CN102015764B - 包含金属蛋白酶抑制剂的化妆品组合物或药物组合物 - Google Patents
包含金属蛋白酶抑制剂的化妆品组合物或药物组合物 Download PDFInfo
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- CN102015764B CN102015764B CN200980114319.4A CN200980114319A CN102015764B CN 102015764 B CN102015764 B CN 102015764B CN 200980114319 A CN200980114319 A CN 200980114319A CN 102015764 B CN102015764 B CN 102015764B
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Abstract
通式(I)的肽:R1AA1-AA2-AA3-AA4-R2、其立体异构体、其混合物或其化妆品上或药学上可接受的盐,获得它们的方法,含有它们的化妆品组合物或药物组合物,和它们用于治疗和/或护理由基质金属蛋白酶(MMP)过表达或MMP活性增加引起的皮肤、粘膜和/或头皮的那些病症、疾病和/或病状的用途。
Description
发明领域
本发明涉及能抑制基质金属蛋白酶(MMP)活性的肽,和涉及含有所述肽的化妆品组合物或药物组合物,所述肽可用于治疗和/或护理皮肤、粘膜和/或头皮,优选地用于治疗和/或护理MMP过表达或MMP活性增加引起的皮肤、粘膜和/或头皮的那些病症、疾病和/或病状。
发明背景
皮肤由两层组成:表皮和真皮。外层是主要由角质形成细胞、黑素细胞和格汉斯细胞组成的表皮,它的基本功能是保持体内水分,充当防御有害化学物质及病原体物质的屏障,并进行细胞更新过程。由成纤维细胞、脂肪细胞和巨噬细胞形成的内层真皮通过基膜与表皮紧密相连,它含有许多提供触觉和温度感觉的神经末梢。真皮还容纳毛囊、汗腺、皮脂腺、顶泌腺和血管,它的主要功能之一是保持皮肤的弹性和外观。
真皮还包括细胞外基质,细胞外基质由一组主要功能是保持皮肤结构的胞外蛋白(纤维蛋白、糖蛋白和蛋白多糖)形成。正确的组织功能和发育取决于细胞外基质的正确形成和取决于它的组份的正确调节[Wiberg C,Klatt A.R.,Wegener R.,Paulsson M.,Bateman J.F.,Heinegard D.和MorgelinM.(2003)“Complexes of matrilin-1 and biglycan or decorin connect collagenVI microfibrils to both collagen II and aggrecan(母系蛋白-1与双糖链蛋白多糖或核心蛋白聚糖复合物将胶原蛋白VI微纤维连接到胶原蛋白II和聚集蛋白聚糖)”J.Biol.Chem.278:37698-37704]。细胞外基质中两种最重要的纤维蛋白是胶原蛋白和弹性蛋白,其负责组织的机械性能如抗张力、压力、伸展和扭转的能力。蛋白多糖具有结构和代谢功能,而糖蛋白和蛋白多糖一起充当基质成分和细胞之间的连接桥梁[Aumailley M.和Gayraud B.(1998)“Structure and biological activity of the extracellular matrix(细胞外基质的结构和生物活性)”J.Mol.Med.76:253-265;Culav E.M.,Clark CH.和Merrilees M.J.(1999)“Connective tissues:matrix composition and itsrelevance to physical therapy(***:基质组成和其与物理治疗的关联)”Phys.Ther.79:308-319;Scott J.E.(2003)“Elasticity in extracellular matrix'shape modules'of tendon,cartilage,etc.Asliding proteoglycan-filament model(腱、软骨等的细胞外基质‘形状模块’中的弹性。滑动的蛋白多糖-纤丝模型)”J.Physiol.553:335-343]。
胶原蛋白是在哺乳动物中构成25%的总蛋白质质量的细胞外基质的纤维蛋白家族。胶原蛋白分为超过20个家族,它们都具有在不同组织中完成特定功能的独特特征。
胶原蛋白的主要特征是富集甘氨酸和脯氨酸的三条多肽链缔合形成的螺旋状结构。其氨基酸组成上的改变导致功能障碍和其机械性能丧失[Culav E.M.,Clark CH.和Merrilees M.J.(1999)“Connective tissues:matrixcomposition and its relevance to physical therapy(***:基质组成和其与物理治疗的关联)”Phys.Ther.79:308-319]。这些多肽链可相互缔合并形成原纤维,其在成熟组织中具有10-300nm的直径和高达数百微米的长度。这些原纤维经常被加入主结构,如缆束,当胶原蛋白纤维的直径为数微米时可通过电子显微术看到。这个过程被称为原纤维形成[Aumailley M.和Gayraud B.(1998)“Structure and biological activity of the extracellular matrix(细胞外基质的结构和生物活性)”J.Mol.Med.76:253-265]。并不是所有的胶原蛋白都具有形成原纤维的能力;只有被称为纤维胶原的I型、II型、Ⅲ型、Ⅴ型和XI型胶原蛋白具有形成原纤维的能力。
成熟的真皮基本上由I型、III型和V型纤维胶原形成。I型胶原蛋白占真皮的总胶原蛋白的80-90%。通常,I型胶原蛋白纤维具有直径较大的特点,这与它能承受较大的机械荷载相关。III型胶原蛋白参与组织延展,随着时间的流逝它被I型胶原蛋白分子取代,该过程是成熟皮肤不如年轻皮肤延展性好的部分原因。V型胶原蛋白联合I型和III型胶原蛋白调整原纤维的直径[“The Biology of the Skin(皮肤生物学)”,FreinkelR.K.和WoodleyD.T.编著The Parthenon Publishing Group,2001;Culav E.M.,Clark CH.和Merrilees M.J.(1999)“Connective tissues:matrix composition and itsrelevance to physical therapy(***:基质组成和其与物理治疗的关联)”Phys.Ther.79:308-319]。
胶原蛋白纤维处于不断更新的过程,但是这种更新随着年龄而下降,导致真皮变薄。此外,虽然胶原蛋白纤维组织化提供带有极大阻力的胶原蛋白网络,胶原蛋白纤维对某些被称为基质金属蛋白酶(MMP)的酶敏感。MMP属于蛋白水解酶家族(内切蛋白酶),其含有与3个半胱氨酸残基配位的锌原子和在其活性中心的1个甲硫氨酸残基,可共同地降解来自细胞外基质和基膜的高分子成分为中性pH(胶原蛋白、弹性蛋白等)。
基质金属蛋白酶家族根据其结构的相似性及其底物特异性分类[Woessner J.F.(1991)“Matrix metalloproteinases and their inhibitors inconnective tissue remodeling(***重塑中的基质金属蛋白酶和其抑制剂)”Faseb J.5:2145-2154;Miyazaki K.和Higashi S.(1996)“Matrixmetalloproteinases:their structures and functions,with special reference totheir roles in tumor invasion and metastasis(基质金属蛋白酶:其结构和功能,特别关于其在肿瘤浸润和转移中的作用)”Seikagaku68:1791-1807]。MMP家族中存在以下:降解纤维状胶原蛋白的胶原酶(MMP-1或间质胶原酶、MMP-8或中性粒细胞胶原酶、MMP-3或胶原酶3),降解IV胶原蛋白或任何其他形式的变性胶原蛋白的明胶酶(MMP-2或明胶酶A72kDa、和MMP-9或明胶酶B92kDa),活性广谱针对细胞外基质蛋白如糖蛋白如纤连蛋白或层粘连蛋白和蛋白多糖以及其他的基质降解酶(MMP-3或基质降解酶1、MMP-10或基质降解酶2、和MMP-11或基质降解酶3),基质溶解因子(MMP-7),金属弹性蛋白酶(MMP-12)或膜金属蛋白酶(MMP-14、MMP-15、MMP-16和MMP-17)。
金属蛋白酶以失活方式(酶原)产生和分泌,其随后在细胞外环境中通过丧失其序列的前肽区域而被活化。这种蛋白质家族的成员可相互活化。MMP活性调节可采取不同的方式:调节基因表达(转录和传递),调节失活过程活化或对活化过程局部作用。
MMP在不同的皮肤、粘膜和/或头皮病症和疾病中发挥重要的作用,其中存在胞外蛋白的降解和破坏[Kahari V.M.和Saarialho-Kere U.(1997)“Matrix metalloproteinases in skin(皮肤中的基质金属蛋白酶)”Exp.Dermatol.6:199-213]。在描述的其中存在***细胞中MMP过表达或MMP活性增加的不同病状中,我们发现有慢性溃疡[Miyoshi H.,KanekuraT.,Aoki T.和Kanzaki T.(2005)“Beneficial effects of tissue inhibitor ofmetalloproteinases-2(TIMP-2)on chronic dermatitis(金属蛋白酶-2的组织抑制剂(TIMP-2)对慢性皮炎的有益作用)”J.Dermatol.32:346-353]、银屑病[Flisiak I.,Mysliwiec H.和Chodynicka B.(2005)“Effect of psoriasistreatment on plasma concentrations of metalloproteinase-1 and tissue inhibitorofmetalloproteinase-1(银屑病治疗对金属蛋白酶-1和金属蛋白酶-1的组织抑制剂的血浆浓度的影响)”J.Eur.Acad.Dermatol.Venereol.9:418-421;Suomela S.,Kariniemi A.L.,ImpolaU.,KarvonenS.L,Snellman E.,UurasmaaT.,Peltonen J.,Saarialho-Kere U.(2003)“Matrix metalloproteinase-19isexpressed by keratinocytes in psoriasis(银屑病中基质金属蛋白酶-19被角质形成细胞表达)”ActaDerm.Venereol.83:108-114]、口腔疾病如牙龈炎和牙周炎[Reynolds J.J.和Meikle M.C.(1997)“The functional balance ofmetalloproteinases and inhibitors in tissue degradation:relevance to oralpathologies(金属蛋白酶和抑制剂在组织降解中的功能平衡:与口腔疾病的关联)”J.R.Coll.Surg.Edinb.42:154-160]、皮肤癌[Ntayi C,Hornebeck W.和Bernard P.(2004)“Involvement of matrix metalloproteinases(MMPs)incutaneous melanoma progression(基质金属蛋白酶(MMP)牵涉在皮肤黑素瘤进展中)”Pathol.Biol.(Paris)52:154-159;Kerkela E.和Saarialho-KereU.(2003)“Matrix metalloproteinases in tumor progression:focus on basal andsquamous cell skin cancer(肿瘤进展中的基质金属蛋白酶:集中在基底和鳞状细胞皮肤癌上)”Exp.Dermatol.12:109-125]、和肿瘤浸润和转移[SatoH.,Takino T.和Miyamori H.(2005)“Roles of membrane-type matrixmetalloproteinase-1 in tumor invasion and metastasis(膜型基质金属蛋白酶在肿瘤浸润和转移中的作用)”Cancer Sci.96:212-217]。
MMP还在其中细胞外基质被降解或重建的不同的生理状况中发挥关键作用,如细胞外基质水解重构,包括发育期间的组织形态建成、组织修复和血管生成[Kahari V.M.和Saarialho-KereU.(1997)“Matrixmetalloproteinases in skin(皮肤中的基质金属蛋白酶)”Exp.Dermatol.6:199-213]。以一种特定的方式,MMP在***重构中具有关键作用[Abraham D.,Ponticos M.和Nagase H.(2005)“Connective tissue remodeling:cross-talk between endothelins and matrix metalloproteinases(***重构:内皮素与基质金属蛋白酶之间的相互沟通)”Curr.Vase.Pharmacol.3:369-379],例如胶原蛋白通过MMP降解使得皮肤看起来皱褶和松弛。
同样地,MMP参与皮肤老化。包括暴露在紫外线(UV)辐射的不同的因素产生胶原蛋白降解,以及它带来的对皮肤结构和/或坚实性的所有后果,特别是对暴露于日光照射的皮肤区域,如脸、耳朵、颈、头皮、臂和手。
已研究了与在UVA光和/或UVB光长期暴露(重复照射)或高度暴露(强烈照射)相关的皮肤损伤,特别地已知:
-UVB光(290-300nm,总UV光的5%)具有更高能的波长,特别是作用于表皮细胞的DNA而影响表皮细胞(角质形成细胞)。
