CN110483258A - 二芳基衍生化合物及包含该化合物的皮肤美白组合物 - Google Patents
二芳基衍生化合物及包含该化合物的皮肤美白组合物 Download PDFInfo
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- CN110483258A CN110483258A CN201910401713.1A CN201910401713A CN110483258A CN 110483258 A CN110483258 A CN 110483258A CN 201910401713 A CN201910401713 A CN 201910401713A CN 110483258 A CN110483258 A CN 110483258A
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- skin
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Abstract
本发明涉及包含作为有效成分的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物,以及包含其的皮肤美白组合物。具体地,根据本发明的化合物具有连接有多酚基和金刚烷基苯基的结构,因此通过抑制黑色素生成来具有美白效果,从而可多用于药物组合物、化妆品组合物或皮肤外用制剂等。此外,与现有技术中的美白物质相比,可以利用供需容易的起始物质进行制备,因此可以进行量产。
Description
技术领域
本发明公开了二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物,以及包含其的用于皮肤美白的组合物。
背景技术
皮肤具有物理及化学的紫外线防御因子,且具有最小限度地防止因多种光化学反应引起的皮肤障碍的作用。角质层通过反射和扩散紫外线来减损其能量。此外,黑色素、SOD(超氧化物歧化酶)、其他的抗氧化成分等可吸收渗透到皮肤内部的紫外线,通过使其能量衰减或清除使紫外线继发的活性氧来抵御皮肤的障碍。
但是,当生物体接收到超过如上所述的防御因子的能力的大量紫外线时,或者其能力随着年龄而减弱时,会发生各种皮肤障碍。
皮肤中存在巨噬细胞、朗格汉斯细胞(Langerhans cells)等在生命系统中负责免疫的各种细胞。而由于紫外线照射,不仅使这些细胞的数量减少,而且还会发生功能上的障碍。占最大部分的是皮肤中黑色素的分布状态和量占肤色的决定因素中的大部分。黑色素(melanin)由黑素细胞(melanocyte)产生,这些黑素细胞含有酪氨酸酶等酶,这些酶共同作用,以一直存在于生物体内的称为酪氨酸(tyrosine)的氨基酸为基质聚合并进行氧化反应,从而形成为深棕色素的黑色素。由此形成的黑色素通过黑素细胞的树突迁移到称为角质形成细胞的表皮细胞。其中,黑色素在细胞核周围形成帽状结构,保护基因免受紫外线的伤害并消除自由基(free radical),从而起到保护细胞内蛋白质等的重要作用。
在生物体内没有分解黑色素的酶,黑色素只在角质形成细胞从表皮脱落时一起从皮肤中去除。然而,当黑色素的产生超过必要时,会诱发如斑点,雀斑和斑等的色素沉着症,在美容上带来不良的后果。
已知影响黑色素生成的几种因素,其中由紫外线引起的黑色素生产亢进并以此产生的色素沉着在化妆品领域非常重要。与美白化妆品中配合的用于预防色素沉着的药物的基本原理是抑制酪氨酸酶(tyrosinase)作用、抑制酪氨酸酶产生、抑制产生黑色素的介质、抑制已有的黑色素的还原和光氧化、促进黑色素排出、以及阻断紫外线等。
根据想要在紫外线照射环境下具有白皙皮肤的女性的愿望,预防和改善皮肤色素异常和色素沉着过度的需求正在增加,因此有必要开发一种防止黑色素过量产生的美白产品,并在此期间已经做出了许多努力。其具体例如有曲酸(kojic acid)和熊果苷(arbutin)等的括抑制酪氨酸酶活性的抑制剂、氢醌、维生素A、维生素C及其衍生物等。然而,由于皮肤的安全性问题、在制剂中的稳定性问题和增白效果不足,使它们的使用受到限制。
此外,已知的新型美白物质,即山菅兰提取物Nivitol(=4-[3-(2,4-二甲氧基-3-甲基-苯基)-丙基]苯-1,3-二醇),由于合成时需要高价的原料,应此不适用于大量的生产。
