CN101087604B - 用于治疗或预防纤维化疾病的药剂 - Google Patents
用于治疗或预防纤维化疾病的药剂 Download PDFInfo
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- CN101087604B CN101087604B CN2005800446331A CN200580044633A CN101087604B CN 101087604 B CN101087604 B CN 101087604B CN 2005800446331 A CN2005800446331 A CN 2005800446331A CN 200580044633 A CN200580044633 A CN 200580044633A CN 101087604 B CN101087604 B CN 101087604B
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- alkyl
- phenyl
- methylene
- anilino
- amino
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Abstract
本发明是涉及在6位被取代的通式(I)的吲哚满酮、互变体、非对映体、对映体、其混合物及其盐特别是其生理可接受盐的新用途。
Description
发明领域
本发明是涉及在6位被取代的如下通式的吲哚满酮(indolinone)
其互变体,非对映体,对映体,混合物,及盐,特别是其生理可接受盐的新颖用途。
背景技术
上述通式I的化合物,其互变体,非对映体,对映体,混合物,及盐,特别是生理可接受盐,已述于WO 04/009547,具有有价值的药理学性质,特别是对于各种激酶,特别是受体酪氨酸激酶,如VEGFR1,VEGFR2,VEGFR3,PDGFRα,PDGFRβ,FGFR1,FGFR3,EGFR,HER2,c-Kit,IGF1R及HGFR,Flt-3,以及对于培养的人类细胞,特别是内皮细胞的增殖,例如在血管形成中,而还对于其他细胞,特别是肿瘤细胞的增殖具有抑制作用。
然而,这些化合物用于治疗或预防本发明中所述纤维化疾病的用途并未述及。
重新塑造为组织受伤及发炎的正常反应,可见于身体的许多组织。在发炎消除及组织伤害修复后,组织一般回复至其原来情况。过度不被控制的组织修复或不能停止不再需要的重新塑造导致称为纤维变性的症状。纤维变性的特征在于细胞外基质成分的过量沉积及成纤维细胞的过度生长。纤维变性可发生于所有组织,但是特别普遍于常暴露于化学及生物学危害的器官,包括肺、皮肤、消化道、肾、及肝(Eddy,1996,J Am Soc Nephrol,7(12):2495-503;Dacic等,2003,Am J Respir Cell Mol Biol,29S:S5-9;Wynn,2004,Nat Rev Immunol,4(8):583-94)。纤维变性通常严重地损害器官的正常功能,许多纤维化疾病事实上威胁生命或严重地毁形,如特发性肺纤维化(IPF),肝硬化,硬皮病,或肾纤维变性。这些疾病的治疗方式通常限于器官移植,为危险而昂贵的手术。
许多文献指出血小板衍生生长因子(PDGF),成纤维细胞生长因子(FGF),血管内皮生长因子(VEGF),表皮生长因子(EGF),及转化生长因子β(TGFb)的生长因子族涉及纤维变性的诱发或持续(Levitzki,CytokineGrowth Factor Rev,2004,15(4):229-35;Strutz等,Kidney Intl,2000,57:1521-38;Strutz等,2003,Springer Semin Immunopathol,24:459-76;Rice等,1999,Amer J Pathol,155(1):213-221;Broekelmann等,1991,Proc NatAcad Sci,88:6642-6;Wynn,2004,Nat Rev Immunol,4(8):583-94)。
PDGF,EGF及FGF族成员为间充质细胞如平滑肌细胞,肌成纤维细胞,及成纤维细胞的有效力有丝***素(Benito等,1993,Growth Regul3(3):172-9;Simm等,1998,Basic Res Cardiol,93(S3):40-3;Klagsburn,ProgGrowth Factor Res,1989,1(4):207-35;Kirkland等,1998,J Am Soc Nephrol,9(8):464-73),这些细胞在纤维变性中取代正常组织,相信在组织重新塑造中发挥重要作用(Abboud,1995,Annu Rev Physiol.,57:297-309;Jinnin等,2004,J Cell Physiol,online;Martinet等,1996,Arch Toxicol18:127-39;Desmouliere,Cell Biology International,1995,19:471-6;Jelaska等,SpringerSemin Immunopathol,2000,21:385-95)。
在实验模型中PDGF的抑制减弱肝纤维变性及肺纤维变性,暗示不同器官的纤维变性可能有共同来源(Borkham-Kamphorst等,2004,BiochemBiophys Res Commun;Rice等,1999,Amer J Pathol,155(1):213-221)。EGF受体激酶抑制剂在此肺纤维变性模型中还有效。EGF族成员HB-EGF在鼠胰脏胰岛中三倍过度表达足以引起外分泌及内分泌室发生纤维变性(Means等,2003,Gastroenterology,124(4):1020-36)。
相似地,缺乏FGF1/FGF2的小鼠在长期暴露于四氯化碳(CCl4)后显示肝纤维变性剧烈减少(Yu等,2003,Am J Pathol,163(4):1653-62)。在与间质瘢痕形成极有关的人类肾间质纤维变性中(Strutz等,2000,Kidney Intl,57:1521-38),及在实验肺纤维变性模型中(Barrios等,1997,Am J Physiol,273(2Pt1):L451-8),FGF的表达增加再次使人相信各组织中纤维变性有共同基础的概念。
此外,VEGF的量增加已发现于哮喘者的数项研究中(Hoshino等,2001,J Allergy Clin Immunol107:1034-39;Hoshino等,2001,J Allergy Clin Immunol107:295-301;Kanazawa等,2002,Thorax57:885-8;Asai等,J Allergy ClinImmunol110:571-5,2002;Kanazawa等,2004,Am J Respir Crit Care Med,169:1125-30)。在转基因鼠模型中VEGF的诱发表达诱发似哮喘的表型,水肿,血管形成,及平滑肌过度增生(Lee等,2004,Nature Med10:1095-1103)。
最后,TGFb刺激细胞外基质蛋白质包括纤连蛋白(fibronectin)及胶原的产生,相信在许多组织的纤维变性中发挥重要作用(Leask等,2004,FASEB J18(7):816-27;Bartram等,2004,Chest125(2):754-65;Strutz等,2003,SpringerSemin Immunopathol,24:459-76;Wynn,2004,Nat Rev Immunol,4(8):583-94)。TGFb产生及信号途径的抑制剂在许多纤维变性动物模型中有效(Wang等,2002,Exp Lung Res,28:405-17;Laping,2003,Curr Opin Pharmacol,3(2):204-8)。
如上述,几种生长因子在纤维变性中上调,并且在纤维变性模型中单一因子的抑制似乎可减少纤维变性的严重性。
发明内容
令人惊奇地,我们发现上述通式I的化合物在治疗及预防特定纤维化疾病中有效。
因此,本发明是涉及上述通式I化合物在制备用于治疗或预防特定纤维化疾病的药物的用途。
本发明还涉及一种治疗或预防特定纤维化疾病的方法,由对于需要的病人施用包含上述通式I的化合物与医药适合的载剂一起的药物组合物。术语“病人”意为包含哺乳类动物,优选为人类。
本发明另涉及用于治疗或预防特定纤维化疾病的药物组合物,其包含上述通式I的化合物单独或组合一或多种其他治疗剂。
发明详述
根据本发明,通式I的化合物为下列化合物
其中
I.在上式I中
X为氧原子,
R1为氢原子,
R2为氟,氯,或溴原子,或氰基,
R3为苯基或被氟、氯、溴或碘原子或被C1-3-烷氧基单取代的苯基,其中上述未被取代及被单取代的苯基可另在3-或4-位被选自下列的基团取代:
氟,氯,或溴原子,
氰基,
C1-3-烷氧基,或C1-2-烷基-羰基-氨基,
氰基-C1-3-烷基,羧基-C1-3-烷基,羧基-C1-4-烷氧基,羧基-C1-3-烷基氨基,羧基-C1-3-烷基-N-(C1-3-烷基)-氨基,C1-4-烷氧基-羰基-C1-3-烷基,C1-4-烷氧基-羰基-C1-3-烷氧基,C1-4-烷氧基-羰基-C1-3-烷基氨基,C1-4-烷氧基-羰基-C1-3-烷基-N-(C1-3-烷基)-氨基,氨基-C1-3-烷基,氨基羰基-C1-3-烷基,(C1-2-烷基-氨基)-羰基-C1-3-烷基,二-(C1-2-烷基)-氨基-羰基-C1-3-烷基,(C1-2-烷基-羰基)-氨基-C1-3-烷基,(C1-4-烷氧基-羰基)-氨基-C1-3-烷基,(C3-6-烷基-羰基)-氨基-C1-3-烷基,(苯基-羰基)-氨基-C1-3-烷基,(C3-6-环烷基-羰基)-氨基-C1-3-烷基,(C3-6-环烷基-C1-3-烷基-羰基)-氨基-C1-3-烷基,(噻吩-2-基-羰基)-氨基-C1-3-烷基,(呋喃-2-基-羰基)-氨基-C1-3-烷基,(苯基-C1-3-烷基-羰基)-氨基-C1-3-烷基,(2-(C1-4-烷氧基)-苯甲酰基-羰基)-氨基-C1-3-烷基,(吡啶-2-基-羰基)-氨基-C1-3-烷基,(吡啶-3-基-羰基)-氨基-C1-3-烷基-,(吡啶-4-基-羰基)-氨基-C1-3-烷基-,或C1-3-烷基-哌嗪-1-基-羰基-C1-3-烷基,羧基-C2-3-烯基,氨基羰基-C2-3-烯基,(C1-3-烷基氨基)-羰基-C2-3-烯基,二-(C1-3-烷基)-氨基-羰基-C2-3-烯基,或C1-4-烷氧基-羰基-C2-3-烯基,其中取代基可相同或不同,
R4为苯基或被下列基团单取代的苯基:
C1-3-烷基,其在末端被氨基,胍基,单或二-(C1-2-烷基)-氨基,N-[ω-二-(C1-3-烷基)-氨基-C2-3-烷基]-N-(C1-3-烷基)-氨基,N-甲基-(C3-4-烷基)-氨基,N-(C1-3-烷基)-N-苄基氨基,N-(C1-4-烷氧基羰基)-氨基,N-(C1-4-烷氧基羰基)-C1-4-烷基氨基,4-(C1-3-烷基)-哌嗪-1-基,咪唑-1-基,吡咯烷-1-基,氮杂环丁-1-基,吗啉-4-基,哌嗪-1-基,硫吗啉-4-基取代,
二-(C1-3-烷基)-氨基-(C1-3-烷基)-磺酰基,2-[二-(C1-3-烷基)-氨基]-乙氧基,4-(C1-3-烷基)-哌嗪-1-基-羰基,{ω-[二-(C1-3-烷基)-氨基]-(C2-3-烷基)}-N-(C1-3-烷基)-氨基-羰基,1-(C1-3-烷基)咪唑-2-基,(C1-3-烷基)-磺酰基,或
下式的基团
其中
R7为C1-2-烷基,C1-2-烷基-羰基,二-(C1-2-烷基)-氨基-羰基-C1-3-烷基,或C1-3-烷基磺酰基,及
R8为C1-3-烷基,ω-[二-(C1-2-烷基)-氨基]-C2-3-烷基,ω-[单-(C1-2-烷基)-氨基]-C2-3-烷基,或
(C1-3-烷基)-羰基,(C4-6-烷基)-羰基,或羰基-(C1-3-烷基),其末端被二-(C1-2-烷基)-氨基,哌嗪-1-基,或4-(C1-3-烷基)-哌嗪-1-基取代,
R4基团中存在的所有二烷基氨基还可以季铵化形式存在,例如以N-甲基-(N,N-二烷基)-铵基,其中平衡离子优选选自碘离子,氯离子,溴离子,甲磺酸根,对-甲苯磺酸根,及三氟醋酸根,
R5为氢原子,及
R6为氢原子,
其中上述烷基包括直链及支链的烷基,其中1至3个氢原子可以被氟原子替代,其中存在的羧基,氨基,或亚胺基可被在活体内可裂解的基团取代,或可以前药基的形式存在,例如以可在活体内转化为羧基的基团形式或可在活体内转化为亚胺基或氨基的基团的形式,
其互变体,对映体,非对映体,混合物,及盐。
II.上式I的特别优选化合物为下述化合物,其中X,R1,R5及R6如I.中定义,及
II.i.R2及R4如I中定义,及
R3为苯基或被氟,氯,溴,或碘原子或C1-3-烷氧基单取代的苯基,其中上述未被取代及被单取代的苯基可另在3-或4-位被选自下列的基团取代:
氟,氯,或溴原子,
氰基,
C1-3-烷氧基,或C1-2-烷基-羰基-氨基,
氰基-C1-3-烷基,羧基-C1-3-烷基,羧基-C1-4-烷氧基,羧基-C1-3-烷基氨基,羧基-C1-3-烷基-N-(C1-3-烷基)-氨基,C1-4-烷氧基-羰基-C1-3-烷基,C1-4-烷氧基-羰基-C1-3-烷氧基,C1-4-烷氧基-羰基-C1-3-烷基氨基,C1-4-烷氧基-羰基-C1-3-烷基-N-(C1-3-烷基)-氨基,氨基-C1-3-烷基,氨基羰基-C1-3-烷基,(C1-2-烷基-氨基)-羰基-C1-3-烷基,二-(C1-2-烷基)-氨基-羰基-C1-3-烷基,(C1-2-烷基-羰基)-氨基-C1-3-烷基,(C1-4-烷氧基-羰基)-氨基-C1-3-烷基,(C3-6-烷基-羰基)-氨基-C1-3-烷基,(苯基-羰基)-氨基-C1-3-烷基,(C3-6-环烷基-羰基)-氨基-C1-3-烷基,(C3-6-环烷基-C1-3-烷基-羰基)-氨基-C1-3-烷基,(噻吩-2-基-羰基)-氨基-C1-3-烷基,(呋喃-2-基-羰基)-氨基-C1-3-烷基,(苯基-C1-3-烷基-羰基)-氨基-C1-3-烷基,(2-(C1-4-烷氧基)-苯甲酰基-羰基)-氨基-C1-3-烷基,(吡啶-2-基-羰基)-氨基-C1-3-烷基,(吡啶-3-基-羰基)-氨基-C1-3-烷基,(吡啶-4-基-羰基)-氨基-C1-3-烷基,或C1-3-烷基-哌嗪-1-基-羰基-C1-3-烷基,羧基-C2-3-烯基,氨基羰基-C2-3-烯基-,(C1-3-烷基氨基)-羰基-C2-3-烯基-,二-(C1-3-烷基)-氨基-羰基-C2-3-烯基,或C1-4-烷氧基-羰基-C2-3-烯基,
其中取代基可相同或不同,
II.ii.R2及R4如I.中定义,及
R3为被选自下列基团取代的苯基:
C1-2-烷基-羰基-氨基,
羧基-C1-3-烷基,羧基-C1-4-烷氧基,C1-4-烷氧基-羰基-C1-3-烷基,C1-4-烷氧基-羰基-C1-3-烷氧基,氨基羰基-C1-3-烷基,(C1-2-烷基-氨基)-羰基-C1-3-烷基,二-(C1-2-烷基)-氨基-羰基-C1-3-烷基,(C1-2-烷基-羰基)-氨基-C1-3-烷基,(C1-4-烷氧基-羰基)-氨基-C1-3-烷基,(苯基-羰基)-氨基-C1-3-烷基,(C3-6-环烷基-羰基)-氨基-C1-3-烷基,(C3-6-环烷基-C1-3-烷基-羰基)-氨基-C1-3-烷基,(噻吩-2-基-羰基)-氨基-C1-3-烷基,(呋喃-2-基-羰基)-氨基-C1-3-烷基,(苯基-C1-3-烷基-羰基)-氨基-C1-3-烷基,(2-(C1-4-烷氧基)-苯甲酰基-羰基)-氨基-C1-3-烷基,(吡啶-2-基-羰基)-氨基-C1-3-烷基,(吡啶-3-基-羰基)-氨基-C1-3-烷基,(吡啶-4-基-羰基)-氨基-C1-3-烷基,或C1-3-烷基-哌嗪-1-基-羰基-C1-3-烷基,
氨基羰基-C2-3-烯基,(C1-3-烷基氨基)-羰基-C2-3-烯基,二-(C1-3-烷基)-氨基-羰基-C2-3-烯基,或C1-4-烷氧基-羰基-C2-3-烯基,
II.iii.R2及R4如I.中定义,及
R3为被羧基-C1-3-烷基或C1-4-烷氧基-羰基-C1-3-烷基取代的苯基;
II.iv.R3及R4如I.中定义,及
R2为氟或氯原子;
II.v.R2及R3如I.中定义,及
R4为苯基或为被选自下列基团单取代的苯基:
C1-3-烷基,在末端被氨基,胍基,单或二-(C1-2-烷基)-氨基,N-[ω-二-(C1-3-烷基)-氨基-C2-3-烷基]-N-(C1-3-烷基)-氨基,N-甲基-(C3-4-烷基)-氨基,N-(C1-3-烷基)-N-苄基氨基,N-(C1-4-烷氧基羰基)-氨基,N-(C1-4-烷氧基羰基)-C1-4-烷基氨基,4-(C1-3-烷基)-哌嗪-1-基,咪唑-1-基,吡咯烷-1-基,氮杂环丁-1-基,吗啉-4-基,哌嗪-1-基,硫吗啉-4-基取代,
二-(C1-3-烷基)-氨基-(C1-3-烷基)-磺酰基,2-[二-(C1-3-烷基)-氨基]-乙氧基,4-(C1-3-烷基)-哌嗪-1-基-羰基,{ω-[二-(C1-3-烷基)-氨基]-(C2-3-烷基)}-N-(C1-3-烷基)-氨基-羰基,1-(C1-3-烷基)咪唑-2-基,(C1-3-烷基)-磺酰基,或
下式的基团
其中
R7为C1-2-烷基,C1-2-烷基-羰基,二-(C1-2-烷基)-氨基-羰基-C1-3-烷基,或C1-3-烷基磺酰基,及
R8为C1-3-烷基,ω-[二-(C1-2-烷基)-氨基]-C2-3-烷基,ω-[单(C1-2-烷基)-氨基]-C2-3-烷基,或
(C1-3-烷基)-羰基,(C4-6-烷基)-羰基,或羰基-(C1-3-烷基),其末端被二-(C1-2-烷基)-氨基,哌嗪-1-基,或4-(C1-3-烷基)-哌嗪-1-基取代,
R4基团中存在的所有二烷基氨基还可以季铵化形式存在,例如以N-甲基-(N,N-二烷基)-铵基,其中平衡离子优选选自碘离子,氯离子,溴离子,甲磺酸根,对-甲苯磺酸根,及三氟醋酸根,
III.可提及的上式I的特别优选化合物的亚组为其中
III.i.X,R1,R2,R5及R6如I.中定义,R3如II.i.中定义,及R4如II.v.中定义;
III.ii.X,R1,R2,R5及R6如I.中定义,R3如II.ii.中定义,及R4如II.v.中定义;
III.iii.X,R1,R2,R5及R6如I.中定义,R3如II.iii.中定义,及R4如II.v.中定义;
III.iv.X,R1,R5及R6如I.中定义,R2如II.iv.中定义,R3如II.i.,II.ii.,或II.iii.中定义,及R4如II.v.中定义。
上式I的化合物的另一优选组为其中
X为氧原子,
R1为氢原子,
R2为氟,氯,或溴原子,或氰基,
R3为苯基或被氟、氯、溴或碘原子或C1-3-烷氧基单取代的苯基,其中上述未被取代及被单取代的苯基可另在3-或4-位被选自下列的基团取代:
氟,氯,或溴原子,
C1-3-烷氧基,或C1-2-烷基-羰基-氨基,
羧基-C1-3-烷基,氨基羰基-C1-3-烷基,(C1-2-烷基-氨基)-羰基-C1-3-烷基,二-(C1-2-烷基)-氨基-羰基-C1-3-烷基,(C1-2-烷基-羰基)-氨基-C1-3-烷基,或(苯基-羰基)-氨基-C1-3-烷基,
其中取代基可相同或不同,
R4为被选自下列基团取代的苯基:
C1-3-烷基,在末端被二-(C1-2-烷基)-氨基取代,或
下式的基团
其中
R7为C1-2-烷基,C1-2-烷基-羰基,二-(C1-2-烷基)-氨基-羰基-C1-3-烷基,或C1-3-烷基磺酰基,及
R8为C1-3-烷基,或ω-[二-(C1-2-烷基)-氨基]-C2-3-烷基,或(C1-3-烷基)-羰基,在末端被二-(C1-2-烷基)-氨基,哌嗪基,或4-(C1-3-烷基)-哌嗪-1-基取代,
R5为氢原子,及
R6为氢原子,
其中上述烷基包括直链及支链的烷基,其中1至3个氢原子可以氟原子替代,
其中存在的羧基,氨基,或亚胺基可被在活体内可裂解的基团取代,
其互变体,对映体,非对映体,混合物,及盐。
下列式I化合物特别优选:
(a)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(b)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(c)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(d)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(e)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(f)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(g)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(h)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(i)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(j)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(k)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(l)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(m)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(n)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(o)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(p)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(q)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)-亚甲基]-6-溴-2-吲哚满酮
