CN1259866A - 皮肤病的治疗方法 - Google Patents
皮肤病的治疗方法 Download PDFInfo
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- CN1259866A CN1259866A CN98804676A CN98804676A CN1259866A CN 1259866 A CN1259866 A CN 1259866A CN 98804676 A CN98804676 A CN 98804676A CN 98804676 A CN98804676 A CN 98804676A CN 1259866 A CN1259866 A CN 1259866A
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- protein kinase
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Abstract
本发明公开了一种用于减少或抑制血管渗透性的方法,特别是减少或抑制与VPF/VEGF相关的血管渗透性增加的方法,以及减少或抑制表现为大疱性类天疱疮、多形性红斑、疱疹样皮炎、接触性皮炎、迟延性过敏症的皮肤水肿的方法,具体采用β-同工酶选择性PKC抑制剂,(S)-3,4-[N,N′-1,1′-((2″-乙氧基)-3′″(O)-4′″-(N,N-二甲氨基)-丁烷)-双-(3,3′-吲哚基)]-1(H)-吡咯-2,5-二酮和其可药用盐。
Description
本申请保护共同未决的在先申请美国专利申请号60/044,431(1997年4月30日申请),该申请引入本文作为参考。
本发明涉及一种用于减少或抑制与皮肤水肿如硬结有关的血管渗透性的方法,特别是涉及一种减少或抑制由血管渗透性因子(VPF)/血管内皮生长因子(VEGF)引起的血管渗透性增加的方法。具体而言,本发明涉及蛋白激酶C(PKC)抑制剂,特别是特定类同工酶选择性PKC抑制剂在治疗大疱性类天疱疮、多形性红斑、疱疹样皮炎、接触性皮炎/迟延性过敏症以及过敏性皮肤疾病中的用途。
皮肤疾病如大疱性类天疱疮、多形性红斑、疱疹样皮炎、接触性皮炎以及过敏性皮肤疾病的特征是皮肤水肿。大疱性类天疱疮通常出现在中年以后,并可能发生于部分或全部皮肤及粘膜表面上。疱疹样皮炎的特征是强烈瘙痒及成群的水疱,其会对称分布于四肢的伸肌表面以及头皮、臀部和背部。
多形性红斑综合征是一种皮肤和粘膜的特征性反应,其与许多种可能的病因有关,包括传染性试剂(疱疹病毒hominis,支原菌属肺炎)和药物(特别是青霉素、退热剂、巴比妥类药物、乙内酰脲和磺胺药物)。在50%的患者中,不能确定病因。多形性红斑中主要的病理学变化是围绕血管急性淋巴组织细胞炎性的浸润,可能包括在毛细管的内皮细胞中的退行性变化,并表现为毛细管皮肤水肿。这种损害以对称分布特征形式发生,并且所述综合征也可包括严重的毒血症、衰竭、高烧、咳嗽以及“空隙性”肺炎。
接触性皮炎/迟延性过敏症是一种在暴露于过敏剂后数小时或数天发生的以皮肤发红发硬的损害为特征的皮肤病。毒葛是引起这种皮肤病的普通过敏剂中的一种。
这些皮肤病均与血管渗透性过高和皮肤水肿有关(Macvicar D等,1963;J Invest Dermatol 41:289;Pierard J and WhimsterI,1961;Br J Dermatol 73:253)。围绕微血管的渗透性过高是接触性皮炎/迟延性过敏症的稳定特征(Voisin等,Ann.Inst.Pasteur.104:169,1963)。近年来的研究还涉及在皮肤水肿和表皮下大疱形成中的VPF/VEGF(Brown L等,1005;J Invest Dermatol104:744)。最近的研究还表明,在接触性皮炎/迟延性过敏症反应的实验模型中,在单核细胞/巨噬细胞和角蛋白细胞中存在VPF/VEGF(Brown等,J Immunol,154:2801,1995)。皮肤损害中VEGF水平显著增加表明存在上述疾病。具体说来,患有上述皮肤病的患者在其患处的大疱中显示出极高的VEGF水平。这些年来,为治疗这些发疱疾病,已开发出诸如皮质类固醇、砜或磺胺吡啶治疗等治疗手段。但是,人们仍寄希望开发一种新型的皮肤损伤治疗剂,特别是靶向VPF/VEGF刺激的血管渗透性的治疗剂。
本发明的目的是提供一种治疗皮肤水肿的方法。
本发明的另一个目的是提供抑制与皮肤水肿相关的VPF/VEGF刺激的血管渗透性的方法。
本发明的这些目的和其它目的可通过下述一个或多个实施方案给出。
