Heterocyclic compounds as physiological coolants

Abstract

The invention relates to new enantiomer compounds, physiological cooling agents, coolant mixtures containing said agents, mixtures of the enantiomer compounds or coolants with flavors, the use of said enantiomer compounds or cooling agents, and consumer products and final preparations containing the enantiomer compounds or the physiological coolants or coolant mixtures.

Description

HETEROCYCLIC COMPOUNDS AS PHYSIOLOGICAL COOLANTS Field of the invention

[0001] The present invention is in the field of physiological cooling agents and relates to new representatives of this group, the use of these cooling agents and articles and preparations comprising these cooling agents. Technological background

[0002] Physiological cooling agents are regularly used to produce a cool sensory impression on the skin or mucous membranes, for example, on the mucous membranes in the mouth, nose, and / or throat, although no actual physical cooling occurs, such as during the evaporation of solvents. Both individual components and mixtures can be used as physiological cooling agents. It should be noted that not all compounds that affect receptors in vitro, which are (also) involved in mediating a physiological cooling effect, actually produce such an effect in vivo on the skin or mucous membranes. In particular, such an effect will not always be identical.This means, for example, that the strength of the mediated physiological cooling effect and the course of the strength of the cooling effect over time cannot be determined solely from the fact that a particular compound is an agonist of a receptor involved in mediating a cooling impression.

[0003] TRP channels play an important role in the perception of temperature (hot-cold). TRP channels (transient receptor potential channels) are a large family of cellular ion channels that can be divided into seven subfamilies.

[0004] The cold-menthol receptor TRPM8 (also called cold-membrane receptor (CMR1) belongs to the family of “transient receptor potential ion channels”, is specifically expressed in a special group of neurons and forms pores in the cell membrane (four units combine to form a tetramer), which selectively absorb Ca 2+Allow ions to pass through. The protein has six transmembrane domains and a cytoplasmic C- and N-terminus. Low temperatures (preferably 10 to 25 °C) stimulate this receptor, resulting in signal transduction that is interpreted by the nervous system as a sensation of cold.

[0005] There is evidence that several TRP channels are important for growth control. Alterations in the expression of some of these channels can contribute to the development of cancer. For example, the expression of the TRPM8 gene is upregulated in prostate carcinomas. Accordingly, TRPM8 is also an attractive target molecule for the treatment of prostate or bladder cancer. State of the art

[0006] Cooling compounds, such as menthol, have long played an important role in the flavor and fragrance industry to create an association with freshness and cleanliness.

[0007] The best-known physiologically effective cooling agent is L-menthol. Menthol has been shown to act as a natural modulator of the TRPM8 receptor. Application of menthol activates TRPM8, causing Ca 2+ -influx into the cold-sensitive neurons. The resulting electrical signal is ultimately perceived as a sensation of cold.

[0008] However, menthol has some disadvantages, such as a strong odor, high volatility, and, in higher concentrations, a bitter and / or sharp taste, as well as a skin irritant effect. Excessive menthol concentrations can also cause irritation and an anesthetic effect on the skin or mucous membranes.

[0009] Previously, there was a search for strong cooling agents that did not have the adverse properties of L-menthol.

[0010] For example, lactic acid esters of menthol(s) were described according to DE 2608226 A1 and mixed carbonates with menthol(s) and polyols according to DE 4226043 A1 and menthone ketals according to EP 0507190 B1.

[0011] In addition, menthol derivatives with similar effects have been described in various publications.

[0012] Menthyl monoesters of diacids according to US 5,725,865 and US 5,843,466 are interesting naturally occurring alternatives, but cannot achieve the strength of the previously described cooling agents in sensory tests.

[0013] It was found that the compounds L-menthanecarboxylic acid ZV-ethylamide (“WS-3”) and especially / \ / a-(L-menthanecarbonyl)glycine ethyl ester (“WS-5”) are strong cooling agents. However, the latter, despite its strong effect, has the disadvantage of being susceptible to hydrolysis and thereby forming the corresponding free acid / \ / a-(L-menthanecarbonyl)glycine, which itself only exhibits a very weak cooling effect. Despite the detailed studies described, a systematic prediction of the properties of potential cooling agents, in particular their bitterness and / or other trigeminal effects, is not possible and has not been described. Thus, many molecules belonging to the class of menthanecarboxylic acid amides are strongly cooling, but often simultaneously exhibit pronounced bitter notes, such asthe menthanecarboxylic acid N-(alkyloxyalkyl)amides according to JP 2004 059474 A2 or are additionally highly irritating, such as N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycine ethyl ester, also known as WS-5, according to US. 2005 0222256 A1 , so that such compounds are not suitable for use in food preparations or the like.

[0014] / Va-(menthanecarbonyl)alkyloxyalkylamides were described in JP 2004 059474 A2. However, despite their strong cooling effect and high hydrolysis stability, these compounds have the disadvantage of being very bitter, and are therefore not suitable for use in food or cosmetic products for facial care.

[0015] Furthermore, menthyl glyoxylates and their hydrates have been described as cooling substances in JP 2005 343795 A2.

[0016] Overviews of the cooling agents produced and used to date are known to the person skilled in the art.

[0017] There are also isolated compounds that are structurally unrelated to menthol and cause significant TRPM8 modulation, such as the cooling agent WS-23 or the compounds listed in patent application WO 2007 019719 A1.

[0018] However, many of the TRPM8 modulators discovered so far have deficiencies in terms of potency, duration of action, skin / mucous membrane irritation, odor, taste, solubility, and volatility.

[0019] WO 2010 026094 A1 discloses individual compounds for modulating the TRPM8 receptor.

[0020] Further compounds for modulating the TRPM8 receptor are also proposed in WO 2011 061330 A2.

[0021] Special coolants with the carboxamide structure (I) are also known from WO 2012 061698 A1.

[0022] On the oral mucosa, many to all of the above-mentioned conventional and state-of-the-art cooling substances exhibit a more or less identical cooling effect. The cooling sensation they convey sets in after about 0.5 minutes, but then, after a peak of 3 to 5 minutes, subsides relatively quickly. The cooling effect is clearly noticeable for a maximum of 30 minutes, and experience has shown that its intensity and duration can be influenced only slightly by changing the dosage. However, consumers desire a in particular, the long-lasting cooling effect, which is associated with a corresponding feeling of freshness and well-being for the user. Object of the invention

[0023] The primary objective of the present invention was therefore to identify novel substances with a particular physiological cooling effect, preferably those that lead to a modulation of the TRPM8 receptor (so-called modulators), which can be used as alternatives, preferably as more suitable agents, to the previously known modulators. Such compounds should be particularly suitable for applications in the fields of cosmetics, nutrition, textiles, OTC products (e.g. burn ointments), pharmaceuticals (e.g. in the field of tumor treatment, bladder weakness) or packaging. The compounds or mixtures of compounds to be specified should preferably have as weak an intrinsic taste as possible, in particular have little or no bitterness and be as non-irritating as possible.

[0024] To achieve the objective of the invention, we primarily sought active ingredients capable of providing a particularly long-lasting cooling sensation. These active ingredients should also preferably be capable of providing particularly intense and / or rapidly onset cooling sensations, or delayed cooling sensations that build up slowly and last for a long time. The cooling agents should be efficient, meaning they should develop a strong cooling effect or sensation even at low concentrations.

[0025] A further object of the present invention was also to identify new compounds / substances which act as a modulator, in particular for in vivo and / or in vitro modulation, of the cold menthol receptor TRPM8, in particular as a TRPM8 receptor agonist or as a TRPM8 receptor antagonist, as a physiological cooling agent, as a flavoring agent, for improving the taste profile of a flavoring agent or as a bitter masking substance.

[0026] To date, there has been no evidence in the prior art that specific enantiomer compounds or enantiomer mixtures of the substance class described in the present invention have an improved cooling effect or the advantageous effects described above

[0027] The problem is solved by the subject matter of the independent patent claims. Further aspects of the present invention emerge from the wording of the dependent patent claims, the following description, and the examples. Detailed description of the invention

[0028] The primary object of the present invention is achieved by a physiological cooling agent selected from the group consisting of compounds represented by the general formula (Va) or by the general formula (Via) where in formulas (Va) and (Via) the radicals R1 and R2 may be the same or different and independently of one another have the following meanings: R1 as defined for formulas (I) to (IV); R2 is as defined for formulas (I) to (IV); or R1 and R2 together with the C atoms to which they are bonded form a conjugated or non-conjugated ring system; Y • is an optionally substituted branched alkyl group; or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted acyl group R-(C=O)-; or • an optionally substituted alkylaryl group; or • is an optionally substituted alkylheteroaryl group; Z • NH2; or • an NHRa group; or in which • an NRaRb group; or generally • an optionally substituted linear or branched alkyl group; mean or Formula • an optionally substituted linear or branched alkenyl (Va) group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted linear or branched alkoxy group; or • OH; or • an optionally substituted cycloalkyl group; or • an optionally substituted heterocycloalkyl group; or • an optionally substituted aryl group; or • is an optionally substituted heteroaryl group; or • is NH and together with X forms a heterocyclic ring; Z in the • NH2; or in general • an NHRa group or an NRaRb group, except for -NH-phenyl and -N(CH3)-phenyl; or Formula • an optionally substituted linear or branched alkyl group; (Via) or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted linear or branched alkoxy group, except -OC2H5 and -C(CH3)3; or • an optionally substituted cycloalkyl group; or • an optionally substituted heterocycloalkyl group; or • an optionally substituted aryl group; or • is an optionally substituted heteroaryl group; or NH and together with X forms a heterocyclic ring; m is 1; wherein the group Q is a radical selected from the group consisting of: halogen, -OA, -SA, -NBB, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -S(O)2 a , -S(O)2OA, -OS(O)2 a , - OS(O)2OA, -P(O)(OA) 2I -P(O)(OA)(OA), -C(O)A, -C(S)A, -C(NA)A, -C(O)OA, -C(S)OA, -C(O)NBB, -C(NA)NBB, -OC(O)A, -OC(S)A, -OC(O)OA, -OC(S)OA, -NAC(O)A, - NAC(S)A, -NAC(O)OA, -NAC(S)OA, -NAC(O)NBB, -NAC(NA)A or -NAC(NA)NBB; where A is selected from the group consisting of: Hydrogen, optionally substituted linear or branched alkyl group, in particular optionally substituted C1- to C18-alkyl group, in particular optionally substituted C1- to C16-alkyl group, particularly optionally substituted C1-, C2-, C3- or C4-alkyl group, optionally substituted linear or branched alkoxy group, in particular optionally substituted C1-C18-alkoxy group, particularly optionally substituted C1-, C2-, C3- or C4-alkoxy group, optionally substituted linear or branched alkylthio group, in particular optionally substituted C1- to C18-alkylthio group, particularly optionally substituted C1-, C2-, C3- or C4-alkylthio group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, optionally substituted heteroaryl group; and / or B represents A or, alternatively, two Bs together with the nitrogen atom to which they are bonded represent a four-, five-, six- or seven-membered heterocycloalkyl ring or heteroaryl ring, wherein the heterocycloalkyl ring or heteroaryl ring may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur; the optionally substituted linear or branched alkyl group is an optionally substituted C1- to C8-alkyl group, in particular an optionally substituted C1- to C8-alkyl group, particularly an optionally substituted C1-, C2-, C3- or C4-alkyl group;the optionally substituted linear or branched alkenyl group is an optionally substituted Ci- to Cw-alkenyl group, in particular an optionally substituted Ci- to C18-alkenyl group, especially an optionally substituted Ci-, C2-, C3- or C4-alkenyl group; the optionally substituted linear or branched alkynyl group is an optionally substituted Ci- to C18-alkynyl group, in particular an optionally substituted Ci- to C18-alkynyl group, especially an optionally substituted Ci-, C2-, C3- or C4-alkynyl group; the optionally substituted linear or branched alkoxy group is an optionally substituted Ci to Cw alkoxy group, in particular an optionally substituted Ci to C10 alkoxy group, especially an optionally substituted Ci, C2, C3 or C4 alkoxy group;the optionally substituted linear or branched alkylthio group is an optionally substituted Ci- to Cw-alkylthio group, in particular an optionally substituted Ci- to C12-alkylthio group, especially an optionally substituted Ci-, C2-, C3- or C4-alkylthio group; in the acyl group R-(C=O)-, the radical R is hydrogen or an optionally substituted linear or branched Ci- to C12-alkyl group, in particular an optionally substituted Ci- to C12-alkyl group; in particular represents an optionally substituted C1, C2, C3 or C4 acyl group; the optionally substituted cycloalkyl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered, monocyclic cycloalkyl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, cycloalkyl group; the optionally substituted aryl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered, monocyclic aryl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic aryl group;the optionally substituted heterocycloalkyl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered monocyclic heterocycloalkyl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, heterocycloalkyl group, wherein the heterocycloalkyl group may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;the optionally substituted heteroaryl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered monocyclic heteroaryl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, heteroaryl group, wherein the heteroaryl group may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Ra • an optionally substituted linear or branched alkyl group, and / or preferably a C1- to C3-alkyl group, preferably a methyl group; or Rb • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted acyl group R-(C=O)-; or • an optionally substituted cycloalkyl group; or • an optionally substituted aryl group; or • an optionally substituted heterocycloalkyl group; or • is / are an optionally substituted heteroaryl group; or • Ra and Rb, as defined above, are linked together to form a saturated or unsaturated ring; wherein the substituents are each selected independently of one another; and its salts, in particular acid addition salts, with inorganic or organic acids, wherein the coolant is present as a pure (R)-enantiomer, as a pure (S)-enantiomer, as a racemate or as a mixture of enantiomers; or represented by the general formula (V1a) or by the general formula (Villa) (Villa) where in the formulas (Vila) and (Villa) the radicals R1 and R2 may be the same or different and independently of one another have the following meanings: R1 as defined for formulas (I) to (IV); R2 is as defined for formulas (I) to (IV); or R1 and R2 together with the C atoms to which they are bonded form a conjugated or non-conjugated ring system; V • S; or • SO2; or • an optionally substituted linear or branched alkyl group; or • an optionally substituted cycloalkyl group; or • Piperidinyl is; Y • is an optionally substituted branched alkyl group; or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted acyl group is R-(C=O)-; Z • NH2; or • an NHRa group; or • an NRaRb group; or • an optionally substituted linear or branched alkyl group; or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted linear or branched alkoxy group; or • OH; or • an optionally substituted cycloalkyl group; or • an optionally substituted heterocycloalkyl group; or • an optionally substituted aryl group; or • is an optionally substituted heteroaryl group; or • NH is and together with the X forms a heterocyclic ring; m 1 ist; where Group Q is a residue selected from the Group consisting of: Halogen, -OA, -SA, -NBB, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -S(O)2A, -S(O)2OA, -OS(O)2A, -O(O)(O)(O) 2I -P(O)(OA)(OA), -C(O)A, -C(S)A, -C(NA)A, -C(O)OA, -C(S)OA, -C(O)NBB, -C(NA)NBB, -OC(O)A, -OC(S)A, -OC(O)OA, -O -NAC(O)OA, -NAC(S)OA, -NAC(O)NBB, -NAC(NA)A or -NAC(NA)NBB; where A selected is from the Group consisting of: Hydrogen, optionally substituted linear or branched alkyl group, in particular optionally substituted Ci- to Cw-alkyl group, in particular optionally substituted Ci- to Cc-alkyl group, particularly optionally substituted Ci-, C2-, C3- or C4-alkyl group, optionally substituted linear or branched alkoxy group, in particular optionally substituted Ci-Cc-alkoxy group, particularly optionally substituted Ci-, C2-, C3- or C4-alkoxy group, optionally substituted linear or branched alkylthio group, in particular optionally substituted Ci- to Ce-alkylthio group, particularly optionally substituted Ci-, C2-, C3- or C4-alkylthio group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, optionally substituted heteroaryl group; and / or B represents A or, alternatively, two Bs together with the nitrogen atom to which they are bonded represent a four-, five-, six- or seven-membered heterocycloalkyl ring or heteroaryl ring, wherein the heterocycloalkyl ring or heteroaryl ring may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur; the optionally substituted linear or branched alkyl group is an optionally substituted C1- to C8-alkyl group, in particular an optionally substituted C1- to C8-alkyl group, particularly an optionally substituted C1-, C2-, C3- or C4-alkyl group;the optionally substituted linear or branched alkenyl group is an optionally substituted Ci- to Cw-alkenyl group, in particular an optionally substituted Ci- to C18-alkenyl group, especially an optionally substituted Ci-, C2-, C3- or C4-alkenyl group; the optionally substituted linear or branched alkynyl group is an optionally substituted Ci- to C18-alkynyl group, in particular an optionally substituted Ci- to C18-alkynyl group, especially an optionally substituted Ci-, C2-, C3- or C4-alkynyl group; the optionally substituted linear or branched alkoxy group is an optionally substituted Ci to Cw alkoxy group, in particular an optionally substituted Ci to C10 alkoxy group, especially an optionally substituted Ci, C2, C3 or C4 alkoxy group;the optionally substituted linear or branched alkylthio group is an optionally substituted Ci- to Cw-alkylthio group, in particular an optionally substituted Ci- to C12-alkylthio group, especially an optionally substituted Ci-, C2-, C3- or C4-alkylthio group; in the acyl group R-(C=O)-, the radical R is hydrogen or an optionally substituted linear or branched Ci- to C12-alkyl group, in particular an optionally substituted Ci- to C12-alkyl group, especially an optionally substituted Ci-, C2-, C3- or C4-acyl group; the optionally substituted cycloalkyl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered, monocyclic cycloalkyl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, cycloalkyl group;the optionally substituted aryl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered, group; monocyclic aryl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, aryl group; the optionally substituted heterocycloalkyl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six-, or seven-membered monocyclic heterocycloalkyl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, heterocycloalkyl group, where the heterocycloalkyl group may comprise one, two, three, or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;the optionally substituted heteroaryl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered monocyclic heteroaryl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, heteroaryl group, wherein the heteroaryl group may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Ra • an optionally substituted linear or branched alkyl group; and / preferably a C1- to C3-alkyl group, preferably a methyl group; or Rb • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted acyl group R-(C=O)-; or • an optionally substituted cycloalkyl group; or • an optionally substituted aryl group; or • an optionally substituted heterocycloalkyl group; or • is / are an optionally substituted heteroaryl group; or • Ra and Rb, as defined above, are linked to one another and form a saturated or unsaturated ring; wherein the substituents are each selected independently of one another; and its salts, in particular acid addition salts, with inorganic or organic acids, wherein the coolant is present as a pure (R)-enantiomer, as a pure (S)-enantiomer, as a racemate or as a mixture of enantiomers.

[0029] The present invention also includes those physiological cooling agents in which the oxazole ring of the basic structure of the general Formula (Vila) the oxygen atom is replaced by a sulfur atom, ie the oxazole ring of the basic structure of the general formula (Vila) is a thiazole ring.

[0030] Of the compounds of general formulas (Va) to (Villa), those compounds in which the heterocyclic ring of the basic structure of general formulas (Va) to (Villa) has at least two nitrogen atoms are particularly preferred due to the free electron pairs suitable for forming a covalent bond (so-called Lewis bases), i.e., compounds of general formula (Va) with a triazine ring in the basic structure, or compounds of general formula (Via) with a pyrazine ring (diazine) in the basic structure, or compounds of general formula (Villa) with an imidazole ring. Such compounds exhibit particularly pronounced cooling attributes, as described below.

[0031] Due to their Lewis base character, compounds of general formula (Va) with a triazine ring in the basic structure and compounds of general formula (Vila) with an oxazole ring in the basic structure are most preferred. Such compounds are characterized by a particularly intense cooling effect.

[0032] In the context of the present invention, in particular for the definition of the general formulas (Va) to (Villa), the following general meanings apply:

[0033] The term "or" or "and / or" is used as a function word to indicate that two words or expressions should be taken together or separately.

[0034] The terms "comprising", "with", "including" and "containing" are to be understood as open terms, i.e. "comprehensive", "including" or "containing", but not "limited to" 1 .

[0035] The endpoints of all scopes that point to the same component or property can be combined inclusively and independently.

[0036] The term "enantiomer" refers to stereoisomers of chemical compounds that are identical in their constitution and behave in their spatial structures like their (non-superimposed) mirror image. Due to this fact, they are also called mirror image isomers. The molecular formula and the connection of the respective atomic formations are the same. This is a form of configurational isomerism; unlike conformational isomers, enantiomers cannot be made to superimpose by rotating atomic bonds. Since enantiomers have the opposite configuration in all stereocenters, theoretically there is always a (-) and a (+) enantiomer, or an (R) and an (S) enantiomer. An enantiomeric mixture or enantiomeric mixture is a mixture of substances in which the mixture consists of two enantiomers. If the mass ratio of the enantiomers is 1:1, the mixture is called Enantiomer mixture or the enantiomer mixture is a racemate. If the mass ratio of the If the ratio of enantiomers is different from 1:1, this mixture of substances is called a non-racemic enantiomer mixture or a non-racemic enantiomer mixture.

[0037] The term "coolant(s)" or "coolant(s) of the present invention" refers to all compounds encompassed by the structural formulas Formula (Va), Formula (Via), Formula (Vila), or Formula (Villa) disclosed herein, and includes each subgenus and all specific compounds within the formula whose structure is disclosed herein. The compounds can be identified either by their chemical structure and / or their chemical name. When the chemical structure and chemical name conflict, the chemical structure determines the identity of the compound. The compounds described herein may contain one or more chiral centers and / or double bonds and may therefore exist as stereoisomers, such as double bond isomers, i.e., geometric isomers, enantiomers, or diastereomers.Accordingly, the chemical structures of the general formulas (Va) to (Villa) presented here include all possible enantiomers and diastereomers or stereoisomers.

[0038] The term “at least one cooling agent 1 in the context of the present invention means that, for example, a composition contains at least one cooling agent, but can also contain two, three, four or even more different cooling agents.

[0039] The term "alkyl" alone or as part of another substituent according to the present invention refers to a saturated or mono- or polyunsaturated linear or branched monovalent hydrocarbon radical obtained by removing a hydrogen atom from a single carbon atom of a corresponding starting alkane.

[0040] In a preferred variant, the term “alkyl” also includes all alkyl parts in radicals derived therefrom, such as alkoxy, alkylthio, alkylsulphonyl saturated linear or branched hydrocarbon radicals having 1 to 10, 1 to 8, 1 to 6 or 1 to 4 carbon atoms.

[0041] When the alkyl radical is further bonded to another atom, it becomes an alkylene radical, or alkyl group. In other words, the term "alkylene" also refers to a divalent alkyl. For example, -CH2CH3 is ethyl, while -CH2CH2- is ethylene.

[0042] The term "alkylene," alone or as part of another substituent, refers to a saturated linear or branched divalent hydrocarbon radical obtained by removing two hydrogen atoms from a single carbon atom or two different carbon atoms of a parent alkane.

[0043] In preferred variants according to the present invention, an alkyl group or an alkylene group comprises 1 to 10 carbon atoms. In other even more In preferred variants, an alkyl group or alkylene group comprises 1 to 6 carbon atoms.

[0044] Most preferred are alkyl groups or alkylene groups having 1 to 4 carbon atoms.

[0045] Preferred alkyl radicals or alkyl groups include, but are not limited to: Ci- bis Ce-Alkyl, umfassend Methyl, Ethyl, Propyl, 1 -Methylethyl, Butyl, 1-Methyl-propyl, 2- Methylpropyl, 1 , 1-Dimethylethyl, Pentyl, 1-Methylbutyl, 2-Methylbutyl, 3-Methylbutyl, 2,2- Dimethylpropyl, 1-Ethylpropyl, Hexyl, 1 ,1 -Dimethylpropyl, 1 ,2-Dimethylpropyl, 1 -Methylpentyl, 2- Methylpentyl, 3-Methylpentyl, 4-Methylpentyl, 1 , 1-Dimethylbutyl, 1 ,2-Dimethylbutyl, 1 ,3- Dimethylbutyl, 2,2-Dimethylbutyl, 2,3-Dimethylbutyl, 3,3-Dimethylbutyl, 1 -Ethylbutyl, 2- Ethylbutyl, 1 ,1 ,2-Trimethylpropyl, 1 ,2,2-Trimethylpropyl, 1-Ethyl-1-methylpropyl und 1-Ethyl-2- methylpropyl; Ci- to Ce-alkoxy, comprising Ci- to C4-alkoxy, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy; as well as pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-Ethyl-2-methylpropoxy.

[0046] Most preferred according to the invention are saturated linear or branched Ci to Ce alkyl groups or saturated linear or branched Ci to Ce alkylene groups.

[0047] The term "alkyl" or "alkylene" also includes radicals or groups with any degree of saturation, ie groups with only single carbon-carbon bonds ("alkyl" or "alkylene"), groups with one or more double carbon-carbon bonds ("alkenyl"), radicals with one or more triple carbon-carbon bonds ("alkynyl") and groups with a mixture of single, double and / or triple carbon-carbon bonds.

[0048] The term "alkenyl," alone or as part of another substituent, according to the present invention refers to an unsaturated linear or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond (C=C double bond). The radical can be in either the cis or trans conformation around the double bond(s). Thus, the term "alkenyl" also encompasses the corresponding cis / trans isomers.

[0049] Typical alkenyl residues or alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2- en-2-yl, cycloprop-1-en-1-yl, cycloprop-2-en-1-yl; Butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl and the like.

[0050] In preferred variants according to the present invention, an alkenyl group comprises 2 to 10 carbon atoms. In other preferred variants, an alkenyl group comprises 2 to 6 carbon atoms. In even more preferred variants, an alkenyl group comprises 2 to 4 carbon atoms.

[0051] Most preferred according to the invention are mono- or di-unsaturated linear or branched Ci- to Ce-alkenyl groups.

[0052] The term "alkynyl" alone or as part of another substituent according to the present invention refers to an unsaturated linear or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond (C=C triple bond).

[0053] Typical alkynyl radicals or alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, and the like.

[0054] In preferred variants according to the present invention, an alkynyl group comprises 2 to 10 carbon atoms. In other preferred variants, an alkynyl group comprises 2 to 6 carbon atoms. In even more preferred variants, an alkynyl group comprises 2 to 4 carbon atoms.

[0055] The term "alkoxy" alone or as part of another substituent according to the present invention refers to a radical of the formula -OR, where R is alkyl or substituted alkyl as defined herein.

[0056] The term "alkylthio" or "thioalkoxy" alone or as part of another substituent according to the present invention refers to a radical of the formula -S- R, where R is alkyl or substituted alkyl as defined herein.

[0057] The term "alkyl" or "alkylene" also encompasses heteroalkyl radicals or heteroalkyl groups according to the invention. The term "heteroalkyl," by itself or as part of other substituents, refers to alkyl groups in which one or more of the carbon atoms is / are independently replaced by the same or another heteroatom or by the same or another heteroatomic group. Typical heteroatoms or heteroatomic groups that can replace the carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, and the like, and combinations thereof. The heteroatoms or heteroatomic groups can be located at any internal position of the alkyl group. Typical heteroatomic groups that can be contained in these groups include: without being limited to, -O-, -S-, -OO-, -SS-, -O-S-, -NRR-, =NN=, -N=N-, -N=N- NRR, -PR-, -P(O)2-, -POR-, -O-P(O)2-, -SO-, -SO2-, -SR2OR- and the like, wherein R independently represents hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl, as defined herein.

[0058] The alkyl group or the alkylene group, as defined above, may further be substituted.

[0059] The term "acyl" alone or as part of another substituent according to the present invention refers to a radical -R(C=O)-, where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl, as defined herein.

[0060] Representative examples include, but are not limited to, formyl, acetyl, propionyl, butyryl, valeryl, benzoyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzylcarbonyl, and the like.

