CN100503599C - 作为组蛋白脱乙酰酶的新颖抑制剂的羰基氨基衍生物 - Google Patents
作为组蛋白脱乙酰酶的新颖抑制剂的羰基氨基衍生物 Download PDFInfo
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- CN100503599C CN100503599C CNB038058847A CN03805884A CN100503599C CN 100503599 C CN100503599 C CN 100503599C CN B038058847 A CNB038058847 A CN B038058847A CN 03805884 A CN03805884 A CN 03805884A CN 100503599 C CN100503599 C CN 100503599C
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Abstract
本发明包括一种新颖的式(I)化合物,其中n、m、t、R1、R2、R3、R4、R5、L、Q、X、Y与如本文中定义,其具有组蛋白脱乙酰酶抑制酶活性;并包括其制法、含其的组合物及其作为药物的用途。
Description
本发明有关具有组蛋白脱乙酰酶(HDAC)抑制酶活性的化合物。并有关其制法、含其的组合物、及其于活体内及活体外抑制HDAC的用途及其作为药物的用途,例如:作为抑制增生性状况如癌症与牛皮癣的药物的用途。
所有真核细胞中,染色质中的基因组DNA与组蛋白结合形成核小体。每个核小体由两个拷贝的各组蛋白H2A、H2B、H3与H4形成的蛋白质八聚体组成。DNA环绕此蛋白质核,组蛋白的碱性氨基酸与DNA的带负电磷酸根交互作用。此等核组蛋白最常见的翻译后修饰作用为保留的高碱性N-端赖氨酸残基的ε-氨基的可逆性乙酰化作用。由竞争组蛋白乙酰基转移酶与本文中称为“HDAC”的组蛋白脱乙酰酶之间的动态平衡建立组蛋白乙酰化作用的稳定状态。组蛋白乙酰化作用与脱乙酰化作用长久以来即与转录控制相关联。近来克隆出编码不同组蛋白乙酰基转移酶及组蛋白脱乙酰酶的基因提供组蛋白乙酰化作用与转录控制之间关系的可能解释。组蛋白的可逆性乙酰化作用可造成染色质再模造并照此作为基因转录的控制机制。通常,组蛋白的过度乙酰化作用会促使基因表现,而组蛋白脱乙酰化作用则与转录阻抑相关。已知组蛋白乙酰基转移酶具有作为转录辅激活物的作用,而组蛋白脱乙酰酶则属于转录阻抑途径。
组蛋白乙酰化与脱乙酰化之间的动态平衡系正常细胞生长所必需。抑制组蛋白脱乙酰酶则可造成细胞周期停滞、细胞分化、细胞程序死亡及转化表型的逆转。因此,HDAC抑制剂在治疗细胞增生疾病或状况上具有极大医疗潜力(Marks等人,Nature Reviews:Cancer 1:194-202,2001)。
有关组蛋白脱乙酰酶(HDAC)的抑制剂研究显示,此等酶的确在细胞增生及分化上扮演重要角色。抑制剂Trichostatin A(TSA)造成G1与G2期的细胞周期停滞,使不同细胞系的转化表型逆转,并诱导弗罗德白血病细胞及其他细胞分化。已有文献指出,TSA(与N-辛二酰苯胺异羟肟酸SAHA)在小鼠体内,可制抑细胞生长,诱导终末分化,及防止肿瘤形成(Finnin等人,Nature,401:188-193,1999)。
亦有文献指出,TSA适用于治疗纤维变性例如:肝纤维变性与肝硬变(Geerts等人,1998年3月11日公告的欧洲专利申请EP 0 827742)。
2001年5月31日公告的专利申请WO 01/38322揭示除了别的以外,通式Cy-L1-Ar-Y1-C(O)-NH-Z的组蛋白脱乙酰酶抑制剂,并提供治疗细胞增生疾病与状况的组合物与方法。
2001年9月27日公告的专利申请WO 01/70675揭示如式Cy2-Cy1-X-Y1-W与Cy-S(O)2-NH-Y3-W的组蛋白脱乙酰酶抑制剂,并进一步提供治疗细胞增生疾病与状况的组合物与方法。
所要解决的问题为提供具有高酶活性的组蛋白脱乙酰酶抑制剂,亦需具备有利性质,如:细胞活性及提高的生体可用率,最好提高口服的生体可用率,且副作用很小或没有。
本发明新颖化合物可解决上述问题。本化合物的结构式不同于现有技术。
本发明化合物展现优越的活体外组蛋白脱乙酰酶抑制酶活性。本发明化合物在细胞活性上具有有利性质,且针对抑制G1与G2关卡处的细胞周期进展具有特异性质(p21诱导力)。本发明化合物具有良好代谢稳定性及高度生体可用率,更特定言的,其展现口服生体可用性。
本发明是有关式(I)化合物
其N-氧化物型、其药理上可接受的加成盐及立体化学异构型,其中
n为0、1、2、或3,且当n为0时,则指的是直接键;
m为0或1,且当m为0时,则指的是直接键;
t为0、1、2、3或4,且当t为0时,则指的是直接键;
各Q为氮或-C≤;
各X为氮或-C≤;
各Y为氮或-C≤;
R1为-C(O)NR8R9、-NHC(O)R10、-C(O)C1-6烷二基SR10、-NR11C(O)N(OH)R10、-NR11C(O)C1-6烷二基SR10、-NR11C(O)C=N(OH)R10或另一个Zn-螯合基,其中R8与R9分别独立选自:氢、羟基、C1-6烷基、羟基C1-6烷基、氨基C1-6烷基或氨基芳基;
R10为氢、C1-6烷基、C1-6烷基羰基、芳基C1-6烷基、C1-6烷基吡嗪基、吡啶酮、吡咯烷酮或甲基咪唑基;
R11为氢或C1-6烷基;
R2为氢、卤基、羟基、氨基、硝基、C1-6烷基、C1-6烷氧基、三氟甲基、二(C1-6烷基)氨基、羟氨基或萘(naphtalenyl)磺酰吡嗪基;
-L-为直接键或选自下列的二价基团:C1-6烷二基、C1-6烷二基氧、氨基、羰基、或氨基羰基;
各R3分别独立代表氢原子,且其中一个氢原子可被选自芳基的取代基代替;
R4为氢、羟基、氨基、羟基C1-6烷基、C1-6烷基、C1-6烷氧基、芳基C1-6基、氨基羰基、羟羰基、氨基C1-6烷基、氨基羰基C1-6烷基、羟羰基C1-6烷基、羟氨基羰基、C1-6烷氧羰基、C1-6烷基氨基C1-6烷基或二(C1-6烷基)氨基C1-6烷基;
R5为氢、C1-6烷基、C3-10环烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、二(C1-6烷基)氨基C1-6烷基或芳基;
其中各s分别为0、1、2、3、4或5;
各R6与R7分别独立选自氢;卤基;羟基;氨基;硝基;三卤代C1-6烷基;三卤代C1-6烷氧基;C1-6烷基;经芳基与C3-10环烷基取代的C1-6烷基;C1-6烷氧基;C1-6烷氧基C1-6烷氧基;C1-6烷基羰基;C1-6烷氧羰基;C1-6烷基磺酰基;氰基C1-6烷基;羟基C1-6烷基;羟基C1-6烷氧基;羟基C1-6烷基氨基;氨基C1-6烷氧基;二(C1-6烷基)氨基羰基;二(羟基C1-6烷基)氨基;(芳基)(C1-6烷基)氨基;二(C1-6烷基)氨基C1-6烷氧基;二(C1-6烷基)氨基C1-6烷基氨基;二(C1-6烷基)氨基C1-6烷基氨基C1-6烷基;芳基磺酰基;芳基磺酰基氨基;芳氧基;芳氧基C1-6烷基;芳基C2-6链烯二基;二(C1-6烷基)氨基;二(C1-6烷基)氨基C1-6烷基;二(C1-6烷基)氨基(C1-6烷基)氨基;二(C1-6烷基)氨基(C1-6烷基)氨基C1-6烷基;二(C1-6烷基)氨基C1-6烷基(C1-6烷基)氨基;二(C1-6烷基)氨基C1-6烷基(C1-6烷基)氨基C1-6烷基;
氨基磺酰基氨基(C1-6烷基)氨基;
氨基磺酰基氨基(C1-6烷基)氨基C1-6烷基;
二(C1-6烷基)氨基磺酰基氨基(C1-6烷基)氨基;
二(C1-6烷基)氨基磺酰基氨基(C1-6烷基)氨基C1-6烷基;氰基;硫代苯基;
经下列基团取代的硫代苯基;二(C1-6烷基)氨基C1-6烷基(C1-6烷基)氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷基、C1-6烷基哌嗪基C1-6烷基、羟基C1-6烷基哌嗪基C1-6烷基、羟基C1-6烷氧基C1-6烷基哌嗪基C1-6烷基、二(C1-6烷基)氨基磺酰基哌嗪基C1-6烷基、C1-6烷氧基哌啶基、C1-6烷氧基哌啶基C1-6烷基、吗啉基C1-6烷基、羟基C1-6烷基(C1-6烷基)氨基C1-6烷基、或二(羟基C1-6烷基)氨基C1-6烷基;
呋喃基;经羟基C1-6烷基取代的呋喃基;苯并呋喃基;咪唑基;噁唑基;经芳基与C1-6烷基取代的噁唑基;C1-6烷基三唑基;四唑基;吡咯烷基;吡咯基;哌啶基C1-6烷氧基;吗啉基;C1-6烷基吗啉基;吗啉基C1-6烷氧基;吗啉基C1-6烷基;吗啉基C1-6烷基氨基;吗啉基C1-6烷基氨基C1-6烷基;哌嗪基;C1-6烷基哌嗪基;C1-6烷基哌嗪基C1-6烷氧基;哌嗪基C1-6烷基;萘磺酰基哌嗪基;萘磺酰基哌啶基;萘磺酰基;C1-6烷基哌嗪基C1-6烷基;C1-6烷基哌嗪基C1-6烷基氨基;C1-6烷基哌嗪基C1-6烷基氨基C1-6烷基;C1-6烷基哌嗪基磺酰基;氨基磺酰基哌嗪基C1-6烷氧基;氨基磺酰基哌嗪基;氨基磺酰基哌嗪基C1-6烷基;二(C1-6烷基)氨基磺酰基哌嗪基;二(C1-6烷基)氨基磺酰基哌嗪基C1-6烷基;羟基C1-6烷基哌嗪基;羟基C1-6烷基哌嗪基C1-6烷基;C1-6烷氧基哌啶基;C1-6烷氧基哌啶基C1-6烷基;哌啶基氨基C1-6烷基氨基;哌啶基氨基C1-6烷基氨基C1-6烷基;
(C1-6烷基哌啶基)(羟基C1-6烷基)氨基C1-6烷基氨基;
(C1-6烷基哌啶基)(羟基C1-6烷基)氨基C1-6烷基氨基C1-6烷基;
羟基C1-6烷氧基C1-6烷基哌嗪基;
羟基C1-6烷氧基C1-6烷基哌嗪基C1-6烷基;
(羟基C1-6烷基)(C1-6烷基)氨基;(羟基C1-6烷基)(C1-6烷基)氨基C1-6烷基;
羟基C1-6烷基氨基C1-6烷基;二(羟基C1-6烷基)氨基C1-6烷基;
吡咯烷基C1-6烷基;吡咯烷基C1-6烷氧基;吡唑基;硫代吡唑基;经选自C1-6烷基或三卤代C1-6烷基中的两个取代基取代的吡唑基;
吡啶基;经C1-6烷氧基、芳氧基或芳基取代的吡啶基;嘧啶基;四氢嘧啶基哌嗪基;四氢嘧啶基哌嗪基C1-6烷基;喹啉基;吲哚基;苯基;经分别独立选自下列的1、2或3个取代基取代的苯基:卤基、氨基、硝基、C1-6烷基、C1-6烷氧基、羟基C1-4烷基、三氟甲基、三氟甲氧基、羟基C1-4烷氧基、C1-4烷基磺酰基、C1-4烷氧基C1-4烷氧基、C1-4烷氧羰基、氨基C1-4烷氧基、
