CN101141890A - 清凉化合物 - Google Patents
清凉化合物 Download PDFInfo
- Publication number
- CN101141890A CN101141890A CNA2006800087988A CN200680008798A CN101141890A CN 101141890 A CN101141890 A CN 101141890A CN A2006800087988 A CNA2006800087988 A CN A2006800087988A CN 200680008798 A CN200680008798 A CN 200680008798A CN 101141890 A CN101141890 A CN 101141890A
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- China
- Prior art keywords
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- compound
- isopropyl
- carbon
- branched alkyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 50
- 238000001816 cooling Methods 0.000 title description 10
- 238000000034 method Methods 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 4
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 4
- 210000004400 mucous membrane Anatomy 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- 239000003507 refrigerant Substances 0.000 claims description 16
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 10
- -1 Isopropyl Isopropyl Methyl Isopropyl Isopropyl Ethyl Ethyl Chemical group 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 6
- 230000035807 sensation Effects 0.000 claims description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 6
- 210000000214 mouth Anatomy 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 150000003278 haem Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 235000019505 tobacco product Nutrition 0.000 claims description 3
- 125000006168 tricyclic group Chemical group 0.000 claims description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 9
- 235000013361 beverage Nutrition 0.000 abstract description 4
- 235000009508 confectionery Nutrition 0.000 abstract description 3
- 239000002537 cosmetic Substances 0.000 abstract description 3
- 239000000551 dentifrice Substances 0.000 abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 2
- 230000035597 cooling sensation Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- GUCPYIYFQVTFSI-UHFFFAOYSA-N 4-methoxybenzamide Chemical compound COC1=CC=C(C(N)=O)C=C1 GUCPYIYFQVTFSI-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 150000003851 azoles Chemical group 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 235000013305 food Nutrition 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
- 239000007788 liquid Substances 0.000 description 2
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- 150000002729 menthone derivatives Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 235000019477 peppermint oil Nutrition 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 150000003505 terpenes Chemical class 0.000 description 2
