BR112020003942B1 - NON-THERAPEUTIC MODULATION METHOD, COMPOUND, COMPOSITION, AND, USE OF A MODULATOR AND COMPOSITION - Google Patents

Abstract

The invention primarily relates to a method of modulation, preferably in vitro and/or in vivo modulation, of the cold and menthol receptor TRPM8, in which the receptor is brought into contact with at least one modulator selected from the group consisting of compounds of the type 1 structure described herein. The present invention further relates to uses and corresponding compositions comprising such compounds.

Description

[001] The invention relates primarily to new modulators of the TRPM8 cold and menthol receptor, to methods of modulating the TRPM8 receptor using these modulators, to the use of the modulators to induce a sensation of cold and to compositions produced using these modulators.

[002] In a specific aspect, the invention relates to a composition comprising at least one such modulator to obtain a cooling effect on the skin or mucosa, advantageously with a longer lasting cooling effect compared to the active ingredients of known cooling agents (actives), for example to N-ethylmenthane-3-carboxamide (WS3) and/or an anticipated effect of the cooling effect compared to known cooling actives, for example FEMA 4809 or FEMA 4496.

[003] Furthermore, a specific aspect of the invention relates to compositions comprising such selected TRPM8 receptor modulators, wherein the compositions serve particular purposes.

[004] Furthermore, the invention also relates to a method of obtaining a physiological cooling effect on the skin or mucosa, in which the mentioned compositions are used.

[005] Additional aspects of the present invention will be evident from the following description, the examples and especially the attached claims.

[006] Physiological cooling actives are regularly used in order to cause a sensory impression of cold on the skin or mucosa, for example on the mucosa in the oral cavity, nasal cavity and/or pharyngeal cavity, although no physical cooling such as, for example, For example, the evaporation of solvents actually occurs. The physiological cooling actives used can be individual components or mixtures. It must be taken into account here that not all compounds that influence receptors in vitro and (also) are involved in communicating a physiological cooling effect actually generate such an effect in vivo on the skin or mucosa. More particularly, such an effect does not always have an identical progression. This means, for example, that the intensity of the communicated physiological cooling effect and the progression of the intensity of the cooling effect over time cannot be concluded solely from the fact that a particular compound is an agonist of a receptor involved in the communication of a cold impression.

[007] The most widely known physiologically active cooling active ingredient is L-menthol, but it has some disadvantages, for example a strong odor impression, high volatility and, in relatively high concentrations, an intrinsic bitter and/or sharp taste or an irritating effect on the skin.

[008] Therefore, there has been previous research into strong cooling actives that do not have the disadvantageous properties of L-menthol. For example, there were descriptions of lactic esters of menthol(ols) in DE 2 608 226 and of carbonates mixed with menthol(ols) and polyols in DE 4 226 043 and of menthone ketals in EP 0 507 190.

[009] Menthyl diacid monoesters according to US 5,725,865 and US 5,843,466 are naturally occurring alternatives of interest, but cannot achieve the intensity of the cooling actives described above in sensory tests.

[0010] J. Soc. Cosmet. chem. 1978, 29, 185-200 presented the results of a study on about 1200 compounds in which the compounds N-ethyl-L-menthanecarboxamide (“WS3”) and especially the ethyl ester of Na-(L-menthanecarbonyl)glycine (“ WS5”) the strongest cooling assets were revealed. But the latter, although it has a strong effect, has the disadvantage of being sensitive to hydrolysis and forming the corresponding free acid of Na-(L-menthanecarbonyl)glycine, which itself has only a very slight cooling effect. Despite the detailed studies described, a systematic prognosis of the properties of potential cooling actives, especially with respect to their bitterness and/or their other trigeminal effects is not possible, nor has it been described. For example, many molecules within the class of menthanecarboxamides also have a strong cooling effect, but often simultaneously have markedly bitter notes (e.g. the N-(alkyloxyalkyl)menthanecarboxamides according to JP 2004059474) or additionally have a strong irritating effect (WS5: N-[[5-methyl-2-(1-methylethyl)cyclohexyl]carbonyl]glycine ethyl ester, US 2005/0222256).

[0011] Na-(Menthanecarbonyl)alkyloxyalkylamides were described in JP 2004059474. Although they have a strong cooling effect and high stability to hydrolysis, they have the disadvantage, however, of being highly bitter and thus are unusable in foods and also in products cosmetics for facial care purposes.

[0012] Furthermore, menthyl glyoxylates and their hydrates were described as cooling substances in JP 2005343795.

[0013] Overviews of cooling actives produced and used to date can be found in M. Erman, Perfumer & Flavorist 32(10), 20-35 (2007) and M. L. Dewis in D. J. Rowe, Chemistry and Technology of Flavors and Fragrances, Blackwell Publishing Ltd, Oxford 2005, p. 212-222.

[0014] The cold and menthol receptor TRPM8 (also referred to as cold membrane receptor (CMR)1) belongs to the transient receptor family of potential ion channels, is specifically expressed in a specific group of neurons and forms pores in the cell membrane ( 4 units in each case combine to form a tetramer) which selectively allows Ca2+ ions to pass through. The protein has 6 transmembrane domains and a cytoplasmic C and N terminus. Low temperatures (preferably 10 to 25°C) stimulate this receptor, resulting in signal transduction that is interpreted as a sensation of cold by the nervous system. The receptor was first described in 2002 as a cold receptor in multiple publications (Peier AM et al, .A TRP channel that senses cold stimuli and menthol. Cell. 8 Mar 2002; 108(5): 705-15; McKemy DD et al. Identification of a cold receptor reveals a general role for TRP channels in thermal sensation 2002 Nature Mar 7;416(6876):52-8; Zuker CS. Neurobiology: A cool ion channel Nature 7 2002 Mar; 416 (6876): 27-8).

[0015] Cooling compounds, for example menthol, have long played an important role in the flavoring and odoriferous industry to create an association with freshness and cleanliness. For the compound menthol, it has been shown to act as a natural modulator of the TRPM8 receptor (McKemy D.D., Molecular Pain 1, 2005, 16; McKemy D.D., Nature 416, 2002, 52-58; Peier A.M., Cell 108, 2002 , 705715; Dhaka A., Annu. Rev. Neurosci. 29, 2006, 135-161). The application of menthol activates TRPM8, which causes an influx of Ca2+ within cold-sensitive neurons. The resulting electrical signal is ultimately perceived as a sensation of cold. Excessive concentrations of menthol lead to irritation and an anesthetic effect. Furthermore, several publications have described menthol derivatives with a similar effect (British Patent 1971 #1315761 Watson H.R., J. Soc. Cosmet. Chem. 29, 1978, 185-200; Furrer S.M., Chem. Percept. 1, 2008, 119 -126). There are also individual compounds structurally unrelated to menthol that carry out significant modulation of TRPM8, for example icilin (Wei E.T., J. Pharm. Pharmacol. 35, 1983, 110-112; WO 2004/026840), WS-23 or the compounds detailed in patent application WO 2007/019719.

[0016] Additional effects of substances that modulate the TRPM8 receptor or its insect analogues are a repellent effect on insects (WO 2002/015692; WO 2004/000023, US 2004/0028714) and activity in antitumor therapy (for example an influence on prostate tumors), activity in the treatment of inflammatory pain/hyperalgesia and an effect as TRPM8 antagonists in the treatment of bladder syndrome or overactive bladder (Beck B. Cell Calcium, 41, 2007, 285-294; Levine J.D. Biochim. Biophys. Acta, Mol. Basis Dis. 1772, 2007, 989-1003; Mukerji G., BMC Urology 6, 2006, 6; US 2003/0207904; US 2005/6893626, thesis by Behrendt H.J. 2004, University of Bochum; Lashinger E.S.R. Am J. Physiol. Renal Physiol. Am J Physiol Renal Physiol. Jun 18, 2008.

[Advanced electronic publishing]; PMID: 18562636).

[0017] However, many of the TRPM8 modulators that have been disclosed to date have disadvantages in relation to intensity of action, duration of action, skin/mucosa irritation, odor, flavor, solubility and/or volatility.

[0018] Applicant's previous international patent application PCT/EP2009/061019 proposes individual compounds for modulating the TRPM8 receptor. For example, the following compounds have been disclosed:

[0019] These compounds are also commercially available: Compound 1 under CAS number: 99602-94-5 (3R-cis form) Compound 2 under CAS number: 165753-08-2 Compound 3 under CAS number: 338771-57 -6 Compound 4 under CAS number: 878942-21-3 Compound 5 under CAS number: 748783-13-3 (no stereochemistry)

[0020] Reference is additionally made at this point to Applicant's international patent application PCT/EP2010/067936, in which compounds for modulating the TRPM8 receptor are also proposed.

[0021] The primary objective of the present invention was to identify new substances that have an exceptional physiological cooling effect, preferably those that lead to modulation of the TRPM8 receptor, which are usable as alternatives to, preferably as more suitable agents than, modulators known to date. Such compounds should also be especially suitable for uses in the cosmetic sector (e.g. hair care, skin care, oral care), food and feed, textile products, OTC products (e.g. burn ointment), pharmaceutical products (e.g. example, tumor treatment, bladder weakness) or packaging. The compounds or mixtures of compounds to be specified should preferably exhibit minimal intrinsic taste and especially have only a slight bitter taste, if any, and cause minimal irritation.

[0022] To achieve the objective of the invention, the research was in particular regarding compositions having active ingredients that could communicate a particularly long-lasting sensation of cold. These compositions should preferably further be capable of communicating impressions of cold that are particularly intense and/or begin quickly.

[0023] In the oral mucosa, many of the aforementioned conventional cooling substances known in the prior art show more or less identical cooling characteristics. The cool cooling sensation they communicate begins after about 0.5 minutes, but then stabilizes again relatively quickly after a peak of 3 to 5 minutes, the cooling being clearly perceptible for a total period of at most 30 minutes. minutes and, as experience has shown, having an intensity and duration which can be influenced only to a lesser degree by a change in dose. On the consumer side, however, there is a desire for an especially long-lasting cooling effect associated, by the user, with a corresponding perception of freshness and well-being.

[0024] It has been revealed that, surprisingly, the compounds to be used according to the invention have the common property of obtaining a particularly long cooling effect on the skin or mucosa in vivo. This was not predictable for the TRPM8 agonists mentioned in this application, nor does it apply to all such agonists.

[0025] There has been no suggestion in the prior art to date that specifically the compounds for use according to the invention are capable of imparting a particularly suitable cooling effect. In order to quantify the long-term cooling effect, it is possible to conduct comparative tests with N-ethylmentane-3-carboxamide. For these comparative tests, the person skilled in the art changes the compound for use according to the invention or the compounds in place of N-ethylmenthane-3-carboxamide (also WS3), preferably in the same concentration. Then the cooling effects of the respective compositions are compared with each other. If the compounds for use according to the invention are present in the composition to be examined in a concentration higher than 100 ppm, it is preferable that, to assess whether the cooling effect is prolonged when compared to WS3, the composition to be tested must be diluted such that the inventive compounds for use are present in a concentration of 100 ppm. The same dilution step should naturally also be implemented for the comparative composition comprising WS3.

[0026] In this connection, it is preferable that, in the corresponding comparisons, the cooling effect of the compositions comprising the compounds for use according to the invention is prolonged preferably by at least 10 minutes, more preferably by at least 15 minutes, so additionally preferably at least 20 minutes and especially preferably at least 30 minutes compared to comparative tests.

[0027] The primary objective of the present invention is obtained according to the invention by a non-therapeutic method of modulation, preferably in vitro and/or in vivo modulation, of the cold and menthol receptor TRPM8, in which the receptor is placed in contact with at least one modulator selected from the group consisting of compounds of the following structure type 1: Structure type 1: where R1 consists of the following structure: where Z is selected from the group consisting of O and S; n = 0 or 1; m - = 1 and Y is hydrogen and R8 is a linear or branched C1 to C5 alkane, preferably a C5 alkane or Y is NR9 or CR9 and R9 together with R8 form a partially or fully saturated 5 or 6 membered ring, or - = 0, 2 or 3 and Y is hydrogen and R8 is a linear or branched C1 to C5 alkane, preferably a C5 alkane or Y is NR9 or CR9 and R9 together with R8 form an aromatic, partial, 5- or 6-membered ring or fully saturated; R2 is a linear or branched C1 to C5 alkyl radical, 5- or 6-membered cycloalkyl radical, or a 5- or 6-membered aryl radical, wherein the alkyl radical, cycloalkyl radical, or aryl radical optionally includes one or two heteroatoms (ring ); R3, R4, R5, R6 and R7 are the same or distinct and are selected from the group consisting of hydrogen; halogens; linear or branched C1 to C6 alkyl groups optionally containing 1, 2, 3 or 4 identical or distinct substituents selected from the group consisting of NH2, OH, SH, halogens and linear or branched C1 to C6 alkyl groups; linear or branched C1 to C6 alkoxy groups optionally containing 1, 2, 3 or 4 identical or distinct substituents selected from the group consisting of NH2, OH, SH, halogens and C1 to C6 alkoxy groups; mono- or polycyclic aryl, arylalkyl and heteroaryl groups optionally containing 1, 2, 3 or 4 identical or distinct substituents selected from the group consisting of NH2, OH, SH, halogens, linear or branched C1 to C6 alkyl groups; where the heteroaryl groups have 1, 2, 3 or 4 heteroatoms in the ring that are the same or distinct and are selected from the group consisting of O, N and S, or two adjacent radicals R3, R4, R5, R6 and R7 together with the carbon atoms to which they are attached form a 4-, 5-, 6-, or 7-membered mono- or polyunsaturated heterocyclic ring optionally containing 1, 2, 3, 4, or 5 identical or distinct substituents selected from the group consisting of C1 alkyl groups to C6 linear or branched and having 1, 2 or 3 ring heteroatoms that are the same or distinct and are selected from the group consisting of O, N and S; X - is selected from the group consisting of Groups -C1- to C4-alkylene; groups -C2- to C4-alkenylene and - groups A-C1- to C4- or -C1- to C4-A-alkylene or -A-C2- to C4- or -C2- to C4-A-alkenylene, where A is O, S or NH; or - is a single chemical bond; - salts of these compounds, especially acid addition salts with inorganic or especially organic, mono- and especially polybasic carboxylic acids; and optionally of these compounds in stereoisomerically pure form or in mixtures of stereoisomers thereof.

[0028] There are several synonyms in the literature for “TRPM8”: TRPP8, LTRPC6, CMR1, MGC2849, member 8 of the transient receptor potential cation channel subfamily M. The scope of the present invention includes all designations. Also included are all functional modifications of the receptor such as, more particularly, splice variants, isoforms, for example TRPM8 CRA_a, TRPM8 CRA_b and all analogous receptors from different organisms, such as human, mouse, rat. The nucleotide or amino acid sequences of the various receptors are known per se and recorded in sequence databases. For example, sequence information for hTRPM8 is registered under number NM_024080.

[0029] A “modulator” in the context of the invention is a compound that can act as an agonist and/or antagonist of the TRPM8 receptor in vivo and/or in vitro, especially in vivo.

[0030] Suitable modulators can act here alone as an antagonist or agonist, especially alone as an agonist or as both an antagonist and an agonist. It is especially possible here to establish an agonistic or antagonistic effect as a function of the concentration of the particular modulator chosen.

[0031] An “agonist” here is a compound that communicates activation of the TRPM8 receptor, that is, it induces an influx of Ca2+ in cold-sensitive neurons and consequently communicates a sensation of cold.

[0032] An “antagonist”, on the contrary, is a compound that can neutralize this activation of the TRPM8 receptor.

[0033] The modulators of the invention can exert their effect by binding reversibly or irreversibly, specifically or nonspecifically, to a TRPM8 receptor molecule. Usually, the bond is non-covalent via ionic and/or non-ionic, for example hydrophobic, interactions with the receptor molecule. “Specific” here exclusively comprises the interaction with one or more molecules other than the TRPM8 receptor (for example TRPM8 molecules of different origin or different isoforms). “Non-specific”, rather, is an interaction of the modulator with multiple different receptor molecules of different function and/or sequence, but as a result of which a desired agonistic and/or antagonistic modulation (as described above) of the TRPM8 receptor can be detected.

[0034] A modulator of the invention serves especially for inducing a sensation of cold in humans and/or animals. There is preferably “induction of a cold sensation” when the compound in the cellular activity test described here shows an agonistic effect on hTRPM8.

[0035] The compositions of the invention comprise, as well as the constituents that are usual for the respective composition, an effective amount of at least one modulator of the invention. “Effective” in this context means a concentration of the modulator sufficient to communicate the desired effect upon application of the composition (e.g. application to the skin), for example a pharmacological effect or sensory effect, for example the olfactory cold effect.

[0036] Unless otherwise established, the following general definitions are applicable in the context of the present invention: Halogen: F, Cl, Br or I Alkyl and all alkyl moieties in the radicals derived therefrom, for example alkoxy, alkylthio, alkoxyalkyl, alkoxyalkoxy, alkylamino and dialkylamino: saturated, linear or branched hydrocarbyl radicals having 1 to 4, 1 to 6, 1 to 8 or 1 to 10 carbon atoms, for example, - C1- to C6 alkyl such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1- dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2, 3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. - C1- to C6 alkoxy, comprising C1- to C4 alkoxy, for example methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy; and, for example, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy , 3-methylpentoxy, 4- methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2 -ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy; Cycloalkyl (ring): carbocyclic radicals having 3 to 20 carbon atoms, for example - C3- to C12 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl; preference is given to cyclopentyl, cyclohexyl, cycloheptyl and also cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or - C3- to C7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl, where the radical can be attached to the rest of the molecule via any suitable carbon atom.

[0037] Alkylene: linear or single or multiply branched hydrocarbon bridge groups having 1 to 20 carbon atoms, for example - C1- to C7 alkylene groups selected from -CH2-, - (CH2)2-, -(CH2) 3-, -(CH2)4-, -(CH2)2-CH(CH3)-, -CH2-CH(CH3)-CH2-, (CH2)4-, -(CH2)5-, -(CH2) 6, -(CH2)7-, -CH(CH3)-CH2-CH2-CH(CH3)- or - CH(CH3)-CH2-CH2-CH2-CH(CH3)- or - C1- to C4 alkylene groups selected from -CH2-, - (CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)2-CH(CH3)-, -CH2-CH(CH3)-CH2-.

[0038] Alkylene: the mono- or polyunsaturated, especially monounsaturated, analogues of the above alkylene groups having 2 to 20 carbon atoms, especially C2- to C7 alkenylenes or C2- to C4 alkenylene, such as -CH=CH-, -CH=CH-CH2-, -CH2-CH=CH-, -CH=CH-CH2-CH2-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -CH(CH3 )-CH=CH-, -CH2- C(CH3)=CH-.

[0039] Aryl: mono- or polycyclic, preferably mono- or bicyclic, optionally substituted aromatic radicals having 6 to 20, especially 6 to 10, carbon atoms in the ring, for example phenyl, biphenyl, naphthyl such as 1- or 2- naphthyl, tetrahydronaphthyl, fluorenyl, indenyl and phenanthrenyl. These aryl radicals may optionally carry 1, 2, 3, 4, 5 or 6 identical or distinct substituents.

[0040] Arylalkyl: aryl-substituted analogues of the above alkyl radicals, where aryl also has the definitions established above, such as C1- to C4 phenyl-alkyl radicals selected from phenylmethyl or phenylethyl.

[0041] Heterocyclyl (heterocyclic ring): saturated, partially unsaturated or aromatic five- to seven-membered heterocycles or heterocyclic radicals containing one, two, three or four heteroatoms from the group of O, N and S, for example - heterocyclyl of 5 or 6 saturated or monounsaturated members, comprising one to two nitrogen atoms and/or one oxygen or sulfur atom or one or two oxygen and/or sulfur atoms as ring members, for example, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydrothienyl, 3-tetrahydrothienyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3- isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4- pyrazolidinyl , 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2-pyrrolin-2-yl, 2-pyrrolin-3- yl, 3-pyrrolin-2-yl, 3-pyrrolin- 3-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan- 5-yl, 2-tetrahydropyranyl, 4- tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl and 2-piperazinyl; - 5-membered aromatic heterocyclyl (= heteroaryl or hetaryl), comprising, 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 members, e.g. , 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; - 5-membered aromatic heterocyclyl (= heteroaryl or hetaryl) having 1, 2, 3 or 4 nitrogen atoms as ring members, such as 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-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; - 5-membered aromatic heterocyclyl (= heteroaryl or hetaryl) having 1 heteroatom selected from oxygen and sulfur and optionally 1, 2 or 3 nitrogen atoms as ring members, for example 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; - 6-membered heterocyclyl (= heteroaryl or hetaryl), comprising, in addition to carbon atoms, one or two or one, two or three, nitrogen atoms as ring members, 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; Substituents, as for the above radicals in particular, are especially selected from keto, -COOH, -COO-alkyl, -OH, -SH, -CN, amino, -NO2, alkyl groups or where one or more hydrogen atoms in the groups alkyl can be replaced by halogen.

[0042] In a preferred embodiment of the method of the invention, compounds of structure type 1 are selected from group A consisting of the following compounds:

[0043] If there are differences between the given name and the respective formula image, the formula image evidence takes precedence.

[0044] Here particular preference is given to compounds of group A which are selected from group B consisting of the following compounds:

[0045] Additional preference is given to compounds from groups A and B that are selected from group C consisting of the following compounds:

[0046] In one embodiment of the present invention, compounds of structure type 1 are not selected from the compounds as described in WO 2011/061330.

[0047] In a preferred embodiment of the present invention, compounds of structure type 1 are therefore not selected from group D consisting of the following compounds: Structure type 1: where R1 consists of the following structure: where Z is selected from the group consisting of O and S; n = 0 or 1; m = 0 and Y is NR9 or CR9 and R9 together with R8 forms a 5- or 6-membered aromatic or fully saturated ring; and wherein R2 is a linear or branched C1 to C5 alkyl radical, 5- or 6-membered cycloalkyl radical, or a 5- or 6-membered aryl radical, wherein the cycloalkyl radical and the aryl radical optionally include one or two (ring) heteroatoms that are the same or different and are selected from O, N and S; R3, R4, R5, R6 and R7 are the same or distinct and are selected from the group consisting of hydrogen; halogens; linear or branched C1 to C6 alkyl groups optionally containing 1, 2, 3 or 4 identical or distinct substituents selected from the group consisting of NH2, OH, SH, halogens and linear or branched C1 to C6 alkyl groups; linear or branched C1 to C6 alkoxy groups optionally containing 1, 2, 3 or 4 identical or distinct substituents selected from the group consisting of NH2, OH, SH, halogens and C1 to C6 alkoxy groups; mono- or polycyclic aryl, arylalkyl and heteroaryl groups optionally containing 1, 2, 3 or 4 identical or distinct substituents selected from the group consisting of NH2, OH, SH, halogens, linear or branched C1 to C6 alkyl groups; where the heteroaryl groups have 1, 2, 3 or 4 heteroatoms in the ring that are the same or distinct and are selected from the group consisting of O, N and S, or two adjacent radicals R3, R4, R5, R6 and R7 together with the carbon atoms to which they are attached form a 4-, 5-, 6-, or 7-membered mono- or polyunsaturated heterocyclic ring, optionally containing 1, 2, 3, 4, or 5 identical or distinct substituents selected from the group consisting of alkyl groups C1 to C6 linear or branched and having 1, 2 or 3 ring heteroatoms that are the same or distinct and are selected from the group consisting of O, N and S; X - is selected from the group consisting of -C1- to C4-alkylene groups; groups -C2- to C4-alkenylene and groups -A- C1- to C4- or -C1- to C4-A-alkylene or groups -A-C2- to C4- or -C2- to C4-A-alkenylene, in that A is O, S or NH; or - is a single chemical bond; and salts of these compounds, especially acid addition salts with inorganic or especially organic, mono- and especially polybasic carboxylic acids; and optionally of these compounds in stereoisomerically pure form or mixtures of stereoisomers thereof.

[0048] In a further preferred embodiment of the present invention, compounds of structure type 1 are not selected from group E consisting of the following compounds:

[0049] In an alternative embodiment of the present invention, the compounds of group D, as described above, are compounds for use with preference within the context of the present invention.

[0050] In a further alternative embodiment, group E compounds, as described above, are compounds for use with preference within the context of the present invention.

[0051] In a method of the invention, especially in its preferred configuration, the receptor is preferably brought into contact with at least one modulator which, in a cellular activity test using cells that recombinantly express the human TRPM8 receptor, modulates the permeability of these cells for Ca2+ ions.

[0052] In a method of the invention, preferably in an embodiment described above as preferred, the modulator has an agonistic or antagonistic action on cellular Ca2+ ion permeability.

[0053] Particular preference is given to carrying out a method of the invention, especially a preferred configuration, in which the modulator is a TRPM8 receptor agonist.

[0054] A further aspect of the present invention comprises the use of a modulator of the invention, especially in one or more of the preferred methods, for the non-therapeutic induction of a sensation of cold in humans and/or animals.

