CN1245967C - 化合物的制药用途 - Google Patents
化合物的制药用途 Download PDFInfo
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- CN1245967C CN1245967C CNB01809743XA CN01809743A CN1245967C CN 1245967 C CN1245967 C CN 1245967C CN B01809743X A CNB01809743X A CN B01809743XA CN 01809743 A CN01809743 A CN 01809743A CN 1245967 C CN1245967 C CN 1245967C
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- cyclohexyl
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Abstract
血管生成、肿瘤生长和金属蛋白酶2(MMP2)与整联蛋白-αvβ3相互作用被一种抑制剂-式(I)化合物抑制:其中G1和G2各自独立地为-NH-C(O)-O-R1、-NH-C(O)-O-(CH2)v-(C6H4)-X3、-NH-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-O-(CH2)v-(C6H4)-X3或-NH-C(O)-CH2-(C6H4)-X3;Y1和Y2各自独立地为-OH、C1-C4烷基、C1-C4羟烷基、C1-C4烷氧基、苯基、苄基或-NH2;R1为C1-C4烷基;X1和X2各自独立地为卤基或C1-C4烷氧基;X3为卤基、硝基、C1-C4烷基、C1-C4烷氧基或C1-C4全氟烷基;Z为-C≡C-、-C6H4-、顺式-CH=CH-、反式-CH=CH-、顺式-CH2-CH=CH-CH2-、反式-CH2-CH=CH-CH2-、1,4-萘基、顺式-1,3-环己基、反式-1,3-环己基、顺式-1,4-环己基或反式-1,4-环己基;A为H或共价键;m和n各自独立地为0或1数值的整数;t为0或1数值的整数;而p、r和v各自独立地为1或2数值的整数;条件是当A为H时,t为0;当A为共价键时,t为1;当m为0时,Y1为C1-C4羟烷基;当n为0时,Y2为C1-C4羟烷基。
Description
发明领域
本发明涉及抑制血管生成和肿瘤生长的方法。更准确地说,本发明涉及应用选择性地结合整联蛋白αvβ3并且阻断整联蛋白αvβ3与基质金属蛋白酶2(MMP2)的相互作用的化合物抑制血管生成和肿瘤生长的方法。
发明背景
血管细胞侵入组织需要包括对胞外基质结构重建的蛋白酶以及识别该临时基质的细胞粘附分子在内的众多因子的协同相互作用。最近的报道指出,72kDa基质金属蛋白酶2(MMP2)是一种在血管发生和血管生成中的关健参与者。例如,Kitoh等(J.Cell Sci.,109,953-8(1996))报道,MMP2及其激活蛋白I型膜-基质金属蛋白酶(MT1-MMP)几乎只在胚胎发育期间由间充质细胞同步表达,表明特定基质重建仅限于这些组织。另外,血管生成和相应的肿瘤生长在MMP2敲除小鼠中减少(参见Itoh等,Cancer Res.,581048-51(1998))。有趣的是,Saftor等(Proc.Natl.Acad.Sci.U.S.A.,89,1557-61(1992))说明结合整联蛋白αvβ3(它本身是已知的血管生成介质)诱导MMP2的产生,表明这两种分子在与血管生成相关的血管重建过程中协同相互作用(另见Bafetti等,J.Biol.Chem.,273,143-9(1998))。事实上,Brooks等证明了MMP2和整联蛋白αvβ3之间的直接相互作用(Cell,85,683-93(1996))。Brooks等后来又证明了在血管侵袭和成熟过程中MMLP2的负调节依赖于αvβ3的表达(Cell,92,391-400(1998))。
虽然已记载了MMP(包括MMP2)的天然抑制剂以及合成抑制剂可抑制血管生成并且伴随性抑制肿瘤生长,但是这些策略在临床上的应用具有有限成功,主要是由于这类广谱抑制剂的毒副作用所致。一般而言,在成年生物中,由于在许多过程中可能需要MMP功能,因此酶功能活性部位的抑制可能对参与组织重建的各种生物过程(例如伤口愈合)有深远的影响。事实上,已记载了在临床研究中用广谱MMP抑制剂治疗各种癌症类型引起严重的副作用,包括炎症性腱炎、多关节炎和肌肉骨骼疼痛综合征,这些疾病是剂量限制性的并且在中断治疗后通常仍持续。已知整联蛋白αvβ3在成年生物中有限分布,然而,人们预测MMP2和αvβ3之间的相互作用限定在新血管形成或细胞侵袭部位应该相应地限制这类治疗相关毒性效应。事实上,MMP2的重组非催化性羧基端血红素结合蛋白结构域(PEX),它介导MMP2与整联蛋白αvβ3的结合,显示在体内有抗血管生成和抗肿瘤活性。这种蛋白大片段的潜在效用、但伴有多个缺点(例如大规模生产问题、FDA质量和安全控制问题和抗原性)提示需要这一问题更实际的解决方法。
因此,需要应用选择性地抑制肿瘤生长部位的MMP活性以及最小程度抑制机体其它部位的MMP的化合物抑制血管生成和肿瘤生长的方法。也需要与整联蛋白αvβ3的MMP2结合部位特异性地结合的方法。
发明概述
本发明提供抑制MMP2与整联蛋白αvβ3相互作用的方法以及抑制含有整联蛋白αvβ3的细胞血管生成的方法。此外,本发明提供通过给予MMP2-αvβ3互作抑制剂抑制肿瘤生长的方法。将下式(I)表示的活性抑制剂化合物与细胞上的整联蛋白αvβ3接触,进而抑制MMP2与所述αvβ3的结合。通过本发明方法抑制MMP2与αvβ3的结合导致抑制血管生成,从而抑制肿瘤生长。另外,由于αvβ3和炎症有关,因此按照本发明方法使用式(I)化合物也可以抑制炎症过程。
式(I)
其中G1和G2各自独立地为-NH-C(O)-O-R1、-NH-C(O)-O-(CH2)v-(C6H4)-X3、-NH-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-O-(CH2)v-(C6H4)-X3或-NH-C(O)-CH2-(C6H4)-X3;Y1和Y2各自独立地为-OH、C1-C4烷基、C1-C4羟烷基、C1-C4烷氧基、苯基、苄基或-NH2;R1为C1-C4烷基;X1和X2各自独立地为卤基或C1-C4烷氧基;X3为卤基、硝基、C1-C4烷基、C1-C4烷氧基或C1-C4全氟烷基;Z为-C≡C-、-C6H4-、顺式-CH=CH-、反式-CH=CH-、顺式-CH2-CH=CH-CH2-、反式-CH2-CH=CH-CH2-、1,4-萘基、顺式-1,3-环己基、反式-1,3-环己基、顺式-1,4-环己基或反式-1,4-环己基;A为H或共价键;m和n各自独立地为0或1数值的整数;t为0或1数值的整数;而p、r和v各自独立地为1或2数值的整数;条件是当A为H时,t为0;当A为共价键时,t为1;当m为0时,Y1为C1-C4羟烷基;当n为0时,Y2为C1-C4羟烷基。
