Heterocyclic compounds as physiological cooling agents

Abstract

The present invention relates to novel enantiomer compounds, physiological cooling agents, cooling agent mixtures containing these novel substances, mixtures of enantiomer compounds or cooling agents with flavorings, the use of these enantiomer compounds or cooling agents, and consumer articles and final preparations containing enantiomer compounds or physiological cooling agents or cooling agent mixtures.

Description

[Technical Field]

[0001] The present invention relates to the field of physiological cooling agents, and more particularly to new representative examples of this group, the use of these cooling agents, and articles and preparations containing these cooling agents. [Background technology]

[0002] Physiological coolants are typically used to produce a cold sensation on the skin or mucous membranes, such as the mucous membranes of the mouth, nose, and / or throat, without actual physical cooling occurring, such as during the evaporation of the solvent. Both individual components and mixtures can be used as physiological coolants. It should be noted that not all compounds that in vitro affect receptors involved in mediating the physiological cool effect will actually produce such an effect in vivo on the skin or mucous membranes. In particular, such effects are not always identical. This means, for example, that the intensity of the physiological cool effect and its progression over time cannot be inferred solely from the fact that a particular compound is an agonist of receptors involved in mediating the cold sensation.

[0003] TRP channels play a crucial role in temperature (high-low) perception. TRP channels (transient receptor potential channels) are a broad family of cellular ion channels that can be divided into seven subfamilies.

[0004] The cold menthol receptor TRPM8 (also known as the cold membrane receptor (CMR1)) belongs to the family of transient receptor potential ion channels and is specifically expressed in a particular group of neurons. 2+ This protein forms pores in the cell membrane that selectively allow ions to pass through (each consisting of four units that assemble into a tetramer). The protein has six transmembrane domains, as well as cytoplasmic C-terminus and N-terminus. Low temperatures (preferably 10–25°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 regulation. Changes in the expression of some of these channels may contribute to cancer development. For example, TRPM8 gene expression is upregulated in prostate cancer. Therefore, TRPM8 is also an attractive target molecule for the treatment of prostate or bladder cancer.

[0006] cutting edge technology Cooling compounds such as menthol have long played an important role in the flavor and aroma industry due to their association with freshness and cleanliness.

[0007] The most well-known physiologically active cooling agent is L-menthol. The compound menthol has been shown to act as a natural modulator of the TRPM8 receptor. Application of menthol activates TRPM8 and increases Ca2+ in cryosensitive neurons. 2+ This triggers an inflow. The resulting electrical signal is ultimately perceived as a feeling of coldness.

[0008] However, menthol has several drawbacks, including a strong odor, high volatility, and at higher concentrations, its own bitter and / or pungent taste, as well as skin irritation. Excessive concentrations of menthol can also cause irritation and have an anesthetic effect on the skin or mucous membranes.

[0009] Previous attempts have been made to find a powerful cooling agent that does not possess the harmful properties of L-menthol.

[0010] For example, German Patent No. 2608226(A1) describes lactic acid ester of menthol, German Patent No. 4226043(A1) describes a mixed carbonate of menthol and polyol, and European Patent No. 0507190(B1) describes menthone ketal.

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

[0012] Menthyl monoesters of dibasic acids, as defined in U.S. Patents No. 5,725,865 and 5,843,466, are interesting naturally occurring alternatives, but in sensory testing, they fail to achieve the cooling intensity described above.

[0013] The compound L-menthanecarboxylic acid N-ethylamide ("WS-3"), in particular Nα-(L-menthanecarbonyl)glycine ethyl ester ("WS-5"), has been found to be a potent cooling agent. However, the latter has the disadvantage of being susceptible to hydrolysis and forming the corresponding free acid Nα-(L-menthanecarbonyl)glycine, which itself has only a very weak cooling effect. Despite the detailed investigations described, systematic prediction of the potential cooling agent properties, in particular their bitterness and / or other trigeminal effects, is not possible and has not been described. For example, many molecules belonging to the menthanecarboxylic acid amide class cool strongly, but often have a pronounced bitter taste, such as menthanecarboxylic acid N-(alkyloxyalkyl)amide according to Japanese Patent Application Publication No. 2004059474(A2), or are highly irritating, such as N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycine ethyl ester according to U.S. Patent Application Publication No. 20050222256(A1). Therefore, such compounds are not suitable for use in food preparations and the like.

[0014] Nα-(menthanecarbonyl)alkyloxyalkylamide is described in Japanese Patent Publication No. 2004059474(A2). However, although these have a strong cooling effect and high hydrolysis stability, they have the disadvantage of being very bitter, and therefore are not suitable for use in food or cosmetics for facial care.

[0015] Furthermore, menthyl glyoxylate and its hydrates are described as cooling substances in Japanese Patent Publication No. 2005343795(A2).

[0016] An overview of the cooling agents that have been produced and used to date is known to those skilled in the art.

[0017] There are also isolated compounds that are not structurally related to menthol, such as the cooling agent WS-23 or the compounds listed in International Publication No. 2007019719 (A1), but that cause significant TRPM8 modulation.

[0018] However, many of the TRPM8 modulators found to date have drawbacks with respect to efficacy, duration of action, skin / mucosal irritation, odor, taste, solubility, and volatility.

[0019] International Publication No. 2010026094 (A1) discloses individual compounds for modulating the TRPM8 receptor.

[0020] Additional compounds for modulating the TRPM8 receptor are also proposed in International Publication No. 2011061330 (A2).

[0021] A special cooling agent having a carboxamide structure (I) is also

[0022]

Chemical formula

[0023] On the oral mucosa, most of the above-mentioned conventional cooling substances known from the prior art exhibit approximately the same cooling behavior. The fresh cooling sensation they impart begins after about 0.5 minutes, but reaches a peak at 3-5 minutes and then levels off relatively rapidly. The cooling effect is clearly noticeable for up to 30 minutes and, based on experience, is only slightly affected in intensity and duration by changes in the dosage. However, consumers desire a cooling effect that lasts particularly long and is associated with a corresponding sense of freshness and well-being for the user.

Summary of the Invention

[0024] Object of the invention Therefore, the main object of the present invention was to identify novel substances having a special physiological cooling effect, preferably substances that lead to the modulation of the TRPM8 receptor (so-called modulators) that can be used as substitutes, and more preferably as more suitable active agents, for modulators known to date. Such compounds should be particularly suitable for use in the fields of cosmetics, nutrition, textiles, OTC products (e.g., burn ointments), pharmaceuticals (e.g., in the fields of tumor treatment and bladder asphyxiation), or packaging. The identified compounds or mixtures of compounds should preferably have as little of their own taste as possible, and in particular, they should have little or no bitter taste and be as non-irritating as possible.

[0025] To address the problems addressed by the present invention, research has focused primarily on active ingredients capable of imparting a particularly long-lasting cooling sensation. Preferably, these active ingredients should also be capable of imparting a particularly strong and / or rapidly-onset cooling sensation, or a slowly accumulating, long-lasting delayed cooling sensation. The cooling agent should be efficient, i.e., it should have a high cooling effect or cooling sensation even at low concentrations.

[0026] Another object of the present invention was to identify novel compounds / substances that can be used, in particular as modulators for in vivo and / or in vitro modulation of the cold menthol receptor TRPM8, especially as TRPM8 receptor agonists or TRPM8 receptor antagonists, as physiological cooling agents, as flavoring agents, to improve the taste profile of flavoring agents, or as bitterness masking agents.

[0027] To date, prior art has not demonstrated that specific enantiomer compounds or enantiomer mixtures of the material class described in the present invention have an improved cooling effect or the advantageous effects described above.

[0028] This problem is resolved by the subject matter of the independent claims. Further aspects of the present invention will become apparent from the language of the dependent claims, the following description, and the examples. [Modes for carrying out the invention]

[0029] The main problem of the present invention is the general formula (Va)

[0030] [ka] Or general formula (VIa)

[0031] [ka] A physiological cooling agent selected from the group consisting of compounds represented by, wherein in formulas (Va) and (VIa),

[0032] [Table 1-1]

[0033] [Table 1-2] and salts thereof, in particular acid addition salts with inorganic or organic acids, wherein the cooling agent exists as a pure (R)-enantiomer, a pure (S)-enantiomer, a racemic mixture, or an enantiomer mixture, physiological cooling agents and salts thereof, Or general formula (VIIa)

[0034] [ka] Alternatively, general formula (VIIIa)

[0035] [ka] A physiological cooling agent represented by formula (VIIa) and (VIIIa),

[0036] [Table 2-1]

[0037] [Table 2-2] The solution is provided by physiological coolants and salts thereof, which are acid addition salts with inorganic or organic acids, wherein the coolant exists as a pure (R)-enantiomer, a pure (S)-enantiomer, a racemic mixture, or an enantiomer mixture.

[0038] The present invention also includes physiological cooling agents in which the oxygen atom in the oxazole ring of the basic structure of general formula (VIIa) is replaced by a sulfur atom, i.e., the oxazole ring of the basic structure of general formula (VIIa) is a thiazole ring.

[0039] Among the compounds of general formulas (Va) to (VIIIa), those in which the heterocycle of the basic structure of general formulas (Va) to (VIIIa) has at least two nitrogen atoms, i.e., compounds of general formula (Va) having a triazine ring in the basic structure, or compounds of general formula (VIa) having a pyrazine ring (diazine) in the basic structure, or compounds of general formula (VIIIa) having an imidazole ring, are particularly preferred due to the presence of free electrons (so-called Lewis bases) that are suitable for forming covalent bonds. Such compounds exhibit particularly pronounced cold-sensitive properties, as described below.

[0040] Due to their Lewis base properties, compounds of general formula (Va) having a triazine ring in the basic structure, and compounds of general formula (VIIa) having an oxazole ring in the basic structure are most preferred. Such compounds are particularly characterized by a strong cooling effect.

[0041] Within the scope of the present invention, in particular, the following general meanings apply to the definitions of general formulas (Va) to (VIIIa).

[0042] The terms "or" or "and / or" are used as functional terms to indicate that two words or expressions are to be interpreted together or separately.

[0043] The terms “comprising,” “with,” “including,” and “containing” are non-restrictive terms, meaning that “comprising,” “including,” or “containing” are not “limited.”

[0044] All endpoints of a range referring to the same component or property are inclusive and can be combined independently of each other.

[0045] The term "enantiomer" refers to stereoisomers of chemical compounds that have identical compositions and behave as corresponding counterparts in their spatial structure, like (mismatched) mirror images of each other. Because of this, they are also called enantiomers. The molecular formulas and bonds of each atom are identical. This is a form of conformational isomerism, and unlike conformational isomers, enantiomers cannot be made identical by rotating the atomic bonds. Since enantiomers have opposite configurations at all stereocenters, theoretically there are always (-) and (+) enantiomers or (R) and (S) enantiomers. An enantiomer mixture is a mixture of two enantiomers. When the mass ratio of the enantiomers is 1:1, the enantiomer mixture is called a racemate. When the mass ratio of the enantiomers is not 1:1, the mixture is called a non-racemic enantiomer mixture.

[0046] The terms “cooling agent” or “cooling agent of the present invention” refer to all compounds encompassed by the structural formulas disclosed herein, i.e., formulas (Va), (VIa), (VIIa), or (VIIIa) disclosed herein, whose structures include any subtypes within the formulas disclosed herein and all specific compounds. Compounds can be identified by either their chemical structure and / or their chemical name. In the event of a conflict between the chemical structure and the chemical name, 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 therefore may exist as stereoisomers such as double bond isomers, i.e., geometric isomers, enantiomers, or diastereomers. Accordingly, the chemical structures of general formulas (Va) to (VIIIa) presented herein include all possible enantiomers and diastereomers or stereoisomers.

[0047] In the context of the present invention, the term "at least one cooling agent" means, for example, that the composition contains at least one cooling agent, but may also contain two, three, four, or even several different cooling agents.

[0048] The term "alkyl," either alone or as part of another substituent according to the present invention, refers to a saturated or monounsaturated linear or branched monovalent hydrocarbon radical obtained by removing a hydrogen atom from a single carbon atom of the corresponding starting alkane.

[0049] In preferred variants, the term “alkyl” also includes all alkyl portions in residues derived from it, such as alkoxy, alkylthio, alkylsulfonyl saturated linear or branched hydrocarbon residues having 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.

[0050] When an 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 divalent alkyl groups. For example, -CH2CH3 is ethyl, while -CH2CH2- is ethylene.

[0051] The term "alkylene," either 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 starting alkane.

[0052] In a preferred variant of the present invention, the alkyl or alkylene group contains 1 to 10 carbon atoms. In another, even more preferred variant of the present invention, the alkyl or alkylene group contains 1 to 6 carbon atoms.

[0053] Alkyl or alkylene groups having 1 to 4 carbon atoms are most preferred.

[0054] Preferred alkyl residues or alkyl groups include: C1-C6 alkyl groups, including methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 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 and 1-ethyl-2-methylpropyl. 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 Examples include, but are not limited to, C1-C6 alkoxys, including C1-C4 alkoxys such as 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.

[0055] According to the present invention, saturated linear or branched C1-C6 alkyl groups, or saturated linear or branched C1-C6 alkylene groups are most preferred.

[0056] The terms “alkyl” or “alkylene” also include residues or groups having any degree of saturation, namely groups having only a single carbon-carbon bond (“alkyl” or “alkylene”), groups having one or more double carbon-carbon bonds (“alkenyl”), residues having one or more triple carbon-carbon bonds (“alkynyl”), and groups having a mixture of single, double, and / or triple carbon-carbon bonds.

[0057] The term "alkenyl," either 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). This radical may be in either a cis or trans conformation around the double bond. Thus, the term "alkenyl" also encompasses the corresponding cis / trans isomers.

[0058] Typical alkenyl residues or alkenyl groups include, but are not limited to, propenyls such as ethenyl, 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, and cycloprop-2-en-1-yl, as well as butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methylprop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, but-1,3-dien-1-yl, and but-1,3-dien-2-yl.

[0059] In a preferred variant according to the present invention, the alkenyl group contains 2 to 10 carbon atoms. In another preferred variant, the alkenyl group contains 2 to 6 carbon atoms. In an even more preferred variant, the alkenyl group contains 2 to 4 carbon atoms.

[0060] According to the present invention, monounsaturated linear or branched C1-C6 alkenyl groups are most preferred.

[0061] The term "alkynyl" in this invention, either alone or as part of another substituent, refers to at least one carbon-carbon triple bond (

[0062] [ka] This refers to unsaturated linear or branched monovalent hydrocarbon radicals having a triple bond.

[0063] Typical alkynyl residues or alkynyl groups include, but are not limited to, propynyl such as ethynyl, prop-1-in-1-yl, and prop-2-in-1-yl, and butynyl such as but-1-in-1-yl, but-1-in-3-yl, and but-3-in-1-yl.

[0064] In a preferred embodiment of the present invention, the alkynyl group contains 2 to 10 carbon atoms. In another preferred embodiment, the alkynyl group contains 2 to 6 carbon atoms. In a further preferred embodiment, the alkynyl group contains 2 to 4 carbon atoms.

[0065] The term "alkoxy" in this invention, either alone or as part of another substituent, refers to a radical of formula -OR, where R represents an alkyl or substituted alkyl as defined herein.

[0066] The terms “alkylthio” or “thioalkoxy” used in this invention, either alone or as part of another substituent, refer to a radical of formula -SR, where R represents an alkyl or substituted alkyl as defined herein.

[0067] The terms “alkyl” or “alkylene” also include heteroalkyl residues or heteroalkyl groups according to the present invention. The term “heteroalkyl,” either alone or as part of another substituent, refers to an alkyl group in which one or more carbon atoms are independently replaced by the same or different heteroatoms or by the same or different heteroatomic groups. Typical heteroatoms or heteroatomic groups that can replace 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 combinations thereof. Heteroatoms or heteroatomic groups can be located at any internal position of the alkyl group. Typical heteroatomic groups that may be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, -NRR-, =NN=, -N=N-, -N=N-NRR, -PR-, -P O 2- 、 -POR-, -OP(O)2- 、 -SO-, -SO2- 、Examples include, but are not limited to, -SR2OR, wherein the formula, 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.

[0068] The alkyl or alkylene group defined above may be further substituted.

[0069] The term “acyl” in this invention, either alone or as part of another substituent, 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.

[0070] Representative examples, though not limited to them, include formyl, acetyl, propionyl, butyryl, valeryl, benzoyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzylcarbonyl.

[0071] The term "cycloalkyl" in this invention, either alone or as part of another substituent, refers to a saturated or monounsaturated non-aromatic cyclic monovalent hydrocarbon radical in which carbon atoms are bonded together in a ring and which does not contain any heteroatoms.

[0072] A carbon ring can arise as a monocyclic compound having only one ring, or as a polycyclic compound having two or more rings.

[0073] In preferred variants, the term "cycloalkyl" includes 3- to 10-membered monocyclic cycloalkyl radicals or cycloalkyl groups, or 9- to 12-membered polycyclic cycloalkyl radicals or cycloalkyl groups. In other, even more preferred variants, the cycloalkyl group includes 3, 4, 5, 6, or 7-membered monocyclic cycloalkyl groups, or 9- to 12-membered bicyclic cycloalkyl groups.

[0074] In the preferred variant according to the present invention, the cycloalkyl residue or cycloalkyl group contains 3 to 20 carbon atoms. In a more preferred variant, the cycloalkyl residue contains 3 to 15 carbon atoms. In the most preferred variant, the cycloalkyl residue contains 3 to 10 carbon atoms. Monocyclic C3-~C7-cycloalkyl groups are most preferred.

[0075] Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl, preferably cyclopentyl, cyclohexyl, cycloheptyl, and cyclopropyl-methyl, cyclopropyl-ethyl, cyclobutyl-methyl, cyclobutyl-ethyl, cyclopentyl-methyl, cyclopentyl-ethyl, and cyclohexyl-methyl, C3-C3 12 Examples include, but are not limited to, saturated carbocyclic radicals having 3 to 20 carbon atoms, such as C3-C7-carbocyrills, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropyl-methyl, cyclopropyl-ethyl, cyclobutyl-methyl, cyclopentyl-ethyl, cyclohexyl-methyl, cyclobuto-1-en-1-yl, cyclobuto-1-en-3-yl, and cyclobuta-1,3-dien-1-yl.

[0076] Preferred saturated polycyclic cycloalkyl radicals or cycloalkyl groups according to the present invention include, but are not limited to, adamantyl groups.

[0077] According to the present invention, the term "cycloalkyl" also includes cycloalkenyls, i.e., unsaturated cyclic hydrocarbon radicals containing a C=C double bond between two carbon atoms of a ring molecule. In a broader sense, cycloalkenyls are compounds having one, two, or more double bonds, thereby the number of possible almost conjugated double bonds in the molecule depends on the size of the ring.

[0078] Typical cycloalkenyls include, but are not limited to, cyclopropenyl, cyclopentenyl, cyclohexenyl, and cyclopentadienyl.

[0079] According to the present invention, the term "cycloalkyl" also refers to cycloalkynyl, i.e., the unsaturated interatomic region between two atoms of a ring molecule containing a cyclic carbon radical.

[0080] [ka] This includes triple bonds, which depend on the ring size due to ring strain.

[0081] A typical example of a cycloalkyne is cyclooctin.

[0082] A cycloalkyl radical or cycloalkyl group can be bonded to the rest of the molecule of formula (I) and / or formula (II) via any suitable carbon atom.

[0083] The cycloalkyl radical or cycloalkyl group defined above may also be substituted.

[0084] The term "aryl," either alone or as part of another substituent, in this invention refers to a monovalent aromatic hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom in an aromatic ring system.

[0085] In preferred variants, the term "aryl" includes a 3- to 10-membered monocyclic aryl radical or aryl group, or a 9- to 12-membered polycyclic aryl radical or aryl group. In other, even more preferred variants, the carboaryl radical includes a 3, 4, 5, 6, or 7-membered monocyclic carboaryl radical, or a 9- to 12-membered bicyclic carboaryl radical.

[0086] In the preferred variant according to the present invention, the aryl radical contains 3 to 20 carbon atoms. In a more preferred variant, the aryl radical contains 3 to 15 carbon atoms. In the most preferred variant, the aryl radical contains 3 to 10 carbon atoms. According to the present invention, monocyclic C3-C 12 -Aryl groups are most preferred. Ultimately, monocyclic C3-C7 aryl groups are the most preferred.

[0087] Typical aryl radicals include, but are not limited to, benzene, phenyl, biphenyl, naphthyl such as 1- or 2-naphthyl, tetrahydronaphthyl, fluorenyl, indenyl, and phenantrenyl. Typical carboaryl radicals also include, but are not limited to, groups derived from aceantrylene, acenaphthylene, acephenantrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, S-indacene, indan, indene, naphthalene, octacene, octafen, octaene, ovalene, penter-2,4-diene, pentacene, pentalene, pentafen, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, etc.

[0088] Preferred aromatic polycyclic aryl radicals or aryl groups according to the present invention include, but are not limited to, naphthalene and biphenyl.

[0089] The aryl radical or aryl group can be bonded to the rest of the molecules of formulas (I) to (VIII) and (Va) to (VIIIa) via any suitable carbon atom.

[0090] The aryl radical or aryl group defined above can also be substituted. For example, an aryl radical can form an anisole group.

