CN1233177A - Vegf相关疾病的治疗 - Google Patents
Vegf相关疾病的治疗 Download PDFInfo
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- CN1233177A CN1233177A CN97196010A CN97196010A CN1233177A CN 1233177 A CN1233177 A CN 1233177A CN 97196010 A CN97196010 A CN 97196010A CN 97196010 A CN97196010 A CN 97196010A CN 1233177 A CN1233177 A CN 1233177A
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Abstract
本发明公开了抑制VEGF刺激的内皮细胞生长(如与肿瘤相关者)和毛细血管渗透(如与肺水肿相关者)的方法,特别是使用β同功酶选择性PKC抑制剂(S)-3,4-[N,N’-1,1’-((2”-乙氧基)-3”’(0)-4”’-N,N-二甲氨基)-丁烷)-双-(3,3’-吲哚基)]-1(H)-吡咯-2,5-二酮盐酸盐的抑制方法。
Description
本申请要求1996年5月1日提交的美国临时申请60/016,658的优先权。
发明背景
1.发明领域
总体上讲,本发明涉及使用蛋白激酶C(PKC)β同功酶抑制剂抑制血管内皮生长因子(VEGF)相关的内皮细胞生长和毛细血管渗透(如VEGF诱导的更高细胞生长和渗透)的方法。该VEGF诱导的疾病与哺乳动物肿瘤和包括肺水肿在内的其它疾病密切相关。
具体而言,本发明涉及使用蛋白激酶C(PKC)β同功酶抑制剂治疗肿瘤以及本文所述的一些其它VEGF相关疾病,所述肿瘤包括毛细血管成血管细胞瘤,乳房癌,Kaposi氏肉瘤,成蚀质细胞瘤,血管瘤,结肠癌,成神经管细胞瘤,胃癌,消化道腺瘤,恶性黑素瘤,卵巢癌,非小细胞性肺癌,前列腺癌,恶性渗漏,肿瘤周边水肿,如与脑肿瘤相关的大脑内水肿和囊肿,膀胱癌,von Hippel Lindau综合征,肾细胞瘤,皮肤癌,甲状腺癌,宫颈癌,肝细胞瘤,横纹肌肉瘤和平滑肌肉瘤。
2.相关技术
VPF/VEGF为具有多种功能的糖基化细胞因子。VPF/VEGF的过量表达与肿瘤和一些其它疾病相关。
VPF/VEGF通过激活囊泡细胞器介导的运输,迁移和伴随形状改变和皱缩的肌动蛋白重排引起内皮细胞增殖,过度渗透。它改变内皮细胞的基因表达,引起组织因子和一些蛋白酶的产生增加,所述蛋白酶包括间质胶原酶以及尿激酶样和组织纤维蛋白溶酶原激活物。这些相同基因的大多数由佛波醇肉豆蔻酸·乙酸酯刺激PKC激活诱导。
大多数已检查过的人和动物肿瘤大量表达和分泌VPF/VEGF。VPF/VEGF可以直接影响肿瘤细胞,如成蚀质母细胞瘤的瘤细胞,并在肿瘤血管生成的诱发中起重要作用(Claffey等,Cancer Research 56,172-181(1996)及其中所引文献)。
VEGF的血管生成潜能由细胞破裂或死亡释放的成纤维细胞生长因子的协同活性增强。(Pepper等,Biochem Biophys Res.Commun.,189:824-831(1992);Muthukrishnan等,J.Cell Physiol.,148:1-16(1991))。
肿瘤生长和迁移与VEGF的表达增加密切相关。来自肿瘤细胞的化学信号可以使静止内皮细胞转变为快速生长。在12种已知的血管生成蛋白中,肿瘤细胞中最常见的似乎是碱性成纤维细胞生长因子(bFGF)和血管内皮生长因子(VEGF),后者也被称为血管通透因子(VPF)(Folkman,J.New England J.Of Medicine.,Vol 999(26):1757-1763(1995)及其中引用的文献)。
认识到肿瘤生长需要新血管和鉴定到介导新血管形成或血管生成的化学因子拓宽了对病理过程的理解,开辟了治疗此类疾病的新途径。9种不同的血管生成抑制物正在进行1期或2期临床试验,用于治疗多种实体性肿瘤,包括乳房癌,结肠癌,肺癌和前列腺癌以及Kaposi氏肉瘤。(Folkman,J.Tumor angiogenesis In Mendelsohn J.Howley PM,IsraelMA.Liotta LA编,癌症的分子基础,Philadelphia:W.B.Saunders.1995:206-232)。这些药物中的一种,TNP-170,是烟曲霉素的合成类似物(Denekamp J.Br J Radiol 66:181-196,1993),它已被FDA批准用于许多实体性肿瘤病人的1期临床试验。现在正在晚期癌症病人中进行临床试验的其它血管生成抑制剂包括血小板因子4,羧基氨基三唑,BB-94和BB-2516,金属蛋白酶抑制剂,硫酸化多糖tecogalan(DS-152);酞胺哌啶酮,白介素-12和linomide。(Flier等,The New England Journalof Medicine,vol333 pp 1757-1763,1995及其中所引的参考文献)。