其中存在的羧基,氨基,或亚胺基可被在活体内可裂解的基团取代,或可以前药基的形式存在,例如以可在活体内转化为羧基的基或可在活体内转化为亚胺基或氨基的基的形式,
其互变体,对映体,非对映体,混合物,及盐。
在活体内可解离的并在体内转化成羧基的基团,意指如羟甲基,以醇酯化的羧基,其中的醇部分优选表示C1-6-烷醇,苯基-C1-3-烷醇,C3-9-环烷醇,而C5-8-环烷醇可另外被1或2个C1-3-烷基所取代,C5-8环烷醇,其中在3或4位上的亚甲基可被氧原子或亚氨基所替代,而亚氨基任选可被C1-3-烷基,苯基-C1-3-烷基,苯基-C1-3-烷氧基-羰基或C1-6-烷基-羰基所取代,且环烷醇部分可另外被1或2个C1-3-烷基所取代,C4-7-环烯醇,C3-5-烯醇,苯基-C3-5-烯醇,C3-5-炔醇或苯基-C3-5-炔醇,其条件为由带有双或三键的碳原子开始至氧原子是没有键的,C3-8-环烷基-C1-3-烷醇,有总共8至10个碳原子的二环烷醇,其可另外在二环烷基部分被1或2个C1-3-烷基所取代,1,3-二氢-3-氧代-1-异苯并呋喃醇或下式的醇
Ra-CO-O-(RbCRc)-OH,
其中
Ra表示C1-8-烷基,C5-7-环烷基,苯基或苯基-C1-3-烷基,
Rb表示氢原子,C1-3-烷基,C5-7-环烷基或苯基且
Rc表示氢原子或C1-3-烷基,
以及在于活体内从氨基或从吲哚满酮部分的N-1原子可解离的基团意指例如羟基,酰基如苄酰基或吡啶酰基,或C1-16-烷基-羰基,如甲酰基,乙酰基,丙酰基,丁酰基,戊酰基或己酰基,烯丙氧基羰基,C1-16-烷氧基-羰基如甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基,叔丁氧羰基,戊氧羰基,己氧羰基,辛氧羰基,壬氧羰基,癸氧羰基,十一烷基氧羰基,十二烷基氧羰基或十六烷基氧羰基,苯基-C1-6-烷氧羰基例如苄氧羰基,苯基乙氧羰基或苯基丙氧羰基,C1-3-烷基磺酰基-C1-4-烷氧羰基,C1-3-烷氧基-C2-4-烷氧基-C2-4-烷氧基-羰基或RaCO-O-(RbCRc)-O-CO-基,其中
Ra表示C1-8-烷基,C5-7-环烷基,苯基或苯基-C1-3-烷基,
Rb表示氢原子,C1-3-烷基,C5-7-环烷基或苯基,且
Rc表示氢原子,C1-3-烷基或RaCO-O-(RbCRc)-O-基,其中Ra至Rc如上文所定义,
且另外,苯二甲酰亚氨基,而上述的酯基也可用作能在活体内可转化成羧基的基团。
对羧基优选的前药基团包括C1-6-烷氧基-羰基,如甲氧羰基,乙氧羰基,正丙氧羰基,异丙氧羰基,正丁氧羰基,正-戊氧羰基,正-己氧羰基或环己氧羰基或苯基-C1-3-烷氧基-羰基,如苄氧羰基,且
对亚氨基或者氨基,C1-9-烷氧基-羰基,如甲氧羰基,乙氧羰基,正丙氧羰基,异丙氧羰,正-丁氧羰基,正-戊氧羰基,正-己氧羰基,环己氧羰基,正-庚氧羰基,正-辛氧羰基或正-壬氧羰基,苯基-C1-3-烷氧基-羰基如苄氧羰基,苯基羰基任选被C1-3-烷基所取代,如苄酰基或4-乙基-苄酰基,吡啶酰基如烟酰基,C1-3-烷基磺酰基-正-C2-3-烷氧基-羰基或C1-3-烷氧基-C2-3-烷氧基-C1-4-烷氧基-羰基,如2-甲基磺酰基乙氧羰基或2-(2-乙氧基)-乙氧羰基。
上述例示的化合物,其互变体,立体异构体,或生理可接受盐,以及其制造方法已经记载在WO 04/009547中,其内容并入本文供参考。
下列具体的化合物例示本发明,并非用于限制其范围:
(1)3-Z-[1-(4-(N-甲基-N-甲基磺酰基氨基)苯胺基)-1-(3-碘苯基)-亚甲基]-6-氯-2-吲哚满酮
(2)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-碘苯基)亚甲基]-6-氯-2-吲哚满酮
(3)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-氯苯基)亚甲基]-6-氯-2-吲哚满酮
(4)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(4-氯苯基)亚甲基]-6-氯-2-吲哚满酮
(5)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-氯苯基)亚甲基]-6-氯-2-吲哚满酮
(6)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(4-氯苯基)亚甲基]-6-氯-2-吲哚满酮
(7)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-氯苯基)亚甲基]-6-氯-2-吲哚满酮
(8)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(3,4-二甲氧基苯基)亚甲基]-6-氯-2-吲哚满酮
(9)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3,4-二甲氧基苯基)亚甲基]-6-氯-2-吲哚满酮
(10)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(3,4-二甲氧基苯基)亚甲基]-6-氯-2-吲哚满酮
(11)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3,4-二甲氧基苯基)-亚甲基]-6-氯-2-吲哚满酮
(12)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲酰基)苯胺基)-1-(3,4-二甲氧基苯基)亚甲基]-6-氯-2-吲哚满酮
(13)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-氰基苯基)-亚甲基]-6-氯-2-吲哚满酮
(14)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-碘苯基)亚甲基]-6-氟-2-吲哚满酮
(15)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-氟苯基)亚甲基]-6-氟-2-吲哚满酮
(16)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(3-氟苯基)亚甲基]-6-氟-2-吲哚满酮
(17)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-氟苯基)亚甲基]-6-氟-2-吲哚满酮
(18)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-(2-乙酰基氨基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(19)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-乙酰基氨基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(20)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-乙酰基氨基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(21)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(22)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-碘苯基)亚甲基]-6-氟-2-吲哚满酮
(23)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(24)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-(N-叔丁氧基羰基-氨基甲基)苯基)亚甲基]-6-氟-2-吲哚满酮
(25)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(26)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(27)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-氰基甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(28)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(N-叔丁氧基羰基-氨基甲基)苯基)亚甲基]-6-氟-2-吲哚满酮
(29)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-(N-叔丁氧基羰基-氨基甲基)苯基)亚甲基]-6-氟-2-吲哚满酮
(30)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-(N-叔丁氧基羰基-2-氨基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(31)3-Z-[1-(4-(N-乙酰基-N-甲基氨基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(32)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(33)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(34)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(35)3-Z-[1-(4-(N-叔丁氧基羰基甲基氨基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(36)3-Z-[1-(4-(4-甲基哌嗪-1-基-羰基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(37)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(38)3-Z-[1-(4-甲基磺酰基苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(39)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(40)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(41)3-Z-[1-(4-(4-甲基哌嗪-1-基-羰基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(42)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(43)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(44)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(45)3-Z-[1-(4-(N-(4-二甲基氨基-丁基羰基)-N-甲基氨基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(46)3-Z-[1-苯胺基-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(47)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(48)3-Z-[1-(4-(4-甲基哌嗪-1-基羰基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(49)3-Z-[1-(4-(N-(二甲基氨基羰基甲基)-N-甲基磺酰基氨基)苯胺基)-1-(4-甲氧基羰基甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(50)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(51)3-Z-[1-(4-(N-甲基-N-乙酰基氨基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(52)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(53)3-Z-[1-(4-甲基磺酰基苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(54)3-Z-[1-(4-(N-(3-二甲基氨基丙基羰基)-N-甲基氨基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(55)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(56)3-Z-[1-苯胺基-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(57)3-Z-[1-(4-甲基磺酰基苯胺基)-1-(3-甲氧基羰基甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(58)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(59)3-Z-[1-(4-(N-(二甲基氨基羰基甲基)-N-甲基磺酰基氨基)苯胺基)-1-(3-甲氧基羰基甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(60)3-Z-[1-(4-(N-(3-二甲基氨基丙基羰基)-N-甲基氨基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(61)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(62)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(63)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(64)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(65)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(3-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(66)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(N-叔丁氧基羰基-氨基甲基)苯基)亚甲基]-6-氟-2-吲哚满酮
(67)3-Z-[1-(4-(N-甲基-N-乙酰基氨基)苯胺基)-1-(3-乙酰基氨基甲基苯基)亚甲基]-6-氯-2-吲哚满酮
(68)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(3-乙酰基氨基甲基苯基)亚甲基]-6-氯-2-吲哚满酮
(69)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(3-乙酰基氨基甲基苯基)亚甲基]-6-氯-2-吲哚满酮
(70)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-乙酰基氨基甲基苯基)亚甲基]-6-氯-2-吲哚满酮
(71)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(72)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(73)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(74)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(75)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(76)3-Z-[1-(4-(N-(3-二甲基氨基丙基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(77)3-Z-[1-(4-(N-(4-二甲基氨基丁基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(78)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(79)3-Z-[1-(4-(N-(4-二甲基氨基丁基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(80)3-Z-[1苯胺基-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(81)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(82)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(83)3-Z-[1-(4-(N-叔丁氧基羰基氨基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(84)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(3-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(85)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(4-甲氧基羰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(86)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(87)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(88)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(4-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(89)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(90)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(91)3-Z-[1-(4-((4-甲基哌嗪-1-基)甲基)苯胺基)-1-(3-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(92)3-Z-[1-(4-(咪唑-1-基甲基)苯胺基)-1-(3-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(93)3-Z-[1-(4-((4-甲基哌嗪-1-基)甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(94)3-Z-[1-(4-(咪唑-1-基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(95)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(96)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(97)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(98)3-Z-[1苯胺基-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(99)3-Z-[1-(4-(N-叔丁氧基羰基氨基甲基)苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(100)3-Z-[1-(4-(N-叔丁氧基羰基甲基氨基甲基)苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(101)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-甲氧基羰基甲氧基-苯基)亚甲基]-6-氟-2-吲哚满酮
