CN1128797C - 抑制法呢基转移酶的经n-或c-键结的咪唑类取代的1,8-相并合的喹啉酮衍生物类 - Google Patents
抑制法呢基转移酶的经n-或c-键结的咪唑类取代的1,8-相并合的喹啉酮衍生物类 Download PDFInfo
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- CN1128797C CN1128797C CN98803064A CN98803064A CN1128797C CN 1128797 C CN1128797 C CN 1128797C CN 98803064 A CN98803064 A CN 98803064A CN 98803064 A CN98803064 A CN 98803064A CN 1128797 C CN1128797 C CN 1128797C
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- alkyl
- phenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
Abstract
本发明为有关下式化合物,其药学上可接受的酸加成盐及立体化学性异构物形式。式中,虚线表示任选的健;X为氧或硫;-A-为该式的二价基;R1及R2各独立为氢、羟基、卤基、氰基、C1-6烷基、三卤甲基、三卤甲氧基、C2-6烯基、C1-6烷氧基、羟基C1-6烷氧基、C1-6烷氧基C1-6烷氧基、C1-6烷氧羰基、氨基C1-6烷氧基、单-或二(C1-6烷基)氨基C1-6烷氧基、Ar、Ar-C1-6烷基、Ar-氧基、Ar-C1-6烷氧基;或于邻接位置的R1及R2连合形成二价基;R3及R4各独立为氢、卤基、氰基、C1-6烷基、C1-6烷氧基、Ar-氧基、C1-6烷硫基、二(C1-6烷基)氨基、三卤甲基、三卤甲氧基;或于邻接位置的R3及R4连合形成二价基;R5为经氢或C1-6烷基取代的咪唑基;C1-6烷氧基羰基或Ar1、或为式-OR10、-SR10、-NR11R12的基团;R6为氢、羟基、卤基、氰基、任选经取代的C1-6烷基、C1-6烷氧羰基或Ar;或式-O-R7、-S-R8、-N-R8R9的基;及Ar为任选经取代的苯基;具法呢基转移醇抑制活性;其制备法、含其的组合物及其作药剂的用途。
Description
发明说明
本发明为有关新颖的1,8-连接的2-喹啉酮(quinolinone)衍生物、其制备法、包括该新颖化合物的药剂组合物及这些化合物作药剂的用途、以及使用该化合物的治疗方法。
致癌基因时常编码讯息转导途径的蛋白质成分而刺激细胞生长及有丝分裂。致癌基因于培育细胞中表现,导致细胞转形,特征在于细胞能生长于软琼脂,且细胞浓厚聚集生长,缺乏非转形细胞展现的接触性抑制。有些致癌基因的突变及/或过度表现常带给人类癌症。已知ras乃致癌基因的一特定组员,已于哺乳类、鸟类、昆虫类、软体动物类、植物类、真菌类及酵母菌类中鉴别出来。哺乳类ras的致癌基因组群由三个主要组员(“等型”):H-ras、K-ras及N-ras致癌基因构成。这些ras致癌基因编码密切相关的蛋白质,一般已知如p21 ras。一旦与质膜附着,突变型或致癌型的p21 ras会提供恶性肿瘤细胞转形及难控制生长的讯息,为达如此转形的可能性,则p21 ras致癌蛋白之前体必须对位于羧基末端四肽的半胱氨酸残基,进行酶催化性法呢基化反应。因此,催化如此修饰的酶(即法呢基蛋白转移酶)的抑制剂,会防止p21 ras的膜附着,且阻止经ras-转形的肿瘤异常生长。于是,此项技艺承认法呢基转移酶抑制剂极有用作由ras助成转形的肿瘤的抗癌剂。
由于ras的突变致癌型时常发现于许多人类癌症,最常见于大于50%的结肠癌及胰腺癌(Kohl等著,科学(Science),260卷,1834页-1837页,1993年),已提示法呢基转移酶抑制剂对抗此等类型癌症非常有用。
于EP-3,371,564号中,记述经(1H-唑-1-基甲基)取代的喹啉及喹啉酮衍生物会抑制视黄酸的原生质消除作用。某些此等化合物亦具有抑制黄体酮形成雄激素的能力及/或芳香酶复合物的抑制作用。
意外地,发现全部在具N-或C-键结的咪唑的1,8-连接的2-喹啉酮部分的第4位具苯基取代基的本新颖化合物,显示法呢基蛋白质转移酶的抑制活性。
-CH=CH- (a-1),
-CH2-CH2- (a-2),
-CH2-CH2-CH2- (a-3),
-CH2-O- (a-4),
-CH2-CH2-O- (a-5),
-CH2-S- (a-6),
-CH2-CH2-S- (a-7),
-CH=N- (a-8),
-N=N- (a-9),或
-CO-NH- (a-10);
式中,任选的-个氢原子可以C1-4烷基或Ar1取代;R1及R2各独立为氢、羟基、卤基、氰基、C1-6烷基、三卤甲基、三卤甲
氧基、C2-6烯基、C1-6烷氧基、羟基C1-6烷氧基、C1-6烷氧基C1-6烷氧
基、C1-6烷氧羰基、氨基C1-6烷氧基、单一或二(C1-6烷基)氨基C1-6
烷氧基、Ar2、Ar2-C1-6烷基、Ar2-氧基、Ar2-C1-6烷氧基;或于邻接位置的R1及R2连合形成下式的二价基,
-O-CH2-O- (b-1),
-O-CH2-CH2-O- (b-2),
-O-CH=CH- (b-3),
-O-CH2-CH2- (b-4),
-O-CH2-CH2-CH2- (b-5),或
-CH=CH-CH=CH- (b-6);R3及R4各独立为氢、卤基、氰基、C1-6烷基、C1-6烷氧基、Ar3-氧
基、C1-6烷硫基、二(C1-6烷基)氨基、三卤甲基、三卤甲氧基、
或于邻接位置的R3及R4连合形成下式的二价基,
-O-CH2-O- (c-1),
-O-CH2-CH2-O- (c-2),或
式中,R13为氢、卤基、Ar4、C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷氧基、C1-6烷硫基、氨基、C1-6烷氧羰基、C1-6烷基S(O)C1-6烷基或C1-6烷基S(O)2C1-6烷基;
R14为氢、C1-6烷基或二(C1-4烷基)胺磺酰基;R6为氢、羟基、卤基、C1-6烷基、氰基、卤基C1-6烷基、羟基C1-6烷
基、氰基C1-6烷基、氨基C1-6烷基、C1-6烷氧基C1-6烷基、
C1-6烷硫基C1-6烷基、胺羰基-C1-6烷基、C1-6烷氧羰基C1-6
烷基、C1-6烷羰基C1-6烷基、C1-6烷氧羰基、单-或二(C1-6烷
基)氨基C1-6烷基、Ar5、Ar5-C1-6烷氧基C1-6烷基、或下式
的基,
-O-R7 (e-1),
-S-R7 (e-2),
-N-R8R9 (e-3);式中R7为氢、C1-6烷基、C1-6烷羰基、Ar6、Ar6-C1-6烷基、C1-6烷
氧羰基C1-6烷基、或下式的基:Alk-OR10或-Alk-NR11R12;R8为氢、C1-6烷基、Ar7或Ar7-C1-6烷基;R9为氢、C1-6烷基、C1-6烷羰基、C1-6烷氧羰基、C1-6烷氨羰基、Ar8、
Ar8-C1-6烷基、C1-6烷羰基C1-6烷基、Ar8-羰基、Ar8-C1-6烷
羰基、氨羰羰基、C1-6烷氧基C1-6烷羰基、羟基、C1-6烷氧基、
氨羰基、二(C1-6烷基)氨基C1-6烷羰基、氨基、C1-6烷氨基、
C1-6烷羰氨基、或下式的基:
-Alk-OR10或Alk-NR11R12;
式中,Alk为C1-6亚烷基;R10为氢、C1-6烷基、C1-6烷羰基、羟基C1-6烷基、Ar9或Ar9-C1-6
烷基;R11为氢、C1-6烷基、C1-6烷羰基、Ar10或Ar10-C1-6烷基;R12为氢、C1-6烷基、Ar11或Ar11-C1-6烷基;及Ar1至Ar11各独立选
自苯基;或经卤基、C1-6烷基、C1-6烷氧基或三氟甲基取代的苯
基。
R13亦可键接至式(d-1)咪唑环的一个氮原子上。如此则键接至氮的R13,意义局限成氢、Ar4、C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷氧羰基、C1-6烷基S(O)-C1-6烷基或C1-6烷基S(O)2C1-6烷基。
于前文定义及后述,卤基一般指氟基、氯基、溴基及碘基;C1-4烷基定义成直链或具支链的1至4个碳原子的饱和烃基,例如甲基、乙基、丙基、丁基、1-甲基乙基、2-甲基丙基等;C1-6烷基包含C1-4烷基及其具5至6个碳原子的高级同系物,例如戊基、2-甲基丁基、己基、2-甲基戊基等;C1-6亚烷基定义成二价的直链或具支链的1至6个碳原子的饱和烃基,例如亚甲基、1,1-亚乙基、1,3-丙基、1,4-亚丁基、1,5-亚戊基、1,6-亚己基及其支链异构物;C2-6烯基定义成直链或具支链的2至6个碳原子和一个双键的烃基,例如乙烯基、2-丙烯基、3-丁烯基、2-戊烯基、3-戊烯基、3-甲基-2-丁烯基等。“S(O)”词语指亚砜,而“S(O)2”词语指砜。
