CN109661224B - 用于降低细胞黑色素含量的化合物 - Google Patents
用于降低细胞黑色素含量的化合物 Download PDFInfo
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- CN109661224B CN109661224B CN201780054564.5A CN201780054564A CN109661224B CN 109661224 B CN109661224 B CN 109661224B CN 201780054564 A CN201780054564 A CN 201780054564A CN 109661224 B CN109661224 B CN 109661224B
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- Prior art keywords
- skin
- melanin content
- compound
- alkyl
- composition
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
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Abstract
本发明涉及能够降低细胞黑色素含量的分子；特别涉及降低黑色素含量，用于诸如皮肤增亮的领域。一直需要具有改善的整体有效性的新美容皮肤增亮剂。因此，本发明的目的是提供用作黑色素含量降低剂的化合物。发现特定的吲哚基化合物可降低黑色素细胞中的黑色素含量。公开了式(I)化合物或其盐用于降低人皮肤的细胞黑色素含量的用途，其中，(i)R是：(a)‑(CH2)n‑A，其中n＝1至6且A是‑OH或‑NH2；或(b)‑O‑(CH2)n‑X，其中n＝1至5且X是卤素；(ii)R2是‑H、烷基、正己基、芳基、烷氧基或芳氧基；(iii)R3是‑H、烷基、芳基、烷氧基或芳氧基：
Description
技术领域
本发明涉及能够降低人皮肤的细胞黑色素含量的分子；特别涉及降低黑色素含量、用于诸如皮肤增亮的领域。
背景技术
大多数人都关心过度色素沉着的皮肤。例如，患有老年斑或雀斑的人可能希望此类色素斑不那么明显，而其他人可能希望减少由于暴露于阳光而引起的皮肤变暗。其他一些人可能希望增亮其天然皮肤颜色或色调。为了满足这种需要，尝试开发调节黑色素细胞中色素产生的产品。然而，迄今为止鉴别的物质往往具有较低的功效或具有不期望的副作用，如例如毒性或皮肤刺激性。因此，一直需要具有改善的整体有效性的新皮肤增亮剂。
期望的皮肤颜色是全世界、尤其是亚洲主要尚未满足的消费者需求。消费者特别期望均匀的皮肤颜色而不是不均匀的色调、不存在老年斑(日光斑)、不存在色素沉着过度和较浅的整体皮肤色调。一种解决方案是使用降低黑色素细胞活性的生物活性物。这些存在于表皮基底层中的细胞产生深色着色的色素黑色素，并将其以称为黑色素体的小输出囊泡输出至邻近的角质形成细胞。据描述，当局部施加至皮肤时，减少黑色素合成的化合物将随着时间而降低皮肤暗度，并可产生更均匀的皮肤色调。酪氨酸酶是调节黑色素细胞产生的常用靶标。然而，一些酪氨酸酶抑制剂与安全性问题例如，黑色素细胞死亡、永久性色素脱失、刺激和过敏反应相关。经常，有效的抑制剂会杀死黑色素细胞(例如氢醌)或引起致敏。因此，需要通过替代和安全机制起作用的安全且有效的皮肤色素产生抑制剂。
Thanigaimalai等(Bioorganic&Medicinal Chem.Letters,21,6824-6828(2011))描述了一系列1-苯基硫脲和1,3-二取代硫脲对黑色素瘤B16细胞系中黑色素形成和蘑菇酪氨酸酶的作用的研究。1-苯基硫脲对酪氨酸酶的抑制活性与它们的黑色素生成抑制平行。因此，1-苯基硫脲在黑色素瘤B16细胞中的黑色素生成抑制可能是酪氨酸酶抑制的结果。然而，所述1,3-二取代硫脲表现为不抑制酪氨酸酶的黑色素生成抑制剂。
CN 19 03 203(复旦大学)公开了多取代酰基硫尿嘧啶衍生物在制备抗病毒药物中的用途。
US 2006/0135618(Jean等)公开了一种药物或化妆品组合物，其包含至少一种通用硫脲，或其一氧化物或二氧化物衍生物中的至少一种，或其混合物。该药物有利地用于抑制酪氨酸酶，并且用作抗诱变剂和抗致癌剂。
US 2002/0044914(Dooley等)公开了使用一系列化合物来减少皮肤色素沉着的方法和配制物，所述化合物选自苯并咪唑、苯基硫脲、苯基硫醇、苯胺、二环酚和多环酚、噻吩胺和硫代苯甲酰胺(benzothiamide)。
