CN108290912B - 用作mmp-12抑制剂的次膦酸肽衍生物 - Google Patents
用作mmp-12抑制剂的次膦酸肽衍生物 Download PDFInfo
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Abstract
本发明涉及作为基质金属蛋白酶‑12(MMP‑12)的选择性抑制剂的化合物,含有它们的美容组合物和药物组合物,以及它们在预防和/或治疗与MMP‑12有关的病恙中的用途。式(I)。
Description
本发明涉及作为基质金属蛋白酶-12(MMP-12)的选择性抑制剂的化合物,含有它们的美容组合物和药物组合物,以及它们在预防和/或治疗与MMP-12有关的病恙(ailments)中的用途。
老化皮肤和过早老化皮肤的一个主要特征是真皮基质的高度碎裂,其中已知MMP在蛋白质降解(例如弹性蛋白和胶原蛋白的降解)中起主要作用,蛋白质降解继而影响真皮的结构完整性。因此,通过减少MMP来保护老化的或光老化的人体皮肤中的细胞外基质蛋白(例如弹性蛋白和胶原蛋白)对于延缓皮肤老化的临床表现(例如皱纹、下垂和松弛)是至关重要的。
在这方面,在人类临床试验中有充分的证据表明,视黄醇处理减少基质金属蛋白酶的表达,并通过对MMP-12等的抑制作用刺激自然老化的、防晒的以及光损伤的皮肤中胶原蛋白和弹性蛋白的合成。然而,已知视黄醇具有严重的副作用,例如皮肤刺激。此外,视黄醇在美容组合物中不是很稳定,因此不容易配制。
因此,持续需要新颖的MMP-12抑制剂,其可潜在地用于处理与老化有关的真皮完整性损伤并因此延迟老化的开始。
出乎意料地,已发现式(I)的特定新颖化合物是在非常低的使用水平下非常有效的MMP-12抑制剂,
其中n为0、1或2,
R1是H或氨基酸侧链,如果存在官能团,则所述氨基酸侧链可任选地被C1-C6烷基、C1-C6烷基羰基或C1-C6烷氧基羰基取代,
R2是H或甲基,且
R3选自H、C1-C6烷基和芳基C1-C6烷基(alkanyl)。此外,它们在配制到美容组合物中之后是稳定的,因此特别适用于处理与老化有关的真皮完整性损伤。
因此,在第一方面,本发明涉及式(I)的化合物或其美容学上可接受的盐
其中n为0、1或2,
R1是H或氨基酸侧链,如果存在官能团,则所述氨基酸侧链可任选地被C1-C6烷基、C1-C6烷基羰基或C1-C6烷氧基羰基取代,
R2是H或甲基,且
R3选自H、C1-C6烷基和芳基C1-C6烷基。
本文中所用的术语“氨基酸”是指任何天然氨基酸或非天然氨基酸。
术语“天然氨基酸”是指遗传密码编码的20种蛋白质形成(proteogenic)(形成蛋白质的)氨基酸。它们是:丙氨酸、亮氨酸、异亮氨酸、缬氨酸、甲硫氨酸、半胱氨酸、丝氨酸、苏氨酸、天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、精氨酸、赖氨酸、色氨酸、组氨酸、苯丙氨酸、酪氨酸、甘氨酸和脯氨酸。非天然氨基酸是指含有胺(-NH2)和羧酸(-COOH)官能团的任何有机化合物。本发明的所有实施方式中特别优选的是通式为H2NCR1R2COOH的氨基酸,通式为H2NCR1R2CH2COOH的β氨基酸和通式为H2NCR1R2CH2CH2COOH的γ氨基酸,其中R1和R2如上文所限定。
本文中所用的术语“取代的”是指存在于各氨基酸的侧链中的官能团(例如-OH、-NH2或-NH-基团)的取代。
C1-C6烷基的实例有无支链的C1-C6烷基或有支链的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。优选的C1-C6烷基是甲基、乙基和1,1-二甲基乙基。在一个最优选的实施方式中,R3选自H、甲基和1,1-二甲基乙基(=叔丁基)。
芳基C1-C6烷基的实例包括但不限于苄基。在本发明的所有实施方式中,最优选的芳基C1-C6烷基是苄基。
