CN108368041B - 用于美容用途的(r)-n-(金刚烷基-2-基)吡咯烷-2-甲酰胺衍生物 - Google Patents
用于美容用途的(r)-n-(金刚烷基-2-基)吡咯烷-2-甲酰胺衍生物 Download PDFInfo
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- CN108368041B CN108368041B CN201680071772.1A CN201680071772A CN108368041B CN 108368041 B CN108368041 B CN 108368041B CN 201680071772 A CN201680071772 A CN 201680071772A CN 108368041 B CN108368041 B CN 108368041B
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- pyrrolidine
- adamantan
- carboxamide
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Classifications
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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
- A61K8/4906—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
本发明涉及新颖的选择性1型11‑β‑羟基类固醇脱氢酶(11β‑HSD1)抑制剂及其用于预防年龄诱发的皮肤结构和功能缺陷的用途。
Description
本发明涉及新颖的选择性1型11-β-羟基类固醇脱氢酶(11β-HSD1)抑制剂及其用于预防年龄诱发的皮肤结构和功能缺陷的用途。
糖皮质激素(GC)过量会不利地影响皮肤完整性,从而诱发变薄和伤口愈合受损。老化皮肤(例如特别是暴露于光的皮肤)共有相似的表型。老化皮肤中提高的11β-HSD1活性导致局部GC产生增加,这可解释与老化相关的真皮完整性损伤,例如真皮和表皮变薄,皮肤脆性增加,真皮胶原减少和经表皮的失水量增加。此外,局部GC浓度提高导致伤口愈合不良[Tiganescu等人,J Clin Invest.2013;123(7):3051-3060]。
因此,局部施用有效量的11β-HSD1抑制剂可用于处理与老化相关的真皮完整性和伤口愈合方面的损伤。用11β-HSD1抑制剂长期处理还可用于延缓老化的开始。
出乎意料地发现:包含(R)-N-(金刚烷基-2-基)吡咯烷-2-甲酰胺残基的式(I)的化合物
其中n、m和p彼此独立地为0或1,
如果n为1,则q为1或2,
R1选自H、C1-C6酰基或羟基乙酰基,
R2是H或C1-C6烷基,且
R3选自H、C1-C6烷基、芳族C1-C6烷基(arC1-C6alkyl)、杂芳基C1-C6烷基和联苯C1-C6烷基,其中芳族芳基、杂芳基或联苯残基可任选地被取代,
或其美容上可接受的盐是高效的11β-HSD1抑制剂,因此特别适合于掺入美容组合物中以处理与老化相关的真皮完整性和伤口愈合方面的损伤。
各自的(S)-异构体以及各自的1-金刚烷基-衍生物显示出无活性或仅显示出非常有限的活性。
因此,在第一方面,本发明涉及式(I)的化合物或其美容上可接受的盐,
其中n、m和p彼此独立地为0或1,
如果n为1,则q为1或2,
R1选自H、C1-C6酰基或羟基乙酰基,
R2是H或C1-C6烷基,且R3选自H、C1-C6烷基、芳族C1-C6烷基、杂芳基C1-C6烷基和联苯C1-C6烷基,其中芳族芳基、杂芳基或联苯残基可任选被取代。
芳族C1-C6烷基、杂芳基C1-C6烷基和联苯C1-C6烷基中的芳族芳基、杂芳基或联苯残基可以未被取代或被一个或多个取代基取代。在本发明的所有实施方式中,这类取代基优选地选自卤素、羟基、硝基、氰基、C1-C6烷基、C1-C6烷氧基和C1-C6烷酰氧基。更优选地,在本发明的所有实施方式中,杂芳基和联苯残基未被取代,而芳基残基被一个下述取代基取代,所述取代基选自F、Cl、羟基、氰基、C1-C3烷基、C1-C3烷氧基和C1-C3烷酰氧基,优选地选自F、羟基、氰基、(m)乙氧基和乙酰氧基。
术语“C1-C6烷基”是指无支链C1-C6烷基或分支的C3-C6烷基,例如甲基、乙基、正丙基、1-甲基乙基、正丁基、1-甲基丙基、2-甲基丙基、1,1-二甲基乙基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、2,2-二甲基丙基、1-乙基丙基、正己基、1,1-二甲基丙基、1,2-二甲基丙基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基和1-乙基-2-甲基丙基。
