CN101331123B - 用作组蛋白脱乙酰酶抑制剂的苯甲酰胺化合物 - Google Patents
用作组蛋白脱乙酰酶抑制剂的苯甲酰胺化合物 Download PDFInfo
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- CN101331123B CN101331123B CN200680047678.9A CN200680047678A CN101331123B CN 101331123 B CN101331123 B CN 101331123B CN 200680047678 A CN200680047678 A CN 200680047678A CN 101331123 B CN101331123 B CN 101331123B
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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Abstract
本发明涉及式(I)的苯甲酰胺化合物或其药学上可接受的盐或其前药形式,其中R1是C-连接的吡唑环,其任选被一或多个选自下列的基团取代:C1-4烷基、C3-4环烷基、C1-4烷氧基和C3-4环烷氧基。本发明还涉及这些化合物的制备方法、含有这些化合物的药用组合物以及它们在制备在预防或治疗肿瘤或其它增殖性病症中用作抗增殖药的药物中的用途,所述增殖性病症对抑制组蛋白脱乙酰酶(HDAC)敏感。
Description
本发明涉及某些新的苯甲酰胺化合物或其药学上可接受的盐,其为酶组蛋白脱乙酰酶(HDAC)的有效抑制剂。本发明还涉及这些新的苯甲酰胺化合物的制备方法、含有它们的药用组合物以及它们在治疗方法中的用途,例如在制备在温血动物如人中抑制HDAC的药物中的用途。
HDAC活性一直与多种疾病状态相关,如癌症(Marks等,自然评述(NatureReviews),1,194-202,(2001))、囊性纤维化(Li,S.等,J.Biol.Chem.,274,7803-7815,(1999))、杭廷顿氏舞蹈病(Steffan,J.S.等,自然(Nature),413,739-743,(2001))和镰刀型细胞贫血(Gabbianelli,M.等,血液(Blood),95,3555-3561,(2000))。因此,本发明还扩展到应用本发明的苯甲酰胺化合物治疗任何上述疾病的方法,以及这些苯甲酰胺化合物在制备用于治疗这些疾病状态的药物中的用途。
在真核细胞中,DNA一般紧密结合以阻止转录因子的趋近性。当细胞被激活时,这种紧密结合的DNA被制成以提供DNA-结合蛋白,从而诱发基因转录(Beato,M.,J.Med.Chem.,74,711-724(1996);Wolffe,A.P.,自然(Nature),387,16-17(1997))。核DNA与被称之为组蛋白的核蛋白联合,形成一种称为染色质的复合物。所述核组蛋白,称为H2A、H2B、H3和H4,被DNA的146个碱基对包围,形成染色质的基本单位,即被称之为的核小体。核组蛋白的N-末端部分含有作为转录后乙酰化位点的赖氨酸残基。赖氨酸侧链上的末端氨基的乙酰化中和该侧链的电位而形成一种正电荷,从而被认为影响染色质的结构。
组蛋白脱乙酰酶(HDACs)是含锌的酶,其催化从聚集在核小体组蛋白的氨基末端附近的赖氨酸残基的ε-氨基末端中除去乙酰基。HDACs可被分为两类,第一类(HDAC1、2、3和8)由酵母Rpd3-样蛋白代表,而第二类(HDAC4、5、6、7、9和10)由酵母Hdal-样蛋白代表。已知乙酰化的可逆过程在转录调节中十分重要。另外,HDAC去调节(deregulation)一直与数种癌症相关,而HDAC抑制剂,如制滴菌素A(一种从吸水链霉菌(Streptomyceshygroscopicus)中分离的天然产物),已呈现出明显的细胞生长抑制作用和抗肿瘤作用(Meinke,P.T.,当代药用化学(CurrentMedicinalChemistry),8,211-235(2001))。Yoshida等(Exper.CellRes.,177,122-131(1988))指出制滴菌素A引起大鼠细胞周期G1和G2期的成纤维细胞的终止,由此涉及细胞周期的调节中HDAC的作用。另外,已表明制滴菌素A能诱发末端分化、抑制细胞生长和阻止小鼠中肿瘤的形成(Finnin等,自然(Nature),401,188-193(1999))。
从出版的国际专利申请号WO03/087057和WO03/092686中已知某些苯甲酰胺衍生物是HDAC的抑制剂。WO03/087057中公开的一种具体化合物为N-(2-氨基苯基)-4-[1-(吡啶-2-基甲基)哌啶-4-基]苯甲酰胺[1](结构见以下所示)。
现已发现带有代替吡啶基的任选取代的吡唑基的某些苯甲酰胺化合物是HDAC的有效抑制剂。另外,还已发现本发明的特定化合物具有其它良好的药用特性,包括有利的细胞或体内效能、有利的DMPK特性(例如,良好的生物利用度方面和/或良好的游离血浆水平和/或良好的半衰期和/或良好的分布体积)以及良好的或增强的溶解性。另外,本发明的苯甲酰胺衍生物一般在hERG-编码的钾通道抑制试验中呈现出特别低的活性,其是临床中不良的和严重的心血管副作用的指示剂。
因此,本发明提供一种式(I)的化合物或其药学上可接受的盐:
其中R1是碳-连接的吡唑环,其任选被一或多个选自下列的基团取代:C1-4烷基、C3-4环烷基、C1-4烷氧基和C3-4环烷氧基。
应清楚的是以上定义的某些式(I)化合物可呈现出互变异构现象。应清楚的是本发明包括具有以上所提及的活性的其定义中的任何这种互变异构形式或其混合物,并且不仅仅受限于结构式图示或实施例命名中所用的任何一种互变异构形式。
当任选的取代基选自“一或多种”取代基时,应清楚该定义包括选自其中之一个特定基团的所有取代基或者选自两或更多个特定基团的取代基。
R1的适当的任选取代基可出现在吡唑环内任何可利用的碳或氮原子上。
R1适合带有1-3个取代基。另外,R1未被取代。
此处所用术语“烷基”指直链或支链。术语“环烷基”包括环状结构,但还可包括环烷基-烷基形式的链。类似的,术语“烷氧基”和“环烷氧基”包括通过氧原子连接的烷基、环烷基或环烷基-烷基。
R1的适合的C1-4烷基或C3-4环烷基取代基包括甲基、乙基、丙基、环丙基、环丁基或环丙基甲基。
R1的适合的C1-4烷氧基和C3-4环烷氧基取代基包括甲氧基、乙氧基、丙氧基、环丙氧基、环丁氧基或甲基环丙氧基。
在本发明一具体实施方案中,R1是碳-连接的吡唑环,其任选被1、2或3个选自C1-4烷基或C1-4烷氧基的基团取代。
在本发明另一实施方案中,R1是碳-连接的吡唑环,其任选被1、2或3个选自C1-2烷基或C1-2烷氧基的基团取代。
R1的实例包括吡唑-3-基、吡唑-4-基、1-甲基吡唑-4-基、3-乙基吡唑-4-基、1,3-二甲基吡唑-5-基、1,3-二甲基吡唑-4-基、1,3,5-三甲基吡唑-4-基、1,3-二甲基-5-甲氧基吡唑-4-基、1,5-二甲基吡唑-4-基、1-乙基-5-甲基吡唑-4-基、1-乙基吡唑-4-基和1-乙基-3-甲基吡唑-4-基(可能时,经历互变异构)。
在本发明另一实施方案中,式(I)化合物包括式(IA)化合物:
其中R2是氢、C1-4烷基或C3-4环烷基,和
R3和R5独立选自氢、C1-4烷基、C3-4环烷基、C1-4烷氧基和C3-4环烷氧基。
应清楚的是一般可按上图所示,将式(IA)的分子的吡唑部分的环原子编号。但是,当R2是氢时,该分子可进行互变异构,其中氢基团从吡唑环的一个氮上转换到另一个氮上,意味着其中R3或R5至少一个不是氢的取代的吡唑必然是各互变异构体的混合物,且因此认为R3和R5是可互相转换的。
在备选的实施方案中,本发明提供一种式(IB)化合物:
其中R2、R3和R5同以上式(IA)的相关定义。
还应清楚的是一般可按上图所描绘的那样,将式(IB)的分子的吡唑部分编号。但是,如以上对式(IA)化合物所讨论的那样,当R2是氢时,该分子也可经历互变异构。
R2的具体实例包括氢、甲基、乙基、丙基、环丙基、甲基环丙基或环丁基。
例如,R2是氢、甲基、乙基、丙基或环丙基。
在一特定实施方案中,R2是氢、甲基或乙基。
在另一实施方案中,R2是氢或甲基。
R3和R5的具体实例是氢、甲基、乙基、丙基、环丙基、环丙基甲基、甲氧基、乙氧基、丙氧基或环丙氧基。
R3和R5的具体实例包括氢、甲基、乙基或甲氧基。
适合的是,R3或R5不超过一个基团为C1-4烷氧基。
在一特定实施方案中,基团R2、R3和R5中至少一个,且优选两个不是氢。
在本发明的一特定实施方案中,化合物具有以上所示的式(IA)的结构,其中R2是氢或C1-4烷基,R3和R5各自独立选自氢、C1-4烷基或C1-4烷氧基。
在另一实施方案中,化合物具有以上所示的结构式(IA),其中R2是氢、甲基或乙基,而R3和R5各自独立选自氢、甲基、乙基或甲氧基。
在另一实施方案中,化合物具有以上所示的结构式(IA),其中R2是氢或甲基,而R3和R5各自独立选自氢、甲基、乙基或甲氧基。
在另一实施方案中,化合物具有以上所示的结构式(IA),其中R2是氢或甲基,而R3和R5各自独立选自氢、甲基或甲氧基。
在另一实施方案中,化合物具有以上所示的结构式(IA),其中R2是氢或甲基,而R3和R5各自独立选自氢或甲基。
在本发明的一特定实施方案中,化合物具有以上所示的结构式(IB),其中R2是氢或C1-4烷基,而R3和R5各自独立选自氢、C1-4烷基或C1-4烷氧基。
在另一实施方案中,化合物具有以上所示的结构式(IB),其中R2是氢、甲基或乙基,而R3和R5各自独立选自氢、甲基、乙基或甲氧基。
在另一实施方案中,化合物具有以上所示的结构式(IB),其中R2是氢或甲基,而R3和R5各自独立选自氢、甲基、乙基或甲氧基。
在另一实施方案中,化合物具有以上所示的结构式(IB),其中R2是氢或甲基,而R3和R5各自独立选自氢、甲基或甲氧基。
本发明的具体化合物包括任一下列化合物或其药学上可接受的盐:
(1)N-(2-氨基苯基)-4-[1-(1H-吡唑-3-基甲基)哌啶-4-基]苯甲酰胺;
(2)N-(2-氨基苯基)-4-{1-[(5-甲氧基-1,3-二甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺;
(3)N-(2-氨基苯基)-4-{1-[(3-乙基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺;
(4)N-(2-氨基苯基)-4-{1-[(1-甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺;
(5)N-(2-氨基苯基)-4-{1-[(1,3-二甲基-1H-吡唑-5-基)甲基]哌啶-4-基}苯甲酰胺;
