CN102711790B - 用于治疗和/或护理皮肤、粘膜和/或毛发的肽、及其在化妆用组合物或药物组合物中的用途 - Google Patents
用于治疗和/或护理皮肤、粘膜和/或毛发的肽、及其在化妆用组合物或药物组合物中的用途 Download PDFInfo
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Abstract
通式(I)的肽:R1-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-R2(I)、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐、制备方法、含有它们的化妆用组合物或药物组合物、及它们用于治疗和/或护理皮肤、粘膜和/或毛发及治疗和/或护理通过Hsp刺激而改善或预防的病况、病症和/或疾病的用途。
Description
发明领域
本发明涉及能够诱导皮肤、粘膜和/或毛发中热激蛋白的表达的肽,且涉及含有这些肽、用于治疗和/或护理皮肤、粘膜和/或毛发的化妆用组合物或药物组合物,优选地用于治疗和/或护理通过刺激热激蛋白合成而改善或预防的皮肤、粘膜和/或毛发的那些病况、病症和/或疾病。
发明背景
皮肤、粘膜和毛发经常暴露于化学性质和物理性质二者的应激因素下。太阳照射、暴露于某些化学剂或高温,会对构成皮肤的细胞具有伤害效应,加速皮肤老化且让皮肤看起来不健康。紫外线辐射(UV)实行这些效应的机制尤其包括形成活性氧物质、造成DNA受损和蛋白质变性。
蛋白质的变性或构象改变可暗示疏水性残基暴露于蛋白质表面,此情况下蛋白质易形成聚集物,因而丧失其功能性。此情况危及细胞完整性,因此其具有对抗前述情况的特化机制:所有活的有机体都具有阻止因错误折叠蛋白质的累积所造成的伤害的机制[Ananthan J.,Goldberg A.L.和Voellmy R.(1986)“Abnormal proteins serve as eukaryotic stress signals andtrigger the activation of heat shock genes(异常蛋白用作真核细胞应激信号并触发热激基因的激活)”Science232:522-524]。
已经观察到,细胞通过增加所谓应激蛋白的合成而对应激的环境响应。这种响应在细胞检测到异常折叠蛋白的累积时开始,造成热激基因的转录增加[Lis J.和Wu C.(1993)“Protein traffic on the heat shock promoter:parking,stalling,and trucking along(热激启动子上的蛋白交通:停靠、抛锚和运输)”Cell74:1-4]。这些基因的产物分成两大类:热激蛋白和葡萄糖调节蛋白质(glucose regulated protein)。术语“热激蛋白”起源于在异常高温下培育的细胞中观察到这些蛋白质的合成增加。这些蛋白质的合成并非仅在细胞经受温度升高时增加,在其他应激的环境诸如暴露于UV照射、氧化应激、渗透压冲击(osmotic shock)、炎症、缺氧、暴露于污染物诸如重金属、缺少营养和缺乏水合作用(lack of hydration)也增加[LindquistS.(1986)“The heat-shock response(热激响应)”Annu.Rev.Biochem.55:1151-1191]。
热激蛋白为一个蛋白质家族,根据其分子量分类,已进行较多研究的是60kDa和70kDa蛋白质,因为它们在所有细胞中组成型表达且直接参与蛋白质成熟的多个方面。Hsp70主要包含两种蛋白质:Hsp73,组成型表达的形式;和Hsp72,可诱导的形式,其被热激因子蛋白1(HSF1)以转录方式调节。这些蛋白质也称为分子伴侣蛋白(chaperone),因为其引导新合成的蛋白质从合并的小球状构象折叠成最终紧致结构的功能,避免出现易形成聚集物的构象,因此,确保其正确功能性。在正常条件下,Hsp70位于细胞核和细胞质中,短暂地与新生蛋白质相互作用,与Hsp60联合作用有助于它们的折叠且促进它们易位通过高尔基体和内质网。然而,在应激的环境中,Hsp70与未折叠蛋白质或错误折叠的蛋白质形成复合体,以拯救蛋白质避免降解和不可逆损坏,或在不可能保护蛋白质的情况下,相反地增加蛋白水解式攻击的可能性[Hayes S.A.和Dice J.F.(1996)“Roles ofmolecular chaperones in protein degradation(分子伴侣蛋白在蛋白降解中的作用)”J.Cell.Biol.132:255-258;Gething M.J.和Sambrook J.(1992)“Protein folding in the cell(细胞中的蛋白折叠)”Nature355:33-45]。Hsp70或Hsp60最后既不形成最终正确折叠蛋白质的一部分,它们也不具备有关折叠的任何特定信息;它们仅阻止建立可能造成错误折叠或导致聚集且因此丧失功能性的不恰当相互作用。然而,蛋白质经由何种机制采用其最终构象是未知的。
除了重建不正确地折叠的蛋白质构象的伴侣蛋白功能外,Hsp70的参与还描述在因UV辐射或电离辐射造成损害的情况下,保护和修复DNA的过程中[Bases R.(2006)“Heat shock protein70enhanced deoxyribonucleicacid base excision repair in human leukemic cells after ionizing radiation(在电离辐射后热激蛋白70增强人类白血病细胞中的脱氧核糖核酸碱基切除修复)”Cell Stress Chaperones 11:240-249;Niu P.,Liu L.,Gong Z.,Tan H.,Wang F.,Yuan J.,Feng Y.,Wei Q.,Tanguay R.M.和Wu T.(2006)“Overexpressed heat shock protein70protects cells against DNA damagecaused by ultraviolet C in a dose-dependent manner(过表达的热激蛋白70以剂量依赖性方式保护细胞免受紫外线C导致的DNA损伤)”Cell Stress &Chaperones 11:162–169]。
对应激的响应构成普遍地保守的细胞防卫机制,反映于所谓获得性耐热性,这一现象是遭遇非致死性热激的细胞在正常生长温度的恢复阶段后,能够在若第一次遭遇将致死的第二次热激下存活[Subjeck J.R.,SciandraJ.J.和Johnson R.J.(1982)“Heat shock proteins and thermotolerance;acomparison of induction kinetics(热激蛋白和耐热性;诱导动力学的比较)”Br.J.Radiol.55:579-584;Angelidis C.E.,Lazaridis I.和Pagoulatos G.N.(1991)“Constitutive expression of heat-shock protein70in mammalian cellsconfers thermoresistance(热激蛋白70在哺乳动物细胞中的组成型表达赋予耐热性)”Eur.J.Biochem.199:35-39;Li G.C.,Li L.G.,Liu Y.K.,Mak J.Y.,Chen L.L.和Lee W.M.(1991)“Thermal response of rat fibroblasts stablytransfected with the human70-kDa heat shock protein-encoding gene(稳定地转染人类70-kDa热激蛋白编码基因的大鼠成纤维细胞的热响应)”Proc.Natl.Acad.Sci.USA88:1681-1685]。已观察到这种获得性耐热性是暂时的,在生长中的细胞中通常持续12和24小时之间,且取决于由起始温度冲击所诱导的变化,诸如冲击蛋白的表达增加程度和累积。在Hsp家族中,已证实Hsp70负责诱导耐热性:Hsp72的转录和合成两者的特异性抑制阻止由热处理诱导的保护效应[Trautinger F.,-Mügge I.,Barlan B.,NeunerP.和Knobler R.M.(1995)“72-kDheat shock protein is a mediator ofresistance to ultraviolet B light(72-kD热激蛋白是对紫外光B的抵抗力的介质)”J.Invest.Dermatol.105:160-162;Simon M.M.,Reikerstorfer A.,SchwarzA.,Krone C.,Luger T.A.,M.和Schwarz T.(1995)“heat shock protein70overexpression affects the response to ultraviolet light in murine fibroblasts.Evidence for increased cell viability and suppression of cytokine release(鼠成纤维细胞中热激蛋白70过表达影响对紫外光的响应。增加细胞存活率和阻遏细胞因子释放的证据)”J.Clin.Invest.95:926-33]。
之后证实,能够诱导对应激的响应的任何剂或处理为面对后续暴露于造成应激的因素的细胞提供保护,而不论应激的来源[Kampinga H.H.,Brunsting J.F.,Stege G.J.J.,Burgman P.W.J.J.和Konings A.W.T(1995)“Thermal protein denaturation and protein aggregation in cells madethermotolerant by various chemicals:role of heat shock protein(被不同化学品变得耐热的细胞中的热蛋白变性和蛋白聚集:热激蛋白的作用)”Exp.Cell Res.219:536-546]。冲击蛋白表达的外源性诱导因此为阻止细胞蛋白质受损且因此保持细胞完整性的可信策略。
文献中描述了由蛋白质异常折叠所造成的不同疾病,诸如大疱性表皮松解症[Gu L.H.和Coulombe P.A.(2005)“Defining the properties of thenonhelical tail domain in type II keratin5:insight from a bullousdisease-causing mutation(定义II型角蛋白5中非螺旋尾结构域的特性:从导致大疱性疾病的突变的洞察)”Mol Biol Cell.16:1427-1438],其是由序列中某些氨基酸突变所造成的角蛋白不正确折叠导致。这些疾病以诱导热激蛋白水平增加的化合物治疗。
相同地,使用诱导热激蛋白表达增加的化合物治疗和/或护理创伤或作为愈合和/或表皮再生过程中的辅助剂。已知创伤愈合和修复过程带来热激蛋白表达的增加。具体地,在皮肤外伤情形中Hsp表达的诱导是皮肤中角质细胞的位置特异性的;因此观察到在表皮角质细胞中诱导Hsp70合成[Laplante A.F.,Moulin V.,Auger F.A.,Landry J.,Li H.,Morrow G.,TanguayR.M.和Germain L.(1998)“Expression of heat shock proteins in mouse skinduring wound healing(热激蛋白在小鼠皮肤中在创伤愈合期间的表达)”J.Histochem.Cytochem.46:1291-301]。还已观察到,外部递送Hsp70蛋白质加速创伤愈合[Kovalchin J.T.,Wang R.,Wagh M.S.,Azoulay J.,Sanders M.和Chandawarkar R.Y.(2006)“In vivo delivery of heat shock protein70accelerates wound healing by up-regulating macrophage-mediatedphagocytosis(热激蛋白70的体内递送通过上调巨噬细胞介导的吞噬作用而加速创伤愈合)”Wound Repair Regen.14:129-137]。还已描述具有受损的创伤愈合和修复的糖尿病患者的皮肤中Hsp70的量降低[Bitar M.S.,Farook T.,John B.和Francis I.M.(1999)“Heat-shock protein72/73andimpaired wound healing in diabetic and hypercortisolemic states(糖尿病和肾上腺皮质醇增多症状态中的热激蛋白72/73和受损的创伤愈合)”Surgery125:594-601;Atalay M.,Oksala N.,Lappalainen J.,Laaksonen D.E.,Sen C.K.和Roy S.(2009)“Heat shock proteins in diabetes and wound healing(糖尿病和创伤愈合中的热激蛋白)”Curr.Protein Pept.Sci.10:85-95;McMurtryA.L.,Cho K.,Young L.J.-T.,Nelson C.F.和Greenhalgh D.G.(1999)“Expression of HSP70in healing wounds of diabetic and nondiabetic mice(糖尿病和非糖尿病小鼠的愈合创伤中HSP70的表达)”J.Surg.Res.86:36-41]。因此,诱导热激蛋白合成是用于治疗和/或护理皮肤和/或粘膜创伤的有效策略,特别是在糖尿病造成的皮肤和/或粘膜创伤的愈合和表皮再生的情况。
现有技术中还已知Hsp70参与毛发生长的调节;具体地,专利申请MX2007-007622描述抑制Hsp70合成的化合物减少毛发生长的应用。Hsp70在调节毛发生长中的牵涉指出使用能够刺激Hsp合成的化合物用于治疗和/或预防脱发症以延迟脱发或诱导毛发生长的用途,尤其是用于治疗因治疗癌症的化疗造成的脱发症,如专利US2002/0001629所述。
在美观的角度而言,异常蛋白质折叠对皮肤也有影响。弹性蛋白和胶原蛋白的正确折叠是保持皮肤弹性和光滑与年轻外观皮肤的基础。年轻成人的皮肤因为能够合成大量Hsp以在合成期间保护蛋白质折叠,特别适合对应激的环境作出快速且有效的响应。然而,因为Hsp70合成随着年龄减少,熟龄人士中保持蛋白质正确折叠的能力降低,造成受损蛋白质累积或不充分地折叠和对细胞死亡的调节较差,造成皮肤老态[Verbeke P,FonagerJ,Clark BF,Rattan SI.(2001)“Heat shock response and ageing:mechanismsand applications(热激蛋白与老化:机制和应用)”Cell Biol.Int.25:845-857]。从美观的角度看来,当皮肤暴露于UV辐射时,蛋白质异常折叠对皮肤的影响恶化,且造成光老化皮肤的外观。UV辐射能够不可逆地伤害皮肤,造成细胞死亡。然而,已证实暴露于高温对细胞具有某种保护效果,减少被UVB诱导的细胞死亡的数量[Trautinger F.,Knobler R.,H.,M.Mayr W.和-Mügge I.(1996)“Increased expressionof the72-kD heat shock protein and reduced sunburn cell formation in humanskin after local hyperthermia(局部高温后人类皮肤中72-kD热激蛋白的表达增加和晒伤细胞形成减少)”J.Invest.Dermatol.107:442-443]。这种对高温的暴露诱导Hsp合成。这些结果造成对所观察到的UV辐射的有害效应的光保护性效果。因此,热激蛋白合成诱导是用于治疗和/或护理皮肤和/或毛发以减少、延迟和/或阻止老化和/或光老化的迹象的有效策略。
