Novel coolant and preparations containing same

Abstract

The present invention relates to novel physiological coolants, mixtures of coolants containing these novel agents, mixtures of coolants and flavors, uses of these coolants, and consumer articles and end preparations containing the physiological coolants or mixtures of coolants.

Description

[Technical Field]

[0001] The present invention is in the field of physiological coolants and relates to new representatives of this group, the use of these coolants and articles, and preparations containing these coolants. [Background technology]

[0002] Physiological coolants are typically used to create the impression of a cooling sensation on the skin or mucous membranes, for example, on the mucous membranes of the mouth, nose, and / or pharynx, without actually causing physical cooling, such as that associated with solvent evaporation. Both individual components and mixtures can be used as physiological coolants. It should be noted that not all compounds that affect receptors in vitro that are involved in mediating physiological cooling effects actually produce such effects in vivo on the skin or mucous membranes. In particular, such effects are not always identical. For example, this means that the intensity of the mediated physiological cooling effect and the time course of the cooling effect cannot be simply inferred from the fact that a particular compound is an agonist of the receptor involved in mediating the cooling effect.

[0003] TRP channels play an important role in temperature perception (hot-cold). TRP channels (Transient Receptor Potential channels) are a widespread family of cellular ion channels that can be divided into seven subfamilies.

[0004] The cold menthol receptor TRPM8 (also known as cold membrane receptor 1 (CMR1)) belongs to the family of "transient receptor potential ion channels" and is specifically expressed in a special group of neurons, where it mediates Ca 2+It forms pores in the cell membrane that selectively allow the passage of ions (four units cluster together to form a tetramer). The protein has six transmembrane domains and cytoplasmic C- and N-termini. The receptor is stimulated by low temperatures (preferably 10-25°C) and transmits a signal that is interpreted by the nervous system as a cooling sensation.

[0005] There is evidence that some TRP channels are important for growth control.The expression change of some of these channels may contribute to the development of cancer.For example, the expression of TRPM8 gene is upregulated in prostate cancer.Therefore, TRPM8 is also an attractive target for the treatment of prostate cancer or bladder cancer. Current state of the technology

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

[0007] The best-known physiologically effective coolant is L-menthol. Menthol compounds have been shown to act as natural modulators of the TRPM8 receptor. Application of menthol activates TRPM8, leading to the delivery of Ca to cold-sensitive neurons. 2+ This triggers an influx of electrical signals that are then felt as a cooling sensation.

[0008] However, menthol has several drawbacks, such as a strong odor, high volatility, and at higher concentrations, its bitter and / or pungent taste, as well as skin irritation. Too high a concentration of menthol can also cause irritation and anesthetic effects on the skin or mucous membranes.

[0009] There has been a search for a strong coolant that does not have the adverse properties of L-menthol.

[0010] For example, lactic acid esters of menthol are described according to DE 2608226 A1, as well as mixed carbonates of menthol and polyols according to DE 4226043 A1, and menthone ketals according to EP 0507190 B1.

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

[0012] Menthyl monoesters of diacids according to US Pat. No. 5,725,865 and US Pat. No. 5,843,466 are interesting natural substitutes, but they are unable to achieve the strength of the coolants already described in sensory tests.

[0013] The compounds L-menthanecarboxylic acid N-ethylamide ("WS-3"), and especially Nα-(L-menthanecarbonyl)glycine ethyl ester ("WS-5"), have been found to be potent coolants. However, the latter Nα-(L-menthanecarbonyl)glycine ethyl ester has the disadvantage of being susceptible to hydrolysis to form the corresponding free acid Nα-(L-menthanecarbonyl)glycine, which itself has only a very weak cooling effect. Despite the above detailed discussion, systematic prediction of the properties of potential coolants, in particular their bitter taste and / or other trigeminal effects, has not been possible or described. For example, many molecules belonging to the class of menthanecarboxylic acid amides, such as menthanecarboxylic acid N-(alkyloxyalkyl)amides according to JP2004059474A2, have a strong cooling effect, but often simultaneously exhibit a pronounced bitter note or are very irritating (such as N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycine ethyl ester according to US20050222256A1), and therefore such compounds are not suitable for use in food preparations, etc.

[0014] Nα-(menthanecarbonyl) alkyloxyalkylamides are described in JP2004059474A2. However, although they have a strong cooling effect and high hydrolytic stability, they have the drawback of being very bitter, and therefore cannot be used in food products or cosmetic products used in facial care.

[0015] Furthermore, in JP2005343795A2, menthyl glyoxylate and its hydrate are described as cooling substances.

[0016] The general outline of coolants that have been produced and used to date is known to those skilled in the art.

[0017] There are also isolated compounds structurally unrelated to menthol that cause significant TRPM8 modulation, such as Coolant WS-23, or the compounds listed in patent application WO2007019719A1.

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

[0019] WO2010026094A1 discloses individual compounds that modulate the TRPM8 receptor.

[0020] Further compounds that modulate the TRPM8 receptor are also proposed in WO2011061330A2.

[0021] Carboxamide Structure (I) [ka] A special coolant having

[0022] On the oral mucosa, many of the conventional cooling substances described above and known from the state of the art all exhibit more or less the same cooling behavior. The cooling sensation they provide begins after about 0.5 minutes, then peaks at 3-5 minutes and levels off relatively quickly, allowing the cooling sensation to be clearly felt for up to 30 minutes, and experience has shown that its intensity and duration can be only slightly affected by changing the dosage. However, consumers desire a particularly long-lasting cooling effect accompanied by a corresponding feeling of freshness and well-being in the user. Summary of the Invention [Problem to be solved by the invention]

[0023] Therefore, the main object of the present invention is to identify new substances with specific physiological cooling effect, preferably new substances (so-called modulators) that produce modulation of TRPM8 receptor, and preferably can be used as a more suitable agent to replace previously known modulators.Such compounds should also be particularly suitable for use in the fields of cosmetics, nutrition, textiles, OTC products (for example, burn ointments), pharmaceuticals (for example, tumor treatment, bladder weakness) or packaging.The disclosed compounds or compound mixtures should preferably have as weak an original taste as possible, in particular, have little or no bitterness, and be as non-irritating as possible.

[0024] To solve the problem of the present invention, the search has been made for active ingredients that can provide a particularly long-lasting cooling sensation.Preferably, these active ingredients should also be able to provide a particularly strong and / or fast cooling sensation.Coolants should be effective, that is, they should have a high cooling effect or cooling sensation even at low concentrations.

[0025] Another challenge has been to counteract the unpleasant odors that many flavors, especially sweeteners such as representatives of the stevioside family, have, especially bitter, astringent and metallic aftertastes.

[0026] The above problem is solved by the object of the independent claims. Further aspects of the invention are evident from the dependent claims, the following description and examples. DETAILED DESCRIPTION OF THE INVENTION

[0027] The main object of the present invention is to provide a compound represented by the general formulas (I) to (IV) [ka] or general formula (II) [ka] or general formula (III) [ka] or general formula (IV) [ka] (Wherein, in each of formulas (I) to (IV), [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] and their salts, preferably acid addition salts with inorganic or organic acids.

[0028] The coolants according to the invention represented by the general formulae (I) to (IV) can exist both in stereoisomerically pure form or as mixtures of different stereoisomers.

[0029] A preferred variant according to the first aspect of the invention is a physiological coolant according to one of the general formulae (I) and (II), in which X is selected from the group consisting of S, SO, NH and O. Even more preferred are coolants according to the invention in which X is S in the general formulae (I) and (II).

[0030] In an alternative preferred variant according to the first aspect of the present invention, the physiological coolant is according to one of the general formulae (III) and (IV), wherein X is selected from the group consisting of S, SO, optionally substituted linear or branched alkyl groups, optionally substituted cycloalkyl groups and piperidinyl.

[0031] In an even more preferred variant according to the first aspect of the invention, the compound of general formula (V) [ka] Or general formula (VI) [ka] (in each case of formulas (V) and (VI), [Table 2-1] [Table 2-2] [Table 2-3] and salts thereof, preferably acid addition salts with inorganic or organic acids; or compounds of the general formula (VII) [ka] Or general formula (VIII) [ka] (in each of formulas (VII) and (VIII), [Table 3-1] [Table 3-2] [Table 3-3] and their salts, preferably acid addition salts with inorganic or organic acids.

[0032] The coolants according to the general formulae (V) to (VIII) of the present invention can exist both in stereoisomerically pure form or as mixtures of different stereoisomers.

[0033] In an even more preferred variant according to the first aspect of the invention, the compound of general formula (Va) [ka] Or general formula (VIa) [ka] (in each case of formulae (Va) and (VIa), [Table 4-1] [Table 4-2] [Table 4-3] and their salts, in particular acid addition salts with inorganic or organic acids, physiological coolants, which can be present in stereoisomerically pure form or as a mixture of different stereoisomers; or compounds of the general formula (VIIa) [ka] Or general formula (VIIIa) [ka] (in each of formulas (VIIa) and (VIIIa), [Table 5-1] [Table 5-2] [Table 5-3] and their salts, in particular acid addition salts with inorganic or organic acids, are physiological coolants, which can be present in stereoisomerically pure form or as a mixture of different stereoisomers.

[0034] The coolants according to the general formulae (Va) to (VIIIa) of the present invention can exist both in stereoisomerically pure form or as mixtures of different stereoisomers.

[0035] The present invention also includes physiological coolants in which the oxygen atom in the oxazole ring of the basic structure of general formula (III), (VII) or (VIIa) is replaced by a sulfur atom, i.e., the oxazole ring of the basic structure of general formula (III), (VII) or (VIIa) is a thiazole ring.

[0036] Among the compounds of general formulae (I) to (VIII) and (Va) to (VIIIa), those compounds in which the heterocyclic ring in the basic structure of general formulae (I) to (VIII) and (Va) to (VIIIa) has at least two nitrogen atoms, i.e., compounds of general formulae (I), (V), and (Va) having a triazine ring in the basic structure, or compounds of general formulae (II), (VI), and (VIa) having a pyrazine ring in the basic structure, are particularly preferred because they have a free electron pair suitable for forming a covalent bond (so-called Lewis base). That is, compounds of general formulae (I), (V), and (Va) having a triazine ring in the basic structure, compounds of general formulae (II), (VI), and (VIa) having a pyrazine ring (diazine) in the basic structure, or compounds of general formulae (IV), (VIII), and (VIIIa) having an imidazole ring are particularly preferred. Such compounds exhibit particularly remarkable cooling properties as described below.

[0037] The compounds of general formulae (I), (V) and (Va) having a triazine ring in the basic structure, and the compounds of general formulae (III), (VII) and (VIIa) having an oxazole ring in the basic structure are most preferred due to their Lewis base properties, and such compounds are particularly characterized by a strong cooling effect.

[0038] In the context of the present invention, in particular with regard to the definitions of the general formulae (I) to (VIII) and (Va) to (VIIIa), the following general meanings apply:

[0039] The terms "or" or "and / or" are used as functional terms to indicate that two words or expressions may be taken together or separately.

[0040] The terms "comprising," "with," "including," and "containing" are to be understood as open terms, i.e., "comprising," "including," or "containing" means "but is not limited to."

[0041] The endpoints of all ranges directed to the same component or property may be combined, inclusively and independently of each other.

[0042] The term "compound" or "compound of the present invention" refers to all compounds encompassed by the structural formulas (I) and / or (II) disclosed herein, including any subgroups and any specific compounds within the formula whose structures are disclosed herein. The compound can be identified by either its chemical structure and / or its chemical name. In the event of a conflict between the chemical structure and the chemical name, the chemical structure is determined to be the same as the compound. The compounds described herein may contain one or more chiral centers and / or double bonds and may therefore exist as stereoisomers, such as double bond isomers, i.e., geometric isomers, enantiomers, or diastereomers. Thus, the chemical structures of the general formulas (I) and / or (II) shown herein include all possible enantiomers and diastereomers or stereoisomers.

[0043] The term "at least one coolant" in the context of the present invention means, for example, that the composition contains at least one coolant, but may also contain two, three, four or even several different coolants.

[0044] The term "alkyl," according to the present invention, alone or as part of another substituent, refers to a monovalent, saturated or mono- or polyunsaturated, linear or branched hydrocarbon radical obtained by removing a hydrogen atom from a single carbon atom of the corresponding initial alkane.

[0045] In a preferred variant, the term "alkyl" also includes all alkyl moieties in radicals derived therefrom, such as alkoxy, alkylthio, alkylsulfonyl, saturated linear or branched hydrocarbon radicals having 1 to 10, 1 to 8, 1 to 6 or 1 to 4 carbon atoms.

[0046] If the alkyl residue is further bonded to another atom, the alkyl residue becomes an alkylene residue or alkyl group. In other words, the term "alkylene" also refers to a divalent alkyl. For example, -CH2CH3 is ethyl, while -CH2CH2- is ethylene.

[0047] The term "alkylene," alone or as part of another substituent, refers to a divalent saturated linear or branched hydrocarbon radical derived by removing two hydrogen atoms from a single carbon atom or from two different carbon atoms of an initial alkane.

[0048] In a preferred variant according to the invention, the alkyl or alkylene group comprises 1 to 10 carbon atoms. In another even more preferred variant, the alkyl or alkylene group comprises 1 to 6 carbon atoms.

[0049] Alkyl or alkylene groups having 1 to 4 carbon atoms are most preferred.

[0050] Preferred alkyl radicals or alkyl groups include, but are not limited to: C1-C6 alkyl, 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. C1-C6-alkoxy including C1-C4-alkoxy such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy; and pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy.

[0051] According to the invention, saturated linear or branched C1-C6-alkyl groups or saturated linear or branched C1-C6-alkylene groups are most preferred.

[0052] The terms "alkyl" or "alkylene" further include radicals or groups with any degree of saturation, i.e., groups with only carbon-carbon single bonds ("alkyl" or "alkylene"), groups with one or more carbon-carbon double bonds ("alkenyl"), radicals with one or more carbon-carbon triple bonds ("alkynyl"), and groups with a mixture of carbon-carbon single, double, and / or triple bonds.

[0053] The term "alkenyl," according to the present invention, alone or as part of another substituent, refers to a monovalent unsaturated linear or branched hydrocarbon radical having at least one carbon-carbon double bond (C=C double bond). The remainder can be in either a cis or trans configuration about the double bond. Thus, the term "alkenyl" also includes the corresponding cis / trans isomers.

[0054] Typical alkenyl radicals or groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl, and cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, and buta-1,3-dien-2-yl; and the like.

[0055] In a preferred variant according to the 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.

[0056] According to the invention, mono- or di-unsaturated linear or branched C1-C6-alkenyl groups are most preferred.

[0057] The term "alkynyl," according to the present invention, alone or as part of another substituent, refers to a monovalent unsaturated linear or branched hydrocarbon radical having at least one carbon-carbon triple bond (C≡C triple bond).

[0058] Typical alkynyl residues or groups include, but are not limited to, ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl.

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

[0060] The term "alkoxy," according to the present invention, alone or as part of another substituent, refers to a radical of the formula --OR, where R is alkyl or substituted alkyl as defined herein.

[0061] The terms "alkylthio" or "thioalkoxy," according to the present invention, by themselves or as part of another substituent, refer to a radical of the formula --SR, where R is alkyl or substituted alkyl as defined herein.

[0062] According to the present invention, the term "alkyl" or "alkylene" also includes heteroalkyl radicals or heteroalkyl groups. The term "heteroalkyl," by itself or as part of another substituent, refers to an alkyl group in which one or more carbon atoms are independently replaced with the same or different heteroatoms or with the same or different heteroatom groups. Typical heteroatoms or heteroatom 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-, etc., and combinations thereof. The heteroatom or heteroatom group may be located at any interior position of the alkyl group. Typical heteroatom groups that may be included in these groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, -NRR-, =NN=, -N=N-, -N=N-NRR, -PR-, -P(O)2-, -POR-, -OP(O)2-, -SO-, -SO2-, -SR2OR-, and the like, wherein R is independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl, as defined herein.

[0063] The alkyl or alkylene groups defined above may also be substituted.

[0064] The term "acyl," according to the present invention, by itself or as part of another substituent, refers to the radical -R(C=O)-, where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, or substituted heteroarylalkyl, as defined herein.

[0065] Representative examples include, but are not limited to, formyl, acetyl, propionyl, butyryl, valeryl, benzoyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzylcarbonyl, and the like.

[0066] The term "cycloalkyl," according to the present invention, alone or as part of another substituent, refers to a monovalent saturated or monounsaturated or diunsaturated, non-aromatic cyclic hydrocarbon radical in which the carbon atoms are joined together in a ring, and which radical does not have heteroatoms.

[0067] Carbocycles can occur as monocyclic compounds, having only a single ring, or as polycyclic compounds, having two or more rings.

[0068] In preferred variations, 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 variations, the cycloalkyl moieties include 3-, 4-, 5-, 6-, or 7-membered monocyclic cycloalkyl moieties, or 9- to 12-membered bicyclic cycloalkyl moieties.

[0069] In a preferred variant according to the invention, the cycloalkyl radical or cycloalkyl group contains 3 to 20 carbon atoms. In an even more preferred variant, the cycloalkyl radical contains 3 to 15 carbon atoms. In the most preferred variant, the cycloalkyl radical contains 3 to 10 carbon atoms. Monocyclic C3-C7-cycloalkyl groups are most preferred.

[0070] Typical cycloalkyl groups include, but are not limited to, C3-C6, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. 12 C3-C7-carbocyclyl, including cyclopentyl, cyclohexyl, cycloheptyl, and cyclopropyl-methyl, cyclopropyl-ethyl, cyclobutyl-methyl, cyclobutyl-ethyl, cyclopentyl-methyl, cyclopentyl-ethyl, cyclohexyl-methyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropyl-methyl, cyclopropyl-ethyl, cyclobutyl-methyl, cyclopentyl-ethyl, cyclohexyl-methyl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1,3-dien-1-yl, etc., are preferred.

[0071] Preferred saturated polycyclic cycloalkyl radicals or cycloalkyl groups according to the present invention include, but are not limited to, adamantyl groups and the like.

[0072] According to the present invention, the term "cycloalkyl" also includes cycloalkenyl, i.e., an unsaturated cyclic hydrocarbon radical containing a C=C double bond between two carbon atoms of the ring molecule. In a broader sense, cycloalkenyl is a compound having one, two or more double bonds, and the number of possible mostly conjugated double bonds in the molecule depends on the ring size.

[0073] Typical cycloalkenyls include, but are not limited to, cyclopropenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.

[0074] According to the present invention, the term "cycloalkyl" also includes cycloalkynyl, i.e., unsaturated cyclic hydrocarbon radicals containing a -C≡C triple bond between two carbon atoms of the ring molecule, the triple bond being due to ring strain depending on the ring size.

[0075] Exemplary cycloalkynes include cyclooctynes.

[0076] The cycloalkyl residue or cycloalkyl group may be bonded to the rest of the molecule of formula (I) and / or formula (II) via any suitable C atom.

[0077] The cycloalkyl residues or cycloalkyl groups defined above may also be substituted.

[0078] The term "aryl," according to the present invention, alone or as part of another substituent, refers to a monovalent aromatic hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom of an aromatic ring system.

[0079] In preferred variations, the term "aryl" includes a 3- to 10-membered monocyclic aryl radical or group, or a 9- to 12-membered polycyclic aryl radical or group. In other even more preferred variations, the carboaryl moiety includes a 3-, 4-, 5-, 6-, or 7-membered monocyclic carboaryl moiety, or a 9- to 12-membered bicyclic carboaryl moiety.

[0080] In a preferred variant according to the invention, the aryl radical contains 3 to 20 carbon atoms. In an even 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 invention, monocyclic C3-C 12-aryl groups are most preferred. Monocyclic C3-C7-aryl groups are most preferred.

[0081] Typical aryl radicals include, but are not limited to, benzene, phenyl, biphenyl, naphthyl (such as 1- or 2-naphthyl), tetrahydronaphthyl, fluorenyl, indenyl, and phenanthrenyl. Typical carboaryl radicals further include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiades, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0082] Preferred aromatic polycyclic aryl radicals or groups according to the present invention include, but are not limited to, naphthalene, biphenyl, and the like.

[0083] The aryl residue or group may be bonded to the remainder of the molecule of formulae (I)-(VIII) and (Va)-(VIIIa) via any suitable C atom.

[0084] The aryl residue or group defined above may also be substituted, for example, the aryl residue forms an anisole group.

[0085] The term "arylalkyl," according to the present invention, alone or as part of another substituent, refers to a chain alkyl group in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or sp carbon atom, is replaced by an aryl group as defined herein. In other words, arylalkyl can also be considered as an alkyl substituted by an aryl. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, etc.

[0086] The term "heteroarylalkyl," alone or as part of another substituent, refers to a cyclic alkyl group in which one or more of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group.

[0087] In a preferred embodiment according to the present invention, the heteroarylalkyl group is a 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl group of the heteroarylalkyl is C1-C6-alkyl and the heteroaryl group is a 5-15 membered heteroaryl group. In another embodiment, the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl group is C1-C3-alkyl and the heteroaryl group is a 5-10 membered heteroaryl.

[0088] The term "heterocycloalkyl," according to the present invention, alone or as part of another substituent, refers to a monovalent saturated non-aromatic cyclic hydrocarbon radical in which one or more carbon atoms are independently replaced by the same or different heteroatoms. Typical heteroatoms replacing carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Typical heterocycloalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidines, morpholines, piperazines, piperidines, pyrazolidines, pyrrolidones, quinuclidines, etc.

[0089] Heterocycloalkyl residues can occur as monocyclic compounds, having only a single ring, or as polycyclic compounds, having two or more rings.

[0090] Preferably, the term "heterocycloalkyl" includes 3- to 7-membered saturated, mono-, or polyunsaturated heterocycloalkyl radicals containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S. The heteroatom(s) may occupy any position within the heterocycloalkyl ring. The heteroatom(s) may occupy any position within the heterocycloalkyl ring.

[0091] In preferred variations, the term "heterocycloalkyl" includes a 3- to 10-membered monocyclic heterocycloalkyl radical or a 9- to 12-membered polycyclic heterocycloalkyl radical. In other even more preferred variations, the heterocycloalkyl moiety includes a 3-, 4-, 5-, 6-, or 7-membered monocyclic heterocycloalkyl moiety or a 9- to 12-membered bicyclic heterocycloalkyl moiety.

[0092] In a preferred variation according to the invention, the "heterocycloalkyl" residue or heterocycloalkyl group contains 3 to 20 ring atoms. In a preferred variation, the heterocycloalkyl moiety contains 3 to 15 ring atoms. In an even more preferred variation, the heterocycloalkyl moiety contains 3 to 10 carbon atoms. Monocyclic heterocycloalkyl radicals containing 3 to 12 carbon atoms are most preferred according to the invention. Monocyclic heterocycloalkyl radicals containing 5 to 7 ring atoms are most preferred.

[0093] Exemplary heterocycloalkyl radicals include, but are not limited to, 3- to 6-membered saturated heterocycloalkyl containing one or two nitrogen atoms, and / or one oxygen or sulfur atom, or one or two oxygen and / or sulfur atoms as ring members, such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 1-piperidinyl, 2-piperidine Includes lysinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl and the like.

[0094] The heterocycloalkyl radical or heterocycloalkyl group defined above may be further substituted.

[0095] The heterocycloalkyl radical or heterocycloalkyl group may be attached to the remainder of the molecule of formulas (I) through (VIII) and (Va) and (VIII) via a ring carbon atom or a ring heteroatom.

[0096] The term "heteroaryl," according to the present invention, by itself 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 groups include, but are not limited to, those derived from acridine, β-carboline, chroman, chromium, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochrome, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazole, xanthene, and the like.

[0097] Heteroaryl residues can occur as monocyclic compounds, having only a single ring, or as polycyclic compounds, having two or more rings.

[0098] In preferred variations, the term "heteroaryl" includes a 3- to 10-membered monocyclic heteroaryl radical or a 9- to 12-membered polycyclic heteroaryl radical. In other even more preferred variations, the heteroaryl moiety includes a 3-, 4-, 5-, 6-, or 7-membered monocyclic heteroaryl moiety or a 9- to 12-membered bicyclic heteroaryl moiety.

[0099] Preferably, the term "heteroaryl" includes 3- to 7-membered monocyclic heteroaryl radicals containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S. The heteroatom(s) may occupy any position within the heteroaryl ring. The heteroatom(s) may occupy any position within the heteroaryl ring.

[0100] In a preferred variant according to the invention, the heteroaryl moiety or group contains 3 to 20 ring atoms. In an even more preferred variant, the heteroaryl moiety contains 6 to 15 ring atoms. In the most preferred variant, the heteroaryl group contains 6 to 10 ring atoms. Monocyclic C3-C7-heteroaryl groups are most preferred according to the invention.

[0101] Particularly preferred heteroaryl radicals or 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.

[0102] Three-membered aromatic heteroaryl radicals containing, in addition to carbon atoms, nitrogen or sulfur or oxygen atoms as ring atoms include azirinyl, oxirenyl or thiirenyl.

[0103] Four-membered aromatic heteroaryl radicals containing, in addition to carbon atoms, nitrogen or sulfur or oxygen atoms as ring atoms include acetyl, oxetium or thietium ions.

[0104] Five-membered aromatic heteroaryl radicals containing, in addition to carbon atoms, one, two or three nitrogen atoms, or one or two nitrogen atoms and one sulfur or oxygen atom as ring atoms include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl and 1,3,4-triazol-2-yl.

[0105] Five-membered aromatic heteroaryl radicals containing one, two, three or four nitrogen atoms as ring atoms are exemplified by 1-, 2- or 3-pyrrolyl, 1-, 3- or 4-pyrazolyl, 1-, 2- or 4-imidazolyl, 1,2,3-[1H]-triazol-1-yl, 1,2,3-[2H]-triazol-2-yl, 1,2,3-[1H]-triazol-4-yl, 1,2,3-[1H]-triazol-5-yl, 1,2,3-[2H]- including triazol-4-yl, 1,2,4-[1H]-triazol-1-yl, 1,2,4-[1H]-triazol-3-yl, 1,2,4-[1H]-triazol-5-yl, 1,2,4-[4H]-triazol-4-yl, 1,2,4-[4H]-triazol-3-yl, [1H]-tetrazol-1-yl, [1H]-tetrazol-5-yl, [2H]-tetrazol-2-yl, [2H]-tetrazol-5-yl, and the like.

[0106] Five-membered aromatic heteroaryl radicals containing as ring atoms an oxygen atom or a sulfur atom and optionally a heteroatom selected from one, two or three nitrogen 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-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl and 1,3,4-oxadiazol-2-yl.

[0107] 6-membered heteroaryl radicals which contain, in addition to carbon atoms, one or two, or one, two or three nitrogen atoms as ring atoms and include, for example, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,2,4-triazin-3-yl; 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl and 1,3,5-triazin-2-yl.

[0108] The heteroaryl residues or groups defined above may also be substituted.

[0109] The heteroaryl radical or group may be attached to the remainder of the molecule of Formula (I) through Formula (VIII) and (Va) and (VIII) via a ring carbon atom or a ring heteroatom.

[0110] Of the above monocyclic heteroaryl radicals, those derived from five- or six-membered saturated compounds including pyrrolidone, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothipyran, or from five- or six-membered aromatic compounds including pyrrole, furan, thiophene, pyridine, pyrylium and thiopyrylium ions, pyrazole, imidazole, imidazoline, pyrimidine, oxazole, thiazole, and 1,4-thiazine are particularly preferred in the context of the present invention.

[0111] The term "arylalkyl," according to the present invention, alone or as part of another substituent, refers to a chain alkyl group in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or sp carbon atom, is replaced by an aryl group as defined herein. In other words, arylalkyl can also be considered as an alkyl substituted by an aryl. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, etc.

[0112] The term "heteroarylalkyl," alone or as part of another substituent, refers to a cyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. In preferred embodiments according to the present invention, the heteroarylalkyl group is a 6- to 20-membered heteroarylalkyl, e.g., the alkanyl, alkenyl, or alkynyl group of the heteroarylalkyl is C1-C6-alkyl, and the heteroaryl group is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkyl is a 6- to 13-membered heteroarylalkyl, e.g., the alkanyl, alkenyl, or alkynyl group is C1-C3-alkyl, and the heteroaryl group is a 5- to 10-membered heteroaryl.

