New cooling agent and preparations containing it

Abstract

The present invention relates to novel physiological coolants, coolant mixtures containing said novel coolants, mixtures of said coolants with flavoring agents, uses of said coolants, and articles and end-consumer preparations containing said physiological coolants or coolant mixtures.

Description

[Technical Field]

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

[0002] Although physiological cooling does not actually occur, as in the evaporation of a solvent, physiological cooling agents are commonly used to produce a sensory impression of coolness on the skin or mucous membranes, e.g., the mucous membranes of the mouth, nose, and / or throat. Both individual components and mixtures can be used as physiological cooling agents. It must be taken into account that not all compounds that affect receptors involved in mediating the physiological cooling effect in vitro actually produce such an effect on the skin or mucous membranes in vivo. In particular, such effects will not always be identical. This means, for example, that the mere fact that a particular compound is an agonist of a receptor involved in mediating the cooling impression does not allow conclusions to be drawn about the course of the intensity of the cooling effect over time and the intensity of the mediated physiological cooling effect.

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

[0004] The cold menthol receptor TRPM8 (also called cold membrane receptor 1 (CMR1)) belongs to the family of "transient photoreceptor potential ion channels" and is specifically expressed in certain groups of neurons. It forms pores in the cell membrane (four units each forming a tetramer), which translocate Ca 2+ It selectively allows ions to pass through. The protein has six transmembrane domains and cytoplasmic C- and N-termini. Cold temperatures (preferably 10-25°C) stimulate this receptor, resulting in a signal that is interpreted by the nervous system as a cold sensation.

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

[0006] Cooling compounds such as menthol have long played an important role in the flavor and perfume industries, creating an association with freshness and cleanliness.

[0007] The best-known physiologically effective cooling agent is L-menthol. The compound menthol has been shown to act as a natural mediator of the receptor TRPM8. Application of menthol activates TRPM8, which then delivers Ca to cold-sensitive neurons. 2+ This generates electrical signals that are ultimately perceived as a sensation of cold.

[0008] However, menthol has several drawbacks, such as a strong odor, high volatility, and at high concentrations, a bitter and / or pungent taste, and an irritating effect on the skin. Excessive menthol concentrations can also cause irritating and anesthetic effects on the skin or mucous membranes.

[0009] There has long been a need for a powerful cooling agent that does not have the harmful properties of L-menthol.

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

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

[0012] The menthyl monoesters of diacids according to US Pat. No. 5,725,865 and US Pat. No. 5,843,466 are interesting naturally occurring alternatives, but fail to reach the strength of the previously described coolants in sensory tests.

[0013] The compounds L-menthanecarboxylic acid-N-ethylamide ("WS-3") and, in particular, Nα-(L-menthanecarbonyl)glycine ethyl ether ("WS-5") have been found to be potent cooling agents. Although potent, the latter has the disadvantage, however, of being prone to hydrolysis, thereby forming the corresponding free acid, Nα-(L-menthanecarbonyl)glycine, which by itself exhibits only a very weak cooling effect. Despite the detailed investigations described, a systematic prediction of the properties of potential cooling agents, in particular their bitter taste and / or trigeminal effects, has not been possible or described. Thus, many more molecules that fall into the class of menthanecarboxylic acid amides are strongly cooling, but at the same time often exhibit a pronounced bitter odor note, e.g., menthanecarboxylic acid N-(alkyloxyalkyl)amides according to JP2004 059474A2, such as, for example, N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycine ethyl ester designated WS-5 according to US2005 0222256A1, are even more strongly pungent, making such compounds unsuitable for use in food preparations, etc.

[0014] Nα-(menthanecarbonyl) alkyloxyalkylamides are described in JP2004 059474A2. However, although they have a strong cooling effect and high hydrolytic stability, they have the disadvantage of being very bitter, which makes them unsuitable for use in foodstuffs and cosmetic products used in facial care.

[0015] Furthermore, menthyl glyoxylate and its hydrolysates are described as cooling substances in JP2005 343795A2.

[0016] A summary of the 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 the cooling agent WS-23 or the compounds listed in patent application WO2007019719A1.

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

[0019] WO201002694A1 discloses individual compounds for modulating the TRPM8 receptor.

[0020] Further compounds for modulating the TRPM8 receptor are also proposed in WO2011061330A2.

[0021] Special coolants with carboxamide structure (I): [ka] is also known from WO2012061698A1.

[0022] On the oral mucosa, many of the conventional and prior art cooling substances mentioned above all exhibit more or less the same cooling behavior. The cooling sensation of freshness they impart begins after about 0.5 minutes, but after a peak at 3-5 minutes, levels off again relatively quickly, so that the cooling is generally noticeable for up to 30 minutes, and experience shows that varying the dosage only slightly affects the intensity and duration. However, on the part of consumers, there is a desire for a particularly long-lasting cooling effect, which is associated with a corresponding feeling of freshness and well-being for the user. Summary of the Invention

[0023] Therefore, the main objective of the present invention is to identify new substances with specific physiological cooling effect, preferably those that modulate TRPM8 receptor (so-called modulators), which can be used as a more suitable drug than previously known modulators, and as an alternative.Such compounds should be particularly suitable for application in the fields of cosmetics, nutrition, textile products, OTC products (e.g., burn ointments), pharmaceuticals (e.g., tumor treatment, bladder weakness) or packaging.The compounds or compound mixtures described should preferably have as weak an inherent taste as possible, in particular little or no bitterness, and preferably be non-irritating.

[0024] To solve the problem of the present invention, the active substances that can provide a particularly long-lasting cooling sensation are mainly searched for.Preferably, these active substances should also be able to provide a particularly strong cooling sensation and / or a rapid onset of the cooling sensation.The cooling agents should be efficient, i.e., they should generate a high cooling effect or cooling sensation even at low concentrations.

[0025] Another challenge is to compensate for the off-flavors exhibited by many flavors, especially sweeteners such as representatives of the stevioside family, which in particular relate to bitter, astringent and metallic aftertastes.

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

[0027] According to the present invention, the main subject of the invention is to provide compounds of general formula (I): [ka] and salts thereof, In the formula, the residues R1 to R7 can be identical or different and independently have the following meanings: TIFF0007813787000003.tif137157TIFF0007813787000004.tif231156TIFF00078137870 00005.tif212156TIFF0007813787000006.tif231157TIFF0007813787000007.tif231155

[0028] For example, if R1 and R7 are the same and R2 and R5 are the same, or R3 and R6 are the same, this can represent a symmetrical amine, which is also a suitable cooling agent in the context of the present invention.

[0029] The cooling agents of the present invention according to formula (I) can exist both in stereoisomerically pure form or as mixtures of different stereoisomers.

[0030] In a preferred embodiment of the first aspect of the present invention, it is of general formula (II): [ka] and salts thereof, In the formula, the residues R1 to R6 and R8 to R12 can each be identical or different and can have the following meanings independently of one another: TIFF0007813787000009.tif160156TIFF0007813787000010.tif247156TIFF00078137870 00011.tif247155TIFF0007813787000012.tif237156TIFF0007813787000013.tif196156

[0031] The cooling agents according to formula (II) of the present invention can also exist both in stereoisomerically pure form or as mixtures of different stereoisomers.

[0032] In the context of the present invention, the following general meanings apply, in particular for the definitions of general formula (I) and general formula (II):

[0033] The terms "or" or "and / or" are used as operands indicating that two words or phrases should be taken together or separately.

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

[0035] The endpoints of all ranges directed to the same component or property are inclusive and independently combinable.

[0036] The term "compound(s)" or "compound(s) of the invention" refers to all compounds encompassed by the structural formulae, Formula (I) and / or Formula (II), disclosed herein, including any subgenera and any specific compounds within the formulae whose structures are disclosed herein. A compound may 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 determinative of the identity of the compound. The compounds described herein may contain one or more chiral centers and / or double bonds and may therefore exist as stereoisomers, such as double bond isomers, i.e., geometric isomers, enantiomers, or diastereomers. Thus, the chemical structures of general Formula (I) and / or general Formula (II) shown herein encompass all possible enantiomers and diastereomers or stereoisomers.

[0037] The term "alkyl," alone or as part of another substituent according to the present invention, refers to a saturated or monounsaturated or polyunsaturated, straight- or branched-chain monovalent hydrocarbon radical derived by removal of a hydrogen atom from a single carbon atom of the corresponding parent alkane.

[0038] In a preferred variant, the term "alkyl" also includes alkyl moieties in residues derived therefrom, such as alkoxy, alkylthio, alkylsulfonyl saturated straight-chain or branched-chain hydrocarbon radicals having 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.

[0039] When an alkyl radical is bonded to another atom, it becomes an alkylene residue or group. In other words, the term "alkylene" also refers to a divalent alkyl. For example, -CH2CH3 is ethyl, while -CH2CH2- is ethylene.

[0040] The term "alkylene" alone or as part of another substituent refers to a saturated, straight- or branched-chain divalent hydrocarbon radical derived by removing two hydrogen atoms from a single carbon atom or from two different carbon atoms of a starting alkane.

[0041] In a preferred variant according to the invention, the alkyl or alkylene group contains 1 to 10 carbon atoms. In another even more preferred variant, the alkyl or alkylene group contains 1 to 6 carbon atoms.

[0042] Most preferred are alkyl or alkylene groups having 1 to 4 carbon atoms.

[0043] Preferred alkyl residues or alkyl groups are 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; for example, methoxy, ethoxy, n-propoxy, 1-methylethyl, 2-methylpropyl, 2-methylpropyl, 2-methylpropyl, 2-methylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl; C1-C6-alkoxy including C1-C4 alkoxy, such as ethoxy, 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-methyl including, but not limited to, pentoxy, 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.

[0044] Most preferred according to the present invention are saturated straight or branched chain C1-C6 alkyl groups or saturated straight or branched chain C1-C6 alkylene groups.

[0045] The terms "alkyl" or "alkylene" further include residues or groups with any degree of saturation, i.e., groups with only one carbon-carbon bond ("alkyl" or "alkylene"), groups with one or more double carbon-carbon bonds ("alkenyl"), residues with one or more triple carbon-carbon bonds ("alkynyl"), and groups with a mixture of single, double, and / or triple carbon-carbon bonds.

[0046] The term "alkenyl," alone or as part of another substituent according to the present invention, refers to an unsaturated, linear or branched, monovalent hydrocarbon radical having at least one carbon-carbon double bond (C=C double bond). The residue may be in either the cis or trans configuration around the double bond(s). Thus, the term "alkenyl" also encompasses the corresponding cis / trans isomers.

[0047] Typical alkenyl residues or groups include, but are not limited to, ethenyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl, cycloprop-2-en-1-yl; butenyl, 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-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl; and the like.

[0048] In a preferred variation according to the present invention, the alkenyl group contains 2 to 10 carbon atoms. In another preferred variation, the alkenyl group contains 2 to 6 carbon atoms. In an even more preferred variation, the alkenyl group contains 2 to 4 carbon atoms.

[0049] Most preferred according to the present invention are monounsaturated or diunsaturated straight or branched chain C1-C6 alkenyl groups.

[0050] The term "alkynyl" alone or as part of another substituent in accordance with the present invention refers to an unsaturated, linear or branched, monovalent hydrocarbon radical having at least one carbon-carbon triple bond (C≡C triple bond).

[0051] Typical alkynyl residues or groups include, but are not limited to, ethynyl; propynyl, such as, for example, prop-1-yn-1-yl, prop-2-yn-1-yl, and the like; butynyl, such as, for example, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, and the like.

[0052] In a preferred variation according to the present invention, the alkenyl group contains 2 to 10 carbon atoms. In another preferred variation, the alkenyl group contains 2 to 6 carbon atoms. In an even more preferred variation, the alkenyl group contains 2 to 4 carbon atoms.

[0053] The term "alkoxy" by itself or as part of another substituent according to the invention refers to a radical of the formula --OR--, where R is alkyl or substituted alkyl as defined herein.

[0054] The terms "alkylthio" or "thioalkoxy" alone or as part of another substituent according to the invention refer to a radical of the formula --SR--, where R is alkyl or substituted alkyl as defined herein.

[0055] According to the present invention, the term "alkyl" or "alkylene" also includes heteroalkyl residues or heteroalkyl groups. The term "heteroalkyl" by itself or as part of another substituent refers to an alkyl group in which one or more of the carbon atoms is independently replaced by the same or another heteroatom or the same or another heteroatom group(s). Typical heteroatoms or heteroatom groups that may 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 the above 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, where R is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl as defined herein.

[0056] An alkyl or alkylene group, as defined above, may be further substituted.

[0057] The term "acyl" by itself or as part of another substituent according to the present invention 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.

[0058] Representative examples include, but are not limited to, formyl, acetyl, propynyl, butyryl, valeryl, benzoyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzylcarbonyl, and the like.

[0059] The term "cycloalkyl," by itself or as part of another substituent according to the present invention, refers to a saturated, monounsaturated, or polyunsaturated non-aromatic cyclic monovalent hydrocarbon radical, wherein the carbon atoms are joined together in the ring and have no heteroatoms.

[0060] Carbocycles can exist as monocyclic compounds, having only one ring, or as polycyclic compounds, having two or more rings.

[0061] In a preferred variation, the term "cycloalkyl" includes a 3- to 10-membered monocyclic cycloalkyl or cycloalkyl group, or a 9- to 12-membered polycyclic cycloalkyl or cycloalkyl group. In another even more preferred variation, the cycloalkyl group includes a 5-, 6-, or 7-membered monocyclic cycloalkyl group, or a 9- to 12-membered bicyclic cycloalkyl moiety.

[0062] In a preferred variation according to the present invention, the cycloalkyl residue or cycloalkyl group contains 3 to 20 carbon atoms. In an even more preferred variation, the cycloalkyl residue contains 6 to 15 carbon atoms. In the most preferred variation, the cycloalkyl residue contains 6 to 10 carbon atoms. Most preferred are monocyclic C3-C7 cycloalkyl groups.

[0063] Typical cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl; preferably cyclopentyl, cyclohexyl, cycloheptyl, and C3-C6 alkyl groups including cyclopropyl-methyl, cyclopropyl-ethyl, cyclobutyl-methyl, cyclobutyl-ethyl, cyclopentyl-methyl, cyclopentyl-ethyl, cyclohexyl-methyl.12 Including, but not limited to, saturated carbocyclic residues having 3 to 20 carbon atoms such as carbocyclyl or C3-C7-carbocyclyl, including 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.

[0064] Preferred saturated polycyclic cycloalkyl residues or cycloalkyl groups according to the present invention include, but are not limited to, for example, adamantyl groups and the like.

[0065] According to the present invention, the term "cycloalkyl group" also includes cycloalkenyls, i.e., unsaturated cyclic hydrocarbon radicals containing a C=C double bond between two carbon atoms of the ring molecule. In the broadest sense, cycloalkenyls are compounds with one, two or more double bond(s), whereby the number of possible, primarily conjugated, double bonds in the molecule depends on the ring size.

[0066] Typical cycloalkenyls include, but are not limited to, cyclopropentyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.

[0067] 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 a factor in the ring tension depending on the ring size.

[0068] Exemplary cycloalkynes include cyclooctynes.

[0069] The cycloalkyl residue or cycloalkyl group can be attached to the rest of the molecule of formula (I) and / or formula (II) via any suitable C atom.

[0070] Cycloalkyl residues or cycloalkyl groups as defined above may be further substituted.

[0071] The term "aryl" alone or as part of another substituent in this invention refers to a monovalent aromatic hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom of an aromatic ring system.

[0072] In a preferred variation, the term "aryl" includes a 3- to 10-membered monocyclic aryl moiety or group, or a 9- to 12-membered polycyclic aryl moiety or group. In another even more preferred variation, the carboaryl moiety includes a 5-, 6-, or 7-membered monocyclic carboaryl moiety, or a 9- to 12-membered bicyclic carboaryl moiety.

[0073] In a preferred variation according to the invention, the aryl moiety contains 3 to 20 carbon atoms. In an even more preferred variation, the aryl moiety contains 6 to 15 carbon atoms. In the most preferred variation, the aryl residue contains 6 to 10 carbon atoms. Most preferred according to the invention are monocyclic C3-C 12 It is an aryl group. Most preferred is a monocyclic C3-C7 aryl group.

[0074] 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 moieties further include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0075] Preferred aromatic polycyclic aryl residues or groups according to the present invention include, but are not limited to, naphthalene, biphenyl, and the like.

[0076] The attachment of the aryl residue or group to the residue of the molecule of formula (I) or formula (II) can be via any suitable C atom.

[0077] The aryl residue or group as defined above may be further substituted, for example, the aryl residue forms an anisole group.

[0078] The term "arylalkyl," alone or as part of another substituent according to the present invention, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or sp carbon atom, is replaced by an aryl group, as defined herein. In other words, an arylalkyl may be considered an alkyl substituted with 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, and the like.

[0079] 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.

[0080] In a preferred embodiment of 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 group. In another embodiment, the heteroarylalkyl group 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.

[0081] The term "heterocycloalkyl," by itself or as part of another substituent according to the present invention, refers to a saturated non-aromatic cyclic monovalent hydrocarbon radical in which one or more carbon atoms are independently replaced with the same or different heteroatom. Typical heteroatoms replacing a carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Typical heterocycloalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidines, morpholines, piperazines, piperidines, pyrazolidines, pyrrolidones, quinuclidines, etc.

[0082] Heterocycloalkyl moieties may exist as monocyclic compounds, having only one ring, or as polycyclic compounds, having two or more rings.

[0083] Preferably, the term "heterocycloalkyl" includes 3- to 7-membered saturated or monounsaturated or polyunsaturated heterocycloalkyl residues containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S. The heteroatom or heteroatoms may occupy any position in the heterocycloalkyl ring.

[0084] In one preferred variation, the term "heterocycloalkyl" includes a 3- to 10-membered monocyclic heterocycloalkyl radical or a 9- to 12-membered polycyclic heterocycloalkyl residue. In another even more preferred variation, the heterocycloalkyl residue includes a 5-, 6-, or 7-membered monocyclic heterocycloalkyl residue or a 9- to 12-membered bicyclic heterocycloalkyl residue.

[0085] In a preferred variation according to the present invention, the "heterocycloalkyl" residue or heterocycloalkyl group contains 3 to 20 ring atoms. In a preferred variation, the heterocycloalkyl residue contains 6 to 15 ring atoms. In an even more preferred variation, the heterocycloalkyl residue contains 6 to 10 carbon atoms. Most preferred according to the present invention are monocyclic heterocycloalkyl residues containing 3 to 12 carbon atoms. Most preferred are monocyclic heterocycloalkyl residues having 5 to 7 ring atoms.

[0086] Typical heterocycloalkyl residues are 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-piperazolidinyl, 4-piperazolidinyl, 5-piperazolidinyl, 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- Including, but not limited to, saturated or monounsaturated 5- or 6-membered heterocycloalkyls containing one or two nitrogen atoms and / or one oxygen or sulfur atom or one or two oxygen and / or sulfur atoms as ring members, including pyrrolin-2-yl, 3-pyrrolin-3-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl, and the like.

[0087] Heterocycloalkyl residues or heterocycloalkyl groups as defined above may be further substituted.

[0088] The heterocycloalkyl radical or heterocycloalkyl group may be attached to the remainder of the molecule of formula (I) or formula (II) through a ring carbon atom or a ring heteroatom.

[0089] The term "heteroaryl" by itself or as part of another substituent in the present invention refers to a monovalent heteroaromatic radical derived by removing a hydrogen atom from a single atom of a heteroaromatic ring system. Typical heteroaryl residues or groups include, but are not limited to, groups derived from acridine, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, 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.

[0090] Heteroaryl residues can exist as monocyclic compounds, having only one ring, or as polycyclic compounds, having two or more rings.

[0091] In a preferred variation, the term "heteroaryl" includes a 3- to 10-membered monocyclic heteroaryl residue or a 9- to 12-membered polycyclic heteroaryl residue. In another even more preferred variation, the heteroaryl moiety includes a 5-, 6-, or 7-membered monocyclic heteroaryl moiety or a 9- to 12-membered bicyclic heteroaryl moiety.

[0092] Preferably, the term "heteroaryl" includes 3- to 7-membered monocyclic heteroaryl residues containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S. The heteroatom or heteroatoms may occupy any position in the heteroaryl ring.

[0093] In a preferred variation according to the present invention, the heteroaryl moiety or heteroaryl group contains 3 to 20 ring atoms. In an even more preferred variation, the heteroaryl moiety contains 6 to 15 ring atoms. In the most preferred variation, the heteroaryl group contains 6 to 10 ring atoms. Most preferred according to the present invention are monocyclic C3-C7 heteroaryl groups.

[0094] Particularly preferred heteroaryl residues 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.

[0095] Five-membered aromatic heteroaryl residues 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.

[0096] Aromatic heteroaryl residues having a five-membered ring containing one, two, three or four nitrogen atoms as ring atoms include 1-, 2- or 3-pyrrolyl, 1-, 3- or 4-pyrazolyl, 1-, 2- or 4-imidazolyl, 1,2,3-[1H]-triazol-1-yl, 1,2,3-[2H]-triazol-2-yl, 1,2,3-[1H]-triazol-4-yl, 1,2,3-[1H]-triazol-5-yl, 1,2,3-[2H]-triazol-6-yl, 1,2,3-[2H]-triazol-7-yl, 1,2,3-[2H]-triazol-8-yl, 1,2,3-[2H]-triazol-9-yl, 1,2,3-[2H]-triazol-10-yl, 1,2,3-[2H]-triazol-11-yl, 1,2,3-[2H]-triazol-12-yl, 1,2,3-[2H]-triazol-13-yl, 1,2,3-[2H]-triazol-14-yl, 1,2,3-[2H]-triazol-16-yl, 1,2,3-[2H]-triazol-18-yl, 1,2,3-[2H]-triazol-19-yl, 1,2,3-[2H]-triazol-21-yl, 1,2,3-[2H]-triazol-22-yl, 1,2,3-[2H]-triazol-23-yl, 1,2,3-[2H]-triazol-24-yl, 1,2,3-[2H]-triazol-25-yl, Includes azole-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, and [2H]-tetrazol-5-yl.

[0097] Five-membered aromatic heteroaryl residues containing oxygen or sulfur and optionally 1, 2 or 3 nitrogen atoms as ring atoms include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3- or 4-isoxazolyl, 3- or 4-isothiazolyl, 2, 4- or 5-oxazolyl, 2, 4- or 5-thiazolyl, 1,2,4-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.

[0098] Heteroaryl residues having 6 members containing, in addition to carbon atoms, 1 or 2, or 1, 2 or 3 nitrogen atoms as ring atoms, include, for example, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,2,4-triazin-3-yl; 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl and 1,3,5-triazin-2-yl.

[0099] Heteroaryl residues or groups as defined above may be further substituted.

[0100] The heteroaryl residue or group may be attached to the remainder of the molecule of formula (I) or formula (II) through a ring carbon atom or a ring heteroatom.

[0101] Of the above-mentioned monocyclic heteroaryl residues, particularly preferred in the context of the present invention are heteroaryl residues derived from saturated compounds with 5- or 6-membered rings, including pyrrolidone, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran, or from aromatic compounds with 5- or 6-membered rings, including pyrrole, furan, thiophene, pyridine, pyryllium ion and thiopyrylium ion, pyrazole, imidazole, imidazoline, pyrimidine, oxazole, thiazole, and 1,4-thiazine.

[0102] Of the above-mentioned polycyclic heterocycloalkyl ring systems, benzimidazole, benzoxazole, quinoline or benzoxazine, 1,3-benzodioxole and benzodioxane are particularly preferred in the context of the present invention.

[0103] Of the polycyclic cycloalkyl ring systems mentioned above, 1,3-benzodioxole is particularly preferred in the context of the present invention.

[0104] Of the polycyclic heteroaryl ring systems mentioned above, those which can be derived from benzothiophene, benzofuran, indole (benzopyrrole) and quinoline, such as quinazoline, quinoxaline, are particularly preferred in the context of the present invention.

[0105] In the context of the present invention, the term "substituted" means that one or more hydrogen atoms of the designated residue or radical are independently replaced by the same or different substituents.

[0106] Substituent or replacement groups useful for replacing saturated carbon atoms in the indicated groups or residues include -X, halo, =O, -OY, -SiR3, -SY, =S, -NZZ, =NY, =N-OY, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY)2, -P(O)(OY)(OY), -C(O)Y, -C(S)Y , -C(NY)Y, -C(O)OY, -C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, -NYC(O)Y, -NYC(S)Y, -NYC(O)OY, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y or -NYC(NY)NZZ; wherein X is optionally substituted alkyl, particularly optionally substituted C-C 10 selected from the group consisting of alkyl, in particular optionally substituted C1-C6 alkyl, in particular optionally substituted C1-, C2-, C3- or C4 alkyl groups, optionally substituted alkoxy residues, in particular optionally substituted C1-C6 alkoxy residues, in particular optionally substituted C1-, C2-, C3- or C4 alkoxy groups, optionally substituted alkylthio residues, in particular optionally substituted C1-C6 alkylthio residues, in particular optionally substituted C1-, C2-, C3- or C4 alkylthio groups, optionally substituted cycloalkyl residues, optionally substituted aryl residues, optionally substituted carboaryl residues, optionally substituted carboarylalkyl residues, optionally substituted heteroalkyl residues, optionally substituted heterocycloalkyl residues, optionally substituted heteroaryl residues and optionally substituted heteroarylalkyl residues, and as defined above; and / or Y represents 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, wherein the heterocycloalkyl or heteroaryl ring may contain 1, 2, 3, or 4 identical or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0107] For example, R2 can also represent an oxygen atom linked to the corresponding C1 atom via a double bond, thereby forming a keto group with the C1 atom, and similarly for R3, R5 and R6 and the C1 or C2 atoms.

[0108] As specific examples, -NZZ is intended to include -NH, -NH-alkyl, N-pyrrolidinyl, and N-morpholinyl. As further specific examples, substitutions are intended to include -alkylene-O-alkyl, -alkylene-heteroaryl, -alkylene-cycloheteroalkyl, -alkylene-C(O)OY, -alkylene-C(O)NYY, and -CH-CH-C(O)-CH, where Y has the meaning above.

[0109] In a further variation, one or more of the substituent(s) may, together with the atom to which they are attached, form a cyclic ring, including a cycloalkyl or heterocycloalkyl.

[0110] Similarly, useful substituents for substituting the unsaturated carbon atom in the indicated group or radical include -X, halo, =O, -OY, -SiR3, -SY, =S, -NZZ, =NY, =N-OY, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2Y, -S(O)2OY, -OS(O)2Y, -OS(O)2OY, -P(O)(OY)2, -P(O)(OY)(OY), -C(O)Y, -C(S )Y, -C(NY)Y, -C(O)OY, -C(S)OY, -C(O)NZZ, -C(NY)NZZ, -OC(O)Y, -OC(S)Y, -OC(O)OY, -OC(S)OY, -NYC(O)Y, -NYC(S)Y, -NYC(O)OY, -NYC(S)OY, -NYC(O)NZZ, -NYC(NY)Y and -NYC(NY)NZZ, wherein X, Y and Z have the same meanings as defined above.

[0111] Substituent or substitution groups for the nitrogen atom in heteroalkyl and heterocycloalkyl residues include, but are not limited to, -X, -OY, -SiR, -SY, -NZZ, trihalomethyl, -CF, -CN, -OCN, -SCN, -NO, -NO, =N, -N 3、 -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 have the same meanings as defined above.

[0112] The term "substituted" specifically provides for one or more substitutions common in the art, i.e., 2, 3, 4, 5, 6 or more, however, it is generally known to those skilled in the art that the substitutions should be selected so as not to adversely affect the useful properties of the compound or its function.

[0113] Suitable substituents in the context of the present invention preferably include halogen groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy groups or heteroaryloxy groups, arylalkyl or heteroarylalkyl groups, arylalkoxy or heteroarylalkoxy groups, amino groups, alkyl and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, carboxyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups, dialkylaminocarbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups, cycloalkyl groups, cyano groups, C1-C6 alkylthio groups, arylthio groups, nitro groups, keto groups, acyl groups, boronate or boronyl groups, phosphate or phosphonyl groups, sulfamyl groups, sulfonyl groups, sulfinyl groups and combinations thereof. In the case of substituted combinations, such as substituted arylalkyl, either the aryl 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.

[0114] Preferred substituents for the abovementioned groups or residues 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, wherein one or more H atoms in the alkyl groups may be replaced by halogen.

[0115] Additionally, suitable substituents may optionally be combined to form one or more rings known to those skilled in the art.

[0116] In the context of the present invention, the term "optionally substituted" denotes the presence or absence of substituent(s), i.e., "substituted" or "unsubstituted." For example, "optionally substituted alkyl" includes both unsubstituted alkyl and substituted alkyl.

[0117] According to the present invention, the substituents used to substitute a particular residue or radical may then be further substituted with one or more identical or different residues, usually selected from the various groups as indicated and defined in detail above.

[0118] The physiological cooling agents according to general formula (I) or (II) are present either in neutral, i.e., uncharged form, or in the form of their salts, for example, acid addition salts with inorganic or organic acids, with mono- or polycarboxylic acids.

[0119] In the context of this invention, the term "salt" refers to a salt of a compound that possesses the desired effect or pharmaceutical activity of the parent compound. Such salts are (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 parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or formed by coordination with an organic base. Includes:

[0120] Among the salts, acid addition salts are again particularly preferred, since the physiological cooling agents according to general formula (I) or (II) contain a protonatable N atom in their C1-N-C2 linker group.

[0121] The inorganic acid that forms an acid addition salt with the physiological cooling agent of the present invention is preferably selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. The most preferred salts are hydrochlorides or sulfates. Particularly preferred are hydrochlorides or sulfates at the central nitrogen atom of the C1-N-C2 linker group.

[0122] Even more preferred are acid addition salts with organic monocarboxylic or polycarboxylic acids. Even more preferred are acid addition salts with organic monocarboxylic or polycarboxylic acids, in which 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 representatives 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.

[0123] The organic acids which form acid addition salts with the physiological cooling agents according to the present invention are preferably amino acids, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, oxalic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanes ... The acid may be selected from the group consisting of carboxylic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert.butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, 4-hydroxybutyric acid, and the like.

[0124] Among the organic acids which form acid addition salts with the physiological cooling agents according to the invention, acetic acid, lactic acid, malonic acid, succinic acid, malic acid, citric acid or tartaric acid are most preferred.