在本发明的一个实施方案中,提供了一种治疗皮肤水肿的方法,该方法包括向需要治疗的哺乳动物给予治疗有效量的蛋白激酶C抑制剂。
在本发明的另一个实施方案中,提供了一种减少或抑制与皮肤水肿相关的VPF/VEGF刺激的血管渗透性的方法,该方法包括向需要治疗的哺乳动物给药治疗有效量的蛋白激酶C抑制剂。
本发明为现有技术提供了治疗(例如减少或抑制)与皮肤水肿相关的如由VPF/VEGF引起的血管渗透性的方法。该方法可有效地治疗大疱性类天疱疮、多形性红斑、疱疹样皮炎、接触性皮炎/迟延性过敏症,和过敏性皮肤病。
本发明发现,使用PKC抑制剂,特别是蛋白激酶C抑制剂一类的PKC抑制剂可减少或抑制与皮肤水肿相关的血管渗透性,特别是减少或抑制由VPF/VEGF引起的血管渗透性的增加。结果,这类化合物可用于治疗与皮肤水肿相关的皮肤病,如大疱性类天疱疮、多形性红斑、疱疹样皮炎、接触性皮炎/迟延性过敏症,和过敏性皮肤病。
本发明的方法优选采用那些可有效地抑制β-同工酶的蛋白激酶C抑制剂。化合物的一个适宜基团通常在现有技术中描述为双-吲哚基马来酰亚胺或大环双-吲哚基马来酰亚胺。现有技术中公知的双-吲哚基马来酰亚胺包括下述美国专利所述的那些:US 5,621,098、5,552,396、5,545,636、5,481,003、5,491,242和5,057,614,所有这些文献均引入本文作为参考。大环双-吲哚基马来酰亚胺具体由式I的化合物表示。这些化合物和其制备方法在US 5,552,396中有述,该文献也引入本文作为参考。这些化合物以治疗有效量(如VPF/VEGF抑制量)给药于哺乳动物,以减少或抑制血管渗透性,特别是减少或抑制VPF/VEGF刺激的血管渗透性。具体说来,这些化合物可用于治疗与血管渗透性相关的皮肤水肿,如大疱性类天疱疮、多形性红斑、疱疹样皮炎、接触性皮炎/迟延性过敏症,和过敏性皮肤病。
用于本发明方法的一类优选化合物或其可药用盐、前药或其酯具有下式:其中:
W为-O-、-S-、-SO、-SO2-、-CO-、C2-C6亚烷基、取代的亚烷基、C2-C6亚烯基、-芳基-、-芳基(CH2)mO-、-杂环基-、-杂环基-(CH2)mO-、-稠合的二环-、-稠合的二环-(CH2)mO-、-NR3-、-NOR3-、-CONH-或-NHCO-;
X和Y独立地为C1-C4亚烷基、取代的亚烷基,或X、Y和W结合形成-(CH2)n-AA-;
R1为氢或至多四个选择性取代基,其独立地选自卤素、C1-C4烷基、羟基、C1-C4烷氧基、卤代烷基、硝基、NR4R5或-NHCO(C1-C4烷基);
R2为氢、CH3CO-、NH2或羟基;
R3为氢、(CH2)m芳基、C1-C4烷基、-COO(C1-C4烷基)、-CONR4R5、-(C=NH)NH2、-SO(C1-C4烷基)、-SO2(NR4R5)或-SO2(C1-C4烷基);
R4和R5独立地为氢、C1-C4烷基、苯基、苄基,或与其键合的氮结合形成饱和或不饱和的5或6元环;
AA为氨基酸残基;
m独立地为0、1、2或3;和
n独立地为2、3、4或5。
用于本发明的更优选的一类化合物由式I代表,其中,-X-W-Y-部分包含4-8个原子,其可被取代或未被取代。最优选的是,-X-W-Y-部分包含6个原子。
用于本发明方法的其它优选的化合物为以下的式I化合物,其中,R1和R2和氢;W为取代的亚烷基、-O-、-S-、-CONH-、-NHCO-或-NR3-。用于本发明的特别优选的化合物为式Ia化合物或其可药其中,Z为-(CH2)p-或-(CH2)p-O-(CH2)p-;R4为羟基、-SH、C1-C4烷基、(CH2)m芳基、-NH(芳基)、-N(CH3)(CF3)、-NH(CF3)或-NR5R6;R5为氢或C1-C4烷基;R6为氢、C1-C4烷基或苄基;p为0、1或2;m独立地为2或3。式Ia最优选的化合物如下:Z为CH2;R4为-NH2、-NH(CF3)或-N(CH3)2。
用于本发明方法中的其它优选化合物为以下的化合物:其中,式I中的W为-O-,Y为取代的亚烷基,X为亚烷基。这些优选的化合物或其可药用盐、前药或其酯由式Ib表示:其中,Z为-(CH2)p-;R4为-NR5R6、-NH(CF3)或-N(CH3)(CF3);R5和R6独立地为氢或C1-C4烷基;p为0、1或2;m独立地为2或3。式Ib最优选的化合物为以下的化合物:其中,p为1;R5和R6为甲基。
