CN104023737A - 抑制被激活受体的肽及其在化妆品组合物或药物组合物中的用途 - Google Patents
抑制被激活受体的肽及其在化妆品组合物或药物组合物中的用途 Download PDFInfo
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Abstract
本发明涉及具有通式(I)R1-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-R2的肽、包含所述肽的化妆品组合物、制备所述肽的方法以及其用于治疗和/或预防搔痒、炎症、疼痛、呼吸道的疾病和/或障碍的用途。
Description
发明领域
本发明涉及能够抑制蛋白酶激活受体-2(Proteinase-ActivatedReceptor-2,PAR-2)的活性的肽以及包含所述肽的化妆品组合物或药物组合物，以及它们用于治疗和/或护理通过抑制PAR-2活性得以改善或预防的病况、障碍和/或疾病的用途。
发明背景
蛋白酶参与许多生物过程，从胃肠道管腔中食物内蛋白质的消化到控制细胞周期。蛋白酶的重要作用是其参与信号转导过程，无论这是通过蛋白水解切割配体或细胞表面受体来产生活性配体，还是相反地，降解和灭活某些受体的激动剂。被蛋白酶攻击从而产生活性配体的这些细胞表面受体的一个类型是蛋白酶激活G蛋白偶联受体PAR(蛋白酶激活受体)的家族，对于该家族，蛋白酶在受体的细胞外N末端结构域上在特定位置内切割，该切割意味着充当锚定配体的新的N末端结构域被暴露，从而造成信号转导的开始[Hollenberg M.D.,“Physiology and pathophisiology of Proteinase Activated Receptors(PARs)：proteinases as hormone-like signal messengers：PARs andmore”,(2005),J.Pharmacol.Sci.,97,8-13]。PAR的家族具有4个成员PAR-1至PAR-4，它们被许多蛋白酶激活，例如凝血级联蛋白酶例如凝血酶或TF-FVIIa-FXa复合物、炎症细胞蛋白酶例如肥大细胞蛋白酶(类胰蛋白酶)和白细胞(组织蛋白酶G、弹性蛋白酶和蛋白酶-3)、消化道蛋白酶例如胰蛋白酶以及胰腺和胰腺外胰蛋白酶原、组织蛋白酶例如激肽释放酶以及非哺乳动物蛋白酶例如细菌蛋白酶、真菌、螨或昆虫的蛋白酶[Ossovskaya V.S.和Bunnet N.W.,“Protease-Activated Receptors-contribution to physiology anddisease”,(2004),Physiol.Rev.,84,579-621]。PAR激活存在一定的选择性；凝血酶例如可以以不同程度的强度激活PAR-1、PAR-3和PAR-4，但不激活PAR-2，而胰蛋白酶和类胰蛋白酶(tryptase)或肥大细胞蛋白酶激活PAR-2。
具体地，PAR-2广泛地分布在人体中，包括皮肤、胃肠道和循环、呼吸以及神经系统中，调节不同的生理功能例如凝血、增殖以及存活、炎症、神经传递和疼痛。在病理状况例如止血或炎症中，已观察到PAR-2的过表达[Nystedt S.等人"The Proteinase-activated Receptor2is induced by inflammatory mediators in human endothelial cells.Comparison with the thrombin receptor",(1996),J.Biol.Chem.,1271(25),14910-14915]以及能够激活PAR-2的蛋白酶的过表达。
在皮肤中，PAR-2在几乎所有细胞类型、特别是角质形成细胞中丰富地表达，并且在颗粒层中特别重要，这意味着其表达可能取决于表皮分化的状态。在角质层中，存在3个蛋白酶家族：特异性的表皮丝氨酸蛋白酶例如激肽释放酶-5(SCTE或角质层胰蛋白酶)或激肽释放酶-7(SCCE或角质层胰凝乳蛋白酶)、半胱氨酸蛋白酶例如组织蛋白酶C、L和V(角质层硫基蛋白酶)和至少一种天冬氨酸蛋白酶(组织蛋白酶D)。这些蛋白酶的活性受到特定抑制剂的密切调节，并且充当皮肤中的几个细胞反应例如炎症和免疫反应、趋化、细胞因子表达、血管功能、组织和细胞凋亡修复的介质。与所述内源蛋白酶一样，表皮中的信号转导还可由一些外源过敏原蛋白酶例如住家螨类、蟑螂、花粉、某些细菌和真菌引起。PAR-2是所有这些蛋白酶的传感器，在皮肤屏障功能的动态平衡维持中起着重要作用。PAR-2在皮肤屏障功能的动态平衡中的参与已在细胞培养物和动物模型中得以证明；培养物的角质形成细胞中PAR-2的激活抑制细胞增殖，这与在小鼠皮肤上局部施用PAR-2肽激动剂或过敏原后观察到的屏障恢复的延迟和板层状体分泌的抑制一致，同时，在PAR-2敲除小鼠中，相较于它们的野生型表型同窝出生小鼠而言，观察到在对所述屏障功能的破坏后板层状体分泌的增加和屏障功能的加速恢复[Derian C.K.等人,"Differential regulation of human keratinocyte growth anddifferentiation by a novel family of protease-activated receptors",(1997),Cell Growth Differ.,8(7),743-749；Hachem J.-P.等人,“Serine protease signaling of epidermal permeability barrierhomeostasis”,(2006),J.Invest.Dermatol.,126(9),2074-2086；JeongS.K.等人,“Mite and cockroach allergens activate Protease-ActivatedReceptor2and delay epidermal permeability barrier recovery”,(2008),J.Invest.Dermatol.,128(8),1930-1939]。
蛋白酶的异常表达或异常活性、因而PAR-2的过度活化与皮肤障碍或疾病例如特异性皮炎、Netherton综合征、银屑病和脱皮综合征相关[Komatsu N.等人,“Elevated human tissue kallikrein levels inthe stratum corneum and serum of peeling skin syndrome-type Bpatients suggests an over-desquamation of corneocytes”,(2006),J.Invest.Dermatol.,126(10),2338-2342]。还已在皮肤炎症或免疫疾病例如扁平苔癣、特异性皮炎、银屑病[Carvalho R.F.等人”Increasedmast cell expression of PAR-2in skin inflammatory diseases andrelease of IL-8upon PAR-2activation”,(2010),Exp.Dermatol.,19(2),117-122]或酒渣鼻[Hachem J.-P.等人,“Serine protease signaling ofepidermal permeability barrier homeostasis”,(2006),J.Invest.Dermatol.,126(9),2074-2086]中描述了PAR-2的升高的水平。
PAR-2还参与炎症性过程的发展。许多在炎症过程中协调免疫系统的反应的细胞表达PAR型受体，例如嗜酸性细胞浸润物表达PAR-2[Miike S.等人,"Trypsin induces activation and inflammatorymediator release from human eosinophils through Protease-ActivatedReceptor-2",(2001),J.Immunol.,167(11),6615-6622]。在炎症性过程中，潜在的内源性PAR-2激活物被释放，例如白细胞弹性蛋白酶、肥大细胞类胰蛋白酶、由角质形成细胞产生的胰蛋白酶家族的蛋白酶类和溶纤级联的蛋白酶例如因子FVIIa或FXa。这些组分激活角质形成细胞、内皮细胞、炎症细胞和表皮感觉神经中的PAR-2，以通过过调节炎症介质来放大炎症。PAR-2的激活引起一氧化氮依赖性血管舒张[Saifeddine M.等人,"Rat Proteinase-Activated Receptor-2(PAR-2)：cDNA sequence and activity of receptor-derived peptides ingastric and vascular tissue”,(1996),Br.J.Pharmacol.,118,521-530；Sobey C.G.等人,"Activation of Protease-Activated Receptor-2(PAR-2)elicits nitric oxide-dependent dilatation of the basilar arteryin vivo”,(1998),Stroke,29(7),1439-1444]，诱导血浆蛋白的外渗和中性粒细胞的浸润[Vergnolle N.等人,"Characterization of theinflammatory response to Proteinase-Activated Receptor-2-activatingpeptides in the rat paw",(1999),Br.J.Pharmacol.,127(5),1083-1090；Kawabata A.等人,"Increased vascular permeability bya specific agonist of Protease-Activated Receptor-2in rat hindpaw",(1998),Br.J.Pharmacol.,125(3),419-422]，并且刺激促炎细胞因子的分泌[Hou L.等人,"Immunolocalization of Protease-ActivatedReceptor-2in skin：receptor activation stimulates interleukin-8secretion by keratinocytes in vitro",(1998),Immunology,94(3),356-362]。此外，已描述了在小鼠耳上的接触超敏反应性的动物模型中，PAR-2敲除小鼠显示耳肿胀和炎症浸润物体积的减小，确证了PAR-2在过敏性皮炎中起着炎症介质的作用[Kawagoe J.等人,“Effect of Protease-Activated Receptor-2deficiency on allergicdermatitis in the mouse ear”,(2002),Jpn.J.Pharmacol.,88(1),77-84]。还描述了PAR-2干预口腔疾病和障碍例如牙周炎的发展；微生物龈紫单胞菌(Porphyromonas gingivalis)的蛋白酶在活跃的口腔中提供PAR-2，并且诱导IL-6的分泌，从而通过某种机制引起齿龈的粒细胞浸润和牙周炎，所述机制包括前列腺素的释放和基质金属蛋白酶的激活，结果破坏支撑牙齿的胶原组织[Lourbakos A.等人,"Arginine-specific protease from Porphyromonas gingivalis activatesProtease-Activated Receptors on human oral epithelial cells andinduces interleukin-6secretion",(2001),Infect.Immun.,69(8),5121-5130；Holzhausen M.,Spolidorio L.C.and Vergnolle N.,"Roleof Protease-Activated Receptor-2in inflammation,and its possibleimplications as a putative mediator of periodontitis”,(2005),Mem.Inst.Oswaldo Cruz.,100(1),177-180]。
慢性炎症过程还可通过PAR-2介导，如在类风湿关节炎的情况下一样。利用PAR-2-激活肽对小鼠膝关节中的PAR-2的激活导致关节的肿胀和充血(炎症的明确指示剂)。炎症和肿胀的持续时间可根据PAR-2-激活肽的性质而变化。同时，在发炎的滑膜中以及在相邻的肌肉和皮肤中检测到PAR-2表达的增加，推定是通过在诱导过程中释放佐剂至所述组织内引起的，这表明PAR-2表达的增加与不同类型的组织中的慢性炎症反应相关。然而，突变PAR-2敲除小鼠免受通过CFA的关节内和关节周围注射诱发的关节炎[Ferrell W.R.等人,"Essential role for Proteinase-Activated Receptor-2in arthritis",(2003),J.Clin.Invest.,111(1),35-41；Kelso E.B.等人,"Therapeuticpromise of Proteinase-Activated Receptor-2antagonism in jointinflammation",(2006),J.Pharmacol.Exp.Ther.,316(3),1017-1024]。
PAR-2不仅参与伤害感受，而且还参与疼痛的传递。鼠类中PAR-2-激动剂亚炎症剂量的注射诱发通过机械和热刺激维持的痛觉过敏，而这种肉体痛觉过敏在PAR-2敲除动物中不存在[Vergnolle N.等人,"Proteinase-Activated Receptor-2and hyperalgesia：a novelpain pathway",(2001),Nat.Med.,7(7),821-826]。还描述了PAR-2特别地参与炎性痛，内脏痛和由癌症引起的疼痛。例如，胰腺炎与胰蛋白酶原在胰腺中的过早激活相关，所述胰蛋白酶原的过早激活通过PAR-2-依赖性机制诱发痛觉过敏[Hoogerwerf W.A.等人,"TheProteinase-Activated Receptor-2is involved in nociception”,(2001),J.Neurosci.,21(22),9036-9042]以及消化道的不同疾病例如肠易激综合征、溃疡性结肠炎和克罗恩病中的内脏痛[Cenac N.,“Role for proteaseactivity in visceral pain in irritable bowel syndrome”,(2007),J.Clin.Invest.,117(3),636-647]。以相同的方式，在癌性进程中引起的机械异常性疼痛在PAR-2敲除小鼠中消失[Lam D.K.and Schmidt B.L.,“Serine proteases and Protease-Activated Receptor-2-dependentallodynia：a novel cancer pain pathway”,(2010),Pain,149(2),263-272]。文献WO 2009/117481 A1描述了PAR-2活性抑制剂用于治疗慢性痛、炎性痛、手术后疼痛、神经性疼痛、由骨折、骨质疏松性骨折、癌症引起的疼痛或由痛风引起的关节痛等的用途。
PAR-2明显地促成神经原性炎症，因为其在周围系统的感受伤害性肽能神经元中表达，所述神经元负责该炎症。在神经原性炎症过程中，不同的内源丝氨酸蛋白酶例如肥大细胞类胰蛋白酶和角质形成细胞胰蛋白酶激活感觉神经末稍中的PAR-2以释放降钙素基因相关肽(CGRP)和物质P(SP)。这些神经肽是促炎性的：它们诱导血管扩张、水肿和白细胞募集反应，导致神经原性炎症[Steinhoff M.等人“Agonists of Proteinase-Activated Receptor-2induce inflammation bya neurogenic mechanism”,(2000),Nat.Med.,6(2),151-158]。
PAR-2激活还介导搔痒的诱发[Shimada S.G.,等人,“Scratchingbehavior in mice induced by the Proteinase-Activated Receptor-2agonist,SLIGRL-NH2”,(2006),Eur.J.Pharmacol.,530(3),281-283]，并且这种搔痒不依赖于组胺。PAR-2的激活触发物质P的释放，其不仅引起搔痒，还促进通过TRK受体和所造成的类胰蛋白酶的释放进行的肥大细胞持续活化，这继而激活PAR-2[Greaves M.,"Recentadvances in pathophysiology and current management of itch",(2007),Ann.Acad.Med.Singapore.,36(9),788-792]。类胰蛋白酶的水平在牵涉搔痒的障碍或疾病中例如特异性皮炎中异常地高，其中类胰蛋白酶的浓度高达在健康皮肤中观察到的所述浓度的4倍[SteinhoffM.等人,"Proteinase-Activated Receptor-2mediates itch：a novelpathway for pruritus in human skin",(2003),J.Neurosci.,23(15),6176-6180]。描述了PAR-2拮抗剂能够抑制胰蛋白酶-诱发的抓挠[Costa R.等人“Evidence for the role of neurogenic inflammationcomponents in trypsin-elicited scratching behaviour in mice”,(2008),Br.J.Pharmacol.,154(5),1094-1103]。该性质开启了通过PAR-2活性抑制剂治疗牵涉搔痒的不同病况、障碍或疾病(例如皮炎，包括接触性皮炎和特异性皮炎、荨麻疹、食物过敏或对昆虫叮咬的过敏等)的大门。
PAR-2使瞬时受体电位辣椒素1(transient receptor potentialvanilloid1，TRPV-1)致敏，所述辣椒素属于TRP通道超家族，能放大对疼痛、炎症和搔痒的反应[Amadesi S.等人,“Protease-ActivatedReceptor2Sensitizes the Capsaicin Receptor Transient ReceptorPotential Vanilloid Receptor1to Induce Hyperalgesia”,(2004),J.Neurosci.,24(18),4300-4312；Dai Y.等人,"Proteinase-ActivatedReceptor2-Mediated Potentiation of Transient Receptor PotentialVanilloid Subfamily1Activity Reveals a Mechanism forProteinase-Induced Inflammatory Pain",(2004),J.Neurosci.,24(18),4293-4299]。
PAR-2也在人和啮齿类动物中枢神经系统的神经元和星形细胞中表达，并且与缺血和神经变性相关发病机制[Smith-Swintowski V.L.等人,"Protease-Activated Receptor-2(PAR-2)is present in the rathippocampus and is associated with neurodegeneration",(1997),J.Neurochem.,69(5),1890-1896]以及多发性硬化症的发展和实验性自身免疫脑脊髓炎(EAE)有关联[Noorbakhsh F.等人,“Proteinase-Activated Receptor-2modulates neuroinflammation inexperimental autoimmune encephalomyelitis and multiple sclerosis”,(2006),J.Exp.Med.,203(2),425-435]。
PAR-2还在调节色素沉着中起着重要作用。对紫外线辐射的暴露诱发角质形成细胞中PAR-2的过表达[Scott G.等人,"Protease-Activated Receptor-2,a receptor involved in melanosometransfer,is upregulated in human skin by ultraviolet irradiation",(2001),J.Invest.Dermatol.,117(6),1412-1420]，其激活诱发了黑色素瘤吞噬作用，这包括黑色素细胞的黑色素向角质形成细胞的转移，结果导致表皮变黑[Seiberg M.,“Keratinocyte–melanocyte interactionsduring melanosome transfer”,(2001),Pigment Cell Res.,14(4),236-242]。皮肤着色许多年来已成为人类的困扰。具体地，消除色素沉着过多(无论是因年龄引起的(痕、雀斑或皮肤的一般老化)还是因障碍或疾病引起的(黑斑病、黄褐斑、炎症后色素沉着过多))的能力对于希望光滑无瑕的皮肤外观的个体是特别吸引人的。同样地，当对紫外线辐射的暴露延长或过度时，癌性色素沉着过度的损伤或黑色素瘤可能会发展[Dooley T.P.,“Recent advances in cutaneous melanomaoncogenesis research”,(1994),Onco.Res.,6,1-9]，同样地因光老化引起的良性色素沉着过度的斑痕也可发展。描述了PAR-2抑制对皮肤具有脱色素作用[Seiberg M.等人,“Inhibition of melanosome transferresults in skin lightening”,(2000),J.Invest.Dermatol.,115(2),162-167]，从而利用PAR-2活性抑制剂对皮肤的治疗是减少皮肤色素沉着的有效策略，如文献EP 0948308 B1、EP 1077063 B1、US 6750229B2和EP 1139974 A1中描述的。
然而，美白或脱色素化合物的使用，无论是为了治疗色素沉着过多的区域或靠近色素沉着过多区域的区域，还是为了减弱天然皮肤颜色的美容原因，其副作用是增加了被紫外线辐射损伤的风险，因为它们减少了黑色素细胞产生的黑色素的量。黑色素是皮肤的天然光保护剂，因为其以热的形式清除了超过99.9％的所吸收的紫外线辐射[Meredith P.等人,"Radiative relaxation quantum yields forsynthetic eumelanin”,(2004),Photochem.Photobiol.,79(2),211-216]。这意味着少于0.1％的所吸收辐射能够产生自由基，引起直接和间接的DNA损伤，从而引起光老化。化妆品和制药工业通过添加光保护物质的制剂或阳光过滤器来补偿增白剂或脱色剂使用中固有的这种保护作用的缺乏。阳光过滤器保护皮肤免受可引起烧伤的UVB辐射，和免受通过引起加速老化或光老化而更长期地损伤皮肤的UVA辐射。然而，这些物质中的许多物质是潜在地刺激性的、致敏的或有毒的，其使用在不同国家有规定，甚至被限制或被禁止。因此，需要开发具有固有光保护功效的美白或脱色素化合物，所述化合物使得能够减少另外的光保护剂的使用。