-UVA光(320-400nm,总UV光的95%)具有较强的渗透级,也作用于表皮细胞如成纤维细胞,它们的作用间接产生自由基。
而且,长期暴露在UV辐射,特别是UVA和/或UVB辐射刺激MMP特别是基质金属弹性蛋白酶1型(MMP-1)表达[Fisher G.J.,DattaS.C,Talwar H.S.,Wang Z.Q.,Varani J.,KangS.和Voorhees J.J.(1996)“Molecularbasis of sun-induced premature skin ageing and retinoid antagonism(阳光引起的过早皮肤老化和类视色素拮抗的分子基础)”Nature379:335-339;FisherG.J.,Wang Z.Q.,Datta S.C,Varani J.,Kang S.和Voorhees J.J.(1997)“Pathophysiology of Prematur Skin Aging Induced by Ultraviolet Light(紫外线引起的过早皮肤老化的病理生理学)”New Eng.J.Med.337:14191429;Fisher G.J.,Choi H.C,Bata-Csorgo Z,Shao Y.,Datta S.,Wang Z.Q.,Kang S.和Voorhees J.J.(2001)“Ultraviolet irradiation increases matrixmetalloproteinase-8protein in human skin in vivo(紫外线照射在体内增加人类皮肤中的基质金属蛋白酶-8蛋白)”J.Invest.Dermatol.117:219-226]。这是光诱导的皮肤老化(或光老化)的组分之一[Rittie L和Fisher G.J.(2002)“UV-light-induced signal cascades and skin aging(紫外线诱导的信号级联和皮肤老化)”AgeingRes.Rev.1:705-720]。此外,已知MMP-1、MMP-2和MMP-9的活性随着年龄而增加,这种增加连同细胞生长减速导致按时间顺序的皮肤老化[EP1005333B1]。类似地,吸烟者的皮肤也具有其中MMP过表达的过早老化的外观[Lahmann C,Bergemann J.,Harrison G.和YoungA.R.(2001)“Matrix metalloproteinase-1 and skin aging in smokers(吸烟者的基质金属蛋白酶-1和皮肤老化)”Lancet357:935-936]。
另一与***中MMP过表达或MMP活性增加相关的皮肤和/或头皮病状或疾病是痤疮[Papakonstantinou E.,Aletras A.J.,Glass E.,Tsogas P.,Dionyssopoulos A.,Adjaye J.,Fimmel S.,Gouvousis P.,Herwig R.,Lehrach H.,Zouboulis CC.和Karakiulakis G.(2005)“Matrix metalloproteinases ofepithelial origin in facial sebum of patients with acne and their regulation byisotretinoin(痤疮患者面部皮脂中上皮来源的基质金属蛋白酶和其被异维A酸调整)”J.Invest.Dermatol.125:673-684]。描述了感染痤疮的皮肤具有高水平的MMP-1。
同样地,红斑痤疮是其中也牵涉MMP的皮肤和/或头皮病状或疾病。红斑痤疮的特征是血管生成增加和炎症。血管生成是指新血管形成的过程,其包括在良性病症如红斑痤疮和恶性过程如癌中。存在于组织细胞外基质中的基质降解酶由于它们允许新血管渗透基质而促进血管生成。MMP代表一种参与这些过程的酶[Sapadin A.N.,FleischmajerR.(2006)“Tetracyclines:Nonantibiotic properties and their clinical implications(四环素类:非抗生素特征和其临床暗示)”J.Am.Acad.Derm.54:258-265]。
具有皮炎包括接触性皮炎和特应性皮炎的人也具有高水平的一些MMP[Herouy Y.,Mellios P.,Bandemir E.,Dichmann S.,Nockowski P.,E.和Norgauer J.(2001)“Inflammation in stasis dermatitis upregulates MMP-1,MMP-2and MMP-13expression(停滞性皮炎中的炎症上调MMP-1、MMP-2和MMP-13表达)”J.Dermatol.Sci.25:198-205;Devillers A.C.,vanToorenenbergen A.W.,Klein Heerenbrink G.J.,Muldert P.G.和Oranje A.P.(2007)“Elevated levels of plasma matrix metalloproteinase-9in patients withatopic dermatitis:a pilot study(特应性皮炎患者中血浆基质金属蛋白酶-9水平升高:预备试验)”Clin.Exp.Dermatol.32:311-313;Miyoshi H.,Kanekura T.,AokiT.和KanzakiT.(2005)“Beneficial effects of tissue inhibitorof metalloproteinases-2(TIMP-2)on chronic dermatitis(金属蛋白酶-2的组织抑制剂(TIMP-2)对慢性皮炎的有益作用)”J.Dermatol.32:346-353]。“皮炎”定义为引起炎症的那些皮肤病症、疾病或病状,包括接触性皮炎、特应性皮炎、敏感性皮肤和湿疹。还已知MMP牵涉在毛囊周围基质的降解中,因此牵涉在脱发中。特别地,细胞因子和表皮生长因子刺激MMP-9在发根的下部上皮层产生,秃发中观察到此机制控制毛状囊退化[Jarrousse F.,Boisnic S.,Branchet M.C.,Beranger J.Y.,Godeau G.,Breton L,Bernard B.A.和Mahe Y.F.(2001)“Identification of clustered cells in human hair follicleresponsible for MMP-9gelatinolytic activity:consequences for the regulationof hair growth(鉴定人类毛囊中负责MMP-9分解明胶活性的成簇细胞:调整毛发生长的结果)”Int.J.Dermatol.40:385-392]。因此,脱发过程中过表达MMP的抑制可以有效地延缓和甚至防止脱发[EP1076549B1]。
并且,MMP活性与在含有胶原蛋白的组织中瘢痕形成有关。“瘢痕形成”定义为由于皮肤上以前的创伤或由于含有胶原蛋白的组织的愈合过程而形成形态异常的胶原蛋白结构。
愈合过程由三个阶段组成:(1)炎症,(2)组织形成和(3)组织重构。愈合过程中的一个必要阶段是细胞外基质降解:为了使细胞在创伤区域增殖和再生创伤区域,必需降解细胞外基质。这种降解是通过MMP。不同MMP之间的平衡调节愈合过程阶段,已描述MMP活性过高导致慢性溃疡。例如,MMP-8的过表达可与腿慢性溃疡的发病机理相关。同样地,糖尿病性溃疡的特征是长期炎症、胶原蛋白合成下降和高MMP水平。
多数瘢痕由不规则组织的胶原蛋白纤维及过量的胶原蛋白组成。瘢痕具有不同的原因(事故、手术、皮肤疾病、烧伤、痤疮、感染和常见事故),但并非所有的瘢痕都相同。不同种类的瘢痕可分为:
-平坦暗淡瘢痕:由于人体自然愈合过程形成。
-凹陷瘢痕:由皮肤连接到更深的结构,如肌肉,或由于内部组织脂肪的损失而形成。这些瘢痕凹进皮肤中,通常是创伤的结果。
-肥厚瘢痕:当愈合过程期间身体产生过量的胶原蛋白时出现。这些瘢痕高出皮肤表面,含有不规则组织的胶原蛋白。
-瘢痕疙瘩:由于愈合过程期间胶原蛋白的生成不平衡而形成。这些瘢痕不仅高出皮肤表面,而且它们延伸超越了原伤口的边界,可继续无限地生长。
-痤疮瘢痕:受痤疮感染的皮肤中形成。该瘢痕可以是凹陷的或成为瘢痕疙瘩。曾经得过水痘的人可能有类似的瘢痕。
-伸展瘢痕:当愈合过程期间愈合伤口周围的皮肤处于张力下时发生。最初,瘢痕可能看起来正常但是可在数周或数月的时间内变宽和变薄。这可发生在伤口接近关节并在移动期间中被拉伸时,或可由于整体健康欠佳或营养不良所致的愈合不良。
-萎缩纹:当皮肤迅速伸展时例如妊娠或***生长突增期间出现。
因此,无论从病理的角度,如纤维化过程期间愈合,还是从化妆品的角度,如软化痤疮或萎缩纹所致瘢痕外观的情况,减少皮肤瘢痕是需要的。
还已描述了脂肪细胞增殖和分化期间,MMP被过表达[Traurig M.T.,Permana P.A.,Nair S.,Kobes S.,Bogardus C.和Baier LJ.(2006)“Differentialexpression of matrix metalloproteinase3(MMP3)in preadipocytes/stromalvascular cells from nonobese nondiabetic versus obese nondiabetic PimaIndians(基质金属蛋白酶3(MMP3)在来自非肥胖非糖尿病或肥胖非糖尿病的印地安人的前成脂肪细胞/基质血管细胞中的差异表达)”Diabetes55:3160-3165]。用若干特异性抑制剂抑制MMP活性阻止了脂肪细胞分化。一个特别有趣的事实是MMP抑制剂能降低脂肪细胞培养物中脂肪生成标记(甘油三酯)的积聚[Demeulemeester D.,Collen D.和Lijnen H.R.(2005)“Effect of matrix metalloproteinase inhibition on adipose tissue development(基质金属蛋白酶抑制对脂肪组织发育的影响)”Biochem.Biophys.Res.Commun.329:105-110]。因此,MMP抑制剂可被开发成抗脂肪团剂,并有助于减少橘皮皮肤外观。
MMP活性还造成***和血管周围的细胞外基质解体。血管周围的基质劣化允许被动的血管舒张,其转而成为毛细管可见性、或毛细血管扩张、或酒糟鼻(couperosis)。此外,这种微毛细管被动扩张可导致局部血管爆裂,其可转而成为眶周区域的眼袋或黑眼圈。而且,MMP对脉壁的机械性能具有影响,其可使静脉脆弱和从而导致形成静脉曲张。
除了MMP与组织基质降解有关,认为与***或基底膜基质的异常代谢同时发生的不同的病状中也牵涉MMP,所述病况如关节炎(类风湿关节炎、骨关节炎等)、骨病(骨质疏松症等)、异位血管生成、多发性硬化、肿瘤转移和组织溃疡(角膜、胃、表皮等)[EP0927161B1]。因此,MMP抑制剂可有效治疗和预防组织基质的异常代谢引起的那些病状。
另外,已广泛接受MMP活性调节对于基底膜和细胞外基质保护,及对于预防和改善老化迹象是非常重要的。在本发明的上下文中,术语“老化”是指随着岁月的流逝(慢性老化),或由于暴露于阳光(光老化),或由于环境因素如烟草烟雾、严寒或有风的天气条件、化学性污染物或污染所致皮肤经历的变化,老化包括所有可见的外部变化及那些通过触摸能感觉到的变化,如例如和不限于,形成皮肤间断面如皱纹、细纹、皲裂、不均匀或粗糙,毛孔尺寸增大,失去弹性,失去坚实性,失去平滑度,变形后失去复原的能力,皮肤下垂如面颊下垂、出现眼袋或双下巴以及其他,皮肤颜色改变如斑点、发红、眼袋、或出现色素沉着过度区如年龄痕迹或雀斑以及其他,异常分化,角化过度,弹性组织变性,角化症,橘皮皮肤,失去胶原蛋白构造,及角质层、真皮、表皮、脉管***(例如出现蜘蛛网状血管或毛细血管扩张)或接近皮肤的那些组织以及其他的其他组织学改变。
在化妆品和药物领域已鉴定出许多有效的用作MMP抑制剂的化合物和植物提取物,在文献中存在关于MMP、与它们过表达或它们活性增加相关的病症和可用于抑制它们的不同的化合物和植物提取物家族的不同书目修订本。在现有技术中已描述了控制MPP活性的不同的模拟法,包括小分子[Levy D.E.,Lapierre E.,Liang W.,Ye W.,Lange CW.,Li X.,Grobelny D.,Casabonne M.,Tyrrell D.,Holme K.,Nadzan A.和Galardy R.E.(1998)“Matrix metalloproteinase inhibitors:A structure activity study(基质金属蛋白酶抑制剂:结构活性研究)”J.Med.Chem.41:199-223;Wojtowicz-Praga S.M.,Dickson R.B.和Hawkins M.J.(1997)“Matrixmetalloproteinase inhibitors(基质金属蛋白酶抑制剂)”Investigational newDrugs15:61-75;Duivenvuurden W.C.M.,Hirte H.W.和Singh G.(1997)“Use oftetracycline as an inhibitor of matrix metalloproteinase activity secreted byhuman bone metastasizing cancer cells(四环素用作人类骨转移癌细胞分泌的基质金属蛋白酶活性的抑制剂)”Invasion and Metas.17:312-322]、肽抑制剂[Odake S.,Monta Y.和Morikawa T.(1994)“Inhibition of matrixmetalloproteinases by peptidyl hydroxamic acids(肽基异羟肟酸对基质金属蛋白酶的抑制)”Biochem.Biophys.Res.Comm.199:1442-1446]或针对MMP的抗体[Su J-L,Becherer D.,Edwards C,Bukhart W.,McMgeehan G.M.和Champion B.R.(1995)“Monoclonal antibodies against human collagenase andstromelysin(针对人类胶原酶和基质溶素的单克隆抗体)”Hybridoma14:383-390]。化妆品工业做出了重大努力以抵消MMP活性和MMP引起的细胞外基质组分的年龄相关的功能丧失。皮肤重要的生物分子如胶原蛋白在产生和降解之间的平衡随着老化向降解过程进展,导致例如真皮逐渐变薄和解体,产生真皮松弛和随后形成皱纹。因此,那些允许延缓或防止细胞外基质降解的方法对成熟皮肤或对老化和/或光老化皮肤具有潜在的有利影响;允许它们部分恢复由于年龄或日光照射和/或环境污染物已丧失的机械性能(弹性、柔韧性和坚实性),因此显示出具有较少皱纹和更光滑皮肤的更好外观。同样地,MMP抑制对化妆品领域除了延缓老化和/或光老化以外的应用也是一个重要方面,所述应用如例如调控毛发生长[EP1076549B1]或治疗伤口[US2004/0127420A1;US2003/0166567A1]。