JP 56 32460(Nihon Tokushu Noyaku Seizo)公开了可用于控制某些致病真菌的通式的酰基吡啶基硫脲衍生物。
Liu等(Chem.Res.Chinese Universities,26(6),929-932(2010))公开了一系列衍生自2,4-二氯苯氧基乙酰基(硫代)脲和S-(+)-3-甲基-2-(4-氯苯基)丁酰胺(butyrannide)的化合物的合成以及随后对其除草和杀真菌活性的测试。
EP2414701 A1(Ajinonoto,2012)公开了具有黑色素生产抑制活性的某些吲哚化合物。
所述吲哚基化合物具有下式：
WO9806695 A1(Sederma)公开了以下通式的亲脂性褪黑激素同系物的合成和用途，其中R＝直链或支链、饱和或不饱和、羟基化或未羟基化的C11至C19烷基链。这些衍生物优选通过5-甲氧基-色胺(tryptemin)的酰化获得。它们被设计用于化妆品或皮肤药物组合物中，用于补水、再生、抗脂溢、抗皱、漂白皮肤处理，以及用于防止由阳光和大气造成的光化性损害。
EP0820767 A2(L'Oreal,1998)公开了用于使人皮肤增白/脱色素的皮肤美容组合物，其包含皮肤增白/脱色素有效量的至少一种具有以下结构式的褪黑激素衍生物或其生理上可接受的盐、溶剂化物或生物前体/前药：其中R1是低级烷基，R2是氢原子或低级烷基，并且R3是氢原子或低级酰基，条件是羟基在吲哚环系上的4-位、6-位或7-位，所述褪黑激素衍生物或其生理上可接受的盐、溶剂化物或生物前体/前药被配制至用于其的局部可施加的化妆品上/皮肤病学上可接受的媒介物、载体或稀释剂中。
EP2196190 A1(Cognis,2010)公开了用于减少皮肤的色素沉着或色素沉着过度的方法，其包括向皮肤施加D-形式、L-形式或外消旋体形式(D,L)的式(I)物质：其中R1选自以下组中：氢基(-H)、甲基(-CH3)、乙基(-CH2CH3)、C3烷基、C4烷基、乙酰基(-C(O)CH3)、丙酰基(-C(O)CH2CH3)、正丁酰基(-C(O)CH2CH2CH3)和2-甲基-丙酰基(-C(O)CH(CH3)2)，R2选自以下组中：氢基(-H)、乙基(CH2CH3)、C3烷基、C4烷基、乙酰基(-C(O)CH3)、丙酰基(-C(O)CH2CH3)、正丁酰基(-C(O)CH2CH2CH3)和2-甲基-丙酰基(-C(O)CH(CH3)2)，R3选自以下组中：羟基(-OH)、氨基(NH2)、甲氧基(OCH3)、乙氧基(-OCH2CH3)、C3烷氧基、C4烷氧基和苄氧基(-OCH2C6H5)，并且X和Y独立地选自以下组中：氢基(-H)、甲基(-CH3)、乙基(-CH2CH3)、C3烷基、C4烷基、卤素基、甲氧基(-OCH3)、乙氧基(-OCH2CH3)、C3烷氧基、C4烷氧基和苄氧基(-OCH2C6H5)，条件是X和Y中的至少一个不为氢基(-H)。包含所述物质的化妆品组合物和/或局部组合物可用于(i)使皮肤增亮和/或(ii)使皮肤增白和/或(iii)减少皮肤色素沉着和/或(iv)减少皮肤色素沉着过度和/或(v)抑制皮肤中的黑色素生成和/或(vi)预防和/或延缓老化迹象和/或改善老化皮肤的皮肤外观。此组合物还可用于治疗由于黑色素合成和/或分泌异常引起的皮肤色素沉着或色素沉着过度。
常规的皮肤增亮组合物基于皮肤增亮剂的使用，据信皮肤增亮剂控制黑色素的分散或抑制酪氨酸酶。这些皮肤增亮剂包括烟酰胺、羧酸如壬二酸和曲酸、植物提取物和氢醌。吲哚类化合物早先已被声称有美容益处。此外，还已知含有带有其它化学基团的核心吲哚基团的吲哚基化合物。此类化合物是可商购得到的，但不知道可用于降低人皮肤的黑色素含量。
因此，本发明的目的是提供降低黑色素含量的化合物。
令人惊讶地，发现特定的吲哚基化合物可降低人皮肤中黑色素细胞的细胞黑色素含量。本发明人已观察到具有相同通用结构的所选化合物能够有效地降低含有角质形成细胞和黑色素细胞的人细胞活皮肤等同物(所谓的MelanodermaTM)中的黑色素。MelanodermaTM是含有人角质形成细胞和黑色素细胞两者的体外3D活皮肤等同物，并且被用作化合物对人皮肤体内功能作用的近似模拟物。
因此，前述通用结构描述了抑制色素产生且可用于有益地改变皮肤颜色、并以安全且有效的方式治疗色素沉着过度病症的化合物。
发明内容
根据第一方面，公开了式(I)化合物或其盐用于降低人皮肤的细胞黑色素含量的用途，其中，
(i)R是：
(a)-(CH2)n-A，其中n＝1至6且A是-OH或-NH2；或