二(C1-4烷基)氨基C1-4烷氧基、二(C1-4烷基)氨基、二(C1-4烷基)氨基羰基、二(C1-4烷基)氨基C1-4烷基、二(C1-4烷基)氨基C1-4烷基氨基C1-4烷基、二(C1-4烷基)氨基(C1-4烷基)氨基、二(C1-4烷基)氨基(C1-4烷基)氨基C1-4烷基、二(C1-4烷基)氨基C1-4烷基(C1-4烷基)氨基、二(C1-4烷基)氨基C1-4烷基(C1-4烷基)氨基C1-4烷基、氨基磺酰基氨基(C1-4烷基)氨基、氨基磺酰基氨基(C1-4烷基)氨基C1-4烷基、二(C1-4烷基)氨基磺酰基氨基(C1-4烷基)氨基、二(C1-4烷基)氨基磺酰基氨基(C1-4烷基)氨基C1-6烷基、氰基、哌啶基C1-4烷氧基、吡咯烷基C1-4烷氧基;氨基磺酰基哌嗪基、氨基磺酰基哌嗪基C1-4烷基、二(C1-4烷基)氨基磺酰基哌嗪基、二(C1-4烷基)氨基磺酰基哌嗪基C1-4烷基、羟基C1-4烷基哌嗪基、羟基C1-4烷基哌嗪基C1-4烷基、C1-4烷氧基哌啶基、C1-4烷氧基哌啶基C1-4烷基、羟基C1-4烷氧基C1-4烷基哌嗪基、羟基C1-4烷氧基C1-4烷基哌嗪基C1-4烷基、(羟基C1-4烷基)(C1-4烷基)氨基、(羟基C1-4烷基)(C1-4烷基)氨基C1-4烷基、二(羟基C1-4烷基)氨基、二(羟基C1-4烷基)氨基C1-4烷基、呋喃基、经以下取代的呋喃基:-CH=CH-CH=CH-、吡咯烷基C1-4烷基、吡咯烷基C1-4烷氧基、吗啉基、吗啉基C1-4烷氧基、吗啉基C1-4烷基、吗啉基C1-4烷基氨基、吗啉基C1-4烷基氨基C1-4烷基、哌嗪基、C1-4烷基哌嗪基、C1-4烷基哌嗪基C1-4烷氧基、哌嗪基C1-4烷基、C1-4烷基哌嗪基C1-4烷基、C1-4烷基哌嗪基C1-4烷基氨基、C1-4烷基哌嗪基C1-4烷基氨基C1-6烷基、四氢嘧啶基哌嗪基、四氢嘧啶基哌嗪基C1-4烷基、哌啶基氨基C1-4烷基氨基、哌啶基氨基C1-4烷基氨基C1-4烷基,
(C1-4烷基哌啶基)(羟基C1-4烷基)氨基C1-4烷基氨基,
(C1-4烷基哌啶基)(羟基C1-4烷基)氨基C1-4烷基氨基C1-4烷基,
吡啶基C1-4烷氧基、羟基C1-4烷基氨基、羟基C1-4烷基氨基C1-4烷基,二(C1-4烷基)氨基C1-4烷基氨基、氨基噻二唑基,
氨基磺酰基哌嗪基C1-4烷氧基、或硫代苯基C1-4烷基氨基;
各R6与R7可置于氮上替代氢;
上述芳基为苯基,或经一个或多个分别独立选自:卤基、C1-6烷基、C1-6烷氧基、三氟甲基、氰基或羟基羰基的取代基取代的苯基。
术语“组蛋白脱乙酰基酶抑制剂”系指可与组蛋白脱乙酰酶交互作用且可抑制其活性,更特定言的抑制其酶活性的化合物。抑制组蛋白脱乙酰酶酶活性意指降低组蛋白脱乙酰酶脱除组蛋白的乙酰基的能力。优选,此等抑制作用为特异性,亦即组蛋白脱乙酰酶抑制剂降低组蛋白脱乙酰酶脱除组蛋白的乙酰基的能力时的浓度低于该抑制剂为了产生一些其他不相关的生物效果时所需的浓度。
如上文与下文中定义所使用的卤基通指氟、氯、溴与碘;C1-4烷基指含有1至4个碳原子的直链与支链饱和烃基,例如:甲基、乙基、丙基、丁基、1-甲基乙基、2-甲基丙基,等等;C1-6烷基包括C1-4烷基及含有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,等等;C1-6烷二基指含有1至6个碳原子的二价直链与支链饱和烃基,例如:亚甲基、1,2-乙二基、1,3-丙二基、1,4-丁二基、1,5-戊二基、1,6-己二基,及其分支的异构体,如:2-甲基戊二基、3-甲基戊二基、2,2-二甲基丁二基、2,3-二甲基丁二基,等等;三卤代C1-6烷基指含有三个相同或相异卤基取代基的C1-6烷基,例如:三氟甲基;C2-6链烯二基指含有一个双键及2至6个碳原子的二价直链与支链烃基,例如:乙烯二基、2-丙烯二基、3-丁烯二基、2-戊烯二基、3-戊烯二基、3-甲基2-丁烯二基,等等;氨基芳基指经氨基取代的芳基;及C3-10环烷基包括含有3至10个碳原子的环状烃基,如:环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、等等。
术语“另一个Zn-螯合基”指可与Zn-离子交互作用的基团,其可存在于酶结合部位。
药理上可接受的加成盐包括药理上可接受的酸加成盐及药理上可接受的碱加成盐。如上述的药理上可接受的酸加成盐包括式(I)化合物可形成的具治疗活性的无毒性酸加成盐型。具有碱性性质的式(I)化合物可通过将其碱型经过适当酸处理后,可转化成其药理上可接受的酸加成盐。适当的酸包括例如:无机酸类,如:氢卤酸,例如:盐酸或氢溴酸;硫酸;硝酸;磷酸,等等酸类;或有机酸类,例如:乙酸、三氟乙酸、丙酸、羟乙酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸(亦即丁二酸)、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己烷基氨基磺酸、水杨酸、对氨基-水杨酸、双羟萘酸,等等酸类。
具有酸性性质的式(I)化合物可通过将其酸型经过适当有机或无机碱处理后,转化成其药理上可接受的碱加成盐。适当的碱盐型包括例如:铵盐、碱金属与碱土金属盐,例如:锂、钠、钾、镁、钙盐等等,与有机碱形成的盐例如:benzathine、N-甲基-D-葡糖胺、hydrabamine的盐类,及与氨基酸(例如:精氨酸、赖氨酸等等形成的盐类。
术语“酸或碱加成盐”亦包括式(I)化合物可形成的水合物及溶剂加成型。此等型式的实例为例如:水合物与醇盐,等等。
本文所采用术语“式(I)化合物的立体化学异构型”指式(I)化合物可能具有的由相同原子按相同键顺序组成但具有无法互换的不同立体结构的所有可能化合物。除非另有说明或指出,否则化合物的化学名称包括该化合物可能出现的所有可能立体化学异构型的混合物。该混合物可包含该化合物基本分子结构的所有非对映异构体与/或对映异构体。呈纯型或彼此混合物的式(I)化合物的所有立体化学异构型均涵括在本发明范围内。
式(I)化合物的N-氧化物型包括式(I)中一个或数个氮原子被氧化成所谓的N-氧化物的化合物,特定言的,式中一个或多个哌啶基、哌嗪基或哒嗪基的氮被N-氧化的N-氧化物。
有些式(I)化合物亦可呈其互变异构型。此等型式虽然未明显示于上式中,但亦包括在本发明范围内。
本文中无论何时使用“式(I)化合物”一词时,意指还包括药理上可接受的加成盐及所有立体异构型。
本文所采用术语“组蛋白脱乙酰酶”与“HDAC”意指可自组蛋白的N-末端赖氨酸残基的ε-氨基上脱除乙酰基的酶族群中的任一种。除非本文中另有说明,否则“组蛋白”一词意指来自任何物种的任何组蛋白的蛋白质,包括H1、H2A、H2B、H3、H4与H5。人类HDAC蛋白质或基因产物包括(但不限于):HDAC-1、HDAC-2、HDAC-3、HDAC-4、HDAC-5、HDAC-6、HDAC-7、HDAC-8、HDAC-9与HDAC-10。组蛋白脱乙酰酶亦可衍生自原虫或真菌来源。
第一组值得注意的化合物包括式(I)中符合下列一项或多项限制的化合物:
a)n为1;
b)m为0或1;
c)t为0、1或2;
e)R1为-C(O)NH(OH);
f)R2为氢或C1-6烷基;
g)-L-为直接键;
h)R4为氢;
i)R5为氢;
k)各s分别独立为0、1、2或3;
l)各R6分别独立选自氢、卤基、C1-6烷基或C1-6烷氧基。
第二组值得注意的化合物包括式(I)中符合下列一项或多项限制的化合物:
a)n为1;
b)为0或1;
c)t为0、1或2;
e)R1为-C(O)NH(OH);
f)R2为氢;
g)-L-为直接键;
h)R4为氢;
i)R5为氢;
k)各s分别独立为0、1、2或3;
l)各R6分别独立选自氢、卤基、C1-6烷基或C1-6烷氧基。
第三组值得注意的化合物包括式(I)中R1为-C(O)NH(OH)的化合物。
第四组值得注意的化合物包括式(I)中R1为-C(O)NH(OH)且-L-为直接键的化合物。
第五组值得注意的化合物包括式(I)中R1为-C(O)NH(OH)且R2为氢的化合物。
第六组值得注意的化合物包括式(I)中R1为-C(O)NH(OH),R2为氢,且-L-为直接键的化合物。
第七组值得注意的化合物包括式(I)中符合下列一项或多项限制的化合物:
a)t为0;
b)m为0;
c)R1为-C(O)NR8R9、-C(O)C1-6烷二基SR10、-NR11C(O)N(OH)R10、-NR11C(O)C1-6烷二基SR10、-NR11C(O)C=N(OH)R10、或另一个Zn-螯合基,
其中R8与R9分别独立选自:氢、羟基、羟基C1-6烷基或氨基C1-6烷基;
d)R2为氢、卤基、羟基、氨基、硝基、C1-6烷基、C1-6烷氧基、三氟甲基或二(C1-6烷基)氨基;
e)-L-为直接键或选自下列的二价基团:C1-6烷二基、C1-6烷二基氧、氨基或羰基;
f)R4为氢、羟基、氨基、羟基C1-6烷基、C1-6烷基、C1-6烷氧基、芳基C1-6烷基、氨基羰基、氨基C1-6烷基、C1-6烷基氨基C1-6烷基或二(C1-6烷基)氨基C1-6烷基;
g)R5为氢;
(a-1),(a-3),(a-4),(a-5),(a-6),(a-7),(a-8),(a-9),(a-10),(a-11),(a-12),(a-13),(a-14),(a-15),(a-16),(a-17),(a-18),(a-19),(a-20),(a-21),(a-22),(a-23),(a-24),(a-25),(a-26),(a-28),(a-29),(a-30),(a-31),(a-32),(a-33),(a-34),(a-35),(a-36),(a-37),(a-38),(a-39),(a-40),(a-41),(a-42),(a-44),(a-45),(a-46),(a-47),(a-48)或(a-51);
i)各s分别为0、1、2、3或4;
j)R6为氢;卤基;羟基;氨基;硝基;三卤代C1-6烷基;三卤代C1-6烷氧基;C1-6烷基;C1-6烷氧基;C1-6烷基羰基;C1-6烷氧羰基;C1-6烷基磺酰基;羟基C1-6烷基;
芳氧基;二(C1-6烷基)氨基;氰基;硫代苯基;呋喃基;经羟基C1-6烷基取代的呋喃基;苯并呋喃基;咪唑基;噁唑基;经芳基与C1-6烷基取代的噁唑基;C1-6烷基三唑基;四唑基;吡咯烷基;吡咯基;吗啉基;C1-6烷基吗啉基;哌嗪基;C1-6烷基哌嗪基;羟基C1-6烷基哌嗪基;C1-6烷氧基哌啶基;吡唑基;经选自C1-6烷基或三卤代C1-6烷基中的一或两个取代基取代的吡唑基;吡啶基;经C1-6烷氧基、芳氧基或芳基取代的吡啶基;嘧啶基;喹啉基、吲哚基;苯基;或经分别独立选自:卤基、C1-6烷基、C1-6烷氧基或三氟甲基中的1或2个取代基取代的苯基;