[0061] The term "cycloalkyl" alone or as part of another substituent according to the present invention refers to a saturated or mono- or polyunsaturated, non-aromatic, cyclic monovalent hydrocarbon radical in which the carbon atoms are linked together in a ring and which does not contain a heteroatom.

[0062] The carbon ring can occur as a monocyclic compound, which has only a single ring, or as a polycyclic compound, which has two or more rings.

[0063] In a preferred variant, the term "cycloalkyl" encompasses a three- to ten-membered monocyclic cycloalkyl radical or cycloalkyl group, or a nine- to twelve-membered polycyclic cycloalkyl radical or cycloalkyl group. In other, even more preferred variants, the cycloalkyl radical encompasses a three-, four-, five-, six-, or seven-membered monocyclic cycloalkyl radical or a nine- to twelve-membered bicyclic cycloalkyl radical.

[0064] In a preferred variant according to the present invention, a cycloalkyl radical or group comprises 3 to 20 carbon atoms. In an even more preferred variant, a cycloalkyl radical comprises 3 to 15 carbon atoms. In a most preferred variant, a cycloalkyl radical comprises 3 to 10 carbon atoms. Most preferred are monocyclic C3 to C12 cycloalkyl groups.

[0065] Typical cycloalkyl groups include, but are not limited to, saturated carbocyclic radicals having 3 to 20 carbon atoms, such as C3 to C12 carbocyclyl, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl; Cyclopentyl, cyclohexyl, cycloheptyl, and cyclopropyl-methyl, cyclopropyl-ethyl, cyclobutyl-methyl, cyclobutyl-ethyl, cyclopentyl-methyl, cyclopentyl-ethyl, cyclohexyl-methyl, or C3- to CyCarbocyclyl, comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropyl-methyl, cyclopropyl-ethyl, cyclobutyl-methyl, cyclopentyl-ethyl, are preferred. Cyclohexyl-methyl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl and the like.

[0066] Preferred saturated polycyclic cycloalkyl radicals or cycloalkyl groups according to the invention include, but are not limited to, adamantyl groups and the like.

[0067] According to the invention, the term "cycloalkyl" also encompasses cycloalkenyls, i.e., unsaturated, cyclic hydrocarbon radicals containing C=C double bonds between two carbon atoms of the ring molecule. In a broader sense, cycloalkenyls are compounds with one, two, or more double bonds, whereby the number of possible, mostly conjugated, double bonds in the molecule depends on the ring size.

[0068] Typical cycloalkenyls include, but are not limited to, cyclopropenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.

[0069] According to the invention, the term “cycloalkyl” also includes cycloalkynyls, ie unsaturated, cyclic hydrocarbon radicals containing -C=C triple bonds between two carbon atoms of the ring molecule, wherein the triple bond depends on the ring size for reasons of ring strain.

[0070] Typical cycloalkynes include cyclooctyne.

[0071] The attachment of the cycloalkyl radical or the cycloalkyl group to the rest of the molecule of formula (I) and / or formula (II) can be via any suitable C atom.

[0072] The cycloalkyl radical or the cycloalkyl group, as defined above, may also be substituted.

[0073] The term "aryl" alone or as part of another substituent according to the present invention refers to a monovalent aromatic hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom of an aromatic ring system.

[0074] In a preferred variant, the term "aryl" encompasses a three- to ten-membered monocyclic aryl radical or aryl group, or a nine- to twelve-membered polycyclic aryl radical or aryl group. In other, even more preferred variants, the carboaryl radical encompasses a three-, four-, five-, six-, or seven-membered monocyclic carboaryl radical or a nine- to twelve-membered bicyclic carboaryl radical.

[0075] In a preferred variant according to the present invention, the aryl radical comprises 3 to 20 carbon atoms. In an even more preferred variant, an aryl radical comprises 3 to 15 carbon atoms. In a most preferred variant, an aryl radical comprises 3 to 10 carbon atoms. Most preferred according to the invention are monocyclic C3 to C12 aryl groups. Most preferred are monocyclic C3 to C12 aryl groups.

[0076] Typical aryl radicals include, but are not limited to, benzene, phenyl, biphenyl, naphthyl such as 1- or 2-naphthyl, tetrahydronaphthyl, fluorenyl, indenyl, and phenanthrenyl. Typical carboaryl radicals further include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0077] Aromatic polycyclic aryl radicals or aryl groups preferred according to the invention include, but are not limited to, naphthalene, biphenyl and the like.

[0078] The attachment of the aryl residue or the aryl group to the rest of the molecule of formulas (I) to (VIII) and (Va) to (Villa) can be via any suitable C atom.

[0047] The aryl radical or group, as defined above, may further be substituted. For example, the aryl radical forms an anisole group.

[0079] The term "arylalkyl," alone or as part of another substituent, according to the present invention refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced by an aryl group as defined herein. In other words, arylalkyl can also be considered aryl-substituted alkyl. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like.

[0080] The term "heteroarylalkyl", alone or as part of another substituent, refers to a cyclic alkyl group in which one or more of the hydrogen atoms attached to a carbon atom are replaced by a heteroaryl group.

[0081] In a preferred variant according to the present invention, the heteroarylalkyl group is a 6- to 20-membered heteroarylalkyl, e.g., the alkanyl, alkenyl, or alkynyl group of the heteroarylalkyl is a C1- to C18-alkyl, and the heteroaryl group is a 5- to 15-membered heteroaryl group. In other embodiments, the heteroarylalkyl is a 6- to 13-membered heteroarylalkyl, e.g., the alkanyl, alkenyl, or alkynyl group is a C1- to C16-alkyl, and the heteroaryl group is a 5- to 10-membered heteroaryl.

[0082] The term "heterocycloalkyl," alone or as part of another substituent, according to the present invention refers to a saturated, non-aromatic, cyclic monovalent hydrocarbon radical in which one or more carbon atoms are independently replaced by the same or another heteroatom. Typical heteroatoms for replacing the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Typical heterocycloalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidone, quinuclidine, and the like.

[0083] The heterocycloalkyl radical can occur as a monocyclic compound having only a single ring or as a polycyclic compound having two or more rings.

[0084] The term "heterocycloalkyl" preferably encompasses three- to seven-membered, saturated or mono- or polyunsaturated heterocycloalkyl radicals comprising one, two, three, or four heteroatoms selected from the group consisting of O, N, and S. The heteroatom(s) may occupy any position in the heterocycloalkyl ring.

[0085] In a preferred variant, the term "heterocycloalkyl" encompasses a three- to ten-membered monocyclic heterocycloalkyl radical or a nine- to twelve-membered polycyclic heterocycloalkyl radical. In other, even more preferred variants, the heterocycloalkyl radical encompasses a three-, four-, five-, six-, or seven-membered monocyclic heterocycloalkyl radical or a nine- to twelve-membered bicyclic heterocycloalkyl radical.

[0086] In a preferred variant according to the present invention, the "heterocycloalkyl" radical or heterocycloalkyl group comprises 3 to 20 ring atoms. In a preferred variant, the heterocycloalkyl radical comprises 3 to 15 ring atoms. In an even more preferred variant, the heterocycloalkyl radical comprises 3 to 10 carbon atoms. Most preferred according to the invention are monocyclic heterocycloalkyl radicals with 3 to 12 carbon atoms. Most preferred are monocyclic heterocycloalkyl radicals with 5 to 7 ring atoms.

[0087] Typical heterocycloalkyl radicals include, but are not limited to: three to six-membered, saturated heterocycloalkyl containing one or two nitrogen atoms and / or one oxygen or sulfur atom or one or two oxygen and / or sulfur atoms as ring members, including aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-Hexahydropyridazinyl, 4-Hexahydropyridazinyl, 2-Hexahydropyrimidinyl, 4- Hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl and the like.

[0088] The heterocycloalkyl radical or group, as defined above, may further be substituted.

[0089] The heterocycloalkyl radical or the heterocycloalkyl group can be bonded to the rest of the molecule of the formulas (I) to (VIII) and (Va) and (VIII) via a ring carbon atom or a ring heteroatom.

[0090] The term "heteroaryl" alone or as part of another substituent according to the present invention refers to a monovalent heteroaromatic radical obtained by removing a hydrogen atom from a single atom of a heteroaromatic ring system. Typical heteroaryl residues or heteroaryl groups include, but are not limited to, those groups derived from acridine, ß-carboline, chromane, chromium, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromium, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazole, xanthene and the like.

[0091] The heteroaryl residue can occur as a monocyclic compound having only a single ring or as a polycyclic compound having two or more rings.

[0092] In a preferred variant, the term "heteroaryl" comprises a three- to ten-membered monocyclic heteroaryl radical or a nine- to twelve-membered polycyclic heteroaryl radical. In other even more preferred variants, the Heteroaryl radical means a three-, four-, five-, six- or seven-membered monocyclic heteroaryl radical or a nine- to twelve-membered bicyclic heteroaryl radical.

[0093] The term "heteroaryl" preferably encompasses three- to seven-membered monocyclic heteroaryl radicals comprising one, two, three, or four heteroatoms selected from the group consisting of O, N, and S. The heteroatom(s) may occupy any position in the heteroaryl ring.

[0094] In a preferred variant according to the present invention, the heteroaryl radical or heteroaryl group comprises 3 to 20 ring atoms. In an even more preferred variant, the heteroaryl radical comprises 6 to 15 ring atoms. In a most preferred variant, the heteroaryl group comprises 6 to 10 ring atoms. Monocyclic C3 to C6 heteroaryl groups are most preferred according to the invention.

[0095] Particularly preferred heteroaryl radicals or heteroaryl groups include, but are not limited to, those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole and pyrazine.

[0096] Three-membered aromatic heteroaryl radicals containing, in addition to carbon atoms, a nitrogen or a sulfur or an oxygen atom as ring atoms include azirinyl, oxirenyl or thiirenyl.

[0097] Four-membered aromatic heteroaryl radicals containing, in addition to carbon atoms, a nitrogen or a sulfur or an oxygen atom as ring atoms include acetyl, oxetium ion or thietium ion.

[0098] Five-membered aromatic heteroaryl radicals containing, in addition to carbon atoms, one, two or three nitrogen atoms or one or two nitrogen atoms and one sulfur or oxygen atom as ring atoms, include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, and 1,3,4-triazol-2-yl.

[0099] Five-membered aromatic heteroaryl radicals containing one, two, three or four nitrogen atoms as ring atoms include 1-, 2- or 3-pyrrolyl, 1-, 3- or 4-pyrazolyl, 1-, 2- or 4-imidazolyl, 1,2,3-[1H]-triazol-1-yl, 1,2,3-[2H]-triazol-2-yl, 1,2,3-[1H]-triazol-4-yl, 1.2.3-[1 H]-Triazol-5-yl, 1 ,2, 3-[2H]-Triazol-4-yl, 1 ,2,4-[1 H]-Triazol-1-yl, 1 ,2 ,4-[1 H]-Triazol-3-yl, 1.2.4-[1 H]-Triazol-5-yl, 1 ,2,4-[4H]-Triazol-4-yl, 1 ,2,4-[4H]-Triazol-3-yl, [1 H]-Tetrazol-1-yl, [1 H]- Tetrazol-5-yl, [2H]-Tetrazol-2-yl, [2H]-Tetrazol-5-yl und dergleichen.

[0100] Fünfgliedrige aromatische Heteroaryl-Reste, enthaltend ein unter Sauerstoff oder Schwefel ausgewähltes Heteroatom und gegebenenfalls ein, zwei oder drei Stickstoffatome als Ringatome, umfassen 2-Furyl, 3-Furyl, 2-Thienyl, 3-Thienyl, 3- oder 4-lsoxazolyl, 3- oder 4-lsothiazolyl, 2-, 4- oder 5-Oxazolyl, 2-, 4- oder 5-Thiazolyl, 1 ,2,4-Thiadiazol-3-yl, 1,2,4- Thiadiazol-5-yl, 1 ,3,4-Thiadiazol-2-yl, 1 ,2,4-Oxadiazol-3-yl, 1,2,4-Oxadiazol-5-yl und 1,3,4- Oxadiazol-2-yl.

[0101] Six-membered heteroaryl radicals containing, in addition to carbon atoms, one or two or one, two or three nitrogen atoms as ring atoms, and include, for example, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,2,4-triazin-3-yl; 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl and 1,3,5-triazin-2-yl.

[0102] The heteroaryl residue or group, as defined above, may also be substituted.

[0103] The heteroaryl residue or group may be bonded to the rest of the molecule of formula (I) to formula (VIII) and (Va) and (VIII) via a ring carbon atom or a ring heteroatom.

[0104] Of the above-mentioned monocyclic heteroaryl radicals, particularly preferred in the context of the present invention are those heteroaryl radicals which are derived from the five- or six-membered saturated compounds comprising pyrrolidone, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothipyran or from the five- or six-membered aromatic compounds comprising pyrrole, furan, thiophene, pyridine, pyrylium ion and thiopyrylium ion, pyrazole, imidazole, imidazoline, pyrimidine, oxazole, thiazole and 1,4-thiazine.

[0105] The term "arylalkyl," alone or as part of another substituent, according to the present invention refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced by an aryl group as defined herein. In other words, arylalkyl can also be considered aryl-substituted alkyl. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like.

[0106] The term "heteroarylalkyl," alone or as part of another substituent, refers to a cyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group.

[0048] In a preferred variant according to the present invention, the heteroarylalkyl group is a 6- to 20-membered heteroarylalkyl, e.g., the alkanyl, alkenyl, or alkynyl group of the heteroarylalkyl is a C1- to C18-alkyl, and the heteroaryl group is a 5- to 15-membered heteroaryl group. In other embodiments, the heteroarylalkyl is a 6- to 13-membered heteroarylalkyl, e.g., the alkanyl, alkenyl, or alkynyl group is a C1- to C16-alkyl, and the heteroaryl group is a 5- to 10-membered heteroaryl.

[0107] The term "substituted" in the context of the present invention means that one or more hydrogen atoms of the specified radical or radical are independently replaced by the same or another substituent.

[0108] Substituents or substituent groups useful for substituting saturated carbon atoms in the indicated group or radical include, but are not limited to, -X, halo, =O, -OY, -SiR3, -SY, =S, -NZZ, =NY, =N-OY, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY) 2I-P(O)(OY)(OY), -C(O)Y, -C(S)Y, -C(NY)Y, -C(O)OY, - C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, -NYC(O)Y, - NYC(S)Y, -NYC(O)OY, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y or -NYC(NY)NZZ; where X is selected from the group consisting of optionally substituted alkyl radical, in particular optionally substituted Ci- to Cw-alkyl group, in particular optionally substituted Ci-Cß-alkyl radical, especially optionally substituted Ci-, C2-, C3- or C4-alkyl group, optionally substituted alkoxy radical, in particular optionally substituted Ci-Cß-alkoxy radical, especially optionally substituted Ci-, C2-, C3- or C4-alkoxy group, optionally substituted alkylthio radical, in particular optionally substituted Ci-Cß-alkylthio radical, especially optionally substituted Ci-, C2-, C3- or C4-alkylthio group, optionally substituted cycloalkyl radical, optionally substituted aryl radical,optionally substituted carboaryl radical, optionally substituted carboarylalkyl radical, optionally substituted heteroalkyl radical, optionally substituted heterocycloalkyl radical, optionally substituted heteroaryl radical and optionally substituted heteroarylalkyl radical, and as defined above; and / or, Y is hydrogen or X; and / or ZY means or alternatively two Z together with the nitrogen atom to which they are attached form a four-, five-, six- or seven-membered heterocycloalkyl or heteroaryl ring, where the heterocycloalkyl or heteroaryl ring may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

[0109] Specific preferred examples of substitution are: OH, methyl, ethyl, methoxy, ethoxy, phenyl, which in turn may be substituted with OH, methyl, ethyl, methoxy, ethoxy or CH3-C(O)- or thiophene.

[0110] In a further variant, the one or more substituent groups, preferably phenyl groups, together with the atoms to which they are attached, may form a cyclic ring, including cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl.

[0111] Similarly, substituent groups useful for substituting unsaturated carbon atoms in the indicated group or radical include, but are not limited to, -X, Halo, =O, -OY, -SiR3, -SY, =S, -NZZ, =NY, =N-OY, Trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2Y, -S(O)2OY, -OS(O)2Y, - OS(O)2OY, -P(O)(OY) 2I-P(O)(OY)(OY), -C(O)Y, -C(S)Y, -C(NY)Y, -C(O)OY, -C(S)OY, - C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, -NYC(O)Y, -NYC(S)Y, - NYC(O)OY, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y and -NYC(NY)NZZ, where X, Y and Z have the same meaning as defined above.

[0112] Substituents or substituent groups for substituting nitrogen atoms in heteroalkyl and heterocycloalkyl radicals include, but are not limited to, -X, -OY, -SiR3, -SY, -NZZ, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2Y, - S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY)2, -P(O)(OY)(OY), -C(O)Y, -C(S)Y, -C(NY)Y, - C(O)OY, -C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, - NYC(O)Y, -NYC(S)Y, -NYC(O)OY, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y and -NYC(NY)NZZ, where X, Y and Z also have the same meaning as defined above.

[0113] The term "substituted" specifically contemplates one or more substitutions—i.e., two, three, four, five, six, or more—that are common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as not to adversely affect the useful properties of the compound or its function.

[0114] Suitable substituents in the context of the present invention preferably include halogen groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy groups or heteroaryloxy groups, arylalkyl or heteroarylalkyl groups, arylalkoxy or heteroarylalkoxy groups, amino groups, alkyl and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, carboxyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups, dialkylaminocarbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups, cycloalkyl groups, cyano groups, Ci- to Cß-alkylthio groups, arylthio groups, nitro groups, keto groups, acyl groups, boronate or boronyl groups, phosphate or phosphonyl groups, Sulfamyl groups, sulfonyl groups, sulfinyl groups and combinations thereof.In the case of substituted combinations such as substituted arylalkyl, either the aryl or the alkyl group may be substituted, or both the aryl and the alkyl group may be substituted with one or more substituents.

[0115] Preferred substituents for the above-mentioned groups or radicals are in particular selected from COOH, COO-alkyl, NH2, NO2, OH, SH, CN, Si, halogens, linear or branched Ci to Cß alkyl groups, linear or branched Ci to Cß alkoxy groups or linear or branched Ci to Cß alkylthio groups, where in the alkyl groups one or more H atoms can be replaced by halogen.

[0116] Additionally, in some cases, suitable substituents may be combined to form one or more rings as known to those skilled in the art.

[0117] The term "optionally substituted" in the context of the present invention refers to the presence or absence of the substituent group(s), i.e., means "substituted" or "unsubstituted." For example, the term "optionally substituted alkyl" encompasses both unsubstituted alkyl and substituted alkyl.

[0118] According to the invention, the substituents used to replace a particular residue or radical may in turn be further substituted, typically with one or more identical or different residues selected from the various groups indicated above and as defined in detail above.

[0119] In a particularly preferred variant according to the first aspect of the present invention, in the general formulas (Va) to (Villa) the radicals R1 and R2 are the same or different.

[0120] Preferably, R1 in the general formulas (Va) to (Villa) represents H or an optionally substituted alkyl group or an optionally substituted phenyl group or an optionally substituted thiophene group.

[0121] More preferably, R2 in the general formulas (Va) to (Villa) represents H or an optionally substituted alkyl group or an optionally substituted phenyl group or an optionally substituted thiophene group.

[0122] Cooling agents with particularly advantageous properties, ie a particularly intensive and effective and preferably at the same time long-lasting cooling effect, are regularly found in structures in which, in the general formula (Va), which have a triazine ring in their basic structure, at least one of the radicals R1 and R2 stands for an optionally substituted phenyl group or an optionally substituted thiophene group.

[0123] Even more preferably, at least one of R1 and R2 is an optionally substituted phenyl group.

[0124] Most preferred are compounds of general formula (Va) in which both R1 and R2 represent an optionally substituted phenyl group.

[0125] Specific preferred examples of substitution of the phenyl group are: OH, methyl, ethyl, methoxy or ethoxy.

[0126] Most preferably, R1 and R2 represent a phenyl group.

[0127] In an even more preferred variant, the two phenyl groups, together with the atoms to which they are attached, form a cyclic ring, including cycloalkyl or heterocycloalkyl.

[0128] Most preferred are those compounds of general formula (Va) in which both R1 and R2 are a phenyl group which is not substituted.

[0129] In a further preferred variant, in the compounds of general formula (Va), R1 and R2 are each a substituted or unsubstituted phenyl group which, together with the C atoms of the core structure to which they are bonded, form a conjugated or non-conjugated ring system.

[0130] It has been shown that, in particular, the previously described compounds of the general formula (Va), in which both R1 and R2 are substituted or unsubstituted phenyl groups, exhibit excellent TRPM8 activities and are capable of producing extraordinarily intense cooling effects even in small amounts.

[0131] Cooling substances with particularly advantageous properties, ie a particularly intensive and effective and preferably at the same time long-lasting cooling effect, can also be found in structures in which, in the general formula (Via), which have a pyrazine ring in their basic structure, at least one of the radicals R1 and R2 stands for an optionally substituted phenyl group or an optionally substituted thiophene group.

[0132] Even more preferably, at least one of the radicals R1 and R2 is an optionally substituted phenyl group

[0133] Most preferred are compounds of the general formula (Via) in which both R1 and R2 represent an optionally substituted phenyl group.

[0134] Specific preferred examples of substitution are: OH, methyl, ethyl, methoxy or ethoxy.

[0135] Most preferably, R1 and R2 represent a phenyl group.

[0136] In an even more preferred variant, the two phenyl groups, together with the atoms to which they are attached, form a cyclic ring, including cycloalkyl or heterocycloalkyl.

[0137] Most preferred are those compounds of the general formula (Via) in which both R1 and R2 are a phenyl group which is not substituted.

[0138] In a further preferred variant, in the compounds of the general formula (Via), R1 and R2 are each a substituted or unsubstituted phenyl group which, together with the C atoms of the core structure to which they are bonded, form a conjugated or non-conjugated ring system.

[0139] It has been shown that in particular the compounds of the general formula (Via), in which both R1 and R2 are substituted or unsubstituted phenyl groups, show excellent TRPM8 activities and are able to induce extraordinarily intense cooling effects even in small amounts.

[0140] Cooling substances with particularly advantageous properties, ie a particularly intensive and effective and preferably at the same time long-lasting cooling effect and / or optionally a particularly efficient masking of undesirable taste impressions, can also be found in structures in which in the general formula (Vila), which have an oxazole ring in their basic structure, at least one of the radicals R1 and R2 stands for an optionally substituted phenyl group or an optionally substituted thiophene group.

[0141] Even more preferably, at least one of the radicals R1 and R2 is an optionally substituted phenyl group

[0142] Most preferred are compounds of the general formula (Vila) in which both R1 and R2 represent an optionally substituted phenyl group.

[0143] Specific preferred examples of substitution are: OH, methyl, ethyl, methoxy or ethoxy.

[0144] Most preferably, R1 and R2 represent a phenyl group.

[0145] In an even more preferred variant, the two phenyl groups, together with the atoms to which they are attached, form a cyclic ring, including cycloalkyl or heterocycloalkyl.

[0146] Most preferred are those compounds of the general formula (Vila) in which both R1 and R2 are a phenyl group which is not substituted.

[0147] In a further preferred variant, in the compounds of the general formula (Vila), R1 and R2 are each a substituted or unsubstituted phenyl group which, together with the C atoms of the core structure to which they are bonded, form a conjugated or non-conjugated ring system.

[0148] It has been shown that in particular the compounds of the general formula (Vila), in which both R1 and R2 are a substituted or unsubstituted phenyl group, show excellent TRPM8 activities and are able to produce extremely intense cooling effects even in small amounts.

[0149] Cooling agents with particularly advantageous properties, ie a particularly intensive and effective and preferably at the same time long-lasting cooling effect, are also found in structures in which, in the general formula (Villa), which have an imidazole ring in their basic structure, at least one of the radicals R1 and R2 stands for an optionally substituted phenyl group or an optionally substituted thiophene group.

[0150] Even more preferably, at least one of the radicals R1 and R2 is an optionally substituted phenyl group

[0151] Most preferred are compounds of the general formula (Villa) in which both R1 and R2 represent an optionally substituted phenyl group.

[0152] Specific preferred examples of substitution are: OH, methyl, ethyl, methoxy or ethoxy.

[0153] Most preferably, R1 and R2 represent a phenyl group.

[0154] In an even more preferred variant, the two phenyl groups, together with the atoms to which they are attached, form a cyclic ring, including cycloalkyl or heterocycloalkyl.

[0155] Most preferred are those compounds of the general formula (Villa) in which both R1 and R2 are a phenyl group which is not substituted.

[0156] In a further preferred variant, in the compounds of the general formula (Villa), R1 and R2 are each a substituted or unsubstituted phenyl group which, together with the C atoms of the core structure to which they are bonded, form a conjugated or non-conjugated ring system.

[0157] It has been shown that in particular the compounds of the general formula (Villa), in which both R1 and R2 are substituted or unsubstituted phenyl groups, show excellent TRPM8 activities and are able to produce extremely intense cooling effects even in small amounts.

[0158] Even more preferred according to the invention are those compounds of the general formulas (Va) to (Villa) in which R1 and R2 are the same or different and independently of one another have the following meanings: R1 represents H or an optionally substituted C1 to C3 alkyl group or an optionally substituted phenyl group; and / or R2 represents H or an optionally substituted C1 to C3 alkyl group or an optionally substituted phenyl group.

[0159] Most preferably, R1 and / or R2 in the general formulas (Va) to (Villa) are an optionally substituted phenyl group.

[0160] Even more preferred according to the invention are those compounds of the general formulas (Va) to (Villa) in which Y represents a branched alkylene group. Preferably, the branched alkylene group is a methylene group substituted by a methyl group, an ethyl group, a linear or branched butyl group, or a linear or branched propyl group. Such compounds are particularly efficient cooling substances, as illustrated below.

[0161] Most preferred according to the invention are compounds of the general formulas (Va) to (Villa) in which the radicals R1 and / or R2 represent an unsubstituted phenyl group or a substituted phenyl group, Y represents a branched alkylene group, preferably a methylene group which is substituted by a methyl group, an ethyl group, a linear or branched propyl group or a linear or branched butyl group and Z has the meaning as defined above for the compounds of the general formulas (I) to (VIII).

[0162] Such compounds exhibit pronounced TRPM8 activities and are extremely intense cooling agents even in small amounts.

[0163] Particularly preferred are those cooling agents of the general formulas (Va) or (Via) which have one of the following structural combinations: R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with a methyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with an ethyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with a linear or branched propyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with a linear or branched butyl group.

[0164] Particularly preferred are also those cooling agents of the general formulas (Vila) or (Villa) which have one of the following structural combinations: R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with a methyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with an ethyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with a linear or branched propyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with a linear or branched butyl group.

[0165] Also preferred are cooling agents of the general formulas (Va) or (Via), which have one of the following structural combinations: R1 and / or R2 = phenyl group and Y = methylene, substituted with a methyl group; or R1 and / or R2 = phenyl group and Y = methylene, substituted with an ethyl group; or R1 and / or R2 = phenyl group and Y = methylene, substituted with a linear or branched propyl group; or R1 and / or R2 = phenyl group and Y = methylene substituted with a linear or branched butyl group.

[0166] Also preferred are cooling agents of the general formulas (Vila) or (Villa), which have one of the following structural combinations: R1 and / or R2 = phenyl group and Y = methylene, substituted with a methyl group; or R1 and / or R2 = phenyl group and Y = methylene, substituted with an ethyl group; or R1 and / or R2 = phenyl group and Y = methylene, substituted with a linear or branched propyl group; or R1 and / or R2 = phenyl group and Y = methylene substituted with a linear or branched butyl group.