化妆品和药学两领域都已对开发能够刺激热激蛋白合成的化合物进行不同试验。热激蛋白在不同病况、病症和疾病中起的作用是现有技术中广为人知的,如可见于例如期刊Heat Shock Proteins inBiology and Medicine(Research Signpost,India)或Cell Stress and Chaperones(Springer,Netherlands)。
已知某些丝氨酸蛋白酶抑制剂能够刺激热激蛋白的产生,但其高毒性妨碍其用于治疗目的的用途。因此,业界需找出具有这些性质且还可对于患者或消费者健康不具风险地使用的药剂。
现有技术中描述了刺激Hsp合成的不同天然提取物,诸如尤其是黑麦籽提取物、梨果仙人掌(Opuntia ficus-indica)提取物、含有芒果苷(mangiferin)的提取物(US2006/0088560)、或文献US2004/0228816、US7128914或FR2834887中所述的那些。获得具有均一品质和已知组成和纯度的提取物的困难度使得其于工业上的开发困难,尤其是在医药领域中。还描述了具有醛或α-酮酯官能性的不同的经修饰的合成肽,其诱导Hsp合成,诸如专利US5942494所述。然而,醛官能性与许多常用于局部(topical)施用制剂中的成分在化学上不相容,还显示在制剂中低稳定性的问题,这限制了其在化妆品或皮肤医学领域的用途。
热激蛋白对皮肤、粘膜和/或毛发的作用的益处还可通过将这些蛋白质直接施加至皮肤、粘膜和/或毛发来获得。在此情况下,专利US5348945描述外源性施加蛋白质Hsp70作为降低被置于应激环境的组织的死亡率的方法,尤其是保存将使用于器官移植的组织。局部施加高分子量蛋白质展现其穿过皮肤和毛发的低渗透性的困难,因此,使其在化妆品或皮肤医学领域中的开发困难。
这是尽管有许多现存的化合物和/或提取物,但对于鉴定比现有技术已知的更有效且更有选择性的刺激热激蛋白合成的新颖化合物仍有需求的原因。
发明详述
本发明为前述问题提供解决方案。本发明的申请人已出乎意料的发现,其序列不包括醛官能性的合成肽能够刺激Hsp70蛋白质合成,因此,能够保护皮肤、粘膜和/或毛发免受因为暴露于应激的环境所致的侵袭。这些肽用于治疗和/或护理皮肤、粘膜和/或毛发,优选地用于治疗和/或护理通过刺激热激蛋白而改善或预防的皮肤、粘膜和/或毛发的那些病况、病症和/或疾病。
定义
为了帮助理解本发明,本文包括一些术语和措词在本发明的上下文中使用时的意义。
在本发明的上下文内,应理解“皮肤”为包含从最外层或角质层至最底层或皮下组织(包括所述二者)的多层。这些层包含不同类型的细胞,尤其是诸如角质细胞、成纤维细胞、黑色素细胞和/或脂肪细胞。
在本发明的上下文中,术语“皮肤”包括头皮。
在本发明的上下文中,“护理皮肤、粘膜和/或毛发”包括预防皮肤、粘膜和/或毛发的病症和/或疾病。
在本发明的上下文中,术语“老化”是指皮肤随着年龄(时间老化)或因暴露于阳光(光老化)或环境因素诸如烟草烟雾、极冷或多风天气、化学污染物或污染而经历的改变,且包括所有外在可见和/或可经由触摸感知的,诸如且不限于,皮肤上不连续性的发展,诸如皱纹、细纹、裂纹、不规则或粗糙、毛孔尺寸增大、失去弹性(elasticity)、失去紧致、失去弹性(resilience)、失去从变形复原的能力、皮肤松垂诸如脸颊松垂、出现眼袋或出现双下巴、皮肤颜色改变,诸如尤其是斑块、发红、眼袋或出现色素沉着过度区域诸如老年斑或雀斑、异常分化、角化过度、弹性组织变性、角化病、脱发、橘皮、失去胶原结构化、和角质层、真皮、表皮、血管系统(例如出现蜘蛛网状静脉或毛细管扩张)、或尤其是接近皮肤的组织的其他组织学变化。术语“光老化”集合一组因为皮肤长期暴露于紫外线辐射而造成皮肤过早老化的过程,呈现与老化相同的生理特征,诸如且不排除松弛、下垂、颜色改变或色素沉着不规则、异常和/或过度角质化。
在本发明的上下文中,“光防护”理解为当在暴露于UV辐射之前施加化合物或制剂时,此化合物或制剂阻止或延迟光老化症状出现的能力。
在本说明书中,用于氨基酸的缩写依照在Eur.J.Biochem.(1984)138:9-37和J.Biol.Chem.(1989)264:633-673中所规定的IUPAC-IUB联合委员会的生化命名规则。
因此,例如,Asn代表NH2-CH(CH2CONH2)-COOH,Asn-代表NH2-CH(CH2CONH2)-CO-,-Asn代表-NH-CH(CH2CONH2)-COOH,且-Asn-代表-NH-CH(CH2CONH2)-CO-。因此,当代表肽键的连字符位于符号右边时,则消除氨基酸(此处表示为非离子化的惯用形式)的1-羧基的OH,当位于符号左边时,则消除氨基酸的2-氨基的H;此两种修饰可应用于相同符号(见表1)。
本说明书中所使用的缩写“Ac-“用来指明乙酰基(CH3-CO-),缩写“Palm-”用以指明棕榈酰基(CH3-(CH2)14-CO-)。
术语“非环状脂族基”在本发明中用以涵盖例如且不限于直链或支链的烷基、烯基和炔基。
术语“烷基”是关于饱和、直链或支链的基团,具有介于1至24个之间、优选介于1至16个之间、更优选介于1至14个之间、甚至更优选介于1至12个之间、又再更优选1、2、3、4、5或6个的碳原子,且以单键与分子的其余部分结合,烷基包括例如且不限于甲基、乙基、异丙基、异丁基、叔丁基、庚基、辛基、癸基、十二烷基、月桂基、十六烷基、十八烷基、戊基、2-乙基己基、2-甲基丁基、5-甲基己基和类似基团。
术语“烯基”是指直链或支链的基团,其具有介于2至24个之间、优选介于2至16个之间、更优选介于2至14个之间、又更优选介于2至12个之间、又再更优选2、3、4、5或6个的碳原子,具有一或多个碳-碳双键,优选具有1、2或3个共轭或非共轭的碳-碳双键,其经由单键与分子的其余部分结合,烯基包括例如且不限于乙烯基、油烯基、亚油烯基(linoleyl)和类似基团。
术语“炔基”是指直链或支链基团,其具有介于2至24个之间、优选介于2至16个之间、更优选介于2至14个之间、又更优选介于2至12个之间、又再更优选2、3、4、5或6个的碳原子,具有一或多个碳-碳三键,优选具有1、2或3个共轭或非共轭的碳-碳三键,其经由单键与分子的其余部分结合,炔基包括例如且不限于乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、戊炔基诸如1-戊炔基和类似基团。
术语“脂环族基团”在本发明中用以涵盖例如且不限于环烷基或环烯基或环炔基。
术语“环烷基”是关于饱和的单环或多环的脂族基团,其具有介于3至24之间、优选介于3至16个之间、更优选介于3至14个之间、又更优选介于3至12个之间、又再更优选3、4、5或6个的碳原子,其经由单键与分子的其余部分结合,环烷基包括例如且不限于环丙基、环丁基、环戊基、环己基、环庚基、甲基环己基、二甲基环己基、八氢茚、十氢萘、十二氢萉(dodecahydro-phenalene)和类似基团。
术语“环烯基”是关于非芳族的单环或多环脂族基团,其具有介于5至24个之间、优选介于5至16个之间、更优选介于5至14个之间、又更优选介于5至12个之间、又再更优选5或6个的碳原子,具有一或多个碳-碳双键,优选具有1、2或3个共轭或非共轭的碳-碳双键,其经由单键与分子的其余部分结合,环烯基包括例如且不限于环戊-1-烯-1-基和类似基团。
术语“环炔基”是关于非芳族的单环或多环脂族基团,其具有介于8至24个之间、优选介于8至16个之间、更优选介于8至14个之间、又更优选介于8至12个之间、又再更优选8或9个碳原子,具有一或多个碳-碳三键,优选具有1、2或3个共轭或非共轭的碳-碳三键,其经由单键与分子的其余部分结合,环炔基包括例如且不限于环辛-2-炔-1-基和类似基团。
术语“芳基”是关于芳族基团,具有介于6至30个之间、优选介于6至18个之间、更优选介于6至10之间、再更优选6或10个的碳原子,其包含以碳-碳键结合或稠合的1、2、3或4个芳族环,且经由单键与分子的其余部分结合,芳基尤其包括例如且不限于苯基、萘基、联苯基、茚基、菲基或蒽基。
术语“芳烷基”是关于以芳族基团取代的烷基,其具有介于7至24个之间的碳原子,且包括例如且不限于-(CH2)1-6-苯基、-(CH2)1-6-(1-萘基)、-(CH2)1-6-(2-萘基)、-(CH2)1-6-CH(苯基)2和类似基团。
术语“杂环基”是关于3-10元杂环或烃环,其中一个或多个环原子,优选1、2或3个环原子是非碳的元素,诸如氮、氧或硫,且可为饱和或未饱和。为了本发明的目的,杂环基可为环状、单环、双环或三环系统,可包括稠合环系统;且杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和的,或可为芳族的。更优选的是,术语杂环是关于5或6元环。
术语“杂芳基烷基”是关于以经取代或未经取代的芳族杂环基取代的烷基,该烷基具有1至6个碳原子,该芳族杂环基具有介于2至24个之间的碳原子和1至3个非碳原子,且杂芳基烷基包括例如且不限于-(CH2)1-6-咪唑基、-(CH2)1-6-三唑基、-(CH2)1-6-噻吩基、-(CH2)1-6-呋喃基、-(CH2)1-6-吡咯烷基和类似基团。
当在本技术领域中使用时,在上述定义基团上可存在某一程度的取代。因此,在本发明的任何基团上可存在取代。在本文中提及本发明的基团中的经取代的基团表示,所述基团可在一或多个可利用位置上被一或多个取代基取代,优选在1、2或3个位置,更优选在1或2个位置,再更优选在1个位置。这些取代基包括例如且不限于C1-C4烷基;羟基;C1-C4烷氧基;氨基;C1-C4氨基烷基;C1-C4羰氧基;C1-C4氧羰基;卤素,诸如氟、氯、溴和碘;氰基;硝基;叠氮基;C1-C4烷基磺酰基;硫醇基;C1-C4烷硫基,芳氧基,诸如苯氧基;-NRb(C=NRb)NRbRc;其中Rb和Rc独立地选自由下列所组成的组:H、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C10环烷基、C6-C18芳基、C7-C17芳烷基、3-10元杂环基、或氨基的保护基。
本发明化合物
本发明的化合物以通式(I)定义:
R1-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-R2
(I)
其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,特征在于:
AA1为-His-;
AA2选自-His-、-Leu-和-Pro-组成的组;
AA3为-Leu-;
AA4选自-Arg-和-Asn-组成的组;
W、X、Y和Z彼此独立地选自编码的氨基酸和非编码的氨基酸组成的组;
n、m、p和q彼此独立地选择,且具有介于0至1之间的值;
n+m+p+q小于或等于2;
R1选自由下列所组成的组:H、经取代或未经取代的非环状脂族基、经取代或未经取代的脂环基、经取代或未经取代的杂环基、经取代或未经取代的杂芳基烷基、经取代或未经取代的芳基、经取代或未经取代的芳烷基和R5-CO-,其中R5选自由下列所组成的组:H、经取代或未经取代的非环状脂族基、经取代或未经取代的脂环基、经取代或未经取代的芳基、经取代或未经取代的芳烷基、经取代或未经取代的杂环基和经取代或未经取代的杂芳基烷基;
R2选自由下列所组成的组:-NR3R4、-OR3和-SR3,其中R3和R4独立的选自由下列所组成的组:H、经取代或未经取代的非环状脂族基、经取代或未经取代的脂环基、经取代或未经取代的杂环基、经取代或未经取代的杂芳基烷基、经取代或未经取代的芳基、和经取代或未经取代的芳烷基;
条件为当AA2为-Leu-,AA4为-Asn-,Y为-Gln-时,则Z不为-Leu-;
且条件为当AA2为-His-,AA4为-Arg-,Y或Z为-Tyr-时,则p+q不为1。
R1和R2基团分别结合于肽序列的氨基末端(N-末端)和羧基末端(C-末端)。
根据本发明的优选实施方案,R1选自H或R5-CO-组成的组,其中R5选自由下列所组成的组:经取代或未经取代的C1-C24烷基、经取代或未经取代的C2-C24烯基、经取代或未经取代的C2-C24炔基、经取代或未经取代的C3-C24环烷基、经取代或未经取代的C5-C24环烯基、经取代或未经取代的C8-C24环炔基、经取代或未经取代的C6-C30芳基、经取代或未经取代的C7-C24芳烷基、具有3至10个环元的经取代或未经取代的杂环基、及具有2至24个碳原子与1至3个非碳原子和具有1至6个碳原子的烷基链的经取代或未经取代的杂芳基烷基。更优选地,R1选自H、乙酰基、叔丁酰基、己酰基、2-甲基己酰基、环己烷羧基(cyclohexancarboxyl)、辛酰基、癸酰基、月桂酰基、肉豆蔻酰基、棕榈酰基、硬脂酰基、油酰基和亚油酰基(linoleoyl)。再更优选地,R1为H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基。在更优选的实施方案中,R1为乙酰基或棕榈酰基。
根据另一优选的实施方案,R2为-NR3R4、-OR3或-SR3,其中R3和R4独立地选自由下列所组成的组:H、经取代或未经取代的C1-C24烷基、经取代或未经取代的C2-C24烯基、经取代或未经取代的C2-C24炔基、经取代或未经取代的C3-C24环烷基、经取代或未经取代的C5-C24环烯基、经取代或未经取代的C8-C24环炔基、经取代或未经取代的C6-C30芳基、经取代或未经取代的C7-C24芳烷基、具有3至10个环元的经取代或未经取代的杂环基、及具有2至24个碳原子与1至3个非碳原子的经取代或未经取代的杂芳基烷基,其中烷基链具有1至6个碳原子。任选地,R3和R4可经由饱和或不饱和碳-碳键结合,与氮原子一起形成环。更优选地,R2是-NR3R4或-OR3。更优选地,R3和R4选自H、甲基、乙基、己基、十二烷基或十六烷基组成的组。再更优选地,R3为H且R4选自H、甲基、乙基、己基、十二烷基或十六烷基组成的组。根据更优选的实施方案,R2选自-OH和-NH2。
根据本发明的另一实施方案,R1选自由下列所组成的组:H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基,AA2为-L-Leu-,AA4为-L-Arg-,且R2为-NR3R4或-OR3,其中R3和R4独立地选自H、甲基、乙基、己基、十二烷基和十六烷基,优选地R2为-OH或-NH2。更优选地,R1为乙酰基或棕榈酰基且R2为-OH。再更优选地,n、m、p和q为0。
根据本发明的另一实施方案,R1选自由下列所组成的组:H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基,AA2为-L-Pro-,AA4为-L-Arg-,且R2为-NR3R4或-OR3,其中R3和R4独立地选自H、甲基、乙基、己基、十二烷基和十六烷基,优选地R2为-OH或-NH2。更优选地,R1为乙酰基或棕榈酰基且R2为-OH。再更优选地,n、m、p和q为0。
优选地,式(I)化合物选自以下组成的组:
Palm-His-Leu-Leu-Arg-NH2,
Palm-His-Leu-Leu-Arg-OH,
Ac-His-Leu-Leu-Arg-NH2,
Ac-His-Leu-Leu-Arg-OH,
Ac-His-Leu-Leu-Arg-NH-(CH2)15-CH3,
Palm-His-Leu-Leu-Asn-NH2,
Palm-His-Leu-Leu-Asn-OH,
Ac-His-Leu-Leu-Asn-NH2,
Ac-His-Leu-Leu-Asn-OH,
Ac-His-Leu-Leu-Asn-NH-(CH2)15-CH3,
Palm-His-Pro-Leu-Arg-NH2,
Palm-His-Pro-Leu-Arg-OH,
Ac-His-Pro-Leu-Arg-NH2,
Ac-His-Pro-Leu-Arg-OH,