在结构式(I)的范围内优选的化合物以结构式(II)表示:
其中R2和R3各自独立地为H、C1-C4烷基、苯基或苄基;X1和X2各自独立地为卤基或C1-C4烷氧基;X4和X5各自独立地为卤基、硝基、C1-C4烷氧基、C1-C4烷基或C1-C4全氟烷基;A为H或共价键;p和r各自独立地为1或2数值的整数;而t为0或1数值的整数,条件是当A为H时,t为0;当A为共价键时,t为1。当A为共价键并且t为1时,则亚氨基二乙酰胺衍生物部分可以与苯连接基团在邻位、间位或对位连接。
当式(I)化合物和式(II)化合物与含有αvβ3的细胞接触时,αvβ3与MMP2的结合被抑制,从而干扰血管生成的必需机制。干扰血管生成也可以通过阻止肿瘤的血管形成、从而使肿瘤缺乏营养来抑制肿瘤生长。因此,抑制血管生成和肿瘤生长的本发明化合物是用来治疗罹患肿瘤或血管生成性疾病的患者的有效治疗药。因为本发明化合物与αvβ3结合,所以也可以用这些化合物抑制炎症过程。
本发明化合物可以配制在合适的药学上可接受的基质中。可以将所述活性化合物的药用组合物给予肿瘤患者,以减低或消除肿瘤生长。可以通过注射或通过在规定时间内逐渐输注或者通过适合于特定剂型的任何其它方法胃肠外给予所述活性化合物。
附图简述
附图中:
图1是用示意图说明MMP2与整联蛋白αvβ3的相互作用及其在血管生成中的作用。
图2描绘了在Boger等,Bioorg.Med.Chem,6,1347-1378(1998)中公开的600种化合物组合文库的结构亚单位A、B和C。
图3图示在与MMP2竞争时60种化合物的组合混合物与整联蛋白αvβ3的结合。
图4说明混合物AxB10与整联蛋白αvβ3的结合以及A6B10C4的10种不同组分的结合。
图5描绘A6B10C4类似物的结构。
图6A图示在与MMP2竞争时A6B10C4(化合物1)的类似物(化合物2-26)与整联蛋白αvβ3的结合。
图6B图示在与MMP2比较时化合物9和化合物19与整联蛋白αvβ3的结合。
图7说明[14C]-标记的化合物19与αvβ3特异性地结合并且可以被25倍过量的非标记化合物19,但不被过量的化合物9、RGD肽或c(RGDfV))肽从所述αvβ3竞争性地取代。
图8显示了化合物19破坏MMP2与整联蛋白αvβ3的结合,但不干扰玻连蛋白与整联蛋白αvβ3的结合。
图9显示了化合物19不直接抑制经纯化的活性MMP2的蛋白酶解。
发明详述
MMP2与整联蛋白αvβ3的结合是血管生成过程中的一个重要机制。该结合相互作用的特异性抑制导致在生长组织例如肿瘤中血管形成减少,从而阻止肿瘤生长。MMP2与整联蛋白αvβ3的相互作用在图1中示意性说明。下文描述的一类新的血管生成和肿瘤生长抑制剂,在与MMP2竞争时特异性地结合整联蛋白αvβ3,从而提供了一种重要的新的治疗工具。
本发明的某些化合物可以具有一个或多个不对称中心,并且可以以旋光形式存在。在诸如烷基的取代基中可能存在另外的不对称中心。纯S-异构体和纯R-异构体、所述异构体的外消旋混合物、以及它们的混合物包括在本发明的范围内。考虑了本发明某些化合物的手性形式,并且具体包括在本发明的范围内。
术语“烷氧基”是指通过醚键连接的氧原子和以下定义的、指定大小的烷基。烷氧基的实例是甲氧基、乙氧基、叔丁氧基等。术语“烷基”是指指定大小的直链或支链碳基团。典型的烷基是甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、2-乙基己基、正辛基、2,4-二甲基戊基等。术语“羟烷基”是指与羟基连接的、以上定义的指定大小烷基。实例包括羟甲基、2-羟乙基、3-羟基-1-丙基、2-羟基-1-丙基、4-羟丁基等。
术语“全氟烷基”是指以下定义的指定大小的、携带取代每个氢的氟取代基的烷基,例如三氟甲基和五氟乙基。
术语“卤基”或“卤素”是指溴、氯、氟和碘。
可用于本发明方法中的化合物由式(I)表示,并且包括与一个连接基团化学连接的亚氨基二乙酰胺衍生物:
其中G1和G2各自独立地为-NH-C(O)-O-R1、-NH-C(O)-O-(CH2)v-(C6H4)-X3、-NH-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-O-(CH2)v-(C6H4)-X3或-NH-C(O)-CH2-(C6H4)-X3;Y1和Y2各自独立地为-OH、C1-C4烷基、C1-C4羟烷基、C1-C4烷氧基、苯基、苄基或-NH2;R1为C1-C4烷基;X1和X2各自独立地为卤基或C1-C4烷氧基;X3为卤基、硝基、C1-C4烷基、C1-C4烷氧基或C1-C4全氟烷基;Z为-C≡C-、-C6H4-、顺式-CH=CH-、反式-CH=CH-、顺式-CH2-CH=CH-CH2-、反式-CH2-CH=CH-CH2-、1,4-萘基、顺式-1,3-环己基、反式-1,3-环己基、顺式-1,4-环己基或反式-1,4-环己基;A为H或共价键;m和n各自独立地为0或1数值的整数;t为0或1数值的整数;而p、r和v各自独立地为1或2数值的整数;条件是当A为H时,t为0;当A为共价键时,t为1;当m为0时,Y1为C1-C4羟烷基;当n为0时,Y2为C1-C4羟烷基。
在结构式(I)的范围内优选的化合物由结构式(II)表示,并且包括在邻位、间位或对位与一个苯连接基团连接的亚氨基二乙酰胺衍生物:
其中R2和R3各自独立地为H、C1-C4烷基、苯基或苄基;X1和X2各自独立地为卤基或C1-C4烷氧基;X4和X5各自独立地为卤基、硝基、C1-C4烷氧基、C1-C4烷基或C1-C4全氟烷基;A为H或共价键;p和r各自独立地为1或2数值的整数;而t为0或1数值的整数,条件是当A为H时,t为0;当A为共价键时,t为1。
优选取代基X1和X2在相对于CH2基团的4-位(即对位取代基)与所述苯环结合。优选X1和X2中至少一个是氟基,最优选X1和X2两个都为对位氟基。优选r和p都为2。X4和X5优选为C1-C4全氟烷基,最优选为对三氟甲基。优选R2和R3基团为氢和甲基。取代基X2和X3可以相同或不同,取代基R2和R3也可以相同或不同。
式(I)化合物和式(II)化合物连同其合成方法详细描述于Boger等,Bioorg.Med.Chem,6,1347-1378(1998),该文献通过引用结合到本文中。
其中A为共价键并且t为1的由式(II)表示的化合物家族中一种特别有活性的化合物是以下流程1中的化合物19。
流程1.