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“或其美容学上可接受的盐”是指以下形式的式(I)的化合物:酸和加成盐,例如氯化物、乙酸盐或三氟乙酸盐,或通过添加碱而形成的盐,例如碱金属盐或碱土金属盐,特别是锂盐、钠盐、钾盐、镁盐或钙盐。根据本发明最优选的是化合物本身或与乙酸或三氟乙酸的其加成盐的形式。最优选的是化合物本身或与三氟乙酸的其加成盐的形式。本领域技术人员容易制备这类盐。
优选的氨基酸侧链是氨基酸的非极性侧链或不带电荷的极性侧链,例如特别是天冬酰胺、谷氨酰胺、苯丙氨酸、甲硫氨酸、缬氨酸、甘氨酸、2,4-二氨基丁酸、2-氨基丁酸、丙氨酸、亮氨酸、异亮氨酸、正亮氨酸、色氨酸、硫代色氨酸、环己基甘氨酸、α-氨基-2-萘丙酸、丝氨酸、苏氨酸、酪氨酸、脯氨酸以及半胱氨酸的侧链。
在本发明的所有实施方式中,特别有利的未取代的氨基酸侧链是苯丙氨酸、甲硫氨酸、缬氨酸、硫代色氨酸、异亮氨酸、色氨酸、2,4-二氨基丁酸、亮氨酸、α-氨基-2-萘丙酸、正亮氨酸、天冬酰胺、丙氨酸、2-氨基丁酸和环己基甘氨酸的侧链,最优选的是硫代色氨酸、异亮氨酸、色氨酸、2,4-二氨基丁酸、亮氨酸、α-氨基-2-萘丙酸、正亮氨酸、天冬酰胺、丙氨酸、2-氨基丁酸和环己基甘氨酸的侧链。
如果存在的话,则氨基酸侧链的官能团优选未被取代或被C1-C6烷氧基羰基取代,例如最优选被叔丁氧基羰基(Boc)基团取代。根据本发明的最优选的经取代的氨基酸侧链是2-氨基-4-(叔丁氧基羰基氨基)丁酸和1-[(1,1-二甲基乙氧基)羰基]-色氨酸的侧链。
特别有利的式(I)的化合物是下述化合物
其中n为0、1或2,优选0或2,
R1是H或硫代色氨酸、异亮氨酸、色氨酸、2,4-二氨基丁酸、亮氨酸、α-氨基-2-萘丙酸、正亮氨酸、天冬酰胺、丙氨酸、2-氨基丁酸、环己基甘氨酸、2-氨基-4-(叔丁氧基羰基氨基)丁酸和1-[(1,1-二甲基乙氧基)羰基]-色氨酸的氨基酸侧链,
R2是H或甲基,优选H,且
R3选自H、甲基、叔丁基和苄基。
甚至更有利的式(I)的化合物是下述化合物
其中n为0或2,
R1是H或硫代色氨酸、异亮氨酸、色氨酸、2,4-二氨基丁酸、亮氨酸、α-氨基-2-萘丙酸、正亮氨酸、天冬酰胺、丙氨酸、2-氨基丁酸、环己基甘氨酸、2-氨基-4-(叔丁氧基羰基氨基)丁酸和1-[(1,1-二甲基乙氧基)羰基]-色氨酸的氨基酸侧链,
R2是H,且
R3选自H、甲基、叔丁基和苄基。
表1中给出了最优选的式(I)的化合物:
表1
根据本发明的特别有利的立体异构体是表2中列出的那些:
表2
根据本发明的式(I)的化合物可以如下文所概述和实施例中所阐示地来制备:
利用常用的偶合技术使2-联苯-4-基-丙烯酸(A)与各氨基酸(AA;R3≠H)的适当酯偶合,所述偶合技术如例如Peptide chemistry:A practical textbook by M Bodansky(Springer-Verlag,Heidelberg.1988)中所述的。随后如Chen等人(J.Med.Chem 2000,43,第1398-1408页)中所述,使所得中间体(B)与(2-苯乙基)次膦酸(C)缩合,从而得到了其中R3≠H的式(I)的化合物,然后可以使该式(I)的化合物经受酯水解,例如,使用在二氯甲烷中的三氟乙酸,以产生其中R3=H的相应的式(I)的化合物。
如此获得的非对映异构体混合物可以原样使用,或者可以进一步通过本领域已知的色谱方法(例如,制备型HPLC(高效液相色谱))分离。
在第二方面,本发明涉及美容组合物,其包含具有上文给出的所有定义和优选的式(I)的化合物和美容学上可接受的载体。
在又一个实施方式中,本发明涉及具有本文给出的所有定义和优选的式(I)的化合物作为MMP-12抑制剂的用途,特别是用于保护弹性蛋白和/或胶原蛋白(凭借减少弹性蛋白/胶原蛋白通过MMP-12的降解),特别是在老化的和/或光损伤的皮肤中。