- 235000007586 terpenes Nutrition 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 2
- 239000000606 toothpaste Substances 0.000 description 2
- 229940034610 toothpaste Drugs 0.000 description 2
- 239000001871 (1R,2R,5S)-5-methyl-2-prop-1-en-2-ylcyclohexan-1-ol Substances 0.000 description 1
- RBMUAGDCCJDQLE-KXUCPTDWSA-N (1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexan-1-amine Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1N RBMUAGDCCJDQLE-KXUCPTDWSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- RBMUAGDCCJDQLE-ZDGBYWQASA-N (2s,5r)-5-methyl-2-propan-2-ylcyclohexan-1-amine Chemical compound CC(C)[C@@H]1CC[C@@H](C)CC1N RBMUAGDCCJDQLE-ZDGBYWQASA-N 0.000 description 1
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- RQXTZKGDMNIWJF-UHFFFAOYSA-N 2-butan-2-ylcyclohexan-1-one Chemical compound CCC(C)C1CCCCC1=O RQXTZKGDMNIWJF-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-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
- MDVYIGJINBYKOM-UHFFFAOYSA-N 3-[[5-Methyl-2-(1-methylethyl)cyclohexyl]oxy]-1,2-propanediol Chemical compound CC(C)C1CCC(C)CC1OCC(O)CO MDVYIGJINBYKOM-UHFFFAOYSA-N 0.000 description 1
- RBMUAGDCCJDQLE-UHFFFAOYSA-N 5-methyl-2-propan-2-ylcyclohexan-1-amine Chemical compound CC(C)C1CCC(C)CC1N RBMUAGDCCJDQLE-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 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
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 description 1
- ZBJCYZPANVLBRK-UHFFFAOYSA-N Menthone 1,2-glyceryl ketal Chemical compound CC(C)C1CCC(C)CC11OC(CO)CO1 ZBJCYZPANVLBRK-UHFFFAOYSA-N 0.000 description 1
- BLILOGGUTRWFNI-UHFFFAOYSA-N Monomenthyl succinate Chemical compound CC(C)C1CCC(C)CC1OC(=O)CCC(O)=O BLILOGGUTRWFNI-UHFFFAOYSA-N 0.000 description 1
- 239000005844 Thymol Substances 0.000 description 1
- 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
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001680 brushing effect Effects 0.000 description 1
- 229960005233 cineole Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940095045 isopulegol Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- NTWLHHBGBISWLH-UHFFFAOYSA-N n-(4,7,7-trimethyl-3-bicyclo[2.2.1]heptanyl)benzamide Chemical compound CC1(C)C(C2)CCC1(C)C2NC(=O)C1=CC=CC=C1 NTWLHHBGBISWLH-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 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