Ac-His-Pro-Leu-Arg-NH-(CH2)15-CH3,
Palm-His-Pro-Leu-Asn-NH2,
Palm-His-Pro-Leu-Asn-OH,
Ac-His-Pro-Leu-Asn-NH2,
Ac-His-Pro-Leu-Asn-OH,
Ac-His-Pro-Leu-Asn-NH-(CH2)15-CH3,
Palm-His-His-Leu-Arg-NH2,
Palm-His-His-Leu-Arg-OH,
Ac-His-His-Leu-Arg-NH2,
Ac-His-His-Leu-Arg-OH,
Ac-His-His-Leu-Arg-NH-(CH2)15-CH3,
Palm-His-His-Leu-Asn-NH2,
Palm-His-His-Leu-Asn-OH,
Ac-His-His-Leu-Asn-NH2,
Ac-His-His-Leu-Asn-OH,
Ac-His-His-Leu-Asn-NH-(CH2)15-CH3,
Ac-Gly-Gly-His-Pro-Leu-Asn-OH,
Ac-His-His-Leu-Asn-Ala-Leu-OH,
Ac-Gly-His-His-Leu-Asn-Ala-OH,
其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐。
本发明的肽可以立体异构体或立体异构体的混合物存在;例如,形成肽的氨基酸可彼此独立地具有L-、D-构型,或为外消旋的。因此,根据不对称碳的数目和存在何种异构体或异构体的混合物,有可能获得异构体的混合物以及外消旋混合物或非对映异构体的混合物,或纯的非对映异构体或对映异构体。本发明肽的优选结构为纯的异构体,即对映异构体或非对映异构体。
例如,当指出AA1可为-His-时,则应理解AA1选自-L-His-、-D-His-或二者的外消旋或非外消旋的混合物。同样的,当指出AA2可为-Leu-时,则应理解其可为-L-Leu-、-D-Leu-或二者的外消旋或非外消旋的混合物。在本文中所描述的制备方法允许本领域技术人员藉由选择具有适当的构型的氨基酸而获得本发明肽的各立体异构体。
在本发明的上下文中,术语“非编码的氨基酸”是关于不由遗传密码编码的那些天然或非天然氨基酸,诸如且不限于尤其是瓜氨酸、鸟氨酸、肌氨酸、锁链素、正缬氨酸、4-氨基丁酸、2-氨基丁酸、2-氨基异丁酸、6-氨基己酸、1-萘基丙氨酸、2-萘基丙氨酸、2-氨基苯甲酸、4-氨基苯甲酸、4-氯苯基丙氨酸、2,3-二氨基丙酸、2,4-二氨基丁酸、环丝氨酸、肉碱、胱氨酸、青霉胺、焦谷氨酸、噻吩基丙氨酸、羟基脯氨酸、别-异亮氨酸、别-苏氨酸、4-哌啶甲酸(isonipecotic acid)、异丝氨酸、苯基甘氨酸、抑胃酶氨酸(statine)、β-丙氨酸、正亮氨酸、N-甲基氨基酸、β-氨基酸或γ-氨基酸以及其衍生物。非天然氨基酸的名单可见于论文“Unusual amino acidsin peptide synthesis(肽合成中的不常见氨基酸)”由D.C.Roberts和F.Vellaccio于The Peptides(肽类),第5卷(1983),第VI章,Gross E.和Meienhofer J.,编著,Academic Press,New York,USA中或此领域中的专门公司的商业目录中,诸如尤其是PolyPeptide Laboratories、Bachem、Novabiochem、Sigma-Aldrich、Peptides International、Advanced ChemTech、Chem-Impex、Maybridge Chemical、Chirotech Technology、PeninsulaLaboratories或RSP Amino Acid Analogues。
在本发明的上下文中,当n、m、p或q不同于0时,应确知W、X、Y和/或Z的性质不会使本发明肽的活性难以实现,而是促进刺激热激蛋白合成,或是对其不具影响。
在本发明的上下文中,本发明还提供肽的化妆品上或药学上可接受的盐。术语“化妆品上或药学上可接受的盐”意指公认可用于动物且尤其是人的盐,包括:用以形成碱加成盐的盐,不论是无机盐,例如且不限于尤其是锂、钠、钾、钙、镁、锰、铜、锌或铝;或是有机盐,诸如且不限于尤其是乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、精氨酸、赖氨酸、组氨酸或哌嗪;或用于形成酸加成盐的盐,不论是有机盐,例如且不限于尤其是乙酸盐、柠檬酸盐、乳酸盐、丙二酸盐、顺丁烯二酸盐、酒石酸盐、反丁烯二酸盐、苯甲酸盐、天冬氨酸盐、谷氨酸盐、琥珀酸盐、油酸盐、三氟乙酸盐、草酸盐、扑酸盐或葡糖酸盐;或无机盐,例如且不限于尤其是盐酸盐、硫酸盐、硼酸盐或碳酸盐。盐的性质不重要,条件为该盐为化妆品上和药学上可接受的。本发明肽的化妆品上和药学上可接受的盐可由现有技术熟知的惯用方法获得[Berge S.M.,Bighley L.D.和Monkhouse D.C.(1977)"Pharmaceutical Salts(药用盐类)"J.Pharm.Sci.66:1-19]。
本发明的一方面涉及用于治疗和/或护理皮肤、粘膜和/或毛发的如本发明所述的通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐。
在另一具体方面,本发明涉及如本发明所述的通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,用于治疗和/或护理通过刺激Hsp蛋白质合成而改善或预防的那些病况、病症和/或疾病,具体地分子量介于20kDa至110kDa间的Hsp家族蛋白质,更具体地介于40kDa至100kDa间的分子量,更具体地包括介于60kDa至80kDa之间的分子量的Hsp蛋白质,尤其是分子量为70kDa的Hsp或Hsp70。
在优选的实施方案中,通过刺激热激蛋白合成而改善或预防的病况、病症和/或疾病选自大疱性表皮松解症和脱发症组成的组,包括因癌症化疗所引起的脱发症。
在另一具体方面,本发明涉及用于治疗和/或护理皮肤、粘膜和/或毛发的如本发明所述的通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,其减轻、延迟和/或阻止由UV辐射、热应激、氧化应激、渗透压冲击、炎症、缺氧、暴露于污染物、缺少营养和缺乏水合作用引起的细胞受损。
在另一方面,本发明涉及一种用于治疗和/或护理皮肤、粘膜和/或毛发的如本发明所述的通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,其减少和/或阻止老化和/或光老化的迹象。
在另一方面,本发明涉及用于治疗和/或护理皮肤和/或粘膜的如本发明所述的通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,其刺激创伤的愈合和/或表皮再生,优选地因糖尿病导致的那些创伤。
在另一具体方面,本发明涉及用于治疗和/或护理皮肤和/或毛发的如本发明所述的通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,其延迟和/或阻止脱发或诱导毛发生长。
制备方法
本发明的肽、其立体异构体或其化妆品上或药学上可接受的盐的合成可根据现有技术已知的惯用方法进行,诸如固相肽合成法[Stewart J.M.和Young J.D.(1984)“Solid Phase Peptide Synthesis(固相肽合成),第2版”Pierce Chemical Company,Rockford,Illinois;BodanzskyM.和Bodanzsky A.(1984)“The practice of Peptide Synthesis(肽合成实践)”Springer Verlag,New Cork;Lloyd-Williams P.,Albericio F.和Giralt E.(1997)“ChemicalApproaches to the Synthesis of Peptides and Proteins(合成肽和蛋白的化学方法)”CRC,Boca Raton,FL,USA]、溶液合成法、固相合成法与溶液合成法的组合或酶催化合成法[Kullmann W.(1980)“Proteases as catalysts forenzymic syntheses of opioid peptides(蛋白酶作为酶催化性合成阿片肽的催化剂)”J.Biol.Chem.255:8234-8238]。肽还可如下获得:发酵经或未经遗传改造的菌株以产生所需序列,或控制动物或植物来源(优选植物来源)的蛋白质水解,以释出含有至少所需序列的肽片段。
例如,获得本发明式(I)的肽的方法包含以下步骤:
-将具有经保护的N-末端和自由C-末端的氨基酸偶合于具有自由N-末端和经保护的或结合至固态支撑物上的C-末端的氨基酸;
-移除N-末端的保护基;
-重复偶合和移除N-末端保护基的顺序,直至得到所需的肽序列;
-移除C-末端的保护基或从固态支撑物裂解出。
优选地,将C-末端结合至固态支撑物,且在固相上进行该方法,因此,包括将具有经保护的N-末端和自由C-末端的氨基酸偶合至具有自由N-末端和与聚合物支撑物结合的C-末端的氨基酸;移除N-末端的保护基;依需要重复此顺序多次直至获到所需长度的肽,最后接着从原始聚合物支撑物裂解出所合成的肽。
在整个合成期间,氨基酸侧链的官能团以暂时或永久性保护基适当地保护,且可在与从聚合物支撑物裂解肽的过程同时或互不相关地(orthogonally)脱保护。
可选地,可藉由将肽偶合于聚合物支撑物上或肽上或预先结合至聚合物支撑物的氨基酸上的收敛性策略,来进行固相合成。收敛性合成策略是本领域技术人员广泛所知的,且描述于Lloyd-Williams P.,Albericio F.和Giralt E.于“Convergent solid-phase Peptide synthesis(收敛性固相肽合成)”(1993)Tetrahedron49:11065-11133中。
该方法可包括使用现有技术已知的标准方法和条件,以不同的次序脱保护N-末端和C-末端和/或从聚合物支撑物裂解肽的另外阶段,随后可修饰这些末端的官能团。N-末端和/或C-末端的任选修饰可对结合于聚合物支撑物的式(I)的肽进行,或在肽已从聚合物支撑物裂解出时进行。
任选地,R1可藉由本发明肽的N-末端与化合物R1-J的反应而引入,其中R1如前文所述且J为离去基,例如且不限于尤其是甲苯磺酰基、甲磺酰基和卤素;经由在适当的碱和溶剂存在下的亲核取代反应而引入,其中具有不牵涉入N-C键形成作用的官能团的片段经暂时性或永久性保护基适当地保护。
任选地和/或另外地,R2基团可藉由其中R2为-OR3、-NR3R4或-SR3的化合物HR2与对应于其中R2为-OH的式(I)肽的互补片段的反应而引入,该反应在适当的溶剂和尤其是碱诸如N,N-二异丙基乙胺(DIEA)或三乙胺,或添加剂诸如1-羟基苯并三唑(HOBt)或1-羟基氮杂苯并三唑(HOAt)和脱水剂诸如碳二亚胺、脲盐、鏻盐或脒基盐(amidinium salt)的存在下进行;或藉由以例如亚硫酰氯预先形成酰基卤化物而引入,藉以获得根据本发明通式(I)的肽,其中具有不牵涉入N-C键形成作用的官能团的片段以暂时或永久性保护基适当地保护,或可选地,其他R2基团可藉由在从聚合物支撑物裂解肽的过程中同时并入而引入。
本领域技术人员可容易理解,C-末端和N-末端的脱保护/裂解步骤及其后续的衍生作用可根据现有技术中已知的方法以不同顺序进行[Smith M.B.和March J.(1999)“March’s Advanced Organic Chemistry Reactions,Mechanisms and Structure(March高级有机化学反应、机理和结构)”,第5版,John Wiley&Sons,2001]。
术语“保护基”是关于封闭官能性有机基团且可在受控制条件下移除的基团。保护基、其相关反应性和保持其为惰性的条件是本领域技术人员已知的。
氨基的代表性保护基的实例尤其为酰胺,诸如酰胺乙酸酯、酰胺苯甲酸酯、酰胺特戊酸酯;氨基甲酸酯,诸如苄氧基羰基(Cbz或Z)、2-氯苄基(ClZ)、对-硝基苄氧基羰基(pNZ)、叔丁氧基羰基(Boc)、2,2,2-三氯乙基氧基羰基(Troc)、2-(三甲基硅烷基)乙氧基羰基(Teoc)、9-芴甲氧基羰基(Fmoc)或烯丙氧基羰基(Alloc)、三苯甲基(Trt)、甲氧基三苯甲基(Mtt)、2,4-二硝基苯基(Dnp)、N-[1-(4,4-二甲基-2,6-二氧代亚环己-1-基)乙基(Dde)、1-(4,4-二甲基-2,6-二氧代-亚环己基)-3-甲基丁基(ivDde)、1-(1-金刚烷基)-1-甲基乙氧基羰基(Adpoc),优选为Boc或Fmoc。
羧基的代表性保护基的实例尤其为酯,诸如叔丁酯(tBu)、烯丙酯(All)、三苯基甲酯(三苯甲酯,Trt)、环己酯(cHx)、苄酯(Bzl)、邻-硝基苄酯、对-硝基苄酯、对-甲氧基苄酯、三甲硅烷基乙酯、2-苯基异丙酯、芴甲酯(Fm)、4-(N-[1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基丁基]氨基)苄酯(Dmab);本发明优选的保护基为All、tBu、cHx、Bzl和Trt酯。
三官能性氨基酸的侧链可在合成过程期间以与N-末端和C-末端的保护基互不相关的暂时性或永久性保护基保护。
精氨酸侧链的胍基可使用以下基团保护:尤其是硝基、烯丙氧基羰基(Alloc)、对-甲苯磺酰基(tosyl,Tos)、2,2,5,7,8-五甲基色满-6-磺酰基(Pmc)、2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基(Pbf)或4-甲氧基-2,3,6-三甲基苯磺酰基(Mtr);组氨酸侧链的咪唑基可使用以下基团保护:尤其是甲苯磺酰基(Tos)、叔丁氧基羰基(Boc)、三苯甲基(Trt)、甲氧基三苯甲基(Mtt)或2,4-二硝基苯基(Dnp);且天冬酰胺侧链的酰胺基可使用三苯甲基(Trt)或占吨基(Xan)保护,或不经保护地使用。
在优选的实施方案中,所使用的保护基策略为其中氨基以Boc保护,羧基以Bzl、cHx或All酯保护,精氨酸侧链以Mtr或Tos保护,天冬酰胺侧链不经保护地使用,组氨酸侧链以Tos或Dnp保护的策略。
在另一优选的实施方案中,所使用的保护基策略是其中氨基以Fmoc保护,羧基以tBu、All或Trt酯保护,精氨酸侧链以Pmc或Pbf保护,天冬酰胺侧链以Trt保护且组氨酸侧链以Trt或Mtt保护的策略。
这些与其他另外的保护基的实例、其引入和移除可见于文献[GreeneT.W.和WutsP.G.M.,(1999)“Protective groups in organic synthesis(有机合成中的保护基)”John Wiley &Sons,New York;Atherton B.和Sheppard R.C.(1989)“Solid Phase Peptide Synthesis:A practical approach(固相肽合成:实用方法)”IRL Oxford University Press]。术语“保护基”也包括在固相合成法中使用的聚合物支撑物。
