CN1516700A - 用作半胱天冬酶激活剂和细胞凋亡诱导剂的取代的4h-色烯和类似物及其应用 - Google Patents
用作半胱天冬酶激活剂和细胞凋亡诱导剂的取代的4h-色烯和类似物及其应用 Download PDFInfo
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- CN1516700A CN1516700A CNA028120671A CN02812067A CN1516700A CN 1516700 A CN1516700 A CN 1516700A CN A028120671 A CNA028120671 A CN A028120671A CN 02812067 A CN02812067 A CN 02812067A CN 1516700 A CN1516700 A CN 1516700A
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Abstract
本发明涉及式(UI)所代表的取代的4H-色烯及其类似物,其中R1-R5、A、Y和Z如说明书中所定义。本发明还涉及关于式(I)化合物是半胱天冬酶激活剂和细胞凋亡诱导剂的发现。因此,本发明的半胱天冬酶激活剂和细胞凋亡诱导剂可用于在其中发生生长失控和异常细胞扩散的各种临床病症中诱导细胞死亡。
Description
发明背景
发明领域
本发明属于药物化学领域。具体来说,本发明涉及取代的4H-色烯和类似物,以及关于这些化合物是半胱天冬酶激活剂和细胞凋亡诱导剂的发现。本发明还涉及这些化合物作为治疗上有效的抗癌剂的应用。
现有技术
生物体通过称为细胞调控死亡、细胞程序死亡或细胞凋亡的过程来消除不需要的细胞。这样的细胞死亡作为动物发育的正常方面以及在组织体内平衡和老化中发生(Glucksmann,A.,Biol.Rev.Cambridge Philos.Soc.26:59-86(1951);Glucksmann,A.,Archives de Biologie 76:419-437(1965);Ellis,等人,Dev.112:591-603(1991);Vaux,等人,Cell 76:777-779(1994))。细胞凋亡调控细胞数目,促进形态形成,除去有害的或异常细胞,并消除已经履行完其功能的细胞。此外,细胞凋亡作为对各种不同的生理应力例如低氧或局部缺血的反应而发生(PCT出版的申请WO 96/20721)。
经历细胞调控死亡的细胞会共同发生很多形态学上的改变,包括胞浆和核膜起泡,细胞收缩(核质和细胞质浓缩),细胞器再定位和压缩,染色质浓缩和生成细胞凋亡体(含有细胞内材料的膜封闭颗粒)(Orrenius,S.,J.Internal Medicine 237:529-536(1995))。
细胞凋亡是通过内源性细胞自杀机制来实现的(Wyllie,A.H.,Cell Death in Biology and Pathology,Bowen和Lockshin,eds.,Chapman和Hall(1981),pp.9-34)。细胞激活其内部编码的自杀程序以作为内部或外来信号的结果。自杀程序是通过激活小心调控的基因程序来进行的(Wyllie,等人,Int.Rev.Cyt.68:251(1980);Ellis,等人,Ann.Rev.Cell Bio.7:663(1991))。在溶解之前,凋亡的细胞和凋亡体通常被邻近细胞或巨噬细胞识别和清除。由于该清除机制,尽管清除了大量细胞,也没有引起炎症(Orrenius,S.,J.Internal Medicine 237:529-536(1995))。
已经发现,有-组蛋白酶是细胞凋亡中的关键成分(参见例如Thornberry,Chemistry and Biology 5:R97-R103(1998);Thornberry,British Med.Bull.53:478-490(1996))。在线虫Caenorhabditis elegans中进行的基因研究表明,细胞程序死亡涉及至少14个基因,其中有2个是原凋亡(死亡促进)ced(关于异常细胞死亡)基因ced-3和ced-4。CED-3与白介素1β-转化酶—一种半胱氨酸蛋白酶,现在称为半胱天冬酶-1有同源性。当把这些数据最终应用于哺乳动物,并进一步广泛研究时,发现哺乳动物细胞凋亡系统似乎涉及半胱天冬酶级联或类似于半胱天冬酶级联的系统。目前,半胱氨酸蛋白酶的半胱天冬酶家族包括14个不同成员,并且在将来可能发现更多。所有已知的半胱天冬酶都是作为酶原合成的,在形成活性酶之前,酶原需要在天冬氨酰残基上裂解。因此,半胱天冬酶能够以放大级联的方式激活其它半胱天冬酶。
据认为,细胞凋亡和半胱天冬酶在癌症的发展中是至关重要的(Apoptosis and Cancer Chemotherapy,Hickman和Dive,eds.,Humana Press(1999))。有标本证据表明,癌细胞虽然含有半胱天冬酶,但是缺少激活半胱天冬酶级联的分子机制部分。这使得癌细胞失去了进行细胞自杀的能力,并且细胞变成不死亡和癌性的。对于细胞凋亡过程,已知存在着控制点,控制点代表干预导致激活的点。这些控制点包括CED-9-BCL-样和CED-3-ICE-样基因家族产物,这些产物是分别调控细胞自杀或死亡决定和实施细胞死亡过程自身的固有蛋白(参见Schmitt,等人,Biochem.Cell.Biol.75:301-314(1997))。BCL-样蛋白包括BCL-xL和BAX-α,BAX-α似乎起着上游半胱天冬酶激活的作用。BCL-xL似乎阻止细胞凋亡蛋白酶级联的激活,而BAX-α促进细胞凋亡蛋白酶级联的激活。
已表明化疗(抗癌)药物可通过激活静止的半胱天冬酶级联来引发癌细胞经历自杀。这可能是已知的抗癌药物的最主要—如果不是全部的话—作用方式的关键方面(Los,等人,Blood 90:3118-3129(1997);Friesen,等人,Nat.Med. 2:574(1996))。当前的抗肿瘤药物的机制经常涉及在细胞周期的特定阶段进行攻击。简言之,细胞周期是指细胞在其生命中正常发展的阶段。在正常情况下,细胞处于称为G0的休止期。在倍增期间,细胞进行至称为S的发生DNA合成的时期。随后,在称为M的时期发生细胞分裂或有丝分裂。抗肿瘤药物例如阿糖胞苷、羟基脲、6-巯基嘌呤和甲氨蝶呤是S期特异性的,而抗肿瘤药物例如长春新碱、长春碱和紫杉醇是M期特异性的。许多生长缓慢的肿瘤,例如结肠癌主要存在于G0期,而迅速增殖的正常组织例如骨髓主要存在于S或M期。因此,药物例如6-巯基嘌呤可引起骨髓毒性,同时对生长缓慢的肿瘤无效。肿瘤疾病化疗的其它方面是本领域技术人员已知的(参见例如Hardman,等人,eds.,Goodman and Gilman’sThe Pharmacological Basis of Therapeutics,Ninth Edition,McGraw-Hill,New York(1996),pp.1225-1287)。因此,很清楚的是,存在激活半胱天冬酶级联的可能性,虽然关于此的确切机制尚不清楚。同样清楚的是,在各种类型的癌症中涉及不足的半胱天冬酶级联活性以及由此所致的细胞凋亡事件不足。开发半胱天冬酶级联激活剂和细胞凋亡诱导剂是开发治疗上有效的抗肿瘤药物的高度可取的目标。此外,因为自身免疫性疾病和-些变性疾病也涉及异常细胞增殖,所以对这些疾病的治疗可能也涉及通过施用适当的半胱天冬酶级联结合剂和细胞凋亡诱导剂来增强细胞凋亡过程。
EP537949公开了用作抗增殖剂的4H-萘并[1,2-b]吡喃化合物:
其中
每个R1独立地为卤素、三氟甲基、C1-4烷氧基、羟基、硝基、C1-4烷基、C1-4烷硫基、羟基-C1-4烷基、羟基-C1-4烷氧基、三氟甲氧基、羧基、其中R5是酯基的-COOR5,-CONR6R7或-NR6R7,其中R6和R7分别是氢或C1-4烷基;
R2是苯基、萘基或选自下列的杂芳基:噻吩基、吡啶基、苯并噻吩基、喹啉基、苯并呋喃基或苯并咪唑基,其中所述苯基、萘基和杂芳基可任选被取代,或者R2是可任选被C1-4烷基取代的呋喃基;
R3是腈;羧基;其中R8是酯基的-COOR8;-CONR9R10,其中R9和R10分别是氢或C1-4烷基;或R11SO2,其中R11是C1-4烷基或任选被取代的苯基;
R4是-NR12R13、-NHCOR12、-N(COR12)2或-N=CHOCH2R12,其中R12和R13分别是氢或任选被羧基取代的C1-4烷基;或者R4是
其中X是C2-4亚烷基,或者R4是-NHSO2R14,其中R14是C1-4烷基或任选被取代的苯基;且
n是0-2。
US5281619公开了用于治疗糖尿病并发症的萘并吡喃化合物:
其中
R1是C1-4烷氧基、OH或COOH;
R2是任选被取代的苯基;
R3是腈,或者R3是羧基或-COOR8,其中R2是被3-硝基或3-三氟甲基取代的苯基,且R8是酯基;
R4是-NR12R13、-NHCOR12、-N(COR12)2或-N=CHOCH2R12,其中R12和R13分别是氢或C1-4烷基;且
n是0-2。
EP599514公开了用作细胞增殖抑制剂的吡喃并喹啉衍生物的制备:
其中R1是任选被取代的苯基或任选被取代的选自下列的杂芳基:噻吩基、吡啶基、苯并噻吩基、喹啉基、苯并呋喃基或苯并咪唑基,或者
R1是可任选被C1-4烷基取代的呋喃基;
R2是腈;羧基;其中R4是酯基的-CO2R4;-CON(R5)R6,其中R5和R6独立地为氢或C1-4烷基;或R7SO2,其中R7是C1-4烷基或任选被取代的苯基;
R3是-NR8R9、-NHCOR8、-N(CO2R8)2、-N=CHOR8,其中R8和R9独立地为H或C1-4烷基;或-NHSO2R10,其中R10是C1-4烷基或任选被取代的苯基;或
其中X是C2-4亚烷基;且
环P代表与苯并吡喃母核稠合的吡啶。
EP618206公开了用作免疫抑制剂和细胞增殖抑制剂的萘并吡喃和吡喃并喹啉化合物的制备:
其中
A-B是CH2CH2或CH=CH;
每个R1独立地为卤素、羧基、三氟甲基、羟基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、羟基-C1-4烷基、羟基-C1-4烷氧基、含氮杂环基、硝基、三氟甲氧基、其中R5是酯基的-COOR5,-COR6、-CONR6R7或-NR6R7,其中R6和R7分别是氢或C1-4烷基;
R2是苯基、萘基或选自下列的杂芳基:噻吩基、吡啶基、苯并噻吩基、喹啉基、苯并呋喃基或苯并咪唑基,其中所述苯基、萘基和杂芳基可任选被取代,或者R2是可任选被C1-4烷基取代的呋喃基;
R3是腈;羧基;其中R8是酯基的-COOR8;-CONR9R10,其中R9和R10分别是氢或C1-4烷基;或-SO2R11,其中R11是C1-4烷基或任选被取代的苯基-C1-4烷基;
R4是1-吡咯基、1-咪唑基或1-吡唑基,每一所述基团可任选被-个或两个C1-4烷基、羧基、羟基-C1-4烷基或-CHO取代,或者R4是1-(1,2,4-三唑基)、1-(1,3,4-三唑基)或2-(1,2,3-三唑基),每-所述基团可任选被C1-4烷基或C1-4全氟烷基取代,或者R4是可任选被C1-4烷基取代的1-四唑基;
X是吡啶或苯环;且
n是0-2。
EP619314公开了4-苯基-4H-萘并(2,1-b)吡喃衍生物的制备:
其中
R1和R2独立地为卤素、三氟甲基、C1-C4烷氧基、羟基、硝基、C1-C4烷基、C1-C4烷硫基、羟基-C1-C4烷基、羟基-C1-C4烷氧基、三氟甲氧基、羧基、其中R4是酯基的-COOR8,-COR9、-CONR9R10或-NR9R10,其中R9和
R10分别是氢或C1-4烷基;
R3是腈、羧基或-CO2R11,其中R11是酯基;
R4是-NR12R13、-NR12COR13、-N(COR12)2或-N=CHOCH2R12,其中R12和R13分别是氢或C1-4烷基,或者R4是
其中X是C2-C4亚烷基,或者R4是任选被取代的1-吡咯基;且m和n分别独立地为0-2。
据述这些化合物可用于治疗再狭窄、免疫疾病和糖尿病并发症。
Smith等人(Bioorg.Med.Chem.Lett.5:2783-2788(1995))报道了一系列2,4-二取代的-4H-萘并[1,2-b]吡喃-3-甲腈化合物的抗风湿作用。它们报道,已证明了4-(3-硝基苯基)-2-(N-琥珀酰亚氨基)-4H-萘并[1,2-b]吡喃-3-甲腈是酸稳定的,并且仍然保持生物活性:
Birch等人(Diabetes 45:642-650(1996))报道,LY290181-一种糖尿病引起的血管机能障碍的抑制剂—通过抑制与佛波醇反应部件结合的转录因子来阻断蛋白激酶C-刺激的转录激活:
Panda等人(J.Biol.Chem.272:7681-7687(1997))报道了LY290181对微管动力学的抑制作用,这有可能是其抗增殖作用的潜在机制。
Wood等人(Mol.Pharmacol.52:437-444(1997))报道,LY290181通过直接的微管蛋白结合来抑制有丝分裂和微管功能。
PCT出版的专利申请WO 9824427公开了抗微管组合物以及治疗或预防炎性疾病的方法。其中列出了LY290181作为抗微管剂。
发明概述
本发明涉及下述发现:式I所代表的取代的4H-色烯和类似物是半胱天冬酶级联激活剂和细胞凋亡诱导剂。因此,本发明的一个方面涉及式I化合物作为细胞凋亡诱导剂的应用。
本发明的第二个方面提供了治疗、预防或改善瘤形成和癌症的方法,包括给需要这种治疗的哺乳动物施用式I化合物。
在本发明范围内的化合物有很多是新化合物。因此,本发明的第三个方面提供了新的式I化合物,以及这些新化合物在治疗、预防或改善瘤形成和癌症中的应用。
本发明的第四个方面提供了用于治疗对诱导细胞凋亡有反应的病症的药物组合物,其中包含有效量的式I化合物以及与其混和的一种或多种可药用载体或稀释剂。
本发明的第五个方面涉及制备新的式I化合物的方法。
发明详述
本发明来自下述发现:式I所代表的取代的4H-色烯和类似物是有效、高效力的半胱天冬酶级联激活剂和细胞凋亡诱导剂。因此,式I化合物可用于治疗对诱导细胞凋亡有反应的病症。
具体来说,可用于本发明该方面的化合物是式I化合物或其可药用盐或前药:
其中
R1-R4独立地为氢、卤素、卤代烷基、芳基、稠合的芳基、碳环基、杂环基、杂芳基、C1-10烷基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、氨基烷基、羧基烷基、硝基、氨基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、烷氧基、羧基、亚甲二氧基、羰基酰氨基或烷硫;或者R1和R2、或R2和R3或R3和R4与它们所连接的原子一起形成芳基、杂芳基、部分饱和碳环基或部分饱和杂环基,其中所述基团可任选被取代;
R5是氢或C1-10烷基;
A是任选被取代的,并且是芳基、杂芳基、饱和碳环基、部分饱和碳环基、饱和杂环基、部分饱和杂环基或芳基烷基;
Y是CN、COR7、CO2R7或CONRxRy,其中R7、Rx和Ry独立地为氢、C1-10烷基、卤代烷基、芳基、稠合的芳基、碳环基、杂环基、杂芳基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基或氨基烷基;或者Rx和Ry与它们所连接的氮一起形成杂环;且
Z是NR8R9、NHCOR8、N(COR8)2、N(COR8)(COR9)、N=CHOR8或N=CHR8,其中R8和R9独立地为H、C1-4烷基或芳基,或者R8和R9与它们所连接的基团一起形成杂环。
优选地,R1和R2与它们所连接的原子一起形成芳基、杂芳基、部分饱和碳环基或部分饱和杂环基,其中所述基团可任选被取代。
定义如下的式I化合物是优选的:其中R1和R2一起形成选自下列的结构:-OCH2O-、-(CH2)3-、-(CH2)4-、-OCH2CH2O-、-CH2N(V)CH2-、-CH2CH2N(V)CH2-、-CH2N(V)CH2CH2-、-N(V)-CH=CH-、-CH=CH-N(V)-、-O-CH=CH-、-CH=CH-O-、-S-CH=CH-、-CH=CH-S-和-N=CH-CH=N-,其中V是氢、C1-10烷基、卤代烷基、芳基、稠合的芳基、碳环基、杂环基、杂芳基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基或氨基烷基。
优选的式I化合物包括定义如下的那些:其中R3和R4分别是氢,更优选地,R3、R4和R5分别是氢。优选的式I化合物包括定义如下的化合物:其中A是苯基、萘基、吡啶基、喹啉基、异喹啉基、噻吩基、呋喃基、吡咯基、吲哚基、2-苯基乙基、二氢苯基、四氢苯基或环己基,任一所述基团可任选被取代。更优选地,A是任选被取代的苯基或任选被取代的吡啶基。优选地,R5是氢,优选地,Z是NH2。优选地,Y是CN。
另一优选的实施方案是式II化合物或其可药用盐或前药:
其中
R1-R5如上文关于式I所定义;且R10-R14独立地为氢、卤素、卤代烷基、芳基、稠合的芳基、碳环基、杂环基、杂芳基、C1-10烷基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、氨基烷基、羧基烷基、硝基、氨基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、烷氧基、羧基、亚甲二氧基、羰基酰氨基或烷硫基;或者R10和R11或R11和R12与它们所连接的原子一起形成芳基、杂芳基、部分饱和碳环基或部分饱和杂环基,其中所述基团可任选被取代。
定义如下的式II化合物是优选的:其中R10和R11或R11和R12一起形成选自下列的结构:-OCH2O-、-(CH2)3-、-(CH2)4-、-OCH2CH2O-、-CH2N(V)CH2-、-CH2CH2N(V)CH2-、-CH2N(V)CH2CH2-、-CH=CH-CH=CH-、-N(V)-CH=CH-、-CH=CH-N(V)-、-O-CH=CH-、-CH=CH-O-、-S-CH=CH-、-CH=CH-S-、-N=CH-CH=CH-、-CH=N-CH=CH-、-CH=CH-N=CH-、-CH=CH-CH=N-和-N=CH-CH=N-,其中V是氢、C1-10烷基、卤代烷基、芳基、稠合的芳基、碳环基、杂环基、杂芳基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基或氨基烷基。
优选的式II化合物包括定义如下的化合物:其中R1-R2独立地为氢、卤素、羟基、C1-10烷基、羟基烷基、氨基烷基、羧基烷基、氨基、酰氨基、酰氧基、烷氧基、亚甲二氧基或烷硫基。R5优选为氢。
另一优选的实施方案是式III化合物或其可药用盐或前药:
其中
R3-R4独立地为氢、卤素、卤代烷基、芳基、稠合的芳基、碳环基、杂环基、杂芳基、C1-10烷基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、氨基烷基、羧基烷基、硝基、氨基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、烷氧基、羧基、亚甲二氧基、羰基酰氨基或烷硫基;
R5是氢或C1-10烷基;
R10-R14独立地为氢、卤素、卤代烷基、芳基、稠合的芳基、碳环基、杂环基、杂芳基、C1-10烷基烷基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、氨基烷基、羧基烷基、硝基、氨基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、烷氧基、羧基、亚甲二氧基、羰基酰氨基或烷硫基;或者
R10和R11或R11和R12与它们所连接的原子一起形成芳基、杂芳基、部分饱和碳环基或部分饱和杂环基,其中所述基团可任选被取代;且D是任选被取代的芳环或杂芳环。
优选的式III化合物包括其中R3-R4是氢的化合物。R5优选为氢。另一组优选的化合物是其中R10和R14是氢的那些。D优选为选自下列的:苯并、吡啶并、呋喃并、噻吩并、吡咯并、咪唑并和吡唑并。
可用于本发明方法的优选化合物的实例包括但不限于:
2-氨基-3-氰基-7-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-二羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-甲基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-8-氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(3-溴苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氰基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲氧基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氯苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-苯基-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(2,4-二甲氧基嘧啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(1,2,3,6-四氢苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-乙基氨基-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-甲氧基-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲氧基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲氧基-吡啶-3-基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲氧基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
3-氰基-2,7,8-三氨基-4-(3-甲氧基苯基)-4H-色烯;
3-氰基-2,7,8-三氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-6-氯-3-氰基-7-甲基-4-苯基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-7-二甲基氨基-4H-色烯;
3-氰基-4-(3-溴-4-羟基-5-甲氧基苯基)-2,7-二氨基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[4,5-b]吡喃;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-氰基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-三氟甲基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-甲基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(喹喔啉-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-甲基-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-7-吡咯烷-4-(3-溴-4,5-苯基)-4H-色烯;