以化合物19的合成为例说明由Boger等描述的生产式(I)化合物和式(II)化合物的通用方法。从市售N-ε-BOC-L-赖氨酸甲酯开始,以三个步骤合成化合物19。4-(三氟甲基)苄醇与N,N-二琥珀酰亚胺基碳酸酯反应,随后加入具有游离α-氨基的活化产物,以99%收率接入氨基甲酸酯,得到中间体化合物27。然后使所述赖氨酸衍生物进行N-BOC去保护(HCl),并且将其用六氟合磷氢酸溴三吡咯烷基磷鎓(PyBrOP,74%)与亚氨基二乙酸单酰胺化合物28的游离羧酸官能基团偶联,得到二酰胺化合物29。在N-BOC去保护(HCl)之后,通过与间苯二酰二氯反应,使其二聚体化,完成所述合成,得到化合物19(60%收率)。将一种放射性标记通过两个甲酯(LiOH,95%)的皂化作用掺入到所述分子中,得到二羧酸化合物30,然后通过1-(3-(二甲氨基)丙基)-3-乙基碳二亚胺盐酸盐(EDCl)和催化性4-二甲基氨基吡啶(DMAP)的介导,与[14C]-甲醇酯化,得到[14C]-化合物1(35%收率)。
式(I)化合物和式(II)化合物的药用制剂可以通过在药学上可接受的载体基质中配制所述化合物来制备。将包含所述活性式(I)化合物和式(II)化合物的药用组合物给予肿瘤患者,以减低或消除肿瘤生长。所述活性化合物可以通过注射或在规定时间内逐渐输注而胃肠外给予。虽然需要治疗的组织最通常通过腹膜内或皮下给药进行治疗,但是所述活性化合物也可以眼内、静脉内、肌内、滑膜内、腔内或透皮给予,以及可以通过蠕动式手段传递。
本文所用的术语“给予”本发明的化合物或组合物是指系统应用,例如以含有需要的常规无毒的药学上可接受的载体、辅料和溶媒的剂型单位制剂采取口服、胃肠外途径给予(吸入喷雾、通过鼻腔、直肠或口腔含化途径给予或者局部给予)。本文所用的术语“胃肠外”包括静脉内、肌内、腹膜内、胸骨内、皮下和关节腔注射和输注技术。
所谓“药学上可接受的”,它是指这样的盐、酰胺和酯:在合理的医疗判断范围内、适用于接触人体组织和低等动物组织而没有过度的毒性、刺激性、变态反应等,而且具有合理的利益/风险比,有效用于治疗肿瘤和和血管生成相关疾病。
药学上可接受的盐是本领域众所周知的。例如S.M Berge等在J.Pharmaceutical Sciences,66,1-19(1977)中详细介绍的药学上可接受的盐。典型的酸加成盐包括盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、醋酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、甲磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、抗坏血酸盐、葡糖庚酸盐、乳糖酸盐、十二烷基硫酸盐等。典型的碱金属盐或碱土金属盐包括钠盐、钙盐、钾盐、镁盐等。
本文所用的术语“药学上可接受的载体”是指无毒的、惰性固体、半固体或液体填充剂、稀释剂、包胶囊材料或任何类型的辅助剂。可以用作药学上可接受的载体的所述材料的部分实例是糖,例如乳糖、葡萄糖和蔗糖;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,例如羟甲基纤维素钠、乙基纤维素和醋酸纤维素;粉状西黄蓍胶;麦芽;明胶;滑石粉;赋形剂,例如可可脂和栓剂蜡;油,例如花生油、棉子油、红花油、芝麻油、橄榄油、玉米油和豆油;二元醇类,例如丙二醇;多元醇,例如甘油、山梨醇、甘露醇和聚乙二醇;酯类,例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁和氢氧化铝;藻酸;无热原水;等渗盐水;Ringer氏溶液;乙醇和磷酸缓冲溶液以及其它在药用制剂中所用的无毒相容的物质。
根据配制者的判断,在所述组合物中也可以存在润湿剂、乳化剂和润滑剂,例如十二烷基硫酸钠和硬脂酸镁,以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂。药学上可接受的抗氧化剂的实例包括水溶性抗氧化剂,例如抗坏血酸、半胱氨酸盐酸盐、亚硫酸氢钠、焦亚硫酸钠、亚硫酸钠等;油溶性抗氧化剂,例如棕榈酸抗坏血酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、镓酸丙酯、α-生育酚等;以及金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本发明药物或化合物的“治疗有效量”是指以适合于任何医学治疗的合适利益/风险比治疗肿瘤和血管生成相关疾病的所述化合物的足够量。然而,人们知道,本发明化合物和组合物的总日用剂量将由主治医师经合理的医疗判断决定。任何具体患者的具体治疗有效剂量水平取决于各种因素,包括所治疗的病症和病症的严重程度、使用的具体化合物活性、使用的具体组合物、患者的年龄、体重、一般健康状况、性别和饮食、给药时间、给药途径和所使用的具体化合物的排泄率、治疗持续时间、联合应用的药物或与所用具体化合物同时使用的药物以及医学领域熟知的类似因素。
本发明还提供单位剂型的药用组合物,所述药用组合物包含治疗有效量的一种或多种本发明化合物以及常规的药用载体。注射制剂,例如无菌注射用水性混悬剂或油状混悬剂可以按照已知的技术使用合适的分散剂或湿润剂和悬浮剂进行配制。无菌注射制剂也可以是在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射的溶液、混悬液或乳液,例如1,3-丁二醇溶液。其中可以使用的所述可接受的溶媒和溶剂是水、Ringer氏溶液、U.S.P.和等渗氯化钠溶液。另外,无菌非挥发性油类常规作为溶剂或悬浮介质使用。为此,可以使用任何刺激性小的非挥发性油,包括合成甘油单酯或甘油二酯。
另外,在所述注射制剂中使用脂肪酸,例如油酸。所述注射制剂可以例如通过阻留细菌的滤膜过滤,或者在临用前可用无菌水或其它无菌注射介质溶解或分散的无菌固体组合物形式中掺入杀菌剂,可使注射制剂无菌。