当合成完全或部分在固相上进行时,本发明方法中所使用的可能的固态支撑物可包括聚苯乙烯支撑物、接枝于聚苯乙烯的聚乙二醇和类似物,例如且不限于对甲基二苯甲胺(MBHA)树脂[Matsueda G.R.和Stewart J.M.(1981)“Ap-methylbenzhydrylamine resin for improved solid-phase synthesisof peptide amides(用于肽酰胺类改进的固相合成的对-甲基二苯甲胺树脂)”Peptides2:45-50]、2-氯三苯甲基树脂[[Barlos K.,Gatos D.,Kallitsis J.,Papaphotiu G.,Sotiriu P.,Wenqing Y.和W.(1989)“Darstellunggeschützter Peptid-Fragmente unter Einsatz substituierterTriphenylmethyl-Harze”Tetrahedron Lett.30:3943-3946;Barlos K.,Gatos D.,Kapolos S.,Papaphotiu G.,W.和Wenqing Y.(1989)“Veresterung vonpartiell geschützten Peptid-Fragmenten mit Harzen.Einsatz von2-Chlorotritylchlorid zur Synthese von Leu1-Gastrin I”Tetrahedron Lett.30:3947-3951]、树脂((Rapp Polymere GmbH)、树脂(Matrix Innovation,Inc)和类似物,其可包括或不包括不稳定的接头,诸如5-(4-氨甲基-3,5-二甲氧基苯氧基)戊酸(PAL)[Albericio F.,Kneib-CordonierN.,Biancalana S.,Gera L.,Masada R.I.,Hudson D.和Barany G.(1990)“Preparation and application of the5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxy phenoxy)valeric acid(PAL)handle for thesolid-phase synthesis of C-terminal peptide amides under mild conditions(用于在温和条件下操纵C端肽酰胺类固相合成的5-(4-(9-芴基甲基氧羰基)氨甲基-3,5-二甲氧基苯氧基)戊酸(PAL)的制备和应用)”J.Org.Chem.55:3730-3743]、2-(AM)[Rink H.(1987)“Solid-phase synthesis of protectedpeptide fragments using atrialkoxy-diphenyl-methylester resin(利用三烷氧基-二苯基-甲基酯树脂固相合成受保护的肽片段)”Tetrahedron Lett.28:3787-3790]、Wang[Wang S.S.(1973)“p-Alkoxybenzyl Alcohol Resin andp-Alkoxybenzyloxycarbonylhydrazide Resin for Solid Phase Synthesis ofProtected Peptide Fragments(用于固相合成受保护的肽片段的对烷氧基苄醇树脂和对烷氧基苄氧羰基肼树脂)”J.Am.Chem.Soc.95:1328-1333]和类似物,允许同时将肽脱保护和从聚合物支撑物裂解肽。
化妆用组合物或药物组合物
在这方面,本发明的另一方面为化妆用组合物或药物组合物,其包含至少一种通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐、连同至少一种化妆品上或药学上可接受的佐剂。这些组合物可以本领域技术人员已知的惯用方法制备[“Harry’sCosmeticology(Harry化妆品学)”,第8版(2000)Rieger M.M.,编著,New York Chemical Pub.,NY,US;“Remington:The Science and Practice of Pharmacy(雷明顿药学理论和实践)”,第20版(2003)Genaro A.R.,编著,Lippincott Williams&Wilkins,Philadelphia,US]。
根据其序列的性质或在N-末端和/或C-末端上任何可能的修饰,本发明的肽在水中具有不同的溶解度。因此,本发明的肽可以水溶液掺入组合物中,不溶于水的那些肽可溶解于化妆品上或药学上可接受的惯用溶剂中,例如且不限于乙醇、丙醇、异丙醇、丙二醇、甘油、丁二醇或聚乙二醇或其任何组合。
应施用本发明的肽的化妆品上或药学上有效量以及其剂量将取决于许多因素,包括患者的年龄、状态、待治疗、护理和/或预防的病况、病症或疾病的性质或严重性、施用途径和频率及尤其是待使用的肽的性质。
应理解,“化妆品上和药学上有效量”是指无毒性但足以提供所需效果的本发明的肽或肽类的量。本发明的肽以实现所需效果的化妆品上或药学上有效浓度用于本发明的化妆用组合物或药物组合物中;在优选形式中,以组合物总重量计介于0.00000001%(以重量计)至20%(以重量计)之间;优选介于0.000001%(以重量计)至20%(以重量计)之间,更优选介于0.0001%(以重量计)至10%(以重量计)之间,且再更优选介于0.0001%(以重量计)至5%(以重量计)之间。
本发明的肽还可被掺入化妆品或药物递送系统和/或持续释放系统中。
术语“递送系统”是关于与本发明的肽一起施用的稀释剂、佐剂、赋形剂或载体。这些化妆用或药学载体可为液体,诸如水、油或表面活性剂,包括石油、动物、植物或合成来源的,诸如且不限于花生油、大豆油、矿油、芝麻油、蓖麻油、聚山梨醇酯、山梨醇酐酯、醚硫酸酯、硫酸酯、甜菜碱、糖苷、麦芽糖苷、脂肪醇、壬苯聚醇(nonoxynol)、泊洛沙姆(poloxamer)、聚氧乙烯、聚乙二醇、右旋糖、甘油、毛地黄皂苷和类似物。在E.W.Martin的"Remington's Pharmaceutical Sciences(雷明顿药学理论和实践)"中,描述了作为适当的载体的稀释剂、佐剂或赋形剂。
术语“持续释放"以惯用意义使用,是关于在一段时间提供逐渐释放化合物的此化合物递送系统,优选在整个一段时间具有相对恒定的化合物释放水平,尽管非必需。
递送系统或持续释放系统的实例有脂质体、混合脂质体、油质体、类脂囊泡(niosome)、醇质体(ethosome)、毫米粒子(milliparticle)、微米粒子、纳米粒子和固态脂质纳米粒子、纳米构造的脂质载体、海棉、环糊精、囊泡、胶束、表面活性剂混合胶束、表面活性剂-磷脂混合胶束、毫米球、微米球和纳米球、脂质球、毫米胶囊、微米胶囊和纳米胶囊,以及微米乳剂和纳米乳剂,可添加这些以实现更大的活性成分渗透和/或改善其药代动力学与药效学性质。优选的递送或持续释放系统为脂质体、表面活性剂-磷脂混合胶束和微米乳剂,更优选为具有反胶束的内部结构的油包水型微米乳剂。
持续释放系统可以现有技术中已知的方法制备,且含有该系统的组合物可以例如局部或经皮施用,包括粘性贴片、非粘性贴片、闭合型贴片和微电贴片,或以全身性施用,例如且不限于口服或肠胃外,包括鼻、直肠或皮下植入或注射,或直接植入或注射至特定身体部位,优选地应释放相对恒定量的本发明的肽。持续释放系统中所含的肽量将取决于例如待施用组合物的位置、本发明肽的释放动力学和持续时间,以及待治疗和/或护理的病况、病症和/或疾病的性质。
本发明的肽还可吸附于固态有机聚合物或固态无机支撑物上,诸如且不限于尤其是滑石、膨润土、硅石、淀粉或麦芽糊精。
含有本发明肽的组合物还可被掺入与皮肤直接接触的织物、非织造织物和医疗装置中,从而释放本发明的肽,不论经由与织物、非织造织物或医疗装置的结合系统的生物降解,或经由织物、非织造织物或医疗装置与身体之间的摩擦、因身体湿度、皮肤pH或体温而释放。此外,可使用织物和非织造织物制造与身体直接接触的衣物。优选地,使用含有本发明肽的织物、非织造织物和医疗装置以治疗和/或护理通过刺激Hsp合成而改善或预防的病况、病症和/或疾病。
为上述的递送系统和/或持续释放系统的织物、非织造织物、衣物、医疗装置和用于固定肽于其上的设备(means)的实例可见于文献且为现有技术已知的[SchaabC.K.(1986)"Impregnating Fabrics With Microcapsules(用微胶囊浸渍织物)",HAPPIMay1986;NelsonG.(2002)“Application ofmicroencapsulation in textiles(微胶囊化在纺织品中的应用)”Int.J.Pharm.242:55-62;“Biofunctional Textiles and the Skin(生物功能的纺织品与皮肤)”(2006)Curr.Probl.Dermatol.第33卷,Hipler U.C.和Elsner P.,编著.S.Karger AG,Basel,Switzerland;MalcomR.K.;McCullaghS.D.,WoolfsonA.D.,Gorman S.P.,Jones D.S.yCuddy J.(2004)“Controlled release of a modelantibacterial drug from a novel self-lubricating silicone biomaterial(模式抗细菌药从新型自润滑硅酮生物材料的控制释放)”J.Cont.Release97:313-320]。优选的织物、非织造织物、衣物和医疗装置为绷带、纱布、T恤、袜子、裤袜、内衣、腰带、手套、尿布、卫生巾、敷料、床罩、擦拭物、粘性贴片、非粘性贴片、闭合型贴片、微电贴片和/或面罩(facemask)。
含有本发明的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐的化妆用组合物或药物组合物可以不同类型的局部或经皮施加的组合物使用,任选地包括用于配制所需施用形式必需的化妆品上或药学上可接受的赋形剂[Faulí i TrilloC.(1993)的“Tratado de FarmaciaGalénica”,Luzán5,S.A.Ediciones,Madrid]。
局部或经皮施用的组合物可制成任何固态、液态或半固态制剂,诸如且不限于乳霜(cream)、复合乳剂(multipleemulsion),诸如且不限于水包油型和/或水包硅酮型乳剂、油包水型和/或硅酮包水型乳剂、水/油/水或水/硅酮/水型乳剂和油/水/油型或硅酮/水/硅酮型乳剂、无水组合物、水性分散液、油、奶状物(milk)、香脂(balsam)、泡沫(foam)、洗剂(lotion)、凝胶、乳胶(creamgel)、水醇溶液、水二醇溶液(hydroglycolicsolution)、水凝胶、搽剂(liniment)、浆液(sera)、皂(soap)、洗发剂(shampoo)、润发乳(conditioner)、浆液(serum)、多糖膜(polysaccharidefilm)、软膏(ointment)、摩丝(mousse)、润发油(pomade)、粉剂(powder)、棒剂(bar)、笔剂(pencil)和喷雾剂(spray)或气雾剂(aerosol)(喷雾剂),包括免冲洗型(leave-on)和冲洗型(rinse-off)制剂。这些局部或经皮施用的制剂可使用本领域技术人员已知的技术掺入不同类型的固态附件中,诸如且不限于绷带、纱布、T恤、袜子、裤袜、内衣、腰带、手套、尿布、卫生巾、敷料、床罩、擦拭物、粘性贴片、非粘性贴片、闭合型贴片、微电贴片或面罩,或可将这些制剂掺入不同化妆产品中,尤其诸如粉底,诸如液态粉底和粉饼、卸妆液、卸妆乳、眼部遮瑕霜、眼影、唇膏、护唇品、唇彩和唇粉。
本发明的化妆用组合物和药物组合物可包括增加本发明的肽经皮吸收的剂,诸如且不限于尤其是二甲亚砜、二甲基乙酰胺、二甲基甲酰胺、表面活性剂、氮酮(1-十二烷基氮杂环庚烷-2-酮)、醇、尿素、乙氧基二甘醇、丙酮、丙二醇或聚乙二醇。此外,本发明的化妆用组合物或药物组合物可以离子电渗(iontophoresis)、超声波导入(sonophoresis)、电穿孔、微电贴片、机械压力、渗透压梯度、闭塞治疗(occlusivecure)、微注射、或借助压力的无针注射诸如借助氧压注射或其任何组合的方式施用于待治疗的局部区域,以实现本发明肽的更大渗透。施用区域由待治疗和/或护理的病况、病症和/或疾病的性质而决定。
另外,含有本发明的肽、其立体异构体或其化妆品上或药学上可接受的盐的化妆用组合物可以不同类型的口服施用制剂使用,优选以口服化妆品和药学药物形式,诸如且不限于胶囊,包括明胶胶囊、软胶囊、硬胶囊、片剂包括糖衣片剂、粉末剂、颗粒剂、咀嚼胶、溶液、悬浮液、乳剂、糖浆、多糖膜、冻胶或明胶,和本领域技术人员已知的任何其他形式。尤其是,本发明的肽可被掺入任何形式的功能性食品或强化食品中,诸如且不限于膳食棒或压制粉末或未压制粉末。这些粉末可溶于水、果汁、苏打水、乳制品、大豆衍生物中,或可被掺入膳食棒中。本发明的肽可与常用于口服组合物或食品补充物的赋形剂和佐剂配制,诸如且不限于食品工业中常用的脂肪成分、水性成分、保湿剂、防腐剂、调质剂、调味剂、香料、抗氧化剂和着色剂。
含有本发明的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐的化妆用组合物或药物组合物还可以局部或经皮途径,以及任何其他适当的途径例如口服或肠胃外途径施用,为这些途径的组合物包括配制所需施用形式必需的药学上可接受的赋形剂。在本发明的上下文中,术语“肠胃外”包括鼻、耳、眼、直肠、尿道、阴道、皮下、皮内、血管内注射诸如静脉内、肌内、眼内、玻璃体内、角膜内、脊椎内、脊髓内、颅内、宫颈内、脑内、脑脊膜内、关节内、肝内、胸腔内、气管内、鞘内和腹膜内,及任何其他类似的注射或输注技术。施用活性成分的不同的药物形式和获得这些形式必需的赋形剂的综述可见于例如“Tratado deFarmacia Galénica”,C.Faulí i Trillo,1993,Luzán5,S.A.Ediciones,Madrid中。
在本发明所述的化妆用组合物或药物组合物中所含有的化妆品上或药学上可接受的佐剂包括用于治疗和/或护理皮肤、粘膜和/或毛发的组合物中常使用的另外成分,诸如且不限于热激蛋白、其他热激蛋白合成刺激剂、乙酰胆碱受体聚集抑制剂(acetylcholine-receptor aggregation inhibitor)、肌肉收缩抑制剂、抗胆碱能剂、弹性蛋白酶抑制剂、基质金属蛋白酶抑制剂、黑色素合成刺激或抑制剂、增白剂或脱色剂、色素原形成剂(pro-pigmenting agent)、仿晒剂、抗老化剂、NO-合酶抑制剂、5α-还原酶抑制剂、赖氨酰基-和/或脯氨酰基羟化酶抑制剂、抗氧化剂、自由基清除剂和/或抗空气污染剂、反应性羰基物类清除剂、抗糖化剂、抗组织胺剂、抗病毒剂、抗寄生剂、乳化剂、润肤剂(emollient)、有机溶剂、液体推进剂、皮肤调理剂,诸如保湿剂(humectant)、保湿物质、α羟酸、β羟酸、湿润剂、表皮水解酶、维生素、氨基酸、蛋白质、颜料或着色剂、染料、胶化聚合物、增厚剂、表面活性剂、软化剂、防皱剂(anti-wrinkle agent)、能够减轻或治疗眼袋的剂、去角质剂、抗微生物剂、抗真菌剂、抑真菌剂、杀细菌剂、抑细菌剂、刺激真皮或表皮大分子合成和/或能够抑制或阻止其降解的剂,诸如例如胶原合成刺激剂、弹性蛋白合成刺激剂、核心蛋白聚糖合成刺激剂、层粘连蛋白合成刺激剂、防御素合成刺激剂、水通道蛋白合成刺激剂、透明质酸合成刺激剂、纤连蛋白合成刺激剂、乙酰化酶合成刺激剂、刺激脂质与角质层的成分(神经酰胺、脂肪酸等)合成的剂、胶原降解抑制剂、其他抑制弹性蛋白降解的剂、丝氨酸蛋白酶诸如组织蛋白酶G的抑制剂、成纤维细胞增殖刺激剂、角质细胞增殖刺激剂、脂肪细胞增殖刺激剂、黑色素细胞增殖刺激剂、角质细胞分化刺激剂、脂肪细胞分化刺激剂、乙酰胆碱酯酶抑制剂、皮肤松弛剂、糖胺聚糖合成刺激剂、抗角化过度剂、粉刺溶解剂、抗牛皮癣剂、DNA修复剂、DNA防护剂、稳定剂、止痒剂、敏感性皮肤治疗和/或护理剂、皮肤紧实剂、除妊娠纹剂、粘合剂、皮脂产生调节剂、解脂剂或脂肪分解刺激剂、抗脂肪小丘剂、止汗剂、愈合刺激剂、愈合辅助剂、表皮再生刺激剂、表皮再生辅助剂、细胞因子生长因子、镇定剂、消炎剂和/或止痛剂、麻醉剂、作用于毛细血管循环和/或微循环的剂、血管生成刺激剂、血管通透性抑制剂、静脉张力剂(venotonicagent)、作用于细胞代谢的剂、改善真皮-表皮接合的剂、毛发生长诱导剂、毛发生长抑制剂或延缓剂、脱发延缓剂、防腐剂、香料、螯合剂、植物提取物、精油、海洋提取物、从生物发酵过程获得的剂、无机盐、细胞提取物与防晒剂(抗紫外线A和/或B的活性有机或无机光防护剂),条件是这些另外成分与组合物的其他成分且尤其是与本发明组合物中所含有的通式(I)的肽在物理上与化学上相容。另外,这些另外成分的性质不应不可接受地改变本发明肽的益处。这些另外成分的性质可为合成或天然的,诸如植物提取物,或由生物技术过程或合成过程与生物技术过程的组合获得。其他的实例可见于CTFA International Cosmetic Ingredient Dictionary&Handbook(国际化妆品原料字典&手册),第12版(2008)。在本发明的上下文中,应理解生物技术过程为在生物体或其部分中产生活性成分或其部分的任何过程。