PKC抑制剂也被用于治疗癌症,见US 5,552,396。但是,PKCβ同功酶抑制剂对特定肿瘤的效果尚不清楚。如果VEGF在某些肿瘤和其它疾病中起作用,则有必要鉴定特异针对VEGF功能的其它药物。
发明概述
本发明的目的之一是提供治疗肿瘤的方法。
本发明的另一个目的是提供治疗类风湿性关节炎的方法。
本发明的又一个目的是提供治疗瘢痕瘤的方法
本发明的再一个目的是提供治疗肺水肿相关疾病如成人呼吸窘迫综合征(ARDS)的方法。
本发明的再一个目的是提供治疗腕管综合征的方法。
这些和本发明的其它目的通过以下所述一个或多个实施方案提供。
在本发明的一个实施方案中,提供了一种治疗肿瘤的方法,包括向该哺乳动物给予治疗有效量的蛋白激酶Cβ同功酶抑制剂。
在本发明的另一个实施方案中,提供了治疗瘢痕瘤的方法,包括向该哺乳动物给予治疗有效量的蛋白激酶Cβ同功酶抑制剂。
在本发明的另一个实施方案中,提供了治疗肺水肿的方法,包括向该哺乳动物给予治疗有效量的蛋白激酶Cβ同功酶抑制剂。
本发明提供了鉴定治疗和预防肿瘤及其它血管内皮生长因子(VEGF)相关疾病有效的化合物的方法。
附图简述
图1显示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-2,5-二酮对重组人VEGF刺激的内皮细胞生长的抑制作用。
图2进一步显示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-2,5-二酮对重组人VEGF刺激的内皮细胞生长的抑制作用。
图3显示PKC抑制剂对缺氧条件下培养的视网膜周皮细胞表达的内源VEGF活性的影响。
图4进一步显示PKC抑制剂对重组人VEGF刺激的内皮细胞生长的抑制作用。
发明详述
本发明发现,特定种类蛋白激酶C抑制剂,即蛋白激酶Cβ同功酶抑制剂,特别是PKCβ同功酶选择性抑制剂的治疗应用抵销了VEGF的作用。具体而言,本发明发现,使用该特定种类的蛋白激酶C抑制剂阻碍内皮细胞生长和毛细血管渗透,特别是由生长因子VEGF刺激的内皮细胞生长和毛细血管渗透。因而,这些化合物可用来治疗VEGF相关疾病,如肿瘤和其它VEGF相关疾病。
本发明的方法优选使用有效抑制β同功酶的蛋白激酶C抑制剂。现有技术中,通常认为双吲哚基马来酰亚胺类或大环双吲哚基马来酰亚胺类是合适的化合物。现有技术中认识较清楚的双吲哚基马来酰亚胺类包括美国专利5621098,5552396,5545636,5481003,5491242和5057614中所述的化合物,所有这些专利在此引作参考。大环双吲哚基马来酰亚胺的典型代表是通式Ⅰ的化合物。这些化合物及其制备方法在美国专利5,552,396中已经公开,该专利在此引作参考。这些化合物以抑制VEGF相关的内皮细胞生长或毛细血管渗透的有效量给予哺乳动物,从而抑制肿瘤和其它疾病如类风湿性关节炎,瘢痕瘤,腕管综合征和肺水肿相关的VEGF作用。这些化合物也可以给予有患上述疾病危险的病人,作预防之用。
用于本发明方法的一类优选化合物具有以下通式或为其可药用的盐,前体药物或酯:(Ⅰ)其中:
W为-O-,-S-,-SO-,-SO2-,CO-,C2-C6亚烷基,取代亚烷基,C2-C6亚链烯基,-芳基-,-芳基(CH2)mO-,-杂环-,-杂环-(CH2)mO-,-稠合双环-,-稠合双环-(CH2)mO-,-NR3-,-NOR3-,-CONH-或-NHCO-;
X和Y独立地是C1-C4亚烷基,取代亚烷基,或X,Y和W共同组成-(CH2)n-AA-;
R1为氢或可达4个任选的取代基,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-C1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独立地是氢,C1-C4烷基,苯基,苄基,或与同其相连的N形成饱和或不饱和的5元或6元环;
AA为氨基酸残基;
m独立地是0,1,2或3;
n独立地是2,3,4或5。
用于本发明的更优选的一类化合物可用式Ⅰ表示,其中-X-W-Y-含4到8个原子,可以是取代或未取代的。最优选-X-W-Y-含6个原子。
用于本发明方法的其它优选化合物为式Ⅰ的化合物,其中R1和R2为氢;W为取代亚烷基,-O-,-S-,-CONH-,-NHCO-或-NR3-。用于本发明的特别优选的化合物为式Ⅰa的化合物或为其可药用的盐,前体药物或酯:(Ⅰa)其中Z为-(CH2)p-或-(CH2)p-O-(CH2)p-;R4为氢,-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独立地是2或3。最优选的式Ⅰa化合物中Z为CH2;R4为-NH2,-NH(CF3)或-N(CH3)2。
用于本发明方法的其它优选化合物为式Ⅰ中W为-O-,Y为取代亚烷基,X为亚烷基的化合物。这些优选化合物由式Ⅰb表示或为其可药用的盐,前体药物或酯:(Ⅰb)其中,Z-(CH2)p-;R4为-NR5R6,-NH(CF3)或-N(CH3)(CF3);R5和R6独立地是氢或C1-C4烷基;p为0,1或2;m独立地是2或3。最优选的式Ⅰb化合物中p为1,R5和R6为甲基。
