CN102271680A - 1-芳酰基-n-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺类和相关化合物的化妆品应用 - Google Patents
1-芳酰基-n-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺类和相关化合物的化妆品应用 Download PDFInfo
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- CN102271680A CN102271680A CN2009801530271A CN200980153027A CN102271680A CN 102271680 A CN102271680 A CN 102271680A CN 2009801530271 A CN2009801530271 A CN 2009801530271A CN 200980153027 A CN200980153027 A CN 200980153027A CN 102271680 A CN102271680 A CN 102271680A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
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- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
公开了包含1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺类的化妆品组合物和使用这种组合物赋予皮肤抗老化有益性的方法。据认为1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺类对皮肤老化中所牵连的一种或多种生化途径具有调节活性。
Description
发明领域
本发明总地涉及局部施用于皮肤的包含1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺类的组合物和这种组合物在给皮肤提供有益性方面的应用。
发明背景
桥粒核心糖蛋白是一族在细胞粘着中起重要作用,从而确保组织内细胞彼此结合的跨膜蛋白。在皮肤中,它们是桥粒中的主要成分。桥粒是上皮与某些其他细胞类型之间的细胞-细胞黏着复合物。它们通过连接到角蛋白中间丝上对角蛋白细胞提供机械完整性。桥粒核心糖蛋白形成附着相邻皮肤细胞的胶粘物。桥粒核心糖蛋白1和3均在复层鳞状上皮中表达。桥粒核心糖蛋白1主要在表皮分化上层中表达且桥粒核心糖蛋白3主要在基底层和上基层中发现。桥粒核心糖蛋白的差异表达模式对于调节表皮功能是重要的。桥粒核心糖蛋白1和3表达模式在动物模型中改变破坏了角化细胞增殖和皮肤屏障功能。刺激桥粒核心糖蛋白所预期的有益性可以是产生较为坚硬的皮肤与较少皱纹的角蛋白细胞之间的锚定和黏着增加。
胶原蛋白是身体的主要结构蛋白且由紧密三股螺旋形式的三种蛋白质链彼此缠绕组成。这种独特的结构得到了拉伸强度大于钢的胶原蛋白。体内约33%的蛋白质是胶原蛋白。这种蛋白质支持组织和器官并且将这些结构与骨连接。实际上,骨还由与某些矿物如钙和磷结合的胶原蛋白组成。胶原蛋白在提供围绕细胞的结构骨架方面起关键作用,这种作用有助于支持细胞形状和分化,与钢柱如何强化混凝土砌块类似。网状胶原蛋白网状结构使细胞彼此结合并且提供支持性构架或环境,其中细胞发育和发挥作用且组织和骨愈合。
胶原蛋白由成纤维细胞产生,它们是位于真皮中的特化的皮肤细胞。成纤维细胞还产生其他皮肤结构蛋白,如弹性蛋白(使皮肤能力很快恢复的蛋白质)和葡糖胺聚糖(GAGs)。GAGs构成使真皮保持含水的基质。为了信号传导或启动皮肤结构蛋白的产生,成纤维细胞在其外膜上具有特别成某种形状的受体,所述的外膜作为具有匹配形状的信号分子可以适合的结合位点起作用。当这些受体被信号分子(称作成纤维细胞生长因子或FGFs)的正确组合结合时,成纤维细胞开始产生胶原蛋白。刺激胶原蛋白可给予皮肤自身的强度、耐久性和光滑、丰满的外观。
皮肤桥蛋白是主要位于皮肤中胶原蛋白纤维表面上的胞外基质的蛋白质成分。据认为皮肤桥蛋白在细胞-基质相互作用和基质装配(胶原蛋白原纤维生成)中起重要作用。研究皮肤桥蛋白敲除小鼠证实皮肤桥蛋白参与皮肤弹性和胶原蛋白蓄积,因为据报道与在野生型小鼠中相比在皮肤桥蛋白-无效小鼠中皮肤弹性模量低57%且胶原蛋白含量低40%。Takeda等人,“Targeted disruption of dermatopontin causesabnormal collagen fibrillogenesis,”J.Invest.Dermatol.,2002Sep;119(3):678-83。
因此,本发明的一个目的在于提供刺激胶原蛋白I、桥粒核心糖蛋白和/或皮肤桥蛋白产生的新组合物和方法。本发明的另一个目的在于通过用包含有效量的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺类的化妆品组合物刺激胶原蛋白I、桥粒核心糖蛋白和/或皮肤桥蛋白产生改善皮肤总体外观,包括处理、逆转和/或预防老化体征,如皮肤皱纹。
提供上述讨论仅为了提供对本领域遇到问题性质的更好理解且不应以任何方式将其视为关于现有技术的承认,也不应将其中引述的任何参考文献视为许可这样的参考文献构成针对本申请的“现有技术”。
发明概述
根据上述目的和其他目的,令人意外地发现1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺类是胶原蛋白I、桥粒核心糖蛋白和/或皮肤桥蛋白产生的有效刺激剂且因此是针对皮肤的各种内在老化和光老化的体征的有益剂。
在本发明的一个方面中,提供了用于改善皮肤美观的化妆品组合物,其包含有效量的在化妆品可接受的媒介物中的强化胶原蛋白I、桥粒核心糖蛋白和/或皮肤桥蛋白的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺,其具有式1的结构:
其中R1、R2、R3、R4、R5、R6和R7独立地是氢或基团-R9-R10;
其中R9在每次出现时独立地表示键(即R9不存在)或如下基团之一:(i)脂族C1-C20烃基;(ii)C1-C20芳香烃基;(iii)C1-C20杂芳基;
R10在每次出现时独立地选自氢;-F;-Cl;-Br;-I;-OH,-OR;-NH2;-NHR;-N(R)2;-N(R)3 +;-N(R)-OH;-N(→O)(R)2;-O-N(R)2;-N(R)-O-R;-N(R)-N(R)2;-C=N-R;-N=C(R)2;-C=N-N(R)2;-C(=NR)-N(R)2;-SH;-SR;-CN;-NC;-CHO;-CO2H;-CO2 -;-CO2R;-(C=O)-S-R;-O-(C=O)-H;-O-(C=O)-R;-S-(C=O)-R;-(C=O)-NH2;-(C=O)-N(R)2;-(C=O)-NHNH2;-O-(C=O)-NHNH2;-(C=S)-NH2;-(C=S)-N(R)2;-N(R)-CHO;-N(R)-(C=O)-R;-(C=NR)-O-R;-O-(C=NR)-R,-SCN;-NCS;-NSO;-SSR;-N(R)-C(=O)-N(R)2;-N(R)-C(=S)-N(R)2;-SO2-R;-O-S(=O)2-R;-S(=O)2-OR;-N(R)-SO2-R;-SO2-N(R)2;-O-SO3 -;-O-S(=O)2-OR;-O-S(=O)-OR;-O-S(=O)-R;-S(=O)-OR;-S(=O)-R;-NO;-NO2;-NO3;-O-NO;-O-NO2;-N3;-N2-R;-N(C2H4);-Si(-R)3;-CF3;-O-CF3;-(C=O)-R;-PR2;-O-P(=O)(OR)2;-P(=O)(OR)2;=O;=S;=NR;脂族C1-C20烃基;C1-C20芳香烃基;或C1-C20杂芳基;