[0125] The metal ions for salt formation that replace the acidic protons present in the starting compound are alkali metal ions, preferably Na + or K + , alkaline earth metal ions, preferably Ca ++ , Mg ++ , and aluminum +++ is selected from the group consisting of:

[0126] The organic bases suitable for salt formation are selected from the group consisting of ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

[0127] In the following description and patent claims, the term "physiological cooling agent" or "compound" includes both the neutral, uncharged form of the cooling agent / compound and equivalently the salt form of the cooling agent / compound.

[0128] Salts of physiological cooling agents according to the invention are particularly preferred due to their better solubility. Better water solubility also means that the cooling agent or compound is easier to use.

[0129] Surprisingly, it has been found that the compounds according to the present invention or their salts share the common property of producing a particularly long-lasting and powerful cooling effect on the skin or mucous membranes in vivo, even at low doses. This means that the cooling compounds according to the present invention or their salts or the cooling mixtures according to the present invention only require low doses to produce a powerful cooling effect. Thus, the compounds described herein are particularly efficient cooling agents. This was unexpected for the TRPM8 modulators mentioned in this application, and does not apply to all of these modulators.

[0130] Furthermore, the cooling agent or the cooling agent mixture according to the present invention is colorless and does not discolor, which is particularly advantageous for the storage and / or application of the final product. As a result, the compounds described herein stand out as particularly suitable additives in various preparations. In addition, since the compounds according to the present invention are almost neutral in taste and odor, they are well suited for incorporation into neutral and / or flavored preparations without creating a negatively perceived taste impression, such as bitterness, or adversely affecting the intended taste or odor impression.

[0131] The salt of the cooling agent of the present invention shows better in vitro effect than its neutral and uncharged counterpart, which is particularly advantageous when used in oral care.In vitro tests also show that the salt of the compound of the present invention shows better TRPM8 activity than its uncharged counterpart, and therefore shows more intense and effective cooling effect at the same time.Therefore, only a small amount of the compound of the present invention is needed to produce a strong cooling effect (low EC50 value).

[0132] As shown below in the experimental section, the acid addition salt of compound 87 has a TRPM8 activation of 133% and an EC50 value of 0.00695 μM. Its counterpart, the neutral, uncharged compound 27, has a TRPM8 activation of the same order of magnitude, i.e., 129.7%, while having an EC50 value of 0.1 μM. As a result, the salt compound exhibits a more intense and efficient cooling effect than its uncharged counterpart at the same concentration. Therefore, a smaller amount of compound 87 is required to produce a strong cooling effect than compound 27 (lower EC50 value).

[0133] Hitherto, there has been no evidence in the prior art that the compounds or salts thereof used in particular according to the invention can have any cooling effect at all, and certainly not a particularly long-lasting cooling effect.

[0134] Also surprising is the fact that the cooling agents or salts thereof of the present invention can mask the known taste shortcomings of flavorings, especially sweeteners such as stevioside, particularly the pungent, bitter, and metallic aftertastes that are effectively masked even with small additions.

[0135] The compounds described herein are therefore particularly suitable as effective cooling substances, which can be particularly well incorporated into various formulations.Due to their better solubility, the salts and even more preferably the acid addition salts of the compounds according to the invention are particularly advantageous for use in the oral care sector.

[0136] Cooling agents of formula (I) with particularly advantageous properties, i.e. a particularly strong and effective and preferably at the same time long-lasting cooling effect and / or a particularly efficient masking of any undesirable taste impression, are those in which R1 is an optionally substituted phenyl group, an optionally substituted benzyl group, an optionally substituted tolyl group, an optionally substituted xylolyl group, an optionally substituted phenol group, an optionally substituted dihydroxybenzene group, an optionally substituted pyridinyl group, an optionally substituted piperidinyl group, an optionally substituted tetrahydropyranyl group, an optionally substituted pyrrolyl group, an optionally substituted imidazolyl group, an optionally substituted pyrimidinyl group, an optionally substituted oxazolyl group, an optionally substituted indolyl group, an optionally substituted benzothiophenyl group, an optionally substituted furanyl group, an optionally substituted benzofuranyl group, an optionally substituted thiophenyl group, an optionally substituted 1,3-benzodioxolyl group, an optionally substituted ... R represents an optionally substituted phenyl group, an optionally substituted tolyl group, an optionally substituted xylolyl group, an optionally substituted phenol group, an optionally substituted dihydroxybenzene group, an optionally substituted pyridinyl group, an optionally substituted piperidinyl group, an optionally substituted tetrahydropyranyl group, an optionally substituted pyrrolyl group, an optionally substituted imidazolyl group, an optionally substituted pyrimidinyl group, an optionally substituted oxazolyl group, an optionally substituted indolyl group, an optionally substituted benzothiophenyl group, an optionally substituted furanyl group, an optionally substituted benzofuranyl group, an optionally substituted thiophenyl group, an optionally substituted benzodioxolyl group, an optionally substituted benzodioxanyl group, an optionally substituted morpholinyl group, or an optionally substituted quinolinyl group.

[0137] Further preferred are compounds in which R1 represents an optionally substituted pyridinyl group, an optionally substituted 1,3-benzodioxolyl group, an optionally substituted indolyl group, an optionally substituted furanyl group, an optionally substituted quinolinyl group, an optionally substituted benzofuranyl group, an optionally substituted benzyl group, an optionally substituted phenyl group, an optionally substituted thiophenyl group, an optionally substituted benzothiophenyl group, and / or R7 represents an optionally substituted pyridinyl group, an optionally substituted piperidinyl group, an optionally substituted 1,3-benzodioxolyl group, an optionally substituted dihydroxybenzene group, an optionally substituted benzodioxanyl group, an optionally substituted phenol group, an optionally substituted phenyl group, an optionally substituted thiophenyl group, and an optionally substituted tolyl group.

[0138] In this context, R1 and R7 may each be selected independently of one another, but may also represent the same group, whereby preferably R1 and R7 each represent an optionally substituted phenyl group and / or an optionally substituted pyridinyl group and / or an optionally substituted thiophenyl group and / or an optionally substituted 1,3-benzodioxolyl group. These compounds exhibit particularly good TRPM8 activity and can produce a sensory cooling effect of exceptional strength even with small doses.

[0139] Also preferred according to the invention are those coolants of formula (I) in which R1 represents an optionally substituted phenyl group, an optionally substituted pyridinyl group, an optionally substituted piperidinyl group, an optionally substituted 1,3-benzodioxolyl group, an optionally substituted benzodioxanyl group or an optionally substituted thiophenyl group, and / or R7 represents an optionally substituted phenyl group, an optionally substituted pyridinyl group, an optionally substituted 1,3-benzodioxolyl group, an optionally substituted indolyl group, an optionally substituted furanyl group, an optionally substituted benzofuranyl group, an optionally substituted thiophenyl group, an optionally substituted benzothiophenyl group or an optionally substituted quinolinyl group.

[0140] Particularly preferred is the following structure: R1 = optionally substituted phenyl and R7 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted benzodioxolyl or optionally substituted indolyl or optionally substituted furanyl or optionally substituted benzofuranyl or optionally substituted thiophenyl or optionally substituted benzothiophenyl or optionally substituted quinolinyl; or R1 = optionally substituted pyridinyl and R7 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted benzodioxolyl or optionally substituted indolyl or optionally substituted furanyl or optionally substituted benzofuranyl or optionally substituted thiophenyl or optionally substituted benzothiophenyl or optionally substituted quinolinyl; or R1 = optionally substituted piperidinyl and R7 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted benzodioxolyl or optionally substituted indolyl or optionally substituted furanyl or optionally substituted benzofuranyl or optionally substituted thiophenyl or optionally substituted benzothiophenyl or optionally substituted quinolinyl; or R1 = optionally substituted benzodioxolyl group and R7 = optionally substituted phenyl group or optionally substituted pyridinyl group or optionally substituted benzodioxolyl group or optionally substituted indolyl group or optionally substituted furanyl group or optionally substituted benzofuranyl group or optionally substituted thiophenyl group or optionally substituted benzothiophenyl group or optionally substituted quinolinyl group; or R1 = optionally substituted benzodioxanyl and R7 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted benzodioxolyl or optionally substituted indolyl or optionally substituted furanyl or optionally substituted benzofuranyl or optionally substituted thiophenyl or optionally substituted benzothiophenyl or optionally substituted quinolinyl; or R1 = optionally substituted thiophenyl and R7 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted benzodioxolyl or optionally substituted indolyl or optionally substituted furanyl or optionally substituted benzofuranyl or optionally substituted thiophenyl or optionally substituted benzothiophenyl or optionally substituted quinolinyl; or R7 = optionally substituted phenyl and R1 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted piperidinyl or optionally substituted benzodioxolyl or optionally substituted benzodioxanyl or optionally substituted thiophenyl; or R7 = optionally substituted pyridinyl and R1 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted piperidinyl or optionally substituted benzodioxolyl or optionally substituted benzodioxanyl or optionally substituted thiophenyl; or R7 = optionally substituted benzodioxolyl and R1 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted piperidinyl or optionally substituted benzodioxolyl or optionally substituted benzodioxanyl or optionally substituted thiophenyl; or R7 = optionally substituted indolyl and R1 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted piperidinyl or optionally substituted benzodioxolyl or optionally substituted benzodioxanyl or optionally substituted thiophenyl; or R7 = optionally substituted furanyl and R1 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted piperidinyl or optionally substituted benzodioxolyl or optionally substituted benzodioxanyl or optionally substituted thiophenyl; or R7 = optionally substituted benzofuranyl and R1 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted piperidinyl or optionally substituted benzodioxolyl or optionally substituted benzodioxanyl or optionally substituted thiophenyl; or R7 = optionally substituted thiophenyl and R1 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted piperidinyl or optionally substituted benzodioxolyl or optionally substituted benzodioxanyl or optionally substituted thiophenyl; or R7 = optionally substituted benzothiophenyl and R1 = optionally substituted phenyl or optionally substituted pyridinyl or optionally substituted piperidinyl or optionally substituted benzodioxolyl or optionally substituted benzodioxanyl or optionally substituted thiophenyl; or Those cooling agents of formula (I) with R7 = optionally substituted quinolinyl group and R1 = optionally substituted phenyl group or optionally substituted pyridinyl group or optionally substituted piperidinyl group or optionally substituted benzodioxolyl group or optionally substituted benzodioxanyl group or optionally substituted thiophenyl group.

[0141] In a further variant, the present invention relates to compounds of general formula (I) in which R1 and R7 are the same or different. Preferably, R1 and R7 are different.

[0142] In a further preferred variant, therefore, in general formula (I), R1 and R7 are the same, or R1 and R7 each independently represent an optionally substituted phenyl group and / or an optionally substituted pyridinyl group and / or an optionally substituted thiophenyl group and / or an optionally substituted 1,3-benzodioxolyl group. Particularly strong TRPM8 activity has been observed for different residues R1 and R7.

[0143] Particularly preferred according to the present invention are cooling agents of formula (II) in which R1 represents an optionally substituted phenyl group, an optionally substituted pyridinyl group, an optionally substituted piperidinyl group, an optionally substituted 1,3-benzodioxolyl group, an optionally substituted benzodioxanyl group or an optionally substituted thiophenyl group, and even more preferred are cooling agents of formula (II) in which R1 represents an optionally substituted phenyl group, an optionally substituted pyridinyl group or an optionally substituted 1,3-benzodioxolyl group or a thiophenyl group, with the phenyl group, pyridinyl group and 1,3-benzodioxolyl group being particularly preferred. Such substances have proven to be particularly effective cooling substances, particularly in sensory studies, and show significantly high cooling strength and TRPM8 activation.

[0144] In an even more preferred variation, R1 and R7, R2 and R5, and R3 and R6 are respectively identical in general formula (I), preferably forming a symmetrical amine compound.

[0145] In a particularly preferred variant of the present invention, general formula (I) contains at least one aromatic structure, for example at least one aromatic substituent R1 to R7, for example an optionally substituted phenyl group and / or an optionally substituted pyridinyl group and / or an optionally substituted thiophenyl group. Surprisingly, these compounds have been shown to produce a particularly intense and at the same time efficient cooling effect due to strong TRPM8 activation, whereby low concentrations of the substances according to the present invention are required to elicit a strong and efficient cooling sensation.

[0146] Furthermore, the aforementioned optionally substituted groups R1 and / or R7 may themselves optionally carry one or more substituents selected from the group consisting of optionally substituted piperidinyl, optionally substituted morpholinyl, optionally substituted hexamethyleneiminyl, optionally substituted pyridinyl, optionally substituted tetrahydropyrrolyl, optionally substituted alkyl-piperidinyl, optionally substituted thiomorpholinyl, optionally substituted pyrrolyl, optionally substituted thioalkoxy, optionally substituted alkoxy, and optionally substituted phenyl. Particularly preferred substituents are optionally substituted pyridinyl and / or optionally substituted alkoxy as substituents.

[0147] To achieve a particularly high TRPM8 activation or an efficient cooling effect, substitution of residues R1 and / or R7 by an optionally substituted piperidinyl group is particularly preferred.

[0148] Of the physiological cooling agents as defined by general formula (I) or general formula (II), compounds having the following structure are expressly excluded: [ka] [ka]

[0149] However, this exclusion does not apply as far as it relates to the use of these particular compounds as described in detail below.

[0150] Particularly preferred are physiological cooling agents of general formula (I) or general formula (II) selected from the group consisting of the compounds shown in Table 1.

[0151] [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 In particular compounds 1, 2, 4, 8, 11, 12, 13, 14, 15, 16, 17, 18, 22, 23, 24, 25, 26, 27, 29, 39, 40, 41, 42, 43, 47, 48, 49, 50, 51, 56, 58, 61, 64, 65, 71, 75, 76, 80, 83, 84, 85 and 87 and more preferably compounds 1 ... 5, 16, 17, 18, 22, 23, 24, 27, 39, 40, 41, 42, 43, 47, 49, 51, 56, 58, 61, 64, 75, 76, 80, 85 and 87 and particularly preferred compounds 1, 8, 11, 13, 14, 16, 17, 18, 22, 23, 24, 27, 39, 40, 41, 49, 56, 58, 61, 75, 76, 80, 85 and 87.

[0152] The coolants according to general formula (I) or (II) listed in Table 1 are present either in neutral, uncharged form or in the form of salts, such as acid addition salts with inorganic or organic acids, mono- or polycarboxylic acids, as described in detail above, and in this respect what has been said before applies here as well.

[0153] The cooling agents according to Table 1 can exist in stereoisomerically pure form or as mixtures of different stereoisomers and can therefore be used in the formulations in this manner.

[0154] Surprisingly, the compounds of the present invention exhibit particularly high TRPM8 activation, making them excellently suited as cooling agents.

[0155] The most preferred cooling agents, i.e., cooling agents that have particularly efficient and potent TRPM8 activation, i.e., efficient and potent cooling effects at low application rates, are compounds 1, 2, 4, 8, 11, 12, 13, 14, 15, 16, 17, 18, 22, 23, 24, 25, 26, 27, 29, 39, 40, 41, 42, 43, 47, 48, 49, 50, 51, 56, 58, 61, 64 , 65, 71, 75, 76, 80, 83, 84, 85 and 87 (TRPM8 activation ≧50%) and in particular compounds 1, 8, 11, 12, 13, 14, 15, 16, 17, 18, 22, 23, 24, 27, 39, 40, 41, 42, 43, 47, 49, 51, 56, 58, 61, 64, 75, 76, 80, 85 and 87 (TRPM8 activation ≧100%). Particularly preferred are compounds 1, 8, 11, 13, 14, 16, 17, 18, 22, 23, 24, 27, 39, 40, 41, 49, 56, 58, 61, 75, 76, 80, 85 and 87, which exhibit exceptionally high TRPM8 activity (TRPM8 activation ≧110%).

[0156] Due to their outstanding relative activation of TRPM8, compounds 8 (174.6% TRPM8 activity), 27 (129.7% TRPM8 activation) and 39 (116.4% TRPM8 activation) are most preferred.

[0157] In addition, compounds of formula (I) and (II) in which n and m are both 1 appear to be preferred with respect to the determined TRPM8 activity.

[0158] Even more preferred are physiological cooling agents of general formula (I) or (II) selected from the group consisting of the compounds shown in Table 2.

[0159] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] In particular, compounds 4, 8, 11, 12, 13, 14, 15, 16, 17, 18, 22, 23, 24, 25, 26, 27, 29, 39, 40, 41, 42, 43, 47, 49, 50, 51, 56, 58, 61, 64, 65, 71, 75, 76, 80, 83, 84, 85 and 87 (TRPM8 activity ≧50%) and more preferably compounds 8, 11, 12, 13, 14, 15, 16, 17, 18, 22, 23, 24, 27, 39, 40, 41, 42, 43, 47, 49, 51, 56, 58, 61, 64, 75, 76, 80, 85 and 87 (TRPM8 activity ≧100%) and particularly preferred compounds 8, 11, 13, 14, 16, 17, 18, 22, 23, 24, 27, 39, 40, 41, 49, 56, 58, 61, 75, 76, 80, 85 and 87 (TRPM8 activity ≧110%).

[0160] The cooling agents according to general formula (I) or (II) listed in Table 2 are present either in neutral, uncharged form or in the form of salts, such as acid addition salts with inorganic or organic acids, mono- or polycarboxylic acids, as described in detail above, and in this respect what has been said before applies here as well.

[0161] Particularly preferred are compounds of general formula (I) or (II) in which R1 is an optionally substituted phenyl group (aryl group) and / or an optionally substituted thiophenyl group (heteroaryl group) and / or an optionally substituted pyridinyl group (heteroaryl group) and / or an optionally substituted 1,3-benzodioxolyl group, and R7 is an optionally substituted phenyl group (aryl group) and / or an optionally substituted thiophenyl group (heteroaryl group) and / or an optionally substituted pyridinyl group (heteroaryl group) and / or an optionally substituted 1,3-benzodioxolyl group. These compounds may exhibit particularly high TRPM8 activity and a powerful cooling effect in sensation. Even with very small doses, the compounds exhibit significantly higher cooling intensity than prior art compounds.

[0162] In terms of their relative activation of TRPM8, compounds 8 (174.6% TRPM8 activation), 27 (129.7% TRPM8 activation) and 39 (116.4% TRPM8 activation) are most preferred.

[0163] Compound 8 is characterized in that R1 represents a benzodioxol-4-yl group and R7 represents a substituted heteroaryl group (here a substituted pyridinyl group). More precisely, the pyridinyl group is substituted by a heterocycloalkyl group (piperidinyl group).

[0164] Compound 27 is characterized in that R1 represents an anisole group, i.e., a substituted cyclic and six-membered aryl residue (here, a phenyl group substituted with an alkoxy group), and R7 represents a substituted heteroaryl group (here, substituted with a pyridinyl group). More precisely, the pyridinyl group is substituted with a heterocycloalkyl group (piperidinyl group).

[0165] In compound 39, on the other hand, for example, the aryl residue, ie, the phenyl group, is not further substituted.

[0166] These compounds have particularly high TRPM8 activity, resulting in a strong and efficient cooling effect, i.e., only small amounts of the compounds of the present invention are needed to produce a strong cooling effect (low EC50 values, see experimental data in Table 5). The strong cooling effect can be demonstrated by sensory evaluation, i.e., tasting representative samples. Thus, panelists evaluated the cooling effect of compound 27 with an EC of 6.84 and that of compound 39 with an EC of 7.02 (in each case at an applied dose of 5 ppm). Therefore, the sensory-evaluated cooling intensity, taking into account the amounts used, far exceeded that measured with the reference cooling substance WS-3 at a 6-fold higher concentration (amount used: 30 ppm; sensory-evaluated cooling intensity: 5.4).

[0167] Compound 40, in which R1 is an optionally substituted thiophenyl group (heteroaryl group) and R7 is an optionally substituted pyridinyl group (heteroaryl group), exhibits very high TRPM8 activity and a cooling effect that is perceived as being intense (sensory cooling intensity: 7.5), making it particularly suitable as an efficient cooling agent.

[0168] All of the compounds mentioned have in common that they contain at least one aromatic structure as residues R1 and / or R7, and they exhibit a very high sensory cooling strength and are characterized by an exceptionally high TRPM8 activation.

[0169] Based on the above table, it can be concluded that compounds of general formula (I) or (II), which may be further summarized and specified under general formula (IIIa) or (IIIb), in particular, exhibit particularly high TRPM8 activity and, consequently, a particularly efficient cooling effect as well as a high cooling strength. [ka] [ka] wherein the residues each have the meaning defined above according to formula (I), with the residues preferably representing the following groups: R1 preferably represents an optionally substituted aryl or heteroaryl group, more preferably an optionally substituted phenyl group or an optionally substituted thiophenyl group or an optionally substituted 1,3-benzodioxolyl group; In this case, preferably at least one of the residues R8, R9, R11 and R12 of the optionally substituted heteroaryl group does not represent a hydrogen atom, but preferably the residue R9 does not represent a hydrogen atom, in which case R9 preferably represents an optionally substituted heterocycloalkyl group, more preferably an optionally substituted piperidinyl group.

[0170] In a preferred variant of formula (IIIa), R represents an optionally substituted phenyl group, an optionally substituted benzyl group, an optionally substituted tolyl group, an optionally substituted xylolyl group, an optionally substituted phenol group, an optionally substituted dihydroxybenzene group, an optionally substituted pyridinyl group, an optionally substituted piperidinyl group, an optionally substituted tetrahydropyranyl group, an optionally substituted pyrrolyl group, an optionally substituted imidazolyl group, an optionally substituted pyrimidinyl group, an optionally substituted oxazolyl group, an optionally substituted indolyl group, an optionally substituted benzothiophenyl group, an optionally substituted furanyl group, an optionally substituted benzofuranyl group, an optionally substituted thiophenyl group, an optionally substituted 1,3-benzodioxolyl group, an optionally substituted benzodioxanyl group, an optionally substituted morpholinyl group, or an optionally substituted quinolinyl group.

[0171] In an even more preferred variation of formula (IIIa), R1 represents an optionally substituted benzodioxolyl group, or R1 represents an optionally substituted phenyl group, or R1 represents an optionally substituted benzodioxanyl group, or R1 represents an optionally substituted thiophenyl group, or R1 represents an optionally substituted pyridinyl group, or R1 represents an optionally substituted furanyl group. Such compounds exhibit particularly high TRPM8 activity.

[0172] In the most preferred variant of general formula (IIIa), R1 represents an optionally substituted benzodioxolyl group, or R1 represents an optionally substituted phenyl group, or R1 represents an optionally substituted thiophenyl group, or R1 represents an optionally substituted pyridinyl group. Such compounds have particularly high TRPM8 activity ≧100%.

[0173] Even more preferably, the R1-benzodioxolyl group of general formula (IIIa) is unsubstituted; or the R1-phenyl group of general formula (IIIa) is substituted with at least one OH group, or with at least one alkyl group, preferably methyl or ethyl or a mixture thereof, or with at least one alkoxy group, preferably ethoxy or methoxy or a mixture thereof, or with at least one phenyl group, or with at least one alkylthio group, preferably methylthio; or the R1-thiophenyl group is substituted with at least one alkoxy group, preferably ethoxy or methoxy or a mixture thereof.

[0174] At least one alkyl or alkoxy substituent is linked to the R-phenyl group at the ortho, meta, or para position relative to the C-N-C linker, preferably at the para position relative to the linker of general formula (IIIa). Such compounds exhibit particularly high TRPM8 activity.

[0175] The residues R2, R3, R4, R5 and R6 of general formula (IIIa) independently of one another represent hydrogen, a linear or branched alkyl group, preferably a methyl, ethyl, propyl, butyl, phenyl or benzyl group.

[0176] Residues R2, R3, R5 or R6 preferably each represent a hydrogen atom and / or an alkyl group. Even more preferred are methyl, ethyl or straight-chain or branched-chain propyl for R2, R3, R5 or R6, respectively, and even more preferred are methyl groups. However, hydrogen radicals are particularly preferred.

[0177] Preferably, R4 on the nitrogen atom of the C2-N-C1 linker is hydrogen, methyl or ethyl.

[0178] The residues R8, R9, R11 and R12 on the pyridine ring in formula (IIIa) independently represent hydrogen, an optionally substituted piperidinyl group, an optionally substituted morpholinyl group, an optionally substituted thiomorpholinyl group, an optionally substituted hexamethyleneimine group, an optionally substituted imidazolyl group, an optionally substituted pyridinyl group, an optionally substituted pyrrolidinyl group, an optionally substituted pyrrolyl group, an optionally substituted phenyl group, an alkylthio group, an alkoxy group, preferably an ethoxy group or a methoxy group, or an -N-(alkyl)2 group, where alkyl is preferably a methyl group or an ethyl group, or an optionally substituted cyclohexyl group.

[0179] In a preferred variant, in general formula (IIIa) at least one of the residues R8, R9, R11 and R12 is a piperidinyl group or a morpholinyl group, an optionally substituted thiomorpholinyl group or a hexamethyleneimine group, or an optionally substituted imidazolyl group, or a pyridinyl group or a pyrrolidinyl group or a pyrrolyl group or a phenyl group or an alkylthio group or an alkoxy group, preferably an ethoxy group or a methoxy group, or an -N-(alkyl)2 group, where alkyl is preferably a methyl group or an ethyl group, or a cyclohexyl group.

[0180] Preferably, at least one of the residues R8, R9, R11 and R12 in general formula (IIIa) is an optionally substituted piperidinyl group. The piperidinyl group is preferably bonded to the pyridine ring of general formula (IIIa) via a nitrogen atom at the ortho, meta or para position. Even more preferably, the piperidinyl group is bonded to the pyridine ring of formula (IIIa) via a nitrogen atom at the ortho position relative to the nitrogen atom.

[0181] Most preferably, the residue R9 in general formula (IIIa) represents a piperidinyl group or a morpholinyl group or a hexamethyleneimine group or a pyridinyl group or a pyrrolidinyl group or a pyrrolyl group or a phenyl group or an alkylthio group or an alkyloxy group, preferably an ethoxy group or a methoxy group, or an -N-(alkyl)2 group, where alkyl is preferably a methyl group or an ethyl group, or a cyclohexyl group, so that the residue defined previously is attached in the ortho position to the nitrogen atom of the pyridine ring of general formula (III).

[0182] Even more preferably, the piperidinyl group as previously defined is in turn at least monosubstituted by an alkyl group, preferably methyl, ethyl or straight or branched chain propyl, or at least monosubstituted by an alkoxy group, preferably methoxy or ethoxy.

[0183] Preferably, in general formula (IIIa), m and n are each independently 0, 1 or 2. Most preferably, m and n are each 1.

[0184] Particularly preferred compounds such as compounds 1, 8, 11, 12, 13, 14, 15, 16, 17, 18, 22, 23, 24, 27, 39, 40, 41, 42, 43, 47, 49, 51, 56, 58, 61, 64, 75, 76, 80, 85 and 87 have particularly good TRPM8 activation > 100%.

[0185] However, it should be noted that the nitrogen atom of the pyridine ring in formula (IIIa) may also be located at other positions on the heteroaromatic ring, for example, ortho or meta relative to the C2-N-C1 chain or C2-N-C1 linker, respectively. Preferably, the nitrogen atom of the pyridine ring is located para to the C2-N-C1 chain.

[0186] In a further variant, the nitrogen atom of the pyridine ring in formula (IIIa) can be replaced by a C atom, so that the aromatic ring with residues R8, R9, R11 and R12 represents phenyl, and the compounds of the present invention are represented by the above general formula (IIIb). For example, compounds 22c, 28, 53, 55, 59, 60, 62, 63, 64, 65, 66, 67, 69, 71, 72 or 82 correspond to this alternative structure of general formula (III).

[0187] For such structures, the definition of the residue or substituent is the same as for general formula (IIIa).

[0188] Preferably, in such structures of general formula (IIIb), R1 represents an optionally substituted benzodioxolyl group, or R1 represents an optionally substituted thiophenyl group, or R1 represents an optionally substituted phenyl group, or R1 is an optionally substituted chromanyl group or R1 represents an optionally substituted pyrimidinyl group.

[0189] In the most preferred variant of general formula (IIIb), R1 represents an optionally substituted benzodioxolyl group, or R1 represents an optionally substituted thiophenyl group, or R1 represents an optionally substituted phenyl group.

[0190] Even more preferably, the R1-benzodioxolyl group of general formula (IIIb) is unsubstituted; or the R1-thiophenyl group of general formula (IIIb) is unsubstituted or substituted with at least one alkyl group, preferably methyl; or the R1-phenyl group of general formula (IIIb) is substituted with at least one OH group, or with at least one alkyl group, preferably methyl or ethyl or a mixture thereof, or with at least one alkoxy group, preferably ethoxy or methoxy or a mixture thereof.

[0191] Most preferably, in general formula (IIIb), residue R1 is an alkoxylated, preferably methoxylated, phenyl group.

[0192] The residues R8, R9, R11 and R12 on the phenyl ring in formula (IIIb) independently of one another represent hydrogen, an optionally substituted pyridinyl group, an alkoxy group, preferably ethoxy or methoxy, or mixtures thereof, an optionally substituted cyclohexyl group, an -N(alkyl)2 group, preferably an -N(methyl)2 group, or an -NH-(C=O)-CH3 group.

[0193] In a preferred variant, in general formula (IIIb), at least one of the residues R8, R9, R11 and R12 is a pyridinyl group, an alkoxy group, preferably ethoxy or methoxy, or a mixture thereof, a cyclohexyl group, an -N(alkyl)2 group, preferably an -N(methyl)2 group, or an -NH-(C=O)-CH3 group.

[0194] Preferably, in general formula (IIIb), m and n are each independently 0, 1 or 2. Most preferably, m and n are each 1.

[0195] Among the compounds of general formula (IIIa) or (IIIb) defined above, compounds of general formula (IIIa) are most preferred. These cooling substances are characterized by high TRPM8 activation and simultaneously exhibit very high cooling intensity. Even at low concentrations, they produce a strong cooling effect, usually well below the EC50 reference value of 1.72 μM for substance WS-3, as shown in the experimental section below.

[0196] Of the physiological cooling agents defined by general formula (IIIa) or (IIIb), compounds having the following structure are expressly excluded: [ka] [ka]

[0197] However, this exclusion does not apply insofar as it relates to the use of these specific compounds as described in detail below.