因为式Ⅰ,Ⅰa和Ⅰb的化合物含有碱性部分,它们也可以可药用的酸加成盐存在。通常用来形成这些盐的酸包括无机酸,如盐酸,氢溴酸,氢碘酸,硫酸和磷酸,以及有机酸如对苯甲磺酸,甲磺酸,草酸,对溴苯磺酸,碳酸,琥珀酸,柠檬酸,苯甲酸,乙酸,和有关的无机酸和有机酸。这些可药用的盐因而包括硫酸盐,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,富马酸盐,马来酸盐,2-丁炔-1,4-二酯,3-丁炔-2,5-二酯,苯甲酸盐,氯苯甲酸盐,羟基苯甲酸盐,甲氧基苯甲酸盐,邻苯二甲酸盐,二甲苯磺酸盐,苯乙酸盐,苯丙酸盐,苯丁酸盐,柠檬酸盐,乳酸盐,马尿酸盐,β-羟基丁酸盐,甘醇酸盐,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。具体使用的为盐酸盐和甲磺酸盐。
除了可药用的盐之外,也可以存在其它盐。它们可以作为化合物纯化,其它盐制备或化合物或中间体鉴定和表征的中间体。
式Ⅰ,Ⅰa和Ⅰb化合物的可药用的盐也可以各种溶剂化物存在,如水,甲醇,乙醇,二甲基甲酰胺,乙酸乙酯的溶剂化物等。也可以制备这些溶剂化物的混合物。这些溶剂化物可以来自结晶溶剂,为制备溶剂或结晶溶剂中固有的,或为溶剂中偶然存在的。
已经认识到,式Ⅰ,Ⅰa和Ⅰb的化合物可以存在各种立体异构体形式,如在取代亚烷基部分,W可以包含手性碳原子。这些化合物通常制备成消旋体,并可以方便地这样使用。或者,如果需要的话,两种对映体可以分离或分别合成。这些消旋体和两种对映体及其混合物形成用于本发明方法的部分化合物。
用于本发明的化合物也包括式Ⅰ,Ⅰa和Ⅰb化合物可药用的前体药物。前体药物是已被化学修饰的药物,在其作用部位可能无生物活性,但其可被一种或多种酶促或其它体内过程降解或修饰成原来的生物活性形式。该前体药物可能具有不同于母化合物的药物动力学,使其较容易穿过粘膜吸收,更容易成盐或更容易溶解,和/或提高系统稳定性(例如,血浆半衰期增加)。一般,这种化学修饰包括:
1)酯或酰胺衍生物,其可被酯酶或脂酶切割;
2)可为特异或非特异蛋白酶识别的肽;或
3)通过前体药物形式或修饰的前体药物形式的膜选择在作用部位聚集的衍生物;或为以上1到3的组合。选择和制备合适的前体药物衍生物的常规方法见,例如,H.Bundgaard,Design of Prodrugs,(1985)。
各种双吲哚基-N-马来酰亚胺的合成见Davis等,美国专利5,057,614,适于在本发明中使用的优选化合物的合成见前述美国专利5,552,396和Faul等,欧洲专利出版物0 657 411 A1,二者均引作参考。
用于本发明方法的一种特别优选的蛋白激酶C抑制剂为上述美国专利5,552,396实施例5g所述的化合物((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)。该化合物为强效蛋白激酶C抑制剂。它选择性作用于蛋白激酶C,对其它激酶影响不明显,并且是高度同功酶选择性的,即它选择性作用于β-1和β-2同功酶。该化合物的其它盐也比较合适,特别是甲磺酸盐。
优选的甲磺酸盐可通过式Ⅱ的化合物:(Ⅱ)与甲磺酸在非反应活性有机溶剂中反应制备,优选溶剂为有机溶剂/水混合物,最优选水-丙酮。其它溶剂如甲醇,丙酮,乙酸乙酯及其混合物也可使用。溶剂与水的比例不严格,通常由反应试剂的溶解性确定。通常优选溶剂与水的比例为二者体积比为0.1∶1到100∶1。优选比例为1∶1到20∶1,最优选5∶1到10∶1。最佳比例取决于选用的溶剂,优选使用丙酮时溶剂与水的比例为9∶1。
反应通常使用大约等摩尔量的两种试剂,但其它比例,特别是甲磺酸过量也可以。加入甲磺酸的速度对反应并不重要,可以快速加入(<5分钟)或在6小时以上缓慢加入。反应可在0℃到回流温度下进行。搅拌反应混合物直至通过X射线粉末衍射测定盐的形成已完成,通常需时5分钟到12小时。
本发明的盐优选以晶体形式制备,这样制备也比较方便。盐的三水合物形式在干燥或20-60%相对湿度下容易转变为一水合物。该盐基本上为表现出确定的熔点,双折射和X射线衍射图案的晶体。通常,晶体含有不到10%的无定形固体,优选不到5%的无定形固体,最优选不到1%的无定形固体。
甲磺酸盐通过过滤或本领域已知的其它分离方法直接从反应混合物中分离,产率为50%到100%。如果需要的话,可以使用重结晶和本领域已知的其它纯化方法进一步纯化该盐。
组织培养中VEGF等生长因子刺激的内皮细胞表现出较基础细胞生长速度更快的生长速度。本发明中的试验证实,蛋白激酶C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-2,5-二酮酸盐,在体外以大约0.1到100nM的浓度使用,显著抑制生长因子(如VEGF)刺激的非基础细胞生长。
重要的是,其它试验已证实该化合物不抑制组织培养中的正常内皮细胞生长,表现为在正常含氧量条件培养基中,该化合物不抑制无VEGF刺激的内皮细胞生长。在缺氧条件培养基中,缺氧细胞产生的内源生长因子VEGF的含量增加,使得细胞生长速度增加。同样,蛋白激酶Cβ同功酶选择性抑制剂(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-2,5-二酮酸盐使得这种缺氧条件引发的细胞生长变得正常。