[0091] The term "arylalkyl" as used in this invention, either alone or as part of another substituent, refers to an acyclic alkyl group in which one of the carbon atoms, typically a hydrogen atom bonded to a terminal or sp-carbon atom, is replaced by an aryl group as defined herein. In other words, arylalkyls can also be considered as alkyls substituted with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, and 2-naphthophenylethane-1-yl.

[0092] The term "heteroarylalkyl," either alone or as part of another substituent, refers to a cyclic alkyl group in which one or more hydrogen atoms bonded to a carbon atom are replaced by a heteroaryl group.

[0093] In preferred variants according to the present invention, the heteroarylalkyl group is a 6-20 member heteroarylalkyl group, for example, the alkanyl, alkenyl, or alkynyl group of the heteroarylalkyl group is C1-C6 alkyl, and the heteroaryl group is a 5-15 member heteroaryl group. In other embodiments, the heteroarylalkyl group is a 6-13 member heteroarylalkyl group, for example, the alkanyl, alkenyl, or alkynyl group is C1-C3 alkyl, and the heteroaryl group is a 5-10 member heteroaryl group.

[0094] The term "heterocycloalkyl" in this invention, either alone or as part of another substituent, refers to a saturated non-aromatic cyclic monovalent hydrocarbon radical in which one or more carbon atoms are independently replaced by the same or different heteroatoms. Typical heteroatoms for replacing carbon atoms include, but are not limited to, N, P, O, S, and Si. Typical heterocycloalkyl groups include, but are not limited to, groups derived from epoxides, azirine, thiirane, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidone, quinuclidine, and others.

[0095] The heterocycloalkyl moiety can arise as a monocyclic compound having only one ring, or as a polycyclic compound having two or more rings.

[0096] Preferably, the term "heterocycloalkyl" includes 3- to 7-membered saturated or mono- or polyunsaturated heterocycloalkyl radicals containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S. One or more heteroatoms may occupy any position within the heterocycloalkyl ring.

[0097] In preferred variants, the term “heterocycloalkyl” includes 3- to 10-membered monocyclic heterocycloalkyl radicals or 9- to 12-membered polycyclic heterocycloalkyl radicals. In other, even more preferred variants, the heterocycloalkyl radical includes 3, 4, 5, 6, or 7-membered monocyclic heterocycloalkyl radicals or 9- to 12-membered bicyclic heterocycloalkyl radicals.

[0098] In preferred variants according to the present invention, the "heterocycloalkyl" radical or heterocycloalkyl group contains 3 to 20 ring atoms. In preferred variants, the heterocycloalkyl radical contains 3 to 15 ring atoms. In even more preferred variants, the heterocycloalkyl radical contains 3 to 10 carbon atoms. According to the present invention, a monocyclic heterocycloalkyl radical having 3 to 12 carbon atoms is most preferred. A monocyclic heterocycloalkyl radical having 5 to 7 ring atoms is most preferred.

[0099] Typical heterocycloalkyl radicals include azilidinyl, oxyranil, thyranil, azetidinyl, oxetanil, thietanil, 2-tetrahydrofuranil, 3-tetrahydrofuranil, 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-imidazo Examples include, but are not limited to, lysinyl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl, and others, which contain one or two nitrogen atoms and / or one oxygen atom or sulfur atom, or one or two oxygen atoms and / or sulfur atoms as ring members.

[0100] The heterocycloalkyl radicals or heterocycloalkyl groups defined above may also be substituted.

[0101] A heterocycloalkyl radical or heterocycloalkyl group can be bonded to the rest of the molecules of formulas (I) to (VIII) and (Va) and (VIII) via a ring carbon atom or a ring heteroatom.

[0102] The term "heteroaryl" in this invention, either alone or as part of another substituent, refers to a monovalent heteroaromatic radical obtained by removing a hydrogen atom from a single atom of a heteroaromatic ring system. Typical heteroaryl radicals or heteroaryl groups include, but are not limited to, groups derived from acridine, β-carbolin, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indidine, isobenzofuran, isochrome, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenantholidine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazole, xanthene, and others.

[0103] Heteroaryl radicals can arise as monocyclic compounds having only one ring, or as polycyclic compounds having two or more rings.

[0104] In preferred variants, the term “heteroaryl” includes 3- to 10-membered monocyclic heteroaryl radicals or 9- to 12-membered polycyclic heteroaryl radicals. In other, even more preferred variants, the term “heteroaryl” includes 3, 4, 5, 6, or 7-membered monocyclic heteroaryl radicals or 9- to 12-membered bicyclic heteroaryl radicals.

[0105] Preferably, the term "heteroaryl" includes 3- to 7-membered monocyclic heteroaryl radicals containing 1, 2, 3, or 4 heteroatoms selected from the group O, N, and S.

[0106] In the preferred variant according to the present invention, the heteroaryl radical or heteroaryl group contains 3 to 20 ring atoms. In a more preferred variant, the heteroaryl radical contains 6 to 15 ring atoms. In the most preferred variant, the heteroaryl group contains 6 to 10 ring atoms. According to the present invention, a monocyclic C3-C7 heteroaryl group is most preferred.

[0107] 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.

[0108] Three-membered aromatic heteroaryl radicals containing a nitrogen, sulfur, or oxygen atom as a ring atom in addition to a carbon atom include azilinyl, oxylenyl, or thyrenyl.

[0109] A four-membered aromatic heteroaryl radical, which includes a nitrogen, sulfur, or oxygen atom as a ring atom in addition to a carbon atom, includes acetyl, oxetium ions, or thietium ions.

[0110] Five-membered aromatic heteroaryl radicals, which include one, two, or three nitrogen atoms as ring atoms in addition to carbon atoms, or one or two nitrogen atoms and one sulfur or oxygen atom, include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrzolyl, 4-pyrzolyl, 5-pyrzolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, and 1,3,4-triazole-2-yl.

[0111] Five-membered aromatic heteroaryl radicals containing 1, 2, 3, or 4 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]-triazole-1-yl, 1,2,3-[2H]-triazole-2-yl, 1,2,3-[1H]-triazole-4-yl, 1,2,3-[1H]-triazole-5-yl, and 1,2,3-[2H]-triazole-1-yl. This includes zole-4-yl, 1,2,4-[1H]-triazole-1-yl, 1,2,4-[1H]-triazole-3-yl, 1,2,4-[1H]-triazole-5-yl, 1,2,4-[4H]-triazole-4-yl, 1,2,4-[4H]-triazole-3-yl, [1H]-tetrazol-1-yl, [1H]-tetrazol-5-yl, [2H]-tetrazol-2-yl, [2H]-tetrazol-5-yl, etc.

[0112] Five-membered aromatic heteroaryl radicals comprising a heteroatom selected from oxygen or sulfur, and optionally comprising one, two, or three nitrogen atoms as ring atoms, include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3- or 4-isoxazolyl, 3- or 4-isothiazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl, 1,3,4-thiadiazole-2-yl, 1,2,4-oxadiazole-3-yl, 1,2,4-oxadiazole-5-yl, and 1,3,4-oxadiazole-2-yl.

[0113] Six-membered heteroaryl radicals containing one or two ring atoms, or one, two, or three nitrogen atoms in addition to carbon atoms, include, for example, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,2,4-triazine-3-yl, 1,2,4-triazine-5-yl, 1,2,4-triazine-6-yl, and 1,3,5-triazine-2-yl.

[0114] The heteroaryl radical or heteroaryl group defined above may also be substituted.

[0115] A heteroaryl radical or heteroaryl group may be bonded to the rest of the molecules of formulas (I) to (VIII) and (Va) and (VIII) via a ring carbon atom or ring heteroatom.

[0116] Of the monocyclic heteroaryl radicals described above, particularly preferred heteroaryl radicals in the context of the present invention are those derived from 5- or 6-membered saturated compounds, including pyrrolidone, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, and tetrahydrothiopyran, or from 5- or 6-membered aromatic compounds, including pyrrole, furan, thiophene, pyridine, pyrylium ions and thiopyrillium ions, pyrazole, imidazole, imidazoline, pyrimidine, oxazole, thiazole, and 1,4-thiazine.

[0117] The term "arylalkyl" as used in this invention, either alone or as part of another substituent, refers to an acyclic alkyl group in which one of the carbon atoms, typically a hydrogen atom bonded to a terminal or sp-carbon atom, is replaced by an aryl group as defined herein. In other words, arylalkyls can also be considered as alkyls substituted with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, and 2-naphthophenylethane-1-yl.

[0118] The term "heteroarylalkyl," either 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.

[0119] In a preferred variant according to the invention, the heteroarylalkyl group is a 6- to 20-member heteroarylalkyl, for example, the alkanil, alkenyl, or alkynyl group of the heteroarylalkyl is a C1-C6-alkyl, and the heteroaryl group is a 5- to 15-member heteroaryl group. In other embodiments, the heteroarylalkyl is a 6- to 13-member heteroarylalkyl, for example, the alkanil, alkenyl, or alkynyl group is a C1-C3-alkyl, and the heteroaryl group is a 5- to 10-member heteroaryl.

[0120] The term "substituted" in the context of the present invention means that one or more hydrogen atoms of the specified residue or radical are independently replaced by the same or different substituents.

[0121] Useful substituents for replacing saturated carbon atoms in the specified group or radical include, but are not limited to, the group consisting of -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)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, or -NYC(NY)NZZ, wherein X is an optionally substituted alkyl radical, particularly an optionally substituted C1-C 10- Selected from the group consisting of alkyl groups, in particular optionally substituted C1-C6-alkyl radicals, in particular optionally substituted C1-, C2-, C3-, or C4-alkyl groups, optionally substituted alkoxy radicals, in particular optionally substituted C1-C6-alkoxy radicals, in particular optionally substituted C1-, C2-, C3-, or C4-alkoxy groups, optionally substituted alkylthio radicals, in particular optionally substituted C1-C6-alkylthio radicals, in particular optionally substituted C1-, C2-, C3-, or C4-alkylthio groups, optionally substituted cycloalkyl radicals, optionally substituted aryl radicals, optionally substituted carboaryl radicals, optionally substituted carboarylalkyl radicals, optionally substituted heteroalkyl radicals, optionally substituted heterocycloalkyl radicals, optionally substituted heteroaryl radicals, and optionally substituted heteroarylalkyl groups, as defined above, and / or Y is either hydrogen or X, and / or Z is Y, or alternatively, two Zs, together with the nitrogen atom to which they are bonded, form a 4, 5, 6, or 7-membered heterocycloalkyl or heteroaryl ring, the heterocycloalkyl or heteroaryl ring may contain one, two, three, or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0122] Specific preferred examples of substitutions are OH, methyl, ethyl, methoxy, ethoxy, and phenyl, which can be substituted with OH, methyl, ethyl, methoxy, ethoxy or CH3-C(O)- or thiophene, respectively.

[0123] In further variants, one or more substituents, preferably phenyl groups, together with the atoms to which they are bonded, may form a cyclic ring comprising a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group.

[0124] Similarly, useful substituents for substituting unsaturated carbon atoms in identified groups or radicals include, in particular, -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)2, -P(O)(OY)(OY), -C( Examples include 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 meanings as defined above.

[0125] Substituents (substituents or substitute groups) for replacing nitrogen atoms in heteroalkyl and heterocycloalkyl residues are not limited to, but include -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 Examples include -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 meanings as defined above.

[0126] The term "substituted" specifically refers to one or more substitutions, i.e., two, three, four, five, six, or more, as is customary in the art. However, it is generally known to those skilled in the art that substituents should be selected so as not to adversely affect the useful properties of the compound or its function.

[0127] Preferred substituents within the scope of the present invention include, but are not limited to, halogen groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxyl groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy 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, C1-~C6-alkylthio groups, arylthio groups, nitro groups, keto groups, acyl groups, boronic acid 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 groups, either the aryl group or the alkyl group may be substituted, or both the aryl group and the alkyl group may be substituted with one or more substituents.

[0128] Preferred substituents on the above groups or radicals are selected in particular from COOH, COO-alkyl, NH2, NO2, OH, SH, CN, Si, halogen, linear or branched C1-C6 alkyl groups, linear or branched C1-C6 alkoxy groups, or linear or branched C1-C6 alkylthio groups, where one or more H atoms in the alkyl group may be replaced by halogens.

[0129] In addition, in some cases, as is known to those skilled in the art, suitable substituents can be combined to form one or more rings.

[0130] In the context of this invention, the term "optionally substituted" refers to the presence or absence of substituents, i.e., "substituted" or "unsubstituted." For example, the term "optionally substituted alkyl" encompasses both unsubstituted alkyls and substituted alkyls.

[0131] According to the present invention, the substituents used to replace a particular radical or group may, in turn, be further substituted with one or more identical or different radicals typically selected from the various groups shown and defined in detail above.

[0132] In a particularly preferred variant according to the first aspect of the present invention, the radicals R1 and R2 in general formulas (Va) to (VIIIa) are either the same or different.

[0133] Preferably, R1 in general formulas (Va) to (VIIIa) represents H, or an optionally substituted alkyl group, or an optionally substituted phenyl group, or an optionally substituted thiophene group.

[0134] More preferably, R2 in general formulas (Va) to (VIIIa) represents H, or an optionally substituted alkyl group, or an optionally substituted phenyl group, or an optionally substituted thiophene group.

[0135] A cooling agent having particularly advantageous properties, namely, being particularly strong and effective, and preferably having a long-lasting cooling effect, is usually found in a structure of general formula (Va) having a triazine ring in its basic structure, wherein at least one of the radicals R1 and R2 represents an optionally substituted phenyl group or an optionally substituted thiophene group.

[0136] It is even more preferable that at least one of the radicals R1 and R2 is an optionally substituted phenyl group.

[0137] Compounds of general formula (Va) in which both R1 and R2 represent optionally substituted phenyl groups are most preferred.

[0138] Particularly preferred examples of phenyl group substitutions are OH, methyl, ethyl, methoxy, or ethoxy.

[0139] Most preferably, R1 and R2 represent phenyl groups.

[0140] In a more preferred variant, the two phenyl groups, together with the atom to which they are bonded, form a cyclic ring containing a cycloalkyl or heterocycloalkyl group.

[0141] Compounds of general formula (Va) in which both R1 and R2 are unsubstituted phenyl groups are most preferred.

[0142] In a more preferred variant, in the compound of general formula (Va), R1 and R2 are substituted or unsubstituted phenyl groups that, together with the C atom of the core structure to which they are bonded, form a conjugated or unconjugated ring system.

[0143] In particular, compounds of the general formula (Va) described above, in which both R1 and R2 are substituted or unsubstituted phenyl groups, have been shown to exhibit excellent TRPM8 activity and to produce a very strong cooling effect even when used in small amounts.

[0144] A cooling agent having particularly advantageous properties, namely, being particularly strong and effective, and preferably having a long-lasting cooling effect, is also found in a structure of general formula (VIa) having a pyrazine ring in its basic structure, wherein at least one of the radicals R1 and R2 represents a substituted phenyl group or a substituted thiophene group.

[0145] More preferably, at least one of the radicals R1 and R2 is an optionally substituted phenyl group.

[0146] Compounds of general formula (VIa) in which both R1 and R2 represent optionally substituted phenyl groups are most preferred.

[0147] Particularly preferred examples of substitutions are OH, methyl, ethyl, methoxy, or ethoxy.

[0148] Most preferably, R1 and R2 represent phenyl groups.

[0149] In a more preferred variant, the two phenyl groups, together with the atom to which they are bonded, form a cyclic ring containing a cycloalkyl or heterocycloalkyl group.

[0150] Compounds of general formula (VIa) in which both R1 and R2 are unsubstituted phenyl groups are most preferred.

[0151] In a more preferred variant, in the compound of general formula (VIa), R1 and R2 are substituted or unsubstituted phenyl groups that, together with the C atom of the core structure to which they are bonded, form a conjugated or unconjugated ring system.

[0152] In particular, compounds of general formula (VIa), in which both R1 and R2 are substituted or unsubstituted phenyl groups, have been shown to exhibit excellent TRPM8 activity and to produce a very strong cooling effect even in small amounts.

[0153] A cooling agent having particularly advantageous properties, namely a particularly strong and effective, preferably long-lasting, cooling effect, and / or optionally, particularly efficient masking of undesirable taste impressions, can also be found in a structure of general formula (VIIa) having an oxazole ring in its basic structure, wherein at least one of the radicals R1 and R2 represents optionally a substituted phenyl group or optionally a substituted thiophene group.

[0154] More preferably, at least one of the radicals R1 and R2 is an optionally substituted phenyl group.

[0155] Compounds of general formula (VIIa) in which both R1 and R2 represent optionally substituted phenyl groups are most preferred.

[0156] Particularly preferred examples of substitutions are OH, methyl, ethyl, methoxy, or ethoxy.

[0157] Most preferably, R1 and R2 represent phenyl groups.

[0158] In a more preferred variant, the two phenyl groups, together with the atom to which they are bonded, form a cyclic ring containing a cycloalkyl or heterocycloalkyl group.

[0159] Compounds of general formula (VIIa) in which both R1 and R2 are unsubstituted phenyl groups are most preferred.

[0160] In a more preferred variant, in the compound of general formula (VIIa), R1 and R2 are substituted or unsubstituted phenyl groups that, together with the C atom of the core structure to which they are bonded, form a conjugated or unconjugated ring system.

[0161] In particular, compounds of general formula (VIIa), in which both R1 and R2 are substituted or unsubstituted phenyl groups, have been shown to exhibit excellent TRPM8 activity and to produce a very strong cooling effect even in small amounts.

[0162] A cooling agent having particularly advantageous properties, namely, being particularly strong and effective, and preferably having a long-lasting cooling effect, is also found in a structure of general formula (VIIIa) having an imidazole ring in its basic structure, wherein at least one of the radicals R1 and R2 represents an optionally substituted phenyl group or an optionally substituted thiophene group.

[0163] More preferably, at least one of the radicals R1 and R2 is an optionally substituted phenyl group.

[0164] Compounds of general formula (VIIIa) in which both R1 and R2 represent optionally substituted phenyl groups are most preferred.

[0165] Particularly preferred examples of substitutions are OH, methyl, ethyl, methoxy, or ethoxy.

[0166] Most preferably, R1 and R2 represent phenyl groups.

[0167] In a more preferred variant, the two phenyl groups, together with the atom to which they are bonded, form a cyclic ring containing a cycloalkyl or heterocycloalkyl group.

[0168] Compounds of general formula (VIIIa) in which both R1 and R2 are unsubstituted phenyl groups are most preferred.

[0169] In a more preferred variant, in the compound of general formula (VIIIa), R1 and R2 are substituted or unsubstituted phenyl groups that, together with the C atom of the core structure to which they are bonded, form a conjugated or unconjugated ring system.

[0170] In particular, compounds of general formula (VIIIa), in which both R1 and R2 are substituted or unsubstituted phenyl groups, have been shown to exhibit excellent TRPM8 activity and to produce a very strong cooling effect even in small amounts.

[0171] According to the present invention, compounds of general formulas (Va) to (VIIIa) are more preferably, where R1 and R2 are the same or different and independently have the following meanings: R1 represents H, or optionally substituted C1-C3 alkyl groups, or optionally substituted phenyl groups, and / or R2 represents H, or optionally substituted C1-C3 alkyl groups, or optionally substituted phenyl groups.

[0172] Most preferably, R1 and / or R2 in general formulas (Va) to (VIIIa) are optionally substituted phenyl groups.

[0173] According to the present invention, compounds of general formulas (Va) to (VIIIa), in which Y represents a branched alkylene group, are even more preferred. Preferably, the branched alkylene group is a methylene group substituted with 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 agents, as illustrated below.

[0174] According to the present invention, compounds of general formulas (Va) to (VIIIa) are most preferred, wherein radicals R1 and / or R2 represent an unsubstituted phenyl group or a substituted phenyl group, Y represents a branched alkylene group, preferably a methyl group, an ethyl group, a linear or branched propyl group, or a methylene group substituted with a linear or branched butyl group, and Z has the meaning defined above for compounds of general formulas (I) to (VIII).

[0175] Such compounds exhibit significant TRPM8 activity and, even in small amounts, are extremely potent cooling agents in terms of perception.

[0176] A cooling agent of general formula (Va) or (VIa) having one of the following structural combinations is particularly preferred: R1 and / or R2 = optionally substituted phenyl group, and Y = methylene substituted with a methyl group, R1 and / or R2 = optionally substituted phenyl group, and Y = substituted methylene group with an ethyl group, R1 and / or R2 = optionally substituted phenyl group, and Y = methylene substituted with a linear or branched propyl group, R1 and / or R2 = optionally substituted phenyl groups, and Y = methylene group substituted with a linear or branched butyl group.

[0177] Furthermore, cooling agents of general formula (VIIa) or (VIIIa) having one of the following structural combinations are also particularly preferred: R1 and / or R2 = optionally substituted phenyl group, and Y = methylene substituted with a methyl group, R1 and / or R2 = optionally substituted phenyl group, and Y = substituted methylene group with an ethyl group, R1 and / or R2 = optionally substituted phenyl group, and Y = methylene substituted with a linear or branched propyl group, R1 and / or R2 = optionally substituted phenyl groups, and Y = methylene group substituted with a linear or branched butyl group.

[0178] Furthermore, cooling agents of general formula (Va) or (VIa) having one of the following structural combinations are also preferred: 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 Methylene is substituted with R1 and / or R2 = phenyl groups, and Y = linear or branched butyl groups.

[0179] Furthermore, cooling agents of general formula (VIIa) or (VIIa) having one of the following structural combinations are also preferred: 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 Methylene is substituted with R1 and / or R2 = phenyl groups, and Y = linear or branched butyl groups.