术语“C1-C6酰基”是指–C(=O)C1-C6烷基,例如乙酰基、丙酰基、正丁酰基、异丁酰基、戊酰基、己酰基和庚酰基。
术语“芳族C1-C6烷基”是指–C1-C6烷基-芳基,其中术语“芳基”有例如苯基、茚满基或萘基。
术语“杂芳基C1-C6烷基”是指–C1-C6烷基-杂芳基,其中术语“杂芳基”是指含有一个或多个杂原子(即N、O或S)的5元或6元芳族环;这些杂芳环可以与其他芳族体系稠合。
术语“联苯C1-C6烷基”是指–C1-C6烷基-联苯,其中术语联苯是指可以在邻位、间位和对位与C1-C6烷基残基连接的1,1'-联苯。
术语“C1-C6烷酰氧基”是指–OC(=O)C1-C6烷基,例如乙酰氧基、丙酰氧基、正丁酰氧基、异丁酰氧基、戊酰氧基、己酰氧基和庚酰氧基。
容易理解,本发明涵盖以下形式的式(I)的化合物,其作为光学纯的异构体,例如作为纯的对映异构体或立体异构体,以及不同异构体的混合物,例如作为外消旋物或非对映异构体的混合物。
术语“或其美容上可接受的盐”是指酸加成盐形式(例如氯化物、乙酸盐或三氟乙酸盐形式)的式(I)的化合物。或者,所述盐可以通过与碱金属碱或碱土金属碱的反应形成,从而产生各自的碱金属盐或碱土金属盐,例如特别是各自的锂盐、钠盐、钾盐、镁盐或钙盐。
在本发明的所有实施方式中,最优选的是式(I)的化合物本身或其乙酸盐或三氟乙酸盐(即作为2,2,2-三氟乙酸盐)形式。本领域技术人员容易制备这类盐。
在本发明的所有实施方式中,R1优选地选自H和C1-C2酰基,最优选地选自H和乙酰基。
在本发明的所有实施方式中,R2优选地选自H和C1-C2烷基,最优选地选自H和甲基。
在本发明的所有实施方式中,R3优选地选自H;C1-C2烷基;芳族C1-C2烷基,所述芳族C1-C2烷基可被一个取代基取代,所述取代基选自F、Cl、羟基、氰基、C1-C3烷基、C1-C3烷氧基和C1-C3烷酰氧基,优选地选自F、羟基、氰基、(m)乙氧基和乙酰氧基;未被取代的杂芳基C1-C2烷基和未被取代的联苯C1-C2烷基。最优选地,在本发明的所有实施方式中,R3选自H、甲基、3-羟基苄基、4-羟基苄基、4-甲氧基苄基、4-乙氧基苄基、4-乙酰氧基苄基、4-氟苄基、2-氰基苄基、4-氰基苄基、1,1’-联苯-3-基甲基和1H-吲哚-3-基甲基。
在一个特别有利的实施方式中,本发明涉及式(I)的化合物或其美容上可接受的盐,例如优选地三氟乙酸盐,
其中n、m和p彼此独立地为0或1,
如果n为1,则q为1,
R1是H或乙酰基,
R2是H或甲基,且
R3选自H、甲基、3-羟基苄基、4-羟基苄基、4-甲氧基苄基、4-乙氧基
苄基、4-乙酰氧基苄基、4-氟苄基、2-氰基苄基、4-氰基苄基、1H-吲
哚-3-基甲基和1,1’联苯-3-基甲基。
在一个非常有利的实施方式中,式(I)的化合物是式(II)的化合物,
其中关于R1和R3的所有限定和优选如上所述。
甚至更优选的是式(II)的化合物,其中R1是H或乙酰基,且R3选自H、甲基、3-羟基苄基、4-羟基苄基、4-甲氧基苄基、4-乙氧基苄基、4-乙酰氧基苄基、4-氟苄基、2-氰基苄基、4-氰基苄基、1H-吲哚-3-基甲基和1,1’联苯-3-基甲基,或其美容上可接受的盐,例如优选地三氟乙酸盐。
在另一个非常有利的实施方式中,式(I)的化合物是式(III)的化合物,更优选地式(IV)的化合物
其中关于R1、R2和R3的所有限定和优选如上所述。
甚至更优选的是式(III)的化合物,例如特别是式(IV)的化合物,其中R1是H或乙酰基,优选H并且R2和R3彼此独立地为H或甲基,或其美容上可接受的盐,例如优选地三氟乙酸盐。
表1列出了根据本发明的最优选的式(I)的化合物:
表1
如实施例中所示,可以通过肽化学中的标准方法从H-D-Pro-NH-2-Ad制备根据本发明的化合物。
在另一个实施方式中,本发明涉及具有本文给出的所有限定和优选的式(I)的化合物作为11β-HSD1抑制剂的用途,特别是用于处理与年龄相关的真皮完整性和伤口愈合方面的损伤以及与此相关的症状例如皱纹和细纹的用途。此外,式(I)的化合物特别适于预防(光)老化诱发的皮肤结构和功能缺陷,例如皮肤变薄和皱纹形成。
因此,本发明还涉及美容组合物,其包含至少一种式(I)的化合物和美容上可接受的载体。
本领域技术人员可以容易地调节美容组合物中式(I)的化合物的量以获得期望的有益效果。优选地,根据本发明的美容组合物中式(I)的化合物的量为至少1ppm,所述量是基于所述美容组合物的总重量。在本发明的所有实施方式中,基于美容组合物的总重量,式(I)的化合物的量优选地选自约0.00001-0.5重量%的范围内,更优选地0.0001-0.25重量%的范围内,最优选地0.0001-0.1重量%的范围内。
