CN101257949A - 清凉化合物 - Google Patents
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- CN101257949A CN101257949A CNA200680029790XA CN200680029790A CN101257949A CN 101257949 A CN101257949 A CN 101257949A CN A200680029790X A CNA200680029790X A CN A200680029790XA CN 200680029790 A CN200680029790 A CN 200680029790A CN 101257949 A CN101257949 A CN 101257949A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 57
- 238000001816 cooling Methods 0.000 title claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 230000000694 effects Effects 0.000 claims abstract description 9
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 6
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000006168 tricyclic group Chemical group 0.000 claims description 5
- WEEGYLXZBRQIMU-UHFFFAOYSA-N Eucalyptol Chemical group C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims 1
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- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 6
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- 229940041616 menthol Drugs 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
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- 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
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- 230000003595 spectral effect Effects 0.000 description 3
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
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- 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
- 230000005923 long-lasting effect Effects 0.000 description 2
- 229930007503 menthone Natural products 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 235000019615 sensations Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003505 terpenes Chemical class 0.000 description 2
- 235000007586 terpenes Nutrition 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
- 229940034610 toothpaste Drugs 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- 239000001871 (1R,2R,5S)-5-methyl-2-prop-1-en-2-ylcyclohexan-1-ol Substances 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
- RQXTZKGDMNIWJF-UHFFFAOYSA-N 2-butan-2-ylcyclohexan-1-one Chemical compound CCC(C)C1CCCCC1=O RQXTZKGDMNIWJF-UHFFFAOYSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-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
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- 244000131522 Citrus pyriformis Species 0.000 description 1
- 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 1
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 description 1
