CN1111454A - 亚芳基和杂亚芳基羟吲哚衍生物及其制备方法 - Google Patents
亚芳基和杂亚芳基羟吲哚衍生物及其制备方法 Download PDFInfo
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Abstract
式Ⅰ的亚芳基和杂亚芳基羟吲哚衍生物或其可
作药用的盐可用作酪氨酸激酶抑制剂。
Description
本发明涉及新的3-亚芳基和3-杂亚芳基-2-羟吲哚衍生物、其制备方法、含有它们的药物组合物以及它们作为治疗剂的应用。本发明提供了具有如下通式(Ⅰ)的化合物及其可作药用的盐:
其中
Y为选自萘、四氢化萘、喹啉和异喹啉的双环系统;
当Y为四氢化萘时R为氢或氧代(=0)基,或当Y为萘、喹啉或异喹啉时R为氢;
R1和R2各自独立地为氢、C1-C6烷基或C2-C6烷酰基;
m为0、1或2;
n为0、1、2或3;
R3和R4各自独立地为氢、卤素、氰基、C1-C6烷基、羧基、硝基或-NR6R7,其中R6和R7各自独立地为氢或C1-C6烷基;
R5为氢或C1-C6烷基;
且其中
a)同时当Y为萘基;R3为氢、卤素、氰基或C1-C6烷基;R5为氢;m为0且n、R和R1的定义同上时,则R4不为氢;
b)同时当Y为喹啉或异喹啉;R3为氢、卤素、氰基或C1-C6烷基;n为0、1或2;R5为氢;m为0且R和R1的定义同上时,则R4不为氢;
c)同时当Y为只有其中的苯基被取代的四氢化萘;R3为氢、卤素、氰基或C1-C6烷基;n为0、1或2;R5为氢;m为0;R为氢且R1的定义同前时,则R4不为氢;
d)同时当Y为萘;m和n为0;R和R3为氢;连于C-4碳原子上的R4为卤素或C1-C4烷基时,则R5不为C1-C2烷基。
本发明在其范围内包括式Ⅰ化合物所有可能的异构体,立体异构体,尤其是Z和E异构体及其混合物,以及它们的代谢物、代谢前体或生理前体(前药)。
烷基以及烷酰基中的烷基部分可为直链或支链烷基。C1-C6烷基优选为C1-C4烷基,如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基,尤其是甲基或乙基。C2-C6烷酰基优选为C2-C4烷酰基,尤其是乙酰基、丙酰基或丁酰基。
卤素优选为氟、氯或溴,尤其是氟或氯。
术语四氢化萘优选指5,6,7,8-四氢化萘环。
当R氧代(=0)基为四氢化萘环上的一取代基时,该氧代基可仅与四氢化萘环上的饱和残基相连,从而产生5-、6-、7-或8-四氢萘酮环,优选8-四氢萘酮。
当Y为四氢化萘时,优选亚羟吲哚取代基位于苯残基上,即R3和R1O-基团则可在任一环上。
当四氢化萘在1'位被亚羟吲哚取代基取代时,优选至少一个OR1基团存在于2'、4'、5'和/或8'位,且优选R3取代基位于4'位。
类似地,当四氢化萘在2'-位被亚羟吲哚取代基取代时,优选至少一个OR1基团存在于1'、3'、4'、5'和/或8',且优选R3取代基存在于4'位。
当Y为萘时,优选R3、R1O-基团和亚羟吲哚取代基位于同一苯残基上。
当Y为喹啉时,优选亚羟吲哚与喹啉环的4'-或5'-位相连,而R3和R1O取代基则可存在于该环系统的任一环上。
当Y为异喹啉时,优选亚羟吲哚基与该异喹啉环的3'-或5'-位相连,而R3和R1O取代基则可存在于该环系统的任一环上。
当Y为喹啉时,优选其4'或5'位被亚羟吲哚取代基取代,且存在至少一个OR1取代基,且优选在8'一位。
优选在2-羟吲哚环上存在至少一个取代基R4或-OR2。优选的取代基位置是4位和5位,尤其是5位。
当R4为羧基、硝基或-NR6R7(其中R6和R7的定义同上)时,优选R3取代基不为羧基、硝基或-NR6R7。或者反过来,当R3为羧基、硝基或-NR6R7(其中R6和R7的定义同上)时,优选R4取代基不为羧基、硝基或-NR6R7。
当然取代基R1O、R2O、R3、R和R4中只有一个能与相同的环位置相连。
本发明化合物可作药用的盐包括与硝酸、盐酸、氢溴酸、硫酸、高氯酸和磷酸等无机酸及乙酸、丙酸、乙醇酸、乳酸、草酸、丙二酸、马来酸、苹果酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸和水杨酸等有机酸形成的酸加成盐,以及与碱金属(尤其是钠或钾)或碱土金属(尤其是钙或镁)等无机碱或者与烷基胺(优选三乙胺)等有机碱形成的盐。
如上所述,本发明在其范围内也包括式Ⅰ化合物可作药用的生物前体(或称前药),即其通式不同于上面的式(Ⅰ),但在给人体服用后可在体内直接或间接转化为式(Ⅰ)化合物的化合物。
优选的本发明化合物是符合上述条件的下列式(Ⅰ)化合物:
Y为四氢化萘、喹啉或异喹啉;
n为0、1、2或3;
m为0或1;
R1和R2各自独立地为氢或C1-C4烷基;
R3和R4各自独立地为氢、卤素、氰基、羧基或氨基;
R5为氢;
R的定义同上,;以及它们可作药用的盐。
更优选的是符合上述条件的下列式Ⅰ化合物及其可作药用的盐:
Y为四氢化萘或喹啉;
n为0、1、2或3;
m为0或1;
R1、R2和R5为氢;
R3和R4各自独立地为氢、氨基或羧基;
R的定义同上。
本发明具体化合物的例子如下,它们根据情况可为Z-或E-非对映异构体或该非对映异构体的Z、E-混合物:
3-[(4'-氨基-1'-四氢萘基)亚甲基]-2-羟吲哚;
3-[(4'-二甲氨基-1'-四氢萘基)亚甲基]-2-羟吲哚;
3-[(4-羧基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(1'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(1'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(1'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(2'-羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4'-羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(2'-羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4'-羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(2'-羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4'-羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4',5'-二羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4',8'-二羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4',5'-二羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4',8'-二羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4',5'-二羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