PAR-2受体也在呼吸通道中，在有纤毛的和无纤毛的上皮细胞中，以及在腺体、平滑肌、血管平滑肌细胞和内皮细胞中表达[D'Andrea M.等人,"Characterization of Protease-Activated Receptor-2immunoreactivity in normal human tissues”,(1998),J.Histochem.Cytochem.,46(2),157-164]。所述受体被内源性蛋白酶例如在气道上皮细胞中产生的胰蛋白酶[Miki M.等人,"Effect of human airwaytrypsin-like protease on intracellular free Ca2+concentration inhuman bronchial epithelial cells",(2003),J.Med.Invest.,50(1-2),95-107]，或人肺肥大细胞中的分离的类胰蛋白酶[Berger P.等人,"Tryptase and agonists of PAR-2induce the proliferation of humanairway smooth muscle cells",(2001),J Appl Physiol.,91(3),1372-1379]，以及被不同过敏原例如蟑螂、螨例如屋尘螨或霉菌的蛋白酶激活[Sun G.等人,"Interaction of mite allergens Der P3and DerP9with Protease-Activated Receptor-2expressed by lung epithelialcells",(2001),J.Immunol.,167(2),1014-1021；King C.等人,"Dustmite proteolytic allergens induce cytokine release from culturedairway epithelium",(1998),J Immunol.,161(7),3645-3651；Page K.等人,“Mucosal sensitization to German cockroach involvesProtease-Activated Receptor-2”,(2010),Respir.Res.,11(1),62；ChiuL.L.等人,“Mold allergen,Pen c13,induced IL-8expression inhuman airway epithelial cells by activated Protease-ActivatedReceptor1and2”,(2007),J.Immunol.,178(8),5237-5244]。
PAR-2的激活与在气道的过敏性炎症中观察到的肥大细胞浸润相关；在PAR-2敲除动物模型中，当在气道中诱导的过敏性炎症发生时，存在更少的嗜酸性细胞的浸润，而过表达PAR-2的突变体呈现该反应的增强[Schmidlin F.等人,"Protease-Activated Receptor-2mediateseosinophil infiltration and hyperreactivity in allergic inflammation ofthe airway",(2002),J.Immunol.,169(9),5315-5321]。同样地，具有哮喘的患者在呼吸上皮细胞中但不在平滑肌或肺泡巨噬细胞中过表达PAR-2[Knight D.A.等人,"Protease-Activated Receptors in humanairways：upregulation of PAR-2in respiratory epithelium frompatients with asthma",(2001),J.Allergy Clin.Immunol.,108(5),797-803]。因此，PAR-2活性的抑制是用于治疗气道的炎性疾病例如变应性鼻炎、慢性阻塞性肺疾病、支气管超反应性和哮喘的有用策略。
PAR-2在不同的肿瘤细胞和组织中表达[D'Andrea M.R.等人,"Differential expression of Protease-Activated Receptors-1and-2instromal fibroblasts of normal,benign,and malignant human tissues",(2001),Am.J.Pathol.,158(6),2031-2041；Elste A.P.and Petersen I.,“Expression of proteinase-activated receptor1-4(PAR1-4)in humancancer”,(2010),J.Mol.Histol.,41(2-3),89-99]，并且在不同恶性肿瘤例如胃、结肠、胰腺、肺、气道、前列腺、子宫和乳腺的恶性肿瘤的侵袭和肿瘤生长中起着重要作用[Darmoul D.等人,"Initiation ofhuman colon cancer cell proliferation by trypsin acting atProtease-Activated Receptor-2”,(2001),Br.J.Cancer,85(5),772-779；Ikeda O.等人,“Signal of Proteinase-Activated Receptor-2contributes to highly malignant potential of human pancreatic cancerby up-regulation of interleukin-8release”,2006,Int.J.Oncol.,28(4),939-946；Jin E.等人,"Protease-Activated Receptor[PAR]-1andPAR-2participate in the cell growth of alveolar capillary endotheliumin primary lung adenocarcinomas”,(2003),Cancer,97(3),703-713；Li Z.等人,“Expression of Protease-Activated Receptor-2(PAR-2)inpatients with nasopharyngeal carcinoma：correlation withclinicopathological features and prognosis”,(2009),Pathol.Res.Pract.,205(8),542-550；Wilson S.等人,“The membrane-anchoredserine protease,TMPRSS2,activates PAR-2in prostate cancer cells”,(2005),Biochem.J.,388(Pt3),967-972；Sánchez-Hernández P.E.等人,“Protease-Activated Receptor-2(PAR-2)in cervical cancerproliferation”,(2008),Gynecol.Oncol.,108(1),19-26；Morris D.R.等人,“Protease-Activated Receptor-2is essential for factor VIIa andXa-induced signaling,migration,and invasion of breast cancer cells”,(2006),Cancer Res.,66(1),307-314]。PAR-2活化产生经典的细胞内信号，包括有助于肿瘤细胞的增殖和迁移的促血管生成因子的广泛文库的诱导；因此PAR-2活性的抑制是限制肿瘤生长和转移的有用策略，如文献US2006/0104944 A1中描述的。
化妆品和制药工业已在许多情况下努力寻求抑制PAR-2的分子或提取物，例如文献WO 2006/035936 A1,WO 2006/127379 A2、US 2004/0266687 A1、US 2006/0142203 A1和US 2006/0183664 A1等中描述的那些分子或提取物。然而，尽管存在现有化合物和/或提取物的库，但化妆品和医药领域仍然热衷于开发现有技术中已知的化合物的替代品以用于治疗和/或护理通过抑制PAR-2活性得到改善或预防的那些病况、障碍和/或疾病。
发明详述
本发明为上述问题提供了解决方案。出人意料地，本发明的发明人已发现PAR-2的活性可以被某些合成肽抑制。所述肽可用于治疗和/或护理能够通过PAR-2活性的抑制而得到改善或预防的那些病况、障碍和/或疾病。
定义
为了便于理解本发明，本文中使用的一些术语和表述的含义被包括在内。
在本发明的背景下，“皮肤”应理解为是构成它的多个层，从最上层或角质层至最下层或皮下组织(二者都包括在内)。这些层由不同类型的细胞组成，如角质形成细胞、成纤维细胞、黑素细胞、肥大细胞、神经元和/或脂肪细胞等。术语“皮肤”也包括头皮。
如在本发明的背景下使用的，术语“治疗”指的是施用根据本发明的肽以减轻或消除一种疾病或障碍或者减少或消除与这种疾病或障碍相关的一种或多种症状。术语“治疗”还涵盖了减轻或消除该疾病或障碍的生理后果的能力。
在本发明的背景下，“护理”包括疾病和/或障碍的预防。
在本发明的背景下使用的术语“预防”，指的是本发明的肽在疾病或障碍出现前防止、延迟、或阻碍其出现或发展的能力。
在本发明的背景下，术语“老化”指的是皮肤随着年龄的增长而经历的变化(慢性老化(chronoaging)),或通过暴露于日光(光老化)或暴露于环境因素如烟草烟雾、寒冷或风的极端气候条件、化学污垢或污染物而经历的变化，包括所有外在可见的和/或通过触摸可感知的变化，例如但不限于：皮肤上的不连续性的发展(如皱纹、细纹、表情纹、妊娠纹、条纹、沟纹、不平整或粗糙、毛孔尺寸增大、水分损失、弹性损失、紧致性损失、平滑性损失、变形恢复能力损失、回弹性损失)、皮肤下垂(如脸颊下垂、眼睛下方出现眼袋、或出现双下巴等)、皮肤颜色的变化(如瘢痕、变红、袋、或出现色素过度沉着区域如老年斑或雀斑等)、异常分化、过度角质化、弹性组织变性、角化症、脱发、橘皮样皮肤、胶原结构损失，以及角质层、真皮、表皮、血管系统(例如出现蜘蛛静脉或毛细血管扩张症)或靠近皮肤的那些组织的其他组织学变化。术语“光老化”统指由于皮肤长期暴露于紫外线辐射而导致皮肤过早老化的这些过程，这些过程呈现出与老化相同的物理特征，例如但不限于：松弛、下垂、在色素沉着中的颜色变化或不平整、异常和/或过度角质化。
在本描述中用于氨基酸的缩写遵循IUPAC-1UB生化命名委员会(IUPAC-1UBCommission of Biochemical Nomenclature)在Eur.J.Biochem.，(1984)，138：9-37中所指定的规则。
因此，例如，Ala表示NH2-CH(CH3)-COOH，Ala-表示NH2-CH(CH3)-CO，-Ala表示-NH-CH(CH3)-COOH，并且-Ala-表示-NH-CH(CH3)-CO-。因此，表示肽键的连字符在位于该符号的右侧时消除了该氨基酸(在此用常规非离子化形式来表示)1-羧基中的OH，在位于该符号的左侧时消除了该氨基酸2-氨基中的H；两种修饰可以应用于同一个符号(见表1)。
表1
缩写“Ac-”在本描述中用来表示乙酰基(CH3-CO-)，缩写“Palm-”用来表示棕桐酰基(CH3-(CH2)14-CO-)。
术语“非环状脂族基”在本发明中用来涵盖直链或支链的烷基、烯基以及炔基。
术语“烷基”指的是饱和的直链或支链基团，该基团具有1至24个、优选1至16个、更优选1至14个、甚至更优选1至12个、还更优选1、2、3、4、5、或6个碳原子，并且该基团通过单键而结合至分子的其余部分，该基团包括例如但不限于：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-甲基己基以及类似基团。
术语“烯基”指的是直链的或支链的基团，该基团具有2至24个、优选2至16个、更优选2至14个、甚至更优选2至12个、还更优选2、3、4、5、或6个碳原子，其中具有一个或多个碳-碳双键，优选具有1、2或3个共轭的或非共轭的碳-碳双键，该基团通过单键而结合至分子的其余部分，该基团包括例如但不限于：乙烯基(-CH2＝CH2)、烯丙基(-CH2-CH＝CH2)、油基、亚油基以及类似基团。
术语“炔基”指的是直链的或支链的基团，该基团具有2至24个、优选2至16个、更优选2至14个、甚至更优选2至12个、还更优选2、3、4、5、或6个碳原子，其中具有一个或多个碳-碳三键、优选具有1、2或3个共轭的或非共轭的碳-碳三键，该基团通过单键而结合至分子的其余部分，该基团包括例如但不限于：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1-戊炔基以及类似基团。炔基还可包含一个或多个碳-碳双键，包括例如但不限于1-丁烯-3-炔基、4-戊烯-1-炔基基团以及类似基团。
术语“环脂族基(alycyclyl group)”在本发明中用来指例如但不限于：环烷基或环烯基或环炔基。
术语“环烷基”指的是饱和的单环或多环脂族基，该基团具有3至24个、优选3至16个、更优选3至14个、甚至更优选3至12个、还更优选3、4、5、或6个碳原子，并且通过单键而结合至分子的其余部分，该基团包括例如但不限于：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、八氢茚基、十氢萘基、十二氢非那烯基以及类似基团。
术语“环烯基”指的是非芳香族的单环或多环脂族基，该基团具有5至24个、优选5至16个、更优选5至14个、甚至更优选5至12个、还更优选5或6个碳原子，其中具有一个或多个碳-碳双键、优选具有1、2或3个共轭的或非共轭的碳-碳双键，并且该基团是通过单键而结合至分子的其余部分，该基团包括例如但不限于：环戊-1-烯-1-基和类似基团。
术语“环炔基”指的是非芳香族的单环或多环脂族基，该基团具有8至24个、优选8至16个、更优选8至14个、甚至更优选8至12个、还更优选8或9个碳原子，其中具有一个或多个碳-碳三键、优选具有1、2或3个共轭的或非共轭的碳-碳三键，并且该基团是通过单键而结合至分子的其余部分，该基团包括例如但不限于：环辛-2-炔-1-基和类似基团。环炔基还可包含一个或多个碳-碳双键，包括例如但不限于环辛-4-烯-2-炔基以及类似基团。
术语“芳基”指的是芳香族基团，该基团具有6至30个、优选6至18个、更优选6至10个、甚至更优选6或10个碳原子，该基团包含通过碳-碳键结合的或稠合的1、2、3、或4个芳环，该基团包括例如但不限于：苯基、萘基、联苯基、茚基、菲基或蒽基等；或芳烷基。
术语“芳烷基”指的是被芳香族基团取代的烷基，其具有7至24个碳原子，该芳烷基包括例如但不限于：-(CH2)1-6-苯基、-(CH2)1-6-(1-萘基)、-(CH2)1-6-(2-萘基)、-(CH2)1-6-CH(苯基)2以及类似基团。
术语“杂环基”指的是具有3至10个成员的碳氢化环，其中该环中的一个或多个原子、优选该环中的1、2、或3个原子是不同于碳的元素如氮、氧、或硫，并且该基团可以是饱和的或不饱和的。为了本发明的目的，杂环可以是环状系、单环系、双环系、或三环系，其可以包括稠环系；并且在杂环基中的氮、碳、或硫原子可以任选地被氧化；氮原子可以任选地被季铵化；并且该杂环基可以是部分或完全地饱和的或者芳香性的。最优选的是，术语“杂环基”指的是具有5或6元环。饱和杂环基团的实例是二噁烷、哌啶、哌嗪、吡咯烷、吗啉和硫吗啉。芳香杂环基团(也称为杂芳基)的实例是吡啶、吡咯、呋喃、噻吩、苯并呋喃、咪唑啉、quinolein、喹啉、哒嗪和二氮萘。
术语“杂芳基烷基”指的是被取代的或未取代的芳香族杂环基取代的烷基，该烷基具有1至6个碳原子，并且该芳香族杂环基具有2至24个碳原子以及1至3个除碳以外的原子，并且该杂芳基烷基包括例如但不限于-(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-吡咯烷基以及类似基团。
如在本技术领域中所理解的，在上述的基团中可以有一定程度的取代。因此，在明确提及时，在本发明的任何基团中都可以有取代。本文件中在本发明的基团中提及取代的基团指的是指定的基团可以在一个或多个可用的位置、优选在1、2、或3个位置、更优选在1或2个位置、还更优选在1个位置上被一个或多个取代基取代。这些取代基包括例如但不限于：C1-C4烷基；羟基；C1-C4烷氧基；氨基；氨基C1-C4烷基；C1-C4羰氧基；C1-C4氧基羰基；卤素如氟、氯、溴以及碘；氰基；硝基；叠氮基；C1-C4烷基磺酰基；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、具有3至10个成员的杂环基、或氨基的保护基。
本发明的化合物
本发明的肽由通式(I)所定义
R1-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-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，其特征在于：
AA1选自-Phe-、-Ser-、-Trp-和-Phg-；
AA2选自-Met-、-Phe-、-Nle-、-Trp-、-Phg-和-Nva-；
AA3选自-Arg-、-Gln-、-Trp-、-Lys-、-Orn-、-His-、-Cit-、-Asn-和-Phg-；
AA4选自-Asp-、-Phe-、-Asn-、-Gln-、-Tyr-、-Trp-和-Phg-；
AA5选自-His-、-Ile-、-Orn-、-Cit-、-Nle-和-Nva-；
AA6选自-Ser-、-Val-、-Thr-、-Nle-、-Ile-、-Ala-和-Nva-；
W、X、Y、Z是氨基酸并且各自独立地选择；
n、m、p、以及q各自独立地选择并且具有0或1的值；
n+m+p+q小于或等于2；
R1选自H、非环状的取代的或未取代的脂肪族基团、取代的或未取代的脂环基、取代的或未取代的杂环基、取代的或未取代的杂芳基烷基、取代的或未取代的芳基、取代的或未取代的芳烷基、以及R5-CO-，其中R5选自H、非环状的取代的或未取代的脂肪族基团、取代的或未取代的脂环基、取代的或未取代的芳基、取代的或未取代的芳烷基、取代的或未取代的杂环基以及取代的或未取代的杂芳基烷基；
R2选自-NR3R4、-OR3和-SR3，其中R3和R4独立地选自H、非环状的取代的或未取代的脂肪族基团、取代的或未取代的脂环基、取代的或未取代的杂环基、取代的或未取代的杂芳基烷基、取代的或未取代的芳基以及取代的或未取代的芳烷基；并且
R1和R2不是α-氨基酸。
基团R1和R2分别地结合至所述肽序列的氨基末端(N-末端)和羧基末端(C-末端)。
根据本发明的一个优选实施方式，R1选自由H或R5-CO-形成的组，其中R5选自取代的或未取代的C1-C24烷基、取代的或未取代的C2-C24烯基、取代的或未取代的C2-C24炔基、取代的或未取代的C3-C24环烷基、取代的或未取代的C5-C24环烯基、取代的或未取代的C8-C24环炔基、取代的或未取代的C6-C30芳基、取代的或未取代的C7-C24芳烷基、具有3至10个环成员的取代的或未取代的杂环基，以及具有2至24个碳原子和1至3个不同于碳的原子以及具有1至6个碳原子的烷基链的取代的或未取代的杂芳基烷基。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、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。在一个甚至更优选的实施方式中，R1是乙酰基或棕榈酰基。
根据另一个优选的实施方式，R2是-NR3R4、-OR3或-SR3，其中R3和R4独立地选自H、取代的或未取代的C1-C24烷基、取代的或未取代的C2-C24烯基、取代的或未取代的C2-C24炔基、取代的或未取代的C3-C24环烷基、取代的或未取代的C5-C24环烯基、取代的或未取代的C8-C24环炔基、取代的或未取代的C6-C30芳基、取代的或未取代的C7-C24芳烷基、取代的或未取代的具有3至10个环成员的杂环基、以及取代的或未取代的具有2至24个碳原子和1至3个不同于碳的原子并且其中烷基链具有1至6个碳原子的杂芳基烷基。任选地，R3和R4可以通过饱和的或不饱和的碳-碳键结合，从而形成带有氮原子的环。更优选地，R2是-NR3R4或-OR3，其中R3和R4独立地选自H、取代的或未取代的C1-C24烷基、取代的或未取代的C2-C24烯基、取代的或未取代的C2-C24炔基、取代的或未取代的C3-C10环烷基、取代的或未取代的C6-C15芳基、以及取代的或未取代的具有3至10个成员的杂环基、取代的或未取代的带有具有3至10个成员的环且具有1至6个碳原子的烷基链的杂芳基烷基。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。甚至更优选地，R3是H并且R4选自H、甲基、乙基、己基、十二烷基、或十六烷基。根据甚至更优选的一个实施方案，R2选自-OH和-NH2。
根据本发明的另一个实施方式，R1选自H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基，AA1是-L-Phe-、AA2是-L-Met-、AA3是-L-Trp-、AA4是-L-Phe-、AA5是-L-His-、AA6是-L-Val-，R2是-NR3R4或-OR3，其中R3和R4独立地选自H、甲基、乙基、己基、十二烷基以及十六烷基，优选地R2是–OH或-NH2。更优选地，R1是乙酰基或棕榈酰基，并且R2是-NH2。甚至更优选地，n、m、p以及q是0。
根据本发明的另一个实施方式，R1选自H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基，AA1为-L-Phe-、AA2为-L-Phe-、AA3为-L-Trp-、AA4为-L-Phe-、AA5为-L-His-、AA6为-L-Val-并且R2为-NR3R4，其中R3和R4独立地选自H、甲基、乙基、己基、十二烷基以及十六烷基，优选地R2为-OH或-NH2。更优选地，R1是乙酰基或棕榈酰基并且R2是-NH2。甚至更优选地，n、m、p以及q是0。
根据本发明的另一个实施方式，R1选自H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基，AA1是-L-Phe-，AA2是-L-Phe-，AA3是-L-Trp-，AA4是-L-Asp-，AA5是-L-Ile-，AA6是-L-Val-，并且R2是-NR3R4或-OR3，其中R3和R4独立地选自H、甲基、乙基、己基、十二烷基以及十六烷基，优选R2是-OH或-NH2。更优选地，R1是乙酰基或棕榈酰基并且R2是-NH2。甚至更优选地，n、m、p、以及q是0。