k)R7为氢;卤基;羟基;氨基;硝基;三卤代C1-6烷基;三卤代C1-6烷氧基;C1-6烷基;C1-6烷氧基;C1-6烷基羰基;C1-6烷氧羰基;C1-6烷基磺酰基;羟基C1-6烷基;
芳氧基;二(C1-6烷基)氨基;氰基;吡啶基;苯基;或经分别独立选自:卤基、C1-6烷基、C1-6烷氧基或三氟甲基中的1或2个取代基取代的苯基。
第八组值得注意的化合物包括式(I)中符合下列一项或多项限制的化合物:
a)R8与R9分别独立选自:氢、羟基、羟基C1-6烷基、氨基C1-6烷基或氨基芳基;
b)R5为氢、C1-6烷基、C3-10环烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基或二(C1-6烷基)氨基C1-6烷基;
(a-1),(a-2),(a-3),(a-4),(a-5),(a-6),(a-7),(a-8),(a-9),(a-10),(a-11),(a-12),(a-13),(a-14),(a-15),(a-16),(a-17),(a-18),(a-19),(a-20),(a-21),(a-22),(a-23),(a-24),(a-25),(a-26),(a-27),(a-28),(a-29),(a-30),(a-31),(a-32),(a-33),(a-34),(a-35),(a-36),(a-37),(a-38),(a-39),(a-40),(a-41),(a-42)(a-43)或(a-44);
d)各R6与R7分别独立选自氢;卤基;羟基;氨基;硝基;三卤代C1-6烷基;三卤代C1-6烷氧基;C1-6烷基;C1-6烷氧基;C1-6烷氧基C1-6烷氧基;C1-6烷基羰基、C1-6烷基磺酰基;氰基C1-6烷基;羟基C1-6烷基;羟基C1-6烷氧基;羟基C1-6烷基氨基;氨基C1-6烷氧基;二(C1-6烷基)氨基羰基;二(羟基C1-6烷基)氨基;芳基(C1-6烷基)氨基;二(C1-6烷基)氨基C1-6烷氧基;二(C1-6烷基)氨基C1-6烷基氨基;芳基磺酰基;芳基磺酰基氨基;芳氧基;芳基C2-6链烯二基;二(C1-6烷基)氨基;二(C1-6烷基)氨基C1-6烷基;二(C1-6烷基)氨基C1-6烷基(C1-6烷基)氨基C1-6烷基;氰基;硫代苯基;经下列基团取代的硫代苯基:二(C1-6烷基)氨基C1-6烷基(C1-6烷基)氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷基、C1-6烷基哌嗪基C1-6烷基或二(羟基C1-6烷基)氨基C1-6烷基;呋喃基;咪唑基;C1-6烷基三唑基;四唑基;吡咯烷基;哌啶基C1-6烷氧基;吗啉基;C1-6烷基吗啉基;吗啉基C1-6烷氧基;吗啉基C1-6烷基;C1-6烷基哌嗪基;C1-6烷基哌嗪基C1-6烷氧基;C1-6烷基哌嗪基C1-6烷基;C1-6烷基哌嗪基磺酰基;氨基磺酰基哌嗪基C1-6烷氧基;氨基磺酰基哌嗪基;氨基磺酰基哌嗪基C1-6烷基;二(C1-6烷基)氨基磺酰基哌嗪基;二(C1-6烷基)氨基磺酰基哌嗪基C1-6烷基;羟基C1-6烷基哌嗪基;羟基C1-6烷基哌嗪基C1-6烷基;C1-6烷氧基哌啶基;C1-6烷氧基哌啶基C1-6烷基;羟基C1-6烷氧基C1-6烷基哌嗪基;
羟基C1-6烷氧基C1-6烷基哌嗪基C1-6烷基;
(羟基C1-6烷基)(C1-6烷基)氨基;(羟基C1-6烷基)(C1-6烷基)氨基C1-6烷基;
吡咯烷基C1-6烷氧基;吡唑基;硫代吡唑基;经选自C1-6烷基或三卤代C1-6烷基中两个取代基取代的吡唑基;
吡啶基;经C1-6烷氧基或芳基取代的吡啶基;嘧啶基;喹啉基;吲哚基;苯基;经分别独立选自下列1、2或3个取代基取代的苯基:卤基、氨基、C1-6烷基、C1-6烷氧基、羟基C1-4烷基、三氟甲基、三氟甲氧基、羟基C1-4烷氧基、C1-4烷氧基C1-4烷氧基、氨基C1-4烷氧基、二(C1-4烷基)氨基C1-4烷氧基、二(C1-4烷基)氨基、二(C1-4烷基)氨基C1-4烷基、二(C1-4烷基)氨基C1-4烷基(C1-4烷基)氨基C1-4烷基、哌啶基C1-4烷氧基、吡咯烷基C1-4烷氧基、氨基磺酰基哌嗪基、氨基磺酰基哌嗪基C1-4烷基、二(C1-4烷基)氨基磺酰基哌嗪基、二(C1-4烷基)氨基磺酰基哌嗪基C1-4烷基、羟基C1-4烷基哌嗪基、羟基C1-4烷基哌嗪基C1-4烷基、C1-4烷氧基哌啶基、C1-4烷氧基哌啶基C1-4烷基、羟基C1-4烷氧基C1-4烷基哌嗪基、羟基C1-4烷氧基C1-4烷基哌嗪基C1-4烷基、(羟基C1-4烷基)(C1-4烷基)氨基、(羟基C1-4烷基)(C1-4烷基)氨基C1-4烷基、吡咯烷基C1-4烷氧基、吗啉基C1-4烷氧基、吗啉基C1-4烷基、C1-4烷基哌嗪基、C1-4烷基哌嗪基C1-4烷氧基、C1-4烷基哌嗪基C1-4烷基、羟基C1-4烷基氨基、二(羟基C1-4烷基)氨基、二(C1-4烷基)氨基C1-4烷基氨基、氨基噻二唑基、氨基磺酰基哌嗪基C1-4烷氧基、或硫代苯基C1-4烷基氨基。
一组优选化合物系由式(I)中如下说明的化合物组成;
R8与R9分别独立选自:氢、羟基、羟基C1-6烷基、氨基C1-6烷基或氨基芳基;
R5为氢、C1-6烷基、C1-10环烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、或二(C1-6烷基)氨基C1-6烷基;
(a-1),(a-2),(a-3),(a-4),(a-5),(a-6),(a-7),(a-8),(a-9),(a-10),(a-11),(a-12),(a-13),(a-14),(a-15),(a-16),(a-17),(a-18),(a-19),(a-20),(a-21),(a-22),(a-23),(a-24),(a-25),(a-26),(a-27),(a-28),(a-29),(a-30),(a-31),(a-32),(a-33),(a-34),(a-35),(a-36),(a-37),(a-38),(a-39),(a-40),(a-41),(a-42)(a-43)或(a-44);
及各R6与R7分别独立选自氢;卤基;羟基;氨基;硝基;三卤代C1-6烷基;三卤代C1-6烷氧基;C1-6烷基;C1-6烷氧基;C1-6烷氧基C1-6烷氧基;C1-6烷基羰基、C1-6烷基磺酰基;氰基C1-6烷基;羟基C1-6烷基;羟基C1-6烷氧基;羟基C1-6烷基氨基;氨基C1-6烷氧基;二(C1-6烷基)氨基羰基;二(羟基C1-6烷基)氨基;芳基(C1-6烷基)氨基;二(C1-6烷基)氨基C1-6烷氧基;二(C1-6烷基)氨基C1-6烷基氨基;芳基磺酰基;芳基磺酰基氨基;芳氧基;芳基C2-6链烯二基;二(C1-6烷基)氨基;二(C1-6烷基)氨基C1-6烷基;二(C1-6烷基)氨基C1-6烷基(C1-6烷基)氨基C1-6烷基;氰基;硫代苯基;经下列基团取代的硫代苯基:二(C1-6烷基)氨基C1-6烷基(C1-6烷基)氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷基、C1-6烷基哌嗪基C1-6烷基或二(羟基C1-6烷基)氨基C1-6烷基;呋喃基;咪唑基;C1-6烷基三唑基;四唑基;吡咯烷基;哌啶基C1-6烷氧基;吗啉基;C1-6烷基吗啉基;吗啉基C1-6烷氧基;吗啉基C1-6烷基;C1-6烷基哌嗪基;C1-6烷基哌嗪基C1-6烷氧基;C1-6烷基哌嗪基C1-6烷基;C1-6烷基哌嗪基磺酰基;氨基磺酰基哌嗪基C1-6烷氧基;氨基磺酰基哌嗪基;氨基磺酰基哌嗪基C1-6烷基;二(C1-6烷基)氨基磺酰基哌嗪基;二(C1-6烷基)氨基磺酰基哌嗪基C1-6烷基;羟基C1-6烷基哌嗪基;羟基C1-6烷基哌嗪基C1-6烷基;C1-6烷氧基哌啶基;C1-6烷氧基哌啶基C1-6烷基;羟基C1-6烷氧基C1-6烷基哌嗪基;
羟基C1-6烷氧基C1-6烷基哌嗪基C1-6烷基;
(羟基C1-6烷基)(C1-6烷基)氨基;(羟基C1-6烷基)(C1-6烷基)氨基C1-6烷基;
吡咯烷基C1-6烷氧基;吡唑基;硫代吡唑基;经选自C1-6烷基或三卤代C1-6烷基中两个取代基取代的吡唑基;吡啶基;经C1-6烷氧基或芳基取代的吡啶基;嘧啶基;喹啉基;吲哚基;苯基;经分别独立选自下列1、2或3个取代基取代的苯基:卤基、氨基、C1-6烷基、C1-6烷氧基、羟基C1-4烷基、三氟甲基、三氟甲氧基、羟基C1-4烷氧基、C1-4烷氧基C1-4烷氧基、氨基C1-4烷氧基、二(C1-4烷基)氨基C1-4烷氧基、二(C1-4烷基)氨基、二(C1-4烷基)氨基C1-4烷基、二(C1-4烷基)氨基C1-4烷基(C1-4烷基)氨基C1-4烷基、哌啶基C1-4烷氧基、吡咯烷基C1-4烷氧基、氨基磺酰基哌嗪基、氨基磺酰基哌嗪基C1-4烷基、二(C1-4烷基)氨基磺酰基哌嗪基、二(C1-4烷基)氨基磺酰基哌嗪基C1-4烷基、羟基C1-4烷基哌嗪基、羟基C1-4烷基哌嗪基C1-4烷基、C1-4烷氧基哌啶基、C1-4烷氧基哌啶基C1-4烷基、羟基C1-4烷氧基C1-4烷基哌嗪基、羟基C1-4烷氧基C1-4烷基哌嗪基C1-4烷基、(羟基C1-4烷基)(C1-4烷基)氨基、(羟基C1-4烷基)(C1-4烷基)氨基C1-4烷基、吡咯烷基C1-4烷氧基、吗啉基C1-4烷氧基、吗啉基C1-4烷基、C1-4烷基哌嗪基、C1-4烷基哌嗪基C1-4烷氧基、C1-4烷基哌嗪基C1-4烷基、羟基C1-4烷基氨基、二(羟基C1-4烷基)氨基、
二(C1-4烷基)氨基C1-4烷基氨基、氨基噻二唑基、氨基磺酰基哌嗪基C1-4烷氧基、或硫代苯基C1-4烷基氨基。
另一组优选化合物系由式(I)中如下说明的化合物组成:
其中t为0;m为0;
R1为-C(O)NR8R9、-C(O)C1-6烷二基SR10、-NR11C(O)N(OH)R10、-NR11C(O)C1-6烷二基SR10、-NR11C(O)C=N(OH)R10或另一个Zn螯合基,其中R8与R9分别独立选自:氢、羟基、羟基C1-6烷基或氨基C1-6烷基;
R2为氢、卤基、羟基、氨基、硝基、C1-6烷基、C1-6烷氧基、三氟甲基或二(C1-6烷基)氨基;
