CN1997622B - 聚阳离子化合物及其用途 - Google Patents
聚阳离子化合物及其用途 Download PDFInfo
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- CN1997622B CN1997622B CN2005800194487A CN200580019448A CN1997622B CN 1997622 B CN1997622 B CN 1997622B CN 2005800194487 A CN2005800194487 A CN 2005800194487A CN 200580019448 A CN200580019448 A CN 200580019448A CN 1997622 B CN1997622 B CN 1997622B
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Abstract
本发明的方面涉及有益于调节血管发生的化合物和方法,以及通过给药聚阳离子化合物治疗或预防与血管发生有关的疾病的方法。本发明涉及用于抑制哺乳动物包括动物和人中血管发生介导的病症的有用方法和组合物。此外,本发明涉及聚阳离子与其他抗血管发生剂组合使用,用于治疗不同的血管发生介导的病症。另外,所述聚阳离子化合物能与多种抗炎剂和细胞毒素剂以及放射治疗剂联合用于癌症患者,预防和治疗肿瘤生长和转移。
Description
相关申请的参照:本申请要求于2004年6月15日提交的,题目为“利用聚阳离子化合物调节血管发生”的美国临时申请系列第60/579,282号,其全部内容在此引入作为参考。
发明背景
血管发生是从已经存在的血管中发育新的血管。生理学上,血管发生确保成熟生物体的适当发育,准备卵子植入的子宫,并且在伤口愈合、骨折恢复以及妊娠的建立和维持中发挥重要作用。血管发生也与病理疾病相关,这些病理疾病与一些疾病状态如癌症、炎症和眼病相关。
血管发生或“新生血管形成”是受到前生成血管因子和抗生成血管因子的平衡的控制的多步骤过程。该过程的后面阶段涉及内皮细胞(EC)的增殖和组织成为管样结构。生长因子(例如成纤维生长因子2(FGF2)和血管内皮生长因子(VEGF))认为在促进内皮细胞生长和分化中是重要的参与者。内皮细胞是血管发生过程的关键组分,并且通过其细胞表面受体和细胞内信号转导机制对许多细胞因子做出反应。
血管发生的控制是复杂的过程,该过程涉及血管生长因子、细胞外基质粘附分子和代谢因子的原位释放。血管中的机械力也起作用。涉及新血管生长的内源生长因子的主要分类是成纤维生长因子(FGF)家族和血管内皮生长因子(VEGF)。促分裂原活化蛋白激酶(MAPK;ERK1/2)信号转导级联涉及在VEGF基因表达和血管内皮细胞分化的控制中。
如果在特定的时间,在一些条件下或特定组织中能够阻止毛细血管的生长和延长,许多疾病和不期望的病症能够受到预防或缓解。可被此处公开的本发明治疗的依赖血管发生的疾病是要求或诱导血管生长的那些疾病/病症。另一方面,在将要建立或延伸血管化作用情形下,例如,但不限于,中风、心脏病、溃疡、硬皮病和不育,促进血管生长是期望的。
已有提议对血管发生的抑制将是限制不受调节的血管生长的有效疗法,例如,在肿瘤生长中。如Folkman等人,Cancer Biology 3:89-96(1992)所建议,通过抑制内皮细胞对生成血管刺激的响应,可以实现对血管发生的抑制,其中描述了内皮细胞响应抑制剂的实例,例如血管生成抑制甾醇(angiostatic steroids)、真菌性衍生产物(例如烟曲霉素(fumagilin))、血小板因子4、血小板反应素、α-干扰素、维生素D类似物和D-青霉胺。对于其它建议的血管发生抑制剂,参见Blood等人,Bioch.Biophys.Acta 1032:89-118(1990),Moses等人,Science 248:1408-1410(1990),和美国专利第5,092,885、5,112,946、5,192,744和5,202,352号。
抑制不期望的血管发生过程可以提供对抗不适当或不期望血管发生的治疗性疗法和/或预防措施。相反的,促进血管发生过程可以提供对那些从血管发生中获益的疾病状态的治疗方法。此处公开的本发明的方面提供具有抗血管发生性质的两亲化合物,例如聚阳离子化合物。抑制血管发生的能力可以提供调节生成血管的疾病和/或病症的有效治疗工具。
发明概述
本发明的一个方面涉及有用于调节血管发生的聚阳离子化合物和包含聚阳离子化合物的组合物。聚阳离子
本发明的另一个方面涉及在需要的动物或人中调节血管发生的方法,包括给所述的动物给药治疗有效量的聚阳离子化合物。
本发明的其它方面还涉及在需要的动物或人中治疗或预防疾病或紊乱的方法,包括给所述的动物给药治疗有效量的聚阳离子化合物。
附图描述
本专利的文件包含至少一个带有颜色制成的照片或附图。经过要求并支付必要费用,可由专利商标局提供本发明带有颜色的附图或照片的复制件。
图1描述了在血管发生的CAM模型中聚阳离子化合物的效果。
图2是描述本发明聚阳离子化合物对凝血因子Xa抑制百分数的柱状图。
图3是描述本发明聚阳离子化合物,化合物110002,在凝固时间上的效果的图。
发明详述
在描述本发明的方法和化合物之前,应当理解本发明不限于所描述的特定分子、组合物、方法学或实验方案,因为这些可以变化。也可以理解的是在描述中所使用的术语仅是为了描述特定的版本或实施方案,并且不意图限制本发明的范围,本发明的范围仅由附加的权利要求书限定。