[0180] Surprisingly, in general formulas (Va) to (VIIIa), R1 and R2 each represent an unsubstituted phenyl group, Y is a branched alkylene group, preferably a methyl group, an ethyl group, a linear or branched propyl group, or a methylene group substituted with a linear or branched butyl group, and Z has the meaning defined above for compounds of general formulas (I) to (VIII), wherein the compound according to the present invention.

[0181] Therefore, a cooling agent of general formula (Va) or (VIa) having one of the following structural combinations: R1 and R2 = phenyl groups, and Y = methylene substituted with a methyl group, or R1 and R2 = phenyl groups, and Y = methylene substituted with an ethyl group, or R1 and R2 = phenyl groups, and Y = methylene substituted with a linear or branched propyl group, or R1 and R2 = phenyl groups, and Y = methylene substituted with a linear or branched butyl group, A cooling agent of general formula (VIIa) or (VIIIa) having one of the following structural combinations is most preferred: R1 and R2 = phenyl groups, and Y = methylene substituted with a methyl group, or R1 and R2 = phenyl groups, and Y = methylene substituted with an ethyl group, or R1 and R2 = phenyl groups, and Y = methylene substituted with a linear or branched propyl group, or R1 and R2 = phenyl groups, and Y = methylene substituted with a linear or branched butyl group.

[0182] Among the latter cooling agents according to general formulas (Va) to (VIIIa), compounds in which Y represents a methylene group substituted with a methyl or ethyl group are most preferred. Such compounds exhibit particularly high TRPM8 activity and can produce a very strong cooling effect even in small amounts.

[0183] In general formulas (Va), (VIa), (VIIa), and (VIIIa), 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, and Ra and / or Rb are It is either a linear or branched alkyl group that has been optionally substituted, or A linear or branched alkenyl group that has been optionally substituted, or A linear or branched alkenyl group that has been optionally substituted, or A linear or branched alkynyl group that has been optionally substituted, or It is a linear or branched alkoxy group that has been optionally substituted, or Whether it is a linear or branched alkylthio group that has been optionally substituted, Or it is an optionally substituted acyl group R-(C=O)-, or It is a cycloalkyl group that has been optionally substituted, or It is an aryl group that has been optionally substituted, or It is either an optionally substituted heterocycloalkyl group, or These are heteroaryl groups that have been optionally substituted.

[0184] In further alternative variants, the radicals Ra and Rb of the NRaRb group defined above bind to form a saturated or unsaturated ring, preferably a saturated or unsaturated 3- to 8-membered ring.

[0185] According to the present invention, cooling agents of general formulas (Va) to (VIIIa) are particularly preferred, in which Ra and / or Rb in the NHRa group or NRaRb group represent a C1-C3 alkyl group, preferably a methyl group.

[0186] According to the present invention, Z is

[0187] [Table 3] A cooling agent of general formula (Va), (VIIa), and (VIIIa), selected from the group consisting of the above, is even more preferred.

[0188] According to the present invention, Z is -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-CH2-tetrahydrofuranyl, -NH-CH2-thiophenyl, -NH- A cooling agent of general formula (VIa) selected from the group consisting of ruoryl, -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, oxatenyl, -CH3, -CH2-CH3, -CH(CH3)2, -C(OH)-CH2-OH, cyclopropyl, phenyl, and -CH2-S-CH3 is even more preferred.

[0189] In general formula (VIa), Z does not represent -NH-phenyl, -N(CH3)-phenyl, -OH, -OC2H5, or -OC(CH3)3.

[0190] Therefore, in a particularly preferred variant according to the first aspect of the present invention, cooling agents of general formulas (Va), (VIa), (VIIa), and (VIIIa) having the following structures are provided:

[0191] [Table 4-1]

[0192] [Table 4-2]

[0193] [Table 4-3]

[0194] [Table 4-4]

[0195] According to the present invention, a cooling agent of general formula (Va) or (VIa) having the following structure is even more preferred.

[0196] [Table 5]

[0197] According to the present invention, a cooling agent of general formula (VIIa) or (VIIIa) having the following structure is even more preferred.

[0198] [Table 6]

[0199] Furthermore, compounds of general formulas (Va) to (VIIIa), where m is 1 in each case, appear to be preferred with respect to the determined TRPM8 activity.

[0200] Among the cooling agents according to general formula (VIa), compounds in general formula (VIa) in which R1 and R2 represent phenyl, Y represents a branched alkyl, and in particular Y represents a methylene substituted with -CH3 or -CH2CO2C2H5, and Z in general formula (VIa) represents -NH-phenyl, -N(CH3)-phenyl, -OH, -OC2H5, or -OC(CH3)3 are specifically excluded.

[0201] According to the present invention,

[0202] [Table 7]

[0203] According to the present invention, the cooling agents of general formulas (Va) to (VIIIa) are particularly preferred as pure (R)-enantiomers.

[0204] Surprisingly, the (R)-enantiomers of compounds of general formula (Va) to (VIIIa) have been found to possess a particularly remarkable cooling effect, namely, a rapidly starting, strong cooling effect. This effect is particularly advantageous in formulations where a rapid cooling effect on the skin or mucous membranes is desired.

[0205] According to the present invention, the cooling agents according to general formulas (Va) to (VIIIa) preferably exist as pure (S)-enantiomers.

[0206] Surprisingly, the (S)-enantiomers of compounds with general formulas (Va) to (VIIIa) have a less pronounced cooling effect, but this has been found to accumulate slowly and last longer than that of the (R)-enantiomers. This effect is particularly desirable in formulations where a long-lasting cooling effect on the skin or mucous membranes is desired.

[0207] According to the present invention, the cooling agent exists more preferably as a racemic mixture or as an enantiomer mixture of the (R)-enantiomer and the (S)-enantiomer.

[0208] A particularly advantageous cooling effect can be achieved when the ratio of (R)-enantiomer to (S)-enantiomer in the enantiomer mixture is greater than 50:50, preferably ≥75:25, more preferably ≥90:10, even more preferably ≥95:5, and most preferably ≥98:2.

[0209] The favorable cooling effect can also be achieved when the ratio of (S)-enantiomer to (R)-enantiomer is greater than 50:50, preferably ≥75:25, more preferably ≥90:10, even more preferably ≥95:5, and most preferably ≥98:2.

[0210] A physiological cooling agent of general formula (Va) or (VIa), selected from the group consisting of compounds shown in Table A, is particularly preferred.

[0211] [Table 8-1]

[0212] [Table 8-2]

[0213] [Table 8-3]

[0214] [Table 8-4]

[0215] [Table 8-5]

[0216] [Table 8-6]

[0217] The cooling agents of the present invention, as listed in Table A, according to general formula (Va) or (VIa), are either neutral, uncharged forms, or, as described in detail above, in the form of salts thereof, such as acid addition salts with inorganic, organic monovalent, or polyvalent carboxylic acids. In this regard, the above description applies equally here.

[0218] Surprisingly, the compounds according to the present invention, listed in Table A, exhibit particularly high TRPM8 activity and have therefore been found to be remarkably suitable as cooling agents.

[0219] The most preferred cooling agents, i.e., those exhibiting particularly efficient and potent TRPM8 activation, i.e., those providing an efficient and concentrated cooling effect with a small application amount, are 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%).

[0220] Cooling agents B-01, B-02, B-03, B-05, and B-07, which exhibit very high TRPM8 activity (TRPM8 activity ≥ 150%), are particularly preferred.

[0221] Due to their remarkable relative TRPM8 activation, the cooling agents B-01 (262% TRPM8 activation), B-02 (227% TRPM8 activation), B-03 (221% TRPM8 activation), B-05 (205% TRPM8 activation), and B-07 (203% TRPM8 activation) are most preferred.

[0222] The cooling agent B-01 (triazine derivative) is characterized in that, in general formula (V), R1 and R2 represent phenyl groups, Y represents a branched methylene group substituted with an ethyl group, and Z represents a -NH-cyclopropyl group.

[0223] The cooling agent B-02 (pyrazine derivative) is characterized in that, in general formula (VI), R1 and R2 represent phenyl groups, Y represents a branched methylene group substituted with an ethyl group, and Z represents a -NH-CH3 group.

[0224] The cooling agent B-03 (triazine derivative) is characterized in that, in general formula (V), R1 and R2 represent phenyl groups, Y represents a branched methylene group substituted with an ethyl group, and Z represents a -NH-CH3 group.

[0225] The cooling agent B-05 (triazine derivative) is characterized in that, in general formula (V), R1 and R2 represent phenyl groups, Y represents a branched methylene group substituted with an ethyl group, and Z represents a -N(CH3)2 group.

[0226] The cooling agent B-07 (triazine derivative) is characterized in that, in general formula (V), R1 and R2 represent phenyl groups that, together with the C atom of the triazine ring to which they are bonded, form a fused ring system, i.e., 1,2,4-triazatriphenylene; Y represents a branched methylene group substituted with a methyl group; and Z represents a -NH-CH3 group.

[0227] According to the present invention, the cooling agents shown in Table A exist as pure (R)-enantiomers, pure (S)-enantiomers, racemates, or enantiomer mixtures, and are used in formulations as such.

[0228] According to the present invention, the cooling agent shown in Table A is particularly preferably present as a pure (R)-enantiomer.

[0229] Surprisingly, the (R)-enantiomer of the cooling agent has been found to have a particularly pronounced cooling effect, namely, a strong cooling effect that begins rapidly. This effect is particularly advantageous in formulations where a rapid cooling effect on the skin or mucous membranes is desired.

[0230] According to the present invention, the cooling agent shown in Table A preferably exists as a pure (S)-enantiomer.

[0231] Surprisingly, the (S)-enantiomer of the cooling agent has a less pronounced cooling effect, which has been found to accumulate slowly and last longer compared to the (R)-enantiomer. This effect is particularly advantageous in formulations where a long-lasting cooling effect on the skin or mucosa is desired.

[0232] According to the present invention, the compound / cooling agent according to Table A is more preferably present in the form of a racemate or an enantiomeric mixture of the (R)-enantiomer and the (S)-enantiomer.

[0233] A particularly advantageous cooling effect can be achieved when the ratio of the (R)-enantiomer to the (S)-enantiomer in the enantiomeric mixture is greater than 50:50, preferably ≥ 75:25, more preferably ≥ 90:10, even more preferably ≥ 95:5, and most preferably ≥ 98:2.

[0234] An advantageous cooling effect can also be achieved when the ratio of the (S)-enantiomer to the (R)-enantiomer is greater than 50:50, preferably ≥ 75:25, more preferably ≥ 90:10, even more preferably ≥ 95:5, and most preferably ≥ 98:2.

[0235] Physiological cooling agents of general formula (VIIa) or (VIIIa) selected from the group consisting of the compounds shown in Table B are equally preferred.

[0236]

Table 9-1

[0237]

Table 9-2

[0238]

Table 9-3

[0239] The cooling agents of the present invention listed in Table B according to general formula (VIIa) or (VIIIa) exist either in a neutral non-charged form or in the form of their salts such as acid addition salts with inorganic or organic monovalent or polyvalent carboxylic acids as described in detail above. In this regard, the above description applies equally here.

[0240] Surprisingly, the compounds according to the present invention listed in Table B show particularly high TRPM8 activation and have thus been found to be excellently suitable as cooling agents.

[0241] The most preferred cooling agents, i.e., those having particularly efficient and strong TRPM8 activation, i.e., having an efficient and intensive cooling effect with a low application amount, are compounds A-01, A-02, A-03, A-05, A-09, A-10, and A-12 (TRPM8 activation ≥ 100%).

[0242] Cooling agents A-01, A-02, A-03, and A-05, which show very high TRPM8 activity (TRPM8 activation ≥ 150%), are particularly preferred.

[0243] Due to their outstanding relative TRPM8 activation, cooling agents A-01 (278% TRPM8 activation), A-02 (265% TRPM8 activation), A-03 (260% TRPM8 activation), and A-05 (190% TRPM8 activation) are most preferred.

[0244] Cooling agent A-01 (an oxazole derivative) is characterized in that in general formula (VII), R1 and R2 represent phenyl groups, X represents an S atom, Y represents a branched methylene group substituted with a methyl group, and Z represents a -NH-CH3 group.

[0245] The cooling agent A-02 (oxazole derivative) is characterized in that, in general formula (VII), R1 and R2 represent phenyl groups, X represents an S atom, Y represents a branched methylene group substituted with a methyl group, and Z represents a -NH-CH3 group.

[0246] The cooling agent A-03 (oxazole derivative) is characterized in that, in general formula (VII), R1 and R2 represent phenyl groups, X represents an S atom, Y represents a branched methylene group substituted with a methyl group, and Z represents a -NH-CH3 group.

[0247] The cooling agent A-05 (oxazole derivative) is characterized in that, in general formula (VII), R1 represents a CH3 group, R2 represents a phenyl group, X represents an S atom, Y represents a branched methylene group substituted with a methyl group, and Z represents a -NH-CH3 group.

[0248] According to the present invention, the cooling agents shown in Table A exist as pure (R)-enantiomers, pure (S)-enantiomers, racemates, or enantiomer mixtures, and are used in formulations as such.

[0249] According to the present invention, the cooling agents listed in Table B are particularly preferred as pure (R)-enantiomers.

[0250] Surprisingly, the (R)-enantiomer of the cooling agent was found to have a particularly pronounced cooling effect, namely, a strong cooling effect that begins rapidly. This effect is particularly advantageous in formulations where a rapid cooling effect on the skin or mucous membranes is desired.

[0251] According to the present invention, the cooling agent shown in Table B preferably exists as a pure (S)-enantiomer.

[0252] Surprisingly, the (S)-enantiomer of the cooling agent, while exhibiting a less pronounced cooling effect, was found to accumulate more slowly compared to the (R)-enantiomer. This effect is particularly advantageous in formulations where a prolonged cooling effect on the skin or mucous membranes is desired.

[0253] According to the present invention, the compounds / cooling agents shown in Table B are more preferably in the form of a racemic mixture or an enantiomer mixture of the (R)-enantiomer and the (S)-enantiomer.

[0254] A particularly advantageous cooling effect can be achieved when the ratio of (R)-enantiomer to (S)-enantiomer in the enantiomer mixture is greater than 50:50, preferably ≥75:25, more preferably ≥90:10, even more preferably ≥95:5, and most preferably ≥98:2.

[0255] The favorable cooling effect can also be achieved when the ratio of (S)-enantiomer to (R)-enantiomer is greater than 50:50, preferably ≥75:25, more preferably ≥90:10, even more preferably ≥95:5, and most preferably ≥98:2.

[0256] Preferred cooling agents B-01, B-02, B-03, B-05, B-07, B-11, B14, B-15, B-18, and B-21, as well as A-01, A-02, A-03, A-05, A-09, A-10, and A-12, have particularly high TRPM8 activity and have been shown to exhibit a strong and simultaneously efficient cooling effect, meaning that only a small amount of the substance according to the present invention, in the low ppm range of about 5 ppm, is needed to produce a strong cooling effect (low EC50 value; see experimental data below).

[0257] In the sensory evaluation, i.e., in the taste test of each sample, a strong cooling effect was detected. The panelists evaluated the cooling effect of cooling agent B-11 at a usage level of 5 ppm with a score of 5.3. Therefore, considering the amount of the compound used, the sensory-evaluated cooling intensity was equivalent to that determined for the cooling substance WS-3 as a reference at a concentration 6 times higher (amount used: 30 ppm, sensory-determined cooling intensity: score 5.4). Compounds A-2 and A-10 also showed very high TRPM8 activity and a strongly perceptible cooling effect in terms of sensation (sensory cooling intensity: score 5.4 and score 5.38, respectively), and are thus particularly efficient cooling agents.

[0258] The cooling agents according to the present invention are also characterized by high TRPM8 activation and a very high cooling intensity determined by sensory evaluation. They produce a strong cooling effect even at low concentrations and generally fall well below the EC50 reference value of 1.72 μM of substance WS-3, as shown in the following experimental section.

[0259] In the most preferred variant, the physiological cooling agent is selected from the group consisting of the compounds shown in Table C, or

[0260] [Table 10-1]

[0261] [Table 10-2]

[0262] [Table 10-3] or The physiological cooling agent of general formula (VIIa) or (VIIIa) is selected from the group consisting of the compounds shown in Table D.

[0263] [Table 11-1]

[0264] [Table 11-2]

[0265] [Table 11-3]

[0266] The cooling agents of the present invention, as listed in Table C according to general formulas (Va) to (VIIIa), exist in either a neutral, uncharged form or, as described in detail above, in the form of salts thereof, such as acid addition salts with inorganic, organic monovalent, or polyvalent carboxylic acids. In this regard, the above description applies equally here.

[0267] According to the present invention, the cooling agents listed in Tables C and D exist as pure (R)-enantiomers, or pure (S)-enantiomers, or as racemates, or as enantiomer mixtures, and are used in formulations as such.

[0268] According to the present invention, the (R)-enantiomers of the cooling agents listed in Tables C and D are particularly preferred.

[0269] Remarkably, the (R)-enantiomers of these cooling agents have been found to possess a particularly pronounced cooling effect, namely, a rapidly starting, strong cooling effect. This effect is particularly advantageous in formulations where a rapid cooling effect on the skin or mucous membranes is desired.

[0270] According to the present invention, the (S)-enantiomers of the cooling agents listed in Tables C and D are even more preferred.

[0271] Surprisingly, the (S)-enantiomers of these cooling agents have a less pronounced cooling effect, but they have been found to accumulate more slowly and last longer compared to the (R)-enantiomers. This effect is particularly advantageous in formulations where a long-lasting cooling effect on the skin or mucous membranes is desired.

[0272] Surprisingly, the enantiomer compounds or cooling agents according to the present invention, listed in Table C or Table D, exhibit common in vivo properties even at low doses within a low ppm range of approximately 5 ppm, achieving a particularly long-lasting and strong cooling effect on the skin or mucous membranes, and were generally found to be well below the EC50 reference value of 1.72 μM of substance WS-3, as shown in the experimental section below. This means that even smaller doses of the cooling agents according to the present invention are required in the final preparation to achieve a strong cooling effect. Therefore, the compounds described above are particularly efficient cooling agents.

[0273] The enantiomer cooling agents according to the present invention, shown in Tables C and D, are also characterized by the fact that their cooling effect begins rapidly, whereas other cooling agents according to the present invention have a cumulative cooling effect, i.e., an effect that increases over time, lasts longer, and is stronger.

[0274] During sensory evaluation, i.e., tasting each sample, a rapidly initiating, strong cooling effect was detected for the (R) enantiomer. Panelists rated the cooling effect of compound A-02 at a concentration of 5 ppm with a score of 5.7. Therefore, considering the amount of compound used, the sensory-evaluated cooling intensity was equivalent to that determined for the cooling substance WS-3 as a reference at a concentration six times higher (amount used: 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 was delayed, slowly accumulated, and long-lasting.

[0275] According to the present invention, the cooling substances according to Tables C and D are more preferably in the form of a racemic mixture or an enantiomer mixture of (R)-enantiomer and (S)-enantiomer.

[0276] A particularly advantageous cooling effect can be achieved when the ratio of (R)-enantiomer to (S)-enantiomer in the enantiomer mixture is greater than 50:50, preferably ≥75:25, more preferably ≥90:10, even more preferably ≥95:5, and most preferably ≥98:2.

[0277] The favorable cooling effect can also be achieved when the ratio of (S)-enantiomer to (R)-enantiomer is greater than 50:50, preferably ≥75:25, more preferably ≥90:10, even more preferably ≥95:5, and most preferably ≥98:2.

[0278] The physiological cooling agents according to general formulas (Va) to (VIII) and Tables A to D exist either in a neutral, i.e., uncharged form, or in the form of salts thereof, such as acid addition salts with inorganic or organic acids.

[0279] In the context of this invention, the term "salt" refers to a salt of a compound having the desired effect or pharmacological activity of the parent compound. Such a salt is (1) an acid addition salt formed with an inorganic acid, or with an organic acid, preferably a monocarboxylic acid or polycarboxylic acid, or (2) The salts are formed when an acidic proton present in the parent compound is substituted by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or when it coordinates with an organic base.

[0280] Among salts, acid addition salts are particularly preferred because physiological cooling agents according to general formulas (I) to (VIII) contain a protonable N atom.

[0281] The inorganic acid that forms the acid addition salt with the physiological cooling agent of the present invention is preferably selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Among the salts, hydrochloride salts or sulfate salts are most preferred. Hydrochloride salts or sulfate salts are particularly preferred.

[0282] Acid addition salts with organic mono- or polycarboxylic acids are even more preferred. Acid addition salts with organic mono- or polycarboxylic acids are even more preferred, and the carboxylic acid is selected from saturated or mono- or polyunsaturated C1-C30 monocarboxylic acids, saturated or mono- or polyunsaturated C3-C10 di- or tricarboxylic acids. The carboxylic acid may be an α-hydroxycarboxylic acid, substituted with one or more hydroxyl groups, preferably the hydroxyl group located on a carbon atom adjacent to a carboxyl group. Many representative examples 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, tartaric acid, or tartaric acid.

[0283] The organic acids that form the acid addition salt with the physiological cooling agent according to the present invention are preferably 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 The following are selected from the group consisting of honic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor-sulfonic acid, 4-methylbicyclo[2.2.2]octo-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, 4-hydroxybutanoic acid, etc.

