CN101677930A - 用作清凉剂的丁酮衍生物 - Google Patents
用作清凉剂的丁酮衍生物 Download PDFInfo
- Publication number
- CN101677930A CN101677930A CN200880016988A CN200880016988A CN101677930A CN 101677930 A CN101677930 A CN 101677930A CN 200880016988 A CN200880016988 A CN 200880016988A CN 200880016988 A CN200880016988 A CN 200880016988A CN 101677930 A CN101677930 A CN 101677930A
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- CN
- China
- Prior art keywords
- isopropyl
- ketone
- methylcyclohexyl
- phenyl
- chemical compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 150000002894 organic compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- -1 2,4-dimethylpent-3-yl Chemical group 0.000 claims abstract description 25
- 238000001816 cooling Methods 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 7
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 6
- 125000002541 furyl group Chemical group 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 4
- 239000003507 refrigerant Substances 0.000 claims description 22
- 210000004877 mucosa Anatomy 0.000 claims description 11
- 230000035807 sensation Effects 0.000 claims description 8
- 210000002200 mouth mucosa Anatomy 0.000 claims description 7
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 3
- 125000005037 alkyl phenyl group Chemical group 0.000 abstract description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 1
- 125000005036 alkoxyphenyl group Chemical group 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 125000004076 pyridyl group Chemical group 0.000 abstract 1
- 239000000047 product Substances 0.000 description 23
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 15
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- 239000000499 gel Substances 0.000 description 12
- 239000000463 material Substances 0.000 description 11
- 235000015218 chewing gum Nutrition 0.000 description 9
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- 239000000376 reactant Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000002537 cosmetic Substances 0.000 description 7
- 239000006071 cream Substances 0.000 description 7
- 210000000214 mouth Anatomy 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 244000269722 Thea sinensis Species 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 150000003505 terpenes Chemical class 0.000 description 6
- 235000007586 terpenes Nutrition 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 235000013361 beverage Nutrition 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 235000013616 tea Nutrition 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229960001866 silicon dioxide Drugs 0.000 description 4