也必须指出的是,如在此处和附加权利要求书中所使用的,单数形式“一”、“一”和“一”包括复数涵义,除非上下文中清楚地另外指出。因此,例如“细胞”的涵义是一个或多个细胞或本领域技术人员所公知的等同物,等等。除非另有定义,此处所使用的所有技术或科学术语具有本领域普通技术人员所通常理解的相同含义。尽管与此处描述的类似或等同的任意方法和物质能够用于实践或测试本发明的实施方案,现在描述优选方法、装置和物质。此处提及的所有出版物在此引入作为参考。在此没有什么应解释成一种许可:由于现有的发明,本发明没有资格写上如此提早的日期的公开内容。
如此处所使用,术语“约”是指待用数的数值加或减10%。因此,约50%是指45%-55%的范围。
术语“血管发生”或“新生血管形成”指的是从现有的血管组织(例如脉管系统)中产生新的血液供给,例如,毛细血管、血管、和静脉。血管发生的过程可以涉及大量的组织细胞类型包括,例如,用来形成所有血管单细胞层衬里并涉及调节血液和外围组织之间交换的内皮细胞。新血管(血管发生)可以通过内皮细胞的向外生长从现有的小血管壁处发育。血管发生也涉及肿瘤生长,因为它为肿瘤细胞存活和增殖(生长)提供给肿瘤所必需的血液供给。
术语“患者”和“受试者”意指所有的动物包括人类。患者或受试者的实例包括人、牛、狗、猫、山羊、绵羊、和猪。
药学组合物中参照的“治疗有效量”为足够减少或预防与医学病症或衰弱有关症状的量,使得导致躯体功能特定损害的疾病或病症中的躯体功能正常化,或者提供该疾病的一或多个临床测量参数的改善。涉及本申请时,聚阳离子化合物的治疗有效量为足够减少或抑制血管发生的量。
本发明的方面涉及在有需求的动物中调节血管发生的方法,包含给药该动物治疗有效量的聚阳离子化合物。本发明的方面也涉及治疗或预防有需求动物中的疾病或病症的方法,包含给药该动物治疗有效量的聚阳离子化合物。
一般地,聚阳离子化合物优选具有刚性或半刚性骨架,以致该结构为扭转束缚的,在骨架的一面显示出阳电荷侧基。阳电荷侧基最佳为沿着骨架长度分布并且最佳由碳间隔段与骨架分离,碳间隔段可以任选含有一或多个杂原子。沿着骨架的扭转自由度可以通过分子内的氢键、空间限制或环化而稳定。当描述优选的多种聚阳离子化合物(例如芳香胺、酰肼、杯芳烃(calixrene)和水杨酰胺)时,可以用来稳定阳电荷的其他合适的侧基,包括,例如,(A-G):
可以使用的其他胺包括,例如,哌啶、4-氨基吡啶、吗啉和氨基噻唑。任选地,氨基的碱性可以通过在链的一个亚甲基上掺入1或2氟而调节。也可以用于硬化骨架(减少扭转自由度)的其他中心环取代物包括,例如(H-K):
在本发明的一个实施方案中,聚阳离子化合物为下式的芳香胺低聚体化合物:
其中X为O或S;
R1为C1-C9直链或支链烷基,其中R1任选被一或多个-NH2或
取代;
Y为键或
Z为键或
R2为氢或C1-C9直链或支链烷基;其中R2任选被一或多个-NH2或
取代,或R2为-X-R1;
R3为
或亚甲基,其中所述的亚甲基被C1-C9直链或支链烷基取代,其中所述的C1-C9直链或支链烷基任选被一或多个-NH2或
取代;
n为2-10;和
m为1或2。
在本发明另一实施方案中,芳香胺低聚体化合物为下式化合物:
其中R1为
在优选实施方案中,该化合物为下式的芳香胺:
X为O或S;
Y为O或S;
R1为H或-C(=O)-A,A为C1至C9直链或支链烷基,其中A任选被一或多个-NH2、-N(CH3)2或
取代;
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R3为C1至C9直链或支链烷基,其中R3任选被一或多个-NH2、-N(CH3)2或
取代;
R4为H、-B或-C(=O)-O-B,其中B为C1至C9直链或支链烷基。
在另一个实施方案中,聚阳离子化合物为下式的酰肼:
其中
n=1-10;
X为O或S;
Y为O或S;
Z为键、C1至C9直链或支链烷基、或1,4-环己基
R1为NH2或NH-A,其中A为C1至C9直链或支链烷基,其中A任选被-NH2、-N(CH3)2或
取代;
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R3为C1至C9直链或支链烷基,其中R3任选被一或多个-NH2、-N(CH3)2或
取代;
R4为H或
在本发明另一实施方案中,聚阳离子化合物为下式的杯芳烃:
其中
n=2-8,更优选4-8;
X为键、O或-O-CH2-C(=O)-O-;
R1为-A或-O-A,其中A为C1至C9直链或支链烷基;
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或取代。
在本发明另一个实施方案中,聚阳离子化合物为下式的水杨酰胺:
n为2~10;
R2为H或
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R3为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R4为OH、NH2或
其中A为OH或NH2。
在进一步的实施方案中,聚阳离子化合物选自:化合物1、化合物2、化合物3、化合物4、化合物5、化合物6、化合物7、化合物8、化合物9、化合物10、化合物11、化合物12、化合物13、化合物14、化合物15、化合物16、化合物17、化合物18、化合物19、化合物20、化合物21、化合物22、化合物23、化合物24、化合物25、化合物26、化合物27、化合物28、化合物29、化合物30、化合物31、化合物32、化合物33、化合物34、化合物35、化合物36、化合物37、化合物38、化合物39、化合物40、化合物41、化合物42、化合物43、化合物44、化合物45、化合物46、化合物47、化合物48、化合物49、化合物50、化合物51、化合物52、化合物53、化合物54和化合物55,参见以下表1中所描述。