尽管存在大量的现有化合物和/或提取物,仍需要鉴定新的更有效的和选择性的MMP抑制剂。
在本发明中描述了模拟内源性MMP抑制剂(TIMP,基质金属蛋白酶组织抑制剂)的起作用方式有效抑制MMP的肽。本发明的肽序列不包含在MMP酶原序列中,所述MMP酶原序列如US2004/0127420A1和US2003/0166567A1描述的肽序列。在不同酶或具有酶活性的序列中发现在羧基-末端(C-末端)没有瓜氨酸残基的类似本发明的肽的序列[WO2004/033668A2;WO99/00489A1];在现有技术中没有任何线索提示本发明的肽作为MMP抑制剂的功效,所以本领域的技术人员不能推断出肽抑制MMP的性质。
发明描述
本发明提供了上述问题的解决方案。意外地,本发明的申请人发现了其氨基酸序列并非来自天然产物的某些肽能够抑制MMP,主要是人类MMP-1、MMP-2、MMP-3和/或MMP-9。
因此,本发明的肽提供了用于治疗和/或护理皮肤、粘膜和/或头皮的简单和有效和无风险的解决方案,所述解决方案包括给哺乳动物在皮肤、粘膜和/或头皮上应用或口服或肠胃外施用具有通式(I)的肽,如下所述。
在第一个方面,本发明涉及根据通式(I)的肽、
R1-AA1-AA2-AA3-AA4-R2
(I)
其立体异构体、其混合物或其化妆品上或药学上可接受的盐,特征在于:
AA1是-Arg-;
AA2选自由-His-和-Asn-组成的组;
AA3AA2选自由-His-和-Arg-组成的组;
AA4是-Cit-;
R1选自由以下组成的组:H、取代或非取代的非环状脂族基、取代或非取代的脂环基、取代或非取代的杂环基、取代或非取代的杂芳烷基、取代或非取代的芳基、取代或非取代的芳烷基,和R5-CO-;且
R2选自由-NR3R4、-OR3和-SR3组成的组;其中R3和R4独立地选自由以下组成的组:H、取代或非取代的非环状脂族基、取代或非取代的脂环基、取代或非取代的杂环基、取代或非取代的杂芳烷基、取代或非取代的芳基、和取代或非取代的芳烷基;
其中R5选自由以下组成的组:H、取代或非取代的非环状脂族基、取代或非取代的脂环基、取代或非取代的芳基、取代或非取代的芳烷基、取代或非取代的杂环基、和取代或非取代的杂芳烷基。
本发明的另一个方面是获得通式(I)的这些肽的方法。
本发明的另一个方面涉及化妆品组合物或药物组合物,所述组合物包含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、其混合物或其化妆品上或药学上可接受的盐,和至少一种化妆品上或药学上可接受的赋形剂或佐剂。
在另一个方面,本发明涉及通式(I)的肽、其立体异构体、其混合物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/或头皮的化妆品组合物或药物组合物中的用途。
发明详述
本发明的肽是非来源于天然产物的肽;所述的肽具有重要的MMP抑制活性,因此它们对于治疗和/或护理MMP过表达或MMP活性增加引起的皮肤、粘膜和/或头皮的那些病症、疾病和/或病状是有用的。
定义
为了更好地理解本发明,特此包括本发明上下文中使用的一些术语和表述的含义。
在本说明书中,氨基酸使用的缩写词遵循在Eur.J.Biochem.(1984)138:9-37和J.Biol.Chem.(1989)264:633-673中指定的IUPAC-IUB联合会的生物化学命名法的规则。
因此,例如Gly表示NH2-CH2-COOH,Gly-表示NH2-CH2-CO-,-Gly表示-NH-CH2-COOH,和-Gly-表示-NH-CH2-CO-。因此,短线表示肽键,当它被放置到符号的右边时从氨基酸(在本文表示为常规的非离子化形式)的1-羧基中去除OH,当它被放置到符号的左边时从氨基酸的2-氨基中去除H;两种修饰可应用于相同的符号(参见表1)。
表1
在本说明书中,缩写“Ac-”用于表示乙酰基(CH3-CO-),且缩写“Palm-”用于表示棕榈酰基(CH3-(CH2)14-CO-)。
在本发明中使用的术语“非环状脂族基”包括,例如和不限于,直链或支链烷基、烯基和炔基。
术语“烷基”是指直链或支链饱和基,具有1和24之间,优选地1和16之间,更优选地1和14之间,甚至更优选地1和12之间,甚至更优选地1、2、3、4、5或6个碳原子,且通过单键与分子其余部分结合,包括,例如和不限于,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-甲基己基及类似物。
术语“烯基”是指具有2和24之间,优选地2和16之间,更优选地2和14之间,甚至更优选地2和12之间,甚至更优选地2、3、4、5或6个碳原子,有一个或多个碳-碳双键,优选地有1、2或3个共轭或非共轭碳-碳双键,且通过单键与分子其余部分结合的基团,包括,例如和不限于,乙烯基、油烯基、亚油烯基及类似物。
术语“炔基”是指具有2和24之间,优选地2和16之间,更优选地2和14之间,甚至更优选地2和12之间,甚至更优选地2、3、4、5或6个碳原子,有一个或多个共轭或非共轭碳-碳三键,优选地有1、2或3个共轭或非共轭碳-碳三键,且通过单键与分子其余部分结合的基团,包括,例如和不限于,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,如例如1-戊炔基及类似物。
本发明使用的术语“脂环基”包括,例如和不限于,环烷基、环烯基或环炔基(cycloalkylnyl)。
术语“环烷基”是指饱和的单环或多环脂族基,其具有3和24之间,优选地3和16之间,更优选地3和14之间,甚至更优选地3和12之间,甚至更优选地3、4、5或6个碳原子,且通过单键与分子其余部分结合,包括,例如和不限于,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、十二氢萉及类似物。
术语“环烯基”是指非芳香族的单环或多环脂族基,其具有5和24之间,优选地5和16之间,更优选地5和14之间,甚至更优选地5和12之间,甚至更优选地5或6个碳原子,有一个或多个碳-碳双键,优选地有1、2或3个共轭或非共轭碳-碳双键,且通过单键与分子其余部分结合,包括,例如和不限于,1-环戊烯-1-基及类似物。
术语“环炔基”是指非芳香族的单环或多环脂族基,其具有5和24之间,优选地5和16之间,更优选地5和14之间,甚至更优选地5和12之间,甚至更优选地5或6个碳原子,有一个或多个碳-碳三键,优选地1、2或3个共轭或非共轭碳-碳三键,且通过单键与分子其余部分结合,包括,例如和不限于,1-环己炔-1-基及类似物。
术语“芳基”是指芳族基,其具有6和30之间,优选地6和18之间,更优选地6和10之间,甚至更优选地6或10个之间的碳原子,包含1、2、3或4个芳香核,通过碳-碳键或稠合结合,包括,例如和不限于,苯基、萘基、二苯基、茚基、菲基或氨茴内酐以及其他,或芳烷基。
术语“芳烷基”是指以芳族基取代的烷基,具有7和24个之间的碳原子,包括,例如和不限于,-(CH2)1-6-苯基、-(CH2)1-6-(1-萘基)、-(CH2)1-6-(2-萘基)、-(CH2)1-6-CH(苯基)2及类似物。
术语“杂环基”是指3-10元烃环,其中环的一个或多个原子,优选地环的1、2或3个原子是除碳以外的元素,如可以是饱和或不饱和的氮、氧或硫。对于本发明,杂环基可以是单环、二环或三环的环***,其可包括稠环***;及在杂环基中氮、氧或硫原子可任选地被氧化;氮原子可任选地被季铵化,且杂环基可以是部分地或完全地饱和的或是芳香族的。术语杂环基更优选地是指5或6元的环。
术语“杂芳烷基”是指以取代或非取代的芳香族杂环基取代的烷基,其中烷基具有1至6个碳原子,芳香族杂环基具有2至24个之间的碳原子和1至3个不同于碳的原子,包括,例如和不限于,-(CH2)1-6-咪唑基、-(CH2)1-6-***基、-(CH2)1-6-噻吩基、-(CH2)1-6-呋喃基、-(CH2)1-6-吡咯烷基及类似物。
如在本技术领域所理解的,在上面定义的基团上可存在某些程度的取代。因此,本发明的任一基团上可存在取代。关于本发明基团上的取代基的文献表明,特定的基可在一个或多个可利用的位置被一个或多个取代基所取代,优选地在1、2或3个位置,更优选地在1或2个位置,和甚至更优选地在1个位置。所述的取代基包括,例如和不限于,C1-C4烷基,羟基,C1-C4烷氧基,氨基,C1-C4氨烷基,C1-C4羰氧基,C1-C4氧羰基,卤素如氟、氯、溴和碘,氰基,硝基,叠氮基,C1-C4烷磺酰基,硫醇,C1-C4烷硫基,芳氧基如苯氧基、-NRb(C=NRb)NRbRc,其中Rb和Rc独立地选自由以下组成的组: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。
本发明的化合物
本发明的化合物由通式(I)所定义
R1-AA1-AA2-AA3-AA4-R2
(I)
其中R1、AA1、AA2、AA3、AA4和R2具有先前所定义的含义。
R1和R2基团结合到肽序列的氨基-末端(N-末端)和羧基-末端(C-末端)。
根据本发明的实施方案,R1选自由H或R5-CO-组成的组,其中R5选自由以下组成的组:取代或非取代的C1-C24烷基、取代或非取代的C2-C24烯基、取代或非取代的C2-C24炔基、取代或非取代的C3-C24环烷基、取代或非取代的C5-C24环烯基、取代或非取代的C5-C24环炔基、取代或非取代的C6-C30芳基、取代或非取代的C7-C24芳烷基、取代或非取代的3-10元杂环基、以及具有2至24个碳原子和1至3个不同于碳的原子并具有1至6个碳原子的烷基链的取代或非取代的杂芳烷基。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、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。甚至更优选地,R1是H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基。在更优选地实施方案中,R1基是H、乙酰基或棕榈酰基。
根据另一优选实施方案,R2是-NR3R4、-OR3或-SR3,其中R3和R4独立地选自由以下组成的组:H、取代或非取代的C1-C24烷基、取代或非取代的C2-C24烯基、取代或非取代的C2-C24炔基、取代或非取代的C3-C24环烷基、取代或非取代的C5-C24环烯基、取代或非取代的C5-C24环炔基、取代或非取代的C6-C30芳基、取代或非取代的C7-C24芳烷基、取代或非取代的3-10元杂环基、以及具有2至24个碳原子和1至3个不同于碳的原子并具有1至6个碳原子的烷基链的取代或非取代的杂芳烷基。任选地,R3和R4可通过饱和或不饱和碳-碳键结合,与氮原子形成环。更优选地,R2是-NR3R4或-OR3,其中R3和R4独立地选自由以下组成的组:H、取代或非取代的C1-C24烷基、取代或非取代的C2-C24烯基、取代或非取代的C2-C24炔基、取代或非取代的C3-C10环烷基、取代或非取代的C6-C15芳基和取代或非取代的3-10元杂环基,以及具有3至10元环和1至6个碳原子的烷基链的取代或非取代的杂芳烷基。更优选地,R3和R4选自由以下组成的组:H、甲基、乙基、己基、十二烷基或十六烷基。更优选地,R3是H且R4选自由H、甲基、乙基、己基、十二烷基或十六烷基组成的组。
根据甚至更优选的实施方案,R2选自-OH和-NH2。
甚至更优选地,R1是乙酰基且R2是-OH。
根据本发明的一个实施方案,AA1是-Arg-,AA2是-His-,AA3是-His-且AA4是-Cit-。
根据本发明的一个实施方案,AA1是-Arg-,AA2是-Asn-,AA3是-Arg-且AA4是-Cit-。
根据本发明的另一个实施方案,R1选自由H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基组成的组,AA1是-L-Arg-,AA2是-L-His-,AA3是-L-His-,AA4是-L-Cit-且R2是-NR3R4或-OR3,其中R3和R4独立地选自由H、甲基、乙基、己基、十二烷基和十六烷基组成的组,优选地R2是-OH或-NH2。甚至更优选地,R1是乙酰基且R2是-OH。
根据本发明的另一个实施方案,R1选自由H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基组成的组,AA1是-L-Arg-,AA2是-L-Asn-,AA3是-L-Arg-,AA4是-L-Cit-且R2是-NR3R4或-OR3,其中R3和R4独立地选自由H、甲基、乙基、己基、十二烷基和十六烷基组成的组,优选地R2是-OH或-NH2。甚至更优选地,R1是乙酰基且R2是-OH。
以优选方式,式(I)的化合物选自由以下组成的组:
Ac-Arg-His-His-Cit-OH,
Ac-Arg-Asn-Arg-Cit-OH,
Ac-Arg-Asn-His-Cit-OH,
Ac-Arg-His-Arg-Cit-OH,
Palm-Arg-His-His-Cit-OH,
Palm-Arg-Asn-Arg-Cit-OH,
Palm-Arg-Asn-His-Cit-OH,
Palm-Arg-His-Arg-Cit-OH,