(b)-O-(CH2)n-X，其中n＝1至5且X是卤素；
(ii)R2是-H、烷基、正己基、芳基、烷氧基或芳氧基；并且
(iii)R3是-H、烷基、芳基、烷氧基或芳氧基。
通过阅读以下详细描述和所附权利要求，这些和其它方面、特征和优点对于本领域普通技术人员将变得明显。为避免疑义，本发明的一个方面的任何特征均可用于本发明的任何其它方面。词语“包括”意在意指“包含”，但不一定是“由……组成”或“由……构成”。换句话说，所列的步骤或选项不必是穷尽性的。应当注意，在下面的描述中给出的实例意在阐明本发明，并不意在将本发明限于这些实例本身。类似地，除非另有指明，否则所有百分比均为重量/重量百分比。除了在操作实施例和比较实施例中或者另有明确指示的情况下以外，本说明书中指示材料的量或反应条件、材料的物理性质和/或用途的所有数字均应理解为由词语“约”修饰。以“x至y”的形式表示的数值范围应理解为包含x和y。当针对特定特征以“x至y”的形式描述多个优选范围时，应理解还涵盖组合不同端点的所有范围。
具体实施方式
如本文所用的“个人护理组合物”意在包括用于局部施加至人的皮肤和/或毛发的太阳暴露区域的组合物。此类组合物可被分类为免洗型或洗去型，并且包括施加于人体用于改善外观、清洁、气味控制或通用美感的任何产品。本发明的组合物可呈液体、乳剂、膏体、泡沫、擦洗剂、凝胶或调色剂的形式，或者用工具或通过面罩、垫或贴片施加。此类组合物的非限制性实例包括免洗型护肤乳、膏体、止汗剂、除臭剂、粉底、睫毛膏、防晒乳剂和洗掉型洗发剂、调理剂和沐浴凝胶。本发明的组合物优选免洗型组合物。
如本文所用的“皮肤”意在包括脸部和身体(例如颈部、胸部、背部、手臂、手臂下、手、腿和头皮)上的皮肤，尤其是其日光暴露部分。组合物还与在人体的任何其它角质基质如毛发上的施加有关，其中可配制产品以实现改善光保护的特定目的。
根据第一方面，公开了式(I)化合物或其盐用于降低人皮肤的细胞黑色素含量的用途，其中，
(i)R是：
(a)-(CH2)n-A，其中n＝1至6且A是-OH或-NH2；或
(b)-O-(CH2)n-X，其中n＝1至5且X是卤素；
(ii)R2是-H、烷基、正己基、芳基、烷氧基或芳氧基；并且
(iii)R3是-H、烷基、芳基、烷氧基或芳氧基。
在一个方面，优选的是当R是-O-(CH2)n-X时，n＝2且X是氯、溴或氟时。或者，当R是-(CH2)n-A时，n＝1且A是-OH或-NH2。
进一步优选地，R是-O-CH2-CH2-Cl或-CH2-NH2。
优选R2是烷基。更优选地，R2是甲基。
优选R3是-H。
优选式(I)化合物的盐是乙酸盐。
特别优选式(I)化合物是2-氯乙基[2-(1H-吲哚-3-基)-1-甲基乙基]氨基甲酸酯。
或者，优选的是，式(I)化合物是2-氨基-N-[2-(1H-吲哚-3-基)-1-甲基乙基]乙酰胺乙酸酯。
式(I)化合物可用于皮肤增亮的应用中。益处尤其可包括治疗黑斑病、治疗炎症后色素沉着过度、治疗老年斑、治疗暗斑和治疗不均匀的皮肤色调。
优选黑色素包含在人体原代黑色素细胞(primary melanocytes)中。
式(I)化合物可出于美容益处而用于组合物中。这些益处尤其用于护理和保持健康的皮肤，在此意义上，此类益处与药物或治疗益处不同。
因此，在一个方面，式(I)化合物或其盐用于降低人皮肤的细胞黑色素含量的用途是用于美容目的的。
或者，在另一方面，式(I)化合物或其盐用于降低人皮肤的细胞黑色素含量的用途是用于非美容目的，其包括治疗或药用目的。此类目的包括治疗导致人皮肤中黑色素含量增加或异常的任何医学病况。
方法和其它方面
根据第二方面，公开了降低人皮肤细胞的黑色素含量的方法，其包括向所述人皮肤施用如第一方面所公开的式(I)化合物或其盐的步骤。
优选所述方法是美容方法。或者，它是药用或治疗方法。
根据第三方面，公开了降低人皮肤细胞的黑色素含量的方法，其包括向对此有此需要的人施加如第一方面所公开的式(I)化合物或其盐的步骤。
优选所述方法是美容方法。或者，它是药用或治疗方法。
根据第四方面，公开了如第一方面所公开的式(I)化合物或其盐在制造用于降低人皮肤的细胞黑色素含量的组合物中的用途。
该组合物主要意在作为用于局部施加至人皮肤的产品，尤其是作为用于防护太阳辐射以及预防或减少皱纹或老化的皮肤或老年斑的出现、或皮肤中任何其它黑色素含量增加或受损的迹象的试剂。
在使用中，将少量组合物如1-5ml，从适合的容器或施加器施加至皮肤的暴露区域，如果需要，然后使用手或手指或适合的装置将其铺展于皮肤上和/或擦进皮肤中。
根据第五方面，公开了如第一方面所公开的式(I)化合物或其盐，其用于降低人皮肤的细胞黑色素含量。
