CN101132833A - 引起清凉感的羧酸酰胺 - Google Patents
引起清凉感的羧酸酰胺 Download PDFInfo
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- CN101132833A CN101132833A CNA2006800066568A CN200680006656A CN101132833A CN 101132833 A CN101132833 A CN 101132833A CN A2006800066568 A CNA2006800066568 A CN A2006800066568A CN 200680006656 A CN200680006656 A CN 200680006656A CN 101132833 A CN101132833 A CN 101132833A
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- carboxylic acid
- amide
- phenyl
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- methyl
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 title description 3
- 230000035597 cooling sensation Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 37
- -1 2-isopropyl-5-methyl-cyclohexyl Chemical group 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 210000000214 mouth Anatomy 0.000 claims description 10
- 239000003507 refrigerant Substances 0.000 claims description 10
- AXKGIPZJYUNAIW-UHFFFAOYSA-N (4-aminophenyl)methanol Chemical compound NC1=CC=C(CO)C=C1 AXKGIPZJYUNAIW-UHFFFAOYSA-N 0.000 claims description 9
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 claims description 9
- IBDVYGIGYPWWBX-UHFFFAOYSA-N 1-methyl-3-propan-2-ylcyclopentane-1-carboxylic acid Chemical compound CC(C)C1CCC(C)(C(O)=O)C1 IBDVYGIGYPWWBX-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 6
- 239000003574 free electron Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003851 azoles Chemical class 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 229940112822 chewing gum Drugs 0.000 claims description 3
- 235000015218 chewing gum Nutrition 0.000 claims description 3
- 239000002537 cosmetic Substances 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 claims description 2
- 230000002500 effect on skin Effects 0.000 claims description 2
- 150000003217 pyrazoles Chemical class 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 18
- 150000001721 carbon Chemical group 0.000 description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 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
- 239000000499 gel Substances 0.000 description 3
- 125000006091 1,3-dioxolane group Chemical class 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 210000002200 mouth mucosa Anatomy 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant 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
- 239000000606 toothpaste Substances 0.000 description 2
