CN110719910B - 新的抑制剂 - Google Patents
新的抑制剂 Download PDFInfo
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- CN110719910B CN110719910B CN201880035826.8A CN201880035826A CN110719910B CN 110719910 B CN110719910 B CN 110719910B CN 201880035826 A CN201880035826 A CN 201880035826A CN 110719910 B CN110719910 B CN 110719910B
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- Prior art keywords
- benzodiazol
- mmol
- amine
- ylmethyl
- alkyl
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Abstract
本发明涉及式(I)的化合物:A‑B‑D‑E(I),或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,其中:A选自单环杂芳基和双环杂芳基,其可独立地被烷基或氨基取代;B选自烷基、杂烷基、烷基‑氨基、芳基、杂芳基、环烷基、杂环基和亚烷基,其中所述基团可独立地被烷基取代;D选自芳基‑氨基、杂芳基‑氨基、环烷基‑氨基、杂环基、杂环基‑氨基、脲、硫代酰胺、硫脲、磺酰胺、亚砜亚胺和氨磺酰基,其中所述芳基、杂芳基、环烷基和杂环基可独立地被取代;并且E选自芳基、杂芳基、环烷基、杂环基,其中所述芳基、杂芳基、环烷基和杂环基可独立地被取代。所述式(I)的化合物为谷氨酰胺酰环化酶(QC,EC 2.3.2.5)的抑制剂。QC催化N端谷氨酰胺残基在释放氨的情况下分子内环化为焦谷氨酸(5‑氧代‑脯氨酰,pGlu*),以及N端谷氨酸残基在释放水的情况下分子内环化为焦谷氨酸。
Description
技术领域
本发明涉及作为谷氨酰胺酰环化酶(QC,EC 2.3.2.5)抑制剂的新的杂环衍生物。QC催化N端谷氨酰胺残基在释放氨的情况下分子内环化为焦谷氨酸(5-氧代-脯氨酰,pGlu*),以及N端谷氨酸残基在释放水的情况下分子内环化为焦谷氨酸。
背景技术
谷氨酰胺酰环化酶(QC,EC 2.3.2.5)催化N端谷氨酰胺残基分子内环化为焦谷氨酸(pGlu*),释放氨。QC最初由Messer于1963年从热带植物番木瓜(Carica papaya)的胶乳中分离(Messer,M.1963Nature 4874,1299)。24年后,在动物垂体中发现相应的酶促活性(Busby,W.H.J.等人1987 J Biol Chem 262,8532-8536;Fischer,W.H.和Spiess,J.1987Proc Natl Acad Sci U S A 84,3628-3632)。对于哺乳动物QC,Gln通过QC转化为pGlu可以由TRH和GnRH的前体证实(Busby,W.H.J.等人1987J Biol Chem 262,8532-8536;Fischer,W.H.和Spiess,J.1987Proc Natl Acad Sci U S A 84,3628-3632)。此外,QC的最初定位实验显示与其推定的催化产物共定位于牛垂体中,进一步增进所提出的在肽激素合成中的功能(Bockers,T.M.等人1995J Neuroendocrinol 7,445-453)。相比之下,植物QC的生理功能较不清楚。在来自番木瓜(C.papaya)的酶的情况下,提出在植物防御致病微生物中的作用(El Moussaoui,A.等人2001 Cell Mol Life Sci 58,556-570)。最近,通过序列比较鉴定了来自其他植物的推定的QC(Dahl,S.W.等人2000Protein Expr Purif20,27-36)。然而,这些酶的生理功能尚不明确。
已知的来自植物和动物的QC表现出对底物的N端位置中的L-谷氨酰胺的严格特异性,并且发现它们的动力学行为遵循Michaelis-Menten方程(Pohl,T.等人1991Proc NatlAcad Sci U S A 88,10059-10063;Consalvo,A.P.等人1988Anal Biochem 175,131-138;Gololobov,M.Y.等人1996Biol Chem Hoppe Seyler 377,395-398)。然而,来自番木瓜的QC的一级结构与来自哺乳动物的高度保守的QC的一级结构的比较未显示任何序列同源性(Dahl,S.W.等人2000Protein Expr Purif20,27-36)。而植物QC看来属于新的酶家族(Dahl,S.W.等人2000Protein Expr Purif 20,27-36),发现哺乳动物QC与细菌氨肽酶具有显著的序列同源性(Bateman、R.C.等人2001Biochemistry 40,11246-11250),从而得出结论来自植物和动物的QC具有不同的进化起源。
最近,据证实重组人QC以及来自脑提取物的QC-活性均催化N端谷氨酰胺酰以及谷氨酸环化。最出人意料的是发现约pH 6.0有利于环化酶催化的Glu1-转化,而Gln1-转化为pGlu-衍生物发生在约8.0的最佳pH。因为抑制重组人QC和来自猪垂体提取物的QC-活性可以抑制pGlu-Aβ-相关肽的形成,所以酶QC是用于治疗阿尔茨海默病的药物开发的靶标。
QC的抑制剂例如描述于WO 2004/098625、WO 2004/098591、WO 2005/039548、WO2005/075436、WO 2008/055945、WO 2008/055947、WO 2008/055950、WO2008/065141、WO2008/110523、WO 2008/128981、WO 2008/128982、WO 2008/128983、WO 2008/128984、WO2008/128985、WO 2008/128986、WO 2008/128987、WO 2010/026212、WO 2011/029920、WO2011/107530、WO 2011/110613、WO 2011/131748和WO 2012/123563。
EP 02 011 349.4公开编码昆虫谷氨酰胺酰环化酶的多核苷酸,以及由其编码的多肽和它们在筛选降低谷氨酰胺酰环化酶活性的物质的方法中的用途。这类物质用作杀虫剂。
定义
术语“ki”或“KI”和“KD”为结合常数,其描述抑制剂结合至酶以及随后从酶释放。另一量度为“IC50”值,其反映在给定的底物浓度下导致50%酶活性的抑制剂浓度。
术语“DP V-抑制剂”或“二肽基肽酶IV抑制剂”是本领域技术人员公知的,并且表示抑制DP IV或DP IV样酶的催化活性的酶抑制剂。
“DP IV-活性”定义为二肽基肽酶IV(DP IV)和DP IV样酶的催化活性。这些酶是在哺乳动物身体的各种组织(包括肾、肝和肠)中发现的脯氨酸后(较少程度地,丙氨酸后、丝氨酸后或甘氨酸后)切割丝氨酸蛋白酶,其中当脯氨酸或丙氨酸形成与生物活性肽序列中的N端氨基酸相邻的残基时,它们高度特异性地从生物活性肽的N端去除二肽。
术语“PEP-抑制剂”或“脯氨酰内肽酶抑制剂”是本领域技术人员公知的,并且表示抑制脯氨酰内肽酶(PEP、脯氨酰寡肽酶、POP)的催化活性的酶抑制剂。
“PEP-活性”定义为能够水解肽或蛋白中脯氨酸后的键的内切蛋白酶的催化活性,其中所述脯氨酸位于从肽或蛋白底物的N端数起第3或更高的氨基酸位置。
如本文所用,术语“QC”包括谷氨酰胺酰环化酶(QC)和QC样酶。QC和QC样酶具有相同或相似的酶促活性,进一步定义为QC活性。在这方面,QC样酶在它们的分子结构上可以完全不同于QC。QC样酶的实例为来自人(GenBank NM_017659)、小鼠(GenBank BC058181)、食蟹猴(Macaca fascicularis)(GenBank AB168255)、猕猴(Macaca mulatta)(GenBank XM_001110995)、犬(Canis familiaris)(GenBank XM_541552)、褐家鼠(Rattus norvegicus)(GenBank XM_001066591)、小家鼠(Mus musculus)(GenBank BC058181)和牛(Bos taurus)(GenBank BT026254)的谷氨酰胺酰肽环化转移酶样蛋白(QPCTL)。
如本文所用,术语“QC活性”定义为在释放氨的情况下,N端谷氨酰胺残基分子内环化为焦谷氨酸(pGlu*),或者N端L-高谷氨酰胺或L-β-高谷氨酰胺分子内环化为环焦高谷氨酰胺衍生物。因此,参见路线1和2。
路线1:谷氨酰胺通过QC环化
路线2:L-高谷氨酰胺通过QC环化
如本文所用,术语“EC”包括QC和QC样酶作为谷氨酸环化酶(EC)的活性,进一步定义为EC活性。
如本文所用,术语“EC活性”定义为N端谷氨酸残基通过QC分子内环化为焦谷氨酸(pGlu*)。因此,参见路线3。
路线3:不带电的谷氨酰肽通过QC(EC)N端环化
术语“QC抑制剂”、“谷氨酰胺酰环化酶抑制剂”是本领域技术人员公知的,并且表示抑制谷氨酰胺酰环化酶(QC)的催化活性或其谷氨酰环化酶(EC)活性的酶抑制剂。
QC抑制的效力
鉴于与QC抑制的关系,在优选的实施方案中,本发明的主题方法和医学用途利用QC抑制的IC50为10μM或更小,更优选1μM或更小,甚至更优选0.1μM或更小或者0.01μM或更小,或者最优选0.001μM或更小的物质。实际上,期望Ki值在较低微摩尔,优选纳摩尔,并且甚至更优选皮摩尔范围内的抑制剂。因此,尽管本文为了方便将活性物质描述为“QC抑制剂”,但是应当理解这样的命名不是为了将本发明的主题限于特定的作用机制。
QC抑制剂的分子量
一般来说,本发明的主题方法或医学用途的QC抑制剂为小分子,例如,具有500g/摩尔或更小、400g/摩尔或更小、优选350g/摩尔或更小、并且甚至更优选300g/摩尔或更小、甚至250g/摩尔或更小的分子量。
如本文所用,术语“个体”指为治疗、观察或实验的对象的动物,优选哺乳动物,最优选人。
如本文所用,术语“治疗有效量”表示在组织系统、动物或人中引起研究者、兽医、医生或其他临床医师所寻求的生物学或医学反应(其包括所治疗的疾病或病症的症状的缓解)的活性化合物或药剂的量。
如本文所用,术语“药学可接受的”包括人和兽医用途:例如术语“药学可接受的”包括兽医学可接受的化合物,或者在人类医学和保健中可接受的化合物。
在整个说明书和权利要求书中,除非特别限定,表述“烷基”表示C1-12烷基,适合地表示C1-8烷基,例如C1-6烷基,例如C1-4烷基。烷基可以是直链或支链的。合适的烷基包括例如甲基、乙基、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、仲丁基和叔丁基)、戊基(例如正戊基)、己基(例如正己基)、庚基(例如正庚基)以及辛基(例如正辛基)。例如在表述“烷氧基”、“卤代烷基”和“硫烷基”中,表述“烷”应按照“烷基”的定义解释。示例性烷氧基包括甲氧基、乙氧基、丙氧基(例如正丙氧基)、丁氧基(例如正丁氧基)、戊氧基(例如正戊氧基)、己氧基(例如正己氧基)、庚氧基(例如正庚氧基)以及辛氧基(例如正辛氧基)。示例性硫烷基包括甲硫基。示例性卤代烷基包括氟烷基,例如CF3。
除非特别限定,表述“亚烷基”表示式-(CH2)n-的链,其中n为整数,例如1-5。
除非特别限定,表述“环烷基”表示C3-10环烷基(即3-10个环碳原子),更适合地表示C3-a环烷基,例如C3-6环烷基。示例性环烷基包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。最合适的环碳原子数目为3-6个。
除非特别限定,表述“杂环基”是指碳环基团,其中一个或多个(例如1个、2个或3个)环原子被选自N、S和O的杂原子代替。杂环基的具体实例是其中一个或多个(例如1个、2个或3个,特别是1个或2个,尤其是1个)环原子被选自N、S或O的杂原子代替的环烷基(例如环戊基或更特别地是环己基)。包含一个杂原子的示例性杂环基包括吡咯烷、四氢呋喃和哌啶;而包含两个杂原子的示例性杂环基包括吗啉、哌嗪、二氧戊环和二氧六环。杂环基的其他具体实例是其中一个或多个(例如1个、2个或3个,特别是1个或2个,尤其是1个)环原子被选自N、S和O的杂原子代替的环烯基(例如环己烯基)。这样的基团的实例为二氢吡喃基(例如3,4-二氢-2H-吡喃-2-基-)。
除非特别限定,表述“芳基”表示C6-12芳基,适合地表示C6-10芳基,更适合地表示C6-8芳基。芳基包含至少一个芳环(例如1个、2个或3个环)。具有一个芳环的典型芳基的实例为苯基。具有两个芳环的典型芳基的实例为萘基。
除非特别限定,表述“杂芳基”表示芳基残基,其中一个或多个(例如1个、2个、3个或4个,适合地1个、2个或3个)环原子被选自N、S和O的杂原子代替,或者表示包含一个或多个(例如1个、2个、3个或4个,适合地为1个、2个或3个)选自N、S和O的环原子的5元芳环。具有一个杂原子的示例性单环杂芳基包括:五元环(例如吡咯、呋喃、噻吩);以及六元环(例如吡啶,如吡啶-2-基、吡啶-3-基和吡啶-4-基)。具有两个杂原子的示例性单环杂芳基包括:五元环(例如吡唑、噁唑、异噁唑、噻唑、异噻唑、咪唑,如咪唑-1-基、咪唑-2-基、咪唑-4-基);六元环(例如哒嗪、嘧啶、吡嗪)。具有三个杂原子的示例性单环杂芳基包括:1,2,3-三唑和1,2,4-三唑。具有四个杂原子的示例性单环杂芳基包括四唑。示例性双环杂芳基包括:吲哚(例如吲哚-6-基)、苯并呋喃、苯并噻吩、喹啉、异喹啉、吲唑、苯并咪唑、苯并噻唑、喹唑啉以及嘌呤。
除非特别限定,表述“-烷基芳基”表示通过亚烷基部分(例如C1-4亚烷基部分)连接的芳基残基。
除非特别限定,表述“-烷基杂芳基”表示通过亚烷基部分(例如C1-4亚烷基部分)连接的杂芳基残基。
术语“卤素”或“卤代”包括氟(F)、氯(Cl)和溴(Br)。
术语“氨基”是指基团-NH2。
当苯并咪唑基显示为以下式表示的苯并咪唑-5-基时:
本领域技术人员应当理解,以下式所表示的苯并咪唑-6-基:
是等价的结构。如本文所用,术语“苯并咪唑-5-基”涵盖苯并咪唑基的这两种形式。
立体异构体
所要求保护的化合物的所有可能的立体异构体均包括在本发明中。
当本发明的化合物具有至少一个手性中心时,它们可以相应地作为对映体存在。当所述化合物具有两个或更多个手性中心时,它们还可以作为非对映体存在。应当理解所有此类异构体及其混合物均涵盖在本发明的范围内。
立体异构体的制备和分离
当用于制备本发明的化合物的方法产生立体异构体的混合物时,这些异构体可以通过诸如制备色谱法的常规技术进行分离。所述化合物可以外消旋形式制备,或者单独的对映体可以通过对映体特异性合成或者通过拆分来制备。例如,可以将所述化合物通过标准技术拆分为它们的组分对映体,例如,通过与诸如(-)-二-对甲苯酰-d-酒石酸和/或(+)-二-对甲苯酰-1-酒石酸的旋光酸形成盐来形成非对映异构体对,然后分级结晶并重新产生游离碱。所述化合物还可以通过形成非对映的酯或酰胺来拆分,然后色谱分离并去除手性助剂。或者,可以利用手性HPLC柱拆分所述化合物。
药学可接受的盐
鉴于游离的化合物与它们的盐或溶剂合物形式的化合物之间的密切关系,在本文中无论何时提到化合物,还意指相应的盐、溶剂合物或多晶型物,只要在这种情况下是可能的或适当的。
适合用于药物的式(I)的化合物的盐和溶剂合物及其生理功能衍生物是其中反荷离子或相关溶剂是药学可接受的那些。然而,具有非药学可接受的反荷离子或相关溶剂的盐和溶剂合物在本发明的范围内,例如,在其他化合物及它们的药学可接受的盐和溶剂合物的制备中用作中间体。
本发明的合适的盐包括与有机和无机酸或碱形成的盐。药学可接受的酸加成盐包括与以下酸形成的酸加成盐:盐酸、氢溴酸、硫酸、硝酸、柠檬酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、三氟乙酸、三苯基乙酸、氨基磺酸、对氨基苯磺酸、琥珀酸、草酸、富马酸、马来酸、苹果酸、扁桃酸、谷氨酸、天冬氨酸、草酰乙酸、甲磺酸、乙磺酸、芳基磺酸(例如对甲苯磺酸、苯磺酸、萘磺酸或萘二磺酸)、水杨酸、戊二酸、葡糖酸、丙三羧酸、肉桂酸、取代的肉桂酸(例如,苯基、甲基、甲氧基或卤素取代的肉桂酸,包括4-甲基肉桂酸和4-甲氧基肉桂酸)、抗坏血酸、油酸、萘甲酸、羟基萘甲酸(例如1-羟基-2-萘甲酸或3-羟基-2-萘甲酸)、萘丙烯酸(例如萘-2-丙烯酸)、苯甲酸、4-甲氧基苯甲酸、2-羟基苯甲酸或4-羟基苯甲酸、4-氯苯甲酸、4-苯基苯甲酸、苯丙烯酸(例如1,4-苯二丙烯酸)、羟乙磺酸、高氯酸、丙酸、羟乙酸、羟乙磺酸、双羟萘酸、环己烷氨基磺酸、水杨酸、糖精酸和三氟乙酸。药学可接受的碱盐包括:铵盐;碱金属盐,如钠盐和钾盐;碱土金属盐,如钙盐和镁盐;以及与诸如二环己基胺和N-甲基-D-萄糖胺的有机碱的盐。
本发明的化合物的所有药学可接受的酸加成盐形式均意图包括在本发明的范围内。
多晶型物晶形
此外,所述化合物的一些晶形可以作为多晶型物存在,并且因此意图包括在本发明中。此外,一些所述化合物可以与水(即水合物)或常用的有机溶剂形成溶剂合物,并且这类溶剂合物也意图包括在本发明的范围内。所述化合物,包括它们的盐,还可以它们的水合物形式获得,或者包含用于它们的结晶的其他溶剂。
前药
本发明在其范围内进一步包括本发明的化合物的前药。一般来说,这类前药是在体内易于转化为期望的治疗活性化合物的所述化合物的官能衍生物。因此,在这些情况下,本发明的治疗方法,术语“给药”应当包括用一种或多种所要求保护的化合物的前药形式治疗各种所述病症,但是所述前药形式在给药个体之后在体内转化为上述化合物。选择和制备合适的前药衍生物的常规方法描述于例如“Design of Prodrugs”,ed.H.Bundgaard,Elsevier,1985。
保护基团
在制备本发明的化合物的任何方法中,可能需要和/或期望保护任何有关分子上的敏感或反应基团。这可以通过常规的保护基团的方式实现,例如Protective Groups inOrganic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973;和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991所述的保护基团,全文援引加入本文。保护基团可以在方便的后续阶段利用本领域已知的方法去除。
如本文所用,术语“组合物”意图包括包含治疗有效量的所要求保护的化合物的产品,以及直接或间接得自所要求保护的化合物的组合的任何产品。
用于盖仑制剂的载体和添加剂
因此,对于液体口服制剂,例如混悬剂、酏剂和溶液剂,合适的载体和添加剂可以有利地包括水、乙二醇、油、醇、增香剂、防腐剂、着色剂等;对于固体口服制剂,例如散剂、胶囊剂、软胶囊剂和片剂,合适的载体和添加剂包括淀粉、糖、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
可以加入混合物的载体包括必需的和惰性的药学赋形剂,包括但不限于合适的粘合剂、悬浮剂、润滑剂、香料、甜味剂、防腐剂、包衣、崩解剂、染料以及着色剂。
作为可靶向的药物载体的可溶性聚合物可以包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺酚、聚羟乙基天冬酰胺-酚或者用棕榈酰残基取代的聚环氧乙烷聚赖氨酸。此外,本发明的化合物可以偶联至用于实现药物的控释的一类生物可降解的聚合物,例如聚乳酸、聚ε己内酯、聚羟基丁酸(polyhydroxy butyeric acid)、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯以及交联或两亲的水凝胶嵌段共聚物。
合适的粘合剂非限制性地包括淀粉,明胶,诸如葡萄糖或β乳糖的天然糖类,玉米甜味剂,诸如阿拉伯胶、黄芪胶的天然和合成树胶或者油酸钠,硬脂酸钠,硬脂酸镁,苯甲酸钠,乙酸钠,氯化钠等。
崩解剂非限制性地包括淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
发明内容
本发明提供式(I)的化合物:
A-B-D-E (I)
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,其中:
A选自单环杂芳基和双环杂芳基,其可独立地被烷基或氨基取代;
B选自烷基、杂烷基、烷基-氨基、芳基、杂芳基、环烷基、杂环基和亚烷基,其中所述基团可独立地被烷基取代;
D选自芳基-氨基、杂芳基-氨基、环烷基-氨基、杂环基、杂环基-氨基、脲、硫代酰胺、硫脲、磺酰胺和亚砜亚胺,其中所述芳基、杂芳基、环烷基和杂环基可独立地被一个或多个取代基取代;
在另一实施方案中,D为氨磺酰基;
E选自芳基、杂芳基、环烷基、杂环基,其中所述芳基、杂芳基、环烷基和杂环基可独立地被一个或多个取代基取代。
在优选的实施方案中提供式(I)的化合物,条件是:
i)当B为烷基或杂烷基时,则D不可以是磺酰胺;并且
ii)所述式(I)的化合物不是选自下列的化合物:
条件i)的化合物由CAS Registrv数据库已知(无任何功能定义),并且选自:
在根据条件i)的优选的实施方案中,所述式(I)的化合物不是选自化合物A至U的化合物。
条件ii)的化合物V由CAS Registry已知(CAS No.2117405-13-5,无功能定义)。条件ii)的化合物W由CAS Registry已知(CAS No.1090606-68-0,无功能定义)。条件ii)的化合物W由CAS Registry已知(CAS No.2093539-54-7,无功能定义)。
当A为单环杂芳基时,A优选选自噻二唑基(例如1,3,4-噻二唑基)、噻唑基和三唑基(例如1,2,4-三唑基)。在本发明的一个实施方案中,所述单环杂芳基被氨基或甲基取代。在另一实施方案中,所述单环杂芳基未被取代。
当环烷基和杂环基被取代时,它们典型地被1个或2个取代基(例如1个取代基)取代。典型地,所述取代基为C1-6烷基(即甲基)或卤素(即氯或氟)。更典型地,环烷基和杂环基是未被取代的。
当芳基和杂芳基被取代时,它们典型地被1个、2个或3个取代基(例如1个或2个)取代。芳基和杂芳基的取代基选自C1-6烷基(例如甲基)、C2-6烯基(例如丁烯-3-基)、C2-6炔基(例如丁炔-3-基)、C1-6卤代烷基(例如氟甲基、三氟甲基)、-C1-6硫烷基(例如-S-甲基)、-SOC1-4烷基(例如-SO甲基)、-SO2C1-4烷基(例如-SO2甲基)、C1-6烷氧基-(例如甲氧基、乙氧基)、-O-C3-8环烷基(例如-O-环戊基或-O-环己基)、C3-8环烷基(例如环丙基、环己基)、-SO2C3-8环烷基(例如-SO2环己基)、-8OC3-6环烷基(例如-SO环丙基)、-O-芳基(例如-O-苯基)、C3-6烯基氧基-(例如-O-丁烯-2-基)、C3-6炔基氧基-(例如-O-丁烯-2-基)、-C(O)C1-6烷基(例如-C(O)乙基)、-C(O)OC1-6烷基(例如-C(O)O-甲基)、C1-6烷氧基-C1-6烷基-(例如甲氧基-乙基-)、硝基、卤素(例如氟、氯、溴)、氰基、羟基、-C(O)OH、-NH2、-NHC1-4烷基(例如-NH甲基)、-N(C1-4烷基)(C1-4烷基)(例如-N(甲基)2)、-C(O)N(C1-4烷基)(C1-4烷基)(例如-C(O)N(甲基)2)、-C(O)NH2、-C(O)NH(C1-4烷基)(例如-C(O)NH甲基)、-C(O)NH(C3-10环烷基)(例如-C(O)NH环丙基)。更典型地,取代基选自C1-6烷基(例如甲基)、C1-6卤代烷基(例如C1-6氟烷基,例如CF3)、C1-6烷氧基(例如OMe)、卤素和羟基。
当E表示芳基时,所述芳基适合地表示任选地被取代的苯基。E的示例性取代的苯基包括2-溴苯基、2-溴-4-氟苯基-、2-溴-5-氟苯基-、2-氟-5-溴苯基、2-氯苯基-、2-氟苯基-、3-氯苯基-、3-溴苯基-、3-氟苯基-、4-氯苯基-、4-氟苯基-、4-溴苯基-、4-溴-2-氟苯基、2-氯-3,6-二氟苯基)、2,3-二氯苯基-、2,3-二氟苯基-、2,3,4-三氟苯基、2,3,5-三氟苯基、2,4-二氯苯基-、2,4-二氟苯基-、2,4,6-三氟苯基-、2,5-二氯苯基-、2,6-二氯苯基-、2,6-二氟苯基-、3,4-二氯苯基-、3,4-二氟苯基-、3,5-二氟苯基-、2,4,5-三氟苯基-、3,4,5-三氟苯基-、2,4-二甲基苯基-、3-甲基苯基-、3,4-二甲基苯基-、4-甲基苯基-、4-异丙基苯基-、4-叔丁基苯基-、2,4,6-三甲基苯基-、2-异丙基-6-甲基苯基-、2-(三氟甲基)苯基-、4-(三氟甲基)苯基-、2,4-双(三氟甲基)苯基-、3,5-双(三氟甲基)苯基-、2-甲氧基苯基-、2,4-二甲氧基苯基-、2,6-二甲氧基苯基-、3-甲氧基苯基-、4-甲氧基苯基-、4-乙氧基苯基-、4-丙氧基苯基-、4-丁氧基苯基-、4-戊氧基苯基-、4-异丙氧基苯基-、3-(环戊基氧基)-4-甲氧基苯基-、3,4,5-三甲氧基苯基-、3,4-二甲氧基苯基-、3,5-二甲氧基苯基-、4-四氟乙氧基苯基、4-氰基苯基-、4-硫甲基苯基-以及4-二甲基氨基苯基。或者,E可以表示未取代的苯基-。其他示例性取代的苯基包括2,3-二氟-4-甲基苯基、2-氟-5-(三氟甲基)苯基-、2-羟基-3-甲氧基苯基-、2-羟基-5-甲基苯基-、3-氟-4-(三氟甲基)苯基-、3-氟-5-(三氟甲基)苯基-、2-氟-4-(三氟甲基)苯基-、2-氟-3-(甲基)苯基-、3-氟-4-(甲氧基)苯基-、3-羟基-4-甲氧基苯基-、4-氯-3-(三氟甲基)苯基-、4-氯-3-甲基苯基、4-溴-4-乙基苯基、2,3,5,6-四氟-4-(甲基)苯基-、2,6-二氟-4-(甲氧基)苯基-以及2-氟-4,5-(二甲氧基)苯基-。
当E表示任选地被取代的杂芳基时,实例包括吡啶基(例如吡啶-2-基和吡啶-4-基)和嘧啶基。可提及的具体取代基为选自卤素、羟基、烷基(例如甲基)和烷氧基-(例如甲氧基-)的一个或多个(例如1个、2个或3个)基团。取代的环的实例为1-氧基-吡啶-4-基-。
在更优选的实施方案中,当A为单环杂芳基时,A选自:
在最优选的实施方案中,当A为单环杂芳基时,A为
在另一最优选的实施方案中,当A为单环杂芳基时,A为
在另一最优选的实施方案中,当A为单环杂芳基时,A为
当A为双环杂芳基时,A优选选自苯并咪唑和咪唑并吡啶,例如咪唑并[1,2-a]吡啶。
在更优选的实施方案中,当A为双环杂芳基时,A选自:
在最优选的实施方案中,当A为双环杂芳基时,A为/>
在另一最优选的实施方案中,当A为双环杂芳基时,A为
在另一最优选的实施方案中,当A为双环杂芳基时,A为
在优选的实施方案中,B选自C3-5-杂烷基、苯基、C5-C6-杂环基和C1-5亚烷基,其中所述C1-5亚烷基可独立地被烷基取代。
更优选地,B选自:
其中X1为烷基、N、O或S,优选为甲基或S;并且n为选自1和2的整数;
其中o为0或1;并且p为0或1;和
其中R1为氢或烷基,并且q为0、1或2。
在最优选的实施方案中,B为
其中X1和n如上文所定义。
在另一最优选的实施方案中,B为
其中o如上文所定义。
在另一最优选的实施方案中,B为
其中R1和p如上文所定义。
在优选的实施方案中,D为选自下列的基团:
以及/>
其中
R不存在或者为氢;或者R连同氮原子共同形成基团B的杂环;
R2为氢、烷基或环烷基;
Y1、Y2、Y3和Y4独立地选自CH、N、S和O。
当D为
时,R优选不存在并且R2优选为氢或烷基。
当D为
时,
R优选为氢。
在另一实施方案中,D为
其中R为氢或烷基。
在另一优选的实施方案中,当D为上述基团之一时,R连同其所连接的氮共同形成基团B的杂环。更优选地,由NR基团形成的所述杂环选自哌啶、吡咯烷、四氢呋喃、吗啉、哌嗪、二氧戊环和二氧六环。最优选地,当D为上述基团之一时,R连同其所连接的氮共同形成具有以下结构的哌啶环:
当D为
时,
Y1至Y4优选为CH或N。
在更优选的实施方案中,Y1至Y4全部为CH。
甚至更优选地,Y1至Y4之一为N,并且另外三个为CH。
在另一更优选的实施方案中,Y1至Y4中两个为N,并且另外两个为CH。
更优选地,Y1,至Y4中三个为N,并且另一个为CH。
更优选地,Y1至Y4全部为N。
当Y4为CH时,Y4可被取代或未被取代。
在优选的实施方案中,Y4为CH并且未被取代。
在另一优选的实施方案中,Y4为CH并且被取代。
当Y4为CH并且被取代时,Y4优选被卤素或烷基取代,最优选被氟或甲基取代。
E优选为
其中
Y5为C;
Y6-Y10独立地选自CH、N或O,并且
R3、R4、R5、R6和R7独立地选自氢、卤素、烷基、O-烷基。
在优选的实施方案中,Y6-Y10独立地选自CH和N。
在优选的实施方案中,R3、R4、R5、R6和R7独立地选自氢、卤素和O-烷基。
在另一优选的实施方案中,R3、R4、R5、R6和R7独立地选自O-苯基和O-环烷基。
当R3、R4、R5、R6和R7独立地为卤素时,R3、R4、R5、R6和R7优选为氟或氯,最优选为氟。
当R3、R4、R5、R6和R7独立地为O-烷基时,R3、R4、R5、R6和R7为O-C1-4烷基,优选为甲氧基、乙氧基、丙氧基或丁氧基,更优选为甲氧基或丙氧基。
当R3、R4、R5、R6和R7独立地为O-烷基时,R3、R4、R5、R6和R7更最优选为甲氧基。
R3、R4、R5、R6和R7可独立地被取代或未被取代。优选地,R3-R7中至多三个被取代,且另外的为氢。
在最优选的实施方案中,E表示吡啶环,其中Y6-Y10之一为N,并且另外的为CH。
在另一最优选的实施方案中,E表示吡啶环,其中Y6-Y10中两个为N,并且另外的为CH。
所述嘧啶环可任选地被卤素或烷基(优选氟和甲氧基)取代。
在特别优选的实施方案中提供式(I)的化合物,其为式(IIa)或式(IIb)的化合物:
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或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
Z选自CH和N;
X1选自烷基、N、O、S,优选选自CH2和S;
n为1或2;
Y1至Y4和Y6至Y10独立地选自CH、N、S和O,优选选自CH和N,
Y5为C;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
在优选的实施方案中,Z为CH。
在另一优选的实施方案中,Z为N。
最优选地,X1为CH2.
