CN108495848B - 一种新型的羟基吡喃酮化合物、其制备方法及包含其的化妆品组合物 - Google Patents
一种新型的羟基吡喃酮化合物、其制备方法及包含其的化妆品组合物 Download PDFInfo
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- CN108495848B CN108495848B CN201680079689.9A CN201680079689A CN108495848B CN 108495848 B CN108495848 B CN 108495848B CN 201680079689 A CN201680079689 A CN 201680079689A CN 108495848 B CN108495848 B CN 108495848B
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Abstract
本发明涉及一种新型的羟基吡喃酮化合物，其制备方法及包含其的化妆品组合物。与已有的脂肪细胞分化促进物质相比，本发明所涉及的新型羟基吡喃酮化合物体现出显著的改善效果，是一种可增进皮肤容积或弹力的理想的化妆品组合物的有效成分。
Description
技术领域
本发明主张基于2015年12月1日韩国专利发明第10-2015-0169644号及2016年11月28日韩国专利发明第10-2016-0159460号的优先权，该韩国专利发明的文献中记载的所有内容被作为本说明书的部分内容。
本发明涉及一种具有脂肪细胞分化促进能力的新型的羟基吡喃酮化合物、其制备方法及包含这一有效成分的化妆品组成物。
背景技术
皮肤的基本结构由皮下脂肪组织维持，这种皮下脂肪组织起到决定皮肤容积和强度的作用。因此，为了保持并提高皮肤的容积和弹力，与赋予皮肤表层的真皮或表皮弹力的方法相比，增加脂肪组织的体积可成为一种根本的解决方法。
具体来说，随着人体老化，皮肤产生皱纹的同时弹性减退。皱纹的产生和弹性减退等皮肤老化问题是由皮肤的构成要素胶原蛋白(collagen)和弹性蛋白(elastin)等皮肤纤维的分解和减少、脂肪细胞的活性减少,或由此引起的脂滴(lipid droplet)减少等引起的复合现象。因此，只要能够促进人体脂肪细胞分化而生成并堆积脂滴，就可以改善皮肤的皱纹及弹力。
对最近利用脂肪细胞的各种研究倾向进行观察，目前包括增加皮肤曲线度和弹力研究的利用脂肪细胞的研究在各领域活跃展开，其中前体脂肪细胞(preadipocyte)具有由胰岛素等分化诱导物质而分化成脂肪细胞的特性，故而被普遍且广泛地使用。
尤其是，在这种前体脂肪细胞中近期备受关注的是与脂肪细胞有关的间充质干细胞(mesenchymal stem cell)。可用将前体脂肪细胞分化成脂肪细胞时使用的方法相似的方法分化源自脂肪的间充质干细胞(Exp.Cell Res.2006，312，1856-1864)，故而被广泛用于脂肪细胞的分化研究(Science 1999，284，143-146)。并且，这种源自脂肪的间充质干细胞不仅可分化成脂肪细胞，还能分化成软骨细胞、骨细胞等其他类型的细胞(J.CellSci.2006，119，2204-2213)，上述源自脂肪的间充质干细胞分布于人体大部分的组织中，因此其可利用性是无穷无尽的。
一直以来，为了改善皮肤的容积和弹性，为了促进脂肪细胞的分化，实际上有过各种尝试，根据先前的研究结果，已有报告显示肉桂酸化合物显示出促进脂肪细胞分化的效果。另外，曾有报告显示与肉桂酸相比，包括肉桂酸母核的羟基吡喃酮衍生物促进脂肪细胞分化的效果大幅增加，就此，对各种衍生物的结构活性相关性进行分析的结果证实肉桂酸的双键发挥重要的作用。
然而，当这些能促进脂肪细胞分化的物质实际包含于化妆品组成物时，对人体内足以体现出增加皮肤容积和弹性功效，其效果还是微小的，作为消费者很难在使用化妆品组成物时获得最大的满足感。
因此，现实需要开发一种功效经改善的用于促进脂肪细胞分化的物质。
[已有文献]
羟基吡喃酮衍生物及其制备方法(大韩民国注册专利第10-0482668号)
发明内容
技术课题