[0167] Surprisingly, outstanding cooling attributes are exhibited by those compounds according to the present invention in which, in the general formulas (Va) to (Villa), R1 and R2 each represent an unsubstituted phenyl group, Y represents a branched alkylene group, preferably a methylene group substituted by a methyl group, an ethyl group, a linear or branched propyl group or a linear or branched butyl group, and Z has the meaning as defined above for the compounds of the general formulas (I) to (VIII).

[0168] Most preferred are therefore coolants of the general formulas (Va) or (Via), which have one of the following structural combinations: R1 and R2 = phenyl group and Y = methylene substituted with a methyl group; or R1 and R2 = phenyl group and Y = methylene substituted with an ethyl group; or R1 and R2 = phenyl group and Y = methylene substituted with a linear or branched propyl group; or R1 and R2 = phenyl group and Y = methylene substituted with a linear or branched butyl group; and Refrigerants of the general formulas (Vila) or (Villa) which have one of the following structural combinations: R1 and R2 = phenyl group and Y = methylene substituted with a methyl group; or R1 and R2 = phenyl group and Y = methylene substituted with an ethyl group; or R1 and R2 = phenyl group and Y = methylene substituted with a linear or branched propyl group; or R1 and R2 = phenyl group and Y = methylene substituted with a linear or branched butyl group.

[0169] Of the latter cooling agents according to the general formulas (Va) to (Villa), those compounds in which Y represents a methylene group substituted by a methyl group or an ethyl group are most preferred. Such compounds exhibit particularly high TRPM 8 activity and are capable of producing exceptionally intense cooling effects even in small amounts.

[0170] In the general formulas (Va), (Via), (Vila) and (Villa), Z is selected from the group consisting of NH2, an NHRa group, an NRaRb group, an optionally substituted linear or branched alkyl group, an optionally substituted linear or branched alkenyl group, an optionally substituted linear or branched alkylthio group, an optionally substituted linear or branched alkoxy group, OH, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein Ra and / or Rb is / are an optionally substituted linear or branched alkyl group, or an optionally substituted linear or branched alkenyl group,or an optionally substituted linear or branched alkynyl group, or an optionally substituted linear or branched alkoxy group, or an optionally substituted linear or branched alkylthio group, or an optionally substituted acyl group R-(C=O)-, or an optionally substituted cycloalkyl group, or an optionally substituted aryl group, or an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group.

[0171] In a further alternative variant, the residues Ra and Rb of the NRaRb group, as defined above, are linked and form a saturated or unsaturated ring, preferably a saturated or unsaturated three- to eight-membered ring.

[0172] Particularly preferred according to the invention are those coolants of the general formulas (Va) to (Villa) in which Ra and / or Rb in the NHRa group or the NRaRb group represents a C1 to C3 alkyl group, preferably a methyl group.

[0173] Even more preferred according to the invention are those coolants of the general formulas (Va), (Vila) and (Villa) in which Z is selected from the group consisting of: -NH2, -NH-CH3, -NH-CH2-CH3, -NH-CH2-CH2-CH3, -NH-CH2-CH2-CH2-CH3, -NH-CH(CH3)-CH(CH3)2, -NH-CH(CH3)-CH2-CH2-CH3, -NH-CH2-CH(CH3)2, -NH-CH2-CH2-O-CH3, -NH-CH(CH3)-CH2-O-CH3, -NH-C(=O)-CH3, -NH-C(=O)-O-CH 3I -NH-CH(CH3)-CH2-OH, -NH-CH2-furanyl, -NH-CH2-tetrahydrofuranyl, -NH-CH2-thiophenyl, -NH-toluolyl, -NH-CH-(CH3)2, -NH-C(CH3)3, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -N(CH3)2, -N(CH3)-cyclohexyl, -N(CH2-CH3)2, azetidinyl, pyrrolidinyl, piperidinyl, azacyclobutadienyl, pyrrolyl, pyridinyl, -O, -OH, -O-CH3, -OC(=O)-CH3, oxetanyl, -CH3, -CH2-CH3, -CH(CH3)2, -C(OH)-CH2-OH, cyclopropyl, phenyl, and -CH2-S-CH3.

[0174] Even more preferred according to the invention are those coolants of the general formula (Via) in which Z is selected from the group consisting of -NH2, -NH-CH3, -NH-CH2-CH3, -NH-CH2-CH2-CH3, -NH-CH2-CH2-CH3, -NH-CH(CH3)-CH(CH3)2, -NH-CH(CH3)-CH2-CH2-CH3, -NH-CH2-CH(CH3)2, -NH-CH2-CH2-O-CH3, -NH-CH(CH3)-CH2-O-CH3, -NH-C(=O)-CH3, -NH-C(=O)-O-CH3, -NH-CH(CH3)-CH2-OH, -NH-CH2-furanyl, -NH-CH2-tetrahydrofuranyl, -NH-CH2-thiophenyl, -NH-toluolyl, -NH-CH-(CH3)2, -NH-C(CH3)3, - NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -N(CH3)2, -N(CH3)-cyclohexyl, -N(CH2- CH3)2, azetidinyl, pyrrolidinyl, piperidinyl, azacyclobutadienyl, pyrrolyl, pyridinyl, -O, -O-CH3, -OC(=O)-CH3, oxetanyl, -CH3, -CH2-CH3, -CH(CH3)2, -C(OH)-CH2-OH, cyclopropyl, phenyl, and -CH2-S-CH3.

[0175] In the general formula (Via), Z does not represent -NH-phenyl, -N(CH3)-phenyl, -OH, -OC2H5 or -OC(CH3)3.

[0176] In a particularly preferred variant according to the first aspect of the present invention, cooling substances of the general formulas (Va), (Via), (Vila) and (Villa) are therefore preferred, which have the following structures:

[0177] Even more preferred according to the invention are those coolants of the general formulas (Va) or (Via) which have the following structures:

[0178] Even more preferred according to the invention are also those cooling agents of the general formulas (Vila) or (Villa) which have the following structures:

[0179] Furthermore, compounds of the general formulas (Va) to (Villa), in which m is 1, appear to be preferred with regard to the determined TRPM8 activity.

[0180] Excluded from the cooling agents according to the general formula (Via) are in particular those compounds in which in the general formula (Via) R1 and R2 are phenyl, Y is branched alkyl, in particular Y is methylene substituted by -CH3 or -CH2CO2C2H5, and Z in the general formula (Via) is -NH-phenyl, -N(CH3)-phenyl, -OH, -OC2H5 or -OC(CH3)3

[0181] Even more preferred according to the invention are those cooling agents in which the aforementioned optionally substituted groups furthermore have one or more substituents, so that (i) when in the aforementioned substituted groups the substitution occurs at a saturated carbon, the substituent at the saturated carbon is selected from the group consisting of: -X, halogen, =O, -OY, -SiR3, -SY, =S, -NZZ, =NY, =N-OY, -CF3, -ON, -OCN, -SON, -NO, -NO2, -S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY)2, -P(O)(OY)(OY), -C(O)Y, -C(S)Y, -C(NY)Y, -C(O)OY, -C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, -NYC(O)Y, -NYC(S)Y, -NYC(O)OY, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y and -NYC(NY)NZZ; (ii) when in the aforementioned substituted groups the substitution occurs on an unsaturated carbon, the substituent on the unsaturated carbon is selected from the group consisting of: -X, halogen, -OY, -SiRa, -SY, -NZZ, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY)2, - P(O)(OY)(OY), -C(O)Y, -C(S)Y, -C(NY)Y, -C(O)OY, -C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, -NYC(O)Y, -NYC(S)Y, -NYC(O)OY, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y and -NYC(NY)NZZ; (iii) when in the aforementioned substituted groups the substitution occurs on a nitrogen atom, the substituent on the nitrogen atom is selected from the group consisting of: -X, -OY, -SY, -NZZ, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY)2, -P(O)(OY)(OY), -C(O)Y, -C(S)Y, -C(NY)Y, -C(O)OY, -C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, -NYC(O)Y, -NYC(S)Y, -NYC(O)OY, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y and -NYC(NY)NZZ; where in cases (i), (ii) and (iii) X is selected from the group consisting of: optionally substituted alkyl group, in particular optionally substituted C1 to C8 alkyl group, in particular optionally substituted C1 to C8 alkyl group, particularly optionally substituted C1, C2, C3 or C4 alkyl group, optionally substituted alkoxy group, in particular optionally substituted C1 to C8 alkoxy group, particularly optionally substituted C1, C2, C3 or C4 alkoxy group, optionally substituted alkylthio group, in particular optionally substituted C1 to C8 alkylthio group, particularly optionally substituted C1, C2, C3 or C4 alkylthio group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, optionally substituted heteroaryl group; and / or Y is selected from the group consisting of: hydrogen or X; and / or Z means Y or alternatively two Z together with the nitrogen atom to which they are attached mean a four-, five-, six- or seven-membered heterocycloalkyl ring or heteroaryl ring, wherein the heterocycloalkyl ring or heteroaryl ring may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

[0182] According to the invention, the cooling agents according to the general formulas (Va) to (Villa) are particularly preferably present as pure (R)-enantiomer.

[0183] Surprisingly, it was found that the (R)-enantiomer of the compounds of the general formulas (Va) to (Villa) has a particularly pronounced cooling effect, i.e., an intensive cooling effect, which also sets in quickly. This effect is particularly advantageous in formulations where a rapid cooling effect on the skin or mucous membranes is desired.

[0184] According to the invention, the coolant according to the general formulas (Va) to (Villa) is further preferably present as a pure (S)-enantiomer.

[0185] Surprisingly, it was found that the (S)-enantiomer of the compounds of general formulas (Va) to (Villa) exhibits a less pronounced cooling effect, although it develops slowly and lasts longer than the (R)-enantiomer. This effect is particularly desirable in formulations where a long-lasting cooling effect on the skin or mucous membranes is desired.

[0186] According to the invention, the cooling agent is even more preferably present as a racemate or in the form of an enantiomer mixture of (R)-enantiomer and (S)-enantiomer.

[0187] Particularly advantageous cooling effects can be achieved when the ratio of (R)-enantiomer to (S)-enantiomer in the enantiomer mixture is greater than 50:50, preferably > 75:25, even more preferably > 90:10, even more preferably > 95:5, and most preferably > 98:2.

[0188] Advantageous cooling effects can also be achieved with an enantiomer mixture in which the ratio of (S)-enantiomer to (R)-enantiomer is greater than 50:50, preferably > 75:25, even more preferably > 90:10, even more preferably > 95:5, and most preferably > 98:2.

[0189] Particularly preferred is the physiological coolant of the general formulas (Va) or (Via) selected from the group consisting of the compounds shown in Table A:

[0190] Table A: Structures according to the invention with relative TRPM8 activation in %

[0191] The inventive coolants listed in Table A according to the general formulas (Va) or (Via) are present either in neutral, uncharged form or in the form of their salts, such as acid addition salts, with inorganic or organic, mono- or polybasic carboxylic acids, as described in detail above. Therefore, the above statements apply equally here as well.

[0192] It has surprisingly been found that the compounds according to the invention according to Table A have particularly high TRPM8 activations and are therefore excellently suitable as cooling agents.

[0193] The most preferred cooling agents, ie cooling agents with a particularly efficient and strong TRPM8 activation, ie efficient and intensive cooling effect with low application quantities, are the compounds B-01, B-02, B-03, B-05, B-07, B-11, B-14, B-15, B-18 and B-21 (TRPM8 activation > 90%).

[0194] Particularly preferred are the cooling substances B-01, B-02, B-03, B-05 and B-07, which show an extraordinarily high TRPM8 activity (TRPM8 activation > 150%).

[0195] Due to their outstanding relative TRPM8 activation, the coolants B-01 (TRPM8 activation of 262%), B-02 (TRPM8 activation of 227%), B-03 (TRPM8 activation of 221%), B-05 (TRPM8 activation of 205%), and B-07 (TRPM8 activation of 203%) are the most preferred.

[0196] The refrigerant B-01 (triazine derivative) is characterized in that in the general formula (V), R1 and R2 represent a phenyl group, Y represents a branched methylene group substituted with an ethyl group, and Z represents an -NH- cyclopropyl group.

[0197] The coolant B-02 (pyrazine derivative) is characterized in that in the general formula (VI) R1 and R2 represent a phenyl group, Y represents a branched Methylene group substituted with an ethyl group, and Z represents an -NH-CH3- group.

[0198] The refrigerant B-03 (triazine derivative) is characterized in that in the general formula (V), R1 and R2 represent a phenyl group, Y represents a branched methylene group substituted with an ethyl group, and Z represents an -NH-CH3- group.

[0199] The refrigerant B-05 (triazine derivative) is characterized in that in the general formula (V), R1 and R2 represent a phenyl group, Y represents a branched methylene group substituted with an ethyl group, and Z represents a -N(CH3)2- group.

[0200] The coolant B-07 (triazine derivative) is characterized in that in the general formula (V) R1 and R2 represent a phenyl group which, together with the C atoms of the triazine ring to which they are bonded, forms a condensed ring system, ie a 1,2,4-triazatriphenylene, Y represents a branched methylene group substituted with a methyl group, and Z represents an -NH-CHs- group.

[0201] According to the invention, the cooling agents according to Table A are present as pure (R)-enantiomer, as pure (S)-enantiomer, as racemate or as enantiomer mixture and are used as such in formulations.

[0202] According to the invention, the coolants according to Table A are particularly preferably present as pure (R)-enantiomer.

[0203] Surprisingly, it was found that the (R)-enantiomer of the cooling agents exhibits a particularly pronounced cooling effect, i.e., an intense cooling effect, which also sets in quickly. This effect is particularly advantageous in formulations where a rapid cooling effect on the skin or mucous membranes is desired.

[0204] According to the invention, the cooling agents according to Table A are further preferably present as pure (S)-enantiomer.

[0205] Surprisingly, it was found that the (S)-enantiomer of the cooling agents exhibits a less pronounced cooling effect, although it develops slowly and lasts longer than the (R)-enantiomer. This effect is particularly advantageous in formulations where a long-lasting cooling effect on the skin or mucous membranes is desired.

[0206] Even more preferably, according to the invention, the compounds / coolants according to Table A are present as a racemate or in the form of an enantiomer mixture of (R)-enantiomer and (S)-enantiomer.

[0207] Particularly advantageous cooling effects can be achieved when the ratio of (R)-enantiomer to (S)-enantiomer in the enantiomer mixture is greater than 50:50, preferably > 75:25, even more preferably > 90:10, even more preferably > 95:5, and most preferably > 98:2.

[0208] Advantageous cooling effects can also be achieved with an enantiomer mixture in which the ratio of (S)-enantiomer to (R)-enantiomer is greater than 50:50, preferably > 75:25, even more preferably > 90:10, even more preferably > 95:5, and most preferably > 98:2.

[0209] Equally particularly preferred are the physiological cooling agents of the general formulas (Vila) or (Villa), selected from the group consisting of the compounds shown in Table B:

[0210] Table B: Structures according to the invention with relative TRPM8 activation in %

[0211] The cooling agents according to the invention listed in Table B according to the general formulas (V1a) or (V1a) are present either in neutral, uncharged form or in the form of their salts, such as acid addition salts, with inorganic or organic, mono- or polybasic carboxylic acids, as described in detail above. Therefore, the above statements apply equally here as well.

[0212] It has surprisingly been found that the compounds according to the invention according to Table B have particularly high TRPM8 activations and are therefore excellently suitable as cooling agents.

[0213] The most preferred cooling agents, i.e. cooling agents with a particularly efficient and strong TRPM8 activation, i.e. efficient and intensive cooling effect with low application quantities, are the compounds A-01, A-02, A-03, A-05, A-09, A-10 and A-12 (TRPM8 activation > 100%).

[0214] Particularly preferred are the cooling substances A-01, A-02, A-03 and A-05, which show an extraordinarily high TRPM8 activity (TRPM8 activation > 150%).

[0215] Due to their outstanding relative TRPM8 activation, the coolants A-01 (TRPM8 activation of 278%), A-02 (TRPM8 activation of 265%), A-03 (TRPM8 activation of 260%) and A-05 (TRPM8 activation of 190%) are the most preferred.

[0216] The refrigerant A-01 (oxazole derivative) is characterized in that in the general formula (VII), R1 and R2 represent a phenyl group, X represents an S atom, Y represents a branched methylene group substituted with a methyl group, and Z represents an -NH-CHs group.

[0217] The refrigerant A-02 (oxazole derivative) is characterized in that in the general formula (VII), R1 and R2 represent a phenyl group, X represents an S atom, Y represents a branched methylene group substituted with a methyl group, and Z represents an -NH-CHs group.

[0218] The refrigerant A-03 (oxazole derivative) is characterized in that in the general formula (VII), R1 and R2 represent a phenyl group, X represents an S atom, Y represents a branched methylene group substituted with a methyl group, and Z represents an -NH-CHs group.

[0219] The refrigerant A-05 (oxazole derivative) is characterized in that in the general formula (VII), R1 represents a CH3 group and R2 represents a phenyl group, X represents an S atom, Y represents a branched methylene group substituted with a methyl group, and Z represents an -NH-CHs group.

[0220] According to the invention, the cooling agents according to Table A are present as pure (R)-enantiomer, as pure (S)-enantiomer, as racemate or as enantiomer mixture and are used as such in formulations.

[0221] According to the invention, the coolants according to Table B are particularly preferably present as pure (R)-enantiomer.

[0222] Surprisingly, it was found that the (R)-enantiomer of the cooling agents exhibits a particularly pronounced cooling effect, i.e., an intense cooling effect, which also sets in quickly. This effect is particularly advantageous in formulations where a rapid cooling effect on the skin or mucous membranes is desired.

[0223] According to the invention, the cooling agents according to Table B are further preferably present as pure (S)-enantiomer.

[0224] Surprisingly, it was found that the (S)-enantiomer of the cooling agents exhibits a less pronounced cooling effect, although it develops more slowly than the (R)-enantiomer. This effect is particularly advantageous in formulations where a long-lasting cooling effect on the skin or mucous membranes is desired.

[0225] Even more preferably according to the invention, the compounds / coolants according to Table B are present as a racemate or in the form of an enantiomer mixture of (R)-enantiomer and (S)-enantiomer.

[0226] Particularly advantageous cooling effects can be achieved when the ratio of (R)-enantiomer to (S)-enantiomer in the enantiomer mixture is greater than 50:50, preferably > 75:25, even more preferably > 90:10, even more preferably > 95:5, and most preferably > 98:2.

[0227] Advantageous cooling effects can also be achieved with an enantiomer mixture in which the ratio of (S)-enantiomer to (R)-enantiomer is greater than 50:50, preferably > 75:25, even more preferably > 90:10, even more preferably > 95:5, and most preferably > 98:2.

[0228] It has been shown that the preferred cooling substances B-01, B-02, B-03, B-05, B-07, B-11, B14, B-15, B-18, and B-21 and A-01, A-02, A-03, A-05, A-09, A-10 and A-12 described above have particularly high TRPM8 activities and consequently show intensive and at the same time efficient cooling effects; ie in order to produce an intensive cooling effect only small amounts in the low ppm range of about 5 ppm of the substance according to the invention are necessary (low EC50 values, see experimental data below).

[0229] During the sensory assessment, i.e. the tasting of the respective samples, intensive cooling effects were demonstrated. The panellists rated the cooling effect of the cooling agent B-11 with a score of 5.3 at a dosage of of 5 ppm. Accordingly, the sensorially assessed cooling intensity, taking into account the compound's application rate, was comparable to that determined for the cooling substance WS-3 as a reference at a six-fold higher concentration (application rate: 30 ppm; sensorially determined cooling intensity: score 5.4). Compounds A-2 and A-10 also exhibit very high TRPM8 activities and intensely perceived cooling effects (sensorially determined cooling intensities: score 5.4 and score 5.38, respectively), making them particularly suitable as efficient cooling agents.

[0230] The cooling agents according to the invention are also characterized by high TRPM8 activation and, at the same time, exhibit very high sensory cooling intensities. They produce intense cooling effects even at low concentrations and are generally well below the EC50 reference value of 1.72 pM for the substance WS-3, as demonstrated in the following experimental section.

[0231] In a most preferred variant, the physiological cooling agent is selected from the group consisting of the compounds shown in Table C: Table C: or wherein the physiological coolant of the general formulas (Vila) or (Villa) is selected from the group consisting of the compounds shown in Table D: Table D:

[0232] The cooling agents according to the invention listed in Table C and Table D according to the general formulas (Va) to (Villa) are either in neutral, uncharged form or are in the form of their salts, such as acid addition salts, with inorganic or organic, mono- or polybasic carboxylic acids, as described in detail above. Therefore, the above statements apply equally here.

[0233] According to the invention, the cooling agents according to Table C and Table D are present either as pure (R)-enantiomer or as pure (S)-enantiomer or as racemate or as enantiomer mixture and are used as such in formulations.

[0234] According to the invention, the (R)-enantiomers of the coolants listed in Table C and Table D are particularly preferred.

[0235] Surprisingly, it was found that the (R)-enantiomer of these cooling agents exhibits a particularly pronounced cooling effect, i.e., an intense cooling effect, which also occurs quickly. This effect is particularly advantageous in formulations where a rapid cooling effect on the skin or mucous membranes is desired.

[0236] According to the invention, further preference is given to the (S)-enantiomers of the cooling agents listed in Table C and Table D.

[0237] Surprisingly, it was found that the (S)-enantiomer of these cooling agents exhibits a less pronounced cooling effect, although it develops slowly and lasts longer than the (R)-enantiomer. This effect is particularly advantageous in formulations where a long-lasting cooling effect on the skin or mucous membranes is desired.

[0238] Surprisingly, it was found that the enantiomer compounds or cooling agents according to Table C or Table D according to the invention have the common property of achieving a particularly long-lasting and intensive cooling effect on the skin or mucous membranes in vivo, even at low dosages in the low ppm range of approximately 5 ppm, and are generally well below the EC50 reference value of 1.72 pM for the substance WS-3, as shown in the following experimental section. This means that a lower dosage of the cooling agent according to the invention is required in the final preparation to achieve an intensive cooling effect. Thus, the compounds described above represent particularly efficient cooling agents.

[0239] The enantiomer cooling agents according to Table C and Table D according to the invention are further characterized by the rapid onset of their cooling effect; other cooling agents according to the invention, however, have a building cooling effect, i.e., a cooling effect that increases over time, producing a longer and more intensive cooling effect.

[0240] During the sensory assessment, i.e., the tasting of the respective samples, an intensive cooling effect was detected for the (R)-enantiomers, which began quickly. The panellists rated the cooling effect of compound A-02 at a dosage of 5 ppm with a score of 5.7. Accordingly, the sensory assessed cooling intensity, taking into account the dosage of the The compound was comparable to that determined for the cooling substance WS-3 as a reference at a six-fold higher concentration (application amount: 30 ppm; sensory cooling intensity: score 5.4). In comparison, the cooling effect of the corresponding (S)-enantiomer was rated with a score of 3.6; the cooling effect had a delayed onset, built up slowly, and lasted for a long time.

[0241] According to the invention, the cooling agents according to Table C and Table D are even more preferably present as a racemate or in the form of an enantiomer mixture of (R)-enantiomer and (S)-enantiomer.

[0242] Particularly advantageous cooling effects can be achieved when the ratio of (R)-enantiomer to (S)-enantiomer in the enantiomer mixture is greater than 50:50, preferably > 75:25, even more preferably > 90:10, even more preferably > 95:5, and most preferably > 98:2.

[0243] Advantageous cooling effects can also be achieved with an enantiomer mixture in which the ratio of (S)-enantiomer to (R)-enantiomer is greater than 50:50, preferably > 75:25, even more preferably > 90:10, even more preferably > 95:5, and most preferably > 98:2.

[0244] The physiological cooling substances according to the general formulas (Va) to (VIII) and Tables A to D are present either in neutral, ie uncharged form, or in the form of their salts, such as acid addition salts, with inorganic or organic acids.

[0245] The term "salt" in the context of the present invention refers to a salt of a compound that possesses the desired effect or pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids or with organic acids, preferably mono- or polybasic carboxylic acids; or (2) Salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion or an aluminum ion; or coordinated with an organic base.

[0246] Among the salts, acid addition salts are particularly preferred, since the physiological coolant according to the general formulas (I) to (VIII) comprises a protonatable N-atom.

[0247] The inorganic acids that form acid addition salts with the physiological cooling agents of the present invention are preferably selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Among the salts, the hydrochlorides or sulfates are most preferred. The hydrochloride salt or the sulfate salt is particularly preferred.

[0248] Even more preferred are acid addition salts with organic mono- or polycarboxylic acids. Further preferred are acid addition salts with organic mono- or polycarboxylic acids, where the carboxylic acid is selected from saturated or mono- or polyunsaturated C1 to C30 monocarboxylic acids, saturated or mono- or polyunsaturated C3 to C10 di- or tricarboxylic acids. The carboxylic acid can be mono- or polysubstituted with hydroxy groups, preferably α-hydroxycarboxylic acids, in which the hydroxy group is located on the carbon atom adjacent to the carboxyl group. Many representatives occur naturally as so-called fruit acids. Preferred α-hydroxycarboxylic acids are: malic acid, citric acid, 2-hydroxy-4-methylmercaptobutyric acid, glycolic acid, isocitric acid, mandelic acid, lactic acid, tartronic acid, or tartaric acid.

[0249] The organic acids which form acid addition salts with the physiological cooling agents according to the present invention are preferably selected from the group consisting of amino acids, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, oxalic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, Trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, 4-hydroxybutanoic acid, and the like.

[0250] Among the organic acids which form acid addition salts with the physiological cooling agents of the present invention, the most preferred are acetic acid, lactic acid, malonic acid, succinic acid, malic acid, citric acid or tartaric acid.

[0251] The metal ions for salt formation, which replace an acidic proton present in the starting compound, are selected from the group consisting of alkali metal ions, preferably Na+ or K+, alkaline earth metal ions, preferably Ca++, Mg++, and aluminum+++.

[0252] The coordinating organic base for salt formation is selected from the group consisting of ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.

[0253] In the following description and in the claims, the terms “physiological coolant” or “compound” include both the neutral, uncharged form of the coolant / compound as well as the salt form of the coolant / compound.

[0254] Due to their better solubility, the salts of the physiological coolants according to the present invention are particularly preferred. The better water solubility also results in better availability of the coolants or compounds during their application.

[0255] Surprisingly, it was found that the compounds or cooling agents according to the invention, or their salts, have the common property of achieving a particularly long-lasting and intense cooling effect on the skin or mucous membranes in vivo, even at low doses in the low ppm range of approximately 5 ppm. This means that a lower dosage of the cooling agent according to the invention or its salt is required in the final preparation to achieve an intense cooling effect. Thus, the compounds described herein represent particularly efficient cooling substances. This was not foreseeable for the TRPM8 modulators mentioned in this application.

[0256] The cooling agents according to the invention are further characterized by the fact that their cooling effect sets in quickly; other cooling agents according to the invention, however, have a building cooling effect, i.e., one that increases over time, producing a longer and more intensive cooling effect.

[0257] The cooling agents according to the invention are also colorless and non-discoloring, which is particularly advantageous for their storage and / or application in the final product. Consequently, the compounds described herein are particularly suitable as additives in various preparations. Furthermore, the compounds according to the invention described here are largely tasteless and odorless, making them ideal for incorporation into neutral and / or flavored preparations without creating a negative, for example, bitter, taste impression or adversely affecting the intended taste or odor impression.