-L-为直接键或选自下列的二价基团:C1-6烷二基、C1-6烷二基氧、氨基或羰基;
R4为氢、羟基、氨基、羟基C1-6烷基、C1-6烷基、C1-6烷氧基、芳基C1-6烷基、氨基羰基、氨基C1-6烷基、C1-6烷基氨基C1-6烷基或二(C1-6烷基)氨基C1-6烷基;
R5为氢;
(a-1),(a-3),(a-4),(a-5),(a-6),(a-7),(a-8),(a-9),(a-10),(a-11),(a-12),(a-13),(a-14),(a-15),(a-16),(a-17),(a-18),(a-19),(a-20),(a-21),(a-22),(a-23),(a-24),(a-25),(a-26),(a-28),(a-29),(a-30),(a-31),(a-32),(a-33),(a-34),(a-35),(a-36),(a-37),(a-38),(a-39),(a-40),(a-41),(a-42),(a-44),(a-45),(a-46),(a-47),(a-48)或(a-51);
各s分别为0、1、2、3或4;
R6为氢;卤基;羟基;氨基;硝基;三卤代C1-6烷基;三卤代C1-6烷氧基;C1-6烷基;C1-6烷氧基;C1-6烷基羰基;C1-6烷氧羰基;C1-6烷基磺酰基;羟基C1-6烷基;
芳氧基;二(C1-6烷基)氨基;氰基;硫代苯基;呋喃基;经羟基C1-6烷基取代的呋喃基;苯并呋喃基;咪唑基;噁唑基;经芳基与C1-6烷基取代的噁唑基;C1-6烷基三唑基;四唑基;吡咯烷基;吡咯基;吗啉基;C1-6烷基吗啉基;哌嗪基;C1-6烷基哌嗪基;羟基C1-6烷基哌嗪基;C1-6烷氧基哌啶基;吡唑基;经选自C1-6烷基或三卤代C1-6烷基中1或2个取代基取代的吡唑基;吡啶基;经C1-6烷氧基或芳基取代的吡啶基;嘧啶基;喹啉基、吲哚基;苯基;或经分别独立选自:卤基、C1-6烷基、C1-6烷氧基或三氟甲基中的1或2个取代基取代的苯基;
且R7为氢;卤基;羟基;氨基;硝基;三卤代C1-6烷基;三卤代C1-6烷氧基;C1-6烷基;C1-6烷氧基;C1-6烷基羰基;C1-6烷氧羰基;C1-6烷基磺酰基;羟基C1-6烷基;
芳氧基;二(C1-6烷基)氨基;氰基;吡啶基;苯基;或经分别独立选自:卤基、C1-6烷基、C1-6烷氧基或三氟甲基中的1或2个取代基取代的苯基;
一组更优选化合物系由式(I)中如下说明的化合物组成:
其中n为1;m为0或1;t为0、1或2;各Q为-C≤;R1为-C(O)NH(OH);R2为氢或C1-6烷基;-L-为直接键;R4为氢;R5为氢;为选自(a-1)、(a-20)、(a-25)、(a-27)、(a-28)、(a-29)、(a-41)或(a-42)的基团;各s分别独立为0、1或2;且各R6分别独立选自氢、卤基、C1-6烷基或C1-6烷氧基。
另一组还更佳化合物系由该等式(I)中如下说明的化合物组成;
其中n为1;m为0或1;t为0、1或2;各Q为-C≤;R1为-C(O)NH(OH);R2为氢或;-L-为直接键;R4为氢;R5为氢;为选自(a-1)、(a-20)、(a-27)、(a-28)、(a-29)、(a-41)或(a-42)的基团;各s分别独立为0、1或2;且各R6分别独立选自氢、卤基、C1-6烷基或C1-6烷氧基。
最优选化合物为No.3化合物。
式(I)化合物及其药理上可接受的盐与N-氧化物及立体化学异构型可依一般方式制备。其一般合成途径包括例如:
a)式(I)中R1为-C(O)NH(OH)的异羟肟酸(称为式(I-a)化合物)的制法可由式(II)中间体与适当酸,例如:三氟乙酸(CF3COOH)反应。该反应系于适当溶剂中进行,例如:甲醇。
b)式(II)中间体的制法可由式(III)中间体与式(IV)中间体于适当试剂的存在下反应,如:N’-(乙基carbonimidoyl)-N,N-二甲基-1,3-丙二胺单盐酸盐(EDC)与1-羟基-1H-苯并三唑(HOBT)。该反应可于合适溶剂中进行,如:DCM与THF的混合物。
c)式(III)中间体的制法可由式(V)中间体与适当碱(如:NaOH),于合适溶剂的存在下反应,如:乙醇。
式(I)化合物亦可使用固相合成技术方便地制备。通常,固相合成法涉及由中间体于合成法中与聚合物载体反应。此由聚合物承载的中间体可再进行许多合成步骤。每一步骤之后,过滤树脂,以各种溶剂洗涤数次,以除去杂质。每一步骤中,树脂可以拆开,以在下一个步骤中与不同中间体反应,以合成大量化合物。流程中最后一个步骤之后,以试剂或方法处理树脂以从样本上断裂树脂。固相化学中所使用技术的更详细说明示于例如:“The Combinatorial Index”(B.Bunin,Academic Press)及Novabiochem′s 1999 Catalogue &Peptide Synthesis Handbook(瑞士Novabiochem AG),其内容已以引用的方式引入本文中。
式(I)化合物及一些中间体在其结构中具有至少一个致立体中心。此致立体中心可呈R或S构型。
依上述制法制备的式(I)化合物可以为对映异构体的外消旋混合物,其可依现有技术已知的拆分法彼此分离。式(I)的外消旋化合物可经由与合适的手性酸反应而转化成相应的非对映异构盐型。该非对映异盐型再经例如:选择性或分级结晶法分离,使用碱释出对映异构体。另一种分离式(I)化合物的对映异构型的方法涉及使用手性固定相进行液相色谱。若该反应为立体专一性反应时,该纯立体化学异构型亦可衍生自适当起始物质的相应纯立体化学异构型。若需要特定的立体异构体时,最好以立体专一性制法合成该化合物。此等方法最好使用对映异构纯的起始物质。
式(I)化合物、其药理上可接受的酸加成盐及立体异构型具有组蛋白脱乙酰酶(HDAC)抑制效果的有价值的药物性质。
本发明提供一种抑制细胞(包括转化细胞)异常生长的方法,其系给药有效量的本发明化合物。细胞的异常生长指细胞不依赖于正常的调节机制生长(比如,丧失接触抑制作用)。其包括直接造成癌细胞生长停滞、终末分化及/或细胞程序死亡,及间接抑制肿瘤的新血管形成来抑制肿瘤生长。
本发明亦提供一种抑制肿瘤生长的方法,其系对有此治疗需要的受试者例如:哺乳动物(更特定言的人类)给药有效量的本发明化合物。特定言之,本发明提供一种抑制肿瘤生长的方法,其系给药有效量的本发明化合物。可受抑制的肿瘤实例(但不限于):肺癌(比如腺癌,并包括非小细胞性肺癌)、胰癌(例如:胰管癌,如,外分泌胰癌)、结肠癌(例如:结肠直肠癌,例如:结肠腺癌与结肠腺瘤)、前列腺癌包括晚期疾病、淋巴谱系血细胞生成肿瘤(例如:急性淋巴细胞性白血病、B-细胞淋巴瘤、伯基氏淋巴瘤)、骨髓白血病(例如:急性骨髓白血病(AML))、甲状腺滤泡癌、脊髓发育不良综合征(MDS)、起因间质的肿瘤(例如:纤维肉瘤与横纹肌肉瘤)、黑素瘤、恶性畸胎瘤、神经母细胞瘤、神经胶质瘤、良性皮肤肿瘤(例如:大角化棘皮瘤)、乳腺癌(例如:晚期乳腺癌)、肾癌、卵巢癌、膀胱癌、与表皮癌。
根据本发明化合物可用于其他医疗目的,例如:
a)在治疗癌症的肿瘤放射法之前、期间或之后给药根据本发明化合物,使肿瘤对放射疗法致敏;
b)治疗关节病与骨病状况,如:类风湿性关节炎、骨关节炎、青年期类风湿性关节炎、痛风、多关节炎、牛皮癣关节炎、关节强直性脊椎炎与全身性红斑狼疮;
c)抑制平滑肌细胞增生,包括血管增生症、动脉粥样硬化及再狭窄;
d)治疗炎性状况与皮肤状况,如:溃疡性结肠炎、克罗恩氏病、过敏性鼻炎、移植物抗宿主病、结膜炎、气喘、ARDS、贝赛特氏病、移植排斥、uticaria、过敏性皮炎、局限性脱发、硬皮病、疹病、湿疹、皮肤肌炎、痤疮、糖尿病、全身性红斑狼疮、川崎氏病、多发性硬化、肺气肿、囊性纤维变性和慢性支气管炎;
e)治疗子宫内膜异位、子宫肌瘤、功能性子宫出血及子宫内膜增生。
f)治疗眼血管形成,包括影响视网膜与脉络膜血管的血管病;
g)治疗心机能障碍;
h)抑制免疫抑制状况,如:治疗HIV感染;
i)治疗肾机能障碍;
j)阻抑内分泌紊乱;
k)抑制糖原异生机能障碍;
l)治疗神经病变,例如:帕金森氏病或造成认知障碍的神经病变,例如:阿尔茨海默氏病或与多谷酰胺有关的神经元病;
m)抑制神经肌肉病变,例如:肌萎缩性侧索硬化;
n)治疗脊髓病性肌萎缩;
o)治疗易于通过增强基因表达而治疗的其他病理状况;
p)增强基因疗法。
因此,本发明揭示以式(I)化合物作为药物的用途及以式(I)化合物制造药物供治疗上述一种或多种状况的用途。
式(I)化合物、其药理上可接受的酸加成盐及立体异构型基于其可用于生物样本中,检测或鉴定HDAC,而具有有价值的诊断性质,其包括检测或测定有标记的化合物与HDAC之间复合体的形成。
该检测或鉴定法可使用标记了如:放射性同位素、酶、荧光物质、发光物质,等等的标记试剂的化合物。放射性同位素实例包括125I、131I、3H与14C。酶的检测通常与适当底物结合后,再催化可检测的反应。其实例包括例如:β-半乳糖甙酶、β-葡糖苷酶、碱性磷酸酶、过氧化酶与苹果酸脱氢酶,以辣根过氧化酶优选。发光物质包括例如:鲁米诺及鲁米诺衍生物、荧光素、水母发光蛋白与荧光素酶。
生物样本的定义为体组织或体液。体液实例为脑脊液、血液、血浆、血清、尿液、痰、唾液,等等。
就其实用的药疗性质而言,本化合物可调制成不同的给药治疗型。
为了制备本发明的药物组合物,使用有效量的碱或酸加成盐型特定化合物作为活性成分,与药理上可接受的载体均匀混合,该载体可呈多种不同形式,取决于投药所需制剂型式而定。此等药物组合物最好呈单位剂量,其适合,优选针对例如:经口、直肠、经皮投药或胃肠外注射给药。例如:制备口服剂型的组合物时,任何常用的医药介质均可使用,例如:水、二醇类、油类、醇类、等等,可用于制备口服用液体制剂,如:悬液、糖浆、酏剂与溶液;或固态载体如:淀粉、糖类、高岭土、润滑剂、粘合剂、崩解剂,等等,可用于制备散剂、丸剂、胶囊、与片剂。
由于片剂与胶囊方便投药,因此代表最有利的口服单位剂型,此时当然使用固态药物载体。胃肠外组合物中的载体通常包括无菌水,至少占大部分,但亦可包含其他成份,例如:有助于溶解的成份。可制备注射液,例如其中载体则包括盐水溶液、葡萄糖溶液或盐水与葡萄糖溶液的混合物。亦可制备注射用悬液,此时则可使用适当液态载体、悬浮剂,等等。适合经皮肤投药的组合物中,载体可视需要包含渗透加强剂及/或合适的润湿剂,可视需要与任何性质的少量合适添加剂组合,该添加剂不对皮肤引起显著的不良效应。此等添加剂可促进投药至皮肤及/或可能有助于制备所需组合物。此等组合物可依各种方法投药,例如:经皮膏药、滴剂(spot-on)、或软膏。
