CN101133030B - 具有清凉性质的薄荷烷甲酰胺衍生物 - Google Patents

具有清凉性质的薄荷烷甲酰胺衍生物 Download PDF

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CN101133030B
CN101133030B CN200680006684XA CN200680006684A CN101133030B CN 101133030 B CN101133030 B CN 101133030B CN 200680006684X A CN200680006684X A CN 200680006684XA CN 200680006684 A CN200680006684 A CN 200680006684A CN 101133030 B CN101133030 B CN 101133030B
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compound
refrigerant
oral cavity
menthane
formula
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CN101133030A (zh
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L·科尔
S·M·弗尔勒
C·加洛宾
P·V·克拉维克
A·马苏尔
J·P·斯莱克
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K8/00—Cosmetics or similar toiletry preparations
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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

Abstract

式(I)化合物，

Description

具有清凉性质的薄荷烷甲酰胺衍生物
本发明涉及具有清凉性质的杂环化合物。
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包括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GB1，351,761-2和美国专利US4,150,052中进行了描述。
现已发现，从这种化合物中特别选择出来的化合物显示出出人意料地强烈且长效的清凉作用。因此，本发明提供式I的化合物：
Figure S06806684X20070904D000011
其中X和Y选自：
(i)X为H，Y选自下列基团：
Figure S06806684X20070904D000012
和
Figure S06806684X20070904D000013
或者
(ii)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-，从而和与其相连的碳原子一起形成5-元环(分别为1，3-二氧戊环、1，3-噁唑环或1，3-噻唑环)。
式I化合物的具体例子如下所示：
Figure S06806684X20070904D000021
该化合物可以采用本领域公知的方法容易地制备和分离。
它们与现有技术中类似化合物的区别在于，其具有出人意料地高的清凉效果(最多可以比类似的已知化合物高100倍)，并且该清凉效果具有长效性，因此增加了其在大量产品中的吸引力。
例如，请一小组调查对象品尝清凉化合物的各种溶液并且指出哪些溶液具有与2ppm薄荷醇溶液类似或略高的清凉强度。结果示于表1中。
表1关于清凉强度的试验
 
化学物质 浓度
1-薄荷醇 2.0ppm
N-4-(吡唑-1-基)-苯基-3-对-薄荷烷甲酰胺 0.02ppm
N-4-([1，2，4]三唑-1-基)-苯基-3-对-薄荷烷甲酰胺 0.02ppm
 