因此,正在积极地研究既能够抑制黑色素生成也具有优异的皮肤美白效果,且原料的供需容易,制备过程简单且可以大量生产的新型化合物。
【现有技术文献】
[专利文献]
(专利文献1)韩国专利公开号10-2016-0026678(2016年03月09日)。
发明内容
技术问题
在一个方面,本发明提供一种通过抑制黑色素的产生而具有优异的皮肤美白效果的新型二芳基衍生化合物、以及包含该化合物的皮肤美白组合物。
技术方案
在一个方面,本发明提供一种新型二芳基衍生物化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物。
在一个方面,本发明提供新型二芳基衍生物化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物的制备方法。
在一个方面,本发明提供包含作为有效成分的新型二芳基衍生物化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物的皮肤美白组合物。
有益效果
在一个方面,本发明的新型二芳基衍生化合物通过抑制黑色素的生成而具有美白效果,因此可用于药物组合物、化妆品组合物或皮肤外用制剂等多种用途。
在另一个方面,与现有美白物质相比,本发明的新型二芳基衍生化合物,可以由供需容易的起始物质所制备,因此可以进行量产。
附图说明
图1示出了制备根据本发明实施例的二芳基衍生物化合物的制备方法。
图2显示了已知的作为现有美白物质的山菅兰提取物(Nivitol)的制备方法。
具体实施方式
术语定义
在本说明书中,当某部分“包括”一个组成要素时,除非有特别说明,是指该部分还包括其他组成要素,而不是将其他组成要素排除在外。
关于示例性实施方式的说明
以下,详述本发明。
在本发明的示例性实施例中,本发明为由以下化学式(1)表示的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物。
[化学式1]
在化学式(1)中
R1和R2相同或不同,分别独立地为具有1-10个碳原子的烷基,
X为-CO-或-CH2-。
在本说明书中,是指与另一取代基连接的部分。此外,在本说明书中,-Me表示甲基(-CH3),-MOM表示甲氧基甲基(-CH2OCH3)。
在本说明书中,所述烷基可以为直链或支链的,并且其碳原子数不受特别限制,但优选为1-10,更优选为1-5,具体地可以为甲基、乙基,丙基等,但不限于此。
在本说明书中,术语“异构体”具体不仅包括光学异构体(optical isomers)(例如,基本上纯的对映异构体(essentially pure enantiomers),基本上纯的非对映异构体(essentially pure diastereomers)或其混合物),还包括构象异构体(conformationisomers)(即,异构体仅在一个或多个化学键的角度上不同),位置异构体(positionisomers)(尤其是互变异构体(tautomers))或几何异构体(geometric isomers)(例如,顺-反式异构体)。
在本说明书中,“基本上纯的(essentially pure)”是指,例如当使用相关的对映异构体,立体异构体或非对映异构体时,以对映异构体,立体异构体或非对映异构体为例的具体化合物所占的量约为90%或以上,优选约为95%(w/w)或以上,较优选约为97%(w/w)或以上、或98%(w/w)或以上,更优选约为99%(w/w)或以上,甚至更优选约为99.5%(w/w)或以上。
在本说明书中,“医学上可接受”是指在使用常规或医药学剂量(medicinaldosage)时,通过避免显着的毒性作用,从而可以获得或获得政府或同等级监管机构的可用于动物,更具体地,可用于人类的批准,或被认定为被列举在食品法典、保健功能食品法典、或一般药典中,或被记载于其他一般文献中。