为了解决上述已有问题，本发明的发明者们以上述已有的研究结果为基础，对促进脂肪细胞分化效果相对现有化合物得到改善的化合物进行了多方位的研究，制备了一种羟基吡喃酮化合物中包括3-(2,6,6-三甲基-2-环己烯基)-丙烯酸(3-(2,6,6-Timethyl-cyclohex-2-enyl)propenoic acid)母核的新型化合物，最终证实了上述新型化合物引起的脂肪细胞分化促进功效得到提高，从而完成了发明。
因此，本发明的目的在于提供一种提高脂肪细胞分化促进功效的新型羟基吡喃酮化合物。
另外，本发明的另一个目的在于提供一种所述新型羟基吡喃酮化合物的制备方法。
另外，本发明的另一个目的在于提供一种含有所述新型羟基吡喃酮化合物这一有效成分的化妆品组成物。
解决课题的手段
为了达到上述目的，本发明提供一种羟基吡喃酮化合物，用以下化学式1表示：
[化学式1]
另外，本发明提供一种用以下反应式1表示的，使下述化学式2的化合物与化学式3的化合物进行反应后制备羟基吡喃酮化合物(化学式1)的制备方法：
[反应式1]
(在上述反应式1中，X和M与说明书中的说明相同)。
另外，本发明提供一种含有用上述化学式1表示的羟基吡喃酮化合物这一有效成分的化妆品组成物。
发明的效果
与已有的生源时光之钥G(Seletinoid G)或其他用于促进脂肪细胞分化的化合物相比，本发明涉及的羟基吡喃酮化合物具有增强的脂肪细胞分化促进效果。
具体来说，由于所述化合物体现出促进人类间充质干细胞分化成脂肪细胞的现象且生成脂滴后增加皮肤容积和弹性的效果，因此可配制成各种化妆品，提高消费者的满意度。
具体实施方式
以下将对本发明进行详细说明。
本发明公开了用下述化学式1表示的一种新型羟基吡喃酮化合物：
[化学式1]
国际纯粹与应用化学联合会(International Union of Pure and AppliedChemistry，IUPAC)将上述化学式1的羟基吡喃酮化合物命名为3-(2,6,6-三甲基-2-环己烯基)-丙烯酸5-羟基-4-氧代-4H-吡喃-2-基甲酯(3-(2,6,6-Trimethyl-cyclohex-2-enyl)-propenoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester)。
上述化学式1的化合物在常温下为米黄色固体化合物。
本发明公开的羟基吡喃酮化合物包括异构体。此时，“异构体”不仅特别包括旋光异构体(Optical isomers)(例如，本质纯净的旋光对映体(essentially pureenantiomers)、本质纯净的局部立体异构体(essentially pure diastereomers)或它们的混合物)，还包括构象异构体(conformation isomers)(即，仅在一个或多个化学键的角度上不同的异构体)、位置异构体(position isomers)(特别是，互变异构体(tautomers))或几何异构体(geometric isomers)(例如，顺反异构体)。
如下述反应式1所示，使下述化学式2的吡喃酮化合物与化学式3的环己烯酯化合物产生反应后制备用所述化学式1表示的化合物：
[反应式1]
(在上述反应式1中，X是卤素元素，M是锂Li、钠Na或钾K)。
参考上述反应式1，通过吡喃酮化合物的卤素元素与环己烯酯化合物的金属间的结合反应制备化学式1的化合物。
此时，在化学式2的吡喃酮化合物中，X为卤素元素，这时的卤素元素可以是氟F、氯Cl、溴Br或碘I，最好是氯Cl。这种化学式2的化合物可购买市售品或直接制备使用。
在本发明的实施例中，X用了氯Cl<5-羟基-2-(氯甲基)-4H-吡喃-4-酮)>，这是<5-羟基-2-(羟甲基)-4H-吡喃-4-酮>与亚硫酰氯(SOCl2)发生反应后直接制备使用的。
另外，化学式3的环己烯酯化合物是<3-(2,6,6-三甲基-2-环己烯基)丙烯酸(3-(2,6,6-timethyl-cyclohex-2-enyl)propenoic acid)>的离子化盐形态，以在3-(2,6,6-三甲基-2-环己烯基)-丙烯酸(3-(2,6,6-timethyl-cyclohex-2-enyl)propenoic acid)的羧基上键结合阳离子(M+)的形态存在。