上述的医药上可接受的酸加成盐意指式(I)化合物能形成的具治疗活性的无毒性酸加成盐型。具碱性质的式(I)化合物,可由该碱型以适当的酸处理而转化成其药学上可接受的酸加成盐。适当的酸包括:例如,无机酸类诸如氢卤酸,如盐酸或氢溴酸;硫酸;硝酸;磷酸等类似酸;或有机酸类诸如乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸(即丁二酸)、顺丁烯二酸、反丁烯二酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对-甲苯磺酸、环己氨基磺酸(cyclamic acid)、柳酸、对-氨基柳酸、帕摩酸(pamoic acid)及类似酸。
酸加成盐词语又包括:式(I)化合物能形成的水合物及溶剂加成型。此等型之实例为例如水合物、醇化物等。
前述所用式(I)化合物的立体化学性异构物形式词语,定义成式(I)化合物可能形成的由相同序列键结的相同原子构成,但具有不能互换的不同三度空间构造的所有可能化合物。除非另有指明,否则此化合物的化学命名涵括该化合物可具有的所有可能的立体化学性异构物形式的混合物,该混合物可含有该化合物的基本分子构造的所有非镜像异构物及/或镜像异构物,式(I)化合物的所有立体化学性异构物形式,无论是纯粹型或彼此成混合物,均包涵于本发明的范围中。
某些式(I)化合物也可以其互变异构物形式存在。此等型虽然于上式中未明示,但仍包含于本发明的范围中。
式(I)化合物根据本领域已知的转化反应彼此转化;或需要的话,式(I)化合物转化成其药学上可接受的酸加成盐,或相反地,式(I)化合物的酸加成盐用碱转化成其自由碱型;及,需要的话,制备成其立体化学性异构物形式。
无论何处,-A-为式(a-4)、(a-5)、(a-6)、(a-7)或(a-8)的二价基时,于该二价基中的CH2或CH部分较佳连接至式(I)化合物或式(II)、(IV)、(VI)、(VII)的中间体的2-喹啉酮部分上的氮原子。
于后文中所用的“式(I)化合物”词语,意指也包含药学上可接受的酸加成盐及所有的立体异构物形式。
一组有益的化合物为那些式(I)化合物构成,式中,满足一或多个条件,如下述:a)虚线表示任选的键;b)X为O或S;c)R1及R2各独立选自氢、卤基、C1-6烷基、C1-6烷氧基、三卤甲基或三卤甲氧基;特别为氢、卤基或C1-4烷基;d)R3及R4一起各独立选自氢、卤基、C1-6烷基、C1-6烷氧基、三卤甲基或三卤甲氧基;特别为氢、卤基或C1-4烷基或C1-4烷氧基;e)R5为式(d-1)的基(式中R13为氢或C1-6烷基);或R5为式(d-2)的基(式中R13为氢或C1-6烷基,及R14为氢或C1-6烷基);f)R6为氢、羟基、卤基C1-6烷基、羟基C1-6烷基、氰基C1-6烷基、C1-6烷氧羰基C1-6烷基、或下式的基:NR8R9,式中R8为氢或C1-6烷基,及R9为氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6烷羰基;尤其R6为氢、羟基、卤基或氨基;g)-A-为(a-1)、(a-2)、(a-3)、(a-4)、(a-5)、(a-8)、(a-9)或(a-10)。
一组特定化合物由那些式(I)化合物构成,式中虚线表示键;X
为O或S;R2为氢及R1为卤基、较佳为氯基,特别为3-氯基;
R4为氢及R3为卤基,较佳为氯基,特别为4-氯基;R5为式
(d-1)的基(式中R13为氢或C1-4烷基);及R6为氢。
另一组特定化合物由那些式(I)化合物构成,式中虚线表示键;X为O或S;R2为氢及R1为卤基,较佳为氯基,特别为3-氯基;及R4为氢和R3为卤基,较佳为氯基,特别为4-氯基;R5为式(d-2)的基(式中R13为氢或C1-4烷基,及R14为氢或C1-4烷基);R6为氢、羟基、卤基或氨基。
较佳的化合物为那些式(I)化合物,式中虚线表示键;X为氧;R1为3-氯基;R2为氢;R3为4-氯基;R4为氢;R5为式(d-1)的基(式中R13为氢或C1-4烷基);R6为氢;及-A-为(a-1)、(a-2)或(a-3)。
其它较佳的化合物为那些式(I)化合物,式中虚线表示键;X为氧;R1为3-氯基;R2为氢;R3为4-氯基;R4为氢;R5为式(d-2)的基(式中R13为氢及R14为C1-4烷基);R6为氨基;及-A-为(a-1)、(a-2)或(a-3)。
最佳的式(I)化合物为
7-(3-氯苯基)-9-〔(4-氯苯基)-1H-咪唑-1-基甲基〕-2,3-二氢-1H,5H-苯并〔ij〕喹嗪-5-酮,
7-(3-氯苯基)-9-〔(4-氯苯基)-1H-咪唑-1-基甲基〕-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-酮,
8-〔氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基〕-6-(3-氯苯基)-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-酮,及
8-〔氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基〕-6-(3-氯苯基)-2,3-二氢-1H,5H-苯并〔ij〕喹嗪-5-酮;
其立体异构物形式及其药学上可接受的酸加成盐。
式(I)化合物〔式中R6为羟基及R5为式(d-2)的基(式中R14为C1-6烷基)〕,该化合物指式(I-a-1)化合物,可使式(II)中间体酮与式(III-1)中间体反应制备。该反应需合宜的强碱(例如丁基锂)于合宜的溶剂(例如四氢呋喃)中,及存在合宜的硅烷衍生物)例如三乙基氯硅烷。于进行处理步骤期间,中间体硅烷衍生物予以水解。其它具与硅烷衍生物类似的保护基的步骤也可进行。
而且,式(I)化合物〔式中R6为羟基及R5为式(d-2)的基(式中R14为氢)〕,该化合物指式(I-a-2)化合物,可使式(II)中间体酮与式(III-2)中间体反应制备。式中PG为保护基例如磺酰基,诸如二甲胺磺酰基,可于加成反应之后移除。该反应如制备式(I-a-1)化合物的类似方式进行,接着移除保护基PG,获得式(I-a-2)化合物。
式(I-g)化合物,定义成式(I)化合物而式中R5表示式(d-1)的基,可使式(XVIII)中间体以式(XVII)中间体进行N-烷化而制备,式中W为合适的离去基,例如氯基、溴基、甲磺酰氧基或苯磺酰氧基。此反应可于反应惰性溶剂例如乙腈中,及视情况在合适碱例如碳酸钠、碳酸钾或三乙胺的存在下进行。搅拌可增加反应速度。反应一般可于室温至反应混合物的回流温度间进行。
而且,式(I-g)化合物可由使式(XIX)中间体(式中,Y为碳或硫)例如1,1′-羰基二咪唑,以式(XVI)中间体进行N-烷化而制备,
该反应一般于反应惰性溶剂(例如四氢呋喃)中,视情况在碱(例如氢化钠)的存在下,于室温至反应混合物的回流温度间进行。
式(I-g)化合物的制备,可依EP-0,293,978号第12页33行至第13页20行所述,使式(XVII)中间体与氨反应,接着以异硫氰酸盐处理。
式(I-a)化合物可转化成式(I-b)化合物〔定义成式(I)化合物而式中R6为氢〕,使式(I-a)化合物于合适的还原条件下进行,例如于有甲酰胺存在的乙酸中搅拌。
再则,式(I-a)化合物可转化成式(I-c)化合物(式中R6为卤基),使式(I-a)化合物与合适的卤化剂(例如亚硫酰氯或三溴化磷)相反应。接着,式(I-c)化合物以式H-NR8R9试剂,于反应惰性溶剂中处理,获得式(I-d)化合物。
式(I-f)化合物(定义成式(I)化合物而式中X为硫)的制备,可使对应的式(I-e)化合物(定义成式(I)化合物而式中X为氧)与试剂〔如五硫化磷或劳桑试剂(lawesson′s reagent)〕于合适溶剂(例如吡啶)中相反应。
式(II-b)中间体(定义成式(II)中间体而虚线表示键)的制备,可使式(II-a)中间体(定义成式(II)中间体而式中虚线不表示键),依此领域已知的氧化法例如以溴于合适溶剂例如溴苯中处理,或以碘于乙酸及乙酸钾的存在下处理,进行氧化。
该氧化反应可产生副产物(式中二价基-A-经氧化)。例如,式(II-a)中间体(式中-A-为(a-2))经氧化可产生式(II-b)中间体(式中-A-为(a-1))。