由于这些化合物包含碱性部分,因此,式I、Ia和Ib的化合物也可以可药用酸加成盐形式存在。常规用于形成这种盐的酸包括无机酸,如盐酸、氢溴酸、氢碘酸、硫酸和磷酸,以及有机酸如对甲苯磺酸、甲磺酸、草酸、对溴苯基磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸,和相关的无机和有机酸。因此,这种可药用盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、癸二酸盐、富马酸盐、马来酸盐、2-丁炔-1,4-二酸盐(dioate)、3-己炔-2,5-二酸盐、苯甲酸盐、氯代苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、对苯二酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、马尿酸盐、B-羟基丁酸盐、羟乙酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐等。特别采用盐酸盐和甲磺酸盐。甲磺酸盐如US 5,710,145所述,该文献引入本文作为参考。
除了可药用盐外,也可能存在其它盐。它们可在化合物纯化过程、其它盐的制备过程或鉴别和标记化合物或中间体中用作中间体。
式I、Ia和Ib化合物的可药用盐也可以各种溶剂化物存在,如与水、甲醇、乙醇、二甲基甲酰胺、乙酸乙酯等的溶剂化物。也可制备这种溶剂化物的混合物。这种溶剂化物可来源于结晶的溶剂,在溶剂的制备或结晶过程中固有的或对该溶剂而言外来的。
可以理解,式I、Ia和Ib化合物可以各种立体异构体形式存在,例如,在取代的亚烷基部分,W可包含手性碳原子。化合物通常是以外消旋体制备,并可便利地以这种外消旋体使用。或者,如果需要的话,也可通过常规技术分离或合成两种单个的对映异构体。这种外消旋体和对映异构体和其混合物构成用于本发明方法的化合物的一部分。
用于本发明的化合物也包括式I、Ia和Ib化合物的可药用前药。所述前药是一种已进行了化学改性并在作用位点处不具有生物活性的药物,但其在体内过程中通过一种或多种酶或其它物质被降解或改性成母体生物活性形式。这种前药有可能具有与其母体不同的药动学,能够易于吸收粘膜上皮,具有更好的成盐性或溶解性,和/或的系统稳定性(例如,增加了血浆的半衰期)。通常,这种化学改性包括:
(1)可通过酯酶或脂酶裂开的酯或酰胺衍生物;
(2)可通过特异性或非特异性蛋白酶识别的肽;或
(3)通过前药形式或改性前药形式的膜选择在作用位点聚集的衍生物;或者,将前述3种进行任意组合。在下述文献中描述了选择和制备适宜的前药衍生物的常规过程:H.Bundgaard,Design ofProdrug,(1985)。
各种双-吲哚-N-马来酰亚胺衍生物的合成方法在US5,057,614(Davis等)中有述,适用于本发明中使用的优选化合物的合成方法在US 5,552,396和EP 657 411A1(Faul等)中有述,这两篇文献均引入本文作为参考。
一种特别优选的用于本发明方法的蛋白激酶C抑制剂描述在上述US 5,552,396的实施例5g中((S)-3,4-[N,N′-1,1′-((2″-乙氧基)-3(O)-4-(N,N-二甲氨基)-丁烷)-双-(3,3′-吲哚基)]-1(H)-吡咯-2,5-二酮盐酸盐)。这种化合物为一种有效的蛋白激酶C抑制剂。其在各种激酶中对蛋白激酶C具有选择性,并且具有高度同工酶选择性,即,其对β-1和β-2同工酶具有选择性。这种化合物的其它盐也将是优选采用的,特别是甲磺酸盐。
(II)其它溶剂如甲醇,丙酮,乙酸乙酯和它们的混合物也是可用的。溶剂与水的比例并不关键,通常由试剂的溶解度确定。溶剂与水的优选比例通常为0.1∶1至100∶1(体积比),优选该比例为1∶1至20∶1,首选5∶1至10∶1。最佳比例取决于所选择的溶剂,优选丙酮与水的比例为9∶1。
反应通常包含大约等摩尔量的两种试剂,当然,在其它比例下,特别是当磺酸过量的情形下反应也可操作。甲磺酸的加入速度对反应并不关键,可迅速(小于5分钟)加入,或者缓慢加入(6小时或多于6小时)。反应在0℃至回流温度下进行。搅拌反应混合物直至完全形成盐,其由X射线粉末衍射法测定,可能需要5分钟至12小时。
本发明的盐是优选采用的,其易于以结晶形式制备。经过干燥或置于20-60℃相对湿度下,盐的三水合物形式可易于转化成一水合物。盐实质上为表现出确定熔点、双折射和X射线衍射图形的结晶。通常,这种结晶具有少于10%的无定形固体,优选少于5%,首选少于1%。
甲磺酸盐通过过滤或其它本领域中公知的分离技术直接从反应混合物中分离出来,收率为50%-100%。如果需要的话,可采用本领域公知的重结晶和其它提纯技术对盐进行纯化。
据信,VPF/VEGF通过PKC的活化,特别是PKC-β的活化,引起与皮肤水肿相关的血管渗透性增加。PKC-β也需要由对敏化剂有反应的单核细胞进行抗原呈递。因而,PKC抑制剂,特别是PKC-β抑制剂可用于减弱或抑制皮肤水肿,特别是与通过VPF/VEGF刺激或引起的细胞和/或血管渗透性增加相关的皮肤水肿。