为了延长药物的作用,通常需要减缓皮下注射或肌内注射的药物吸收。最常用的方式是通过注射水溶性差的结晶或无定形物质的混悬液来实现。那么药物的吸收速率取决于药物的溶解速率,而溶解速率又可能取决于药物的物理状态,例如晶体大小和晶型。延迟药物吸收的另一种方法是药物以油溶液或油混悬液给予。也可以通过使药物和生物可降解聚合物例如聚丙交酯-聚乙交酯形成微囊骨架,制备注射贮库型剂型。根据药物与聚合物的比例和所述聚合物的组成,可以控制药物释放速率。其它生物可降解聚合物的实例包括聚-原酸酯和聚酐类。还可将药物包埋在与机体组织相容的脂质体或微乳中,制备贮库型注射制剂。
可以通过使所述药物与适宜的非刺激性赋形剂例如可可脂和聚乙二醇混合,制备用于直肠给药的栓剂,所述赋形剂在常温下为固体,但在直肠温度下为液体,因此在直肠内熔融而释放出所述药物。
用于口服给药的固体剂型可包括胶囊剂、片剂、丸剂、粉剂、prills和颗粒剂,在这样的固体剂型中,可以将所述活性化合物与至少一种惰性稀释剂例如蔗糖、乳糖或淀粉混合。根据常规实践,这样的剂型还可以包含除惰性稀释剂以外的其它物质,例如制片润滑剂和其它制片助剂,例如硬脂酸镁和微晶纤维素。如果为胶囊剂、片剂和丸剂,所述剂型还可以包含缓冲剂。另外,还可用肠溶包衣和其它控释包衣剂制备片剂和丸剂。利用诸如乳糖或奶糖以及高分子量聚乙二醇等的这类赋形剂,相似类型的固体组合物也可用作填充软明胶胶囊和填充硬明胶胶囊的填充物。
用于口服给药的液体剂型可以包含药学上可接受的、含有本领域常用的惰性稀释剂例如水的乳剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。这样的组合物还可以包含辅料,例如湿润剂;乳化剂和悬浮剂;甜味剂、矫味剂和芳香剂。如果需要,可以将本发明化合物掺入到缓释或定向给药系统,例如聚合物骨架、脂质体和微球体。可以例如通过阻留细菌的滤膜过滤,或者在临用前可用无菌水或某些其它无菌注射介质溶解的无菌固体组合物形式中掺入杀菌剂,可使所述制剂无菌。所述活性化合物也可以为具有如上所述的一种或多种赋形剂的微囊化形式。
可以用包衣和壳体例如肠溶包衣和药物配制领域熟知的其它包衣剂制备片剂、糖锭剂、胶囊剂、丸剂和颗粒剂固体剂型。它们可以任选包含遮光剂,而且也可以为这样的组合物:它们任选以延迟方式仅在或优选在某部分肠道释放所述有效成分。可以使用的包埋组合物的实例包括聚合物物质和蜡。用于局部给予或透皮给予本发明化合物的剂型还包括软膏剂、糊剂、乳油、洗液、凝胶剂、粉剂、溶液剂、喷雾剂、吸入剂或贴剂。可以使所述有效成分在无菌条件下与药学上可接受的载体和任何所需防腐剂或可能需要的缓冲剂进行混合。
在本发明的范围内也考虑了眼用制剂、滴耳剂、眼膏剂、粉剂和溶液剂。所述软膏剂、糊剂、乳油和凝胶剂除含有本发明的活性化合物外,还可以含有赋形剂,例如动物和植物的脂肪、油、蜡、石蜡、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、皂土、硅酸、滑石粉和氧化锌或它们的混合物。
粉剂和喷雾剂除含有本发明化合物外,还可以含有赋形剂,例如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉或这些物质的混合物。另外,喷雾剂还可以含有常规的抛射剂,例如含氯氟烃。
透皮贴剂具有提供使化合物控制释放到机体的附加优点。通过使所述化合物在适宜介质中溶解或分散,可以制备这样的剂型。也可使用吸收促进剂增加所述化合物通过皮肤。其速率可以或者受提供的速率控制膜控制或者通过使所述化合物在聚合物骨架或凝胶中分散而控制。
以与给药制剂匹配的方式和以治疗有效量给予含有所述活性化合物的组合物。给药量和给予时间取决于待治疗的宿主、宿主系统利用所述有效成分的能力以及所需治疗效应的程度。需要给予的所述有效成分的准确量取决于主治医师的判断,并且对于每个个体而言都是特有的。
本文公开了用于系统应用的合适剂量范围,所述剂量范围取决于给药途径。合适的给药方案也是可变化的,但通常为在初次给药后,以一种或多种预定间隔通过后续注射或其它给药途径重复给药。
本发明还提供可用于实施本文所述治疗方法的药用组合物。所述组合物含有上文所述的活性化合物以及药学上可接受的载体。
用于胃肠外给予本发明化合物或组合物的制剂包括无菌的水溶液或非水溶液剂、混悬剂和乳剂。非水溶剂的实例是丙二醇、聚乙二醇、植物油例如橄榄油和可注射的有机酯例如油酸乙酯。水性载体包括水、醇溶液/水溶液、乳液或混悬液,包括盐水和缓冲介质。原溶媒包括氯化钠溶液、Ringer氏葡萄糖、葡萄糖和氯化钠、乳酸化Ringer氏或非挥发性油类。静脉内溶媒包括液体营养补充剂、电解质补充剂(例如基于Ringer氏葡萄糖的补充剂)等。也可以存在防腐剂和其它添加剂,例如抗菌剂、抗氧化剂、螯合剂、惰性气体等。
本发明的另一方面提供抑制MMP2与整联蛋白αvβ3相互作用、从而抑制肿瘤组织中的血管生成的方法。所述抑制方法包括给予所述宿主包含血管生成抑制量的上文所述化合物的组合物。通过使αvβ3与本发明化合物接触,抑制MMP2与αvβ3相互作用。
血管生成是从现有的宿主血管形成新血管网络,并且肿瘤生长超过1-2mm3需要血管生成。对于本发明的目的而言,只要血管生成和血管生成介导的病症得以缓解,则抑制了血管生成。
给予宿主所述活性化合物的剂量范围取决于针对特定肿瘤或整联蛋白的具体活性化合物及其效力。无需过多实验,本领域技术人员可容易地确定具体活性化合物的准确剂量。所述宿主可以是任何哺乳动物。所述剂量应该大到足以产生所需治疗效应,其中血管生成和血管生成介导的病症得以缓解,并且通常是将所述活性化合物的血浆水平足以维持在以下范围内的量:约0.01微摩尔-约100微摩尔(μM),优选约0.2μM-约20μM,更优选约1μM-约10μM。然而,所述剂量不应大到引起毒副作用。每公斤(kg)体重的剂量可以在每剂1-20mg的范围内变化,每日给予一剂或多剂,持续一天或数天或长期给予。
为了抑制血管生成,所述治疗有效量是足以在治疗的组织中产生可测量到的血管生成抑制的活性化合物的量,即血管生成抑制量或MMP2-αvβ3相互作用抑制量。可以通过本文所述的免疫组织化学或者通过本领域技术人员已知的其它方法,原位测定血管生成的抑制。
另外,本发明还提供可用于实施本文所述治疗方法的药用组合物。所述组合物含有上文定义的活性化合物以及药学上可接受的载体。
本发明还提供诱导肿瘤细胞凋亡的方法。该方法包括给予所述宿主治疗有效量的、足以引起肿瘤细胞凋亡的活性化合物。
