more aroma substances without a physiological cooling action
and/or
(e) one or more substances without a physiological cooling action which have a trigeminal or salivatory action
and optionally in turn a constituent (b) as defined above (i.e. one or more compounds of the formulae (Ma), (Mb), (Mc), (ent-Ma), (ent-Mb) and (ent-llc)).
Blends according to the invention which are particularly preferred are those which, in addition to constituent (a), comprise as constituent (c) one or more further substances having a physiological cooling action, these latter substances causing no flavor effect and no aroma action, but instead merely a (substantially) "pure" cooling action without any further sensory effect. This prevents the aroma profile of the blend being for example shifted towards "mint" (peppermint). Blends according to the invention which are very particularly preferred are those consisting of or comprising a constituent (a) and as constituent (d) one or more aroma substances without a physiological cooling action and/or as constituent (e) one or more substances which cause other trigeminal stimuli or a salivatory action. Such blends according to the invention have a pleasant cooling action and balanced sensory profile simultaneously combined with elevated impact, i.e. a strong initial flavor impression.
The one or more further substances having a physiological cooling action which may be used as constituent (c) in a blend according to the invention are here preferably selected from the following list: menthol and menthol derivatives (for example L-menthol, D-menthol, racemic menthol, isomenthol, neoisomenthol, neomenthol), menthyl ethers (for example (l-menthoxy)-1 ,2-propanediol, (I- menthoxy)-2-methyl-1 ,2-propanediol, l-menthyl methyl ether), menthyl esters (for example menthyl formate, menthyl acetate, menthyl isobutyrate, menthyl lactates, L-menthyl L-lactate, L-menthyl D-lactate, menthyl (2-methoxy)acetate, menthyl (2-methoxyethoxy)acetate, menthyl pyroglutamate), menthyl carbonates
(for example menthyl propylene glycol carbonate, menthyl ethylene glycol carbonate, menthyl glycerol carbonate or mixtures thereof), the semiesters of menthols with a dicarboxylic acid or the derivatives thereof (for example mono- menthyl succinate, mono-menthyl glutarate, mono-menthyl malonate, O-menthyl succinic acid ester N,N-(dimethyl)amide, O-menthyl succinic acid ester amide), menthane carboxamides other than those stated in the present invention (for example menthane carboxylic acid N-ethylamide [WS3], N α -(menthanecarbonyl) glycine ethyl ester [WS5], menthane carboxylic acid N-(4-cyanophenyl)amide, menthane carboxylic acid N-(alkoxyalkyl)amides), menthone and menthone derivatives (for example L-menthone glycerol ketal), 2,3-dimethyl-2-(2-propyl)- butanoic acid derivatives (for example 2,3-dimethyl-2-(2-propyl)-butanoic acid N- methylamide [WS23]), isopulegol or the esters thereof (l-(-)-isopulegol, l-(-)- isopulegol acetate), menthane derivatives (for example 3,8-p-menthanediol), cubebol or synthetic or natural blends containing cubebol, pyrrolidone derivatives of cycloalkyldione derivatives (for example 3-methyl-2(1-pyrrolidinyl)-2- cyclopenten-1-one) or tetrahydropyrimidin-2-one (for example icilin or related compounds, as described in WO 2004/026840).
The one or more further substances having a physiological cooling action which may be used as constituent (c) of a blend according to the invention are preferably substances which at least substantially cause a physiological cooling action without simultaneously causing a flavor action. Such preferred substances are: menthyl ethers (for example (l-menthoxy)-1 ,2-propanediol, (l-menthoxy)-2- methyl-1 ,2-propanediol), relatively highly polar menthyl esters (for example menthyl lactates, L-menthyl L-lactate, L-menthyl D-lactate, menthyl (2- methoxy)acetate, menthyl (2-methoxyethoxy)acetate, menthyl pyroglutamate), menthyl carbonates (for example menthyl propylene glycol carbonate, menthyl ethylene glycol carbonate, menthyl glycerol carbonate), the semiesters of menthol with a dicarboxylic acid or the derivatives thereof (for example mono- menthyl succinate, mono-menthyl glutarate, mono-menthyl malonate, O-menthyl succinic acid ester N,N-(dimethyl)amide, O-menthyl succinic acid ester amide), menthane carboxamides other than those stated in the present invention (for example menthane carboxylic acid N-ethylamide [WS3], N α -(menthanecarbonyl)
glycine ethyl ester [WS5], menthane carboxylic acid N-(4-cyanophenyl)amide, menthane carboxylic acid N-(alkoxyalkyl)amides), menthone derivatives (for example L-menthone glycerol ketal), 2,3-dimethyl-2-(2-propyl)-butanoic acid derivatives (for example 2,3-dimethyl-2-(2-propyl)-butanoic acid N-methylamide), pyrrolidone derivatives of cycloalkyldione derivatives (for example 3-methyl-2(1- pyrrolidinyl)-2-cyclopenten-1-on) or tetrahydropyrimidin-2-one (for example icilin or related compounds which are described in WO 2004/026840).