其中R在每次出现时独立地是氢或饱和、部分饱和或芳香C1-C20烃基、包括其卤代和全卤代衍生物;
且其中任意两个相邻基团R1、R2、R3、R4和R5可以与所连接的苯环一起形成5-元或6-元脂族或芳香环,其任选被一个或多个基团R10取代且任选在环上包括一个或多个选自O、N、S的杂原子。在一些实施方案中,R1-5与所连接的苯环一起(碎片ArR1-5)任选形成取代的5-元或6-元杂芳环,在环上包括一个或多个选自N、O、S的杂原子。
还提供了处理一种或多种皮肤老化的体征的方法,包括对有此需要的皮肤局部施用式I的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺,其用量有效强化胶原蛋白I、桥粒核心糖蛋白和/或皮肤桥蛋白。
在本发明的另一个方面中,提供了处理、改善和/或预防人体皮肤细线或皱纹或下垂的方法,包括对有此需要的皮肤局部施用一种组合物,包括直接施用于皱纹或细线,该组合物包含式I的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺,其用量有效强化胶原蛋白I、桥粒核心糖蛋白和/或皮肤桥蛋白。
本发明的这些和其他方面将通过参照如下详细描述和附图得以更好地理解。
详细描述
除非另有提供,否则本文所用的全部术语旨在具有其一般含义。
本发明提供了用于局部施用的组合物,其包含有效量的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺类或相关化合物,以处理、逆转、改善和/或预防皮肤老化体征。这种皮肤老化体征包括、但不限于如下:
(a)处理、减少和/或预防细线或皱纹;
(b)皮肤毛孔大小减小;
(c)皮肤厚度、丰满度和/或紧固度改善;
(d)皮肤柔软度和/或柔软性改善;
(e)肤色、光泽度和/或透明度改善;
(f)前胶原和/或胶原蛋白产生改善;
(g)弹性蛋白维持和重塑改善;
(h)皮肤肌理改善和/或质构化增强;
(i)皮肤屏障修复和/或功能改善;
(j)皮肤轮廓外观改善;
(k)皮肤光泽和/或亮度恢复;
(l)皮肤中的必需营养素和/或成分得到补充;
(m)因绝经而减弱的皮肤外观改善;
(n)皮肤保湿改善;
(o)皮肤弹性和/或弹力增加;或
(p)处理、减少和/或预防皮肤下垂。
实际上,本发明的组合物施用于需要处理的皮肤。即,在任何上述属性方面存在缺陷或缺失、否则就是得益于任何上述皮肤属性改善的皮肤。
在某优选的实施方案中,本发明的组合物和方法涉及预防、处理和/或改善皮肤中的细线和/或皱纹。在这种情况中,将所述组合物施用于需要治疗的皮肤,其含义是具有皱纹和/或细线的皮肤。优选将组合物直接施用于细线和/或皱纹。这些组合物和方法适合于处理任意皮肤表面上的细线和/或皱纹,包括、但不限于面部、颈部和/或手部皮肤。
用于处理与胶原蛋白和/或弹性蛋白纤维丧失相关的皮肤情况的化妆品组合物在化妆品可接受的媒介物中包含有效强化胶原蛋白I、桥粒核心糖蛋白和/或皮肤桥蛋白的用量的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺类。这些胶原蛋白I、桥粒核心糖蛋白和/或皮肤桥蛋白强化剂可以具有式(1)的结构:
在式(I)中,R1、R2、R3、R4、R5、R6和R7独立地是氢或基团-R9-R10。在一个实施方案中,苯环上的至少一个取代基R1、R2、R3、R4和R5可以是基团-R9-R10,而在其他实施方案中,R3是基团-R9-R10,R1、R2、R4和R5是氢,使得苯环在对位上被取代;或R1是基团-R9-R10,R2、R2、R4和R5是氢,使得苯环在邻位上被取代;或R2是基团-R9-R10,R1、R3、R4和R5是氢,使得苯环在间位上被取代。
在一个实施方案中,R7和/或R8表示氢。在其他实施方案中,R7和R8独立地表示氢或基团-R9-R10,其中R9典型地不存在,其中R10优选是低级烷基(例如甲基、乙基、丙基、丁基等),典型地是甲基。R6可以是氢,但通常是基团-R9-R10。在式(I)的一些实施方案中,至少一个R6、R7和R8表示基团-R9-R10,而在其他实施方案中,R6基团-R9-R10,而R7和R8独立地表示氢或低级烷基(例如甲基、乙基、丙基、丁基等),典型地是甲基。
在式(I)的化合物中,R9在每次出现时独立地表示键(即,R9不存在)或如下基团之一:(i)脂族C1-C20烃基;包括脂族C1-C12烃基、脂族C1-C8烃基或脂族C1-C6烃基,以取代或未取代的支链、直链或环状烷基、烯基(例如,乙烯基、烯丙基等)和炔基部分为典型;(ii)C6-C20芳香烃基,包括C6-C12芳香烃基、C6-C10芳香烃基或C6芳香烃基,以取代或未取代的芳基(例如,苯基)、烷基-芳基(例如,苄基)、芳基-烷基等为典型;(iii)C1-C20杂芳基,在环上包括一个或多个选自O、N和S的杂原子;包括C1-C12杂芳香基团、C1-C8杂芳香基团和C1-C6杂芳香基团,以杂芳基、烷基-杂芳基、杂芳基-烷基等为典型。
在一些实施方案中,R9在一次或多次出现时不存在,使得它表示连接R10的键,而R10直接与苯基或1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺的氮原子连接。在其他实施方案中,R9在每次出现时独立地表示键(即R9不存在)或选自形式-(CH2)a-的直链烷基部分的基团,其中“a”是1-6的整数,包括,例如-CH2-(亚甲基)、-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-;-C(CH3)2-、-CH(CH3)CH2-、-C(CH3)2CH2-、-C6H4-、-CH2-C6H4-;一般形式-(CH2)aO-或-O(CH2)a-的直链烷氧基部分,其中“a”是1-6的整数,包括,例如-CH2O-或-OCH2-、-CH2CH2O-或-OCH2CH2-、-CH2CH2CH2O-或-OCH2CH2CH2-;-O(CH2)aO-,其中“a”如上述所定义;或形式-(CH2)bO(CH2)c-、-(CH2)bS(CH2)c-或-(CH2)bNR(CH2)c-的部分,其中“b”和“c”独立地是0(零)-6的整数,R如上述所定义。在一些实施方案中,R9表示键、羰基-(C=O)-或亚甲基-CH2-。
