CN100390154C - 用作pdgf-受体和/或lck酪氨酸激酶抑制剂的喹啉和喹喔啉化合物 - Google Patents
用作pdgf-受体和/或lck酪氨酸激酶抑制剂的喹啉和喹喔啉化合物 Download PDFInfo
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- CN100390154C CN100390154C CNB998157880A CN99815788A CN100390154C CN 100390154 C CN100390154 C CN 100390154C CN B998157880 A CNB998157880 A CN B998157880A CN 99815788 A CN99815788 A CN 99815788A CN 100390154 C CN100390154 C CN 100390154C
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- Prior art keywords
- quinoxaline
- dimethoxy
- carbon atom
- base
- amine
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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- C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
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- C07—ORGANIC CHEMISTRY
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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- C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
- C07D241/54—Nitrogen atoms
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
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Abstract
本发明涉及式(I)的喹啉/喹喔啉化合物,所述化合物能抑制血小板衍生生长因子或p56lck酪氨酸激酶活性。本发明还涉及包含这些化合物的药物组合物,这些化合物在治疗患有或易患有涉及细胞分化、增殖、细胞外基质产生或介质释放和/或T细胞活化和增殖的疾病/病症的患者中的应用。
Description
相关申请案介绍
本申请是在1998年11月24日提交的第09/198,718号美国专利申请的延续,而该美国专利申请又是在1998年5月28日提交的第PCT/US98/11036号国际专利申请的延续,该国际专利申请是在1997年11月18日提交的第08/972,614号美国专利申请的延续,该美国专利申请是在1997年5月18日提交的、现在已经放弃的第08/864,455号美国专利申请的延续。
发明背景
1.发明领域
本发明涉及使用可用作蛋白质酪氨酸激酶抑制剂(TKIs)的喹啉/喹喔啉化合物来抑制细胞增殖和/或细胞基质产生和/或细胞运动(趋化性)和/或T细胞活化和增殖。
细胞信号传导是通过相互作用系统介导的,包括细胞-细胞接触或细胞-基质接触或细胞外受体-底物接触。细胞外信号经常通过酪氨酸激酶介导的磷酸化事件传递到细胞的其它部分,该磷酸化事件影响细胞膜结合的信号传导复合物的下游底物蛋白。特定的受体-酶例如胰岛素受体、表皮生长因子受体(EGF-R)或血小板衍生生长因子受体(PDGF-R)是参与细胞信号传导的酪氨酸激酶的实例。对于有效的酶介导的、含有酪氨酸残基的底物蛋白的磷酸化,酶的自身磷酸化是必需的。已知这些底物引起很多细胞事件,包括细胞增殖、细胞基质产生、细胞迁移和细凋亡(这只是其中的一小部分事件)。
众所周知,有大量疾病是由于失控的细胞增殖或细胞基质过度生成或失控的编程性细胞死亡(细胞凋亡)引起的。这些疾病涉及多种细胞类型,并包括病症例如白血病、癌症、成胶质细胞瘤、牛皮癣、炎性疾病、骨疾病、纤维变性疾病、动脉粥样硬化和冠状动脉、股动脉或肾动脉的血管成形术后发生的再狭窄,或纤维增生性疾病例如关节炎,肺、肾和肝脏的纤维变性。此外,冠状动脉旁路手术后会发生失控的细胞增殖。据信抑制酪氨酸激酶活性可用于控制失控的细胞增殖或细胞基质过度生成或失控的编程性细胞死亡(细胞凋亡)。
已知有一些酪氨酸激酶抑制剂可以与一类以上的酪氨酸激酶相互作用。而有一些酪氨酸激酶对于身体正常功能是至关重要的。例如,在大多数情况下并不希望抑制胰岛素的作用。因此,能在有效地抑制胰岛素受体激酶的浓度以下的浓度抑制PDGF-R酪氨酸激酶活性的化合物可以给特征是细胞增殖和/或细胞基质产生和/或细胞运动(趋化性)的疾病例如再狭窄的选择性治疗提供有价值的治疗剂。
本发明涉及调节和/或抑制细胞信号传导、细胞增殖、细胞外基质产生、趋化性,控制异常的细胞生长和细胞炎性反应。更具体来说,本发明涉及取代的喹喔啉化合物的应用,所述化合物能通过有效地抑制血小板衍生生长因子受体(PDGF-R)酪氨酸激酶活性和/或Lck酪氨酸激酶活性而选择性地抑制分化、增殖或介质释放。
2.报道进展
有许多文献报道描述了对于酪氨酸激酶受体酶例如EGF-R或PDGF-R或非受体胞质酪氨酸激酶例如v-abl、p561ck或c-src有选择性的酪氨酸激酶抑制剂。Spada和Myers(Exp.Opin.Ther.Patents 1995.,5(8).805)与Bridges(Exp.Opin.Ther.Patents 1995,5(12),1245)的近期综述分别总结了关于酪氨酸激酶抑制剂和EGF-R选择性抑制剂的文献。此外,Law和Lydon总结了酪氨酸激酶抑制剂的抗癌潜力(Emerging Drugs:The Prospect ForImproved Medicines 1996,241-260)。
已知的PDGF-R酪氨酸激酶活性抑制剂包括Maguire等人(J.Med.Chem.1994,37,2129)和Dolle等人(J.Med.Chem.1994,37,2627)报道的基于喹啉的抑制剂。最近下述作者报道了一类基于苯基氨基嘧啶的抑制剂:Traxler等人在EP 564409中,和Zimmerman,J.;和Traxler,P.等人(Biorg.&Med.Chem.Lett.1996,6(11),1221-1226)和Buchdunger,E.等人(Proc.Nat.Acad.Sci.1995,92,2558)。尽管在本领域内取得了这些进展,但是在这些类化合物当中,没有一种被批准用来在人中治疗增殖性疾病。
在整个科学文献中,多因子再狭窄疾病与PDGF和PDGF-R之间的关系有广泛的文献报道。然而,最近关于肺纤维变性疾病的病因(Antoniades,H.N.;等人.J.Clin.Invest.1990,86,1055)、肾和肝脏纤维变性疾病的病因(Peterson,T.C.Hepatology,1993,17,486)的研究进展表明PDGF和PDGF-R可能也在这些疾病中起作用。例如,肾小球肾炎是肾衰竭的主要原因,据鉴定在体外对于肾小球细胞,PDGF是有力的促细胞分裂剂,Shultz等人(Am.J.Physiol.1988,255,F674)和Floege等人(Clin.Exp.Immun.1991,86,334)证实了这一点。Thornton,S.C.等人(Clin.Exp.Immun.1991,86,79)等人报道,TNF-α和PDGF(得自类风湿性关节炎患者)是参与滑液细胞增殖的主要细胞因子。此外,已经鉴定出了过度表达PDGF蛋白或受体、并由此通过自分泌或旁分泌机制导致失控的癌细胞生长的具体肿瘤细胞类型(参见Silver,B.J.,BioFactors,1992,3,217),例如成胶质细胞瘤和卡波西肉瘤。由此,预计PDGF酪氨酸激酶抑制剂可用于治疗多种表面上看来无关的、但是特征是在其病因中涉及PDGF和/或PDGF-R的人类疾病。
Hanke等人(Inflamm.Res.1995,44,357)与Bolen和Brugge(Ann.Rev.Immunol.,1997,15,371)总结回顾了非受体酪氨酸激酶例如p56lck(下文中称为″Lck″)在涉及T细胞活化和增殖的炎症相关性病症中的作用。这些炎性病症包括变态反应、自身免疫性疾病、类风湿性关节炎和移植排斥。另一篇近期综述总结了各类酪氨酸激酶抑制剂,包括具有Lck抑制活性的化合物(Groundwater等人,医用化学进展(Progress in Medicinal Chemistry),1996,33,233)。Lck酪氨酸激酶活性抑制剂包括通常是非选择性酪氨酸激酶抑制剂的几种天然产物,例如星形孢菌素、金雀异黄素、一些黄酮和制表菌素。虎刺醇是最近报道的低纳摩尔Lck抑制剂(Faltynek,等人,Biochemistry,1995,34,12404)。Lck合成抑制剂的实例包括:据报道具有低微摩尔-亚微摩尔活性的一系列二羟基异喹啉抑制剂(Burke,等人,J.Med.Chem.1993,36,425);和Lck IC50为610微摩尔的活性差很多的喹啉衍生物。研究人员已经公开了在微摩尔-亚微摩尔低浓度下抑制Lck的一系列4-取代的喹唑啉(Myers等人,WO95/15758和Myers等人,Bioorg.Med.Chem.Lett.1997,7,417)。Pfizer的研究人员(Hanke等人,J.Biol.Chem.1996,271,695)公开了具有抗Lck和Fyn(另一Src家族激酶)的低毫微摩尔效力的称为PP1和PP2的两种具体吡唑并嘧啶抑制剂。没有报道过任何关于基于喹啉或喹喔啉的化合物的Lck抑制剂。因此,预计基于喹啉或喹喔啉的Lck酪氨酸激酶活性抑制剂可用于治疗多种表面上看来无关的、但是特征是在其病因中涉及Lck酪氨酸激酶信号传导的人类病症。
发明概述
本发明涉及式I化合物、其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐:
其中
X是L1H或L2Z2;
L1是(CR3aR3b)r或(CR3aR3b)m-Z3-(CR3’aR3’b)n;
L2是(CR3aR3b)p-Z4-(CR3’aR3’b)q或乙烯基;
Z1是CH或N;
Z2是任选取代的环烷基、任选取代的环烯基、任选取代的杂环基或任选取代的杂环烯基;
Z3是O、NR4、S、SO或SO2;
Z4是O、NR4、S、SO、SO2、或一个键;
m是0或1;
n是2或3,且n+m=2或3;
p和q独立地为0、1、2、3或4,并且当Z4是一个键时,p+q=0、1、2、3或4,当Z4不是一个键时,p+q=0、1、2或3;
r是2、3或4;
R1a和R1b独立地为任选取代的烷基、任选取代的芳基、任选取代的杂芳基、羟基、酰氧基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、任选取代的杂环基羰基氧基、任选取代的芳氧基、任选取代的杂芳氧基、氰基、R5R6N-或酰基R5N-,或者R1a和R1b当中一个是氢或卤素,另一个是任选取代的烷基、任选取代的芳基、任选取代的杂芳基、羟基、酰氧基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、任选取代的杂环基羰基氧基、任选取代的芳氧基、任选取代的杂芳氧基、氰基、R5R6N-或酰基R5N-;
R1c是氢、任选取代的烷基、任选取代的芳基、任选取代的杂芳基、羟基、酰氧基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、任选取代的芳氧基、任选取代的杂芳氧基、卤素、氰基、R5R6N-或酰基R5N-;
R3a、R3b、R3’a和R3’b独立地为氢或烷基;
R4是氢、烷基或酰基;且
R5和R6独立地为氢或烷基,或者R5和R6与它们所连接的氮原子一起形成氮杂杂环基。
本发明另一方面涉及含有药物学有效量的式I化合物或其可药用盐和可药用载体的药物组合物。本发明还涉及用于制备式I化合物的中间体,制备所述中间体和式I化合物的方法,以及式I化合物在治疗患有或易患有涉及细胞分化、增殖、细胞外基质产生或介质释放和/或T细胞活化和增殖的疾病/病症的患者中的应用。
发明详述
除非另有说明,否则在上文和整个本发明说明书中使用的下述语具有下述含义:
定义
“患者”包括人和其它哺乳动物。
“有效量”是指能有效抑制PDGF-R酪氨酸激酶活性和/或Lck酪氨酸激酶活性、从而产生期望疗效的本发明化合物的量。
“烷基”是指具有约1-约10个碳原子的支链或直链脂族烃基。优选的烷基是具有约1-约6个碳原子、更优选具有约1-约4个碳原子的“低级烷基”。支链是指一个或多个低级烷基例如甲基、乙基或丙基接在直链烷基链上。烷基还可任选被烷氧基、卤素、羧基、羟基或R5R6N-取代。烷基的实例包括甲基、氟甲基、二氟甲基、三氟甲基、乙基、正丙基、异丙基、丁基、仲丁基、叔丁基、戊基和己基。
“链烯基”是指含有碳-碳双键、在链中具有约2-约10个碳原子的直链或支链脂族烃基。优选的链烯基在链中具有2-约6个碳原子;更优选在链中具有约2-约4个碳原子。支链是指一个或多个低级烷基例如甲基、乙基或丙基接在直链链烯基链上。“低级链烯基”是指在直链或支链的链中具有约2-约4个碳原子。链烯基可被烷氧羰基取代。链烯基的实例包括乙烯基、丙烯基、正丁烯基、异丁烯基、3-甲基丁-2-烯基、正戊烯基、庚烯基、辛烯基、环己基丁烯基和癸烯基。
“1,2-亚乙烯基(ethylenyl)”是指-CH=CH-。
“环烷基”是指具有约3-约10个碳原子的非芳族单环或多环环状系统。作为变量R1a、R1b或R1c一部分的环烷基可任选被一个或多个、优选1-3个、更优选1-2个下述“环烷基的取代基”取代:烷基、羟基、酰氧基、烷氧基、卤素、R5R6N-、酰基R5N-、羧基或R5R6NCO-取代基,或者在邻近碳原子上被二价氧(-O-)取代以形成环氧化物,更优选的取代基是烷基、羟基、酰氧基、烷氧基、二价氧和R5R6NCO-。作为变量Z2一部分的环烷基可任选被一个或多个、优选1-3个、更优选1-2个下述“环烷基的取代基”取代:烷基、烷氧基、卤素、R5R6N-、酰基R5N-、羧基或R5R6NCO-取代基,或者在邻近碳原子上被二价氧(-O-)取代以形成环氧化物,更优选的取代基是烷基、羟基、酰氧基、烷氧基、二价氧和R5R6NCO-。此外,当环烷基被至少两个羟基取代基取代时,则至少两个羟基取代基可以与具有1-6个碳原子的醛或酮发生缩酮化或缩醛化作用,以形成相应的缩酮或缩醛。偕二醇的缩酮化导致形成螺稠合环系。优选的螺环烷基环是1,4-二氧杂螺[4,5]癸-8-基。优选的未取代或取代的单环环烷基环包括环戊基、氟环戊基、环己基和环庚基;更优选环己基和环戊基。多环环烷基环的实例包括1-十氢化萘、金刚烷(1-或2-)基、[2.2.1]二环庚烷基(降冰片基)和[2.2.2]二环辛烷基;更优选[2.2.1]二环庚烷基和[2.2.2]二环辛烷基。
“环烯基”是指包含碳-碳双键、并具有约3-约10个碳原子的非芳族单环或多环环状系统。作为变量R1a、R1b或R1c一部分的环烯基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。作为变量Z2一部分的环烯基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。优选的未取代或取代的单环环烯基环包括环戊烯基、环己烯基和环庚烯基;更优选环戊烯基和环己烯基。优选的多环环烯基环包括[2.2.1]二环庚烯基(降冰片烯基)和[2.2.2]二环辛烯基。
“芳基”是指包含约6-约10个碳原子的芳族碳环基团。芳基的实例包括苯基或萘基,或者被一个或多个相同或不同的芳基的取代基取代的苯基或萘基,其中“芳基的取代基”包括氢、羟基、卤素、烷基、烷氧基、羧基、烷氧羰基或Y1Y2NCO-,其中Y1和Y2独立地为氢或烷基。优选的芳基的取代基包括氢、卤素和烷氧基。
“杂芳基”是指约5元-约10元芳族单环或多环烃环状系统,其中环状系统中的一个或多个碳原子是非碳元素,例如氮、氧或硫。作为前缀加在杂芳基前面的氮杂、氧杂或硫杂称谓是定义分别存在至少一个氮原子、氧原子或硫原子作为环原子。“杂芳基”也可以被一个或多个如上所述的“芳基的取代基”取代。杂芳基的实例包括取代的吡嗪基、呋喃基、噻吩基、吡啶基、嘧啶基、异噁唑基、异噻唑基、噁唑基、噻唑基、吡唑基、呋咱基、吡咯基、咪唑并[2,1-b]噻唑基、苯并呋咱基、吲哚基、吖吲哚基、苯并咪唑基、苯并噻吩基、喹啉基、咪唑基和异喹啉基。