根据本发明的另一个实施方式，R1选自H、乙酰基、月桂酰基、肉豆蔻酰基以及棕榈酰基，优选地R1选自H、乙酰基和棕榈酰基，并且R2选自-OH和-NH2。
根据本发明的另一个实施方式，n、m、p以及q是0。
具体地，根据式(I)所示的抑制本发明的PAR-2活性的肽选自表2中概述的序列，其中详述了它们的序列标识符：
表2
它们的立体异构体、其混合物和/或其化妆品上或药学上可接受的盐。
本发明的肽可以作为立体异构体或立体异构体的混合物存在；例如，构成它们的氨基酸可以具有L-、D-的构型、或彼此独立地是外消旋的。因此，有可能获得同分异构混合物以及外消旋混合物或非对映混合物、或纯的非对映异构体或对映异构体，这取决于不对称碳的数目和存在什么同分异构体或同分异构混合物。本发明的这些肽的优选的结构是纯的同分异构体，即对映异构体或非对映异构体。
例如，当指出AA1可以是Ser-时，应理解AA1选自-L-Ser-、-D-Ser-或两者的混合物，可以是外消旋的或非外消旋的。在本文件中描述的制备方法使本领域的普通技术人员能够通过选择具有正确构型的氨基酸来获得本发明的肽的每种立体异构体。
在本发明的背景下，术语“氨基酸”包括由遗传密码编码的氨基酸和非编码的氨基酸，不论它们是天然的或非天然的。非编码的氨基酸的实例有，但不限于，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、羟脯氨酸、别-异亮氨酸、别-苏氨酸、异哌啶酸、异丝氨酸、苯基甘氨酸、他汀、β-丙氨酸、正亮氨酸、N-甲基氨基酸、α氨基酸以及β氨基酸等以及其衍生物。非天然氨基酸的列表可以见于D.C.Roberts和F.Vellaccio的论文"Unusual aminoacids in peptide synthesis",in The Peptides,第5卷(1983),第VI章,Gross E.and Meienhofer J.,Eds.,Academic Press,New York,USA或本领域的专业化公司的商业目录中。
在本发明的背景下，当n、m、p、或q不是0时，应清楚地理解W、X、Y和/或Z的性质不会妨碍本发明的肽的活性，但是它有助于抑制PAR-2的活性或对其无作用。
由本发明提供的肽的化妆品上和药学上可接受的盐也在本发明的领域内。术语“化妆品上或药学上可接受的盐”意指被认可它在动物并且更确切地说人类中的使用的盐，包括用于形成碱加成盐的盐，它们或者是无机的，例如但不限于，锂、钠、钾、钙、镁、锰、铜、锌或铝等，它们或者是有机的，例如但不限于，乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、精氨酸、赖氨酸、组氨酸或哌嗪等；或用于形成酸加成盐的盐，它们或者是有机的，例如但不限于，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、三氟乙酸盐、草酸盐、扑酸盐(pamoate)或葡萄糖酸盐等，它们或者是无机的，例如但不限于，氯化物、硫酸盐、硼酸盐或碳酸盐等。盐的性质不是关键性的，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熟知的常规方法来获得[BergeS.M.等人,"Pharmaceutical Salts",(1977),J.Pharm.Sci.,66,1-19]。
本发明的另一个方面涉及本发明中所述的具有通式(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PAR-2活性的抑制中的使用。
在本发明的又一个具体方面，本发明涉及本发明中描述的具有通式(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药剂中的使用。
在另一个具体方面，本发明涉及本发明中描述的具有通式(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搔痒、炎症、疼痛、气道的疾病和/或障碍的治疗和/或预防中的使用。
在一个优选实施方案中，搔痒选自与病况、疾病和/或障碍相关的搔痒，所述疾病是例如但不限于皮炎、特异性皮炎、接触性皮炎、尿布皮炎、疱疹样皮炎、光照性皮肤病、光敏感性、与怀孕相关的皮肤病、与绝经相关的皮肤病、湿疹、敏感性皮肤、银屑病、水痘、疱疹、带状疱疹、Netherton综合征、脱皮综合征、扁平苔癣、粉刺、头皮屑、皮脂溢、皮脂溢皮炎、脱发、运动员足、念珠菌病、痔疮、阴道搔痒、肛门搔痒症、肛生殖道搔痒症、晒斑、荨麻疹、搔痒性耳炎、老年皮肤搔痒症、水源性搔痒症、结节性痒疹、prurigoplanus、玫瑰糠疹、干燥病和干性皮肤、或与透析、HIV感染、恶性肿瘤、何杰金氏病、白血病、骨髓瘤、淋巴瘤、实体瘤、腺癌、肺癌、肝病、黄疸、胆汁淤积、肝功能衰竭、肝硬化、红细胞增多症、高嗜酸细胞增多综合征、原发性血小板增多症、骨髓增生异常综合征、缺铁引起的贫血、系统性红斑狼疮、内分泌疾病、甲状腺疾病、甲状腺功能亢进、甲状腺功能减退、甲状旁腺疾病、糖尿病、肾病、肾功能衰竭、尿毒症、寄生虫病、疥疮、虱、蛔虫、过敏反应、对药物的过敏、食物过敏、对化学制品的过敏、对有毒植物的暴露、对虫咬的暴露、化学疗法、压力和焦虑等相关的搔痒。
在另一个具体实施方案中，疼痛选自例如但不限于急性痛、慢性痛、伤害性疼痛、神经性疼痛、炎性痛、内脏痛、腹痛、消化系统痛、呼吸系统痛、泌尿生殖系统痛、内分泌系统痛、心脏痛、胰痛、肝痛、因胆石引起的疼痛、胆汁淤积、肠痛、胃痛、因十二指肠溃疡引起的疼痛、因食道炎引起的疼痛、因胃食管返流疾病引起的疼痛、脾痛、血管中的疼痛、豆状核后综合征痛、肠易激综合征、与克罗恩病相关的疼痛、与溃疡性结肠炎、憩室炎、胃肠道粘膜炎相关的疼痛、头痛、紧张性头痛,与窦炎相关的头痛、偏头痛、眼痛、干眼综合征、手术后疼痛、由外科切口引起的手术后疼痛,由骨中植入物插入引起的手术后疼痛,由骨置换引起的手术后疼痛、因感染引起的手术后疼痛、由截肢引起的手术后疼痛、由骨折引起的疼痛、由癌症引起的疼痛、由骨癌引起的疼痛、与良性骨肿瘤相关的疼痛、与骨样骨瘤相关的疼痛、与成骨细胞瘤相关的疼痛、由癌症治疗引起的疼痛、由化学疗法引起的疼痛、由呕吐引起的疼痛、由化学治疗导致的呕吐引起的疼痛、肌肉骨骼痛、痉挛肌肉疼痛、纤维肌痛、复杂区域疼痛综合征、精神性疼痛、神经痛、由脱髓鞘疾病引起的疼痛、与颈肌张力障碍相关的颈痛、背痛、腰部疼痛、坐骨神经痛、神经原性感染、神经炎、皮肤灼痛、接触敏感性、寒冷敏感性、热敏感性、皮肤刺激、毛发去除后皮肤刺激、剃毛后皮肤刺激、银屑病、敏感性皮肤、皮炎、特异性皮炎、接触性皮炎、尿布皮炎、皮脂溢皮炎、湿疹、扁平苔癣、烧伤、晒斑、关节炎、类风湿关节炎、骨关节炎、牛皮癣关节炎、葡萄膜炎,由神经损伤引起的疼痛、神经痛、疱疹后神经痛、神经病、周围神经病、幻痛、异常性疼痛、痛觉过敏、冷痛觉过敏、由腕管综合征引起的疼痛、灼痛、Grierson-Gopalan综合征(更好地称为烧灼样足综合征)、口灼伤综合征、感觉错乱、Fabry病、面部疼痛、三叉神经痛、由糖尿病引起的神经性疼痛、由AIDS引起的神经性疼痛、口面疼痛、牙痛、由拔牙引起的疼痛、由智齿拔除引起的疼痛、牙齿对冷的敏感性、牙齿对热的敏感性、口腔粘膜炎、颞下颌关节痛、由痛风引起的关节痛、与纹身或纹身去除过程相关的疼痛、拇滑囊肿痛、睾丸痛、肌盘膜痛、膀胱痛、泌尿道痛、膀胱炎、由肾脏结石引起的疼痛、肾绞痛、外阴痛、阴道痛、产后痛、月经疼痛、阴囊痛、会阴痛、骨盆痛或过敏症、皮肤痛或手术后刺激、利用强脉冲光疗法(IPL)治疗后刺激、利用单色脉冲光治疗(激光)进行治疗后的刺激、利用化学剥脱剂治疗后的刺激或对攻击性外部试剂过度暴露后的刺激以及由长期酒精滥用引起的疼痛。
在另一个具体方面，炎症选自例如但不限于神经原性感染、关节炎症、腱炎症、肌肉炎症、败血病、血管炎症、呼吸系统炎症、慢性阻塞性肺疾病、鼻炎、变应性鼻炎、哮喘、耳炎、肠炎、克罗恩病、胰腺炎、肝炎、与慢性炎症相关的病况、急性炎症、肾炎、系统性红斑狼疮、关节炎、类风湿关节炎、成人和青少年类风湿关节炎、斯蒂尔病、牛皮癣关节炎、骨关节炎、由痛风引起的关节炎、类风湿性脊柱炎、肾小球肾炎、神经炎、神经组织炎症、多发性硬化、免疫系统障碍、综合征、动脉粥样硬化、心肌炎、心包炎、脉管炎、炎症性皮肤病况、银屑病、敏感性皮肤、皮炎、特异性皮炎、接触性皮炎、尿布皮炎、皮脂溢皮炎、湿疹、过度增生性皮肤病、烧伤、晒斑、阴道黏液的炎症、外阴痛、阴道炎、口腔粘膜炎症、牙龈炎、牙周炎、炎症性眼病、葡萄膜炎、眼和春季结膜炎、肉瘤样病、溃疡病、荨麻疹、大疱性类天疱疮、纤硬皮病化、纤维化、血管性水肿、过敏反应、脱发、肝硬化、再狭窄、风湿性多肌痛、血清阴性脊柱关节病，包括强直性脊柱炎和Reiter’s综合征、皮肌炎、包涵体肌炎、多肌炎和淋巴管平滑肌增多。
在另一个具体实施方案中，呼吸道的疾病和/或障碍选例如但不限于哮喘,慢性阻塞性肺疾病,变应性鼻炎和支气管高反应性。
在另一个具体方面，本发明涉及本发明中描述的具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐在癌症治疗中的使用。
在另一个具体实施方案中，癌症选自例如但不限于淋巴网状内皮细胞肿瘤、骨癌、骨肉瘤、脂肪肉瘤、乳腺癌、胃癌、胰腺癌、膀胱癌、肠癌、子宫内膜癌、子宫癌、头颈癌、肺癌、呼吸道的癌症、黑色素瘤、卵巢癌、前列腺癌、皮肤癌和直肠癌等。
在另一个具体方面，本发明涉及本发明中所描述的具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于消化系统的病况、障碍和/或疾病的治疗和/或护理。
在另一个具体方面，消化系统的病况、障碍和/或疾病选自例如但不限于乳糜泻、食物过敏、克罗恩病、胃肠炎、炎性肠病、肠绞痛、肝炎、结肠炎、溃疡性结肠炎、肠易激综合征、食道炎、胃食管返流疾病、特发性胃肌轻瘫、胰腺炎包括慢性胰腺炎和胃与十二指肠溃疡。
本发明的另一个方面涉及本发明中描述的具有通式(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皮肤和粘膜的治疗和/或护理中的使用。
在另一个具体方面，本发明涉及本发明中描述的具有通式(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刺激和/或护理皮肤屏障功能中的使用。
在另一个具体方面，本发明涉及本发明中描述的具有通式(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皮肤和/或粘膜的上皮再形成和/或愈合中的使用。
在另一个具体方面，本发明涉及本发明中描述的具有通式(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皮肤的脱色素化和/或光保护中或在那些皮肤病况、障碍和/或疾病(所述皮肤病况、障碍和/或疾病通过减少皮肤的色素沉着或通过皮肤的光保护得到改善或预防)的治疗和/或护理中的使用。
在另一个具体方面，通过减少皮肤的色素沉着或通过皮肤的光保护得到改善或预防的皮肤病况、障碍和/或疾病选自例如但不限于雀斑、雀斑样痣、黑斑病、花斑、爱迪生病、白斑、因对UV辐射的暴露而引起的斑点、因老化或光老化而引起的斑点、因炎症而引起的斑点，和特别地因激光或ILPL治疗或美容手术后而引起的炎症、因粉刺、湿疹、褐黄病而引起的斑点、因疤痕和/或激素失调而引起的斑点例如黑变病和黑斑病。
在另一个具体方面，本发明涉及本发明中描述的具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐在头皮的治疗中和/或毛细血管卫生中的使用，特别地在脱发、头皮屑和/或脂溢性皮炎的治疗和/或护理中的使用。
在另一个具体方面，本发明涉及本发明中描述的具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐在口腔粘膜的治疗中和/或口腔卫生中的使用，特别地在牙周炎和/或牙龈炎的治疗和/或护理中的使用。
在另一个具体方面，本发明涉及本发明中描述的具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐在阴道粘液的治疗和/或个人卫生中的使用，特别地在念珠菌病、阴道搔痒、肛门搔痒症、肛生殖道搔痒症和/或痔疮的治疗和/或护理中的使用。
在另一个具体方面，发明涉及本发明中描述的具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐在皮肤致敏剂，特别地化妆品组合物中的过敏原的抑制中的使用。
在另一个具体方面，本发明涉及本发明中描述的具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐通过局部、经皮肤、口服或胃肠外途径施用。
在另一个具体方面，本发明涉及在本发明中所描述的具有通式(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，其中该局部或透皮施用是通过离子导入、超声促渗、电穿孔、机械压迫、渗透压梯度、闭合性疗法(occlusive cure)、显微注射、借助于压力的无针注射、通过微电子贴剂、面膜或其任何组合来进行。
在另一个具体方面，该治疗和/或护理是通过口服给药来进行。
本发明的肽的制备过程
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合成可以根据现有技术中已知的常规方法来进行，如使用固相肽合成的方法[Stewart J.M.和Young J.D.,“Solid PhasePeptide Synthesis,2nd edition”,(1984),Pierce Chemical Company,Rockford,Illinois；Bodanzsky M.和Bodanzsky A.,“The practice ofPeptide Synthesis”,(1994),Springer Verlag,Berlin；Lloyd-WilliamsP.等人,“Chemical Approaches to the Synthesis of Peptides andProteins”,(1997),CRC,Boca Raton,FL,USA]、在溶液中合成、固相合成与在溶液中合成的方法的组合或酶合成[Kullmann W.“Proteasesas catalysts for enzymic syntheses of opioid peptides”,(1980),J.Biol.Chem.,255(17),8234-8238]。肽还可以通过细菌菌株(修饰或未修饰的)的发酵，通过以产生所希望的序列为目标的基因工程法、或通过具有动物或植物来源，优选植物来源的蛋白质的受控水解来获得，这释放至少含有所希望的序列的肽片段。
例如，获得本发明的肽⑴、其立体异构体及其混合物的方法包括以下步骤：
-将具有受保护的N-末端和游离的C-末端的氨基酸与具有游离的N-末端和受保护的或与固体载体结合的C-末端的氨基酸偶联；
-消除N-末端的保护基团；
-重复该偶联顺序和消除N-末端的保护基团，直到获得所希望的肽序列；
-消除C-末端的保护基团或从该固体载体裂解。
优选地，C-末端与固体载体结合并且该方法在固相上进行，因此，其包括将具有受保护的N-末端和游离的C-末端的氨基酸与具有游离的N-末端和与聚合物载体结合的C-末端的氨基酸偶联；消除N-末端的保护基团；并且重复此顺序所需要的次数以便由此获得具有所希望的长度的肽，最后从最初的聚合物载体切下所合成的肽。
在整个合成中氨基酸的侧链的官能团用临时或永久的保护基团来保持方便地保护，并且可以与从该聚合物载体切下肽的过程同时地或正交地脱保护。
或者，固相合成可以使用将肽与该聚合物载体或与预先与该聚合物载体结合的氨基酸偶联的趋同策略(convergent strategy)来进行。趋同合成策略是本领域的普通技术人员广泛已知的并且在Lloyd-Williams P.等人,“Convergent Solid-Phase Peptide Synthesis”,(1993),Tetrahedron,49(48),11065-11133中进行了描述。
该方法可以包括使用现有技术中已知的标准方法和条件、以非确定的顺序对N-末端和C-末端脱保护和/或从该聚合物载体切下肽的另外步骤，在此之后可以修饰这些末端的官能团。可以对与该聚合物载体锚定的具有化学式(I)的肽进行N-末端和C-末端的任选修饰，或在该肽从该聚合物载体分离之后进行N-末端和C-末端的任选修饰。
可任选地，可以通过以下方式来引入R1：通过本发明的肽的N-末端与R1-X化合物的反应，其中R1具有上述含义并且X是离去基团，例如但不限于，甲苯磺酰基基团、甲磺酰基基团以及卤素基团等；通过在适当的碱和溶剂存在的情况下的亲核取代反应，其中具有不参与N-C键形成的官能团的片段用临时或永久的保护基团来适合地保护。
任选地和/或另外地，可以通过以下方式来引入这些R2基团：通过化合物HR2(其中R2是-OR3、-NR3R4或-SR3)与对应于具有化学式⑴的肽(其中R2是-OH)的互补片段在合适溶剂和碱(如N，N-二异丙基乙胺(DIEA)或三乙胺)或添加剂(如1-羟基苯并三唑(HOBt)或1-羟基氮杂苯并三唑(HOAt))以及脱水剂(如碳二亚胺、脲盐、盐或脒盐(amidinium salt)等)存在的情况下的反应；或通过用例如亚硫酰氯预先形成酰基卤，由此获得根据本发明的具有通式(I)的肽，其中具有不参与N-C键形成的官能团的片段用临时或永久的保护基团适合地保护；或可替代地，其他R2基团可以通过与从该聚合物载体的肽裂解过程的同时结合来引入。
本领域的普通技术人员将会容易地理解可以根据现有技术中已知的方法以不同的顺序来进行C-末端和N-末端的脱保护/裂解步骤及其随后的衍生化。
术语“保护基团”涉及封闭有机官能团并且可以在受控制的条件下去除的基团。所述保护基团、其相对反应性以及它们保持惰性的条件是本领域的普通技术人员已知的。
氨基基团的代表性保护基团的实例是酰胺，如乙酸酰胺、苯甲酸酰胺、新戊酸酰胺；氨基甲酸酯如苄氧基羰基(Cbz或Z)、2-氯苄基(CIZ)、对-硝基苄氧基羰基(pNZ)、叔丁氧基羧基(Boc)、2,2,2-三氯乙氧基羰基(Troc)、2-(三甲基甲硅烷基)乙氧基羰基(Teoc)、9-芴基甲氧基羰基(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-2,6-二氧代环己-1-亚基)乙基(Dde)、N-(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)等,优选Boc或Fmoc。
羧基基团的代表性保护基团的实例是酯，如叔丁酯(tBu)、烯丙酯(All)、三苯甲基酯(triphenylmethyl ester)(Trt酯)、环己酯(cHx)、苄酯(Bzl)、邻-硝基苄酯、对-硝基苄酯、对-甲氧基苄酯、三甲基甲硅烷基乙酯、2-苯基异丙酯、芴基甲酯(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)等；本发明的优选的保护基团是All、tBu、cHex、Bzl以及Trt酯。
这些三官能的氨基酸的侧链可以在合成过程中用与N-末端和C-末端的保护基团正交的临时或永久保护基团来保护。
酪氨酸侧链的羟基基团可以用2-溴苄氧基羰基基团(2-BrZ)、tBu、All、Bzl或2,6-二氯苄基(2,6-diCIZ)等来保护。苏氨酸和丝氨酸侧链可用选自tBu、Bzl、Trt和Ac的保护基团来保护。组氨酸侧链可由选自Tos、Dnp、甲基(Me)、Boc、苄氧甲基(Bom)、Bzl、Fmoc、Mts、Trt和Mtt的保护基团来保护。谷氨酰胺和天冬酰胺侧链可用Trt基团或 吨基(Xan)来保护或可在不保护的情况下使用。为了保护天冬氨酸侧链的羧基，可使用酯例如tBu酯、All酯、三苯甲基酯(Trt酯)、cHx酯、Bzl酯、邻-硝基苄酯、对-硝基苄酯、对-甲氧基苄酯、三甲基甲硅烷基乙酯、2-苯基异丙酯、Fm酯或Dmab酯等。精氨酸侧链由选自Tos、4-甲氧基-2,3,6-三甲基苯磺酰基(Mtr)、Alloc、硝基、2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基(Pbf)以及2,2,5,7,8-五甲基色满-6-磺酰基(Pmc)的保护基团来保护。色氨酸侧链的吲哚基团可用甲酰基(For)、Boc、Mts来保护或可在不保护的情况下使用。为了保护赖氨酸和鸟氨酸侧链的氨基，可使用酰胺例如乙酸酰胺、苯甲酸酰胺、新戊酸酰胺；氨基甲酸酯如Cbz或Z、ClZ、pNZ、Boc、Troc、Teoc、Fmoc或Alloc、Trt、Mtt、Dnp、Dde、ivDde、Adpoc等。甲硫氨酸侧链可以亚砜形式来进行保护或可在不保护的情况下使用。
在一个优选实施方案中，所使用的保护基团策略是以下策略，其中氨基由Boc保护，羧基基团由Bzl、cHx、或All酯保护，酪氨酸侧链用2-BrZ或Bzl保护，丝氨酸和苏氨酸侧链由Bzl基保护，组氨酸侧链由Tos或Bom基团保护，天冬氨酸侧链由Bzl、cHx或All保护，谷氨酰胺和天冬酰胺可在不保护其侧链的情况下使用，甲硫氨酸可在不保护其侧链的情况下使用，精氨酸侧链由Tos保护，色氨酸侧链由For或Mts保护，赖氨酸和鸟氨酸侧链由ClZ、Fmoc或Alloc保护。
在另一个优选的实施方式中，所使用的保护基团策略是以下策略，其中氨基基团由Fmoc保护，羧基基团由tBu、All或Trt酯保护，酪氨酸侧链由tBu保护，苏氨酸和丝氨酸侧链由tBu基团保护，组氨酸侧链是由Trt或Mtt基团保护，天冬氨酸侧链由tBu或All保护，谷氨酰胺和天冬酰胺以在其侧链内被Trt基团保护的形式使用，甲硫氨酸在不保护其侧链的情况下使用，精氨酸侧链由Pmc或Pbf基团保护，色氨酸侧链由Boc保护或在不保护的情况下使用，赖氨酸和鸟氨酸侧链由Boc、Trt或Alloc保护。
这些和另外的保护基团、其引入以及去除的实例可见于文献[Atherton B.和Sheppard R.C.,“Solid Phase Peptide Synthesis：Apractical approach”,(1989),IRL Oxford University Press]。术语“保护基团”还包括在固相合成中所使用的聚合物载体。