- NFLGAXVYCFJBMK-UHFFFAOYSA-N Menthone Chemical compound CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-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
- 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
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 229960005233 cineole Drugs 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229940095045 isopulegol Drugs 0.000 description 1
- -1 menthone glycerol acetal Chemical class 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004877 mucosa Anatomy 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
- 230000002688 persistence Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000014214 soft drink Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- 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
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
- A23L2/56—Flavouring or bittering agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
- A61K2800/24—Thermal properties
- A61K2800/244—Endothermic; Cooling; Cooling sensation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/92—Oral administration
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Epidemiology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Birds (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Cosmetics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Medicinal Preparation (AREA)
- Fats And Perfumes (AREA)
Abstract
一种向产品提供清凉效果的方法，包括将至少一种式I化合物结合至产品中，其中，m为0－2的数，X、Y和Z独立地选自H、卤素、OH、Me、Et、MeO和EtO，R1、R2和R3一起包含至少6个碳，其以如下方式进行选择：(a)(i)R1选自H、Me、Et、异丙基和C4－C5支链烷基；和(ii)R2和R3独立地选自Me、Et、异丙基和C4－支链烷基；或(b)R1、R2和R3中的任意两个或全部一起形成具有最多10个碳的单环、二环或三环基团。所述化合物向施用于皮肤或口服摄入的组合物，例如牙膏、漱口液、食品、饮料、糖果、烟草制品、皮肤乳霜和软膏赋予实质性的清凉效果。
Description
本发明涉及清凉化合物。
清凉化合物，即赋予皮肤或身体黏膜清凉感觉的化学化合物，已经为本领域所公知，而且广泛用于各种产品，例如食物、烟草制品、饮料、洁齿剂、漱口剂和化妆用品中。
一类相当成功的清凉化合物为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GB 1,351,761、GB 1,351,762和美国专利US 4,150,052中进行了描述。
现在发现，特别选择的这种化合物显示令人惊讶地强烈和长效的清凉作用。因此，提供一种向产品提供清凉作用的方法，其包括将至少一种式I化合物结合至产品中，
其中，m为0-2的数，X、Y和Z独立地选自H、卤素、OH、Me、Et、MeO和EtO，R1、R2和R3一起包含至少6个碳，其以如下方式进行选择：
(a)(i)R1选自H、Me、Et、异丙基和C4-C5支链烷基；和
(ii)R2和R3独立地选自Me、Et、异丙基和C4-支链烷基；或
(b)R1、R2和R3中的任意两个或全部一起形成具有最多10个碳的单环、二环或三环基团。
Me定义为甲基，Et定义为乙基。
上述(b)中定义的环状基团的例子包括3-对-薄荷基、冰片基和金刚烷基。
式(I)化合物可以包括一个或多个手性中心，这样其就可能作为立体异构体混合物而存在，或者可以被拆分为异构纯的形式。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作为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，则可以根据本领域已知的方法，例如制备性HPLC和GC或通过立体选择性合成法来实现该目的。
在一些实施方案中，所述化合物为其中X、Y、Z为H、OH、Me或OMe的化合物。在某些实施方案中，所述化合物为其中m为2，X、Y和Z为H或Me，且R1、R2和R3按照表1进行选取而形成的化合物。
表1：示例性R1、R2和R3基团
特别有效的化合物是其中R1为H，且R2和R3一起形成3-对-薄荷基环的化合物。
有效的化合物的例子为(1R，2S，5R)-2-异丙基-5-甲基-N-(吡啶烷基)环己烷甲酰胺和(2S，5R)-2-异丙基-5-甲基-N-(吡啶烷基)环己烷甲酰胺。这些化合物的特殊例子为(1R，2S，5R)-2-异丙基-5-甲基-N-(2-(吡啶-4-基)乙基)环己烷甲酰胺和(2S，5R)-2-异丙基-5-甲基-N-(2-(吡啶-4-基)乙基)环己烷甲酰胺。