Ac-Arg-His-His-Cit-NH-(CH2)15-CH3,
Ac-Arg-Asn-Arg-Cit-NH-(CH2)15-CH3,
H-Arg-His-His-Cit-NH2,和
H-Arg-Asn-Arg-Cit-NH2,
其混合物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混合物存在;例如,形成它们的氨基酸可具有L-构型、D-构型或它们可相互独立地为外消旋的。因此,可能获得的同质异构体混合物及外消旋或非对映体混合物或纯的非对映异构体或对映异构体,取决于不对称碳的数量和存在哪种同质异构体或同质异构体的混合物。对于本发明的肽的优选结构是纯的同质异构体,即,对映异构体或非对映异构体。
例如当说到AA1可以是-Arg-时,理解为AA1选自-L-Arg-、-D-Arg-或外消旋或非-外消旋的它们两者的混合物。同样地,当说到AA2可以是-His-时,理解为它可以是-L-His-、-D-His-或外消旋或非-外消旋的它们两者的混合物。本文件中描述的方法允许本领域技术人员通过选择具有适当构型的氨基酸以获得本发明的肽的每种立体异构体。
在本发明的范围内,还包括本发明所提供的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”是指普遍地认可它在动物中和更特别地在人类中使用的盐,包括用于形成碱加成盐的无机盐或有机盐,无机盐如例如和不限于,锂、钠、钾、钙、镁或铝以及其他,有机盐如例如和不限于,乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、精氨酸、赖氨酸、组氨酸或哌嗪以及其他;或用于形成酸加成盐的有机盐或无机盐,有机盐如例如和不限于,乙酸盐、柠檬酸盐、乳酸盐、丙二酸盐、马来酸盐、酒石酸盐、延胡索酸盐、苯甲酸盐、天冬氨酸盐、谷氨酸盐、琥珀酸盐、油酸盐、三氟醋酸盐、草酸盐、双羟萘酸盐或葡糖酸盐以及其他,无机盐如例如和不限于,盐酸盐、硫酸盐、硼酸盐或碳酸盐以及其他。盐的性质不是关键,只要它是化妆品上或药学上可接受的。本发明的肽的化妆品上或药学上可接受的盐可以通过现有技术中已熟知的常规方法获得[BergeS.M.,Bighley LD.和Monkhouse D.C.(1977)“Pharmaceutical Salts(药物盐)”J.Pharm.Sci.66:1-19]。
制备方法
本发明的肽合成,其立体异构体或其化妆品上或药学上可接受的盐可以通过现有技术中已知的常规方法制成,如通过固相中肽合成方法[StewartJ.M.和Young J.D.(1984)“Solid Phase Peptide Synthesis(固相肽合成),第2版”Pierce Chemical Company,Rockford,Illinois;Bodanzsky M.和BodanzskyA.(1984)“The practice of Peptide Synthesis(肽合成实践)”Springer Vehag,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]、液相合成、固相和液相方法组合合成或酶催化合成[Kullmann W.(1980)“Proteases as catalysts for enzymic synthesesof opioid peptides(蛋白酶作为阿片样肽的酶催化合成的催化剂)”J.Biol.Chem.255:8234-8238]。肽还可通过修改或未修改的菌株发酵而获得,通过遗传工程以获得所需的序列,或通过控制的动物或植物蛋白水解,优选地植物蛋白,以释放含有至少所需序列的肽片段。
例如,获得具有式(I)的本发明的肽的方法,包括以下阶段:
-具有受保护的N-末端和游离的C-末端的氨基酸偶联到有游离的N-末端和受保护的C-末端的氨基酸,或连接到固体载体;
-从N-末端去除保护基;
-重复序列偶联和去除N-末端直至获得所需的肽序列;
-从C-末端去除保护基或切除固体载体。
优选地,C-末端连接到固体载体,该过程在固相中进行,因此,其包括具有受保护的N-末端和游离的C-末端的氨基酸偶联到具有游离的N-末端的氨基酸上,且C-末端连接到聚合物载体;从N-末端去除保护基;和根据需要重复此顺序若干次直至获得四肽,和最后通过切除将最初在聚合物载体合成的肽去除。
氨基酸侧链中的功能基在合成过程中由暂时的或永久的保护基适当地保护,并可同时地或正交地去保护以从聚合物载体切除肽。
可选择地,固相合成可通过汇集策略进行,将二肽或三肽偶联到聚合物载体或先前连接到聚合物载体的二肽或氨基酸上。汇集合成策略是本领域技术人员普遍所知的,在Lloyd-Williams P.、Albericio F.和Giralt E.en的“Convergent solid-phase peptide synthesis(汇集固相肽合成)”(1993)Tetrahedron49:11065-11133中描述。
该方法可包括另外的阶段,如使用本领域已知的标准方法和条件将N-末端和C-末端去保护和/或以任意顺序的聚合物载体肽切除,之后该末端的官能团可被修饰。可对锚定在聚合物载体的式(I)的肽或已从聚合物载体上去除的肽进行任选的N-末端和C-末端的末端修饰。
任选地,可通过本发明的肽的N-末端与R1-X反应将R1引入,其中R1具有上述的含义且X是凸出基,如例如和不限于,甲苯磺酰基、甲磺酰基和卤素基以及其他,在有合适的碱和溶剂存在下,其中这些片段具有不参与N-C键形成的那些功能基,通过亲核取代反应由暂时的或永久的保护基适当地保护。
任选地和/或另外地,R2基可由HR2化合反应引入,其中R2是-OR3、-NR3R4或-SR3,具有对应于式(I)的肽的互补片段,其中当有合适的溶剂和碱存在时R2是-OH,所述的溶剂或碱如例如N,N二异丙基乙胺或三乙胺,或添加剂如1-羟基苯并***(HOBt)或羟基苯并***(HOAt)和脱水剂如碳二亚胺、铀盐、鏻盐或脒盐以及其他,或通过与例如亚硫酰氯预先形成酰卤,以获得根据本发明的通式(I)的肽,其中这些片段存在那些不参与N-C键形成的功能基,由暂时的或永久的保护基适当地保护,或可选择地,通过同时掺入聚合物载体肽切除的过程可引入其他的R2基。
本领域技术人员应容易地理解,C-末端和N-末端的末端去保护/切除阶段以及之后的衍生化可根据本领域已知的方法按照任何顺序进行[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、机制与结构)”,第5版,John Wiley&Sons,2001]。
术语“保护基”是指阻断有机功能基和可在控制条件下去除的基团。本领域技术人员已知保护基、它们相对的反应性和它们保持惰性的条件。
对于氨基典型的保护基的实例是酰胺,如乙酰胺、苯甲酰胺、特戊酰胺;氨基甲酸酯如苄氧羰基(Cbz)、对硝基苄氧羰基(pNZ)、叔丁氧羰基(Boc)、2,2,2-三氯乙氧羰基(Troc)、2-(三甲基甲硅烷基)乙氧羰基(Teoc)、9-芴甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、以及其他;优选地,Boc或Fmoc。
对于羧基典型的保护基团的实例是酯类,如叔丁酯(tBu)、烯丙酯(All)、三苯甲酯(三苯甲基酯,Trt)、环己酯(cHex)、苄酯(Bzl)、邻硝基苄酯、对硝基苄酯、对甲氧基苄酯、三甲基甲硅烷基酯,以及其他;本发明优选的保护基是All、tBu、cHex、Bzl和Trt酯。
在合成过程中用暂时的或永久的正交保护基可以保护三官能氨基酸的N-末端和C-末端的保护基。可用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)、对甲苯磺酰基(甲苯磺酰基,Tos)或4-甲氧基-2,3,6-三甲基苯磺酰基(Mtr)以及其他保护精氨酸的胍基;可用甲苯磺酰基(Tos)、叔丁基氧羰基(Boc)、三苯甲基(Trt)、甲基三苯甲基(Mtt)或2,4-二硝基苯基(Dnp)以及其他保护组氨酸的咪唑基;和可用三苯甲基(Trt)或呫吨基(Xan)保护天冬酰胺的酰胺基或使用而不保护酰胺基。
在优选实施方案中,使用的基团保护策略是其中通过Boc保护氨基,通过Bzl、cHex或All保护羧基,用Mtr或Tos保护精氨酸侧链,天冬酰胺链无保护,和用Tos或Dnp保护组氨酸链的策略。
在另一优选实施方案中,使用的基团保护策略是其中通过Fmoc保护氨基,用tBu、All或Trt保护羧基,用Pmc或Pbf保护精氨酸侧链,用Trt保护天冬酰胺链,和用Trt或Mtt保护组氨酸链。
这些和其他另外的保护基的实例、保护基的引入和去除的描述可见于[Greene TW.和Wuts P.GM.,(1999)“Protective groups in organic synthesis(有机合成中的保护基)”John Wiley&Sons,New York;Atherton B.和SheppardR.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”还包括固相合成中使用的聚合物载体。
当合成完全地或部分地在固相进行时,本发明的方法中使用的一些固体载体是聚苯乙烯载体、接枝在聚苯乙烯中的聚乙二醇和类似物,如例如和不限于,对甲基二苯甲基胺树脂(MBHA)[Matsueda G.R.和Stewart JM.(1981)“A p-methylbenzhydrylamine resin for improved solid-phase synthesis ofpeptide amides(用于肽酰胺的改进的固相合成的对甲基二苯甲基胺树脂)”Peptides2:45-50]、2-三苯甲基氯树脂[Barlos K.,Gatos D.,Kallitsis J.,Papaphotiu G.,Sotiriu P.,Wenqing Y.和Schafer W.(1989)“DarstellungPeptid-fragmente unter Einsatz substituierterTriphenylmethyl-harze”Tetrahedron Lett.30:3943-3946;Barlos K.,Gatos D.,Kapolos S.,Papaphotiu G.,Schafer W.和Wenqing Y.(1989)“Veresterung vonpartiell Peptid-fragmenten mit Harzen.Einsatz von2-Chlorotritylchlorid zur Synthese von Leu15-gastrin I”Tetrahedron Lett.30:3947-3951]、树脂(Rapp PolymereGmbH)、Chem树脂(Matrix Innovation,Inc)和类似物,其可能包括或不包括不稳定的间隔物如5-(4-氨甲基-3,5-二甲氧基-苯氧基)戊酸(PAL)[Albericio F.,Kneib-Cordonier N.,Biancalana S.,Gera L,Masada R.I.,Hudson D.和BaranyG.(1990)“Preparation and application of the5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxy-phenoxy)-valeric acid(PAL)handle for the solid-phase synthesis of C-terminal peptideamides under mild conditions(用于在温和条件下操纵固相合成C末端肽酰胺的5-(4-(9-芴甲氧羰基)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-[4-氨甲基-(2,4-二甲氧基苯基)]、苯氧乙酸(AM)[Rink H.(1987)“Solid-phase synthesis of protected peptidefragments using a trialkoxy-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树脂[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]、和能同时去保护和切除聚合物载体上的肽的类似物。
化妆品组合物或药物组合物
本发明的肽可通过任何使得肽与哺乳动物,优选地人类体内其作用位点接触的方式施用以抑制MMP,和以包含所述肽的组合物的形式。
从这个意义上,本发明的另一个方面是包含至少一种通式(I)的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐与至少一种化妆品上或药学上可接受的佐剂的化妆品组合物或药物组合物。这些组合物可通过本领域技术人员已知的常规方法制备[“Harry’s Cosmeticology(Harry化妆品学)”,第八版(2000)Rieger MM.编著,New York Chemical Pub.,NY,US;“Remington:The Science and Practice of Pharmacy(雷明顿:药学理论与实践)”,第二十版(2003)GenaroA.R.编著,Lippincott Williams & Wilkins,Philadelphia,US]。
根据肽序列的性质或它们在N-末端和/或C-末端具有的可能修饰,本发明的肽具有可变的水溶性。因此,本发明的肽可加入到水溶液方式的组合物中,那些不溶于水的肽可溶于常规化妆品上或药学上可接受的溶剂,如例如和不限于,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。
治疗病症、疾病和/或病状所要施用的本发明的肽的化妆品上或药学上的有效量及它们的剂量取决于不同的因素,包括年龄、患者的病症、疾病或病状的严重程度、施用的途径和频率及取决于所要使用的肽的具体性质。