2-氨基-3-氰基-7-哌嗪-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-N-吗啉-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-吡咯-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基苯基-4-甲基色烯;
2-氨基-3-氰基-4-苯基-4-甲基色烯;
2-氨基-3-氰基-4-(3-溴-4-磷酸-二哌啶盐-5-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-苯并硫吡喃;
2-氨基-3-氰基-4-苯基-1,4-二氢喹啉;
2-氨基-3-乙氧基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-甲基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-咪唑并[4,5-h]色烯;
3-氰基-4-(3-溴-4,5-二甲氧基苯基)-2-甲基氨基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-噻吩并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2,7-二氨基-3-氰基-4-苯基-4H-色烯;
2,7-二氨基-3-氰基-4-(3-碘苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-(2-甲基丁酰基氨基)-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-苯基丁酰氧基)-苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-甲基丁酰氧基)-苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
及其可药用盐或前药。
本发明还涉及在式I-III范围内的下列新化合物:
2-氨基-3-氰基-7-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-二羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-甲基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-8-氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(3-溴苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氰基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲氧基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氯苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-苯基-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(2,4-二甲氧基嘧啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(1,2,3,6-四氢苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-乙基氨基-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-甲氧基-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲氧基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲氧基-吡啶-3-基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲氧基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
3-氰基-2,7,8-三氨基-4-(3-甲氧基苯基)-4H-色烯;
3-氰基-2,7,8-三氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-6-氯-3-氰基-7-甲基-4-苯基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-7-二甲基氨基-4H-色烯;
3-氰基-4-(3-溴-4-羟基-5-甲氧基苯基)-2,7-二氨基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[4,5-b]吡喃;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-氰基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-三氟甲基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-甲基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(喹喔啉-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-甲基-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-7-吡咯烷-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-哌嗪-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-N-吗啉-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-吡咯-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基-苯基-4-甲基色烯;
2-氨基-3-氰基-4-苯基-4-甲基色烯;
2-氨基-3-氰基-4-(3-溴-4-磷酸-二哌啶盐-5-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-苯并硫吡喃;
2-氨基-3-氰基-4-苯基-1,4-二氢喹啉;
2-氨基-3-乙氧基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-甲基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-咪唑并[4,5-h]色烯;
3-氰基-4-(3-溴-4,5-二甲氧基苯基)-2-甲基氨基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-噻吩并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2,7-二氨基-3-氰基-4-苯基-4H-色烯;
2,7-二氨基-3-氰基-4-(3-碘苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-(2-甲基丁酰基氨基)-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-苯基丁酰氧基)苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-甲基丁酰氧基)苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
及其可药用盐和前药。
有用的烷基包括直链或支链C1-10烷基,更优选C1-6烷基。典型的C1-10烷基包括甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、3-戊基、己基和辛基,这些基团可任选被取代。
有用的烷氧基包括被一个可任选被取代的上述C1-10烷基取代的氧。
有用的烷硫基包括被-个可任选被取代的上述C1-10烷基取代的硫。还包括这样的烷硫基的亚砜和砜。
有用的氨基包括-NH2、-NHR15和-NR15R16,其中R15和R16是C1-10烷基或环烷基,或者R15和R16与N以及其它基团一起形成环例如哌嗪。所述烷基可任选被取代。
烷基上的任选取代基包括一个或多个卤素、羟基、羧基、氨基、硝基、氰基、C1-C6酰基氨基、C1-C6酰氧基、C1-C6烷氧基、芳氧基、烷硫基、C6-C10芳基、C4-C7环烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、饱和和不饱和杂环基或杂芳基。芳基、芳烷基和杂芳基上的任选取代基包括一个或多个卤素、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C1-C6)烷基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、C1-C6羟基烷基、硝基、氨基、脲基、氰基、C1-C6酰基氨基、羟基、巯基、C1-C6酰氧基、叠氮基、C1-C6烷氧基或羧基。
有用的芳基包括C6-14芳基,优选C6-10芳基。典型的C6-C14芳基包括苯基、萘基、菲基、蒽基、茚基、奥基、联苯基、亚联苯基(biphenylenyl)和芴基。
有用的环烷基是C3-8环烷基。典型的环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。
有用的饱和或部分饱和碳环基是如上所述的环烷基以及环烯基例如环戊烯基、环庚烯基和环辛烯基。
有用的卤素或卤素基团包括氟、氯、溴和碘。
有用的芳基烷基包括被任一上述C6-14芳基取代的C1-10烷基。芳基烷基优选是苄基、苯乙基或萘甲基。
有用的卤代烷基包括被一个或多个氟、氯、溴或碘原子取代的C1-10烷基,例如氟甲基、二氟甲基、三氟甲基、五氟乙基、1,1-二氟乙基、氯甲基、氯氟甲基和三氯甲基。
有用的酰基氨基(酰氨基)是连接在氨基氮上的任何C1-6酰基(链烷酰基),例如乙酰氨基、氯乙酰氨基、丙酰氨基、丁酰氨基、戊酰氨基和己酰氨基,以及芳基取代的C1-6酰基氨基,例如苯甲酰氨基和五氟苯甲酰氨基。
有用的酰氧基是连接在氧基(-O-)上的任何C1-6酰基(链烷酰基,例如甲酰氧基、乙酰氧基、丙酰氧基、丁酰氧基、戊酰氧基和己酰氧基。
有用的饱和或部分饱和杂环基包括四氢呋喃基、吡喃基、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、咪唑啉基、二氢吲哚基、异二氢吲哚基、奎宁环基、吗啉基、异色满基、色满基、吡唑烷基、吡唑啉基、tetronoyl和tetramoyl。
有用的杂芳基包括噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、色烯基、夹氧蒽基、吩噻恶基(phenoxanthiinyl)、2H-吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲嗪基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹唑啉基、噌啉基、喋啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、萘嵌间二氮杂苯基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异恶唑基、呋咱基、吩恶嗪基、1,4-二氢喹喔啉-2,3-二酮、7-氨基异香豆素、吡啶并[1,2-a]嘧啶-4-酮、1,2-苯并异恶唑-3-基、苯并咪唑基、2-羟吲哚基和2-氧代苯并咪唑基。当杂芳基在环中含有氮原子时,这样的氮原子可以呈N-氧化物形式,例如吡啶基N-氧化物、吡嗪基N-氧化物和嘧啶基N-氧化物。
一些本发明化合物可以作为立体异构体,包括旋光异构体存在。本发明包括所有立体异构体和这样的立体异构体的外消旋混合物,以及可以依据本领域技术人员众所周知的方法分离出来的单独的对映体。
可药用加成盐的实例包括无机和有机酸加成盐,例如盐酸盐、氢溴酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐;以及与碱例如钠羟基、三(羟基甲基)氨基甲烷(TRIS,氨丁三醇)和N-甲基葡糖胺形成的无机和有机碱加成盐。
本发明化合物的前药的实例包括含有羧酸的化合物的简单酯(例如依据本领域已知方法通过与C1-4醇缩合而获得的酯);含有羟基的化合物的酯(例如依据本领域已知方法通过与C1-4羧酸、C3-6二酸或其酸酐例如琥珀酸酐和富马酸酐缩回而获得的酯);含有氨基的化合物的亚胺(例如依据本领域已知方法通过与C1-4醛或酮缩回而获得的那些);含有氨基的化合物的氨基甲酸酯,例如Leu等人(J.Med.Chem.42:3623-3628(1999))和Greenwald等人(J.Med.Chem.42:3657-3667(1999))描述的那些;含有醇的化合物的醛缩醇或酮缩醇(例如依据本领域已知方法通过与氯甲基甲基醚或氯甲基乙基醚缩回而获得的那些);和膦酸酯以及膦酰基化合物(例如通过与磷酸酯、三氯氧化磷或磷酸缩回而获得的那些),包括膦酰基的可药用一元和二元加成盐,例如与胺类碱,包括氨、哌啶和吗啉成的盐。
本发明化合物可使用本领域技术人员已知的方法或本发明新方法制得。具体来说,具有式I-III的本发明化合物可如反应方案1中的反应实例所示制得。将苯酚与苯甲醛和丙二腈在碱例如哌啶或N,N-二异丙基乙胺存在下反应,以生成取代的色烯。该反应还可以这样进行:如反应方案2中的反应实例所示,首先将醛与丙二腈在碱例如哌啶存在下反应,然后用苯酚处理所得中间体,并环合以生成终产物。如反应方案3所示,将3-氨基苯酚与苯甲醛和丙二腈在碱例如哌啶存在下反应,以生成取代的色烯。
反应方案1
反应方案3
具有式I-III的本发明化合物还可以如反应方案4中的反应实例所示制得。将取代的苯酚例如2,3-亚甲二氧基苯酚与取代的苯甲醛例如3-甲氧基苯甲醛和丙二腈在碱例如哌啶或N,N-二异丙基乙胺存在下反应以生成7,8-稠合的色烯。
反应方案4
类似地,其它7,8-稠合的色烯可如反应方案5所示制得。
反应方案5
或者,如反应方案6所示,将2,3-二取代的苯酚例如2,3-二氨基苯酚与取代的苯甲醛例如3-甲氧基苯甲醛和丙二腈在碱例如哌啶或N,N-二异丙基乙胺存在下反应,以生成相应的7,8-二氨基色烯,然后可在不同条件下将其环合,以生成不同的7,8-稠合的色烯。例如,当与甲酸缩合时,是获得稠合的咪唑。当与乙二醛缩回时,是获得稠合的吡唑。
反应方案6
化合物2-氨基-3-氰基-4-苯基-4H-色烯可如反应方案7所示制得。
反应方案7
具有吸电子基团例如Br或Cl的取代的色烯可如反应方案8所示制得。用氧化剂例如2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)将取代的2-氨基-4H-色烯例如4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-2,7-二氨基-4H-色烯氧化,以生成取代的7-氨基-2-亚氨基-2H-色烯。于CuBr2存在下在7-位将氨基重氮化,以把氨基转化成Br。用还原剂例如NaBH4将取代的2-亚氨基-2H-色烯还原,以将取代的2-亚氨基-2H-色烯转化成取代的2-氨基-4H-色烯,生成7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-2-氨基-4H-色烯。
反应方案8
某些3-取代的苯酚可如反应方案9中的反应实例所示制得。
反应方案9
在7-位被吡咯取代的色烯可如反应方案10中的反应实例所示制得。
反应方案10
在4-位被甲基取代的色烯可如反应方案11中的反应实例所示制得。
反应方案11
在4-苯基上被磷酸基团取代的色烯可如反应方案12中的反应实例所示制得。
反应方案12
4H-苯并硫吡喃可如反应方案13中的反应实例所示制得。
反应方案13
1,4-二氢喹啉可如反应方案14中的反应实例所示制得。
反应方案14
在3-位具有酯基的色烯可如反应方案11中的反应实例所示制得。
反应方案15
本发明的一个重要方面是发现了具有式I-III的化合物是半胱天冬酶激活剂和细胞凋亡诱导剂。因此,这些化合物可用于多种其中存在失控的细胞生长和异常细胞扩散的临床病症例如癌症。
本发明的一个重要方面是下述发现:在具有抗药性的癌细胞例如乳腺癌和前列腺癌细胞中,具有式I-III的化合物是有效、高效力的半胱天冬酶激活剂和细胞凋亡诱导剂,这使得这些化合物能够杀死这些具有抗药性的癌细胞。与之相比,在相同条件下,大部分标准抗癌药物不能有效地杀死具有抗药性的癌细胞。因此,本发明化合物可用于在动物中治疗抗药性癌症。
本发明包括用于在体内调节细胞凋亡或者在体内控制瘤形成疾病的治疗方法,包括给需要这种治疗的个体施用有效量的起半胱天冬酶级联激活剂和细胞凋亡诱导剂作用的式I-III化合物或其可药用盐或前药。
本发明还包括治疗方法,包括给动物施用有效量的式I-III化合物或其可药用盐或前药,其中所述治疗方法是用于治疗癌症—特征是失控的细胞生长或异常细胞扩散的一组疾病,这样的疾病包括但不限于霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、覃样霉菌病、头或颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、成神经细胞瘤、横纹肌肉瘤、卡波西肉瘤、泌尿生殖器癌、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多、肾上腺皮质癌、皮肤癌和前列腺癌。
在实施本发明治疗方法时,给表现出一种或多种这些病症的症状的个体施用有效量的组合物,所述组合物含有治疗有效浓度的化合物,被配制成用于口服、静脉内、局限区域和局部给药的形式,并且可用于治疗瘤形成疾病和其中涉及半胱天冬酶级联介导的生理反应的其它疾病。给药量是有效地改善或消除病症的一个或多个症状的量。对于特定疾病的治疗,有效量是足以改善或以某些方式减轻与疾病有关的症状的量。这样的量可作为单一剂量施用,或者可依据有效的治疗方案给药。给药量可治愈疾病,但是给药通常是为了改善疾病。一般需要反复给药来实现所需的症状改善。
在另一个实施方案中提供了药物组合物,其中含有起半胱天冬酶级联激活剂和细胞凋亡诱导剂作用的式I-III化合物或其可药用盐和可药用载体。
本发明另一个实施方案涉及能有效地抑制瘤形成的组合物,其中包含起半胱天冬酶级联激活剂和细胞凋亡诱导剂作用的式I-III化合物或其可药用盐或前药和与其联合使用的至少一种已知的癌症化疗剂或所述化疗剂的可药用盐。可用于联合治疗的已知抗癌剂的实例包括但不限于烷化剂例如白消安、顺铂、丝裂霉素C和卡铂;抗有丝分裂剂例如秋水仙碱、长春碱、紫杉醇和多西他赛;拓扑异构酶I抑制剂例如喜树碱和托泊替康;拓扑异构酶II抑制剂例如阿霉素和依托泊苷;RNA/DNA抗代谢物例如5-氮杂胞苷、5-氟尿嘧啶和甲氨蝶呤;DNA抗代谢物例如5-氟-2’-去氧尿苷、ara-C、羟基脲和硫鸟嘌呤;和ntibodies例如Herceptin和Rituxan。可用于联合治疗的其它已知抗癌剂包括美法仑、苯丁酸氮芥、环磷酰胺、异环磷酰胺、长春新碱、米托胍腙、表柔比星、阿柔比星、博来霉素、米托蒽醌、依利醋铵、氟达拉滨、奥曲肽、视黄酸、他莫昔芬和阿拉诺新。
在实施本发明方法时,可就本发明化合物与至少一种已知化疗剂作为单一药物组合物的部分一起给药。或者,可将本发明化合物与至少一种已知化疗剂分开给药。在一个实施方案中,将本发明化合物与至少一种已知化疗剂基本上同时给药,即化合物同时给药或相继给药,只要化合物在血液中同时达到治疗水平即可。在另一个实施方案中,将本发明化合物与至少一种已知化疗剂依据起独立的给药方案给药,只要化合物在血液中到达治疗水平即可。
本发明另一个实施方案涉及能有效地抑制瘤形成的组合物,其中包含起半胱天冬酶级联激活剂和细胞凋亡诱导剂作用的式I-III化合物与至少一种已知在治疗上有用的抗体例如Herceptin或Rituxan,生长因子例如DGF、NGF,细胞因子例如IL-2、IL-4,或与细胞表面结合的任何分子的生物缀合物。抗体和其它分子将把式I-III化合物递送到其靶位点中,并让它们成为有效的抗癌剂。所述生物缀合物还能提高在治疗上有用的抗体例如Herceptin或Rituxan的抗癌作用。
类似地,本发明另一个实施方案涉及能有效地抑制瘤形成的组合物,其中包含起半胱天冬酶级联激活剂和细胞凋亡诱导剂作用的式I-III化合物或其可药用盐或前药和与其联合使用的放射治疗。在一个实施方案中,可将本发明化合物与放射治疗同时或在不同时间施用。
本发明另一个实施方案涉及用于在手术后有效地治疗癌症的组合物,其中包含起半胱天冬酶级联激活剂和细胞凋亡诱导剂作用的式I-III化合物或其可药用盐或前药。本发明还涉及治疗癌症的方法,包括手术除去癌,然后用一种本文所述的药物组合物治疗动物。
在经受感染物质之后,有多种免疫机制迅速起作用。根据感染类型,T和B淋巴细胞会迅速克隆扩充以对抗感染。在感染后,消除效应细胞是维持免疫体内稳定的主要机制当中的一种。已经表明这种反应性细胞的缺失是由称为细胞凋亡的现象调控的。最近,自身免疫性疾病已鉴定为失调细胞死亡的后果。在一些自身免疫性疾病中,免疫系统指导起强大的细胞毒害效应器机制来对抗专门的细胞例如多发性硬化中的少突神经胶质细胞、糖尿病中胰腺里的胰岛细胞和Hashimoto’s甲状腺炎中的甲状腺细胞(Ohsako,S.& Elkon,K.B.,Cell Death Differ.6:13-21(1999))。据报道,编码淋巴细胞凋亡受体Fas/APO-l/CD95的基因突变与缺陷的淋巴细胞凋亡和自身免疫性淋巴增殖综合症(ALPS)有关,其中ALPS的特征是慢性、组织学良性脾大以及泛化淋巴结病、血丙球蛋白过多、和自身抗体形成(Infante,A.J.,等人,J.Pediatr.133:629-633(1998)和Vaishnaw,A.K.,等人,J.Clin.Invest.103:355-363(1999))。据报道,在转基因小鼠的发育性B细胞中,在T细胞依赖性共刺激信号存在下,Bcl-2-具有细胞凋亡活性的编程性细胞死亡调节器的bcl-2基因家族的一个成员导致生成修饰的B细胞所有组成部分和产生病原性自身抗体(Lopez-Hoyos,M.,等人,Int.J.Mol.Med.1:475-483(1998))。因此很明显,有多种类型的自身免疫性疾病是由于缺乏细胞凋亡过程所致,并且一种治疗策略是在引起自身免疫性疾病的淋巴细胞中开始细胞凋亡(O’Reilly,L.A.& Strasser,A.,Inflamm.Res.48:5-21(1999))。