本发明确认的化合物可用于治疗各种与皮肤水肿相关的皮肤病临床表现。皮肤水肿的特征是由血管容积引出的流体积聚入皮肤组织间隙,其可能会形成水疱。水疱形成通常表现为两种主要形式:水疱和大疱,它们为包含流体的局限性病灶。
皮肤水肿为许多种皮肤疾病的主要特征:一些细菌和病毒感染;过敏性皮肤病,如血管神经性水肿和特应性皮炎;由于机械、热或化学试剂导致的创伤;和最重要的不知病因的大疱性疾病,如天疱疮。具体而言,已发现皮肤水肿是大疱性类天疱疮、多形性红斑、疱疹样皮炎、接触性皮炎/迟延性过敏症,和由各种敏化剂引起的过敏性皮肤病。所有上述皮肤病均可用本发明的化合物治疗。
本领域的技术人员可以理解,本发明蛋白激酶C抑制剂的治疗有效量(如VPF/VEGF抑制量)为足以抑制血管渗透性、与血管渗透性相关的VPF/VEGF活性或皮肤水肿的量,特别是,该量根据皮肤损害的大小和类型、治疗制剂中化合物的含量以及患者的状况改变。体内试验和体外试验可用于确定需要抑制血管渗透性和皮肤水肿的化合物用量。例如,经给予本发明的化合物,通过荧光素、漏出血管系统并进入皮肤的台盼蓝或本领域公知的任一种方法来测量血管渗透性;皮肤水肿易于通过临床检验由有经验的医务人员检测。接触性皮炎的啮齿动物模型(Brown等,J.Immunol 154:2801,1995)可用来评价本发明化合物的有效性。由毒葛得到的提取物漆酚也可用在人体中通过测量皮肤水肿的大小如损伤硬结来测试化合物的有效性。通常,通过临床医生决定用于治疗与皮肤水肿相关的皮肤损害的作为治疗剂给药的蛋白激酶C抑制剂用量。一般原则是,当施以适宜剂量时,需考虑损害的程度、患者的体重和年龄。
通常,适宜的剂量应使蛋白激酶C抑制剂在治疗位点处的浓度为0.5nM-200μM,更优选20nM-80nM。预期在大多数情形下,20nM-80nM的血清浓度应足够。
为了获得这些治疗浓度,患者治疗所需的给药量通常为约0.1mg/天/kg体重至1.5mg/天/kg体重,通常需要要不超过约1.0mg/天/kg体重的蛋白激酶C抑制剂。如上所述,上述用量可以针对具体情况进行变化。
本发明也关注预防使用本发明所述化合物以防止或抑制这种皮肤病的加重。可以考虑,适宜的预防剂量通常低于需用于治疗疾病的剂量范围的下限。
式I的化合物和优选的式Ia和Ib化合物优选在给药前进行配制。适宜的药物制剂可根据公知的方法和易得的配料制备。在制备适用于本发明方法的组合物时,活性成分通常与载体混合,或用载体稀释,或包封在载体中,载体可为胶囊、小药囊、纸或其它有形体形式。当载体作为稀释剂使用时,其可为用作活性成分载体、赋形剂或介质的固体、半固体或液体。因此,化合物可为片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、悬浮剂、乳剂、溶液、糖浆、气雾剂(作为固体或液体介质)、软和硬明胶胶囊、栓剂、无菌注射溶液和用于口服或局部涂敷的无菌包装粉末。
适宜的载体、赋形剂和稀释剂的实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸钠、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、糖浆、甲基纤维素、甲基和丙基羟基苯甲酸酯、滑石、硬脂酸镁和矿物油。制剂中还可包含润滑剂、增湿剂、乳化剂和悬浮剂、防腐剂、甜味剂或矫味剂。本发明的组合物可配制成在患者给药后使活性成分快速释放、持续释放或延迟释放的制剂。组合物优选配制成单位剂量形式,每一剂量包含约0.05mg-约3g的活性成分,更优选约64mg。但是,可以理解,给药的治疗剂量将由主治医师根据相应情形确定,包括所治疗疾病的严重程度、所选择的给药化合物以及所选择的给药方式。因而,上述剂量范围并不是对本发明范围的限定。术语“单位剂量形式”是指适用于病人和其它哺乳动物单次剂量的物理分散单位,每一单位包含经计算的预定量活性物质和适宜的药用载体,以产生所需的治疗效果。
除了上述大多数可口服给药的制剂外,用于本发明方法的化合物也可以且多数时候将采用局部给药。局部制剂包括软膏剂、霜剂和凝胶剂。
软膏剂的制备过程通常采用:(1)一种油脂性基料即由不挥发油或烃如白凡士林或矿物油组成的基料,或(2)一种吸收基料,即一种由无水物质组成的可吸水的基料,如无水羊毛脂。通常,不论是油脂性基料还是吸收剂,在基料的制剂中可将活性成分(化合物)根据所需浓度加至一定量。