[0198] As can be seen from the table, compounds according to formula (III) in which R1 represents an optionally substituted phenyl group and R9 represents an optionally substituted piperidinyl group, which can be derived from the following basic structure according to formula (IV), are also particularly preferred: [ka] During the ceremony, At the 1, 2, 4 or 5 position or at the 1, 2, 3, 4 or 5 of the 1', 2', 3', 4' or 5' positions of each aromatic moiety of general formula (IV), a substituent / residue as shown in formula (III) may in each case be optionally located, such as, for example, a piperidinyl group at the 2 position of a heteroaromatic ring or, for example, a methoxy group at the 3' position of a phenyl group. Suitable substituents are derived from the above description in conjunction with general formula (I) or (II) and the residues described therein.

[0199] Again, compounds in which m and n are each 1 and / or hydrogen atoms are preferred as residues, but compounds in which R2 to R6 preferably represent hydrogen atoms and / or alkyl groups such as methyl groups appear to be particularly advantageous.

[0200] Also preferred are compounds which can be derived from the following alternative structures according to formula (V), in which n and m are preferably each 1, and in which the above also applies with regard to the substitution possibilities: [ka]

[0201] With respect to the above description, the following preferred structures according to general formula (VI) are therefore also inherent: [ka] wherein at the 1, 2, 4 or 5 position or at 1, 2, 3 or 4 of the 1', 2' or 3' positions of each aromatic moiety of general formula (VI), substituents / residues may in each case be optionally located, such as, for example, a piperidinyl group at the 2-position of the heteroaromatic ring. Suitable substituents are derived from the above description in conjunction with general formula (I) or (II) and the residues described therein, so that the substitution possibilities and residues according to the above definitions within the framework of formula (I) and (II) are also retained and applicable here.

[0202] With respect to formulas (IV)-(VI), it should be noted that the nitrogen atom can be located at different positions on the heteroaromatic ring, such as ortho or meta relative to the C2-N-C1 chain. However, preferably, the nitrogen atom is located as shown. Such structures have been shown to be capable of inducing particularly high and efficient cooling effects and TRPM8 activity.

[0203] Since the optionally substituted heterocycloalkyl group, and particularly preferably the optionally substituted piperidinyl group, is preferably located at the 2-position, it has also been shown that optional substitution at the 1", 2", 3", 4", or 5" position of the piperidinyl group according to formula (VII) below results in particularly efficient cooling agents: [ka] wherein the residues R2 to R6 and R8, R11 and R12 and each substituent at the 1", 2", 3", 4", or 5" position may independently be a functional group as defined above or in the context of formulae (I) and (II), and R1 preferably represents an optionally substituted aryl or heteroaryl group, even more preferably an optionally substituted phenyl group or an optionally substituted thiophenyl group or an optionally substituted 1,3-benzodioxolyl group.

[0204] Here again, m and n are preferably 1.

[0205] These structures are particularly preferred because they are characterized by efficient cooling effect and high TRPM8 activity.

[0206] The physiological amine coolants of the present invention are not known from the prior art, but can be prepared according to generally known standard methods of preparative organic chemistry, which are shown in generalized form in the following scheme:

[0207] [ka]

[0208] The haloalkyl derivative is dissolved in anhydrous DCM and reacted with the corresponding pyridine derivative and a nitrogen-containing base.

[0209] [ka]

[0210] The aldehyde is dissolved in THF and reacted with the corresponding amine, followed by the addition of a reducing agent.

[0211] [ka]

[0212] The corresponding halogen derivative and amine were dissolved in anhydrous toluene and reacted with tri-tert-butylphosphine and potassium phosphate. The corresponding halogen derivative (1.0 equiv.) and amine (1.1 equiv.) were dissolved in anhydrous toluene and tri-tert-butylphosphine (0.1 equiv.) and potassium phosphate (3.0 equiv.) were added. The reaction mixture was purged with argon for 15 minutes, Pd2(dba)3 was added, and the mixture was purged with argon again for 15 minutes. The reaction mixture was stirred at 100 °C overnight. Water (160 mL) and DCM (160 mL) were added for workup. The resulting phases were separated, and the aqueous phase was extracted with DCM (3 × 160 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent removed in vacuo. The crude product was purified by column chromatography (reverse phase, 0–100% acetonitrile in water).

[0213] [ka]

[0214] A suspension of the amine and Cs2CO3 in DCM is reacted with the desired halogen substitution reagent.

[0215] [ka]

[0216] The corresponding carboxylic acid, HBTU and EDC×HCl are dissolved and then reacted with the desired amine and DIPEA.

[0217] [ka]

[0218] The desired amine is dissolved in anhydrous THF under an argon atmosphere, and borane dimethyl sulfide complex is added slowly at 0°C.

[0219] In principle, the present invention is directed to the individual compounds of formula (I) and formula (II) (and consequently formulae (III) to (VII)) and their use as coolants or coolant mixtures. Nevertheless, the compounds are also suitable for mixing with other, already known, coolants.

[0220] Therefore, another object of the present invention is to (a) one, two, three or more coolants of formula (I) or (II), or as set out in Table 1 or Table 2, and as defined above; and optionally (b) at least one additional physiological cooling agent; and / or optionally (c) at least one solvent The present invention relates to a physiological cooling agent mixture comprising or consisting of:

[0221] In a preferred embodiment, the present invention relates to a cooling agent mixture comprising at least one compound according to formula (I) and / or (II) or (III) to (VII) as defined above. Optionally, the cooling agent mixture also comprises a further physiological cooling agent and optionally at least one suitable solvent.

[0222] A particular advantage of such a coolant mixture is that a synergistic enhancement of the cooling effect can be observed.

[0223] Suitable cooling agents forming component (b) and different from the cooling agents forming component (a) include menthol, menthol methyl ether (FEMA GRAS 4054), monomethyl glutamate (FEMA GRAS 4006), menthoxy-1,2-propanediol (FEMA GRAS 3784), dimethyl 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 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 carbonate propylene glycol (FEMA GRAS 3806), N-ethyl menthyl oxamate, monomethyl succinate (FEMA GRAS 3810), WS-3 (N-ethyl-p-menthane-3-carboxamide, FEMA GRAS 3455), menthol carbonate ethylene glycol (FEMA GRAS 3805), WS-5 (3-(p-menthane-3-carboxamide) 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 GRAS 4053), 2,3-dihydroxy-p-menthane, 3,3,5-trimethylcyclohexanone glycerol ketal, menthyl pyrrolidone carboxylic acid, (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 GRAS 4285), 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, a mixture of 2,2,5,6,6-pentamethyl-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)-2-isopropyl-5-methylcyclohexanecarboxamide, 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)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 Diphenol, 1-(4-methoxyphenyl)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)vinyl-4-methoxybenzoic acid, 2-(1-isopropyl-6-methyl-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoic acid, (Z)-2-(1-isopropyl-5-methyl-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)vinyl-4-methoxybenzoic acid Fragrance acids, 3-alkyl-p-methane-3-ol derivatives, fenchyl, D-bornyl, L-bornyl, exo-norbornyl, 2-methylisobornyl, 2-ethylfenchyl, 2-methylbornyl, cis-pinan-2-yl, verbanyl and isobornyl derivatives, menthyl oxamate derivatives, menthyl 3-oxocarboxylic acid esters, N-alpha-(menthanecarbonyl) amino acid amides, p-menthanecarboxamides and WS-23 analogs, (-) The substance is selected from the group consisting of -(1R,2R,4S)-dihydroumbellrol, 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 Ingredient Manufacturers of America, and GRAS is defined as Good As Safe. The FEMA GRAS designation means that the substance has been examined by standard methods and is deemed toxicologically safe.

[0224] In principle, all known substances with a cooling effect are suitable as component (b). However, for food safety reasons, compounds with FEMA GRAS designation are preferred, or if the cooling mixture in question requires this.

[0225] A first important representative of substances forming component (b) is monomenthyl succinate (FEMA GRAS 3810). Its succinate ester and the analogous monomenthyl glutarate (FEMA GRAS 4006) are important representatives of monomenthyl esters based on dicarboxylic and polycarboxylic acids.

[0226] A next important group of menthol compounds that are preferred in the sense of the present invention comprises carbonate esters of menthol and polyols, such as glycols, glycerol, or carbohydrates, such as menthol ethylene glycol carbonate (FEMA GRAS 3805 = Frescolat® MGC), menthol propylene glycol carbonate (FEMA GRAS 3784 = Frescolat® MPC), menthol 2-methyl-1,2-propanediol carbonate (FEMA GRAS 3849), or the corresponding sugar derivatives. Also preferred are N-(4-cyanomethylphenyl)-p-menthanecarboxamide (FEMA GRAS 4496), N-(2-(pyridin-2-yl)ethyl)-3-p-menthanecarboxamide (FEMA GRAS 4549) and (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide (FEMA GRAS 4788) as component (b).

[0227] In the context of the present invention, the menthol compounds menthyl lactate (FEMA GRAS 3748 = Frescolat® ML) and in particular menthone glyceryl acetal (FEMA GRAS 3807) or menthone glyceryl ketal (FEMA GRAS 3808), marketed under the name Frescolat® MGA, are preferred.

[0228] This group of compounds also includes 3-(1-methoxy)-1,2-propanediol, also known as Coolant 10 (FEMA GRAS 3784), and 3-(1-methoxy)-2-methyl-1,2-propanediol, which has an additional methyl group (FEMA GRAS 3849).

[0229] Among the above-mentioned substances, menthone glyceryl acetal / ketal and menthone lactate and menthol ethylene glycol carbonate and menthol propylene glycol carbonate, which are marketed by the Applicant under the names Frescolat® MGA, Frescolat® ML, Frescolat® MGC and Frescolat® MPC, have proven to be particularly advantageous.

[0230] Further preferred compounds are taken from the table below (Table 3).

[0231] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0232] In the 1970s, the first menthol compounds were developed that have a C-C bond in the 3-position, many of which can be used in the context of the present invention. These substances are generally called WS-type. The basic entity is a menthol derivative (WS-1) in which the hydroxyl group is replaced by a carboxyl group. All other WS-type compounds, such as, for example, the preferred species WS-3, WS-4, WS-5, WS-12, WS-14, WS-23, WS-27, and WS-30 in the context of the present invention, or the esters or N-substituted amides of the aforementioned compounds, are derived from this structure.

[0233] More particularly preferred is the coolant 2-(p-tolyloxy)-N-(1H-pyrazol-5-yl)-N-((thiophen-2-yl)methyl)acetamide (FEMA GRAS 4809), as well as 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).

[0234] The coolant mixture of the present invention may contain component (a) and component (b) in a weight ratio of about 0.1:99.9 to about 99.0 to 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.

[0235] In order to utilize and optimize the cooling effect of the coolant and ensure easy processing in flavors and semi-finished or other finished products, the coolant needs to be converted into a solution before processing. However, in some cases the solubility of the coolant according to the invention is insufficient, which causes problems during storage, handling or further processing.

[0236] On the other hand, the aforementioned coolant forming component (b) of the coolant mixture may act as a solvent for the coolant(s) forming component (a) of the coolant mixture.

[0237] Advantageously, the coolant mixture according to the invention also comprises at least one solvent as a further component (c).

[0238] Single solvents or solvent systems have proven advantageous, in which the solvent is selected from the group consisting of benzyl alcohol, 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and mixtures thereof.

[0239] Optamint is, for example, a mixture of over 50 different natural essential oils or natural or naturally occurring flavoring substances. Optamint preferably has a variable composition of various (partially fractionated) oils, representing, for example, a mixture of various peppermint and spearmint oils, and eucalyptus globulus oil, star anise oil, menthol, menthone, isomenthone, menthyl acetate, anethole, eucalyptol, etc. Therefore, exact reproduction of the composition of Optamint is not possible. The Optamint® product series is commercially available from Symrise AG.

[0240] For example, benzyl alcohol or 2-phenylethanol or benzyl benzoate may be used as solvents in the coolant mixture according to the invention.

[0241] Benzyl alcohol or 2-phenylethanol or benzyl benzoate, for example, can be used to put the coolants of the present invention into solution and provide a stable solution, i.e., a coolant mixture for proper storage.

[0242] Solvent systems, i.e. solvent combinations of two or more solvents, can also be used to dissolve the cooling agent according to the invention. Particularly with regard to the latter field of application, the use of solvents that can also exhibit a cooling effect can avoid further steps in the (final) manufacturing process.

[0243] In an exemplary embodiment, therefore, 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).

[0244] Suitable according to the invention are, for example, binary solvent systems of benzyl alcohol and a further substance selected from the group consisting of 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol, and further coolants as described above as component (b).

[0245] Also suitable are combinations or mixtures of binary solvents containing or consisting of benzyl alcohol together with another solvent, such as those selected from the group consisting of 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), and benzyl alcohol and menthone carboxylic acid esters and amides.

[0246] Furthermore, the following binary solvent combinations or mixtures are suitable: mixtures are 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).

[0247] Suitable coolant mixtures within the meaning of the present invention therefore contain as solvent (c) combinations or mixtures of binary solvents, for example as described above.

[0248] A mixture of binary solvents in the sense of the present invention has, for example, the following ratios of solvent (1):solvent (2): a ratio of 10:1 to 1:10, preferably a ratio of 8:2 to 2:8, even more preferably a ratio of 6:4 to 4:6, most preferably a ratio of 5:5.

[0249] The aforementioned preferred binary solvent mixtures are capable of dissolving the coolant of the present invention and stably retaining the coolant in a wide range of solvents, preferably in amounts of 2% to 50% by weight, more preferably 5% to 40% by weight, and even more preferably 5% to 20% by weight, depending on the solvent or combination of solvents.

[0250] In another exemplary embodiment, the solvent or solvent system for the coolant of the present invention is a ternary system of three solvents selected from the group consisting of benzyl alcohol, 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol, and an additional coolant such as those described above as component (b).

[0251] Suitable here are, for example, ternary solvent combinations or mixtures of benzyl alcohol with two further 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 further coolants as described above as component (b).

[0252] Suitable are, for example, ternary solvent combinations or mixtures which contain or consist of benzyl alcohol together with two further solvents, such as 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 The menthol and menthol propylene glycol carbonate are selected from the group consisting of menthone carboxylate esters and amides, 2-phenylethanol and menthol propylene glycol carbonate (Frescolat® MPC), triacetin and benzyl benzoate, 2-phenylethanol and peppermint oil, anethole and triacetin, peppermint oil and menthyl lactate (Frescolat® ML), triacetin and menthol glyceryl acetal (Frescolat® MGA), Optamint and menthyl lactate (Frescolat® ML), triethyl citrate and menthol ethylene glycol carbonate (Frescolat® MGC), benzyl benzoate and menthol ethylene glycol carbonate (Frescolat® MGC), 2-phenylethanol and triethyl citrate, triethyl citrate and diethyl succinate, peppermint oil and menthyl lactate (Frescolat® ML), and ethanol and menthyl lactate (Frescolat® ML).

[0253] Additionally, the following ternary solvent combinations or mixtures: e.g. triethyl citrate, triacetin and 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 and menthol carbonate ethylene glycol (Frescolat® MGC) and anethole, 2-phenylethanol, Optamint and propylene glycol, Diethyl succinate, triacetin and menthol, triacetin, benzyl benzoate and menthyl lactate (Frescolat® ML), Anethole and 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 carboxylic acid menthane esters and amides, Triacetin, 2-phenylethanol, and menthol propylene glycol carbonate (Frescolat® MPC), Menthyl lactate (Frescolat® ML) with 2-phenylethanol and peppermint oil, Anethole, triacetin and menthone glyceryl acetal (Frescolat® MGA), Optamint with benzyl benzoate and menthyl lactate (Frescolat® ML), and Also suitable is benzyl benzoate, triethyl citrate and menthol ethylene glycol carbonate (Frescolat® MGC).

[0254] Ternary solvent mixtures in the sense of the present invention have, 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.

[0255] The aforementioned preferred ternary solvent mixtures have been shown to be particularly good in their ability to dissolve the coolants of the present invention, stably and variably maintaining the coolants in solution over a wide range in amounts of 2% to 50% by weight, preferably 5% to 40% by weight, and more preferably 5% to 20% by weight, depending on the solvent or combination of solvents.

[0256] This has the advantage that the cooling agent(s) according to the invention can thereby be prepared in variable amounts suitable for the final formulation, thereby providing a wide range of cooling agent mixtures in which the cooling agent(s) are present in dissolved form.

[0257] In another preferred embodiment, the solvent or solvent system for the coolant according to the present invention is a quaternary system of four solvents selected from the group consisting of benzyl alcohol, 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol and a further coolant as described above as component (b).

[0258] Suitable here are, for example, quaternary solvent combinations of benzyl alcohol with three further 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 further coolants as described above as component (b).

[0259] A suitable quaternary solvent combination or mixture is, for example, one that contains or consists of benzyl alcohol together with three additional solvents, 2-phenylethanol, triethyl citrate, and triacetin, Peppermint oil, 2-phenylethanol, and triethyl citrate, Triethyl citrate and 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 methoxy-2-methyl-1,2-propanediol, Menthone glyceryl acetal (Frescolat® MGA), triacetin and anethole are selected from the group consisting of:

[0260] The following quaternary solvent combinations and solvent mixtures: Anethole, triacetin, peppermint oil, menthol carbonate, ethylene glycol (Frescolat® MGC), Triacetin, ethanol, 2-phenylethanol, and peppermint oil, 2-phenylethanol, Optamint, diethyl succinate, and peppermint oil, Anethole, 2-phenylethanol, benzyl alcohol and triacetin are also suitable.

[0261] The aforementioned preferred quaternary solvent mixtures have been shown to be particularly good at dissolving the coolants of the present invention, and have been shown to stably and variably maintain the coolants in solution over a wide range of amounts, depending on the solvent or combination of solvents, from 2% to 50% by weight, preferably from 5% to 40% by weight, and more preferably from 5% to 20% by weight.

[0262] This has the advantage that the cooling agent(s) according to the invention can thereby be prepared in variable amounts suitable for the final formulation, thereby providing a wide range of cooling agent mixtures in which the cooling agent(s) are present in dissolved form.

[0263] 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 very particularly preferably 5% to 8% by weight, based on the total coolant mixture, with the proviso that components (a) and / or (b) and / or (c) together amount to 100%.

[0264] This composition of the coolant mixture according to the present invention is particularly advantageous as it allows for control of the amount of coolant(s) in the final formulation.

[0265] In particular for oral care compositions, the final product preferably contains the coolant(s) 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, even more preferably 0.5% to 15% by weight or 1% to 5% by weight based on the weight of the final product.

[0266] A suitable coolant mixture according to the invention may, for example, have the following composition: 5-10% by weight of refrigerant(s) in 95-90% by weight of benzyl alcohol, or 8-10% by weight of refrigerant(s) in 92-90% by weight of benzyl alcohol, or 1-4% by weight of refrigerant(s) in 99-96% by weight of triethyl citrate, or 1-3% by weight of coolant(s) in 99-97% by weight of triacetin, or 3-6% by weight of refrigerant(s) in 97-94% by weight of diethyl succinate, or 5-15% by weight of refrigerant(s) in 95-85% by weight of 2-phenylethanol, or 5-10% by weight of a cooling agent(s) in 95-90% by weight of benzyl benzoate, or 1-3% by weight of coolant(s) in 99-97% by weight Optamint, or 1 to 4 wt. % of a refrigerant(s) in 99 to 96 wt. % of another refrigerant listed above as component (b), or 2-4% by weight of refrigerant(s) in 98-96% by weight of propylene glycol, or 0.5 to 2% by weight of refrigerant(s) in 95.5 to 98% by weight of ethanol, or 0.5 to 2% by weight of coolant(s) in 95.5 to 98% by weight of menthyl acetate, or 1-4% by weight of cooling agent(s) in 99-96% by weight of peppermint oil, or · consisting of or having 2-5% by weight of coolant(s) in 98-95% by weight of anethole; Thereby, both components in the coolant mixture (coolant(s) and solvent) always add up to 100% by weight. For example, a suitable coolant mixture according to the invention consists of 5-10% by weight of coolant(s) in 95-90% by weight of benzyl alcohol, particularly preferably 8-10% by weight of coolant(s) in 92-90% by weight of benzyl alcohol.

[0267] Another aspect of the present invention is (d) one, two, three or more refrigerants of formula (I) or formula (II) (or any of formulas (I) to (VII)), or as set out in Table 1 or Table 2 and as defined above; (e) at least one flavoring agent.

[0268] A particular advantage of these mixtures or flavor preparations is that the cooling agents, even at low concentrations, are able to mask the unpleasant, e.g., bitter or astringent, taste of flavorings, especially sweeteners, while at the same time imparting a strong and efficient cooling effect.

[0269] The preparations according to the invention may contain 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, citronellyl acetate, cyclohexyl acetate, cymene, damascone, decalactone, dihydrochloride, benzophenone, benzothiazole, benzo ...thiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole, benzothiazole Marine, dimethyl anthranilate, dimethyl anthranilate, dodecalactone, ethoxyethyl acetate, ethyl butyrate, ethyl butyrate, ethyl caprate, ethyl caproate, ethyl crotonate, ethyl furaneol, ethyl guaiacol, ethyl isobutyrate, ethyl isovalerate, ethyl lactate, ethyl methyl butyrate, ethyl propionate, eucalyptol, eugenol, ethyl heptylate, 4-(p-hydroxyphenyl)-2-butanone, gamma-decalactone, geraniol, geranyl acetate, geranyl acetate, grapefruit aldehyde, dihydrojas Methyl monoate (e.g., Hedion®), heliotropin, 2-heptanone, 3-heptanone, 4-heptanone, trans-2-heptenal, cis-4-heptenal, trans-2-hexenal, cis-3-hexenol, trans-2-hexenoic acid, trans-3-hexenoic acid, cis-2-hexenyl acetate, cis-3-hexenyl acetate, cis-3-hexenyl caproate, trans-2-hexenyl caproate, cis-3-hexenyl formate, cis-2-hexyl acetate, cis-3-hexyl acetate, trans acetate ans-2-hexyl, cis-3-hexyl formate, para-hydroxybenzyl acetone, isoamyl alcohol, isoamyl isovalerate, isobutyl butyrate, isobutyraldehyde, isoeugenol methyl ether, isopropyl methylthiazole, lauric acid, levulinic acid, linalool, linalool oxide, linalyl acetate, menthol, menthofuran, methyl anthranilate, methylbutanol, methylbutyric acid, 2-methylbutyl acetate, methyl caproate, methyl cinnamate, 5-methylfurfural, 3,2,2-methylcyclopentenolone, 6,5,2-Methylheptenone, methyl dihydrojasmonate, methyl jasmonate, 2-methyl methylbutyrate, 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, 2-octanol, 3-octanol, 1,3-octenol, 1-octyl acetate, 3-octyl acetate, palmitic acid, paraldehyde, phellandrene, pentanedione, phenylethyl acetate, phenylethyl alcohol, phenylethyl alcohol, phenylethyl isovalerate, piperonal, propionaldehyde Hydride, propyl butyrate, pulegone, pulegol, sinensal, sulfurol, terpinene, terpineol, terpinolene, 8,3-thiomenthanone, 4,4,2-thiomethylpentanone, thymol, delta-undecalactone, gamma-undecalactone, valencene, valeric acid, vanillin, acetoin, ethyl vanillin, ethyl vanillin isobutyrate (= 3-ethoxy-4-isobutyryloxybenzaldehyde), 2,5-dimethyl-4-hydroxy-3(2H)-furanone and its derivatives (preferably homofuraneol (= 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone), 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, massoilactone, deltadecalactone, tuberolactone), methyl sorbate, divanillin, 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone, 2-hydroxy-3-methyl-2-cyclopentenone, 3-hydroxy-4,5 -Dimethyl-2(5H)-furanone, acetic acid isoamyl ester, butyric acid ethyl ester, butyric acid n-butyl ester, butyric acid isoamyl ester, 3-methylbutyric acid ethyl ester, n-hexanoic acid ethyl ester, n-hexanoic acid allyl ester, n-hexanoic acid n-butyl ester, n-octanoic acid ethyl ester, 3-methyl-3-phenylglycidic acid ethyl ester, 2-trans-4-cis-decadienoic acid ethyl ester, 4-(p-hydroxyphenyl)-2-butanone, 1,1-dimethoxy-2,2,5-trimethyl-4-hexane, 2,6-dimethyl- 5-heptan-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 Pyrazine, 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, 1-penten-3-one, 4-hydroxy-2,5-dimethyl-3(2H)-furanone, guaiacol, 3-hydroxy-4,It may contain one or more flavoring substances (component (e)) selected from the group formed by 5-dimethyl-2(5H)-furanone, 3-hydroxy-4-methyl-5-ethyl-2(5H)-furanone, cinnamaldehyde, cinnam alcohol, methyl salicylate, isopulegol, and the stereoisomers, enantiomers, positional isomers, diastereomers, cis / trans isomers or epimers of these substances (not expressly mentioned here).

[0270] For purposes of the present invention, artificial and natural sweeteners and sweetener enhancers are also particularly suitable as flavoring substances of component (e). These include: Sugar alcohols (e.g., erythritol, threitol, arabitol, ribotol, xylitol, sorbitol, mannitol, dulcitol, lactitol); Proteins (e.g., miraculin, monellin, thaumatin, curculin, brazzein); Artificial sweeteners (e.g., Magap, sodium cyclamate, acesulfame K, neohesperidin dihydrochalcone, saccharin sodium salt, aspartame, super aspartame, neotame, alitame, sucralose, stevinoside, rebaudioside, ragduname, carrelam, sucrononate, sucrooctate, monatin, phenylodulcin); Sweet-tasting amino acids (e.g., glycine, D-leucine, D-threonine, D-asparagine, D-phenylalanine, D-tryptophan, L-proline); Sweet-tasting low molecular weight substances, such as hernandulcin, dihydrochalcone glycosides, glycyrrhizin, glycyrrhetinic acid, their derivatives and salts, extracts of licorice (Glycyrrhizza glabra ssp.), extracts of Lippia dulcis, extracts of Momordica ssp. and / or Plant extracts, such as Momordica grosvenori [Luo Han Guo] and the mogrosides obtained therefrom, Hydrangea dulcis or Stevia ssp. (e.g. Stevia rebaudiana) extracts or steviosides obtained therefrom, may be selected from the group consisting of:

[0271] Component (e) comprises at least one of the flavoring substances mentioned above.

[0272] The flavored product of the present invention may contain component (d) and component (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 particularly about 40:60 to about 60:40.

[0273] In a further preferred variant, the one or more cooling agent(s) or cooling agent mixtures or aroma formulations are present in encapsulated form. This is particularly interesting, for example, when capsules loaded with one or more cooling agent(s) are applied to fabric surfaces, for example as components of fabric softeners or laundry post-treatment agents, or when capsules loaded with one or more cooling agent(s) are used to obtain a finish, for example, by force application onto pantyhose.

[0274] Capsules are spherical aggregates containing at least one solid or liquid core enclosed in at least one continuous shell. During encapsulation, one or more cooling agent(s) or cooling agent mixtures or flavor preparations are encapsulated by a coating / envelope material such that they are in the form of macrocapsules with a diameter of about 0.1 to about 5 mm or microcapsules with a diameter of about 0.0001 to about 0.1 mm.

[0275] Consequently, a further embodiment of the present invention also relates to a physiological cooling agent or a physiological cooling agent mixture or a flavor preparation in encapsulated form.

[0276] Suitable coating materials are, for example, starch, including its degradation products and chemically or physically produced derivatives (especially 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.

[0277] Among the above-mentioned coating materials, gelatin (especially pork, beef, chicken and / or fish gelatin) having a swelling ratio of 20 or more, preferably 24 or more, is preferred. Furthermore, gelatin is particularly preferred because it is readily available and can be obtained with a variety of swelling ratios.

[0278] Also preferred are maltodextrins (especially based on cereals, in particular corn, wheat, tapioca or potato), preferably having a DE value in the range of 10 to 20. Further preferred are celluloses (e.g. cellulose ethers), alginates (sodium alginate), carrageenans (e.g. beta-, iota-, lambda- and / or kappa-carrageenans), gum arabic, curdlan and / or agar.

[0279] Also preferred are alginate capsules such as those described in detail in the following publications: EP 0389700 A1, US Pat. No. 4,251,195, US Pat. No. 6,214,376, WO 2003055587 or WO 2004050069 A1.

[0280] In another preferred embodiment, the capsule shell is composed of a melamine-formaldehyde resin or a coacervation product of a cationic monomer or biopolymer (e.g., chitosan) and an anionic monomer, such as a (meth)acrylate or alginate.

[0281] Capsules are generally microdispersed or solid phases coated with a film-forming polymer; during their production, the polymer is deposited on the material to be coated after emulsification and coacervation or interfacial polymerization. Another process incorporates molten wax into a matrix ("microsponge"), which can then be coated with film-forming polymer as microparticles. A third method involves coating the particles instead with polyelectrolytes of different charges (layer-by-layer method). Microscopically small capsules can be dried and used like powders.

[0282] In addition to mononuclear microcapsules, polynuclear aggregates, also called microspheres, containing two or more nuclei distributed within a continuous shell material are also known. Mononuclear or polynuclear microcapsules can also be encapsulated by additional secondary, tertiary, etc. shells. The shells may be made of natural, semi-synthetic, or synthetic materials. Natural shell materials include, for example, gum arabic, agar, agarose, maltodextrin, alginic acid or its salts, 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 encapsulating materials include chemically modified celluloses, particularly cellulose esters and ethers, such as cellulose acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and carboxymethyl cellulose, and starch derivatives, particularly starch ethers and esters. Synthetic coating materials are, for example, polymers such as polyacrylates, polyamides, polyvinyl alcohols or polyvinylpyrrolidones.

[0283] Examples of prior art coating / encapsulating materials for the production of microcapsules are the following commercially available products (in each case the encapsulating material is indicated in brackets): Hallcrest Microcapsules (gelatin, gum arabic), Coletica Thalaspheres (marine collagen), Lipotec Millicapseln (alginic acid, 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) and Primaspheres and Primasponges (chitosan, alginate) and Primasys (phospholipids).

[0284] Chitosan microcapsules and methods for their preparation are well known from the prior art: WO01 / 01926, WO01 / 01927, WO01 / 01928, 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 substance are, for example, (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) The dispersed matrix can be obtained by treating it with an aqueous solution of an anionic polymer, optionally removing the oil phase in the process.

[0285] The above steps (1) and (3) are interchangeable in that an anionic polymer is used in place of a cationic polymer in step (1) and vice versa.

[0286] Capsules can also be produced by alternatively coating the active substance with layers of differently charged polyelectrolytes (layer-by-layer technique). In this context, reference is made to European Patent EP 1064088 B1 (Max Planck Society).