另外最优选地,X1为S。
最优选地,n为1。
优选地,Y1、Y2、Y3和Y4中的一个、两个、三个或全部四个为N。
在更优选的实施方案中,
·Y1、Y2、Y3和Y4为CH;或者
·Y1为N并且Y2、Y3和Y4为CH;或者
·Y1和Y2为N并且Y3和Y4为CH;或者
·Y1为CH,Y2为N并且Y3和Y4为CH;或者
·Y1和Y3为N并且Y2和Y4为CH;或者
·Y1和Y3为CH并且Y2和Y4为N;或者
·Y1和Y2为CH并且Y3和Y4为N;或者
·Y1、Y2和Y3为CH并且Y4为N。
优选地,Y6至Y10中的一个或两个为N,并且Y6至Y10中的其他者为CH。
在更优选的实施方案中,
·Y6、Y7、Y8、Y9和Y10为CH;或者
·Y6为N并且Y7、Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为N,Y7、Y8、Y9为CH并且Y10为N;或者
·Y6和Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N,Y8为CH,Y9为N并且Y10为CH;或者
·Y6和Y7为CH,Y8为N,Y9为CH并且Y10为N;或者
·Y6和Y7为CH,Y8为N,Y9和Y10为CH;或者
·Y6为N,Y7和Y8为CH,Y9为N并且Y10为CH;或者
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5和R6均为氢;或者
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(IIIa)或式(IIIb)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
X1选自烷基、N、O、S;
n为1或2;
Y1至Y4和Y6至Y10独立地选自CH、N、S和O,优选选自CH和N,
Y5为C;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
最优选地,X1为CH2。
另外最优选地,X1为S。
最优选地,n为1。
优选地,Y1、Y2、Y3和Y4中的一个、两个、三个或全部四个为N。
在更优选的实施方案中,
·Y1、Y2、Y3和Y4为CH;或者
·Y1为N并且Y2、Y3和Y4为CH;或者
·Y1和Y2为N并且Y3和Y4为CH;或者
·Y1为CH,Y2为N并且Y3和Y4为CH;或者
·Y1和Y3为N并且Y2和Y4为CH;或者
·Y1和Y3为CH并且Y2和Y4为N;或者
·Y1和Y2为CH并且Y3和Y4为N;或者
·Y1、Y2和Y3为CH并且Y4为N。
优选地,Y6至Y10中的一个或两个为N,并且Y6至Y10中的其它者为CH。
在更优选的实施方案中,
·Y6、Y7、Y8、Y9和Y10为CH;或者
·Y6为N并且Y7、Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为N,Y7、Y8、Y9为CH并且Y10为N;或者
·Y6和Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N,Y8为CH,Y9为N并且Y10为CH;或者
·Y6和Y7为CH,Y8为N,Y9为CH并且Y10为N;或者
·Y6和Y7为CH,Y8为N,Y9和Y10为CH;或者
·Y6为N,Y7和Y8为CH,Y9为N并且Y10为CH;或者
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5和R6均为氢;或者
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(IVa)或式(IVb)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
Z选自CH和N;
o为0或1;
p为0或1;
Y1至Y4和Y6至Y10独立地选自CH、N、S和O,优选选自CH和N,
Y5为C;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
在另一实施方案中,R5为O-苯基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
在优选的实施方案中,Z为CH。
在另一优选的实施方案中,Z为N。
最优选地,o为0。
最优选地,p为0。
在另一最优选的实施方案中,p为1。
优选地,Y1、Y2、Y3和Y4中的一个、两个、三个或全部四个为N。
在更优选的实施方案中,
·Y1、Y2、Y3和Y4为CH;或者
·Y1为N并且Y2、Y3和Y4为CH;或者
·Y1和Y2为N并且Y3和Y4为CH;或者
·Y1为CH,Y2为N并且Y3和Y4为CH;或者
·Y1和Y3为N并且Y2和Y4为CH;或者
·Y1和Y3为CH并且Y2和Y4为N;或者
·Y1和Y2为CH并且Y3和Y4为N;或者
·Y1、Y2和Y3为CH并且Y4为N。
优选地,Y6至Y10中的一个或两个为N,并且Y6至Y10中的其它者为CH。
在更优选的实施方案中,
·Y6、Y7、Y8、Y9和Y10为CH;或者
·Y6为N并且Y7、Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为N,Y7、Y8、Y9为CH并且Y10为N;或者
·Y6和Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N,Y8为CH,Y9为N并且Y10为CH;或者
·Y6和Y7为CH,Y8为N,Y9为CH并且Y10为N;或者
·Y6和Y7为CH,Y8为N,Y9和Y10为CH;或者
·Y6为N,Y7和Y8为CH,Y9为N并且Y10为CH;或者
R5优选为氢、氟或甲氧基。
更优选地,R5为丙氧基或O-苯基。
R6优选为氢或甲氧基。
更优选地,
·R5和R6均为氢;或者
·R5为氟并且R6为氢;或者
·R5为甲氧基并且R6为氢;或者
·R5和R6均为甲氧基;或者
·R5为丙氧基并且R6为氢;或者
·R5为O-苯基并且R6为氢;或者。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(Va)或式(Vb)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
o为0或1;
p为0或1;
Y1至Y4和Y6至Y10独立地选自CH、N、S和O,优选选自CH和N,
Y5为C;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
在另一实施方案中,R5为O-苯基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
在优选的实施方案中,Z为CH。
在另一优选的实施方案中,Z为N。
最优选地,o为0。
最优选地,p为0。
在另一最优选的实施方案中,p为1。
优选地,Y1、Y2、Y3和Y4中的一个、两个、三个或全部四个为N。
在更优选的实施方案中,
·Y1、Y2、Y3和Y4为CH;或者
·Y1为N并且Y2、Y3和Y4为CH;或者
·Y1和Y2为N并且Y3和Y4为CH;或者
·Y1为CH,Y2为N并且Y3和Y4为CH;或者
·Y1和Y3为N并且Y2和Y4为CH;或者
·Y1和Y3为CH并且Y2和Y4为N;或者
·Y1和Y2为CH并且Y3和Y4为N;或者
·Y1和Y2为CH;Y3为N并且Y4为CH,或者
·Y1、Y2和Y3为CH并且Y4为N。
优选地,Y6至Y10中的一个或两个为N,并且Y6至Y10中的其他者为CH。
在更优选的实施方案中,
·Y6、Y7、Y8、Y9和Y10为CH;或者
·Y6为N并且Y7、Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为N,Y7、Y8、Y9为CH并且Y10为N;或者
·Y6和Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N,Y8为CH,Y9为N并且Y10为CH;或者
·Y6和Y7为CH,Y8为N,Y9为CH并且Y10为N;或者
·Y6和Y7为CH,Y8为N,Y9和Y10为CH;或者
·Y6为N,Y7和Y8为CH,Y9为N并且Y10为CH;或者
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5和R6均为氢;或者
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(VI)的化合物:
/>
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
Z选自CH和N;
X1选自烷基、N、O、S,优选选自CH2或S;
n为1或2;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
在优选的实施方案中,Z为CH。
在另一优选的实施方案中,Z为N。
最优选地,X1为CH2。
另外最优选地,X1为S。
最优选地,n为1。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(VII)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
Z选自CH和N;
X1选自烷基、N、O、S,优选选自CH2或S;
n为1或2;
R2选自烷基和环烷基,优选选自甲基和环丙基;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
在优选的实施方案中,Z为CH。
在另一优选的实施方案中,Z为N。
最优选地,X1为CH2。
另外最优选地,X1为S。
最优选地,n为1。
在优选的实施方案中,R2为甲基。
在另一优选的实施方案中,R2为环丙基。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(VIII)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
X1选自烷基、N、O、S,优选选自CH2或S;
n为1或2;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
最优选地,X1为CH2。
另外最优选地,X1为S。
最优选地,n为1。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(IX)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
X1选自烷基、N、O、S,优选选自CH2或S;
n为1或2;
R2选自烷基和环烷基,优选选自甲基和环丙基;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
最优选地,X1为CH2。
另外最优选地,X1为S。
最优选地,n为1。
在优选的实施方案中,R2为甲基。
在另一优选的实施方案中,R2为环丙基。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(X)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
o为0或1;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
最优选地,o为0。
最优选地,p为0。
甚至更优选地,p为1。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(XI)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
o为0或1;
R2选自烷基和环烷基,优选选自甲基和环丙基;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
最优选地,o为0。
最优选地,p为0。
甚至更优选地,p为1。
在优选的实施方案中,R2为甲基。
在另一优选的实施方案中,R2为环丙基。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(XIIa)或式(XIIb)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
Z选自CH和N;
Y1至Y4和Y6至Y10独立地选自CH、N、S和O,优选选自CH和N,
Y5为C;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
在优选的实施方案中,Z为CH。
在另一优选的实施方案中,Z为N。
优选地,Y1、Y2、Y3和Y4中的一个、两个、三个或全部四个为N。
在更优选的实施方案中,
·Y1、Y2、Y3和Y4为CH;或者
·Y1为N并且Y2、Y3和Y4为CH;或者
·Y1和Y2为N并且Y3和Y4为CH;或者
·Y1为CH,Y2为N并且Y3和Y4为CH;或者
·Y1和Y3为N并且Y2和Y4为CH;或者
·Y1和Y3为CH并且Y2和Y4为N;或者
·Y1和Y2为CH并且Y3和Y4为N;或者
·Y1、Y2和Y3为CH并且Y4为N。
优选地,Y6至Y10中的一个或两个为N,并且Y6至Y10中的其他者为CH。
在更优选的实施方案中,
·Y6、Y7、Y8、Y9和Y10为CH;或者
·Y6为N并且Y7、Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为N,Y7、Y8、Y9为CH并且Y10为N;或者
·Y6和Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N,Y8为CH,Y9为N并且Y10为CH;或者
·Y6和Y7为CH,Y8为N,Y9为CH并且Y10为N;或者
·Y6和Y7为CH,Y8为N,Y9和Y10为CH;或者
·Y6为N,Y7和Y8为CH,Y9为N并且Y10为CH;或者
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5和R6均为氢;或者
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(XIII)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
Z选自CH和N;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
在优选的实施方案中,Z为CH。
在另一优选的实施方案中,Z为N。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(XIV)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(XVa)或式(XVb)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
Y1至Y4和Y6至Y10独立地选自CH、N、S和O,优选选自CH和N,
Y5为C;
R5选自卤素、烷基、O-烷基、O-苯基和O-环烷基,优选选自卤素、O-C1-4烷基、O-苯基和O-环烷基。
在更优选的实施方案中,R5为氟或氯,最优选为氟。
在另一更优选的实施方案中,R5为O-C1-4烷基,例如甲氧基、乙氧基、丙氧基或丁氧基,最优选为甲氧基、丙氧基或丙-2-基氧基。
在另一更优选的实施方案中,R5为O-苯基。
在另一更优选的实施方案中,R5为O-环烷基,最优选为O-环己基。
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
优选地,Y1、Y2、Y3和Y4中的一个、两个、三个或全部四个为N。
在更优选的实施方案中,
·Y1、Y2、Y3和Y4为CH;或者
·Y1为N并且Y2、Y3和Y4为CH;或者
·Y1和Y2为N并且Y3和Y4为CH;或者
·Y1为CH,Y2为N并且Y3和Y4为CH;或者
·Y1和Y3为N并且Y2和Y4为CH;或者
·Y1和Y3为CH并且Y2和Y4为N;或者
·Y1和Y2为CH并且Y3和Y4为N;或者
·Y1为N,Y2和Y3为CH并且Y4为N;或者
·Y1、Y2和Y3为CH并且Y4为N。
当Y4为CH时,Y4可被取代或未被取代。
在优选的实施方案中,Y4为CH并且未被取代。
在另一优选的实施方案中,Y4为CH并且被取代。
当Y4为CH并且被取代时,Y4优选被卤素或烷基取代,最优选被氟或甲基取代。
优选地,Y6至Y10中的一个或两个为N,并且Y6至Y10中的其他者为CH。
在更优选的实施方案中,
·Y6、Y7、Y8、Y9和Y10为CH;或者
·Y6为N并且Y7、Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为N,Y7、Y8、Y9为CH并且Y10为N;或者
·Y6和Y7为N并且Y8、Y9和Y10为CH;或者
·Y6为CH,Y7为N,Y8为CH,Y9为N并且Y10为CH;或者
·Y6和Y7为CH,Y8为N,Y9为CH并且Y10为N;或者
·Y6和Y7为CH,Y8为N,Y9和Y10为CH;或者
·Y6为N,Y7和Y8为CH,Y9为N并且Y10为CH;或者
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5和R6均为氢;或者
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(XVI)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(XVII)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
R2选自烷基和环烷基,优选选自甲基和环丙基;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
在优选的实施方案中,R2为甲基。
在另一优选的实施方案中,R2为环丙基。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在另一特别优选的实施方案中提供式(I)的化合物,其为式(XVIII)的化合物:
或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,
其中
X1选自烷基、N、O、S,优选选自CH2或S;
n为1或2;
R5选自卤素、烷基和O-烷基,优选选自氟和甲氧基;并且
R6选自氢、烷基和O-烷基,优选选自氢和甲氧基。
最优选地,X1为CH2。
另外最优选地,X1为S。
最优选地,n为1。
R5优选为氢、氟或甲氧基。
R6优选为氢或甲氧基。
更优选地,
·R5为氟并且R6为氢;或者
·R5和R6均为甲氧基。
在一个实施方案中,所述式(I)的化合物为实施例1至1323中任一个的化合物或者其药学可接受的盐、溶剂合物或多晶型物,包括所有互变异构体和立体异构体。
在优选的实施方案中,所述式(I)的化合物为选自下列的化合物:
5-[3-({4′-氟-[1,1′-联苯]-2-基}氨基)丙基]-1,3,4-噻二唑-2-胺;
5-{[2-({4′-氟-[1,1′-联苯]-2-基}氨基)乙基]硫烷基}-1,3,4-噻二唑-2-胺;
5-{[2-({3′,4′-二甲氧基-[1,1′-联苯]-2-基}氨基)乙基]硫烷基}-1,3,4-噻二唑-2-胺;
4′-氟-N-[3-(4-甲基-4H-1,2,4-三唑-3-基)丙基]-[1,1′-联苯]-2-胺;
3′,4′-二甲氧基-N-[3-(4-甲基-4H-1,2,4-三唑-3-基)丙基]-[1,1′-联苯]-2-胺;
5-[4-({4′-氟-[1,1′-联苯]-2-基}氨基)苯基]-1,3,4-噻二唑-2-胺;
5-(4-{[2-(3,4-二甲氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-胺;
5-(4-{[2-(4-甲氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-胺;
N-[4-(5-氨基-1,3,4-噻二唑-2-基)苯基]-3-(4-甲氧基苯基)吡啶-2-胺;
N-[4-(5-氨基-1,3,4-噻二唑-2-基)苯基]-3-(4-甲氧基苯基)吡啶-4-胺;
N-[4-(5-氨基-1,3,4-噻二唑-2-基)苯基]-3-(3,4-二甲氧基苯基)吡啶-4-胺;
N-[4-(5-氨基-1,3,4-噻二唑-2-基)苯基]-3-(4-氟苯基)吡啶-2-胺;
N-[4-(5-氨基-1,3,4-噻二唑-2-基)苯基]-3-(4-氟苯基)吡嗪-2-胺;
5-(4-{[2-(4-苯氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-胺;
5-(4-{[2-(4-丙氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-胺;
5-[4-({2-[4-(丙-2-基氧基)苯基]苯基}氨基)苯基]-1,3,4-噻二唑-2-胺;
4′-氟-N-[4-(4-甲基-4H-1,2,4-三唑-3-基)苯基]-[1,1′-联苯]-2-胺;
3′,4′-二甲氧基-N-[4-(4-甲基-4H-1,2,4-三唑-3-基)苯基]-[1,1′-联苯]-2-胺;
N-[2-(4-甲氧基苯基)苯基]-4-(4-甲基-4H-1,2,4-三唑-3-基)苯胺;
2-(4-甲氧基苯基)-N-[4-(4-甲基-4H-1,2,4-三唑-3-基)苯基]吡啶-3-胺;
2-(4-氟苯基)-N-[4-(4-甲基-4H-1,2,4-三唑-3-基)苯基]吡啶-3-胺;
4-(4-甲基-4H-1,2,4-三唑-3-基)-N-[2-(4-苯氧基苯基)苯基]苯胺;
3-(3,4-二甲氧基苯基)-N-[4-(4-甲基-4H-1,2,4-三唑-3-基)苯基]吡啶-4-胺;
N-[3-(5-氨基-1,3,4-噻二唑-2-基)丙基]-4-氟苯-1-磺酰胺;
N-{2-[(5-氨基-1,3,4-噻二唑-2-基)硫烷基]乙基}-4-氟苯-1-磺酰胺;
5-(3-{[(4-氟苯基)(甲基)氧代-λω-硫酮]氨基}丙基)-1,3,4-噻二唑-2-胺;
4-氟-N-[3-(4-甲基-4H-1,2,4-三唑-3-基)丙基]苯-1-磺酰胺;
4-氟-N-{2-[(4-甲基-4H-1,2,4-三唑-3-基)硫烷基]乙基}苯-1-磺酰胺;
[(3,4-二甲氧基苯基)氨磺酰基]({2-[(4-甲基-4H-1,2,4-三唑-3-基)硫烷基]乙基})胺;
N-[4-(2-氨基-1,3-噻唑-5-基)苯基]-4-氟苯-1-磺酰胺;
N-[4-(2-氨基-1,3-噻唑-5-基)苯基]-3,4-二甲氧基苯-1-磺酰胺;
5-(1-{4′-氟-[1,1′-联苯]-2-基}哌啶-4-基)-1,3,4-噻二唑-2-胺;
5-[1-(4-氟苯磺酰基)哌啶-4-基]-1,3-噻唑-2-胺;
5-[1-(4-氟苯磺酰基)哌啶-4-基]-1,3,4-噻二唑-2-胺;
1-(4-氟苯磺酰基)-4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶;
N-[(1H-1,3-苯并二唑-5-基)甲基]-4′-氟-[1,1′-联苯]-2-胺;
N-[(1H-1,3-苯并二唑-5-基)甲基]-3′,4′-二甲氧基-[1,1′-联苯]-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)吡啶-3-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡啶-4-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-4-(4-甲氧基苯基)吡啶-3-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-5-(4-甲氧基苯基)嘧啶-4-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-4-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-氟苯基)吡啶-3-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-氟苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-氟苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-苯氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-[4-(环己基氧基)苯基]苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-丙氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-[4-(丙-2-基氧基)苯基]苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)-3-甲基苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-甲基苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-氯苯基)-3-氟苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-氟苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-氟-2-(4-氟苯基)苯胺;
N-[(1H-1,3-苯并二唑-5-基)甲基]-4-氟苯-1-磺酰胺;和
[(1H-1,3-苯并二唑-5-基)甲基][(4-氟苯基)(甲基)氧代-λω-硫酮]胺;
或者其药学可接受的盐、溶剂合物或多晶型物,包括所有互变异构体和立体异构体。
在更优选的实施方案中,所述式(I)的化合物为选自下列的化合物:
5-(1-{4′-氟-[1,1′-联苯]-2-基}哌啶-4-基)-1,3,4-噻二唑-2-胺;
N-[(1H-1,3-苯并二唑-5-基)甲基]-4′-氟-[1,1′-联苯]-2-胺;
N-[(1H-1,3-苯并二唑-5-基)甲基]-3′,4′-二甲氧基-[1,1′-联苯]-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)吡啶-3-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡啶-4-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-4-(4-甲氧基苯基)吡啶-3-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-5-(4-甲氧基苯基)嘧啶-4-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-4-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-氟苯基)吡啶-3-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-氟苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-氟苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-苯氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-[4-(环己基氧基)苯基]苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-丙氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-[4-(丙-2-基氧基)苯基]苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)-3-甲基苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-甲基苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-氯苯基)-3-氟苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-氟苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-氟-2-(4-氟苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)-3-甲基苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-甲基苯胺;和
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-氟苯胺;
或者其药学可接受的盐、溶剂合物或多晶型物,包括所有互变异构体和立体异构体。
在同样优选的实施方案中,所述式(I)的化合物为选自下列的化合物:
5-(1-{4′-氟-[1,1′-联苯]-2-基}哌啶-4-基)-1,3,4-噻二唑-2-胺;
N-[(1H-1,3-苯并二唑-5-基)甲基]-4′-氟-[1,1′-联苯]-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-4-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-苯氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-[4-(环己基氧基)苯基]苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-[4-(丙-2-基氧基)苯基]苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)-3-甲基苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-甲基苯胺;和
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-氟苯胺;
或者其药学可接受的盐、溶剂合物或多晶型物,包括所有互变异构体和立体异构体。
在最优选的实施方案中,所述式(I)的化合物为选自下列的化合物:
N-[(1H-1,3-苯并二唑-5-基)甲基]-4′-氟-[1,1′-联苯]-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)-3-甲基苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-甲基苯胺;和
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-氟苯胺;
或者其药学可接受的盐、溶剂合物或多晶型物,包括所有互变异构体和立体异构体。
在另一最优选的实施方案中,所述式(I)的化合物为:
5-(1-{4′-氟-[1,1′-联苯]-2-基}哌啶-4-基)-1,3,4-噻二唑-2-胺;
或者其药学可接受的盐、溶剂合物或多晶型物,包括所有互变异构体和立体异构体。
在另一最优选的实施方案中,所述式(I)的化合物为:
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-氟苯胺;
或者其药学可接受的盐、溶剂合物或多晶型物,包括所有互变异构体和立体异构体。
合成方法
本发明的式(I)的化合物可通过选自如下文实施例部分中描述的合成方法A至R的方法制备。因此,本发明还涉及合成方法A、B、C、D、E、F、G、H、I、K、L、M、N、O、P、Q和R。
在优选的实施方案中,本发明的式(I)的化合物根据合成方法A制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法B制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法C制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法D制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法E制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法F制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法G制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法H制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法I制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法K制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法L制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法M制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法N制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法O制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法P制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法Q制备。
在另一优选的实施方案中,本发明的式(I)的化合物根据合成方法R制备。
治疗用途
哺乳动物中QC(EC)的生理学底物为例如淀粉样蛋白β-肽(3-40)、(3-42)、(11-40和(11-42),ABri,ADan,胃泌素,神经降压素,FPP,CCL2,CCL7,CCL8,CCL16,CCL18,CXXXC趋化分子,食欲肽A,[Gln3]-胰高血糖素(3-29),[Gln5]-物质P(5-11)以及肽QYNAD。进一步的细节参见表1。本发明的化合物和/或组合以及包含至少一种QC(EC)抑制剂的药物组合物可以用于治疗可以通过调节QC活性来治疗的疾病状况。