“化妆品上或药学上的有效量”是指足以提供所需的效果的肽的无毒的量。用于本发明的化妆品组合物或药物组合物中的本发明的肽为化妆品上或药学上有效地达到预期效果的浓度;优选地,相对于组合物的总重量,在0.00000001%(按重量计)和20%(按重量计)之间;优选地在0.000001%(按重量计)和20%(按重量计)之间,更优选地在0.0001%(按重量计)和10%(按重量计)之间,甚至更优选地在0.0001%(按重量计)和5%(按重量计)之间。
本发明的肽还可加入到化妆品或药物递送***和/或缓释***中。术语“递送***”是指与本发明的肽一起施用的稀释剂、佐剂、赋形剂或载体。此化妆品或药物载体可以是液体的,如水、油或表面活性剂,包括有含石油的、动物、植物或合成来源的,如例如和不限于花生油、大豆油、矿物油、芝麻油、蓖麻油、聚山梨酸酯、山梨聚糖酯、醚硫酸盐、硫酸盐、甜菜碱、葡糖苷、麦芽糖苷、脂肪醇、壬苯醇醚、泊洛沙姆、聚氧乙烯、聚乙二醇、右旋糖、甘油、毛地黄皂苷及类似物。
E.W.Martin的“Remington's Pharmaceutical Sciences(雷明顿药物科学)”中有描述为合适的载体的溶剂、佐剂或赋形剂。
术语“缓释”以其常规意义使用,是指在一段时期内提供所述化合物逐步释放的对于化合物的递送***,优选地,尽管不是必需,在整个时期内化合物以恒定水平释放。
递送***或缓释***的实例是脂质体、混合脂质体、毫米粒子(milliparticles)、微米粒子(microparticles)、纳米粒子(nanoparticles)、固体脂质纳米粒子、海绵、环糊精、囊泡、胶束、表面活性剂混合胶束、磷脂-表面活性剂混合胶束、毫米球(millispheres)、微米球(microspheres)、纳米球(nanospheres)、脂质球、毫米胶囊(millicapsules)、微米胶囊(microcapsules)、纳米胶囊(nanocapsules)及微米乳剂和纳米乳剂,可加入所述递送***或缓释***以获得活性成分的更高渗透性和/或改善它们的药代动力学和药效动力学特性。
缓释制剂可通过现有技术中已知的方法制备,含有其的组合物可施用,例如通过局部施用,包括粘性贴剂和非粘性贴剂和微电流贴剂,或***施用,如例如和不限于,通过口腔、鼻腔、直肠途径,皮下植入或注射、或在身体的特定部位直接植入或注射,优选地,它们必须释放相对恒定量的本发明的肽。缓释制剂中包含的肽的量取决于,例如,施用部位、本发明的肽的释放动力学和持续时间,及所需治疗或预防的病症、疾病和/或病状的性质。
本发明的肽还可吸附到固体有机聚合物或固体矿物载体,如例如和不限于,滑石粉、膨润土、硅石、淀粉和麦芽糊精以及其他。
本发明的肽还可加入到直接与皮肤、粘膜和/或头皮接触的织物、非织造织物或医疗器械中,以便它们释放本发明的肽,通过锚定织物、非织造织物或医疗器械的锚定***的生物降解,或通过织物、非织造织物或医疗器械与身体的摩擦、通过身体水分、通过皮肤的pH或通过体温。同样地,织物、非织造织物可用于制作直接与身体接触的服装。优选地,含有本发明的肽的织物、非织造织物或医疗器械用于治疗和/或护理那些由MMP过表达或MMP活性增加引起的皮肤、粘膜和/或头皮的病症、疾病和/或病状。
包括上面所描述的递送***和/或缓释***的织物、非织造织物、服装、医疗器械和将肽固定到它们上的手段的实例在文献中有所描述,是现有技术中已知的[Schaab C.K.(1986)“Impregnating Fabrics With Microcapsules(以微米胶囊浸渍织物)”,HAPPIMay1986;Nelson G.(2002)“Applicationof microencapsulation in textiles(微囊化在织物中的应用)”Int.J.Pharm.242:55-62;“Biofunctional Textiles and the Skin(生物功能的织物与皮肤)”(2006)Curr.Probl.Dermatol,v.33,Hipler U.C.和Eisner P.编著.S.Karger AG,Basel,Switzerland;Malcom R.K.,McCullagh S.D.,Woolfson A.D.,GormanS.P.,Jones D.S.和Cuddy J.(2004)“Controlled release of a modelantibacterial drug from a novel self-lubricating silicone biomaterial(模式抗菌药物从新型自润滑的硅酮生物材料受控的释放)”J.Cont.Release97:313-320]。优选的织物、非织造织物、服装、医疗器械是绷带、纱布、T恤衫、短袜、裤袜、内衣、腰带、手套、尿布、卫生巾、敷料、床罩、擦拭物、水凝胶、粘性贴剂、非粘性贴剂、微电流贴剂和/或面罩。
含有本发明的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐的化妆品或药物制剂可用于不同类型的局部或透皮应用制剂,其包括,任选地,配制所需剂型必要的化妆品上或药学上可接受的赋形剂[Faulí i Thllo C.(1993)“Tratado de Farmacia Galénica”,Luzán5,S.A.Ediciones,Madrid]。
局部或透皮应用制剂可以任何固体、液体或半固体剂型存在,如例如和不限于,乳膏剂、复合乳剂如例如和不限于水中油和/或硅酮的乳剂、油和/或硅酮中水的乳剂、水/油/水或水/硅酮/水类型的乳剂、和油/水/油或硅酮/水/硅酮类型的乳剂、无水组合物、水分散剂、油、乳液、香脂、泡沫、洗液、凝胶、乳膏凝胶(cream gels)、水醇溶液(hydroalcoholic solutions)、水二醇溶液(hydroglycolic solutions)、搽剂、盐水溶液、肥皂、洗发剂、调节剂(conditioners)、浆液、多糖膜、油膏、摩丝、软膏、粉剂、棒剂、笔剂(pencils)和气雾剂或喷雾剂,包括驻留制剂和冲洗制剂。这些局部或透皮应用制剂可通过本领域技术人员已知的技术加入到不同类型的固体辅助件中,如例如和不限于,擦拭物、水凝胶、粘性贴剂、非粘性贴剂、微电流贴剂或面罩;或它们可加入到不同的化妆品系列产品中,如化妆粉底,如例如液体或固体化妆粉底、卸妆洗液、卸妆乳液、眼袋遮瑕膏(under eyeconcealers)、眼影、口红(lipsticks)、护唇膏(lip protectors)、唇彩和唇粉(lipglosses and powders),以及其他。
本发明的化妆品组合物或药物组合物可包括增加本发明的肽经皮吸收的药剂,如例如和不限于,二甲基亚砜、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-2-酮)、乙醇、尿素、乙氧基二甘醇、丙酮、丙二醇或聚乙二醇以及其他。同样地,本发明的化妆品组合物或药物组合物可应用到待治疗的局部区域,通过离子导入、超声波导入、电穿孔、微电流贴剂、机械压力、渗透压梯度、包扎疗法、显微注射或通过加压的无针压力注射(pressure needle-free injection)如例如氧压力注射,或其任何组合,以实现本发明的肽的更强的渗透。应用区域取决于所要预防或治疗的病症、疾病和/或病状的性质而确定。
同样地,含有本发明的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐的化妆品组合物可以不同类型的用于口服的制剂使用,优选地以口服化妆品的形式,如例如和不限于,包括明胶胶囊的胶囊剂,包括糖衣片剂的片剂、粉剂、颗粒形式、口香糖、溶液、悬浮液、乳剂、糖浆、多糖膜、冻胶或明胶及由本领域技术人员已知的任何其他代表形式。特别地,本发明的肽可加入到任何形式的功能性食品或强化食品,如例如和不限于,饮食棒或压缩粉末或非压缩粉末。此粉末可溶解于水、苏打、乳制品、大豆衍生物中,或它们可加入到饮食棒剂中。本发明的肽可与通常用于口服组合物或食品增补剂的赋形剂和佐剂一起配制,如例如和不限于,常见于食品工业的脂肪组分、水组分、湿润剂、防腐剂、造型剂、香料、香味、抗氧化剂和着色剂。
含有本发明的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐的化妆品组合物或药物组合物不仅可通过透皮或局部途径施用,还可通过任何其他类型的适当途径施用,例如通过口服或肠胃外途径,为此它们包括配制所需剂型必要的药学上可接受的赋形剂。本发明的上下文中,术语“肠胃外”包括鼻途径;直肠途径;皮下、皮内或血管内注射,如静脉内、肌内、玻璃体内、脊髓、颅内、关节内、鞘内和腹膜内注射;及任何其他类似的注射或输液技术。活性成分的不同药物剂型和用于获得所述剂型的必要的赋形剂的修订版可见于“Tratado de Farmacia Galénica”,C.Faulíi Trillo,1993,Luzán5,S.A.Ediciones,Madrid中。
本发明所描述的化妆品上或药学上可接受的佐剂中,包括常用于治疗和/或护理皮肤、粘膜和/或头皮的组合物中的另外的成分,例如和不限于,其他MMP抑制剂,黑素合成刺激剂或抑制剂,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,抗氧化剂,自由基清除剂和/或抗大气污染剂,抗糖化剂,乳化剂,润肤剂,有机溶剂,液体推进剂,皮肤调节剂(skin conditioners)如湿润剂、保留水分的物质、α羟基酸、β羟基酸、保湿剂、表皮水解酶、维生素、色素或着色剂,染料,凝胶聚合物,增厚剂,表面活性剂,软化剂,抗皱剂,能够减少或治疗眼袋的药剂,去角质剂,抗微生物剂,杀真菌剂,抑真菌剂,杀细菌剂,抑细菌剂,真皮或表皮大分子合成刺激剂和/或能够阻止或抑制真皮或表皮大分子降解的药剂,胶原蛋白合成刺激剂,弹性蛋白合成刺激剂,核心蛋白多糖(decorine)合成刺激剂,层粘连蛋白合成刺激剂,防御素合成刺激剂,分子伴侣合成刺激剂,水通道蛋白合成刺激剂,透明质酸合成刺激剂,脂质和角质层的组分(神经酰胺、脂肪酸等)合成刺激剂,其他胶原蛋白降解抑制剂,弹性蛋白降解抑制剂,成纤维细胞增殖刺激剂,角质形成细胞增殖刺激剂,脂肪细胞增殖刺激剂,黑素细胞增殖刺激剂,角质形成细胞分化刺激剂,脂肪细胞分化刺激剂,乙酰胆碱酯酶抑制剂,皮肤弛缓剂,糖胺聚糖合成刺激剂,DNA修复剂,DNA保护剂,止痒剂,用于治疗和/或护理敏感皮肤的药剂,固化剂,抗萎缩纹剂,收敛剂,调节皮脂产生的药剂,脂肪分解刺激剂,抗蜂窝组织剂,愈合刺激剂,辅助愈合剂,上皮再形成刺激剂,辅助上皮再形成剂,细胞因子生长因子,镇静剂,抗炎剂,作用于毛细管循环和/或微循环的药剂,血管生成刺激剂,血管通透性抑制剂,作用于细胞代谢的药剂,用于改善真皮-表皮接合的药剂,促进毛发生长的药剂,抑制或延缓毛发生长的药剂,防腐剂,芳香剂,螯合剂,植物提取物,精油,海洋提取物,来自生物发酵过程的药剂,矿物盐,细胞提取物和遮光剂(针对紫外线A和/或紫外线B起作用的有机的或矿物的光保护剂)以及其他,只要它们与组合物的其余组分特别是与本发明的组合物中含有的通式(I)的肽是物理和化学上相容的。同样地,这些另外成分的性质不应无法接受地改变本发明的肽的益处。所述的另外成分可以是合成的或天然的,如例如植物提取物,或来自生物发酵过程。另外的实例可见于CTFA CosmeticIngredient Handbook(CTFA化妆品原料手册),第11版(2006)。
本发明的另外的方面涉及含有以下的化妆品组合物或药物组合物:化妆品上或药学上有效量的至少一种本发明的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐,和化妆品上或药学上有效量的有抑制MMP活性的至少一种合成组分、天然提取物或生物发酵过程所得产物,如例如和不限于,含有熊果酸的天然提取物、异黄酮如染料木素、槲皮素、类胡萝卜素、番茄红素、大豆提取物、蓝莓提取物、迷迭香提取物、红车轴草(Trifolium pratense)(红三叶草)提取物、新西兰麻(Phormium tenax)(formio)提取物、葛根汤提取物、鼠尾草提取物、视黄醇及其衍生物、视黄酸及其衍生物,皂甙元如例如和不限于,薯蓣皂甙元、海柯皂甙元、异菝葜皂甙元、萨洒皂甙元、替告皂甙元、亚莫皂甙元和丝兰皂甙元以及其他,Coletica/Engelhard销售的[INCI:水解麦芽提取物]、Juvenesce[INCI:乙氧基二甘醇(Ethoxydiglicol)和辛酸甘油三酯、视黄醇、熊果酸、维生素K1、伊洛马司他(llomastat)]或EquiStat[INCI苹果果实提取物、野生大豆籽提取物],Pentapharm销售的[INCI:人类寡肽-20]、Regu-Age[INCI:水解米糠蛋白、野生大豆蛋白质、氧化还原酶]或Colhibin[INCI:水解米蛋白],Lipotec销售的Lipeptide[INCI:水解植物蛋白],Laboratories Serobiologiques/Cognis销售的LitchidermTM[INCI:荔枝果皮提取物]或ArganylTM[INCI:刺阿干树叶提取物],AtriumInnovations销售的MDI[INCI:葡糖氨基葡聚糖]或[INCI:水(水)、葡聚糖、三肽-2],Soliance销售的Dakaline[INCI:甜扁桃、光滑果榆绿木树皮提取物],Provital销售的Homeostatine[INCI:扁浒苔、刺云实],Infinitec Activos销售的Timp-Peptide[建议的INCI:乙酰基六肽]或ECM Moduline[建议的INCI:棕榈酰三肽],Institut Europeen deBiologie Cellulaire销售的IP2000[INCI:葡聚糖、三氟乙酰基三肽-2],Expanscience Laboratories销售的Actimp[INCI:水解羽扇豆蛋白],Rahn销售的[INCI:乙醇、水(水)、甘油、水解米蛋白、枸骨叶冬青提取物、熊果酸钠、石竹素钠],阿达帕林,四环素及其衍生物如,米诺环素、罗利环素、金霉素、美他环素、土霉素、强力霉素、地美环素和其盐、巴马司他[BB94;[4-(N-羟胺)-2R-异丁基-3S-(噻吩-2-基硫代甲基)丁二酰基]-L-苯丙氨酸-N-甲基酰胺]、马立马司他[BB2516;[2S-[N4(R*),2R*,3S]]-N4[2,2-二甲基-1-[甲氨基羰基]丙基]-N1,2-二羟基-3-(2-甲基丙基)丁二胺],以及其他。