对于本发明的目的而言,如果在治疗的靶肿瘤中观察到肿瘤细胞凋亡增加,则诱发了肿瘤细胞凋亡。通过本文所述方法或本领域熟知的方法,可以测定肿瘤细胞凋亡。
提供以下非限制性实施例说明本发明的各个方面。
材料和方法
抗体细胞和试剂。CS-1仓鼠黑素瘤细胞和用人β3-整联蛋白亚基转染的CS-1细胞(β3CS-1细胞)先前已有描述(Cell,85,683-93(1996);Cell,92,391-400(1998))。缀合辣根过氧化物酶(HRP)的单克隆抗体抗生物素mAb BN-34和抗肌动蛋白mAb AC-40得自Sigma(St.Louis,MO)。抗-von Willebrand Factor(vWF)多克隆抗体(pAb)得自DAKO(Glostrup,丹麦)。环肽cRGDfV和cRADfV和整联蛋白-αvβ3由MerckKGaA(Darmstadt,德国)提供。纯化proMMP2和整联蛋白-αvβ3由Chemicon International(Temecula,CA)提供。纯化活性MMP2得自Calbiochem(La Jolla,CA)。碱性成纤维细胞生长因子(bFGF)由Scios(Mountain View,CA)友好提供。
实施例1.固相整联蛋白结合测定
将纯化整联蛋白在微量滴定孔上吸附过夜(1-5μg/ml,50μg/孔),然后用Caseinblocker(Pierce,Rockford,IL)封闭。在存在或不存在试验化合物、环RGD或RAD肽、或单独的缓冲溶媒的情况下,将在结合缓冲液(50mM Tris,pH 8,150mM NaCl,1mM MgCl2,0.5mMMnCl2)中的纯化生物素化MMP2(bMMP2,3-5nM)加入到各孔中。对照孔不加入整联蛋白。生物素化玻连蛋白(bVN,1μg/ml)用作参比物。结合蛋白用HRP-抗生物素mAb检测,并且于450nm用3,3′,5,5′-四甲基联苯胺溶液(TMB;所述过氧化物酶的底物)(BioRad,Hercules,CA)进行定量。
为了评价化合物19直接结合整联蛋白,将αvβ3和α5β1(10μg/ml,50μl/孔)包被在Immulon-4微量滴定孔(Dynatech Laboratories,Chantilly,VA)上,基本被封闭后,与逐渐增量的[14C]-化合物19一起孵育,然后加入150μl含有0.1%吐温-20的结合缓冲液,吸出所有液体。分离干燥的各孔,然后将其浸渍在BetaMat液体闪烁混合剂(ICNBiochemicals,Costa Mesa,CA)中以供定量。根据该结合曲线,在存在和不存在25倍摩尔过量(75μl)的未标记化合物19或化合物9、或100μM环RGD或RAD肽的情况下,检查[14C]-化合物19的亚饱和浓度(3μM)。对照为bVN,如上所述进行使用和检测。
实施例2.MMP2细胞结合测定和[
3
H]-胶原蛋白IV降解测定
将CS-1细胞或β3CS-1细胞在含有以下成分的粘附缓冲成纤维细胞基础培养基(FBM)中于37℃孵育45分钟,然后洗涤,加入到[3H]-胶原蛋白IV包被的各孔中:仅含有4nM纯化活性MMP2或者组合有10μM化合物19或化合物9并且补充0.5%牛血清白蛋白(BSA)、0.4mM MnCl2和10μg/ml抑蛋白酶肽。用50μl 0.414mCi/ml[3H]-胶原蛋白IV(ICN Biochemicals,Costa Mesa,CA)将各孔包被过夜,充分洗涤直到在回收的洗涤溶液中的放射性达到本底值。或者,在不存在MMP2的情况下如上处理细胞,或者将所述MMP2溶液直接加到无细胞的各孔中,作为对照。根据液体闪烁计数器测定,通过测量释放到50μl培养基的放射性,对胶原蛋白IV的降解定量。为了评价生物素化MMP2与CS-1细胞的结合,将细胞悬浮于粘附缓冲液中,在存在或不存在10μM化合物19或化合物9的情况下,与12nMbMMP2一起于37℃孵育45分钟。随后洗涤细胞,然后裂解并且加工以供SDS-PAGE使用,用抗生物素mAb进行免疫印迹法。
实施例3.化合物27的合成
将N,N’-二琥珀酰亚胺碳酸酯(95.38g,21mmol)的乙腈(150ml)溶液用4-(三氟甲基)苄醇(2.87ml,21mmol)和三乙胺(Et3N;5.8ml,42mmol)处理,于25℃下搅拌。3小时后,将该溶液加到装有N-ε-BOC-赖氨酸甲酯(4.2g,14mmol)的乙腈溶液的烧瓶中,再搅拌3小时。将溶剂蒸发,残余物溶于CH2Cl2(250ml)中,然后用10%盐酸(2×200ml)和饱和碳酸氢钠水溶液(200ml)洗涤。经快速色谱(SiO2,3∶1CH2Cl2/EtOAc),得到6.4g(99%)为浅黄色油状物的化合物27:[α]D 25-8.95.55,CH3OH;1H NMR(CDCl3,400MHz)δ7.57(d,J=8.1Hz,2H),7.39(d,J=8.1Hz,2H),5.70(d,J=7.9Hz),5.13(m,2H),4.71(m,lH),4.28(m,1H),3.67(s,3H),3.03(m,2H),1.78(m,1H),1.64(m,1H),1.46-1.32(m,4H),1.35(s,9H);13C NMR(CDCl3,100MHz)δ172.9,156.2,155.8,140.4,130.1(q,J=32.0Hz),127.8,125.3,122.9,(q J=270.0Hz),79.05,65.8,53.7,52.3,39.8,31.7,29.5,28.4,22.2;IR(膜)νmax3357,2952,1790,1745,1524cm-1;FABHRMS(NBA-NaI)m/z 463.2044(M+H+,C21H29F3N2O6理论值463.2056)。
实施例4.化合物29的合成