在本说明书中,“医学上可接受的盐”是指根据本发明的一个方面的盐,其为常规或药学上可接受的,并具有母体化合物(parent compound)的理想活性的盐。所述盐包括(1)由盐酸、氢溴酸、硫酸、硝酸、磷酸等无机酸形成的;或由乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、4-甲基双环[2,2,2]-辛-2-烯-1-羧酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、叔乙酸丁酯、十二烷基硫酸盐、葡萄糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸、粘康酸等有机酸形成的酸加成盐(acid addition salt);或(2)母体化合物中存在的酸性质子被取代而形成的盐。
在本说明书中,术语“水合物(hydrate)”是指与水结合的化合物,且为包括在水和化合物之间不具有化学键合力的包合化合物的广义概念。
在本说明书中,术语“溶剂合物”是指在溶质的分子或离子与溶剂的分子或离子之间形成的高阶化合物。
在一个实施例中,所述化学式(1)可以由以下化学式(1-1)或(1-2)表示。
[化学式1-1]
[化学式1-2]
所述化学式1-1的二芳基衍生化合物的IUPAC名称为4-[3-(5-金刚烷-1-基-2,4-二甲氧基-苯基)-丙基]苯-1,3-二醇(4-[3-(5-Adamantan-1-yl-2,4-dimethoxy-phenyl)-propyl]-benzene-1,3-diol)。
所述化学式1-2的二芳基衍生化合物的IUPAC名称为1-(5-金刚烷-1-基-2,4-二甲氧基-苯基-3-(2,4-二羟基-苯基)丙-1-酮(1-(5-Adamantan-1-yl-2,4-dimethoxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propan-1-one)。
所述化学式1-1的化合物在常温下为淡黄色固体化合物,所述化学式1-2化合物在常温下为粉红色固体化合物。
在本发明的一个示例性实施例中,本发明为一种用于制备上述二芳基衍生化合物的方法,可利用以下化学式(2)所示的化合物作为起始物质。
[化学式2]
在化学式(2)中,R1和R2如化学式(1)中所定义。
所述起始物质可以按照以下式进行制备,具体地,可以在酸性条件下通过FriedelCraft烷基化反应取代金刚烷基。
在所述式中,R1和R2如同化学式(1)中所定义。
在一个实施例中,上述二芳基衍生物化合物的制备方法可包括由以下反应式(1)表示的反应步骤。具体地,通过使用强碱性氢氧化钾(甲醇溶液),可以将起始物质与由保护基所保护的苯甲醛(benzaldehyde)进行Aldol缩合反应,而合成查尔酮衍生物(chalconederivative)。
[反应式1]
在反应式1中,R1和R2如化学式1中所定义,保护基(Protect)为
在一个实施例中,上述制备二芳基衍生化合物的方法,还可包括由以下反应式(2)表示的反应步骤。具体地,通过使用钯/活性炭催化剂,在1大气压的氢气条件下,通过加氢反应,对查尔酮衍生物进行还原,可以用丙烷(propane)或丙酮(Propanone)链制备连接基团。
[反应式2]
在反应式2中,R1、R2和X如化学式1中所定义,保护基如反应式1中所定义。
然后,从反应式2的最终化合物中将保护基进行去保护(deprotection),最后得到由所述化学式1表示的二芳基衍生化合物。
在本发明的示例性实施例中,本发明提供一种皮肤美白组合物,其包含作为有效成分的由所述化学式1表示的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物。
在一个实施例中,所述有效成分的浓度可以为基于组合物总重量的0.01-20重量%。
在一个实施例中,所述有效成分可以为基于组合物总重量的0.01-20重量%,例如,可以为0.01重量%或以上、0.1重量%或以上、0.2重量%或以上、0.3重量%或以上、0.4重量%或以上、0.5重量%或以上、0.7重量%或以上、0.8重量%或以上、0.9重量%或以上、或1重量%或以上,且可以为15重量%或以下、10重量%或以下、9重量%或以下、8重量%或以下、7重量%或以下、6重量%或以下、5重量%或以下、4重量%或以下、3重量%或以下、2重量%或以下、或1重量%或以下。在本发明的一个实施例中,所述有效成分的浓度优选为0.01-5重量%。
当所述浓度低于0.01重量%时,抗炎症或皮肤抗老化作用可能甚微;当浓度大于20重量%,可能会出现细胞毒性。