此外,本发明涉及具有本文给出的所有定义和优选的式(I)的化合物用于保护弹性蛋白免受UV-A光诱导的降解的用途。
特别优选地,根据本发明的用途是美容用途,即用于人体皮肤的美容处理(以美化皮肤)。
由于增强的弹性蛋白和/或胶原蛋白保护导致皮肤老化迹象减少,例如皱纹、细纹、下垂和松弛减少,因此本发明还涉及预防和/或处理老化皮肤或衰老皮肤的方法,例如优选地以抚平皱纹和细纹,减小其体积和深度,和/或处理皮肤松弛和改善皮肤紧实度,所述方法包括以下步骤:将具有本文给出的所有定义和优选的根据本发明的美容组合物施用到受影响区域并任选地评价效果。
在另一个实施方式中,本发明涉及保护细胞外基质蛋白(例如特别是弹性蛋白和/或胶原蛋白)的方法,所述方法包括以下步骤:将具有本文给出的所有定义和优选的根据本发明的美容组合物施用到有此需要的区域。
术语“美容组合物”是指用于处理、护理或改善皮肤和/或头皮的外观的组合物。特别有利的美容组合物是护肤组合物。
根据本发明的美容组合物优选旨在用于局部应用,其应被理解为外部应用到角质物质,例如特别是皮肤。
本文中所用的术语“美容学上可接受的载体”是指与角质物质相容的生理学上可接受的介质。合适的载体在本领域中是公知的并且基于最终用途应用进行选择。优选地,本发明的载体适合应用到皮肤(例如,防晒剂、霜剂、乳剂、洗剂、面膜、精华、水分散剂(hydrodispersions)、粉底、霜剂、凝胶霜(creamgels)或凝胶等)。这种载体是本领域普通技术人员公知的,其可以包括一种或多种适合应用到皮肤的相容性液体或固体填充剂稀释剂、赋形剂、添加剂或载剂(vehicle)。载体的确切量取决于式(I)的化合物以及本领域普通技术人员会归类为不同于载体的任何其他任选成分(例如,其它活性组分)的水平。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配制成多种不同的产品类型,包括霜剂、蜡状物、糊剂、洗剂、乳剂、摩丝、凝胶、油、活肤剂(tonics)和喷雾剂。优选地,将式(I)的化合物配制成洗剂、霜剂、凝胶和喷雾剂。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。配制这类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按常规选择。
如果将本发明的组合物配制成气溶胶并作为喷涂产品应用到皮肤,则向组合物中加入推进剂。
美容组合物中式(I)的化合物的量可以容易地由本领域技术人员来调节以实现期望的有益效果。优选地,基于美容组合物的总重量,根据本发明的美容组合物中式(I)化合物的量为至少1ppm。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)化合物的量优选选自约0.00001-0.5重量%的范围,更优选0.0001-0.25重量%的范围,最优选0.0001-0.1重量%的范围。
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定义和优选的式(I)化合物与美容学上可接受的载体混合。
本发明的美容组合物(包括载体)可以包含另外的常规美容辅剂和添加剂,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,美学组分例如芳香剂,表面活性剂,填料,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,磨料,吸附剂,螯合剂和/或掩蔽剂,精油,皮肤感知剂(skin sensates),收敛剂,颜料或通常配制到这类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常规用于美容组合物中的其他美容活性成分。示例性的活性成分包括亮肤剂;UV-滤光剂,用于处理色素沉着过度的试剂;用于预防或减少炎症的试剂;紧实剂、保湿剂、舒缓剂和/或醒肤(energizing)剂以及改善弹性和皮肤屏障的试剂。