“杂环基”是指约4元-约10元单环或多环环状系统,其中环状系统中的一个或多个原子是选自氮、氧和硫的非碳元素。作为变量R1a、R1b或R1c一部分的杂环基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。作为变量Z2一部分的杂环基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。作为前缀加在杂环基前面的氮杂、氧杂或硫杂称谓是定义分别存在至少一个氮原子、氧原子或硫原子作为环原子。单环杂环基的实例包括哌啶基、吡咯烷基、哌嗪基、吗啉基、硫代吗啉基、噻唑烷基、1,3-二氧杂环戊烷基(1,3-dioxolanyl)、1,4-二氧杂环己烷基(1,4-dioxanyl)、四氢呋喃基、四氢噻吩基、四氢噻喃基等。杂环基部分的实例包括奎宁环基(quinuclidyl)、硫杂己环、四氢吡喃基、四氢噻吩基、吡咯烷基、四氢呋喃基、7-氧杂二环[2.2.1]庚烷基、或4-哌啶子基哌啶。
“杂环基羰基氧基”是指杂环基-C(O)O-,其中杂环基如本文所定义。杂环基羰基氧基的实例是[1,4’]-联哌啶基-1’-羰基氧基(4-哌啶子基哌啶-1-基羰基氧基)。
“杂环烯基”是指约4元-约10元部分不饱和单环或多环环系,其中环系中的一个或多个原子是选自氮、氧和硫的非碳元素。作为变量R1a、R1b或R1c一部分的杂环烯基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。作为变量Z2一部分的杂环烯基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。作为前缀加在杂环烯基前面的氮杂、氧杂或硫杂称谓是定义分别存在至少一个氮原子、氧原子或硫原子作为环原子。单环氮杂杂环烯基的实例包括1,2,3,4-四氢吡啶基、1,2-二氢吡啶基、1,4-二氢吡啶基、1,2,3,6-四氢吡啶基、1,4,5,6-四氢嘧啶基、2-吡咯啉基、3-吡咯啉基、2-咪唑啉基、2-吡唑啉基等。氧杂杂环烯基的实例包括3,4-二氢-2H-吡喃、二氢呋喃基、和氟二氢呋喃基。多环氧杂杂环烯基的实例是7-氧杂二环[2.2.1]庚烯基。单环硫杂杂环烯基的实例包括二氢噻吩基和二氢噻喃基。
“酰基”是指H-CO-或烷基-CO-,其中烷基如上所定义。优选的酰基包含低级烷基。酰基的实例包括甲酰基、乙酰基、丙酰基、2-甲基丙酰基、丁酰基和己酰基。
“芳酰基”是指芳基-CO-,其中烷基如上所定义。其实例包括苯甲酰基与1-萘甲酰基和2-萘甲酰基。
“烷氧基”是指烷基-O-,其中烷基如上所定义。优选的烷氧基是具有约1-约6个碳原子的“低级烷氧基”。烷氧基可任选被一个或多个氨基、烷氧基、羧基、烷氧羰基、羧基芳基、氨基甲酰基或杂环基取代。烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、庚氧基、2-(吗啉-4-基)乙氧基、2-(乙氧基)乙氧基、2-(4-甲基哌嗪-1-基)乙氧基、羧基甲氧基和甲氧基羰基甲氧基。
“环烷氧基”是指环烷基-O-,其中环烷基如上所定义。环烷氧基的实例包括环戊基氧基和环己基氧基。
“杂环氧基”是指杂环基-O-,其中杂环基如上所定义。杂环氧基的实例包括奎宁环氧基、硫杂己环氧基、四氢吡喃基氧基、四氢噻吩基氧基、吡咯烷基氧基、四氢呋喃基氧基和7-氧杂二环[2.2.1]庚烷氧基。
“芳氧基”是指芳基-O-,其中芳基如上所定义。
“杂芳氧基”是指杂芳基-O-,其中杂芳基如上所定义。
“酰氧基”是指酰基-O-,其中酰基如上所定义。
“羧基”是指HO(O)C-(羧酸)基。
“R5R6N-”是指取代或未取代的氨基,其中R5和R6如上所定义。其实例包括氨基(H2N-)、甲基氨基、乙基甲基氨基、二甲基氨基和二乙基氨基。
“R5R6NCO-”是指取代或未取代的氨基甲酰基,其中R5和R6如上所定义。其实例是氨基甲酰基(H2NCO-)、N-甲基氨基甲酰基(MeNHCO-)、和N,N-二甲基氨基甲酰基(Me2NCO-)。
“酰基R5N-”是指酰基氨基,其中R5和酰基如上所定义。
“卤素”是指氟、氯、溴或碘。优选氟、氯或溴,更优选氟或氯。
“前药”是指式I化合物这样的形式,它们适于给患者施用,不引起不适的毒性、刺激、过敏反应等,并能有效地实现其预期应用,包括缩酮、酯和两性离子形式。前药在体内转化成式I母体化合物,例如通过在血液中水解转化成母化合物。T.Higuchi和V.Stella,“作为新的递送系统的前药”(Pro-drues as Novel Delivery Systems),the A.C.S.Symposium Series第14卷,和Edward B.Roche,编,“药物设计中生物可逆转的载体”(Bioreversible Carriers in Drug Design),AmericanPharmaceutical Association and Pergamon Press,1987中对前药作了充分论述,二者引入本发明以作参考。
“溶剂合物”是指本发明化合物与一个或多个溶剂分子形成的物理结合体。该物理结合体涉及不同程度的离子键和共价键,包括氢键。在某些情况下,例如当一个或多个溶剂分子掺入到结晶固体的晶格中时,溶剂合物能被分离出来。“溶剂合物”包括溶液相和可分离溶剂合物。溶剂合物的实例包括乙醇合物、甲醇合物等。“水合物”是溶剂分子是H2O的溶剂合物。
优选实施方案
优选的本发明化合物是定义如下的式I化合物、其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐,其中
L1是(CR3aR3b)m-Z3-(CR3’aR3’b)n;
L2是(CR3aR3b)p-Z4-(CR3’aR3’b)q;
Z2是任选取代的环烷基、任选取代的环烯基、或任选取代的杂环基;
Z4是O和NR4;
m是0;
n是2或3;
p+q=0或1;
R1a和R1b独立地为任选取代的烷基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、或R5R6N-,或者R1a和R1b当中一个是氢或卤素,另一个是任选取代的烷基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、或R5R6N-;
R1c是氢、任选取代的烷基、或任选取代的烷氧基;
R3a、R3b、R3’a和R3’b独立地为氢或低级烷基;
R4是氢;且
R5和R6与它们所连接的氮原子一起形成氮杂杂环基。
另外优选的本发明化合物是定义如下的式I化合物、其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐,其中
X是L2Z2;
L2是(CR3aR3b)p-Z4-(CR3’aR3’b)q;
Z2是任选取代的环烷基或任选取代的环烯基;
Z3是O和NR4;
p是0;
q是0或1;
R1a和R1b独立地为任选取代的烷基、任选取代的烷氧基、任选取代的环烷氧基、或任选取代的杂环氧基,或者R1a和R1b当中一个是氢或卤素;
R1c是氢;
R3’a和R3’b独立地为氢;且
R4是氢。
另外优选的本发明化合物是L1H为低级烷基的式I化合物。
另外优选的本发明化合物是Z1为CH的式I化合物。
另外优选的本发明化合物是Z1为N的式I化合物。
另外优选的本发明化合物是Z2为任选取代的环烷基的式I化合物。
另外优选的本发明化合物是Z2为烷基取代的单环环烷基、更优选为甲基环戊基或甲基环己基的式I化合物。
另外优选的本发明化合物是Z2为多环环烷基、更优选为[2.2.1]二环庚烷基(降冰片烷基)和[2.2.2]二环辛烷基的式I化合物。
另外优选的本发明化合物是Z2为任选取代的环烯基、更优选为环戊烯基和环己烯基的式I化合物。优选的多环环烯基包括[2.2.1]二环庚烯基(降冰片烯基)和[2.2.2]二环辛烯基。
另外优选的本发明化合物是Z2为环戊烯基和环己烯基的式I化合物。
另外优选的本发明化合物是Z2为多环环烯基、更优选为[2.2.1]二环庚烯基(降冰片烯基)和[2.2.2]二环辛烯基的式I化合物。
另外优选的本发明化合物是p和q为O的式I化合物。
另外优选的本发明化合物是p+q=1的式I化合物。
另外优选的本发明化合物是Z4为O的式I化合物。
另外优选的本发明化合物是Z4为O、且p和q为O的式I化合物。
另外优选的本发明化合物是Z4为O、且p+q=1的式I化合物。
另外优选的本发明化合物是Z4为NR4的式I化合物。
另外优选的本发明化合物是Z4为NR4、且p和q为O的式I化合物。
另外优选的本发明化合物是Z4为NR4、且m+n=1的式I化合物。
另外优选的本发明化合物是Z4为S的式I化合物。
另外优选的本发明化合物是Z4为S、且p和q为O的式I化合物。
另外优选的本发明化合物是Z4为S、且p+q=1的式I化合物。
另外优选的本发明化合物是R1a和R1b独立地为任选被羟基取代的低级烷基、羟基、低级烷氧基、环烷氧基、杂环氧基,或者R1a和R1b中一个是氢或卤素的式I化合物。
另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b独立地为杂环基羰基氧基或任选取代的低级烷氧基;更优选低级烷氧基为甲氧基或乙氧基。
另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b为低级烷基;更优选低级烷基为甲基或乙基。
另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是低级烷氧基,另一个是卤素;更优选低级烷氧基为甲氧基或乙氧基,卤素为氯或溴。
另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是低级烷基,另一个是低级烷氧基;更优选低级烷氧基为甲氧基或乙氧基,低级烷基为甲基或乙基。
另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是低级烷氧基,另一个是环烷氧基;更优选低级烷氧基为甲氧基或乙氧基,环烷氧基为环戊氧基或环己氧基。
另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是氢,另一个是低级烷氧基、环烷氧基或杂环氧基;更优选低级烷氧基为甲氧基或乙氧基,环烷氧基为环戊氧基或环己氧基,且杂环氧基更优选为呋喃基氧基。
另外优选的本发明化合物是这样的式I化合物,其中R1c是氢、低级烷基或低级氧烷基;更优选低级烷氧基为甲氧基或乙氧基。
另外优选的本发明化合物是Z2为(羟基或烷基)取代的羟基环烷基、更优选为(低级烷基)羟基环烷基的式I化合物。
另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b是低级烷氧基,其中所述低级烷氧基可任选被烷氧基、杂环基、羧基、烷氧羰基或氨基甲酰基取代。
另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是未取代的低级烷氧基,另一个是被烷氧基、杂环基、羧基、烷氧羰基或氨基甲酰基取代的低级烷氧基。
另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是甲氧基,另一个是[1,4′-]-联哌啶-1′-基羰基氧基、2-(乙氧基)乙氧基、2-(4-吗啉基)乙氧基、2-(4-甲基哌嗪-1-基)乙氧基、羧基甲氧基、甲氧基羰基甲氧基、氨基羰基甲氧基、N-甲基氨基羰基甲氧基、或N,N-二甲基氨基羰基甲氧基。
优选的本发明化合物选自:
3-环己氧基-6,7-二甲氧基喹啉;
2-环己基氨基-6,7-二甲氧基喹喔啉;
外-二环[2.2.1]庚-2-基-(6-氯-7-甲氧基喹喔啉-2-基)胺;
外-二环[2.2.1]庚-2-基-(7-氯-6-甲氧基喹喔啉-2-基)胺;
二环[2.2.1]庚-2-基-(6,7-二甲基喹喔啉-2-基)胺;
2-环庚基氨基-6,7-二甲氧基喹喔啉;
2-环戊基氨基-6,7-二甲氧基喹喔啉;
2-环己基氨基-6-甲氧基喹喔啉;
3-氨基环己基-6,7-二甲氧基喹啉;
(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺;
2-环己基氨基-6-甲氧基-7-溴喹喔啉盐酸盐;
(6,7-二甲氧基喹啉-3-基)-顺式/反式-(3-(R)-甲基环己基)胺;
(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基-环己基)胺;
(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基-环己基)胺;
(6.7-二甲氧基喹啉-3-基)-(3-甲基环戊基)胺;
环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)胺;
2,7-二环己氧基-6-甲氧基喹喔啉;
环己基-(6,7-二甲氧基喹喔啉-2-基甲基)胺;
(6,7-二甲氧基喹啉-3-基)异丁基胺;
环己基-(6-甲氧基-7-吗啉-4-基喹喔啉-2-基)胺;
(±)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
外-二环[2.2.1]庚-5-烯-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
环己基-(6,8-二甲基喹喔啉-2-基)胺;
内-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
(6,7-二甲氧基喹喔啉-2-基)-(4-甲氧基环己基)胺;
外-二环[2.2.1]庚-2-基-(6-甲氧基喹喔啉-2-基)胺;
外-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;
2-(二环[2.2.2]辛-2-基氧基)-6,7-二甲氧基喹喔啉;
内-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;
外-2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;
2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;
2-环己氧基-6,7-二甲氧基喹喔啉;
2-环戊硫基-6,7-二甲氧基喹喔啉;
6,7-二甲氧基-2-环戊氧基喹喔啉;
2-环戊基甲基氧基-6,7-二甲氧基喹喔啉;
6,7-二甲氧基-2-四氢吡喃-4-氧基喹喔啉;
外,外-6,7-二甲氧基-2-(5,6-环氧二环[2.2.1]庚烷-2-基氧基)喹喔啉;
顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸;
6,7-二甲氧基-2-(4-甲氧基-环己氧基)喹喔啉;
3-环己氧基-6,7-二甲氧基喹喔啉1-氧化物;
(1R,2R,4S)-(+)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
(1S,2S,4R)-(-)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
2-(6,7-二甲氧基喹喔啉-2-基)-2-氮杂-二环[2.2.2]辛烷-3-酮;
顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;
顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸;
顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;
反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;
(6,7-二甲氧基喹喔啉-2-基)-顺式/反式-(3-(R)-甲基环己基)胺;
(6,7-二甲氧基喹喔啉-2-基)-反式-(3-(R)-甲基环己基)胺;
(6,7-二甲氧基喹喔啉-2-基)-顺式-(3-(R)-甲基环己基)胺;和
顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸甲酯;
或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。
更优选的化合物是:
2-环己基氨基-6,7-二甲氧基喹喔啉;
外-二环[2.2.1]庚-2-基-(6-氯-7-甲氧基喹喔啉-2-基)胺;
外-二环[2.2.1]庚-2-基-(7-氯-6-甲氧基喹喔啉-2-基)胺;
二环[2.2.1]庚-2-基-(6,7-二甲基-喹喔啉-2-基)胺;
2-环庚基氨基-6,7-二甲氧基喹喔啉;
2-环戊基氨基-6,7-二甲氧基喹喔啉;
3-氨基环己基-6,7-二甲氧基喹啉;
(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基-环己基)胺;
(6,7-二甲氧基喹啉-3-基)-顺式/反式-(3-(R)-甲基-环己基)胺;
(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基环己基)胺;