式(XVI)中间体(式中R6为氢)(该化合物以式(XVI-a)表示)的制备,可使式(II)中间体与合适的还原剂(例如硼氢化钠)于合适溶剂(例如甲醇)中相反应。或则,式(XVI)中间体可转化成式(XVII)中间体(式中R6为氢) (该化合物以式(XVII-a)表示),使(XVI-a)以合适试剂(例如甲磺酰氧氯)或卤化试剂(例如POCl3或SOCl2)处理。
或者,式(II-a)中间体可由二步骤合成。使式(IV)中间体于聚磷酸(PPA)的存在下进行环化,接着所得中间体(VI)以式(VIII)中间体,于PPA的存在下处理。该二步骤合成可由“单槽”合成法进行,需要的话,式(VI)中间体可于式(V)中间体相反应之前,予以分离及纯化。
式(IV)中间体的制备,可使式(VIII)中间体(式中X为氧或硫及Z为羟基或卤基),以式(VII)中间体于反应惰性溶剂(例如二氯甲烷)中,及碱(例如三乙胺)的存在下进行处理。同时于反应期间回收所产生的酸。
式(II-b-1)中间体(乃式(II-b)中间体而式中X为氧及-A′-为式(a-4)或(a-5)的二价基)的制备,由式(IX)中间体起始。该中间体(IX)制备时,一般以此项技艺已知的对应酮予以保护。式(IX)中间体与式(X)中间体,于碱(例如氢氧化钠)存在的合适溶剂(例如醇,如甲醇)中一齐搅拌。所得式(XI)中间体转化成式(XII)中间体,于合适试剂(例如酸,如TiCl3)的存在下,及水的存在下进行;或于酸性条件下及合适的催化剂(如铂-碳)的存在下进行氢化反应;及以乙酸酐接续处理。式(XII)中间体于碱(例如叔丁氧钾)的存在下进行闭环反应,接着进行水解,获得式(XIII)中间体。式(XVIII)中间体以合适剂(例如三溴化硼)处理,使甲氧基转化成羟基后,式(XIV)中间体以式(XV)中间体(式中A′为式(a-4)或(a-5)的二价基)处理,获得式(II-b-1)中间体。
式(I)化合物及某些中间体于构造上具有至少一个立体中心。立体中心以R或S构型存在。
由上述方法制备的式(I)化合物,一般为镜像异构物的消旋混合物,可依此项技艺已知的解析程序彼此分离,式(I)的消旋混合物可与适当的非对称酸相反应,而转化成对应的非镜像构型盐。该非镜像构型盐接着予以分离,例如进行选择性或分级结晶,则镜像物由碱释出。分离式(I)化合物的镜像异构物形式的另一方式,包含用非对称固定相的液态层析术,该纯立体化学异构的型也可衍生自适当起始物的对应纯立体化学性异构物形式,但是反应须以立体专一性方式发生。若需要特定的立体异构物,则该化合物较佳以立体专一性制备法合成。这些方法用镜像异构性纯起始物较有利。
式(I)化合物,其医药上可接受的酸加成盐及其立体异构物形式,由药理实例C-1及C-2的结果证明,能抑制法呢基蛋白质转移酶(FPTase)而具有价值的药理性质。
再则,相信式(I)化合物(式中R5为式(d-2)的基)也能抑制香叶草基香叶草基转移酶(GGTase)。
本发明提供一种细胞(包含转形细胞)异常生长的抑制方法,即使用有效量的本发明化合物。以控制细胞的不正常成长,细胞异常生长指细胞的生长不依循正常规则机制(如失去接触性抑制)。这包含下述细胞的异常生长:(1)表现活化ras致癌基因的肿瘤细胞(肿瘤);(2)肿瘤细胞,其中另一基因致癌性突变结果,使得ras蛋白质经活化;(3)发生异常ras活化的其它增生性疾病的良性及恶性细胞。况且文献中已经建议,ras臻癌基因不仅通过对肿瘤细胞生长的直接影响,也间接地,即促进肿瘤诱发的血管生成,而于体内帮助肿瘤生长(Rak.J.等著,癌症研究(Cancer Research),55期,4575-4580页,1995年)。因此,具药理性目标的突变ras致癌基因,相信能由抑制肿瘤诱发的血管生成,而预期抑制体内的实体肿瘤生长。
本发明也提供一种将有效量的本发明化合物给予需此治疗的个体如哺乳类(更特别为人类)以抑制肿瘤生长的方法。尤其,本发明提供一种通过给予有效量的本发明化合物以抑制表现活化ras致癌基因的肿瘤成长的方法。可受抑制的肿瘤实例(但不限于)肺癌(如腺癌)、胰腺癌(例如胰腺癌,诸如外分泌性胰腺癌)、结肠癌(例如结肠直肠腺癌,诸如结肠腺癌及结肠腺瘤)、淋巴造血性肿瘤(如急性淋巴球性白血病、B-细胞淋巴瘤、布金特氏淋巴瘤(Burkitt′s lymphoma)、骨髓白血病(例如急性骨髓白血病(AML))、甲状腺滤泡性癌、脊髓发育不良征候群(MDS)、间叶起端的肿瘤(如纤维肉瘤及横纹肌肉瘤)、黑色瘤、畸胎瘤、神经母细胞瘤、神经胶瘤、皮肤的良性肿瘤(如角质棘皮瘤)、乳癌、肾脏癌、卵巢癌、膀胱癌及表皮癌。
本发明也提供一种良性及恶性的增生性疾病的抑制方法,其中基因致癌性突变结果使得ras蛋白质异常地被活化即ras基因本身未经突变活化成致癌基因型,而达该抑制情形要将有效量的本文化合物给予需此治疗的个体。例如,良性增生性失调的纤维神经瘤病,或由于酪胺酸激酶致癌基因突变或过度表现使得ras活化的肿瘤,均可由本发明化合物予以抑制。
于是,本发明揭示用作药剂的式(I)化合物,及以这些式(I)化合物制造治疗一或多种上述病况的药剂的用途。
就其有用的药理性质而言,目标化合物可调配成适于约药目的的各种医药剂型。
为制备本发明的药理组合物,作有效成分的有效量特定化合物(碱或酸加成盐型),与药学上可接受的载剂密切混合,此载剂依所要使用的制剂形式而成各种剂型。这些药剂组合物较佳依经口、直肠、经皮或非经肠注射给药而成合适的单位剂型。例如,制备口服剂型时,若成口服液体制剂例如悬浮剂、浆液剂、酏液剂及溶液剂,则可用任何常用的医药介质,例如水、二醇类、油类、醇类等;或成粉剂、丸剂、胶囊剂及锭剂,则用固体载剂例如淀粉、糖、高岭土、润滑剂、粘合剂、崩解剂等。由于易于给药,以片剂及胶囊剂为最有利的口服单位剂型,则显然使用固体药剂载剂。制备非经肠组合物时,虽有其它成分,载剂仍常包括,至少大部分是,无菌水,以助溶解。制备注射溶液剂时,载剂包括盐水溶液、葡萄糖溶液、或盐水及葡萄糖溶液的混合液。制备注射悬浮剂时,可用适当的液体载剂、悬浮剂等。制备经皮投予的组合物时,载剂视情况包括渗透剂、增强剂及/或适当的湿润剂,视情况与任何性质的占较少比例的适当添加剂混合,这些添加剂对皮肤不引起显著的劣化。该添加剂可帮助投至皮肤及/或有益于制备所要的组合物。这些组合物可用各种方式投予,例如成经皮贴布、点剂、软膏方式投予。尤其使上述药剂组合物调配成容易投予及剂量均匀的单位剂型较有利。于本文的说明书及权利要求书中,所用的单位剂型指适宜作单位剂型的物理分立单位,各单位含有经计算能产生所要治疗效果的预定量活性成分以及所需的药剂剂量。单位剂型的实例为片剂(包括核心或涂覆片剂)、胶囊剂、丸剂、粉包剂、糯米纸囊剂、注射溶液剂或悬浮剂、茶匙剂、汤匙剂等,及其分离的多倍剂量。
熟悉此项技艺的人士容易自后述测试结果决定出有效量,一般而言,预料有效量为0.01毫克/千克至100毫克/千克体重,特别为0.05毫克/千克至10毫克/千克体重,所需的剂量适宜以2、3、4或多次细分剂量,于全天里合适的间隔时间投予。该细分剂量可调配成单位剂型,例如每单位剂型含有活性成分0.5至500毫克,特别是1毫克至200毫克。
下述实例仅用以说明本发明。试验部分
后文“ACN”意指乙腈、“THF”意指四氢呋喃,“DIPE”意指二异丙醚,“DCM”意指二氯甲烷及“DMF”意指N,N-二甲基甲酰胺。
于某些式(I)化合物中,立体化学性绝对构型未经试验决定。在此情况下,则就立体化学性异构物形式,首先分离者称作“A”而其次分离者称作“B”,没有进一步指出真实的立体化学性构型。A.中间体的制备 实例A.1
于室温加三乙胺(9.2毫升)至二氢吲哚(20克)于DCM(200毫升)的溶液中,混合物经冷却至5℃。滴加间-氯基肉桂酰氯(40克)于DCM(100毫升)的溶液,混合物于室温搅拌48小时。加水,有机层予以倾析、以水洗涤、使之干燥、过滤移除及蒸发。残物以硅胶管柱层析(溶离液:环己烷/乙酸乙酯90/10)进行纯化,获得41克(73%)1-〔3-(3-氯苯基)-1-氧代-2-丙烯基〕-2,3-二氢-1H-吲哚(中间体37号)。
依此类似方式,合成得1-〔3-(3-氯苯基)-1-氧代-2-丙烯基〕-1,2,3,4-四氢喹啉(中间体38号)。实例A.2
中间体37号(40克)及聚磷酸(350克)于140℃搅拌加热16小时。加4-氯苯甲酸(44克),溶液于140℃搅拌加热2小时又30分钟。混合物经冷却至80℃,小心加入冰,混合物升至室温。沉淀物经过滤移除,以水洗涤及以氨水溶液调成碱性。沉淀物以DCM处理及过滤移除。有机层使之干燥、予以过滤及蒸发。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH 99.5/0.5至99/1)进行纯化,获得12克(20%)(±)-8-(4-氛苯甲酰基)-6-(3-氯苯基)-1,2,5,6-四氢-4H-吡咯并(3,2,1-ij)喹啉-4-酮(中间体11号)。