[0055] Preferably, such a modulator of the invention in the use described above is preferably used for the non-therapeutic induction of a sensation of cold through a packaging or textile product comprising the modulator.

[0056] In an alternative use of the invention, preference is given to the use of a composition comprising at least one, two, three or more of the modulators of the invention, especially of the preferred configurations, preferably in a (total) amount of 0. 1 ppm at 10% by weight, based on the total weight of the composition, to achieve a cooling effect on the skin or mucosa that is preferably prolonged compared to the cooling effect of a composition of the same constitution as the ) modulator(s) was/were merely exchanged in place of N-ethylmenthanecarboxamide, preferably at the same concentration, preferably for at least 10 minutes and/or a cooling effect that starts earlier compared to the cooling effect of a composition of the same constitution in which the modulator(s) was/were merely exchanged in place of FEMA 4809 or FEMA 4496, preferably in the same concentration.

[0057] In order to quantify the long-term cooling effect of the compounds to be used according to the invention, preference is given to conducting comparative experiments with N-ethylmentane-3-carboxamide (as described above).

[0058] Preferably, the modulator(s) of the invention is/are for one of the uses described as preferred, selected from the respective group A, group B or group C already described or in another embodiment of group D or group E .

[0059] A further aspect of the present invention relates to a modulator as described above for use as a modulator of the TRPM8 receptor, preferably for use in a therapeutic method of modulating the TRPM8 receptor.

[0060] The present invention additionally relates to new compounds of structure type 1 per se. More particularly, the present invention relates to compounds selected from group A, group B or group C or group D or group E, as respectively described herein or a salt of such a compound, especially selected from acid addition salts with carboxylic acids. inorganic or especially organic, mono- or especially polybasic.

[0061] The present invention additionally refers, regardless of the uses described herein, to compositions comprising new compounds of structure type 1, especially compounds selected from group A, group B or group C or group D or group E, as respectively described herein .

[0062] A further aspect of the present invention relates to a composition comprising at least one modulator as described above for use as a modulator of the TRPM8 receptor, preferably for use in a therapeutic method of modulating the TRPM8 receptor.

[0063] In a preferred embodiment, such a composition of the invention is for use as a modulator of the TRPM8 receptor, preferably for use in a therapeutic method of modulating the TRPM8 receptor, selected from the group consisting of a) food, preferably ice cream, mousse, cream, drinks and sweets, b) oral care products, preferably toothpaste, mouthwash and chewing gum, c) personal care products, preferably skin care or hair care products, e.g. example sunscreen, sunburn cream, lotions and shampoos and plasters, d) foams and gels.

[0064] In a particularly preferred embodiment, a composition of the invention is for use as a modulator of the TRPM8 receptor, preferably for use in a therapeutic method of modulating the TRPM8 receptor, especially in an embodiment described above as preferred, selected of the group consisting of aroma mixtures and formulations for nutritional, oral hygiene or recreational purposes or cosmetic formulations, comprising one, two, three or more of the modulators as described above, wherein said modulator(s) is/are present in an amount (total) of 0.05 ppm to 10% by weight, preferably from 0.1 ppm to 10% by weight, based on the total weight of the flavor mixture or formulation.

[0065] Preferably, such a composition of the invention for use as a modulator of the TRPM8 receptor, preferably for use in a therapeutic method for modulating the TRPM8 receptor, additionally comprises: (1) one or more additional substances having physiological cooling, in which the additional substance or one, more than one or all of the additional substances (i) cause(s) a flavoring effect or (ii) do not cause(s) a flavoring effect, and/or (2) a or more flavors without any physiological cooling effect and/or (3) one or more substances having a trigeminal or saliva production stimulating effect without any physiological cooling effect and/or (4) (iii) a compound or (iv ) two or more compounds that, independently or collectively in case (iv), additionally cause(s) a flavor modulating effect and/or a trigeminal stimulus and/or stimulating saliva production.

[0066] Additional substances having a physiological cooling effect include, for example, those as described in WO 2014/090293 A1, preferably menthol, menthol compounds, Optamint or peppermint oils.

[0067] The menthol compounds are preferably selected from the group consisting of menthol, methyl methyl ether, menthone glyceryl acetal (Frescolat® MGA, FEMA GRAS 3807), menthone glyceryl ketal (FEMA GRAS 3808), menthyl lactate (Frescolat® ML, FEMA GRAS 3748), menthol ethylene glycol carbonate (Frescolat® MGC, FEMA GRAS 3805), menthol propylene glycol carbonate (Frescolat® MPC, FEMA GRAS 3806), menthyl N-ethyl oxamate (Frescolat®), monomethyl succinate (FEMA GRAS 3810), monomenthyl glutarate (FEMA GRAS 4006), menthoxy-1,2-propanediol (FEMA GRAS 3784), menthoxy-2-methyl-1,2-propanediol (FEMA GRAS 3849) and menthanecarboxylic esters and -carboxamides, for example WS-3 (FEMA GRAS 3455), WS-5 (FEMA GRAS 4309), WS-12 (Frescolat® SC-1, FEMA GRAS 4681) and WS-23 (FEMA GRAS 3804) and mixtures thereof.

[0068] Optamint is a mixture of more than 50 different natural essential oils and natural or natural-identical aromas. Optamints have varying compositions of several oils (partially fractionated) which are preferably a mixture of, for example, different peppermint oils and peppermint oils and Eucalyptus globulus oil, star anise oil, menthol, menthone, isomenthone, mint, anethole, eucalyptol etc. An exact statement of the composition of Optamints is therefore not possible. The Optamint® product series is commercially available from Symrise AG.

[0069] In a preferred embodiment of the use of a modulator of the invention, especially in one or more of the preferred methods, for non-therapeutic induction of a sensation of cold in humans and/or animals to obtain a physiological cooling effect on the skin and/or mucosa, the cooling effect was prolonged by at least 10 minutes compared to the cooling effect of a composition of the same constitution in which the modulator(s) was/were merely exchanged in place of the N- ethylmenthane-carboxamide, preferably in the same concentration and/or the cooling effect begins earlier compared to the cooling effect of a composition of the same constitution in which the modulator(s) was/were merely exchanged in place of FEMA 4809 or FEMA 4496, preferably in the same concentration, comprising the following step: applying an amount of a composition as described above, especially in one or more preferred embodiments, that is sufficient to obtain a physiological cooling effect for the skin and/or mucosa.

[0070] More preferably, the modulator(s) in such a use of the invention is/are selected from group A described above.

[0071] The active ingredients of the invention have a wide field of use in cosmetics and human care, especially in skin care and hair care, but they are also usable pharmacologically and in food and textile products, but also as repellents and as a constituent of insecticidal compositions.

[0072] In particular, the compositions of the invention can be skin cosmetics, hair cosmetics, dermatological, hygiene or pharmaceutical products. More particularly, the active ingredients of the invention, especially having a cooling effect, are used for skin cosmetics and/or hair cosmetics or as oral care compositions.

[0073] The hair care or skin care compositions or formulations of the invention are especially in the form of an emulsion, a dispersion, a suspension, in the form of an aqueous surfactant preparation, a milk, a lotion, a cream, a balm, an ointment, a gel, granules, a powder, a stick preparation, for example a lipstick, a foam, an aerosol or a spray. Such formulations are highly suitable for topical preparations. Suitable emulsions are oil-in-water emulsions and water-in-oil emulsions or microemulsions.

[0074] In general, the hair or skin cosmetic formulation is used for application to the skin (topical) or hair. "Topical preparations" are here understood to mean those formulations suitable for applying the active ingredients to the skin in fine distribution, for example in a form absorbable through the skin. Suitable examples for this purpose are aqueous and aqueous-alcoholic solutions, sprays, foams, foaming aerosols, ointments, aqueous gels, O/W or W/O type emulsions, microemulsions or cosmetic stick preparations.

[0075] In one embodiment of the cosmetic composition of the invention, this comprises a carrier. Preferred carriers are water, a gas, a water-based liquid, an oil, a gel, an emulsion or microemulsion, a dispersion or a mixture thereof. The specified carriers exhibit good skin compatibility. Aqueous gels, emulsions or microemulsions are particularly advantageous for topical preparations.

[0076] The disclosure of the invention also comprises the use of the active ingredients described herein in pharmaceutical products for the treatment of an individual, preferably a mammal, especially a human being, farm animal or domestic animal. For this purpose, the actives are administered in the form of pharmaceutical compositions comprising a pharmaceutically compatible excipient together with at least one active of the invention and optionally additional actives. These compositions can be administered, for example, orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.

[0077] Examples of suitable pharmaceutical formulations or compositions are solid drug forms such as powders, granules, tablets, lozenges, sachets, stamps, sugar-coated tablets, capsules such as soft and hard gelatin capsules, suppositories or vaginal drug forms , semi-solid drug forms such as ointments, creams, hydrogels, pastes or plasters and liquid drug forms such as solutions, emulsions, especially oil-in-water emulsions, suspensions, for example lotions, injection and infusion formulations, eye and ear drops. Implanted delivery devices can also be used to administer the inhibitors of the invention. Furthermore, it is also possible to use liposomes, microspheres or polymeric matrices.

[0078] In the production of products or formulations or compositions of the invention, the active ingredients of the invention are usually mixed or diluted with an excipient. Excipients can be solid, semi-solid or liquid materials that serve as a vehicle, carrier or medium for the active ingredient. The active ingredient content (of one or more active ingredients of the invention present simultaneously) can vary here within a wide range and is, for example, based in each case on the total weight of the composition, within the ppm range of about 0. 05 ppm to 10% by weight, preferably 0.1 ppm to 10% by weight.

[0079] Suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Furthermore, the formulations may comprise customary pharmaceutically acceptable carriers or auxiliaries, such as lubricants, for example tallow, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; antioxidants; anti-irritants; chelating agents; coating aids; emulsion stabilizers; foam formers; gel formers; odor maskers; flavor correctors; resins; hydrocolloids; solvents; solubilizers; neutralizing agents; permeation accelerators; pigments; quaternary ammonium compounds; fat replacement agents and superfatters; ointment, cream or oil bases; silicone derivatives; spreading aids; stabilizers; sterilants; suppository bases; tableting aids such as binders, fillers, lubricants, disintegrants or coatings; propellants; desiccants; opacifiers; thickeners; waxes; plasticizers; white oils. This type of configuration is based on specialized knowledge, as represented, for example, in Fiedler, H. P. Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Dictionaries of Auxiliaries for Pharmacy, Cosmetics and Related Fields], 4th edition, Aulendorf: ECV- Editio-Kantor-Verlag, 1996 or Hager's Handbuch der Pharmazeutischen Praxis [Hager's Handbook of Pharmaceutical Practice], Spaneler Verlag, Heidelberg.

[0080] The compositions of the invention may, as well as usual additives or auxiliaries, additionally comprise cosmetic and/or dermatological and/or pharmacological active ingredients.

[0081] Non-limiting examples of suitable additional actives include: Suitable cosmetic and/or dermatological actives are, for example, color actives, skin and hair pigmentation agents, dyeing agents, tanning agents, whiteners, skin hardening substances. keratin, antimicrobial actives, photofilter actives, repellent actives, hyperemic substances, keratolytic and keratoplastic substances, anti-dandruff actives, antiphlogistic, keratinizing substances, antioxidant actives and actives that act as free radical decontaminants, humidifying or skin moisturizing substances, active fat replacement, anti-erythematous or anti-allergic active ingredients, branched fatty acids, such as 18-methyleicosanoic acid and mixtures thereof.

[0082] Artificial tanning actives suitable for tanning the skin without natural or artificial irradiation with UV rays; these are, for example, dihydroxyacetone, alloxane and walnut shell extract. Suitable keratin hardening substances are generally active as well as used in antiperspirants, for example potassium aluminum sulfate, aluminum hydroxychloride, aluminum lactate etc.

[0083] Antimicrobial actives that are used to destroy microorganisms or inhibit their growth. They thus serve both as a preservative substance and as a deodorizer that reduces the development or intensity of body odor. These include, for example, the usual preservatives known to those skilled in the art, such as p-hydroxybenzoic esters, imidazolidinylurea, formaldehyde, sorbic acid, benzoic acid, salicylic acid, etc. Examples of such deodorizing substances include zinc ricinoleate, triclosan, undecylenoic acid alkylolamides, triethyl citrate, chlorhexidine, etc.

[0084] Auxiliaries and additives suitable for producing cosmetic hair or skin cosmetic preparations are known to the person skilled in the art and can be found in cosmetic manuals, for example Schrader, Grundlagen und Rezepturen der Kosmetika [Fundamentals and Formulations of Cosmetics], Hüthig Verlag, Heidelberg, 1989, ISBN 3-7785-1491-1. The auxiliaries and additives are preferably cosmetically and/or pharmaceutically acceptable auxiliaries. Pharmaceutically acceptable auxiliaries are auxiliaries that are known for use in the field of pharmacy, food technology and related fields, in particular those listed in the relevant pharmacopoeia (e.g. DAB, Ph. Eur., BP, NF) and other auxiliaries whose properties do not prevent physiological application.

[0085] Suitable auxiliaries may be: lubricants, wetting agents, emulsifying and suspending agents, preservatives, antioxidants, anti-irritants, chelating agents, emulsion stabilizers, film formers, gel formers, odor maskers, hydrocolloids, solvents , solubilizers, neutralizing agents, permeation accelerators, pigments, quaternary ammonium compounds, fat replacement agents and superfatters, ointment, cream or oil bases, silicone derivatives, stabilizers, sterilants, propellants, desiccants, opacifiers, thickeners, wax , plasticizers, white oils. This type of configuration is based on specialized knowledge, as represented, for example, in Fiedler, H. P. Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, 4th ed., Aulendorf: ECV- Editio-Kantor-Verlag, 1996.

[0086] Other suitable additives are selected from perfume oils, hair polymers, hair and skin conditioners, graft polymers, water-soluble or water-dispersible silicone-containing polymers, light stabilizers, brighteners, care agents, dyes, dyes, tanning agents, pigments, bulking agents, humectants, fat replacement agents, collagen, protein hydrolysates, lipids, antioxidants, defoamers, antistatics, emollients, plasticizers, peroxide decomposers.

[0087] Examples of suitable auxiliaries and additives include: (1) Antioxidants selected from amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g., urocanic acid) and derivatives thereof, peptides such as D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof (e.g. anserine), carotenoids, carotenes (e.g. ß-carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof , lipoic acid and derivatives thereof (e.g., dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, Y—linoleyl, cholesteryl and glyceryl esters thereof) and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (e.g., buthionine sulfoximine, homocysteine sulfoximine, buthionine sulfone, penta-, hexa-, heptathione sulfoximine), especially in very small, tolerated doses (e.g., in the pmol to µmol/kg range) and also chelators (metal) (e.g. a-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), a-hydroxy acids (e.g. citric acid, lactic acid, malic acid), humic acid, bile acid, extracts bile, bilirubin, biliverdin, EDTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g., Y-linolenic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives thereof (e.g., sodium ascorbate, ascorbyl palmitate, Mg ascorbylphosphate, ascorbyl acetate), tocopherol and derivatives (e.g., vitamin E acetate, tocotrienol), vitamin A and derivatives (vitamin palmitate A) and benzoin coniferyl benzoate, rutic acid and derivatives thereof, a-glucosylrutin, ferulic acid, furfurylideneglucitol, carnosine, butylhydroxytoluene, butylhydroxyanisole, nordihydroguaiac resin acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, zinc and derivatives thereof (e.g. ZnO, ZnSO4), selenium and derivatives thereof (e.g. selenomethionine), stilbenes and derivatives thereof (e.g. stilbene oxide, trans-stilbene oxide ).

[0088] (2) Peroxide decomposers, that is, compounds capable of decomposing peroxides, more preferably lipid peroxides. These are understood to mean organic substances, for example pyridine-2-thiol-3-carboxylic acid, 2-methoxypyrimidinolcarboxylic acids, 2-methoxypyridinecarboxylic acids, 2-dimethylaminopyrimidinolcarboxylic acids, 2-dimethylaminopyridinecarboxylic acids.

[0089] (3) Thickeners such as cross-linked polyacrylic acids and derivatives thereof, polysaccharides and derivatives thereof, such as xanthan gum, agar-agar, alginates or tyloses, cellulose derivatives, for example, carboxymethylcellulose or hydroxycarboxymethylcellulose, fatty alcohols, monoglycerides and fatty acids, polyvinyl alcohol and polyvinylpyrrolidone. In particular, nonionic thickeners are used.

[0090] (4) Preservatives listed below with their E number:

[0091] Also suitable according to the invention are preservatives or preservative aids customary in cosmetics, such as dibromodicyanobutane (2-bromo-2-bromomethylglutaronitrile), 3-iodo-2-propynyl butylcarbamate, 2-bromo-2- nitropropane-1,3-diol, imidazolidinylurea, 5-chloro-2-methyl-4-isothiazolin-3-one, 2-chloroacetamide, benzalkonium chloride, benzyl alcohol, formaldehyde emitters.

[0092] Also suitable as preservatives are phenyl hydroxyalkyl ethers, especially the compound known as phenoxyethanol, due to its bactericidal and fungicidal effects on various microorganisms.

[0093] Other antimicrobial agents are also equally suitable for incorporation into the preparations of the invention. Advantageous substances are, for example, 2,4,4'-trichloro-2'-hydroxydiphenyl ether (irgasan), 1,6-di(4-chlorophenylbiguanido)hexane (chlorhexidine), 3,4,4'-trichlorocarbanilide, quaternary ammonium compounds, clove oil, peppermint oil, thymus oil, triethyl citrate, farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol) and the active ingredients or combinations of assets described in patent descriptive reports open to the public DE-37 40 186, DE 39 38 140, DE-42 04 321, DE-42 29 707, DE-43 09 372, DE-44 11 664, DE-195 41 967 , DE-195 43 695, DE-195 43 696, DE-195 47 160, DE-196 02 108, DE- 196 02 110, DE 196 02 111, DE-196 31 003, DE-196 31 004 and DE- 196 34 019 and the patent specifications DE-42 29 737, DE-42 37 081, DE-43 24 219, DE-44 29 467, DE-44 23 410 and DE-195 16 705. can be used advantageously. Antimicrobial polypeptides can also be used.

[0094] (5) Photofilter actives that absorb UV rays in the UV-B and/or UV-A region. Suitable UV filters are, for example, 2,4,6-triaryl-1,3,5-triazines in which the aryl groups may in each case carry at least one substituent which is preferably selected from hydroxy, alkoxy, specifically methoxy, alkoxycarbonyl, specifically methoxycarbonyl and ethoxycarbonyl and mixtures thereof. Additionally suitable are p-aminobenzoic esters, cinnamic esters, benzophenones, camphor derivatives and UV-blocking pigments such as titanium dioxide, talc and zinc oxide.

[0095] Useful UV filter substances include any desired UV-A and UV-B filter substances. Examples include:

[0096] The cosmetic and dermatological compositions or formulations of the invention may advantageously also comprise inorganic pigments that block UV rays, based on metal oxides and/or other sparingly water-soluble or water-insoluble metal compounds selected from the group of zinc oxides ( ZnO), titanium (TiO2), iron (e.g. Fe2O3), zirconium (ZrO2), silicon (SiO2), manganese (e.g. MnO), aluminum (Al2O3), cerium (e.g. Ce2O3), mixed oxides of corresponding metals and combinations of such oxides.

[0097] The inorganic pigments here may be in coated form, that is, they may have been treated on the surface. This surface treatment may, for example, consist of providing the pigments with a thin hydrophobic layer by a method known per se, as described in DE-A-33 14 742.

[0098] (6) Repellent active ingredients, that is, compounds capable of repelling or scaring away certain animals, particularly insects, from humans. These include, for example, 2-ethyl-1,3-hexanediol, N,N-diethyl-m-toluamide etc.

[0099] (7) Suitable hyperemic substances, which stimulate skin perfusion, are, for example, essential oils, such as dwarf pine extract, lavender extract, rosemary extract, juniper berry extract, roast chestnut extract , birch leaf extract, grass seed extract, ethyl acetate, camphor, menthol, peppermint oil, rosemary extract, eucalyptus oil etc.

[00100] (8) Suitable keratolytic and keratoplastic substances are, for example, salicylic acid, calcium thioglycolate, thioglycolic acid and its salts, sulfur, etc. Suitable anti-dandruff actives are, for example, sulfur, sulfur polyethylene glycol sorbitan monooleate, sulfur ricinol polyethoxylate, zinc pyrithione, aluminum pyrithione etc.

[00101] (9) Suitable antiphlogistics, which act against skin irritation, are, for example, allantoin, bisabolol, Dragosantol, chamomile extract, panthenol, etc.

[00102] (10) Cosmetically or pharmaceutically acceptable polymers, such as cationic, amphoteric and neutral polymers.

[00103] Suitable polymers are, for example, cationic polymers with the name INCI Polyquaternium, for example, copolymers of vinylpyrrolidone/N-vinylimidazolium salts (Luviquat FC, Luviquat HM, Luviquat MS, Luviquat Care), copolymers of N-vinylpyrrolidone /dimethylaminoethyl methacrylate, quaternized with diethyl sulfate (Luviquat PQ 11), N-vinylcaprolactam/N-vinylpyrrolidone/N-vinylimidazolium salts copolymers (Luviquat E Hold), cationic cellulose derivatives (Polyquaternium-4 and -10), copolymers of acrylamide (Polyquaternium-7) and chitosan.

[00104] Suitable cationic (quaternized) polymers are also Merquat (polymer based on dimethyldialylammonium chloride), Gafquat (quaternary polymers formed by the reaction of polyvinylpyrrolidone with quaternary ammonium compounds), JR Polymer (hydroxyethylcellulose with cationic groups) and cationic polymers plant-based, for example, guar polymers such as Rhodia's Jaguar products.

[00105] Additional suitable polymers are also neutral polymers, such as polyvinylpyrrolidones, copolymers of N-vinylpyrrolidone and vinyl acetate and/or vinyl propionate, polysiloxanes, polyvinylcaprolactam and other copolymers with N-vinylpyrrolidone, polyethyleneimines and salts thereof, polyvinylamines and salts thereof, cellulose derivatives, polyaspartic acid salts and derivatives thereof. These include, for example, Luviflex® Swing (partially saponified copolymer of polyvinyl acetate and polyethylene glycol, BASF).

[00106] Suitable polymers are also non-ionic, water-soluble or water-dispersible polymers or oligomers, such as polyvinylcaprolactam, for example, Luviskol® Plus (BASF) or polyvinylpyrrolidone and copolymers thereof, in particular with vinyl esters, such as vinyl acetate, e.g. Luviskol® VA 37 (BASF); polyamides, for example based on itaconic acid and aliphatic diamines, as described, for example, in DE-A-43 33 238.

[00107] Suitable polymers are also amphoteric or zwitterionic polymers, such as octylacrylamide/methyl methacrylate/tert-butylaminoethyl methacrylate/hydroxypropyl methacrylate copolymers available under the names Amphomer (National Starch) and zwitterionic polymers, as disclosed, by example, in German patent applications DE 39 29 973, DE 21 50 557, DE 28 17 369 and DE 37 08 451. Acrylamidopropyltrimethylammonium chloride/acrylic acid or methacrylic acid copolymers and alkali metal and ammonium salts thereof are polymers preferred zwitterionics. Additional suitable zwitterionic polymers are methacryloylethyl betaine/methacrylate copolymers, which are commercially available under the name Amersette (AMERCHOL), and copolymers of hydroxyethyl methacrylate, methyl methacrylate, N,N-dimethylaminoethyl methacrylate and acrylic acid (Jordapon (D) ).

[00108] Suitable polymers are also nonionic, siloxane-containing, water-soluble or water-dispersible polymers, for example, polyether siloxanes, such as Tegopren® (Goldschmidt) or Besi (Wacker).

[00109] Below is a detailed elucidation by way of example of forms of individual private use of active ingredients of the invention.

Cooling Products for Skin Care and Hair Care:

[00110] In a preferred embodiment, the compositions of the invention are a cooling product for hair care or skin care or skin cleanser or hair shampoo.

[00111] Preferred skin cleansers or hair shampoos are soaps of liquid to gel consistency, such as clear soaps, luxury soaps, deodorant soaps, creamy soaps, baby soaps, skin protection soaps, abrasive soaps and syndets, paste soaps, greasy soaps and washing pastes, exfoliating soaps, moistening cloths, liquid washes, bath and bath preparations, such as washing lotions, shower baths and gels, bubble baths, oil baths and preparations scrubs, foams, lotions and shaving creams.

[00112] In a further preferred embodiment, the compositions of the invention are a shower gel, a shampoo formulation or a bath preparation. Formulations of this type comprise at least one active ingredient of the invention and typically anionic surfactants as base surfactants and amphoteric and/or non-ionic surfactants as cosurfactants. Additional suitable actives and/or auxiliaries are generally selected from lipids, perfume oils, pigments, organic acids, preservatives and antioxidants and thickeners/gel formers, skin conditioners and humidifiers.