R10在每次出现时独立地选自氢;-F;-Cl;-Br;-I;-OH,-OR;-NH2;-NHR;-N(R)2;-N(R)3 +;-N(R)-OH;-N(→O)(R)2;-O-N(R)2;-N(R)-O-R;-N(R)-N(R)2;-C=N-R;-N=C(R)2;-C=N-N(R)2;-C(=NR)-N(R)2;-SH;-SR;-CN;-NC;-CHO;-CO2H;-CO2 -;-CO2R;-(C=O)-S-R;-O-(C=O)-H;-O-(C=O)-R;-S-(C=O)-R;-(C=O)-NH2;-(C=O)-N(R)2;-(C=O)-NHNH2;-O-(C=O)-NHNH2;-(C=S)-NH2;-(C=S)-N(R)2;-N(R)-CHO;-N(R)-(C=O)-R;-(C=NR)-O-R;-O-(C=NR)-R,-SCN;-NCS;-NSO;-SSR;-N(R)-C(=O)-N(R)2;-N(R)-C(=S)-N(R)2;-SO2-R;-O-S(=O)2-R;-S(=O)2-OR;-N(R)-SO2-R;-SO2-N(R)2;-O-SO3 -;-O-S(=O)2-OR;-O-S(=O)-OR;-O-S(=O)-R;-S(=O)-OR;-S(=O)-R;-NO;-NO2;-NO3;-O-NO;-O-NO2;-N3;-N-R2;-N(C2H4);-Si(-R)3;-CF3;-O-CF3;-(C=O)-R;-PR2;-O-P(=O)(OR)2;-P(=O)(OR)2;=O;=S;=NR;脂族C1-C20烃基;包括脂族C1-C12烃基、脂族C1-C8烃基或脂族C1-C6烃基,以取代或未取代的支链、直链或环状烷基、烯基(例如,乙烯基、烯丙基等)和炔基部分为典型;C6-C20芳香烃基,包括C6-C12芳香烃基、C6-C10芳香烃基或C6芳香烃基,以取代或未取代的芳基(例如,苯基)、烷基-芳基(例如,苄基)、芳基-烷基等为典型;或C1-C20杂芳基,在环上包括一个或多个选自O、N和S的杂原子;包括C1-C12杂芳香基团、C1-C8杂芳香基团和C1-C6杂芳香基团,以杂芳基、烷基-杂芳基、杂芳基-烷基等为典型。
R在每次出现时独立地是氢或饱和、部分饱和或芳香C1-C20烃基、C1-C12烃基、C1-C8烃基或C1-C6烃基,其各自任选包括一个或多个杂原子,如氧、硫和氮原子。优选R选自取代或未取代的支链、直链或环状C1-C20烷基、烯基、炔基、芳基、苄基、杂芳基、烷基-芳基、芳基-烷基、烷基-杂芳基、杂芳基-烷基、杂芳基-芳基、双环烷基、芳基或杂芳基及其组合;其中上述基团可以被任意部分取代,包括,例如羟基、氨基、氰基、卤素、氧代、羧基、甲酰胺、硝基、偶氮、烷氧基、烷基、烷氨基、烷氨基、二烷氨基、硫代烷氧基及其组合。R可以是,例如,在每次出现时独立地是氢、甲基、乙基、丙基、丁基、戊基、己基、苯基、苄基等,包括其卤代和全卤代衍生物。在一些实施方案中,R是氢、甲基、乙基、苯基或苄基,最典型地是甲基或苯基。
在式(I)中,还将被理解的是任意两个相邻基团R1、R2、R3、R4和R5可以与所连接的苯环一起形成5-元或6-元脂族或芳香环,其任选被一个或多个基团R10取代且任选在环上包括一个或多个选自O、N、S的杂原子。在一些实施方案中,任意两个相邻基团R1、R2、R3、R4和R5可以与所连接的苯环一起形成与苯环稠合的杂环,该杂环可以是芳香的、部分饱和的或完全饱和的,包括、但不限于4元环(氮杂环丁烷、环氧丙烷、硫杂环丁烷等)、5元环(吡咯、吡咯烷、呋喃、氧戊环、噻吩、硫戊环、吡唑、咪唑、咪唑烷、唑、异唑、唑烷、噻唑、异噻唑、噻唑烷、二氧戊环、二硫戊环、1,2,3-三唑、1,2,4-三唑、二噻唑、四唑等)和6元环(哌啶、吡啶、四氢吡喃、吡喃、噻蒽、硫酮、哌嗪、二嗪、嗪、噻嗪、二噻烷、二烷、二英、吗啉、喹啉等)。
此外,任意的氮原子可任选被氧化成N-氧化物或可以被例如低级烷基卤季铵化,所述低级烷基卤例如甲基氯、乙基氯、丙基氯和丁基氯、甲基溴、乙基溴、丙基溴和丁基溴和甲基碘、乙基碘、丙基碘和丁基碘;硫酸二烷基酯,如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯;长链卤化物,例如癸基氯、月桂基氯、肉豆蔻基氯和硬脂酰氯、癸基溴、月桂基溴、肉豆蔻基溴和硬脂酰溴和癸基碘、月桂基碘、肉豆蔻基碘和硬脂酰碘;芳烷基卤,例如苄基溴和苯乙基溴等。
在式(I)的一个实施方案中,R1、R2、R4、R5、R7和R8表示氢,如式(Ia)所示。
其中R3和R6独立地是氢或如上述所定义的基团-R9-R10。在一些实施方案中,R3是基团-OR(即,R9不存在,R10是-OR),其中R表示氢、甲基、乙基、丙基、异-丙基、丁基、异-丁基、仲-丁基、叔-丁基、戊基、己基、苯基或苄基及其卤代和全卤代衍生物,例如三氟甲基。在一个实施方案中,R3是基团-OR,其中R表示用于定义苯环对位上的甲氧基的甲基,如式(Ib)所示:
其中R6是氢或如上述所定义的基团-R9-R10。优选R6是氢或基团-R9-R10,其中R9不存在,其中R10选自:(i)形式-(C=O)-R的酰基,其中R如上述所定义,但典型地选自甲基、乙基、丙基、丁基、戊基、己基、苯基、甲苯甲酰基或苄基(优选苯基);和(ii)-SO2-R基团,其中R如上述所定义,但典型地选自甲基、乙基、丙基、丁基、戊基、己基、苯基、甲苯甲酰基或苄基(优选甲基)。
在一个具体的实施方案中,化妆品组合物在化妆品可接受的媒介物,优选油包水型或水包油型乳剂中包含约0.0001%-约90%重量的具有如下结构的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺:
或其化妆品可接受的盐。
在另一个具体的实施方案中,化妆品组合物在化妆品可接受的媒介物,优选油包水型或水包油型乳剂中包含约0.0001%-约90%重量的具有如下结构的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺:
或其化妆品可接受的盐。
式(I)的化合物包含哌嗪环上的一个立体中心和内酰胺环上的一个立体中心。这些立体中心各自可以是R或S构型。因此,式(i)的化合物就其流过手性中心而言可以作为纯(R,R)、(R,S)、(S,R)或(S,S)非对映异构体存在或可以包含两种或多种非对映异构体的混合物。所谓“纯”意指特定的非对映异构体占式(I)化合物总重至少95%重量,且优选至少98%或至少99%重量。
本发明包括化妆品或药学可接受的(例如无毒性和/或无刺激性)盐的应用。本发明化合物的盐的实例包括与碱金属如钠和钾形成的盐;与碱土金属例如钙和镁形成的盐;与胺类例如单乙醇胺形成的盐;与无机酸如颜色和硫酸形成的盐;和与有机酸如柠檬酸和乙酸形成的盐。特别举出的是盐酸盐。
可以将本发明的化妆品组合物配制成各种适合于局部施用的形式且包含约0.0001%-约90%重量的一种或多种式(I)的化合物且优选包含约0.001%-约25%重量且更优选约0.01%-约10%重量。该组合物包含有效量的式(I)1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺化合物,其含义是在局部施用于其上时用量足以强化指定皮肤区域中的胶原蛋白I、桥粒核心糖蛋白和/或皮肤桥蛋白。
可以将组合物配制成各种产品形式,例如洗剂、霜剂、浆液、喷雾剂、气雾剂、饼状物、软膏剂、精油、凝胶、糊剂、贴剂、笔状物、小毛巾、面膜、棒状物、泡沫、酏剂、浓缩物等,特别用于局部给药。优选将组合物配制成洗剂、霜剂、软膏剂或凝胶。
组合物可以包含化妆品可接受的媒介物。这种媒介物可以采用适合于施用于皮肤的本领域任意公知的形式且可以包括水;植物油;矿物油;酯类,如棕榈酸辛酯、肉豆蔻酸异丙酯和棕榈酸异丙酯;氧烷,如二辛基醚和二甲基异山梨醇;醇类,如乙醇和异丙醇;脂肪醇类,如鲸蜡醇、鲸蜡硬脂醇、十八烷醇和联苯醇;异链烷烃,例如异辛烷、异十二烷和异十六烷;硅油类,如环甲基硅酮、聚二甲基硅氧烷、聚二甲基硅氧烷交联聚合物、聚硅氧烷类及其衍生物,优选有机改性的衍生物;烃油,如矿物油、凡士林油、异二十碳烷和聚异丁烯;多元醇类,如丙二醇、甘油、丁二醇、戊二醇和己二醇;蜡,如蜂蜡和植物蜡;或上述物质的任意组合或混合物。
媒介物可以包含水相、油相、醇、硅氧烷相或其混合物。化妆品可接受的媒介物还可以包含乳剂。适合的乳剂的非限制性实例包括油包水型乳剂、水包油型乳剂、水包硅氧烷型乳剂、硅氧烷包水型乳剂、水包蜡型乳剂、水包油包水型三元乳剂等,其具有霜剂、凝胶或微乳外观。乳剂可以包括乳化剂,如非离子型、阴离子型或两性表面活性剂。
乳剂的油相具有一种或多种有机化合物,包括软化剂;保湿剂(例如丙二醇和甘油);其他水可分散或水溶性成分,包括增稠剂,如硅酸镁铝或羟基烷基纤维素;胶凝剂,如高MW聚丙烯酸,即CARBOPOL 934;及其混合物。乳剂可以具有一种或多种能够乳化组合物中存在的各种成分的乳化剂。