霜剂为油/水乳剂。它们由油相(内相)和水相(连续相)组成,油相包含常规不挥发油,烃等,如蜡、凡士林、矿物油等,水相包含水和水溶性物质,如加入的盐。两相采用乳化剂进行稳定化处理,所述稳定剂例如为表面活性剂,如月桂基硫酸钠、亲水胶体,如阿拉伯胶、胶态粘土、胶体铝镁硅酸盐等。在乳液形成后,将活性成分(化合物)以一定量加入以达到所需的浓度。
凝胶包含一种选自油脂性基料、水或乳液-悬浮液基料的基料。向该基料中加入一种在基料中形成基质的胶凝剂,增加其粘度。胶凝剂的实例为羟丙基纤维素、丙烯酸聚合物等。通常,将活性成分(化合物)以所需浓度在加入胶凝剂时加入制剂中。
掺入局部制剂中的化合物的量并不关键;该浓度应足以允许以一定的量备用制剂至受作用的组织区域,所述量将传送所需量的化合物至所需治疗位置。
涂敷至治疗组织的局部制剂的常规用量将取决于受治疗组织大小和制剂中化合物的浓度。通常,制剂将按照约1-约500μg化合物/cm2治疗组织的用量涂敷。优选化合物的涂敷量为约30至300μg/cm2,更优选约50至约200μg/cm2,首选约60至约100μg/cm2。
下述制剂实施例用于说明本发明,它们并非对本发明范围的限定。
制剂1
硬明胶胶囊,采用下述成分制备:
用量(mg/胶囊)
活性成分 250
无水淀粉 200
硬脂酸镁 10
总计 460mg将上述成分混合,并将460mg成分填充入硬明胶胶囊中。
制剂2片剂,采用下述成分制备:
用量(mg/片)
活性成分 250
微晶纤维素 400
煅制二氧化硅 10
硬脂酸 5
总计 665mg将各组分掺混,并压制形成重665mg的药片。
制剂3每一片包含60mg活性成分的片剂,采用下述成分制备:
用量(mg/片)
活性成分 60mg
淀粉 45mg
微晶纤维素 35mg聚乙烯吡咯烷酮(10%水溶 4mg
液)
羧甲基淀粉钠 4.5mg
硬脂酸镁 0.5mg
滑石 1mg
总计 150mg
将活性成分、淀粉和纤维素通过美国45目筛,并充分混合。将聚乙烯吡咯烷酮的溶液与形成的通过美国14目筛的粉末混合。所产生的颗粒在50℃下干燥,并通过美国18目筛。然后,向颗粒中加入已通过美国60目筛的羧甲基淀粉钠、硬脂酸镁和滑石,混合后,在压片机上压制,得到每片重150mg的药片。
以上描述了本发明的原理、优选实施方案和操作方式。但是,本发明并不受上述所描述的具体形式的限制,它们仅用来说明本发明而不起限定作用。在不背离本发明的精神实质下,本领域的技术人员可以做出各种改变和变化。
Claims (14)
1、一种通过减少VPF/VEGF刺激的血管渗透性来治疗皮肤水肿的方法,该方法包括向需要进行治疗的哺乳动物给予治疗有效量的蛋白激酶C抑制剂。
2、根据权利要求1的方法,其中,蛋白激酶C抑制剂对同工酶具有选择性。
3、根据权利要求2的方法,其中,蛋白激酶C抑制剂选择性地抑制蛋白激酶C的β同工酶。
(I)其中:
W为-O-、-S-、-SO、-SO2-、-CO-、C2-C6亚烷基、取代的亚烷基、C2-C6亚烯基、-芳基-、-芳基(CH2)mO-、-杂环基-、-杂环基-(CH2)mO-、-稠合的二环-、-稠合的二环-(CH2)mO-、-NR3-、-NOR3-、-CONH-或-NHCO-;
X和Y独立地为C1-C4亚烷基、取代的亚烷基,或X、Y和W结合形成-(CH2)n-AA-;
R1为氢或至多四个选择性取代基,其独立地选自卤素、C1-C4烷基、羟基、C1-C4烷氧基、卤代烷基、硝基、NR4R5或-NHCO(C1-C4烷基);
R2为氢、CH3CO-、NH2或羟基;
R3为氢、(CH2)m芳基、C1-C4烷基、-COO(C1-C4烷基)、-CONR4R5、-(C=NH)NH2、-SO(C1-C4烷基)、-SO2(NR4R5)或-SO2(C1-C4烷基);
R4和R5独立地为氢、C1-C4烷基、苯基、苄基,或与其键合的氮结合形成饱和或不饱和的5或6元环;
AA为氨基酸残基;
m独立地为0、1、2或3;和
n独立地为2、3、4或5。
7、根据权利要求3的方法,其中,蛋白激酶C抑制剂为(S)-3,4-[N,N′-1,1′-((2″-乙氧基)-3(O)-4-(N,N-二甲氨基)-丁烷)-双-(3,3′-吲哚基)]-1(H)-吡咯-2,5-二酮或其酸加成盐。
8、一种通过减少VPF/VEGF刺激的血管渗透性来治疗水疱形成的方法,该方法包括向需要进行治疗的哺乳动物给予治疗有效量的蛋白激酶C抑制剂。
9、根据权利要求8的方法,其中,蛋白激酶C抑制剂对同工酶具有选择性。
10、根据权利要求9的方法,其中,蛋白激酶C抑制剂选择性地抑制蛋白激酶C的β同工酶。
11、根据权利要求10的方法,其中,蛋白激酶C抑制剂或其酸加成盐具有下式:其中:
W为-O-、-S-、-SO、-SO2-、-CO-、C2-C6亚烷基、取代的亚烷基、C2-C6亚烯基、-芳基-、-芳基(CH2)mO-、-杂环基-、-杂环基-(CH2)mO-、-稠合的二环-、-稠合的二环-(CH2)mO-、-NR3-、-NOR3-、-CONH-或-NHCO-;