(102)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-甲氧基羰基甲氧基-苯基)亚甲基]-6-氟-2-吲哚满酮
(103)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-乙氧基羰基-乙氧基)苯基)亚甲基]-6-氟-2-吲哚满酮
(104)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(105)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(106)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(107)3-Z-[1-(3-二甲基氨基甲基苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(108)3-Z-[1-(3-二甲基氨基甲基苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(109)3-Z-[1-(3-二甲基氨基甲基苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(110)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3,4-二甲氧基苯基)-亚甲基]-6-氰基-2-吲哚满酮
(111)3-Z-[1-(4-(N-甲基-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-甲氧基羰基乙烯基)苯基)亚甲基]-6-氯-2-吲哚满酮
(112)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-(2-甲氧基羰基-乙烯基)苯基)亚甲基]-6-氯-2-吲哚满酮
(113)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-(2-氨基甲酰基-乙烯基)苯基)亚甲基]-6-氟-2-吲哚满酮
(114)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-(2-甲氧基羰基-乙烯基)苯基)亚甲基]-6-氟-2-吲哚满酮
(115)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-(2-甲氧基羰基-乙烯基)苯基)亚甲基]-6-氟-2-吲哚满酮
(116)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(117)3-Z-[1-(4-(N-甲基-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(118)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(119)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(120)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(121)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-氨基甲基苯基)-亚甲基]-6-氯-2-吲哚满酮
(122)3-Z-[1-(4-(N-((4-甲基哌嗪-1-基)甲基羰基)-N-甲基氨基)苯胺基)-1-(4-氨基甲基苯基)亚甲基]-6-氯-2-吲哚满酮
(123)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-氨基甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(124)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(3-(2-氨基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(125)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-氨基甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(126)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-氨基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
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(128)3-Z-[1-(4-(甲基氨基甲基)苯胺基)-1-(4-(2-甲基氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(129)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-氨基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(130)3-Z-[1-(4-(氨基甲基)苯胺基)-1-(4-(2-甲氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(131)3-Z-[1-(4-(氨基甲基)苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(132)3-Z-[1-(4-(甲基氨基甲基)苯胺基)-1-(3-(2-乙氧基羰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(133)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(134)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(135)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-羧甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(136)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(137)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-羧甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(138)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(139)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(140)3-Z-[1-(4-(N-甲基-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(141)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(142)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(143)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(144)3-Z-[1-(4-(N-叔丁氧基羰基甲基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(145)3-Z-[1-(4-(4-甲基哌嗪-1-基羰基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(146)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(147)3-Z-[1-(4-甲基磺酰基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(148)3-Z-[1-(4-(4-甲基哌嗪-1-基羰基)苯胺基)-1-(3-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(149)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(150)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(151)3-Z-[1-(4-(N-(4-二甲基氨基丁基羰基)-N-甲基氨基)苯胺基)-1-(3-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(152)3-Z-[1-苯胺基-1-(3-羧甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(153)3-Z-[1-(4-甲基磺酰基苯胺基)-1-(3-羧甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(154)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(3-羧甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(155)3-Z-[1-(4-(N-(二甲基氨基羰基甲基)-N-甲基磺酰基氨基)苯胺基)-1-(3-羧甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(156)3-Z-[1苯胺基-1-(4-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(157)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(4-羧甲基苯基)-亚甲基]-
(158)6-氟-2-吲哚满酮
(159)3-Z-[1-(4-(N-(3-二甲基氨基丙基羰基)-N-甲基氨基)苯胺基)-1-(4-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(160)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(161)3-Z-[1-(4-(4-甲基哌嗪-1-基-羰基)苯胺基)-1-(4-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(162)3-Z-[1-(4-甲基磺酰基苯胺基)-1-(4-羧甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(163)3-Z-[1-(4-(N-甲基-N-乙酰基氨基)苯胺基)-1-(4-羧甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(164)3-Z-[1-(4-(N-(二甲基氨基羰基甲基)-N-甲基磺酰基氨基)苯胺基)-1-(4-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(165)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(4-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(166)3-Z-[1-(4-(N-(3-二甲基氨基丙基羰基)-N-甲基氨基)苯胺基)-1-(4-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(167)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(168)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(3-羧甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(169)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(170)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(171)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(172)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(173)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(174)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(175)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(176)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(177)3-Z-[1-(4-(N-(3-二甲基氨基丙基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(178)3-Z-[1-(4-(N-(4-二甲基氨基-丁基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(179)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(180)3-Z-[1-(4-(N-(4-二甲基氨基丁基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(181)3-Z-[1苯胺基-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(182)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(183)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(184)3-Z-[1-(4-氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(185)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(3-羧甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(186)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(4-羧甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(187)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(188)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(189)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(190)3-Z-[1-(4-((4-甲基哌嗪-1-基)甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(191)3-Z-[1-(4-(咪唑-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(192)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(193)3-Z-[1-(4-((4-甲基哌嗪-1-基)甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(194)3-Z-[1-(4-(咪唑-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(195)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(196)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(197)3-Z-[1苯胺基-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(198)3-Z-[1-(4-氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(199)3-Z-[1-(4-甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(200)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-羧基甲氧基-苯基)-亚甲基]-6-氟-2-吲哚满酮
(201)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-羧基甲氧基-苯基)苯基)亚甲基]-6-氟-2-吲哚满酮
(202)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(203)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(204)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)-亚甲基]-6-溴-2-吲哚满酮
(205)3-Z-[1-(3-二甲基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(206)3-Z-[1-(3-二甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(207)3-Z-[1-(3-二甲基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(208)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-氨基甲酰基-乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(209)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-甲基氨基甲酰基-乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(210)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-甲基氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(211)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-二甲基氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(212)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(213)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-甲基氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(214)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-二甲基氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(215)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-氨基甲酰基甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(216)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-甲基氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(217)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-氨基甲酰基甲基苯基)-亚甲基]-6-氟-2-吲哚满酮