当化合物1和化合物2包含同样的芳香胺结构时,化合物1和化合物2是在不同的条件下合成的并表现出不同的纯度。聚合期间,化合物2使用DCM(二氯甲烷)为溶剂而化合物1使用NMP(1-甲基-2-吡咯烷酮)为溶剂。NMP中聚合有更少效率,因此,化合物1为n=2~10,而化合物2为n=10。
表1.聚阳离子化合物
在更优选的实施方案中,聚阳离子化合物包含化合物26、化合物28、化合物29、化合物34、化合物48、或化合物50或它们的组合。
本发明方法中有用的其他聚阳离子化合物是那些描述在2002年3月7日申请的题目为“作为抗感染剂的表面两亲聚合物”WO 02/072007中的、在2002年3月7日申请的题目为“作为抗感染剂的表面两亲聚合物”WO 02/100295中的和在2004年3月17日申请的题目为“表面两亲聚合物和低聚物及其用途”WO 04//082634中的聚阳离子化合物。
在另一个实施方案中,提供用于调节血管发生的化合物,其包含治疗有效量的聚阳离子化合物。
在本发明的一个实施方案中聚阳离子化合物为下式的芳香胺低聚体化合物:
其中为O或S;
R1为C1-C9直链或支链烷基,其中R1任选被一或多个-NH2或
取代;
Y为键或
Z为键或
R2为氢或C1-C9直链或支链烷基;其中所述的R2任选被一或多个-NH2或
取代、或R2为-X-R1;
R3为
或亚甲基,其中所述的亚甲基被C1~C9直链或支链烷基取代,其中所述的C1~C9直链或支链烷基任选被一或多个-NH2或
取代;
n为2-10;和
m为1或2。
在优选实施方案中,该化合物为下式的芳香胺:
X为O或S;
Y为O或S;
R1为H或-C(=O)-A,A为C1至C9直链或支链烷基,其中A任选被一或多个-NH2、-N(CH3)2或
取代;
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R3为C1至C9直链或支链烷基,其中R3任选被一或多个-NH2、-N(CH3)2或
取代;
R4为H、-B或-C(=O)-O-B,其中B为C1至C9直链或支链烷基。
在另一个实施方案中,聚阳离子化合物为下式的酰肼:
n=1~10;
X为O或S;
Y为O或S;
Z为键、C1至C9直链或支链烷基、或1,4-环己基
R1为NH2或NH-A,其中A为C1至C9直链或支链烷基,其中A任选被-NH2、-N(CH3)2或
取代;
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R3为C1至C9直链或支链烷基,其中R3任选被一或多个-NH2、-N(CH3)2或
取代;
R4为H或
在另一实施方案中,聚阳离子化合物为下式的杯芳烃:
n=2-8,更优选4-8;
X为键、O或-O-CH2-C(=O)-O-;
R1为-A或-O-A,其中A为C1至C9直链或支链烷基;
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代。
在本发明另一个实施方案中,聚阳离子化合物为下式的水杨酰胺:
n为2~10;
R1为H或
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R4为OH、NH2或
其中A为OH或NH2。
在优选的实施方案中,化合物包含化合物1、化合物2、化合物3、化合物4、化合物5、化合物6、化合物7、化合物8、化合物9、化合物10、化合物11、化合物12、化合物13、化合物14、化合物15、化合物16、化合物17、化合物18、化合物19、化合物20、化合物21、化合物22、化合物23、化合物24、化合物25、化合物26、化合物27、化合物28、化合物29、化合物30、化合物31、化合物32、化合物33、化合物34、化合物35、化合物36、化合物37、化合物38、化合物39、化合物40、化合物41、化合物42、化合物43、化合物44、化合物45、化合物46、化合物47、化合物48、化合物49、化合物50、化合物51、化合物52、化合物53、化合物54、化合物55、或它们的组合。
在更优选的实施方案中,化合物包含化合物26、化合物28、化合物29、化合物34、化合物48、或化合物50或它们的组合。
水杨酰胺聚阳离子化合物可以如下合成:
在另一个实施方案中,提供用于调节血管发生的化合物,其包括治疗有效量的聚阳离子化合物。
在一个实施方案中,化合物可以含有治疗有效量的聚阳离子化合物用于促进血管发生。在优选的实施方案中,化合物可以含有治疗有效量的聚阳离子化合物用于抑制血管发生。
在优选实施方案中,该化合物为下式的芳香胺:
X为O或S;
Y为O或S;
R1为H或-C(=O)-A,A为C1至C9直链或支链烷基,其中A任选被一或多个-NH2、-N(CH3)2或
取代;
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CHz3)2或
取代;
R3为C1至C9直链或支链烷基,其中R3任选被一或多个-NH2、-N(CH3)2或
取代;
R4为H、-B或-C(=O)-O-B,其中B为C1至C9直链或支链烷基。
在另一个实施方案中,聚阳离子化合物为下式的酰肼:
n=1~10;
X为O或S;
Y为O或S;
Z为键、C1至C9直链或支链烷基、或1,4-环己基
R1为NH2或NH-A,其中A为C1至C9直链或支链烷基,其中A任选被-NH2、-N(CH3)2或
取代;
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R3为C1至C9直链或支链烷基,其中R3任选被一或多个-NH2、-N(CH3)2或
取代;
R4为H或
在本发明另一实施方案中,聚阳离子化合物为下式的杯芳烃:
n=2-8,更优选4-8;
X为键、O或-O-CH2-C(=O)-O-;
R2为-A或-O-A,其中A为C1至C9直链或支链烷基;