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 3
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- JHUYNQGHNWXETM-UHFFFAOYSA-M [Br-].[Mg+]CCCC1=CC=CC=C1 Chemical compound [Br-].[Mg+]CCCC1=CC=CC=C1 JHUYNQGHNWXETM-UHFFFAOYSA-M 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 230000001680 brushing effect Effects 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
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- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
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- 108010011485 Aspartame Proteins 0.000 description 2
- 239000004857 Balsam Substances 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- WEEGYLXZBRQIMU-UHFFFAOYSA-N Eucalyptol Chemical compound C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 244000018716 Impatiens biflora Species 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 235000006679 Mentha X verticillata Nutrition 0.000 description 2
- 235000002899 Mentha suaveolens Nutrition 0.000 description 2
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 2
- NFLGAXVYCFJBMK-UHFFFAOYSA-N Menthone Chemical compound CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000010358 acesulfame potassium Nutrition 0.000 description 2
- 239000000619 acesulfame-K Substances 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000000551 dentifrice Substances 0.000 description 2
- 235000021185 dessert Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000428 dust Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000015203 fruit juice Nutrition 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 2
- ZYTMANIQRDEHIO-KXUCPTDWSA-N isopulegol Chemical compound C[C@@H]1CC[C@@H](C(C)=C)[C@H](O)C1 ZYTMANIQRDEHIO-KXUCPTDWSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229930007503 menthone Natural products 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000019505 tobacco product Nutrition 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 239000001871 (1R,2R,5S)-5-methyl-2-prop-1-en-2-ylcyclohexan-1-ol Substances 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- STUUDCDCCITXBK-UHFFFAOYSA-N 2,3-dimethyl-2-propan-2-ylbutanal Chemical compound CC(C)C(C)(C=O)C(C)C STUUDCDCCITXBK-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical class CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- RCORSHSFJCXHTF-UHFFFAOYSA-N 2-ethenyl-1,3-dioxan-5-ol Chemical compound OC1COC(C=C)OC1 RCORSHSFJCXHTF-UHFFFAOYSA-N 0.000 description 1
