CN1518447A - 作为抗血管生成剂的新的苯邻二甲酰亚胺模拟物的合成和评估 - Google Patents
作为抗血管生成剂的新的苯邻二甲酰亚胺模拟物的合成和评估 Download PDFInfo
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- CN1518447A CN1518447A CNA028124685A CN02812468A CN1518447A CN 1518447 A CN1518447 A CN 1518447A CN A028124685 A CNA028124685 A CN A028124685A CN 02812468 A CN02812468 A CN 02812468A CN 1518447 A CN1518447 A CN 1518447A
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及新的沙利度胺衍生化合物,该化合物具有抗血管生成化合物的活性。特别是,所述化合物具有所述通式结构:其中R1选自H、卤代基、烷基、卤代烷基、-NH2、羟基和烷氧基;R2选自任选取代的二环、任选取代的芳基和R6是H或C1-C8烷基;R19是任选取代的芳基;和m是0-6。
Description
相关申请
本申请根据35 USC§119(e)要求于2001年4月23日提交的美国临时申请顺序号60/285,745和于2001年12月10日提交的美国临时申请顺序号60/338,955的优先权,所述优先权申请的公开内容结合到本文中作为参考。
发明领域
本发明涉及新的取代的苯邻二甲酰亚胺和异喹啉衍生物以及这些衍生物作为治疗药物的用途。已发现这些化合物具有抗血管生成活性。
发明背景
不适当的血管生成是许多疾病状态的原因或加重的因素。例如,与年龄相关的视网膜黄斑变性(ARMD)指窃走中心视力而留下周边视力完整的疾病。所述疾病可以以几种形式出现并影响到大约1/5的65岁以上年龄的人以及1/4的75岁以上的人。这相当于大约2千万美国人。
视网膜黄斑变性有两种类型:干性视网膜黄斑变性和湿性视网膜黄斑变性。干性类型,其中黄斑细胞缓慢开始衰变,90%的黄斑变性病例诊断为此类型。它可以发生在一只眼或双眼。湿性类型,尽管它仅占所述病例的10%,但可以导致90%的人失明。对于湿性类型更糟的情况是,病人开始在黄斑后面有不正常的血管生长。这些血管非常脆弱并渗出液体和血液(由此称为‘湿性’黄斑变性),引起对黄斑的快速损坏。至今没有特效的药物治疗。
由新血管生成(新血管形成)导致的ARMD的湿性类型和其它眼部疾病是导致失明的主要原因之一。因此,特别需要发现新的药物以便治疗所述眼疾病。一种方法是给予药物抗血管生成剂以预防不适当的新血管形成。
新的抗血管生成化合物也具有抗癌药物的效用。恶性肿瘤是以肿瘤的生长和扩散为特征。在该疾病的发展过程中的一个重要因素是血管生成,一个其中毛细血管在有序事件中生长的复杂过程。一旦肿瘤开始生长,肿瘤细胞群的每一次增加必然是新的毛细血管增加在前,所述毛细血管集中在肿瘤上并给细胞提供氧和营养。因此,只要防止激活伴随的血管生长过程,肿瘤可以是对它们所在的组织无害和受到限制的。由于在肿瘤形成过程中血管生长依赖步骤为所有病因学的实体肿瘤所共享,因此,能够抑制与肿瘤相关的血管生成是对抗癌症的有希望的方法。
实验证据的实质性部分支持这样的假设,即肿瘤血管生成是实体肿瘤生长和转移的基础[Folkman,J.Natl.Cancer Inst.,第82卷,第4-6页(1989);N.Weidner等,Amer.J.Pathol.,第143卷,第401-409页(1993)]。的确,大多数实体肿瘤临床不易发现直至出现新生血管形成,在实体肿瘤中的新生血管形成是由一个或更多个生成血管的因素引起。