此外,本发明还涉及抚平皱纹和细纹并/或减小其体积和深度的方法,所述方法包括将具有本文给出的所有限定和优选的根据本发明的美容组合物应用到受影响区域的步骤。
术语“美容组合物”是指用于处理、护理或改善皮肤和/或头皮外观的组合物。特别有利的美容组合物是皮肤护理组合物。
根据本发明的美容组合物优选用于局部应用,其应被理解为外部应用到角质物质,例如特别是皮肤。
在本文中使用时,术语“美容上可接受的载体”是指与角质物质相容的生理上可接受的介质。合适的载体在本领域中是公知的,并且基于最终用途应用来选择。优选地,本发明的载体适合应用到皮肤(例如,遮光剂、霜、乳、洗剂、面膜、精华、水分散体、粉底、霜、凝霜或凝胶等)。这种载体对于本领域普通技术人员而言是公知的,可以包括适合应用到皮肤的一种或多种相容的液体或固体填充剂稀释剂、赋形剂、添加剂或载剂。载体的确切量取决于式(I)的化合物和任何其他任选的下述成分的水平,所述成分会被本领域普通技术人员归类为不同于载体(例如,其它活性组分)。本发明的组合物优选包含以组合物的重量计约75%至约99.999%、更优选约85%至约99.99%、还更优选90%至约99%、最优选约93%至约98%的载体。
本发明的美容组合物可被配制成多种产品类型,包括霜、蜡状物、糊剂、洗剂、乳、摩丝、凝胶、油、化妆水(tonics)和喷雾剂。式(I)的化合物优选被配制成洗剂、霜、凝胶和化妆水。这些产品形式可用于许多应用,包括但不限于手部和身体洗剂、面部保湿剂、抗老化制品、化妆品包括粉底,等等。配制这些产品所需的任何附加组分因产品类型而异,并且可由本领域技术人员常规选择。
如果将本发明的组合物配制成气雾剂并作为喷涂产品应用到皮肤上,则向组合物中加入推进剂。
可以通过本领域的常规方法来制备根据本发明的美容组合物,例如通过将具有本文给出的所有限定和优选的式(I)的化合物与与美容上可接受的载体混合。本发明的美容组合物(包括载体)可以包含其它常规的美容佐剂和添加剂,例如防腐剂/抗氧化剂,脂肪物质/油,水,有机溶剂,硅酮,增稠剂,软化剂,乳化剂,消泡剂,美学组分例如香料,表面活性剂,填充剂,阴离子聚合物、阳离子聚合物、非离子聚合物或两性聚合物或其混合物,推进剂,酸化剂或碱化剂,染料,着色剂/染色剂,研磨剂,吸收剂,螯合剂(chelating agents)和/或螯合分散剂(sequestering agents),精油,皮肤感觉剂(skin sensates),收敛剂,颜料或通常配制到这种组合物中的任何其他成分。
依照本发明,根据本发明的美容组合物还可以包含美容组合物中常规使用的其它美容活性成分。示例性的活性成分包括亮肤剂;UV-过滤剂,用于处理色素沉着过度的试剂;预防或减轻炎症的试剂;紧致剂、保湿剂、舒缓剂和/或活力剂(energizing agent)以及改善弹性和皮肤屏障的试剂。
适用于本发明美容组合物中的皮肤护理行业中常用的美容赋形剂、稀释剂、佐剂、添加剂以及活性成分的实例例如描述于可通过在线INFOBASE(http://online.personalcarecouncil.org/jsp/Home.jsp)访问的个人护理产品委员会的国际化妆品原料字典和手册(International Cosmetic Ingredient Dictionary&Handbook byPersonal Care Product Council;http://www.personalcarecouncil.org/),但不限于此。
基于期望的产品形式和应用,本领域技术人员可以容易地确定活性成分以及美容赋形剂、稀释剂、助剂、添加剂等的必需量。可以视情况将额外的成分加入到油相中,水相中或者分别加入。
本文中可用的美容活性成分在一些情况下能够提供多于一种益处或通过多于一种作用模式发挥作用。
当然,本领域技术人员应小心地选择上述任选的附加成分、助剂、稀释剂和添加剂和/或其量,使得与根据本发明的组合内在相关的有利性质不受或基本上不受所设想的一种或多种添加的不利影响。
根据本发明的美容组合物可以是在溶剂或脂肪物质中的悬浮物或分散体的形式,或者其形式可以是乳剂或微乳剂(特别是水包油(O/W)或油包水(W/O)型,水包硅酮(Si/W)或硅酮包水(W/Si)型,PIT-乳剂,多重乳剂(例如油包水包油(O/W/O)或水包油包水(W/O/W)型),皮克林乳剂(pickering emulsion),水凝胶,醇凝胶,脂质凝胶,单相溶液或多相溶液或泡状分散体或其它常用形式,还可以通过笔、作为面膜或喷雾来应用。
如果美容组合物是乳剂,例如特别是O/W、W/O、Si/W、W/Si、O/W/O、W/O/W多重乳剂或者皮克林乳剂,那么基于美容组合物的总重量,这种美容乳剂中存在的油相的量优选为至少10重量%,例如10-60重量%的范围、优选15-50重量%的范围、最优选15-40重量%的范围。