[0287] Two essential properties of new cooling substances or new cooling substance mixtures are, as mentioned, on the one hand, to modulate the TRPM8 receptor as an antagonist or agonist and in this way induce a physiological response, i.e., a strong and efficient cooling effect on the skin or mucous membranes, and, on the other hand, to reduce or mask unpleasant flavors. However, the main emphasis should be placed on the ability to induce a strong and efficient cooling effect even when small amounts are applied.

[0288] Therefore, a further aspect of the present invention relates to the use of a physiological cooling agent or a mixture of physiological cooling agents 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.

[0289] In the use according to the invention, the TRPM8 receptor is contacted with at least one cooling agent according to the invention or a physiological cooling agent mixture according to the invention, and a Ca2+ level is measured in a cellular activity assay using cells recombinantly expressing the human TRPM8 receptor. 2+ It regulates the permeability of these cells to ions.

[0290] Suitable modulators can act either as antagonists or agonists only, particularly as agonists only, or as both antagonists and agonists, particularly where agonist or antagonist effects can occur depending on the concentration of each modulator selected.

[0291] The "agonist" mediates activation of the TRPM8 receptor, i.e., Ca delivery to cold-sensitive neurons. 2+It induces the inflow of ions, providing a cooling sensation.

[0292] On the other hand, an "antagonist" is a compound that is able to oppose this activation of the TRPM8 receptor.

[0293] The modulator of the present invention, i.e., a physiological cooling agent or mixture of cooling agents, can exert its effect by binding reversibly or irreversibly, specifically or nonspecifically, to the TRPM8 receptor molecule. Typically, binding occurs non-covalently through ionic and / or non-ionic, e.g., hydrophobic, interactions with the receptor molecule. The term "specific" includes both exclusive interactions with one or more different TRPM8 receptor molecules (e.g., TRPM8 molecules of different origins or different isomers). On the other hand, the term "non-specific" refers to the case where the modulator interacts with multiple different receptor molecules that differ in function and / or sequence, resulting in the desired agonistic and / or antagonistic modulation of the TRPM8 receptor (as described above).

[0294] In the use according to the invention, preferably in the variants described above as preferred, the modulator is a modulator of cellular Ca 2+ It has an agonist or antagonist effect on ion permeability.

[0295] Particularly preferred is a variant of the use according to the invention in which the modulator is a TRPM8 receptor agonist.

[0296] Due to its physiological properties of inducing a cooling effect on the skin or mucous membranes, another aspect of the present invention relates to the use of the cooling agent according to the invention or the cooling agent mixture according to the invention for producing a physiological cooling effect on the skin or mucous membranes in humans or animals.

[0297] Alternatively, the cooling agent of the present invention or the cooling agent mixture of the present invention is used to induce a cooling effect by packaging containing the physiological cooling agent or physiological cooling agent mixture, or by fabrics containing the physiological cooling agent or physiological cooling agent mixture.

[0298] Due to its additional property, i.e., the property of reducing or masking unpleasant, e.g., bitter or astringent, flavors, a further aspect of the present invention relates to the use of the physiological cooling agent according to the present invention or the cooling agent mixture according to the present invention to improve the flavor characteristics of flavors. In this way, known taste drawbacks of flavors, especially sweeteners, such as stevioside, can be reduced or masked. In particular, hot, bitter or metallic aftertastes are effectively reduced or masked even in small amounts.

[0299] The cooling agent according to the invention or the physiological cooling agent mixture according to the invention or the flavor preparation according to the invention have a wide range of applications, in particular in food, nutritional supplements, cosmetics or pharmaceuticals, animal feed, textiles, packaging or tobacco products.

[0300] In particular, due to their cooling and / or flavor enhancing properties, the physiological cooling agents or physiological cooling agent mixtures or flavor preparations according to the invention are used in the manufacture of foods, dietary supplements, cosmetics or pharmaceuticals, animal feed, textiles, packaging or tobacco products.

[0301] Therefore, a further aspect of the present invention is the use of one or more cooling agents according to the invention or a cooling agent mixture according to the invention or a flavor preparation according to the invention for the production of a food, a dietary supplement, a cosmetic or pharmaceutical product, an animal feed, a textile, packaging or a tobacco product.

[0302] Based on the described advantageous properties, the cooling agent according to the invention as represented and defined by general formula (I) or (II) is suitable for the use according to the invention, i.e. for producing a physiological cooling effect on the skin or mucous membranes of humans or animals, or for inducing a cooling effect, or for improving the taste properties of flavoring substances, in particular for reducing or masking unpleasant tastes, or for use as a modulator for the preparation of foods, dietary supplements, cosmetics or pharmaceuticals, animal feed, textiles, packaging or tobacco products, or for use as a drug, as described in detail herein, preferably selected from the group consisting of the compounds set out in Table 4.

[0303] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15]

[0304] Of the above compounds, the use of compounds 8, 27 and 39 is most preferred due to their significant TRPM8 activation, EC50 values ​​and cooling potency.

[0305] In a further aspect, the present invention therefore also encompasses a food, dietary supplement, cosmetic or pharmaceutical product, animal feed, textile, packaging or tobacco product comprising the physiological cooling agent or physiological cooling agent mixture according to the present invention or the flavor preparation according to the present invention.

[0306] The content of one or more cooling agents depends on the type and use of the product, and is preferably about 0.1 ppm to 10% by weight, preferably 1% to 10% by weight, based on the total weight of the final product. For oral care applications, such as toothpaste or mouthwash, the content is 0.1 ppm to 500 ppm of one or more cooling agents.

[0307] Broad concentration ranges typically used to provide the desired level of sensitivity modulation 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.

[0308] Preferably, the food product is a bakery or confectionery product, e.g. bread, dry biscuits, cakes, other pastries, confectionery (e.g. chocolate, chocolate bar products, other bar products, fruit gums, hard and soft caramels, chewing gum), alcoholic or non-alcoholic beverages (e.g. coffee, tea, iced tea, wine, wine-based drinks, beer, beer-based drinks, liqueurs, spirits, brandy, (carbonated) fruit-based soft drinks, (carbonated) isotonic drinks, (carbonated) soft drinks, nectar, spirits, fruit and vegetable Juices, fruit 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 sausage or raw sausage preparations, seasoned or marinated fresh or smoked meat products), eggs or egg products (dried eggs, egg whites, egg yolks), cereal products (e.g., breakfast cereals, cereal bars, pre-cooked prepared rice products), dairy products (e.g., milk drinks, buttermilk drinks, fresh ice cream, yogurt, kefir, cream cheese, soft cheese, hard cheese, These include: dairy products (such as oat cheese, milk powder, whey, whey drinks, butter, buttermilk, partially or totally hydrolyzed milk protein products), products made from soy protein or other soy fractions (such as soy milk and products made therefrom, fruit drinks containing soy protein, preparations containing soy lecithin, fermented products such as tofu or tempeh or products derived therefrom), products derived from other plant protein sources, such as oat protein drinks, fruit preparations (such as jams, fruit ice cream, fruit sauces, fruit fillings), vegetable preparations (such as ketchup, sauces, dried vegetables, frozen vegetables, pre-cooked vegetables, canned vegetables), snack foods (such as baked or fried chips or potato dough products, corn or peanut based extrusions), fat-based products or emulsions thereof (such as mayonnaise, tartar sauce, dressings), other ready-to-eat foods and soups (such as dry soups, instant soups, pre-cooked soups), spices, seasoning mixtures and condiments used in particular, for example, in the snacks sector.

[0309] The above-mentioned food products contain, in addition to conventional food ingredients, at least an effective, i.e. cooling, amount of at least one cooling agent according to the invention or a cooling agent mixture according to the invention or a flavor preparation according to the invention.

[0310] The content of the cooling agent or cooling agent mixture or flavor preparation in these preparations is preferably from about 0.1% to about 10% by weight, in particular from about 1% to about 2% by weight, based on the total weight of the final preparation.

[0311] Suitable excipients may be used in the preparation of food products according to the present invention, including, but not limited to, emulsifiers, thickeners, food acids, acidity regulators, vitamins, antioxidants, flavor enhancers, agents for masking unpleasant flavors, food colorants, and the like.

[0312] Emulsifiers are characterized by the important property of being soluble in both water and fat. They usually consist of a fat-soluble portion and a water-soluble portion. They are used whenever water and oil are to be mixed into a consistent, homogeneous mixture.

[0313] Emulsifiers: Suitable emulsifiers used in the food processing industry are ascorbyl palmitate (E304), lecithin (E322), phosphoric acid (E338), sodium phosphate (E339), potassium phosphate (E340), calcium phosphate (E341), magnesium orthophosphate (E343), propylene glycol alginate (E405), polyoxyethylene stearate (8) (E430), polyoxyethylene stearate (E431), ammonium phosphatide (E442), sodium and potassium phosphate (E450), sodium salts of fatty acids (E470a), mono- and diglycerides of fatty acids (E471), acetic acid. The fatty acids are selected from monoglycerides (E472a), lactic acid monoglyceride (E472b), citric acid monoglyceride (E472c), tartaric acid monoglyceride (E472d), diacetyltartaric acid monoglyceride (E472e), sugar esters of fatty acids (E473), sugar glycerides (E474), polyglycerides of fatty acids (E475), polyglycerol polyricinoleate (E476), propylene glycol esters of fatty acids (E477), sodium stearoyl lactylate (E481), calcium stearoyl 2-lactylate (E482), stearyl tartrate (E483), sorbitan monostearate (E491), stearic acid (E570).

[0314] Thickeners: Thickeners are substances that are primarily capable of binding water. Removing unbound water increases the viscosity. Above a characteristic concentration of each thickener, this effect is supplemented by a network effect, which usually leads to a disproportionate increase in viscosity. In this case, the molecules "communicate" with each other, or "entangle" with each other. Most thickeners are linear or branched polymers (e.g., polysaccharides or proteins) that can interact with each other via intermolecular interactions such as hydrogen bonding, hydrophobic interactions, or ionic relationships. Extreme examples of thickeners are layered silicates (bentonite, hectorite) or hydrated SiO2 particles that are dispersed as particles and are able to bind water in a solid-like structure or interact with each other due to the interactions described. Examples are: E400-Alginate E401-Sodium alginate E402-Potassium alginate E403-Ammonium alginate E404- Calcium alginate E405-Propylene glycol alginate E406-Agar E407- Coloragin, Furceleran E407- Locust Bean Gum E412- Guar Gum E413-Tragacanth E414- Gum Arabic E41- Xanthan gum E416-Karaya (Indian Tragacanth) E417-Tara gum (Peruvian locust bean gum) E418-Guerlain E440- Pectin, Opecta E440ii-amidated pectin E460- Microcrystalline cellulose, cellulose powder E461- Methylcellulose E462- Ethyl cellulose E46 3-Hydroxypropylcellulose E465- Methylethylcellulose E466 - Carboxymethylcellulose, sodium carboxymethylcellulose.

[0315] Food acids: Foods may contain carboxylic acids. Acids in the sense of the present invention are preferably acids permitted in food, in particular the acids mentioned herein: E260-Acetic acid E270-Lactic Acid E290 - Carbon dioxide E296-Malic acid E297-Fumaric acid E330-Citric Acid E331-Sodium citrate E332-Potassium citrate E333-Calcium citrate E334-Tartaric acid E335-Sodium tartrate E336-Potassium tartrate E337-Sodium potassium tartrate E338-phosphate E353-Metatartaric acid E354-Calcium tartrate E355-Adipic acid E363-Succinic acid E380 - Triammonium citrate E513-Sulfuric acid E574-Gluconic acid E575-Glucono-delta-lactone

[0316] Acidity regulators: Acidity regulators are food additives that maintain the desired pH value of foods by maintaining their acidity or basicity. They are mostly organic acids and their salts, carbonates, and more rarely inorganic acids and their salts. The addition of acidity regulators partially increases the stability and concentration of foods, causes the desired precipitation, and improves the effectiveness of preservatives. In contrast to acidifiers, they are not used to change the taste of foods. Their effect is based on the formation of a buffer system in foods where the pH value does not change or changes only slightly upon the addition of acidic or basic substances. Examples are: E170-Calcium Carbonate E260-263 - Acetic acid and acetate salts E270-Lactic Acid E296-Malic acid E297-Fumaric acid E325-327-Lactate (lactic acid) E330-333 - Citric acid and citrate salts E334~337-Tartaric acid and tartrates E339~341-orthophosphates E350-352-Malate (Malic acid) E450~452-Di-, tri- and polyphosphates E500-504- Carbonates (carbonic acid) E507-Hydrogen Acid and Chlorides E513~517-Sulfuric acid and sulfate salts E524~528-hydroxide E529~530-Oxide E355-357-Adipic acid and adipate salts E574-578 - Gluconic acid and gluconate.

[0317] Vitamins: In another embodiment of the present invention, the food additive may include vitamins as another optional group of additives. Vitamins act through a wide variety of biochemical mechanisms. Some act like hormones, regulate mineral metabolism (e.g., vitamin D), or affect cell and tissue growth and cell differentiation (e.g., some forms of vitamin A). Others are antioxidants (e.g., vitamin E and, under certain circumstances, vitamin C). Most vitamins (e.g., vitamin B) are precursors for enzyme cofactors that help enzymes catalyze specific metabolic processes. In this context, vitamins can bind tightly to enzymes, for example, as part of a prosthetic group; an example is biotin, which is part of an enzyme involved in the accumulation of fatty acids. On the other hand, vitamins can bind less tightly and then act as cocatalysts, for example, as chemical groups that can easily split and transfer electrons between molecules. For example, folic acid delivers methyl, formyl, and methylene groups to cells. While their support in enzyme-substrate reactions is well known, other properties are also very important for the body.

[0318] In the context of the present invention, vitamins Vitamin A (retinol, retinal, beta-carotene), Vitamin B1 (thiamine), Vitamin B2 (lioflavin), Vitamin B3 (niacin, niacinamide), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine, pyridoxyamine, palidoxal), Vitamin B7 (biotin), Vitamin B9 (folic acid, folinic acid), Vitamin B 12(cyanobalamin, hydroxycobalamin, methylcobalamin), Vitamin C (ascorbic acid), Vitamin D (cholecalciferol), Vitamin E (tocopherol, tocotrienol) and Vitamin K (phylloquinone, menaquinone) The substance is selected from the group consisting of: In addition to ascorbic acid, preferred vitamins are from the group of tocopherols.

[0319] Antioxidants: Both natural and artificial antioxidants are used in the food industry. The main difference between natural and artificial antioxidants is that the former are naturally present in foods, while the latter are artificially produced. For example, natural antioxidants, when used as food additives, are derived from vegetable oils. For example, vitamin E, also known as tocopherol, is often produced from soybean oil. Synthetic antioxidants, such as propyl gallate, octyl gallate, and dodecyl gallate, on the other hand, are obtained by chemical synthesis. Gallates may cause allergies in sensitive individuals.Other antioxidants that can be used in the compositions of the invention are sulfur dioxide (E220), sulfites, sodium sulfite (E221), sodium hydrogen sulfite (E222), sodium disulfite (E223), potassium disulfite (E224), calcium sulfite (E226), calcium hydrogen sulfite (E227), potassium hydrogen sulfite (E228), lactic acid (E270), ascorbic acid (E300), sodium L-ascorbate (E301), calcium L-ascorbate (E302), potassium hydroxybenzoate (E303), potassium hydroxybenzoate (E304), potassium hydroxybenzoate (E305), potassium hydroxybenzoate (E306), potassium hydroxybenzoate (E307), potassium hydroxybenzoate (E308), potassium hydroxybenzoate (E309), potassium hydroxybenzoate (E310), potassium hydroxybenzoate (E311), potassium hydroxybenzoate (E312), potassium hydroxybenzoate (E313), potassium hydroxybenzoate (E314), potassium hydroxybenzoate (E315), potassium hydroxybenzoate (E316), potassium hydroxybenzoate (E317), potassium hydroxybenzoate (E318), potassium hydroxybenzoate (E319), potassium hydroxybenzoate (E320), potassium hydroxybenzoate (E321), potassium hydroxybenzoate (E322), potassium hydroxybenzoate (E323), potassium hydroxybenzoate (E324), potassium hydroxybenzoate (E325), potassium hydroxybenzoate (E326), potassium hydroxybenzoate (E327), potassium hydroxybenzoate (E328), potassium hydroxybenzoate (E329), potassium hydroxybenzoate (E330), potassium hydroxybenzoate (E331), potassium hydroxybenzoate (E332), potassium hydroxybenzoate (E333), potassium hydroxybenzoate (E334), potassium hydroxybenzoate (E335), potassium hydroxybenzoate (E3 (E302), ascorbic acid esters (E304), tocopherols (E306), alpha-tocopherol (E307), gamma-tocopherol (E308), delta-tocopherol (E309), propyl gallate (E310), octyl gallate (E311), dodecyl gallate (E312), isoascorbic acid (E315), sodium isoascorbate (E316), tertiary butylhydroquinone (TBHQ, E319), butylhydroquinone (TBHQ, E319). Dihydroxyanisole (E320), butylhydroxytoluene (E321), lecithin (E322), citric acid (E330), salts of citric acid (E331 and E332), sodium citrate (E331), potassium citrate (E332), calcium disodium EDTA (E385), diphosphates (E450), disodium diphosphate (E450a), trisodium diphosphate (E450b), tetrasodium diphosphate (E450c), dipotassium diphosphate (E450d). , tripotassium diphosphate (E450e), dicalcium diphosphate (E450f), dibasic calcium diphosphate (E450g), triphosphate (E451), pentasodium triphosphate (E451a), pentapotassium triphosphate (E451b), polyphosphate 452), sodium polyphosphate (E452a), potassium polyphosphate (E452b), sodium calcium polyphosphate (E452c), calcium polyphosphate (E452d), tin(II) chloride (E512).

[0320] Flavor enhancers: These preparations may contain flavor mixtures and additional flavoring substances to enhance the salty, possibly slightly sour, and / or umami flavor impression. Thus, the products or flavor mixtures according to the invention are used in combination with at least one further substance suitable for enhancing a pleasant taste impression (salty, umami, optionally slightly sour). Preferred compounds are salty compounds and salt-enriched compounds. Preferred compounds are disclosed in WO2007 / 045566. Also preferred are umami compounds as described in WO2008 / 046895 and EP1989944.

[0321] Flavoring agents: Furthermore, the flavor preparations and products thereof preferred according to the invention may also contain flavoring substances (flavoring agents) that mask the perception of bitter and / or astringent taste. (Further) flavoring agents are, for example, those listed below: nucleotides (e.g., adenosine 5'-monophosphate, cytidine 5'-monophosphate) or pharmaceutically acceptable salts thereof, lactisole, sodium salts (e.g., sodium chloride, sodium lactate, sodium citrate, sodium acetate, sodium gluconate), further hydroxyflavanones (e.g., eriodictyol, homoeriodictyol or their sodium salts), in particular according to US 2002 / 0188019, DE 10 2004 041 Hydroxybenzoic acid amides according to 496 (e.g., 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-dihydroxybenzoic acid-N-2-(4-hydroxybenzoyl)amide hydroxy-3-methoxyphenyl)-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 (adancamide), 4-hydroxybenzoic acid vanillylamide), hydroxydeoxybenzoins (e.g. 2-(4-hydroxy-3-methoxyphenyl)-1-(2,4,6-trihydroxyphenyl)ethanone, 1-(2,4-dihydroxyphenyl)-2-(4-hydroxy-3-methoxyphenyl)ethanone, 1-(2-hydroxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxy-phenyl)ethanone), amino acids (e.g. gamma-aminobutyric acid according to WO 2005 / 096841 for reducing or masking unpleasant taste impressions such as bitterness), malic acid glycoside according to WO 2006 / 003107, salty taste mixtures according to PCT / EP2006 / 067120, diacetyl trimer according to WO 2006 / 058893, mixtures of whey protein with substances that mask bitterness such as lecithin and / or ginger in accordance with WO 2007 / 003527.

[0322] Flavoring substances: Preferred flavoring substances are those that cause a sweet odor impression, whereby further flavoring substances that cause a sweet odor impression are preferably vanillin, ethyl vanillin, ethyl vanillin isobutyrate (=3-ethoxy-4-isobutyryloxybenzaldehyde), furaneol (2,5-dimethyl-4-hydroxy-3(2H)-furanone) and derivatives (e.g., homofuraneol, 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone), homofuranol (2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone), 2H)-furanone and 5-ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and derivatives (e.g., ethyl maltol), coumarin and derivatives, gamma-lactones (e.g., gamma-undecalactone, gamma-nonalactone), delta-lactones (e.g., 4-methyldeltalactone, massoilactone, deltadecalactone, tuberolactone), methyl sorbate, divanillin, 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)furanone, 2-hydroxy-3-methyl-2 -cyclopentenone, 3-hydroxy-4,5-dimethyl-2(5H)-furanone, fruit esters and fruit lactones (e.g., n-butyl acetate, isoamyl acetate, ethyl propionate, ethyl butyrate, n-butyl butyrate, isoamyl butyrate, 3-methylbutyrate ethyl ester, n-hexanoic acid ethyl ester, n-hexanoic acid allyl ester, n-hexanoic acid n-butyl ester, n-octanoic acid ethyl ester, 3-methyl-3-phenylglycidic acid ethyl ester, 2-trans- 4-(p-hydroxyphenyl)-2-butanone, 1,1-dimethoxy-2,2,5-trimethyl-4-hexane, 2,6-dimethyl-5-heptan-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.

[0323] Active substances for masking unpleasant tastes: Furthermore, the oral preparations may also contain additional substances that help mask bitter and / or astringent taste impressions. These additional taste masking agents are, for example, those listed below: nucleotides (e.g., adenosine 5'-monophosphate, cytidine 5'-monophosphate) or their physiologically acceptable salts, lactisole, 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 (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-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 as 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 as described in WO 2006 / 106023); hydroxyphenylalkanediones, for example gingeredione-[2], gingeredione-[3], gingeredione-[4], dehydrogingeredione-[2], dehydrogingeredione-[3], dehydrogingeredione-[4]) (especially as described in WO 2007 / 003527); diacetyl trimer (especially W gamma-aminobutyric acid (especially as described in WO 2006 / 058893); divanillin (especially as described in WO 2004 / 078302) and 4-hydroxydihydrochalcones (preferably as described in US 2008 / 0227867 A1), in particular phloretin and davidigenin; mixtures of amino acids or whey proteins with lecithin; hesperetin as disclosed in WO 2007 / 014879; 4-hydroxydihydrochalcones as disclosed in WO 2007 / 107596 or propentylphenylglycosides (chavicol glycosides) as described in EP 1955601 A1 or Rubus as described in EP 2298084 A1. The umami compounds are selected from extracts from Hydrangea suavissimus, extracts from Hydrangea macrophylla, pellitorinus and the derived aroma compositions as described in EP 2008530 A1, umami compounds as described in WO 2008 / 046895 A1 and EP 1989944 A1, umami compounds as described in EP 2064959 A1 resp. EP 2135516 A1, vanillyl lignans, enterodiol, and N-decadienoyl amino acids and mixtures thereof;

[0324] Food Colorants: Food colorants, or colorants for short, are food additives used to color foods. Colorants are divided into the groups of natural colorants and synthetic colorants. Colorants found in nature are also of synthetic origin. Naturally occurring colorants are synthetic replicas of naturally occurring coloring substances.Suitable colorants for use in the present compositions are curcumin (E100), riboflavin (lactoflavin, vitamin B2, E101), tartrazine (E102), quinoline yellow (E104), yellow orange S (yellow orange RGL, E110), cochineal (carminic acid, true carmine, E120), azorubine (carmoisine, E122), amaranth (E123), cochineal red A (ponceau 4R, Victoria scarlet 4R, E124), erythrosine (E127), aloe barbadensis leaf extract (E128), citric acid (E129), citric acid (E130), citric acid (E131), citric acid (E132), citric acid (E133), citric acid (E134), citric acid (E135), citric acid (E136), citric acid (E137), citric acid (E138), citric acid (E139), citric acid (E140), citric acid (E141), citric acid (E142), citric acid (E143), citric acid (E144), citric acid (E145), citric acid (E146), citric acid (E147), citric acid (E148), citric acid (E149), citric acid (E150), citric acid (E151), citric acid (E152), citric acid (E153), citric acid (E154), citric acid (E155), citric acid (E156), citric acid (E157), citric acid (E158), citric acid (E159), citric acid (E160), citric acid (E161), citric acid (E162), La Red AC (E129), Patent Blue V (E131), Indigotin (Indigo Carmine, E132), Brilliant Blue FCF (Patent Blue AE, Amido Blue AE, E133), Chlorophyll, Chlorophyllin (E140), Copper complex of chlorophyll, Copper chlorophyllin complex (E141), Brilliant Acid Green (Green S, E142), Caramel colour (Sugar tone, E150a), Caustic sulphite caramel (E150b), Ammonia caramel (E150c), Ammonium sulphite Near Caramel (E150d), Brilliant Black FCF, Brilliant Black PN, Black PN (E151), Vegetable Charcoal Powder (E153), Brown FK (E154), Brown HT (E155), Carotene (Carotene, E160a), Annatto (Bixin, Norbixin, E160b), Capsanthin (Capsorubin, E160c), Lycopene (E160d), Beta-Apo-8'-Carotenal (Apocarotenal, Beta-Apocarotenal, E160e), Beta-Apo-8'- The additives are selected from the group consisting of carotenic acid ethyl ester (C30), apocarotenic acid ester, beta-carotenic acid ester (E160f), lutein (xanthophyll, E161b), canthaxanthin (E161g), betaine, bethene red (E162), anthocyanins (E163), calcium carbonate (E170), titanium dioxide (E171), iron oxide, iron hydroxide (E172), aluminium (E173), silver (E174), gold (E175), little brinjal black, ruby ​​black (E180).

[0325] Another aspect of the present invention relates to cosmetic or pharmaceutical preparations containing one or more of the cooling agents according to the present invention or the cooling agent mixtures according to the present invention or the flavor preparations according to the present invention.

[0326] The compositions according to the invention may in particular be skin cosmetic, hair cosmetic, skin, hygiene or pharmaceutical compositions, and in particular the active ingredients according to the invention, in particular those with a cooling effect, are used in skin and / or hair cosmetics or as oral care agents.

[0327] The hair or skin care compositions or preparations according to the present invention are preferably in the form of emulsions, dispersions, suspensions, aqueous surfactant preparations, milky lotions, creams, balms, ointments, gels, granules, powders, sticks such as lipstick, foams, aerosols, or sprays. Such formulations are well suited for topical preparations. Suitable emulsions are oil-in-water emulsions, water-in-oil emulsions, or microemulsions. Hair or skin cosmetics are typically used for application to the skin (topical) or hair. A "topical preparation" is, for example, a preparation suitable for applying an active substance to the skin in a fine distribution that can be absorbed by the skin. Suitable preparations for this purpose are, for example, aqueous and aqueous-alcoholic solutions, sprays, foams, foam aerosols, ointments, aqueous gels, O / W or W / O emulsions, microemulsions, or cosmetic sticks. According to one embodiment of the cosmetic composition of the present invention, the cosmetic composition comprises a carrier. Preferred carriers are water, gas, aqueous liquids, oils, gels, emulsions or microemulsions, dispersions, or mixtures thereof, which exhibit good skin compatibility. Particularly advantageous for topical preparations are aqueous gels, emulsions, or microemulsions.

[0328] The teachings of the present invention also include the use of the active ingredients described herein for medical purposes, in particular in pharmaceutical compositions for the treatment of individuals, preferably mammals, in particular humans, livestock or domestic animals. For this purpose, the active ingredients are administered in the form of a pharmaceutical composition comprising at least one active ingredient according to the present invention and optionally further active ingredients, together with a pharmaceutically acceptable excipient. These compositions may be administered, for example, orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.

[0329] Examples of suitable pharmaceutical formulations or compositions include solid dosage forms such as powders, granules, tablets, lozenges, sachets, cachets, dragees, capsules, e.g., hard or soft gelatin capsules; semi-solid dosage forms such as suppositories or vaginal dosage forms; ointments, creams, hydrogels, pastes, or plasters; and liquid dosage forms such as solutions, emulsions, particularly oil-in-water emulsions, suspensions, e.g., lotions, preparations for injection and infusion, eye drops, and ear drops. Implantable delivery devices can also be used to administer the inhibitors of the present invention. Liposomes, microspheres, or polymer matrices can also be used. Pharmaceutical formulations that can be used include, for example, cooling syrups, wound ointments, or wound sprays. Active substances that have an unpleasant taste themselves can also be incorporated into plasters or tablets.

[0330] A further aspect of the invention therefore includes the cooling agent or cooling agent mixture according to the invention as a medicament, in particular for use in relieving pain and inflammatory conditions of the skin and mucous membranes. Due to their cooling properties, the cooling agents according to the invention are particularly suitable for preventing, combating or relieving coughs, colds, inflammation, sore throat or hoarseness.

[0331] Furthermore, the substances and preparations described herein are suitable for the treatment of inflammatory conditions of the skin and mucous membranes and joints due to their efficient cooling effect.

[0332] Due to its property of regulating the receptor TRPM8, its gene expression, i.e., the expression of the TRPM8 gene, is upregulated in cancer, for example, prostate cancer, and the medicament of the present invention is preferably used in oncology, preferably in the treatment of prostate cancer or bladder cancer, or also for the treatment of bladder weakness. The corresponding protein in a cell is coded by the corresponding gene in the cell nucleus. The reading (transcription) of a gene in the nucleus leads to the production of messenger RNA (mRNA), which is then "translated" (translation) into protein in the cell by ribosomes. The totality of both processes is often referred to as gene expression.

[0333] However, astringent, bitter and / or metallic tastes are not only found with flavors and sweeteners as described above, but also with many active pharmaceutical ingredients, which make them difficult to take, especially in children. Typical examples of such active pharmaceutical ingredients are aspirin, minoxidil, erythromycin, phenistil, 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.

[0334] The present invention therefore also encompasses a medicament comprising one or more cooling agents according to the invention or cooling agent mixtures according to the invention or aromatic preparations according to the invention in combination with at least one further active pharmaceutical ingredient selected from the group consisting of aspirin, minoxidil, erythromycin, phenistil, betamethasone, ibuprofen, ketoprofen, dicyclofenac, metronidazole, acyclovir, imiquimod, terbafine, cyclopiroxolamine, paracetamol, and mixtures thereof.