3-[(4'-氨基-2'-四氢萘基)亚甲基]-2-羟吲哚;
3-[(4'-羧基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(1'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(3'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(1'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(3'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(1'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(3'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(3',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(3',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(3',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(3',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(3',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(3',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(1',4',5'-三羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(1',4',8'-三羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
3-[(8'-氧代-1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(5'-喹啉)亚甲基]-2-羟吲哚;
5-氨基-3-[(5'-喹啉)亚甲基]-2-羟吲哚;
5-羧基-3-[(5'-喹啉)亚甲基]-2-羟吲哚;
5-羟基-3-[(4'-喹啉基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4'-喹啉基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4'-喹啉基)亚甲基]-2-羟吲哚;
5-羟基-3-[(8'-羟基-5'-喹啉)亚甲基]-2-羟吲哚;
5-氨基-3-[(8'-羟基-5'-喹啉)亚甲基]-2-羟吲哚;
5-羧基-3-[(8'-羟基-5'-喹啉)亚甲基]-2-羟吲哚;
5-羟基-3-[(8'-羟基-4'-喹啉)亚甲基]-2-羟吲哚;
5-氨基-3-[(8'-羟基-4'-喹啉)亚甲基]-2-羟吲哚;
5-羧基-3-[(8'-羟基-4'-喹啉)亚甲基]-2-羟吲哚;
5-溴-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟吲哚;
5-氟-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟吲哚;
5-甲氧基-3-[(2'-四氢萘基)亚甲基]-2-羟吲哚;
5-乙酸基-3-[(2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4'-羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
以及其可作药用的盐。
本发明的再一个目的是提供了下列化合物及其可作药用的盐,它们是新化合物,虽然它们已包括在WO 91/13055和WO 93/01182所公开的化学通式中,但在其中并未作为具体的化学实例公开:
3-[(8'-羟基-7'-喹啉基)亚甲基]-2-羟吲哚;
3-[(5'-羟基-4'-喹啉基)亚甲基]-2-羟吲哚;
3-[(8'-羟基-4'-喹啉基)亚甲基]-2-羟吲哚;
3-[(2'-甲基-3'-吲哚基)亚甲基]-2-羟吲哚;
3-[(5'-氰基-3'-吲哚基)亚甲基]-2-羟吲哚;
3-[(5'-羟基-3'-吲哚基)亚甲基]-2-羟吲哚;
3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟吲哚;
5-羟基-3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟吲哚;
5-氨基-3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟吲哚;
5-羟基-3-[(2'-甲基-3'-吲哚基)亚甲基]-2-羟吲哚;
2-氰基-3-(4-喹啉基)丙烯酰胺;
2-氰基-3-(3-喹啉基)丙烯酰胺;
2-氰基-3-(1,4-二羟基-2-四氢萘基)丙烯酰胺;
2-氰基-3-(1,4-二羟基-2-四氢萘基)硫代丙烯酰胺;
2-氰基-3-(2-羟基-1-萘基)丙烯腈;
2-氰基-3-(2-萘基)丙烯酰胺;
2-氰基-3-(2-萘基)硫代丙烯酰胺;
2-氰基-3-(3,5-二羟基-2-萘基)丙烯酰胺;和
2-(4-羟苯基)-3-(1,4-二甲氧基-2-萘基)丙烯腈;
它们根据情况可为Z-或E-非对映异构体或其Z、E-混合物。
如上定义的式(Ⅰ)化合物及其可作药用的盐可按如下方法获得:将式(Ⅱ)的醛
(其中Y、n、R、R1和R3的定义同上)与式(Ⅲ)化合物缩合
(其中m、R2、R4和R5定义同上);并根据需要将一种式(Ⅰ)化合物转化为另一种式(Ⅰ)化合物,和/或根据需要将式(Ⅰ)化合物转化为其可作药用的盐,和/或根据需要将盐能化为游离化合物,和/或根据需要将式(Ⅰ)化合物的异构体混合物分离成单一异构体。
式(Ⅱ)化合物中各个取代基-OR1、R3和-CHO可各自独立地存在于双环系统的任一环残基上。
式(Ⅱ)化合物与式(Ⅲ)化合物的缩合反应可按下面所述的已知方法进行。例如,可按由G.Jones在Organic Reaction 15,204(1967)中所述的诺文葛耳反应条件下进行。合适的催化剂是有机碱,如吡啶、哌啶或二乙胺。缩合反应可于约0℃-100℃的温度下在吡啶、乙醇、甲醇、苯或二噁烷等惰性有机溶剂中进行。优选在哌啶催化剂存在下在热乙醇中进行该反应。