在一个实施方式中,根据本发明的美容组合物有利地为水包油(O/W)乳剂的形式,其包含在O/W乳化剂的存在下分散在水相中的油相。这种O/W乳剂的制备是本领域技术人员公知的。
如果根据本发明的美容组合物是O/W乳剂,那么其有利地含有至少一种的O/W-乳化剂或Si/W-乳化剂,其选自甘油基硬脂酸酯柠檬酸酯、甘油基硬脂酸酯SE(自乳化)、硬脂酸,硬脂酸的盐,聚甘油基-3-甲基葡萄糖二硬脂酸酯。其他合适的乳化剂为磷酸酯及其盐,如鲸蜡醇磷酸酯(例如,来自DSM Nutritional Products Ltd.的A)、二乙醇胺鲸蜡醇磷酸酯(例如来自DSM Nutritional Products Ltd.的DEA)、鲸蜡醇磷酸酯钾(例如来自DSM Nutritional Products Ltd.的)、鲸蜡硬脂醇硫酸酯钠、甘油油酸酯磷酸酯钠、氢化植物油甘油酯类磷酸酯和其混合物。其他合适的乳化剂为失水山梨醇油酸酯、失水山梨醇倍半油酸酯、失水山梨醇异硬脂酸酯、失水山梨醇三油酸酯、鲸蜡硬脂基葡糖苷、月桂基葡糖苷、癸基葡糖苷、硬脂酰谷氨酸钠、蔗糖多硬脂酸酯和水合聚异丁烯。此外,一种或多种合成聚合物可被用作乳化剂。例如,PVP二十碳烯共聚物、丙烯酸酯/C10-30烷基丙烯酸酯交联聚合物及其混合物。
基于美容组合物的总重量,至少一种O/W乳化剂和Si/W乳化剂的用量优选分别为0.5-10重量%,特别是0.5-6重量%,例如更特别是0.5-5重量%,例如最特别是1-4重量%。
待用于根据本发明的美容组合物中的特别合适的O/W乳化剂包括磷酸酯乳化剂,例如有利地包括8-10烷基乙基磷酸酯、C9-15烷基磷酸酯、鲸蜡硬脂醇聚醚-2磷酸酯、鲸蜡硬脂醇聚醚-5磷酸酯、鲸蜡醇聚醚-8磷酸酯、鲸蜡醇聚醚-10磷酸酯、鲸蜡醇磷酸酯、C6-10链烷醇聚醚-4磷酸酯、C12-15链烷醇聚醚-2磷酸酯、C12-15链烷醇聚醚-3磷酸酯、DEA-鲸蜡硬脂醇聚醚-2磷酸酯、DEA-鲸蜡醇磷酸酯、DEA-油醇聚醚-3磷酸酯、鲸蜡醇磷酸酯钾、癸醇聚醚-4磷酸酯、癸醇聚醚-6磷酸酯和三月桂醇聚醚-4磷酸酯。
另一类特别合适的O/W乳化剂是从橄榄油衍生的非离子型自乳化体系,例如以商品名OLIVEM 1000出售的(INCI名)鲸蜡硬脂醇橄榄油酸酯和失水山梨醇橄榄油酸酯(化学组成:橄榄油脂肪酸的失水山梨醇酯和鲸蜡硬脂酯)。
在一个具体的实施方式中,本发明涉及具有本文给出的所有限定和优选的O/W乳剂形式的美容组合物,其包含在O/W乳化剂的存在下分散在水相中的油相,其中所述O/W乳化剂是鲸蜡醇磷酸酯钾。这种O/W乳剂中油相的量优选为至少10重量%,更优选为10-60重量%,最优选为15-50重量%,例如15-40重量%。
根据本发明的美容组合物通常具有3至10范围内的pH,优选4至8范围内的pH,最优选4至7.5范围内的pH。可以根据需要用合适的酸或碱根据本领域的标准方法容易地调节pH,所述酸例如柠檬酸,所述碱例如氢氧化钠(例如作为水溶液)、三乙醇胺(TEA Care)、氨基丁三醇(Trizma Base)和氨甲基丙醇(AMP-Ultra PC 2000)。
待应用到皮肤上的皮肤组合物的量不是关键的,且可由本领域的技术人员容易地调节。优选地,所述量选自0.1-3mg/cm2皮肤的范围,例如优选0.1-2mg/cm2皮肤的范围,最优选0.5-2mg/cm2皮肤的范围。
根据本发明的化合物的其他合适的用途包括药物应用。因此,根据本发明的化合物可用来制备药物组合物,其用于在有此需要的患者中治疗、预防和/或防治期望抑制11β-HSD1的任何病症和疾病,例如,用于治疗、预防和/或防治以下病症、失调症或疾病:代谢综合征、胰岛素抵抗、血脂异常、高血压、肥胖、2型糖尿病、葡萄糖耐量受损(IGT)、空腹血糖受损以及糖尿病并发症包括心血管疾病、动脉硬化、动脉粥样硬化、神经变性和精神疾病。根据本发明的化合物还可用于延缓或预防从IGT到2型糖尿病的进展以及代谢综合征成为2型糖尿病的进展。所述化合物可以局部应用、经口应用以及肠胃外应用,但不限于此。
参考以下非限制性实施例进一步阐释本发明,其中除非另有说明,否则所有百分比都是基于总重量的重量。
实验部分
1.基本信息
缩略语:
AA 氨基酸
Ad 金刚烷基
Boc 叔丁氧羰基
DCM 二氯甲烷
DIPEA N,N-二异丙基乙基胺
DMAP N,N-二甲基氨基吡啶
DMF 二甲基甲酰胺
Fmoc 芴基甲氧基羰基
HPLC 高压液相色谱
Pro 脯氨酸
TFA 三氟乙酸
TBTU O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓四氟硼酸盐