[0335] Tests with volunteers have shown that the cooling agent according to the invention or the cooling agent mixture according to the invention enhances the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), especially ibuprofen and ketoprofen, beyond the cooling effect, which was also unexpected for a person skilled in the art. Therefore, the present invention also relates to the use in combination with pharmaceutical agents, especially of the non-steroidal anti-inflammatory drug (NSAID) type.

[0336] Such pharmaceutical combinations are therefore particularly beneficial for use in the treatment of inflammatory conditions of the skin and mucous membranes and joints.

[0337] The medicament may contain the cooling agent according to the invention or the cooling agent mixture according to the invention and the pharmaceutically active substance in a weight ratio of about 1:99 to about 10:90, in particular 2:98 to 5:95.

[0338] The physiological cooling effect is also used in the formulation of ointments for wounds and burns as well as preparations for insect bites.

[0339] In the preparation of the cosmetic or pharmaceutical product according to the invention, the cooling agent(s) or cooling agent mixture according to the invention is usually mixed with or diluted with 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 (one or more simultaneously contained cooling active ingredients according to the invention) can vary within a wide range and is in each case approximately from about 0.05 ppm to 10% by weight, preferably from 0.1 ppm to 10% by weight, based on the total weight of the preparation.

[0340] Suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Furthermore, the formulation may contain pharmaceutically acceptable carriers or common excipients, such as lubricants, e.g., tallow, magnesium stearate, and mineral oil, wetting agents, emulsifiers and suspending agents, preservatives, e.g., methyl and propyl hydroxybenzoates; antioxidants; anti-irritants; chelating agents; lubrication aids; emulsion stabilizers, film-forming agents; gel-forming agents; odor masking agents; taste correctors; resins; hydrocolloids; solvents; solubilizers; neutralizing agents; permeation accelerators; pigments; quaternary ammonium compounds; refatting and superfatting agents; ointments; cream or oil bases; silicone derivatives; spreading aids; stabilizers; sterilizing agents; suppository bases; tablet excipients, e.g., binders, fillers, lubricants, disintegrants, or coating agents; propellants; desiccants; opacifiers; thickeners; waxes; plasticizers; and white oils. Relevant embodiments are based on expert knowledge and are fully described in the relevant technical literature.

[0341] The preparations according to the invention may further contain cosmetic and / or dermatological and / or pharmaceutical active ingredients in addition to conventional additives or excipients. Non-limiting examples of suitable further active substances are:

[0342] Cosmetic and / or skin active ingredients: Suitable cosmetic and / or skin active ingredients include, for example, coloring active ingredients, skin and hair pigmentation agents, light colorants; tanning agents, bleaching agents, keratin-hardening agents, antibacterial active ingredients, light filter active ingredients, water-repellent active ingredients, superemulsifying active ingredients, keratolytic and keratinogenic active ingredients, antidandruff active ingredients, anti-inflammatory agents, keratinizing active ingredients, antioxidant or free radical scavenging active ingredients, skin moisturizing or humectants, refatting active ingredients, active ingredients with antierythema or antiallergic activity, branched-chain fatty acids such as 18-methyleicosanoic acid and mixtures thereof. Artificial skin tanning active ingredients suitable for tanning skin without natural or artificial UV irradiation include, for example, dihydroxyacetone, alloxan, and walnut shell extract. Suitable keratin-hardening agents are typically active ingredients used in antiperspirants, such as potassium aluminum sulfate, aluminum hydroxychloride, and aluminum lactate.

[0343] Antibacterial agents: Antibacterial agents are used to destroy microorganisms and inhibit their growth. Therefore, they serve as both antiseptics and deodorizing substances to reduce the occurrence or intensity of body odor. These include, for example, common antiseptics known to those skilled in the art, such as p-hydroxybenzoic acid esters, imidazolidinyl urea, formaldehyde, sorbic acid, benzoic acid, salicylic acid, etc. Examples of such deodorizing substances include zinc ricinoleate, triclosan, undecylenic acid alkylolamide, citric acid triethyl ester, chlorhexidine, etc.

[0344] Auxiliary substances and additives: Auxiliary substances and additives suitable for the production of hair or skin cosmetics are familiar to those skilled in the art and can be found in the cosmetic manuals, i.e., the corresponding technical literature. The excipients and additives added are preferably cosmetically and / or pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are those known to be usable in the fields of pharmaceutics, food technology, and related fields, in particular those listed in the relevant pharmacopoeias (e.g., DAB, Ph.Eur., BP, NF), as well as other excipients whose properties are consistent with physiological application.

[0345] Suitable excipients may be lubricants, wetting agents, emulsifiers and suspending agents, preservatives, antioxidants, anti-irritants, chelating agents, emulsion stabilizers, film-forming agents, gel-forming agents, odor masking agents, hydrocolloids, solvents, solubilizers, neutralizing agents, permeation accelerators, pigments, quaternary ammonium compounds, refatting and superfatting agents, ointment, cream or oil bases; silicone derivatives, stabilizers, sterilizing agents, propellants, desiccants, opacifiers, thickeners, waxes, plasticizers, white oils. Design in this respect is based on expert knowledge as found in the relevant technical literature.

[0346] Other suitable additives are selected from perfume oils, hair polymers, hair and skin conditioners, graft polymers, water-soluble or dispersible silicone-containing polymers, light stabilizers, bleaches, care products, colorants, tints, tanning agents, dyes, viscosity enhancers, moisturizers, refatting agents, collagen, protein hydrolysates, lipids, antioxidants, antifoaming agents, antistatic agents, emollients, plasticizers, peroxide decomposers.

[0347] The preparations according to the invention may further contain typical adjuvants and additives, such as mild surfactants, oil bodies, emulsifiers, pearlescent waxes, viscosity agents, thickeners, superfatting agents, stabilizers, polymers, silicone compounds, fats, waxes, lecithin, phospholipids, UV photoprotective factors, moisturizers, biogenic agents, antioxidants, deodorants, antiperspirants, antidandruff agents, film-forming agents, swelling agents, insect repellents, self-tanning agents, tyrosine inhibitors (demipigmenting agents), hydrotropes, solubilizers, preservatives, perfume oils, colorants, etc.

[0348] Surfactants: Anionic, nonionic, cationic, and / or amphiphilic or amphoteric surfactants may be present as surface active agents, and their proportion in the drug is usually about 1% to 70% by weight, preferably 5% to 50% by weight, in particular 10% to 30% by weight.

[0349] Anionic surfactants: Typical examples of anionic surfactants are soaps, alkylbenzenesulfonates, alkane sulfonates, olefin sulfonates, alkyl ether sulfonates, glycerol ether sulfonates, α-methyl ether sulfonates, sulfofatty acids, alkyl sulfates, alkyl ether sulfates, glycerol ether sulfates, fatty acid ether sulfates, hydroxyether sulfates, monoglyceride (ether) sulfates, fatty acid amide (ether) sulfates, mono- and dialkyl sulfosuccinates, mono- and dialkyl sulfosuccinamates, sulfotriglycerides, amide soaps, ether carboxylic acids and their salts, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, N-acylamino acids, alkyl oligoglucoside sulfates, protein fatty acid condensates (especially wheat-based plant products), and alkyl (ether) phosphates.If anionic surfactants contain polyglycol ether chains, they may have conventional, but preferably narrow homolog distributions. Particularly preferred in this context are: (a) acyl glutarates, such as sodium acyl glutarate, di-TEA palmitoyl aspartate and sodium caprylic / capric glutarate, acyl amino acid salts such as acyl peptides, such as palmitoyl hydrolyzed milk protein, sodium cocoyl hydrolyzed soy protein and sodium / potassium cocoyl hydrolyzed collagen and alaninate; (b) Acyl lactylate, lauroyl lactylate, caproyl lactylate (c) Sulfates, e.g. Alkyl ether sulfates, such as, in particular, sodium, ammonium, magnesium, MIPA, TIPA laureth sulfate, sodium myreth sulfate and sodium C12-13 pareth sulfate; Alkyl sulfates, such as sodium, ammonium and TEA lauryl sulfate; Glyceride sulfates, such as sodium coco monoglyceride sulfate, Amidosulfates, such as magnesium PEG-3 cocamide sulfate; (d) sulfonates, e.g. alkyl sulfonates, Alkylaryl sulfonates, especially sodium C12-14 olefin sulfonate, (e) sulfosuccinates, such as dioctyl sodium sulfosuccinate, disodium laureth sulfosuccinate, disodium lauryl sulfosuccinate, and disodium undecyl enamide MEA sulfosuccinate; (f) sulfoacetates, such as sodium lauryl sulfoacetate; (g) Sarcosinates, such as myristoyl sarcosine, TEA lauroyl sarcosinate, sodium lauroyl sarcosinate, and sodium cocoyl sarcosinate (l) isethionates, e.g., sodium / ammonium cocoyl isethionate (h) Taurates, such as sodium lauroyl taurate and sodium methyl cocoyl taurate, (i) Carboxylate, e.g. Soaps, e.g., TEA stearate, ether carboxylates, such as sodium laureth-13-carboxylate and sodium PEG-6-cocamide carboxylate, (j) Phosphates, such as cetyl phosphate (mono-, di-cetyl and mixtures thereof), potassium cetyl phosphate, (mono-, di-cetyl and mixtures thereof), DEA cetyl phosphate (mono-, di-cetyl and mixtures thereof), DEA oleth-10-phosphate, and dilaureth-4-phosphate.

[0350] Nonionic surfactants: Typical examples of nonionic surfactants are fatty alcohol polyglycol ethers, alkylphenol polyglycol ethers, fatty acid polyglycol esters, fatty acid amide polyglycol ethers, fatty acid amine polyglycol ethers, alkoxylated triglycerides, mixed ethers or mixed formals, optionally partially oxidized alkyl(en)yl oligoglycosides or glucuronic acid derivatives, fatty acid N-alkylglucamides, protein hydrolysates (especially wheat-based plant products), polyol fatty acid esters, sugar esters, sorbitan esters, polysorbates and amine oxides. If the nonionic surfactants contain polyglycol ether chains, they may have a conventional, but preferably narrow, homolog distribution.

[0351] Cationic surfactants: Cationic surfactants contain at least one N atom covalently bonded to four alkyl or aryl groups. This results in a positive charge regardless of the pH value. Alkyl betaines, alkylamidopropyl betaines, and alkylamidopropyl hydroxysulfines are advantageous. The cationic surfactants used are more preferably selected from the group consisting of quaternary ammonium compounds, in particular benzyltrialkylammonium chloride or bromide, such as benzyldimethylstearylammonium chloride, and alkyltrialkylammonium salts, such as cetyltrimethylammonium chloride or bromide, alkyldimethylhydroxyethylammonium chloride or bromide, dialkyldimethylammonium chloride or bromide, alkylamidoethyltrimethylammonium ether sulfate, alkylpyridinium salts, such as lauryl chloride or cetylpyridinium chloride, imidazoline derivatives, and compounds with cationic character, such as amine oxides, such as alkyldimethylamine oxides or alkylaminoethyldimethylamine oxides. Cetyltrimethylammonium salts are particularly advantageously used. Particularly preferred are: alkylamine, alkylimidazole, ethoxylated amines, Quaternary ammonium salts; RNH2CH2CH2COO - (at pH=7) RNHCH2CH2COO - B + (at pH=12) B+=any desired cation, and Esthequat is.

[0352] Amphiphilic or amphoteric surfactants: Typical examples of amphiphilic or amphoteric surfactants are alkylbetaines, alkylamidobetaines, aminopropionates, aminoglycinates, imidazolinium betaines and sulfobetaines. The surfactants mentioned are exclusively known compounds.

[0353] Typical examples of particularly suitable mild, i.e. particularly skin-compatible surfactants are fatty alcohol polyglycol ether sulfates, monoglyceride sulfates, mono- and / or dialkyl sulfosuccinates, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates, α-olefin sulfonates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucamides, alkylamidobetaines, amphoacetals and / or protein fatty acid condensates, the latter preferably based on wheat protein.

[0354] Oil bodies: Examples of oil bodies are Guerbet alcohols, based on fatty alcohols with 6 to 18, preferably 8 to 10, carbon atoms, linear or branched C6-C 22 Straight chain C6-C with fatty alcohols 22 Esters of fatty acids or C6-C 22 Branched chain C6-C with fatty alcohols 13Esters of carboxylic acids, for example, myristyl myristate, myristyl palmitate, myristyl stearate, myristyl isostearate, myristyl oleate, myristyl behenate, myristyl erucate, cetyl myristate, cetyl palmitate, cetyl stearate, cetyl isostearate, cetyl oleate, cetyl behenate, cetyl erucate, stearyl myristate, stearyl palmitate, stearyl stearate, stearyl isostearate, stearyl oleate, stearyl behenate, stearyl erucate, isostearyl myristate, isostearyl palmitate, isostearyl stearate, isostearyl stearate oleyl, isostearyl isostearate, isostearyl oleate, isostearyl behenate, isostearyl oleate, oleyl myristate, oleyl palmitate, oleyl stearate, oleyl isostearate, oleyl oleate, oleyl behenate, oleyl erucate, behenyl myristate, behenyl palmitate, behenyl stearate, behenyl isostearate, behenyl oleate, behenyl behenate, behenyl erucate, erucyl myristate, erucyl palmitate, erucyl stearate, erucyl isostearate, erucyl oleate, erucyl behenate, and erucyl erucate. Particularly preferred are cetearyl ethylhexanoate, cetearyl nonanoate, stearyl heptanoate, and stearyl caprylate, and mixtures thereof.

[0355] In addition, linear C6-C with branched alcohols, especially 2-ethylhexanol 22 Esters of fatty acids, straight or branched chain C6-C 22 C with fatty alcohols, especially dioctyl malate 18 -C 38 Esters of alkylhydroxycarboxylic acids, esters of linear or branched C6-C13 carboxylic acids with linear or branched C6-C13 alcohols, for example ethylhexyl isononanoate, esters of linear and / or branched fatty acids with polyhydric alcohols (for example propylene glycol, dimer diol or trimer triol) and / or Guerbet alcohols, C6-C 10 Triglycerides based on fatty acids, C6-C18 Liquid mono- / di- / triglyceride mixture based on fatty acids, C6-C 22 Esters of fatty alcohols and / or Guerbet alcohols with aromatic carboxylic acids, in particular benzoic acid, C2-C 12 Esters of dicarboxylic acids with linear or branched alcohols having 1 to 22 carbon atoms or polyols having 2 to 10 carbon atoms and 2 to 6 hydroxyl groups, vegetable oils, branched primary alcohols, substituted cyclohexanes, linear and branched C6-C 22 Fatty alcohol carbonates, such as dicaprylyl carbonate (Cetiol® CC), Guerbet carbonates based on fatty alcohols with 6 to 18, preferably 8 to 10, C atoms, linear and / or branched C6-C benzoates 22 Suitable are esters with alcohols (e.g. Finsolv® TN), linear or branched, symmetrical or asymmetrical dialkyl ethers having 6 to 22 carbon atoms per alkyl group, e.g. dicaprylyl ether (Cetiol® OE), ring-opening products of epoxidized fatty acid esters with polyols, silicone oils (cyclomethicone, silicon methicone type, etc.) and / or aliphatic or naphthenic hydrocarbons, e.g. squalane, squalene or dialkylcyclohexanes.

[0356] The amount used can be between 5% and 80% by weight, preferably between 10% and 50% by weight, especially between 20% and 40% by weight, based on the final formulation.

[0357] Emulsifiers: Suitable emulsifiers include, for example, nonionic surfactants from at least one of the following groups: addition products of 2 to 30 moles of ethylene oxide and / or 0 to 5 moles of propylene oxide to linear fatty alcohols having 8 to 22 carbon atoms, to fatty acids having 12 to 22 carbon atoms, to alkylphenols having 8 to 15 carbon atoms in the alkyl group and to alkylamines having 8 to 22 carbon atoms in the alkyl group; Alkyl and / or alkenyl oligoglycosides having 8 to 22 carbon atoms in the alkyl / alkenyl residue and their ethoxylated analogues; addition products of 1 to 15 moles of ethylene oxide onto castor oil and / or hydrogenated castor oil; addition products of 15 to 60 moles of ethylene oxide onto castor oil and / or hydrogenated castor oil; partial esters of glycerol and / or sorbitan with unsaturated, linear or saturated, branched fatty acids having 12 to 22 carbon atoms and / or hydroxycarboxylic acids having 3 to 18 carbon atoms and their adducts with 1 to 30 moles of ethylene oxide; partial esters of polyglycerol (average degree of self-condensation 2-8), polyethylene glycol (molecular weight 400-5000), trimethylolpropane, pentaerythritol, sugar alcohols (e.g., sorbitol), alkyl glucosides (e.g., methyl glucoside, butyl glucoside, lauryl glucoside) and polyglucosides (e.g., cellulose) with saturated and / or unsaturated, linear or branched fatty acids having 12-22 carbon atoms and / or hydroxycarboxylic acids having 3-18 carbon atoms, and their adducts with 1-30 moles of ethylene oxide; mixed esters of pentaerythritol, fatty acids, citric acid and fatty alcohols and / or mixed esters of fatty acids having 6 to 22 carbon atoms, methyl glucose and polyols, preferably glycerol or polyglycerol; Wool wax alcohol; polysiloxane-polyalkyl-polyether copolymers or corresponding derivatives; Block copolymers, such as polyethylene glycol-30 dipolyhydroxystearic acid; polymeric emulsifiers, for example, the Pemulen type (TR-1, TR-2) from Lubrizol or Cosmedia® SP from BASF; Polyalkylene glycol and Glycerol carbonate.

[0358] Particularly suitable emulsifiers are described in more detail below.

[0359] Alkoxylates: Addition products of ethylene oxide and / or propylene oxide onto fatty alcohols, fatty acids, alkylphenols or castor oil are known products available commercially. They are homologous mixtures whose average degree of alkoxylation corresponds to the ratio of the amounts of ethylene oxide and / or propylene oxide involved in the addition reaction to the substrate. The C of the addition products of ethylene oxide onto glycerol 12 / 18 Fatty acid monoesters and diesters are known as refatting agents in cosmetics.

[0360] Alkyl and / or alkenyl oligoglycosides: Alkyl and / or alkenyl oligoglycosides, their preparation and use are known from the prior art. Their preparation is carried out, in particular, by reacting glucose or oligosaccharides with primary alcohols having 8 to 18 carbon atoms. With regard to the glycosidic residue, monoglycosides in which the cyclic sugar residue is glycosidically linked to the fatty alcohol and oligoglycosides, preferably with a degree of oligomerization of up to about 8, are preferred. The degree of oligomerization is a statistical average value based on the homolog distribution that is typical for such technical products.

[0361] Partial glycerides: Typical examples of suitable partial glycerides are hydroxystearic acid monoglyceride, hydroxystearic acid diglyceride, isostearic acid monoglyceride, isostearic acid diglyceride, oleic acid monoglyceride, oleic acid diglyceride, ricinoleic acid monoglyceride, ricinoleic acid diglyceride, linoleic acid monoglyceride, linoleic acid diglyceride, linolenic acid monoglyceride, linoleic acid diglyceride, erucic acid monoglyceride, erucic acid diglyceride, tartaric acid monoglyceride, tartaric acid diglyceride, citric acid monoglyceride, citric acid diglyceride, malic acid monoglyceride, malic acid diglyceride and technical mixtures thereof, which may still contain small amounts of triglycerides resulting from the manufacturing process. Also suitable are addition products of 1 to 30 mol, preferably 5 to 10 mol, of ethylene oxide onto the mentioned partial glycerides.

[0362] Sorbitan Esters: Sorbitan esters include sorbitan monoisostearate, sorbitan sesquiisostearate, sorbitan diisostearate, sorbitan triisostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan dioleate, sorbitan trioleate, sorbitan monoerucate, sorbitan sesquierucate, sorbitan dierucate, sorbitan trierucate, sorbitan monoricinoleate, sorbitan sesquiricinoleate, sorbitan diricinoleate, and sorbitan triricinoleate. Examples of suitable sorbitan esters include sorbitan monohydroxystearate, sorbitan sesquihydroxystearate, sorbitan dihydroxystearate, sorbitan trihydroxystearate, sorbitan monotartrate, sorbitan sesqui-tartrate, sorbitan ditartrate, sorbitan tritartrate, sorbitan monocitrate, sorbitan sesquicitrate, sorbitan dicitrate, sorbitan tricitrate, sorbitan monomaleate, sorbitan sesquimaleate, sorbitan dimaleate, sorbitan trimaleate and technical mixtures thereof. Also suitable are addition products of 1 to 30 mol, preferably 5 to 10 mol, of ethylene oxide onto the sorbitan esters mentioned.

[0363] Polyglycerol esters: Typical examples of suitable polyglycerol esters are polyglyceryl-2 dipolyhydroxystearate (Dehymuls® PGPH), polyglycerol-3 diisostearate (Lameform® TGI), polyglyceryl-4 isostearate (Isolan® GI 34), polyglyceryl-3 oleate, diisostearoyl polyglyceryl-3 diisostearate (Isolan® PDI), polyglyceryl-3 methyl glucose distearate (Tego Care® 450), polyglyceryl-3 beeswax (Cera Bellina®), polyglyceryl-4 caprate (polyglycerol caprate T2010 / 90), polyglyceryl-3 cetyl ether (Chimexane® NL), polyglyceryl-3 distearate (Cremophor® GS32), and polyglyceryl polyricinoleate (Admul® WOL1403), polyglyceryl isostearate dimerate, and mixtures thereof. Further examples of suitable polyol esters are the mono-, di-, and tri-esters of trimethylolpropane or pentaerythritol with lauric acid, coconut fatty acid, tallow fatty acid, palmitic acid, stearic acid, oleic acid, behenic acid, etc., optionally reacted with 1 to 30 moles of ethylene oxide.

[0364] Anionic emulsifiers: Typical anionic emulsifiers are, for example, aliphatic fatty acids with 12 to 22 carbon atoms, such as palmitic acid, stearic acid or behenic acid, and dicarboxylic acids with 12 to 22 carbon atoms, such as azelaic acid or sebacic acid.

[0365] Also suitable are mono-, di- and trialkyl phosphates and mono-, di- and / or tri-PEG-alkyl phosphates and their salts, such as potassium cetyl phosphate and citrate esters, especially glyceryl oleate citrate and glyceryl stearyl citrate.

[0366] Amphiphilic and Cationic Emulsifiers: Amphoteric surfactants can also be used as opacifiers. Surface-active compounds containing at least one quaternary ammonium group, at least one carboxylic acid group, and one sulfonic acid group in the molecule are called zwitterionic surfactants. Particularly suitable zwitterionic surfactants are, for example, N-alkyl-N,N-dimethylammonium glycinates, each containing 8 to 18 carbon atoms in the alkyl or acyl group, such as coconut alkyl dimethyl ammonium glycinate, N-acylaminopropyl-N,N-dimethylammonium glycinate, such as coconut acylaminopropyl dimethyl ammonium glycinate, and so-called betaines, such as 2-alkyl-3-carboxylmethyl-3-hydroxyethyl imidazoline and coconut acylaminoethyl hydroxyethyl carboxymethyl glycinate. Fatty acid amide derivatives known under the CTFA designation cocamidopropyl betaine are particularly preferred. Further suitable emulsifiers are amphiphilic surfactants. Amphiphilic surfactants are surface-active compounds that contain at least one free amino group and at least one COOH or -SO3H group in addition to a C8 / 18 alkyl or acyl group in the molecule and are capable of forming inner salts. Suitable examples of amphiphilic surfactants are N-alkylglycines, N-alkylpropionic acids, N-alkylaminobutyric acids, N-alkylimidodipropionic acids, N-hydroxyethyl-N-alkylamidopropylglycines, N-alkyltaurines, N-alkylsarcosines, 2-alkylaminopropionic acids, and alkylaminoacetic acids, each having approximately 8 to 18 carbon atoms in the alkyl group. Particularly preferred amphiphilic surfactants are N-coconut alkylaminopropionates, coconut acylaminoethylaminopropionates, and C 12 / 18 Finally, cationic surfactants can also be considered as emulsifiers, whereby those of the esterquat type, preferably methyl-quaternized difatty acid triethanolamine ester salts, are particularly preferred.

[0367] The amount of emulsifier used is usually in the range of about 0.5% by weight to about 10% by weight, preferably about 1% by weight to about 5% by weight.

[0368] Fats and waxes: Typical examples of fats are glycerides, i.e., solid or liquid plant or animal products consisting essentially of mixed glycerol esters of higher fatty acids. Waxes include, inter alia, natural or synthetic waxes such as candelilla wax, carnauba wax, Japan wax, Esperata wax, cork wax, guaruma wax, rice bran oil wax, sugarcane wax, ouricury wax, montan wax, beeswax, shellac wax, spermaceti, lanolin (wool wax), brushing fat, ceresin, ozokerite (earth wax), petrolatum, paraffin wax, microcrystalline wax; chemically modified waxes (hard waxes), such as montan ester wax, sasol wax, hydrogenated jojoba wax, and synthetic waxes, such as polyalkylene waxes and polyethylene glycol waxes. In addition to fats, fat-like substances, such as lecithin and phospholipids, can also be used as additives. By the term lecithin, those skilled in the art understand a glycerophospholipid formed by esterification of fatty acids, glycerol, phosphoric acid, and choline. Therefore, lecithin is often referred to in the art as phosphatidylcholine (PC). An example of a natural lecithin is cephalin, also known as phosphatidic acid, which is a derivative of 1,2-diacyl-sn-glycerol-3-phosphate. In contrast, phospholipids are usually monoesters and preferably diesters of phosphoric acid with glycerol (glycerophosphate) and are generally classified as fats. Additionally, sphingosine or sphingolipids are also considered.

[0369] Pearlescent waxes: Suitable pearlescent waxes are, for example, alkylene glycol esters, in particular ethylene glycol distearate; fatty acid alkanolamides, in particular coconut fatty acid diethanolamide; partial glycerides, in particular stearic acid monoglyceride; esters of polyhydric, optionally hydroxy-substituted carboxylic acids with fatty alcohols having 6 to 22 carbon atoms, in particular long-chain esters of tartaric acid; fatty substances, for example fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers and fatty carbonates having a total of at least 24 carbon atoms, in particular laurone and distearyl ether; fatty acids, for example stearic acid, hydroxystearic acid or behenic acid, ring-opening products of olefinic epoxides having 12 to 22 carbon atoms with fatty alcohols having 12 to 22 carbon atoms and / or polyols having 2 to 15 carbon atoms and 2 to 10 hydroxyl groups, and mixtures thereof.

[0370] Viscosity enhancers and thickeners: partial glycerides, fatty acids or hydroxy fatty acids as well as fatty alcohols or hydroxy fatty alcohols having 12 to 22, preferably 16 to 18 carbon atoms can be considered viscosity enhancers. Preference is given to combining these substances with alkyl oligoglucosides and / or fatty acid N-methylglucamides of the same chain length and / or polyglycerol poly-12-hydroxystearates. Suitable thickeners are, for example, Aerosil types (hydrophilic silicas), polysaccharides, especially xanthan gum, guar gum, agar, alginates and tylose, carboxymethylcellulose and hydroxyethyl and hydroxypropylcellulose, even higher molecular weight polyethylene glycol mono- and diesters of fatty acids, polyacrylates (e.g., Carbopole® and Pemulen types from Lubrizol; Synthalene® from Sigma; Keltrol types from Kelco; Seppic Sepigel types; Salcare types from BASF), polyacrylamides, polymers, polyvinyl alcohol and polyvinylpyrrolidone. Bentonites, such as Bentone® Gel VS-5PC (Elementis), which are mixtures of cyclopentasiloxane, disteardimonium hectorite and propylene carbonate, have also proven particularly effective. Other possible surfactants include ethoxylated fatty acid glycerides, esters of fatty acids with polyols, e.g., pentaerythritol or trimethylolpropane, narrow homolog distribution fatty alcohol ethoxylates or alkyl oligoglucosides, and electrolytes such as sodium chloride and ammonium chloride.

[0371] Superfatting agents and stabilizers: Substances such as lanolin and lecithin and polyethoxylated or acylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides, and fatty acid alkanolamides can be used as superfatting agents, the latter also serving as foam stabilizers. Metal salts of fatty acids, such as magnesium stearate, aluminum stearate, and / or zinc stearate, or ricinoleates, can be used as stabilizers.

[0372] Polymers: Suitable cationic polymers are, for example, cationic cellulose derivatives, such as quaternized hydroxyethylcellulose available under the name Polymer JR 400® from Dow, cationic starch, copolymers of diallylammonium salts and acrylamide, quaternized vinylpyrrolidone / vinylimidazole polymers, such as Luviquat® (BASF), condensation products of polyglycols and amines, quaternized collagen polypeptides, such as lauryldimonium hydroxypropyl hydrolyzed collagen (Lamequat® L, BASF), quaternized wheat polypeptides, polyethylenimines, cationic silicone polymers, such as amodimethicone, copolymers of adipic acid and dimethylaminohydroxypropyldiethylenetriamine (Cartaretine®, Sandoz), dichlorodimethicone of acrylic acid. copolymers with ethyl-diallylammonium (Merquat® 550, Lubrizol), polyaminopolyamides and their crosslinked, water-soluble polymers, cationic chitin derivatives, optionally distributed in finely crystalline form, such as quaternized chitosan, condensation products of dihaloalkylenes, such as dibromobutane, with bisdialkylamines, such as bis-dimethylamino-1,3-propane, cationic guar gum, such as Jaguar® CBS, Jaguar® C-17, Jaguar® C-16 (Solvay), quaternized ammonium salt polymers, such as Mirapol® A-15, Mirapol® AD-1, Mirapol® AZ-1 (Solvay).

[0373] Examples of anionic, amphoteric, amphiphilic and nonionic polymers are vinyl acetate / crotonic acid copolymers, vinylpyrrolidone / vinyl acrylate copolymers, vinyl acetate / butyl maleate / isobornyl acrylate copolymers, methyl vinyl ether / maleic anhydride copolymers and their esters, non-crosslinked and polyol-crosslinked polyacrylic acids, acrylamidopropyltrimethylammonium chloride / acrylic acid copolymers, octylacrylamide / methyl methacrylate / tert-butylaminoethyl methacrylate / 2-hydroxypropyl methacrylate copolymers, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, vinylpyrrolidone / dimethylaminoethyl methacrylate / vinyl caprolactam terpolymers and optionally derivatized cellulose ethers and silicones.