可按已知方法将一种式(Ⅰ)化合物转化为另一种式(Ⅰ)化合物。例如,可按J.F.N.McOmie在Tetrahedron 24,2289(1965)中所述的方法将其中存在一个或多个-OR1和/或-OR2甲氧基的式(Ⅰ)化合物与三溴化硼进行去醚化反应,得到相应的羟基取代的衍生物。该反应可于约-78℃至室温的温度下在惰性环境(如氮气)中于二氯中烷或苯等惰性有机溶剂中进行。
可按已知方法将其中R3和/或R4为硝基的式(Ⅰ)化合物转化为其中R3和/或R4为氨基的相应的式(Ⅰ)化合物,例如与各种还原剂,如氢化醇中的硫化钠、水溶性溶剂中的带有氯化铵的金属铁反应,或者在低氢气压下在惰性有机溶剂中利用披钯炭催化剂进行催化氢化。通过在高沸芳族溶剂(如二甲苯)中与氢化钠和C1-6烷基碘反应,可使其中-OR1和/或-OR2为羟基的式(Ⅰ)化合物烷基化,得到其中-OR1和/或-OR2为C1-C6烷氧基的相应式(Ⅰ)化合物。
通过在一碱性试剂存在下于室温至回流温度的温度条件下与一合适的羧酸酐反应,可使其中-OR1和/或-OR2为羟基的式(Ⅰ)化合物酰基化,得到相应地其中-OR1和/或-OR2为C1-C6烷酰氧基的式(Ⅰ)化合物。
任选的式(Ⅰ)化合物的成盐反应和由盐至游离化合物的转化反应以及将异构体混合物分离为单一异构体的反应均可按已知方法进行。例如,通过从合适的溶剂中分级结晶或通过层析(柱层析或HPLC)可分离几何异构体,如Z-和E-异构体的混合物。
式(Ⅱ)化合物可按已知方法从式Ⅳ化合物获得:
其中Y、R、n、R3和R1的定义同前。例如,当式(Ⅳ)化合物含有酚基,即R1O-为羟基时,可使用熟知的Reimer-Tiemenn方法,即在水溶性或加氢醇溶液中用氯仿和碱性氢氧化物处理酚化合物。H、Gross等人在Chem.Ber.96,308(1963)中叙述了另一种合成芳族或酚族醛的有用方法,即于0℃-60℃在Friedel-Crafts催化剂(如四氯化钛或三氯化铝)存在下在惰性溶剂(如二氯甲烷或硝基苯)中用二氯甲基醚(如二氯甲基甲醚)处理其中存在或不存在OR1基团的式(Ⅳ)化合物。
式(Ⅲ)和式(Ⅳ)化合物是已知的,或者可用已知的方法制得。
可按与上面所述制备式(Ⅰ)化合物相同的方法,制得首次在这里公开且包括在WO 91/13055和WO 93/01182中的新亚羟吲哚衍生物及其可作药用的盐。
类似地,公开于WO 91/13055并作为具体的化学实施首次在这里提到的由式(Ⅰ)所包括的新的丙烯酰胺、硫代丙烯酰胺和丙烯腈衍生物可按WO 91/13055中所述的方法制得,即将含适的喹啉、四氢化萘或萘-羧醛分别与氰基乙酰胺、氰基硫代乙酰胺或4-羟基苄基氰化物反应。当本发明的化合物或用于制备本发明化合物的中间产物中存在需要在进行上述反应前予以保护的基团时,可以按照有机化学中熟知的方法在反应发生之前将它们保护起来,然后在反应结束时去保护。由本发明所提供的新化合物,即如上定义的式(Ⅰ)化合物和这里所具体公开的且包括在WO 91/13055和WO 93/01182中的新化合物,均称作“本发明化合物”
药理活性
本发明化合物具有专一的酪氨酸激酶抑制活性。据信酪氨酸激酶抑制剂在失控细胞繁殖,细胞繁殖失调的控制方面具有重要作用。因此,本发明化合物可用于治疗包括人在内的哺乳动物的病源性增殖失调。
因此,可通过服用治疗有效量的本发明化合物之一来治疗人或动物,如哺乳动物。通过这一方式可使人或动物的条件得到改善,从而可达到人或动物疾病状态的改善。这类疾病的典型实施是肿瘤,包括白血病(如成髓细胞性白血病)、淋巴瘤、内瘤、成神经细胞瘤、Wilm氏肿瘤以及膀胱、乳腺、肺或胸腺的恶性肿瘤;和牛皮癣。本发明化合物也可用于抑制粉瘤性鼠疫的发展、控制血管生成及作为抗转移剂。
最近在分子基础上或肿瘤转移上的研究已鉴定出一族称作致肿瘤基因的基因,其异常表达引起肿瘤发生。例如,RNA肿瘤病毒具有这样一段致肿瘤基因序列,其表达决定了被感染细胞的肿瘤转化。其致肿瘤基因编码的几种蛋白质如pp60V-arc、p70gag-yes、p130gag-fps和p70gag-fgr显示出蛋白质酪氨酸激酶的活性,即它们催化γ-磷酸根由三磷酸腺甙(ATP)转移至蛋白质底物的酪氨酸残基上。在正常细胞中,几种生长因子受体,如PDGF、EGF、α-TGF和胰岛素的受体显示出酪氨酸激酶活性。
生长因子(GF)的结合激活了酪氨酸激酶去进行自身磷酸化并使酪氨酸上紧密相邻的分子磷酸化。因此,据信这些酪氨酸激酶受体的磷酸化在信号的转导中发挥了重要作用,且酪氨酸激酶在正常细胞中的活性的主要作用是调节细胞生长。由或者过量产生和/或显示出底物专一些的改变的致肿瘤酪氨酸激酶引起的这种活性的紊乱引起了生长控制的丧失和/或肿瘤的转移。因此,酪氨酸激酶的专一性抑制剂可被用于研究癌发生、细胞繁殖和分化的机制,并可有效地预防和化学治疗癌症和其它病源性增殖性疾病,如前面所述疾病。本发明化合物的酪氨酸专一性蛋白质激酶活性是通过它们在下面所述的体外和体内试验中具有活性这一事实而得以证实的。
体外检测
p45V v-abl激酶的纯化
用于试验的酶是p45 v-abl酪氨酸激酶,它代表了Abelson酪氨酸激酶(自Abelson鼠白血病病毒中分离)的催化区。按照Wang等人在J.Biol.Chem.260,64(1985)和由Ferguson等人在J.Biol.Chem.260,3652(1985)及在Biochem.J.257,321(1989)中所述的方法产生和分离p45 v-abl激酶。
p45V v-abl激酶检测
按以下方式进行(val5)-血管紧张肽Ⅱ的磷酸化:在含有Tris-HCl(25mM、pH8.0)、MgCl2(10mM)和二硫苏糖醇(0.1mM)的50μl缓冲液(激酶缓冲液)中与40ng纯化的abl-激酶和(γ-32P)-ATP一起保温。于30℃保温混合物所示时间,通过加入50μl5%三氯乙酸终止反应。在冰上稍微保温后,离心试管。将上清液倒在磷酸纤维素滤纸(Whetmen p-81)上,并在乙酸中充分洗涤。在液体闪烁计数器上测定结合至干燥的磷酸纤维素纸块上的放射活性。通过每一实验点的三次测定计算出IC50。在固定浓度的肽(2mM)和ATP(50μM)存在下,在0-400μg的浓度范围内试验每种抑制剂。
体内检测
K562细胞生长抑制检测
在有或没有10%胎牛血清存在的情况下,将1ml悬浮生长的K562细胞在1μCi[3H]胸苷存在的情况下温育66h。收集细胞,在冷PBS中洗涤三次,并在冰上用5%三氯乙酸处理5分钟。在乙醇∶乙醚2∶1中洗涤后,通过于室温下用0.5N NaOH处理2h提取DNA。提取物在液体闪烁计数器上计数。
得自上面所述的体外p45V v-abl激酶检测和人慢性骨髓瘤K562细胞生长体内抑制检测的本发明代表性化合物的抑制活性数据列于下面的表1。
表1
p45V v-abl激酶和K562细胞生长的抑制作用
FCE 27518代表:5-氨基-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟吲哚;
FCE 27566代表:3-[(2'-甲基-3'-吲哚基)亚甲基]-2-羟吲哚;
FCE 27565代表:3-[(5'-氰基-3'-吲哚基)亚甲基]-2-羟吲哚;