另外,血管生成在其它一些病理过程中也是重要的,包括关节炎、银屑病、糖尿病性视网膜病、慢性炎症、硬皮病、血管瘤、晶状体后纤维组织形成和血友病者关节中不正常的毛细血管增生、延长的经期和出血,以及其它女性生殖系统的疾病。
因此,需要一些具有如抗血管生成剂活性并且可以安全给予病人以便治疗与生成血管有关的疾病的化合物。本发明涉及一种组合物,它包含抗-血管生成化合物,用于治疗与血管生成有关的疾病以及恶性肿瘤,包括抑制原发性肿瘤的生长、肿瘤的发展和转移。更具体地说,本发明涉及沙利度胺衍生物以及它们作为抗血管生成组合物的用途。
沙利度胺最初作为镇静药,然而,当发现它是潜在的引起严重的胎儿缺陷、特别是影响肢体发育的致畸胎药后,它被停止使用。由沙利度胺导致的肢体畸形(肢体缺陷)是因为抑制了在发育胎儿肢体胚基中的血管生长。尽管其影响的是形成血管(影响毛细血管床的形成),但研究已证实沙利度胺也抗血管生成(影响从先前存在的血管生长部位上形成新的血管床)。当非妊娠的成人服用时,沙利度胺是相对无毒的并且现阶段在第二期临床实验中作为潜在的抗癌药并用于治疗血管性眼疾病如糖尿病性视网膜病、早产儿的视网膜病以及视网膜黄斑变性。
Folkman等(PNAS,91(9):4082-5,1994)已报道沙利度胺具有明显的抗血管生成效果。已有报道(Kruse等,Graefes Archive for Clinical&Experimental Ophthalmology.236(6):461-6,1998)沙利度胺对通过血管内皮生长因子(VEGF)引起的角膜血管生成具有作用。在Kruse等所述中,在兔体内通过载有500或750ng的VEGF的基质内颗粒引起角膜新血管形成。动物接受每天两次喂饲200mg/kg的沙利度胺,治疗第五天后产生角膜血管生成的统计学上有意义的抑制(P<0.0001)。该实验表明沙利度胺对于VEGF诱导的眼新血管生长具有明显的抗血管生成效果。
在碱性成纤维细胞生长因子(bFGF)诱导的兔角膜微囊测定和在小鼠模型的口服测定中,也已经证实了沙利度胺对于血管生成的抑制效果(Joussen等,Graefes Archive for Clinical & ExperimentalOphthalmology.237(12):952-61,1999和Kenyon等,Experimental EyeResearch.64(6):971-8,1997)。已报道沙利度胺和沙利度胺类似物(cc-1069)抑制体外内皮细胞增殖(该细胞构成血管系统)。所述研究的结果揭示在用沙利度胺和/或cc-1069处理的培养物中内皮细胞增殖明显减少。总而言之,这些数据支持沙利度胺在抗血管生成潜能和抑制内皮细胞增殖之间的密切相关性。
研究显示,沙利度胺的S(-)-对映体在VEGF诱导和bFGF诱导的角膜新血管形成中具有最强的抗-血管生成活性。该对映体选择性倾向于支持可能的受体介导的机理。本发明涉及新的一系列沙利度胺类似物以及这些类似物作为血管生成抑制剂的用途。更具体地说,本发明的沙利度胺类似物没有沙利度胺的哌啶-2,6-二酮部分。
本发明概述
本发明涉及具有如下通用结构的化合物:
和
其中R1选自H、卤代基、烷基、卤代烷基、-NR5R6、羟基和烷氧基;
R2选自任选取代的二环、任选取代的芳基和
R3选自烷基、苯基、取代的苯基、苄基和取代的苄基;
R8选自H或C1-C6烷基,或者R8和R3与相邻的环一起可以形成任选取代的5-或6-元芳基;
R5和R6独立是H或C1-C8烷基;
R19是任选取代的芳基;以及m是0-6。本发明也涉及含有这些化合物的组合物以及这些组合物抑制血管生成的用途。
本发明详述
在本发明的叙述中,以下术语将按照以下所述的定义使用。
如在本文中使用的术语“纯化的”和类似术语指基本上不含有与天然或自然环境下通常与其有关的污染物的分子或化合物的分离形式。