[0113] The term "substituted," in the context of this invention, means that one or more hydrogen atoms of the specified radical or the specified radical are independently replaced with the same or a different substituent.

[0114] Useful substituents or groups of substituents for replacing saturated carbon atoms in the specified groups or moieties include, but are not limited to, -X, halo, =O, -OY, -SiR3, -SY, =S, -NZZ, =NY, =N-OY, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY)2, -P(O)(OY)(OY), -C(O)Y, -C( and X is an optionally substituted alkyl radical as defined above, in particular an optionally substituted C1-C6 alkyl radical ... 10alkyl 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 radicals, and / or Y means hydrogen or X; and / or Z is Y, or alternatively, two Zs together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl or heteroaryl ring, which may contain 1, 2, 3, or 4 of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0115] Specific preferred examples of substitutions are OH, methyl, ethyl, methoxy, ethoxy, phenyl, which in turn may be substituted by OH, methyl, ethyl, methoxy, ethoxy or CH3-C(O)- or thiophene.

[0116] In a further variation, one or more substituent groups, preferably phenyl groups, together with the atom to which they are attached may form a cyclic ring, including a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl.

[0117] Similarly, useful substituent groups for replacing unsaturated carbon atoms in the specified groups or radicals include, but are not limited to, -X, halo, =O, -OY, -SiR3, -SY, =S, -NZZ, =NY, =N-OY, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY)2, -P(O)(OY)( and -NYC(NY)NZZ, wherein X, Y, and Z have the same meanings as defined above.

[0118] The substituent or groups of substituents for substitution of a nitrogen atom in heteroalkyl and heterocycloalkyl radicals include, but are not limited to, -X, -OY, -SiR, -SY, -NZZ, trihalomethyl, -CF, -CN, -OCN, -SCN, -NO, -NO, =N, -N, -S(O)Y, -S(O)OY, -OS(O)Y, -OS(O)OY, -P(O)(OY), -P(O)(OY)(OY), -C(O )Y, -C(S)Y, -C(NY)Y, -C(O)OY, -C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, -NYC(O)Y, -NYC(S)Y, -NYC(O)OY, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y and -NYC(NY)NZZ, wherein X, Y and Z still have the same meanings as defined above.

[0119] The term "substituted" specifically refers to one or more substitutions, i.e., two, three, four, five, six, or more, as is common in the art. However, it is generally recognized by those skilled in the art that the substituents should be selected so as not to adversely affect the useful properties of the compound or its function.

[0120] Suitable substituents within the scope of the present invention preferably include halogen, perfluoroalkyl, perfluoroalkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, aryl or heteroaryl, aryloxy or heteroaryloxy, arylalkyl or heteroarylalkyl, arylalkoxy or heteroarylalkoxy, amino, alkylamino and dialkylamino, carbamoyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, cycloalkyl, cyano, C1-C6-alkylthio, arylthio, nitro, keto, acyl, boronate or boronyl, phosphate or phosphonyl, sulfamyl, sulfonyl, sulfinyl and combinations thereof. In the case of substituted combinations, such as substituted arylalkyl, 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.

[0121] Preferred substituents for the above groups or radicals are in particular selected 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, in which one or more H atoms in the alkyl group may be replaced by halogen.

[0122] Additionally, in some cases, suitable substituents may be combined to form one or more rings known to those of ordinary skill in the art.

[0123] The term "optionally substituted" in the context of the present invention denotes the presence or absence of a substituent group, i.e., means "substituted" or "unsubstituted." For example, the term "optionally substituted alkyl" includes both unsubstituted alkyl and substituted alkyl.

[0124] According to the present invention, a particular radical or a substituent used to replace a radical may in turn be further substituted, typically with one or more of the same or different radicals selected from the various groups shown and defined in detail above.

[0125] In a particularly preferred variant according to the first aspect of the invention, the radicals R1 and R2 in the general formulae (I) to (VIII) and (Va) and (VIII) are the same or different.

[0126] Preferably, R1 in the general formulae (I) to (VIII) and (Va) to (VIIIa) represents H or an optionally substituted alkyl group or an optionally substituted phenyl group or an optionally substituted thiophene group.

[0127] More preferably, R2 in the general formulae (I) to (VIII) and (Va) to (VIIIa) represents H or an optionally substituted alkyl group, an optionally substituted phenyl group, or an optionally substituted thiophene group.

[0128] Coolants with particularly advantageous properties, i.e., particularly strong and effective, preferably at the same time long-lasting cooling action, are usually found in structures of general formula (I), (V) or (Va) which have a triazine ring in their basic structure, and in which at least one of the radicals R1 and R2 represents an optionally substituted phenyl group or an optionally substituted thiophene group.

[0129] Even more preferably, at least one of the radicals R1 and R2 is an optionally substituted phenyl group.

[0130] Most preferred are compounds of general formula (I), (V) or (Va) in which both R1 and R2 represent an optionally substituted phenyl group.

[0131] Specific preferred examples of substitutions on the phenyl group are OH, methyl, ethyl, methoxy or ethoxy.

[0132] Most preferably, R1 and R2 represent a phenyl group.

[0133] In an even more preferred variation, two phenyl groups together with the atom to which they are attached form a cyclic ring, including a cycloalkyl or heterocycloalkyl.

[0134] Compounds of general formula (I), (V) or (Va) in which both R1 and R2 are unsubstituted phenyl groups are the most preferred compounds.

[0135] In a further preferred variant, in the compounds of general formula (I), (V) or (Va), R1 and R2 are each a substituted or unsubstituted phenyl group, which together with the C atom of the core structure to which they are attached form a conjugated or non-conjugated ring system.

[0136] It has been shown that compounds of the above general formula (I), (V) or (Va), in which both R1 and R2 are substituted or unsubstituted phenyl groups, in particular, exhibit excellent TRPM8 activity and can produce very strong sensory cooling effects even when used in small amounts.

[0137] Coolants with particularly advantageous properties, i.e. particularly strong and effective, preferably at the same time long-lasting cooling action, are also found in structures of general formula (II), (VI) or (VIa) which have a pyrazine ring in their basic structure, and in which at least one of the radicals R1 and R2 represents an optionally substituted phenyl group or an optionally substituted thiophene group.

[0138] Even more preferably, at least one of the radicals R1 and R2 is an optionally substituted phenyl group.

[0139] Most preferred are compounds of general formula (II), (VI) or (VIa) in which both R1 and R2 represent an optionally substituted phenyl group.

[0140] Specific preferred examples of substitutions are OH, methyl, ethyl, methoxy or ethoxy.

[0141] Most preferably, R1 and R2 represent a phenyl group.

[0142] In an even more preferred variation, two phenyl groups together with the atom to which they are attached form a cyclic ring, including a cycloalkyl or heterocycloalkyl.

[0143] Compounds of general formula (II), (VI) or (VIa) in which both R1 and R2 are unsubstituted phenyl groups are the most preferred compounds.

[0144] In a further preferred variant, in the compounds of general formula (II), (VI) or (VIa), R1 and R2 are each a substituted or unsubstituted phenyl group, which together with the C atom of the core structure to which they are attached form a conjugated or non-conjugated ring system.

[0145] In particular, compounds of general formula (I), (V) or (Va) in which both R1 and R2 are substituted or unsubstituted phenyl groups have been shown to exhibit excellent TRPM8 activity and to be capable of producing very strong sensory cooling effects even when used in small amounts.

[0146] Coolants having particularly advantageous properties, i.e. a particularly strong and effective, preferably at the same time long-lasting cooling action, and / or possibly, in particular, effective masking of undesirable taste impressions, are also found in structures of the general formulae (III), (VII) or (VIIa) which have an oxazole ring in their basic structure, and in which at least one of the radicals R1 and R2 represents an optionally substituted phenyl group or an optionally substituted thiophene group.

[0147] Even more preferably, at least one of the radicals R1 and R2 is an optionally substituted phenyl group.

[0148] Most preferred are compounds of general formula (III), (VII) or (VIIa) in which both R1 and R2 represent an optionally substituted phenyl group.

[0149] Specific preferred examples of substitutions are OH, methyl, ethyl, methoxy or ethoxy.

[0150] Most preferably, R1 and R2 represent a phenyl group.

[0151] In an even more preferred variation, two phenyl groups together with the atom to which they are attached form a cyclic ring, including a cycloalkyl or heterocycloalkyl.

[0152] Compounds of general formula (III), (VII) or (VIIa) in which both R1 and R2 are unsubstituted phenyl groups are the most preferred compounds.

[0153] In a further preferred variant, in the compounds of general formula (III), (VII) or (VIIa), R1 and R2 are each a substituted or unsubstituted phenyl group, which together with the C atom of the core structure to which they are attached form a conjugated or non-conjugated ring system.

[0154] In particular, compounds of general formula (III), (VII) or (VIIa), in which both R1 and R2 are substituted or unsubstituted phenyl groups, have been shown to exhibit excellent TRPM8 activity and to be capable of producing very strong sensory cooling effects even in small amounts.

[0155] Coolants with particularly advantageous properties, i.e., a particularly strong and effective, preferably at the same time long-lasting cooling action, are also found in structures of general formula (IV), (VIII) or (VIIIa) which have an imidazole ring in their basic structure, and in which at least one of the radicals R1 and R2 represents an optionally substituted phenyl group or an optionally substituted thiophene group.

[0156] Even more preferably, at least one of the radicals R1 and R2 is an optionally substituted phenyl group.

[0157] Most preferred are compounds of general formulae (IV), (VIII) and (VIIIa) in which both R1 and R2 represent an optionally substituted phenyl group.

[0158] Specific preferred examples of substitutions are OH, methyl, ethyl, methoxy or ethoxy.

[0159] Most preferably, R1 and R2 represent a phenyl group.

[0160] In an even more preferred variation, two phenyl groups together with the atom to which they are attached form a cyclic ring, including a cycloalkyl or heterocycloalkyl.

[0161] Compounds of general formula (IV), (VIII) or (VIIIa) in which both R1 and R2 are unsubstituted phenyl groups are the most preferred compounds.

[0162] In a further preferred variant, in the compounds of general formula (IV), (VIII) or (VIIIa), R1 and R2 are each a substituted or unsubstituted phenyl group, which together with the C atom of the core structure to which they are attached form a conjugated or non-conjugated ring system.

[0163] It has been shown that these compounds, particularly those of general formula (IV), (VIII) or (VIIIa), in which both R1 and R2 are substituted or unsubstituted phenyl groups, exhibit excellent TRPM8 activity and can produce very strong sensory cooling effects even in small amounts.

[0164] Likewise, the coolants of the general formulas (I) to (VIII) are further preferred according to the present invention, in which Y represents a linear alkylene group, an optionally branched alkylene group, an alkylaryl group, or an alkylheteroaryl group. Preferably, the alkylene group is a methylene group -CH-, an ethylene group -CH-CH-, or a propylene group -CH-CH-CH-. Alternatively, Y in the general formulas (I) to (VIII) can also represent a branched alkylene group, preferably a methylene group, which is substituted by a methyl group, an ethyl group, a linear or branched propyl group, or a linear or branched butyl group.

[0165] Even more preferred according to the invention are compounds of general formulae (I) to (VIII) in which Y represents a methylene group or a methylene group substituted by a methyl group, an ethyl group, a linear or branched propyl group, or a linear or branched butyl group, which have particularly pronounced cooling properties, as described below.

[0166] Even more preferred are coolants of general formula (I) or (V) having one of the following structural combinations: R1 and / or R2 = optionally substituted phenyl group and Y = methylene; R1 and / or R2 = optionally substituted phenyl group and Y = linear ethylene; or R1 and / or R2 = optionally substituted phenyl group and Y = linear or branched propylene; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted by methyl group, ethyl group, linear or branched propyl group or linear or branched butyl group.

[0167] Likewise preferred are coolants of general formula (II) or (VI) having one of the following structural combinations: R1 and / or R2 = optionally substituted phenyl group and Y = methylene; R1 and / or R2 = optionally substituted phenyl group and Y = linear ethylene; or R1 and / or R2 = optionally substituted phenyl group and Y = linear or branched propylene; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted by methyl group, ethyl group, linear or branched propyl group or linear or branched butyl group.

[0168] Further preferred are such coolants of general formula (III) or (VII) having one of the following structural combinations: R1 and / or R2 = optionally substituted phenyl group and Y = methylene; R1 and / or R2 = optionally substituted phenyl group and Y = linear ethylene; or R1 and / or R2 = optionally substituted phenyl group and Y = linear or branched propylene; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted by methyl group, ethyl group, linear or branched propyl group or linear or branched butyl group.

[0169] Further preferred are such coolants of general formula (IV) or (VIII) having one of the following structural combinations: R1 and / or R2 = optionally substituted phenyl group and Y = methylene; R1 and / or R2 = optionally substituted phenyl group and Y = linear ethylene; or R1 and / or R2 = optionally substituted phenyl group and Y = linear or branched propylene; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted by methyl group, ethyl group, linear or branched propyl group or linear or branched butyl group.

[0170] Even more preferred are such coolants of general formula (I) or (V) having one of the following structural combinations: R1 and / or R2 = phenyl group and Y = methylene; R1 and / or R2 = phenyl group and Y = linear ethylene; or R1 and / or R2 = phenyl group and Y = linear or branched propylene; or R1 and / or R2 = phenyl group and Y = methylene substituted with methyl group, ethyl group, linear or branched propyl group or linear or branched butyl group.

[0171] Likewise preferred are coolants of general formula (II) or (VI) having one of the following structural combinations: R1 and / or R2 = phenyl group and Y = methylene; R1 and / or R2 = phenyl group and Y = linear ethylene; or R1 and / or R2 = phenyl group and Y = linear or branched propylene; or R1 and / or R2 = phenyl group and Y = methylene substituted with methyl group, ethyl group, linear or branched propyl group or linear or branched butyl group.

[0172] Further preferred are coolants of general formula (III) or (VII) having one of the following structures: R1 and / or R2 = phenyl group and Y = methylene; R1 and / or R2 = phenyl group and Y = linear ethylene; or R1 and / or R2 = phenyl group and Y = linear or branched propylene; or R1 and / or R2 = phenyl group and Y = methylene substituted with methyl group, ethyl group, linear or branched propyl group or linear or branched butyl group.

[0173] Further preferred are coolants of general formula (IV) or (VIII) having one of the following structures: R1 and / or R2 = phenyl group and Y = methylene; R1 and / or R2 = phenyl group and Y = linear ethylene; or R1 and / or R2 = phenyl group and Y = linear or branched propylene; or R1 and / or R2 = phenyl group and Y = methylene substituted with methyl group, ethyl group, linear or branched propyl group or linear or branched butyl group.

[0174] Of the last-mentioned coolants according to general formulas (I) to (VIII), those compounds in which Y represents a methylene group substituted by a methyl or ethyl group are most preferred.

[0175] Such compounds are particularly characterized by a strong cooling effect.

[0176] In the general formulae (I) to (VIII), Z is selected from the group consisting of NH, NHRa, NRaR, 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 an optionally substituted linear or branched alkyl group, or an optionally substituted linear or branched alkenyl group, or an optionally substituted linear or branched alkenyl group, or an optionally substituted linear or branched alkynyl group, or an optionally substituted linear or branched alkoxy group, or an optionally substituted linear or branched alkylthio group; or an optionally substituted acyl group R—(C═O)—; or an optionally substituted cycloalkyl group; or an optionally substituted aryl group; or an optionally substituted heterocycloalkyl group; or It is an optionally substituted heteroaryl group.

[0177] In a further alternative variation, the Ra and Rb radicals of the NRaRb group defined above are linked to form a saturated or unsaturated ring, preferably a 3- to 8-membered saturated or unsaturated ring.

[0178] Coolants of general formulae (I) to (VIII) in which Ra and / or Rb in the NHRa or NRaRb group represent a C1-C3 alkyl group, preferably a methyl group, are particularly preferred according to the invention.

[0179] Even more preferred according to the invention are such coolants of general formulas (I) to (VIII), in which Z is selected from the group consisting of: -NH2, -NH-CH3, -NH-CH2-CH3, -NH-CH2-CH2-CH3, -NH-CH2-CH2-CH2-CH3, -NH-CH(CH3)-CH(CH3)2, -NH-CH(CH3)-CH2-CH2-CH3, -NH-CH2-CH(CH3)2, -NH-CH2-CH2-O-CH3, -NH-CH(CH3)-CH2-O-CH3, -NH-C(=O)-CH3, -NH-C(=O)-O-CH3, -NH-CH(CH3)-CH2-OH, -NH-CH2-furanyl, -NH-CH2-tetrahydrofuranyl, -NH-CH2-thiophenyl, -NH-toluolyl, -NH-CH-(CH3)2, -NH-C(CH3)3, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -N(CH3)2, -N(CH3)-cyclohexyl, -N(CH2-CH3)2, azetidinyl, Pyrrolidinyl, piperidinyl, azacyclobutadienyl, pyrrolyl, Pyridinyl, -O, -OH, -O-CH3, -OC(=O)-CH3, oxetanyl, -CH3, -CH2-CH3, -CH(CH3)2, -C(OH)-CH2-OH, Cyclopropyl, phenyl, and -CH2-S-CH3.

[0180] Thus, preferred variants according to the first aspect of the invention are coolants of general formula (I) to (VIII) having the following structure: [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6]

[0181] Even more preferred according to the invention are coolants of general formula (I), (II), (V) or (VI) having the following structure: [Table 7-1] [Table 7-2]

[0182] Even more preferred according to the invention are coolants of general formula (III), (IV), (VII) or (VIII) having the following structure: [Table 8-1] [Table 8-2]

[0183] Likewise, with regard to the determined TRPM8 activity, compounds of general formulae (I) to (VIII) in which n and m are each 1 are preferred.

[0184] Among the physiological coolants defined and described above, those of general formulae (I) to (IV) in which X represents a sulfur atom are particularly preferred. Such compounds have particularly pronounced cooling properties, as described below.

[0185] Particularly advantageous cooling properties are surprisingly exhibited by the compounds according to the invention of the general formulae (I) to (VIII), in which R1 and R2 each represent an unsubstituted phenyl group, X represents a sulfur atom, Y represents a methylene group or a methylene group substituted by a methyl group, an ethyl group, a linear or branched propyl group or a linear or branched butyl group, and Z has the meaning defined above.

[0186] Such compounds are particularly effective cooling agents, as exemplified below.

[0187] Most preferred according to the invention are compounds of the general formulae (Va) to (VIIIa) in which the radicals R1 and / or R2 represent an unsubstituted or substituted phenyl group, Y represents a branched alkylene group, preferably a methylene group substituted by a methyl group, an ethyl group, a linear or branched propyl group or a linear or branched butyl group, and Z has the meaning defined above for the compounds of the general formulae (I) to (VIII).

[0188] Such compounds exhibit significant TRPM8 activity and are highly potent sensory coolants, even in small amounts.

[0189] Particularly preferred are coolants of general formula (Va) or (VIa) having one of the following structural combinations: R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with methyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with an ethyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with a linear or branched propyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted by a linear or branched butyl group.

[0190] Also particularly preferred are such coolants of general formula (VIIa) or (VIIIa) having one of the following structural combinations: R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with methyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with an ethyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted with a linear or branched propyl group; or R1 and / or R2 = optionally substituted phenyl group and Y = methylene substituted by a linear or branched butyl group.

[0191] Likewise preferred are coolants of general formula (Va) or (VIa) having one of the following structural combinations: R1 and / or R2 = phenyl group and Y = methylene substituted with methyl group; or R1 and / or R2 = phenyl group and Y = methylene substituted with ethyl group; or R1 and / or R2 = phenyl group and Y = methylene substituted with linear or branched propyl group; or R1 and / or R2 = phenyl group and Y = methylene substituted with linear or branched butyl group.

[0192] Likewise preferred are coolants of general formula (VIIa) or (VIIIa) having one of the following structural combinations: R1 and / or R2 = phenyl group and Y = methylene substituted with methyl group; or R1 and / or R2 = phenyl group and Y = methylene substituted with ethyl group; or R1 and / or R2 = phenyl group and Y = methylene substituted with linear or branched propyl group; or R1 and / or R2 = phenyl group and Y = methylene substituted with linear or branched butyl group.

[0193] Surprisingly, extremely good cooling properties are exhibited by the compounds according to the invention of general formulae (Va) to (VIIIa), in which R1 and R2 each represent an unsubstituted phenyl group, Y represents a branched alkylene group, preferably a methylene group substituted by a methyl group, an ethyl group, a linear or branched propyl group or a linear or branched butyl group, and Z has the meaning defined above for the compounds of general formulae (I) to (VIII).

[0194] Thus, 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 linear or branched butyl groups a coolant of general formula (Va) or (VIa) having the formula: 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

[0195] R1 and R2 = phenyl groups and Y = methylene substituted with linear or branched butyl groups Most preferred are coolants of general formula (VIIa) or (VIIIa) having the formula:

[0196] Of the last-mentioned coolants according to general formulae (Va) to (VIIIa), those compounds in which Y represents a methylene group substituted by a methyl or ethyl group are most preferred.

[0197] Such compounds have particularly high TRPM8 activity and can produce very strong sensory cooling effects even when used in small amounts.

[0198] In the general formulae (Va), (VIa), (VIIa) and (VIIIa), Z is selected from the group consisting of NH, NHRa, NRaR, 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 heterocycloalkyl 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 an optionally substituted linear or branched alkyl group, or an optionally substituted linear or branched alkenyl group, or an optionally substituted linear or branched alkenyl group, or an optionally substituted linear or branched alkynyl group, or an optionally substituted linear or branched alkoxy group, or an optionally substituted linear or branched alkylthio group; or an optionally substituted acyl group R—(C═O)—; or an optionally substituted cycloalkyl group; or an optionally substituted aryl group; or an optionally substituted heterocycloalkyl group; or It is an optionally substituted heteroaryl group.

[0199] In a further alternative variation, the Ra and Rb radicals of the NRaRb group defined above are linked to form a saturated or unsaturated ring, preferably a 3- to 8-membered saturated or unsaturated ring.

[0200] Coolants of general formulae (Va) to (VIIIa), in which Ra and / or Rb in the NHRa or NRaRb group represent a C1-C3 alkyl group, preferably a methyl group, are particularly preferred according to the invention.

[0201] Even more preferred according to the invention are such coolants of general formulae (Va), (VIIa) and (VIIIa), in which Z is selected from the group consisting of: -NH2, -NH-CH3, -NH-CH2-CH3, -NH-CH2-CH2-CH3, -NH-CH2-CH2-CH2-CH3, -NH-CH(CH3)-CH(CH3)2, -NH-CH(CH3)-CH2-CH2-CH3, -NH-CH2-CH(CH3)2, -NH-CH2-CH2-O-CH3, -NH-CH(CH3)-CH2-O-CH3, -NH-C(=O)-CH3, -NH-C(=O)-O-CH3, -NH-CH(CH3)-CH2-OH, -NH-CH2-furanyl, -NH-CH2-tetrahydrofuranyl, -NH-CH2-thiophenyl, -NH-toluolyl, -NH-CH-(CH3)2, -NH-C(CH3)3, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -N(CH3)2, -N(CH3)-cyclohexyl, -N(CH2-CH3)2, azetidinyl, Pyrrolidinyl, piperidinyl, azacyclobutadienyl, pyrrolyl, Pyridinyl, -O, -OH, -O-CH3, -OC(=O)-CH3, oxetanyl, -CH3, -CH2-CH3, -CH(CH3)2, -C(OH)-CH2-OH, Cyclopropyl, phenyl, and -CH2-S-CH3.

[0202] 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-toluoyl, -NH-CH- Even more preferred according to the invention are such coolants of the general formula (VIa) selected from the group consisting of (CH3)2, -NH-C(CH3)3, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -N(CH3)2, -N(CH3)-cyclohexyl, -N(CH2-CH3)2, azetidinyl, pyrrolidinyl, piperidinyl, azacyclobutadienyl, pyrrolyl, pyridinyl, -O, -O-CH3, -OC(=O)-CH3, oxetanyl, -CH3, -CH2-CH3, -CH(CH3)2, -C(OH)-CH2-OH, cyclopropyl, phenyl and -CH2-S-CH3.

[0203] In general formula (VIa), Z does not represent -NH-phenyl, -N(CH3)-phenyl, -OH, -OC2H5 or -OC(CH3)3.

[0204] Thus, preferred variants according to the first aspect of the invention are coolants of general formula (Va) to (VIIIa) having the following structure: [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6]

[0205] Even more preferred according to the invention are coolants of general formula (Va) or (VIa) having the following structure: [Table 10]

[0206] Even more preferred according to the invention are also such coolants of general formula (VIIa) or (VIIIa) having the following structure: [Table 11]

[0207] Furthermore, compounds of general formulae (Va) to (VIIIa) in which m is 1 in each case appear to be preferred with regard to the determined TRPM8 activity.

[0208] In general formula (VIa), R1 and R2 represent phenyl, Y represents branched alkyl, in particular Y represents methylene substituted by -CH3 or -CH2CO2C2H5, and in general formula (VIa), Z represents -NH-phenyl, -N(CH3)-phenyl, -OH, -OC2H5 or -OC(CH3)3, in particular such compounds are excluded from the coolants according to general formula (VIa).

[0209] The physiological coolants according to the general formulae (I) to (VIII) and (Va) to (VIII) exist either in neutral form, i.e., uncharged form, or in the form of their salts, for example, as acid addition salts with inorganic or organic acids.

[0210] The term "salt", in the context of this invention, refers to a salt of a compound that possesses the desired effect or pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids or with organic acids, preferably mono- or polycarboxylic acids; or (2) Salts formed when an acidic proton present in the starting compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or salts coordinated with an organic base.

[0211] Among the salts, acid addition salts are also particularly preferred, since the physiological coolants according to general formulas (I) to (VIII) contain a protonatable N atom.

[0212] The inorganic acid that forms an acid addition salt with the physiological coolant of the present invention is preferably selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Among the salts, hydrochloride or sulfate is most preferred, especially hydrochloride or sulfate.

[0213] Acid addition salts with organic monocarboxylic or polycarboxylic acids are even more preferred. The carboxylic acid is selected from saturated, monounsaturated, or polyunsaturated C1-C30 monocarboxylic acids, saturated, monounsaturated, or polyunsaturated C3-10 dicarboxylic or tricarboxylic acids. The carboxylic acid may be mono- or polysubstituted with a hydroxy group, preferably an α-hydroxycarboxylic acid in which the hydroxy group is located on the carbon atom adjacent to the carboxy group. Many representative examples occur in nature as so-called fruit acids. Preferred α-hydroxycarboxylic acids are malic acid, citric acid, 2-hydroxy-4-methylmercaptobutyric acid, glycolic acid, isocitric acid, mandelic acid, lactic acid, tartronic acid, or tartaric acid.

[0214] Organic acids which form acid addition salts with physiological coolants according to the invention include 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, Preferably selected from the group consisting of benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert.butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, 4-hydroxybutanoic acid, and the like.

[0215] Of the organic acids that form acid addition salts with the physiological coolants of the present invention, acetic acid, lactic acid, malonic acid, succinic acid, malic acid, citric acid or tartaric acid are most preferred.

[0216] The metal ions for salt formation, which replace the acidic protons present in the starting compounds, are selected from the group consisting of alkali metal ions, preferably Na+ or K+, alkaline earth metal ions, preferably Ca++, Mg++ and aluminum+++.

[0217] The coordinating organic base for salt formation is selected from the group consisting of ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

[0218] In the following description and in the claims, the term "physiological coolant" or "compound" includes both the neutral, uncharged form of the coolant / compound as well as the salt form of the coolant / compound.

[0219] The salts of physiological coolants according to the invention are particularly preferred due to their excellent water solubility, which also leads to their excellent availability during use of the coolant or compound.

[0220] Surprisingly, it has been found that the compounds or coolants according to the present invention, or their salts, have the common property of achieving a particularly long-lasting and powerful cooling effect on the skin or mucous membranes in vivo, even at low doses in the range of about 5 ppm.This means that in the final preparation, a smaller dose of the coolant or its salt according to the present invention is required to achieve a powerful cooling effect.Therefore, the compounds described herein become particularly effective cooling substances, which was unexpected for the TRPM8 modulators mentioned in this application.