将化合物27(2.2g,48.8mmol)的CH2Cl2(3ml)溶液用4N HCl-二噁烷(10ml)处理,于25℃下搅拌20分钟。减压除去溶剂和过量的酸,将粗盐酸盐溶于DMF(40ml)中,用N-((叔丁氧基)羰基)-N’-(2-(4-氟苯基)乙基)亚氨基二乙酸单酰胺(化合物28)(1.68g,4.8mmol)、PyBrOP(3.3g,7.1mmol)和二异丙基乙胺(i-Pr2NEt;5.0ml,29mmol)处理,于25℃下搅拌1小时。反应混合物用EtOAc(400ml)稀释,用10%盐酸水溶液(2×300ml)和饱和碳酸氢钠水溶液(300ml)洗涤。经快速色谱(SiO2,1∶1 CH2Cl2/EtOAc),得到2.47g(74%)为白色泡沫状固体的化合物29:[α]D 25-7.14.50,CH3OH;1H NMR(CDCl3,400MHz)δ8.23和7.59(m,和1H),7.58(d,J=8.1Hz,2H),7.43(m,2H),7.13(m,2H),7.06和6.78(m,和1H),6.94(m,2H),5.70(dd,J=12.9和8.2Hz,1H),5.11(m,2H),4.31(m,1H),3.85-2.72(m,4H),3.71(s,3H),3.49(m,2H),3.22(m,2H),2.79(m,2H),1.81-1.39(m,6H),1.38(s,9H);13CNMR(CDCl3,100MHz)δ172.8,170.0,169.9,155.8,154.8,161.4(d,J=242.7Hz),140.2,134.4,130.1(q,J=33.4Hz),130.0,127.7,125.3(q,J=3.0Hz),,123.8(q,J=299.9Hz),115.0,81.2,65.7,53.9,53.3,52.2,40.8,38.6,34.4,31.5,28.0,22.4;IR(膜)νmax3367,2935,1708,1657,1511cm-1;FABHRMS(NBA-CsI)m/z 831.2026(M+Cs+,C33H42F4N4O8理论值831.1993)。
实施例5.化合物19的合成
将化合物29(50mg,0.075mmol)的CH2Cl2(1ml)溶液用4N HCl-二噁烷(1ml)处理,于25℃下搅拌1小时。在氮气流下除去溶剂和过量的酸,将粗盐酸盐悬浮于CH2Cl2(1ml)中,用间苯二酰二氯(7.6mg,0.038mmol)和i-Pr2NEt(0.05ml,0.3mmol)处理,于25℃下搅拌12小时。反应混合物用EtOAc(50ml)稀释,用10%盐酸(3×30ml)、饱和碳酸氢钠水溶液(30ml)和饱和氯化钠水溶液(30ml)洗涤。经快速色谱(SiO2,1∶4.5∶4.5 MeOH/CH2Cl2/EtOAc),得到30mg(60%)为白色粉末的化合物19:1H MR(CD3OD,400MHz)δ7.62(m,4H),7.52(m,4H),7.42(m,4H),7.19(m,4H),6.96(m,4H),5.14(m,4H),4.16(m,2H),4.13(m,2H),4.08(m,2H),3.99(m,4H),3.68(s,6H),3.45-3.35(m,4H),3.25-3.11(m,4H),2.82-2.70(m,4H),1.82(m,2H),1.69(m,2H),1.60-1.34(m 8H);IR(膜)νmax3291,2936,1725,1651,1326cm-1;FABHRMS(NBA-CsI)m/z 1459.4015(M+Cs+,C64H70F8N8O14理论值1459.3938)。
实施例6.化合物30的合成
将化合物19(13mg,0.01mmol)的叔丁醇(0.3ml)溶液用在H2O(0.15ml)中溶解的LiOH·H2O(0.91mg,0.22mmol)处理,于0℃下搅拌2小时。然后反应混合物用HCO2H(1ml)猝灭,用EtOAc(10ml)稀释,用饱和氯化钠水溶液(2×10ml)洗涤。干燥(Na2SO4)并蒸发,得到12mg(95%)为白色粉末的化合物30:1H NMR(DMSO-d6,400MHz)δ12.54(br s,2H)8.63(m,1H),8.43(m,2H),8.30(m,1H),7.74(m,4H),7.69(m,2H),7.57(m,4H),7.40(m,4H),7.24(m,4H),7.09(m,4H),5.15(m,4H),4.14(m,2H),4.02-3.87(m,8H),3。31(m,4H),3.208(m,4H),2.74(m,4H),1.71(m,2H),1.62(m,2H)1.50-1.34(m,8H);IR(膜)νmax3287,2928,1705,1659,1320cm-1;MALDIHRMS m/z 1321.4493(M+Na+,C62H66F8N8O14理论值1321.4468)。
实施例7.[
14
C]-化合物19的合成
将化合物27(1.7mg,1.3mmol)和EDCI(2.0mg,10.3mmol)的DMF(20ml)溶液用0.3ml 14CH3OH的CH2Cl2(57mCi/mmol,5.2mmol14CH3OH)溶液和35ml DMAP的CH2Cl2(0.6mmol DMAP)储备液处理,于0℃下搅拌4小时。然后反应混合物用EtOAc(3L)稀释,用10%盐酸(3×3ml)和饱和碳酸氢钠水溶液(3ml)洗涤,干燥(Na2SO4)。在PTLC上纯化(SiO2,2∶3∶3 EtOH/CHCl3/EtOAc),得到0.6mg(35%)为白色膜状物的[14C]-化合物19。通过1H NMR和HPLC,该物质与相应未标记的二甲酯化合物1相同。相对活度约为104mCi/mmol:1HNMR(CD3OD,400MHz)δ7.62(m,4H),7.52(m,4H),7.42(m,4H),7.19(m,4H),6.96(m,4H),5.14(m,4H),4.16(m,2H),4.13(m,2H),4.08(m,2H),3.99(m,4H),3.68(s,6H),3.45-3.35(m,4H),3.25-3.11(m,4H),2.82-2.70(m,4H),1.82(m,2H),1.69(m,2H),1.60-1.34(m 8H)。
结果和讨论