已知Fas-Fas配体(FasL)相互作用是保持免疫体内稳定所必需的。特征是自身反应性T和B细胞反应和显著的甲状腺淋巴细胞渗入的实验性自身免疫性甲状腺炎(EAT)是研究FasL的治疗作用的良好模型。Batteux,F.,等人,(J.Immunol.162:603-608(1999))报道,通过将编码FasL的DNA表达载体直接注射到发炎的甲状腺中,观察到甲状腺淋巴细胞渗入的发展受到了抑制,并且诱导了渗入性T细胞死亡。这些结果表明,FasL在甲状腺细胞上的表达可能通过诱导病原性自身反应性渗入性T淋巴细胞的死亡而对发展的EAT有治愈作用。
已知二吲哚基马来酰亚胺VIII能在人星形细胞瘤1321N1细胞和Molt-4T细胞中增强Fas介导的细胞凋亡,其中在没有二吲哚基马来酰亚胺VIII存在下,人星形细胞瘤1321N1细胞和Molt-4T细胞都对抗-Fas抗体诱导的细胞凋亡作用有抗性。据报道,二吲哚基马来酰亚胺VIII增强Fas-介导的细胞凋亡的作用对于激活的T细胞、而不是未激活的T细胞有选择性,并且是Fas-依赖性的。Zhou T.,等人(Nat.Med.5:42-48(1999))报道了在两个模型—实验性变应性脑炎Lewis大鼠模型和Lewis助剂关节炎模型中,在自身抗原刺激期间,施用二吲哚基马来酰亚胺VIII阻止了T细胞介导的自身免疫性疾病的症状发展。因此,施用Fas-依赖性细胞凋亡增强剂例如二吲哚基马来酰亚胺VIII可在治疗上用于更有效地消除有害细胞和抑制T细胞介导的自身免疫性疾病。因此,有效量的起半胱天冬酶级联激活剂和细胞凋亡诱导剂作用的式I-III化合物或其可药用盐或前药可有效地治疗自身免疫性疾病。
牛皮癣是一种特征为鳞状红斑的慢性皮肤病。补骨脂内酯加紫外线A(PUVA)是广泛使用的治疗寻常牛皮癣的有效手段,并且Coven等人在Photodermatol.Photoimmunol.Photomed. 15:22-27(1999)中报道,用补骨脂内酯8-MOP或TMP加UVA治疗的淋巴细胞表现出的DNA降解模式的细胞凋亡。Ozawa等人在J.Exp.Med.189:711-718(1999)中报道,诱导T细胞凋亡可能是312-nm UVB消除牛皮癣皮肤损伤的主要机制。低剂量的甲氨蝶呤可用于治疗牛皮癣以恢复临床上正常的皮肤。Heenen等人在Arch.Dermatol.Res.290:240-245(1998)中报道,低剂量的甲氨蝶呤可诱导细胞凋亡,并且该作用方式可解释用甲氨蝶呤治疗牛皮癣期间表皮增生减轻的原因。因此,有效量的起半胱天冬酶级联激活剂和细胞凋亡诱导剂作用的式I-III化合物或其可药用盐或前药可有效地治疗高增殖性疾病例如牛皮癣。
滑液细胞增生是类风湿性关节炎(RA)患者的特征。RA滑液细胞的过度增殖以及滑液细胞死亡的缺乏可能是滑液细胞增生的原因。Wakisaka等人在Clin.Exp.Immunol.114:119-128(1998)中报道了下述发现:虽然RA滑液细胞可通过经由Fas/FasL途径的细胞凋亡来死亡,但是存在于滑膜内的促炎性细胞因子抑制了滑液细胞的凋亡,并提出,在RA患者中,促炎性细胞因子的细胞凋亡抑制作用可导致滑液细胞过度生长,并且导致血管翳形成和关节破坏。因此,有效量的起半胱天冬酶级联激活剂和细胞凋亡诱导剂作用的式I-III化合物或其可药用盐或前药可有效地治疗类风湿性关节炎。
已经有令人信服的证据表明细胞凋亡在促进急性炎性反应的消除中起主要作用。中性白细胞在组成上程序化地经历细胞凋亡,由此限制了其促炎性可能和导致被巨噬细胞与半专门噬吞细胞迅速、特异性和非炎性识别(Savill,J.,J.Leukoc.Biol.61:375-380(1997))。Boirivant等人在Gastroenterology 116:557-565(1999)中报道了从局限性回肠炎、溃疡性结肠炎和表现出CD2途径诱导的细胞凋亡下降的其它炎性病症中的发炎区域内分离出了lamina propria T细胞,并且对从发炎的局限性回肠炎组织中分离出的细胞进行的研究表明,这种缺陷是由于Bcl-2水平增高所致。因此,有效量的起半胱天冬酶级联激活剂和细胞凋亡诱导剂作用的式I-III化合物或其可药用盐或前药可有效地治疗炎症和炎性肠病。
在本发明范围内的组合物包括其中本发明化合物以有效地实现其预期目的的量包含在内的所有组合物。虽然个体需要不同,但是每一组分的有效量的最佳范围的确定在本领域技术人员的能力范围内。一般可将本发明化合物以每天O.0025-50mg/kg化合物或等价量其可药用盐/kg所治疗哺乳动物体重的剂量对哺乳动物例如人口服给药,来治疗细胞凋亡介导的病症。优选口服施用约0.01-约10mg/kg来治疗或预防这样的病症。对于肌内注射,该剂量一般为口服剂量的大约一半。例如,合适的肌内剂量是约0.0025-约25mg/kg,最优选为约0.01-约5mg/kg。如果已经施用了已知的癌症化疗剂,则以能有效地实现其预期目的的量进行给药。有效地治疗癌症的这样的已知癌症化疗剂的量是本领域技术众所周知的。
单位口服剂量可由约0.01-约50mg,优选约0.1-约10mg本发明化合物组成。单位剂量可作为一个或多个片剂每天给药一次或多次,其中每个片剂含有约0.1-约10,适宜地约0.25-50mg本发明化合物或其溶剂化物。
在局部给药用制剂中,本发明化合物可以以约0.01-100mg/g载体的浓度存在。
本发明化合物除了作为未加工化学药品给药以外,还可以作为含有合适的可药用载体的药物制剂的一部分给药,所述可药用载体包括有助于将化合物加工成可药用制剂的赋形剂和辅助剂。优选地,制剂,特别是可口服给药的制剂,和可用于优选给药剂型例如片剂、糖锭剂和胶囊的制剂,以及可直肠给药的制剂例如栓剂,和用于注射或口服给药的适当溶液剂含有约0.01-99%,优选约0.25-75%的活性化合物和赋形剂。
本发明化合物的无毒可药用盐也在本发明范围内。酸加成盐可通过将特定的本发明细胞凋亡诱导剂的溶液与可药用无毒酸的溶液混和来形成,其中所述酸有例如盐酸、富马酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸、草酸等。碱加成盐是通过将将特定的本发明细胞凋亡诱导剂的溶液与可药用无毒碱的溶液混和而形成的,所述碱有例如氢氧化钠、氢氧化钾、胆碱氢氧化物、碳酸钠、Tris、N-甲基-葡糖胺等。
可将本发明药物组合物施用给其中能表现出本发明化合物有益作用的动物。在这样的动物当中,最重要的是哺乳动物,例如人和兽医动物,但是本发明不限于次。
本发明化合物可通过能实现其预期目的的任意途径给药。例如,可通过非胃肠道、皮下、静脉内、肌内、腹膜内、透皮、颊、鞘内、颅内、鼻内或局部途径进行给药。另外或并行地,可通过口服途径给药。给药剂量取决于受治疗者的年龄、健康状况和体重,如果有的话并行治疗的类型,治疗频率以及所需效果的性质。
本发明药物制剂可通过自身已知的方式,例如常规混和、制粒、糖锭剂制备、溶解或冷冻干燥方法制得。因此,口服使用的药物制剂可这样制得:将活性化合物与固体赋形剂混和,任选将所得混合物磨碎,如果需要或必需的话,加入合适的辅助剂,将颗粒混合物加工以获得片剂或糖锭剂核芯。
合适的赋形剂特别是填充剂,例如糖类如乳糖或蔗糖、甘露醇或山梨醇;纤维素制备物和/或磷酸钙例如磷酸三钙或磷酸氢钙;以及粘合剂例如使用如玉米淀粉、小麦淀粉、大米淀粉、土豆淀粉的淀粉糊,明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠,和/或聚乙烯吡咯烷酮。如果需要的话,可加入崩解剂例如上述淀粉以及羧甲基淀粉钠、交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐如藻酸钠。辅助剂特别是流动调节剂和润滑剂,例如二氧化硅、滑石粉、硬脂酸或其盐例如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。可给糖锭剂核芯提供合适的包衣,如果需要的话,这样的包衣是抗胃液的。对于此,可使用浓的糖溶液,其中可任选含有阿拉伯胶、滑石粉、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛,漆溶液和适当的有机溶剂或溶剂混合物。为了制备抗胃液的包衣,使用合适的纤维素制备物例如醋酸邻苯二甲酸纤维素或邻苯二甲酸羟丙基甲基纤维素。可向片剂或糖锭剂包衣中加入染料或色素以例如鉴别或表明活性化合物剂量的特征。
可口服使用的其它药物制剂包括用明胶制成的推入配合型胶囊,以及用明胶和增塑剂例如甘油或山梨醇制成的软的密封胶囊。推入配合型胶囊可含有颗粒形式的活性化合物,活性化合物颗粒可以与下述组分混和:填充剂例如乳糖;粘合剂例如淀粉;和/或润滑剂例如滑石粉或硬脂酸镁,和任选地稳定剂。在软胶囊中,优选将活性化合物溶解或悬浮在合适的液体例如脂肪油或液体石蜡中。此外,可加入稳定剂。
可直肠使用的可能药物制剂包括例如由一种或多种活性化合物与栓剂基质组成的栓剂。合适的栓剂基质是例如天然或合成甘油三酯或石蜡烃。此外,还能够使用由活性化合物与基质的混合物组成的直肠用胶囊。可能的基质材料包括例如液体甘油三酯、聚乙二醇或石蜡烃。
合适的非胃肠道给药用制剂包括水溶形式例如水溶性盐形式的活性化合物的水溶液和碱性溶液。此外,可以施用作为适当油注射悬浮液的活性化合物的悬浮液。合适的亲脂性溶剂或载体包括脂肪油例如芝麻油或合成脂肪酸酯例如油酸乙酯或甘油三酯或聚乙二醇-400(活性化合物溶于PEG-400中)或聚氧乙烯蓖麻油或环糊精。水注射悬浮液可含有能提高悬浮液浓度的物质,包括例如羧甲基纤维素钠、山梨醇和/或葡聚糖。悬浮液还任选含有稳定剂。
依据本发明一个方面,本发明化合物在局部且非胃肠道给药用制剂中使用,并且可用于治疗皮肤癌。
本发明局部给药用组合物优选通过选择合适的载体来配制成油性制剂、霜剂、洗剂、软膏剂等。合适的载体包括植物油或矿物油、白凡士林(白软石蜡)、支链脂肪或油、动物脂肪和高分子量醇(大于C12)。优选的载体是活性组分溶于其中的载体。还可以包含软化剂、稳定剂、湿润剂和抗氧化剂,以及如果需要的话着色剂或香料。此外,可在这些局部给药用制剂中使用透皮促进剂。这样的促进剂的合适的实例可参见U.S.专利3,989,816和4,444,762。
霜剂可优选用矿物油、自乳化蜂蜡和水的混合物配制,其中将溶解在少量油例如杏仁油中的活性组分与该混合物混和在一起。这样的霜剂的典型实例是包括约40份水、约20份蜂蜡、约40份矿物油和约1份杏仁油的霜剂。
软膏剂可通过通过将活性组分在植物油例如杏仁油中的溶液与温热的软石蜡混和,让该混合物冷却来配制而成。这样的软膏剂的典型石蜡是含有约30%重量的杏仁油和约70%重量的白软石蜡的软膏剂。
下列实施例近是举例说明,而不是限制本发明的方法和组合物。对于在临床治疗中通常会遇见的各种病症和参数所作的对于本领域技术人员来说是显而易见的其它适当改变和改进在本发明实质和范围内。
实施例1
2-氨基-3-氰基-7-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯
向3,4-二甲氧基-5-溴亚苄基丙二腈(293mg,1mmol)和间苯二酚(110mg,1mmol)在乙醇(2mL)内的混合物中加入哌啶(0.1mL,1mmol)。将该混合物回流2小时。将溶剂蒸发,通过硅胶色谱纯化残余物,用EtOAc和己烷(1∶2)洗脱,获得了240mg(59.5%)本标题化合物。
1H NMR(DMSO-d6):9.77(brs,1H),6.96-6.86(m,5H),6.52(d,J=8.1,1H),6.41(s,1H),4.65(s,1H),3.80(s,3H),3.70(s,3H).
实施例2A
2-氨基-3-氰基-7-乙基氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯
向5-溴藜芦醛(245mg,1mmol)和丙二腈(66mg,1mmol)在乙醇(2mL)内的混合物中加入哌啶(0.1ml,1mmol)和3-乙基胺苯酚(140mg,1mmol)。将该混合物在室温搅拌过夜。将溶剂蒸发,通过硅胶色谱纯化残余物,用EtOAc和己烷(1∶2)洗脱,获得了(330mg,76.7%)本标题化合物。 1H NMR(CDCl3):
6.88(d,J=0.9Hz,1H),6.71(d,J=8.4Hz,2H),6.32(dd,J=2.1Hz,1H),
6.19(d,J=2.1Hz,1H),4.59(s,2H),4.54(s,1H),3.83(d,J=0.6Hz,3H),
3.82(d,J=0.9Hz,1H),3.68(brs,1H),3.12(q,J=7.2Hz,2H),1.28-1.23
(m,3H).
按照类似于实施例2A中描述的方法制得了下列化合物。
实施例2B
2-氨基-3-氰基-7-羟基-4-(3-氰基苯基)-4H-色烯
1H NMR(DMSO-d6):7.70-7.65(m,2H),7.55-7.47(m,2H),6.99(brs,2H),6.79(d,J=8.9Hz,1H),6.48(dd,J=2.5,8.4Hz,1H),6.40(d,J=2.5Hz,1H),4.76(s,1H)ppm.
实施例2C
2-氨基-3-氰基-7,8-二羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯
1H NMR(CDCl3):6.88(d,J=1.6Hz,1H),6.80(d,J=1.6Hz,1H),6.54(d,J=8.5Hz,1H),6.30(d,J=8.5Hz,1H),4.95(brs,4H),4.58(s,1H),3.78(s,3H),3.74(s,3H).
实施例2D
2-氨基-3-氰基-7-氨基-4-(3,5-二氯苯基)-4H-色烯
1H NMR(Acetone-d6):7.34(t,J=1.8Hz,1H),7.24(d,J=2.0Hz,2H),6.76(d,J=8.4Hz,1H),6.44 dd,J=8.3,2.2Hz,1H),6.37(d,J=2.2Hz,1H),6.21(brs,2H),4.92-4.90(m,2H),4.70(s,1H).
实施例2E
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氯苯基)-4H-色烯
1H NMR(CDCl3):7.24-7.23(m,1H),7.07-7.06(m,2H),6.83(d,J=8.6Hz,1H),6.65(dd,J=2.2,8.6Hz,1H),6.55(d,J=2.6Hz,1H),4.65(s,1H),4.64(s,2H),3.79(s,3H).
实施例2F
2-氨基-3-氰基-4-(3,5-二氯苯基)-4H-吲哚并[4,5-b]吡喃
1H NMR(Acetone-d6):10.45(brs,1H),7.38(t,J=2.7Hz,1H),7.34(t,J=2.0Hz,1H),7.29(d,J=1.8Hz,2H),7.20(dd,J=8.4,1.0Hz,1H),6.78(d,J=8.4Hz,1H),6.57-6.56(m,1H),6.36(brs,2H),4.94(s,1H).
实施例2G
2-氨基-3-氰基-4-(3-氯苯基)-4H-吲哚并[4,5-b]吡喃
1H NMR(CDCl3):8.26(brs,1H),7.23-7.14(m,6H),7.10(d,J=8.4Hz,1H),6.72(d,J=8.4Hz,1H),6.66-6.65(m,1H),4.82(s,1H),4.69(brs,2H).
实施例2H
2-氨基-3-氰基-7-氨基-8-甲基-4-(3-溴-4,5-二甲氧基苯基)-4H-色
烯
1H NMR(CDCl3):6.85(d,J=1.6Hz,1H),6.80(d,J=1.6Hz,1H),6.59(d,J=8.5Hz,1H),6.49(d,J=8.4Hz,1H),4.55(s,1H),3.81(s,3H),3.76(s,3H),2.14(s,3H).
实施例2I
2-氨基-3-氰基-7-羟基-8-氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯
1H NMR(CD3OD):6.87(d,J=1.8Hz,1H),6.80(d,J=1.8Hz,1H),6.47(d,J=8.4Hz,1H,),6.20(d,J=8.4Hz,1H),4.56(s,1H),3.79(s,3H),3.75(s,3H).
实施例2J
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氟苯基)-4H-色烯
1H NMR(CDCl3):6.86(d,J=8.6Hz,1H),6.74-6.64(m,4H),6.55(d,J=2.3Hz,1H),4.67(s,1H),4.63(brs,2H),3.86(s,3H).
实施例2K
2-氨基-3-氰基-4-(3,5-二氟苯基)-4H-吲哚并[4,5-b]吡喃
1H NMR(Acetone-d6):7.38-7.37(m,1H),7.19(d,1H),6.96-6.91(m,2H),6.86(tt,J=2.3,9.0Hz,1H),6.79(d,J=8.4Hz,1H),6.56(d,J=2.3Hz,1H),6.33(brs,1H),4.93(s,1H).
实施例2L
2-氨基-3-氰基-4-(3-氟苯基)-4H-吲哚并[4,5-b]吡喃
1H NMR(Acetone-d6):10.47(brs,1H),7.37-7.32(m,2H),7.17(dd,J=1.0,8.4Hz,1H),7.12(dt,J=1.2,7.6Hz,1H),7.04-6.94(m,2H),6.76(d,J=8.4Hz,1H),6.58-6.56(m,1H),6.26(brs,2H),4.89(s,1H).
实施例2M
2-氨基-3-氰基-7-氨基-4-(3-氟苯基)-4H-色烯
1H NMR(Acetone-d6):7.38-7.32(m,1H),7.08(d,J=7.8Hz,1H),6.99-6.95(m,2H),6.73(d,J=8.2Hz,1H),6.41(dd,J=23,8.4Hz,1H),6.35(d,J=2.3Hz,1H),6.10(brs,1H),4.85(dd,J=8.8Hz,1H),4.64(s,1H).
实施例2N
2-氨基-3-氰基-7-甲氧基-4-(3-氟苯基)-4H-色烯
1H NMR(Acetone-d6):7.40-7.34(m,1H),7.12-7.10(m,1H),7.02-6.97(m,3H),6.69(dd,J=2.5,8.6Hz,1H),6.59(d,J=2.5Hz,1H),6.22(brs,1H),4.77(s,1H),3.79(s,3H).
实施例2O
2-氨基-3-氰基-7-氨基-4-(3,5-二氟苯基)-4H-色烯
1H NMR(Acetone-d6):6.91-6.83(m,3H),6.77(d,J=8.4Hz,1H),6.43(dd,J=2.2,8.3Hz,1H),6.36(d,J=2.2Hz,1H),6.17(brs,1H),4.89(bd,J=7.6Hz,1H),4.70(s,1H).
实施例3
2-氨基-3-氰基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和3,4,5-三甲氧基苯甲醛以7%的产率制得的。
1H NMR(CDCl3):6.90(d,J=9.6Hz,1H),6.64(dd,J=2.7Hz,1H),6.55(d,J=2.4Hz,1H),6.37(s,2H),4.62(s,1H),4.59(s,2H),3.82-3.79(m,12H).
实施例4
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和3-三甲氧基苯甲醛以12%的产率制得的。
1H NMR(CDCl3):7.21(d,J=7.8Hz,1H),6.89(d,J=8.4Hz,1H),6.80-6.75(m,2H),6.72(d,J=1.8Hz,1H),6.61(dd,J=2.4Hz,1H),6.54(d,J=2.4Hz,1H),4.65(s,1H),4.57(s,2H),3.78(s,6H).
实施例5
2-氨基-3-氰基-7-甲氧基-4-(3-氰基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和3-氰基苯甲醛以24%的产率制得的。
1H NMR(CDCl3):7.55-7.41(m,4H),6.80(d,J=8.7Hz,1H),6.64(dd,J=2.7Hz,1H),6.58(d,J=2.7Hz,1H),4.74(s,1H),4.68(s,2H),3.80(s,3H).
实施例6
2-氨基-3-氰基-7-甲氧基-4-(3-溴苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和3-溴苯甲醛以27%的产率制得的。
1H NMR(CDCl3):7.39-7.35(m,1H),7.29-7.28(m,1H),7.22-7.14(m,2H),6.85(d,J=8.7Hz,1H),6.63(dd,J=2.7Hz,1H),6.55(d,J=2.7Hz,1H),4.65(s,1H),4.62(s,2H),3.79(s,3H).
实施例7
2-氨基-3-氰基-7-乙基氨基-4-(3-溴苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-乙基氨基苯酚和3-溴苯甲醛以46%的产率制得的。
1H NMR(CDCl3):7.36-7.33(m,1H),7.29-7.28(m,1H),7.20-7.14(m,2H),6.69(d,J=8.7Hz,1H),6.30(dd,J=2.4Hz,1H),6.20(d,J=2.4Hz,1H),4.59-4.57(m,3H),3.67(brs,1H),3.12(q,J=7.2Hz,2H),1.25(t,J=7.2Hz,3H).
实施例8
2-氨基-3-氰基-7-乙基氨基-4-(3-氯苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-乙基氨基苯酚和3-氯苯甲醛以17%的产率制得的。
1H NMR(CDCl3):7.24-7.10(m,4H),6.70(d,J=8.4Hz,1H),6.30(dd,J=2.4Hz,1H),6.20(d,J=2.4Hz,1H),4.60(s,1H),4.56(s,2H),3.67(brs,1H),3.12(q,J=6.9Hz,2H),1.25(t,J=7.2Hz,3H).
实施例9
2-氨基-3-氰基-7-乙基氨基-4-(3-硝基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-乙基氨基苯酚和3-硝基苯甲醛以42%的产率制得的。
1H NMR(CDCl3):8.11-8.08(m,1H),8.02(s,1H),7.59(d,J=7.5Hz,1H),7.50(t,J=7.8Hz,1H),6.66(d,J=8.4Hz,1H),6.30(dd,J=2.4Hz,1H),6.22(d,J=2.1Hz,1H),4.77(s,1H),4.64(brs,2H),3.71(brs,1H),3.13(m,2H),1.25(t,J=7.2Hz,3H).