表1:具有易于环化为最终的pGlu的N端谷氨酰胺残基的生理活性肽的氨基酸序列
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谷氨酸存在于淀粉样蛋白β-肽的位置3、11和22。其中位置22中谷氨酸(E)突变为谷氨酰胺(Q)(对应于淀粉样蛋白前体蛋白APP 693,Swissprot P05067)已描述为所谓的荷兰型脑动脉淀粉样蛋白突变。
已报告在位置3、11和/或22中具有焦谷氨酸残基的β-淀粉样蛋白肽比淀粉样蛋白β-肽1-40(42/43)细胞毒性更强并更疏水(Saido T.C.2000Medical Hypotheses 54(3):427-429)。
多种N端变体,例如Aβ(3-40)、Aβ(3-42)、Aβ(11-40)和Aβ(11-42)可以通过β-分泌酶β-位淀粉样蛋白前体蛋白裂解酶(BACE)在不同位点产生(Huse J.T.等人2002J.Biol.Chem.277(18):16278-16284),和/或通过氨肽酶或二肽基氨肽酶加工从全长肽Aβ(1-40)和Aβ(1-42)产生。在所有情况下,其后N端存在的谷氨酸残基环化是通过QC催化的。
跨上皮转导细胞,特别是胃泌素(G)细胞,在食物进入胃时协调胃酸分泌。最新研究显示从胃泌素前体产生多种活性产物,并且在胃泌素生物合成中有多个控制点。生物合成的前体和中间体(前胃泌素和Gly-胃泌素)是推定的生长因子;它们的产物酰胺化的胃泌素调节上皮细胞增殖、产酸壁细胞和分泌组胺的肠嗜铬样(ECL)细胞的分化、以及与ECL细胞中的组胺合成和储存相关的基因的表达,以及强烈刺激酸分泌。胃泌素还刺激表皮生长因子(EGF)家族成员的产生,其继而抑制壁细胞功能但刺激表面上皮细胞的生长。血浆胃泌素浓度在具有幽门螺杆菌(Helicobacter pylori)的个体中升高,已知所述个体罹患十二指肠溃疡病和胃癌的风险增高(Dockray,G.J.1999J Physiol 15 315-324)。
已知从胃窦G细胞释放的肽激素胃泌素通过CCK-2受体刺激泌酸粘膜中从ECL细胞合成和释放组胺。可移动的组胺通过结合至位于壁细胞上的H(2)受体来诱导酸分泌。最新研究表明完全酰胺化形式和较少加工形式的胃泌素(前胃泌素和甘氨酸延长的胃泌素)均为胃肠道的生长因子。已确定酰胺化的胃泌素的主要营养作用是用于胃的泌酸粘膜,其中它引起胃干细胞和ECL细胞的增殖增加,导致壁细胞和ECL细胞量增加。另一方面,较少加工的胃泌素(例如甘氨酸延长的胃泌素)的主要营养靶标看来是结肠粘膜(Koh,T.J.和Chen,D.2000Regul Pept 9337-44)。
神经降压素(NT)是与精神分裂症的病理生理学相关的神经肽,它特异性地调节之前已证实在此病症中失调的神经递质系统。其中已测量脑脊液(CSF)NT浓度的临床研究揭示了通过有效的抗精神病药治疗得以恢复的CSF NT浓度降低的精神分裂症患者亚群。还有相当多的证据支持NT系统参与抗精神病药的作用机制。中枢给药的NT与全身给药的抗精神病药的行为和生物化学效应相似,并且抗精神病药增加NT神经传递。这一系列发现导致以下假设:NT起到内源性抗精神病药的作用。此外,典型的和非典型的抗精神病药差异地改变黑质纹状体和中脑边缘的多巴胺末端区域中的NT神经传递,并且这些影响分别预示副作用的倾向性和效力(Binder,E.B.等人2001Biol Psychiatry50 856-872)。
促甲状腺素释放激素(TRH)相关的三肽受精促进肽(FPP)存在于精浆中。体外和体内获得的最新证据显示FPP在调节精子能育性中起重要作用。具体地,FPP最初刺激不受精的(未获能的)精子“启动”并更快地变得能育,但是随后停滞获能,从而精子不进行自发性顶体脱离并因此不丧失受精潜力。模拟这些反应,并且的确由已知调节腺苷酸环化酶(AC)/cAMP信号转导途径的腺苷放大。已表明FPP和腺苷均刺激未获能的细胞中的cAMP生成但在获能的细胞中抑制其生成,同时FPP受体以某种方式与腺苷受体和G蛋白相互作用以实现对AC的调节。这些事件影响各种蛋白的酪氨酸磷酸化状态,其中某些在最初的“启动”中很重要,其他的可能参与顶体反应本身。降钙素和血管紧张素II也存在于精浆中,在体外对未获能的精子具有相似的效应,并且可以放大对FPP的反应。这些分子在体内具有相似效应,通过刺激然后保持受精潜力来影响能育性。男性不育症归因于FPP、腺苷、降钙素和血管紧张素II的可用性降低或者它们的受体缺陷(Fraser,L.R.和Adeoya-Osiguwa,S.A.2001VitamHorm 63,1-28)。
CCL2(MCP-1)、CCL7、CCL8、CCL16、CCL18和CXXXC趋化分子在病理生理状况中起重要作用,例如骨髓祖细胞增殖的抑制、瘤形成、炎性宿主反应、癌症、银屑病、类风湿性关节炎、动脉粥样硬化、脉管炎、体液和细胞介导的免疫应答、内皮处的白细胞粘附和迁移过程、炎性肠病、再狭窄、肺纤维化、肺动脉高压、肝纤维化、肝硬化、肾硬化、心室重塑、心力衰竭、器官移植后的动脉病和静脉移植失败。
许多研究已特别强调MCP-1对动脉粥样硬化(Gu,L.等人,(1998)Mol.Cell 2,275-281;Gosling,J.等人,(1999)J Clin.Invest 103,773-778);类风湿性关节炎(Gong,J.H.等人,(1997)J Exp.Med 186,131-137;Ogata,H.等人,(1997)J Pathol.182,106-114);胰腺炎(Bhatia,M.等人,(2005)Am.J Physiol Gastrointest.Liver Physiol 288,G1259-G1265);阿尔茨海默病(Yamamoto,M.等人,(2005)Am.J Pathol.166,1475-1485);肺纤维化(Inoshima,I.等人,(2004)Am.J Physiol Lung Cell Mol.Physiol 286,L1038-L1044);肾纤维化(Wada,T.等人,(2004)J Am.Soc.Nephrol.15,940-948),以及移植排斥(Saiura,A.等人,(2004)Arterioscler.Thromb.Vasc.Biol.24,1886-1890)的发展的重要作用。此外,MCP-1还可以在妊娠中毒中起作用(Katabuchi,H.等人,(2003)Med Electron Microsc.36,253-262),在肿瘤发展中作为旁分泌因子(Ohta,M.等人,(2003)Int.J Oncol.22,773-778;Li,S.等人,(2005)J Exp.Med 202,617-624),在神经性疼痛(White,F.A.等人,(2005)Proc.Natl.Acad.Sci.U.S.A)和AIDS(Park,I.W.,Wang,J.F.和Groopman,J.E.(2001)Blood97,352-358;Coll,B.等人,(2006)Cytokine 34,51-55)中起作用。
MCP-1水平在AD患者和表现出轻度认知障碍(MCI)的患者的CSF中升高(Galimberti,D.等人,(2006)Arch.Neurol.63,538-543)。此外,MCP-1在患有MCI和早期AD的患者的血清中表现出升高的水平(Clerici,F.等人,(2006)Neurobiol.Aging 27,1763-1768)。
针对乙型肝炎、人免疫缺陷病毒和黑素瘤的几种基于细胞毒性T淋巴细胞肽的疫苗最近进入临床试验研究。一种单独或与其他肿瘤抗原组合的引人关注的黑素瘤候选疫苗为十肽ELA。这种肽是具有N端谷氨酸的Melan-A/MART-1抗原免疫显性肽类似物。已报道谷氨酸的氨基和γ-羧基以及谷氨酰胺的氨基和γ-羧酰胺基团容易地缩合形成焦谷氨酸衍生物。为了克服这个稳定性问题,已开发几种具有焦谷氨酸代替N端谷氨酰胺或谷氨酸且不损失药理学性质的具有药学意义的肽。不幸的是,与ELA相比,焦谷氨酸衍生物(PyrELA)及N端乙酰基-加帽的衍生物(AcELA)均不能引起细胞毒性T淋巴细胞(CTL)活性。尽管在PyrELA和AcELA中引入明显很小的修饰,但是这两种衍生物很可能具有比ELA更低的对特异性I类主要组织相容性复合物的亲和力。因此,为了保留ELA的全部活性,必须避免形成PyrELA(BeckA.等人2001,J Pept Res 57(6):528-38.)。
食欲肽A是在调节食物摄取和睡眠-觉醒中可能通过协调这些互补的稳态功能的复杂的行为和生理反应来起重要作用的神经肽。其还在能量代谢、自主神经功能、激素平衡的稳态调节以及体液的调节中起作用。
最近,确认在患有多发性硬化或格-巴二氏综合征的患者的脑脊液(CSF)中与健康个体相比五肽QYNAD的水平升高(Brinkmeier H.等人2000,Nature Medicine 6,808-811)。关于五肽Gln-Tyr-Asn-Ala-Asp(QYNAD)的作用机制在文献中存在很大争议,特别是其与钠通道相互作用并阻断钠通道,导致轴突功能障碍升级的效力,这与中枢神经系统的炎性自身免疫性疾病有关。但是最近,可以证实不是QYNAD,而其环化的焦谷氨酸形式pEYNAD才是阻断钠通道而导致轴突功能障碍升级的活性形式。钠通道在有髓鞘的轴突中高密度表达,并且在哺乳动物的脑和脊髓内沿着轴突传导动作电位中起必要的作用。因此,推断它们涉及炎性自身免疫性疾病,特别是多发性硬化、格-巴二氏综合征和慢性炎性脱髓鞘多发性神经根神经病(chronic inflammatory demyelinizing polyradiculoneuropathy)的病理生理学的几个方面。
此外,QYNAD是谷氨酰胺酰环化酶(QC,EC 2.3.2.5)的底物,所述谷氨酰胺酰环化酶也存在于哺乳动物的脑中,特别是人脑中。谷氨酰胺酰环化酶有效地催化从其前体QYNAD形成pEYNAD。
因此,本发明提供式(I)的化合物在制备用于预防或缓解或治疗选自以下组中的疾病的药物中的用途:轻度认知障碍、阿尔茨海默病、家族性英国型痴呆、家族性丹麦型痴呆、唐氏综合征中的神经变性、亨廷顿病、肯尼迪病、溃疡病、有或无幽门螺杆菌感染的十二指肠癌、结直肠癌、佐-埃综合征、有或无幽门螺杆菌感染的胃癌、致病性精神病症、精神分裂症、不育、瘤形成、炎性宿主反应、癌症、恶性转移、黑素瘤、银屑病、类风湿性关节炎、动脉粥样硬化、胰腺炎、再狭窄、体液和细胞介导的免疫应答受损、内皮中的白细胞粘附和迁移过程、食物摄取受损、睡眠-觉醒受损、能量代谢的稳态调节受损、自主神经功能受损、激素平衡受损或者体液调节受损、多发性硬化、格-巴二氏综合征以及慢性炎性脱髓鞘多发性神经根神经病。
此外,通过向哺乳动物给药本发明的化合物可以刺激骨髓祖细胞的增殖。
此外,给药本发明的QC抑制剂可以导致抑制雄性生育力。
在一优选实施方案中,本发明提供QC(EC)活性抑制剂联合其他药剂的用途,特别是用于治疗神经元疾病、动脉粥样硬化和多发性硬化。
本发明还提供治疗上述疾病的方法,所述方法包括向哺乳动物给药治疗活性量的至少一种式(I)的化合物,所述哺乳动物优选为人。
最优选地,所述方法及相应的用途是用于治疗选自以下组中的疾病:轻度认知障碍、阿尔茨海默病、家族性英国型痴呆、家族性丹麦型痴呆、唐氏综合征中的神经变性、帕金森病和亨廷顿舞蹈症,其包括向哺乳动物给药治疗活性量的至少一种式(I)的化合物,所述哺乳动物优选为人。
甚至更优选地,本发明提供用于治疗类风湿性关节炎、动脉粥样硬化、胰腺炎和再狭窄的治疗方法及相应的用途。
药物组合
在一优选实施方案中,本发明提供组合物,优选药物组合物,其包含至少一种QC抑制剂,所述QC抑制剂任选地与至少一种选自下列的其他药剂组合:促智剂、神经保护剂、抗震颤麻痹药、淀粉样蛋白沉积抑制剂、β淀粉样蛋白合成抑制剂、抗抑郁药、抗焦虑药、抗精神病药以及抗多发性硬化药。
最优选地,所述QC抑制剂为本发明的式(I)的化合物。
更具体地,上述其他药剂选自β-淀粉样蛋白抗体、疫苗、半胱氨酸蛋白酶抑制剂、PEP-抑制剂、LiCl、乙酰胆碱脂酶(AChE)抑制剂、PIMT增强剂、β分泌酶抑制剂、γ分泌酶抑制剂、氨肽酶抑制剂,优选二肽基肽酶抑制剂,最优选DPIV抑制剂、中性内肽酶抑制剂、磷酸二酯酶-4(PDE-4)抑制剂、TNFa抑制剂、毒蕈碱M1受体拮抗剂、NMDA受体拮抗剂、σ-1受体抑制剂、组胺H3拮抗剂、免疫调节剂、免疫抑制剂、MCP-1拮抗剂,或者选自antegren(那他珠单抗)、Neurelan(氨吡啶缓释片)、campath(阿仑珠单抗)、IR 208、NBI 5788/MSP 771(替利莫肽)、紫杉醇、Anergix.MS(AG 284)、SH636、达芙文(CD 271、阿达帕林)、BAY 361677(白介素-4)、基质金属蛋白酶-抑制剂(例如BB76163)、干扰素-τ(滋养层素(trophoblastin))和SAIK-MS的药剂。
此外,所述其他药剂可以是例如抗焦虑药或抗抑郁药,其选自:
(a)苯二氮类,例如阿普唑仑、氯氮/>(chlordiazepoxide)、氯巴占、氯硝西泮、氯氮/>(clorazepate)、地西泮、氟地西泮、氯氟/>酯(loflazepate)、劳拉西泮、甲喹酮、奥沙西泮、普拉西泮、氯/>酸钾制剂,
(b)选择性5-羟色胺重摄取抑制剂(SSRI),例如西酞普兰、氟西汀、氟伏沙明、依他普仑、舍曲林、帕罗西汀,
(c)三环抗抑郁药,例如阿米替林、氯米帕明、地昔帕明、多塞平、丙米嗪
(d)单胺氧化酶(MAO)抑制剂,
(e)氮哌酮类(Azapirone),例如丁螺环酮、坦度螺酮,
(f)5-羟色胺-去甲肾上腺素重摄取抑制剂(SNRI),例如文拉法辛、度洛西汀,
(g)米氮平,
(h)去甲肾上腺素重摄取抑制剂(NRI),例如瑞波西汀,
(i)安非他酮,
(j)奈法唑酮,
(k)β-阻断剂,
(1)NPY-受体配体:NPY激动剂或拮抗剂。
在另一实施方案中,所述其他药剂可以是例如抗多发性硬化药,其选自:
a)二氢乳清酸脱氢酶抑制剂,例如SC-12267、特立氟胺、MNA-715、HMR-1279(与HMR-1715、MNA-279同义),
b)自身免疫抑制剂,例如拉喹莫德,
c)紫杉醇,
d)抗体,例如AGT-1、抗粒细胞-巨噬细胞集落刺激因子(GM-CSF)单克隆抗体、Nogo受体调节剂、ABT-874、阿仑珠单抗(CAMPATH)、抗OX40抗体、CNTO-1275、DN-1921、那他珠单抗(与AN-100226、Antegren、VLA-4Mab同义)、达克珠单抗(与Zenepax、Ro-34-7375,SMART抗Tac同义)、J-695、普立昔单抗(与Centara、CEN-000029、cM-T412同义)、MRA、Dantes、抗IL-12抗体,
e)肽核酸(PNA)制剂,例如reticulose,
f)干扰素α,例如Alfaferone、人α干扰素(与Omniferon、Alpha Leukoferon同义),
g)干扰素β,例如Frone,干扰素β-1a如Avonex、Beton(Rebif)、干扰素β类似物,干扰素β-转铁蛋白融合蛋白,重组干扰素β-1b如Betaseron,
h)干扰素τ,
i)肽,例如AT-008、AnergiX.MS、Immunokine(a-Immunokine-NNSO3)、环肽如ZD-7349,
j)治疗性酶,例如可溶性CD8(sCD8),
k)多发性硬化特异性自身抗原编码质粒和细胞因子编码质粒,例如BHT-3009;
l)TNF-α抑制剂,例如BLX-1002、沙利度胺、SH-636,
m)TNF拮抗剂,例如索利司他、来那西普(与RO-45-2081、Tenefuse同义)、奥那西普(sTNFR1)、CC-1069,
n)TNFa,例如依那西普(与Enbrel、TNR-001同义)
o)CD28拮抗剂,例如阿巴西普,
p)Lck酪氨酸激酶抑制剂,
q)组织蛋白酶K抑制剂,
r)靶向神经元的膜转运蛋白牛磺酸和来源于植物的钙蛋白酶抑制剂亮肽素的类似物,例如Neurodur,
s)趋化因子受体-1(CCR1)拮抗剂,例如BX-471,
t)CCR2拮抗剂,
u)AMPA受体拮抗剂,例如ER-167288-01和ER-099487、E-2007、他仑帕奈,
v)钾通道阻断剂,例如氨吡啶,
w)VLA-4/VCAM相互作用的甲苯磺酰基-脯氨酸-苯丙氨酸小分子拮抗剂,例如TBC-3342,
x)细胞粘附分子抑制剂,例如TBC-772,
y)反义寡核苷酸,例如EN-101,
z)结合至肥大细胞受体的游离免疫球蛋白轻链(IgLC)的拮抗剂,例如F-991,
aa)凋亡诱导抗原,例如Apogen MS,
bb)α-2肾上腺素受体激动剂,例如替扎尼定(与Zanaflex、Temelin、Sirdalvo、Sirdalud、Mionidine同义),
cc)L-酪氨酸、L-赖氨酸、L-谷氨酸和L-丙氨酸的共聚物,例如醋酸格拉默(与Copaxone、COP-1、共聚物-1同义),
dd)拓扑异构酶II调节剂,例如盐酸米托蒽醌,
ee)腺苷脱氨酶抑制剂,例如克拉屈滨(与Leustatin、Mylinax、RWJ-26251同义),
ff)白介素-10,例如伊洛白介素(与Tenovil、Sch-52000、CSIF同义),
gg)白介素-12拮抗剂,例如利索茶碱(lisofylline)(与CT-1501R、LSF、利索茶碱(lysofylline)同义),
hh)乙铵,例如SRI-62-834(与CRC-8605、NSC-614383同义),
ii)免疫调节剂,例如SAIK-MS、PNU-156804、α-胎蛋白肽(AFP)、IPDS,
jj)类视黄醇受体激动剂,例如阿达帕林(与达芙文、CD-271同义),
kk)TGF-β,例如GDF-1(生长和分化因子1),
ii)TGF-β-2,例如BetaKine,
mm)MMP抑制剂,例如glycomed,
nn)磷酸二酯酶4(PDE4)抑制剂,例如RPR-122818,
oo)嘌呤核苷磷酸化酶抑制剂,例如9-(3-吡啶基甲基)-9-脱氮鸟嘌呤、培得星(与BCX-34、TO-200同义),
mm)α-4/β-1整联蛋白拮抗剂,例如ISIS-104278,
qq)反义α4整联蛋白(CD49d),例如ISIS-17044、ISIS-27104,
rr)细胞因子诱导剂,例如核苷、ICN-17261,
ss)细胞因子抑制剂,
tt)热休克蛋白疫苗,例如HSPPC-96,
uu)神经调节蛋白生长因子,例如GGF-2(与神经调节蛋白、胶质细胞生长因子2同义),
vv)组织蛋白酶S-抑制剂,
ww)溴匹立明类似物,例如PNU-56169、PNU-63693,
xx)单核细胞趋化蛋白-1抑制剂,例如苯并咪唑,如MCP-1抑制剂、LKS-1456、PD-064036、PD-064126、PD-084486、PD-172084、PD-172386。
此外,本发明提供例如用于肠胃外、肠或口服给药的药物组合物,其包含至少一种QC抑制剂,任选地与上述其他药剂中的至少一种组合。
这些组合提供特别有益的效果。因此显示这类组合对治疗上述疾病有效并且可用于治疗上述疾病。相应地,本发明提供用于治疗这些疾病状况的方法。
所述方法包括共给药至少一种QC抑制剂和所述其他药剂中的至少一种,或者顺序给药。
共给药包括给药包含至少一种QC抑制剂和所述其他药剂中的至少一种的制剂,或者基本上同时给药各种药剂的不同制剂。
β-淀粉样蛋白抗体以及包含β-淀粉样蛋白抗体的组合物描述于例如WO/2009/065054、WO/2009/056490、WO/2009/053696、WO/2009/033743、WO/2007/113172、WO/2007/022416、WO 2006/137354、WO 2006/118959、WO 2006/103116、WO 2006/095041、WO 2006/081171、WO 2006/066233、WO 2006/066171、WO 2006/066089、WO 2006/066049、WO 2006/055178、WO 2006/046644、WO 2006/039470、WO 2006/036291、WO 2006/026408、WO 2006/016644、WO 2006/014638、WO 2006/014478、WO 2006/008661、WO 2005/123775、WO 2005/120571、WO 2005/105998、WO 2005/081872、WO 2005/080435、WO 2005/028511、WO 2005/025616、WO 2005/025516、WO 2005/023858、WO 2005/018424、WO 2005/011599、WO 2005/000193、WO 2004/108895、WO 2004/098631、WO 2004/080419、WO 2004/071408、WO 2004/069182、WO 2004/067561、WO 2004/044204、WO 2004/032868、WO 2004/031400、WO 2004/029630、WO 2004/029629、WO 2004/024770、WO 2004/024090、WO 2003/104437、WO 2003/089460、WO 2003/086310、WO 2003/077858、WO 2003/074081、WO 2003/070760、WO 2003/063760、WO 2003/055514、WO 2003/051374、WO 2003/048204、WO 2003/045128、WO 2003/040183、WO 2003/039467、WO 2003/016466、WO 2003/015691、WO 2003/014162、WO 2003/012141、WO 2002/088307、WO 2002/088306、WO 2002/074240、WO 2002/046237、WO 2002/046222、WO 2002/041842、WO 2001/062801、WO 2001/012598、WO 2000/077178、WO 2000/072880、WO 2000/063250、WO 1999/060024、WO 1999/027944、WO 1998/044955、WO 1996/025435、WO 1994/017197、WO 1990/014840、WO 1990/012871、WO 1990/012870、WO 1989/006242。
所述β-淀粉样蛋白抗体可以选自例如多克隆、单克隆、嵌合(chimenic)或人源化抗体。此外,所述抗体可以用于开发主动和被动免疫疗法,即疫苗和单克隆抗体。
合适的β-淀粉样蛋白抗体的实例为ACU-5A5、huC091(Acumen/Merck);PF-4360365、RI-1014、RI-1219、RI-409、RN-1219(Rinat Neuroscience Corp(Pfizer Inc));Ablynx/Boehringer Ingelheim的纳米抗体(nanobody)治疗剂;IntellectNeurosciences/IBL的β-淀粉样蛋白特异性人源化单克隆抗体;m266、m266.2(Eli Lilly&Co.);AAB-02(Elan);巴匹珠单抗(Elan);BAN-2401(Bioarctic Neuroscience AB);ABP-102(Abiogen Pharma SpA);BA-27、BC-05(Takeda);R-1450(Roche);ESBA-212(ESBATechAG);AZD-3102(AstraZeneca)和Mindset BioPharmaceuticals Inc的β-淀粉样蛋白抗体。
特别优选识别Aβ肽的N端的抗体。识别Aβ-N端的适合的抗体例如Acl-24(ACImmune SA)。
抗β-淀粉样蛋白肽的单克隆抗体公开于WO 2007/068412、WO/2008/156621和WO/2010/012004。各自的嵌合和人源化抗体公开于WO 2008/011348和WO/2008/060364。用于治疗淀粉样蛋白相关疾病的疫苗组合物公开于WO/2002/096937、WO/2005/014041、WO 2007/068411、WO/2007/097251、WO/2009/029272、WO/2009/054537、WO/2009/090650WO/2009/095857、WO/2010/016912、WO/2010/011947、WO/2010/011999、WO/2010/044464。
用于治疗淀粉样蛋白相关疾病的合适的疫苗例如Affitopes AD-01和AD-02(GlaxoSmithKline)、ACC-01和ACC-02(Elan/Wyeth)、CAD-106(Novartis/CytosBiotechnology)。
合适的半胱氨酸蛋白酶抑制剂为组织蛋白酶B抑制剂。组织蛋白酶B抑制剂以及包含这类抑制剂的组合物描述于例如WO/2008/077109、WO/2007/038772、WO 2006/060473、WO2006/042103、WO 2006/039807、WO 2006/021413、WO 2006/021409、WO 2005/097103、WO2005/007199、WO2004/084830、WO 2004/078908、WO 2004/026851、WO 2002/094881、WO2002/027418、WO 2002/021509、WO 1998/046559、WO 1996/021655。
合适的PIMT增强剂的实例为分别描述于WO 98/15647和WO 03/057204的10-氨基脂肪族基-二苯并[b,f]噁庚英(10-aminoaliphatyl-dibenz[b,f]oxepine)。根据本发明的其他有用的实例为描述于WO 2004/039773的PIMT活性调节剂。
β分泌酶的抑制剂以及包含这类抑制剂的组合物描述于例如WO/2010/094242、WO/2010/058333、WO/2010/021680、WO/2009/108550、WO/2009/042694、WO/2008/054698、WO/2007/051333、WO/2007/021793、WO/2007/019080、WO/2007/019078、WO/2007/011810、WO03/059346、WO2006/099352、WO2006/078576、WO2006/060109、WO2006/057983、WO2006/057945、WO2006/055434、WO2006/044497、WO2006/034296、WO2006/034277、WO2006/029850、WO2006/026204、WO2006/014944、WO2006/014762、WO2006/002004、US 7,109,217、WO2005/113484、WO2005/103043、WO2005/103020、WO2005/065195、WO2005/051914、WO2005/044830、WO2005/032471、WO2005/018545、WO2005/004803、WO2005/004802、WO2004/062625、WO2004/043916、WO2004/013098、WO03/099202、WO03/043987、WO03/039454、US 6,562,783、WO02/098849以及WO02/096897。
为了本发明的目的,合适的β分泌酶抑制剂的实例为WY-25105(Wyeth);Posiphen、(+)-芬赛林(TorreyPines/NIH);LSN-2434074、LY-2070275、LY-2070273、LY-2070102(EliLilly&Co.);PNU-159775A、PNU-178025A、PNU-17820A、PNU-33312、PNU-38773、PNU-90530(Elan/Pfizer);KMI-370、KMI-358、kmi-008(Kyoto University);OM-99-2、OM-003(Athenagen Inc.);AZ-12304146(AstraZeneca/Astex);GW-840736X(GlaxoSmithKlineplc.)、DNP-004089(De Novo Pharmaceuticals Ltd.)以及CT-21166(CoMentis Inc.)。
γ分泌酶的抑制剂以及包含这类抑制剂的组合物描述于例如WO/2010/090954、WO/2009/011851、WO/2009/008980、WO/2008/147800、WO/2007/084595、WO2005/008250、WO2006/004880、US 7,122,675、US 7,030,239、US 6,992,081、US 6,982,264、WO2005/097768、WO2005/028440、WO2004/101562、US 6,756,511、US 6,683,091、WO03/066592、WO03/014075、WO03/013527、WO02/36555、WO01/53255、US 7,109,217、US 7,101,895、US 7,049,296、US 7,034,182、US 6,984,626、WO2005/040126、WO2005/030731、WO2005/014553、US 6,890,956、EP 1334085、EP 1263774、WO2004/101538、WO2004/00958、WO2004/089911、WO2004/073630、WO2004/069826、WO2004/039370、WO2004/031139、WO2004/031137、US 6,713,276、US 6,686,449、WO03/091278、US 6,649,196、US 6,448,229、WO01/77144以及WO01/66564。
为了本发明的目的,合适的γ分泌酶抑制剂的实例为GSI-953、WAY-GSI-A、WAY-GSI-B(Wyeth);MK-0752、MRK-560、L-852505、L-685-458、L-852631、L-852646(Merck&Co.Inc.);LY-450139、LY-411575、AN-37124(Eli Lilly&Co.);BMS-299897、BMS-433796(Bristol-Myers Squibb Co.);E-2012(Eisai Co.Ltd.);EHT-0206、EHT-206(ExonHitTherapeutics SA);NGX-555(TorrevPines Therapeutics Inc.)以及司马西特(Semagacestat)(Eli Lilly)。
DP IV抑制剂以及包含这类抑制剂的组合物描述于例如US6,011,155、US6,107,317、US6,110,949、US6,124,305、US6,172,081、WO99/61431、WO99/67278、WO99/67279、DE19834591、WO97/40832、WO95/15309、WO98/19998、WO00/07617、WO99/38501、WO99/46272、WO99/38501、WO01/68603、WO01/40180、WO01/81337、WO01/81304、WO01/55105、WO02/02560、WO01/34594、WO02/38541、WO02/083128、WO03/072556、WO03/002593、WO03/000250、WO03/000180、WO03/000181、EP1258476、WO03/002553、WO03/002531、WO03/002530、WO03/004496、WO03/004498、WO03/024942、WO03/024965、WO03/033524、WO03/035057、WO03/035067、WO03/037327、WO03/040174、WO03/045977、WO03/055881、WO03/057144、WO03/057666、WO03/068748、WO03/068757、WO03/082817、WO03/101449、WO03/101958、WO03/104229、WO03/74500、WO2004/007446、WO2004/007468、WO2004/018467、WO2004/018468、WO2004/018469、WO2004/026822、WO2004/032836、WO2004/033455、WO2004/037169、WO2004/041795、WO2004/043940、WO2004/048352、WO2004/050022、WO2004/052850、WO2004/058266、WO2004/064778、WO2004/069162、WO2004/071454、WO2004/076433、WO2004/076434、WO2004/087053、WO2004/089362、WO2004/099185、WO2004/103276、WO2004/103993、WO2004/108730、WO2004/110436、WO2004/111041、WO2004/112701、WO2005/000846、WO2005/000848、WO2005/011581、WO2005/016911、WO2005/023762、WO2005/025554、WO2005/026148、WO2005/030751、WO2005/033106、WO2005/037828、WO2005/040095、WO2005/044195、WO2005/047297、WO2005/051950、WO2005/056003、WO2005/056013、WO2005/058849、WO2005/075426、WO2005/082348、WO2005/085246、WO2005/087235、WO2005/095339、WO2005/095343、WO2005/095381、WO2005/108382、WO2005/113510、WO2005/116014、WO2005/116029、WO2005/118555、WO2005/120494、WO2005/121089、WO2005/121131、WO2005/123685、WO2006/995613、WO2006/009886、WO2006/013104、WO2006/017292、WO2006/019965、WO2006/020017、WO2006/023750、WO2006/039325、WO2006/041976、WO2006/047248、WO2006/058064、WO2006/058628、WO2006/066747、WO2006/066770以及WO2006/068978。