本发明的试验证实VEGF等生长因子也影响毛细血管渗透。试验证实,在动物模型中,VEGF显著增加毛细血管通透性达3倍。该VEGF依赖的毛细血管通透性增加也是剂量依赖的。根据动物体内试验,在使用VEGF之前,以大约25毫克/千克/日使用蛋白激酶C抑制剂显著抑制了VEGF引发的毛细血管渗透。具体使用浓度为1nM到5mM,优选1nM到500nM。抑制可达80%,通常特异针对生长因子引发的毛细血管渗透。毛细血管渗透可通过荧光素血管造影术测定。
本发明的PKCβ抑制剂可用于治疗与内皮细胞生长和毛细血管渗透相关的疾病,特别是肿瘤和其它VEGF相关疾病。
肺水肿也可以使用本发明的化合物治疗。肺水肿的特征是由于毛细血管通透性增加,肺间质液体含量增加。肺水肿与包括成人呼吸窘迫综合征(ARDS)的几种疾病有关。它可能主要与肺泡毛细血管膜破裂引起缺氧和VEGF含量增加有关。这种破裂也可以激活PKCβ。因而,本发明鉴定的化合物可以干扰生长因子对毛细血管渗透的刺激和/或PKCβ,缓解导致肺水肿的疾病。
本发明的PKC抑制剂也可以用来治疗哺乳动物的肿瘤和其它VEGF相关疾病。VEGF的信号传导途径对肿瘤细胞具有直接的作用,并介导多种肿瘤和非肿瘤疾病的血管生成活性。已在多种人类肿瘤中证实了VEGF的表达,所述肿瘤包括毛细血管成血管细胞瘤,乳房癌,Kaposi氏肉瘤,成蚀质细胞瘤,血管瘤,结肠癌,成神经管细胞瘤,胃癌,消化道腺瘤,恶性黑素瘤,卵巢癌,非小细胞性肺癌,前列腺癌,膀胱癌,von HippelLindau综合征,肾细胞瘤,皮肤癌,甲状腺癌,宫颈癌,肝细胞瘤,横纹肌肉瘤和平滑肌肉瘤。
肿瘤预后不良经常与同VEGF表达相偶联的肿瘤血管供应程度有关。若无血管供应,则肿瘤生长受到限制。因而,使用抗血管生成药剂或抗VEGF药剂可能通过限制血管供应,阻止肿瘤进一步生长,引发肿瘤消退。抗VEGF药剂可能也直接影响肿瘤细胞,如VEGF直接影响恶性黑素瘤细胞。
VEGF的表达由多种机制控制。VEGF的产生可由缺氧、一些癌基因和包括转化生长因子β、血小板衍生生长因子在内的几种细胞因子正调节。
在一些实施方案中,PKCβ抑制剂可用于抗VEGF治疗,用来治疗肿瘤病人。本发明的PKCβ抑制剂可影响所有表达VEGF的肿瘤如以上所列肿瘤的生长。特别优选抗VEGF治疗用来治疗患以下肿瘤的病人:不可切除的原发性肿瘤,手术或放射治疗方法未完全消除的原发性肿瘤,已经适当治疗但很有可能转移的肿瘤,以及已经发生转移的病人。预后极差具有高度血管供应的肿瘤,如乳房癌,膀胱癌,结肠癌,恶性黑素瘤,非小细胞性肺癌和头/颈癌,是本发明抗VEGF治疗或PKCβ抑制剂治疗的极好对象。
婴儿血管瘤在白种婴儿中发病率为10-12%。通常,它不是致命的疾病,但在某些情况下,由于大小或解剖位置,可能引发较高的发病率和死亡率。VEGF与这些肿瘤的生长有关。目前,干扰素α-2a用来引发这种肿瘤的消退。考虑到这种肿瘤的血管生成特性,使用PKCβ抑制剂的抗VEGF治疗应该象干扰素α-2a一样有效,或在干扰素α-2a治疗失败的情况下,作为补救治疗。
PKCβ抑制剂或抗VEGF治疗可用来治疗肿瘤引发的腹水,恶性胸膜渗漏和肿瘤周边水肿。由于患有排卵诱发的卵巢激素过多综合征的女性acitic液中VEGF增加,PKCβ抑制剂可用于这种疾病。VEGF是强效的血管通透因子,例如其效力较组胺强50,000倍。由因恶性肿瘤而引起胸膜和腹膜渗漏的病人身上取得的样液中,VEGF浓度升高。向裸鼠腹膜内注入肿瘤细胞引起腹水积聚,这与分泌到腹膜内的VEGF增加在时间上相对应。中枢神经系统肿瘤如成蚀质细胞瘤的肿瘤周边水肿与高水平VEGF相关。抗VEGF治疗会减轻恶性肿瘤相关的腹水和胸膜渗漏以及卵巢激素过多综合征。这种治疗可以减少重复穿刺/胸腔穿刺的需求,降低这些方法的并发症如感染、蛋白质减少、肺萎缩的发病率。这种治疗特别优选用于抑制封闭的解剖部位如中枢神经系统中发生的肿瘤周边水肿。
用于本发明的PKCβ抑制剂可用于抗VEGF治疗,用来治疗与VEGF表达相关的其它疾病。
类风湿性关节炎的特征在于具有高度血管供应的高可塑性滑膜关节翳,它侵入并破坏了正常的关节结构。此外,滑液的渗出特性表明了高度的毛细血管通透性。VEGF可以刺激胶原酶表达,进一步恶化破坏过程。与骨关节炎病人相比,类风湿性关节炎病人的滑液中,VEGF水平明显升高。VEGF的产生已被定位于浸润性巨噬细胞。因而,类风湿性关节炎可以通过抗VEGF治疗给予PKCβ抑制剂治疗。
瘢痕瘤的特征在于伤口愈合过程中形成高度增生的肉芽组织,从而导致过度生长的疤痕。这种疾病一般见于黑种人,并易于复发。向过度生长的肉芽组织局部给予PKC抑制剂可以减少血管生成,减轻随后的疤痕形成。
腕管综合征也称截流性神经病,其特征在于神经压迫,从而导致感觉异常、肌肉衰弱和肌肉萎缩。它是由于正中神经通过腕骨和横向腕部韧带形成的空间时,受到压迫所致。腕管综合征为糖尿病相关综合征,或发生于非糖尿病人群中。
腕管综合征中神经水合作用增强可由VEGF水平升高所致。神经周围组织VEGF水平升高通过引起血管渗透和液体流入神经周边组织,可导致神经截流。在腕管综合征中,胶原合成的改变和/或降解可由高水平TGFβ引起。TGFβ表达增加能促进细胞外蛋白包括胶原合成,并降低其降解,这导致神经周围组织中细胞外基质沉积增加。已证实PKC激活通过刺激活化蛋白1活性,引发TGFβ的转录。因而,在腕管综合征中,本发明的PKCβ抑制剂可用来抵销VEGF和/或TGFβ活性。