皮肤增亮组合物
可通过皮肤增亮组合物使本发明在工业上实用。此类组合物含有下文所述的其它成分。
皮肤有益试剂
所述组合物可以另外包含选自以下的皮肤有益试剂：羟基酸、多羟基酸、羟基脂肪酸(特别是12-羟基硬脂酸)、曲酸、脱色素寡肽、加拉定(galardin)、多酚抗氧剂、巯基抗氧剂(thiolic antioxidant)、半胱胺盐酸盐、氢醌、叔丁基氢醌、维生素C衍生物、维生素E衍生物、维生素B衍生物、类视黄醇、4-取代的间苯二酚衍生物以及它们的混合物。
化妆品上可接受的媒介物
皮肤增亮组合物可进一步包含化妆品上可接受的媒介物，所述媒介物可用作用于所述组合物中使用的皮肤增亮剂的稀释剂、分散剂和/或载体，以在将所述组合物施加至皮肤时促进所述皮肤增亮剂的分布。适用于皮肤增亮组合物中的化妆品上的可接受的媒介物可以是含水的、无水的或乳液；最优选含水的或乳液，尤其是油包水或水包油乳液。当存在时，水通常构成组合物的其余部分。
除水之外，有机溶剂也可用作载体。
润肤剂
润肤剂也可用作皮肤增亮组合物中的化妆品上可接受的载体。润肤剂通常呈硅油和合成酯的形式。硅油可以是挥发性或非挥发性的。挥发性硅油优选选自含有3至9个、优选4至5个硅原子的环状或线性聚二甲基硅氧烷。可用作润肤剂的非挥发性硅油包括聚烷基硅氧烷、聚烷基芳基硅氧烷和聚醚硅氧烷共聚物。可用于本文中的基本上非挥发性的聚烷基硅氧烷包括例如聚二甲基硅氧烷。
可使用的酯类润肤剂是：
(i)具有10至20个碳原子的脂肪酸的烯基酯或烷基酯。其实例包括新戊酸异花生酯、异壬酸异壬酯、肉豆蔻酸油烯基酯、硬脂酸油烯基酯和油酸油烯基酯；
(ii)醚酯，如乙氧基化脂肪醇的脂肪酸酯；
(iii)多元醇酯，如乙二醇单脂肪酸酯和乙二醇二脂肪酸酯、二甘醇单脂肪酸酯和二甘醇二脂肪酸酯、聚乙二醇(200-6000)单脂肪酸酯和聚乙二醇(200-6000)二脂肪酸酯、丙二醇单脂肪酸酯和丙二醇二脂肪酸酯、聚丙二醇2000单油酸酯、聚丙二醇2000单硬脂酸酯、乙氧基化丙二醇单硬脂酸酯、单脂肪酸甘油酯和二脂肪酸甘油酯、多甘油多脂肪酯、乙氧基化单硬脂酸甘油酯、1,3-丁二醇单硬脂酸酯、1,3-丁二醇二硬脂酸酯、聚氧乙烯多元醇脂肪酸酯、脱水山梨糖醇脂肪酸酯和聚氧乙烯脱水山梨糖醇脂肪酸酯是令人满意的多元醇酯；
(iv)蜡酯，如蜂蜡、鲸蜡、肉豆蔻酸肉豆蔻基酯、硬脂酸硬脂基酯和山萮酸花生酯；和
(v)固醇酯，其中胆固醇脂肪酸酯是实例。
润肤剂可以按组合物重量计0.1％至50％、优选1％至20％中的任意量存在于组合物中。
脂肪酸
具有10至30个碳原子的脂肪酸也可被包含作为化妆品上可接受的载体。此类脂肪酸的说明性实例是壬酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、异硬脂酸、羟基硬脂酸、油酸、亚油酸、蓖麻油酸、花生酸、山萮酸、芥酸和其混合物。
湿润剂
多元醇类型的湿润剂也可用作化妆品上可接受的载体。湿润剂有助于增加润肤剂的有效性，减少脱皮，刺激积聚皮屑的去除并改善皮肤感觉。典型的多元醇包括甘油、聚亚烷基二醇，更优选亚烷基多元醇和它们的衍生物，包括丙二醇、双丙甘醇、聚丙二醇、聚乙二醇和其衍生物、山梨糖醇、羟丙基山梨糖醇、己二醇、1,3-丁二醇、1,2,6-己三醇、乙氧基化甘油、丙氧基化甘油和其混合物。为了获得最佳结果，湿润剂优选丙二醇或透明质酸钠。组合物中湿润剂的浓度可以是以组合物的重量计0.5％至30％且优选1％至15％范围内的任意值。
增稠剂
增稠剂也可用作组合物的化妆品上可接受的载体的一部分。典型的增稠剂包括交联的丙烯酸酯(例如Carbopol 982)、疏水改性的丙烯酸酯(例如Carbopol 1382)、纤维素衍生物和天然胶。在有用的纤维素衍生物中有羧甲基纤维素钠、羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、乙基纤维素和羟甲基纤维素。天然胶适合地包括瓜尔胶、黄原胶、菌核、角叉菜胶、果胶以及这些胶的组合。组合物中增稠剂的浓度可在以所述组合物的重量计0.0001％至5％、通常0.001％至1％、最佳0.01％至0.5％范围。水、溶剂、硅氧烷、酯、脂肪酸、湿润剂和/或增稠剂可以共同构成化妆品上可接受的载体，其量为以所述组合物的重量计1％至99.9％、优选80％至99％。
表面活性剂
