CN106243006B - (3-烷硫基)丙烯酸衍生化合物及其化妆应用 - Google Patents
(3-烷硫基)丙烯酸衍生化合物及其化妆应用 Download PDFInfo
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- CN106243006B CN106243006B CN201610397730.9A CN201610397730A CN106243006B CN 106243006 B CN106243006 B CN 106243006B CN 201610397730 A CN201610397730 A CN 201610397730A CN 106243006 B CN106243006 B CN 106243006B
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Classifications
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- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
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- A—HUMAN NECESSITIES
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- 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
- A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
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- 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
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
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- A—HUMAN NECESSITIES
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- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
Landscapes
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Birds (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Cosmetics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrrole Compounds (AREA)
Abstract
本发明提供一种(Z)‑3‑(烷硫基)丙烯酸衍生化合物及其在化妆组合物中的应用,以及包含其的化妆或医学护肤组合物。
Description
技术领域
本发明的主题包括由3-(烷硫基)丙烯酸衍生的缀合化合物家族,以及其作为日光照射的光防护剂在化妆品中的应用。本发明还涉及用于对皮肤或附属物进行光防护的化妆组合物。
背景技术
除了有益效果(支持维生素D和褪黑素产生、抗抑郁、幸福感等),日光还会对皮肤产生短期和长期的不利影响:红斑、组织过早老化、光照性皮肤病、癌、黑色素瘤(IchihashiM.等,Toxicology,2003,vol.189,pp.21-39)。在到达地球表面的各种射线中,紫外线,但限于紫外-A(λ320-400nm,UV-A)或紫外-B(λ290-320nm,UV-B)照射,已经被确定为是这些不利影响的原因。
不过,皮肤具有固有的防御系统,使其能够抵御日光损伤。因此,作为日光照射的结果,已经表现出所谓的天然或内在光防护,其通过光防护性黑色素的产生或通过以表皮中更多数量的角化细胞层增厚角质层,来确保所述光防护。反式尿刊酸是组氨酸代谢物,并以高浓度存在于上层表皮中、特别是角质层中,其还通过发挥针对UV-B有害作用的内源性防护功能而参与所述天然光防护(Barresi C.等,J.Invest.Dermatol.2011,vol.131,pp.188-194)。