- CFJYNSNXFXLKNS-UHFFFAOYSA-N p-menthane Chemical compound CC(C)C1CCC(C)CC1 CFJYNSNXFXLKNS-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/20—Synthetic spices, flavouring agents or condiments
- A23L27/204—Aromatic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/20—Synthetic spices, flavouring agents or condiments
- A23L27/205—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/18—Treatment of tobacco products or tobacco substitutes
- A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
- A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances
- A24B15/301—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances by aromatic compounds
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/18—Treatment of tobacco products or tobacco substitutes
- A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
- A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances
- A24B15/36—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances containing a heterocyclic ring
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/18—Treatment of tobacco products or tobacco substitutes
- A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
- A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances
- A24B15/36—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances containing a heterocyclic ring
- A24B15/38—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances containing a heterocyclic ring having only nitrogen as hetero atom
- A24B15/385—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances containing a heterocyclic ring having only nitrogen as hetero atom in a five-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
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/42—Amides
-
- 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
-
- 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
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract
一种通过施加式(I)化合物而向身体皮肤或黏膜提供清凉感觉的方法，其中，X为H或(CH2)n－R，n为0或1，Y和Z独立地选自H、OH、苯基、C1－C4直链或支链烷基或C1－C4直链或支链烷氧基，或者X和Y一起形成选自－O－CH2－O－、－N＝CH－O－和－N＝CH－S－的二价基团，所述二价基团和与其相连的碳原子一起形成5－元环；和R为带有未成键电子的基团，R1为H或C1－C5支链烷基，R2和R3为C1－C4支链烷基，或者R2和R3一起形成最多具有10个碳的单环、二环或三环基团，条件是R1、R2和R3一起包括至少6个碳。可以将该化合物结合到产品中，例如洁齿剂、食品、糖果、饮料，以及化妆品和药物制剂中。
Description
本发明涉及一种提供清凉感觉的方法以及提供该作用的化合物。
清凉化合物，即赋予身体皮肤或黏膜清凉感觉的化学化合物，已经为本领域所公知，而且其广泛用于各种产品，例如食品、烟草制品、饮料、洁齿剂、漱口液和化妆品中。
一类相当成功的清凉化合物即为N-取代的对-薄荷烷甲酰胺。这些化合物的例子在例如英国专利GB1,421,744中进行了描述。
虽然已经成功地将现有技术中的一些化合物商业化，但是甲酰胺部分的复杂结构仍使其难以制备。这些化学品只能以高价提供，这就限制了其在消费产品中的使用。
现已发现，一类简单的式I的芳基甲酰胺是良好的清凉化合物，而且可以由可商购获得的苯甲酸容易地制备。因此，本发明提供一种通过施加式I化合物而向身体皮肤或黏膜提供清凉感觉的方法，