本领域的技术人员应理解,根据本发明使用的蛋白激酶Cβ抑制剂的治疗有效量为足以通过抑制VEGF而抑制内皮细胞生长或毛细血管渗透形成的剂量,该剂量可以变化,特别取决于受影响的组织大小、治疗用制剂中化合物的浓度和病人体重。通常,用作治疗上述肿瘤和其它VEGF相关疾病的治疗药剂的蛋白激酶C抑制剂的量由主治医师根据病情决定。原则是,确定合适剂量时,应考虑新血管形成的程度、病人体重和年龄。
通常,合适的剂量是在治疗部位蛋白激酶C抑制剂的浓度为0.5到200μM,更一般的情况是0.5到200nM。预计血浆浓度为0.5到100nM在大多数情况下应该足够。
优选式Ⅰ的化合物和式Ⅰa和式Ⅰb的优选化合物在使用之前制成制剂。合适的药用制剂使用众所周知、易于获得的成分通过已知方法制备。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,或封装于胶囊、小药囊、纸或其它容器形式的载体中。当载体作为稀释剂时,它可以是固体、半固体或液体材料,作为活性成分的载剂、赋形剂或介质。因而,组合物可以是片剂、丸剂、粉末、锭剂、粉剂、扁囊剂、酏剂、悬液、乳剂、溶液、糖浆、气溶胶(作为固体或在液体介质中)、软和硬明胶胶囊、栓剂、无菌注射液和用于口服或局部用药的无菌包装粉末。
合适的载体、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、阿拉伯树胶、磷酸钙、藻蛋白酸盐、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盐、滑石、硬脂酸镁和矿物油。制剂中还可包括润滑剂、湿润剂、乳化剂和悬浮剂、防腐剂、甜味剂或风味剂。本发明的组合物可以配制成适当的形式,使其向病人给药后,提供活性成分的快速、持续或延迟释放。该组合物优选配制成单位剂量形式,每剂含活性成分大约0.05mg到3g,更一般的情况是大约750mg。但是,应理解,使用的治疗剂量要由医师根据相关情况决定,包括待治疗疾病的严重性、选用的化合物和给药途径。因此,上述剂量范围决不意味着限制本发明的范围。“单位剂量形式”指用于人类和其它哺乳动物的单一剂量的物理上分离的单位,它与可药用载体组合,每一单位含预定量的活性成分,根据计算它能产生所需的治疗作用。
上述制剂中,多数是口服,除此之外,用于本发明方法的化合物也可以局部用药。局部制剂包括软膏、乳膏和凝胶。
软膏通常通过以下方法制备:(1)使用油质基底,即由固体油或烃如白凡士林或矿物油组成的基底,或(2)使用吸收基底,即由无水物质或吸水物质如无水羊毛脂组成的基底。通常,在油质或吸收基底形成后,加入活性成分(化合物),直至达到所需浓度。
乳膏为油/水乳剂。它们由油相(内部相)和水相(连续相)组成,油相一般包括固体油、烃等,如蜡、凡士林、矿物油等,水相包括水相和任何水溶性物质,如加入的盐。两相通过使用乳化剂来稳定,乳化剂如十二烷基硫酸钠等表面活性剂;阿拉伯胶状粘土、veegum等亲水胶等等。形成乳剂之后,通常加入活性成分(化合物),直至达到所需浓度。
凝胶包括选自油质基底、水或乳化-悬浮基底的基底。向基底加入胶凝剂,它在基底上形成基质,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,活性成分(化合物)在加入胶凝剂之前加入制剂中,至所需浓度。
局部制剂中化合物的量不严格;其浓度应允许制剂在所需部位直接使用,在此释放所需量的化合物。
用于感染组织的局部制剂的常用量取决于感染组织大小和制剂中化合物的浓度。通常,该制剂在感染组织的用量应向每平方厘米该组织提供大约1到500μg化合物。优选化合物的用量为大约30到300μg/cm2,更优选化合物的用量为大约50到200μg/cm2,最优选化合物的用量为大约60到100μg/cm2。
以下制剂实施例仅用来说明,决不意味着限制本发明的范围。
制剂1
硬明胶胶囊使用下列成分制备:
用量(毫克/胶囊)
活性成分 250毫克
干淀粉 200毫克
硬脂酸镁 10毫克
总计 460毫克
上述成分混合并460毫克的量装入硬明胶胶囊。
制剂2
片剂使用下列成分制备:
用量(毫克/胶囊)
活性成分 250毫克
微晶纤维素 400毫克
雾化二氧化硅 10毫克
硬脂酸 5毫克
总计 665毫克
上述成分混和并压成片剂,每片重665毫克。
制剂3
每片含活性成分60毫克的片剂按如下制备:
用量(毫克/胶囊
活性成分 60毫克
淀粉 45毫克
微晶纤维素 35毫克
聚乙烯吡咯烷酮(10%水溶液) 4毫克
羧甲基淀粉钠 4.5毫克
硬脂酸镁 0.5毫克
滑石 1毫克
总计 150毫克
活性成分、淀粉和纤维素通过美国标准45号筛,充分混合。聚乙烯吡咯烷酮溶液与所得粉末混合,然后通过美国标准14号筛。产生的颗粒在50℃干燥,通过美国标准18号筛。羧甲基淀粉钠、硬脂酸镁和滑石预先通过美国标准60号筛,然后加入至颗粒中,混合后,在压片机上压片,得到每个重150毫克的片剂。