表面活性剂也可存在于组合物中。表面活性剂的总浓度可以在以所述组合物的重量计0.1％至40％、优选1％至20％、最佳1％至5％的范围。表面活性剂可选自由阴离子型活性物、非离子型活性物、阳离子型活性物和两性活性物组成的组。特别优选的非离子型表面活性剂是具有以下的那些：C10-C20脂肪醇或脂肪酸的疏水物，其与每摩尔疏水物2至100摩尔氧化乙烯或氧化丙烯缩合；与2至20摩尔氧化烯缩合的C2-C10烷基酚；乙二醇单脂肪酸酯和乙二醇二脂肪酸酯；脂肪酸甘油单酯；脱水山梨糖醇单C8-C20脂肪酸和脱水山梨糖醇二C8-C20脂肪酸；嵌段共聚物(氧化乙烯/氧化丙烯)；和聚氧乙烯山梨糖醇酐以及其组合。烷基聚糖苷和糖脂肪酰胺(例如甲基葡糖酰胺)也是适合的非离子型表面活性剂。
优选的阴离子表面活性剂包括皂、烷基醚硫酸盐和烷基醚磺酸盐、烷基硫酸盐和烷基磺酸盐、烷基苯磺酸盐、烷基磺基琥珀酸盐和二烷基磺基琥珀酸盐、C8-C20酰基羟乙磺酸盐、酰基谷氨酸盐、C8-C20烷基醚磷酸盐和其组合。
防晒剂
防晒剂包括通常用于阻挡紫外光的那些材料。示例性化合物是PABA、肉桂酸酯和水杨酸酯的衍生物。例如，可使用阿伏二苯甲酮(avobenzophenone)(Parsol
)、甲氧基肉桂酸辛酯和2-羟基-4-甲氧基二苯甲酮(也称为羟苯甲酮)。甲氧基肉桂酸辛酯和2-羟基-4-甲氧基二苯甲酮可分别以商标Parsol MCX和二苯甲酮-3商购得到。还可使用以商标Mexoryl SX出售的依莰舒(Ecamsule)(亚苄基樟脑衍生物)，和以商标Mexoryl XL出售的甲酚曲唑三硅氧烷(drometrizole trisiloxane)，其是一种苯并三唑。其它实例包括奥克立林(octocrylene)、苯基苯并咪唑磺酸(也称为恩索利唑(ensulizole))、水杨酸乙基己酯、萘二甲酸二乙基己酯(diethylhexyl naphthylate)、双乙基己氧基苯酚甲氧基苯三嗪(bimotrizinole)(商标为Tinosorb S)和双辛酚三唑(bisoctrizole)(Tinosorb M)。无机防晒剂包括反射或散射太阳光线的氧化物，如二氧化钛和氧化锌。用于组合物中的防晒剂的确切量可取决于对太阳UV辐射所期望的防护程度而变化。还可采用反射或散射太阳光线的添加剂。这些添加剂包括氧化物，如氧化锌和二氧化钛。
芳香剂
芳香剂可用于局部皮肤增亮组合物中。可使用的芳香剂类型的说明性非限制性实例包括包含萜烯和萜烯衍生物的那些，如Bauer,K.等，Common Fragrance and FlavorMaterials,VCH Publishers(1990)中所述的那些。可用于本发明中的芳香剂类型的说明性但非限制性的实例包括香叶烯、二氢月桂烯醇(dihydromyrenol)、柠檬醛、万寿菊酮(tagetone)、顺式香叶酸、香茅酸、其混合物等。
CTFA Cosmetic Ingredient Handbook(第二版，1992)描述了适用于本发明组合物中的通常用于皮肤护理工业中的各种非限制性的化妆品和药物成分，其全部内容通过引用结合在此。
各种任选的活性成分可用于局部皮肤增亮组合物中。活性物定义为除润肤剂之外以及除仅改进组合物的物理特性的成分之外的皮肤有益试剂。尽管不限于该类别，但一般实例包括增量剂颜料，如滑石和二氧化硅，以及α-羟基酸、β-羟基酸和锌盐。
β-羟基酸包括例如水杨酸。氧化锌和吡硫翁锌是可用于局部皮肤增亮组合物中的锌盐的实例。
许多组合物、尤其是含水的那些组合物应当受到保护，以防止潜在的有害微生物的生长。因此，抗微生物化合物如三氯生和防腐剂通常是必需的。适合的防腐剂包括对羟基苯甲酸的烷基酯、乙内酰脲衍生物、丙酸盐和各种季铵化合物。特别优选的防腐剂是对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯氧基乙醇和苄醇。防腐剂通常可以在以所述组合物的重量计0.1％至2％范围的量采用。
可与组合物使用的其它任选成分包括二酸(例如丙二酸和癸二酸)，抗氧剂如维生素E、类视黄醇类物质，包括视黄酸、视黄醛、视黄醇和视黄酯，如丙酸视黄酯和棕榈酸视黄酯，共轭亚油酸，岩芹酸和其混合物，以及众所周知的用于减少皱纹(如透明质酸、泛醌、茉莉酸衍生物、胶原蛋白、肽和玻色因(proxylane))、抗痤疮作用和减少皮脂影响的任何其它常规成分。
用于局部皮肤增亮组合物的包装可以是贴片、瓶、管、滚珠施加器、推进剂驱动的气溶胶装置、挤压容器或带盖子的罐。
现在将借助于以下的非限制性实施例来进一步说明本发明。
实施例
有关实验程序的描述如下。