如在本文中使用的术语“治疗”包括特定疾病或病症的预防,或与特定疾病或病症有关症状的缓解和/或预防或消除所述症状。
如在本文中使用的术语“卤代基”或“卤代基”指Cl、Br、F、I。特别优选的卤代基包括Cl、Br和F。本文中所使用的术语“卤代烷基”指具有至少一个卤代基取代基的C1-C4烷基例如氯代甲基、氟代乙基或三氟代甲基等。
如在本文中使用的术语“C1-Cn烷基”其中n是一个整数,代表具有1到特定数目碳原子的支链或直链烷基。典型的C1-C6烷基包括、但不限于甲基、乙基、正-丙基、异-丙基、丁基、异-丁基、仲-丁基、叔-丁基、戊基、己基等。
如在本文中使用的术语“C2-Cn链烯基”其中n是一个整数,指具有2到特定数目的碳原子和至少一个双键的烯属不饱和支链或直链基团。此类基团的实例包括、但不限于1-丙烯基、2-丙烯基、1,3-丁二烯基、1-丁烯基、己烯基、戊烯基等。
术语“C2-Cn炔基”其中n是一个整数,指具有2到特定数目的碳原子和至少一个三键的不饱和支链或直链基团。此类基团的实例包括、但不限于1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基等。
术语“C3-Cn环烷基”其中n是一个整数,指环状非芳族基团,例如C3-C8环烷基,代表环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
如在本文中使用的术语“低级烷基”指含有1-8个碳原子的支链或直链烷基,包括甲基、乙基、丙基、异丙基、正-丁基、叔-丁基、新戊基等。
如在本文中使用的术语“任选取代的”指从0-4个取代基,其中所述取代基每一个为独立选择的。所述独立选择的每一个取代基可以与其它取代基相同或不相同。
如在本文中使用的术语“芳基”指具有一个或两个芳族环的单或二环碳环系统,包括但不限于苯基、苄基、萘基、四氢萘基、2,3-二氢化茚基、茚基等。“任选取代的芳基”包括具有0-4个取代基的芳基化合物,以及“取代的芳基”包括具有1-3个取代基的芳基化合物,其中所述取代基包括烷基、卤代基或氨基取代基。术语(C5-C8烷基)芳基指任何通过烷基连接到母体部分的芳基基团。
术语“杂环基团”指含有1-3个杂原子的单或双碳环的环系统,其中所述杂原子选自氧、硫和氮。
如在本文中使用的术语“杂芳基”指含有1-2个芳族环的单或二环碳环的环系统,所述芳族环含有1-3个杂原子,包括但不限于呋喃基、噻吩基、吡啶基等。
术语“二环的”代表不饱和或饱和稳定的7-到12-元桥接或稠合的二环的碳环。所述二环可以连接在任何碳原子上以提供一个稳定结构。所述术语包括但不限于萘基、二环己基、二环己烯基等。
如在本文中使用的术语“药学上可接受的载体”包括任何标准药用载体,例如磷酸缓冲盐溶液、水和乳剂如油/水或水/油乳剂,以及不同类型的润湿剂。
如在本文中使用,“有效量”指足以产生所需效果的量。例如邻苯二酰亚胺衍生物的有效量为在体内或体外足以减少内皮细胞增殖、或降低血管生长速度的化合物的量。
术语“胃肠外”指不通过消化道而是通过一些其它途径如皮下、肌内、脊柱内或静脉内给药。
如在本文中使用的术语“血管生成”指新的血管增殖到组织或器官中。
如在本文中使用的术语“血管生成有关的”疾病或病症指所述疾病状况或病症由不适当的或过量的血管生成引起或使其加重的疾病。例如,被认为与血管生成有关的疾病包括癌症以及血管性眼疾病如糖尿病性视网膜病、早产儿视网膜病以及黄斑变性。
本发明的具有一个或更多个不对称碳原子的化合物可以存在任选纯的对映体,或任选纯的非对映体,以及对映体的混合物,非对映体的混合物和这些立体异构体的外消旋混合物。本发明包括所有这些异构体以及它们的混合物的范围。
本发明