化学物质 浓度
N-3-(噁唑-5-基)-苯基-3-对-薄荷烷甲酰胺 0.1ppm
N-4-(吗啉-4-基)-苯基-3-对-薄荷烷甲酰胺 0.2ppm
N-4-(噁唑-5-基)-苯基-3-对-薄荷烷甲酰胺 0.5ppm
N-苯并噁唑-4-基-3-对-薄荷烷甲酰胺 0.02ppm
N-苯并[1，3]二氧戊环-5-基-3-对-薄荷烷甲酰胺 0.02ppm
N-苯并噻唑-6-基薄荷烷甲酰胺 0.3ppm
从表1中可以看出，式I化合物比对照清凉化合物薄荷醇的清凉作用强烈达100倍。式I清凉化合物还比WS-3的清凉作用强得多并且持续时间长，而WS-3是现有技术中最好的清凉化合物。
本发明的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。本发明还提供一种给皮肤或口腔提供清凉感觉的组合物，其含有上面定义的化合物。
下面将借助以下的非限定性实施例对发明作进一步的描述，这些实施例描述了优选的实施方案。
实施例1
N-苯并噁唑-4-基3-对-薄荷烷甲酰胺的制备
向烧瓶中加入0.5g(3.7mmol)苯并噁唑-4-基胺，0.7mL三乙胺和10mL二氯甲烷。将混合物冷却至0℃并用5分钟时间滴加0.71g3-对-薄荷烷羧基氯。将反应混合物搅拌过夜。向反应混合物中加入10mL水。分离混合物。用EtOAc(3×5mL)洗涤水层。用5mL水洗涤结合起来的有机层。在Na2SO4上干燥有机层。真空蒸发溶剂得到粗产物，其经硅胶纯化得到0.46g所需产物，该产物具有下列光谱性质：
MS：300([M+])，133，97，83
1H NMR(300MHz；CDCl3)δ：8.35(s，1H)，8.14(d，1H)，7.68(d，1H)，7.54(br.s，1H)，7.18(dd，1H)，2.25(t，1H)，1.91-1.61(m，5H)，1.5-1.23(m，2H)，1.17-0.9(m，2H)，0.94(d，3H)，0.93(d，3H)，0.85(d，3H)
实施例2
N-苯并噁唑-6-基3-对-薄荷烷甲酰胺的制备：
按照类似于实施例1中描述的方法进行制备，得到所需产物，其具有下列光谱性质：
MS：300([M+])，133，97，83
1H NMR(300MHz；CD3OD)δ：8.33(s，1H)，8.02(m，2H)，7.23(dd，1H)，2.4(ddd，1H)，1.88-1.54(m，5H)，1.37(m，1H)，1.0-1.3(m，3H)，0.98(d，3H)，0.86(d，3H)，0.82(d，3H)
实施例3
N-苯并噻唑-6-基薄荷烷甲酰胺的制备：
按照类似于实施例1中描述的方法进行制备，得到所需产物，其具有下列光谱性质：
MS：316([M+])，150，97，83
1H NMR(300MHz；CD3OD)δ：9.12(s，1H)，8.49(d，1H)，7.91(d，1H)，7.54(d，1H)，2.2(ddd，1H)，1.88-1.54(m，5H)，1.21-1.47(m，4H)，0.99(d，3H)，0.93(d，3H)，0.85(d，3H)
实施例4
N-4-([1，2，4]三唑-1-基)-苯基-3-对-薄荷烷甲酰胺的制备：
按照类似于实施例1中描述的方法进行制备，得到所需产物，其具有下列光谱性质：
MS：326([M+])，160，97，83
1H NMR(300MHz；CD3OD)δ：8.98(s，1H)，8.07(s，1H)，7.84(s，4H)，2.26(t，1H)，1.9-1.5(m，5H)，1.45-1.3(m，1H)，1.25-1(m，3H)，0.94(d，3H)，0.86(d，3H)，0.8(d，3H)
实施例5
N-4-(噁唑-5-基)-苯基-3-对-薄荷烷甲酰胺的制备：
按照类似于实施例1中描述的方法进行制备，得到所需产物，其具有下列光谱性质：
MS：326([M+])，160,139，97，83
1H NMR(300MHz；CD3OD)δ：8.19(s，1H)，7.66(s，4H)，7.42(s，1H)，2.35(ddd，1H)，1.88-1.54(m，5H)，1.4-1.35(m，1H)，1.0-1.3(m，3H)，0.95(d，3H)，0.91(d，3H)，0.84(d，3H)
实施例6
N-3-(噁唑-5-基)-苯基-3-对-薄荷烷甲酰胺的制备：
按照类似于实施例1中描述的方法进行制备，得到所需产物，其具有下列光谱性质：
MS：326([M+])，160,139，97，83
实施例7
在漱口剂中的应用
乙醇95％                                                177mL
山梨糖醇70％                                            290g
实施例1的化合物，其为在乙醇中形成的1％溶液              10mL
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所得溶液放入口腔中，来回搅动、漱口并吐出。口腔的每一区域及嘴唇都感到非常清凉。清凉感觉持续数小时。
实施例8
在牙膏中的应用
不透明牙凝胶                                        98.000g
实施例6的化合物，其为在PG中的2％溶液                1.500g
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强烈的清凉感。清凉感持续数小时。

Claims (4)

1.式I化合物
Figure FA20192639200680006684X01C00011
其中X和Y选自：
(i)X为H，Y选自下列基团：
或者
(ii)X和Y一起形成二价基团，所述二价基团选自-N＝CH-O-和-N＝CH-S-，从而和与其相连的碳原子一起形成5-元环。
2.一种给口腔或皮肤提供清凉作用的方法，所述方法包括向口腔或皮肤施用含有根据权利要求1的化合物的产品。
3.一种给皮肤或口腔提供清凉感觉的组合物，所述组合物含有根据权利要求1的化合物。
4.式I化合物，所述化合物选自：
Figure FA20192639200680006684X01C00021
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EP1853565B1 (en) 2010-09-22
BRPI0607407A2 (pt) 2009-09-01
DE602006017038D1 (de) 2010-11-04
US7868004B2 (en) 2011-01-11
KR20070107083A (ko) 2007-11-06

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