- 229940034610 toothpaste Drugs 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- NFLGAXVYCFJBMK-RKDXNWHRSA-N (+)-isomenthone Natural products CC(C)[C@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-RKDXNWHRSA-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
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-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
- 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
- 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
- 239000005711 Benzoic acid Substances 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
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-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
- 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
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960005233 cineole Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229940095045 isopulegol Drugs 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229930007503 menthone Natural products 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 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
- 230000000050 nutritive effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 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
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 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
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 235000019505 tobacco product Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- A23G4/00—Chewing gum
- A23G4/06—Chewing gum characterised by the composition containing organic or inorganic 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
- A61K8/40—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
- 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
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/61—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
-
- 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
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Birds (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及式(I)的清凉化合物,其中R1、R2、R3、X、Y、Z和m与说明书中的定义相同。本发明还涉及制备所述化合物的方法和包括所述化合物的产品组合物。
Description
本发明涉及清凉化合物,即给皮肤和口腔黏膜提供生理清凉作用的化合物。本发明进一步涉及所述化合物的制备方法和包括所述化合物的产品组合物。
在调味剂和香料工业中,对具有独特的清凉感觉的化合物正有不断的需求,这种化合物为使用者提供愉快的清凉作用而且其非常适用于各种产品,特别是可摄取和局部用的产品。
英国专利GB1,421,744中报导发现了具有生理清凉作用的简单的N-取代酰胺。这些化合物是多种多样的,因为其可以完全通过合成方式制得。与美国专利US 4,150,052中描述的N-取代的对-薄荷烷甲酰胺不同,其原料并不依赖于天然来源。
已经惊讶地发现一类特定的甲酰胺显示出强烈的清凉效果。因此,本发明的一个方面涉及式I化合物作为清凉剂的用途:
其中,
X为(CH2)n-R,其中R为包括至少一个自由电子对的基团并且n为0或1;和
Y和Z独立地选自H、OH、C1-C4烷基(例如甲基、乙基、异丙基)和C1-C4烷氧基(例如甲氧基和乙氧基);
或者