本发明涉及预期具有抗血管生成活性的新的取代的邻苯二甲酰亚胺和异喹啉衍生物系列。尤其是,本发明涉及沙利度胺衍生物系列,其中所述哌啶-2,6-二酮部分已由其它取代基如以下所示取代基取代:
根据一种实施方案,提供具有选自以下基团的通式结构的新的化合物:
其中R1选自H、卤代基、C1-C8烷基、C1-C8卤代烷基、-NR5R7、羟基和C1-C8烷氧基;
R2选自任选取代的二环、任选取代的芳基,和
R3选自
R8选自H、C1-C8烷基,或R3和R8与相邻的环一起可以形成任选取代的5-或6-元芳族环;
R10和R11独立选自H、卤代基、C1-C8烷基、C1-C8卤代烷基、-NR5R7、羟基和C1-C8烷氧基或R10和R11与相邻的环一起可以形成任选取代的5-或6-元芳族环;
R5和R7独立是H,或C1-C8烷基;
R6选自H、或C1-C12烷基、C2-C8链烯基和C2-C8炔基;
n是0-2的一个整数;以及m是0-6的一个整数。
根据一个实施方案,抗血管生成化合物具有以下通式结构:
其中R1选自H、卤代基、C1-C4烷基、羧基和C1-C8烷氧基;
R2选自
R3选自
R8选自H、C1-C8烷基,或R3和R8与相邻的环一起可以形成任选取代的5-或6-元杂芳基;
R4选自H、C1-C8烷基、苯基和苄基;
R13和R9独立选自H、卤代基和C1-C8烷氧基或R13和R9与相邻的环一起可以形成任选取代的C5-C6环烷基或任选取代的C5-C6芳族环;
R10和R11独立选自H、卤代基、C1-C8烷基、C1-C8卤代烷基、-NR5R7、羟基和C1-C8烷氧基或R10和R11与相邻的环一起可以形成任选取代的C5-C6环烷基或任选取代的C5-C6芳族环;
R5和R7独立选自H、或C1-C8烷基;
R6选自H、或C1-C12烷基、C2-C8链烯基和C2-C8炔基;
R12选自H、卤代基、C1-C4卤代烷基、-NR5R6、C1-C8烷基、羟基和C1-C8烷氧基;
n是1-3的一个整数和m是0-6的一个整数。在一个实施方案中,R1、R4和R8每一个是H,n是1和m是0。
在一个实施方案中,抗血管生成化合物具有以下通式结构:
其中R1选自H、卤代基、C1-C8烷基、羟基和C1-C8烷氧基和R3选自
其中R6为H或C1-C8烷基;R10和R11独立选自H、卤代基、C1-C8烷基、C1-C8卤代烷基、-NR5R7、羟基和C1-C8烷氧基,或R10和R11与相邻的环一起可以形成任选取代的C5-C6环烷基或C5-C6芳族环;R5和R7独立为H或C1-C8烷基;以及m是0-6的一个整数。在一个实施方案中,R1是H和R3选自苯基;
其中R6是H或C1-C8烷基;R10和R11独立选自H、卤代基、C1-C8烷基、C1-C8卤代烷基、-NR5R7、羟基和C1-C8烷氧基以及R5和R7独立是H、或C1-C8烷基。
在一个实施方案中,抗血管生成化合物具有以下通式结构:
其中R1选自H、卤代基、C1-C8烷基、羟基和C1-C8烷氧基;和
R2选自
其中R10和R11独立选自H、卤代基、C1-C8烷基、C1-C8卤代烷基、-NR5R7、羟基和C1-C8烷氧基或R10和R11与相邻的环一起可以形成任选取代的C5-C6环烷基或任选取代的C5-C6芳族环;
m是0-3的一个整数。
R5和R7独立是H或C1-C8烷基;
R6选自H、C1-C12烷基、C2-C8链烯基和C2-C8炔基;
R12选自H、卤代基、C1-C4卤代烷基、-NR5R6、C1-C8烷基、羟基和C1-C8烷氧基;和
n是1-3的一个整数。
在一个实施方案中,本发明的化合物具有以下通式结构:
其中R2选自
其中R10和R11独立选自H、卤代基、C1-C4卤代烷基、-NR5R7、羟基和C1-C8烷氧基;和
R5和R7独立是H或C1-C4烷基;
R12选自H、卤代基和C1-C8烷氧基;和
R6是C1-C8烷基。在一个优选的实施方案中,R2选自