依此类似方式,合成得(±)-9-(4-氯苯甲酰基)-7-(3-氯苯基)-2,3,6,7-四氢-1H,5H-苯并〔ij〕喹嗪-5-酮(中间体8号)。实例A.3
溴(4.2毫升)于溴苯(80毫升)的混合物,于室温滴加至中间体11号(34.2克)于溴苯(300毫升)的溶液。混合物经搅拌回流过夜。混合物冷却至室温,以氨水溶液调成碱性。溶剂予以蒸发。残物于DCM及水间分配。有机层予以分离、使之干燥及过滤,溶剂予以蒸发。残物以硅胶管柱层析(溶离液:DCM)进行纯化,收集2个溶离份,获得16克8-(4-氯苯甲酰基)-6-(3-氯苯基)-1,2-二氢-4H-吡咯并(3,2,1-ij)喹啉-4-酮(中间体24号)及2.1克(6.2%)8-(4-氯苯甲酰基)-6-(3-氯苯基)-4H-吡咯并(3,2,1-ij)喹啉-4-酮(中间体25号)实例A.4
中间体(9号)(20.9克)、碘(32.8克)及乙酸钾(19克)于乙酸(150毫升)的混合物,于130℃搅拌3天。混合物倒出于冰及NaHSO3上持温,以DCM萃取。有机层予以分离、使之干燥及过滤,溶剂经蒸发至干。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH=99/1至97/3)进行纯化,收集纯溶离份,溶剂予以蒸发。残物以乙醚处理,予以过滤及使之干燥,获得16.9克(81%)8-(4-氯苯甲酰基)-1,2-二氢-6-苯基-4H-吡咯并(3,2,1-ij)喹啉-4-酮(中间体21号)。实例A.5
a)(4-氯苯基)(3-甲氧基-4-硝苯基)甲酮(40.7克)、1,2-乙二醇(31.2毫升)及4-甲苯磺酸(5.31克)于甲苯(320毫升)的混合物,以迪安-斯塔克设备(Dean-Stark)予以搅拌及回流。混合物以K2CO3(10%)洗涤及以DCM萃取。有机层予以分离、使之干燥及过滤,溶剂予以蒸发。残物自DIPE中结晶析出。沉淀物经过滤移除及使之干燥,获得22.48克(50.4%)2-(4-氯苯基)-2-(3-甲氧基-4-硝苯基)-1,3-二氧戊环(中间体39号)。
b)中间体(39号)(22.48克)及3-氯苯乙腈(15毫升)加至氢氧化钠(11.25克)于甲醇(91毫升)的溶液。混合物经搅拌回流24小时。加冰水。沉淀物经过滤移除,以水及乙醇洗涤,使之干燥。残物以硅胶管柱层析(溶离液:CH2Cl2/环己烷60/40)进行纯化。收集纯溶离份,溶剂予以蒸发,获得8.5克(27.3%)3-(3-氯苯基)-5-〔2-(4-氯苯基)-1,3-二氧戊环-2-基〕-7-甲氧基-2,1-苯并异噁唑(中间体40号)。
c)中间体(40号)(14克)于浓HCl(3.5毫升)及THF(140毫升)的混合物,在噻吩于甲醇(0.35毫升)的10%溶液存在下,以铂-碳(5%;1.4克)作催化剂,于2.4×105(帕)(2.4巴)压力下,进行氢化6小时。吸收适量H2后,催化剂经赛力特硅藻土(celite)过滤,而滤液经蒸发至干。残物以2-丙酮及DIPE处理。沉淀物经过滤移除及使之干燥,获得11.8克(84.3%)〔2-氨基-5-(4-氯苯甲酰基)-3-甲氧苯基〕(3-氯苯基)甲酮(中间体41号)。
d)中间体(41号)(11.7克)及乙酸酐(28毫升)于甲苯(150毫升)的混合物,予以搅拌回流24小时。溶剂经蒸发至干。产物直接利用,无须进一步纯化,获得14.5克N-乙酰基-N-〔2-(3-氯苯甲酰基)-4-(4-氯苯甲酰基)-6-甲氧苯基〕乙酰胺(中间体42号)。
e)叔丁氧钾(13.5克)分次加至中间体(42号)(14.5克)于二甲醚(150毫升)的混合物。此混合物于室温搅拌16小时,然后进行水解。溶剂予以蒸发,加水。混合物以DCM萃取后倾析。有机层使之干燥及过滤,溶剂经蒸发至干,获得11克(86.6%)6-(4-氯苯基)-4-(3-氯苯基)-8-甲氧基-2(1H)-喹啉酮(中间体43号)。
f)三溴化硼于DCM的溶液(1M;95毫升),于0℃滴加至中间体(43号)(10克)于DCM(100毫升)的混合物。此混合物于室温搅拌过夜,然后进行水解,以K2CO3(10%)调成碱性,以CH2Cl2/CH3OH 90/10萃取。有机层予以分离,使之干燥及过滤,溶剂经蒸发至干。产物直接利用,无须进一步纯化,获得9.6克6-(4-氯苯基)-4-(3-氯苯基)-8-羟基-2(1H)-喹啉酮(中间体44号)。
g)中间体(44号)(15克)、1,2-二溴乙烷(12.6毫升)、碳酸钾(20.2克)及氯化三辛酰甲铵(Aliquat 336号)(1.6毫升)于ACN(120毫升)及DCM(180毫升)的混合物,于50℃搅拌24小时,然后冷却至室温。加水。混合物经倾析后,以DCM萃取。有机层予以分离、使之干燥及过滤,溶剂经蒸发至干。残物以硅胶管柱层析(溶离液:CH2Cl2/EtOAc95/5)进行纯化。收集二个纯溶离份,蒸发其溶剂,获得4.5克(28.6%)9-(4-氯苯基)-7-(3-氯苯基)-2,3-二氢-5H-吡啶并〔1,2,3-de〕-1,4-苯并噁嗪-5-酮(中间体45号)。
h)硼氢化钠(NaBH4)(0.21克)于5℃加至中间体(45号)(2.5克)于甲醇(30毫升)及THF(30毫升)的混合物中。此混合物于5℃搅拌30分钟,然后进行水解、以DCM萃取及倾析。有机层使之干燥及过滤,溶剂经蒸发至干,获得2.3克(±)-7-(3-氯苯基)-9-〔(4-氯苯基)羟甲基〕-2,3-二氢-5H-吡啶并〔1,2,3-de〕-1,4-苯并噁嗪-5-酮(中间体46号)。
i)中间体(46号)(2.3克)于亚硫酰氯(30毫升)的混合物,于室温搅拌16小时。溶剂经蒸发至干。产物直接利用,无须进一步纯化,获得2.6克(±)-9-〔氯基(4-氯苯基)甲基〕-7-(3-氯苯基)-2,3-二氢-5H-吡啶并〔1,2,3-de〕-1,4-苯并噁嗪-5-酮(中间体47号)。
依此类似方式,又制备得(±)-8-〔氯基(4-氯苯基)甲基〕-6-(3-氯苯基)-2H,4H-噁唑并〔5,4,3-ij〕喹啉-4-酮(中间体48号)。实例A.6
中间体(37号)(23克)及聚磷酸(PPA)(120克)于140℃搅拌24小时。混合物倒至冰水中,予以过滤、以水洗涤、于NH3(aq.)中搅拌、以水洗涤及以DCM萃取。有机层予以分离、使之干燥及过滤,溶剂予以蒸发。残物以硅胶管柱层析(溶离液:DCM)进行纯化。收集纯溶离份,蒸发溶剂。此溶离份的部分自乙醚/2-丙酮中结晶析出。沉淀物经过滤移除及使之干燥,获得0.6克(±)-6-(3-氯苯基)-1,2,5,6-四氢-4H-吡咯并(3,2,1-ij)喹啉-4-酮(中间体3号)。实例A.7
a)吡啶(25毫升)加入3,4-二氢-2H-1,4-苯并噁嗪(17.8克)于DCM(200毫升)的混合物,此混合物于冰浴上冷却,倒至间-氯基-肉桂酰氯(33克)于DCM(100毫升)的混合物中。此混合物于室温搅拌过夜。加水,混合物予以倾析。有机层使之干燥及过滤,溶剂经蒸发至干,获得的残物以硅胶管柱层析(溶离液:环己烷/乙酸乙酯80/20)进行纯化,自ACN/乙醚中再结晶析出,获得26克(65.8%)4-〔3-(3-氯苯基)-1-氧代-2-丙烯-1-基〕-2,3-二氢-4H-1,4-苯并噁嗪(中间体51号)。
b)AlCl3(7.2克)加至中间体(51号)(5克)于氯苯(50毫升)的混合物。此混合物于80℃搅拌回流2小时,然后倒至冰上,以DCM萃取。有机层予以分离。使之干燥过滤,溶剂予以蒸发。残物以DCM处理、过滤移除、以CH2Cl2/乙醚洗涤及使之干燥,获得的残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH 99/1)进行纯化,获得3.4克(62%)(±)-7-(3-氯苯基)-2,3,6,7-四氢-5H-吡啶并〔1,2,3,-de〕-1,4-苯并噁嗪-5-酮(中间体7号)。实例A.8
a)丁基锂(1.6M于己烷中,22.4毫升)于-70℃氮气流下加至1-甲基咪唑(2.94克)于THF(50毫升)的混合物。此混合物于-70℃搅拌30分钟。加三乙硅烷基氯(6毫升)。混合物升至室温后冷却至-70℃。加丁基锂(1.6M于己烷中,22.4毫升)。混合物于-70℃搅拌1小时,然后升至-15℃,又冷却至-70℃。分次加中间体12号(3.8克)。混合物升至-10℃。加水,混合物以乙酸乙酯及少量甲醇萃取。有机层予以分离,使之干燥及过滤,溶剂予以蒸发。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 95/5/0.2)进行纯化。收集纯溶离份,溶剂予以蒸发,获得4克(88%)(±)-4-(3-氯苯基)-6-〔(4-氯苯基)羟基(1-甲基-1H-咪唑-5-基)甲基〕-8-甲氧基-2(1H)-喹啉酮(中间体49号)。