抵御日光照射的皮肤防护还可以从外部诱导(Lacour等,Annals of Dermatologyand Venereology,2007,vol.134,pp.18-24)。通常,这种光防护与天然光防护相比可以称作是人工防护,其通过外部方式来确保,所述外部方式除了衣物覆盖之外还包括局部敷用光防护性化妆产品。这些产品或制剂通常含有溶解或分散在载剂中的防护性物质,所述防护性物质可分为三大类:遮光剂,其作用是反射所有日光照射,从而阻止其穿透皮肤;过滤剂,其作用是吸收部分日光照射,通常为紫外-A(320-400nm)和B(290-320nm)射线,随后通过与皮肤的热交换而释放所吸收的光子能;最后是光防护剂,其与遮光剂和过滤剂相比是所述的活性物质,并且通常是能够捕获活性氧物种(英文缩写为"EOR"或"ROS")的物质,活性氧物种在天然存在于皮肤中的分子吸收辐射时产生/形成(光敏机制)。
这种局部制剂通常以日光防护系数(法文缩写为"FPS",英文缩写为"SPF")来表征,其为抵御红斑(晒伤)的防护水平的指标,并且根据日光条件和特殊皮肤光类型来调整。对于高SPF的日光防护制品,包含了遮光剂和过滤剂。
这种制剂中的遮光剂大多是矿物来源的惰性物质(粉末:氧化锌、二氧化钛等)。然而,在遮光剂制剂中使用它们是不舒适的,在涂抹它们时会出现白色印记。以纳米颗粒形式存在改善了这种遮光剂的市场销售,不过其在这种形式下的安全性数年来一直具有挑战性:其具有穿透皮肤的潜在风险。
有机化学过滤剂通常是合成来源,或者当其为源自植物的油或提取物时是天然来源。其有效性由紫外光吸收效果构成,该效果归因于结构上存在能够吸收并随后发散特定波长的光线的生色团。这些化学过滤剂中的生色团几乎系统性地为带有单环或多环芳香环(苯基、苄基、苯亚甲基、苯甲酰基、萘基、蒽基等)的化合物,该芳香环与羰基或脂肪族不饱和体系缀合,以在所吸收的辐射的影响下使电子有更大离域(激发态),随后随着所接收的光子能的耗散和/或较不危险的辐射(例如红外线)的再发射而返回稳态。
因此,在这些属于现有技术(R.Rai等,Indian J.Dermatol.,2012,vol.57(5),pp.335-342)和可商购获得的生色团化学过滤剂中,可以提及吸收光谱偏UV-B特异性的以下化合物:
-对氨基苯甲酸(PABA)酯衍生物,例如2-乙基己基-4-二甲基氨基苯甲酸酯(Padimate O),
-甲氧基肉桂酸衍生物,例如辛基甲氧基肉桂酸酯(奥西诺酯或OMC)和2-乙氧基乙基甲氧基肉桂酸酯(西诺沙酯),
-水杨酸衍生物,例如乙基己基水杨酸酯(水杨酸辛酯)和水杨酸三乙醇胺,
-2-乙基己基-2-氰基-3,3-二苯基-2-丙烯酸酯化合物(氰双苯丙烯酸辛酯),
-苯基苯并咪唑磺酸(恩索利唑)。
还可以提及吸收光谱偏UV-A特异性的以下化合物:
-二苯甲酰甲烷衍生物,例如丁基甲氧基二苯甲酰甲烷(阿伏苯宗),
-对苯亚甲基二樟脑磺酸(依茨舒或Mexoryl)。
最后可以提及吸收光谱更广(UV-B和UV-A辐射)的以下化合物:
-二苯甲酮,例如二苯甲酮-3(氧苯酮)和二苯甲酮-8(二羟苯宗),
-羟基苯并三唑衍生物,
-新三嗪,例如苯并噁嗪(Bruge等,PLoS ONE,2014,9,e83401.)。
对于主要以物理-化学标准(SPF、吸收光谱、对皮肤表面的持久性)来选择的多种这些有机过滤剂而言,除了在过去数年间报道过(Uther W.等,Contact Dermatitis,2014,vol.71,pp.162-9)的一些潜在过敏失调(接触过敏、光过敏、发痒)外,发现对这些生色团的光化学无害性/安全性并非总有报道,特别是其降解产物,例如光致异构化产物。
最近,已经开发出其他防护策略:在防晒制品中引入活性剂,例如DNA修复酶和更常见的诸如维生素C和E或多酚等抗氧化剂(MS Matsui等,J.Invest.Dermatol.,2009,vol.14,pp.56-59)。最近关于可见光(400-700nm)和近红外光(700-1440nm)照射引起皮肤中ROS形成的证据(F Liebel等,J.Invest Dermatol,2012,vol 132,pp.1901-1907;Schroeder P.等,Exp Gerontol,2008,vol 43,pp.629-632)增强了对该策略的兴趣。再次,这样的活性成分包含在局部制剂中并非没有带来问题:缺乏稳定性,成本问题,特别是当接触氧或其反应性物种时形成毒理学往往未知的副产物。
发明内容
因此,对于这些不同的记载,申请人致力于鉴定出用于化妆目的并且具有抵抗日光照射的广谱防护的新光防护化合物,同时设计出不形成皮肤可能耐受不良的降解副产物或光转换副产物的产品。所关注的物质的无害性/安全性的确凿证据,以及由目标化妆活动产生的反应副产物的无害性/安全性的确凿证据,在化妆品或医学护肤(dermocosmetic)行业中具有高优先度。
为了实现这些目的,申请人最先对含硫抗氧化剂化合物3-甲硫基丙烯酸(TMPA)发生兴趣,其在某些植物中以缀合物形式得到鉴定,例如反式3-甲硫基丙烯酸(E-TMPA)与乙醇胺的酰胺缀合物。该缀合物分离自豆科植物的种子中,据报道其具有抗炎潜力(IkegamiF.等,Chem.Pharm.Bull.,1989,Vol.37,pp.1932-1933)。