实施例10
2-氨基-3-氰基-7-甲氧基-4-(3-氯苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和3-氯苯甲醛以15%的产率制得的。
1H NMR(CDCl3):7.28-7.19(m,2H),7.13-7.10(m,2H),6.85(d,J=8.7Hz,1H),6.63(dd,J=2.4Hz,1H),6.55(d,J=2.7Hz,1H),4.67(s,1H),4.63(brs,2H),3.79(s,3H).
实施例11
2-氨基-3-氰基-7-甲氧基-4-(3-硝基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和3-硝基苯甲醛以18%的产率制得的。
1H NMR(CDCl3):8.13-8.10(m,1H),8.02(t,J=2.1Hz,1H),7.60-7.57(m,1H),7.51(t,J=7.8Hz,1H),6.82(d,J=8.4Hz,1H),6.64(dd,J=2.4Hz,1H),6.59(d,J=2.4Hz,1H),4.84(s,1H),4.70(brs,2H),3.80(s,3H).
实施例12
2-氨基-3-氰基-7-甲氧基-4-(3,5-二甲氧基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和3,5-二甲氧基苯甲醛以15%的产率制得的。
1H NMR(CDCl3):6.91(d,J=9.0Hz,1H),6.62(dd,J=2.4Hz,1H),6.53(d,J=2.7Hz,1H),6.33(s,3H),4.60(s,1H),4.57(brs,2H),3.78-3.76(m,9H).
实施例13
2-氨基-3-氰基-7-乙基氨基-4-(3,4,5-三甲氧基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-乙基氨基苯酚和3,4,5-三甲氧基苯甲醛以79%的产率制得的。
1H NMR(CDCl3):6.75(d,J=8.4Hz,1H),6.39(s,2H),6.32(dd,J=2.4Hz,1H),6.20(d,J=2.4Hz,1H),4.58-4.56(m,3H),3.82-3.81(m,9H),3.67(brs,1H),3.12(q,J=7.2Hz,2H),1.25(t,J=7.2Hz,3H).
实施例14
2-氨基-3-氰基-7-乙基氨基-4-(3,5-二甲氧基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-乙基氨基苯酚和3,5-二甲氧基苯甲醛以28%的产率制得的。
1H NMR(CDCl3):6.76(d,J=8.4Hz,1H),6.35-6.28(m,4H),6.18(d,J=2.7Hz,1H),4.54-4.53(m,3H),3.75(s,6H),3.64(brs,1H),3.11(q,J=6.9Hz,2H),1.24(t,J=6.9Hz,3H).
实施例15
2-氨基-3-氰基-7-乙基氨基-4-(3-甲氧基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-乙基氨基苯酚和3-甲氧基苯甲醛以31%的产率制得的。
1H NMR(CDCl3):7.21(t,J=7.8Hz,1H),6.80-6.71(m,4H),6.29(dd,J=2.4Hz,1H),6.19(d,J=2.1Hz,1H),4.59(s,1H),4.54(brs,2H),3.77(s,3H),3.64(brs,1H),3.11(q,J=7.2Hz,2H),1.24(t,J=7.2Hz,3H).
实施例16
2-氨基-3-氰基-7-乙基氨基-4-(3-氰基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-乙基氨基苯酚和3-氰基苯甲醛以15%的产率制得的。
1H NMR(CDCl3):7.53-7.39(m,4H),6.64(d,J=9.0Hz,1H),6.31(dd,J=2.1,1H),6.22(d,J=2.1Hz,1H),4.67-4.64(m,3H),3.72(brs,1H),3.13(q,J=7.2Hz,2H),1.26(t,J=7.2Hz,3H).
实施例17
2-氨基-3-氰基-7-甲氧基-4-(3-吡啶基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和3-吡啶甲醛以15%的产率制得的。
1H NMR(DMSO-d6):8.48-8.44(m,2H),7.54-7.51(m,1H),7.37-7.33(m,1H),7.03(brs,2H),6.93(d,J=8.7Hz,1H),6.69(d,J=8.7Hz,1H),6.59(s,1H),4.80(s,1H),3.75-3.74(m,3H).
实施例18
2-氨基-3-氰基-4-(3-吡啶基)-4H-吲哚并[4,5-b]吡喃
本标题化合物是按照类似于实施例2中描述的方法,由4-羟基吲哚和3-吡啶甲醛以10%的产率制得的。
1H NMR(DMSO-d6):11.32(s,1H),8.49-8.41(m,2H),7.53(d,J=8.1Hz,1H),7.37-7.30(m,2H),7.11(d,J=8.4Hz,1H),7.01(brs,2H),6.67(d,J=8.4Hz,1H),6.47(s,1H),4.88(s,1H).
实施例19
2,7-二氨基-3-氰基-4-(3-溴苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-氨基苯酚和3-溴苯甲醛以56%的产率制得的。
1H NMR(CDCl3):7.37-7.34(m,1H),7.29-7.27(m,1H),7.18-7.15(m,2H),6.70(d,J=8.7Hz,1H),6.39(dd,J=2.1Hz,1H),6.31(d,J=2.1Hz,1H),4.59-4.57(m,3H),3.74(s,2H).
实施例20
2,7-二氨基-3-氰基-4-(3-氰基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-氨基苯酚和3-氰基苯甲醛以44%的产率制得的。
1H NMR(CDCl3):7.54-7.40(m,4H),6.66(d,J=8.4 Hz,1H),6.39(dd,J=2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.67-4.64(m,3H),3.78(s,2H).
实施例21
2,7-二氨基-3-氰基-4-(3-甲氧基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-氨基苯酚和3-甲氧基苯甲醛以71%的产率制得的。
1H NMR(CDCl3):7.22(t,J=7.8Hz,1H),6.80-6.71(m,4H),6.39-6.35(m,1H),6.30(d,J=1.8Hz,1H),4.59(s,1H),4.53(brs,2H),3.77(s,3H),3.70(s,2H).
实施例22
2,7-二氨基-3-氰基-4-(3-氯苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-氨基苯酚和3-氯苯甲醛以34%的产率制得的。
1H NMR(CDCl3):7.25-7.17(m,2H),7.13-7.09(m,2H),6.70(d,J=8.1Hz,1H),6.38(dd,J=2.4Hz,1H),6.31(d,J=2.7Hz,1H),4.60(s,1H),4.58(brs,2H),3.74(s,2H).
实施例23
2,7-二氨基-3-氰基-4-(3-甲基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-氨基苯酚和3-甲基苯甲醛以40%的产率制得的。
1H NMR(CDCl3):7.18(t,J=7.8Hz,1H),7.04-6.97(m,3H),6.73(d,J=8.4Hz,1H),6.37(dd,J=2.1Hz,1H),6.31(d,J=2.4Hz,1H),4.57(s,1H),4.53(brs,2H),3.70(s,2H),2.31(s,3H).
实施例24
2,7-二氨基-3-氰基-4-(3-吡啶基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-氨基苯酚和3-吡啶甲醛以44%的产率制得的。
1H NMR(CDCl3):8.50-8.48(m,2H),7.51-7.48(m,1H),7.25-7.22(m,1H),6.69(d,J=7.2Hz,1H),6.36(dd,J=2.4Hz,1H),6.32(d,J=2.4Hz,1H),4.67(s,1H),4.63(brs,2H),3.76(s,2H).
实施例25
2,7-二氨基-3-氰基-4-(3-硝基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-氨基苯酚和3-硝基苯甲醛以44%的产率制得的。
1H NMR(CDCl3):8.12-8.09(m,1H),8.02(t,J=2.1Hz,1H),7.60-7.47(m,2H),6.67(d,J=8.4Hz,1H),6.40-6.39(m,2H),4.77(s,1H),4.66(brs,2H),3.79(s,2H).
实施例26
2-氨基-3-氰基-7-甲氧基-4-苯基-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和苯甲醛以12%的产率制得的。
1H NMR(CDCl3):7.34-7.29(m,2H),7.25-7.17(m,3H),6.87(d,J=8.7Hz,1H),6.61(dd,J=2.7Hz,1H),6.55(d,J=2.4Hz,1H),4.68(s,1H),4.57(brs,2H),3.78(s,3H).
实施例27
2-氨基-3-氰基-7-甲氧基-4-(2,4-二甲氧基嘧啶基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和5-甲酰基-2,4-二甲氧基嘧啶以12%的产率制得的。
1H NMR(CDCl3):7.98(s,1H),6.93(d,J=8.4Hz,1H),6.62(d,J=8.7Hz,1H),6.53(d,J=2.7Hz,1H),4.85(s,1H),4.62(brs,2H),3.96(s,6H),3.78(s,3H).
实施例28
2-氨基-3-氰基-7-甲氧基-4-(1,2,3,6-四氢苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法,由3-甲氧基苯酚和1,2,3,6-四氢苯甲醛以2.5%的产率制得的。
1H NMR(CDCl3):7.05-7.01(m,1H),6.71-6.67(m,1H),6.51(t,J=2.7Hz,1H),5.60(d,J=2.4Hz,2H),4.85(s,1H),4.58(brs,2H),3.79(s,3H),3.48(dd,J=3.0Hz,1H),2.05-1.57(m,6H),1.45-1.26(m,1H).
实施例29
2-氨基-3-氰基-4-苯基-4H-色烯
方法A
a)3-氰基-2-亚氨基-4-苯基-2H-色烯
向2-羟基二苯甲酮(2.0g,10mmol)和丙二腈(661mg,10mmol)在乙醇(15mL)内的混合物中加入哌啶(0.5mL,5.0mmol)。将该混合物在0-5℃搅拌2小时。将溶剂蒸发,通过硅胶色谱纯化残余物,用乙酸乙酯和己烷(1∶2)洗脱,获得了1.2g(8%)本标题化合物。1H NMR(CDCl3):7.74-7.29(m,7H),7.20-7.13(m,2H).
b)2-氨基-3-氰基-4-苯基-2H-色烯
在0-5℃,向3-氰基-2-亚氨基-4-苯基-2H-色烯(120mg,0.49mmol)在甲醇(15mL)内的混合物中加入NaBH4(20mg,0.5mmol)。将该混合物在室温搅拌过夜,然后用2N盐酸中和。将溶剂蒸发,通过硅胶色谱纯化残余物,用乙酸乙酯和己烷(1∶2)洗脱,获得了5mg(29%)本标题化合物。
1H NMR(CDCl3):7.35-7.18(m,6H),7.06-6.96(m,3H),4.75(s,1H),4.61(brs,2H).
方法B
向亚硝酸叔丁酯(0.027g,0.26mmol)在无水DMF内的溶液中一次性加入2,7-二氨基-3-氰基-4-苯基-4H-色烯(53mg,0.201mmol)。立即将反应浸泡在65℃油浴内。发生了缓慢的气体释放。在65℃搅拌1.5小时后,通过加入水(5mL)来中止反应,用EtOAc(3×10mL)萃取。用盐水(2×5mL)洗涤EtOAc萃取液,用硫酸镁干燥,并蒸发。通过硅胶色谱纯化残余物,用EtOAc和己烷(1∶2)洗脱,获得了6mg(12%)本标题化合物,为浅黄色固体。
1H NMR(CD3Cl,300MHz):7.35-7.17(m,6H),7.06-6.96(m,3H),4.75(s,1H),4.61(brs,2H).
实施例30
2-氨基-3-氰基-7-甲氧基-4-(5-甲基-3-吡啶基)-4H-色烯
向5-甲基吡啶-3-甲醛(120mg,0.99mmol)和3-甲氧基苯酚(128mg,1.03mmol)在无水乙醇(10mL)内的溶液中加入丙二腈(68mg,1.03mmol)和哌啶(0.1mL,1.01mmol)。在室温搅拌2.5小时,再加入3-甲氧基苯酚(128mg,1.03mmol)。将该混合物搅拌24小时。将溶剂蒸发,通过硅胶色谱纯化残余物,用EtOAc和己烷(1∶4至1∶1)洗脱。收集一个级分(151mg),是产物及其亚胺异构体(2-亚氨基-7-甲氧基-4-(5-甲基-吡啶-3-基)-色烯-3-甲腈)。将一部分该混合物(25mg,0.085mmol)与几滴哌啶在无水乙醇(5mL)中回流18小时。将溶剂蒸发,通过硅胶色谱纯化残余物,用EtOAc和己烷(1∶1)洗脱,获得了13mg(52%)本标题化合物,为黄色固体。
1H NMR(CDCl3):8.33(d,J=1.8Hz,1H),8.29(d,J=1.8Hz,1H),7.28(t,J=1.8Hz,1H),6.82(dd,J=8.4,0.6Hz,1H),6.63(dd,J=8.4,2.7Hz,1H),6.56(d,J=2.7Hz,1H),4.72(brs,2H),4.69(s,1H),3.79(s,3H),2.30(d,J=0.6Hz,3H).
实施例31
2-氨基-3-氰基-7-乙基氨基-4-(5-甲基-3-吡啶基)-4H-色烯
向5-甲基-吡啶-3-甲醛(60mg,0.5mmol)和丙二腈(33mg,0.5mmol)在无水乙醇(5mL)内的溶液中加入哌啶(0.1mL,1.0mmol)。在室温搅拌2.5小时后,加入3-乙基氨基苯酚(133mg,0.97mmol)。将该混合物搅拌18小时,然后回流0.5小时。将溶剂蒸发。通过硅胶色谱纯化残余物,用EtOAc和己烷(1∶1和2∶1)洗脱,获得了59mg(39%)本标题化合物,为浅黄色固体。 1H
NMR(CDCl3 with drops of CD3OD):8.25(dd,J=2.1,0.6Hz,1H),8.23(d=
2.4Hz,1H),7.29(m,1H),6.65(dd,J=2.7,0.6Hz,1H),6.29(dd,J=8.1,2.4
Hz,1H),6.20(d,J=2.4Hz,1H),4.86(s,2H),4.61(s,1H),3.10(q,J=7.2
Hz,2H),2.28(d,J=0.6Hz,3H),1.23(t,J=7.2Hz,3H).
实施例32
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-乙基氨基-4H-色烯
由5-溴-吡啶-3-甲醛、丙二腈和3-乙基氨基苯酚获得了本标题化合物,为黄色固体。 1H NMR
(CDCl3):8.54(d,J=2.1Hz,1H),8.42(d,J=2.1Hz,1H),7.60(t,J=2.1Hz,
1H),6.66(dd,J=8.4,0.6Hz,1H),6.32(dd,J=8.4,2.4Hz,1H),6.21(d,J=
2.4Hz,1H),4.70(brs,2H),4.65(s,1H),3.13(q,J=14.3Hz,2H),1.26(t,J=
7.2Hz,3H).
实施例33
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-甲氧基-4H-色烯
由5-溴-吡啶-3-甲醛、丙二腈和3-甲氧基苯酚获得了本标题化合物,为黄色固体。 1H NMR(CDCl3):
8.57(m,1H),8.43(m,1H),7.60(d,J=2.1Hz,1H),6.83(d,J=8.4Hz,1H),
6.66(dd,J=8.4,2.4Hz,1H),6.58(d,J=2.4Hz,1H),4.75(brs,2H),4.72(s,
1H),3.80(s,3H).
实施例34
2,7-二氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-色烯
由5-甲基-吡啶-3-甲醛、丙二腈和3-乙基氨基苯酚获得了本标题化合物,为黄色固体。 1H NMR(CDCl3
and drops of CD3OD):8.21(m,1H),8.18(m,1H),7.28(m,1H),6.63 (d,J=
8.4Hz,1H),6.35(dd,J=8.4,2.4Hz,1H),6.30(d,J=2.4Hz,1H),4.58(s,
1H),2.27(s,3H).
实施例35
2-氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-吲哚并[4,5-b]吡喃
由5-甲基-吡啶-3-甲醛、丙二腈和4-羟基吲哚获得了156mg(52%)本标题化合物,为黄色固体。
1H NMR(CD3OD):8.22(m,2H),7.45(m,1H),7.25(d,J=3.0Hz,1H),7.10(dd,J=8.7,0.9Hz,1H),6.64(d,J=8.7Hz,1H),6.61(dd,J=3.3,0.9Hz,1H),4.85(s,1H),2.29(s,3H).
实施例36
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-吲哚并[4,5-b]吡喃
向5-溴-吡啶-3-甲醛(94mg,0.505mmol)和丙二腈(34mg,0.505mmol)在无水乙醇(2.5mL)内的溶液中加入4-羟基吲哚(70mg,0.526mmol)和哌啶(0.1ml,1.0mmol)。在室温搅拌25小时后,通过过滤收集浅黄色固体(94mg,51%),用乙醚(5mL)洗涤,并真空干燥。
1H NMR(CDCl3 and CD3OD):8.51(d,J=1.8,1H),8.44(d,J=2.1Hz,1H),7.65(t,J=1.8Hz,1H),7.24(d,J=3.3Hz,1H),7.13(d,J=8.7Hz,1H),7.64(m,2H),4.87(s,1H).
实施例37
2,7-二氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-色烯
按照类似于实施例36中描述的方法,由5-溴-吡啶-3-甲醛、3-氨基苯酚和丙二腈以44%的产率制得了本标题化合物。
1H NMR (CDCl3 and drops ofCD3OD):8.47(d,J=2.1Hz,1H),8.33(d,J=1.8Hz,1H),7.58(t,J=2.0Hz,1H),6.62(d,J=8.4Hz,1H),6.36(dd,J=8.4,2.1Hz,1H),6.30(d,J=2.1Hz,1H),4.61(s,1H).
实施例38
5-甲氧基吡啶-3-甲醛
a)5-溴-3-甲氧基吡啶
向2,5-二溴吡啶(2.188g,9.2mmol)在无水MeOH(10mL)内的搅拌着的溶液中加入NaOMe(10mL 25%NaOMe的MeOH溶液,42mmol)。将该混合物回流3天,然后倒入搅拌着的冷的5%碳酸氢钠水溶液(75mL)内。用乙醚(4×10mL)萃取,用盐水(3×10mL)洗涤萃取液。将有机层干燥(无水硫酸钠),并蒸发。通过硅胶色谱纯化粗产物,用己烷∶EtOAc(4∶1~2∶1)洗脱,获得了1.02g(61%)本标题化合物。
1H NMR(CD3OD):8.17(s,1H),8.12(s,1H),7.24(s,1H),3.74(s,3H).
b)5-甲氧基吡啶-3-甲醛
在-78℃,向5-溴-3-甲氧基吡啶(0.815g,4.35mmol)在THF(15mL)内的搅拌着的溶液中加入n-BuLi(4.6mmol)。1小时后,加入DMF(0.64g,8.20mmol),并继续在-78℃搅拌30分钟。将该冷的混合物倒入5%碳酸氢钠水溶液(25mL)内,用乙醚(3×15mL)萃取。将萃取液蒸发,通过硅胶色谱纯化粗产物,用己烷∶EtOAc(4∶1~2∶1)洗脱,获得了155mg(0.26%)本标题化合物。
1H NMR(CD3OD):9.88(s,1H),8.44(s,1H),8.32(s,1H),3.70(s,3H).
实施例39
2,7-二氨基-3-氰基-4-(5-甲氧基-3-吡啶基)-4H-色烯
向5-甲氧基吡啶-3-甲醛(69.2mg,0.5mmol)和丙二腈(34mg,0.5mmol)在乙醇(2.5mL)内的溶液中加入哌啶(0.1mL,1mmol)和3-氨基苯酚(60mg,0.55mmol)。将该混合物在室温于氩气氛下搅拌2小时。将溶剂蒸发,通过硅胶色谱纯化残余物,用己烷∶EtOAc(4∶1~1∶1)洗脱,获得了44mg(31%)本标题化合物。
1H NMR(CD3OD):8.02(s,1H),7.88(s,1H),6.93(s,1H),6.75(s,1H),6.51(d,J=8.4Hz,1H),6.18(d,J=8.4Hz,1H),6.09(s,1H),5.15(br,1H),4.49(s,1H),3.66(s,3H).
实施例40
2-氨基-3-氰基-7-甲氧基-4-(5-甲氧基-吡啶-3-基)-4H-色烯
由5-甲氧基吡啶-3-甲醛、丙二腈和3-甲氧基苯酚获得了本标题化合物。
1H NMR(CD3OD):8.17(s,1H),8.13(s,1H),7.15(s,1H),7.0(d,J=8.7Hz,1H),6.69(d,J=8.7Hz,1H),6.60(s,1H),6.26(s,2H),4.80(s,1H),3.84(s,3H),3.80(s,3H).