(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺;
环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)胺;
2,7-二环己氧基-6-甲氧基喹喔啉;
(6,7-二甲氧基喹啉-3-基)异丁基胺;
(±)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
外-二环[2.2.1]庚-5-烯-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
内-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
外-二环[2.2.1]庚-2-基-(6-甲氧基喹喔啉-2-基)胺;
外-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;
2-(二环[2.2.2]辛-2-基氧基)-6,7-二甲氧基喹喔啉;
内-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;
外-2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;
2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;
2-环己氧基-6,7-二甲氧基喹喔啉;
2-环戊硫基-6.7-二甲氧基喹喔啉;
6,7-二甲氧基-2-环戊氧基喹喔啉;
2-环戊基甲氧基-6,7-二甲氧基喹喔啉;
6,7-二甲氧基-2-四氢吡喃-4-氧基喹喔啉;
外,外-6,7-二甲氧基-2-(5,6-环氧二环[2.2.1]庚烷-2-基氧基)喹喔啉;
6,7-二甲氧基-2-(4-甲氧基-环己氧基)喹喔啉;
(1R,2R,4S)-(+)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
(1S,2S,4R)-(-)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;
顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;
反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;
(6,7-二甲氧基喹喔啉-2-基)-顺式/反式-(3-(R)-甲基环己基)胺;
(6,7-二甲氧基喹喔啉-2-基)-反式-(3-(R)-甲基环己基)胺;
(6,7-二甲氧基喹喔啉-2-基)-顺式-(3-(R)-甲基环己基)胺;
顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸甲酯;
或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。
应当理解,本发明包括本文特定和优选组的所有适当组合。
本发明化合物可通过使用文献中已知的方法由已知化合物或易于制得的中间体制得。一般方法的实例如下。
此外,式I化合物是依据下述反应方案I-VIII制得的,其中各变量如上文所述,但是本领域技术人员可理解的与所述方法不相容的变量除外。
反应方案I
反应方案II
反应方案III
反应方案IV
反应方案V
反应方案VI
其中R1a、R1b和R1c当中至 其中R1a、R1b和R1c当中至
少有一个是低级烷氧基, 少有一个如本文所定义,
且X”’是L1OP’或L2Z2,其 且X是L1OP’,然后除去保
中P’是适于在碱和烷化剂 护基P’以生成相应的OH
存在下保护羟基部分的保 部分
护基
在反应方案VI、VII和VIII中,R代表如本文所定义的R1a、R1b或R1c的前体基团,这样在反应方案VI、VII和VIII中所描述的条件下,RBr、ROH、或RCOCl与芳羟基的反应导致形成R1a、R1b或R1c。
代表性的RBr包括溴乙酸和溴乙酸甲酯与溴乙酸乙酯。
代表性的ROH包括2-乙氧基乙醇、2-(4-吗啉基)乙醇和3-(4-甲基哌嗪基)丙醇。
代表性的RCOCl是[1,4’]-联哌啶-1’-基羰基氯。
反应方案VII
反应方案VIII
反应方案IX
反应方案X
I.一般方法:
1.将2-氯取代的喹喔啉与胺或苯胺偶联
将2-氯-6,7-二甲氧基喹喔啉(1当量)与胺(约1-约5当量)的混合物在约160-约180℃加热约3小时至过夜。将该深棕色残余物溶于甲醇/二氯甲烷(0%-10%)中,并通过硅胶色谱纯化,用己烷/乙酸乙酯或甲醇/二氯甲烷(0%-100%)洗脱,获得所需产物。可通过在甲醇、二氯甲烷或甲醇/水中重结晶来将所需产物进一步纯化。
2.将2-氯取代的喹喔啉与醇或苯酚偶联
将醇或硫醇(1当量)与氢化钠(约1-约3当量)在无水DMF/THF(0%-50%)中的悬浮液回流1小时,然后加入2-氯-6,7-二甲氧基喹喔啉(1当量)。将所得混合物回流约1-约4小时。将该悬浮液中和至约pH 5-8,并在二氯甲烷与盐水之间分配。将二氯甲烷浓缩后,通过硅胶色谱纯化残余物,用己烷/乙酸乙酯或甲醇/二氯甲烷(0%-100%)洗脱,获得所需产物。
3.将氨基喹啉与醛或酮进行还原胺化反应
将适当取代的3-氨基喹啉(1当量)与1当量合适的醛或酮在甲醇(或另一合适的溶剂混合物)中搅拌直至TLC表明亚胺形成已完全。加入过量NaCNBH4或NaBH4、或另一种合适的还原剂,将该混合物搅拌直至TLC表明亚胺中间体已完全反应。将该混合物浓缩,通过硅胶色谱纯化残余物,用己烷/乙酸乙酯(0-100%)或氯仿/甲醇(0-20%)洗脱,获得所需产物。
4.将3-氨基取代的喹啉与溴苯基化合物偶联
在惰性气氛例如氩气氛下,将适当取代的3-氨基喹啉(1当量)与~1.4当量强碱例如叔丁醇钠、1当量合适的溴苯基化合物、和催化量的2,2’-二(二苯基膦基)-1,1’-联萘(S-BINAP)与二(二亚苄基丙酮)钯(Pd(dba)2)搅拌混合在惰性有机溶剂例如甲苯中,并在约80℃加热过夜。将该混合物冷却,用溶剂例如乙醚稀释,过滤,浓缩并通过色谱法纯化,用50%EtOAc/己烷洗脱,获得所需产物。
5.通过Mitsunobu条件由3-羟基取代的喹啉形成醚
用各1当量的所需醇、三苯膦和最后的偶氮二甲酸二乙酯(DEAD)或适当的等同物处理适当取代的羟基喹喔啉的THF溶液(在约0-约25℃)。通过TLC监测反应进程,反应完全后(约1-约24小时),将该混合物浓缩,通过硅胶色谱纯化残余物,获得所需产物。
6.低级烷氧基取代的喹啉或喹喔啉的脱烷基化、和随后的烷基化
用过量乙硫醇钠(通常约2或更多当量)处理在DMF中的适当低级烷氧基取代的喹啉或喹喔啉(1当量),在搅拌下将该反应混合物加热约1-约24小时。将该混合物在水与乙酸乙酯之间分配。萃取,如果需要的话然后进行色谱纯化,获得了相应的羟基取代的所需喹啉或喹喔啉产物。
可用如上所详述的Mitsunobu反应条件将所得羟基取代的喹啉或喹喔啉产物烷基化。或者,采用本领域众所周知的方法,在合适的溶剂中使用NaH或另一适当碱,用活性烷基卤或苄基卤进行简单烷基化,以生成所需烷基化产物。
7.将喹啉或喹喔啉中的氮氧化成相应的N-氧化物。
式(I)喹啉或喹喔啉化合物中的亚胺(=N-)部分可转化成该亚胺部分被氧化成N-氧化物的相应化合物,优选通过与过酸例如在乙酸中的过乙酸或在惰性溶剂例如二氯甲烷中的间氯过苯甲酸于约室温-回流温度、优选提高的温度下反应来进行氧化。
游离碱或游离酸或可药用盐形式的本发明化合物都是有用的。所有这些形式都在本发明范围内。
当本发明化合物被碱性部分取代时,可形成酸加成盐,并且其只是更便于使用的形式;实际上,使用该盐形式本质上相当于使用游离碱形式。可用于制备酸加成盐的酸优选包括当与游离碱合并时能生成可药用盐的酸,可药用盐是表示在该盐的药用剂量下其阴离子对患者没有毒性,这样该游离碱所固有的对PDGF的有益抑制作用就不被阴离子的副作用所失效。虽然所述碱性化合物的可药用盐是优选的,但是所有酸加成盐都可用作游离碱形式的来源,即使特定的盐自身仅作为中间产物而需要,例如形成该盐仅是为了纯化和鉴定,或者该盐用作通过离子交换方法制备可药用盐的中间体。在本发明范围内的可药用盐是用下述酸形成的盐:无机酸例如盐酸、硫酸、磷酸、和氨基磺酸;和有机酸例如乙酸、柠檬酸、乳酸、酒石酸、丙二酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己基氨基磺酸、奎尼酸等。相应的酸加成盐分别包含下述盐:氢卤酸盐例如盐酸盐和氢溴酸盐,硫酸盐、磷酸盐、硝酸盐、氨基磺酸盐、乙酸盐、柠檬酸盐、乳酸盐、酒石酸盐、丙二酸盐、草酸盐、水杨酸盐、丙酸盐、琥珀酸盐、富马酸盐、马来酸盐、亚甲基二-β-羟基萘甲酸盐、2,5-二羟基苯甲酸盐、甲磺酸盐、羟乙基磺酸盐和二对甲苯甲酰基酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、环己基氨基磺酸盐和奎尼酸盐。
依据本发明另一方面,本发明化合物的酸加成盐可通过使用已知方法或对已知方法作改动将游离碱与合适的酸反应而制得。例如,本发明化合物的酸加成盐可这样制得:将游离碱溶于含有适当酸的水溶液或含水醇溶液或其它合适溶剂中,并通过蒸发该溶液分离出所生成的盐;或者将游离碱与酸在有机溶剂中反应,在这种情况下,盐直接分离出来,或者可通过将溶液浓缩来获得盐。
通过使用已知方法或对已知方法作改动,可从酸加成盐再生出本发明化合物。例如,本发明母体化合物可通过用碱例如碳酸氢钠水溶液或氨水溶液处理而从其酸加成盐再生出来。
当本发明化合物被酸性部分取代时,可形成碱加成盐,并且其只是更便于使用的形式;实际上,使用该盐形式本质上相当于使用游离酸形式。可用于制备碱加成盐的碱优选包括当与游离酸合并时能生成可药用盐的碱,可药用盐是表示在该盐的药用剂量下其阳离子对动物机体没有毒性,这样该游离酸所固有的对PDGF的有益抑制作用就不被阳离子的副作用所失效。在本发明范围内的可药用盐,包括例如碱金属盐和碱土金属盐,是用下述碱形成的盐:氢化钠、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁、氢氧化锌、氨、三甲胺、三乙胺、乙二胺、N-甲基葡糖胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N’-二苄基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯乙胺、二乙胺、哌嗪、三(羟基甲基)氨基甲烷、氢氧化四甲基铵等。
本发明化合物的金属盐可通过将游离酸形式的本发明化合物与所选金属的氢化物、氢氧化物、碳酸盐或类似活性化合物在含水溶剂或有机溶剂中接触来制得。所用的含水溶剂可以是水,或者可以是水与有机溶剂的混合物,所述有机溶剂优选为醇例如甲醇或乙醇,酮例如丙酮,脂族醚例如四氢呋喃,或酯例如乙酸乙酯。这样的反应通常是在室温进行的,但是如果需要的话,可以在加热条件下进行。
本发明化合物的胺盐可通过将游离酸形式的本发明化合物与胺在含水溶剂或有机溶剂中接触来制得。合适的含水溶剂可以是水以及水与下述有机溶剂的混合物:醇例如甲醇或乙醇,醚例如四氢呋喃,腈例如乙腈,或酮例如丙酮。氨基酸盐可通过类似方法制得。
通过使用已知方法或对已知方法作改动,可从碱加成盐再生出本发明化合物。例如,本发明母体化合物可通过用酸例如盐酸处理其碱加成盐而从中再生出来。
除了用作活性化合物以外,本发明化合物的盐还可用于纯化本发明化合物,例如,通过采用本领域技术人员众所周知的技术,利用该盐与母体化合物、副产物和/或原料之间的溶解度差异来进行纯化。
本发明化合物可含有不对称中心。这些不对称中心可独立地呈R或S构型。某些式I化合物还可能表现出几何异构现象,这对于本领域技术人员来说也是显而易见的。几何异构体包括顺式和反式形式的本发明化合物,即在环系上有链烯基部分或取代基的化合物。此外,二环环系包括内型和外型异构体。本发明包含单独的几何异构体、立体异构体、对映体和它们的混合物。
通过使用已知方法或对已知方法作改动,例如使用色谱技术和重结晶技术,可从其混合物中分离出这样的异构体,或者可用其中间体的适当异构体分开地制备它们,例如通过使用或改变本文所述方法来进行制备。
原料和中间体是通过使用已知方法或对已知方法作改动,例如使用在参考实施例中描述的方法或其明显的化学同等方法,或者通过依据本发明描述的方法制得的。
描述本发明化合物制备的下述示例性实施例进一步举例说明了本发明,但不是对本发明的限制。
此外,下述实施例是用于合成本发明化合物的代表性方法。
实施例1 3-环己氧基-6,7-二甲氧基喹啉
在0℃,向THF溶液(30mL)中加入3-羟基-6,7-二甲氧基喹啉(0.237g,1.15mmol)、环己醇(0.347g,3.46mmol)、Ph3P(0.908g,3.46mmol)。分批加入偶氮二甲酸二乙酯直至该溶液保持深红色为止(0.663g,3.81mmol)。4小时后,将该溶液浓缩,通过色谱法纯化残余物(50%EtOAc的己烷溶液)。用异丙醇/己烷将该产物重结晶,获得了其盐酸盐,为白色固体(m.p.229-232℃,分解温度)。
实施例2 2-苯氨基-6-异丙氧基喹喔啉盐酸盐
在氩气氛下,向NaH(0.033g,0.84mmol)加入1mL DMF。分批加入在1.5mL DMF中的2-苯氨基-6-喹喔啉醇(0.1g,0.42mmol)。30分钟后,滴加2-溴丙烷,将该溶液在50℃加热1.5小时。用水处理该冷却的反应混合物,在EtOAc与水之间分配,依次用H2O(3×)、盐水洗涤,干燥(MgSO4),并浓缩。通过色谱法纯化残余物(30%EtOAc/己烷),获得了0.05g二烷基化产物和0.1g本标题化合物。将IPA(异丙醇)/HCl加到该游离碱的Et2O/IPA溶液中以制得盐酸盐(m.p.205-210℃,分解温度),将其用作盐酸盐分析样本。
元素分析C17H17N3O·HCl
计算值:C,64.65;H,5.74;N,13.31;
实测值:C,64.51;H,5.90;N,13.09。
实施例3 2-环己基氨基-6,7-二甲氧基喹喔啉
向0.3g(1.34mmol)2-氯-6,7-二甲氧基喹喔啉中加入约1mL环己基胺。将该混合物在105℃加热过夜,然后在135℃加热10小时。将该混合物在二氯甲烷和饱和NaHCO3之间分配。将有机层干燥(MgSO4)并浓缩。通过色谱法纯化所得浆状物(1∶1EtOAc∶CH2Cl2),以69%的产率获得了0.265g产物,为浅棕色固体(m.p.188-189.5℃)。
元素分析C16H21N3O2
计算值:C,66.88;H,7.37;N,14.62
实测值:C,66.82;H,7.28;N,14.45。
采用上述标准偶联方法,用适当原料制得了下述化合物:
外-二环[2.2.1]庚-2-基-(6-氯-7-甲氧基喹喔啉-2-基)胺
(m.p.171-173℃)
元素分析C16H18N3OCl
计算值:C,63.26;H,5.97;N,13.83
实测值:C,63.37;H,5.91;N,13.83。
外-二环[2.2.1]庚-2-基-(7-氯-6-甲氧基喹喔啉-2-基)胺
(m.p.146-147.5℃)
元素分析C16H18N3OCl
计算值:C,63.26;H,5.97;N,13.83
实测值:C,63.34;H,5.93;N,13.77。
二环[2.2.1]庚-2-基-(6,7-二甲基喹喔啉-2-基)胺
(m.p.155-157℃)
元素分析C17H21N3
计算值:C,76.37;H,7.92;N,15.72
实测值:C,75.58;H,7.55;N,15.38。
2-环庚基氨基-6,7-二甲氧基喹喔啉
(m.p.134-136℃)
元素分析C17H23N3O2
计算值:C,67.75;H,7.69;N,13.94
实测值:C,67.80;H,7.61;N,13.77。
2-环戊基氨基-6,7-二甲氧基喹喔啉
(m.p.149-151℃)
元素分析C15H19N3O2
计算值:C,65.91;H,7.01;N,15.37
实测值:C,66.04;H,6.96;N,15.47。
2-环己基氨基-6-甲氧基喹喔啉
(m.p.242-248℃)
实施例4 3-氨基环己基-6,7-二甲氧基喹啉
在氩气氛下,向分子筛粉末(0.11g)的MeOH(3mL)溶液中加入3-氨基-6,7-二甲氧基喹啉盐酸盐(0.17g,0.68mmol)和NaOMe(0.039g,0.71mmol)。将该反应混合物在室温搅拌30分钟,依次滴加环己酮(0.074mL,0.71mmol)和吡啶·硼烷(0.072mL,0.071mmol)。将该混合物搅拌4.5小时,然后滴加5N HCl(1.4mL,6.8mmol)。将该反应混合物搅拌45分钟,然后用5N NaOH将其碱化至呈强碱性。将该混合物在EtOAc和水之间分配,用EtOAc(2×)洗涤水层。用盐水(1×)洗涤合并的有机层,干燥(MgSO4),通过色谱法纯化(50%EtOAc/己烷),并用EtOAc/己烷重结晶,以57%的产率获得了0.112g浅黄色固体(m.p.164-165℃)。