[0258] The salts of the cooling agents according to the invention show better solubility in vitro than their neutral, uncharged equivalents, which is particularly advantageous when used in the oral care sector.

[0259] Thus, the compounds described herein are particularly suitable as efficient cooling substances that can be incorporated particularly well into a wide variety of formulations. Due to their better solubility, the salts, especially the acid addition salts, of the cooling substances according to the invention are advantageous for use in the oral care sector.

[0260] In a further aspect, the present invention relates to a compound selected from the group consisting of the compounds shown in Table E: Table E: or wherein the compound is selected from the group consisting of the compounds shown in Table F: Table F:

[0261] The compounds according to the invention listed in Table E and Table F are present either in neutral, uncharged form or in the form of their salts, such as acid addition salts, with inorganic or organic, mono- or polybasic carboxylic acids, as described in detail above in connection with the coolants according to the invention. In this respect, the above statements apply equally here as well.

[0262] According to the invention, the compounds according to Table E and Table F are present either as pure (R)-enantiomer or as pure (S)-enantiomer or as racemate or as enantiomer mixture and are used as such in formulations.

[0263] According to the invention, the (R)-enantiomers of the compounds listed in Table E and Table F are particularly preferred.

[0264] According to the invention, further preference is given to the (S)-enantiomers of the compounds listed in Table E and Table F.

[0265] Even more preferably according to the invention, the compounds according to Table E and Table F are present as a racemate or in the form of an enantiomeric mixture of (R)-enantiomer and (S)-enantiomer.

[0266] Particularly advantageous effects can be achieved when the ratio of (R)-enantiomer to (S)-enantiomer in the enantiomer mixture is greater than 50:50, preferably > 75:25, even more preferably > 90:10, even more preferably > 95:5, and most preferably > 98:2.

[0267] Advantageous effects can also be achieved with an enantiomer mixture in which the ratio of (S)-enantiomer to (R)-enantiomer is greater than 50:50, preferably > 75:25, even more preferably > 90:10, even more preferably > 95:5, and most preferably > 98:2.

[0268] Surprisingly, the (R)- and (S)-enantiomer compounds according to Table E and Table F are particularly efficient as modulators, in particular for in vivo and / or in vitro modulation, of the cold menthol receptor TRPM8, in particular as TRPM8 receptor agonists or as TRPM8 receptor antagonists, as physiological cooling agents, as flavoring agents, as substances for improving the taste of flavoring agents or as bitter-masking substances.

[0269] In principle, the present invention encompasses all mixtures of the individual coolants of the general formulas (Va) to (Villa) or as listed in Tables A to D and defined above, or of the individual compounds as listed in Tables E and F and defined above, and their use as coolants or coolant mixtures. Nevertheless, the present compounds are also suitable for mixing with other, already known coolants.

[0270] A further subject of the invention therefore relates to a physiological coolant mixture comprising or consisting of: (a) one, two, three or more refrigerant(s) of the general formulae (Va) to (Villa) or as listed in Table A to Table D and defined above or one, two, three or more compound(s) as listed in Table E and Table F and defined above; and optionally (b) at least one further physiological cooling agent; and / or optionally (c) at least one solvent.

[0271] In a preferred embodiment, the present invention relates to a coolant mixture comprising or consisting of two or more of the coolants according to the invention of the general formulas (Va) to (Villa) or as listed in Table A to Table D and defined above, or comprising or consisting of two or more of the compounds according to the invention as listed in Table E and Table F and defined above.

[0272] Optionally, the coolant mixture also includes another physiological coolant and optionally at least one suitable solvent.

[0273] The particular advantage of such coolant mixtures is that a synergistic enhancement of the cooling effect can be observed.

[0274] Suitable cooling agents which form component (b) and are different from the cooling agent(s) which form component (a) are selected from the group consisting of menthol, menthol methyl ether (FEMA GRAS 4054), monomenthyl glutamate (FEMA GRAS 4006), menthoxy-1,2-propanediol (FEMA GRAS 3784), dimenthyl glutarate (FEMA GRAS 4604), hydroxymethylcyclohexylethanone (FEMA GRAS 4742), 2-(4-ethylphenoxy)-N-(1 H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide (FEMA GRAS 4880), WS-23 (2-isopropyl-N,2,3-trimethylbutyramide, FEMA GRAS 3804), N-(4- (Cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexan carboxamid (FEMA GRAS 4882), N-(3-Hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexan-carboxamid (FEMA GRAS 4881), N-(2-Hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexan-1- carboxamid (FEMA GRAS 4896), 3, 4-Methylenedioxy Zimtsäure, (E)-3-Benzo[1 ,3]dioxol-5-yl- N,N-diphenyl-2-propenamid (FEMA GRAS 4788), Menthol Propylen Glykol Carbonat (FEMA GRAS 3806), Menthyl-N-ethyloxamat, Monomethyl Succinat (FEMA GRAS 3810), WS-3 (N- Ethyl-p-menthan-3-carboxamide, FEMA GRAS 3455), Menthol Ethylen Glykol Carbonat (FEMA GRAS 3805), WS-5 (Ethyl-3-(p-menthan-3-carboxamido)acetat, FEMA GRAS 4309), WS-12 (1 R,2S,5R)-N-(4-Methoxyphenyl)-p-menthancarboxamid (FEMA GRAS 4681), WS-27 (N-Ethyl-2,2-diisopropylbutanamid, FEMA GRAS 4557), N-Cyclopropyl-5-methyl-2- isopropylcyclohexancarboxamid (FEMA GRAS 4693), WS-116 (N-(1 ,1-Dimethyl-2- hydroxyethyl)-2,2-diethylbutanamid, FEMA GRAS 4603), Menthoxyethanol (FEMA GRAS 4154),N-(4-Cyanomethylphenyl)-p-menthancarboxamid (FEMA GRAS 4496), N-(2-(Pyridin- 2-yl)ethyl)-3-p-menthancarboxamid (FEMA GRAS 4549), N-(2-Hydroxyethyl)-2-isopropy-1- 2,3-dimethylbutanamid (FEMA GRAS 4602), (2S,5R)-N-[4-(2-Amino-2-oxoethyl)phenyl]-p- menthancarboxamid (FEMA GRAS 4684), N-Cyclopropyl-5-methyl-2- isopropylcyclohexancarboncarboxamid (FEMA GRAS 4693), 2-[(2-p-Menthoxy)ethoxy]- ethanol (FEMA GRAS 4718), (2,6-Diethyl-5-isopropyl-2-methyltetrahydropyran (FEMA GRAS 4680), trans-4-tert-Butylcyclohexanol (FEMA GRAS 4724), 2-(p-Tolyloxy)-N-(1 H-pyrazol-5- yl)-N-((thiophen-2-yl)methyl)acetamid (FEMA GRAS 4809), Menthon glycerol ketal (FEMA GRAS 3807 und 3808), (-)-Menthoxypropan-1 ,2-diol, 3-(1-Menthoxy)-2-methylpropan-1 ,2- diol (FEMA GRAS 3849), Isopulegol, (+)-cis und (-)-trans-p-Menthan-3,8-diol (62:38, FEMA GRAS 4053), 2-methyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one (FEMA, GRAS 4970) und dessen Enantiomere, 2,3-Dihydroxy-p-menthan, 3,3,5- trimethylcyclohexanon glycerol ketal, Menthyl pyrrolidon carboxylat, (1R,3R,4S)-3-menthyl- 3.6-dioxaheptanoat, (1R,2S,5R)-3-menthyl methoxyacetat, (1 R,2S,5R)-3-Menthyl-3,6,9- trioxadecanoat, (1 R,2S,5R)-3-menthyl-3,6,9-trioxadecanoat, (1 R,2S,5R)-3-Menthyl-(2- hydroxyethoxy)acetat, (1R,2S,5R)-Menthyl-11-hydroxy-3,6,9-trioxaundecanoat, Cubebol (FEMA GRAS 4497), 2-lsopropyl-5-methylcyclohexyl-4-(dimethylamino)-4-oxobutanoat (FEMA GRAS 4230), Menthyllactat (FEMA GRAS 3748), 6-lsopropyl-3,9-dimethyl-1,4- dioxaspiro[4.5]decan-2-on (FEMA GRAS 4285), N-Benzo[1,3]-dioxol-5-yl-3-p- menthancarboxamid, N-(1-lsopropyl-1,2-dimethylpropyl)-1,3-benzodioxol-5-carboxamid, N- (R)-2-Oxotetrahydrofuran-3-yl-(1 R,2S,5R)-p-menthan-3-carboxamid, Mischung aus 2.2.5.6.6-Pentamethyl-2,3,6,6a-tetrahydropentalen-3a(1 H)-ol und 5-(2-Hydroxy-2- methylpropyl)-3,4,4-trimethylcyclopent-2-en-1-on; (2S,5R)-2-lsopropyl-5-methyl-N-(2- (pyridin-4-yl)ethyl)cyclohexancarboxamide; (1S,2S,5R)-N-(4-(cyanomethyl)phenyl)-2- isopropyl-5-methylcyclohexancarboxamid, 1,7-lsopropyl-4,5-methyl-bicyclo[2.2.2]oct-5-en Derivate, 4-Methoxy-N-phenyl-N-[2-(pyridin-2-yl)ethyl]benzamid, 4-Methoxy-N-phenyl-N-[2- (pyridin-2-yl)ethyl]benzensulfonamid, 4-Chloro-N-phenyl-N-[2-(pyridin-2- yl)ethyl]benzensulfonamid, 4-Cyano-N-phenyl-N-[2-(pyridin-2-yl)ethyl]-benzensulfonamid, 4- ((Benzhydrylamino)methyl)-2-methoxyphenol, 4-((Bis(4- methoxyphenyl)methylamino)methyl)-2-methoxyphenol, 4-((1,2-diphenylethylamino)methyl)- 2-methoxyphenol, 4-((Benzhydryloxy)methyl)-2- methoxyphenol, 4-((9H-Fluoren-9- ylamino)methyl)-2-methoxyphenol, 4- ((benzhydrylamino)methyl)-2-ethoxyphenol, 1-(4- Methoxyphenyl)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)vinyl-4-methoxybenzoat,2-(1-isopropyl-6-methyl-1H-enzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoate, (Z)-2-(1-isopropyl-5-methyl-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoate, 3-Alkyl-p-methan-3-ol derivatives, derivatives of fenchyl, D-bornyl, L-bornyl, exo-norbornyl, 2-methylisobornyl, 2-ethylfenchyl, 2-methylbornyl, cis-pinan-2-yl, verbanyl and isobornyl, menthyl oxamate derivatives, menthyl 3-oxocarboxylic acid esters, N-alpha-(menthanecarbonyl)amino acid amides, p-menthane carboxamide and WS-23 analogues, (-)-(1R,2R,4S)-Dihydroumbellulene, p-Menthane alkyloxyamide, cyclohexane derivatives, butanone derivatives, mixtures of 3-menthoxy-1-propanol and 1-menthoxy-2-propanol, 1-[2-hydroxyphenyl]-4-[2-nitrophenyl]-1,2,3,6-tetrahydropyrimidin-2-one, 4-methyl-3-(1-pyrrolidinyl)-2-[5H]-furanone, and mixtures thereof. FEMA stands for "Flavor and Extracts Manufacturers Association" and GRAS is defined as "Generally Regarded As Safe." A FEMA GRAS designation meansthat the substance so labelled has been tested according to standard methods and is considered toxicologically safe.

[0275] In principle, all known substances with a cooling effect are suitable as component (b). However, for food safety reasons, those compounds with a FEMA GRAS designation are preferred, or if the cooling mixture in question requires it.

[0276] A first important representative of the substances that form component (b) is Monomenthyl Succinate (FEMA GRAS 3810). Both the succinate and the analogue Monomenthyl glutarate (FEMA GRAS 4006) are important representatives of monomenthyl esters based on di- and polycarboxylic acids.

[0277] The next important group of menthol compounds preferred in the sense of the invention comprises carbonate esters of menthol and polyols, such as glycols, glycerol or carbohydrates, such as menthol ethylene glycol carbonate (FEMA GRAS 3805 = Frescolat® MGC), menthol propylene glycol carbonate (FEMA GRAS 3784 = Frescolat® MPC), menthol 2-methyl-1,2-propanediol carbonate (FEMA GRAS 3849) or the corresponding sugar derivatives. Also preferred are N-(4-cyanomethylphenyl)-p-menthanecarboxamide (FEMA GRAS 4496), N-(2-(pyridin-2-yl)ethyl)-3-p-menthanecarboxamide (FEMA GRAS 4549) and (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide (FEMA GRAS 4788) as component (b).

[0278] For the purposes of the invention, the menthol compounds menthyl lactate (FEMA GRAS 3748 = Frescolat® ML) and in particular menthone glyceryl acetal (FEMA GRAS 3807) or menthone glyceryl ketal (FEMA GRAS 3808), which is marketed under the name Frescolat® MGA, are preferred.

[0279] This group of compounds also includes 3-(1-menthoxy)-1,2-propanediol, also known as Cooling Agent 10 (FEMA GRAS 3784), as well as 3-(1-menthoxy)-2-methyl-1,2-propanediol (FEMA GRAS 3849), which has an additional methyl group.

[0280] Among the above-mentioned substances, menthone glyceryl acetal / ketal, menthyl lactate, menthol ethylene glycol carbonate and menthol propylene glycol carbonate have proven particularly advantageous, which the applicant markets under the names Frescolat® MGA, Frescolat® ML, Frecolat® MGC and Frescolat® MPC.

[0281] Further preferred components (b) are shown in Table 1 below:

[0282] Table 1 : Other suitable substances as component (b)

[0283] In the 1970s, menthol compounds were first developed that possess a CC bond in the 3-position, and several of these compounds can also be used within the meaning of the invention. These substances are generally referred to as WS types. The basic structure is a menthol derivative in which the hydroxyl group is replaced by a carboxyl group (WS-1). All other WS types are derived from this structure, such as the species WS-3, WS-4, WS-5, WS-12, WS-14, WS-23, WS-27, and WS-30, which are also preferred within the meaning of the invention, or the esters or N-substituted amides of the aforementioned compounds.

[0284] Furthermore, the coolant 2-(p-tolyloxy)-N-(1H-pyrazol-5-yl)-N-((thiophen-2-yl)methyl)acetamide (FEMA GRAS 4809) is particularly preferred. Also preferred are 2-(4-ethylphenoxy)-N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide (FEMA GRAS 4880) and / or N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexane carboxamide (FEMA GRAS 4881) and / or N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexane carboxamide (FEMA GRAS 4882).

[0285] Further preferred components (b) which are reacted with at least one coolant according to the invention of the general formulas (Va) to (Villa) or as listed in one of Tables A to D and defined above or with at least one compound of the invention as listed in one of Tables E and F and defined above, are shown in Table 2 below:

[0286] Table 2: Other suitable substances as component (b) and their salts, preferably acid addition salts, with inorganic or organic acids.

[0287] The coolant mixtures according to the invention can contain components (a) and (b) in a weight ratio of about 0.1:99.9 to about 99.0:0.1, preferably from about 1:99 to about 99:1, even more preferably from about 10:90 to about 90:10, even more preferably from about 25:75 to about 75:25 and in particular from about 40:60 to about 60:40, based on the total coolant mixture.

[0288] Advantageously, the coolant mixture according to the invention comprises, on the other hand, as further component (c), at least one solvent.

[0289] On the one hand, the aforementioned cooling agents which form component (b) of the cooling agent mixture can act as solvents for the cooling agent or the cooling agent / compound or compounds which form component (a) of the cooling agent mixture.

[0290] Individual solvents or solvent systems have proven advantageous, wherein the solvent is selected from the group consisting of: benzyl alcohol, 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and mixtures thereof.

[0291] Optamint, for example, is a blend of more than 50 different natural essential oils and natural or nature-identical flavorings. Optamints have variable compositions of different (partially fractionated) oils, which is preferably a mixture of, for example, different peppermint oils and spearmint oils, as well as eucalyptus globulus oil, star anise oil, menthol, menthone, isomenthone, menthyl acetate, anethole, eucalyptol, etc.

[0292] For example, benzyl alcohol or 2-phenylethanol or benzyl benzoate can be used as solvents in the coolant mixture according to the invention.

[0293] The use of benzyl alcohol or 2-phenylethanol or benzyl benzoate can be used, for example, to dissolve the cooling agents according to the invention and thereby also to obtain a stable solution, ie cooling agent mixture, for appropriate storage.

[0294] Solvent systems, i.e., solvent combinations of two or more solvents, can also be used to dissolve the cooling agents or compounds according to the invention. Especially with regard to the subsequent application, the use of solvents that can also exhibit a cooling effect can eliminate a further step in the (final) production process.

[0295] In an exemplary embodiment, the solvent in the coolant mixture is therefore a binary system of two solvent substances selected from the group consisting of benzyl alcohol, 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and other coolants as described above as component (b).

[0296] Suitable according to the present invention are, for example, binary solvent systems of benzyl alcohol and a further substance selected from the group consisting of 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and further cooling agents as described above as component (b).

[0297] Binary solvent combinations or mixtures, which contain or consist of, for example, benzyl alcohol with another solvent, are also suitable. The binary solvent combinations or mixtures selected from the following are also suitable in this case: benzyl alcohol and 2-phenylethanol, benzyl alcohol and benzyl benzoate, benzyl alcohol and diethyl succinate, benzyl alcohol and triethyl citrate, benzyl alcohol and triacetin, benzyl alcohol and ethanol, benzyl alcohol and peppermint oil, benzyl alcohol and anethole, benzyl alcohol and optamint, benzyl alcohol and propylene glycol, benzyl alcohol and menthol, benzyl alcohol and menthyl lactate (Frescolat® ML), benzyl alcohol and menthol propylene glycol carbonate (Frescolat® MPC), benzyl alcohol and menthol ethylene glycol carbonate (Frescolat® MGC), benzyl alcohol and menthone glyceryl acetal (Frescolat® MGA), benzyl alcohol and menthane carboxylic acid esters and amides.

[0298] Furthermore, the following binary solvent combinations or mixtures are also suitable: 2-phenylethanol and menthol propylene glycol carbonate (Frescolat® MPC), diethyl succinate and 2-phenylethanol, triacetin and benzyl benzoate, triethyl citrate and triacetin, 2-phenylethanol and peppermint oil, 2-phenylethanol and Optamint, anethole and triacetin, peppermint oil and menthyl lactate (Frescolat® ML), triacetin and menthone glyceryl acetal (Frescolat® MAG), Optamint and menthyl lactate (Frescolat® ML), triethyl citrate and menthol ethylene glycol carbonate (Frescolat® MGC).

[0299] Suitable coolant mixtures within the meaning of the present invention therefore contain, for example, a binary solvent combination or mixture as solvent (c), as described above.

[0300] The binary solvent mixtures in the sense of the present invention have, for example, the following ratios: solvent (1) : solvent (2) in a ratio of 10 : 1 to 1 : 10, preferably in a ratio of 8 : 2 to 2 : 8, even more preferably from 6 : 4 to 4 : 6 and most preferably in a ratio of 5 : 5.

[0301] The aforementioned suitable solvent mixtures can dissolve the cooling agents according to the invention or the compounds according to the invention and, depending on the solvent or combination of the solvents mentioned, can keep the cooling agents stable in solution in an amount of 2 wt.% to 50 wt.%, preferably 5 wt.% to 40 wt.% and more preferably 5 wt.% to 20 wt.%.

[0302] In a further exemplary embodiment, the solvent or solvent system for the cooling agents or the compounds according to the invention is a ternary system of three solvents selected from the group consisting of benzyl alcohol, 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and other cooling agents as described above as component (b).

[0303] Suitable for this purpose are, for example, ternary solvent combinations or mixtures of benzyl alcohol and two other substances selected from the group consisting of 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and other cooling agents, as also described above as component (b).

[0304] Suitable are ternary solvent combinations or mixtures which, for example, contain or consist of benzyl alcohol with two other solvents, wherein the two other solvents are selected from the group consisting of: 2-phenylethanol and benzyl benzoate, 2-phenylethanol and diethyl succinate, triethyl citrate and triacetin, triacetin and ethanol, triacetin and peppermint oil, menthol ethylene glycol carbonate (Frescolat® MGC) and anethole, 2-phenylethanol and Optamint, Optamint and propylene glycol, diethyl succinate and menthol, triacetin and menthyl lactate (Frescolat® ML), anethole and menthol propylene glycol carbonate (Frescolat® MPC), triacetin and menthol ethylene glycol carbonate (Frescolat® MGC), 2-phenylethanol and menthone glyceryl acetal (Frescolat® MGA), 2-phenylethanol and menthanecarboxylic acid esters and amides, 2-phenylethanol and menthol propylene glycol carbonate (Frescolat® MPC), triacetin and benzyl benzoate, 2-phenylethanol and peppermint oil, anethole and triacetin, peppermint oil and menthyl lactate (Frescolat® ML), triacetin and menthone glyceryl acetal (Frescolat® MGA), Optamint and menthyl lactate (Frescolat® ML), triethyl citrate and menthol ethylene glycol carbonate (Frescolat® MGC). Benzyl benzoate and menthol ethylene glycol carbonate (Frescolat® MGC), 2-phenylethanol and triethyl citrate, triethyl citrate and diethyl succinate, peppermint oil and menthyl lactate (Frescolat® ML), and ethanol and menthyl lactate (Frescolat® ML).

[0305] The following ternary solvent combinations or mixtures are also suitable: Triethyl citrate, triacetin, menthyl lactate (Frescolat® ML), Triacetin, 2-phenylethanol and peppermint oil, 2-phenylethanol, Optamint and peppermint oil, 2-Phenylethanol, Triacetin and Optamint, Anethole, benzyl alcohol and triacetin, 2-Phenylethanol, Benzyl Benzoate and Optamint 2-Phenylethanol, Diethylsuccinate and Optamint Triethyl citrate, triacetin and peppermint oil, Optamint, triacetin and ethanol, Triacetin, Menthol Ethylene Glycol Carbonate (Frescolat® MGC) and Anethole, 2-Phenylethanol, Optamint and Propylene Glycol, Diethyl Succinate, Triacetin and Menthol, Triacetin, Benzyl Benzoate and Menthyl Lactate (Frescolat® ML), Anethole, Menthol Propylene Glycol Carbonate (Frescolat® MPC) and Menthol Ethylene Glycol Carbonate (Frescolat® MGC), Triacetin, 2-phenylethanol and menthone glyceryl acetal (Frescolat® MGA), peppermint oil, 2-phenylethanol and menthanecarboxylic acid esters and amides, triacetin, 2-phenylethanol and menthol propylene glycol carbonate (Frescolat® MPC), menthyl lactate (Frescolat® ML), 2-phenylethanol and peppermint oil, anethole, triacetin and menthone glyceryl acetal (Frescolat® MGA), Optamint, benzyl benzoate and menthyl lactate (Frescolat® ML), and benzyl benzoate, triethyl citrate and menthol ethylene glycol carbonate (Frescolat® MGC).

[0306] The ternary solvent mixtures in the sense of the present invention have, for example, the following ratios: solvent (1) : solvent (2) : solvent (3) in a ratio of 10 : 1 : 15 to 5 : 1 : 3, or in a ratio of 4 : 1 : 7 to 7 : 1 : 4, or in a ratio of 2 : 2 : 4 to 4 : 4 : 2.

[0307] The above-mentioned suitable ternary solvent mixtures proved particularly good in the property of dissolving the cooling agents according to the invention or the compounds according to the invention and of keeping the cooling agents or the compounds stable in solution in an amount of 2 wt.% to 50 wt.%, preferably 5 wt.% to 40 wt.% and more preferably 5 wt.% to 20 wt.%, in a wide range, depending on the solvent or combination of the solvents mentioned.

[0308] This has the advantage that the cooling agent(s) or the compound(s) according to the invention can be presented in a variable amount suitable for the final formulation, so that the range of cooling agent mixtures in which the cooling agent(s) is / are present in dissolved form is broadly based.

[0309] In a further suitable embodiment, the solvent or solvent system for the cooling agents or compounds according to the invention is a quaternary system of four solvents selected from the group consisting of: benzyl alcohol, 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and other cooling agents as described above as component (b).

[0310] Suitable for this purpose are, for example, quaternary solvent combinations of benzyl alcohol and three other substances selected from the group consisting of: 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and other cooling agents as described above as component (b).

[0311] Suitable quaternary solvent combinations or mixtures are those which, for example, contain or consist of benzyl alcohol with three other solvents, wherein the three other solvents are selected from the group consisting of: 2-phenylethanol, triethyl citrate and triacetin, Peppermint oil, 2-phenylethanol and triethyl citrate, Triethyl citrate, menthyl lactate (Frescolat® ML) and diethyl succinate Triethyl citrate, triacetin and anethole, 2-Phenylethanol, Triacetin, and Optamint, Peppermint oil, benzyl alcohol and menthyl lactate (Frescolat® ML), Optamint, ethanol and menthyl lactate (Frescolat® ML), 2-phenylethanol, benzyl benzoate and diethyl succinate, Triethyl citrate, triacetin and ethanol, Peppermint oil, anethole and Optamint, 2-phenylethanol, benzyl benzoate and propylene glycol, 2-Phenylethanol, Benzyl Benzoate and Menthol Propylene Glycol Carbonate (Frescolat® MPC), Triethyl Citrate, Optamint and Ethanol, Triacetin, benzyl benzoate and menthoxy-2-methyl-1,2-propanediol, Menthone Glyceryl Acetal (Frescolat® MGA), Triacetin and Anethole.

[0312] The following quaternary solvent combinations and solvent mixtures are also suitable: Anethole, triacetin, peppermint oil and menthol ethylene glycol carbonate (Frescolat® MGC), triacetin, ethanol, 2-phenylethanol and peppermint oil, 2-phenylethanol, Optamint, diethyl succinate and peppermint oil, anethole, 2-phenylethanol, benzyl alcohol and triacetin.

[0313] The above-mentioned suitable quaternary solvent mixtures proved particularly good in the property of dissolving the coolants or compounds according to the invention and of keeping the coolants stable in solution in a wide range, depending on the solvent or combination of the solvents mentioned, in an amount of 2 wt.% to 50 wt.%, preferably 5 wt.% to 40 wt.% and more preferably 5 wt.% to 20 wt.%.

[0314] This has the advantage that the cooling agent(s) or the compound(s) according to the invention can be presented in a variable amount suitable for the final formulation, so that the range of cooling agent mixtures in which the cooling agent(s) or the compound(s) are present in dissolved form is broadly based.

[0315] The coolant mixtures according to the invention preferably contain or consist of component (a) and / or component (b) in an amount of 2 wt.% to 20 wt.%, preferably from 2 wt.% to 10 wt.%, even more preferably from 5 wt.% to 10 wt.%, very particularly preferably from 5 wt.% to 8 wt.%, and / or component (c) in an amount of 80 wt.% to 98 wt.%, preferably 90 wt.% to 98 wt.%, even more preferably from 90 wt.% to 95 wt.%, very particularly preferably from 92 wt.% to 95 wt.%, based on the total coolant mixture, with the proviso that components (a) and / or (b) and / or (c) together amount to 100 wt.%.

[0316] This composition of the coolant mixture according to the invention is particularly advantageous because it allows the amount of coolant(s) or compound(s) in the final formulation to be controlled.

[0317] Preferably, the final product contains the cooling agent(s) or compound in an amount of approximately 0.00001 wt% to 50 wt%, preferably 0.0001 wt% to 10 wt%, more preferably 0.001 wt% to 5 wt%, and even more preferably 0.005 wt% to 1 wt% or 0.1 wt% to 20 wt%, more preferably 0.5 wt% to 15 wt% or 1 wt% to 5 wt% based on the weight of the final product, especially in the case of oral care compositions.