同样地,本发明的化妆品组合物或药物组合物可另外地含有化妆品上或药学上有效量的至少一种旨在减少炎症过程相关的肿胀和刺激的镇痛剂和/或抗炎化合物,其中所述炎症过程存在MMP过表达和/或过度活化性。这些化合物中我们可强调合成的化合物,如氢化可的松、氯倍他索、***、***、对乙酰氨基酚、乙酰水杨酸、amoxiprin、贝诺酯、水杨酸胆碱、二氟尼柳、faislamine、水杨酸甲酯、水杨酸镁、双水杨酯、双氯芬酸、醋氯芬酸、阿西美辛、溴芬酸、依托度酸、茚甲新、舒林酸、托美丁、布洛芬、卡洛芬、芬布芬、非诺洛芬、氟比洛芬、酮洛芬、酮咯酸、洛索洛芬、萘普生、奥沙普秦、噻洛芬酸、舒洛芬、甲芬那酸、甲氯灭酸盐、甲氯芬那酸、托芬那酸、萘丁美酮、苯基丁氮酮、阿扎丙酮、安乃近、羟布宗、磺吡酮、吡罗昔康、氯诺昔康、美洛昔康、替诺昔康、塞来考昔、艾托考昔、罗美昔布、帕瑞考昔、罗非考昔、伐地考昔、尼美舒利、利克飞龙(licofelone)、ω-3脂肪酸和其生物代谢物、***、可待因、羟考酮、氢可酮、二乙酰***、哌替啶、曲马多、丁丙诺啡(brupenorphine)、苯佐卡因、利多卡因、氯普鲁卡因、丁卡因、普鲁卡因、三环抗忧郁药、阿米替林、卡马西平、加巴喷丁、普加巴林、红没药醇(sabolol)、泛醇、生物素、月桂亚氨基二丙酸生育酚磷酸酯、二钠、环吡酮胺、去甲二氢愈创木酸,Atrium Innovations销售的NeutrazenTM[INCI:水(水)、丁二醇、葡聚糖、棕榈酰四肽-8]、Institut Europeen de Biologie Cellulaire销售的[INCI:葡聚糖、乙酰基七肽-1]、辅酶Q10或烷基甘油醚,或有镇痛和/或抗炎活性的天然提取物或精油,如例如和不限于,羟基积雪草甙、海胆碱、苋菜籽油、檀香油、胎盘提取物、桃树叶提取物、芦荟(Aloevera)、山金车(Arnica montana)、北艾(Artemisia vulgaris)、大叶马蹄香(Asarummaximum)、金盏花(Calendula officinalis)、辣椒属(Capsicum)、石胡荽(Centipedacunninghamii)、洋甘菊(Chamomilla recutita)、文殊兰(Crinumasiaticum)、北美金缕梅(Hamamelis virginiana)、南非钩麻(Harpagophytumprocumbens)、贯叶连翘(Hypericum perforatum)、白花百合(Liliumcandidum)、锦葵(Malva sylvestris)、互叶白千层(Melaleuca alternifolia)、马郁兰(Origanum majorana)、白柳(Salix alba)、水飞蓟(Silybummarianum)、艾菊(Tanacetum parthenium)或圭亚那钩藤(Uncariaguianensis),以及其他。
此外,本发明涉及一种化妆品组合物或药物组合物,所述组合物包含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、其混合物或其化妆品上或药学上可接受的盐,还包含化妆品上或药学上有效量的有愈合和/或上皮再形成活性或在愈合和/或上皮再形成过程中有效用作辅助佐剂的至少一种提取物或提取物组合,如以下提取物:积雪草(Centellaasiatica)、麝香玫瑰(Rosa moschata)、狭叶松果菊(Echinacea angustifolia)、聚合草(Symphytum officinal)、问荆(Equisetum arvense)、贯叶连翘(Hypericum perforatum)、细花含羞草(Mimosa tenuiflora)、芦荟(Aloevera)、Provital销售的Epithelizing[INCI:金盏花、贯叶连翘、洋甘菊、迷迭香]、Laboratories Serobiologiques/Cognis销售的LS9028[INCI:水解酪蛋白、水解酵母蛋白、赖氨酸HCl]或Coletica/Engelhard销售的[INCI:玉米(玉米)谷粒提取物]以及其他,和/或化妆品上或药学上有效量的来自生物发酵过程的有愈合和/或上皮再形成活性或在愈合和/或上皮再形成过程中有效用作辅助佐剂的至少一种合成的化合物、提取物或产物,如例如和不限于,钙粘着蛋白、整合素、选择素、透明质酸受体、免疫球蛋白、成纤维细胞生长因子、***生长因子、血小板生长因子、血管内皮生长因子、表皮生长因子、***、角质形成细胞生长因子、集落刺激因子、转化生长因子-β、肿瘤坏死因子-α、干扰素、白细胞介素、基质金属蛋白酶、蛋白酪氨酸磷酸酶受体、Lipotec销售的[INCI:假交替单胞菌(Pseudoalteromonas)发酵提取物]或DecorinylTM[INCI:三肽-10瓜氨酸],以及其他。
本发明另外的方面涉及一种化妆品组合物或药物组合物,所述组合物包含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、其混合物或其化妆品上或药学上可接受的盐,还包含化妆品上或药学上有效量的至少一种有抗皱和/或抗老化活性的提取物,如例如和不限于以下提取物:葡萄(Vitis vinifera)、狗牙蔷薇(Rosa canina)、姜黄(Curcuma longa)、香根鸢尾(Iris pallida)、可可(Theobroma cacao)、银杏(Ginkgo biloba)或盐生杜氏藻(Dunaliella salina)以及其他,和/或至少一种来自生物发酵过程的有抗皱和/或抗老化活性的合成的化合物、提取物或产物,如例如和不限于,Sederma销售的[INCI:棕榈酰五肽-3]或Matrixyl[INCI:棕榈酰四肽-3、棕榈酰寡肽],Pentapharm销售的[INCI:五肽-3]或[INCI:二肽二氨基丁酰基苄基酰胺二乙酸酯],Laboratoires Serobiologiques/Cognis销售的MyoxinolTM[INCI:水解咖啡黄葵提取物],Exsymol销售的[INCI:甲基硅烷醇甘露糖醛酸酯]或Hydroxyprolisilane[INCI:甲基硅烷醇羟脯氨酸酯天冬氨酸酯],Lipotec销售的[INCI:乙酰基六肽-8](Acetylhexapeptide-8)、[INCI:五肽-18](Pentapeptido-18)、[INCI:水解小麦蛋白、水解大豆蛋白、三肽-1]、TrylagenTM[INCI:假交替单胞菌发酵提取物、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]或Lipochroman-6[INCI:二甲基甲氧基色原烷醇],Institut Europeen de Biologie Cellulaire销售的[INCI:三肽-1、葡聚糖],Vincience销售的[INCI:六肽-9]或[INCI:水、丁二醇、二肽-4],Infinitec Activos销售的BONT-L-Peptide[建议的INCI:棕榈酰六肽],Ca2+通道拮抗剂如阿尔维林、锰盐或镁盐,某些仲胺或叔胺,视黄醇及其衍生物,艾地苯醌及其衍生物,辅酶Q10和衍生物,乳香酸及其衍生物,或氯化物通道的激动剂,以及其他。
本发明另外的方面涉及一种化妆品组合物或药物组合物,所述组合物包含化妆品上或药学上有效量的至少一种通式(I)的肽,还包含化妆品上或药学上有效量的具有再紧致、再增厚和/或重构活性的至少一种提取物或提取物组合,如例如和不限于,红叶金虎尾(Malpighia punicitolia)、菜蓟(Cynara scolymus)、草本棉(Gossypium herbaceum)、库拉索芦荟(AloeBarbadensis)、稷(Panicum miliaceum)、黑桑(Morus nigra)、芝麻(Sesamumihdicum)、野生大豆(Glycine soy)、小麦(Triticum vulgare),Provital销售的Refirming HSC[INCI:小麦、水飞蓟、野生大豆、问荆、羽衣草、紫苜蓿、萝卜]或Refirming[INCI:紫松果菊、积雪草、墨角藻、葫芦巴]、Atrium Innovations销售的[INCI:山梨醇、藻提取物]、Pentapharm销售的[INCI:天然的营养因子],或含有异黄酮的植物提取物,或另外至少一种来自生物发酵过程的具有再紧致、再增厚和/或重构活性的合成的化合物、提取物或产物,如例如和不限于,Sederma销售的Biopeptide ELTM[INCI:棕榈酰寡肽]、Biopeptide CLTM[INCI:棕榈酰寡肽]、[INCI:水(水)、丙二醇、卵磷脂、咖啡因、棕榈酰肉碱]、[INCI:棕榈酰五肽-3]、[INCI:棕榈酰四肽-3、棕榈酰寡肽]或Bio-BustylTM[INCI:甘油聚甲基丙烯酸酯、拉恩氏菌大豆蛋白发酵产物、水(水)、丙二醇、甘油、PEG-8、棕榈酰寡肽],Laboratoires Serobiologiques/Cognis销售的HC[INCI:甘油、水(水)、葡糖胺基葡聚糖、糖原]、[INCI:甘露糖醇、环糊精、糖原、熊果(Aratostaphylos Uva Ursi)叶提取物]、LS[INCI:水解酪蛋白、水解酵母蛋白、赖氨酸HCL]或LS9120[INCI:榄仁树叶提取物、西洋接骨木(Sambucus Negra)花提取物、聚乙烯基吡咯烷酮、鞣酸],Silab销售的[INCI:水解小麦蛋白]、[INCI:水解大豆粉]或Ridulisse[水解大豆蛋白],Lipotec销售的[INCI:六肽-10]或DecorinylTM[INCI:三肽-10瓜氨酸],Coletica/Engelhard销售的[INCI:卵磷脂、熊果酸、去端肽胶原、黄原胶、软骨素硫酸钠]或[INCI:水解麦芽提取物],Pentapharm销售的棕榈酰三肽-5],Atrium Innovations销售的[INCI:水(水)、葡糖胺基葡聚糖、菌核胶],或InstitutEuropeen de Biologie Cellulaire销售的IP2000[INCI:葡聚糖,三氟乙酰基三肽-2],以及其他。
应用
本发明的另一个方面涉及用于治疗和/或护理得益于MMP抑制的哺乳动物,优选地人类中皮肤、粘膜和/或头皮的那些病症、疾病和/或病状的美容方法或药学方法;包括施用有效量的至少一种通式(I)的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐,优选地含有它们的化妆品组合物或药物组合物。本发明还提供了美容方法或药学方法以抑制MMP,优选地皮肤、粘膜和/或头皮的MMP。
同样地,本发明提供了用于治疗和/或护理由MMP过表达或由MMP活性增加引起的皮肤、粘膜和/或头皮的那些病症、疾病和/或病状的美容方法或药学方法,包括在皮肤、粘膜和/或头皮上应用或口服或肠胃外施用含有至少一种本发明的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐的化妆品组合物或药物组合物。
优选地,待治疗和/或护理的由MMP过表达或由MMP活性增加引起的皮肤、粘膜和/或头皮的病症、疾病和/或病状,包括痤疮、红斑痤疮、银屑病、皮炎、特应性皮炎、湿疹、敏感皮肤、牙龈炎、牙周炎、皮肤癌、肿瘤浸润、老化皮肤、光老化皮肤、皱纹、表情纹、萎缩纹、瘢痕疙瘩、肥厚性瘢痕、蜂窝组织炎、橘皮皮肤、肿瘤转移、溃疡、糖尿病性溃疡、毛细血管扩张、酒糟鼻(cuperosis)、静脉曲张、黑眼圈、眼袋、秃发和脱发。
根据治疗和/或护理病症、疾病和/或病状的需要,含有本发明的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐的组合物可在皮肤、粘膜和/或头皮上应用或口服或肠胃外施用。
应用或施用频率可以有很大的不同,取决于每个个体的需要;建议从每月一次至每天十次的范围内应用或施用,优选地从每周一次到每天四次,更优选地从每周三次到每天三次,甚至更优选地,每天一次或两次。
本发明的另外的方面涉及至少一种通式(I)的肽、其立体异构体、其混合物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/或头皮的化妆品组合物或药物组合物中的用途。
此外,本发明涉及至少一种通式(I)的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐在制备用于抑制MMP,优选地皮肤、粘膜和/或头皮MMP的化妆品组合物或药物组合物中的用途。
同样地,本发明的另一个方面涉及至少一种通式(I)的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐在制备用于治疗和/或护理由MMP过表达或由MMP活性增加引起的皮肤、粘膜和/或头皮的那些病症、疾病和/或病状的化妆品组合物或药物组合物中的用途。优选地,制造化妆品组合物或药物组合物以治疗和/或护理那些受痤疮、红斑痤疮、银屑病、皮炎、特应性皮炎、湿疹、敏感皮肤、牙龈炎、牙周炎、皮肤癌、肿瘤浸润、老化皮肤、光老化皮肤、皱纹、表情纹、萎缩纹、瘢痕疙瘩、肥厚性瘢痕、蜂窝组织炎、橘皮皮肤、肿瘤转移、溃疡、糖尿病性溃疡、毛细血管扩张、酒糟鼻(cuperosis)、静脉曲张、黑眼圈、眼袋、秃发和脱发影响的皮肤、粘膜和/或头皮区域。
根据另一个重要方面,本发明涉及通式(I)的肽在制备用于治疗皮肤旨在减少、延缓和/或阻止老化和光老化迹象的化妆品组合物或药物组合物中的用途。
在另外的实施方案中,本发明涉及至少一种通式(I)的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐在制备用于口腔处理或口腔清洁的化妆品组合物或药物组合物中的用途。优选地,化妆品组合物或药物组合物用于治疗或预防牙龈炎和牙周炎。口腔清洁的化妆品组合物或药物组合物的实例包括牙膏、用于口腔冲洗的口腔酏剂、或口香糖、以及其他。
本发明的另外的方面涉及至少一种通式(I)的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐在制备用于毛发处理或毛发清洁的化妆品组合物或药物组合物中的用途。优选地,化妆品组合物或药物组合物用于治疗或预防秃发和脱发。毛发清洁的化妆品组合物或药物组合物的实例包括洗发剂、护发素、头发洗剂、滋发剂或头皮罩,以及其他。