其中，
X为H或(CH2)n-R，n为0或1，Y和Z独立地选自H、OH、苯基、C1-C4直链或支链烷基或C1-C4直链或支链烷氧基，或者X和Y一起形成选自-O-CH2-O-、-N＝CH-O-和-N＝CH-S-的二价基团，所述二价基团和与其相连的碳原子一起形成5-元环，即，分别形成1，3-二氧戊环、1，3-_唑环或1，3-噻唑环；和
R为带有未成键电子的基团，R1为H、CH3、C2H5或C3-C5支链烷基，R2和R3为CH3，、C2H5或C3-C4支链烷基，或者R1、R2和R3中的两个或多个一起形成最多具有10个碳原子的单环、二环或三环基团，条件是R1、R2和R3一起包括至少6个碳。
R1、R2、R3和与其相连的碳一起可以为，例如对-薄荷基、冰片基或金刚烷基。
R1、R2、R3可以为手性或外消旋基团。
特定的化合物是其中R1为甲基且R2和R3为异丙基的化合物，以及其中R1、R2和R3全部为乙基的化合物。
特定的化合物是其中X位于4-位的那些化合物。其它的特定化合物是其中X位于4-位且Y和Z为H、OH、OMe或甲基的化合物，或者X和Y一起形成选自-O-CH2-O-、-N＝CH-O-和-N＝CH-S-的二价基团，从而和与其相连的碳原子一起形成5-元环，即，分别形成1，3-二氧戊环、1，3-_唑环或1，3-噻唑环的化合物。
带有未成键电子的特定基团R为卤素、OH、OMe、NO2、CN、Ac、SO2NH2、CHO、CO2H、CONH2、C1-C4烷基羧酸酯基如CO2Et、C1-C4烷基酰胺如CONHMe或杂环，例如：
特定的R1、R2和R3组合为：
| R1 | R2 | R3 |
| H | 冰片基 | |
| H | 3-对-薄荷基 | |
| H | 异丙基 | 异丙基 |
| 甲基 | 异丙基 | 异丙基 |
| 乙基 | 乙基 | 乙基 |
上述定义的许多化合物都是新的。因此，本发明的进一步的实施方案中提供式I的化合物：
其中
X、Y、Z、R1、R2、R3如上述定义，而且其中适用下列限制条件之一：
(a)R1和X不为H，且R1、R2、R3和与其相连的碳形成非环部分；
(b)R1为H，且R2、R3和与其相连的碳形成非环部分，R2、R3中仅有一个基团为异丙基或叔丁基；
(c)R1为H，R2和R3均为异丙基，X位于4-位且不为H、卤素、Me、MeO、NO2、芳基、亚甲基二芳基、N-(4-甲脒基(carbamimidoyl)-苯基)-6-甲氧基-吡啶-2-甲酰胺、N-(4-甲脒基-苯基)-苯甲酰胺、血红素衍生物，并且R不为吗啉、N’-苯基哌嗪、苯基硫醇、对-氯苯基硫醇、异喹啉、N-连接的磺酰胺衍生物或芳基，
(d)R1为H且R2和R3均为叔丁基；X不为H；
(e)R1为H，R2和R3和与其相连的碳一起形成对-薄荷烷环，且X、Y和Z不为H；
(f)R1为H，R2和R3和与其相连的碳一起形成对-薄荷烷环，Z为H，且X或Y均不为H或OH；
(g)R1为H，R2和R3和与其相连的碳一起形成对-薄荷烷环，Z为H，Y为OH且X不为甲酰胺或NO2；
(h)R1为H，R2和R3和与其相连的碳一起形成对-薄荷烷环，Z和Y均为H，且X不为H、COOH、喹啉基磺酰胺、CF3、亚甲基二芳基或血红素衍生物。
这样的化合物的特定例子为：在适用限制条件(a)、(b)和(c)时对应于式II、III和IV的那些化合物，在适用限制条件(e)、(f)、(g)和(h)时对应于式V的那些化合物：
有用的立体异构体的特定例子为(1R，2S，5R)-5-甲基-2-(1-甲基乙基)-环己胺[(1R，2S，5R)-薄荷基]和(2S，5R)-5-甲基-2-(1-甲基乙基)-环己胺[(2S，5R)-薄荷基]。
用胺或氯化铵盐对苯甲酰氯进行酰胺化可以容易地制备该化合物。根据Schopohl，M.等人，Synthesis 2003，17，2689，R1＝H的胺可以由其相应的酮制备。根据Jirgensons，A等人，Synthesis 2000，12，1709-1712，R1为C1-C5烷基的胺可以由其相应的醇制备。
本发明还提供一种向口服摄入、施用于皮肤或用在烟草制品中的产品提供清凉作用的方法，该方法包括在该产品中结合有效量的如上定义的化合物。本发明进一步提供一种向皮肤或口腔提供清凉感觉的组合物，该组合物包括有效量的如上定义的化合物。可以使用如上定义的化合物的组合物类型包括个人护理产品，例如洁齿剂(牙膏、牙凝胶、漱口液)、化妆品和药物制剂，例如片剂、锭剂、液体制剂、霜剂和喷雾剂、食品和糖果、硬糖、饮料等。
取决于化合物和组合物的性质、应用类型和所希望的清凉作用的程度和性质，所要求的“有效量”很自然地在非常大的范围内变化。结果，给定的任何量最多也只能是近似值。但是，常用浓度的最大值为5000ppm，也就是组合物的0.5重量％。作为普遍的规则，50-3000ppm都是固体组合物所要求的浓度。对于饮料而言，低至15ppm就可足以产生所希望的清凉作用。
除了清凉化合物之外，组合物还可以以所属技术领域公知的量含有本领域已知的、可用于这种组合物中的所有一般成分。
根据本发明，可以将不止一种的上述类型化合物用于组合物中。此外，该化合物可以与其它已知的和/或可商购的清凉化合物结合使用。这种化合物包括薄荷醇、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(Frescolat_MGA)、琥珀酸单-薄荷酯(Physcool_)、戊二酸单-薄荷酯、O-薄荷基丙三醇(CoolAct_10)和2-仲丁基环己酮(Freskomenthe_)。
完全采用常规方式就可以将该化合物结合到组合物中。
现在参考下列非限制性实施例对本发明作进一步地说明。
实施例1
薄荷基胺的制备