本发明的另一方面涉及一种化妆用组合物或药物组合物,含有化妆品上或药学上有效量的至少一种根据通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,以及化妆品上或药学上有效量的至少一种刺激Hsp合成的提取物、合成化合物或生物发酵产物,诸如且不限于:尤其是梨果仙人掌(Opuntia ficus indica)、白柳(Salix alba)、羽扇豆属(Lupinus spp)、黑麦(Secale cereale)的提取物、紫菜属(Porphyra)红藻的提取物、卤虫属(Artemia)的甲壳类的提取物、荷荷芭籽油、葡萄籽提取物、绿茶提取物、香叶基香叶基丙酮、南蛇藤素(celastrol)、锌及其盐、2-环戊烯-1-酮、蛋白酶体抑制剂,诸如且不限于尤其是硼替佐米(bortezomib);前列腺素及其衍生物、羟胺及其衍生物,诸如且不限于氯吡哌醇(bimoclomol);查耳酮(chalcone)及其衍生物,高渗剂,诸如且不限于山梨糖醇及其衍生物、甘露醇及其衍生物或甘油及其衍生物、异山梨醇、脲或水杨酸及其衍生物、或其混合物。
本发明的另一方面涉及含有化妆品上或药学上有效量的至少一种根据通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐的化妆用组合物或药物组合物,且该组合物还含有化妆品上或药学上有效量的至少一种为防皱剂和/或抗老化剂的提取物,诸如且不限于尤其是葡萄(Vitis vinifera)、狗蔷薇(Rosa canina)、姜黄(Curcuma longa)、香根鸢尾(Iris pallida)、可可(Theobroma cacao)、银杏(Ginkgo biloba)、火绒草(Leontopodium Alpinum)或盐藻(Dunaliella salina)的提取物,或另外至少一种为防皱剂和/或抗老化剂的合成化合物或生物发酵产物,诸如且不限于由Sederma销售的[INCI:棕榈酰基五肽-4]、Matrixyl[INCI:棕榈酰基四肽-7、棕榈酰基寡肽]、EssenskinTM[INCI:羟基甲硫氨酸钙]、Renovage[INCI:替普瑞酮(teprenone)]或[INCI:棕榈酰基寡肽],由Pentapharm/DSM销售的[INCI:五肽-3]、[INCI:二肽二氨基丁酰基苄基酰胺二乙酸酯]、-Coll[INCI:棕榈酰基三肽-5]、Phytaluronate[INCI:角豆(Ceratonia Siliqua)胶]或[INCI:野生大豆(Glycine Soya)(大豆)蛋白、氧化还原酶],由LaboratoiresSérobiologiques/Cognis销售的MyoxinolTM[INCI:水解的黄秋葵(HibiscusEsculentus)提取物]、SyniorageTM[INCI:乙酰基四肽-11]、DermicanTM[INCI:乙酰基四肽-9]或DN-AGETMLS[INCI:翅荚决明(Cassia Alata)叶提取物],由Exsymol销售的Algisum[INCI:甲基硅烷醇甘露糖醛酸酯]或Hydroxyprolisilane[INCI:甲基硅烷醇羟基脯氨酸天冬氨酸酯],[INCI:乙酰基六肽-8]、SNAP-7[INCI:乙酰基七肽-4]、SNAP-8[INCI:乙酰基八肽-3]、[INCI:五肽-18]、InylineTM[INCI建议:乙酰基六肽-25]、[INCI:水解小麦蛋白、水解大豆蛋白、三肽-1]、PreventheliaTM[INCI:二氨基丙酰基三肽-33]、[INCI:三肽-10瓜氨酸]、[INCI:假交替单胞菌(Pseudoalteromonas)发酵提取物、水解小麦蛋白、水解大豆蛋白、三肽-10瓜氨酸、三肽-1]、[INCI:乙酰基四肽-5]、肽AC29[INCI:乙酰基三肽-30瓜氨酸]、RelistaseTM[INCI建议:乙酰基四肽-30]、Lipochroman-6[INCI:二甲基甲氧基色原烷醇]、ChromabrightTM[INCI:二甲基甲氧基色满基棕榈酸酯]、由Lipotec销售的[INCI:假交替单胞菌发酵提取物]或VilasteneTM[INCI:盐酸赖氨酸、卵磷脂、三肽-10瓜氨酸],由InstitutEuropeen de Biologie Cellulaire销售的[INCI:三肽-1、右旋糖酐],由Vincience/ISP销售的IS[INCI:六肽-9]、Laminixyl ISTM[INCI:七肽]、OrsirtineTMGL[INCI:水稻(Oryza Sativa)(稻)提取物]、D’OrientineTMIS[INCI:海枣(Phoenix Dactylifera)(椰枣)种子提取物]、PhytoquintescineTM[INCI:单谷小麦(Einkorn)(一粒小麦(TriticumMonococcum))提取物]或QuintescineTMIS[INCI:二肽-4],由InfinitecActivos销售的BONT-L-肽[INCI:棕榈酰基六肽-19],由Seppic销售的DeepalineTMPVB[INCI:棕榈酰基水解小麦蛋白]或DPHP[INCI:二棕榈酰基羟基脯氨酸],由Gattefossé销售的Expression[INCI:印度金钮扣(Acmella oleracea)提取物]、In-Tense[INCI:金钮扣(Spilanthes Acmella)花提取物]或Age Defense2[INCI:胡桃(Juglans Regia)(胡桃)种子提取物],由Biotechmarine销售的ThalassineTM[INCI:藻类提取物],由Atrium Innovations/Unipex Group销售的ChroNOlineTM[INCI:己酰基四肽-3]或Thymulen-4[INCI:乙酰基四肽-2],由Coletica/Engelhard/BASF销售的EquiStat[INCI:苹果(PyrusMalus)果提取物、野生大豆种子提取物]或Juvenesce[INCI:乙氧基二甘醇和辛酸甘油三酯、视黄醇、熊果酸、维生素K1、伊洛马司他(Ilomastat)],由MibelleBiochemistry销售的Ameliox[INCI:肌肽、生育酚、水飞蓟(SilybumMarianum)果提取物]或PhytoCellTec Malus Domestica[INCI:苹果(MalusDomestica)果细胞培养物],由Silab销售的Bioxilift[INCI:茴芹(PimpinellaAnisum)提取物]或SMS Anti-[INCI:番荔枝(Annona Squamosa)种子提取物],Ca2+通道拮抗剂,诸如且不限于阿尔维林(alverine)、锰盐或镁盐、某些仲胺或叔胺、视黄醇及其衍生物、艾地苯醌(idebenone)及其衍生物、辅酶Q10及其衍生物、乳香酸及其衍生物、GHK及其衍生物和/或盐类、肌肽及其衍生物、DNA修复酶,诸如且不限于光解酶、T4核酸内切酶V或氯化物通道激动剂。
另外,本发明是关于化妆用组合物或药物组合物,其包含化妆品上或药学上有效量的至少一种根据通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,且另外含有化妆品上或药学上有效量的至少一种刺激愈合和/或表皮再生的提取物或提取物组合、或愈合和/或表皮再生的辅助剂,诸如且不限于以下的提取物:积雪草(Centella asiatica)、麝香玫瑰(Rosa moschata)、狭叶松果菊(Echinacea angustifolia)、聚合草(Symphytum officinal)、问荆(Equisetum arvense)、贯叶金丝桃(Hypericumperforatum)、细花含羞草(Mimosa tenuiflora)、芦荟(Aloe vera)、由Provital销售的Epithelizing[INCI:金盏菊(Calendula officinalis)、金丝桃、母菊(Chamomilla recutita)、迷迭香(Rosmarinus officinalis)]、由Laboratories Serobiologiques/Cognis销售的LS9028[INCI:水解酪蛋白、水解酵母蛋白、盐酸赖氨酸]、或由Coletica/Engelhard/BASF销售的[INCI:玉蜀黍(Zea mays)(玉米)谷粒提取物]、和/或化妆品上或药学上有效量的刺激愈合和/或表皮再生的至少一种合成化合物、提取物或生物发酵产物,诸如且不限于尤其是钙粘蛋白、整联蛋白、选择蛋白、透明质酸受体、免疫球蛋白、成纤维细胞生长因子、结缔组织生长因子、血小板衍生的生长因子、血管内皮生长因子、表皮生长因子、胰岛素样生长因子、角质细胞生长因子、集落刺激因子、转化生长因子-β、肿瘤坏死因子-α、干扰素、白介素、基质金属蛋白酶、蛋白质酪氨酸磷酸酶受体、由Lipotec销售的[INCI:假交替单胞菌发酵提取物]或[INCI:三肽-10瓜氨酸]、或其混合物。
本发明另一方面是关于一种化妆用组合物或药物组合物,其包含化妆品上或药学上有效量的至少一种根据通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐、且另外含有化妆品上或药学上有效量的至少一种延迟脱发或诱导毛发生长的提取物或提取物组合,诸如且不限于尤其是款冬(Tussilago farfara)或千叶蓍(Achillea millefolium)的提取物、和/或化妆品上或药学上有效量的至少一种延迟脱发或诱导毛发生长的化合物,诸如且不限于烟酸酯,诸如烟酸C3-C6烷基酯,诸如烟酸甲基酯或烟酸己基酯、烟酸苄酯或生育酚烟酸酯;类固醇和非类固醇抗炎剂,诸如且不限于氢化可的松、其盐和衍生物或尼氟灭酸;类视黄醇,诸如且不限于全反式视黄酸或维甲酸、异维甲酸、视黄醇或维生素A及其衍生物,诸如乙酸酯、棕榈酸酯、丙酸酯、莫维A胺(motretinide)、依曲替酯(etretinate)和反式视黄酸锌(zinc trans retinoate);抗菌素,诸如且不限于大环内酯、吡喃糖苷和四环素、红霉素;钙通道拮抗剂,诸如且不限于肉桂苯哌嗪(cinnarizine)和地尔硫卓(diltiazem);激素,诸如且不限于雌三醇、其类似物或酪氨酸、其类似物和/或其盐;抗雄激素剂,诸如且不限于氧雄龙(oxendolone)、螺旋内酯或己烯雌酚;抗自由基剂,诸如且不限于二甲亚砜;酯化寡糖,诸如且不限于文献EP0211610和EP0064012中所述的那些;聚己糖酸(hexasaccharide acids)的衍生物,诸如且不限于葡萄糖糖酸(glucose saccharide acid)或文献EP0375388中所述的那些;葡糖苷酶抑制剂,诸如且不限于D-葡糖二酸-1,5-内酰胺或文献EP0334586中所述的那些;糖胺聚糖和蛋白聚糖抑制剂,诸如且不限于L-半乳糖-1,4-内酯或文献EP0277428中所述的那些;酪氨酸激酶抑制剂,诸如且不限于1-酰胺-1-氰基(3,4-二羟苯基)乙烯或文献EP0403238中所述的那些,二氮嗪类,诸如且不限于7-(乙酰基硫基)-4’,5’-二氢螺[雄-4-烯-17,2’-(3H)呋喃]-3-酮、3-甲基-7-氯[2H]-1,2,4-苯并噻二嗪或螺噁嗪1,1-二氧化物;磷脂,诸如且不限于卵磷脂;水杨酸及其衍生物、羟基羧酸或酮羧酸及其酯、内酯及其盐;蒽林、二十碳-5,8,11-三烯酸及其酯或酰胺、或米诺地尔(minoxidil)及其衍生物、或其混合物。
本发明另一方面涉及一种化妆用组合物或药物组合物,其包含化妆品上或药学上有效量的至少一种根据通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,且另外含有化妆品上或药学上有效量的至少一种防晒剂,诸如且不限于尤其是氨基苯甲酸酯、肉桂酸酯、水杨酸酯、二苯酰甲烷的衍生物、樟脑的衍生物、三嗪的衍生物、二苯甲酮的衍生物、β,β’-二苯基丙烯酸酯的衍生物、苯并三唑的衍生物、苄基丙二酸酯的衍生物、苯并咪唑的衍生物、咪唑啉、苯并烯丙基的衍生物、对氨基苯甲酸的衍生物、聚合物和硅酮、烷基苯乙烯的衍生物、金属氧化物的纳米颜料,诸如且不限于二氧化钛或氧化锌或基于碳纳米管的滤光剂(filter)、或其混合物。
本发明另一另外方面涉及一种化妆用组合物或药物组合物,其包含化妆品上或药学上有效量的至少一种根据通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,且另外含有化妆品上或药学上有效量的至少一种来自Hsp家族的蛋白质,诸如且不限于尤其是Hsp70,包括Hsp72和Hsp73、Hsp60、Hsp27或Hsp90。
应用
本发明的一方面涉及至少一种通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐在制备用于治疗和/或护理皮肤、粘膜和/或毛发的化妆用组合物或药物组合物中的用途。
本发明另一方面涉及至少一种通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐在制备用于治疗和/或护理通过刺激Hsp蛋白质合成而改善或预防的那些病况、病症和/或疾病的化妆用组合物或药物组合物中的用途,所述Hsp蛋白质尤其是分子量介于20kDa至110kDa间的Hsp家族蛋白质,尤其是介于40kDa至100kDa间的分子量,更优选地分子量包含介于60kDa至80kDa间的Hsp蛋白质,特别是分子量为70kDa的Hsp或Hsp70。
在优选实施方案中,通过刺激热激蛋白合成而改善或预防的病况、病症和/或疾病选自大疱性表皮松解症和脱发症组成的组,包括癌症化疗所导致的脱发症。
根据优选的实施方案,本发明涉及式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐在制备用于治疗和/或护理皮肤、粘膜和/或毛发的化妆用组合物或药物组合物中的用途,所述组合物减轻、延迟和/或阻止因UV辐射、热应激、氧化应激、渗透压冲击、炎症、缺氧、暴露于污染物、缺少营养和缺乏水合作用所诱导的细胞损坏。
根据优选的实施方案,本发明涉及式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐在制备用于治疗和/或护理皮肤和/或毛发的化妆用组合物或药物组合物中的用途,所述组合物减经、延迟或阻止老化和/或光老化的迹象。
类似地,本发明涉及式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐在制备用于治疗和/或护理皮肤、粘膜和/或毛发的化妆用组合物或药物组合物中的用途,所述组合物刺激创伤的愈合和/或表皮再生,优选因糖尿病所致的那些创伤。
根据优选的实施方案,本发明涉及式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐在制备用于治疗和/或护理皮肤和/或毛发的化妆用组合物或药物组合物中的用途,所述组合物延迟和/或阻止脱发或诱导毛发生长。