适用于本发明的美容组合物中的通常用于护肤行业中的美容赋形剂、稀释剂、辅剂、添加剂以及活性成分的示例例如描述在通过在线的INFO BASE(http://online.personalcarecouncil.org/jsp/Home.jsp)能够进入的个人护理产品委员会(http://www.personalcarecouncil.org/)的国际化妆品成分词典&手册中,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、辅剂、添加剂等的必需量。可以视情况将附加成分添加到油相、水相中或单独添加。
在某些情况下,本文中有用的美容活性成分可提供多于一种益处或通过多于一种作用模式运作。
当然,本领域技术人员会仔细选择上述任选的附加成分、辅剂、稀释剂和添加剂和/或它们的用量,使得与根据本发明的组合有内在关联的有利特性不会或基本不会被预想的一种或多种添加有害地影响。
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液或分散体的形式,或者是下述形式:乳液或微乳液,特别是水包油(O/W)或油包水(O/W)类型、水包硅酮(Si/W)或硅酮包水(W/Si)类型、PIT-乳液、多重乳液(例如,油包水包油(O/W/O)或水包油包水(W/O/W)类型)、皮克林(pickering)乳液、水凝胶、醇凝胶、脂质体凝胶、单相或多相溶液或囊泡分散体或其他常见形式,其也可以通过笔,作为面膜或作为喷雾被施用。
如果美容组合物是乳液,例如特别是O/W、W/O、Si/W、W/Si、O/W/O、W/O/W多重或皮克林乳液,那么基于美容组合物的总重量,这种美容乳液中存在的油相的量优选为至少10重量%,例如在10-60重量%的范围内,优选在15-50重量%的范围内,最优选在15-40重量%的范围内。
在一个实施方式中,根据本发明的美容组合物的形式有利地是在O/W乳化剂存在下的包含分散在含水相中的油相的水包油(O/W)乳液。本领域技术人员公知此类O/W乳液的制备。
如果根据本发明的美容组合物是O/W乳液,则有利地,其包含至少一种选自以下列表的O/W-或Si/W-乳化剂:甘油硬脂酸柠檬酸酯、甘油硬脂酸酯SE(自乳化)、硬脂酸、硬脂酸盐、聚甘油-3-甲基葡萄糖二硬脂酸酯。另一些合适的乳化剂是磷酸酯及其盐例如鲸蜡磷酸酯(例如作为来自DSM Nutritional Products Ltd.的A)、二乙醇胺鲸蜡磷酸酯(例如作为来自DSM Nutritional Products Ltd.的DEA)、鲸蜡磷酸酯钾(例如作为来自DSM Nutritional Products Ltd.的K)、鲸蜡硬脂醇硫酸酯钠、甘油油酸酯磷酸钠、氢化植物性甘油磷酸酯及其混合物。另一些合适的乳化剂是失水山梨醇油酸酯、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的聚异丁烯(hydrated polyisobutene)。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或Si/W乳化剂的用量优选地为0.5-10重量%,特别地在0.5-6重量%的范围内,例如更特别地在0.5-5重量%的范围内,例如最特别地在1-4重量%的范围内。
待被用在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乳化剂是来源于橄榄油的非离子型自乳化体系,例如被称为(INCI名称)鲸蜡硬脂醇橄榄油酸酯和山梨坦橄榄油酸酯(化学组成:橄榄油脂肪酸的山梨坦酯和鲸蜡硬脂醇酯),以商品名OLIVEM 1000出售。