[0284] Among the organic acids that form an acid addition salt with the physiological cooling agent of the present invention, acetic acid, lactic acid, malonic acid, succinic acid, malic acid, citric acid, or tartaric acid are most preferred.

[0285] The metal ions for salt formation that replace the acidic protons present in the starting compound are selected from the group consisting of alkali metal ions, preferably Na+ or K+, and alkaline earth metal ions, preferably Ca++, Mg++, and aluminum+++.

[0286] The coordinating organic base for salt formation is selected from the group consisting of ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and others.

[0287] In the following description and in the claims, the terms “physiological cooling agent” or “compound” encompass both the neutral, uncharged form of the cooling agent / compound and, similarly, the salt form of the cooling agent / compound.

[0288] Due to their good solubility, salts of physiological cooling agents according to the present invention are particularly preferred. Better water solubility also results in better availability of the cooling agent or compound when used.

[0289] Surprisingly, the compounds or cooling agents or salts thereof according to the present invention have been found to share the common property of achieving a particularly long-lasting and strong cooling effect on the skin or mucous membranes in vivo, even at low doses within a low ppm range of about 5 ppm. This means that even smaller doses of the cooling agents or salts thereof according to the present invention are required in the final preparation to achieve a strong cooling effect. Therefore, the compounds described herein represent particularly efficient cooling substances. This was not predictable for the TRPM8 modulators referred to in this application.

[0290] The cooling agents according to the present invention are also characterized by the fact that their cooling effect begins rapidly, whereas other cooling agents according to the present invention have a cumulative cooling effect, i.e., an effect that increases over time, lasts longer, and is stronger.

[0291] The cooling agents according to the present invention are also colorless and do not cause discoloration, which is particularly advantageous for their storage and / or use in the final product. Therefore, the compounds described herein are particularly suitable as additives in various preparations. In addition, according to the present invention, the compounds described herein are mostly tasteless and odorless, making them ideal for incorporation into neutral and / or flavored preparations without imparting negative taste impressions such as bitterness or adversely affecting the intended taste or smell.

[0292] The salts of the cooling agents according to the present invention exhibit better solubility in vitro than their neutral, uncharged equivalents, which is particularly advantageous when used in oral care.

[0293] Therefore, the compounds described herein are particularly suitable as highly efficient cooling agents that can be incorporated particularly well into a variety of formulations. Due to their better solubility, salts of the cooling agents according to the present invention, and more preferably acid addition salts, are particularly advantageous for use in the oral care sector.

[0294] In a further embodiment, the present invention relates to a compound selected from the group consisting of the compounds shown in Table E,

[0295] [Table 12-1]

[0296] [Table 12-2]

[0297] [Table 12-3] or The compound is selected from the group consisting of the compounds shown in Table F.

[0298] [Table 13-1]

[0299] [Table 13-2]

[0300] [Table 13-3]

[0301] The compounds according to the present invention, listed in Tables E and F, exist either in a neutral, uncharged form, or in the form of salts thereof, such as acid addition salts with inorganic, monovalent, or polyvalent carboxylic acids, as described in detail above in relation to the cooling agents according to the present invention. In this regard, the above description applies equally here.

[0302] According to the present invention, the compounds shown in Tables E and F exist as pure (R)-enantiomers, or pure (S)-enantiomers, or as racemates, or as enantiomer mixtures, and are used in formulations as such.

[0303] According to the present invention, the (R)-enantiomers of the compounds listed in Tables E and F are particularly preferred.

[0304] The (S)-enantiomers of the compounds listed in Tables E and F are even more preferred according to the present invention.

[0305] According to the present invention, the compounds shown in Tables E and F are more preferably in the form of a racemic mixture or an enantiomer mixture of the (R)-enantiomer and the (S)-enantiomer.

[0306] 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, more preferably ≥90:10, even more preferably ≥95:5, and most preferably ≥98:2.

[0307] Favorable effects can also be achieved when the ratio of (S)-enantiomer to (R)-enantiomer is greater than 50:50, preferably ≥75:25, more preferably ≥90:10, even more preferably ≥95:5, and most preferably ≥98:2.

[0308] Surprisingly, the (R)- and (S)-enantiomer compounds shown in Tables E and F are particularly efficient as modulators of the cold menthol receptor TRPM8, especially for in vivo and / or in vitro modulation, particularly as TRPM8 receptor agonists or TRPM8 receptor antagonists, as physiological cooling agents, flavoring agents, substances for improving the taste of flavoring agents, or bitterness masking agents.

[0309] In principle, the present invention encompasses all mixtures of the individual cooling agents of general formulas (Va) to (VIIIa), or those listed in Tables A to D and defined above, or those listed in Tables E and F and defined above, as well as their use as cooling agents or mixtures of cooling agents. Nevertheless, the compounds are also suitable for mixing with other known cooling agents.

[0310] Therefore, a further subject of the present invention is, (a) One, two, three, or more cooling agents of general formula (Va) to (VIIIa), or listed in Tables A to D and defined above, or one, two, three, or more compounds listed in Tables E and F and defined above, and optionally, (b) at least one further physiological cooling agent, and / or optionally, (c) relating to a physiological cooling agent mixture comprising or consisting of at least one solvent.

[0311] In preferred embodiments, the present invention relates to a mixture of cooling agents comprising or consisting of two or more of the cooling agents of general formula (Va) to (VIIIa), or those listed in Tables A to D and defined above, or two or more of the compounds listed in Tables E and F and defined above, and defined above.

[0312] Optionally, the cooling agent mixture also comprises a further physiological cooling agent and, optionally, at least one suitable solvent.

[0313] A particular advantage of such a cooling agent mixture is that a synergistic enhancement of the cooling effect can be observed.

[0314] A suitable cooling agent different from the cooling agent that forms component (b) and component (a) is menthol, menthol methyl ether (FEMA GRAS 4054), monomentyl glutamate (FEMA GRAS 4006), menthoxy-1,2-propanediol (FEMA GRAS 3784), dimentyl glutarate (FEMA GRAS 4604), hydroxymethylcyclohexyl ethanolone (FEMA GRAS 4742), 2-(4-ethylphenoxy)-N-(1H-pyrazole-3-yl)-N-(thiophen-2-ylmethyl)acetamide (FEMA GRAS 4880), WS-23 (2-isopropyl-N,2,3-trimethylbutylamide, FEMA GRAS 3804), N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide (FEMA FEMA GRAS 4882), N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide (FEMA GRAS 4881), N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexane-1-carboxamide (FEMA GRAS 4896), 3,4-methylenedioxycinnamic acid, (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide (FEMA GRAS 4788), menthol propylene glycol carbonate (FEMA GRAS 3806), menthyl N-ethyl oxamate, monomethyl succinate (FEMA GRAS 3810), WS-3 (N-ethyl-p-menthane-3-carboxamide, FEMA GRAS 3455), Menthol ethylene glycol carbonate (FEMA GRAS 3805), WS-5 (ethyl-3-(p-menthane-3-carboxamide) acetate, FEMA GRAS 4309), WS-12 (1R,2S,5R)-N-(4-methoxyphenyl)-p-menthanecarboxamide (FEMA GRAS 4681), WS-27 (N-ethyl-2,2-diisopropylbutanamide, FEMA GRAS 4557), N-cyclopropyl-5-methyl-2-isopropylcyclohexanecarboxamide (FEMA GRAS 4693), WS-116 (N-(1,1-Dimethyl-2-hydroxyethyl)-2,2-diethylbutanamide, FEMA (GRAS 4603), Menthoxyethanol (FEMA GRAS 4154), N-(4-cyanomethylphenyl)-p-menthanecarboxamide (FEMA GRAS 4496), N-(2-(pyridine-2-yl)ethyl)-3-p-menthanecarboxamide (FEMA GRAS 4549), N-(2-hydroxyethyl)-2-isopropyl-1-2,3-dimethylbutanamide (FEMA GRAS 4602), (2S,5R)-N-[4-(2-amino-2-oxoethyl)phenyl]-p-menthanecarboxamide (FEMA GRAS 4684), N-cyclopropyl-5-methyl-2-isopropylcyclohexanecarboxamide (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-(1H-pyrazole-5-yl)-N-((thiophen-2-yl)methyl)acetamide (FEMA GRAS 4809), menthol glycoside ketal (FEMA GRAS 3807 and 3808), (-)-menthoxypropane-1,2-diol, 3-(1-menthoxy)-2-methylpropane-1,2-diol (FEMA GRAS 3849), isopuregol, (+)-cis and (-)-trans-p-menthane-3,8-diol (62:38, FEMA GRAS 4053), 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one (FEMA GRAS 4970) and its enantiomer, 2,3-dihydroxy-p-menthane, 3,3,5-trimethylcyclohexanone glycerol ketal, menthylpyrrolidone carboxylate, (1R,3R,4S)-3-menthyl-3,6-dioxaheptanoate, (1R,2S,5R)-3-menthyl methoxyacetate, (1R,2S,5R)-3-menthyl-3,6,9-trioxadecanoate, (1R,2S,5R)-3-menthyl-3,6,9-Trioxadecanoate, (1R,2S,5R)-3-Menthyl-(2-hydroxyethoxy)acetate, (1R,2S,5R)-Menthyl-11-hydroxy-3,6,9-trioxaundecanoate, cubebol (FEMA GRAS 4497), 2-Isopropyl-5-methylcyclohexyl-4-(dimethylamino)-4-oxobutanoate (FEMA GRAS 4230), Menthyl lactate (FEMA GRAS 3748), 6-Isopropyl-3,9-dimethyl-1,4-dioxaspiro[4,5]decane-2-one (FEMA GRAS 4285), N-benzo[1,3]-dioxol-5-yl-3-p-menthanecarboxamide, N-(1-isopropyl-1,2-dimethylprolyl)-1,3-benzodioxol-5-carboxamide, N-(R)-2-oxotetrahydrofuran-3-yl-(1R,2S,5R)-p-menthane-3-carboxamide, 2,2,5,6,6-pentamethyl-2 A mixture of 3,6,6a-tetrahydropentalen-3a(1H)-ol and 5-(2-hydroxy-2-methylpropyl)-3,4,4-trimethylcyclopent-2-en-1-one, (2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridine-4-yl)ethyl)cyclohexanecarboxamide, (1S,2S,5R)-N-(4-(cyanomethyl )phenyl)-2-isopropyl-5-methylcyclohexanecarboxamide, 1,7-isopropyl-4,5-methyl-bicyclo[2.2.2]octo-5-ene derivative, 4-methoxy-N-phenyl-N-[2-(pyridine-2-yl)ethyl]benzamide, 4-methoxy-N-phenyl-N-[2-(pyridine-2-yl)ethyl]benzenesulfonamide, 4-chloro-N-phenyl-N-[2-(pyridine-2-yl)ethyl]benzenesulfonamide, 4-cyano-N-phenyl-N-[2-(pyridine-2-yl)ethyl]benzenesulfonamide, 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]imidazole-2-yl)vinyl-4-methoxybenzoate, 2-(1-isopropyl-6-methyl-1H-benzo[d]imidazole-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoate, (Z)-2-(1-isopropyl-5-methyl-1H-benzo[d]imidazole-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoate, 3-alkyl-p-methane-3-ol derivatives, fenquil, D-bornyl, Selected from the group consisting of L-bornyl, exo-norbornyl, 2-methylisobornyl, 2-ethylfenquil, 2-methylbornyl, cis-pyran-2-yl, verbanyl, and derivatives of isobornyl, menthyl oxamate derivatives, menthyl 3-oxocarboxylic acid esters, N-alpha-(menthanecarbonyl)amino acid amides, p-menthanecarboxamide and WS-23 analogs, (-)-(1R,2R,4S)-dihydroumbellol, p-menthanealkyloxiamide, 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-tetrahydropyrimidine-2-one, 4-methyl-3-(1-pyrrolidinyl)-2-[5H]-furanone, and mixtures thereof. FEMA stands for the "Flavour and Extracts Manufacturers Association," and GRAS is defined as "Generally Regarded As Safe." A FEMA GRAS designation means that a substance labeled as such has been tested using standard methods and is considered toxicologically safe.

[0315] In principle, all known substances that have a cooling effect are suitable as component (b). However, for food safety reasons, compounds with FEMA GRAS designation are preferred, or preferred if the cooling mixture in question requires it.

[0316] A key representative example of the substance forming component (b) is monomenthyl succinate (FEMA GRAS 3810). Both succinates and their analogue monomenthyl glutarate (FEMA GRAS 4006) are key representative examples of monomenthyl esters based on dicarbons and polycarboxylic acids.

[0317] In the present invention, the following important groups of preferred menthol compounds include 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 corresponding sugar derivatives, which include carbonate esters of menthol and polyols such as glycol, glycerin, or carbohydrates. In addition, N-(4-cyanomethylphenyl)-p-menthanecarboxamide (FEMA GRAS 4496), N-(2-(pyridine-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) are also preferred as component (b).

[0318] For the present invention, menthyl lactate (FEMA GRAS 3748 = Frescolat® ML), a menthol compound, is preferred, particularly menthol glycosylated acetal (FEMA GRAS 3807) or menthol glycosylated ketal (FEMA GRAS 3808), which are commercially available under the name Frescolat® MGA.

[0319] This group of compounds also includes 3-(1-menthoxy)-1,2-propanediol (FEMA GRAS 3784), also known as cooling agent 10, and 3-(1-menthoxy)-2-methyl-1,2-propanediol (FEMA GRAS 3849), which has an additional methyl group.

[0320] Among the above substances, menthol glycoyl acetal / ketal, menthyl lactate, menthol ethylene glycol carbonate, and menthol propylene glycol carbonate have been proven to be particularly advantageous. The applicant sells these under the names Frescolat® MGA, Frescolat® ML, Frescolat® MGC, and Frescolat® MPC.

[0321] Further preferred components (b) are shown in Table 1 below.

[0322] [Table 14-1]

[0323] [Table 14-2]

[0324] [Table 14-3]

[0325] [Table 14-4]

[0326] [Table 14-5]

[0327] [Table 14-6]

[0328] In the 1970s, menthol compounds having a carboxyl bond at the 3-position were first developed, and some of these can also be used in the present invention. These substances are generally referred to as WS-type compounds. The basic structure is a menthol derivative (WS-1) in which a hydroxyl group is replaced by a carboxyl group. Similarly, all other WS-type compounds, such as WS-3, WS-4, WS-5, WS-12, WS-14, WS-23, WS-27, and WS-30, which are preferred in the sense of the present invention, or esters or N-substituted amides of the aforementioned compounds, are derived from this structure.

[0329] The cooling agent 2-(p-tolyloxy)-N-(1H-pyrazole-5-yl)-N-((thiophen-2-yl)methyl)acetamide (FEMA GRAS 4809) is also particularly preferred. Also preferred are 2-(4-ethylphenoxy)-N-(1H-pyrazole-3-yl)-N-(thiophen-2-ylmethyl)acetamide (FEMA GRAS 4880), and / or N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide (FEMA GRAS 4881), and / or N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide (FEMA GRAS 4882).

[0330] Further preferred components (b) that are combined with at least one cooling agent according to the present invention, which is listed in one of Tables A to D and has a general formula (Va) to (VIIIa), or with at least one compound according to the present invention as defined above, or which is listed in one of Tables E and F and has a general formula (Va) to (VIIIa), are shown in Table 2 below.

[0331] [Table 15-1]

[0332] Table 15-2

[0333] Table 15-3

[0334] Table 15-4

[0335] Table 15-5

[0336] Table 15-6

[0337] Table 15-7

[0338] Table 15-8

[0339] Table 15-9

[0340] Table 15-10

[0341] [Table 15-11]

[0342] [Table 15-12]

[0343] [Table 15-13]

[0344] [Table 15-14]

[0345] [Table 15-15] and salts thereof, preferably acid addition salts with inorganic or organic acids.

[0346] The cooling agent mixture according to the present invention may contain component (a) and component (b) in a weight ratio of about 0.1:99.9 to about 99:0:0.1, preferably about 1:99 to about 99:1, more preferably about 10:90 to about 90:10, even more preferably about 25:75 to about 75:25, and in particular about 40:60 to about 60:40, based on the total cooling agent mixture.

[0347] Advantageously, the cooling mixture according to the present invention comprises at least one solvent as a further component (c).

[0348] On the other hand, the aforementioned cooling agent that forms component (b) of the cooling agent mixture can act as a cooling agent that forms component (a) of the cooling agent mixture, or as a cooling agent / compound or solvent for a compound.

[0349] Individual solvents or solvent systems have been proven to be advantageous, and thereafter, 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.

[0350] For example, Optamint is a mixture of more than 50 different natural essential oils and natural or identical flavorings. Preferably, Optamint has a variable composition of different (partially fractionated) oils, such as different peppermint oils and spearmint oils, and mixtures of Eucalyptus globulus oil, star anise oil, menthol, menthone, isomenthon, menthyl acetate, anethole, eucalyptol, etc.

[0351] For example, benzyl alcohol, 2-phenylethanol, or benzyl benzoate can be used as a solvent in the cooling mixture according to the present invention.

[0352] Benzyl alcohol, 2-phenylethanol, or benzyl benzoate can be used to dissolve, for example, the cooling agent according to the present invention, thereby obtaining a stable solution for proper storage, i.e., a cooling agent mixture.

[0353] The cooling agent or compound according to the present invention can also be dissolved using a solvent system, i.e., a combination of two or more solvents. In particular, with respect to subsequent application fields, the use of a solvent that can also have a cooling effect can eliminate further steps in the (final) production step.

[0354] Therefore, in exemplary embodiments, the solvent in the cooling agent mixture is a two-component 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 cooling agents described above as component (b).

[0355] According to the present invention, for example, a two-component solvent system comprising benzyl alcohol and another 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 other cooling agents described above as component (b) is preferred.

[0356] For example, combinations or mixtures of two-component solvents containing benzyl alcohol and another solvent, or comprising them, are also preferred. In this case, combinations or mixtures of two-component solvents selected from the following are also preferred: 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 optamine, 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 menthol glycoside acetal (Frescolat® MGA), benzyl alcohol and menthane carboxylic acid esters and amides.

[0357] The following combinations or mixtures of two-component solvents are also preferred: 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 menthol glyceryl acetal (Frescolat® MAG), Optamint and menthyl lactate (Frescolat® ML), triethyl citrate and menthol ethylene glycol carbonate (Frescolat® MGC).

[0358] Therefore, a suitable cooling agent mixture within the scope of the present invention contains, for example, a combination or mixture of the two-component solvents described above as solvent (c).

[0359] A two-component solvent mixture within the scope of the present invention has, for example, the following ratio: solvent (1):solvent (2), preferably 8:2 to 2:8, more preferably 6:4 to 4:6, and most preferably 5:5.

[0360] The aforementioned suitable solvent mixtures can dissolve the cooling agent or compound according to the present invention and, depending on the solvent or combination of solvents mentioned, can retain the cooling agent in the solution in a wide range of 2% to 50% by weight, preferably 5% to 40% by weight, and more preferably 5% to 20% by weight.

[0361] In further exemplary embodiments, the solvent or solvent system for the cooling agent or compound according to the present invention is a three-component 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 described above as component (b).

[0362] Suitable examples include combinations or mixtures of three-component solvents 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 listed above as component (b).

[0363] For example, a combination or mixture of a three-component solvent containing benzyl alcohol and two other solvents is preferred, the two other solvents being 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 menthol glycoside acetal (Frescolat® MGA), 2-phenylethanol and menthol Tanocarboxylic 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 lactic acid (Frescolat® ML), triacetin and menthol 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) are selected from the group.

[0364] For example, the following combinations or mixtures of three-component solvents 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, diethyl succinate, 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 menthol 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 menthol glyceryl acetal (Frescolat® MGA), Optamint, benzyl benzoate, and menthyl lactate (Frescolat® ML), and Benzyl benzoate, triethyl citrate, and menthol ethylene glycol carbonate (Frescolat® MGC).

[0365] A three-component solvent mixture within the scope of the present invention includes, 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.

[0366] The aforementioned preferred three-component solvent mixtures have proven particularly effective in dissolving the cooling agent or compound of the present invention, and depending on the solvent or combination of solvents mentioned, they were able to stably maintain the cooling agent or compound in solution within a wide range of 2% to 50% by weight, preferably 5% to 40% by weight, and more preferably 5% to 20% by weight.

[0367] This has the advantage that the cooling agent or compound according to the present invention can be presented in a variable amount suitable for the final formulation, so as to broaden the range of cooling agent mixtures in which the cooling agent is dissolved.

[0368] In a further preferred embodiment, the solvent or solvent system for the cooling agent or compound according to the present invention is a tetracomponent 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 described above as component (b).

[0369] Suitable examples include combinations of a four-component solvent 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 listed above as component (b).

[0370] For example, a combination or mixture of a four-component solvent containing benzyl alcohol and three other solvents is preferred, and the three other solvents are: 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, optamine, and ethanol, Triacetin, benzyl benzoate, and menthoxy-2-methyl-1,2-propanediol Selected from the group consisting of henon glyceryl acetal (Frescolat® MGA), triacetin, and anethole.

[0371] For example, the following combinations of four-component solvents 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.

[0372] The aforementioned preferred four-component solvent mixtures have proven particularly effective in dissolving the cooling agent or compound according to the present invention, and depending on the solvent or combination of solvents mentioned, they were able to stably maintain the cooling agent in the solution within a wide range of 2% to 50% by weight, preferably 5% to 40% by weight, and more preferably 5% to 20% by weight.