[0318] Suitable coolant mixtures according to the invention have, for example, the following composition or consist, for example, of: 5 - 10 wt.% coolant(s) or compound(s) in 95 - 90 wt.% benzyl alcohol, or - 8 - 10 wt.% coolant(s) or compound(s) in 92 - 90 wt.% benzyl alcohol, or 1 - 4 wt.% cooling agent(s) or compound(s) in 99 - 96 wt.% triethyl citrate, or 1 - 3 wt.% cooling agent(s) or compound(s) in 99 - 97 wt.% triacetin, or 3 - 6 wt.% cooling agent(s) or compound(s) in 97 - 94 wt.% diethyl succinate, or 5 - 15 wt.% coolant(s) or compound(s) in 95 - 85 wt.% 2-phenylethanol, or 5 - 10 wt.% coolant(s) or compound(s) in 95 - 90 wt.% benzyl benzoate, or 1 - 3 wt% coolant(s) or compound(s) in 99 - 97 wt% Optamint, or 1 - 4 wt.% cooling agent(s) or compound(s) in 99 - 96 wt.% further cooling agents as described above as component (b), or 2 - 4 wt% coolant(s) or compound(s) in 98 - 96 wt% propylene glycol, or 0.5 - 2 wt% coolant(s) or compound(s) in 95.5-98 wt% ethanol, or 0.5 - 2 wt.% cooling agent(s) or compound(s) in 95.5 - 98 wt.% menthyl acetate, or 1 - 4 wt% cooling agent(s) or compound(s) in 99 - 96 wt% peppermint oil, or 2-5 wt.% coolant(s) or compound(s) in 98-95 wt.% anethole, whereby both components (coolant(s) or compound(s) and solvent) in the coolant mixture always add up to 100 wt.%. For example, a suitable coolant mixture according to the invention consists of 5-10 wt.% coolant(s) or compound(s) in 95-90 wt.% benzyl alcohol, particularly preferably 8-10 wt.% coolant(s) or compound(s) in 92-90 wt.% benzyl alcohol.

[0319] Another object of the present invention relates to a flavor preparation comprising or consisting of (d) one, two, three or more refrigerant(s) of the general formulae (Va) to (Villa) or as listed in Table A to Table D and defined above or one, two, three or more compound(s) as listed in Table E and Table F and defined above; and (e) at least one flavouring substance.

[0320] The particular advantage of these mixtures or flavor preparations is that the cooling substances are able to mask unpleasant, for example bitter or astringent, taste impressions of flavors, especially sweeteners, even in small concentrations, while at the same time providing an intensive and efficient cooling effect.

[0321] The above applies equally to component (d) as to component (a) of the physiological cooling agent mixture according to the invention, comprising or consisting of: (a) one, two, three or more refrigerant(s) of the general formulae (Va) to (Villa) or as listed in any of Tables A to D and defined above or one, two, three or more compound(s) as listed in Table E and Table F and defined above.

[0322] The aroma preparations according to the invention comprise one or more aroma substances as component (e) which is / are selected from the group formed by acetophenone, allyl capronate, alpha-ionone, beta-ionone, anisaldehyde, anisyl acetate, anisyl formate, anethole, benzaldehyde, benzothiazole, benzyl acetate, benzyl alcohol, benzyl benzoate, beta-ionone, butyl butyrate, butyl capronate, butylidene phthalide, carvone, camphene, caryophyllene, cineole, cinnamyl acetate, citral, citronellol, citronellal, citronellyl acetate, cyclohexyl acetate, cymene, damascone, decalactone, dihydrocoumarin, dimethyl anthranilate, dodecalactone, ethoxyethyl acetate, ethyl butyric acid, ethyl butyrate, ethyl caprinate, ethyl capronate, ethyl crotonate, Ethyl furaneol, ethyl guaiacol, ethyl isobutyrate, ethyl isovalerianate, ethyl lactate, ethyl methyl butyrate, ethyl propionate, eucalyptol, eugenol, ethyl heptylate, 4-(p-hydroxyphenyl)-2-butanone, gamma-decalactone, geraniol, geranyl acetate, geranyl acetate, grapefruit aldehyde,Methyldihydrojasmonat (z.B. Hedion®), Heliotropin, 2-Heptanon, 3-Heptanon, 4-Heptanon, trans-2-Heptenal, cis-4- Heptenal, trans-2-Hexenal, cis-3-Hexenol, trans-2-Hexensäure, trans-3-Hexensäure, cis-2- Hexenylacetat, cis-3-Hexenylacetat, cis-3-Hexenylcapronat, trans-2-Hexenylcapronat, cis-3- Hexenylformiat, cis-2-Hexylacetat, cis-3-Hexylacetat, trans-2-Hexylacetat, cis-3- Hexylformiat, para-Hydroxybenzylaceton, Isoamylalkohol, Isoamylisovalerianat, Isobutylbutyrat, Isobutyraldehyd, Isoeugenolmethylether, Isopropylmethylthiazol, Laurinsäure, Leavulinsäure, Linalool, Linalooloxid, Linalylacetat, Menthol, Menthofuran, Methylanthranilat, Methylbutanol, Methylbuttersäure, 2-Methylbutylacetat, Methylcapronat, Methylcinnamat, 5-Methylfurfural, 3,2,2-Methylcyclopentenolon, 6,5,2-Methylheptenon, Methyldihydrojasmonat, Methyljasmonat, 2-Methylmethylbutyrat, 2-Methyl-2-Pentenolsäure, Methylthiobutyrat, 3,1-Methylthiohexanol, 3-Methylthiohexylacetat, Nerol, Nerylacetat, trans, trans-2,4-Nonadienal,2,4-Nonadienol, 2,6-Nonadienol, 2,4-Nonadienol, Nootkaton, delta Octalacton, gamma Octalacton, 2-Octanol, 3-Octanol, 1 ,3-Octenol, 1-Octylacetat, 3- Octylacetat, Palmitinsäure, Paraldehyd, Phellandren, Pentandion, Phenylethylacetat, Phenylethylalkohol, Phenylethylalkohol, Phenylethylisovalerianat, Piperonal, Propionaldehyd, Propylbutyrat, Pulegon, Pulegol, Sinensal, Sulfurol, Terpinen, Terpineol, Terpinoien, 8,3-, Thiomenthanone, 4,4,2-thiomethylpentanone, thymol, delta-undecalactone, gamma-undecalactone, valencene, valeric acid, vanillin, acetoin, ethyl vanillin, ethyl vanillin isobutyrate (= 3-ethoxy-4-isobutyryloxybenzaldehyde), 2,5-dimethyl-4-hydroxy-3(2H)-furanone and its derivatives (preferably homofuraneol (= 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone), homofuronol (= 2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone and 5-ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and maltol derivatives (preferably ethyl maltol), coumarin and coumarin derivatives, gamma-lactones (preferably gamma-undecalactone, gamma-nonalactone, gamma-decalactone), delta-lactones (preferably 4-methyldeltadecalactone, massoilactone, deltadecalactone, tuberolactone), methyl sorbate, divanillin, 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone, 2-hydroxy-3-methyl-2- cyclopentenon, 3-Hydroxy-4,5-dimethyl-2(5H)-furanon, Essigsäureisoamylester, Buttersäureethylester, Buttersäure-n-butylester, Buttersäureisoamylester, 3-Methyl- buttersäureethylester, n-Hexansäureethylester, n-Hexansäureallylester, n-Hexansäure-n- butylester, n-Octansäureethylester, Ethyl-3-methyl-3-phenylglycidat, Ethyl-2-trans-4-cis- decadienoat, 4-(p-Hydroxyphenyl)-2-butanon, 1,1-Dimethoxy-2,2,5-trimethyl-4-hexan, 2,6- Dimethyl-5-hepten-1-al und Phenylacetaldehyd, 2-Methyl-3-(methylthio)furan, 2-Methyl-3- furanthiol, bis(2-Methyl-3-furyl)disulfid, Furfurylmercaptan, Methional, 2-Acetyl-2-thiazolin, 3- Mercapto-2-pentanon, 2,5-Dimethyl-3-furanthiol, 2,4,5-Trimethylthiazol, 2-Acetylthiazol, 2,4- Dimethyl-5-ethylthiazol, 2-Acetyl-1-pyrrolin, 2-Methyl-3-ethylpyrazin, 2-Ethyl-3,5- dimethylpyrazin, 2-Ethyl-3,6-dimethylpyrazin, 2,3-Diethyl-5-methylpyrazin, 3-lsopropyl-2- methoxypyrazin, 3-lsobutyl-2-methoxypyrazin, 2-Acetylpyrazin, 2-Pentylpyridin, (E,E)-2,4- Decadienal, (E,E)-2,4-Nonadienal, (E)-2-Octenal, (E)-2-Nonenal, 2-Undecenal, 12-Methyltridecanal, 1-Penten-3-one, 4-Hydroxy-2,5-dimethyl-3(2H)-furanone, Guaiacol, 3-Hydroxy-4,5-dimethyl-2(5H)-furanone, 3-Hydroxy-4-methyl-5-ethyl-2(5H)-furanone, Cinnamaldehyde, cinnamyl alcohol, methyl salicylate, isopulegol as well as (not explicitly mentioned here) stereoisomers, enantiomers, positional isomers, diastereomers, cis / trans isomers or epimers of these substances.

[0323] For the purposes of the present invention, flavorings of component (e) include, in particular, artificial and natural sweeteners and sweetener enhancers. These can be selected from the group consisting of: • sugar alcohols (e.g. erythritol, threitol, arabitol, ribotol, xylitol, sorbitol, mannitol, dulcitol, lactitol); • Proteins (e.g. miraculin, monellin, thaumatin, curculin, brazzein); • Synthetic sweeteners (e.g. Magap, sodium cyclamate, acesulfame K, neohesperidin dihydrochalcone, saccharin sodium salt, aspartame, superaspartame, neotame, alitame, sucralose, stevioside, rebaudioside, lugduname, carrelame, sucrononate, sucrooctate, monatin, phenylodulcin); • Sweet tasting amino acids (e.g. glycine, D-leucine, D-threonine, D-asparagine, D-phenylalanine, D-tryptophan, L-proline); • Sweet tasting low molecular weight substances such as hernandulcin, dihydrochalcone glycosides, glycyrrhizin, glycerrhetinic acid, their derivatives and salts, extracts of licorice (Glycyrrhizza glabra ssp.), Lippia dulcis extracts, Momordica ssp. extracts and / or • Plant extracts, such as Momordica grosvenori [Luo Han Guo] and the mogrosides derived therefrom, Hydrangea dulcis or Stevia ssp. (e.g. Stevia rebaudiana) extracts or steviosides derived therefrom.

[0324] Component (e) comprises at least one of the above-mentioned flavoring substances.

[0325] The aroma preparations according to the invention can contain components (d) and (e) in a weight ratio of about 1 : 99 to about 99 : 1, preferably about 10:90 to about 90:10, more preferably about 25:75 to about 75:25 and especially about 40:60 to 60:40.

[0326] In a further preferred variant, the one or more cooling agents or the one or more compounds or the cooling agent mixture or the aroma preparation is present in encapsulated form. This is of particular interest, for example, when the capsules loaded with the one or more cooling agents or the one or more compounds are applied to textile surfaces, for example as a component of fabric softeners or laundry aftertreatment agents, or when a finish is achieved by using capsules loaded with the one or more cooling agents, by forced application, for example on tights.

[0327] Capsules are spherical aggregates containing at least one solid or liquid core enclosed by at least one continuous shell. During encapsulation, the one or more cooling agents, the cooling agent mixture, or the flavor preparation are encapsulated using a coating / shell material, resulting in macrocapsules with diameters of approximately 0.1 to approximately 5 mm or microcapsules with diameters of approximately 0.0001 to approximately 0.1 mm.

[0328] Consequently, a further embodiment of the present invention also relates to physiological cooling agents or physiological cooling agent mixtures or aroma preparations in encapsulated form.

[0329] Suitable coating materials include, for example, starches, including their degradation products and chemically or physically produced derivatives (in particular dextrins and maltodextrins), gelatin, gum arabic, agar-agar, ghatti gum, gellan gum, modified and non-modified celluloses, pullulan, curdlan, carrageenans, alginic acid, alginates, pectin, inulin, xanthan gum and mixtures of two or more of these substances.

[0330] The two essential properties of the new cooling agents, compounds, or mixtures are, firstly, their ability to modulate the TRPM8 receptor as antagonists or agonists, thus triggering a physiological response—namely, an intense and efficient cooling effect on the skin or mucous membranes—and, secondly, their ability to reduce or mask unpleasant flavors. However, the primary emphasis is on the ability to produce intense and efficient cooling effects even in small amounts.

[0331] A further aspect of the present invention therefore relates to the use of the physiological cooling substances according to the invention or the compounds according to the invention or the physiological cooling substance mixture according to the invention as a modulator, preferably for the in vivo and / or in vitro modulation of the cold menthol receptor TRPM8, in particular as a TRPM8 receptor agonist or as a TRPM8 receptor antagonist.

[0332] In the use according to the invention, the receptor TRPM8 is brought into contact with at least one cooling agent according to the invention or a physiological cooling agent mixture according to the invention, which in a cellular activity test using cells which recombinantly express the human TRPM8 receptor, determines the permeability of these cells for Ca 2+ -Ions modulated / modulate.

[0333] Suitable modulators can act either solely as an antagonist or agonist, in particular solely as an agonist, or both as an antagonist and agonist. In particular, an agonistic or antagonistic effect can occur depending on the particular modulator concentration selected.

[0334] An "agonist" is a substance that mediates activation of the TRPM8 receptor, i.e. a Ca 2+ -ion ​​influx into the cold-sensitive neurons and thus conveys a feeling of cold.

[0335] An "antagonist," on the other hand, is a compound that can counteract this activation of the TRPM8 receptor.

[0336] The modulators according to the invention, i.e., the physiological coolants according to the invention or the compounds according to the invention or the coolant mixture, can exert their effect by binding reversibly or irreversibly, specifically or non-specifically, to a TRPM8 receptor molecule. Usually, the binding occurs non-covalently via ionic and / or non-ionic, such as hydrophobic, interactions with the receptor molecule. The term "specific" encompasses both exclusive interaction with one or more different TRPM8 receptor molecules (such as TRPM8 molecules of different origin or different isoforms). The term "non-specific," in contrast, refers to an interaction of the modulator with several different receptor molecules of different function and / or sequence, whereby, as a result, a desired agonistic and / or antagonistic modulation (as described above) of the TRPM8 receptor can be observed.

[0337] In a use according to the invention, preferably in a variant described above as preferred, the modulator acts on the cellular Ca 2+ -Ion permeability agonistic or antagonistic.

[0338] Particularly preferred is a variant of the use according to the invention in which the modulator is a TRPM8 receptor agonist.

[0339] Due to its physiological property of causing a cooling effect on skin or mucous membrane, a further aspect of the present invention relates to the Use of the cooling agent according to the invention or the compound according to the invention or the cooling agent mixture according to the invention for producing a physiological cooling effect on the skin or mucous membrane of a human or an animal.

[0340] Alternatively, the cooling substances according to the invention or the compounds according to the invention or the cooling substance mixture according to the invention are used to induce a cooling effect by a packaging containing the physiological cooling substance or the compound according to the invention or the physiological cooling substance mixture or a textile containing the physiological cooling substance or the compound according to the invention or the physiological cooling substance mixture.

[0341] In a further variant, the cooling agents according to the invention or the compounds according to the invention or the cooling agent mixture according to the invention or the flavoring preparation according to the invention are used as a flavoring agent to impart a flavor to a preparation.

[0342] In a further variant, the cooling agents or the compounds or the cooling agent mixture or the flavoring preparation according to the invention are used to improve the flavor profile of a flavoring. This allows the flavor properties of flavors to be enhanced or individual flavors to be emphasized.

[0343] Due to their additional properties, namely reducing or masking unpleasant, for example, bitter or astringent, flavors, a further aspect of the present invention relates to the use of the physiological cooling agents according to the invention or the compounds according to the invention or the cooling agent mixture according to the invention for masking bitter substances. This allows known taste disadvantages of flavors, especially also of sweeteners such as steviosides, to be reduced or masked. In particular, the pungent, bitter, or metallic aftertaste is effectively reduced or masked even with the addition of small amounts.

[0344] The cooling agents according to the invention or the compounds according to the invention or the physiological cooling agent mixtures according to the invention or the flavoring preparations according to the invention have a broad field of application, in particular in foodstuffs, in food supplements, cosmetic or pharmaceutical preparations, animal feeds, textiles, packaging or tobacco products.

[0207] In particular, the physiological cooling agents according to the invention or the compounds according to the invention or the physiological cooling agent mixtures or the flavoring preparations are used because of their cooling properties and / or taste-improving properties for the production of foodstuffs, food supplements, cosmetic or pharmaceutical preparations, animal feed, textiles, packaging or tobacco products.

[0345] The present invention therefore further relates to the use of one or more cooling agents according to the invention or one or more compounds according to the invention or the cooling agent mixture according to the invention or the flavoring preparation according to the invention for the production of foodstuffs, food supplements, cosmetic or pharmaceutical preparations, animal feeds, textiles, packaging or tobacco products.

[0346] Due to the advantageous properties described, the cooling substances according to the invention, as represented and defined by the general formulas (Va) to (Villa) or as listed in one of Tables A to D and defined above or the compounds according to the invention as listed in Tables E and F and defined above, are preferably selected from the group in the uses according to the invention, namely the use as a modulator, for producing a physiological cooling effect on the skin or mucous membrane in humans or animals or for inducing a cooling effect, for improving the taste properties of flavorings, for reducing or masking an unpleasant taste, for producing foodstuffs, food supplements, cosmetic or pharmaceutical preparations, animal feed, textiles, packaging or tobacco products, or for use as a medicament, as described in detail herein,consisting of the compounds shown in Table 3 or Table 4.,

[0347] Table 3: Preferred structures according to the invention

[0348] Table 4: Preferred structures according to the invention

[0349] Of the above-mentioned compounds, the use of compounds B-01, B-02, B-03, B-05, B-07, B-11, B14, B-15, B-18 and B-21 and the use of compounds A-01, A-02, A-03, A-05, A-09, A-10, A-12 and A-69 are preferred because of their pronounced TRPM8 activation, EC50 value and cooling intensity.

[0350] Most preferred, however, is the use of one of the physiological cooling substances or compounds B-01-R, B-01-S, B-02-R, B-02-S, B-03-R, B-03-S, B-05-R, B-05-S, B-07-R, B-07-S, B-11-R, B-11-S, B-14-R, B-14-S, B-15-R, B-15-S, B-18-R, B-18-S, B-21-R and B-21-S as well as the use of one of the physiological cooling substances or compounds A-01-R, A-01-S, A-02-R, A-02-S, A-03-R, A-03-S, A-05-R, A-05-S, A-09-R, A- 09-S, A-10-R, A-10-S, A-11-R, A-11-S, A-12-R, A-12-S, A-69-R and A-69-S because of their outstanding TRPM8 activation, EC50 value and cooling intensity.

[0351] During the sensory assessment, i.e. the tasting of the respective samples, an intensive cooling effect was demonstrated for the (R)-enantiomers, which began quickly. The panelists rated the cooling effect of compound A-02-R at an application rate of 5 ppm with a score of 5.7. Accordingly, the sensory-assessed cooling intensity, taking into account the application rate of the compound, was comparable to that determined for the cooling substance WS-3 as a reference at a six times higher concentration (application rate: 30 ppm; sensory-determined cooling intensity: score 5.4). In comparison, the cooling effect of the corresponding (S)-enantiomer A-02-S was rated with a score of 3.6; the cooling effect began with a delay, built up slowly, and lasted for a long time.

[0352] In a further aspect, the present invention therefore also encompasses foodstuffs, food supplements, cosmetic or pharmaceutical preparations, animal feed, textiles, packaging or tobacco products which comprise a physiological cooling agent according to the invention or a physiological cooling agent mixture according to the invention or an aroma preparation according to the invention.

[0353] The content of the one or more cooling agents or of the one or more compounds depends on the type and use of the aforementioned products and is preferably approximately 0.1 ppm to 10 wt.%, preferably 1 wt.% to 10 wt.%, based on the total weight of the final product. In oral care applications, for example, in toothpastes or mouthwashes, the content is 0.1 ppm to 500 ppm of the one or more cooling agents.

[0354] A broad range of concentrations typically used to provide the desired degree of sensation modulation may be about 0.001 ppm to 1000 ppm, or about 0.01 ppm to about 500 ppm, or about 0.05 ppm to about 300 ppm, or about 0.1 ppm to about 200 ppm, or about 0.5 ppm to about 150 ppm, or about 1 ppm to about 100 ppm.

[0355] The foodstuffs are preferably baked goods, for example bread, biscuits, cakes, other pastries, sweets (for example chocolates, chocolate bar products, other bar products, fruit gums, hard and soft caramels, chewing gum), alcoholic or non-alcoholic beverages (for example coffee, tea, iced tea, wine, wine-based beverages, beer, beer-based beverages, liqueurs, schnapps, brandies, (carbonated) fruit-based lemonades, (carbonated) isotonic drinks, (carbonated) soft drinks, nectars, spritzers, fruit and vegetable juices, fruit or vegetable juice preparations, instant beverages (for example instant cocoa drinks, instant tea drinks, instant coffee drinks, instant fruit drinks), meat products (for example ham, fresh sausage or raw sausage preparations, seasoned or marinated fresh or cured meat products), eggs or egg products (dried egg, egg white, egg yolk),Cereal products (e.g. breakfast cereals, muesli bars, pre-cooked ready-to-eat rice products), dairy products (e.g. milk drinks, buttermilk drinks, milk ice cream, yogurt, kefir, cream cheese, soft cheese, hard cheese, dried milk powder, whey, whey drinks, butter, buttermilk, partially or fully hydrolyzed milk protein-containing products), products made from soy protein or other soybean fractions (e.g. soy milk and products made from it, fruit drinks with soy protein, preparations containing soy lecithin, fermented products such as tofu or tempeh or products made from them), products from other vegetable protein sources, for example oat protein drinks, fruit preparations (e.g. jams, fruit ice cream, fruit sauces, fruit fillings), vegetable preparations (e.g. ketchup, sauces, dried vegetables, frozen vegetables, pre-cooked vegetables, canned vegetables),Snacks (e.g., baked or fried potato chips or potato dough products, corn- or peanut-based extrudates), fat- and oil-based products or emulsions thereof (e.g., mayonnaise, tartar sauce, dressings), other ready meals and soups (e.g., dried soups, instant soups, pre-cooked soups), spices, seasonings, and, in particular, seasonings, which are used, for example, in the snack sector.

[0356] The above-mentioned foods contain, in addition to conventional food ingredients, at least an effective, ie cooling-acting, amount of at least one cooling agent according to the invention or a cooling agent mixture according to the invention or a flavoring preparation according to the invention.

[0357] The content of cooling agent or compound or cooling agent mixture or flavoring preparation according to the invention in these preparations is preferably about 0.1 wt.% to about 10 wt.% and in particular about 1 wt.% to 2 wt.%, based on the total weight of the finished preparation.

[0358] Suitable excipients can be used to produce the products according to the invention, such as food, dietary supplements, cosmetic or pharmaceutical preparations, animal feed, textiles, packaging, or tobacco products. Suitable excipients include, but are not limited to, emulsifiers, thickeners, food acids, acidity regulators, vitamins, antioxidants, flavor enhancers, agents for masking unpleasant taste impressions, food colorings, and the like.

[0359] In particular, other conventional additives or excipients can be added to the above-mentioned products according to the invention, such as flavorings or active ingredients for masking unpleasant taste impressions.

[0360] Flavorings: Preferred flavorings are those that cause a sweet odor impression, wherein the further flavoring(s) that cause a sweet odor impression are preferably selected from the group consisting of: vanillin, ethyl vanillin, ethyl vanillin isobutyrate (= 3 ethoxy-4-isobutyryloxybenzaldehyde), furaneol (2,5-dimethyl-4-hydroxy-3(2H)-furanone) and derivatives (e.g. homofuraneol, 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone), homofuronol (2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone and 5-ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and derivatives (e.g. ethyl maltol), coumarin and derivatives, gamma-lactones (e.g. gamma-undecalactone, gamma-nonalactone), delta-lactones (e.g. 4-methyldeltalactone, massoilactone, deltadecalactone, tuberolactone), methyl sorbate, divanillin, 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)furanone, 2-hydroxy-3-methyl-2-cyclopentenone, 3-Hydroxy-4,5-dimethyl-2(5H)-furanone, fruit esters and fruit lactones (e.gAcetic acid n-butyl ester, Acetic acid isoamyl ester, Propionic acid ethyl ester, Butyric acid n-butyl ester, Butyric acid isoamyl ester, 3-Methyl-butyric acid ethyl ester, n-Hexanoic acid ethyl ester, n-Hexanoic acid allyl ester, n-Hexanoic acid n-butyl ester, n-Octanoic acid ethyl ester, Ethyl 3-methyl-3-phenylglycidate, Ethyl 2-trans-4-cis-decadienoate), 4-(p-Hydroxyphenyl)-2-butanone, 1,1-Dimethoxy-2,2,5-trimethyl-4-hexane, 2,6-Dimethyl-5-hepten-1-al, 4-Hydroxycinnamic acid, 4-Methoxy-3-hydroxycinnamic acid, 3-Methoxy-4-hydroxycinnamic acid, 2-Hydroxycinnamic acid, 2,4-Dihydroxybenzoic acid, 3-hydroxybenzoic acid, 3,4-Dihydroxybenzoic acid, vanillic acid, homovanillic acid, vanillomandelic acid and phenylacetaldehyde.

[0361] Active ingredients to mask unpleasant taste impressions: Furthermore, the oral preparations may also contain other substances that also serve to mask bitter and / or astringent taste impressions. These further taste correctors are selected, for example, from the following list: from nucleotides (e.g. adenosine 5'-monophosphate, cytidine 5'-monophosphate) or their physiologically acceptable salts, lactisoles, sodium salts (e.g. sodium chloride, sodium lactate, sodium citrate, sodium acetate, sodium gluconoate), hydroxyflavanones, preferably eriodictyol, sterubin (eriodictyol 7-methyl ether), homoeriodictyol, and their sodium, potassium, calcium, magnesium or zinc salts (in particular those as described in EP 1258200 A2), hydroxybenzoic acid amides, preferably 2,4-dihydroxybenzoic acid vanillylamide, 2,4-dihydroxybenzoic acid / V-(4-hydroxy-3-methoxybenzyl)amide, 2,4,6-trihydroxybenzoic acid / V-(4-hydroxy-3-methoxybenzyl)amide,2- Hydroxy-benzoesäure- / V-4-(hydroxy-3-methoxybenzyl)amid, 4-Hydroxybenzoesäure- / V-(4- hydroxy-3-methoxybenzyl)amid, 2,4-Dihydroxybenzoesäure- / V-(4-hydroxy-3-methoxy- benzyl)amid-Mono-natriumsalz, 2,4-Dihydroxybenzoesäure- / V-2-(4-hydroxy-3-methoxy- phenyl)ethylamid, 2,4-Dihydroxybenzoesäure- / V-(4-hydroxy-3-ethoxybenzyl)amid, 2,4- Dihydroxybenzoesäure- / V-(3,4-dihydroxybenzyl)amid und 2-Hydroxy-5-methoxy-N-[2-(4- hydroxy-3-methoxyphenyl)ethyl]amid; 4-Hydroxybenzoesäurevanillylamiden (insbesondere solche wie beschrieben in WO 2006 / 024587); Hydroxydeoxybenzoinen, dabei vorzugsweise 2-(4-Hydroxy-3-methoxyphenyl)-1-(2,4,6-trihydroxyphenyl)ethanon, 1-(2,4-Dihydroxyphenyl)-, 2-(4-hydroxy-3-methoxyphenyl)-ethanon und 1-(2-Hydroxy-4-methoxyphenyl)-2-(4-hydroxy- 3-methoxyphenyl)ethanone) (in particular those as described in WO 2006 / 106023); hydroxyphenylalkanediones, such as gingerdione-[2], gingerdione-[3], gingerdione-[4], dehydrogingerdione-[2], dehydrogingerdione-[3], dehydrogingerdione-[4]) (in particular those as described in WO 2007 / 003527); diacetyl trimers (in particular those as described in WO 2006 / 058893); gamma-aminobutyric acids (in particular those as described in WO 2005 / 096841);Divanillins (in particular those as described in WO 2004 / 078302) and 4-hydroxydihydrochalcones (preferably as described in US 2008 / 0227867 A1), in particular phloretin and davidigenin, amino acids or mixtures of whey proteins with lecithins, hesperetin as disclosed in WO 2007 / 014879, 4-hydroxydihydrochalcones as disclosed in WO 2007 / 107596, or propenylphenyl glycosides (chavicol glycosides) as described in EP 1955601 A1, or extracts from Rubus suavissimus, extracts from Hydrangea macrophylla as described in EP 2298084 A1, pellitorin and derived aroma compositions as described in EP 2008530 A1, umami compounds as described in WO 2008 / 046895 A1 and EP 1989944 A1, umami compounds as described in EP 2064959 A1 and EP 2135516 A1, vanillyl lignans, enterodiol, and N-decadienoyl amino acids and mixtures thereof.;

[0362] A further subject matter of the invention relates to cosmetic or pharmaceutical preparations which contain either one or more of the cooling agent(s) according to the invention or one or more of the compound(s) according to the invention or a cooling agent mixture according to the invention or an aroma preparation according to the invention.