X和Y独立地为C1-C4亚烷基、取代的亚烷基,或X、Y和W结合形成-(CH2)n-AA-;
R1为氢或至多四个选择性取代基,其独立地选自卤素、C1-C4烷基、羟基、C1-C4烷氧基、卤代烷基、硝基、NR4R5或-NHCO(C1-C4烷基);
R2为氢、CH3CO-、NH2或羟基;
R3为氢、(CH2)m芳基、C1-C4烷基、-COO(C1-C4烷基)、-CONR4R5、-(C=NH)NH2、-SO(C1-C4烷基)、-SO2(NR4R5)或-SO2(C1-C4烷基);
R4和R5独立地为氢、C1-C4烷基、苯基、苄基,或与其键合的氮结合形成饱和或不饱和的5或6元环;
AA为氨基酸残基;
m独立地为0、1、2或3;和
n独立地为2、3、4或5。
14、根据权利要求10的方法,其中,蛋白激酶C抑制剂为(S)-3,4-[N,N′-1,1′-((2″-乙氧基)-3(O)-4-(N,N-二甲氨基)-丁烷)-双-(3,3′-吲哚基)]-1(H)-吡咯-2,5-二酮或其酸加成盐。
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US4443197P | 1997-04-30 | 1997-04-30 | |
US60/044,431 | 1997-04-30 |
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CN1259866A true CN1259866A (zh) | 2000-07-12 |
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CN98804676A Pending CN1259866A (zh) | 1997-04-30 | 1998-04-21 | 皮肤病的治疗方法 |
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US (1) | US6093740A (zh) |
EP (1) | EP0903145A3 (zh) |
JP (1) | JP2002501501A (zh) |
KR (1) | KR20010020381A (zh) |
CN (1) | CN1259866A (zh) |
AU (1) | AU7131898A (zh) |
BR (1) | BR9809343A (zh) |
CA (1) | CA2289257A1 (zh) |
EA (1) | EA199900987A1 (zh) |
HU (1) | HUP0002836A2 (zh) |
ID (1) | ID23528A (zh) |
IL (1) | IL132520A0 (zh) |
NO (1) | NO995231L (zh) |
PL (1) | PL336760A1 (zh) |
TR (1) | TR199902682T2 (zh) |
WO (1) | WO1998048795A1 (zh) |
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CN110300584A (zh) * | 2016-12-19 | 2019-10-01 | 克罗马德姆公司 | 治疗色素沉着过度病症的方法 |
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JP4731016B2 (ja) * | 1998-12-22 | 2011-07-20 | ジェネンテック, インコーポレイテッド | 血管内皮細胞増殖因子アンタゴニストとその用途 |
AU781444B2 (en) * | 1999-12-22 | 2005-05-26 | Scripps Research Institute, The | Angiogenesis and vascular permeability modulators and inhibitors |
US8846039B2 (en) * | 2002-04-26 | 2014-09-30 | Asan Laboratories Company (Cayman), Limited | Method for ameliorating pruritus |
US8163764B2 (en) * | 2002-04-26 | 2012-04-24 | Asan Laboratories Company (Cayman) Limited | Skincare methods |