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代。
在本发明另一个实施方案中,聚阳离子化合物为下式的水杨酰胺:
n为2~10;
R1为H或
R2为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R3为C1至C9直链或支链烷基,其中R2任选被一或多个-NH2、-N(CH3)2或
取代;
R4为OH、NH2或
其中A为OH或NH2。
在本发明的一个方面,本发明的聚阳离子化合物可以有益于治疗与血管发生有关的疾病或病症。在优选实施方案,化合物包含治疗有效量的化合物26、化合物28、化合物29、化合物34、化合物48、或化合物50或它们的组合。
在本发明另一实施方案中,聚阳离子化合物可以用于治疗或预防与不足的血管发生有关的疾病或病症。这样的疾病包括,例如,中风、心脏病、溃疡、不育和硬皮病。
在本发明一个实施方案中,聚阳离子化合物可以用于治疗或预防与过度的血管发生有关的疾病或病症。这样的疾病包括,例如,癌、类风湿性关节炎、艾滋病并发症、牛皮癣和失明。
普遍地,癌指的是异常的和不受控制的细胞分裂引起的任何恶性赘生物或肿瘤;它可以通过淋巴系统或血流扩散到身体的其他部分。癌包括实体瘤和血液携带瘤(blood-borne tumors)。实体瘤包括,例如但不限于卡波济氏肉瘤、肝血管瘤、实体瘤、血液携带瘤、乳腺癌、肺癌、卵巢癌、睾丸癌、结肠癌、横纹肌肉瘤、视网膜成神经细胞瘤、尤因氏肉瘤、成神经细胞瘤、和骨肉瘤。血管发生也与血液携带瘤有关,例如白血病,骨髓的任何种急性或慢性肿瘤性疾病,其中白细胞出现无限制的增殖,通常伴随贫血、受损的血液凝固、和淋巴结、肝和脾的增大。相信血管发生在引起白血病样肿瘤的骨髓异常情况下发挥作用。
在本发明的再一个实施方案中,疾病或病症为肺癌、乳腺癌、前列腺癌、结肠癌、肾癌、膀胱癌、胰腺癌、成胶质细胞瘤、成神经细胞瘤、失明、黄斑变性、糖尿病性视网膜病、角膜移植、近视性变性、艾滋病相关的并发症、关节炎、类风湿性关节炎、牛皮癣、硬皮病、炎性肠病、中风、心脏病、溃疡和不育。例如,但不受其限制,癌、炎性关节炎(例如类风湿性关节炎)、糖尿病性视网膜病、以及眼睛的其他新生血管性疾病(例如角膜新生血管形成、新生血管性青光眼、晶状体后纤维组织增生症和黄斑变性)、动静脉畸形、过量流血疾患(月经过多)、Osler-Webber综合症、心肌血管发生、斑块新生血管形成(plaque neovascularization)、毛细血管扩张、血友病的关节、血管纤维瘤、和伤口肉芽发生。在此处提供抗生成血管的组合物也有益于治疗内皮细胞过度或异常兴奋的疾病。这些疾病包括但不限于为肠粘连、克隆氏病、动脉粥样硬化、硬皮病、和肥大性瘢(即瘢痕疙瘩)。
可以用所提供的聚阳离子化合物治疗或预防的其他适合的血管发生-介导的病症包括但不限于:肿瘤和癌有关的病症(例如,视网膜肿瘤生长、良性肿瘤(例如血管瘤、听神经瘤、神经纤维瘤、沙眼、和脓性肉芽肿)、实体瘤、血液携带瘤(例如白血病、血管纤维瘤、和卡波西肉瘤)、瘤转移、和要求新生血管形成以支持肿瘤生长的其他癌)、眼睛新生血管性病症(例如糖尿病性视网膜病、黄斑变性、早产儿视网膜病、新生血管性青光眼、角膜移植片排斥、和其他的眼睛血管发生-介导的病症)、炎性病症(例如免疫和非免疫炎症、类风湿性关节炎、慢性关节风湿病、炎性肠疾病、牛皮癣、和其他的慢性炎性病症)、子宫内膜异位、其他的与不适当的或不合时机的血管侵袭有关的病症(如晶状体后纤维组织增生症、潮红、和动脉粥样硬化斑块与骨质疏松症中的毛细管增殖)、Osler-Webber综合征、心肌血管发生、斑块新生血管形成、毛细血管扩张、血友病的关节、和伤口肉芽发生。本领域技术人员已知血管发生在其中担任维持或增进病理状态作用的其他疾病,同样地被意图包括在此处使用的血管发生-介导的术语的含义内。
在一个实施方案中,聚阳离子化合物与其他的血管发生抑制剂结合使用。生成血管抑制剂在本领域内是已知并能由已知的方法制得。生成血管抑制剂和靶子的说明参见,例如Chen等,Cancer Res.55:4230-4233(1995);Good等,Proc.Natl.Acad.Sci.USA87:6629-6628(1990);O′Reilly等,Cell 79:315-328(1994);Parangi等,Proc.Natl.Acad.Sci.USA 93:2002-2007(1996);Rastinejad等,Cell 56:345-355(1989);Gupta等,Proc.Natl.Acad.Sci.USA 92:7799-7803(1995);Maione等,Science 247:77-79(1990);Angiolillo等,J.Exp.Med.182:155-162(1995);Strieter等,Biochem.Biophys.Res.Comm.210:51-57(1995);Voest等,J.Natl.Cancer Inst.87:581-586(1995);Cao等,J.Exp.Med.182:2069-2077(1995);和Clapp等,Endocrinology 133:1292-1299(1993);它们的全部内容在此引入作为参考。至于另外的生成血管抑制剂的说明参见,例如Blood等,Bioch.Biophys Acta.,1032:89-118(1990);Moses等,Science,248:1408-1410(1990);Ingber等,Lat Invest.,59:44-51(1988),和美国专利号5,092,885和5,112,946,它们的全部内容在此引入作为参考。