制备型HPLC纯化:在配备有Waters 2767样品管理器和Waters FCII自动化级分收集器的Waters高效液相色谱仪LC-2525上进行,其中使用Grom Saphir 110C18 10μm 50×300mm2制备柱以及在220nm和254nm下运行的Waters 2487双波长UV-Vis检测器。
使用H2O+0.07%TFA(A”相)和MeCN+0.07%TFA(B”相)作为洗脱剂,流量为55mL/min。
2.合成策略
合成前体:H-D-Pro-NH-2Ad*HCl
将2.48g(13.2mmol,1.1当量)2金刚烷胺盐酸盐的悬浮物悬浮在15ml DMF和2.31ml(13.2mmol,1.1当量)DIPEA中。将12mmol Boc-D-Pro-OH溶解在15ml DMF中,然后加入3.85g(12mmol,1当量)TBTU和6.9ml(39.6mmol,3.3当量)DIPEA。4分钟后,向2金刚烷胺盐酸盐悬浮物中加入预活化的氨基酸溶液。在室温下60分钟后,利用乙酸乙酯和水将反应混合物转移到分液漏斗中。用乙酸乙酯反萃取水相。用5%NaHCO3、1M KHSO4和卤水洗涤合并的有机相。用Na2SO4干燥有机相,在2mbar/40℃水浴中除去所有挥发性化合物。将残余物在乙酸乙酯中稀释并用47ml 2M HCl的二乙醚溶液和66ml 4M HCl的二恶烷溶液处理。将混合物搅拌过夜,真空浓缩并用200ml二乙醚稀释。将沉淀物过滤并干燥。产率:3.32g(11.5mmol,96%)。
程序1:Ac-AA1-D-Pro-NH-2-Ad
将214mg(0.75mmol,1.0当量)如上所述获得的H-D-Pro-NH-2Ad*HCl溶解在2.5mlDMF和0.13ml(0.75mmol,1.0当量)DIPEA中。在一个单独的烧杯中,通过向在2.5ml DMF中的0.863mmol(1.15当量)Ac-AA1-OH的溶液中加入277mg(0.863mmol,1.15当量)TBTU和0.432ml(2.475mmol,3.3当量)DIPEA,将如下所示的乙酰化氨基酸AA1预活化4分钟。合并溶液,并使其在室温下反应1小时。利用乙酸乙酯和水将反应混合物转移到分液漏斗中。用乙酸乙酯反萃取水相。用5%NaHCO3、1M KHSO4和卤水洗涤合并的有机相。用Na2SO4干燥有机相,在2mbar/40℃水浴中除去所有挥发性化合物。通过制备型HPLC纯化各自的粗产物。
(I-a):AA1=β-丙氨酸:227mg(0.62mmol,83%)
(I-b):AA1=甘氨酸:211mg(0.60mmol,80%)
程序2a:H-AA2-D-Pro-NH-2-Ad*TFA
将427mg(1.5mmol,1.0当量)如上所述获得的H-D-Pro-NH-2Ad*HCl溶解在5ml DMF和0.26ml(1.5mmol,1.0当量)DIPEA中。在一个单独的烧杯中,通过向在5ml DMF中的1.15当量Fmoc-AA2-OH的溶液中加入1.15当量TBTU和3.3当量DIPEA,将如下所示的Fmoc氨基酸AA2预活化4分钟。合并溶液,并使其在室温下反应1小时。利用乙酸乙酯和水将反应混合物转移到分液漏斗中。用乙酸乙酯反萃取水相。用5%NaHCO3、1M KHSO4和卤水洗涤合并的有机相。用Na2SO4干燥有机相,在2mbar/40℃水浴中除去所有挥发性化合物。将粗制的Fmoc-保护的物质溶解在15ml DCM中并用50当量二乙胺处理2小时。通过制备型HPLC纯化各自的粗产物。
(I-c):AA2=L-酪氨酸:311mg(0.58mmol,39%)
(I-d):AA2=L-色氨酸:208mg(0.37mmol,50%)(0.75mmol规模)
程序2b:H-AA2-D-Pro-NH-2-Ad*TFA
通过向在5ml DMF中的1.0当量Boc-AA2-OH的溶液中加入1.0当量TBTU和3.3当量DIPEA来预活化如下所示的Boc氨基酸AA2。4分钟后,加入0.542mmol(1.0当量)H-D-Pro-NH-2Ad*HCl。使混合物在室温下反应1小时。利用乙酸乙酯和水将反应混合物转移到分液漏斗中。用5%NaHCO3、1M KHSO4和卤水洗涤合并的有机相。用Na2SO4干燥有机相,在2mbar/40℃水浴中除去所有挥发性化合物。将粗制的Boc-保护的物质溶解在20ml/4M HCl的二恶烷溶液中,持续45分钟。通过制备型HPLC纯化粗产物。
(I-g):AA2L-3-苯基-苯丙氨酸:221mg(0.37mmol,72%)
(I-i):AA2=L-3-(3-羟基苯基)丙氨酸:85mg(0.16mmol,32%)
(I-k):AA2=L-3-(4-乙氧基苯基)丙氨酸:246mg(0.78mmol,78%)
(1mmol规模)
程序2c:H-O-甲基-Tyr-D-Pro-NH-2-Ad