[0374] Silicone Compounds: Suitable silicone compounds include, for example, dimethylpolysiloxane, methylphenylpolysiloxane, cyclic silicones, and amino-, fatty acid-, alcohol-, polyether-, epoxy-, fluorine-, glycoside-, and / or alkyl-modified silicone compounds, which may exist in liquid or resinous form at room temperature. Simethicone, a mixture of dimethicone with an average chain length of 200 to 300 dimethylsiloxane units and hydrosilicate, is also suitable.

[0375] UV light protection filters: It has been found that the diesters according to the invention are particularly able to overcome the viscosity typical of many UV filters. Therefore, another aspect of the invention relates to preparations which, in addition to the diester, also comprise at least one UV filter. In particular (a) 1,3-propanediol dicaprylate / caprate; and (b) at least one UV light filter, provided that component (a) is produced entirely on a plant basis, is preferred. (a) about 0.1% by weight to about 30% by weight of 1,3-propanediol dicaprylate / caprate; (b) Preparations containing from about 1% to about 50% by weight of UV light filters, with the proviso that the amount of solvents and other cosmetic adjuvants and additives is up to a maximum of 100% by weight.

[0376] UV photoprotective filters (often also synonymously referred to as UV photoprotective agents) are, for example, organic substances that are liquid or crystalline at room temperature and are capable of absorbing ultraviolet radiation and releasing the absorbed energy in the form of long-wave radiation, for example heat. Typically, UV photoprotective filters are present in an amount of 0.1% to 50% by weight, preferably 1% to 45% by weight.

[0377] Typical UV-A filters are, for example, derivatives of benzoylmethane such as 1-(4'-tert-butylphenyl)-3-(4'-methoxyphenyl)propane-1,3-dione, 4-tert-butyl-4'-methoxydibenzoylmethane (Parsol® 1789), 2-(4-diethylamino-2-hydroxybenzoyl)-benzoic acid hexyl ester (Uvinul® A Plus), 1-phenyl-3-(4'-isopropylphenyl)propane-1,3-dione, and enamine compounds. Particularly preferred are terephthalylidene dibornane sulfonic acid and its salts (Mexoryl® SX); hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate (Uvinul® A Plus); 2,2'-(1,4-phenylene)bis-[1H-benzimidazole-4,5-disulfonic acid], disodium salt (Neo Heliopan® AP); Menthyl anthranilate (Neo Heliopan® MA); Avobenzone (Neo Heliopan® 357) and mixtures thereof.

[0378] UVB filters can be oil-soluble or water-soluble. Oil-soluble substances include, for example: Octocrylene; Homosalate; Octyl salicylate; p-aminobenzoic acid; Ethyl p-aminobenzoate + 25EO; 2-ethylhexyl p-dimethylaminobenzoate; Triethanolamine salicylate (Neo Heliopan® TS); Menthyl anthranilate (Neo Heliopan® MA); 2-ethylhexyl p-methoxycinnamate (Neo Heliopan® AV); isoamyl p-methoxycinnamate (Neo Heliopan® E 1000); 2-phenylbenzimidazole sulfonic acid (Neo Heliopan® Hydro) and its salts; 3-(4'-trimethylammonium)benzylidenebornan-2-one methyl sulfate; 3-(4'-sulfo)benzylidenebornan-2-one and its salts; 3-(4'-methylbenzylidene)-d,1-camphor (Neo Heliopan® MBC); N-[(2,4)-[2-(oxoborn-3-ylidene)methyl]benzyl]acrylamide polymer; 4,4'-[(6-[4-(1,1-dimethyl)aminocarbonyl)phenylamino]-1,3,5-triazine-2,4-diyl)diimino]bis(benzoic acid-2-ethylhexyl ester) (Uvasorb® HEB); Malonate benzylidene polysiloxane (Parsol® SLX); tris(2-ethylhexyl)-4,4',4"-(1,3,5-triazine-2,4,6-triyltriimino)tribenzoate (Uvinul® T150); Methoxypropylaminocyclohexenylideneethoxyethyl cyanoacetate and mixtures thereof.

[0379] Suitable broadband filters include, for example: 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid (Sulisobenzone, Benzophenone-4) and its salts; 2-hydroxy-4-methoxybenzophenone (Neo Heliopan® BB); Disodium-2,2'-dihydroxy-4,4'-dimethoxy-5,5'-disulfobenzophenone; Phenol-(2H-benzotriazol-2-yl-4-methyl-6-(2-methyl-3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl), (Mexoryl® XL); 2,2′-methylenebis(6-(2H-benzotriazol-2-yl)-4-1,1,3,3-tetramethylbutyl)-phenol (Tinosorb® M); tris-biphenyltriazine (Tinosorb® A2B); Bemotrizinol (Neo Heliopan® BMT); 2,4-bis[[(4-(3-sulfonato)-2-hydroxypropyloxy)-2-hydroxy]phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine sodium salt; 2,4-bis[[(3-(2-propyloxy)-2-hydroxypropyloxy)-2-hydroxy]phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine; 2,4-bis[[4-(2-ethylhexyloxy)-2-hydroxy]phenyl]-6-[4-(2-methoxyethylcarbonyl)phenylamino]-1,3,5-triazine; 2,4-bis[[4-(3-(2-propyloxy)-2-hydroxypropyloxy)-2-hydroxy]phenyl]-6-[4-(2-ethyl carboxyl)phenylamino]-1,3,5-triazine; 2,4-bis[[4-(2-ethylhexyloxy)-2-hydroxy]phenyl]-6-(1-methylpyrrol-2-yl)-1,3,5-triazinee; 2,4-bis[[4-tris(trimethylsiloxysilylpropyloxy)-2-hydroxy]phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine; 2,4-bis[[4-(2"-methylpropentyloxy)-2-hydroxy]phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine; 2,4-bis[[4-(1',1',1',3',5',5',5'-heptamethylsiloxy-2"-methylpropyloxy)-2 hydroxy]phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine; (5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)bis(1,2,4-triazine) and mixtures thereof.

[0380] Of course, UV-A filters and UV-B filters can also be used in mixtures. A particularly advantageous combination consists of a benzoylmethane derivative, such as 4-tert-butyl-4'-methoxydibenzoylmethane (Parsol® 1789) and 2-cyano-3,3-phenylcinnamic acid-2-ethylhexyl ester (octocrylene), in combination with a cinnamic acid ester, preferably 4-methoxycinnamic acid-2-ethylhexyl ester and / or 4-methoxycinnamic acid propyl ester and / or 4-methoxycinnamic acid isoamyl ester. Advantageously, such a combination is combined with a water-soluble filter, such as 2-phenylbenzimidazole-5-sulfonic acid and its alkali metal salts, alkaline earth metal salts, ammonium salts, alkylammonium salts, alkanolammonium salts, and glucamonium salts.

[0381] Pigments, especially photoprotective pigments: In addition to the soluble substances mentioned, insoluble photoprotective pigments, i.e., finely dispersed metal oxides or metal salts, can also be used for this purpose. Examples of suitable metal oxides are, in particular, zinc oxide and titanium dioxide, as well as oxides of iron, zirconium, silicon, manganese, aluminum, and cerium, and mixtures thereof. Silicates (talc), barium sulfate, or zinc stearate can be used as salts. The oxides and salts are used in the form of pigments in skin care emulsions, skin protection emulsions, and decorative cosmetics. The particles should have an average diameter of less than 100 nm, between 5 and 50 nm, and especially between 15 and 30 nm. They may have a spherical shape, although particles with an ellipsoidal or otherwise deviating spherical shape may also be used. The pigments may be surface-treated, i.e., hydrophilized or hydrophobized. Typical examples are coated titanium dioxide, such as titanium dioxide T805 (Degussa) or Eusolex® T2000, Eusolex® T, Eusolex® T-ECO, Eusolex® TS, Eusolex® T-Aqua, Eusolex® T-45D (all Merck), and Uvinul TiO2 (BASF). Silicones, and in particular trialkoxyoctylsilanes or simethicones, are used as hydrophobic coating agents. So-called micropigments or nanopigments are preferably used in sunscreens. Micronized zinc oxide, such as Z-COTE® or Z-COTE HP1®, is preferably used.

[0382] Humectants: Humectants further optimize the sensory properties of the composition and help regulate skin moisture. At the same time, they increase the low-temperature stability of the preparations according to the invention, especially in the case of emulsions. Humectants are usually present in an amount of 0.1% to 15% by weight, preferably 1% to about 10% by weight, and more preferably 5% to 10% by weight.

[0383] Suitable substances according to the invention include amino acids, pyrrolidone carboxylic acid, lactic acid and its salts, lactitol, urea and urea derivatives, uric acid, glucosamine, creatinine, collagen, cleavage products of chitosan or chitosan salts / derivatives, and in particular polyols and polyol derivatives (e.g. glycerol, diglycerol, triglycerol, ethylene glycol, propylene glycol, butylene glycol, erythritol, 1,2,6-hexanetriol, polyethylene glycols, e.g. PEG-4, PEG-6, PEG-7, PEG-8, PEG-9, PEG-10, Examples of suitable humectants include PEG-12, PEG-14, PEG-16, PEG-18, PEG-20, sugars and sugar derivatives (including fructose, glucose, maltose, maltitol, mannitol, inositol, sorbitol, sorbitylsilanediol, sucrose, trehalose, xylose, xylitol, glucuronic acid and their salts), ethoxylated sorbitol (sorbeth-6, sorbeth-20, sorbeth-30, sorbeth-40), honey and hydrogenated honey, hydrogenated starch hydrolysates, and mixtures of hydrogenated wheat protein with PEG-20 acetate copolymer. Preferred humectants according to the present invention are glycerol, diglycerol, triglycerol, and butylene glycol.

[0384] Biogenic active ingredients and antioxidants: Biogenic active ingredients are, for example, tocopherol, tocopherol acetate, tocopherol palmitate, ascorbic acid, (deoxy)ribonucleic acid and its fragmentation products, β-glucan, retinol, bisabolol, allantoin, phytantriol, pentenol, AHA acids, amino acids, ceramides, pseudoceramides, essential oils, plant extracts such as cherry blossom extract, bambaranus extract and vitamin complexes.

[0385] Antioxidants interrupt the photochemical reaction chain that occurs when ultraviolet light penetrates the skin. Typical examples include amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g., urocanic acid) and their derivatives, peptides (e.g., D,L-carnosine, D-carnosine, L-carnosine and their derivatives (e.g., anserine), carotenoids, carotenes (e.g., α-carotene, β-carotene, lycopene) and their derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (e.g., dihydrolipoic acid), aurothioglucose, propylthiouracil, and others. Thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine and their glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, γ-linoleyl, cholesteryl and glyceryl esters) and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and their derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts), and those with very low tolerated doses (e.g., pm Sulfoximine compounds (e.g., buthionine sulfoximine, homocysteine ​​sulfoximine, buthionine sulfone, penta-, hexa-, and heptathionine sulfoximine) in concentrations ranging from 0.1 to 0.2 μmol / kg, as well as (metal) chelating agents (e.g., α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), α-hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, bile acids, bile extracts, bilirubin, biliverdin, EDTA, EGTA, and their derivatives, unsaturated fatty acids and their derivatives (e.g., γ-lysine, nolenic acid, linoleic acid, oleic acid), folic acid and their derivatives, ubiquinone and ubiquinol and their derivatives, vitamin C and derivatives (e.g., ascorbyl palmitate, Mg-ascorbyl phosphate, ascorbyl acetate), tocopherol and derivatives (e.g., vitamin E acetate), vitamin A and derivatives (vitamin A palmitate), and benzoic acid resin coniferyl benzoate, rutinic acid and its derivatives, α-glycosylrutin, ferulic acid, furfurylidene glucitol, carnosine, butylhydroxytoluene,Butylhydroxyanisole, nordihydroguaiaric acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, superoxide dismutase, zinc and its derivatives (e.g., ZnO, ZnSO), selenium and its derivatives (e.g., selenomethionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide), and derivatives (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids) of these active substances according to the present invention.

[0386] Deodorants and disinfectants: Cosmetic deodorants (deodorants) combat, mask, or eliminate body odor. Body odor is caused by the action of skin bacteria in the apocrine sweat glands, which leads to the formation of unpleasant-smelling decomposition products. Therefore, deodorants contain active ingredients that act as bacteria inhibitors, enzyme inhibitors, odor absorbers, or odor maskers.

[0387] Bactericides: In principle, all substances that are effective against gram-positive bacteria, such as, for example, 2-methyl-5-cyclohexylpentanol, 1,2-decylene glycol, 4-hydroxybenzoic acid and its salts and esters, N-(4-chlorophenyl)-N'-(3,4-dichlorophenyl)urea, 2,4,4'-trichloro-2'-hydroxy-diphenyl ether (triclosan), 4-chloro-3,5-dimethyl-phenol, 2,2'-methylene-bis(6-bromo-4-chlorophenol), 3-methyl-4-(1-methylethyl)-phenol, 2-benzyl-4-chlorophenol, 3-(4- Suitable disinfectants include chlorophenoxy)-1,2-propanediol, 3-iodo-2-propynyl butylcarbamate, chlorhexidine, 3,4,4'-trichlorocarbanilide (TTC), antibacterial fragrances, thymol, thyme oil, eugenol, clove oil, menthol, mint oil, farnesol, phenoxyethanol, glycerol monocaprate, glycerol monocaprylate, glycerol monolaurate (GML), diglycerol monocaprate (DMC), and salicylic acid-N-alkylamides, such as salicylic acid-n-octylamide or salicylic acid-n-decylamide.

[0388] Enzyme inhibitors: Suitable enzyme inhibitors are, for example, esterase inhibitors. These are preferably trialkyl citrates such as trimethyl citrate, tripropyl citrate, triisopropyl citrate, tributyl citrate, and especially triethyl citrate (Hydagen® CAT). These substances inhibit enzyme activity and therefore reduce odor formation. Other substances that can be considered esterase inhibitors are sterol sulfates or phosphates, such as lanosterol sulfate or phosphate, cholesterol, campesterol, stigmasterol, and sitosterol; dicarboxylic acids and their esters, such as glutaric acid, glutaric acid monoethyl ester, glutaric acid diethyl ester, adipic acid, adipic acid monoethyl ester, adipic acid diethyl ester, malonic acid, and malonic acid diethyl ester; hydroxycarboxylic acids and their esters, such as citric acid, malic acid, tartaric acid, or the diethyl ester of tartaric acid; and zinc glycinate.

[0389] Odor absorbers: Suitable odor absorbers are substances capable of absorbing and largely retaining odor-forming compounds. They reduce the partial pressure of the individual components, thereby slowing their rate of dispersion. It is important that the fragrance remains unaffected during this process. Odor absorbers are not effective against bacteria. They contain, for example, complex zinc salts of ricinoleic acid as their base, or special, nearly odorless fragrances, such as labdanum or styrax extracts or certain abietic acid derivatives, known to those skilled in the art as "fixatives." In addition to their odor-masking function, fragrances or perfume oils also act as odor-masking agents, imparting their respective fragrant notes to deodorizers. Perfume oils are, for example, mixtures of natural and synthetic fragrances. Natural fragrances include extracts of flowers, stems and leaves, fruits, peels, rhizomes, woods, herbs and grasses, needles and twigs, resins, and balsams. Animal sources, such as civet and bead-like fragrance, are also used. Typical synthetic fragrance compounds are ester, ether, aldehyde, ketone, alcohol and hydrocarbon products. Ester fragrance compounds include benzyl acetate, p-tert-butylcyclohexyl acetate, linalyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, allyl cyclohexyl propionate, styrene propionate and benzyl salicylate. Ethers include, for example, benzyl ethyl ether; aldehydes include, for example, linear alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial, and bourgeonal; ketones include, for example, ionones and methyl cedryl ketone; alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol, and terpineol; and hydrocarbons include primarily terpenes and balsams. However, mixtures of various perfumes that together produce an attractive fragrance are preferred.The less volatile essential oils most commonly used as fragrance ingredients, such as sage oil, chamomile oil, clove oil, melissa oil, mint oil, cinnamon leaf oil, lime flower oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, labdanum oil and lavender oil, are also suitable as perfume oils. Preferably, bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, α-hexyl cinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, Boisambrene Forte, ambroxan, indole, edione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclovertal, lavandin oil, muscat surge oil, β-damascone, geranium oil bourbon, cyclohexyl salicylate, Vertofix Coeur, Iso-E-Super, Fixolide NP, Evernyl, Iraldein Gamma Gamma), phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romilate, irotyl and floramat are used alone or in mixtures.

[0390] Antiperspirants: Antiperspirants reduce sweating by affecting the activity of the eccrine sweat glands, thereby reducing axillary wetness and body odor. Aqueous or anhydrous antiperspirant formulations usually contain the following ingredients: Astringent active ingredient, oil component, nonionic emulsifiers, Co-emulsifier, viscosity imparting agents, excipients such as thickening or complexing agents and / or Non-aqueous solvents such as ethanol, propylene glycol and / or glycerin.

[0391] Aluminum, zirconium or zinc salts are particularly suitable as astringent antiperspirants.Such suitable antiperspirant active ingredients include, for example, aluminum chloride, chloroaluminum, dichloroaluminum, sesquichloroaluminum, and their complexes with, for example, propylene glycol-1,2, aluminum hydroxyalanine, aluminum chlorotartrate, trichloroaluminum zirconium, tetrachloroaluminum zirconium, pentachloroaluminum zirconium, and their complexes with, for example, amino acids, for example, glycine.In addition, antiperspirants may contain small amounts of common oil-soluble and water-soluble excipients.Such oil-soluble excipients include, for example, Anti-inflammatory, skin-protecting, or aromatic essential oils, Synthetic skin protective active substances and / or It may also be an oil-soluble perfume oil.

[0392] Common water-soluble additives are, for example, preservatives, water-soluble flavorings, pH adjusters, e.g., buffer mixtures, water-soluble thickeners, e.g., water-soluble natural or synthetic polymers, e.g., xanthan gum, hydroxyethyl cellulose, polyvinylpyrrolidone or high molecular weight polyethylene oxide.

[0393] Film-forming agents: Common film-forming agents are, for example, chitosan, microcrystalline chitosan, quaternized chitosan, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polymers of the acrylic acid series, quaternary cellulose derivatives, hydrolyzed jojoba esters, collagen, hyaluronic acid or its salts, and similar compounds.

[0394] Antidandruff Agents: Antidandruff agents include piroctone olamine (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-(1H)-pyridinone monoethanolamine salt), Crinipan® AD (Climbazole), Ketoconazol®, (4-acetyl-1-{-4-[2-(2,4-dichlorophenyl)r-2-(1H-imidazol-1-ylmethyl)-1,3-dioxiran-c-4-ylmethoxyphenyl}piperazine, ketoconazol ethanol, elubiol, selenium disulfide, colloidal sulfur, sulfur polyethylene glycol sorbitan monooleate, sulfur uridinol polyethoxylate, sulfur tar distillate, salicylic acid (or in combination with hexachlorophene), undecylenic acid monoethanolamide sulfosuccinic acid sodium salt, Lamepon® UD (protein undecylenic acid condensate), zinc pyrithione, aluminum pyrithione, and magnesium sulfate pyrithione / magnesium dipyrithione.

[0395] Swelling agents: Montmorillonite, clay minerals, Pemulen and alkyl-modified Carbopol types (Lubrizol) can serve as swelling agents for the aqueous phase. Other suitable polymers or swelling agents are known to those skilled in the art from the relevant technical literature.

[0396] Insect repellents: N,N-diethyl-m-toluamide, 1,2-pentanediol, or ethyl butylacetylaminopropionate are suitable insect repellents. Dihydroxyacetone is suitable as a self-tanning agent. Tyrosine inhibitors that prevent melanin formation and are used in depigmenting agents include arbutin, ferulic acid, kojic acid, coumaric acid, and ascorbic acid (vitamin C).

[0397] Hydrotropes: Hydrotropes such as ethanol, isopropyl alcohol or polyols can also be used to improve the flow behavior; these substances mostly 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 contain further functional groups, especially amino groups, or may be modified with nitrogen. Typical examples are: glycerol; Alkylene glycols, such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, pentylene glycol, caprylyl glycol and polyethylene glycols with an average molecular weight of 100 to 1000 daltons; technical oligoglycerol mixtures with an intrinsic degree of condensation of 1.5 to 10, for example technical diglycerol mixtures with a diglycerol content of 40 to 50% by weight; Methylol compounds, such as, in particular, trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol and dipentaerythritol; Lower alkyl glucosides, especially those having 1 to 8 carbons in the alkyl residue, such as methyl glucoside and butyl glucoside; Sugar alcohols with 5 to 12 carbon atoms, such as sorbitol or mannitol; sugars with 5 to 12 carbon atoms, such as glucose or sucrose; Amino sugars, for example, glucamine; Dialcoholamines, for example diethanolamine or 2-amino-1,3-propanediol.

[0398] Preservatives: Suitable preservatives are, for example, phenoxyethanol, formaldehyde solution, parabens, o-cymen-5-ol, 4-hydroxyacetophenone, tropolone or sorbic acid and the silver complexes known under the name Surfacine®, and other classes of substances known to those skilled in the art as they can be found in the relevant literature.

[0399] Perfume oils and fragrances: Perfume oils include both natural and synthetic fragrances. Natural fragrances are extracts of flowers (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, cumin, juniper), peels (bergamot, lemon, orange), rhizomes (mace, angelica, celery, cardamom, costus, iris, carmus), woods (pine, sandalwood, guaiac, cedar, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and twigs (spruce, fir, pine, tamarack), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Animal sources such as civet and bead are also used. Typical synthetic fragrance compounds are ester, ether, aldehyde, ketone, alcohol and hydrocarbon products. Ester fragrance compounds include benzyl acetate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, ethylmethylphenyl glycinate, allylcyclohexyl propionate, styryl propionate and benzyl salicylate. Ethers include, for example, benzyl ethyl ether; aldehydes include, for example, linear alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial, and bourgeon; ketones include, for example, ionone, α-isomethylionone, and methyl cedryl ketone; alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol, and terpineol; and hydrocarbons include primarily terpenes and balsams. Preferably, however, mixtures of various fragrances are used that together produce an appealing fragrance.The less volatile essential oils most commonly used as fragrance ingredients, such as sage oil, chamomile oil, clove oil, melissa oil, mint oil, cinnamon leaf oil, lime flower oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, labdanum oil and lavender oil, are also suitable as perfume oils. Preferred are bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, α-hexylcinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, Boisambrene Forte, ambroxan, indole, edione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, and cyclovertal, and also preferred are lavandin oil, muscat surge oil, β-damascone, geranium oil bourbon, cyclohexyl salicylate, Vertofix Coeur, Iso-E-Super, Fixolide NP, Evernyl, and Iraldein Gamma. Gamma), phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romilate, irotyl and floramat are used alone or in mixtures.

[0400] Suitable fragrances include peppermint oil, spearmint oil, anise oil, star anise oil, caraway oil, eucalyptus oil, fennel oil, lemon oil, wintergrass oil, clove oil, menthol, and the like.

[0401] Coloring substances: for example, cochineal red A (CI 16255), patent blue V (CI 42051), indigotin (CI 73015), chlorophyllin (CI 75810), quinoline yellow (CI 47005), titanium dioxide (CI 77891), indanthrene blue RS (CI 69800) and madder lake (CI 58000) may be suitable and approved for cosmetic or pharmaceutical use as listed in the technical literature. These dyes are usually used in concentrations of 0.001% to 0.1% by weight, based on the total mixture.

[0402] Preferred preparations according to the invention are selected from the group consisting of products for treating, protecting, caring for and cleaning the skin and / or hair, or as finishing cosmetics, either as leave-on products or rinse-off products.

[0403] Formulations include, for example, dispersions, suspensions, creams, lotions or milks depending on the manufacturing method and ingredients, gels (including hydrogels, e.g., water-dispersed gels, oleogels), sprays (e.g., pump sprays or sprays with propellant), foams or impregnations for wiping, soaps, washing-up liquids, shower and bath additives, bath products (capsules, oils, tablets, salts, bath salts, soaps, etc.), foams, skin care products, e.g., emulsions, ointments, pastes, gels (as described above), oils, balms, serums, powders (e.g., face powders, body powders), masks, sticks, roll-on sticks, aerosols (foaming, non-foaming or post-foaming), deodorants and / or antiperspirants, mouthwashes and mouth rinses, antiperspirants ... insecticides, sunscreens, after-sun preparations, shaving products, after-shave balms, pre-shave and after-shave lotions, depilatories, hair care products such as shampoos (shampoos with rinse, anti-dandruff shampoos, body shampoos, shampoos for dry scalp, concentrated shampoos), conditioners, hair tonics, hair conditioners, hair styling creams, pomades, lotions for perming and setting, hair sprays, styling aids (e.g. gels or waxes), hair straighteners (detanglers, straighteners), hair dyes, e.g. temporary hair dyes, semi-permanent hair dyes, permanent hair dyes, hair conditioners, hair mousses, eye care products, finishing products, finishing strippers or baby products.

[0404] 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, e.g. a Pickering emulsion, an emulsion with a low oil content, a microemulsion or nanoemulsion, a gel (including hydrogels, hydrodispersible gels, oleogels) or a solution.

[0405] The total proportion of excipients and additives may be 1% to 50% by weight, preferably 5% to 40% by weight, based on the final preparation. The preparation of the drug may be carried out by conventional cold or hot processes, preferably using the phase inversion temperature method.

[0406] The present invention also includes oral care compositions containing one or more of the cooling agents according to the present invention or the cooling agent mixture according to the present invention or the flavor preparation according to the present invention.

[0407] Oral care compositions according to the invention, such as toothpastes, tooth gels or aqueous or aqueous-alcoholic oral care compositions (mouthwashes), may be formulated in a manner known per se.

[0408] Toothpaste or dentifrice is generally understood to be a gel-like or paste-like preparation of water, thickeners, humectants, abrasives or cleaning agents, surfactants, sweeteners, flavoring agents, deodorizing agents, and oral and dental medications. For example, conventional cleansing agents such as chalk, calcium diphosphate, insoluble sodium metaphosphate, aluminum silicate, calcium pyrophosphate, finely divided synthetic resins, silicic acid, aluminum oxide, and aluminum oxide trihydrate can all be used in toothpastes according to the invention.

[0409] Preferably, suitable detergents for the toothpaste according to the invention are micronized xerogel silica, hydrogel silica, precipitated silica, alumina trihydrate, and micronized alpha-alumina, all of the above, in amounts of 15 to 40% by weight of the toothpaste, or mixtures of these detergents. Suitable humectants are mainly low molecular weight polyethylene glycols, glycerol, sorbitol, or mixtures of these products, in amounts of up to 50% by weight. Among known thickeners, thickening particulate gel silicas and hydrocolloids, such as carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl guar, hydroxyethyl starch, polyvinylpyrrolidone, high molecular weight polyethylene glycols, vegetable gums such as tragacanth, agar, carrageenan, gum arabic, xanthan gum, and carboxyvinyl polymers (for example, Carbopol® type), are suitable. In addition to the mixture of menthofuran and menthol compounds, oral and dental care agents may in particular contain surface-active substances, preferably anionic and nonionic high-foaming surfactants, such as those already mentioned above, but especially alkyl ether sulfates, alkyl polyglucosides and mixtures thereof.

[0410] Other common toothpaste additives include: Preservatives and antibacterial agents, such as methyl, ethyl or propyl p-hydroxybenzoate, sodium sorbate, sodium benzoate, bromochlorophene, phenyl salicylate, thymol; Anti-calculus agents, for example organophosphates, such as 1-hydroxyethane-1,1-diphosphate, 1-phosphonpropane-1,2,3-tricarboxylic acid and others 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; sweeteners, such as sodium saccharin, sodium cyclamate, sucrose, lactose, maltose, fructose or Apartam®, (L-aspartyl-L-phenylalanine methyl ester), Stivia extract or its sweet components, in particular rebaudiosides; Additional fragrances, such as eucalyptus oil, anise oil, fennel oil, caraway oil, methyl acetate, cinnamaldehyde, anethole, vanillin, thymol and mixtures thereof and other natural and synthetic fragrances; pigments such as titanium dioxide; dye; 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.

[0411] Hydrotropes such as ethanol, isopropyl alcohol, or polyols can also be used to improve the flow behavior; these substances largely correspond to the carriers described at the beginning. The polyols considered here preferably have 2 to 15 carbon atoms and at least two hydroxyl groups. The polyols may contain further functional groups, especially amino groups, or may be modified with nitrogen. Typical examples are: glycerol; Alkylene glycols, such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, pentylene glycol, caprylyl glycol and polyethylene glycols with an average molecular weight of 100 to 1000 daltons; technical oligoglycerol mixtures with an intrinsic degree of condensation of 1.5 to 10, for example technical diglycerol mixtures with a glycerol content of 40 to 50% by weight; Methylol compounds, such as, in particular, trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol and dipentaerythritol; Lower alkyl glucosides, especially those having 1 to 8 carbons in the alkyl residue, e.g., methyl and butyl glucoside; Sugar alcohols with 5 to 12 carbon atoms, such as sorbitol or mannitol; sugars with 5 to 12 carbon atoms, such as glucose or sucrose; Amino sugars, for example, glucamine; Dialcoholamines, for example diethanolamine or 2-amino-1,3-propanediol.

[0412] Suitable preservatives include, for example, phenoxyethanol, formaldehyde solution, parabens, pentanediol or sorbic acid and silver complexes known under the name Surfacine®, as well as other classes of substances known to those skilled in the art and suitable for this purpose.

[0413] Perfume oils are those already defined above: in particular peppermint oil, spearmint oil, anise oil, star anise oil, caraway oil, eucalyptus oil, fennel oil, citron oil, wintergrass oil, clove oil, menthol, etc. may be used as fragrances.

[0414] A preferred embodiment of the cosmetic product is a toothpaste in the form of an aqueous paste-like dispersion containing abrasives, moisturizers, viscosity modifiers and optionally other conventional ingredients, as well as a mixture of menthofuran and menthol compounds in an amount of 0.5 to 2% by weight.

[0415] In mouthwashes, various degrees of combination of essential oils, emulsifiers, astringent and tonic extracts, anti-tartar agents, antibacterial additives, and flavor enhancers in aqueous-alcoholic solutions are readily possible. Another preferred embodiment of the present invention is a mouthwash in the form of an aqueous or aqueous-alcoholic solution containing a mixture of menthofuran and menthol compounds in an amount of 0.5 to 2% by weight. In mouthwashes that are diluted before use, sufficient effect can be achieved at even higher concentrations, depending on the intended dilution ratio.