本发明的另一个方面涉及至少一种通式(I)的肽、其立体异构体、其混合物或其化妆品上或药学上可接受的盐在制备用于身体处理或清洁的化妆品组合物或药物组合物中的用途。
下面的特定实施例用于说明本发明的性质。这些实施例仅为了说明目的被包括,不应理解为对本发明的限制。
实施例
一般方法
所有的试剂和溶剂都是合成级的,不经任何另外处理而使用。
缩写
氨基酸使用的缩写词遵循在Eur.J.Biochem.(1984)138:9-37和J.Biol.Chem.(1989)264:633-673中指定的IUPAC-IUB联合会的生物化学命名法。
Ac,乙酰基;All,烯丙基;Alloc,烯丙氧羰基;AM,2-[4-氨甲基(2,4二甲氧基苯基)]酸;Arg,精氨酸;Asn,天冬酰胺;Boc,叔丁氧羰基;Bzl,苄基;Cbz,苄氧羰基;cHex,环己基;Cit,瓜氨酸;2-氯三苯甲基树脂;cps,厘泊;C-末端,羧基-末端;DCM,二氯甲烷;DIEA,N,N-二异丙胺;DIPCDI,N,N’-二异丙基碳二亚胺;DMF,N,N-二甲基甲酰胺;Dnp,2,4-二硝基苯基;DPPC,二棕榈酰磷脂酰胆碱;equiv,当量;ESI-MS,电喷雾质谱法;Fmoc,9-芴甲氧羰基;His,组氨酸;HOAt,1-羟基苯并***;HOBt,1-羟基苯并***;HPLC,高效液相色谱法;INCI,国际化妆品原料命名法;MBHA,树脂对-甲基二甲苯胺树脂;MeCN,乙腈;MeOH,甲醇;mLV,多层囊泡;MMP,基质金属蛋白酶;Mtr,4-甲氧基-2,3,6三甲基苯磺酰基;Mtt,甲基三苯甲基;N-末端,氨基-末端;PAL,5-(4-氨甲基-3,5-二甲氧基苯氧基)戊酸;Palm,棕榈酰基;Pbf,2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基;Pmc,2,2,5,7,8-五甲基-色满-6-磺酸基;pNZ,对硝基苄氧羰基;树脂;tBu,叔丁基;Teoc,2-(三甲基甲硅烷基)乙氧羰基;TFA,三氟乙酸;THF,四氢呋喃;TIMP,基质金属蛋白酶的组织抑制剂;TIS,三异丙基硅烷;Tos,对甲苯磺酰基或甲苯磺酰基;Troc,2,2,2-三氯乙基-氧羰基;Trt,三苯基甲基或三苯甲基;ULV,单层囊泡;UV,紫外线;Xan,呫吨基。
化学合成
所有的合成过程用配备多孔聚乙烯片的聚丙烯注射器或在配备多孔板的反应器中完成。可溶性溶剂和试剂通过抽吸去除。用哌啶-DMF(2:8,v/v)(1×1min,1×5min;5mL/g树脂)进行Fmoc基的去除[Lloyd-WilliamsP.,Albericio F.和Giralt,E.(1997)“Chemical Approaches tothe Synthesis of Peptides and Proteins(合成肽和蛋白的化学方法)”CRC,Boca Raton,FL,USA]。
在去保护阶段、偶联阶段和再去保护阶段之间用DMF(3×1min)进行冲洗,每次使用10mL溶剂/g树脂。用3mL溶剂/g树脂进行偶联反应。通过茚三酮试验进行偶联控制[Kaiser E.,Colescott R.L,BossingerCD.和Cook P.I.(1970)“Color test for detection of free terminal amino groups in thesolid-phase synthesis of peptides(固相肽合成中用于检测自由末端氨基的显色试验)”Anal.Biochem.34:595-598]。所有合成转化和冲洗在室温进行。
实施例1
获得Fmoc-AA1-AA2-AA3-AA4-O-2-ClTrt-
将3.5gFmoc-L-Cit-OH(8.8mmol,1当量)加入、溶解于55mLDCM,然后将1.3mLDIEA(7.6mmol,0.86当量)加入到干燥的2-氯三苯甲基树脂(5.5g,8.8mmol)上。溶液保持搅拌5分钟,之后加入2.5mLDIEA(14.6mmol,1.66当量)。然后,其反应40分钟。通过用4.4mL的MeOH处理封闭剩余的盐酸基。
如一般方法中所描述将FmocN-末端基团去保护,在DIPCDI(3.39mL,22mmol,2.5当量)和HOBt(3.37g,22mmol,2.5当量)存在下用DMF作为溶剂在一小时过程将13.63gFmoc-L-His(Trt)-OH或14.27gFmoc-L-Arg(Pbf)-OH(22mmol,2.5当量)加入肽基-树脂。然后,如一般方法中所述冲洗树脂,重复Fmoc基去保护处理以掺入随后的氨基酸。遵照所描述的方案,有每个37gHOBt(22mmol,2.5当量)和3.39mLDIPCDI(22mmol,2.5当量)偶联存在下13.63gFmoc-L-His(Trt)-OH或13.13gFmoc-L-Asn(Trt)-OH(22mmol,2.5当量)和14.27g的Fmoc-L-Arg(Pbf)-OH(22mmol,2.5当量)相继被偶联。
合成结束后,将肽基-树脂用DCM(5×3min)冲洗和通过氮气流干燥。
实施例2
获得Fmoc-AA1-AA2-AA3-AA4-AM-MBHA-
根据所描述的方案用哌啶-DMF处理6.85g官能化的Fmoc-AM-MBHA树脂0.73mmol/g(5mmol)以去除Fmoc基。在DIPCDI(3.85mL,25mmol,5当量)和HOBt(3.85g,25mmol,5当量)存在下用DMF作为溶剂在1小时过程将9.9gFmoc-L-Cit-OH(25mmol,5当量)加入到去保护的树脂。
随后如一般方法中所描述的冲洗树脂,重复Fmoc基去保护处理以掺入随后的氨基酸。根据所描述的方案,在每个3.85gHOBt(25mmol,5当量)与3.85mL DIPCDI(25mmol,5当量)偶联存在下,15.49gFmoc-L-His(Trt)-OH或16.22gFmoc-L-Arg(Pbf)-OH(25mmol,5当量)、15.49gFmoc-L-His(Trt)-OH或14.92gFmoc-L-Asn(Trt)-OH(25mmol,5当量)和16.22gFmoc-L-Arg(Pbf)-OH(25mmol,5当量)相继被偶联。
合成结束后,将肽基-树脂用DCM(5×3min)冲洗和通过氮气流干燥。
实施例3
FmocN-末端保护基的一般切除方法
如一般方法所描述将FmocN-末端基团从实施例1和实施例2获得的肽基-树脂去保护(DMF中20%哌啶,1×5min+1×20min)。将肽基-树脂用DMF(5×1min)、DCM(4×1min)、***(4×1min)冲洗和真空干燥。
实施例4
R1棕榈酰基的引入方法:获得Palm-AA1-AA2-AA3-AA4-O-2-ClTrt-和Palm-AA1-AA2-AA3-AA4-AM-MBHA-
在1.53gHOBt(10mmol,10当量)和1.54mLDIPCDI(10mmol,10当量)存在下,将预溶解于DMF(1mL)中2.56g的棕榈酸(10mmol,10当量)加入到实施例3中获得的1mmol的肽基-树脂上。将它们保持反应15小时,之后将树脂用THF(5×1min)、DCM(5×1min)、DMF(5×1min)、MeOH(5×1min)、DMF(5×1min)、THF(5×1min)、DMF(5×1min)、DCM(4×1min)、***(3×1min)冲洗和真空干燥。
实施例5
R1乙酰基的引入方法:获得Ac-AA1-AA2-AA3-AA4-O-2-ClTrt-和Ac-AA1-AA2-AA3-AA4-AM-MBHA-
在25当量DIEA存在下使用5mLDMF作为溶剂,用25当量乙酸酐处理实施例3中获得的1mmol肽基-树脂。将它们保持反应30min,之后将肽基-树脂用DMF(5×1min)、DCM(4×1min)、***(4×1min)冲洗和真空干燥。
实施例6
聚合物载体切除方法:获得H-AA1-AA2-AA3-AA4-OH、Ac-AA1-AA2-AA3-AA4-OH、Palm-AA1-AA2-AA3-AA4-OH、H-AA1-AA2-AA3-AA4-NH2、Ac-AA1-AA2-AA3-AA4-NH2和Palm-AA1-AA2-AA3-AA4-NH2。
在室温和搅拌条件下用5mL的TFA-TIS-H2O(90:5:5)在2小时过程处理实施例3、4和5获得的200mg干燥的肽基-树脂。通过配备多孔聚乙烯片的聚丙烯注射器过滤和用50mL***冲洗5次,在50mL冷***中收集过滤。将最后的沉淀物真空干燥。
在H2O(+0.1%TFA)中MeCN(+0.07%TFA)梯度中获得的肽的HPLC分析显示在所有情况下纯度高于85%。通过ES-MS确认获得的肽的特性。
实施例7
聚合物载体的切除方法和用取代的R2胺官能化:获得Ac-AA1-AA2-AA3-AA4-NH-(CH2)15-CH3。
在KOH存在下,将预先真空干燥的来自实施例6的150mg的Ac-AA1-AA2-AA3-AA4-O-2-ClTrt-肽基-树脂用3mLDCM中的3%的TFA溶液在5分钟过程处理获得有完全保护的侧链的Ac-AA1-AA2-AA3-AA4-OH肽。在50mL的冷***中收集过滤,重复处理3次。在室内干燥度和温度下将醚溶液旋转蒸发,将沉淀再悬浮于H2O中50%MeCN中和冷冻干燥。称量获得的10mg粗制肽,加入3当量十六烷基胺和25mLDMF酐。加入2当量DIPCDI,在47℃保持磁搅拌反应。由HPLC通过起始物料的消失控制反应,反应24-48小时后完成。蒸发干燥溶剂,与DCM共蒸发两次。获得的残余物[有完全保护的侧链的AC-AA1-AA2-AA3-AA4-NH-(CH2)15-CH3]再悬浮于25mL的TFA-DCM-苯甲醚(49:49:2)的混合物中,在室温保持反应30分钟。加入250mL的冷***,将溶剂减压蒸发,与***再共蒸发两次。将残余物溶解于H2O中50%MeCN的混合物,冷冻干燥。
对在水(+0.1%TFA)中梯度的MeCN(+0.07%TFA)中获得的肽的HPLC分析显示在所有情况下纯度高于70%。通过ES-MS确认获得的肽的特性。
实施例8
胶原酶抑制试验
在0.5%DMSO存在下将肽再悬浮于水中。试验在具有96孔的黑色微孔板上进行,使用的明胶酶/胶原酶测定试剂盒(MolecularProbes)。为此,将2mg/mL的肽与0.1单位/mL的IV型胶原酶在室温和缓慢搅拌条件预孵育1小时,所述时间后,加入荧光素共轭底物(DQTM明胶)至25μg/mL的终浓度,在室温和搅拌和避光条件孵育反应物2小时。荧光被抑制的底物被导入释放荧光片段的胶原酶,用FLUOstar galaxy读数器(BMG Lab Technologies)监测荧光,使用485nm滤光片激发和520nm发射。
表2胶原酶抑制值高于25%的那些肽的详情。相对于介质抑制的基础值将抑制值标准化。
实施例9
MMP-1、MMP-2、MMP-3和MMP-9抑制
将人类MMP在pH7.6的50mMTris-HCl、150mMNaCl、5mMCaCl2、0.2mMNaN3中重构,通过在37℃与10mM的4-乙酸氨基苯汞(溶解于0.01MNaOH)以10:1的比率反应4-6h而活化。活化的蛋白酶(0.35μg/mL)与终浓度至0.5mM的肽在室温在96-孔黑色微孔板中预孵育1小时。预孵育后,将25μg/mL底物(DQTM明胶)加入孔中,将各样品在室温和避光条件孵育16小时。用自动多板荧光读数器测量通过显著的明胶消化释放的荧光,在485nm激发和在520nm读数。
结果根据MMP和无产物中的基础荧光值校正,并相对于对照荧光标准化。表3详述了对于肽的最佳抑制值。
实施例10
含有Palm-L-Arg-L-Asn-L-His-L-Cit-NH2制剂的化妆品组合物。
如本发明中所描述地制备下面的制剂:
在足够大的反应器中称量A相组分,在80℃加热混合物以熔蜡。在足够容纳全部组分的容器中称量B相组分,在70℃加热。在强烈搅拌下将A相缓慢加入到B相,随后在搅拌下将C相加入到混合物中。加入后,保持冷却和温和搅拌,当混合物在室温时将Palm-L-Arg-L-Asn-L-His-L-Cit-NH2和卵磷脂的水溶液加入,均质并用三乙醇胺校正pH。
获得的乳膏剂中pH是6-7,粘度是10.000-15.000cps(6/50)。
实施例11
含有Ac-L-Arg-L-His-L-His-L-Cit-OH制剂的脂质体
称量二棕榈酰磷脂酰胆碱(DPPC)并溶解于氯仿。将溶剂真空蒸发直至获得精细的磷脂层,将所述的层在55℃用肽的水溶液处理以水合到所需的浓度(含有),获得MLV脂质体。通过在55℃将MLV脂质体以5分钟间隔浸入超声波浴中2分钟8周期来获得ULV脂质体。通过使ULV脂质体经过高压挤压***来减小ULV脂质体的大小。
实施例12
含有H-L-Arg-L-His-L-Arg-L-Cit-NH2的面霜组合物
制备:
-混合A相组分并在70℃加热。
-混合B相组分并在70℃加热。
-在5分钟过程中将C相加入到均质器(Silverson)搅拌的B相。
-将A相逐渐地加入到B相和C相的混合物中并用均质器保持均质5分钟。
-启动冷却至30-35℃并温和搅拌。在50℃加入D相。保持搅拌。在35-38℃加入预先溶解的E相和F相。
实施例13
含有Ac-L-Arg-L-His-L-His-L-Cit-OH的脂质体凝胶组合物制品
在温和搅拌下将实施例11的脂质体扩散于有防腐剂(EDTA、咪唑烷基脲和)的水中。加入200[INCI:水、甘油、甘油聚丙烯酸酯]并温和搅拌直至获得均质混合物。
实施例14
含有Ac-L-Arg-L-His-L-His-L-Cit-OH制剂的混合胶束组合物
在对于全部样品合适的容器中,称量A相组分,在30℃轻微加热以有助于溶解部分防腐剂。之后,加入B相组分,在缓慢搅拌下均质化。
然后,在持续搅拌下加入C相,之后以缓慢搅拌加入D相以免产生泡沫。
调节pH至5.5-6.5。
实施例15
用于治疗和/或预防萎缩纹的含有Ac-L-Arg-L-His-L-His-L-Cit-OH的组合物
在对于全部样品合适的容器中,称量A相组分,在30℃轻微加热以有助于溶解部分防腐剂。之后,混合B相组分并加入到A相,在缓慢搅拌下使组合物均质化。