[00113] In principle, the active ingredient content can vary over a wide range, for example 0.05 ppm to 10% by weight, preferably 0.1 ppm to 10% by weight.

i) Specific configurations for compositions for application to the skin:

[00114] Suitable cosmetics for skin compositions are, for example, facial toners, facial masks, deodorants and other cosmetic lotions. Products for use in decorative cosmetics include, for example, concealing sticks, stage makeup, mascara and shadows, sticks, kohl pencils, eyeliners, blushers, powders and eyebrow pencils.

[00115] Furthermore, the dermatological compositions of the invention can be used in nose strips for cleaning pores, in anti-acne compositions, repellents, shaving compositions, after-shave and pre-shave care compositions, post sun exposure care, hair removal compositions, hair dyes, intimate care compositions, foot care compositions and baby care compositions.

[00116] The skin care compositions of the invention are especially W/O or O/W skin creams, day creams and night creams, eye creams, facial creams, anti-wrinkle creams, sun protection creams, moisturizing creams, whitening products, self-tanning creams, vitamin creams, skin care lotions, care lotions and moisturizing lotions.

[00117] Skin cosmetics and dermatological compositions especially comprise at least one active ingredient of the invention in a proportion of about 0.05 ppm to 10% by weight, preferably 0.1 ppm to 10% by weight, based on weight total composition.

[00118] According to the field of application, the skin cosmetic compositions of the invention can be applied in a form suitable for skin care, for example in the form of a cream, foam, gel, stick, mousse, milk , spray (pump spray or spray containing propellant) or lotion.

[00119] As well as the active ingredients of the invention and suitable carriers, skin cosmetic preparations can also comprise active ingredients and auxiliaries common in skin cosmetics, as described above. These preferably include emulsifiers, preservatives, perfume oils, cosmetic actives such as phytantriol, vitamin A, E and C, retinol, bisabolol, panthenol, light stabilizers, whiteners, dyes, dyes, tanning agents, collagen, enzymes, hydrolysates of protein, stabilizers, pH regulators, pigments, salts, thickeners, gel formers, bulking agents, silicones, humectants, fat replacement agents and additional customary additives.

[00120] The oily and fatty components of skin cosmetics and dermatological compositions are the aforementioned mineral and synthetic oils, for example paraffins, silicone oils and aliphatic hydrocarbons having more than 8 carbon atoms, animal and vegetable oils, e.g. sunflower oil, coconut oil, avocado oil, olive oil, lanolin or waxes, fatty acids, fatty acid esters, e.g. triglycerides of C6- to C30 fatty acids, wax esters, e.g. jojoba oil, fatty alcohols, petroleum jelly, hydrogenated lanolin and acetylated lanolin and mixtures thereof.

[00121] To establish particular properties, for example improving haptics, spreading characteristics, water resistance and/or the binding of actives and auxiliaries, such as pigments, skin cosmetics and dermatological preparations may additionally also comprise substances conditioners based on silicone compounds. Suitable silicone compounds are, for example, polyalkylsiloxanes, polyarylsiloxanes, polyarylalkylsiloxanes, polyether siloxanes or silicone resins.

[00122] Cosmetic or dermatological preparations are produced by the usual methods known to those skilled in the art.

[00123] The dermatological compositions of the invention can be produced by mixing or diluting the active ingredients with a suitable auxiliary (excipient). Excipients can be solid, semi-solid or liquid materials that can serve as a vehicle, carrier or medium for the active ingredient. Additional auxiliaries are added, if desired, in a manner known to the person skilled in the art. Furthermore, the polymers and dispersions are suitable as pharmaceutical aids, preferably as or in coating(s) or binder(s) for suitable solid drug forms. They can also be used in creams and as tablet coatings and tablet binders.

[00124] Preferably, the cosmetic and dermatological compositions are in emulsion forms, in particular water-in-oil (W/O) or oil-in-water (O/W) emulsions. However, it is also possible to choose other types of formulation, for example gels, oils, oleo-gels, multiple emulsions, for example in the form of W/O/W or O/W/O emulsions, anhydrous ointments or ointment bases, etc. Emulsifier-free formulations such as hydrodispersions, hydrogels or a Pickering emulsion are also advantageous embodiments.

[00125] Emulsions are produced by known methods. As well as at least one active ingredient of the invention, emulsions generally comprise customary constituents such as fatty alcohols, fatty acid esters and especially fatty acid triglycerides, fatty acids, lanolin and derivatives thereof, natural or synthetic oils or waxes and emulsifiers in the presence of water. The selection of specific additives for the emulsion type and the production of suitable emulsions are described, for example, in Schrader, Grundlagen und Rezepturen der Kosmetika, Hüthig Buch Verlag, Heidelberg, 2nd edition, 1989, part three, which is hereby explicitly incorporated by reference.

[00126] A suitable emulsion in the form of a W/O emulsion, for example for a skin cream etc., generally comprises an aqueous phase emulsified into an oily or grease phase using a suitable emulsifier system. To provide the aqueous phase, a polyelectrolyte complex can be used.

[00127] The preferred fatty components that may be present in the grease phase of emulsions are: hydrocarbon oils, such as paraffin oil, purceline oil, perhydrosqualene and solutions of microcrystalline waxes in these oils; animal or vegetable oils, such as sweet almond oil, avocado oil, calophillum oil, lanolin and derivatives thereof, castor oil, sesame oil, olive oil, jojoba oil, shea oil, hoplostetus oil; mineral oils whose starting point for distillation under atmospheric pressure is about 250°C and whose distillation end point is at 410°C, for example vaseline oil; esters of saturated or unsaturated fatty acids, such as alkyl myristates, for example, i-propyl, butyl or cetyl myristate, hexadecyl stearate, ethyl or isopropyl palmitate, octanoic or decanoic acid triglycerides and cetyl ricinoleate.

[00128] The grease phase may also comprise silicone oils soluble in other oils, such as dimethylpolysiloxane, methylphenylpolysiloxane and silicone glycol copolymer, fatty acids and fatty alcohols.

[00129] As well as the active ingredients of the invention, it is also possible to use waxes, for example carnauba wax, candelilla wax, beeswax, microcrystalline wax, ozokerite wax and calcium, magnesium and aluminum oleates, calcium, magnesium and aluminum myristates , calcium, magnesium and aluminum linoleates and calcium, magnesium and aluminum stearates.

[00130] Furthermore, an inventive emulsion can take the form of an O/W emulsion. Such an emulsion typically comprises an oil phase, emulsifiers that stabilize the oil phase in the aqueous phase, and an aqueous phase that is usually in thickened form. Useful emulsifiers are preferably O/W emulsifiers, such as polyglyceryl esters, sorbitan esters or partially esterified glycerides.

[00131] In a further preferred embodiment, the compositions of the invention are a shower gel, a shampoo formulation or a bath preparation.

[00132] Formulations of this type comprise at least one active ingredient of the invention and typically anionic surfactants as base surfactants and amphoteric and/or non-ionic surfactants as cosurfactants. Additional suitable actives and/or auxiliaries are generally selected from lipids, perfume oils, pigments, organic acids, preservatives and antioxidants and thickeners/gel formers, conditioners and skin humidifiers.

[00133] These formulations especially comprise 2% to 50% by weight, such as 5% to 40% by weight or 8% to 30% by weight, of surfactants, based on the total weight of the formulation.

[00134] In washing, showering and bathing preparations, it is possible to use any of the usual anionic, neutral, amphoteric or cationic surfactants used in personal cleansers.

[00135] Suitable anionic surfactants are, for example, alkyl sulfates, alkyl ether sulfates, alkylsulfonates, alkylarylsulfonates, alkyl succinates, alkyl sulfosuccinates, N-alcoylsarcosinates, acyl taurates, acyl isethionates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates , alpha-olefinsulfonates, especially the alkali and alkaline earth metal salts, for example, the sodium, potassium, magnesium, calcium and ammonium salts and triethanolamine. Alkyl ether sulfates, alkyl ether phosphates and alkyl ether carboxylates may have between 1 and 10 ethylene oxide or propylene oxide units, preferably 1 to 3 ethylene oxide units, in the molecule.

[00136] These include, for example, sodium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate, ammonium lauryl ether sulfate, sodium lauryl sarcossinate, sodium oleyl succinate, ammonium lauryl sulfosuccinate, sodium dodecylbenzenesulfonate, triethanolamine dodecylbenzene sulfonate.

[00137] Suitable amphoteric surfactants are, for example, alkyl betaines, alkylamidopropyl betaines, alkyl sulfobetaines, alkyl glycinates, alkyl carboxyglycinates, alkyl amphoacetates or alkyl amphopropionates, alkyl amphodiacetates or alkyl amphodipropionates.

[00138] For example, it is possible to use cocodimethylsulfopropyl betaine, lauryl betaine, cocamidopropyl betaine or sodium cocamphopropionate.

[00139] Examples of suitable non-ionic surfactants are the reaction products of aliphatic alcohols or alkylphenols having 6 to 20 carbon atoms in the alkyl chain, which can be linear or branched, with ethylene oxide and/or propylene oxide. The amount of alkylene oxide is about 6 to 60 mol per mol of alcohol. Furthermore, alkylamine oxides, mono- or dialkylalkanolamides, fatty acid esters of polyethylene glycols, ethoxylated fatty acid amides, alkyl polyglycosides or sorbitan ether esters are suitable.

[00140] Washing, shower and bath preparations can also comprise customary cationic surfactants, for example quaternary ammonium compounds, for example cetyltrimethylammonium chloride.

[00141] Furthermore, shower gel/shampoo formulations may comprise thickeners, such as, for example, sodium chloride, PEG 55, propylene glycol oleate, PEG 120 methylglucose dioleate and others and additional preservatives, actives and auxiliaries and water. ii) Specific configurations for compositions for application to hair:

[00142] In an additional preferred embodiment, the compositions of the invention are a hair treatment composition.

[00143] The hair treatment compositions of the invention especially comprise at least one active ingredient of the invention in an amount in the range of about 0.05 ppm to 10% by weight, preferably 0.1 ppm to 10% by weight, based in the total weight of the composition.

[00144] Preferably, the hair treatment compositions of the invention take the form of a fixing foam, hair mousse, hair gel, shampoo, hair spray, hair foam, finishing fluid, wave neutralizer perms, hair dye and bleaching or hot oil treatments. According to the field of application, cosmetic hair preparations can be applied in the form of spray (aerosol), foam (aerosol), gel, gel spray, cream, lotion or wax. Hairsprays include both aerosol sprays and pump sprays without propellant gas. Hair foams include both aerosol foams and foams in pumps without propellant gas. Hair sprays and hair foams preferably comprise predominantly or exclusively water-soluble or water-dispersible components. If the compounds used in the inventive hair sprays and hair foams are water dispersible, they can be used in the form of aqueous microdispersions having particle diameters typically from 1 to 350 nm, preferably from 1 to 250 nm. The solid contents of these preparations are typically within a range of about 0.5 ppm to 20% by weight. These microdispersions generally do not require any emulsifier or surfactant for their stabilization.

[00145] In a specific embodiment, the cosmetic formulations for hair of the invention comprise a) 0.0001% to 50% by weight or 0.001% to 10% by weight or 0.005% to 1% by weight of at least one active ingredient of the invention, b) 20% to 99.95% by weight of water and/or alcohol, c) 0% to 50% by weight of at least one propellant gas, d) 0% to 5% by weight of at least one emulsifier , e) 0% to 3% by weight of at least one thickener and up to 25% by weight of additional constituents.

[00146] “Alcohol” is understood to mean any alcohols usual in cosmetics, for example, ethanol, isopropanol, n-propanol.

[00147] Also included here are all known styling polymers and conditioners in cosmetics that can be used in combination with the active ingredients of the invention if very specific properties are to be established.

[00148] Conventional cosmetic polymers suitable for hair are, for example, the previously mentioned cationic, anionic, neutral, nonionic and amphoteric polymers, to which reference is made here.

[00149] To establish certain properties, the preparations may additionally also comprise conditioning substances based on silicone compounds. Suitable silicone compounds are, for example, polyalkylsiloxanes, polyarylsiloxanes, polyarylalkylsiloxanes, polyethersiloxanes, silicone resins or dimethicone copolyols (CTFA) and amino-functional silicone compounds such as amodimethicones (CTFA).

[00150] The polymers of the invention are particularly suitable as fixing agents in hair styling preparations, especially hair sprays (aerosol sprays and pump sprays without propellant gas) and hair mousses (aerosol mousses and pump mousses without gas propellant).

[00151] In a preferred embodiment, the spray preparations comprise a) 0.0001% to 50% by weight or 0.001% to 10% by weight or 0.005% to 1% by weight of at least one active ingredient of the invention, b) 20% to 99.9% by weight of water and/or alcohol, c) 0% to 70% by weight of at least one propellant, d) 0% to 20% by weight of additional constituents.

[00152] Propellants are the propellants commonly used for hair sprays or aerosol foams. Preference is given to mixtures of propane/butane, pentane, dimethyl ether, 1,1-difluoroethane (HFC-152 a), carbon dioxide, nitrogen or compressed air.

[00153] An aerosol hair foam formulation that is preferred according to the invention comprises a) 0.0001% to 50% by weight or 0.001% to 10% by weight or 0.005% to 1% by weight of at least an active ingredient of the invention, b) 55% to 99.8% by weight of water and/or alcohol, c) 5% to 20% by weight of a propellant, d) 0.1% to 5% by weight of an emulsifier , e) 0% to 10% by weight of additional constituents.

[00154] The emulsifiers used can be any of the emulsifiers commonly used in hair foams. Suitable emulsifiers may be non-ionic, cationic or anionic or amphoteric.

[00155] Examples of nonionic emulsifiers (INCI nomenclature) are laurets, for example, Lauret-4; cetets, for example, Cetet-1, polyethylene glycol cetyl ether; cetearets, e.g. Cetearet-25, polyglycol fatty acid glycerides, hydroxylated lecithin, lactyl esters of fatty acids, alkyl polyglycosides.

[00156] Examples of cationic emulsifiers are cetyldimethyl-2-hydroxyethylammonium dihydrogen phosphate, cetyltrimonium chloride, cetyltrimonium bromide, cocotrimonium methyl sulfate, Quaternium-1 to x (INCI).

[00157] Anionic emulsifiers can be selected, for example, from the group of alkyl sulfates, alkyl ether sulfates, alkylsulfonates, alkylarylsulfonates, alkyl succinates, alkyl sulfosuccinates, N-alcoylsarcosinates, acyl taurates, acyl isethionates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, alpha-olefinsulfonates, in particular the alkali metal and alkaline earth metal salts, for example the sodium, potassium, magnesium, calcium and ammonium salts and triethanolamine. Alkyl ether sulfates, alkyl ether phosphates and alkyl ether carboxylates may have between 1 and 10 ethylene oxide or propylene oxide units, preferably 1 to 3 ethylene oxide units, in the molecule.

[00158] A suitable formulation according to the invention for styling gels may, for example, be of the following composition: a) 0.0001% to 50% by weight or 0.001% to 10% by weight or 0.005% to 1% by weight of at least one active ingredient of the invention, b) 80% to 99.85% by weight of water and/or alcohol, c) 0% to 3% by weight, preferably 0.05% to 2% by weight, of a gel former, d) 0% to 20% by weight of additional constituents.

[00159] The use of gel formers can be advantageous in order to establish the specific rheological or performance properties of gels. The gel formers used can be any gel formers customary in cosmetics. These include lightly cross-linked polyacrylic acid, e.g. Carbomer (INCI), cellulose derivatives, e.g. hydroxypropyl cellulose, hydroxyethyl cellulose, cationically modified celluloses, polysaccharides, e.g. xanthan gum, caprylic/capric triglyceride, sodium acrylate copolymers, Polyquaternium- 32 (e) Liquid Paraffin (INCI), sodium acrylate copolymers (e) Liquid Paraffin (e) PPG-1 Tridecet-6, acrylamidopropyltrimonium chloride/acrylamide copolymers, Stearet-10 allyl ether acrylate copolymers, Polyquaternium -37 (e) Liquid Paraffin (e) PPG-1 Tridecet-6, Polyquaternium 37 (e) propylene glycol dicaprate dicaprylate (e) PPG-1 Tridecet-6, Polyquaternium- 7, Polyquaternium-44.

[00160] Specific shampoo formulations comprise a) 0.0001% to 50% by weight or 0.001% to 10% by weight or 0.005% to 1% by weight of at least one active ingredient of the invention, b) 25% to 94 .95% by weight of water, c) 5% to 50% by weight of surfactants, c) 0% to 5% by weight of an additional conditioner, d) 0% to 10% by weight of additional cosmetic constituents.

[00161] In shampoo formulations it is possible to use any of the anionic, neutral, amphoteric or cationic surfactants commonly used in shampoos.

[00162] Suitable anionic surfactants are, for example, alkyl sulfates, alkyl ether sulfates, alkylsulfonates, alkylarylsulfonates, alkyl succinates, alkyl sulfosuccinates, N-alcoylsarcosinates, acyl taurates, acyl isethionates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, alpha-olefinsulfonates, especially the alkali metal and alkaline earth metal salts, for example, the sodium, potassium, magnesium, calcium and ammonium salts and triethanolamine. Alkyl ether sulfates, alkyl ether phosphates and alkyl ether carboxylates may have between 1 and 10 ethylene oxide or propylene oxide units, preferably 1 to 3 ethylene oxide units, in the molecule.

[00163] For example, sodium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate, ammonium lauryl ether sulfate, sodium lauryl sarcosinate, sodium oleyl succinate, ammonium lauryl sulfosuccinate, sodium dodecylbenzenesulfonate, triethanolamine dodecylbenzenesulfonate are appropriate.

[00164] Suitable amphoteric surfactants are, for example, alkyl betaines, alkylamidopropyl betaines, alkyl sulfobetaines, alkyl glycinates, alkyl carboxyglycinates, alkyl amphoacetates or amphopropionates, alkyl amphodiacetates or amphodipropionates.

[00165] For example, it is possible to use cocodimethylsulfopropyl betaine, lauryl betaine, cocamidopropyl betaine or sodium cocamphopropionate.

[00166] Examples of suitable non-ionic surfactants are the reaction products of aliphatic alcohols or alkylphenols having 6 to 20 carbon atoms in the alkyl chain, which can be linear or branched, with ethylene oxide and/or propylene oxide. The amount of alkylene oxide is about 6 to 60 mol per mol of alcohol. Additionally suitable are alkylamine oxides, mono- or dialkylalkanolamides, fatty acid esters of polyethylene glycols, alkyl polyglycosides or sorbitan ether esters.

[00167] Furthermore, shampoo formulations may comprise customary cationic surfactants, for example quaternary ammonium compounds, for example cetyltrimethylammonium chloride.

[00168] In shampoo formulations, particular effects can be obtained using usual conditioners in combination with the active ingredients of the invention.

[00169] These include, for example, the cationic polymers mentioned above with the name INCI Polyquaternium, especially copolymers of vinylpyrrolidone/N-vinylimidazolium salts (Luviquat FC, Luviquat HM, Luviquat MS, Luviquat Care), copolymers of N-vinylpyrrolidone/methacrylate dimethylaminoethyl, quaternized with diethyl sulfate (Luviquat D PQ 11), N-vinylcaprolactam/N-vinylpyrrolidone/N-vinylimidazolium salts copolymers (Luviquat D Hold), cationic cellulose derivatives (Polyquaternium-4 and -10), copolymers of acrylamide (Polyquaternium-7). Furthermore, it is possible to use protein hydrolysates and conditioning substances based on silicone compounds, for example polyalkylsiloxanes, polyarylsiloxanes, polyarylalkylsiloxanes, polyethersiloxanes or silicone resins. Suitable additional silicone compounds are dimethicone copolyols (CTFA) and aminofunctional silicone compounds such as amodimethicones (CTFA). Furthermore, it is possible to use cationic guar derivatives such as guar hydroxypropyltrimonium chloride (INCI). Oral Care Cooling Compositions:

[00170] The oral care compositions of the invention can be formulated in a manner known per se, for example as toothpaste, dental gel or aqueous or aqueous-alcoholic mouthwashes.

[00171] The oral care compositions of the invention comprise, based on the weight of the composition, preferably 0.05 ppm to 10% by weight, more preferably 0.1 ppm to 10% by weight, of the total amount of at least one active of the invention.

[00172] Furthermore, oral care compositions, especially toothpastes, may also comprise abrasives such as hydrated silicon oxide, dicalcium phosphate dihydrate, calcium carbonate, sodium hydrogen carbonate, calcium pyrophosphate and aluminum oxide. For example, it is also possible to use a mixture of precipitated silicon thickener and precipitated silicon abrasive [Handbook of Pharmaceutical Excipients, The Pharmaceutical Society of Great Britain, 1 Lambet High Street, London SE 1 7JN, England, pages 253-256]. The former is used due to its thixotropic properties, the latter due to its better effectiveness in removing substances adhered to tooth surfaces. The use of these products guarantees a lower abrasive effect since the materials are amorphous solids of moderate hardness that at the same time are totally and completely compatible with the fluoride used as a mineralizer, since they do not contain any limestone salt that would make them insoluble. and would reduce its bioavailability.

[00173] The formulation of the oral care compositions of the invention, for example toothpaste, may also comprise suitable additives and carriers in order to improve their properties and facilitate production. These are selected, for example, from binders, thickeners, fragrances, pigments, preservatives, wetting agents or humectants, surfactants, lubricants, opacifiers, remineralizers, surfactants, buffers, alcohols, vitamins, water, additional actives and mixtures thereof.

[00174] The binder used can be any agent normally used in the production of this type of formulations, for example gum tragacanth. The binder may be present in the formulation in an amount of 0.5 to 1.5% by weight of the total amount.

[00175] It is also possible for organic thickeners to be incorporated into the oral care composition, such as sodium carboxymethyl cellulose, cellulose ethers, xanthan gum, carrageenans, sodium alginate and Carbopols. It is also possible to use inorganic thickeners such as silica thickeners, sodium aluminum silicates and clays to provide the appropriate rheology. The thickener may be present in the formulation in an amount of 0.5 to 5% by weight of the total amount.

[00176] The toothpaste can be flavored by adding a suitable customary fragrance, for example a peppermint flavoring. Essential oils including clove oil, cinnamon oil, peppermint oil and spearmint oil, inter alia, are equally suitable. The fragrance may be present in the formulation in an amount of 0.5 to 15% by weight of the total amount.

[00177] Any pigment commonly used in the production of toothpaste can be used as a pigment, for example Brilliant Blue FCF, C.42090 [KIRSCH PHARMA]. The pigment may be present in the formulation in an amount of 0.001 to 0.005% by weight of the total amount.

[00178] The preservative can be any usual agent, for example a benzoic acid derivative, for example p-hydroxymethyl benzoate. The preservative may be present in the formulation in an amount of 0.1 to 0.3% by weight of the total amount.

[00179] Sodium saccharin or cyclamic acid and its derivatives, for example, sodium cyclamate, can be used as a sweetener. The sweetener may be present in the formulation in an amount of 0.08 to 0.15% by weight of the total amount.

[00180] The wetting agent or humectant used to prevent the toothpaste from drying and hardening is specially selected from liquid glycerol, sorbitol, propylene glycol, xylitol and polyethylene glycols, especially a mixture of sorbitol, glycerol and xylitol, e.g. a proportion of 1 to 60% by weight of the total quantity.

[00181] The lubricant can be any agent commonly used in the formulation of a toothpaste, for example, dimethicone (dimethylpolysiloxane polymer), which is a surfactant that contributes to imparting good rheological properties to the toothpaste of the invention. The lubricant may be present in the formulation in an amount of 0.25% to 0.75% by weight of the total amount.

[00182] Any of the typically used agents can be used as an opacifier, for example titanium dioxide. The opacifier may be present in the formulation in an amount of 0.05% to 1% by weight of the total amount.

[00183] A source of fluoride is used as the remineralizing agent, for example sodium fluoride, tin (II) fluoride and sodium monofluorophosphate, since, in this way, 100% of an active fluoride as an agent for remineralizing the white lesions caused by organic acids that are a consequence of bacterial metabolism. The remineralizing agent may be present in the formulation in an amount of 0.2% to 0.4% by weight of the total amount.

[00184] Typically, it is additionally possible for the usual constituents to be present, such as anionic surfactants, for example sodium lauryl sulfate, sodium N-lauryl sarcosinate, sodium lauryl sulfoacetate and sodium alkyl glyceryl ether sulfonate. The surfactant may be present in the formulation in an amount of 0.05% to 5% by weight of the total amount.