[0416] The oral care preparation according to the invention preferably contains from 0.1 ppm to 10% by weight, preferably from 1 ppm to 10% by weight, of at least one active ingredient, i.e., a cooling agent or active ingredient mixture, i.e., a cooling agent mixture or a flavor preparation, according to the invention, based on the total weight of the composition.

[0417] The present invention also includes chewing gum containing one or more cooling agents according to the invention or a cooling agent mixture according to the invention or a flavor preparation according to the invention.

[0418] Chewing gum compositions typically contain water-insoluble and water-soluble components. The water-insoluble base, also referred to as "gum base," typically comprises 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 dyes, antioxidants, and the like, provided that these are water-soluble in at most trace amounts.

[0419] Suitable synthetic elastomers are, for example, polyisobutylene having an average molecular weight (by GPC) of 10,000 to 100,000, and preferably 50,000 to 80,000, isobutylene-isoprene copolymers (butyl elastomers), styrene-butadiene copolymers (styrene:butadiene ratio, for example, 1:3 to 3:1), polyvinyl acetate having an average molecular weight (by GPC) of 2,000 to 90,000, and preferably 10,000 to 65,000, polyisoprene, polyethylene, vinyl acetate-vinyl laurate copolymers, and mixtures thereof. Examples of suitable natural elastomers include rubbers such as smoked or liquid latex or guayule rubber, and natural rubbers such as jelutong, lechi caspi, perillo, sorba, massaranduba balata, massaranduba chocolate, nispero, rosindinha, chicle, gutta hang kang, and mixtures thereof. The choice of synthetic and natural elastomers and their mixing ratios are essentially determined by whether the chewing gum is intended to create bubbles ("bubble gum"). Elastomer mixtures containing jelutong, chicle, sorba, and massaranduba are preferably used.

[0420] Since elastomers are often too hard to deform during processing, it is also advantageous to use special plasticizers, which of course must meet all the requirements for approval as food additives. In this regard, esters of resin acids, such as esters of lower aliphatic alcohols or polyols with fully or partially cured monomeric or oligomeric resin acids, are particularly suitable. In particular, methyl esters, glycerol esters, or pentaerythritol esters, as well as mixtures thereof, are used for this purpose. Alternatively, terpene resins, which can be derived from α-pinene, β-pinene, δ-limonene, or mixtures thereof, can also be considered.

[0421] Suitable fillers or texturizing agents include magnesium or calcium carbonate, pumice powder, silicates, especially magnesium or aluminum silicate, clay, aluminum oxide, talc, titanium dioxide, calcium mono-, di- and triphosphate and cellulose polymers.

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

[0423] Suitable colorants and whiteners are, for example, types FD and C approved for coloring foods, plant and fruit extracts, and titanium dioxide.

[0424] The base compound may contain wax or may be wax-free; examples of wax-free compositions can be found, inter alia, in patent specification US Pat. No. 5,286,500.

[0425] In addition to the water-insoluble gum base, chewing gum preparations usually contain a water-soluble portion formed by softeners, sweeteners, fillers, flavorings, flavor enhancers, emulsifiers, colorants, acidifiers, antioxidants, etc., provided that the constituents have at least sufficient water solubility. Depending on the water solubility of a particular representative, individual components can therefore belong to both the water-insoluble and the water-soluble phase. However, it is also possible to use, for example, a combination of water-soluble and water-insoluble opacifiers, in which case the individual representatives are in different phases. Typically, the water-insoluble portion constitutes 5 to 95% by weight of the preparation, preferably 20 to 80% by weight.

[0426] Water-soluble softeners or plasticizers are added to chewing gum compositions to improve chewability and chewability, and are usually present 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 sweeteners, used in amounts of 5 to 95% by weight, preferably 20 to 80% by weight, and particularly 30 to 60% by weight, based on the chewing gum composition. Typical saccharide sweeteners are sucrose, dextrose, maltose, dextrin, dry invert sugar, fructose, levulose, galactose, corn syrup, and mixtures thereof. Sugar substitutes include sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates, maltitol, and mixtures thereof. Furthermore, 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, monellin, and the like, alone or in mixtures, may also be considered as additives. Particularly effective are also hydrophobic HIAS, the subject of International Patent Application WO2002091849A1 (Wrigleys), and stevia extract and its active ingredients, in particular rebaudioside A. The amounts of these substances used depend mainly on their performance capacity and are usually in the range of 0.02 to 8% by weight.

[0428] For example, fillers such as polydextrose, raftilose, rafutilin, fructooligosaccharides (NutraFlora), palatinose oligosaccharides, guar gum hydrolysate (Sun Fiber) and dextrins are particularly suitable for the production of low calorie chewing gum.

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

[0430] The chewing gum may also contain excipients and additives, such as chlorhexidine, CPC or triclosan, which are suitable for dental care, especially to combat plaque and gingivitis. Furthermore, it may contain pH adjusters (e.g., buffers or urea), active ingredients against dental caries (e.g., phosphates or fluorides), active ingredients of biological origin (antibodies, enzymes, caffeine, plant extracts), as long as these substances are food-approved and do not interact with each other in an undesirable way.

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

[0432] The plaster according to the present invention is prepared by conventional methods.

[0433] In its simplest form, the matrix system consists of three parts: a flexible support film, an adhesive matrix containing the active ingredient, and a release film. If a non-adhesive matrix is ​​used, the support film must be provided with an adhesive in a contoured area for adhesion to the skin.

[0434] Membrane systems, on the other hand, have at least five parts: a flexible support membrane, 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 release membrane.

[0435] In nonwoven systems, the active ingredient-containing layer consists of an absorbent nonwoven fabric or porous polymer impregnated with a solution or suspension of the active ingredient. This layer is tightly connected to a support film, which is then covered with a peel-off film. The support film is contoured to provide an 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 commonly used in the production of plasters. In addition to the adhesive, a polymer with a glass transition temperature between -70 and -10°C, especially between -55 and -25°C, and a carrier film that is covered with this adhesive, and the active ingredient, emulsifiers, thickeners, substances intended to influence the release of the active ingredient, and other auxiliary substances are often added.

[0437] Self-adhesive polymers with the low glass transition temperatures mentioned above 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 are intended to be greater than its adhesion to human skin, so that they can be largely removed again 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 numerous other comonomers as copolymerized units, such as (meth)acrylic acid, (meth)acrylonitrile, (meth)acrylamide, N-tert-butyl (meth)acrylamide, vinyl esters such as vinyl acetate, vinyl propionate, or vinyl butyrate, other vinyl compounds such as styrene, and also butadiene. Particular emphasis is placed on butyl acrylate and 2-ethylhexyl acrylate. The polymer may be crosslinked by addition of small amounts of comonomers having two or more copolymerizable double bonds, i.e., for example, diacrylates, such as butanediol diacrylate, or divinyl compounds, such as divinylbenzene, or by addition of other crosslinking agents, such as melamine formaldehyde resins. Additionally, polyisobutylene and polyvinyl ethers of various molecular weights can be used as adhesive polymers.

[0438] The particle size of the dispersion should be between 50 and 500 nm, in particular 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. A small particle size and a high degree of crosslinking can lead to an increased release of the active substance.

[0439] Matrix patch can be prepared in a conventional manner by dissolving or finely dispersing active ingredient in suitable polymer solution, and then spreading this self-adhesive mass containing active ingredient by roller or doctor blade coating process to form a thin film.In some cases, it is beneficial to dissolve or finely disperse active ingredient in organic solvent, such as ethanol or acetone, before adding it to polymer solution.In this way, the active ingredient can be more effectively distributed in the polymer.

[0440] Patches can also be prepared by incorporating the active ingredient in finely divided form (particle size below 200 μm, especially below 50 μm) into an aqueous latex dispersion, or by dispersing or dissolving it in an aqueous emulsifier solution and mixing this mixture with the aqueous latex dispersion at temperatures between 10 and 80° C., especially between 30 and 70° C. In addition, a salt of the active ingredient in aqueous solution can be mixed with the polymer dispersion at a pH where the active ingredient is predominantly present in its water-soluble, ionized form. The active ingredient is then converted to an uncharged, water-insoluble form by a pH shift, while simultaneously being emulsified in the dispersion.

[0441] It is advantageous to prepare the active substance, add an opacifier and water, and then mix it with the polymer dispersion. The dispersion containing the active substance obtained in this way is optionally provided with additional excipients and, as mentioned above, is stretched by a method known per se to form a thin film on a support film and dried. The drying temperature can be between room temperature and 100°C, whereby the optimum value between 35°C and 45°C is obtained between the desired rapid drying and the avoidance of air bubble formation in the film and thermal stress on the active substance. This process has the great advantage of avoiding organic solvents. However, in principle, all other common processes for producing matrix matches can also be considered.

[0442] The resulting thin film has a thickness of 10 to 800 μm, preferably 50 to 300 μm. Thin film production can be continuous or discontinuous. The coating process can be repeated several times until the desired thickness of the thin film is reached. The adhesive polymer layer contains the active ingredient in a concentration ranging from 1 to 40% by weight, in particular 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 impregnated into the nonwoven fabric or porous polymer in nonwoven fabric systems.

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

[0444] The desired viscosity of the ready-to-extract mass can be adjusted by adding, for example, polyacrylic acid or cellulose derivatives. Melamine-formaldehyde resins, for example, can be used as additional crosslinkers, which improve the cohesive strength and therefore the adhesive properties of the thin film.

[0445] Swelling agents such as polyvinylpyrrolidone, cellulose derivatives or polyacrylates have the effect of improving the release of the active ingredient, since the membrane can absorb more water, thereby reducing the diffusion resistance. The release of the active ingredient can also be improved by adding hydrophilic plasticizers such as glycerol, polyethylene glycol 1,2-propanediol, and lipophilic plasticizers such as triacetin, dibutyl phthalate or isopropyl myristate.

[0446] Matrix patches usually provide first order release of the active ingredient. For example, the use of fillers that absorb the active ingredient, such as aerosil, microcrystalline cellulose, or lactose, can provide near zero order release.

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

[0448] Plasters according to the present invention constructed according to the membrane system are also prepared in the usual way. Plasters constructed according to the nonwoven system are prepared by impregnating a nonwoven fabric or porous polymer connected to a support film with a solution or dispersion of the active substance in a hydrophilic or lipophilic solvent or solvent mixture, followed by application of an impermeable peel-off film.

[0449] In principle, the content of active ingredient 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] Furthermore, the invention relates to textile products provided with the coolant or coolant mixture according to the invention.

[0451] Finishing fabrics with cooling substances is used, especially when the garments are in direct contact with the skin, so that the active substance can exert its effect via transdermal migration, for example, locally or systemically. Recently, fabrics equipped with so-called health additives, i.e., substances that promote health, have been reported.

[0452] On the other hand, insecticidal finishes are of interest for material protection, for example finishing fabrics against moth damage, but also in particular for repelling parasitic insects such as mosquitoes.

[0453] A fundamental problem in the finishing of fabrics with active substances is the binding of the active substance to the fabric carrier, which on the one hand must ensure the performance of the finish, and on the other hand must be selected in such a way that the active substance does not lose its effectiveness. Various approaches have been proposed in the state of the art.

[0454] For example, cyclodextrins have been proposed for binding active ingredients to fabrics. 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, and eight α-1,4-linked glucose units, respectively. A distinctive feature of cyclodextrin molecules is their ring structure, which is largely of invariant size. 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 guest molecules, especially hydrophobic guest molecules, in varying amounts up to saturation.

[0455] The state of the art describes the finishing of fabrics with perfumes and other low-molecular-weight organic active ingredients that are bound to the fabric via amylose-containing substances with an amylose content of at least 30%. The amylose-containing substances bind the active ingredients to the fabric and release them in a controlled manner so that the effect is maintained over a long period of time. It is assumed that, similar to cyclodextrins, the active ingredients are reversibly bound to the cavities formed by the amylose helical structure in the sense of an inclusion compound, thereby achieving, on the one hand, fixation of the active ingredients to the surface of the fabric and, on the other hand, allowing for controlled release.

[0456] In addition to amylose, all substances having an amylose content of at least 30% by weight, especially at least 40% by weight, are suitable for finishing the fabrics according to the present invention, particularly starches containing amylose, i.e., native starches, modified starches, and starch derivatives. The starch may be native, obtained by partial digestion of native starch, or chemically modified, such as corn starch, wheat starch, potato starch, sorghum starch, rice starch, or maranta starch. Also suitable is pure amylose, such as enzymatically obtained amylose, e.g., amylose obtained from sucrose. 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. All weight percentages referring to amylose or amylose-containing substances, here and below, are understood to always refer to the total weight of amylose + starch in the case of mixtures of amylose and starch, unless expressly stated otherwise. Particularly preferred according to the present invention are amylose-containing substances, especially amylose and amylose-containing starches, whose amylose content is at least 40% by weight, especially at least 45% by weight, based on the total weight of the substance. Typically, the amylose content does not exceed 90% by weight, especially 80% by weight. Such substances are known and commercially available. For example, amylose-containing starches are sold by Cerestar under the trade name Amylogel® and by National Starch under the trade names HYLON® V and VII.

[0457] To achieve binding of the active substance(s) to the fabric, the amylose-containing substance may be applied to the fabric in an amount typically of at least 0.5 wt.%, preferably at least 1 wt.%, and especially at least 2 wt.%, based on the weight of the fabric. Typically, the amylose-containing substance is used in an amount of 25 wt.% or less, often 20 wt.% or less, especially 15 wt.% or less, based on the weight of the fabric, so as not to adversely affect the tactile properties of the fabric. First, the textile material is finished with the amylose-containing substance, and then the finished fabric is treated with a suitable preparation of the active substance. In this way, the active substance is loaded onto the amylose-containing substance present on the fabric. However, it is also possible to finish the fabric using the amylose-containing substance together with the active substance. In this case, the active substance and the amylose-containing substance can be used both as a mixture of separate components and in the already preformed form of an amylose-active substance complex. Typically, the active substance is used in an amount sufficient to achieve the desired effect. The upper limit is determined by the maximum absorption capacity of the amylose units of the amylose-containing material used and is usually no more than 20% by weight, often no more than 10% by weight, based on the amylose content of the material. If desired, the active substance is generally used in an amount of 0.00001 to 15%, 0.0001 to 10%, 0.001 to 5%, 0.005 to 1%, or 0.1 to 10%, or 0.5 to 5% by weight, based on the amylose portion of the amylose-containing material.

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

[0459] In principle, any organic compound or mixture of organic compounds known to be an active substance and capable of inducing a physiological effect in living organisms, such as humans or animals, including microorganisms, is suitable as an additional active substance. Mention should be made of active substances known to be capable of forming inclusion compounds with cyclodextrins. Particularly suitable are active substances having hydrocarbon groups, especially aliphatic, alicyclic, and / or aromatic structures. The molecular weight of the active ingredient is usually below 1,000 daltons, often in the range of 100 to 600 daltons. Also suitable are inorganic compounds, such as hydrogen peroxide, known to be capable of binding to cyclodextrins.

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

[0461] Preferred active pharmaceutical ingredients are those known to be absorbable through the skin, such as ibuprofen, flurbiprofen, acetylsalicylic acid, acetamidophen, apomorphine, butylated hydroxytoluene, chamazulene, guaiazulene, chlorthalidone, cholecalciferol, dicumarol, digoxin, diphenylhydantoin, furosemide, hydroflumethiazine, indomethacin, iproniazid phosphate, nitroglycerin, nicotine, nicotinamide, oubain, oxyprenolol, papaverine alkaloids such as papaverine, laudanosine, ethaverine and narcotine, and berberine, as well as retionol, trans-retinoic acid, pretinol, spiro Nolactone, sulpiride, theophylline, theobromine, corticosteroids and derivatives, including testosterone, 17-methyltestosterone, cortisone, corticosterone, dexamethasone, triamcinolone, methylprednisolone, fludrocortisone, fluocortolone, prednisone, prednisolone, progesterone, 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 active ingredients suitable according to the present invention that are active against parasites include nematicides, fungicides, fungicides, insecticides, moth 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 and tin, copper oxines, 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 halide compounds, especially chlorides (benzalkonium chloride); Aliphatic nitrogen fungicides and bactericides, such as cymoxanil, dodine, dodizin, guazidine, iminoctadine, dodemorph, fenpropimorph, fenpropidin, tridemorph; Substances with peroxide groups, such as hydrogen peroxide, and organic peroxides, such as dibenzoyl peroxide; Organochlorine compounds, such as chlorhexidine; Triazole fungicides such as azaconazole, cyproconazole, diclobutrazol, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, metconazole, propiconazole, tetraconazole, tebuconazole and triticonazole; strobilurins such as dimoxystrobin, fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin and trifloxystrobin; Sulfonamides such as tolylfluanid and dichlofluanid; Iodine compounds, such as diiodomethyl-p-tolylsulfone, napcoside 3-rhodo-2-propynyl alcohol, 4-chlorophenyl-3-iodopropargyl formal, 3-bromo-2,3-diiodo-3-propentylethyl carbonate, 2,3,3-triiodoallyl alcohol, 3-iodo-2-propynyl n-hexylcarbamate, 3-bromo-2,3-diiodo-2-propentyl alcohol, 3-iodo-2-propynyl phenylcarbamate, 3-iodo-2-propynyl n-butylcarbamate, 0-1-(6-iod-3-oxohex-5-ynyl)phenyl carbamate, 0-1-(6-iod-3-oxohex-5-ynyl)butyl carbamate; Isothiazolinones, such as N-methylisothiazolin-3-one, 5-chloro-N-methylisothiazolin-3-one, 4,5-dichloro-N-octylisothiazolin-3-one, 1,2-benzisothiazol-3(2H)one, 4,5-trimethylisothiazol-3-one and N-octyl-isothiazolin-3-one.

[0462] Examples of insecticides and acaricides are organophosphates such as acephate, azamethiphos, azinphos-methyl, chlorpyrifos, chlorpyrifos-methyl, chlorfenvinphos, diazinon, dichlorvos, dicrotophos, dimethoate, disulfon, ethion, fenitrothion, fenthion, isoxathion, malathion, methamidophos, methidathion, methyl parathion, mevinphos, monocrotophos, oxydemeton-methyl, paraoxon, parathion, Rhthion, fenthopate, phosalone, phosmet, phosphamidon, phorate, phoxim, pirimiphos-methyl, profenophos, prothiophos, sulprofos, triazophos, trichlorfon; in particular pyrethroids, for example acrinathrin, allethrin, bioallethrin, bartholin, bifenthrin, bioethanometrin, cyclethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin Phosphorus, 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, pyresmethrin, resmethrin, bioresmethrin, cismethrin, tefluthrin, telalethrin, tetramethrin, tralomethrin, transfluthrin, etofenprox, flufenprox, halfenprox, protrifenbute and silaflufen; pyrrole and pyrazole insecticides such as acetoprole, ethiprole, fipronil, tebufenpyrad, tolfenpyrad, chlorfenapyr and vaniliprole.

[0463] Examples of insect repellent active ingredients are, in particular, anthraquinone, acridine base, copper naphthenate, butopyronoxyl, dibutyl phthalate, dimethyl phthalate, dimethyl carbonate, ethohexadiol, hexamide, methoquin-butyl, N-methylneodecanamide, camphor, bergamot oil, daisy flower, 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 health 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, etc.; fatty acids, such as omega-6 fatty acids, linolenic acid, linoleic acid; waxes of animal or vegetable origin, such as beeswax, candelilla wax, shea butter, sal butter, mango seed butter, Japan wax, etc.; vitamins, in particular fat-soluble vitamins, such as tocopherol, vitamin E, vitamin A, etc.; corticosteroids, such as cortisone, corticosterone, dexamethasone, triamcinolone, methylprednisolone, fludrocortisone, fluocortolone, prednisone, prednisolone, progesterone; amino acids, such as arginine, methionine; plant extracts, such as algae extract, horse chestnut extract, mango extract, etc.

[0464] To improve the cleaning performance of the finish according to the invention, it has been found to be beneficial to fix the amylose-containing material to the fabric with a binder. Suitable binders include film-forming, water-insoluble polymers and low-molecular-weight reactive materials that polymerize upon heating. Typically, 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 especially in the range of 2:1 to 20:1.

[0465] Typically, film-forming polymers are used in the form of an aqueous dispersion of finely divided polymer particles. Particle size is of secondary importance to the success of the present invention, however, it is generally below 5 μm (weight average), and usually ranges from 50 nm to 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. If the polymer binder comprises several polymer 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, more preferably -20 to +40°C. Preferably, all polymer components have glass transition temperatures in these ranges. The glass transition temperatures indicated refer to the "midpoint temperature" determined by DSC according to 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 classes of polymers: (1) Polyurethane resin; (2) acrylic 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 with vinyl propionate; (6) vinyl ester olefin copolymers, such as vinyl acetate / ethylene copolymers; (7) Acrylate vinyl ester 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 materials 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, Permutex® from Stahl, and BASF SE, Waalwijk, Netherlands, or can be prepared according to known processes, for example, those described in the relevant technical literature. The film-forming polymer may be self-crosslinking, i.e., the polymer has functional groups (crosslinkable groups) that react with the functional groups of amylose or a low-molecular-weight crosslinker to form bonds when the composition dries, optionally upon heating. Examples of crosslinkable functional groups include aliphatically bound OH groups, NH-CH2-OH groups, carboxylic acid groups, anhydride groups, capped isocyanate groups, and amino groups. In many cases, polymers with free OH groups remaining as reactive groups will be used. Typically, the ratio of reactive functional groups is 0.1 to 3 moles per kg of polymer. Crosslinking can be achieved within the polymer by reaction of complementary reactive functional groups. Preferably, crosslinking of the polymer is achieved by adding a crosslinker having a reactive group complementary to the functional group of the crosslinker. Suitable pairs of functional groups with complementary reactivity are known to those skilled in the art. Examples of such pairs are OH / COOH, OH / NCO, NH2 / COOH, NH2 / NCO, and M. 2+ / COOH, where M 2+ is Zn 2+ , Ca 2+ , or Mg 2+Examples of suitable crosslinking agents are the diols or polyols mentioned below for polyurethanes; primary or secondary diamines, preferably primary diamines, such as alkylenediamines, for example, hexamethylenediamine, diethylenetriamine, triethylenetetraamine, tetraethylenepentamine, N,N-bis[(aminopropyl)amino]ethane, 3,6-dioxaoctanediamine, 3,7-dioxanediamine, 3,6,9-trioxaundecanediamine or Jeffamine, (4,4-diaminodicyclohexyl)methane, ( Examples of suitable crosslinking agents include 4,4'-diamino-3,3-dimethyldicyclohexylmethane; aminoalcohols such as ethanolamine and hydroxypropylamine; ethoxylated di- and oligoamines; dihydrazides of aliphatic or aromatic dicarboxylic acids such as adipic 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 which are reversibly blocked, e.g., with bisulfite. In this case, the weight ratio of crosslinking agent to polymer binder is such 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 polymer binder (calculated as solids) to 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 amylose-containing substances by water-insoluble polymers, amylose or amylose-containing substances can also be fixed to the textile material by reactive compounds having at least one group reactive towards the OH groups of amylose and at least one further functional group reactive towards functional groups, such as OH, NH or COOH groups, on the fibers of the textile material. Reactive compounds include the crosslinkers mentioned above and substances proposed in DE 4035378A for fixing cyclodextrins, 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 such as 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, for example, in the form of aqueous formulations for finishing textiles, from BASF SE under the trade names Fixapret® and Fixapret®-eco. Reactive substances that can be used to fix amylose-containing substances to textile materials include, in particular, compounds with two, three, four or more (possibly reversibly blocked) isocyanate groups, especially those with bisulfites or CH-acidic compounds or oximenes, such as butanone oxime, reversibly blocked polyisocyanate prepolymers based on polyether and polyester urethanes, as described in DE 2837851, DE 19919816 and the earlier patent application EP 03015121. Such products are also commercially available, for example under the trade names PROTOLAN® 367 and PROTOLAN® 357 from Rotta GmbH, Mannheim.

[0470] For the immobilization of amylose-containing substances, the procedures known for the immobilization of cyclodextrins can also be used in an analogous manner, with the cyclodextrin, or in this case the amylose-containing substance, being provided with a reactive anchor by treating it with a dicarboxylic acid or dicarboxylic acid anhydride, for example maleic acid, fumaric acid, maleic anhydride, succinic acid, succinic anhydride, with a diisocyanate, for example toluene diisocyanate, isophorone diisocyanate, tetramethylene diisocyanate or hexamethylene diisocyanate, or with an aminocarboxylic acid, in a manner known per se, so that only one of the functionalities present in these compounds reacts with the OH group of the amylose-containing substance, the others being retained for bonding to the reactive groups of the fiber material. Reactive anchors can also be created on amylose-containing materials 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 be used to anchor amylose.

[0471] In principle, all textile materials, i.e., non-manufactured and manufactured products, can be finished in this way. Textile materials, here and below, include woven fabrics, knitted fabrics, warp-knitted fabrics, and nonwoven fabrics. Textile materials can be composed of natural fiber yarns, synthetic fiber yarns, and / or mixed yarns. In principle, all textile materials commonly used in textile manufacturing can be considered textile materials. These include cotton, wool, hemp fiber, sisal fiber, flax, ramie, polyacrylonitrile fiber, polyester fiber, polyamic acid fiber, viscose fiber, silk, acetate fiber, triacetate fiber, aramid fiber, etc., and mixtures of these textile materials.

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

[0473] For example, mention should be made of processes in which the amylose-containing substance, optionally in complex with an active ingredient, is already spun into the fibres, fibrils and / or yarns from which the textile 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. Typically, the textile is treated with an aqueous solution containing a sufficient amount of the amylose-containing substance and, optionally, the active ingredient. Depending on the type of application to which the amylose-containing substance is to be applied and the desired amount, the concentration of the amylose-containing substance in the solution is in the range of 1 to 40 wt. %, in particular in the range of 2 to 20 wt. %, in particular in the range of 4 to 15 wt. %.

[0475] The type of treatment is of secondary importance and can be applied, for example, as a minimal application, e.g., by spray application, as a regular application with a padder, or as a moist application. In this case, the textile material is immersed in the aqueous solution. If necessary, excess solution can then be removed by squeezing until the solution absorption reaches about 30-120%. 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 solution in water containing the desired amount of amylose-containing substance and possibly the active ingredient, e.g., 0.5-20 wt.% (based on the mass of the textile to be finished). The textile material is immersed in the treatment solution for a specific time, e.g., 10-60 min, in a finishing unit suitable for this purpose (e.g., reel skid, roll skid, paddle, etc.), and then squeezed and / or spun off as described above. The solution ratio here is usually in the range of 1:2 to 1:50, in particular 1:3 to 1:20.

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

[0477] Treatment with the solution is usually followed by a drying process. The temperature is usually in the range of 100-200°C, preferably in the range of 120-180°C. Drying can be carried out in equipment customary for this purpose, for example by rotary drum drying at the temperatures specified above in the case of ready-made products. In the case of non-manufactured products, the textile material is usually passed through one or more tenter frames after application.

[0478] If an amylose-containing substance is used together with a film-forming polymer, drying results in the fixation of the amylose-containing substance on the textile fibers. Typically, the drying temperature is not lower than 100°C, preferably in the range of 120-200°C, especially in the range of 140-180°C. Although longer drying times are also suitable, drying is generally carried out for 1-10 minutes, especially 1-2 minutes. For treatment with an aqueous solution, it has been shown to be advantageous if the aqueous solution contains, in addition to the amylose-containing substance and, optionally, an active substance, at least one surface-active substance (or surfactant) suitable for dispersing the amylose-containing substance and the active substance in the aqueous solution. Preferably, the surfactant is an oligomeric or polymeric dispersant. The term oligomeric or polymeric dispersant includes dispersants whose number-average molecular weight is usually at least 2,000 Daltons, e.g., in the range of 2,000 to about 100,000 Daltons, especially about 3,000 to 70,000 Daltons, in contrast to low-molecular-weight surfactants. Typically, the aqueous solution contains the oligomeric or polymeric dispersant in an amount of 0.5 to 20% by weight, preferably 1 to 18% by weight, especially 5 to 15% by weight, based on the amylose-containing material.

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

[0480] Preferred anionic oligomeric or polymeric dispersants are characterized by the fact that they contain carboxyl and / or sulfonic acid groups and are usually used as salts, for example alkali metal or ammonium salts. Preferred anionic dispersants are, for example, carboxylated derivatives of cellulose, such as carboxymethylcellulose, homopolymers of ethylenically unsaturated C3-C8 monocarboxylic 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 and C4-C8 dicarboxylic acids, as mentioned above, and copolymers of at least one of the above-mentioned ethylenically unsaturated C3-C8 monocarboxylic and 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 aforementioned ethylenically unsaturated carboxylic acids such as acrylamide and methacrylamide, hydroxy-C1-C4 alkyl (meth)acrylates such as acrylic acid and hydroxyethyl methacrylate, esters of ethylenically unsaturated C3-C8 mono- or C4- to C8-dicarboxylic acid polyethers such as esters of acrylic acid or methacrylic acid with polyethylene oxide or ethylene oxide / propylene oxide block copolymers, vinyl aromatic compounds such as styrene and C2- to C16-olefins such as ethylene, propene, 1-hexene, 1-octene, 1-decene, 1-dodecene, etc. Further preferred are homopolymers of ethylenically unsaturated sulfonic acids such as styrenesulfonic acid and acrylamidopropanesulfonic acid and their copolymers with the aforementioned comonomers. In the copolymers, the proportion of ethylenically unsaturated acids is generally at least 20% by weight and does not exceed values ​​of 90% by weight and in particular 80% by weight, based in each case on the total weight of all the monomers constituting the polymer.Copolymers of at least one of the abovementioned acids and at least one comonomer are known for this purpose, for example copolymers of acrylic acid and maleic acid are sold commercially under the trademark Sokalan from BASF SE.

[0481] Preferred anionic dispersants are also phenolsulfonic acid-formaldehyde condensates and naphthalenesulfonic acid-formaldehyde condensates (eg Tamol and Setamol trademarks of BASF) and lignosulfonates.

[0482] Suitable dispersants are also low-molecular-weight anionic, nonionic, cationic, amphoteric, and amphoteric surfactants. Suitable surfactants include, for example, C8-C18 alkyl sulfate alkali metal salts, ammonium salts, or amine salts, 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. Preferred are alkyl sulfates and alkyl sulfonates.