为了本发明的目的,合适的DP IV抑制剂例如西格列汀、脱-氟-西格列汀(Merck&Co.Inc.);维格列汀、DPP-728、SDZ-272-070(Novartis);ABT-279、ABT-341(AbbottLaboratories);地格列汀、TA-6666(GlaxoSmithKline plc.);SYR-322(Takeda San DiegoInc.);他波司他(Point Therapeutics Inc.);Ro-0730699、R-1499、R-1438(RocheHolding AG);FE-999011(Ferring Pharmaceuticals);TS-021(Taisho PharmaceuticalCo.Ltd.);GRC-8200(Glenmark Pharmaceuticals Ltd.);ALS-2-0426(AlantosPharmaceuticals Holding Inc.);ARI-2243(Arisaph Pharmaceuticals Inc.);SSR-162369(Sanofi-Synthelabo);MP-513(Mitsubishi Pharma Corp.);DP-893、CP-867534-01(Pfizer Inc.);TSL-225、TMC-2A(Tanabe Seiyaku Co.Ltd.);PHX-1149(PhenomenixCorp.);沙格列汀(Bristol-Myers Squibb Co.);PSN-9301((OSI)Prosidion)、S-40755(Servier);KRP-104(ActivX Biosciences Inc.);sulphostin(Zaidan Hojin);KR-62436(Korea Research Institute of Chemical Technology);P32/98(Probiodrug AG);BI-A、BI-B(Boehringer Ingelheim Corp.);SK-0403(Sanwa Kagaku Kenkyusho Co.Ltd.);以及NNC-72-2138(Novo Nordisk A/S)。
其他优选的DPIV抑制剂为
(i)二肽样化合物,公开于WO 99/61431,例如N-缬氨酰脯氨酰、O-苯甲酰胲、丙氨酰吡咯烷、异亮氨酰噻唑烷如L-别-异亮氨酰噻唑烷、L-苏式-异亮氨酰吡咯烷以及它们的盐,特别是富马酸盐,以及L-别-异亮氨酰吡咯烷及其盐;
(ii)肽结构,公开于WO 03/002593,例如三肽;
(iii)肽基酮,公开于WO 03/033524;
(vi)取代的氨基酮,公开于WO 03/040174;
(v)局部活性的DPIV抑制剂,公开于WO 01/14318;
(vi)DP IV抑制剂的前药,公开于WO 99/67278和WO 99/67279;以及
(v)基于谷氨酰胺酰的DPIV抑制剂,公开于WO 03/072556和WO 2004/099134。
为了本发明的目的,合适的β淀粉样蛋白合成抑制剂例如Bisnorcymserine(Axonyx Inc.);(R)-氟比洛芬(MCP-7869;弗禄里赞)(Myriad Genetics);硝基氟比洛芬(NicOx);BGC-20-0406(Sankyo Co.Ltd.)和BGC-20-0466(BTG plc.)、RQ-00000009(RaQualia Pharma Inc)。
为了本发明的目的,合适的淀粉样蛋白沉积抑制剂例如SP-233(SamaritanPharmaceuticals);AZD-103(Ellipsis Neurotherapeutics Inc.);AAB-001(巴匹珠单抗)、AAB-002、ACC-001(Elan Corp plc.);Colostrinin(ReGen Therapeutics plc.);曲米沙特(Neurochem);AdPEDI-(淀粉样蛋白-β1-6)11)(Vaxin Inc.);MPI-127585、MPI-423948(Mayo Foundation);SP-08(Georgetown University);ACU-5A5(Acumen/Merck);甲状腺素运载蛋白(State University of New York);PTI-777、DP-74、DP 68、Exebryl(ProteoTechInc.);m266(Eli Lilly&Co.);EGb-761(Dr.Willmar Schwabe GmbH);S PI-014(SatoriPharmaceuticals Inc.);ALS-633、ALS-499(Advanced Life Sciences Inc.);AGT-160(ArmaGen Technologies Inc.);TAK-070(Takeda Pharmaceutical Co.Ltd.);CHF-5022、CHF-5074、CHF-5096和CHF-5105(Chiesi Farmaceutici SpA.)、SEN-1176和SEN-1329(Senexis Ltd.)、AGT-160(ArmaGen Technologies)、Davunetide(Allon Therapeutics)、ELND-005(Elan Corp/Transition Therapeutics)以及尼伐地平(ArcherPharmaceuticals)。
为了本发明的目的,合适的PDE-4抑制剂例如多索茶碱(Instituto BiologicoChemioterapica ABC SpA.);idudilast滴眼剂、泰鲁司特、异丁司特(KyorinPharmaceutical Co.Ltd.);茶碱(Elan Corp.);西洛司特(GlaxoSmithKline plc.);Atopik(Barrier Therapeutics Inc.);妥非司特、CI-1044、PD-189659、CP-220629、PDE 4d抑制剂BHN(Pfizer Inc.);阿罗茶碱、LAS-37779(Almirall Prodesfarma SA.);罗氟司特、羟基普马芬群(Altana AG)、替托司特(Otska Pharmaceutical Co.Ltd.);泰鲁司特、异丁司特(Kyorin Pharmaceutical)、CC-10004(Celgene Corp.);HT-0712、IPL-4088(Inflazyme Pharmaceuticals Ltd.);MEM-1414、MEM-1917(Memory PharmaceuticalsCorp.);奥米司特、GRC-4039(Glenmark Pharmaceuticals Ltd.);AWD-12-281、ELB-353、ELB-526(Elbion AG);EHT-0202(ExonHit Therapeutics SA.);ND-1251(Neuro3d SA.);4AZA-PDE4(4AZA Bioscience NV.);AVE-8112(Sanofi-Aventis);CR-3465(RottapharmSpA.);GP-0203、NCS-613(Centre National de la Recherche Scientifique);KF-19514(Kyowa Hakko Kogyo Co.Ltd.);ONO-6126(Ono Pharmaceutical Co.Ltd.);OS-0217(Dainippon Pharmaceutical Co.Ltd.);IBFB-130011、IBFB-150007、IBFB-130020、IBFB-140301(IBFB Pharma GmbH);IC-485(ICOS Corp.);RBx-14016和RBx-11082(RanbaxyLaboratories Ltd.)。优选的PDE-4抑制剂为咯利普兰。
MAO抑制剂以及包含这类抑制剂的组合物描述于例如WO2006/091988、WO2005/007614、WO2004/089351、WO01/26656、WO01/12176、WO99/57120、WO99/57119、WO99/13878、WO98/40102、WO98/01157、WO96/20946、WO94/07890以及WO92/21333。
为了本发明的目的,合适的MAO抑制剂例如利奈唑胺(Pharmacia Corp.);RWJ-416457(RW Johnson Pharmaceutical Research Institute);布地品(Altana AG);GPX-325(BioResearch Ireland);异卡波肼;苯乙肼;反苯环丙胺;茚他多(ChiesiFarmaceutici SpA.);吗氯贝胺(Roche Holding AG);SL-25.1131(Sanofi-Synthelabo);CX-1370(Burroughs Wellcome Co.);CX-157(Krenitsky Pharmaceuticals Inc.);去氧骆驼蓬碱(desoxypeganine)(HF Arzneimittelforschung GmbH&Co.KG);二苯美伦(Mitsubishi-Tokyo Pharmaceuticals Inc.);RS-1636(Sankyo Co.Ltd.);乙磺普隆(BASFAG);雷沙吉兰(Teva Pharmaceutical Industries Ltd.);拉多替吉(HebrewUniversity of Jemsalem);沙非酰胺(Pfizer)、NW-1048(Newron PharmaceuticalsSpA.)、EVT-302(Evotec)。
为了本发明的目的,合适的组胺H3拮抗剂例如ABT-239、ABT-834(AbbottLaboratories);3874-H1(Aventis Pharma);UCL-2173(Berlin Free University)、UCL-1470(BioProjet,Societe Civile de Recherche);DWP-302(Daewoong PharmaceuticalCo Ltd);GSK-189254A、GSK-207040A(GlaxoSmithKline Inc.);西拉利生、GT-2203(Gliatech Inc.);环丙沙芬(INSERM)、1S,2S-2-(2-氨基乙基)-1-(1H-咪唑-4-基)环丙烷(Hokkaido University);JNJ-17216498、JNJ-5207852(Johnson&Johnson);NNC-0038-0000-1049(Novo Nordisk A/S);以及Sch-79687(Schering-Plough)。
PEP抑制剂以及包含这类抑制剂的组合物描述于例如JP 01042465、JP 03031298、JP 04208299、WO 00/71144、US 5,847,155:JP 09040693、JP 10077300、JP 05331072、JP05015314、WO 95/15310、WO 93/00361、EP 0556482、JP 06234693、JP 01068396、EP0709373、US 5,965,556、US 5,756,763、US 6,121,311、JP 63264454、JP 64000069、JP63162672、EP 0268190、EP 0277588、EP 0275482、US 4,977,180、US 5,091,406、US 4,983,624、US 5,112,847、US 5,100,904、US 5,254,550、US 5,262,431、US 5,340,832、US 4,956,380、EP 0303434、JP 03056486、JP 01143897、JP 1226880、EP 0280956、US 4,857,537、EP 0461677、EP 0345428、JP 02275858、US 5,506,256、JP 06192298、EP 0618193、JP03255080、EP 0468469、US 5,118,811、JP 05025125、WO 9313065、JP 05201970、WO9412474、EP 0670309、EP 0451547、JP 06339390、US 5,073,549、US 4,999,349、EP0268281、US 4,743,616、EP 0232849、EP 0224272、JP 62114978、JP 62114957、US 4,757,083、US 4,810,721、US 5,198,458、US 4,826,870、EP 0201742、EP 0201741、US 4,873,342、EP 0172458、JP 61037764、EP 0201743、US 4,772,587、EP 0372484、US 5,028,604、WO91/18877、JP 04009367、JP 04235162、US 5,407,950、WO 95/01352、JP 01250370、JP02207070、US 5,221,752、EP 0468339、JP 04211648、WO 99/46272、WO 2006/058720以及PCT/EP2006/061428。
为了本发明的目的,合适的脯氨酰内肽酶抑制剂例如Fmoc-Ala-Pyrr-CN、Z-Phe-Pro-苯并噻唑(Probiodrug)、Z-321(Zeria Pharmaceutical Co Ltd.);ONO-1603(OnoPharmaceutical Co Ltd);JTP-4819(Japan Tobacco Inc.)和S-17092(Servier)。
根据本发明可以与QC抑制剂联合使用的其他合适的化合物为NPY,NPY模拟物或者NPY激动剂或拮抗剂,或者NPY受体的配体。
根据本发明优选NPY受体的拮抗剂。
合适的NPY受体的配体或拮抗剂是如WO 00/68197所公开的3a,4,5,9b-四氢-1h-苯并[e]吲哚-2-基胺衍生的化合物。
可以提及的NPY受体拮抗剂包括公开于欧洲专利申请EP 0 614 911、EP 0 747357、EP 0 747 356和EP 0 747 378;国际专利申请WO 94/17035、WO 97/19911、WO 97/19913、WO 96/12489、WO 97/19914、WO 96/22305、WO 96/40660、WO 96/12490、WO 97/09308、WO 97/20820、WO 97/20821、WO 97/20822、WO 97/20823、WO 97/19682、WO 97/25041、WO 97/34843、WO 97/46250、WO 98/03492、WO 98/03493、WO 98/03494和WO 98/07420;WO 00/30674、美国专利号5,552,411、5,663,192和5,567,714;6,114,336、日本专利申请JP 09157253;国际专利申请WO 94/00486、WO 93/12139、WO 95/00161和WO 99/15498;美国专利第5,328,899号;德国专利申请DE 393 97 97;欧洲专利申请EP 355 794和EP 355793;以及日本专利申请JP 06116284和JP 07267988的NPY受体拮抗剂。优选的NPY拮抗剂包括具体公开于这些专利文件的那些化合物。更优选的化合物包括基于氨基酸和非肽的NPY拮抗剂。可以提及的氨基酸和基于非肽的NPY拮抗剂包括公开于欧洲专利申请EP 0 614911、EP 0 747 357、EP 0 747 356和EP 0 747 378;国际专利申请WO 94/17035、WO 97/19911、WO 97/19913、WO 96/12489、WO 97/19914、WO 96/22305、WO 96/40660、WO 96/12490、WO 97/09308、WO 97/20820、WO 97/20821、WO 97/20822、WO 97/20823、WO 97/19682、WO 97/25041、WO 97/34843、WO 97/46250、WO 98/03492、WO 98/03493、WO 98/03494、WO 98/07420和WO 99/15498;美国专利号5,552,411、5,663,192和5,567,714;以及日本专利申请JP 09157253的基于氨基酸和非肽的NPY拮抗剂。优选的基于氨基酸和非肽的NPY拮抗剂包括具体公开于这些专利文件的那些化合物。
特别优选的化合物包括基于氨基酸的NPY拮抗剂。可以提及的基于氨基酸的化合物包括公开于国际专利申请WO 94/17035、WO 97/19911、WO 97/19913、WO 97/19914或者优选WO 99/15498的化合物。优选的基于氨基酸的NPY拮抗剂包括具体公开于这些专利文件的那些NPY拮抗剂,例如BIBP3226,特别是(R)-N2-(二苯基乙酰基)-(R)-N-[1-(4-羟基-苯基)乙基]精氨酸酰胺(国际专利申请WO 99/15498的实施例4)。
M1受体激动剂以及包含这类抑制剂的组合物描述于例如WO2004/087158、WO91/10664。
为了本发明的目的,合适的M1受体拮抗剂例如CDD-0102(CognitivePharmaceuticals);西维美林(Evoxac)(Snow Brand Milk Products Co.Ltd.);NGX-267(TorreyPines Therapeutics);沙可美林(GlaxoSmithKline);阿伐美林(H Lundbeck A/S);LY-593093(Eli Lilly&Co.);VRTX-3(Vertex Pharmaceuticals Inc.);WAY-132983(Wyeth)、CI-101 7/(PD-151832)(Pfizer Inc.)和MCD-386(Mitridion Inc.)。
乙酰胆碱酯酶抑制剂以及包含这类抑制剂的组合物描述于例如WO2006/071274、WO2006/070394、WO2006/040688、WO2005/092009、WO2005/079789、WO2005/039580、WO2005/027975、WO2004/084884、WO2004/037234、WO2004/032929、WO03/101458、WO03/091220、WO03/082820、WO03/020289、WO02/32412、WO01/85145、WO01/78728、WO01/66096、WO00/02549、WO01/00215、WO00/15205、WO00/23057、WO00/33840、WO00/30446、WO00/23057、WO00/15205、WO00/09483、WO00/07600、WO00/02549、WO99/47131、WO99/07359、WO98/30243、WO97/38993、WO97/13754、WO94/29255、WO94/20476、WO94/19356、WO93/03034以及WO92/19238。
为了本发明的目的,合适的乙酰胆碱酯酶抑制剂例如多奈哌齐(Eisai Co.Ltd.);利凡斯的明(Novartis AG);(-)-芬赛林(TorreyPines Therapeutics);拉多替吉(HebrewUniversity of Jerusalem);石杉碱甲(Mayo Foundation);加兰他敏(Johnson&Johnson);Memoquin(Universita di Bologna);SP-004(Samaritan Pharmaceuticals Inc.);BGC-20-1259(Sankyo Co.Ltd.);毒扁豆碱(Forest Laboratories Inc.);NP-0361(Neuropharma SA);ZT-1(Debiopharm);他克林(Warner-Lambert Co.);美曲膦酯(BayerCorp.)、INM-176(WhanIn)、石杉碱甲(Neuro-Hitech/Xel Pharmaceutical)、米莫派唑(Debiopharm)和Dimebon (Medivation/Pfizer)。
NMDA受体拮抗剂以及包含这类抑制剂的组合物描述于例如WO2006/094674、WO2006/058236、WO2006/058059、WO2006/010965、WO2005/000216、WO2005/102390、WO2005/079779、WO2005/079756、WO2005/072705、WO2005/070429、WO2005/055996、WO2005/035522、WO2005/009421、WO2005/000216、WO2004/092189、WO2004/039371、WO2004/028522、WO2004/009062、WO03/010159、WO02/072542、WO02/34718、WO01/98262、WO01/94321、WO01/92204、WO01/81295、WO01/32640、WO01/10833、WO01/10831、WO00/56711、WO00/29023、WO00/00197、WO99/53922、WO99/48891、WO99/45963、WO99/01416、WO99/07413、WO99/01416、WO98/50075、WO98/50044、WO98/10757、WO98/05337、WO97/32873、WO97/23216、WO97/23215、WO97/23214、WO96/14318、WO96/08485、WO95/31986、WO95/26352、WO95/26350、WO95/26349、WO95/26342、WO95/12594、WO95/02602、WO95/02601、WO94/20109、WO94/13641、WO94/09016以及WO93/25534。
为了本发明的目的,合适的NMDA受体拮抗剂例如美金刚(Merz&Co.GmbH);托吡酯(Johnson&Johnson);AVP-923(Neurodex)(Center for Neurologic Study);EN-3231(EndoPharmaceuticals Holdings Inc.);奈拉美生(MRZ-2/579)(Merz and Forest);CNS-5161(CeNeS Pharmaceuticals Inc.);地塞比诺(HU-211;Sinnabidol;PA-50211)(Pharmos);EpiCept NP-1(Dalhousie University);茚他多(V-3381;CNP-3381)(Vernalis);培净福太(EAA-090、WAY-126090、EAA-129)(Wyeth);RGH-896(Gedeon Richter Ltd.);曲索罗地(CP-101606)、贝生罗地(PD-196860、CI-1041)(Pfizer Inc.);CGX-1007(Cognetix Inc.);德芦西明(NPS-1506)(NPS Pharmaceuticals Inc.);EVT-101(Roche Holding AG);阿坎酸(Synchroneuron LLC.);CR-3991、CR-2249、CR-3394(Rottapharm SpA.);AV-101(4-Cl-犬尿氨酸(4-Cl-KYN))、7-氯-犬尿喹啉酸(7-Cl-KYNA)(VistaGen);NPS-1407(NPSPharmaceuticals Inc.);YT-1006(Yaupon Therapeutics Inc.);ED-1812(Sosei R&DLtd.);himantane(N-2-(金刚烷基)-六亚甲基-亚胺盐酸盐)(RAMS);拉尼西明(Lancicemine)(AR-R-15896)(AstraZeneca);EVT-102、Ro-25-6981和Ro-63-1908(Hoffmann-La Roche AG/Evotec)、奈拉美生(Merz)。
此外,本发明涉及可用于治疗动脉粥样硬化、再狭窄或关节炎的联合治疗,给药QC抑制剂联合另一治疗剂,以提供相对于各单独的单一疗法组分有益的或协同的治疗效果,所述治疗剂选自血管紧张素转换酶(ACE)抑制剂;血管紧张素II受体阻断剂;利尿剂;钙通道阻断剂(CCB);β-阻断剂;血小板聚集抑制剂;胆固醇吸收调节剂;HMG-Co-A还原酶抑制剂;高密度脂蛋白(HDL)增加化合物;肾素抑制剂;IL-6抑制剂;抗炎皮质甾类;抗增殖剂;一氧化氮供体;细胞外基质合成抑制剂;生长因子或细胞因子信号转导抑制剂;MCP-1拮抗剂和酪氨酸激酶抑制剂。
血管紧张素II受体阻断剂理解为结合至血管紧张素II受体的AT1-受体亚型但不导致该受体活化的那些活性物质。由于AT1受体的阻断,这些拮抗剂可以例如用作抗高血压剂。
可以用于本发明的组合的合适的血管紧张素II受体阻断剂包括具有不同结构特征的AT1受体拮抗剂,优选具有非肽类结构的那些阻断剂。例如,可以提到的化合物选自缬沙坦(EP 443983)、氯沙坦(EP 253310)、坎地沙坦(EP 459136)、依普罗沙坦(EP 403159)、厄贝沙坦(EP 454511)、奥美沙坦(EP 503785)、他索沙坦(EP 539086)、替米沙坦(EP522314)、命名为E-41 77的下式的化合物
命名为SC-52458的下式的化合物
以及命名为ZD-8731的下式的化合物
或者,在每种情况中,其药学可接受的盐。
优选的AT1-受体拮抗剂是已获批准并上市的那些药剂,最优选缬沙坦,或者其药学可接受的盐。
用ACE抑制剂阻断血管紧张素酶促降解为血管紧张素II是用于调节血压的成功变体,并且因此还使得可以获得用于治疗高血压的治疗方法。
用于本发明的组合的合适的ACE抑制剂例如化合物,其选自阿拉普利、贝那普利、贝那普利拉、卡托普利、西罗普利、西拉普利、地拉普利、依那普利、依那普利拉(enaprilat)、福辛普利、咪达普利、赖诺普利、莫维普利(moveltopril)、培哚普利、喹那普利、雷米普利、螺普利、替莫普利和群多普利,或者在每种情况下,其药学可接受的盐。
优选的ACE抑制剂是已上市的那些药剂,最优选贝那普利和依那普利。
利尿剂例如选自氯噻嗪、氢氯噻嗪、甲氯噻嗪(methylclothiazide)和氯噻酮(chlorothalidon)的噻嗪衍生物。最优选的利尿剂为氢氯噻嗪。利尿剂还包括保钾利尿剂,例如阿米洛利或氨苯蝶啶(triameterine),或者其药学可接受的盐。
CCB类基本上包括二氢吡啶(DHP)和非DHP,如地尔硫型和维拉帕米型CCB。
可用于所述组合的CCB优选DHP代表物,所述DHP代表物选自氨氯地平、非洛地平、ryosidine、伊拉地平、拉西地平、尼卡地平、硝苯地平、尼古地平、尼鲁地平、尼莫地平、尼索地平、尼群地平和尼伐地平(nivaldipine),并且还优选非DHP代表物,所述非DHP代表物选自氟桂利嗪、普尼拉明、地尔硫芬地林、戈洛帕米、米贝拉地尔、阿尼帕米、噻帕米和维拉帕米,以及在每种情况下,其药学可接受的盐。所有这些CCB在治疗上用作例如抗高血压药、抗心绞痛药或抗心律不齐药。
优选的CCB包括氨氯地平、地尔硫伊拉地平、尼卡地平、硝苯地平、尼莫地平、尼索地平、尼群地平和维拉帕米,或者,例如,取决于具体的CCB,其药学可接受的盐。作为DHP特别优选的是氨氯地平或其药学可接受的盐,特别是苯磺酸盐。特别优选的非DHP代表物是维拉帕米或其药学可接受的盐,特别是盐酸盐。
适合用于本发明的β-阻断剂包括β-肾上腺素能阻断剂(β-阻断剂),其与肾上腺素竞争β-肾上腺素能受体并干扰肾上腺素的作用。优选地,与α-肾上腺素能受体相比,所述β-阻断剂对β-肾上腺素能受体具有选择性,因此没有显著的α-阻断效应。合适的β-阻断剂包括选自醋丁洛尔、阿替洛尔、倍他洛尔、比索洛尔、卡替洛尔、卡维地洛、艾司洛尔、拉贝洛尔、美托洛尔、纳多洛尔、氧烯洛尔、喷布洛尔、吲哚洛尔、普萘洛尔、索他洛尔和噻吗洛尔的化合物。其中所述β-阻断剂为酸或碱,或者能够形成药学可接受的盐或前药,这些形式考虑包括在本文内,并且应当理解所述化合物可以游离形式或者以药学可接受的盐或前药(如生理上可水解和可接受的酯)的形式给药。例如,美托洛尔适合地作为其酒石酸盐给药,普萘洛尔适合地作为盐酸盐给药等。
血小板聚集抑制剂包括(氯吡格雷硫酸氢盐)、/>(西洛他唑)和阿司匹林。
胆固醇吸收调节剂包括(依泽麦布)和KT6-971(KotobukiPharmaceutical Co.Japan)。
HMG-Co-A还原酶抑制剂(也称为β-羟基-β-甲基戊二酰辅酶A还原酶抑制剂或他汀类)应当理解为可以用来降低血液中包括胆固醇在内的脂质水平的那些活性物质。
HMG-Co-A还原酶抑制剂类包括具有不同结构特征的化合物。例如,可以提及化合物,其选自阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀和辛伐他汀,或者在每种情况下,其药学可接受的盐。
优选的HMG-Co-A还原酶抑制剂是已上市的那些药剂,最优选的是阿托伐他汀、匹伐他汀或辛伐他汀,或者其药学可接受的盐。
HDL增加化合物包括但不限于,胆固醇酯转移蛋白(CETP)抑制剂。CETP抑制剂的实例包括于2002年7月30日授权的美国专利第6,426,365号的实施例26所公开的JTT7O5,以及其药学可接受的盐。
白介素6介导的炎症的抑制可以间接地通过调节内源性胆固醇合成和类异戊二烯减少来实现,或者通过直接抑制信号转导途径,利用白介素-6抑制剂/抗体、白介素-6受体抑制剂/抗体、白介素-6反义寡核苷酸(ASON)、gp130蛋白抑制剂/抗体、酪氨酸激酶抑制剂/抗体、丝氨酸/苏氨酸激酶抑制剂/抗体、促分裂原活化蛋白(MAP)激酶抑制剂/抗体、磷脂酰肌醇3-激酶(PI3K)抑制剂/抗体、核因子κB(NF-κB)抑制剂/抗体、IκB激酶(IKK)抑制剂/抗体、激活蛋白-1(AP-1)抑制剂/抗体、STAT转录因子抑制剂/抗体、改变的IL-6、IL-6或IL-6受体的部分肽、或SOCS(细胞因子信号转导抑制因子)蛋白、PPARγ和/或PPARβ/δ激活剂/配体或其功能性片段。
合适的抗炎皮质甾类为地塞米松。
合适的抗增殖剂为克拉立滨、雷帕霉素、长春新碱和泰素(taxol)。
合适的细胞外基质合成抑制剂为卤夫酮。
合适的生长因子或细胞因子信号转导抑制剂例如ras抑制剂R115777。
合适的酪氨酸激酶抑制剂为酪氨酸磷酸化抑制剂。
合适的肾素抑制剂描述于例如WO 2006/116435。优选的肾素抑制剂为阿利吉仑,优选其半富马酸盐形式。
MCP-1拮抗剂可以例如选自抗MCP-1抗体,优选单克隆抗体或人源化单克隆抗体,MCP-1表达抑制剂,CCR2拮抗剂,TNF-α抑制剂,VCAM-1基因表达抑制剂以及抗C5a单克隆抗体。
MCP-1拮抗剂以及包含这类抑制剂的组合物描述于例如WO02/070509、WO02/081463、WO02/060900、US2006/670364、US2006/677365、WO2006/097624、US2006/316449、WO2004/056727、WO03/053368、WO00/198289、WO00/157226、WO00/046195、WO00/046196、WO00/046199、WO00/046198、WO00/046197、WO99/046991、WO99/007351、WO98/006703、WO97/012615、WO2005/105133、WO03/037376、WO2006/125202、WO2006/085961、WO2004/024921、WO2006/074265。
合适的MCP-1拮抗剂例如C-243(Telik Inc.);NOX-E36(Noxxon Pharma AG);AP-761(Actimis Pharmaceuticals Inc.);ABN-912、NIBR-177(Novartis AG);CC-11006(Celgene Corp.);SSR-150106(Sanofi-Aventis);MLN-1202(Millenium PharmaceuticalsInc.);AGI-1067、AGIX-4207、AGI-1096(AtherioGenics Inc.);PRS-211095、PRS-211092(Pharmos Corp.);抗C5a单克隆抗体,例如neutrazumab(G2 Therapies Ltd.);AZD-6942(AstraZeneca plc.);2-巯基咪唑(Johnson&Johnson);TEI-E00526、TEI-6122(Deltagen);RS-504393(Roche Holding AG);SB-282241、SB-380732、ADR-7(GlaxoSmithKline);抗MCP-1单克隆抗体(Johnson&Johnson)。
QC抑制剂与MCP-1拮抗剂的组合一般可以用于治疗炎性疾病,包括神经变性疾病。
QC抑制剂与MCP-1拮抗剂的组合优选用于治疗阿尔茨海默病。
最优选地,所述QC抑制剂与选自下组中的一种或多种化合物组合:
PF-4360365、m266、巴匹珠单抗、R-1450、Posiphen、(+)-芬赛林、MK-0752、LY-450139、E-2012、(R)-氟比洛芬、AZD-103、AAB-001(巴匹珠单抗)、曲米沙特、EGb-761、TAK-070、多索茶碱、茶碱、西洛司特、妥非司特、罗氟司特、替托司特、泰鲁司特、异丁司特、HT-0712、MEM-1414、奥米司特、利奈唑胺、布地品、异卡波肼、苯乙肼、反苯环丙胺、茚他多、吗氯贝胺、雷沙吉兰、拉多替吉、沙非酰胺、ABT-239、ABT-834、GSK-189254A、环丙沙芬、JNJ-17216498、Fmoc-Ala-Pyrr-CN、Z-Phe-Pro-苯并噻唑、Z-321、ONO-1603、JTP-4819、S-17092、BIBP3226、(R)-N2-(二苯基乙酰基)-(R)-N-[1-(4-羟基苯基)乙基]精氨酸酰胺、西维美林、沙可美林、(PD-151832)、多奈哌齐、利凡斯的明、(-)-芬赛林、拉多替吉、加兰他敏、他克林、美曲膦酯、美金刚、托吡酯、AVP-923、EN-3231、奈拉美生、缬沙坦、贝那普利、依那普利、氢氯噻嗪、氨氯地平、地尔硫伊拉地平、尼卡地平、硝苯地平、尼莫地平、尼索地平、尼群地平、维拉帕米、氨氯地平、醋丁洛尔、阿替洛尔、倍他洛尔、比索洛尔、卡替洛尔、卡维地洛、艾司洛尔、拉贝洛尔、美托洛尔、纳多洛尔、氧烯洛尔、喷布洛尔、吲哚洛尔、普萘洛尔、索他洛尔、噻吗洛尔、/>(氯吡格雷硫酸氢盐)、/>(西洛他唑)、阿司匹林、/>(依泽麦布)和KT6-971、他汀类、阿托伐他汀、匹伐他汀或辛伐他汀、地塞米松、克拉屈滨、雷帕霉素、长春新碱、泰素、阿利吉仑、C-243、ABN-912、SSR-150106、MLN-1202和倍泰龙。
特别地,考虑以下组合:
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合阿托伐他汀,以用于治疗和/或预防动脉粥样硬化,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合免疫抑制剂,优选雷帕霉素,以用于预防和/或治疗再狭窄,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合免疫抑制剂,优选紫杉醇,以用于预防和/或治疗再狭窄,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合AChE抑制剂,优选多奈哌齐,以用于预防和/或治疗阿尔茨海默病,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合干扰素,优选Aronex,以用于预防和/或治疗多发性硬化,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合干扰素,优选倍泰龙,以用于预防和/或治疗多发性硬化,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合干扰素,优选Rebif,以用于预防和/或治疗多发性硬化,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合Copaxone,以用于预防和/或治疗多发性硬化,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合地塞米松,以用于预防和/或治疗再狭窄,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合地塞米松,以用于预防和/或治疗动脉粥样硬化,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合地塞米松,以用于预防和/或治疗类风湿性关节炎,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合HMG-Co-A-还原酶抑制剂,以用于预防和/或治疗再狭窄,其中所述HMG-Co-A-还原酶抑制剂选自阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀和辛伐他汀,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合HMG-Co-A-还原酶抑制剂,以用于预防和/或治疗动脉粥样硬化,其中所述HMG-Co-A-还原酶抑制剂选自阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀和辛伐他汀,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合HMG-Co-A-还原酶抑制剂,以用于预防和/或治疗类风湿性关节炎,其中所述HMG-Co-A-还原酶抑制剂选自阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀和辛伐他汀,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合淀粉样蛋白-β抗体,以用于预防和/或治疗轻度认知障碍,其中所述淀粉样蛋白-β抗体为Acl-24,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合淀粉样蛋白-β抗体,以用于预防和/或治疗阿尔茨海默病,其中所述淀粉样蛋白-β抗体为Acl-24,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合淀粉样蛋白-β抗体,以用于预防和/或治疗唐氏综合征中的神经变性,其中所述淀粉样蛋白-β抗体为Acl-24,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合β-分泌酶抑制剂,以用于预防和/或治疗轻度认知障碍,其中所述β-分泌酶抑制剂选自WY-25105、GW-840736X和CTS-21166,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合β-分泌酶抑制剂,以用于预防和/或治疗阿尔茨海默病,其中所述β-分泌酶抑制剂选自WY-25105、GW-840736X和CTS-21166,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合β-分泌酶抑制剂,以用于预防和/或治疗唐氏综合征中的神经变性,其中所述β-分泌酶抑制剂选自WY-25105、GW-840736X和CTS-21166,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合γ-分泌酶抑制剂,以用于预防和/或治疗轻度认知障碍,其中所述γ-分泌酶抑制剂选自LY-450139、LY-411575和AN-37124,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合γ-分泌酶抑制剂,以用于预防和/或治疗阿尔茨海默病,其中所述γ-分泌酶抑制剂选自LY-450139、LY-411575和AN-37124,
-QC抑制剂,优选式(I)的QC抑制剂,更优选选自实施例1-1323中任一个的QC抑制剂,联合γ-分泌酶抑制剂,以用于预防和/或治疗唐氏综合征中的神经变性,其中所述γ-分泌酶抑制剂选自LY-450139、LY-411575和AN-37124。
这样的联合治疗对于AD、FAD、FDD和唐氏综合征中的神经变性以及动脉粥样硬化、类风湿性关节炎、再狭窄和胰腺炎特别有用。
这类联合治疗可能导致比单独使用任一药剂更好的疗效(较少增殖以及较少炎症,增殖刺激)。
关于QC抑制剂与其他化合物的具体组合,在这方面特别参考WO 2004/098625,其援引加入本文。
药物组合物
为了制备本发明的药物组合物,可以将任选地与上述其他药剂中的至少一种组合的至少一种式(I)的化合物用作活性成分。根据常规药学复合技术将活性成分与药学载体紧密地混合,所述载体可以采用多种形式,这取决于期望给药的制剂形式,例如,口服或肠胃外,如肌肉内。在制备口服剂型的组合物中,可以采用任何常规药学介质。因此,对于液体口服制剂,例如混悬剂、酏剂和溶液剂,合适的载体和添加剂包括水、乙二醇、油、醇、增香剂、防腐剂、着色剂等;对于固体口服制剂,例如散剂、胶囊剂、软胶囊剂和片剂,合适的载体和添加剂包括淀粉类、糖、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。由于易于给药,片剂和胶囊剂代表最有利的口服剂量单位形式,其中显而易见地采用固体药学载体。如果期望,片剂可以通过标准技术进行糖包衣或肠包衣。对于肠胃外给药制剂,载体通常包含无菌水,但可以包括其他成分,例如,为了如增溶或防腐的目的。
还可以制备可注射的混悬剂,其中可以采用适当的液体载体、悬浮剂等。本发明的药物组合物每剂量单位(例如片剂、胶囊剂、散剂、注射剂、一茶匙量等)会包含如上文所述递送有效剂量所需的活性成分的量。本发明的药物组合物每剂量单位(例如片剂、胶囊剂、散剂、注射剂、栓剂、一茶匙量等)会包含约0.03mg-100mg/kg(优选0.1-30mg/kg),并且可以约0.1-300mg/kg/天(优选1-50mg/kg/天)的各种活性成分或其组合的剂量给药。但是,所述剂量可以根据患者的要求、治疗的疾病状况的严重程度和采用的化合物而变化。可以采用每日给药或者后周期性给药(post-periodic dosing)。
优选地,这些组合物为单位剂型,例如片剂、丸剂、胶囊剂、散剂、颗粒剂、无菌肠胃外溶液剂或混悬剂、计量的气雾剂或液体喷雾剂、滴剂、安瓿、自动注射装置或栓剂;用于口服、肠胃外、鼻内、舌下或直肠给药,或者用于通过吸入或吹入给药。或者,所述组合物可以表现为适合于每周一次或每月一次给药的形式;例如,所述活性化合物的不溶性盐如癸酸盐可以适应提供用于肌肉内注射的贮库制剂。为了制备固体组合物如片剂,将主要活性成分与药学载体混合以形成包含本发明的化合物或其药学可接受的盐的均匀混合物的固体预配制组合物,所述药学载体例如常规的压片成分,如玉米淀粉、乳糖、蔗糖、山梨醇、滑石、硬脂酸、硬脂酸镁、磷酸二钙或树胶,以及其他药学稀释剂例如水。当提到这些预配制组合物是均匀的时,表示活性成分均匀地分散于整个组合物中,从而组合物可以容易地细分为同等有效的剂型,如片剂、丸剂和胶囊剂。然后将此固体预配制组合物细分为含有0.1-约500mg的本发明的各种活性成分或其组合的上述类型的单位剂型。
可以将本发明的组合物的片剂或丸剂包衣或者复合以提供具有持久作用优点的剂型。例如,所述片剂或丸剂可以包含内剂量组分和外剂量组分,后者为覆盖前者的封套形式。这两个组分可以由肠溶层分隔,所述肠溶层用来阻止在胃中崩解并允许所述内组分完整地通过进入十二指肠或延迟释放。各种物质可以用于这类肠溶层或包衣,这类物质包括许多聚合酸,和诸如虫胶、鲸蜡醇和醋酸纤维素的物质。
可以将本发明的组合物掺入其中以用于口服或通过注射给药的液体形式包括:水溶液剂、适合地矫味的糖浆剂、水性或油性混悬剂、以及用诸如棉子油、芝麻油、椰子油或花生油的食用油矫味的乳剂,以及酏剂和相似的药学媒介物。用于水性混悬剂的合适的分散剂或悬浮剂包括合成和天然树胶,例如黄蓍胶、阿拉伯胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。
所述药物组合物可以包含约0.01mg-100mg,优选约5-50mg的各种化合物,并且可以构成适合所选给药模式的任何形式。载体包括必需的和惰性的药学赋形剂,包括但不限于粘合剂、悬浮剂、润滑剂、香料、甜味剂、防腐剂、染料和包衣剂。适合口服给药的组合物包括固体形式,例如丸剂、片剂、胶囊形片剂、胶囊剂(各自包括即释制剂、定时释放制剂和持续释放制剂)、颗粒剂和散剂;以及液体形式,例如溶液剂、糖浆剂、酏剂、乳剂和混悬剂。可用于肠胃外给药的形式包括无菌溶液剂、乳剂和混悬剂。
有利地,本发明的化合物可以单次每日剂量给药,或者每日总剂量可以分成每日两次、三次或四次的剂量给药。此外,本发明的化合物可以通过体表使用合适的鼻内媒介物以鼻内形式给药,或者通过本领域技术人员公知的透皮贴剂给药。为了以透皮递送系统的形式给药,在整个给药方案中剂量给药当然是连续的而不是间歇的。
例如,对于以片剂或胶囊剂形式口服给药,活性药物组分可以与口服无毒性的药学可接受的惰性载体如乙醇、甘油、水等混合。此外,当期望或必需时,还可以将合适的粘合剂、润滑剂、崩解剂和着色剂掺入混合物中。合适的粘合剂非限制性地包括淀粉,明胶,诸如葡萄糖或β乳糖的天然糖类,玉米甜味剂,诸如阿拉伯胶、黄芪胶的天然和合成树胶或者油酸钠,硬脂酸钠,硬脂酸镁,苯甲酸钠,乙酸钠,氯化钠等。崩解剂非限制性地包括淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
所述液体剂形成于合适的矫味的悬浮剂或分散剂中,如合成和天然树胶,例如黄芪胶、阿拉伯胶、甲基-纤维素等。对于肠胃外给药,期望无菌的混悬剂和溶液剂。当期望静脉内给药时,采用通常包含合适的防腐剂的等渗制剂。
本发明的化合物或组合还可以脂质体递送系统的形式给药,例如小单层囊泡、大单层囊泡和多层囊泡。脂质体可以由各种磷脂形成,例如胆固醇、硬脂胺或磷脂酰胆碱。
本发明的化合物或组合还可以通过使用与所述化合物分子偶联的单克隆抗体作为单独的载体递送。本发明的化合物还可以与作为可靶向药物载体的可溶性聚合物偶联。这类聚合物可以包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺酚、聚羟乙基天冬酰胺酚、或者被棕榈酰残基取代的聚氧化乙烯聚赖氨酸。此外,本发明的化合物可以偶联至用于实现药物的控释的一类生物可降解的聚合物,例如聚乳酸、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯以及交联或两亲的水凝胶嵌段共聚物。
无论何时需要治疗所述病症,可以任何上述组合物的形式并且根据本领域建立的给药方案给药本发明的化合物或组合。
所述产品的每日剂量可以在0.01-1.000mg每哺乳动物每日的大范围内变化。对于口服给药,所述组合物优选以片剂形式提供,所述片剂包含0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、150、200、250和500毫克的各种活性成分或其组合,用于对待治疗的患者根据症状调整剂量。有效量的所述药物通常以约0.1mg/kg-约300mg/kg体重每日的剂量水平提供。优选地,所述范围为约1-约50mg/kg体重每日。所述化合物或组合可以按照每日1-4次的方案给药。
给药的最佳剂量可以容易地由本领域技术人员确定,并且会随着所用的特定化合物、给药模式、制剂强度、给药模式和疾病状况的进展而变化。此外,与治疗的特定患者相关的因素,包括患者年龄、体重、饮食和给药时间,会导致需要调整剂量。
在另一方面,本发明还提供制备药物组合物的方法,所述药物组合物包含至少一种式(I)的化合物,所述化合物任选地与上述其他药剂中的至少一种以及药学可接受的载体组合。
所述组合物优选为适合相关每日剂量的量的单位剂型。
本发明的化合物的合适的剂量(特别地包括单位剂量)包括已知剂量,包括例如英国和美国药典、Remington′s Pharmaceutical Sciences(Mack Publishing Co.)、Martindale The Extra Pharmacopoeia(London,The Pharmaceutical Press)(例如参见其中的第31版,341页及其中引用的页)的参考文本或上文提及的出版物中所述或提及的这些化合物的单位剂量。
实施例
在另一实施方案中,本发明提供式(IIa)和(IIb)的化合物,其中X1、n、Z、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、R5和R6如实施例1至265中所定义:
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在另一实施方案中,本发明提供式(IIIa)和(IIIb)的化合物,其中X1、n、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、R5和R6如实施例266至443中所定义:
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在另一实施方案中,本发明提供式(IVa)和(IVb)的化合物,其中X1、o、Z、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、R5和R6如实施例444至795中所定义:
在式(IVa)和(IVb)二者中,o为0。
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在另一实施方案中,本发明提供式(IVa)和(IVb)的化合物,其中X1、o、Z、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、R5和R6如实施例1289至1296中所定义:
在式(IVa)和(IVb)二者中,o为0。
在另一实施方案中,本发明提供式(Va)和(Vb)的化合物,其中o、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、R5和R6如实施例796至971中所定义:
在式(Va)和(Vb)二者中,o为0。
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在另一实施方案中,本发明提供式(Va)和(Vb)的化合物,其中o、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、R5和R6如实施例1297至1300中所定义:
在式(Va)和(Vb)二者中,o为0。
在另一实施方案中,本发明提供式(VI)的化合物,其中X1、n、Z、R5和R6如实施例972至977中所定义:
化合物 | X1 | Z | n | R5 | R6 |
972 | CH2 | CH | 1 | F | H |
973 | CH2 | N | 1 | F | H |
974 | S | N | 1 | F | H |
975 | CH2 | CH | 1 | OMe | OMe |
976 | CH2 | N | 1 | OMe | OMe |
977 | S | N | 1 | OMe | OMe |
在另一实施方案中,本发明提供式(VII)的化合物,其中X1、n、Z、R2、R5和R6如实施例978至54中所定义:
化合物 | X1 | Z | n | R2 | R5 | R6 |
978 | CH2 | CH | 1 | Me | F | H |
979 | CH2 | N | 1 | Me | F | H |
980 | S | N | 1 | Me | F | H |
981 | CH2 | CH | 1 | Me | OMe | OMe |
982 | CH2 | N | 1 | Me | OMe | OMe |
983 | S | N | 1 | Me | OMe | OMe |
984 | CH2 | CH | 1 | 环丙基 | F | H |
985 | CH2 | N | 1 | 环丙基 | F | H |
986 | S | N | 1 | 环丙基 | F | H |
987 | CH2 | CH | 1 | 环丙基 | OMe | OMe |
988 | CH2 | N | 1 | 环丙基 | OMe | OMe |
989 | S | N | 1 | 环丙基 | OMe | OMe |
在另一实施方案中,本发明提供式(VIII)的化合物,其中X1、n、R5和R6如实施例990至993中所定义:
化合物 | X1 | n | R5 | R6 |
990 | CH2 | 1 | F | H |
991 | S | 1 | F | H |
992 | CH2 | 1 | OMe | OMe |
993 | S | 1 | OMe | OMe |
在另一实施方案中,本发明提供式(IX)的化合物,其中X1、n、R2、R5和R6如实施例994至1001中所定义:
在另一实施方案中,本发明提供式(X)的化合物,其中o、R5和R6如实施例1002至1005中所定义:
O为0。
化合物 | p | R5 | R6 |
1002 | 0 | F | H |
1003 | 0 | OMe | OMe |
1004 | 1 | F | H |
1005 | 1 | OMe | OMe |
在另一实施方案中,本发明提供式(XI)的化合物,其中o、R2、R5和R6如实施例1006至1013中所定义:
O为0。
化合物 | p | R2 | R5 | R6 |
1006 | 0 | Me | F | H |
1007 | 0 | Me | OMe | OMe |
1008 | 0 | 环丙基 | F | H |
1009 | 0 | 环丙基 | OMe | OMe |
1010 | 1 | Me | F | H |
1011 | 1 | Me | OMe | OMe |
1012 | 1 | 环丙基 | F | H |
1013 | 1 | 环丙基 | OMe | OMc |
在另一实施方案中,本发明提供式(XIIa)和(XIIb)的化合物,其中Z、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、R5和R6如实施例1014至1189中所定义:
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在另一实施方案中,本发明提供式(XIII)的化合物,其中Z、R5和R6如实施例1190至1193中所定义:
化合物 | Z | R5 | R6 |
1190 | CH | F | H |
1191 | N | F | H |
1192 | CH | OMe | OMe |
1193 | N | OMe | OMe |
在另一实施方案中,本发明提供式(XIV)的化合物,其中R5和R6如实施例1194至1195中所定义:
化合物 | R5 | R6 |
1194 | F | H |
1195 | OMe | OMe |
在另一实施方案中,本发明提供式(XVa)和(XVb)的化合物,其中Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、R5和R6如实施例1196至1282中所定义:
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在另一实施方案中,本发明提供式(XVa)和(XVb)的化合物,其中Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、R5和R6如实施例1310至1319中所定义:
在另一实施方案中,本发明提供式(XVI)的化合物,其中R5和R6如实施例1283至1284中所定义:
化合物 | R5 | R6 |
1283 | F | H |
1284 | OMe | OMe |
在另一实施方案中,本发明提供式(XVII)的化合物,其中R2、R5和R6如实施例1285至1288中所定义:
化合物 | R2 | R5 | R6 |
1285 | Me | F | H |
1286 | Me | OMe | OMe |
1287 | 环丙基 | F | H |
1288 | 环丙基 | OMe | OMe |
在另一实施方案中,本发明提供式(XVIII)的化合物,其中X1,n、R5和R6如实施例1320至1323中所定义:
化合物 | X1 | n | R5 | R6 |
1320 | CH2 | 1 | F | H |
1321 | S | 1 | F | H |
1322 | CH2 | 1 | OMe | OMe |
1323 | S | 1 | OMe | OMe |
在优选的实施方案中,本发明提供式(I)的化合物或者其药学可接受的盐、溶剂合物或多晶型物,包括其所有互变异构体和立体异构体,其中所述式(I)的化合物选自:
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实施例的合成
合成方法A
4-({4′-氟-[1,1′-联苯]-2-基}氨基)丁腈将4′-氟-[1,1′-联苯]-2-胺(0.5g,2.7mmol)、氰基硼氢化钠(.25g,4.0mmol)和4-氧代丁腈(0.44g,5.3mmol)在干燥MeOH(15mL)中溶解,并加入乙酸(0.5mL)。将反应物搅拌2h,直至通过UPLC分析观察到胺的完全消耗。在那之后,将反应混合物用饱和碳酸氢钠溶液(40mL)稀释,并用乙酸乙酯(3x 20mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发,并通过柱色谱法(使用含乙酸乙酯的己烷(10-20%)作为洗脱液)纯化,以得到纯的标题化合物(0.17g,12%)。
5-[3-({4′-氟-[1,1′-联苯]-2-基}氨基)丙基]-1,3,4-噻二唑-2-胺(A2)将4-({4′-氟-[1,1′-联苯]-2-基}氨基)丁腈(0.16g,0.6mmol)和硫代氨基脲(0.06g,0.7mmol)在三氟乙酸(1.3mL)中溶解。将反应通过UPLC分析监测。反应完成后,将溶剂真空移除,并将粗产物通过柱色谱法(使用含MeOH的DCM(0-2%)作为洗脱液)纯化,以得到纯的标题化合物(70mg,33%)。LCMS-方法10(200nm):RT=5.81min,95.2%纯度,[M+1]=329.2,1HNMR(300MHz,DMSO-d6)δ7.46-7.36(m,2H),7.32-7.23(m,2H),7.20-7.11(m,1H),7.05-6.89(m,3H),6.76-6.55(m,2H),4.61(t,J=5.9Hz,1H),3.10(q,J=6.6Hz,2H),2.82(t,J=7.5Hz,2H),1.85(p,J=7.2Hz,2H).
合成方法B
步骤1
将2-取代的苯胺(1.0eq.)、氰基硼氢化钠(1.5eq.)和叔丁基二甲基硅氧基乙醛(2.0eq.)在干燥MeOH(30.0vol.)中溶解,并加入乙酸(1.0vol.)。将反应物搅拌1-2h,直至通过UPLC分析观察到胺的完全消耗。在那之后,将反应混合物用饱和碳酸氢钠溶液(40mL)稀释,并用乙酸乙酯(3x 20mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发,将其在未进一步纯化下在下一步骤中使用。
步骤2
将步骤1的产物(1.0eq.)和四丁基氟化铵三水合物(1.05eq.)在THF(40.0vol.)中溶解。将反应通过UPLC分析监测。在反应完成后,将溶剂真空移除,并将粗产物带入步骤3。
5-{[2-({4′-氟-[1,1′-联苯]-2-基}氨基)乙基]硫烷基}-1,3,4-噻二唑-2-胺(A3).向2-({4′-氟-[1,1′-联苯]-2-基}氨基)乙-1-醇(0.58g,2.5mmol)、2-氨基-5-巯基-噻二唑(0.50g,3.8mmol)和三苯基膦(1.18g,4.5mmol)在无水THF(16.0mL)中的溶液滴加偶氮二甲酸二乙酯(diethyleneazodicarboxylate)(0.66g,3.8mmol)。将反应混合物在室温下搅拌过夜。在此之后,将溶剂真空移除。将粗产物通过柱色谱法(使用含0-3%MeOH的DCM)纯化,并通过制备TLC方法(使用含MeOH的DCM作为洗脱液)进行另外的再次纯化。通过制备型HPLC方法进行最终的再次纯化,以得到纯产物(40mg,7%)LCMS-方法7(200nm):RT=5.81min,98.7%纯度,[M]=346.0,1H NMR(300MHz,甲醇-d4)δ7.48-7.31(m,1H),7.27-7.10(m,2H),7.01(dd,J=7.4,1.6Hz,1H),6.84-6.52(m,1H),3.47(t,J=6.6Hz,1H),3.26(t,J=6.6Hz,1H).
5-{[2-({3′,4′-二甲氧基-[1,1′-联苯]-2-基}氨基)乙基]硫烷基}-1,3,4-噻二唑-2-胺(A4).向2-({3′,4′-二甲氧基-[1,1′-联苯]-2-基}氨基)乙-1-醇(0.9g,8.3mmol)、2-氨基-5-巯基-噻二唑(1.0g,7.5mmol)和三苯基膦(2.17g,8.3mmol)在无水THF(10.0mL)中的溶液滴加5mL无水四氢呋喃中的偶氮二甲酸二乙酯(diethyleneazadicarboxylate)(2.25g,9.8mmol)。将反应混合物在室温下搅拌过夜。在此之后,将溶剂真空移除。将粗产物通过柱色谱法(使用含0-3%MeOH的DCM)纯化,并通过制备型HPLC方法再次纯化,以得到纯产物(80mg,7%)LCMS-方法7(205nm):RT=5.27min,98.1%纯度,[M]=386.9,1H NMR(300MHz,DMSO-d6)δ7.30(s,1H),7.14(td,J=7.8,7.3,1.7Hz,1H),7.09-6.96(m,2H),6.89(dd,J=8.2,2.0Hz,0H),6.75-6.61(m,1H),4.94(t,J=6.0Hz,1H),3.79(d,J=1.8Hz,3H),3.38(d,J=6.5Hz,1H),3.24(t,J=6.4Hz,1H).
合成方法C
步骤1
向胺(4.27mmol)在MeOH(25.0mL)中的溶液加入4-氧代丁酸甲酯(0.99g,8.54mmol)和乙酸(0.8mL)。将反应混合物在环境温度下搅拌1.5小时。在那之后,加入NaBH3CN(0.40mg,6.41mmol),并将混合物搅拌1h。将反应用NaHCO3的饱和溶液淬灭。将水层用DCM(3x20mL)萃取。将合并的有机层用硫酸钠干燥、过滤、蒸发以得到产物。
4-({4′-氟-[1,1′-联苯]-2-基}氨基)丁酸甲酯(0.875g,71%)使用4′-氟-[1,1′-联苯]-2-胺。将粗品(1.47g)通过柱色谱法(使用100%DCM作为洗脱液)纯化。UPLC(254nm):RT=4.14min,76%纯度,[M+H]=288.20.
4-({3′,4′-二甲氧基-[1,1′-联苯]-2-基}氨基)丁酸甲酯(1.00g,71%)使用3′,4′-二甲氧基-[1,1′-联苯]-2-胺。将粗产物通过柱色谱法(使用含0-20%EA的己烷作为洗脱液)纯化。
步骤2
向相应原料(3.04mmol)在EtOH(30mL)中的溶液加入含50%肼的H2O(5.0eq)。将反应混合物在80℃下搅拌18小时。在那之后,将溶剂蒸发以得到纯化合物。
4-({4′-氟-[1,1′-联苯]-2-基}氨基)丁酰肼(0.85g,96%).将4-({4′-氟-[1,1′-联苯]-2-基}氨基)丁酸甲酯(0.875g,3.04mmol)用作原料。UPLC(254nm):RT=3.06min,[M+H]=288.35.
4-({3′,4′-二甲氧基-[1,1′-联苯]-2-基}氨基)丁酰肼(0.97g,97%).将4-({3′,4′-二甲氧基-[1,1′-联苯]-2-基}氨基)丁酸甲酯(1,0g,3.04mmol)用作原料。UPLC(254nm):RT=2.82min,[M+H]=330.30.
步骤3
向相应原料(2.6mmol)在MeOH(8mL)中的溶液加入N,N-二甲基甲酰胺二甲基乙缩醛(311mg,2.6mmol)。将反应混合物在80℃下搅拌1小时。在那之后,将溶剂蒸发以得到期望产物。
N′-[(1E)-(二甲基氨基)亚甲基]-4-({4′-氟-[1,1′-联苯]-2-基}氨基)丁酰肼(0.894g,100%).将4-({4′-氟-[1,1′-联苯]-2-基}氨基)丁酰肼(0.75g,2.61mmo1)用作原料。UPLC(254nm):RT=3.40min,[M+H]=343.15.
4-({3′,4′-二甲氧基-[1,1′-联苯]-2-基}氨基)-N′-[(1E)-(二甲基氨基)亚甲基]-丁酰肼(1.014g,100%).将4-({3′,4′-二甲氧基-[1,1′-联苯]-2-基}氨基)丁酰肼(0.869g,2.64mmol)用作原料。UPLC(254nm):RT=3.40min,[M+H]=385.30.
步骤4
在氩气气氛下,将THF中的MeNH2 2M(20eq)加入至相应原料在无水THF(10.0mL)的溶液中。将反应混合物冷却至0℃,并小心地加入乙酸(2mL)。将反应混合物在100℃下搅拌18小时。在那之后,将反应物冷却至室温,并加入水(5mL)。分层,并将水层用EA(3x20mL)萃取三次。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗品通过柱色谱法(使用含0-4%MeOH的DCM作为洗脱液)纯化,然后通过制备型HPLC再次纯化。将含有纯品形式的标题化合物的流分浓缩以得到产物。
4′-氟-N-[3-(4-甲基-4H-1,2,4-三唑-3-基)丙基]-[1,1′-联苯]-2-胺(B1)(101mg,11%)N′-[(1E)-(二甲基氨基)亚甲基]-4-({4′-氟-[1,1′-联苯]-2-基}氨基)丁酰肼(1.00g,2.92mmol)用作原料。LCMS-方法2(220nm):RT=4.78min,98.89%纯度。1H NMR(300MHz,DMSO-d6)δ8.32(s,1H),7.46-7.36(m,2H),7.32-7.21(m,2H),7.21-7.14(m,1H),6.95(d,J=1.7Hz,1H),6.72-6.61(m,2H),4.10(q,J=5.3Hz,2H),3.54(s,3H),2.69(d,J=7.5Hz,2H),1.95-1.84(m,2H).
3′,4′-二甲氧基-N-[3-(4-甲基-4H-1,2,4-三唑-3-基)丙基]-[1,1′-联苯]-2-胺(B3)(5mg,0.4%).4-({3′,4′-二甲氧基-[1,1′-联苯]-2-基}氨基)-N′-[(1E)-(二甲基氨基)-亚甲基]-丁酰肼(1.10g,2.86mmol)用作原料。LCMS-方法8(210nm):RT=12.12min,99.45%纯度。1H NMR(300MHz,DMSO-d6)δ8.32(s,1H),7.09-6.84(m,4H),6.66(d,J=7.9Hz,2H),4.11(q,J=5.4Hz,2H),3.79(d,J=5.4Hz,3H),3.53(s,3H),3.40(t,J=7.0Hz,2H),3.18(d,J=5.3Hz,3H),1.89-1.96(m,2H).
合成方法D
步骤1
N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺将5-(4-溴苯基)-1,3,4-噻二唑-2-胺(0.5g,2.0mmol)、三乙胺(0.54mL,4.0mmol)在DCM(5mL)中溶解,并在5℃下滴加乙酰氯(0.17g,2.15mmol),将反应物在室温下搅拌1h,在此时后在5℃下加入另外部分的三乙胺和乙酰氯,并将反应混合物搅拌另外30min。将混合物用DCM(15.0mL)稀释,并用碳酸氢钠的饱和溶液(20mL)、水(20mL)洗涤。获得乙酰化胺(UPLC(254nm):RT=3.13min[M+H]=297.9)和二乙酰化胺(UPLC(254nm):RT=3.58min[M+H]=338.9)的1∶1混合物形式的标题化合物(0.40g,60%)。在未纯化下于下一步骤中使用。
步骤2
N-{5-[4-({4′-氟-[1,1′-联苯]-2-基}氨基)苯基]-1,3,4-噻二唑-2-基}乙酰胺将N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(0.2g,0.67mmol)、4′-氟-[1,1′-联苯]-2-胺(0.12g,0.56mmol)、叔丁醇钠(0.15mg,1.56mmol)和XantPhos(40mg,0.07mmol)在1,4-二氧六环(6ml)中悬浮,将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)-氯仿加合物(35mg,0.035mmol)。将反应物在100℃下搅拌过夜。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用含MeOH的DCM(0-3%)作为洗脱液)纯化,以得到纯产物(0.24g,88%)。UPLC(254nm):RT=3.78min,85%纯度,[M+H]=404.8.