(6)N-(2-氨基苯基)-4-{1-[(1,3-二甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺;
(7)N-(2-氨基苯基)-4-{1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺;
(8)N-(2-氨基苯基)-4-{1-[(1,5-二甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺;
(9)N-(2-氨基苯基)4-{1-[(1-乙基-5-甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺;
(10)N-(2-氨基苯基)-4-{1-[(1-乙基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺;
(11)N-(2-氨基苯基)-4-{1-[(1-乙基-3-甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺。
应清楚的是某些上述式I化合物可以以未溶剂化的形式以及可溶剂化的形式存在,如水合物形式。应清楚的是本发明包括具有抗增殖活性的所有这些溶剂化形式。
还应清楚的是某些式I化合物可以存在多晶现象,且本发明包括具有抗增殖活性的所有这些形式。
式I化合物的适合的药学上可接受的盐是例如式I化合物的酸加成盐,例如与诸如以下无机或有机酸所成的酸-加成盐:盐酸、氢溴酸、硫酸、三氟乙酸、柠檬酸或马来酸;或者例如具有足够酸性的式I化合物的盐,例如碱金属或碱土金属盐,如钙或镁盐或者铵盐。式I化合物的另一种适合的药学上可接受的盐是例如在给予式I化合物后在人或动物体内形成的盐。
可将本发明化合物以前药形式给予,前药即在人或动物体内分解释放出本发明化合物的化合物。可使用前药改变本发明化合物的物理性质和/或药物代谢动力学性质。当本发明化合物含有可连接改变性质基团的适当基团或取代基时,可形成前药。前药的实例包括可在式I化合物的氨基处形成的体内可断裂的酰胺衍生物。
因此,本发明包括以上定义的那些式I化合物,其当通过有机合成制备可得到以及当在人或动物体内通过断裂其前药可得到。因此,本发明包括通过有机合成途径制备的那些式I化合物,以及在人或动物体内通过前体化合物代谢产生这些化合物,即式I化合物为可被合成产生的化合物或代谢产生的化合物。
式I化合物的适合的药学上可接受的前药是基于合理医学判断的化合物,其能适合于给予人或动物体内,而无不良的药理学活性且无不适当的毒性。
各种形式的前药已在例如下列文献中描述:
a)K.Widder等编辑的酶学方法(MethodsinEnzymology),Vol.42,p.309-396(AcademicPress,1985);
b)H.Bundgaard等编辑的前药的设计(DesignofPro-drugs)(Elsevier,1985);
c)Krogsgaard-Larsen和H.Bundgaard编辑的药物设计和开发教科书(ATextbookofDrugDesignandDevelopment),第五章H.Bundgaard的″前药的设计和应用(DesignandApplicationofPro-drugs)″,p113-191(1991);
d)H.Bundgaard,当代药物传递评述(AdvancedDrugDeliveryReviews),8,1-38(1992);
e)H.Bundgaard,等,药物科学杂志(JournalofPharmaceuticalSciences).77,285(1988);
f)N.Kakeya,等,Chem.Pharm.Bull..32,692(1984);
g)T.HiguchiandV.Stella,″作为新的传递系统的前药(Pro-DrugsasNovelDeliverySystems)″,A.C.S.SymposiumSeries,Volume14;和
h)E.Roche(主编),″药物设计中的生物可逆性载体(BioreversibleCarriersinDrugDesign)″,PergamonPress,1987。
式I化合物的适合的药学上可接受的前药是例如一种其体内可裂解的酰胺衍生物。由氨基形成的适合的药学上可接受的酰胺包括例如由(1-10C)烷酰基基团,如乙酰基、苯甲酰基、苯乙酰基和取代的苯甲酰基和苯乙酰基形成的酰胺。苯乙酰基和苯甲酰基上的环取代基的实例包括氨基甲基、N-烷基氨基甲基、N,N-二烷基氨基甲基、吗啉代甲基、哌嗪-1-基甲基和4-(1-4C)烷基哌嗪-1-基甲基。
在给予式I化合物后,可通过在人或动物体内形成的一或多个代谢物部分地发挥式I化合物的体内作用。如上所述,式I化合物的体内作用也可通过前体化合物(前药)的代谢途径发挥。
式I化合物的制备
本领域技术人员了解在以上提及的某些过程/反应中,必须/要求对化合物中的任何敏感基团进行保护。必须或要求进行保护的情况以及提供这些保护的适当的方法对本领域技术人员来讲是熟知的。可根据标准操作规程(例如,参见T.W.Green&P.G.M.Wuts,有机合成的保护基(ProtectiveGroupsinOrganicSynthesis),第3版,JohnWileyandSons,1999),使用常规的保护基。因此,如果反应物包括诸如氨基、羧基或羟基的基团,在以上提及的某些反应中,可要求保护所述基团。
本文所述过程中所用的任何保护基一般可选自文献中所述的或者技术熟练化学家已知的适合作为有关基团保护的任何基团,并可通过常规方法引入。保护基可通过文献中所述的常规方法或者技术熟练化学家已知的适合除去有关保护基的方法除去,所选的方法能除去保护基,同时对分子中其它处的基团干扰最小。
为方便起见,以下给出保护基的具体实例,其中“低级”,如在低级烷基中所用,表示所用基团优选具有1-4个碳原子。应清楚的是这些实例并非穷举。当以下给出除去保护基的方法的具体实例时,它们同样地也并非是穷举的。未特别提及的保护基的用法和脱保护的方法当然也包括在本发明的范围之内。
氨基或烷基氨基的适当的保护基是例如酰基,如烷酰基,如乙酰基,烷氧基羰基,例如甲氧基羰基、乙氧基羰基或叔丁氧基羰基,芳基甲氧基羰基,例如苄氧基羰基,或者芳酰基,例如苯甲酰基。以上保护基的脱保护条件必须随保护基的选择而变化。因此,例如酰基,如烷酰基或烷氧基羰基或芳酰基,例如可通过用适当的碱,如碱金属氢氧化物(如氢氧化锂或氢氧化钠)水解除去。另外,酰基,如叔丁氧基羰基,例如可通过用适当的酸,如盐酸、硫酸或磷酸或三氟乙酸处理除去,而芳基甲氧基羰基(如苄氧基羰基)例如可通过经催化剂(如披钯碳)氢化除去,或者通过用路易斯酸(例如三(三氟乙酸)硼)处理除去。伯胺的另一种适合的保护基是例如邻苯二甲酰基,其可通过用烷基胺(例如二甲氨基丙胺)或用肼处理除去。
羟基的适合的保护基是,例如酰基,如烷酰基,如乙酰基,芳酰基,例如苯甲酰基,或者芳基甲基,如苄基。以上保护基的脱保护条件必须随保护基的选择而变化。因此,例如酰基,如烷酰基或芳酰基,例如可通过用适当的碱,如碱金属氢氧化物(如氢化化锂或钠)水解除去。另外,芳基甲基,如苄基,例如可通过经催化剂(如披钯碳)氢化除去。
羧基的适合的保护基是,例如酯化基团,例如甲基或乙基,其可例如通过用碱(如氢氧化钠)水解除去,或者例如叔丁基,其可例如通过用诸如有机酸(如三氟乙酸)的酸处理除去,或者例如苄基,其可通过经催化剂(如披钯碳)氢化除去。
所述保护基可在合成中的任何方便阶段,采用化学领域熟知的常规技术除去。
在另一方面,本发明提供一种制备式(I)化合物或其药学上可接受的盐的方法,该方法包括:
(a)在还原剂存在下,使式(II)化合物:
其中苯胺部分可被适当地保护;
与式(III)化合物反应
R1CHO
(III)
其中R1如本文定义,
然后,如果必要,除去可存在的任何残留的保护基。
方法(a)中适合的还原剂包括例如无机硼氢化物盐,如硼氢化钠、三乙酰氧基硼氢化钠或氰基硼氢化钠,和氢。使用氢的还原性氨化任选在适当的催化剂,如Pd/C、Pd(OH)2/C、Pt/C、PtO2或载于氧化铝上的Rh的存在下进行,还可在例如1-10巴压力下,在例如0-150℃温度范围内进行。
方法(a)可在适当的酸存在下进行。方法(a)的适当的酸包括布忍司特酸,如甲酸、乙酸、三氟乙酸、盐酸、硫酸、对甲苯磺酸或樟脑磺酸;或者式MQz的路易斯酸,其中M是金属,Q是活性基团,如卤代或磺酰氧基,如氯代、溴代、碘代、甲磺酰氧基、三氟甲磺酰氧基或甲苯-4-磺酰氧基,z的范围在1-6,且z值取决于金属M。适合的路易斯酸的典型实例包括三氟化硼、三氟甲磺酸钪(III)、氯化锡(VI)、异丙醇钛(IV)或氯化锌(II)。
另外,式(I)化合物可通过
(b)在适当的碱存在下,使式(II)化合物:
其中苯胺可被适当保护,与式(IV)化合物反应制备:
R1CH2X
(IV)
其中X是活性基团;
然后,如果必要,除去可存在的任何残留的保护基。
适合的活性基团X是例如卤代或磺酰氧基,例如氯代、溴代、碘代、甲磺酰氧基、三氟甲磺酰氧基或甲苯-4-磺酰氧基。
以上方法(b)中使用的适合的碱是例如有机胺碱,如吡啶、2,6-二甲基吡啶、三甲基吡啶、4-二甲氨基吡啶、三乙胺、吗啉、二异丙基乙胺(DIPEA)、N-甲基吗啉或二氮杂双环[5.4.0]十一碳-7-烯,或者例如碱金属或碱土金属的碳酸盐或氢氧化物,如碳酸钠、碳酸钾、碳酸钙、氢氧化钠或氢氧化钾,或者例如碱金属氢化物,如氢化钠,碱土金属碳酸氢盐,如碳酸氢钠,或者金属醇化物,如乙醇钠。
苯胺部分或哌啶环的适当的保护基可以是氨基甲酸酯,如叔丁氧基羰基或苄氧基羰基。
R1的具体实例如上所述。
方法(a)和(b)中定义的反应一般在适当的惰性溶剂或稀释剂存在下进行,例如烷醇或酯,如甲醇、乙醇、异丙醇或乙酸乙酯,卤化溶剂,如二氯甲烷、氯仿或四氯化碳,醚,如四氢呋喃、1,2-二甲氧基乙烷或1,4-二氧六环,芳族溶剂,如甲苯,或偶极非质子溶剂,如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷-2-酮或二甲亚砜。
原料的制备
式II化合物的制备
以上式II化合物可通过下列任一方法制备:
(c)在适当的碱存在下,使式(V)化合物,其中苯胺可被适当地保护,
其中X是如上定义的活性基团,
与式(VI)化合物反应
其中M是金属,L是配基,整数z是0-3,且四氢吡啶环可被保护;
或者
在适当的碱存在下,使式(VII)化合物,
其中苯胺和四氢吡啶可被适当地保护,且M、L和z如上定义,与式(VIII)化合物反应:
其中X是如上定义的活性基团;
然后,如果必要,以任何适当的顺序或组合进行下列步骤:
从四氢吡啶中除去任何保护基,和/或
还原四氢吡啶为哌啶,和/或
除去存在的任何残留保护基。