b)三溴化硼于DCM的溶液(1M;27.6毫升)于10℃滴加至中间体(49号)(2.8克)于DCM(30毫升)的溶液。混合物于室温搅拌5小时。缓慢加水。混合物于室温搅拌过夜。沉淀物经过滤移除,以水洗涤及使之干燥,获得2.9克(100%)(±)-4-(3-氯苯基)-6-〔(4-氯苯基)羟基(1-甲基-1H-咪唑-5-基)甲基〕-8-羟基-2(1H)-喹啉酮(中间体50号)。实例A.9
硼氢化钠(0.51克)于室温分次加至中间体(23号)(2.9克)于甲醇(20毫升)及THF(10毫升)的溶液,混合物于室温搅拌1小时。混合物倒至水中,予以蒸发。加甲醇,混合物以DCM萃取后倾析。有机层使之干燥、过滤及蒸发,获得2.9克(100%)(±)-7-(3-氯苯基)-9-(羟基(4-氯苯基)甲基〕-2,3-二氢-1H,5H-苯并〔ij〕喹嗪-5-酮(中间体52号)。
依此类似方式,合成得(±)-7-(3-氯苯基)-9-〔羟基(4-氯苯基)甲基〕-2,3,6,7-四氢-1H,5H-苯并〔ij〕喹嗪-5-酮(中间体53号)实例A.10
甲磺酰氯(1.6毫升)于室温滴加至中间体(52号)(2.6克)及三乙胺(4.1毫升)于DCM(30毫升)的溶液,混合物于室温搅拌2小时。混合物倒至水中后予以倾析、有机层使之干燥、过滤及蒸发,获得3.4克(±)-7-(3-氯苯基)-9-〔羟基(4-氯苯基)甲基〕-2,3,6,7-四氢-1H,5H-苯并〔ij〕喹嗪-5-酮(中间体54号)实例A.11
a)1,1′-羰基二咪唑(41克)于室温分次加至2-氨基-5-溴基-3-硝基-苯甲酸(55克)于DCM(700毫升)的混合物。此混合物于室温搅拌1小时。加N-甲氧基-甲胺盐酸盐(24.6克)。混合物于室温搅拌过夜,以水进行水解。沉淀物经过滤移除,滤液予以倾析。有机层使之干燥及过滤,溶剂经蒸发至干。残物以硅胶管柱层析(溶离液:CH2Cl2/乙酸乙酯98/2)进行纯化。收集纯溶离份,溶剂予以蒸发,沉淀物以HCl 3N(250毫升)处理。混合物于室温搅拌4小时。沉淀物经过滤移除,以水洗涤及使之干燥,获得23克2-氨基-5-溴基-N-甲氧基-N-甲基-3-硝基苯酰胺(中间体55号,熔点129℃)。
b)1-溴基-3-氯苯基(37.3毫升)于THF(300毫升)的混合物,滴加至镁(7.7克)于少量THF的混合物,同时使温度保持于50℃~60℃。混合物于室温搅拌1小时后冷却至5℃。滴加中间体(55号)(30.7克)于THF(300毫升)的混合物。此混合物于5℃搅拌15分钟、进行水解、以乙酸乙酯萃取、经赛力特硅藻土过滤及倾析。有机层使之干燥及过滤,溶剂经蒸发至干。残物以硅胶管柱层析(溶离液:CH2Cl2/环己烷50/50)进行纯化。收集纯溶离份,溶剂予以蒸发,获得17.5克(46.4%)(2-氨基-5-溴基-3-硝苯基)(3-氯苯基)甲酮(中间体56号,134℃)。
c)TiCl3(15%于H2O中,400毫升)于室温加至中间体(56号)(16克)于THF(230毫升)的溶液。混合物于室温搅拌过夜、加水,混合物以DCM萃取2次。混合的有机层以K2CO310%洗涤,使之干燥及过滤,溶剂予以蒸发,获得18克(2,3-二氨基-5-溴苯基)(3-氯苯基)甲酮(中间体57号)。
d)中间体(57号)(18克)及乙酸酐(19毫升)于甲苯(400毫升)的混合物,经搅拌回流4小时,然后冷却至室温。沉淀物经过滤移除,以DIPE洗涤及使之干燥,获得13.2克(90%)N,N′-〔5-溴基-3-(3-氮苯甲酰基)-1,2-亚苯基〕二乙酰胺(中间体58号)。
e)叔丁氧钾(18克)于室温加至中间体(58号)(13.2克)于DME(140毫升)的混合物。此混合物于室温搅拌过夜。加水,混合物以HCl 3N中和。沉淀物经过滤移除、以水及DIPE洗涤、使之干燥。获得10.75克(86%)N-〔6-溴基-4-(3-氯苯基)-1,2-二氢-2-氧代-8-喹啉基〕乙酰胺(中间体59号)。
f)中间体(59号)(10.75克)、甲基碘(3.57毫升)及Ag2CO3(16.93克)于DMF(150毫升)的混合物,于80℃ N2气流下搅拌90分钟。使混合物冷却至室温。加水。混合物以赛力特硅藻土过滤、以水洗涤及以DCM萃取。有机层予以分离、使之干燥及过滤,溶剂予以蒸发,获得10.9克(98%)N-〔6-溴基-4-(3-氯苯基)-2-甲氧基-8-喹啉基〕乙酰胺(中间体60号)。
g)丁基锂(1.6M于己烷中,18.5毫升)于-70℃ N2气流下滴加至中间体(60号)(5克)于THF(70毫升)的混合物。此混合物于-70℃搅拌30分钟,升至-40℃,又冷却至-70℃。加(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲酮(6.5克)。混合物加温至室温,然后进行水解。加乙酸乙酯。有机层予以分离、使之干燥及过滤,溶剂经蒸发至干。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH95/5/0.1)进行纯化。收集纯溶离份,予以蒸发,自2-丙酮、ACN及DIPE中再结晶析出,获得1.3克(32.5%)(±)-N-〔4-(3-氯苯基)-6-〔(4-氯苯基)羟基(1-甲基-1H-咪唑-5-基)甲基〕-2-甲氧基-8-喹啉基〕乙酰胺(中间体61号,熔点143℃)。
h)中间体(61号)(3克)于HBr(48%于H2O中,45毫升)及1,4-二噁烷(40毫升)的混合物,于80℃搅拌3小时。混合物冷却至室温、倒至冰上、以K2CO3固体饱和及以乙酸乙酯萃取。有机层予以分离、使之干燥、过滤、蒸发及以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 95/5/0.5)进行纯化。收集纯溶离份,溶剂予以蒸发。残物以CH3OH及DIPE处理。沉淀物经过滤移除及使之干燥,获得0.4克(55%)(±)-8-氨基-4-(3-氯苯基)-6-〔(4-氯苯基)羟基(1-甲基-1H-咪唑-5-基)甲基〕-2(1H)-喹啉酮(中间体62号)。
表I-1至I-2列出根据上述实例之一制备的中间体。表I-1:
*:CH2部分连接于2-喹啉酮部分的氮原子上表I-2: *:CH2部分连接于2-喹啉酮部分的氮原子上B.最后化合物的制备 实例B.1
中间体号 | 实例号 | -A- | R1 | R2 | 物理数据 |
1234567 | A.6A.6A.6A.6A.6A.6A.7 | -(CH2)3--(CH2)2--(CH2)2--(CH2)2--(CH2)2--(CH2)2--(CH2 *)2-O- | 3-Cl3-Br3-Cl4-Cl3-Cl3-CH33-Cl | HHHH4-ClHH | --mp.138℃---- |
1-甲基咪唑(4.55毫升)于THF(200毫升)的溶液,经冷却至-70℃。加丁基锂(1.6M于己烷中,35.9毫升),混合物于-70℃搅拌30分钟。加三乙硅烷基氯(10.4毫升),混合物缓慢加温至室温。混合物经冷却至-70℃,滴加丁基锂(1.6M于己烷中,35.9毫升),混合物于-70℃搅拌1小时,然后温至-15℃。移除液浴,混合物冷却至-70℃。加中间体(24号)(20克),混合物于-70℃搅拌30分钟。混合物进行水解,以乙酸乙酯萃取。有机层予以分离、使之干燥及过滤,溶剂予以蒸发。残物以管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 97/3/0.1)进行纯化。获得24克(±)-6-(3-氯苯基)-8-〔(4-氯苯基)羟基(1-甲基-1H-咪唑-5-基)甲基〕-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-酮(化合物5号,213.6℃)。实例B.2
化合物1号(2.5克)于甲酰胺(10毫升)及乙酸(20毫升)的混合物,于160℃搅拌4小时。混合物倒至冰上、以氨水溶液调成碱性及以DCM萃取。有机层予以分离、使之干燥及过滤,溶剂予以蒸发。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 97/3/0.1)进行纯化。收集纯溶离份,溶剂予以蒸发。残物以2-丙酮/DIPE处理。沉淀物经过滤移除及使之干燥,获得1克(41%)(±)-6-(3-氯苯基)-8-〔(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基〕-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-酮一水合物(化合物6号,147.0℃)。实例B.3