特别有利的是以剂量单位型调配上述药物组合物,以方便投药且剂量一致性。本说明书与权利要求所使用的单位剂型指物理上分开适合作为单位剂量的单位,每单位包含经计算可产生所需治疗效果的预定量活性成分,与所需的药物载体组合。此等单位剂型实例为片剂(包括刻痕或包衣片剂)、胶囊、丸剂、散剂包、糯米纸囊剂、注射用溶液或悬液、满茶匙剂,满大汤匙剂,等等,及分开的多重剂型。
本领域技术人员很容易即可由下文出示的试验结果决定有效量。通常,治疗有效量预期为每公斤体重0.005毫克至100毫克,特定言之每公斤体重0.005毫克至10毫克。适宜的是在一天内将所需剂量分成2、3、4或更多个亚剂量按适当间隔给药。该亚剂量可调配成单位剂型,例如:每单位剂型包含0.5至500毫克,特定言之10至500毫克活性成分。
本发明另一方面,预期HDAC-抑制剂与其它抗癌剂的组合,尤其用为药物,更具体言之,用于治疗癌症或相关疾病。
治疗上述状况时,本发明化合物宜用于与一种或多种其他医药剂组合,更特定言之,与其他抗癌剂组合。抗癌剂的实例为:
- 铂配位化合物,例如:顺铂,碳化铂或oxalyplatin;
- 紫杉烷(taxane)化合物,例如:paclitaxel或docetaxel;
- 拓扑异构酶I抑制剂,如:喜树碱(camptothecin)化合物,例如:irinotecan或topotecan;
- 拓扑异构酶II抑制剂,如:抗肿瘤鬼臼毒素衍生物,例如:etoposide或teniposide;
- 抗肿瘤长春花生物碱,例如:长春花碱、长春花新碱或vinorelbine;
- 抗肿瘤核苷衍生物,例如:5-氟尿嘧啶、gemcitabine或capecitabine;
- 烷基化剂,如:氮芥或亚硝基脲,例如:环磷酰胺、苯丁酸氮芥、亚硝脲氮芥或罗氮介;
- 抗肿瘤蒽环类抗生素衍生物,例如:红比霉素、阿霉素、去甲氧柔红霉素或mitoxantrone;
- HER2抗体,例如:trastuzumab;
- 雌激素受体拮抗剂或选择性雌激素受体调制剂,例如:它莫西芬、托若米芬、droloxifene、faslodex或raloxifene;
- 芳香酶(aromatase)抑制剂,如:exemestane、anastrozole、letrazole与vorozole;
- 分化剂,如:视黄醛衍生物、维生素D与视黄酸代谢抑制剂(RAMBA)例如:阿克特恩;
- DNA甲基转移酶抑制剂,例如:氮胞苷;
- 激酶抑制剂,例如:flavoperidol、imatinib甲磺酸盐或gefitinib;
- 法尼基转移酶抑制剂;或
- 其他HDAC抑制剂。
“铂配位化合物”一词在本文中指可抑制任何肿瘤细胞生长的铂配位化合物,其提供离子形式的铂。
“紫杉烷基化合物”一词指一类具有紫杉烷环系且与某些种类紫杉(红豆杉)树木的提取物相关或其所衍生的化合物。
“拓扑异构酶抑制剂”一词系指可改变真核细胞中DNA拓扑结构的酶。其对重要细胞功能及细胞增生具有重要性。真核细胞中有两类拓扑异构酶,亦即I与II型。拓扑异构酶I为一种分子量约100,000的单体酶。该酶结合DNA,引入暂时单链断裂,解旋双螺旋(或使之解旋),然后使断裂再封密后,再自DNA链上解离。拓扑异构酶II的作用机制类似,其涉及引入DNA链断裂或形成游离基。
“喜树碱化合物”系指与喜树碱母体化合物有关或其所衍生的化合物,其系衍生自中国树种Camptothecin acuminata及印度树种Nothapodytes foetida的不可溶于水的生物碱。
“鬼臼毒素化合物”一词指与毒参茄植物提取的鬼臼毒素母体化合物有关或其所衍生的化合物。
“抗肿瘤长春花生物碱”一词指与自蔓长春花(Vinca rosea)植物的提取物有关或其所衍生的化合物。
“烷基化剂”一词包括不同类共同特征为在生理条件下有能力将烷基供给生物活性大分子如DNA的化学物。大多数的较重要制剂如:氮芥及亚硝基脲,活性烷基化部分系于活体内经复杂降解反应(其中有些为酶催的)之后产生。烷基化剂的最重要医药作用为特别在DNA合成与细胞分裂过程中干扰与细胞增生有关的基本机制。烷基化剂在快速增生组织中干扰DNA功能与整合性的能力作为其治疗用途及其许多毒性特性的基础。
“抗肿瘤蒽环类抗生素衍生物”一词包括得自霉菌Strep.peuticus var.caesius的抗生素及其衍生物,其特征在于具有四环素环结构,利用糖苷键结合了稀有糖:六碳氨糖。
已知初期乳腺癌中人类表皮生长因子受体2蛋白质(HER2)的扩增作用与某些患者的临床预后不佳有相关性。Trastuzumab为一种高纯的重组DNA-衍生的人源化单克隆IgG1卡巴抗体,其与HER2受体的胞外域高度亲合性而特异性地结合。
许多乳癌有雌激素受体,且此等肿瘤的生长可受到雌激素刺激。“雌激素受体拮抗剂”及“选择性雌激素受体调制剂”系指与雌激素受体(ER)结合的雌二醇的竞争性抑制剂。选择性雌激素受体调制剂与ER结合时,会诱导受体三维形状改变,抑制其与DNA上雌激素反应元素(ERE)的结合。
停经后妇女的循环雌激素主要来源泉为肾上腺与卵巢雄激素(雄烯二醇与睾酮)经由外周组织中芳香酶转化成雌激素(雌酮与雌二醇)。经由抑制芳香酶或失活而剥夺雌激素可有效且选择性治疗患与激素相关的乳癌的某些停经后的患者。
“抗雌激素剂”一词不仅包括雌激素受体拮抗剂与选择性雌激素受体调制剂,而且如上述包括芳香酶抑制剂。
“分化剂”一词包括可依不同方式抑制细胞增生及诱导分化的化合物。已知维生素D与视黄醛衍生物在调节多种正常及恶性细胞类型的生长与分化上扮演重要角色。视黄酸代谢抑制剂(RAMBA)藉由抑制细胞色素P450介导的视黄酸代谢而提高内源视黄酸含量。
DNA的甲基化变化为人类瘤形式中最常见的异常现象。选定基因的启动子中过度甲基化通常与所涉及的基因失活有关。“DNA甲基转移酶抑制剂”一词指通过DNA甲基转移酶的药理抑制效果及使肿瘤抑制基因表达再活化而发挥作用的化合物。
“激酶抑制剂”一词包括细胞周期进展及程序性细胞死亡中所涉及的激酶的强力抑制剂。
“法尼基转移酶抑制剂”一词指其设计用于防止Ras及其他细胞内蛋白质的法尼基化的化合物。已知其可影响恶性细胞增生与存活。
“其他HDAC抑制剂”一词包括(但不限于):
- 短链脂肪酸,例如:丁酸酯、4-苯基丁酸酯或丙戊酸;
- 异羟肟酸,例如:N-辛二酰苯胺异羟肟酸(SAHA)、二芳基异羟肟酸酯A-161906、双环芳基-N-羟基羧酰胺、pyroxamide、CG-1521、PDX-101、磺酰胺异羟肟酸、LAQ-824、trichostatin A(TSA)、oxamflatin、scriptaid、间羧基肉桂酸双异羟肟酸或trapoxin-异羟肟酸类似物;
- 环状四肽,例如:trapoxin、apidicin或depsipeptide;
- 苯甲酰胺,例如:MS-275或CI-994或
- depudecin。
为治疗癌症,根据本发明化合物可配合照射,依上述给药患者。照射指电离辐射,特定言之指迦玛辐射,尤指由直线加速器发射的或由现在常用的核素发射的。核素照射肿瘤可外用或内用。
本发明亦有关抗癌剂与根据本发明HDAC抑制剂的根据本发明的组合。
本发明亦有关以根据本发明的组合于例如:抑制肿瘤细胞生长的治疗上的用途。
本发明亦有关抑制肿瘤细胞生长的根据本发明的组合。
本发明亦有关抑制人体受试者中肿瘤细胞生长的方法,其包括对该受试者给药有效量的根据本发明的组合。
本发明亦有关抑制细胞(包括转化细胞)异常生长的方法,其系给药有效量的根据本发明的组合。
其他医药剂与HDAC抑制剂可同时(例如:分开或单一组合物)或按任何次序先后投药。后项作法中,两种化合物将在一段时期内投药,其用量与方式应足以确保达成有利或协同效用。要明白,该组合中各成分的优选投药法与投药顺序及各自剂量与规程将依所给药的特定的其他医药剂及HDAC抑制剂、其投药途径、所治疗的特定肿瘤及所治疗的特定宿主而定。理想的投药方法及顺序及剂量与规程很容易由本领域技术人员使用常用方法,依据本文中所示的信息决定。
铂配位化合物的合宜投药剂量为每平方米体表面积使用1至500毫克(mg/m2),例如:50至400mg/m2,特定言之,每次治疗过程的顺铂剂量为约75mg/m2,碳化铂剂量约300mg/m2。
紫杉烷基化合物的合宜投药剂量为每平方米体表面积使用50至400毫克(mg/m2),例如:75至250mg/m2,特定言之,每次治疗过程的paclitaxel剂量为约175至250mg/m2,及docetaxel的剂量为约75至150mg/m2.
喜树碱化合物的合宜投药剂量为每平方米体表面积使用0.1至400毫克(mg/m2),例如:1至300mg/m2,特定言之,每次治疗过程的irinotecan剂量为约100至350mg/m2,topotecan剂量为约1至2mg/m2.
抗肿瘤鬼臼毒素衍生物的合宜投药剂量为每平方米体表面积使用30至300毫克(mg/m2),例如:50至250mg/m2,特定言之,每次治疗过程的etoposide剂量为约35至100mg/m2,teniposide剂量为约50至250mg/m2.
肮肿瘤长春花生物碱的合宜投药剂量为每平方米体表面积使用2至30毫克(mg/m2),特定言之,每次治疗过程的长春花碱剂量为约3至12mg/m2,长春花新碱剂量为约1至2mg/m2,vinorelbine剂量为约10至30mg/m2.
抗肿瘤核苷衍生物的合宜投药剂量为每平方米体表面积使用200至2500毫克(mg/m2),例如:700至1500mg/m2,特定言之,每次治疗过程的5-FU剂量为200至500mg/m2,gemcitabine剂量为约800至1200mg/m2,capecitabine剂量为约1000至2500mg/m2.
烷基化剂,如:氮芥或亚硝基脲的合宜投药剂量为每平方米体表面积使用100至500毫克(mg/m2),例如:120至200mg/m2,特定言之,每次治疗过程的环磷酰胺剂量为约100至500mg/m2,苯丁酸氮芥剂量为约0.1至0.2mg/m2,亚硝腺氮芥剂量为约150至200mg/m2,罗氮介剂量为约100至150mg/m2.
抗肿瘤蒽环类抗生素衍生物的合宜投药剂量为每平方米体表面积使用10至75毫克(mg/m2),例如:15至60mg/m2,特定言之,每次治疗过程的阿霉素剂量为约40至75mg/m2,红比霉素剂量为约25至45mg/m2,去甲氧柔红霉素剂量为约10至15mg/m2.
Trastuzumab的合宜投药剂量为每平方米体表面积使用1至5毫克(mg/m2),特定言之,每次治疗过程剂量为2至4mg/m2.