实施例41
2-氨基-3-氰基-4-(5-甲氧基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃
由5-甲氧基吡啶-3-甲醛、丙二腈和4-羟基吲哚获得了本标题化合物。 1H NMR(acetone-d6):
10.44(br,1H),8.17(d,J=1.8Hz,1H),8.15(d,J=2.7Hz,1H),7.36(t,J=
2.7Hz,1H),7.17(m,2H),6.76(d,J=8.1Hz,1H),6.56(s,1H),6.29(s,1H),
4.92(s,1H),3.82(s,3H).
实施例42
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃
向5-溴藜芦醛(245mg,1mmol)和丙二腈(66mg,1mmol)在乙醇(4mL)内的溶液中加入哌啶(0.05mL,0.5mmol)和7-羟基吲哚(133.2mg,1mmol)。将该混合物在室温搅拌过夜。将溶剂蒸发,通过硅胶色谱纯化残余物,用EtOAc和己烷(1∶2)洗脱,获得了56mg(13%)本标题化合物。 1H NMR(CDCl3):
8.39(brs,1H),7.34-7.25(m,2H),6.91(d,J=2.1Hz,1H),6.76(d,J=2.1
Hz,1H),6.67(d,J=8.1Hz,1H),6.56(q,J=2.1Hz,1H),4.80(s,1H),4.67
(brs,2H),3.84(s,3H),3.83(s,3H).
实施例43
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃
按照类似于实施例42中描述的方法,由7-羟基吲哚和3-甲氧基苯甲醛以25%的产率制得了本标题化合物。
1H NMR(CDCl3):8.38(brs,1H),7.31-7.19(m,3H),6.84-6.68(M,4H),6.53(q,J=2.1Hz,1H),4.83(s,1H),4.62(brs,2H),3.76(s,3H).
实施例44
3-氰基-2,7,8-三氨基-4-(3-甲氧基苯基)-4H-色烯
向间甲氧基苯甲醛(544mg,4.0mmol)和丙二腈(264mg,4.0mmol)在乙醇(10mL)内的混合物中加入哌啶(0.4mL)和2,3-二氨基苯酚(496mg,4.0mmol)。将该混合物在室温于氩气氛下搅拌2小时,然后将其用水(20mL)稀释。过滤沉淀,获得了1.08g(88%)本标题化合物,为棕色固体。
1H NMR(CD3OD):8.02(s,1H),7.05(t,J=7.8Hz,1H),6.58-6.66(m,3H),6.30(d,J=7.8Hz,1H),6.08(d,J=7.8Hz,1H),4.41(s,1H),3.60(s,3H).
实施例45
3-氰基-2,7,8-三氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯
向5-溴藜芦醛(980mg,4.0mmol)和丙二腈(246mg,4.0mmol)在乙醇(10mL)内的混合物中加入哌啶(0.4mL)和2,3-二氨基苯酚(496mg,4.0mmol)。将该混合物在室温于氩气氛下搅拌2小时,然后将其用水(20mL)稀释。过滤沉淀,获得了1.367g(85%)本标题化合物,为棕色固体。
1H NMR(CD3OD):6.25(s,1H),6.1825(s,1H),6.34(d,J=7.8,1H),6.10(d,J=7.8,1H),4.43(s,1H),3.68(s,3H),3.64(s,3H).
实施例46
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃
向4-羟基吲哚(500mg,3.76mmol)、3-甲氧基苯甲醛(511mg,3.76mmol)和丙二腈(250mg,3.76mmol)在乙醇(10mL)内的溶液中加入哌啶(0.18mL,1.62mmol)。将该溶液在室温搅拌过夜,真空除去溶剂。通过快速柱色谱纯化粗产物(3∶1己烷∶乙酸乙酯)洗脱,获得了300mg(25%)本标题化合物,为白色固体。
1H NMR(CDCl3):8.26(brs,1H),7.26-7.18(m,2H),7.09-7.06(m,1H),6.84-6.74(m,4H),6.65-6.63(m,1H),4.80(s,1H),4.65(brs,2H),3.76(s,3H).
实施例47
2-氨基-6-氯-3-氰基-7-甲基-4-苯基-4H-色烯
a)7-甲基-6-氯-3-氰基-2-亚氨基-4-苯基-2H-色烯
向4-甲基-5-氯-2-羟基二苯甲酮(500mg,2mmol)和丙二腈(132mg,2mmol)在乙醇(15mL)内的混合物中加入哌啶(0.1mL,1.0mmol)。将该混合物回流2小时。通过硅胶柱色谱纯化残余物,用乙酸乙酯和己烷(1∶2)洗脱,获得了100mg(17%)本标题化合物。
b)2-氨基-6-氯-3-氰基-7-甲基-4-苯基-4H-色烯
在0-5℃,向7-甲基-6-氯-3-氰基-2-亚氨基-4-苯基-2H-色烯(100mg,0.34mmol)在甲醇(5mL)内的混合物中加入NaBH4(26mg,0.68mmol)。将该混合物在室温搅拌2小时,将溶剂蒸发,把残余物溶解在乙酸乙酯中。将有机相用饱和氯化铵水溶液和盐水洗涤,用硫酸钠干燥。真空除去溶剂。通过硅胶柱色谱纯化粗产物,用乙酸乙酯和己烷(1∶2)洗脱,获得了3mg(3%)本标题化合物。
1H NMR(CDCl3):7.33-7.17(m,5H),6.94-6.90(d,J=11.4Hz,2H),4.67(s,1H),4.57(brs,2H),2.32(s,3H).
实施例48
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-7-二甲基氨基-4H-色烯
a)3-溴-4-羟基-5-甲氧基亚苄基:
向3-溴-4-羟基-5-甲氧基苯甲醛(2.31g,10mmol)和丙二腈(660mg,10mmol)在20mL乙醇内的混合物中加入哌啶(0.5mL,0.5mmol)。将该溶液在室温搅拌过夜,观察到沉淀。通过过滤收集沉淀,干燥,获得了2.14g(77%)本标题化合物,为红色固体。
b)2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-7-二甲基氨基-4H-色烯
向3-溴-4-羟基-5-甲氧基亚苄基(279mg,1mmol)和3-二甲基氨基苯酚(137mg,1mmol)在10mL乙醇内的混合物中加入哌啶(0.05mL,0.5mmol),将该溶液回流过夜。真空除去溶剂。通过柱色谱纯化粗产物(2∶1己烷∶乙酸乙酯),获得了35mg(8.4%)本标题化合物。
1H NMR(CDCl3):6.88(d,J=2.1Hz,1H),6.78(d,J=8.7Hz,1H),6.67(d,J=2.1Hz,1H),6.44(dd,J=2.4,8.7Hz,1H),6.28(d,J=2.4Hz,1H),5.81(s,1H),4.55(brs,3H),3.87(s,3H),2.94(s,6H).
实施例49
3-氰基-4-(3-溴-4-羟基-5-甲氧基苯基)-2,7-二氨基-4H-色烯
向3-溴-4-羟基-5-甲氧基亚苄基(279mg,1mmol)和3-氨基苯酚(109mg,1mmol)在10mL乙醇内的混合物中加入哌啶(0.05mL,0.5mmol),将该溶液回流过夜。真空除去溶剂。通过柱色谱纯化粗产物(2∶1己烷∶乙酸乙酯),获得了36mg(9.3%)本标题化合物。
1H NMR(DMSO-d6):6.80-6.76(m,3H),6.67(d,J=8.4Hz,1H),6.28(dd,J=2.1,8.4Hz,1H),6.19(d,J=2.4Hz,1H),5.24(brs,2H),4.47(s,1H),3.78(s,3H).
实施例50
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[4,5-b]
吡喃
本标题化合物是按照类似于实施例49中描述的方法,由4-羟基吲哚和3-溴-4-羟基-5-甲氧基亚苄基以2.7%的产率制得的。
1H NMR(CDCl3):8.27(brs,1H),7.31-7.27(m,1H),7.12-7.10(m,1H),6.91(d,J=2.1Hz,1H),6.75-6.70(m,2H),6.65(s,1H),5.82(s,1H),4.76(s,1H),4.68(brs,2H),3.86(s,3H).
实施例51
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[7,6-b]
吡喃
本标题化合物是按照类似于实施例49中描述的方法,由7-羟基吲哚和3-溴-4-羟基-5-甲氧基亚苄基以5.3%的产率制得的。
1H NMR(CDCl3):8.39(brs,1H),7.31(d,J=8.7Hz,1H),7.26-7.25(m,1H),6.90(d,J=2.1Hz,1H),6.71-6.65(m,2H),6.56-6.54(m,1H),5.84(s,1H),4.78(s,1H),4.66(brs,2H),3.87(s,3H).
实施例52
2-氨基-3-氰基-4-(3,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃
本标题化合物是按照类似于实施例46中描述的方法,由7-羟基吲哚和3,5-二甲氧基亚苄基以23%的产率制得的。
1H NMR(CDCl3):8.39(brs,1H),7.30(d,J=8.1Hz,1H),7.23-7.21(m,1H),6.71(d,J=8.4Hz,1H),6.54-6.52(m,1H),6.38(d,J=2.1Hz,2H),6.34-6.32(m,1H),4.78(s,1H),4.63(brs,2H),3.75(s,6H).
实施例53
2-氨基-3-氰基-4-(3-氰基-苯基)-4H-吲哚并[7,6-b]吡喃
本标题化合物是按照类似于实施例46中描述的方法,由7-羟基吲哚和3-氰基苯甲醛以35%的产率制得的。
1H NMR(CDCl3):8.43(brs,1H),7.55-7.51(m,2H),7.47-7.40(m,2H),7.33(dd,J=0.9,8.1Hz,1H),7.28-7.25(m,1H),6.61-6.55(m,2H),4.92(s,1H),4.73(brs,2H).
实施例54
2-氨基-3-氰基-4-(3-三氟甲基-苯基)-4H-吲哚并[7,6-b]吡喃
本标题化合物是按照类似于实施例46中描述的方法,由7-羟基吲哚和3-三氟甲基苯甲醛以26%的产率制得的。
1H NMR(CDCl3):8.41(brs,1H),7.51-7.42(m,4H),7.31(d,J=8.4Hz,1H),7.27-7.25(m,1H),6.62(dd,J=0.6,8.4Hz,1H),6.56-6.54(m,1H),4.95(s,1H),4.71(brs,2H).
实施例55
2-氨基-3-氰基-4-(5-甲基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃
本标题化合物是按照类似于实施例46中描述的方法,由7-羟基吲哚和5-甲基吡啶-3-甲醛以45%的产率制得的。
1H NMR(DMSO-d6):11.24(brs,1H),8.30(dd,J=2.1,13.5Hz,2H),7.36-7.35(m,2H),7.23(d,J=8.1Hz,1H),6.79(brs,2H),6.57(d,J=8.4Hz,1H),6.45-6.43(m,1H),4.89(s,1H),2.24(s,3H).
实施例56
2-氨基-3-氰基-4-苯基-4H-吲哚并[4,5-b]吡喃
本标题化合物是按照类似于实施例46中描述的方法,由4-羟基吲哚和苯甲醛以42%的产率制得的。
1H NMR(DMSO-d6):11.30(brs,1H),7.37-7.08(m,7H),6.90(brs,2H),6.67(d,J=8.1Hz,1H),6.46(s,1H),4.77(s,1H).
实施例57
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃
向5-甲酰基烟腈(0.0063g,0.048mmol)、乙醇(0.24mL)和丙二腈(0.0031g,0.0048mmol)的澄清溶液中加入4-羟基吲哚(0.0064g,0.048mmol)和哌啶(2.4μL,0.024mmol)。将所得深绿色溶液在室温搅拌6小时,浓缩至灰色固体,用EtOAC(30mL)萃取。将有机层用水(5mL)洗涤,用硫酸镁干燥,经由烧结玻璃滤器过滤,获得了0.012g(80%)绿色固体。通过柱色谱纯化(用EtOAc∶己烷,1∶2洗脱),获得了0.006g(40%)上述化合物,为白色固体。
1H-NMR(Acetone-d6):10.54(s,1H),8.83(t,J=2.20,1.65Hz,2H),8.09(t,J=2.20,1.92Hz,1H),7.39(t,J=2.75Hz,1H),7.20(dd,J=8.24,0.82Hz,1H),6.77(dd,J=8.24Hz,1H),6.58(m,J=2.20,1.92,0.82Hz,1H),6.42(s,2H),5.09(s,1H).
实施例58
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[4,5-b]吡喃
本标题化合物是按照类似于实施例57中描述的方法,由6-甲基-吡嗪-2-甲醛、丙二腈和4-羟基吲哚以22%的产率制得的。
1H-NMR(DMSO-d6):11.30(brs,1H),8.44(dd,J=15.6,1.10Hz,2H),7.36(dd,J=3.03,0.83Hz,1H),7.09(d,J=8.51Hz,1H),7.00(s,2H),6.69(d,J=8.24Hz,1H),6.45(m,J=3.03,1.10,0.83Hz,1H),4.97(s,1H),2.44(s,3H).
实施例59
2-氨基-3-氰基-4-(喹喔啉-2-基)-4H-吲哚并[4,5-b]吡喃
本标题化合物是按照类似于实施例5 7中描述的方法,由喹喔啉-2-甲醛、丙二腈和4-羟基吲哚以79%的产率制得的。
1H-NMR(Acetone-d6):10.54(brs,1H),8.86(s,1H),8.07(m,2H),7.86(m,3H),7.39(t,J=2.74,5.49Hz,1H),7.17(dd,J=8.51,0.82Hz,1H),6.81(dd,J=8.51Hz,1H),6.61(m,1H),6.51(s,2H),5.25(s,1H).
实施例60
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃
本标题化合物是按照类似于实施例57中描述的方法,由5-甲酰基-烟腈、丙二腈和7-羟基吲哚以59%的产率制得的。
1H-NMR(Acetone-d6):10.54(brs,1H),8.84(m,J=2.20,1.90Hz,2H),8.12(t,J=2.20,1.90Hz,1H),7.39(m,J=3.03Hz,1H),7.32(dd,J=8.00Hz,1H),6.68(dd,J=8.20Hz,1H),6.51(m,J=3.03Hz,1H),6.22(s,2H),5.13(s,1H).
实施例61
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[7,6-b]吡喃
本标题化合物是按照类似于实施例5 7中描述的方法,由6-甲基-吡嗪-2-甲醛、丙二腈和7-羟基吲哚以82%的产率制得的。
1H-NMR(DMSO-d6):10.43(brs,1H),8.50(d,J=1.37Hz,1H),8.38(d,J=0.82Hz,1H),7.35(m,J=2.47,2.20,1.10,0.83Hz,1H),7.27(d,J=8.24Hz,1H),6.72(dd,J=8.24,0.55Hz,1H),6.47(m,J=2.20,0.55Hz,1H),6.11(brs,2H),5.05(s,1H),2.47(s,3H).
实施例62
2-氨基-7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-4H-色烯
a)7-氨基-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-2-亚氨基-2H-色烯:
向4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-2,7-二氨基-4H-色烯(1.002g,2.49mmol)和分子筛(4)(1.0g)在无水CH2Cl2(50mL)内的悬浮液中加入2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ,0.601g,2.64mmol),将该反应混合物在室温搅拌1.5小时。将该反应混合物用EtOAc(500mL)稀释,用饱和碳酸氢钠(250mL)、盐水(50mL)洗涤,用硫酸镁干燥,蒸发,获得了0.978g(98%)产物,为黄色固体。
1H NMR(DMSO-d6):8.36(brs,1H),7.28(dd,J=2.4,9.3Hz,1H),7.20(d,J=1.8Hz,1H),6.79(d,J=8.7Hz,1H),6.63(brs,2H),6.41(dd,J=1.8,8.4Hz,1H),6.33(d,J=2.1Hz,1H),3.86(s,3H),3.83(d,J=0.3Hz,3H).
b)7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-2-亚氨基-2H-色烯:
在0℃,向亚硝酸叔丁酯(34mg,0.33mmol)、CuBr2(68mg,0.30mmol)在无水乙腈(1.5mL)内的悬浮液中加入7-氨基-3-氰基-2-亚氨基-4-(3-溴-4,5-二甲氧基-苯基)-2H-色烯(100mg,0.25mmol)。将该混合物在0℃搅拌4小时,然后用EtOAc(50mL)稀释,用饱和碳酸氢钠(25mL)、盐水(10mL)洗涤,用硫酸镁干燥,蒸发,获得了黄色固体。通过柱色谱纯化粗产物(硅胶,EtOAc:己烷,1∶2至1∶1),获得了50mg(43%)本标题化合物,为黄色固体。
1HNMR(CDCl3):7.82(brs,1H),7.38(m,1H),7.30(dd,J=2.1,8.7Hz,1H),7.18(d,J=2.1Hz,1H),7.09(d,J=9.0Hz,1H),6.93(m,1H),3.96(s,3H),3.92(s,3H).
c)2-氨基-7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-4H-色烯:
向7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-2-亚氨基-2H-色烯(50mg,0.108mmol)在无水THF(5mL)内的溶液中加入NaBH4(8mg,0.216mmol)。将该反应混合物在室温搅拌4小时,将溶剂蒸发。向残余物中加入水(10mL),用EtOAc(2×25mL)萃取。将EtOAc萃取液用盐水(10mL)洗涤,用硫酸镁干燥,蒸发,获得了白色固体。通过柱色谱纯化粗产物(硅胶,EtOAc∶己烷,1∶2),获得了34mg(68%)灰白色固体。
1H NMR(CDCl3)7.21-7.18(m,2H),6.88-6.84(m,2H),6.69(d,J=2.1Hz,1H),4.67(brs,2H),4.62(s,1H),3.84(s,3H),3.83(s,3H).
实施例63
2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-4H-色烯
a)4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-2-亚氨基-2H-色烯:
本标题化合物是按照类似于实施例62b中描述的方法,由7-氨基-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-2-亚氨基-2H-色烯(82mg,0.205mmol)、亚硝酸叔丁酯(0.8mL,6mmol)和CuCl2(104mg,0.774mmol)制得的,并且是作为黄色固体(16mg)分离出来。
1HNMR(CDCl3):7.82(s,1H),7.22-7.16(m,4H),6.94(d,J=1.8Hz,1H),3.96(s,3H),3.92(s,3H).
b)2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-4H-色烯:
本标题化合物是按照类似于实施例62c中描述的方法,由4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-2-亚氨基-2H-色烯以66%的产率制得的。
1H NMR(CDCl3):7.07-7.04(m,2H),6.92(dd,J=0.9,9.0Hz,1H),6.88(d,J=1.8Hz,1H),6.69(d,J=1.8Hz,1H),4.70(brs,2H),4.63(s,1H),3.84(s,3H),3.84(s,3H).
实施例64
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-咪唑并[4,5-h]色
烯
在室温于氩气氛下,向2,7,8-三氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯(0.16mg,0.4mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(76.7mg,0.4mmol)和1-羟基苯并三唑水合物(48.9mg,0.4mmol)在DMF(6mL)内的混合物中加入甲酸(18.5mg,0.4mmol),将该混合物搅拌过夜。将该混合物在110℃于氩气氛下搅拌24小时。将溶剂真空蒸发。通过硅胶色谱纯化残余物,用己烷∶EtOAc(8∶2~5∶5)洗脱,获得了61.5mg(36%)本标题化合物。
1H NMR(CD3OD):8.03(s,1H),7.34(d,J=9.9,1H),6.93(m,1H),6.84(d,J=9.9Hz,1H),6.75(s,1H).
实施例65
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-甲基-4H-咪唑并
[4,5-h]色烯
在0℃于氩气氛下,向2,7,8-三氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯(160mg,0.4mmol)在3 mL THF内的混合物中滴加乙酰氯(37.7mg,0.48mmol),将该混合物搅拌1小时。将稳定升至50℃,将该混合物搅拌5小时。将溶剂在高度真空下蒸发。通过硅胶色谱纯化残余物,用己烷∶EtOAc(2∶1)洗脱,获得了109mg(62%)本标题化合物。
1H NMR(Acetone-d6):8.75(s,1H),7.03(s,1H),6.98(s,1H),6.94(d,J=8.1Hz,1H),6.38(d,J=8.1,1H),4.71(s,1H),3.87(s,3H),3.76(s,3H),2.10(s,3H).
实施例66A
2-氨基-3-氰基-7-吡咯烷-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯
a)1-(3-甲氧基-苯基)-吡咯烷.