四氢呋喃环的适当的保护基是诸如叔丁氧基羰基(在此也称为“BOC”)或苄氧基羰基的基团。苯胺部分的适合的保护基也可以是氨基甲酸酯,如BOC或苄氧基羰基。
方法(c)的适合的碱是例如有机胺碱,如吡啶、2,6-二甲基吡啶、三甲基吡啶、4-二甲氨基吡啶、三乙胺、吗啉、N-甲基吗啉或二氮杂双环[5.4.0]十一碳-7-烯,或者例如碱金属或碱土金属的碳酸盐或氢氧化物,如碳酸钠、碳酸钾、碳酸钙、碳酸铯、氢氧化钠或氢氧化钾,或者例如碱金属氢化物,如氢化钠,碱土金属碳酸氢盐,如碳酸氢钠,或者金属醇盐,如乙醇钠。
以上方法(c)中定义的反应一般在适当的惰性溶剂或稀释剂存在下进行,例如烷醇或酯,如甲醇、乙醇、异丙醇或乙酸乙酯,卤化溶剂,如二氯甲烷、氯仿或四氯化碳,醚,如四氢呋喃、1,2-二甲氧基乙烷或1,4-二氧六环,芳族溶剂,如甲苯,或偶极非质子溶剂,如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷-2-酮或二甲亚砜。该反应一般在例如10-250℃的温度范围内,优选在40-80℃的温度范围内进行。
金属M可以是文献中已知的能形成有机金属化合物的任何金属,其能进行催化交联偶合反应。适合金属的实例包括硼、锡、锌和镁。
整数z的适当的值依据金属M而定,但通常为0-3。
配基L,当存在时,其适当的值包括,例如羟基、卤代、(1-4C)烷氧基或(1-6C)烷基配基,例如羟基、溴代、氯代、氟代、碘代、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、甲基、乙基、丙基、异丙基或丁基配基,或者当整数z是2且M是硼时,存在的两个配基可连接,使得与其连接的硼原子一起形成环。基团ML2适合为式-BL1L2的基团,其中B是硼,L1和L2按以上对配基L的定义。尤其是,配体L1和L2可连接,使得与其连接的硼原子一起形成环。例如L1和L2可以一起定义氧基-(2-4C)亚烷基-氧基基团,例如氧基亚乙基氧基、频哪醇基(pinacolato)(-O-C(CH3)2C(CH3)2-O-)或者氧基亚丙基氧基,使得与其连接的硼原子一起形成环硼酸酯基团。
方法(c)的适合的催化剂包括例如金属催化剂,如钯(0)、钯(II)、镍(0)或镍(II)催化剂,例如四(三苯膦)钯(0)、氯化钯(II)、溴化钯(II)、氯化二(三苯膦)钯(II)、四(三苯膦)镍(0)、氯化镍(II)、溴化镍(II)、氯化二(三苯膦)镍(II)或二氯[1-1’-二(三苯膦)二茂铁]合钯(II)。另外,一般可加入游离基引发剂,例如偶氮化合物,如偶氮(双异丁腈)。
在以上方法(c)中,通过氢化,可适合将四氢吡啶环还原为哌啶环。氢化任选在适当的催化剂存在下进行,如Pd/C、Pd(OH)2/C、Pt/C、PtO2或载于氧化铝上的Rh,并还可在压力下进行,如1-10巴。氢化还适合在适当的酸存在下进行,例如氢溴酸、盐酸、柠檬酸、乙酸和甲磺酸存在下,并在适合的溶剂或溶剂混合物,如水、乙醇、四氢呋喃(THF)、甲醇、乙腈或丙-2-醇中进行。
d)在适当溶剂存在下,使式(IX)化合物,
其中Q1是-OH、-Cl或-O-Q2 +(其中Q2+是阳离子),与式(X)化合物反应,且其中式(X)化合物中的一个氨基可被保护;
形成式(XI)化合物
其中苯胺可被保护;
然后:
通过使用适当的还原剂和/或适当的还原条件,将吡啶-4-基环还原为哌啶-4-基环,而将式(XI)化合物转化为式(II)化合物;和
任选除去任何存在的残留保护基。
Q1的适合值是-O-Na+(即-O-Q2 +,其中Q2 +是Na+)。式(X)化合物的一个氨基适合被如上定义的适当氨基保护基(如BOC基团)保护。
式(XI)化合物的苯胺适合被如上定义的适当的氨基保护基(如BOC基团)保护。
任何适合的溶剂,如本文以上提及的那些,都可用于化合物IX和X的反应。
使用适当的还原剂和/或适当的还原条件,可将式(XI)化合物转化为式(II)化合物。适合的方法是氢化。氢化任选在适合的催化剂存在下进行,如Pd/C、Pd(OH)2/C、Pt/C、PtO2或载于氧化铝上的Rh,并还可在压力下进行,如1-10巴。氢化还适合在适当的酸存在下进行,例如氢溴酸、盐酸、柠檬酸、乙酸和甲磺酸存在下,并在适合的溶剂或溶剂混合物,如水、乙醇、四氢呋喃(THF)、甲醇、乙腈或丙-2-醇中进行。
制备式(XI)化合物的适当的方法包括将式(IX)化合物转化为羧酸的活性衍生物(其可在原位产生并且不必分离),接着与式(X)化合物进行后续反应。
羧酸的适当的活性衍生物是例如酰卤,例如酸和无机酰氯反应形成的酰氯,例如亚硫酰氯;混酐,例如酸和氯甲酸酯(如氯甲酸异丙酯)反应形成的酐;活性酯,酸和碳二亚胺(如二环己基碳二亚胺)反应形成的产物;或者酸与氯化4-(4,6-二甲氧基-1,3,5-三嗪基-2-基)-4-甲基吗啉鎓(DMTMM)反应形成的产物,或者酸与1,1’-羰基二咪唑(CDI)反应形成的产物。
式(III)和(IV)化合物或者可由商业来源提供,例如FlurochemLtd,OldGlossop,DerbyshireSKl37RY,UK,或者它们可用本领域技术人员已知的方法和/或文献报道的方法合成,例如Makino,K.;Kim,H.SandKurasawaY;J.HeterocyclicChem.1998,35,489-497及其其中的文献。
测定法
可使用下列测定法(a)-(c)测定本发明一或多个化合物作为HDAC抑制剂、作为在Hi5昆虫细胞中产生的重组人HDAC1体外抑制剂以及作为在全细胞或肿瘤中组蛋白H3乙酰化的体外和体内诱发剂的作用。他们还评估了这些化合物抑制人肿瘤细胞增殖的能力。
(a)重组HDAC1体外酶测定法
筛选抗Hi5昆虫细胞中产生的重组人HDAC1的HDAC抑制剂。将该酶用FLAG标记物在基因的C-末端克隆,然后用SIGMA(A2220)的抗-FLAGM2琼脂糖进行纯化亲和力。
脱乙酰酶测定在50μl反应液中进行。室温下,将在15μl反应缓冲液(25mMTrisHCl(pH8)、137mMNaCl、2.7mMKCl、1mMMgCl2)中稀释的HDAC1(75ng酶)或者与缓冲液本身(10μl)或者与含有化合物的缓冲液(10μl)混合30分钟。然后将用25μl缓冲液稀释的25μM乙酰化组蛋白H4肽(KI174Biomol)加入到反应物中,室温下孵育1小时。加入等体积(50μl)的含有2μM制滴菌素A的FluordeLys显影剂(Biomol)终止反应。室温下,使反应物显影30分钟,然后在激发波长360nM和发射波长465nM处测定荧光。通过进行各化合物的剂量相应曲线并测定在最大信号(稀释剂对照)中产生50%降低的抑制剂浓度,来测定HDAC酶抑制剂的IC50值。
(b)全细胞中体外增殖抑制测定
全细胞中增殖抑制作用采用Promega细胞滴度测定96水溶液增殖测定法(Promega#G5421)测定。将HCT116细胞以1×103细胞/孔的量接种于96孔板中,使粘附过夜。用抑制剂处理72小时。向各孔中加入20μl四唑鎓染料MTS,将各板再培养3小时。然后在490nM处,在96孔读板器上测定吸收度。通过进行各化合物的剂量反应曲线并测定在最大信号(稀释剂对照)中产生50%降低的抑制剂浓度,来测定HDAC酶抑制剂的IC50值。
(c)全细胞中组蛋白脱乙酰酶活性的体外酶测定
全细胞中的组蛋白H3乙酰化采用免疫组织化学法测定,并使用Cellomics筛选分析仪(arrayscan)分析。将A549或HCT116细胞以1×104细胞/孔的量接种于96孔板中,使粘附过夜。用抑制剂处理24小时,然后用在tris缓冲盐水(TBS)中的1.8%甲醛固定1小时。将细胞用冰冷的甲醇透化处理5分钟,用TBS漂洗,然后在TBS3%低脂干乳中封闭90分钟。然后将细胞与对乙酰化组蛋白H3(Upstate#06-599)具有特异性的多克隆抗体(以1∶500稀释于TBS3%奶中)培养1小时。将细胞用TBS漂洗3次,然后在添加1%牛血清白蛋白(Sigma#B6917)的TBS中与荧光素轭合的次级抗体培养(MolecularProbes#A11008)&Hoechst333542(1μg/ml)(MolecularProbes#H3570)1小时。将未结合的抗体通过用TBS漂洗3次除去,将最终漂洗的100μl的TBS加入到细胞中,将各板密封,用Cellomics筛选分析仪分析。
HDAC抑制剂的EC50值通过各化合物的剂量反应曲线,并随后测定产生最大信号的50%降低的抑制剂浓度(参比化合物对照-制滴菌素A(Sigma))。
还可采用以下所示的(d)-(f)测定法,评估本发明化合物的hERG活性和溶解度。
(d)hERG-编码的钾通道抑制作用测定
细胞培养
在37℃、潮湿环境(5%CO2)下,在包含L-谷氨酰胺、10%胎牛血清(FCS)和0.6mg/ml潮霉素(均得自Sigma)的F-12Ham培养基中,使表达hERG-编码通道的中国仓鼠卵巢(CHO)细胞生长至半融合。使用前,用预温热(37℃)的3ml等份Versene1∶5,000(Invitrogen)洗涤该单层。抽吸该溶液后,在37℃培养箱中,将培养瓶与另外2mlVersene1∶5,000培养6分钟。然后通过轻扣,从烧瓶底部分离细胞,然后向烧瓶中加入含有钙(0.9mM)和镁(0.5mM)的10mlDulbecco′s-PBS(PBS)(Invitrogen),抽吸到15ml离心管中,然后离心(50g,4分钟)。
弃去得到的上清液,将沉淀温和地再混悬于3ml等份PBS中。移出0.5ml等份细胞混悬液进行自动细胞计数(InnovatisCedex),并用PBS调节细胞混悬液的终体积,得到所要求的终细胞浓度。
电生理学
该装置的原理和操作先前已有描述(Schroeder等.,JournalofBiomolecularScreening(2003)8(1),50-64)。简单地讲,该技术基于一种384-孔板(PatchPlateTM),其中试图通过抽吸定位并将细胞保持在小孔上,而将两种分离的流体腔分开,来对各孔进行记录。一经发生加封,立即将PatchPlateTM下面的溶液改换为含有两性霉素B(Sigma)的溶液。其渗透过覆盖在各孔内孔穴上的细胞膜碎片,实际上使得在各孔中记录一种穿破的、全细胞膜片箝记录。
对于IonWorksTMHT的各运转,在室温下(约21℃)以下列方式进行操作。将“缓冲器”位置中的“船”装载4mlPBS,并且将“细胞”位置装载如上所述的CHO-hERG细胞混悬液。将含有待测化合物(3X其终试验浓度)的96-孔板(V-bottom,GreinerBio-one)置于“板1”位置,并且将PatchPlateTM置于该装置中,使用PatchPlateTM盖保持位置。