然后在进行了结构-活性研究以优化TMPA缀合物的抗氧化物能力后,申请人发现了由TMPA非天然立体异构体(立体选择性地制备的顺式3-甲硫基丙烯酸(Z-TMPA))(Fariade Medeiros E.等,J.Chem.Soc.,Perkin trans I,1991No.11,pp.27525-2730)获得的一组新酰胺缀合物展示出了令人预料不到的以下能力:非常高效地吸收UV-B辐射,并通过异构化产生其反式构型立体异构体而将所捕获的能量耗散掉。而后,申请人观察到该特征所伴随的性质是对抗上文中提到的天然光保护剂(即,反式尿刊酸)的光诱导内源异构化。该情况的优点是保存了皮肤固有防御系统的防护活性,但尤其是对抗了与反式尿刊酸的光致异构化相关联的负面效果。实际上,目前充分确定的是,其“天然遮光”行为(吸收光能)使得反式尿刊酸(或"E-UCA")转化为顺式尿刊酸(或"Z-UCA"),而顺式尿刊酸不利地抵消了E-UCA的益处,其促进促氧化行为,引起细胞内损伤,特别是DNA损伤(Mc Loone P.等,J.Invest.Dermatol,2005,vol.124,pp.1071-1074;Gibbs NK and al,J.InvestDermatol,2011,vol.131,pp.14-17及所引用的文献)。Z-UCA还不利地参与了紫外辐射对免疫系统的抑制效果。皮肤水平上的例如“UV诱导的免疫抑制”导致对敏化剂的免疫响应的缺陷,以及对感染的灵敏性提高和皮肤癌风险增加(Poon T.S.C.等,J.Invest.Dermatol.,2003,vol.121,pp.184-190)。目前,对抗紫外辐射所诱导的免疫抑制是光防护的另一主要目的,并为此定义了免疫防护系数(英文缩写为"IPF")(Wolf P.等,J.Invest.Dermatol.,2003,vol.121,pp.1080-1087),并且其在某些日光防护制品中有所提及。
整体上,所鉴定出的这组新的来自顺式3-甲硫基丙烯酸的酰胺类缀合物实现了安全地提供对抗日光照射的广谱防护的目标,这归功于:
-抗氧化物粉末,使得它们能够对抗涉及内源生色团(卟啉、醌、黄素等)的光敏化反应和诸如紫外、可见和近红外等各种辐射所产生的氧化应激。这样的效果因此能够对抗角鲨烯中单线态氧反应所导致的氢过氧化物(SqOOH)的形成[见以下测试1]。根据初步研究结果,这样的效果还对抗了"顺式UCA"的产生所诱导的细胞内氧化应激。除此之外,在关注反应副产物的合乎需要的无害性时,重点强调的是该抗氧化物粉末产生了本发明缀合物的硫醚基的氧化形式,依次为亚砜和砜,二者均可被皮肤细胞良好耐受[见以下测试2];
-能够从使用低浓度的活性物开始以剂量依赖性方式提高暴露于UV-B细胞毒性剂量的表皮细胞(称为"HaCaT"的永生化角化细胞系)的存活率[见以下测试3];
-能够如过滤剂那样强烈吸收UV-B紫外辐射,然后通过异构化为无毒性衍生物而消散所吸收的能量[见以下测试4],并且不会如尿刊酸那样形成不利的活性。这种行为在光引发的代谢物因其天然存在而是“天然等同”化合物时还受到更多关注;
-最后,能够对抗反式尿刊酸的光诱导异构化,这能够最终限制紫外辐射的免疫抑制效果[参见以下测试5]。
就目前的技术水平和申请人的知识而言,现有技术公开了在日光防护制剂中作用紫外过滤剂的苯亚甲基樟脑衍生物的相同的光致异构化以及所关注的活性的保存(BeckI.等,Int.J.Cosmetic Science,1981,vol.3,pp.139-152)。但这些樟脑衍生物在结构上不同于本发明的那些主题化合物。
关于抑制紫外线所诱导的从反式尿刊酸向免疫抑制性顺式尿刊酸的转变,现有技术中公开了宣称为“免疫保护剂”的一些试剂,例如磺酸苯基苯并咪唑酸(Hurks H.M.H.等,J.Invest.Dermatol.,1997,vol.109,pp.699-703)、肉桂酸酯、二苯甲酮及其他二苯甲酰甲烷(Fillay DD-Jones等,Mutation Res.,1998,vol.422,pp.155-159)等等。它们均在结构上不同于本发明的主题化合物。
而且,除这些方面之外,可以注意到涉及也具有硫丙烯酰胺单元的引起多种兴趣的化合物的现有技术(专利US 5,464,832和EP 0410726;专利US 5,300,672和US 3,914,301)。不过,在这些文献中,目标化合物清楚地展示出抗微生物、杀真菌、杀细菌和生物杀伤等性质。
因此本发明的第一目的是纯的顺式或(Z)-异构体缀合物的家族:其通过(Z)-3-(烷硫基)丙烯酸与伯或仲烷基胺或者选定的羟基化和不可电离的极性氨基酸之间的偶联反应而获得,其特征在于,所述家族由以下通式(I)表示:
其中:
Y=S或SO;
R1是直链或支化C1-C4烷基;
R2是氢原子、直链或支化C1-C4烷基;
R3是:
·C1-C18烷基、C1-C18烯基、C3-C4炔基,所述烷基、烯基或炔基为直链或支化的,并可选地取代有羟基、羟苯基或二羟苯基;
·选自酪氨酸、羟脯氨酸、丝氨酸及其高丝氨酸和异丝氨酸类似物、苏氨酸及其高苏氨酸和异苏氨酸类似物的氨基酸的侧链。
根据本发明的优选实施方式,本发明的(Z)-异构体缀合物由下式(II)表示:
其中:
Y=S或SO;
R1是直链或支化C1-C4烷基;
R2是氢原子、直链或支化C1-C4烷基;
R3是C1-C4烷基、C3-C4烯基、C3-C4炔基,所述烷基、烯基或炔基为直链或支化的,并可选地取代有羟基、羟苯基或二羟苯基。
有利的是,式(I)或(II)的(Z)-异构体缀合物中Y=S。
有利的是,式(I)或(II)的(Z)-异构体缀合物中R1是甲基。
有利的是,式(I)或(II)的(Z)-异构体缀合物中R3是取代有羟基、羟苯基或二羟苯基的乙基。
因此,作为与顺式3-甲硫基丙烯酸(Z-TMPA)进行偶联反应的烷基胺的实例,可举出乙醇胺、酪胺、儿茶酚胺如多巴胺、肾上腺素或去甲肾上腺素。
作为式(I)或(II)的(Z)-异构体缀合物的非穷举性实例,可举出以下化合物,其光致异构化诱导的产物(反式异构体)在植物中天然存在:
(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺;
(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺。
目前据申请人所知,上式(I)的(Z)-异构体缀合物是新型化合物,除了2-顺式榼藤酰胺(entadamide)A、N-甲基-顺式3-(甲硫基)丙烯酰胺(isopenangin)、N-乙基-顺式3-(丁硫基)丙烯酰胺和N-乙基-顺式3-(甲硫基)丙烯酰胺化合物以外。
式(I)的缀合物通过本申请人开发的以下制备方法合成:
i)通过丙炔酸与硫氰酸钾的反应立体选择性地制备(Z)-3-氰硫基丙烯酸;
ii)利用烷基碘、优选甲基碘使i)的(Z)-3-氰硫基丙烯酸在低温下进行烷基化反应,然后形成所得合成物(Z)-3-(烷硫基)丙烯酸,优选(Z)-3-甲硫基丙烯酸;
iii)使ii)的(Z)-3-(烷硫基)丙烯酸、优选(Z)-3-甲硫基丙烯酸在室温下与伯或仲烷基胺或极性氨基酸、优选直链或支化伯烷基胺、更优选乙醇胺或酪胺进行偶联反应,形成所得缀合衍生物,优选为(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺和(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺。该偶联反应用本领域技术人员熟知的偶联剂(优选N,N'-二环己基碳二亚胺)和(Z)-3-烷硫基丙烯酸合成物的羧基官能激活剂(亦为本领域技术人员熟知)(优选羟基苯并三唑)来进行。
这些(Z)-异构体缀合物为固体粉末形式,可溶于醇介质,并且粉末和溶液形式均保持稳定超过28天。
上述缀合物(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺和(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺具有以下物理-化学特性和光谱学特性,
-(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺:
Rf=0.40(CHCl3/MeOH,90:10);
m.p.=112℃;
1H NMR(CD3OD):δ=2.32ppm(s,3H,CH3),3.31(t,2H,J=6Hz,CH2-NH),3.60ppm(t,2H,J=6Hz,CH2-OH),5.89ppm(d,1H,J=10Hz,CH=),6.93ppm(d,1H,J=10Hz,CH=);
13C NMR(CD3OD):δ=19.2ppm(CH3),42.8ppm(N-CH2),61.8ppm(CH2-O),115.9ppm(=CH),148.6ppm(=CH-S),169.2ppm(C=O)。
-(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺
Rf=0.35(甲苯/丙酮/乙酸,100:50:2);
m.p.=132℃;
1H NMR(CD3OD):δ=2.31ppm(s,3H,CH3-S),2.69(t,2H,J=7.5Hz,CH2-Ph),3.35ppm(t,2H,J=7.5Hz,CH2-N),5.83ppm(d,1H,J=10Hz,CH=),6.90ppm(d,1H,J=10Hz,CH=),6.70ppm(d,2H,J=8.5Hz,CPh-H),7.02ppm(d,2H,J=8.5Hz,CPh-H);
13C NMR(CD3OD):δ=19.2ppm(CH3-S),35.9ppm(CH2-Ph),42.2ppm(CH2-N),116ppm(CH=),116.2ppm(酚),130.7ppm(酚),131.3ppm(酚),148.4ppm(=CH),156.9ppm(酚),169ppm(C=O)。
根据第二方面,本发明还涉及用于化妆或医学护肤应用的组合物,以进行光防护,特别是皮肤或附属物的光防护。该组合物包含皮肤或附属物生理学上可接受的任何添加剂,以及作为主要活性成分的以下通式(III)的化合物:
其中,Y、R1、R2和R3的定义同以上对式(I)化合物的定义。
有利的是,本发明的化妆或医学护肤组合物包含作为主要活性成分的通式(IV)化合物:
其中:
Y=S或SO;
R1是直链或支化C1-C4烷基;
R3是直链或支化C1-C4烷基,可选地取代有羟基、羟苯基或二羟苯基。
通式(III)包括式(IIIa)的Z-异构体、式(IIIb)的E-异构体和这些异构体的混合物,选外消旋物:
相似的是,通式(IV)包括式(IVa)的Z-异构体、式(IVb)的E-异构体和这些异构体的混合物,优选外消旋物:
在本发明的背景下,术语"主要活性成分"是指能够对抗日光照射的有害影响的活性物质。
有利的是,所述组合物中通式(III)或(IV)化合物的量相对于组合物的总重量为0.001重量%至0.1重量%,优选0.005重量%至0.05重量%。
就所述组合物中通式(III)或(IV)化合物的建议摩尔浓度而言,有利的是0.05mM至5mM,优选0.25mM至2.5mM,如下文示例性测试中所示。
有利的是,通式(III)或(IV)化合物中Y=S。
有利的是,通式(III)或(IV)化合物中R1是甲基。
有利的是,通式(III)或(IV)化合物中R3是取代有羟基、羟苯基或二羟苯基的乙基。因此,作为与Z-TMPA和E-TMPA酸进行偶联反应的相应伯烷基胺或仲烷基胺的实例,可举出乙醇胺、酪胺、儿茶酚胺如多巴胺、肾上腺素或去甲肾上腺素。
对于本发明的组合物非常特别的是,通式(III)或(IV)的化合物分别为由(Z)-3-(烷硫基)丙烯酸衍生出的式(IIIa)或(IVa)的(Z)-异构体缀合物。
最优选的是,本发明的组合物包含作为主要成分的(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺或(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺。
本发明的组合物适合于局部皮肤施用,可以以通常用于这种施用的所有形式存在。作为指示性但非限制性的实例,组合物可以为悬浮液、洗剂、乳膏、水性或水醇凝胶、粉末和各种乳液(可以为微乳液或纳米乳液)等形式。
本发明的组合物可以含有作为生理学可接受的添加剂的本领域技术人员已知并且与化妆或医学护肤领域相容的至少一种添加剂,选自油、蜡、有机硅弹性体、表面活性剂、助表面活性剂、增稠剂和/或胶凝剂、湿润剂、润肤剂、有机或无机过滤剂、光稳定剂、除醛供体防腐剂外的防腐剂、染料、吸油剂(matifying agent)、紧肤剂(tensor)、螯合剂、香料等,以及它们的混合物。
所述有机或无机日光滤光剂对UV-A和/或UV-B有活性,选自:邻氨基苯甲酸盐(或酯)、肉桂酸衍生物、二苯甲酰甲烷衍生物、水杨酸衍生物、樟脑衍生物、三嗪衍生物、二苯甲酮衍生物、β,β-二苯基丙烯酸酯(或盐)衍生物、苯并三唑衍生物、苯亚甲基丙二酸酯(或盐)衍生物、苯并咪唑衍生物、咪唑啉、双苯并吡咯(bis-benzoazolyl)衍生物、苯并噁唑衍生物、对氨基苯甲酸(PABA)衍生物、亚甲基双(羟基苯基苯并三唑)衍生物、滤光剂聚合物和聚硅氧烷、由α-烷基苯乙烯衍生的二聚体、4,4-二芳基丁二烯、包覆或未包覆的金属氧化物颜料或纳米颜料(钛、锌、铁、锆和铈的氧化物),以及它们的混合物。
本发明的组合物还可包含一种或多种额外活性成分,不过本领域技术人员会确保将可能的活性补充剂以及其比例选择成不影响本发明的组合物的所认识到的有利性质。这些额外活性成分可选自但不限于:去糖化剂、提高胶原蛋白或弹性蛋白的合成或防止其降解的试剂、提高糖胺聚糖或蛋白多糖的合成或防止其降解的试剂、增加细胞增殖的试剂、脱色素剂或促着色剂、抗氧化剂或抗自由基剂或防污染剂、补水剂、刺激脂分解的试剂、排水或排毒剂、抗炎剂、渗透增强剂、脱屑剂、舒缓剂和/或抗刺激剂、收敛剂、作用于微循环的试剂等,和它们的混合物。
本发明的组合物因此可包含至少皮肤晒黑剂和/或变褐剂。
本发明的另一目的涉及此前所述的式(III)或(IV)化合物作为日光照射的光防护剂在化妆组合物或医学护肤组合物中的应用。
本发明的另一目的涉及一种抵御日光照射的光防护方法,所述方法包括涂施上文定义的包含式(III)或(IV)化合物的化妆组合物或医学护肤品。
优选的是,在上述应用和方法中,式(III)或(IV)化合物分别为由(Z)-3-(烷硫基)丙烯酸衍生出的式(IIIa)或(IVa)的(Z)-异构体缀合物,尤其是(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺或(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺。
具体实施方式
实施例1
出于说明性目的,下文给出了包含上述通式(I)的顺式3-甲硫基丙烯酸衍生缀合物的本发明的组合物的四种制品实例:
配方A(乳膏)
(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺:0.008%
配方B(凝胶)
配方C(洗剂)