FCE 27866代表:3-[(5'-羟基-3'-吲哚基)亚甲基]-2-羟吲哚;
FCE 27564代表:3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟吲哚;
FCE 27996代表:5-溴-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟吲哚;
FCE 28359代表:5-羟基-3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟吲哚;
FCE 28436代表:5-氨基-3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟吲哚;
FCE 28337代表:5-羟基-3-[(4'-羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
FCE 28360代表:5-溴-3-[(1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
从表1所示的活性数据可以看出,本发明化合物具有有用的生物学性质。
鉴于其高活性和低毒性,本发明化合物可安全地用于医药中。
本发明化合物可以各种剂量形式服用,例如以片剂、胶囊、糖前或覆膜片剂、液体溶剂或悬浮剂的形式口服给药;以栓剂的形式经直肠给药;以肌内或静脉注射或输液的方式非肠道给药;或局部给药。剂量取决于患者年龄、体重、状态和给药途径;例如,给成人口服化合物3-[(5'-甲氧基-3-吲哚基)亚甲基]-2-羟吲哚和5-溴-3-[(8'-羟基-5'-喹啉)亚甲基]-2-羟吲哚所采用的剂量范围为每剂约10至150-200mg,每日1-5次。当然,可对这些剂量方式进行调整,以产生最佳治疗效果。
本发明包括含有本发明化合物或其可作药用的盐以及可作药用的赋形剂(可为载体或稀释剂)的药物组合物。
含有本发明化合物的药物组合物通常是按下述常规方法制得并按可作药用的形式给药。
例如。固体口服形式除含有活性化合物外还可含有稀释剂,如乳糖、葡萄糖、蔗糖、纤维素、玉米淀粉或马玲薯淀粉;润滑剂,如硅胶、滑石、硬脂酸、硬脂酸镁或硬酯酸钙,和/或聚乙二醇;粘合剂,如淀粉、阿拉伯树胶、白明胶、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮;解聚剂,如淀粉、藻酸、藻酸盐或羟基乙酸淀粉钠、起泡混合物;着色剂;甜化剂;湿润剂,如卵磷脂、多乙氧基醚、十二烷基硫酸钠;以及用于药物制剂中的一般无毒且无药理活性的物质。以上药物制剂可按已知方法制备,例如通过混合、造粒、片剂化、糖衣或覆膜等方法制备。
用于口服的液体分散液可为例如糖浆、乳液和悬浮液。
糖浆可含有作为载体的蔗糖或蔗糖及甘油和/或甘露糖醇和/或山梨糖醇。
悬浮液和乳液可含有作为载体的天然树胶、琼脂、藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇。
用于肌内注射的悬浮液或溶液除含有活性化合物外,还可含有可作药用的载体,如无菌水、橄榄油、油酸乙酯、二元醇(如丙二醇),并根据需要还含有适量的利多卡因盐酸盐。
用于静脉注射或输液的溶液可含有作为载体的无菌水,或优选它们为无菌水溶性等渗盐溶液形式。
栓剂可含有活性化合物及可作药用的载体,如可可油、聚乙二醇、聚氧乙烯脱水山梨糖醇脂肪酸酯表面活性剂或卵磷酯。
用于局部给药的组合物,如乳油、洗液或糊剂,可通过将活性成分与常规油脂性或乳化赋形剂混合制得。
本发明的另一目的是式(Ⅰ)化合物及其可作药用的盐:
其中
Y为选自萘、四氢化萘、喹啉和异喹啉的双环系统;
当Y为四氢化萘时R为氢或氧代(=0)基,或当Y为萘、喹啉或异喹啉时R为氢;
R1和R2各自独立地为氢、C1-C6烷基或C2-C6烷酰基;
m为0、1或2;
n为0、1、2或3;
R3和R4各自独立地为氢、卤素、氰基、C1-C6烷基、羧基、硝基或-NR6R7,其中R6和R7各自独立地为氢或C1-C6烷基;
R5为氢或C1-C6烷基;
且其中
a)同时当Y为萘基;R3为氢、卤素、氰基或C1-C6烷基;R5为氢;m为0且n、R和R1的定义同上时,则R4不为氢;
b)同时当Y为喹啉或异喹啉;R3为氢、卤素、氰基或C1-C6烷基;n为0、1或2;R5为氢;m为0且R和R1的定义同上时,则R4不为氢;
c)同时当Y为只有其中的苯基被取代的四氢化萘;R3为氢、卤素、氰基或C1-C6烷基;n为0、1或2;R5为氢;m为0;R为氢且R1的定义同前时,则R4不为氢;
在制备用作酪氨酸激酶抑制剂的药物组合物中的应用,尤其是在治疗前面所述的病理性疾病中的应用。
本发明的再一个目的是提供一种对患有癌症的包括人在内的哺乳动物进行治疗或改善其状况的结合方法,该方法包括按足以产生治疗效果的量和接近的时间服用
1)本发明化合物或其可作药物的盐,和
2)其它抗肿瘤剂。
本发明也提供了含有本发明化合物或其可作药用的盐以及其它抗肿瘤剂的产品,它们是组合制剂,可在抗癌症治疗中同时、分别或依次使用。
术语“抗肿瘤剂”按照临床实践总指既包括单个抗肿瘤药,也包括这类药用的混合物。
可与本发明化合物配制在一起的或者可在结合治疗方法中给药的抗肿瘤剂的例子包括阿霉素、道诺霉素、epirubicin、idarubicin、鬼臼乙叉甙、氟尿嘧啶、左旋溶肉瘤素、安道生、争光霉素、长青花碱、自力霉素或其两种或多种的混合物。
因此,本发明化合物可用在治疗上以改善癌症症状。可将它们与上述抗肿瘤剂(如阿霉素、道诺霉素、epirubicin或idarubicin等蒽环糖苷)一起给患有可治疗癌症的患者服用。
可将本发明化合物和蒽环糖苷等抗肿瘤剂一起给患有白血病(如成髓细胞性白血病)、淋巴病、肉瘤、成神经细胞瘤、Wilm氏肿瘤或膀胱、乳腺、肺或胸腺等的恶性肿瘤的患者服用,以改善其病性。
以下实施例说明而不是限制本发明。
实施例1
5-羟基-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟基吲哚
将8-羟基喹啉-5-羧醛(173mg,1mmol)、5-羟基-2-羟基吲哚(149mg,1mmol)和哌啶(60mg,0.7mmol)的无水乙醇(10ml)溶液于60-70℃在氮气环境下加热3h。然后冷却反应混合物,并真空蒸发干燥。残余物进行硅胶柱层析,以二氯甲烷/乙醇(4%)作洗脱剂,得到纯的标题化合物,产率约60%。
或者,真空浓缩反应混合物后冷却至0-5℃,过滤沉淀,用冰冷的乙醇洗涤残余物,最后真空干燥。经乙醇进一步结晶,得到更高纯度的化合物
C18H12N2O3理论值:C71.05 H3.98 N9.20
实测值:C71.01 H3.85 N9.15
MS m/z 304
NMR δ ppm:6.5-6.7(m,3H),7.20(d,1H),7.62(dd,1H),7.83(d,1H),7.93(s,1H),8.33(dd,1H),8.85(bs,1H),8.93(dd,1H),10.30(bs,1H).