元素分析C17H22N2O2
计算值:C,71.30;H,7.74;N,9.78
实测值:C,71.45;H,7.49;N,9.80。
实施例5 2-环己基氨基-6-甲氧基-7-溴喹喔啉盐酸盐
在密封管中,向0.75g(2.7mmol)7∶1 7-溴-6-甲氧基喹喔啉-2-醇∶6-溴-7-甲氧基喹喔啉-2-醇中加入5mL环己基胺。将该反应混合物在120℃加热2小时。将环己基胺减压除去,把残余物在EtOAc/H2O之间分配。将有机层依次用H2O(2×)、盐水(1×)洗涤,并干燥(MgSO4)。通过色谱法纯化所得残余物(20%然后是30%EtOAc/己烷),以88%的产率获得了0.81g主产物。通过将约0.13g该游离碱转化成其盐酸盐(m.p.280℃,分解温度)来获得分析样本。
元素分析C15H18N3OBr·HCl
计算值:C,48.34;H,5.14;N,11.27
实测值:C,48.51;H,4.98;N,11.09。
实施例6(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺二盐酸盐和(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基环己基)胺二盐酸盐
将通过3-氨基-6,7-二甲氧基喹啉和3-(R)-甲基环己酮的还原胺化制得的(6,7-二甲氧基喹啉-3-基)-(3-(R)-甲基环己基)胺的顺式/反式混合物通过RP-HPLC分离。将所得两个样本都再次进行色谱处理(70%EtOAc/己烷)以获得纯游离碱。通过将游离碱分别单独转化成无定形且有几分吸湿的二盐酸盐来获得各异构体的分析样本。产物的500Mhz 1H NMR是一致的,并且LC/MS和FAB证实了各异构体的M+H=301。
实施例7 环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)胺
在-78℃,向反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇(303mg,1mmol)在10mL THF内的溶液中加入三苯基膦(524mg,2mmol)和偶氮二甲酸二乙酯(1mL)。将该混合物在-78℃搅拌1小时,然后加入4-硝基苯甲酸(334mg,2mmol)。在-78℃搅拌1小时后,将该混合物再在室温继续搅拌1小时,然后浓缩。通过硅胶色谱纯化残余物(乙醚),获得了250mg(87.7%)环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)胺。
实施例8 2-苯氨基-6-喹喔啉醇
按照Feutrill,G.I.;Mirrington,R.N.Tet.Lett.1970,1327的方法,将芳基甲基醚转化成苯酚衍生物。在氩气氛下,向DMF中的2-苯氨基-6-甲氧基喹喔啉(0.27g,1.07mmol)中加入乙硫醇钠(0.19g,2mmol)。将该反应混合物在110℃加热过夜。将该混合物浓缩,并在乙酸乙酯与水/5%酒石酸之间分配,使得水层的pH大约为4。依次用水(4×)、2.5%氢氧化钠(4×)洗涤有机层。将碱性层合并,用乙酸乙酯(2×)洗涤,用5%酒石酸再酸化,并用EtOAc乙酸乙酯洗涤多次。将有机层合并,用盐水洗涤,干燥(硫酸钠)并浓缩。通过色谱法纯化残余物(50%EtOAc/己烷)。用Et2O将产物研制,获得了黄色粉末(m.p.211-213℃),将其用作分析样本。
元素分析C14H11N3O
计算值:C,70.88;H,4.67;N,17.71;
实测值:C,70.64;H,4.85;N,17.58。
实施例9 苯基-[6-(四氢呋喃-3-(R)-基氧基)喹喔啉-2-基]胺
在0℃、氩气氛下,向THF溶液中加入2-苯氨基-6-喹喔啉醇(0.23g,0.97mmol)、(S)-(+)-3-羟基四氢呋喃(0.086mL,1.3mmol)和三苯基膦(0.31g,1.2mmol)。滴加DEAD(0.18mL,1.2mmol)。将该反应混合物升至室温,并搅拌1.5小时。将该混合物浓缩,并在乙酸乙酯和水之间分配。依次用水和盐水洗涤有机层,干燥(MgSO4),并浓缩。通过色谱法纯化所得黄色油状物(50%EtOAc/己烷),并置于Et2O/IPA。滴加HCl/Et2O溶液,将所得红橙色粉末真空干燥。通过在含有洗涤过的(3×H2O、5×MeOH)碱离子交换树脂的甲醇中搅拌来除去所得粉末中的碱。将该混合物搅拌30分钟,过滤,浓缩,并用EtOAc/己烷重结晶,分两批获得了产物(m.p.173-175℃)。
元素分析C18H17N3O2
计算值:C,70.35;H,5.57;N,13.67;
实测值:C,70.19;H,5.60;N,13.66。
实施例10 2,7-二环己氧基-6-甲氧基喹喔啉
在氩气氛下,向NaH(0.32g,8mmol)的DMF溶液(5mL)中滴加环己醇(0.7mL,6.7mmol)。将该混合物在室温搅拌25分钟,然后滴加2-氯-6,7二甲氧基喹喔啉。将该反应在室温搅拌15分钟,在90℃搅拌2小时,在110℃搅拌1小时。将该混合物冷却,用水处理,并在EtOAc/H2O之间分配。用水和盐水洗涤有机层,干燥(MgSO4),并通过色谱法纯化(10%EtOAc/己烷),获得了蜡状白色固体(m.p.75-78℃)。
元素分析C21H28N2O3
计算值:C,70.76;H,7.92;N,7.86;
实测值:C,70.81;H,7.79;N,7.70。
实施例11 环己基-(6,7-二甲氧基喹喔啉-2-基甲基)胺
向0.067M 6,7-二甲氧基-2-喹喔啉甲醛在2∶1 MeOH/1,2-二氯乙烷(7.5mL,0.5mmol)内的溶液中加入环己基胺(0.11mL,0.9mmol)。将该反应在室温搅拌过夜,然后加入NaBH4(0.038g,1mmol),并将该反应混合物搅拌过夜。然后将该混合物浓缩,并通过色谱法纯化(50%EtOAc/己烷-约5%MeOH在50%EtOAc/己烷中的溶液)。将所得油状物溶于EtOAc/己烷,并用HCl的EtOH溶液处理。将所得溶液浓缩,异丙醇研制所得固体,在60℃真空干燥,获得了白色固体(m.p.185-190℃,分解温度)。
元素分析C17H23N3O2·HCl
计算值:C,60.44;H,7.16;N,12.44;
实测值:C,60.48;H,6.88;N,12.07。
实施例12(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基环己基)胺和(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺
按照与上述制备类似的方式,用3-氨基-6,7-二甲氧基喹啉的游离碱(0.32g,1.6mmol)与(R)-(+)-3-甲基环己酮(0.23mL,1.9mmol)进行反应。通过色谱法纯化所得产物混合物(70%EtOAc/己烷),并用EtOAc/己烷重结晶,获得了白色固体(1∶1的顺式和反式异构体混合物)(m.p.153-160℃)。
元素分析C18H24N2O2
计算值:C,71.97;H,8.05;N,9.33;
实测值:C,72.12;H,7.85;N,9.29。
采用上述标准偶联方法,用适当原料制得了下述化合物:
(6,7-二甲氧基喹啉-3-基)-(3-甲基环戊基)胺
(m.p.106-109℃)
元素分析C17H22N2O2
计算值:C,71.30;H,7.74;N,9.78
实测值:C,71.24;H,7.56;N,9.61。
实施例13 3-(6,7-二甲氧基喹啉-3-基氨基)-2,2-二甲基丙-1-醇
按照与实施例11中的制备相类似的方式进行反应。在氩气氛下,向分子筛粉末(0.35g)的MeOH溶液中加入3-氨基-6,7-二甲氧基喹啉(0.32g,1.6mmol)和2,2-二甲基-3-羟基丙醛(0.19g,1.9mmol)。通过色谱法纯化该产物混合物(3%MeOH/CHCl3),获得了0.10g物质,将其在CH2Cl2/10%NaOH之间分配。依次用10%NaOH、H2O和盐水洗涤有机层,然后干燥(MgSO4),并用EtOAc/己烷重结晶,获得了浅橙色固体(m.p.170-173.5℃)
元素分析C16H22N2O3
计算值:C,66.18;H,7.64;N,9.65;
实测值:C,66.11;H,7.49;N,9.33。
采用上述标准偶联方法,用适当原料制得了下述化合物:
(6,7-二甲氧基喹啉-3-基)异丁基胺
(m.p.158-162℃)
元素分析C15H20N2O2
计算值:C,69.20;H,7.74;N,10.76
实测值:C,69.06;H,7.82;N,11.01。
实施例14 环己基-(6-甲氧基-7-吗啉-4-基-喹喔啉-2-基)胺
该制备是通过将Buchwald,等人在J.Am.Chem.Soc.,1996,118,7215中描述的方法作适当改动而进行的。在氩气氛下,向2-环己基氨基-6-甲氧基-7-溴喹喔啉(0.1g,0.3mmol)的甲苯溶液中加入吗啉(0.1g,0.3mmol)、叔丁醇钠(0.04g,0.42mmol)、S-(-)-BINAP(催化剂,0.001g)、和二(二亚苄基丙酮)钯(催化剂,0.001g)。将该反应混合物在80℃加热过夜。将该混合物冷却,用乙醚稀释,过滤,浓缩,并通过色谱法纯化(50%EtOAc/己烷)。用EtOAc/己烷将产物重结晶,分两批获得了黄色固体(m.p.194-196℃)。
元素分析C19H26N4O2
计算值:C,66.64;H,7.65;N,16.36;
实测值:C,66.60;H,7.60;N,16.51。
实施例15 反式-4-(7-氯-6-甲氧基喹喔啉-2-氨基)环己醇和反式-4-(6-氯-7-甲氧基喹喔啉-2-基-氨基)环己醇
在氩气氛下,向装配有迪安-斯达克分水器和冷凝器的反应烧瓶中加入6∶1 2,7-二氯-6-甲氧基喹喔啉∶2,6-二氯-7-甲氧基喹喔啉(0.30g,1.3mmol)和反式-4-氨基环己醇(0.35g,3mmol)。将该反应混合物在170℃加热约10小时,然后浓缩,进行2次色谱分离(7%MeOH/CHCl3,然后是5%MeOH/CHCl3)。用EtOAc/己烷将产物重结晶,获得了浅黄色固体(m.p.144-147℃)。
元素分析C19H26N4O2·0.4H2O
计算值:C,57.20;H,6.02;N,13.34;
实测值:C,57.21;H,5.97;N,13.08。
1H NMR分析表明产物是2∶1的反式-4-(7-氯-6-甲氧基喹喔啉-2-氨基)环己醇∶反式-4-(6-氯-7-甲氧基喹喔啉-2-基-氨基)环己醇混合物。
实施例16 反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇
将反式-4-氨基环己醇(0.11g,2当量)与2-氯-6,7-二甲氧基喹喔啉(0.1g,1当量)混合,并在160-180℃加热4-8小时。将该深棕色悬浮液过滤并浓缩。通过快速柱色谱法纯化残余物,用3%甲醇/二氯甲烷洗脱,获得了产物,为黄色粉末,熔点为119-123℃。
元素分析C16H21N3O3
计算值:C,62.33;H,7.05;N,13.63;
实测值:C,62.35;H,7.09;N,13.18。
可通过下述方法将该化合物重结晶。将0.2g黄色粉末在2.5mL水与1.25mL甲醇的混合物中回流以获得澄清的橙色溶液。将该热溶液静止,并逐渐冷却。通过过滤收集橙色针状结晶,并在高度真空下干燥,获得了黄色固体(m.p.119-120℃)。
或者,按如下所述制备本标题化合物的盐酸盐:在0℃,向反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇的异丙醇溶液中加入HCl溶液。将该混合物搅拌15分钟,然后过滤。将所收集的固体在高度真空下干燥,获得了反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇盐酸盐。
元素分析C16H22ClN3O3·1.2H2O
计算值:C,53.19;H,6.80;N,11.63;Cl,9.81;
实测值:C,53.14;H,6.85;N,11.24;Cl,10.28。
或者,按如下所述制备本标题化合物的硫酸盐:按照常规操作,将反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇溶于丙酮或另一适当有机溶剂中,并按照需要温热至45℃。在快速搅拌下向所得溶液中小心地加入硫酸水溶液(1当量,1M溶液)。收集由此形成的盐并干燥,以>80%的产率获得了硫酸盐。
实施例17(±)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺
方法A:将2-氯-6,7-二甲氧基喹喔啉(5g,22.3mmol)与(±)-外-降冰片烷基-2-胺(10g,90mmol)的混合物在160-180℃加热过夜。将该深棕色残余物溶于200mL二氯甲烷中,并用1N NaOH(50mL)洗涤。用硫酸镁将有机层干燥,然后过滤。浓缩后,通过硅胶色谱纯化残余物,用己烷/乙酸乙酯(80%)洗脱,获得了所需产物,为黄色固体,可将其在甲醇中重结晶。
方法B:将2-氯-6,7-二甲氧基喹喔啉(9g,40.1mmol)与(±)-外降冰片烷-2-胺(5.77g,52mmol)、叔丁醇钠(4.22g,44mmol)、2,2’-二(二苯基膦基)-1,1’-联萘(BINAP,120mg)以及二(二亚苄基丙酮)钯(Pd(dba)2,40mg)在80mL甲苯中的混合物在80℃加热8小时。加入另一部分BINAP(60mg)和Pd(dba)2(20mg),将该混合物在100℃加热过夜。用200mL二氯甲烷稀释后,用1NNaOH(100mL)洗涤该反应混合物。用硫酸镁将有机层干燥并过滤。浓缩后,通过硅胶色谱法纯化残余物,用己烷/乙酸乙酯(80%)洗脱,获得了所需产物,为浅黄色固体(m.p.188-189℃)。
元素分析C17H21N3O3
计算值:C,68.20;H,7.07;N,14.04;
实测值:C,68.18;H.7.03;N,14.03。
用适当原料以类似方法(方法A)制备下述化合物:
外-二环[2.2.1]庚-5-烯-2-基-(6,7-二甲氧基喹喔啉-2-基)胺
(m.p.175-177℃)
元素分析C17H19N3O2·0.4H2O
计算值:C,60.94;H,6.56;N,13.78;
实测值:C,66.98;H,6.62;N,12.73。
环己基-(6,8-二甲基喹喔啉-2-基)胺
[MS m/z:255(M+)]
元素分析C16H21N3
计算值:C,75.26;H,8.29;N,16.46;
实测值:C,75.08;H,8.28;N,15.86。
内-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺
(m.p.79-82℃)。
(6,7-二甲氧基喹喔啉-2-基)-(4-甲氧基环己基)胺
(m.p.58-68℃)。
元素分析C17H23N3O3·0.5H2O
计算值:C,62.56;H,7.41;N,12.87;
实测值:C,62.53;H,7.22;N,12.22。
外-二环[2.2.1]庚-2-基-(6-甲氧基喹喔啉-2-基)胺
(m.p.98-100℃)
元素分析C16H19N3O
计算值:C,71.35;H,7.11;N,15.60;
实测值:C,70.38;H,7.03;N,15.05。
实施例18 外-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉
将外-2-降冰片(223mg,2mmol)和NaH(60%,100mg,2.5mmol)在10mL无水THF中的混合物回流0.5小时,然后加入2-氯-6,7-二甲氧基喹喔啉(336mg,1.5mmol)。将所得混合物继续回流2小时。过滤并浓缩后,通过硅胶色谱纯化残余物(50%乙醚/己烷),获得了所需产物,为白色固体(m.p.135-137C)。
元素分析C17H20N2O3
计算值:C,67.98;H,6.71;N,9.33;
实测值:C,67.96;H,6.762;N,9.19。
用适当原料以标准偶联方法制备下述化合物:
2-(二环[2.2.2]辛-2-基氧基)-6,7-二甲氧基喹喔啉
(m.p.147-148℃)。
内-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉
(m.p.110-111℃)。
外-2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉
(m.p.108-110℃).
元素分析C17H18N2O3
计算值:C,68.44;H,6.08;N,9.39;
实测值:C,68.54;H,6.23;N,9.27。
2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉
(m.p.93-95℃).