X和Y一起形成二价基团,所述二价基团选自-O-CH2-O-、-N=CH-O-和-N=CH-S-并和与其相连的碳原子一起形成5-元环,即分别为1,3-二氧戊环、1,3-唑环和1,3-噻唑环;和
Z选自H、OH、C1-C4烷基(例如甲基、乙基和异丙基)和C1-C4烷氧基(例如甲氧基和乙氧基);
m为0、1或2;
R1为H或C1-C4烷基,优选H或甲基;和
R2和R3和与其相连的碳原子一起形成3-10元,优选5-7元单-或双环碳环(carboxylic ring),例如,环己基、环戊基、二环[2.2.1]庚基和二环[2.2.1]庚烯基,其任选被含有最多4个碳原子,优选1-3个碳原子的烷基(例如叔丁基、异丙基、甲基)取代,并且该环可以包括一个或多个氧原子,例如苯并[1,3]二氧杂环戊烯基;条件是R2和R3和与其相连的碳原子一起不为2-异丙基-5-甲基-环己基;
或者
R1、R2和R3和与其相连的碳原子一起形成6-10元三环碳环,其任选被含有最多4个碳原子,优选1-3个碳原子的烷基(例如叔丁基、异丙基、甲基)取代,并且该环可以包括一个或多个氧原子,优选R1、R2和R3和与其相连的碳原子一起为金刚烷基。
式I化合物可以包括若干个手性中心,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。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HPLC和GC、结晶或者立体选择性合成法来进行合成。
特别优选的式I化合物为下述化合物:其中对于单环化合物,即式I化合物中的R2和R3和与其相连的碳原子一起形成单环,X位于2、4或6-位。最优选的化合物是其中X在2、4或6-位且Y和Z独立地代表氢、羟基、甲氧基或甲基的化合物。
同样优选的是下述式I化合物,其中对于双-和三环化合物,即式I化合物中的R2和R3和与其相连的碳原子一起形成双环碳环以及式I化合物中的R1、R2和R3和与其相连的碳原子一起形成三环碳环,X位于3或5-位。
特别优选的式I化合物选自下列基团组成的组:
1-甲基-环己烷羧酸(3-甲氧基-苯基)-酰胺(实施例1),
1-甲基-环己烷-羧酸(4-氰基-苯基)-酰胺(实施例2A),
2-甲基-二环[2.2.1]庚-5-烯-2-羧酸(4-氰基-苯基)-酰胺(实施例2B),
2-甲基-二环[2.2.1]庚-5-烯-2-羧酸(4-甲氧基-苯基)-酰胺(实施例2C),
3-异丙基-1-甲基-环戊烷羧酸(4-甲氧基-苯基)-酰胺(实施例2D),
3-异丙基-1-甲基-环戊烷羧酸(3-氰基-苯基)-酰胺(实施例2E),
金刚烷-1-羧酸(4-甲氧基-苯基)-酰胺(实施例2F),
金刚烷-1-羧酸(4-甲氧基-苯基)-酰胺*,
金刚烷-1-羧酸(3-硝基苯基)-酰胺*,
2-叔丁基-环戊烷羧酸(4-甲氧基-苯基)-酰胺(实施例2G),
2-叔丁基-环己烷羧酸(2-甲氧基-苯基)-酰胺(实施例2H),
2-叔丁基-环戊烷羧酸(4-羟基甲基-苯基)-酰胺(实施例2I),
2-叔丁基-环戊烷羧酸(4-乙酰基-苯基)-酰胺(实施例2J),
2-叔丁基-环戊烷羧酸(4-氰基-苯基)-酰胺(实施例2K),
2-叔丁基-环己烷羧酸(4-羟基甲基-苯基)-酰胺(实施例2L),
2-叔丁基-环己烷羧酸(4-乙酰基-苯基)-酰胺(实施例2M),和
2-叔丁基-环己烷-羧酸(4-氰基-苯基)-酰胺(实施例2N)。
*:可购自Sigma-Aldrich
虽然文献中描述了一些化合物,但是并未对其它化合物进行描述,这些化合物仍然是新的。因此,在本发明的另一方面中提供一种式Ia的化合物:
其中,
X为(CH2)n-R,其中R为包括至少一个自由电子对的基团并且n为0或1;和
Y和Z独立地选自H、OH、C1-C4烷基(例如甲基、乙基、异丙基)和C1-C4烷氧基(例如甲氧基和乙氧基);
或者
X和Y一起形成二价基团,所述二价基团选自-O-CH2-O-、-N=CH-O-和-N=CH-S-并和与其相连的碳原子一起形成5-元环,即分别为1,3-二氧戊环、1,3-唑环和1,3-噻唑环;和
Z选自H、OH、C1-C4烷基(例如甲基、乙基和异丙基)和C1-C4烷氧基(例如甲氧基和乙氧基);
m为0、1或2;
R1为H或C1-C4烷基,优选H或甲基;和
R2和R3和与其相连的碳原子一起形成3-10元,优选5-7元单-或双环碳环,例如环己基、环戊基、二环[2.2.1]庚基和二环[2.2.1]庚烯基,其任选被含有最多4个碳原子,优选1-3个碳原子的烷基(例如叔丁基、异丙基、甲基)取代,并且该环可以包括一个或多个氧原子,例如苯并[1,3]二氧杂环戊烯基;条件是R2和R3和与其相连的碳原子一起不为2-异丙基-5-甲基-环己基。
包括至少一个自由电子对的基团优选选自下列基团组成的组:卤素(例如Cl、F和Br)、氰基、羟基、甲氧基、乙氧基、NO2、乙酰基、SO2NH2、CHO、COOH、羧酸C1-C4烷基酯(例如COOC2H5和COOCH3)、式C(O)NH-R’的甲酰胺(其中R’为氢、甲基、乙基、丙基、异丙基、叔丙基、正丁基、叔丁基或异丁基)和杂环体系(优选选自5-和6-元杂环体系,例如唑、三唑、吡唑和吗啉)。
式I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,包括向口腔或皮肤施用含有上述化合物的产品。
施用于口腔的产品可以包括由口腔摄入和吞咽的食物和饮料,这些产品的摄入并不是因为其营养价值,所述产品例如为片剂、漱口液、喷喉剂、牙膏和口香糖。施用于皮肤的产品可以选自适用于人体皮肤的香水、化妆品、乳液、油和膏,无论是医疗或其它目的均可。因此,本发明的进一步方面涉及一种包括一定量的式I化合物或其混合物的组合物,其中的化合物足以刺激与该组合物接触的皮肤或黏膜区域内的清凉受体,从而增强所希望的清凉效果。通过将包括至少5000ppm,优选300-3000ppm的式I化合物的液体产品施用于黏膜,例如口腔黏膜可以实现清凉作用。