[0221] Coolants according to the invention are further characterized by a rapid onset of their cooling action, whereas other coolants according to the invention have a cumulative cooling action, i.e. a cooling action that increases over time to produce a longer and more intense cooling action.

[0222] The coolant according to the present invention is also colorless and non-fading, which is particularly advantageous for storage and / or use in the final product.Therefore, the compounds described herein are characterized as particularly suitable additives in various preparations.In addition, the compounds according to the present invention described herein are almost tasteless and odorless, so that they are also highly suitable for incorporation into neutral and / or flavored preparations without producing an unpleasant taste impression, for example, a bitter taste, or without adversely affecting the intended taste or odor impression.

[0223] The coolant salts according to the invention exhibit greater in vitro solubility than their neutral, uncharged counterparts, which is particularly advantageous when said coolant salts are used in the oral care sector.

[0224] So far, there is no evidence in the prior art that the compounds used according to the invention or their salts are in any way capable of producing a cooling effect, and in particular that they do not produce a long-lasting cooling effect.

[0225] It was equally surprising that the coolant or salt thereof according to the invention is able to mask the known drawbacks of flavours, especially the taste of sweeteners such as stevioside: in particular, the pungency, bitterness and metallic aftertaste are effectively masked even when added in small amounts.

[0226] The compounds described herein, which can thus be particularly well incorporated into various formulations, are suitable as particularly effective cooling substances. The salts of the compounds according to the invention, and even more preferably the acid addition salts, are particularly advantageous for use in the oral care sector due to their improved solubility.

[0227] Physiological coolants of general formula (I), (II), (V) or (VI) selected from the group consisting of the compounds shown in Table 1 are particularly preferred.

[0228] Table 12-1 Table 12-2 Table 12-3 Table 12-4 Table 12-5 Table 12-6 Table 12-7 Table 12-8 Table 12-9 Table 12-10 Table 12-11 Table 12-12

[0229] The coolants of the present invention listed in Table 1 according to general formula (I), (II), (V) or (VI) are either present in neutral, uncharged form or in the form of their salts, for example as acid addition salts with the inorganic or organic mono- or polycarboxylic acids detailed above. In this respect, what has been said above also applies here.

[0230] The coolants according to Table 1 can be present in stereoisomerically pure form or as mixtures of different stereoisomers and can therefore also be used in formulations as such.

[0231] Surprisingly, the compounds according to Table 1 have been shown to have particularly high TRPM8 activation and are therefore ideally suited as coolants.

[0232] The most preferred coolants, i.e., coolants which have particularly effective and strong TRPM8 activation, i.e., effective and strong cooling action at low application doses, are compounds B-01, B-02, B-03, B-04, B-05, B-06, B-07, B-11, B14, B-15, B-17, B-18, B-19 and B-21 (TRPM8 activation ≧90%), and in particular compounds B-01, B-02, B-03, B-04, B-05, B-06, B-07, B-11, B-14, B-15, B-17, B-18 and B-19 (TRPM8 activation ≧100%). Compounds B-01, B-02, B-03, B-04, B-05, B-06, and B-07, which exhibit very high TRPM8 activity (TRPM8 activation ≧150%), are particularly preferred.

[0233] Compounds B-01 (262% TRPM8 activation), B-02 (227% TRPM8 activation), B-03 (221% TRPM8 activation), B-04 (210% TRPM8 activation), B-05 (205% TRPM8 activation), B-06 (205% TRPM8 activation) and B-07 (203% TRPM8 activation) are most preferred due to their superior relative TRPM8 activation.

[0234] Compound 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 an -NH-cyclopropyl group.

[0235] Compound 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 an -NH-CH3- group.

[0236] Compound 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 an -NH-CH3- group.

[0237] Compound B-04 (pyrazine derivative) is characterized in that in the general formula (VI), R1 and R2 represent a phenyl group, Y represents a methylene group, and Z represents a -NH-CH3- group.

[0238] Compound 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 -N(CH3)2-.

[0239] Compound B-06 (triazine derivative) is characterized in that, in general formula (V), R1 and R2 represent a phenyl group, Y represents a methylene group, and Z represents an azetidine group.

[0240] Compound B-07 (triazine derivative) is characterized in that in general formula (V), R1 and R2 represent phenyl groups which, together with the C atoms of the triazine ring to which they are attached, 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 an -NH-CH3- group.

[0241] Even more preferred are physiological coolants of general formula (Va) or (VIa) selected from the group consisting of the compounds shown in Table A.

[0242] [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7]

[0243] The coolants of the invention listed in Table A according to general formula (Va) or (VIa) are either present in neutral, uncharged form or in the form of their salts, for example as acid addition salts with the inorganic or organic mono- or polycarboxylic acids detailed above. In this respect, what has been said above also applies here.

[0244] The coolants according to Table A can be present in stereoisomerically pure form or as mixtures of different stereoisomers and can therefore also be used in formulations as such.

[0245] Surprisingly, compounds according to Table A have been shown to have particularly high TRPM8 activation and are therefore ideally suited as coolants.

[0246] The most preferred coolants, i.e., coolants that have particularly effective and strong TRPM8 activation, i.e., effective and strong cooling effect at low application doses, are compounds B-01, B-02, B-03, B-05, B-07, B-11, B14, B-15, and B-18 (TRPM8 activation ≧100%). Compounds B-01, B-02, B-03, B-05, and B-07 are particularly preferred because they show significantly high TRPM8 activity (TRPM8 activation ≧150%).

[0247] Compounds 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 due to their superior relative TRPM8 activation.

[0248] Likewise, physiological coolants of general formula (III), (IV), (VII) or (VIII) selected from the group consisting of the compounds shown in Table 2 are particularly preferred.

[0249] [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6] [Table 14-7] [Table 14-8] [Table 14-9] [Table 14-10] [Table 14-11] [Table 14-12]

[0250] The coolants of the invention listed in Table 2 according to general formula (III), (IV), (VII) or (VIII) are either present in neutral, uncharged form or in the form of their salts, for example as acid addition salts with the inorganic or organic mono- or polycarboxylic acids detailed above. In this respect, what has been said above also applies here.

[0251] The coolants according to Table 2 can be present in stereoisomerically pure form or as mixtures of different stereoisomers and can therefore also be used in formulations as such.

[0252] Surprisingly, the compounds according to the invention have been shown to have a particularly high TRPM8 activation and are therefore ideally suited as coolants.

[0253] The most preferred coolants, i.e., coolants which have particularly effective and strong TRPM8 activation, i.e., effective and strong cooling action at low application doses, are compounds A-01, A-02, A-03, A-04, A-05, A-06, A-07, A-08, A-09, A-10, A-11, A-12, A-15, A-16 and A-17 (TRPM8 activation ≧90%), and in particular compounds A-01, A-02, A-03, A-04, A-05, A-06, A-07, A-08, A-09, A-10, A-11, A-12, A-15 and A-16 (TRPM8 activation ≧100%). Compounds A-01, A-02, A-03, A-04, A-05, A-06, A-07 and A-08, which exhibit very high TRPM8 activity (TRPM8 activation ≧150%), are particularly preferred.

[0254] Compounds A-01 (278% TRPM8 activation), A-02 (265% TRPM8 activation), A-03 (260% TRPM8 activation), A-04 (215% TRPM8 activation), A-05 (190% TRPM8 activation), A-06 (186% TRPM8 activation) and A-07 (183% TRPM8 activation) and A-08 (177% TRPM8 activation) are most preferred due to their superior relative TRPM8 activation.

[0255] Compound A-01 (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 an -NH-CH3- group.

[0256] Compound 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 an -NH-CH3- group.

[0257] Compound 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 an -NH-CH3- group.

[0258] Compound A-04 (oxazole derivative) is characterized in that in general formula (VII), R1 and R2 represent a phenyl group, X represents a cis-cyclopropyl group, and Z represents a -NH-CH3- group.

[0259] Compound 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 an -NH-CH3- group.

[0260] Compound A-06 (oxazole derivative) is characterized in that, in general formula (VII), R1 and R2 represent a phenyl group, X represents an S atom, Y represents a methylene group, and Z represents an -NH-cyclopropyl group.

[0261] Compound A-07 (oxazole derivative) is characterized in that in general formula (VII), R1 and R2 represent phenyl groups, X and Y represent methylene groups, and Z represents a -NH-CH2-CH3- group.

[0262] Even more preferred are physiological coolants of general formula (VIIa) or (VIIIa) selected from the group consisting of the compounds shown in Table B.

[0263] [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4]

[0264] The coolants according to the invention listed in Table B according to general formula (VIIa) or (VIIIa) are either present in neutral, uncharged form or in the form of their salts, for example as acid addition salts with the inorganic or organic mono- or polycarboxylic acids described in detail above. In this respect, what has been said above also applies here.

[0265] The coolants according to Table B can be present in stereoisomerically pure form or as mixtures of different stereoisomers and can therefore also be used in formulations as such.

[0266] Surprisingly, compounds according to Table B have been shown to have particularly high TRPM8 activation and are therefore ideally suited as coolants.

[0267] The most preferred coolants, i.e., coolants that have particularly effective and strong TRPM8 activation, i.e., effective and strong cooling action at low application doses, are compounds A-01, A-02, A-03, A-05, A-09, A-10, and A-12 (TRPM8 activation ≧100%). Compounds A-01, A-02, A-03, and A-05 are particularly preferred because they exhibit significantly high TRPM8 activity (TRPM8 activation ≧150%).

[0268] Compounds A-01 (278% TRPM8 activation), A-02 (265% TRPM8 activation), A-03 (260% TRPM8 activation) and A-05 (190% TRPM8 activation) are most preferred due to their superior relative TRPM8 activation.

[0269] The above-mentioned preferred compounds B-01, B-02, B-03, B-04, B-05, B-06, B-07, B-11, B14, B-15, B-17, B-18, B-19 and B-21, as well as A-01, A-02, A-03, A-04, A-05, A-06, A-07, A-08, A-09, A-10, A-11, A-12, A-15, A-16 and A-17 have particularly high TRPM8 activity, and therefore exhibit a strong and effective cooling effect.That is, to produce a strong cooling effect, only a small amount of the substance according to the present invention is required, in the range of about 5 ppm (low EC50, see experimental data below).A strong cooling effect was also demonstrated during sensory evaluation, i.e., tasting of individual samples. For example, the panel's listing graded the cooling effect of compound B-11, with 5.3 being the score at an application level of 5 ppm. The sensory rating of cooling intensity was therefore comparable, taking into account the amount of compound used, to that determined for the benchmark cooling substance WS-3 at a 6-fold higher concentration (application amount: 30 ppm; sensory rating of cooling intensity: score 5.4).

[0270] Compounds A-2 and A-10 also exhibited very high TRPM8 activity and a strongly perceived cooling effect (perceptual cooling intensity: score 5.4 and score 5.38, respectively), and are therefore suitable as particularly effective coolants.

[0271] Among the compounds of the general formulae (I) to (IV) defined above, the compounds of the general formulae (V), (VI), (VII) and (VIII) are most preferred. The compounds of the general formulae (Va), (VIa), (VIIa) and (VIIIa) are most preferred. These coolants are characterized by high TRPM8 activation and at the same time exhibit very high sensory cooling power. Even at low concentrations, these compounds produce a strong cooling effect, which is generally significantly lower than the EC50 reference value of 1.72 μM for the substance WS-3, as shown in the following experimental section.

[0272] Although the physiological amine coolants according to the invention are not yet known from the prior art, they can be produced according to generally known standard methods of preparation in organic chemistry and are shown in generalized form as examples in the following diagrams:

[0273] Scheme 1: [ka]

[0274] Scheme 2: [ka]

[0275] Scheme 3: [ka]

[0276] Scheme 4: [ka]

[0277] Scheme 5: [ka]

[0278] Scheme 6: [ka]

[0279] Scheme 7: [ka]

[0280] Scheme 8: [ka]

[0281] Scheme 9: [ka]

[0282] Scheme 10: [ka]

[0283] Scheme 11: [ka]

[0284] In principle, the present invention includes, as coolants or coolant mixtures, all mixtures of the individual compounds of the general formulae (I) to (IV), and therefore also of the general formulae (V) to (VIII) or (Va) to (VIII). Nevertheless, the compounds are also suitable for mixing with other already known coolants.

[0285] A further object of the present invention therefore relates to a physiological coolant mixture comprising or consisting of: (a) one, two, three or more coolants of general formula (I) to (VIII), (Va), (VIa), (VIIa) or (VIIIa) or listed in Table 1, Table 2, Table A or Table B and defined above, and optionally (b) at least one other physiological coolant; and / or optionally (c) at least one solvent.

[0286] In a preferred embodiment, the present invention relates to a coolant mixture comprising or consisting of at least one of the compounds according to the invention of general formulae (I) to (VIII), (Va), (VIa), (VIIa) or listed in Table 1, Table 2, Table A or Table B and as defined above. Optionally, the coolant mixture further comprises a physiological coolant and, optionally, at least one suitable solvent.

[0287] A particular advantage of such coolant mixtures is that a synergistic enhancement of the cooling effect can be observed.

[0288] Suitable coolants that form component (b) and that are different from the coolant that forms component (a) include menthol, menthol methyl ether (FEMA GRAS 4054), monomenthyl glutamate (FEMA GRAS 4006), menthoxy-1,2-propanediol (FEMA GRAS 3784), dimenthyl glutarate (FEMA GRAS 4604), hydroxymethylcyclohexylethanone (FEMA GRAS 4742), 2-(4-ethylphenoxy)-N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide (FEMA GRAS 4880), WS-23 (2-isopropyl-N,2,3-trimethylbutyramide, FEMA GRAS 3804), N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide (FEMA GRAS 4742). 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), N-ethyl menthyl 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 (3-(p-menthane-3-carboxamido) ethyl 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-(pyridin-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-pyrazol-5-yl)-N-((thiophen-2-yl)methyl)acetamide (FEMA GRAS 4809), menthone glycerol ketal (FEMA GRAS 3807 and 3808), (-)-menthoxypropane-1,2-diol, 3-(1-menthoxy)-2-methylpropane-1,2-diol (FEMA GRAS 3849), isopulegol, (+)-cis and (-)-trans-p-menthane-3,8-diol (62:38, FEMA GRAS4053), 2,3-dihydroxy-p-menthane, 3,3,5-trimethylcyclohexanone glycerol ketal, menthyl pyrrolidonecarboxylate, (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]decan-2-one (FEMA GRAS4285), N-benzo[1,3]-dioxol-5-yl-3-p-menthanecarboxamide, N-(1-isopropyl-1,2-dimethylpropyl)-1,3-benzodioxole-5-carboxamide, N-(R)-2-oxotetrahydrofuran-3-yl-(1R,2S,5R)-p-menthane-3-carboxamide, 2,2,5,6,6-pentamethyl A mixture of 2,3,6,6a-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-(pyridin-4-yl)ethyl)cyclohexanecarboxamide; (1S,2S,5R)-N-(4-(cyanomethyl) phenyl)phenyl)-2-isopropyl-5-methylcyclohexanecarboxamide, 1,7-isopropyl-4,5-methyl-bicyclo[2.2.2]oct-5-ene derivatives, 4-methoxy-N-phenyl-N-[2-(pyridin-2-yl)ethyl]benzamide, 4-methoxy-N-phenyl-N-[2-(pyridin-2-yl)ethyl]benzenesulfonamide, 4-chloro-N-phenyl-N-[2-(pyridin-2-yl)ethyl]benzenesulfonamide, 4-cyano-N-phenyl-N-[2-(pyridin-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]imidazol-2-yl)vinyl-4-methoxybenzoate, 2-(1-isopropylamino)-2-(1-isopropylamino)-4-methylbenzoate (Z)-2-(1-isopropyl-5-methyl-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoate, (Z)-2-(1-isopropyl-5-methyl-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoate, 3-alkyl-p-methane-3-ol derivatives, fenchyl derivatives, D-bornyl, L-bornyl The compound is selected from the group consisting of cis-pinan-2-yl, verbanyl, and isobornyl, menthyl oxamate derivatives, 3-oxocarboxylic acid menthyl esters, N-alpha-(menthanecarbonyl) amino acid amides, p-menthanecarboxamides and WS-23 analogs, (-)-(1R,2R,4S)-dihydroumbellulol, p-menthane alkyloxyamides, cyclohexane derivatives, butanone derivatives, a mixture of 3-menthoxy-1-propanol and 1-menthoxy-2-propanol, 1-[2-hydroxyphenyl]-4-[2-nitrophenyl]-1,2,3,6-tetrahydropyrimidin-2-one, 4-methyl-3-(1-pyrrolidinyl)-2-[5H]-furanone, and mixtures thereof. FEMA stands for "Flavor and Extracts Manufacturers Association," and GRAS stands for "Generally Regarded As Safe." The FEMA GRAS designation means that a substance so labeled has been tested in accordance with standard methods and is deemed toxicologically safe.

[0289] In principle, all known substances with cooling properties are suitable as component (b), but for food safety reasons, compounds that have the FEMA GRAS designation are preferred, or if this is required for the cooling mixture in question.

[0290] The first important representative of the substances forming component (b) is monomenthyl succinate (FEMA GRAS 3810). Both the succinate salt and the analogue monomenthyl glutarate (FEMA GRAS 4006) are important representatives of monomenthyl esters based on dicarboxylic and polycarboxylic acids.

[0291] A next important group of menthol compounds that are preferred within the meaning of the present invention comprises carbonate esters of menthol with polyols, such as glycols, glycerol or carbohydrates, such as menthol ethylene glycol carbonate (FEMA GRAS 3805 = Frescolat® MGC), menthol propylene glycol carbonate (FEMA GRAS 3784 = Frescolat® MPC), menthol 2-methyl-1,2-propanediol carbonate (FEMA GRAS 3849) or the corresponding sugar derivatives. Similarly, N-(4-cyanomethylphenyl)-p-menthanecarboxamide (FEMA GRAS 4496), N-(2-(pyridin-2-yl)ethyl)-3-p-menthanecarboxamide (FEMA GRAS 4549), and (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide (FEMA GRAS 4788) are preferred as component (b).

[0292] The menthol compound menthyl lactate (FEMA GRAS 3748 = Frescolat® ML), marketed under the name Frescolat® MGA, and in particular menthone glyceryl acetal (FEMA GRAS 3807) or menthone glyceryl ketal (FEMA GRAS 3808), are preferred for the purposes of the present invention.

[0293] This group of compounds also includes 3-(1-menthoxy)-1,2-propanediol, also known as Coolant 10 (FEMA GRAS 3784), and 3-(1-menthoxy)-2-methyl-1,2-propanediol (FEMA GRAS 3849), which has an additional methyl group.

[0294] Among the substances mentioned above, menthone glyceryl acetal / ketal, menthyl lactate, menthol ethylene glycol carbonate and menthol propylene glycol carbonate, marketed by the Applicant under the names Frescolat® MGA, Frescolat® ML, Frescolat® MGC and Frescolat® MPC, have proven to be particularly advantageous.

[0295] Further preferred components (b) are shown in Table 3 below:

[0296] [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5]

[0297] In the 1970s, menthol compounds were first developed, which have a C-C bond at the 3-position, and some representatives thereof can also be used in the context of the present invention. These compounds are generally referred to as WS-type compounds. The basic structure is a menthol derivative in which the hydroxyl group is replaced by a carboxyl group (WS-1). All other WS-type compounds, such as species WS-3, WS-4, WS-5, WS-12, WS-14, WS-23, WS-27, and WS-30, are derived from this structure, and these compounds, or esters or N-substituted amides of the aforementioned compounds, are also preferred in the context of the present invention.

[0298] Furthermore, the coolant 2-(p-tolyloxy)-N-(1H-pyrazol-5-yl)-N-((thiophen-2-yl)methyl)acetamide (FEMA GRAS 4809) is particularly preferred. Likewise, 2-(4-ethylphenoxy)-N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide (FEMA GRAS 4880) and / or N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide (FEMA GRAS 4881) and / or N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide (FEMA GRAS 4882) are preferred.

[0299] Further preferred components (b) in combination with at least one coolant according to the invention of general formulas (I) to (VIII) or listed in Table 1 or Table 2 and defined above are shown in Table 4 above:

[0300] [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7] [Table 17-8] [Table 17-9] [Table 17-10] [Table 17-11] [Table 17-12] [Table 17-13] [Table 17-14] and salts thereof, preferably acid addition salts with inorganic or organic acids.

[0301] The coolant mixture according to the present invention may contain components (a) and (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, even more preferably about 10:90 to about 90:10, even more preferably about 25:75 to about 75:25, and especially about 40:60 to about 60:40, based on the total coolant mixture.

[0302] To be able to explore and optimize the cooling effect of the coolant and to ensure easier processing in flavors and semi-finished or other final products, the coolant must be converted into a solution before processing. However, the solubility of the coolant according to the invention is in some cases not sufficient, which in turn causes problems during storage, handling or further processing.

[0303] Alternatively, the aforementioned coolant forming component (b) of the coolant mixture can act as a solvent for the coolant or as a coolant forming component (a) of the coolant mixture.

[0304] Advantageously, the coolant mixture according to the invention also comprises, as further component (c), at least one solvent.

[0305] Individual solvents or solvent systems have proven advantageous, the solvent being 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.

[0306] For example, Optamint is a mixture of over 50 natural essential oils and natural or homogenous flavorings. Optamint is a diverse composition of various (partially fractionated) oils, preferably a mixture of, for example, various peppermint oils and spearmint oils, as well as eucalyptus leaf oil, star anise oil, menthol, menthone, isomenthone, menthyl acetate, anethole, eucalyptol, etc. Therefore, exact reproduction of the composition of Optamint is impossible. Optamint® products are commercially available from Symrise AG.

[0307] For example, benzyl alcohol or 2-phenylethanol or benzyl benzoate can be used as solvents in the coolant mixture according to the invention.

[0308] The use of benzyl alcohol or 2-phenylethanol or benzyl benzoate, for example, can be used to put the coolant according to the invention into solution, and likewise to obtain a solution, i.e., a coolant mixture, that is stable for proper storage.

[0309] Solvent systems, i.e. solvent combinations of two or more solvents, can also be used to dissolve the coolant according to the invention. In particular, with regard to the subsequent field of application, the use of solvents that can also have a cooling effect can save further steps in the (final) production process.

[0310] Thus, in an exemplary embodiment, the solvent in the coolant mixture is a binary system of two solvent materials 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 the additional coolants described above as component (b).

[0311] For example, binary solvent systems of benzyl alcohol and a further substance selected from the group consisting of 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and the further coolants mentioned above as component (b) are suitable according to the invention.

[0312] Also suitable are binary solvent combinations or mixtures comprising or consisting of, for example, benzyl alcohol and a further solvent. Also suitable in this case are binary solvent combinations or mixtures selected from the following: benzyl alcohol and 2-phenylethanol, benzyl alcohol and benzyl benzoate, benzyl alcohol and diethyl succinate, benzyl alcohol and triethyl citrate, benzyl alcohol and triacetin, benzyl alcohol and ethanol, benzyl alcohol and peppermint oil, benzyl alcohol and anethole, benzyl alcohol and Optamint, benzyl alcohol and propylene glycol, benzyl alcohol and menthol, benzyl alcohol and menthyl lactate (Frescolat® ML), benzyl alcohol and menthol propylene glycol carbonate (Frescolat® MPC), benzyl alcohol and menthol ethylene glycol carbonate (Frescolat® MGC), benzyl alcohol and menthone glyceryl acetal (Frescolat® MGA), benzyl alcohol and menthane carboxylic acid esters and amides.

[0313] The following binary solvent combinations or mixtures are also suitable: 2-phenylethanol and menthol propylene glycol carbonate (Frescolat® MPC), diethyl succinate and 2-phenylethanol, triacetin and benzyl benzoate, triethyl citrate and triacetin, 2-phenylethanol and peppermint oil, 2-phenylethanol and optamint, anethole and triacetin, peppermint oil and menthyl lactate (Frescolat® ML), triacetin and menthone glyceryl acetal (Frescolat® MAG), optamint and menthyl lactate (Frescolat® ML), triethyl citrate and menthol ethylene glycol carbonate (Frescolat® MGC).

[0314] Suitable coolant mixtures within the meaning of the present invention therefore contain as solvent (c) for example the abovementioned binary solvent combinations or mixtures.

[0315] The binary solvent mixture according to the present invention has, for example, the following ratios of solvent (1):solvent (2): from 10:1 to 1:10, preferably from 8:2 to 2:8, even more preferably from 6:4 to 4:6, and most preferably a ratio of 5:5.

[0316] The above suitable binary solvent mixtures are capable of dissolving the coolant according to the present invention and stably maintaining the coolant in solution in amounts ranging widely from 2% to 50% by weight, preferably from 5% to 40% by weight, and more preferably from 5% to 20% by weight, depending on the solvent or combination of solvents.

[0317] In a further exemplary embodiment, the solvent or solvent system for a coolant according to the present invention is a three-component system consisting 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 the additional coolants listed above as component (b).

[0318] For example, ternary solvent combinations or mixtures of benzyl alcohol with 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 the other coolants also mentioned above as component (b) are suitable for this purpose.

[0319] In this regard, ternary solvent combinations or mixtures are preferred. For example, ternary solvent combinations or mixtures containing or consisting of benzyl alcohol and two further solvents are suitable, the two further 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 menthone glyceryl acetal (Frescolat® MGA), 2-phenylethanol and kaolin. 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, menthol and menthol lactate (Frescolat® ML), and ethanol and menthyl lactate (Frescolat® ML).

[0320] For example, the following ternary solvent combinations or mixtures are also suitable: Triethyl citrate, triacetin, menthyl lactate (Frescolat® ML), Triacetin, 2-phenylethanol and peppermint oil, 2-phenylethanol, Optamint and peppermint oil, 2-phenylethanol, triacetin and Optamint, anethole, benzyl alcohol and triacetin, 2-phenylethanol, benzyl benzoate and Optamint, 2-phenylethanol, 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 menthone glyceryl acetal (Frescolat® MGA), Peppermint oil, 2-phenylethanol, and menthanecarboxylic acid esters and amides, Triacetin, 2-phenylethanol and menthol propylene glycol carbonate (Frescolat® MPC), Menthyl lactate (Frescolat® ML), 2-phenylethanol and peppermint oil, anethole, triacetin and menthone glyceryl acetal (Frescolat® MGA), Optamint, benzyl benzoate and menthyl lactate (Frescolat® ML) and Benzyl benzoate, triethyl citrate and menthol ethylene glycol carbonate (Frescolat® MGC).

[0321] The ternary solvent mixture according to the present invention has, for example, the following ratios of solvent (1):solvent (2):solvent (3): from 10:1:15 to 5:1:3, or from 4:1:7 to 7:1:4, or from 2:2:4 to 4:4:2.

[0322] The preferred ternary solvent mixtures described above have shown to be particularly capable of dissolving the coolant according to the invention and keeping it stable in solution in amounts ranging from 2% to 50% by weight, preferably from 5% to 40% by weight, and more preferably from 5% to 20% by weight, depending on the solvent or combination of solvents.

[0323] This has the advantage that the coolant according to the invention can be supplied in variable amounts suitable for the final formulation, resulting in a wide range of coolant mixtures in which the coolant is in solution.

[0324] In a further preferred embodiment, the solvent or solvent system for the coolant according to the invention is a four-component system consisting 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 as component (b) further other coolants as mentioned above.

[0325] A suitable solvent combination is, for example, a quaternary solvent combination of benzyl alcohol with 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 the other coolants listed above as component (b).

[0326] A suitable quaternary solvent combination or mixture is, for example, one that contains or consists of benzyl alcohol and three further solvents, the three further solvents being selected from the group consisting of: 2-phenylethanol, triethyl citrate and triacetin, Peppermint oil, 2-phenylethanol and triethyl citrate, triethyl citrate, menthyl lactate (Frescolat® ML) and diethyl succinate, Triethyl citrate, triacetin and anethole, 2-phenylethanol, triacetin and Optamint, Peppermint oil, benzyl alcohol and menthyl lactate (Frescolat® ML), Optamint, ethanol and menthyl lactate (Frescolat® ML), 2-phenylethanol, benzyl benzoate and diethyl succinate, Triethyl citrate, triacetin and ethanol, Peppermint oil, anethole and optamint, 2-phenylethanol, benzyl benzoate and propylene glycol, 2-phenylethanol, benzyl benzoate and menthol propylene glycol carbonate (Frescolat® MPC), Triethyl citrate, Optamint and ethanol, triacetin, benzyl benzoate and menthoxy-2-methyl-1,2-propanediol, Menthone glyceryl acetal (Frescolat® MGA), triacetin and anethole.