所述阳离子(M+)是选自Li+、Na+、K+构成的族群中的一种。最好是3-(2,6,6-三甲基-2-环己烯基)-丙烯酸(3-(2,6,6-timethyl-cyclohex-2-enyl)propenoic acid)与Na+的离子键结合物，为了制备所述离子键结合物，举例来说可将3-(2,6,6-三甲基-2-环己烯基)-丙烯酸<3-(2,6,6-timethyl-cyclohex-2-enyl)propenoic acid)>与氢氧化钠一同溶解至甲醇进行离子化，蒸馏甲醇后获取。
在本发明的优选实施例中，通过作为化学式2的化合物的<5-羟基-2-(氯甲基)-4H-吡喃-4-酮>与作为化学式3的化合物的钠3-(2,6,6-甲基-环己酮-2-烯基)-丙酸酯(Sodium 3-(2,6,6-timethyl-cyclohex-2-enyl)propenoate)的酯键结合而制备化学式1的羟基吡喃酮化合物。
此时，在本发明中对反应并无特别限定，在所述卤素-金属结合反应可充分完成的条件下进行。
反应温度为溶剂的回流温度，例如在50℃至250℃下反应0.5小时至5小时，反应1至3小时最佳。
此时，溶剂可以是能充分溶解化学式2和化学式3的任何一种化合物，例如选自N,N-二甲基甲酰胺(N,N-dimethylformamide，DMF)、四氢呋喃(THF)、二甲基亚砜(DMSO)、乙腈、二恶烷、苯、甲苯、醚、甲醇、己烷、环己烷、吡啶、N-甲基吡咯啶酮及它们组合构成的群组中的一种，使用DMF为佳。
反应后，蒸馏所述溶剂，然后经过常规的清洗、干燥、提纯等后处理过程而获取高纯度的化合物。
本发明涉及的化学式1的羟基吡喃酮化合物可应用于各种领域，用作化妆品组合物的有效成分最佳。此时，所述化学式1的化合物促进脂肪细胞分化，藉此可生成并堆积脂滴，从而改善皮肤皱纹和弹性。
当所述羟基吡喃酮化合物用作化妆品组合物的有效成分时，其含量根据配制而存在差异，可使用0.001重量％至99重量％。当有效成分含量在上述范围内时，不仅能恰当地显现本发明的预期效果，而且可同时满足组合物的稳定性和溶解性，在性价比方面也是最有效的。
化妆品组合物可制备成本领域中常规制备的任一剂型，例如可配制为溶液悬浮液、乳浊液、糊剂、凝胶、乳霜、润肤乳、粉、油、粉末状粉底、乳浊液粉底、蜡粉底及喷雾等，但并不限定于此。更具体来说，可制备成防晒霜、柔软化妆水、收敛化妆水、营养化妆水、营养霜、按摩霜、精华液、眼霜、面膜、喷雾或散粉等剂型。
另外，本发明的化妆品组合物可包括脂肪物质、有机溶剂、溶解剂、浓缩剂、凝胶剂、软化剂、抗氧化剂、悬浮剂、稳定剂、发泡剂(foaming agent)、芳香剂、界面活性剂、水、离子型或非离子型乳化剂、填充剂、金属离子封阻剂、螯合剂、保存剂、维生素、阻隔剂、润湿剂、精油、染料、颜料、亲水性或亲脂性活性剂、脂质囊泡或在化妆品中通常使用的任意的其他成分等在化妆品学或皮肤科学领域中通常使用的辅助剂。按照化妆品学或皮肤科学领域中通常使用的量导入所述辅助剂。
当上述制剂为糊剂、乳霜或凝胶时，可利用动物性油、植物性油、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载体成分。
当上述制剂为粉末或喷雾时，可用乳糖、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，尤其是喷雾时，还可包括氯氟烃、丙烷/丁烷或二甲醚等推进剂。
当上述制剂为溶液或乳浊液时，用溶剂、溶解剂或乳浊剂作为载体成分，如水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苄基苯甲酸酯、丙二醇、1,3-丁二醇油、甘油脂肪族酯、聚乙二醇或脱水山梨糖醇的脂肪酸酯。
当上述制剂为悬浮液时，用水、乙醇或丙二醇等液态稀释剂、乙氧基化异硬脂醇、聚氧乙烯山梨糖醇酯和聚氧乙烯山梨糖醇酯等悬浮剂、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。
以下，为了更详细地对本发明的内容及效果进行说明而公开实施例及试验例。只是，下述内容仅仅是有关本发明的一个范例，本发明的权利范围和效果并不仅限于此。