其中R10和R11独立选自H、卤代基和C1-C8烷氧基。
在一个优选的实施方案中,所述化合物具有以下结构:
其中R6是C1-C8烷基和R10和R11独立选自H和C1-C4烷氧基或R10和R11与相邻的环一起可以形成任选取代的5-或6-元芳族环。
本发明的一方面涉及治疗与血管生成有关的疾病或病症的方法。尤其是,本发明的一个实施方案涉及在温血脊椎动物体内包括人体内抑制不需要的血管生成。所述方法包括给予人或动物含有有效量的以下通式化合物的组合物:
和
其中R1选自H、卤代基、C1-C8烷基、C1-C8卤代烷基、-NR5R7、羟基和C1-C8烷氧基;
R2选自任选取代的二环、任选取代的芳基,和
R3选自
R8选自H和C1-C8烷基或R3和R8与相邻的环一起可以形成任选取代的5-或6-元芳族环。
R10和R11独立选自H、卤代基、C1-C8烷基、C1-C8卤代烷基、-NR5R7、羟基和C1-C8烷氧基或R10和R11与相邻的环一起可以形成任选取代的C5-C6环烷基或任选取代的C5-C6芳族环;
R5和R7独立是H或C1-C8烷基;
R6选自H或C1-C8烷基、C2-C8链烯基和C2-C8炔基;
n是0-2的一个整数;和m是0-6的一个整数。
在一个实施方案中,抑制血管生成的方法包括给予具有以下通式的化合物:
其中R1是H、卤代基或C1-C4卤代烷基;
R2选自
其中R10和R11独立选自H、卤代基、C1-C4卤代烷基、-NR5R7、羟基和C1-C8烷氧基;
R5和R7独立是H或C1-C4烷基;
R12选自H、卤代基和C1-C8烷氧基;和
R6是C1-C8烷基。在一个实施方案中,R10和R11独立是H、卤代基或C1-C4烷氧基,R1和R12是H,以及R6是C1-C6烷基。
根据一个实施方案,所述本发明的沙利度胺衍生物化合物可以通过将所述化合物与一种或更多种药学上可接受的载体结合制备成药用组合物。这些制剂可以通过标准途径给药。通常,所述组合物可以通过局部、经皮、口服、直肠或胃肠外(例如静脉内、皮下或肌内)途径给药。另外,所述组合物可以掺入到可以持续释放化合物的生物可降解的聚合物中,将所述聚合物植入到希望药物释放例如肿瘤部位的周围。适合本发明使用的生物可降解的聚合物是本领域技术人员已知的并在例如Brem等J,Neurosurg.74:441-446(1991)中有详细叙述。
除了这些药用组合物作为抗血管生成化合物的用途外,沙利度胺衍生的化合物和相应的组合物也具有作为钠通道阻断剂、钙通道阻断剂、避孕药、抗炎药和抗癌药的效用。在一个实施方案中,本发明的含有沙利度胺衍生物的组合物用于治疗年龄相关的黄斑变性。
根据本发明的一个实施方案所述组合物经口服或胃肠外给药。当口服给药时,所述化合物以液体溶液、散剂、片剂、胶囊或锭剂的形式给药。所述化合物可以与一种或更多种常规的用于制备片剂、胶囊、锭剂和其它口服给药形式的药用添加剂或赋形剂结合使用。当胃肠外给药时,并且更优选静脉给药时,本发明的衍生物可以与盐水溶液和/或常规IV溶液混合。
所述活性化合物的剂量可以根据所治疗的疾病、具体化合物以及其它临床因素如人或动物的体重和状况以及所述化合物的给药途径而决定。应该理解,本发明化合物适合人和兽医使用。对于病人的口服给药,通常足够的剂量为大约0.1-300mg/kg/天,优选大约0.5-50mg/kg/天,更优选大约1-10mg/kg/天。
应该理解,除了活性的抗血管生成化合物外,本发明的组合物可以包括常规用于本领域中的其它试剂包括增溶剂、惰性填充剂、稀释剂、赋形剂和调味剂。
根据一个实施方案,通过给予含有以下通式结构的化合物可以治疗与角膜新血管形成有关的疾病:
和
其中R1选自H、卤代基、烷基、卤代烷基、-NR5R6、羟基和烷氧基;
R2选自
R3选自
R8选自H和烷基,或R3和R8与相邻的环一起可以形成任选取代的C5-C6环烷基或C5-C6芳族环;