[0327] The following quaternary solvent combinations and solvent mixtures are also suitable: Anethole, triacetin, peppermint oil and menthol ethylene glycol carbonate (Frescolat® MGC), Triacetin, ethanol, 2-phenylethanol and peppermint oil, 2-phenylethanol, Optamint, diethyl succinate and peppermint oil, Anethole, 2-phenylethanol, benzyl alcohol and triacetin.

[0328] The preferred quaternary solvent mixtures described above have shown to be particularly capable of dissolving the coolant according to the invention and keeping it stable in solution in amounts ranging from 2% to 50% by weight, preferably from 5% to 40% by weight, and more preferably from 5% to 20% by weight, depending on the solvent or combination of solvents.

[0329] This has the advantage that the coolant according to the invention can be supplied in variable amounts suitable for the final formulation, resulting in a wide range of coolant mixtures in which the coolant is in solution.

[0330] The coolant mixture according to the invention preferably contains or consists of component (a) and / or component (b) in an amount of 2% to 20% by weight, preferably 2% to 10% by weight, even more preferably 5% to 10% by weight and most preferably 5% to 8% by weight, based on the total coolant mixture, 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 and most preferably 92% to 95% by weight, with the proviso that the sum of components (a) and / or (b) and / or (c) amounts to 100% by weight.

[0331] The composition of the coolant mixture according to the present invention is particularly advantageous because it allows for control of the amount of coolant in the final formulation.

[0332] Preferably, the final product, in particular for oral care compositions, contains the coolant 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, more preferably 0.5% to 15% by weight or 1% to 5% by weight, based on the weight of the final product.

[0333] Suitable coolant mixtures according to the invention have, for example, the following composition: 5-10% by weight of coolant in 95-90% by weight of benzyl alcohol or 8-10% by weight of coolant in 92-90% by weight of benzyl alcohol, or 1-4% by weight coolant in 99-96% by weight triethyl citrate, or 1-3% by weight of coolant in 99-97% by weight of triacetin, or 3-6% by weight of coolant in 97-94% by weight of diethyl succinate, or 5-15% by weight of coolant in 95-85% by weight of 2-phenylethanol, or 5-10% by weight of coolant in 95-90% by weight of benzyl benzoate, or 1-3% coolant by weight in 99-97% Optamint by weight, or 1 to 4% by weight of a coolant in 99 to 96% by weight of the other coolant listed above as component (b), or 2-4% by weight coolant in 98-96% by weight propylene glycol, or 0.5 to 2% by weight of coolant in 95.5 to 98% by weight of ethanol, or 0.5 to 2% by weight of coolant in 95.5 to 98% by weight of menthyl acetate, or 1-4% by weight of coolant in 99-96% by weight of peppermint oil, or 2-5% by weight of coolant in 98-95% by weight of anethole It consists of Both components (coolant and solvent) in a coolant mixture always add up to 100% by weight. For example, a suitable coolant mixture according to the invention comprises 5-10% by weight of coolant in 95-90% by weight of benzyl alcohol, particularly preferably 8-10% by weight of coolant in 92-90% by weight of benzyl alcohol.

[0334] Another object of the present invention is to provide a method for producing a pharmaceutical composition comprising: (d) one, two, three or more coolants of the general formulae (I) to (VIII) or listed in Table 1 or Table 2 and defined above; and (e) at least one flavoring agent The present invention relates to a flavoring preparation comprising or consisting of:

[0335] A particular advantage of these mixtures or flavor preparations is that the coolant, even at low concentrations, is able to mask the unpleasant, e.g., bitter or astringent, impression of flavors, especially sweeteners, while at the same time providing a strong and effective cooling effect.

[0336] The above applies to component (d) as well as to component (a) of the physiological coolant mixture according to the invention, which comprises or consists of one, two, three or more coolants of the general formulae (I) to (VIII), (Va), (VIa), (VIIa) or (VIIIa) or listed in Table 1, Table 2, Table A or Table B and defined above.

[0337] The flavor preparation according to the invention comprises, as component (e), one or more flavoring substances, such as 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, butylidenephthalide, carvone, camphene, caryophyllene, cineole, cinnamyl acetate, citral, citronellol, citronellal, citral acetate, citronellol, citronellal, citronellol ... Loneryl, cyclohexyl acetate, cymol, damascone, decalactone, dihydrocoumarin, dimethyl anthranilate, dimethyl anthranilate, dodecalactone, ethoxyethyl acetate, ethyl butyrate, ethyl butyrate, ethyl caprylate, ethyl caproate, ethyl crotonate, ethyl furaneol, ethyl guaiacol, ethyl isobutyrate, ethyl isovalerate, ethyl lactate, ethyl methyl butyrate, ethyl propionate, eucalyptol, eugenol, ethyl heptylate, 4-(p-hydroxyphenyl)-2-butanone, gamma-decalactone, geraniol Raniol, geranyl acetate, geranyl acetate, grapefruit aldehyde, methyl dihydrojasmate (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-2-hexyl acetate, cis-3-hexyl formate, para-hydroxybenzyl acetone, isoamyl alcohol, isoamyl isovalerate, isobutyl butyrate, isobutyraldehyde, isoeugenol methyl ether, isopropylmethylthiazole, lauric acid, levulinic acid, linalool, linalool oxide, linalyl acetate, menthol, menthofuran, methyl anthranilate, methyl butanol, methyl butyrate, 2-methylbutyl acetate, methyl caproate,Methyl cinnamate, 5-methylfurfural, 3,2,2-methylcyclopentenolone, 6,5,2-methylheptenone, methyl dihydrojasmate, methyl jasmate, 2-methylmethylbutyrate, 2-methyl-2-pentenoic 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 Ton, 2-octanol, 3-octanol, 1,3-octenol, 1-octyl acetate, 3-octyl acetate, palmitic acid, paraldehyde, phellandrene, pentanedione, phenylethyl acetate, phenylethyl alcohol, phenylethyl isovalerate, piperonal, propionaldehyde, propyl butyrate, pulegone, pulegol, sinensal, sulfolol, terpinene, terpineol, terpinolene, 8,3-thiomenthanone, 4,4,2-thiomethylpentanone, thymol, delta-undecalactone Ton, gamma-undecalactone, valencene, valeric acid, vanillic 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), homofuranol (= 2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone and 5-ethyl-2-methyl-4-hydroxy-3(2H) -furanone), maltol and maltol derivatives (preferably ethyl maltol), coumarin and coumarin derivatives, gamma-lactones (preferably gamma-undecalactone, gamma-nonalactone, gamma-decalactone), delta-lactones (preferably 4-methyldeltadecalactone, massolactone, deltadecalactone, tuberolactone), methyl sorbate, divanillin, 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone, 2-hydroxy-3-methyl-2-cyclopentenone,3-Hydroxy-4,5-dimethyl-2(5H)-furanone, acetic acid isoamyl ester, butyric acid ethyl ester, butyric acid n-butyl ester, butyric acid isoamyl ester, 3-methyl-butyric acid ethyl ester, n-hexanoic acid ethyl ester, n-hexanoic acid allyl ester, n-hexanoic acid n-butyl ester, n-octanoic acid ethyl ester, ethyl 3-methyl-3-phenylglycidate, ethyl 2-trans-4-cis-decadienoate, 4-(p-hydroxyphenyl)-2-butanone, 1,1-dimethoxamine 2,2,5-trimethyl-4-hexane, 2,6-dimethyl-5-hepten-1-al and phenylacetaldehyde, 2-methyl-3-(methylthio)furan, 2-methyl-3-furanthiol, bis(2-methyl-3-furyl)disulfide, furfuryl mercaptan, methional, 2-acetyl-2-thiazoline, 3-mercapto-2-pentanone, 2,5-dimethyl-3-furanthiol, 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-isobutyl-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 methyl salicylate, isopulegol, 1-penten-3-one, 4-hydroxy-2,5-dimethyl-3(2H)-furanone, guaiacol, 3-hydroxy-4,5-dimethyl-2(5H)-furanone, 3-hydroxy-4-methyl-5-ethyl-2(5H)-furanone, cinnamaldehyde, cinnamic alcohol, methyl salicylate, isopulegol, and the stereoisomers, enantiomers, positional isomers, diastereomers, cis / trans isomers or epimers of these substances (not explicitly mentioned here).

[0338] For purposes of this invention, artificial sweeteners, as well as natural sweeteners and sweetness enhancers, may also be considered flavoring agents of component (e). These may be selected from the group consisting of: Sugar alcohols (e.g., erythritol, threitol, arabitol, ribotol, xylitol, sorbitol, mannitol, dulcitol, lactitol); · Proteins (e.g., miraculin, monellin, thaumatin, curculin, bratzein); Synthetic sweeteners (e.g., Magap, sodium cyclamate, acesulfame K, neohesperidin dihydrochalcone, saccharin sodium salt, aspartame, superaspartame, neotame, alitame, sucralose, stevioside, rebaudioside, lugusum, carrelame, sucuronate, sucuroctate, monatin, phenylodulcin); Sweet amino acids (e.g., glycine, D-leucine, D-threonine, D-asparagine, D-phenylalanine, D-tryptophn, L-proline); Sweet low molecular weight substances (such as hernandulcin, dihydrochalcone glycosides, glycyrrhizin, glycerrhetinic acid, its derivatives and salts, licorice (Glycyrrhizza glabra subsp.) extract, Amami kousa extract, Momordica subsp. extract), and / or Plant extracts (such as Monk Fruit and the mogrosides derived therefrom, sweet tea or stevia subspecies (e.g., Stevia) extracts, or steviosides derived therefrom).

[0339] Component (e) comprises at least one of the flavoring agents described above.

[0340] The aroma preparation according to the present invention may contain components (d) and (e) in a weight ratio of about 1:99 to about 99:1, preferably about 10:90 to about 90:10, more preferably about 25:75 to about 75:25, and in particular about 40:60 to 60:40.

[0341] In a further preferred variant, the coolant(s) or coolant mixture(s) or aroma preparation(s) are present in encapsulated form, which is particularly interesting, for example, when capsules filled with the coolant(s) are applied to textile surfaces, for example as a component of a softener or post-wash treatment, or when finishing is carried out using capsules filled with the coolant(s), for example by force application to tights.

[0342] Capsules are spherical agglomerates containing at least one solid or liquid core enclosed within at least one continuous shell. During encapsulation, one or more coolants, or coolant mixtures, or flavor preparations are encapsulated with the aid of a coating / encapsulating material, resulting 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.

[0343] Therefore, a further embodiment of the present invention also relates to a physiological coolant or a physiological coolant mixture or a flavoring preparation in encapsulated form.

[0344] Suitable coating materials are, for example, starch (including its degradation products and chemically or physically produced derivatives, in particular dextrins and maltodextrins), gelatin, gum arabic, agar, gum ghatti, 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.

[0345] Among the above coating materials, gelatin (especially porcine, bovine, poultry and / or fish gelatin) having a swelling ratio of at least 20, preferably at least 24, is preferred. Gelatin is also particularly preferred because it is readily available and can be obtained with a variety of swelling ratios.

[0346] Likewise preferred are maltodextrins (especially those based on cereals, especially corn, wheat, tapioca or potato), preferably having a DE value in the range of 10 to 20. Also preferred are celluloses (e.g. cellulose ethers), alginates (e.g. sodium alginate), carrageenans (e.g. beta-, iota-, lambda- and / or kappa-carrageenans), gum arabic, curdlan and / or agar.

[0347] Likewise preferred are alginate capsules, such as those described in detail in the following publications: EP0389700A1, US4,251,195, US6,214,376, WO2003055587 or WO2004050069A1.

[0348] In a further preferred embodiment, the capsule shell consists of a melamine-formaldehyde resin or a coacervation product of a cationic monomer or biopolymer (such as chitosan) and an anionic monomer (such as a (meth)acrylate or alginate).

[0349] Capsules are generally a microdispersed liquid phase or a solid phase coated with a film-forming polymer, during which the polymer is deposited on the surface of the material to be coated after emulsification and coacervation or interfacial polymerization. According to another method, molten wax is incorporated into a matrix ("microsponge"), which can also be coated with a film-forming polymer as a microparticle. According to a third method, particles are alternately coated with polyelectrolytes of different charges ("layer-by-layer" method). The microscopically small capsules can be dried and used like a powder.

[0350] In addition to mononuclear microcapsules, polynuclear aggregates, also known as microspheres, are known, which contain two or more nuclei dispersed within a continuous shell material. Mononuclear or polynuclear microcapsules can also be encapsulated by additional secondary, tertiary, or other shells. Shells can be made of natural, semi-synthetic, or synthetic materials. Natural shell materials include gum arabic, agar, agarose, maltodextrin, alginic acid or its salts, such as sodium or calcium alginate, fats and fatty acids, cetyl alcohol, collagen, chitosan, lecithin, gelatin, albumin, shellac, polysaccharides (such as starch or dextran), polypeptides, protein hydrolysates, sucrose, and waxes. Semi-synthetic coating materials include chemically modified celluloses, particularly cellulose esters and cellulose ethers, such as cellulose acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and carboxymethyl cellulose, as well as starch derivatives, particularly starch ethers and starch esters. Synthetic coating materials are, for example, polymers such as polyacrylates, polyamides, polyvinyl alcohols or polyvinylpyrrolidones.

[0351] Examples of prior art coating / shell materials for producing microcapsules are the following commercially available products (shell material is indicated in parentheses): Hallcrest Microcapsules (gelatin, gum arabic), Coletica Thalaspheres (marine collagen), Lipotec Millicapseln (alginate, agar), Induchem Unispheres (lactose, microcrystalline cellulose, hydroxypropyl methylcellulose), Unicerin C30 (lactose, microcrystalline cellulose, hydroxypropyl methylcellulose), Kobo Glycospheres (modified starch, fatty acid esters, phospholipids), Softspheres (modified agar) and Kuhs Probiol Nanospheres (phospholipids), as well as Primaspheres and Primasponges (chitosan, alginate) and Primasys (phospholipids).

[0352] Chitosan microcapsules and methods for producing them are well known in the state of the art from WO01 / 01926, WO01 / 01927, WO01 / 01928 and WO01 / 01929. Microcapsules having an average diameter in the range of 0.0001 mm to 5 mm, preferably 0.001 mm to 0.5 mm, in particular 0.005 mm to 0.1 mm, and consisting of a shell membrane and a matrix containing an active ingredient are known, for example, from (1) preparing a matrix from a gel-forming agent, a cationic polymer, and an active ingredient; (2) Dispersing the matrix in the oil phase as needed (3) Treating the dispersed matrix with an aqueous solution of an anionic polymer and, if necessary, removing the oil phase. can be obtained by

[0353] The above steps (1) and (3) are interchangeable as long as an anionic polymer is used in place of a cationic polymer in step (1), and vice versa.

[0354] Capsules can also be produced by coating the active ingredient with alternating layers of polyelectrolytes with different charge states (layer-by-layer technique). In this context, reference is made to European Patent EP 1064088 B1 (Max Planck Society).

[0355] The two essential properties of the novel coolant or novel coolant mixture are, as already mentioned, on the one hand, to modulate the TRPM8 receptor as an antagonist or agonist, thus causing a physiological response, i.e., a strong and effective cooling effect on the skin or mucous membranes, and, on the other hand, to reduce or mask unpleasant flavors. However, what should stand out primarily is the ability to produce a strong and effective cooling effect, even in small amounts.

[0356] Therefore, a further aspect of the present invention relates to the use of a physiological coolant according to the invention or a physiological coolant mixture according to the invention as a modulator of the cold menthol receptor TRPM8, in particular as a TRPM8 receptor agonist or as a TRPM8 receptor antagonist, preferably for in vivo and / or in vitro modulation.

[0357] In the use according to the invention, the receptor TRPM8 is contacted with at least one coolant according to the invention or a physiological coolant mixture according to the invention, thereby resulting in the production of Ca in a cell activity test using cells recombinantly expressing the human TRPM8 receptor. 2+ The permeability of these cells to ions is modulated.

[0358] Suitable modulators can act either as antagonists or agonists only, particularly as agonists only, or as both antagonists and agonists, particularly where agonistic or antagonistic effects can occur depending on the particular modulator concentration selected.

[0359] "Agonists" are substances that mediate activation of the TRPM8 receptor, i.e., Ca2+ It is a substance that induces the influx of ions into cold-sensitive neurons, thus conveying a cooling sensation.

[0360] On the other hand, an "antagonist" is a compound that can attenuate such activation of the TRPM8 receptor.

[0361] The modulator according to the present invention, i.e., a physiological coolant or coolant mixture, can exert its effect by binding reversibly or irreversibly, specifically or nonspecifically, to TRPM8 receptor molecules. The binding is usually non-covalent, ionic and / or non-ionic, for example, through hydrophobic interaction with receptor molecules. The term "specific" includes both exclusive interaction with one or more different TRPM8 receptor molecules (such as various original TRPM8 molecules or different isoforms). On the other hand, the term "non-specific" refers to the interaction of a modulator with several different receptor molecules consisting of different functions and / or sequences, which can result in the desired agonistic and / or antagonistic modulation of TRPM8 receptor (as described above).

[0362] In the use according to the invention, preferably in the preferred variants described above, the modulator is a modulator of cellular Ca 2+ It has agonistic or antagonistic effects on ion permeability.

[0363] Particularly preferred is the variant of the use according to the invention in which the modulator is a TRPM8 receptor agonist.

[0364] Due to the physiological properties of the coolant or coolant mixture according to the invention, which induce a cooling effect on the skin or mucous membranes, a further aspect of the invention relates to the use of the coolant or coolant mixture described above for producing a physiological cooling effect on the skin or mucous membranes of humans or animals.

[0365] Alternatively, the coolant according to the invention or the coolant mixture according to the invention is used to induce a cooling effect by means of a package containing the physiological coolant or the physiological coolant mixture or by means of a textile product containing the physiological coolant or the physiological coolant mixture.

[0366] Due to the additional property of reducing or masking unpleasant tastes, such as bitterness or astringency, a further aspect of the present invention relates to the use of the physiological coolant or coolant mixture according to the present invention to improve the taste characteristics of flavorings, thereby making it possible to reduce or mask known taste defects of flavorings, especially sweeteners such as stevioside. In particular, pungency, bitterness or metallic aftertastes are effectively reduced or masked, even when added in small amounts.

[0367] The coolant according to the invention or the physiological coolant mixture according to the invention or the aroma preparation according to the invention has a wide range of applications, in particular in food, nutritional supplements, cosmetic or pharmaceutical preparations, animal feed, textiles, packaging or tobacco products.

[0368] In particular, the physiological coolant or physiological coolant mixture or flavoring preparation according to the invention is used in the manufacture of foods, dietary supplements, cosmetic or pharmaceutical preparations, animal feed, textile products, packaging or tobacco products due to its cooling and / or flavor enhancing properties.

[0369] A further object of the present invention is therefore the use of one or more coolants according to the invention, or a coolant mixture according to the invention, or a flavoring preparation according to the invention, for the production of food, nutritional supplements, cosmetic or pharmaceutical preparations, animal feed, textile products, packaging or tobacco products.

[0370] Due to the advantageous properties described, the coolants according to the invention, which are represented and defined by the general formulae (I) to (VIII), (Va), (VIa), (VIIa) or (VIIIa) or which are shown in Table 1, Table 2, Table A or Table B, are suitable for use according to the invention, i.e. as modulators, preferably selected from the group consisting of the compounds shown in Table 5 or Table 6, for producing or inducing a physiological cooling effect on the skin or mucous membranes of humans or animals, for improving the taste properties of flavoring substances, in particular for reducing or masking unpleasant tastes, for the manufacture of foods, dietary supplements, cosmetic or pharmaceutical preparations, animal feed, textile products, packaging or tobacco products, or for use as medicines.

[0371] [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5] [Table 18-6] [Table 18-7] [Table 18-8] [Table 18-9] Table 18-10 Table 18-11 Table 18-12 Table 18-13

[0372] Table 19-1 Table 19-2 Table 19-3 Table 19-4 Table 19-5 Table 19-6 Table 19-7 Table 19-8 Table 19-9 [Table 19-10] [Table 19-11] [Table 19-12] [Table 19-13] [Table 19-14] [Table 19-15]

[0373] Among the above compounds, the use of compounds B-01, B-02, B-03, B-04, B-05, B-06, B-07, B-11, B14, B-15, B-17, B-18, B-19 and B-21, and the use of compounds A-01, A-02, A-03, A-04, A-05, A-06, A-07, A-08, A-09, A-10, A-11, A-12, A-15, A-16 and A-17 are preferred due to their pronounced TRPM8 activation, their EC50 values ​​and their cooling potency. However, the use of one of compounds B-01, B-02, B-03, B-04, B-05, B-06, B-07 and B-11 and the use of one of compounds A-01, A-02, A-03, A-04, A-05, A-06, A-07, A-08, A-09, A-10, A-11 and A-12 is most preferred due to their very good TRPM8 activation, their EC50 values ​​and their cooling potency.

[0374] Therefore, in a further aspect, the present invention also comprises a food, a dietary supplement, a cosmetic or pharmaceutical preparation, an animal feed, a textile product, packaging or a tobacco product comprising a physiological coolant or a physiological coolant mixture according to the invention, or a flavoring preparation according to the invention.

[0375] The content of the coolant(s) depends on the type and use of the product as described above, and is preferably between about 0.1 ppm and 10% by weight, preferably between 1% and 10% by weight, based on the total weight of the final product. For oral care applications, for example in toothpaste or mouthwash, the content of the coolant(s) is between 0.1 ppm and 500 ppm.

[0376] To achieve the desired level of sensitivity modulation, the broad concentration range typically used may be from about 0.001 ppm to 1000 ppm, or from about 0.01 ppm to about 500 ppm, or from about 0.05 ppm to about 300 ppm, or from about 0.1 ppm to about 200 ppm, or from about 0.5 ppm to about 150 ppm, or from about 1 ppm to about 100 ppm.

[0377] Preferably, the food product is a bakery product, such as bread, dried cookies, cakes, other baked goods, confectionery (e.g. chocolate, chocolate bar products, other bar products, fruit gum, hard and soft caramel, chewing gum), alcoholic or non-alcoholic beverage, such as coffee, tea, iced tea, wine, wine-based beverages, beer, beer-based beverages, liqueurs, spirits, brandy, (carbonated) fruit-based soft drinks, (carbonated) isotonic drinks, (carbonated) soft drinks, nectar, spritzer, fruit juices, juice and vegetable juices, fruit juice or vegetable juice preparations, instant drinks (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 salted meat products), eggs or egg products (dried eggs, egg whites, egg yolks), cereal products (e.g., breakfast cereals, muesli bars, ready-to-cook instant rice products), dairy products (e.g., milk drinks, buttermilk drinks, milk ice cream, yogurt, soy protein or other soy fractions (e.g. soy milk and products made therefrom, fruit drinks containing soy protein, preparations containing soy lecithin, fermented products such as tofu or tempeh or products made therefrom), products made from other plant protein sources, e.g. oat protein drinks, fruit preparations (e.g. jams, fruit ice cream, fruit sauces, fruit fillings), products made from soy protein or other soy fractions (e.g. soy milk and products made therefrom, fruit preparations (e.g. jams, fruit ice cream, fruit sauces, fruit fillings), vegetable preparations (e.g. ketchup, sauces, dried vegetables, frozen vegetables, cooked vegetables, boiled vegetables), snacks (e.g. baked or fried potato chips or potato dough products, corn or peanut based extrudates),Fat and oil-based products or emulsions thereof (e.g. mayonnaise, remoulade, dressings), other prepared meals and soups (e.g. dry soups, instant soups, prepared soups), spices, seasoning mixtures, and in particular condiments used in snack foods, e.g. condiments used in the snack sector.

[0378] In addition to conventional food ingredients, the food product comprises at least one effective, i.e., cooling, amount of at least one coolant according to the invention, or a coolant mixture according to the invention, or a flavoring preparation according to the invention.

[0379] The content of the coolant or coolant mixture or flavoring preparation in these preparations is preferably from about 0.1% to about 10% by weight, in particular from about 1% to 2% by weight, relative to the total weight of the finished preparation.

[0380] Suitable excipients may be used to manufacture products according to the invention, such as foods, dietary supplements, cosmetic or pharmaceutical preparations, animal feed, textile products, packaging or tobacco products, etc. Suitable excipients include, but are not limited to, emulsifiers, thickeners, food acids, acidity regulators, vitamins, antioxidants, flavor enhancers, active ingredients that mask unpleasant taste impressions, food colorants, etc.

[0381] Other customary additives or auxiliary substances, such as flavorings or active ingredients for masking unpleasant taste impressions, may be added to the products according to the invention described above.

[0382] Flavoring agents: Preferred flavoring agents are those that produce a sweet odor impression, and further flavoring agents that produce a sweet odor impression are 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), homofuranol (2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone and 5-ethyl-4-hydroxy-3(2H)-furanone), ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and derivatives (e.g., ethyl maltol), coumarin and derivatives, gamma-lactones (e.g., gamma-undecalactone, gamma-nonalactone), delta-lactones (e.g., 4-methyldeltalactone, massolactone, deltadecalactone, tuberolactone), methyl sorbate, divanillin, 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone, 2-hydroxy-3-methyl-2-cyclopentenone, 3-Hydroxy-4,5-dimethyl-2(5H)-furanone, fruit esters and fruit lactones (e.g., acetate n-butyl ester, acetate isoamyl ester, propionic acid ethyl ester, butyric acid ethyl ester, butyric acid n-butyl ester, butyric acid i-isoamyl ester, 3-methyl-butyric acid ethyl ester, n-hexanoic acid ethyl ester, n-hexanoic acid allyl ester, n-hexanoic acid n-butyl ester, n-octanoic acid ethyl ester, ethyl 3-methyl-3-phenylglycidate, ethyl 2-trans-4-citric acid s-decadienoate), 4-(p-hydroxyphenyl)-2-butanone, 1,1-dimethoxy-2,2,5-trimethyl-4-hexane, 2,6-dimethyl-5-hepten-1-al, 4-hydroxycinnamic acid, 4-methoxy-3-hydroxycinnamic acid, 3-methoxy-4-hydroxycinnamic acid, 2-hydroxycinnamic acid, 2,4-dihydroxybenzoic acid, 3-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, vanillic acid, homovanillic acid, vanillomandelic acid and phenylacetaldehyde.

[0383] Active ingredients for masking unpleasant taste sensations: Furthermore, the oral preparations may also contain further substances which also serve to mask the impression of bitterness and / or astringency. These further flavour masking agents are, for example, those listed below: nucleotides (e.g. adenosine 5'-monophosphate, cytidine 5'-monophosphate) or physiologically acceptable salts thereof, lactisol, sodium salts (e.g. sodium chloride, sodium laurate), sodium salts (e.g. sodium chloride, sodium lactate, sodium citrate, sodium acetate, sodium gluconate), hydroxyflavanones, preferably eriodictyol, sterubin (eriodictyol-7-methyl ether), homoeriodictyol and their sodium, potassium, calcium, magnesium or zinc salts (e.g. sodium chloride, sodium lactate, sodium citrate, sodium acetate, sodium gluconate), magnesium or zinc salts thereof (e.g. sodium chloride, sodium lactate, sodium citrate, sodium acetate, sodium gluconate), magnesium or zinc salts thereof (especially those described in EP 1 258 200 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-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-dihydro 2,4-dihydroxybenzoic acid-N-2-(4-hydroxy-3-methoxy-phenyl)ethylamide, 2,4-dihydroxybenzoic acid-N-(4-hydroxy-3-ethoxybenzyl)amide, 2,4-dihydroxybenzoic acid-N-(3,4-dihydroxybenzyl)amide and 2-hydroxy-5-methoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]amide; 4-hydroxybenzoic acid vanillylamide (especially those described in WO 2006 / 024587);Hydroxydeoxybenzoins, preferably 2-(4-hydroxy-3-methoxyphenyl)-1-(2,4,6-trihydroxyphenyl)ethanone, 1-(2,4-dihydroxyphenyl)-2-(4-hydroxy-3-methoxyphenyl)-ethanone and 1-(2-hydroxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxyphenyl)ethanone (especially those described in WO 2006 / 106023); hydroxyphenylalkanediones (gingerdione di diacetyl trimer (especially those described in WO2006 / 058893); gamma-aminobutyric acid (especially those described in WO2005 / 096841); divanillin (especially those described in WO2004 / 078302); and 4-hydroxydihydrochalcones (preferably as described in US2008 / 0227867A1), in particular whey protein mixtures containing phloretin and davidigenin, amino acids or lecithin, hesperetin as disclosed in WO2007 / 014879, 4-hydroxydihydrochalcones as disclosed in WO2007 / 107596 or propenylphenylglycosides (chavicolglycosides) as described in EP1955601A1. coside), or extracts from sweet tea, extracts from hydrangea described in EP 2298084 A1, pellitrin and the induced aroma compositions described in EP 2008530 A1, umami compounds described in WO 2008 / 046895 A1 and EP 1989944 A1, umami compounds described in EP 2064959 A1 and EP 2135516 A1, vanillyl lignans, enterodiol and N-decadienoyl amino acids, and mixtures thereof;

[0384] A further object of the invention relates to cosmetic or pharmaceutical preparations containing either one or more coolants according to the invention, or a coolant mixture according to the invention, or a fragrance preparation according to the invention.