将一组吲哚基化合物以在100％DMSO中10mM的储备物购自SIGMA-ALDRICH。最初在细胞培养物中以25μM的浓度(表1)检查它们降低黑色素含量的能力，然后在不同剂量(表2)下检查。新生儿包皮原代人表皮黑色素细胞来源于Cascade Biologicals(标记为P0代)。将黑色素细胞维持在补充有人黑色素细胞生长补充剂(Cascade；目录编号S-002-5)的培养基254CF(Cascade目录编号M-254CF-500)(下文称为MGM)中。将细胞在具有5％CO2气氛的加湿培育箱中维持在37℃。
细胞存活力和黑色素含量测定
将50,000个细胞接种在MGM的24孔板中。在24小时后，用各种浓度的测试材料处理培养物，且再保持72小时不受干扰。还同时平行设置0.25％(v/v)DMSO的比较媒介物对照。在温育期结束时，使用钙黄绿素法确定细胞存活力。
简单地说，去除耗尽细胞培养物的培养基，并用0.4ml 1×PBS-Ca-Mg溶液将细胞洗涤一次。添加新鲜的1μM钙黄绿素-AM(0.2ml/孔)，包括向没有细胞的对照孔中添加。将板用铝箔覆盖，并在常规CO2培育箱中在37℃温育30分钟。然后在TECAN M1000 Infinite系列板读数器中测量(λex 490nm和λem 520nm)钙黄绿素荧光。
黑色素含量测定
在获得钙黄绿素荧光读数后，排出细胞并每孔添加新鲜的125μl 1N的NaOH(在10％的DMSO中)。通过再悬浮和温育(60℃/1小时)裂解细胞。然后将该裂解产物转移至新鲜的384孔板中，并在TECAN M1000板读数器中测量OD405nm(相对黑色素含量的估计值)。
计算
钙黄绿素荧光值是在0至100数值范围内转换的比率(存活力％)，100表示0.25％DMSO样品的值。将百分比黑色素含量计算为任何样品的OD405nm值与DMSO参考样品的OD405nm值之间的比率。然后将归一化的黑色素含量值计算为100*(黑色素含量％)/(细胞存活力％)。
黑色素含量的降低％估算为[100-(归一化的黑色素含量)]
实施例1：各种化合物对黑色素含量的技术影响
测试了以下三种化合物。化合物1和3在本发明的范围内。化合物2虽然具有类似的结构，但在本发明的范围之外。
化合物1：2-氯乙基[2-(1H-吲哚-3-基)-1-甲基乙基]氨基甲酸酯
化合物2：N-[2-(1H-吲哚-3-基)-1-甲基乙基]乙酰胺
化合物3：2-氨基-N-[2-(1H-吲哚-3-基)-1-甲基乙基]乙酰胺乙酸盐
在所有测试的吲哚基化合物中，化合物1和3显示出显著的黑色素减少。
表1：细胞黑色素含量的数据
以上表格表明化合物1直接通过其在黑色素含量水平上的作用而有利地比较，而化合物3更多地通过细胞数展现其作用。然而，化合物2(本发明范围之外的化合物)的作用相对不明显。
实施例2：不同剂量的化合物1的作用
进一步检查化合物1在不同剂量下对另一批新鲜的人体原代黑色素细胞的作用，并将其与众所周知的皮肤增亮剂(曲酸)进行比较。
表2：细胞黑色素含量数据
表2中的数据清楚地表明本发明的化合物1优于曲酸，因为化合物1在远低于曲酸的浓度下都更有效。
Claims (10)
1.式(I)化合物或其盐在制造用于降低人皮肤的细胞黑色素含量的组合物中的用途，
其中，
(i)R是：
(a)-(CH2)n-A，其中n＝1至6且A是-NH2；或
(b)-O-(CH2)n-X，其中n＝1至5且X是卤素；
(ii)R2是-H、烷基、正己基、芳基、烷氧基或芳氧基；并且
(iii)R3是-H、烷基、芳基、烷氧基或芳氧基
其中所述式(I)化合物或其盐在所述组合物中的含量为6.25μM或以上。
2.根据权利要求1所述的用途，其中，当R为-O-(CH2)n-X时，n＝2且X为氯、溴或氟。
3.根据权利要求1所述的用途，其中，当R为-(CH2)n-A时，n＝1且A为-OH或-NH2。
4.根据权利要求1至3中任一项所述的用途，其中所述R2是烷基。
5.根据权利要求1至3中任一项所述的用途，其中R3是-H。
6.根据权利要求1至3中任一项所述的用途，其中所述化合物是2-氯乙基[2-(1H-吲哚-3-基)-1-甲基乙基]氨基甲酸酯。
7.根据权利要求1至3中任一项所述的用途，其中所述化合物是2-氨基-N-[2-(1H-吲哚-3-基)-1-甲基乙基]乙酰胺乙酸盐。
8.根据权利要求1至3中任一项所述的用途，其中所述化合物的所述盐是乙酸盐。
9.根据权利要求1至3中任一项所述的用途，其中所述黑色素包含在人体原代黑色素细胞内。
10.根据权利要求1至3中任一项所述的用途，其中所述用途用于美容目的。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP16187446 | 2016-09-06 | ||
| EP16187446.6 | 2016-09-06 | ||