因此,本发明进一步涉及一种终产品,其选自:局部用产品、口腔护理产品、鼻部护理产品、化妆用品、可摄取产品和口香糖,该终产品包括产品基质和有效量的式I的清凉化合物或其混合物。
本发明的化合物可以单独使用或者与本领域已知的其它清凉化合物结合使用,例如,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、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)。
式I化合物可以通过在本领域公知的反应条件下将通式R1R2R3C-COOH的酸氯化为相应的酰氯,所述酰氯再与式II的胺发生进一步反应而制得:
其中R1、R2和R3,m、X、Y和Z与式I化合物中的定义相同。式R1R2R3C-COOH的一些酸可以商购获得。通常,其可以例如通过Tetrahedron,1980,36(6),775-7或者Journal of Chemical Research,1978,2,46中描述的方法制备。
下面将通过下列非限制性实施例对本发明作进一步的描述。
实施例1:1-甲基-环己烷羧酸(3-甲氧基-苯基)-酰胺
向烧瓶中加入5.9g(50mmol)4-氨基苯甲腈、4mL吡啶和100mLMtBE。经5分钟向该混合物中滴加8g 1-甲基环己烷羧酰氯。将反应混合物搅拌24h。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,其经硅胶色谱纯化得到8.3g 1-甲基-环己烷羧酸(3-甲氧基-苯基)-酰胺。
MS:242,118,97,55
实施例2:
按照与实施例1相同的步骤合成表1中列出的化合物。
表1:
No. | 名称 | 物理数据 |
A | 1-甲基-环己烷羧酸(4-氰基-苯基)-酰胺 | MS:247,123,97,55 |
B | 2-甲基-二环[2.2.1]庚-5-烯-2-羧酸(4-氰基-苯基)-酰胺 | MS:252,187,107,69 |
C | 2-甲基-二环[2.2.1]庚-5-烯-2-羧酸(4-甲氧基-苯基)-酰胺 | MS:252,192,191,107,69 |
D | 3-异丙基-1-甲基-环戊烷羧酸(4-甲氧基-苯基)-酰胺 | MS:275,123,125,69 |
E | 3-异丙基-1-甲基-环戊烷羧酸(3-氰基-苯基)-酰胺 | MS:270,153,125,69 |
F | 金刚烷-1-羧酸(4-甲氧基-苯基)-酰胺 | MS:285,135,122 |
G | 2-叔丁基-环戊烷羧酸(4-甲氧基-苯基)-酰胺 | MS:275,260,218,123,69,57 |
H | 2-叔丁基-环己烷羧酸(2-甲氧基-苯基)-酰胺 | MS:289,274,232,123,108,83,57 |
I | 2-叔丁基-环戊烷羧酸(4-羟基甲基-苯基)-酰胺 | MS:275,260,218,123,69,57 |
J | 2-叔丁基-环戊烷羧酸(4-乙酰基-苯基)-酰胺 | MS:287,272,230,153,135,12,69,57 |
K | 2-叔丁基-环戊烷羧酸(4-氰基-苯基)-酰胺 | MS:270,255,213,153,125,69,57 |
L | 2-叔丁基-环己烷羧酸(4-羟基甲基-苯基)-酰胺 | MS:289,232,167,123,83,57 |
M | 2-叔丁基-环己烷羧酸(4-乙酰基-苯基)-酰胺 | MS:301,286,244,139,135,120,83,57,43 |
N | 2-叔丁基-环己烷羧酸(4-氰基-苯基)-酰胺 | MS:284,269,227,167,118,83,57 |
实施例3:在漱口液中的应用
乙醇95% 177mL
山梨糖醇70% 250g
2-叔丁基-环己烷羧酸(4-羟基甲基-苯基)-酰胺
(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 0.639
苯甲酸 1.500g
PluronicF127 5.000g
糖精钠 0.600g
柠檬酸钠 0.300g
柠檬酸 0.100g
水 适量至1升
PluronicF127为双官能团的嵌段共聚物表面活性剂(BASF的商标)
混合所有成分。将30mL所得溶液放入口腔中,来回搅动,漱口并吐出。口腔中的每个区域都感觉到强烈的清凉感。
实施例4:在牙膏中的应用
不含调味剂和香料的不透明牙凝胶基质 97.0g
金刚烷-1-羧酸(4-甲氧基-苯基)-酰胺(PG*中的2%溶液) 2.5g
无萜薄荷油 0.5g
*PG=丙二醇
将化合物混合在牙凝胶中,将1g牙凝胶放于牙刷上并且让调查对象用于刷牙。用水漱口并且将水吐出。调查对象口腔中的每一区域都感觉到清凉感。
Claims (12)
1.式I化合物作为清凉剂的用途,
其中,
X为(CH2)n-R,其中R为包括至少一个自由电子对的基团并且n为0或1;
m为0、1或2;和
Y和Z独立地选自H、OH、C1-C4烷基、C1-C4烷氧基;
或者
X和Y一起形成二价基团,所述二价基团选自-O-CH2-O-、-N=CH-O-和-N=CH-S-并和与其相连的碳原子一起形成5-元环;和
Z选自H、OH、C1-C4烷基、C1-C4烷氧基;
R1为H或C1-C4烷基;和
R2和R3和与其相连的碳原子一起形成3-10元单-或双环碳环,其任选被含有最多4个碳原子的烷基取代,并且该环可以包括一个或多个氧原子;条件是R2和R3和与其相连的碳原子一起不为2-异丙基-5-甲基-环己基;
或者
R1、R2和R3和与其相连的碳原子一起形成6-10元三环碳环,其任选被含有最多4个碳原子的烷基取代,并且该环可以包括一个或多个氧原子。
2.根据权利要求1的化合物作为清凉剂的用途,其中X为(CH2)n-R,其中n为0或1,R选自氰基、羟基、甲氧基、乙氧基、CHO、C(O)NH2、C(O)NHCH3、COOCH3、COOC2H5和乙酰基。