R10和R11独立选自H、卤代基、C1-C4卤代烷基、-NR5R7、羟基和C1-C8烷氧基或R10和R11与相邻的环一起可以形成任选取代的C5-C6环烷基或任选取代的C5-C6芳族环;
R5和R7独立是H或C1-C4烷基;
R12选自H、卤代基或C1-C8烷氧基;
m是0-4的一个整数;和
R6是C1-C8烷基。在一个实施方案中,所述化合物具有以下通式结构
其中R1是H或卤代基;和
R2选自
其中R10和R11独立是H、卤代基或C1-C4烷氧基,R1和R12是H,以及R6是C1-C6烷基。
根据本发明可以治疗的其它疾病是类风湿性关节炎。相信血管在关节的滑膜中进行血管生成。除了形成新的血管网外,内皮细胞释放导致血管翳生长和软骨破坏的因子和反应性氧物质。所述涉及血管生成的因子可积极性促进和帮助维持类风湿性关节炎的慢性炎症状态。
也预期本发明的沙利度胺衍生化合物用于治疗多种与血管生成有关的疾病或病症,包括糖尿病性视网膜病、早产儿视网膜病、角膜移植排斥、新血管形成性青光眼和晶状体后纤维组织形成、流行性角结膜炎、维生素A缺乏、带隐性眼镜的过度损伤(contact lensoverwear)、特应性角膜炎、上支性角膜炎、翼状胬肉角膜炎干燥症、斯耶格伦综合征、红色痤疮、phylectenulosis、梅毒、分枝干菌感染、脂质变性、化学灼伤、细菌性溃疡、真菌性溃疡、单纯疱疹感染、带状疱疹感染、原虫感染、卡波济氏肉瘤、莫伦溃疡、Terrien’s缘变性、缘角质层分离、创伤、类风湿性关节炎、系统性红斑狼疮、多动脉炎、韦格纳结节病、巩膜炎、史蒂文斯-约翰逊病、类天疱疮(pemphigold)放射状角膜切开术和角膜标记排斥(corneal graphrejection)。根据本发明也可以治疗的与视网膜/脉络膜新血管生成有关的疾病包括、但不限于糖尿病性视网膜病、黄斑变性、镰状细胞性贫血、肉样瘤、梅毒、弹力纤维性假黄瘤、佩吉特病、静脉闭塞、动脉闭塞、颈动脉阻塞性疾病、慢性葡萄膜炎/玻璃体炎(vitritis)、分支杆菌感染、莱姆氏病、系统性红斑狼疮、早产儿视网膜病、伊尔斯病、Bechets病、感染引起的视网膜炎或脉络膜炎、假定的眼组织胞浆菌病、Bests病、近视、眼部溃疡、施塔加特病、扁平部睫状体炎、慢性视网膜脱离、高粘滞性综合征、弓形体病、创伤和激光后并发症。
实施例1
分子模型用来便于新的异喹啉类系列的设计。首先,考虑将一个碳加入到二酰亚胺环上以制备以下通式结构的化合物:
连接在多腺苷磷酸核糖聚合酶(polyADP-ribose polymerase)的晶体结构中的邻苯二甲酰亚胺类似物的构象分析显示所申请结构模拟邻苯二甲酰亚胺的构象的相似性。考虑到这一点,提出两种初始类似物系列的合成作为合成目标的初级构型。
A系列 B系列
化合物 | R20 | R21 | 氨基酸 | n |
A系列 | ||||
1 | H | H | 甘氨酸 | |
2-(±) | CH3 | H | 丙氨酸 | |
3-(±) | 苄基 | H | 苯丙氨酸 | |
4-(±) | HO-苄基 | H | 酪氨酸 | |
5 | 苯基 | 苯基 | ||
6-(±) | 苯基 | H | ||
7-(±) | 苯基 | CH3 | ||
B系列 | ||||
8 | 2 | |||
9 | 3 | |||
10 | 4 |
这些化合物代表第一代类似物,对重要结构和对映选择性关系进行异喹啉类的研究。模拟物1-10的合成列在流程I中并代表适当文献中所报道的有机转化。这种合成流程的作用为便于连接多种多样的官能团。另外,所述合成设计便于通过加入选择性的手性氨基酸直接合成对映体纯的最终产物。
流程I.用于该研究中类似物的合成流程
实施例2