在一个实施例中,所述皮肤美白组合物可以应用于各种领域,例如,作为药物组合物、化妆品组合物或皮肤外用制剂进行使用,并且优选用作化妆品组合物的活性成分。具体地,当包含所述二芳基衍生化合物作为有效成分时,可以抑制黑色素的生成,从而表现出皮肤美白效果。
根据本发明实施例的皮肤美白组合物可以为药物组合物,并且可以进一步包含防腐剂、稳定剂、可湿性粉剂或乳化剂、如盐和/或缓冲剂等的用于控制渗透压的药物辅助剂,以及其它对治疗有用的物质,并可根据常规方法配制成各种口服剂型或肠胃外剂型。
所述口服剂型,例如可为片剂、丸剂、硬和软胶囊、液体、悬浮液、乳剂、糖浆、粉剂、散剂、细粒剂、颗粒剂和微丸剂等,而这些剂型除了包含有效成分以外,还可以包含界面活性剂、稀释剂(例如:乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纤维素和甘氨酸)、润滑剂(例如:二氧化硅、滑石、硬脂酸及其镁盐或钙盐、以及聚乙二醇)。此外,片剂还可包含,例如硅酸镁铝、淀粉糊、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠和聚乙烯吡咯烷酮的粘合剂,并根据情况可包含,如淀粉、琼脂、海藻酸或其钠盐的崩解剂、吸收剂、着色剂、香料和甜味剂等的药物添加剂。所述片剂可通过常规的混合,制粒或包衣方法进行制备。此外,所述肠胃外给药剂型可为经皮给药剂型,例如可为注射剂、滴剂、软膏剂、洗剂、凝胶剂、霜剂、喷雾剂、混悬剂、乳剂、栓剂、贴剂等剂型,但不限于此。
所述药物组合物可以通过肠胃外、直肠、局部、经皮、皮下等途径进行给药。
所述有效成分的给药剂量在本领域普通技术人员的水平内,并且药物的日剂量可以根据待施用的受试者的进展程度、发病时间、年龄、健康状况和并发症等的各种因素而变化,当以成人为基准时,通常所述组合物可以为1μg/kg-100mg/kg,例如0.1mg/Kg-20mg/Kg、0.5mg/Kg-20mg/Kg、或1mg/kg-20mg/kg,优选5mg/kg-10mg/kg,每天分为1至3次进行给药,并且给药剂量不以任何方式限制本发明的范围。
根据本发明一个实施例的所述用于皮肤美白的组合物可以为化妆品组合物,并且化妆品组合物的外形包含化妆品学或皮肤科学可接受的介质或基质。其可以为适用于局部施用的所有制剂,例如可以制备成溶液,凝胶,固体,糊状无品,通过将油相分散在水相中获得的乳液、悬浮液、微乳液、微胶囊、微小颗粒球、或以离子型(脂质体)和非离子型囊泡分散剂的形态、或霜、爽肤水、乳液、粉末、软膏,喷雾剂或遮瑕棒的形式。可以根据本领域的常规方法制备这些组合物。根据本发明的组合物还可以用作泡沫的形态、或进一步含有压缩的推进剂的气溶胶组合物的形态。
根据本发明的一个实施例的所述化妆品组合物,其制剂没有特别限制,例如可以制备为柔肤化妆水、收敛化妆水、营养化妆水、营养霜、按摩霜、精华素、眼霜、眼部精华、洁面霜、洁面泡沫、洁面水、面膜、粉末、身体乳、身体霜、身体油和身体精华等的化妆品。
当本发明的制剂为糊剂、霜剂或凝胶时,可使用动物纤维、植物纤维、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅、膨润土、二氧化硅、滑石或氧化锌等作为在载体成分。
当本发明的制剂为粉末或喷雾时,可使用乳糖、滑石、二氧化硅、氢氧化铝、硅酸钙或聚酰胺粉末作为载体成分,尤其当剂型为喷雾时,可进一步包含如氯氟烃、丙烷/丁烷或二甲醚的推进剂。
当本发明的制剂为溶液或乳胶时,可使用溶剂、溶剂化剂或破乳化剂作为载体成分,例如水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇油、甘油脂肪酸酯、聚乙二醇或脱水山梨糖醇的脂肪酸酯。
当本发明的制剂为悬浮液时,可使用如水、乙醇或丙二醇的液体稀释剂、如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇酯和聚氧乙烯脱水山梨糖醇酯等的悬浮剂、微晶纤维素、偏氢氧化铝、膨润土、琼脂或黄蓍胶等作为载体成分。
当根据本发明的制剂为含有界面活性剂的洁面剂时,可使用脂肪醇硫酸钠、脂肪醇醚硫酸钠、磺基琥珀酸单酯、羟乙基磺酸钠、咪唑烷衍生物、甲基牛磺酸钠、肌氨酸钠、脂肪酸酰胺醚硫酸钠、烷基酰胺甜菜碱、脂肪醇、脂肪酸甘油酯、脂肪酸二乙醇酰胺、植物油、亚麻酸衍生物或乙氧基化甘油脂肪酸酯作为载体成分。