将溴苯甲醚(63μL)、吡咯烷(50μL)、叔丁醇钠(67mg)、三(二亚苄基丙酮)二钯(1.1mg)和R(+)-BINAP(2.33mg)在甲苯(2.5mL)中于-78℃、氮气氛下逐一混和。让该反应混合物温热至室温,然后加热至80℃并保持过夜。将该反应冷却,用乙醚稀释,过滤并蒸发。通过键洗脱硅胶柱纯化该化合物,用0~2%乙酸乙酯/己烷洗脱,获得了70mg(79%)所需化合物。
1H NMR(CDCl3):7.14(t,J=8.2Hz,1H),6.26-6.20(m,2H),6.12(brs,1H),3.81(s,3H),3.30-3.27(m,4H),2.01-1.97(m,4H).
b)3-吡咯烷-1-基-苯酚
将1-(3-甲氧基-苯基)-吡咯烷(70mg)用乙酸(1.2mL)和47%氢碘酸水溶液(1.2mL)处理,在120℃加热3小时。让该反应混合物冷却至室温,并静置过夜。第二天将该反应混合物在120℃搅拌4小时,然后冷却,缓慢地倒入饱和碳酸氢钠溶液内。将该反应混合物用乙酸乙酯萃取,用盐水洗涤,干燥并浓缩,获得了3-吡咯烷-1-基-苯酚(60mg)。
1H NMR(CDCl3):7.01(t,J=8.13Hz,1H),6.18-6.09(m,3H),4.70(brs,1H),3.24-3.20(m,4H),1.98-1.90(m,4H).
c)2-氨基-3-氰基-7-吡咯烷-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯
本标题化合物是按照类似于实施例2A中描述的方法由3-吡咯烷-1-基-苯酚合成的。
1H NMR(DMSO-d6):6.93(d,J=2.0Hz,1H),6.87(brs,2H),6.83-6.80(m,2H),6.28(dd,J=2.4,8.6Hz,1H),6.04(d,J=2.4Hz,1H),4.56(s,1H),3.78(s,3H),3.68(s,3H),3.16(m,4H),1.92-1.89(m,4H).
下列两种化合物是用类似于实施例66A中描述的方法合成的。
实施例66B
2-氨基-3-氰基-7-哌嗪-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯
1H NMR(CD3OD):6.89-6.83(m,3H),6.71(dd,J=2.5,8.6Hz,1H),6.60(d,J=2.5Hz,1H),4.60(s,1H),3.81(s,3H),3.76(s,3H),3.34(s,2H),3.15-3.13(m,4H),2.97-2.95(m,4H).
实施例66C
2-氨基-3-氰基-7-N-吗啉-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯
1H NMR(CD3OD):6.95(d,J=2.0Hz,1H),6.93-6.90(m,3H),6.83(d,J=2.0Hz,1H),6.69(dd,J=2.4,8.7Hz,1H),6.45(d,J=2.4Hz,1H),4.64(s,1H),3.79(s,3H),3.69-3.67(m,7H),3.07-3.05(m,4H).
实施例67
2-氨基-3-氰基-7-吡咯-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯
将2-氨基-3-氰基-7-氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯(10mg)溶解在0.5mL甲苯中,用乙酸(0.3mL)处理,然后用2,5-二甲氧基四氢呋喃(5μL)处理。将该反应混合物回流15分钟,然后冷却,用饱和碳酸氢钠溶液中和。将该反应混合物用二氯甲烷萃取,用盐水洗涤,干燥并浓缩。通过键洗脱硅胶色谱纯化该残余物,用10%-30%乙酸乙酯/己烷洗脱,获得了5.5mg所需化合物。
1H NMR(DMSO-d6):7.37(t,J=2.2Hz,1H),7.31(dd,J=2.4,8.4Hz,1H),7.21(d,J=2.4Hz,1H),7.16(d,J=8.8Hz,1H),7.07(brs,2H),7.01(d,J=2.1Hz,1H),6.91(d,J=2.0Hz,1H),6.24(t,J=2.2Hz,1H),4.78(s,1H),3.80(s,3H),3.69(s,3H).
实施例68A
2-氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基苯基)-4-甲基
色烯
a)2-亚氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基苯基)-色烯:
将4分子筛(20mg)加到在二氯甲烷(1mL)内的2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-甲基色烯(20mg,0.05mmol)中。将该溶液搅拌15分钟。然后加入2,3-二氯-5,6-二氰基-1,4-苯醌(10mg,0.05mmol,1当量),并继续在室温搅拌1小时。将该反应混合物用乙酸乙酯(20mL)稀释,用饱和碳酸氢钠溶液(20mL)、盐水(20mL)洗涤,用硫酸钠干燥,浓缩,获得了17mg(79%)所需化合物。
1H NMR(DMSO-d6):8.33(s,1H),7.28(d,J=1.9Hz,1H),7.21(d,J=1.9Hz,1H),6.87(d,J=9.1Hz,1H),6.56(dd,J=2.5,9.1Hz,1H),6.40(d,J=2.5Hz,1H),3.84(s,3H),3.82(s,3H),3.03(s,6H).
b)2-氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基苯基)-4-甲基色烯:
将溴化铜二甲基硫醚(71mg,0.35mmol,5当量)悬浮在无水四氢呋喃(1mL)中,并冷却至-78℃,在相同温度下将0.7M甲基锂乙醚溶液(1mL,0.7mmol,10当量)加到该混合物中,并搅拌1小时。将上述亚氨基色烯(30mg,0.07mmol)溶解在最小量的四氢呋喃中,加到该反应混合物中。将该橙色溶液在-78℃搅拌30分钟,然后用饱和氯化铵溶液(10mL)中止反应,用乙酸乙酯(10mL)萃取,用盐水(10mL)洗涤,用硫酸钠干燥并浓缩。通过硅胶纯化该残余物,用30%乙酸乙酯/己烷洗脱。
1H NMR(acetone-d6):6.92-6.84(m,3H),6.50(dd,J=2.6,8.9Hz,1H),6.26(d,J=2.6Hz,1H),5.90(brs,1H),3.76(s,3H),3.73(s,3H),2.91(s,6H),2.05(s,3H).
下述化合物是按照类似于实施例68A中描述的方法制得的。
实施例68B
2-氨基-3-氰基-4-苯基-4-甲基色烯
1H NMR(CDCl3):7.31-6.97(m,9H),4.54(brs,2H),1.95(s,3H).
实施例69
2-氨基-3-氰基-4-(3-溴-4-磷酸-二哌啶盐-5-甲氧基苯基)-4H-吲哚
并[4,5-b]吡喃
a)磷酸2-溴-4-甲酰基-6-甲氧基-苯基酯二-(2-氰基乙基)酯:
将无水二氯甲烷(2mL)冷却至0℃。向其中加入吡啶(0.64mL,7.92mmol),并搅拌5分钟。在搅拌下向该溶液中缓慢地加入三氯氧化磷(0.246mL,2.64mmol),搅拌15分钟。然后向该反应混合物中加入在无水二氯甲烷(4mL)内的5-溴香草醛(412mg,1.78mmol),在室温搅拌1.75小时,TLC表明原料已全部消失。然后加入吡啶(0.64mL,7.92mmol)和3-羟基丙腈(0.54mL,7.92mmol),继续搅拌过夜。用二氯甲烷稀释该混合物,用水洗涤4次。用硫酸钠将有机层干燥,蒸发,通过色谱法纯化残余物,用乙酸乙酯洗脱,获得了磷酸2-溴-4-甲酰基-6-甲氧基-苯基酯二-(2-氰基乙基)酯(465mg,63%),为无色油状物。
1H NMR(CDCl3):9.88(s,1H),7.69(dd,J=1.0,1.9Hz,1H),7.45(d,J=1.8Hz,1H),4.48-4.54(m,4H),4.00(s,3H),2.84-2.87(m,4H).
b)2-氨基-3-氰基-4-(3-溴-4-磷酸氰基乙酯-一哌啶盐-5-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃:
向在无水乙醇内的4-羟基吲哚(148mg,1.11mmol)、丙二腈(74mg,1.11mmol)和磷酸2-溴-4-甲酰基-6-甲氧基-苯基酯二-(2-氰基乙基)酯(465mg,1.11mmol)中加入哌啶(0.22mL,2.22mmol)。将该反应在室温搅拌过夜。将溶剂蒸发,获得了黄色泡沫状物,通过快速色谱法纯化。用20%乙酸乙酯/己烷至5%甲醇/二氯甲烷洗脱色谱柱以除去杂质。用15%-20%甲醇/二氯甲烷洗脱,获得了磷酸一氰基乙酯的哌啶盐(557mg,84%)(1H NMR表明含有20%磷酸二氰基乙酯)。
1H NMR).1H NMR(CD3OD):7.23(d,J=3.1Hz,1H),7.09(dd,J=5.5,7.3Hz,1H),6.93(d,J=2.0Hz,1H),6.83(d,J=1.8Hz,1H),6.71(d,J=8.4Hz,1H),6.58 dd,J=3.1,7.3Hz,1H),4.73(s,1H),4.24(m,2H),3.79(s,3H),3.06(m,4H,(piperidine salt)),2.82(m,2H),1.6-1.8(m,6H,(piperidine salt)).
c)2-氨基-3-氰基-4-(3-溴-4-磷酸-二哌啶盐-5-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃:
向在无水乙醇(0.5mL)内的磷酸一氰基乙酯的哌啶盐(27mg,0.04mmol)中加入哌啶(0.012mL,0.12mmol)。将该反应在65℃加热7小时,此时TLC表明原料已全部消失。将溶剂蒸发,获得了棕色残余物。加入甲醇(2mL)后,从溶液中沉淀出了固体,过滤并干燥,经证实是二哌啶盐形式的所需化合物(15.4mg,80%)。 1H NMR
(D2O):7.20(d,J=3.2Hz,1H),7.03(d,J=8.3Hz,1H),6.84(d,J=1.8Hz,
1H),6.60(m,2H),6.47(d,J=3.1Hz,1H),4.45(s,1H),3.57(s,3H),2.94
(m,8H,(piperidine salt)),1.4-1.6(m,12H,(piperidine salt)).
实施例70
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-苯并硫吡喃
a)2-羟基-4-甲氧基苯基-(3’-甲氧基苯基)-甲酮:
在0℃,向3-甲氧基苯酚(500μL,4.55mmol)在5mL无水甲苯内的溶液中加入间甲氧基苯甲酰氯(640μL,4.55mmol),然后加入三氯化硼(4.55mL 1.0M的二甲苯溶液,4.55mmol)。将所得混合物温热,在85℃搅拌24小时。然后将其用40mL乙醚稀释,用25ml饱和碳酸氢钠水溶液洗涤2次,用硫酸钠干燥,浓缩,通过快速色谱法纯化。用20%乙酸乙酯/己烷洗脱,获得了883mg本标题化合物,为无色油状物。
1HNMR(CDCl3):7.53(d,J=8.9Hz,1H),7.39(dd,J=7.5,0.5Hz,1H),7.18-7.20(m,1H),7.15-7.16(m,1H),7.10(ddd,J=8.3,2.6,1.0Hz,1H),6.52(d,J=2.5Hz,1H),6.41(dd,J=9.0,2.6Hz,1H),3.87(s,3H),3.86(s,3H).
b)二甲基硫代氨基甲酸O-[5-甲氧基-2-(3’-甲氧基苯甲酰基)苯基]酯:
将(2-羟基-4-甲氧基苯基)-(3’-甲氧基苯基)-甲酮(872mg,3.38mmol)、二甲基硫代氨基甲酰氯(835mg,6.76mmol)和1,4-二氮杂二环[2.2.2]辛烷(758mg,6.76mmol)在10mL DMF中的混合物于室温搅拌过夜。加入一份100mL乙醚,用饱和碳酸氢钠水溶液将所得混合物洗涤2次,用硫酸钠干燥并浓缩。通过快速色谱法纯化,用15%-20%乙酸乙酯/己烷洗脱,获得了975mg(83%)二甲基硫代氨基甲酸O-[5-甲氧基-2-(3’-甲氧基苯甲酰基)苯基]酯,为淡黄色油状物。
1H NMR(CDCl3):7.51(d,J=8.6Hz,1H),7.33-7.35(m,2H),7.08-7.11(m,1H),6.83(dd,J=8.6 and 2.5Hz,1H),6.41(d,J=2.4Hz,1H),3.90(s,3H),3.85(s,3H),3.32(s,3H),3.16(s,3H).
c)二甲基硫代氨基甲酸S-[5-甲氧基-2-(3’-甲氧基苯甲酰基)苯基]酯:
将二甲基硫代氨基甲酸O-[5-甲氧基-2-(3’-甲氧基苯甲酰基)苯基]酯(879mg,2.54mmol)在8mL N,N-二甲基苯胺中于215℃搅拌3小时。冷却至室温后,加入一份100mL乙醚。将所得混合物用10%盐酸洗涤2次,用饱和碳酸氢钠水溶液洗涤1次,用硫酸钠干燥并浓缩。通过快速色谱法纯化粗产物,用20%乙酸乙酯/己烷洗脱,获得了502mg(57%)二甲基硫代氨基甲酸S-[5-甲氧基-2-(3’-甲氧基苯甲酰基)苯基]酯,为淡黄色油状物。
1H NMR(CDCl3):7.40(d,J=8.5Hz,1H),7.30-7.34(m,2H),7.19(d,J=2.6Hz,1H),7.07-7.10(m,1H),6.95-6.97(m,1H),3.88(s,3H),3.82(s,3H),2.89(s,6H).
d)(2-巯基-4-甲氧基-苯基)-(3’-甲氧基-苯基)-甲酮:
将二甲基硫代氨基甲酸S-[5-甲氧基-2-(3’-甲氧基苯甲酰基)苯基]酯(164mg,0.475mmol)和氢氧化钾(200mg,3.56mmol)的混合物在2mL无水甲醇中于70℃搅拌1.5小时。冷却至室温后,除去溶剂。通过快速色谱法纯化所获得的粗产物,用20%乙酸乙酯/己烷洗脱,获得了35mg(27%)(2-巯基-4-甲氧基-苯基)-(3’-甲氧基-苯基)-甲酮,为淡黄色油状物。
1H NMR(CDCl3):7.50(d,J=8.8Hz,1H),7.33-7.37(m,1H),7.22-7.27(m,2H),7.10(ddd,J=8.2,2.6 and 1.0Hz,1H),6.90(d,J=2.5Hz,1H),6.65(dd,J=8.8 and 2.5Hz,1H),4.76(s,1H),3.85(s,3H),3.84(s,3H).
e)2-亚氨基-3-氰基-7-甲氧基-4-(3’-苯基)-2H-苯并硫吡喃:
在0℃,向(2-巯基-4-甲氧基-苯基)-(3’-甲氧基-苯基)-甲酮(35mg,0.13mmol)和丙二腈(8.5mg,0.13mmol)在200μL无水乙醇内的混合物中加入哌啶(7.0μL,0.06mmol)。将所得混合物在0℃搅拌2.5小时。将溶剂蒸发,通过快速色谱法纯化残余物(25%乙酸乙酯/己烷),获得了31mg(75%)2-亚氨基-3-氰基-7-甲氧基-4-(3’-甲氧基苯基)-2H-苯并硫吡喃,为橙色蜡状油状物。
1H NMR(CDCl3):9.31(brs,1H),7.42-7.46(m,1H),7.03-7.11(m,2H),6.91(d,J=7.8Hz,1H),6.85-6.86(m,1H),6.80(brs,1H),6.68(dd,J=9.1 and 2.6Hz,1H),3.85(s,3H),3.84(s,3H).
f)2-氨基-3-氰基-4-苯基-1,4-二氢喹啉:
在0℃,将2-亚氨基-3-氰基-7-甲氧基-4-(3’-甲氧基苯基)-2H-苯并硫吡喃(25mg,0.077mmol)在2.3 mL无水甲醇中的溶液用硼氢化钠(5.0mg,0.13mmol)处理。将所得混合物在室温搅拌过夜。然后将其用3滴1N盐酸中和,溶解在20mL乙醚中,用10mL饱和碳酸氢钠水溶液洗涤2次,用硫酸钠干燥。将溶剂蒸发,通过快速色谱法纯化残余物,用25%乙酸乙酯/己烷洗脱,获得了15.9mg(63%)2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-苯并硫吡喃,为淡黄色固体。
1H NMR(CDCl3):7.14-7.21(m,2H),6.79-6.82(m,3H),6.72-6.76(m,2H),4.82(s,1H),4.66(brs,2H),3.79(s,3H),3.75(s,3H).
实施例71
2-氨基-3-氰基-4-苯基-1,4-二氢喹啉
将氰基硼氢化钠(10mg)加到2-氨基-4-苯基-喹啉-3-甲腈(5mg)在乙酸(0.25mL)内的溶液中。在室温搅拌85分钟后,TLC这不再有任何改变,因此再加入氰基硼氢化钠(15mg)。将该反应混合物搅拌20分钟,然后用饱和碳酸氢钠溶液中和,用乙酸乙酯萃取。用饱和氯化钠溶液洗涤萃取液,干燥。将除去溶剂而获得的粗产物流经键洗脱柱(4∶1-7∶3己烷-乙酸乙酯),获得了2mg 2-氨基-3-氰基-4-苯基-1,4-二氢喹啉。
1H NMR(CD3OD):7.22-7.26(m,2H),7.12-7.19(m,3H),7.07(dt,J=7.8,1.6Hz,1H),6.92(finely split doublet,J=7.8Hz,1H),6.82(dt,J=7.6,1.2Hz,1H),6.77(dd,J=8.1,1.2Hz,1H),4.76(s,1H).
实施例72
2-氨基-3-乙氧基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并
[4,5-b]吡喃
向羟基吲哚(528mg,3.97mmol,1当量)、溴藜芦醛(973mg,3.97mmol,1当量)和氰基乙酸乙酯(449mg,3.97mmol,1当量)在无水乙醇(20mL)内的溶液中加入哌啶(0.78μL,7.94mmol,2当量)。将该反应混合物在室温搅拌过夜。将溶剂蒸发,通过快速色谱法纯化粗产物,用20-50%乙酸乙酯/己烷洗脱,获得了泡沫状固体(354mg,19%)。
1H NMR(DMSO-d6):7.64(brs,2H),7.33(m,1H),7.08(dd,J=8.4,0.9Hz,1H),6.94(d,J=1.9Hz,1H),6.87(d,J=8.4Hz,1H),6.76(d,J=1.9Hz,1H),6.46(m,1H),4.90(s,1H),4.02-3.92(m,2H),3.75(s,3H),3.61(s,3H),1.16-1.13(t,J=7.2Hz,3H).
实施例73
2-氨基-3-甲氧基羧基-4-(3-溴-4,5-二甲氧基-4H-吲哚并[4,5-b]吡
喃
向羟基吲哚(138mg,1.04mmol,1当量)、溴藜芦醛(254mg,1.04mmol,1当量)和氰基乙酸甲酯(103mg,1.04mmol,1当量)在无水乙醇内的溶液中加入哌啶(0.20μL,2.08mmol,2当量)。将该反应混合物在室温搅拌过夜。将溶剂蒸发,通过快速色谱法纯化粗产物,用30%乙酸乙酯/己烷洗脱,获得了粉红色固体(69mg,14%)。
1H NMR(CD3OD):7.21(m,1H),7.08(dd,J=0.9,8.4Hz,1H),6.91(d,J=1.8Hz,1H),6.84-6.80(m,2H),6.60-6.59(dd,J=0.9,3.1Hz,1H),4.92(s,1H),3.77(s,3H),3.71(s,3H),3.63(s,3H).
实施例74
2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色
烯
a)2,3-二羟基苯胺:
将2,3-二甲氧基苯胺(500mg,3.26mmol)溶解在乙酸(10mL)中。加入47%盐酸(10mL),将该溶液在回流状态下搅拌8小时。将该反应冷却至室温,搅拌3天。真空除去溶剂,将黄色固体溶解在水中,用饱和碳酸氢钠水溶液中和。用乙酸乙酯(4×20mL)萃取水层。合并有机层,用10%硫代硫酸钠(30mL)、水(30mL)、盐水(30mL)洗涤,用硫酸钠干燥,过滤并浓缩。通过Biotage(cartridge 40S,SiO2)纯化粗产物,用1%、2%和4%甲醇在二氯甲烷中的混合物洗脱,获得了188mg(46%)2,3-二羟基苯胺,为米色固体。
1H NMR(CD3OD):6.47(t,J=8.0Hz,1H),6.28(dd,J=8.0,1.6Hz,1H),6.24(dd,J=8.0,1.6Hz,1H).
b)2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯:
将2,3-二羟基苯胺(80mg,0.64mmol)、5-溴藜芦醛(157mg,0.64mmol)和丙二腈(42mg,0.64mmol)溶解在乙醇(4mL)中。加入哌啶(127μL,1.28mmol),将该反应在室温搅拌过夜。将该反应混合物真空浓缩,通过用2%和5%甲醇在二氯甲烷中的混合物洗脱的Biotage快速色谱(cartridge 12M)分离出所需产物,获得了97mg(36%)所需的2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯,为棕色固体。
1H NMR(CD3OD):6.86(s,1H),6.80(s,1H),6.47(d,J=8.0Hz,1H),6.29(d,J=8.0Hz,1H),4.56(s,1H),3.78(s,3H),3.75(s,3H).