制备附加的化合物,其中沙利度胺的哌啶-2,6-二酮部分被具有以下通式结构的刚性的(rigid)或开环结构替代,其中R22为H、C1-C12烷基、C2-C12链烯基或C2-C12炔基,或R22和R23与插入的碳一起形成芳基。用于制备这些化合物合成流程如下:
2-2,3-二氢化茚-5-基-1,3-二氧代-2,3-二氢-1H-异吲哚-5-羧酸的合成
也可以通过以下反应制备化合物5-7:
2-(1,2,3,4-四氢-萘-1-基)-异吲哚-1,3-二酮的合成3天
化合物号
R 24
n
化合物号
R 24
n
产率
8 H 3 10 H 3 78%
9 3-F 3 11 3-F 3 100%
化合物号
R 24
n
产率
化合物号
R 24
R 25
n
产率
12 H 1 16 1 98%
13 H 3 70% 17 H H 3 100%
14 H 3 18 H 3-CH3 3 76%
15 3-F 3 48% 19 3-F 2-F 3 62%
20 3-F 3-CH3 3 50%
21 H 2-F 3 72%
22 H H 2 84%
2-(10,11-二氢-5H-二苯并[a,d]-环庚烯-5-基)-异吲哚-1,3-二酮的合成
2-(1-萘-2-基-丙基)-异吲哚-1,3-二酮的合成
2-[1-(3,4-二甲氧基-苯基)-庚基]-异吲哚-1,3-二酮的合成
2-异喹啉-1-基-异吲哚-1,3-二酮的合成
N-(2-苯乙基)-苯邻二甲酰亚胺的合成
苯基取代的苯邻二甲酰亚胺的合成
4-羟基-2H-异喹啉-1-酮的合成
吡咯并[1,2-b]异喹啉-5,10-二酮的合成
3H-喹唑啉-4-酮类的合成
评估这些化合物抑制角膜新血管生成和内皮细胞增殖的能力。
实施例3
内皮细胞增殖的测定
将人血管内皮细胞(HUVECS)在20%血清中培养到周边汇合(80%)并用沙利度胺(标准物)或它的类似物(40-400μM)处理。20小时后,用2-4小时将[3H]-沙利度胺(2μCi/ml)加入到培养基中。用冰冷却的PBS(洗涤3次)停止[3H]-沙利度胺的结合并将所述细胞与冷的10%三氯乙酸(TCA)在4℃下温育10分钟。将所述细胞与TCA在室温下再温育10分钟并用PBS洗涤三次。将细胞用1N NaOH溶解过夜并用相当量的1N NCl中和,然后确定放射性。计算沙利度胺或它的类似物的抗增殖活性作为HUVECS促有丝分裂反应对20%血清(胎牛血清)的百分抑制作用。
对于沙利度胺抑制3H-胸苷进入内皮细胞的评估揭示该化合物具有200μM的IC50。对于化合物的第一组实验对象的初步IC50数据揭示在抑制3H-胸苷结合进入内皮细胞方面四种化合物(5、29、32和50)具有比沙利度胺强2-4倍的效能(参见表1)。这种结构活性关系(SAR)证实所述哌啶-2,6-二酮部分对于增加内皮细胞增殖的抑制作用是不需要的。
表1.对于所述研究中类似物的生物学数据
实施例4
可以根据以下流程制备具有以下通式结构的4-氧代-喹唑啉衍生物:
其中n是1-4:
化合物 | 手性中心 | R30 | R31 | %产率 |
33 | H | H | 76 | |
34 | R | C6H5 | H | 83 |
35 | S | C6H5 | H | 75 |
36 | S | HOC6H4 | H | -- |
37 | R | CH3 | H | 42 |
38 | S | CH3 | H | 68 |
39 | S | CH2C6H4 | H | 90 |
40 | R | CH2C6H4 | H | 16 |
扩环结构的制备:
Claims (10)
1.一种由选自以下通式结构代表的化合物:
和
其中R1选自H、卤代基、C1-C4烷基、羧基和C1-C8烷氧基;
R2选自
R3选自
R8选自H、C1-C8烷基、苯基和苄基,或R3和R8与相邻的环一起可以形成任选取代的5-或6-元杂芳基;
R9和R13独立选自卤代基、甲氧基和C3-C8烷氧基;