根据本发明的一个实施例的化妆品组合物中,除了包含所述有效成分以外,还可以包含功能性添加剂和通常的化妆品组合物中包含的成分。所述功能性添加剂可包括选自水溶性维生素、油溶性维生素、聚合肽、聚合多糖、鞘脂和海藻提取物中的成分。
此外,本发明的化妆品组合物中,除了所述功能性添加剂外,还可以根据需要搭配通常化妆品组合物中包含的成分。除此之外包含的配合成分例如有有机成分、保湿剂、润肤剂、界面活性剂、有机和无机颜料、有机粉末、紫外线吸收剂、防腐剂、杀菌剂、抗氧化剂、植物提取物、pH调节剂、乙醇、色素、香料、血液循环促进剂、冷却剂、止汗剂、纯净水等。
此外,根据本发明的一个实施例的用于皮肤美白的组合物可以为皮肤外用制剂,并且所述皮肤外用制剂为包括涂抹于皮肤外部的任何制剂的总称,其中包括各种制剂的化妆品和医药品。
在本发明的示例性实施例中,本发明涉及由以下化学式(1)表示的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物在制备皮肤美白组合物中的用途。
[化学式1]
在化学式1中,
R1和R2相同或不同,各自独立地为具有1-10个碳原子的烷基,
X是-CO-或-CH2-。
以下,将通过以下实施例更具体地描述本发明。但是,以下实施例的明目在于帮助理解本发明,本发明的范围和范畴不限此限制。
实施例
实施例:新型二芳基化合物的制备
【实施例1】4-[3-(5-金刚烷-1-基-2,4-二甲氧基-苯基)-丙基]苯-1,3-二醇)的制备
(1)1-(5-金刚烷-1-基-2,4-二甲氧基-苯基)-乙酮的制备
将1-(2,4-二甲氧基苯基)-乙酮(26.1g)和1-金刚烷醇(23.2g)溶解在氯仿(400mL)中并搅拌。向其中逐滴加入浓硫酸(8mL)后,回流5小时。将水(200mL)加入到搅拌的混合溶液中并用碳酸氢钠进行中和。将有机层干燥并减压浓缩后,通过用二氯甲烷和己烷进行再结晶,从而得到1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-乙酮(28.3g)。
1H NMR(300MHz,DMSO-d6)7.54(s,1H),6.66(s,1H),3.92(s,3H),3.91(s,3H),2.46(s,3H),1.98(s,9H),1.71(s,6H)。
(2)1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-3-(2,4-二异丙氧基苯基)-丙烯酮的制备
将所述(1)中得到的1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-乙酮(6.29g)溶解在甲醇(100mL)中,将溶解在甲醇(20mL)中的氢氧化钾(5.6g)进行滴加10分钟。将2,4-二异丙氧基苯甲醛(5.33g)溶解在甲醇(20mL)中并滴加到该溶液中,再将混合液回流6小时。将温度降至常温,通过用2N盐酸水溶液,将pH调节至2,通过过滤收集所生成的固体,对该固体用二氯甲烷和己烷进行再结晶,从而得到1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-3-(2,4-二异丙氧基苯基)-丙烯酮(11.3g)。
1H NMR(300MHz,DMSO-d6)7.74~7.42(m,4H),6.69~6.54(m,3H),4.75~4.69(m,2H),3.92(s,3H),3.91(s,3H),2.01(s,9H),1.72(s,6H),1.31~1.21(m,12H)。
(3)1-{5-[3-(2,4-二异丙氧基苯基)-丙基]-2,4-二甲氧基苯基}-金刚烷的制备
将所述(2)中得到1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-3-(2,4-二异丙氧基苯基)-丙烯酮(2.07g)溶解于三氟乙酸(5mL)中,滴加入三乙基硅烷(3.67g)后,在常温下搅拌24小时。将反应溶液用水(100mL)进行稀释,再用二氯甲烷(100mL×3)进行萃取,干燥并浓缩后,通过柱色谱进行分离,得到无色透明液体生成物(0.55g)。