- CTMTYSVTTGVYAW-FRRDWIJNSA-N 5-[(1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl]oxy-5-oxopentanoic acid Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)CCCC(O)=O CTMTYSVTTGVYAW-FRRDWIJNSA-N 0.000 description 1
- JGVWYJDASSSGEK-UHFFFAOYSA-N 5-methyl-2-propan-2-ylidenecyclohexan-1-ol Chemical compound CC1CCC(=C(C)C)C(O)C1 JGVWYJDASSSGEK-UHFFFAOYSA-N 0.000 description 1
- 244000153158 Ammi visnaga Species 0.000 description 1
- 235000010585 Ammi visnaga Nutrition 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 244000043261 Hevea brasiliensis Species 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
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- UJNOLBSYLSYIBM-WISYIIOYSA-N [(1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl] (2r)-2-hydroxypropanoate Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H](C)O UJNOLBSYLSYIBM-WISYIIOYSA-N 0.000 description 1
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- 230000001166 anti-perspirative effect Effects 0.000 description 1
- 239000003213 antiperspirant Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
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- 235000020279 black tea Nutrition 0.000 description 1
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- 229960005233 cineole Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 235000014510 cooky Nutrition 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
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- 230000001815 facial effect Effects 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000009569 green tea Nutrition 0.000 description 1
- 239000008269 hand cream Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 229940095045 isopulegol Drugs 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- LWLPYZUDBNFNAH-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CCC[CH2-] LWLPYZUDBNFNAH-UHFFFAOYSA-M 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
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- 239000001683 mentha spicata herb oil Substances 0.000 description 1
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- 239000002088 nanocapsule Substances 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- ZYTMANIQRDEHIO-UHFFFAOYSA-N neo-Isopulegol Natural products CC1CCC(C(C)=C)C(O)C1 ZYTMANIQRDEHIO-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000008935 nutritious Nutrition 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