Specific blends of menthane carboxamides with cooling active ingredients such as acyclic carboxamides and L-menthyl lactate and optionally further cooling active ingredients or trigeminal stimulants are described for example in US 2005/0117811 ; said document, however, makes no mention of using the menthane carboxylic acid N-(alkylthioalkyl)amides according to the invention (compounds of the formulae (I) and (ent-l)). The substituents stated in US 2005/0117811 also provide no indication regarding the use of an alkylthioalkyl group.
The compounds according to the invention of the formulae (I) and (ent-l) or corresponding mixtures are preferably synthesized by reacting the corresponding menthane carboxylic acid, a corresponding menthane carboxylic acid chloride or another corresponding activated menthane carboxylic acid derivative with a corresponding alkylthioalkylamine or a corresponding salt. A menthane carboxylic acid comprising more than 90 wt.%, preferably more than 95 wt.%, of L-menthane carboxylic acid or an (L)-menthane carboxylic acid chloride or other activated (L)-menthane carboxylic acid derivative produced therefrom is preferably used for this purpose. Synthesis may proceed in accordance with per se known acylation methods. The invention furthermore also relates to a corresponding method for the production of a compound according to the invention or for the production of a mixture of compounds according to the invention.
A preferred synthetic pathway may be illustrated with reference to the following reaction scheme, which gives rise to a compound of the formula (I). A
corresponding synthetic pathway is, of course, preferred for the production of a compound of the formula (ent-l) and for the production of compounds of the formulae (Ma), (Mb), (Mc), (ent-Ma), (ent-Mb), (ent-Mc).
The L-menthane carboxylic acid (M1 ) may here be converted, for example using known methods, into the corresponding acid chloride (M2) by means of SOCI 2 , (COCI) 2 or PCI 3 .
This reaction may optionally proceed in the presence of other (auxiliary) substances or additives, for example in the presence of
(i) one or more solvents or diluents (for example water, water/1 ,4-dioxane mixtures, tetrahydrofuran, water/tetrahydrofuran mixtures, other ethers, chloroform, methylene chloride, ethyl acetate, acetone, acetone/water mixtures, alkanes, alcohols)
and/or
(ii) inorganic or organic auxiliary bases (for example triethylamine, other trialkylated amines, carbonates, hydroxides, basic oxides or hydrogencarbonates of alkali and/or alkaline earth metals, basic ion exchangers),
and/or
(iii) phase-transfer catalysts (for example peralkylated/perarylated ammonium salts or phosphonium salts, crown ethers),
and/or
(iv) enzymes and/or suitable microorganisms (in particular hydrolytic enzymes such as lipases, amidases, peptidases).
The crude products of the synthesis are preferably purified or concentrated by physical, optionally also enantioselective or enantiospecific separation methods, for example extraction, partition methods, crystallization, distillation, chromatography, sublimation, steam distillation, reverse osmosis, permeation or the like, the separation method preferably being selected such that, after the separation operation, the L-menthane carboxylic acid N-(alkylthioalkyl)amides of the formula (I) or (ent-l) or mixtures thereof are present in a proportion of greater than 90 wt.%, preferably greater than 95 wt.%, relative to the total quantity of compounds of the formulae (I), (ent-l), (Na), (Mb), (lie), (ent-lla), (ent-llb) and (ent- lie) (i.e. compounds of the general formula (III)) present in the purified product.
Preferred blends according to the invention have already been described above, which, in addition to a compound according to the invention or a mixture of compounds according to the invention (as constituent (a)), comprise as constituent (c) one or more further substances having a physiological cooling action. It has already been explained in this connection that the further substance or one, several or all of the further substances which are used as constituent (c) preferably cause no flavor effect; preferred corresponding further substances having a physiological cooling action have been stated. Particularly preferred blends according to the invention contain 0.05 to 90 wt.% of constituent (a) and 0.01 to 90 wt.% of constituent (c), wherein the respective explanations with regard to preferred developments of constituents (a) and (c) should be noted. In addition to constituents (a) and (c), such a preferred blend may obviously additionally comprise one or more of constituents (d), (e) or (b), as are stated further above. A preferred blend according to the invention may additionally
comprise one or more components from the group consisting of: solvents, carriers, other auxiliaries (such as for example dyes, preservatives, stabilizers and/or thickeners).