实施例75
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-咪唑并
[4,5-b]色烯
a)4-羟基-3H-苯并咪唑:
将2,3-二氨基苯酚(1.242g,10mmol)、原甲酸三乙酯(1.483g,10mmol)和对甲苯磺酸(95mg,0.5mmol)的混合物在120℃加热。1小时后,TLC表明原料已消耗完,使用迪安-斯榻克蒸馏头收集了约1mL乙醇。然后将该反应混合物蒸发,真空干燥,获得了4-羟基-3H-苯并咪唑与4-羟基-1H-苯并咪唑的混合物,为深色固体。
1H NMR(CDCl3):9.15(brs,1H),8.28(s,1H),7.11(d,J=2.1Hz,1H),7.10(s,1H),6.72(d,J=3.3Hz,1H)and 6.71(d,J=3.3Hz,1H).
b)2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-咪唑并[4,5-h]色烯:
向5-溴藜芦醛(247mg,1.01mmol)和上面获得的4-羟基-3H-苯并咪唑与4-羟基-1H-苯并咪唑的混合物(139mg,1.03mmol)在无水乙醇(10mL)内的搅拌着的溶液中加入丙二腈(68mg,1.03mmol)和哌啶(0.1mL)。将该反应混合物在室温搅拌过夜。将溶剂减压蒸发,通过柱色谱纯化所得残余物(硅胶,EtOAc∶己烷,3∶1加5%MeOH和1%Et3N),获得了169mg(38%)2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9H-4H-咪唑并[4,5-h]色烯和2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-7H-4H-咪唑并[4,5-h]色烯,为灰白色固体。
1H NMR(acetone-d6):8.23(s,1H),7.31(d,J=8.1Hz,1H),7.05(d,J=1.8Hz,1H),7.02(d,J=2.1Hz,1H),6.94(d,J=8.4Hz,1H),6.40(brs,2H),4.88(s,1H)3.85(s,3H),3.76(s,3H).
将上述混合物(52mg,0.12mmol)、碘甲烷(10μL,0.16mmol)和碳酸铯(24mg,0.074mmol)在丙酮(2mL)中于室温搅拌42小时。将溶剂减压蒸发,将残余物溶解在EtOAc(50mL)中。加入水(0.5mL)以将不溶性无机盐溶解。然后用硫酸镁将该混合物干燥,蒸发,获得了48mg浅棕色固体。通过柱色谱纯化所得残余物(硅胶,EtOAc∶己烷,3∶1加5%MeOH和1%Et3N),获得了2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-咪唑并[4,5-h]色烯,为灰白色固体。
1H NMR(CDCl3):7.80(s,1H),7.48(d,J=8.4Hz,1H),6.89(d,J=2.1Hz,1H),6.83(d,J=8.4Hz,1H),6.77(d,J=2.1Hz,1H),4.81(s,1H),4.66(brs,2H),4.12(s,3H),3.86(s,3H),3.84(s,3H).
还获得了另一种产物2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-7-甲基-4H-咪唑并[4,5-h]色烯。
1H NMR(CDCl3):7.88(s,1H),7.11(d,J=8.4Hz,1H),6.92(d,J=1.8Hz,1H),6.90(d,J=8.7Hz,1H),6.72(d,J=2.1Hz,1H),4.84(brs,2H),4.80(s,1H),3.85(s,3H),3.83(s,3H),3.81(s,1H).
实施例76
3-氰基-4-(3-溴-4,5-二甲氧基苯基)-2-甲基氨基-9-甲基-4H-吡咯
并[3,2-h]色烯
向2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-4H-吡咯并[3,2-h]色烯(200mg,0.47mmol)和甲基碘(0.12mL,1.88mmol)在丙酮(5mL)内的溶液中加入碳酸铯(306.3mg,0.94mmol)。将该混合物在室温搅拌过夜。通过过滤除去固体。将滤液真空浓缩,通过柱色谱纯化粗产物(1∶1己烷/乙酸乙酯),获得了50mg(24%)本标题化合物,为白色固体。
1HNMR(CDCl3):8.43(brs,1H),7.59-7.48(m,2H),7.31(d,J=2.1Hz,1H),7.26-7.22(m,2H),6.58-6.56(m,1H),4.91(s,1H),3.88-3.85(m,9H),1.81(s,3H).
实施例77
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-吡咯并
[3,2-h]色烯
a)1-甲基-吲哚-7-醇:
将7-苄氧基吲哚(300mg,1.34mmol)、草酸二甲酯(317mg,2.68mmol)和叔丁醇钾(302mg,2.68mmol)在5mL DMF中的混合物于110℃搅拌过夜。将该溶液倒入饱和碳酸氢钠溶液(20mL)中,用EtOAc萃取。分离出有机层,用盐水洗涤,用硫酸钠干燥。真空除去溶剂,获得了200mg 7-苄氧基-1-甲基吲哚,通过5%Pd/C在20mL甲醇中于氢气(50psi)将其氢化,获得了90mg(45.5%)本标题化合物。 1H
NMR(CDCl3):7.19-7.16(m,1H),6.94(d,J=3Hz,1H),6.86(t,J=7.5Hz,
1H),6.48-6.46(m,1H),6.40(d,J=3Hz,1H),5.05(s,1H),4.07(s,3H).
b)2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-吡咯并[3,2-h]色烯:
本标题化合物是由1-甲基-吲哚-7-醇(90mg,0.61mmol)、5-溴藜芦醛(150mg,0.61mmol)、丙二腈(41mg,0.61mmol)和哌啶(0.05mL,0.31mmol)制得的,获得了140mg(52%)白色固体。
1H NMR(CDCl3):7.27(d,J=8.4Hz,1H),6.99(d,J=3.3Hz,1H),6.90(d,J=1.8Hz,1H),6.77(d,J=2.4Hz,1H),6.61(d,J=8.1Hz,1H),6.42(d,J=3.0Hz,1H),4.79(s,1H),4.62(brs,2H),4.09(s,3H),3.85(s,3H),3.83(s,3H).
实施例78
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡嗪并[2,3-h]色烯
向2,7,8-三氨基-3-氰基-4-(3-甲氧基苯基)-4H-色烯(0.124g,0.4mmol)在3mL THF内的混合物中加入乙二醛(0.06mL,40%水溶液,0.4mmol)。将该混合物在室温于氩气氛下搅拌3小时,然后回流3小时。将溶剂在高度真空下蒸发。通过硅胶色谱纯化残余物,用己烷∶EtOAc(8∶2~5∶5)洗脱,获得了0.021g(16%)本标题化合物。
1H NMR(CD3OD):8.90(m,2H),7.79(d,J=9.0Hz,1H),7.36(d,J=9.0Hz,1H),7.26(t,J=7.80Hz),6.85(m,2H),6.80(s,1H).4.91(s,1H),3.77(s,3H).
实施例79
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吡嗪并[2,3-h]色
烯
本标题化合物是由2,7,8-三氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯和乙二醛制得的。
1H NMR(CD3OD):8.93(m,2H),7.83(d,J=9.0Hz,1H),7.39(d,J=9.0Hz,1H),6.97(s,1H),6.77(s,1H),4.88(s,1H),3.84(d,6H).
实施例80
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-氧代-4,7,8,9-四
氢咪唑并[4,5-h]色烯
在0℃、氩气氛下,向2,7,8-三氨基-3-氰基-6-(3-溴-4,5-二甲氧基苯基)-4H-色烯(112mg,0.3mmol)和碳酸钾(207mg,1.5mmol)在二氯甲烷(6mL)内的混合物中加入光气(10mL,20%的甲苯溶液),将该混合物搅拌过夜。将该混合物在110℃于氩气氛下搅拌1小时。将溶剂在高度真空下蒸发。通过硅胶色谱纯化残余物,用己烷∶EtOAc(2∶1)洗脱,获得了42.5mg(3 2%)本标题化合物。 1H NMR
(acetone-d6):7.03(d,J=2.2Hz,1H),7.01(d,J=2.2Hz,1H),6.80(d,J=
7.5Hz,1H),6.70(d,J=7.5Hz,1H),6.04(s,1H),4.79(s,1H),3.86(s,3H),
3.76(s,3H).
实施例81
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃
本标题化合物是按照类似于实施例2A中描述的方法由4-羟基吲哚和3-甲氧基苯甲醛以25%的产率制得的。
1H NMR(CDCl3):8.26 (bts,1H),7.26-7.18(m,2H),7.09-7.06(m,1H),6.84-6.74(m,4H),6.65-6.63(m,1H),4.80(s,1H),4.65(brs,2H),3.76(s,3H).
实施例82
在实体瘤细胞中鉴定2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃和类似物作为半胱天冬酶级联激活剂和细
胞凋亡诱导剂的用途
在5%CO2-95%湿度的培养器内于37℃,让人乳腺癌细胞系T-47D和ZR-75-1在American Type Culture Collection指定的培养基组分混合物+10%FCS(Invitrogen Corporation)中生长。在0.1-0.6×106个细胞/ml的细胞密度下,让T-47D和ZR-75-1细胞保持30-80%铺满的细胞密度。以600×g收获细胞,以0.65×106个细胞/mL重悬在适当培养基+10%FCS中。将45μl等份试样的细胞加到96孔微量滴定板的孔中,其中微量滴定板的孔中含有5μl 10%DMSO在RPMI-1640培养基溶液中的混合物,所述培养基溶液含有0.16-10μM2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃(实施例42)或其它测试化合物(终浓度为0.016-1μM)。将45μl等份试样的细胞加到96孔微量滴定板的孔中,其中微量滴定板的孔中含有5μl 10%DMSO在RPMI-1640培养基溶液中的混合物,并且所述培养基溶液不含测试化合物,以由此用作对照样本。通过搅拌将样本混和,然后在5%CO2-95%湿度的培养器内于37℃培养24小时。培养后,将样本从培养器中取出,加入50μl含有下列组分的溶液:20μMN-(Ac-DEVD)-N’-乙氧基羰基-R110(SEQ ID NO:1)荧光底物(Cytovia,Inc.;WO 99/18856)、20%蔗糖(Sigma)、20mM DTT(Sigma)、200mMNaCl(Sigma)、40mM Na PIPES缓冲液pH 7.2(Sigma)和500μg/ml溶血卵磷脂(Calbiochem)。通过搅拌将样本混和,并在室温培养。使用荧光平板读数器(Model 1420 Wallac Instruments),采用485nm的激发波长和530nm的发射波长,在加入底物溶液约1-2分钟后记录初始读数(T=0),以确定对照样本的背底荧光。培养3小时后,如上所述读取样本的荧光(T=3小时)。
计算:
如下所示,使用相对荧光单位值(RFU)来计算样本读数值:RFU(T=3小时)-对照RFU(T=0)=净RFU(T=3小时)
通过2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃或其它测试化合物的净RFU值与对照样本的净RFU值的比值来确定半胱天冬酶级联激活活性。通过乙状剂量-反应计算(Prism2.0,GraphPad Software Inc.)确定EC50(nM)。表I中总结了半胱天冬酶活性(比值)和效力(EC50)。
表I.半胱天冬酶活性和效力
Example | T47DRatio EC50(nM) | ZR-75-1Ratio EC50(nM) | ||
1 | 5.1 | 153 | 10.8 | 94 |
2A | 4.0 | 72 | 4.1 | 14 |
2B | 1.2 | >10,000 | 1.9 | >10,000 |
2C | 1.1 | >10,000 | 0.9 | >10,000 |
2D | 4.4 | 78 | 4.4 | 50 |
2E | 4.1 | 39 | 4.4 | 29 |
2F | 4.7 | 44 | 4.4 | 26 |
2G | 5.6 | 56 | 4.5 | 25 |
2H | 5.5 | 29 | 3.9 | 16 |
2I | 6.2 | 50.4 | ||
2J | 5.0 | 34 | 7.4 | 21 |
2K | 5.6 | 37 | 6.9 | 16 |
2L | 4.5 | 63 | 7.4 | 41 |
2M | 5.8 | 1,387 | 6.9 | 786 |
2N | 4.2 | 57 | 6.8 | 47 |
2O | 6.4 | 323 | 7.1 | 193 |
3 | 8.4 | 29 | 4.5 | 16 |
4 | 8.1 | 37 | 5.6 | 33 |
5 | 6.9 | 37 | 7.1 | 46 |
6 | 6.8 | 54 | 12.8 | 30 |
7 | 5.4 | 108 | 10.7 | 53 |
8 | 8.5 | 126 | 10.1 | 62 |
9 | 7.6 | 116 | 12.8 | 50 |
10 | 6.1 | 48 | 9.0 | 36 |
11 | 4.5 | 45 | 6.6 | 28 |
12 | 6.1 | 14 | 6.7 | 9 |
13 | 4.4 | 25 | 7.0 | 14 |
14 | 7 | 10 | 7.7 | 10 |
15 | 5.9 | 7 | 6.3 | 4 |
16 | 7 | 11 | 6.7 | 6 |
17 | 5.9 | 254 | 8.2 | 147 |
18 | 9.0 | 56 | 8.8 | 38 |
19 | 5.9 | 274 | 9.2 | 206 |
20 | 4.0 | 120 | 5.2 | 58 |
21 | 6.0 | 697 | 9.2 | 562 |
22 | 5.8 | 4803 | 8.0 | 2482 |
23 | 4.6 | 146 | 5.2 | 102 |
24 | <2 | >10,000 | <2 | >10.000 |
25 | 6.1 | 463 | 9.7 | 325 |
26 | 3.5 | 140 | 6.4 | 82 |
27 | <2 | >10,000 | <2 | >10,000 |
28 | 3.4 | 158 | 5.2 | 154 |
29 | <2 | >10,000 | <2 | >10,000 |
30 | 7.5 | 24 | 13.2 | 14 |
31 | 7.9 | 27 | 11.0 | 12 |
32 | 7.2 | 17 | 9.5 | 4 |
33 | 7.0 | 7 | 10.4 | 7 |
34 | 4.7 | 107 | 5.6 | 43 |
35 | 6.9 | 3 | 5.5 | 8 |
36 | 5.9 | 10 | 2.9 | 3 |
37 | 6.4 | 57 | 3.4 | 31 |
39 | 8.4 | 283 | 14 | 177 |
40 | 7.9 | 27.4 | 8.9 | 16.9 |
41 | 6.8 | 13.9 | 7.2 | 6.6 |
42 | 7.6 | 30 | 13.1 | 25 |
43 | 6.5 | 143.1 | 5.9 | 81.9 |
44 | 7.0 | 256.1 | 9.6 | 137.6 |
45 | 6.0 | 41.8 | 11.9 | 35.4 |
46 | 6.4 | 61.8 | 7.1 | 26.3 |
47 | 1.9 | >1,000 | 7.3 | 552.0 |
48 | 10.5 | 36.8 | 6.1 | 23.8 |
49 | 10.1 | 67.7 | 5.8 | 35.9 |
50 | 10.1 | 16.5 | 10.6 | 14.8 |
51 | 11.5 | 36.8 | 6.7 | 18.6 |
52 | 11.8 | 26.0 | 9.9 | 22.7 |
53 | 10.1 | 79.7 | 7.0 | 26.4 |
54 | 7.3 | 314.3 | 7.5 | 216.5 |
55 | 7.4 | 15.3 | 7.2 | 4.0 |
56 | 8.3 | 252.1 | 7.7 | 157.1 |
57 | 7.2 | 58.0 | 7.3 | 27.9 |
58 | 4.1 | 2898.2 | 7.0 | 1631.0 |
59 | 1.1 | >10,000 | 1.2 | >10,000 |
60 | 6.7 | 388.3 | 5.5 | 57.0 |
61 | 4.1 | 2,898 | 7.0 | 1,631 |
62 | 6.6 | 144.3 | 6.0 | 75.3 |
63 | 9.1 | 147.0 | 10.1 | 114.2 |
64 | 8.0 | 28.8 | 4.8 | 13.2 |
65 | 1.5 | >1000 | 6.0 | 570.1 |
66A | 3.7 | 110.1 | 6.0 | 79.4 |
66B | 5.7 | 2906.1 | 6.8 | 1471.1 |
66C | 10.4 | 165.9 | 7.4 | 86.8 |
67 | 9.2 | 348.8 | 6.9 | 148.1 |
68A | 6.8 | 1980.5 | 6.5 | 1472.6 |
68B | 1.0 | >10,000 | 1.8 | >10,000 |
69 | 3.5 | 582.5 | 5.6 | 283.7 |
70 | 9.1 | 90.7 | 6.6 | 45.3 |
71 | 3.1 | 7851.0 | 4.1 | 3717.0 |
72 | 1.2 | >1000 | 3.6 | 567.3 |
73 | 7.5 | 29.4 | 9.0 | 26.7 |
74 | 7.4 | 149.2 | 8.9 | 99.3 |
75 | 6.3 | 345.3 | 3.4 | 146.2 |
76 | 2.0 | >10,000 | 2.3 | 4101.0 |
77 | 4.2 | 27.7 | 3.1 | 23.9 |
78 | 1.8 | >1000 | 3.6 | 537.0 |
79 | 8.3 | 209.2 | 10.2 | 102.7 |
80 | 8.8 | 50.5 | 7.5 | 21.5 |
81 | 6.4 | 62 | 7.1 | 26 |
因此,经鉴定,2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃(实施例42)和类似物在实体瘤细胞中是有效的半胱天冬酶级联激活剂和细胞凋亡诱导剂。
表II中总结了在本发明范围内的某些其它化合物:
表II.半胱天冬酶活性和效力
化合物 | T-47D比值 EC50(nM) | ZR-75-1比值 EC50(nM) | ||
2,7-二氨基-3-氰基-4-苯基-4H-色烯 | 6.3 | 5628 | 8.6 | 2883 |
2,7-二氨基-3-氰基-4-(3-碘苯基)-4H-色烯 | 4.8 | 33 | 5.1 | 18 |
2,7-二氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-色烯 | 4.2 | 30 | 3.5 | 15 |
2-氨基-3-氰基-7-羟基-4-(3,4,5-三甲氧基苯基)-4H-色烯 | 7.3 | 456 | 10.3 | 208 |
2-氨基-3-氰基-7-(2-甲基-丁酰基氨基)-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯 | 无活性 | 无活性 | 无活性 | 无活性 |
虽然已经充分地描述了本发明,但是本领域技术人员应当理解,可在不影响本发明范围或其任何实施方案的情况下,在广泛且等同的病症、制剂和其它参数范围内进行相同实施。本文所引用的所有专利、专利申请和出版物都全文引入本文以供参考。
序列表
<110>Cytovia,Inc.