[0363] The agents according to the invention can be, in particular, skin cosmetic, hair cosmetic, dermatological, hygiene, or pharmaceutical agents. In particular, the active ingredients according to the invention, especially those with a cooling effect, are used for skin and / or hair cosmetics or as oral care products.

[0364] The hair or skin care products or preparations according to the invention are preferably in the form of an emulsion, a dispersion, a suspension, an aqueous surfactant preparation, a milk, a lotion, a cream, a balm, an ointment, a gel, granules, a powder, a stick preparation such as a lipstick, a foam, an aerosol, or a spray. Such formulations are well suited for topical preparations. Suitable emulsions are oil-in-water emulsions, water-in-oil emulsions, or microemulsions. As a rule, the hair or skin cosmetic preparation is used for application to the skin (topically) or hair. "Topical preparations" are understood to mean preparations suitable for applying the active ingredients to the skin in a fine distribution, for example in a form that can be absorbed through the skin. Suitable for this purpose are, for example,Aqueous and aqueous-alcoholic solutions, sprays, foams, foam aerosols, ointments, aqueous gels, O / W or W / O emulsions, microemulsions, or cosmetic stick preparations. According to one embodiment of the cosmetic agent according to the invention, it contains a carrier. Preferred carriers are water, a gas, a water-based liquid, an oil, a gel, an emulsion or microemulsion, a dispersion, or a mixture thereof. These carriers exhibit good skin compatibility. Aqueous gels, emulsions, or microemulsions are particularly advantageous for topical preparations.

[0365] The teaching of the invention also encompasses the use of the active ingredients described herein for medical purposes, in particular in pharmaceutical compositions for treating an individual, preferably a mammal, in particular a human, farm animal, or domestic animal. The active ingredients are administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient with at least one active ingredient according to the invention and optionally other active ingredients. These compositions can be administered, for example, orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly, or intranasally.

[0366] Examples of suitable pharmaceutical formulations or compositions are solid dosage forms, such as powders, granules, tablets, lozenges, sachets, cachets, coated tablets, capsules such as hard and soft gelatin capsules, suppositories or vaginal dosage forms, semi-solid dosage forms such as ointments, creams, hydrogels, pastes or plasters, as well as liquid dosage forms such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection and infusion preparations, eye and ear drops. Implanted delivery devices can also be used to administer inhibitors according to the invention. Furthermore, liposomes, Microspheres or polymer matrices are used. Pharmaceutical agents such as cold syrups, wound ointments, or wound sprays are possible. It is also possible to incorporate the substances into plasters or tablets, especially if these contain active ingredients that themselves have an unpleasant taste.

[0367] A further subject matter of the present invention therefore encompasses the cooling agents or compounds or cooling agent mixtures according to the invention as medicaments, in particular as medicaments for use in relieving pain and inflammation of the skin and mucous membranes. Due to their cooling properties, the cooling agents according to the invention are particularly suitable for preventing, combating, or alleviating symptoms of coughs, colds, inflammation, sore throats, or hoarseness.

[0368] In addition, the substances and preparations described herein are suitable for the treatment of inflammatory conditions of the skin and mucous membranes as well as the joints due to their efficient cooling effect.

[0369] Due to their ability to modulate the TRPM8 receptor, whose gene expression, i.e., that of the TRPM8 gene, is upregulated in cancers, for example, in prostate carcinomas, the pharmaceutical preparations according to the invention are preferably also used in oncology, preferably in the treatment of prostate or bladder carcinomas, or for the treatment of bladder weakness. The corresponding proteins in the cell are encoded by corresponding genes in the cell nucleus. The transcription of the genes in the nucleus (transcription) leads to the generation of messenger RNA (mRNA), which is then "translated" into a protein by ribosomes in the cell (translation). The combined effect of both processes is often referred to as gene expression.

[0370] However, astringent, bitter, and / or metallic tastes are not only found in flavors and sweeteners as described above, but also in connection with many pharmaceutical active ingredients, making their administration difficult, especially in children. Typical examples of such pharmaceutical active ingredients are the following: aspirin, minoxidil, erythromycin, fenistil, betamethasone, ibuprofen, ketoprofen, dicyclofenac, metronidazole, acyclovir, imiquimod, terbafine, cyclopirox olamine, paracetamol, and other pharmaceutical active ingredients of the nonsteroidal anti-inflammatory drug (NSAID) type and mixtures thereof.

[0371] The present invention therefore also encompasses medicaments which contain one or more cooling agents according to the invention or a cooling agent mixture according to the invention or an aroma preparation according to the invention in combination with at least one further pharmaceutical active ingredient selected from the group consisting of aspirin, minoxidil, erythromycin, fenistil, betamethasone, ibuprofen, ketoprofen, dicyclofenac, metronidazole, Acyclovir, imiquimod, terbafine, cyclopiroxolamine, paracetamol and mixtures thereof.

[0372] Furthermore, studies with volunteers have shown that the cooling agents or cooling agent mixtures according to the invention enhance the pain-relieving properties of nonsteroidal anti-inflammatory drugs (NSAIDs), in particular ibuprofen and ketoprofen, beyond the cooling effect, which would also not have been expected by the person skilled in the art. Therefore, the present invention also relates in particular to the combination with pharmaceutical active ingredients of the nonsteroidal anti-inflammatory drug (NSAID) type.

[0373] Such pharmaceutical combinations are therefore particularly advantageous for use in the treatment of inflammatory conditions of the skin and mucous membranes as well as the joints.

[0374] The medicaments may contain the cooling agents according to the invention or the compounds according to the invention or the cooling agent mixtures according to the invention and the pharmaceutical active ingredients in a weight ratio of about 1:99 to about 10:90 and in particular 2:98 to about 5:95.

[0375] The physiological cooling effect is also used in the formulation of wound and burn ointments as well as preparations for insect bites.

[0376] In the manufacture of the cosmetic or pharmaceutical preparations according to the invention, the cooling agent(s) or the compound(s) according to the invention or the cooling agent mixture according to the invention are usually mixed or diluted with an excipient. Excipients can be solid, semi-solid, or liquid materials that serve as vehicles, carriers, or medium for the active ingredient. The active ingredient content (of one or more cooling agents according to the invention present simultaneously) can vary within a wide range and is approximately, based in each case on the total weight of the preparation, from about 0.05 ppm to 10 wt.%, preferably 0.1 ppm to 10 wt.%.

[0377] Suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Furthermore, the formulations may contain pharmaceutically acceptable carriers or conventional excipients, such as lubricants, for example talc, magnesium stearate, and mineral oil; wetting agents, emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; antioxidants; antiirritants; chelating agents; coating agents; emulsion stabilizers; film formers; gelling agents; odor masking agents; flavor correctors; resins; hydrocolloids; solvents; solubilizers; neutralizing agents; permeation enhancers; pigments; quaternary Ammonium compounds; refatting and superfatting agents; ointment, cream, or oil bases; silicone derivatives; spreading agents; stabilizers; sterilants; suppository bases; tablet excipients such as binders, fillers, lubricants, disintegrants, or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers; white oils. Such design is based on expert knowledge and is adequately described in the relevant specialist literature.

[0378] In addition to conventional additives or excipients, the preparations according to the invention may also contain cosmetically and / or dermatologically and / or pharmacologically active ingredients. Non-limiting examples of suitable additional active ingredients include: cosmetically and / or dermatologically active ingredients; antimicrobial agents; Surfactants (anionic surfactants, non-ionic surfactants, cationic surfactants, amphoteric or zwitterionic surfactants), oil components, emulsifiers, fats and waxes, pearlescent waxes, consistency regulators and thickeners, superfatting agents and stabilizers, polymers, silicone compounds, UV light protection filters, pigments, especially light protection pigments, humectants, biogenic active ingredients and antioxidants, deodorants and germicidal agents, enzyme inhibitors, odor absorbers, antiperspirants, film formers, anti-dandruff active ingredients, swelling agents, insect repellents, hydrotropes, preservatives, perfume oils and flavors, dyes, etc.

[0379] Preferred preparations according to the invention are selected from the group of products for the treatment, protection, care and cleansing of the skin and / or hair or as a make-up product, either as leave-on or rinse-off products.

[0380] The formulations include, for example, dispersions, suspensions, creams, lotions or milks, depending on the manufacturing method and ingredients, gels (including hydrogels, e.g. hydrodispersion gels, oleogels), sprays (e.g. pump sprays or sprays with propellant), foams or impregnating solutions for cosmetic wipes, soaps, washing liquids, shower and bath preparations, bath products (capsules, oil, tablets, salts, bath salts, soaps, etc.), effervescent preparations, skin care products, such as emulsions, ointments, pastes, gels (as described above), oils, balms, serums, powders (e.g. face powder, body powder), masks, sticks, roll-on sticks, aerosols (foaming, non-foaming or post-foaming), deodorants and / or antiperspirants, mouthwashes and mouth rinses, insect repellents, sunscreens, after-sun preparations, shaving preparations, aftershave balms, pre- and Aftershave lotions, depilatories, hair care products such asShampoos (including 2-in-1 shampoos, anti-dandruff shampoos, baby shampoos, shampoos for dry scalp, concentrated shampoos), conditioners, hair tonics, hair water, hair rinses, styling creams, pomades, perming and setting lotions, hair sprays, e.g. styling aids (e.g. gel or wax), hair relaxers (detanglers, relaxers), hair dyes such as temporary hair dyes, semi-permanent hair dyes, permanent hair dyes. Hair conditioners, hair mousses, eye care products, makeup, makeup removers or baby products.

[0381] The formulations according to the invention are particularly preferably in the form of an emulsion, in particular in the form of a W / O, O / W, W / O / W, O / W / O emulsion, PIT emulsion, e.g. a Pickering emulsion, an emulsion with a low oil content, a micro- or nanoemulsion, a gel (including hydrogel, hydrodispersion gel, oleogel) or a solution.

[0382] The total proportion of excipients and additives can be from 1% to 50% by weight, preferably from 5% to 40% by weight, based on the final preparation. The preparations can be produced using conventional cold or hot processes; the phase inversion temperature method is preferred.

[0383] The present invention also encompasses oral care products containing one or more cooling agents according to the invention or one or more compounds according to the invention or a cooling agent mixture according to the invention or a flavoring preparation according to the invention.

[0384] Oral hygiene products according to the invention can be formulated in a manner known per se, e.g. as toothpaste, tooth cream, tooth gel, tooth powder, tooth cleaning liquid, tooth cleaning foam, aqueous or aqueous-alcoholic oral care products (mouthwash), mouthwash as a 2-in-1 product, lozenges, mouth spray, dental floss and dental care chewing gum.

[0385] Toothpastes or tooth creams are generally understood to be gel-like or pasty preparations consisting of water, thickeners, humectants, abrasives or cleaning agents, surfactants, sweeteners, flavorings, deodorizing agents, and agents for treating oral and dental diseases. All conventional cleaning agents, such as chalk, dicalcium phosphate, insoluble sodium metaphosphate, aluminum silicates, calcium pyrophosphate, finely divided synthetic resins, silicas, aluminum oxide, and aluminum oxide trihydrate, can be used in the toothpastes according to the invention.

[0386] Preferred abrasive agents for the toothpastes according to the invention are, above all, finely divided xerogel silicas, hydrogel silicas, precipitated silicas, aluminum oxide trihydrate, and finely divided alpha-aluminum oxide, or mixtures of these abrasive agents in amounts of 15 to 40% by weight of the toothpaste. Humectants that can be used are primarily low-molecular-weight polyethylene glycols, glycerin, sorbitol, or mixtures of these products in amounts of up to 50% by weight. Among the known thickeners, the thickening, finely divided gel silicas and hydrocolloids, such as carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylguar, hydroxyethyl starch, polyvinylpyrrolidone, high-molecular-weight polyethylene glycol, plant gums such as tragacanth, agar-agar, carrageenan moss, gum arabic, xantham gum, and carboxyvinyl polymers (e.g., Carbopol® types). In addition to the mixtures of menthofuran and Menthol compounds can be used in oral and dental care products, in particular surface-active substances, preferably anionic and non-ionic high-foam surfactants, such as those already mentioned above, but in particular alkyl ether sulfate salts, alkyl polyglucosides and mixtures thereof.

[0387] Other common toothpaste additives include: • Preservatives and antimicrobials such as p-hydroxybenzoic acid methyl, ethyl or propyl ester, sodium sorbate, sodium benzoate, bromochlorophene, phenylsalicylic acid ester, thymol and the like; • Antitartar agents, e.g. organophosphates such as 1-hydroxyethane-1,1-diphosphonic acid, 1-phosphonopropane-1,2,3-tricarboxylic acid and others, which are known e.g. from US 3,488,419, DE 2224430 A1 and DE 2343196 A1; • other caries-inhibiting substances such as sodium fluoride, sodium monofluorophosphate, stannous fluoride; • Sweeteners such as sodium saccharin, sodium cyclamate, sucrose, lactose, maltose, fructose or Apartam® (L-aspartyl-L-phenylalanine methyl ester), Stivia extracts or their sweetening components, in particular ribeaudiosides; • Additional flavors such as eucalyptus oil, anise oil, fennel oil, caraway oil, methyl acetate, cinnamaldehyde, anethole, vanillin, thymol and mixtures of these and other natural and synthetic flavors; • Pigments such as titanium dioxide; • Dyes; • Buffer substances such as primary, secondary or tertiary alkali phosphates or citric acid / sodium citrate; • wound-healing and anti-inflammatory substances such as allantoin, urea, azulene, chamomile active ingredients and acetylsalicylic acid derivatives.

[0388] To improve flow behavior, hydrotropes such as ethanol, isopropyl alcohol, or polyols can also be used; these substances largely correspond to the carriers described above. Suitable polyols preferably have 2 to 15 carbon atoms and at least two hydroxyl groups. The polyols may also contain other functional groups, particularly amino groups, or be modified with nitrogen.

[0389] Suitable preservatives include, for example, phenoxyethanol, formaldehyde solution, parabens, pentanediol or sorbic acid as well as the silver complexes known under the name Surfacine® and other suitable classes of substances known to the person skilled in the art.

[0390] Perfume oils include those already defined above. Flavorings include, in particular, peppermint oil, spearmint oil, anise oil, star anise oil, caraway oil, eucalyptus oil, fennel oil, lemon oil, wintergreen oil, clove oil, menthol, and the like.

[0391] A preferred embodiment of the cosmetic preparations are toothpastes in the form of an aqueous, pasty dispersion containing polishing agents, humectants, viscosity regulators and optionally other customary components, as well as the mixture of menthofuran and menthol compounds in amounts of 0.5 to 2 wt.%.

[0392] In mouthwashes, a combination of aqueous-alcoholic solutions of varying strengths of essential oils, emulsifiers, astringent and tonic drug extracts, tartar-inhibiting and antibacterial additives, and flavor correctors is readily possible. A further preferred embodiment of the invention is a mouthwash in the form of an aqueous or aqueous-alcoholic solution containing the mixture of menthofuran and menthol compounds in amounts of 0.5 to 2 wt.%. In mouthwashes that are diluted before use, sufficient effects can be achieved with higher concentrations, depending on the intended dilution ratio.

[0393] Oral care preparations according to the invention contain, based on the total weight of the composition, preferably 0.1 ppm to 1 wt.%, more preferably 1 ppm to 0.2 wt.%, of at least one active ingredient according to the invention, ie a cooling agent, or an active ingredient mixture, ie cooling agent mixture or aroma preparation.

[0394] The total content of the active ingredient or of the several active ingredients according to the invention or of the cooling agent mixture or flavoring preparation according to the present invention in ready-to-use mouthwashes is preferably 0.01 to 1 wt.%, preferably 0.05 to 0.5 wt.%, particularly preferably a content of 0.1 to 0.3 wt.%, in each case based on the total mouthwash.

[0395] In mouthwash concentrates, the total content of the active ingredient or of the several active ingredients according to the invention or of the cooling agent mixture or flavoring preparation according to the present invention is 0.1 to 15 wt.%, preferably a content of 0.5 to 8 wt.%, particularly preferably 1 to 5 wt.%, in each case based on the total mouthwash concentrate.

[0396] In toothpastes, the total content of the active ingredient or of the several active ingredients according to the invention or of the cooling agent mixture or flavoring preparation according to the present invention is 0.1 to 5 wt.%, preferably 0.5 to 2 wt.%, particularly preferably 0.8 to 1.5 wt.%, in each case based on the total toothpaste.

[0397] The present invention also encompasses chewing gum containing one or more cooling agents according to the invention or a cooling agent mixture according to the invention or a flavor preparation according to the invention.

[0398] Chewing gum compositions typically contain a water-insoluble and a water-soluble component. The water-insoluble base, also referred to as the "gum base," typically comprises natural or synthetic elastomers, resins, fats and oils, plasticizers, fillers, dyes, and optionally waxes. The proportion of the base in the total composition typically amounts to 5 to 95 wt.%, preferably 10 to 50 wt.%, and especially 20 to 35 wt.%. In a typical embodiment of the invention, the base consists of 20 to 60 wt.% synthetic elastomers, 0 to 30 wt.% natural elastomers, 5 to 55 wt.% plasticizers, 4 to 35 wt.% fillers, and minor amounts of additives such as dyes, antioxidants, and the like, with the proviso that they are water-soluble at most in minor amounts.

[0399] Suitable synthetic elastomers include, for example, polyisobutylenes with average molecular weights (according to GPC) of 10,000 to 100,000 and preferably 50,000 to 80,000, isobutylene-isoprene copolymers (butyl elastomers), styrene-butadiene copolymers (styrene:butadiene ratio e.g. 1:3 to 3:1), polyvinyl acetates with average molecular weights (according to GPC) of 2,000 to 90,000 and preferably 10,000 to 65,000, polyisoprenes, polyethylene, vinyl acetate-inyl laurate copolymers and mixtures thereof. Examples of suitable natural elastomers are rubbers such as smoked or liquid latex or guayule, as well as natural gums such as jelutong, lechi caspi, perillo, sorva, massaranduba balata, massaranduba chocolate, nispero, rosindinba, chicle, gutta hang 1 kang and mixtures thereof.The selection of synthetic and natural elastomers and their mixing ratios depends essentially on whether the chewing gum is intended to produce bubbles ("bubble gums") or not. Elastomer mixtures containing jelutong, chicle, sorva, and massaranduba are preferably used.

[0400] Magnesium or calcium carbonate, ground pumice, silicates, especially magnesium or aluminum silicates, clays, aluminum oxides, talc, titanium dioxide, mono-, di- and tricalcium phosphate as well as cellulose polymers can be used as fillers or texturizing agents.

[0401] Suitable emulsifiers are tallow, hydrogenated tallow, hydrogenated or partially hydrogenated vegetable oils, cocoa butter, partial glycerides, lecithin, triacetin and saturated or unsaturated fatty acids having 6 to 22 and preferably 12 to 18 carbon atoms and mixtures thereof.

[0402] Examples of dyes and whitening agents that can be used are FD and C types approved for coloring food, plant and fruit extracts, and titanium dioxide.

[0403] The base compositions may contain waxes or be wax-free; examples of wax-free compositions can be found, among others, in patent US 5,286,500.

[0404] In addition to the water-insoluble gum base, chewing gum preparations regularly contain a water-soluble component, which may be formed, for example, by softeners, sweeteners, fillers, flavorings, flavor enhancers, emulsifiers, colorings, acidulants, antioxidants, and the like, provided that the components have at least sufficient water solubility. Depending on the water solubility of the specific components, individual components can therefore belong to both the water-insoluble and the water-soluble phase. However, it is also possible to use combinations, for example, of a water-soluble and a water-insoluble emulsifier, with the individual components then being in different phases. The water-insoluble component typically makes up 5 to 95% by weight and preferably 20 to 80% by weight of the preparation.

[0405] Water-soluble softeners or plasticizers are added to chewing gum compositions to improve chewability and chewing sensation and are typically present in the mixtures in amounts of 0.5 to 15% by weight. Typical examples are glycerin, lecithin, and aqueous solutions of sorbitol, hydrogenated starch hydrolysates, or corn syrup.

[0406] Both sugar-containing and sugar-free compounds can be used as sweeteners, and are used in amounts of 5 to 95% by weight, preferably 20 to 80% by weight, and especially 30 to 60% by weight, based on the chewing gum composition. Typical saccharide sweeteners are sucrose, dextrose, maltose, dextrin, dried invert sugar, fructose, levulose, galactose, corn syrup, and mixtures thereof. Suitable sugar substitutes include sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates, maltitol, and mixtures thereof. Furthermore, so-called HIAS ("High Intensity Artificial Sweeteners") can be considered as additives, such as sucralose, aspartame, acesulfame salts, alitame, saccharin and saccharin salts, cyclamic acid and its salts, glycyrrhizins, dihydrochalcones, thaumatin, monellin and the like, alone or in mixtures.Also particularly effective are the hydrophobic HIAS, which are the subject of international patent application WO 2002 091849 A1 (Wrigley's), as well as stevia extracts and their active ingredients, particularly ribeaudioside A. The amount of these substances used depends primarily on their performance and typically ranges from 0.02 to 8 wt.%.

[0407] Fillers such as polydextrose, raffinose, raffinyl, fructooligosaccharides (NutraFlora), palatinose oligosaccharides, guar gum hydrolysates (Sun Fiber) and dextrins are particularly suitable for the production of low-calorie chewing gum.

[0408] The choice of additional flavorings is virtually unlimited and not critical to the essence of the invention. Typically, the total proportion of all flavorings is 0.1 to 15 wt.%, and preferably 0.2 to 5 wt.%, based on the chewing gum composition. Suitable additional flavorings include, for example, essential oils, synthetic flavors, and the like, such as anise oil, star anise oil, caraway oil, eucalyptus oil, fennel oil, lemon oil, wintergreen oil, clove oil, and the like, as are also used, for example, in oral and dental care products.

[0409] The chewing gum may also contain excipients and additives suitable for dental care, specifically for combating plaque and gingivitis, such as chlorhexidine, CPC, or trichlosan. Furthermore, pH regulators (e.g., buffers or urea), anti-caries agents (e.g., phosphates or fluorides), and biogenic active ingredients (antibodies, enzymes, caffeine, plant extracts) may be included, as long as these substances are approved for food use and do not interact adversely with each other.

[0410] The present invention also encompasses cooling plasters. Plasters according to the invention can be constructed in any desired manner, for example, according to a matrix system, a membrane system, or a nonwoven system. The plasters according to the invention are manufactured in a conventional manner.

[0411] Furthermore, the present invention relates to textile products which are provided with a cooling agent according to the invention or a compound according to the invention or a cooling agent mixture according to the invention.

[0412] The treatment of textiles with cooling agents is particularly useful where garments may come into direct contact with the skin, allowing the active ingredient to exert its effects, e.g., locally or systemically, through transdermal transmission. Recently, there have been reports of textiles treated with so-called wellness additives, i.e., substances that promote well-being.

[0413] The cooling agents or compounds or cooling agent mixtures according to the invention can be used to finish any textiles, i.e., both non-finished and finished goods. Textile materials here and below include woven, knitted, warp-knitted, and nonwoven fabrics. The textile materials can be composed of natural fiber yarns, synthetic fiber yarns, and / or blended yarns. Suitable fiber materials include, in principle, all fiber materials commonly used for the production of textiles. These include cotton, wool, hemp fibers, sisal fibers, flax, ramie, polyacrylonitrile fibers, polyester fibers, polyamide fibers, viscose fibers, silk, acetate fibers, triacetate fibers, aramid fibers, and the like, as well as mixtures of these fiber materials. Also suitable are glass fibers and mixtures of the aforementioned fiber materials with glass fibers, e.g., glass fiber / Kevlar blends.The type of textile material depends primarily on. The desired application. The textiles to be finished can be finished products such as clothing, including underwear and outerwear, such as shirts, trousers, jackets, outdoor, trekking, and military equipment, roofs, tents, nets, such as insect nets and curtains, hand and bath towels, bed linen, and the like. Finishing can also be applied to the raw material in bales or rolls.

[0414] The present invention further relates to cooling tobacco products.

[0415] The active ingredients according to the invention, ie, the cooling active ingredient according to the invention, or the compounds according to the invention, or the cooling agent mixture according to the invention, or the flavoring preparation according to the invention, can also be advantageously used for the production of tobacco products. Examples of such tobacco products include cigars, cigarettes, pipe tobacco, chewing tobacco, and snuff. The production of tobacco products supplemented with cooling additives is known per se.

[0416] In principle, the active ingredient content, ie the content of the cooling agent according to the invention or the cooling agent mixture according to the invention, can vary over a wide range, such as 0.05 ppm to 10 wt.%, preferably 0.1 ppm to 10 wt.%.

[0208] The active ingredients according to the invention are also advantageously suitable for the production of packaging materials.

[0417] Production also takes place in a conventional manner. The active ingredients can be incorporated into the packaging material, in free or, for example, encapsulated form, or applied to the packaging material, in free or encapsulated form. Thus, appropriately treated plastic packaging materials can be produced according to the information in the literature on the production of polymer films. The production of suitably coated papers is also known to those skilled in the art.

[0418] Finally, the present invention relates to a method for modulating, in particular for in vitro and / or in v / o modulation, the cold menthol receptor TRPM8, comprising the following steps: (i) providing at least one compound according to the invention or at least one physiological cooling agent according to the invention or a physiological cooling agent mixture according to the invention or providing a cosmetic or pharmaceutical preparation according to the invention; and (ii) bringing the compound or cooling agent or cooling agent mixture or cosmetic or pharmaceutical preparation from step (i) into contact with the receptor; or for producing a physiological cooling effect on skin or mucous membranes, comprising the following steps: (iii) providing at least one compound according to the invention or at least one physiological cooling agent according to the invention or a physiological cooling agent mixture according to the invention or providing a cosmetic or pharmaceutical preparation according to the invention; and (iv) bringing the compound or cooling agent or cooling agent mixture or the cosmetic or pharmaceutical preparation from step (iii) into contact with human skin or mucous membrane; or for improving the taste properties of flavorings, comprising the following steps: (v) providing at least one compound according to the invention or at least one physiological cooling agent according to the invention or a physiological cooling agent mixture according to the invention or providing a cosmetic or pharmaceutical preparation according to the invention and at least one flavoring agent; (vi) mixing the two components from step (v); and optionally (vii) incorporating the mixture into an oral preparation; or for masking bitter substances, comprising the following steps: (viii) providing at least one compound according to the invention or at least one physiological cooling agent according to the invention or a physiological cooling agent mixture according to the invention or providing a cosmetic or pharmaceutical preparation according to the invention and at least one bittering agent; (ix) mixing the two components from step (viii); and optionally (x) Incorporation of the mixture into an oral preparation.