R10和R11独立选自H、卤代基、C1-C8烷基、C1-C8卤代烷基、-NR5R7、羟基和C1-C8烷氧基或R10和R11与相邻的环一起可以形成任选取代的C5-C6环烷基或任选取代的C5-C6芳族环;
R5和R7独立选自H、或C1-C8烷基;
R6选自H、或C1-C12烷基、C2-C8链烯基和C2-C8炔基;
R12选自H、卤代基、C1-C4卤代烷基、-NR5R6、C1-C8烷基、羟基和
C1-C8烷氧基;
n是1-3的一个整数和m是0-6的一个整数。
4.权利要求3的化合物,其中R1是H。
5.一种药用组合物,它含有权利要求1的化合物和药学上可接受的载体。
6.一种在温血脊锥动物体内抑制血管生成的方法,所述方法包括给予所述脊锥动物含有以下通式结构的化合物的组合物步骤
其中R2选自
和
R3选自
R8选自H、C1-C8烷基、苯基和苄基或R3和R8与相邻的环一起可以形成任选取代的5-或6-元杂芳基;
R10和R11独立选自H、卤代基、C1-C8烷基、C1-C8卤代烷基、-NR5R7、羟基和C1-C8烷氧基或R10和R11与相邻的环一起可以形成任选取代的
C5-C6环烷基或任选取代的C5-C6芳族环;
R5和R7独立是H或C1-C8烷基;
R6选自H或C1-C12烷基、C2-C8链烯基和C2-C8炔基;
R12选自H、卤代基、C1-C4卤代烷基、-NR5R6、C1-C8烷基、羟基和C1-C8烷氧基;和
m是0-6的一个整数。
9.权利要求8的组合物,其中R1是H以及R10和R11独立选自H和C1-C8烷氧基。
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EP (1) | EP1389103A4 (zh) |
JP (2) | JP2004532848A (zh) |
CN (1) | CN1518447A (zh) |
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- 2002-04-22 US US10/475,363 patent/US7893071B2/en not_active Expired - Fee Related
- 2002-04-22 WO PCT/US2002/012655 patent/WO2002086078A2/en active Application Filing
- 2002-04-22 CA CA2444704A patent/CA2444704C/en not_active Expired - Fee Related
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CN102138921B (zh) * | 2005-11-08 | 2012-12-26 | 北京恩华医药研究院 | 邻苯二甲酰亚胺衍生物在制备抗新血管生成的药物中的用途 |
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US20040122030A1 (en) | 2004-06-24 |
CA2444704A1 (en) | 2002-10-31 |
CA2444704C (en) | 2012-07-10 |
EP1389103A4 (en) | 2005-09-14 |
AU2002257195A1 (en) | 2002-11-05 |
EP1389103A2 (en) | 2004-02-18 |
JP2008308501A (ja) | 2008-12-25 |
US7893071B2 (en) | 2011-02-22 |
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