(218)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-二甲基氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(219)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-(4-甲基哌嗪-1-基-羰基)乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(220)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(221)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(222)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-二甲基氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(223)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-甲基氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(224)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-甲基氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(225)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-二甲基氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(226)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-甲基氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(227)3-Z-[1-(4-(N-甲基-N-乙酰基氨基)苯胺基)-1-(4-(2-甲基氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(228)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-甲基氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(229)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-甲基氨基甲酰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(230)3-Z-[1-(4-(N-叔丁氧基羰基甲基氨基甲基)苯胺基)-1-(4-(2-甲基氨基甲酰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(231)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(4-(2-甲基氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(232)3-Z-[1-(4-甲基磺酰基苯胺基)-1-(4-(2-甲基氨基甲酰基-乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(233)3-Z-[1-(4-(4-甲基哌嗪-1-基羰基)苯胺基)-1-(4-(2-甲基氨基甲酰基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(234)3-Z-[1-(4-(4-甲基哌嗪-1-基羰基)苯胺基)-1-(3-甲基氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
(235)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-甲基氨基甲酰基甲基苯基)亚甲基]-6-氟-2-吲哚满酮
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(333)3-Z-[1-(4-(N-(3-甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(334)3-Z-[1-(4-(3-二甲基氨基丙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(335)3-Z-[1-(4-乙基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(336)3-Z-[1-(4-甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(337)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(338)3-Z-[1-(4-(4-甲基哌嗪-1-基羰基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(339)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(340)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-丙基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(341)3-Z-[1-(4-氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(342)3-Z-[1-(3-(二甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(343)3-Z-[1-(3-(甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(344)3-Z-[1-(3-(2-二甲基氨基乙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(345)3-Z-[1-(3-(3-二甲基氨基丙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(346)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(347)3-Z-[1-(4-(N-(二甲基氨基羰基甲基)-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(348)3-Z-[1-(4-(N-甲基-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(349)3-Z-[1-(4-(N-甲基-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(350)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(351)3-Z-[1-(4-(N-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(352)3-Z-[1-(4-(2-二乙基氨基乙基磺酰基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(353)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(354)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(355)3-Z-[1-(4-(2-二甲基氨基乙氧基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(356)3-Z-[1-(4-(N-(4-二甲基氨基丁基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(357)3-Z-[1-(4-(N-(3-二甲基氨基丙基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(358)3-Z-[1-(4-(甲基乙基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(359)3-Z-[1-(4-(甲基丙基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(360)3-Z-[1-(4-(甲基苄基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(361)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(362)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基亚甲基]-6-氯-2-吲哚满酮
(363)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(364)3-Z-[1-(4-(氮杂环丁-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(365)3-Z-[1-(4-((4-甲基哌嗪-1-基)甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(366)3-Z-[1-(4-(哌嗪-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(367)3-Z-[1-(4-(吗啉-4-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(368)3-Z-[1-(4-(硫吗啉-4-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(369)3-Z-[1-(4-(咪唑-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(370)3-Z-[1-(4-(N-(2-甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(371)3-Z-[1-(4-(N-(3-甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(372)3-Z-[1-(4-(3-二甲基氨基丙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(373)3-Z-[1-(4-乙基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(374)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(375)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-丙基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(376)3-Z-[1-(3-(甲基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(377)3-Z-[1-(3-(2-二甲基氨基乙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(378)3-Z-[1-(3-(3-二甲基氨基丙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(379)3-Z-[1-(4-(N-(二甲基氨基羰基甲基)-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(380)3-Z-[1-(4-(N-甲基-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(381)3-Z-[1-(4-(N-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(382)3-Z-[1-(4-(2-二乙基氨基乙基磺酰基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(383)3-Z-[1-(4-(2-二甲基氨基乙氧基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(384)3-Z-[1-(4-(N-(3-二甲基氨基丙基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(385)3-Z-[1-(4-(甲基乙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(386)3-Z-[1-(4-(甲基丙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(387)3-Z-[1-(4-(甲基苄基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(388)3-Z-[1-(4-(氮杂环丁-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(389)3-Z-[1-(4-(哌嗪-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(390)3-Z-[1-(4-(吗啉-4-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(391)3-Z-[1-(4-(硫吗啉-4-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(392)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(393)3-Z-[1-(4-(N-(2-甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(394)3-Z-[1-(4-(N-(3-甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(395)3-Z-[1-(4-(3-二甲基氨基丙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(396)3-Z-[1-(4-乙基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(397)3-Z-[1-(4-(4-甲基哌嗪-1-基羰基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(398)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(399)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-丙基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(400)3-Z-[1-(3-(甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(401)3-Z-[1-(3-(2-二甲基氨基乙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(402)3-Z-[1-(3-(3-二甲基氨基丙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(403)3-Z-[1-(4-(N-(二甲基氨基羰基甲基)-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(404)3-Z-[1-(4-(N-甲基-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(405)3-Z-[1-(4-(N-甲基-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(406)3-Z-[1-(4-(N-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(407)3-Z-[1-(4-(2-二乙基氨基乙基磺酰基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(408)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(409)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(410)3-Z-[1-(4-(2-二甲基氨基乙氧基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(411)3-Z-[1-(4-(甲基乙基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(412)3-Z-[1-(4-(甲基丙基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(413)3-Z-[1-(4-(甲基苄基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(414)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(415)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(416)3-Z-[1-(4-(氮杂环丁-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(417)3-Z-[1-(4-(哌嗪-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(418)3-Z-[1-(4-(吗啉-4-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(419)3-Z-[1-(4-(硫吗啉-4-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(420)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(421)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(422)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(423)3-Z-[1-(4-(N-(2-甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(424)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(425)3-Z-[1-(4-(N-(3-甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(426)3-Z-[1-(4-(3-二甲基氨基丙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(427)3-Z-[1-(4-乙基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(428)3-Z-[1-(4-甲基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