Cai,Sui Xiong
Hong,Zhang
Songchun,Jiang
Richard,Storer
<120>用作半胱天冬酶激活剂和细胞凋亡诱导剂的取代的4-色烯和
类似物
<130>1735.063PC01
<150>Us 60/290,997
<151>2001-05-16
<160>1
<170>PatentIn version 3.1
<210>1
<211>4
<212>PRT
<213>人工序列
<220>
<221>MISC_FEATURE
<222>(1)..(1)
<223>Xaa可以是N-酰基天冬氨酸
<220>
<221>MISC_FEATURE
<222>(4)..(4)
<223>Xaa可以是天冬氨酸-N’-乙氧基羰基-R110
<400>1
Xaa Glu Val Xaa
1
Claims (46)
1.在动物中治疗对诱导细胞凋亡有反应的病症的方法,包括给需要这样的治疗的动物施用有效量的选自下列的化合物:
2-氨基-3-氰基-7-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-二羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-甲基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-8-氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(3-溴苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氰基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲氧基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氯苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-苯基-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(2,4-二甲氧基嘧啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(1,2,3,6-四氢苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-乙基氨基-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-甲氧基-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲氧基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲氧基-吡啶-3-基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲氧基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
3-氰基-2,7,8-三氨基-4-(3-甲氧基苯基)-4H-色烯;
3-氰基-2,7,8-三氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-6-氯-3-氰基-7-甲基-4-苯基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-7-二甲基氨基-4H-色烯;
3-氰基-4-(3-溴-4-羟基-5-甲氧基苯基)-2,7-二氨基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[4,5-b]吡喃;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-氰基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-三氟甲基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-甲基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(喹喔啉-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-甲基-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-7-吡咯烷-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-哌嗪-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-N-吗啉-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-吡咯-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基苯基)-4-甲基色烯;
2-氨基-3-氰基-4-苯基-4-甲基色烯;
2-氨基-3-氰基-4-(3-溴-4-磷酸-二哌啶盐-5-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-苯并硫吡喃;
2-氨基-3-氰基-4-苯基-1,4-二氢喹啉;
2-氨基-3-乙氧基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-甲基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-咪唑并[4,5-h]色烯;
3-氰基-4-(3-溴-4,5-二甲氧基苯基)-2-甲基氨基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-噻吩并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2,7-二氨基-3-氰基-4-苯基-4H-色烯;
2,7-二氨基-3-氰基-4-(3-碘苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-(2-甲基丁酰基氨基)-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-苯基丁酰氧基)-苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-甲基丁酰氧基)-苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
或其可药用盐或前药。
2.权利要求1的方法,其中所述化合物选自:
2-氨基-3-氰基-7-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(3-溴苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氰基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲氧基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氯苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-苯基-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(2,4-二甲氧基嘧啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(1,2,3,6-四氢苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-乙基氨基-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-甲氧基-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲氧基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲氧基-吡啶-3-基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲氧基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
3-氰基-2,7,8-三氨基-4-(3-甲氧基苯基)-4H-色烯;
3-氰基-2,7,8-三氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-噻吩并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2,7-二氨基-3-氰基-4-苯基-4H-色烯;
2,7-二氨基-3-氰基-4-(3-碘苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-(2-甲基丁酰基氨基)-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-苯基丁酰氧基)-苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-甲基丁酰氧基)-苯基)-4H-色烯;和
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;或其可药用盐或前药。
3.权利要求1的方法,其中所述化合物选自:
2-氨基-3-氰基-7-羟基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-二羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-甲基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-8-氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-6-氯-3-氰基-7-甲基-4-苯基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-7-二甲基氨基-4H-色烯;
3-氰基-4-(3-溴-4-羟基-5-甲氧基苯基)-2,7-二氨基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[4,5-b]吡喃;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[7,6-b]吡喃;2-氨基-3-氰基-(3,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-氰基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-三氟甲基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-甲基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(喹喔啉-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-甲基-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-7-吡咯烷-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-哌嗪-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-N-吗啉-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-吡咯-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基苯基)-4-甲基色烯;
2-氨基-3-氰基-4-苯基-4-甲基色烯;
2-氨基-3-氰基-4-(3-溴-4-磷酸-二哌啶盐-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-苯并硫吡喃;
2-氨基-3-氰基-4-苯基-1,4-二氢喹啉;
2-氨基-3-乙氧基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-甲基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-咪唑并[4,5-h]色烯;
3-氰基-4-(3-溴-4,5-二甲氧基苯基)-2-甲基氨基-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;和
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
或其可药用盐。
4.权利要求1的方法,其中所述动物是哺乳动物。
5.权利要求1的方法,其中所述病症是癌症。
6.权利要求5的方法,其中所述癌症选自:霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、恶性黑素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、覃样霉菌病、头或颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、成神经细胞瘤、横纹肌肉瘤、卡波西肉瘤、泌尿生殖器癌、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多、肾上腺皮质癌、皮肤癌和前列腺癌。
7.权利要求1的方法,其中所述病症是具有抗药性的癌症。
8.权利要求5或7的方法,其中还包括施用至少-种已知的癌症化疗剂或其可药用盐。
9.权利要求8的方法,其中所述已知癌症化疗剂选自白消安、顺铂、丝裂霉素C、卡铂、秋水仙碱、长春碱、紫杉醇、多西他赛、喜树碱、托泊替康、阿霉素、依托泊苷、5-氮杂胞苷、5-氟尿嘧啶、甲氨蝶呤、5-氟-2’-去氧尿苷、ara-C、羟基脲、硫鸟嘌呤、美法仑、苯丁酸氮芥、环磷酰胺、异环磷酰胺、长春新碱、米托胍腙、表柔比星、阿柔比星、博来霉素、米托蒽醌、依利醋铵、氟达拉滨、奥曲肽、视黄酸、他莫昔芬、Herceptin、Rituxan和阿拉诺新。
10.权利要求5或7的方法,其中还包括用放疗来治疗所述动物。
11.权利要求5或7的方法,其中所述化合物是在所述动物的癌症手术治疗之后施用。
12.权利要求1的方法,其中所述病症是自身免疫性疾病。
13.权利要求1的方法,其中所述病症是类风湿性关节炎。
14.权利要求1的方法,其中所述病症是炎症或炎性肠病。
15.权利要求1的方法,其中所述病症是皮肤病。
16.权利要求15的方法,其中所述病症是牛皮癣。
17.药物组合物,其中包含可药用赋形剂或载体和选自下列的化合物:
2-氨基-3-氰基-7-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-二羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-甲基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-8-氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(3-溴苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氰基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲氧基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氯苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-苯基-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(2,4-二甲氧基嘧啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(1,2,3,6-四氢苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-乙基氨基-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-甲氧基-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲氧基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲氧基-吡啶-3-基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲氧基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
3-氰基-2,7,8-三氨基-4-(3-甲氧基苯基)-4H-色烯;
3-氰基-2,7,8-三氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-6-氯-3-氰基-7-甲基-4-苯基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-7-二甲基氨基-4H-色烯;
3-氰基-4-(3-溴-4-羟基-5-甲氧基苯基)-2,7-二氨基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[4,5-b]吡喃;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-氰基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-三氟甲基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-甲基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(喹喔啉-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-甲基-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-7-吡咯烷-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-哌嗪-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-N-吗啉-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-吡咯-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基苯基)-4-甲基色烯;
2-氨基-3-氰基-4-苯基-4-甲基色烯;
2-氨基-3-氰基-4-(3-溴-4-磷酸-二哌啶盐-5-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-苯并硫吡喃;
2-氨基-3-氰基-4-苯基-1,4-二氢喹啉;
2-氨基-3-乙氧基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-甲基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-咪唑并[4,5-h]色烯;
3-氰基-4-(3-溴-4,5-二甲氧基苯基)-2-甲基氨基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-噻吩并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2,7-二氨基-3-氰基-4-苯基-4H-色烯;
2,7-二氨基-3-氰基-4-(3-碘苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-(2-甲基丁酰基氨基)-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-苯基丁酰氧基)-苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-甲基丁酰氧基)-苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
或其可药用盐或前药。
18.权利要求17的药物组合物,其中所述化合物选自:
2-氨基-3-氰基-7-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(3-溴苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氰基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲氧基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氯苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-苯基-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(2,4-二甲氧基嘧啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(1,2,3,6-四氢苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-乙基氨基-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-甲氧基-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲氧基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲氧基-吡啶-3-基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲氧基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
3-氰基-2,7,8-三氨基-4-(3-甲氧基苯基)-4H-色烯;
3-氰基-2,7,8-三氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-噻吩并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2,7-二氨基-3-氰基-4-苯基-4H-色烯;
2,7-二氨基-3-氰基-4-(3-碘苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-(2-甲基丁酰基氨基)-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-苯基丁酰氧基)-苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-甲基丁酰氧基)-苯基)-4H-色烯;和
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
或其可药用盐或前药。
19.权利要求17的药物组合物,其中所述化合物选自:
2-氨基-3-氰基-7-羟基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-二羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-甲基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-8-氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-6-氯-3-氰基-7-甲基-4-苯基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-7-二甲基氨基-4H-色烯;
3-氰基-4-(3-溴-4-羟基-5-甲氧基苯基)-2,7-二氨基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[4,5-b]吡喃;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[7,6-b]吡喃;2-氨基-3-氰基-(3,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-氰基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-三氟甲基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-甲基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(喹喔啉-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-甲基-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-7-吡咯烷-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-哌嗪-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-N-吗啉-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-吡咯-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基苯基)-4-甲基色烯;
2-氨基-3-氰基-4-苯基-4-甲基色烯;
2-氨基-3-氰基-4-(3-溴-4-磷酸-二哌啶盐-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-苯并硫吡喃;
2-氨基-3-氰基-4-苯基-1,4-二氢喹啉;
2-氨基-3-乙氧基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-甲基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-咪唑并[4,5-h]色烯;
3-氰基-4-(3-溴-4,5-二甲氧基苯基)-2-甲基氨基-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;和
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
或其可药用盐。
20.权利要求17的药物组合物,其中所述组合物还包含至少-种已知的癌症化疗剂或其可药用盐。
21.权利要求20的药物组合物,其中所述已知癌症化疗剂选自白消安、顺铂、丝裂霉素C、卡铂、秋水仙碱、长春碱、紫杉醇、多西他赛、喜树碱、托泊替康、阿霉素、依托泊苷、5-氮杂胞苷、5-氟尿嘧啶、甲氨蝶呤、5-氟-2’-去氧尿苷、ara-C、羟基脲、硫鸟嘌呤、美法仑、苯丁酸氮芥、环磷酰胺、异环磷酰胺、长春新碱、米托胍腙、表柔比星、阿柔比星、博来霉素、米托蒽醌、依利醋铵、氟达拉滨、奥曲肽、视黄酸、他莫昔芬、Herceptin、Rituxan和阿拉诺新。
22.权利要求17的药物组合物,其中所述赋形剂或载体选自糖类、淀粉糊、明胶、黄蓍胶、纤维素制备物、磷酸钙和聚乙烯吡咯烷酮。
23.权利要求22的药物组合物,其中所述赋形剂或载体选自乳糖、蔗糖、甘露醇和山梨醇。
24.权利要求17的药物组合物,其中所述赋形剂或载体是亲脂性溶剂。
25.权利要求24的药物组合物,其中所述亲脂性溶剂选自脂肪油、脂肪酸酯、聚乙二醇和石蜡烃。
26.权利要求24的药物组合物,其中所述亲脂性溶剂选自芝麻油、油酸乙酯、甘油三酯、聚乙二醇-400、聚氧乙烯蓖麻油和环糊精。
27.权利要求17的药物组合物,其中所述赋形剂或载体选自植物油、矿物油、白凡士林、支链脂肪、支链油、动物脂肪和高分子量醇(大于C12)。
28.权利要求17的药物组合物,其中所述赋形剂或载体是盐水溶液。
29.选自下列的化合物:
2-氨基-3-氰基-7-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-二羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-甲基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-8-氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-4-(3,5-二氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(3-溴苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氰基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲氧基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氯苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-苯基-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(2,4-二甲氧基嘧啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(1,2,3,6-四氢苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-乙基氨基-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-甲氧基-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2,7-二氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲氧基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲氧基-吡啶-3-基)-4H-色烯;
2-氨基-3-氰基-4-(5-甲氧基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
3-氰基-2,7,8-三氨基-4-(3-甲氧基苯基)-4H-色烯;
3-氰基-2,7,8-三氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-6-氯-3-氰基-7-甲基-4-苯基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-7-二甲基氨基-4H-色烯;
3-氰基-4-(3-溴-4-羟基-5-甲氧基苯基)-2,7-二氨基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[4,5-b]吡喃;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-氰基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-三氟甲基-苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-甲基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(喹喔啉-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-甲基-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-7-吡咯烷-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-哌嗪-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-N-吗啉-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-吡咯-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基-苯基-4-甲基色烯;
2-氨基-3-氰基-4-苯基-4-甲基色烯;
2-氨基-3-氰基-4-(3-溴-4-磷酸-二哌啶盐-5-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-苯并硫吡喃;
2-氨基-3-氰基-4-苯基-1,4-二氢喹啉;
2-氨基-3-乙氧基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-甲基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-咪唑并[4,5-h]色烯;
3-氰基-4-(3-溴-4,5-二甲氧基苯基)-2-甲基氨基-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-噻吩并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
2,7-二氨基-3-氰基-4-苯基-4H-色烯;
2,7-二氨基-3-氰基-4-(3-碘苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-(2-甲基丁酰基氨基)-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-苯基丁酰氧基)苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-甲基丁酰氧基)苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
或其可药用盐和前药。
30.权利要求29的化合物,其中所述化合物是2-氨基-3-氰基-7-甲氧基-4-(1,2,3,6-四氢苯基)-4H-色烯或其可药用盐或前药。
31.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-7-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-溴苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(3-氰基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-溴苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氰基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲氧基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-氯苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-甲基苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-硝基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-苯基-4H-色烯;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-亚甲二氧基-4-(3-甲氧基苯基)-4H-色烯;
3-氰基-2,7,8-三氨基-4-(3-甲氧基苯基)-4H-色烯;
3-氰基-2,7,8-三氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-苯基丁酰氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-(2-甲基丁酰氧基)-苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-苯基-4H-色烯;
2,7-二氨基-3-氰基-4-(3-碘苯基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-4-(3,4,5-三甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-(2-甲基丁酰基氨基)-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;和
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
或其可药用盐或前药。
32.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-7-羟基-4-(3-氰基苯基)-4H-色烯;
2-氨基-3-氰基-7,8-二羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氯苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-8-甲基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-羟基-8-氨基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(3-氟苯基)-4H-色烯;
2-氨基-3-氰基-7-氨基-4-(3,5-二氟苯基)-4H-色烯;
2-氨基-6-氯-3-氰基-7-甲基-4-苯基-4H-色烯;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-7-二甲基氨基-4H-色烯;
3-氰基-4-(3-溴-4-羟基-5-甲氧基苯基)-2,7-二氨基-4H-色烯;
2-氨基-7-溴-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-4H-色烯;
2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-7-氯-3-氰基-4H-色烯;
2-氨基-3-氰基-7-吡咯烷-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-哌嗪-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-N-吗啉-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-吡咯-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
2-氨基-3-氰基-7-二甲基氨基-4-(3-溴-4,5-二甲氧基苯基)-4-甲基色烯;
2-氨基-3-氰基-4-苯基-4-甲基色烯;和
2-氨基-3-氰基-7-氨基-8-羟基-4-(3-溴-4,5-二甲氧基苯基)-4H-色烯;
或其可药用盐或前药。
33.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-7-甲氧基-4-(3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-甲氧基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-7-乙基氨基-4-(5-甲基-3-吡啶基)-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-乙基氨基-4H-色烯;
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-7-甲氧基-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-色烯;
2,7-二氨基-3-氰基-4-(5-甲氧基-3-吡啶基)-4H-色烯;和
2-氨基-3-氰基-7-甲氧基-4-(5-甲氧基-3-吡啶基)-4H-色烯;
或其可药用盐或前药。
34.权利要求29的化合物,其中所述化合物是2-氨基-3-氰基-7-甲氧基-4-(2,4-二甲氧基嘧啶基)-4H-色烯,或其可药用盐或前药。
35.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-7-乙基-4H-吡咯并[2,3-h]色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-环丙基甲基-4H-吡咯并[2,3-h]色烯;和
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-7-(2-二乙基氨基-乙基)-4H-吡咯并[2,3-h]色烯;
或其可药用盐或前药。
36.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-4-(3,5-二氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氯苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3,5-二氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-氟苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(3-溴-4-磷酸-二哌啶盐-5-甲氧基苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-乙氧基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-甲基羧基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吲哚并[4,5-b]吡喃;或其可药用盐。
37.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-4-(3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-甲基-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-甲氧基-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;和
2-氨基-3-氰基-4-(5-溴-3-吡啶基)-4H-吲哚并[4,5-b]吡喃;
或其可药用盐或前药。
38.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[4,5-b]吡喃。
39.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3,4,5-三甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-硝基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;和
2-氨基-3-氰基-4-(3,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
或其可药用盐或前药。
40.权利要求29的化合物,其中所述化合物选自:
2-氨基-4-(3-溴-4-羟基-5-甲氧基苯基)-3-氰基-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-(3,5-二甲氧基苯基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(3-氰基-苯基)-4H-吲哚并[7,6-b]吡喃;和
2-氨基-3-氰基-4-(3-三氟甲基-苯基)-4H-吲哚并[7,6-b]吡喃;
或其可药用盐或前药。
41.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-咪唑并[4,5-h]色烯;和
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-咪唑并[4,5-h]色烯;
或其可药用盐或前药。
42.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-甲基-4H-咪唑并[4,5-h]色烯;和
2-氨基-4-(3-溴-4,5-二甲氧基-苯基)-3-氰基-9-甲基-4H-咪唑并[4,5-h]色烯;
或其可药用盐或前药。
43.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡唑并[2,3-h]色烯;和
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-吡唑并[2,3-h]色烯;
或其可药用盐或前药。
44.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-呋喃并[2,3-h]色烯;和
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-呋喃并[2,3-h]色烯;
或其可药用盐或前药。
45.权利要求29的化合物,其中所述化合物是2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基苯基)-4H-噻吩并[2,3-h]色烯;或其可药用盐或前药。
46.权利要求29的化合物,其中所述化合物选自:
2-氨基-3-氰基-4-(5-甲基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(5-氰基-吡啶-3-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-4-(喹喔啉-2-基)-4H-吲哚并[4,5-b]吡喃;
2-氨基-3-氰基-4-(6-甲基-吡嗪-2-基)-4H-吲哚并[7,6-b]吡喃;
2-氨基-3-氰基-7-甲氧基-4-(3-甲氧基苯基)-4H-苯并硫吡喃;
2-氨基-3-氰基-4-苯基-1,4-二氢喹啉;
3-氰基-4-(3-溴-4,5-二甲氧基苯基)-2-甲基氨基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-4-(3-溴-4,5-二甲氧基苯基)-3-氰基-9-甲基-4H-吡咯并[3,2-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4H-吡嗪并[2,3-h]色烯;
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-8-氧代-4,7,8,9-四氢咪唑并[4,5-h]色烯;
2-氨基-3-氰基-4-(3-甲氧基苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;和
2-氨基-3-氰基-4-(3-溴-4,5-二甲氧基-苯基)-4,7,8,9,10-五氢-8,9-二氧基吡嗪并[2,3-h]色烯;
或其可药用盐或前药。
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US29099701P | 2001-05-16 | 2001-05-16 | |
US60/290,997 | 2001-05-16 |
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EP (1) | EP1392683B1 (zh) |
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CN (1) | CN100564377C (zh) |
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-
2002
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- 2002-05-16 JP JP2002589478A patent/JP4593880B2/ja not_active Expired - Fee Related
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Cited By (8)
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CN103328463A (zh) * | 2010-11-12 | 2013-09-25 | 德国癌症研究中心 | 作为Wnt通路拮抗剂的色烯衍生物及其类似物 |
CN107235954A (zh) * | 2010-11-12 | 2017-10-10 | 德国癌症研究中心 | 作为Wnt通路拮抗剂的色烯衍生物及其类似物 |
CN103328463B (zh) * | 2010-11-12 | 2018-04-03 | 德国癌症研究中心 | 作为Wnt通路拮抗剂的色烯衍生物及其类似物 |
CN104860915B (zh) * | 2015-04-10 | 2016-11-23 | 昆明理工大学 | 一种4h-4-芳基苯并吡喃类化合物的制备方法 |
CN108715589A (zh) * | 2018-06-19 | 2018-10-30 | 华侨大学 | 一种用作caspase-3激活剂的香豆素类衍生物及其应用 |
CN108715589B (zh) * | 2018-06-19 | 2021-04-20 | 华侨大学 | 一种用作caspase-3激活剂的香豆素类衍生物及其应用 |
CN109134493A (zh) * | 2018-09-19 | 2019-01-04 | 浙江师范大学 | 一种具有抗菌活性的2-氧代色烯并噻吩衍生物及其合成方法和应用 |
CN110590793A (zh) * | 2019-08-30 | 2019-12-20 | 浙江工业大学 | 一种2,4-二苯基吡啶并[3,2-c]香豆素的合成方法 |
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US7053117B2 (en) | 2006-05-30 |
ES2337558T3 (es) | 2010-04-27 |
CA2447010C (en) | 2011-08-02 |
WO2002092594A8 (en) | 2004-06-24 |
ATE450531T1 (de) | 2009-12-15 |
DE60234589D1 (de) | 2010-01-14 |
CA2447010A1 (en) | 2002-11-21 |
CN100564377C (zh) | 2009-12-02 |
JP4593880B2 (ja) | 2010-12-08 |
EP1392683A1 (en) | 2004-03-03 |
AU2009200374B2 (en) | 2011-10-27 |
WO2002092594A1 (en) | 2002-11-21 |
JP2004530692A (ja) | 2004-10-07 |
EP1392683B1 (en) | 2009-12-02 |
EP1392683A4 (en) | 2005-10-26 |
US20060035925A1 (en) | 2006-02-16 |
AU2009200374A1 (en) | 2009-03-26 |
US20030065018A1 (en) | 2003-04-03 |
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