按照上述方法,制得下列化合物:
5-氨基-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟基吲哚;
C18H12N2O2理论值:C74.98 H4.20 N9.72
实测值:C74.76 H4.31 N9.43
MS m/z 288
NMR δ ppm:6.4-6.6(mm,3H),7.18(d,1H),7.62(dd,1H),7.84(d,1H),7.87(s,1H),8.34(dd,1H),8.93(dd,1H),10.14(bs,1H).
3-[(2'-甲基-3'-吲哚基)亚甲基]-2-羟基吲哚
C18H14N2O 理论值:C78.81 H5.14 N10.21
实测值:C78.56 H5.01 N10.11
MS m/z 274
NMR δ ppm:2.46(s,3H),6.7-6.8(m,2H),6.85(d,1H),7.0-7.2(m,4H),7.41(d,1H),7.80(s,1H),10.48(bs,1H),11.86(bs,1H).
3-[(5'-氰基-3'-吲哚基)亚甲基]-2-羟基吲哚
C18H11N3O 理论值:C75.77 H3.89 N14.73
实测值:C75.71 H3.55 N14.51
MS m/z 285
NMR δ ppm:6.8-7.2(m,3H),7.57(dd,1H),7.69(d,1H),7.95(d,1H),8.21(s,1H),8.85(d,1H),9.52(s,1H),10.62(bs,1H),12.4(bs,1H).
3-[(5'-羟基-3'-吲哚基)亚甲基]-2-羟基吲哚
C17H12N2O2理论值:C73.89 H4.38 N10.14
实测值:C73.55 H4.36 N9.97
MS m/z 276
NMR δ ppm:6.75(m,1H),6.82(d,1H),6.9-7.0(m,1H),7.0-7.2(m,1H),7.29(d,1H),7.42(d,1H),7.80(d,1H),7.97(s,1H),8.96(s,1H),9.34(d,1H),10.42(s,1H),11.8(bs,1H).
3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟基吲哚
C18H14N2O2理论值:C74.47 H4.86 N9.65
实测值:C74.35 H4.72 N9.54
MS m/z 290
NMR δ ppm:3.87(s,3H),6.8-6.9(m,2H),7.12(ddd,1H),7.38(d,1H),7.72(d,1H),7.91(d,1H),8.13(s,1H),9.40(s,1H),10.49(bs,1H),11.88(bs,1H).
3-[(8'-羟基-7'-喹啉基)亚甲基]-2-羟基吲哚
C18H12N2O2理论值:C74.98 H4.20 N9.72
实测值:C79.81 H4.31 N9.43
MS m/z 288
NMR δ ppm:6.8-6.9(m,2H),7.21(t,1H),7.48(m,2H),7.64(dd,1H),7.81(d,1H),7.89(s,1H),8.38(dd,1H),8.91(dd,1H),10.6(bs,1H).
5-羟基-3-[(2'-甲基-3'-吲哚基)亚甲基]-2-羟基吲哚
NMR δ ppm:2.42(s,3H),6.30(d,1H),6.54(dd,1H),6.63(d,1H),7.0-7.2(m,3H),7.41(d,1H),7.73(s,1H),8.71(s,1H),10.16(s,1H),11.79(s,1H).
3-[(4'-氨基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
3-[(4'-二甲氨基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
3-[(4'-羧基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(2'-羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(4'-羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
NMR δ ppm:1.69(m,4H),2.5-2.7(m,4H),6.57(dd,1H),6.62(d,1H),6.72(d,1H),6.88(d,1H),7.26(d,1H),7.53(s,1H),8.87(s,1H),9.8(bs,1H),10.17(s,1H).
5-氨基-3-[(2'-羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(4'-羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(2'-羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(4'-羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(4',5'-二羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(4',8'-二羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(4',5'-二羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(4',8'-二羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(4',5'-二羟基-1'-四氢萘基)亚甲基]-2-羟基吲哚;
3-[(4'-氨基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
3-[(4'-羧基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(1'-羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(3'-羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(4'-羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(1'-羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(3'-羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(4'-羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(1'-羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(3'-羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(4'-羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(4',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(4',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(3',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(3',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
NMR δ ppm:1.69(m,4H),2.58(m,4H),6.86(s,1H),6.94(d,1H),7.15(dd,1H),7.60(d,1H),7.75(s,1H),8.4(bs,1H),8.9(bs,1H),9.7(bs,3H),10.71(s,1H).
5-氨基-3-[(4',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(4',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(3',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(3',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(4',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(4',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(3',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(3',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(1',4',5'-三羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(1',4',8'-三羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
3-[(8'-氧代-1,4'-二羟基-2'-四氢萘基)亚甲基]-2-羟基吲哚;
NMR δ ppm:2.03(m,2H),2.70 and 2.89(two m,4H),6.7-7.0(m,2H),7.1-7.3(m,1H),7.51(s,1H),7.54(d,1H),7.58(d,1H),7.61(s,1H),7.87(s,1H),8.46(s,1H),9.38(s,1H),9.56(s,1H),10.58(s,1H),10.59(s,1H),12.5(bs,1H),12.8(bs,1H).
5-羟基-3-[(5'-喹啉基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(5'-喹啉基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(5'-喹啉基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(4'-喹啉基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(4'-喹啉基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(4'-喹啉基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟基吲哚;
5-氨基-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟基吲哚;
5-羧基-3-[(8'-羟基-4'-喹啉基)亚甲基]-2-羟基吲哚;
5-溴-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟基吲哚;
NMR δ ppm:6.76(d,1H),6.83(d,1H),7.12(d,1H),7.17(d,1H),7.22(d,1H),7.3-7.4(m,2H),7.6-7.7(m,2H),7.89(d,1H),8.08(s,1H),8.17(d,1H),8.36(dd,1H),8.46(s,1H),8.8-9.0(m,4H),10.66(s,1H),10.77(s,1H).
5-氟-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟基吲哚;
NMR δ ppm:6.8-6.9(m,2H),7.04(ddd,1H),7.22(d,1H),7.63(dd,1H),7.89(d,1H),8.08(s,1H),8.37(dd,1H),8.94(dd,1H),10.5(bs,1H),10.65(s,1H).