[0373] This has the advantage of being able to present a variable amount of the cooling agent or compound according to the present invention that is suitable for the final formulation, thereby broadening the range of cooling agent mixtures in which the cooling agent and / or compound is dissolved.

[0374] The cooling agent mixture according to the present invention preferably contains, or consists of, a total amount of component (a) and / or component (b) in an amount of 2% to 20% by weight, preferably 2% to 10% by weight, more preferably 5% to 10% by weight, most preferably 5% to 8% by weight, and / or component (c) in an amount of 80% to 98% by weight, preferably 90% to 98% by weight, even more preferably 90% to 95% by weight, most preferably 92% to 95% by weight, provided that components (a) and / or (b) and / or (c) together total 100% by weight.

[0375] This composition of the cooling agent mixture according to the present invention is particularly advantageous because it allows for control over the amount of cooling agent or compound in the final formulation.

[0376] Preferably, the final product, especially in the case of an oral care composition, contains a cooling agent or compound in an amount of about 0.00001% to 50% by weight, preferably 0.0001% to 10% by weight, more preferably 0.001% to 5% by weight, even more preferably 0.005% to 1% by weight or 0.1% to 20% by weight, preferably 0.5% to 15% by weight or 1% to 5% by weight, based on the weight of the final product.

[0377] A suitable cooling agent mixture according to the present invention has, for example, the following composition, or, for example, 5-10% by weight of a cooling agent or compound in 95-90% by weight of benzyl alcohol, - 8 to 10% by weight of a cooling agent or compound in 92 to 90% by weight of benzyl alcohol, or · 1-4% by weight of a cooling agent or compound in 99-96% by weight of triethyl citrate, · 1-3% by weight of a cooling agent or compound in 99-97% by weight of triacetin, or · 3 to 6% by weight of a cooling agent or compound in 97 to 94% by weight of diethyl succinate, or · 5 to 15% by weight of a cooling agent or compound in 95 to 85% by weight of 2-phenylethanol, or 5-10% by weight of a cooling agent or compound in 95-90% by weight of benzyl benzoate, or · 1-3% by weight of a cooling agent or compound in 99-97% by weight of Optamint, or • As component (b), 1 to 4% by weight of a cooling agent or compound in 99 to 96% by weight of other cooling agents as described above, · 2 to 4% by weight of a cooling agent or compound in 98 to 96% by weight of propylene glycol, · 0.5 to 2% by weight of a cooling agent or compound in 95.5 to 98% by weight of ethanol, or · 0.5 to 2% by weight of a cooling agent or compound in 95.5 to 98% by weight of menthyl acetate, or • 1-4% by weight of a cooling agent or compound in 99-96% by weight of peppermint oil, • Consists of 2-5% by weight of a cooling agent or compound in 98-95% by weight of anethole. Both components in the cooling agent mixture (cooling agent or compound and solvent) always total 100% by weight. For example, a suitable cooling agent mixture according to the present invention consists of 5 to 10% by weight of a cooling agent or compound in 95 to 90% by weight of benzyl alcohol, and particularly preferably 8 to 10% by weight of a cooling agent or compound in 92 to 90% by weight of benzyl alcohol.

[0378] Another subject of the present invention is, (d) One, two, three or more cooling agents of general formula (Va) to (VIIIa), or listed in Tables A to D and defined above, or one, two, three or more compounds listed in Tables E and F and defined above, (e) relating to an aromatic preparation comprising or comprising at least one flavoring agent.

[0379] A particular advantage of these mixtures or flavor preparations is that the cooling agent can mask unpleasant taste impressions, such as bitterness or astringency, of flavorings, especially sweeteners, even at low concentrations, while simultaneously providing a strong and efficient cooling effect.

[0380] With respect to component (d), the above applies equally to component (a) of the physiological cooling mixture according to the present invention, which includes, or consists of, one, two, three, or more cooling agents of general formula (Va) to (VIIIa), or listed in one of Tables A to D as defined above, or one, two, three, or more compounds listed in Tables E and F as defined above.

[0381] The flavor preparation according to the present invention includes, as component (e), acetophenone, allyl caproate, alpha-ionone, beta-ionone, anisaldehyde, anisyl acetate, anisyl formate, anethole, benzaldehyde, benzothiazole, benzyl acetate, benzyl alcohol, benzyl benzoate, beta-ionone, butyl butyrate, butyl caproate, butylidene phthalide, carvone, camphene, caryophyllene, cineole, cinnamyl acetate, citral, citronellol, citronellal, citronellyl acetate, cyclohexyl acetate, cymol, dam Scone, Decalactone, Dihydrocoumarin, Dimethyl Anthranilate, Dimethyl Anthranilate, Dodecalactone, Ethoxyethyl Acetate, Ethyl Butyrate, Ethyl Butyrate, Ethyl Caprate, Ethyl Caproate, Ethyl Crotonate, Ethyl Furaneol, Ethyl Guaiacol, Ethyl Isobutyrate, Ethyl Isovalerate, Ethyl Lactate, Ethyl Methylbutyrate, Ethyl Propionate, Eucalyptol, Eugenol, Ethyl Heptylate, 4-(p-Hydroxyphenyl)-2-Butanone, Gamma-Decalactone, Geraniol, Geranyl Acetate, Grapefruit Alcohol Dehyde, methyl dihydrojasmonate (e.g., Hedion®), heliotropin, 2-heptanone, 3-heptanone, 4-heptanone, trans-2-heptenal, cis-4-heptenal, trans-2-hexenal, cis-3-hexenol, trans-2-hexenoic acid, trans-3-hexenoic acid, cis-2-hexenyl acetate, cis-3-hexenyl acetate, cis-3-hexenyl caproate, trans-2-hexenyl caproate, cis-3-hexenyl formate, cis-2-hexyl acetate, cis-3-hexyl acetate, trans acetate 2-Hexyl Formate, 3-Hexyl Formate, para-hydroxybenzylacetone, isoamyl alcohol, isoamyl isovalerate, isobutyl butyrate, isobutyraldehyde, isoeugenol methyl ether, isopropylmethylthiazole, lauric acid, levulinic acid, linalool, linalool oxide, linalyl acetate, menthol, mentfuran, methyl anthranilate, methylbutanol, methylbutyric acid, 2-methylbutyl acetate, methyl caproate, methyl cinnamate, 5-methylfurfural, 3,2,2-methylcyclopentenolone, 6,5,2-Methylheptenone, methyl dihydrojasmonate, methyl jasmonate, 2-methylmethylbutyrate, 2-methyl-2-pentenolic acid, methyl thiobutyrate, 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-octanol, 1-Octyl Acetate, 3-Octyl Acetate, Palmitic Acid, Paraaldehyde, Phellandrene, Pentanedione, Phenylethyl Acetate, Phenylethyl Alcohol, Phenylethyl Alcohol, Phenylethyl Isovalerate, Piperonal, Propionaldehyde, Propyl Butyrate, Pulegone, Pulegol, Sinensal, Sulfurol, Terpinene, Terpineol, Terpinolene, 8,3-Thiomentanone, 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), homoflonol (=2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone and 5-ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and maltol derivatives Body (preferably ethyl maltol), coumarin and coumarin derivatives, gamma-lactone (preferably gamma-undecalactone, gamma-nonalactone, gamma-decalactone), delta-lactone (preferably 4-methyl-delta-decalactone, massoialactone, delta-decalactone, 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, 3-Methyl Butyrate, 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-Heptene -1-R and phenylacetaldehyde, 2-methyl-3-(methylthio)furan, 2-methyl-3-frantiol, bis(2-methyl-3-furyl)disulfide, furfuryl mercaptan, methional, 2-acetyl-2-thiazoline, 3-mercapto-2-pentanone, 2,5-dimethyl-3-frantiol, 2,4,5-trimethylthiazole, 2-acetylthiazole, 2,4-dimethyl-5-ethylthiazole, 2-acetyl-1-pyrroline, 2-methyl-3-ethylpyridine 2-ethyl-3,5-dimethylpyrazine, 2-ethyl-3,6-dimethylpyrazine, 2,3-diethyl-5-methylpyrazine, 3-isopropyl-2-methoxypyrazine, 3-isopropyl-2-methoxypyrazine, 2-acetylpyrazine, 2-pentylpyridine, (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-hydrox The product comprises cy-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, and one or more flavoring agents selected from the group consisting of stereoisomers, enantiomers, positional isomers, diastereomers, cis / trans isomers, and epimers of these substances (not explicitly described herein).

[0382] Within the scope of the present invention, artificial and natural sweeteners and sweetener enhancers are also particularly suitable as flavoring agents for component (e). These are, • Sugar alcohols (e.g., erythritol, treitol, arabitol, ribitol, xylitol, sorbitol, mannitol, dulcitol, lactitol), • Proteins (e.g., miraculin, monellin, thaumatin, curculin, blazein), • Artificial sweeteners (e.g., magap, sodium cyclamate, acesulfame K, neohesperidin dihydrochalcone, sodium saccharin, aspartame, super aspartame, neotame, alitame, sucralose, stevioside, rebaudioside, ruguzunam, kaleramm, sucrononate, sucrooctate, monatin, phenyrodulcin), • Sweet amino acids (e.g., glycine, D-leucine, D-threonine, D-asparagine, D-phenylalanine, D-tryptophan, L-proline), Hernandulcin, dihydrochalcone glycosides, glycyrrhizin, glycyrrhizic acid, their derivatives and salts, sweet low molecular weight substances such as licorice (Glycyrrhiza glabra ssp.) extract, Lippia dulcis extract, Momordica ssp. extract, and / or The following may be selected from the group consisting of Momordica grosvenori [Luo Han Guo] and mogrosides obtained therefrom, Hydrangea dulcis or Stevia ssp. (e.g., Stevia rebaudiana) extracts or steviosides obtained therefrom.

[0383] Component (e) contains at least one of the flavor substances listed above.

[0384] The flavor preparation according to the present invention may contain component (d) and component (e) in a weight ratio of about 1:99 to about 99:1, preferably 10:90 to about 90:10, more preferably about 25:75 to about 75:25, and particularly about 40:60 to 60:40.

[0385] In a more preferred variant, one or more cooling agents or one or more compounds or a mixture of cooling agents or fragrance preparations exist in encapsulated form. This is of particular interest, for example, when capsules containing one or more cooling agents or one or more compounds are applied to the surface of a textile product as an ingredient in a fabric softener or post-laundry treatment, or when a finishing agent is applied to tights, for example, by mandatory application using capsules containing one or more cooling agents.

[0386] A capsule is understood to be a spherical aggregate containing at least one solid or liquid core surrounded by at least one continuous shell. During encapsulation, one or more cooling agents or cooling agent mixtures or fragrance preparations are encapsulated using a coating / casing material so as to exist in the form of macrocapsules having a diameter of about 0.1 to about 5 mm or microcapsules having a diameter of about 0.0001 to about 0.1 mm.

[0387] As a result, further embodiments of the present invention also relate to encapsulated physiological cooling agents or mixtures of physiological cooling agents or flavor preparations.

[0388] Suitable coating materials include, for example, starch, gelatin, gum arabic, agar, ghatti gum, gellan gum, modified and unmodified cellulose, pullulan, curdlan, carrageenan, alginic acid, alginates, pectin, inulin, xanthan gum, and mixtures of two or more of these substances, including their decomposition products and chemically or physically produced derivatives (especially dextrin and maltodextrin).

[0389] The two main properties of a new cooling agent, new compound, or new cooling agent mixture are, on the one hand, to modulate the TRPM8 receptor as an antagonist or agonist, thereby inducing a physiological response, namely a strong and efficient cooling effect on the skin or mucous membranes; and on the other hand, to reduce or mask unpleasant tastes. However, the main emphasis is placed on their ability to produce a strong and efficient cooling effect even when used in small amounts.

[0390] Accordingly, another aspect of the present invention preferably relates to the use of the physiological cooling agent according to the present invention, or a compound according to the present invention, or a mixture of physiological cooling agents according to the present invention, as a modulator for in vivo and / or in vitro modulation of the cold menthol receptor TRPM8, in particular as a TRPM8 receptor agonist or TRPM8 receptor antagonist.

[0391] In the use according to the present invention, the TRPM8 receptor is brought into contact with at least one cooling agent or physiological cooling agent mixture according to the present invention, which in a cell activity test using cells recombinantly expressing the human TRPM8 receptor, Ca 2+ It regulates the permeability of these cells to ions.

[0392] A suitable modulator can act as either an antagonist or an agonist, and more specifically, as an agonist only, or as both an antagonist and an agonist. In particular, the agonist or antagonist effect may arise depending on the respective selected modulator concentration.

[0393] "Agonists" mediate the activation of TRPM8 receptors, that is, Ca2+ in cryosensitive neurons. 2+ It is a substance that induces the influx of ions and, therefore, mediates the sensation of cold.

[0394] On the other hand, "antagonists" are compounds that can counteract this activation of the TRPM8 receptor.

[0395] The modulators according to the present invention, i.e., the physiological cooling agents according to the present invention, or the compounds or cooling agent mixtures according to the present invention, can exert their effects by specifically or nonspecifically binding to TRPM8 receptor molecules, reversibly or irreversibly. Typically, the binding is non-covalent, mediated by ionic and / or nonionic interactions, such as hydrophobic interactions, with the receptor molecule. The term "specific" encompasses both exclusive interactions with one or more different TRPM8 receptor molecules (such as TRPM8 molecules of different origins or different isoforms). The term "nonspecific," on the other hand, refers to the interaction of the modulator with several different receptor molecules of different functions and / or sequences, thereby allowing for the observation of desired agonist and / or antagonist modulation of the TRPM8 receptor (as described above).

[0396] In use according to the present invention, preferably, in the mutants described above as preferred, the modulator is cellular Ca 2+ It acts operatively or antagonistically on ion permeability.

[0397] A variant of the use according to the present invention in which the modulator is a TRPM8 receptor agonist is particularly preferred.

[0398] Due to its physiological properties, namely the induction of a cooling effect on the skin or mucous membrane, a further aspect of the present invention relates to the use of a cooling agent, a compound, or a mixture of cooling agents according to the present invention for producing a physiological cooling effect on the skin or mucous membrane of a human or animal.

[0399] Alternatively, the cooling agent according to the present invention, or the compound according to the present invention, or a mixture of the cooling agent according to the present invention may be used to induce a cooling effect by packaging containing the physiological cooling agent, the compound according to the present invention, or a mixture of the physiological cooling agent according to the present invention, or by textile products containing the physiological cooling agent, the compound according to the present invention, or a mixture of the physiological cooling agent according to the present invention.

[0400] In further variants, the cooling agent according to the present invention, or the compound according to the present invention, or the cooling agent mixture according to the present invention, or the fragrance preparation according to the present invention, are used as flavorings to impart fragrance to the preparation.

[0401] In further variations, the cooling agents, compounds, mixtures, or aromatic preparations according to the present invention are used to improve the taste profile of flavors. This allows for the enhancement of the taste characteristics of the aromas or the emphasis on individual aromas.

[0402] Due to its additional properties, namely the reduction or masking of unpleasant taste characteristics such as bitterness or astringency, further aspects of the present invention relate to the use of physiological cooling agents, compounds, or cooling agent mixtures according to the present invention for masking bitter substances. This allows for the reduction or masking of known taste disadvantages of flavors, particularly sweeteners such as stevioside. In particular, irritating, bitter, or metallic aftertastes are effectively reduced or masked even when added in small amounts.

[0403] The cooling agents, compounds, physiological cooling agent mixtures, or flavor preparations according to the present invention have a wide range of applications, particularly in foods, nutritional supplements, cosmetics or pharmaceuticals, animal feed, textile products, packaging, or tobacco products.

[0404] In particular, the physiological cooling agents, compounds, mixtures of cooling agents, or flavor preparations according to the present invention are used in the manufacture of foods, nutritional supplements, cosmetics or pharmaceuticals, animal feed, textile products, packaging, or tobacco products due to their cooling properties and / or taste-enhancing properties.

[0405] Therefore, a further subject of the present invention is the use of one or more cooling agents, one or more compounds, a mixture of cooling agents, or a flavoring preparation according to the present invention for the production of food, nutritional supplements, cosmetics or pharmaceuticals, animal feed, textile products, packaging, or tobacco products.

[0406] Due to the advantageous properties described herein, the cooling agents according to the present invention, represented and defined by general formulas (Va) to (VIIIa), or enumerated and defined above in one of Tables A to D, or the compounds according to the present invention enumerated and defined above in Tables E and F, are used in the applications of the present invention, namely as modulators, for producing or inducing a physiological cooling effect on the skin or mucous membranes of humans or animals, for improving the taste characteristics of flavorings, for reducing or masking unpleasant tastes, for the manufacture of foods, nutritional supplements, cosmetics or pharmaceuticals, animal feed, textile products, packaging or tobacco products, or for use as agents selected from the group of compounds shown in Table 3 or Table 4, as described in detail herein.

[0407] [Table 16-1]

[0408] [Table 16-2]

[0409] [Table 16-3]

[0410] [Table 16-4]

[0411] [Table 16-5]

[0412] [Table 16-6]

[0413] [Table 16-7]

[0414] [Table 17-1]

[0415] [Table 17-2]

[0416] [Table 17-3]

[0417] [Table 17-4]

[0418] Of the above 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, as well as the use of compounds A-01, A-02, A-03, A-05, A-09, A-10, A-12, and A-69, is preferred due to their remarkable TRPM8 activation, their EC50 values, and their cold sensitivity.

[0419] However, the use of physiological cooling agents or one of the 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, and physiological cooling agents or compound A The use of one of the following is most preferred due to their prominent TRPM8 activation, their EC50 value, and their cold sensitivity.

[0420] In sensory evaluation, i.e., tasting of each sample, the (R) enantiomer was found to have a rapidly starting, strong cooling effect. Panelists rated the cooling effect of compound A-02 at a usage level of 5 ppm with a score of 5.7. Therefore, considering the amount of compound used, the sensory-evaluated cooling intensity was equivalent to that determined for the cooling substance WS-3 as a reference at a concentration six times higher (amount used: 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 was delayed, slowly accumulated, and lasted for a long time.

[0421] Accordingly, in further embodiments, the present invention also includes foods, nutritional supplements, cosmetics or pharmaceuticals, animal feed, textile products, packaging or tobacco products, comprising a physiological cooling agent according to the present invention, a mixture of physiological cooling agents according to the present invention, or an aromatic preparation according to the present invention.

[0422] The content of one or more cooling agents or one or more compounds depends on the type and use of the product as described above, and is preferably about 0.1 ppm to 10% by weight, preferably 1% to 10% by weight, based on the total weight of the final product. For oral care applications, such as toothpaste or mouthwash, the content is one or more cooling agents in a concentration of 0.1 ppm to 500 ppm.

[0423] A broad concentration range typically used to provide a desired degree of sensory 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.

[0424] Preferably, the food is, for example, baked food, such as bread, dried biscuits, cakes, other pastries, confectionery (such as chocolate, chocolate bar products, other bar products, fruit gum, hard and soft caramels, chewing gum), alcohol or non-alcoholic beverages (such as coffee, tea, iced tea, wine, wine-based beverages, beer, beer-based beverages, liqueurs, schnapps, brandy, fruit-based lemonade (including carbonated drinks), isotonic beverages (including carbonated drinks), soft drinks (including carbonated drinks), Nectar, spritzer, fruit and vegetable juices, fruit or vegetable juice preparations, instant beverages (e.g., instant cocoa drinks, instant tea drinks, instant coffee drinks, instant fruit drinks), meat products (e.g., ham, fresh sausages or raw sausage preparations, seasoned or marinated fresh or preserved processed meat products), eggs or egg products (dried eggs, egg whites, egg yolks), cereal products (e.g., breakfast cereals, muesli bars, pre-cooked rice products), dairy products (e.g., milk drinks, buttermilk drinks, milk ice cream, yolks) (Yogurt, kefir, cream cheese, soft cheese, hard cheese, dried milk powder, whey, whey beverages, buttermilk, partially or fully hydrolyzed milk protein products), products made from soy protein or soy fractions (e.g., soy milk and products made therefrom, fruit beverages containing soy protein, preparations containing soy lecithin, fermented products such as tofu or tempeh or products made therefrom), products from other plant protein sources, e.g., oat protein beverages, fruit preparations (e.g., jams, fruit ice cream, fruit sauces, fruit This includes fillings, vegetable preparations (e.g., ketchup, sauces, dried vegetables, frozen vegetables, cooked vegetables, boiled vegetables), snack foods (e.g., baked or fried potato chips, or potato dough products, corn or peanut-based extruded products), fats and oil-based products or emulsions thereof (e.g., mayonnaise, remoulade, dressings), other cooked foods and soups (e.g., dried soups, instant soups, prepared soups), spices, seasoning mixes, and in particular, seasonings used in snacks.

[0425] In addition to conventional food ingredients, the above food contains at least one effective amount, i.e., a cooling amount, of at least one cooling agent according to the present invention, or a mixture of cooling agents according to the present invention, or a flavor preparation according to the present invention.

[0426] The content of the cooling agent, compound, cooling agent mixture, or flavoring preparation according to the present invention in these preparations is preferably about 0.1% to about 10% by weight, and particularly about 1% to 2% by weight, based on the total weight of the finished preparation.

[0427] Products according to the present invention, such as foods, nutritional supplements, cosmetics or pharmaceuticals, animal feed, textile products, packaging, or tobacco products, can be manufactured using suitable excipients. Suitable excipients include, but are not limited to, emulsifiers, thickeners, food acids, acidity regulators, vitamins, antioxidants, flavor enhancers, active ingredients for masking unpleasant tastes, and food colorants.