在另一个实施方案中,聚阳离子化合物与其他的治疗结合使用,例如与标准的抗炎疗法、标准的眼睛治疗、标准的皮肤治疗、放射疗法、肿瘤外科手术、和直接抗实体瘤并控制转移灶建立的常规化学疗法结合。一般地在化学疗法期间或之后的某时进行给药血管发生抑制剂,此时肿瘤组织将通过诱导血管发生对毒性袭击产生响应,并通过供应血液补给和营养素至肿瘤组织而使之恢复。另外,优选在切除实体瘤手术后给药血管发生抑制剂作为抗转移预防用药。细胞毒素药物或化学治疗药物是本领域已知的那些药物,例如氮丙啶塞替派、烷基磺酸酯、亚硝基脲、铂合成物、一氧化氮类烃化剂、叶酸类似物、嘌呤类似物、腺苷类似物、嘧啶类似物、取代的脲、抗肿瘤抗生素、微管药物、和asprignase。
本发明的另一方面涉及聚阳离子化合物在抑制血管发生-介导的进程中的用途,可以单独使用或者与其他的现有抗炎药、抗血管发生、抗癌、和眼睛治疗并用。聚阳离子化合物代表一种有效的策略,用来预防和治疗癌、炎症、和眼睛疾病中的血管发生-介导的病症。
上述化合物可以以制剂给予,该制剂中包括聚阳离子化合物和衍生物以及用于给药方式的可接受的载体。含有该活性成份的任何制剂或药物递送系统能被使用(这是适合预期用途的),如本领域技术人员普遍知道的。本领域技术人员已知用于口腔、直肠、局部或肠胃外(包括皮下、腹膜内、肌内和静脉)给药的适合的药学上可接受的载体。载体必须是药学上可接受的,意为与制剂的其他成份相容的并对其接受者没有毒的。
适合肠胃外给药的制剂适宜地包括活性化合物的无菌水制剂,优选与接受者血液的等渗制剂。因此,这种制剂可以合宜地含有蒸馏水、5%的葡萄糖蒸馏水液或盐水。有用的制剂也包括含有式(I)化合物的浓溶液或固体制剂,然后用适当的溶剂稀释可得到适合上面的肠胃外给药的溶液。
至于肠内给药,化合物可以掺入惰性载体中形成分离的单元,例如胶囊、扁胶囊、片剂或锭剂,其各含有预定量的活性化合物;例如粉剂或颗粒剂;或混悬液或者水溶液或非水溶液(例如糖浆、酏剂、乳剂或顿服剂)。适合的载体可以是淀粉或糖并且包括润滑剂、调味剂、粘合剂、和同样性质的其他物质。
片剂可以压制或模制,任选地含有一或多种助剂。压制片剂可以在适合的压片机通过压紧活性化合物制得,其中活性化合物为自由流动的形式,例如粉末或颗粒,并任选地混合助剂例如粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂。模制片可以在适合的机器中把粉状的活性化合物与任何适合的载体的混合物放在模子里制成。
糖浆或混悬液的制备为:将活性化合物加至浓缩的、糖(例如蔗糖)水溶液中,其中也可以加入任何助剂。这种助剂可以包括调味剂、延缓糖结晶剂或增加任何其他成分溶解性的剂,例如多元醇如甘油或山梨醇。
用于直肠给药的制剂可以作为栓剂出现,具有常规的载体,例如可可脂或WitepsolS55(德国Dynamite Nobel Chemical的商标名)用作栓剂基质。
选择地,化合物可以以脂质体或微球(或微粒)给药。本领域技术人员众所周知制备给患者给药的脂质体和微球的方法。美国专利第4,789,734号描述了将生物材料装入脂质体的方法,其内容在此引入作为参考。大体上,这种材料被溶于水溶液中,适当的磷脂和类脂被加入,如果需要的话随同加入表面活性剂,需要时将材料透析或超声。已知方法的综述参见G.Gregoriadis,第14章,“Liposomes,”Drug Carriers in Biologyand Medicine,pp.287-341(Academic Press,1979)。
聚合物或蛋白质构成的微球或毫微球是本领域技术人员众所周知的,并能够适用于使之通过胃肠道直接进入血液。选择地,可以掺入化合物,并将微球/毫微球或两者的复合物植入用于数天至数月范围内缓释。参见,例如美国专利第4,906,474、4,925,6733,625,214号以及Jein,TIPS 19:155-157(1998),在此引入这些中的内容作为参考。
本发明聚阳离子化合物在体外和体内均显示抗生成血管效果。另外,本发明聚阳离子化合物显示对抗肝素的拮抗效应。虽然不希望受理论所束缚,聚阳离子化合物的抗生成血管效果可能归因于,至少部分归因于聚阳离子化合物能够对抗肝素在促进FGF和VEGF受体激活中的作用。
为了下列实施例,可如下获得各种材料。所有的试剂为化学纯并购自SigmaChemical Co.(St.Louis,MO)或者通过VWR Scientific(Bridgeport,NJ)获得。醋酸可的松、牛血清白蛋白(BSA)、和明胶溶液(2%牛皮肤的B型)购自Sigma Chemical Co.(St.Louis,MO)。具有Earl′s盐的M199菌种生长培养基、碱性FGF、胰岛素-转铁蛋白-硒-G补充物(I-T-Se)100X、含有或不含有Ca+2和Mg+2的Dulbecco′s磷酸盐缓冲盐溶液(PBS)、和0.5M EDTA来自Gibco BRL(Grand Island,NY)。人脐静脉内皮细胞(HUVEC)、内皮细胞基础培养基(无血清的,EBM),内皮生长培养基(EGM)(补充生长因子、胎牛血清)、和0.025%胰蛋白酶/0.01%EDTA溶液购自Clonetics Inc.(San Diego,CA)。人的前列腺(TSU-Pr)肿瘤细胞获自American Type Culture Collection(Rockville,MD)。Matrigel基质和人胶原III型购自Becton Dickinson(Bedford,MA)。HEMA-3固定剂和染色液购自Biochemical Sciences,Inc.(Swedesboro,NJ)。受精的鸡蛋购自Charles River实验室,SPAFAS Avian Products & Services(North Franklin,CT)。体内新生血管形成的检测是通过Auerbach等以前描述的方法进行的(Auerbach等,J.Dev.Biol.,41:391-394(1974),其全部内容在此引入作为参考)。