适用于油相的化合物包括、但不限于植物油;酯类,如棕榈酸辛酯、肉豆蔻酸异丙酯和棕榈酸异丙酯;氧烷,如二辛基醚;脂肪醇类,如鲸蜡醇、鲸蜡硬脂醇、十八烷醇和山萮醇;异链烷烃,例如异辛烷、异十二烷和异十六烷;硅油类,如聚二甲基硅氧烷、环甲基硅酮和聚硅氧烷类;烃油,如矿物油、凡士林油、异二十碳烷和聚异丁烯;天然或合成蜡等。适合的疏水性烃油可以是饱和或不饱和的,其具有脂族特性并且是直链或支链的或包含脂环或芳香环。含油相可以由单独的油或不同油的混合物组成。
烃油包括具有6-20个碳原子、更优选10-16个碳原子的那些。有代表性的烃类包括癸烷、十二烷、十四烷、十三烷和C8-20异链烷烃。石蜡族烃类购自Exxon、商品名ISOPARS并且购自Permethyl Corporation。此外,还预期Permethyl Corporation生产的具有商品名Permethyl99ATM的C8-20石蜡族烃类如C12异链烷烃(异十二烷)也是适合的。各种商购C16异链烷烃如异十六烷(具有商品名Permethyl室温M)也是适合的。优选的挥发性烃类的实例包括聚癸烷类,如异十二烷和异癸烷,包括,例如,Permethyl-99A(Presperse Inc.)和C7-C8-C12-C15异链烷烃类,如购自Exxon Chemicals的Isopar Series。有代表性的烃溶剂是异十二烷。
油相可以包含一种或多种蜡,包括,例如,米糠蜡、巴西棕榈蜡、小冠巴西棕蜡、小烛树蜡、蒙旦蜡、甘蔗蜡、地蜡、聚乙烯蜡、费-托合成过程中得到的蜡、蜂蜡、微晶蜡、硅氧烷蜡、氟化蜡及其任意组合。
非限制性乳化剂包括乳化蜡、乳化多元醇类、聚醚多元醇类、聚氧烷、多元醇的单-或二-酯、乙二醇单-硬脂酸酯类、甘油单-硬脂酸酯、甘油二-硬脂酸酯类、含硅氧烷的乳化剂、大豆甾醇类、脂肪酸醇类如鲸蜡醇、脂肪酸如硬脂酸、脂肪酸盐及其混合物。优选的乳化剂包括大豆甾醇、鲸蜡醇、硬脂酸、乳化蜡及其混合物。其他可以用于本发明组合物的具体的乳化剂包括、但不限于一种或多种如下成分:山梨坦酯类;聚甘油基-3-二异硬脂酸酯;硬脂山梨坦、三硬脂山梨坦、倍半油酸山梨坦、去水山梨糖醇单油酸酯;甘油酯类如单硬脂酸甘油酯和甘油单油酸酯;聚氧乙烯苯酚类如聚氧乙烯辛基苯酚和聚氧乙烯壬基苯酚;聚氧乙烯氧烷如聚氧乙烯鲸蜡醚和聚氧乙烯硬脂酰醚;聚氧乙烯乙二醇酯类;聚氧乙烯山梨坦酯类;聚二甲基硅氧烷共聚醇;聚甘油基酯类如聚甘油基-3-二异硬脂酸酯;月桂酸甘油酯;硬脂醇聚醚-2、硬脂醇聚醚-10和硬脂醇聚醚-20等。其他乳化剂在INCI Ingredient Dictionary andHandbook第11版2006中提供,将该文献的公开内容引入本文作为参考。
这些乳化剂在组合物中的存在量典型地为约0.001%-约10%重量,特别是约0.01%-约5%重量且更优选低于1%重量。
油相可以包含一种或多种挥发性和/或不挥发性硅油类。挥发性硅氧烷包括环状和直链挥发性二甲基硅氧烷硅酮。在一个实施方案中,挥发性硅氧烷可以包括环聚二甲基硅氧烷,包括四聚体(D4)、五聚体(D5)和六聚体(D6)、环甲基硅酮或其混合物。特别举出的是挥发性环甲基硅酮-六甲基环三硅氧烷、八甲基-环四硅氧烷和十甲基-环五硅氧烷。适合的聚二甲基硅氧烷购自Dow Corning、商品名Dow CorningFluid并且具有0.65-600,000厘沲以上的粘度。适合的非极性挥发性液体硅氧烷公开于美国专利US4,781,917中,将该文献完整地引入本文作为参考。其他的挥发性硅氧烷描述在Todd等人,“Volatile Silicone Fluidsfor Cosmetics”,Cosmetics and Toiletries,91:27-32(1976)中,将该文献完整地引入本文作为参考。直链挥发性硅氧烷在25℃具有低于约5厘沲的粘度,而环硅氧烷在25℃具有低于约10厘沲的粘度。不同粘度的挥发性硅氧烷的实例包括Dow Corning 200、Dow Corning 244、Dow Corning 245、Dow Corning 344和Dow Corning 345,(Dow CorningCorp.);SF-1204和SF-1202 Silicone Fluids(G.E.Silicones)、GE 7207和7158(General Electric Co.);和SWS-03314(SWS Silicones Corp.)。直链挥发性硅氧烷包括低分子量聚二甲基硅氧烷化合物,如六甲基二硅氧烷、八甲基三硅氧烷、十甲基四硅氧烷和十二甲基五硅氧烷等。
非挥发性硅油典型地包含聚烷基硅氧烷类、聚芳基硅氧烷类、聚烷基芳基硅氧烷类或其混合物。聚二甲基硅氧烷是优选的非挥发性硅油。非挥发性硅油典型地在25℃具有约10-约60,000厘沲的粘度,优选约10-约10,000厘沲且更优选约10-约500厘沲;且沸点在大气压下高于250℃。非限制性实例包括二甲基聚硅氧烷(聚二甲基硅氧烷)、苯基三甲硅油和二苯基聚二甲基硅氧烷。挥发性和非挥发性硅油可以任选被不同官能团取代,如烷基、芳基、胺基、乙烯基、羟基、卤代烷基、烷基芳基和丙烯酸酯基等。
可以用非离子型表面活性剂(乳化剂)乳化硅氧烷包水型乳剂,例如聚二有机硅氧烷-聚氧化亚烷基嵌段共聚物,包括美国专利US 4,122,029中所述的那些,将其公开内容引入本文作为参考。这些乳化剂一般包含具有-(EO)m-和/或-(PO)n-基团的聚二有机硅氧烷骨架,典型地是聚二甲基硅氧烷,其中EO是亚乙二氧基,PO是1,2-亚丙二氧基,侧链典型地被氢或低级烷基封端或被终止(例如,C1-6,典型地C1-3)。其他适合的硅氧烷包水型乳化剂公开在美国专利US 6,685,952中,将其公开内容引入本文作为参考。商购硅氧烷包水型乳化剂包括购自Dow Corning的那些,商品名为3225C和5225C FORMULATION AID;购自General Electric的SILICONE SF-1528;购自Goldschmidt Chemical Corporation(Hopewell,VA)的ABIL EM 90和EM 97;和OSI Specialties(Danbury,CT)销售的SILWET系列乳化剂。
硅氧烷包水型乳化剂的实例包括、但不限于聚二甲基硅氧烷PEG10/15交联聚合物、聚二甲基硅氧烷共聚醇、鲸蜡基聚二甲基硅氧烷共聚醇、PEG-15月桂基聚二甲基硅氧烷交联聚合物、月桂基甲硅油交联聚合物、环甲基硅酮和聚二甲基硅氧烷共聚醇、聚二甲基硅氧烷共聚醇(和)辛酸/癸酸甘油三酯类、聚甘油基-4异硬脂酸酯(和)鲸蜡基聚二甲基硅氧烷共聚醇(和)月桂酸己酯和聚二甲基硅氧烷共聚醇(和)环五硅氧烷。硅氧烷包水型乳化剂的优选实例包括、但不限于PEG/PPG-18/18聚二甲基硅氧烷(商品名5225C,Dow Corning)、PEG/PPG-19/19聚二甲基硅氧烷(商品名BY25-337,Dow Corning)、鲸蜡基PEG/PPG-10/1聚二甲基硅氧烷(商品名Abil EM-90,Goldschmidt Chemical Corporation)、PEG-12聚二甲基硅氧烷(商品名SF 1288,General Electric)、月桂基PEG/PPG-18/18甲硅油(商品名5200 FORMULATION AID,Dow Corning)、PEG-12聚二甲基硅氧烷交联聚合物(商品名9010和9011硅氧烷弹性体掺合物,Dow Corning)、PEG-10聚二甲基硅氧烷交联聚合物(商品名KSG-20,Shin-Etsu)和聚二甲基硅氧烷PEG-10/15交联聚合物(商品名KSG-210,Shin-Etsu)。