元素分析C17H18N2O3
计算值:C,68.44;H,6.08;N,9.39;
实测值:C,68.32;H,5.98;N,9.25。
2-环己氧基-6,7-二甲氧基喹喔啉
(m.p.104-106℃)。
2-环戊硫基-6,7-二甲氧基喹喔啉
(m.p.123-124℃)。
元素分析C15H18N2O2S
计算值:C,62.04;H,6.25;N,9.65
实测值:C,61.90;H,6.02;N,9.48。
6,7-二甲氧基-2-环戊氧基喹喔啉
(m.p.87-89℃)
元素分析C15H18N2O3
计算值:C,65.68;H,6.61;N,10.21
实测值:C,65.63;H,6.52;N,10.13。
2-环戊基甲氧基-6,7-二甲氧基喹喔啉
(m.p.99-102℃)
元素分析C16H20N2O3
计算值:C,66.65;H,6.99;N,9.72
实测值:C,66.66;H,7.03;N,9.70。
6,7-二甲氧基-2-四氢吡喃-4-氧基喹喔啉
(m.p.155-158℃)
元素分析C15H18N2O4
计算值:C,62.06;H,6.25;N,9.65
实测值:C,62.26;H,6.27;N,9.67。
外,外-6,7-二甲氧基-2-(5,6-环氧二环[2.2.1]庚烷-2-基氧基)喹喔啉
(m.p.173-175℃)。
实施例19 顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸
将顺式/反式-4-羟基-环己烷甲酸(144mg,1mmol)和NaH(60%,160mg,4mmol)在无水THF/DMF(10mL/2mL)中的混合物回流1小时,然后加入2-氯-6,7-二甲氧基喹喔啉(225mg,1mmol)。将所得混合物继续回流4小时。将所得混合物中和至pH 5,并用乙酸乙酯萃取(2×50mL)。用硫酸镁干燥合并的有机溶液,并过滤。浓缩后,通过硅胶色谱纯化残余物(乙酸乙酯,然后甲醇),获得了所需产物,为白色固体(m.p.90-93℃)。
元素分析C17H20N2O5·0.5H2O
计算值:C,59.89;H,6.19;N,8.22;
实测值:C,59.91;H,6.62;N,7.90。
实施例20 6,7-二甲氧基-2-(4-甲氧基环己氧基)喹喔啉
将顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己醇(170mg,0.56mmol)和NaH(60%,22.4mg,0.56mmol)在无水THF/DMF(10mL/2mL)中的混合物在0℃搅拌10分钟,然后加入甲基碘(50μL,0.56mmol)。在室温搅拌4小时后,用水(0.5mL)中止该反应,然后浓缩。用二氯甲烷(2×20mL)萃取水层,用盐水(5mL)洗涤合并的有机溶液。浓缩后,通过硅胶色谱纯化残余物(30%乙酸乙酯/己烷),获得了80mg(45%)所需产物(m.p.85-90℃)。
实施例21 3-环己氧基-6,7-二甲氧基喹喔啉1-氧化物
将2-环己氧基-6,7-二甲氧基喹喔啉(110mg,0.38mmol)和间氯过苯甲酸(70%,113mg,0.46mmol)在10mL二氯甲烷中的混合物于室温搅拌一天。过滤后,将该溶液浓缩,通过硅胶色谱纯化残余物(20%乙酸乙酯/己烷),获得了所需产物(m.p.167-169℃)。以类似方法制备反式-4-(6,7-二甲氧基-4-氧基喹喔啉-2-基氨基)环己醇(m.p.220-222℃)。
元素分析C16H21N3O4·0.2H2O
计算值:C,59.42;H,6.69;N,12.99;
实测值:C,59.43;H,6.64;N,12.95。
实施例22(1R,2R,4S)-(+)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺
将实施例17的(±)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺在手性HPLC柱(Chiralpac AD,25×2cm,含有10mM(1S)-(+)-樟脑磺酸的60%庚烷/40%乙醇,12mL/分钟)上拆分,获得了作为首批洗脱物的上述标题产物。合并所收集的级分,用50mL1N NaOH洗涤,然后干燥(MgSO4)。过滤后,将该溶液在旋转蒸发仪上蒸发,然后在高度真空下干燥。获得了黄色固体。[α]d 20+19.5°(c=0.20,CH2Cl2)m.p.184-186℃。
元素分析C17H21N3O2x0.3H2O
计算值:C,66.90;H,7.15;N,13.77
实测值:C,66.86;H,7.01;N,13.86。
实施例23(1S,2S,4R)-(-)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺
(i)将实施例17的(±)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺在手性HPLC柱(Chiralpac AD,25×2cm,含有10mM(1S)-(+)-樟脑磺酸的60%庚烷/40%乙醇,12mL/分钟)上拆分,获得了作为第二批洗脱物的上述标题产物。合并所收集的级分,用50mL 1N NaOH洗涤,然后用硫酸镁干燥。过滤后,将该溶液在旋转蒸发仪上蒸发,然后在高度真空下干燥。获得了黄色固体。[α]d 20-19.5°(c=0.22,CH2Cl2)m.p.185-187℃。
(ii)将2-氯-6,7-二甲氧基喹喔啉(462mg,2.06mmol)与(1S,2S,4R)降冰片烷基-2-胺(300mg,2.7mmol)、叔丁醇钠(220mg,2.3mmol)、BINAP(9mg)和Pd(dba)2(3mg)在10mL甲苯中的混合物在80-100℃加热过夜。通过硅胶色谱纯化该悬浮液,用己烷/乙酸乙酯(60%)洗脱,获得了370mg(60%)所需产物,为黄色固体,在上述手性HPLC条件下,该产物的保留时间与首批洗脱物相同。[α]d 20-19°(c=0.19,CH2Cl2)。
实施例24 2-(6,7-二甲氧基喹喔啉-2-基)-2-氮杂二环[2.2.2]辛烷-3-酮
将2-氮杂二环[2.2.2]辛烷-3-酮(228mg,2.3mmol)溶于THF/DMF(5mL/3mL)混合物中,并用NaH(60%,184mg,4.6mmol)处理。将所得混合物在60℃加热0.5小时,然后加入2-氯-6,7-二甲氧基喹喔啉(344mg,1.5mmol)。在80℃加热过夜后,将该反应混合物浓缩。通过硅胶色谱纯化残余物(50%乙酸乙酯/己烷),获得了164mg(23%)黄色固体(m.p.158-159℃)。
实施例25 顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯
向2-(6,7-二甲氧基喹喔啉-2-基)-2-氮杂二环[2.2.2]辛烷-3-酮(100mg,0.32mmol)在10mL甲醇内的溶液中加入新制备的NaOMe/甲醇溶液(54mg,1mmol),将该混合物在室温搅拌0.5小时,然后浓缩。使用二氯甲烷进行萃取,然后用硫酸镁干燥。过滤并浓缩后,通过硅胶色谱纯化残余物(40%乙酸乙酯),获得了85mg(77%)顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯,为浅黄色固体(m.p.68-80℃)。
实施例26 顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸
当在上述方法中用NaOH替换NaOMe时,则2-(6,7-二甲氧基喹喔啉-2-基)-2-氮杂二环[2.2.2]辛烷-3-酮被转化成顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸。
实施例27 顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯和反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯
通过制备性TLC,由顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸酯分离顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯[MS m/z:345(M+)]和反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯[MS m/z:345(M+)],用65%乙酸乙酯/己烷洗脱,二者分别作为首批和第二批洗脱物被分离出来。
实施例28 反式-4-[7-甲氧基-6-(2-吗啉-4-基乙氧基)喹喔啉-2-基氨基]环己醇和反式-4-[6-甲氧基-7-(2-吗啉-4-基-乙氧基)喹喔啉-2-基氨基]环己醇
本标题化合物是这样制得的:使用实施例1的方法,将6-羟基-7-甲氧基-2-氯喹喔啉∶7-(2-吗啉-4-基乙氧基)-6-甲氧基-2-氯喹喔啉与2-(吗啉-4-基)乙醇反应进行Mitsunobu偶联,并使用实施例11的方法将所得6-(2-吗啉-4-基乙氧基)-7-甲氧基-2-氯喹喔啉∶7-(2-吗啉-4-基乙氧基)-6-甲氧基-2-氯喹喔啉与反式-4-氨基-环己醇反应。
实施例29 2-[2-(反式-4-羟基环己基氨基)-7-甲氧基喹喔啉-6-基氧基]-1-乙酸和2-[2-(反式-4-羟基-环己基氨基)-6-甲氧基喹喔啉-7-基氧基]-1-乙酸
本标题化合物是这样制得的:按照实施例8的方法,用乙硫醇的钠盐在DMF中将4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇脱烷基化,然后如一般方法6中所述,在碱存在下用溴乙酸烷基化。
实施例30 2-[2-(反式-4-羟基环己基氨基)-7-甲氧基喹喔啉-6-基氧基]-N,N-二甲基乙酰胺和2-[2-(反式-4-羟基环己基氨基)-6-甲氧基喹喔啉-7-基氧基]-N,N-二甲基乙酰胺
本标题化合物是用二甲基胺将实施例29的化合物氨解而制得的。
实施例31(6,7-二甲氧基喹喔啉-2-基)-(3-(R)-甲基环己基)胺及其顺式和反式异构体
该化合物首先是作为顺式和反式异构体的混合物制得的。它们是这样制得的:将3-(R)-甲基环己酮的肟还原成环己基胺,然后在标准条件下将该胺与2-氯-6,7-二甲氧基喹喔啉偶联。通过制备性RP-HPLC获得了各异构体的分析样本。300Mhz 1H NMR和MS与这两种异构体的结构都一致,虽然不能确定携带氮的环己基碳的相对立体化学。
实施例32 顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸甲酯
通过用标准技术将实施例19的产物酯化制得了本标题化合物。
M.p.130-132℃.
元素分析C18H22N2O5
计算值:C,62.42;H,6.40;N,8.09
实测值:C,62.60;H,6.55;N,7.89。
中间体实施例1 4-溴-5-甲氧基-苯-1,2-二胺二盐酸盐
在氩气氛下,向EtOAc(50mL)与5-溴-4-甲氧基-2-硝基-苯基胺(2.5g,10mmol)的溶液中加入5%Pd/C(0.5g)。将该反应混合物在50psi氢化1小时。将该反应混合物经由硅藻土过滤到HCl/IPA/EtOAc溶液中,用EtOAc洗涤滤垫。滤出所得沉淀,获得了白色固体。
中间体实施例2 7-溴-6-甲氧基喹喔啉-2-醇和6-溴-7-甲氧基喹喔啉-2-醇
在氩气氛下,向MeOH(15mL)中加入粉碎的NaOH颗粒(0.86g,21mmol)和4-溴-5-甲氧基-苯-1,2-二胺二盐酸盐(2.7g,9.3mmol)。将该混合物搅拌10分钟,然后滴加45%乙醛酸乙酯的甲苯溶液(2.7g,12mmol)。将该反应混合物回流1小时,然后冷却,加入水,之后将该悬浮液过滤。依次用水、MeOH、IPA、和Et2O洗涤所得固体,获得了黄色粉末。
中间体实施例3 7-溴-2-氯-6-甲氧基喹喔啉和6-溴-2-氯-7-甲氧基喹喔啉
向7-溴-6-甲氧基喹喔啉-2-醇和6-溴-7-甲氧基喹喔啉-2-醇的混合物(1g,3.9mmol)中加入POCl3(5mL)。将该反应混合物回流1小时,倒入冰水中,过滤,然后用水洗涤,获得了浅褐色固体。1HNMR证实7-溴-2-氯-6-甲氧基喹喔啉∶6-溴-2-氯-7-甲氧基喹喔啉比例约为7∶1。
中间体实施例4 5-氯-4-甲氧基-2-硝基苯胺
向N-(5-氯-4-甲氧基-2-硝基苯基)乙酰胺(2g,8.2mmol)在5NHCL(20mL)内的溶液中加入1,4-二氧杂环己烷(10mL),将该混合物在60℃搅拌1.5小时。将该反应混合物浓缩,并在EtOAc/2N NaOH之间分配。将水层用EtOAc(3×)、盐水洗涤,干燥(MgSO4),吸附在硅胶上,并通过色谱法纯化(70%EtOAc/己烷),获得了橙色粉末。
中间体实施例5 4-氯-5-甲氧基-苯-1,2-二胺二盐酸盐
在氩气氛下,向EtOAc(50mL)与5-氯-4-甲氧基-2-硝基苯基胺(1.6g,7.9mmol)的溶液中加入5%Pd/C(0.5g)。将该反应混合物在50psi氢化1小时。在N2气氛中将该反应混合物经由硅藻土过滤到1N HCl/Et2O的EtOAc溶液中,用EtOAc洗涤滤垫。滤出所得沉淀,获得了白色固体。
中间体实施例6 7-氯-6-甲氧基-喹喔啉-2-醇和6-氯-7-甲氧基-喹喔啉-2-醇
在0℃、氩气氛下,向4-氯-5-甲氧基-苯-1,2-二胺二盐酸盐(1.8g,7.2mmol)在EtOH(15mL)内的溶液中加入TEA(2.5mL,18mmol)。将该混合物搅拌20分钟,然后滴加45%乙醛酸乙酯的甲苯溶液(2.1g,9.3mmol)。将该反应混合物升至室温,回流1.5小时,然后冷却,加入水,然后将该悬浮液过滤,并依次用水、IPA、和Et2O洗涤,获得了浅黄色粉末。用甲苯将该产物共沸数次,并在使用前真空干燥。
中间体实施例7 2,7-二氯-6-甲氧基喹喔啉和2,6-二氯-7-甲氧基喹喔啉
在用CaCl2干燥的试管内,向7-氯-6-甲氧基喹喔啉-2-醇和6-氯-7-甲氧基喹喔啉-2-醇(1g,4.7mmol)的混合物中加入POCl3(5mL)。将该反应混合物回流30分钟,倒入冷的饱和碳酸氢钠溶液中,过滤,然后用水洗涤,获得了固体。1H NMR证实2,7-二氯-6-甲氧基喹喔啉∶2,6-二氯-7-甲氧基喹喔啉的比例约为6∶1。
中间体实施例8(1S,2S,4R)-降冰片烷基-2-胺
(3a):在-78℃,向R-(+)-内-降冰片(2.24g,20mmol)在20mLTHF内的溶液中加入三苯基膦(6.55g,25mmol)、邻苯二甲酰亚胺(3.68g,25mmol)和偶氮二甲酸二乙酯(4.4mL,28mmol)。将该混合物在室温搅拌过夜,然后浓缩。通过硅胶色谱纯化残余物(20%乙酸乙酯/己烷),获得了4.6g(95%)(1S,2S,4R)-2-二环[2.2.1]庚-2-基异吲哚-1,3-二酮。
(3b):将(1S,2S,4R)-2-二环[2.2.1]庚-2-基异吲哚-1,3-二酮(1.2g,5mmol)和H2NNH2一水合物(300mg,6mmol)在10mL甲醇中的混合物回流4小时,然后浓缩至干。用二氯甲烷(2×100mL)萃取,通过过滤滤出固体。将二氯甲烷蒸发,获得了300mg(54%)(1S,2S,4R)-降冰片烷基-2-胺。
中间体实施例9 外-二环[2.2.1]庚-5-烯-2-胺
外-二环[2.2.1]庚-5-烯-2-胺按照与中间体实施例12相同的方法由5-降冰片烯-2-醇经由通用中间体外-2-二环[2.2.1]庚-5-烯-2-基异吲哚-1,3二酮制得的。
中间体实施例10 2-甲基-6,7-二甲氧基喹喔啉