实施例1
以下的实例说明本发明示例性的聚阳离子化合物的抗生成血管的效果。将购自Spafas,Inc.(Preston,CT)十天龄的胚胎于37℃、55%相对湿度下孵育。在黑暗中透光检验灯的帮助,用皮下针刺入外壳形成一个小孔,用来隐蔽气囊。当在透光检验观察下,在蛋较宽的一面刺入外壳形成第二个小孔,它直接穿过胚胎薄膜的无血管的部分。通过应用负压至第一个孔而在第二个孔下建立假气囊,这使得绒毛膜尿囊膜(CAM)与壳分离。使用小工艺砂轮(Dremel,Division of Emerson Electric Company Racine,Wisconsin)在壳上越过脱落的CAM切出大约1.0cm2的窗孔,允许直接接近下面的CAM。将#1滤纸的滤片(Whatman International,United Kingdom)浸泡在含3mg/mL醋酸可的松(Sigma,St.Louis,MO)的95%乙醇和水的溶液中随后在无菌条件空气干燥。用在十天龄的鸡胚CAM上使用FGF2(Life Technologies,Gaithersburg,Maryland)以生长血管。将吸附溶于PBS的1μg/mL FGF2的无菌滤片置于正生长的CAM上。将吸附溶于PBS的1μg/mL FGF2中的无菌滤片置于正生长的CAM上。在第24小时,将测试化合物或对照载体直接局部地加至CAM。
将直接位于FGF2-饱和的滤片下面的CAM组织用测试化合物或对照处理48小时后,从胚中切除。将组织用PBS洗涤三次。将切片放入35-mm有盖培养皿(Nalgen Nunc,Rochester,New York)中,并在SV6立体显微镜(Karl Zeiss,Thomwood,New York)下以50X的放大倍数检测。通过使用3-CCD彩色照相机系统(Toshiba America,New York,NY)收集邻近滤纸的CAM切片的数字图像,并使用Image-Pro Plus软件(MediaCybernetics,Silver Spring,MD)分析。表4含有包含在环状区域的血管分支点的数目,该区域等于每个切片计算的滤片面积。
将直接位于FGF2-饱和的滤片下面的CAM组织用化合物或对照处理48小时后,从胚中切除。将组织用PBS洗涤三次。将切片放入35-mm有盖培养皿(Nalgen Nunc,Rochester,New York)中,并在SV6立体显微镜(Karl Zeiss,Thomwood,New York)下以50X的放大倍数检测。通过使用3-CCD彩色照相机系统(Toshiba America,New York,NY)收集邻近滤纸的CAM切片的数字图像,并使用Image-Pro Plus软件(MediaCybernetics,Silver Spring,MD)分析。聚阳离子化合物对血管发生的效果显示在表2、3和4中。这种效果也显示在图1中。
表2:聚阳离子化合物在CAM模型中抗血管发生的效力
CAM处理 | 分支点±SEM | 抑制%±SEM |
PBS(对照) | 69±16.0 | |
FgF(1.0ug/ml) | 155±10 | |
化合物29(1.2ug)+FGF2(1ug ) | 82±5 | 85±6 |
数据表示平均数+SEM,n=8
表3:聚阳离子化合物在CAM模型中抗血管发生的效力
分支点±SEM | 抑制%±SEM | |
CAM处理 | ||
PBS(对照) | 80±7 | |
FgF2(1.0ug/ml) | 177±10 | |
化合物26(1.0ug)+FGF2(1ug) | 123±7 | 55±8 |
化合物34(1.0ug)+FGF2(1ug) | 156±9 | 21±9 |
化合物40(0.1ug)+FGF2(1ug) | 142±6 | 36±6 |
化合物36(1.0ug)+FGF2(1ug) | 156±6 | 21±6 |
化合物33(1.0ug)+FGF2(1ug) | 160±18 | 17±18 |
化合物27(0.1ug)+FGF2(1ug) | 144±9 | 34±9 |
表4.聚阳离子化合物在CAM模型中抗血管发生的效力
处理组 | 平均抑制%±SEM |
PBS(对照) | |
FGF2(1.0ug/ml) | |
化合物50(1.0ug)+FGF2(1ug) | 21±9 |
化合物50(3.0ug)+FGF2(1ug) | 42±8 |
化合物50(10ug)+FGF2(1ug) | 66±7 |
化合物48(1.0ug)+FGF2(1ug) | 16±6 |
化合物48(3.0ug)+FGF2(1ug) | 38±8 |
化合物48(10ug)+FGF2(1ug) | 55±7 |
数据表示平均数±SEM,n=8
如上表2,3和4所述,在血管发生的CAM模型中聚阳离子化合物阻滞FGF2-诱导的血管发生。
实施例2
以下的实例说明本发明聚阳离子化合物对内皮细胞管生成的抑制。使用Grant等开发的方法(Grant等,In Vitro Cell Dev.Biol.,27A:327-336(1991)检测内皮细胞的分化。无酚红的Matrigel基质(商业上可得自Becton Dickinson,Bedford,MA)在4℃下融化过夜。使用冷的吸管尖头,将3.0mg/孔Matrigel基质放入冷的24孔板。在37℃下孵育30分钟期间允许Matrigel基质聚合。
在37℃、5%CO2和95%湿度下将人脐静脉内皮细胞(HUVEC)维持在带有2%胎牛血清(EGM)的内皮细胞生长液中。内皮细胞基础培养基(EBM)中执行管测定,用0.5%牛血清白蛋白(BSA)和1∶100稀释的胰岛素-转铁蛋白-硒-G补充物(I-T-Se,100X)补充培养基。将胰蛋白酶作用于HUVEC,离心,随后在磷酸盐缓冲盐水(PBS)中洗涤两次。计数后,调节细胞密度至35,000个细胞/mL。