在一个具体实施方式中,本发明涉及这样的美容组合物,其具有本文中给出的所有定义和优选,且其形式为在O/W乳化剂存在下包含分散在含水相中的油相的O/W乳液,其中所述O/W乳化剂为鲸蜡醇磷酸酯钾。这种O/W乳液中油相的量优选为至少10重量%,更优选在10-60重量%的范围内,最优选在15-50重量%的范围内,例如在15-40重量%的范围内。
根据本发明的美容组合物的pH通常在3-10的范围内,优选地在4-8的pH范围内,最优选地在4-7.5的pH范围内。可根据本领域中的标准方法用合适的酸(例如,柠檬酸)或碱(例如氢氧化钠(例如,作为水溶液)、三乙醇胺(TEA Care)、氨丁三醇(Trizma Base)和氨甲基丙醇(AMP-Ultra PC 2000))按照所期望地容易地调节pH。
待被施用在皮肤上的美容组合物的量并不关键并可由本领域技术人员容易地调节。优选地,所述量选自0.1-3mg/cm2皮肤的范围内,例如优选地0.1-2mg/cm2皮肤的范围内,最优选地0.5-2mg/m2皮肤的范围内。
根据本发明的化合物的其他合适用途涵盖药物应用。因此,根据本发明的化合物可用于与药学上可接受的载体、稀释剂或赋形剂一起制备药物组合物,以治疗、预防和/或防治其中期望在有此需要的患者中抑制MMP-12的任何病症和疾病,例如,用于治疗、预防和/或防治癌症、类风湿性关节炎、骨关节炎。
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,否则所有百分数均基于总重量以重量计。
实验部分
1.一般信息
缩略语:
AA 氨基酸
DMF: N,N-二甲基甲酰胺
EtOAc: 乙酸乙酯
DCM: 二氯甲烷
MeCN: 乙腈
DIPEA: N,N-二异丙基乙胺
BTU: O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲-四氟硼酸盐
BSA: N,O-双(三甲基硅烷基)乙酰胺
TFA: 三氟乙酸
n.a.: 未分析
FCS 胎牛血胎
P/S 青青素/链青素
TGFb1 转化生转因子,β1
HBSS 汉克平汉盐溶液
PBS 磷酸盐缓磷盐水
BSA 胎血胎白蛋白
在Waters Alliance 2695HPLC系统上测量MS/HPLC-光谱,该系统配备有WatersSymmetry C18,3.5μm,4.6mm X 50mm分析柱和在200-400nm波转范围内运行的Waters 2996光电二极管阵列检测器(PDA),所述PDA偶联到以正电喷雾电离(ESI+)模式运行并在m/z范围100-1500内检测的Waters ZQ 4000(单四极杆检测器)质谱仪。使用H2O+0.07%TFA(A相)和MeCN+0.07%TFA(B相)作为洗脱液,流速为1.0mL/min。
制备型HPLC纯化:在Waters Prep LC 2000系统上进行,该系统配备有GromSaphir 110,C18,10μm,50mm X 300mm制备柱以及在220nm和254nm下运行的Waters 2487双波转UV-Vis检测器。
使用H2O+0.07%TFA(A相)和MeCN+0.07%TFA(B相)作为洗脱液,流速为65mL/min。
在下文中,举例说明了根据本发明的两种化合物(I)-J和(I)-N的制备。表1、表2和表3中列出的其他化合物已相应地制备。
实施例1
制备((2S)-3-([1,1'-联苯]-4-基)-2((羟基(苯乙基)磷酰基)甲基)-丙酰基)-L-丙氨酸(I)-J和((2R)-3-([1,1'-联苯]-4-基)-2-((羟基-(苯乙基)-磷酰基)甲基)丙酰基)-L-丙氨酸(I)-J’