配方D(乳液)
实施例2
仅作为信息,下文通过以下测试来阐释本发明,所述测试在上文对本发明进行描述时有所提及(测试1至5)。
测试1:式(IIIa)和(IIIb)的化合物对抗单线态氧引起的角鲨烯氢过氧化的抗氧
化潜力的证据
原理:目的是证明本发明的化合物对角鲨烯氢过氧化物的可能的清除效果(“淬灭”),所述角鲨烯氢过氧化物在光敏化剂(亚甲基蓝)的存在下因溶解的分子氧对角鲨烯的作用而产生。
实验中,在溶于100mL甲醇(HPLC级)后,制备了5g/100mL的角鲨烯溶液、5mM的亚甲基蓝溶液和本发明化合物的溶液(1至5mM)或对照化合物(甲硫基丙基氨基乙酰基甲硫氨酸-AMDM)溶液。然后在UV-B箱中,将各溶液以相等份数倾倒入未加盖的陪替培养皿中,然后施加1.42J.cm-2的照射剂量(1D)。照射结束后,回收溶液体积,以甲醇调整为20mL,然后通过HPLC测定进行分析,而后取出亚甲基蓝。然后通过以下等式推算出“淬灭”率:
结果如下表1所示:
表1
化合物 | %角鲨烯保护 |
对照(AMDM,1mM) | 3 |
对照(AMDM,5mM) | 15 |
(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺(1mM) | 24 |
(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺(5mM) | 25 |
(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺(1mM) | 35 |
(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺(5mM) | 44 |
(E)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺(1mM) | 21 |
(E)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺(1mM) | 30 |
表1的结果表明,本发明的化合物能够有效对抗角鲨烯至氢过氧化物的光诱导氧化。
测试2:式(I)的(Z)-异构体缀合物的氧化副产物不具有细胞毒性的证据
实验中,通过在37℃和5%CO2的湿润气氛中在完全培养基"DMEM"(含10%胎牛血清)中进行传代培养来维持"HaCaT"永生化角化细胞的细胞系,并用该细胞系进行测试。将HaCaT细胞以1x105个细胞/孔的比率接种在24孔板中。
在以化学计量暴露于过氧化氢(H2O2)之后,合成了式(I)的(Z)-异构体缀合物的亚砜和砜衍生物,然后纯化并最终定量。
在每孔中加入PBS中浓度为2.5mM的本发明缀合物的亚砜和砜氧化副产物500μl。去除培养基后,利用"MTT法"或3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴化物(500μg/ml的溶液)并通过分光光度法(550nm吸光度)测量HaCaT角化细胞的活力。结果如下表2所示,将结果表示为从三次独立实验获得的平均值,并与未经照射的细胞获得的结果相比较。
表2
化合物 | %细胞活力 |
对照(未经照射的细胞) | 100 |
(Z)-N-(2-羟基乙基)-3-(甲硫基亚磺酰基)丙烯酰胺(2.5mM) | 94,3 |
(Z)-N-(2-羟基乙基)-3-(甲硫基磺酰基)丙烯酰胺(2.5mM) | 93,1 |
(Z)-N-(4-羟基苯乙基)-3-(甲硫基亚磺酰基)丙烯酰胺(2.5mM) | 95,6 |
(Z)-N-(4-羟基苯乙基)-3-(甲硫基磺酰基)丙烯酰胺(2.5mM) | 95,0 |
表2的结果表明,式(I)的(Z)-异构体缀合物的氧化副产物没有毒性。
测试3:式(I)的(Z)-异构体缀合物能够使暴露于UV-B细胞毒性剂量的角化细胞系
存活的证据
实验中,还对以8000个细胞/平方厘米(即,在0.5ml培养基中(含10%胎牛血清)中15200个细胞/孔)接种在24孔板中的"HaCaT"永生化角化细胞的细胞系进行了研究。
以PBS中0.05mM至0.5mM的浓度在每孔中加入500μl的本发明的缀合物。然后在活性成分存在下将细胞暴露于100mJ.cm-2的中等剂量的紫外照射(UV-B),然后将其置于无活性成分的培养基中24小时。去除培养基后,也利用"MTT法"(250μg/ml的溶液)并通过分光光度法(570nm的吸光度)测量HaCaT角化细胞的细胞活力。从3次独立的实验获得平均值,结果如下表3所示,并与由两个对照(未经照射的细胞和经过照射但未以本发明缀合物处理的细胞)获得的结果进行比较。
表3
化合物 | %细胞活力 |
对照(未经照射的细胞) | 100 |
对照+UV-B照射=100mJ/cm<sup>2</sup> | 46 |
(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺(0.1mM) | 64 |