It is particularly preferred in blends according to the invention to use one or more aroma substances without a physiological cooling action (constituent (d)), wherein these aroma substances, in addition to their actual odorous aroma value, preferably also cause a flavor impression, a flavor-modulating effect or a trigeminal, but non-cooling effect or a salivatory stimulus. If said aroma substances cause a trigeminal or salivatory stimulus, they may simultaneously be regarded as constituent (e) of a blend according to the invention. It is preferred to use aroma substances which causes one or more of the following preferred flavor impressions, flavor-modulating effects or trigeminal stimuli:
preferred flavor impressions: sweet, umami, bitter, salty, sour;
preferred flavor-modulating effects: bitter-masking, umami-enhancing, sweet- enhancing, salt-enhancing, sour-masking;
preferred trigeminal stimuli: spiciness, heat, tingling, pungency.
Pellitorines according to WO 2004/000787 or US 2004/0241312 and alkene carboxylic acid N-alkylamides according to DE 103 51 422 are particularly preferred as constituent (d) of a blend according to the invention, i.e. as aroma substances without a physiological cooling action.
The invention furthermore also relates to preparations consumed for nutrition or for pleasure or used for oral hygiene or to pharmaceutical or cosmetic preparations, which preparations, in order to achieve a physiological cooling action on the skin and/or mucous membranes, comprise a sufficient quantity (a) of a compound according to the invention or a mixture according to the invention (preferably in a development which is stated to be preferred) or (b) of a blend according to the invention (preferably in a development which is stated to be
preferred). In particular, the quantity of the compound, mixture or blend used should be sufficient to achieve a physiological cooling action on the mucous membranes in the oral, nasal and/or pharyngeal cavities.
Preferred preparations according to the invention comprise conventional basic materials, auxiliary substances and additives for preparations consumed for nutrition or for pleasure or used for oral hygiene or for pharmaceutical or cosmetic preparations. Preferred preparations according to the invention contain
0.0001 wt.% to 20 wt.%, preferably 0.0001 to 10 wt.%, particularly preferably
0.001 wt.% to 0.5 wt.% of compounds of the formula (I), relative to the total weight the preparation. Further constituents, in particular compounds of the formula (ent-l) and constituents (b), (c), (d) and/or (e) and further conventional basic materials, auxiliary substances and additives may be present in quantities of 0.0000001 to 99.99 wt.%, preferably of 10 to 80 wt.%, relative to the total weight of the preparation. The preparations according to the invention may furthermore contain water in a quantity of up to 99.99 wt.%, preferably of 5 to
80 wt.%, relative to the total weight of the preparation.
The preparations consumed for nutrition or for pleasure are for example bakery products (for example bread, dry biscuits, cakes, other pastry products), confectionery (for example chocolates, chocolate bar products, other bar products, fruit gums, hard and soft caramels, chewing gum), alcoholic or nonalcoholic beverages (for example coffee, tea, wine, beverages containing wine, beer, beverages containing beer, liqueurs, spirits, brandies, fruit-containing carbonated beverages, isotonic beverages, soft drinks, nectars, fruit and vegetable juices, fruit or vegetable juice preparations), instant beverages (for example instant cocoa beverages, instant tea beverages, instant coffee beverages), meat products (for example ham, fresh or cured sausage preparations, spiced or marinated fresh or cured meat products), eggs or egg products (dried egg, egg white, egg yolk), cereal products (for example breakfast cereals, muesli bars, precooked ready rice products), dairy products (for example milk beverages, milk ice cream, yogurt, kefir, curd cheese, soft cheese, hard cheese, dried milk powder, whey, butter, buttermilk), fruit preparations (for
example jams, fruit ice cream, fruit sauces, fruit fillings), vegetable preparations (for example ketchup, sauces, dried vegetables, deep-frozen vegetables, precooked vegetables, preserved vegetables), snack articles (for example baked or fried potato chips or potato dough products, maize- or peanut-based extrudates), fat- or oil-based products or emulsions thereof (for example mayonnaise, remoulade, dressings), other ready-to-serve meals and soups (for example dried soups, instant soups, precooked soups), spices, seasoning mixtures and in particular powdered seasonings, which are for example used in snack food applications. The preparations for the purposes of the invention may also be used as semifinished products for the production of further preparations consumed for nutrition or for pleasure. The preparations for the purposes of the invention may also be nutritional supplements in the form of capsules, tablets (uncoated and coated tablets, for example coatings resistant to gastric juices), sugar-coated tablets, granules, pellets, mixtures of solids, dispersions in liquid phases, as emulsions, as powders, as solutions, as pastes or as other swallowable or chewable preparations.
Preparations for oral hygiene purposes are in particular dental care products such as toothpastes, tooth gels, tooth powders, mouthwashes, chewing gum and other oral care products.