化合物5号(2克)于亚硫酰氯(8毫升)的混合物,于室温搅拌过夜。溶剂经蒸发至干。产物直接利用,无须进一步纯化,获得2.07克(100%)(±)-8-〔氯基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基〕-6-(3-氯苯基)-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-酮单盐酸盐(化合物7号)。实例B.4
化合物7号(2.07克)于THF(15毫升)的混合物,于室温倒至氨水溶液(40毫升)中。混合物于室温搅拌4小时,然后以DCM萃取及倾析。有机层使之干燥及过滤,溶剂予以蒸发。残物以硅胶管柱层析(溶离液:甲苯/2-丙醇/NH4OH 50/50/1)进行纯化。收集纯溶离份,溶剂予以蒸发。残物自CH2Cl2/乙醚中再结晶析出。沉淀物经过滤移除及使之干燥,获得0.65克(±)-8-〔氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基〕-6-(3-氯苯基)-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-酮(化合物8号)。实例B.5
化合物8号(12.4克)予以分离及以Chiracel OD非对称管柱层析(溶离液:100%CH3OH)进行纯化。收集二组纯溶离份。第-组溶离份的溶剂予以蒸发。残物自2-丙醇(200毫升)及DIPE(200毫升)中结晶析出。沉淀物经过滤移除及使之干燥,获得4.4克(A)-8-〔氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基〕-6-(3-氯苯基)-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-酮(化合物9号;〔α〕D 20=-27.94°(c=9.1毫克/毫升于甲醇中))。
第二组溶离份的溶剂予以蒸发。残物自2-丙醇(250毫升)及DIPE(350毫升)中结晶析出。沉淀物经过滤移除及使之干燥,获得4.1克(B)-8-〔氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基〕-6-(3-氯苯基)-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-酮(化合物10号;〔α〕D 20=+28.21°(c=9毫克/毫升,于甲醇中))。实例B.6
中间体(50号)(2.7克)、二溴甲烷(3毫升)及碳酸钾(2.8克)于DMF(90毫升)的混合物,于80℃搅拌3小时。加水。混合物以赛力特硅藻土过滤、以水洗涤及以DCM萃取。有机层予以分离、使之干燥及过滤,溶剂予以蒸发。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 96/4/0.2)进行纯化。收集纯溶离份,溶剂予以蒸发。残物自2-丙酮及乙醚中结晶析出。沉淀物经过滤移除及使之干燥,获得0.86克(31%)(±)-6-(3-氯苯基)-8-〔(4-氯苯基)羟基(1-甲基-1H-咪唑-5-基)甲基〕-2H,4H-噁唑并〔5,4,3-ij〕喹啉-4-酮(化合物15号)。实例B.7
化合物6号(1.2克)及硫化磷(2.4克)于吡啶(30毫升)的混合物,经搅拌回流6小时,然后倒入水中。沉淀物经过滤移除、以水充分清洗、以DCM处理、使之干燥及过滤,溶剂经蒸发至干。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 98/2/0.1)进行纯化。收集纯溶离份,溶剂予以蒸发。残物自ACN及DIPE中结晶析出。沉淀物经过滤移除及使之干燥,获得0.36克(29.2%)(±)-6-(3-氯苯基)-8-〔(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基〕-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-硫酮(化合物27号)。实例B.8
中间体(62号)(1.8克)及亚胺乙酸乙酯(0.9克)于甲醇(40毫升)的混合物,予以搅拌回流4小时。溶剂经蒸发至干。残物以DCM及K2CO3(10%于H2O中)处理。有机层予以分离、使之干燥及过滤,溶剂予以蒸发。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH95/5/0.5)进行纯化。收集纯溶离份,溶剂予以蒸发。残物自DIPE中结晶析出。沉淀物经过滤移除及使之干燥,获得0.4克(21.2%)(±)-6-(3-氯苯基)-8-〔(4-氯苯基)羟基(1-甲基-1H-咪唑-5-基)甲基〕-2-甲基-4H-咪唑并〔4,5,1-ij〕喹啉-4-酮(化合物30号,熔点170℃)。
依此类似方式,又制备得(±)-6-(3-氯苯基)-8-〔(4-氯苯基)羟基(1-甲基-1H-咪唑-5-基)甲基〕-2-苯基-4H-咪唑并〔4,5,1-ij〕喹啉-4-酮(化合物31号)。实例B.9
中间体(62号)(2.1克)1,1′-羰基二咪唑(4.1克)于THF(60毫升)的混合物,经搅拌回流3小时。混合物倒至水中,以DCM萃取。有机层予以分离、以水洗涤、使之干燥及过滤,溶剂经蒸发至干。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 90/10/0.5)进行纯化。收集纯溶离份,溶剂予以蒸发。残物自CH3OH及DIPE中结晶析出。沉淀物经过滤移除及使之干燥,获得0.7克(31.8%)(±)-6-(3-氯苯基)-8-〔(4-氯苯基)羟基(1-甲基-1H-咪唑-5-基)甲基〕-4H-咪唑并〔4,5,1-ij〕喹啉-2,4(1H)-二酮(化合物34号,熔点256℃)。实例B.10
中间体(62号)(2.1克)于水(21毫升)及硫酸(36N,42毫升)的混合物,于冰浴上冷却至5℃。滴加NaNO2(3.6毫升;溶液80克/100毫升),同时温度保持于5℃。混合物于冰浴上搅拌1小时、倒至冰水中,以浓NH4OH溶液调成碱性及以DCM萃取。有机层予以分离、使之干燥及过滤,溶剂予以蒸发。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1)进行纯化。收集纯溶离份,溶剂予以蒸发。残物自2-丙酮及DIPE中结晶析出。沉淀物经过滤移除及使之干燥,获得0.35克(16.3%)(±)-6-(3-氯苯基)-8-〔(4-氯苯基)羟基(1-甲基-1H-咪唑-5-基)甲基〕-4H-1,2,3-三唑并〔4,5,1-ij〕喹啉-4-酮(化合物35号,熔点226℃)。实例B.11
中间体(54号)(3.4克)及咪唑(2.01克)于ACN(40毫升)的混合物,经搅拌回流3小时。混合物予以蒸发,残物以DCM处理。有机层以水洗涤、使之干燥、过滤移除及蒸发。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 97/3/0.1)进行纯化。收集纯溶离份,予以蒸发。自乙酸乙酯及DIPE中结晶析出。获得1.9克(65%)(±)-7-(3-氯苯基)-9-〔(4-氯苯基)-1H-咪唑-1-基甲基〕-2,3-二氢-1H,5H-苯并〔ij〕喹嗪-5-酮(化合物36号,熔点195.2℃)。实例B.12
1,1'-羰基二咪唑(4克)于室温加至中间体(53号)(5.4克)于THF(70毫升)的溶液,混合物于室温经搅拌16小时。加水,混合物以DCM萃取。有机层使之干燥、过滤及蒸发。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1)进行纯化。收集纯溶离份,予以蒸发。残物以硅胶管柱层析(溶离液:环己烷/2-丙醇/NH4OH 80/20/0.1)进行纯化。收集纯溶离份,予以蒸发。残物以乙醚处理,过滤移除,获得1.3克(22%)(±)-7-(3-氯苯基)-9-〔(4-氯苯基)-1H-咪唑-1-基甲基〕-2,3,6,7-四氢-1H,5H-苯并〔ij〕喹嗪-5-酮(化合物37号,熔点93.6℃)。实例B.13