TWI324604B (en) | 2003-06-18 | 2010-05-11 | Novartis Ag | New use of staurosporine derivatives |
US20070032479A1 (en) * | 2003-12-03 | 2007-02-08 | Leventer Steven M | Treatment of inflammatory disorders of the epithelium with low dose 2,3-benzodiazepines |
DE102004019413A1 (de) * | 2004-04-19 | 2005-11-24 | Phenos Gmbh | Hemmung der Proteinkinase C epsilon zur Behandlung von Krankheiten |
ES2396440T3 (es) * | 2006-01-18 | 2013-02-21 | The General Hospital Corporation | Métodos de aumentar la función linfática |
US7455447B2 (en) * | 2006-05-19 | 2008-11-25 | Mediatek Inc. | Method and apparatus for a portable device |
CN101380317B (zh) * | 2007-09-07 | 2010-12-08 | 英属开曼群岛商安盛开发药物股份有限公司 | 减缓搔痒症的药学组合物 |
MX349146B (es) * | 2011-06-13 | 2017-07-14 | Univ Illinois | Composiciones de peptidos y metodos para tratar lesion pulmonar, asma, anafilaxis, angioedema, sindromes de permeabilidad vascular sistemica, y congestion nasal. |
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NZ227850A (en) * | 1988-02-10 | 1991-11-26 | Hoffmann La Roche | Indole substituted pyrrole derivatives; preparatory process and medicaments for use against inflammatory immunological, bronchopulmonary or vascular disorders |
UA44690C2 (uk) * | 1993-12-07 | 2002-03-15 | Елі Ліллі Енд Компані | Макроциклічна сполука іміду біс-індол-малеїнової кислоти, спосіб її одержання та фармацевтична композиція, макроциклічні сполуки іміду біс-індол-малеїнової кислоти та біс-індол-малеїнового ангідриду, спосіб одержання (варіанти) |
IL111851A (en) * | 1993-12-07 | 1998-09-24 | Lilly Co Eli | Improved synthesis of bisindolylsimilides and process for its preparation |
US5624949A (en) * | 1993-12-07 | 1997-04-29 | Eli Lilly And Company | Protein kinase C inhibitors |
US5545636A (en) * | 1993-12-23 | 1996-08-13 | Eli Lilly And Company | Protein kinase C inhibitors |
US5481003A (en) * | 1994-06-22 | 1996-01-02 | Eli Lilly And Company | Protein kinase C inhibitors |