[0385] The agents according to the invention can be, in particular, skin cosmetics, hair cosmetics, skin preparations, hygiene preparations or pharmaceutical preparations. In particular, the active ingredients according to the invention, which have a cooling effect, are used in particular for skin and / or hair cosmetics or as oral care products.

[0386] The hair care or skin care compositions 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. Suitable emulsions are oil-in-water emulsions and water-in-oil emulsions or microemulsions. Hair or skin cosmetic preparations are generally used for application to the skin (topical) or hair. The term "topical preparation" refers to a preparation suitable for applying active ingredients to the skin in a finely dispersed form, e.g., a form that can be absorbed through the skin. 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 suitable for this purpose. According to one embodiment of the cosmetic composition according to the present invention, it comprises a carrier. Preferred carriers are water, gas, water-based liquid, oil, gel, emulsion or microemulsion, dispersion, or mixtures thereof. The above carriers exhibit good skin compatibility. Aqueous gels, emulsions, or microemulsions are particularly advantageous for topical preparations.

[0387] The teachings of the present invention include the use of the active ingredients described herein for medical purposes, particularly in pharmaceutical compositions for treating individuals, preferably mammals, especially humans, livestock or domestic animals.For this purpose, the active ingredient is administered in the form of a pharmaceutical composition comprising at least one active ingredient according to the present invention, and optionally a pharmaceutically acceptable excipient containing a further active ingredient.These compositions can be administered, for example, orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.

[0388] Examples of suitable pharmaceutical formulations or compositions include solid dosage forms such as pulver, powder, granule, tablet, pastille, sachet, cachet, coated tablet, etc., capsules such as hard and soft gelatin capsules, suppositories or vaginal dosage forms, semi-solid dosage forms such as ointments, creams, hydrogels, pastes or patches, and liquid dosage forms such as solutions, emulsions, especially oil-in-water emulsions, suspensions, creams, hydrogels, pastes or patches, creams, hydrogels, pastes or patches, as well as liquid dosage forms such as solutions, emulsions, especially oil-in-water emulsions, suspensions, e.g. lotions, injectable and infusion preparations, eye drops and ear drops. Implanted delivery devices can also be used to administer the inhibitors according to the present invention. In addition, liposomes, microspheres or polymer matrices can also be used. Possible pharmaceutical agents include cooling syrups, wound ointments or wound sprays. It is also possible to incorporate substances into plasters or tablets, especially if they contain active ingredients that themselves have an unpleasant taste.

[0389] A further object of the present invention therefore comprises a coolant or coolant mixture according to the invention as a medicine, in particular for use in the relief of pain and inflammatory conditions of the skin and mucous membranes. Due to their cooling properties, the coolant according to the invention is particularly suitable for preventing, treating or alleviating the symptoms of coughs, colds, irritations, sore throats or hoarseness.

[0390] The substances and preparations described herein are also suitable for treating inflammatory conditions of the skin, mucous membranes and joints because of their effective cooling action.

[0391] Because of its property of modulating receptor TRPM8, its gene expression, i.e., the expression of TRPM8 gene, is upregulated in cancer diseases, such as prostate cancer, and the pharmaceutical preparation of the present invention is also preferably used in oncology, preferably in the treatment of prostate cancer or bladder cancer, or for the treatment of bladder weakness.The corresponding protein in cells is coded by the corresponding gene in cell nucleus.By reading (transcription) the gene in nucleus, messenger RNA (mRNA) is produced, which is then "translated" (translation) into protein on ribosome in cells.The whole of both processes is often called gene expression.

[0392] However, astringent, bitter and / or metallic tastes are not only found in the above-mentioned flavors and sweeteners, but also in association with many active pharmaceutical ingredients, making them difficult to ingest, especially by children. Typical examples of such active pharmaceutical ingredients are aspirin, minoxidil, erythromycin, phenistir, betamethasone, ibuprofen, ketoprofen, dicyclofenac, metronidazole, acyclovir, imiquimod, terbafine, ciclopiroxolamine, paracetamol, and other pharmaceutical agents of the non-steroidal anti-inflammatory drug (NSAID) type, and mixtures thereof.

[0393] The present invention therefore also comprises medicaments containing one or more coolants according to the invention, or a coolant mixture according to the invention, or a flavoring preparation according to the invention, in combination with at least one further active pharmaceutical ingredient selected from the group consisting of aspirin, minoxidil, erythromycin, phenistir, betamethasone, ibuprofen, ketoprofen, dicyclofenac, metronidazole, acyclovir, imiquimod, terbafine, cyclopiroxolamine, paracetamol and mixtures thereof.

[0394] In the subject, the coolant according to the invention or the coolant mixture according to the invention has been shown to enhance the pain-relieving properties of non-steroidal anti-inflammatory drugs (NSAIDs), in particular ibuprofen and ketoprofen, in addition to the cooling effect, which was also not expected by those skilled in the art.The present invention therefore also particularly relates to combinations with pharmaceutical agents of the non-steroidal anti-inflammatory drug (NSAID) type.

[0395] Such pharmaceutical combinations are therefore particularly advantageous for use in the treatment of inflammatory conditions of the skin and mucous membranes, and of the joints.

[0396] The medicament may contain the coolant according to the invention or the coolant mixture according to the invention and the active pharmaceutical ingredient in a weight ratio of about 1:99 to about 10:90, in particular 2:98 to about 5:95.

[0397] For example, physiological cooling effects are also used in the formulation of ointments for wounds and burns, and in preparations for insect bites.

[0398] In preparing the cosmetic or pharmaceutical compositions according to the invention, the coolant or coolant mixture according to the invention is usually mixed with or diluted by an excipient. The excipient may be a solid, semi-solid, or liquid substance that serves as a vehicle, carrier, or medium for the active ingredient. The content of the active ingredient (in one or more simultaneously contained coolants according to the invention) can vary over a wide range, being in each case approximately from 0.05 ppm to 10% by weight, preferably from 0.1 ppm to 10% by weight, based on the total weight of the preparation.

[0399] Suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. In addition, the formulation may contain pharmaceutically acceptable carriers or conventional excipients such as lubricants, for example, tallow, magnesium stearate, and mineral oil, wetting agents, emulsifiers, and suspending agents, preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate, antioxidants, anti-irritants, chelating agents, coating agents, emulsion stabilizers, film-forming agents, gel-forming agents, odor masking agents, flavoring agents, resins, hydrocolloids, solvents, solubilizers, neutralizing agents, penetration enhancers, pigments, quaternary ammonium compounds, refatting and superfatting agents, ointments, creams, or oily bases, silicone derivatives, spreading aids, stabilizers, sterilizing agents, suppository bases, tablet excipients such as binders, fillers, lubricants, disintegrants, or coating agents, propellants, desiccants, opacifiers, thickeners, waxes, plasticizers, and white oils.Related embodiments are based on specialized knowledge and are appropriately described in the relevant technical literature. In addition to conventional additives or adjuvants, the preparations according to the invention may also contain aesthetic and / or dermatological and / or pharmacological active agents. Non-limiting examples of suitable additional active ingredients include aesthetic and / or dermatological active ingredients, antibacterial active ingredients, surfactants (anionic surfactants, nonionic surfactants, cationic surfactants, amphoteric or zwitterionic surfactants), oil bodies, emulsions, emulsifiers, antimicrobial agents and other active ingredients (zwitterionic surfactants), oil bodies, emulsions, fats and waxes, pearlescent waxes, thickeners and thickeners, superfatting agents and stabilizers, polymers, silicone compounds, UV light protection filters, pigments, especially photoprotective pigments, moisturizers, biogenic active ingredients and antioxidants, deodorants and bacterial inhibitors, enzyme inhibitors, odor absorbers, antiperspirants, film formers, antidandruff agents, swelling agents, insect repellents, hydrotropes, preservatives, perfume oils and aromas, dyes, etc.

[0400] Preferred preparations according to the invention are selected from the group of products for treating, protecting, caring for and cleansing the skin and / or hair, or as make-up products, as leave-on or rinse-off products.

[0401] Formulations may, for example, depending on the manufacturing method and ingredients, be dispersions, suspensions, creams, lotions or emulsions, gels (including hydrogels, e.g. hydrodispersed gels, oleogels), sprays (e.g. pump sprays or sprays with propellants), foams or impregnating solutions for cosmetic wipes, soaps, washing-up solutions, shower and bath preparations, bath additives (capsules, oils, tablets, salts, bath salts, soaps etc.), effervescent preparations, skin care products (emulsions, ointments, pastes, gels (as above) etc.), oils, balms, serums, powders (e.g. face powders, body powders), masks, sticks, roll-on sticks, aerosols (foaming, non-foaming or after-foaming), deodorants and / or antiperspirants, mouthwashes and mouthwashes. including rinses, insect repellents, sunscreens, after-sun products, shaving products, after-shave balms, pre-shave and after-shave lotions, depilatories, hair care products (such as shampoos (including 2-in-1 shampoos, anti-dandruff shampoos, baby shampoos, dry scalp shampoos, thick 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 smoothers (detangling agents, hair straighteners), hair dyes (such as temporary hair dyes, semi-permanent hair dyes, permanent hair dyes), hair conditioners, hair foams, eye care products, make-up, make-up removers or baby products.

[0402] Particularly preferably, the formulation according to the invention is in the form of an emulsion, in particular a W / O, O / W, W / O / W, O / W / O emulsion, a PIT emulsion, for example a Pickering emulsion, an emulsion with a low oil content, a micro- or nano-emulsion, a gel (including hydrogels, hydrodisperse gels, oleogels) or a solution.

[0403] The total proportion of excipients and additives can be 1% to 50% by weight, preferably 5% to 40% by weight, based on the final preparation. The preparation of the active agent can be carried out by conventional cold processing or hot processing. Preferably, the phase inversion temperature method is used.

[0404] The present invention also comprises oral care compositions comprising one or more coolants according to the invention, or a coolant mixture according to the invention, or a flavoring preparation according to the invention.

[0405] The oral hygiene products according to the invention are formulated in a manner known per se, for example as toothpastes, tooth creams, tooth gels, tooth powders, toothpastes, tooth foams, aqueous or hydroalcoholic oral care products (mouthwashes), mouthwashes as 2-in-1 products, lozenges, mouth sprays, dental floss and dental care chewing gums.

[0406] Toothpaste or tooth cream is generally understood to be a gel-like or paste-like preparation of water, a thickener, a moisturizer, an abrasive or cleaning agent, a surfactant, a sweetener, a flavoring agent, a deodorizing active ingredient, and an active ingredient against oral and dental diseases. In the toothpaste according to the present invention, all of the conventional detergents can be used, such as chalk, dicalcium phosphate, insoluble sodium metaphosphate, aluminum silicate, calcium pyrophosphate, finely divided synthetic resins, silica, aluminum oxide, and aluminum oxide trihydrate.

[0407] Detergents suitable for toothpastes according to the invention include, inter alia, particulate xerogel silica, hydrogel silica, precipitated silica, aluminum oxide trihydrate, and particulate alpha-aluminum oxide, or mixtures of these detergents, in amounts of 15 to 40% by weight of the toothpaste. Low-molecular-weight polyethylene glycols, glycerol, sorbitol, or mixtures of these products can be used as humectants in amounts of up to 50% by weight. Among known thickeners, thickening finely divided gel silicas and hydrocolloids, such as carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl guar, hydroxyethyl starch, polyvinylpyrrolidone, high-molecular-weight polyethylene glycols, vegetable gums (tragacanth, agar, carrageenan, gum arabic, xanthan gum, etc.), and carboxyvinyl polymers (e.g., Carbopol® type), are preferred. In addition to the mixture of menthofuran and menthol compounds, the oral and dental care compositions contain in particular surface-active substances, preferably anionic and nonionic high-foaming surfactants such as those already mentioned above, but may in particular include alkyl ether sulfate salts, alkyl polyglucosides and mixtures thereof.

[0408] Other common toothpaste additives include: · Preservatives and antimicrobial substances such as methyl, ethyl or propyl p-hydroxybenzoate, sodium sorbate, sodium benzoate, bromochlorophene, phenyl salicylate, thymol; anti-tartaric agents, for example organic phosphates such as 1-hydroxyethane-1,1-diphosphonic acid, 1-phosphonopropane-1,2,3-tricarboxylic acid, as known, for example, from US Pat. No. 3,488,419, DE 2224430 A1 and DE 2343196 A1; · Other caries inhibitors such as sodium fluoride, sodium monofluorophosphate, and stannous fluoride; sweetening agents such as sodium saccharin, sodium cyclamate, sucrose, lactose, maltose, fructose or Apartam® (L-aspartyl-L-phenylalanine methyl ester), stevia extracts or their sweet components, in particular rebaudiosides; · Additional flavors such as eucalyptus oil, anise oil, fennel oil, caraway oil, methyl acetate, cinnamaldehyde, anethole, vanillin, thymol and mixtures thereof, and other natural and synthetic flavors; · Pigments such as titanium dioxide; · Coloring agents; Buffer substances such as primary, secondary or tertiary alkaline phosphates or citric acid / sodium citrate · Wound healing and anti-inflammatory substances such as allantoin, urea, azulene, chamomile active ingredients and acetylsalicylic acid derivatives.

[0409] Hydrotropes such as ethanol, isopropyl alcohol, or polyols can also be used to improve the flow behavior. These substances primarily correspond to the carriers mentioned at the beginning. The polyols considered here preferably have 2 to 15 carbon atoms and at least two hydroxyl groups. The polyols may also contain other functional groups, in particular amino groups, or be modified with nitrogen.

[0410] Suitable preservatives include phenoxyethanol, formaldehyde solution, parabens, pentanediol or sorbic acid, and the silver complexes known as Surfacine®, as well as other classes of materials known to those skilled in the art as suitable.

[0411] Perfume oils are those already defined above. In particular, peppermint oil, spearmint oil, anise oil, star anise oil, caraway oil, eucalyptus oil, fennel oil, lemon oil, wintergreen oil, clove oil, menthol, etc. may be considered as aromas.

[0412] A preferred embodiment of the cosmetic preparation is a toothpaste in the form of an aqueous pasty dispersion containing abrasives, moisturizers, viscosity modifiers and optionally other customary constituents, as well as a mixture of menthofuran and menthol compounds in an amount of 0.5 to 2% by weight.

[0413] In the mouthwash, various grades of essential oils, emulsions, astringents and tonifying drug extracts, anti-tartar agents, antibacterial additives, and taste-masking agents can be easily combined with the aqueous alcoholic solution. A further 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 menthol compounds in an amount of 0.5 to 2% by weight. For mouthwashes that are diluted before use, higher concentrations can be used to obtain sufficient effectiveness, depending on the intended dilution ratio.

[0414] The oral care composition according to the invention preferably contains from 0.1 ppm to 1% by weight, preferably from 1 ppm to 0.2% by weight, of at least one active ingredient, i.e. a coolant, or active ingredient mixture, i.e. a coolant mixture or a flavoring preparation, according to the invention, relative to the total weight of the composition.

[0415] The total content of the active ingredient or active ingredients according to the invention, or of the coolant mixture or flavoring preparation according to the invention, in the ready-to-use mouthwash is preferably 0.01 to 1% by weight, preferably 0.05 to 0.5% by weight, in particular a content of 0.1 to 0.3% by weight in each case relative to the total mouthwash.

[0416] In the mouthwash concentrate, the total content of the active ingredient or active ingredients according to the invention or of the coolant mixture or flavoring preparation according to the invention is from 0.1 to 15% by weight, preferably a content of 0.5 to 8% by weight, particularly preferably 1 to 5% by weight, in each case based on the total mouthwash concentrate.

[0417] In toothpastes, the total content of the active ingredient or active ingredients according to the invention, or of the coolant mixtures or flavoring preparations according to the invention, is in each case from 0.1 to 5% by weight, preferably from 0.5 to 2% by weight, particularly preferably from 0.8 to 1.5% by weight, based on the total toothpaste.

[0418] The present invention also comprises chewing gums comprising one or more coolants according to the invention, or a coolant mixture according to the invention, or a flavoring preparation according to the invention.

[0419] Chewing gum compositions typically contain water-insoluble and water-soluble components. The water-insoluble base, also known as "gum base," typically contains natural or synthetic elastomers, resins, fats and oils, plasticizers, fillers, colorants, and optionally waxes. The base typically accounts for 5-95% by weight, preferably 10-50% by weight, and particularly 20-35% by weight of the total composition. In a typical embodiment of the present invention, the base comprises 20-60% by weight of synthetic elastomers, 0-30% by weight of natural elastomers, 5-55% by weight of plasticizers, 4-35% by weight of fillers, and trace amounts of additives such as colorants and antioxidants, provided that at most small amounts of these additives are water-soluble.

[0420] Suitable synthetic elastomers include, for example, polyisobutylene having an average molecular weight (by GPC) of 10,000 to 100,000, preferably 50,000 to 80,000, isobutylene / isoprene copolymers ("butyl elastomers"), styrene / butadiene copolymers (styrene:butadiene ratios, for example, 1:3 to 3:1), polyvinyl acetate having an average molecular weight (by GPC) of 2,000 to 90,000, preferably 10,000 to 65,000, polyisoprene, polyethylene, vinyl acetate-vinyl laurate copolymers, and mixtures thereof. Examples of suitable natural elastomers are rubbers such as smoked or liquid latex or guayule, and natural rubbers such as jelutong, lechi caspi, perillo, sorva, massaranduba balata, massaranduba chocolate, nispero, rosindinba, chicle, guttahang 1kang, and mixtures thereof. The choice of synthetic and natural elastomers and their mixing ratios depend substantially on whether the chewing gum is intended to produce balloons ("bubble gum"). Elastomer mixtures containing jelutong, chicle, sorva, and massaranduba are preferably used.

[0421] Possible fillers or texture modifiers include magnesium or calcium carbonate, ground pumice, silicates, especially magnesium or aluminum silicate, clay, aluminum oxide, talc, titanium dioxide, mono-, dicalcium and tricalcium phosphate, and cellulose polymers.

[0422] Suitable emulsifying agents are tallow, hardened tallow, hardened or partially hardened vegetable oils, cocoa butter, partial glycerides, lecithin, triacetin, and saturated or unsaturated fatty acids having 6 to 22, preferably 12 to 18, carbon atoms, and mixtures thereof.

[0423] Contemplated coloring and whitening agents include FD and C types approved for food coloring, plant and fruit extracts, and titanium dioxide.

[0424] The base composition can contain wax or can be wax-free. Examples of wax-free compositions can be found, inter alia, in patent specification US 5,286,500.

[0425] In addition to the water-insoluble gum base, chewing gum preparations typically contain a water-soluble portion formed by, for example, softeners, sweeteners, fillers, flavorings, flavor enhancers, emulsifiers, colorants, acidifiers, antioxidants, etc. (provided that these components have at least sufficient water solubility). Thus, individual components can reside in both the water-insoluble and water-soluble phases, depending on the water solubility of the particular representative. However, it is also possible to use, for example, a combination of water-soluble and water-insoluble emulsifiers, so that the individual agents are then present in different phases. Typically, the water-insoluble portion accounts for 5 to 95% by weight of the preparation, preferably 20 to 80% by weight.

[0426] To improve chewability and chewing sensation, water-soluble softeners or plasticizers are added to chewing gum compositions, usually present in the mixture in amounts of 0.5 to 15% by weight. Typical examples are aqueous solutions of glycerol, lecithin, and sorbitol, hydrogenated starch hydrolysates, or corn syrup.

[0427] Both sugar-containing and sugar-free compounds are suitable as sweeteners, and are used in amounts of 5 to 95% by weight, preferably 20 to 80% by weight, and particularly 30 to 60% by weight, of the chewing gum composition. Typical saccharide sweeteners are sucrose, dextrose, maltose, dextrin, dry invert sugar, fructose, levulose, galactose, corn syrup, and mixtures thereof. Sorbitol, mannitol, xylitol, hardened starch hydrolysates, maltitol, and mixtures thereof can be used as sugar substitutes. In addition, so-called "HIAS" ("high-intensity artificial sweeteners"), such as sucralose, aspartame, acesulfame salts, alitame, saccharin and saccharin salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, and monellin, are also contemplated as additives, either alone or in mixtures. Also particularly effective are hydrophobic HIAS, the subject of International Patent Application WO2002091849A1 (Wrigleys), and stevia extract and its active ingredients, especially libeudioside A. The amounts of these substances used depend mainly on their performance and are usually in the range of 0.02 to 8% by weight.

[0428] Fillers such as polydextrose, raftilose, rafficillin, fructooligosaccharides (NutraFlora), palatinose oligosaccharides, guar gum hydrolysate (Sun Fiber) and dextrins are particularly suitable for producing low calorie chewing gum.

[0429] Furthermore, the choice of flavoring agent is virtually unlimited and not critical to the essence of the present invention. Typically, the total amount of all flavoring agents is 0.1 to 15% by weight, and preferably 0.2 to 5% by weight, based on the chewing gum composition. Suitable additional flavoring agents are, for example, essential oils such as anise oil, star anise oil, caraway oil, eucalyptus oil, fennel oil, lemon oil, wintergreen oil, clove oil, synthetic flavors, and the like, which are also used, for example, in oral care and dental care compositions.

[0430] The chewing gum may also contain auxiliary substances and additives suitable for dental care, especially for combating plaque and gingivitis, such as, for example, chlorhexidine, CPC or triclosan. The chewing gum may also contain pH adjusting agents (e.g., buffers or urea), anti-caries agents (e.g., phosphates or fluorides), biological agents (antibodies, enzymes, caffeine, plant extracts), as long as these substances are approved for use in food and do not interact with each other in an undesirable way.

[0431] The present invention includes a cooling patch. The patch according to the present invention can be constructed in any desired manner, for example, by a matrix system, a membrane system or a nonwoven system.

[0432] The plaster according to the invention is produced in the usual manner.

[0433] The Matrix system consists of three simple parts: a flexible support film, an adhesive matrix containing the active ingredient, and a peel-off film. If a non-adhesive matrix is ​​used, an adhesive must be applied to one edge of the support film to ensure adhesion to the skin.

[0434] On the other hand, a membrane system has at least five parts: a flexible support film, a reservoir containing the dissolved or suspended active ingredient, a membrane for controlling the release of the active ingredient, an adhesive layer applied to the membrane, and a peel-off film.

[0435] In nonwoven systems, the active ingredient-containing layer consists of an absorbent nonwoven or porous polymer impregnated with a solution or suspension of the active ingredient. This layer is firmly attached to a support film, which is then covered by a peel-off film. The edges of the support film are provided with adhesive for application to the skin.

[0436] In principle, all active ingredients according to the present invention can be formulated in this way. The excipients used are those conventional for producing plasters. In addition to the adhesive, a polymer having a glass transition temperature of -70 to -10°C, in particular -55 to -25°C, and a carrier film coated with this adhesive are usually added, and the active ingredient, emulsion, thickener, substances intended to affect the release of the active ingredient, and other auxiliary substances are often added.

[0437] Self-adhesive polymers with the above-mentioned low glass temperature are known. Self-adhesive tapes and films are intended to adhere to human skin by simple contact, but the cohesive strength of the adhesive layer and its adhesion to the carrier film should be greater than its adhesion to the skin, so that they can be removed again, mainly without leaving any residue. These are usually copolymers based on acrylic and methacrylic acid esters of alcohols having 2 to 12, especially 4 to 8, carbon atoms, which may contain, for example, (meth)acrylic acid, (meth)acrylonitrile, (meth)acrylamide, N-tert-butyl (meth)acrylamide, vinyl esters (such as vinyl acetate, vinyl propionate, or butyl butyrate), other vinyl compounds (such as styrene), and numerous other comonomers polymerized with butadiene. Butyl acrylate and 2-ethylhexyl acrylate are particularly noteworthy. The polymer can be crosslinked by adding small amounts of comonomers with two or more copolymerizable double bonds, such as diacrylates (e.g., butanediol diacrylate) or divinyl compounds (e.g., divinylbenzene), or by adding other crosslinking agents (e.g., melamine-formaldehyde resins). Polyisobutylene and polyvinyl ethers of different molecular weights can also be used as adhesive polymers.

[0438] The particle size of the dispersion should be between 50 and 500 nm, particularly between 50 and 200 nm. The particle size and degree of crosslinking can be adjusted by known methods depending on the polymerization conditions and comonomers. The smaller the particle size and the greater the degree of crosslinking, the greater the release amount of the active ingredient.

[0439] Matrix patch can be produced by dissolving or finely dispersing active ingredient in suitable polymer solution, and then using roller or doctor blade application process to spread the self-adhesive mass containing this active ingredient into a film.In some cases, it is advisable to dissolve or finely disperse active ingredient in organic solvent, such as ethanol or acetone, and then add it to polymer solution.This can achieve good distribution of active ingredient in polymer.

[0440] Patches can also be produced by incorporating the active ingredient in finely divided powder form (particle size less than 200 μm, especially less than 50 μm) into an aqueous latex dispersion, or by dispersing or dissolving the active ingredient in an aqueous emulsion solution and mixing this mixture with the aqueous latex dispersion at temperatures between 10 and 80°C, especially between 30 and 70°C. Furthermore, a salt of the active ingredient in aqueous solution can be mixed with the polymer dispersion at a pH value at which the active ingredient is present primarily in its water-soluble, ionized form. By changing the pH, the active ingredient is then converted into a water-insoluble, uncharged form and simultaneously emulsified in the dispersion.

[0441] The active ingredient is conveniently prepared, and the emulsion and water are added, followed by mixing with the polymer dispersion. The active ingredient-containing dispersion thus obtained may be further supplemented with additives and, as described above, stretched to form a film on a support film, which is then dried by a method known per se. The drying temperature can be between room temperature and 100°C, with the optimum value generally being 35-45°C, which achieves the desired rapid drying, avoids bubble formation in the film, and thermal stress on the active ingredient. This process has the significant advantage of avoiding the use of organic solvents. However, in principle, all other conventional manufacturing processes for matrix patches can also be considered.

[0442] The resulting film has a thickness of 10 to 800 μm, preferably 50 to 300 μm. The film can be produced continuously or discontinuously. The coating process can be repeated several times until the film reaches the desired thickness. The adhesive polymer layer contains the active ingredient in a concentration ranging from 1 to 40% by weight, especially from 5 to 25% by weight. The same concentration applies to the reservoir liquid in membrane systems and to the solution or dispersion of the active ingredient with which the nonwoven or porous polymer is impregnated in nonwoven systems.

[0443] As emulsifiers for both the active ingredient according to the invention, i.e. the coolant according to the invention or the coolant mixture according to the invention, or the fragrance preparation according to the invention, and the polymer, surfactants commonly used for this purpose are used, such as sodium salts of sulfuric acid half esters of long-chain fatty acids and (optionally oxethylated) fatty alcohols as examples of anionic surfactants, and polyoxyethylated alkylphenols and long-chain fatty alcohols (e.g. hexadecan-(1)-ol and glycerol fatty acid partial esters) as examples of nonionic surfactants and co-emulsifiers.