将41.69g羟基胺盐酸盐溶解在200mL水中。在冰浴冷却下加入40gNaOH颗粒。待NaOH溶解之后，经10分钟加入61.7gL-薄荷酮。在室温下将混合物搅拌70小时。用MTBE萃取含有白色固体球的该混合物两次。有机层用水和盐水洗涤，在MgSO4上干燥并浓缩，得到67g白色固体，其在冰浴冷却下于300mL MTBE中与12g氢化锂铝反应。在室温下搅拌混合物96小时。用丙酮和40mL HCl(1N)处理浅灰色的悬浮液。用HCl(37％)酸化淡黄色的上清液并用MTBE萃取两次。有机层用HCl(1N)洗涤。用NaOH颗粒将结合起来的水层中和至pH为13并用MTBE萃取两次。有机层用盐水洗涤，在MgSO4上干燥并浓缩，得到42.3g淡黄色的液体，其通过蒸馏纯化。
实施例2
1-甲基-1-异丙基异丁基氯化铵的制备
将18.1g 1-甲基-1-异丙基异丁基醇和15.74g氯乙腈溶解在27.2mL乙酸中并在冰浴中冷却混合物。经20分钟加入27.3g硫酸。在0℃下搅拌混合物1小时并在室温下再搅拌4小时。用冰将混合物骤冷并用MTBE萃取。有机层用NaHCO3、盐水洗涤两次，在MgSO4上干燥并浓缩，回收得到32.3g含有N-1-甲基-1-异丙基异丁基1-氯乙酰胺的黄色油，所含化合物具有下列性质：
1H NMR(300MHz，CDCl3)δppm(两个旋光异构体(rotomer))：6.4和6.05(宽s，1H)，3.92和3.97(d，2H)，2.09和1.93(m，2H)，1.37和1.32(d，3H)，0.93和0.84(m，12H)
13C NMR(75MHz，CDCl3)δppm(两个旋光异构体)：165，164.5，63.1，58.2，45.25，43.4，43.1，34.35，26.95，26.9，24.6，24.2，17.7，17.5，14.7，16.6，8.35
MS/EI：207(M+·)，205(M+·)，192，190，164，162，150，148，136，134，97
将该油与13.7g硫脲和50mL乙酸混合在250mL乙醇中。将混合物在回流下加热过夜。加入500mL水并在室温下搅拌悬浮液30分钟。加入NaOH颗粒用以将溶液调整至碱性pH。用戊烷萃取该淡黄色溶液三次，有机层用盐水洗涤并在MgSO4上干燥。加入1L溶于Et2O中的HCl(1M)，并在室温下搅拌混合物1小时。浓缩混合物得到5.3g白色结晶，其具有下列物理性质：
1H NMR(300MHz，CD3OD)δppm(两个旋光异构体)：2.12和2.02(七重峰，2H)，1.37和1.31(s，3H)，1.03(ddd，6H)，0.92(dd，6H)
13C NMR(75MHz，CD3OD)δppm(两个旋光异构体)：63.3，59.3，47.2，33.8，27.75，24.5，24.3，24.2，17.7，17.4，17.1，16.9，8.5
MS/EI：263(M+·)，248，220，192，152，135，107，92
实施例3
1，1-二乙基丙基胺的制备
按照类似于实施例2的方式处理16gl，1-二乙基丙醇，得到所希望的产物，其具有下列物理性质：
1H NMR(300MHz，CDCl3)δppm：1.33(qd，6H)，0.82(td，9H)
13C NMR(75MHz，CDCl3)δppm：53.2，31.4，7.6
MS/EI：114(M-1+)，98，86，69，56
实施例4
N-1-甲基-1-异丙基异丁基茴香酰胺的制备
将0.10g得自实施例2的1-甲基-1-异丙基异丁基氯化铵和0.20g吡啶溶解在5mL MTBE中并加入0.16g对-茴香酰氯。在室温下将混合物搅拌过夜。
使所得的悬浮液在MTBE和NaHCO3之间进行分配，并用MTBE萃取。有机层用盐水洗涤，在MgSO4上干燥并浓缩，得到0.38g粗产物，其通过在己烷中重结晶而纯化。
1H NMR(300MHz，CDCl3)δppm(两个旋光异构体)：8.1和7.68(d，2H)，6.99和6.90(d，2H)，5.88(宽s，1H)，3.83和3.9(s，3H)，2.19和2.04(七重峰，2H)，1.44和1.2(s，3H)，0.99(dd，6H)，0.86(dd，6H)
13C NMR(75MHz，CDCl3)δppm(两个旋光异构体)：166，163，133，128.5，128，114.5，113.5，57.9，55.3，49.7，44.8，27.0，26.9，25.5，24.7，24.4，17.9，8.5
实施例5
按照与实施例4相同的步骤合成表1中所列的化合物。
表1
实施例6：
清凉作用
根据下述的等强度(isointensity)法，由4-8人的受训鉴定小组确定化合物的清凉强度。
制备各种浓度的化合物水溶液并品尝。将每个溶液的清凉强度与参考化合物，即薄荷醇的2ppm水溶液进行比较。结果在下面列表中给出。
| 实施例 | 化合物名称 | 相对清凉强度 |
| 4 | N-1-甲基-1-异丙基异丁基茴香酰胺 | 1.1 |
| 5A | N-(1-甲基-1-异丙基丁基)苯甲酰胺 | 0.1 |
| 5B | N-(1-甲基-1-异丙基丁基)4-氰基苯甲酰胺 | 1.0 |
| 5C | N-(1-甲基-1-异丙基-异丁基)O-甲基对苯二甲酰胺 | 1.7 |
| 5D | N-(3-对-薄荷基)O-甲基对苯二甲酰胺 | 2.5 |
| 5E | N-(1，1-二乙基丙基)联苯基-4-甲酰胺 | 1.2 |
| 5F | N-(1-甲基-1-异丙基-异丁基)联苯基-4-甲酰胺 | 1.5 |
| 5G | N-(1-异丙基异丁基)3-氰基苯甲酰胺 | 0.2 |
| 5H | N-(1-异丙基-异丁基)苯并[1，3]二氧杂环戊烯基-5-甲酰胺 | 0.9 |
| 5K | N-(1-甲基-1-异丙基-异丁基)苯并[1，3]二氧杂环戊烯基-5-甲酰胺 | 0.9 |
| 5L | N-(1，1-二乙基丙基)苯并[1，3]二氧杂环戊烯基-5-甲酰胺 | 0.3 |
| 5M | N-冰片基苯甲酰胺 | 0.6 |
实施例7
在漱口液中的应用
乙醇95％ 177mL
山梨糖醇70％ 250g
实施例4的化合物，其为乙醇中的1％溶液 50mL