抗雌激素剂的合宜投药剂量为每天约1至100毫克,依所使用的特定药剂及所治疗状况而定。它莫西芬的合宜口服剂量为一天服用两次5至50毫克,优选为10至20毫克,持续治疗一段足够时间,以达成及维持治疗效果。托若米芬的合宜口服剂量为一天服用一次约60毫克,持续治疗一段足够时间,以达成及维持治疗效果。Anastrozole的合宜口服剂量为一天服用一次约1毫克。Droloxifene的合宜口服剂量为一天服用一次约20-100毫克。Raloxifene的合宜口服剂量为一天服用一次约60毫克。Exemestane的合宜口服剂量为一天服用一次约25毫克。
此等剂量可以比如每次治疗过程投药一次、两次或多次,可以比如每7、14、21或28天重复。
就其有用的药物性质而言,根据本发明的组合中的成分(亦即其他医药剂与HDAC抑制剂)可调配成各种投药用药物型式。各成分可于独立的药物组合物中单独调配,或于单一药物组合物中调配,其含有两种成分。
因此本发明亦有关包含其他医药剂与HDAC抑制剂及一种或多种药物用载体的药物组合物。
本发明亦有关呈药物组合物形式的根据本发明的组合,其包含抗癌剂与根据本发明HDAC抑制剂及一种或多种药物用载体。
本发明亦有关根据本发明的组合于制造抑制肿瘤细胞生长的药物组合物上的用途。
本发明亦有关一种产品,其包含根据本发明HDAC抑制剂作为第一活性成分,及包含抗癌剂作为第二活性成分,作为组合制剂,供同时、独立或顺序用于治疗癌症患者。
实验部分
下列实施例供说明用。
下文中,“BINAP”指2,2′-双(二苯基膦基)-1,1-联萘,“Boc”指叔丁氧羰基,“BSA”指牛血清白蛋白,“DCM”指二氯甲烷,“DIC”指二异丙基碳二亚胺,“DIEA”指二异丙基乙胺,“DIPE”指二异丙基醚,“DMAP”指二甲氨基吡啶,“DMF”指二甲基甲酰胺,“DMSO”指二甲亚砜,“EDC”指N′-(乙基carbonimidoyl)-N,N-二甲基-1,3-丙二胺单盐酸盐,“EDTA”指乙二胺四乙酸,“EtOAc”指乙酸乙酯,“Hepes”指4-(2-羟乙基)-1-哌嗪乙磺酸,“HOBT”指羟基苯并三唑,“MeOH”指甲醇,“MTT”指3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-四唑鎓溴化物,“NMP”指N-甲基吡咯烷酮,“PBS”指磷酸盐缓冲盐水,“TEA”指三乙胺,“TFA”指三氟乙酸,“TIS”指三异丙基硅烷,“THF”指四氢呋喃,“THP”指四氢吡喃基,及“TMSOTf”指三甲基甲硅烷基三氟甲磺酸酯。
A.中间体的制备
实施例A1
a)中间体1的制备
将4-甲氧基-2-喹啉羧酸(0.00024mol;1.2当量)、DMF(2ml)、树脂联碳二亚胺(0.200g;2当量)(供应商:Argonaut 800369)与1-羟基苯并三唑(0.040g;1.5当量)在DCM(3ml)中的混合物于室温下振荡15分钟,添加6-(4-氨基-1-哌啶基)-3-吡啶羧酸乙酯(0.0002mol)。反应混合物于室温下振荡20小时。添加MP-碳酸酯(0.150g;4.5当量)(供应商:Argonaut 800267),反应混合物于室温下振荡20小时。混合物过滤,滤液蒸发,产生中间体1(定量收率)。
b)中间体2的制备
将中间体1(最高0.0002mol)的氢氧化钠(1.5ml),THF(4ml)与MeOH(1ml)混合物于60℃下搅拌6小时,然后于室温下度过整个周末。反应混合物经1N HCl中和后,添加DCM(4ml)。混合物经extrelute(Isolute HM-N 3ml体积,供应商:IST 800-0220-EM)过滤,滤液蒸发,产生中间体2(定量收率)。
c)中间体3的制备
添加N,N-二甲基-4-吡啶胺(0.018g)至含有树脂联HOBT(0.200g)(供应商:Novabiochem 01-64-0425)的DCM/DMF5/1(6ml)中。添加中间体2(最高0.0002mol),混合物振荡15分钟。添加N,N′-甲烷四基双-2-丙胺(0.070ml),反应混合物于室温下振荡4小时。滤出树脂,依序以DCM(3x),DMF(3x),DCM(3x),DMF(3x)及DCM(3x)洗涤。添加O-(四氢-2H-吡喃-2-基)-羟基胺(0.030g,0.00026mol)的DCM(5ml)溶液至树脂中,反应混合物于室温下振荡一夜。滤出树脂过滤,以DCM(3x)洗涤,滤液蒸发。残留物溶于DCM(5ml)中。添加树脂联甲苯磺酰氯(0.100g)(供应商:Argonaut800276)与树脂联吗啉(0.100g)(吗啉代甲基聚苯乙烯HL供应商:Novabiochem 01-64-0171)。反应混合物振荡48小时。滤出树脂,DCM洗涤,滤液蒸发,产生中间体3(定量收率)。
实施例A2
a)中间体4的制备
于0℃下添加2-萘碳酰氯(0.0102mol)的DCM(40ml)溶液至4-(氨基甲基)-1-哌啶羧酸1,1-二甲基乙酯(0.0093mol)与TEA(0.0158mol)的DCM(40ml)混合物中。混合物于室温下搅拌一夜,倒至冰水中,以DCM萃取。有机层经10% K2CO3洗涤,干燥(MgSO4),过滤及蒸发溶剂。残留物(3.1g)自乙醚中结晶。滤出沉淀,干燥,产生2.52g(74%)中间体4,熔点153℃.
b)中间体5的制备
将中间体4(0.0068mol)的HCL 3N(25ml)与THF(5ml)混合物于80℃下搅拌12小时,倒至冰水中,以NH4OH碱化,以DCM萃取。有机层以水洗涤,干燥(MgSO4),过滤,蒸发溶剂。残留物(1g)自乙醚/CH3CN中结晶。滤出沉淀及干燥,产生0.8g(44%)中间体5,熔点209℃。
c)中间体6的制备
于0℃下在N2气流下添加氢化钠(0.0044mol)至,中间体5(0.0029mol)的THF(10ml)混合物中。混合物搅拌1小时。添加2-(甲磺酰基)-5-嘧啶羧酸乙酯(0.0035mol)的THF(10ml)溶液。混合物于室温下搅拌2小时,倒至冰水中,以EtOAc萃取。有机层经水洗涤,干燥(MgSO4),过滤,蒸发溶剂。残留物自CH3CN/乙醚中结晶。滤出沉淀,干燥,产生0.56g中间体6,熔点161℃。
d)中间体7的制备
将中间体6(0.0013mol)与氢氧化钠(0.0026mol)的乙醇(15ml)混合物回流搅拌12小时后冷却。滤出沉淀,以乙醚洗涤,干燥,产生0.44g(83%)中间体7。
e)中间体8的制备
于室温下依序添加1-羟基苯并三唑(0.0014mol)的THF(10ml)溶液及N′-(乙基carbonimidoyl)-N,N-二甲基-1,3-丙二胺单盐酸盐(0.0014mol)的DCM(10ml)溶液至中间体7(0.0011mol)与0-(四氢-2H-吡喃-2-基)-羟基胺(0.0014mol)的DCM(10ml)与THF(10ml)混合物中。混合物于室温下搅拌12小时,倒至水中,以DCM萃取。分离有机层,干燥(MgSO4),过滤,蒸发溶剂。残留物(0.9g)经硅胶柱色谱法纯化(洗脱液:CH2Cl2/CH3OH/NH4OH 97/3/0.1;15-40μm)。收集纯级分,蒸发溶剂。残留物(0.47g)自乙醚/DIPE中结晶。滤出沉淀,干燥,产生0.4g中间体8,熔点149℃。
B.最终化合物的制备
实施例B1
a)树脂(1)的制备
将Novabiochem 01-64-0261商品树脂(200mg,负载量:0.94mmol/g)、单N-Boc-4-氨基哌啶(188mg)与异丙醇钛(IV)(Ti(OiPr)4)(277μl)的DCM(4ml)混合物于室温下温和振荡90分钟。添加三乙酰氧基氢硼化钠(199mg),反应混合物于室温下温和振荡一夜后,滤出树脂,以DCM洗涤一次,以MeOH洗涤一次后,以DCM/DIEA 10%洗涤2次,再先以DCM洗涤3次后,以甲醇洗涤3次,以3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH洗涤。结果产生的树脂鉴定为树脂(1),未进一步纯化即用于下一个反应步骤。
b)树脂(2)的制备
树脂(1)经DCM洗涤3次。在树脂(1)中添加2-萘碳酰氯(175mg)的4ml DCM混合物与DIEA(307μl)混合物,温和振荡树脂一夜,滤出树脂,以3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH洗涤。结果产生的树脂为树脂(2),未进一步纯化即用于下一个反应步骤。
c)树脂(3)的制备
树脂(2)经DCM洗涤3次。在树脂(2)中添加4ml TMSOTf-2,6-二甲基吡啶(1M/1.5M)的DCM混合物,树脂于室温下温和振荡3小时,滤出树脂,以3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeoH,,3xDCM,3xMeOH,3xDCM,3xMeOH洗涤。结果产生的树脂为树脂(3),未进一步纯化即用于下一个反应步骤。
d)树脂(4)的制备
树脂(3)经甲苯洗涤3次。在树脂(3)中添加4-溴甲基苯甲酸酯(606mg)的3ml甲苯溶液及BINAP(117mg)与Cs2CO3(326mg),树脂于室温与氮气下温和振荡45分钟。添加含Pd(OAc)2的1ml甲苯至反应混合物中。树脂于110℃与氮气下温和振荡18小时。趁热滤出树脂,树脂经80℃ 3xDMF,80℃ 3xH2O,80℃ 3x DMF洗涤,于室温下以3xDMF,3xH2O,3xDMF,3xMeOH,3xDCM,3xMeOH,3xDCM洗涤。结果产生的树脂为树脂(4),未进一步纯化即用于下一个反应步骤。
e)树脂(5)的制备
树脂(4)经NMP洗涤3次。在树脂(4)中添加含三甲基硅烷醇钾(KOSiMe3)(240mg)的4ml NMP,树脂于50℃下温和振荡24小时,滤出树脂,以3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH,3xDCM,3xMeOH洗涤。结果产生的树脂为树脂(5),未进一步纯化即用于下一个反应步骤。
f)中间体9的制备
树脂(5)经DCM洗涤3次。在树脂(5)中添加5mlTFA/TIS/DCM(5:2:93),树脂于室温下温和振荡2小时,滤出树脂,以DCM洗涤。滤液于氮气下在50℃下吹干,添加DCM(2ml),再于氮气下及50℃下吹干,添加DCM(2ml),然后于氮气下在50℃吹干。结果产生游离羧酸(中间体30)的TFA-盐,收量58mg.
g)树脂(6)的制备,方法A:
中间体9于50℃与氮气下,与亚硫酰氯(SOCl2)(1ml)浓缩,添加DCM(2ml),于氮气下及50℃下吹干,添加DCM(2ml),再于氮气下及50℃下吹干。添加DCM(3ml),溶液加至树脂联HOBT中(300mg,负载量:1.3mmol/g)(供应商:Novabiochem 01-64-0425),在混合物中添加1ml of 2,6-二甲基吡啶与1ml DCM。树脂温和振荡1小时,滤出树脂,以3xDMF,3xDCM,3xDMF洗涤。结果产生树脂(7),未进一步纯化即用于下一个反应步骤。
h)树脂(6)的制备,方法B:
中间体9经DCM、NEt3与H2O及几滴MeOH处理,经extrelute干燥(Isolute HM-N 3ml体积,供应商:IST 800-0220-EM),于氮气下及50℃下吹干。添加DCM(3ml)3次及于氮气下及50℃下吹干。游离碱溶于DCM/DMF 4ml/1ml中,溶液加至树脂联HOBT中(300mg,负载量:1.3mmol/g)(供应商:Novabiochem 01-64-0425),在混合物中添加DMAP(10mg)。树脂于室温下温和振荡15分钟,添加DIC(70μl)。树脂于室温下温和振荡4小时,滤出树脂,以3xDMF,3xDCM,3xDMF洗涤。结果产生树脂(7),未进一步纯化即用于下一个反应步骤。
i)中间体10的制备:
在树脂(6)中添加含O-(四氢-2H-吡喃基)-羟基胺(60mg)的4ml DCM,树脂于室温下温和振荡18小时,滤出树脂,以DCM(2ml)洗涤。过滤及于氮气下及50℃下吹干。结果产生中间体10。
j)化合物1的制法:
中间体10于含5% TFA的MeOH(5ml)中搅拌一夜,将反应混合物倒至4ml H2O与NaHCO3(300mg)中,以DCM(5ml)萃取产物2次,DCM层经MgSO4干燥,过滤及于氮气下及50℃下吹干。结果产生最终化合物1,收量2.3mg。
实施例B2
化合物2的制法
中间体3(最高0.0002mol)于5% CF3COOH/CH3OH(q.s.)中,于室温下搅拌一周末。蒸发溶剂,产生(模型反应):0.058g(纯度87%)化合物2。
实施例B3
化合物3的制法
于0℃添加三氟乙酸(0.5ml)至含中间体8(0.0006mol)的MeOH(5ml)混合物中。使混合物回升室温后,搅拌48小时。滤出沉淀,以MeOH洗涤后,以乙醚洗涤,干燥,产生0.168g(65%)化合物3,熔点226℃.