[0428] In particular, other common additives or auxiliary substances, such as flavorings or active ingredients for masking unpleasant taste impressions, can be added to the above-mentioned product according to the present invention.

[0429] Flavorings: Preferred flavorings are those that produce a sweet scent, and additional flavorings that produce a sweet scent are preferably 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), homoflonol (2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone and 5-ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and derivatives (e.g., ethylmaltol), coumarin and derivatives, gamma-lactones (e.g., gamma-undecalactone, gamma-nonalactone), delta-lactones (e.g., 4-methyl-delta-lactone, massoialactone, deltadecalactone, tuberolactone), methyl sorbate, divanillin, 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)furanone, 2-hydroxy-3-methyl-2-cyclo Pentenone, 3-hydroxy-4,5-dimethyl-2(5H)-furanone, fruit esters and fruit lactones (e.g., n-butyl acetate, isoamyl acetate, ethyl propionate, ethyl butyrate, n-butyl butyrate, isoamyl butyrate, 3-methyl-butyrate, ethyl n-hexanoate, allyl n-hexanoate, n-butyl n-hexanoate, ethyl n-octanoate, ethyl 3-methyl-3-phenylglycidate, ethyl 2-trans-4-sulfate) Selected from the group consisting of sudecadinoate, 4-(p-hydroxyphenyl)-2-butanone, 1,1-dimethoxy-2,2,5-trimethyl-4-hexane, 2,6-dimethyl-5-heptene-1-arl, 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, vanillylmandelic acid, and phenylacetaldehyde.

[0430] Active ingredients for masking unpleasant tastes: Furthermore, oral preparations may also contain other substances that help mask bitter and / or astringent tastes. These additional flavor modifiers include, for example, the following list: nucleotides (e.g., adenosine 5'-phosphate, cytidine 5'-phosphate) or physiologically acceptable salts thereof, lactisol, sodium salts (e.g., sodium chloride, sodium lactate, sodium citrate, sodium acetate, sodium gluconate), hydroxyflavanones, preferably eriodictiol, stervin (eriodictiol-7-methyl ether), homoeriodictiol, and their sodium, potassium, calcium, magnesium, or zinc salts (especially those described in European Patent No. 1258200(A2)), hydroxybenzoic acid amides, preferably 2,4-dihydroxybenzoic acid vanillylamide, 2,4-dihydroxybenzoic acid N-(4-hydroxy-3-methoxybenzyl)amide, 2,4,6-trihydroxybenzoic acid N-(4-hydroxy-3-methoxybenzyl)amide, 2-hydroxybenzoic acid Acid N-4-(-hydroxy-3-methoxybenzyl)amide, 4-hydroxybenzoic acid N-(4-hydroxy-3-methoxybenzyl)amide, 2,4-dihydroxybenzoic acid N-(4-hydroxy-3-methoxybenzyl)amide monosodium salt, 2,4-dihydroxybenzoic acid N-2-(4-hydroxy-3-methoxybenzyl)ethylamide, 2,4-dihydroxybenzoic acid N-(4-hydroxy-3-ethoxybenzyl)amide, 2,4-dihydroxy Roxybenzoic acid N-(3,4-dihydroxybenzyl)amide, and 2-hydroxy-5-methoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]amide, 4-hydroxybenzoic acid vanillylamide (especially as described in International Publication No. 2006 / 024587), hydroxydeoxybenzoin, preferably 2-(4-hydroxy-3-methoxyphenyl)-1-(2,4,6-trihydroxyphenyl)ethanone, 1-(2,Hydroxyphenyl alkanedions such as 4-dihydroxyphenyl)-2-(4-hydroxy-3-methoxyphenyl)-ethanone and 1-(2-hydroxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxyphenyl)ethanone (especially those described in International Publication No. 2006 / 106023), gingerdione-[2], gingerdione-[3], gingerdione-[4], dehydrogingerdione-[2], dehydrogingerdione-[3], dehydrogingerdione-[4] (especially those described in International Publication No. 2007 / 003527), diacetyl trimers (especially those described in International Publication No. 2006 / 058893), gamma-aminobutyric acid (especially This includes, in particular, those described in International Publication No. 2005 / 096841, divanillin (especially those described in International Publication No. 2004 / 078302), and 4-hydroxydihydrochalcone (preferably those described in U.S. Patent Application Publication No. 2008 / 0227867(A1)), in particular phloretin and dabidigenin, amino acids, or mixtures of whey protein and lecithin, hesperetin as disclosed in International Publication No. 2007 / 014879, 4-hydroxydihydrochalcone as disclosed in International Publication No. 2007 / 107596, or propenylphenyl glycoside (chavicol glycoside) as described in European Patent No. 1955601(A1), or Rubus Selected from extracts from suavissimus, extracts from Hydrangea macrophylla as described in European Patent No. 2298084(A1), perithrin and inducing aromatic compositions as described in European Patent No. 2008530(A1), umami compounds as described in International Publication No. 2008 / 046895(A1) and European Patent No. 1989944(A1), umami compounds as described in European Patent No. 2064959(A1) and No. 2135516(A1), vanillyl lignans, enterodiols, and N-decadienoyl amino acids, and mixtures thereof.

[0431] A further subject of the present invention relates to cosmetics or pharmaceuticals containing one or more cooling agents according to the present invention, one or more compounds according to the present invention, a mixture of cooling agents according to the present invention, or an aromatic preparation according to the present invention.

[0432] The agents according to the present invention may be, in particular, skin cosmetics, hair cosmetics, dermatological agents, sanitary agents, or pharmaceutical agents. In particular, the active ingredients of the present invention, especially those having a cooling effect, may be used in skin and / or hair cosmetics, or as oral care products.

[0433] The hair or skin care products or preparations according to the present invention are preferably in the form of emulsions, dispersions, suspensions, aqueous surfactant preparations, milks, lotions, creams, balms, ointments, gels, granules, powders, stick preparations such as lipsticks, foams, aerosols, or sprays. Such formulations are well suited for topical preparations. Oil-in-water emulsions and water-in-oil emulsions or microemulsions are preferred as emulsions. In principle, hair or skin cosmetics are used for application to the skin (topically) or hair. A “topical preparation” is understood to be a preparation suitable for applying active ingredients to the skin in a fine distribution, for example, in a form that can be absorbed through the skin. For this purpose, 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 are preferred. According to one embodiment of the cosmetic preparation according to the present invention, it contains a carrier. Preferred carriers are water, gas, aqueous liquid, oil, gel, emulsion or microemulsion, dispersion, or mixture thereof. The aforementioned carriers have good skin tolerance. Aqueous gels, emulsions, or microemulsions are particularly advantageous for topical preparations.

[0434] The teachings of the present invention also encompass the use of the active ingredients described herein for medical purposes, particularly in pharmaceuticals for treating individuals, preferably mammals, in particular humans, farm animals, or livestock. The active ingredients are administered in the form of a pharmaceutical composition comprising at least one active ingredient according to the present invention, and optionally further active ingredients, together with pharmaceutically acceptable excipients. These compositions may be administered, for example, orally, rectally, percutaneously, subcutaneously, intravenously, intramuscularly, or intranasally.

[0435] Examples of suitable pharmaceutical formulations or compositions include 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 ointments, and liquid dosage forms such as solutions, emulsions, especially oil-in-water emulsions, suspensions, for example, lotions, injections and infusion preparations, eye drops and ear drops. Implantable delivery devices can also be used to administer the inhibitor according to the present invention. Separately, liposomes, microspheres, or polymer matrices can also be used. Pharmaceuticals such as cold medicines, wound ointments, or wound sprays are possible options. In particular, if these contain active ingredients that have an unpleasant taste of their own, it is also possible to incorporate the substance into an ointment or tablet.

[0436] Accordingly, another subject of the present invention includes the cooling agents, compounds, or mixtures of cooling agents according to the present invention, as pharmaceuticals, particularly for use in relieving pain and inflammation of the skin and mucous membranes. Due to their cooling properties, the cooling agents according to the present invention are particularly suitable for preventing, treating, or relieving symptoms of cough, cold, inflammation, sore throat, or hoarseness.

[0437] In addition, the substances and preparations described herein are suitable for treating inflammatory conditions of the skin, mucous membranes, and joints due to their efficient cooling effect.

[0438] Due to their ability to modulate the TRPM8 receptor, which is upregulated in cancers such as prostate cancer, the pharmaceutical preparations according to the present invention are also used, preferably in oncology, preferably in the treatment of prostate or bladder cancer, or in the treatment of bladder weakness. The corresponding proteins in cells are encoded by the corresponding genes in the cell nucleus. The reading (transcription) of genes in the nucleus leads to the development of messenger RNA (mRNA), which is then "translated" (translated) into proteins in the cell at ribosomes. The entirety of both processes is often referred to as gene expression.

[0439] However, astringent, bitter, and / or metallic tastes are found not only in flavorings and sweeteners as described above, but also in connection with many active pharmaceutical ingredients, which makes them difficult to ingest, especially for children. Typical examples of such active pharmaceutical ingredients are listed below: aspirin, minoxidil, erythromycin, phenistil, betamethasone, ibuprofen, ketoprofen, diclofenac, metronidazole, acyclovir, imiquimod, terbafine, cyclopirox olamine, paracetamol, and other non-steroidal anti-inflammatory drugs (NSAIDs), as well as mixtures thereof.

[0440] Accordingly, the present invention also includes agents containing one or more cooling agents according to the present invention, or a mixture of cooling agents according to the present invention, or an aromatic preparation according to the present invention, in combination with at least one other pharmaceutically active ingredient selected from the group consisting of aspirin, minoxidil, erythromycin, phenistil, betamethasone, ibuprofen, ketoprofen, diclofenac, metronidazole, acyclovir, imiquimod, terbafine, cyclopirox olamine, paracetamol, and mixtures thereof.

[0441] In human trials, the cooling agents or mixtures of cooling agents according to the present invention have been shown to enhance the pain-relieving properties of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly ibuprofen and ketoprofen, beyond their cooling effect, which was also unexpected by those skilled in the art. Therefore, the present invention also relates, in particular, to combinations with nonsteroidal anti-inflammatory drug (NSAID) type pharmaceutically active ingredients.

[0442] Therefore, such pharmaceutical combinations are particularly advantageous for use in the treatment of inflammatory conditions of the skin and mucous membranes as well as the joints.

[0443] The drug may contain the cooling agent according to the present invention, or the compound according to the present invention, or a mixture of cooling agents according to the present invention, and a pharmaceutically active ingredient in a weight ratio of about 1:99 to about 10:90, particularly 2:98 to about 5:95.

[0444] The physiological cooling effect is also utilized, for example, in the formulation of wound and burn ointments and preparations for insect bites.

[0445] In the manufacture of cosmetics or pharmaceuticals according to the present invention, the cooling agent, compound, or mixture of cooling agents according to the present invention is usually mixed with or diluted with an excipient. The excipient may be a solid, semi-solid, or liquid material that functions as a vehicle, carrier, or medium for the active ingredient. The active ingredient content (of one or more cooling agents of the present invention contained together) can vary over a wide range, and is about 0.05 ppm to 10% by weight, preferably 0.1 ppm to 10% by weight, based on the total weight of the preparation.

[0446] Suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, 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, e.g., animal fats, magnesium stearate, and mineral oils; wetting agents, emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; antioxidants; anti-irritants; chelating agents; coating aids; emulsion stabilizers; film-forming agents; gel-forming agents; odor masking agents; flavor modifiers; resins; hydrophilic colloids; solvents; solubilizers; neutralizing agents; penetration enhancers; dyes; quaternary ammonium compounds; humectants and superfatting agents; ointments, creams, or oil bases; silicone derivatives; diffusion aids; stabilizers; sterilizing agents; suppository bases; binders; fillers; lubricants; disintegrants; or tablet excipients such as coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers; and white oils. The design of such preparations is based on expertise and is described in sufficient detail in the relevant technical literature.

[0447] In addition to conventional additives or excipients, preparations according to the present invention may also contain cosmetically and / or dermatologically and / or pharmacologically active ingredients. Not limited examples of suitable additional active ingredients include cosmetically and / or dermatologically active ingredients, antimicrobial agents, surfactants (anionic surfactants, nonionic surfactants, cationic surfactants, amphoteric or zwitterionic surfactants), oils, emulsifiers, fats and waxes, pearlescent waxes, consistency and thickeners, superfatting agents and stabilizers, polymers, silicone compounds, ultraviolet filters, pigments, especially photoprotective pigments, humectants, bioactive ingredients and antioxidants, deodorants and antibacterial inhibitors, enzyme inhibitors, odor absorbers, antiperspirants, film-forming agents, anti-dandruff agents, leavening agents, insect repellents, hydrotropes, preservatives, fragrances and oils, and colorants.

[0448] Preferred preparations according to the present invention are selected from the group of products for the treatment, protection, care, and cleansing of skin and / or hair, or as makeup products, either as leave-in or rinse-off products.

[0449] The formulations include, for example, depending on the manufacturing method and ingredients, dispersions, suspensions, creams, lotions, or emulsions, gels (including hydrogels, e.g., hydrodispersion gels, oleogels), sprays (e.g., pump sprays or sprays containing propellants), foams or impregnating solutions for cosmetic wipes, soaps, cleansing solutions, shower and bath preparations, bath products (capsules, oils, tablets, salts, bath salts, soaps, etc.), foaming preparations, emulsions, ointments, pastes, gels (as described above), oils, balms, serums, powders (e.g., face powders, body powders), masks, sticks, roll-on sticks, aerosols (foaming, non-foaming, or post-foaming), deodorants and / or antiperspirants, and other skin care products, mouthwashes and mouthwashes, insect repellents, etc. This includes sunscreens, after-sun preparations, shaving preparations, aftershave balms, pre- and aftershave lotions, depilatory agents, shampoos (including 2-in-1 shampoos, anti-dandruff shampoos, baby shampoos, shampoos for dry scalps, and concentrated shampoos), conditioners, hair tonics, hair lotions, hair rinses, styling creams, pomades, perm and setting lotions, hair sprays, styling aids (e.g., gels or waxes), hair straighteners (detangle removers, hair straighteners), hair dyes such as temporary hair dyes, semi-permanent hair dyes, and permanent hair dyes, hair care products such as hair conditioners and hair mousses, eye care products, makeup, makeup removers, or baby products.

[0450] The formulations according to the present invention are particularly preferred in the form of emulsions, especially W / O, O / W, W / O / W, O / W / O emulsions, PIT emulsions, for example, Pickering emulsions, emulsions with low oil content, micro or nanoemulsions, gels (including hydrogels, hydrodispersion gels, and oleogels), or solutions.

[0451] The total proportion of excipients and additives may be 1% to 50% by weight, preferably 5% to 40% by weight, based on the final preparation. The drug can be manufactured using conventional low-temperature or high-temperature processes, preferably using a phase reversal temperature method.

[0452] The present invention also includes an oral care product containing one or more cooling agents according to the present invention, one or more compounds according to the present invention, a mixture of cooling agents according to the present invention, or an aromatic preparation according to the present invention.

[0453] The oral hygiene products according to the present invention can be formulated in a manner that is known in itself, for example, as toothpaste, tooth cream, tooth gel, toothpaste, tooth rinse solution, tooth rinse foam, aqueous or aqueous-alcoholic oral care products (mouthwash), mouthwash as a 2-in-1 product, lozenges, mouth spray, dental floss, and dental chewing gum.

[0454] Toothpaste or tooth cream is generally understood to be a gel-like or paste-like preparation comprising water, thickeners, humectants, abrasives or detergents, surfactants, sweeteners, flavorings, deodorants, and active ingredients for oral and dental diseases. All conventional detergents, such as chalk, dicalcium phosphate, insoluble sodium metaphosphate, aluminum silicate, calcium pyrophosphate, micronized synthetic resins, silicic acid, aluminum oxide, and aluminum oxide trihydrate, can be used in the toothpaste of the present invention.

[0455] Preferred cleaning agents for toothpaste according to the present invention are, in particular, 15 to 40% by weight of micronized xerogelsilicic acid, hydrogelsilicic acid, precipitated silicic acid, aluminum oxide trihydrate, and micronized alpha-aluminum oxide, or mixtures thereof, of the toothpaste. Low molecular weight polyethylene glycol, glycerin, sorbitol, or mixtures thereof, in amounts up to 50% by weight, are mainly preferred as humectants. Among known thickeners, thickening micronized gelsilicic acid, as well as plant gums such as carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl guar, hydroxyethyl starch, polyvinylpyrrolidone, high molecular weight polyethylene glycol, tragacanth, agar, carrageenan, gum arabic, xanthan gum, and hydrophilic colloids such as carboxyvinyl polymers (e.g., Carbopol® type), are preferred. In addition to mixtures of menthofuran and menthol compounds, oral and dental care products may contain surfactants, preferably anionic and nonionic highly foaming surfactants such as those described above, and may particularly contain alkyl ether sulfates, alkyl polyglucosides, and mixtures thereof.

[0456] Other common toothpaste additives are, Preservatives and antimicrobial substances such as p-hydroxybenzoate methyl, ethyl or propyl esters, sodium sorbate, sodium benzoate, bromochlorophene, phenylsalicylate, and thymol. • Anti-calculus agents, such as 1-hydroxyethane-1,1-diphosphonic acid, 1-phosphonopropane-1,2,3-tricarboxylic acid, and other organophosphate esters, such as those known from U.S. Patent No. 3,488,419, German Patent No. 2224430(A1) and German Patent No. 2343196(A1). Other caries inhibitors such as sodium fluoride, sodium monofluorophosphate, and tin fluoride, Sodium saccharin, sodium cyclamate, sucrose, lactose, maltose, fructose, or Apartam® (L-aspartyl-L-phenylalanine methyl ester), stevia extract or their sweetening components, especially sweeteners such as rebaudioside. • Additional flavorings, such as eucalyptus oil, anise oil, fennel oil, caraway oil, methyl acetate, cinnamaldehyde, anethole, vanillin, thymol, and mixtures thereof and other natural and synthetic flavorings. • Pigments such as titanium dioxide, • Coloring agents, • Primary, secondary, or tertiary alkaline phosphates, or buffering substances such as citrate / sodium citrate, • These are wound-healing and anti-inflammatory substances such as allantoin, urea, azulene, chamomile active ingredients, and acetylsalicylic acid derivatives.

[0457] Hydrotropes such as ethanol, isopropyl alcohol, or polyols can also be used to improve flow properties, and these substances largely correspond to the carriers described above. Polyols suitable for this purpose preferably have 2 to 15 carbon atoms and at least 2 hydroxyl groups. Polyols may contain additional functional groups, in particular amino groups, or may be modified with nitrogen.

[0458] Suitable preservatives include, for example, phenoxyethanol, formaldehyde solution, parabens, pentanediol, or sorbic acid, as well as silver complexes known as Surfacine®, and other suitable classes of substances known to those skilled in the art.

[0459] Aromatic oils are as already defined above. Suitable fragrances include peppermint oil, spearmint oil, anise oil, star anise oil, caraway oil, eucalyptus oil, fennel oil, lemon oil, wintergreen oil, clove oil, and menthol.

[0460] A preferred form of the cosmetic is a toothpaste in the form of an aqueous paste-like dispersion containing an abrasive, a humectant, a viscosity modifier, and optionally other conventional ingredients, as well as a mixture of menthofuran and menthol compounds in an amount of 0.5 to 2% by weight.

[0461] In mouthwashes, various grades of essential oils, emulsifiers, astringent and skin-conditioning drug extracts, tartar inhibitors, antibacterial additives, and flavor modifiers can be readily combined with aqueous or alcoholic solutions. Another preferred embodiment of the present invention is a mouthwash in the form of an aqueous or aqueous-alcoholic solution containing a mixture of menthofuran and a menthol compound in an amount of 0.5 to 2% by weight. In mouthwashes that are diluted before use, sufficient effects can be achieved at higher concentrations according to the intended dilution ratio.

[0462] The oral care preparation according to the present invention contains, based on the total weight of the composition, preferably 0.1 ppm to 1% by weight, preferably 1 ppm to 0.2% by weight, at least one active ingredient according to the present invention, i.e., a cooling agent, or a mixture of active ingredients, i.e., a mixture of cooling agents, or an aromatic preparation.

[0463] The total content of one or more active ingredients according to the present invention, or the cooling agent mixture or flavor preparation according to the present invention, in a ready-to-use mouthwash is preferably 0.01 to 1% by weight, more preferably 0.05 to 0.5% by weight, and has a particularly preferred content of 0.1 to 0.3% by weight, based on the total mouthwash.

[0464] In the mouthwash concentrate, the total content of one or more active ingredients according to the present invention, or the cooling agent mixture or flavor preparation according to the present invention, is 0.1 to 15% by weight, preferably 0.5 to 8% by weight, and particularly preferably 1 to 5% by weight, in each case based on the total mouthwash concentrate.

[0465] In toothpaste, the total content of one or more active ingredients according to the present invention, or the cooling agent mixture or flavor preparation according to the present invention, is 0.1 to 5% by weight, preferably 0.5 to 2% by weight, and particularly preferably 0.8 to 1.5% by weight, in each case based on the total amount of toothpaste.

[0466] The present invention also includes chewing gum containing one or more cooling agents according to the present invention, a mixture of cooling agents according to the present invention, or a flavor preparation according to the present invention.