5-[4-({4′-氟-[1,1′-联苯]-2-基}氨基)苯基]-1,3,4-噻二唑-2-胺(C2)向N-{5-[4-({4′-氟-[1,1′-联苯]-2-基}氨基)苯基]-1,3,4-噻二唑-2-基}乙酰胺(0.17g,0.42mmol)在甲醇(2.5mL)中的溶液滴加浓盐酸(2.5mL)。将反应混合物回流过夜。在此时后,将反应物用饱和碳酸氢钠溶液(20mL)稀释,并用DCM(6x15mL)萃取,将有机层合并,用硫酸钠干燥,过滤并蒸发。将粗品通过制备型HPLC方法进行纯化,以得到纯产物(40mg,25%)LCMS-方法6(200nm):RT=20.57min,91.6%纯度,[M+H]=363.14,LCMS(340nm):RT=20.57min,99.2%纯度,[M+H]=363.14,1H NMR(300MHz,DMSO-d6)δ7.82(s,1H),7.59-7.33(m,7H),7.27-7.04(m,5H),6.89-6.54(m,2H).
N-{5-(4-{[2-(3,4-二甲氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-基}乙酰胺使N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(100mg,0.34mmol)、2-(3,4-二甲氧基苯基)苯胺(60mg,0.28mmol)、叔丁醇钠(75mg,1.56mmol)和XantPhos(40mg,0.035mmol)在1,4-二氧六环(3ml)中悬浮,将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)-氯仿加合物(17mg,0.017mmol)。将反应物在100℃下搅拌过夜。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用含MeOH的DCM(0-3%)作为洗脱液)纯化,以得到纯产物(0.2g,80%)。UPLC(254nm):RT=3.64min,85%纯度,[M+H]=447.15.
5-(4-{[2-(3,4-二甲氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-胺(C3).向N-{5-(4-{[2-(3,4-二甲氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-基}乙酰胺(0.20g,0.42mmol)在甲醇(3.0mL)中的溶液滴加浓盐酸(3.0mL)。将反应混合物回流过夜。在此时后,将反应物用饱和碳酸氢钠溶液(20mL)稀释,并用DCM(6x 15mL)萃取,将有机层合并,用硫酸钠干燥,过滤并蒸发。将粗产物通过制备型HPLC方法纯化,以得到纯产物(44mg,25%)LCMS(LCMS-方法10,200nm)、RT=5.22min,96.1%纯度,[M+H]=405.11,1H NMR(300MHz,DMSO-d6)δ7.87(s,1H),7.55-7.31(m,6H),7.37-7.13(m,5H),6.81-6.64(m,2H),3.53(s,3H),3.50(s,J=7.0Hz,3H).
N-[5-(4-{[2-(4-甲氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺.将N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(128mg,0.43mmol)、2-(4-甲氧基苯基)苯胺(102mg,0.51mmol)、碳酸铯(279mg,0.86mmol)和XantPhos(50mg,0.09mmol)在1,4-二氧六环(3.8mL)中悬浮。将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)(35mg,0.04mmol)。将反应物在100℃下搅拌96小时。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用DCM/MeOH 1∶0→98∶2作为洗脱液)纯化,以得到黄色固体形式的产物(62.5mg,35.01%)。UPLC(254nm):RT=7.14min,80.9%纯度,[M+H]=417.10.
5-(4-{[2-(4-甲氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-胺C4.向N-[5-(4-{[2-(4-甲氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺(63mg,0.15mmol)在甲醇(1.0mL)中的溶液滴加浓盐酸(1.0mL)。将反应混合物回流过夜。在那之后,将反应物用饱和碳酸氢钠溶液(20mL)稀释,将甲醇蒸发,并用乙酸乙酯(2x 10mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过制备TLC(用Hex/EtOAc/MeOH 70∶25∶5洗脱)进行纯化,以得到黄色固体形式的期望产物(19.6mg,35%)。LCMS(LCMS-方法11,200nm):RT=2.75min,98.9%纯度,[M+H]=375.21.1H NMR(300MHz,DMSO-d6)δ7.74(s,1H),7.50-7.43(m,2H),7.40-7.28(m,5H),7.23-7.14(m,3H),6.98-6.91(m,2H),6.84-6.78(m,2H),3.75(s,3H).
N-[5-(4-{[3-(4-甲氧基苯基)吡啶-2-基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺.将N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(87mg,0.29mmol)、3-(4-甲氧基苯基)吡啶-2-胺(70mg,0.35mmol)、碳酸铯(190mg,0.58mmol)和XantPhos(34mg,0.06mmol)在1,4-二氧六环(2.6mL)中悬浮。将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)(24mg,0.03mmol)。将反应物在100℃下搅拌72小时。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用DCM/MeOH 1∶0→95∶5作为洗脱液)纯化,以得到浅黄色固体形式的产物(114mg,93.6%)。UPLC(254nm):RT=5.35min,65%纯度,[M+H]=418.70.
N-[4-(5-氨基-1,3,4-噻二唑-2-基)苯基]-3-(4-甲氧基苯基)吡啶-2-胺(C5).向N-[5-(4-{[3-(4-甲氧基苯基)吡啶-2-基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺(114mg,0.27mmol)在甲醇(1.7mL)中的溶液滴加浓盐酸(1.7mL)。将反应混合物回流过夜。在那之后,将反应物用饱和碳酸氢钠溶液(20mL)稀释,将甲醇蒸发,并用乙酸乙酯(2x15mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过制备TLC(用DCM/MeOH 9∶1洗脱)进行纯化,以得到淡黄色固体形式的期望产物(16.4mg,16%)。LCMS-方法5(200nm):RT=1.75min,99.3%纯度,[M+H]=376.19.1H NMR(300MHz,DMSO-d6)δ8.20(dd,J=4.9,1.9Hz,1H),7.96(s,1H),7.67-7.56(m,4H),7.53(dd,J=7.4,1.9Hz,1H),7.47-7.40(m,2H),7.25(s,2H),7.10-7.04(m,2H),6.98(dd,J=7.4,4.9Hz,1H),3.82(s,3H).
N-[5-(4-{[3-(4-甲氧基苯基)吡啶-4-基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺.将N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(100mg,0.34mmol)、3-(4-甲氧基苯基)吡啶-4-胺(81mg,0.40mmol)、碳酸铯(219mg,0.67mmol)和XantPhos(39mg,0.07mmol)在1,4-二氧六环(3mL)中悬浮。将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)(27mg,0.03mmol)。将反应物在100℃下搅拌72小时。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用DCM/MeOH1∶0→95∶5作为洗脱液)纯化,以得到黄色固体形式的产物(75mg,53.6%)。UPLC(310nm):RT=3.96min,93%纯度,[M+H]=418.95.
N-[4-(5-氨基-1,3,4-噻二唑-2-基)苯基]-3-(4-甲氧基苯基)吡啶-4-胺(C6).向N-[5-(4-{[3-(4-甲氧基苯基)吡啶-4-基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺(75mg,0.18mmol)在甲醇(1.12mL)中的溶液滴加浓盐酸(1.12mL)。将反应混合物回流过夜。在那之后,将反应物用饱和碳酸氢钠溶液(20mL)稀释,将甲醇蒸发,并用乙酸乙酯(2x15mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过制备TLC(用DCM/MeOH 9∶1洗脱)纯化。通过制备TLC(用DCM/MeOH 9∶1洗脱)进行再次纯化,以得到发白固体形式的期望产物(32.0mg,47%)。LCMS-方法3(200nm):RT=3.01min,99.8%纯度,[M+H]=376.18.1H NMR(300MHz,DMSO-d6)δ8.26-8.20(m,2H),8.00(s,1H),7.66-7.61(m,2H),7.45-7.40(m,2H),7.32-7.18(m,5H),7.07-7.02(m,2H),3.80(s,3H).
N-[5-(4-{[3-(3,4-二甲氧基苯基)吡啶-4-基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺.将N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(100mg,0.34mmol)、3-(3,4-二甲氧基苯基)吡啶-4-胺(93mg,0.40mmol)、碳酸铯(219mg,0.67mmol)和XantPhos(39mg,0.07mmol)在1,4-二氧六环(3mL)中悬浮。将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)(27mg,0.03mmol)。将反应物在100℃下搅拌72小时。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用DCM/MeOH 1∶0→95∶5作为洗脱液)纯化,以得到浅黄色固体形式的产物(49mg,32.7%)。UPLC(310nm):RT=4.72min,100%纯度,[M+H]=448.15.
N-[4-(5-氨基-1,3,4-噻二唑-2-基)苯基]-3-(3,4-二甲氧基苯基)吡啶-4-胺(C7).向N-[5-(4-{[3-(3,4-二甲氧基苯基)吡啶-4-基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺(49mg,0.11mmol)在甲醇(0.75mL)中的溶液滴加浓盐酸(0.75mL)。将反应混合物回流过夜。在那之后,将反应物用饱和碳酸氢钠溶液(10mL)稀释,将甲醇蒸发,并用乙酸乙酯(2x 10mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过制备TLC(用DCM/MeOH 95∶5洗脱)进行纯化,以得到淡黄色固体形式的期望产物(11mg,24.8%)。LCMS-方法3(200nm):RT=2.90min,99.6%纯度,[M+H]=406.17.1H NMR(300MHz,DMSO-d6)δ8.28-8.22(m,2H),8.01(s,1H),7.67-7.60(m,2H),7.33-7.17(m,5H),7.09-6.99(m,3H),3.77(d,J=12.1Hz,6H).
N-[5-(4-{[3-(4-氟苯基)吡啶-2-基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺.将N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(100mg,0.34mmol)、3-(4-氟苯基)吡啶-2-胺(52mg,0.28mmol)、碳酸铯(219mg,0.67mmol)和XantPhos(39mg,0.07mmol)在1,4-二氧六环(3mL)中悬浮。将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)(27mg,0.03mmol)。将反应物在100℃下搅拌72小时。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用DCM/MeOH1∶0→99∶1作为洗脱液)纯化,以得到淡黄色固体形式的产物(75mg,55.6%)。UPLC(254nm):RT=5.92min,96.8%纯度,[M+H]=406.95.
N-[4-(5-氨基-1,3,4-噻二唑-2-基)苯基]-3-(4-氟苯基)吡啶-2-胺(C8).向N-[5-(4-{[3-(4-氟苯基)吡啶-2-基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺(75mg,0.18mmol)在甲醇(1.2mL)中的溶液滴加浓盐酸(1.2mL)。将反应混合物回流过夜。在那之后,将反应物用饱和碳酸氢钠溶液(20mL)稀释,将甲醇蒸发,并用乙酸乙酯(2x15mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过制备TLC(用DCM/MeOH 95∶5洗脱)纯化。通过制备TLC(用DCM/MeOH 95∶5洗脱)进行再次纯化,以得到微黄色固体形式的期望产物(4.3mg,6.4%)。LCMS-方法2(200nm):RT=4.69min,98.9%纯度,[M+H]=364.18.1HNMR(300MHz,甲醇-d4)δ8.22(dd,J=5.0,1.9Hz,1H),7.68-7.61(m,2H),7.60-7.47(m,5H),7.30-7.20(m,2H),7.02(dd,J=7.4,5.0Hz,1H).
N-[5-(4-{[3-(4-氟苯基)吡嗪-2-基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺.将N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(100mg,0.34mmol)、3-(4-氟苯基)吡嗪-2-胺(76mg,0.40mmol)、碳酸铯(219mg,0.67mmol)和XantPhos(39mg,0.07mmol)在1,4-二氧六环(3mL)中悬浮。将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)(27mg,0.03mmol)。将反应物在100℃下搅拌72小时。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用DCM/MeOH 1∶0→97∶3作为洗脱液)纯化,以得到淡黄色固体形式的产物(68mg,49.8%)。UPLC(254nm):RT=5.88min,95.5%纯度,[M+H]=407.05.
N-[4-(5-氨基-1,3,4-噻二唑-2-基)苯基]-3-(4-氟苯基)吡嗪-2-胺(C9).向N-[5-(4-{[3-(4-氟苯基)吡嗪-2-基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺(68mg,0.17mmol)在甲醇(1mL)中的溶液滴加浓盐酸(1mL)。将反应混合物回流过夜。在那之后,将反应物用饱和碳酸氢钠溶液(20mL)稀释,将甲醇蒸发,并用乙酸乙酯(2x 15mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过制备TLC(用DCM/MeOH 9∶1洗脱)纯化。通过制备TLC(用DCM/MeOH 95∶5洗脱)进行再次纯化,以得到黄色固体形式的期望产物(20.2mg,33.2%)。LCMS-方法4(328nm):RT=2.44min,97.0%纯度,[M+H]=365.15.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.19(s,2H),7.86-7.79(m,2H),7.64(s,4H),7.46-7.27(m,4H).
N-[5-(4-{[2-(4-苯氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺.将N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(100mg,0.34mmol)、2-(4-苯氧基苯基)苯胺(105mg,0.40mmol)、碳酸铯(219mg,0.67mmol)和XantPhos(39mg,0.07mmol)在1,4-二氧六环(3mL)中悬浮。将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)(27mg,0.03mmol)。将反应物在100℃下搅拌72小时。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用DCM/MeOH 1∶0→98∶2作为洗脱液)纯化,以得到黄色固体形式的产物(115mg,71.7%)。UPLC(254nm):RT=7.96min,88.6%纯度,[M+H]=479.15.
5-(4-{[2-(4-苯氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-胺(C10).向N-[5-(4-{[2-(4-苯氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺(95mg,0.20mmol)在甲醇(1.4mL)中的溶液滴加浓盐酸(1.4mL)。将反应混合物回流过夜。在那之后,将反应物用饱和碳酸氢钠溶液(20mL)稀释,将甲醇蒸发,并用乙酸乙酯(2x 15mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过制备TLC(用DCM/MeOH 8∶2洗脱)纯化。通过制备TLC(用Hex/EtOAc/MeOH 70∶25∶5洗脱)进行再次纯化,以得到淡黄色固体形式的期望产物(17.2mg,19.9%)。LCMS-方法11(200nm):RT=3.57min,97.5%纯度,[M+H]=437.16.1H NMR(300MHz,甲醇-d4)δ7.52-7.43(m,2H),7.41-7.15(m,8H),7.10-7.01(m,1H),6.97-6.84(m,4H),6.82-6.72(m,2H).
N-[5-(4-{[2-(4-丙氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺.将N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(120mg,0.40mmol)、2-(4-丙氧基苯基)苯胺(110mg,0.48mmol)、碳酸铯(262mg,0.80mmol)和XantPhos(47mg,0.08mmol)在1,4-二氧六环(3.6mL)中悬浮。将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)(33mg,0.04mmol)。将反应物在100℃下搅拌72小时。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用DCM/MeOH 1∶0→97∶3作为洗脱液)纯化,以得到淡黄色固体形式的产物(55.7mg,31.1%)。UPLC(254nm):RT=8.07min,86.8%纯度,[M+H]=445.30.
5-(4-{[2-(4-丙氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-胺(C11).向N-[5-(4-{[2-(4-丙氧基苯基)苯基]氨基}苯基)-1,3,4-噻二唑-2-基]乙酰胺(56mg,0.13mmol)在甲醇(0.84mL)中的溶液滴加浓盐酸(0.84mL)。将反应混合物回流过夜。在那之后,将反应物用饱和碳酸氢钠溶液(10mL)稀释,将甲醇蒸发,并用乙酸乙酯(2x 10mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过制备TLC(用Hex/EtOAc/MeOH 70∶25∶5洗脱)纯化。通过用乙醚浸渍进行再次纯化,以得到淡褐色固体形式的期望产物(11mg,22%)。LCMS-方法4(200nm):RT=3.67min,98.9%纯度,[M+H]=403.19.1H NMR(300MHz,甲醇-d4)δ7.56-7.47(m,2H),7.41-7.27(m,5H),7.17(td,J=7.3,1.5Hz,1H),6.96-6.81(m,4H),3.94(t,J=6.5Hz,2H),1.79(dtd,J=13.8,7.4,6.4Hz,2H),1.04(t,J=7.4Hz,3H).
N-{5-[4-({2-[4-(丙-2-基氧基)苯基]苯基}氨基)苯基]-1,3,4-噻二唑-2-基}乙酰胺.将N-[5-(4-溴苯基)-1,3,4-噻二唑-2-基]乙酰胺(100mg,0.34mmol)、2-[4-(丙-2-基氧基)苯基]苯胺(91mg,0.40mmol)、碳酸铯(219mg,0.67mmol)和XantPhos(39mg,0.07mmol)在1,4-二氧六环(3mL)中悬浮。将反应混合物用氩气流脱气20min,并加入三(二亚苄基丙酮)二钯(0)(27mg,0.03mmol)。将反应物在100℃下搅拌72小时。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用DCM/MeOH 1∶0→97∶3作为洗脱液)纯化,以得到淡黄色固体形式的产物(87.4mg,58.6%)。UPLC(254nm):RT=7.59min,87.6%纯度,[M+H]=445.15.
5-[4-({2-[4-(丙-2-基氧基)苯基]苯基}氨基)苯基]-1,3,4-噻二唑-2-胺(C12).向N-{5-[4-({2-[4-(丙-2-基氧基)苯基]苯基}氨基)苯基]-1,3,4-噻二唑-2-基}乙酰胺(87mg,0.20mmol)在甲醇(1.3mL)中的溶液滴加浓盐酸(1.3mL)。将反应混合物回流过夜。在那之后,将反应物用饱和碳酸氢钠溶液(15mL)稀释,将甲醇蒸发,并用乙酸乙酯(2x 15mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过制备TLC(用Hex/EtOAc/MeOH 70∶25∶5洗脱)纯化。通过用甲醇浸渍进行再次纯化,以得到黄色固体形式的期望产物(7mg,8.8%)。LCMS-方法4(200nm):RT=3.54min,97.4%纯度,[M+H]=403.20.1H NMR(300MHz,甲醇-d4)δ7.55-7.47(m,2H),7.41-7.27(m,5H),7.18(td,J=7.3,1.5Hz,1H),6.94-6.81(m,4H),4.59(dq,J=12.1,6.1Hz,1H),1.30(d,J=6.0Hz,6H).
合成方法E
向4-(氯苯基)-4-甲基-4-H-1,2,4-三唑(100mg,0.52mmol)和相应的碱(1.20mmol,2.3eq)在1,4-二氧六环(3.0mL)中的溶液加入胺(1.0eq)。将反应混合物脱气30分钟。然后加入xantphos(30mg,0.05mmol)和相应的催化剂,并将混合物在100℃下搅拌5天。将反应混合物通过硅藻土过滤,将滤液浓缩,并通过柱色谱法(使用含0-10%MeOH的DCM作为洗脱液)纯化。将含有标题化合物的流分合并并浓缩。将产物通过P-TLC(使用含4%MeOH的DCM作为洗脱液)进行再次纯化。
4′-氟-N-[4-(4-甲基-4H-1,2,4-三唑-3-基)苯基]-[1,1′-联苯]-2-胺(D1)(34mg,19%).使用4′-氟-[1,1′-联苯]-2-胺(97mg,0.52mmol)、t-BuONa(115mg,1.2mmol)、三(二亚苄基丙酮)二钯(0)的氯仿加合物(26mg 0.05mmol)、四(三苯基膦)钯(0)(30mg,0.05mmol)。LCMS-方法2(200nm):RT=5.54min,97.6%纯度,[M+H]=345.15.1H NMR(300MHz,DMSO-d6)δ8.46(s,1H),7.82(s,1H),7.45-7.49(m,4H),7.34-7.40(m,3H),7.17-7.25(m,3H),6.88(d,J=9.0Hz,2H),3.69(s,3H).
3′,4′-二甲氧基-N-[4-(4-甲基-4H-1,2,4-三唑-3-基)苯基]-[1,1′-联苯]-2-胺(D2)(45mg,28%).使用3′,4′-二甲氧基-[1,1′-联苯]-4-胺(120mg,0.52mmol)、Cs2CO3(396mg,1.2mmol)、三(二亚苄基丙酮)二钯(0)的氯仿加合物(26mg 0.05mmol)。LCMS-方法2(200nm)RT=4.8min,98.7%纯度,[M+H]=387.14.1H NMR(300MHz,DMSO-d6)δ8.46(s,1H),7.74(s,1H),7.47(d,J=9Hz,2H),7.31-7.42(m,3H),7.19-7.25(m,1H),6.99(d,2H,J=6Hz),6.88(d,2H,J=9Hz),3.76(s,3H),3.68(s,3H),3.62(s,3H).
N-[2-(4-甲氧基苯基)苯基]-4-(4-甲基-4H-1,2,4-三唑-3-基)苯胺(D3).向4-(氯苯基)-4-甲基-4-H-1,2,4-三唑(73mg,0.38mmol)和Cs2CO3(285mg,0.87mmol)在1,4-二氧六环(2.25mL)中的溶液加入2-(4-甲氧基苯基)苯胺(75mg,0.38mmol)。将反应混合物脱气30分钟。然后加入xantphos(22mg,0.04mmol)和三(二亚苄基丙酮)二钯(0)的氯仿加合物(19mg0.02mmol),并将混合物在100℃下搅拌过夜。将反应混合物通过硅藻土过滤,用MeOH洗涤。将滤液浓缩,并通过柱色谱法(使用含0-10%MeOH的DCM作为洗脱液)纯化。将含有标题化合物的流分合并并浓缩。将产物通过P-TLC(使用含4%MeOH的DCM作为洗脱液)进行再次纯化,以得到橙色固体形式的期望产物(13mg,10%)。LCMS-方法2(200nm):RT=5.38min,94.03%纯度,[M+H]=357.21.1H NMR(300MHz,甲醇-d4)δ8.48(s,1H),7.45(d,J=8.8Hz,2H),7.39(s,1H),7.37-7.28(m,4H),7.29-7.13(m,1H),6.94(dd,J=8.8,3.3Hz,4H),3.80(s,3H),3.78(s,3H).
2-(4-甲氧基苯基)-N-[4-(4-甲基-4H-1,2,4-三唑-3-基)苯基]吡啶-3-胺(D4).向4-(氯苯基)-4-甲基-4-H-1,2,4-三唑(68mg,0.35mmol)和Cs2CO3(264mg,0.81mmol)在1,4-二氧六环(2.10mL)中的溶液加入2-(4-甲氧基苯基)吡啶-3-胺(70mg,0.35mmol)。将反应混合物脱气30分钟。然后加入xantphos(20mg,0.03mmol)和三(二亚苄基丙酮)二钯(0)的氯仿加合物(18mg 0.02mmol),并将混合物在100℃下搅拌过夜。将反应混合物通过硅藻土过滤,用MeOH洗涤。将滤液浓缩,并通过柱色谱法(使用含0-10%MeOH的DCM作为洗脱液)纯化。将含有标题化合物的流分合并并浓缩。将产物通过P-TLC(使用含4%MeOH的DCM作为洗脱液)进行再次纯化,以得到白色固体形式的期望产物(35mg,28%)。LCMS-方法1(200nm):RT=5.58min,96.3%纯度,[M+H]=358.22.1H NMR(300MHz,DMSO-d6)δ8.67(s,1H),8.43(d,J=5.9Hz,1H),8.24(s,1H),7.84(d,J=8.8Hz,1H),7.71(d,J=8.8Hz,2H),7.54(d,J=8.3Hz,2H),7.39(dd,J=8.1,4.7Hz,3H),6.98(t,J=9.1Hz,4H),3.78(s,3H),3.74(s,3H).
2-(4-氟苯基)-N-[4-(4-甲基-4H-1,2,4-三唑-3-基)苯基]吡啶-3-胺(D5).向4-(氯苯基)-4-甲基-4-H-1,2,4-三唑(77mg,0.40mmol)和Cs2CO3(301mg,0.92mmol)在1,4-二氧六环(2.25mL)中的溶液加入2-(4-氟苯基)吡啶-3-胺(75mg,0.40mmol)。将反应混合物脱气30分钟。然后加入xantphos(23mg,0.04mmol)和三(二亚苄基丙酮)二钯(0)的氯仿加合物(20mg 0.02mmol),并将混合物在100℃下搅拌过夜。将反应混合物通过硅藻土过滤,用MeOH洗涤。将滤液浓缩,并通过柱色谱法(使用含0-10%MeOH的DCM作为洗脱液)纯化。将含有标题化合物的流分合并并浓缩。将产物通过P-TLC(使用含4%MeOH的DCM作为洗脱液)进行再次纯化,以得到淡橙色固体形式的期望产物(5mg,4%)。LCMS-方法1(205nm):RT=5.82min,99.46%纯度,[M+H]=346.22.1H NMR(300MHz,甲醇-d4)δ8.50(s,1H),8.37(dd,J=4.7,1.5Hz,1H),7.89(d,J=7.2Hz,1H),7.70(dd,J=9.1,5.6Hz,2H),7.51(d,J=8.8Hz,2H),7.42(dd,J=8.2,4.7Hz,1H),7.16(t,J=8.7Hz,2H),7.01(d,J=8.8Hz,2H),3.78(s,3H).
4-(4-甲基-4H-1,2,4-三唑-3-基)-N-[2-(4-苯氧基苯基)苯基]苯胺(D6).向4-(氯苯基)-4-甲基-4-H-1,2,4-三唑(74mg,0.38mmol)和Cs2CO3(289mg,0.89mmol)在1,4-二氧六环(3.00mL)中的溶液加入2-(4-苯氧基苯基)苯胺(100mg,0.38mmol)。将反应混合物脱气30分钟。然后加入xantphos(22mg,0.04mmol)和三(二亚苄基丙酮)二钯(0)的氯仿加合物(20mg 0.02mmol),并将混合物在100℃下搅拌过夜。将反应混合物通过硅藻土过滤,用MeOH洗涤。将滤液浓缩,并通过柱色谱法(使用含0-5%MeOH的DCM作为洗脱液)纯化。将含有标题化合物的流分合并并浓缩。将产物通过P-TLC(使用含4%MeOH的DCM作为洗脱液)进行再次纯化,以得到白色固体形式的期望产物(25mg,16%)。LCMS-方法5(200nm):RT=2.25min,99.51%纯度,[M+H]=419.20.1H NMR(300MHz,甲醇-d4)δ8.47(s,1H),7.74-7.14(m,11H),7.09(t,J=7.9Hz,1H),7.09-6.77(m,6H),3.75(s,3H).
3-(3,4-二甲氧基苯基)-N-[4-(4-甲基-4H-1,2,4-三唑-3-基)苯基]吡啶-4-胺(D7).向4-(氯苯基)-4-甲基-4-H-1,2,4-三唑(59mg,0.30mmol)和Cs2CO3(230mg,0.71mmol)在1,4-二氧六环(2.10mL)中的溶液加入3-(3,4-二甲氧基苯基)吡啶-4-胺(70mg,0.30mmol)。将反应混合物脱气30分钟。然后加入xantphos(18mg,0.03mmol)和三(二亚苄基丙酮)二钯(0)的氯仿加合物(16mg 0.02mmol),并将混合物在100℃下搅拌过夜。将反应混合物通过硅藻土过滤,用MeOH洗涤。将滤液浓缩,并通过柱色谱法(使用含0-10%MeOH的DCM作为洗脱液)纯化。将含有标题化合物的流分合并并浓缩。将产物通过P-TLC(使用含4%MeOH的DCM作为洗脱液)进行再次纯化,以得到白色固体形式的期望产物(20mg,16%)。LCMS-方法3(305nm):RT=2.69min,98.21%纯度,[M+H]=388.24.1H NMR(300MHz,甲醇-d4)δ8.55(s,1H),8.26-8.19(m,2H),7.72-7.58(m,2H),7.43-7.25(m,3H),7.09(d,J=4.2Hz,3H),3.89(s,3H),3.85(s,3H),3.82(s,3H).
合成方法F
5-(3-溴丙基)-1,3,4-噻二唑-2-胺.将三氯氧磷(7.37mL,79.0mmol)加入至氨基硫脲(2.185g,24.0mmol)和4-溴丁酸中。将混合物在85℃下搅拌过夜,冷却并倒入冰中。将饱和碳酸氢钠溶液加入至溶液中,并将水层用EA(3x80mL)萃取三次。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过柱色谱法(使用含0-10%DCM的MeOH作为洗脱液)纯化。将含有标题化合物的流分合并并浓缩(3.301g,62%)。UPLC(254nm):RT=1.91min,68%纯度,[M-H]=223.7.
N-[5-(3-溴丙基)-1,3,4-噻二唑-2-基]乙酰胺.在氩气气氛下,向5-(3-溴丙基)-1,3,4-噻二唑-2-胺(3.3g,14.8mmol)在无水DCM(35mL)中的溶液加入三乙胺(4.14mL,29.7mmol)和乙酰氯(1.16mL,16.3mmol)。将反应混合物在环境温度下搅拌6小时。在那之后,加入1M HCl(50mL),并将水层用DCM(3x80mL)萃取三次。将合并的有机层用硫酸钠干燥、过滤、蒸发以得到纯产物(3.144g,80%)。UPLC(254nm):RT=2.43min,89%纯度,[M+H]=265.65.