(429)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(430)3-Z-[1-(4-(4-甲基哌嗪-1-基羰基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(431)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(432)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-丙基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(433)3-Z-[1-(4-氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(434)3-Z-[1-(3-(二甲基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(435)3-Z-[1-(3-(甲基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(436)3-Z-[1-(3-(2-二甲基氨基乙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(437)3-Z-[1-(3-(3-二甲基氨基丙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(438)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(439)3-Z-[1-(4-(N-(二甲基氨基羰基甲基)-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(440)3-Z-[1-(4-(N-甲基-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(441)3-Z-[1-(4-(N-甲基-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(442)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(443)3-Z-[1-(4-(N-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(444)3-Z-[1-(4-(2-二乙基氨基乙基磺酰基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(445)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(446)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(447)3-Z-[1-(4-(2-二甲基氨基乙氧基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(448)3-Z-[1-(4-(N-(4-二甲基氨基丁基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(449)3-Z-[1-(4-(N-(3-二甲基氨基丙基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(450)3-Z-[1-(4-(甲基乙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(451)3-Z-[1-(4-(甲基丙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(452)3-Z-[1-(4-(甲基苄基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(453)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(454)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)-苯基亚甲基]-6-溴-2-吲哚满酮
(455)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(456)3-Z-[1-(4-(氮杂环丁-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(457)3-Z-[1-(4-((4-甲基哌嗪-1-基)甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(458)3-Z-[1-(4-(哌嗪-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(459)3-Z-[1-(4-(吗啉-4-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(460)3-Z-[1-(4-(硫吗啉-4-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(461)3-Z-[1-(4-(咪唑-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(462)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(463)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(464)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(465)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(466)3-Z-[1-(4-(N-(2-甲基氨基乙基)-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(467)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(468)3-Z-[1-(4-(N-(3-甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(469)3-Z-[1-(4-(3-二甲基氨基丙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(470)3-Z-[1-(4-乙基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(471)3-Z-[1-(4-甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(472)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(473)3-Z-[1-(4-(4-甲基哌嗪-1-基羰基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(474)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(475)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-丙基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(476)3-Z-[1-(4-氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(477)3-Z-[1-(3-(二甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(478)3-Z-[1-(3-(甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(479)3-Z-[1-(3-(2-二甲基氨基乙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(480)3-Z-[1-(3-(3-二甲基氨基丙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(481)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(482)3-Z-[1-(4-(N-(二甲基氨基羰基甲基)-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(483)3-Z-[1-(4-(N-甲基-N-甲基磺酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(484)3-Z-[1-(4-(N-甲基-N-乙酰基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(485)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(486)3-Z-[1-(4-(N-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(487)3-Z-[1-(4-(2-二乙基氨基乙基磺酰基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(488)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(489)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(490)3-Z-[1-(4-(2-二甲基氨基乙氧基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(491)3-Z-[1-(4-(N-(4-二甲基氨基丁基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(492)3-Z-[1-(4-(N-(3-二甲基氨基丙基羰基)-N-甲基氨基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(493)3-Z-[1-(4-(甲基乙基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(494)3-Z-[1-(4-(甲基丙基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(495)3-Z-[1-(4-(甲基苄基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(496)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(497)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基氨基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基亚甲基]-6-溴-2-吲哚满酮
(498)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(499)3-Z-[1-(4-(氮杂环丁-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(500)3-Z-[1-(4-((4-甲基哌嗪-1-基)甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(501)3-Z-[1-(4-(哌嗪-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(502)3-Z-[1-(4-(吗啉-4-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(503)3-Z-[1-(4-(硫吗啉-4-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(504)3-Z-[1-(4-(咪唑-1-基甲基)苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(505)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-羧甲基氨基苯基)-亚甲基]-6-氟-2-吲哚满酮
(506)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-羧甲基氨基-苯基)-亚甲基]-6-氟-2-吲哚满酮
(507)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(N-甲基-羧甲基氨基)苯基)亚甲基]-6-氟-2-吲哚满酮
(508)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(N-甲基-羧甲基氨基)苯基)亚甲基]-6-氟-2-吲哚满酮
(509)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-羧基甲氧基苯基)-亚甲基]-6-氯-2-吲哚满酮
(510)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-羧基甲氧基苯基)-亚甲基]-6-氯-2-吲哚满酮
(511)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-羧甲基氨基苯基)-亚甲基]-6-氯-2-吲哚满酮
(512)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-羧甲基氨基苯基)-亚甲基]-6-氯-2-吲哚满酮
(513)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(N-甲基-羧甲基氨基)苯基)亚甲基]-6-氯-2-吲哚满酮
(514)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(N-甲基-羧甲基氨基)苯基)亚甲基]-6-氯-2-吲哚满酮
(515)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-羧基甲氧基苯基)-亚甲基]-6-溴-2-吲哚满酮
(516)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-羧基甲氧基苯基)-亚甲基]-6-溴-2-吲哚满酮
(517)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-羧甲基氨基苯基)-亚甲基]-6-溴-2-吲哚满酮
(518)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-羧甲基氨基苯基)-亚甲基]-6-溴-2-吲哚满酮
(519)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(N-甲基-羧甲基氨基)苯基)亚甲基]-6-溴-2-吲哚满酮
(520)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(N-甲基-羧甲基氨基)苯基)亚甲基]-6-溴-2-吲哚满酮,
及其互变体,立体异构体,或生理可接受盐。
通式I化合物,其互变体,立体异构体,或生理可接受盐适合用于预防或治疗一种选自下列疾病的特定纤维化疾病:
在慢性阻塞性肺病(COPD),慢性支气管炎,及肺气肿中肺组织的纤维变性及重新塑造(remodeling);
肺纤维变性及具有纤维化成分的肺疾病包括,但不限于,特发性肺纤维化(IPF),巨细胞间质性肺炎(GIP),结节病(sarcodosis),囊性纤维化病,呼吸窘迫综合征(ARDS),肉芽肿病,硅肺病,药物引起的肺纤维变性(例如博莱霉素,卡氮芥,环磷酰胺,胺碘酮,普鲁卡因胺,青霉胺,金或硝基呋喃妥因(nitrofurantoin)药物引起的)、硅肺病、石棉沉着病,全身性硬皮病;
哮喘中纤维变性及重新塑造;
类风湿性关节炎中纤维变性;
病毒引起的肝硬化,例如C型肝炎;
放射引起的纤维变性;
血管成形术后再狭窄;
肾病,包括慢性肾小球肾炎,接受环孢霉素(cyclosporine)的病人的肾纤维变性,及由于高血压造成的肾纤维变性;
具有纤维化成分的皮肤疾病,包括,但不限于,硬皮病,结节病,全身性红斑狼疮;
过度瘢痕形成。
在根据本发明的一个优选具体实施例中,通式I的化合物,其互变体,立体异构体,或生理可接受盐特别适合用于预防或治疗特发性肺纤维化。
生物学活性
下列实验结果例示本发明,并非限制其范围。
简写
DEPC(焦碳酸二乙酯)
dNTP(去氧核苷三磷酸)
CT(扩增达到设定阈值的周期)
DNA(去氧核糖核酸)
cDNA(互补DNA)
RNA(核糖核酸)
mRNA(信使RNA)
PCR(聚合酶链式反应)
实施例B1:
在下列实施例B1的实验中,实施例A表示化合物3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮,其为化合物名单中的化合物(134)及优选化合物名单中的化合物(b)。
(A)代表性化合物对于博莱霉素引起的肺纤维变性的肺形态学的影响
材料及方法
博莱霉素硫酸盐(博莱霉素HEXALTM)从当地药房购买。
博莱霉素施用及治疗方法
所有实验是根据德国动物福利的指导,由合格的动物工作者进行,并由负责机构核准。雄性Wistar大鼠在暴露于***异氟烷(Isofluorane)5分钟后使用导管(0.5毫米内径,1.0毫米外径)经由鼻通道经气管内注射博莱霉素硫酸盐(10U/公斤体重于300微升盐水中)或仅盐水(盐水对照)。次日,大鼠以实施例A(化合物(134))或盐水悬浮于1毫升0.1%纤维素羟乙基醚(Natrosol)中口服给药。对照大鼠施用1毫升0.1%纤维素羟乙基醚(Natrosol)(媒液对照)。
检测总共30只鼠,分组并处理,如表1所示。
表1
经气管滴入 | 动物数目 | 化合物 | 治疗时间表 |
博莱霉素10U/公斤 | 10 | 实施例A(化合物(134)) | 第1-21天 |
博莱霉素10U/公斤 | 10 | 仅溶媒 | 第1-21天 |
盐水(300微升) | 10 | 仅溶媒 | 第1-21天 |
博莱霉素滴入后21天,大鼠以NarcorenTM(戊巴比妥(Pentobarbital)钠,Rhone Merieux)的致死腹膜内注射杀死。然后取出肺,吸干,一半于液态氮中迅速冷冻,贮存在-80℃。另一半固定于4%福马啉(formalin)中用于其后石蜡包埋及组织学观察。
组织学
固定于4%福马啉中的肺组织包埋于石蜡中,使用显微镜用薄片切片机(microtome)(Leica SM200R)切5微米切片,放于涂覆聚-L-赖氨酸的玻片上。然后切片在玻片上干燥(60℃2小时),然后在室温冷却。使用马森(Masson’s)三色(Trichrome)染色评估胶原的沉积。
结果
图1A显示经气管内接受盐水及媒液替代博莱霉素的对照组所获得的结果。
经气管内以博莱霉素及媒液处理的大鼠发生严重的肺纤维变性,如图1B所示。肺泡由成纤维细胞及细胞外基质大量替代,正常肺结构几乎消灭。
博莱霉素处理的鼠每天以50毫克/公斤的实施例A(化合物(134))治疗,在此模型中显示肺纤维变性不断地几乎完全恢复。典型实施例示于图1C。肺泡完整,极少或无成纤维细胞浸润或细胞外基质沉积发生。正常肺结构维持,由图1C与图1A的比较证明。
(B)代表性化合物对于博莱霉素诱发肺纤维变性后纤维化标记基因表达的影响
mRNA的提取及cDNA的合成
利用无菌手术刀片将一部分转用于研究基因表达的冷冻肺组织切成小片。然后将大约100mg的组织放置在2ml的Eppendorf试管中并加入1.5ml的Trizol(Invitrogen)。然后向试管中加入无菌的碳化钨小球(Qiagen),并将试管在频率为30.0Hz的Retsch MM300组织破碎机(Qiagen)中放置8分钟。此后,除去小球并将样品在12000rpm下离心10分钟以除去组织碎片。利用Trizol提供的修订版的制造商规程提取RNA。简而言之,将0.3ml氯仿加到试管中并剧烈摇动该试管,然后将其放置以在室温下培养5分钟,其后,将试管在4℃下以12000rpm离心15分钟。然后收集上面无色的水相,并将其加到750μl异丙醇中。将其剧烈摇动并于-80℃下贮存过夜。然后将样品在室温下培养15分钟,其后将样品在4℃下以12000rpm离心40分钟。然后除去上清液并加入500μl70%的乙醇以洗涤团块(pellet),接着将样品在4℃下以12000rpm离心10分钟,将该洗涤步骤重复两次,之后,将团块放置以干燥10~15分钟。最后,将团块悬浮于20μl无核糖核酸酶(RNase)的水中并于-80℃下贮存。然后利用分光光度计测量各样品的浓度。