将350mg(1.47mmol)2-联苯-4-基丙烯酸溶解在4ml DMF中并冷却至5℃。随后加入495mg TBTU和512μl DIPEA,然后加入320mg H-Ala-OtBu·HCl(1.76mmol)在3ml DMF中的溶液以及299μl DIPEA。在5℃下搅拌30分钟并在室温下过夜后,通过蒸发溶剂来分离粗产物。将残余物溶解在30ml EtOAc中,并用10%柠檬酸、10%NaHCO3和饱和NaCl溶液顺续洗涤。经Na2SO4干燥并蒸发溶剂后,获得了500mg油。HPLC(220nm)–95%,[M+H]+,测量值为366(理论值为366)。在氩气流下,将获得的中间体(475mg,1.3mmol)与265mg(1.56mmol)(2-苯乙基)-次膦酸一起溶解在5ml BSA中,随后加热至约70℃,持续62小时(转化率为94%)。将反应混合物用100ml EtOAc稀释,并通过加入10ml水来猝灭BSA。用新鲜水和饱和NaCl溶液充分洗涤后,经Na2SO4干燥,过滤并蒸发溶剂,获得了630mg淡黄色油。使用制备型HPLC对粗产物进行色谱分离以分离冻干后产生的两种形成的非对映异构体:
主要由(S/S)-异构体(80%)组成的295mg(2-([1,1'-联苯]-4-基甲基)-3-(-1-(叔丁氧基)-1-氧代丙-2-基)氨基)-3-氧代丙基)(苯乙基)次膦酸和主要由(R/S)-异构体(82%)组成的146mg。
ESI-MS[M+H]+:两个峰的测量值均为536.4(理论值:536.3)。
通过将各化合物溶解在2ml DCM中并加入2ml 95%TFA,使各级分水解成相应的酸。在酯水解和溶剂蒸发完成之后,利用制备型HPLC色谱分离粗产物,得到了
171mg(I)-J,为无色粉末,纯度:98%(HPLC),ESI-MS[M+H]+:480.3(理论值:480.2)和
62mg(I)-J’,为灰白色粉末,纯度:97%(HPLC),ESI-MS[M+H]+:测量值为480.3(理论值:480.2)。
实施例2
((S)-2-([1,1'-联苯]-4-基甲基)-3-(((S)-1-甲氧基-1-氧代己-2-基)氨基)-3-氧代丙基)(苯乙基)次膦酸(I)-H和(2S)-2-((2R)-3-([1,1'-联苯]-4-基)-2-((羟基(苯乙基)磷酰基)甲基)丙酰胺基)己酸(I)-N
将350mg(1.47mmol)2-联苯-4-基丙烯酸溶解在4ml DMF中并冷却至5℃。随后加入495mg TBTU和512μl DIPEA,然后加入320mg H-Nle-OMe·HCl(1.76mmol)在3ml DMF中的溶液以及299μl DIPEA。在5℃下搅拌30分钟并在室温下过夜后,通过蒸发溶剂来分离粗产物。将残余物溶解在30ml EtOAc中,并用10%柠檬酸、10%NaHCO3和饱和NaCl溶液顺续洗涤。经Na2SO4干燥、过滤并蒸发溶剂后,获得了523mg油。HPLC(220nm)–83%,LC-MS:[M+H]+,测量值为366(理论值为366)。在氩气流下,将中间体(523mg,1.33mmol)与285mg(1.68mmol)(2-苯乙基)-次膦酸一起溶解在5ml BSA中,然后加热至约70℃。15小时后,HPLC监测指示约70%的转化率。在氩气下加入新鲜的BSA以及200mg的(2-苯乙基)-次膦酸并继续搅拌,持续共4天。将反应混合物用100ml EtOAc稀释,并通过加入10ml水来猝灭BSA。用新鲜水和饱和NaCl溶液充分洗涤后,经Na2SO4干燥,过滤并蒸发溶剂,获得了710mg淡黄色油。使用制备型HPLC对粗产物进行色谱分离以分离冻干后产生的两种形成的非对映异构体:
36mg作为灰白色粉末的((S)-2-([1,1'-联苯]-4-基甲基)-3-(((S)-1-甲氧基-1-氧代己-2-基)氨基)-3-氧代丙基)(苯乙基)次膦酸(I)-H,和
69mg作为灰白色粉末的((R)-2-([1,1'-联苯]-4-基甲基)-3-(((S)-1-甲氧基-1-氧代己-2-基)氨基)-3-氧代丙基)(苯乙基)次膦酸(I)-H’,和