当合成全部或部分地在固相上发生时，在本发明的方法中所使用的可能的固体载体涉及聚苯乙烯载体、接枝至聚苯乙烯上的聚乙二醇以及类似物，例如但不限于，对-甲基二苯甲基胺树脂(MBHA)[Matsueda G.R.等人,“A p-methylbenzhydrylamine resinfor improved solid-phase synthesis of peptide amides”,(1981),Peptides,2,45-50]、2-氯三苯甲基树脂[Barlos K.等人,“Darstellunggeschützter Peptid-Fragmente unter Einsatz substituierterTriphenylmethyl-Harze”,(1989),Tetrahedron Lett.,30,3943-3946；Barlos K.等人,“Veresterung von partiell geschütztenPeptid-Fragmenten mit Harzen.Einsatz von2-Chlorotritylchlorid zurSynthese von Leu1-Gastrin I”,(1989),Tetrahedron Lett.,30,3947-3951]、TentaGer树脂(Rapp Polymere GmbH)、ChemMatrix树脂(Matrix Innovation,Inc)和类似物质，其可以包括或不包括不稳定的接头，如5-(4-氨基甲基-3,5-二甲氧基苯氧基)戊酸(PAL)[AlbericioF.等人,“Preparation and application of the5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxy-phenoxy)valeric acid(PAL)handle for the solid-phase synthesis ofC-terminal peptide amides under mild conditions”,(1990),J.Org.Chem.,55,3730-3743]、2-[4-氨基甲基-(2,4-二甲氧基苯基)]苯氧基乙酸(AM)[Rink H.,“Solid-phase synthesis of protected peptidefragments using a trialkoxy-diphenyl-methylester resin”,(1987),Tetrahedron Lett.,28,3787-3790]，Wang[Wang S.S.,“p-AlkoxybenzylAlcohol Resin and p-Alkoxybenzyloxycarbonylhydrazide Resin forSolid Phase Synthesis of Protected Peptide Fragments”,(1973),J.Am.Chem.Soc.,95,1328-1333]以及类似物质，它们使得能够同时脱保护和从该聚合物载体裂解该肽。
本发明的化妆品组合物或药物组合物
可以通过引起肽与哺乳动物体内的作用部位(优选人体内的作用部位)之间相接触的任何手段、并且以含有它们的组合物的形式来施用本发明的肽以便抑制PAR-2活性。
在这方面，本发明的另一个方面是化妆品组合物或药用组合物，该组合物包含至少一种具有通式(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、以及至少一种化妆品上或药学上可接受的佐剂或赋形剂。这些组合物可以通过本领域的普通技术人员已知的常规手段来制备[“Harry’s Cosmeticology”,Seventh edition,(1982),Wilkinson J.B.,Moore R.J.,ed.Longman House,Essex,GB]。
本发明的肽依它们的序列的性质，或N-末端和/或C-末端中的任何可能的修饰而具有可变的水溶解度。因此，本发明的肽可以通过水溶液而掺入至组合物中，不可溶于水中的那些可以溶解于化妆品上或药学上可接受的常规溶剂中，这些溶剂例如但不限于乙醇、丙醇、异丙醇、丙二醇、甘油、丁二醇、或聚乙二醇或其任意组合。
应该施用的化妆品上或药学上有效量的本发明的这些肽以及它们的药剂量将取决于许多因素，包括患者的年龄、状态、有待治疗和/或护理的病况、障碍或疾病的性质或严重性、施用的途径和频率以及有待使用的肽的具体性质。
“化妆品上和药学上有效量”应理解为意指无毒的但足以提供所希望的作用的本发明肽的量。本发明的肽以用于实现所希望的作用的化妆品上或药学上有效的浓度用于本发明的化妆品组合物或药用组合物中；在优选形式中，相对于该组合物的总重量，在0.00000001％(按重量计)与20％(按重量计)之间；优选地在0.000001％(按重量计)与15％(按重量计)之间，更优选地在0.00001％(按重量计)与10％(按重量计)之间，并且甚至更优选地在0.001％(按重量计)与5％(按重量计)之间。
本发明的肽或其功能上相当的变体、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也可被包含至化妆品或药用递送和/或缓释系统中。
术语“递送系统”涉及与本发明的肽一起施用的稀释剂、佐剂、赋形剂或载体。这些化妆品或药用载体可以是液体，如水、油、或表面活性剂类，包括石油、动物、植物或合成来源的那些，例如但不限于，花生油、大豆油、矿物油、芝麻油、蓖麻油、聚山梨酸酯、脱水山梨糖醇酯、醚硫酸酯、硫酸酯、甜菜碱、糖苷类、麦芽糖苷、脂肪醇、壬苯醇类、泊洛沙姆、聚氧乙烯类、聚乙二醇类、右旋糖、甘油、毛地黄皂苷以及类似物质。本领域的普通技术人员已知在可以施用本发明的肽的不同递送系统中可以使用的稀释剂、佐剂或赋形剂。
术语“缓释”是以涉及化合物的递送系统的常规含义使用，该递送系统提供该化合物在一段时期过程内的逐渐释放，并且优选地、但不是必须地，在一段时期内具有相对恒定的化合物释放水平。
递送或缓释系统的实例包括，但不限于，脂质体、混合脂质体、油质体、非离子型表面活性剂脂质体囊泡(niosome)、醇质体、毫米颗粒、微颗粒、纳米颗粒和固体脂质纳米颗粒、纳米结构的脂质载体、海绵状物、环糊精、囊泡、胶束、表面活性剂的混合胶束、表面活性剂-磷脂混合胶束、毫米球、微球和纳米球、脂质球、毫米胶囊、微米胶囊和纳米胶囊，以及微乳剂和纳米乳剂，可以添加这些递送或缓释系统以便实现有效成分的更好渗透和/或改进它的药物代谢动力学和药效动力学特性。优选的递送或缓释系统是脂质体、表面活性剂-磷脂混合胶束、微乳剂，更优选具有反胶束内部结构的油包水型微乳剂和包含微乳剂的纳米胶囊。
这些缓释系统可以通过现有技术中已知的方法来制备，并且包含它们的组合物可以例如通过以下方式来施用：通过局部或透皮给药，包括粘附贴剂、非粘附贴剂、闭合贴剂、以及微电子贴剂；或通过全身给药例如但不限于，口服或胃肠外途径，包括鼻、直肠、皮下植入或注射，或直接植入或注射至特定身体部位中，并且优选地应该释放相对恒定量的本发明的肽。在该缓释系统中包含的肽的量将取决于例如该组合物将被施用的部位、本发明的肽的释放动力学和持续时间、以及有待治疗和/或护理的病况、障碍和/或疾病的性质。
本发明的肽还可以吸附在固体有机聚合物或固体无机载体上，例如但不限于，滑石、膨润土、二氧化硅、淀粉或麦芽糊精等。
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组合物可以被掺入至与皮肤直接接触的织物、无纺织物以及医疗设备中，从而由于身体湿度、皮肤的PH或身体温度而通过结合系统而生物降解至该织物、无纺织物或医疗设备中、或通过它们与身体之间的摩擦来释放本发明的肽。此外，本发明的这些肽可以被掺入至用于制作与身体直接接触的衣服的织物和无纺织物中。优选地，含有本发明的这些肽的织物、无纺织物以及医疗设备被用于治疗和/或护理通过抑制PAR-2活性得以改善或预防的病况、障碍和/或疾病。
织物、无纺织物、衣服、医疗设备、以及用于将肽固定至它们的手段的实例(包括以上描述的递送系统和/或缓释系统)可以见于文献中并且在现有技术中是已知的[Schaab C.K.(1986)HAPPI May1986；Nelson G.,“Application of microencapsulation in textiles”,(2002),Int.J.Pharm.,242(1-2),55-62；“Biofunctional Textiles and the Skin”(2006)Curr.Probl.Dermatol.v.33,Hipler U.C.and Elsner P.,eds.S.Karger AG,Basel,Switzerland；Malcolm R.K.等人,”Controlledrelease of a model antibacterial drug from a novel self-lubricatingsilicone biomaterial“,(2004),J.Cont.Release,97(2),313-320]。优选的织物、无纺织物、衣服、以及医疗设备是绷带、纱布、t-恤衫、短袜、裤袜、内衣、腰带、手套、尿布、卫生巾、敷料、床罩、擦拭巾、粘附贴剂、非粘附贴剂、封闭贴剂、微电子贴剂和/或面膜。
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这些化妆品组合物或药用组合物可以用于局部或透皮施用的不同类型的组合物中，所述组合物任选地包含用于配制所希望的给药形式所必需的化妆品上或药学上可接受的赋形剂。本领域的技术人员已知可以用于含有本发明肽的化妆品组合物或药用组合物中的不同赋形剂。
局部或透皮施用的组合物可以生产为任何固体、液体或半固体制剂，例如但不限于，乳膏、多重乳状液(例如但不限于水包油和/或硅酮乳剂、油和/或硅酮包水乳剂、水/油/水或水/硅酮/水型乳剂以及油/水/油或硅酮/水/硅酮型乳剂)、无水组合物、含水分散体、油、奶、香膏、泡沫、洗剂、凝胶、乳膏凝胶、水醇溶液、水甘醇溶液、水凝胶、搽剂、浆液、皂、洗发水、护发乳、血清(serum)、多糖膜、软膏、摩丝、润发油、粉末、杆剂(bars)、笔剂以及喷雾剂或气雾剂(喷雾剂)，包括保留型和冲洗型制剂。这些局部或透皮施用制剂可以使用本领域的普通技术人员已知的技术而掺入至不同类型的固体配件中，例如但不限于，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、擦拭巾、粘附贴剂、非粘附贴剂、封闭贴剂、微电子贴剂或面膜，或它们可以被掺入至不同化妆产品中，如化妆粉底(如粉底液和粉饼)、卸妆液、卸妆乳、眼部遮瑕膏、眼影、口红、润唇膏、唇彩以及唇粉等。
本发明的化妆品组合物或药用组合物可以包括增加本发明肽的经皮吸收的药剂，例如但不局限于，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、脲、乙氧基二甘醇、丙酮、丙二醇、或聚乙二醇等。此外，本发明的化妆品组合物或药用组合物可以通过离子导入、超声促渗、电穿孔、微电子贴剂、机械压迫、渗透压梯度、包扎疗法、显微注射、或借助于压力的无针注射(如通过氧气压力的注射)、或其任何组合而被施用至有待治疗的局部区域，以便实现本发明的肽的更大渗透。该施用区域将是由有待治疗和/或护理的病况、障碍和/或疾病的性质来确定。
此外，含有本发明的肽、其立体异构体和/或其化妆品上或药学上可接受的盐的这些化妆品组合物可以在用于口服给药的不同类型的制剂中使用，优选地以口服化妆品或药物的形式，例如但不限于，胶囊剂，包括明胶胶囊剂、软胶囊剂、硬胶囊剂；片剂，包括糖衣片剂、片剂、丸剂、粉末剂、颗粒剂、口香糖；溶液；混悬液；乳剂；糖浆剂；酏剂；多糖膜；胶冻或明胶；以及本领域的普通技术人员已知的任何其他形式。具体地说，本发明的肽可以被结合至任何形式的功能性食品或强化食品中，例如但不限于，膳食条或压缩或非压缩粉末。这些粉末可以溶解于水、苏打水、乳制品、大豆衍生物，或可以被包含于膳食条中。本发明的肽可以与用于口服组合物或食品补充剂的常见赋形剂和佐剂一起配制，例如但不限于，在食品工业中常见的脂肪组分、水性组分、保湿剂、防腐剂、增稠剂、调味剂、香味剂、抗氧化剂以及着色剂。
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品组合物或药用组合物通过局部或透皮途径施用之外，还可以通过任何其他适当的途径如口服或胃肠外途径来施用，为此目的，所述组合物将包括用于配制所希望的给药形式所必需的药学上可接受的赋形剂。在本发明的背景下，术语“胃肠外的”包括经鼻、耳、眼、直肠、尿道、阴道、皮下、皮内途径、血管内注射如静脉内、肌肉内、眼内、玻璃体内、角膜内、脊柱内、髓内、颅内、颈内、脑内、脑膜内、关节内、肝内、胸内、气管内、鞘内和腹膜内，以及任何其它类似注射或输注技术。本领域的普通技术人员已知可籍以施用含有本发明肽的化妆品组合物或药用组合物的不同手段。
在本发明中所描述的化妆品组合物或药用组合物中所包含的化妆品上或药学上可接受的佐剂之中包括：通常用于化妆品组合物或药物组合物中的另外成分，例如但不限于，抑制PAR-2活性的其它试剂、其它抗炎和/或镇痛剂、其它抗搔痒剂、镇定剂、麻醉剂、乙酰胆碱受体聚集抑制剂、肌肉收缩抑制剂、抗胆碱能剂、黑色素合成刺激或抑制剂、增白剂或脱色素剂、色素原形成剂、自晒黑剂(self-tanningagents)、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、抗组胺剂、抗病毒剂、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、保湿剂、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、生物聚合物、胶化聚合物、增稠剂、表面活性剂、软化剂、乳化剂、粘合剂、防腐剂、防皱剂、能够减少或治疗眼袋的药剂、表皮剥落剂(exfoliating agent)、去角质剂(keratolytic agents)、角质剥离剂(desquamating agents)、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药剂、胶原合成刺激剂、弹性蛋白合成刺激剂、饰胶蛋白聚糖(decorin)合成刺激剂、层粘连蛋白合成刺激剂、防御素合成刺激剂、伴侣蛋白合成刺激剂、cAMP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、热休克蛋白、热休克蛋白合成刺激剂、刺激脂质和角质层成分合成的试剂、神经酰胺、脂肪酸、胶原降解抑制剂、基质金属蛋白酶抑制剂、弹性蛋白降解抑制剂、丝氨酸蛋白酶例如组织蛋白酶G抑制剂、刺激成纤维细胞增殖的药剂、刺激角质形成细胞增殖的药剂、刺激脂肪细胞增殖的药剂、刺激黑色素细胞增殖的药剂、刺激角质形成细胞分化的药剂、刺激或延迟脂肪细胞分化的试剂、抑制乙酰胆碱酯酶的药剂、皮肤松弛剂、刺激糖胺聚糖合成的药剂、抗角化过度剂、粉刺溶解剂、抗银屑病剂、DNA修复剂、DNA防护剂、稳定剂、用于治疗和/或护理敏感性皮肤的试剂、固化剂、紧致剂(anti-stretch mark agents)、粘合剂、调节皮脂产生的药剂、脂肪分解剂或刺激脂解的试剂、脂肪形成剂、调节PGC-1α合成的试剂、调节PPARγ活性的试剂、增加或减少脂肪细胞的甘油三酯含量的试剂、抗蜂窝组织剂、止汗剂、刺激愈合的药剂、协助愈合的药剂、刺激再上皮化的试剂、协助再上皮化的试剂、细胞因子生长因子、作用于毛细血管循环和/或微循环的试剂、刺激血管生成的试剂、抑制血管渗透性的药剂、静脉紧张剂、作用于细胞代谢的药剂、用于改善真皮-表皮接合的试剂、诱导毛发生长的药剂、毛发生长抑制剂或延缓剂、延迟毛发丢失的试剂、防腐剂、香料、螯合剂、植物提取物、精油、海洋提取物、获自生物技术过程的试剂、无机盐、细胞提取物、防晒剂以及有效抗A和/或B紫外线和/或红外A射线或其混合物的有机或无机光防护剂，其条件是它们与该组合物中的其余组分，特别是与本发明肽在物理上和化学上是相容的。同样，这些另外成分的性质不应不可接受地改变本发明的肽的益处。这些另外成分的性质可以是合成的或天然的如植物提取物、或来自生物技术方法，或来自合成方法与生物技术方法的组合。另外的实例可以见于“CTFA国际化妆品成分字典和手册(CTFAInternational Cosmetic IngredientDictionary&Handbook)，第12版(2008)。在本发明的背景下，生物技术方法应理解为用于在有机体内、或在有机体的一部分内产生该活性成分或该活性成分的一部分的任何方法。
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，以及化妆品上或药学上有效量的至少一种提取物、合成化合物或生物技术来源的产物(可以为防皱剂和/或抗老化剂)的化妆品组合物或药物组合物，所述提取物、合成化合物或产物是例如但不限于葡萄、狗蔷薇、姜黄、香根莺尾、可可(Theobroma cacao)、银杏(Ginkgo biloba)、火绒草或盐藻(Dunaliella salina)等的提取物或水解提取物；由Sederma/Croda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]、Synthe’6TM[INCI：甘油、水、羟丙基环糊精、棕榈酰三肽-38]、EsSenskinTM[INCI：羟基甲硫氨酸钙]、Renovage[INCI：替普瑞酮]、ResistemTM[INCI：心叶球花发酵物]或[INCI：棕榈酰寡肽]，由Pentapharm/DSM销售的[INCI：五肽-3]、 [INCI：二肽二氨基丁酰基苯甲基酰胺二乙酸酯(盐)]、-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Laboratoires Serobiologiques/Cognis销售的MyoxinolTM[INCI：水解的黄秋葵(Hibiscus Esculentus)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]，由Lipotec销售的[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：乙酰基六肽-30]、[INCI：水解小麦蛋白质、水解大豆蛋白质、三肽-1]、PreventheliaTM[INCI：二氨基丙酰基三肽-33]、DecorinylTM[INCI：三肽-10瓜氨酸]、TrylagenTM[INCI：假交替单胞菌发酵提取物、水解小麦蛋白质、水解大豆蛋白质、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：乙酰基精氨酰色氨酰二苯基甘氨酸]、[INCI：乙酰基四肽-22]、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]、[INCI：假交替单胞菌发酵提取物]、dGlyageTM[INCI：盐酸赖氨酸、卵磷脂、三肽-9瓜氨酸]、VilasteneTM[INCI：盐酸赖氨酸、卵磷脂、三肽-10瓜氨酸]、HyadisineTM[INCI：假交替单胞菌发酵提取物]、DiffuporineTM[INCI：乙酰基六肽-37]、SilusyneTM[INCI：大豆(大豆油)油、倍半油酸脱水山梨醇酯(Sorbitan Sesquioleate)、异十六烷、透明质酸钠、Lauryldimonium Hydroxypropyl Hydrolized Soy Protein、乙酰基六肽-39]或AdifylineTM[INCI：乙酰基六肽-38]、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(OryzaSativa)(稻)提取物]、D'OrientineTMIS[INCI：海枣(PhoenixDactylifera)(枣)籽提取物]、PhytoquintescineTM[INCI：单谷小麦(Einkorn)(一粒小麦(Triticum Monococcum))提取物]或QuintescineTMIS[INCI：二肽-4]，由Infinitec Activos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质]或DPHP[INCI：二棕榈酰羟脯氨酸]，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(Walnut))籽提取物]，由Biotechmarine销售的ThalassineTM[INCI：藻类提取物]，由AtriumInnovations/Unipex Group销售的ChroNOlineTM[INCI：己酰基(caprooyl)四肽-3]或Thymulen-4[INCI：乙酰基四肽-2]，由Coletica/Engelhard/BASF销售的EquiStat[INCI：苹果(Pyrus Malus)水果提取物、野生大豆(Glycine Soja)籽提取物]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Mibelle Biochemistry销售的Ameliox[INCI：肌肽，生育酚，水飞蓟(Silybum marianum)水果提取物]或PhytoCelliTec Malus Domestica[INCI：苹果(Malus Domestica)水果细胞培养物]，由Silab销售的Bioxilift[INCI：茴芹(PimpinellaAnisum)提取物]或SMS Anti-[INCI：番荔枝(AnnonaSquamosa)籽提取物]、Ca2+通道拮抗剂，例如但不限于阿尔维林(alverine)、锰盐或镁盐、某些仲胺或叔胺、视黄醇和其衍生物、艾地苯醌(idebenone)和其衍生物、辅酶Q10和其衍生物、乳香酸和其衍生物、GHK和其衍生物和/或盐、肌肽和其衍生物、DNA修复酶，例如但不限于光解酶或T4核酸内切酶V，或氯化物通道拮抗剂等，和/或其混合物。