通过向在5ml DMF中的1.0当量Boc-AA2-OH的溶液中加入1.0当量TBTU和3.3当量DIPEA来预活化L-Boc-O-甲基-酪氨酸-OH。4分钟后,加入4.5mmol(1.0当量)H-D-Pro-NH-2Ad*HCl。使混合物在室温下反应1小时。利用乙酸乙酯和水将反应混合物转移到分液漏斗中。用5%NaHCO3、1M KHSO4和卤水洗涤合并的有机相。用Na2SO4干燥有机相,在2mbar/40℃水浴中除去所有挥发性化合物。将粗制的Boc-保护的物质溶解在20ml/4M HCl的二恶烷溶液中,持续45分钟。利用NaHCO3将溶液的pH调节至8,并用乙酸乙酯萃取游离碱。用Na2SO4干燥有机相,在2mbar/40℃水浴中除去所有挥发性化合物。在程序3和6中,中间体无需进一步纯化即可使用。
(中间体1):AA2=L-O-甲基-酪氨酸:2105mg(4.5mmol,>99%)
程序2d:H-AA2-D-Pro-NH-2-Ad*HCl
通过向在5ml DMF中的1.0当量Boc-4-氟-Phe-OH的溶液中加入1.0当量TBTU和4当量DIPEA来预活化如下所示的Boc氨基酸AA2。4分钟后,加入1.5mmol(1.0当量)H-D-Pro-NH-2Ad*HCl。使混合物在室温下反应1小时。利用乙酸乙酯和水将反应混合物转移到分液漏斗中。用5%NaHCO3、1M KHSO4和卤水洗涤合并的有机相。用Na2SO4干燥有机相,在2mbar/40℃水浴中除去所有挥发性化合物。将粗制的Boc-保护的物质溶解在25ml/4M HCl的二恶烷溶液中,持续30分钟。通过添加100ml二异丙基醚使盐酸盐沉淀,然后滤出并干燥。
(中间体2):AA2=L-(4-氟-苯基)丙氨酸:573mg(1.26mmol,84%)
(中间体3):AA2=L-(2-氰基-苯基)丙氨酸:443mg(0.97mmol,97%),以1.0mmol规模进行实验
程序3:Ac-AA2-D-Pro-NH-2-Ad
将0.5mmol(1.0当量)来自程序2a至2d的H-AA2-D-Pro-NH-2-Ad悬浮或溶解在2mlDCM中。加入在1ml DCM中的47微升吡啶和47微升乙酸酐的混合物。15分钟后,加入另外的在1ml DCM中的47微升吡啶和47微升乙酸酐的混合物。15分钟后,利用乙酸乙酯和5%NaHCO3将反应混合物转移到分液漏斗中。用5%NaHCO3、1M KHSO4和卤水洗涤合并的有机相。用Na2SO4干燥有机相,在2mbar/40℃水浴中除去所有挥发性化合物。通过制备型HPLC纯化粗产物。
(I-e):142mg(0.31mmol,63%)
(I-f):41mg(0.08mmol,16%)
(I-h):317mg(0.69mmol,55%)
(I-1):246mg(0.53mmol,43%)(以1.25mmol规模进行实验)
(I-n):408mg(0.86mmol,57%)(以1.5mmol规模进行实验)
(I-s):321mg(0.69mmol,69%)(以1.0mmol规模进行实验)
程序4:Gly-L-O-甲基-Tyr-D-Pro-NH-2-Ad*TFA
将0.75mmol(1.0当量)来自程序2c的H-O-甲基-Tyr-D-Pro-NH-2-Ad溶解在DMF中。通过添加1.1当量TBTU和1.9当量DIPEA,在DMF中预活化0.788mmol(1.1当量)Boc-Gly-OH。4分钟后,合并溶液并使其在室温下反应1小时。利用乙酸乙酯和水将反应混合物转移到分液漏斗中。用乙酸乙酯反萃取水相。用5%NaHCO3、1M KHSO4和卤水洗涤合并的有机相。在2mbar/40℃水浴中除去所有挥发性化合物。将粗制的Boc-保护的物质溶解在10ml 4M HCl的二恶烷溶液中,持续45分钟。通过制备型HPLC纯化粗产物。
(I-j):276mg(0.46mmol,61%)
程序5:H-AA3-AA2-NH-(CH2)2-D-Pro-NH-2-Ad*TFA
将4mmol如上所述制备的H-D-Pro-NH-2Ad*HCl溶解在50ml乙腈和12mmol DIPEA中。加入6mmol叔丁基(2-溴乙基)氨基甲酸酯并将混合物搅拌过夜。加入另外0.58mmol叔丁基(2-溴乙基)氨基甲酸酯并将混合物搅拌过夜。加入另外0.58mmol叔丁基(2-溴乙基)氨基甲酸酯并将混合物搅拌过夜。在2mbar 40℃水浴中除去所有挥发性化合物并通过制备型HPLC纯化残余物。