[00185] If desired, the toothpaste proposed by the invention may also comprise a vitamin selected from the group formed by vitamin A, vitamin B5, vitamin C and vitamin E, mixtures thereof. In the case of use, each vitamin may be present in the formulation in an amount of 0.1% to 5% by weight of the total amount. These vitamins can be used as such, in the form of provitamins or in the form of pharmaceutically acceptable salts. Vitamin A, which is generally used in the form of its palmitate salt, promotes the epithelialization of the oral mucosa and protects the gums. Vitamin B5, more specifically D-panthenol, has analgesic, healing and anti-inflammatory effects, protects the epithelial mucosa, promotes the epithelialization of wounds and softens scars; It is suitable for the treatment of wounds resulting from tooth extraction, gingivitis, stomatitis, pain after the insertion of dental prostheses, ulcers, traumatic mucosal injuries, chronic and recurrent mouth ulcers. Vitamin C regenerates the epithelium of the oral mucosa, promotes collagen synthesis and the immune system (inflammation mechanism) and increases the ability of phagocytes to protect against bacteria. Vitamin E, which is normally used in the form of its acetate salt, has an analgesic and anti-inflammatory effect, protects the oral mucosa from excessive oxidation of fats due to the formation of free radicals and environmental contaminants (ozone, smoke smoking etc.) and promotes wound healing. By virtue of the addition of one or more of these vitamins, the invention gives a toothpaste which, as well as the previously mentioned properties, also has anti-inflammatory characteristics and analgesic effects that increase the capacity of the oral mucous membranes to provide protection and reduce the index of plaque and tartar formation and that of bacterial contamination.

[00186] Additional actives are, for example, antimicrobial and plaque penetrating agents, such as beta-naphthol, thymol, chlorothymol and hexylresorcinol; or antibacterial compounds, such as quaternary ammonium compounds; tartar control agents such as tetrasodium pyrophosphate, GANTREZ Polymer® S-70, sodium tripolyphosphate and zinc citrate; peroxide compounds such as hydrogen peroxide and inorganic peroxides.

[00187] A buffer may optionally also be used, which is present in concentrations suitable for maintaining a pH of about 6 to 8, for example alkali metal phosphate buffer. The presence of potassium ions additionally exerts a relieving effect on excessive sensitivity.

[00188] Water or alcohol may be present in a proportion of 1% to 20% by weight of the total amount of the composition.

[00189] In combination with alcohol or in place of alcohol, it is also possible to use glycol compounds such as glycerol, sorbitol or propylene glycol.

[00190] The oral care composition of the invention can be easily produced by mixing suitable quantities of the various constituents in a reactor equipped, for example, with stirring paddles.

Cooling plasters:

[00191] In principle, the active ingredient content can vary over a wide range, for example 0.05 ppm to 10% by weight, preferably 0.1 ppm to 10% by weight.

[00192] The patches of the invention can be constructed in any desired manner, for example by the matrix system, the membrane system or the non-woven system (Drug Dev. Ind. Pharm. 14 (1988), 183209; Drug Dev. Ind. Pharm 13 (1987), 589-651; Drugs of Today 23 (1987), 625-646).

[00193] The matrix system in its simplest form consists of 3 parts: the flexible support sheet, the adhesive matrix containing the active and a removal sheet. If a non-sticky matrix is used, an edge zone of the backing sheet must be provided with adhesive for adhesion to the skin.

[00194] A membrane system, in contrast, has at least 5 parts: a flexible backing sheet, a reservoir containing dissolved or suspended active, a membrane for controlling active release, an adhesive layer attached to the membrane and a sheet for removal.

[00195] In the non-woven system, the layer comprising the active consists of a non-woven or porous absorptive polymer impregnated with a solution or suspension of the active. This layer, firmly attached to the backing sheet, is covered by a sheet for removal. The edge of the backing sheet has been provided with adhesive for application to the skin.

[00196] In principle, all assets of the invention can be formulated in this way.

[00197] The auxiliaries to be used are the usual auxiliaries for the production of plasters. As well as the adhesive agent, generally a polymer having a glass transition temperature between -70 and -10°C, especially -55 and -25°C and a carrier film coated with this adhesive agent and the active, emulsifiers, thickeners and substances intended to influence the release of active release and other auxiliaries are often added.

[00198] Sticky polymers with the low glass transition temperatures mentioned above are known, for example from US Patents 2,973,282 and 3,307,544. Self-adhesive tapes and films must stick to human skin upon simple contact, but the cohesion of the layer adhesive and their adhesion to the carrier film must be greater than their adhesion to the skin, such that they can be removed again widely without residue. These generally comprise copolymers which are based on acrylic and methacrylic acids of alcohols having 2 to 12, especially 4 to 8, carbon atoms and may comprise numerous other comonomers in copolymerized form, for example (meth)acrylic acid, (meth)acrylonitrile, (meth)acrylamide, N-tert-butyl(meth)acrylamide, vinyl esters such as vinyl acetate, propionate or butyrate, other vinyl compounds such as styrene and butadiene. Particular emphasis should be given to butyl acrylate and 2-ethylhexyl acrylate. The polymers may have been cross-linked by the addition of small amounts of comonomers having 2 or more copolymerizable double bonds, i.e., for example, of diacrylates such as butanediol diacrylate or divinyl compounds such as divinylbenzene, or by the addition of other cross-linkers, e.g. , melamine-formaldehyde resins. Sticky polymers used can also be polyisobutylenes and polyvinyl ethers of different molecular weight.

[00199] The particle size of the dispersions should be between 50 and 500 nm, especially between 50 and 200 nm. The particle size and degree of cross-linking can be adjusted in a known manner depending on the polymerization conditions and comonomers. Smaller particle sizes and a high level of cross-linking can result in increased active release.

[00200] Matrix plasters can be produced in a customary manner by dissolving or finely dispersing the active in a suitable polymeric solution and then pulling this active-containing self-adhesive composition through roller or squeegee application methods to give a film. In some cases, it is appropriate to dissolve or ultrafinely disperse the active in an organic solvent, for example, ethanol or acetone, before addition to the polymer solution. This can achieve better distribution of the active in the polymer.

[00201] Plasters can also be produced according to German patent application P 38 07 283.1 by incorporating the active in fine powder form (particle size below 200 µm, especially below 50 µm) in the aqueous dispersion of latex or dispersing or dissolving the same in an aqueous emulsifying solution and mixing this mixture into the aqueous latex dispersion at a temperature of 10 to 80°C, especially 30 to 70°C. Furthermore, the salt of an active in aqueous solution can also be mixed with the polymeric dispersion at a pH at which the active is predominantly in the water-soluble ionized form. By adjusting the pH, the active ingredient is then converted to the neutral, water-insoluble form and simultaneously emulsified in the dispersion.

[00202] Suitably, the active is initially loaded, the emulsifier and water are added and then they are mixed with the polymeric dispersion. The active-containing dispersion thus obtained is optionally provided with additional auxiliaries and, as mentioned, drawn in a manner known per se onto a support sheet to form a film and dried. The drying temperature here can be between room temperature and 100°C, with a more favorable condition between the objectives of rapid drying and the avoidance of bubble formation in the film and thermal stress on the active generally 35 to 45°C.

[00203] This process has the enormous advantage of avoiding organic solvents. However, all other usual production methods for matrix plasters are also useful in principle.

[00204] The resulting films have thicknesses of 10 to 800 µm, preferably 50 to 300 µm. Films can be produced continuously or in batches. The application method can be repeated multiple times until the film has reached the desired thickness. The sticky polymer layer comprises the active in a concentration in the range of 1% to 40% by weight, especially 5% to 25% by weight. The same concentration also applies to the reservoir liquid in the membrane system and to the active solution or dispersion with which the nonwoven in the case of the nonwoven system or the porous polymer are impregnated.

[00205] The emulsifiers used for both the active ingredients and the polymers are the usual surfactants for the purpose, such as the sodium salt of relatively long-chain fatty acids and the sulfuric monoester of a fatty alcohol (optionally ethoxylated) as examples of anionic surfactants and polyethoxylated alkylphenols and relatively long-chain fatty alcohols (e.g. hexadecan-1-ol) and glycerol fatty acid partial esters as examples of non-ionic surfactants and coemulsifiers.

[00206] The desired viscosity of the dough ready for pulling can be adjusted, for example, with polyacrylic acids or cellulose derivatives.

[00207] Examples of additional crosslinking agents that can be used to improve the cohesion and consequently the bonding properties of films include melamine-formaldehyde resins.

[00208] Swelling agents such as polyvinylpyrrolidone, cellulose derivatives or polyacrylates are effective for the purpose of improving active release, as the film can absorb an increased amount of water and consequently fails to resist diffusion. The release of active ingredients can also be improved by the addition of hydrophilic plasticizers such as glycerol, propane-1,2-diol, polyethylene glycols and lipophilic plasticizers such as triacetin, dibutyl phthalate or isopropyl myristate.

[00209] Matrix patches typically give 1st order active release. The use of fillers that absorb the active ingredient, such as aerosil, microcrystalline cellulose or lactose, results in almost order 0 release.

[00210] The backing sheet on which the self-adhesive composition containing the active is dried is suitably virtually impermeable to both the active and water vapor. It may consist, for example, of an aluminum-plastic composite sheet, a metallized plastic sheet, a polymeric film provided with a barrier layer of polyvinylidene chloride, for example, on the active side or of a simple polymeric film, e.g. example, polyester film.

[00211] The plasters of the invention constructed by the membrane system are also produced in a customary manner (for example, EP 0 186 071 A2, US 4 262 003).

[00212] Plasters constructed by the non-woven system are produced by impregnating non-woven or porous polymers attached to the support sheet with a solution or dispersion of the active in a hydrophilic or lipophilic solvent or mixture of solvents. Subsequently, the waterproof sheet for removal is fixed. Cooling Foods:

[00213] The cooling foods of the invention (at room temperature) can be in solid, liquid, semisolid, pasty, creamy or foamed form. Like conventional food constituents, they comprise at least an effective (i.e., cooling-effective) amount of at least one active ingredient of the invention.

[00214] Typical constituents here are fats, carbohydrates, proteins, dietary fiber, water, alcohol and the like.

[00215] The protein content can, for example, be from 0% to 50% by weight, based on the total weight of the food; fat content can, for example, be from 0% to 50% by weight, based on the total weight of the food; the carbohydrate content can, for example, be from 0% to 90% by weight, based on the total weight of the food; the dietary fiber content may, for example, be from 0% to 90% by weight, based on the total weight of the food; the water content can, for example, be from 0% to 95% by weight, based on the total weight of the food; the alcohol content can, for example, be from 0% to 15% by weight, based on the total weight of the food; the proportion of active ingredients of the invention may, for example, be in the range of 0.05 ppm to 10% by weight, preferably 0.1 ppm to 10% by weight, based on the total weight of the food.

[00216] Examples of carbohydrates are, for example, mono- and disaccharides, glucose, galactose, mannose, lactose, maltose and sucrose; fructose and mannose; polysaccharides, for example starches, maltodextrins; flour.

[00217] The term “dietary fiber” refers to soluble, insoluble, fermentable, non-fermentable or any combination of such dietary fibers. Dietary fiber may comprise, for example, soybean fiber, pectin, particular resistant starches, oligofructose, inulins, oat fiber, pea fiber, guar gum, acacia gum, modified cellulose.

[00218] The fat constituent can be any lipid or fat of known suitability for use in foods. Typical fats include milk fat, safflower oil, canola oil, egg yolk lipid, olive oil, cottonseed oil, coconut oil, palm oil, palm oil, soybean oil, sunflower oil, fish oil and fractions of all previously mentioned oils that derive therefrom, such as palmolein, intermediate chain triglycerides (MCTs) and fatty acid esters, where the fatty acids are, for example, arachidonic acid, linoleic acid, palmitic acid , stearic acid, docosahexaenoic acid, eicosapentaenoic acid, linolenic acid, oleic acid, lauric acid, capric acid, caprylic acid, caproic acid. Forms of various oils having a high oleic acid content are also considered suitable for the present use, such as high oleic sunflower oil and high oleic safflower oil.

[00219] The protein can be any protein and/or amino acid mixture of known suitability for use in foods. Typical proteins are animal proteins, vegetable proteins such as soy protein, milk proteins such as skimmed milk protein, whey protein and casein, and amino acids (or salts thereof) such as isoleucine, phenylalanine, leucine, lysine, methionine, threonine, tryptophan, arginine, glutamine, taurine, valine. Preferred protein sources are whey protein, sodium caseinate or calcium caseinate, optionally with added amino acids. For some applications, a preferred protein source is hydrolyzed protein (protein hydrolyzate), optionally with added amino acids.

[00220] The protein hydrolyzate can be any suitable protein hydrolyzate that is used in a food, such as soy protein hydrolyzate, casein hydrolyzate, whey protein hydrolyzate, other animal and vegetable protein hydrolyzates and mixtures of the same. The protein hydrolyzate in the composition of the invention is preferably a soy protein, whey protein or casein protein hydrolyzate comprising short peptides and amino acids and optionally with additional amino acids added. In a preferred embodiment, suitable protein hydrolysates according to the invention comprise a high proportion of free amino acids (e.g. more than 40%) and low molecular weight peptide fragments.

[00221] The hydrolyzed protein in the composition of the invention was also preferably mixed with various free amino acids in order to provide a nutritionally balanced amino acid content. Examples of such free amino acids include L-tryptophan, L-methionine, L-cystine, L-tyrosine and L-arginine.

[00222] The foods of the invention optionally also comprise vitamins and minerals. The person skilled in the art is familiar with the minimum requirements that have been established for particular vitamins and minerals that are necessary for normal physiological function. The person skilled in the art also knows that additional amounts of vitamin and mineral constituents suitable for foods must be added in order to compensate for certain losses in the processing and storage of such compositions. The composition of the invention optionally contains significant amounts of vitamins and minerals for nutritional purposes.

[00223] Examples of minerals, vitamins and other nutrients that may be present in the composition of the invention include vitamin A, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, inositol, taurine, folic acid, thiamine , riboflavin, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chloride, potassium, sodium, beta-carotene, nucleotides, selenium, chromium, molybdenum and L-carnitine. Minerals are typically added in salt form.

[00224] The composition of the invention optionally also typically comprises emulsifiers and/or stabilizers such as lecithin (e.g. from egg or soy), modified lecithin (e.g. enzymatic or acetylated), carrageenan, xanthan gum, mono- and diglycerides, guar gum , carboxymethyl cellulose, stearoyl lactylates, succinylated monoglycerides, sucrose esters of fatty acids, diacetyltartaric esters of monoglycerides, polyglycerol esters of fatty acids or any mixtures thereof.

[00225] The composition of the invention optionally comprises one or more natural or synthetic flavor carriers to improve palatability. It is possible to use any flavor carrier used in the sector, such as strawberry, cherry, chocolate, orange, coconut, vanilla; condiments such as nutmeg and cinnamon; or citric acid. In some cases where natural flavor carriers such as coconut chips are used the constituent contributes to the overall nutritional profile of the composition, meaning that it contributes to the quality and quantity of the fat, protein and/or carbohydrate constituents.

[00226] The composition of the invention optionally also comprises various other constituents that contribute to the nutritional profile of the composition and/or may impart desirable flavor properties, such as flavor enhancement or mouthfeel. Such constituents include peanuts, raisins, cheese powder, vinegar, salt, baking soda. In the case of bars, the composition is typically provided with a chocolate or flavored (e.g., chocolate, vanilla, strawberry, etc.) coating.

[00227] The composition of the invention optionally also comprises natural or synthetic pigments in order to improve the visual impression.

[00228] The compositions of the invention may be in multiple physical manifestations, for example in the form of liquid enteral foods or beverages for adults or children, in a semi-solid form such as blancmange, cream, mousse or a solid form such as a bar nutritional or biscuit.

[00229] The composition of the invention can be produced by standard methods known in food technology, for example by methods analogous to those described in the following publications: US Patents 4,670,268, 4,497,800, 4,900,566, 5,104,677, 5,389. 395 and 5,223,285; Chocolate, Cocoa and Confectionery: Science and Technology, 3rd edition, Bernard W. Minifie, Van Nostrand Reinhold, New York, 1989, p. 502-506; which are fully incorporated by reference.

[00230] In the case of nutritional bars and cookies, the objective is typically to bake the composition after physical modeling.

[00231] The composition of the invention may if desired be sterilized by known methods, for example by heat treatment such as autoclaving or sterilization or irradiation or produced and packaged by sterile methods.

[00232] The composition of the invention can be packaged in any type of container or packaging known to be suitable for storing food, such as paper, glass, coated cardboard, plastic or coated metal cans.

[00233] The composition of the invention can be nutritionally balanced. The term “nutritionally balanced” is understood to mean that the composition comprises appropriate nutrients to maintain healthy human life over prolonged periods of time.

Textile products modified with active ingredients of the invention:

[00234] The modification of textile products with active ingredients of the invention is of interest from several points of view.

[00235] For example, the modification of textile products with cooling compounds finds use especially where clothing items come into direct contact with the skin, such that the active, through transdermal transfer, can demonstrate its effects, for example local or systemically. Recently, there have been reports of textile products modified with “wellness additives”, that is, substances that promote well-being (R. Breier “Megatrend Wellness - Innovative Ideen für die Textilausrüstung [Wellbeing, The Megatrend - Innovative Ideas for Textile Modification]”, 31. Aachener Textiltage November 2004).

[00236] Insecticidal modification is again of interest with respect to material protection, for example modification of the textile product to act against damage by moths etc., but especially also to repel parasitic insects such as mosquitoes.

[00237] A fundamental problem in modifying textile products with actives is the connection of the active to the textile carrier, which on the one hand must guarantee the permanence of the modification and on the other hand must be chosen such that the active does not lose its effect. Several methods are proposed in the prior art for this purpose.

[00238] For example, cyclodextrins have been suggested for binding actives to textile products (see, for example, DE-A-19810951 and EP-A-0 392 608). Cyclodextrins are cyclic oligosaccharides that are formed by the enzymatic degradation of starch. The most common cyclodextrins are α-, ß- and Y-cyclodextrins, consisting respectively of six, seven and eight α-1,4-linked glucose units. A characteristic property of cyclodextrin molecules is their ring structure with largely unchangeable dimensions. The inner diameter of the rings is about 570 pm for α-cyclodextrin, about 780 pm for ß-cyclodextrin and about 950 pm for Y-cyclodextrin. Due to their structure, cyclodextrins are capable of including guest molecules, especially hydrophobic guest molecules, in varying amounts until saturation.

[00239] EP-A-1710345 describes the modification of textile products with fragrances and other low molecular weight organic active ingredients that are linked to the textile product by means of an amylose-containing substance with an amylose content of at least 30%.

[00240] As a result of the amylose contents of the amylose-containing substance, the active is bound to the textile product and released in a controlled manner, such that the effect is maintained over a long period of time. It is assumed that the active, in a manner similar to cyclodextrins, is reversibly bound within the cavities formed by the helical conformation of amylose in the manner of an inclusion compound, which firstly fixes the active on the surface of the textile carrier product and secondly allows controlled release.

[00241] For the inventive modification of textile products, as well as amylose, all substances are suitable in principle, especially amylose-containing starches, i.e. native starches, modified starches and starch derivatives, having an amylose content of at least 30 % by weight and especially at least 40% by weight. The starch may be native, for example corn starch, wheat starch, potato starch, sorghum starch, rice starch or arrowroot starch or may have been obtained or chemically modified by partial digestion of native starch. Pure amylose as such is also suitable, for example amylose obtained by enzymatic means, for example 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. It will be evident that all weight % values relating to amylose or amylose-containing substances here and below, in the case of mixtures of amylose and starch, are always based on the total weight of amylose + starch, unless explicitly stated otherwise. established way.

[00242] Particularly suitable according to the invention are amylose-containing substances, especially amylose and amylose-containing starches and amylose/starch mixtures, in which the amylose content is at least 40% by weight and especially at least 45% by weight, based on the total weight of the substance. Overall, the amylose content will not exceed 90% by weight and especially 80% by weight. Such substances are known and commercially available. For example, amylose-containing starches are marketed by Cerestar under the trade name Amilogel® and National Starch under the trade names HILON® V and VII.

[00243] To achieve the binding of the active(s) and the textile product, the textile product can be modified with the amylose-containing substance generally in an amount of at least 0.5% by weight, preferably at least 1 % by weight and especially at least 2% by weight, based in each case on the weight of the textile product. In general, the amylose-containing substance will be used in an amount of no more than 25% by weight, often no more than 20% by weight, and especially no more than 15% by weight, based on the weight of the textile product, so as not to adversely affect the tactile properties of the textile product.

[00244] First, the textile material is modified with the amylose-containing substance as such and then the textile product thus modified is treated with a suitable preparation of the active ingredient. In this way, the amylose-containing substance present in the textile material is loaded with the active ingredient.

[00245] Alternatively, it is possible to use the amylose-containing substance together with an active to modify the textile product. It is possible here to use the active ingredient and the amylose-containing substance as a mixture of separate components or in the already pre-made form of the amylose/active complex.

[00246] In general, the active will be used in an amount sufficient for the desired effect. The upper limit is determined by the maximum absorption capacity of the amylose units of the amylose-containing substance used and generally does not exceed 20% by weight and often 10% by weight, based on the amylose content of the substance. If desired, the active is generally used in an amount of 0.00001% to 15% by weight, 0.0001% to 10% by weight, 0.001% to 5% by weight, 0.005% to 1% by weight or 0. 1% to 10% by weight or 0.5% to 5% by weight, based on the amylose content of the amylose-containing substance.

[00247] Modification of the textile product can also be carried out using combinations of active ingredients of the invention with other active ingredients known per se that are suitable for modifying the textile product.

[00248] Suitable additional actives are in principle all organic compounds and mixtures of organic compounds that are known as active and induce a physiological effect on life forms such as humans and animals, including microorganisms. These include those actives that are known to form inclusion compounds with cyclodextrins. Particularly suitable actives are those that have hydrocarbyl groups and especially aliphatic, cycloaliphatic and/or aromatic structures. The molecular weight of actives is typically below 1000 daltons and often in the range of 100 to 600 daltons. Also suitable are inorganic compounds such as hydrogen peroxide which, as is well known, can be bound within cyclodextrins (in this regard see F. Vogtle, Supramolecular Chemistry, 2nd edition, B. G. Teubner, Stuttgart 1992, cyclodextrins and literature cited therein). .

[00249] Additional actives especially include pharmaceutical actives and actives that promote the well-being of life forms, especially human beings and which are also commonly referred to as “well-being additives”. Unlike pharmaceutical active ingredients, wellness additives do not necessarily have to have a therapeutic effect. Instead, the well-being-promoting effect may be based on a multitude of factors such as care effects, inductive effects, cosmetic effects or other effects. Equally suitable are organic active ingredients that act against parasitic organisms. These include, for example, actives that act against fungi and/or microorganisms, for example, fungicides and bactericides or that act against animal pests such as slugs, caterpillars, mites, insects and/or rodents, for example, nematicides, molluscicides, insecticides, acaricides, rodenticides and repellent actives and also active against weeds, i.e. herbicides or fragrances.

[00250] Preferred pharmaceutical actives are those that are known to be absorbed through the skin. These include, for example, ibuprofen, flurbiprofen, acetylsalicylic acid, acetamyophene, apomorphine, butillary hydroxitoluenous, camazulene, guaiazulene, chloridone, cholecalciferol, dicumarol, digoxin, diphenilhidoin, furosemide, hydroflumetiazide, indomethacin, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate, phosphate zida, nitroglycerin, nicotine, nicotinamide, ouabain, oxprenolol, papaverine akaloids such as papaverine, laudanosine, etaverine and narcotine and also berberine and additionally retinol, trans-retinoic acid, pretinol, spironolactone, sulpiride, theophylline, theobromine, corticosteroids and derivatives such as testosterone, 17-methyltestosterone, cortisone , corticosterone, dexamethasone, triamcinolone, methylprednisolone, fludrocortisone, fluocortolone, prednisone, prednisolone, progesterone, inter alia, estrogens and gestagens such as estradiol, estriol, ethinylestradiol 3-methyl ether, norethisterone and ethisterone and also phenethylamine and derivatives such as tyramine, adrenaline , norepinephrine and dopamine.

[00251] Examples of suitable active ingredients according to the invention that have an effect against parasitic organisms are the nematicides, bactericides, fungicides, insecticides, insect repellents, acaricides and molluscicides mentioned at www.reith-pfister.de/w.list .html and at www.hclrss.demon.co.uk/class_pesticides.html.