3-[(5'-羟基-4'-喹啉基)亚甲基]-2-羟基吲哚;
3-[(8'-羟基-4'-喹啉基)亚甲基]-2-羟基吲哚;
5-羟基-3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟基吲哚;
NMR δ ppm:3.86(s,3H),6.5-6.7(m,2H),6.82(dd,1H),7.36(m,2H),7.68(d,1H),7.99(s,1H),8.82(s,1H),9.37(d,1H),10.15(s,1H),11.8(bs,1H).
5-氨基-3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟基吲哚;
NMR δ ppm:3.87(s,3H),6.87(dd,1H),6.90(d,1H),7.07(dd,1H),7.42(d,1H),7.66(d,1H),7.81(d,1H),8.18(s,1H),9.44(d,1H),9.65(bs,3H),10.67(s,1H),12.03(d,1H).
5-羟基-3-[(2'-甲基-3'-吲哚基)亚甲基]-2-羟基吲哚。
实施例2
5-羟基-3-[(1'-四氢萘基)亚甲基]-2-羟基吲哚
于-78℃氮气环境下,在10分钟内向5-甲氧基-3-[(1'-四氢萘基)亚甲基]-2-羟吲哚(305mg,1mmol)的无水二氯甲烷(10ml)搅拌溶液中加入1.0M三溴化硼的二氯甲烷(3ml,3mmol)溶液。所得混合物于-78℃再搅拌1h,然后温热至室温。于20-25℃搅拌1.5h后,冷却混合物至-10℃,在10分钟内加入10ml水终止反应。加入乙酸乙酯,分离出有机层,水洗,Na2SO4干燥,并真空蒸发至干燥。经用乙醇结晶残余物后,得到纯标题化合物(产率70%)。
C19H17NO2理论值:C78.30 H5.88 N4.81
实测值:C78.15 H5.75 N4.71
MS m/z 291
IR cm-1:3600-2600(NH,OH),1655(amide),1610(amide),1585,1535(C=C).
实施例3
5-氨基-3-[(1'-四氢萘基)亚甲基]-2-羟基吲哚
向5-硝基-3-[(1'-四氢萘基)亚甲基]-2-羟基吲哚(320mg,1mmol)的无水乙醇(20ml)溶液中加入20mg披钯炭,并将混合物在室温及大气压下氢化,直至3当量氢气被吸收。将氢气吸入量对时间作图。过滤催化剂,真空浓缩溶液至开始结晶。然后冷却混合物至0-5℃,过滤,用冰冷乙醇洗涤残余物,并真空干燥。得到几乎纯的标题化合物,产率约80%。
C19H18N2O 理论值:C78.59 H6.25 N9.65
实测值:C78.45 H6.13 N9.55
MS m/z 290
IR cm-1:3400-3200(NH),1660(amide),1610(amide),1580,1530(C=C).
实施例4
5-甲氧基-3-[(2'-四氢萘基)亚甲基]-2-羟基吲哚
在搅拌条件下将5-羟基-3-[(2'-四氢萘基)亚甲基]-2-羟基吲哚(291mg,1mmol)的DMF(5ml)溶液在15分钟内加至用冰-丙醇浴冷却的95%氢化钠(28mg,1.1mmol)的DMF(10ml)悬浮液中。当氢气停止蒸发后,在15分钟内加入碘甲烷(156mg,1.1mmol)的DMF(5ml)溶液,并将混合物于室温下搅拌3h。真空下蒸馏掉绝大部分DMF,然后向残余物中加水,并将产物萃取至乙酸乙酯中。干燥含所需产物的有机溶液,蒸发溶剂,通过用乙醇研磨结晶残余的油,从而得到纯标题化合物,产率约60%。
C20H19NO2理论值:C78.66 H6.27 N4.59
实测值:C78.51 H6.11 N4.35
MS m/z 305
IR cm-1:3400-3200,1655,1605(amide),1580,1530(C=C).
实施例5
5-乙酸基-3-[(2'-四氢萘基)亚甲基]-2-羟基吲哚
向冷却的5-羟基-3-[(2'-四氢萘基)亚甲基]-2-羟基吲哚(291mg,1mmol)的无水吡啶溶液中加入乙酸酐(306mg,3mmol),并维持混合物0-5℃过夜。然后真空浓缩混合物,将残余物溶于二氯甲烷,水洗有机层,然后减压蒸发。粗产物自氯仿/甲醇中结晶,得到几乎纯的标题化合物(产率80%)。
C21H19NO3理论值:C75.66 H5.74 N4.20
实测值:C75.59 H5.81 N4.15
MS m/z 333.
实施例6
1,4-二羟基-2-四氢萘羧醛
向1,4-二羟基-四氢化萘(1.640g,0.01mmol)的二氯甲烷(50ml)溶液中加入四氯化钛(5.69g,0.03mmol)。然后在剧烈搅拌下滴加1,1-二氯代二甲醚(1.73g,0.015mol),并于室温下继续搅拌反应混合物3h。最后在冰冷却下加入5%盐酸(10ml)。分离有机相,残余的水相重复用乙醚萃取。合并有机相,用饱和盐水洗涤,于Na2SO4上干燥,并真空蒸发。由苯中结晶残余物或者将残余物进行硅胶快速层析(利用苯/乙酸乙酯85∶15),得到纯的标题化合物(60%,1.080g),m.p.145℃.MS m/z 180
NMR δ ppm:10.4(bs,OH),9.7(s,CHO),9.1(bs,OH),6.9(s,H arom),2.8(m,5-CH2,8-CH2),1.9(m,6-CH2,7-CH2).
实施例7
按照上面实例1以及WO 91/13055实施例1、2和7中所述的方法,分别以合适的喹啉-四氢化萘-或萘-羧醛和氰基乙酰胺、氰基硫代乙酰胺或4-羟基苯基氰化物作为起溶物,可制得下列化合物:
2-(4-羟基苯基)-3-(1,4-二甲氧基-2-萘基)丙烯腈
C16H14N2O3理论值:C68.07 H5.00 N9.93
实测值:C67.98 H5.02 N9.92
MS m/z 282
NMR δ ppm:3.90(3H,s),3.99(3H,s),7.60(1H,s),7.70(2H,m),7.8,8.0(2H,two S),8.15(2H,m),8.49(1H,s).
2-氰基-3-(4-喹啉基)丙烯酰胺
C13H9N3O 理论值:C69.95 H4.06 N18.82
实测值:C69.86 H4.01 N18.75
MS m/z 223
IR cm-1:3400,3299(NH),2210(CN),1680(CO),1610,1590,1580(C=C).