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- 229920001542 oligosaccharide Polymers 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- CFJYNSNXFXLKNS-UHFFFAOYSA-N p-menthane Chemical compound CC(C)C1CCC(C)CC1 CFJYNSNXFXLKNS-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000011962 puddings Nutrition 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 230000001256 tonic effect Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/29—Saturated compounds containing keto groups bound to rings
- C07C49/303—Saturated compounds containing keto groups bound to rings to a six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/35—Ketones, e.g. benzophenone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/292—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with chromium derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
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Abstract
式(I)的清凉化合物和包含该化合物的产品组合物。其中R1选自氢、甲基、C1-C3烷氧基、苯基、C1-C3烷基苯基、C1-C3烷氧基苯基、噻吩基、吡啶基、呋喃基和吲哚基;R2选自氢和羟基,或R2与它连接的碳原子一起形成羰基;R3选自2,4-二甲基戊-3-基、2,3,4-三甲基戊-3-基、金刚烷基和2-异丙基-5-甲基-环己基-1-基。
Description
公开了清凉化合物,即赋予身体皮肤或黏膜清凉感觉的化合物。
在调味剂和香料工业中持续需要为使用者提供愉悦的清凉效果并且适用于各种产品,尤其是摄入品和局部用品的、具有独特清凉性质的化合物。
清凉化合物已经为本领域所公知,而且其广泛用于各种产品如食品、烟草制品、饮料、香口胶、洁齿剂、嗽口水和化妆品中。
已经发现了一类新型的清凉化合物。因此,此处公开了通过向皮肤或口腔黏膜上施用一定量的至少一种足以产生所需程度的清凉感觉的化合物而向皮肤或口腔黏膜提供清凉感觉的方法,该化合物包括式(I)的化合物:
其中R1选自氢、甲基、C1-C3烷氧基、苯基、C1-C3烷基苯基(例如甲基苯基、乙基苯基、异丙基苯基)、C1-C3烷氧基苯基(例如乙氧基苯基)、噻吩基、吡啶基(吡啶-2-基、吡啶-3-基、吡啶-4-基)、呋喃基和吲哚基;
R2选自氢和羟基,或R2与它连接的碳原子一起形成羰基;和
R3选自2,4-二甲基戊-3-基、2,3,4-三甲基戊-3-基、金刚烷基和2-异丙基-5-甲基-环己基-1-基(优选(1R,2S,5R)。
式(I)的化合物可包含一种或多种手性中心,因此其可以作为立体异构体的混合物存在,或者可以被拆分为异构体纯的形式。立体异构体的拆分为这些化合物的制备和纯化增加了复杂性,因此仅仅出于经济原因优选使用立体异构体混合物形式的化合物。但是,如果希望制备单独的立体异构体,则可以按照现有技术中已知的方法,例如制备HPLC和GC或通过立体选择合成。
非限制性实例为其中R3为2-异丙基-5-甲基-环己基-1-基的式(I)的化合物。
特别地,实施方案为选自如下的式(I)的化合物:1-((1R,2S,5R)-2-异丙基-5-甲基环己基)丁-1-酮、1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-苯基丁-1-酮、1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-(吡啶-2-基)丁-1-酮、5-异丙基-5,6-二甲基-1-苯基庚-4-酮、1-((2S,5R)-2-异丙基-5-甲基环己基)-4-甲氧基丁-1-酮和1-((2S,5R)-2-异丙基-5-甲基环己基)戊-1-酮。
式(I)的化合物可以用在施用于如口腔粘膜的黏膜上或皮肤上的产品中,以产生清凉感觉。“施用”意指任何形式的接触,例如口腔摄入、局部使用,或者对于烟草制品而言为吸入。在施用于皮肤的情况下,可以例如将化合物包括在乳霜或药膏中,或者包括在可喷射的组合物中。因此还提供向黏膜或皮肤提供清凉感觉的方法,其通过将包含有效量的上述化合物的产物施用于黏膜或皮肤。
施用于口腔黏膜的产品可以包括摄入口中并吞咽的食品和饮料,和并非因为其营养价值而被服用的产品,例如药片、片剂、嗽口水、喷喉剂、牙粉和香口胶。施用于皮肤的产品可以选自可施用于人体皮肤的香水、化妆品、美容产品如乳液、油、药膏和沐浴制剂,无论是医用或其他目的均可。因此,在另一方面提供一种组合物,其包含足以对与该组合物接触的皮肤或黏膜区域内的冷觉受体产生刺激从而促进所需的清凉效果的量的至少一种式(I)的化合物。通过将包含少于5000ppm,在某些实施方案中为50-3000ppm,如约500ppm的式(I)的化合物的产品,例如嗽口水或香口胶施用于黏膜,例如口腔黏膜可以实现清凉效果。如果用于饮料则添加约15ppm就可能足以实现冷却效果。用于美容产品,该产品可包含约50-约5000ppm。当时,应当理解本领域技术人员可能以上述范围之外的量采用上述式(I)的化合物,以实现感觉效果。