将粗制的Boc-NH-(CH2)2-D-Pro-NH-2-Ad溶解在10ml二恶烷和2ml TFA中过夜。在2mbar/40℃水浴中除去所有挥发性化合物。将H2N-(CH2)2-D-Pro-NH-2-Ad*TFA溶解在DMF和2当量DIPEA中。通过添加1.1当量TBTU和3.3当量DIPEA,在DMF中预活化1.1当量Boc-AA2-OH。4分钟后,合并溶液并使其在室温下反应1小时。利用乙酸乙酯和水将反应混合物转移到分液漏斗中。用5%NaHCO3、1M KHSO4和卤水洗涤合并的有机相。在2mbar/40℃水浴中除去所有挥发性化合物。将粗制的Boc-AA2-NH-(CH2)2-D-Pro-NH-2-Ad溶解在15ml 4M HCl的二恶烷溶液中过夜。在2mbar/40℃水浴中除去所有挥发性化合物。将H-AA2-NH-(CH2)2-D-Pro-NH-2-Ad*HCl溶解在DMF和2当量DIPEA中。通过添加1.5当量TBTU和4.5当量DIPEA,在DMF中预活化1.5当量Boc AA3-OH。4分钟后,合并溶液并使其在室温下反应1小时。在2mbar/40℃水浴中除去所有挥发性化合物。将粗制的Boc-保护的物质溶解在15ml 4M HCl的二恶烷溶液中过夜。通过制备型HPLC纯化粗产物。
(I-o):310mg(0.47mmol,73%)(针对四个步骤计算产率)
(I-p):258mg(0.38mmol,59%)(针对四个步骤计算产率)
程序6:羟基乙酰基-L-O-甲基-Tyr-D-Pro-NH-2-Ad
将0.75mmol(1.0当量)来自持续2c的H-O-甲基-Tyr-D-Pro-NH-2-Ad溶解在DMF中。通过添加1.1当量TBTU和1.9当量DIPEA,在DMF中预活化0.788mmol(1.1当量)tBuO-Ac-OH。4分钟后,合并溶液并使其在室温下反应1小时。利用乙酸乙酯和水将反应混合物转移到分液漏斗中。用乙酸乙酯反萃取水相。用5%NaHCO3、1M KHSO4和卤水洗涤合并的有机相。在2mbar/40℃水浴中除去所有挥发性化合物。将粗制的Boc-保护的物质溶解在10ml 4M HCl的二恶烷溶液中,持续45分钟,然后通过添加2×10ml TFA并搅拌过夜来进行去保护。通过制备型HPLC纯化粗产物。
(I-r):157mg(0.32mmol,42%)
3.活性试验
3.1.1型11-β-羟基类固醇脱氢酶的抑制作用
制备细胞裂解物
将表达11β-HSD1和己糖-6-磷酸脱氢酶(所谓的HHH7克隆)的稳定转染的人胚胎肾(HEK-293)细胞在达尔伯克改良伊格尔培养基(Dulbecco’s modified Eagle medium,DMEM)中培养48小时,所述DMEM含有4.5g/L葡萄糖、10%胎牛血清、100U/mL青霉素、0.1mg/mL链霉素、1×MEM非必需氨基酸和10mM HEPES缓冲液,pH为7.4。然后用磷酸盐缓冲盐水洗涤细胞,并以150×g离心4分钟。除去上清液之后,将细胞沉淀物在干冰上快速冷冻并储存在-80℃下直至进一步使用。
细胞裂解物中的活性试验
将细胞裂解物在37℃下在TS2缓冲液(100mM NaCl,1mM EGTA,1mM EDTA,1mMMgCl2,250mM蔗糖,20mM Tris-HCl,pH 7.4)中孵育10分钟,终体积为22.2μL,含有如表3-1中所示各浓度的溶剂(0.1%DMSO)或抑制剂。使用以下条件测量酶活性:192nM未标记的可的松,8nM放射性标记的可的松,450μM NADPH。
加入过量的未标记的可的松和皮质醇(1:1,2mM,在甲醇中)10分钟后,反应停止。使用甲醇-氯仿(1:9)作为溶剂,通过TLC分离类固醇,然后闪烁计数并计算底物浓度。从四次独立测量中收集数据(标准偏差<10%)。
表3-1:酶试验的结果
na=未分析
3.3.人角化细胞试验
细胞培养:在湿润的5%CO2-空气气氛中,在37℃下,将从CellNTec advancedCell Systems获得的原代人皮肤角化细胞保持在CnT-PR培养基中。在细胞达到汇合之前进行传代培养。
评估11β-HSD1活性:在完全培养基(CnT-PR,CellNTec)中预培养人原代角化细胞至90%汇合。随后用PBS缓冲液洗涤细胞两次以去除剩余的皮质类固醇,并将培养基换成定制的不含氢化可的松的培养基。然后用1000nM可的松与表3-2所示的不同浓度的抑制剂联合处理细胞。48小时后,收集细胞培养物上清液,然后利用皮质醇参数分析试剂盒(Cortisol Parameter Assay Kit,R&D Systems)按照流程说明并使用Multiskan Ascent读板仪(Labsystems)评估皮质醇水平。
计算:剩余11β-HSD1活性的%=(含抑制剂时的皮质醇水平/不含抑制剂时的皮质醇水平)*100%
表3-2:结果
3.3.可的松和可的松/抑制剂处理后的总真皮胶原