(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺(0.25mM) | 85 |
(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺(0.5mM) | 94 |
(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺(0.1mM) | 70 |
(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺(0.25mM) | 93 |
(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺(0.5mM) | 100 |
(Z)-N-乙基-3-(甲硫基)丙烯酰胺(0.5mM) | 86 |
表3的结果表明,本发明的化合物以剂量依赖性方式影响细胞活力,其从0.1mM起对角化细胞提供光防护,并在0.5mM时提供完全或几乎完全的光防护。
测试4:式(I)的(Z)-异构体缀合物能够通过光致异构化而吸收紫外辐射的证据
原理:目的是检查本发明的缀合物是否能够在UV-B照射下发生异构化。
实验中,将2ml的5g/100mL角鲨烯溶液和2mL的浓度为25mM的本发明化合物的甲醇溶液引入20ml量筒中,然后用20mL甲醇进行补充。将所获得的制剂倾倒至陪替培养皿中,其中在UV-B箱中施加1J.cm-2的照射剂量。照射结束后,收集溶液并通过HPLC剂量进行分析。事先以甲醇对体积进行标准化。
由此获得色谱图,并研究E-异构体的形成。通过与对照图比较来最终确定异构化率。所得结果如下表4所示:
表4
化合物 | %异构化 |
(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺(2.5mM) | 62 |
(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺(2.5mM) | 95 |
(Z)-N-乙基-3-(甲硫基)丙烯酰胺(2.5mM) | 60 |
(Z)-N-(2-羟基乙基)-3-(甲硫基亚磺酰基)丙烯酰胺(2.5mM) | 64 |
表4的结果表明本发明的化合物由于其反式构型立体异构体的产生而能够有效吸收照射。
测试5:式(I)的(Z)-异构体缀合物能够对抗反式尿刊酸的光诱导异构化的证据
原理:目的是检查本发明的缀合物是否能够对抗反式尿刊酸的光致异构化。
实验中,与以上测试1和4几乎相同的方式进行研究。事先已查明,在限定的实验条件下,反式尿刊酸产生大量的顺式尿刊酸,其能够通过HPLC分析来测量。对于浓度为5mM的化合物,照射剂量(1D)为31mJ.cm-2。结果如下表5所示:
表5
化合物 | (E)-尿刊酸的%抑制 |
(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺(5mM) | 75 |
(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺(5mM) | 78 |
表5的结果表明,本发明的化合物在低剂量或中等剂量时能有效保护反式尿刊酸抵御UV-B照射。
Claims (25)
1.一种化妆品,其包含通式(I)表示的(Z)-3-(烷硫基)丙烯酸衍生化合物作为日光照射的光防护剂:
其中,
Y=S或SO;
R1是直链或支化的C1-C4烷基;
R2是氢原子、直链或支化的C1-C4烷基;
R3是直链或支化的C1-C18烷基,并可选地取代有羟基、羟苯基或二羟苯基。
2.如权利要求1所述的化妆品,其特征在于,所述化合物由以下通式(II)表示:
其中,
Y=S或SO;
R1是直链或支化的C1-C4烷基;
R3是直链或支化的C1-C4烷基,并可选地取代有羟基、羟苯基或二羟苯基。
3.如权利要求1或2所述的化妆品,其特征在于Y是S。
4.如权利要求1或2所述的化妆品,其特征在于,R1是甲基。
5.如权利要求3所述的化妆品,其特征在于,R1是甲基。
6.如权利要求1或2所述的化妆品,其特征在于,R3是取代有羟基、羟苯基或二羟苯基的C2烷基。
7.如权利要求3所述的化妆品,其特征在于,R3是取代有羟基、羟苯基或二羟苯基的C2烷基。
8.如权利要求4所述的化妆品,其特征在于,R3是取代有羟基、羟苯基或二羟苯基的C2烷基。
9.如权利要求5所述的化妆品,其特征在于,R3是取代有羟基、羟苯基或二羟苯基的C2烷基。
10.如权利要求1所述的化妆品,其特征在于,所述化合物为(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺或(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺。
11.(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺。