[0444] The desired viscosity of the instantly extractable mass can be adjusted using, for example, polyacrylic acid or cellulose derivatives. For example, melamine-formaldehyde resins can be used as additional crosslinking agents to improve the cohesive strength, i.e., adhesive properties, of the film.

[0445] Swelling agents such as polyvinylpyrrolidone, cellulose derivatives or polyacrylates improve the release of active ingredients by allowing the film to absorb more water, thereby reducing the diffusion resistance. The addition of hydrophilic plasticizers such as glycerin, polyethylene glycol 1,2-propanediol, and lipophilic plasticizers such as triacetin, dibutyl phthalate or isopropyl myristate can improve the release of active ingredients.

[0446] Matrix patches typically provide first-order release of the active ingredient. The use of fillers that adsorb the active ingredient, such as aerosil, microcrystalline cellulose, or lactose, results in near-zero-order release.

[0447] The support film on which the active ingredient-containing self-adhesive composition is dried is substantially impermeable to both the active ingredient and water vapor. It can consist, for example, of an aluminum-plastic composite film, a metallized plastic film, a plastic film provided on the active ingredient side with a barrier layer, for example of polyvinylidene chloride, or a simple plastic film, for example a polyester film.

[0448] The patches according to the present invention, constructed according to the membrane system, are also produced in the usual way. Plasters constructed according to the nonwoven system are produced by immersing a nonwoven fabric or porous polymer attached to a support film in a solution or dispersion of the active ingredient in a hydrophilic or lipophilic solvent or solvent mixture. An impermeable peel-off film is then applied.

[0449] In principle, the active ingredient content in the preparations according to the invention can vary over a wide range, for example from 0.1 ppm to 10% by weight, preferably from 1 ppm to 10% by weight.

[0450] The invention also relates to textile products provided with a coolant according to the invention or a coolant mixture according to the invention.

[0451] The finishing of textiles with cooling coolants is used in particular when the article of clothing can come into direct contact with the skin, so that the active ingredients can exert their action locally or systemically, for example by transdermal migration.Recently, textiles equipped with so-called wellness additives, i.e. substances that promote health, have been reported.

[0452] On the other hand, insecticidal finishes are interesting for the protection of materials, for example finishing textiles against moth damage, and in particular for repelling parasitic insects such as mosquitoes.

[0453] The basic problem in finishing textiles with active ingredients is the binding of the active ingredient to the textile carrier, which must on the one hand ensure the permanence of the finished product, and on the other hand be selected so that the active ingredient does not lose its action. In the state of the art, various methods have been proposed.

[0454] For example, cyclodextrins have been proposed for binding active ingredients to textiles. Cyclodextrins are cyclic oligosaccharides formed by the enzymatic degradation of starch. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of six, seven, or eight α-1,4-linked glucose units. A distinctive feature of cyclodextrin molecules is their ring structure, which has nearly constant dimensions. The internal diameter of the ring is approximately 570 pm for α-cyclodextrin, approximately 780 pm for β-cyclodextrin, and approximately 950 pm for γ-cyclodextrin. Due to their structure, cyclodextrins can capture various amounts of guest molecules, particularly hydrophobic guest molecules, until saturation occurs.

[0455] The latest technology describes the finishing of textiles using fragrances and other low-molecular-weight organic active ingredients that are bound to textiles via amylose-containing materials with an amylose content of at least 30%. The amylose content of the amylose-containing materials allows the active ingredients to bind to the textile and release them in a controlled manner, resulting in a long-lasting effect. Similar to cyclodextrins, the active ingredients are presumably reversibly bound to the cavities formed by the helical conformation of amylose in the sense of an inclusion compound, immobilizing the active ingredients on the surface of the textile carrier and enabling controlled release on the other hand.

[0456] In addition to amylose, all substances, especially amylose-containing starches, i.e., native starches, modified starches, and starch derivatives, whose amylose content is at least 30% by weight, especially at least 40% by weight, are suitable for the finishing of textiles according to the present invention. The starch can be native starch, such as corn starch, wheat starch, potato starch, sorghum starch, rice starch, or maranta starch, obtained by partial digestion of native starch, or chemically modified. Thus, pure amylose, such as enzymatically obtained amylose, e.g., amylose obtained from sucrose, is also suitable. Mixtures of amylose and starch are also suitable, provided that the total amylose content is at least 30% by weight, based on the total weight of the mixture. Here and below, all references to amylose or amylose-containing substances in weight percent are understood to always refer to the total weight of amylose and starch in the case of mixtures of amylose and starch, unless otherwise specified. Amylose-containing substances, especially amylose and amylose-containing starches, as well as amylose / starch mixtures, are particularly preferred according to the present invention, and their amylose content is at least 40% by weight, especially at least 45% by weight, based on the total weight of the substance. Generally, the amylose content does not exceed 90% by weight, especially not more than 80% by weight. Such substances are known and commercially available. For example, amylose-containing starches are marketed by Cerestar under the trade name Amylogel® and by National Starch under the trade names HYLON® V and VII.

[0457] To achieve the binding of the active ingredient to the textile, the textile can generally be finished with an amylose-containing substance in an amount of at least 0.5 wt.%, preferably at least 1 wt.%, particularly at least 2 wt.%, based on the weight of the textile. Generally, the amylose-containing substance is used in an amount of not more than 25 wt.%, often not more than 20 wt.%, particularly not more than 15 wt.%, based on the weight of the textile, so as not to adversely affect the tactile properties of the textile. First, the textile material is finished with the amylose-containing substance in this way, and then the finished fiber is treated with a suitable preparation of the active ingredient. In this way, the amylose-containing substance on the textile material is loaded with the active ingredient. However, the amylose-containing substance can also be used together with the active ingredient to finish the textile. In this case, the active ingredient and the amylose-containing substance can be used both as a mixture of separate components and in the form of a pre-formed amylose-active ingredient complex. Generally, the active ingredient is used in an amount sufficient for the desired effect. The upper limit is determined by the maximum absorption capacity of the amylose units of the amylose-containing material used and generally will not exceed 20% by weight, and often will not exceed 10% by weight, based on the amylose content of the material. If desired, the active ingredient is generally used in an amount of 0.00001 to 15%, 0.0001 to 10%, 0.001 to 5%, 0.005 to 1%, 0.1 to 10%, or 0.5 to 5% by weight, based on the amylose content of the amylose-containing material.

[0458] Combinations of the active substances according to the invention with other active substances which are known per se and suitable for textile finishing can also be used in textile finishing.

[0459] In principle, all organic compounds and mixtures of organic compounds known as active substances and capable of inducing a physiological effect in living organisms, including humans and animals (including microorganisms), are suitable as active substances. These include active substances known to form inclusion compounds with cyclodextrins. Active substances having hydrocarbon groups, especially aliphatic, alicyclic, and / or aromatic structures, are particularly suitable. The molecular weight of the active ingredient is usually less than 1,000 daltons, often in the range of 100 to 600 daltons. Inorganic compounds, such as hydrogen peroxide, known to be capable of binding to cyclodextrins are also suitable.

[0460] Other active ingredients include, in particular, pharmaceutical active ingredients and active ingredients that promote the health of living organisms, especially humans, and are also commonly referred to as "health additives." Unlike pharmaceutical active ingredients, health additives do not necessarily have to have a therapeutic effect. Rather, the health-promoting effect can be based on various factors, such as care, stimulation, beauty, or other effects. Organic active ingredients that act against parasites are also suitable. These include, for example, active ingredients that act against fungi and / or microorganisms, such as fungicides and bactericides, or active ingredients that act against pests such as snails, worms, mites, insects, and / or rodents, such as nematicides, molluscicides, insecticides, acaricides, rodenticides, and repellents, as well as active ingredients against weeds, i.e., herbicides, or fragrances.

[0461] Preferred active pharmaceutical ingredients are those known to be absorbed through the skin, including, for example, ibuprofen, flurbiprofen, acetylsalicylic acid, acetamidophen, apomorphine, butylated hydroxytoluene, camzulene, gjazalene, chlorthalidone, cholecalciferol, dicumarol, digoxin, diphenylhydantoin, furosemide, hydroflumethiazide, indomethacin, iproniazid phosphate, nitroglycerin, nicotine, nicotinamide, ouabain, oxprenolol, papaverine alkaloids (such as papaverine, laudanosine, ethaverine, and narcotine), berberine, retinol, trans-retinoic acid, prethiazol-1, hydroxybenzoates, benzophenone, benzophenone-1, benzophenone-2, benzophenone-3, benzophenone-4, benzophenone-5, benzophenone-6, benzophenone-7, benzophenone-8, benzophenone-9, benzophenone-11, benzophenone-12, benzophenone-13, benzophenone-14, benzophenone-15, benzophenone-16, benzophenone-17, benzophenone-18, benzophenone-19, benzophenone-20, benzophenone-21, benzophenone-22, benzophenone-23, benzophenone-24, benzophenone-25, benzophenone-26, benzophenone-27, benzophenone-28, benzophenone-29, benzophenone-30, benzophenone-31, benzophenone-32, benzophenone-33, benzophenone-34, benzophenone-35, benzophenone-36, benzophenone-37, benzophenone-38, benzophen These include ethanol, spironolactone, sulpiride, theophylline, theobromine, corticosteroids and derivatives such as testosterone, 17-methyltestosterone, cortisone, corticosterone, dexamethasone, triamcinolone, methylprednisolone, fludrocortisone, fluocortolone, prednisone, prednisolone, progesterone, especially estrogens and gestagens such as estradiol, estriol, ethinylestradiol-3-methyl ether, norethisterone and ethisterone, and phenethylamines and derivatives such as tyramine, adrenaline, noradrenaline and dopamine. Examples of suitable active substances according to the present invention that are effective against parasites include, for example, nematicides, bactericides, fungicides, insecticides, insect repellents, acaricides and molluscicides. Examples of bactericidal and fungicidal substances include: Antibiotics, such as cycloheximide, griseofulvin, kasugamycin, natamycin, polyoxins, streptomycin, penicillin or gentamicin; Complexes of organic compounds and biocidal metals, for example, complexes of silver, copper, tin and / or zinc such as bis-(tributyltin) oxide, copper naphthenate, zinc naphthenate and stannous naphthenate, oxine-copper such as Cu-8, tris-N-(cyclohexyldiazeniumdioxy)-aluminum, N-(cyclohexyldiazeniumdioxy)-tributyltin, bis-N-(cyclohexyldiazeniumdioxy)-copper; Quaternary ammonium salts, such as benzyl-Cs- to cis-alkyldimethylammonium halides, especially chlorides (benzalkonium chloride); Aliphatic nitrogen fungicides and bactericides such as cymoxanil, dodine, dodizin, guazidine, iminoctadin, dodemorph, fenpropimorph, fenpropidin, tridemorph; Substances with peroxide groups, such as hydrogen peroxide, and organic peroxides, such as dibenzoyl perodide; organochlorines such as chlorhexidine; Triazole antifungals such as azaconazole, cyproconazole, diclobutrazol, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, metconazole, propiconazole, tetraconazole, tebuconazole and triticonazole; strobilurins such as dimoxystrobin, fluoxastrobin, cresoxim-methyl, metominostrobin, oryzastrobin, picoxystrobin, pyraclostrobin and trifloxystrobin; sulfonamides such as tolylfluanid and dichlofluanid; Iodine compounds such as diiodomethyl-p-tolylsulfone, napcoside, 3-iodo(iod)-2-propynyl alcohol, 4-chlorophenyl-3-iodopropyl formal, 3-bromo-2,3-diiodo-3-propenylethyl carbonate, 2,3,3-triiodoallyl alcohol, 3-iodo-2-propynyl-n-hexylcarbamate, 3-bromo-2,3-diiodo-2-propenyl alcohol, 3-iodo-2-propynylphenylcarbamate, 3-iodo-2-propynyl-n-butylcarbamate, O-1-(6-iodo-3-oxohex-5-ynyl)phenylcarbamate, and O-1-(6-iodo-3-oxohex-5-ynyl)butylcarbamate: Isothiazolinones such as N-methylisothiazolin-3-one, 5-chloro-N-methylisothiazolin-3-one, 4,5-dichloro-N-octylisothiazolin-3-one(on), 1,2-benzisothiazol-3(2H)one, 4,5-trimethylisothiazol-3-one and N-octyl-isothiazolin-3-one.

[0462] Examples of insecticides and acaricides are: acephate, azamethiphos, azinphos-methyl, chlorpyrifos, chlorpyrifos-methyl, chlorfenvinphos, diazinon, dichlorvos, dicrotophos, dimethoate, disulfoton, ethion, fenitrothion, fenthion, isoxathion, malathion, methamidophos, methidathion, methyl-parathion, mevinphos, monocrotophos, oxydemeton-methyl, paraoxon, parathion, fen Organic phosphates such as thoate, phosalone, phosmet, phosphamidon, phorate, phoxim, pirimiphos-methyl, profenofos, prothiofos, sulprofos, triazophos, trichlorfon; in particular acrinathrin, allethrin, bioallethrin, bartholin, bifenthrin, bioethanomethrin, cyclethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin, cypermethrin , α-cypermethrin, β-cypermethrin, λ-cypermethrin, zeta-cypermethrin, cyphenothrin, deltamethrin, dimefluthrin, dimethrin, empenthrin, fenfluthrin, fenplythrin, fenpropathrin, fenvalerate, esfenvalerate, flucythrinate, fluvinate, tau-fluvinate, frethrin, permethrin, biopermethrin, trans-permethrin, fenothrin, prallethrin, profluthrin pyrethroids such as pyrethrin, pyresmethrin, resmethrin, bioresmethrin, cismethrin, tefluthrin, telarethrin, tetramethrin, tralomethrin, transfluthrin, etofenprox, flufenprox, halfenprox, protrifenbut and silaflufen; pyrrole and pyrazole insecticides such as acetoprole, ethiprole, fipronil, tebufenpyrad, tolfenpyrad, chlorfenapyr and vaniliprole.

[0463] Examples of repellent active ingredients are, in particular, anthraquinone, acridine base, copper naphthenate, butopyronoxyl, dibutyl phthalate, dimethyl phthalate, dimethylcarbate, ethohexadiol, hexamide, metho-quin-butyl, N-methylneodecanamide, camphor, bergamot oil, pyrethrum, clove oil, geranium oil, thyme oil, and, in particular, diethyl-m-toluamide and 1-piperidinecarboxylic acid-2-(2-hydroxyethyl)-1-methylpropyl ester (picardin). Examples of wellness additives are, in particular, the substances and mixtures of substances listed below, for example fats, preferably of vegetable origin, such as lecithin, vegetable oils such as jojoba oil, tea tree oil, clove oil, evening primrose oil, almond oil, coconut oil, avocado oil, soybean oil, fatty acids, such as omega-6 fatty acids, linolenic acid, linoleic acid, waxes of animal or vegetable origin (beeswax, candelilla wax, shea butter, shorea butter, mango seed oil, Japanese wax, etc.), vitamins, in particular fat-soluble vitamins, such as tocopherol, of animal or vegetable origin. Sources of vitamins (beeswax, candelilla wax, shea butter, shorea butter, mango seed oil, Japanese wax, etc.), such as tocopherol, vitamin E, vitamin A, etc., corticosteroids (cortisone, corticosterone, dexamethasone, triamcinolone, methylprednisolone, fludrocortisone, fluocortolone, prednisone, prednisolone, progesterone, etc.), amino acids such as arginine and methionine; and plant extracts such as algae extract, horse chestnut extract, and mango extract.

[0464] To improve the wash durability of the finished product according to the invention, it has proven useful to fix the amylose-containing material to the textile using a binder. Suitable binders include film-forming, water-insoluble polymers and low-molecular-weight reactive substances that polymerize upon heating. Generally, the binder is used in an amount such that the weight ratio of amylose-containing material to water-insoluble polymer is in the range of 1:1 to 100:1, preferably in the range of 1.5:1 to 50:1, and in particular in the range of 2:1 to 20:1.

[0465] Generally, the film-forming polymer is used in the form of an aqueous dispersion of finely divided polymer particles. Particle size is of secondary importance to the success of the invention, but is generally less than 5 μm (weight average), usually between 50 nm and 2 μm.

[0466] In particular, the film-forming polymer may have a glass transition temperature TG in the range of -40 to 100°C, preferably -30 to +60°C, and especially -20 to +40°C. When the polymer binder comprises several polymeric components, at least the major component should have a glass transition temperature in this range. In particular, the glass transition temperature of the major component is in the range of -30 to +60°C, especially preferably in the range of -20 to +40°C. Preferably, all polymeric components have glass transition temperatures in these ranges. The specified glass transition temperature refers to the "midpoint temperature" determined using DSC in accordance with ASTM-D3418-82. In the case of crosslinkable binders, the glass transition temperature refers to the uncrosslinked state.

[0467] Examples of suitable film-forming polymers are based on the following polymer classes: (1) Polyurethane resin; (2) acrylate resins (pure acrylates: copolymers of alkyl acrylates and alkyl methacrylates); (3) styrene acrylate (copolymer of styrene and alkyl acrylate); (4) styrene / butadiene copolymer; (5) Polyvinyl esters, especially polyvinyl acetate and copolymers of vinyl acetate and vinyl propionate. (6) vinyl ester olefin copolymers, such as vinyl acetate / ethylene copolymers; (7) Vinyl ester acrylate copolymers, such as vinyl acetate / alkyl acrylate copolymers and vinyl acetate / alkyl acrylate ethylene terpolymers.

[0468] Such polymers, for example, polymers of classes (2) to (7) in the form of aqueous dispersions under the names ACRONAL, STYROFAN, BUTOFAN (BASF-AG), MOWILITH, MOWIPLUS, APPRETAN (Clariant), VINNAPAS, VINNOL (WACKER), are known and commercially available. Aqueous polyurethane dispersions (1) suitable for the process according to the invention are in particular those used for coating textiles. Suitable substances are well known to those skilled in the art. Aqueous polyurethane dispersions are commercially available, for example, under the trade names Alberdingk® from Alberdingk, Impranil® from BAYER AG, and Permutex® from Stahl (Waalwijk, The Netherlands) from BASF SE, or can be produced according to known methods, such as those described in the relevant technical literature. The film-forming polymer may be self-crosslinking. That is, the polymer has functional groups (crosslinkable groups) that react with the functional groups of amylose or with a low-molecular-weight crosslinking agent to form bonds when the composition is dried or heated. Examples of crosslinkable functional groups include aliphatically bonded OH groups, NH-CH2-OH groups, carboxylate groups, anhydride groups, capped isocyanate groups, and amino groups. Polymers that still have free OH groups as reactive groups are often used. Generally, the proportion of reactive functional groups is 0.1 to 3 mol per kg of polymer. Crosslinking can be achieved within the polymer by the reaction of complementary reactive functional groups. Preferably, crosslinking of the polymer is achieved by adding a crosslinker having reactive groups complementary in reactivity to the functional groups of the crosslinker. Suitable pairs of functional groups with complementary reactivities are known to those skilled in the art. Examples of such pairs include OH / COOH, OH / NCO, NH2 / COOH, NH2 / NCO, and M. 2+ / COOH, M 2+ Zn 2+ , Ca 2+ or Mg 2+Examples of suitable crosslinking agents are, in the case of polyurethanes, diols or polyols as described below; primary or secondary diamines, preferably primary diamines, such as hexamethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, N,N-bis[(aminopropyl)amino]ethane, 3,6-dioxaoctanediamine, 3,7-dioxanonanediamine, 3,6,9-trioxaundecanediamine or Jeffamine (4,4-diaminodicyclohexyl)methane, (4,4'-diamino-3, Examples of suitable crosslinking agents include alkylenediamines such as 3-dimethyldicyclohexylmethane; aminoalcohols such as ethanolamine and hydroxypropylamine; ethoxylated diamines and oligoamines; dihydrazides of aliphatic or aromatic dicarboxylic acids such as adipic acid dihydrazide; dialdehydes such as glyoxal; partially or completely O-methylated melamine; and compounds or oligomers containing an average of two or more, preferably three or more, isocyanate groups, or reversibly blocked isocyanate groups, e.g., with hydrogen sulfite. In this case, the ratio of the crosslinking agent to the polymer binder is calculated so that the molar ratio of reactive groups in the polymer binder (total number of reactive groups in the polymer) to reactive groups in the crosslinking agent is typically in the range of 1:10 to 10:1, preferably 3:1 to 1:3. The weight ratio of the polymer binder (calculated as solids) to the crosslinking agent is typically in the range of 100:1 to 1:1, especially 50:1 to 5:1.

[0469] As an alternative to immobilizing the amylose-containing substance with a water-insoluble polymer, amylose or the amylose-containing substance can also be immobilized on the textile material by means of a reactive compound having at least one group reactive with the OH group of amylose and at least one further functional group reactive with functional groups, e.g., OH, NH2 or COOH groups, on the fibers of the textile material. Reactive compounds include the above-mentioned crosslinkers and substances proposed in DE 4035378 A for immobilizing cyclodextrin, such as N-hydroxymethyl and N-alkoxymethyl derivatives of urea, or urea-like compounds such as dimethylol urea (bis(hydroxymethyl)urea), di(methoxymethyl)urea, dimethylolalkanediol diurethanes (N,N-dimethylolethylene urea (N,N-bis(hydroxymethyl)imidazolin-2-one), N,N-dimethylol-dihydroxyethylene urea (N,N-bis(hydroxymethyl)-4,5-dihydroxyimidazolin-2-one), dimethylolpropylene urea, etc.). Such substances are commercially available in the form of aqueous formulations for finishing textiles, for example, from BASF SE under the trade names Fixapret® and Fixapret®-eco. Reactive materials that can be used to fix amylose-containing substances to textile materials include, in particular, compounds having two, three, four or more (possibly reversibly blocked) isocyanate groups, especially polyisocyanate prepolymers based on polyether and polyester urethanes that are reversibly blocked with bisulfites or CH acid compounds or oximes, such as butanone oxime, as described in DE 2837851, DE 19919816, and the previous patent application EP 03015121. Such products are also commercially available, for example, from Rotta GmbH (Mannheim) under the trade names PROTOLAN® 367 and PROTOLAN® 357.

[0470] To immobilize amylose-containing substances, known procedures for immobilizing cyclodextrins can also be used in a similar manner. Cyclodextrins, or in this case, amylose-containing substances, can be provided with reactive anchors by mixing them with, for example, dicarboxylic acids or dicarboxylic anhydrides (such as maleic acid, fumaric acid, maleic anhydride, succinic acid, succinic anhydride, or adipic acid), diisocyanates such as toluene diisocyanate, isophorone diisocyanate, tetramethylene diisocyanate, or hexamethylene diisocyanate, or aminocarboxylic acids in a manner known per se, so that only one of the functional groups present in these compounds reacts with the OH group of the amylose-containing substance, while the other functional groups remain available for bonding to the reactive groups of the fiber material. Reactive anchors can also be produced on amylose-containing substances by reaction with 1,3,5-trichlorotriazine, 2,3-dichloroquinoxaline-5,6-carboxylic acid chloride, and chlorodifluoropyrimidine. Additionally, alkoxysilanes such as diethoxydimethylsilane, dimethoxydimethylsilane, triethoxyphenylsilane, tetraethoxysilane, and dimers, trimers, and higher condensation products of these compounds can also be used to immobilize amylose.

[0471] In principle, all textile materials, i.e., non-manufactured and manufactured products, can be finished in this way. Textile materials, as used herein and below, include woven fabrics, knitted fabrics, and knitted nonwoven fabrics. They can be composed of natural fiber yarns, synthetic fiber yarns, and / or blended yarns. In principle, all textile materials commonly used in the manufacture of textiles can be considered textile materials. This includes 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.

[0472] The textile material can be finished or treated with the amylose-containing substance in a manner known per se, for example by the methods described for finishing textiles with cyclodextrins.

[0473] Examples include methods in which the amylose-containing material, possibly as a complex with an active ingredient, is already spun into the fibers, filaments and / or yarns from which the fabric is made.

[0474] However, textile materials are often treated with an amylose-containing substance or a complex of an amylose-containing substance and an active ingredient before or after finishing. Generally, textiles are treated with an aqueous liquid containing a sufficient amount of the amylose-containing substance, and optionally an active ingredient. Depending on the type of application and the desired amount of amylose-containing substance to be applied, the concentration of the amylose-containing substance in the liquid is in the range of 1 to 40% by weight, particularly in the range of 2 to 20% by weight, and especially in the range of 4 to 15% by weight.

[0475] The type of treatment is of secondary importance and can be applied, for example, by spraying, as a minimal application, as a regular application, e.g., with a padder, or as a high-moisture application. In this case, the textile material is immersed in an aqueous liquor. If necessary, excess liquid can then be removed, for example, by squeezing until a liquid absorption of about 30 to 120% is reached. Another possibility for treating textiles with an amylose-containing substance or a complex of an amylose-containing substance and an active ingredient is to prepare a liquor containing the desired amount of amylose-containing substance and, if necessary, the active ingredient, for example, 0.5 to 20% by weight (based on the mass of the textile to be finished). The textile material is immersed in the treatment liquor for a certain time, for example, 10 to 60 minutes, in a suitable finishing unit (reel skid, roller skid; paddle, etc.), and then squeezed and / or centrifuged as described above. The liquor ratio is generally in the range of 1:2 to 1:50, particularly 1:3 to 1:20.

[0476] Such methods are known to those skilled in the art from the relevant technical literature.

[0477] Treatment with the liquid is generally followed by a drying step. The temperature is usually in the range of 100 to 200°C, preferably in the range of 120 to 180°C. Drying can be carried out in the devices customary for this purpose, for example by drying at the temperatures mentioned above, in the case of finished products. In the case of non-manufactured products, the textile material is usually passed through one or more tenter frames after application.

[0478] When an amylose-containing substance is used together with a film-forming polymer, the amylose-containing substance is fixed to the fiber surface of the textile product by drying. Generally, the drying temperature is then not lowered below 100°C, and is preferably in the range of 120-200°C, in particular in the range of 140-180°C. Drying is generally carried out for 1-10 minutes, in particular for 1-2 minutes, although longer drying times are also suitable. In the case of treatment with an aqueous liquid, it has been found to be advantageous if the aqueous liquid contains, in addition to the amylose-containing substance and possibly the active substance, at least one surface-active substance (or surfactants) suitable for dispersing the amylose-containing substance and the active substance in the aqueous liquid. Preferably, the surfactant is an oligomeric or polymeric dispersant. In contrast to low molecular weight surface-active substances, the term oligomeric or polymeric dispersant includes such dispersants whose number average molecular weight is generally at least 2000 Daltons, for example 2000 to about 100,000 Daltons, in particular in the range of about 3000 to 70,000 Daltons. Generally, the aqueous liquid contains the polymeric or oligomeric dispersant in an amount of 0.5 to 20% by weight, preferably 1 to 18% by weight, in particular 5 to 15% by weight, relative to the amylose-containing material.

[0479] Suitable oligomeric or polymeric dispersants are water-soluble and include neutral and amphoteric water-soluble polymers, as well as cationic and anionic polymers, the latter being preferred. Examples of neutral polymeric dispersants are polyethylene oxide, ethylene oxide / propylene oxide copolymers, preferably block copolymers, polyvinylpyrrolidone, and copolymers of vinyl acetate and vinylpyrrolidone.