中间体(48号)(2.3克)及咪唑(1.8克)于ACN(50毫升)的混合物,经搅拌回流4小时。溶剂经蒸发至干。残物以DCM处理,以水洗涤及倾析。有机层使之干燥及过滤,溶剂经蒸发至干。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/NH4OH 98/2/0.1)进行纯化。收集纯溶离份,溶剂予以蒸发。残物自ACN及DIPE中结晶析出。沉淀物经过滤移除及使之干燥,获得1.3克(±)-6-(3-氯苯基)-8-〔(4-氯苯基)-1H-咪唑-1-基甲基〕-2H,4H-噁唑并〔5,4,3-ij〕喹啉-4-酮(化合物52号)。实例B.14
硫化磷(6克)加至化合物38号(3克)于吡啶(40毫升)的混合物。此混合物经搅拌回流6小时。加冰水。沉淀物经过滤移除,以水洗涤及以DCM处理。有机层予以分离、使之干燥及过滤,溶剂经蒸发至干。残物以硅胶管柱层析(溶离液:CH2Cl2/CH3OH/98.5/1.5)进行纯化。收集纯溶离份,溶剂予以蒸发。残物自ACN及DIPE中结晶析出。沉淀物经过滤移除及使之干燥,获得1.1克(±)-6-(3-氯苯基)-8-〔(4-氯苯基)-1H-咪唑-1-基甲基〕-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-硫酮(化合物50号)。
表F-1及F-3列出根据上述实例之-制备得的化合物。表F-1:
*:CH2部分连接于2-喹啉酮部分的氮原子上(1):水合物(1∶1)(2):盐酸盐(1∶1)表F-2:
(3):乙二酸盐(1∶1)水合物(1∶1)表F-3: *:CH2部分连接于2-喹啉酮部分的氮原子上(1):乙二酸盐(2∶3)盐C.药理实例 实例C.1:“于体外法呢基蛋白质转移酶的抑制分析”
化合物号 | 实例号 | X | -A- | R1 | R2 | R3 | R4 | R6 | 物理数据 |
1234567 | B.1B.3B.4B.1B.1B.2B.3 | OO0OOOO | -(CH2)2--(CH2)2--(CH2)2--(CH2)2--(CH2)2--(CH2)2--(CH2)2- | HHH3-Br3-Cl3-Cl3-Cl | HHHHHHH | 4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl | HHHHHHH | OHClNH2OHOHHCl | mp.240℃(2)mp.218℃mp.210℃mp.213.6℃mp.147.0℃;(1)(2) |
化合物号 | 实例号 | X | -A- | R1 | R2 | R3 | R4 | R6 | 物理数据 |
89101112131415161718192021222324252627303132333435 | B.4B.5B.5B.1B.1B.3B.4B.6B.3B.1B.4B.lB.3B.4B.1B.1B.1B.1B.1B.7B.8B.6B.3B.4B.9B.10 | OOOOOOOOOOOOOOOOOOOSOOOOOO | -(CH2)2--(CH2)2--(CH2)2--(CH2)3--(CH2)3--(CH2)3--(CH2)3--CH2 *-O--(CH2)2-O--(CH2 *)2-O--(CH2 *)2-O--(CH2)2--(CH2)2--(CH2)2--(CH2)2--(CH2)2--(CH2)2--(CH2)2--(CH2)2--(CH2)2--CH(CH3)=N--CH(C6H5)=N--CH(C6H5)=N--CH(C6H5)=N--CO-NH--N=N- | 3-Cl3-Cl3-Cl3-Cl3-Cl3-Cl3-Cl3-Cl4-Cl3-Cl3-Cl3-Cl3-Cl3-Cl3-Cl3-Cl3-Cl3-Cl3-CH33-C13-Cl3-Cl3-Cl3-Cl3-Cl3-Cl | HHHHHHHHHHHHHHHHHHHHHHHHHH | 4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl4-F4-F4-F3-ClH4-CH32-Cl4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl4-Cl | HHHHHHHHHHHHHHHHHHHHHHHHHH | NH2NH2NH2OHOHClNH2OHClOHNH2OHClNH2OHOHOHOHOHHOHOHClNH2OHOH | mp.165℃(A):[α]D 20=-27.94°(B)[α]D 20=+28.21°mp.210℃(dec.mp.232℃;(2)(2)mp.190℃mp.196℃(2)mp.252℃mp.210℃mp.224℃(2)mp.235℃mp.220℃mp.260℃mp.245℃mp.210℃;(1)mp.242℃mp.138℃mp.170℃mp.176℃(1)mp.215℃mp.256℃mp.226℃ |
化合物号 | 实例号 | X | -A- | R1 | R2 | R3 | R4 | R6 | 物理数据 |
2829 | B.1B.1 | OO | -(CH2)2--(CH2)3- | 3-Cl3-Cl | HH | 4-Cl4-Cl | HH | OHOH | mp.248℃(3):mp.154℃ |
人类法呢基蛋白质转移酶基本上依〔Y.Reiss等著,方法:酶方法手册(Methods:A Companion to Methods in Enzymology),1卷,241-245页,1990年〕所述制备。克斯敦(Kirsten)病毒转形人类骨肉瘤(KHOS)细胞〔美国标准培养采集中心(American TypeCulture Collection),罗克维尔,马里兰州,美国〕长成固体肿瘤于裸小鼠或长成单层细胞培养物,作人类酶来源。简言之,细胞或肿瘤于含有50mM Tris、1mM EDTA,1mM GETA及0.2mM苯甲磺酰氟(pH7.5)的缓冲液中均质化。均质液以28,000×g离心60分钟,收集上清液。制备30-50%硫酸铵部分,所得沉淀物再悬浮于少量(10至20毫升)含有20mM Tris、1mM二硫苏糖醇及20μM ZnCl2的透析缓冲液。硫酸铵部分以相同缓冲液(更换二次)透析过夜。透析物置于以补充0.05M NaCl的100毫升透析缓冲液预平衡之10×1厘米Q Fast Flow Sepharose(Pharmacia LKB生物技术公司,皮斯卡塔伟,纽泽西州,美国)上。管柱以另份50毫升透析缓冲液加0.05MNaCl洗涤,接着以梯度0.05M至0.25M NaCl制备成的透析缓冲液洗涤。酵素活性以线性梯度0.25至1.0M NaCl制备成的透析缓冲液溶离测定。收集含4至5毫升量管柱溶离液的部分,分析法呢基蛋白质转移酶活性。收集具酵素活性的部分,补充以100μM ZnCl2。酵素样品于-70℃冷冻贮存。
法呢基蛋白质转移酶的活性用法呢基转移酶〔3H〕闪烁接近分析(the Famesyl Transferase〔3H〕Scintillation Proximity Assay,Amersham国际plc.英国),于制造商指示的条件下测定。分析酶的抑制剂时,0.20μci〔3H〕-法呢基焦磷酸盐受质及生物素化薄片质(lamin)B肽受质(生物素-YRASNRSCAIM)与受试化合物混合于由50mM HEPES、30mM MgCl2、20mM KCl、5mM二硫苏糖醇、0.01%Triton X-100组成的反应缓冲液。受试化合物释出于10μl量二甲亚砜(DMSO)成浓度1及10μg/ml于最后量100μl中。反应混合物加温至37℃。加20μl稀释的人类法呢基蛋白质转移酶以起始酵素反应。于37℃及60分钟反应培育期间,加足量酵素制剂以产生4000至15000cpm反应产物。又加STOP/闪烁接近珠试剂(Amersham)使反应终止。反应产物〔3H〕-法呢基-(Cys)-生物素薄片质B肽捕获于抗生蛋白链菌素(streptavidin)连接之闪烁接近珠。于有或无受试人物存在下合成的〔3H〕-法呢基-(Cys)-生物素薄片质B肽,由瓦雷1480型微贝他液体闪烁计数器(Wallac Model 1480 MicrobetaLiquid Scintillation Counter)计量成cpm。产物的cpm视为法呢基蛋白质转移酶活性。于受试化合物存在下观察得的蛋白质法呢基转移酶活性,以抑制百分率表示。依另外的研究,某些受试化合物对法呢基蛋白质转移酶展示50%或更高的抑制率,则评估成酶活性的浓度-依赖性抑制率。依这些研究,用VAX电脑,由R.W.詹森医药研究所科学资讯部(斯普林毫斯,宾西凡尼亚州,美国)〔R.W.JohnsonPharmaceutical Research Institute(Spring House,PA,USA)〕书写的LGIC50电脑程序,计算受试化合物的效果成IC50(对酶活性产生50%抑制率的受试化合物浓度)。