食品和饮料的特定实例可包括但不限于含酒精或不含酒精的饮料如果汁饮料、果汁、牛奶饮料、碳酸饮料、提神饮料和保健营养饮料;冷藏糖食品如冰淇淋和果汁冰糕;餐后甜点如果子冻和布丁;糖果如蛋糕、饼干、巧克力和香口胶;果酱;糖;面包;茶饮料如绿茶、红茶、甘菊茶、桑叶茶、路易保斯茶、薄荷茶;香皂;调料;速溶饮料;点心等。
局部产用品的进一步实例可包括但不限于皮肤护理化妆品如清洁棉纸、爽身粉、面霜、乳液、滋补品和凝胶、护手霜、护手和皮肤乳液、抗脂肪/苗条霜和乳液、乳液、香膏、凝胶、喷雾和乳霜;晒斑化妆品,包括防晒乳液、香膏、凝胶、喷雾和乳霜;晒后乳液、喷雾和乳霜;香皂、牙签、唇膏、沐浴制剂、除臭剂和止汗剂、洗面乳、按摩霜等。
因此,进一步提供选自施用于口腔黏膜的产品或施用于皮肤的产品中的至少一种的终产品,如局部用品、口腔护理产品、鼻部护理产品、化妆用品、可摄入产品和香口胶等,其中该终产物包含产品基质和有效量的至少一种本文中上面所定义的式(I)的清凉化合物。
上面描述的化合物可以单独使用或与本领域已知的其它清凉化合物结合使用,所述化合物例如为薄荷醇、薄荷酮、异胡薄荷醇、N-乙基对薄荷烷甲酰胺(WS-3)、N,2,3-三甲基-2-异丙基丁酰胺(WS-23)、乳酸薄荷酯、薄荷酮甘油缩醛琥珀酸单薄荷酯戊二酸单薄荷酯、甘油O-薄荷醇酯和2-仲丁基环己酮薄荷烷、樟脑、胡薄荷醇、桉树脑、薄荷油、薄荷油、荷兰薄荷油、桉树油、3-1-薄荷烷氧基丙烷-1,2-二醇、3-1-薄荷烷氧基-2-甲基丙烷-1,2-二醇、对薄荷烷-3,8-二醇、2-1-薄荷烷氧基乙-1-醇、3-1-薄荷烷氧基丙-1-醇和4-1-薄荷烷氧基丁-1-醇。清凉化合物的进一步实例可以在例如WO2005/049553、WO 2006/125334和WO 2007/019719中找到,将其引入作为参考。
简单地通过将化合物与产品直接混合就可以将化合物用在产品中,或者可以在之前的步骤中用捕集物质对其进行捕集,所述捕集物质例如为聚合物、胶囊、微胶囊和纳米胶囊、脂质体、膜形成物、诸如环状低聚糖的吸收剂,或者其可以化学键合在基质上,键合后的物质在经历诸如温度、酶等的外部刺激时易于释放清凉化合物,随后释放物再与产品混合。或者可以在使用醇或多羟基醇,例如甘油、丙二醇、triazethine和mygliol、天然橡胶如阿拉伯树胶,或表面活性剂如甘油脂肪酸酯和糖类脂肪酸酯来溶解、分散或稀释时将其加入。
上述化合物中的大部分本身是新的。因此,还提供了一种式(I)的化合物
其中R1选自氢、甲基、C1-C3烷氧基、苯基、C1-C3烷基苯基(例如甲基苯基、乙基苯基、异丙基苯基)、C1-C3烷氧基苯基(例如乙氧基苯基)、噻吩基、吡啶基(吡啶-2-基、吡啶-3-基、吡啶-4-基)、呋喃基和吲哚基;
R2选自氢和羟基,或R2与它连接的碳原子一起形成羰基;和
R3选自2,4-二甲基戊-3-基、2,3,4-三甲基戊-3-基、金刚烷基和2-异丙基-5-甲基-环己基-1-基(优选(1R,2S,5R);
条件是R1和R2不同时为氢;并且
如果R1为甲氧基且R2与它连接的碳原子一起形成羰基,则R3不为金刚烷基。
通过使相应的醛与合适的格氏试剂反应并随后在现有技术已知的条件下氧化,可以制备式(I)的化合物,其中R1具有如此性质,以至它不干扰格氏试剂,例如其为烷氧基、苯基、烷基苯基。
使用卤素-杂环如2-溴吡啶与合适炔的Sonogashira偶联,可以制备其中R1为杂环如吡啶的式(I)的化合物。
现在参考下列非限制性实施例对组合物和方法进行进一步描述。
这些实施例仅仅是为了说明的目的,应该理解本领域熟练技术人员在不脱离本发明精神和范围的情况下,可以进行改变和改进。应该理解所描述的实施方案不仅仅是可选方案,也可以结合。
实施例1:1-((1R,2S,5R)-2-异丙基-5-甲基环己基)丁-1-酮
a)1-((1R,2S,5R)-2-异丙基-5-甲基环己基)丁-1-醇
在0℃下向(1R,2S,5R)-2-异丙基-5-甲基环己烷甲醛(4.64g,27.6mmol)的THF(120mL)溶液中缓慢地添加丙基溴化镁(2M在THF中,28mL)。在进行反应并加温至室温超过1小时后,将其再次冷却到0℃。用1N HCl使反应淬灭并分配在盐水和MTBE之间。将有机层干燥(MgSO4)并浓缩。用硅胶色谱法纯化残余物得到所需的醇(1.65g)。
b)向1-((1R,2S,5R)-2-异丙基-5-甲基环己基)丁-1-醇(0.50g,2.4mmol)的二氯甲烷(2.5mL)溶液中添加活化的3埃分子筛(1.5g)和吡啶重铬酸盐(1.0g,3.5mmol)。将反应物在室温下整夜搅拌,然后通过硅胶垫过滤,将其用MTBE洗涤。在将有机溶液浓缩后,通过硅胶色谱法纯化残余物得到标题酮(379mg)。
1H NMR(300MHz,CDCl3)δ2.48-2.32(m,3H),1.75-1.52(m,7H),1.37-1.33(m,1H),1.04-0.87(m,12H),0.77(d,3H);13C NMR(75MHz,CDCl3)δ214.8,54.3,44.0,43.9,38.6,34.6,32.4,28.8,23.8,22.3,21.4,16.8,16.0,13.8。
实施例2:1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-苯基丁-1-酮
按照实施例1的一般步骤,从(1R,2S,5R)-2-异丙基-5-甲基环己烷甲醛和(3-苯基丙基)溴化镁开始制备标题化合物。