用溶于EBM介质中的100ng/ml的重组人成纤维细胞生长因子要素(FGF2)和聚阳离子化合物(参见表1B)处理终浓度为35,000个细胞/mL/孔。处理过的细胞在37℃、5%CO2和95%湿度下孵育过夜,允许细胞相附。
随后,将培养基吸气,固定细胞并使用改良的HEMA-3染色试剂盒使之染色。使用DKC5000 3-CCD彩色照相机系统(Toshiba America,New York,NY)收集微滴定孔切片的数字图像,并使用Image-Pro Plus软件(Media Cybernetics,Silver Spring,Maryland)分析。在Matrigel基质表面(Becton Dickinson,Bedford,PA)测量具有管形的染色细胞的面积和主轴长度,每孔5个图像中计算。
如下表5说明,在体外聚阳离子化合物为有效的EC管生成的抑制剂。
表5.聚阳离子化合物在人内皮管生成测定中抗血管发生的效力
处理组 | 平均抑制%±SEM |
化合物29(0.01ug) | 25±7 |
化合物29(0.1ug) | 42±5 |
化合物29(1.0ug) | 76±6 |
数据表示平均数±SEM,n=3
实施例3
本实施例涉及细胞的迁移测定。使用8μm孔径的Neuroprobe96孔一次性的趋化性容器执行这些测定。本容器允许定量测定细胞向玻璃体结合蛋白或者向骨桥蛋白梯度迁移。遵循标准方法使用EDTA/胰蛋白酶(0.01%/0.025%)移开培养细胞。移开随后,将细胞洗涤两次,重悬浮(2×106/ml)于EBM(内皮细胞基础培养基,Clonetics Inc.)中。将0.0125-100μg/ml玻璃体结合蛋白或者骨桥蛋白(33μl)加至一次性的趋化性容器的更低的孔中,然后使用预装配过滤器收集。将细胞悬液(45μl)加至含有5μl不同浓度测试剂的聚丙烯板中,并在22℃孵育10分钟。将25μl细胞/测试剂混悬液加至较高的过滤器孔中,然后在增湿的细胞培养保温中箱孵育过夜(37℃下22小时)。孵育过夜后,使用12槽吸量管和细胞刮棒轻轻地移开非迁移细胞和过量培养基。然后在PBS(无Ca+2或Mg+2)中将过滤器洗涤两次,用1%甲醛固定。用Triton X-100(0.2%)渗透迁移细胞的细胞膜然后用PBS洗涤2-3次。用玫瑰红毒伞素(12.8IU/ml)将迁移细胞的肌动蛋白丝染色30分钟(22℃)。每周新鲜配制玫瑰红毒伞素并且在4℃避光贮存下至多重复使用3天。使用细胞荧光素II(530激发/590发射)由荧光检测定量地测定趋化性。使用独特设计处理/洗涤站进行所有的细胞处理和随后的洗涤。该站包括6个单独的试剂单元,每个具有30ml容积容量。单独的单元充满下列试剂之一:PBS、甲醛、TritonX-100、或玫瑰红毒伞素。使用这种技术,过滤器被轻轻地浸泡适当的溶液中,因此,将迁移细胞的损失减到最少。这种技术允许细胞迁移的最大定量并提供可再现的结果,具有最小的内部和彼此之间测定差异(Bozarth等,Methods In Cell Science,19(3):179-187,1997;Penno等J.Method InCell Science,19(3):189-195,1997。
如下表6所说明,本发明聚阳离子化合物抑制人脐静脉内皮迁移。
表6.聚阳离子化合物在人内皮细胞迁移测定中的效果
处理组 | 平均抑制%±SEM |
化合物29(0.01uM) | 19±2 |
化合物29(0.1uM) | 40±3 |
化合物29(1.0uM) | 67±5 |
数据表示平均数±SEM,n=3
实施例4
以下的实例说明本发明聚阳离子化合物的肝素拮抗效应。为了测定聚阳离子化合物的抗肝素活性,使用聚阳离子化合物的固定浓度或引起人红细胞50%溶解的聚阳离子化合物的浓度,执行一种测量抑制百分数的测定。
将10IU的抗凝血酶溶于10ml缓冲液中,形成1IU/ml的抗凝血酶母液(250x)。将1IU/ml(250x)的抗凝血酶母液和336mM NaCl母液稀释到总容量50μl缓冲液中,以致最终的抗凝血酶浓度为0.004IU/样品孔和NaCl为150mM/样品孔。1μl用于测试的化合物,终浓度10μg/ml(相应于0.5对数对抗物稀释),被加至样品孔中。将样品混合并允许在室温孵育20分钟。将50μl溶于缓冲液中的凝血因子Xa加至样品孔中,终浓度0.14knat/孔(2μl的7.1knat/ml母液至100μl终样品孔缓冲液体积)。将样品混合并在室温进一步孵育10分钟。将10μl的4mM底物S-2765母液加至每个样品孔中,每个样品孔中的终浓度为0.4mM。将样品混合,水解显色底物Z-D-Arg-Gly-Arg-pNA(S-2765),因此释放发色团pNA(对硝基苯胺),在405nm检验。每30秒混合样品以维持均匀混合。ThermoLabsystems Multiskan Spectrum分光光度计用来测量光谱吸收度。吸收度增加与酶(凝血因子Xa)活性成比例。使用标准曲线测定凝血因子Xa的抑制%。结果描述于表7中。也说明抑制百分数的条线图出现于图2中。
表7.凝血因子Xa抑制%:单一浓度(10ug/ml)
化合物# | 抑制% | 化合物# | 抑制% |
9 | 16.24689847 | 25 | 0 |
10 | 20.80146834 | 26 | 48.14324 |
11 | 1.903402332 | 27 | 8.885942 |
12 | 9.381054349 | 28 | 44.29708 |
13 | 36.84443085 | 30 | 49.96431121 |