用于治疗和/或护理皮肤、粘膜和/或毛发的化妆用组合物或药物组合物的实例尤其包括乳霜、复合乳剂,诸如且不限于水包油型和/或水包硅酮型乳剂、油包水型和/或硅酮包水型乳剂、水/油/水型或水/硅酮/水型乳剂和油/水/油型或硅酮/水/硅酮型乳剂、无水组合物、水性分散液、油、奶状物、香脂、泡沫、洗剂、凝胶、乳凝胶、水醇溶液、水二醇溶液、水凝胶、搽剂、浆液、皂、洗发剂、润发乳、浆液、多糖膜、软膏、摩丝、润发油、粉剂、棒剂、笔剂和喷雾剂或气雾剂(喷雾剂),包括免冲洗型和冲洗型制剂、绷带、纱布、T恤、袜子、裤袜、内衣、腰带、手套、尿布、卫生巾、敷料、床罩、擦拭物、粘性贴片、非粘性贴片、闭合型贴片、微电贴片或面罩、化妆产品,诸如粉底,诸如液态粉底(fluid foundation)和粉饼(compact foundation)、卸妆液(make-up removal lotion)、卸妆乳(make-upremoval milk)、眼部遮瑕膏(under-eye concealer)、眼影(eye shadow)、唇膏(lipstick)、护唇品(lip protector)、唇彩(lip gloss)和唇粉(lip powder)。
含有本发明肽的组合物可如所需地施用于皮肤或可经口服或肠胃外施用以治疗和/或护理病况、病症和/或疾病。
本发明涉及的化妆用组合物或药物组合物可经由离子电渗、超声波导入、电穿孔、微电贴片、机械压力、渗透压梯度、闭塞治疗、微注射或借助压力的无针注射诸如借助氧压注射或其任何组合的方式施用至皮肤,以实现本发明肽的更大渗透。
本发明另一方面涉及一种治疗和/或护理皮肤、粘膜和/或毛发的方法,其包括施用化妆品上或药学上有效量的至少一种通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,优选以含有它们的化妆用组合物或药物组合物的形式。
本发明另一方面涉及一种用于治疗和/或护理哺乳类,优选人类的通过刺激热激蛋白优选Hsp70合成而改善或预防的那些病况、病症和/或疾病的方法;其包括施用有效量的至少一种通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,优选地以含它们的化妆用组合物或药物组合物的形式。
在优选的实施方案中,通过刺激热激蛋白合成而改善或预防的病况、病症和/或疾病选自大疱性表皮松解症和脱发症组成的组,包括因癌症化疗所导致的脱发症。
本发明另一另外的方面涉及一种治疗和/或护理皮肤、粘膜和/或毛发的方法,其减轻、延迟和/或阻止因UV辐射、热应激、氧化应激、渗透压冲击、炎症、缺氧、暴露于污染物、缺少营养和缺乏水合作用所致的细胞损坏;其包括施用有效量的至少一种通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,优选地以含它们的化妆用组合物或药物组合物的形式。
根据另外的方面,本发明涉及减少、延迟和/或阻止老化和/或光老化的迹象的治疗和/或护理,其包括施用有效量的至少一种通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,优选地以含它们的化妆用组合物或药物组合物的形式。
本发明另一另外的方面涉及一种用于治疗和/或护理皮肤和/或粘膜的方法,其刺激创伤的愈合和/或表皮再生,优选地因糖尿病所致的创伤,其包括施用有效量的至少一种通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,优选地以含它们的化妆用组合物或药物组合物的形式。
本发明另一另外的方面涉及一种用于治疗和/或护理皮肤和/或毛发的方法,其延迟和/或阻止脱发或诱导毛发生长,其包括施用有效量的至少一种通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,优选地以含它们的化妆用组合物或药物组合物的形式。
在更具体的方面,本发明的治疗和/或护理通过局部或经皮施加来进行;优选地,局部或经皮施加经由离子电渗、超声波导入、电穿孔、机械压力、渗透压梯度、闭塞治疗、微注射、借助压力的无针注射、借助微电贴片或其任何组合来进行。
在另一具体的方面,该治疗和/或护理经由口服施用来进行。
另一特别方面中,该治疗和/或护理经由肠胃外施用来进行。
施加或施用频率可取决于各个受治疗者的需求和待治疗或护理的病况、病症或疾病的严重性而极大地改变,建议的施加或施用范围从每月一次至每日十次,优选每周一次至每日四次,更优选每周三次至每日三次,再更优选每日一次或两次。
本文提供的以下特定实施例说明本发明的性质。所包括的这些实施例仅以说明为目的,不应解释为对本文所要求保护的本发明构成限制。
实施例
一般方法
所有试剂和溶剂均为合成质量,且未经另外处理地使用。
缩写
氨基酸所用的缩写依照在Eur.J.Biochem.(1984)138:9-37和J.Biol.Chem.(1989)264:633-673中所规定的IUPAC-IUB联合委员会的生化命名规则。
树脂;Ac,乙酰基;DNA,脱氧核糖核酸;Adpoc,1-(1-金刚烷基)-1-甲基乙氧基-羰基;All,烯丙基;Alloc,烯丙氧基羰基;AM,2-[4-氨基甲基-(2,4-二甲氧基苯基)]苯氧基乙酸;Arg,精氨酸;Asn,天冬酰胺;Boc,叔丁氧基羰基;2-BrZ,2-溴苄基氧基羰基;Bzl,苄基;Cbz,羧基苄基;cHx,环己基;2-氯三苯甲基树脂;ClZ,2-氯苄基;cps,厘泊;C-末端,羧基末端;DCM,二氯甲烷;Dde,N-[1-(4,4-二甲基-2,6-二氧代亚环己-1-基)乙基;2,6-diClZ,2,6-二氯苄基;DIEA,N,N-二异丙基乙胺;DIPCDI,N,N’-二异丙基碳二亚胺;Dmab,4-(N-[1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基丁基]氨基)苄基;DMEM,Dulbecco修改的Eagle培养基;DMF,N,N-二甲基甲酰胺;DMSO,二甲亚砜;Dnp,2,4-二硝基苯酚;DPPC,二棕榈酰基磷脂酰胆碱;EDTA,乙二胺四乙酸;ELISA,酶联免疫吸附测定;equiv,当量;ESI-MS,电喷射电离质谱;Fm,芴甲基;Fmoc,9-芴甲氧基羰基;Gln,谷氨酰胺;grp,葡萄糖调节蛋白质;His,组氨酸;HOAt,1-羟基-7-氮杂苯并三唑;HOBt,1-羟基苯并三唑;HPLC,高效液相色谱;Hsp,热激蛋白;INCI,国际化妆品成分命名法;ivDde,1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基-丁基;kDa,千道尔顿;Leu,亮氨酸;MBHA,对甲基二苯甲胺;MeCN,乙腈;MeOH,甲醇;MLV,多层囊泡;MPD,最低着色剂量;Mtt,甲氧基三苯甲基或甲基三苯甲基;MTT,3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑鎓;N-末端,氨基末端;PAL,5-(4-氨基甲基-3,5-二甲氧基苯氧基)戊酸;Palm,棕榈酰基;PBS,磷酸盐缓冲盐水;pNZ,对硝基苄氧基羰基;Pro,脯氨酸;rpm,每分钟转数;qs,适量;q.s.p.,适量至;tBu,叔丁基;Teoc,2-(三甲基硅烷基)乙氧基羰基;TFA,三氟乙酸;THF,四氢呋喃;TIS,三异丙基硅烷;Troc,2,2,2-三氯乙氧基羰基;Trt,三苯基甲基或三苯甲基;Trt,三苯甲基;Tyr,酪氨酸;ULV,单层囊泡;UV,紫外线;Z,苄氧基羰基。
化学合成
所有合成方法在装配有多孔聚乙烯盘的聚丙烯注射筒或装配有多孔板的反应器中进行。通过抽气移除溶剂和可溶试剂。以哌啶-DMF(2:8,v/v)(1×1min,1×5min,5mL/g树脂)移除Fmoc基团[Lloyd-Williams P.,Albericio F.和Giralt E.(1997)“Chemical Approaches to the Synthesis ofPeptides and Proteins(合成肽和蛋白的化学方法)”CRC,Boca Raton,FL,USA]。在脱保护、偶合和再次脱保护的各阶段之间以DMF(3×1min)进行洗涤,每次各使用10mL溶剂/g树脂。以3mL溶剂/g树脂进行偶合反应。偶合的控制藉由进行茚三酮试验[Kaiser E.,Colescott R.L.,Bossinger C.D.和Cook P.I.(1970)“Color test for detection of free terminal amino groups inthe solid-phase synthesis of peptides(固相肽合成中用于检测自由端氨基的显色试验)”Anal.Biochem.34:595-598]或四氯苯醌(chloranil)试验[Christensen T.(1979)“A qualitative test for monitoring couplingcompleteness in solid-phase peptide synthesis using chloranil(用于在固相肽合成中利用四氯苯醌监测偶合完成程度的定性检验)”Acta Chem.Scand.33B:763-766]而进行。所有合成反应和洗涤在室温下进行。
HPLC色谱分析以Shimadzu设备(Kyoto,Japan)使用使用恒温于30℃反相柱进行(250×4.0mm,Kromasil C8,5μm,Akzo Nobel,Sweden)。使用乙腈(+0.07%TFA)在水中(+0.1%TFA)的梯度以流速1mL/min进行洗脱,且在220nm处进行检测。
实施例1
获得Fmoc-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-O-2-ClTrt-其中AA1为-L-His-;AA2为-L-His-、-L-Leu-或-L-Pro-;AA3为-L-Leu-;AA4为-L-Arg-或-L-Asn-;且n、m、p和q为0。
将5.71gFmoc-L-Arg(Pbf)-OH或5.25gFmoc-L-Asn(Trt)-OH(8.8mmol;1当量)溶于添加有1.3mL DIEA(7.6mmol;0.86当量)的55mL DCM中,偶合于干燥2-氯三苯甲基树脂(5.5g;8.8mmol)上。搅拌5min,之后添加2.5mL DIEA(14.6mmol;1.66当量)。允许混合物反应40min。残留氯基通过以4.4mL MeOH处理而封闭。
N-末端Fmoc基团如一般方法中所述的脱保护,将7.77gFmoc-L-Leu-OH(22mmol;2,5当量)在DIPCDI(3.39mL,22mmol,2.5当量)和HOBt(3.37g,22mmol,2.5当量)存在下使用DMF作溶剂偶合至肽基树脂持续1小时。随后如一般方法中所述的洗涤树脂,重复Fmoc基团的脱保护处理,以偶合下一个氨基酸。依照所述实验方案,顺序地偶合13.63gFmoc-L-His(Trt)-OH、7.77gFmoc-L-Leu-OH或7.42gFmoc-L-Pro-OH(22mmol;2.5当量);且之后13.63g Fmoc-L-His(Trt)-OH(22mmol;2.5当量),每次均在3.37g HOBt(22mmol;2.5当量)和3.39mL DIPCDI(22mmol;2.5当量)存在下偶合。
合成后,肽基树脂以DCM(5×3min)洗涤和以氮流干燥。
实施例2
获得Fmoc-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-AM-MBHA-其中AA1为-L-His-;AA2为-L-His-、-L-Leu-或-L-Pro-;AA3为-L-Leu-;AA4为-L-Arg-或-L-Asn-;且n、m、p和q为0。
官能度为0.73mmol/g(5mmol)的6.85g Fmoc-AM-MBHA树脂根据所述一般方法以哌啶-DMF处理,以移除Fmoc基团。16.22gFmoc-L-Arg(Pbf)-OH或14.92g Fmoc-L-Asn(Trt)-OH(25mmol;5当量)在DIPCDI(3.85mL;25mmol;5当量)和HOBt(3.85g;25mmol;5当量)存在下使用DMF为溶剂掺入到脱保护的树脂上持续1小时。
随后如一般方法中所述的洗涤树脂,重复Fmoc基团的脱保护处理,以偶合下一个氨基酸。依先前所述方法,顺序地偶合8.84g Fmoc-L-Leu-OH(25mmol;5当量);15.49g Fmoc-L-His(Trt)-OH、8.84g Fmoc-L-Leu-OH或8.44g Fmoc-L-Pro-OH(25mmol;5当量);且之后15.49gFmoc-L-His(Trt)-OH(25mmol;5当量),每次均在3.85g HOBt(25mmol;5当量)和3.85mL DIPCDI(25mmol;5当量)存在下偶合。
合成后,肽基树脂以DCM(5×3min)洗涤和以氮流干燥。
实施例3
移除Fmoc N-末端保护基的一般方法。
将实施例1和2所得的肽基树脂的N-末端Fmoc基团如一般方法中所述的脱保护(20%哌啶于DMF中,1×5min+1×20min)。肽基树脂以DMF(5×1min)、DCM(4×1min)、二乙醚(4×1min)洗涤且在真空下干燥。
实施例4
将R1棕榈酰基引入实施例3所得肽基树脂上的方法。
在1.53gHOBt(10mmol;10当量)和1.54mL DIPCDI(10mmol;10当量)存在下将预溶于DMF(1mL)中的2.56g棕榈酸(10mmol;10当量)添加至1mmol实施例3所得的肽基树脂。允许其反应15小时,之后树脂以THF(5×1min)、DCM(5×1min)、DMF(5×1min)、MeOH(5×1min)、DMF(5×1min)、THF(5×1min)、DMF(5×1min)、DCM(4×1min)、乙醚(3×1min)洗涤,在真空下干燥。
实施例5
将R1乙酰基引入实施例3所得肽基树脂上的方法。
将1mmol实施例3所得的肽基树脂在25当量DIEA存在下,使用5mLDMF作为溶剂以25当量乙酸酐处理。允许其反应30min,之后以DMF(5×1min)、DCM(4×1min)、二乙醚(4×1min)洗涤肽基树脂,在真空下干燥。
实施例6
从实施例3、4和5所得的肽基树脂的聚合物支撑物裂解的方法
将200mg实施例3、4和5获得的干燥肽基树脂于室温在搅拌下以5mLTFA:TIS:H2O(90:5:5)处理2小时。将滤液收集于50mL冷二乙醚上,经装配有多孔聚乙烯盘的聚丙烯注射器过滤,以50mL二乙醚洗涤5次。在真空下干燥最终沉淀物。
将所得肽在MeCN(+0.07%TFA)在H2O(+0.1%TFA)中的梯度进行HPLC分析,显示所有情况下的纯度超过80%。所得肽的身份以ESI-MS确认。
实施例7
聚合物支撑物的裂解方法和以经取代的R2胺的官能化:获得Ac-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-NH-(CH2)15-CH3,其中AA1为-L-His-;AA2为-L-His-、-L-Leu-或-L-Pro-;AA3为-L-Leu-;AA4为-L-Arg-或-L-Asn-;且n、m、p和q为0。
具有完全经保护的侧链的肽Ac-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-OH是通过以3mL3%TFA的DCM溶液处理在真空下在KOH存在下预先干燥的150mg实施例5的肽基树脂Ac-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-O-2-ClTrt-持续5min来获得。将滤液收集于50mL冷二乙醚上且该处理重复三次。乙醚溶液于减压下在室温下蒸干,将沉淀物再溶于50%MeCN/H2O中且冻干。将10mg所得粗制肽在烧瓶中称重,添加3当量十六烷基胺和25mL无水DMF。添加2当量DIPCDI,于47℃在磁力搅拌下留置反应。由HPLC监测反应,直至初始产物消失,反应于24至48小时后完成。将溶剂蒸干,且以DCM共蒸发两次。将所得残留物[具有完全经保护的侧链的Ac-Wn-Xm-AA1-AA2-AA3-AA4-Yp-Zq-NH-(CH2)15-CH3]再溶于25mLTFA-DCM-苯甲醚的混合物(49:49:2)并留置于室温反应30min。添加250mL冷二乙醚,于减压下蒸发溶剂,再以乙醚进行两次另外的共蒸发。将残留物溶于50%MeCN/H2O的混合物中且冷冻干燥。