实施例
以下实施例证实使用(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-2,5-二酮盐酸盐抑制VEGF刺激的体外内皮细胞生长和体内毛细血管通透性增加。
实施例1
该实施例使用重组人VEGF测定了上述化合物对VEGF刺激的内皮细胞生长的抑制作用。
牛视网膜内皮细胞通过匀浆和一系列过滤步骤分离自新鲜小牛眼。原代内皮细胞培养物培养在纤连蛋白(NYBen Reagents,New York BloodCenter)包被的培养皿(Costar)中,培养基为Dulbecco改良Eagle’s培养基(DMEM),其中含5.5mM葡萄糖,10%血浆衍生马血清(Wheaton,Scientific),肝素50mg/L,内皮细胞生长因子50U/L(BoehringerMannheim)。细胞生长至汇合后,将培养基换成含5%胎牛血清(HyClonc)的培养基。每三天更换培养基。内皮细胞的均一性使用抗因子Ⅷ的抗体证实。
上述PKC抑制剂在体外对VEGF作用的抑制作用通过使用牛视网膜微血管内皮细胞的稀疏平板培养物评价,所述培养物已加入VEGF刺激其生长。牛视网膜内皮细胞稀疏涂布(每孔约2500细胞)于24孔培养皿上(Costar),在含10%胎牛血清的DMEM(GIBCO)中温育过夜。第二天更换培养基。
为测定上述PKC抑制剂对内皮细胞生长的抑制,进行了一组试验,其中未给予任何活性药物的细胞生长作为对照,然后在VEGF存在(25ng/ml;Genentech)和不存在时,测定加入上述PKC抑制剂的影响。37℃温育4天,然后细胞在0.1%十二烷基硫酸钠(SDS)中裂解,使用Hoechst33258染料和荧光计(TKO-100;Hoefer)测定DNA含量。
所有测定至少做三个重复,试验至少重复三次。所有试验结果表示为平均值±SD。体外试验结果通过非配对Student t测验分析。P值小于0.050被认为有统计学意义。
图1示出使用重组VEGF所得的结果。如图中最左边3栏的数字所示,加入上述PKC抑制剂至内皮细胞培养物中基本上对基础细胞生长速度无影响(第1栏)。加入VEGF明显增加生长速度(第4栏)。加入大于0.5nM的上述PKC抑制剂显著降低生长速度(最右边4栏)。
实施例2
该实施例类似于图1报导的试验,使用重组人VEGF进一步说明上述PKC抑制剂对VEGF刺激的内皮细胞生长的抑制作用。
按实施例1的方法,分离和培养牛视网膜内皮细胞;然后制备稀疏涂布的培养物。再按照实施例1的方法进行上述试验,测定存在(25ng/ml;Genetech)和不存在VEGF时上述PKC抑制剂对内皮细胞生长的影响。37℃温育4天后,细胞在0.1%十二烷基硫酸钠(SDS)中裂解,使用Hoechst 33258染料和荧光计(TKO-100;Hoefer)测定DNA含量。
图2示出该试验的结果。如图注VEGF上方各栏所示,向内皮细胞培养物加入上述PKC抑制剂0.1nM到100nM对细胞的基础生长速度基本上无影响。用重组人VEGF(25ng/ml)刺激内皮细胞4天后,与未刺激细胞相比,细胞DNA含量显著增加,表明生长速度增加(-VEGF0与+VEGF0比较)。加入上述PKC抑制剂该生长速度明显降低(图注+VEGF上方最右边4栏)。具体而言,加入PKC抑制剂0.1nM略微降低VEGF的刺激能力,加入1nM及更多的PKC抑制剂,则基本上消除了VEGF刺激能力。
实施例3
该实施例测定上述PKC抑制剂对缺氧条件下培养的视网膜周皮细胞表达内源VEGF活性的影响。
牛视网膜内皮细胞和视网膜周皮细胞通过匀浆和一系列过滤步骤分离自新鲜小牛眼。按实施例1的方法培养内皮细胞并稀疏涂布平板。使用类似的方法,将牛视网膜周皮细胞培养在含20%胎牛血清的DMEM/5.5mM葡萄糖中。
按照下述方法分别制备用于内源VEGF表达的缺氧条件培养基和正常含氧量对照培养基。使用Lab-Line Instruments计算机控制、带有减氧控制的远红外水夹套CO2培养箱(480型),将汇合的视网膜周皮细胞单层培养物置于2%O2/5%CO2/93%N2下24小时。所有细胞在37℃下培养,光镜下未见形态变化,除去台盼蓝染料(>98%),然后可以正常传代。在正常含氧量条件(95%空气/5%CO3)下培养的同一批细胞和其传代物作为对照。随后收集培养基并在使用前过滤(Nalgene;0.22μm)。
在该实施例的试验中,测定在正常含氧量条件培养基或缺氧条件培养基中上述PKC抑制剂对内皮细胞生长的影响。如以上实施例,在37℃下培养4天后,细胞在0.1%十二烷基硫酸钠(SDS)中裂解,使用Hoechst33258染料和荧光计(TKO-100;Hoefer)测定DNA含量。
图3所示的试验中,上述PKC抑制剂的使用浓度为10nM。如图3所示,来自缺氧条件下培养的视网膜周皮细胞的条件培养基刺激视网膜内皮细胞生长,已知缺氧条件诱导VEGF表达(图3中第1栏与第3栏比较)。该生长刺激作用在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-2,5-二酮盐酸盐存在时被抑制(成为正常)。
实施例4