1H NMR(300MHz,DMSO-d6)6.97~6.94(m,1H),6.81(s,1H),6.55(s,1H),6.43~6.36(m,2H),4.57~4.51(m,2H),3.78(s,3H),3.76(s,3H),2.45~2.40(m,4H),1.98(s,9H),1.70~1.65(m,8H),1.21(t,J=6.6Hz,12H)。
(4)4-[3-(5-金刚烷-1-基-2,4-二甲氧基苯基)-丙基]苯-1.3-二醇的制备
将按照与所述(3)相同的方法所得到的1-{5-[3-(2,4-二异丙氧基苯基)-丙基]-2,4-二甲氧基苯基}-金刚烷(1.5g)溶解在二氯甲烷(100mL)中,将溶液的温度降至0℃,滴加三氯硼烷(18ml)后,随着将温度提高至常温,对混合液进行搅拌10分钟。用冷水终止反应,通过使用二氯甲烷进行萃取,干燥并浓缩后,通过柱色谱法进行分离,从而得到固体生成物(0.43g)。其分子量为422.5565g/mol。
1H NMR(300MHz,DMSO-d6)8.97(s,1H),8.89(s,1H),6.81~6.74(m,2H),6.53(s,1H),6.21(s,1H),6.09~6.08(m,1H),3.76(s,3H),3.74(s,3H),2.44~2.36(m,4H),1.96(s,9H),1.68(s,6H),1.64~1.63(m,2H)。
【实施例2】1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-3-(2,4-二羟基苯基)丙-1-酮的制备
(1)1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-3-(2,4-双甲氧基甲氧基苯基)-丙烯酮的制备
将所述(1)中得到的1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-乙酮(6.29g)溶解在甲醇(100mL)中,并将氢氧化钾甲醇溶液(5.6g KOH/20mL MeOH)滴加10分钟。将2,4-双-甲氧基甲氧基-苯甲醛(5.43g)溶解在甲醇(50mL)中并滴加到该溶液中,再将混合溶液回流18小时。将反应溶液恢复至常温后,用2N盐酸水溶液终止反应。通过过滤获得的所生成的固体,将其溶解在二氯甲烷中,用水萃取,干燥有机层,减压并浓缩后,通过柱色谱进行分离,从而得到黄色泡沫状生成物(7.9g)。
1H NMR(300MHz,DMSO-d6)7.79~7.46(m,4H),6.81~6.69(m,3H),5.31(s,2H),5.23(s,2H),3.92(s,6H),3.43(s,3H),3.38(s,3H),2.00(s,9H),1.71(s,6H)。
(2)1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-3-(2,4-双甲氧基甲氧基苯基)丙-1-酮的制备
将所述实施例2的(1)中得到的1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-3-(2,4-双甲氧基甲氧基苯基)-丙烯酮(3g)溶解在乙醇(80mL)中,加入5%钯/活性炭催化剂(20mg)后,在氢气(1个大气压)下,进行加氢反应2.5小时。反应结束后,将混合液过滤并减压浓缩,得到液体生成物(3g)。
1H NMR(300MHz,DMSO-d6)7.51(s,1H),7.05(d,J=5.1Hz,1H),6.70(d,J=1.2Hz,1H),6.64(s,1H),6.59~6.56(m,1H),5.19(s,2H),5.12(s,2H),3.90(s,3H),3.88(s,3H),3.37(s,3H),3.36(s,3H),3.11(t,J=4.5Hz,2H),2.78(t,J=4.5Hz,2H),2.01~1.97(m,9H),1.71(s,6H)。
(3)1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-3-(2,4-二羟基苯基)丙-1-酮的制备
将所述实施例2的(2)中得到的1-(5-金刚烷-1-基-2,4-二甲氧基苯基)-3-(2,4-双甲氧基甲氧基苯基)丙-1-酮(1.5g)溶解在甲醇(40mL)中,加入3N盐酸水溶液(2.5mL),在室温下搅拌24小时。待反应结束后,将反应溶液用二氯甲烷进行稀释,再用水进行萃取,干燥有机层,减压并浓缩后,通过柱色谱进行分离,从而得到棕色固体生成物(0.5g)。其分子量为436.5400g/mol。