Dental care products (as the basis for preparations for oral care purposes) which contain the compounds, mixtures or blends according to the invention generally comprise an abrasive system (abrasive or polishing agent), such as for example silicas, calcium carbonates, calcium phosphates, aluminum oxides and/or hydroxyapatites, surface-active substances such as for example sodium lauryl sulfate, sodium lauryl sarcosinate and/or cocamidopropyl betaine, humectants such as for example glycerol and/or sorbitol, thickeners, such as for example carboxymethylcellulose, polyethylene glycols, carrageenan and/or Laponite ® , sweeteners, such as for example saccharin, sodium cyclamate, sucralose, acesulfame-K or sugar alcohol flavor-correcting agents for unpleasant flavor impressions such as for example hydroxyflavanones according to US 2002/0188019, flavor-correcting agents for further, generally not unpleasant
flavor impressions, flavor-modulating substances (for example inositol phosphate, nucleotides such as guanosine monophosphate, adenosine monophosphate or other substances such as sodium glutamate or 2- phenoxypropionic acid), cooling active ingredients such as for example menthol, menthol derivatives (for example L-menthol, L-menthyl lactate, L-menthyl alkylcarbonates, menthone ketals, menthane carboxamides), 2,2,2- trialkylacetamides (for example 2,2-diisopropyl propionic acid methylamide), icilin and icilin derivatives, stabilizers and active ingredients, such as for example sodium fluoride, sodium monofluorophosphate, tin difluoride, quaternary ammonium fluorides, zinc citrate, zinc sulfate, tin pyrophosphate, tin dichloride, blends of different pyrophosphates, triclosan, cetylpyridinium chloride, aluminum lactate, potassium citrate, potassium nitrate, potassium chloride, strontium chloride, hydrogen peroxide, aromas and/or sodium bicarbonate or flavor- correcting agents.
Chewing gums (as a further example of the preparations for oral care purposes) which contain the compounds, mixtures or blends according to the invention generally comprise a chewing gum base, i.e. a chewable mass which becomes plastic on chewing, sugars of various kinds, sugar substitutes, other sweet- tasting substances, sugar alcohols, flavor-correcting agents for unpleasant flavor impressions, other flavor modulators for further, generally not unpleasant flavor impressions, flavor-modulating substances (for example inositol phosphate, nucleotides such as guanosine monophosphate, adenosine monophosphate or other substances such as sodium glutamate or 2-phenoxypropionic acid), humectants, thickeners, emulsifiers, aromas and stabilizers or flavor-correcting agents.
Pharmaceutical preparations according to the invention which are preferred for the purposes of the invention are oral preparations, which for example assume the form of capsules, tablets (uncoated and coated tablets, for example coatings resistant to gastric juices), sugar-coated tablets, granules, pellets, mixtures of solids, dispersions in liquid phases, as emulsions, as powders, as solutions, as pastes or as other swallowable or chewable preparations and are used as
prescription-only, drugstore-only or other medicaments or as nutritional supplements.
Cosmetic preparations according to the invention may for example be present in one of the following forms: soap, synthetic detergent, a liquid washing, shower or bath preparation, emulsion (as a solution, dispersion, suspension; cream, lotion or milk depending on the production method and constituents of the "water-in-oil" (VWO), "oil-in-water" (O/W) or multiple emulsion, PIT emulsion, emulsion foam, microemulsion, nanoemulsion or Pickering emulsion type), ointment, paste, gel (including hydrogel, hydrodispersion gel, oleogel), oil, toner, balsam, serum, powder, eau de toilette, toilet water, eau de cologne, perfume, wax, as a stick, roll-on, (pump) spray, aerosol (foaming, non-foaming or post-foaming), as a foot care product (including keratolytics, deodorant), beard shampoo or care preparations, insect-repellent product, sunscreen product, aftersun preparation, shaving preparation (for example shaving foams, soaps or gels) or aftershave preparation (balm, lotion), depilatory product, hair care product such as for example shampoo (including 2-in-1 shampoo, antidandruff shampoo, baby shampoo, shampoo for a dry scalp, shampoo concentrate), conditioner, hair tonic, hair water, hair rinse, hairdressing cream, pomade, permanent wave and setting lotion, hair smoothing product (detangling product, relaxer), hair strengthener, styling aid (for example gel or wax), blonding product, hair lightener, hair conditioner, hair foam, hair toning product, hair dyes (for example temporary, substantive, semipermanent, permanent hair dyes), nail care products such as for example nail polish and nail polish remover, deodorant and/or antiperspirant, mouthwash, water pick, makeup, makeup remover, eye care preparation, lip cosmetics, lip care preparation, decorative cosmetics (for example powder, eye shadows, kohl pencil, lipstick), bath articles (for example capsules) or mask.
Preparations according to the invention which comprise compounds according to the invention, a mixture according to the invention, or a blend according to the invention are preferably produced by incorporating the compound, the mixture or the blend, for example a blend comprising a solid or liquid carrier in addition to a
compound according to the invention, into a base preparation. Advantageously, blends according to the invention, which are initially in solution form and comprise a compound according to the invention, are converted into a solid preparation by spray drying.