无萜薄荷油 0.300g
水杨酸甲酯 0.640g
桉油精 0.922g
百里酚 0.639g
苯甲酸 1.500g
Pluronic F127 5.000g
糖精钠 0.600g
柠檬酸钠 0.300g
柠檬酸 0.100g
水 适量至1升
混合所有成分。将30mL所得溶液放入口中，来回搅动、漱口并吐出。口腔的每一区域都感觉到令人愉快的清凉感。
实施例8
在牙膏中的应用
不透明牙凝胶 97.000g
实施例5B的化合物，其为PG中的2％溶液 2.500g
无萜薄荷油 0.500g
将各成分混合在牙凝胶中，将一条牙凝胶放在牙刷上并且给鉴定小组成员用来刷牙。用水漱口并将水吐出。鉴定小组成员口腔中的每一区域都感觉到持久的清凉感。
Claims (11)
1.一种通过施加式I化合物而向身体皮肤或黏膜提供清凉感觉的方法：
其中，
X为H或(CH2)n-R，n为0或1，Y和Z独立地选自H、OH、苯基、C1-C4直链或支链烷基或C1-C4直链或支链烷氧基，或者X和Y一起形成选自-O-CH2-O-、-N＝CH-O-和-N＝CH-S-的二价基团，所述二价基团和与其相连的碳原子一起形成5-元环；和
R为带有未成键电子的基团，R1为H或C1-C5支链烷基，R2和R3为C1-C4支链烷基，或者R2和R3一起形成最多具有10个碳的单环、二环或三环基团，条件是R1、R2和R3一起包括至少6个碳。
2.根据权利要求1的方法，其中R选自OH、OMe、NO2、CN、Ac、SO2NH2、CHO、CO2H、CONH2、C1-C4烷基羧酸酯、C1-C4烷基酰胺和杂环。
3.根据权利要求2的方法，其中杂环选自：
4.根据权利要求1的方法，其中R1为甲基且R2和R3为异丙基，和其中R1、R2和R3均为乙基。
5.根据权利要求1的方法，其中R1、R2和R3根据下表进行选择：
6.根据权利要求1的方法，其中X位于4-位。
7.根据权利要求6的方法，其中Y和Z独立地选自H、OH、OMe和甲基。
8.根据权利要求1的方法，其中在口服摄入、施用于皮肤或用于烟草制品中的产品中提供清凉作用。
9.一种向皮肤或口腔提供清凉感觉的组合物，其包括有效量的式I化合物：
其中，
X为H或(CH2)n-R，n为0或1，Y和Z独立地选自H、OH、苯基、C1-C4直链或支链烷基或C1-C4直链或支链烷氧基，或者X和Y一起形成选自-O-CH2-O-、-N＝CH-O-和-N＝CH-S-的二价基团，所述二价基团和与其相连的碳原子一起形成5-元环；和
R为带有未成键电子的基团，R1为H或C1-C5支链烷基，R2和R3为C1-C4支链烷基，或者R2和R3一起形成最多具有10个碳的单环、二环或三环基团，条件是R1、R2和R3一起包括至少6个碳。
10.式I化合物：
其中，
X、Y、Z、R1、R2、R3如权利要求1中所定义，而且其中适用下列限制条件之一：
(a)R1和X不为H，且R1、R2、R3和与其相连的碳形成非环部分；
(b)R1为H，且R2、R3和与其相连的碳形成非环部分，R2、R3中仅有一个基团为异丙基或叔丁基；
(c)R1为H，R2和R3均为异丙基，X位于4-位且不为H、卤素、Me、MeO、NO2、芳基、亚甲基二芳基、N-(4-甲脒基-苯基)-6-甲氧基-吡啶-2-甲酰胺、N-(4-甲脒基-苯基)-苯甲酰胺、血红素衍生物，并且R不为吗啉、N，-苯基哌嗪、苯基硫醇、对-氯苯基硫醇、异喹啉、N-连接的磺酰胺衍生物或芳基，
(d)R1为H且R2和R3均为叔丁基；X不为H；
(e)R1为H，R2和R3和与其相连的碳一起形成对-薄荷烷环，且X、Y和Z不为H；
(f)R1为H，R2和R3和与其相连的碳一起形成对-薄荷烷环，Z为H，且X或Y均不为H或OH；
(g)R1为H，R2和R3和与其相连的碳一起形成对-薄荷烷环，Z为H，Y为OH且X不为甲酰胺或NO2；
(h)R1为H，R2和R3和与其相连的碳一起形成对-薄荷烷环，Z和Y均为H，且X不为H、COOH、喹啉基磺酰胺、CF3、亚甲基二芳基或血红素衍生物。
11.根据权利要求10的化合物，其中在适用限制条件(a)、(b)和(c)时，该化合物对应于式II、III和IV之一，在适用限制条件(e)、(f)、(g)和(h)时，该化合物对应于式V：
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| US66480405P | 2005-03-24 | 2005-03-24 | |
| US60/664,804 | 2005-03-24 |
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| EP (1) | EP1860960A1 (zh) |
| JP (1) | JP2008535806A (zh) |
| KR (1) | KR20070115975A (zh) |
| CN (1) | CN101141890A (zh) |
| BR (1) | BRPI0609447A2 (zh) |
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| CN110981862A (zh) * | 2019-12-11 | 2020-04-10 | 中国烟草总公司郑州烟草研究院 | 一种化合物及其合成方法、应用、烟草制品 |
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| JP4786544B2 (ja) | 2003-11-21 | 2011-10-05 | ジボダン エス エー | Ｎ置換ｐ−メンタンカルボキサミド類 |
| ES2668361T3 (es) | 2005-08-15 | 2018-05-17 | Givaudan Sa | Compuestos refrigerantes |