硅氧烷包水型乳化剂在组合物中的存在量典型地为约0.001%-约10%重量,特别是约0.01%-约5%重量且更优选低于1%重量。
乳剂的水相可以包括一种或多种其他溶剂,包括低级醇类,如乙醇、异丙醇等。挥发性溶剂也可以是化妆品可接受的酯,如乙酸丁酯或乙酸乙酯;酮类,如丙酮或乙基甲基酮等。
基于乳剂的总重,含油相典型地约占10%-约99%、优选约20%-约85%且更优选约30%-约70%重量,水相典型地占总乳剂的约1%-约90%、优选约5%-约70%且更优选约20%-约60%重量。水相典型地包含约25%-约100%、更典型地约50%-约95%重量的水。
组合物可以包括脂质体。脂质体可以包含其他添加剂或物质和/或可以被改性以便在给药后更具体地达到或保留在部位。
组合物可以任选包含其他化妆品活性成分和赋形剂,这对本领域技术人员而言显而易见,包括、但不限于填充剂、乳化剂、抗氧化剂、表面活性剂、成膜剂、螯合剂、胶凝剂、增稠剂、软化剂、保湿剂、增湿剂、维生素、矿物、粘度和/或流变调节剂、遮光剂、角质层分离剂、维生素a酸类、激素化合物、α-羟基酸、α-酮基酸、抗分枝杆菌剂、抗真菌剂、抗微生物剂、抗病毒剂、止痛药、脂类化合物、抗过敏药、H1或H2抗组胺剂、抗炎药、抗刺激剂、抗肿瘤药、免疫系统加强剂、免疫系统抑制剂、抗痤疮药、麻醉药、抗菌药、驱虫药、皮肤降温化合物、皮肤防护化合物、皮肤渗透促进剂、剥脱剂、润滑剂、香料、着色剂、脱色剂、色素减少剂、防腐剂、稳定剂、药剂、光稳定剂、遮光剂及其混合物。除上述外,本发明的化妆品组合物还可以包含其他用于治疗皮肤病的化合物。
着色剂可以包括,例如,有机和无机色素和珠光剂。适合的无机色素包括、但不限于氧化钛、氧化锆和氧化铈以及氧化锌、氧化铁、氧化铬和铁蓝。适合的有机色素包括钡、锶、钙和铝色淀和碳黑。适合的珠光剂包括涂敷氧化钛、氧化铁或天然色素的的云母。
可以加入各种填充剂和其他成分。填充剂通常以占组合物总重约0重量%-约20重量%的量存在,优选约0.1重量%-约10重量%。适合的填充剂包括、但不限于二氧化硅、处理的二氧化硅、滑石粉、硬脂酸锌、云母、高岭土、尼龙粉如OrgasolTM、聚乙烯粉、TeflonTM、淀粉、一氮化硼、共聚物微球如ExpancelTM(Nobel Industries)、PolytrapTM(DowCorning)和硅氧烷树脂微珠(来自Toshiba的TospearlTM)等。
在本发明的一个实施方案中,组合物可以包含另外的皮肤活性成分,例如、但不限于植物药、角质溶解药、脱屑剂、角化细胞增殖促进剂、胶原酶抑制剂、弹性酶抑制剂、脱色剂、抗炎药、类固醇、抗痤疮剂、抗氧化剂、水杨酸或水杨酸酯类、硫二丙酸或其酯类和改进的糖化终产物(AGE)抑制剂。
在一个具体的实施方案中,组合物包含至少一种另外的植物药,例如植物药提取物、精油或植物药自身。适合的植物药包括、但不限于来自印度冷杉、儿茶、臭魔芋、宽叶榆绿木、Asmunda japonica、印楝、紫铆、紫矿、雪松、攀援鱼藤、余甘子、榕树、甘草、马达加斯加哈伦加那、葎草、冬青、Innula racemosa、川芎(Ligusticum chiangxiong)、女贞、粗糠柴、蜜茱萸、西班牙樱桃、海巴戟、油椒木、补血草、夹竹桃、马齿苋、Po室温ulaca sativa、补骨脂、毛瓣无患子、Sesbaniagrandaflora、乌毛蕨、Taliacora triandra、毛诃子、蕃茄糖脂的提取物及其混合物。
组合物可以包含具有抗老化有益性的另外的活性成分,因为关注可以使用这种组合得到的协同改善。典型的抗老化成分包括、但不限于植物药(例如,紫铆提取物);硫二丙酸(TDPA)及其酯类;维生素a酸类(例如全反式维甲酸、9-顺式维a酸、植烷酸等);羟酸类(包括α-羟酸类和β-羟酸类)、水杨酸和水杨酸盐酯类;剥脱剂(例如,乙醇酸、3,6,9-三氧杂十一二酸等)、雌激素合成酶刺激化合物(例如,咖啡因和衍生物);能够抑制5α-还原酶活性的化合物(例如,亚麻酸、亚油酸、非那雄胺及其混合物);屏障功能促进剂(例如,神经酰胺类、甘油酯类、胆固醇及其酯类、α-羟基和ω-羟基脂肪酸及其酯类等);胶原酶抑制剂;和弹性酶抑制剂等。
典型的维生素a酸类包括、但不限于维a酸(例如,全反构象或13-顺式)及其衍生物、视黄醇(维生素A)及其酯类如棕榈酸维生素A、醋酸维生素A和丙酸维生素及其盐。
在另一个实施方案中,本发明的局部组合物还可以包括一种或多种如下成分:透皮吸收促进剂、软化剂、皮肤润滑剂、光学扩散剂、防晒霜、剥脱剂和抗氧化剂。
软化剂提供增强皮肤光滑和减少细线和粗皱纹外观的功能有益性。实例包括肉豆蔻酸异丙酯、凡士林油、羊毛脂酸异丙酯、硅氧烷(例如,甲硅油、聚二甲基硅氧烷)、油、脂肪酸酯类或其任意混合物。乳化剂可以优选以占组合物总重的约0.1wt%-约50wt%量存在。
皮肤润滑剂用作皮肤的胶原蛋白强化剂。适合和优选的皮肤润滑剂的实例是棕榈酰寡肽。其他皮肤润滑剂是胶原蛋白和/或其他糖胺聚糖(GAG)强化剂。如果存在,则皮肤润滑剂可以占组合物总重的约0.1wt%-约20wt%。
光学扩散剂是改变皮肤表面光泽(optometrics)的颗粒,导致视觉模糊和例如线和皱纹的减轻。可以用于本发明的光学扩散剂的实例包括、但不限于一氮化硼、云母、尼龙、聚甲基丙烯酸甲酯(PMMA)、聚氨基甲酸酯粉末、绢云母、二氧化硅、硅氧烷粉末、特氟隆、二氧化钛、氧化锌或其任意混合物。如果存在,则光学扩散剂可以占组合物总重的约0.01wt%-约20wt%。
还可以包括用于防止皮肤受到紫外线损伤的防晒霜。优选的防晒霜是广泛UVB和UVA防护的那些,如氰双苯丙烯酸辛酯、阿伏苯宗(Parsol1789)、甲氧肉桂酸辛酯、水杨酸辛酯、羟苯甲酮、高水杨酸酯(homosylate)、二苯酮、樟脑衍生物、氧化锌和二氧化钛。如果存在,则防晒霜可以占组合物的约0.01wt%-约70wt%。
适合的剥脱剂包括,例如,α-羟酸类、β-羟酸类、含氧酸、含氧二酸及其衍生物如酯类、酸酐类及其盐。适合的羟基酸包括,例如,乙醇酸、乳酸、苹果酸、酒石酸、柠檬酸、2-羟基链烷酸、扁桃酸、水杨酸及其衍生物。优选的剥脱剂是乙醇酸。如果存在,则剥脱剂可以占组合物的约0.1wt%-约80wt%。
抗氧化剂起从皮肤中清除自由基的功能,以防止皮肤受到环境侵害。可以用于本发明的抗氧化剂的实例包括具有酚羟基官能团的化合物,如抗坏血酸及其衍生物/酯类;β胡萝卜素;西阿尼醇;姜黄素;阿魏酸衍生物(例如,阿魏酸乙酯、阿魏酸钠);棓酸衍生物(例如棓酸丙酯);番茄红素;还原酸;罗丹酚酸;鞣酸;四氢姜黄素;生育酚及其衍生物;尿酸;或其任意的混合物。其他适合的抗氧化剂是具有一个或多个硫氢基官能团(-SH)还原或非还原形式的那些,如谷胱甘肽、硫辛酸、巯乙酸和其他巯基化合物。抗氧化剂可以是无机物,如亚硫酸氢盐、偏亚硫酸氢盐、亚硫酸盐或其他无机盐和包含硫的酸。本发明的组合物可以包含抗氧化剂,其优选占组合物总重的约0.001wt%-约10wt%且更优选约0.01wt%-约5wt%。
其他常用的添加剂包括:维生素,如生育酚和抗坏血酸;维生素衍生物如单棕榈酸抗坏血酸酯;增稠剂如羟基烷基纤维素;胶凝剂;结构剂,如皂粘土、蒙脱石、硅酸镁铝和硅酸镁锂;金属螯合剂如EDTA;色素如氧化锌和二氧化钛;着色剂;软化剂;和保湿剂。
优选组合物基本上不含具有强化潜能的成分,包括,例如有机或无机过氧化物。所谓“基本上不含”这些成分的含义是存在量不足以对1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺类的胶原蛋白I、桥粒核心糖蛋白和/或皮肤桥蛋白的强化活性具有可测定的影响。在一些实施方案中,以相对于1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺的用量为基础,其低于1%。