According to an alternative, preferred embodiment, preparations according to the invention may be produced by initially incorporating the compounds, mixtures or blends according to the invention, optionally with further constituents of the preparation according to the invention, into emulsions, into liposomes, for example starting from phosphatidyl choline, into microspheres, into nanospheres or also into capsules, granules or extrudates prepared from a matrix suitable for foodstuffs and products consumed for pleasure, for example prepared from starch, starch derivatives (for example modified starch), cellulose or cellulose derivatives (for example hydroxypropylcellulose), other polysaccharides (for example dextrin, alginate, curdlan, carageenan, chitin, chitosan, pullulan), natural fats, natural waxes (for example beeswax, carnauba wax), prepared from proteins, for example gelatin or other natural products (for example shellac) or non-natural matrix materials (such as polyurea). In said embodiment, depending on the matrix, the products may be treated by spray drying, spray granulation, melt granulation, coacervation, coagulation, extrusion, melt extrusion, emulsion methods, coating or other suitable encapsulation methods and optionally a suitable combination of the above-stated methods.
In a further preferred production method, the compounds, mixtures or blends according to the invention are initially complexed with one or more suitable complexing agents, for example with cyclodextrins or cyclodextrin derivatives, preferably alpha-, beta- or gamma-cyclodextrin, and in used in this complexed form.
A particularly preferred preparation according to the invention is one in which the matrix is selected such that the compounds, mixtures or blends according to the invention, in particular blends comprising further cooling active ingredients and/or
aromas, are released from the matrix in delayed manner, such that a long-lasting cooling action is achieved.
Constituents for preparations consumed for nutrition or for pleasure according to the invention which may be used are conventional basic materials, auxiliary substances and additives for foodstuffs or products consumed for pleasure, for example water, mixtures of fresh or processed, plant or animal basic or raw materials (for example raw, roasted, dried, fermented, smoked and/or boiled meat, bone, cartilage, fish, vegetables, fruit, herbs, nuts, vegetable or fruit juices or pastes or mixtures thereof), digestible or non-digestible carbohydrates (for example sucrose, maltose, fructose, glucose, dextrins, amylose, amylopectin, inulin, xylans, cellulose, tagatose), sugar alcohols (for example sorbitol, erythritol), natural or hardened fats (for example tallow, lard, palm fat, coconut oil, hardened vegetable fat), oils (for example sunflower oil, peanut oil, maize germ oil, olive oil, fish oil, soya oil, sesame oil), fatty acids or the salts thereof (for example potassium stearate), proteinogenic or non-proteinogenic amino acids and related compounds (for example γ-aminobutyric acid, taurine), peptides (for example glutathione), native or processed proteins (for example gelatin), enzymes (for example peptidases), nucleic acids, nucleotides, flavor-correcting agents for unpleasant flavor impressions, further flavor-modulators for further generally not unpleasant flavor impressions, other flavor-modulating substances (for example inositol phosphate, nucleotides such as guanosine monophosphate, adenosine monophosphate or other substances such as sodium glutamate or 2- phenoxypropionic acid), emulsifiers (for example lecithins, diacylglycerols, gum arabic), stabilizers (for example carrageenan, alginate), preservatives (for example benzoic acid, sorbic acid), antioxidants (for example tocopherol, ascorbic acid), chelating agents (for example citric acid), organic or inorganic acidulants (for example malic acid, acetic acid, citric acid, tartaric acid, phosphoric acid), bitter substances (for example quinine, caffeine, limonene, amarogentin, humolone, lupolone, catechins, tannins), mineral salts (for example sodium chloride, potassium chloride, magnesium chloride, sodium phosphates), substances preventing enzymatic browning (for example sulfite, ascorbic acid), essential oils, plant extracts, natural or synthetic dyes or coloring pigments (for
example carotenoids, flavonoids, anthocyans, chlorophyll and the derivatives thereof), spices, trigeminally active substances or plant extracts containing such trigeminally active substances, synthetic, natural or nature-identical aroma substances or odoriferous substances and flavor-correcting agents.
Another aspect of the present invention relates to the use
(i) of a compound according to the invention or of a mixture according to the invention (as defined above, preferably in an above-described preferred development),
(ii) of a blend according to the invention (as described above, preferably in a development described as being preferred) or
(iii) of a preparation according to the invention (as described above, preferably in a development which is stated to be preferred),
(a) as a cooling substance, in particular for non-therapeutic purposes
or
(b) for the production of a medicament, in particular for the production of a medicament having a physiological cooling action.
A related aspect of the present invention relates to a method for achieving a physiological cooling action on the skin and/or mucous membranes. Such a method according to the invention may be carried out for therapeutic or non- therapeutic (for example cosmetic) purposes and comprises the following step:
application of a quantity sufficient for achieving a physiological cooling action
(i) of a compound according to the invention or of a mixture according to the invention (as defined above, preferably in an above-described preferred development),
(ii) of a blend according to the invention (as described above, preferably in a development described as being preferred) or
(iii) of a preparation according to the invention (as described above, preferably in a development which is stated to be preferred), onto the skin and/or mucous membranes.