N-[5-(3-叠氮基丙基)-1,3,4-噻二唑-2-基]乙酰胺.在氩气气氛下,向N-[5-(3-溴丙基)-1,3,4-噻二唑-2-基]乙酰胺(1.0g,3.8mmol)在无水DMF(20.0mL)中的溶液加入叠氮化钠(0.37g,5.7mmol)。将反应混合物搅拌2小时。在那之后,加入水(10mL),并将水层用DCM(3x80mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发以得到纯产物(0.6g,71%)。UPLC(254nm):RT=2.29min,98%纯度,[M+H]=227.0.
N-[5-(3-氨基丙基)-1,3,4-噻二唑-2-基]乙酰胺.在氩气气氛下,将甲基N-[5-(3-叠氮基丙基)-1,3,4-噻二唑-2-基]乙酰胺(0.6g,2.7mmol)在无水四氢呋喃(7mL)中的溶液滴加至LAH团块(0.1g,2.8mmol)在无水THF(5mL)的悬浮液中。将反应混合物在环境温度下搅拌1h。在那之后,加入LAH(0.1g,2.8mmol)。继续搅拌2小时。在那之后,加入0.2mL水,随后加入0.4mL的20%NaOH和0.6mL水。将悬浮液通过硅藻土过滤,并用DCM/MeOH 9∶1洗涤。蒸发溶剂得到标题化合物(0.22g,41%)。UPLC(254nm):RT=1.17min,57%纯度,[M-H]=201.2.
N-{5-[3-(4-氟苯磺酰胺基)丙基]-1,3,4-噻二唑-2-基}乙酰胺.向3,4-二氯苯磺酰氯(165mg,0.85mmol)在DCM(1.0mL)和吡啶(1.0mL)的混合溶剂中的溶液加N-[5-(3-氨基丙基)-1,3,4-噻二唑-2-基]乙酰胺(170mg,0.85mmol)。将反应混合物在环境温度下搅拌18小时。在那之后,蒸发溶剂,并向残渣中加入1M HCl,并将水层用DCM(3x20mL)萃取。将合并的有机层用硫酸钠干燥、过滤、蒸发以得到产物(0.02g,7%)。UPLC(254nm):RT=2.56min,98%纯度,[M+H]=358.85.
N-[3-(5-氨基-1,3,4-噻二唑-2-基)丙基]-4-氟苯-1-磺酰胺(E2).将N-{5-[3-(4-氟苯磺酰胺基)丙基]-1,3,4-噻二唑-2-基}乙酰胺(20mg,0.06mmol)在HCl(2mL)和MeOH(2mL)的溶液中溶解。将反应混合物在80℃下搅拌18小时。在那之后,加入碳酸氢钠的溶液,并将水层用DCM(3x10mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过P-TLC(使用含4%甲醇的二氯甲烷)纯化,得到期望产物(3mg,17%)。LCMS-方法1(200nm):RT=2.56min,96.0%纯度。[M+H]=317.15.1H NMR(300MHz,MeOH-d4)δ7.87-7.94(m,2H),7.29-7.39(m,2H),2.86-2.97(m,4H),1.82-1.91(m,2H).
合成方法G
N-(2-氯乙基)-4-氟苯-1-磺酰胺将2-氯乙基胺盐酸盐(0.25g,2.2mmol)、4-氟苯磺酰氯(0.42g,2.2mmol)在DCM(2.5mL)和吡啶(2.5mL)中溶解。将反应物在室温下搅拌过夜。将混合物用DCM(15.0mL)稀释,并用1M盐酸溶液(20mL)洗涤。将有机层用硫酸钠干燥、过滤并蒸发。获得黄色油形式的标题化合物(0.5g,86%收率)。1H NMR(300MHz,CDCl3)δ7.82-7.95(m,2H),7.25-7.33(m,2H),4.92(t,1H),3.54-3.64(t,2H),3.32-3.44(dt,2H).
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N-{2-[(5-氨基-1,3,4-噻二唑-2-基)硫烷基]乙基}-4-氟苯-1-磺酰胺(E3)将N-(2-氯乙基)-4-氟苯-1-磺酰胺(0.18g,0.75mmol)、2-氨基-5-巯基-1,3,4-噻二唑(0.10g,0.75mmol)、碳酸钾(0.31g,2.25mmol)在乙腈(2.0mL)中溶解,并在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用含MeOH的DCM(0-5%)作为洗脱液)纯化,以得到纯产物(120mg,48%)LCMS-方法2(200nm):RT=4.24min,99.71%纯度,[M+H]=334.97,1H NMR(300MHz,DMSO-d6)δ7.92(br s,1H),7.80-7.90(m,2H),7.37-7.47(m,2H),7.30(br s,2H),3.07(m,4H).
4-氟-N-{2-[(4-甲基-4H-1,2,4-三唑-3-基)硫烷基]乙基}苯-1-磺酰胺(G2)将N-(2-氯乙基)-4-氟苯-1-磺酰胺(0.21g,0.87mmol)、3-巯基-4-甲基-4H-1,2,4-三唑(0.10g,0.87mmol)、碳酸钾(0.36g,2.61mmol)在乙腈(2.0mL)中溶解,并在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用含MeOH的DCM(0-5%)作为洗脱液)纯化,以得到纯产物(200mg,73%)LCMS-方法2(200nm):RT=3.79min,97.39%纯度,[M+H]=317.05,1H NMR(300MHz,DMSO-d6)δ8.53(s,1H),7.97(s,1H),7.88-7.77(m,2H),7.49-7.35(m,2H),3.53(s,3H),3.21-2.99(m,4H).
合成方法H
根据E2中描述的操作合成N-[5-(3-溴丙基)-1,3,4-噻二唑-2-基]乙酰胺。
N-[5-(3-{[(4-氟苯基)(甲基)氧代-λ6-硫酮]氨基}丙基)-1,3,4-噻二唑-2-基]乙酰胺.在氩气气氛下,向(4-氟苯基)(亚胺基)甲基-λ6-sulfanone(0.1g,0.58mmol)在无水DMSO(4mL)中的溶液加入KOH(0.065g,1.15mmol)。将悬浮液在环境温度下搅拌1.5小时。在那之后,缓慢(1.5小时)滴加N-[5-(3-溴丙基)-1,3,4-噻二唑-2-基]乙酰胺(0.229g,0.87mmol)在无水DMSO(4mL)中的溶液。在滴加完成后,将反应物立即用水(5mL)淬灭。将水层用DCM(10mL)萃取,然后用氯仿/异丙醇3∶1(5x 20mL)的混合物萃取5次。将合并的有机层用硫酸钠干燥、过滤、蒸发以得到纯产物(0.06g,29%)。UPLC(254nm):RT=2.2min,61%纯度,[M+H]=357.2
5-(3-{[(4-氟苯基)(甲基)氧代-λ6-硫酮]氨基}丙基)-1,3,4-噻二唑-2-胺(F2).将N-[5-(3-{[(4-氟苯基)(甲基)氧代-λ6-硫酮]氨基}丙基)-1,3,4-噻二唑-2-基]乙酰胺(20mg,0.06mmol)在HCl(2mL)和MeOH(2mL)中的溶液溶解。将反应混合物在80℃下搅拌3小时。在那之后,加入碳酸氢钠的溶液,并将水层用DCM(3x10 mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过P-TLC(使用含4%甲醇的二氯甲烷)纯化,得到期望产物(5mg,9%)。LCMS(245nm):RT=5.91min,98.88%纯度。[M+H]=315.171H NMR(300MHz,CDCl3)δ7.98-7.87(m,2H),7.22-7.26(m,2H),5.21(s,2H),3.11(s,2H),2.89-3.09(m,2H),1.97-2.00(m,2H).
合成方法I
甲基-4-(4-氟苯磺酰胺基)丁酸酯.向3,4-二氯苯磺酰氯(633mg,3.25mmol)在DCM(3.0mL)中的溶液加入三乙胺(1.3mL,9.76mmol)和甲基-4-氨基丁酸酯盐酸盐(500mg,3.25mmol)。将反应混合物在环境温度下搅拌18小时。在那之后,加入1M HCl(5mL),并将水层用DCM(3x5 mL)萃取。将合并的有机层用硫酸钠干燥、过滤、蒸发以得到产物(0.605g,68%)。UPLC(254nm):RT=2.89min,[M+H]=275.85.
4-氟-N-[3-(肼羰基)丙基]苯-1-磺酰胺.向甲基-4-(4-氟苯磺酰胺基)丁酸酯(605mg,2.09mmol)在EtOH(10mL)中的溶液加入含50%肼的H2O(0.65mL,10.4mmol)。将反应混合物在80℃下搅拌1小时。在那之后,将反应混合物冷却,加入水(20mL),并将水层用EA(3x10 mL)萃取三次。将合并的有机层用硫酸钠干燥、过滤并蒸发以得到纯产物(180mg,31%)。UPLC(254nm):RT=I.88min,65%纯度,[M+H]=276.2.
N-(3-{N′-[(1-二甲基氨基)亚甲基]肼羰基}丙基)-4-氟苯-1-磺酰胺.向4-氟-N-[3-(肼羰基)丙基]苯-1-磺酰胺(180mg,0.65mmol)在MeOH(2mL)中的溶液加入N,N-二甲基甲酰胺二甲基乙缩醛(78mg,0.65mmol)。将反应混合物在80℃下搅拌1小时。在那之后,将溶剂蒸发以得到期望产物(216mg,100%)。UPLC(254nm):RT=1.78min,60%纯度,[M+H]=331.3.
4-氟-N-[3-(4-甲基-4H-1,2,4-三唑-3-基)丙基]苯-1-磺酰胺(G1).在氩气气氛下,将THF中的MeNH2 2M(32mL,3.3mmol)加入至N-(3-{N′-[(1-二甲基氨基)亚甲基]肼羰基}丙基)-4-氟苯-1-磺酰胺(216mg,0.63mmol)在无水THF(5.0mL)中的溶液。将反应混合物冷却至0℃,并小心地加入乙酸(2mL)。将反应混合物在100℃下搅拌1小时。在那之后,将反应物冷却至室温,并加入水(5mL),并将水层用EA(3x20 mL)萃取三次。将合并的有机层用硫酸钠干燥、过滤并蒸发。将粗产物通过柱色谱法(使用含0-4%MeOH的DCM作为洗脱液)纯化。将获得的40mg产物通过P-TLC(使用含4%MeOH的DCM作为洗脱液)再次纯化,然后通过制备型HPLC再次纯化。将含有纯品形式的标题化合物的流分浓缩(3mg,2%)。LCMS-方法1(200nm):RT=6.17min,99.5%纯度,[M+H]=299.2.1H NMR(300MHz,CDCl3)δ8.09(s,1H),7.84-7.90(m,2H),7.15-7.23(m,2H),5.62(t,J=5.6Hz,1H),3.64(s,3H),3.12(q,J=3.1Hz,2H),2.85(t,J=6.6Hz,2H)2.06-2.15(m,2H).
合成方法K
N-(2-氯乙基)氨磺酰氯将2-氯乙基胺盐酸盐(0.50g,4.3mmol)、硫酰氯(3.49g,2.10mL,25.8mmol)在乙腈(5.0mL)中溶解,将反应物在80℃下搅拌过夜。将混合物浓缩,并在下一步骤中直接使用。获得黄色油形式的标题化合物(0.5g,86%收率)。1H NMR(300MHz,d6-DMSO)δ11.0(bs,1H),3.83(t,2H),3.36(t,2H)
(2-氯乙基)[(3,4-二甲氧基苯基)氨磺酰基]胺将N-(2-氯乙基)氨磺酰氯(0.14g,0.78mmol)和3,4-二甲氧基苯胺(0.12g,0.78mmol)在DCM(1.2mL)和吡啶(1.2mL)中溶解。将反应物在室温下搅拌过夜。在那之后,将反应混合物冷却至室温。将混合物用DCM(15.0mL)稀释,并用1M盐酸溶液(20mL)洗涤。将有机层用硫酸钠干燥、过滤并蒸发。获得黄色油形式的标题化合物(0.23g,100%收率)。将化合物在未进一步纯化下在下一步骤中使用。UPLC(280nm):RT=3.14min,11%纯度,[M+H]=294.95
[(3,4-二甲氧基苯基)氨磺酰基]({2-[(4-甲基-4H-1,2,4-三唑-3-基)硫烷基]乙基})胺(G5)将(2-氯乙基)[(3,4-二甲氧基苯基)氨磺酰基]胺(0.085g,0.74mmol)、3-巯基-4-甲基-4H-1,2,4-三唑(0.22g,0.74mmol)、碳酸钾(0.31g,2.21mmol)在乙腈(1.7mL)中溶解,并在80℃下搅拌3小时。在那之后,将反应混合物冷却至室温,通过硅藻土过滤,蒸发,并通过柱色谱法(使用含MeOH的DCM(0-5%)作为洗脱液)纯化,以得到纯产物(8mg,3%)LCMS-方法2(200nm):RT=3.08min,99.1%纯度,[M+H]=374.03,1HNMR(400MHz,DMSO-d6)δ7.57(s,1H),6.96-6.75(m,2H),6.72-6.63(m,1H),3.71(d,J=2.7Hz,6H),3.51(s,3H),3.23-3.08(m,4H).
合成方法L
[4-(4-氟苯磺酰胺基)苯基]硼酸将4-氨基苯基硼酸(1.5g,8.7mmol)和4-氟苯基磺酰氯(1.53g,7.9mmol)在吡啶(43mL)中溶解。将混合物在50℃下搅拌过夜,冷却至室温,并将溶剂真空移除。将粗产物在未经任何进一步纯化下于下一步骤中使用(5.4g,200%)。UPLC(254nm):RT=2.88min,50%纯度,[M-2H]=293.5.
[4-(3,4-二甲氧基苯磺酰胺基)苯基]硼酸将4-氨基苯基硼酸(2.35g,11.6mmol)和3,4-二甲氧基苯基磺酰氯(1.53g,7.9mmol)在吡啶(80mL)中溶解。将混合物在50℃下搅拌过夜,冷却至室温,并将溶剂真空移除。将粗产物在未经任何进一步纯化下于下一步骤中使用(8.1g,200%)。UPLC(254nm):RT=2.77min,50%纯度,[M-2H]=335.6.
N-[4-(2-氨基-1,3-噻唑-5-基)苯基]-4-氟苯-1-磺酰胺(I1).将[4-(4-氟苯磺酰胺基)苯基]硼酸(2.75g,9.2mmol)、2-氨基-5-溴-噻唑氢溴酸盐(2.00g,7.7mmol)和碳酸钾(3.21g,23.1mmol)在1,4-二氧六环(40.0mL)和水(4.0mL)中的溶液用氩气流脱气20分钟,并一次性加入[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)与二氯甲烷的络合物(0.84g,1.2mmol)。将反应混合物在130℃下搅拌过夜。在此之后,将反应物通过硅藻土过滤,然后将其用DCM洗涤,加入水(40mL),分层,并将水层用DCM(3x 25mL)萃取三次,将有机层合并,用硫酸钠干燥、过滤并蒸发。将粗产物通过柱色谱法(使用含甲醇的DCM(0-3%)作为洗脱液)纯化,并将含有产物的流分通过制备型HPLC方法进行额外的纯化,以得到红色固体形式的纯产物(48mg,2%)。LCMS-方法1(254nm):RT=6.73min,99.6%纯度,[M+H]=349.7.1H NMR(300MHz,DMSO-d6)δ10.36(s,1H),7.84-7.76(m,2H),7.45-7.36(m,2H),7.28(dd,J=6.6,2.0Hz,3H),7.14-6.97(m,4H).
N-[4-(2-氨基-1,3-噻唑-5-基)苯基]-3,4-二甲氧基苯-1-磺酰胺(I2).将[4-(3,4-二甲氧基苯磺酰胺基)苯基]硼酸(1.64g,5.5mmol)、2-氨基-5-溴-噻唑氢溴酸盐(1.20g,4.6mmol)和碳酸钾(3.21g,23.1mmol)在1,4-二氧六环(40.0mL)和水(4.0mL)中的溶液用氩气流脱气20分钟,并一次性加入[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)与二氯甲烷的络合物(0.51g,0.7mmol)。将反应混合物在130℃下搅拌过夜。在此之后,将反应物通过硅藻土过滤,然后将其用DCM洗涤,加入水(40mL),分层,并将水层用DCM(3x 25mL)萃取三次,将有机层合并,用硫酸钠干燥、过滤并蒸发。将粗产物通过柱色谱法(使用含甲醇的DCM(0-3%)作为洗脱液)纯化,并将含有产物的流分通过制备型HPLC方法进行额外的纯化,以得到橙色固体形式的纯产物(45mg,3%)。LCMS-方法2(200nm):RT=2.99min,99.9%纯度,[M+H]=392.0.1H NMR(300MHz,DMSO-d6)δ8.16(s,1H),7.34-7.22(m,5H),7.13-6.95(m,5H),3.79(s,3H),3.76(s,3H).
合成方法M
2-溴-4′-氟-1,1′-联苯将1,2-二溴苯(8.26g,35.0mmol)、4-氟苯基硼酸(2.5g,17.9mmol)和碳酸钠(3.79g,35.0mmol)在乙醇(35.0mL)、甲苯(35.0mL)和水(35.0mL)中的溶液用氩气流脱气,并一次性加入四(三苯基膦)钯(0)(1.00g,0.9mmol)。将反应混合物在100℃下搅拌过夜。在此之后,将反应物通过硅藻土过滤,分层,并将水层用乙酸乙酯(2x15mL)萃取两次,将有机层合并,用硫酸钠干燥、过滤并蒸发。将粗产物通过柱色谱法(使用己烷作为洗脱液)纯化,以得到标题产物(5.50g,122%)。UPLC(254nm):RT=4.33min,91%纯度,[M+H]=未观测到.
1-{4′-氟-[1,1′-联苯]-2-基}哌啶-4-甲腈将2-溴-4′-氟-1,1′-联苯(0.3g,1.2mmol)、哌啶-4-甲腈(0.2g,1.8mmol)、XantPhos(0.14g,0.24mmol)和碳酸铯(0.78g,2.4mmol)在无水1,4-二氧六环(3.0mL)中的溶液用氩气流脱气,并一次性加入三(二亚苄基丙酮)二钯(0)(0.11g,0.12mmol)。将反应混合物在100℃下搅拌过夜。在此之后,将反应物通过硅藻土过滤,用乙酸乙酯洗涤,并蒸发。将粗产物通过柱色谱法(使用含乙酸乙酯的己烷(0-4%)作为洗脱液)纯化,以得到标题产物(0.18g,54%)。UPLC(254nm):RT=4.25min,90%纯度,[M+H]=281.4.
5-(1-{4′-氟-[1,1′-联苯]-2-基}哌啶-4-基)-1,3,4-噻二唑-2-胺(L2)将1-{4′-氟-[1,1′-联苯]-2-基}哌啶-4-甲腈(0.18g,0.7mmol)和硫代氨基脲(0.09g,1.05mmol)在三氟乙酸(1.5mL)中的的溶液在65℃下搅拌2小时。在此时后,将反应物冷却至室温,用饱和碳酸氢钠溶液(15mL)稀释,并用DCM(3x 15mL)萃取,将有机层合并,用硫酸钠干燥,过滤并蒸发。将粗产物用乙酸乙酯(1mL)研磨,过滤并真空干燥以得到纯产物(100mg,45%)LCMS(LCMS方法:LCMS-002-20-80-95-12-05-25(Gemini-BCM)-UV,200nm):RT=4.97min,96.7%纯度,[M+H]=355.2.1H NMR(300MHz,DMSO-d6)δ7.70-7.58(m,2H),7.38-7.17(m,4H),7.16-6.89(m,4H),3.05(d,J=11.8Hz,2H),2.87(ddd,J=11.5,7.6,3.9Hz,1H),2.62(t,J=11.3Hz,2H),1.86(d,J=12.7Hz,2H),1.54(qd,J=12.0,3.8Hz,2H).
合成方法N
4-(2-氨基-1,3-噻唑-5-基)哌啶-1-羧酸叔丁酯根据文献中的两步法合成(总收率:60%)。
4-(2-乙酰胺基-1,3-噻唑-5-基)哌啶-1-羧酸叔丁酯.在氩气气氛下,向4-(2-氨基-1,3-噻唑-5-基)哌啶-1-羧酸叔丁酯(3.75g,13.23mmol)在无水DCM(35mL)中的溶液加入三乙胺(3.69mL,26.4mmol)和乙酰氯(1.00mL,14.6mmol)。将反应混合物在环境温度下搅拌48小时。在那之后,加入水(50mL),并将水层用DCM(5x80mL)萃取五次。将合并的有机层用硫酸钠干燥、过滤并蒸发以得到纯产物(4.175g,97%)。UPLC(254nm):RT=4.27min,[M+H]=326.25.
N-[5-(哌啶-4-基)-1,3-噻唑-2-基]乙酰胺.向(2-乙酰胺基-1,3-噻唑-5-基)哌啶-1-羧酸叔丁酯(4.175g,12.83mmol)在THF(90.0mL)中的溶液加入二氧六环中的4M HCl(10mL)。将反应混合物搅拌18小时。在那之后,将反应混合物过滤,将沉淀用EA(2x40mL)洗涤,并在减压下干燥以得到纯产物(2.752g,82%)。UPLC(254nm):RT=2.1min,[M+H]=226.25.
N-{5-[1-(4-氟苯磺酰基)哌啶-4-基]-1,3-噻唑-2-基}乙酰胺.向3,4-二氯苯磺酰氯(182mg,0.94mmol)在DCM(3.0mL)和吡啶(3.0mL)的混合溶剂中的溶液加入N-[5-(哌啶-4-基)-1,3-噻唑-2-基]乙酰胺(211mg,0.94mmol)。将反应混合物在环境温度下搅拌48小时。在那之后,将溶剂蒸发,并将粗品带入下一步骤。
5-[1-(4-氟苯磺酰基)哌啶-4-基]-1,3-噻唑-2-胺(M1).将N-{5-[1-(4-氟苯磺酰基)哌啶-4-基]-1,3-噻唑-2-基}乙酰胺(300mg,0.78mmol)在HCl(12mL)和MeOH(12mL)的溶液中溶解。将反应混合物在80℃下搅拌18小时。在那之后,加入饱和碳酸氢钠的溶液,并将水层用DCM(3x80mL)萃取。将合并的有机层用硫酸钠干燥,过滤,蒸发并通过柱色谱法(使用含0-10%MeOH的DCM作为洗脱液)纯化。将含有标题化合物的流分合并并浓缩。将产物通过P-TLC(使用含4%MeOH的DCM作为洗脱液)进行再次纯化(16mg,6%)。LCMS-方法1(220nm):RT=6.37min,95.99%纯度,[M+H]=342.07.1H NMR(300MHz,CD3OD)δ7.85-7.90(m,2H),7.35-7.41(m,2H),6.7(s,1H),3.82(d,J=12.0Hz,2H),2.61-2.73(m,1H),2.40-2.49(m,2H),1.98-2.04(m,2H),1.60-1.75(m,2H).
1-(4-氟苯磺酰基)哌啶-4-甲腈.向哌啶-4-甲腈(500mg,4.54mmol)在DCM(5.0mL)和吡啶的混合溶剂中的溶液加入4-氟苯磺酰氯(880mg,4.54mmol)。将反应混合物在环境温度下搅拌16小时。将反应混合物用1M HCl(50ml)和DCM(50ml)稀释,并分层。将有机层用1MHCl(2x50ml)洗涤两次,并浓缩以得到米黄色固体形式的期望产物。1H NMR(400MHz,氯仿-d)δ7.98-7.66(m,2H),7.36-7.12(m,2H),3.29-3.06(m,4H),2.91-2.71(m,1H),2.17-1.89(m,4H).
5-[1-(4-氟苯磺酰基)哌啶-4-基]-1,3,4-噻二唑-2-胺(M2).将1-(4-氟苯磺酰基)哌啶-4-甲腈(500mg,1.86mmol)和硫代氨基脲(190mg,2.05mmol)在TFA(4.0mL)中溶解,并将反应混合物在60℃下搅拌2小时。在那之后,将溶剂浓缩,并将残渣在DCM∶MeOH(4.0ml,95∶5;vol∶vol)溶液中悬浮,并将沉淀过滤以得到白色固体形式的期望化合物(610mg,96.0%)。LCMS-方法2(方法:LCMS方法2(Gemini BCM)-UV,200nm):RT=4.29min,97.59%纯度,[M+H]=343.13.1H NMR(300MHz,DMSO-d6)δ8.20-7.71(m,2H),7.51(t,J=8.8Hz,2H),3.66(dt,J=12.2,3.7Hz,2H),2.95(ddd,J=11.3,7.5,3.8Hz,1H),2.43(dd,J=11.8,2.6Hz,2H),2.10-1.91(m,2H),1.76-1.43(m,2H).
合成方法O
4-{N′-[(1E)-(二甲基氨基)亚甲基]肼羰基}哌啶-1-羧酸叔丁酯.向4-(肼羰基)哌啶-1-羧酸叔丁酯(500mg,2.05mmol)在DMF(5mL)中的溶液加入N,N-二甲基甲酰胺二甲基乙缩醛(245mg,2.05mmol)。将反应混合物在100℃下搅拌18小时。在那之后,将溶剂蒸发以得到期望产物(601mg,98%)。
4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-羧酸叔丁酯.在氩气气氛下,将THF中的MeNH2 2M(15mL,40.2mmol)加入至4-{N′-[(1E)-(二甲基氨基)亚甲基]肼羰基}哌啶-1-羧酸叔丁酯(600mg,2.01mmol)在无水THF(6.0mL)中的溶液。将反应混合物冷却至0℃,并小心地加入乙酸(2mL)。将反应混合物在100℃下搅拌18小时。在那之后,将反应物冷却至室温,并加入水(20mL),并将水层用EA(3x50mL)萃取三次。将合并的有机层用硫酸钠干燥、过滤并蒸发以得到粗产物(511mg,95%)。
4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶.向4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶-1-羧酸叔丁酯(511mg,1.71mmol)在THF(5.0mL)中的溶液加入二氧六环中的4M HCl(6.0mL)。将反应混合物搅拌18小时。在那之后,将反应混合物过滤,将沉淀用EA(2x40mL)洗涤,并在减压下干燥以得到产物(347mg,100%)。
1-(4-氟苯磺酰基)-4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶(N1).向4-氟苯磺酰氯(117mg,0.60mmol)在吡啶(1.0mL)中的溶液加入4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶(100mg,0.60mmol)。将反应混合物在环境温度下搅拌18小时。在那之后,将溶剂蒸发,并加入1M Hcl(5mL),并将水层用DCM(3x10mL)萃取。将合并的有机层用硫酸钠干燥、过滤并蒸发。将产物通过P-TLC(使用含5%MeOH的DCM作为洗脱液)进行纯化(6mg,3%)。LCMS-方法2(220nm):RT=3.63min,96.34%纯度,[M+H]=325.11 1H NMR(300MHz,CDCl3)δ8.05(s,1H),7.77-7.90(m,2H),7.20-7.28(m,2H),7.78-7.83(m,1H),3.62(s,3H),2.60-2.86(m,4H),2.02-2.15(m,4H).
合成方法P
5-甲基-1H-1,3-苯并二唑-1-羧酸叔丁酯将5-甲基-1H-1,3-苯并二唑(0.5g,7.6mmol)、Boc酸酐(2.44g,11.4mmol)、DMAP(92mg,0.76mmol)和三乙胺(2.11mL,15mmol)在乙腈(10mL)中溶解。将混合物在80℃下搅拌过夜,冷却,并将溶剂真空移除。将粗产物通过柱色谱法(使用DCM作为洗脱液)纯化。将含有标题化合物的流分合并并浓缩(0.80g,46%)。UPLC(254nm):RT=3.75min,93.2%纯度,[M+H]=233.2.
5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯.将5-甲基-1H-1,3-苯并二唑-1-羧酸叔丁酯(0.8g,3.44mmol)、N-溴丁二酰亚胺(0.64g,3.62mmol)、过氧化苯甲酰(22mg,0.1mmol)在四氯甲烷(16ml)中悬浮,将反应混合物在90℃下搅拌过夜。在那之后,将反应混合物冷却至0℃,将沉淀滤出,并将滤液真空浓缩以得到淡黄色油形式的期望产物(0.95g,89%)。UPLC(254nm):RT=3.75min,80%纯度,[M+H]=312.75.
4′-氟-[1,1′-联苯]-2-胺.将2-溴苯胺(1.5g,8.7mmol)、4-氟苯基硼酸(1.46g,10.5mmol)和碳酸钾(4.16g,30.1mmol)在1,4-二氧六环(15.0mL)和水(15.0mL)中的溶液用氩气流脱气20分钟,并一次性加入[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)与二氯甲烷的络合物(0.43g,0.5mmol)。将反应混合物在100℃下搅拌过夜。在此之后,将反应物通过硅藻土过滤,分层,并将水层用乙酸乙酯(2x 15mL)萃取两次,将有机层合并,用硫酸钠干燥、过滤并蒸发。将粗产物通过柱色谱法(使用含10%乙酸乙酯的己烷作为洗脱液)纯化,以得到纯产物(1.65g,100%)。UPLC(254nm):RT=3.31min,99%纯度,[M+H]=187.9.