12.用于光防护的化妆或医学护肤组合物,其特征在于,其包含:皮肤或附属物生理上可接受的任何添加剂,以及作为主要活性成分的式(IIIa)的化合物、式(IIIb)的化合物或这些化合物的混合物:
其中,
Y=S或SO;
R1是直链或支化的C1-C4烷基;
R2是氢原子、直链或支化的C1-C4烷基;
R3是直链或支化的C1-C18烷基,并可选地取代有羟基、羟苯基或二羟苯基。
13.如权利要求12所述的化妆或医学护肤组合物,所述组合物包含作为主要活性成分的式(IVa)的化合物、式(IVb)的化合物或这些化合物的混合物:
其中,
Y=S或SO;
R1是直链或支化的C1-C4烷基;
R3是直链或支化的C1-C4烷基,可选地取代有羟基、羟苯基或二羟苯基。
14.如权利要求12或13所述的化妆或医学护肤组合物,其特征在于,所述混合物是外消旋物。
15.如权利要求12或13所述的化妆或医学护肤组合物,其特征在于,Y是S,R1是甲基,R3是取代有羟基、羟苯基或二羟苯基的C2烷基。
16.如权利要求14所述的化妆或医学护肤组合物,其特征在于,Y是S,R1是甲基,R3是取代有羟基、羟苯基或二羟苯基的C2烷基。
17.如权利要求12或13所述的化妆或医学护肤组合物,其特征在于,其包含作为主要活性成分的(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺或(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺。
18.如权利要求14所述的化妆或医学护肤组合物,其特征在于,其包含作为主要活性成分的(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺或(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺。
19.如权利要求12或13所述的化妆或医学护肤组合物,其特征在于,所述主要活性成分的含量为所述组合物总重量的0.001重量%至0.1重量%。
20.如权利要求12或13所述的化妆或医学护肤组合物,其特征在于,其还包含对UV-A和/或UV-B有活性的有机或无机日光滤光剂,所述日光滤光剂选自:邻氨基苯甲酸盐/酯、肉桂酸衍生物、二苯甲酰甲烷衍生物、水杨酸衍生物、樟脑衍生物、三嗪衍生物、二苯甲酮衍生物、β,β-二苯基丙烯酸酯/盐衍生物、苯并三唑衍生物、苯亚甲基丙二酸酯/盐衍生物、苯并咪唑衍生物、咪唑啉、双苯并吡咯衍生物、苯并噁唑衍生物、对氨基苯甲酸(PABA)衍生物、亚甲基双(羟基苯基苯并三唑)衍生物、滤光剂聚合物、4,4-二芳基丁二烯、包覆或未包覆的金属氧化物颜料或纳米颜料,以及它们的混合物。
21.如权利要求20所述的化妆或医学护肤组合物,其特征在于,所述金属氧化物颜料或纳米颜料是钛、锌、铁、锆或铈的氧化物。
22.如权利要求12或13所述的化妆或医学护肤组合物,其特征在于,其还包含选自以下的一种或多种活性成分:去糖化剂、提高胶原蛋白或弹性蛋白的合成或防止其降解的试剂、提高糖胺聚糖或蛋白多糖的合成或防止其降解的试剂、增加细胞增殖的试剂、脱色素剂或促着色剂、抗氧化剂或抗自由基剂或防污染剂、补水剂、刺激脂分解的试剂、排水或排毒剂、抗炎剂、渗透增强剂、脱屑剂、舒缓剂和/或抗刺激剂、收敛剂、作用于微循环的试剂,和它们的混合物。
23.权利要求12中所述的式(IIIa)的化合物或式(IIIb)的化合物或这些化合物的混合物作为日光照射的光防护剂在制备化妆组合物或医学护肤组合物中的应用。
24.如权利要求23所述的应用,其中,所述混合物是外消旋物。
25.如权利要求23所述的应用,其特征在于,式(IIIa)的化合物是(Z)-N-(2-羟基乙基)-3-(甲硫基)丙烯酰胺或(Z)-N-(4-羟基苯乙基)-3-(甲硫基)丙烯酰胺。
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FLAVONOIDS, AMIDOSULFOXIDES AND AN ALKALOID FROM THE LEAVES OF GL YCOSMIS CITRIFOLIA;TIAN-SHUNG Wu et al;《Phytochemistr》;19951231;第39卷(第6期);第1454页化合物6 * |
Herbicidal Activity of Novel Acrylamides;Tetsuji Iwasaki et al;《J. Agrie. Food Chem.》;19771231;第25卷(第6期);第1415页Table1 * |
NEW SULFUR-CONTAINING AMIDES FROM CLINACANTHUS NUTANS;Iung-Jr Lin Wu et al;《ejbps》;20150824;第2卷(第3期);第80页化合物2 * |
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