[0467] Chewing gum compositions typically contain water-insoluble and water-soluble components. The water-insoluble base, also called the "gum base," usually comprises natural or synthetic elastomers, resins, fats and oils, plasticizers, fillers, colorants, and optionally waxes. The proportion of the base in the total composition is usually 5 to 95% by weight, preferably 10 to 50% by weight, and particularly 20 to 35% by weight. In a typical embodiment of the present invention, the base comprises 20 to 60% by weight of synthetic elastomer, 0 to 30% by weight of natural elastomer, 5 to 55% by weight of plasticizer, 4 to 35% by weight of filler, and small amounts of additives such as colorants and antioxidants, provided that they are water-soluble and present in small amounts at most.

[0468] Suitable synthetic elastomers include, for example, polyisobutylene, isobutylene-isoprene copolymer (butyl elastomer), styrene-butadiene copolymer (styrene:butadiene ratio, e.g., 1:3 to 3:1) having an average molecular weight (by GPC) of 10,000 to 100,000, preferably 50,000 to 80,000, polyvinyl acetate, polyisoprene, polyethylene, vinyl acetate-vinyl laurate copolymer, and mixtures thereof, having an average molecular weight (by GPC) of 2,000 to 90,000, preferably 10,000 to 65,000. Examples of suitable natural elastomers include rubbers such as smoked latex or liquid latex or guayule, as well as natural gum substances such as Jelutong, Reticaspi, Perillo, Solva, Massaranduba Barata, Massaranduba Chocolate, Nispero, Rosin Dimba, Chicle, Guttahan 1 Can, and mixtures thereof. The selection of synthetic and natural elastomers and their mixing ratios primarily depends on whether the chewing gum is intended for use in making balloons ("bubble gum"). Elastomer mixtures containing jelton, chicle, sorba, and massaranduba are preferred.

[0469] Magnesium carbonate or calcium, crushed pumice, silicates, particularly magnesium silicate or aluminum, clay, aluminum oxide, talc, titanium dioxide, monocalcium phosphate, dicalcium phosphate, and tricalcium polymers are suitable as fillers or texturing agents.

[0470] Suitable emulsifiers include animal fats, hydrogenated animal fats, hydrogenated or partially hydrogenated vegetable oils, cocoa butter, partial glycerides, lecithin, triacetin, and saturated or unsaturated fatty acids having 6 to 22, preferably 12 to 18, carbon atoms, as well as mixtures thereof.

[0471] Suitable colorants and whitening agents include, for example, FD and C type titanium dioxide approved for food coloring, plant and fruit extracts, and titanium dioxide.

[0472] The base mass may or may not contain wax; examples of wax-free compositions can be found, among others, in U.S. Patent No. 5,286,500.

[0473] In addition to a water-insoluble gum base, chewing gum preparations typically contain water-soluble components, which may consist of, for example, softeners, sweeteners, fillers, flavorings, flavor enhancers, emulsifiers, colorants, acidifiers, antioxidants, etc., provided that these components have at least sufficient water solubility. Therefore, depending on the water solubility of specific representative examples, individual components may belong to both the water-insoluble and water-soluble phases. However, it is also possible to use, for example, a combination of water-soluble and water-insoluble emulsifiers, in which case, then individual representative examples reside in different phases. Typically, the water-insoluble portion accounts for 5 to 95% by weight, preferably 20 to 80% by weight, of the preparation.

[0474] Water-soluble softeners or plasticizers are added to chewing gum compositions to improve chewability and chewing sensation, and are typically present in the mixture in amounts of 0.5 to 15% by weight. Typical examples include glycerin, lecithin, and sorbitol, hydrolyzed starch, or aqueous solutions of corn syrup.

[0475] Both sugar-containing and sugar-free compounds can be used as sweeteners, and these are used in amounts of 5-95% by weight, preferably 20-80% by weight, and especially 30-60% by weight, based on the chewing gum composition. Typical saccharide sweeteners include sucrose, dextrose, maltose, dextrin, dried invert sugar, fructose, levose, galactose, corn syrup, and mixtures thereof. Sorbitol, mannitol, xylitol, hydrolyzed starch, maltitol, and mixtures thereof are suitable sugar substitutes. Furthermore, so-called HIAS ("High Intensity Artificial Sweeteners") such as sucralose, aspartame, acesulfame salts, aritum, saccharin and saccharin salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcone, thaumatin, and monellin can also be considered additives, either alone or in mixtures. Hydrophobic HIAS, the subject of International Publication No. 2002091849(A1) (Wrigleys), as well as stevia extracts and their active ingredients, particularly rebaudioside A, are also particularly effective. The amount of these substances used depends mainly on their performance and is typically in the range of 0.02 to 8% by weight.

[0476] Fillers such as polydextrose, raphtyrose, raphytilin, fructooligosaccharide (NutraFlora), palatinose oligosaccharide, guar gum hydrolysate (Sun Fiber), and dextrin are particularly suitable for the production of low-calorie chewing gum.

[0477] The selection of other flavorings is substantially unlimited and not important to the essence of the present invention. The total proportion of all flavorings is usually 0.1 to 15% by weight, preferably 0.2 to 5% by weight, based on the chewing gum composition. Suitable additional flavorings include, for example, essential oils such as anise oil, star anise oil, caraway oil, eucalyptus oil, fennel oil, lemon oil, wintergreen oil, and clove oil, as well as synthetic flavorings, when used in oral and dental care products.

[0478] Chewing gum may also contain excipients and additives such as chlorhexidine, CPC, or triclosan, which are suitable for dental care, particularly for combating plaque and gingivitis. It may also contain pH adjusters (e.g., buffers or urea), caries-fighting active ingredients (e.g., phosphates or fluorides), and bioactive ingredients (antibodies, enzymes, caffeine, plant extracts), provided that these substances are approved for use in food and do not interact with each other in an undesirable manner.

[0479] The present invention also includes cooling ointments. Patches according to the present invention can be constructed in any manner, for example, according to a matrix system, a membrane system, or a fleece system. Patches according to the present invention are manufactured in a conventional manner.

[0480] In addition, the present invention relates to textile products equipped with a cooling agent according to the present invention, a compound according to the present invention, or a cooling agent mixture according to the present invention.

[0481] The finishing of textile products with cooling substances is particularly used when the garment can come into direct contact with the skin, so that the active ingredients can exert their effects, for example, locally or systemically, through transdermal penetration. In recent years, textile products equipped with so-called happiness additives, i.e., substances that promote happiness, have been reported.

[0482] Any textile product, i.e., both unfinished and finished products, can be treated using the cooling agent according to the present invention, or the compound according to the present invention, or a mixture of the cooling agent according to the present invention. Hereinafter, textile product materials include woven fabrics, knitted fabrics, and fleece. Textile product materials can be made from natural fiber yarns, synthetic fiber yarns, and / or blended yarns. In principle, all textile materials commonly used in the manufacture of textile products can be considered textile materials. 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, etc., as well as mixtures of these textile materials. Glass fibers and mixtures of the aforementioned textile materials with glass fibers, for example, glass fiber / Kevlar mixtures, are also suitable. The type of textile product material depends mainly on the desired application. The textile products to be finished may include underwear and outerwear, such as clothing including shirts, trousers, and jackets; outdoor, trekking, and military equipment; roofs, tents, nets, such as insect screens and curtains; hand and bath towels; and bed linens. Similarly, finishing can be performed on raw materials in bale or roll form.

[0483] The present invention also relates to a cooling tobacco product.

[0484] The active ingredients according to the present invention, namely the cooling active ingredients, compounds, cooling mixtures, or flavor preparations according to the present invention, can also be advantageously used in the manufacture of tobacco products. Examples of such tobacco products include cigars, cigarettes, pipe tobacco, chewing tobacco, and snuff. The manufacture of tobacco products supplemented with cooling additives is known in itself.

[0485] In principle, the content of the active ingredient, i.e., the content of the cooling agent or cooling agent mixture according to the present invention, can vary over a wide range, for example, from 0.05 ppm to 10% by weight, preferably from 0.1 ppm to 10% by weight.

[0486] The active ingredient according to the present invention is also advantageously suitable for the production of packaging materials.

[0487] These too are manufactured in known manner. The active ingredients can be incorporated into the packaging material in a free form or, for example, in an encapsulated form, or applied to the packaging material in a free or encapsulated form. Thus, appropriately equipped plastic packaging materials can be produced according to the information in the literature on the production of polymer films. The production of suitably coated paper is also known to those skilled in the art.

[0488] Ultimately, the present invention provides a method for modulating the cold menthol receptor TRPM8, particularly for in vitro and / or in vivo modulation, comprising the following steps: (i) the step of providing at least one compound according to the present invention, or at least one physiological cooling agent according to the present invention, or a mixture of physiological cooling agents according to the present invention, or the step of providing a cosmetic or pharmaceutical according to the present invention, (ii) a step of bringing the compound from step (i), or a cooling agent, or a mixture of cooling agents, or a cosmetic or pharmaceutical product into contact with a receptor, or To produce a physiological cooling effect on the skin or mucous membrane, follow these steps: (iii) the step of providing at least one compound according to the present invention, or at least one physiological cooling agent according to the present invention, or a mixture of physiological cooling agents according to the present invention, or the step of providing a cosmetic or pharmaceutical according to the present invention, (iv) a step of bringing the compound from step (iii), or a cooling agent, or a mixture of cooling agents, or a cosmetic or pharmaceutical product into contact with human skin or mucous membranes, or To improve the taste characteristics of flavorings, follow these steps: (v) Providing at least one compound according to the present invention, or at least one physiological cooling agent according to the present invention, or a mixture of physiological cooling agents according to the present invention, or providing a cosmetic or pharmaceutical product and at least one flavoring agent according to the present invention, (vi) A step of mixing the two components from step (v), and optionally, (vii) a step of incorporating the mixture into an oral preparation, or To mask the bitter substances, follow these steps: (viii) the step of providing at least one compound according to the present invention, or at least one physiological cooling agent according to the present invention, or a mixture of physiological cooling agents according to the present invention, or the step of providing a cosmetic or pharmaceutical and at least one bitter substance according to the present invention, (ix) A step of mixing the two components from step (viii), and optionally, The present invention relates to a method comprising the step of (x) incorporating a mixture into an oral preparation.

[0489] Further aspects of the present invention will become apparent from the following examples and the appended claims. [Examples]

[0490] The following examples serve to illustrate the invention without limiting it. Unless otherwise specified, all information refers to weight.

[0491] Production of active ingredients: The active ingredients / cooling agents and compounds used in accordance with the present invention can be produced by those skilled in the art of organic synthesis using known synthesis methods.

[0492] Cloning of human TRPM8 The starting point for cloning the human TRPM8 receptor is the LnCaP cDNA library. This can be commercially available (e.g., from BioChain, Hayward, USA) or produced from androgen-sensitive human prostate cancer cell lines LnCaP (e.g., ATCC, CRL1740, or ECACC, 891 1021 1) using standard kits.

[0493] The coding TRPM8 sequence (see, for example, http: / / www.ncbi.nlm.nih.gov / entrez / viewer.fcgi?db=nuccore&id=109689694) can be amplified and cloned using standard PCR methods. The plasmid plnd_M8 was produced using the human TRPM8 gene isolated in this manner. Alternatively, the TRPM8 gene can also be produced synthetically.

[0494] Generation of HEK293 test cells We used human TRPM8 DNA as the test cell line to produce a stably transfected HEK293 cell line. HEK293 is preferred because it offers the potential to induce TRPM8 expression via tetracycline through the introduced plasmid.

[0495] Methods for producing suitable test cell lines are known to those skilled in the art and can be found in the relevant technical literature.

[0496] TRPM8 modulator assay The trial will be conducted as described in the literature by Behrendt HJ et al., Br.J.Pharmacol. 141, 2004, 737-745. 2+ The agonist or antagonist activity of the receptor can be quantified using sensitive dyes (e.g., FURA, Fluo-4, etc.). Agonists alone are effective against Ca 2+ The antagonist causes an increase in the signal, for example, menthol (Ca 2+Using the dye Fluo-4, which has different fluorescence properties due to ions, Ca is detected in each case in the presence of ( 2+ This causes a reduction in the signal.

[0497] First, fresh cultures of transformed HEK cells are prepared in cell culture bottles in the usual manner. Test cells HEK293-TRPM8 are detached from the cell culture bottles using trypsin, and 40,000 cells / well are seeded with 100 μl of medium in 96-well plates (coated with Greiner #655948 poly-D-lysine). To induce the TRPM8 receptor, tetracycline is added to the growth medium (DMEM / HG, 10% FCS, tetracycline-free, 4 mM L-glutamine, 15 μg / ml blastosidine, 100 μg / ml hygromycin B, 1 μg / ml tetracycline).

[0498] The following day, the cells are loaded with Fluo-4AM dye and the test is performed. This is done as follows: 100 μl / well of Ca-4 kit (RB 141, Molecular Devices) dye solution is added to 100 μl of culture medium (DMEM / HG, 10% FCS, tetracycline-free, 4 mM L-glutamine, 15 μg / ml blastosidine, 100 μg / ml hygromycin B, 1 μg / ml tetracycline).

[0499] Incubation in an incubator, 30 minutes / 37°C / 5% CO2, 30 minutes / RT.

[0500] Preparation of test substances (different concentrations in 200 μl of HBSS buffer), as well as positive controls (different concentrations of menthol, ishirin, or ronomycin in 200 μl of HBSS buffer) and negative controls (200 μl of HBSS buffer only); addition of 50 μl / well of test substance; measurement of fluorescence changes (e.g., in a FLIPR assay device, Molecular Devices, or NovoStar, BMG) at 485 nm excitation and 520 nm emission; and evaluation of the potency of various substances / concentrations and determination of EC50 values.

[0501] The test substance is used in the assay at three different concentrations, from 0.1 to 200 μM. Typically, the compound is kept in DMSO solution and diluted to a maximum DMSO concentration of 2% for the assay. Surprisingly, our own evaluation when performing the described assay showed that the compound used according to the present invention (as described herein) is particularly suitable as an agonist for TRPM8.

[0502] The assay described is used to determine the activity of active substances in relation to the activation of the TRPM8 channel. This is performed in a concentration-dependent manner. For each active substance, concentrations of 6–10 are measured as standards. From the determined activity values, the EC50 value can be determined as an inflection point of an S-shaped curve using mathematical methods (4-parameter or 5-parameter logistic curve fitting). These are standard methods in biochemistry that are well known to those skilled in the art.

[0503] The EC50 values ​​determined for exemplary selected modulators according to the present invention are shown in Tables 7 and 8 below. An EC50 value of 1.72 μM was determined for reference material WS-3.

[0504] [Table 18-1]

[0505] [Table 18-2]

[0506] [Table 19-1]

[0507] [Table 19-2]

[0508] The EC50 value describes the concentration of the cooling substance required for half of the maximum effect, and is therefore a measure of the potency of an agonist drug (the drug's potency as a function of dose or concentration), thereby potency corresponding to the inverse value of EC50. Thus, a low EC50 value corresponds to high drug potency.

[0509] Therefore, from Tables 5 and 6 above, it can be seen that the cooling agents and compounds described herein according to the present invention have excellent cooling properties and can produce a strong cooling effect even at low concentrations, and in general, for substance WS-3, the EC50 reference value at 1.72 μM is well below the reference value.

[0510] As shown in Table 5 above, the structures of general formulas (Va) and (VIa) have been proven to be particularly advantageous, in which R1 and R2 each represent a phenyl group, Y represents a methylene group or a methylene group substituted with a methyl or ethyl group, and Z represents -NH-cyclopropyl, -NH-CH3, -N(CH3)2, or azetidine. Furthermore, it has been observed that in these structures, m and n each represent 1.

[0511] As shown in Table 6 above, structures of general formulas (VIIa) to (VIIIa) are particularly preferred, where R1 and R2 represent phenyl groups, Y represents a methylene group or a methylene group substituted with a methyl group, and Z represents -NH-CH3, -NH-CH2-CH3, -NH-cyclopropyl, or -CS-CH3. Furthermore, it has been observed that in these structures, m is either 0 or 1, or n is 1.

[0512] Therefore, compounds B-01, B-02, B-03, B-05, and B-07 having an EC50 value ≤ 1.0 μM, and compounds A-01, A-02, A-03, and A-05 having an EC50 value ≤ 1.0 μM, are particularly preferred with respect to the EC50 value.

[0513] Particularly efficient cooling effects in terms of TRPM8 activity and EC50 value 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 ≤ 1.0 μM).

[0514] In addition to the TRPM8 activity and drug efficacy (EC50 value) described above, the cooling agent and compounds according to the present invention also exhibit a strong cooling effect.

[0515] To quantify the cooling effect, comparative tests are performed using menthane-3-carboxylic acid N-ethylamide as a reference. For these comparative tests, those skilled in the art will replace one or more compounds used according to the present invention with menthane-3-carboxylic acid N-ethylamide (also known as WS-3). The intensity of the cooling effect of each compound or active ingredient is then subjectively evaluated by trained panelists (n=10-11) and compared with one another as described below.

[0516] The cooling sensation intensity was investigated as follows: A test solution containing 5 ppm of the compound according to the present invention was tested in a 5% sugar solution and a corresponding solution containing 30 ppm of the reference substance WS-3. This concentration of WS-3 was chosen because it has been shown that WS-3 exhibits a good cooling effect at such a concentration. Panelists tasted the corresponding test solution for exactly 40 seconds, rinsing their entire mouths with the corresponding test solution during that time, and then spitting out the sample or reference solution. Following the taste test, the subjects rated the respective cooling sensation intensity on a scale of 1 (very weak) to 9 (very strong) after 1 minute.

[0517] The results of sensory evaluations of exemplary cooling agents / compounds according to the present invention are shown in Tables 9 and 10 below.

[0518] [Table 20]

[0519] [Table 21]

[0520] Surprisingly, the compounds described herein have been shown to produce significantly stronger or equivalent cooling effects compared to the WS-3 reference sample. In particular, while the reference sample containing WS-3 showed a cooling intensity of approximately 5.4 in sensory evaluation, the substances according to the present invention, such as compound B-01, were 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.

[0521] In sensory evaluation, i.e., tasting of each sample, the (R)-enantiomer was found to have a rapidly starting, strong cooling effect. Panelists rated the cooling effect of compound A-02 at a usage level of 5 ppm with a score of 5.7. Therefore, considering the amount of compound used, the sensory-evaluated cooling intensity was equivalent to that determined for the cooling substance WS-3 as a reference at a concentration six times higher (amount used: 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 was delayed, slowly accumulated, and lasted for a long time.

[0522] It should also be noted that WS-3 can produce a significantly lower cooling intensity despite being six times more concentrated. Conversely, significantly lower concentrations of the compounds according to the present invention are required to produce a significantly stronger cooling effect compared to conventional cooling substances (such as WS-3). This indicates that the compounds according to the present invention produce a strong, and therefore very effective, cooling effect even when used at low concentrations, and that only small amounts are always needed in corresponding final formulations, such as product formulations containing these cooling substances, to produce a cooling effect that is perceived as strong.

[0523] In this context, in the corresponding comparison, the cooling effect of the sample containing the compound used according to the present invention is preferably extended by at least 10 minutes, preferably at least 15 minutes, more preferably at least 20 minutes, even more preferably at least 30 minutes, particularly preferably at least 60 minutes, and most preferably at least 90 minutes, compared to the comparative sample containing WS-3.

[0524] Formulation example Examples of cosmetic formulations The following formulation examples F1 to F10 represent a wide variety of formulations for cosmetics and pharmaceuticals. Cooling agent 1 refers to compound B-11-R according to the present invention, cooling agent 2 refers to compound A-02-R, cooling agent 3 refers to compound A-09-S, and cooling agent 4 refers to compound A-10-S. The above cooling agents were used in a pure form without any further additives.

[0525] In the table below, decimal points are represented by periods.

[0526] [Table 22]

[0527] [Table 23]

[0528] [Table 24]

[0529] [Table 25]

[0530] [Table 26]

[0531] [Table 27]

[0532] [Table 28]

[0533] [Table 29]

[0534] [Table 30]

[0535] [Table 31]

[0536] Examples of food preparation formulations Examples F11-F15 below illustrate a wide variety of formulations for food preparations. Cooling agent 1 refers to compound B-11-R according to the present invention, cooling agent 3 refers to compound A-09-R, and cooling agent 4 refers to compound A-10. The above cooling agents were used in their pure form, without any further additives.

[0537] [Table 32]

[0538] [Table 33]

[0539] [Table 34]

[0540] [Table 35]

[0541] Table 36

Claims

1. Compounds selected from the group consisting of the compounds shown in the table below: Table 1 Table 1-2 Table 1-3 and salts thereof, in particular acid addition salts with inorganic or organic acids, wherein the compound exists as a pure (R)-enantiomer, a pure (S)-enantiomer, a racemic mixture, or an enantiomer mixture, and salts thereof. or Compounds selected from the group consisting of the compounds shown in the table below: Table 2-1 Table 2-2 Table 2-3 and salts thereof, in particular acid addition salts with inorganic or organic acids, wherein the compound exists as a pure (R)-enantiomer, a pure (S)-enantiomer, a racemic mixture, or an enantiomer mixture.

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

2.