3.根据权利要求1或2的化合物作为清凉剂的用途,其中Y和Z独立地代表氢、羟基、甲氧基或甲基。
4.根据权利要求1的化合物作为清凉剂的用途,所述化合物选自:
1-甲基-环己烷羧酸(3-甲氧基-苯基)-酰胺,
1-甲基-环己烷-羧酸(4-氰基-苯基)-酰胺,
2-甲基-二环[2.2.1]庚-5-烯-2-羧酸(4-氰基-苯基)-酰胺,
2-甲基-二环[2.2.1]庚-5-烯-2-羧酸(4-甲氧基-苯基)-酰胺,
3-异丙基-1-甲基-环戊烷羧酸(4-甲氧基-苯基)-酰胺,
3-异丙基-1-甲基-环戊烷羧酸(3-氰基-苯基)-酰胺,
金刚烷-1-羧酸(4-甲氧基-苯基)-酰胺,
2-叔丁基-环戊烷羧酸(4-甲氧基-苯基)-酰胺,
2-叔丁基-环己烷羧酸(2-甲氧基-苯基)-酰胺,
2-叔丁基-环戊烷羧酸(4-羟基甲基-苯基)-酰胺,
2-叔丁基-环戊烷羧酸(4-乙酰基-苯基)-酰胺,
2-叔丁基-环戊烷羧酸(4-氰基-苯基)-酰胺,
2-叔丁基-环己烷羧酸(4-羟基甲基-苯基)-酰胺,
2-叔丁基-环己烷羧酸(4-乙酰基-苯基)-酰胺,
2-叔丁基-环己烷-羧酸(4-氰基-苯基)-酰胺,
金刚烷-1-羧酸(4-甲氧基-苯基)-酰胺,和
金刚烷-1-羧酸(3-硝基苯基)-酰胺。
5.通过向口腔或皮肤施用包括式I化合物的产品而给口腔或皮肤提供清凉作用的方法,
其中,
X为(CH2)n-R,其中R为包括至少一个自由电子对的基团并且n为0或1;
m为0、1或2;和
Y和Z独立地选自H、OH、C1-C4烷基、C1-C4烷氧基;
或者
X和Y一起形成二价基团,所述二价基团选自-O-CH2-O-、-N=CH-O-和-N=CH-S-并和与其相连的碳原子一起形成5-元环;和
Z选自H、OH、C1-C4烷基、C1-C4烷氧基;
R1为H或C1-C4烷基;和
R2和R3和与其相连的碳原子一起形成3-10元单-或双环碳环,其任选被含有最多4个碳原子的烷基取代,并且该环可以包括一个或多个氧原子;条件是R2和R3和与其相连的碳原子一起不为2-异丙基-5-甲基-环己基;
或者
R1、R2和R3和与其相连的碳原子一起形成6-10元三环碳环,其任选被含有最多4个碳原子的烷基取代,并且该环可以包括一个或多个氧原子。
6.一种选自局部用产品、口腔护理产品、鼻部护理产品、化妆用品、可摄取产品和口香糖的产品,所述产品包括产品基质和有效量的如权利要求1-4中任一项定义的式I的清凉化合物。
7.式I化合物:
其中,
X为(CH2)n-R,其中R为包括至少一个自由电子对的基团并且n为0或1;
m为0、1或2;和
Y和Z独立地选自H、OH、C1-C4烷基、C1-C4烷氧基;
或者
X和Y一起形成二价基团,所述二价基团选自-O-CH2-O-、-N=CH-O-和-N=CH-S-并和与其相连的碳原子一起形成5-元环;和
Z选自H、OH、C1-C4烷基、C1-C4烷氧基;
R1为H或C1-C4烷基;和
R2和R3和与其相连的碳原子一起形成3-10元单-或双环碳环,其任选被含有最多4个碳原子的烷基取代,并且该环可以包括一个或多个氧原子;条件是R2和R3和与其相连的碳原子一起不为2-异丙基-5-甲基-环己基。
8.根据权利要求7的化合物,其中X为(CH2)n-R,其中n为0或1,R选自氰基、羟基、甲氧基、乙氧基、CHO、C(O)NH2、C(O)NHCH3、COOCH3、COOC2H5和乙酰基。
9.根据权利要求7或8的化合物,其中Y和Z为氢。
10.根据权利要求7的化合物,其中R选自5-和6-元杂环体系。
11.根据权利要求10的化合物,其中R选自唑、三唑、吡唑和吗啉。
12.根据权利要求7的化合物,所述化合物选自:
1-甲基-环己烷羧酸(3-甲氧基-苯基)-酰胺,
1-甲基-环己烷-羧酸(4-氰基-苯基)-酰胺,
2-甲基-二环[2.2.1]庚-5-烯-2-羧酸(4-氰基-苯基)-酰胺,
2-甲基-二环[2.2.1]庚-5-烯-2-羧酸(4-甲氧基-苯基)-酰胺,
3-异丙基-1-甲基-环戊烷羧酸(4-甲氧基-苯基)-酰胺,
3-异丙基-1-甲基-环戊烷羧酸(3-氰基-苯基)-酰胺,
金刚烷-1-羧酸(4-甲氧基-苯基)-酰胺,
2-叔丁基-环戊烷羧酸(4-甲氧基-苯基)-酰胺,
2-叔丁基-环己烷羧酸(2-甲氧基-苯基)-酰胺,
2-叔丁基-环戊烷羧酸(4-羟基甲基-苯基)-酰胺,
2-叔丁基-环戊烷羧酸(4-乙酰基-苯基)-酰胺,
2-叔丁基-环戊烷羧酸(4-氰基-苯基)-酰胺,
2-叔丁基-环己烷羧酸(4-羟基甲基-苯基)-酰胺,
2-叔丁基-环己烷羧酸(4-乙酰基-苯基)-酰胺,和
2-叔丁基-环己烷-羧酸(4-氰基-苯基)-酰胺。
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ES2342466T7 (es) | 2003-11-21 | 2012-11-19 | Givaudan Sa | P-mentanocarboxamidas n-substituidas. |
JP5383191B2 (ja) | 2005-08-15 | 2014-01-08 | ジボダン エス エー | 清涼化合物 |
CN101583287A (zh) * | 2006-12-20 | 2009-11-18 | 奇华顿荷兰服务有限责任公司 | N-取代-对薄荷烷-3-甲酰胺及其用途 |
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 |
WO2010128026A2 (en) | 2009-05-05 | 2010-11-11 | Givaudan Sa | Organic compounds |
ES2377785B2 (es) | 2010-09-08 | 2012-09-26 | Universidad Miguel Hernández De Elche | Composición farmacéutica para el tratamiento del ojo seco. |