[00252] Examples of bactericidal and fungicidal substances include: antibiotics, for example, cycloheximide, grisseofulvin, cassugamycin, natamycin, polyoxin, streptomycin, penicillin or gentamicin; organic compounds and biocidal metal complexes, for example, silver, copper, iron and/or zinc complexes, such as bis(tributyltin oxide), copper, zinc and tin naphthenates, oxygen-copper such as Cu-8, tris -N-(cyclohexyldiazeniodioxy)aluminum, N-(cyclohexyldiazeniodioxy)tributyltin, bis-N-(cyclohexyldiazeniodioxy)copper; quaternary ammonium salts, for example, benzylalkyl C8 to C18 dimethylammonium halides, especially chlorides (benzalkonium chlorides); nitrogenous aliphatic fungicides and bactericides such as cymoxanil, dodine, dodicine, guazidine, iminoctadine, dodemorph, fenpropimorph, fenpropidine, tridemorph; substances having peroxide groups such as hydrogen peroxide and organic peroxides such as dibenzoyl peroxide; organic chlorine compounds, for example 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 dimoxyestrobin, fluoxaestrobin, kresoxim methyl, metominoestrobin, orisastrobin, picoxystrobin, pyracloestrobin and trifloxyestrobin; sulfonamides such as tolylfluanide and diclofluanide; iodine compounds such as diiodomethyl p-tolyl sulfone, napcocide, 3-iodo-2-propynyl alcohol, 4-chlorophenyl 3-iodopropargyl formal, 3-bromo-2,3-diiodo-3-propenyl ethylcarbonate, 2,3,3-triiodoallyl alcohol, 3-iodo-2-propynyl n-hexylcarbamate, 3-bromo-2,3-diiodo-2-propenyl alcohol, 3-iodo-2-propynyl phenylcarbamate, 3-iodo-2-propynyl n-butylcarbamate, O-1-(6-iodo-3-oxohex-5-ynyl) phenylcarbamate, O-1-(6-iodo-3-oxohex-5-ynyl) butylcarbamate ); isothiazolinones such as N-methylisothiazolin-3-one, 5-chloro-N-methylisothiazolin-3-one, 4,5-dichloro-N-octylisothiazolin-3-one, 1,2-benzisothiazol-3(2H)one, 4 ,5-trimethylisothiazol-3-one and N-octylisothiazolin-3-one.

[00253] Examples of insecticides and acaricides are organophosphates such as acephate, azamethiphos, azinphos-methyl, chlorpyrifos, chlorpyrifos-methyl, chlorfenvinphos, diazinone, dichlorvos, dicrotophos, dimethoate, disulfoton, ethion, fenitrothion, fenthion, isoxation, malathion, methamidophos , metidathion, methyl-parathion, mevinfos, monocrotophos, oxidemeton-methyl, paraoxon, parathion, phentoate, phosalone, phosmet, phosfamidone, phorate, phoxim, pirimiphos-methyl, profenofos, prothiophos, sulprophos, triazophos, trichlorphone; especially pyrethroids such as acrinathrin, alethrin, bioalethrin, barthrin, bifenthrin, bioethanothrin, ciclethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyalothrin, lambda-cyalothrin, cypermethrin, a-cypermethrin, ß-cypermethrin, A-cypermethrin, zeta-cypermethrin, cyfenothrin, deltamethrin, dimefluthrin, dimethrin, empenthrin, fenfluthrin, fenpritrin, fenpropatrin, fenvalerate, esfenvalerate, flucitrinate, fluvinate, tau-fluvinate, furetrin, permethrin, biopermethrin, trans-permethrin, fenothrin, pralethrin, profluthrin, piresmethrin, resmetrin, bioresmetrin, cismetrin, teflutrin, teraletrin, tetramethrin, tralometrin, transflutrin, etofenprox, flufenprox, halfenprox, protrifenbuto and silafulfen; pyrrole and pyrazole insecticides such as acetoprol, etiprol, fipronil, tebufenpyrad, tolfenpyrad, chlorfenapyr and vaniliprole.

[00254] Examples of repellent actives are especially anthraquinone, acridine bases, copper naphthenate, butopyronoxyl, dibutyl phthalate, dimethyl phthalate, dimethyl carbate, ethexadiol, hexamide, methoquin-butyl, N-methylneodecanamide, camphor, oil of bergamot, peretro, clove oil, geranium oil, thyme oil and especially diethyl-m-toluamide and 2-(2-hydroxyethyl)-1-methylpropyl 1-piperidinecarboxylate (picaridin).

[00255] Examples of wellness additives are especially the substances and mixtures of substances listed below, for example fats, preferably of vegetable origin, for example lecithins, vegetable oils such as jojoba oil, tea tree oil, clove oil, evening primrose oil, almond oil, coconut oil, avocado oil, soybean oil and the like, fatty acids, e.g. w-6-fatty acids, linolenic acid, linoleic acid, waxes of animal origin or vegetable, such as beeswax, candelilla wax, shea butter, shorea butter, mango seed butter, Japanese wax and the like, vitamins, especially fat-soluble vitamins, for example tocopherols, vitamin E, vitamin A and similar, corticosteroids such as cortisone, corticosterone, dexamethasone, triamcinolone, methylprednisolone, fludrocortisone, fluocortolone, prednisone, prednisolone, progesterone, amino acids, for example arginine, methionine, plant extracts such as algae extract, horse chestnut extract, mango and the like.

[00256] For improving the washing stability of the modification of the invention, it has been found to be useful when the amylose-containing substance is fixed to the textile product with a binder. Useful binders include firstly water-insoluble, film-forming polymers and secondly low molecular weight reactive substances that polymerize when heated. In general, the binder will be used in such an amount that the weight ratio of amylose-containing substance 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.

[00257] In general, film-forming polymers are used in the form of an aqueous dispersion of finely divided polymer particles. Particle size is of minor importance to the success of the invention. However, it is generally below 5 µm (weight average) and is generally 50 nm to 2 µm.

[00258] The film-forming polymer can especially have a glass transition temperature TG in the range of -40 to 100°C, preferably - 30 to +60°C, especially -20 to +40°C. If the polymeric binder comprises multiple polymeric components, at least the main constituent must have a glass transition temperature within this range. The glass transition temperature of the main constituent is especially in the range of -30°C to +60°C and more preferably in the range of -20°C to +40°C. All polymeric constituents preferably have a glass transition temperature within these ranges. Reported glass transition temperatures refer to the midpoint temperature determined via DSC in accordance with ASTM-D 3418-82. In the case of crosslinkable binders, the glass transition temperature refers to the non-crosslinked state.

[00259] Examples of suitable film-forming polymers are based on the following polymer classes: (1) polyurethane resins; (2) acrylate resins (straight acrylates: copolymers of alkyl acrylates and alkyl methacrylates); (3) styrene acrylates (copolymers of styrene and alkyl acrylates); (4) styrene/butadiene copolymers; (5) polyvinyl esters, especially polyvinyl acetates and copolymers of vinyl acetate with vinyl propionate; (6) vinyl ester-olefin copolymers, e.g., vinyl acetate/ethylene copolymers; (7) vinyl ester-acrylate copolymers, for example, vinyl acrylate/alkyl acrylate copolymers and vinyl acrylate/alkyl acrylate/ethylene terpolymers.

[00260] Such polymers are known and are commercially available, for example polymers of classes (2) to (7) in the form of aqueous dispersions under the following names: ACRONAL, STYROFAN, BUTOFAN (BASF AG), MOWILITH, MOWIPLUS, APPRETAN ( Clariant), VINNAPAS, VINNOL (WACKER). Aqueous polyurethane dispersions (1) suitable for the process of the invention are especially those that are used for coating textile products (see, for example, J. Hemmrich, Int. Text. Bull. 39, 1993, No. 2, p 53-56; “Wãssrige Poliuretan-Beschichtungssysteme” [Aqueous Polyurethane Coating Systems] Chemiefasern/Textilind. 39 91 (1989) T149, T150; W. Schroer, Textilveredelung [Textile Finishing] 22, 1987, pp. 459-467 ). Aqueous polyurethane dispersions are commercially available, for example under the following trade names: Alberdingk® from Alberdingk, Impranil® from BAYER AG, Permutex® from Stahl, Waalwijk, Netherlands, from BASF SE or they can be prepared by known methods as described , for example, in “Herstellverfahren für Poliuretane” [Production methods for polyurethanes] in Houben-Weila, “Methoden der organischen Chemie” [Methods of Organic Chemistry], volume E 20/Makromolekulare Stoffe [Macromolecular Substances], p. 1587, D. Dietrich et al., Angew. chem. 82 (1970), p. 53 ff., Angew. Makrom. chem. 76, 1972, 85 ff. and Angew. Makrom. chem. 98, 1981, 133-165, Progress in Organic Coatings, 9, 1981, p. 281-240 or Rompp Chemielexikon [Rompp's Chemical Dictionary], 9th edition, volume 5, p. 3575.

[00261] Film-forming polymers can be self-crosslinking, meaning that the polymers have functional groups (crosslinkable groups) that, when the composition is dried, optionally with heating, react with each other, with the amylose functional groups or with a low molecular weight crosslinker to form bonds.

[00262] Examples of functional crosslinkable groups include aliphatically linked OH groups, NH-CH2-OH groups, carboxylate groups, anhydride groups, capped isocyanate groups and amino groups. A polymer still having free OH groups as reactive groups will often be used. In general, the proportion of reactive functional groups is 0.1 to 3 mol/kg of polymer. Cross-linking can be carried out within the polymer by the reaction of functional groups having complementary reactivity. Preferably, cross-linking of the polymer is carried out by adding a cross-linker having reactive groups that are complementary with respect to their reactivity with the functional groups of the cross-linker. Suitable pairs of functional groups having complementary reactivity are known to the person skilled in the art. Examples of such pairs are OH/COOH, OH/NCO, NH2/COOH, NH2/NCO and M2+/COOH, where M2+ is a divalent metal ion such as Zn2+, Ca2+ or Mg2+. Examples of suitable crosslinkers are the di- or polyols mentioned below for polyurethanes; primary or secondary diamines, preferably primary diamines, for example alkylenediamines such as hexamethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, N,N-bis[(aminopropyl)amino]ethane, 3,6-dioxaoctanediamine, 3,7-dioxanonane- diamine, 3,6,9-trioxaundecanediamine or Jeffamines, (4,4'-diaminodicyclohexyl)methane, (4,4'-diamino-3,3-dimethyldicyclohexyl)methane; amino alcohols such as ethanolamine, hydroxypropylamine; ethoxylated di- and oligoamines; dihydrazides of aliphatic or aromatic dicarboxylic acids such as adipic dihydrazide; dialdehydes such as glyoxal; partially or fully O-methylated melamines and compounds or oligomers that have an average of two or more, preferably three or more, isocyanate groups or reversibly blocked, for example, hydrogen sulfite blocked, isocyanate groups. In this case, the ratio of crosslinker to polymeric binder is such that the molar ratio of the reactive groups in the polymeric binder (total amount of reactive groups in the polymers) to the reactive groups in the crosslinker is generally in the range of 1:10 to 10:1 and preferably in the range of 3:1 to 1:3. Typically, the weight ratio of polymeric binder (calculated as solids) to crosslinker is in the range of 100:1 to 1:1 and especially in the range of 50:1 to 5:1.

[00263] As an alternative to fixing the amylose-containing substance with water-insoluble polymers, the amylose or the amylose-containing substance can also be fixed on the textile material with reactive compounds having at least one reactive group for the OH groups of the amylose and at least at least one additional functional reactive group with the functional groups in the fibers of the textile material, for example OH groups, NH2 groups or COOH groups. Reactive compounds include the cross-linkers mentioned above and the substances proposed in DE-A 40 35 378 for fixing cyclodextrins, for example N-hydroxymethyl and N-alkoxymethyl derivatives of urea or urea-like compounds such as dimethylolurea (bis(hydroxymethyl) urea), di(methoxymethyl)urea, dimethylalkanedioldiurethanes such as N,N-dimethylolethyleneurea (N,N-bis(hydroxymethyl)imidazolin-2-one), N,N-dimethylol-dihydroxyethyleneurea (N,N-bis(hydroxymethyl)- 4,5-dihydroxyimidazolin-2-one), dimethylolpropyleneurea and the like. Such materials are in the form of aqueous formulations for the commercial modification of textile products, for example under the trade names Fixapret® and Fixapret®-eco from BASF SE. Reactive materials that can be used for fixing the amylose-containing substance to the textile material especially also include compounds having 2, 3, 4 or more isocyanate groups (optionally reversibly blocked), specifically polyisocyanate prepolymers that have been reversibly blocked with bisulfite. or CH-acid compounds or oximers, e.g. butanone oxime and are based on polyether- and polyesterurethanes, which are described in DE 2837851, DE 19919816 and before European patent application 03015121. Such products are also commercially available, for example under the trade names PROTOLAN®367 and PROTOLAN®357 from Rotta GmbH, Mannheim.

[00264] The amylose-containing substance can also be fixed using the known procedure for fixing cyclodextrins in an analogous manner, in which the cyclodextrin or, in the present case, the amylose-containing substance is provided with reactive anchors, for example by reacting it in a manner known per se with dicarboxylic acids or dicarboxylic anhydrides such as maleic acid, fumaric acid, maleic anhydride, succinic acid, succinic anhydride or adipic acid, with isocyanates, for example, toluene diisocyanate, isophorone diisocyanate, tetramethylene diisocyanate or hexamethylene diisocyanate or with aminocarboxylic acids, in such a way that only one of the functionalities present in these compounds reacts with the OH groups of the amylose-containing substance and the other is preserved for binding to the reactive groups of the fiber material. Reactive anchors can also be generated in the amylose-containing substance by reaction with 1,3,5-trichlorotriazine, 2,3-dichloroquinoxaline-5,6-carbonyl chloride and with chlorodifluoropyrimidine.

[00265] Furthermore, amylose fixation can also be carried out using alkoxysilanes, such as diethoxydimethylsilane, dimethoxydimethylsilane, triethoxyphenylsilane, tetraethoxysilane and dimeric, trimeric and higher condensation products of these compounds.

[00266] In this way, it is possible in principle to modify all textile materials, that is, unfinished material or finished material. The textile materials here and below include woven cloths, knitted loop cloths, loop formed knitted cloths and non-woven cloths. Textile materials may have been constructed from natural fiber yarns, synthetic fiber yarns and/or mixed yarns. Useful fiber materials in principle include all fiber materials commonly used for the production of textile products. These include cotton, wool, hemp fibers, sisal fibers, linen, ramie, polyacrylonitrile fibers, polyester fibers, polyamide fibers, viscose fibers, silk, acetate fibers, triacetate fibers, aramid fibers and the like and mixtures of these fibrous materials.

[00267] The modification or treatment of textile materials with the amylose-containing substance can be carried out in a manner known per se, for example by means of the methods described in DE-A 4035378 for the modification of textile products with cyclodextrins.

[00268] Mention should be made by way of example of methods in which the amylose-containing substance, optionally as a complex with the active, has already been spun into the fiber, filament and/or yarn from which the cloth was produced.

[00269] Often, however, the textile material, before or after finishing, will be treated with the amylose-containing substance or a complex of amylose-containing substance and the active. In general, for this purpose, the textile product will be treated with an aqueous liquid comprising the amylose-containing substance and optionally the active in a sufficient quantity. According to the manner of application and the desired amount in which the amylose-containing substance is to be applied, the concentration of amylose-containing substance in the liquid is in the range of 1% to 40% by weight, particularly in the range of 2% to 20%. by weight and especially in the range of 4% to 15% by weight.

[00270] The manner of treatment is of minor importance and can be carried out, for example, in the form of a minimal application, for example by spray application, in the form of a normal application in a pad ironer or as a high humidity application . The textile material here is soaked with the aqueous liquid. Optionally, excess liquid can then be removed, for example by squeezing it until a collection of about 30% to 120%.

[00271] Another way of treating the textile product with amylose-containing substance or complex of amylose-containing substance and active is that of composing a liquid with water in which the desired amount of amylose-containing substance and optionally active is present, for example, 0 .5% to 20% by weight (based on the mass of the textile products to be modified). The textile material is soaked with the liquid treatment in the modification aggregates suitable for the purpose (e.g. winch beck; roller beck; paddle; etc.) in a certain period of time, e.g. 10 to 60 min and then squeezed and/or centrifuged as specified above. The net ratio here is generally in the range of 1:2 to 1:50 and especially in the range of 1:3 to 1:20.

[00272] Such methods are known to the person skilled in the art, for example from H. K. Rouette, Lexikon der Textilveredlung [Dictionary of Textile Finishing], Laumann-Verlag, Dülmen 1995, p. 669 ff.

[00273] In general, the liquid treatment is followed by a drying operation. Temperatures here are generally in the range of 100°C to 200°C and preferably in the range of 120°C to 180°C. Drying can be carried out in the usual apparatus for the purpose in the case of finished material, for example by drum drying at the specific temperatures above. In the case of unfinished material, the application will generally be followed by guiding the textile material through one or more tension clamps.

[00274] If the amylose-containing substance is used together with a film-forming polymer, drying leads to the fixation of the amylose-containing substance in the textile fibers. In general, the drying temperature in this case will not be lower than 100°C and is preferably in the range of 120°C to 200°C and especially in the range of 140°C to 180°C. In general, drying is carried out over a period of 1 to 10 min, especially 1 to 2 min, although longer drying times are equally suitable.

[00275] For treatment with an aqueous liquid, it has been found to be advantageous when the aqueous liquid, as well as the amylose-containing substance and optionally the active, comprise at least one active substance on the surface (or active substance at the interface) suitable for dispersing the substance containing amylose and the active in the aqueous liquid. The active substance on the surface is preferably an oligomeric or polymeric dispersant. The term "oligomeric or polymeric dispersant", as opposed to low molecular weight surface-active substances, encompasses those dispersants having a number average molecular weight of generally at least 2000 daltons, for example 2000 to about 100,000 daltons and especially in the range from about 3000 to 70,000 daltons.

[00276] In general, the aqueous liquid comprises the polymeric or oligomeric dispersant in an amount of 0.5% to 20% by weight, preferably 1% to 18% by weight and especially 5% to 15% by weight, based on the substance containing amylose.

[00277] Suitable oligomeric or polymeric dispersants are water-soluble and include both neutral and amphoteric water-soluble polymers and cationic and anionic polymers, preference being given to the latter.

[00278] Examples of neutral polymeric dispersants are polyethylene oxide, ethylene oxide/propylene oxide copolymers, preferably block copolymers, polyvinylpyrrolidone and vinyl acetate copolymers with vinylpyrrolidone.

[00279] It is an aspect of preferred anionic oligomeric or polymeric dispersants that they have carboxyl groups and/or sulfonic acid groups and are typically used as salts, for example as alkali metal salts or ammonium salts.

[00280] Preferred anionic dispersants are, for example, carboxylated cellulose derivatives such as carboxymethyl cellulose, homopolymers of ethylenically unsaturated C3- to C8-mono- and C4- to C8-dicarboxylic acids, for example acrylic acid, methacrylic acid , of maleic acid, of itaconic acid, copolymers of at least two different ethylenically unsaturated C3- to C8-mono- and C4- to C8-dicarboxylic acids as specified above and copolymers of at least one of the C3- to C8-mono- or previously mentioned ethylenically unsaturated C4- to C8-dicarboxylic acids with at least one neutral comonomer. Examples of neutral comonomers are N-vinylactams such as N-vinylpyrrolidone, vinyl esters of C2- to C16-aliphatic carboxylic acids such as vinyl acrylate, vinyl propionate, amides of the aforementioned ethylenically unsaturated carboxylic acids such as acrylamide, methacrylamide and the like, C1- to C4- hydroxyalkyl (meth)acrylate such as hydroxyethyl acrylate and methacrylate, esters of C3- to C8-mono- or C4- to C8-dicarboxylic acids ethylenically unsaturated with polyethers, for example esters of acrylic acid or methacrylic acid with polyethylene oxides or ethylene oxide/propylene oxide block copolymers, vinyl aromatics such as styrene and C2- to C16- olefins such as ethylene, propene, 1-hexene, 1-octene, 1- decene, 1-dodecene and the like. Preference is further given to homopolymers of ethylenically unsaturated sulfonic acids such as styrenesulfonic acid and acrylamidopropanesulfonic acid and copolymers thereof with the aforementioned comonomers. In copolymers, the proportion of the ethylenically unsaturated acid will generally be at least 20% by weight and does not exceed a value of 90% by weight and especially 80% by weight, based in each case on the total weight of all monomers constituting the polymer.

[00281] Copolymers of at least one of the acids mentioned above and at least one comonomer are known for this purpose and are commercially available, for example copolymers of acrylic acid and maleic acid such as Sokalan brands from BASF SE.

[00282] Anionic dispersants that are equally preferred are phenolsulfonic acid-formaldehyde condensates and naphthalenesulfonic acid-formaldehyde condensates (for example, BASF brands Tamol and Setamol) and lignosulfonates.

[00283] Usable dispersants are also low molecular weight anionic, non-ionic, cationic, ampholytic and zwitterionic surfactants. Suitable surfactants are, for example, alkali metal, ammonium or amine salts of C8- to C18 alkyl sulfates, such as sodium lauryl sulfate; C8- to C18 alkylsulfonates, such as dodecylsulfonate; C8- to C18-alkyl ether sulfates; and C8- to C18- alkyl ethoxylates; polyoxyethylenesorbitan esters; C8- to C18 alkyl glycinates; C8- to C18-dimethylamine alkyl oxides; betaines etc. Preference is given to alkylsulfates and alkylsulfonates.

[00284] If the amylose-containing substance is not used together with a water-insoluble, film-forming polymer, the textile product can be treated with the polymer in a separate step. More particularly, treatment is carried out together with the amylose-containing substance. Accordingly, a particular embodiment relates to a method in which the aqueous liquid additionally comprises a dispersed, water-insoluble, film-forming polymer of the type described above. The amount of film-forming polymer is chosen here such that the weight ratio of amylose-containing substance 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.

[00285] The textile product can be modified with the active in a separate operation or in an operation together with the modification with the amylose-containing substance.

[00286] If the textile product is modified with the active in a separate operation, the textile product will be treated appropriately equally with an aqueous liquid of the active. For this purpose, the active, which is typically insoluble in water, will generally be emulsified or dispersed in water, optionally with the use of suitable surface-active substances. Suitable surface-active substances are especially the aforementioned low molecular weight surfactants and among these preferably non-ionic surfactants, especially polyoxyethylene sorbitan esters, esters of mono- or oligosaccharides with C6 to C18 fatty acids and more preferably C8- to C18 alkyl ethoxylates. C18-, especially those with an ethoxylation level in the range of 6 to 50. In general, the aqueous liquid comprises the active in an amount of 0.1% to 10% by weight and especially in an amount of 0.2% to 5% by weight. The amount of active substance on the surface is generally in the range of 0.5% to 50% by weight and especially in the range of 3% to 30% by weight, based on the active. The active ingredient can be applied from the aqueous liquid by the usual methods for the purpose, for example by means of a pad calender.

[00287] Alternatively, it is possible to carry out the modification with active and amylose-containing substance in one operation. The procedure here can be in principle as described for the modification with the amylose-containing substance, wherein the aqueous liquid of the amylose-containing substance now additionally comprises the at least one active. The active ingredient can be added to the liquid separately or in the form of an inclusion compound, that is, in the form of a host-guest complex with the amylose-containing substance.

[00288] The present invention can be used by modifying any textile products, including woven cloths, knitted cloths, non-woven cloths and the like. The type of textile material is guided primarily by the desired end use.

[00289] The textile products to be modified can be ready-finished products such as clothing, including underwear and upper clothing, for example shirts, pants, jackets, outerwear, hiking clothes and military uniform, covers, tents, screens, for example insect screens and curtains, hand and bath towels, bed linen and the like.

[00290] Likewise, the modification can be carried out on the material in the form of a bale or roll.

[00291] Textile products that have been modified with active ingredients against parasitic organisms such as insects and mites are suitable not only for the protection of humans, but also particularly in animal protection for protection against ticks, mites, fleas and the like.

[00292] The textile materials may have been constructed from natural fiber yarns, synthetic fiber yarns and/or mixed yarns, where the cloths typically have a basis weight in the range of 10 to 500 g/m2, preferably 20 to 250 g/m2. Useful fiber materials in principle include all fiber materials commonly used for the production of textile products. These include cotton, wool, hemp fibers, sisal fibers, linen, ramie, polyacrylonitrile fibers, polyester fibers, polyamide fibers, viscose fibers, silk, acetate fibers, triacetate fibers, aramid fibers and the like and mixtures of these fibrous materials. Also suitable are glass fibers and mixtures of the aforementioned fibrous materials with glass fibers, for example glass fiber/Kevlar mixtures.

[00293] With an amylose-based active modification described above, the active ingredients remain in the textile products modified with this even after several washes. Furthermore, the textile products thus modified have a pleasant touch, which is especially advantageous for the comfort of wearing clothes made from these textile products.

Cooling Tobacco Products:

[00294] In principle, the active ingredient content can vary over a wide range, for example 0.05 ppm to 10% by weight, preferably 0.1 ppm to 10% by weight.

[00295] The active ingredients of the invention can also be used advantageously for the production of tobacco products. Examples of such tobacco products include cigars, cigarettes, pipe tobacco, chewing tobacco and snuff.

[00296] The production of tobacco products supplemented with cooling additions is known per se and is described, for example, in US 3,111,127, US 5,752,529 and US 2005/0000529, which are expressly incorporated by reference.

Cooling packaging materials:

[00297] The active ingredients of the invention are also advantageously suitable for the production of packaging materials.

[00298] They are also produced in a manner known per se. The actives can be incorporated here into the packaging material, in free or, for example, encapsulated form, or applied to the packaging material, in free or encapsulated form.

[00299] For example, correspondingly modified plastic packaging materials are producible according to the details in the literature regarding the production of polymeric films (e.g., Ullmann, 6th edition, 2003. Vol. 36, p. 567). The production of coated papers in a suitable manner is also known and is described, for example, in Ullmann, Vol. 25, p. 106 ff, 6th edition, 2003.