安排各化合物板,使得能够构建十个、8-浓度效应曲线;将板上余下的两列加入用以确定测定基线的溶媒(0.33%DMSO),以及用以确定100%抑制水平的西沙比利(10μM)的最大阻断浓度。然后IonWorksTMHT的流控技术头部(F-头)向PatchPlateTM的各孔中加入3.5μlPBS,将其底面用含有下列组分(mM)的“内部”溶液灌注:K-葡萄糖酸钾(K-Gluconate)100、KCl40、MgCl23.2、EGTA3和HEPES5(均自Sigma)(用10MKOH调节至pH7.25-7.30)。启动并排气泡后,该电子设备头部(E-头)然后围绕PatchPlateTM移动进行钻洞试验(即用一电压脉冲测定各孔中的洞是否打开)。然后F-头向PatchPlateTM的各孔分配3.5μl如上所述的细胞混悬液,给细胞200秒到达并密封各孔中的洞。然后E-头围绕PatchPlateTM移动。以测定各孔中得到的封闭阻力。
然后将PatchPlateTM底部的溶液换成具有下列组分(mM)的“通路(Access)”溶液:KCl140、EGTA1、MgCl21和HEPES20(均自Sigma)(用10MKOH调节至pH7.25-7.30)加上100μg/ml两性霉素B。9分钟使碎屑发生穿孔后,E-头然后围绕该碎屑板的所有384个孔移动,得到预混合hERG电流的测定。然后F-头向PatchPlateTM的4个孔中加入3.5μl来自化合物板的各孔中的溶液。按程序由化合物板上最稀释的孔开始,并移动到最高浓度孔,以使任何携带污染影响降到最小。
在进行大约3.5分钟孵育后,E-头然后围绕PatchPlateTM板的所有384个孔移动,得到混合后hERG电流的测定。在该方法中,可产生非累积性浓度-影响曲线,而前提是在足够百分比的孔内达到验收标准(见下),试验化合物的各浓度的影响基于1和4细胞间的记录。
各孔的验收标准为:扫描前密封阻力>60MΩ,扫描前hERG尾部电流幅度>0.15nA;扫描后密封阻力>60MΩ。混合前后hERG电流通过以下构成的电压脉冲诱发:-70mV保持20秒,160ms至-60mV,100m回至-70mV,1秒升至+40mV,2秒至-30mV,最后500ms至-70mV。在混合前后电压脉冲之间,不存在持续的膜电位。
e)水溶液溶解度的测定
将试验化合物称重(1-1.6mgs),加入到小瓶中,加入1ml的0.1M磷酸盐缓冲液(pH7.4)。1.0-1.6mg之间的试验化合物一般溶解于小瓶中的1.8mlDMSO中,将其用作标准溶液。将两种溶液在25℃下搅拌24小时。然后将饱和的水溶液和DMSO标准溶液转移至深96-孔板中。将饱和的缓冲溶液板以4310g的相对离心力离心,然后将水性液上清液转移至第二个深孔板内,离心。再用缓冲液转移水性上清液和50%稀释液后,将终样品板和DMSO标准板用HPLC-UV-MS分析。通过比较在250nm处(如果250nm不适合,可选择其它波长)样本与标准UK峰面积,定量样本溶解度,化合物峰通过MS确证。
f)缓冲液和模拟肠液中水溶液溶解度的测定
在特定温度下,测定在下列介质中的溶解度:
模拟肠液(Fasted)FaSSIF(Galia和Dressman等,PharmsRes,15(5),1998,p698)。
牛磺胆酸钠(3mM)、卵磷脂(0.75mM)、KH2PO4(0.03M)、KCl(0.1M);NaOH(调节pH至6.5)。在37℃下测定。氏磷酸盐缓冲液(生物化学手册(HandbookofBiochemistry,pg234-237)).
溶液A0.067M磷酸二氢钾
溶液B0.067M磷酸氢二钠
在25℃和37℃下测定。
将准确定量(由以上溶解度试验(f)和/或预测的pH溶解度曲线确定)的研究中的化合物一式两份称量到2-dram玻璃管中。
向各套重复管中,加入最小量1.50ml加入了pH6.8氏磷酸盐缓冲液或FaSSIF的适当介质。所有重量必须足以饱和各种情况下的介质。
将包被磁跟踪器的PTFE加入到各管中,然后将其密封,置于Variomag磁反应搅拌器区域(CamLab)。将该磁搅拌器区域保持在适合的温度下(见上),盖上铝箔以降低曝光,以800r.p.m速度轮流方向搅拌。
在规定时间点,将各管取样以测试介质。以下列方式,在各时间点,先后测定各样品的pH和有效含量。
pH
使用适当的pH计(Hydrus400-Fisher)、电极和标准pH缓冲液,在室温下在pH4.01和7.00处校正仪器。
将电极置于各重复样本中,室温下测定pH,将结果以小数点后一位记录。将电极用去离子水漂洗,在各次测定之间擦干。
HPLC测定有效含量
从各样本中,将0.4ml等份样转移至聚碳酸酯超速离心管(Beckman)中。在适合所测试的介质的温度下,用TL最优化超速离心机(Beckman)以40000r.p.m转速,将样本旋转15分钟。将各离心管中的上清液转移至第二个超速离心管中,再在相同条件下旋转一次。
在研究得到的化合物的最优化HPLC方法下,分析各样本的上清液,外标法测定有效含量。上清液可能需要用适当的溶剂稀释,以使其浓度处于该HPLC方法的线性范围之内。一般可由水中预定的pH溶解度和已加入的化合物的量中共溶的情况估计。
虽然式I化合物的药理学性质按预期随结构变化而变化,但通常式I化合物具有的活性可按以上一或多种测试(a)、(b)、(c)或(d)中的下列浓度或剂量证明:
试验(a):-IC50范围,例如100nM或更低;
试验(b):-IC50范围,例如1μM或更低;
试验(c):-IC50范围,例如1μM或更低;
试验(d):-IC50,例如大于30μM。
通过该实例,使用抑制HDAC1的试验(a)和抑制全细胞增殖的试验(b),本文实施例4中所述的化合物给出下表A中所示的IC50结果。该表还包括N-(2-氨基苯基)-4-(1-(吡啶-2-基甲基)哌啶-4-基)苯甲酰胺(以上化合物[1])的对应的结果:
表A
实施例化合物 | IC50试验(a) (抑制HDAC1的体外 试验) | IC50试验(b) (抑制全细胞增殖的体 外试验) |
4 | 0.081μM | 0.508μM |
对比化合物1 | 0.1μM | 1.433μM |
在本发明待测化合物的有效剂量下,在试验(d)中未观察到生理上不能接受的毒性。因此,当以随后定义的剂量范围给予式I化合物或其药学上可接受的盐时,没有预期的不适的毒理学作用。
另外,虽然式I化合物的溶解度如所期望的那样必然随结构变化而变化,但式I化合物一般具有通过以上试验(e)测定的溶解度,例如大于100μM。
本发明另一方面提供一种药用组合物,其包含如上定义的式(I)的化合物或其药学上可接受的盐或前药,以及药学上可接受的稀释剂或载体。
本发明的组合物可以是适于口服使用(例如片剂、锭剂、硬或软胶囊、水性或油性混悬液、乳液、分散性粉末或颗粒、糖浆剂或酏剂)、局部使用(例如作为霜剂、软膏剂、凝胶剂或水性或油性溶液或混悬液)、供吸入给药(例如作为分散极细的粉末剂或液体气雾剂)、供吹入给药(例如作为极细分散的粉末剂)或供非肠道给药(例如作为无菌水性或油性溶液供静脉内、皮下、肌肉或肌内给药或者作为栓剂供直肠给药)的形式。
本发明的组合物可通过常规方法,使用常规的本领域熟知的药用赋形剂获得。因此,用于口服使用的组合物可包含例如一或多种着色剂、甜味剂、矫味剂和/或防腐剂。
片剂的适合的药学上可接受的赋形剂包括例如惰性稀释剂,如乳糖、碳酸钠、磷酸钙或碳酸钙;制粒剂和崩解剂,如玉米淀粉或藻酸;粘合剂,如淀粉;润滑剂,如硬脂酸镁、硬脂酸或滑石粉;防腐剂,如对羟基苯甲酸乙酯或丙酯,以及抗氧剂,如抗坏血酸。片剂可以是素片或者将其包衣片以改善其崩解和随后在胃肠道内的活性成分的吸收,或者改善其溶解性和/或外观,在任一情况下,均可使用本领域熟知的常规包衣剂和方法进行。
口服使用的组合物可以是硬明胶胶囊形式,其中将活性成分与例如碳酸钙、磷酸钙或高岭土等惰性稀释剂混合,或者为软明胶胶囊形式,其中将活性成分与水或油(如花生油、液体石蜡、豆油、椰子油、或优选橄榄油)或者任何其它可接受的介质混合。
水性混悬液一般包含以极细粉末化形式的活性成分以及一或多种悬浮剂,如羧甲基纤维素钠、甲基纤维素、羟丙甲基纤维素、藻酸钠、聚乙烯-吡咯烷酮、西黄蓍胶和阿拉伯胶;分散或湿润剂,如卵磷脂或烷氧化物与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯),或者环氧乙烷与长链脂肪醇的缩合产物(例如十七碳亚乙基氧基鲸蜡醇),或者环氧乙烷与源自脂肪酸与己糖醇的偏酯的缩合产物(例如聚氧乙烯山梨糖醇单油酸酯),或者环氧乙烷与长链脂肪醇的缩合产物(例如十七碳亚乙基氧基鲸蜡醇),或者环氧乙烷与源自脂肪酸与己糖醇的偏酯的缩合产物(例如聚氧乙烯山梨糖醇单油酸酯),或者环氧乙烷与源自脂肪酸与己糖醇酐的偏酯的缩合产物(例如聚乙烯脱水山梨糖醇单油酸酯)。该水性混悬液还可包含一或多种防腐剂(例如对羟基苯甲酸乙酯或丙酯)、抗氧剂(如抗坏血酸)、着色剂、矫味剂和/或甜味剂(如蔗糖、糖精或阿司帕坦)。
油性混悬液可通过将活性成分混悬于植物油(如花生油、橄榄油、芝麻油或椰子油)或矿物油(如液体石蜡)中制备。油性混悬液还可含有增厚剂,如蜂蜡、硬石蜡或十六烷醇。可加入诸如以上提到的甜味剂和矫味剂,以提供适口的口服制剂。这些组合物可通过加入抗氧剂(如抗坏血酸)防腐。
适于通过加入水制成水性混悬液或溶液的可分散或冻干粉末或颗粒剂,一般含有活性组分以及分散或湿润剂、悬浮剂和一或多种防腐剂。适合的分散剂或湿润剂和悬浮剂可通过以上已提到的那些实例例证。还可存在其它的赋形剂,如甜味剂、矫味剂或着色剂。
本发明的药用组合物还可以是水包油的乳液形式。油相可以是植物油,如橄榄油或花生油,或者为矿油,如液体石蜡或任何这些的混合物。适合的乳化剂可以是例如天然存在的胶,如阿拉伯胶或西黄蓍胶,天然存在的磷脂,如大豆、卵磷脂、脂肪酸与己糖醇酐的酯或偏酯(例如脱水山梨糖醇单油酸酯)以及该偏酯与环氧乙烷的缩合产物(如聚氧乙烯脱水山梨糖醇单油酸酯)。乳化剂还可包含甜味剂、矫味剂和防腐剂。
糖浆剂或酏剂可用甜味剂,如甘油、丙二醇、山梨糖醇、阿司帕坦或蔗糖制备,并还可包含湿润剂、防腐剂、矫味剂和/或着色剂。
所述药用组合物还可以是无菌可注射水性或油性混悬液、溶液、乳化液或特定系统的形式,其可通过已知的方法,采用一或多种以上已提及的适当的分散剂或湿润剂和混悬剂制备。无菌注射剂还可以是在无毒性胃肠外可接受的稀释剂或溶剂中的无菌注射溶液或混悬液,例如聚乙二醇溶液。
栓剂可通过将活性成分与适当的非刺激性赋形剂混合制备,所述赋形剂在常温下为固体,但在直肠内为液体,因此在直肠内溶化释放出药物。适合的赋形剂包括,例如可可脂和聚乙二醇。
局部制剂,如霜剂、软膏剂、凝胶剂和水性或油性溶液或混悬剂,一般可通过采用本领域熟知的常规方法,将活性成分与常规、局部可接受的介质或稀释剂制成制剂。
吹入给药的组合物可以是分散极细的粉末形式,其包含的平均粒径为例如30μm或以下,优选5μm或以下,更优选在5μm-1μm之间,所述粉末本身或者只含有活性成份或者用一或多种药理学上可接受的载体(如乳糖)稀释。然后一般将吹入的粉末剂保留在含有例如1-50mg活性成分的胶囊中,供用涡轮吸入器装置使用,如用于已知药物色甘酸钠(sodiumcromoglycate)的吹入。