在一个实施方案中,包含1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺的本发明组合物可以具有约1-约8的pH。在某些实施方案中,组合物的pH将为酸性,即,低于7.0且优选为约2-约7,更优选约3.5-约5.5。
本发明提供了处理老化皮肤的方法,通过在受侵害区域局部施用一种组合物来进行,该组合物优选在化妆品可接受的媒介物中包含1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺,所施用的时间期限足以减轻、改善、逆转或预防老化皮肤体征。该方法特别用于处理皮肤光老化和内在老化的体征。
一般而言,情况和/或美观的改善选自:减少实足年龄老化、光老化、激素老化和/或光化性老化的皮肤病体征;预防和/或减少线和/或皱纹外观;减少面部线和皱纹的可注意性、面颊、前额面部皱纹、眼之间的垂直皱纹、眼上部和口周围的水平皱纹、木偶线和特别是深部皱纹或皱褶;预防、减少和/或缩小线和/或皱纹外观和/或深度;改善眼眶下线和/或眼窝线外观;减少鱼尾纹外观;恢复和/或复活皮肤、特别是老化皮肤生气;减轻皮肤脆性;预防和/或逆转糖胺聚糖和/或胶原蛋白缺失;改善雌激素失衡效应;预防皮肤萎缩;预防、减少和/或治疗色素沉着过多;将皮肤脱色降至最低;改善皮品质、光泽、澄明度和/或紧固度;预防、减少和/或改善皮肤下垂;改善皮肤硬度、光泽度、柔软度和/或柔软性;改善前胶原蛋白和/或胶原蛋白产生;改善皮肤肌理和/或促进再织构化;改善皮肤屏障修复和/或功能;改善皮肤轮廓外观;恢复皮肤光泽和/或亮度;将品疲劳和/或紧张的皮肤病体征减至最少;抗环境应激;补充因老化和/或绝经而减少的皮肤成分;改善皮肤细胞中的通讯;增加细胞增殖和/或倍增化;因老化和/或绝经而减少的增加皮肤细胞代谢;减缓细胞老化;改善皮肤保湿;强化皮肤厚度;增加皮肤弹性和/或弹力;增强剥脱;改善微循环;减少和/或预防蜂窝组织形成;及其任意组合。
不希望受到任何特定理论约束,认为本发明的组合物通过刺激胶原蛋白和/或通过经刺激桥粒核心糖蛋白改善角蛋白细胞之间的细胞与细胞粘着强化和改善皮肤美观。
典型地将组合物每日施用于一次、两次或三次,条件是有必要实现期望的抗老化效果。这种处理方案可以包含每日施用,持续至少1周、至少2周、至少4周、至少8周或至少12周。还关注长期处理方案。
将1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺活性成分局部适合于“有此需要的个体”,其含义是该个体持续得益于皮肤损伤或老化可见体征减轻。在一个具体的实施方案中,提供在药学、生理学、化妆品和皮肤病学可接受的媒介物、稀释剂或载体中的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺成分,其中将组合物局部施用于受侵害的皮肤区域并且保留在受侵害区域,其用量可有效改善皮肤情况和美观。
在一个实施方案中,处理细线和皱纹的方法包括对有此需要的个体皮肤局部施用本发明1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺组合物,例如局部直接施用于细线和/或皱纹足以减轻细线和/或皱纹或预防或抑制新细线和/或皱纹形成的严重性的时间。可以定性评价组合物对细线和皱纹形成或外观的效果,例如通过视觉检查;或定量评价,例如通过显微镜或计算机辅助的皱纹形态测量(例如每单位皮肤面积上的皱纹数量、深度、长度、面积、体积和/或宽度)。该实施方案包括处理手、臂、腿、颈、胸和面部包括前额皮肤上的皱纹。
还关注本发明的组合物用于处理薄皮肤,通过将该组合物局部施用于有此需要的个体薄皮肤进行。“薄皮肤”预以包括因实足年龄、绝经或光损伤导致的皮肤变薄。在一些实施方案中,处理针对男性的薄皮肤,而其他实施方案处理绝经前或停经后的女性的薄皮肤,因为认为皮肤因男性和女性年龄且特别是处于不同生命阶段的女性而在变薄方面有差异。
本发明的方法可以预防性地用于阻止老化,包括尚未显现皮肤老化体征的患者,最常见的是25岁年龄以下的个体。一旦出现,则该方法还可以逆转或处理老化体征,如在25岁以上患者中常见的。
实施例
1.实施例1:胶原蛋白I的刺激
将人表皮成纤维细胞(Cascade Biologics)在96-孔组织培养板中的生长培养基(DMEM、5%FBS、1% L-Glut和1%抗生素)中培养并且在37℃温育24小时。然后用该生长培养基稀释的测试活性成分处理细胞并且在37℃温育48小时,此后收集培养基并且测定存在的前胶原蛋白1。使用来自Takara(Procollagen Type-1 C-Peptide EIA Kit,TakaraBio Inc.)的试剂盒、根据每一制造商的说明测定前胶原蛋白1水平。用5μg/ml的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺处理的成纤维细胞显示与对照相比胶原蛋白合成增加75.4%。
2.实施例2:桥粒核心糖蛋白的刺激
在96孔组织培养处理的平板中的具有生长补体(CascadeBiologics Inc.)的培养基中培养正常人角蛋白细胞。在具有10%CO2的加湿37℃温育箱中用生长培养基稀释的测试物质或二甲亚砜媒介物对照品处理细胞24小时。温育后,从每一平板中取出生长培养基并且向各孔中加入100μl裂解缓冲液且将其置于具有10%CO2的加湿37℃温育箱中30分钟。在温育期结束时,将细胞收集在冷藏平板中并且置于-80℃冷藏箱内直到分析为止。使用应用分枝DNA技术的Panomics Quantigene多路测定法分析处理后的桥粒核心糖蛋白3(DSG3)的mRNA改变。通过比较提取物的测试结果与对照结果计算每一终点的mRNA增加(%)。
用浓度为0.0005%的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺处理的角蛋白细胞显示24小时后桥粒核心糖蛋白1表达增加95%。所观察到的效果是测定的三份样品的平均值并且在p<0.05具有统计学显著性。用0.00005%测试物质处理未显示桥粒核心糖蛋白1表达的具有统计学显著性的增加。
3.实施例3:皮肤桥蛋白产生的刺激
在包含适合培养基的96孔组织培养处理的平板培养正常人表皮成纤维细胞。在具有10%CO2的加湿37℃温育箱中用生长培养基稀释的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺测试物质将细胞处理24小时。温育后,从每一平板中取出生长培养基并且向各孔中加入100μl裂解缓冲液且将其置于具有10%CO2的加湿37℃温育箱中30分钟。在温育结束时,将细胞收集在冷藏平板中并且置于-80℃冷藏箱内直到分析为止。使用应用分枝DNA技术的Panomics Quantigene多路测定法分析处理后的桥粒核心糖蛋白3(DSG3)的mRNA改变。通过比较测试结果与媒介物对照结果计算MT2A的mRNA增加百分比。用0.0005%或0.00005%的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺处理的成纤维细胞显示皮肤桥蛋白的mRNA水平分别得到62%和43%刺激。全部报道的结果在p<0.05具有统计学显著性。
4.实施例4:有代表性的制品
表1中提供了包含有效量的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺活性剂的护肤产品的有代表性的制品。
表1.