某些所述化合物是新的。因此提供如上所述的式I化合物，其中m＝2，X、Y、Z、R1、R2、R3具有上述含义，条件是当R2和R3形成对-薄荷基环时，R1、X、Y和Z中的至少一个不为H。
还提供根据上述式I的下述化合物，其中X、Y、Z、R1为H，R2，R3具有上述含义。
在某些实施方案中，R1为氢，R2和R3独立地选自Me、Et和C3-C4支链烷基；或者R1、R2和R3一起形成最多具有10个碳的单环、二环或三环基团。
通过本领域已知的方法可以容易地制备和分离所述化合物。
它们与现有技术中类似化合物的区别在于其出人意料的高清凉效果(最多可以比类似的已知化合物高100倍)和该清凉效果的长效性。这些化合物在油性溶剂例如薄荷油，和酸性水溶液例如软饮料中还具有高溶解性。这些特征扩展了清凉化合物在更多产品中的用途。
所述化合物可以在施用于口腔或皮肤的产品中使用，以便得到清凉感。“施用”是指任何形式的接触，例如口服摄取，或者对于烟草制品而言是指吸入。当施用于皮肤时，可以例如在乳霜或软膏或者在可喷式组合物中包含该化合物。因此，本发明还提供一种给口腔或皮肤提供清凉作用的方法，包括向其施用含有上述化合物的产品。
可以使用所述化合物的产品的范围非常大，仅作为例子而言包括洁齿剂例如牙膏和牙凝胶、漱口液、食品、饮料、糖果、烟草制品、皮肤乳霜和软膏，既包括化妆品也包括医药制品。
所述化合物可以单独使用也可以与本领域已知的其他清凉化合物结合使用，所述其他清凉化合物例如为
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(FrescolatTM ML)、薄荷酮甘油乙缩醛(FrescolatTM MGA)、琥珀酸单薄荷酯(PhyscoolTM)、戊二酸单薄荷酯、甘油单薄荷酯(CoolActTM 10)、薄荷基-N，N-二甲基琥珀酰胺酸酯和2-仲丁基环己酮(FreskomentheTM)。
现在借助下列非限制性实施例对某些实施方案做进一步描述。
实施例1
N-(4-吡啶基)对-薄荷烷甲酰胺[(1R，2S，5R)-2-异丙基-5-甲基-N-(2-(吡啶-4-基)乙基)环己烷甲酰胺]的制备
向烧瓶中加入4.7g(50mmol)吡啶-4-基胺、4.04mL吡啶和100mLMtBE。经5分钟向该混合物中滴加10g对-薄荷烷甲酰氯。搅拌反应混合物24小时。向反应混合物中加入50mL水。分离混合物。有机层用50mL水和50mL盐水洗涤。在MgSO4上干燥有机层。真空蒸发溶剂得到粗产物，其从己烷中重结晶而得到6.2g希望的产品，其具有下列光谱性质：
MS：260([M+·])，217，149，121，95
1H NMR(300MHz；CDCl3)δ：8.49(d，2H)，7.77(s，1H)，7.52(d，2H)，2.22(td，1H)，1.9(宽d，2H)，1.85-1.57(m，3H)，1.44-1.22(m，2H)，1.16-0.99(m，2H)，0.94(d，3H)，0.91(d，3H)，0.81(d，3H)
13C NMR(75MHz；CDCl3)δ：175.4，150.5，145.0，113.4，50.7，44.3，39.25，34.3，32.1，28.7，23.7，22.1，21.2，16.1
实施例2
N-(2-吡啶-2-基乙基)对-薄荷烷甲酰胺[(1R，2S，5R)-2-异丙基-5-甲基-N-(2-(吡啶-2-基)乙基)环己烷甲酰胺]的制备：
按照与实施例1中所述的类似的方法制备得到希望的产品，其具有下列光谱性质：
MS：288([M+·])，273，245，149，121，95
1H NMR(300MHz；DMSO)δ：8.53(d，1H)，7.62(td，1H)，7.16(m，2H)，6.43(s，1H)，3.67(九重峰，2H)，3.00(t，2H)，1.95(td，1H)，1.84-1.53(m，4H)，1.47(宽t，1H)，1.4-1.1(m，2H)，0.87(d，3H)，0.84(d，3H)，0.66(d，3H)
13C NMR(75MHz；DMSO)δ：175.8，159.7，148.9，136.7，123.6，121.55，49.8，44.3，39.4，38.35，36.9，34.6，32.3，28.55，23.9，22.3，21.3，15.95
实施例3
2-异丙基-2，3-二甲基-N-(2-(吡啶-2-基)乙基)丁酰胺的制备：
按照与实施例1中所述的类似的方法，使用2-异丙基-2，3-二甲基丁酰氯制备得到希望的产品，其具有下列光谱性质：
MS：262([M+])，220，205，149，121，106，93
1H NMR(300MHz；CDCl3)8.53(d，1H)，7.63(t，1H)，7.16(m，2H)，6.69(s，1H)，3.67(dd，2H)，2.99(t，2H)，1.96(m，2H)，0.96(s，3H)，0.85(d，6H)，0.79(d，6H)
13C(75MHz；CDCl3)175.6，160.0，149.1，136.6，123.4，121.5，51.4，38.4，36.9，32.6，18.1，17.4，14.1
实施例4
对清凉效果的评价
让一小组鉴定组人员品尝清凉化合物的各种水溶液，并指出哪个溶液与2ppm的薄荷醇溶液具有类似或稍高的清凉强度。让同一鉴定组品尝选定浓度下的这些溶液并在规律的时间间隔下记录清凉强度，直至口中不再有清凉感觉为止。结果示于表2中。
表2：清凉强度和持续性试验
| 化合物 | 浓度 | 持续时间 |
| l-薄荷醇 | 2.0ppm | 35分钟 |
| N-乙基对-薄荷烷甲酰胺(WS-3) | 1.5ppm | 57分钟 |
| 式I，m＝0，X＝Y＝Z＝R1＝H，R2+R3＝对薄荷基(实施例1化合物) | 0.5ppm | 50分钟 |
| 式I，m＝2，X＝Y＝Z＝R1＝H，R2+R3＝对薄荷基(实施例2化合物) | 0.02ppm | 60分钟 |
| 式I，m＝2，X＝Y＝Z＝H，R1＝甲基，R2＝R3＝异丙基(实施例3化合物) | 0.4ppm |
从表2中可以看出，式I化合物比参考性清凉化合物薄荷醇的强度和持续时间高出最多100倍。式I化合物还比现有技术中最好的清凉化合物WS-3强烈许多。