1H NMR(300MHz,DMSO-d6)9.09(s,1H),8.94(s,1H),7.49(s,1H),6.78(d,J=5.1Hz,1H),6.64(s,1H),6.25~6.24(m,1H),6.11~6.09(m,1H),3.90(s,3H),3.89(s,3H),3.04(t,J=4.5Hz,2H),2.65(t,J=4.5Hz,2H),2.02~1.98(m,9H),1.71(s,6H)。
此外,准备山菅兰提取物(Nivitol,购自Jinan Rouse Industry Co.Ltd)和熊果苷(Arbutin,购自Sigma Aldrich)作为比较例1和2。
实验实施例:对黑色素生成的抑制效果的确定
通过Dooley方法,测量上述实施例中制备的化合物对黑素细胞中黑色素产生的抑制作用。
使用的细胞系为购自韩国细胞株库的源自小鼠的B16F10(黑素瘤细胞)。细胞培养所需的DMEM(目录号11995)、FBS(目录号16000-044)和抗生素-抗真菌剂(目录号15240-062)购自赛默飞世尔(Invitrogen)(GIBCO)公司。在37℃和5%CO2的条件下进行培养细胞株。通过用0.05%胰蛋白酶-EDTA除去所培养的B16F10细胞,并再次以相同的数量(1×104个细胞/孔)接种到48-培养容器(孔板)中,然后从第二填开始,连续3天,用分别含有10ppm的实施例1和2及比较例1和2的培养基进行替换。将使用熊果苷的比较例2作为阳性对照组。
待5天后,用1N NaOH进行处理,并在60℃下反应2小时,将细胞中含有的黑色素溶解而出,通过测定405nm处的吸光度,以测定黑色素的量。为了将黑素细胞中的黑色素生成减少至一半,将所需的实施例1和2以及比较例1和2的浓度(IC50)换算为μM单位,并示于下表1中。
【表1】
参照上述结果,实施例1的化合物仅以2.8μM的浓度可以抑制50%的黑色素生成,表现出最优异的效果,而对于实施例2的化合物,需要用5μM或更高的浓度来抑制50%的黑色素生成。
然而,当使用相同浓度(5μM)的山菅兰提取物(比较例1)和实施例2的化合物时,相比于山菅兰提取物(比较例1)抑制37%的黑色素生成,实施例2的化合物通过抑制约45%黑色素生成,从而可知实施例2具有更加优异的皮肤美白效果。其原因在于,因为根据本发明实施例的化合物在结构上由于含有与山菅兰提取物不同的金刚烷基,具有优异的亲脂性,从而更利于细胞吸收。
因此,包含实施例1及2的化合物的组合物与之前被认作优秀美白剂的山菅兰提取物(比较例1)及熊果苷(比较例2)相比,具有非常优异的抑制黑色素的效果,因此可推测出具有优异的皮肤美白效果。
以下,如上所述,将描述根据本发明的一个方面的具有皮肤美白效果的组合物的制剂实施例,然而,本发明可以应用于各种其他制剂,本发明不受其限制,仅是为了更加具体地说明本发明。
【制剂实施例1】化妆水
根据常规方法,按照下表2中所述示的成分制备化妆水。
【表2】
【制剂实施例2】营养霜
根据常规方法,按照下表3中所述示的成分制备营养霜。
【表3】
【制剂实施例3】按摩霜
根据常规方法,按照下表4中所述示的成分制备按摩霜。
【表4】
成分 | 含量(重量%) |
4-[3-(5-金刚烷-1-基-2,4-二甲氧基-苯基)-丙基]苯-1,3-二醇 | 1.0 |
蜂蜡 | 10.0 |
聚山梨醇酯60 | 1.5 |
PEG 60硬化蓖麻油 | 2.0 |
脱水山梨糖醇硬脂酸酯 | 0.8 |
液体石蜡 | 40.0 |
角鲨烷 | 5.0 |
辛酸/癸酸甘油三酯 | 4.0 |
甘油 | 5.0 |
丁二醇 | 3.0 |
丙二醇 | 3.0 |
三乙醇胺 | 0.2 |
防腐剂、色素、香料 | 适量 |
纯净水 | 适量 |
【制剂实施例4】面膜
根据常规方法,按照下表5中所述示的成分制备面膜。
【表5】
成分 | 含量(重量%) |
4-[3-(5-金刚烷-1-基-2,4-二甲氧基-苯基)-丙基]苯-1,3-二醇 | 0.2 |
聚乙烯醇 | 13.0 |
羧甲基纤维素钠 | 0.2 |
甘油 | 5.0 |
尿囊素 | 0.1 |
乙醇 | 6.0 |
PEG 12壬基苯基醚 | 0.3 |
聚山梨醇酯60 | 0.3 |