本发明的另外的方面涉及化妆品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作为美白和/或脱色素剂或黑色素合成抑制剂的提取物，例如但不限于以下的提取物：千叶蓍、芦荟、Aradirachta indica、Asmuna japonica、面包果树、鬼针草、构树、普通小球藻、总状升麻、Emblica officinalis、光果甘草、甘草、冬青、Ligusticum lucidum、川芎、粗糙帽果、海巴戟、白桑、鸡桑、补血草、Prunus domesticus、太子参、皱叶酸模、西酸模、无患子、虎耳草、Scutellaria galericulate、垂盆草、繁缕、软粒小麦、熊果或睡茄等，和/或除此之外，还含有化妆品或药学上有效量的至少一种具有脱色素或美白活性或抑制黑色素合成的合成化合物、提取物或生物技术来源的产物，例如但不限于由Lipotec销售的Lipochroman-6[INCI：二甲基甲氧基色原烷醇]、[INCI：二甲基甲氧基色满基棕榈酸酯]、由AlbanMuller销售的Whitami[INCI：麦芽糊精、木瓜蛋白酶、二氧化钛、东当归根提取物、防风根提取物、硫辛酸、白陶土、抗坏血酸基葡糖苷、海岸松树皮寡聚物原花青素]；由Arch销售的Asafetida提取物[INCI：水(水)、丁二醇、乙氧基二甘醇、香阿魏提取物]；由Campo Research销售的甘草根提取物[INCI：甘草(光果甘草)提取物]；由CLR销售的BelidesTM[INCI：Bellis Perennis(雏菊)花提取物]；由Codif销售的Algowhite[INCI：泡叶藻提取物]；由Coletica/Engelhard/BASF销售的BiowhiteTM[INCI：草莓虎耳草提取物、欧洲种葡萄(葡萄)果提取物、丁二醇、水、鸡桑根提取物、黄芩根提取物、EDTA二钠]、Melarrest A[INCI：甘油、乳酸、曲酸、抗坏血酸]、L[INCI：水、环戊硅氧烷、丁二醇、丙二醇、磷脂、光果甘草(甘草)提取物、曲酸、甘草酸单铵盐]、Vitagen[INCI：氨基丙基抗坏血酸磷酯]；由DC Ingredients销售的DC Skin BrightTM[INCI：PEG-12甘油二硬脂酸酯、二羟基苯甲酸甲酯、乙氧基二甘醇、聚乙烯、水]；由Doosan销售的DS-WHITEKLE[INCI：乙酰植物鞘氨醇]；由Evonik Goldschmidt销售的TEGO Cosmo C250[INCI：1-甲基乙内酰脲-2-酰亚胺]；由Exsymol销售的[INCI：氨乙基次膦酸、丁二醇、水]；由Gattefossé销售的SynerlightTM[INCI：猕猴桃(Kiwi)果水、丁二醇、醇、苦参根提取物]；由Greentech销售的ClerilysTM[INCI：水、黄瓜、桑树提取物、玫瑰茄提取物、葡萄酒提取物]；由IEB/Unipex销售的-5[INCI：右旋糖酐、九肽-1]；由L.Serobiologiques/Cognis/BASF销售的ActiwhiteTM[INCI：水、甘油、蔗糖二月桂酸酯、聚山梨酸酯20、豌豆提取物]、PowderWhiteness[INCI：水、甲基丙烯酸月桂酯/二醇二甲基丙烯酸酯共聚物、丁二醇、二辛基醚、二氧化钛、藻类、柠檬酸、柠檬酸钠、蛇婆子叶提取物、阿魏酸、聚甘油-2二聚羟基硬脂酸酯]、NF LS9410[INCI：甘露醇、葡萄糖酸钠、柠檬酸、柠檬酸钠、蛇婆子叶提取物、糊精、阿魏酸]、RadianskinTM[INCI：羟基苯氧基丙酸]；由Lipochemicals销售的HCA-4[INCI：PEG-4、对羟基桂皮酸]；由Lucas Meyer销售的WhitessenceTM[INCI：本菠萝籽提取物、麦芽糊精、磷酸氢二钠、磷酸钠]；由Merck销售的EmblicaTM[INCI：余甘子果提取物]；由Mibelle销售的SulforaWhite[INCI：水芹芽提取物、甘油、卵磷脂、苯氧乙醇、水]、DelentigoTM[INCI：水芹芽提取物、卵磷脂、大豆异黄酮、聚山梨醇80、醇、甘油、苯氧乙醇、水]；由Pentapharm/DSM销售的α-熊果苷[INCI：α-熊果苷]、Gigawhite[INCI：水、甘油、欧锦葵(锦葵)提取物、辣薄荷叶提取物、黄花九轮草提取物、羽衣草提取物、药用婆婆纳提取物、香蜂花叶提取物、千叶蓍提取物]、-J[INCI：水、熊果叶提取物、甘油、抗坏血酸磷酸镁]；由Rahn销售的White[INCI：水、变性酒精、烟酰胺、咯烷酮羧酸锌、普通小球藻/白羽扇豆蛋白质发酵物、水田芥菜提取物]、[INCI：甘油、水(水)、油橄榄叶提取物、抗坏血酸基葡糖苷、咯烷酮羧酸锌]；由Sederma/CRODA销售的ArlatoneTM Dioic DCA[INCI：十八碳烯二酸、BHT]、EtiolineTM[INCI：甘油、丁二醇、熊果叶提取物、粗糙帽果提取物]、LumiskinTM[INCI：己酸/癸酸甘油三酯、芦米亮白因子]、MelaclearTM2[INCI：甘油、水、二硫杂辛二醇、葡糖酸、舒替兰酶、β胡萝卜素]、LumisphereTM[INCI：水(水)、二氧化钛、聚山梨酸酯20、鲸蜡基羟乙基纤维素、聚甲基丙烯酸甲酯、三月桂精、芦米亮白因子]、O.D.A.whiteTM[INCI：十八碳烯二酸]、WonderlightTM[INCI：啤酒花(Hops)毬果]；由Seppic销售的SepiwhiteTMMSH[INCI：十一碳烯酰基苯丙氨酸]、SepicalmTMVG[INCI：棕榈酰脯氨酸钠、白睡莲花提取物]；由Silab销售的Clariskin II[INCI：软粒小麦提取物]、[INCI：旱金莲提取物]、[INCI：掌叶树提取物]；由Sinerga销售的[INCI：壬二酰二甘氨酸钾]；由Soliance销售的Whitesphere Premium[INCI：蔗糖棕榈酸酯、丁二醇、亚油酸甘油酯、甜扁桃、杏仁油、水(水)、光果甘草(甘草)根提取物、抗坏血酸磷酸镁、裙带菜提取物]、Axolight[INCI：小麦提取物]；由Symrise销售的[INCI：苯乙基间苯二酚]、ExtraponeTMNutgrass GW[INCI：香附根提取物]；由Sytheon销售的HR[INCI：己雷琐辛]；由Unipex销售的β-White[INCI：水、丁二醇、氢化卵磷脂、油酸钠、寡肽-68、EDTA二钠]；由Vincience/ISP销售的AchromaxylTM[INCI：欧洲油菜提取物]；熊果苷及其异构体、曲酸及其衍生物、维生素C及其衍生物，例如但不限于6-O-棕榈酰基抗坏血酸、二棕榈酰基抗坏血酸、来自抗坏血酸-2-磷酸的镁盐(MAP)、来自抗坏血酸-2-磷酸的钠盐(NAP)、抗坏血酸基葡糖苷或抗坏血酸基四异棕榈酸酯(VCIP)等，视黄醇及其衍生物，包括维甲酸和异维甲酸、艾地苯醌、3-羟基苯甲酸及其衍生物、类黄酮、大豆提取物、柠檬的提取物、橙子的提取物、银杏的提取物、黄瓜的提取物、老鹳草的提取物、熊果的提取物、角豆树的提取物、肉桂的提取物、墨角兰的提取物、迷迭香的提取物、丁香的提取物、甘草的可溶性提取物、黑莓叶的提取物、烟酰胺、甘草素、间苯二酚及其衍生物、氯醌、α-生育酚、γ-生育酚、壬二酸、白藜芦醇、汞盐、亚油酸盐、α-硫辛酸、二氢硫辛酸、α羟酸、β羟酸、鞣花酸、阿魏酸、桂皮酸、齐墩果酸、芦荟苦素及其衍生物和/或丝氨酸蛋白酶活性抑制剂，例如但不限于类胰蛋白酶、胰蛋白酶或PAR-2活性的抑制剂等。
本发明的另外的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上或药学上有效量的至少一种本发明肽或其立体异构体、其混合物和/或其化妆上或药学上可接受的盐，以及化妆上或药学上有效量的至少一种作为抗搔痒剂的天然提取物或精油，例如但不限于如下的提取物：咖啡黄葵、Actaea alba、米兰、紫朱牛舌草、药蜀葵、细青皮、须芒草、裸茎楤木、美洲楤木、蓟罂粟、黄花假杜鹃、叶茶、肉荚云实、凌霄、刺黄果、尖刺红花、决明、野菊、总状升麻、樟树、葡萄叶铁线莲、大花菟丝子、乌木、Enicostema axillare、金缕梅、细裂叶珊瑚、熏衣草、宽叶薰衣草、苏合香树、白果紫草、长叶马府油、角胡麻、紫花苜蓿、黄兰、Mikania glomerata、含羞草、水稻、菜豆、叶下珠、黄珠子草、阿月浑子、水蓼、常青栎、Rauvolfia caffra、蓖麻、覆盆子、欧洲慈姑、山陀儿、无患子、久树、大花田菁、甜槟榔青、椴树属、红椿、Tragia involucrata、五角栝楼、麦蓝菜、Ventilago madraspatana、白藜芦或苍耳等，或至少一种作为抗搔痒剂的合成化合物或生物技术来源的产物，例如但不限于美吡拉敏(吡拉明)、安他唑啉、苯海拉明、卡比沙明、多西拉敏、氯马斯汀、茶苯海明、非尼拉敏、扑尔敏(氯苯那敏)、右氯苯那敏、溴苯那敏、曲普利啶、赛克力嗪、氯环利嗪、羟嗪、敏克静、西替利嗪、左西替利嗪、异丙嗪、噻苯哌胺、阿立马嗪(三甲泼拉嗪)、赛庚啶、azatidine、酮替芬、阿伐斯汀、阿司咪唑、西替利嗪、氯雷他定、地氯雷他定、咪唑斯汀、特非那定、非索非那定、非索非那定、氮卓斯汀、左卡巴斯汀、奥洛他定、皮质类固醇类例如可的松、氢化可的松、地塞米松、泼尼松；由Atrium Innovations/Unipex Group销售的NeutrazenTM[INCI：水、丁二醇、右旋糖酐、棕榈酰基三肽-8]、由Institut Européen de Biologie Cellulaire/Unipex Group销售的[INCI：右旋糖酐、乙酰基七肽-1]、由LaboratoiresSérobiologiques/Cognis销售的SkinasensylTM[INCI：乙酰基四肽-15]、由Symrise销售的1609[INCI：4-叔丁基环己醇]、由BASF销售的SymbiocellTM[INCI：来自夜香树的提取物]、由Gattefossé销售的Derma-Sensitive[INCI：辛基十二醇肉豆蔻酸酯、刺山柑果提取物]或由Mibelle销售的MAXnolia[INCI：厚朴树皮提取物、葡萄/欧洲种葡萄(葡萄)籽提取物、生育酚]等。
本发明的另外的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、其混合物和/或其化妆上或药学上可接受的盐，以及化妆上或药学上有效量的至少一种用于治疗敏感性皮肤的天然提取物或精油，例如但不限于以下的提取物：咖啡黄葵、苋菜红籽油、来自紫朱牛舌草木、芦荟、药蜀葵、细青皮、须芒草、裸茎楤木、美洲楤木、蓟罂粟,山金车、北艾、大叶马蹄香、黄花假杜鹃、金盏花、叶茶、肉荚云实、凌霄、辣椒、刺黄果、尖刺红花、决明、石胡荽、母菊、野菊、总状升麻、樟树、葡萄叶铁线莲、大花菟丝子、文殊兰、乌木、Enicostema axillare、北美金缕梅、南非钩麻、贯叶连翘、细裂叶珊瑚、熏衣草、宽叶薰衣草、白花百合、苏合香树、白果紫草、长叶马府油、锦葵、角胡麻、互生叶白千层、紫花苜蓿、黄兰、Mikaniaglomerata、含羞草、甘牛至、牛至、水稻、菜豆、叶下珠、黄珠子草、阿月浑子、水蓼、桂樱、迷迭香、常青栎、Rauvolfia caffra、蓖麻、覆盆子、欧洲慈姑、白柳、山陀儿、无患子、久树、大花田菁、水飞蓟、extracts of甜槟榔青、小白菊、百里香、椴树属、红椿、Tragia involucrata、五角栝楼、猫爪藤或麦蓝菜、Vaccinummyrtillus、Ventilago madraspatana、白藜芦或苍耳等；辅酶Q10或烷基甘油醚、由Atrium/Unipex销售的[INCI：水、深海酵母提取物、丁二醇]、AldavineTM[INCI：水、泡叶藻提取物、刺海门冬提取物、山梨醇]、NeutrazenTM[INCI：水、丁二醇、右旋糖酐、棕榈酰三肽-8]或[INCI：葡聚糖、乙酰基六肽-1]；由Mibelle销售的[INCI：甘油、仙桃仙人掌茎提取物、苯氧乙醇、水溶液]、CalmosensineTM[INCI：丁二醇、水、聚乙二醇单十二醚-3、羟乙基纤维素、乙酰基二肽-1鲸蜡酯]、CaresoftTM[INCI：丙二醇、甘油、水、仙茅根提取物]、CM-Glucan[INCI：羧甲基钠、β-葡聚糖、苯氧乙醇、咪唑烷基脲、水(水溶液)]或MAXnolia[INCI：厚朴树皮提取物、葡萄/欧洲种葡萄(葡萄)籽提取物、生育酚]；由Sederma/CRODA销售的BacocalmineTM[INCI：PEG-8、假马齿苋提取物、水(水溶液)、羟乙基纤维素]；由Rahn销售的[INCI：辛基十二醇、车前叶蓝蓟籽油、倒地铃提取物、向日葵籽油Unsaponifiables]；由Doosan销售的DS-植物鞘氨醇[INCI：植物鞘氨醇]、DS-TAPS[INCI：四乙酰植物鞘氨醇]或DS-WHITEKLE[INCI：乙酰植物鞘氨醇]；由Pentapharm/DSM销售的[INCI：野大豆蛋白质、水、甘油、椰油酰基二乙酸二钠]；由Gattefossé销售的Derma-Sensitive[INCI：辛基十二醇肉豆蔻酸酯、刺山柑果提取物]；由Exsymol销售的[INCI：水溶液、焦谷氨酰胺乙基吲哚]或Glistin[INCI：谷氨酰胺基乙基吲哚、水(Aqua)]；由BASF销售的InhipaseTM[INCI：野葛根提取物、丁二醇]或SymbiocellTM[INCI：夜香木宽叶提取物]；由Institut Européen deBiologie Cellulaire/Unipex Group销售的[INCI：右旋糖酐、乙酰基七肽-1]；由Arch Chemicals销售的Arnica提取物[INCI：Arnica蒙大拿花提取物、藻类提取物]；由Soliance销售的Ocaline[INCI：海水、水溶液、西葫芦(西葫芦)籽提取物]；由EvonikGoldschmidt销售的植物鞘氨醇[INCI：植物鞘氨醇]；由Greentech销售的Protectol[INCI：二丙二醇、白桦树皮提取物、林生玄参提取物]；由L.Serobiologiques/Cognis/BASF销售的SkinasensylTM[INCI：水、甘油、椰油基葡糖苷、乙酰基四肽-15]；由Symrise销售的1609[INCI：戊二醇、4-叔丁基环己醇]；由Pentapharm/DSM销售的Stimu-AS[INCI：废麦芽粕蜡、牛油树(乳木果油)提取物、摩洛哥坚果油]；由Seppic销售的TimecodeTM[INCI：棕榈酰甘氨酸]；由Induchem销售的UnisoothST-32[INCI：水(水溶液)、戊二醇、酸豆籽提取物、甜菊糖]或由ISP销售的Vital[INCI：月桂亚氨基二丙酸生育酚磷酸二钠]等。
同样地，在另一个具体实施方案中，愈合刺激剂、辅助愈合剂、再上皮化刺激剂和/或辅助愈合剂选自例如但不限于以下的提取物：蛇根马兜铃、积雪草、磨香玫瑰、狭叶松果菊、聚合草、问荆、贯叶金丝桃、细花含羞草、芦荟、Persea gratísima、Prunus africanum、Tormentilla erectea、由Provital销售的Epithelizing[INCI：金盖菊、金丝桃、母菊、迷迭香]、由LaboratoriesSerobiologiques/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(玉米)谷粒提取物]、尿囊素、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]、[INCI：三肽-10瓜氨酸]、[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]、BodyfensineTM[INCI：乙酰基二肽-3氨基己酸酯]或DiffuporineTM[INCI：乙酰基六肽-37]或其混合物等。
在另一个具体实施方案中，抗炎剂和/或止痛剂选自例如但不限于以下的提取物：积雪草苷、松果菊属、览属植物籽油、檀香油、桃树叶提取物、芦荟提取物、山金车、艾蒿、大花细辛、金盖花、辣椒属、石古月荽、洋甘菊)、文殊兰、北美金缕梅、南非钩麻、贯叶连、白花百合、欧锦赛、互叶白千层、马郁兰、牛至草、月桂樱、迷迭香、白柳、水飞蓟、小白菊、普通百里香、Uncaria guianensis或欧洲越桔、莫米松糠酸酯(mometasone furoate)和强的松龙、非类固醇消炎药物，包括环加氧酶或脂加氧酶抑制剂、苄达明(benzydamine)、乙酰水杨酸、迷迭香酸(rosmarinic acid)、熊果酸、甘草酸酯的衍生物、α-没药醇(α-bisabolol)、azulene和类似物、水田芥(sericoside)、鲁斯可皂甙元(ruscogenin)、七叶皂苷(escin)、氯化丁二酰胆碱(scoline)、芸香苷和类似物、氢化皮质酮、氯倍他索(clobetasol)、地塞米松、halobetasol、二氟拉松、醋酸氟轻松、安西奈德、曲安西龙、氟替卡松、肤轻松、丙酮缩氟氢羟龙、泼尼卡酯、泼尼松、扑热息痛、amoxiprin、贝诺酉旨、胆碱水杨酸盐、二氟尼柳(diflunisal)、faisIamine、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、吲哚美辛、奥沙美辛、丙谷美辛、舒林酸、托美丁、布洛芬、右布洛芬、卡洛芬、芬布芬、非诺洛芬、氟比洛芬、酮洛芬、右酮洛芬、酮咯酸、氯索洛芬、萘普生、咪洛芬、奥沙普秦、普拉洛芬、噻洛芬酸、舒洛芬、甲芬那酸、甲氯芬那酸酯、甲氯芬那酸、氟芬那酸、托芬那酸、萘丁美酮、保泰松、阿扎丙宗、氯菲宗、凯布宗、安乃近、莫菲布宗、羟布宗、非那宗、苯磺唑酮、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、萘普西洛、氟丙喹宗或利克飞龙；ω-3和ω-6脂肪酸、吗啡、可待因、氧可酮、氧可酮、海洛因、哌替啶、曲马多、丁丙诺啡叔丁啡、苯佐卡因、力多卡因、氯普鲁卡因、丁卡因、普鲁卡因、三环抗抑郁剂、阿米替林、痛痉宁、加巴喷丁、普瑞巴林、没药醇、由Atrium Innovations/Unipex Group销售的NeutrazenTM[INCI：水、丁二醇、右旋糖酐、棕榈酰三肽-8]、由Institut Euroopeen deBiologie Cellulaire/Unipex Group销售的[INCI：右旋糖酐、乙酰基七肽-1]、由Laboratoires Serobiologiques/Cognis销售的SkinasenylTM[INCI：乙酰基四肽-15]或AnasensylTM[INCI：甘露醇、甘草酸单铵盐、咖啡因、七叶树(马栗树)提取物]、由Sederma销售的CalmosensineTM[INCI:乙酰基二肽-1]，辅酶Q10或烷基甘油醚类。
应用
本发明的一个方面涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备抑制PAR-2活性的化妆品组合物或药物组合物的用途。
在一个具体实施方案中，本发明涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备用于治疗和/或预防搔痒、炎症、疼痛、呼吸道的疾病和/或障碍的化妆品组合物或药物组合物的用途。
在一个优选实施方案中，搔痒选自与病况、疾病和/或障碍相关的搔痒，所述疾病是例如但不限于皮炎、特异性皮炎、接触性皮炎、尿布皮炎、疱疹样皮炎、光照性皮肤病、光敏感性、与怀孕相关的皮肤病、与绝经相关的皮肤病、湿疹、敏感性皮肤、银屑病、水痘、疱疹、带状疱疹、Netherton综合征、脱皮综合征、扁平苔癣、粉刺、头皮屑、皮脂溢、皮脂溢皮炎、脱发、运动员足、念珠菌病、痔疮、阴道搔痒、肛门搔痒症、肛生殖道搔痒症、晒斑、荨麻疹、搔痒性耳炎、老年皮肤搔痒症、水源性搔痒症、结节性痒疹、prurigoplanus、玫瑰糠疹、干燥病和干性皮肤、或与透析、HIV感染、恶性肿瘤、何杰金氏病、白血病、骨髓瘤、淋巴瘤、实体瘤、腺癌、肺癌、肝病、黄疸、胆汁淤积、肝功能衰竭、肝硬化、红细胞增多症、高嗜酸细胞增多综合征、原发性血小板增多症、骨髓增生异常综合征、缺铁引起的贫血、系统性红斑狼疮、内分泌疾病、甲状腺疾病、甲状腺功能亢进、甲状腺功能减退、甲状旁腺疾病、糖尿病、肾病、肾功能衰竭、尿毒症、寄生虫病、疥疮、虱、蛔虫、过敏反应、对药物的过敏、食物过敏、对化学制品的过敏、对有毒植物的暴露、对虫咬的暴露、化学疗法、压力和焦虑相关的搔痒等。
在另一个具体实施方案中，疼痛选自例如但不限于急性痛、慢性痛、伤害性疼痛、神经性疼痛、炎性痛、内脏痛、腹痛、消化系统痛、呼吸系统痛、泌尿生殖系统痛、内分泌系统痛、心脏痛、胰痛、肝痛、因胆石引起的疼痛、胆汁淤积、肠痛、胃痛、因十二指肠溃疡引起的疼痛、因食道炎引起的疼痛、因胃食管返流疾病引起的疼痛、脾痛、血管中的疼痛、豆状核后综合征疼痛、肠易激综合征、与克罗恩病相关的疼痛、与溃疡性结肠炎相关的疼痛、憩室炎、胃肠道粘膜炎、头痛、紧张性头痛、与窦炎相关的头痛、偏头痛、眼痛、干眼综合征、手术后疼痛、因外科切口引起的手术后疼痛、因骨中植入物插入引起的手术后疼痛,因骨置换引起的手术后疼痛、因感染引起的手术后疼痛、因截肢引起的手术后疼痛、与骨折相关的疼痛、由癌症引起的疼痛、由骨癌引起的疼痛、与良性骨肿瘤相关的疼痛、与骨样骨瘤相关的疼痛、与成骨细胞瘤相关的疼痛、由癌症治疗引起的疼痛、由化学疗法引起的疼痛、由呕吐引起的疼痛、由化学治疗导致的呕吐引起的疼痛、肌肉骨骼痛、痉挛肌肉疼痛、纤维肌痛、复杂区域疼痛综合征、精神性疼痛、神经痛、由脱髓鞘疾病引起的疼痛、与颈肌张力障碍相关的颈痛、背痛、腰部疼痛、坐骨神经痛、神经原性感染、神经炎、皮肤灼痛、接触敏感性、寒冷敏感性、热敏感性、皮肤刺激、毛发去除后皮肤刺激、剃毛后皮肤刺激、银屑病、敏感性皮肤、皮炎、特异性皮炎、接触性皮炎、尿布皮炎、皮脂溢皮炎、湿疹、扁平苔癣、烧伤、晒斑、关节炎、类风湿关节炎骨关节炎、牛皮癣关节炎、葡萄膜炎,由神经损伤引起的疼痛、神经痛、疱疹后神经痛、神经病、周围神经病、幻痛、异常性疼痛、痛觉过敏、冷痛觉过敏、由腕管综合征引起的疼痛、灼痛、Grierson-Gopalan综合征(更好地称为烧灼样足综合征)、口灼伤综合征、感觉错乱、Fabry病、面部疼痛、三叉神经痛、由糖尿病引起的神经性疼痛、由AIDS引起的神经性疼痛、口面疼痛、牙痛、由拔牙引起的疼痛、由智齿拔除引起的疼痛、牙齿对冷的敏感性、牙齿对热的敏感性、口腔粘膜炎、颞下颌关节痛、由痛风引起的关节痛、与纹身或纹身去除过程相关的疼痛、拇滑囊肿痛、睾丸痛、肌盘膜痛、膀胱痛、泌尿道痛、膀胱炎、由肾脏结石引起的疼痛、肾绞痛、外阴痛、阴道痛、产后痛、月经疼痛、阴囊痛、会阴痛、骨盆痛或过敏症、皮肤痛或术后刺激、利用强脉冲光疗法(IPL)治疗后刺激、利用单色脉冲光治疗(激光)进行治疗后的刺激、利用化学剥脱剂治疗后的刺激或对攻击性外部试剂过度暴露后的刺激以及由长期酒精滥用引起的疼痛。
在另一个具体方面，炎症选自但不限于神经原性感染、关节炎症、腱炎症、肌肉炎症、败血病、血管炎症、呼吸系统炎症、慢性阻塞性肺疾病、鼻炎、变应性鼻炎、哮喘、耳炎、肠炎、克罗恩病、胰腺炎、肝炎、与慢性炎症相关的病况、急性炎症、肾炎、系统性红斑狼疮、关节炎、类风湿关节炎、成人和青少年类风湿关节炎、斯蒂尔病、牛皮癣关节炎、骨关节炎、由痛风引起的关节炎、类风湿性脊柱炎、肾小球肾炎、神经炎、神经组织炎症、多发性硬化、免疫系统障碍、综合征、动脉粥样硬化、心肌炎、心包炎、脉管炎、炎症性皮肤病况、银屑病、敏感性皮肤、皮炎、特异性皮炎、接触性皮炎、尿布皮炎、皮脂溢皮炎、湿疹、过度增生性皮肤病、烧伤、晒斑、阴道黏液的炎症、外阴痛、阴道炎、口腔粘膜炎症、牙龈炎、牙周炎、炎症性眼病、葡萄膜炎、眼和春季结膜炎、肉瘤样病、溃疡病、荨麻疹、大疱性类天疱疮、纤硬皮病化、纤维化、血管性水肿、过敏反应、脱发、肝的肝硬化、再狭窄、风湿性多肌痛、血清阴性脊柱关节病，包括强直性脊柱炎和Reiter’s综合征、皮肌炎、包涵体肌炎、多肌炎和淋巴管平滑肌增多。
在另一个具体实施方案中，呼吸道的疾病和/或障碍选自例如但不限于哮喘、慢性阻塞性肺疾病、变应性鼻炎和支气管高反应性。
在另一个具体实施方案中，本发明提及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备用于治疗癌症的药物组合物的用途。
在一个优选实施方案中，癌症选自但不限于淋巴网状内皮细胞瘤、骨癌、骨肉瘤、脂肪肉瘤、乳腺癌、胃癌、胰腺癌、膀胱癌、肠癌,子宫内膜癌、子宫癌、头颈癌、肺癌、呼吸道的癌症、黑色素瘤、卵巢癌、前列腺癌、皮肤癌和直肠癌等。
在另一个具体实施方案中，本发明涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备用于治疗和/或扩理消化系统的病况、障碍和/或疾病的药物组合物的用途。
在一个优选实施方案中，消化系统的病况、障碍和/或疾病选自例如但不限于乳糜泻、食物过敏、克罗恩病、胃肠炎、炎性肠病、肠绞痛、肝炎、结肠炎、溃疡性结肠炎、肠易激综合征、食道炎、胃食管返流疾病、特发性胃肌轻瘫、胰腺炎(包括慢性胰腺炎)和胃与十二指肠溃疡)。
本发明的另一个方面涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备用于治疗和/或护理皮肤和/或粘膜的化妆品组合物或药物组合物的用途。
在另一个优选实施方案中，本发明涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备刺激和/或护理皮肤屏障功能的化妆品组合物或药物组合物的用途。