实施例：3-(2,6,6-三甲基-环己烯-2-烯基)-丙烯酸5-羟基-4-氧代-4H-吡喃-2-
基甲酯(Trimethyl-cyclohex-2-enyl)-propenoic acid5-hydroxy-4-oxo-4H-pyran-2-
ylmethyl ester)的制备
根据下述反应式2制备了本发明的化学式1的羟基吡喃酮化合物，即3-(2,6,6-三甲基-环己烯-2-烯基)-丙烯酸5-羟基-4-氧代-4H-吡喃-2-基甲酯
(3-(2,6,6-Trimethyl-cyclohex-2-enyl)-propenoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester)。
[反应式2]
上述反应式2的具体的操作过程如下。
将50g的5-羟基-2-(羟甲基)-4H-吡喃-4-酮(0.35mmol)溶解至250ml的N,N-二甲基甲酰胺，在10℃的冰水浴中冷却后在30分钟内滴加50g(0.42mol)的亚硫酰氯。在常温下搅拌2小时，然后将反应液加入至2000ml的冰水中。过滤所产生的固体，在1000ml的乙酸乙酯中溶解固体(过滤物)。加入硫酸镁与活性碳进行干燥、脱色并过滤后，浓缩滤液并加入核酸后获得结晶。进行真空干燥而获取39.5g(70％)的黄色固体状反应生成物，即化学式2-1的5-羟基-2-(氯甲基)-4H-吡喃-4-酮。
然后，将5g(0.026mol)的3-(2,6,6-三甲基-环己烯-2-烯基)-丙烯酸(3-(2,6,6-Timethyl-cyclohex-2-enyl)propenoic acid)与1.3g(0.031mol)的氢氧化钠溶解至40ml的甲醇，将蒸馏甲醇后残留的残渣溶解至70ml的N,N-二甲基甲酰胺而制备化学式3-1的化合物。
在所制备的上述化学式3-1的化合物中加入4.2g(0.026mol)的所制备的上述化学式2-1的5-羟基-2-(氯甲基)-4H-吡喃-4-酮，在110℃的油浴中加热搅拌2小时。蒸馏溶剂并将残渣溶解至300ml的乙酸乙酯，然后用5％盐酸与蒸馏水清洗乙酸乙酯溶液，加入硫酸镁与活性碳进行了干燥、脱色。然后，滤除不溶物，在减压条件下蒸发滤液而获取5.9g的米黄色固体状的反应生成物(产率为69％)。
TLC(乙酸乙酯：己烷＝1：1)Rf＝0.43
1H NMR(DMSO-d6,δ):9.23(s,1H),8.09(s,1H),7.45(d,1H,J＝16.2Hz),6.48(s,1H),5.94(d,1H,J＝16.2Hz),5.04(s,2H),2.07(m,2H),1.75(s,3H),1.59(m,2H),1.42(m,2H),1.04(s,6H)
试验例：证实脂肪细胞分化促进效果
为了证实上述实施例中制备化合物促进脂肪细胞分化的效果而进行了如下操作。
脂联素是由脂肪细胞分泌的一种典型的蛋白质激素。已有报告显示这种脂联素的表达随着脂肪细胞的分化而增加。因此，用本发明公开的新型化合物处理时，测定作为脂肪细胞分化促进指标的脂联素由细胞培养基表达的量，从而确认了促进脂肪细胞分化的效果。
脂肪细胞分化是购自龙沙公司(Lonza,Inc.Walkersville，MD，USA)的源自人体脂肪的间充质干细胞(human adipose tissue derived mesenchymal stem cells，hAT-MSCs)并根据龙沙公司的说明书培养。脂肪细胞分化使用曲格列酮(troglitazone，TRO)代替了吲哚美辛(indomethacin)来诱导源自脂肪的间充质干细胞的脂肪细胞分化，另外还使用了龙沙公司建议的方法进行。具体来说，在间充质干细胞的培养液中加入由1g/ml胰岛素、1M地塞米松(Dexamethasone，DEXA)、0.5mM异丁基甲基黄嘌呤(isobutylmethylxanthine，IBMX)及2M的TRO混合而成的脂肪细胞分化用培养基(以下称为IDX)并进行培养，将间充质干细胞分化成脂肪细胞。
为了测定脂联素的表达量，在分化第14天萃取所述脂肪细胞分化用培养基，之后利用脂联素ELISA Kit(酵素结合免疫吸附分析试剂盒,R&D systems，cat.No.DY1065)对脂联素的量进行定量(用对比组修正各数据值)。使用脂联素ELISA Kit的具体测定方法如下。