24 | 1.835423677 | 31 | 75.45630672 |
5 | 39.767513 | 32 | 23.1127426 |
19 | 59.82121614 | 33 | 32.01794636 |
15 | 5.710206995 | 34 | 99.99660107 |
14 | 40.99112879 | 37 | 62.40440502 |
17 | 15.02328269 | 35 | 79.60300466 |
18 | 13.25583767 | 38 | 65.05557255 |
1 | 22.29699874 | 39 | 56.49026206 |
2 | 41.05910744 | 41 | 7.817545291 |
4 | 0.951701166 | 46 | 59.14142959 |
3 | 2.855103498 | 42 | 79.46704735 |
6 | 2.583188879 | 43 | 59.68525883 |
7 | 5.506271031 | 45 | 77.83565963 |
8 | 7.409673363 | 44 | 74.36864824 |
9 | 10.87658475 | 52 | 45.47772 |
20 | 7.851534618 | 53 | 43.03048843 |
21 | 1.495530403 | 54 | 19.98572448 |
22 | 1.291594439 | 55 | 46.49739982 |
23 | 1.223615785 | 马加宁 | 4.418612556 |
16 | 30.38645865 | 马加宁-T | 23.1127426 |
如图2和上表7所说明,本发明聚阳离子化合物抑制凝血因子Xa。
凝血因子Xa抑制:EC50。为测定引起人红细胞约50%溶解的聚阳离子化合物的浓度,使用固定的肝素浓度和加入不同量的肝素拮抗药。结果描述于表8中。
表8.凝血因子Xa抑制:EC50
化合物 | MW | EC50(μM) | HC50(μg/ml) | HC50(μM) |
化合物27 | 783 | 9.7 | >2,000 | |
化合物25 | 615 | 5.3 | >2,000 | |
化合物26 | 927 | 2.0 | >2,000 | |
化合物7 | 921 | 3.7 | 715 | 519 |
化合物50 | 1126 | 0.36 | 637 | 377 |
化合物48 | 1238 | 0.077 | 261 | 144 |
化合物47 | 933 | 5.54 | ||
化合物51 | 1070 | 16.7 | ||
化合物49 | 849 | 22 |
如上表7中所说明,本发明聚阳离子化合物显示不同程度地抑制凝血因子Xa。
实施例5
以下的实例说明本发明聚阳离子化合物对凝血时间的效果。使用如此描述的抗肝素测定。测定含有1mg/L、2mg/L或者4mg/l肝素和加入渐增量的化合物26。表9和图3描述化合物26对凝血时间的效果。
表9.化合物26对凝血时间的效果和肝素的效力
肝素(mg/L) | 化合物26(mg/L) | 凝血时间(s) | 肝素的效力 |
1 | 0 | 50.8 | 1 |
1 | 1.25 | 42.8 | 0.65065 |
1 | 2 | 33.4 | 0.24017 |
1 | 2.5 | 31.3 | 0.14847 |
1 | 4 | 27.9 | -1,67E-08 |
2 | 0 | 110.8 | 1 |
2 | 2.5 | 40.2 | 0.11083 |
2 | 4 | 33.9 | 0.031486 |
2 | 5 | 31.9 | 0.0062972 |
2 | 6 | 31.8 | 0.0050378 |
2 | 10 | 34.4 | 0.037783 |
4 | 0 | 214.9 | 1 |
4 | 2.5 | 124.8 | 0.51297 |
4 | 4 | 87.4 | 0.31081 |
4 | 5 | 55.8 | 0.14 |
4 | 6 | 35.4 | 0.02973 |
10 | 29.9 | -2.06E-09 |
如以上图3和表9中所说明,化合物26,本发明的一种聚阳离子化合物在不同浓度的肝素中减少凝血时间,证明化合物能够对抗肝素的活性。
尽管在此处已经描述和详细地叙述优选的实施方案,对相关技术领域技术人员来说在没有脱离本发明主旨下能够进行多种修饰、添加、和替换等,这是显而易见的,因此这些被考虑在本发明的范围内,本发明的范围如随后的权利要求中所确定的。根据对本说明书或此处公开的本发明实践的考虑,本发明其他的实施方案对本领域技术人员来说将是显而易见的。意图将说明书和实施例只看作示例,本发明的实际的范围和主旨由下列权利要求所指明。
Claims (14)
3.如权利要求1所述的化合物,其中所述的化合物是
4.如权利要求1所述的化合物,其中所述的化合物是
8.如权利要求6所述的应用,其中所述化合物是
10.下式化合物在制备在需求的动物中治疗或预防与过度的血管发生有关的疾病或病症的药物中的应用:
其中,
X为O或S;
Y为O或S;
R4为H、-B或-C(=O)-B,其中B为C1-C9直链或支链烷基,
其中所述的疾病或病症选自肺癌、乳腺癌、前列腺癌、结肠癌、肾癌、膀胱癌、胰腺癌、成胶质细胞瘤、成神经细胞瘤、失明、黄斑变性、糖尿病性视网膜病、角膜移植、近视性变性、艾滋病相关的并发症、关节炎、类风湿性关节炎、牛皮癣、硬皮病、炎性肠病、中风、心脏病、溃疡和不育。
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