[0209] Further aspects of the present invention will become apparent from the following examples and the appended claims. Examples

[0419] The following examples serve to illustrate the invention without limiting it. Unless otherwise stated, all data are by weight.

[0420] Preparation of active ingredients: The active ingredients / coolants and compounds used according to the invention can be prepared by a person skilled in the art of organic synthesis using known synthesis methods.

[0421] Cloning of human TRPM8

[0422] The starting point for cloning the human TRPM8 receptor is a LnCaP cDNA library. This is commercially available (e.g., from BioChain, Hayward, USA) or can be prepared from the androgen-sensitive human prostate adenocarcinoma cell line LnCaP (e.g., ATCC, CRL1740 or ECACC, 891 1021 1) using standard kits.

[0423] The TRPM8 coding sequence (see, for example, http: / / www.ncbi.nlm.nih.gov / entrez / viewer.fcgi?db=nuccore&id=109689694) can be PCR amplified and cloned using standard methods. The human TRPM8 gene isolated in this way was used to generate the plasmid plnd_M8. Alternatively, the TRPM8 gene can also be produced synthetically.

[0424] Generation of HEK293 test cells

[0425] As a test cell system, a stably transfected HEK293 cell line was generated using human TRPM8 DNA. HEK293 was preferred, as the introduced plasmid allows for the induction of TRPM8 expression using tetracycline.

[0426] Methods for producing suitable test cell systems are known to the person skilled in the art and can be found in the relevant specialist literature.

[0427] Assay for TRPM8 modulators

[0428] A test is carried out similar to the test already described in the literature by Behrendt HJ et al., Br. J. Pharmacol. 141 , 2004, 737 - 745. The agonization or antagonization of the receptor can be determined using a Ca 2+ -sensitive dye (e.g. FURA, Fluo-4 etc.). Agonists alone cause an increase in Ca 2+ - signals; antagonists in the presence of e.g. menthol cause a reduction of Ca 2+ - signals (each detected via the dye Fluo-4, which is activated by Ca 2+ -ions have different fluorescence properties).

[0429] First, a fresh culture of transformed HEK cells is prepared in cell culture flasks using conventional methods. The HEK293-TRPM8 test cells are detached from the cell culture flasks using trypsin, and 40,000 cells per well are seeded with 100 μl of medium in 96-well plates (Greiner #655948 poly-D-lysine coated). To induce the TRPM8 receptor, tetracycline is added to the growth medium (DMEM / HG, 10% tetracycline-free FCS, 4 mM L-glutamine, 15 pg / ml blasticidin, 100 pg / ml hygromycin B, 1 pg / ml tetracycline).

[0430] The following day, the cells are loaded with Fluo-4AM dye, and the assay is performed. The procedure is as follows: Add 100 μl / well of the Ca-4 Kit staining solution (RB 141, Molecular Devices) to 100 μl of medium (DMEM / HG, 10% tetracycline-free FCS, 4 mM L-glutamine, 15 pg / ml blasticidin, 100 pg / ml hygromycin B, 1 pg / ml tetracycline).

[0431] Incubation in an incubator, 30 minutes / 37 °C / 5% CO2, 30 minutes / RT.

[0432] Preparation of the test substances (different concentrations in 200 pl HBSS buffer), as well as positive controls (different concentrations of menthol, icilin or ionomycin in 200 pl HBSS buffer) and negative controls (only 200 pl HBSS buffer). Addition of the test substances in amounts of 50 pl / well and measurement of the fluorescence change (e.g. in the assay device FLIPR, Molecular Devices or NovoStar, BMG) at 485 nm excitation, 520 nm emission, and evaluation of the potency of the different substances / concentrations and determination of the EC50 values.

[0433] The test substances are used in triplicate at concentrations ranging from 0.1 to 200 pM in the assay. Typically, the compounds are kept in DMSO solutions and diluted to a maximum DMSO concentration of 2% for the assay. Our own evaluations while conducting the described assay surprisingly showed that the compounds to be used according to the invention (as described herein) are particularly suitable as TRPM8 agonists.

[0434] Using the described assay, the activity of the active substances in activating the TRPM8 channel is determined. This is done in a concentration-dependent manner. Six to ten concentrations are measured for each active substance as standard. From the determined activity values, the EC50 value can be determined as the inflection point of the sigmoidal curve using a mathematical method (4-parameter or 5-parameter logistic curve fitting). These are standard biochemical methods that are familiar to experts.

[0435] The determined EC50 values ​​of exemplary selected modulators according to the invention are shown in the following Table 7 and Table 8. For the substance WS-3, an EC50 value of 1.72 pM was determined, which serves as a reference.

[0436] Table 5: EC50 values ​​of modulators according to the invention

[0437] Table 6: EC50 values ​​of modulators according to the invention

[0438] The EC50 value describes the concentration of the cooling substance required for half-maximal effect and is thus a measure of the potency of an agonist drug (the potency of a drug as a function of dose or concentration), with potency being the reciprocal of the EC50. Consequently, a low EC50 value corresponds to a high drug potency.

[0439] Thus, it can be seen from Tables 5 and 6 above that the cooling agents and compounds according to the invention described herein have excellent cooling agent properties and can produce intensive cooling effects even in low concentrations and are generally well below the EC50 reference value of 1.72 pM for the substance WS-3.

[0440] As shown in Table 5 above, those structures of general formulas (Va) and (Via) have proven particularly advantageous in which R1 and R2 each represent a phenyl group, Y represents a methylene group or a methylene group substituted by a methyl or ethyl group, and Z represents -NH-cyclopropyl, -NH-CH3, -N(CH3)2, or an azetidine. Furthermore, it was observed that in said structures, m and n each represent 1.

[0441] As shown in Table 6 above, those structures of the general formulas (Vila) to (Villa) have proven particularly advantageous in which R1 and R2 each represent a phenyl group, Y represents a methylene group or a methylene group substituted by a methyl group, and Z represents -NH-CH3, -NH-CH2-CH3, -NH-cyclopropyl, or -CS-CH3. Furthermore, it was observed that in these structures, m stands for 0 or 1, and n stands for 1.

[0442] Particularly preferred with regard to the EC50 values ​​are therefore especially the compounds B-01, B-02, B-03, B-05 and B-07 with an EC50 value < 1.0 pM as well as the compounds A-01, A-02, A-03 and A-05 with an EC50 value < 1.0 pM.

[0443] Particularly efficient cooling effects with regard to TRPM8 activity as well as EC50 values ​​can be observed for compounds B-01, B-02, B-03, B-05 and B-07 as well as for compounds A-01, A-02 and A-03 (TRPM8 activity > 100% and EC value of < 1.0 pM).

[0444] In addition to the TRPM8 activity and active ingredient potency (EC50 value) described above, the cooling agents and compounds according to the invention also have an intensive cooling effect.

[0445] To quantify the cooling effect, comparative tests are conducted using menthane-3-carboxylic acid N-ethylamide as a reference. For these comparative tests, the person skilled in the art replaces the compound(s) to be used according to the invention with menthane-3-carboxylic acid N-ethylamide (also referred to as WS-3). The intensities of the cooling effects of the respective compounds or active ingredients are then sensorially evaluated and compared by trained panelists (n = 10 to 11), as described below.

[0446] The cooling intensity was investigated as follows: Test solutions containing 5 ppm of the compounds according to the invention were each tasted in a 5% sugar solution, as well as a corresponding solution containing 30 ppm of the reference substance WS-3. This concentration for WS-3 was chosen because WS-3 has been shown to exhibit good cooling effects at such concentrations. The panelists tasted the corresponding test solutions for a period of exactly 40 seconds, rinsing the entire mouth with the corresponding test solution and then spitting out the sample or reference solution. Following the tasting, the test subjects rated the respective cooling intensity after one minute on a scale of 1 (very weak) to 9 (very strong).

[0447] The results of the sensory tasting of exemplary cooling agents / compounds according to the invention are shown in the following Table 9 and Table 10.

[0448] Table 7: Results of the sensory tasting of exemplary cooling agents / compounds

[0449] Table 8: Results of the sensory tasting of exemplary cooling agents / compounds

[0450] It has surprisingly been found that the compounds described herein produce a noticeably more intense or comparable cooling effect compared to the WS-3 reference sample. In particular, the reference sample containing WS-3 exhibited a cooling intensity of approximately 5.4 in the sensory evaluation, while the cooling intensity of the substances according to the invention, such as compound B-01, was rated at 4.2, compound B-02 at 4.1, compound B-11 at 5.3, compound A-02 at 5.4, compound A-09 at 4.66, and compound A-10 at 5.38.

[0451] During the sensory assessment, i.e. the tasting of the respective samples, an intensive cooling effect was demonstrated for the (R)-enantiomers, which began quickly. The panelists rated the cooling effect of compound A-02 at an application rate of 5 ppm with a score of 5.7. Accordingly, the sensory-assessed cooling intensity, taking into account the application rate of the compound, was comparable to that determined for the cooling substance WS-3 as a reference at a six times higher concentration (application rate: 30 ppm; sensory-determined cooling intensity: score 5.4). In comparison, the cooling effect of the corresponding (S)-enantiomer was rated with a score of 3.6; the cooling effect began with a delay, built up slowly, and lasted for a long time.

[0452] It should also be noted that, despite a six-fold higher concentration, WS-3 is capable of producing noticeably lower cooling intensities. Conversely, significantly lower concentrations of the compounds according to the invention are necessary to produce significantly more intense cooling effects than conventional cooling substances (such as WS-3). This demonstrates that the compounds according to the invention produce an intense and thus highly effective cooling effect even when used in low concentrations, and that in corresponding final formulations, such as product formulations containing these cooling substances, only very small amounts need to be used to produce perceived intense cooling effects.

[0453] In this context, it is preferred that in the corresponding comparisons, the cooling effect of the samples containing the compound(s) to be used according to the invention is preferably prolonged by at least 10 minutes, preferably by at least 15 minutes, more preferably by at least 20 minutes, even more preferably by at least 30 minutes, particularly preferably by at least 60 minutes, most preferably by at least 90 minutes compared to the comparison samples containing WS-3.

[0454] Formulation examples

[0455] Formulation examples for cosmetic preparations

[0456] The following formulation examples F1 to F10 demonstrate a wide variety of formulations for cosmetic and pharmaceutical preparations. Cooling agent 1 denotes the inventive compound B-11-R, cooling agent 2 denotes compound A-02-R, cooling agent 3 denotes compound A-09-S, and cooling agent 4 denotes compound A-10-S. The above-mentioned cooling agents were used in pure form without any further additives.

[0457] In the following tables, the decimal point is represented as a dot.

[0458] Table F1 Transparent liquid soap (amounts in wt.%)

[0459] Table F2 Shampoo (amounts in wt.%)

[0460] Table F3 Shaving foam (amounts in wt.%) Ingredients (INCI)

[0461] Table F4 Deodorant formulation as roll-on gel (amounts in wt.%)

[0462] Table F5 Antiseptic wound cream (amounts in wt.%)

[0463] Table F6 Sunscreen formulation (amounts in wt.%)

[0464] Table F7 After Sun Gel (amounts in wt.%)

[0465] Table F8 Textile cleaners (amounts in wt.%)

[0466] Table F9 Toothpaste (amounts in wt.%)

[0467] Table F10 Mouthwash (amounts in wt.%)

[0468] Formulation examples for food preparations

[0469] The following formulation examples F11 to F15 show a wide variety of formulations for food preparations. Cooling agent 1 denotes the inventive compound B-11-R, cooling agent 3 denotes compound A-09-R, and cooling agent 4 denotes compound A-10-S. The cooling agents were used in pure form without any further additives.

[0470] Table F11 Chewing gum (amounts in wt.%)

[0471] Table F12 Pudding, recipe (for 100 ml) (quantities in grams)

[0472] Table 13 Chewy sweets (amounts in wt.%)

[0473] Table 14 Fruit gums (amounts in wt.%)

[0474] Table F15 Throat lozenges with a liquid-viscous center filling (centrefilled hard candy) ((amounts in wt.%)

Claims

Patent claims 1. Compound selected from the group consisting of the compounds shown in the table below: and their salts, in particular acid addition salts, with inorganic or organic acids, where the compound is present as a pure (R)-enantiomer, as a pure (S)-enantiomer, as a racemate or as a mixture of enantiomers, or Compound selected from the group consisting of the compounds shown in the table below: and their salts, in particular acid addition salts, with inorganic or organic acids, wherein the compound is present as a pure (R)-enantiomer, as a pure (S)-enantiomer, as a racemate or as a mixture of enantiomers.

2. A compound according to claim 1, wherein in the enantiomeric mixture the ratio of (R) to (S) enantiomer is greater than 50:50, preferably >75:25, even more preferably >90:10, even more preferably >95:5 and most preferably >98:2; or wherein in the enantiomeric mixture the ratio of (S) to (R) enantiomer is greater than 50:50, preferably >75:25, even more preferably >90:10, even more preferably >95:5 and most preferably >98:

2.

3. A compound according to claim 1 or claim 2, wherein the compound is a modulator, in particular for in vivo and / or in vitro modulation, of the cold menthol receptor TRPM8, in particular a TRPM8 receptor agonist or a TRPM8 receptor antagonist, a physiological cooling agent, a flavoring agent, a substance for improving the taste profile of a flavoring agent, or a bitter-masking substance.

4. Physiological coolant of the general formula (Va) or the general formula (Via) where in formulas (Va) and (Via) the radicals R1 and R2 may be the same or different and independently of one another have the following meanings: R1 • H; or • a group Q; or • an optionally substituted linear or branched alkyl group; or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted acyl group -R(C=O)-; or • an optionally substituted cycloalkyl group; or • an optionally substituted aryl group; or • an optionally substituted heterocycloalkyl group; or an optionally substituted heteroaryl group; R2 • H; or • a group Q; or • an optionally substituted linear or branched alkyl group; or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted acyl group R-(C=O)-; or • an optionally substituted cycloalkyl group; or • an optionally substituted aryl group; or • an optionally substituted heterocycloalkyl group; or • is an optionally substituted heteroaryl group; or R1 and R2 together with the C atoms to which they are attached form a conjugated or non-conjugated ring system; Y • is an optionally substituted branched alkyl group; or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted acyl group R-(C=O)-; or • an optionally substituted alkylaryl group; or • is an optionally substituted alkylheteroaryl group; Z • NH2; or in the • an NHRa group; or in general • an NRaRb group; or inen • an optionally substituted linear or branched alkyl group; formula oder (Va) ,ejne optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted linear or branched alkoxy group; or • OH; or • an optionally substituted cycloalkyl group; or • an optionally substituted heterocycloalkyl group; or • an optionally substituted aryl group; or • is an optionally substituted heteroaryl group; or • is NH and together with X forms a heterocyclic ring; Z in the • NH2; or general • an NHRa group or an NRaRb group, except for -NH-phenyl and -N(CH3)-phenyl; or Formula • an optionally substituted linear or branched alkyl group; (Via) or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted linear or branched alkoxy group, except -OC2H5 and -OC(CH3)3; or • an optionally substituted cycloalkyl group; or • an optionally substituted heterocycloalkyl group; or • an optionally substituted aryl group; or • is an optionally substituted heteroaryl group; or NH and together with X forms a heterocyclic ring; m is 1; wherein the group Q is a radical selected from the group consisting of: halogen, -OA, -SA, -NBB, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -S(O)2 a , -S(O)2OA, -OS(O)2 a , - OS(O)2OA, -P(O)(OA) 2I-P(O)(OA)(OA), -C(O)A, -C(S)A, -C(NA)A, -C(O)OA, -C(S)OA, -C(O)NBB, -C(NA)NBB, -OC(O)A, -OC(S)A, -OC(O)OA, -O -NAC(O)OA, -NAC(S)OA, -NAC(O)NBB, -NAC(NA)A or -NAC(NA)NBB; where A selected is from the Group consisting of: Hydrogen, optionally substituted linear or branched alkyl group, in particular optionally substituted C1- to C8-alkyl group, in particular optionally substituted C1- to C8-alkyl group, particularly optionally substituted C1-, C2-, C3- or C4-alkyl group, optionally substituted linear or branched alkoxy group, in particular optionally substituted C1-C8-alkoxy group, particularly optionally substituted C1-, C2-, C3- or C4-alkoxy group, optionally substituted linear or branched alkylthio group, in particular optionally substituted C1- to C8-alkylthio group, particularly optionally substituted C1-, C2-, C3- or C4-alkylthio group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, optionally substituted heteroaryl group; and / or B represents A or, alternatively, two Bs together with the nitrogen atom to which they are bonded represent a four-, five-, six- or seven-membered heterocycloalkyl ring or heteroaryl ring, wherein the heterocycloalkyl ring or heteroaryl ring may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur; the optionally substituted linear or branched alkyl group is an optionally substituted C1- to C8-alkyl group, in particular an optionally substituted C1- to C8-alkyl group, particularly an optionally substituted C1-, C2-, C3- or C4-alkyl group;the optionally substituted linear or branched alkenyl group is an optionally substituted Ci- to Cw-alkenyl group, in particular an optionally substituted Ci- to C18-alkenyl group, especially an optionally substituted Ci-, C2-, C3- or C4-alkenyl group; the optionally substituted linear or branched alkynyl group is an optionally substituted Ci- to C18-alkynyl group, in particular an optionally substituted Ci- to C18-alkynyl group, especially an optionally substituted Ci-, C2-, C3- or C4-alkynyl group; the optionally substituted linear or branched alkoxy group is an optionally substituted Ci to Cw alkoxy group, in particular an optionally substituted Ci to C10 alkoxy group, especially an optionally substituted Ci, C2, C3 or C4 alkoxy group;the optionally substituted linear or branched alkylthio group is an optionally substituted Ci- to Cw-alkylthio group, in particular an optionally substituted Ci- to C12-alkylthio group, especially an optionally substituted Ci-, C2-, C3- or C4-alkylthio group; in the acyl group R-(C=O)-, the radical R is hydrogen or an optionally substituted linear or branched Ci- to C12-alkyl group, in particular an optionally substituted Ci- to C12-alkyl group; in particular represents an optionally substituted C1, C2, C3 or C4 acyl group; the optionally substituted cycloalkyl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered, monocyclic cycloalkyl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, cycloalkyl group; the optionally substituted aryl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered, monocyclic aryl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic aryl group;the optionally substituted heterocycloalkyl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered monocyclic heterocycloalkyl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, heterocycloalkyl group, wherein the heterocycloalkyl group may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;the optionally substituted heteroaryl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered monocyclic heteroaryl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, heteroaryl group, wherein the heteroaryl group may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Ra • an optionally substituted linear or branched alkyl group, and / or preferably a C1- to C3-alkyl group, preferably a methyl group; or Rb • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted acyl group R-(C=O)-; or • an optionally substituted cycloalkyl group; or • an optionally substituted aryl group; or • an optionally substituted heterocycloalkyl group; or • is / are an optionally substituted heteroaryl group; or • Ra and Rb, as defined above, are linked together to form a saturated or unsaturated ring; wherein the substituents are each selected independently of one another; and its salts, in particular acid addition salts, with inorganic or organic acids, wherein the coolant is present as a pure (R)-enantiomer, as a pure (S)-enantiomer, as a racemate or as a mixture of enantiomers; or of the general formula (Vila) or the general formula (Villa) (Villa) where in the formulas (Vila) and (Villa) the radicals R1 and R2 may be the same or different and independently of one another have the following meanings: R1 • H; or • a group Q; or • an optionally substituted linear or branched alkyl group; or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted acyl group -R(C=O)-; or • an optionally substituted cycloalkyl group; or • an optionally substituted aryl group; or • an optionally substituted heterocycloalkyl group; or an optionally substituted heteroaryl group; R2 • H; or • a group Q; or • an optionally substituted linear or branched alkyl group; or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted acyl group R-(C=O)-; or • an optionally substituted cycloalkyl group; or • an optionally substituted aryl group; or • an optionally substituted heterocycloalkyl group; or • is an optionally substituted heteroaryl group; or R1 and R2 together with the C atoms to which they are bonded form a conjugated or non-conjugated ring system; V • S; or • SO2; or • an optionally substituted linear or branched alkyl group; or • an optionally substituted cycloalkyl group; or • Piperidinyl is; Y • is an optionally substituted branched alkyl group; or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted acyl group is R-(C=O)-; Z • NH2; or • an NHRa group; or • an NRaRb group; or • an optionally substituted linear or branched alkyl group; or • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted linear or branched alkoxy group; or • OH; or • an optionally substituted cycloalkyl group; or • an optionally substituted heterocycloalkyl group; or • an optionally substituted aryl group; or • is an optionally substituted heteroaryl group; or • is NH and together with X forms a heterocyclic ring; m is 1; where the group Q is a radical selected from the group consisting of: halogen, -OA, -SA, -NBB, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -S(O)2A, -S(O)2OA, -OS(O)2A, - OS(O)2OA, -P(O)(OA) 2I-P(O)(OA)(OA), -C(O)A, -C(S)A, -C(NA)A, -C(O)OA, -C(S)OA, -C(O)NBB, -C(NA)NBB, -OC(O)A, -OC(S)A, -OC(O)OA, -O -NAC(O)OA, -NAC(S)OA, -NAC(O)NBB, -NAC(NA)A or -NAC(NA)NBB; where A selected is from the Group consisting of: Hydrogen, optionally substituted linear or branched alkyl group, in particular optionally substituted C1- to C8-alkyl group, in particular optionally substituted C1- to C8-alkyl group, particularly optionally substituted C1-, C2-, C3- or C4-alkyl group, optionally substituted linear or branched alkoxy group, in particular optionally substituted C1-C8-alkoxy group, particularly optionally substituted C1-, C2-, C3- or C4-alkoxy group, optionally substituted linear or branched alkylthio group, in particular optionally substituted C1- to C8-alkylthio group, particularly optionally substituted C1-, C2-, C3- or C4-alkylthio group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, optionally substituted heteroaryl group; and / or B represents A or, alternatively, two B's together with the nitrogen atom to which they are attached represent a four-, five-, six- or seven-membered heterocycloalkyl ring or heteroaryl ring, wherein the heterocycloalkyl ring or heteroaryl ring may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; the optionally substituted linear or branched alkyl group is an optionally substituted Ci- to Cw-alkyl group, in particular an optionally substituted Ci- to C18-alkyl group, particularly an optionally substituted Ci-, C2-, C3- or C4-alkyl group; the optionally substituted linear or branched alkenyl group is an optionally substituted Ci- to C18-alkenyl group, in particular an optionally substituted Ci- to C18-alkenyl group, particularly an optionally substituted Ci-, C2-, C3- or C4-alkenyl group; the optionally substituted linear or branched alkynyl group is an optionally substituted Ci- to C18-alkynyl group, in particular an optionally substituted Ci- to C18-alkynyl group, particularly an optionally substituted Ci-, C2-, C3- or C4-alkynyl group;the optionally substituted linear or branched alkoxy group is an optionally substituted Ci- to Cw-alkoxy group, in particular an optionally substituted Ci- to C10-alkoxy group, especially an optionally substituted Ci-, C2-, C3- or C4-alkoxy group; the optionally substituted linear or branched alkylthio group is an optionally substituted Ci- to C10-alkylthio group, in particular an optionally substituted Ci- to C10-alkylthio group, especially an optionally substituted Ci-, C2-, C3- or C4-alkylthio group; in the acyl group R-(C=O)- the radical R represents hydrogen or an optionally substituted linear or branched Ci- to Cw-alkyl group, in particular an optionally substituted Ci- to C1-alkyl group, especially an optionally substituted Ci-, C2-, C3- or C4-acyl group;the optionally substituted cycloalkyl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six-, or seven-membered, monocyclic cycloalkyl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, cycloalkyl group; the optionally substituted aryl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six-, or seven-membered, monocyclic aryl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic aryl group;the optionally substituted heterocycloalkyl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered monocyclic heterocycloalkyl group or an optionally substituted nine- to twelve-membered polycyclic, in particular bicyclic, heterocycloalkyl group, where the heterocycloalkyl group may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; the optionally substituted heteroaryl group is an optionally substituted three- to ten-membered, in particular three-, four-, five-, six- or seven-membered monocyclic heteroaryl group or an optionally substituted nine- to; twelve-membered polycyclic, in particular bicyclic, heteroaryl group, wherein the heteroaryl group may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Ra • an optionally substituted linear or branched alkyl group; and / preferably a C1- to C3-alkyl group, preferably a methyl group; or Rb • an optionally substituted linear or branched alkenyl group; or • an optionally substituted linear or branched alkynyl group; or • an optionally substituted linear or branched alkoxy group; or • an optionally substituted linear or branched alkylthio group; or • an optionally substituted acyl group R-(C=O)-; or • an optionally substituted cycloalkyl group; or • an optionally substituted aryl group; or • an optionally substituted heterocycloalkyl group; or • is / are an optionally substituted heteroaryl group; or • Ra and Rb, as defined above, are linked to one another and form a saturated or unsaturated ring; wherein the substituents are each selected independently of one another; and its salts, in particular acid addition salts, with inorganic or organic acids, wherein the coolant is present as a pure (R)-enantiomer, as a pure (S)-enantiomer, as a racemate or as a mixture of enantiomers.

5. Physiological coolant according to claim 4 or claim 5, wherein in the general formulas (Va) to (Villa) the radicals R1 and R2 may be the same or different and independently of one another have the following meanings: R1 represents H or an optionally substituted C1 to C3 alkyl group or an optionally substituted phenyl group, preferably an optionally substituted phenyl group; and / or R2 represents H or an optionally substituted C1 to C3 alkyl group or an optionally substituted phenyl group, preferably an optionally substituted phenyl group.

6. Physiological coolant according to claim 4, wherein in the general formulas (Va) to (Villa) Y stands for a substituted methylene group, preferably for a methylene group which is substituted by a methyl group, an ethyl group, a linear or branched butyl group or a linear or branched propyl group.