[00300] Additional aspects of the present invention will be evident from the examples that follow and the attached claims.

Examples:

[00301] The examples serve to illustrate the invention without restricting it thereby. Unless otherwise stated, all values are based on weight.

Asset production:

[00302] The assets of structure type 1 used according to the invention are known compounds per se or can be prepared by the person skilled in the art in the field of organic synthesis based on known synthesis methods.

Cloning of human TRPM8:

[00303] The starting point for cloning the human TRPM8 receptor is a LnCaP cDNA bank. This is, for example, commercially available (e.g., by BioChain, Hayward, USA), or can be produced from the androgen-sensitive human prostatic adenocarcinoma cell line (e.g., ATCC, CRL1740 or ECACC, 89110211) using standard kits.

[00304] The TRPM8 coding sequence (see, for example, http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore& id=109689694) can be amplified by PCR and cloned using methods standard. The human TRPM8 gene thus isolated was used for the production of plasmid pInd_M8.

[00305] Alternatively, the TRPM8 gene can also be produced synthetically.

Generation of the HEK293 test cells:

[00306] The test cell system produced, with human TRPM8 DNA, was a stably transfected HEK293 cell line. Preference is given here to HEK293 which, through the introduced plasmid, offer the option of inducing TRPM8 expression using tetracycline.

[00307] Methods of producing suitable test cell systems are known to the person skilled in the art. For example, the production of the cells used can be deduced from the details in Behrendt H.J. et al., Br. J. Pharmacol. 141, 2004, 737-745 or the thesis by Behrendt “Vergleichende funktionale Untersuchungen des Hitze-Capsaicin-Rezeptors (TRPV1) und des Kalte-Mentol-Rezeptors (TRPM8) in rekombinanten und nativen Zellssystemen” [Comparative Functional Studies of the Heat Receptor of Capsaicin (TRPV1) and the cold and menthol receptor (TRPM8) in Recombinant and Native Cell Systems], available for example at http://www-brs.ub.ruhr-uni-bochum.de/netahtml/HSS/Diss /BehrendtHansJoe rg/diss.pdf.

[00308] Disclosure of these publications is explicitly incorporated by reference.

Assay for TRPM8 modulators:

[00309] A test comparable to the test already described in the literature by Behrendt H.J. et al., Br. J. Pharmacol. 141, 2004, 737-745, is conducted. Receptor agonism or antagonism can be quantified using a Ca2+-sensitive dye (e.g., FURA, Fluo-4, etc.). Agonists alone result in an increase in the Ca2+ signal; antagonists in the presence of menthol, for example, result in a reduction in the Ca2+ signal (in each case detected using the dye Fluo-4 which is caused to have different fluorescence properties by Ca2+).

[00310] First, in a manner known per se, a fresh culture of transformed HEK cells is produced in cell culture bottles. HEK293-TRPM8 test cells are detached from cell culture bottles via trypsin and 40,000 cells/well are seeded with 100 µl of medium in 96-well plates (Greiner #655948 coated with poly-D-lysine). For TRPM8 receptor induction, tetracycline is added to the culture medium (DMEM/HG, 10% tetracycline-free FCS, 4 mM L-glutamine, 15 µg/mL blasticidin, 100 µg/mL hygromycin B, 1 µg/mL tetracycline). The next day, the cells are loaded with Fluo-4AM dye and the test is conducted. The procedure for this purpose is as follows: - Add to each well 100 µl/well of dyeing solution from the Ca-4 Kit (RB 141, Molecular Devices) for every 100 µl of medium (DMEM/HG, 10% free FCS tetracycline, 4 mM L-glutamine, 15 µg/mL blasticidin, 100 µg/mL hygromycin B, 1 µg/mL tetracycline) - Incubation in an incubator, 30 minutes / 37°C / 5% CO2, 30 minutes / RT - Preparation of test substances (different concentrations in 200 µl of HBSS buffer) and positive controls (different concentrations of menthol, icillin and ionomycin in 200 µl of HBSS buffer) and negative controls (only 200 µl of HBSS buffer) - Addition of the test substances in quantities of 50 µl/well and measurement of the change in fluorescence (e.g. on the FLIPR, Molecular Devices or NovoStar, BMG test instrument) at 485 nm excitation, 520 nm emission and evaluation of the intensity of action of different substances/concentrations and determination of EC50 values.

[00311] The test substances are used in the test in triplicates at concentrations of 0.1 to 200 µM. Typically, compounds are maintained in DMSO solutions and diluted for testing to a maximum DMSO concentration of 2%.

[00312] Internal evaluations in the case of the performance of the described assay have surprisingly shown that the compounds to be used according to the invention (as described herein) are particularly suitable as TRPM8 agonists.

[00313] The EC50 values determined for the modulators of the invention selected by way of example are shown in the table below. Synthesis examples: Preparation of N-ethyl-2-methylsulfanylethanamine

[00314] 1,1-Dimethoxy-2-(methylthio)ethane (21.5 mL, 161.07 mmol, 1.0 eq) is dissolved in HCl solution (0.5 M, 323 mL, 1.0 eq ) and stirred at 50°C for 1 h. The reaction mixture is cooled to RT and extracted with CH2Cl2 (500 mL). The combined organic phases are dried over Na2SO4. The aldehyde solution is diluted with THF (500 mL), cooled to 0°C and then mixed with ethylamine (70% solution in water, 15.57 mL, 241.61 mmol, 1.5 eq), acetic acid ( 9.1 mL, 161.07 mmol, 1.0 eq) and Na2SO4 (250 g). After 16 h, the reaction mixture is filtered through Na2SO4 and mixed with sodium triacetoxyborohydride (37.6 g, 177.17 mmol, 1.1 eq). The reaction mixture is stirred at RT for 16 h. The solids are filtered through diatomaceous earth and the solution is concentrated under reduced pressure. The crude product is distilled under reduced pressure (7 mbar, 60°C). The compound is used without further analysis.

[00315] Yield: 23%. Preparation of N-ethyl-3-methylsulfanylpropan-1-amine

[00316] Methional (25.0 g, 240.0 mmol, 1.0 eq) is dissolved in THF (1000 mL), cooled to 0°C and then mixed with ethylamine (70% solution in water, 23.2 mL, 360.0 mmol, 1.5 eq), acetic acid (13.6 mL, 240.0 mmol, 1.0 eq) and Na2SO4 (250 g). After 16 h, the reaction mixture is filtered through Na2SO4 and mixed with sodium triacetoxyborohydride (55.95 g, 264.0 mmol, 1.1 eq). The reaction mixture is stirred at RT for 16 h. The solids are filtered through diatomaceous earth and the solution is concentrated under reduced pressure. The crude product is distilled under reduced pressure (7 mbar, 60°C). The compound is used without further analysis.

[00317] Yield: 31%. Preparation of N-pyridine-, N-phenyl- and N-1H-pyrazoloamines

[00318] 1,1-Dimethoxy-2-(methylthio)ethane (1.0 eq) is dissolved in HCl solution (0.5 M, 1.0 eq) and stirred at 50°C for 1 h. The reaction mixture is cooled to RT and extracted with CH2Cl2 (3 mL/mmol total). The combined organic phases are dried over Na2SO4. The aldehyde solution is cooled to 0°C and then mixed with amine (1.0 eq), sodium triacetoxyborohydride (1.5 eq), and acetic acid (1.0 eq). The reaction mixture is stirred at RT for 16 h. The reaction is completed by the addition of NaHCO3 solution. The aqueous phase is extracted three times with CH2Cl2, and the combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by flash chromatography (hexane:EtOAc = 19:1). N-(2-methylsulfanilethyl)pyridine-2-amine

[00319] The compound is used without further analysis. N-(2-methylsulfanilethyl)aniline Yield: 85%

[00320] The compound is used without further analysis. N-(2-methylsulfanilethyl)-1H-pyrazol-5-amine Yield: 84%

[00321] The compound is used without further analysis. Preparation of N-(2-methoxyethyl)aniline

[00322] 1,1-Dimethoxy-2-(methyloxy)ethane (10 g, 83.23 mmol, 1.0 eq) is dissolved in HCl solution (0.5 M, 1.0 eq) and stirred at 50 °C for 1 h. The reaction mixture is cooled to RT and extracted with CH2Cl2 (3 mL/mmol total). The combined organic phases are dried over Na2SO4. The aldehyde solution is cooled to 0°C and then mixed with aniline (7.75 g, 83.23 mmol, 1.0 eq), sodium cyanoborohydride (5.75 g, 91.55 mmol, 1.1 eq). ) and acetic acid (4.7 mL, 83.23 mmol, 1.0 eq). The reaction mixture is stirred at RT for 16 h. The reaction is completed by the addition of NaHCO3 solution. The aqueous phase is extracted three times with CH2Cl2, and the combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by flash chromatography (hexane: EtOAc = 19:1).

[00323] Yield: 19%

[00324] The compound is used without further analysis.

Preparation of cinnamides or phenoxyacetamides of the invention Method A

[00325] Cinnamic acid or phenoxyacetic acid (1.5 eq) and N-methylformanilide (MFA) (1 drop) are dissolved in CH2Cl2 (5 mL/mmol), cooled to 0°C and mixed with oxalyl chloride (3. 0 eq). The reaction mixture is stirred at RT for 2 h and at 40 ° C for 1 h and concentrated under reduced pressure. Triethylamine (4.0 eq) and the respective amine (1.0 eq) are dissolved in CH2Cl2 (4 mL/mmol) and cooled to 0°C. The crude product is dissolved in CH2Cl2 (1 mL/mmol) and slowly added dropwise. The reaction mixture is stirred at RT for 16 h. The reaction is completed by the addition of NaHCO3 solution. The aqueous phase is extracted with CH2Cl2 (3x), and the combined organic phase is dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by flash chromatography.

Method B:

[00326] Cinnamic acid or phenoxyacetic acid (2.0 eq) and MFA (1 drop) are dissolved in CH2Cl2 (5 mL/mmol), cooled to 0°C and mixed with oxalyl chloride (4.2 eq). The reaction mixture is stirred at RT for 2 h at 40°C for 1 h and concentrated under reduced pressure. Pyridine (2.0 eq) and the respective amine (1.0 eq) are dissolved in CH2Cl2 (4 mL/mmol) and cooled to 0°C. The crude product is dissolved in CH2Cl2 (1 mL/mmol) and slowly added dropwise. The reaction mixture is stirred at RT for 16 h. The reaction is completed by the addition of NaHCO3 solution. The aqueous phase is extracted with CH2Cl2 (3x), and the combined organic phase is dried over Na2SO4 and concentrated under reduced pressure. The crude product is dissolved in ethanol (15 mL/mmol) and mixed with NaOH (5.0 eq). After 15 min, the solvent is removed under reduced pressure and the crude product is mixed with water and extracted three times with CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The product is purified by flash chromatography (EtOAc:hexane = 25:75 ^ 45:55). Method A: 71% yield

[00327] 1H NMR (400 MHz, chloroform-d) d 7.59 (d, J = 15.5 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.41 - 7.35 (m, 1H), 7.28 - 7.22 (m, 2H), 6.85 (dd, J = 8.1, 1.7 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 1.7 Hz, 1H), 6.10 (d, J = 15.4 Hz, 1H), 5.93 (s, 2H), 4.06 - 3.99 (m, 2H), 2.74 - 2.68 (m, 2H), 2.16 (s, 3H). Preparation of 2-(4-methylphenoxy)-N-(2-methylsulfanilethyl)-N-phenyl-acetamide Method A: 87% yield

[00328] 1H NMR (400 MHz, chloroform-d) d 7.46 (dd, J = 8.3, 6.4 Hz, 2H), 7.43 - 7.37 (m, 1H), 7.30 - 7.23 (m, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 4.34 (s, 2H) , 3.98 - 3.90 (m, 2H), 2.70 - 2.61 (m, 2H), 2.25 (s, 3H), 2.13 (s, 3H). Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-ethyl-N-(2-methylsulfanyl-ethyl)prop-2-enamide Method A: 31% yield

[00329] 1H NMR (400 MHz, chloroform-d) d 7.63 (d, J = 15.2 Hz, 2H), 7.06 - 6.96 (m, 4H), 6.81 (d, J = 8.0 Hz, 2H), 6.66 (dd, J = 15.0, 6.4 Hz, 2H), 6.00 (s, 4H), 3.62 (dd, J = 8.6, 6.4 Hz, 4H), 3.52 (q, J = 7.2 Hz, 4H), 2.78 - 2.68 (m, 4H), 2.19 (s, 6H), 1.26 ( t, J = 7.2 HZ, 3H), 1.19 (t, J = 7.3 Hz, 3H). Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanilethyl)-N-(2-pyridyl)prop-2-enamide Method A: 5% yield

[00330] 1H NMR (400 MHz, chloroform-d) d 8.55 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 7.75 (td, J = 7.7, 2.0 Hz, 1H), 7.64 (d, J = 15.4 Hz, 1H), 7.23 (ddd, J = 7.4, 2.7, 1.0 Hz, 2H), 6, 90 (dd, J = 8.2, 1.7 Hz, 1H), 6.81 (d, J = 1.7 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.26 (d, J = 15.4 Hz, 1H), 5.96 (s, 2H), 4.26 - 4.16 (m, 2H), 2.89 - 2.75 (m, 2H) , 2.15 (s, 3H). Preparation of (E)-N-(2-methylsulfanilethyl)-3-(P-tolyl)-N-(2-pyridyl)prop-2-enamid Method A: 10% yield

[00331] 1H NMR (400 MHz, chloroform-d) d 8.55 (dd, J = 5.4, 2.0 Hz, 1H), 7.75 (td, J = 7.8, 2.0 Hz , 1H), 7.71 (d, J = 15.4 Hz, 1H), 7.29 - 7.21 (m, 4H), 7.12 (d, J = 7.9 Hz, 2H), 6 .40 (d, J = 15.5 Hz, 1H), 4.30 - 4.16 (m, 2H), 2.87 - 2.74 (m, 2H), 2.33 (s, 3H), 2.15 (s, 3H). Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanilethyl)-N-(1H-pyrazol-3-yl)prop-2-enamide Method B: 10% yield

[00332] 1H NMR (400 MHz, chloroform-d) d 7.63 (d, J = 15.2 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 6.90 ( d, J = 7.9 Hz, 1H), 6.83 (s, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 14.7 Hz, 1H), 6.25 (s, 1H), 5.95 (s, 2H), 4.03 (t, J = 7.3 Hz, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.16 (s, 3H). Preparation of (E)-N-ethyl-N-(2-methylsulfanilethyl)-3-(p-tolyl)prop-2-enamide Method A: 41% yield

[00333] Two rotamers on nitrogen are evident in the spectrum.

[00334] 1H NMR (400 MHz, chloroform-d) d 7.69 (d, J = 15.3 Hz, 2H), 7.42 (d, J = 7.8 Hz, 4H), 7.18 ( d, J = 7.9 Hz, 4H), 6.79 (dd, J = 15.4, 5.7 Hz, 2H), 3.67 - 3.57 (m, 4H), 3.53 (q , J = 7.1 Hz, 4H), 2.78 - 2.68 (m, 4H), 2.37 (s, 6H), 2.19 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). Preparation of (E)-N-ethyl-3-(4-methoxyphenyl)-N-(2-methylsulfanilethyl)prop-2-enamide Method A: 12% yield

[00335] 1H NMR (400 MHz, chloroform-d) d 7.69 (d, J = 15.3 Hz, 1H), 7.53 - 7.44 (m, 2H), 6.96 - 6.83 (m, 2H), 6.70 (d, J = 15.3 Hz, 1H), 3.83 (s, 3H), 3.62 (dd, J = 8.5, 6.6 Hz, 2H) , 3.53 (q, J = 7.1 Hz, 2H), 2.78 - 2.69 (m, 2H), 2.19 (s, 3H), 1.27 - 1.19 (m, 3H ). Preparation of (E)-N-(2-methylsulfanilethyl)-N-phenyl-3-(p-tolyl)prop-2- Enamide Method A: 79% yield

[00336] 1H NMR (400 MHz, chloroform-d) d 7.65 (d, J = 15.5 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.41 - 7.35 (m, 1H), 7.29 - 7.23 (m, 2H), 7.19 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H) , 6.23 (d, J = 15.5 Hz, 1H), 4.07 - 3.99 (m, 2H), 2.75 - 2.67 (m, 2H), 2.31 (s, 3H ), 2.16 (s, 3H). Preparation of (E)-3-(4-methoxyphenyl)-N-(2-methylsulfanilethyl)-N-phenylprop-2-enamide s\ Method A: 85% yield

[00337] 1H NMR (400 MHz, chloroform-d) d 7.64 (d, J = 15.5 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.42 - 7.34 (m, 1H), 7.28 - 7.21 (m, 4H), 6.82 - 6.78 (m, 2H), 6.15 (d, J = 15.5 Hz, 1H), 4, 06 - 4.00 (m, 2H), 3.78 (s, 3H), 2.75 - 2.67 (m, 2H), 2.16 (s, 3H). Preparation of 2-(4-methoxyphenoxy)-N-(2-methylsulfanilethyl)-N-phenyl-Acetamide Method A: 89% yield

[00338] 1H NMR (400 MHz, chloroform-d) d 7.50 - 7.41 (m, 2H), 7.40 (s, 1H), 7.29 - 7.22 (m, 2H), 6 .76 (t, J = 9.1 Hz, 2H), 6.71 (s, 2H), 4.32 (s, 2H), 3.99 - 3.88 (m, 2H), 3.73 ( s, 3H), 2.72 - 2.59 (m, 2H), 2.13 (s, 3H). Preparation of (E)-N-ethyl-N-(3-methylsulfanylpropyl)-3-(P-tolyl)prop-2- Enamide Method A: 50% yield

[00339] Two rotamers on nitrogen are evident in the spectrum. 1H NMR (400 MHz, chloroform-d) d 7.69 (d, J = 15.3 Hz, 2H), 7.47 - 7.39 (m, 4H), 7.18 (d, J = 7, 9 Hz, 4H), 6.93 (d, J = 15.4 Hz, 1H), 6.79 (d, J = 15.4 Hz, 1H), 3.51 (dt, J = 14.2, 7.8 Hz, 8H), 2.55 (t, J = 7.0 Hz, 4H), 2.37 (s, 6H), 2.11 (s, 6H), 1.99 - 1.87 ( m, 4H), 1.39 - 1.08 (m, 6H). Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-ethyl-N-(3-methylsulfanyl-propyl)prop-2-enamide Method A: 66% yield

[00340] Two rotamers on nitrogen are evident in the spectrum.

[00341] 1H NMR (400 MHz, chloroform-d) d 7.62 (d, J = 15.3 Hz, 2H), 7.11 - 6.97 (m, 4H), 6.87 - 6.76 (m, 2H), 6.66 (d, J = 15.3 Hz, 2H), 5.99 (s, 4H), 3.59 - 3.43 (m, 8H), 2.62 - 2, 49 (m, 4H), 2.12 (s, 6H), 1.99 - 1.90 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), 1.19 (t , J = 7.1 Hz, 3H). Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(3-methylsulfanylpropyl)-N-phenylprop-2-enamide Method A: 98% yield

[00342] 1H NMR (400 MHz, chloroform-d) d 7.57 (d, J = 15.4 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.41 - 7.34 (m, 1H), 7.23 - 7.18 (m, 2H), 6.85 (dd, J = 8.1, 1.7 Hz, 1H), 6.73 - 6.72 (m, 2H ), 6.72 (d, J = 8.0 Hz, 1H), 6.10 (d, J = 15.4 Hz, 1H), 5.93 (s, 2H), 3.95 - 3.89 (m, 2H), 2.56 - 2.49 (m, 2H), 2.06 (s, 3H), 1.94-1.84 (m, 2H). Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methoxyethyl)-N-phenyl-prop-2-enamide Method A: 61% yield

[00343] 1H NMR (400 MHz, chloroform-d) d 7.58 (d, J = 15.5 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.40 - 7.33 (m, 1H), 7.29 - 7.24 (m, 2H), 6.85 (dd, J = 8.1, 1.6 Hz, 1H), 6.73 (d, J = 1.8 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.12 (d, J = 15.4 Hz, 1H), 5.93 (s, 2H), 4.00 ( t, J = 5.8 Hz, 2H), 3.60 (t, J = 5.8 Hz, 2H), 3.33 (s, 3H). Preparation of (E)-3-(4-methoxyphenyl)-N-(2-methylsulfanilethyl)-N-(2-pyridyl)prop-2-enamide Method A: 10% yield

[00344] 1H NMR (400 MHz, chloroform-d) d 8.55 (d, J = 5.7 Hz, 1H), 7.75 (td, J = 7.7, 2.0 Hz, 1H), 7.69 (d, J = 15.5 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.23 (dd, J = 7.5, 4.5 Hz, 2H), 6 .94 - 6.73 (m, 2H), 6.31 (d, J = 15.4 Hz, 1H), 4.26 - 4.18 (m, 2H), 3.80 (s, 3H), 2.85 - 2.76 (m, 2H), 2.15 (s, 3H). Preparation of 2-(4-methylphenoxy)-N-(2-methylsulfanilethyl)-N-(2-pyridyl)-Acetamide Method A: 19% yield

[00345] 1H NMR (400 MHz, chloroform-d) d 8.50 - 8.44 (m, 1H), 7.77 (td, J = 7.8, 2.0 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.23 (ddd, J = 7.3, 5.0, 0.7 Hz, 1H), 7.01 (d, J = 8.3 Hz, 2H), 6.64 (d, J = 8.5 Hz, 2H), 4.68 (s, 2H), 4.10 - 4.00 (m, 2H), 2.77 - 2.69 (m, 2H) , 2.25 (s, 3H), 2.12 (s, 3H). Preparation of (E)-N-(2-methylsulfanilethyl)-3-(p-tolyl)-N-(1H-pyrazol-3-yl)prop-2-enamide Method B: 50% yield

[00346] 1H NMR (600 MHz, chloroform-d) d 10.91 (s, 1H), 7.69 (d, J = 15.5 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 5.5 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H), 6.46 (d, J = 14.6 Hz, 1H), 6.24 (s, 1H), 4.04 (t, J = 13.1, 6.2 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2, 32 (s, 3H), 2.16 (s, 3H). Preparation of 2-(4-methylphenoxy)-N-(2-methylsulfanilethyl)-N-(1H-pyrazol-3-yl)acetamide Method B: 64% yield

[00347] 1H NMR (400 MHz, chloroform-d) d 7.57 (d, J = 2.5 Hz, 1H), 7.00 (d, J = 8.2 Hz, 2H), 6.71 ( d, J = 8.4 Hz, 2H), 6.23 (d, J = 2.4 Hz, 1H), 4.53 (s, 2H), 4.01 - 3.83 (m, 2H), 2.77 - 2.62 (m, 2H), 2.23 (s, 3H), 2.11 (s, 3H). Preparation of 2-(4-methoxyphenoxy)-N-(2-methylsulfanilethyl)-N-(1H-pyrazol-3-yl)acetamide Method B: 53% yield

[00348] 1H NMR (400 MHz, chloroform-d) d 10.72 (s, 1H), 7.58 (d, J = 2.4 Hz, 1H), 6.77 (s, 4H), 6, 24 (d, J = 2.4 Hz, 1H), 4.54 (s, 2H), 3.93 (dd, J = 8.5, 6.3 Hz, 2H), 3.73 (s, 3H ), 2.72 (dd, J = 8.6, 6.2 Hz, 2H), 2.13 (s, 3H). Preparation of (E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl chloride

[00349] An initial charge of 52.7 g (274.2 mmol) of 3,4-dioxymethylenecinnamic acid, 529 mL of toluene and 1.60 g of DMF is heated to 57°C. Within 30 min, 44.1 g (371 mmol) of thionyl chloride is added to the drops at 57 to 60°C. The solution is stirred at 60 to 65°C for an additional 1 h and then concentrated to a volume of about 300 ml. 3 x 289 mL of toluene are added, and each portion is separated by distillation once again under standard pressure. Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-phenyl-N-tetrahydrofuran-3-ylprop-2-enamide

[00350] To 0.72 g (3.4 mmol) of 3,4-methylenedioxycyanamoyl chloride in 7.5 g of toluene is added, at 50°C, 0.52 g (5.14 mmol) of triethylamine and then 0.52 g (3.19 mmol) of N-phenyloxane-3-amine in 4 ml of toluene. The mixture is stirred at 60°C for 8 h and cooled to RT. The organic phase is washed with water, 1N hydrochloric acid, water, saturated NaHCO3 solution and water again, dried over Na2SO4, filtered and concentrated.