A further aspect of the invention relates to the use of preparations according to the invention containing a compound according to the invention, a mixture according to the invention or a blend according to the invention, preferably a blend according to the invention which comprises one or more aroma substances and/or one or more further cooling active ingredients (cooling active ingredients which are not a compound of the general formula (III)), as semifinished products ("aroma blends") for aromatizing finished products produced using the semifinished products.
Further aspects of the present invention emerge from the following Examples and the appended claims.
Examples
The Examples merely serve to illustrate the invention without thereby limiting it. Unless otherwise stated, all stated values relate to weight.
Example 1 : Synthesis of L-menthane carboxylic acid N-(2- methylthioethvDamide
2-Methylthioethylamine (0.94 g, 10 mmol) and triethylamine (1.07 g, 10 mmol) are initially introduced into chloroform (30 ml) and, at 20-25°C, a solution of technical L-menthane carboxylic acid chloride (also contains L-neomenthane carboxylic acid chloride, 2.03 g, 10 mmol) in chloroform (10 ml) is added. The reaction mixture is stirred for 16 h at 20-25°C, then extracted by stirring with dilute hydrochloric acid (1 mol/l, 30 ml). The phases are separated and the organic phase is evaporated under a vacuum at 40°C in a rotary evaporator. The crude product (2.7 g) is purified on silica gel 60 with the eluents n-hexane/ethyl acetate from 3:1 on 1 :1 (vol/vol), L-menthane carboxylic acid N-(2- methylthioethyl)amide being obtained (crystalline, 820 mg, 94% according to GC).
MS (El): m/z = 257 (M+., 25%), 184 (100%), 83 (44%), 74 (100%), 55 (30%), 41 (22%), 139 (14%)
1 H-NMR (400 MHz, CDCI3): δ = 5.89 (1 H, NH), 3.47 (1 H, ddd, J = 14 Hz, J = 6.3 Hz, J = 5.8 Hz, H-1 '), 3.45 (1 H, ddd, J = 13.9 Hz, J = 6.4 Hz, J = 5.8 Hz, H-1 '),
2.66 (1H, dd, J = 14.3 Hz, J = 6.3 Hz, H-2'), 2.62 (1H, dd, J= 14.3 Hz, J= 6.3 Hz, H-2'), 2.19 (3H, s, S-CH 3 ), 2.02 (1H, dd J = 11.5 Hz, J = 3.4 Hz, H-3), 1.8-1.6 (4H, m), 1.53 (1H, tt, J= 11.3 Hz, J= 3.1 Hz), 1.35 (1H, m, H-1), 1.28-1.18 (1H, m), 1.06-0.92 (1 H, m, H-4), 0.90 (3H, d, J = 6.8 Hz, H-7 or 9), 0.89 (3H, d, J = 6.4 Hz, H-9or7), 0.79 (3H, d, J= 6.9 Hz, H-10)ppm.
Example 2: Synthesis of L-neomenthane carboxylic acid N-(2- methylthioethvDamide (compound of the formula (Ha-Et), not according to the invention)
The L-neomenthane carboxylic acid N-(2-methylthioethyl)amide (480 mg, 95% according to GC) is found in the first runnings of the chromatographic purification of the crude reaction product from Example 1.
MS (El): m/z = 257 (M+., 34%), 184 (98%), 83 (42%), 74 (100%), 55 (31%), 41 (30%), 139(14%)
1 H-NMR (400 MHz, CDCI3): δ = 5.84 (1 H, NH), 3.47 (1 H, ddd, J = 14 Hz, J = 6.4 Hz, J = 5.9 Hz, H-1'), 3.40 (1H, ddd, J = 13.8 Hz, J = 6.3 Hz, J = 5.7 Hz, H-1'), 2.65 (1H, dd, J = 13.7 Hz, J= 6.4 Hz, H-2'), 2.61 (1H, dd, J= 13.7 Hz, J= 6.4 Hz, H-2'), 2.57 (1H, m, H-3), 2.11 (3H, s, S-CH 3 ), 1.93-1.76 (5H, m), 1.70-1.56 (3H, m), 1.18 (1 H, dd, J= 5.7 Hz, J=LOHz), 1.05-0.97 (1 H, m, H-4), 0.91 (3H, d, J = 6.4 Hz, H-7, 9 or 10), 0.89 (3H, d, J = 6.5 Hz, H-9, 10 or 7), 0.83 (3H, d, J = 6.4 Hz, H-10, 7or9)ppm.
Example 3: Synthesis of L-menthane carboxylic acid N-(3- methylthiopropyDamide
L-Menthane carboxylic acid N-(3-methylthiopropyl)amide (crystalline, 0.93 g, 95%) is prepared from 3-methylthiopropylamine (1.07 g, 10 mmol) and technical L-menthane carboxylic acid chloride (2.02 g, 10 mmol) in a manner similar to Example 1.