在另一个具体实施方案中，本发明涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备用于治愈和/或再上皮化皮肤的化妆品组合物或药物组合物的用途。
在另一个具体实施方案中，本发明涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备化妆品组合物或药物组合物的用途，所述化妆品组合物或药物组合物用于使皮肤脱色素和/或光保护，或用于治疗和/或护理通过皮肤的色素沉着减少或通过皮肤的光保护得到改善或预防的皮肤病况、障碍和/或疾病。
在一个优选实施方案中，通过皮肤的色素沉着减少或通过皮肤的光保护得到改善或预防的皮肤病况、障碍和/或疾病选自例如但不限于雀斑,雀斑样痣,黑斑病,花斑,爱迪生病,白斑,因对UV辐射的暴露而引起的斑点,因老化或光老化而引起的斑点,因炎症而引起的斑点，特别是因激光或ILPL治疗或美容手术后而引起的炎症,因粉刺,湿疹,褐黄病而引起的斑点,因疤痕和/或激素失调而引起的斑点例如黑变病和黑斑病。
在另一个具体实施方案中，本发明涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备用于治疗头皮和/或毛细血管卫生的化妆品组合物或药物组合物的用途，特别地其用于治疗和/或护理脱发、头皮屑和/或皮脂溢皮炎的用途。
在另一个具体实施方案中，本发明涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备用于治疗口腔粘膜和/或口腔卫生的化妆品组合物或药物组合物的用途，特别其用于治疗和/或护理牙周炎和/或牙龈炎的用途。
在另一个具体实施方案中，本发明涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备用于治疗阴道粘膜和/或和/或个人卫生的化妆品组合物或药物组合物的用途，特别地其用于治疗和/或护理念珠菌病、阴道搔痒、肛门搔痒症、肛生殖道搔痒症和/或痔疮的用途。
在另一个具体实施方案中，本发明涉及至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐用于制备用于抑制皮肤致敏剂(特别地化妆品组合物中的过敏原)的化妆品组合物或药物组合物的用途。
在另一个方面，本发明涉及用于抑制PAR-2活性的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
在另一个具体方面，本发明涉及用于治疗和/或预防搔痒、炎症、疼痛、呼吸道的疾病或病况的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
在另一个具体方面，本发明涉及用于治疗癌症的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
在另一个具体方面，本发明涉及用于治疗和/或护理消化系统的那些病况、障碍和/或疾病的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
或者，本发明涉及用于治疗和/或扩理皮肤和/或粘膜的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
在另一个具体方面，本发明涉及用于刺激和/或护理皮肤屏障功能的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
在另一个具体方面，本发明涉及治愈和/或再上皮化皮肤的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
在另一个具体方面，本发明涉及用于使皮肤脱色素和/或光保护、或治疗和/或护理可通过色素沉着的减少和/或通过皮肤的光保护得到改善或预防的皮肤病况、障碍和/或疾病的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
在另一个具体方面，本发明涉及用于治疗头皮或用于毛细血管卫生的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
在另一个具体方面，本发明涉及用于治疗口腔粘膜或用于口腔卫生的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
在另一个具体方面，本发明涉及用于治疗阴道粘膜或用于个人卫生的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
在另一个具体方面，本发明涉及用于抑制皮肤致敏剂的方法，所述方法包括施用化妆上或药学上有效量的至少一种具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐。
应用或施用的频率可取决于每一个受试者的需求而有很大的不同，建议的应用或施用范围是每月一次至每天十次，优选每周一次至每天四次，更优选每周三次至每天三次，更优选每天一次或二次。
本文所提供的下列特定实施例举例说明本发明的性质。所包括的这些实施例仅以举例说明为目的，不应将其解释为对本文所要求保护的发明的限制。
实施例
下列实施例用于举例说明本发明，不应当解释为对其范围的限制。
缩写
使用的氨基酸的缩写依照Eur.J.Biochem.(1984)138：9-37中概述的1983IUPAC-IUB联合委员会的生化命名规则。
树脂；2,6-di ClZ，2,6-二氯苄基；2-BrZ，2-溴苄氧羰基；2-2-氯三苯甲基树脂；Ac，乙酰基；Adpoc，1-(1-金刚烷基)-1-甲基乙氧基-羰基；AIDS：获得性免疫缺陷综合征；Ala，丙氨酸；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)]苯氧基醋酸；Arg，精氨酸；Asn，天冬酰胺；Asp，天冬氨酸；Boc，叔丁氧基羰基；Bom，苄氧基甲基；Brz,溴苄氧基羰基；Bzl，苄基；Cbz，羧基苄基；CGRP，降钙素基因相关肽；CAMP，环腺苷酸单磷酸，AMP，环磷酸腺苷；cHx，环己基；Cit，瓜氨酸；ClZ，2-氯苄基；CFA，完全弗氏佐剂；C-末端，羧基-末端；DCM，二氯甲烷，亚甲基氯(methylene chloride)；Dde，N-[1-(4,4-二甲基-2,6-二氧代环己-1-亚基)乙基；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，杜氏改良伊格尔培养基；DMF，N,N-二甲基甲酰胺；DNA，脱氧核糖核酸；Dnp，2,4-二硝基酚；DRG，背根神经节；EAE，实验性自身免疫脑脊髓炎；EDTA，乙二胺四乙酸；ELISA，酶联免疫吸附测定；equiv：当量；ESI-MS，电喷雾离子化质谱法；FBS，胎牛血清；Fm，芴基甲基；Fmoc，9-芴基甲氧基羰基；For，甲酰基；FVIIa，凝血因子VIIa；Fxa，凝血因子Xa；Gln，谷氨酰胺；HBSS，Hank平衡盐溶液；HDFa，人皮肤成纤维细胞，成人；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；IBD，肠易激综合征；IL-6，白细胞介素-6；IL-8，白细胞介素-8；Ile，异亮氨酸；INCI，国际化妆品原料命名法；IPL，强脉冲光；ivDde，1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基-丁基；LDMA-25，月桂基铵(laurdimonium)水解的蛋白质；Lys，赖氨酸；MAP，抗坏血酸基-2磷酸镁；MBHA，对-甲基二苯甲胺；Me，甲基；MeCN，乙腈；MeOH，甲醇；Met，甲硫氨酸；mRNA，信使核糖核酸；Mtr，4-甲氧基-2,3,6-三甲基苯磺酰基；Mts，均三甲基苯磺酰基(mesitylenesulfonyl)；Mtt，甲氧基三苯甲基或甲基三苯甲基；Nle，正亮氨酸；N-末端，氨基末端；Nva，正缬氨酸；Orn，鸟氨酸；PAL，5-(4-氨基甲基-3,5-二甲氧基苯氧基)戊酸；Palm，棕榈酰基；PAR，蛋白酶激活受体；Pbf，2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基；PBS，磷酸缓冲盐水；PEG，聚乙二醇；Phe，苯丙氨酸；Phg，苯基甘氨酸；PGC-1α，PPARγ1α辅激活因子；Pmc，2,2,5,7,8-五甲基色满-6-磺酰基；PPAR，过氧化物酶体增殖物激活受体γ；pNZ，对硝基苄氧羰基；q.s，足量；q.s.p，对于......足量；RHE，重建人表皮；RNA，核糖核酸；SCCE，角质层胰凝乳蛋白酶；SCTE，角质层胰蛋白酶；Ser，丝氨酸；SP，物质P；tBu，叔-丁基；TAPS，四乙酰基植物鞘氨醇；Teoc，2-(三甲基甲硅烷基)乙氧基羰基；TF，组织因子；TFA，三氟乙酸；THF，四氢呋喃；Thr，苏氨酸；TIS，三异丙基硅烷；Tos，甲苯磺酰基或对-甲苯磺酰基；TRK，原肌球蛋白受体激酶；Troc，2,2,2三氯乙氧基羰基；TRP，瞬时受体电位；Trp，色氨酸；TRPV-1，瞬时受体电位辣椒素家族(transient receptor potential vanilloid subfamily)1；Trt，三苯甲基或三苯甲游基；Tyr，酪氨酸；IUPAC，国际纯粹与应用化学联合会；IUB，国际生化联合会；ULV，单层小囊泡；UVA，紫外线辐射A；UVB，紫外线辐射B；Val，缬氨酸；VCIP，抗坏血酸基四异棕榈酸酯；Xan，呫吨基(xanthyl)；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器中进行。所有试剂和溶剂是合成质量并且无需任何另外处理而使用。通过抽气移除溶剂和可溶试剂。Fmoc基团用哌啶-DMF(2:8,v/v)(1x1min,1x5min,5mL/g树脂)去除[Lloyd-Williams P.等人,“ChemicalApproaches to the Synthesis of Peptides and Proteins”,(1997),CRC,Boca Raton(FL,USA)]。在脱保护、偶联、以及再次脱保护的步骤之间用DMF(3X1min)进行洗涤，每次使用10mL溶剂/g树脂。偶联反应用3mL溶剂/g树脂进行。通过进行茚三酮(ninhydrin)试验[Kaiser E.等人,“Color test for detection of free terminal amino groups in thesolid-phase synthesis of peptides”,(1970),Anal.Biochem.,34(2),595-598]或四氯苯醌(chloranil)试验[Christensen T.,“A QualitativeTest for Monitoring Coupling Completeness in Solid Phase PeptideSynthesis Using Chloranil“,(1979),Acta Chem.Scand.,33B,763-766]来进行所述偶联的控制。所有合成反应和洗涤在25℃下进行。
HPLC色谱分析以Shimadzu设备(Kyoto,Japan)使用恒温于30℃的反相柱进行(250x4.0mm,Kromasil C8,5μm,Akzo Nobel,Sweden)。使用乙腈(+0.07％TFA)在水中(+0.1％TFA)的梯度以1mL/min的流速进行洗脱，在220nm处进行检测。在WATERSAlliance ZQ2000检测器中、使用MeCN:H2O4:1(+0.1％TFA)的混合物作为流动相并且以0.2mL/min的流速进行电喷雾离子化质谱分析。
实施例1
获得Fmoc-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-O-2--ClTrt-其中AA1为-L-Phe-、-L-Ser-、-L-Trp-或-L-Phg-；AA2为-L-Met-、-L-Phe-、-L-Nle-、-L-Trp-、-L-Phg-或-L-Nva-；AA3为-L-Arg-、-L-Gln-、-L-Trp-、-L-Lys-、-L-Orn-、-L-His-、-L-Cit-、-L-Asn-或-L-Phg-；AA4为-L-Asp-、-L-Phe-、-L-Asn-、-L-Gln-、-L-Tyr-、-L-Trp-或-L-Phg-；AA5为-L-His-、-L-Ile-、-L-Orn-、-L-Cit-、-L-Nle-或-L-Nva-；AA6为-L-Ser-、-L-Val-、-L-Thr、-L-Nle-、-L-Ile-、-L-Ala-或-L-Nva-；并且n、m、p和q为0。
将溶解在其中掺入了0.86当量的DIEA的55mL DCM中的8.8mmol(1当量)Fmoc-L-Ser(tBu)-OH、Fmoc-L-Val-OH、Fmoc-L-Thr(tBu)-OH、Fmoc-L-Nle-OH、Fmoc-L-Ile-OH、Fmoc-L-Ala-OH或Fmoc-L-Nva-OH添加至2-氯三苯甲基树脂(5.5g；8.8mmol)无水树脂。将其搅拌5分钟，然后添加1.66当量的DIEA。让混合物反应40分钟。通过利用4.4mL的MeOH的处理来封闭剩余氯基团。
将N-末端Fmoc基团如一般方法中所述地脱保护，将2.5当量的Fmoc-L-His(Trt)-OH,Fmoc-L-Ile-OH,Fmoc-L-Orn(Boc)-OH,Fmoc-L-Cit-OH,Fmoc-L-Nle-OH或Fmoc-L-Nva-OH在2.5当量DIPCDI和2.5当量HOBt存在的情况下使用DMF作为溶剂经1小时偶联在肽基树脂上。接着将树脂如一般方法中所述地清洗，并且重复Fmoc基团的脱保护处理，以偶联下一个氨基酸。如上述方法中所述，洗涤树脂，重复脱保护处理以偶联下一个氨基酸。在所述方案之后，将2.5当量的Fmoc-L-Asp(OtBu)-OH、Fmoc-L-Phe-OH、Fmoc-L-Asn(Trt)-OH、Fmoc-L-Gln(Trt)-OH、Fmoc-L-Tyr(tBu)-OH、Fmoc-L-Trp(Boc)-OH或Fmoc-L-Phg-OH；2.5当量的Fmoc-L-Arg(Pbf)-OH、Fmoc-L-Gln(Trt)-OH、Fmoc-L-Trp(Boc)-OH、Fmoc-L-Lys(Boc)-OH、Fmoc-L-Orn(Boc)-OH、Fmoc-L-His(Trt)-OH、Fmoc-L-Cit-OH、Fmoc-L-Asn(Trt)-OH或Fmoc-L-Phg-OH；2.5当量的Fmoc-L-Met-OH、Fmoc-L-Phe-OH、Fmoc-L-Nle-OH、Fmoc-L-Trp(Boc)-OH、Fmoc-L-Phg-OH或Fmoc-L-Nva-OH和最终2.5当量的Fmoc-L-Phe-OH、Fmoc-L-Ser(tBu)-OH、Fmoc-L-Trp(Boc)-OH或Fmoc-L-Phg-OH相继地偶联，在每一次偶联时存在2.5当量的HOBt和2.5当量的DIPCDI。
合成之后，将肽基树脂以DCM(5X3min)清洗且以氮气流干燥。
实施例2
获得Fmoc-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-AM--MBHA-其中AA1为-L-Phe-、-L-Ser-、-L-Trp-或-L-Phg-；AA2为-L-Met-、-L-Phe-、-L-Nle-、-L-Trp-、-L-Phg-或-L-Nva-；AA3为-L-Arg-、-L-Gln-、-L-Trp-、-L-Lys-、-L-Orn-、-L-His-、-L-Cit-、-L-Asn-或-L-Phg-；AA4为-L-Asp-、-L-Phe-、-L-Asn-、-L-Gln-、-L-Tyr-、-L-Trp-或-L-Phg-；AA5为-L-His-、-L-Ile-、-L-Orn-、-L-Cit-、-L-Nle-或-L-Nva-；AA6为-L-Ser-、-L-Val-、-L-Thr、-L-Nle-、-L-Ile-、-L-Ala-或-L-Nva-；并且n、m、p和q为0。
根据所述的一般方案，将5mmol(1当量)具有0.73mmol/g官能化的Fmoc-AM-MBHA树脂以哌啶-DMF处理，以移除Fmoc基团。将2.5当量的Fmoc-L-Ser(tBu)-OH、Fmoc-L-Val-OH、Fmoc-L-Thr(tBu)-OH、Fmoc-L-Nle-OH、Fmoc-L-Ile-OH、Fmoc-L-Ala-OH或Fmoc-L-Nva-OH在2.5当量DIPCDI和2.5当量HOBt存在的情况下使用DMF作为溶剂经历1小时掺入脱保护的树脂上。
随后如一般方法中所述洗涤树脂，重复Fmoc基团的脱保护处理以偶联下一个氨基酸。如一般方法中所述对Fmoc N-末端基团进行脱保护，将2.5当量的Fmoc-L-His(Trt)-OH、Fmoc-L-Ile-OH、Fmoc-L-Orn(Boc)-OH、Fmoc-L-Cit-OH、Fmoc-L-Nle-OH或Fmoc-L-Nva-OH；2.5当量的Fmoc-L-Asp(OtBu)-OH、Fmoc-L-Phe-OH、Fmoc-L-Asn(Trt)-OH、Fmoc-L-Gln(Trt)-OH、Fmoc-L-Tyr(tBu)-OH、Fmoc-L-Trp(Boc)-OH或Fmoc-L-Phg-OH；2.5当量的Fmoc-L-Arg(Pbf)-OH、Fmoc-L-Gln(Trt)-OH、Fmoc-L-Trp(Boc)-OH、Fmoc-L-Lys(Boc)-OH、Fmoc-L-Orn(Boc)-OH、Fmoc-L-His(Trt)-OH、Fmoc-L-Cit-OH、Fmoc-L-Asn(Trt)-OH或Fmoc-L-Phg-OH；2.5当量的Fmoc-L-Met-OH、Fmoc-L-Phe-OH、Fmoc-L-Nle-OH、Fmoc-L-Trp(Boc)-OH、Fmoc-L-Phg-OH或Fmoc-L-Nva-OH和最终2.5当量的Fmoc-L-Phe-OH、Fmoc-L-Ser(tBu)-OH、Fmoc-L-Trp(Boc)-OH或Fmoc-L-Phg-OH掺入肽基树脂上，在每一次偶联时存在2.5当量HOBt和2.5当量DIPCDI。
在合成之后，将肽基树脂以DCM(5X3min)清洗且以氮气流干燥。
实施例3
用于移除Fmoc的N-末端保护基的一般方法
将实施例1和2中所获得的肽基树脂的N-末端Fmoc基团如一般方法中所述地脱保护(在DFM中的20％哌啶，1×5min+1×20min)。将肽基树脂以DMF(5×1min)、DCM(4×1min)、二乙醚(4×1min)清洗且在真空下干燥。
实施例4
在实施例3中所获得的肽基树脂上引入R1棕榈酰基的方法。
将预先溶解在DMF(1毫升)中的10当量棕榈酸在10当量HOBt和10当量DIPCDI存在的情况下掺入在实施例3中所获得的1mmol(1当量)肽基树脂上。让其反应15小时，然后将树脂以THF(5X1min)、DCM(5X1min)、DMF(5X1min)、MeOH(5X1min)、DMF(5X1min)、THF(5X1min)、DMF(5X1min)、DCM(4X1min)、乙醚(3X1min)清洗且在真空下干燥。
实施例5
在实施例3中所获得的肽基树脂上引入R1乙酰基的方法。
将实施例3中所获得的1mmol(1当量)肽基树脂在25当量DIEA存在的情况下下使用5mL DMF作为溶剂，利用25当量乙酸酐进行处理。让其反应30分钟，然后将肽基树脂以DMF(5×1min)、DCM(4×1min)、二乙醚(4×1min)清洗且在真空下干燥。
实施例6
从聚合物支持物上切割实施例3、4和5中所获得的肽基树脂的方法。
将实施例3、4和5中所获得的200mg干燥肽基树脂在室温和搅拌下以5mL TFA:TIS:H2O(90:5:5)处理2小时。将滤液收集在50毫升冷二乙醚上，将其经由配备有多孔聚乙烯盘的聚丙烯注射器过滤，以50mL二乙醚清洗5次。将最终沉淀物在真空下干燥。
所获得的肽在H2O(+0.1％TFA)中的MeCN(+0.07％TFA)梯度中的HPLC分析显示在所有情况中的纯度均超过80％。所获得的肽的身份通过ESI-MS进行确认。
实施例7
聚合物支持物的切割方法和以经R2取代的胺官能化：获得Ac-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-NH-(CH2)15-CH3，其中AA1为-L-Phe-、-L-Ser-、-L-Trp-或-L-Phg-；AA2为-L-Met-、-L-Phe-、-L-Nle-、-L-Trp-、-L-Phg-或-L-Nva-；AA3为-L-Arg-、-L-Gln-、-L-Trp-、-L-Lys-、-L-Orn-、-L-His-、-L-Cit-、-L-Asn-或-L-Phg-；AA4为-L-Asp-、-L-Phe-、-L-Asn-、-L-Gln-、-L-Tyr-、-L-Trp-或-L-Phg-；AA5为-L-His-、-L-Ile-、-L-Orn-、-L-Cit-、-L-Nle-或-L-Nva-；AA6为-L-Ser-、-L-Val-、-L-Thr、-L-Nle-、-L-Ile-、-L-Ala-或-L-Nva-；并且n、m、p和q为0。
具有完全保护的侧链的肽Ac-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-OH通过利用3mL的DCM中的3％TFA溶液处理事先在真空下在KOH存在的情况下干燥的实施例5的150mg肽基树脂Ac-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-O-2-ClTrt-分钟而获得。将滤液收集在50毫升冷二乙醚上，重复处理3次。将醚溶液在减压和室温下蒸发至干燥，将沉淀物再溶解在H2O中的50％MeCN中且冻干。将10mg所获得的粗肽称重至烧瓶中且添加3当量十六烷基胺和25毫升无水DMF。添加2当量DIPCDI，置于47℃下以磁力搅拌反应。反应通过HPLC监测，直到初产物消失为止，其在24-48小时之后完成。将溶剂蒸发至干燥且与DCM共蒸发两次。将所获得的残余物[具有完全保护的侧链的Ac-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-NH-(CH2)15-CH3]再溶解在25mL TFA:DCM:茴香醚(49:49:2)的混合物中且置于室温下反应30分钟。添加250毫升冷二乙醚，将溶剂在减压下蒸发，且与醚进行两次另外的共蒸发。将剩余物溶解在H2O中的50％MeCN的混合物中且冻干。
对所获得的肽在H2O(+0.1％TFA)中的MeCN(+0.07％TFA)为梯度的HPLC分析显示在所有情况中的纯度均超过60％。所获得的肽的身份通过ESI-MS进行确认。
实施例8
本发明的肽对PAR-2活性的抑制。
将人角质细胞以10,000个细胞/孔的的密度于100μL完全DMEM培养基中接种在96孔板中。48小时后，除去培养基，将细胞用100μL1mg/mL本发明肽的溶液在37℃于CO2培养箱中温育1小时。温育后，将100μL的来自Fluo-4NW(Invitrogen)荧光钙探针与丙磺舒的混合物添加至按照提供商的说明书(Invitrogen)制备的每一个孔，将板在37℃于CO2培养箱中温育30min，随后通过用1μg/mL的PAR-2激动剂I(Calbiochem)处理来激活PAR-2。