表F-1列出根据上述一种实施例制备的化合物。表中采用下列缩写:Co.No.代表化合物编号,Ex.[Bn0]指与Bn0实施例中所述的相同方法。有些化合物已用熔点(mp.)表征。
C.药物实施例
组蛋白脱乙酰酶抑制作用的活体外测定(参见实施例C.1)系测定式(I)化合物所得的HDAC酶活性抑制效果.
式(I)化合物的细胞活性系于A2780肿瘤细胞上,采用细胞毒性或存活率的比色测定法测定(Mosmann Tim,Journal of ImmunologicalMethods 65:55-63,1983)(参见实施例C.2)。
于水性介质中的动态溶解性系测定该化合物于稀释时保持在含水溶液中的能力(参见实施例C.3)。
DMSO母液经单一水性缓冲溶剂,于连续3个步骤中稀释。每次稀释的浊度均使用浊度计测定。
药物的通透性表现其由一种介质移动至或通过另一种介质的能力。具体言之,其移动通过肠膜进入血流与/或自血流进入革巴的能力。通透性(参见实施例C.4)的测定法可测定滤器固定化的人工膜磷脂双层的形成。滤器固定化的人工膜测定法中,与96孔微量滴定板和96孔过滤板形成“夹层”,使得每个复合孔被分成两个室,底部为供体溶液,顶部为受体溶液,由125微米微量滤片(0.45微米孔径)分隔,涂以2%(重量/体积)二油酰基磷脂酰胆碱的十二烷溶液,其条件是,当该系统接触到水性缓冲液时,滤器通道内会形成多层的双层。测定通过此人工膜的化合物通透性,以厘米/秒表示。其目的为检视药物在两种不同pH:4.0与7.4下通过平行人工膜的通透情况。采用UV光谱测定法,于250至500nm之间的最适当波长下进行化合物检测。
药物的代谢指脂溶性生外化合物或生物体内生化合物经酶催转化成极性、水溶性且可排泄的代谢物。药物代谢作用的主要器官为肝脏。代谢产物的活性通常低于母体化合物或无活性。然而,有些代谢物可能具有加强活性或毒性效果。因此,药物代谢作用可包括“解毒”与“中毒”过程。一个决定生物处理药物与化学物的能力的主要酶系统代表为细胞色素P450单加氧酶,其系依赖NADPH的酶。化合物的代谢稳定性可于活体外,使用亚细胞人类组织测定(参见实施例C.5)。本文中化合物的代谢稳定性系由此等化合物与微粒体培育15分钟后的药物代谢百分率表示。以LC-MS分析法为化合物定量。
肿瘤抑制剂p53可响应DNA损伤,转录激活许多基因,包括WAF1/CIP1基因。WAF1基因的21kDa产物出现在正常细胞中包括细胞周期蛋白、依赖于细胞周期蛋白的激酶(CDK)及增生细胞核抗原(PCNA)的复合体中,但不出现在转化细胞中,且似乎为CDK活性的通用抑制剂。p21WAF1结合并抑制CDK的一种后果为防止依赖CDK的磷酸化反应及随后使Rb蛋白质失活,后者系细胞周期进展所必要的。因此,响应于与HDAC抑制剂细胞接触而诱导p21WAF1为G1与G2两个关卡处细胞周期进展抑制作用的强力且特异性的指示。
化合物诱导p21WAF1的能力系采用p21WAF1酶联免疫吸附测定法测定(致癌基因的WAF1ELISA)。p21WAF1测定法为一种兼使用小鼠单克隆抗体与兔子多克隆抗体的“夹心”酶免疫测定法。对人类WAF1蛋白质具特异性的兔子多克隆抗体已固定在试剂盒中提供的塑料孔表面上。样本中所要测定的任何存在的p21WAF会与捕捉抗体结合。生物素化检测物单克隆抗体亦识别人类p21WAF1蛋白质,而且会与捕捉抗体所滞留的任何p21WAF1结合。检测物抗体则随后被辣根过氧化物酶结合链霉抗生物素结合。辣根过氧化物酶催化显色底物四甲基联苯胺从无色溶液转化成蓝色溶液(或当添加终止反应剂后,则转成黄色),其强度与结合在板上的p21WAF1蛋白质的量成比例。采用分光光度计定量有色反应产物。使用已知浓度的p21WAF1(冷冻干燥形式)从标准曲线的结构进行定量(参见实施例C.6)。
实施例C.1:组蛋白脱乙酰酶的抑制作用的活体外测定法
将60μg/ml HeLa核提取物(供应商:Biomol)与2×10-8M放射性标记肽底物培养。测定HDAC活性所使用的底物为合成肽,亦即组蛋白H4的氨基酸14-21。该底物的NH2末端部分经6-氨基己酸间隔进行生物素化,其COOH-末端部分则被酰胺基保护,并于赖氨酸16上特异性[3H]乙酰化。添加底物:生物素-(6-氨基己酸)Gly-Ala-([H3]-乙酰基-Lys-Arg-His-Ary-Lys-Val-NH2)至含25mM Hepes、1M蔗糖、0.1mg/ml BSA与0.01%Triton X-100的pH7.4缓冲液中。30分钟后,添加HCl与乙酸终止脱乙酰化反应(终浓度分别为0.035mM与3.8mM)。反应停止后,以乙酸乙酯萃取游离的3H-乙酸酯。混合与离心后,于β-计数器上计算上层有机相等分试样的放射性。每个实验均平行进行对照组(含HeLa核提取物与DMSO,但不含化合物)、空白培养组(含DMSO,但不含HeLa核提取物或化合物)及样本试验组(含溶于DMSO中的化合物与HeLa核提取物)。第一种情况中,化合物的试验浓度为10-5M。当化合物于10-5M展现活性时,则在10-5M与10-12M之间浓度测试化合物,制成浓度响应曲线。每个试验中,对照组与样本组的值均扣除空白组值。对照组样本代表100%底物脱乙酰化。各样本的放射性以对照组平均值的百分比表示。若适当时,采用概率分析法对分级数据计算IC50值(使代谢物量下降至对照组的50%时所需药物浓度)。此时,以pIC50(IC50值的负对数值)表示试验化合物的效果。所有试验化合物在10-5M的试验浓度下均展现酶活性,有13种化合物的pIC50 >5(参见表F-2)。
实施例C.2:于A2780细胞上测定抗增生活性
所有试验化合物均溶于DMSO中,再于培养基中进一步稀释。细胞增生测定法中的最终DMSO浓度不可超过0.1%(v/v)。对照组含有A2780细胞及DMSO,不含化合物,而空白组则含有DMSO,但不含细胞。取MTT溶于PBS中,5mg/ml。制备甘氨酸缓冲液,其包含0.1M甘氨酸与0.1M NaCl,经1N NaOH缓冲至pH10.5(所有试剂均来自Merck)。
取人类A2780卵巢癌细胞(系美国宾州Fox Chase癌症中心T.C.Hamilton博士的热心捐赠)于补充2mM L-谷氨酰胺、50μg/ml庆大霉素与10%胎牛血清的RPMI 1640培养基中培养。细胞按常规于37℃保持为单层培养物,在加湿5% CO2气氛中。每周使用胰蛋白酶/EDTA溶液传代细胞一次,分裂比为1:40。所有培养基与补充物均得自Life Technologies。采用Gen-Probe支原体组织培养物试剂盒(供应商:BioMerieux)测得细胞没有支原体污染。
将细胞接种在NUNCTM96孔培养平板中(供应商:LifeTechnologies),使之粘着在塑料上一夜。用于平板接种的密度为每孔1500个细胞,总体积为200μl培养基。细胞粘着在培养平板上后,改变培养基,添加药物与/或溶剂至最终体积200μl。培养4天后,以200μl新鲜培养基更换培养基,采用基于MTT的测定法评价细胞密度与活力。每孔中添加25μlMTT溶液,细胞再于37℃下培养2小时。小心吸出培养基,依序添加25μl甘氨酸缓冲液及100μlDMSO,使蓝色MTT-甲产物溶解。微量培养板于微量培养板摇动器上振摇10分钟,使用Emax96孔分光光度计(供应商:Sopachem)测定540nm的吸光度。实验中,各实验条件的结果均为3个重复孔的平均值。为初始筛选,化合物系于单一固定浓度10-6M下测试。活性化合物则重复试验,以建立完整的浓度-响应曲线。每个实验的对照组(不含药物)及空白培养组(不含细胞或药物)均平行进行。所有对照组与样本组值均扣除空白组值。每个样本的细胞生长平均值(以吸光度为单位)均以对照组细胞生长平均值的百分比表示。若适当时,采用概率分析法对分级数据(Finney,D.J.,Probit Analyses,第2版,第10章,GradedResponses,Cambridge University Press,Cambridge,1962)计算IC50值(使细胞生长下降至对照组的50%时所需药物浓度)。本文中以pIC50(IC50值的负对数值)表示试验化合物的效果。大多数试验化合物在10-6M的试验浓度下展现细胞活性且有12种化合物的pIC50≥5(参见表F-2)。
实施例C.3:于水性介质中的动态溶解性
第一个稀释步骤中,10μl活性化合物的浓缩母液,溶于DMSO中(5mM),加至100μl磷酸盐柠檬酸盐缓冲液pH7.4中,混合。第二个稀释步骤中,第一个稀释步骤的等分试样(20μl)进一步分液至100μl磷酸盐柠檬酸盐缓冲液pH7.4中,混合。最后,第三个稀释步骤中,取一部分(20μl)第二个稀释步骤样品再加至100μl磷酸盐柠檬酸盐缓冲液pH7.4中稀释,混合。所有稀释均于96孔板中进行。最后一个稀释步骤后,立即使用浊度计测定相继3个稀释步骤的浊度。每种化合物的稀释均进行三次重复,以排除偶然误差。依据浊度测定值,评分成3级。高溶解度的化合物得到3分,此等化合物的第一次稀释呈澄清。中度溶解度的化合物得到2分。此等化合物的第一次稀释不澄清,但第二次稀释即澄清。低溶解度的化合物得到1分。此等化合物的第一次与第二次稀释均不澄清。测定52种化合物的溶解度。其中有9种化合物得到3分,及1种化合物得到1分(参见表F-2)。
实施例C.4:平行人工膜通透性分析
于含2ml水性缓冲液系统pH4或pH7.4(PSR4系统溶液浓缩物(pION))的深孔或预混合板中稀释母液样本(10μl于100%DMSO中5mM母液的等分试样)。添加样本至参考板中之前,先添加150μl缓冲液至孔中,测定空白UV值。之后,丢弃缓冲液,此板用为参考板。所有测定均于耐UV的板上进行(供应商:Costar或Greiner)。
测定参考板的空白值后,添加150μl稀释的样本至参考板中,添加200μl稀释样本至供体板1中。使用4μl人工膜形成溶液(1,2-二油酰基-sn-Glycer-3-磷酸胆碱处于含0.1%2,6-二叔丁基-4-甲基苯酚的十二碳烷中)涂布受体滤板1(供应商:Millipore,类型:MAIPN45),置于供体板1顶上,形成“夹层”。分液缓冲液(200μl)至上方的受体孔中。此夹层加盖,保存在室温与黑暗中18小时。
添加150μl缓冲液至孔中后,测定UV值,由此测定受体板2的空白值。受体板2测定空白值后,丢弃缓冲液,自受体滤板1中将150μl受体溶液移至受体板2中。然后自夹层中取出受体滤板1。测定供体板2的空白值(如上述)后,自供体板1中将150μl供体溶液移至供体板2中。扫描供体板2、受体板2及参考板孔的UV光谱(使用SpectraMAX190)。所有光谱均经PSR4p Command软件处理以计算通透性。所有化合物均进行三次重复。每个实验均使用卡马西平、灰黄霉毒、acycloguanisine、氨酰心安、速尿、氯噻嗪作为标准物。化合物评级成三类:低通透性(平均效应<0.5 x 10-6cm/s;得分1),中通透性(1 x 10-6cm/s>平均效应≥0.5 x 10-6cm/s;得分2)或高通透性(≥0.5 x 10-6cm/s;得分3)。试验一种化合物,其在两种测定pH下只得到1分。
实施例C.5:代谢稳定性