257mg(I)-H(51%)和(I)-H’(47%)的混合物。
ESI--MS[M+H]+:两个峰的测量值均为536.4(理论值:536.3)。
通过溶解在THF中并加入1.1当量的LiOH,将各级分温和皂化成相应的酸。酯水解完成后,将各反应混合物酸化并用EtOAc萃取,利用制备型HPLC对粗产物进行色谱分离,得到了
88mg作为灰白色粉末的(2S)-2-((2S)-3-([1,1'-联苯]-4-基)-2-((羟基(苯乙基)磷酰基)甲基)-丙酰胺基)己酸(I)-N’。纯度:99%(HPLC);ESI-MS[M+H]+:测量值为522.2(理论值:522.2),和
80mg作为灰白色粉末的(2S)-2-((2R)-3-([1,1'-联苯]-4-基)-2-((羟基(苯乙基)磷酰基)甲基)-丙酰胺基)己酸(I)-N。纯度:90%(HPLC);ESI-MS[M+H]+:测量值为522.2(理论值:522.2)。
实施例3:MMP-12的抑制
使用MMP-12荧光药物发现试剂盒(Enzo Life Sciences Inc.,Farmingdale,NY,USA),根据制造商的说明,通过荧光分析对MMP-12抑制剂活性进行定量。
表3-1:试验结果
实施例4-1:抑制由人类真皮成纤维细胞产生的弹性蛋白纤维的降解
将人类真皮成纤维细胞在DMEM,10%FCS,1%P/S中预培养48小时,然后在DMEM,0.2%FCS,1%P/S中饥饿24小时。为了诱导弹性蛋白纤维产生,加入TGFb1(10ng/ml)并孵育5天。与TGFb1一起孵育后,小心弃去培养基,并用试验缓磷液(HBSS,25μMH HEPES)洗涤细胞。与此同时,在试验缓磷液中混合MMP-12(200U/ml)和化合物并使其相互作用30分钟。然后将该混合物加入细胞中并在37℃下孵育2小时。
然后将细胞用冰冷的甲醇固定5分钟并通过PBS再水化。用PBS中的1%BSA在室温下封闭非特异性位点1小时。使用抗弹性蛋白的第一抗体检测弹性蛋白纤维,并用AlexaFluor 488缀合的第二抗体检测第一抗体。最后,用DAPI复染核。利用ThermoScientific ArrayScan XTI Live High Content Platform分析染色细胞。利用20倍物镜获得每孔49张图片,并使用弹性蛋白纤维所覆盖的面积作为读数(readout)。以下列方式计算弹性蛋白纤维降解的抑制%:
弹性蛋白纤维网络降解的保护%=100–[(最大面积–最小面积)/(最大面积–抑制剂面积)*100],其中
最大面积=未处理的对照细胞的弹性蛋白纤维所覆盖的面积
最小面积=用MMP12处理的细胞的弹性蛋白纤维所覆盖的面积
抑制剂面积=用MMP12和抑制剂处理的细胞的弹性蛋白纤维所覆盖的面积。
下表4-1中概述了结果。
表4-1
Δ纯立体异构体
*立体异构体混合物
实施例4-2:UV辐照后的总真皮弹性蛋白
使用归类为“中间体(Intermediate)”(ITA°角=53°)的来自腹部整形手术的人类皮肤。将皮肤样品切成约8×3mm(厚度)的片,并在与培养基(改良的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6天,培养基每三天更新一次。每种处理使用八个皮肤样本。用棉垫温和胎洁每个片的表面随后用的递送膜覆盖后,每天两次局部应用每种试验样品(4μl)到每个片的上部,UV辐照后应用4小时后更新,每天重复上述程序。使用采用的BIO-SUN系统(Vilber Lourmat),每天辐照等于45J/cm2UVA剂量的日光生物有效剂量(BED;Del Bino等人,Pigment Cell research,19,2006)的800%。在第6天,用小鼠单克隆抗弹性蛋白抗体(Sigma cat#E4013)对十二个皮肤切片进行免疫染色。选择乳头状真皮进行分析。通过使用IMAGE J(NIH)分析软件估计颜色强度和分布来进行评估。通过图像采集和相关分析(即每种处理12张图像)来处理每个皮肤样本的两张载玻片。非UV处理样品的真皮弹性蛋白评分被设定为100%。