[0480] Preferred anionic oligomeric or polymeric dispersants are characterized by having carboxyl and / or sulfonic acid groups and are usually used as salts, for example, alkali metal salts or ammonium salts. Preferred anionic dispersants are, for example, carboxylated derivatives of cellulose, such as carboxymethylcellulose, homopolymers of ethylenically unsaturated C3-C8 mono- and C4-C8 dicarboxylic acids, such as acrylic acid, methacrylic acid, maleic acid, itaconic acid, copolymers of at least two different ethylenically unsaturated C3-C8 monocarboxylic acids and C4-C8 dicarboxylic acids, and copolymers of at least one of the aforementioned ethylenically unsaturated C3-C8 monocarboxylic acids or C4-C8 dicarboxylic acids with at least one neutral comonomer. Examples of neutral comonomers are N-vinyl lactams such as N-vinylpyrrolidone, vinyl esters of aliphatic C2-C16 carboxylic acids such as vinyl acetate and vinyl propionate, amides of the above-mentioned ethylenically unsaturated carboxylic acids such as acrylamide and methacrylamide, hydroxy-C1-C4 alkyl (meth)acrylates such as hydroxyethyl acrylate and methacrylate, esters of ethylenically unsaturated C3-C8 monocarboxylic or C4-C8 dicarboxylic acids with polyethers, such as esters of acrylic acid with polyethers, such as esters of acrylic acid or methacrylic acid with polyethylene oxide or ethylene oxide / propylene oxide block copolymers, vinyl aromatics such as styrene, and C2-C16 olefins such as ethylene, propene, 1-hexene, 1-octene, 1-decene, and 1-dodecene. Homopolymers of ethylenically unsaturated sulfonic acids such as styrene sulfonic acid and acrylamidopropane sulfonic acid, and their copolymers with the above-mentioned comonomers are also preferred. The proportion of ethylenically unsaturated acid in the copolymer is generally at least 20% by weight and in each case does not exceed 90% by weight, in particular 80% by weight, based on the total weight of all monomers constituting the polymer. Copolymers of at least one of the above-mentioned acids with at least one comonomer are known for this purpose, for example, copolymers of acrylic acid and maleic acid are commercially available under the Sokalan brand from BASF SE.

[0481] Other preferred anionic dispersants are phenolsulfonic acid-formaldehyde condensates, and naphthalenesulfonic acid-formaldehyde condensates (eg, Tamol and Setamol brands from BASF), and lignosulfonates.

[0482] Suitable dispersants include low-molecular-weight anionic, nonionic, cationic, amphoteric, and zwitterionic surfactants. Suitable surfactants include, for example, alkali metal, ammonium, or amine salts of C8-C18 alkyl sulfates, such as sodium lauryl sulfate; C8-C18 alkyl sulfonates, such as dodecyl sulfonate; C8-C18 alkyl ether sulfates; and C8-C18 alkyl ethoxylates; polyoxyethylene sorbitan esters; C8-C18 alkyl glycinates; C8-C18 alkyl dimethylamine oxides; and betaines. Alkyl sulfates and alkyl sulfates are preferred.

[0483] If the amylose-containing substance is not used together with the water-insoluble film-forming polymer, the textile can be treated with the polymer in a separate step. In particular, this treatment is carried out together with the amylose-containing substance. Therefore, a particular embodiment relates to a method in which the aqueous liquid further comprises a dispersed water-insoluble film-forming polymer of the type described above. The amount of film-forming polymer is selected so that the weight ratio of the amylose-containing substance to the water-insoluble polymer is in the range of 1:1 to 100:1, preferably in the range of 1.5:1 to 50:1, and in particular in the range of 2:1 to 20:1.

[0484] The finishing of the textile with the coolant according to the invention or with the coolant mixture according to the invention can be carried out in a separate operation from the finishing with the amylose-containing material or can be carried out in one operation.

[0485] If the textile is treated with an active ingredient in a separate process, the textile is also treated with an aqueous solution of the active ingredient. For this purpose, the active ingredient, which is not normally soluble in water, is usually emulsified or dispersed in water, if necessary, using a suitable surfactant. Suitable surfactants are, in particular, the low-molecular-weight surfactants mentioned above, preferably nonionic surfactants, in particular polyoxyethylene sorbitan esters, esters of monosaccharides or oligosaccharides with C6-C18 fatty acids, and particularly preferably C8-C18 alkyl ethoxylates, especially those with an ethoxylation degree in the range of 6-50.

[0486] Typically, the aqueous solution contains the active substance in an amount of 0.1 to 10% by weight, in particular 0.2 to 5% by weight. The amount of surface-active substance is generally in the range of 0.5 to 50% by weight, in particular 3 to 30% by weight, based on the active substance. The active ingredient can be applied from the aqueous solution using conventional methods, for example, by fural. However, it is also possible to apply the active ingredient and the amylose-containing substance in a single operation. In this case, it is possible to proceed as described for the finishing process with the amylose-containing substance, whereby the aqueous solution of the amylose-containing substance also contains at least one active ingredient. The active ingredient can be added to the solution individually or in the form of an inclusion compound, i.e., a host-guest complex with the amylose-containing substance.

[0487] The coolant or coolant mixture according to the present invention can be used in the finishing of any textile product, i.e., non-manufactured or manufactured. Here, and hereafter, textile materials include woven fabrics, knitted fabrics, knitted fabrics, and nonwoven fabrics. The textile material can be composed of natural fiber yarns, synthetic fiber yarns, and / or blended yarns. In principle, all textile materials commonly used in the manufacture of textiles can be considered textile materials. This includes cotton, wool, hemp fiber, sisal fiber, flax, ramie, polyacrylonitrile fiber, polyester fiber, polyamide fiber, viscose fiber, silk, acetate fiber, triacetate fiber, aramid fiber, etc., as well as mixtures of these textile materials. Glass fiber and mixtures of the aforementioned textile materials with glass fiber, such as glass fiber / Kevlar, are also suitable. The type of textile material depends primarily on the desired application. The textile products to be finished can be ready-made garments, including underwear and outerwear, e.g., shirts, pants, jackets, outdoor, trekking and military gear, roofs, tents, netting, e.g., insect netting and curtains, hand and bath towels, bed linen, etc. Similarly, finishing can be carried out on raw materials in bale or roll form.

[0488] The amylose-based active ingredient finish ensures that the active ingredient remains in the finished textile even after several washes. Furthermore, textiles finished in this way are characterized by a pleasant feel against the skin, which is particularly advantageous for the wearer's comfort of garments made from these textiles.

[0489] In addition to protecting humans, textiles containing active substances against insects and parasites such as acarids are also particularly suitable for protecting animals against ticks, mites, fleas, etc.

[0490] The present invention also relates to a cooling tobacco product.

[0491] The active ingredient according to the present invention, i.e. the coolant according to the present invention, or the coolant mixture according to the present invention, or the flavoring preparation 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 refreshing additives is known per se.

[0492] In principle, the content of active substance, ie the content of the coolant or coolant mixture according to the 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.

[0493] The active ingredients according to the invention are also advantageously suitable for the production of packaging materials.

[0494] Also, preparation is carried out by a method known per se.Active ingredient can be incorporated into packaging material in free form or, for example, in encapsulated form, or can be applied to packaging material in free form or encapsulated form.In this way, according to the information in the literature about the production of polymer film, suitable plastic packaging material can be produced.The production of suitable coated paper is also known to those skilled in the art.

[0495] Finally, the present invention relates to a method for modulating the cold menthol receptor TRPM8, in particular for modulating it in vitro and / or in vivo, comprising the following steps: (i) providing at least one physiological coolant according to the invention or a physiological coolant mixture according to the invention or providing a cosmetic or pharmaceutical preparation according to the invention; and (ii) contacting the coolant or coolant mixture or cosmetic or pharmaceutical preparation of step (i) with a receptor; or 1. A method for producing a physiological cooling effect on the skin or mucous membranes, comprising the steps of: (iii) providing at least one physiological coolant according to the invention or a physiological coolant mixture according to the invention, or providing a cosmetic or pharmaceutical preparation according to the invention; and (iv) contacting the coolant or coolant mixture or cosmetic or pharmaceutical preparation of step (iii) with human skin or mucous membranes or 1. A method for improving the taste characteristics of an aroma substance, comprising the steps of: (v) providing at least one physiological coolant according to the invention or a physiological coolant mixture according to the invention, or providing a cosmetic or pharmaceutical preparation according to the invention and at least one fragrance; (vi) mixing the two components; and, where appropriate, (vii) incorporating the mixture into an oral preparation The present invention relates to a method comprising:

[0496] Further aspects of the present invention will be apparent from the following examples and appended claims. Example

[0497] The following examples serve to illustrate the invention without limiting it. Unless otherwise stated, all data refer to weight.

[0498] Preparation of the Active Ingredient: The active ingredients / coolants used in accordance with the present invention can be prepared by those skilled in the art of organic synthesis using known synthetic methods, as described in more detail below.

[0499] Cloning of human TRPM8

[0500] The starting point for cloning the human TRPM8 receptor is the LnCaP cDNA bank, which is either commercially available (e.g., BioChain, Hayward, USA) or can be generated using standard kits from the androgen-sensitive human prostate glandular cell line LnCaP (e.g., ATCC CRL1740 or ECACC, 891 1021 1).

[0501] The coding TRPM8 sequence (see, e.g., http: / / www.ncbi.nlm.nih.gov / entrez / viewer.fcgi?db=nuccore&id=109689694) can be PCR amplified and cloned using standard methods. The human TRPM8 gene isolated in this manner was used to generate the plasmid plnd_M8. Alternatively, the TRPM8 gene can also be produced synthetically.

[0502] Generation of HEK293 test cells

[0503] We used human TRPM8 DNA to generate a stably transfected HEK293 cell line as a test cell line. HEK293 was prioritized because the introduced plasmid allows for the possibility of inducing TRPM8 expression using tetracycline.

[0504] Methods for generating suitable test cell lines are known to the practitioner and can be found in the relevant specialist literature.

[0505] Assays for TRPM8 Modulators

[0506] Tests similar to those already described in the literature by Behrendt HJ et al., Br. J. Pharmacol. 141, 2004, 737-745 are carried out. Receptor agonism or antagonism is measured by Ca 2+ Agonists alone can be used to quantify Ca. 2+Antagonists, for example, in the presence of menthol, cause an increase in the Ca 2+ causing a decrease in signal (in each case, Ca 2+ ions, which have different fluorescent properties and are detected using Fluo-4 dye).

[0507] First, a new culture of transfected HEK cells was prepared in a cell culture flask using standard methods. HEK293-TRPM8 test cells were detached from the cell culture flask using trypsin and seeded at 40,000 cells / well in 100 μl of medium into a 96-well plate (Greiner #655948 poly-D-lysine coated). To induce TRPM8 receptor expression, tetracycline was added to the growth medium (DMEM / HG, 10% FCS tetracycline-free, 4 mM L-glutamine, 15 μg / ml blasticidin, 100 μg / ml hygromycin B, 1 μg / ml tetracycline).

[0508] The next day, cells are loaded with Fluo-4 AM dye and tested as follows: 100 μl of medium (DMEM / HG, 10% FCS tetracycline-free, 4 mM L-glutamine, 15 μg / ml blasticidin, 100 μg / ml hygromycin B, 1 μg / ml tetracycline) is added per well to 100 μl of staining solution Ca-4 kit (RB141, Molecular Devices).

[0509] Incubate in an incubator for 30 minutes at 37°C / 5% CO2 and 30 minutes at room temperature.

[0510] Test substances (various concentrations in 200 μI HBSS buffer), as well as positive controls (various concentrations of menthol, icilin, or lonomycin in 200 μI HBSS buffer) and negative controls (200 μI HBSS buffer only) are prepared. Test substances are added in an amount of 50 μI / well, and the change in fluorescence is measured (e.g., with an assay device FLIPR, Molecular Devices, or NovoStar, BMG) at an excitation of 485 nm and an emission of 520 nm to assess the potency of various substances / concentrations and determine EC50 values.

[0511] In this assay, test substances are used in triplicate at concentrations of 0.1 to 200 μM. Typically, compounds are already maintained in DMSO solution and diluted in this assay to a maximum DMSO concentration of 2%. Surprisingly, our own evaluation when performing the described assay showed that the compounds used according to the present invention (described herein) are particularly suitable as agonists of TRPM8.

[0512] The activity of active substances with respect to the activation of TRPM8 channels is determined using the assay described. This is performed in a concentration-dependent manner. For each active substance, 6 to 10 concentrations are measured as standards. Using mathematical methods (four- or five-parameter logistic curve fitting), the EC50 value can be calculated from the determined activity values ​​as the inflection point of the S-shaped curve. These are standard biochemical methods familiar to experts.

[0513] The EC50 values ​​determined for selected exemplary modulators according to the invention are shown below in Tables 7 and 8. For the substance WS-3, which serves as a reference, an EC50 value of 1.72 μM was determined.

[0514] [Table 20-1] [Table 20-2] Table 20-3 Table 20-4 Table 20-5 Table 20-6 Table 20-7 Table 20-8 Table 20-9 Table 20-10 Table 20-11 Table 20-12

[0515] Table 21-1 Table 21-2 Table 21-3 Table 21-4 [Table 21-5] [Table 21-6] [Table 21-7] [Table 21-8] [Table 21-9] [Table 21-10] [Table 21-11] [Table 21-12] [Table 21-13] [Table 21-14]

[0516] The EC50 value describes the concentration of a cooling substance required for half-maximal effect and is therefore a measure of the potency of an agonist drug (drug potency as a function of dose or concentration); potency thus corresponds to the reciprocal of EC50. A low EC50 value therefore corresponds to high drug potency.

[0517] Thus, as can be seen from Tables 7 and 8 above, the compounds according to the invention described herein have excellent cooling properties and are able to cause a strong cooling effect even at low concentrations, which are generally well below the EC50 reference value of 1.72 μM for substance WS-3.

[0518] As shown in Table 7 above, it has been found that such structures of general formulae (I), (II), (V) and (VI) are particularly advantageous, in which R1 and R2 each represent a phenyl group, X represents an S atom, Y represents a methylene group or a methylene group substituted by a methyl or ethyl group, and Z represents -NH-cyclopropyl, -NH-CH3, -N(CH3)2 or azetidine. Furthermore, it can be observed that in said structures, m and n each represent 1.

[0519] As shown in Table 8 above, it has been found that such structures of general formulae (III), (IV), (VII) and (VIII) are particularly advantageous, in which R1 and R2 each represent a phenyl group, X represents an S atom or a cyclopropyl group or a CH2 group or piperidine, Y represents a methylene group or a methylene group substituted by a methyl group, and Z represents -NH-CH3, -NH-CH2-CH3, -NH-cyclopropyl or -CS-CH3. Furthermore, it has been observed that in said structures, m represents 0 or 1 or n represents 1.

[0520] Thus, compounds B-01, B-02, B-03, B-04, B-05, B-06 and B-07, which have EC50 values ​​of ≦1.0 μM, and compounds A-01, A-02, A-03, A-04, A-06, A-07 and A-08, which have EC50 values ​​of ≦1.0 μM, are particularly preferred in terms of EC50 values.

[0521] In particular, for compounds B-01, B-02, B-03, B-04, B-05, B-06 and B-07, and for compounds A-01, A-02, A-03, A-04, A-06, A-07 and A-08, a significant cooling effect can be observed in terms of TRPM8 activity and EC50 values ​​(TRPM8 activity ≥ 100% and EC50 values ​​≤ 1.0 μM).

[0522] In addition to the above-mentioned TRPM8 activity and potency of the active ingredients (EC50 values), the compounds according to the present invention also exhibit a strong cooling effect.

[0523] To quantify the cooling effect, comparative tests are carried out using menthane-3-carboxylic acid-N-ethylamide as a reference. In these comparative tests, a person skilled in the art replaces the compound(s) used according to the present invention with menthane-3-carboxylic acid-N-ethylamide (also known as WS-3). The cooling effect intensity of each compound or active ingredient is then evaluated by trained panelists (n=10-11) as described below and compared with each other.

[0524] The cooling intensity was tested as follows: a test solution containing 5 ppm of the compound according to the present invention was tasted in a 5% sugar solution and a corresponding solution containing 30 ppm of the reference substance WS-3. This concentration of WS-3 was selected because WS-3 has been shown to have good cooling effects at such concentrations. Panelists tasted the corresponding test solution for exactly 40 seconds, rinsed their entire mouth with the corresponding test solution, and then spat out the sample or reference solution. After tasting, the cooling intensity of each test subject was graded after 1 minute according to a scale from 1 (very weak) to 9 (very strong).

[0525] The sensory tasting results of selected exemplary compounds according to the present invention are shown in Tables 9 and 10 below.

[0526] [Table 22]

[0527] [Table 23-1] [Table 23-2]

[0528] 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, the reference sample containing WS-3 exhibited a cooling intensity of about 5.4 in sensory evaluation, while the cooling intensities of the materials according to the present invention were shown to be 4.2 for compound B-01, 4.1 for compound B-02, 5.3 for compound B-11, 5.4 for compound A-02, 4.66 for compound A-09, and 5.38 for compound A-10, etc.

[0529] It should also be noted that WS-3, despite being six times more concentrated, is capable of producing significantly lower cooling intensity. Conversely, significantly lower concentrations of the compounds according to the present invention are required to produce a significantly stronger cooling effect than conventional cooling substances (WS-3). This demonstrates that the compounds according to the present invention produce a strong, and therefore highly effective, cooling effect even when used at low concentrations, and that only trace amounts need be used in corresponding final formulations, such as product formulations containing these cooling substances, to produce a cooling effect that is perceived as being strong.

[0530] In this context, it is preferred that in a corresponding comparison, the cooling effect of a sample comprising a compound used according to the invention is preferably prolonged 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, most preferably at least 90 minutes, compared to a reference sample containing WS-3.

[0531] Synthesis Examples:

[0532] Preparation of compounds according to the invention

[0533] Method A [ka]

[0534] The 2-oxazolethiol derivative (1 equivalent) and bromocarboxylic or chlorocarboxylic acid (1.2 equivalents) were dissolved in dry DMF, and N,N-diisopropylethylamine (1.5 equivalents) was added at room temperature. The reaction solution was stirred at room temperature until complete conversion was indicated by uHPLC control. The reaction mixture was then diluted with water and acidified to approximately pH 3 with 1 M hydrochloric acid. The reaction mixture was extracted with DCM, and the combined organic phase was washed with water and filtered through a phase separator. After concentration of the organic phase, the 2-oxazolecarboxylic acid derivative was obtained in sufficient purity for use in the next reaction step.

[0535] The 2-oxazolecarboxylic acid derivative (1 equivalent) obtained from Method A and the required amine (as a THF solution, if necessary) (3 equivalents) were dissolved in ethyl acetate, and HATU (1.5 equivalents) followed by N,N-diisopropylethylamine (5 equivalents) were added at room temperature. Further DIPEA was added dropwise until the pH was adjusted to approximately 9. The reaction solution was stirred at room temperature until complete conversion was indicated by uHPLC control. The reaction solution was then diluted with saturated NaHCO3 solution and extracted with DCM. The combined organic phase was filtered through a phase separator. After concentration of the organic phase, the crude product was purified by column chromatography to give the desired product as an oil or solid.

[0536] Method B: [ka]

[0537] The 2-oxazolethiol derivative (1 equiv.) and either the bromamide or chloramide (1.2 equiv.) were dissolved in dry acetone and added with K2CO3 (2 equiv.) at room temperature, or dissolved in dry DMF and added with diisopropylethylamine (1.5 equiv.) at room temperature. The reaction solution was heated to 40 °C and stirred until complete conversion was indicated by uHPLC control. The reaction solution was then diluted with water and extracted with either EtOAc or DCM. The combined organic phase was washed with water and saturated NaCl solution and dried over MgSO4. After concentration of the organic phase, the crude product was purified by column chromatography to give the desired product as an oil or solid.

[0538] Method C: [ka]

[0539] The carboxylic acid derivative (1 equiv.) was dissolved in dry DCE and cooled to 0-5°C. The hydrochloride salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.1 equiv.) was added and stirred for 30 min. Next, benzoin (1 equiv.) and then DMAP (1.2 equiv.) were added. The reaction mixture was allowed to warm to room temperature and stirred for 24 h. The mixture was then diluted with DCM and filtered through a phase separator, first with 10 wt.% citric acid solution three times and then with saturated NaHCO3 solution. After concentration of the organic phase, the ester was obtained in sufficient purity for use in the next reaction step. If it was cool, the product was purified by column chromatography to give the desired product as an oil or solid.

[0540] The ester (1 equivalent) and ammonium acetate (5 equivalents) were dissolved in acetic acid and stirred under reflux for 90 minutes. After cooling to room temperature, the reaction mixture was added to water and extracted with dichloromethane. The combined organic phase was filtered through a phase separator and concentrated. The product could be used in the next reaction step without further purification. If it was cool, the product was purified by column chromatography to obtain the desired product as an oil or solid.

[0541] The oxazole derivative (1 equivalent) was dissolved in a mixture of THF and water (1:1) and cooled to 0°C. LiOH monohydrate (2 equivalents) was then added. LiOH monohydrate (2 equivalents) was then added, and the mixture was slowly warmed to room temperature and stirred until complete conversion was detected. The reaction solution was then diluted with water and acidified to pH 3 with 10% by weight citric acid. This aqueous solution was extracted with DCM. The combined organic phases were dried over MgSO4 and concentrated. The carboxylic acid derivative could be used in the next reaction step without further purification. If it was cool, the product was purified by column chromatography to obtain the desired product as an oil or solid.

[0542] The carboxylic acid derivative (1 equivalent) and the required amine (as a THF solution, if necessary) (1 equivalent) were dissolved in DMF and cooled to 0 °C. HATU (1 equivalent) was then added, followed by N,N-diisopropylethylamine (3 equivalents). HATU (1 equivalent) was then added, followed by N,N-diisopropylethylamine (3 equivalents). The reaction solution was stirred at room temperature until complete conversion was indicated by uHPLC control. The reaction solution was then diluted with water and extracted with DCM. The combined organic phases were washed with water, 10% by weight citric acid three times, and finally saturated NaHCO3, and filtered through a phase separator. The solvent was removed under vacuum. The crude product was purified by column chromatography to give the desired product as an oil or solid.

[0543] Method D: [ka] Diphenyl azidophosphate (1.1 equiv.) and triethylamine (1.1 equiv.) were added to a solution of the oxaprozin derivative (1 equiv.) in dry toluene and stirred at room temperature. The reaction progress was monitored by HPLC. After complete conversion, the reaction was diluted with toluene and washed with water. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was dissolved in MeOH and stirred at 75 °C for 24 h, then concentrated in vacuo. The crude product was purified by column chromatography (reverse phase) to give the desired product as an oil or solid. The carbamate (1 equiv.) was dissolved in THF / MeOH (2:1) and 2 M NaOH solution (16 equiv.) was added. The reaction mixture was heated to 70 °C and stirred until HPLC control showed complete conversion. The reaction mixture was then cooled to room temperature and diluted with water. The reaction mixture was extracted three times with a mixture of chloroform and isopropanol (7:3), and the combined organic phase was filtered through a phase separator and concentrated. The product could be used in the next reaction step without further purification. If it was cool, the product was purified by column chromatography to give the desired product as an oil or solid.

[0544] The amine derivative (1 equivalent) was dissolved in dry DCM, and triethylamine (2 equivalents) was added, followed by acetyl chloride (1.2 equivalents). The reaction mixture was stirred at room temperature until HPLC control showed complete conversion. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The organic phase was filtered through a phase separator and concentrated in vacuo. The crude product was purified by column chromatography to give the desired product as an oil or solid.

[0545] Method E: [ka]

[0546] Oxazolecarboxylic acid (1 eq.) and N,O-dimethylhydroxylamine hydrochloride (1 eq.) were dissolved in DMF. HATU (1.5 eq.) and diisopropylethylamine (5 eq.) were added, and the reaction mixture was stirred at room temperature until HPLC control showed complete conversion. The reaction mixture was diluted with semi-saturated NaHCO3 solution and extracted three times with DCM. The combined organic phases were washed with water and saturated NaCl solution, filtered through a phase separator, and concentrated in vacuo. The crude product was purified by column chromatography to give the desired product as an oil or solid. The Weinreb amide (1 equiv.) was dissolved in dry THF and cooled to 0 °C. The Grignard solution in THF was added slowly at 0 °C, and after the addition was complete, the reaction mixture was stirred at room temperature until complete conversion was indicated by HPLC control. The reaction was quenched by the addition of saturated NH4Cl solution, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography to give the desired product as an oil or solid.

[0547] Method F: [ka]

[0548] The 2-imidazolethiol derivative (1 equivalent) was dissolved in dry dimethylformamide, and the corresponding organohalogen compound (1.2 equivalents) was added, followed by diisopropylethylamine (1.5 equivalents). The reaction mixture was stirred at room temperature until complete conversion was confirmed by HPLC control. The reaction mixture was diluted with water and extracted with DCM. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography to give the desired product as an oil or solid.

[0549] Method G: [ka]

[0550] The benzyl derivative (1 equivalent), dimethoxyester (1.3 equivalents), and ammonium acetate (7 equivalents) were dissolved in acetic acid and stirred under reflux in a nitrogen atmosphere until complete conversion was confirmed by HPLC control. The reaction mixture was then cooled to room temperature and added to water. The reaction mixture was made basic with 25% by weight ammonia solution and extracted with DCM. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The product could be used in the next reaction step without further purification. The final product was purified by column chromatography to give the desired product as an oil or solid. The corresponding carboxylic acids and amides were prepared as described in Method D.

[0551] Method H: [ka]

[0552] In the case of pyrazines: The benzyl derivative (1 equivalent) was dissolved in methanol, and glycinamide hydrochloride (1.1 equivalents) was added, followed by NaOH (2 equivalents), and the mixture was stirred at 70°C for 4 hours. The reaction mixture was then cooled to room temperature, and 2M hydrochloric acid was added and stirred for 30 minutes. Saturated NaHCO3 solution was then added, and the solid was filtered off and washed with methanol. The crude product was purified by column chromatography to give the desired product as an oil or solid.

[0553] For 1,2,4-triazines: The benzyl derivative (1 equivalent) was dissolved in acetic acid and heated to 100°C. Thiosemicarbazide (2 equivalents) or the corresponding semicarbazide hydrochloride (1 equivalent) was added. Thiosemicarbazide (2 equivalents) or the corresponding semicarbazide hydrochloride (1 equivalent) was added and stirred under reflux for 6 hours. The reaction mixture was then cooled to 5°C, and the resulting solid was filtered off and washed with water. After drying in vacuo, the solid could be used in the next reaction step without further purification.

[0554] Method I: [ka]

[0555] A suspension of Lawesson's reagent (2 equivalents) and pyrazine alcohol (1 equivalent) in THF was stirred under reflux overnight. The reaction mixture was then cooled to room temperature and diluted with water. The reaction mixture was extracted with diethyl ether, and the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to give the desired product as an oil or solid.

[0556] Method J: [ka]

[0557] Thiol, alcohol, or amine derivatives (1 equiv.) were dissolved in acetone and Na2CO3 (1.5-6 equiv.) was added. Bromine compounds (1.1-1.5 equiv.) were added to the suspension and stirred under reflux until complete conversion was indicated by DC reaction control. The solid was filtered off and washed with acetone. The filtrate was co-evaporated with silica. After purification by column chromatography, the desired product was obtained as an oil or solid.

[0558] Method K: [ka]

[0559] Thiol, alcohol, or amine derivatives (1 equiv.) were dissolved in acetone, and Na2CO3 (1.5–6 equiv.) was added. 2-Bromomethyl ester (1 equiv.) was added to the suspension and stirred at 60 °C until complete conversion was indicated by DC reaction control. The reaction mixture was then cooled to room temperature, filtered, and washed with acetone. The filtrate was concentrated, and the resulting crude product was purified by column chromatography to give the desired methyl ester as an oil or solid. The methyl ester (1 equiv.) was stirred in a 2 M amine solution in THF (10 equiv.) at 80 °C overnight. The reaction solution was then concentrated in vacuo. The crude product was purified by column chromatography to give the desired amide as an oil or solid.

[0560] Methods L and L': [ka]

[0561] The thiol (1 equiv.) was dissolved in acetone, and Na2CO3 (1.5 equiv.) and then methyl iodide (1 equiv.) were added. The reaction mixture was stirred at 60 °C until complete conversion was indicated by DC control. The reaction mixture was then filtered and washed with acetone. The filtrate was concentrated. The product could be used in the next reaction step without further purification. The final product was purified by column chromatography to give the desired product as an oil or solid. The methyl thioether (1 equiv.) and the required amine (10 equiv.) were stirred at elevated temperatures (up to 120 °C) until complete conversion was indicated by DC control. The reaction mixture was then concentrated in vacuo, and the resulting crude product was purified by column chromatography. The methyl thioether (1 equiv.) and the required alcohol (1 equiv.) were dissolved in dry DMF, and Cs2CO3 (1 equiv.) was added. The reaction mixture was stirred at 100 °C until complete conversion was indicated by DC control. The reaction mixture was then filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography.