通过在FLUOstar Galaxy读数器(BMG LabTechnologies)中，使用500nm滤光片(对于激发)和520nm滤光片(对于发射)读取荧光，记录在PAR-2激活之前和之后的荧光，由此测定PAR-2活性。针对每一个测量的对应的本底荧光来使修正荧光测量，将其针对在利用PAR-2激动剂I的处理中观察到的最大荧光进行标准化。通过将对应于利用激动剂I的PAR-2激活的最大荧光与每一个处理的值相比较来计算PAR-2活性的抑制值。表3详述了对于本发明的肽获得的PAR-2活性的最佳抑制值。
表3
实施例9
培养物中的感觉神经元内通过PAR-2活性介导的TRPV1致敏的抑制。
CGRP水平的测定。
PAR-2激活诱导肽能感觉神经元中瞬时受体电位辣椒素亚家族1(TRPV-1)的致敏作用，从而导致Ca2+的进入，其激活细胞内信号转导级联，同时伴随地导致促炎性肽例如物质P(SP)和α-降钙素基因相关肽(CGRP)的释放，从而放大了对疼痛、炎平和搔痒的反应[Dai Y.等人,"Proteinase-Activated Receptor2-Mediated Potentiation ofTransient Receptor Potential Vanilloid Subfamily1Activity Reveals aMechanism for Proteinase-Induced Inflammatory Pain",(2004),J.Neurosci.,24(18),4293-4299]。因此，评价肽在大鼠DRG神经元培养物中因通过PAR-2活性介导的TRPV-1致敏作用而引起的α-CGRP释放的抑制中的效力和潜能。
在37℃以不同的处理(以缓冲培养基HBSS(Hank’s平衡盐溶液)中的指定浓度)温育培养中的DRG神经元15min，随后在37℃通过30μM的PAR-2激动剂I处理来敏化神经元15分钟。最后，在37℃通过用1μM辣椒辣素(capsaicin)处理5min来诱导α-CGRP释放。收集上清液，按照提供商的说明书，使用Rat CGRP EIA试剂盒(SPI-Bio,Sociétéde Pharmacologie et d’Immunologie-BIO,France)通过酶免疫测定来测定释放的α-CGRP的量。通过在405nm读取吸光度而测定的颜色的强度与释放的CGRP的量成正比。针对阴性对照(利用HBSS处理的细胞)的CGRP基线释放和通过利用PAR-2激动剂I和辣椒辣素处理细胞诱导的CGRP的最大释放，通过双标准化来测定释放的CGRP的相对值。表4详述了对于不同处理测定的CGRP值。
表4
所述肽能够以20-40％(在25μg/mL时)和约80％(在0.5mg/mL时)的水平抑制通过PAR-2活性介导的TRPV1的致敏作用诱导的CGRP的释放。
实施例10
人角质形成细胞中PAR-2活性诱导的IL-6释放的抑制。
将人角质形成细胞培养在补充型培养基中，直至达到汇合。随后通过用胰蛋白酶处理而分离细胞，将其以18,000个细胞/孔的密度接种在利用胶原基质预处理的96孔板中。在于37℃、5％CO2的潮湿大气下在补充型培养基中温育48小时后，添加具有不同浓度的本发明产物和50μM的PAR2激动剂I的新鲜培养基。添加利用补充型培养基处理的细胞作为阴性对照(对照)。在相同的条件下将细胞温育另外48小时，随后收集上清液，按照提供商的说明书，使用人IL-6ELISA Ready-SET-商品化试剂盒(eBioscience,Inc.)测定释放的IL-6的量。通过在450nm读取分光光度计Multiskan Ascent读数器来测定每一个孔的吸光度，针对其在570nm的对应读数修正每一个测定值。通过针对对应于利用PAR-2激动剂I(在该细胞模型中IL-6的最大释放)进行的细胞处理的吸光度标准化来计算IL-6的相对水平。
表5
所述肽能够以递增的药剂量-反应来抑制PAR-2活性诱导的IL-6的释放。
实施例11
Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2对培养的人表皮角质形成细胞的增殖的作用。
通过基于荧光的细胞活力法评价细胞增殖，其中活细胞与死细胞的区别在于钙荧光素(calcein)-AM向其荧光形式的酶促转化。
将人角质形成细胞培养于补充有胎牛血清(FBS)的DMEM中，直至达到汇合。随后用胰蛋白酶分离细胞，将其以100,000个细胞/孔的密度接种在96孔板中。在于37℃下、5％CO2的潮湿大气下在DMEM中温育24小时后，添加具有不同浓度的本发明产物的新鲜培养基。使用利用DMEM处理的细胞作为阴性对照。在相同的条件下将细胞温育另外24小时，随后利用100μl的于磷酸缓冲盐溶液(PBS)中稀释的钙荧光素-AM(Molecular Probes)0.4μM替换培养基。在于37℃温育30分钟后，在平板读数器(Genios,Tecan)中在激发波长485nm和发射波长530nm下测量荧光。总的生长百分比计算为T/C x100，其中T为利用本发明的肽处理的孔的荧光，C为利用DMEM处理的对照孔的荧光。
表6显示在利用本发明的肽以指定的浓度温育后人表皮角质形成细胞增殖的刺激的值，计算为[(T-C)/C]。
表6
肽Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2在25μg/mL上刺激人角质形成细胞的增殖23％，从而改善皮肤的屏障功能。
实施例12
评估培养的人表皮角质形成细胞中通过利用Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的处理引起的愈合诱导。
将人角质形成细胞培养在补充有胎牛血清(FBS)的DMEM中，直至达到汇合。随后使用胰蛋白酶分离细胞，将其以50,000个细胞/孔的密度接种在48孔板中。在于37℃下在5％CO2的潮湿大气中于DMEM中温育48小时后，利用移液器尖头在培养物中切割以产生无细胞的区域以模拟损伤，利用配备有AxioCam MRc5照相机的Zeiss Axiovert40CFL显微镜拍摄所述区域的照片，使用(A0)设备软件计算无细胞区域的面积。随后添加具有不同浓度的本发明肽的新鲜培养基。将用DMEM处理的细胞用作阴性对照，将利用DMEM和FBS处理的细胞用作阳性愈合对照。将细胞在相同条件下温育另外48小时以使得细胞能够迁移至损伤区域，随后再次拍摄损伤区域的照片，计算无细胞区域的对应面积(A48)。
将愈合百分比计算为48小时后无细胞区域面积的减少与在用肽温育前无细胞区域面积的比率[(A0-A48)/A0]。表7显示以指定的浓度利用本发明的肽温育后的愈合值。
表7
肽Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2在0.5mg/mL时刺激人角质形成细胞的愈合达45％，从而改善皮肤愈合。
实施例13
Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2在培养的人皮肤成纤维细胞中的光保护效力的测定。
将人皮肤成纤维细胞在96孔板中维持在培养物中24小时以形成单层，在37℃和5％CO2的潮湿空气中，将细胞于黑暗中利用10μg/mL的Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2或磷酸缓冲盐溶液(被照射的对照，IC)预温育。随后在室温利用日光模拟灯，使用37J/cm2的能量照射细胞150min。将对照板在室温(非照射对照,NIC)保持在黑暗中进行相同的时间。在照射期后，利用新鲜培养基替换细胞培养基，随后将细胞温育另外24小时。通过中性红染料测定细胞活力，在分光光度计中在540nm测量光密度，将每一个样品的值针对非照射对照样品(CVNIC)的细胞活力进行标准化。
表8显示Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的光保护效力，其通过将利用本发明的肽处理的细胞中获得的活力(CVi)与被照射的对照细胞反应(CVIC)相比较，利用公式(CVi-CVIC)/CVIC来进行测定。
表8
实施例14
包含Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的纳米结构脂质载体的团聚体(coacervates)的制备
在适当的烧杯中，按该顺序添加下列物质：水[INCI：水]、羟丙基淀粉磷酸盐[INCI：羟丙基淀粉磷酸盐]、菌类植物胶(sclerotiumgum)[INCI：菌类植物胶]、透明质酸钠[INCI：透明质酸钠]、丙二醇[INCI：丙二醇]、苯氧乙醇[INCI：苯氧乙醇](A相成分)。搅拌其直至形成完全溶液，随后将其加热至70℃。
在分开的烧杯中，将下列物质混合在一起：倍半油酸脱水山梨醇酯[INCI：倍半油酸脱水山梨醇酯]、辛酸/癸酸甘油三酯[INCI：辛酸/癸酸甘油三酯]和异十六烷[INCI：异十六烷]直至完全均一，加热至85℃，随后添加肽Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2。
在获得两个相后，在搅拌的条件下逐渐地将相B添加至相A，随后利用高压减小混合物颗粒的尺寸。
分别地，将QUAT-SOY LDMA-25[INCI：水(水溶液)、Lauryldimonium hydroxypropyl Hydrolyzed Soy Protein在另一个烧杯中溶解在水[INCI：水(水溶液)]中，随后添加至先前的混合物中。最后，在搅拌的条件下逐渐添加相D，获得具有表9中显示的比例的化妆品组合物。
表9
实施例15
包含Ac-L-Phe-L-Met-L-Trp-L-Phe-L-His-L-Val-NH2的脂质体的制备
在适当的烧杯中，将防腐剂丙二醇[INCI：丙二醇]、苯氧乙醇[INCI：苯氧乙醇]与水混合直至形成完全溶液(相A)。随后，在搅拌的条件下将卵磷脂[INCI：卵磷脂]逐渐地掺入至相A，维持搅拌直至获得均一的分散体。在分开的烧杯中将辛酸/癸酸甘油三酯[INCI：辛酸/癸酸甘油三酯]和异十六烷[INCI：异十六烷]混合，随后将肽Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2(相C)分散。接着，将相C缓慢地添加至相A和B，搅拌直至完全均一化。最后，将混合物通过高压
表10
实施例16
包含Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的脸用化妆品组合物的制备
在适当的烧杯中，将甜菜碱[INCI：甜菜碱]和EDTA二钠[INCI：EDTA二钠]溶解在水[INCI：水](相A)中，随后添加相B，搅拌直至完全掺入。在分开的烧杯中，将辛酸/癸酸甘油三酯[INCI：辛酸/癸酸甘油二酯]、醋酸生育酚[INCI：醋酸生育酚](相C)混合在一起，直至完全均一化，随后添加至A与B的混合物上的相C。在另一个分开的烧杯中，将柠檬酸[INCI：柠檬酸]溶解于水[INCI：水]中，随后掺入丁二醇[INCI：丁二醇]，最后添加Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2(相E)。在溶解所得的混合物后，将相D和E添加至A、B与C的混合物。随后，在持续搅拌的条件下添加聚甲基丙烯酸甲酯[INCI：聚甲基丙烯酸甲酯](相F)和MIKROKILL ECT(相G)直至完全掺入。将pH调整至6.0，随后在搅拌的条件下添加来自相I的香料。
表11
实施例17
包含Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的面用化妆品组合物的制备
在适当的烧杯中，将戊二醇[INCI：戊二醇]和苯甲醇[INCI：苯甲醇]与水[INCI：水](相A)混合在一起。随后，在持续搅拌的条件下添加卡波姆[INCI：卡波姆]和鲸蜡基磷酸钾[INCI：鲸蜡基磷酸钾]，随后将混合物加热至70-75℃。在分开的烧杯中，将组分乙基己基椰油酸酯[INCI：乙基己基椰油酸酯]、C12-15烷基苯甲酸酯[INCI：C12-15烷基苯甲酸酯]、苯氧乙醇[INCI：苯氧乙醇]、PHYTOCREAM[INCI：硬脂酸甘油酯、鲸蜡硬脂醇、棕榈酰钾水解小麦蛋白]和醋酸生育酚[INCI：醋酸生育酚](相B)混合在一起，并加热至70-75℃。将加热的相B添加至相A+A1+A2，利用涡轮搅拌以形成乳液。维持搅拌直至其达到40℃，随后添加肽Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2，水[INCI：水]中的柠檬酸[INCI：柠檬酸]、丁二醇[INCI：丁二醇](相C)和二甲聚硅氧烷硅树脂[INCI：二甲聚硅氧烷]。在搅拌的条件下添加305[INCI：聚丙烯酰胺、水(水),C13-14异链烷烃、LAURETH-7]，随后添加香气[INCI：香气(香料)]。最后，逐渐添加相G直至pH被调整至5.5–7.0。
表12
实施例18
包含Ac-L-Phe-L-Phe-L-Trp-L-Asp-L-Ile-L-Val-NH2的润肤露的制备
在适当的烧杯中，将戊二醇[INCI：戊二醇]、丙二醇[INCI：丙二醇]、甘油[INCI：甘油]、泛醇[INCI：泛醇]和苯甲醇[INCI：苯甲醇]与水[INCI：水](相A)在恒定轻微搅拌的条件下溶解。在均一化后，添加相A1，维持搅拌直至产生完全溶液。在分开的烧杯中，将来自相B的组分混合在一起，在均一化后，在恒定搅拌的条件下将相B逐渐添加至相A。在另一个分开的烧杯中，将柠檬酸[INCI：柠檬酸]溶解在水[INCI：水]中，添加丁二醇[INCI：丁二醇]，随后将本发明的肽溶解。将该混合物在恒定搅拌的条件下添加至相A+B。随后，也在恒定搅拌的条件下添加相D。在使混合物均一后，添加305，利用相F将pH调整至6.0-6.5。最后，添加香料。
表13
实施例19
包含Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的毛细血管洗剂的制备
在适当的烧杯中，在恒定轻轻搅拌的条件下溶解相A的组分。在分开的烧杯中，将柠檬酸溶解于水中，添加丁二醇，随后添加本发明的肽。在均一化后，在恒定搅拌的条件下将相B添加至相A，直至完全均一化。
表14
实施例20
包含Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的漱口液的制备
在适当的烧杯中，在恒定轻轻搅拌的条件下溶解相A的成分。在分开的烧杯中，将柠檬酸溶解于水中，添加丁二醇，随后溶解本发明的肽。在均一化后，在搅拌的条件下将相B添加至相A中直至完全均一化。
表15
实施例21
实施例17的组合物对因辣椒辣素在皮肤的施用引起的螫刺的减弱作用。
对12个选择的在螫刺测试(在对前臂施用辣椒辣素的溶液后螫刺强度的主观评价)中具有1-3(0无螫刺，3强烈的螫刺)的反应程度的年龄为20至45岁的高加索人志愿者进行通过施用辣椒辣素诱导的螫刺的研究。在整个研究的持续过程中，受试者在测试的区域不使用不同的产物，并避免对UV照射的暴露。志愿者将实施例17的组合物施用至一个前臂，将安慰剂组合物(来自实施例17的无肽的相同组合物)施用至另一个前臂，每天2次进行7天，随后将0.05％的向日葵籽油中的小米椒(Capsicum frutescens)的溶液施用至每一个前臂(0.03％的辣椒辣素终浓度)。在施用辣椒辣素后15min再次进行螫刺强度的主观自我评价，测定每一个测量点相对于利用安慰剂组合物处理的前臂而言螫刺感觉的减弱。
通过用来自实施例17的乳膏处理皮肤获得的螫刺减弱示于表16。
表16
所获得的结果显示实施例17的制剂在辣椒辣素施用后15min使皮肤上的螫刺相对于安慰剂制剂而言减弱38.5％。
实施例22
包含Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的纳米结构脂质载体的团聚体的化妆品组合物的制备
制备实施例17的化妆品组合物，但利用实施例14的团聚化纳米结构脂质载体和利用表17的量替代该实施例的肽。
化妆品的组成
表17
实施例23
包含Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的脸用化妆品组合物的制备
在适当的烧杯中将戊二醇[INCI：戊二醇]和苯甲醇[INCI：苯甲醇]于水[INCI：水]中混合在一起，随后在搅拌的条件下逐渐添加卡波姆[INCI：卡波姆]直至形成完全的溶液。随后，在恒定搅拌的条件下将鲸蜡基磷酸钾[INCI：鲸蜡基磷酸钾]添加至分散体，将混合物加热至70-75℃(相A+A1+A2)。在分开的烧杯中，将组分乙基己基椰油酸酯[INCI：乙基己基椰油酸酯]、C12-15烷基苯甲酸酯[INCI：C12-15烷基苯甲酸酯]、苯氧乙醇[INCI：苯氧乙醇]、PHYTOCREAM[INCI：硬脂酸甘油酯、鲸蜡硬脂醇、棕榈酰钾水解小麦蛋白]和醋酸生育酚[INCI：醋酸生育酚](相B)混合在一起，加热至70-75℃。将加热的相B添加至相A+A1+A2，利用涡轮搅拌以形成乳液。维持搅拌直至其达到50℃，随后添加肽Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2、水[INCI：水]中的柠檬酸[INCI：柠檬酸]、丁二醇[INCI：丁二醇](相C)和二甲聚硅氧烷硅酮[INCI：二甲聚硅氧烷]。在搅拌的条件下添加305[INCI：聚丙烯酰胺、水、C13-14异链烷烃、LAURETH-7]。随后还在搅拌的条件下添加香料[INCI：香气(香料)]、肉桂醛[INCI：肉桂醛]和法尼醇[INCI：法尼醇]。最后，逐渐添加相G，直至pH被调整至6.0–6.5。
脸用化妆品的组成
表18
实施例24
皮肤水合的体内研究
实施例22的化妆品组合物及其安慰剂组合物的皮肤水化能力比较性体内研究，除本发明的肽Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2(所述肽被水替代)外，所述安慰剂组合物以与实施例22的组合物相同的百分比包含与其相同的成分。
在使测试的人在生物气候室(22℃；60％相对湿度)中适应45分钟(目的是在测量过程中维持温度和湿度恒定)后进行该研究的测量。使用CM825(Courage&Khazaka,Germany)在腿上进行皮肤水合的测量。20个年龄为18至55岁、在她们的腿上具有敏感性皮肤和搔痒感觉的妇性参与本研究；她们被教导在研究持续过程中或在开始研究前7天不施用除研究中使用的化妆品或皮肤用药组合物外的任何化妆品或皮肤用组合物。
所有志愿者对她们的右腿施用安慰剂组合物，对她们的左腿施用来自实施例22的化妆品组合物，每天2次，进行4周，总是对右腿施用安慰剂组合物，对左腿施用来自实施例22的组合物。志愿者在进行仪器测量之前不施用任何化妆品组合物至少10小时。在各自测试区域内的3个不同位置上测量皮肤测量值。将记录的值进行平均。
在研究开始之前和在先前组合物的第一次施用后1和4周进行皮肤水化测量。
表19显示实施例22的化妆品组合物相对于安慰剂组合物的皮肤湿度平均改变，计算为[(实施例22的组合物的平均改善)-(安慰剂组合物的平均改善)]/(安慰剂组合物的平均改善)*100。
时间 针对各自安慰剂组合物的差异％
1周 34.0％
4周 39.2％
表19
表中的结果明显地显示，来自实施例22的组合物具有比安慰剂组合物更强的皮肤水合能力，因而证实了化合物Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2在体内改善皮肤的水合作用。
实施例25
包含Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的实施例23的化妆乳膏在重建人表皮(RHE)中的抗敏化潜能。
包含香料的化妆乳膏通常显示由一些过敏性组分如肉桂醛或法尼醇引起的过敏反应。本实验的目的是评价实施例23的包含肉桂醛、法尼醇和肽Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2的化妆乳膏相较于安慰剂乳膏(无相C成分的实施例23组合物)的抗敏化潜能。为了测定抗敏化潜能，在乳膏施用后24h，对于两种乳膏测量RHE组织中的白细胞介素-8(IL-8)的水平。
以一式三份利用15μg的实施例23组合物和安慰剂组合物在组织的表面上处理商品化RHE组织(SkinEthic,Lyon,RHE/S/17)(0.5cm2)。在37℃、5％CO2的潮湿大气中于生长培养基中进行24小时的温育后，按照提供商的说明书，使用ELISA Interleukin检测试剂盒(Invitrogen)测定经处理的RHE组织中的IL-8表达。通过在450nm读取分光光度计Synergy MX,Biotek的值来测定吸光度。
表20
测试显示实施例23的组合物相对于安慰剂组合物而言其IL-8的表达有减少，从而证明了肽Ac-L-Phe-L-Phe-L-Trp-L-Phe-L-His-L-Val-NH2高度地抵消由化妆品过敏原例如肉桂醛和法尼醇诱导的细胞因子的释放。
Claims (49)
1.一种具有通式(I)的肽
R1-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-R2 (I)
其立体异构体、其混合物和/或其化妆上或药学上可接受的盐，其特征在于：
AA1选自-Phe-、-Ser-、-Trp-和-Phg-；
AA2选自-Met-、-Phe-、-Nle-、-Trp-、-Phg-和-Nva-；
AA3选自-Arg-、-Gln-、-Trp-、-Lys-、-Orn-、-His-、-Cit-、-Asn-和-Phg-；
AA4选自-Asp-、-Phe-、-Asn-、-Gln-、-Tyr-、-Trp-和-Phg-；
AA5选自-His-、-Ile-、-Orn-、-Cit-、-Nle-和-Nva-；
AA6选自-Ser-、-Val-、-Thr-、-Nle-、-Ile-、-Ala-和-Nva-；
W、X、Y、Z为氨基酸并且它们本身独立地选择；
n、m、p和q本身独立地选择并且具有0或1的值；
n+m+p+q小于或等于2；
R1选自H、取代的或未取代的非环状脂肪族基团、取代的或未取代的脂环基、取代的或未取代的杂环基、取代的或未取代的杂芳基烷基、取代的或未取代的芳基、取代的或未取代的芳烷基、以及R5-CO-，其中R5选自H、取代的或未取代的非环状脂肪族基团、取代的或未取代的脂环基、取代的或未取代的芳基、取代的或未取代的芳烷基、取代的或未取代的杂环基以及取代的或未取代的杂芳基烷基；
R2选自-NR3R4、-OR3和-SR3，其中R3和R4独立地选自H、取代的或未取代的非环状脂肪族基团、取代的或未取代的脂环基、取代的或未取代的杂环基、取代的或未取代的杂芳基烷基、取代的或未取代的芳基以及取代的或未取代的芳烷基；
并且
R1或R2不是α-氨基酸。
2.权利要求1的肽，其特征在于R1选自H或R5-CO-，其中R5选自取代的或未取代的C1-C24烷基、取代的或未取代的C2-C24烯基、取代的或未取代的C2-C24炔基、取代的或未取代的C3-C24环烷基、取代的或未取代的C5-C24环烯基、取代的或未取代的C8-C24环炔基、取代的或未取代的C6-C30芳基、取代的或未取代的C7-C24芳烷基、取代的或未取代的具有3至10个环成员的杂环基，以及取代的或未取代的具有2至24个碳原子和1至3个不同于碳的原子以及1至6个碳原子的烷基链的杂芳基烷基。