实施例16
含有Ac-L-Arg-L-Asn-L-His-L-Cit-NH2的头发洗剂组合物
制备:
-混合A相组分。
-混合B相组分。
-缓慢地将B相加入到A相并搅拌直至完全均质化。
实施例17
含有Ac-L-Arg-L-His-L-His-L-Cit-OH的漱口剂组合物
混合组分直至完全均质化。
Claims (15)
1.一种通式(I)的肽
R1-AA1-AA2-AA3-AA4-R2
(I)
其特征在于:
AA1是-Arg-;
AA2选自由-His-和-Asn-组成的组;
AA3选自由-His-和-Arg-组成的组;
AA4是-Cit-;
R1选自由以下组成的组:H、乙酰基或棕榈酰基;且
R2选自由-NR3R4和-OR3组成的组;其中R3和R4是H。
2.根据权利要求1所述的肽,其特征在于AA2是-His-且AA3是-His-。
3.根据权利要求1所述的肽,其特征在于AA2是-Asn-且AA3是-Arg-。
4.根据权利要求1至2任一项所述的肽,其特征在于R1是乙酰基,AA1是-L-Arg-,AA2是-L-His-,AA3是-L-His-,AA4是-L-Cit,且R2是-OR3,其中R3是H。
5.根据权利要求1和3任一项所述的肽,其特征在于R1是乙酰基,AA1是-L-Arg-,AA2是-L-Asn-,AA3是-L-Arg-,AA4是-L-Cit,且R2是-OR3,其中R3是H。
6.一种用于获得权利要求1至5任一项所界定的通式(I)的肽的方法,其特征在于所述方法在固相上或在溶液中实施。
7.一种化妆品组合物或药物组合物,所述组合物包含化妆品上或药学上有效量的权利要求1至5任一项所界定的至少一种通式(I)的肽和至少一种化妆品上或药学上可接受的赋形剂。
8.根据权利要求7所述的化妆品组合物或药物组合物,其特征在于所述通式(I)的肽被加入到化妆品或药物递送***和/或缓释***中和/或被吸附到化妆品上或药学上可接受的固体载体上,所述化妆品或药物递送***和/或缓释***选自由以下组成的组: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、微米乳剂、纳米乳剂、毫米粒子、微米粒子和纳米粒子,所述化妆品上或药学上可接受的固体载体选自由滑石粉、膨润土、硅石、淀粉和麦芽糊精组成的组。
9.根据权利要求7至8任一项所述的化妆品组合物或药物组合物,其特征在于所述组合物选自由以下组成的组:乳膏剂、无水组合物、水分散剂、油、香脂、泡沫、凝胶、肥皂、洗发剂、调节剂、油膏、摩丝、软膏剂、粉剂、棒剂、笔剂、喷雾剂、气雾剂、胶囊剂、片剂、颗粒形式、口香糖、溶液、悬浮液、乳剂、多糖膜、冻胶和明胶。
10.根据权利要求7至8任一项所述的化妆品组合物或药物组合物,其特征在于所述组合物是选自由眼袋去除剂、化妆粉底、卸妆洗液、卸妆乳液、眼影、口红、唇彩和唇粉组成的组的产品。
11.根据权利要求7至8任一项所述的化妆品组合物或药物组合物,其特征在于所述通式(I)的肽被加入到织物或医疗器械中。
12.根据权利要求7至11任一项所述的化妆品组合物或药物组合物,其特征在于所述组合物另外包含化妆品上或药学上有效量的至少一种选自由以下组成的组的活性剂:基质金属蛋白酶抑制剂,黑素合成刺激剂或抑制剂,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,抗氧化剂,自由基清除剂和/或抗大气污染剂,抗糖化剂,乳化剂,有机溶剂,保湿剂、表皮水解酶、维生素、色素,凝胶聚合物,增厚剂,表面活性剂,抗皱剂,能够减少或治疗眼袋的药剂,去角质剂,抗微生物剂,抑真菌剂,抑细菌剂,真皮或表皮大分子合成刺激剂和/或能够阻止或抑制真皮或表皮大分子降解的药剂,胶原蛋白合成刺激剂,弹性蛋白合成刺激剂,核心蛋白多糖合成刺激剂,层粘连蛋白合成刺激剂,防御素合成刺激剂,分子伴侣合成刺激剂,水通道蛋白合成刺激剂,透明质酸合成刺激剂,脂质和角质层的组分合成刺激剂,神经酰胺合成刺激剂,胶原蛋白降解抑制剂,弹性蛋白降解抑制剂,成纤维细胞增殖刺激剂,角质形成细胞增殖刺激剂,脂肪细胞增殖刺激剂,黑素细胞增殖刺激剂,角质形成细胞分化刺激剂,脂肪细胞分化刺激剂,乙酰胆碱酯酶抑制剂,皮肤弛缓剂,糖胺聚糖合成刺激剂,DNA修复剂,DNA保护剂,止痒剂,用于治疗和/或护理敏感皮肤的药剂,固化剂,抗萎缩纹剂,收敛剂,调节皮脂产生的药剂,脂肪分解刺激剂,抗蜂窝组织剂,愈合刺激剂,愈合辅助佐剂,上皮再形成刺激剂,上皮再形成辅助佐剂,镇静剂,抗炎剂,作用于毛细管循环和/或微循环的药剂,血管生成刺激剂,血管通透性抑制剂,作用于细胞代谢的药剂,用于改善真皮-表皮接合的药剂,促进毛发生长的药剂,抑制或延缓毛发生长的药剂,防腐剂,芳香剂,螯合剂,植物提取物,精油,海洋提取物,来自生物发酵过程的药剂,矿物盐,细胞提取物和遮光剂,针对紫外线A和/或紫外线B起作用的有机的或矿物的光保护剂,或其混合物。
13.权利要求1至5任一项所述的通式(I)的肽在制备用于治疗和/或护理皮肤、粘膜和/或头皮的化妆品组合物或药物组合物中的用途。
14.根据权利要求13所述的用途,其中所述治疗和/或护理由抑制至少一种皮肤、粘膜和/或头皮基质金属蛋白酶组成。
15.根据权利要求13至14任一项所述的用途,用于治疗和/或护理由基质金属蛋白酶过表达或由基质金属蛋白酶活性增加引起的皮肤、粘膜和/或头皮的病症、疾病和/或病状。
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PCT/EP2009/001419 WO2009106343A1 (en) | 2008-02-29 | 2009-02-27 | Cosmetic or pharmaceutical compositions comprising metalloproteinase inhibitors |
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AU737376B2 (en) | 1997-02-25 | 2001-08-16 | Regents Of The University Of Michigan, The | Methods and compositions for preventing and treating chronological aging in human skin |
EP1002064B1 (en) * | 1997-06-25 | 2007-10-10 | Novozymes A/S | A modified polypeptide |
FR2778558B1 (fr) | 1998-05-12 | 2001-02-16 | Oreal | Utilisation d'inhibiteur de metalloproteinases pour induire et/ou stimuler la croissance des cheveux ou des poils et/ou freiner leur chute |
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US6906036B2 (en) * | 2001-08-16 | 2005-06-14 | Kimberly-Clark Worldwide, Inc. | Anti-aging and wound healing compounds |
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KR20050052666A (ko) * | 2002-10-10 | 2005-06-03 | 다이버사 코포레이션 | 프로테아제, 이를 암호화하는 핵산, 및 이를 제조하고사용하는 방법 |
ES2330291B1 (es) * | 2008-02-29 | 2010-10-18 | Lipotec Sa | Peptidos utiles en el tratamiento de la piel, mucosas y/o cuero cabelludo y su uso en composiciones cosmeticas o farmaceuticas. |
-
2008
- 2008-02-29 ES ES200800597A patent/ES2330291B1/es not_active Expired - Fee Related
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2009
- 2009-02-27 BR BRPI0906064A patent/BRPI0906064B8/pt active IP Right Grant
- 2009-02-27 MX MX2010009485A patent/MX2010009485A/es active IP Right Grant
- 2009-02-27 WO PCT/EP2009/001419 patent/WO2009106343A1/en active Application Filing
- 2009-02-27 EP EP09715427A patent/EP2254908B1/en not_active Not-in-force
- 2009-02-27 PT PT97154272T patent/PT2254908E/pt unknown
- 2009-02-27 AU AU2009218680A patent/AU2009218680B2/en not_active Ceased
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- 2009-02-27 CN CN200980114319.4A patent/CN102015764B/zh not_active Expired - Fee Related
- 2009-02-27 ES ES09715427T patent/ES2399581T3/es active Active
- 2009-02-27 CA CA2716650A patent/CA2716650A1/en not_active Abandoned
- 2009-02-27 SI SI200930509T patent/SI2254908T1/sl unknown
- 2009-02-27 DK DK09715427.2T patent/DK2254908T3/da active
- 2009-02-27 PL PL09715427T patent/PL2254908T3/pl unknown
- 2009-02-27 KR KR1020107021674A patent/KR101656533B1/ko active IP Right Grant
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2010
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- 2010-09-28 ZA ZA2010/06889A patent/ZA201006889B/en unknown
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Patent Citations (1)
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CN1502625A (zh) * | 2002-11-20 | 2004-06-09 | 中国人民解放军军事医学科学院放射医 | 基质金属蛋白酶2的小肽抑制剂 |
Also Published As
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IL207808A0 (en) | 2010-12-30 |
US20110002969A1 (en) | 2011-01-06 |
BRPI0906064B1 (pt) | 2020-04-14 |
AU2009218680A1 (en) | 2009-09-03 |
JP5613062B2 (ja) | 2014-10-22 |
KR101656533B1 (ko) | 2016-09-09 |
BRPI0906064A2 (pt) | 2015-06-30 |
WO2009106343A1 (en) | 2009-09-03 |
JP2011514891A (ja) | 2011-05-12 |
ES2330291B1 (es) | 2010-10-18 |
EP2254908A1 (en) | 2010-12-01 |
PL2254908T3 (pl) | 2013-04-30 |
US9315564B2 (en) | 2016-04-19 |
PT2254908E (pt) | 2013-01-25 |
KR20120058371A (ko) | 2012-06-07 |
HK1151301A1 (en) | 2012-01-27 |
ZA201006889B (en) | 2011-05-25 |
DK2254908T3 (da) | 2013-03-04 |
EP2254908B1 (en) | 2012-11-21 |
ES2399581T3 (es) | 2013-04-02 |
BRPI0906064B8 (pt) | 2021-05-25 |
AU2009218680B2 (en) | 2013-11-21 |
CN102015764A (zh) | 2011-04-13 |
ES2330291A1 (es) | 2009-12-07 |
MX2010009485A (es) | 2011-02-15 |
IL207808A (en) | 2014-02-27 |
CA2716650A1 (en) | 2009-09-03 |
SI2254908T1 (sl) | 2013-06-28 |
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