在第二个试验中，让同一鉴定组品尝具有不同浓度的各种化合物溶液，并指出哪个溶液与2ppm的薄荷醇溶液具有类似或稍高的清凉强度。这就是“等强浓度”。结果示于表3中。
表3：当R2+R3＝对-薄荷烷，R1＝X＝Y＝Z＝H时化合物的强度
| m值(链长) | 主要部分所在的环位置 | 等强浓度 |
| 0 | 2或6 | 0.2ppm |
| 0 | 3或5 | 0.4ppm |
| 0 | 4 | 0.5ppm |
| 1＊ | 2或6＊ | 0.67ppm |
| 1 | 3或5 | 0.25ppm |
| 1 | 4 | 0.2ppm |
| 2 | 2或6 | 0.02ppm |
| 2 | 3或5 | 0.004ppm |
| 2＊＊ | 4＊＊ | 0.05ppm |
＊实施例1的化合物
＊＊实施例2的化合物
从表2和3中可以看出，具有不同链长和取代形式的式I化合物都比参考性清凉化合物薄荷醇和WS-3具有更低的使用水平。
实施例5
在漱口液中的应用
乙醇95％ 177mL
山梨糖醇70％ 250g
实施例1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
PluronicTM F127非离子表面活性剂 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。口腔的每一区域和嘴唇都感觉到冰凉感。
实施例6
在牙膏中的应用
不透明牙凝胶 97.000g
实施例2的化合物，其为在丙二醇中的2％溶液 2.500g
无萜薄荷油 0.500g
将化合物混合在牙凝胶中，将一条牙凝胶放于牙刷上并且给鉴定组人员用于刷牙。用水漱口并且将水吐出。鉴定组人员口腔中的每一区域都感觉到强烈的清凉感。
实施例7
在饮料中的应用
将1.5mg实施例2的化合物溶解在355mL(12 fl oz.)的澄清柠檬/酸橙苏打罐中。鉴定组人员在口腔中体验到一定时间令人愉悦的清凉感，无喉咙灼烧感。未体察到不愉快的余味。
虽然通过上面的详细描述和前面的实施例对本发明进行了描述，但是这些实施例仅仅用于说明目的，应该理解在不偏离本发明的精神和范围的情况下本领域熟练技术人员可以进行变化和变型。应该理解上述实施方案不仅可以相互替换而且可以结合起来。
Claims (6)
1、一种向产品提供清凉效果的方法，包括将至少一种式I化合物结合至产品中，
其中，m为0-2的数，X、Y和Z独立地选自H、卤素、OH、Me、Et、MeO和EtO，R1、R2和R3一起包含至少6个碳，其以如下方式进行选择：
(a)(i)R1选自H、Me、Et、异丙基和C4-C5支链烷基；和
(ii)R2和R3独立地选自Me、Et、异丙基和C4-支链烷基；或
(b)R1、R2和R3中的任意两个或全部一起形成具有最多10个碳的单环、二环或三环基团。
2、根据权利要求1的方法，其中在该化合物中X、Y、Z独立地选自H、OH、Me和OMe。
3、根据权利要求1的方法，其中m为2；X、Y和Z独立地选自H和Me，R1、R2和R3根据下表进行选择：
4、根据权利要求1的方法，其中R1为H，R2和R3一起形成3-对-薄荷基环。
5、一种适于施用于皮肤或口服摄入的产品，其包括至少一种根据式I的化合物：
其中，m为0-2的数，X、Y和Z独立地选自H、卤素、OH、Me、Et、MeO和EtO，R1、R2和R3一起包含至少6个碳，其以如下方式进行选择：
(a)(i)R1选自H、Me、Et、异丙基和C4-C5支链烷基；和
(ii)R2和R3独立地选自Me、Et、异丙基和C4-支链烷基；或
(b)R1、R2和R3中的任意两个或全部一起形成具有最多10个碳的单环、二环或三环基团。
6、式I化合物：
其中，m＝2，X、Y和Z独立地选自H、卤素、OH、Me、Et、MeO和EtO，R1、R2和R3一起包含至少6个碳，其以如下方式进行选择：
(a)(i)R1选自H、Me、Et、异丙基和C4-C5支链烷基；和
(ii)R2和R3独立地选自Me、Et、异丙基和C4-支链烷基；或
(b)R1、R2和R3中的任意两个或全部一起形成具有最多10个碳的单环、二环或三环基团；
条件是当R2和R3形成对-薄荷烷环时，R1、X、Y和Z中的至少一个不为H。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106860034A (zh) * | 2011-02-23 | 2017-06-20 | 奇华顿股份有限公司 | 有机化合物 |
| CN106860034B (zh) * | 2011-02-23 | 2020-05-19 | 奇华顿股份有限公司 | 有机化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| US11059783B2 (en) | 2021-07-13 |
| JP5383191B2 (ja) | 2014-01-08 |
| US10221136B2 (en) | 2019-03-05 |
| BRPI0616821B1 (pt) | 2022-06-07 |
| JP2009507778A (ja) | 2009-02-26 |
| EP1917074B1 (en) | 2018-02-28 |
| WO2007019719A1 (en) | 2007-02-22 |
| US20190194134A1 (en) | 2019-06-27 |
| US20100035938A1 (en) | 2010-02-11 |
| CN101257949B (zh) | 2011-01-19 |
| US20170008845A1 (en) | 2017-01-12 |
| EP1917074A1 (en) | 2008-05-07 |
| US9452982B2 (en) | 2016-09-27 |
| ES2668361T3 (es) | 2018-05-17 |
| BRPI0616821A2 (pt) | 2012-04-24 |
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