包括式(I)化合物和式(II)化合物在内的化合物的组合文库连同其合成方法详细描述于Boger等,Bioorg.Med.Chem,6,1347-1378(1998)。Boger等分别介绍了10种化合物的60种混合物的组合文库的制备,其中所述混合物中的每种化合物由如图2中所示的偶联一起的三个亚单位组成。所述化合物的亚单位被称为A、B和C。所述文库从6个不同的A单位(A1-A6)、10个不同的B单位(B1-B10)和10个不同的C连接基团(C1-C10)构建。每个A单位与每个B单位偶联,形成60种不同的AB化合物。然后单个AB化合物与10个不同的C连接基团的混合物偶联,分别形成10种化合物的60种混合物,称为AxBy,其中所述x和y分别表示被掺入到所述混合物的所述化合物中的单个A亚单位和单个B亚单位。所述化合物组合文库的A亚单位、B亚单位和C亚单位示于图2中。
评价在竞争性整联蛋白αvβ3结合测定中上文所述的60种混合物与MMP2的竞争表明,数种所述混合物抑制MMP2与整联蛋白αvβ3的结合。评价测定结果示于图3中。特别有活性的混合物包括A1B6、A1B7、A1B8、A4B1、A5B4、A5B5、A5B6、A5B10和A6B10。活性最高的混合物是A6B10,因此,分别合成所述混合物的10种单个化合物,以相同测定进行检测,其结果示于图4中。在所述测定中所有的单个组分A6B10C1-A6B10C10在3μM浓度都有活性。
也评价了图5中所示的A6B10C4(化合物1)的类似物化合物(2-26)。化合物2-26的结合测定结果示于图6A中。除化合物8、9和23之外,所有的所述化合物都抑制MMP2与整联蛋白结合。
式(I)和式(II)包括本发明的活性MMP2/整联蛋白-αv-β3结合抑制剂。
详细检测了化合物19,以测定其专一性靶并确定其生物特性。尽管苯甲酰胺化合物9具有总体结构相似物和相似的物理特性(例如溶解度和疏水性),但是由于在所述结合测定中发现其缺乏拮抗剂活性,所以选择所述苯甲酰胺化合物9作为可供这些研究中的许多研究用的合适阴性对照化合物。如图6B所示,化合物19浓度依赖性抑制MMP2与整联蛋白结合。
将一种放射性标记(14C)掺入到化合物19的酯取代基中(相对活度约104mCi/mmol)。与固定αvβ3一起孵育(3μM)后,然后洗涤,正如图7所证明的,发现该化合物粘附于所述整联蛋白。在25倍摩尔过量的冷的化合物19存在下孵育显著减少所述观测到的结合物的量,而在25倍摩尔过量的(冷的)对照化合物9存在下孵育不影响[14C]-化合物19的结合。在一个测定[14C]-化合物19与固定MMP2的相互作用的类似实验中,没有观测到结合。这些结果表明,在MMP2-αv-β3结合测定中观测到的所述拮抗剂活性来源于化合物19与αv-β3的特异性结合。化合物19-αv-β3相互作用的性质与识别Arg-Gly-Asp序列的整联蛋白位点无关。环RGD肽环(Arg-Gly-Asp-D-Phe-Val)不影响[14C]-化合物19的结合(图7)。事实上,如图8所示,化合物19不抑制玻连蛋白、即αvβ3的典型高亲和性配体与所述整联蛋白的结合,与化合物19的结合部位与结合RGD-配体的结合部位不同的构思一致。
在一种测定内皮细胞利用MMP2降解蛋白质基质(血管生成中的一个关键步骤)的能力的细胞测定中,也研究了化合物19。先前的研究表明,破坏MMP2与αvβ3的结合抑制胶原蛋白IV的降解。发现用αvβ3转染的CS-1黑素瘤细胞,降解固定化[3H]-胶原蛋白IV远远高于降解β3阴性CS-1细胞(它缺乏αvβ3)。如图9所示,用化合物19处理这些细胞显著减少所述被增加的基质降解,与所述细胞不能利用MMP2相一致,所述MMP2不与所述整联蛋白表面结合。然而,因为没有细胞的纯化(活性)酶能够在存在或不存在化合物19的情况下在相似程度上降解[3H]-胶原蛋白IV,所以化合物19不直接抑制MMP2的蛋白酶解活性。
这些结果支持的命题是,式(I)化合物破坏肿瘤细胞以与PEX类似的方式利用MMP2降解ECM蛋白的能力。式(I)化合物不干扰αvβ3与其典型的RGD配体的结合,它们也不作为直接蛋白酶抑制剂起作用。
前面的说明和实施例是说明性的,而不是限制性的。在本发明的精神和范围内的其它变化对于本领域技术人员而言是可能的并且本身是显而易见的。
Claims (37)
1.下式化合物在制备用于抑制基质金属蛋白酶2与宿主细胞整联蛋白αvβ3相互作用的药物中的用途:
其中G1和G2各自独立地为-NH-C(O)-O-R1、-NH-C(O)-O-(CH2)v-(C6H4)-X3、-NH-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-O-(CH2)v-(C6H4)-X3或-NH-C(O)-CH2-(C6H4)-X3;Y1和Y2各自独立地为-OH、C1-C4烷基、C1-C4羟烷基、C1-C4烷氧基、苯基、苄基或-NH2;R1为C1-C4烷基;X1和X2各自独立地为卤基或C1-C4烷氧基;X3为卤基、硝基、C1-C4烷基、C1-C4烷氧基或C1-C4全氟烷基;Z为-C≡C-、-C6H4-、顺式-CH=CH-、反式-CH=CH-、顺式-CH2-CH=CH-CH2-、反式-CH2-CH=CH-CH2-、1,4-萘基、顺式-1,3-环己基、反式-1,3-环己基、顺式-1,4-环己基或反式-1,4-环己基;A为共价键;m和n各自独立地为0或1数值的整数;t为1;而p、r和v各自独立地为1或2数值的整数;条件是当m为0时,Y1为C1-C4羟烷基;当n为0时,Y2为C1-C4羟烷基。
2.权利要求1的用途,其中G1和G2为-NH-C(O)-O-(CH2)v-(C6H4)-X3,v为1。
3.权利要求2的用途,其中X3为三氟甲基。
4.权利要求2的用途,其中Y1和Y2为-OH,m为1,n为1。
5.权利要求2的用途,其中X1和X2中至少一个为对位氟基。
6.权利要求2的用途,其中m为1,n为1,R2和R3中至少一个为甲基。
7.权利要求2的用途,其中R2和R3为H,m和n为1,X1和X2为氟基,X3为三氟甲基。
8.下式化合物在制备用于抑制基质金属蛋白酶2与宿主细胞整联蛋白αvβ3相互作用的药物中的用途:
其中R2和R3各自独立地为H、C1-C4烷基、苯基或苄基;X1和X2各自独立地为卤基或C1-C4烷氧基;X4和X5各自独立地为卤基、硝基、C1-C4烷氧基、C1-C4烷基或C1-C4全氟烷基;A为共价键;p和r各自独立地为1或2数值的整数;而t为1。
9.权利要求8的用途,其中X4和X5中至少一个为C1-C4全氟烷基。