2-氰基-3-(3-吲哚基)丙烯酰胺
C12H9N3O 理论值:C68.24 H4.29 N19.89
实测值:C68.11 H4.21 N19.85
MS m/z 211
IR cm-1:3400,3150(NH),2220(CN),1680(CO),1605,1590,1580(C=C).
2-氰基-3-(1,4-二羟基-2-四氢萘基)丙烯酰胺
C14H14N2O3理论值:C65.10 H5.46 N10.85
实测值:C65.16 H5.58 N10.67
MS m/z 258
IR cm-1:3200-3400(NH,OH),2210(CN),1680(CO),1610,1595(C=C).
2-氰基-3-(1,4-二羟基-2-四氢萘基)硫代丙烯酰胺
C14H14N2O2S 理论值:C61.30 H5.14 N10.21 S11.69
实测值:C61.25 H5.01 N10.05 S11.65
MS m/z 274
IR cm-1:3100-3400(NH,OH),2200(CN),1620,1570(C=C).
2-氰基-3-(2-羟基-1-萘基)丙烯腈
C14H8N2O 理论值:C76.33 H3.66 N12.72
实测值:C76.11 H3.71 N12.73
MS m/z 220
NMR δ ppm:7.36(d,1H),7.5-7.9(m,2H),7.99(d,1H),
8.17(d,1H),9.47(d,1H),8.79(d,1H),9.17(d,1H).
2-氰基-3-(2-萘基)丙烯酰胺
C14H10N2O 理论值:C75.66 H4.54 N12.60
实测值:C75.63 H4.51 N12.65
MS m/z 225
IR cm-1:3390(NH),3180(NH),2210(CN),1690(CO),1615(amide),1595,1585(arom).
2-氰基-3-(2-萘基)硫代丙烯酰胺
C14H10N2S 理论值:C70.56 H4.23 N11.76 S13.45
实测值:C69.12 H4.35 N11.98 S13.10
MS m/z 238
NMR δ ppm:7.65(2H,m),8.05(4H,m),8.24(1H,s),8.44(1H,s),9.68,10.15(2H,bs).
2-氰基-3-(3,5-二羟基-2-萘基)丙烯酰胺
C14H10N2O3理论值:C66.13 H3.97 N11.02
实测值:C66.98 H3.85 N10.72
MS m/z 254.
实施例8
每片重0.150g且含有25mg活性物质的片剂可按如下方法制备:
组成(每10,000片):
5-氨基-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟基吲哚 250g
乳糖 800g
玉米淀粉 415g
滑石粉 30g
硬脂酸镁 5g
将5-氨基-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟基吲哚、乳糖及一半的玉米淀粉混合;然后将混合物通过0.5mm筛子。
将10g玉米淀粉悬浮在热水(90ml)中,并用所得糊状物粒化粉末。干燥颗粒,在1.4mm筛上粉碎,然后加入剩余量的淀粉、滑石和硬脂酸镁,仔细混合,并加工成片剂。
实施例9
每剂重0.200g且含20ml活性成分的胶囊可按如下方法制得:
组成(每500个胶囊):
3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟吲哚 10g
乳糖 80g
玉米淀粉 5g
硬脂酸镁 5g
将该配方包裹在两片硬明胶胶囊中,且每一胶囊0.200g。
Claims (13)
1、具有如下通式(Ⅰ)的化合物及其可作药用的盐:
其中
Y为选自萘、四氢化萘、喹啉和异喹啉的双环系统;
当Y为四氢化萘时R为氢或氧代(=0)基,或当Y为基、喹啉或喹啉时R为氢;
R1和R2各自独立地为氢、C1-R6烷基或R2-R6烷酰基;
m为0、1或2;
n为0、1、2或3;
R3和R4各自独立地为氢、卤素、氰基、C1-C6烷基、羧基、硝基或-NR6R7,其中R6和R7各自独立地为氢或C1-C6烷基;
R5为氢或C1-C6烷基;
且其中
a)同时当Y为萘基;R3为氢、卤素、氰基或C1-C6烷基;R5为氢;m为0且n、R和R1的定义同上时,则R4不为氢;
b)同时当Y为喹啉或异喹啉;R3为氢、卤素、氰基或C1-C6烷基;n为0、1或2;R5为氢;m为0且R和R1的定义同上时,则R4不为氢;
c)同时当Y为只有其中的苯基被取代的四氢化萘;R3为氢、卤素、氰基或C1-C6烷基;n为0、1或2;R5为氢;m为0;R为氢且R1的定义同前时,则R4不为氢;
d)同时当Y为萘;m和n为0;R和R3为氢;连于C-4碳原子上的R4为卤素或C1-C4烷基时,则R5不为C1-C2烷基。
2、根据权利要求1的式(Ⅰ)化合物,或其可作药用的盐,其中Y为四氢化萘、喹啉或异喹啉;
n为0、1、2或3;
m为0或1;
R1和R2各自独立地为氢或C1-C4烷基;
R3和R4各自独立地氢为、卤素、氰基、羧基或氨基;
R5为氢;且
R的定义同权利要求1
3、根据权利要求1的式(Ⅰ)化合物或其可作药用的盐,其中Y为四氢化萘或喹啉;
n为0、1、2或3;
m为0或1;
R1、R2和R5为氢;
R3和R4各自独立地为氢、氨基或羧基;且
R的定义同权利要求1。
4、一种选自下面的化合物或其可作药用的盐:
3-[(4’-氨基-1’-四氢萘基)亚甲基]-2-羟吲哚;
3-[(4’-二甲氨基-1’-四氢萘基)亚甲基]-2-羟吲哚;
3-[(4’-羧基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(1’-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(1’-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(1’-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(2’-羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4’-羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(2’-羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4’-羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(2’-羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4’-羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4’,5’-二羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4’,8’-二羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4’,5’-二羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4’,8’-二羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4’,5’-二羟基-1’-四氢萘基)亚甲基]-2-羟吲哚;
3-[(4’-氨基-2’-四氢萘基)亚甲基]-2-羟吲哚;
3-[(4’-羧基-2’-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(2’-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(2’-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(2’-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(1’-羟基-2’-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(3’-羟基-2’-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4’-羟基-2’-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(1’-羟基-2’-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(3’-羟基-2’-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4’-羟基-2’-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(1’-羟基-2’-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(3'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4'-羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(3',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(3',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(3',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-氨基-3-[(3',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4',8'-二羟基-2'-四氢萘基)亚甲 基]-2-羟吲哚;