1 H-NMR (400 MHz, CDCI3): δ = 5.70 (1 H, d, J = 5.3 Hz, NH), 3.39 (1 H, ddd, J = 13.5 Hz, J = 6.8 Hz, J = 6.1 Hz, H-1'), 3.33 (1 H, ddd, J = 13.5 Hz, J = 6.8 Hz, J =
5.9 Hz, H-1'), 2.53 (2 H, t, J = 7.1 Hz, H-3'), 2.11 (3H, s, S-CH3), 1.98 (1 H, ddd, J
= 12 Hz, J = 1 1.3 Hz, J = 4 Hz, H-3), 1.81 (1 H, m, J = 7 Hz, H-2'), 1.8-1.6 (6H, m), 1.52 (1 H, tt, J = 11.3 Hz, J = 3 Hz), 1.35 (1 H, m, H-1 ), 1.23 (1 H, m, J = 12
Hz), 1.05-0.92 (1 H, m, H-4), 0.90 (3H, d, J = 6.9 Hz, H-7 or 9), 0.89 (3H, d, J = 6.4 Hz, H-9 or 7), 0.78 (3H, d, J = 7 Hz, H-10) ppm.
Example 4: Synthesis of L-neomenthane carboxylic acid N-(3- methylthiopropyPamide (compound of the formula (Na-Pr), not according to the invention)
The L-neomenthane carboxylic acid N-(3-methylthiopropyl)amide (345 mg, 88% according to GC) is found in the first runnings of the chromatographic purification of the crude reaction product from Example 3.
1 H-NMR (400 MHz, CDCI 3 ): δ = 5.69 (1 H, s, NH), 3.37 (1 H, ddd, J = 13.6 Hz, J = 6.6 Hz, J = 6.1 Hz, H-1'), 3.29 (1 H, ddd, J = 13.6 Hz, J = 6.7 Hz, J = 5.8 Hz, H- V), 2.52 (2 H, t, J = 7.1 Hz, H-3'), 2.51 (1 H, m, H-3), 2.1 1 (3H, s, S-CH 3 ), 1.95- 1.75 (6H, m), 1.70-1.56 (3H, m), 1.17 (1 H, ddd, J = 13.4 Hz 1 J = 12.3 Hz, J = 5.3 Hz), 1.05-0.97 (1 H, m, H-4), 0.90 (3H, d, J = 6.7 Hz, H-7, 9 or 10), 0.89 (3H, d, J = 6.6 Hz, H-9, 10 or 7), 0.82 (3H, d, J = 6.5 Hz, H-10, 7 or 9) ppm.
Example of application 1 : Cooling action
The compounds from Examples 1 , 2 and 3 were tested for their sensory properties, in particular their cooling action. To this end, they were dissolved, in each case in a specific final concentration, in a mass prepared from sucrose
(saccharose) and water (confectioner's fondant, supplier Nordzucker AG,
Nordstemmen) and evaluated by a panel of experts. Sensory impressions were rated and the cooling action was assessed on a scale from 1 (no cooling action) to 9 (extremely strong cooling action).
Profile of L-menthane carboxylic acid N-(2-methylthioethyl)amide (Example 1 ) at a concentration of 0.05 wt.%, relative to the complete preparation: somewhat herbaceous, somewhat bitter, cooling action 7
Profile of L-neomenthane carboxylic acid N-(2-methylthioethyl)amide (Example 2, compound (Ha-Et), not according to the invention) at a concentration of 0.05 wt.%, relative to the complete preparation: herbaceous, strongly bitter, cooling action 1-2
Profile of L-menthane carboxylic acid N-(3-methylthiopropyl)amide (Example 3) at a concentration of 0.05%, relative to the complete preparation: somewhat bitter, cooling action 5
Exam le of a lication 2: Aroma blend for achievin a coolin action
A strongly cooling, but otherwise virtually flavorless and odorless aroma blend which is liquid at room temperature (20°C) is obtained by blending the components.
Exam le of a lication 3: Aroma blend for achieving a cooling action
A strongly cooling, but otherwise virtually flavorless and odorless aroma blend which is liquid at room temperature (20°C) is obtained by blending the components.
Example of application 4: Aroma blend for achieving an aromatizing and cooling action
A strongly cooling aroma blend with a strong odor of peppermint is obtained by blending the components.
Example of application 5: Aroma blend for achieving a cooling action with a simultaneous tingling effect
A strongly cooling aroma blend which stimulates salivation and causes a tingling effect is obtained by blending the components.
Example of application 6: Use in the form of an aroma blend in a toothpaste
The constituents of parts A and B were in each case individually premixed and in each case thoroughly stirred under a vacuum at 25-30°C for 30 minutes. Part C was premixed and added to A and B; D was added and the blend was thoroughly stirred under a vacuum at 25-30°C for a further 30 minutes. After relieving the vacuum, the toothpaste was ready and could be packaged.