1H NMR(300MHz,CDCl3)δ7.30-7.15(m,5H),2.64-2.34(m,5H),1.91-1.50(m,8H),1.01-0.72(m,12H);13C NMR(75MHz,CDCl3)δ214.7,141.7,128.5,128.3,125.9,54.4,44.0,41.2,38.8,35.1,34.6,32.5,28.9,24.8,23.8,22.4,21.5,16.0。
实施例3:1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-(吡啶-2-基)丁-1-酮
a)1-((1R,2S,5R)-2-异丙基-5-甲基环己基)丁-3-炔-1-醇。
在0℃下向(1R,2S,5R)-2-异丙基-5-甲基环己烷甲醛(1.0g,6.0mmol)的THF(10mL)溶液中缓慢地添加炔丙基溴化镁(1M,8.9mmol)。在使反应加温至室温整夜后,添加1.5当量的另外的炔丙基溴化镁并使反应物搅拌另外6小时。将反应物再次冷却到0℃,然后用1N HCl淬灭并分配在盐水和MTBE之间。将有机层干燥(MgSO4)并浓缩。用硅胶色谱法纯化残余物得到所需的醇(0.47g)。
b)1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-(吡啶-2-基)丁-3-炔-1-醇
向圆底烧瓶中添加1-((1R,2S,5R)-2-异丙基-5-甲基环己基)丁-3-炔-1-醇(0.47g,2.3mmol)、三乙胺(10mL)、2-溴吡啶(0.28mL,2.7mmol)、双(三苯基膦)二氯化钯(II)(16mg,0.023mmol)和碘化铜(I)(9mg,0.045mmol)。在将该混合物搅拌并在60℃下整夜加热后,使其冷却到室温。将反应物直接与硅胶混合、浓缩并用硅胶色谱法纯化,得到所需的偶联产品(286mg)。
c)1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-(吡啶-2-基)丁-1-醇
使用氮气吹洗1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-(吡啶-2-基)丁-3-炔-1-醇(286mg,1.00mmol)的乙醇(6.0mL)溶液。添加在碳/钯(10%,100mg)并用氮气再次吹洗反应物。然后在氢气氛围下将反应物在室温下整夜搅拌。将反应物通过硅胶垫过滤并通过硅胶色谱法纯化,得到所需的氢化产品(190mg)。
d)1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-(吡啶-2-基)丁-1-酮
向1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-(吡啶-2-基)丁-1-醇(177mg,0.61mmol)的二氯甲烷(2.0mL)溶液中添加活化的3埃分子筛(0.75g)和吡啶重铬酸盐(0.27g,3.5mmol)。将反应物在室温下整夜搅拌,然后通过硅胶垫过滤,将其用MTBE洗涤。在将有机溶液浓缩后,通过硅胶色谱法纯化残余物得到标题酮(80mg)。
1H NMR(300MHz,CDCl3)δ8.53-8.51(m,1H),7.62-7.56(m,1H),7.17-7.08(m,2H),2.80(t,2H),2.59-2.40(m,3H),2.06-1.98(m,2H),1.71-1.53(m,5H),1.41-1.25(m,1H),1.02-0.93(m,3H),0.89-0.85(m,6H),0.74(d,3H);13C NMR(75MHz,CDCl3)δ214.5,161.5,149.2,136.3,122.8,121.0,54.4,44.0,41.2,38.7,37.5,34.6,32.4,28.9,23.8,23.3,22.3,21.4,16.0。
实施例4:5-异丙基-5,6-二甲基-1-苯基庚-4-酮
按照实施例1的-般步骤,从2-异丙基-2,3-二甲基丁醛和(3-苯基丙基)溴化镁开始制备标题化合物。
1H NMR(300MHz,CDCl3)δ7.32-7.19(m,5H),2.64(t,2H),2.41(t,2H),2.04(sep.,2H),1.88(quint,2H),1.09(s,3H),1.83(d,12H),1.41-1.25(m,1H);13C NMR(75MHz,CDCl3)δ215.9,142.0,128.4,128.3,125.8,56.3,41.3,35.3,32.9,25.0,18.2,17.6。
实施例5:1-((2S,5R)-2-异丙基-5-甲基环己基)-4-甲氧基丁-1-酮
按照实施例1的一般步骤,从(1R,2S,5R)-2-异丙基-5-甲基环己烷甲醛和(3-苯基丙基)溴化镁开始制备标题化合物。
1H NMR(300MHz,CDCl3)δ3.37(t,2H),3.31(s,3H),2.59-2.42(m,3H),1.87-1.54(m,8H),1.04-0.87(m,9H),0.77(d,3H);13C NMR(75MHz,CDCl3)δ214.5,71.7,58.4,54.6,43.9,38.7,38.3,34.6,32.4,28.9,23.8,23.3,22.3,21.4,16.0。
实施例6:1-((2S,5R)-2-异丙基-5-甲基环己基)戊-1-酮
按照实施例1的一般步骤,从(1R,2S,5R)-2-异丙基-5-甲基环己烷甲醛和溴化丁基镁开始制备标题化合物。
1H NMR(300MHz,CDCl3)δ2.47-2.36(m,3H),1.78-1.49(m,7H),1.34-1.27(m,3H),1.03-0.78(m,12H),0.76(d,3H);13C NMR(75MHz,CDCl3)δ215.1,54.4,44.0,41.8,38.7,34.6,32.5,28.9,25.5,23.8,22.4,22.4,21.4,16.0,13.9。