化合物36号的IC50值为21nM,而化合物38号的IC50值为15nM。实例C.2:“ras-转形细胞表型反转分析”
活化致癌基因(例如突变ras基因)插入至小鼠NIH 3T3细胞,使细胞转化成转型表型,细胞变成致瘤的,于半固体培养质上固定独立生长,且失去接触性抑制,失去接触性抑制使得细胞培养物不再形成均匀单层。反之,细胞积聚成多细胞小瘤,极高度饱实稠密地生长于塑胶组织培养皿。药剂例如能回复ras转形表型的蛋白质法呢基转移酶抑制剂,使细胞培育恢复成均匀单层生长型态。回复状态由计数组织培养皿中的细胞数而轻易监测。转形细胞比回复成非转形表型的细胞获得更多细胞数。会回复转形表型的化合物对具ras基因突变的肿瘤能产生抗肿瘤效果。方法:
化合物于组织培养基中筛选经T24活化的人类H-ras基因转形的NIH 3T3细胞。细胞以初始密度每凹洞(9.6厘米2表面积)200,000个细胞播种于6凹洞密集组织培养皿。受试化合物立即加至含3.0μl量DMSO的3.0ml细胞生长培养质,而DMSO于细胞生长培养基的最后浓度为0.1%。受试化合物以浓度5、10、50、100及500nM浓度进行,以经DMSO处理媒物作对照组。(若于5nM为高活性,则受试化合物用较低浓度)。细胞增殖72小时,然后以1.0ml胰蛋白质酶-EDTA细胞分离培养液剥离细胞,用Coulter颗粒计数器计数。测定:
细胞数用Coulter颗粒计数器测量,以每凹洞的细胞数表示。所有细胞计数均减数200,000以对初始细胞置入密度作校准。
对照组细胞计数=〔以DMSO媒液培育细胞的细胞计数-200,000〕。
受试化合物组细胞计数=〔以受试化合物培育细胞的细胞计数-200,000〕。
若数据充分,计算出IC50值(即,能抑制50%酶活性所需的受试化合物浓度),概述于表C.2。表C.2:
实例C.3:“法呢基蛋白质转移酶抑制续发性肿瘤模型”
化合物号 | IC50(nM) |
1345681012141517181921222324252627282930313334354041444548495153 | 14251507.8326.43.2667.34863>5002401835244212372137.1100184373>50073.1>500>500>500>500353>500>500>500>500>500 |
酶法呢基转移酶催化法呢基焦磷酸盐衍生的法呢基部分与致癌基因产物p21ras共价附著,使得p21ras附著至质膜。一旦附著至质膜,p21ras的突变或致癌基因型会提供讯息使恶性肿瘤细胞转形及难控制生长。因此,蛋白质法呢基转移酶的抑制剂会防阻p21ras的膜附著,及抑制ras-转形的肿瘤生长。
裸小鼠经腹股沟区皮下接种1×106个T24活化人类H-ras基因转形NIH 3T3纤维组织母细胞(T24细胞)。经3天肿瘤建立后,由口服途径开始以受试化合物处理。受试化合物溶于20%β-环糊精于0.1N HCl溶液,以每10g小鼠体重经口投予0.1ml化合物溶液。常规剂量为6.25、12.5及25毫克/千克。于随后15天处理期间,监测体重及肿瘤大小。结束处理时,杀死动物,称取肿瘤重量。
“平均载体处理的肿瘤重量”定义作以受试化合物处理10至15只小鼠后的平均肿瘤重量。
Claims (10)
-CH=CH- (a-1),
-CH2-CH2- (a-2),
-CH2-CH2-CH2- (a-3),
-CH2-O- (a-4),
-CH2-CH2-O- (a-5),
-CH=N- (a-8),
-N=N- (a-9),或
-CO-NH- (a-10);
式中,任选地-个氢原子可以C1-4烷基或Ar1代替;R1及R2各独立为氢、羟基、卤基、氰基、C1-6烷基、三卤甲基、三卤甲
氧基、C2-6烯基、C1-6烷氧基、羟基C1-6烷氧基、C1-6烷氧基C1-6烷
氧基、C1-6烷氧羰基、氨基C1-6烷氧基、单或二(C1-6烷基)氨基C1-6
烷氧基;或R3及R4各独立为氢、卤基、氰基、C1-6烷基、C1-6烷氧基、Ar3-氧基、
C1-6烷硫基、二(C1-6烷基)氨基、三卤甲基、三卤甲氧基,
-O-R7 (e-1),
-N-R8R9 (e-3);式中R7为氢;R8为氢;R9为氢;及Ar1至Ar4各独立选自苯基;或经卤基、C1-6烷基、C1-6烷氧基或三氟甲基取代的苯基。
2.根据权利要求1的化合物,其中虚线表示任选的键;X为O或S;R1及R2各独立选自氢、卤基、C1-6烷基、C1-6烷氧基、三卤甲基或三卤甲氧基;R3及R4各独立选自氢、卤基、C1-6烷基、C1-6烷氧基、三卤甲基或三卤甲氧基;R5为式(d-1)的基,式中R13为氢,或R5为式(d-2)的基,式中R13为氢或C1-6烷基,及R14为氢或C1-6烷基;R6为氢、羟基、卤基,或下式的基:-NR8R9,式中R8为氢,及R9为氢。
3.根据权利要求1或2中任一项的化合物,其中X为氧;虚线表示键;R1为3-卤基;R2为氢;R3为4-卤基;R4为氢,R5为式(d-1)的基,式中R13为氢,或R5为式(d-2)的基式中R13为氢,及R14为C1-4烷基;R6为氢,卤基、羟基或氨基;及-A-为(a-1)、(a-2)或(a-3)。
4.根据权利要求1的化合物,其中化合物为
7-(3-氯苯基)-9-〔(4-氯苯基)-1H-咪唑-1-基甲基〕-2,3-二氢-1H,5H-苯并〔ij〕喹嗪-5-酮;
7-(3-氯苯基)-9-〔(4-氯苯基)-1H-咪唑-1-基甲基〕-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-酮;
8-〔氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基〕-6-(3-氯苯基)-基)-1,2-二氢-4H-吡咯并〔3,2,1-ij〕喹啉-4-酮;或
8-〔氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基〕-6-(3-氯苯基)-2,3-二氢-1H,5H-苯并〔ij〕喹嗪-5-酮;
其立体异构物形式及其药学上可被接受的酸加成盐。
5.一种药学组合物,包括:药学上可接受的载剂,及作有效成分的、治疗有效量的如根据权利要求1至4中任一项的化合物。
6.一种如权利要求5的药学组合物的制法,其中治疗有效量的
如根据权利要求1至4中任一项的化合物与药学上可接受的载剂密切混合。
7.一种下式(II)化合物,其酸加成盐或其立体化学性异构物形式,式中虚线表示任选的键;X、R1、R2、R3、R4及-A-的定义如权利要求1所述。
8.根据权利要求1至4中任一项的化合物,用于药剂制备中的用途。
9.权利要求1的化合物的制备方法,其中
c)式(XVIII)中间体以式(XVII)中间体,于反应惰性溶剂及任选的合宜碱存在下,进行N-烷化,
d)式(XIX)中间体以式(XVI)化合物进行N-烷化,式中,于上述反应图,虚线及基X、R1、R2、R3、R4、R5、R6、R8、R9及R13和-A-的定义如权利要求1所述,W为适当的离去基;及Y为碳或硫;
e)或,式(I)化合物根据本领域已知的转化反应彼此转化;或需要的话,式(I)化合物转化成其药学上可接受的酸加成盐,或相反地,式(I)化合物的酸加成盐用碱转化成其自由碱型;及,需要的话,制备成其立体化学性异构物形式。
10.权利要求7的式(II)中间体的制备方法,式中
c)式(II-a)中间体,即式(II)中虚线不表示键的中间体,可经氧化反应转化成式(II-b)中间体,即式(II)中虚线表示一个键的中间体,于上述反应式中,基X、R1、R2、R3、R4及-A-的定义如权利要求1所述;
d)或,式(II-a)化合物依此领域已知的转化反应彼此转化;
或需要的话,式(II-a)化合物转化成其药学上可接受的酸加成盐,或相反地,式(II-a)化合物的酸加成盐以碱转化成其自由碱型;及,需要的话,制备成其立体化学性异构物型。
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CA2002859C (en) | 1988-11-29 | 1998-12-29 | Jean P. F. Van Wauwe | Method of treating epithelial disorders |
GB9212833D0 (en) | 1992-06-17 | 1992-07-29 | Glaxo Group Ltd | Chemical compounds |
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