吹入给药的组合物可以是常规的加压气雾剂,设计使其以含有分散极细的固体气雾或液滴的形式分散所述活性成分。可使用常规气雾推进剂,如挥发性氟化烃或烃,一般设计该气雾剂装置使其分散计量定量的活性成份。
有关制剂的进一步信息,读者可参考PergamonPress1990版药用化学大全(ComprehensiveMedicinalChemistry)第5卷第25.2章(CorwinHansch;ChairmanofEditorialBoard)。
一般可按常规方法,使用常规赋形剂制备上述组合物。
一般将式(I)化合物以单位剂量给予温血动物,该单位剂量范围为每m2动物体表面积5-5000mg,即约0.1-100mg/kg,并且其一般提供一种治疗有效剂量。单位剂量形式(如片剂或胶囊剂)一般包含例如1-250mg活性成分。优选使用1-50mg/kg范围的日剂量。但是,该日剂量必须随着所治疗的宿主、具体的给药途径和所治疗的疾病的严重程度而变化。因此,最佳的剂量由正在治疗任何具体患者的医生来决定。
我们已发现本发明定义的化合物或其药学上可接受的盐是有效的细胞周期抑制剂(抗细胞增殖剂),并认为该特性源于其HDAC抑制活性。我们还认为本发明化合物可能涉及血管生成的抑制、细胞凋亡和分化的激活。因此,期望本发明的化合物可用于在需要此种治疗的温血动物中治疗由HDAC酶单独或部分介导的疾病或医学病症,即所述化合物可用于产生HDAC抑制作用。因此,本发明化合物提供一种特征为抑制HDAC酶的治疗恶性细胞增殖的方法,即所述化合物可用于产生由HDAC的抑制作用单独或部分介导的抗增殖作用。
根据本发明的另一方面,提供一种如上定义的式(I)化合物或其药学上可接受的盐或前药,其用于通过医疗法治疗人或动物体的方法中。
因此,根据本发明的另一方面,提供一种用作药物的如上定义的式(I)化合物或其药学上可接受的盐或前药。
根据本发明的另一方面,提供如上定义的式(I)化合物或其药学上可接受的盐或前药在制备一种药物中的用途,该药物用于在温血动物如人中产生HDAC抑制作用。
根据本发明该方面的另一特征,提供一种在需要此种治疗的温血动物如人中产生HDAC抑制作用的方法,其包括给予该动物一种有效量的如上定义的式(I)的化合物或其药学上可接受的盐或前药。
根据本发明的另一方面,提供如上定义的式(I)化合物或其药学上可接受的盐或前药在制备一种药物中的用途,该药物用于在温血动物如人中产生细胞周期抑制(抗细胞增殖)作用。
根据本发明该方面的另一特征,提供一种在需要此种治疗的温血动物如人中产生细胞周期抑制(抗细胞增殖)作用的方法,其包括给予该动物一种有效量的如上定义的式(I)的化合物或其药学上可接受的盐或前药。
根据本发明的另一特征,提供一种在需要此种治疗的温血动物如人中治疗癌症的方法,其包括给予该动物一种有效量的如上定义的式(I)的化合物或其药学上可接受的盐或前药。
根据本发明的另一特征,提供一种在制备用于治疗癌症的药物中的如上定义的式(I)化合物或其药学上可接受的盐或其前药。根据本发明该方面的另一特征,提供用于治疗癌症的如上定义的式(I)化合物或其药学上可接受的盐或其前药。
根据本发明该方面的另一特征,提供如上定义的式(I)化合物或其药学上可接受的盐或其前药的用途,其用于制备用于治疗癌症的药物。
在本发明的另一方面,提供如上定义的式(I)化合物或其药学上可接受的盐或其前药在制备一种药物中的用途,该药物用于肺癌、结肠直肠癌、乳腺癌、前列腺癌、淋巴瘤和/或白血病。
在本发明的另一方面,提供一种在需要此种治疗的温血动物如人中治疗肺癌、结肠直肠癌、乳腺癌、前列腺癌、淋巴瘤和/或白血病的方法,其包括给予该动物一种有效量的如上定义的式(I)的化合物或其药学上可接受的盐或前药。
能用本发明化合物治疗的癌症包括食管癌、骨髓瘤、肝细胞、胰脏和宫颈癌、尤因氏瘤、成神经细胞瘤、卡波济氏肉瘤、卵巢癌、乳腺癌、结肠直肠癌、前列腺癌、膀胱癌、黑素瘤、肺癌[包括非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC)]、胃癌、头颈癌、脑癌、肾癌、淋巴瘤和白血病。
可将以上定义的HDAC抑制活性作为一种单独疗法使用,或者除本发明化合物外,还可包括一或多种其它药物和/或疗法使用。这种的联合疗法可通过该疗法的各单一组分的同时、连续或分别给药达到。在肿瘤治疗领域,一般习惯联合使用不同形式的疗法来治疗各癌症患者。在肿瘤治疗中,这种联合疗法,除以上定义的细胞周期抑制疗法外,还可包括的其它疗法可以是:手术、放疗或化疗。这种化疗可包括一或多种下列分类的抗肿瘤剂:
(i)抗增殖/抗肿瘤药物及其组合,如医学肿瘤学中使用的那些,如烷化剂(例如顺铂、卡铂、环磷酰胺、氮芥、美法兰、苯丁酸氮芥、
(i)抗增殖/抗肿瘤药物及其组合,如医学肿瘤学中使用的那些,如烷化剂(例如顺铂、卡铂、环磷酰胺、氮芥、美法兰、苯丁酸氮芥、白消安和亚硝基脲)、抗代谢物(例如抗叶酸剂,如氟嘧啶,例如5-氟尿嘧啶和替加氟(tegafur)、雷替曲塞、甲氨喋呤、阿糖胞苷和羟基脲;抗肿瘤抗生素(例如蒽环类抗生素,如阿霉素、博来霉素、多柔比星、柔红霉素、表柔比星、伊达比星、丝裂霉素C、放线菌素D和光辉霉素);抗有丝分裂剂(例如长春花碱,如长春新碱、长春碱、长春地辛和长春瑞滨,以及紫杉烷类,如紫杉酚和泰索帝);和拓扑异构酶抑制剂(例如表鬼臼脂素(epipodophyllotoxins),如依托泊苷和替尼泊苷、安吖啶、托泊替堪和喜树碱);
(ii)细胞生长抑制剂,如抗雌激素药(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬和iodoxyfene)、雌激素受体下调剂(例如氟维司群)、抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特和醋酸环丙孕酮),LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕激素(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿拉曲唑、来曲唑、伏氯唑和依西美坦)和5α-还原酶抑制剂,如非那雄胺;
(iii)抑制癌细胞侵袭药物(例如金属蛋白酶抑制剂,如马立马司他,以及尿激酶纤维蛋白溶酶原激活剂受体功能的抑制剂);
(iv)生长因子功能抑制剂,如这些抑制剂包括生长因子抗体、生长因子受体抗体(例如抗-erbb2抗体曲妥单抗[HerceptinTM]和抗-erbbl抗体西妥昔单抗[C225])、法尼基转化酶抑制剂、MEK抑制剂、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂,例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代乙氧基)喹唑啉-4-胺(吉非替尼(gefitinib)),N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(埃罗替尼(erlotinib),OSI-774)和6-丙烯酰氨基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)喹唑啉-4-胺(CI1033)),例如血小板衍生的生长因子家族的抑制剂和例如肝细胞生长因子家族的抑制剂;
(v)抗血管生成剂,如抑制血管内皮生长因子作用的那些药物(例如抗血管内皮细胞生长因子抗体贝伐单抗[AvastinTM],诸如国际专利申请WO97/22596、WO97/30035、WO97/32856和WO98/13354中公开的那些化合物)和通过其它机理作用的化合物(例如利诺胺,整联蛋白αvβ3功能的抑制剂以及血管生长抑素);
(vi)血管损伤剂,如考布他汀A4以及国际专利申请WO99/02166、WO00/40529、WO00/41669、WO01/92224、WO02/04434和WO02/08213中公开的那些化合物;
(vii)反义疗法,例如涉及以上所列靶标的那些反义疗,如ISIS2503,一种反义anti-ras;
(viii)基因疗法途径,包括例如代替异常基因的途径,如异常p53或异常BRCA1或BRCA2,GDEPT(基因定向酶前药疗法)途径,如使用胞嘧啶脱氨基酶、胸腺嘧啶核苷激酶或细菌硝基还原酶的那些途径,以及增加患者对化疗或放疗的耐受性的方法,如多种药物抗性基因疗法。
(ix)免疫途径,包括例如增加患者肿瘤细胞的免疫原性的体外和体内途径,如用白介素2、白介素4或粒细胞-巨噬细胞集落刺激因子等细胞因子转染,降低T-细胞无反应性途径,使用诸如细胞因子-转染的树突细胞的转染免疫细胞的途径,使用细胞因子转染的肿瘤细胞系的途径和使用抗-个体遗传型抗体的途径;
(x)细胞周期抑制剂,包括例如CDK抑制剂(例如黄酮类抗肿瘤药(flavopiridol))和细胞周期关卡的其它抑制剂(例如关卡激酶);涉及有丝分裂和胞质分裂调节的极光激酶和其它激酶(例如有丝分裂激酶)的抑制剂;以及其它组蛋白脱乙酰酶抑制剂;和
(xi)分化剂(例如维甲酸和维生素D)。
根据本发明的这个方面,提供一种用于联合治疗癌症的药用组合物,其包含如上定义的式(I)化合物和如上定义的另一种抗肿瘤物质。
还提供一种如上定义的式(I)化合物或其药学上可接受的盐或前药,其用于治疗炎性疾病、自身免疫性疾病和过敏性/特异性疾病的方法中。
尤其是提供用于治疗下列疾病方法中的如上定义的式(I)化合物或其药学上可接受的盐:关节炎(尤其是风湿性关节炎、骨关节炎和痛风)、胃肠道炎症(尤其是炎性肠病、溃疡性结肠炎和胃炎)、皮肤炎症(特别是牛皮癣、湿疹、皮炎)、多发性硬化症、动脉粥样硬化、脊椎关节病(强直性脊椎炎、牛皮癣关节炎、与溃疡性结肠炎有关的关节炎)、AIDS-相关的神经病、全身性红斑狼疮、哮喘、慢性阻塞性肺病、支气管炎、胸膜炎、成人呼吸窘迫综合症、败血病和急性及慢性肝炎(或者为病毒性、细菌性或毒性)。
还提供一种如上定义的式(I)化合物或其药学上可接受的盐或前药,其用作在温血动物如人中治疗炎性疾病、自身免疫性疾病和过敏性/特异性疾病的药物。
特别是提供一种如上定义的式(I)化合物或其药学上可接受的盐或前药,其用作治疗以下疾病的药物:关节炎(尤其是风湿性关节炎、骨关节炎和痛风)、胃肠道炎症(尤其是炎性肠病、溃疡性结肠炎和胃炎)、皮肤炎症(特别是牛皮癣、湿疹、皮炎)、多发性硬化症、动脉粥样硬化、脊椎关节病(强直性脊椎炎、牛皮癣关节炎、与溃疡性结肠炎有关的关节炎)、AIDS-相关的神经病、全身性红斑狼疮、哮喘、慢性阻塞性肺病、支气管炎、胸膜炎、成人呼吸窘迫综合症、败血病和急性及慢性肝炎(或者为病毒性、细菌性或毒性)。