所得肽于MeCN(+0.07%TFA)在H2O(+0.1%TFA)中的梯度中进行HPLC分析,所有情况下显示超过65%纯度。所得肽的身份以ESI-MS确认。
实施例8
Hsp70合成刺激测定。
Hsp70合成刺激是在人类角质细胞系中在本发明肽存在下评价。接种细胞(106个细胞/6孔板)并于DMEM中培育24小时,之后于培养基中添加肽至200μM,培育另外16至24小时。使用10μM蛋白酶体抑制剂MG-132作为阳性对照且使用载体(培养基)作为阴性对照。在培育阶段后,以PBS洗涤细胞,溶解且于12,000rpm在4℃离心10min。收集上清液,通过按照市售试剂盒(DuoSet IC人类/小鼠总HSP70ELISA试剂盒,R&D SystemsInc.)的实验方案进行竞争型ELISA测定而确定Hsp70水平。
表2提供肽的细节,显示Hsp70刺激水平值大于15%。Hsp70水平按照平均基础值标准化。
实施例9
Ac-L-His-L-Pro-L-Leu-L-Arg-OH和Ac-L-His-L-Leu-L-Leu-L-Arg-OH在人类角质细胞培养物中的光保护效力的测定。
将人类角质细胞于96孔板中保持培养24小时以形成单层,细胞于黑暗中在37℃在培养基中与0.1mMAc-L-His-L-Pro-L-Leu-L-Arg-OH、Ac-L-His-L-Leu-L-Leu-L-Arg-OH或载体(培养基)预先培养2小时。之后以800J/m2能量的UVB照射细胞。带有载体的对照板于室温下保持于黑暗中不照射持续相同时间。照射阶段之后,细胞培养基以新鲜培养基替换,细胞培育另外24小时。通过MTT方法确定细胞存活力,将5mg/mLMTT溶液添加至各孔,使板在37℃培养4小时,之后移除培养基,添加100μLDMSO,使板于室温搅拌15min。各孔的光密度在分光光度计中在570nm下测量。
光保护效力通过比较经Ac-L-His-L-Pro-L-Leu-L-Arg-OH或Ac-L-His-L-Leu-L-Leu-L-Arg-OH处理的细胞所得的存活力与经照射和未经照射的对照细胞的响应而确定。
实施例10
含Palm-L-His-L-Pro-L-Leu-L-Asn-NH2的化妆用组合物的制备。
将A相于适当的反应器中溶解。在另一反应器中混合B相,此相由305[INCI:水剂(水)、聚丙烯酰胺、C13-C14链异烷烃、Laureth-7]、308[INCI:辛酸/癸酸甘油三酯]和椰油酸乙基己酯形成,在均质化后,于搅拌下将其缓缓添加至A相上。随后于搅拌下添加C相,之后于35℃添加F相。以D相将pH调整至5.5至7.0,添加E相。
实施例11
含Ac-L-His-L-Leu-L-Leu-L-Arg-OH的脂质体的制备。
将二棕榈酰基磷脂酰胆碱(DPPC)称重且溶于氯仿。于真空下蒸发溶剂,直至得到磷脂薄层(fine phospholipid layer),将此层于55℃以所需浓度的肽水溶液(含)处理而水化,得到MLV脂质体。将MLV脂质体浸入55℃超声浴中,持续8次间隔5min的2min循环而得到ULV脂质体。ULV脂质体的尺寸藉由将其通过高压挤压系统而缩小。
实施例12
含有Ac-L-His-L-Leu-L-Leu-L-Arg-OH的脂质体凝胶形式的组合物的制备。
将实施例11的脂质体在轻度搅拌下分散于含有防腐剂(EDTA、咪唑烷基脲和)的水中。添加200[INCI:水剂(水)、甘油、聚丙烯酸甘油酯]且轻轻搅拌直至得到均匀混合物。
实施例13
含Ac-L-His-L-Pro-L-Leu-L-Arg-OH的面霜组合物。
制备
-混合A相组分且加热至70℃。
-混合B相组分且加热至70℃。
-以均质器(Silverson)搅拌将C相添加至B相持续5分钟。
-以均质器逐渐地将A相添加至B相与C相的混合物中,且保持均质化15分钟。
-于轻度搅拌下开始冷却至30至35℃。于50℃添加D相。保持搅拌。于35至38℃添加已预先溶解的E相和F相。
实施例14
含Ac-L-His-L-Leu-L-Leu-L-Arg-OH的混合胶束的组合物的制备。
将A相的成分称重于适于完全样品的容器中,稍微温热至约30℃,以帮助溶解某些防腐剂。接着,添加B相组分,于适当搅拌下均质化。
之后于连续搅拌下添加C相,之后于缓慢搅拌下添加D相(CG110[INCI:水剂(水)、辛基/癸基葡萄糖苷])以避免发泡。
将pH调至5.5至6.5。
实施例15
含Palm-L-His-L-Pro-L-Leu-L-Asn-NH2的微米乳剂组合物。
B相的成分称重于适于完全样品的容器中。接着,将D相添加至B相且于连续搅拌下均质化。随后将A相添加至混合物。最后,添加C相。
实施例16
含有Ac-L-His-L-Leu-L-Leu-L-Arg-OH的毛细洗剂组合物。
将A相组分于搅拌下缓缓混合。于搅拌下缓缓添加B相至A相,直至完成均质化。
Claims (24)
1.一种通式(I)的肽,
其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,特征在于:
AA1为-His-;
AA2选自-Leu-和-Pro-组成的组;
AA3为-Leu-;
AA4为-Arg-;
W、X、Y和Z彼此独立地选自编码的氨基酸和非编码的氨基酸组成的组;
n、m、p和q具有0的值;
R1选自由下列所组成的组:H和R5-CO-,其中R5选自由取代或未取代的C1-C24烷基所组成的组;
R2选自由下列所组成的组:-NR3R4和-OR3,其中R3和R4是H。
2.如权利要求1所述的肽,特征在于:R1选自由下列所组成的组:H、乙酰基、叔丁酰基、己酰基、2-甲基己酰基、辛酰基、癸酰基、月桂酰基、肉豆蔻酰基、棕榈酰基、硬脂酰基、油酰基和亚油酰基。
3.如权利要求1所述的肽,特征在于:R1选自由下列所组成的组:H、乙酰基、月桂酰基、肉豆蔻酰基和棕榈酰基,AA2为-L-Leu-,AA4为-L-Arg-,且R2为-NR3R4或-OR3,其中R3和R4是H。
4.如权利要求1所述的肽,特征在于:R1选自由下列所组成的组:H、乙酰基、月桂酰基、肉豆蔻酰基和棕榈酰基,AA2为-L-Pro-,AA4为-L-Arg-,且R2为-NR3R4或-OR3,其中R3和R4是H。
5.如权利要求1至4任一项所述的肽在制备用于治疗和/或护理皮肤、粘膜和/或毛发的化妆用组合物或药物组合物中的用途。
6.如权利要求5所述的肽的用途,其中所述化妆用组合物或药物组合物用于治疗和/或护理通过刺激至少一种热激蛋白合成而改善或预防的皮肤、粘膜和/或毛发的那些状况、紊乱和/或疾病。
7.如权利要求6所述的肽的用途,特征在于:所述热激蛋白具有介于20kDa至110kDa之间的分子量。
8.如权利要求7所述的肽的用途,特征在于:所述热激蛋白为Hsp70。
9.如权利要求5所述的肽的用途,特征在于:所述治疗和/或护理减少、延迟和/或阻止因为UV辐射、热应激、氧化应激、渗透压冲击、炎症、缺氧、暴露于污染物、缺少营养和缺乏水合作用所造成的细胞受损。
10.如权利要求5所述的肽的用途,其中所述治疗和/或护理减少、延迟和/或阻止老化的迹象。
11.如权利要求10所述的肽的用途,其中所述老化是光老化。
12.如权利要求5所述的肽的用途,其中所述治疗和/或护理延迟和/或阻止脱发或诱导毛发生长。
13.如权利要求5所述的肽的用途,其中所述治疗和/或护理刺激创伤的愈合和/或表皮再生。
14.如权利要求13所述的肽的用途,其中所述创伤是糖尿病导致的。
15.如权利要求6所述的肽的用途,其中所述病症和/或疾病选自大疱性表皮松解症和脱发症组成的组。
16.一种制备如权利要求1至4任一项所述的通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐的方法,特征在于:所述方法在固相或溶液中进行。
17.一种化妆用组合物或药物组合物,包含化妆品上或药学上有效量的至少一种如权利要求1至4任一项所述的通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐,及至少一种化妆品上或药学上可接受的赋形剂或佐剂。
18.如权利要求17所述的组合物,特征在于:所述通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐以相对于所述组合物总重量计介于0.000001重量%至20重量%之间的浓度存在。
19.如权利要求17所述的组合物,特征在于:所述通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐被掺入选自由下列所组成的组的化妆品或药物递送系统和/或持续释放系统中:脂质体、毫米胶囊、微米胶囊、纳米胶囊、海绵、环糊精、囊泡、胶束、毫米球、微米球、纳米球、脂质球、微米乳剂、纳米乳剂、毫米粒子、微米粒子、纳米粒子和纳米构造的脂质载体或被吸附于选自由下列所组成的组的固态有机聚合物或固态无机支撑物上:滑石、膨润土、硅石、淀粉和麦芽糊精。
20.如权利要求17所述的组合物,特征在于:所述组合物以选自由下列所组成的组的制剂呈现:霜、无水组合物、水性分散液、油、奶状物、香脂、泡沫、洗剂、凝胶、搽剂、皂、洗发剂、润发乳、浆液、软膏、摩丝、粉剂、棒剂、笔剂、喷雾剂、气雾剂、胶囊、片剂、颗粒剂、咀嚼胶、溶液、悬浮液、乳状液、多糖膜、冻胶和明胶。
21.如权利要求20所述的组合物,其中所述浆液是糖浆。
22.如权利要求17所述的组合物,特征在于:所述组合物被掺入选自由下列所组成的组的产品中:眼部遮瑕膏、粉底、卸妆液、卸妆乳、眼影、唇膏、唇彩、护唇品和唇粉。
23.如权利要求17所述的组合物,特征在于:所述通式(I)的肽、其立体异构体、其混合物和/或其化妆品上或药学上可接受的盐被掺入织物或医疗装置中。
24.如权利要求17所述的组合物,特征在于:所述组合物还包含化妆品上或药学上有效量的至少一种选自由下列所组成的组的佐剂:热激蛋白、热激蛋白合成刺激剂、乙酰胆碱受体聚集抑制剂、肌肉收缩抑制剂、抗胆碱能剂、弹性蛋白酶抑制剂、基质金属蛋白酶抑制剂、黑色素合成刺激或抑制剂、增白剂或脱色剂、色素原形成剂、仿晒剂、抗老化剂、NO-合酶抑制剂、5α-还原酶抑制剂、赖氨酰基-和/或脯氨酰基羟化酶抑制剂、抗氧化剂、自由基清除剂和/或抗空气污染剂、抗糖化剂、抗组织胺剂、抗寄生虫剂、乳化剂、润肤剂、有机溶剂、液体推进剂、皮肤调理剂、α羟酸、β羟酸、湿润剂、表皮水解酶、维生素、氨基酸、蛋白质、颜料、胶化聚合物、增厚剂、表面活性剂、软化剂、防皱剂、能够减少或治疗眼袋的剂、去角质剂、抗微生物剂、刺激真皮或表皮大分子合成和/或能够抑制或阻止其降解的剂、胶原合成刺激剂、弹性蛋白合成刺激剂、核心蛋白聚糖合成刺激剂、层粘连蛋白合成刺激剂、防御素合成刺激剂、水通道蛋白合成刺激剂、透明质酸合成刺激剂、纤连蛋白合成刺激剂、乙酰化酶合成刺激剂、刺激脂质和角质层的成分神经酰胺、脂肪酸的合成的剂、胶原降解抑制剂、弹性蛋白降解抑制剂、丝氨酸蛋白酶抑制剂、成纤维细胞增殖刺激剂、角质细胞增殖刺激剂、脂肪细胞增殖刺激剂、黑色素细胞增殖刺激剂、角质细胞分化刺激剂、脂肪细胞分化刺激剂、乙酰胆碱酯酶抑制剂、皮肤松弛剂、糖胺聚糖合成刺激剂、抗角化过度剂、粉刺溶解剂、抗牛皮癣剂、DNA修复剂、DNA防护剂、稳定剂、止痒剂、敏感性肌肤治疗和/或护理剂、皮肤紧实剂、除妊娠纹剂、粘合剂、皮脂产生调节剂、解脂剂或脂肪分解刺激剂、抗脂肪小丘剂、止汗剂、愈合刺激剂、愈合辅助剂、表皮再生刺激剂、表皮再生辅助剂、细胞因子生长因子、镇定剂、消炎剂和/或止痛剂、麻醉剂、作用于微循环的剂、血管生成刺激剂、血管通透性抑制剂、静脉张力剂、作用于细胞代谢的剂、改善真皮-表皮接合的剂、毛发生长诱导剂、毛发生长抑制剂或延缓剂、脱发延缓剂、防腐剂、香料、螯合剂、植物提取物、精油、海洋提取物、从生物发酵过程获得的剂、无机盐、细胞提取物和防晒剂、或其混合物。
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Families Citing this family (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI655213B (zh) * | 2012-07-13 | 2019-04-01 | 目立康股份有限公司 | 自我組織化肽衍生物的製造方法 |
RU2514003C1 (ru) * | 2012-11-14 | 2014-04-27 | Ольга Ивановна Бурлуцкая | Комплексное косметическое средство |
US9023399B2 (en) | 2012-11-16 | 2015-05-05 | NU Technology, LLC | Water-soluble anti-inflammatory cream with natural ingredients base |
US20140142522A1 (en) * | 2012-11-16 | 2014-05-22 | NU Technology, LLC | Moist dressing with honeycomb pattern and drain channels |
EP2740484A1 (en) * | 2012-12-05 | 2014-06-11 | Lipotec, S.A. | Compounds useful in the treatment and/or care of the skin, hair and/or muccous membranes and their cosmetic or pharmaceutical compositions |
KR102041803B1 (ko) * | 2013-01-10 | 2019-11-07 | (주) 수파드엘릭사 | 염증 또는 피부노화의 예방 또는 치료용 약학 조성물 및 염증 또는 피부노화 개선용 화장료 조성물 |
AU2014234400B2 (en) | 2013-03-21 | 2017-11-16 | Sanofi-Aventis Deutschland Gmbh | Synthesis of hydantoin containing peptide products |
ES2624961T3 (es) | 2013-03-21 | 2017-07-18 | Sanofi-Aventis Deutschland Gmbh | Síntesis de productos de péptido que contienen imida cíclica |
TWI516272B (zh) | 2013-06-05 | 2016-01-11 | 財團法人工業技術研究院 | 應用於生髮之方法及醫藥組成物 |
KR101511425B1 (ko) * | 2013-07-10 | 2015-04-13 | 한솔바이오 주식회사 | 나노 구조체 |
US9402876B2 (en) | 2013-11-27 | 2016-08-02 | Industrial Technology Research Institute | Method and pharmaceutical composition for hair growth |
CN111671658A (zh) | 2014-01-27 | 2020-09-18 | 考司美德制药株式会社 | 遮瑕贴及其制造方法、肌肤美白护肤方法和抗痘护肤方法 |
EP2990027A1 (en) * | 2014-09-01 | 2016-03-02 | Institut Curie | Skin whitening peptide agents |