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

4. General formula (Va) 【Chemistry 1】 Or general formula (VIa) 【Chemistry 2】 A physiological cooling agent wherein, in the above formulas (Va) and (VIa), Table 3-1 Table 3-2 Table 3-3 and salts thereof, in particular acid addition salts with inorganic or organic acids, wherein the cooling agent exists as a pure (R)-enantiomer, a pure (S)-enantiomer, a racemic mixture, or an enantiomer mixture, physiological cooling agents and salts thereof, Or general formula (VIIa) 【Transformation 3】 Alternatively, general formula (VIIIa) 【Chemistry 4】 A physiological cooling agent, wherein in the above formulas (VIIa) and (VIIa), Table 4-1 Table 4-2 A physiological cooling agent and its salts, particularly an acid addition salt with an inorganic or organic acid, wherein the cooling agent exists as a pure (R)-enantiomer, a pure (S)-enantiomer, a racemic mixture, or an enantiomer mixture.

5. In the above general formulas (Va) to (VIIIa), the radicals R1 and R2 may be the same or different, and independently have the following meanings: R1 represents H, or optionally substituted C1-C3 alkyl groups, or optionally substituted phenyl groups, preferably optionally substituted phenyl groups, and / or The physiological cooling agent according to claim 4 or 5, wherein R2 represents H, or optionally substituted C1-C3 alkyl groups, or optionally substituted phenyl groups, preferably optionally substituted phenyl groups.

6. The physiological cooling agent according to claim 4, wherein in the general formulas (Va) to (VIIIa), Y represents a substituted methylene group, preferably a methyl group, an ethyl group, a linear or branched butyl group, or a methylene group substituted with a linear or branched propyl group.

7. In the general formulas (Va), (VIIa), and (VIIIa), Z is -NH ３ , ２ , ３ , ３ , ２ , ２ , ２ , ２ , ３ , ２ , ２ , ２ , ３ , ３ , ２ , ２ , ３ , ２ , ３ , ２ , ３ , ３ , ３ , ３ , ２ , ３ , ３ ,<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​, -OC(=O)-CH ３ , oxetanil, -CH ３ ien-CH ２ -CH ３ , -CH(CH ３ ) ２ , -C(OH)-CH ２ -OH, cyclopropyl, phenyl, and -CH ２ -S-CH ３ Selected from the group consisting of, In the general formula (VIa), Z is -NH ２ , -NH-CH ３ , -NH-CH ２ -CH ３ , -NH-CH ２ -CH ２ -CH ３ , -NH-CH ２ -CH ２ -CH ２ -CH ３ , -NH-CH(CH ３ )-CH(CH ３ ) ２ , -NH-CH(CH ３ )-CH ２ -CH ２ -CH ３ , -NH-CH ２ -CH(CH ３ ) ２ , -NH-CH ２ -CH ２ -O-CH ３ , -NH-CH(CH ３ )-CH ２ -O-CH ３ , -NH-C(=O)-CH ３ , -NH-C(=O)-O-CH ３ , -NH-CH(CH ３ )-CH ２ -OH, -NH-CH ２ -furanyl, -NH-CH ２ -tetrahydrofuranyl, -NH-CH ２ -thiophenyl, -NH-tolyl, -NH-CH-(CH ３ ) ２ , -NH-C(CH ３ ) ３ , -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -N(CH ３ ) ２ , -N(CH ３ )-cyclohexyl, -N(CH ２ -CH ３ ) ２ , azetidinyl, pyrrolidinyl, piperidyl, azacyclobutadienyl, pyrrolyl, pyridinyl, -O, -O-CH ３ , -O-C(=O)-CH ３ , oxetanil, -CH ３ ien-CH ２ -CH ３ , -CH(CH ３ ) ２ , -C(OH)-CH ２ -OH, cyclopropyl, phenyl, and -CH ２ -S-CH ３ A physiological cooling agent according to any one of claims 4 to 6, selected from the group consisting of the following.

8. Furthermore, Table 5

9. The physiological cooling agent of the general formula (Va) or (VIa) is one of the compounds shown in the following table: Table 6-1 Table 6-2 Table 6-3 Table 6-4 Table 6-5 Table 6-6 Table 6-7 and salts thereof, particularly acid addition salts with inorganic or organic acids, selected from the group, the cooling agent exists as a pure (R)-enantiomer, a pure (S)-enantiomer, a racemic mixture, or an enantiomer mixture, preferably the physiological cooling agent is selected from the group consisting of compounds B-01, B-02, B-03, B-05, B-07, B-11, B-14, B-15, B-18, and B-21, or The physiological cooling agent of the general formula (VIIa) or (VIIIIa) is one of the compounds shown in the following table: Table 7-1 Table 7-2 Table 7-3 A physiological cooling agent according to any one of claims 4 to 8, wherein the cooling agent is selected from the group consisting of and salts thereof, particularly acid addition salts with inorganic or organic acids, and the cooling agent exists as a pure (R)-enantiomer, a pure (S)-enantiomer, a racemic mixture, or an enantiomer mixture, and preferably the physiological cooling agent is selected from the group consisting of compounds A-01, A-02, A-03, A-05, A-09, A-10, A-12, and A-69.

10. The cooling agent is one of the compounds shown in the following table: Table 8-1 Table 8-2 Table 8-3 and salts thereof, in particular, selected from the group consisting of acid addition salts with inorganic or organic acids, wherein the cooling agent exists as a pure (R)-enantiomer, a pure (S)-enantiomer, a racemic mixture, or an enantiomer mixture. or The physiological cooling agent of the general formula (VIIa) or (VIIIIa) is one of the compounds shown in the following table: Table 9-1 Table 9-2 Table 9-3 A physiological cooling agent according to any one of claims 4 to 9, selected from the group consisting of and salts thereof, particularly acid addition salts with inorganic or organic acids, wherein the cooling agent exists as a pure (R)-enantiomer, a pure (S)-enantiomer, a racemic mixture, or an enantiomer mixture.

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

12. The aforementioned compound or the salt of the cooling agent, (1) Acid addition salts formed with an inorganic acid, or with an organic acid, preferably a monocarboxylic acid or polycarboxylic acid, or (2) A compound according to any one of claims 1 to 3 or a physiological cooling agent according to any one of claims 4 to 11, selected from the group consisting of salts formed when an acidic proton present in the starting compound is substituted with a metal ion, particularly an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinated with an organic base.

13. A physiological cooling agent mixture, (a) 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, optionally, (b) at least one further physiological cooling agent, and / or optionally, (c) A physiological cooling agent mixture comprising or consisting of at least one solvent.

14. The physiological cooling agent forming component (b) is menthol, menthol methyl ether (FEMA GRAS 4054), monomenthyl glutamate (FEMA GRAS 4006), menthoxy-1,2-propanediol (FEMA GRAS 3784), dimenthyl glutarate (FEMA GRAS 4604), hydroxymethylcyclohexyl ethanolone (FEMA GRAS 4742), 2-(4-ethylphenoxy)-N-(1H-pyrazole-3-yl)-N-(thiophen-2-ylmethyl)acetamide (FEMA GRAS 4880), WS-23 (2-isopropyl-N,2,3-trimethylbutylamide, FEMA GRAS 3804), N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide (FEMA GRAS 4882), N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide (FEMA GRAS 4881), N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexane-1-carboxamide (FEMA GRAS 4896), 3,4-methylenedioxycinnamic acid, (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide (FEMA GRAS 4788), menthol propylene glycol carbonate (FEMA GRAS 3806), Menthyl N-ethyl oxamate, monomethyl succinate (FEMA GRAS 3810), WS-3 (N-ethyl-p-menthane-3-carboxamide, FEMA GRAS 3455), Menthol ethylene glycol carbonate (FEMA GRAS 3805), WS-5 (ethyl-3-(p-menthane-3-carboxamide) acetate, FEMA GRAS 4309), WS-12 (1R,2S,5R)-N-(4-methoxyphenyl)-p-menthanecarboxamide (FEMA GRAS 4681), WS-27 (N-ethyl-2,2-diisopropylbutanamide, FEMA GRAS 4557), N-cyclopropyl-5-methyl-2-isopropylcyclohexanecarboxamide (FEMA GRAS 4693), WS-116 (N-(1,1-dimethyl-2-hydroxyethyl)-2,2-Diethylbutanamide, FEMA GRAS 4603), Menthoxyethanol (FEMA GRAS 4154), N-(4-Cyanomethylphenyl)-p-Menthanecarboxamide (FEMA GRAS 4496), N-(2-(Pyridine-2-yl)ethyl)-3-p-Menthanecarboxamide (FEMA GRAS 4549), N-(2-Hydroxyethyl)-2-Isopropyl-1-2,3-Dimethylbutanamide (FEMA GRAS 4602), (2S,5R)-N-[4-(2-Amino-2-Oxoethyl)phenyl]-p-Menthanecarboxamide (FEMA GRAS 4684), N-Cyclopropyl-5-Methyl-2-Isopropylcyclohexanecarboxamide (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-(1H-pyrazole-5-yl)-N-((thiophen-2-yl)methyl)acetamide (FEMA GRAS 4809), menthol glycoside ketal (FEMA GRAS 3807 and 3808), (-)-menthoxypropane-1,2-diol, 3-(1-menthoxy)-2-methylpropane-1,2-diol (FEMA GRAS 3849), isopuregol, (+)-cis and (-)-trans-p-menthane-3,8-diol (62:38, FEMA GRAS 4053), 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazole-2-yl)piperidine-1-yl)butan-1-one (FEMA GRAS 4970) and its enantiomer, 2,3-dihydroxy-p-menthane, 3,3,5-trimethylcyclohexanone glycerol ketal, menthylpyrrolidone carboxylate, (1R,3R,4S)-3-menthyl-3,6-dioxaheptanoate, (1R,2S,5R)-3-menthyl methoxyacetate, (1R,2S,5R)-3-menthyl-3,6,9-trioxadecanoate, (1R,2S,5R)-3-menthyl-3,6,9-trioxadecanoate, (1R,2S,5R)-3-menthyl-(2-hydroxyethoxy)acetate, (1R,2S,5R)-menthyl-11-hydroxy-3,6,9-trioxaundecanoate, cubebol (FEMA GRAS 4497), 2-isopropyl-5-methylcyclohexyl-4-(dimethylamino)-4-oxobutanoate (FEMA GRAS 4230), menthyl lactate (FEMA GRAS 3748), 6-isopropyl-3,9-dimethyl-1,4-dioxaspiro[4.5]decane-2-one (FEMA GRAS 4285), N-benzo[1,3]-dioxol-5-yl-3-p-menthanecarboxamide, N-(1-isopropyl-1,2-dimethylprolyl)-1,3-benzodioxol-5-carboxamide, N-(R)-2-oxotetrahydrofuran-3-yl-(1R,2S,5R)-p-menthane-3-carboxamide, 2,2,5,6,6-pentamethyl-2 A mixture of 3,6,6a-tetrahydropentalen-3a(1H)-ol and 5-(2-hydroxy-2-methylpropyl)-3,4,4-trimethylcyclopent-2-en-1-one, (2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridine-4-yl)ethyl)cyclohexanecarboxamide, (1S,2S,5R)-N-(4-(cyanomethyl )phenyl)-2-isopropyl-5-methylcyclohexanecarboxamide, 1,7-isopropyl-4,5-methyl-bicyclo[2.2.2]octo-5-ene derivative, 4-methoxy-N-phenyl-N-[2-(pyridine-2-yl)ethyl]benzamide, 4-methoxy-N-phenyl-N-[2-(pyridine-2-yl)ethyl]benzenesulfonamide, 4-chloro-N-phenyl-N-[2-(pyridine-2-yl)ethyl]benzenesulfonamide, 4-cyano-N-phenyl-N-[2-(pyridine-2-yl)ethyl]benzenesulfonamide, 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]imidazole-2-yl)vinyl-4-methoxybenzoate, 2-(1-isopropyl-6-methyl-1H-benzo[d]imidazole-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoate, (Z)-2-(1-isopropyl-5-methyl-1H-benzo[d]imidazole-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoate, 3-alkyl-p-methane-3-ol derivatives, fenquil, D-bo Lunyl, L-bornyl, exo-norbornyl, 2-methylisobornyl, 2-ethylfenquil, 2-methylbornyl, cis-pyran-2-yl, pervanyl, and derivatives of isobornyl, menthyl oxamate derivatives, menthyl 3-oxocarboxylic acid esters, N-alpha-(menthanecarbonyl)amino acid amides, p-menthanecarboxamide and WS-23 analogs, (-)-(1R,2R,4S)-dihydroumbellol, p-menthanealkyloxiamide, 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-tetrahydropyrimidine-2-one, 4-methyl-3-(1-pyrrolidinyl)-2-[5H]-furanone, and cooling agents as shown in the table below: Table 10-1 Table 10-2 Table 10-3 Table 10-4 Table 10-5 In addition, the cooling agents listed in the table below: Table 11-1 Table 11-2 Table 11-3 Table 11-4 Table 11-5 Table 11-6 Table 11-7 Table 11-8 Table 11-9 Table 11-10 Table 11-11 Table 11-12 Table 11-13 Table 11-14 A physiological cooling agent mixture according to claim 13, selected from the group consisting of salts thereof, in particular acid addition salts with inorganic or organic acids, and mixtures of the aforementioned cooling agents / compounds.

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

1.

16. The physiological cooling agent mixture according to any one of claims 13 to 15, wherein the solvent-forming 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, (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, (e) A flavor preparation comprising or consisting of at least one flavoring agent.

18. Flavoring agent forming component (e) is acetophenone, allyl caproate, alpha-ionone, beta-ionone, anisaldehyde, anisyl acetate, anisyl formate, anethole, benzaldehyde, benzothiazole, benzyl acetate, benzyl alcohol, benzyl benzoate, beta-ionone, butyl butyrate, butyl caproate, butylidene phthalide, carvone, camphene, caryophyllene, cineole, cinnamyl acetate, citral, citronellol, citronellal, citronellyl acetate, cyclohexyl acetate, cymol, damascone, decalac Ton, dihydrocoumarin, dimethyl anthranilate, dimethyl anthranilate, dodecalactone, ethoxyethyl acetate, ethyl butyrate, ethyl butyrate, ethyl caprate, ethyl caproate, ethyl crotonate, ethyl furaneol, ethyl guaiacol, ethyl isobutyrate, ethyl isovalerate, ethyl lactate, ethyl methylbutyrate, ethyl propionate, eucalyptol, eugenol, ethyl heptylate, 4-(p-hydroxyphenyl)-2-butanone, gamma-decalactone, geraniol, geranyl acetate, grapefruit aldehyde, di Methyl hydrojasmonate (e.g., Hedion®), heliotropin, 2-heptanone, 3-heptanone, 4-heptanone, trans-2-heptenal, cis-4-heptenal, trans-2-hexenal, cis-3-hexenol, trans-2-hexenoic acid, trans-3-hexenoic acid, cis-2-hexenyl acetate, cis-3-hexenyl acetate, cis-3-hexenyl caproate, trans-2-hexenyl caproate, cis-3-hexenyl formate, cis-2-hexyl acetate, cis-3-hexyl acetate, trans acetate -2-hexyl, cis-3-hexyl formate, para-hydroxybenzylacetone, isoamyl alcohol, isoamyl isovalerate, isobutyl butyrate, isobutyraldehyde, isoeugenol methyl ether, isopropylmethylthiazole, lauric acid, levulinic acid, linalool, linalool oxide, linalyl acetate, menthol, mentfuran, methyl anthranilate, methylbutanol, methylbutyric acid, 2-methylbutyl acetate, methyl caproate, methyl cinnamate, 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, nocatone, delta-octalactone, gamma-octalactone, 2-octanol, 3-octanol, 1,3-octanol, 1-Octyl Acetate, 3-Octyl Acetate, Palmitic Acid, Paraaldehyde, Phellandrene, Pentanedione, Phenylethyl Acetate, Phenylethyl Alcohol, Phenylethyl Alcohol, Phenylethyl Isovalerate, Piperonal, Propionaldehyde, Propyl Butyrate, Pulegone, Pulegol, Sinensal, Sulfurol, Terpinene, Terpineol, Terpinolene, 8,3-Thiomentanone, 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), homoflonol (= 2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone and 5-ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and maltol derivatives Form (preferably ethyl maltol), coumarin and coumarin derivatives, gamma-lactone (preferably gamma-undecalactone, gamma-nonalactone, gamma-decalactone), delta-lactone (preferably 4-methyl-delta-decalactone, massoialactone, delta-decalactone, 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, 3-Methyl Butyrate, 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-Heptene-1-A Al and phenylacetaldehyde, 2-methyl-3-(methylthio)furan, 2-methyl-3-frantiol, bis(2-methyl-3-furyl)disulfide, furfuryl mercaptan, methional, 2-acetyl-2-thiazoline, 3-mercapto-2-pentanone, 2,5-dimethyl-3-frantiol, 2,4,5-trimethylthiazole, 2-acetylthiazole, 2,4-dimethyl-5-ethylthiazole, 2-acetyl-1-pyrroline, 2-methyl-3-ethylpyrazine, 2-ethyl-3,5-dimethylpyrazine, 2-ethyl-3,6-dimethylpyrazine, 2,3-diethyl-5-methylpyrazine, 3-isopropyl-2-methoxypyrazine, 3-isopropyl-2-methoxypyrazine, 2-acetylpyrazine, 2-pentylpyridine, (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-hydro A selection from the group consisting of xy-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, and (not explicitly described herein) stereoisomers, enantiomers, positional isomers, diastereomers, cis / trans isomers, or epimers of these substances, and / or The aforementioned flavoring agent forming component (e) is erythritol, treitol, arabitol, ribitol, xylitol, sorbitol, mannitol, dulcitol, lactitol, miraculin, monellin, thaumatin, curculin, blazein, magap, sodium cyclamate, acesulfame K, neohesperidin dihydrochalcone, sodium saccharin salt, aspartame, super aspartame, neotame, and A flavor preparation according to claim 17, selected from the group consisting of ritame, sucralose, stevioside, rebaudioside, ruguznam, kaleramm, scrononate, scrooctate, monatin, phenylodulsine, glycine, D-leucine, D-threonine, D-asparagine, D-phenylalanine, D-tryptophan, L-proline, hernandulsine, dihydrochalcone glycoside, glycyrrhizin, glycyrrhizic acid, its derivatives and salts, extract of licorice (Glycyrrhiza glabra ssp.), Lippia dulcis extract, Momordica ssp. extract, mogroside, Hydrangea dulcis and stevioside, and mixtures thereof.

19. The flavor preparation according to claim 17 or 18, wherein component (d) and component (e) are contained 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 cooling agent according to any one of claims 4 to 12, or a physiological cooling agent mixture according to any one of claims 13 to 16, or a flavor preparation according to any one of claims 17 to 19, in encapsulated form.

21. In particular, the use of any one of the compounds according to claims 1 to 3, 12, and 20 as modulators for in vivo and / or in vitro modulation of the cold menthol receptor TRPM8, in particular as TRPM8 receptor agonists or TRPM8 receptor antagonists, or the physiological cooling agent according to any one of claims 4 to 12 and 20, or the physiological cooling agent mixture according to any one of claims 13 to 16 and 20.

22. Use of a compound according to any one of claims 1 to 3, 12, and 20, or a 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, for the purpose of producing a physiological cooling effect on the skin or mucous membranes of a human or animal, or for the purpose of inducing a cooling effect by packaging containing the compound, the physiological cooling agent, or the physiological cooling agent mixture, or by textile products containing the compound, the physiological cooling agent, or the physiological cooling agent mixture.

23. Use of a compound according to any one of claims 1 to 3, 12, and 20, or a 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, for the purpose of improving or enhancing the taste characteristics of flavorings, or reducing or masking unpleasant tastes.

24. Use of a compound according to any one of claims 1 to 3, 12 and 20, or a 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 a flavor preparation according to any one of claims 17 to 19 and 20, for the manufacture of food, nutritional supplements, cosmetics or pharmaceuticals, animal feed, textile products, packaging, or tobacco products.

25. Foods, nutritional supplements, cosmetics or pharmaceuticals, animal feed, textile products, packaging, or tobacco products comprising, in particular, 0.1 ppm to 10% by weight, particularly 1% to 10% by weight, a compound according to any one of claims 1 to 3, 12 and 20, or a 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 a flavor preparation according to any one of claims 17 to 19 and 20, based on the total weight of the final product.

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

27. A pharmaceutical product according to claim 25 or 26, for use as a medicine, particularly for the prevention or treatment of painful and inflammatory conditions of the skin and mucous membranes, particularly for the 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 cancer, or for the treatment of bladder failure.

28. A method for modulating the cold menthol receptor TRPM8, particularly for in vitro and / or in vivo modulation, comprising the following steps: (ia) The steps of 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 according to any one of claims 25 to 27, (iia) a step of bringing the cooling agent or cooling agent mixture or preparation from step (ia) into contact with the receptor, or To produce a physiological cooling effect on the skin or mucous membrane, follow these steps: (ib) The steps of 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 according to any one of claims 25 to 27, (iib) a step of bringing the compound or cooling agent or cooling agent mixture or preparation from step (iib) into contact with human skin or mucous membrane, or To improve the taste characteristics of flavorings, follow these steps: (ic) A step of 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) A step of mixing the two components from step (ic), and optionally, (iiiic) The step of incorporating the mixture into an oral preparation, or To mask the bitter substances, follow these steps: (id) A step of 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 mixture of physiological cooling agents according to any one of claims 13 to 16 and 20, and at least one bitter substance, (iid) A step of mixing the two components from step (id), and optionally, A method comprising the step of incorporating (iii) mixture into an oral preparation.

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