[00351] Yield: 39%1H NMR (500 MHz, CDCl3) d 7.56 (d, J = 15.4 Hz, 1H); 7.50 - 7.38 (m, 3H); 7.22 - 7.12 (m, 2H); 6.81 (dd, J = 8.2, 1.6 Hz, 1H); 6.71 (d, J = 8.0 Hz, 1H); 6.67 (d, J = 1.6 Hz, 1H); 5.96 - 5.85 (m, 3H); 5.29 (dq, J = 8.3, 5.5 Hz, 2H); 4.04 (dd, J = 9.3, 6.7 Hz, 1H); 3.79 (dd, J = 9.3, 5.1 Hz, 1H); 3.74 - 3.53 (m, 1H); 2.20 - 2.12 (m, 1H); 1.96 - 1.77 (m, 1H). Preparation of (E)-N-phenyl-3-(P-tolyl)-N-tetrahydrofuran-3-ylprop-2- Enamide

[00352] To a solution of 0.56 g (3.0 mmol) of 4-methylcyanamoyl chloride in 7.5 mL of toluene, 0.46 g (4.5 mmol) of triethylamine is added dropwise. Subsequently, within 2 min, a suspension of 0.46 g (2.8 mmol) of N-phenyltetrahydrofuran-3-amine in 4 mL of toluene is dosed. The mixture is stirred at RT for 46 h and at 50°C for 11 h. 20 mL of water is added for work, and the organic phase is removed and concentrated in a rotary evaporator. The residue is recrystallized from ethyl acetate/heptane.

[00353] Yield: 0.32 g of product 1H NMR (500 MHz, CDCl3) d 7.63 (d, 1H), 7.50 - 7.40 (m, 3H), 7.22 (d, 2 H) , 7.14 (d, 2H), 7.07 (d, 2H), 6.06 (d, 1H), 5.34 - 5.26 (m, 1H), 4.05 (t, 1H), 3.83 - 3.78 (m, 1H), 3.71 (dd, 1H), 3.61 (dd, 1H), 2.30 (s, 3H); 2.25 - 2.14 (m, 1 H); 1.90 - 1.81 (m, 1H). Preparation of N-phenyltetrahydrothiophene-3-amine

[00354] A reactor is initially charged with 91.1 g (0.968 mol) of 2-aminopyridine, 1591 mL of toluene, 98.4 g (0.963 mol) of tetrahydrothiophene-3-one and 81.6 g of acid acetic. At room temperature, 288 g (1.36 mol) of sodium triacetoxyborohydride are added in portions within 30 min. The residue is rinsed with 115 mL of toluene and the mixture is stirred at room temperature for 21 h. Subsequently, the mixture is dosed with 4.85 L of 10% aqueous Na2CO3 solution at 15°C and mixed with an additional 500 mL of toluene. Stirring is continued at 15 to 20°C for about 20 minutes, and the aqueous phase is removed and extracted once again with 500 mL of toluene. The organic phases are combined and mixed with 2 L of water and 280 g of 10% HCl. The mixture is stirred for an additional 10 min and the organic phase is removed and discarded. The aqueous phase is washed 2 x with 500 ml of toluene each time, which are also discarded. Subsequently, the aqueous phase is mixed with 2 L of water and 1 L of toluene, and adjusted to pH 10.3 with 274 mL of 10% NaOH. The mixture is stirred for an additional 10 min, the organic phase is removed and the aqueous phase is re-extracted once more with 250 mL of toluene. The combined organic phases are washed 1x with 200 ml of water, quenched in Na2SO4 and concentrated.

[00355] Residue: 45.3 g (28%) Preparation of (E)-3-(1,3-benzodioxol-5-yl)-N-(2-pyridyl)-N-tetrahydro-thiophene-3-ylprop -2-enamide

[00356] To a solution of about 57.7 g (274 mmol) of 3,4-methylenedioxycyanamoyl chloride in about 235 mL of toluene are added, at about 50°C, 41.6 g (0.411 mol) of triethylamine and 46.5 g (258 mmol) of N-phenyltetrahydrothiophene-3-amine in 264 mL of toluene. The mixture is stirred at 55°C for 1 h and then at RT overnight. The suspension is cooled to 0°C and filtered. The filter residue is collected in 2 L of ethyl acetate and, at 40°C, washed 3 x with 500 mL of water each time. The mixture is concentrated to a volume level of about 600 mL at standard pressure, cooled to about 0°C within 3 h and stirred for an additional 1 h. This is followed by filtration and washing the filter cake with 80 mL of ice-cold ethyl acetate. The filter cake is dried, collected in 1670 mL of isopropanol and heated to reflux (solution). The mixture is concentrated to a volume level of 670 mL, cooled to 20°C and filtered. The residue is washed with 50 ml of ice-cold i-PrOH and dried.

[00357] Residue: 59.8 g (yield: 62%) 1H NMR (500 MHz, CDCl3) d 8.63 (d, 1H); 7.84 (td, J = 7.7, 2.0 Hz, 1H); 7.60 (d, J = 15.3 Hz, 1H); 7.39 (ddd, J = 7.5, 4.9, 0.9 Hz, 1H); 7.22 (d, J = 7.8 Hz, 1H), 6.82 (d, 1H); 6.72 (d, J = 8.0 Hz, 1H); 6.68 (d, J = 1.6 Hz, 1H); 5.94 (s, 2H); 5.80 (d, J = 15.3 Hz, 1H); 5.32 - 5.15 (m, 1H); 3.12 (dd, J = 10.1, 6.9 Hz, 1H); 2.94 - 2.81 (m, 2H); 2.72 (ddd, J = 10.3, 7.8, 2.4 Hz, 1H); 2.35 - 2.25 (m, 1H); 1.90 - 1.79 (m, 1H). Preparation of (E)-3-(p-tolyl)-N-(2-pyridyl)-N-tetrahydrothiophene-3-ylprop - 2-enamide

[00358] To an initial charge of 0.74 g (4.1 mmol) 4-methylcyanamoyl chloride in 10 mL of toluene, 0.52 g (5.1 mmol) of triethylamine is added. Subsequently, 0.65 g (3.4 mmol) of N-tetrahydrothiophene-3-ylpyridine-2-amine in 4.8 ml of toluene is dosed and the mixture is stirred at 50°C for 1 h. The mixture is quenched at RT with 20 mL of water. The precipitated solids were separated by filtration, washed with water and a little MTBE, and dried.

[00359] Yield: 57%1H NMR (500 MHz, CDCl3) d 8.64 (br s, 1H); 7.83 (td, J = 7.7, 2.0 Hz, 1H); 7.67 (d, J = 15.4 Hz, 1H); 7.39 (dd, J = 7.5, 4.9 Hz, 1H); 7.22 (d, J = 7.8 Hz, 1H); 7.16 (d, J = 8.1 Hz, 2H); 7.07 (d, J = 8.0 Hz, 2H); 5.94 (d, J = 15.4 Hz, 1H); 5.32 - 5.20 (m, 1H); 3.13 (dd, J = 10.2, 6.9 Hz, 1H); 2.96 - 2.80 (m, 2H); 2.78 - 2.66 (m, 1H); 2.40 - 2.23 (m, 4H); 1.94 - 1.78 (m, 1H). Preparation of (E)-3-(4-methoxyphenyl)-N-(2-pyridyl)-N-tetrahydrothiophene-3-ylprop-2-enamide

[00360] To an initial charge of 0.81 g (4.1 mmol) of 4-methoxyyanamoyl chloride in 11 mL of toluene, 0.52 g (5.1 mmol) of triethylamine is added. Subsequently, 0.65 g (3.4 mmol) of N-tetrahydrothiophene-3-ylpyridine-2-amine in 4.8 ml of toluene is dosed and the mixture is stirred at 50 to 60 ° C for 1 h. The mixture is quenched at RT with 20 mL of water. The precipitated solids were separated by filtration, washed with water and a little MTBE, and dried.

[00361] Yield: 69%1H NMR (500 MHz, CDCl3) d 8.65 (d, 1H); 7.83 (td, J = 7.7, 1.8 Hz, 1H); 7.65 (d, J = 15.4 Hz, 1H); 7.39 (dd, J = 7.3, 5.0 Hz, 1H); 7.22 (d, J = 8.6 Hz, 3H); 6.80 (d, J = 8.7 Hz, 2H); 5.85 (d, J = 15.4 Hz, 1H); 5.32 - 5.20 (m 1H), 3.78 (s, 3H); 3.13 (dd, J = 10.1, 6.9 Hz, 1H); 2.97 - 2.80 (m, 2H); 2.75 - 2.69 (m, 1H); 2.35 - 2.25 (m, 1H); 1.94 - 1.74 (m, 1H). Preparation of (E)-3-phenyl-N-(2-pyridyl)-N-tetrahydrothiophene-3-ylprop-2-enamide

[00362] To an initial charge of 0.68 g (4.1 mmol) of cyanamoyl chloride in 9 mL of toluene, 0.52 g (5.1 mmol) of triethylamine is added. Subsequently, 0.65 g (3.4 mmol) of N-tetrahydrothiophene-3-ylpyridine-2-amine in 4.8 ml of toluene is dosed and the mixture is stirred at 50 to 60 ° C for 1 h. The mixture is quenched at RT with 20 mL of water and the organic phase is washed once again with 20 mL of water. The organic phase is dried over Na2SO4, filtered and concentrated by rotary evaporation. This is followed by recrystallization from n-heptane/EtOAc.

[00363] Yield: 50%1H NMR (500 MHz, CDCl3) d 8.65 (dd, J = 4.8, 1.8 Hz, 1H); 7.84 (td, J = 7.7, 2.0 Hz, 1H); 7.70 (d, J = 15.4 Hz, 1H); 7.42 - 7.35 (m, 1H); 7.32 - 7.12 (m, 6H); 5.99 (d, J = 15.4 Hz, 1H); 5.35 - 5.13 (m, 1H); 3.14 (dd, J = 10.2, 6.9 Hz, 1H); 2.97 - 2.81 (m, 2H); 2.72 (m, 1H); 2.31 (m, Hz, 1H); 1.99 - 1.70 (m, 1H). Preparation of N-(tetrahydrofuran-2-ylmethyl)aniline

[00364] 96.1 g (1.0 mol) of furfural are initially loaded into 400 g of methylene chloride. Subsequently, 111.8 g (1.2 mol) of aniline are added to the drops at 40°C. The mixture is cooled to 0°C, and 400 g of methanol and 56.7 g (1.5 mol) of sodium boronate are added cautiously, and the mixture is stirred at 0 to 5°C for 1 h. The mixture is quenched with water, and methanol is the distillate. After that, the mixture is neutralized with 450 g of HCl (10%) and extracted with MTBE. The organic phase is dried and condensed, and the product is distilled and used without further purification.

[00365] 100 g of furfurylphenylamine are initially charged in 250 mL of ethanol, and 4 g of Pd/C are added. The reactor is supplied with hydrogen (10 bar) and the mixture is stirred at 50°C for 18 h. The mixture is filtered at RT and distilled directly.

[00366] Yield: 58% Preparation of (E)-3-81,3-benzodioxo-5-yl)-N-phenyl-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide

[00367] 1.14 g (11.3 mmol) of triethylamine and 1.95 g (11 mmol) of 2-tetrahydrofurfurylphenylamine are initially charged in 30 g of toluene. Subsequently, 4.52 g (21.5 mmol) of 3,4-methylenedioxycyanamoyl chloride are dosed and the mixture is stirred at 100°C for an additional 2 h. The mixture is poured into 50 g of water at RT and the solids are separated by suction filtration. After phase separation, the organic phase is dried, filtered and concentrated by rotary evaporation. This is followed by passage through a silica gel (EtOAc) column.

[00368] Yield: 76%

[00369] 1H NMR (400 MHz, chloroform-d) d 7.58 (d, J = 15.5 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.39 - 7.33 (m, 2H), 7.33 - 7.28 (m, 1H), 6.84 (dd, J = 8.1, 1.7 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 6.13 (d, J = 15.5 Hz, 1H), 5.92 (s, 2H), 4.21 - 4.08 (m, 1H), 4.00 (dd, J = 13.7, 4.8 Hz, 1H), 3.89 - 3.81 (m, 1H), 3.84 - 3.75 ( m, 1H), 3.77 - 3.68 (m, 1H), 1.98 (ddd, J = 6.9, 4.2, 1.9 Hz, 1H), 1.96 - 1.79 ( m, 2H), 1.68 - 1.54 (m, 1H).

[00370] The following compounds can also be prepared analogously to the methods described above: (E)-3-(4-Methoxyphenyl)-N-phenyl-N-tetrahydrofuran-3-ylprop-2-enamide

[00371] 1H NMR (500 MHz, CD2Cl2) d 7.52 (d, 1H); 7.48 - 7.35 (m, 3H); 7.27 - 7.11 (m, 4H); 6.77 (d, 2H); 5.97 (d, 1H); 5.29 - 5.13 (m, 1H); 3.95 (dd, 1H); 3.74 (s, 3H); 3.70 (dd, 1H); 3.63 (q, 1H); 3.54 (td, 1H); 2.21 - 2.05 (m, 1H); 1.74 - 1.36 (m, 1H). 2-(4-Methylphenoxy)-N-phenyl-N-tetrahydrofuran-3-ylacetamide

[00372] 1H NMR (500 MHz, CDCl3) d 7.56 - 7.36 (m, 3H); 7.30 - 7.16 (m, 2H); 7.02 (d, 2H); 6.66 (d, 2H); 5.25 - 5.09 (m, 1H); 4.25 (d, 1H); 4.21 (d, 1H); 3.98 (dd, 1H); 3.78 (dd, 1H); 3.67 (td, 1H); 3.60 - 2.48 (m, 1H), 2.25 (s, 3H); 2.23 - 2.07 (m, 1H); 1.85 - 1.75 (m, 1H). 2-(4-Methylphenoxy)-N-phenyl-N-tetrahydrothiophene-3-ylacetamide

[00373] 1H NMR (500 MHz, CDCl3) d 7.55 - 7.35 (m, 3H); 7.24 - 7.15 (m, 2H); 7.02 (d, 2H); 6.66 (d, 2H); 5.34 - 4.97 (m, 1H); 4.22 (s, 2H); 3.04 (dd, 1H); 2.84 (td, 1H); 2.74 - 2.50 (m, 2H); 2.37 - 2.10 (m, 4H); 1.65 (qd, 1H). (E)-N-Cyclohexyl-3-(4-methoxyphenyl)-N-(3-thienyl)prop-2-enamide

[00374] 1H NMR (500 MHz, CDCl3) d 7.60 (d, 1H); 7.37 (dd, 1H); 7.25 (d, 2H); 7.08 (dd, 1H); 6.88 (dd, 1H); 6.81 (d, 2H); 6.05 (d, 1H); 4.71 - 4.61 (m, 1H); 3.79 (s, 3H); 1.86 (d, 2H); 1.76 (d, 2H); 1.61 (d, 1H); 1.44 (qt, 2H); 1.13 (qd, 2H); 1.03 - 0.90 (m, 1H). N-Cyclohexyl-2-(4-methylphenoxy)-N-(3-thienyl)acetamide

[00375] 1H NMR (500 MHz, CDCl3) d 7.45 -7.30 (m, 1H); 7.16-7.08 (m, 1H); 7.02 (d, 2H); 6.87 (dd, 1H); 6.69 (d, 2H); 4.61 - 4.49 (m, 1H); 4.28 (s, 2H); 2.25 (s, 3H); 1.83 (m, 2H); 1.74 (d, 2H); 1.59 (d, 1H); 1.39 (q, 2H); 1.09 (qd, 2H); 0.94 (qt, 1H). N-Cyclohexyl-2-(4-methoxyphenoxy)-N-(3-thienyl)acetamide

[00376] 1H NMR (500 MHz, CDCl3) d 7.38 (dd, 1H); 7.11 (dd, 1H); 6.87 (dd, 1H); 6.82 - 6.62 (m, 4H); 4.62 - 4.48 (m, 1H); 4.26 (s, 2H); 3.74 (s, 3H); 1.82 (d, 2H); 1.73 (d, 2H); 1.59 (d, 1H); 1.39 (qt, 2H); 1.09 (qd, 2H); 0.94 (qt, 1H). (E)-3-(1,3-benzodioxol-5-yl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrothiophene-2-ylmethyl)prop-2-enamide

[00377] 1H NMR (500 MHz, CDCl3) d 7.68 - 7.54 (m, 2H); 6.89 (d, 1H); 6.81 (s, 1H); 6.74 (d, 1H); 6.31 (d, 1H); 6.24 (s, 1H); 5.96 (s, 2H); 4.29 - 4.17 (m, 1H); 3.67 (br s, 2H); 2.92 (dt, 1H); 2.81 (dt, 1H); 2.18 - 1.81 (m, 4H). (E)-3-(P-Tolyl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrothiophene-2-ylmethyl)prop-2-enamide

[00378] The preparation is carried out using N-(tetrahydrothiophene-2-ylmethyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-3-amine and final deprotection with tetrabutylammonium fluoride in THF.

[00379] 1H NMR (500 MHz, CDCI3) d 7.75 - 7.55 (m, 2H); 7.32 - 7.20 (m, 2H); 7.09 (d, 2H); 6.43 (d, 1H); 6.22 (s, 1H); 4.30 - 4.18 (m, 1H); 3.75 - 3.62 (m, 2H); 2.96 - 2.86 (m, 1H); 2.85 - 2.74 (m, 1H); 2.31 (s, 3H); 2.13 - 1.77 (m, 4H). (E)-3-(4-methoxyphenyl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrothiophene-2-ylmethyl)prop-2-enamide

[00380] The preparation is carried out using N-(tetrahydrothiophene-2-ylmethyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-3-amine and final deprotection with tetrabutylammonium fluoride in THF.

[00381] 1H NMR (500 MHz, CDCl3) d 7.73 (d, 1H); 7.65 (s, 1H); 7.32 (d, 2H); 6.84 (d, 2H); 6.38 (d 1H); 6.26 (s, 1H); 4.37 - 4.21 (m, 1H); 3.79 (s, 3H); 3.75 - 3.61 (m, 2H); 3.00 - 2.89 (m, 1H); 2.89 - 2.79 (m, 1H); 2.18 - 1.83 (m, 4H). 2-(4-Methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(tetrahydrothiophene-2-ylmethyl)-acetamide

[00382] 1H NMR (500 MHz, CDCl3) d 7.57 (d, 1H); 7.00 (d, 2H); 6.71 (d, 2H); 6.24 (d, 1H); 4.55 (q, 2H); 4.18 - 4.04 (m, 1H); 3.68 - 3.50 (m, 2H); 2.93 - 2.67 (m, 2H); 2.23 (s, 3H); 2.08 - 1.80 (m, 4H). 2-(4-Methoxyphenoxy)-N-(1H-pyrazol-3-yl)-N-(tetrahydrothiophene-2-ylmethyl)-acetamide

[00383] 1H NMR (500 MHz, CDCl3) d 7.58 (d, 1H); 6.76 (s, 4H), 6.24 (d, 1H); 4.53 (q, 2H); 4.13 (q, 1H); 3.72 (s, 3H); 3.65 - 3.46 (m, 2H); 2.94 - 2.84 (m, 1H); 2.84 - 2.74 (m, 1H); 2.09 - 1.73 (m, 4H). (E)-3-(P-Tolyl)-N-(1H-pyrazol-3-yl)-N-tetrahydrothiophene-3-ylprop-2-enamid

[00384] 1H NMR (500 MHz, CDCl3) d 7.76 - 7.56 (m, 2H); 7.21 (d, 2H); 7.07 (d, 2H); 6.24 (d, 1H); 6.17 (d, 1H); 5.37 - 5.22 (m, 1H); 3.10 (dd, 1H); 2.92 - 2.80 (m, 1H); 2.76 (t, 1H); 2.69 (ddd, 1H); 2.36 - 2.22 (m, 4H); 1.78 (qd, 1H). (E)-3-(4-Methoxyphenyl)-N-(1H-pyrazol-3-yl)-N-tetrahydrothiophene-3-ylprop-2-enamide

[00385] 1H NMR (500 MHz, CDCI3) d 7.77 - 7.53 (m, 2H); 7.25 (d, 2H); 6.79 (d, 2H); 6.24 (d, 1H); 6.09 (d, 1H); 5.40 - 5.16 (m, 1H); 3.79 (s, 3H); 3.10 (dd, 1H); 2.92 - 2.82 (m, 1H); 2.76 (t, 1H); 2.75 - 2.65 (m, 1H); 2.31 - 2.22 (m, 1H); 1.85 - 1.70 (m, 1H). 2-(4-Methoxyphenoxy)-N-(1H-pyrazol-3-yl)-N-tetrahydrothiophene-3-yl-acetamide

[00386] 1H NMR (500 MHz, CDCl3) d 7.62 (d, 1H); 6.76 (s, 4H); 6.23 (d, 1H); 5.25 - 5.14 (m, 1H); 4.35 (s, 2H); 3.73 (s, 3H); 3.07 (dd, 1H); 2.84 (dd, 1H); 2.78 - 2.59 (m, 2H); 2.34 - 2.15 (m, 1H); 1.84 - 1.70 (m, 1H). (E)-3-(1,3-Benzodioxol-5-yl)-N,N-bis(2-pyridyl)prop-2-enamide

[00387] 1H NMR (400 MHz, CDCl3) d 8.48 (d, 2H); 7.80 (t, 2H); 7.73 (d, 1H); 7.52 (d, 2H); 7.25 - 7.16 (m, 2H); 6.92 (d, 1H); 6.80 (s, 1H); 6.77 (d, 1H); 6.19 (d, 1H); 5.97 (s, 2H). (E)-3-(1,3-benzodioxol-5-yl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide

[00388] 1H NMR (400 MHz, chloroform-d) d 7.61 (d, J = 15.5 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 6.90 ( d, J =7.7 Hz, 1H), 6.83 (s, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 15.2 Hz, 1H), 6.21 (s, 1H), 5.95 (s, 2H), 4.22 (qd, J = 7.2, 4.2 Hz, 1H), 4.13 (dd, J = 13 .8, 4.1 Hz, 1H), 3.95 - 3.84 (m, 1H), 3.78 (td, J = 7.9, 6.2 Hz, 1H), 3.68 - 3, 60 (m, 1H), 2.10 - 1.96 (m, 1H), 1.99 - 1.82 (m, 2H), 1.62 (ddt, J = 15.6, 12.0, 8 ,1Hz, 1H). (E)-3-(p-tolyl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide

[00389] 1H NMR (400 MHz, chloroform-d) d 11.26 (s, 1H), 7.68 (d, J = 15.5 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 6.55 (d, J = 15.6 Hz, 1H), 6.21 (s, 1H), 4.22 (qd, J = 7.1, 4.1 Hz, 1H), 4.18 - 4.10 (m, 1H), 3.90 (dt , J = 8.3, 6.8 Hz, 1H), 3.78 (td, J = 7.9, 6.1 Hz, 1H), 3.73 - 3.57 (m, 1H), 2, 32 (s, 3H), 2.12 - 1.96 (m, 1H), 1.98 - 1.80 (m, 2H), 1.61 (ddt, J = 12.0, 8.4, 7 .2Hz, 1H). (E)-3-(4-methoxyphenyl)-N-(1H-pyrazol-3-yl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide

[00390] 1H NMR (600 MHz, chloroform-d) d 8.15 (d, J = 3.0 Hz, 1H), 7.90 (d, J = 15.8 Hz, 1H), 7.63 - 7.61 (m, 2H), 7.62 (d, J = 15.9 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 5.92 (d, J = 3 .0 Hz, 1H), 4.14 (qd, J = 7.1, 3.6 Hz, 1H), 3.97 - 3.87 (m, 1H), 3.85 (s, 3H), 3 .83 - 3.73 (m, 1H), 3.57 - 3.47 (m, 1H), 3.32 - 3.25 (m, 1H), 2.04 (dddt, J = 9.5, 8.4, 6.9, 4.9 Hz, 1H), 1.98 - 1.88 (m, 2H), 1.69 (ddt, J = 12.1, 8.6, 7.1 Hz, 1H). 2-(4-methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(tetrahydrofuran-2-ylmethyl)-acetamide

[00391] 1H NMR (400 MHz, chloroform-d) d 7.54 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.1 Hz, 2H), 6.72 ( d, J = 8.0 Hz, 2H), 6.28 (s, 1H), 4.66 - 4.48 (m, 2H), 4.2 - 4.1 (m, 1H), 4.0 - 3.9 (m, 1H), 3.9 - 3.8 (m, 1H), 3.8 - 3.7 (m, 1H), 3.64 (dd, J = 13.6, 7, 7 Hz, 1H), 2.24 (s, 3H), 2.03 - 1.78 (m, 3H), 1.66 - 1.52 (m, 1H). (E)-3-(1,3-benzodioxol-5-yl)-N-(2-pyridyl)-N-(tetrahydrofuran-2-ylmethyl)-prop-2-enamide

[00392] 1H NMR (600 MHz, chloroform-d) d 8.53 (ddd, J = 4.9, 2.0, 0.8 Hz, 1H), 7.75 (ddd, J = 8.1, 7.4, 2.0 Hz, 1H), 7.63 (d, J = 15.3 Hz, 1H), 7.33 (dt, J = 8.1, 1.0 Hz, 1H), 7, 22 (ddd, J = 7.4, 4.9, 1.0 Hz, 1H), 6.89 (dd, J = 8.1, 1.6 Hz, 1H), 6.80 (d, J = 1.7 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 15.3 Hz, 1H), 5.95 (s, 2H), 4 .24 - 4.18 (m, 2H), 4.04 - 3.98 (m, 1H), 3.73 (ddd, J = 8.3, 7.2, 6.5 Hz, 1H), 3 .67 (td, J = 8.0, 5.9 Hz, 1H), 1.99 (dddd, J = 11.9, 8.6, 6.5, 5.2 Hz, 1H), 1.94 - 1.87 (m, 1H), 1.87 - 1.79 (m, 1H), 1.63 (ddt, J = 12.2, 8.6, 6.9 Hz, 1H). (E)-3-(p-tolyl)-N-(2-pyridyl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide

[00393] 1H NMR (600 MHz, chloroform-d) d 8.53 (dt, J = 4.8, 1.9, 0.7 Hz, 1H), 7.74 (td, J = 7.7, 2.0 Hz, 1H), 7.69 (d, J = 15.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.25 (s, 2H), 7 .22 (ddd, J = 7.4, 4.9, 0.9 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.40 (d, J = 15.4 Hz, 1H), 4.25 - 4.21 (m, 2H), 4.05 - 3.99 (m, 1H), 3.77 - 3.70 (m, 1H), 3.67 (td, J = 8.0, 6.0 Hz, 1H), 2.33 (s, 3H), 2.04 - 1.96 (m, 1H), 1.96 - 1.87 (m, 1H), 1 .87 - 1.78 (m, 1H), 1.64 (ddt, J = 12.3, 8.5, 7.0 Hz, 1H). (E)-3-(4-methoxyphenyl)-N-(2-pyridyl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide

[00394] 1H NMR (400 MHz, chloroform-d) d 8.53 (ddd, J = 5.0, 2.0, 0.8 Hz, 1H), 7.74 (td, J = 7.7, 2.0 Hz, 1H), 7.68 (d, J = 15.4 Hz, 1H), 7.34 (dd, J = 7.5, 1.0 Hz, 1H), 7.32 - 7, 28 (m, 2H), 7.21 (ddd, J = 7.4, 4.9, 1.0 Hz, 1H), 6.85 - 6.78 (m, 2H), 6.33 (d, J = 15.4 Hz, 1H), 4.27 - 4.17 (m, 2H), 4.07 - 3.96 (m, 1H), 3.80 (s, 3H), 3.93 - 3 .62 (m, 2H), 2.09 - 1.75 (m, 3H), 1.64 (ddt, J = 11.6, 8.2, 6.7 Hz, 1H). (E)-3-(1,3-benzodioxol-5-yl)-N-ethyl-N-(tetrahydrofuran-2-ylmethyl)prop-2- Enamide

[00395] Two rotamers on nitrogen are evident in the spectrum.