7. Physiological cooling agent according to one of claims 4 to 6, wherein in the general Formulas (Va), (Vila) and (Villa) Z is selected from the group consisting of: -NH2, -NH-CH3, -NH-CH2-CH3, -NH-CH2-CH2-CH3, -NH-CH2-CH2-CH2-CH3, -NH-CH(CH3)- CH(CH3)2, -NH-CH(CH3)-CH2-CH2-CH3, -NH-CH2-CH(CH3)2, -NH-CH2-CH2-O-CH3, -NH- CH(CH3)-CH2-O-CH3, -NH-C(=O)-CH3, -NH-C(=O)-O-CH3, -NH-CH(CH3)-CH2-OH, -NH- CH2-Furanyl, -NH-CFh-Tetrahydrofuranyl, -NH-CFh-thiophenyl, -NH-toluolyl, -NH-CH- (CH3)2, -NH-C(CH3)3, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -N(CH3)2, - N(CH3)-cyclohexyl, -N(CH2-CH3)2, azetidinyl, pyrrolidinyl, piperidinyl, azacyclobutadienyl, pyrrolyl, pyridinyl, -O, -OH, -O-CH3, -OC(=O)-CH3, oxetanyl, -CH3, -CH2-CH3, -CH(CH3)2, -C(OH)-CH2-OH, cyclopropyl, phenyl, and -CH2-S-CH3; and wherein in the general formula (Via) Z is selected from the group consisting of -NH2, -NH-CH3, -NH-CH2-CH3, -NH-CH2-CH2-CH3, -NH-CH2-CH2-CH2-CH3, -NH-CH(CH3)-CH(CH3)2, -NH-CH(CH3)-CH2-CH2-CH3, -NH-CH2-CH(CH3)2, -NH-CH2-CH2-O-CH3, -NH-CH(CH3)-CH2-O-CH3, -NH-C(=O)-CH 3I-NH-C(=O)-O-CH 3I -NH-CH(CH3)- CH2-OH, -NH-CH2-furanyl, -NH-CH2-tetrahydrofuranyl, -NH-CH2-thiophenyl, -NH- toluolyl, -NH-CH-(CH3)2, -NH-C(CH3)3, -NH-cyclopropyl, -NH-cyclobutyl, -NH- cyclopentyl, -N(CH3)2, -N(CH3)-cyclohexyl, -N(CH2-CH3)2, azetidinyl, pyrrolidinyl, piperidinyl, azacyclobutadienyl, pyrrolyl, pyridinyl, -O, -O-CH3, -OC(=O)-CH3, Oxetanyl, -CH3, -CH2-CH3, -CH(CH3)2, -C(OH)-CH2-OH, cyclopropyl, phenyl, and -CH2-S-CH3.

8. Physiological coolant according to any one of claims 4 to 7, wherein the aforementioned optionally substituted groups further comprise one or more substituents such that: (i) when in the aforementioned substituted groups the substitution occurs at a saturated carbon, the substituent at the saturated carbon is selected from the group consisting of: -X, halogen, =O, -OY, -SiRs, -SY, =S, -NZZ, =NY, =N-OY, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY)2, -P(O)(OY)(OY), -C(O)Y, -C(S)Y, -C(NY)Y, -C(O)OY, -C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, -NYC(0)Y, -NYC(S)Y, -NYC(0)0Y, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y and -NYC(NY)NZZ; (ii) when in the aforementioned substituted groups the substitution occurs on an unsaturated carbon, the substituent on the unsaturated carbon is selected from the group consisting of: -X, halogen, -OY, -SiRs, -SY, -NZZ, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY)2, -P(O)(OY)(OY), -C(O)Y, -C(S)Y, -C(NY)Y, -C(O)OY, -C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, -NYC(O)Y, -NYC(S)Y, - NYC(0)0Y, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y and -NYC(NY)NZZ; (iii) when in the aforementioned substituted groups the substitution occurs on a nitrogen atom, the substituent on the nitrogen atom is selected from the group consisting of: -X, -OY, -SY, -NZZ, -CF3, -CN, -OCN, -SCN, -NO, -NO2, - S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY) 2I-P(O)(OY)(OY), -C(O)Y, -C(S)Y, -C(NY)Y, -C(O)OY, -C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y,O)S(-OC)(-OC) -NYC(O)Y, -NYC(S)Y, -NYC(O)OY, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y und -NYC(NY)NZZ; wobei in the Faults (i), (ii) and (iii) X is selected from the group consisting of: optionally substituted alkyl group, in particular optionally substituted C1- to C8-alkyl group, in particular optionally substituted C1- to C9-alkyl group, particularly optionally substituted C1-, C2-, C3- or C4-alkyl group, optionally substituted alkoxy group, in particular optionally substituted C1-C9-alkoxy group, particularly optionally substituted C1-, C2-, C3- or C4-alkoxy group, optionally substituted alkylthio group, in particular optionally substituted C1- to C9-alkylthio group, particularly optionally substituted C1-, C2-, C3- or C4-alkylthio group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, optionally substituted heteroaryl group; and / or Y is selected from the group consisting of: hydrogen or X; and / or Z means Y or alternatively two Z's together with the nitrogen atom to which they are attached mean a four-, five-, six- or seven-membered heterocycloalkyl ring or heteroaryl ring, wherein the heterocycloalkyl ring or heteroaryl ring may comprise one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

9. Physiological coolant according to any one of claims 4 to 8, wherein the physiological coolant of the general formulas (Va) or (Via) is selected from the group consisting of the compounds shown in the following table: and its salts, in particular acid addition salts, with inorganic or organic acids, wherein the cooling agent is present as a pure (R)-enantiomer, as a pure (S)-enantiomer, as a racemate or as an enantiomer mixture, preferably wherein the physiological cooling agent is selected from the group consisting of the compounds B-01, B-02, B-03, B-05, B-07, B-11, B-14, B-15, B18 and B-21; or wherein the physiological cooling agent of the general formulas (V1a) or (V1a) is selected from the group consisting of the compounds shown in the table below: and its salts, in particular acid addition salts, with inorganic or organic acids, wherein the cooling agent is present as a pure (R)-enantiomer, as a pure (S)-enantiomer, as a racemate or as an enantiomer mixture, preferably wherein the physiological cooling agent is selected from the group consisting of the compounds A-01, A-02, A-03, A-05, A-09, A-10, A-12 and A-69.

10. Physiological coolant according to any one of claims 4 to 9, wherein the coolant is selected from the group consisting of the compounds shown in the table below: and its salts, in particular acid addition salts, with inorganic or organic acids, wherein the cooling agent is present as a pure (R)-enantiomer, as a pure (S)-enantiomer, as a racemate or as an enantiomer mixture or wherein the physiological cooling agent of the general formulas (Vila) or (Villa) is selected from the group consisting of the compounds shown in the following table: and its salts, in particular acid addition salts, with inorganic or organic acids, wherein the coolant is present as a pure (R)-enantiomer, as a pure (S)-enantiomer, as a racemate or as a mixture of enantiomers.

11. Physiological cooling agent according to one of claims 4 to 10, wherein in the enantiomer mixture the ratio of (R)- to (S)-enantiomer is greater than 50:50, preferably >75:25, even more preferably >90:10, even more preferably >95:5 and most preferably >98:2; or wherein in the enantiomer mixture the ratio of (S)- to (R)-enantiomer is greater than 50:50, preferably >75:25, even more preferably > 90 : 10, more preferably > 95 : 5 and most preferably > 98 :

2.

12. A compound according to any one of claims 1 to 3 or a physiological coolant according to any one of claims 4 to 11, wherein the salt of the compound or coolant is selected from the group consisting of (1) acid addition salts formed with inorganic acids or with organic acids, preferably mono- or polybasic carboxylic acids; or (2) Salts formed when an acidic proton present in the starting compound is replaced by a metal ion, in particular an alkali metal ion, an alkaline earth ion or an aluminum ion; or coordinated with an organic base.

13. Physiological cooling agent mixture comprising or consisting of: (a) one, two, three or more compounds according to any one of claims 1 to 3 and 12 or one, two, three or more coolants according to any one of claims 4 to 12; and optionally (b) at least one further physiological cooling agent; and / or optionally (c) at least one solvent.

14. Physiological cooling agent mixture according to claim 13, wherein the physiological Kühlstoff, der die Komponente (b) bildet, ausgewählt ist aus der Gruppe, bestehend aus: Menthol, Menthol Methyl Ether (FEMA GRAS 4054), Monomenthyl Glutamat (FEMA GRAS 4006), Menthoxy-1 ,2-propandiol (FEMA GRAS 3784), Dimenthylglutarat (FEMA GRAS 4604), Hydroxymethylcyclohexylethanon (FEMA GRAS 4742), 2-(4- Ethylphenoxy)-N-(1 H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamid (FEMA GRAS 4880), WS-23 (2-lsopropyl-N,2,3-trimethylbutyramid, FEMA GRAS 3804), N-(4- (Cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexan carboxamid (FEMA GRAS 4882), N-(3-Hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexan- carboxamid (FEMA GRAS 4881), N-(2-Hydroxy-2-phenylethyl)-2-isopropyl-5,5- dimethylcyclohexan-1-carboxamid (FEMA GRAS 4896), 3,4-Methylenedioxy Zimtsäure, (E)-3-Benzo[1 ,3]dioxol-5-yl-N,N-diphenyl-2-propenamid (FEMA GRAS 4788), Menthol Propylen Glykol Carbonat (FEMA GRAS 3806), Menthyl-N-ethyloxamat, Monomethyl Succinat (FEMA GRAS 3810), WS-3 (N-Ethyl-p-menthan-3-carboxamide,FEMA GRAS 3455), Menthol Ethylen Glykol Carbonat (FEMA GRAS 3805), WS-5 (Ethyl-3-(p- menthan-3-carboxamido)acetat, FEMA GRAS 4309), WS-12 (1 R,2S,5R)-N-(4- Methoxyphenyl)-p-menthancarboxamid (FEMA GRAS 4681), WS-27 (N-Ethyl-2,2- diisopropylbutanamid, FEMA GRAS 4557), N-Cyclopropyl-5-methyl-2- isopropylcyclohexancarboxamid (FEMA GRAS 4693), WS-116 (N-(1 ,1-Dimethyl-2- hydroxyethyl)-2,2-diethylbutanamid, FEMA GRAS 4603), Menthoxyethanol (FEMA GRAS 4154), N-(4-Cyanomethylphenyl)-p-menthancarboxamid (FEMA GRAS 4496), N- (2-(Pyridin-2-yl)ethyl)-3-p-menthancarboxamid (FEMA GRAS 4549), N-(2-, Hydroxyethyl)-2-isopropy-1-2,3-dimethylbutanamid (FEMA GRAS 4602), (2S,5R)-N-[4- (2-Amino-2-oxoethyl)phenyl]-p-menthancarboxamid (FEMA GRAS 4684), N- Cyclopropyl-5-methyl-2-isopropylcyclohexancarboncarboxamid (FEMA GRAS 4693), 2- [(2-p-Menthoxy)ethoxy]-ethanol (FEMA GRAS 4718), (2,6-Diethyl-5-isopropyl-2- methyltetrahydropyran (FEMA GRAS 4680), trans-4-tert- Butylcyclohexanol (FEMA GRAS 4724), 2-(p-Tolyloxy)-N-(1 H-pyrazol-5-yl)-N-((thiophen-2-yl)methyl)acetamid (FEMA GRAS 4809), Menthon glycerol ketal (FEMA GRAS 3807 und 3808), (-)- Menthoxypropan-1 ,2-diol, 3-(1-Menthoxy)-2-methylpropan-1 ,2-diol (FEMA GRAS 3849), Isopulegol, (+)-cis und (-)-trans-p-Menthan-3,8-diol (62:38, FEMA GRAS 4053), 2- methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (FEMA GRAS 4970) und dessen Enantiomere, 2,3-Dihydroxy-p-menthan, 3,3,5-trimethylcyclohexanon glycerol ketal, Menthyl pyrrolidon carboxylat, (1R,3R,4S)-3-menthyl-3,6-dioxaheptanoat, (1 R,2S,5R)-3-menthyl methoxyacetat, (1 R,2S,5R)-3-Menthyl-3,6,9-trioxadecanoat, (1 R,2S,5R)-3-menthyl-3,6,9-trioxadecanoat,(1 R,2S,5R)-3-Menthyl-(2- hydroxyethoxy)acetat, (1 R,2S,5R)-Menthyl-11-hydroxy-3,6,9-trioxaundecanoat, Cubebol (FEMA GRAS 4497), 2-lsopropyl-5-methylcyclohexyl-4-(dimethylamino)-4- oxobutanoat (FEMA GRAS 4230), Menthyllactat (FEMA GRAS 3748), 6-lsopropyl-3,9- dimethyl-1,4-dioxaspiro[4.5]decan-2-on (FEMA GRAS 4285), N-Benzo[1,3]-dioxol-5-yl-, 3-p-menthancarboxamid, N-(1-lsopropyl-1 ,2-dimethylpropyl)-1 ,3-benzodioxol-5- carboxamid, N-(R)-2-Oxotetrahydrofuran-3-yl-(1R,2S,5R)-p-menthan-3-carboxamid, Mischung aus 2,2,5,6,6-Pentamethyl-2,3,6,6a-tetrahydropentalen-3a(1 H)-ol und 5-(2- Hydroxy-2-methylpropyl)-3,4,4-trimethylcyclopent-2-en-1-on; (2S,5R)-2-lsopropyl-5- methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexancarboxamide; (1S,2S,5R)-N-(4- (cyanomethyl)phenyl)-2-isopropyl-5-methylcyclohexancarboxamid, 1 ,7-lsopropyl-4,5- methyl-bicyclo[2.2.2]oct-5-en Derivate, 4-Methoxy-N-phenyl-N-[2-(pyridin-2- yl)ethyl]benzamid, 4-Methoxy-N-phenyl-N-[2-(pyridin-2-yl)ethyl]benzensulfonamid, 4- Chloro-N-phenyl-N-[2-(pyridin-2- yl)ethyl]benzensulfonamid, 4-Cyano-N-phenyl-N-[2- (pyridin-2-yl)ethyl]-benzensulfonamid, 4-((Benzhydrylamino)methyl)-2-methoxyphenol, 4-((Bis(4-methoxyphenyl)methylamino)methyl)-2-methoxyphenol, 4-((1 ,2- diphenylethylamino)methyl)-2-methoxyphenol, 4-((Benzhydryloxy)methyl)-2- methoxyphenol, 4-((9H-Fluoren-9-ylamino)methyl)-2-methoxyphenol, 4- ((benzhydrylamino)methyl)-2-ethoxyphenol, 1-(4-Methoxyphenyl)-2-(1-methyl-1H- benzo[d]imidazol-2-yl)vinyl-4-methoxybenzoat, 2-(1-lsopropyl-6-methyl-1H- benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoat, (Z)-2-(1-lsopropyl- 5-methyl-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoate, 3-alkyl-p-methane-3-ol derivatives, derivatives of fenchyl, D-bornyl, L-bornyl, exo-norbornyl, 2-methylisobornyl, 2-ethylfenchyl, 2-methylbornyl, cis-pinan-2-yl, verbanyl and isobornyl, menthyl oxamate derivatives, menthyl 3-oxocarboxylic acid esters, N-alpha-(menthanecarbonyl)amino acid amides, p-menthane carboxamide and WS-23 analogues, (-)-(1R,2R,4S)-dihydroumbellulol, p-menthane alkyloxyamide, cyclohexane derivatives, Butanone derivatives, mixture of 3-menthoxy-1-propanol and 1-menthoxy-2-propanol, 1-[2-hydroxyphenyl]-4-[2-nitrophenyl]-1,2,3,6-tetrahydropyrimidin-2-one, 4-methyl-3-(1-pyrrolidinyl)-2-[5H]-furanone, as well as the cooling agents according to the following table: as well as the coolants shown in the table below: and its salts, in particular acid addition salts, with inorganic or organic acids and mixtures of the aforementioned coolants / compounds.

15. A physiological coolant mixture according to claim 13 or claim 14, wherein component (a) and component (b) are present in a weight ratio of about 0.1:99 to about 99:0.

1.

16. A physiological coolant mixture according to any one of claims 13 to 15, wherein the solvent constituting component (c) is selected from the group consisting of: benzyl alcohol, 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and mixtures thereof.

17. Flavoring preparation comprising or consisting of (d) one, two, three or more compounds according to any one of claims 1 to 3 and 12 or one, two, three or more cooling agents according to any one of claims 4 to 12 or a physiological cooling agent mixture according to any one of claims 13 to 16; and (e) at least one flavouring substance.

18. Aroma preparation according to claim 17, wherein the flavoring substance forming component (e) is selected from the group consisting of: acetophenone, allyl capronate, alpha-ionone, beta-ionone, anisaldehyde, anisyl acetate, anisyl formate, anethole, benzaldehyde, benzothiazole, benzyl acetate, benzyl alcohol, benzyl benzoate, beta-ionone, butyl butyrate, butyl capronate, butylidene phthalide, carvone, camphene, caryophyllene, cineole, cinnamyl acetate, citral, citronellol, citronellal, citronellyl acetate, cyclohexyl acetate, cymene, damascone, decalactone, dihydrocoumarin, dimethyl anthranilate, dodecalactone, ethoxyethyl acetate, ethyl butyric acid, ethyl butyrate, ethyl caprinate, ethyl capronate, ethyl crotonate, Ethyl furaneol, ethyl guaiacol, ethyl isobutyrate, ethyl isovalerianate, ethyl lactate, ethyl methyl butyrate, ethyl propionate, eucalyptol, eugenol, ethyl heptylate, 4-(p-hydroxyphenyl)-2-butanone, gamma-decalactone, geraniol, geranyl acetate, geranyl acetate, grapefruit aldehyde, Methyldihydrojasmonate (e.g. Hedion®), heliotropin, 2-heptanone, 3-heptanone, 4-heptanone, trans-2-heptenal, cis-4-heptenal, trans-2-hexenal, cis-3-hexenol, trans-2-hexenic acid, trans-3-hexenoic acid, cis-2-hexenyl acetate, cis-3-hexenyl acetate, cis-3-hexenyl capronate, trans-2-hexenyl capronate, cis-3-hexenyl formate, cis-2-hexyl acetate, cis-3-hexyl acetate, trans-2-hexyl acetate, cis-3-hexyl formate, para-hydroxybenzylacetone, isoamyl alcohol, isoamyl isovalerate, isobutyl butyrate, isobutyraldehyde, isoeugenol methyl ether, Isopropylmethylthiazole, lauric acid, leavulinic acid, linalool, linalool oxide, linalyl acetate, menthol, menthofuran, methyl anthranilate, methylbutanol, methylbutyric acid, 2-methylbutylacetate, methylcaproate, methylcinnamate, 5-methylfurfural, 3,2,2-methylcyclopentenolone, 6,5,2-methylheptenone, Methyl dihydrojasmonate, methyl jasmonate, 2-methylmethylbutyrate, 2-methyl-2-pentenolic acid, methylthiobutyrate, 3,1-methylthiohexanol, 3-methylthiohexyl acetate, nerol, neryl acetate, trans, trans-2,4-nonadienal, 2,4-nonadienol, 2,6-nonadienol, 2,4-nonadienol, nootkatone, delta octalactone, gamma octalactone, 2-octanol, 3-octanol, 1,3-octenol, 1-octyl acetate, 3-octyl acetate, palmitic acid, paraldehyde, phellandrene, pentanedione, phenylethyl acetate, phenylethyl alcohol, phenylethyl alcohol, phenylethyl isovalerate, Piperonal, Propionaldehyde, Propyl Butyrate, Pulegone, Pulegol, Sinensal, sulfurol, terpinene, terpineol, terpinolene, 8,3-thiomenthanone, 4,4,2-thiomethylpentanone, thymol, delta-undecalactone, gamma-undecalactone, valencene, valeric acid, vanillin, acetoin, ethyl vanillin, ethyl vanillin isobutyrate (= 3-ethoxy-4-isobutyryloxybenzaldehyde), 2,5-dimethyl-4-hydroxy-3(2H)-furanone and its derivatives (preferably homofuraneol (= 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone),Homofuronol (= 2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone and 5-ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and maltol derivatives (preferably ethylmaltol), coumarin and coumarin derivatives, gamma-lactones (preferably gamma-undecalactone, gamma-nonalactone, gamma-decalactone), delta-lactones (preferably 4-methyldeltadecalactone, massoilactone, deltadecalactone, tuberolactone), methyl sorbate, divanillin, 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone, 2-hydroxy-3-methyl-2-cyclopentenone, 3-hydroxy-4,5-dimethyl-2(5H)-furanone, Isoamyl acetate, ethyl butyrate, n-butyl butyrate, isoamyl butyrate, ethyl 3-methylbutyrate, ethyl n-hexanoate, allyl n-hexanoate, n-butyl n-hexanoate, ethyl n-octanoate, ethyl 3-methyl-3-phenylglycidate, ethyl 2-trans-4-cis-decadienoate, 4-(p-hydroxyphenyl)-2-butanone, 1,1-dimethoxy-2,2,5-trimethyl-4-hexane, 2,6-dimethyl-5-hepten-1-al and phenylacetaldehyde,2-Methyl-3-(methylthio)furan, 2-Methyl-3-furanthiol, bis(2-Methyl-3- furyl)disulfid, Furfurylmercaptan, Methional, 2-Acetyl-2-thiazolin, 3-Mercapto-2- pentanon, 2,5-Dimethyl-3-furanthiol, 2,4,5-Trimethylthiazol, 2-Acetylthiazol, 2,4- Dimethyl-5-ethylthiazol, 2-Acetyl-1-pyrrolin, 2-Methyl-3-ethylpyrazin, 2-Ethyl-3,5- dimethylpyrazin, 2-Ethyl-3,6-dimethylpyrazin, 2,3-Diethyl-5-methylpyrazin, 3-lsopropyl- 2-methoxypyrazin, 3-lsobutyl-2-methoxypyrazin, 2- Acetyl pyrazin, 2-Pentylpyridin, (E,E)- 2,4-Decadienal, (E,E)-2,4-Nonadienal, (E)-2-Octenal, (E)-2-Nonenal, 2-Undecenal, 12- Methyltridecanal, 1-Penten-3-on, 4-Hydroxy-2,5-dimethyl-3(2H)-furanon, Guajakol, 3- Hydroxy-4,5-dimethyl-2(5H)-furanon, 3-Hydroxy-4-methyl-5-ethyl-2(5H)-furanon, Cinnamaldehyde, cinnamyl alcohol, methyl salicylate, isopulegol and (not explicitly mentioned here) stereoisomers, enantiomers, positional isomers, diastereomers, cis / trans isomers or epimers of these substances; and / or wherein the flavoring agent forming component (e) is selected from the group consisting of: erythritol, threitol, arabitol, ribotol, xylitol, sorbitol, mannitol, dulcitol, lactitol, miraculin, monellin, thaumatin, curculin, brazzein, magap, sodium cyclamate, acesulfame K, neohesperidin dihydrochalcone, saccharin sodium salt, aspartame, superaspartame, neotame, alitame, sucralose, stevioside, rebaudioside, lugduname, carrelame, sucrononate, sucrooctate, monatin, phenylodulcin, glycine, D-leucine, D-threonine, D-asparagine, D-phenylalanine, D-tryptophan, L-proline, hernandulcin, dihydrochalcone glycosides, glycyrrhizin, Glycerrhetinic acid, its derivatives and salts, extracts of liquorice (Glycyrrhizza glabra ssp.), Lippia dulcis extracts, Momordica ssp.Extracts, mogrosides, Hydrangea dulcis and steviosides and mixtures thereof.

19. A flavoring preparation according to claim 17 or claim 18, wherein component (d) and component (e) are present in a weight ratio of 1:99 to 99:

1.

20. A compound according to any one of claims 1 to 3 and 12 or a physiological coolant according to any one of claims 4 to 12 or a physiological coolant mixture according to any one of claims 13 to 16 or an aroma preparation according to any one of claims 17 to 19 in encapsulated form.

21. Use of the compound according to any one of claims 1 to 3, 12 and 20 or of the physiological coolant according to any one of claims 4 to 12 and 20 or of the physiological coolant mixture according to any one of claims 13 to 16 and 20 as a modulator, in particular for in vivo and / or in vitro modulation, of the cold menthol receptor TRPM8, in particular as a TRPM8 receptor agonist or as a TRPM8 receptor antagonist.

22. Use of the compound according to any one of claims 1 to 3, 12 and 20 or of the physiological cooling agent according to any one of claims 4 to 12 and 20 or of the physiological cooling agent mixture according to any one of claims 13 to 16 and 20 for producing a physiological cooling effect on the skin or mucous membrane in humans or animals or for inducing a cooling effect by means of a package containing the compound or the physiological cooling agent or the physiological cooling agent mixture or a textile containing the compound or the physiological cooling agent or the physiological cooling agent mixture.

23. Use of the compound according to any one of claims 1 to 3, 12 and 20 or of the physiological cooling agent according to any one of claims 4 to 12 and 20 or of the physiological cooling agent mixture according to any one of claims 13 to 16 and 20 for improving or enhancing the taste properties of flavorings or for reducing or masking an unpleasant taste.

24. Use of the compound according to any one of claims 1 to 3, 12 and 20 or of the physiological coolant according to any one of claims 4 to 12 and 20 or of the physiological coolant mixture according to any one of claims 13 to 16 and 20 or of the flavoring preparation according to any one of claims 17 to 19 and 20 for the production of foodstuffs, food supplements, cosmetic or pharmaceutical preparations, animal feed, textiles, packaging or tobacco products.

25. Food, food supplements, cosmetic or pharmaceutical Preparations, animal feed, textiles, packaging or tobacco products, comprising a compound according to any one of claims 1 to 3, 12 and 20 or a physiological coolant according to any one of claims 4 to 12 and 20 or a physiological coolant mixture according to any one of claims 13 to 16 and 20 or an aroma preparation according to any one of claims 17 to 19 and 20, in particular in an amount of 0.1 ppm to 10 wt.%, in particular 1 wt.% to 10 wt.%, based on the total weight of the end product.

26. Pharmaceutical preparation according to claim 25, comprising further pharmaceutical active ingredients selected from the group consisting of: aspirin, minoxidil, erythromycin, fenistil, betamethasone, ibuprofen, ketoprofen, dicyclofenac, metronidazole, acyclovir, imiquimod, terbafine, cyclopiroxolamine, paracetamol, and other pharmaceutical active ingredients of the nonsteroidal anti-inflammatory drug (NSAID) type and mixtures thereof.

27. Pharmaceutical preparation according to claim 25 or claim 26 for use as a medicament, in particular for use in the prevention or treatment of pain and inflammatory conditions of the skin and mucous membranes, in particular prevention or treatment of symptoms of cough, cold, inflammation, sore throat or hoarseness or for use in the treatment of inflammatory conditions of the skin and mucous membranes and joints or for use in the treatment of prostate or bladder carcinoma or for the treatment of bladder weakness.

28. A method for modulating, in particular for in vitro and / or in vivo modulation, the cold menthol receptor TRPM8, comprising the following steps: (ia) providing at least one compound according to any one of claims 1 to 3, 12 and 20 or at least one physiological cooling agent according to any one of claims 4 to 12 and 20 or a physiological cooling agent mixture according to any one of claims 13 to 16 and 20 or providing a cosmetic or pharmaceutical preparation according to any one of claims 25 to 27; and (iia) contacting the cooling agent or cooling agent mixture or preparation from step (ia) with the receptor; or for producing a physiological cooling effect on skin or mucous membranes, comprising the following steps: (ib) providing at least one compound according to any one of claims 1 to 3, 12 and 20 or at least one physiological cooling agent according to any one of claims 4 to 12 and 20 or a physiological cooling agent mixture according to any one of claims 13 to 16 and 20 or providing a cosmetic or pharmaceutical preparation according to any one of claims 25 to 27; and (üb) contacting the compound or cooling agent or cooling agent mixture or preparation from step (ib) with human skin or mucous membrane; or for improving the taste properties of flavorings, comprising the following steps: (ic) providing at least one compound according to any one of claims 1 to 3, 12 and 20 or at least one physiological cooling agent according to any one of claims 4 to 12 and 20 or a physiological cooling agent mixture according to any one of claims 13 to 16 and 20 and at least one flavoring agent; (iic) mixing the two components from step (ic); and optionally (iiic) incorporating the mixture into an oral preparation; or for masking bitter substances, comprising the following steps: (id) providing at least one compound according to any one of claims 1 to 3, 12 and 20 or at least one physiological cooling agent according to any one of claims 4 to 12 and 20 or a physiological cooling agent mixture according to any one of claims 13 to 16 and 20 and at least one bittering agent; (iid) mixing the two components from step (id); and optionally (iiid) incorporating the mixture into an oral preparation.

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