| PCT/EP2017/070550 WO2018046243A1 (en) | 2016-09-06 | 2017-08-14 | Compounds for reducing cellular melanin content |
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| Publication Number | Publication Date |
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| CN109661224A CN109661224A (zh) | 2019-04-19 |
| CN109661224B true CN109661224B (zh) | 2022-05-24 |
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| Country | Link |
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| EP (1) | EP3509566B1 (zh) |
| CN (1) | CN109661224B (zh) |
| MX (1) | MX2019002572A (zh) |
| WO (1) | WO2018046243A1 (zh) |
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| US20220280405A1 (en) * | 2019-08-28 | 2022-09-08 | Conopco, Inc. , d/b/a UNILEVER | Novel compounds for skin lightening |
| WO2023191901A1 (en) * | 2022-03-31 | 2023-10-05 | Agarwal Neeru | Topical compositions for tanscreen comprising ecamsule and uses thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0820767A2 (fr) * | 1996-07-25 | 1998-01-28 | L'oreal | Utilisation de dérivés de la mélatonine pour la dépigmentation de la peau et compositions les comprenant |
| WO1998006695A1 (fr) * | 1996-08-09 | 1998-02-19 | Sederma S.A. | Derives de la melatonine et leur utilisation dans les compositions cosmetiques ou dermopharmaceutiques |
| EP2196190A1 (en) * | 2008-12-09 | 2010-06-16 | Cognis IP Management GmbH | Skin whitening |
| EP2412701A1 (en) * | 2009-03-25 | 2012-02-01 | Ajinomoto Co., Inc. | Novel amide derivative and skin whitening agent |
| CN105050663A (zh) * | 2013-03-11 | 2015-11-11 | 拜尔斯道夫股份有限公司 | 美容和皮肤病学上安全的取代迈克尔受体防止、降低或预防人类皮肤酪氨酸酶活性和/或亮肤的用途 |
| WO2016107697A1 (en) * | 2014-12-30 | 2016-07-07 | Unilever N.V. | A skin lightening composition comprising 4-hexylresorcinol and ilomastat |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5578159A (en) | 1978-12-06 | 1980-06-12 | Sadahatsu Araki | Intake air cleaner for engine |