JP2017527580A (ja) * | 2014-09-12 | 2017-09-21 | ザ プロクター アンド ギャンブル カンパニー | 老化防止スキンケア組成物及びレジメン |
SG11201703214SA (en) | 2014-10-31 | 2017-05-30 | Lubrizol Advanced Mat Inc | Thermoplastic polyurethane film for delivery of active agents to skin surfaces |
KR20230125097A (ko) | 2014-12-04 | 2023-08-28 | 마리 케이 인코포레이티드 | 트리플루오로아세틸 트리펩타이드-2를 포함하는 국소피부 케어 조성물 |
RU2608901C2 (ru) * | 2015-02-10 | 2017-01-26 | Рамиль Рафаилевич Рахматуллин | Персонализированное косметическое средство |
CA3003871A1 (en) | 2015-11-05 | 2017-05-11 | Lubrizol Advanced Materials, Inc. | Thermoformable dual network hydrogel compositions |
KR20180086510A (ko) * | 2015-12-18 | 2018-07-31 | 마리 케이 인코포레이티드 | 국소 화장품 제형 |
KR20180114911A (ko) | 2016-02-04 | 2018-10-19 | 앨러스틴 스킨케어, 인크. | 침습 및 비침습 시술적 피부 관리를 위한 조성물 및 방법 |
US10449349B2 (en) * | 2016-12-14 | 2019-10-22 | L'oreal | Systems, devices, and methods including encapsulated cosmetics |
KR102093209B1 (ko) | 2017-05-11 | 2020-03-25 | (주)케어젠 | 이소트레티노인과 펩타이드의 결합체 |
KR20200036007A (ko) | 2017-08-03 | 2020-04-06 | 앨러스틴 스킨케어, 인크. | 피부 이완 및 신체 윤곽의 개선을 위한 조성물 및 방법 |
WO2020092851A1 (en) * | 2018-10-31 | 2020-05-07 | George Lambridis | Dry composition for removing oils from hair and methods for fabrication of dry compositions |
US11147749B2 (en) | 2017-10-04 | 2021-10-19 | Mana Products, Inc. | Dry composition for removing oils from hair and methods for fabrication of dry compositions |
KR101898441B1 (ko) | 2018-03-28 | 2018-09-13 | (주)셀트리온 | 에피제네틱 조절 기능을 갖는 펩타이드를 포함하는 화장료 조성물 및 약학적 조성물 |
TWI795561B (zh) * | 2018-05-02 | 2023-03-11 | 大江生醫股份有限公司 | 芒果果實萃取物及由其所得生物活性物質用於護膚及保健的用途 |
WO2020009548A1 (ko) * | 2018-07-06 | 2020-01-09 | 애니젠 주식회사 | 펩타이드 복합체를 유효성분으로 함유하는 미세먼지 제거 또는 흡착용 화장료 조성물 |
US11103455B2 (en) | 2018-08-02 | 2021-08-31 | ALASTIN Skincare, Inc. | Liposomal compositions and methods of use |
EP3906013A1 (en) | 2019-01-02 | 2021-11-10 | The Procter & Gamble Company | Skin care compositions containing peptide compound and aphanothece sacrum exopolysaccharide extract |
KR102065171B1 (ko) | 2019-02-20 | 2020-01-13 | (주)케어젠 | 대기오염물질에 의한 피부 손상 방지 및 항노화용 펩타이드와 이의 용도 |
KR102203424B1 (ko) * | 2019-03-15 | 2021-01-15 | (주)진셀팜 | Zdhhc13 유래 생리활성 펩타이드, 및 이의 용도 |
US20220142899A1 (en) * | 2019-03-28 | 2022-05-12 | Lipotrue, S.L. | Peptides and compositions for use in cosmetics |
IT201900008364A1 (it) * | 2019-06-07 | 2020-12-07 | Espikem S R L | Peptidi bioattivi e composizioni che li comprendono |
CN111793116B (zh) * | 2020-07-20 | 2022-03-04 | 广州和佳润颜医药有限公司 | 一种透皮七肽、含有该透皮七肽的美容组合物及制备方法 |
KR20230149286A (ko) * | 2020-09-24 | 2023-10-26 | 가부시키가이샤 아쥬반트 홀딩스 | 육모제 |
US11571378B2 (en) | 2021-01-22 | 2023-02-07 | The Procter & Gamble Company | Skin care composition and method of using the same |
US11771637B2 (en) | 2021-01-22 | 2023-10-03 | The Procter & Gamble Company | Skin care composition and method of using the same |
CN115340592B (zh) * | 2021-09-09 | 2024-07-09 | 禾美生物科技(浙江)有限公司 | 一种活性肽及其相关用途 |
CN115990240A (zh) | 2021-10-20 | 2023-04-21 | 富比积生物科技股份有限公司 | 寡肽在治疗牙龈发炎、牙龈萎缩及修复口腔黏膜中的用途 |
KR20240086709A (ko) * | 2022-11-18 | 2024-06-19 | (주)케어젠 | 피부 상태 개선 활성을 갖는 펩타이드 및 이의 용도 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101102815A (zh) * | 2004-10-11 | 2008-01-09 | 格莱亚皮肤有限公司 | 用于治疗皮肤病学状况的装置 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2504535B1 (fr) | 1981-04-28 | 1987-08-14 | Choay Sa | Disaccharides derives d'un acide uronique et d'une glucosamine et compositions pharmaceutiques les contenant pour le controle de la coagulation sanguine |
GB8519416D0 (en) | 1985-08-01 | 1985-09-04 | Unilever Plc | Oligosaccharides |
GB8630721D0 (en) | 1986-12-23 | 1987-02-04 | Unilever Plc | Cosmetic compositions |
GB8806892D0 (en) | 1988-03-23 | 1988-04-27 | Unilever Plc | Lactams their synthesis & use in cosmetic compositions |
GB8830019D0 (en) | 1988-12-22 | 1989-02-15 | Unilever Plc | Cosmetic composition |
GB8913708D0 (en) | 1989-06-14 | 1989-08-02 | Unilever Plc | Cosmetic composition |
US5348945A (en) | 1990-04-06 | 1994-09-20 | Wake Forest University | Method of treatment with hsp70 |
US5942494A (en) | 1995-10-06 | 1999-08-24 | The Trustees Of Columbia University In The City Of New York | Stimulation of gene expression and synthesis of heat shock protein 72/73 (HSP 70) |
US20040228816A1 (en) | 1998-12-30 | 2004-11-18 | Carine Nizard | Cosmetic or dermatological composition containing an active agent which stimulates synthesis of the protein HSP 32 in the skin |
CA2386499A1 (en) * | 1999-10-05 | 2001-04-12 | Epimmune, Inc. | Inducing cellular immune responses to human immunodeficiency virus-1 using peptide and nucleic acid compositions |
US20010034042A1 (en) * | 2000-01-20 | 2001-10-25 | Srivastava Pramod K. | Complexes of peptide-binding fragments of heat shock proteins and their use as immunotherapeutic agents |
US7405080B2 (en) | 2000-03-23 | 2008-07-29 | Voellmy Richard W | Compositions and methods relating to prevention of chemotherapy-induced alopecia |
EP1387678A1 (en) * | 2001-05-03 | 2004-02-11 | Max-Planck-Gesellschaft Zur Förderung Der Wissenschaften E.V. | Compounds that inhibit hsp90 and stimulate hsp70 and hsp40, useful in the prevention or treatment of diseases associated with protein aggregation and amyloid formation |
US7186693B2 (en) * | 2001-08-16 | 2007-03-06 | Kimberly - Clark Worldwide, Inc. | Metalloproteinase inhibitors for wound healing |
JP2005508999A (ja) | 2001-11-14 | 2005-04-07 | ラレナ | アマノリ属紅藻の抽出物を含有する製品およびそれの細胞保護剤としての使用 |
FR2834887B1 (fr) | 2002-01-24 | 2007-06-15 | Vincience | Utilisation d'un extrait d'artemia pour le traitement des peaux agees |
FR2876906B1 (fr) | 2004-10-21 | 2007-04-13 | Biolog Vegetale Yves Rocher Sa | Utilisation cosmetique de mangiferine |
US20060134048A1 (en) | 2004-12-22 | 2006-06-22 | Douglas Shander | Reduction of hair growth |
BRPI0710637A2 (pt) | 2006-04-21 | 2012-03-13 | Wyeth | análise do perfil de expressão diferencial de fenótipos de cultura celular e seus usos |
WO2007123489A1 (en) * | 2006-04-21 | 2007-11-01 | Agency For Science, Technology And Research | Method for recombinant protein production in cho cells |
US20100119533A1 (en) | 2007-03-07 | 2010-05-13 | Cornelius Joseph Clancy | Polynucleotides and Polypeptides Identified by IVIAT Screening and Methods of Use |
-
2009
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101102815A (zh) * | 2004-10-11 | 2008-01-09 | 格莱亚皮肤有限公司 | 用于治疗皮肤病学状况的装置 |
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CL2012001029A1 (es) | 2012-09-14 |
ES2621542T3 (es) | 2017-07-04 |
US8993716B2 (en) | 2015-03-31 |
CN102711790A (zh) | 2012-10-03 |
AU2010310108B2 (en) | 2015-02-05 |
WO2011047868A3 (en) | 2011-06-16 |
ES2358829B1 (es) | 2012-06-25 |
RU2012118581A (ru) | 2013-11-27 |
ES2358829A1 (es) | 2011-05-16 |
BR112012009264A2 (pt) | 2021-09-08 |
TWI499425B (zh) | 2015-09-11 |
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