依据Gorrod等人(Xenobiotica 5:453-462,1975)制备亚细胞组织制剂,其系使组织经过机械匀浆后离心分离。肝组织于冰冷0.1MTris-HCl(pH7.4)缓冲液中漂洗,以洗除过量血液。随后吸干组织,称重,使用手术剪刀粗略剪断。组织碎片于3体积冰冷的0.1M磷酸盐缓冲液(pH7.4)中,使用装有特氟隆研杵的Potter-S(意大利Braun公司)或Sorvall Omni-Mix匀浆器匀浆7×10秒。在两种情况下,在匀浆过程中容器保持在冰中/上。
组织匀浆于4℃下,使用Sorvall离心机或Beckman超速离心机,于9000xg下离心20分钟。所得上清液保存在-80℃下,称为“S9”。
此S9部分再使用Beckman超速离心机,于100.000xg下离心60分钟(4℃)。小心吸出所得上清液,等分并称为“细胞溶胶”。沉淀再悬浮于0.1M磷酸盐缓冲液中(pH7.4),终体积为每0.5克原始组织重量为1ml,称为“微粒体”。
所有亚细胞部分等分后,立即于液态氮中冷冻,保存在-80℃下,直到使用时为止。
对于试验样本,培养混合物含有PBS(0.1M)、化合物(5μM)、微粒体(1mg/ml)与NADPH-生成系统(0.8mM葡萄糖-6-磷酸、0.8mM氯化镁及0.8单位葡萄糖-6-磷酸脱氢酶)。对照组样本含有相同材料,但微粒体改为热失活(95℃下10分钟)的微粒体。对照组样本中化合物的回收率总是100%。
混合物于37℃下预培养5分钟。添加0.8mM NADP的零时间点(t=0)开始反应,样本培养15分钟(t=15)。添加2体积DMSO停止反应。样本随后于900xg下离心10分钟,分析前贮存在室温下的上清液不可超过24小时。所有培养均进行二次重复。采用LC-MS分析法分析上清液。于Xterra MS C18(50 x 4.6mm,5μm,美国Waters公司)上洗脱样本。采用Alliance 2790(供应商:美国Waters公司)HPLC系统。洗脱使用缓冲液A(含于H20/乙腈(95/5)中的25mM乙酸铵(pH5.2)),溶剂B为乙腈,且溶剂C为甲醇,流速为2.4ml/分钟。所使用的梯度为以线性方式,在5分钟内使有机相浓度由0%提高超过50%B和至50%C,于1分钟内至100%B,并且再保持有机相浓度稳定1.5分钟。样本总注射体积为25μl。
采用配有ESI源的Quattro(供应商:英国曼彻斯特市Micromass公司)三重四极质谱仪作为检测器。源与去溶剂化温度分别设定在120与350℃,使用氮气作为雾化剂及干燥气体。以正扫描模式取得数据(单离子反应),锥电压设定在10V,采样时间为1秒。
代谢稳定性用化合物于活性微粒体(E(act))的存在下15分钟培养后的代谢%表示(代谢%=100%-((E(act)于t=15时的总离子电流(TIC)/E(act)于t=0时的TIC)X 100)。代谢百分比小于20%的化合物则定义为具高度代谢稳定性.代谢百分比在20与70%之间的化合物则定义为具中度稳定性,而代谢百分比高于70%的化合物则定义为具低度代谢稳定性。当进行代谢稳定性筛选时,总是包含3种参考化合物。使用Verapamil作为低度代谢稳定性的化合物(代谢%=73%)。使用Cisapride作为中度代谢稳定性的化合物(代谢%=45%)。使用丙醇作为中度至高度代谢稳定性的化合物(代谢%=25%)。使用此等参考化合物确认代谢稳定性测定法的有效性。
试验2种化合物,其代谢%均小于20%。
实施例C.6:D21诱导能力
采用下列方案,于人类A2780卵巢癌细胞中测定p21蛋白质表达水平。将A2780细胞(20000个细胞/180μl)接种在96微孔板中,至补充2mM L-谷氨酰胺、50μg/ml庆大霉素与10%胎牛血清的RPMI1640培养基中。溶解细胞前24小时,添加化合物使最终浓度为10-5、10-6、10-7与10-8M。所有试验化合物均溶在DMSO中,再于培养基中稀释。添加化合物24小时后,从细胞除去的上清液。以200μl冰冷PBS洗涤细胞。抽吸孔,添加30μl溶胞缓冲液(50mM Tris.HCl(pH7.6),150mMNaCl,1%Nonidet p40与10%甘油)。板于-70℃下培养一夜。
自箔袋中取出适当数目的微量滴定孔,置入空的孔固定器中。制备洗涤缓冲液(20 x 板洗涤浓缩液:100ml PBS与界面活性剂的20倍浓缩液。含有2%氯乙酰胺)的工作液(1x)。冷冻干燥的p21WAF标准物用蒸馏水重组,再经样本稀释液(由试剂盒中供应)稀释。
样本经在样本稀释液中稀释1:4而制备。将样本(100μl)与p21WAF1标准物(100μl)移液至适当孔中,于室温下培养2小时。以1x洗涤缓冲液洗涤孔3次后,移液100μl检测物抗体试剂(生物素化单克隆p21WAF1抗体溶液)加至各孔中。孔于室温下培养1小时后,以1x洗涤缓冲液洗涤3次。稀释400x结合物(过氧化物酶链霉抗生物素结合物:400倍浓缩溶液),取100μl 1x溶液加至孔中。孔于室温下培养30分钟后,以1x洗涤缓冲液洗涤3次,以蒸馏水洗涤1次。添加底物溶液(显色底物)(100μl)至孔中,于黑暗中室温下将孔培养30分钟。依前述添加的底物溶液的相同顺序添加终止溶液至各孔中。采用分光光度板读出器,于450/595nm双波长下测定各孔吸光度。每个实验均平行进行对照组(不含药物)与空白培养组(不含细胞或药物)。所有对照组与样本组值均扣除空白组值。各样本的p21WAF1诱导值(单位为吸光度)以对照组中存在的p21WAF1的值的百分比表示。诱导百分比高于130%时,定义为显著诱导。本测定法中,试验3种化合物,其中2种展现显著的诱导作用。
表F-2:表F-2出示依据实施例C.1、C.2与C.3试验的化合物的结果。
Co.No. | 酶活性pIC50 | 细胞活性pIC50 | 溶解性记分 |
1 | 5.649 | 5.346 | |
2 | 6.794 | 5.748 | 3 |
3 | 8.103 | 6.881 | 1 |
4 | <5 | 5.554 | |
5 | 6.861 | 5.664 | |
6 | 6.951 | 5.86 | 3 |
7 | 6.416 | 5.331 | 3 |
8 | 6.94 | 5.497 | 3 |
9 | 6.774 | 5.579 | 3 |
10 | 7.19 | 5.747 | 3 |
11 | 6.215 | <5 | 3 |
12 | 6.909 | 5.562 | 3 |
13 | 7.061 | <5 | |
14 | 6.611 | 5.175 | 3 |
D.组合物实施例:膜衣片剂
片剂核的制备
将100g式(I)化合物、570g乳糖与200g淀粉的混合物混合均匀后,用5g十二烷基硫酸钠及10g聚乙烯基吡咯烷酮的约200ml水溶液润湿。湿粉末混合物经过筛、干燥及再过筛。然后添加100g微晶纤维素与15g氢化植物油。全部混合均匀,压成片剂,产生10.000片片剂,每片含10mg式(I)化合物。
包衣
添加5g乙基纤维素的150ml二氯甲烷溶液至10g甲基纤维素的75ml变性乙醇溶液中。然后添加75ml二氯甲烷与2.5ml 1,2,3-丙三醇。取10g聚乙二醇熔化及溶解于75ml二氯甲烷中。后项溶液加至前项溶液中,然后添加2.5g十八烷酸镁、5g聚乙烯吡咯烷酮与30ml浓缩色料悬浮液,全部均质化。于包覆设备中,以所得混合物包覆片剂核。
Claims (9)
1.式(I)化合物
其药理上可接受的加成盐,其中
n为1;
m为0或1,且当m为0时,则指的是直接键;
t为0、1或2,且当t为0时,则指的是直接键;
各Q为
R1为-C(O)NH(OH);
R2为氢或C1-6烷基;
-L-为直接键;
各R3分别独立代表氢原子,且其中一个氢原子任选被选自芳基的取代基代替;
R4为氢;
R5为氢;
(a-41) 或
其中各s分别为0、1或2;
各R6分别独立选自氢、卤基、C1-6烷基或C1-6烷氧基;
各R7分别独立选自氢、卤基、C1-6烷基或C1-6烷氧基;
各R6与R7任选置于氮上替代氢;
上述芳基为苯基,或经一个或多个分别独立选自:卤基、C1-6烷基、C1-6烷氧基、三氟甲基、氰基或羟基羰基的取代基取代的苯基。
4.药物组合物,其包含药理上可接受的载体及作为活性成分的治疗有效量的根据权利要求第1至3任一项的化合物。
5.制备根据权利要求第4项的药物组合物的方法,其中均匀混合药理上可接受的载体及根据权利要求第1至3任一项的化合物。
6.根据权利要求第1至3项中任一项的化合物在制备用于治疗前列腺癌、脊髓发育不良综合征、骨髓白血病或急性淋巴细胞性白血病的药物中的应用。
8.权利要求1的化合物在制备用于检测或鉴定生物样本中组蛋白脱乙酰酶的试剂中的应用。
9.包含抗癌剂与根据权利要求第1至3项中任一项的化合物的药盒。
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US8071615B2 (en) | 2011-12-06 |
AU2003212336A1 (en) | 2003-09-22 |
NZ534831A (en) | 2007-01-26 |
AU2003212336B2 (en) | 2008-12-18 |
OA12789A (en) | 2006-07-10 |
US7446109B2 (en) | 2008-11-04 |
US20050148613A1 (en) | 2005-07-07 |
PL370982A1 (en) | 2005-06-13 |
CA2476067C (en) | 2011-09-20 |
US8394831B2 (en) | 2013-03-12 |
ATE398105T1 (de) | 2008-07-15 |
NO20044146L (no) | 2004-09-30 |
EP1485348B1 (en) | 2008-06-11 |
ES2306858T3 (es) | 2008-11-16 |
EA007908B1 (ru) | 2007-02-27 |
WO2003076395A1 (en) | 2003-09-18 |
TW200404794A (en) | 2004-04-01 |
AR039564A1 (es) | 2005-02-23 |
JP4648628B2 (ja) | 2011-03-09 |
DK1485348T3 (da) | 2008-09-29 |
MXPA04008796A (es) | 2004-11-26 |
HRP20040805A2 (en) | 2005-04-30 |
BR0307607A (pt) | 2004-12-21 |
EP1485348A1 (en) | 2004-12-15 |
KR20040090981A (ko) | 2004-10-27 |
PL205531B1 (pl) | 2010-04-30 |
US20090042920A1 (en) | 2009-02-12 |
JP2005519950A (ja) | 2005-07-07 |
US20120041001A1 (en) | 2012-02-16 |
EA200401200A1 (ru) | 2005-02-24 |
CN1642907A (zh) | 2005-07-20 |
DE60321548D1 (de) | 2008-07-24 |
CA2476067A1 (en) | 2003-09-18 |
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