| EP1940791B1 (en) | 2005-10-25 | 2009-09-16 | Givaudan SA | Organic compounds |
| BRPI0721140A2 (pt) * | 2006-12-20 | 2014-04-01 | Givaudan Nederland Services Bv | P-mentano-3-carboxamida n-substituída e usos da mesma. |
| EP1989944B1 (de) | 2007-05-08 | 2010-06-02 | Symrise GmbH & Co. KG | Substituierte Cyclopropancarbonsäure(3-methyl-cyclohexyl)amide als Geschmacksstoffe |
| US8655677B2 (en) * | 2007-06-12 | 2014-02-18 | Bruce Reiner | Productivity workflow index |
| WO2008151460A2 (en) * | 2007-06-13 | 2008-12-18 | Givaudan Sa | Cooling compounds |
| EP2064959B1 (de) * | 2007-10-31 | 2012-07-25 | Symrise AG | Aromatische Neo-Menthylamide als Geschmacksstoffe |
| WO2009076792A1 (en) * | 2007-12-19 | 2009-06-25 | Givaudan Sa | Cooling compounds |
| WO2009089641A1 (en) * | 2008-01-17 | 2009-07-23 | Givaudan Sa | Benzimidazole derivatives and their use as cooling agents |
| US8664261B2 (en) | 2009-05-05 | 2014-03-04 | Givaudan S.A. | Organic compounds having cooling properties |
| GB201103103D0 (en) | 2011-02-23 | 2011-04-06 | Givaudan Sa | Organic compounds |
| US10392371B2 (en) | 2015-10-01 | 2019-08-27 | Senomyx, Inc. | Compounds useful as modulators of TRPM8 |
| BR112019023827A2 (pt) | 2017-05-15 | 2020-06-09 | Firmenich & Cie | composições que compreendem óleos essenciais |
| US11389383B2 (en) | 2017-12-20 | 2022-07-19 | Firmenich Sa | Oral care compositions |
| JP7431800B2 (ja) | 2018-08-10 | 2024-02-15 | フィルメニッヒ インコーポレイテッド | Ｔ２ｒ５４の拮抗薬ならびにその組成物および使用 |
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| US4150052A (en) * | 1971-02-04 | 1979-04-17 | Wilkinson Sword Limited | N-substituted paramenthane carboxamides |
| GB1421744A (en) | 1972-04-18 | 1976-01-21 | Wilkinson Sword Ltd | Aliphatic n-substituted tertiary amides possessing physiological cooling activity |
| NZ597500A (en) * | 2003-08-06 | 2014-08-29 | Senomyx Inc | Novel flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof |
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| CN110981862A (zh) * | 2019-12-11 | 2020-04-10 | 中国烟草总公司郑州烟草研究院 | 一种化合物及其合成方法、应用、烟草制品 |
| CN110981862B (zh) * | 2019-12-11 | 2021-03-12 | 中国烟草总公司郑州烟草研究院 | 一种化合物及其合成方法、应用、烟草制品 |
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| WO2006099762A1 (en) | 2006-09-28 |
| KR20070115975A (ko) | 2007-12-06 |
| CA2597961A1 (en) | 2006-09-28 |
| MX2007010576A (es) | 2007-10-04 |
| JP2008535806A (ja) | 2008-09-04 |
| BRPI0609447A2 (pt) | 2010-04-06 |
| US20080319055A1 (en) | 2008-12-25 |
| EP1860960A1 (en) | 2007-12-05 |
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