3.权利要求2的肽，其特征在于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。
4.前述权利要求中任一项的肽，其特征在于R2是-NR3R4或-OR3，其中R3和R4独立地选自H、取代的或未取代的C1-C24烷基、取代的或未取代的C2-C24烯基、取代的或未取代的C2-C24炔基、取代的或未取代的C3-C24环烷基、取代的或未取代的C5-C24环烯基、取代的或未取代的C8-C24环炔基、取代的或未取代的C6-C30芳基、取代的或未取代的C7-C24芳烷基、取代的或未取代的具有3至10个环成员的杂环基、以及取代的或未取代的具有2至24个碳原子和1至3个不同于碳的原子以及1至6个碳原子的烷基链的杂芳基烷基。
5.权利要求4的肽，其特征在于R3和R4独立地选自H、甲基、乙基、己基、十二烷基和十六烷基。
6.前述权利要求中任一项的肽，其特征在于R1选自H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基，AA1是-L-Phe-、AA2是-L-Met-、AA3是-L-Trp-、AA4是-L-Phe-、AA5是-L-His-、AA6是-L-Val-并且R2是-NR3R4或-OR3，其中R3和R4独立地选自H、甲基、乙基、己基、十二烷基以及十六烷基。
7.权利要求1至权利要求5中任一项的肽，其特征在于R1选自H、乙酰基、月桂酰基、豆蔻酰基或棕榈酰基，AA1为-L-Phe-、AA2为-L-Phe-、AA3为-L-Trp-、AA4为-L-Phe-、AA5为-L-His-、AA6为-L-Val-并且R2为-NR3R4或-OR3，其中R3和R4独立地选自H、甲基、乙基、己基、十二烷基以及十六烷基。
8.权利要求1至权利要求5中任一项的肽，其特征在于R1选自H、乙酰基、月桂酰基、肉豆蔻酰基或棕榈酰基，AA1是-L-Phe-，AA2是-L-Phe-，AA3是-L-Trp-，AA4是-L-Asp-，AA5是-L-Ile-，AA6是-L-Val-，并且R2是-NR3R4或-OR3，其中R3和R4独立地选自H、甲基、乙基、己基、十二烷基以及十六烷基。
9.前述权利要求中任一项的肽，其特征在于R1选自H、乙酰基以及棕榈酰基，并且R2选自-OH和-NH2。
10.权利要求1的肽，其特征在于n、m、p和q为0。
11.前述权利要求中任一项的肽，其用于抑制PAR-2受体活性。
12.权利要求1至10的肽，其用于药剂。
13.权利要求11至12中任一项的肽，其用于治疗和/或预防搔痒、炎症、疼痛、呼吸道的疾病和/或障碍。
14.权利要求13的肽，其中所述疼痛选自急性疼痛、慢性疼痛、伤害性疼痛、神经性疼痛、炎性痛、内脏痛、腹痛、消化系统痛、呼吸系统痛、泌尿生殖系统痛、内分泌系统痛、心脏痛、胰痛、肝痛、因胆石引起的疼痛、胆汁淤积、肠痛、胃痛、因十二指肠溃疡引起的疼痛、因食道炎引起的疼痛、因胃食管返流疾病引起的疼痛、脾痛、血管中的疼痛、豆状核后综合征痛、肠易激综合征、与克罗恩病相关的疼痛、与溃疡性结肠炎、憩室炎、胃肠道粘膜炎相关的疼痛、头痛、紧张性头痛,与窦炎相关的头痛、偏头痛、眼痛、干眼综合征、手术后疼痛、由外科切口引起的手术后疼痛,由骨中植入物插入引起的手术后疼痛,由骨置换引起的手术后疼痛、因感染引起的手术后疼痛、由截肢引起的手术后疼痛、由骨折引起的疼痛、由癌症引起的疼痛、由骨癌引起的疼痛、与良性骨肿瘤相关的疼痛、与骨样骨瘤相关的疼痛、与成骨细胞瘤相关的疼痛、由癌症治疗引起的疼痛、由化学疗法引起的疼痛、由呕吐引起的疼痛、由化学治疗导致的呕吐引起的疼痛、肌肉骨骼痛、痉挛肌肉疼痛、纤维肌痛、复杂区域疼痛综合征、精神性疼痛、神经痛、由脱髓鞘疾病引起的疼痛、与颈肌张力障碍相关的颈痛、背痛、腰部疼痛、坐骨神经痛、神经原性感染、神经炎、皮肤灼痛、接触敏感性、寒冷敏感性、热敏感性、皮肤刺激、毛发去除后皮肤刺激、剃毛后皮肤刺激、银屑病、敏感性皮肤、皮炎、特异性皮炎、接触性皮炎、尿布皮炎、皮脂溢皮炎、湿疹、扁平苔癣、烧伤、晒斑、关节炎、类风湿关节炎、骨关节炎、牛皮癣关节炎、葡萄膜炎,由神经损伤引起的疼痛、神经痛、疱疹后神经痛、神经病、周围神经病、幻痛、异常性疼痛、痛觉过敏、冷痛觉过敏、由腕管综合征引起的疼痛、灼痛、Grierson-Gopalan综合征、口灼伤综合征、感觉错乱、Fabry病、面部疼痛、三叉神经痛、由糖尿病引起的神经性疼痛、由AIDS引起的神经性疼痛、口面疼痛、牙痛、由拔牙引起的疼痛、由智齿拔除引起的疼痛、牙齿对冷的敏感性、牙齿对热的敏感性、口腔粘膜炎、颞下颌关节痛、由痛风引起的关节痛、与纹身或纹身去除过程相关的疼痛、拇滑囊肿痛、睾丸痛、肌盘膜痛、膀胱痛、泌尿道痛、膀胱炎、由肾脏结石引起的疼痛、肾绞痛、外阴痛、阴道痛、产后痛、月经疼痛、阴囊痛、会阴痛、骨盆痛或过敏症、皮肤痛或手术后刺激、利用强脉冲光疗法治疗后刺激、利用单色脉冲光治疗进行治疗后的刺激、利用化学剥脱剂治疗后的刺激或对攻击性外部试剂过度暴露后的刺激以及由长期酒精滥用引起的疼痛。
15.权利要求13的肽，其中所述炎症选自神经原性炎症、关节炎症、腱炎症、肌肉炎症、败血病、血管炎症、呼吸系统炎症、慢性阻塞性肺疾病、鼻炎、变应性鼻炎、哮喘、耳炎、肠炎、克罗恩病、胰腺炎、肝炎、与慢性炎症相关的病况、急性炎症、肾炎、系统性红斑狼疮、关节炎、类风湿关节炎、成人和青少年类风湿关节炎、斯蒂尔病、牛皮癣关节炎、骨关节炎、由痛风引起的关节炎、类风湿性脊柱炎、肾小球肾炎、神经炎、神经组织炎症、多发性硬化、免疫系统障碍、综合征、动脉粥样硬化、心肌炎、心包炎、脉管炎、炎症性皮肤病况、银屑病、敏感性皮肤、皮炎、特异性皮炎、接触性皮炎、尿布皮炎、皮脂溢皮炎、湿疹、过度增生性皮肤病、烧伤、晒斑、阴道黏液的炎症、外阴痛、阴道炎、口腔粘膜炎症、牙龈炎、牙周炎、炎症性眼病、葡萄膜炎、眼和春季结膜炎、肉瘤样病、溃疡病、荨麻疹、大疱性类天疱疮、纤硬皮病化、纤维化、血管性水肿、过敏反应、脱发、肝硬化、再狭窄、风湿性多肌痛、血清阴性脊柱关节病，包括强直性脊柱炎和Reiter’s综合征、皮肌炎、包涵体肌炎、多肌炎和淋巴管平滑肌增多。
16.权利要求13的肽，其中所述搔痒选自与选自下述的病况、疾病和/或障碍相关的搔痒：皮炎、特异性皮炎、接触性皮炎、尿布皮炎、疱疹样皮炎、光照性皮肤病、光敏感性、与怀孕相关的皮肤病、与绝经相关的皮肤病、湿疹、敏感性皮肤、银屑病、水痘、疱疹、带状疱疹、Netherton综合征、脱皮综合征、扁平苔癣、粉刺、头皮屑、皮脂溢、皮脂溢皮炎、脱发、运动员足、念珠菌病、痔疮、阴道搔痒、肛门搔痒症、肛生殖道搔痒症、晒斑、荨麻疹、搔痒性耳炎、老年皮肤搔痒症、水源性搔痒症、结节性痒疹、prurigo planus、玫瑰糠疹、干燥病和干性皮肤、或与透析、HIV感染、恶性肿瘤、何杰金氏病、白血病、骨髓瘤、淋巴瘤、实体瘤、腺癌、肺癌、肝病、黄疸、胆汁淤积、肝功能衰竭、肝硬化、红细胞增多症、高嗜酸细胞增多综合征、原发性血小板增多症、骨髓增生异常综合征、缺铁引起的贫血、系统性红斑狼疮、内分泌疾病、甲状腺疾病、甲状腺功能亢进、甲状腺功能减退、甲状旁腺疾病、糖尿病、肾病、肾功能衰竭、尿毒症、寄生虫病、疥疮、虱、蛔虫、过敏反应、对药物的过敏、食物过敏、对化学制品的过敏、对有毒植物的暴露、对虫咬的暴露、化学疗法、压力和焦虑相关的搔痒等。
17.权利要求13的肽，其中所述呼吸道的疾病或障碍选自哮喘、慢性阻塞性肺疾病、变应性鼻炎和支气管高反应性。
18.权利要求11至12中任一项的肽，其用于治疗癌症。
19.权利要求11至12中任一项的肽，其用于治疗和/或护理消化系统的病况、障碍和/或疾病。
20.权利要求1至10中任一项的肽，其用于治疗和/或护理皮肤和/或粘膜。
21.权利要求20的肽，其用于皮肤屏障功能的刺激和/或护理。
22.权利要求20的肽，其用于皮肤和/或粘膜的再上皮化和/或治愈。
23.权利要求20的肽，其用于使皮肤脱色素和/或光保护，或用于治疗和/或护理通过皮肤的色素沉着的减少或通过皮肤的光保护得到改善或预防的皮肤病况、障碍和/或疾病。
24.权利要求20的肽，其用于治疗头皮和/或毛细血管卫生。
25.权利要求20的肽，其用于治疗口腔粘膜层和/或口腔卫生。
26.权利要求20的肽，其用于治疗阴道粘膜和/或个人卫生。
27.权利要求11至26中任一项的肽，其中通过局部、经皮肤、口服或胃肠外途径施用所述肽来进行使用。
28.权利要求27的肽，其中所述局部或透皮施用是通过离子导入、超声促渗、电穿孔、机械压迫、渗透压梯度、包扎疗法、显微注射、借助于压力的无针注射、通过微电子贴剂、面膜或其任何组合来进行。
29.权利要求1至10中任一项的具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐的制备方法，其特征在于在固相或溶液中进行。
30.权利要求29的方法，其特征在于游离氨基的保护基团选自Boc、Fmoc、Trt、Troc、Teoc、Alloc、Mtt、Z、CIZ、Dnp、Dde、ivDde和Adpoc，游离羧基的保护基团选自tBu、Bzl、Chx、All、Dmab、2-苯基异丙基、Fm和Trt酯，酪氨酸侧链利用tBu基团来保护，丝氨酸和苏氨酸侧链利用tBu基团来保护，组氨酸侧链利用Trt或Mtt基团来保护，天冬氨酸侧链利用tBu或All来保护，谷氨酰胺和天冬酰胺侧链利用Trt基因来保护，甲硫氨酸侧链未受保护而使用，精氨酸侧链利用Pmc或Pbf来保护，色氨酸侧链利用Boc来保护或以未受保护的形式使用，以及赖氨酸和鸟氨酸侧链利用Boc、Trt或Alloc来保护。
31.一种化妆品组合物或药物组合物，其包含化妆上或药学上有效量的至少一种根据权利要求1至10中任一项的具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐，和至少一种化妆上或药学上可接受的赋形剂或佐剂。
32.权利要求31的组合物，其特征在于具有通式(I)的肽的浓度为，相对于组合物的总重量，按重量计0.000001％至20％。
33.权利要求32的组合物，其特征在于具有通式(I)的肽浓度为，相对于组合物的总重量，按重量计0.0001％至5％。
34.权利要求31至33中任一项的组合物，其特征在于将所述具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐掺入选自下述的化妆品或药物递送系统或持续释放系统：脂质体、混合的脂质体、油质体、非离子型表面活性剂脂质体囊泡、醇质体、毫米胶囊、微胶囊、纳米胶囊、纳米结构的脂质载体、海绵状物、环糊精、囊泡、胶束、表面活性剂的混合胶束、表面活性剂-磷脂混合胶束、毫米球、微球、纳米球、脂质球、微米乳剂、纳米乳剂、毫米颗粒、微米颗粒、纳米颗粒和固体脂质纳米颗粒。
35.权利要求34的组合物，其特征在于所述纳米胶囊是包含微乳剂的纳米胶囊。
36.权利要求31至35中任一项的组合物，其特征在于具有通式(I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐经发现吸附在选自滑石、膨润土、二氧化硅、淀粉或麦芽糊精之中的化妆上或药学上可接受固体有机聚合物或固体无机载体上。
37.权利要求31至35中任一项的组合物，其特征在于其以选自下述的制剂形式提供：乳膏、多重乳状液、无水组合物、含水分散体、油、奶、香膏、泡沫、洗剂、凝胶、乳膏凝胶、水醇溶液、水甘醇溶液、水凝胶、搽剂、浆液、皂、洗发水、护发乳、血清、多聚膜、软膏、摩丝、润发油、粉末、杆剂、笔剂、喷雾剂、气雾剂、胶囊、明胶胶囊、软胶囊、硬胶囊、片剂、糖衣片剂、颗粒剂、口香糖、溶液、混悬液、乳剂、糖浆剂、酏剂、多糖膜、胶冻或明胶。
38.权利要求31至37中任一项的组合物，其特征在于将其掺入选自眼部遮瑕膏、化妆粉底、卸妆液、卸妆乳、眼影、口红、唇彩、润唇膏以及唇粉的产品中。
39.权利要求31至37中任一项的组合物，其特征在于将具有通式I)的肽、其立体异构体、其混合物和/或其化妆上或药学上可接受的盐掺入织物、无纺织物或医疗设备中。
40.权利要求39的组合物，其特征在于所述织物、无纺织物或医疗装置选自绷带、纱布、t-恤衫、裤袜、短袜、内衣、腰带、手套、尿布、卫生巾、敷料、床罩、擦拭巾、粘附贴剂、非粘附贴剂、封闭贴剂、微电子贴剂和面膜。
41.权利要求31至40中任一项的组合物，其特征在于其还包括化妆上或药学上有效量的至少一种佐剂，其选自抑制PAR-2活性的其它试剂、其它抗炎和/或镇痛剂、其它抗搔痒剂、镇定剂、麻醉剂、乙酰胆碱受体聚集抑制剂、肌肉收缩抑制剂、抗胆碱能剂、黑色素合成刺激或抑制剂、增白剂或脱色素剂、色素原形成剂、自晒黑剂、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、抗组胺剂、抗病毒剂、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、保湿剂、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、生物聚合物、胶化聚合物、增稠剂、表面活性剂、软化剂、乳化剂、粘合剂、防腐剂、防皱剂、能够减少或治疗眼袋的药剂、表皮剥落剂、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药剂、胶原合成刺激剂、弹性蛋白合成刺激剂、饰胶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、伴侣蛋白合成刺激剂、cAMP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(sirtuin)合成刺激剂、热休克蛋白、热休克蛋白合成刺激剂、刺激脂质和角质层成分合成的试剂、神经酰胺、脂肪酸、胶原降解抑制剂、基质金属蛋白酶抑制剂、弹性蛋白降解抑制剂、丝氨酸蛋白酶例如组织蛋白酶G抑制剂、刺激成纤维细胞增殖的药剂、刺激角质形成细胞增殖的药剂、刺激脂肪细胞增殖的药剂、刺激黑色素细胞增殖的药剂、刺激角质形成细胞分化的药剂、刺激或延迟脂肪细胞分化的试剂、抑制乙酰胆碱酯酶的药剂、皮肤松弛剂、刺激糖胺聚糖合成的药剂、抗角化过度剂、粉刺溶解剂、抗银屑病剂、DNA修复剂、DNA防护剂、稳定剂、用于治疗和/或护理敏感性皮肤的试剂、固化剂、紧致剂、粘合剂、调节皮脂产生的药剂、脂肪分解剂或刺激脂解的试剂、脂肪形成剂、调节PGC-1α合成的试剂、调节PPARγ活性的试剂、增加或减少脂肪细胞的甘油三酯含量的试剂、抗蜂窝组织剂、止汗剂、刺激愈合的药剂、协助愈合的药剂、刺激再上皮化的试剂、协助再上皮化的试剂、细胞因子生长因子、作用于毛细血管循环和/或微循环的试剂、刺激血管生成的试剂、抑制血管渗透性的药剂、静脉紧张剂、作用于细胞代谢的药剂、用于改善真皮-表皮接合的试剂、诱导毛发生长的药剂、毛发生长抑制剂或延缓剂、延迟毛发丢失的试剂、防腐剂、香料、螯合剂、植物提取物、精油、海洋提取物、获自生物技术过程的试剂、无机盐、细胞提取物、防晒剂以及有效抗A和/或B紫外线和/或红外A射线的有机或无机光防护剂或其混合物。
42.权利要求41的组合物，其特征在于所述佐剂是合成来源的活性剂或为植物提取物或来自生物技术法或来自合成法与生物技术法的组合。
43.权利要求41或42中任一项的组合物，其特征在所述佐剂选自脱色素剂或美白剂或黑色素合成抑制剂。
44.权利要求43的组合物，其特征在于所述美白剂或脱色素剂或黑色素合成抑制剂选自二甲基甲氧基色原烷醇(Chromanol)和二甲基甲氧基色满基棕榈酸酯。
45.权利要求41至42中任一项的组合物，其特征在于所述佐剂选自刺激愈合的试剂、协助愈合的试剂、刺激再上皮化的试剂或协助再上皮化的试剂。
46.权利要求45的组合物，其特征在于所述刺激愈合的试剂、协助愈合的试剂、刺激再上皮化的试剂或协助再上皮化的试剂选自假交替单胞菌发酵提取物、三肽-10瓜氨酸、乙酰基二肽-3、氨基己酸、乙酰基六肽-37或假交替单胞菌发酵提取物、水解小麦蛋白质、水解大豆蛋白质、三肽-10瓜氨酸和三肽-1的混合物。
47.权利要求41至42中任一项的组合物，其特征在于所述佐剂选自防皱剂或抗老化剂。
48.权利要求47的组合物，其特征在于所述防皱剂或抗老化剂选自乙酰基六肽-8、乙酰基七肽-4、乙酰基八肽-3、五肽-18、乙酰基六肽-30，水解小麦蛋白质、水解大豆蛋白质和三肽-1的混合物，二氨基丙酰基三肽-33、三肽-10瓜氨酸，假交替单胞菌发酵提取物、水解小麦蛋白质、水解大豆蛋白质、三肽-10瓜氨酸和三肽-1的混合物，乙酰基四肽-5、乙酰基三肽-30瓜氨酸、乙酰基精氨酰色氨酰二苯基甘氨酸、乙酰基四肽-22、二甲基甲氧基色原烷醇、二甲基甲氧基色满基棕榈酸酯、假交替单胞菌发酵提取物，盐酸赖氨酸、卵磷脂和三肽-9瓜氨酸的混合物，盐酸赖氨酸、卵磷脂和三肽-10瓜氨酸的混合物，乙酰基六肽-37，大豆油、倍半油酸脱水山梨醇酯、异十六烷、透明质酸钠、月桂基二甲基铵羟丙基(Lauryldimonium Hydroxypropyl)水解的大豆蛋白和乙酰基六肽-39的混合物，和乙酰基六肽-38。
49.权利要求20的肽，其用于抑制皮肤致敏剂。
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- 2012-10-31 KR KR1020147015123A patent/KR102025923B1/ko active Active
- 2012-10-31 EP EP12788482.3A patent/EP2773366B1/en active Active
- 2012-10-31 AU AU2012331140A patent/AU2012331140A1/en not_active Abandoned
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- 2012-10-31 WO PCT/EP2012/071637 patent/WO2013064583A1/en active Application Filing
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Cited By (22)
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| CN107735099A (zh) * | 2015-05-25 | 2018-02-23 | 崖柏健康与福利私人有限公司 | 组合物和其用途 |
| CN108495646A (zh) * | 2015-12-10 | 2018-09-04 | 路博润先进材料公司 | 用于治疗和/或护理皮肤、毛发、指甲和/或粘膜的化合物 |
| CN108495646B (zh) * | 2015-12-10 | 2022-07-08 | 路博润先进材料公司 | 用于治疗和/或护理皮肤、毛发、指甲和/或粘膜的化合物 |
| CN106333869A (zh) * | 2016-11-02 | 2017-01-18 | 广州美尔生物科技有限公司 | 一种具有美白祛斑作用的护肤品及其制备方法 |
| CN106333869B (zh) * | 2016-11-02 | 2020-05-19 | 广州美尔生物科技有限公司 | 一种具有美白祛斑作用的护肤品及其制备方法 |
| CN107778349A (zh) * | 2017-11-29 | 2018-03-09 | 陕西慧康生物科技有限责任公司 | 一种低成本合成ghk醋酸盐的方法 |
| CN107778349B (zh) * | 2017-11-29 | 2021-05-04 | 陕西慧康生物科技有限责任公司 | 一种合成ghk醋酸盐的方法 |
| CN111712252A (zh) * | 2017-12-13 | 2020-09-25 | 纽约州立大学研究基金会 | 用于治疗疼痛和提高疼痛敏感性的肽和其它药剂 |
| CN110279644A (zh) * | 2018-10-25 | 2019-09-27 | 广州暨大美塑生物科技有限公司 | 一种具有舒缓修复作用的组合物及其在化妆品中的应用 |
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| CN115120701A (zh) * | 2022-07-22 | 2022-09-30 | 陕西中鸿科瑞再生医学研究院有限公司 | 一种改善抑郁的组合物及其制备方法和应用 |
| CN115581626B (zh) * | 2022-08-12 | 2023-07-14 | 植物医生(广东)生物科技有限公司 | 一种保湿、抗氧化、舒缓组合物及其应用 |
| CN115581626A (zh) * | 2022-08-12 | 2023-01-10 | 植物医生(广东)生物科技有限公司 | 一种保湿、抗氧化、舒缓组合物及其应用 |
| CN116711659A (zh) * | 2023-06-13 | 2023-09-08 | 中国科学院南海海洋研究所 | 假交替单胞菌在促进珊瑚幼虫高产生物膜和诱导珊瑚幼虫附着生长中的应用 |
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| CN117618400A (zh) * | 2023-11-29 | 2024-03-01 | 北京烨桦疑难病中医研究院 | 一种提高免疫力的复合中药吸雾制剂及其制备方法 |
| CN118402988A (zh) * | 2024-04-17 | 2024-07-30 | 广州环亚化妆品科技股份有限公司 | 一种含多肽的抗皱组合物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6148676B2 (ja) | 2017-06-14 |
| TW201333045A (zh) | 2013-08-16 |
| JP2014533245A (ja) | 2014-12-11 |
| KR20140090657A (ko) | 2014-07-17 |
| WO2013064583A1 (en) | 2013-05-10 |
| CN104023737B (zh) | 2018-02-06 |
| TWI631141B (zh) | 2018-08-01 |
| EP2773366A1 (en) | 2014-09-10 |
| US9333152B2 (en) | 2016-05-10 |
| KR102025923B1 (ko) | 2019-09-26 |
| US20140322307A1 (en) | 2014-10-30 |
| AU2018201997B2 (en) | 2019-11-21 |
| AU2018201997A1 (en) | 2018-04-12 |
| EP2773366B1 (en) | 2017-03-01 |
| AU2012331140A1 (en) | 2014-05-08 |
| ES2625847T3 (es) | 2017-07-20 |
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