首先，将捕获(Capture)抗体放至96孔板使其反应，用清洗缓冲溶液清洗后，加入下表1所列的物质使其在常温下反应2小时。之后每完成一个步骤就清洗3次(washing)，并依次加入检测抗体(detection antibody)、辣根过氧化物酶(HRP enzyme)、基质溶液(substrate solution)、反应终止液(stop solution)并按照操作程序中要求的时间进行反应。最终反应后，用分光亮度计(Spectrophotometer)在450nm的波长下测定吸亮度。
通过上述过程获得的结果如表1所示。
[表1]
参照上表1，在确认脂联素表达量的实验中，进行曲酸处理时脂联素的表达量并没有增加。相反地，在进行本发明涉及的实施例的化学式1的化合物羟基吡喃酮衍生物处理时，可确认表达量的增加和阳性对比组的格列本脲几近相似。这相当于用以往的脂肪细胞分化促进化合物即生源时光之钥G进行处理时的表达量也显著增加。
因此，证实本发明涉及的化学式1的羟基吡喃酮化合物促进脂肪细胞分化的能力优异，将其作为有效成分包含于化妆品组成物可增加皮肤的容积和弹力。
以下将公开本说明书部分涉及的化妆品组成物的剂型范例。但是，含有本发明涉及的羟基吡喃酮化合物的化妆品剂型并不仅限于下述示例。
剂型示例1(化妆水)
根据下表2中所列组成用常规方法制备了化妆水。
[表2]
| 成分 | 含量(重量％) |
| 化学式1的化合物(实施例) | 0.1 |
| 甘油 | 3.0 |
| 丁二醇 | 2.0 |
| 丙二醇 | 2.0 |
| 羧基乙烯基聚合物 | 0.1 |
| PEG 12壬基苯醚 | 0.2 |
| 聚山梨醇酯80 | 0.4 |
| 乙醇 | 10.0 |
| 三乙醇胺 | 0.1 |
| 防腐剂、色素、香料 | 适量 |
| 纯化水 | 剩余量 |
剂型示例2(牛奶润肤乳)
根据下表3中所列组成用常规方法制备了牛奶润肤乳。
[表3]
| 配制成分 | 含量(重量％) |
| 化学式1的化合物(实施例) | 1.0 |
| 甘油 | 3.0 |
| 丁二醇 | 3.0 |
| 丙二醇 | 3.0 |
| 羧基乙烯基聚合物 | 0.1 |
| 蜂蜡 | 4.0 |
| 聚山梨醇酯60 | 1.5 |
| 辛酸/癸酸三甘油酯 | 5.0 |
| 角鲨烷 | 5.0 |
| 山梨醇酐倍半油酸酯 | 1.5 |
| 液态石蜡 | 0.5 |
| 鲸蜡硬脂醇 | 1.0 |
| 三乙醇胺 | 0.2 |
| 防腐剂、色素、香料 | 适量 |
| 纯化水 | 剩余量 |
剂型示例3(营养霜)
根据下表4所列组成用常规方法制备了营养霜。
[表4]
剂型示例4(按摩霜)
根据下表5所列组成用常规方法制备了按摩霜。
[表5]
| 成分 | 含量(重量％) |
| 化学式1的化合物(实施例) | 1.0 |
| 蜂蜡 | 10.0 |
| 聚山梨醇酯60 | 1.5 |
| PEG 60氢化蓖麻油 | 2.0 |
| 山梨醇酐倍半油酸酯 | 0.8 |
| 液态石蜡 | 40.0 |
| 角鲨烷 | 5.0 |
| 辛酸/癸酸三甘油酯 | 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 |
| 纯化水 | 剩余量 |
剂型示例5(面膜)
根据下表6所列组成用常规方法制备了面膜。
[表6]
Claims (4)
1.一种羟基吡喃酮化合物，用下列化学式1表示：
[化学式1]
2.一种羟基吡喃酮化合物的制备方法，用下列反应式1表示，使化学式2的吡喃酮化合物与化学式3的环己烯酯化合物反应后制备用化学式1表示羟基吡喃酮化合物，[反应式1]
上述反应式1中，X为卤素元素，M为Li、Na或K。
3.一种化妆品组成物，包含用下列化学式1表示的羟基吡喃酮化合物这一有效成分：
[化学式1]
4.根据权利请求项3所述的化妆品组成物，其特征是，所述化妆品组成物是具有脂肪细胞分化促进能力的化妆品组合物。
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