采用SuperscriptTMIII(Invitrogen,Paisley,UK)RT-第一链合成试剂盒,利用修订版的制造商规程逆转录2μg的各mRNA样品。简而言之,利用DEPC处理的水,使2μgRNA、1μl随机六聚体引物(50ng/μl)和1μl dNTP混合物(10mM)的混合物总计达到10μl,并将其在65℃下培养5分钟,之后,将其在冰上放置5分钟。接着,向每个反应中,加入2μl RT缓冲液(10X),4μl MgCl2(25mM),2μl DTT(0.1M),1μl RNaseOUTTM(40U/μl)和1μlSuperScriptTMIII酶(200U/μl),并在下列条件下将该混合物置于热循环仪中(Applied Biosystems):25℃下10分钟,50℃下50分钟,及85℃下5分钟,之后,加入1μl的RNase H并于37℃下培养20分钟。在假设RT反应将所有mRNA完全转录成cDNA且浓度为100ng/μl的前题下,将所合成的cDNA稀释至5ng/μl。
-利用实时PCR的基因表达的研究
利用Applied Biosystems7700序列检测***,研究各样品中的基因表达。采购18S内源性对照的引物作为预开发的试验试剂盒,而利用PrimerExpressTM(Applied Biosystems)设计前胶原I和纤连蛋白的引物和探针(见下面的表2),确保每组中引物或探针至少之一覆盖内含子/外显子接合处,从而消除cDNA样品中扩增任何污染基因组DNA的可能性。所采购的PDAR也只扩增cDNA。
表2
利用每个反应25ng(5μl)的cDNA,在25μl的反应物中进行实时PCR。采购定量的PCR核心试剂盒(Eurogentec)并制备主混合物(master-mix)如下以用于100个反应:500μl10X反应缓冲液,500μl MgCl2(50mM),200μl dNTP混合物溶液(5mM),25μl Hot Goldstar酶,75μl18S PDAR,22.5μl正向引物,22.5μl逆向引物,15μl探针,及640μl DEPC处理的水。然后将20μl该主混合物加到25ng(5μl)的靶cDNA中。每个分析一式三份。
为了定量化基因表达,构建每个引物组的标准曲线并使其包含在每个板上。标准曲线由研究的所有cDNA的混合物组成;该cDNA混合物连续地地稀释10,20,50,100,100倍。标准曲线的构成是所得到的CT(扩增达到设定阈值的循环)对稀释因子的LOG10。绘制靶基因和18S rRNA内源性对照的曲线。然后利用标准曲线,将每个样品两个靶的CT值转化稀释倍数,并将靶基因值归一化到18S基因值。
统计
所有统计分析是使用GraphPad Prism V4.02软件进行。使用非参数T-检验(Mann-Whitney U试验)比较,显著值为p≤0.05。
结果
结果示于图2(前胶原I)及3(纤连蛋白)。各数据点表由一只大鼠的肺分离的RNA。
经气管内施用博莱霉素及随后仅以媒液处理显示肺内前胶原I及纤连蛋白的基因表达大量增加,如图2及3所示,与图1B所示组织学上明显肺纤维变性一致。
博莱霉素处理的大鼠每天以50毫克/公斤实施例A(化合物(134))治疗显示此模型中纤维化标记基因的表达显著抑制(p≤0.0001),如图2及3所示。
此实验证明纤维化标记基因的表达及因此细胞外基质的沉积可以用实施例A(化合物(134))治疗而大大减少。
因此,纤维化标记基因的表达及因此细胞外基质的沉积可以根据本发明的化合物治疗而大大减少。
根据生物学性质,根据本发明的化合物可单独治疗使用或与其他药理学上活性化合物联合使用。该药理学上活性化合物可为例如在治疗纤维变性中也为药理学上活性的化合物。该药理学上活性化合物还可为具有分泌溶解(secretolytic),支气管扩张(broncholytic)及/或抗发炎活性的物质。
在根据本发明的一个优选具体实施例中,该药理学上活性化合物优选选自抗胆碱能药,β-2模拟物,类固醇,PDE-IV抑制剂,p38MAP激酶抑制剂,NK1拮抗剂,LTD4拮抗剂,EGFR抑制剂,及内皮素拮抗剂。
抗胆碱能药优选可选自硫托品(tiortropium)盐,噁托品(oxitropium)盐,氟托品(flutropium)盐,衣巴托品(ipratro-pium)盐,糖吡咯(glycopyrronium)盐,及托螺吡咯(trospium)盐。
β-2模拟物优选可选自例如US 4,460,581中所公开的β-2模拟物,其并入本文供参考。
PDE-IV抑制剂优选可选自因普叶素(enprofyllin),茶碱,罗氟司特,阿里福洛(ariflo)(西洛司特,cilomilast),CP-325,366,BY343,D-4396(Sch-351591),AWD-12-281(GW-842470),N-(3,5-二氯-1-氧代-吡啶-4-基)-4-二氟甲氧基-3-环丙基甲氧基苯甲酰胺,NCS-613,蒲马芬亭(pumafentine),(-)-对-[(4aR*,10bS*)-9-乙氧基-1,2,3,4,4a,10b-六氢-8-甲氧基-2-甲基苯并[s][1,6]二氮杂萘-6-基]-N,N-二异丙基苯甲酰胺,(R)-(+)-1-(4-溴苄基)-4-[(3-环戊基氧基)-4-甲氧基苯基]-2-吡咯烷酮,3-(环戊基氧基-4-甲氧基苯基)-1-(4-N’-[N-2-氰基-S-甲基-异硫脲基]苄基)-2-吡咯烷酮,顺式[4-氰基-4-(3-环戊基氧基-4-甲氧基苯基)环己烷-1-碳酸],2-甲氧羰基-4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)-环己烷-1-酮,顺式[4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己烷-1-醇],(R)-(+)-乙基)[4-(3-环戊基氧基-4-甲氧基苯基)吡咯烷-2-亚基]醋酸酯,(S)-(-)-乙基[4-(3-环戊基氧基-4-甲氧基苯基)吡咯烷-2-亚基]醋酸酯,CDP840,Bay-198004,D-4418,PD-168787,T-440,T-2585,芳叶素(arofyllin),阿替卓元(atizoram),V-11294A,C1-1018,CDC-801,CDC-3052,D-22888,YM-58997,Z-15370,9-环戊基-5,6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-***并[4,3-a]吡啶,及9-环戊基-5,6-二氢-7-乙基-3-(叔丁基)-9H-吡唑并[3,4-c]-1,2,4-***并[4,3-a]吡啶。这些化合物,如可得,可以其消旋物,对映体,或非对映体的形式,或以其药理学上可接受的酸加成盐形式,或以其溶剂化物及/或水合物形式使用。
类固醇优选可选自***龙,***,布替索可丙酸盐(butixocortpropionate),RPR-106541,氟尼缩松,倍氯米松,氟羟***龙,布***,氟替卡松,莫米松,环索奈德,罗氟奈德,ST-126,***,6α,9α-二氟-17α-[(2-呋喃基羰基)氧基]-11β-羟基-16α-甲基-3-氧代-雄甾-1,4-二烯-17β-硫羧酸(S)-氟甲基酯,及6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰基氧基-雄甾-1,4-二烯-17β-硫羧酸(S)-(2-氧代-四氢呋喃-3S-基)酯。这些化合物,如可得,可以其消旋物,对映体,或非对映体的形式,或以其药理学上可接受的酸加成盐形式,或以其溶剂化物及/或水合物形式使用。
p38MAP激酶抑制剂优选可选自例如US5,716,972、US5,686,455、US5,656,644、US5,593,992、US5,593,991、US5,663,334、US5,670,527、US5,559,137、US5,658,903、US5,739,143、US5,756,499、US6,277,989、US6,340,685、及US5,716,955、及PCT申请WO92/12154、WO94/19350、WO95/09853、WO95/09851、WO95/09847、WO95/09852、WO97/25048、WO97/25047、WO97/33883、WO97/35856、WO97/35855、WO97/36587、WO97/47618、WO97/16442、WO97/16441、WO97/12876、WO98/25619、WO98/06715、WO98/07425、WO98/28292、WO98/56377、WO98/07966、WO98/56377、WO98/22109、WO98/24782、WO98/24780、WO98/22457、WO98/52558、WO98/52559、WO98/52941、WO98/52937、WO98/52940、WO98/56788、WO98/27098、WO98/47892、WO98/47899、WO98/50356、WO98/32733、WO99/58523、WO99/01452、WO99/01131、WO99/01130、WO99/01136、WO99/17776、WO99/32121、WO99/58502、WO99/58523、WO99/57101、WO99/61426、WO99/59960、WO99/59959、WO99/00357、WO99/03837、WO99/01441、WO99/01449、WO99/03484、WO99/15164、WO99/32110、WO99/32111、WO99/32463、WO99/64400、WO99/43680、WO99/17204、WO99/25717、WO99/50238、WO99/61437、WO99/61440、WO00/26209、WO00/18738、WO00/17175、WO00/20402、WO00/01688、WO00/07980、WO00/07991、WO00/06563、WO00/12074、WO00/12497、WO00/31072、WO00/31063、WO00/23072、WO00/31065、WO00/35911、WO00/39116、WO00/43384、WO00/41698、WO00/69848、WO00/26209、WO00/63204、WO00/07985、WO00/59904、WO00/71535、WO00/10563、WO00/25791、WO00/55152、WO00/55139、WO00/17204、WO00/36096、WO00/55120、WO00/55153、WO00/56738、WO01/21591、WO01/29041、WO01/29042、WO01/62731、WO01/05744、WO01/05745、WO01/05746、WO01/05749、WO01/05751、WO01/27315、WO01/42189、WO01/00208、WO01/42241、WO01/34605、WO01/47897、WO01/64676、WO01/37837、WO01/38312、WO01/38313、WO01/36403、WO01/38314、WO01/47921、WO01/27089、DE19842833及JP200086657中所公开的p38激酶抑制剂,其公开全部并入本文供参考。其中特别有利于根据本发明联用的为US6,277,989、US6,340,685、WO00/12074、WO00/12497、WO00/59904、WO00/71535、WO01/64676、WO99/61426、WO00/10563、WO00/25791、WO01/37837、WO01/38312、WO01/38313、WO01/38314、WO01/47921、WO99/61437、WO99/61440、WO00/17175、WO00/17204、WO00/36096、WO98/27098、WO99/00357、WO99/58502、WO99/64400、WO99/01131、WO00/43384、WO00/55152、WO00/55139及WO01/36403中所公开的p38抑制剂。在一个优选具体实施方案中,p38激酶抑制剂选自WO99/01131中所公开的下式(I)的化合物
其中
R1为4-吡啶基,嘧啶基,4-哒嗪基,1,2,4-三嗪-5-基,喹啉基,异喹啉基,或喹唑啉-4-基环,该环经Y-Ra及任选地被选自C1-4烷基,卤素,羟基,C1-4烷氧基,C1-4烷基硫基,C1-4烷基亚磺酰基,CH2OR12,氨基,一及二-C1-6烷基取代的胺基,N-杂环基环,该环具有5至7员及任选地含有另一个选自氧,硫,或NR15,N(R10)C(O)Rb或NHRa的杂原子的独立取代基取代;
Y为氧或硫;
R4为苯基,萘-1-基或萘基,或杂芳基,其任选地被一或二个各自独立选择的取代基取代,对于4-苯基,4-萘-1-基,5-萘-2-基,或6-萘-2-基取代基,为卤素,氰基,硝基,C(Z)NR7R17,C(Z)OR16,(CR10R20)vCOR12,SR5,SOR5,OR12,卤代的C1-4烷基,C1-4烷基,ZC(Z)R12,NR10C(Z)R16,或(CR10R20)vNR10R20,对于其他取代位置,为卤素,氰基,C(Z)NR13R14,C(Z)OR3,(CR10R20)m”COR3,S(O)mR3,OR3,卤代的C1-4烷基,C1-4烷基,(CR10R20)m”R10C(Z)R3,NR10S(O)m’R8,NR10S(O)m’NR7R17,ZC(Z)R3,或(CR10R20)m”NR13R14;
Z为氧或硫;
n为1至10的整数;
m为0,或整数1或2;
m’为整数1或2;
m”为0,或1至5的整数;
v为0,或1至2的整数;
R2为-C(H)(A)(R22);
A为任选地被取代的芳基,杂环基,或杂芳基环,或A为被取代的C1-10烷基;
R22为任选地被取代的C1-10烷基;
Ra为芳基,芳基C1-6烷基,杂环基,杂环基C1-6烷基,杂芳基,杂芳基C1-6烷基,其中这些基团任选地被取代;
Rb为氢,C1-6烷基,C3-7环烷基,芳基,芳基C1-4烷基,杂芳基,杂芳基C1-4烷基,杂环基,或杂环基C1-4烷基,其中这些基团任选地被取代;
R3为杂环基,杂环基C1-10烷基,或R8;
R5为氢,C1-4烷基,C2-4烯基,C2-4炔基,或NR7R17,排除SR5为SNR7R17及SOR5为SOH;
R6为氢,可药用阳离子,C1-10烷基,C3-7环烷基,芳基,芳基C1-4烷基,杂芳基,杂芳基C1-4烷基,杂环基,芳基,或C1-10烷酰基;
R7及R17各独立选自氢或C1-4烷基,或R7及R17与相接的氮一起形成5至7员杂环,该环任选地含有选自氧,硫,或NR15的其他的杂原子;
R8为C1-10烷基,卤代的C1-10烷基,C2-10烯基,C2-10炔基,C3-7环烷基,C5-7环烯基,芳基,芳基C1-10烷基,杂芳基,杂芳基C1-10烷基,(CR10R20)nOR11,(CR10R20)nS(O)mR18,(CR10R20)nNHS(O)2R18,(CR10R20)nNR13R14;其中芳基,芳基烷基,杂芳基,杂芳基烷基可任选地被取代;
R9为氢,C(Z)R11或任选地被取代的C1-10烷基,S(O)2R18,任选地被取代的芳基或任选地被取代的芳基C1-4烷基;
R10及R20各独立选自氢或C1-4烷基;
R11为氢,C1-10烷基,C3-7环烷基,杂环基,杂环基C1-10烷基,芳基,芳基C1-10烷基,杂芳基,或杂芳基C1-10烷基,其中这些基团任选地被取代;
R12为氢或R16;
R13及R14各独立选自氢或任选地被取代的C1-4烷基,任选地被取代的芳基,或任选地被取代的芳基C1-4烷基,或与相接的氮一起形成5至7员杂环,该环任选地含有选自氧,硫,或NR9的其他的杂原子;
R15为R10或C(Z)-C1-4烷基;
R16为C1-4烷基,卤代的C1-4烷基,或C3-7环烷基;
R18为C1-10烷基,C3-7环烷基,杂环基,芳基,芳基C1-10烷基,杂环基,杂环基-C1-10烷基,杂芳基,或杂芳基C1-10烷基;
或其可药用盐。
NK1拮抗剂优选可选自N-[2-(3,5-双-三氟甲基-苯基)-乙基]-2-{4-环丙基甲基-哌嗪-1-基}-N-甲基-2-苯基-乙酰胺(B11F1149),CP-122721,FK-888,NKP608C,NKP608A,CGP60829,SR48968(Saredutant),SR140333(苯磺诺匹坦铵/盐酸盐),LY303870(拉奈匹坦),MEN-11420(奈帕坦特),SB223412,MDL-105172A,MDL-103896,MEN-11149,MEN-11467,DNK333A,SR-144190,YM-49244,YM-44778,ZM-274773,MEN-10930,S-19752,纽若龙(Neuronorm),YM-35375,DA-5018,阿普利比(Aprepitant)(MK-869),L-754030,CJ-11974,L-758298,DNK-33A,6b-I,CJ-11974,TAK-637,GR205171,及下通式(VIII)的芳基甘氨酸酰胺衍生物
其中
R1及R2与相接的N原子一起形成下式的环
其中r及s独立表数目2或3;
R6表H,-C1-C5-烷基,C3-C5-烯基,丙炔基(propinyl),羟基(C2-C4)烷基,甲氧基(C2-C4)烷基,二-(C1-C3)烷基氨基(C2-C4)烷基,胺基(C2-C4)烷基,氨基,二-(C1-C3)烷基氨基,单氟至全氟(C1-C2)烷基,N-甲基哌啶基,吡啶基,嘧啶基,吡嗪基,或哒嗪基,
R7表下列(a)至(d)定义的任一基团;
(a)羟基
(b)4-哌啶基哌啶基
(c)
其中R16及R17独立表示H,(C1-C4)烷基,(C3-C6)环烷基,羟基(C2-C4)烷基,二羟基(C2-C4)烷基,(C1-C3)烷氧基(C2-C4)烷基,苯基(C1-C4)烷基,或二-(C1-C3)烷基氨基(C2-C4)烷基,及
R8表H,
任选地呈对映体,对映体的混合物,或消旋物的形式。
上述式(VIII)化合物记载在WO96/32386,WO97/32865及WO02/32865中。这些国际专利申请案的公开全部并入本文供参考。
LTD4拮抗剂优选选自孟鲁司特(montelukast),1-(((R)-(3-(2-(6,7-二氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)苯基)硫基)甲基)环丙烷-醋酸酯,1-(((1-(R)-(3-(3-(2-(2,3-二氯噻吩并[3,2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)丙基)硫基)甲基)环丙烷-醋酸酯,普仑司特(pranlukast),扎鲁司特(zafirlukast),[2[[2-(4-叔丁基-2-噻唑基)-5-苯并呋喃基]氧基甲基]苯基]醋酸酯,MCC-847(ZD-3523),MN-001,MEN-91507(LM-1507),VUF-5078,VUF-K-8707,及L-733321。这些化合物,如可得,可以其消旋物,对映体,或非对映体的形式,或以其药理学上可接受的酸加成盐形式,或以其溶剂化物及/或水合物形式使用。