本标题化合物是通过将Tamao等人在Tetrahedron,1982,38,3347-3354中公开的方法作改进而制得的。在氩气氛下向THF溶液中加入2-氯-6,7-二甲氧基喹喔啉(5g,26mmol)和NiCl2(dppp)(0.14g,0.26mmol)。将该反应混合物冷却至0℃,向其中滴加3MMeMgBr的乙醚溶液(13mL,39mmol)。将该反应混合物升至室温,搅拌1小时,然后回流1.5小时。将该混合物冷却,用10%HCl中止反应,搅拌10分钟,然后用5%NaOH碱化。向该反应混合物中加入CH2Cl2和H2O,将该反应混合物搅拌过夜,然后加入CH2Cl2、H2O、和NaCl,过滤该混合物。将所得溶液倒入分液漏斗中,用二氯甲烷将水层洗涤3次。合并有机层,用盐水洗涤,干燥(MgSO2),浓缩到硅胶上,并通过色谱法处理(50%-80%EtOAc/己烷),获得了橙色固体(产率为49%)。
中间体实施例11 6,7-二甲氧基-2-喹喔啉甲醛
在氩气氛下,向反应烧瓶中加入1,4-二氧杂环己烷(20mL)、2-甲基-6,7-二甲氧基喹喔啉(1.09g,5.3mmol)和SeO2(1.8g,16mmol)。将该混合物在100℃加热2小时45分钟,冷却,并经由硅藻土过滤。用EtOAc和CH2Cl2将滤垫洗涤数次。将所得溶液浓缩,置于MeOH/CH2Cl2中,施加到硅胶柱上,进行色谱处理(30%EtOAc/CH2Cl2),获得了黄白色固体(产率为73%)。
中间体实施例12(2外,5外)-5-氨基二环[2.2.1]庚烷-2-乙酸酯
依据R.Gagnon(J.Chem.Soc.,Perkin trans.1,15051995)的方法、并作较小改进,由二环[2.2.1]庚-2,5-二烯制备外-5-乙酰氧基二环[2.2.1]庚烷-2-酮和外-6-乙酰氧基二环[2.2.1]庚烷-2-酮。
在室温,向外-5-乙酰氧基二环[2.2.1]庚烷-2-酮(350mg,2.08mmol)在10mL THF内的溶液中加入1M硼烷/THF溶液(1.2mL,1.2mmol)。将该混合物搅拌0.5小时,然后在0℃用甲醇(3mL)和1NHCl(1.5mL)中止反应。用乙酸乙酯(3×30mL)萃取,并用硫酸镁干燥。过滤并浓缩后,通过硅胶色谱纯化,获得了(2内,5外)-5-乙酰氧基二环[2.2.1]庚烷-2-醇。
在0℃,向(2内,5外)-5-乙酰氧基二环[2.2.1]庚烷-2-醇(350mg,2.06mmol)在THF(10mL)内的溶液中加入邻苯二甲酰亚胺(454mg,3.09mmol)、三苯基膦(810mg,3.09mmol)和偶氮二甲酸二乙酯(0.49mL.3.09mmol)。将该反应混合物搅拌过夜,然后用旋转蒸发仪浓缩,通过色谱柱纯化残余物(20%乙酸乙酯/己烷),获得了所需产物,为黄色固体。
将上述固体(300mg,1mmol)和肼(0.126mL,2.2mmol)在5mL甲醇中的混合物加热回流6小时。除去甲醇后,用二氯甲烷(3×30mL)萃取残余物。将溶剂浓缩,获得了(外,外)-5-氨基二环[2.2.1]庚烷-2-乙酸酯(127mg,75%),不用进一步纯化直接用于偶联反应。
同样,由适当原料制备(2内,5外)-5-氨基二环[2.2.1]庚烷-2-乙酸酯、(2内,6外)-6-氨基二环[2.2.1]庚烷-2-乙酸酯和(2外,6外)-6-氨基二环[2.2.1]庚烷-2-乙酸酯。
中间体实施例13 2-甲氧基-4,5-二氨基苯酚二盐酸盐
本标题化合物是依据Ehrlich等人,J.Org.Chem.,1947,12,522的方法,通过将2-甲氧基-4,5-二硝基苯酚氢化而制得的。
中间体实施例14 7-羟基-6-甲氧基喹喔啉-2-醇和6-羟基-7-甲氧基喹喔啉-2-醇
按照中间体实施例2的方法,通过将4-甲氧基-5-羟基苯-1,2-二胺二盐酸盐与NaOH和乙醛酸乙酯反应制得了本标题化合物。
中间体实施例15 7-羟基-6-甲氧基-2-氯喹喔啉和6-羟基-7-甲氧基-2-氯喹喔啉。
按照中间体实施例3的方法,通过将7-羟基-6-甲氧基喹喔啉-2-醇和6-羟基-7-甲氧基喹喔啉-2-醇与POCl3反应制得了本标题化合物。
本发明式I化合物通过抑制PDGF-R酪氨酸激酶活性而抑制细胞增殖和/或细胞基质产生和/或细胞运动(趋化性)。有大量疾病是由于失控的细胞增殖或细胞基质过度生成或失控的编程性细胞死亡(细胞凋亡)引起的。这些疾病涉及多种细胞类型,并包括病症例如白血病、癌症、成胶质细胞瘤、牛皮癣、炎性疾病、骨疾病、纤维变性疾病、动脉粥样硬化和冠状动脉、股动脉或肾动脉的血管成形术后发生的再狭窄,或纤维增生性疾病例如关节炎,肺、肾和肝脏的纤维变性。具体地,据报道,PDGF和PDGF-R参与多种特定类型的癌症和肿瘤,例如脑癌、卵巢癌、结肠癌、前列腺癌、肺癌、卡波西肉瘤和恶性黑素瘤。此外,冠状动脉旁路手术后会发生失控的细胞增殖。据信抑制酪氨酸激酶活性可用于控制失控的细胞增殖或细胞基质过度生成或失控的编程性细胞死亡(细胞凋亡)。
本发明涉及调节和/或抑制细胞信号传导、细胞增殖和/或细胞基质产生和/或细胞运动(趋化性),控制异常的细胞生长和细胞炎性反应。更具体来说,本发明涉及取代的喹啉和喹喔啉化合物的应用,所述化合物能通过有效地抑制血小板衍生生长因子受体(PDGF-R)酪氨酸激酶活性而选择性地抑制分化、增殖、基质产生、趋化性或介质释放。
抑制自身磷酸化,即生长因子受体自身的磷酸化,和细胞内底物的受体的磷酸化是在细胞信号传导、细胞增殖、基质产生、趋化性和介质释放过程中涉及的一些生物事件。
通过有效地抑制Lck酪氨酸激酶活性,本发明化合物还可用于治疗移植抵抗和自身免疫性疾病例如类风湿性关节炎、多发性硬化和全身性红斑狼疮,移植物排斥,移植物对宿主疾病,过度增殖性(hyperproliferative)疾病例如肿瘤和牛皮癣,和其中细胞接受促炎性信号的疾病例如哮喘、炎性肠病和胰腺炎。在治疗移植物排斥时,本发明化合物可用于预防人体对移植的器官或组织的不良反应,或者在发生这样的反应后对其进行治疗。当预防性地使用时,在进行移植手术前将本发明化合物施用给患者或欲进行移植的组织或器官。预防性治疗还包括在移植手术后、但是在观察到任何移植不良反应征兆之前进行给药治疗。当发生不良反应后再给药时,在表现出外在抵抗症状之后,将本发明化合物直接对患者给药以治疗对移植物的抵抗性。
依据本发明另一个方面,本发明提供了抑制PDGF酪氨酸激酶活性的方法,包括将权利要求1的化合物与含有PDGF酪氨酸激酶的组合物接触。
依据本发明另一个方面,本发明提供了抑制Lck酪氨酸激酶活性的方法,包括将权利要求1的化合物与含有Lck酪氨酸激酶的组合物接触。
依据本发明另一个方面,本发明提供了治疗患有或易患可通过施用PDGF-R酪氨酸激酶活性和/或Lck酪氨酸激酶活性抑制剂而得到改善或阻止的疾病例如上述疾病之患者的方法,包括给所述患者施用有效量的式I化合物或含有式I化合物的组合物,或其可药用盐。
本文所提及的治疗包括预防性治疗和治疗已发疾病。
本发明范围还包括含有可药用量的至少一种式I化合物与可药用载体例如辅药、稀释剂、包衣和赋形剂的药物组合物。
在实践中,本发明化合物或组合物可以以任意合适的形式给药,例如吸入给药、局部给药、肠胃外给药、直肠给药或口服给药,更优选口服给药。更具体的给药途径包括静脉内给药、肌内给药、皮下给药、眼内给药、滑膜内给药、结肠给药、腹膜给药、经上皮给药包括经皮给药、眼(ophthalmic)给药、舌下给药、颊给药、皮肤给药、眼(ocular)给药、通过吹入法的鼻吸入给药、和喷雾给药。
式I化合物可在能容许以大多数合适途径给药的剂型中施用,并且本发明还涉及含有至少一种适于用作治疗患者的药物的本发明化合物的药物组合物。这些组合物可依据常规方法,用一种或多种可药用辅料或赋形剂制得。辅料尤其包括稀释剂、无菌含水介质和各种无毒有机溶剂。本发明组合物可呈片剂、丸剂、粒剂、粉剂、水溶液或悬浮剂、注射液、酏剂或糖浆剂的形式,并且为了获得可药用制剂,本发明组合物可含有一种或多种选自下述物质的辅助剂:甜料例如蔗糖、乳糖、果糖、糖精或,矫味剂例如薄荷油、冬绿油、或樱桃或橙子调味剂,着色剂,或稳定剂例如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯。
载体的选择和活性物质在载体中的含量通常是由产物的溶解性和化学性质、特定给药方式和药物实践中所遵守的原则决定的。例如,赋形剂如乳糖、柠檬酸钠、碳酸钙、磷酸二钙和崩解剂例如淀粉、藻酸和一些复合硅胶以及润滑剂例如硬脂酸镁、十二烷基硫酸钠和滑石粉可用于制备片剂、锭剂、丸剂、胶囊等。为了制备胶囊,使用乳糖和液体载体例如高分子量聚乙二醇是有利的。可使用各种其它物质以用作包衣或修饰剂量单位的物理形态。例如,可用虫胶、糖或虫胶和糖将片剂、丸剂或胶囊包衣。当使用水悬浮剂时,其可含有乳化剂或促进悬浮的物质。还可以使用稀释剂例如蔗糖、乙醇、多元醇例如聚乙二醇、丙二醇和甘油、和氯仿或它们的混合物。此外,可将活性化合物配制成缓释制剂。
为了口服给药,可将活性化合物与例如惰性稀释剂或可同化的可食用载体一起给药,或者可将其包封在硬或软明胶胶囊壳中,或者可将其压制成片,或者直接与食品混合,或者与赋形剂混合,并以吞服片、口腔片、锭剂、胶囊、酏剂、悬浮剂、糖浆剂、糯米纸囊剂(wafer)等形式使用。
为了非胃肠道给药,可使用本发明化合物在植物油例如芝麻油、花生油或橄榄油,或含水有机溶液例如水和丙二醇,可注射有机酯例如油酸乙酯,以及可药用盐的无菌水溶液等中的乳剂、悬浮剂或溶液剂。注射剂型的流动性必须达到易于注射的程度,并且可通过例如使用包衣如卵磷脂,通过维持所需粒剂大小(对于分散体)和通过使用表面活性剂来维持适当流动性。可通过使用延迟吸收的物质例如一硬脂酸铝和明胶来延长注射组合物的吸收。本发明产物的盐的溶液尤其适用于通过肌内或皮下注射进行给药。作为游离碱或可药用盐的活性化合物的溶液可在适当与表面活性剂例如羟丙基纤维素混合的水中制备。还可以在甘油、液体聚乙二醇、和它们的混合物以及油中制备分散体。包含所述盐在纯蒸馏水中的溶液的水溶液可用于静脉内给药,条件是适当地调节其pH,将其适当地缓冲和用足量葡萄糖或氯化钠使其等渗,并通过加热、辐射、微量过滤、和/或通过各种抗菌剂和杀真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等将其灭菌。
无菌注射液是通过将必需量的活性化合物与各种其它上述组分(按照需要)混合在适当溶剂中、然后过滤灭菌制得的。分散体一般是通过将各种灭菌的活性组分加到含有分散基质和必需的其它上述组分的无菌载体中制得的。对于制备无菌注射液的无菌粉末,优选的制备方法是真空干燥和冷冻干燥技术,通过使用这样的技术可由其无菌过滤溶液制得活性组分与任意其它所需组分的粉末。
对于局部给药,可使用含有本发明化合物的凝胶剂(以水或醇为基质)、霜剂或软膏剂。还可将本发明化合物掺入到用于在贴剂中施用的凝胶或基质中,其中贴剂能经由经皮屏障控制化合物释放。
对于吸入给药,可将本发明化合物溶解或悬浮在用于喷雾器或悬浮液或溶液气雾剂的适当载体中,或者可将本发明化合物吸收或吸附在用于干粉吸入器的适当固体载体上。
直肠给药固体组合物包括依据已知方法配制的并含有至少一种式I化合物的栓剂。
还可以将本发明组合物配制成这样的制剂,它们抵抗通过对流和/或扩散从血管(动脉和静脉)壁中的快速清除,因此延长了药物在所需作用位点的停留时间。可使用含有本发明化合物的外膜周围贮药库来进行持续释放。一种适用于施用本发明化合物的这样的贮药库可以是被硅化橡胶壳环绕的共聚物基质,例如乙烯-乙酸乙烯酯共聚物或聚乙烯醇凝胶。或者,可从植入在外膜中的硅氧烷聚合物中局部释放本发明化合物。
将在经皮、经血管递送期间本发明化合物的冲失程度降至最小的方法包括使用不可扩散的药物洗脱(drug-eluting)微颗粒。微颗粒可以由多种合成聚合物例如聚交酯(polyactide)或天然物包括蛋白质或多糖构成。这样的微颗粒能以预定方式控制包括药物总剂量及其释放动力学在内的可变参数。可通过多孔囊式导管或固定在斯滕特固定模上的囊有效地将微颗粒注射到动脉或静脉壁内,并且在血管壁和外膜周组织中保持至少2周。Reissen等人的(J.Am.Coll.Cardiol.1994;23:1234-1244)中描述了用于局部血管内定点递送治疗剂的制剂和方法,该文献全文引入本发明以作参考。
本发明组合物还可包含水凝胶,这样的水凝胶是由可用作药物吸收海绵的任何生物相容或无毒(均聚或或杂聚)聚合物例如亲水性聚丙烯酸聚合物制得的。这样的聚合物描述在例如WO93/08845中,该文献全文引入本发明以作参考。其中一些聚合物,例如得自乙烯和/或氧化丙烯的聚合物可商业获得。
在使用本发明化合物来治疗与过度增殖性病症有关的疾病时,可以以不同方法施用本发明化合物。为了治疗再狭窄,通过血管成形术囊将本发明化合物直接施加到血管中,所述囊包衣着用本发明化合物饱和的亲水性膜(例如水凝胶),或通过含有化合物输注室(infusion chamber)的任何其它导管施用本发明化合物,其中能以精确方式将这样的导管施用到预治疗位点,并使得化合物在所治疗的细胞位置局部且高效地释放。该给药方法能有利地使化合物与需要治疗的细胞迅速接触。
本发明治疗方法优选包括将本发明化合物导入到治疗位点。例如,可将含有组合物的水凝胶直接放置在欲治疗组织的表面,例如在手术期间放置。有利起见,通过下述方式将水凝胶引入到目的血管内位点上:包衣导管例如囊导管,并递送到血管壁,优选在血管成形术期间递送。在一种特别有利的方式中,通过囊导管将饱和水凝胶引入到治疗位点。在将导管放置到靶血管中时,可用保护鞘保护囊,以使得在导管引入到血流内后药物冲失降至最小。
在本发明另一实施方案中,通过灌注囊施用本发明化合物。这些灌注囊能够通过囊的膨胀维持血流,并因此降低心肌缺血的危险性,还能使得化合物在常压下释放20分钟以上的较长时间,这可能是实现其最佳作用所必需的。或者,可使用具有通道的囊式导管(“具有通道的囊式血管成形术用导管”,Mansfield Medical,BostonScientific Corp.,Watertown,MA)。后者由包衣着一层24个有孔通道的常规囊构成,这些有孔通道通过另外的输注口经由独立的腔灌注。可用于实施本发明的各种类型囊式导管,例如双重囊、多孔囊、微孔囊、通道囊、固定在斯滕特固定模上的囊、和水凝胶导管公开在Reissen等人.(1994)的文献中,该文献全文引入本发明以作参考。
使用灌注囊式导管是特别有利的,因为能同时获得将囊维持膨胀较长时间(通过保持促进的滑行性)和维持水凝胶的位点特异性这两个效果。
本发明另一方面涉及含有本发明化合物和泊咯沙姆的药物组合物,例如Poloxamer 407是市售的无毒的生物相容多元醇(BASF,Parsippany,NJ)。
可将浸渗有本发明化合物的泊咯沙姆直接放在治疗组织的表面,例如在手术期间放置。泊咯沙姆具有与水凝胶基本上相同的优点,同时具有较低粘度。
使用含有浸渗着本发明化合物的泊咯沙姆的通道囊式导管是特别有利的。在这种情况下,优点是能在保持促进的滑行性的情况下同时获得将囊维持膨胀较长时间和维持泊咯沙姆的位点特异性这两个效果。
活性组分在本发明组合物中的百分比可以变化,其必须占一定比例以获得合适的剂量。很明显,可大约同时施用几个单位剂型。所用剂量可由医师或有资格的医疗执业人员确定,并取决于所期望的治疗效果、给药途径和治疗持续时间、以及患者的身体状况。对于成人,当吸入给药时,剂量一般为约0.001-约50、优选约0.001-约5mg/kg体重/天,当口服给药时,剂量一般为约0.01-约100、优选0.1-70、更优选0.5-10mg/kg体重/天,当静脉内给药时,剂量一般为约0.001-约10、优选0.01-10mg/kg体重/天。在每一特定情况下,剂量是依据欲治疗患者的特定因素,例如年龄、体重、一般健康状况和可影响本发明化合物效力的其它因素确定的。
本发明化合物/组合物可以按照需要频繁给药以获得所需疗效。某些患者可能会对较高或较低剂量迅速起反应,并且可能很低的维持剂量就足够了。对于其它患者,可能需要依据每一特定患者的生理需要以1-4次给药/天的速度进行长期治疗。本发明活性产物通常每天口服给药1-4次。当然,对于其它患者,必须每天给药不超过1次或2次。
还可以将本发明化合物配制成与其它治疗剂例如活性剂联合使用或者与治疗技术联合使用的形式,以治疗可通过施用式I化合物得以改善的病症,例如:
本发明化合物可用于治疗使用任何方法例如气囊扩张术、消融术(ablation)或激光技术的血管成形术后的再狭窄。本发明化合物可用于在将斯滕特固定模(stent)置于血管系统中之后在下述两种情况下治疗再狭窄,1)初次治疗血管阻塞,或者2)在使用装置的血管成形术未能给患者提供动脉的情况。优选地,所选再狭窄处在通过血管成形术治疗动脉粥样硬化损伤时所产生的动脉壁机械损伤位点上。本发明化合物可通过口服、肠胃外给药来使用,或者本发明化合物可通过放置在特定装置中或者适当地配制成在斯滕特固定模装置上的包衣来局部施用。
在一个方面,斯滕特固定模上的包衣是通过将掺合着本发明化合物的聚合材料涂敷在斯滕特固定模装置的至少一个表面上而形成的。
适于掺合本发明化合物的聚合材料包括具有低加工温度的聚合物,例如聚己内酯、聚(乙烯共聚乙酸乙烯酯)或聚乙酸乙烯酯或硅氧烷树胶橡胶以及具有类似较低加工温度的聚合物。其它合适的聚合物包括能携带和递送治疗药物的不可降解聚合物,例如胶乳、尿烷、聚硅氧烷、苯乙烯-乙烯/丁烯-苯乙烯嵌段共聚物(SEBS),和能携带与递送治疗药物的生物可降解、生物可吸收的聚合物,例如聚-DL-乳酸(DL-PLA)、和聚-L-乳酸(L-PLA)、聚原酸酯、聚亚氨基碳酸酯、脂族聚碳酸酯、和聚磷腈。
还可以通过将porosigen与治疗药物一起加到聚合物中来把porosigen掺入到负载药物的聚合物中,以形成多孔负载药物的聚合膜。“Porosigen”是指当浸在体液中时能溶解或降解以在聚合材料中留下多孔网络的任何部分,例如氯化钠、乳糖或肝素钠的微粒。这样的porosigen留下的孔一般可大至10微米。通过porosigen例如聚乙二醇(PEG)、聚氧化乙烯/聚氧化丙烯(PEO/PPO)共聚物形成的孔可例如小于1微米,当然从连续的药物负载聚合基质中形成相分离、并且随后可被体液浸滤出的类似材料也可用于形成小于1微米的孔。可将聚合材料涂敷在斯滕特固定模上,同时治疗药物和porosigen材料包含在聚合材料中,这样当把斯滕特固定模置于血管中时porosigen溶解或降解,或者可将porosigen溶解并从聚合材料中除去以在聚合材料中形成孔,然后将与斯滕特固定模结合的聚合材料放置在血管中。
如果需要的话,还可在药物负载聚合物上涂敷控速膜以限制本发明化合物的释放速度。可通过从溶液中涂敷上包衣或直接涂敷上分层包衣来加上控速膜。涂敷在聚合材料上的控速膜可包含porosigen在控速膜中的均匀分散体,在控速膜中的porosigen可溶解并在控速膜中形成通常大至10微米或小至1微米的孔,但是所形成的孔也可以小于1微米。在控速膜中的porosigen可以是例如氯化钠、乳糖、肝素钠、聚乙二醇、聚氧化乙烯/聚氧化丙烯共聚物以及它们的混合物。
另一方面,斯滕特固定模装置上的包衣可这样形成:将本发明化合物施加在斯滕特固定模装置的至少一个表面上以形成生物活性层,然后在生物活性层上施加一层或多层具有足够厚度以提供化合物控释效果的多孔聚合材料包衣。
多孔聚合材料可由通过不使用催化剂的蒸气沉积由聚酰胺、聚对亚苯基二甲基或聚对亚苯基二甲基衍生物组成。“聚对亚苯基二甲基”是指基于对苯二甲基的聚合物,并且是按照在US 5824049中描述的汽相聚合法制得的,该文献引入本发明以作参考。
或者,通过等离子体沉积涂敷多孔聚合材料。适用于等离子体沉积的代表性聚合物包括聚(氧化乙烯)、聚(乙二醇)、聚(氧化丙烯),和甲烷、硅氧烷、四氟乙烯四甲基二硅氧烷的聚合物等。
其它合适的聚合物系统包括源自可光聚合的单体例如液体单体的聚合物,所述单体优选具有至少两个可交联的C-C(碳碳)双键,并且是可非气相加成聚合的烯不饱和化合物,在常压下的沸点大于100℃,分子量约为100-1500,并且能易于形成高分子量加聚物。更优选地,单体优选为含有2个或更多个丙烯酸酯或异丁烯酸酯基团/分子的可加成光聚合的多烯不饱和丙烯酸酯或异丁烯酸酯或它们的混合物。这样的多官能团丙烯酸酯的代表性实例是乙二醇二丙烯酸酯、乙二醇二异丁烯酸酯、三羟甲基丙烷三丙烯酸酯、三羟甲基丙烷三异丁烯酸酯、季戊四醇四丙烯酸酯、或季戊四醇四异丁烯酸酯、1,6-己二醇二异丁烯酸酯、和二甘醇二异丁烯酸酯。
在某些特别情况中,也可使用一丙烯酸酯例如丙烯酸正丁酯、异丁烯酸正丁酯、丙烯酸2-乙基己酯、丙烯酸月桂酯、和丙烯酸2-羟基丙酯。少量(甲基)丙烯酸的酰胺例如N-羟甲基异丁烯酰胺丁基醚也是合适的,N-乙烯基化合物例如N-乙烯吡咯烷酮、脂族一元羧酸的乙烯基酯例如油酸乙烯酯、二醇的乙烯基醚例如丁二醇-1,4-二乙烯基醚和烯丙基醚以及烯丙基酯也是合适的。还包括其它单体例如二环氧化物或多环氧化物例如丁二醇-1,4-一缩二甘油醚或双酚A一缩二甘油醚与(甲基)丙烯酸的反应产物。对于具体应用,可合适地选择单体或其混合物来改变光聚合液体分散介质的特征。
其它有用的聚合物系统包括生物相容的、并且当植入斯滕特固定模时将对血管壁的刺激降至最小的聚合物。根据所需的释放速度或者所需的聚合物稳定性程度,聚合物可以是生物稳定或可生物吸收的聚合物。可使用的可生物吸收的聚合物包括聚(L-乳酸)、聚己内酯、聚(丙交酯-共聚-乙交酯)、聚(羟基丁酸酯)、聚(羟基丁酸酯-共聚-戊酸酯)、聚二氧杂环己酮、聚原酸酯、聚酐、聚(乙醇酸)、聚(D,L-乳酸)、聚(乙醇酸-共聚-碳酸亚丙基酯)、聚磷酸酯、聚磷酸酯尿烷、聚(氨基酸)、氰基丙烯酸酯、聚(碳酸亚丙基酯)、聚(亚氨碳酸酯)、共聚(醚-酯)(例如PEO/PLA)、聚亚烷基草酸酯、聚磷腈,和生物分子例如纤维蛋白、纤维蛋白原、纤维素、淀粉、胶原和透明质酸。还可以使用具有较低慢性组织反应的生物稳定聚合物,例如聚氨酯、硅氧烷和聚酯,也可以使用能溶解并固化或聚合在斯滕特固定模上的其它聚合物,例如聚烯烃、聚异丁烯和乙烯-α烯烃共聚物;丙烯酸聚合物和共聚物、乙烯基卤聚合物和共聚物例如聚氯乙烯;聚乙烯基醚,例如聚乙烯基甲基醚;聚偏二卤代乙烯,例如聚偏二氟乙烯和聚偏二氯乙烯;聚丙烯腈,聚乙烯基酮,聚乙烯基芳族化合物例如聚苯乙烯,聚乙烯基酯例如聚乙酸乙烯酯;乙烯基单体彼此间的共聚物和乙烯基单体与烯烃的共聚物,例如乙烯-异丁烯酸甲酯共聚物、丙烯腈-苯乙烯共聚物、ABS树脂、和乙烯-乙酸乙烯酯共聚物;聚酰胺,例如Nylone 66和聚己内酰胺;烷基树脂,聚碳酸酯;聚甲醛;聚酰亚胺、聚醚;环氧树脂、聚氨酯;人造纤维;三乙酸人造纤维;纤维素、乙酸纤维素、丁酸纤维素;乙酸丁酸纤维素;玻璃纸、硝酸纤维素;丙酸纤维素;纤维素醚;和羧甲基纤维素。
除了等离子体沉积和气相沉积以外,可采用在斯滕特固定模表面上涂敷各种包衣的其它技术。例如,可将聚合物溶液涂敷在斯滕特固定模上,并让溶剂蒸发,由此在斯滕特固定模表明上留下了聚合物和治疗物质的包衣。在斯滕特固定模上涂敷溶液一般可通过将溶液喷雾到斯滕特固定模上或者将斯滕特固定模浸泡在聚合物溶液中来进行。
本发明化合物可用于与任何抗凝血剂、抗血小板剂、抗血栓形成剂或血纤维蛋白原溶解剂(profibrinolytic agent)联合使用来治疗再狭窄。通常在手术前、手术期间或手术后用这些类治疗剂对患者进行并行治疗,以使手术能安全地进行或者防止血栓形成的有害作用。作为已知抗凝血剂、抗血小板剂、抗血栓形成剂或血纤维蛋白原溶解剂的治疗剂的一些实例包括肝素、低分子量肝素、戊糖、血纤蛋白原受体拮抗剂、凝血酶抑制剂、Xa因子抑制剂或VIIa因子抑制剂的所有制剂。
本发明化合物可用于与抗高血压剂或胆固醇或脂质调节剂联合使用来实施与高血压或动脉粥样硬化治疗并行进行的再狭窄或动脉粥样硬化的治疗。可用于治疗高血压的治疗剂的一些实例包括下述种类的化合物:β-阻滞剂、ACE抑制剂、钙通道拮抗剂和α-受体拮抗剂。可用于治疗高胆固醇水平或失调的脂质水平的治疗剂的一些实例包括作为已知HMGCoA还原酶抑制剂的化合物、fibrate类化合物。
本发明化合物还可单独使用或者与可用于治疗癌症的已知化合物联合使用来治疗各种类型癌症。
应当理解,本发明包括本发明化合物与一种或多种上述类型治疗剂的组合。
在依据文献描述进行的试验中,在本发明范围内的化合物表现出显著的药理活性,我们相信这些试验结果与在人和其它哺乳动物中的药理活性相关。下述体外和体内药理试验结果是本发明化合物的典型特征。
药物组合物制备和药理试验部分
在本发明范围内的化合物表现出显著的蛋白酪氨酸激酶抑制剂活性,并具有下述治疗价值:作为抗细胞增殖剂用于治疗一些病症包括牛皮癣、动脉粥样硬化和再狭窄损伤。在本发明范围内的化合物表现出调节和/或抑制细胞信号传导和/或细胞增殖和/或基质产生和/或趋化性和/或细胞炎性反应的活性,并且可用于预防或延迟这样的病症的发作或复发或治疗这样的病症。
为了确定本发明化合物的有效性,使用在本领域内接受的、并且被公认与在哺乳动物中的药理活性相关的下述药理试验。已在这些不同试验中测试了在本发明范围内的化合物,并且认为所得结果与有用的细胞分化介质活性相关。相信这些试验结果能给药理和药物化学领域的技术人员提供足够的信息,以确定出在一个或多个其中所述的治疗中使用所研究化合物的参数。
1.PDGF-R酪氨酸激酶自身磷酸化ELISA测定
本标题测定是按照Dolle等人(J.Med.Chem 1994,37,2627)的方法进行的(该文献引入本发明以作参考),但是不同之处在于使用如下所述的来自人主动脉平滑肌细胞(HAMSC)的细胞溶解产物。
2.有丝分裂测定一般方法
a.细胞培养
将人主动脉平滑肌细胞(第4-9代)以6000个细胞/孔的浓度铺在含有生长支持培养基的96孔平板中,并生长2-3天。在达到大约85%融合时,用不含血清的培养基(SFM)中止细胞生长。
b.有丝分裂测定
剥夺血清24小时后,除去培养基,并代之以在SFM中的测试化合物/载体(200μl/孔)。化合物是以10mM的浓度溶解在细胞培养物DMSO中,并在SFM中进一步稀释。
与化合物预孵育30分钟后,用PDGF以10ng/mL的浓度刺激细胞。对于每一化合物浓度,用刺激和未刺激的孔以一式两份的方式进行测定。
4小时后,加入1μCi 3H胸腺嘧啶核苷/孔。
加入生长因子24小时后,中止培养物的生长。用胰蛋白酶解离细胞,并用自动细胞收获器(Wallac MachII96)将细胞收获到滤器垫上。将该滤器垫在闪烁计数器(Wallac Betaplate)中计数,以测定掺入DNA的标记。
3.趋化性测定
从ATCC获得早代人主动脉平滑肌细胞(HASMC)。将细胞在Clonetics SmGM 2 SingleQuots(培养基)中生长,使用第4-10代细胞。当细胞达到80%汇合时,向培养基中加入荧光探针-钙黄绿素AM(5mM,Molecular Probe),将细胞培养30分钟。用HEPES缓冲盐水洗涤后,用胰蛋白酶解离细胞,并用含有0.1%BSA、10mM谷氨酰胺和10%胎牛血清的MCDB 131缓冲液(Gibco)中和。离心后,将细胞再洗涤一次,并以30000个细胞/50mL的浓度重悬在不含胎牛血清的相同缓冲液中。将细胞与不同浓度的式I化合物(终DMSO浓度=1%)在37℃培养30分钟。为了测定趋化性,使用96孔改进的Boyden室(Neuroprobe,Inc.)和具有8mm孔的聚碳酸酯膜(Poretics,CA)。用胶原(Sigma C3657,0.1mg/mL)包被该膜。将含有和不含有式I化合物的在缓冲液中的PDGF-ββ(3ng/mL)加到下面的室中。将含有和不含有抑制剂的细胞(30000)加到上部的室中。将细胞培养4小时。取出滤膜,并除去在膜上侧的细胞。干燥后,使用CytofluorII(Millipore)在485/530nm的激发/发射波长测定在膜上的荧光。在每一实验中,从6个平行测定中获得平均细胞迁移。由使用DMSO处理的对照值确定抑制百分比。从5个点的浓度-依赖性抑制计算IC50值。所得结果以从5个这样实验获得的平均值±SEM表示。
4.EGF-受体纯化
按照Yarden和Schlessinger的方法纯化EGF-受体。将A431细胞在80cm2瓶中生长至汇合(2×107个细胞/瓶)。用PBS将细胞洗涤2次,并用含有11.0mmol EDTA的PBS收获细胞(在37℃1小时,并以600g离心10分钟)。将细胞以2×107个细胞/mL的浓度溶解在冷的溶解缓冲液(50mmol Hepes缓冲液,pH 7.6,1%Triton X-100,150mmol NaCl,5mmol EGTA,1mmol PMSF,50mg/mL抑酶肽,25mmol苄脒,5mg/mL亮抑蛋白酶肽,和10mg/mL大豆胰蛋白酶抑制剂)中,在4℃保持20分钟。以100000g离心30分钟后,将上清液施加到WGA-琼脂糖柱上(100mL填充树脂/2×107细胞),并在4℃摇动2小时。除去未吸收的材料,将树脂依次用HTN缓冲液(50mmol Hepes,pH 7.6,0.1%Triton X-100,150mmol NaCl)洗涤2次、用含有1MNaCl的HTN缓冲液洗涤2次、和用HTNG缓冲液(50mmol Hepes,pH7.6,0.1%Triton X-100,150mmol NaCl,和10%乙二醇)洗涤2次。用含有0.5M N-乙酰基-D-葡萄糖胺的HTNG缓冲液分批洗脱EGF受体(200mL/2×107细胞)。将洗脱物以等分试样的形式在-70℃贮存,在使用前用TMTNG缓冲液(50mmol Tris-Mes缓冲液,pH 7.6,0.1%Triton X-100,150mmol NaCl,10%乙二醇)稀释。
5.抑制EGF-R自身磷酸化
将A431细胞在包被着人纤连蛋白的组织培养皿中生长至汇合。用冰冷的PBS洗涤2次后,加入500mL/培养皿裂解缓冲液(50mmolHepes,pH 7.5,150mmol NaCl,1.5mmol MgCl2,1mmol EGTA,10%甘油,1%tritonX-100,1mmol PMSF,1mg/mL抑酶肽,1mg/mL亮抑蛋白酶肽)将细胞裂解,在4℃培养5分钟。用EGF刺激(500mg/mL 10分钟,37℃)后,用抗EGF-R(Ab 108)进行免疫沉淀,将自身磷酸化反应(50mL等分试样,3mCi[g-32P]ATP)样品在2或10mM本发明化合物存在下于4℃反应2分钟。通过加入电泳样品缓冲液中止该反应。进行SDA-PAGE分析(7.5%els),然后进行放射自显影分析,通过X-射线胶片测光密度扫描定量测定该反应。
a.细胞培养
如下所述制备称为HER 14和K721A的细胞:用野生型EGF-受体或缺乏酪氨酸激酶活性的EGF-受体突变体(在ATP-结合位点的Lys 721被Ala残基替代)的cDNA结构转染缺乏内源性EGF-受体的NIH3T3细胞(克隆2.2)(得自C.Fryling,NCI,NIH)。将所有细胞在含有10%胎牛血清的DMEM中(Hyclone,Logan,Utah)生长。
6.使用市售试剂盒测定对PKA和PKC的选择性
a.Pierce Colorimetric PKA测定试剂盒,Spinzyme Format
方案简述:
PKA酶(牛心脏)1U/分析管
Kemptide肽(染料标记的)底物
45分钟于30℃
在570nm的吸光度
b.Pierce Colorimetric PKC测定试剂盒,Spinzyme Format
方案简述:
PKC酶(大鼠脑)0.025U/分析管
Neurogranin肽(染料标记的)底物
30分钟于30℃
在570nm的吸光度
7.p56 lck 酪氨酸激酶抑制活性测定
依据在US 5714493中公开的方法测定p56lck酪氨酸激酶抑制活性,该文献引入本发明以作参考。