该实施例类似于图1和图2报导的试验,使用重组人VEGF进一步说明上述PKC抑制剂对VEGF刺激的内皮细胞生长的抑制作用。
按实施例1的方法,分离和培养牛视网膜内皮细胞;然后制备稀疏涂布的培养物。再按照实施例1的方法进行上述试验,测定存在(25ng/ml;Genetech)和不存在VEGF(-VEGF)时上述PKC抑制剂对内皮细胞生长的影响。同上述,37℃温育4天后,细胞在0.1%十二烷基硫酸钠(SDS)中裂解,使用Hoechst 33258染料和荧光计(TKO-100;Hoefer)测定DNA含量。
图4示出该试验的结果。如图注VEGF上方各栏所示,向内皮细胞培养物加入上述PKC抑制剂10nM对细胞的基础生长速度基本上无影响。用重组人VEGF(25ng/ml)刺激内皮细胞后,与未刺激细胞相比,细胞DNA含量显著增加,表明生长速度增加(-VEGF对照与+VEGF对照比较)。加入上述PKC抑制剂10nM该生长速度明显降低。
上述结果证实,本发明公开的PKC抑制剂,特别是(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,在体外阻止外源和缺氧诱导的VEGF对视网膜内皮细胞生长的刺激作用。由于VEGF表达与黄斑变性有关的新血管形成密切相关,这些结果支持使用PKC抑制剂治疗黄斑变性。
本发明的原则、优选实施方案和操作方式已在上面说明书中叙述。但是,本发明的保护范围并不限于此处公开的具体细节,因为这些细节是用来说明,而非限制本发明。在不偏离本发明精神的情况下,本领域技术人员可以对本发明进行改变和变换。
Claims (14)
1.治疗肿瘤的方法,包括向需要该治疗的哺乳动物给予治疗有效量的蛋白激酶Cβ同功酶抑制剂。
2.权利要求1的方法,其中蛋白激酶Cβ同功酶抑制剂为双吲哚基马来酰亚胺或大环双吲哚基马来酰亚胺。
3.权利要求1的方法,其中抑制剂为同功酶选择性,选择性同功酶选自β-1和β-2同功酶。
W为-O-,-S-,-SO-,-SO2-,CO-,C2-C6亚烷基,取代亚烷基,C2-C6亚链烯基,-芳基-,-芳基(CH2)mO-,-杂环-,-杂环-(CH2)mO-,-稠合双环-,-稠合双环-(CH2)mO-,-NR3-,-NOR3,-CONH-或-NHCO-;
X和Y独立地是C1-C4亚烷基,取代亚烷基,或X,Y和W共同组成-(CH2)n-AA-;
R1为氢或可达4个任选的取代基,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独立地是氢,C1-C4烷基,苯基,苄基,或与同其相连的N形成饱和或不饱和的5元或6元环;
AA为氨基酸残基;
m独立地是0,1,2或3;
n独立地是2,3,4或5。
5.权利要求4的方法,其中蛋白激酶C抑制剂具有下列通式或为其其中Z为-(CH2)p-或-(CH2)p-O-(CH2)p-;R4为氢,-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。
6.权利要求4的方法,其中蛋白激酶C抑制剂具有下列通式或为其可药用的盐,前体药物或酯:(Ⅰb)其中,Z-(CH2)p-;R4为-NR5R6,-NH(CF3)或-N(CH3)(CF3);R5和R6独立地是氢或C1-C4烷基;p为0,1或2;m独立地是2或3。
7.权利要求5的方法,其中蛋白激酶C抑制剂包括(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-2,5-二酮或其可药用的酸盐。
8.权利要求1的方法,其中肿瘤选自毛细血管成血管细胞瘤,乳房癌,Kaposi氏肉瘤,成蚀质细胞瘤,血管瘤,婴儿血管瘤,结肠癌,成神经管细胞瘤,胃癌,消化道腺瘤,恶性黑素瘤,卵巢癌,非小细胞性肺癌,前列腺癌,恶性渗漏,肿瘤周边水肿,膀胱癌,von Hippel Lindau综合征,肾细胞瘤,皮肤癌,甲状腺癌,宫颈癌,肝细胞瘤,横纹肌肉瘤和平滑肌肉瘤。
9.权利要求10的方法,其中肿瘤选自毛细血管成血管细胞瘤,乳房癌,Kaposi氏肉瘤,成蚀质细胞瘤,血管瘤,婴儿血管瘤,结肠癌,恶性黑素瘤,卵巢癌,非小细胞性肺癌,前列腺癌,恶性渗漏,肿瘤周边水肿,膀胱癌。
10.治疗类风湿性关节炎的方法,包括向需要该治疗的哺乳动物给予治疗有效量的蛋白激酶Cβ同功酶抑制剂。
11.治疗肺水肿的方法,包括向需要该治疗的哺乳动物给予治疗有效量的蛋白激酶Cβ同功酶抑制剂。
12.治疗与肺水肿相关的VEGF刺激的毛细血管渗透的方法,包括向需要该治疗的哺乳动物给予治疗有效量的蛋白激酶Cβ同功酶抑制剂。
13.治疗瘢痕瘤的方法,包括向需要该治疗的哺乳动物给予治疗有效量的蛋白激酶Cβ同功酶抑制剂。
14.治疗腕管综合征的方法,包括向需要该治疗的哺乳动物给予治疗有效量的蛋白激酶Cβ同功酶抑制剂。
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SK75289A3 (en) | 1988-02-10 | 1998-05-06 | Hoffmann La Roche | Substituted pyrroles, their use for producing a drug, and the drug on their base |