Example of application 7: Use as cooling active ingredient in a sugar-free chewing gum
Parts A to D were mixed and vigorously kneaded. The crude mixture was processed into ready-to-use chewing gum, for example in the form of thin strips.
Example of application 8: Use as cooling active ingredient in a mouthwash
The constituents of parts A and B were in each case individually mixed. Part B was slowly stirred into part A until the blend was homogeneous.
Example of application 9: Throat candies with liquid/viscous core filling (centre-filled hard candy)
Candies with a liquid/viscous core were produced on the basis of the methods described in US 6,432,441 (Example 1 therein) and those described in US 5,458,894 or US 5,002,791. The two blends A and B were separately processed to form bases for the shell (blend A) or core (blend B). When consumed by affected individuals, the filled throat candies obtained by means of coextrusion were effective against coughing, sore throat and hoarseness.
Example of application 10: Chewing gum
Chewing gum base K2 consisted of the following ingredients: 28.5% terpene resin, 33.9% polyvinyl acetate (MW = 14,000), 16.25% hydrogenated vegetable oil, 5.5% mono- and diglycerides, 0.5% polyisobutene (MW 75,000), 2.0% butyl rubber (isobutene/isoprene copolymer), 4.6% amorphous silicon dioxide (water content approx. 2.5%), 0.05% antioxidant tert.-butylhydroxytoluene (BHT), 0.2% lecithin, and 8.5% calcium carbonate. Chewing gum base K2 and the chewing gum were produced in a similar manner to US 6,986,907.
The chewing gums of formulations (I) and (II) were shaped into strips, the chewing gum of formulation (III) was shaped into pellets.
Example of application 1 1 : Gelatin capsules for direct consumption
Gelatin capsules I, II, III suitable for direct consumption were produced according to WO 2004/050069 and in each case had a diameter of 5 mm, the weight ratio of core material to shell material being 90:10. The capsules in each case opened in the mouth within less than 10 seconds and dissolved completely within less than 50 seconds.
Example of application 12: Chewable candy
Manufacturing instructions:
a) allow gelatin to swell in water (1.8 times the quantity of gelatin) at 70°C for 2 hours;
b) boil sugar, syrup, water, fat and lecithin at 123°C;
c) slowly mix gelatin solution with the boiled batch;
d) stir in aroma from Example 2 and optionally color;
e) leave the resultant mass to adjust to approx. 70°C on a cooling table, then add fondant and aerate for approx. 3 minutes on a pulling machine;
f) then chop and package the chewable candy mass.
When the chewable candy is consumed, a fresh, cooling raspberry flavor is perceived during chewing.
Example of application 13: Extrudate
Manufacturing instructions (see also WO 03/092412):
All constituents were mixed and conveyed into an extruder by single point apportionment. Extrusion temperatures were between 100 and 120°C, specific energy input being 0.2 kWh/kg. The strands emerging from the die plate, which is provided with 1 mm holes, were chopped by rotating blades into approx. 1 mm diameter particles immediately on leaving the die.
Example of application 14: Fluidized bed granules
A solution consisting of 44 wt.% water, 8 wt.% lemon aroma, 3 wt.% aroma blend from Example of application 4, 13 wt.% gum arabic and 32 wt.% hydrolyzed
starch (Maltodextrin DE 15-19) and a little green dye is granulated in a granulating apparatus of the type presented in EP 163 836 (with the following features: diameter of distributor base plate: 225 mm, spray nozzle: two-fluid nozzle; pneumatic classifying discharge: zig-zag pneumatic classifier; filter: internal bag filter). The solution is sprayed into the fluidized bed granulator at a temperature of 32°C. The bed contents are fluidized by blowing in nitrogen in a quantity of 140 kg/h. The inlet temperature of the fluidizing gas is 140°C. The temperature of the exhaust gas is 76°C. The pneumatic classifying gas used is likewise nitrogen in an amount of 15 kg/h with a temperature of 50°C. The contents of the fluidized bed amounts to approx. 500 g. Granulation output amounts to approx. 2.5 kg per hour. Free-flowing granules are obtained having an average particle diameter of 360 micrometers. The granules are round and exhibit a smooth surface. On the basis of the constant pressure drop of the filter and of the likewise constant bed contents, steady-state conditions may be assumed to prevail with regard to the granulation process.
Example of application 15: Tea bag with rooibos or black tea and extrudates from Example of application 13 or granules from Example of application 14
800 g portions of red bush tea (rooibos tea) were mixed in one case with 33 g of the extrudates from Example of application 13 and in one case with 30 g of granules from Example of application 14, portioned and then packaged in tea bags.
800 g portions of black tea (leaf grade: fannings) were mixed in one case with 33 g of the extrudates from Example of application 13 and in one case with 30 g of granules from Example of application 14, portioned and then packaged in tea bags.