EGFR抑制剂优选可选自4-[(3-氯-4-氟苯基)氨基]-6-{[4-(吗啉-4-基)-1-氧代-2-丁烯-1-基]-氨基}-7-环丙基甲氧基-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二乙基氨基)-1-氧代-2-丁烯-1-基]-氨基}-7-环丙基甲氧基-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-环丙基甲氧基-喹唑啉、4-[(R)-(1-苯基-乙基)氨基]-6-{[4-(吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-环戊氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{[4-((R)-6-甲基-2-氧代-吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-环丙基甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{[4-((R)-6-甲基-2-氧代-吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-[(S)-(四氢呋喃-3-基)氧基]-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{[4-((R)-2-甲氧基甲基-6-氧代-吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-环丙基甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-[2-((S)-6-甲基-2-氧代-吗啉-4-基)-乙氧基]-7-甲氧基-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-({4-[N-(2-甲氧基-乙基)-N-甲基-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-环丙基甲氧基-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-环戊氧基-喹唑啉、4-[(R)-(1-苯基-乙基)氨基]-6-{[4-(N,N-双-(2-甲氧基-乙基)-氨基)-1-氧代-2-丁烯-1-基]氨基}-7-环丙基甲氧基-喹唑啉、4-[(R)-(1-苯基-乙基)氨基]-6-({4-[N-(2-甲氧基-乙基)-N-乙基-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-环丙基甲氧基-喹唑啉、4-[(R)-(1-苯基-乙基)氨基]-6-({4-[N-(2-甲氧基-乙基)-N-甲基-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-环丙基甲氧基-喹唑啉、4-[(R)-(1-苯基-乙基)氨基]-6-({4-[N-(四氢吡喃-4-基)-N-甲基-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-环丙基甲氧基-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((R)-四氢呋喃-3-基氧基)-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-({4-[N-(2-甲氧基-乙基)-N-甲基-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-环戊氧基-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N-环丙基-N-甲基-氨基)-1-氧代-2-丁烯-1-基]氨基}-7-环戊氧基-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-[(R)-(四氢呋喃-2-基)甲氧基]-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-[(S)-(四氢呋喃-2-基)甲氧基]-喹唑啉、4-[(3-乙炔基-苯基)氨基]-6,7-双-(2-甲氧基-乙氧基)-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-7-[3-(吗啉-4-基)-丙基氧基]-6-[(乙烯基羰基)氨基]-喹唑啉、4-[(R)-(1-苯基-乙基)氨基]-6-(4-羟基-苯基)-7H-吡咯并[2,3-d]嘧啶、3-氰基-4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-乙氧基-喹唑啉、4-{[3-氯-4-(3-氟-苄基氧基)-苯基]氨基}-6-(5-{[(2-甲磺酰基-乙基)氨基]甲基}-呋喃-2-基)喹唑啉、4-[(R)-(1-苯基-乙基)氨基]-6-{[4-((R)-6-甲基-2-氧代-吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-{[4-(吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-[(四氢呋喃-2-基)甲氧基]-喹唑啉、4-[(3-氯-4-氟苯基)氨基]-6-({4-[N,N-双-(2-甲氧基-乙基)-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-[(四氢呋喃-2-基)甲氧基]-喹唑啉、4-[(3-乙炔基-苯基)氨基]-6-{[4-(5,5-二甲基-2-氧代-吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-[2-(2,2-二甲基-6-氧代-吗啉-4-基)-乙氧基]-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-[2-(2,2-二甲基-6-氧代-吗啉-4-基)-乙氧基]-7-[(R)-(四氢呋喃-2-基)甲氧基]-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-7-[2-(2,2-二甲基-6-氧代-吗啉-4-基)-乙氧基]-6-[(S)-(四氢呋喃-2-基)甲氧基]-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{2-[4-(2-氧代-吗啉-4-基)-哌啶-1-基]-乙氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-[1-(叔丁基氧基羰基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(反式-4-氨基-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(反式-4-甲磺酰基氨基-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(四氢吡喃-3-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(1-甲基-哌啶-4-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(吗啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(甲氧基甲基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(哌啶-3-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-[1-(2-乙酰基氨基-乙基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(四氢吡喃-4-基氧基)-7-乙氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-((S)-四氢呋喃-3-基氧基)-7-羟基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(四氢吡喃-4-基氧基)-7-(2-甲氧基-乙氧基)-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{反式-4-[(二甲基氨基)磺酰基氨基]-环己烷-1-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{反式-4-[(吗啉-4-基)羰基氨基]-环己烷-1-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{反式-4-[(吗啉-4-基)磺酰基氨基]-环己烷-1-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(四氢吡喃-4-基氧基)-7-(2-乙酰基氨基-乙氧基)-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(四氢吡喃-4-基氧基)-7-(2-甲磺酰基氨基-乙氧基)-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(哌啶-1-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(1-氨基羰基甲基-哌啶-4-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(顺式-4-{N-[(四氢吡喃-4-基)羰基]-N-甲基-氨基}-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(顺式-4-{N-[(吗啉-4-基)羰基]-N-甲基-氨基}-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(顺式-4-{N-[(吗啉-4-基)磺酰基]-N-甲基-氨基}-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(反式-4-乙磺酰基氨基-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(1-甲磺酰基-哌啶-4-基氧基)-7-乙氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(1-甲磺酰基-哌啶-4-基氧基)-7-(2-甲氧基-乙氧基)-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-[1-(2-甲氧基-乙酰基)-哌啶-4-基氧基]-7-(2-甲氧基-乙氧基)-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(顺式-4-乙酰基氨基-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-乙炔基-苯基)氨基]-6-[1-(叔丁基氧基羰基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉、4-[(3-乙炔基-苯基)氨基]-6-(四氢吡喃-4-基氧基]-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(顺式-4-{N-[(哌啶-1-基)羰基]-N-甲基-氨基}-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(顺式-4-{N-[(4-甲基-哌嗪-1-基)羰基]-N-甲基-氨基}-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{顺式-4-[(吗啉-4-基)羰基氨基]-环己烷-1-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[2-(2-氧代吡咯烷-1-基)乙基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(吗啉-4-基)羰基]-哌啶-4-基氧基}-7-(2-甲氧基-乙氧基)-喹唑啉、4-[(3-乙炔基-苯基)氨基]-6-(1-乙酰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉、4-[(3-乙炔基-苯基)氨基]-6-(1-甲基-哌啶-4-基氧基)-7-甲氧基-喹唑啉、4-[(3-乙炔基-苯基)氨基]-6-(1-甲磺酰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(1-甲基-哌啶-4-基氧基)-7(2-甲氧基-乙氧基)-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(1-异丙基氧基羰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(顺式-4-甲基氨基-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{顺式-4-[N-(2-甲氧基-乙酰基)-N-甲基-氨基]-环己烷-1-基氧基}-7-甲氧基-喹唑啉、4-[(3-乙炔基-苯基)氨基]-6-(哌啶-4-基氧基)-7-甲氧基-喹唑啉、4-[(3-乙炔基-苯基)氨基]-6-[1-(2-甲氧基-乙酰基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉、4-[(3-乙炔基-苯基)氨基]-6-{1-[(吗啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(顺式-2,6-二甲基-吗啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(2-甲基-吗啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(S,S)-(2-氧杂-5-氮杂-二环[2.2.1]庚-5-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(N-甲基-N-2-甲氧基乙基-氨基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(1-乙基-哌啶-4-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(2-甲氧基乙基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(3-甲氧基丙基-氨基)-羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-[顺式-4-(N-甲磺酰基-N-甲基-氨基)-环己烷-1-基氧基]-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-[顺式-4-(N-乙酰基-N-甲基-氨基)-环己烷-1-基氧基]-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(反式-4-甲基氨基-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-[反式-4-(N-甲磺酰基-N-甲基-氨基)-环己烷-1-基氧基]-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(反式-4-二甲基氨基-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(反式-4-{N-[(吗啉-4-基)羰基]-N-甲基-氨基}-环己烷-1-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-[2-(2,2-二甲基-6-氧代-吗啉-4-基)-乙氧基]-7-[(S)-(四氢呋喃-2-基)甲氧基]-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(1-甲磺酰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉、4-[(3-氯-4-氟-苯基)氨基]-6-(1-氰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉、西妥昔单抗(Cetuximab),曲妥单抗(Trastuzumab),ABX-EGF及Mab ICR-62。这些化合物,如可得,可以其消旋物,对映体,或非对映体的形式,或以其药理学上可接受的酸加成盐形式,或以其溶剂化物及/或水合物形式使用。这些化合物公开于现有技术,例如WO96/30347,WO97/02266,WO99/35146,WO00/31048,WO00/78735,WO01/34574,WO01/61816,WO01/77104,WO02/18351,WO02/18372,WO02/18373,WO02/18376,WO02/50043,WO03/082290,Cancer Research2004,64:11(3958-3965),Am J Health-Syst Pharm2000,57(15),2063-2076,ClinicalTherapeutics1999,21(2),309-318,WO98/50433,及WO95/20045中。
内皮素拮抗剂优选可选自替唑生坦(tezosentan),波生坦(bosentan),恩拉生坦(enrasentan),希塔山坦(sixtasentan),T-0201、BMS-193884、K-8794、PD-156123、PD-156707、PD-160874、PD-180988、S-0139及ZD-1611。本发明范围内任何述及内皮素拮抗剂包括可由内皮素拮抗剂形成的盐,优选为药理学上可接受的酸加成盐,或衍生物。
这些联用药可同时或依序施用。
用于药用,根据本发明的化合物优选用于温血脊椎动物,特别是人类,以0.0001-100毫克/公斤体重的剂量。
这些化合物可以单独或与其他活性物质联合经静脉内,经皮下,经肌肉内,经腹膜内,或经鼻内途径,经吸入,或经皮,或经口施用,气溶胶制剂特别适合用于吸入。
其可与一或多种常规惰性固体,半固体,或液体载剂,例如淀粉,不同种类的纤维素,乳糖,甘露醇,山梨醇,葡萄糖,磷酸钙,硬脂,脂肪醇,甘油,中链三酸甘油酯及有关酯,聚乙二醇,精制特级油,水,水/乙醇,水/甘油,水/山梨醇,水/聚乙二醇,丙二醇,及/或功能赋形剂,例如聚乙烯基吡咯烷酮,羟基丙基甲基纤维素,羧甲基纤维素钠,淀粉羟乙酸钠,二氧化硅,聚山梨酸酯,泊洛沙姆(poloxamers),单硬脂酸甘油酯(gelucires),硬脂酸镁,柠檬酸,酒石酸,或其适当混合物调配成常规盖伦制剂,如普通或包衣片剂,胶囊,粉末,注射溶液,安瓿,悬浮液,溶液,喷雾液,或栓剂施用。
下列制剂实施例是例示本发明,并非限制其范围。
实施例F1:含有75毫克活性物质的包衣片剂
组成
1片芯含有:
活性物质 75.0毫克
磷酸钙 131.0毫克
聚乙烯基吡咯烷酮 10.0毫克
羧甲基纤维素钠 10.0毫克
二氧化硅 2.5毫克
硬脂酸镁 1.5毫克
230.0毫克
制备(直接压缩)
活性物质与所有成分混合,过筛,在制片机中压缩,形成所欲形状的片剂。
片芯的重量: 230毫克
片芯的表观: 9毫米,双凸面
所产生的片芯涂覆主要包含羟基丙基甲基纤维素的薄膜。
包衣片剂的重量: 240毫克
实施例F2:含有100毫克活性物质的片剂
组成
1片剂含有:
活性物质 100.0毫克
乳糖 80.0毫克
玉米淀粉 34.0毫克
羟基丙基甲基纤维素 4.0毫克
硬脂酸镁 2.0毫克
220.0毫克
制备(湿法制粒)
活性物质,乳糖,及淀粉混合在一起,以羟基丙基甲基纤维素的水溶液均匀润湿。在湿组合物过筛(2.0毫米网目大小)及在架(rack)型干燥器中于50℃干燥后,再过筛(1.5毫米网目大小),加入润滑剂。完成的混合物压缩形成片剂。
片剂的重量: 220毫克
片剂的表观: 10毫米,扁平面具有斜边及在一面上
中断刻痕
实施例F3:含有150毫克活性物质的片剂
组成
1片剂含有:
活性物质 150.0毫克
乳糖 85.0毫克
微晶纤维素 40.0毫克
聚乙烯基吡咯烷酮 10.0毫克
二氧化硅 10.0毫克
硬脂酸镁 5.0毫克
300.0毫克
制备(干法制粒)
活性物质与乳糖,聚乙烯基吡咯烷酮,及部分微晶纤维素,硬脂酸镁混合,压缩,例如在辊压缩器上。带状物(ribbons)被0.8毫米网目大小的筛断裂成细小颗粒。在随后被0.5毫米网目大小的筛筛过及与剩余成分掺合后,由混合物压成片剂。
片剂的重量: 300毫克
片剂的表观: 10毫米,扁平
实施例F4:含有150毫克活性物质的硬明胶胶囊
组成
1胶囊含有:
活性物质 150.0毫克
乳糖 85.0毫克
微晶纤维素 40.0毫克
聚乙烯基吡咯烷酮 10.0毫克
二氧化硅 10.0毫克
硬脂酸镁 5.0毫克
制备
活性物质与乳糖,聚乙烯基吡咯烷酮,及部分微晶纤维素,硬脂酸镁混合,压缩,例如在辊压缩器上。带状物(ribbons)被0.8毫米网目大小的筛断裂成细小颗粒。在随后被0.5毫米网目大小的筛筛过及与剩余成分掺合后,由混合物压成片剂。
片剂的重量: 300毫克
片剂的表观: 1号硬明胶胶囊
实施例F5:含有150毫克活性物质的栓剂
组成
1栓剂含有:
活性物质 150.0毫克
聚乙二醇1500 800.0毫克
聚乙二醇6000 850.0毫克
聚乙二醇40氢化蓖麻油 200.0毫克
2000.0毫克
制备
栓剂基质熔化后,活性物质均匀地分散在其中并且将熔融体倾倒到冷却的模具中。
实施例F6:含有50毫克活性物质的悬浮剂
100ml的悬浮剂包含
活性物质 1.00克
羧甲基纤维素钠 0.10克
对-羟基苯甲酸甲酯 0.05克
对-羟基苯甲酸丙酯 0.01克
葡萄糖 10.00克
甘油 5.00克
70%山梨醇溶液 20.00克
调味剂 0.30克
蒸馏水 加至 100毫升
制备
蒸馏水加热至70℃。对-羟基苯甲酸甲酯及丙酯与甘油及羧甲基纤维素的钠盐一起搅拌溶于其中。溶液冷却至周围温度,活性物质加入,以搅拌均匀分散于其中。在糖,山梨醇溶液,及调味剂加入及溶解后,悬浮液以搅拌抽空以去除空气。
因此,5毫升悬浮液含有50毫克活性物质。
实施例F7:含有10毫克活性物质的安瓿
组成:
活性物质 10.0毫克
0.01N盐酸 适量
双重蒸馏水 加至2.0毫升
制备
活性物质溶于需要量的0.01N HCl中,以氯化钠作成等张,过滤灭菌,移入2毫升安瓿中。
实施例F8:含有50毫克活性物质的安瓿
组成:
活性物质 50.0毫克
0.01N盐酸 适量
双重蒸馏水 加至10.0毫升
制备
活性物质溶于需要量的0.01N HCl中,以氯化钠作成等张,过滤灭菌,移入10毫升安瓿中。