使用来自腹部整形手术的人类皮肤。将皮肤样品切成 的片,并在与培养基(经改进的Williams'E培养基)接触的不锈钢穿孔环中的空气-液体界面中培养至第6天,同时在第3天更新培养基。每个试验样品使用六个皮肤样本。在用棉垫清洁每个片的表面之后,在每个片之上局部应用每种试验样品(4μl),随后用的递送膜覆盖,每天重复该程序。6天后,用天狼猩红(Picrosirius Red)组织化学染色对皮肤切片染色,其将胶原纤维染成紫红色。选择乳头状真皮进行分析。使用去卷积矩阵将图片的不同颜色分开。去卷积后,只使用粉红色的图像。在这些图像中,通过使用IMAGE J(NIH)分析软件估计颜色强度和分布来评估真皮胶原。通过图像采集和相关分析处理每个皮肤样品的两张玻片(即每种处理12张图像)。
表3-3:在第6天,对比处理相较于0.1μl可的松的结果
*未处理样品(#1)的真皮胶原的评分被设定为100%
°胶原抑制的阳性对照(-23%vs.未处理(#1))
从表3-3所示结果能够得出:根据本发明的11β-HSD1抑制剂通过恢复乳头状真皮中的总胶原来抵消可的松活性。
4.参照
作为参照,通过类似于上文概述的程序制备表4-1中概述的1-金刚烷基取代的式1的化合物,并在酶测试中进行检测。从表4-1可以看出,这些化合物显示出几乎没有活性或根本没有活性(在1μM浓度时)。
表4-1:对比数据
5.美容组合物
表5-1概述了示例性的O/W乳剂,其中以所示的量掺入一种选自表1(和表3-1)中概述的(I-a)至(I-s)的化合物。
表5-1:示例性的O/W乳剂
Claims (11)
2.根据权利要求1所述的化合物,其中R1选自H和C1-C2酰基。
3.根据权利要求1或2所述的化合物,其中R2选自H和C1-C2烷基。
4.根据权利要求1或2所述的化合物,其中所述美容上可接受的盐是乙酸盐或三氟乙酸盐。
5.根据权利要求3所述的化合物,其中所述美容上可接受的盐是乙酸盐或三氟乙酸盐。
6.根据权利要求1所述的式(II)、(III)或(IV)的化合物,其为
(R)-1-(3-乙酰胺基丙酰基)-N-(金刚烷-2-基)吡咯烷-2-甲酰胺(I-a),
(R)-1-(乙酰基甘氨酰基)-N-(金刚烷-2-基)吡咯烷-2-甲酰胺(I-b),
(R)-1-(L-酪氨酰基)-N-(金刚烷-2-基)吡咯烷-2-甲酰胺三氟乙酸盐(I-c),
(R)-1-(L-色氨酰基)-N-(金刚烷-2-基)吡咯烷-2-甲酰胺三氟乙酸盐(I-d),
(R)-1-(乙酰基-L-酪氨酰基)-N-(金刚烷-2-基)吡咯烷-2-甲酰胺(I-e),
4-((S)-2-乙酰胺基-3-((R)-2-(金刚烷-2-基氨基甲酰)吡咯烷-1-基)-3-氧代丙基)苯基乙酸酯(I-f),
(R)-1-((S)-3-([1,1'-联苯]-3-基)-2-氨基丙酰基)-N-(金刚烷-2-基)吡咯烷-2-甲酰胺三氟乙酸盐(I-g),
(R)-1-((S)-2-乙酰胺基-3-(4-氟苯基)丙酰基)-N-(金刚烷-2-基)-吡咯烷-2-甲酰胺(I-h),
(R)-N-(金刚烷-2-基)-1-((S)-2-氨基-3-(3-羟基-苯基)丙酰基)吡咯烷-2-甲酰胺三氟乙酸盐(I-i),
(R)-N-(金刚烷-2-基)-1-((S)-2-(2-氨基乙酰胺基)-3-(4-甲氧基苯基)-丙酰基)吡咯烷-2-甲酰胺三氟乙酸盐(I-j),
(R)-N-(金刚烷-2-基)-1-((S)-2-氨基-3-(4-乙氧基苯基)丙酰基)吡咯烷-2-甲酰胺三氟乙酸盐(I-k),
(R)-1-((S)-2-乙酰胺基-3-(4-氰基苯基)-丙酰基)-N-(金刚烷-2-基)吡咯烷-2-甲酰胺(I-l),
(R)-1-((S)-2-乙酰胺基-3-(4-甲氧基苯基)-丙酰基)-N-(金刚烷-2-基)吡咯烷-2-甲酰胺(I-n),
(R)-N-(金刚烷-2-基)-1-(2-(2-((S)-2-氨基丙酰胺基)乙酰胺基)乙基)吡咯烷-2-甲酰胺双三氟乙酸盐(I-o),
(R)-N-(金刚烷-2-基)-1-(2-((S)-2-(2-氨基乙酰胺基)丙酰胺基)乙基)吡咯烷-2-甲酰胺双三氟乙酸盐(I-p),
(R)-N-(金刚烷-2-基)-1-(甘氨酰基-L-色氨酰基)吡咯烷-2-甲酰胺三氟乙酸盐(I-q),
(R)-N-(金刚烷-2-基)-1-((S)-2-(2-羟基乙酰胺基)-3-(4-甲氧基-苯基)丙酰基)-吡咯烷-2-甲酰胺三氟乙酸盐(I-r),或
(R)-1-((S)-2-乙酰胺基-3-(2-氰基苯基)-丙酰基)-N-(金刚烷-2-基)吡咯烷-2-甲酰胺(I-s),
或其美容上可接受的盐。
7.一种美容组合物,其包含至少一种根据权利要求1至6中任一项所述的化合物和美容上可接受的载体。
8.根据权利要求7所述的美容组合物,其特征在于:基于所述美容组合物的总重量,所述式(II)、(III)或(IV)的化合物的总量在0.00001-0.5重量%的范围内。
11.一种抚平皱纹和细纹并/或减小其体积和深度的美容方法,所述方法包括将根据权利要求7或8所述的美容组合物应用到受影响区域的步骤。
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