或者依据下述方法测定酪氨酸激酶抑制活性。首先如下所述将底物(含有酪氨酸的底物,p56lck识别的Biot-(βAla)3-Lys-Val-Glu-Lys-Ile-Gly-Glu-Gly-Thr-Tyr-Glu-Val-Val-Tyr-Lys-(NH2),1μM)磷酸化:在有或没有给定浓度的测试化合物存在下,给予一定量的从克隆酵母中纯化(该酶的纯化是通过标准方法进行的)的酶(通过在酵母结构中表达p56lck基因而制得的酶),在ATP(10μM),MgCl2(2.5mM),MnCl2(2.5mM),NaCl(25mM),DTT(0.4mM)存在下,在Hepes 50mM,pH 7.5中于室温磷酸化10分钟。总的反应体积是50μl,在黑色96-孔氟平板中进行反应。通过加入150μl终止缓冲液(100mM Hepes pH 7.5,KF 400mM,EDTA 133mM,BSA 1g/l)来终止反应,该终止缓冲液含有0.8μg/ml用Europium穴合物(PY20-K)标记的抗酪氨酸抗体和4μg/ml用别藻蓝蛋白标记的链霉抗生物素蛋白(XL665)。链霉抗生物素蛋白和抗酪氨酸抗体的标记是通过Cis-Bio Intemational(法国)进行的。用能测定时间分辨均匀荧光转移(在337nm激发,在620nm和665nm读取)的PackardDiscovery计数器将该混合物计数。磷酸化酪氨酸的浓度以665nm信号/620nm信号比例表示。通过用缓冲液替换酶来获得空白。特异信号是不用抑制剂获得的该比例与使用空白所获得的比例的差异。计算特异信号的百分比。IC50是使用Xlfit软件由一式两份的10个抑制剂浓度计算的。参照化合物是staurosporine(Sigma),其IC50为30±6nM(n=20)。
8.测定体外肿瘤抑制
按如下所述测定本发明化合物在体外抑制肿瘤的生长:
将C6大鼠神经胶质瘤细胞系(得自ATCC)以单层形式在含有2mML-谷氨酰胺、200U/ml青霉素、200μg/ml链霉素、并补充有10%(v/v)热失活的胎牛血清的Dubelcco’s Modified Eagle Medium中生长。用胰蛋白酶处理指数生长期的细胞,用PBS洗涤,并在完全培养基中稀释至终浓度为6500个细胞/ml。向该细胞悬浮液(2.5ml)中加入50μl测试药物或对照溶剂,加入保持在45℃的0.4ml 2.4%Noble Difco琼脂,并混合。将该混合物立即倒入培养皿中,在4℃放置5分钟。在5%CO2气氛下于37℃培养12天后,测定细胞克隆(>60个细胞)的数目。每一药物都是以一式两份的方式以10、1、0.1和0.01μg/ml(在琼脂中的终浓度)的浓度测试的。结果以相对于未处理对照组的克隆发生抑制百分比表示。IC50是从对于每一药物浓度所测定的平均值的半对数图中以图解方式确定的。
9.测定体内肿瘤抑制
使用如US 5700823和US 5760066中所描述的皮下异种移植模型测定本发明化合物在体内对肿瘤生长的抑制,在所述模型中,给小鼠移植C6神经胶质瘤细胞,并用游标卡尺测定肿瘤生长。
通过上述实验方法获得的结果表明,在本发明范围内的化合物具有有用的PDGF受体蛋白酪氨酸激酶抑制特性或p56lck酪氨酸激酶抑制特性,因此具有治疗价值。对于特定治疗目标,上述药理试验结果可用于确定剂量和给药方式。
本发明可以以不背离其精神或必要技术特征的其它具体形式实施。
Claims (29)
1.斯滕特固定模装置,其特征在于聚合物包衣,该包衣掺有抑制再狭窄有效量的式I化合物、或其N-氧化物、其水合物、其溶剂合物、或其可药用盐:
其中
X是L1H或L2Z2;
L1是(CR3aR3b)m-Z3-(CR3′aR3′b)n;
L2是(CR3aR3b)p-Z4-(CR3′aR3′b)q;
Z1是CH或N;
Z2是任选取代的具有3-10个碳原子的环烷基、任选取代的具有3-10个碳原子的环烯基或任选取代的4元-10元杂环基,其中Z2所述取代的取代基是具有1-6个碳原子的烷基、羟基、具有1-6个碳原子的烷氧基、或羧基;
Z3是NR4;
Z4是O、NR4或S;
m是0;
n是2或3,且n+m=2或3;
p和q独立地为0或1,并且p+q=0或1;
R1a和R1b独立地为具有1-6个碳原子的烷基、具有1-6个碳原子的烷氧基、羟基、具有3-10个碳原子的环烷基氧基、经羧基取代的具有1-6个碳原子的烷氧基、4元-10元杂环氧基、经4元-10元杂环基取代的具有1-6个碳原子的烷氧基、经具有1-6个碳原子的烷氧基取代的具有1-6个碳原子的烷氧基、或经氨基甲酰基取代的具有1-6个碳原子的烷氧基,或者R1a和R1b当中一个是氢或卤素,另一个是具有1-6个碳原子的烷基、具有1-6个碳原子的烷氧基、羟基、具有3-10个碳原子的环烷基氧基、4元-10元杂环氧基、或被羧基、4元-10元杂环基、具有1-6个碳原子的烷氧基或氨基甲酰基取代的具有1-6个碳原子的烷氧基,或者,R1a和R1b当中一个是甲氧基,另一个是N-甲基氨基羰基甲氧基或N,N-二甲基氨基羰基甲氧基;
R1c是氢、或具有1-6个碳原子的烷基;
R3a和R3b独立地为氢;
R3′a和R3′b独立地为氢或具有1-10个碳原子的烷基;
R4是氢。
2.权利要求1的斯滕特固定模装置,其中
X是L2Z2;
L2是(CR3aR3b)p-Z4-(CR3′aR3′b)q;
Z2是任选取代的环己基或任选取代的降冰片烷基,其中Z2所述取代的取代基为具有1-6个碳原子的烷基、羟基、具有1-6个碳原子的烷氧基、或羧基;
Z4是O或NR4;
p是0;
q是0或1;
R1a和R1b独立地为具有1-6个碳原子的烷基、具有1-6个碳原子的烷氧基、具有3-10个碳原子的环烷氧基、或4元-10元杂环氧基,或者R1a和R1b当中一个是氢或卤素,另一个是具有1-6个碳原子的烷基、具有1-6个碳原子的烷氧基、具有3-10个碳原子的环烷氧基、或4元-10元杂环氧基;
R1c是氢;
R3′a和R3′b独立地为氢;且
R4是氢。
3.权利要求1的斯滕特固定模装置,其中Z1为CH。
4.权利要求1的斯滕特固定模装置,其中Z1为N。
5.权利要求1的斯滕特固定模装置,其中Z2是甲基环戊基、甲基环己基、[2.2.1]二环庚烷基、[2.2.2]二环辛烷基、环戊烯基、环己烯基、[2.2.1]二环庚烯基或[2.2.2]二环辛烯基。
6.权利要求1的斯滕特固定模装置,其中Z4为O。
7.权利要求1的斯滕特固定模装置,其中Z4为NR4。
8.权利要求1的斯滕特固定模装置,其中Z4为S。
9.斯滕特固定模装置,其特征在于聚合物包衣,该包衣掺有抑制再狭窄有效量的下列化合物、或其N-氧化物、其水合物、其溶剂合物、或其可药用盐:
3-环己氧基-6,7-二甲氧基喹啉;
2-环己基氨基-6,7-二甲氧基喹喔啉;
外-二环[2.2.1]庚-2-基-(6-氯-7-甲氧基喹喔啉-2-基)胺;
外-二环[2.2.1]庚-2-基-(7-氯-6-甲氧基喹喔啉-2-基)胺;
二环[2.2.1]庚-2-基-(6,7-二甲基喹喔啉-2-基)胺;
2-环庚基氨基-6,7-二甲氧基喹喔啉;
2-环戊基氨基-6,7-二甲氧基喹喔啉;
2-环己基氨基-6-甲氧基喹喔啉;
3-氨基环己基-6,7-二甲氧基喹啉;
2-环己基氨基-6-甲氧基-7-溴喹喔啉盐酸盐;
(6,7-二甲氧基喹啉-3-基)-顺式/反式-(3-(R)-甲基环己基)胺;
(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基-环己基)胺;
(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基-环己基)胺;
(6,7-二甲氧基喹啉-3-基)-(3-甲基环戊基)胺;
环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)-胺;
2,7-二-环己氧基-6-甲氧基-喹喔啉;
环己基-(6,7-二甲氧基喹喔啉-2-基甲基)胺;
(6,7-二甲氧基喹啉-3-基)-异丁基胺;
环己基-(6-甲氧基-7-吗啉-4-基喹喔啉-2-基)胺;
(±)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
外-二环[2.2.1]庚-5-烯-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
环己基-(6,8-二甲基-喹喔啉-2-基)-胺;
内-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
(6,7-二甲氧基喹喔啉-2-基)-(4-甲氧基环己基)胺;
外-二环[2.2.1]庚-2-基-(6-甲氧基喹喔啉-2-基)胺;
外-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;
2-(二环[2.2.2]辛-2-基氧基)-6,7-二甲氧基喹喔啉;
内-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;
外-2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;
2-(二环[2.2.1 ]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;
2-环己氧基-6,7-二甲氧基喹喔啉;
2-环戊基硫基-6,7-二甲氧基-喹喔啉;
6,7-二甲氧基-2-环戊氧基-喹喔啉;
2-环戊基甲基氧基-6,7-二甲氧基-喹喔啉;
6,7-二甲氧基-2-四氢吡喃-4-氧基-喹喔啉;
外,外-6,7-二甲氧基-2-(5,6-环氧二环[2.2.1]庚烷-2-基氧基)喹喔啉;
顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸;
6,7-二甲氧基-2-(4-甲氧基环己氧基)喹喔啉;
(1R,2R,4S)-(+)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
(1S,2S,4R)-(-)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;
(6,7-二甲氧基喹喔啉-2-基)-2-氮杂二环[2.2.2]辛烷-3-酮;
顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;
顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸;
顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;
反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;
(6,7-二甲氧基喹喔啉-2-基)-顺式/反式-(3-(R)-甲基环己基)胺;
(6,7-二甲氧基喹喔啉-2-基)-反式-(3-(R)-甲基环己基)胺;
(6,7-二甲氧基喹喔啉-2-基)-顺式-(3-(R)-甲基环己基)胺;或
顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸甲酯。
10.权利要求1-9任一项的斯滕特固定模装置,其中,所述包衣是通过将掺合着所述化合物的聚合材料涂敷在斯滕特固定模装置的至少一个表面上而形成的。
11.权利要求10的斯滕特固定模装置,其中所述聚合物是具有相对低加工温度的聚合物、能携带和递送治疗药物的不可降解聚合物、或能携带和递送治疗药物的生物可降解、生物可吸收的聚合物。
12.权利要求11的斯滕特固定模装置,其中所述聚合物是聚己内酯、聚(乙烯共聚乙酸乙烯酯)、聚乙酸乙烯酯、硅氧烷树胶橡胶、胶乳、尿烷、聚硅氧烷、苯乙烯-乙烯/丁烯-苯乙烯嵌段共聚物、聚-DL-乳酸、聚-L-乳酸、聚原酸酯、聚亚氨基碳酸酯、脂族聚碳酸酯或聚磷腈。
13.权利要求10的斯滕特固定模装置,其中在所述聚合物中掺入了porosigen,形成负载药物的多孔聚合膜。
14.权利要求13的斯滕特固定模装置,其中porosigen是氯化钠、乳糖、肝素钠、聚乙二醇、聚氧化乙烯/聚氧化丙烯共聚物或其混合物。
15.权利要求10的斯滕特固定模装置,其中在所述聚合物上涂敷有控速膜以限制所述化合物的释放速度。
16.权利要求15的斯滕特固定模装置,其中控速膜包含porosigen。
17.权利要求1-9任一项的斯滕特固定模装置,其中所述聚合物包衣是这样形成的:将所述化合物施加在斯滕特固定模装置的至少一个表面上以形成生物活性层,然后在生物活性层上施加一层或多层具有足够厚度以提供化合物控释效果的多孔聚合材料包衣。
18.权利要求17的斯滕特固定模装置,其中多孔聚合材料由通过不使用催化剂的蒸气沉积施加至斯滕特固定模装置上的聚酰胺、聚对亚苯基二甲基或聚对亚苯基二甲基衍生物组成。
19.权利要求17的斯滕特固定模装置,其中多孔聚合材料是适于等离子体沉积涂敷的聚合物。
20.权利要求19的斯滕特固定模装置,其中聚合物是聚(氧化乙烯)、聚(乙二醇)、聚(氧化丙烯)或甲烷、硅氧烷、四氟乙烯四甲基二硅氧烷的聚合物。
21.权利要求17的斯滕特固定模装置,其中多孔聚合材料是源自可光聚合的单体的聚合物。
22.权利要求21的斯滕特固定模装置,其中所述单体具有至少两个可交联的C-C双键,并是可非气相加成聚合的烯不饱和化合物,在常压下的沸点大于100℃,分子量为100-1500,并能易于形成高分子量加聚物。
23.权利要求22的斯滕特固定模装置,其中所述单体为含有2个或更多个丙烯酸酯或异丁烯酸酯基团/分子的可加成光聚合的多烯不饱和丙烯酸酯或异丁烯酸酯或它们的混合物。
24.权利要求17的斯滕特固定模装置,其中多孔聚合材料是生物相容的、并且当植入斯滕特固定模时对血管壁的刺激降至最小的聚合物。
25.权利要求24的斯滕特固定模装置,其中聚合物是生物稳定或可生物吸收的聚合物。
26.权利要求24的斯滕特固定模装置,其中聚合物是具有较低慢性组织反应的生物稳定聚合物。
27.权利要求1-9任一项的斯滕特固定模装置,其中包衣是通过等离子体沉积、气相沉积或在斯滕特固定模表面涂敷各种包衣的其它技术施加至斯滕特固定模表面上的。
28.式I的化合物、或其N-氧化物、其水合物、其溶剂合物或其可药用盐在制备用于治疗再狭窄患者的斯滕特固定模装置中的用途,其特征在于将有效量的所述化合物掺入到包衣在所述斯滕特固定模表面上的聚合物材料中,
其中
X是L1H或L2Z2;
L1是(CR3aR3b)m-Z3-(CR3′aR3′b)n;
L2是(CR3aR3b)p-Z4-(CR3′aR3′b)q;
Z1是CH或N;
Z2是任选取代的具有3-10个碳原子的环烷基、任选取代的具有3-10个碳原子的环烯基或任选取代的4元-10元杂环基,其中Z2所述取代的取代基是具有1-6个碳原子的烷基、羟基、具有1-6个碳原子的烷氧基、或羧基;
Z3是NR4;
Z4是O、NR4或S;
m是0;
n是2或3,且n+m=2或3;
p和q独立地为0或1,并且p+q=0或1;
R1a和R1b独立地为具有1-6个碳原子的烷基、具有1-6个碳原子的烷氧基、羟基、具有3-10个碳原子的环烷基氧基、经羧基取代的具有1-6个碳原子的烷氧基、4元-10元杂环氧基、经4元-10元杂环基取代的具有1-6个碳原子的烷氧基、经具有1-6个碳原子的烷氧基取代的具有1-6个碳原子的烷氧基、或经氨基甲酰基取代的具有1-6个碳原子的烷氧基,或者R1a和R1b当中一个是氢或卤素,另一个是具有1-6个碳原子的烷基、具有1-6个碳原子的烷氧基、羟基、具有3-10个碳原子的环烷基氧基、4元-10元杂环氧基、或被羧基、4元-10元杂环基、具有1-6个碳原子的烷氧基或氢基甲酰基取代的具有1-6个碳原子的烷氧基,或者R1a和R1b当中一个是甲氧基,另一个是N-甲基氨基羰基甲氧基或N,N-二甲基氨基羰基甲氧基;
R1c是氢、或具有1-6个碳原子的烷基;
R3a和R3b独立地为氢;
R3′a和R3′b独立地为氢或具有1-10个碳原子的烷基;
R4是氢。
29.根据权利要求28的用途,其中所述再狭窄处在通过血管成形术治疗动脉粥样硬化损伤时所产生的动脉壁机械损伤位点上。
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US09/198,718 US6180632B1 (en) | 1997-05-28 | 1998-11-24 | Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases |
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