还提供如上定义的式(I)化合物或其药学上可接受的盐在制备一种药物中的用途,该药物用于在温血动物如人中治疗炎性疾病、自身免疫性疾病和过敏性/特异性疾病。
如上所述,治疗或预防性治疗特定细胞增殖性疾病所需要的剂量的大小必须随所治疗的宿主、给药途径和所治疗的疾病的严重程度而变化。单位剂量的范围可为例如1-100mg/kg,优选1-50mg/kg。
除用于治疗药物的用途外,式(I)化合物及其药学上可接受的盐还可用作研究中的药理学工具以及体外或体内测试系统的标准物,作为探索研究新治疗剂的部分,用以评估试验动物(如猫、狗、兔、猴、大鼠和小鼠)中细胞周期活性的抑制剂的作用。
现通过下列实施例示例性说明本发明,其中:一般地,
(i)除另有说明,操作在室温下,即17-25℃范围内,在惰性气体(如氩气)气氛下进行;
(ii)蒸发通过真空旋转蒸发进行,后处理步骤在通过过滤除去残留固体后进行;
(iii)柱层析(快速方法)和中压液相层析(MPLC)在德国E.Merck,Darmstadt的MerckKieselgel硅胶(Art.9385)或MerckLichroprepRP-18(Art.9303)反相硅胶上进行,或者使用使用者的预填充正相硅胶柱进行,例如得自PresearchLtd.,Hitchin,UK的Redisep(TM)一次性层析柱,或者高效液相层析(HPLC)在C18反相硅胶柱上进行,例如DynamaxC-1860制备反相柱;
(iv)收率,当出现时,不必是可达到的最大量;
(v)式(I)的终产物的结构一般通过核磁共振(NMR)和/或质谱技术确认,快速原子轰击(FAB)质谱数据采用Platform光谱仪记录,适当时,收集正离子数据或负离子数据;NMR化学位移值以δ值测定,质子磁共振光谱使用在400MHz场强下操作的JeolJNMEX400光谱仪、在300MHz场强下操作的VarianGemini2000光谱仪、在400MHz场强下操作的BrukerDPX-400光谱仪或在300MHz场强下操作的BrukerAM300光谱仪进行-除另有说明,测定在室温下进行。
(vi)中间体一般不完全定性,纯度通过薄层层析、HPLC、红外(IR)和/或NMR分析评定;
(vii)熔点未经校正,采用MettlerSP62自动熔点仪或油浴测定,式(I)的终产物的熔点在用常规有机溶剂如乙醇、甲醇、丙酮、乙醚或己烷(单独或混合物)结晶后测定。
(viii)使用下列缩写:
DMSO二甲亚砜
THF四氢呋喃
DIPEAN,N-二异丙基乙胺
IPA异丙醇
Boc/BOC叔丁氧基羰基
HCl盐酸
Cbz/CBZ苄氧基羰基
Tf三氟甲基磺酰基
LiHMDS六甲基二甲硅烷基氨基锂
PhNTf2N-苯基-双(三氟甲基磺酰亚胺)
DME1,2-二甲氧基乙烷
CDMT2-氯-4,6-二甲氧基-1,3,5-三嗪
实施例1
N-(2-氨基苯基)-4-{1-[(1-甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺
向装有1-甲基-1H-吡唑-4-甲醛(84.5mg,0.77mmol)的反应容器中,加入2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯(按以下方法1中所述制备;300mg,0.76mmol)在二氯甲烷(7ml)和N,N-二甲基甲酰胺(0.5ml)的溶液。也可根据以下方法4中所述方法制备2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯。加入乙酸(50μl,0.87mmol),将反应混合物在室温下搅拌45分钟。然后加入三乙酰氧基硼氢化钠(250mg,1.18mmol),将反应物再搅拌76小时。然后用甲醇稀释,直接倒入一SCX-2柱(10g)上。将该柱用甲醇(80ml)充分洗涤,然后将产物用2M氨的甲醇溶液(50ml)洗脱。将相关部分蒸发至干,将得到的残留物再溶解于二氯甲烷(3ml)中,用三氟乙酸(1ml)处理。将该混合物在室温下搅拌2小时,然后用甲醇稀释,直接倒入一SCX-2柱(5g)上。将该柱用甲醇(20ml)洗涤,然后将产物用2M氨的甲醇溶液(20ml)洗脱。将含氨部分蒸发至干,得到的残留物经硅胶快速层析纯化,用10%甲醇的二氯甲烷溶液洗脱,得到标题化合物(117mg,40%);NMR光谱:
(DMSOd6)δ1.70(m,4H),2.01(t,2H),2.57(m,1H),2.95(m,2H),3.38(s,2H),3.81(s,3H),4.86(s,2H),6.60(m,1H),6.78(m,1H),6.97(m,1H),7.18(m,1H),7.31(s,1H),7.37(d,2H),7.57(s,1H),7.91(d,2H),9.56(s,1H);
质谱:M+H+390。
实施例2
使用实施例1中描述的类似方法,使2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯与适当的吡唑甲醛原料(SM)反应,得到表1中所述的化合物。
表1
实施例3
N-(2-氨基苯基)-4-[1-(1H-吡唑-3-基甲基)哌啶-4-基]苯甲酰胺
室温下,将2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯(按以下方法1中所述制备;200mg,0.51mmol)和1H-吡唑-3-甲醛(50.7mg,0.53mmol)在二氯甲烷(5ml)中搅拌1小时。加入三乙酰氧基硼氢化钠(150mg,0.71mmol),将混合物在室温下搅拌48小时。将得到的溶液吸收至SCX-2柱上,用甲醇洗涤(2个柱体积),然后将产物用2M氨的甲醇溶液洗脱(2个柱体积),得到一种泡沫状物。将其溶解于1,4-二氧六环(2ml)中,加入4M氯化氢的1,4-二氧六环(2ml)溶液,将该溶液在室温下搅拌48小时。过滤产物,用乙醚洗涤,空气干燥。将得到的固体溶解于水中,用2N氢氧化钠碱化,将得到的固体过滤,用水洗涤,真空干燥,得到标题化合物(61mg,44%)。NMR光谱:1HNMR(DMSOd6)δ1.71(m,4H),2.07(m,2H),2.56(m,1H),2.95(m,2H),3.53(s,2H),4.86(s,2H),6.16(s,1H),6.60(m,1H),6.78(d,1H),6.97(t,1H),7.18(d,1H),7.37(d,2H),7.64(m,1H),7.91(d,2H),9.55(s,1H),12.59(m,1H);
质谱:M+H+376。
实施例4
N-(2-氨基苯基)-4-{1-[(5-甲氧基-1,3-二甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺
使用实施例3中描述的类似的方法,使2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯(按以下方法1中所述制备;200mg,0.51mmol)与5-甲氧基-1,3-二甲基-1H-吡唑-4-甲醛(92.6mg,0.60mmol)反应,得到标题化合物(68mg,36%);NMR光谱:
(DMSOd6)δ1.63(m,2H),1.78(m,2H),2.00(m,2H),2.06(s,3H),2.57(m,1H),2.94(m,2H),3.25(s,2H),3.50(s,3H),3.99(s,3H),4.86(brs,2H),6.60(m,1H),6.78(d,1H),6.97(m,1H),7.17(d,1H),7.37(d,2H),7.91(d,2H),9.55(s,1H);
质谱:M+H+434。
实施例5
N-(2-氨基苯基)-4-{1-[(3-乙基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺
在室温下,将2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯(按以下方法1中所述制备;395mg,1.0mmol)和3-乙基-1H-吡唑-4-甲醛(149mg,1.2mmol)在二氯甲烷(10ml)中搅拌1小时。加入三乙酰氧基硼氢化钠(297mg,1.4mmol),将混合物在室温下搅拌24小时。将得到的溶液吸收至SCX-2柱上,用甲醇洗涤(2个柱体积),然后将产物用2M氨的甲醇溶液(2个柱体积)洗脱,得到为白色泡沫状产物。经硅胶层析纯化,用10%甲醇的二氯甲烷溶液洗脱。将残留物溶解于二氯甲烷(4ml)中,加入三氟乙酸(1ml),将混合物在室温下搅拌3小时。将得到的溶液吸收至SCX-2柱上,用甲醇洗涤(2个柱体积),然后将产物用2M氨的甲醇溶液(2个柱体积)洗脱,得到标题化合物(232mg,75%)。NMR光谱:
(DMSOd6)δ1.18(t,3H),1.65(m,2H),1.77(m,2H),2.00(m,2H),2.57(m,3H),2.95(m,2H),3.34(s,2H),4.86(brs,2H),6.60(m,1H),6.78(d,1H),6.97(m,1H),7.17(d,1H),7.29(brs,1H),7.37(d,2H),7.91(d,2H),9.55(s,1H),12.39(s,1H);
质谱:M+H+404。
实施例6
N-(2-氨基苯基)-4-{1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺
使用实施例5中描述的类似的方法,使2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯(按以下方法1中所述制备;200mg,0.51mmol)与1,3,5-三甲基-1H-吡唑-4-甲醛(83.5mg,0.60mmol)反应,得到标题化合物(70mg,56%);NMR光谱:
(DMSOd6)δ1.65(m,2H),1.77(m,2H),1.98(m,2H),2.09(s,3H),2.18(s,3H),2.57(m,1H),2.92(m,2H),3.24(s,2H),3.63(s,3H),4.86(brs,2H)6.60(m,1H),6.78(d,1H),6.97(m,1H),7.17(d,1H),7.37(d,2H),7.91(d,2H),9.55(s,1H);
质谱:M+H+418。
实施例7A
N-(2-氨基苯基)-4-{1-[(1,3-二甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺
将(2-{[4-(1-{1,3-二甲基-1H-吡唑-4-基甲基}哌啶-4-基)苯甲酰基]氨基}苯基)氨基甲酸叔丁基酯(按以下方法6中所述制备;7.61g,15.11mmol)溶解于1,4二氧六环(70ml)中,然后用冰水浴冷却至0℃。然后慢慢加入4M氯化氢的1,4二氧六环溶液(150ml,600mmol)。将得到的混悬液温热至室温,用玻璃棒搅拌打碎硬块。将反应混合物在室温下搅拌18小时。将混合物抽吸过滤。将得到的固体溶解于水(200ml)中,慢慢加入2M氢氧化钠水溶液调节溶液至pH12。将得到的混合物用二氯甲烷提取(300ml),分离有机层。再将水相用二氯甲烷提取(200ml),将合并的提取液用盐水洗涤,经硫酸镁干燥,过滤,蒸发,得到澄清胶状物。将该胶状物溶于乙醚中,再蒸发至干,得到标题化合物(5.69g,93%);NMR光谱:
(CDCl3)δ1.81(m,4H),2.07(m,2H),2.25(s,3H),2.56(m,1H),3.04(m,2H),3.39(s,2H),3.81(s,3H),3.85(s,2H),6.84(m,2H),7.08(m,1H),7.24(s,1H),7.33(m,3H),7.82(m,3H).
质谱:M+H+404。
实施例7B
N-(2-氨基苯基)-4-{1-[(1,3-二甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺
将(2-{[4-(1-{1,3-二甲基-1H-吡唑-4-基甲基}哌啶-4-基)苯甲酰基]氨基}苯基)氨基甲酸叔丁基酯(以下方法6;92.3g,183.3mmol)于甲醇(754ml)和水(141ml)中搅浆,然后冷却至0-5℃。加入浓盐酸,同时保持温度低于20℃。在室温下,将反应混合物搅拌20小时。将反应物冷却至0-5℃,加入氢氧化钠水溶液直至pH达到12-14,同时保持温度低于20℃。将反应混合物加热至回流温度下30分钟,然后用月约4小时冷却至20℃。过滤收集产物,用甲醇水溶液洗涤,然后在45℃下真空干燥至恒重,得到标题化合物(63.3g86%)。NMR光谱:
(DMSOd6),1.65(m,2H),1.73(m,2H),1.96(t,2H),2.08(s,3H),2.55(m,1H),2.92(d,2H),3.28(s,2H),3.75(s,3H),4.87(s,2H),6.59(m,1H),6.77(m,1H),6.96(m,1H),7.2(d,1H),7.35(d,2H),7.44(s,1H),7.90(d,2H),9.56(s,1H).
质谱:M+H+404。
实施例8
N-(2-氨基苯基)-4-{1-[(1,5-二甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺
将{2-[(4-{1-[(1,5-二甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰基)氨基]苯基}氨基甲酸叔丁基酯(按方法7中所述制备;308mg,0.61mmol)溶解于二氯甲烷(2ml)中,加入三氟乙酸(1ml)。将反应混合物在室温下搅拌1小时,然后倒入到SCX-3柱(5g)上。将柱用二氯甲烷(50ml)和甲醇(50ml)洗涤,然后用2M氨的甲醇溶液(50ml)洗脱。蒸发含氨的部分,得到白色固体(182mg),经反相制备HPLC纯化,得到标题化合物(134mg,55%);NMR光谱:
(DMSOd6)δ1.70(m,4H),2.01(m,2H),2.22(s,3H),2.57(m,1H),2.95(m,2H),3.28(s,2H),3.71(s,3H),4.86(s,2H),6.60(m,1H),6.78(m,1H),6.97(m,1H),7.17(m,1H),7.23(s,1H),7.37(d,2H),7.90(d,2H),9.55(s,1H);
质谱:M+H+404。
实施例9
N-(2-氨基苯基)-4-{1-[(1-乙基-5-甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺
将1-乙基-5-甲基-1H-吡唑-4-甲醛(141mg,1.02mmol)的二氯甲烷(1ml)溶液加入到2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯(按以下方法1中所述制备;300mg,0.76mmol)的二氯甲烷(6.5ml)溶液中。加入乙酸(45μl,0.79mmol),将反应混合物搅拌4小时。然后加入N,N-二甲基甲酰胺(1ml),再继续搅拌30分钟,然后加入固体的三乙酰氧基硼氢化钠(245mg,1.16mmol)。然后将反应混合物在室温下搅拌18小时(过夜)。通过加入甲醇,将反应混合物稀释至二倍体积,直接倒入预冲洗的(用甲醇)SCX-2柱(10g)上。将柱用甲醇(60ml)洗涤,然后用2M氨的甲醇溶液(50ml)洗脱产物。蒸发含氨的洗脱液,得到无色胶状物(420mg),将其溶解于二氯甲烷(5ml)中,用三氟乙酸(2ml)处理。将混合物搅拌2小时,然后用二氯甲烷(10ml)稀释,倒入预冲洗的(用甲醇)SCX-2柱(10g)上。将该柱用二氯甲烷(40ml)、甲醇(50ml)完全冲洗,然后用2M氨的甲醇溶液(50ml)洗脱产物。蒸发含氨的部分,得到浅黄色胶状物(300mg),经反相制备HPLC纯化,得到标题化合物(172mg,54%);NMR光谱:
(DMSOd6)δ1.27(t,3H),1.66(m,4H),1.98(m,2H),2.21(s,3H),2.56(m,1H),2.92(m,2H),3.29(s,2H),4.02(q,2H),4.85(s,2H),6.59(m,1H),6.77(m,1H),6.95(m,1H),7.16(m,1H),7.23(s,1H),7.35(d,2H),7.89(d,2H),9.54(s,1H);
质谱:M+H+418。
实施例10和11
使用实施例9中描述的类似方法,使2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯(按以下方法1中所述制备)与适当的吡唑甲醛原料反应,得到表2中所述的化合物。
表2
方法部分-原料的制备
方法1
{2-[(4-哌啶-4-基苯甲酰基)氨基]苯基}氨基甲酸叔丁基酯
向4-{4-[({2-[(叔丁氧基羰基)氨基]苯基}氨基)羰基]苯基}-3,6-二氢吡啶-1(2H)-羧酸苄基酯(269g,524mmol;按以下方法2中所述制备)的甲醇(3000ml)溶液中,加入10%披钯碳(10g)。将反应混合物置于5巴氢气压下,并加热至50℃1小时。将反应混合物冷却至室温,通过硅藻土垫过滤,减压蒸发溶剂。将得到的泡沫状物在乙醚中研磨,过滤得到白色固体。将产物精细研磨,与95∶5乙醚/乙酸乙酯一起搅拌,然后抽气过滤收集。将该固体用乙醚、异己烷洗涤,真空干燥得到标题化合物(167g,81%);NMR光谱:
(DMSO-d6)1.45(s,9H),1.57(m,2H),1.72(m,2H),2.61(t,2H),2.69(m,1H),3.07(m,2H),7.18(m,2H),7.40(d,2H),7.53(d,2H),7.91(d,2H),8.70(brs,1H),9.82(brs,1H);
质谱:M+H+396。
方法2
4-{4-[({2-[(叔丁氧基羰基)氨基]苯基}氨基)羰基]苯基}-3,6-二氢吡啶-1(2H)-羧酸苄基酯
将四(三苯膦)钯(0)(8.0g,6.92mmol)加入到N-(2-叔丁氧基羰基氨基苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂戊环-2-基)苯甲酰胺(288g,657mmol;按国际专利公布号WO03/087057中方法13,第60页中所述制备)和4-{[(三氟甲基)磺酰基]氧基}-3,6-二氢吡啶-1(2H)-羧酸苄基酯(240g,657mmol;按以下方法3中所述制备)的1,2-二甲氧基乙烷(3000ml)和饱和碳酸氢钠水溶液(3000ml)的搅拌的混悬液中。将反应混合物加热至80℃下7小时,然后在搅拌下冷却至室温。然后将反应混合物倒入水中(2000ml),用乙酸乙酯提取。然后有机提取液经硫酸镁干燥,过滤,蒸发至干,得到粗产物,为灰色固体。经硅胶快速柱层析纯化,用乙酸乙酯/己烷(30∶70v/v)洗脱,得到标题化合物(279g,82%);NMR光谱:
(DMSO-d6)δ1.44(s,9H),2.56(m,2H),3.66(m,2H),4.14(m,2H),5.13(s,2H),6.34(m,1H),7.18(m,2H),7.33(m,1H),7.40(m,4H),7.54(m,2H),7.62(d,2H),7.94(d,2H),8.64(brs,1H),9.81(brs,1H);
质谱:MNa+550。
方法3
4-{[(三氟甲基)磺酰基]氧基}-3,6-二氢吡啶-1(2H)-羧酸苄基酯
在氮气氛下,将4-氧代哌啶-1-羧酸苄基酯(147g,630mmol)溶解于四氢呋喃(500ml)中。用2小时时间,将该溶液滴加到氮气下的、搅拌的六甲基二甲硅烷基氨基锂的溶液(20%的四氢呋喃溶液,556ml,662mmol)中,其间保持反应温度低于-70℃。将反应混合物在-75℃下再搅拌1小时,然后用2小时滴加入N-苯基-双(三氟甲基亚磺酰胺(sulfonimide))(236g,661mmol)的四氢呋喃(950ml)溶液,其间再保持反应温度低于-70℃。然后将反应物温热至室温过夜,接着分次加入2M氢氧化钠水溶液(800ml)。分离各层,将有机层再用2M氢氧化钠水溶液(600ml)洗涤,然后蒸发至干。将得到的固体溶解于乙醚中,用水洗涤。然后将有机层通过硅藻土过滤,经硫酸钠干燥,蒸发至干,得到标题化合物(140g,61%),其无需进一步纯化直接用于下一阶段。
方法4
{2-[(4-哌啶-4-基苯甲酰基)氨基]苯基}氨基甲酸叔丁基酯(备选方法)
向{2-[4-吡啶-4-基苯甲酰基)氨基]苯基}氨基甲酸叔丁基酯(20g,51.35mmol;按以下方法5A或5B中所述制备)、10%披钯碳(3.17g)和柠檬酸(4.75g,24.65mmol)中加入水(80ml)和IPA(80ml)。将反应混合物置于4巴氢气压下,并加热至70℃下5小时。将反应混合物冷却至50℃,通过硅藻土垫过滤。将混合物加热至70℃,然后用10分钟加入20%w/w氢氧化钠水溶液(15ml)至pH10-11。再加入水(30ml),然后用1小时将混合物冷却至40℃,然后再用30分钟加热至60℃,然后再冷却至室温。过滤收集得到的沉淀,用水洗涤(2×20ml),在50℃下真空干燥,得到标题化合物(17.6g,84%);NMR光谱:NMRSpectrum:(DMSO-d6)δ1.45(s,9H),1.53(m,2H),1.70(m,2H),2.58(m,1H),2.66(m,2H),3.03(m,2H),3.31(brs,1H),7.17(m,2H),7.35(d,2H),7.54(m,2H),7.89(d,2H),8.65(brs,1H),9.75(brs,1H).