将制品1-4局部施用于皮肤,包括面部皮肤,以预防、治疗和/或减轻光老化和/或内在老化体征,例如细线和皱纹。将这些制品局部施用于皮肤足以提供皮肤老化的一种或多种体征的临床可测定的减轻的时间,典型地需要每日一次、两次或三次治疗1、2或3周至约8周以上,包括长期治疗。
5.实施例5:有代表性化合物的合成
如下由吡嗪2-甲酸合成有代表性的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺如下合成路线中所示。表2显示了该过程的吞吐量。以2-3kg规模将该过程充分优化一直到步骤4。以350g规模优化步骤5、6、7和8。
表2
1这些步骤以>2Kg规模进行。
2步骤5-7以>350g规模进行。
3步骤8以50g规模进行。
化合物1的合成
在-5-0℃向预冷却的甲醇(24900mL,3体积)中加入NaOMe(3683g,68.2mol.,1.8当量)(温度从-5升至25℃)。向这种溶液中加入L-鸟氨酸甲酯盐酸盐(8300g)在甲醇(41500mL,5体积),以维持温度低于0℃。将该反应混合物搅拌2小时,通过1H NMR监测。反应完成后,如1H NMR所示,向反应混合物中加入MTBE(50000mL,6体积),以维持温度低于0℃。将该淤浆搅拌30分钟,通过C盐床过滤,用50%MTBE的MeOH溶液(2x2000mL)洗涤。高度真空(1mm)浓缩滤液,保持浴温在30-35℃,得到固体物质,与THF(2x2000mL)一起共沸。析出期望的产物,为淡黄色固体(4320g,100%),终产物以1H NMR表征,符合无主要杂质。
化合物5的合成
在室温向5-L,3-颈RB-烧瓶中加入甲醇(1800mL)。在室温加入化合物2(300g,1.369mol,1.0当量)。将该反应混合物冷却至-2℃,通过维持温度在-5至-2℃(另外的时间1小时)加入25wt%NaOMe的甲醇溶液(532.3mL,2.46mol,1.8当量)。将该反应混合物在-5至-2℃搅拌2小时,通过1H NMR监测。加入MTBE(1800mL,6体积),维持温度在5-10℃,搅拌30分钟。用C盐床过滤该淤浆(过滤缓慢且需要1小时)。滤液总体积是3600mL,将其减压浓缩至300mL(旋转蒸发,浴温30℃)。将该溶液进行成盐反应。
在室温向5-L,3-颈RB-烧瓶中加入N-甲基-2-吡咯烷酮(NMP,1200mL,7vol)。在室温加入化合物4(169.86g,1.369mol.,1当量)。化合物4在室温部分可溶且由此加热至40-45℃以得到澄清溶液。观察到化合物3(体积300mL)在30℃15分钟内放热(30℃-44℃)。将该淤浆在室温搅拌3小时,加入MTBE(2000mL)。将该反应混合物在30分钟内冷却至5-10℃,过滤。将固体在MTBE(2000mL)中搅拌成淤浆,在室温搅拌15分钟。过滤该淤浆,真空干燥,得到化合物7,为白色固体(240g,86%)。分离的盐的1H NMR显示58∶42的胺(3)与酸(4)之比。
化合物6的合成
在室温向100-L加套反应器中加入1-甲基-2-吡咯烷酮(22L)。加入化合物5(2.7Kg,11.34mol,1当量),然后加入HOBt(345g,2.25mol.,0.2当量),然后逐步加入EDC·HCl(2.7Kg,14.0mol.,1.25当量),以维持温度在室温(观察到一定程度放热,温度从25℃升至30℃)。将该反应混合物在室温搅拌24小时,通过HPLC和ELSD监测。未观察到原料。在室温加入MeOH(5.4L),然后加入MTBE(21L),搅拌30分钟,维持温度在5-10℃。过滤固体,用MTBE(12L)洗涤。真空烘箱内干燥产物。
化合物7的合成
将N-(2-氧代哌啶-3-基)吡嗪-2-甲酰胺(5)(2.6Kg,通过HPLC测定纯度99%)和Pd(OH)2(520g)加入到50-L反应器中,加入乙醇(39L,15体积)。用氮气将该混合物净化两次,在70℃和氢气气氛中(80psi)搅拌12小时。TLC(50∶50MeOH/乙酸乙酯)分析显示产物形成(无原料)。将该反应混合物冷却至室温,通过C盐床过滤。用EtOH/CH2Cl2(50∶50)(2x19.5L)洗涤C盐床。减压蒸发溶剂。得到产物,为浓稠液体。向其中加入二氯甲烷(10体积),在45℃减压交换残留乙醇。加入二氯甲烷(2x5体积),在45℃减压交换残留溶剂。得到产物,为黄白色固体(2.85kg)。1H NMR一致且通过ELSD显示4%乙醇和94%纯度。然后干燥产物。
化合物8的合成
化合物8的合成以350.0g(6)规模进行。
表3
1未分离;根据等分部分的LOD确定收率
在0-5℃和6小时内向化合物6(350g,1.0当量)在甲醇(1.0体积)和二氯甲烷(14体积)中的溶液中滴加(Boc)2O(0.9当量)的CH2Cl2(5体积)溶液。通过TLC和ELSD监测反应进程。添加完成后,未观察到原料。向该反应混合物中加入盐水溶液(400mL,5体积),搅拌15分钟,然后分离水层,用二氯甲烷(3x500mL)萃取。加入15%柠檬酸溶液(7体积),搅拌15分钟。分离水层,用3N NaOH溶液(5体积)碱化,然后用二氯甲烷(30体积)碱化。用盐水(750mL)洗涤有机相,浓缩至约10体积,取该溶液(KF 0.1%)用于下一步。基于小等分部分的LOD分析测定8的收率为51.5%。还可以用水优化单Boc保护。
化合物9的合成
表4
1未分离;来自上述步骤的溶液进入该步骤;根据等分部分的LOD确定收率。
向化合物8的二氯甲烷溶液中加入Et3N(2.0当量),将该混合物在0-5℃搅拌10分钟,然后在30分钟内滴加4-甲氧基苯甲酰氯。通过TLC监测反应进程,1小时后,未观察到原料。向该反应混合物中加入15%柠檬酸溶液(5体积),用1N NaOH溶液(5体积)洗涤分离的有机层。用盐水洗涤有机相,浓缩至约2体积,然后加入5vol IPAc。再浓缩该溶液至约2体积(样品进行OVI分析)。最终用3体积IPAc(总计5体积,1.75L)稀释澄清溶液(进行KF分析),取其用于下一步。推定该溶液的收率是定量的。
化合物10的合成
表5
1根据来自Boc保护步骤的溶液LOD确定来自上述步骤的粗收率。
2包含40%的IPAc,干燥在进行中。可以使用热EtOAc淤浆提升纯度。
在10℃向来自上述步骤的化合物9的溶液中缓慢加入5M HCl的二烷溶液(2.5当量),将该淤浆在室温搅拌14小时。通过TLC和HPLC监测反应进程,通过HPLC显示11%原料(反应混合物是淤浆且分析不精确)。用2体积IPAc稀释该混合物,搅拌1小时。过滤固体,用IPAc洗涤。湿wt:515g(通过NMR分析发现包含40%IPAc)。收率:3步内50%(Boc保护、苯甲酰化和脱保护)。