GB201103103D0 (en) | 2011-02-23 | 2011-04-06 | Givaudan Sa | Organic compounds |
JP2013195289A (ja) | 2012-03-21 | 2013-09-30 | Takasago Internatl Corp | 感覚刺激成分の評価方法 |
EP3356356B1 (en) | 2015-10-01 | 2021-05-26 | Firmenich Incorporated | Compounds useful as modulators of trpm8 |
WO2018131575A1 (ja) | 2017-01-10 | 2018-07-19 | 高砂香料工業株式会社 | メチルメントール誘導体及びそれを含有する冷感剤組成物 |
CA3078909A1 (en) | 2017-10-16 | 2019-04-25 | Takasago International Corporation | Cool-sensation imparter composition containing 2,2,6-trimethylcyclohexanecarboxylic acid derivative |
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 |
US20220062173A1 (en) * | 2019-01-08 | 2022-03-03 | Johnson & Johnson Consumer Inc. | Liquid compositions |
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Publication number | Priority date | Publication date | Assignee | Title |
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AU7593174A (en) * | 1973-12-12 | 1976-06-03 | Wilkinson Sword Ltd | Compounds having a physiological cooling effect |
GB1471894A (en) | 1973-12-12 | 1977-04-27 | Wilkinson Sword Ltd | Compositions for application to or consumption by the body and containing a compound having a physiological cooling effect |
US6399614B1 (en) * | 1997-08-01 | 2002-06-04 | Recordati S.A. Chemical And Pharmaceutical Company | 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring |
US6348625B1 (en) * | 2000-11-10 | 2002-02-19 | Gloria Long Anderson | Method for preparing some 1-adamantancecarboxamides |
US8093290B2 (en) | 2002-10-28 | 2012-01-10 | Givaudan Sa | Coolant solutions and compositions comprising the same |
US7169377B2 (en) * | 2003-10-15 | 2007-01-30 | Wei Edward T | Radioligands for the TRP-M8 receptor and methods therewith |
ES2342466T7 (es) | 2003-11-21 | 2012-11-19 | Givaudan Sa | P-mentanocarboxamidas n-substituidas. |
US20050187211A1 (en) | 2004-02-23 | 2005-08-25 | Wei Edward T. | N-arylsalkyl-carboxamide compositions and methods |
GB0425661D0 (en) | 2004-11-23 | 2004-12-22 | Givaudan Sa | Organic compounds |
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- 2006-02-27 WO PCT/CH2006/000119 patent/WO2006092076A2/en active Application Filing
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US7893110B2 (en) | 2011-02-22 |
WO2006092076A2 (en) | 2006-09-08 |
GB0504194D0 (en) | 2005-04-06 |
US20080176945A1 (en) | 2008-07-24 |
EP1853353A2 (en) | 2007-11-14 |
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