[0562] Method M: [ka]

[0563] The thioether (1 equiv.) was dissolved in dry DCM and cooled to 0°C. 3-Chloroperbenzoic acid (3 equiv.) was added, and the reaction solution was allowed to warm to room temperature and stirred overnight. The reaction was then quenched with 5 wt% aqueous sodium disulfite solution and stirred for 1 hour. The phases were separated, and the organic phase was washed with water, filtered through a phase separator, and concentrated in vacuo. The crude product was purified by column chromatography to give the desired product as an oil or solid.

[0564] Table 11 below lists analytical data for identifying synthetic compounds according to the invention. In the values, decimal points are represented by dots.

[0565] [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5] [Table 24-6] [Table 24-7] [Table 24-8] [Table 24-9] [Table 24-10] [Table 24-11] [Table 24-12] [Table 24-13] [Table 24-14] [Table 24-15] [Table 24-16] [Table 24-17] [Table 24-18] [Table 24-19] [Table 24-20]

[0566] Formulation Examples

[0567] Formulation Examples for Cosmetic Preparations

[0568] The following formulation examples F1 to F54 show a wide range of formulations for cosmetic and pharmaceutical preparations. Coolant 1 here refers to compound B-11 according to the invention, Coolant 2 refers to compound A-02, Coolant 3 refers to compound A-09, and Coolant 4 refers to compound A-10. The coolants were used in pure form.

[0569] In the table below, decimal points are shown as dots.

[0570] [Table 25]

[0571] [Table 26]

[0572] [Table 27]

[0573] [Table 28]

[0574] [Table 29]

[0575] [Table 30]

[0576] [Table 31]

[0577] [Table 32]

[0578] Table 33

[0579] Table 34

[0580] Table 35

[0581] Table 36

[0582] Table 37

[0583] Table 38

[0584] Table 39

[0585] Table 40

[0586] Table 41

[0587] Table 42

[0588] Table 43

[0589] Table 44

[0590] Table 45

[0591] Table 46

[0592] Table 47

[0593] Table 48

[0594] Table 49

[0595] Table 50

[0596] Table 51

[0597] Table 52

[0598] Table 53

[0599] Table 54

[0600] Table 55

[0601] Table 56

[0602] Table 57

[0603] Table 58

[0604] Table 59

[0605] Table 60

[0606] Table 61

[0607] Table 62

[0608] Table 63

[0609] Table 64

[0610] Table 65

[0611] Table 66

[0612] Table 67

[0613] Table 68

[0614] Table 69

[0615] Table 70

[0616] Table 71

[0617] Table 72

[0618] Table 73

[0619] Table 74

[0620] [Table 75]

[0621] [Table 76]

[0622] [Table 77]

[0623] [Table 78]

[0624] Food Preparation Formulation Examples

[0625] The following formulation examples F55 to F63 show a wide range of formulations for food preparations. Coolant 1 here refers to compound B-11 according to the invention, Coolant 2 refers to compound A-02, Coolant 3 refers to compound A-09, and Coolant 4 refers to compound A-10. The coolants were used in pure form.

[0626] [Table 79]

[0627] [Table 80]

[0628] [Table 81]

[0629] [Table 82]

[0630] Table 83

[0631] Table 84

[0632] Table 85

[0633] Table 86

[0634] Table 87

Claims

1. General formula (Va) 【Chemical Formula 1】 or General formula (Via) [Chemical Formula 2] [In formula (Va) and (Via), in each case,[[]] 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 and their salts, especially acid addition salts with inorganic or organic acids (the coolant may exist in pure form as stereoisomers or as a mixture of different stereoisomers)]] or General formula (VIIa) 【Chemical Formula 3】 or General formula (VIIIa) 【Chemical Formula 4】 [In each of formula (VIIa) and (VIIIa),[[]] 【Table 2-1】 【Table 2-2】 【Table 2-3】 and their salts, especially acid addition salts with inorganic or organic acids (the coolant may exist in pure form as stereoisomers or as a mixture of different stereoisomers)]] The physiological coolant of.

2. In general formulas (Va) to (VIIIa), Y represents a methylene group substituted by a substituted methylene group, preferably a methyl group, an ethyl group, a linear or branched butyl group, or a linear or branched prop pyl group substituted methylene group, the physiological coolant according to claim 1.

3. The physiological coolant of general formula (Va) or (Via) is selected from the group consisting of the compounds 【Table 3-1】 【Table 3-2】 【Table 3-3】 【Table 3-4】 【Table 3-5】 【Table 3-6】 【Table 3-7】 according to Table A below and their salts, especially acid addition salts with inorganic or organic acids, and the coolant may exist in pure form as stereoisomers or as a mixture of different stereoisomers, preferably the physiological coolant is selected from the group consisting of compounds B-01, B-02, B-03 , B-05, B-07, B-11 and B-18, or The physiological coolant of general formula (VIIa) or (VIIIa) is the compound according to Table B below 【Table 4-1】 【Table 4-2】 【Table 4-3】 【Table 4-4】 and their salts, especially acid addition salts with inorganic or organic acids, and the coolant may exist in pure form as stereoisomers or as a mixture of different stereoisomers, preferably the physiological coolant is selected from the group consisting of compounds A-02, A-05, A-09, A-10 and A-12, The physiological coolant according to claim 1.

4. General formula (I) [Chemical Formula 5] or General formula (II) [Chemical Formula 6] or General formula (III) 【Chemical Formula 7】 or General formula (IV) 【Chemical 8】 [In the formula, in each of formula (I) to (IV),[[]] 【Table 5-1】 【Table 5-2】 【Table 5-3】 【Table 5-4】 and their salts, especially acid addition salts with inorganic or organic acids (the coolant may exist in pure form as stereoisomers or as a mixture of different stereoisomers)]] The physiological coolant of.

5. In general formulas (I) and (II), · X represents S; and / or - Y represents a linear or branched alkyl group which may be substituted; and / or is - m represents 0 or 1; and / or or In general formulas (III) and (IV), - X is S, or SO ２ , or a linear or branched alkyl optionally substituted a kill group, or a cycloalkyl group which may be substituted, or piperidinyl ; and / or - Y represents a linear or branched alkyl group which may be substituted; and / or is - m represents 0 or 1, The physiological coolant according to claim 4.

6. General formula (V) 【Chemical Formula 9】 or general formula (VI) 【Chemical 10】 [In formulas (V) and (VI), in each case, 【Table 6-1】 【Table 6-2】 【Table 6-3】 and their salts, in particular, acid addition salts with inorganic or organic acids (the coolant may exist in the form of pure stereoisomers or as a mixture of different stereoisomers)] represented by or General formula (VII) 【Chemical 11】 or general formula (VIII) 【Chemical Formula 12】 [In each of formulas (VII) and (VIII), 【Table 7-1】 【Table 7-2】 【Table 7-3】 and their salts, in particular, acid addition salts with inorganic or organic acids (the coolant may exist as pure stereoisomers or as a mixture of different stereoisomers)] The physiological coolant according to claim 4, represented by

7. Furthermore, the group which may be substituted in the above case has one or more substituents , and thus 【Table 8】 The physiological coolant according to any one of claims 4 to 6.

8. In general formulas (I) to (VIII) and (Va) to (VIIIa), radicals R1 and R2 may be the same or different and, independently of each other, have the following meanings: R1 is H or a C1-C3-alkyl group which may be substituted or a phenyl group which may be substituted, preferably a phenyl group which may be substituted; and / or R2 is H or a C1-C3-alkyl group which may be substituted or a phenyl group which may be substituted, preferably represents a phenyl group which may be substituted, The physiological coolant according to any one of claims 1 to 6.

9. In general formulas (I) to (VIII), Y represents a methyl group, or a methyl group substituted by a methyl group, an ethyl group, a butyl group or a propyl group, the physiological coolant according to any one of claims 4 to 6.

10. In general formulas (I) to (VIII) and (Va), (VIIa) and (VIIIa),

11. ​ ​ ​ ​ 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(C H ３ ) ２ , NH-CH(CH ３ )-CH ２ -CH ２ -CH ３ , -NH-CH ２ -CH(C H 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-C H(CH ３ )-CH ２ -OH, -NH-CH ２ -furanyl, -NH-CH ２ -tetrahydro Roflanyl, -NH-CH ２ -thiophenyl, -NH-toluoyl, -NH-CH-(C H ３ ) ２ , -NH-C(CH ３ ) ３ , -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -N(CH ３ ), -N(CH ２ ), -N(CH ３ ), -N(cyclohexyl), -N( CH ２ -CH ３ ) ２ , azetidinyl, pyrrolidinyl, piperidinyl, azacyclobutadiene nil, pyrrolyl, pyridinyl, -O, -OH, -O-CH ３ , -O-C(=O)-CH ３ , oxetanyl, -CH ３ , -CH ２ -CH ３ , -CH(CH ３ ) ２ , -C(OH)-C H ２ -OH, cyclopropyl, phenyl and -CH ２ -S-CH ３ selected from the group consisting of is formed; in 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 , -NH-CH ２ , -furanyl , -NH-CH ２ , -tetrahydrofuranyl, -NH-CH ２ , -thiophenyl, -NH-t Royle, -NH-CH-(CH ３ ), -NH-C(CH ２ ), -NH-cycloprop ３ ), -NH-C(CH ３ ), -NH-cycloprop Pill, -NH-cyclobutyl, -NH-cyclopentyl, -N(CH ３ ), -N(CH ２ , -N(CH ３ ) - cyclohexyl, -N(CH ２ -CH ３ ) ２ , acetidinyl, pyrrolidinyl, piper Rizinyl, azacyclobutadienyl, pyrrolyl, pyridinyl, -O, -O-CH ３ , -O -C(=O)-CH ３ , oxetanyl, -CH ３ , -CH ２ , -CH ３ , -CH(CH ３ ) ２ 、 -C(OH)-CH ２ -OH, cyclopropyl, phenyl and -CH ２ -S-CH ３ The physiological coolant according to any one of claims 1 to 6, selected from the group consisting of ​ The physiological coolants of general formula (I), (II), (V) or (VI) are selected from the group consisting of the compounds according to Table 1 below : 【Table 9-1】 【Table 9-2】 【Table 9-3】 【Table 9-4】 【Table 9-5】 【Table 9-6】 【Table 9-7】 【Table 9-8】 【Table 9-9】 【Table 9-10】 【Table 9-11】 【Table 9-12】 and their salts, in particular acid addition salts with inorganic or organic acids, and the coolant may be present in pure form as a stereoisomer or as a mixture of different stereoisomers, preferably the physiological coolant is selected from the group consisting of compounds B-01, B-02, B-03 , B-04, B-05, B-06, B-07, B-11, B-18 and B-19, or The physiological coolants of general formula (III), (IV), (VII) or (VIII) are the compounds according to Table 2 below : and their salts, in particular acid addition salts with inorganic or organic acids, and the coolant may be present in pure form as a stereoisomer or as a mixture of different stereoisomers, preferably the physiological coolant is selected from the group consisting of compounds A-02, A-04, A-05 , A-06, A-07, A-08, A-09, A-10, A-12, A-16, A-17 and A-18, 【Table 10-1】 【Table 10-2】 【Table 10-3】 【Table 10-4】 【Table 10-5】 【Table 10-6】 【Table 10-7】 【Table 10-8】 【Table 10-9】 【Table 10-10】 【Table 10-11】 【Table 10-12】 The physiological coolant according to any one of claims 4 to 6.

12. The salt of the coolant is (1) an acid addition salt formed with an inorganic acid or an organic acid, preferably a monovalent or polyvalent carboxylic acid, or when the acidic proton present in the starting compound is replaced by a metal ion, in particular an alkali metal ion , an alkaline earth ion or an aluminum ion; or a salt coordinated with an organic base selected from the group consisting of, the physiological coolant according to any one of claims 1 to 6.

13. (a) one, two, three or more coolants according to any one of claims 1 to 6; and optionally, (b) at least one other physiological coolant; and / or optionally a physiological coolant mixture comprising or consisting of (c) at least one solvent.

14. The physiological coolant forming component (b) is menthol, menthyl methyl ether (FEMA GRAS 4054), monomethyl glutamate (FEMA GRAS 4 006), menthoxy-1,2-propanediol (FEMA GRAS 3784), di-menthyl glutarate (FEMA GRAS 4604), hydroxymethyl cyclohexyl ​ ​ ​ ​ ​ ​ ​ ​ Ethanone (FEMA GRAS 4742), 2-(4-ethylphenoxy)-N-(1H -pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide (FEM A GRAS 4880), WS-23 (2-isopropyl-N,2,3-trimethylbut ylamide, 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-dimethylcyclohex ane-1-carboxamide (FEMA GRAS 4896), 3,4-methylenedioxy cinnamic acid, (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl- 2-propenamide (FEMA GRAS 4788), menthol propylene glycol carbonate (FEMA GRAS 3806), N-ethyl oxamic acid menthyl, coha lic acid monomethyl (FEMA GRAS 3810), WS-3 (N-ethyl-p-menthan -3-carboxamide, FEMA GRAS 3455), menthol ethylene glycol carbonate (FEMA GRAS 3805), WS-5 (3-(p-menthane-3-car boxamide) acetic acid ethyl, FEMA GRAS 4309), WS-12 (1R,2S, 5R)-N-(4-methoxyphenyl)-p-menthane carboxamide (FEMA GR AS 4681), WS-27 (N-ethyl-2,2-diisopropylbutanamide, FE MA GRAS 4557), N-cyclopropyl-5-methyl-2-isopropylcyclo hexanecarboxamide (FEMA GRAS 4693), WS-116 (N-(1,1 -dimethyl-2-hydroxyethyl)-2,2-diethylbutanamide, FEMA GR AS 4603), menthoxyethanol (FEMA GRAS 4154), N-(4-si anomethylphenyl)-p-menthane carboxamide (FEMA GRAS 4496), N-(2-(pyridin-2-yl)ethyl)-3-p-menthane carboxamide (FEM A GRAS 4549), N-(2-hydroxyethyl)-2-isopropyl-1-2, 3-Dimethylbutanamide (FEMA GRAS 4602), (2S,5R)-N-[4 -(2-Amino-2-oxoethyl)phenyl]-p-menthane carboxamide (FEMA GRAS 4684), N-Cyclopropyl-5-methyl-2-isopropyl cyclohex ane carboxamide (FEMA GRAS 4693), 2-[(2-p-menthoxy) ethoxy]-ethanol (FEMA GRAS 4718), (2,6-Diethyl-5-is opropyl-2-methyltetrahydropyran (FEMA GRAS 4680), tran s-4-tert-Butylcyclohexanol (FEMA GRAS 4724), 2-( p-Tolyloxy)-N-(1H-pyrazol-5-yl)-N-((thiophen-2- yl)methyl)acetamide (FEMA GRAS 4809), Mentonglycerol ket al (FEMA GRAS 3807 and 3808), (-)-Mentoxypropane- 1,2-diol, 3-(1-Mentoxy)-2-methylpropane-1,2-diol ( FEMA GRAS 3849), Isopulegol, (+)-cis and (-)-tra ns-p-menthane-3,8-diol (62:38, FEMA GRAS 4053), 2,3-Dihydroxy-p-menthane, 3,3,5-Trimethylcyclohexanone glyce rol ketal, Menthyl pyrrolidonecarboxylate, (1R,3R,4S)-3-Menthyl -3,6-dioxaheptanoate, (1R,2S,5R)-3-Menthylmethoxyacetate, (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, Cubeb ball (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-Benz[1,3]-dioxol-5-yl-3-p-menthane carboxamide, N -(1-Isopropyl-1,2-dimethylpropyl)-1,3-benzodioxole-5 -carboxamide, N-(R)-2-oxotetrahydrofuran-3-yl-(1R,2 S,5R)-p-menthane-3-carboxamide, 2,2,5,6,6-pentamethyl- 2,3,6,6a-tetrahydropentalen-3a(1H)-ol and 5-(2-hydroxy xy-2-methylpropyl)-3,4,4-trimethylcyclopenta-2-en-1-one mixture ； (2S,5R)-2-Isopropyl-5-methyl-N-(2-(pyridin -4-yl)ethyl)cyclohexanecarboxamide; (1S,2S,5R)-N-(4 -(cyanomethyl)phenyl)-2-isopropyl-5-methylcyclohexanecarbox amide, 1,7-isopropyl-4,5-methyl-bicyclo[2.2.2]oct-5- ene derivative, 4-methoxy-N-phenyl-N-[2-(pyridin-2-yl)ethyl] benzamide, 4-methoxy-N-phenyl-N-[2-(pyridin-2-yl)ethyl benzenesulfonamide, 4-chloro-N-phenyl-N-[2-(pyridin-2-yl l)ethyl]benzenesulfonamide, 4-cyano-N-phenyl-N-[2-(pyridin -2-yl)ethyl]-benzenesulfonamide, 4-((benzhydrylamino)meth yl)-2-methoxyphenol, 4-((bis(4-methoxyphenyl)methylamino )methyl)-2-methoxyphenol, 4-((1,2-diphenylethylamino)meth yl)-2-methoxyphenol, 4-((benzhydryloxy)methyl)-2-methox yphenol, 4-((9H-fluoren-9-ylamino)methyl)-2-methoxyphen ol, 4-((benzhydrylamino)methyl)-2-ethoxyphenol, 1-( 4-methoxyphenyl)-2-(1-methyl-1H-benzo[d]imidazol-2-yl l)vinyl-4-methoxybenzoate, 2-(1-isopropyl-6-methyl-1H- benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)vinyl-4-meth oxybenzoate, (Z)-2-(1-isopropyl-5-methyl-1H-benzo[d imidazol-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxyben zoate, 3-alkyl-p-methane-3-ol derivative, fenchyl derivative, D-bor Lunil, L-bornyl, exo-norbornyl, 2-methylisobornyl, 2-ethyl fenchyl, 2-methylbornyl, cis-pinan-2-yl, verbanil and isobor nyl, menthyl oxamate derivatives, menthyl 3-oxocarboxylate, N- alfa-(menthane-carbonyl)amino acid amides, p-menthane-carboxamide and WS -23 analogs, (-)-(1R,2R,4S)-dihydroumbellol, p-menthane alkyl oxyamides, cyclohexane derivatives, butanone derivatives, 3-menthoxy-1 -propanol and a mixture of 1-menthoxy-2-propanol, 1-[2-hydroxy phenyl]-4-[2-nitrophenyl]-1,2,3,6-tetrahydropyrimidin- 2-one, 4-methyl-3-(1-pyrrolidinyl)-2-[5H]-furanone, and the following table: 【Table 11-1】 【Table 11-2】 【Table 11-3】 【Table 11-4】 【Table 11-5】 Coolants according to, and the following table: 【Table 12-1】 【Table 12-2】 【Table 12-3】 【Table 12-4】 【Table 12-5】 【Table 12-6】 【Table 12-7】 【Table 12-8】 【Table 12-9】 【Table 12-10】 【Table 12-11】 【Table 12-12】 【Table 12-13】 【Table 12-14】 and their salts, in particular, acid addition salts with inorganic or organic acids, and the above coolant / chemical A physiological coolant mixture according to claim 13, consisting of a coolant selected from the group consisting of a mixture of compounds.

15. The physiological coolant mixture according to claim 13, wherein the components (a) and (b) are present in a weight ratio of about 0.1:99 to about 99:0.

1.

16. 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 their mixtures, the physiological coolant mixture according to claim 13.

17. (d) One, two, three or more physiological coolants according to any one of claims 1 to 6, and (e) At least one flavoring substance A flavoring preparation comprising or consisting of.

18. The flavoring agent forming component (e) is acetophenone, allyl caproate, alpha- ionone, beta-ionone, anisaldehyde, anisyl acetate, anisyl formate, aneth ol, benzaldehyde, benzothiazole, benzyl acetate, benzyl alcohol, benzo ic acid benzyl, beta-ionone, butyl butyrate, butyl caproate, butylidene phthalide ​ ​ ​ , Carvon, Camphene, Caryophyllene, Cineole, Cinnamyl acetate, Citral, Citronellol, Citronellal, Citronellyl acetate, Cyclohexyl acetate, Cymene, Damascone, Decalactone, Dihydrocoumarin, Dimethyl anthranilate, Dimethyl anthranilate, Dodecalactone, Ethoxyethyl acetate, Ethyl butyrate, Ethyl butyrate, Ethyl caprylate, 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, Geranyl acetate, Grapefruit aldehyde, Methyl dihydrojasmonate (e.g., Hedion (registered trademark)), 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-2-Hexyl acetate, cis-3-Hexyl formate, Para-hydroxybenzyl acetone, Isoamyl alcohol, Isoamyl isovalerate, Isobutyl butyrate, Isobutyl aldehyde, Isoeugenol methyl ether, Isopropyl methylthiazole, Lauric acid, Levulinic acid, Linalool, Linalool oxide, Linaryl acetate, Menthol, Menthofuran, Methyl anthranilate, Methyl butanol, Methyl butyrate, 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-pentenoic acid, Methyl thiobutyrate, 3,1-Methylthiohexanol, 3-Methylthiohexyl acetate, Nerol, Neryl acetate, trans,trans-2,4-Nonadienal, 2,4-Nonadiene ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Norell, 2,6-nonadienol, 2,4-nonadienol, note catone, delta oct Tractone, gamma octalactone, 2-octanol, 3-octanol, 1,3-o Ctenol, 1-octyl acetate, 3-octyl acetate, palmitic acid, paraaldehyde, f Elandrene, pentanedione, phenylethyl acetate, phenylethyl alcohol, ph Nil ethyl alcohol, phenylethyl isovalerate, piperonal, propionaldehyde D, propyl butyrate, pregone, pregol, cinnensal, sulforol, terpinene Terpineol, terpinolene, 8,3-thiomenthanone, 4,4,2-thiomethylpe Ntanone, thymol, delta-undecalactone, gamma-undecalactone, valencene Valeric acid, vanillic acid, vanillin, acetoin, ethyl vanillin, ethyl vanillin iso Butyrate (=3-ethoxy-4-isobutyryloxybenzaldehyde), 2,5-di Methyl-4-hydroxy-3(2H)-furanone and its derivatives (preferably, homoph Raneol (=2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone), ho Mofronol (=2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone) and 5-ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and Maltol derivatives (preferably, ethyl maltol), coumarin and coumarin derivatives Gamma-lactone (preferably, gamma-undecalactone, gamma-nonalactone Gamma-decalactone), delta-lactone (preferably, 4-methyldelta-decalact Tone, massoia lactone, 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 Ster, n-butyl butyrate, isoamyl butyrate, ethyl 3-methyl-butyrate Ster, ethyl n-hexanoate, allyl n-hexanoate, n-hexane N-butyl n-hexanoate, ethyl n-octanoate, ethyl 3-methyl-3-phenyl Glycidate, ethyl 2-trans-4-cis-decadienoate, 4-(p-hi Droxyphenyl)-2-butanone, 1,1-dimethoxy-2,2,5-trimethyl-4 -hexane, 2,6-dimethyl-5-hepten-1-al and phenylacetalde hyde, 2-methyl-3-(methylthio)furan, 2-methyl-3-furanthiol, bis (2-methyl-3-furyl)disulfide, furfuryl mercaptan, methional, 2 -acetyl-2-thiazoline, 3-mercapto-2-pentanone, 2,5-dimethyl-3 -furanthiol, 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-dimeth ylpyrazine, 2,3-diethyl-5-methylpyrazine, 3-isopropyl-2-methoxy pyrazine, 3-isobutyl-2-methoxy pyrazine, 2-acetylpyrazine, 2-pent ylpyridine, (E,E)-2,4-decadienal, (E,E)-2,4-nonadienal, (E)-2-octenal, (E)-2-nonenal, 2-undecenal, 12- methyltridecanal, 1-penten-3-one, 4-hydroxy-2,5-dimethyl- 3(2H)-furanone, guaiacol, 3-hydroxy-4,5-dimethyl-2(5H )-furanone, 3-hydroxy-4-methyl-5-ethyl-2(5H)-furanone, sin namaldehyde, cinnamic alcohol, methyl salicylate, isopregol, and these stereoisomers, enantiomers, positional isomers, diastereomers, cis / trans isomers or epimers (where not explicitly mentioned); and / or epimers of these substances selected from the group consisting of; and / or the perfume forming component (e) is erythritol, threitol, arabinitol, ribitol, xylitol, sorbitol, mannitol, dulcitol, lactitol, miraculin, monellin, thaumatin, curculin, brazzein, magap, cyclam ate sodium, acesulfame K, neohesperidin dihydrochalcone, saccharin na trate, aspartame, sparsweet aspartame, neotame, alitame, sucra lose, stevioside, rebaudioside, lugduname, caleleram, scrononate, s ​ ​ Chloroactate, monatin, phenyllouzursin, glycine, D-leucine, D-threonine, D-asparagine, D-phenylalanine, D-tryptophan, L-proline, hernanzursin, dihydrochalcone glycoside, glycyrrhizin, glycyrrhetinic acid, its derivatives and salts, extracts of Glycyrrhiza glabra subsp., extracts of Amami kouzuiboku, extracts of Momordica subspecies, mogroside, sweet tea and stevioside, and mixtures thereof The flavoring preparation according to claim 17, selected from the group consisting of and mixtures thereof Extracts of Glycyrrhiza glabra subsp. (licorice), extracts of Amami kouzuiboku Extracts of Momordica subspecies, mogroside, sweet tea and stevioside, and The flavoring preparation according to claim 17, selected from the group consisting of mixtures thereof

19. The flavoring preparation according to claim 17, wherein the constituent (d) and the constituent (e) are present in a weight ratio of 1:99 to 99:1 The flavoring preparation according to claim 17

20. The physiological coolant according to any one of claims 1 to 6 in encapsulated form

21. In particular, for modulation in vivo and / or in vitro, as a modulator of the cold menthol receptor TRPM8, in particular as a TRPM8 receptor agonist, or As a TRPM8 receptor antagonist, the use of the physiological coolant according to any one of claims 1 to 6

22. For producing a physiological cooling effect on the skin or mucosa in humans or animals, or For inducing a cooling effect by means of a packaging containing a physiological coolant or a mixture of physiological coolants, or a textile product containing a physiological coolant or a mixture of physiological coolants, the use of the physiological coolant according to any one of claims 1 to 6

23. For improving the taste characteristics of a flavoring agent, in particular for reducing or masking an unpleasant taste, the use of the physiological coolant according to any one of claims 1 to 6

24. For the manufacture of food, dietary supplements, cosmetics or pharmaceutical preparations, animal feed, textile products, packaging or tobacco products, the use of the physiological coolant according to any one of claims 1 to 6

25. A food, dietary supplement, cosmetic or pharmaceutical preparation, animal feed, textile product, packaging or tobacco product containing the physiological coolant according to any one of claims 1 to 6 in an amount of, in particular, 0.1 ppm to 10% by weight, in particular 1% to 10% by weight, based on the total weight of the final product

26. Aspirin, minoxidil, erythromycin, phenistil, betamethasone, ib ​ ​ ​ ​ ​ Profens, ketoprofen, diclofenac, metronidazole, acyclovir, im iquimod, terbinafine, ciclopiroxolamine, paracetamol, and other medicaments of the non-steroidal anti-inflammatory drug (NSAID) type, and mixtures thereof, a pharmaceutical preparation according to claim 25, comprising a further pharmaceutically active ingredient selected from the group consisting of.

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

28. A method for modulating the cold menthol receptor TRPM8, in particular for modulating in vitro and / or in vivo, comprising the following steps: (ia) preparing at least one physiological coolant according to any one of claims 1 to 6; and (iia) contacting the physiological coolant of step (ia) with the receptor A method comprising; or A method for producing a physiological cooling effect on the skin or mucous membranes, comprising the following steps: (ib) preparing at least one physiological coolant according to any one of claims 1 to 6; and (iib) contacting the physiological coolant of step (ib) with human skin or mucous membranes A method comprising; or A method for improving the taste properties of a flavoring substance, comprising the following steps: ic) preparing at least one physiological coolant according to any one of claims 1 to 6 and at least one flavoring agent; (iic) mixing the two components; and optionally, (iiic) incorporating the mixture into an oral preparation A method comprising. ​

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