11(1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺)的合成
有代表性的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺的合成以45.0g规模进行。
表6
向化合物10(45.0g游离碱,0.125mol,1.0当量)在二氯甲烷(10vol)中的溶液中加入三乙胺(25.4g,0.25mol,2.0当量),在0-5℃将该反应混合物搅拌10分钟,然后滴加甲磺酰氯(1.1当量)。添加完成后,将该反应混合物搅拌1小时(通过TLC和HPLC监测反应进程)。当<2%原料保留时,认为反应完成。用饱和碳酸氢钠溶液(225mL,5体积)使反应混合物猝灭,用200mL二氯甲烷稀释。分离有机相,用1N HCl洗涤,干燥,浓缩至得到化合物11(1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺)(40.0g,73%),为黄白色固体。1H NMR一致且通过HPLC测定和纯度95.5%。可以将化合物10的HCl盐用于按比例放大的反应。
将全部参考文献包括专利申请和其中引述的公开文献完整引入本文作为参考,并且为所有目的而引入至与为所有目的特别和分别将每篇公开文献或专利或专利申请各自完整引入作为参考一样。正如本领域技术人员显而易见的,可以在不脱离其精神和范围的情况下对本发明进行许多变型和改变。本文所述的具体实施方案仅借助于实施例提供且本发明仅限于所附权利要求与这样的权利要求所赋予的等同技术方案的全部范围。
Claims (20)
1.给人体皮肤提供有益性的方法,包括对有此需要的个体皮肤局部施用有效量的在化妆品可接受的媒介物中的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺或其化妆品可接受的盐。
2.权利要求1的方法,其中所述1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺具有式I的结构:
其中R1、R2、R3、R4、R5、R6和R7独立地是氢或基团-R9-R10;
R9在每次出现时独立地表示键;脂族C1-C20烃基;C1-C20芳香烃基;或C1-C20杂芳基;
R10在每次出现时独立地选自氢;-F;-Cl;-Br;-I;-OH,-OR;-NH2;-NHR;-N(R)2;-N(R)3 +;-N(R)-OH;-N(→O)(R)2;-O-N(R)2;-N(R)-O-R;-N(R)-N(R)2;-C=N-R;-N=C(R)2;-C=N-N(R)2;-C(=NR)-N(R)2;-SH;-SR;-CN;-NC;-CHO;-CO2H;-CO2 -;-CO2R;-(C=O)-S-R;-O-(C=O)-H;-O-(C=O)-R;-S-(C=O)-R;-(C=O)-NH2;-(C=O)-N(R)2;-(C=O)-NHNH2;-O-(C=O)-NHNH2;-(C=S)-NH2;-(C=S)-N(R)2;-N(R)-CHO;-N(R)-(C=O)-R;-(C=NR)-O-R;-O-(C=NR)-R,-SCN;-NCS;-NSO;-SSR;-N(R)-C(=O)-N(R)2;-N(R)-C(=S)-N(R)2;-SO2-R;-O-S(=O)2-R;-S(=O)2-OR;-N(R)-SO2-R;-SO2-N(R)2;-O-SO3 -;-O-S(=O)2-OR;-O-S(=O)-OR;-O-S(=O)-R;-S(=O)-OR;-S(=O)-R;-NO;-NO2;-NO3;-O-NO;-O-NO2;-N3;-N2-R;-N(C2H4);-Si(-R)3;-CF3;-O-CF3;-(C=O)-R;-PR2;-O-P(=O)(OR)2;-P(=O)(OR)2;=O;=S;=NR;脂族C1-C20烃基;C1-C20芳香烃基;或C1-C20杂芳基;
其中R在每次出现时独立地是氢或饱和、部分饱和或芳香C1-C20烃基或其卤代衍生物;
其中R1-5与它们所连接的苯环一起任选形成取代的5-元或6-元杂芳基环,其在环上包括一个或多个选自N、O、S的杂原子;
且其中任意两个相邻基团R1、R2、R3、R4和R5可以与它们所连接的苯环一起形成5-元或6-元脂族或芳香环,其任选被一个或多个基团R10取代且任选在环上包括一个或多个选自O、N、S的杂原子。
3.权利要求2的方法,其中R1、R2、R4和R5表示氢。
4.权利要求2的方法,其中R3表示基团-OR。
5.权利要求4的方法,其中R3表示-OCH3。
6.权利要求2的方法,其中R7和R8表示氢。
7.权利要求2的方法,其中R6是基团-(C=O)-R,其中R选自甲基、乙基、丙基、丁基、戊基、己基、苯基、甲苯甲酰基或苄基。
8.权利要求7的方法,其中R6是基团-(C=O)-(C6H5)。
9.权利要求2的方法,其中R6是基团-SO2-R,其中R选自甲基、乙基、丙基、丁基、戊基、己基、苯基、甲苯甲酰基或苄基。
10.权利要求9的方法,其中R6是基团-SO2-CH3。
11.权利要求11的方法,其中所述皮肤有益性选自:
(a)处理、减少和/或预防细线或皱纹;
(b)皮肤毛孔大小减小;
(c)皮肤厚度、丰满度和/或紧固度改善;
(d)皮肤柔软度和/或柔软性改善;
(e)肤色、光泽度和/或透明度改善;
(f)前胶原和/或胶原蛋白产生改善;
(g)弹性蛋白维持和重塑改善;
(h)皮肤肌理改善和/或质构化增强;
(i)皮肤屏障修复和/或功能改善;
(j)皮肤轮廓外观改善;
(k)皮肤光泽和/或亮度恢复;
(l)皮肤中的必需营养素和/或成分得到补充;
(m)因绝经而减弱的皮肤外观改善;
(n)皮肤保湿改善;
(o)皮肤弹性和/或弹力增加;或
(p)处理、减少和/或预防皮肤下垂。
12.权利要求11的方法,其中所述皮肤有益性是处理、减少和/或预防细线或皱纹。
13.权利要求11的方法,其中所述皮肤有益性是处理、减少和/或预防皮肤下垂。
16.处理皱纹和/或细线的方法,包括对有此需要的个体皮肤上的所述皱纹和/或细线局部施用有效量的在化妆品可接受的媒介物中的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺或其化妆品可接受的盐一定时间,该时间足以减轻所述皱纹或细线的严重性。
17.化妆品组合物,包含约0.0001%-约25%重量的在化妆品可接受的媒介物中的1-芳酰基-N-(2-氧代-3-哌啶基)-2-哌嗪甲酰胺。
18.权利要求17的化妆品组合物,其中所述化妆品可接受的媒介物包含油包水型或水包油型乳剂。
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