5-羧基-3-[(3',5'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羧基-3-[(3',8'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(1',4',5'-三羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(1',4',8'-三羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
3-[(8'-氧代-1',4'-二羟基-2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(5'-喹啉)亚甲基]-2-羟吲哚;
5-氨基-3-[(5'-喹啉)亚甲基]-2-羟吲哚;
5-羧基-3-[(5'-喹啉)亚甲基]-2-羟吲哚;
5-羟基-3-[(4'-喹啉基)亚甲基]-2-羟吲哚;
5-氨基-3-[(4'-喹啉基)亚甲基]-2-羟吲哚;
5-羧基-3-[(4'-喹啉基)亚甲基]-2-羟吲哚;
5-羟基-3-[(8'-羟基-5'-喹啉)亚甲基]-2-羟吲哚;
5-氨基-3-[(8'-羟基-5'-喹啉)亚甲基]-2-羟吲哚;
5-羧基-3-[(8'-羟基-5'-喹啉)亚甲基]-2-羟吲哚;
5-羟基-3-[(8'-羟基-4'-喹啉)亚甲基]-2-羟吲哚;
5-氨基-3-[(8'-羟基-4'-喹啉)亚甲基]-2-羟吲哚;
5-羧基-3-[(8'-羟基-4'-喹啉)亚甲基]-2-羟吲哚;
5-溴-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟吲哚;
5-氟-3-[(8'-羟基-5'-喹啉基)亚甲基]-2-羟吲哚;
5-甲氧基-3-[(2'-四氢萘基)亚甲基]-2-羟吲哚;
5-乙酸基-3-[(2'-四氢萘基)亚甲基]-2-羟吲哚;
5-羟基-3-[(4'-羟基-1'-四氢萘基)亚甲基]-2-羟吲哚;
每一化合物为Z-或E-非对映异构体或其混合物。
5、一种选自下面的化合物及其可作药用的盐:
3-[(8'-羟基-7'-喹啉基)亚甲基]-2-羟吲哚;
3-[(5'-羟基-4'-喹啉基)亚甲基]-2-羟吲哚;
3-[(8'-羟基-4'-喹啉基)亚甲基]-2-羟吲哚;
3-[(2'-甲基-3'-吲哚基)亚甲基]-2-羟吲哚;
3-[(5'-氰基-3'-吲哚基)亚甲基]-2-羟吲哚;
3-[(5'-羟基-3'-吲哚基)亚甲基]-2-羟吲哚;
3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟吲哚;
5-羟基-3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟吲哚;
5-氨基-3-[(5'-甲氧基-3'-吲哚基)亚甲基]-2-羟吲哚;
5-羟基-3-[(2'-甲基-3'-吲哚基)亚甲基]-2-羟吲哚;
其中每一化合物为Z-或E-非对映异构体或其混合物。
6、一种选自下面的化合物及其可作药用的盐:
2-氰基-3-(4-喹啉基)丙烯酰胺;
2-氰基-3-(3-喹啉基)丙烯酰胺;
2-氰基-3-(1,4-二羟基-2-四氢萘基)丙烯酰胺;
2-氰基-3-(1,4-二羟基-2-四氢萘基)硫代丙烯酰胺;
2-氰基-3-(2-羟基-1-萘基)丙烯腈;
2-氰基-3-(2-萘基)丙烯酰胺;
2-氰基-3-(2-萘基)硫代丙烯酰胺;
2-氰基-3-(3,5-二羟基-2-萘基)丙烯酰胺;和
2-(4-羟苯基)-3-(1,4-二甲氧基-2-萘基)丙烯腈;
每一化合物为Z-或E-非对映异构作形式或其混合物。
8、一种药物组合物,它含有合适的载体和/或稀释剂以及作为活性成分的权利要求1、5或6所述的式(Ⅰ)化合物或其可作药用的盐。
9、用作酪氨酸激酶抑制剂的权利要求1、5或6的化合物或其可作药用的盐。
10、用作抗繁殖剂的权利要求9的化合物或盐。
11、权利要求9的化合物或盐,它用作抗转移剂或抗肿瘤剂以抑制粉瘤鼠疫的发展或控制血管生成。
12、式(Ⅰ)化合物及其可作药用的盐
其中
Y为选自萘、四氢化萘、喹啉和异喹啉的双环系统;
当Y为四氢化萘时R为氢或氧代(=0)基,或当Y为萘、喹啉或异喹啉时R为氢;
R1和R2各自独立地为氢、C1-R6烷基或R2-R6烷酰基;
m为0、1或2;
n为0、1、2或3;
R3和R4各自独立地为氢、卤素、氰基、C1-C6烷基、羧基、硝基或-NR6R7,其中R6和R7各自独立地为氢或C1-C6烷基;
R5为氢或C1-C6烷基;
且其中
a)同时当Y为萘基;R3为氢、卤素、氰基或C1-C6烷基;R5为氢;m为0且n、R和R1的定义同上时,则R4不为氢;
b)同时当Y为喹啉或异喹啉;R3为氢、卤素、氰基或C1-C6烷基;n为0、1或2;R5为氢;m为0且R和R1的定义同上时,则R4不为氢;
c)同时当Y为只有其中的苯基被取代的四氢化萘;R3为氢、卤素、氰基或C1-C6烷基;n为0、1或2;R5为氢;m为0;R为氢且R1的定义同前时,则R4不为氢;
在制备用作酪氨酸激酶抑制剂的药物组合物中的应用。
13、一种在抗癌治疗中作为结合制剂同时、分别或依次使用的产物,它含有权利要求12、5或6所述的化合物或其可作药用的盐以及另一种抗肿瘤剂。
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GB9501567D0 (en) * | 1995-01-26 | 1995-03-15 | Pharmacia Spa | Hydrosoluble 3-arylidene-2-oxindole derivatives as tyrosine kinase inhibitors |
US6906093B2 (en) | 1995-06-07 | 2005-06-14 | Sugen, Inc. | Indolinone combinatorial libraries and related products and methods for the treatment of disease |
US6147106A (en) | 1997-08-20 | 2000-11-14 | Sugen, Inc. | Indolinone combinatorial libraries and related products and methods for the treatment of disease |
US5880141A (en) * | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
RU2145852C1 (ru) * | 1996-01-17 | 2000-02-27 | Тайхо Фармасьютикал Ко., Лтд | Ингибитор гипертрофии интимы, применение оксиндолового производного для получения ингибитора гипертрофии интимы, композиция для ингибирования гипертрофии интимы, способ предупреждения и лечения гипертрофии интимы |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102115469A (zh) * | 2011-03-21 | 2011-07-06 | 浙江大学 | 吲哚啉-2-酮类衍生物的制备和用途 |
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