质谱:M+H+396。
方法5A
{2-[4-吡啶-4-基苯甲酰基)氨基]苯基}氨基甲酸叔丁基酯
用3小时,向4-(4-吡啶基)苯甲酸钠(55.2g,236.2mmol)、叔丁氧基羰基邻苯二胺(45.7g.o217.6mmol)和N-甲基吗啉(24ml)的乙腈(300ml)溶液中,加入2-氯-4,6-二甲氧基-1,3,5-三嗪(48.5g,270.5mmol)的乙腈(152ml)的屏蔽溶液。将混合物搅拌22小时,然后加入水(460ml)。过滤收集得到的沉淀,用50%乙腈水溶液(3×100ml)洗涤,在50℃下真空干燥,得到标题化合物(75.6g,90%);NMR光谱:
(DMSO-d6):δ1.45(s,9H),7.17(m,2H),7.56(m,2H),7.81(d,2H),7.99(d,2H),8.11(d,2H),8.69(d,2H),9.94(brs,1H).
质谱:M+H+390。
方法5B
{2-[4-吡啶-4-基苯甲酰基)氨基]苯基}氨基甲酸叔丁基酯
将4-(4-吡啶基)苯甲酸钠(10g,45.2mmol)的乙腈(60ml)溶液加热至70℃,然后加入亚硫酰氯(6.6ml,90.4mmol)。将反应物在回流温度下加热5小时,然后冷却至室温。小心加入三乙胺(12.6ml,90.4mmol),接着用10分钟加入叔丁氧基羰基邻苯二胺(9.42g,45.2mmol)在乙腈(15ml)中的温热溶液。加入氢氧化钠(8.6g,109mmol)的水(60ml)溶液,过滤收集得到的固体,用水(20ml)洗涤,然后在50℃下真空干燥,得到标题化合物(12.6g,68%);NMR光谱:
(DMSO-d6):δ1.45(s,9H),(7.17(m,2H),7.56(m,2H),7.81(d,2H),7.99(d,2H),8.11(d,2H)8.69(d,2H),9.94(brs,1H).
质谱:M+H+390。
方法6A
(2-{[4-(1-{1,3-二甲基-1H-吡唑-4-基甲基}哌啶-4-基)苯甲酰基]氨基}苯基)氨基甲酸叔丁基酯
将{2-[(4-哌啶-4-基苯甲酰基)氨基]苯基}氨基甲酸叔丁基酯(6.83g,17.3mmol)和1,3-二甲基-1H-吡唑-4-甲醛(3.0g,24.2mmol)溶解于二氯甲烷(150ml)中。然后加入乙酸(996μl,17.3mmol),将反应混合物在室温下搅拌4小时。然后加入三乙酰氧基硼氢化钠(5.49g,25.9mmol),将反应混合物再搅拌18小时。然后小心加入饱和碳酸氢钠水溶液(300ml),接着加入二氯甲烷(100ml)。分离有机相,将水层用更多的二氯甲烷(150ml)再提取。将合并的有机提取物经硫酸镁干燥,过滤,蒸发至干。得到的残留物经硅胶快速层析纯化,用5%(v/v)甲醇的二氯甲烷溶液、梯度提高的5-10%(v/v)甲醇的二氯甲烷溶液依次洗脱,得到澄清胶状物,将其溶解于乙醚中,蒸发至干,得到标题化合物(7.61g,87%);NMR光谱:
(DMSOd6)δ1.43(s,9H),1.69(m,4H),1.98(m,2H),2.10(s,3H),2.56(m,1H),2.92(m,2H),3.26(s,2H),3.70(s,3H),7.15(m,2H),7.40(m,3H),7.52(m,2H),7.87(d,2H),8.60(s,1H),9.73(s,1H);
质谱:M+H+504。
方法6B
(2-{[4-(1-{1,3-二甲基-1H-吡唑-4-基甲基}哌啶-4-基)苯甲酰基]氨基}苯基)氨基甲酸叔丁基酯
将2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯(按以上方法4中所述制备;108.1g,273.3mmol)、1,3-二甲基-1H-吡唑-4-甲醛(35.6g,287mmol)和披钯碳(3.09g,1.37mmol)装入一适合的压力容器中。加入四氢呋喃(920ml)、水(54ml)和乙酸(32.8g,546.7mmol),在3巴氢气下,将该搅拌的混合物加热至60℃,直至确信反应完成。然后将混合物冷却至40℃,加入2M氢氧化钠溶液(410ml,820mmol)。冷却至25℃,过滤混合物以除去催化剂,然后加入四氢呋喃(650ml),分离有机相。将有机相通过蒸馏部分浓缩,然后加入甲苯(575ml)。继续蒸馏,同时再加入甲苯(690ml)以保持反应体积。用约3小时,将混合物冷却至室温,期间产物结晶。过滤收集固体,用甲苯(460ml)和乙酸乙酯(230ml)依次洗涤,然后在45℃下真空干燥至恒重,得到标题化合物(114.9g,83%)。光谱:
(DMSOd6),δ1.434(s,9H),1.70(m,4H),1.98(m,2H),2.11(s,3H),2.56(m,1H),2.93(m,2H),3.28(s,2H),3.71(s,3H),7.16(m,2H),7.40(m,3H),7.52(m,2H),7.87(d,2H),8.60(s,1H),9.73(s,1H);
质谱:M+H+504。
方法7
{2-[(4-{1-[(1,5-二甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰基)氨基]苯基}氨基甲酸叔丁基酯
将1,5-二甲基-1H-吡唑-4-甲醛(114mg,0.92mmol)加入到2-[(4-哌啶-4-基苯甲酰基)氨基]苯基氨基甲酸叔丁基酯(289mg,0.73mmol)的二氯甲烷(6ml)的溶液中,接着加入乙酸(50μl,0.87mmol)。在氮气下,将反应混合物搅拌2.5小时。加入三乙酰氧基硼氢化钠(233mg,1.10mmol),将反应混合物在室温下搅拌18小时(过夜)。然后向反应物中加入饱和碳酸氢钠水溶液(10ml),再搅拌15分钟。分离有机相,将水相用二氯甲烷再提取(10ml)。将合并的有机相用水洗涤,经硫酸镁干燥,蒸发至干,得到为无色胶状物的产物(308mg,84%),其无需进一步纯化而使用;质谱:M+H+504。
Claims (7)
1.化合物N-(2-氨基苯基)-4-{1-[(1,3-二甲基-1H-吡唑-4-基)甲基]哌啶-4-基}苯甲酰胺或其药学上可接受的盐。
2.一种药用组合物,其包含权利要求1的化合物或其药学上可接受的盐以及药学上可接受的稀释剂或载体。
3.权利要求1的化合物或其药学上可接受的盐在制备药物中的用途,该药物用于在温血动物中产生HDAC抑制作用。
4.权利要求3的用途,其中所述温血动物为人。
5.权利要求1的化合物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途,其中所述癌症选自肺癌、结肠直肠癌、乳腺癌、前列腺癌、淋巴瘤和/或白血病。
6.权利要求1的化合物或其药学上可接受的盐在制备用于治疗特定类型癌症的药物中的用途,其中所述癌症选自食管癌、骨髓瘤、肝细胞癌、胰腺癌、宫颈癌、尤因氏瘤、成神经细胞瘤、卡波济氏肉瘤、卵巢癌、膀胱癌、黑素瘤、胃癌、头颈癌、脑癌和肾癌。
7.一种制备权利要求1的化合物或其药学上可接受的盐的方法,该方法包括或者:
(a)在还原剂存在下,使式(II)化合物:
其中苯胺部分可被适当地保护;
与式(III)化合物反应
其中R2和R3为甲基,R5为氢;或者
(b)在适当的碱存在下,使如上定义的式(II)化合物与式(IV)化合物反应:
其中R2和R3为甲基,R5为氢,且X是活性基团,所述活性基团选自卤代或磺酰氧基;
然后,如果必要,除去可能存在的任何残留的保护基。
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