[00396] 1H NMR (400 MHz, chloroform-d) d 7.66 - 7.55 (m, 2H), 7.06 - 6.95 (m, 4H), 6.81 - 6.74 (m, 3H), 6.70 (d, J = 15.3 Hz, 1H), 5.98 (s, 4H), 4.17 - 4.02 (m, 2H), 3.93 - 3.82 (m , 3H), 3.82 - 3.69 (m, 2H), 3.69 - 3.56 (m, 4H), 3.56 - 3.42 (m, 2H), 3.20 (dd, J = 13.8, 7.3 Hz, 1H), 2.08 - 1.97 (m, 2H), 1.97 - 1.79 (m, 3H), 1.63 - 1.52 (m, 3H ), 1.23 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). N-ethyl-2-(4-methoxyphenoxy)-N-(tetrahydrofuran-2-ylmethyl)acetamide

[00397] Two rotamers on nitrogen are evident in the spectrum.

[00398] 1H NMR (400 MHz, chloroform-d) d 6.93 - 6.86 (m, 4H), 6.82 (dd, J = 9.2, 1.7 Hz, 4H), 4.71 (dd, J = 14.6, 1.3 Hz, 2H), 4.66 (dd, J = 14.1, 1.0 Hz, 2H), 4.15 - 4.06 (m, 1H), 4.06 - 3.99 (m, 1H), 3.90 - 3.80 (m, 2H), 3.76 (s, 6H), 3.79 - 3.69 (m, 2H), 3, 66 - 3.57 (m, 1H), 3.54 (q, J = 7.1 Hz, 2H), 3.47 - 3.31 (m, 3H), 3.13 (dd, J = 13, 9, 7.5 Hz, 2H), 2.07 - 1.94 (m, 2H), 1.94 - 1.78 (m, 4H), 1.58 - 1.44 (m, 2H), 1 .21 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H). (E)-N-phenyl-3-(P-tolyl)-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide

[00399] 1H NMR (400 MHz, chloroform-d) d 7.65 (d, J = 15.5 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.38 - 7.33 (m, 1H), 7.33 - 7.28 (m, 2H), 7.18 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H) , 6.26 (d, J = 15.5 Hz, 1H), 4.21 - 4.14 (m, 1H), 4.01 (dd, J = 13.7, 4.8 Hz, 1H), 3.88 - 3.69 (m, 3H), 2.30 (s, 3H), 2.02 - 1.78 (m, 3H), 1.67 - 1.56 (m, 1H). (E)-3-(4-methoxyphenyl)-N-phenyl-N-(tetrahydrofuran-2-ylmethyl)prop-2-enamide

[00400] 1H NMR (400 MHz, chloroform-d) d 7.63 (d, J = 15.5 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.38 - 7.32 (m, 1H), 7.32 - 7.28 (m, 2H), 7.27 - 7.21 (m, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6, 17 (d, J = 15.5 Hz, 1H), 4.17 (qd, J = 6.8, 4.9 Hz, 1H), 4.02 (dd, J = 13.6, 4.9 Hz , 1H), 3.88 - 3.80 (m, 1H), 3.82 - 3.75 (m, 1H), 3.78 (s, 3H), 3.73 (ddd, J = 8.3 , 7.4, 5.8 Hz, 1H), 2.06 - 1.94 (m, 1H), 2.03 - 1.78 (m, 2H), 1.68 - 1.56 (m, 1H ). 2-(4-methylphenoxy)-N-phenyl-N-(tetrahydrofuran-2-ylmethyl)acetamide

[00401] 1H NMR (400 MHz, chloroform-d) d 7.43 (dd, J = 8.2, 6.4 Hz, 2H), 7.41 - 7.35 (m, 1H), 7.34 - 7.29 (m, 2H), 7.01 (d, J = 8.3 Hz, 2H), 6.72 - 6.64 (m, 2H), 4.36 (d, J = 14.6 Hz, 1H), 4.31 (d, J = 14.7 Hz, 1H), 4.12 (qd, J = 6.6, 4.6 Hz, 1H), 3.89 - 3.78 (m , 2H), 3.72 (td, J = 7.8, 5.9 Hz, 2H), 2.24 (s, 3H), 2.04 - 1.78 (m, 3H), 1.62 - 1.53 (m, 1H). 2-(4-methoxyphenoxy)-N-phenyl-N-(tetrahydrofuran-2-ylmethyl)acetamide

[00402] 1H NMR (400 MHz, chloroform-d) d 7.47 - 7.40 (m, 2H), 7.40 - 7.34 (m, 1H), 7.34 - 7.28 (m, 2H), 6.77 (d, J = 9.3 Hz, 2H), 6.72 (d, J = 9.4 Hz, 2H), 4.38 - 4.24 (m, 2H), 4, 17 - 4.06 (m, 1H), 3.88 - 3.78 (m, 2H), 3.78 - 3.69 (m, 2H), 3.73 (s, 3H), 2.05 - 1.77 (m, 3H), 1.64 - 1.53 (m, 1H). (E)-3-(1,3-benzodioxol-5-yl)-N-ethyl-N-[2-(2-thienyl)ethyl]prop-2-enamide

[00403] 1H NMR (400 MHz, chloroform-d) d 7.65 (d, J = 15.2 Hz, 1H), 7.54 (d, J = 15.2 Hz, 1H), 7.18 - 7.10 (m, 2H), 7.06 - 6.98 (m, 2H), 6.97 - 6.89 (m, 4H), 6.88 - 6.83 (m, 2H), 6, 79 (t, J = 8.2 Hz, 2H), 6.66 (d, J = 15.3 Hz, 1H), 6.44 (d, J = 15.3 Hz, 1H), 5.98 ( s, 4H), 3.66 (t, J = 7.5 Hz, 4H), 3.50 (q, J = 7.1 Hz, 2H), 3.37 (q, J = 7.2 Hz, 2H), 3.19 - 3.09 (m, 4H), 1.19 (t, J = 7.1 Hz, 6H).

Sensory Assessment: Cooling intensity of inventive amides compared to FEMA 4809:

[00404] Test solutions with 2 or 20 ppm of the inventive amides in a 5% solution were sensorially evaluated by trained panelists (n = 10 to 11) and compared with a solution containing 2 ppm of the comparative compound FEMA 4809. What was evaluated here was initial cooling intensity, overall cooling intensity and long-lasting action on a scale from 1 (very weak) to 9 (very strong).

[00405] N.B.: The compounds were pre-dissolved as a 1% ethanol solution.

[00406] What is clearly evident is the faster onset of the cooling effect, an evident cooling profile comparable to or better than the reference, and the distinctly long-lasting cooling effect for the inventive amides.

Intensity profile with time of the inventive amides compared to reference compounds (FEMA 4809, 4496) and WS3:

[00407] To establish an intensity profile over time, the oral cavity of trained panelists (n = 8 to 11) was rinsed for 40 seconds with a dollop of a sample solution (2 ppm FEMA 4809 or 50 ppm FEMA 4496 or 50 ppm from 1) to 5)). Subsequently, perceived cooling intensity was assessed at defined time intervals using a scale.

[00408] For the inventive amides, distinctly faster or at least comparably rapid onset of cooling activity was found with respect to WS3. Furthermore, the cooling effect lasted longer than for WS3 and for a comparatively long period with that for the reference compounds (FEMA 4809, FEMA 4496), but these showed a distinctly delayed onset of the cooling action.

Usage examples: Toothpaste

[00409] Suitable toothpastes can be produced according to the following base formulation:

Assessment of the progression of cooling intensities of compounds for use according to the invention with time in the illustrative toothpaste:

[00410] The cooling substances for use according to the invention were incorporated into the toothpaste as follows: All values in % by weight

[00411] The sensory properties of the resulting toothpaste were evaluated by a panel of trained people (of 6 people). For this purpose, the teeth were first cleaned with the toothpaste comprising the compounds of the invention for 30 seconds, then the toothpaste foam was spit out and the mouth was rinsed once with water. The tasters evaluated the intensity of the cold sensation on a scale from 0 (no cold sensation) to 9 (extremely strong cold sensation). The sensation of cold was assessed after 30 seconds and after 1, 5, 10, 20, 30, 45 and 60 minutes.

[00412] The compounds of the invention tested by example were the compounds (E)-N-phenyl-3-(p-tolyl)-N-tetrahydrofuran-3-ylprop-2-enamide, (E)-3-( 4-methoxyphenyl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide, (E)-3-(1,3-benzodioxol-5-yl)-N-phenyl-N-( tetrahydrofuran-2-ylmethyl)prop-2- enamide, (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanilethyl)-N-phenylprop-2- enamide, 2-(4 -methylphenoxy)-N-(2-methylsulfanilethyl)-N-phenylacetamide, (E)-3-(1,3-benzodioxol-5-yl)-N-ethyl-N-(2-methylsulfanilethyl)prop-2-enamide and (E)-N-(2-methylsulfanilethyl)-3-(p-tolyl)-N-(2-pyridyl)prop-2-enamide, but especially the compounds (E)-3-(1,3-benzodioxol -5-yl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide, (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanilethyl )-N-(2-pyridyl)prop-2-enamide, (E)-3-(p-tolyl)-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide, (E) -3-phenyl-N-(2-pyridyl)-N-tetrahydrothiophen-3-ylprop-2-enamide, (E)-3-(1,3-benzodioxol-5-yl)-N-phenyl-N-tetrahydrofuran -3-ylprop-2-enamide and (E)-3-(1,3-benzodioxol-5-yl)-N-(2-methylsulfanilethyl)-N-(1H-pyrazol-3-yl)prop-2- enamide.

[00413] By way of comparison, toothpastes with the same composition but comprising N-ethylmenthane-3-carboxamide ("WS 3", see also US 4,150,052) as a conventional cooling substance were tested.

[00414] The result showed that the cooling substances of the invention are distinctly superior to those used conventionally both in terms of quickly perceptible intensity and in terms of duration of perception of coldness. Thus, the cooling substances of the invention, even after 1 hour after teeth cleaning, impart a very distinctly perceptible sensation of cold, whereas this has already completely disappeared after this time in the case of conventional comparative compounds.

Bubble gum

[00415] Suitable chewing gums can be produced according to the following base formulation:

[00416] For “sugar-free formulations”, it is also possible to replace glucose syrup and icing sugar with the sugar alcohols mannitol, xylitol and sorbitol, “Palatinit” and other synthetic sweeteners such as saccharin, cyclamate, acesulfame -K and aspartame.

Cosmetic sunscreen formulation

[00417] The following formulations describe a cosmetic sunscreen formulation comprising a combination of at least inorganic pigment and organic UV filter.

[00418] The formulations specified below are produced in a customary manner known to the person skilled in the art. Blancmange Recipe (for 100 ml)

Preparation:

[00419] Heat nine-tenths of the water to 43.3°C. Dissolve skimmed milk powder in water. Heat the oil to 60°C and add the carrageenan and oil-soluble vitamins to the oil. Mix the [oil into the product. Add the other constituents except for the modified starch, vanilla flavor and vitamin premix. Homogenize the mixture. Gradually add the starch. Add active ingredient, vitamins and flavoring. Standardize solids content. Heat in sterile units and package in doses.

Modification of the textile product with active ingredients of the invention

[00420] First, an aqueous starch slurry containing amylose is prepared by mixing 570 g of deionized water with 10 g of a standard commercial preservative. 20 g of carboxymethyl cellulose was dissolved therein, then 400 g of an amylose-containing starch having an amylose content of 50% by weight was added and a slurry was produced under stirring.

[00421] This was followed by the production of aqueous starch liquids containing amylose by one of the following two methods: Method 1: The respective slurry is adjusted to a starch content of 5% or 15% by weight by dilution with water.

[00422] Method 2: The respective slurry is first diluted with water to a starch content of 5% or 15% by weight and then mixed with 30 g/L of a 30% by weight aqueous polyurethane dispersion (non-ionogenic ).

[00423] This is followed by modification of a cloth woven with amylose-containing starch and active ingredient of the invention.

[00424] The woven cotton cloth specimen with a basis weight of 124 g/m2 is treated with one of the liquids prepared above by means of a pad calender until a liquid collection of 80% by weight, based on the weight of the cloth . This is followed by drying at 120°C for 2 min.

[00425] Subsequently, the cloth specimens thus modified are treated with an aqueous formulation of active by applying an aqueous emulsion/suspension of an active of the invention having an active content of 1% to 7% by weight to the cloth specimen for through a padded calender until a liquid collection of 79-80% by weight. Subsequently, the cloth specimens thus treated are dried in a household dryer to a residual moisture content of 15%.

[00426] The active-loaded cloths thus produced can then be further examined, for example for their cooling effect in contact with the skin or their repellent effect on insects.

Mouthwash flavorings

[00427] Production of mouthwash flavorings with cooling action using the cooling substances of the invention: The following were mixed (all values, unless otherwise stated, in % by weight):

[00428] The flavorings were each incorporated into a ready-to-use mouthwash at a concentration of 0.15% by weight or into a mouthwash concentrate at a concentration of 3% by weight. Sensory evaluation by a trained panel of experts showed that the flavorings led to a rapid onset of a very long-lasting freshness effect that lasted for a period of almost 1 h after use of the mouthwash.

Chewable sweets

[00429] Production of a cooling raspberry flavored chewy candy using the cooling substances of the invention.

[00430] All values, unless otherwise stated, in % by weight:

[00431] Production instructions: a) let the gelatin swell with water (1.8 times the amount of gelatin) at 70°C for 2 hours; b) boil sugar, syrup, water, fat and lecithin at 123°C; c) mix the gelatin solution gradually with the boiled mixture; d) mixing the raspberry flavoring, menthyl lactate and the cooling substances of the invention and optionally stirring in coloring; e) bring the resulting mass to around 70°C on a refrigerated table, then add fondant and aerate in a pulling machine for around 3 minutes; f) then cut the chewy candy mixture and package it.

[00432] When consuming the chewable sweets, a fresh and cooling raspberry flavor is perceived during chewing. Fruit Gummies

[00433] Production of fruit gums with a long-lasting fresh cooling flavor using the cooling substances of the invention.

[00434] All values, unless otherwise stated, in % by weight:

[00435] The above examples of use can be applied to other products of the respective product group - if appropriate through modifications that the person skilled in the art will not find difficulties in undertaking. It is not difficult for the person skilled in the art to observe based on the present description that the compounds of the invention - possibly with minor modifications - are mutually interchangeable without any greater complexity. The concentration of the compound or mixture of the invention used is also variable as readily apparent to the person skilled in the art. Furthermore, the additional product-specific constituents in the respective example of use, in a manner readily appreciable to the person skilled in the art, are equally interchangeable with other typical constituents of the product or can be supplemented thereby. A multitude of such product-specific constituents are disclosed in the above description.

Claims (20)

1. Non-therapeutic modulation method, preferably IN VITRO and/or IN VIVO modulation, of the TRPM8 cold and menthol receptor, characterized by the fact that the receptor is brought into contact with at least one modulator selected from the group that consists of compounds of the following structure type 1: Structure type 1: where R1 consists of the following structure: where Z is selected from the group consisting of O and S; n = 0 or 1; m - = 1 and Y is hydrogen and R8 is a linear or branched C1 to C5 alkyl radical, preferably a C5 alkyl radical, or Y is NR9 or CR9 and R9 together with R8 form a partially or fully saturated 5- or 6-membered ring , or - = 0, 2 or 3 and Y is hydrogen and R8 is a linear or branched C1 to C5 alkyl radical, preferably a C5 alkyl radical, or Y is NR9 or CR9 and R9 together with R8 form a partial or fully saturated aromatic ring with 5 or 6 members; R2 is a linear or branched C1 to C5 alkyl radical, a 5- or 6-membered cycloalkyl radical, or a 5- or 6-membered aryl radical, wherein the alkyl radical, the cycloalkyl radical, or the aryl radical optionally includes one or two heteroatoms (ring); R3, R4, R5, R6 and R7 are identical or distinct, and are selected from the group consisting of hydrogen; halogens; linear or branched C1- to C6 alkyl groups, optionally containing 1, 2, 3 or 4 identical or different substituents selected from the group consisting of NH2, OH, SH, halogens and linear or branched C1- to C6 alkyl groups; linear or branched C1- to C6 alkoxy groups, optionally containing 1, 2, 3 or 4 identical or different substituents selected from the group consisting of NH2, OH, SH, halogens and C1- to C6 alkoxy groups; mono- or polycyclic aryl, arylalkyl and heteroaryl groups optionally containing 1, 2, 3 or 4 identical or different substituents selected from the group consisting of NH2, OH, SH, halogens, linear or branched C1- to C6 alkyl groups; wherein the heteroaryl groups have 1, 2, 3 or 4 identical or different ring heteroatoms and are selected from the group consisting of O, N and S, or two adjacent radicals R3, R4, R5, R6 and R7 together with the carbon atoms to which they are attached, form a 4-, 5-, 6- or 7-membered mono- or polyunsaturated heterocyclic ring, optionally containing 1, 2, 3, 4 or 5 identical or different substituents selected from the group which consists of linear or branched C1- to C6 alkyl groups and having 1, 2 or 3 ring heteroatoms that are identical or different and are selected from the group consisting of O, N and S; X - is selected from the group consisting of -C1- to C4-alkylene groups; -C2- to C4-alkenylene groups and -A-C1- to C4- or -C1- to C4-A-alkylene groups or -A-C2- to C4- or -C2- to C4-A-alkenylene groups, in that A is O, S or NH; or - is a single chemical bond; and salts of these compounds, especially acid addition salts with inorganic or especially organic, mono- and especially polybasic carboxylic acids; and optionally of these compounds in stereoisomerically pure form or in mixtures of stereoisomers thereof. 2. Method according to claim 1, characterized by the fact that compounds of structure type 1 are selected from group A consisting of the following compounds: 3. Method according to claim 1 or 2, characterized in that the receptor is brought into contact with at least one modulator which, in a cellular activity test using cells that recombinantly express the human TRPM8 receptor, modulates the permeability of these cells for Ca2+ ions. 4. Method according to any one of claims 1 to 3, characterized in that the modulator has an agonistic or antagonistic effect on cellular Ca2+ ion permeability. 5. Method according to any one of claims 1 to 4, characterized in that the modulator is a TRPM8 receptor agonist. 6. Use of a modulator used in the method as defined in claim 5, characterized by the fact that it is for non-therapeutic induction of a sensation of cold in humans and/or animals. 7. Use according to claim 6, characterized in that it is for non-therapeutic induction of a sensation of cold by means of a packaging or fabric comprising the modulator. 8. Use according to claim 6, characterized by the fact that a composition comprising at least one, two, three or more of the modulators used in the method as defined in claim 5, preferably in a (total) amount of 0.1 ppm at 10% by weight, based on the total weight of the composition, is used to achieve a cooling effect on the skin or mucosa that is preferably prolonged compared to the cooling effect of a composition of the same constitution in which the modulator(s) was/were just exchanged for N-ethylmenthanecarboxamide at the same concentration, preferably for at least 10 minutes, and/or a cooling effect that starts earlier compared to the cooling effect of a composition of the same constitution in which the modulator(s) was/were just exchanged for FEMA 4809 or FEMA 4496 at the same concentration. 9. Use according to claim 7 or 8, characterized by the fact that the modulator(s) is/are selected from group A as defined in claim 2. 10. Use of a modulator used in the method as defined in any one of claims 1 to 5, characterized in that it is to prepare a medicament for modulating a TRPM8 receptor. 11. Compound, characterized by the fact that it is selected from group A which consists of the following compounds: or a salt of such a compound, especially selected from acid addition salts with inorganic or especially organic, mono- or especially polybasic carboxylic acids. 12. Composition, characterized by the fact that it comprises a compound as defined in claim 11. 13. Composition, characterized by the fact that it comprises at least one modulator used in the method as defined in any one of claims 1 to 5. 14. Composition according to claim 12 or 13, characterized by the fact that it is for use as a TRPM8 receptor modulator, preferably for use in a therapeutic method for modulating the TRPM8 receptor, wherein the composition is selected from the group that consists of a) food, preferably ice cream, mousse, cream, drinks and confectionery, b) oral care products, preferably toothpaste, mouthwash and chewing gum, c) personal care products, preferably skin care products or hair, e.g. sunscreen, sunburn cream, lotions and shampoos, and plasters, d) foams and gels. 15. Composition according to any one of claims 12 to 14, characterized in that the composition is selected from the group consisting of mixtures and flavor formulations for the purposes of nutrition, oral hygiene or delight, or cosmetic formulations, comprising one, two, three or more of the modulators used in the method as defined in any one of claims 1 to 5, wherein said modulator(s) is/are present in a (total) amount of 0. 05 ppm to 10% by weight, preferably from 0.1 ppm to 10% by weight, based on the total weight of the flavor mixture or formulation. 16. Composition according to any one of claims 12 to 15, characterized in that the composition additionally comprises: (1) one or more additional substances with physiological cooling action, wherein the additional substance or one, more than one or all additional substances (i) cause(s) a flavoring effect or (ii) do not cause(s) a flavoring effect, and/or (2) one or more flavors without a physiological cooling effect and/or (3) one or more substances with temporomandibular effect or activation of saliva production without any physiological cooling effect and/or (4) (iii) a compound or (iv) two or more compounds that, independently or collectively, in case (iv), additionally cause( m) taste modulating effect and/or a temporomandibular stimulus or the activation of saliva production. 17. Use according to claim 6, characterized in that it is to achieve a physiological cooling effect on the skin and/or mucosa that has been prolonged for at least 10 minutes compared to the cooling effect of a composition of the same constitution in which the modulator(s) was/were merely exchanged for N-ethylmenthanecarboxamide at the same concentration, and/or a cooling effect that starts earlier compared to the cooling effect of a composition of the same constitution in which the modulator(s) was/were merely exchanged for FEMA 4809 or FEMA 4496 in the same concentration, comprising the following step: - applying an amount of a composition as defined in any one of claims 12 to 15 that is sufficient to obtain a physiological cooling effect on the skin and/or mucosa. 18. Use according to claim 17, characterized by the fact that the modulator(s) is/are selected from group A as defined in claim 2. 19. Use of a composition as defined in any one of claims 12 to 16, characterized in that it is to prepare a medicament for modulating a TRPM8 receptor. 20. Use of a TRPM8 receptor modulator, characterized by the fact that it is for preparing a pharmaceutical composition as defined in any one of claims 12 to 16 to obtain a physiological cooling effect on the skin and/or mucosa.