实施例F9:用于粉末吸入的含有5毫克活性物质的胶囊
1胶囊含有:
活性物质 5.0毫克
吸入用乳糖 15.0毫克
20.0毫克
制备
活性物质与吸入用乳糖混合。混合物在胶囊制造机中填充入胶囊(空胶囊的重量约50毫克)。
胶囊的重量:70.0毫克
胶囊的大小=3号
实施例F10:用于手持雾化器吸入的含有2.5毫克活性物质的溶液1喷含有:
活性物质 2.500毫克
苯扎氯铵 0.001毫克
1N盐酸 适量
乙醇/水(50/50) 加至15.000毫克
制备
活性物质及苯扎氯铵溶于乙醇/水(50/50)中。溶液的pH以1N盐酸调节。生成的溶液过滤,移入用于手持雾化器的适当容器(药筒)中。
容器的含量:4.5克。
Claims (3)
1.下述通式的吲哚满酮、其互变体,非对映体,对映体,混合物,及盐在制备用于预防或治疗选自下列的纤维变性的药物中的用途:慢性阻塞性肺病中肺组织的纤维变性及重新塑造,慢性支气管炎中肺组织的纤维变性及重新塑造,肺气肿中肺组织的纤维变性及重新塑造,肺纤维变性及具有纤维化成分的肺疾病,哮喘中纤维变性及重新塑造,
其中
X为氧原子,
R1为氢原子,
R2为氟,氯,或溴原子,或氰基,
R3为苯基或被氟、氯、溴或碘原子或被CX-烷氧基单取代的苯基,其中上述未被取代及被单取代的苯基可另在3-或4-位被下列的基团取代:
氟,氯,或溴原子,
氰基,
C1-3-烷氧基,或C1-2-烷基-羰基-氨基,
氰基-C1-3-烷基,羧基-C1-3-烷基,羧基-C1-4-烷氧基,羧基-C1-3-烷基氨基,羧基-C1-3-烷基-N-(C1-3-烷基)-氨基,C1-4-烷氧基-羰基-C1-3-烷基,C1-4-烷氧基-羰基-C1-3-烷氧基,C1-4-烷氧基-羰基-C1-3-烷基氨基,C1-4-烷氧基-羰基-C1-3-烷基-N-(C1-3-烷基)-氨基,氨基-C1-3-烷基,氨基羰基-C1-3-烷基,(C1-2-烷基-氨基)-羰基-C1-3-烷基,二-(C1-2-烷基)-氨基-羰基-C1-3-烷基,(C1-2-烷基-羰基)-氨基-C1-3-烷基,(C1-4-烷氧基-羰基)-氨基-C1-3-烷基,(C3-6-烷基-羰基)-氨基-C1-3-烷基,(苯基-羰基)-氨基-C1-3-烷基,(C3-6-环烷基-羰基)-氨基-C1-3-烷基,(C3-6-环烷基-C1-3-烷基-羰基)-氨基-C1-3-烷基,(噻吩-2-基-羰基)-氨基-C1-3-烷基,(呋喃-2-基-羰基)-氨基-C1-3-烷基,(苯基-C1-3-烷基-羰基)-氨基-C1-3-烷基,(2-(C1-4-烷氧基)-苯甲酰基-羰基)-氨基-C1-3-烷基,(吡啶-2-基-羰基)-氨基-C1-3-烷基,(吡啶-3-基-羰基)-氨基-C1-3-烷基-,(吡啶-4-基-羰基)-氨基-C1-3-烷基-,或C1-3-烷基-哌嗪-1-基-羰基-C1-3-烷基,羧基-C2-3-烯基,氨基羰基-C2-3-烯基,(C1-3-烷基氨基)-羰基-C2-3-烯基,二-(C1-3-烷基)-氨基-羰基-C2-3-烯基,或C1-4-烷氧基-羰基-C2-3-烯基,其中取代基可相同或不同,
R4为苯基或被下列基团单取代的苯基:
C1-3-烷基,其在末端被氨基,胍基,单或二-(C1-2-烷基)-氨基,N-[ω-二-(C1-3-烷基)-氨基-C2-3-烷基]-N-(C1-3-烷基)-氨基,N-甲基-(C3-4-烷基)-氨基,N-(C1-3-烷基)-N-苄基氨基,N-(C1-4-烷氧基羰基)-氨基,N-(C1-4-烷氧基羰基)-C1-4-烷基氨基,4-(C1-3-烷基)-哌嗪-1-基,咪唑-1-基,吡咯烷-1-基,氮杂环丁-1-基,吗啉-4-基,哌嗪-1-基,硫吗啉-4-基,
二-(C1-3-烷基)-氨基-(C1-3-烷基)-磺酰基,2-[二-(C1-3-烷基)-氨基]-乙氧基,4-(C1-3-烷基)-哌嗪-1-基-羰基,{ω-[二-(C1-3-烷基)-氨基]-(C2-3-烷基)}-N-(C1-3-烷基)-氨基-羰基,1-(C1-3-烷基)咪唑-2-基,(C1-3-烷基)-磺酰基,或
下式的基团
其中
R7为C1-2-烷基,C1-2-烷基-羰基,二-(C1-2-烷基)-氨基-羰基-C1-3-烷基,或C1-3-烷基磺酰基,及
R8为C1-3-烷基,ω-[二-(C1-2-烷基)-氨基]-C2-3-烷基,ω-[单(C1-2-烷基)-氨基]-C2-3-烷基,或
(C1-3-烷基)-羰基,(C4-6-烷基)-羰基,或羰基-(C1-3-烷基),其末
端被二-(C1-2-烷基)-氨基,哌嗪-1-基,或4-(C1-3-烷基)-哌嗪-1-基,
在R4基团中存在的所有二烷基氨基还可以季铵化形式,例如以N-甲基-(N,N-二烷基)-铵基存在,其中平衡离子优选选自碘离子,氯离子,溴离子,甲磺酸根,对-甲苯磺酸根,及三氟醋酸根,
R5为氢原子,及
R6为氢原子,
其中上述烷基包括直链及支链的烷基,其中另有1至3个氢原子可以被氟原子替代,
其中存在的羧基,氨基,或亚胺基可另被在活体内可裂解的基团取代,或可以前药基团的形式存在,例如以可在活体内转化为羧基的基或可在活体内转化为亚胺基或氨基的基团的形式存在。
2.如权利要求1所述的用途,其中被取代的通式I的吲哚满酮选自:
(a)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(b)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(c)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(3-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(d)3-Z-[1-(4-(N-(4-甲基哌嗪-1-基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(e)3-Z-[1-(4-(N-(2-二甲基氨基乙基)-N-甲基磺酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(f)3-Z-[1-(4-(N-(3-二甲基氨基丙基)-N-乙酰基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(g)3-Z-[1-(4-(1-甲基咪唑-2-基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(h)3-Z-[1-(4-(N-(二甲基氨基甲基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(i)3-Z-[1-(4-(N-(2-二甲基氨基乙基羰基)-N-甲基氨基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(j)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(k)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氟-2-吲哚满酮
(l)3-Z-[1-(4-(2-二甲基氨基乙基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(m)3-Z-[1-(4-二甲基氨基甲基苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(n)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-氯-2-吲哚满酮
(o)3-Z-[1-(4-(吡咯烷-1-基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮
(p)3-Z-[1-(4-(二甲基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)苯基)亚甲基]-6-溴-2-吲哚满酮,以及
(q)3-Z-[1-(4-(二乙基氨基甲基)苯胺基)-1-(4-(2-羧基乙基)-亚甲基]-6-溴-2-吲哚满酮,
其互变体,非对映体,对映体,混合物,及盐。
3.如权利要求1或2中任一项的用途,其中该疾病为特发性肺纤维化。
Applications Claiming Priority (3)
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EP04030769 | 2004-12-24 | ||
EP04030769.6 | 2004-12-24 | ||
PCT/EP2005/057013 WO2006067175A1 (en) | 2004-12-24 | 2005-12-21 | Medicaments for the treatment or prevention of fibrotic diseases |
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CN101087604A CN101087604A (zh) | 2007-12-12 |
CN101087604B true CN101087604B (zh) | 2010-10-13 |
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CN2005800446331A Expired - Fee Related CN101087604B (zh) | 2004-12-24 | 2005-12-21 | 用于治疗或预防纤维化疾病的药剂 |
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US (3) | US20060148883A1 (zh) |
EP (1) | EP1835907B1 (zh) |
JP (1) | JP5748386B2 (zh) |
KR (1) | KR20070092305A (zh) |
CN (1) | CN101087604B (zh) |
AR (1) | AR052439A1 (zh) |
AT (1) | ATE429222T1 (zh) |
AU (1) | AU2005318136B2 (zh) |
BR (1) | BRPI0519351A2 (zh) |
CA (1) | CA2591089C (zh) |
DE (1) | DE602005014145D1 (zh) |
DK (1) | DK1835907T3 (zh) |
EA (1) | EA200701181A1 (zh) |
ES (1) | ES2326277T3 (zh) |
HR (1) | HRP20090312T1 (zh) |
IL (1) | IL184124A0 (zh) |
MX (1) | MX2007007676A (zh) |
NO (1) | NO20073830L (zh) |
PE (1) | PE20061155A1 (zh) |
PL (1) | PL1835907T3 (zh) |
PT (1) | PT1835907E (zh) |
RS (1) | RS50833B (zh) |
SI (1) | SI1835907T1 (zh) |
TW (1) | TW200637544A (zh) |
WO (1) | WO2006067175A1 (zh) |
ZA (1) | ZA200703600B (zh) |
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US7514468B2 (en) * | 2002-07-23 | 2009-04-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6 position, the preparation thereof and their use as pharmaceutical compositions |
US7169936B2 (en) * | 2002-07-23 | 2007-01-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
WO2007057399A2 (en) * | 2005-11-15 | 2007-05-24 | Boehringer Ingelheim International Gmbh | Treatment of cancer with indole derivatives |
MY150753A (en) * | 2007-03-02 | 2014-02-28 | Mitsui Chemicals Inc | Non-woven fabric laminate |
EP2220079A2 (en) * | 2007-11-15 | 2010-08-25 | Boehringer Ingelheim International GmbH | Substituted amides, manufacturing and use thereof as medicaments |
US20090131359A1 (en) * | 2007-11-19 | 2009-05-21 | Atamas Sergei P | Antifibrotic therapy |
ES2394239T3 (es) * | 2008-01-25 | 2013-01-23 | Boehringer Ingelheim International Gmbh | Formas salinas de un derivado de 6-fluoro-1,2-dihidro-2-oxo-3H-indol-3-ilideno, procedimiento para su preparación y composiciones farmacéuticas que las contienen |
US8759010B2 (en) | 2008-09-26 | 2014-06-24 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Host cell kinases as targets for antiviral therapies against HCV infection |
WO2012103520A1 (en) * | 2011-01-28 | 2012-08-02 | Board Of Regents Of The University Of Nebraska | Methods and compositions for modulating cyclophilin d |
US10450295B2 (en) | 2013-08-09 | 2019-10-22 | Acclaim BioMed USA LLC | Method of using an indolinone molecule and derivatives for inhibiting liver fibrosis and hepatitis |
CN114732910A (zh) | 2017-10-05 | 2022-07-12 | 弗尔康医疗公司 | P38激酶抑制剂降低dux4和下游基因表达以用于治疗fshd |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
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DK1115704T3 (da) * | 1998-09-25 | 2003-09-29 | Boehringer Ingelheim Pharma | Substituerede indolinoner med inhiberende virkning for forskellige kinaser og cyclin/CDK komplekser |
US6762180B1 (en) * | 1999-10-13 | 2004-07-13 | Boehringer Ingelheim Pharma Kg | Substituted indolines which inhibit receptor tyrosine kinases |
DE10117204A1 (de) * | 2001-04-06 | 2002-10-10 | Boehringer Ingelheim Pharma | In 6-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
US7169936B2 (en) * | 2002-07-23 | 2007-01-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
PE20040701A1 (es) * | 2002-07-23 | 2004-11-30 | Boehringer Ingelheim Pharma | Derivados de indolinona sustituidos en posicion 6 y su preparacion como medicamentos |
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- 2005-12-21 KR KR1020077017059A patent/KR20070092305A/ko not_active Application Discontinuation
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- 2005-12-21 CN CN2005800446331A patent/CN101087604B/zh not_active Expired - Fee Related
- 2005-12-21 AT AT05823903T patent/ATE429222T1/de active
- 2005-12-21 JP JP2007547510A patent/JP5748386B2/ja not_active Expired - Fee Related
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2009
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Also Published As
Publication number | Publication date |
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ZA200703600B (en) | 2008-07-30 |
DK1835907T3 (da) | 2009-08-03 |
ATE429222T1 (de) | 2009-05-15 |
HRP20090312T1 (en) | 2009-07-31 |
IL184124A0 (en) | 2007-10-31 |
AU2005318136A1 (en) | 2006-06-29 |
NO20073830L (no) | 2007-07-23 |
DE602005014145D1 (de) | 2009-06-04 |
PT1835907E (pt) | 2009-06-16 |
CN101087604A (zh) | 2007-12-12 |
EP1835907B1 (en) | 2009-04-22 |
MX2007007676A (es) | 2007-08-14 |
TW200637544A (en) | 2006-11-01 |
EA200701181A1 (ru) | 2008-02-28 |
EP1835907A1 (en) | 2007-09-26 |
JP2008525374A (ja) | 2008-07-17 |
CA2591089A1 (en) | 2006-06-29 |
US20140128409A1 (en) | 2014-05-08 |
AR052439A1 (es) | 2007-03-21 |
BRPI0519351A2 (pt) | 2009-01-20 |
PL1835907T3 (pl) | 2009-08-31 |
RS50833B (sr) | 2010-08-31 |
KR20070092305A (ko) | 2007-09-12 |
WO2006067175A1 (en) | 2006-06-29 |
AU2005318136B2 (en) | 2012-02-09 |
US20120004202A1 (en) | 2012-01-05 |
PE20061155A1 (es) | 2006-12-16 |
CA2591089C (en) | 2014-02-11 |
US20060148883A1 (en) | 2006-07-06 |
JP5748386B2 (ja) | 2015-07-15 |
SI1835907T1 (sl) | 2009-10-31 |
ES2326277T3 (es) | 2009-10-06 |
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