EP0699204B1 (en) * | 1993-05-28 | 1998-04-15 | Cephalon, Inc. | Use of indolocarbazole derivatives to treat a pathological condition of the prostate |
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KR100340159B1 (ko) * | 1993-12-07 | 2002-11-23 | 일라이 릴리 앤드 캄파니 | 단백질키나제c억제제 |
DE69418978T2 (de) | 1993-12-07 | 1999-10-28 | Lilly Co Eli | Synthese von Bisindolylmaleimiden |
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 |
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1997
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- 1997-05-01 IL IL12683797A patent/IL126837A0/xx not_active IP Right Cessation
- 1997-05-01 NZ NZ332645A patent/NZ332645A/xx unknown
- 1997-05-01 KR KR1019980708798A patent/KR20000065171A/ko not_active Application Discontinuation
- 1997-05-01 CA CA002253608A patent/CA2253608A1/en not_active Abandoned
- 1997-05-01 JP JP53929397A patent/JP2002504086A/ja active Pending
- 1997-05-01 PL PL97329851A patent/PL329851A1/xx unknown
- 1997-05-01 AU AU29355/97A patent/AU736333B2/en not_active Ceased
- 1997-05-01 WO PCT/US1997/007752 patent/WO1997040830A1/en not_active Application Discontinuation
- 1997-05-01 CN CN97196010A patent/CN1233177A/zh active Pending
- 1997-05-01 EA EA199800969A patent/EA001779B1/ru not_active IP Right Cessation
- 1997-05-01 CZ CZ983500A patent/CZ350098A3/cs unknown
- 1997-05-01 BR BR9710706A patent/BR9710706A/pt not_active IP Right Cessation
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1998
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1999
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NO985066D0 (no) | 1998-10-30 |
KR20000065171A (ko) | 2000-11-06 |
BR9710706A (pt) | 1999-08-17 |
CZ350098A3 (cs) | 1999-11-17 |
EA199800969A1 (ru) | 1999-06-24 |
JP2002504086A (ja) | 2002-02-05 |
WO1997040830A1 (en) | 1997-11-06 |
EP0915698A4 (en) | 1999-08-11 |
PL329851A1 (en) | 1999-04-12 |
NO985066L (no) | 1998-12-21 |
NZ332645A (en) | 2000-07-28 |
IL126837A0 (en) | 1999-09-22 |
EP0915698A1 (en) | 1999-05-19 |
AU2935597A (en) | 1997-11-19 |
CA2253608A1 (en) | 1997-11-06 |
US6284751B1 (en) | 2001-09-04 |
EA001779B1 (ru) | 2001-08-27 |
AU736333B2 (en) | 2001-07-26 |
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