表4-2:第6天的真皮弹性蛋白
((真皮弹性蛋白样品–真皮弹性蛋白-UV)/真皮弹性蛋白UV*100%)
从表4-2中概述的结果能够得出,根据本发明的化合物抵消UV损伤,同时恢复或甚至增加乳头状真皮中的真皮弹性蛋白。
实施例5:美容组合物
表5-1概述了示例性的O/W乳液,其中将选自I(a-r)[表1]和(I)-(A-V)[表2]的一种化合物(最终作为立体异构体的混合物)以指定的量掺入。
表5-1:示例性的O/W乳液
Claims (18)
2.根据权利要求1所述的化合物,所述氨基酸侧链选自苯丙氨酸、甲硫氨酸、缬氨酸、硫代色氨酸、异亮氨酸、色氨酸、2,4-二氨基丁酸、亮氨酸、α-氨基-2-萘丙酸、正亮氨酸、天冬酰胺、丙氨酸、2-氨基丁酸和环己基甘氨酸的侧链。
3.根据权利要求1所述的化合物,所述氨基酸侧链选自硫代色氨酸、异亮氨酸、色氨酸、2,4-二氨基丁酸、亮氨酸、α-氨基-2-萘丙酸、正亮氨酸、天冬酰胺、丙氨酸、2-氨基丁酸和环己基甘氨酸的侧链。
4.根据权利要求1至3所述的化合物,其特征在于,所述氨基酸侧链具有被C1-C6烷氧基羰基基团取代的官能团。
5.根据权利要求4所述的化合物,其特征在于,所述氨基酸侧链具有被叔丁氧基羰基(Boc)基团取代的官能团。
6.根据权利要求1或2所述的化合物或其美容学上可接受的盐,
其中n为0、1或2,
R1是H或硫代色氨酸、异亮氨酸、色氨酸、2,4-二氨基丁酸、亮氨酸、α-氨基-2-萘丙酸、正亮氨酸、天冬酰胺、丙氨酸、2-氨基丁酸、环己基甘氨酸、2-氨基-4-(叔丁氧基羰基氨基)丁酸和1-[(1,1-二甲基乙氧基)羰基]-色氨酸的氨基酸侧链,
R2是H或甲基,且
R3选自H、甲基、叔丁基和苄基。
7.根据权利要求6所述的化合物或其美容学上可接受的盐,其中R2是H。
8.根据权利要求1或2所述的化合物或其美容学上可接受的盐,
其中n为0或2,
R1是H或硫代色氨酸、异亮氨酸、色氨酸、2,4-二氨基丁酸、亮氨酸、α-氨基-2-萘丙酸、正亮氨酸、天冬酰胺、丙氨酸、2-氨基丁酸、环己基甘氨酸、2-氨基-4-(叔丁氧基羰基氨基)丁酸和1-[(1,1-二甲基乙氧基)羰基]-色氨酸的氨基酸侧链,
R2是H,且
R3选自H、甲基、叔丁基和苄基。
11.美容组合物,其包含根据权利要求1至10中任一项所述的式(I)的化合物和美容学上可接受的载体。
12.根据权利要求11所述的美容组合物,其中基于所述组合物的总重量,所述式(I)化合物的存在量选自0.00001-0.5重量%的范围。
13.根据权利要求1至10中任一项所述的化合物用作MMP-12抑制剂的非治疗用途。
14.根据权利要求13所述的非治疗用途,其用于抑制人类皮肤中的弹性蛋白和/或胶原蛋白的降解。
15.根据权利要求1至9中任一项所述的化合物用于保护人类皮肤中的细胞外基质蛋白的方法中的非治疗用途,所述方法包括以下步骤:将根据权利要求11或12中任一项所述的美容组合物施用到受影响区域。
16.根据权利要求15所述的非治疗用途,其用于保护人类皮肤中的弹性蛋白和/或胶原蛋白的方法中,所述方法包括以下步骤:将根据权利要求11或12中任一项所述的美容组合物施用到受影响区域。
17.根据权利要求1至9中任一项所述的化合物用于预防和/或处理老化皮肤或衰老皮肤的方法中的非治疗用途,所述方法包括以下步骤:将根据权利要求11或12中任一项所述的美容组合物施用到受影响区域。
18.根据权利要求17所述的非治疗用途,其中所述化合物用于抚平皱纹和细纹,减小其体积和深度,处理皮肤下垂和/或改善皮肤紧实度。
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