实施例7:清凉强度
由一组评审员品尝式(I)化合物的不同水溶液,并且指出哪个溶液与2ppm的薄荷醇溶液具有类似或略微高的清凉强度。结果示于表1。
表1:
化学品 | 浓度 | 气味 |
对比例:1-薄荷醇 | 2.0ppm | 薄荷香味 |
对比例:N-乙基对-薄荷烷甲酰胺(WS-3) | 1.5ppm | 无 |
1-((1R,2S,5R)-2-异丙基-5-甲基环己基)丁-1-酮(实施例1) | 2.0ppm | 无 |
1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-苯基丁-1-酮(实施例2) | 2.0ppm | 无 |
1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-(吡啶-2-基)丁-1-酮(实施例3) | 0.01ppm | 无 |
5-异丙基-5,6-二甲基-1-苯基庚-4-酮(实施例4) | 3.0ppm | 无 |
实施例8:在牙膏中的应用
a)对照物,薄荷油
不透明牙凝胶 99.20g
薄荷油,无萜 0.50g
糖精 0.30g
将化学品混合在牙凝胶中,将一条牙凝胶放在牙刷上并且给调查对象用来刷牙。用水漱口并将水吐出。调查对象口腔中的每一区域都感觉到清凉感。清凉感持续40分钟。
b)1-((1R,2S,5R)-2-异丙基-5-甲基环己基)丁-1-酮(实施例1)
不透明牙凝胶 99.15g
实施例1的化合物 0.05g
薄荷油,无萜 0.50g
糖精 0.30g
将化学品混合在牙凝胶中,将一条牙凝胶放在牙刷上并且给调查对象用来刷牙。用水漱口并将水吐出。调查对象口腔中的每一区域都感觉到强烈的清凉感。评定该清凉感高于对照物的并且持续72分钟。
c)1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-苯基丁-1-酮(实施例2)
不透明牙凝胶 99.15g
实施例2的化合物 0.05g
薄荷油,无萜 0.50g
糖精 0.30g
将化学品混合在牙凝胶中,将一条牙凝胶放在牙刷上并且给调查对象用来刷牙。用水漱口并将水吐出。调查对象口腔中的每一区域都感觉到强烈的清凉感。评定该清凉感高于对照物的并且持续70分钟。
实施例9:在香口胶中的应用
a)对照物,薄荷油
胶基Solsona-T 30g
山梨糖醇粉末 50.6g
麦芽糖醇糖浆85% 9g
甘露糖醇粉末 5g
甘油 5g
乙酰舒泛钾(CAS 55589-62-3) 0.09g
天冬甜素 0.21g
薄荷油,无萜 0.50g
将胶基和一半的山梨糖醇混合,添加麦牙糖醇糖浆并与胶料物质混合。添加余下的粉末(余下的为山梨糖醇、甘露糖醇、乙酰舒泛钾、天冬甜素)并混合约1分钟,然后添加甘油并将胶料物质混合约5分钟,以形成空白香口胶物质。将薄荷油加入到该物质中,使调查对象咀嚼一片所形成的胶(2g)20分钟并吐出。调查对象口腔中的每一区域都感觉到清凉感。清凉感持续50分钟。
b)1-((1R,2S,5R)-2-异丙基-5-甲基环己基)丁-1-酮
实施例1的化合物 0.05g
薄荷油,无萜 0.50g
将化学品和薄荷油加入到来自于实施例12a)的空白香口胶物质中,使调查对象咀嚼一片所形成的胶(2g)20分钟并吐出。调查对象口腔中的每一区域都感觉到清凉感。评定该清凉感比对照物的高49%并且持续超过60分钟。
c)1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-苯基丁-1-酮
实施例2的化合物 0.05g
薄荷油,无萜 0.50g
将化学品和薄荷油加入到来自于实施例12a)的空白香口胶物质中,使调查对象咀嚼一片所形成的胶(2g)20分钟并吐出。调查对象口腔中的每一区域都感觉到清凉感。评定该清凉感比对照物的高49%并且持续超过60分钟。
Claims (8)
2.根据权利要求1的用途,其中式(I)的化合物选自:1-((1R,2S,5R)-2-异丙基-5-甲基环己基)丁-1-酮、1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-苯基丁-1-酮、1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-(吡啶-2-基)丁-1-酮、5-异丙基-5,6-二甲基-1-苯基庚-4-酮、1-((2S,5R)-2-异丙基-5-甲基环己基)-4-甲氧基丁-1-酮和1-((2S,5R)-2-异丙基-5-甲基环己基)戊-1-酮。
3.通过向皮肤或黏膜施用至少一种如权利要求1中所定义的式(I)的化合物而向皮肤或黏膜提供清凉感觉的方法。
4.通过向皮肤或黏膜施用包含至少一种选自如权利要求1中所定义的式(I)的化合物的产品而向皮肤或黏膜提供清凉感觉的方法。
5.向皮肤或黏膜提供清凉感觉的产品,所述产品包含至少一种如权利要求1中所定义的式(I)的化合物。
6.选自施用到口腔粘膜的产品和施用到皮肤的产品中的产品,该产品包含产品基质和有效量的如权利要求1中所定义的式(I)的清凉化合物或其混合物。
8.根据权利要求7的化合物,其选自:1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-苯基丁-1-酮、1-((1R,2S,5R)-2-异丙基-5-甲基环己基)-4-(吡啶-2-基)丁-1-酮、5-异丙基-5,6-二甲基-1-苯基庚-4-酮、1-((2S,5R)-2-异丙基-5-甲基环己基)-4-甲氧基丁-1-酮和1-((2S,5R)-2-异丙基-5-甲基环己基)戊-1-酮。
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