防腐剂、色素、香料 | 适量 |
纯净水 | 适量 |
【制剂实施例5】凝胶
根据常规方法,按照下表6中所述示的成分制备凝胶。
【表6】
成分 | 含量(重量%) |
4-[3-(5-金刚烷-1-基-2,4-二甲氧基-苯基)-丙基]苯-1,3-二醇 | 0.5 |
乙二胺乙酸钠 | 0.05 |
甘油 | 5.0 |
羧基乙烯基聚合物 | 0.3 |
乙醇 | 5.0 |
PEG 60硬化蓖麻油 | 0.5 |
三乙醇胺 | 0.3 |
防腐剂、色素、香料 | 适量 |
纯净水 | 适量 |
[制剂实施例6]软膏
根据常规方法,按照下表7中所述示的成分制备软膏。
【表7】成分 | 含量(重量%) |
4-[3-(5-金刚烷-1-基-2,4-二甲氧基-苯基)-丙基]苯-1,3-二醇 | 1.5 |
甘油 | 8.0 |
丁二醇 | 4.0 |
液体石蜡 | 15.0 |
Beta葡聚糖 | 7.0 |
卡波姆 | 0.1 |
辛酸/癸酸甘油三酯 | 3.0 |
角鲨烷 | 1.0 |
鲸蜡硬脂基葡糖苷 | 1.5 |
脱水山梨糖醇硬脂酸酯 | 0.4 |
鲸蜡硬脂醇 | 1.0 |
蜂蜡 | 4.0 |
防腐剂、色素、香料 | 适量 |
纯净水 | 适量 |
Claims (11)
1.二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物,所述二芳基衍生化合物被表示为以下化学式(1):
[化学式1]
化学式(1)中,R1和R2相同或不同,并分别独立地为具有1-10个碳原子的烷基,
X为-CO-或-CH2-。
2.根据权利要求1所述的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物,其特征在于,所述化学式1由以下化学式1-1或1-2表示。
[化学式1-1]
[化学式1-2]
3.根据权利要求1或2所述的二芳基衍生化合物的制备方法,该方法包括由以下反应式1表示的反应步骤:
[反应式1]
在反应式1中,
R1和R2如化学式1中所定义,
保护基为
4.根据权利要求3所述的二芳基衍生化合物的制备方法,其特征在于,该方法还包括由以下反应式2表示的反应步骤:
[反应式2]
在反应式2中,
R1、R2和X如同化学式1中所定义,
保护基如同反应式1中所定义。
5.二芳基衍生化合物、其异构体、其药学上可接受的盐、、其水合物或其溶剂合物在制备皮肤美白组合物中的用途,所述二芳基衍生化合物由以下化学式(1)表示,
[化学式1]
在化学式1中,
R1和R2相同或不同,各自独立地为具有1-10个碳原子的烷基,
X是-CO-或-CH2-。
6.根据权利要求5所述的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物的用途,其特征在于,所述化学式1由以下化学式1-1或1-2表示。
[化学式1-1]
[化学式1-2]
7.根据权利要求5所述的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物的用途,其特征在于,所述二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物的浓度为基于组合物总重量的0.01-20重量%。
8.根据权利要求5所述的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物的用途,其特征在于,所述皮肤美白组合物抑制黑色素生成。
9.根据权利要求5所述的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物的用途,其特征在于,所述皮肤美白的组合物为药物组合物。
10.根据权利要求5所述的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物的用途,其特征在于,所述皮肤美白的组合物为化妆品组合物。
11.根据权利要求5所述的二芳基衍生化合物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物的用途,其特征在于,所述用于皮肤美白的组合物为皮肤外用制剂。
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