US5491242A (en) * | 1994-06-22 | 1996-02-13 | Eli Lilly And Company | Protein kinase C inhibitors |
BR9611724A (pt) * | 1995-11-20 | 1999-06-01 | Lilly Co Eli | Inibidor de quinase c de proteína |
UA54427C2 (uk) * | 1996-05-01 | 2003-03-17 | Елі Ліллі Енд Компані | Спосіб лікування очних захворювань, які пов'язані з фактором васкулярного ендотеліального росту |
PL329851A1 (en) * | 1996-05-01 | 1999-04-12 | Lilly Co Eli | Treatment of diseases associated with vegf |
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- 1998-04-21 CA CA002289257A patent/CA2289257A1/en not_active Abandoned
- 1998-04-21 AU AU71318/98A patent/AU7131898A/en not_active Abandoned
- 1998-04-21 HU HU0002836A patent/HUP0002836A2/hu unknown
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- 1998-04-21 KR KR1019997010003A patent/KR20010020381A/ko not_active Application Discontinuation
- 1998-04-21 BR BR9809343-6A patent/BR9809343A/pt not_active Application Discontinuation
- 1998-04-21 CN CN98804676A patent/CN1259866A/zh active Pending
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- 1998-04-21 JP JP54706598A patent/JP2002501501A/ja active Pending
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Cited By (1)
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CN110300584A (zh) * | 2016-12-19 | 2019-10-01 | 克罗马德姆公司 | 治疗色素沉着过度病症的方法 |
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BR9809343A (pt) | 2000-07-04 |
EA199900987A1 (ru) | 2000-08-28 |
EP0903145A3 (en) | 2001-02-07 |
JP2002501501A (ja) | 2002-01-15 |
HUP0002836A2 (hu) | 2001-02-28 |
IL132520A0 (en) | 2001-03-19 |
CA2289257A1 (en) | 1998-11-05 |
AU7131898A (en) | 1998-11-24 |
US6093740A (en) | 2000-07-25 |
NO995231L (no) | 1999-12-27 |
ID23528A (id) | 2000-04-27 |
WO1998048795A1 (en) | 1998-11-05 |
PL336760A1 (en) | 2000-07-17 |
TR199902682T2 (xx) | 2000-05-22 |
NO995231D0 (no) | 1999-10-26 |
KR20010020381A (ko) | 2001-03-15 |
EP0903145A2 (en) | 1999-03-24 |
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