10.权利要求8的用途,其中R2和R3中至少一个为H。
11.权利要求8的用途,其中R2和R3中至少一个为甲基。
12.权利要求8的用途,其中X4和X5为三氟甲基,R2和R3各自为甲基。
13.权利要求8的用途,其中R2和R3为甲基,X4和X5为三氟甲基,X1和X2为氟基,m为1,n为1。
14.下式化合物在制备用于抑制宿主体内血管生成的药物中的用途:
其中G1和G2各自独立地为-NH-C(O)-O-R1、-NH-C(O)-O-(CH2)v-(C6H4)-X3、-NH-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-O-(CH2)v-(C6H4)-X3或-NH-C(O)-CH2-(C6H4)-X3;Y1和Y2各自独立地为-OH、C1-C4烷基、C1-C4羟烷基、C1-C4烷氧基、苯基、苄基或-NH2;R1为C1-C4烷基;X1和X2各自独立地为卤基或C1-C4烷氧基;X3为卤基、硝基、C1-C4烷基、C1-C4烷氧基或C1-C4全氟烷基;Z为-C≡C-、-C6H4-、顺式-CH=CH-、反式-CH=CH-、顺式-CH2-CH=CH-CH2-、反式-CH2-CH=CH-CH2-、1,4-萘基、顺式-1,3-环己基、反式-1,3-环己基、顺式-1,4-环己基或反式-1,4-环己基;A为共价键;m和n各自独立地为0或1数值的整数;t为1;而p、r和v各自独立地为1或2数值的整数;条件是当m为0时,Y1为C1-C4羟烷基;当n为0时,Y2为C1-C4羟烷基。
15.按照权利要求14的用途,其中G1和G2为-NH-C(O)-O-(CH2)v-(C6H4)-X3,v为1。
16.按照权利要求15的用途,其中X3为三氟甲基。
17.按照权利要求15的用途,其中Y1和Y2为-OH,m为1,n为1。
18.按照权利要求15的用途,其中X1和X2中至少一个为对位氟基。
19.按照权利要求15的用途,其中m为1,n为1,R2和R3中至少一个为甲基。
20.按照权利要求15的用途,其中R2和R3为甲基,m和n为1,X1和X2为氟基,X3为三氟甲基。
21.按照权利要求14的用途,其中所述药物是腹膜内、皮下、静脉内、透皮、滑膜内、肌内或口服给药的。
22.下式化合物在制备用于抑制宿主体内肿瘤生长的药物中的用途:
其中G1和G2各自独立地为-NH-C(O)-O-R1、-NH-C(O)-O-(CH2)v-(C6H4)-X3、-NH-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-O-(CH2)v-(C6H4)-X3或-NH-C(O)-CH2-(C6H4)-X3;Y1和Y2各自独立地为-OH、C1-C4烷基、C1-C4羟烷基、C1-C4烷氧基、苯基、苄基或-NH2;R1为C1-C4烷基;X1和X2各自独立地为卤基或C1-C4烷氧基;X3为卤基、硝基、C1-C4烷基、C1-C4烷氧基或C1-C4全氟烷基;Z为-C≡C-、-C6H4-、顺式-CH=CH-、反式-CH=CH-、顺式-CH2-CH=CH-CH2-、反式-CH2-CH=CH-CH2-、1,4-萘基、顺式-1,3-环己基、反式-1,3-环己基、顺式-1,4-环己基或反式-1,4-环己基;A为共价键;m和n各自独立地为0或1数值的整数;t为1;而p、r和v各自独立地为1或2数值的整数;条件是当m为0时,Y1为C1-C4羟烷基;当n为0时,Y2为C1-C4羟烷基。
23.按照权利要求22的用途,其中G1和G2为-NH-C(O)-O-(CH2)v-(C6H4)-X3,v为1。
24.按照权利要求23的用途,其中X3为三氟甲基。
25.按照权利要求23的用途,其中Y1和Y2为-OH,m为1,n为1。
26.按照权利要求23的用途,其中X1和X2中至少一个为对位氟基。
27.按照权利要求23的用途,其中m为1,n为1,R2和R3中至少一个为甲基。
28.按照权利要求23的用途,其中R2和R3为甲基,m和n为1,X1和X2为氟基,X3为三氟甲基。
29.按照权利要求22的用途,其中所述药物是腹膜内、皮下、静脉内、透皮、滑膜内、肌内或口服给药的。
30.下式化合物在制备用于诱导肿瘤细胞凋亡的药物中的用途:
其中G1和G2各自独立地为-NH-C(O)-O-R1、-NH-C(O)-O-(CH2)v-(C6H4)-X3、-NH-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-NH-(CH2)v-(C6H4)-X3、-O-C(O)-O-(CH2)v-(C6H4)-X3或-NH-C(O)-CH2-(C6H4)-X3;Y1和Y2各自独立地为-OH、C1-C4烷基、C1-C4羟烷基、C1-C4烷氧基、苯基、苄基或-NH2;R1为C1-C4烷基;X1和X2各自独立地为卤基或C1-C4烷氧基;X3为卤基、硝基、C1-C4烷基、C1-C4烷氧基或C1-C4全氟烷基;Z为-C≡C-、-C6H4-、顺式-CH=CH-、反式-CH=CH-、顺式-CH2-CH=CH-CH2-、反式-CH2-CH=CH-CH2-、1,4-萘基、顺式-1,3-环己基、反式-1,3-环己基、顺式-1,4-环己基或反式-1,4-环己基;A为共价键;m和n各自独立地为0或1数值的整数;t为1;而p、r和v各自独立地为1或2数值的整数;条件是当m为0时,Y1为C1-C4羟烷基;当n为0时,Y2为C1-C4羟烷基。
31.按照权利要求30的用途,其中G1和G2为-NH-C(O)-O-(CH2)v-(C6H4)-X3,v为1。
32.按照权利要求31的用途,其中X3为三氟甲基。
33.按照权利要求31的用途,其中Y1和Y2为-OH,m为1,n为1。
34.按照权利要求31的用途,其中X1和X2中至少一个为对位氟基。
35.按照权利要求31的用途,其中m为1,n为1,R2和R3中至少一个为甲基。
36.按照权利要求31的用途,其中R2和R3为甲基,m和n为1,X1和X2为氟基,X3为三氟甲基。
37.按照权利要求30的用途,其中所述药物是腹膜内、皮下、静脉内、透皮、滑膜内、肌内或口服给药的。
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