[0483] If the amylose-containing substance is not used together with the water-insoluble film-forming polymer, the fabric can be treated with the polymer in a separate step. In particular, the treatment is carried out together with the amylose-containing substance. Accordingly, certain embodiments relate to a process in which the aqueous solution 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 1:50, and particularly in the range of 2:1 to 20:1.

[0484] The finishing of the fabric with the cooling substance according to the invention or the cooling substance mixture according to the invention can be carried out in a separate operation from the finishing with the amylose-containing substance or together in one operation.

[0485] If the fabric is treated with an active ingredient in a separate step, the fabric is also treated with an aqueous solution of the active ingredient. For this purpose, the active ingredient, which is usually water-insoluble, 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, among which nonionic surfactants are preferred, in particular polyoxyethylene sorbitan esters, esters of mono- or disaccharides with C6-C18 fatty acids, and particularly preferably C8-C18 alkyl ethoxylates, in particular 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, especially 0.2 to 5% by weight. The amount of surface-active substance is usually in the range of 0.5 to 50% by weight, especially 3 to 30% by weight, based on the active substance. Application of the active substance from the aqueous solution can be carried out by methods customary for this purpose, such as a padder. However, it is also possible to finish the active substance and the amylose-containing substance in one step. In this case, the process can proceed essentially as described for finishing with the amylose-containing substance, whereby the aqueous solution of the amylose-containing substance now further contains at least one active substance. The active substance can be added to the solution separately or in the form of an inclusion compound, i.e., a host-guest complex with the amylose-containing substance.

[0487] The present invention can be used to finish any textile, i.e., manufactured and non-manufactured products. Textile materials, as used herein and hereinafter, include woven fabrics, knitted fabrics, warp-knitted fabrics, and nonwoven fabrics. Textile materials can be composed of natural fiber yarns, synthetic fiber yarns, and / or mixed yarns. In principle, all textile materials commonly used in textile manufacturing can be considered textile materials. These include 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. Also suitable are glass fibers and blends of the aforementioned textile materials with glass fibers, such as glass fiber / Kevlar® blends. The type of textile material depends primarily on the desired application. The fabrics to be finished may be ready-made articles such as garments including underwear and outerwear, e.g., shirts, trousers, jackets, outdoor gear, trekking gear and military equipment, roofing, tents, netting, e.g., insect netting and curtains, hand and bath towels, sheets and pillowcases, etc. Similarly, finishing can be done on raw fabric in bale or roll form.

[0488] By using amylose-based active ingredients, the active ingredients remain on the finished fabrics even after several washes. In addition, the finished fabrics are characterized by a comfortable feel that is particularly advantageous for the wearability of garments made from these fabrics.

[0489] Fabrics with active substances against insects and parasites such as mites are particularly suitable in animal protection for protection against ticks, mites, fleas, etc., in addition to protecting humans.

[0490] The present invention further relates to chilled tobacco products.

[0491] The active ingredients according to the invention, i.e. the cooling active ingredients according to the invention, or the cooling agent mixtures according to the invention, or the flavor preparations according to the invention, can also be advantageously used to produce tobacco products. Examples of such tobacco products include cigars, sowing tobacco, pipe tobacco, chewing tobacco and snuff. The production of tobacco products supplemented with cooling additives is known per se.

[0492] In principle, the content of active ingredient, i.e. the content of the coolant according to the invention or the 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] Manufacture can also be 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, suitable finished plastic packaging material can be manufactured according to the information in the literature about the manufacture of polymer thin film.The manufacture of suitable coated paper is also known to those skilled in the art.

[0495] Finally, the present invention provides a method for producing a method of manufacturing a semiconductor device comprising the steps of: (i) providing at least one physiological cooling agent or cooling agent mixture according to the present invention, or providing a cosmetic or pharmaceutical product according to the present invention; (ii) a method for modulating the cold menthol receptor TRPM8, in particular in vitro and / or in vivo, comprising contacting the receptor with the cooling agent or cooling agent mixture or cosmetic or pharmaceutical product of step (i); or The following steps: (iii) providing at least one physiological cooling agent or cooling agent mixture according to the present invention, or providing a cosmetic or pharmaceutical product according to the present invention; (iv) contacting the cooling agent or cooling agent mixture or cosmetic or pharmaceutical product of step (iii) with human skin or mucosa; or The following steps: (v) providing at least one physiological cooling agent according to the present invention or a cooling agent mixture according to the present invention, or providing a cosmetic or pharmaceutical product according to the present invention and at least one flavoring agent; (vi) mixing the two components and, if necessary, (vii) incorporating the mixture into an oral preparation.

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

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

[0498] Preparation of the Active Substances: The active substances used in accordance with the present invention can be prepared by those skilled in the art of organic synthesis according to 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 commercially available (e.g., BioChain, Hayward, USA) and can be generated from the androgen-sensitive human prostate adenocarcinoma cell line LnCaP (e.g., ATCC CRL1740 or ECACC 891 1021 1) using standard kits.

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

[0502] Generation of HEK293 test cells

[0503] As a test cell line, we created a HEK293 cell line stably transfected with human TRPM8 DNA. We preferentially use HEK293 because it offers the possibility of inducing TRPM8 expression with tetracycline via the introduced plasmid.

[0504] Methods for producing suitable test cell lines are known to those skilled in the art and can be found in the relevant technical 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 assessed by Ca 2+ This can be quantified using a Ca sensitive dye (e.g., FURA, Fluo-4, etc.). For example, in the presence of menthol, Ca is not quantified by agonist alone. 2+ signal, and the antagonist 2+ causing a decrease in signal (in each case Ca 2+ It is detected via the dye Fluo-4, which has different fluorescent properties due to the ion.

[0507] First, a fresh culture of transfected HEK cells is prepared in a cell culture flask by a method known per se. The HEK293-TRPM8 test cells are detached from the cell culture flask using trypsin and seeded at 40,000 cells / well in 100 μl of medium in a 96-well plate (Greiner #655948, coated with poly-D-lysine). Tetracycline is added to the growth medium to induce TRPM8 receptor expression (DMEM / HG, tetracycline-free 10% FCS, 4 mM L-glutamine, 15 μg / ml blasticidin, 100 μg / ml hygromycin B, 1 μg / ml tetracycline).

[0508] The next day, cells were loaded with Fluo-4 AM dye and the assay was performed as follows: Add 100 μl / well of staining solution from the Ca-4 kit (RB141, Molecular Devices) to 100 μl of medium (DMEM / HG, 10% FCS without tetracycline, 4 mM L-glutamine, 15 μg / ml blasticidin, 100 μg / ml hygromycin B, 1 μg / ml tetracycline).

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

[0510] Preparation of test substances (various concentrations in 200 μl of HBSS buffer), as well as positive controls (various concentrations of menthol, icilin or ionomycin in 200 μl of HBSS buffer) and negative controls (200 μl of HBSS buffer only); addition of test substances in a volume of 50 μl / well and measurement of the change in fluorescence at an excitation of 485 nm and an emission of 520 nm (in the assay device FLIPR, Molecular Devices or NovoStar, BMG), and evaluation of the potency / concentration of the various substances and determination of the EC50 value.

[0511] Test substances are used in triplicate in the assay at concentrations ranging from 0.1 to 200 μM. Typically, compounds are prepared in DMSO and diluted to a maximum DMSO concentration of 2% for the assay. Surprisingly, our own evaluations in performing the described assays have shown that the compounds used in accordance with the present invention (as described herein) are particularly suitable as agonists of TRPM8.

[0512] The activity of active substances with respect to TRPM8 channel activation is determined using the described assay. This is concentration-dependent. As a reference, 6 to 10 concentrations of each active substance are measured. From the determined activity values, the EC50 value can be determined as the inflection point of the S-shaped curve using mathematical methods (four- or five-parameter logistic curve fitting). These are routine biochemical methods well known to those skilled in the art.

[0513] The EC50 values ​​determined for selected modulators according to the invention are shown below in Table 5. An EC50 value of 1.72 μM was determined for the substance WS-3, which served as a reference.

[0514] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0515] The EC50 value describes the concentration of a cooling substance required for half-maximal effect and is therefore a measure of the efficacy of an agonist drug (drug efficacy as a function of dose or concentration), where efficacy corresponds to the reciprocal value of the EC50 value. Consequently, a low EC50 value corresponds to a high efficacy of the active substance.

[0516] Thus, from Table 5 above, it can be seen that the compounds of the invention described herein have excellent cooling properties and are able to produce a strong cooling effect even at low concentrations, generally well below the EC50 reference value of 1.72 μM for substance WS-3.

[0517] As the above table shows, those structures of general formula (I) in which R1 represents an optionally substituted phenyl group or an optionally substituted 1,3-benzodioxolyl group and R7 represents an optionally substituted pyridinyl group have proven to be particularly advantageous. The latter is preferably substituted with a piperidinyl group. Corresponding particularly preferred structures can also be found in formulae (III) to (VII).

[0518] Furthermore, it has been observed that in said structures m and n are mostly 1. Consequently, structures according to general formulae (I) to (VII) in which m and / or n are 1 are preferred.

[0519] Thus, compounds 1, 8, 13, 17, 14, 17, 22, 23, 24, 27, 34, 39, 41, 49, and 56 (EC50 values ​​≦1.0 μM) are particularly preferred in terms of EC50 values. The lowest EC50 value, i.e., the highest potency of the active substance, is exhibited by the acid addition salt of compound 87, with a value of 0.00695 μM. The corresponding compound, i.e., the neutral, uncharged compound 27, has an EC50 value of 0.1 μM. As a result, the salt compounds exhibit stronger activation of TRPM8 than the equivalent uncharged compounds at the same concentration.

[0520] A particularly efficient cooling effect in terms of TRPM8 activity and EC50 value can be observed for compounds 1, 8, 13, 17, 14, 17, 22, 23, 24, 27, 34, 39, 41, 49 and 56. A particularly efficient cooling effect in terms of TRPM8 activation and EC50 value is shown by the acid addition salt of compound 87.

[0521] In addition to the TRPM8 activity and potency of the active ingredients (EC50 values) described above, the compounds according to the invention also exhibit a potent cooling effect.

[0522] To quantify the cooling effect, comparative tests are conducted using menthane-3-carboxylic acid-N-ethylamide as a reference. For these comparative tests, a person skilled in the art replaces the compound or compounds used according to the present invention with menthane-3-carboxylic acid-N-ethylamide (also known as WS-3). The intensity of the cooling effect of each compound or active substance is then sensorily evaluated by a panel of trained people (n=10-11) as described below and compared with each other.

[0523] The cooling intensity study was conducted as follows: test solutions containing 5 ppm of the compounds of the present invention were tested in 5% sugar solution, as were corresponding solutions containing 30 ppm of the reference substance WS-3. This concentration of WS-3 was selected because at such concentrations, WS-3 has been shown to exhibit good cooling effects. Panelists tasted the corresponding test solutions for exactly 40 seconds, rinsed their entire mouths with the corresponding test solutions, and then spat into the sample or reference solution. Following tasting, panelists rated each cooling intensity after 1 minute according to a scale of 1 (very weak) to 9 (very strong).

[0524] The sensory tasting results of exemplary selected compounds according to the invention are shown in Table 6 below.

[0525] [Table 6-1] [Table 6-2] [Table 6-3]

[0526] Surprisingly, the compounds described herein have been shown to produce a significantly more intense cooling effect than the WS-3 reference sample. In particular, while the reference sample containing WS-3 exhibited a cooling intensity of about 5.4 in the sensory evaluation, the cooling intensity of compounds according to the invention, such as compound 51, was surprisingly rated at 5.5; compound N-(1,3-benzodioxol-4-ylmethyl)-1-[2-(1-piperidyl)-4-pyridyl]ethanamine (compound 1) was rated at about 5.8, while compound 13 was rated at 5.95; 1-(4-methoxyphenyl)-N-[[2-(1-piperidyl)-4-pyridyl]methyl]methanamine (compound 27) was surprisingly highly rated at 6.84, compound 8 was rated at 7, 1-phenyl-N-[[2-(1-piperidyl)-4-pyridyl]methyl]methanamine (compound 39) was 7.02, and 1-[2-(1-piperidyl)-4-pyridyl]-N-(2-thienylmethyl)methanamine (compound 40) was 7.5. Compounds 39, 40, 41, and 42 received scores of 7.02, 7.5, 7.2, and 5.91, respectively. Compound 81 also received a high score of 7.

[0527] It should also be noted that WS-3, despite being a six-fold higher concentration, can produce significantly lower cooling intensity. Conversely, significantly lower concentrations of the compounds of the present invention are required to produce a significantly stronger cooling effect than the common cooling substance (WS-3). This indicates that the compounds of the present invention are so potent when used at low concentrations that they already produce a highly effective cooling effect, and that only small amounts need to be used in corresponding final formulations, such as product formulations containing these cooling substances, to produce a cooling effect that is perceived as being powerful.

[0528] Among the cooling substances examined, a particularly striking combination of TRPM8 activation, EC50 value and cooling potency was exhibited by compounds 1, 8, 13, 23, 27, 39 and 41, which is why these compounds are most preferred.

[0529] In this context, it is preferred that in a corresponding comparison, the cooling effect of the sample with the compound(s) used according to the invention is prolonged compared to the reference sample, preferably by at least 10 minutes, preferably by at least 15 minutes, more preferably by at least 20 minutes, particularly preferably by at least 30 minutes.

[0530] Synthesis Examples

[0531] In the following examples, the decimal point is represented by a dot.

[0532] Preparation of the amines according to the invention

[0533] [ka]

[0534] The haloalkyl derivative (1.0 equiv.) was dissolved in anhydrous DCM, and the corresponding pyridine derivative (1.1 equiv.) and nitrogen-containing base (2.0 equiv.) were added. The reaction mixture was stirred at room temperature overnight. Water and DCM were added to the reaction solution, and the two phases were separated. The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude material was purified by column chromatography to give the desired product as an oil or solid.

[0535] [ka]

[0536] The aldehyde (1.0 equiv.) was dissolved in THF and the corresponding amine (1.0 equiv.) was added at room temperature. This was followed by the addition of acetic acid (3.0 equiv.). The reaction mixture was stirred for 5 minutes, and then STAB (1.5 equiv.) was added as a reducing agent. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. The precipitated crystals were filtered off and washed with THF. The filtrate was concentrated in vacuo, and the crude material was purified by column chromatography (DCM:MeOH, 95:5). The desired product was obtained as a colorless oil.

[0537] [ka]

[0538] The corresponding halogen derivative (1.0 equiv.) and amine (1.1 equiv.) were dissolved in anhydrous toluene, and tri-tert-butylphosphine (0.1 equiv.) and potassium phosphate (3.0 equiv.) were added. The reaction mixture was purged with argon for 15 min, followed by the addition of Pd2(dba)3, and purged again with argon for 15 min. The reaction mixture was stirred at 100 °C overnight. For workup, water (160 mL) and DCM (160 mL) were added. The resulting phases were separated, and the aqueous phase was extracted with DCM (3 × 160 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude product was purified by column chromatography (reverse phase, 0–100% acrylonitrile in water).

[0539] [ka]

[0540] To a suspension of amine (1.0 equiv.) and Cs2CO3 (3.0 equiv.) in DMF at 0 °C was added the desired halogen substitution reagent (1.7 equiv.). The reaction was heated to 40 °C and stirred for 48 h. Water and dichloromethane (1:4 ratio) were then added to the reaction solution. The two phases were separated, and the aqueous phase was washed three times with dichloromethane. The combined organic phases were dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude material was purified by preparative thin-layer chromatography to give the desired product as an oil or solid.

[0541] [ka]

[0542] The corresponding carboxylic acid (1.0 equiv.), HBTU (1.15 equiv.), and EDC × HCl (1.3 equiv.) were dissolved in DMF and stirred at room temperature for 3 hours. The desired amine (1.1 equiv.) and the base DIPEA (3.5 equiv.) were then added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water was then added to the reaction, and the product was extracted twice with a mixture of hexane / ethyl acetate (1:3). The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude material was purified by preparative thin-layer chromatography to give the desired product as an oil or solid.

[0543] [ka]

[0544] The desired amine was dissolved in anhydrous THF under an argon atmosphere. The reaction mixture was cooled to 0°C, and borane dimethyl sulfide complex was added slowly. The reaction was stirred at room temperature for 16 hours, after which water and 2M NaOH were carefully added. DCM was then added, and the phases were separated. The aqueous phase was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (reverse phase), and the product was isolated as the BH3 complex. This complex was dissolved in MeOH, water, and 35% HCl, and the reaction mixture was he...

Claims

1. General formula (VII): is represented by Physiological cooling agents, including compounds in which the residues R1 to R6 and R8, R11 and R12 can be identical or different and which independently of one another have the following meanings or the acid addition salts thereof formed with inorganic or organic acids: In this regard, said physiological cooling agent may be present in stereoisomerically pure form or as a mixture of different stereoisomers.

2. The compound contained in the physiological cooling agent is 10. The physiological cooling agent of claim 1, selected from the group consisting of:

3. The acid addition salt of the compound contained in the physiological cooling agent (1) The physiological cooling agent according to claim 1 or 2, which is selected from acid addition salts formed with inorganic acids or with organic acids selected from mono- or polycarboxylic acids.

4. (a) one, two, three or more physiological cooling agent(s) according to any one of claims 1 to 3, and optionally (b) at least one additional physiological cooling component; and / or optionally (c) a physiological coolant mixture comprising or consisting of at least one solvent.

5. The physiological cooling component (b) Menthol, menthol methyl ether (FEMA GRAS 4054), monomethyl glutamate (FEMA GRAS 4006), menthoxy-1,2-propanediol (FEMA GRAS 3784), dimethyl 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 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 carbonate propylene glycol (FEMA GRAS 3806), N-ethyl menthyl oxamate, monomethyl succinate (FEMA GRAS 3810), WS-3 (N-ethyl-p-menthane-3-carboxamide, FEMA GRAS 3455), menthol carbonate ethylene glycol (FEMA GRAS 3805), WS-5 (ethyl 3-(p-menthane-3-carboxamide)acetate, FEMA GRAS 4309), WS-12 (1R,2S,5R)-N-(4-methoxyphenyl)-p-menthanecarboxamide (FEMA GRAS 4681), WS-27 (N-ethyl-2,2-diisopropylbutanamide, FEMA GRAS 4557), N-cyclopropyl-5-methyl-2-isopropylcyclohexanecarboxamide (FEMA GRAS 4693), WS-116 (N-(1,1-dimethyl-2-hydroxyethyl)-2,2-Diethylbutanamide, FEMA GRAS 4603), menthoxyethanol (FEMA GRAS 4154), N-(4-cyanomethylphenyl)-p-menthanecarboxamide (FEMA GRAS 4496), N-(2-(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 GRAS 4053), 2,3-dihydroxy-p-menthane, 3,3,5-trimethylcyclohexanone glycerol ketal, menthyl pyrrolidone carboxylate, (1R,3R,4S)-3-menthyl-3,6-dioxaheptanoate, (1R,2S,5R)-3-menthyl-methoxyacetate, (1R,2S,5R)-3-menthyl-3,6,9-trioxadecanoate, (1R,2S,5R)-3-menthyl-3,6,9-trioxadecanoate, (1R,2S,5R)-3-menthyl-(2-hydroxyethoxy)acetate, (1R,2S,5R)-menthyl-11-hydroxy-3,6,9-trioxaundecanoate, cubebol (FEMA GRAS 4497), 2-isopropyl-5-methylcyclohexyl-4-(dimethylamino)-4-oxobutanoate (FEMA GRAS 4230), menthyl lactate (FEMA GRAS 3748), 6-isopropyl-3,9-dimethyl-1,4-dioxaspiro[4.5]decan-2-one (FEMA GRAS 4285), 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, a mixture of 2,2,5,6,6-pentamethyl-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)-2-isopropyl-5-methylcyclohexanecarboxamide, 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)ethyl]benzenesulfonamide benzosulfonamide, 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 phenol, 4-((benzhydrylamino)methyl)-2-ethoxyphenol, 1-(4-methoxyphenyl)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)vinyl-4-methoxybenzoate, 2-(1-isopropyl-6-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, D-bornyl, L-bornyl, exo-norbornyl, 2-methylisobornyl, 2-ethylfenchyl, 2-methylbornyl, cis-pinan-2-yl, verbanyl and isobornyl derivatives, menthyl oxamate derivatives, menthyl 3-oxocarboxylic acid esters, N-alpha-(menthanecarbonyl) amino acid amides, p-menthanecarboxamides and WS-23 analogs, (-)-(1R,2R,4S)-Dihydroumberlol, p-menthane alkyloxyamide, 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:

5. The physiological cooling agent mixture of claim 4, wherein the physiological cooling agent mixture is selected from the group consisting of:

6. 6. The physiological cooling agent mixture according to claim 4 or 5, wherein component (a) and component (b) are contained in a weight ratio of 0.1:99 to 99:0.

1.

7. 7. The physiological coolant composition of any one of claims 4 to 6, wherein the solvent is selected from the group consisting of benzyl alcohol, 2-phenylethanol, benzyl benzoate, diethyl succinate, triethyl citrate, triacetin, ethanol, peppermint oil, anethole, optamint, propylene glycol, phenoxyethanol, and mixtures thereof.

8. An aroma preparation, (d) one, two, three or more physiological cooling agent(s) according to any one of claims 1 to 3, or a physiological cooling agent mixture according to any one of claims 4 to 7; (e) at least one flavoring agent.

9. The flavoring substances forming component (e) are 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, citronellyl acetate, cyclohexyl acetate, cymene, damascone, and decalactone. , Dihydrocoumarin, Dimethyl Anthranilate, Dimethyl Anthranilate, Dodecalactone, Ethoxyethyl Acetate, Ethyl Butyrate, Ethyl Butyrate, Ethyl Caprate, Ethyl Caproate, Ethyl Crotonate, Ethyl Furaneol, Ethyl Guaiacol, Ethyl Isobutyrate, Ethyl Isovalerate, Ethyl Lactate, Ethyl Methyl Butyrate, Ethyl Propionate, Eucalyptol, Eugenol, Ethyl Heptylate, 4-(p-Hydroxyphenyl)-2-butanone, Gamma-Decalactone, Geraniol, Geranyl Acetate, Geranyl Acetate, Grapefruit Aldehyde Hydride, methyl dihydrojasmonate, 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, 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, methylbutanol, methylbutyric acid, 2-methylbutyl acetate, methyl caproate, methyl cinnamate, 5-methylfurfural, 3,2,2-methylcyclopentenolone, 6,5,2-Methylheptenone, methyl dihydrojasmonate, methyl jasmonate, 2-methyl methylbutyrate, 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, 2-octanol, 3-octanol, 1,3-octenol, 1-octyl acetate, 3-octyl acetate, palmitate Acetic acid, paraldehyde, phellandrene, pentanedione, phenylethyl acetate, phenylethyl alcohol, phenylethyl isovalerate, piperonal, propionaldehyde, propyl butyrate, pulegone, pulegol, sinensal, sulfurol, terpinene, terpineol, terpinolene, 8,3-thiomenthanone, 4,4,2-thiomethylpentanone, thymol, delta-undecalactone, gamma-undecalactone, valencene, valeric acid, vanillin, acetoin, ethyl vanillin, ethyl vanillin isobutyrate (= 3-ethoxy-4-isobutyryloxybenzaldehyde), 2,5-dimethyl-4-hydroxy-3(2H)-furanone and its derivatives, homofuranol (=2-ethyl-5-methyl-4-hydroxy-3(2H)-furanone and 5-ethyl-2-methyl-4-hydroxy-3(2H)-furanone), maltol and maltol derivatives, coumarin and coumarin derivatives, gamma-lactone, delta-lactone, 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-methylbutyric acid ethyl ester, n-hexanoic acid ethyl ester, n-hexanoic acid allyl ester, n-hexanoic acid n-butyl ester, n-octanoic acid ethyl ester, 3-methyl-3-phenylglycidic acid ethyl ester, 2-trans-4-cis-decadienoic acid ethyl ester, 4-(p-hydroxyphenyl)-2-butanone, 1,1-dimethoxy-2,2,5-trimethyl-4-hexane, 2,6-dimethyl-5-heptan-1-ol 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 ... and / or, selected from the group consisting of methyl-2-methoxypyrazine, 2-acetylpyrazine, 2-pentylpyridine, (E,E)-2,4-decadienal, (E,E)-2,4-nonadienal, (E)-2-octenal, (E)-2-nonenal, 2-undecenal, 12-methyltridecanal, 1-penten-3-one, 4-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, cinnam alcohol, methyl salicylate, isopulegol, and the stereoisomers, enantiomers, positional isomers, diastereomers, cis / trans isomers or epimers of these substances; and / or The flavoring substances forming component (e) are erythritol, threitol, arabitol, ribotol, xylitol, sorbitol, mannitol, dulcitol, lactitol, miraculin, monellin, thaumatin, curculin, brazzein, magap, sodium cyclamate, acesulfame K, neohesperidin dihydrochalcone, saccharin sodium salt, aspartame, super aspartame, neotame, alite, 9. The aroma formulation of claim 8, wherein the active ingredient is selected from the group consisting of glycerin, sucralose, stevinoside, rebaudioside, ragduname, caleram, sucrononate, sucrooctate, monatin, phenylodulcin, glycine, D-leucine, D-threonine, D-asparagine, D-phenylalanine, D-tryptophan, L-proline, hernandulcin, dihydrochalcone glycoside, glycyrrhizin, glycyrrhetinic acid, derivatives and salts thereof, licorice (Glycyrrhiza glabra ssp.) extract, Lippia dulcis extract, Momordica ssp. extract, mogroside, Hydrangea dulcis, and stevinoside, and mixtures thereof.

10. 10. The aroma preparation according to claim 8, wherein the component (d) and the component (e) are contained in a weight ratio of 1:99 to 99:

1.

11. The physiological cooling agent according to any one of claims 1 to 3, in encapsulated form.

12. The physiological cooling agent mixture according to any one of claims 4 to 7, in encapsulated form.

13. The aroma preparation according to any one of claims 8 to 10, which is in an encapsulated form.

14. Use of a physiological cooling agent according to any one of claims 1 to 3 and 11 for improving the taste characteristics of flavouring substances, for reducing or masking unpleasant tastes.

15. Use of a physiological cooling agent mixture according to any one of claims 4 to 7 and 12 for improving the taste characteristics of flavouring substances, for reducing or masking unpleasant tastes.

16. Use of a physiological cooling agent according to any one of claims 1 to 3 and 11 for the manufacture of foodstuffs, dietary supplements, cosmetics or pharmaceuticals, animal feed, textiles, packaging or tobacco products.

17. Use of a physiological cooling agent mixture according to any one of claims 4 to 7 and 12 for the production of foodstuffs, dietary supplements, cosmetics or pharmaceuticals, animal feed, textiles, packaging or tobacco products.

18. Use of an aroma formulation according to any one of claims 8 to 11 and 13 for the production of foodstuffs, dietary supplements, cosmetics or pharmaceuticals, animal feed, textiles, packaging or tobacco products.

19. A foodstuff comprising a physiological cooling agent according to any one of claims 1 to 3 and 11, or a physiological cooling agent mixture according to any one of claims 4 to 7 and 12, or an aromatic preparation according to any one of claims 8 to 11 and 13, in an amount of 0.1 ppm to 10% by weight based on the total weight of the final product.

20. A dietary supplement comprising a physiological cooling agent as defined in any one of claims 1 to 3 and 11, or a physiological cooling agent mixture as defined in any one of claims 4 to 7 and 12, or an aromatic formulation as defined in any one of claims 8 to 11 and 13, in an amount of 0.1 ppm to 10% by weight based on the total weight of the final product.

21. A cosmetic comprising a physiological cooling agent as defined in any one of claims 1 to 3 and 11, or a physiological cooling agent mixture as defined in any one of claims 4 to 7 and 12, or an aroma formulation as defined in any one of claims 8 to 11 and 13, in an amount of 0.1 ppm to 10% by weight based on the total weight of the final product.

22. A pharmaceutical product comprising a physiological cooling agent according to any one of claims 1 to 3 and 11, or a physiological cooling agent mixture according to any one of claims 4 to 7 and 12, or an aroma formulation according to any one of claims 8 to 11 and 13, in an amount of 0.1 ppm to 10% by weight based on the total weight of the final product.

23. An animal feed comprising a physiological cooling agent according to any one of claims 1 to 3 and 11, or a physiological cooling agent mixture according to any one of claims 4 to 7 and 12, or an aroma formulation according to any one of claims 8 to 11 and 13, in an amount of 0.1 ppm to 10% by weight based on the total weight of the final product.

24. A fabric comprising a physiological cooling agent as defined in any one of claims 1 to 3 and 11, or a physiological cooling agent mixture as defined in any one of claims 4 to 7 and 12, or an aroma formulation as defined in any one of claims 8 to 11 and 13, in an amount of 0.1 ppm to 10% by weight based on the total weight of the final product.

25. A package containing a physiological cooling agent as defined in any one of claims 1 to 3 and 11, or a physiological cooling agent mixture as defined in any one of claims 4 to 7 and 12, or an aroma formulation as defined in any one of claims 8 to 11 and 13, in an amount of 0.1 ppm to 10% by weight based on the total weight of the final product.

26. A tobacco product comprising a physiological cooling agent according to any one of claims 1 to 3 and 11, or a physiological cooling agent mixture according to any one of claims 4 to 7 and 12, or an aroma formulation according to any one of claims 8 to 11 and 13, in an amount of 0.1 ppm to 10% by weight based on the total weight of the final product.

27. 23. A pharmaceutical product according to claim 22, further comprising an active pharmaceutical ingredient selected from the group consisting of aspirin, minoxidil, erythromycin, phenistil, 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.

28. 28. A pharmaceutical product as claimed in claim 22 or 27 for use in preventing or treating painful and inflammatory conditions of the skin and mucous membranes, for use in preventing or treating coughs, colds, inflammatory sore throat or hoarseness, or for use in treating inflammatory conditions of the skin and mucous membranes and joints, or for use in treating prostate cancer or bladder cancer, or for use as a medicament for treating bladder weakness.

29. 1. A method for improving the flavor characteristics of a flavoring substance, comprising the steps of: (ic) providing at least one physiological cooling agent according to any one of claims 1 to 3 and 11 or a physiological cooling agent mixture according to any one of claims 4 to 7 and 12 and at least one flavoring agent comprising a flavoring substance; (iic) mixing the two components, and optionally (iii) incorporating the mixture obtained in the previous step into an oral preparation.

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