| ATE367157T1 (de) | 2000-02-29 | 2007-08-15 | Mediquest Therapeutics Inc | Melanocyt-tyrosinase hemmer als topische hautdepigmentierende mittel |
| FR2845599B1 (fr) | 2002-10-11 | 2005-01-07 | Lmd | Medicament comprenant une thiouree pour son utilisation en tant que depigmentant |
| CN1903203A (zh) | 2005-07-26 | 2007-01-31 | 复旦大学 | 多取代酰基硫脲嘧啶衍生物在制备抗病毒药物中的用途 |
| FI121484B (fi) | 2009-03-30 | 2010-11-30 | Waertsilae Finland Oy | Sovitelma ja menetelmä mäntämoottorin värähtelyn vaimentamiseksi sekä mäntämoottori |
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- 2017-08-14 CN CN201780054564.5A patent/CN109661224B/zh active Active
- 2017-08-14 MX MX2019002572A patent/MX2019002572A/es unknown
- 2017-08-14 EP EP17758089.1A patent/EP3509566B1/en active Active
- 2017-08-14 WO PCT/EP2017/070550 patent/WO2018046243A1/en active Search and Examination
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0820767A2 (fr) * | 1996-07-25 | 1998-01-28 | L'oreal | Utilisation de dérivés de la mélatonine pour la dépigmentation de la peau et compositions les comprenant |
| WO1998006695A1 (fr) * | 1996-08-09 | 1998-02-19 | Sederma S.A. | Derives de la melatonine et leur utilisation dans les compositions cosmetiques ou dermopharmaceutiques |
| EP2196190A1 (en) * | 2008-12-09 | 2010-06-16 | Cognis IP Management GmbH | Skin whitening |
| EP2412701A1 (en) * | 2009-03-25 | 2012-02-01 | Ajinomoto Co., Inc. | Novel amide derivative and skin whitening agent |
| CN105050663A (zh) * | 2013-03-11 | 2015-11-11 | 拜尔斯道夫股份有限公司 | 美容和皮肤病学上安全的取代迈克尔受体防止、降低或预防人类皮肤酪氨酸酶活性和/或亮肤的用途 |
| WO2016107697A1 (en) * | 2014-12-30 | 2016-07-07 | Unilever N.V. | A skin lightening composition comprising 4-hexylresorcinol and ilomastat |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3509566B1 (en) | 2020-11-04 |
| EP3509566A1 (en) | 2019-07-17 |
| WO2018046243A1 (en) | 2018-03-15 |
| MX2019002572A (es) | 2019-06-06 |
| CN109661224A (zh) | 2019-04-19 |
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