N-[(1H-1,3-苯并二唑-5-基)甲基]-4′-氟-[1,1′-联苯]-2-胺(O1).向4′-氟-[1,1′-联苯]-2-胺(100mg,0.53mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(244mg,0.59mmol)在DMF(1.0mL)中的溶液加入碳酸钠(170mg,1.6mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物用乙酸乙酯(15.0mL)稀释,并用半饱和盐水(3x20mL)洗涤。将有机层用硫酸钠干燥、过滤、蒸发以得到粗产物,将其通过柱色谱法(使用含MeOH的DCM 0-2%作为洗脱液)纯化,以得到灰白色固体形式的期望产物(48mg,22%)LCMS-方法2(200nm):RT=4.13min,97.2%纯度,[M+H]=318.25.1H NMR(300MHz,DMSO-d6)δ8.15(s,1H),7.62-7.43(m,3H),7.32(t,J=8.9Hz,2H),7.18(d,J=8.2Hz,1H),7.05(ddd,J=8.5,7.4,1.6Hz,1H),6.97(dd,J=7.5,1.6Hz,1H),6.70-6.44(m,2H),5.32(s,1H),4.40(d,J=5.9Hz,2H).
3′,4′-二甲氧基-[1,1′-联苯]-2-胺.将2-溴苯胺(3.0g,17.4mmol)、3,4-二甲氧基苯基硼酸(3.81g,20.9mmol)和碳酸钾(8.32g,30.1mmol)在1,4-二氧六环(30.0mL)和水(30.0mL)中的溶液用氩气流脱气20分钟,并一次性加入[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)与二氯甲烷的络合物(0.85g,1.1mmol)。将反应混合物在100℃下搅拌过夜。在此之后,将反应物通过硅藻土过滤,分层,并将水层用乙酸乙酯(2x 15mL)萃取两次,将有机层合并,用硫酸钠干燥、过滤并蒸发。将粗产物通过柱色谱法(使用含乙酸乙酯的己烷(2-10%)作为洗脱液)纯化,以得到纯产物(3.2g,80%)。UPLC(254nm):RT=3.25min,90%纯度,[M+H]=229.9.
N-[(1H-1,3-苯并二唑-5-基)甲基]-3′,4′-二甲氧基-[1,1′-联苯]-2-胺(O2).向3′,4′-二甲氧基-[1,1′-联苯]-2-胺(200mg,0.87mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(0.398g,0.96mmol)在DMF(1.0mL)中的溶液加入碳酸钠(277mg,2.62mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物用乙酸乙酯(15.0mL)稀释,并用半饱和盐水(3x20mL)洗涤。将有机层用硫酸钠干燥、过滤、蒸发以得到粗产物,将其通过柱色谱法(使用含MeOH的DCM 0-2%作为洗脱液)纯化,以得到灰白色固体形式的期望产物(70mg,17%)LCMS-方法2(205nm):RT=3.66min,96.5%纯度,[M+H]=360.1.1H NMR(300MHz,DMSO-d6)δ8.16(s,1H),7.52(d,J=8.3Hz,2H),7.20(dd,J=8.3,1.6Hz,1H),7.12-6.87(m,5H),6.61(ddd,J=8.3,5.9,1.2Hz,2H),5.26(t,J=5.9Hz,1H),4.40(d,J=5.9Hz,2H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)苯胺(O3).向2-(4-甲氧基苯基)苯胺(90mg,0.45mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(156mg,0.50mmol)在DMF(1.0mL)中的溶液加入碳酸钠(144mg,1.36mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH 100∶0→98∶2)纯化。通过制备TLC(用DCM/MeOH 95∶5洗脱)进行再次纯化,以得到灰白色固体形式的期望产物(35mg,23%)。LCMS-方法2(230nm):RT=3.90min,96.6%纯度,[M+H]=330.24.1H NMR(300MHz,甲醇-d4)δ8.13(s,1H),7.56(d,J=5.5Hz,2H),7.36(d,J=8.8Hz,2H),7.25(dd,J=8.4,1.2Hz,1H),7.15-6.93(m,4H),6.75-6.63(m,2H),4.45(s,2H),3.84(s,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)吡啶-3-胺(O4).向2-(4-甲氧基苯基)吡啶-3-胺(90mg,0.45mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(155mg,0.50mmol)在DMF(1.0mL)中的溶液加入碳酸钠(143mg,1.36mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH/NH3100∶0∶0→9∶1∶0.1)纯化。通过制备TLC(用DCM/MeOH/NH395∶5∶0.1洗脱)进行再次纯化,以得到灰白色固体形式的期望产物(10mg,7%)。LCMS-方法1(205nm):RT=4.66min,97.8%纯度,[M+H]=331.27.1H NMR(300MHz,甲醇-d4)δ8.14(s,1H),7.81(d,J=5.7Hz,1H),7.58(t,J=3.9Hz,4H),7.27(d,J=9.6Hz,1H),7.20-6.97(m,4H),4.49(s,2H),3.86(s,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡啶-2-胺(O5).向3-(4-甲氧基苯基)吡啶-2-胺(100mg,0.50mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(202mg,0.65mmol)在DMF(1.0mL)中的溶液加入碳酸钠(159mg,1.50mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH/NH395∶5∶0→9∶1∶0.1)纯化。通过制备TLC(用DCM/MeOH/NH395∶5∶0→9∶1∶0.1洗脱)进行再次纯化,以得到白色固体形式的期望产物(4mg,2.5%)。LCMS-方法3(200nm):RT=2.66min,96.3%纯度,[M+H]=331.11.1H NMR(300MHz,甲醇-d4)δ8.12(s,1H),7.97(dd,J=5.2,1.8Hz,1H),7.62-7.51(m,2H),7.35(t,J=8.7Hz,3H),7.25(d,J=9.7Hz,1H),7.03(d,J=8.8Hz,2H),6.69(dd,J=7.2,5.2Hz,1H),4.69(s,2H),3.83(s,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡啶-4-胺(O6).向3-(4-甲氧基苯基)吡啶-4-胺(100mg,0.50mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(172mg,0.55mmol)在DMF(1.0mL)中的溶液加入碳酸钠(159mg,1.50mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH/NH395∶5∶0→9∶1∶0.1)纯化。通过制备TLC(用DCM/MeOH/NH395∶5∶0→9∶1∶0.1洗脱)进行再次纯化,以得到白色固体形式的期望产物(12mg,7%)。LCMS-方法3(245nm):RT=2.36min,97.4%纯度,[M+H]=331.25.1H NMR(300MHz,甲醇-d4)δ8.28(s,1H),8.26-8.18(m,2H),7.77-7.67(m,2H),7.42-7.32(m,3H),7.11(d,J=6.7Hz,2H),6.98(d,J=7.1Hz,1H),5.52(s,2H).3.87(s.3H).
N-(1H-1,3-苯并二唑-5-基甲基)-4-(4-甲氧基苯基)吡啶-3-胺O7.向4-(4-甲氧基苯基)吡啶-3-胺(100mg,0.50mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(172mg,0.55mmol)在DMF(1.0mL)中的溶液加入碳酸钠(159mg,1.50mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH/NH395∶5∶0→9∶1∶0.1)纯化。通过制备型HPLC进行再次纯化,以得到白色固体形式的期望产物(5mg,4%)。LCMS(LCMS-方法3,245nm):RT=2.43min,73.7%纯度,[M+H]=331.25.1H NMR(300MHz,甲醇-d4)δ8.36(s,1H),8.30(s,1H),8.23(d,J=6.0Hz,1H),7.91(s,1H),7.73(d,J=8.3Hz,1H),7.67-7.51(m,4H),7.44(d,J=8.3Hz,1H),7.12(d,J=8.8Hz,2H),6.92(d,J=8.4Hz,1H),5.77(s,2H),3.88(s,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-5-(4-甲氧基苯基)嘧啶-4-胺(O8).向5-(4-甲氧基苯基)嘧啶-4-胺(50mg,0.25mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(86mg,0.28mmol)在DMF(0.5mL)中的溶液加入碳酸钠(79mg,0.75mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗产物,将其通过制备型HPLC纯化,以得到淡黄色固体形式的期望产物(1.96mg,1.8%)。LCMS-方法12(200nm):RT=4.5min,100.0%纯度,[M+H]=332.20.1H NMR(300MHz,甲醇-d4)δ8.86(d,J=1.9Hz,1H),8.30(s,1H),8.22(d,J=1.9Hz,1H),7.80(s,1H),7.72(d,J=8.3Hz,1H),7.44-7.35(m,3H),7.14-7.06(m,2H),5.51(s,2H),3.87(s,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡嗪-2-胺(O9).向3-(4-甲氧基苯基)吡嗪-2-胺(140mg,0.70mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(240mg,0.77mmol)在DMF(1.0mL)中的溶液加入碳酸钠(221mg,2.09mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH/NH395∶5∶0→9∶1∶0.1)纯化。通过制备TLC(用DCM/MeOH/NH395∶5∶0→9∶1∶0.1洗脱)进行再次纯化,以得到灰白色固体形式的期望产物(5mg,2%)。LCMS-方法3(270nm):RT=3.04min,87.4%纯度,[M+H]=332.24.1H NMR(300MHz,甲醇-d4)δ8.13(s,1H),7.96(d,J=2.9Hz,1H),7.76(d,J=2.9Hz,1H),7.58(dd,J=12.8,8.6Hz,4H),7.29(dd,J=8.3,1.4Hz,1H),7.09(d,J=8.8Hz,2H),4.73(s,2H),3.86(s,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-4-胺(O10).向3-(3,4-二甲氧基苯基)吡啶-4-胺(100mg,0.43mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(214mg,0.69mmol)在DMF(1.0mL)中的溶液加入碳酸钠(137mg,1.30mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH 95∶5→9∶1)纯化。将包含产物的流分收集并蒸发。将残渣在MeOH中悬浮,并过滤以得到白色固体形式的期望产物(11mg,7%)。LCMS-方法9(200nm):RT=2.8min,95.2%纯度,[M+H]=361.16.1HNMR(300MHz,甲醇-d4)δ8.28(d,J=2.2Hz,2H),8.21(dd,J=7.2,1.9Hz,1H),7.75(s,2H),7.37(dd,J=8.4,1.5Hz,1H),7.13(d,J=8.2Hz,1H),7.07-6.94(m,3H),5.52(s,2H),3.90(s,3H),3.88(s,3H).
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N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-2-胺(O11).向3-(3,4-二甲氧基苯基)吡啶-2-胺(100mg,0.43mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(150mg,0.48mmol)在DMF(1.0mL)中的溶液加入碳酸钠(138mg,1.30mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH/NH395∶5∶0→9∶1∶0.1)纯化。通过制备TLC(用DCM/MeOH/NH395∶5∶0→9∶1∶0.1洗脱)进行再次纯化,以得到灰白色固体形式的期望产物(11mg,7%)。LCMS-方法1(200nm):RT=4.98min,93.2%纯度,[M+H]=361.25.1H NMR(300MHz,甲醇-d4)δ8.13(s,1H),7.98(dd,J=5.2,1.8Hz,1H),7.55(d,J=8.7Hz,2H),7.37(dd,J=7.2,1.8Hz,1H),7.27(dd,J=8.3,1.4Hz,1H),7.09-6.91(m,3H),6.69(dd,J=7.2,5.2Hz,1H),4.70(s,2H),3.85(s,3H),3.79(s,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡嗪-2-胺(O12).向3-(3,4-二甲氧基苯基)吡嗪-2-胺(100mg,0.43mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(175mg,0.56mmol)在DMF(1.0mL)中的溶液加入碳酸钠(137mg,1.30mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH/NH395∶5∶0→9∶1∶0.1)纯化。通过制备TLC(用DCM/MeOH/NH3 95∶5∶0→9∶1∶0.1洗脱)进行再次纯化,以得到灰白色固体形式的期望产物(8mg,5%)。LCMS-方法3(200nm):RT=2.97min,87.7%纯度,[M+H]=362.21.1H NMR(300MHz,甲醇-d4)δ8.14(s,1H),7.98(d,J=2.8Hz,1H),7.77(d,J=2.8Hz,1H),7.65-7.44(m,2H),7.37-7.20(m,3H),7.09(d,J=8.2Hz,1H),4.73(s,2H),3.89(s,3H),3.85(s,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-氟苯基)吡啶-3-胺(O13).向2-(4-氟苯基)吡啶-3-胺(110mg,0.58mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(202mg,0.65mmol)在DMF(1.0mL)中的溶液加入碳酸钠(186mg,1.75mmo1)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH/NH395∶5∶0→9∶1∶0.1)纯化。通过制备TLC(用DCM/MeOH/NH395∶5∶0→9∶1∶0.1洗脱)进行再次纯化,以得到灰白色固体形式的期望产物(8mg,4%)。LCMS-方法1(200nm):RT=3.04min,96.1%纯度,[M+H]=319.23.1H NMR(300MHz,1H NMR(300MHz,)δ8.20(s,1H),7.84(d,J=4.5Hz,1H),7.77-7.51(m,4H),7.30(t,J=8.6Hz,3H),7.23-7.01(m,2H),4.53(s,2H).
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-氟苯基)吡啶-2-胺(O14).向3-(4-氟苯基)吡啶-2-胺(70mg,0.37mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(128mg,0.41mmol)在DMF(0.7mL)中的溶液加入碳酸钠(118mg,1.12mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗产物,将其通过制备型HPLC纯化。通过制备TLC(用DCM/MeOH/NH395∶5∶0.1洗脱)进行再次纯化,以得到白色固体形式的期望产物(7.7mg,4.95%)。LCMS-方法1(200nm):RT=5.04min,97.1%纯度,[M+H]=319.23.1H NMR(300MHz,甲醇-d4)δ8.09(s,1H),8.00(dd,J=5.2,1.8Hz,1H),7.58-7.41(m,4H),7.34(dd,J=7.2,1.8Hz,1H),7.25-7.14(m,3H),6.70(dd,J=7.2,5.2Hz,1H),4.69(s,2H).
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-氟苯基)吡嗪-2-胺(O15).向3-(4-氟苯基)吡嗪-2-胺(100mg,0.53mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(214mg,0.69mmol)在DMF(1.0mL)中的溶液加入碳酸钠(137mg,1.30mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH/NH395∶5∶0→9∶1∶0.1)纯化。通过制备TLC(用DCM/MeOH/NH395∶5∶0→9∶1∶0.1洗脱)进行再次纯化,以得到灰白色固体形式的期望产物(3mg,2%)。LCMS-方法1(202nm):RT=3.08min,95.4%纯度,[M+H]=320.22.1H NMR(300MHz,甲醇-d4)δ8.13(s,1H),8.00(d,J=2.8Hz,1H),7.79(d,J=2.8Hz,1H),7.70(dd,J=8.8,5.4Hz,2H),7.62-7.51(m,2H),7.33-7.23(m,3H),4.73(s,2H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-苯氧基苯基)苯胺(O16).向2-(4-苯氧基苯基)苯胺(100mg,0.38mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(132mg,0.42mmol)在DMF(1.0mL)中的溶液加入碳酸钠(122mg,1.15mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH 1∶0→96∶4)纯化。通过制备TLC(用DCM/MeOH/NH3 95∶5∶0.1洗脱)进行再次纯化,以得到白色固体形式的期望产物(25mg,16.7%)。LCMS-方法2(205nm):RT=4.99min,99.6%纯度,[M+H]=392.26.1H NMR(300MHz,甲醇-d4)δ8.13(s,1H),7.57(d,J=8.1Hz,2H),7.47-7.33(m,4H),7.27(dd,J=8.5,1.5Hz,1H),7.17-7.02(m,7H),6.71(ddd,J=7.8,6.2,1.2Hz,2H),4.48(s,2H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-[4-(环己基氧基)苯基]苯胺(O17).向2-[4-(环己基氧基)苯基]苯胺(100mg,0.37mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(129mg,0.42mmol)在DMF(1.0mL)中的溶液加入碳酸钠(119mg,1.12mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过制备TLC(用DCM/MeOH 95∶5洗脱)纯化。通过制备TLC(用DCM/MeOH 95∶5洗脱)进行再次纯化,以得到白色固体形式的期望产物(4.9mg,3.3%)。LCMS-方法2(200nm):RT=5.17min,100%纯度,[M+H]=398.26.1H NMR(300MHz,甲醇-d4)δ8.12(s,1H),7.55(d,J=7.9Hz,2H),7.377.21(m,3H),7.11-6.96(m,4H),6.68(ddd,J=8.6,5.5,1.3Hz,2H),4.44(s,2H),4.34(tt,J=8.4,3.6Hz,1H),2.06-1.75(m,4H),1.66-1.28(m,6H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-丙氧基苯基)苯胺(O18).向2-(4-丙氧基苯基)苯胺(100mg,0.44mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(152mg,0.49mmol)在DMF(1.0mL)中的溶液加入碳酸钠(140mg,1.32mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH 1∶0→98∶2)纯化。通过制备TLC(用DCM/MeOH 95∶5洗脱)进行再次纯化,以得到白色固体形式的期望产物(34.4mg,21.9%)。LCMS-方法2(200nm):RT=4.58min,100%纯度,[M+H]=358.25.1H NMR(300MHz,甲醇-d4)δ8.09(s,1H),7.53(d,J=7.8Hz,2H),7.36-7.25(m,2H),7.20(dd,J=8.4,1.5Hz,1H),7.10-6.89(m,4H),6.66(t,J=7.3Hz,2H),4.37(s,2H),3.90(t,J=6.5Hz,2H),1.77(dtd,J=13.8,7.4,6.4Hz,2H),1.02(t,J=7.4Hz,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-[4-(丙-2-基氧基)苯基]苯胺(019).向2-[4-(丙-2-基氧基)苯基]苯胺(100mg,0.44mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(152mg,0.49mmol)在DMF(1.0mL)中的溶液加入碳酸钠(140mg,1.32mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH 1∶0→99∶1)纯化。通过制备TLC(用DCM/MeOH 95∶5洗脱)进行再次纯化,以得到白色固体形式的期望产物(24.3mg,15.5%)。LCMS-方法4(200nm):RT=2.42min,97.3%纯度,[M+H]=358.26.1H NMR(300MHz,甲醇-d4)δ8.10(s,1H),7.54(d,J=7.9Hz,2H),7.37-7.26(m,2H),7.21(dd,J=8.4,1.5Hz,1H),7.10-6.91(m,4H),6.66(t,J=7.3Hz,2H),4.57(hept,J=12.0,6.0Hz,1H),4.39(s,2H),1.31(d,J=6.0Hz,6H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)-3-甲基苯胺(O20).向2-(4-甲氧基苯基)-3-甲基苯胺(100mg,0.47mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(162mg,0.52mmol)在DMF(1.0mL)中的溶液加入碳酸钠(149mg,1.41mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH 1∶0→97∶3)纯化。通过制备TLC(用DCM/MeOH9∶1洗脱)进行再次纯化,以得到白色固体形式的期望产物(40.7mg,25.3%)。LCMS(LCMS-方法4,205nm):RT=2.14min,98.9%纯度,[M+H]=344.27.1H NMR(300MHz,DMSO-d6)δ12.33(d,J=11.8Hz,1H),8.14(s,1H),7.57-7.36(m,2H),7.18-7.05(m,5H),6.93(t,J=7.8Hz,1H),6.54-6.38(m,2H),4.44(d,J=17.8Hz,1H),4.34(d,J=5.1Hz,2H),3.81(s,3H),1.88(s,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-甲基苯胺(O21).向2-(3,4-二甲氧基苯基)-3-甲基苯胺(100mg,0.41mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(142mg,0.46mmol)在DMF(1.0mL)中的溶液加入碳酸钠(131mg,1.23mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH 1∶0→97∶3)纯化。通过制备TLC(用DCM/MeOH 95∶5洗脱)进行再次纯化,以得到白色固体形式的期望产物(47.5mg,31%)。LCMS(LCMS-方法4,205nm):RT=1.99min,97.3%纯度,[M+H]=374.27.1H NMR(300MHz,DMSO-d6)δ12.33(s,1H),8.14(s,1H),7.52(s,1H),7.41(s,1H),7.10(t,J=7.8Hz,2H),6.93(t,J=7.8Hz,1H),6.796.71(m,2H),6.47(dd,J=15.8,7.8Hz,2H),4.55(s,1H),4.34(d,J=6.0Hz,2H),3.79(d,J=9.0Hz,6H),1.92(s,3H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-氯苯基)-3-氟苯胺(O22).向2-(4-氯苯基)-3-氟苯胺(100mg,0.45mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(156mg,0.50mmol)在DMF(1.0mL)中的溶液加入碳酸钠(143mg,1.35mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH 1∶0→97∶3)纯化。通过制备TLC(用DCM/MeOH 95∶5洗脱)进行再次纯化,以得到白色固体形式的期望产物(40.6mg,25.6%)。LCMS(LCMS-方法4,200nm):RT=2.29min,94.2%纯度,[M+H]=344.27.1H NMR(300MHz,DMSO-d6)δ12.33(d,J=17.3Hz,1H),8.15(d,J=4.1Hz,1H),7.58(dd,J=8.8,7.0Hz,3H),7.50-7.36(m,3H),7.20-7.10(m,1H),7.05(td,J=8.3,6.8Hz,1H),6.46-6.34(m,2H),5.48(dt,J=16.2,6.0Hz,1H),4.38(t,J=6.0Hz,2H).
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-氟苯胺(O23).向2-(3,4-二甲氧基苯基)-3-氟苯胺(100mg,0.40mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(140mg,0.45mmol)在DMF(1.0mL)中的溶液加入碳酸钠(129mg,1.21mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH 1∶0→97∶3)纯化。通过制备TLC(用DCM/MeOH 9∶1洗脱)进行再次纯化,以得到白色固体形式的期望产物(29.3mg,19.2%)。LCMS(LCMS-方法4,200nm):RT=1.92min,90.1%纯度,[M+H]=378.23.1H NMR(300MHz,DMSO-d6)δ12.38(s,1H),8.16(s,1H),7.50(s,2H),7.21-6.98(m,3H),6.93-6.85(m,2H),6.45-6.37(m,2H),5.27(s,1H),4.39(d,J=6.0Hz,2H),3.80(d,J=7.1Hz,6H).
N-(1H-1,3-苯并二唑-5-基甲基)-3-氟-2-(4-氟苯基)苯胺(O24).向3-氟-2-(4-氟苯基)苯胺(100mg,0.49mmol)和5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(168mg,0.54mmol)在DMF(1.0mL)中的溶液加入碳酸钠(155mg,1.46mmol)。将反应混合物在80℃下搅拌过夜。在那之后,将反应混合物冷却至室温,并通过硅藻土过滤。将硅藻土垫用MeOH洗涤。将滤液蒸发以得到粗品,将其通过柱色谱法(使用DCM/MeOH 1∶0→97∶3)纯化。通过制备TLC(用DCM/MeOH 9∶1洗脱)进行再次纯化,以得到白色固体形式的期望产物(29.3mg,19.2%)。LCMS(LCMS-方法4,205nm):RT=2.12min,96.6%纯度,[M+H]=336.23.1H NMR(300MHz,DMSO-d6)δ12.32(s,1H),8.15(s,1H),7.55(s,1H),7.45-7.32(m,5H),7.15(s,1H),7.10-6.99(m,1H),6.46-6.36(m,2H),5.37(s,1H),4.39(d,J=6.0Hz,2H).
合成方法Q
N-[(1H-1,3-苯并二唑-5-基)甲基]-4-氟苯-1-磺酰胺(P1)将(1H-1,3-苯并二唑-5-基)甲胺二盐酸盐(0.25g,1.15mmol)在吡啶(7mL)中溶解,并在室温下搅拌30min。然后加入4-氟苯基磺酰氯(0.21 g,1.08mmol),并将反应混合物加热至70℃,并搅拌过夜。将混合物用10mL 20%的氢氧化钠水溶液淬灭,并在70℃下搅拌又一个晚上。分层,并将吡啶真空蒸发。将粗产物通过柱色谱法(使用含MeOH的DCM(0-3%)作为洗脱液)纯化。将含有标题化合物的流分合并并浓缩(55mg,19%)。LCMS-方法1(200nm):RT=5.81min,93.2%纯度,[M+ACN]=347.27.1H NMR(300MHz,DMSO-d6)δ8.17(s,1H),8.04-7.66(m,2H),7.56-7.31(m,4H),7.05(d,J=8.4Hz,1H),4.10(s,2H).
合成方法R
[(1H-1,3-苯并二唑-5-基)甲基][(4-氟苯基)(甲基)氧代-λ6-硫酮]胺(Q1)将DMSO(13.0mL)中的(4-氟苯基)(亚胺基)甲基-λ6-sulfanone(250mg,1.5mmol)和氢氧化钾(234mg,2.18mmol)在50℃下搅拌1h。在此之后,将反应物冷却至室温,并加入5-(溴甲基)-1H-1,3-苯并二唑-1-羧酸叔丁酯(650mg,2.10mmol)。将反应物搅拌过夜,并在此之后,加入水(50mL),并用DCM(5x 30mL)萃取。将合并的有机层用硫酸钠干燥、过滤。蒸发以得到粗产物在DMSO中的溶液,将其通过制备型HPLC方法纯化,以得到无色油形式的标题化合物(26mg,5%)LCMS-方法1(200nm):RT=5.72min,96.3%纯度,[M+H]=304.15.1H NMR(300MHz,DMSO-d6)δ8.14(s,1H),8.03-7.91(m,2H),7.54(s,1H),7.517.42(m,3H),7.12(dd,J=8.3,1.6Hz,1H),4.15(d,J=14.4Hz,1H),3.98(d,J=14.5Hz,1H),3.25(s,3H).
分析方法
NMR
在BRUKER FOURIER 300上记录1H NMR-谱(300MHz)。除非另有说明,溶剂为DMSO-D6。化学位移表示从四甲基硅烷起低磁场方向的百万分比(ppm)。分裂模式指定如下:s(单峰)、d(双峰)、dd(二组双峰)、t(三峰)、m(多峰)以及br(宽信号)。
HPLC-MS
LCMS-方法1
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:Gemini-NX 3μ C18(4.6x50mm),110A,柱no.OOB-4453-EO,内部柱no.002
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:0.5ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:14min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[ml/min] |
0.0 | 95 | 5 | 0.5 |
2.0 | 95 | 5 | 0.5 |
9.5 | 20 | 80 | 0.5 |
10.5 | 20 | 80 | 0.5 |
12.0 | 95 | 5 | 0.5 |
14.0 | 95 | 5 | 0.5 |
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12000amu/sec
LCMS-方法2
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:Gemini-NX 3μ C18(4.6x50mm),110A,柱no.OOB-4453-EO,内部柱no.002
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:0.5ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:12min
-洗脱:梯度
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12000amu/sec
LCMS-方法3
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:2.6μm XB-C18(4.6x50mm),110A,柱no.OOB-4496-E0,内部柱no.019
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:1.0ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:7min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[ml/min] |
0.0 | 95 | 5 | 1.0 |
1.0 | 95 | 5 | 1.0 |
4.75 | 20 | 80 | 1.0 |
5.25 | 20 | 80 | 1.0 |
6.0 | 95 | 5 | 1.0 |
7.0 | 95 | 5 | 1.0 |
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12 000amu/sec
LCMS-方法4
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:2.6μm XB-C18(4.6x50mm),110A,柱no.00B-4496-E0,内部柱no.019
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:1.0ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:6min
-洗脱:梯度
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12 000amu/sec
LCMS-方法5
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:2.6μm XB-C18(4.6x50mm),110A,柱no.OOB-4496-E0,内部柱no.019
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:1.0ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:7min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[ml/min] |
0.0 | 80 | 20 | 1.0 |
2.0 | 20 | 80 | 1.0 |
2.35 | 20 | 80 | 1.0 |
2.45 | 5 | 95 | 1.0 |
4.25 | 5 | 95 | 1.0 |
5.0 | 80 | 20 | 1.0 |
7.0 | 80 | 20 | 1.0 |
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12 000amu/sec
HPLC-方法6
仪器:具有梯度泵和DAD检测器的HPLC-MERCK CHROMASTER
柱:XBridge C18 3.5μ(4.6x150mm),柱no.186003034,内部柱no.009
试剂:
-用于HPLC的甲醇,超高梯度HPLC级,Baker
-硼酸≥99.5%,Sigma-Aldrich
-氢氧化钠分析级,Eurochem BGD
-用于HPLC的纯化水
HPLC条件:
-波长:210.0nm±4.0nm
-流速:0.5mL/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:5μL
-分析时间:30min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[mL/min] |
0.0 | 50 | 50 | 0.5 |
22.0 | 5 | 95 | 0.5 |
25.0 | 5 | 95 | 0.5 |
27.0 | 50 | 50 | 0.5 |
30.0 | 50 | 50 | 0.5 |
流动相A:
硼酸盐缓冲液c=5mM,pH=9.6
制备:将置于2L容量瓶中的0.618g硼酸在1.5L纯净水中溶解。将pH值使用1M的NaOH溶液(6mL)调节至9.6。最后,使用纯净水将溶液稀释至标记处。
流动相B:
1L MeOH,其具有与相A类似量的1M NaOH(3mL)。
用于注射器清洗的溶液:乙腈
LCMS-方法7
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:Gemini-NX 3μ C18(4.6x50mm),110A,柱no.OOB-4453-EO,内部柱no.002
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:0.5ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:12min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[ml/min] |
0.0 | 60 | 40 | 0.5 |
6.7 | 20 | 80 | 0.5 |
7.5 | 20 | 80 | 0.5 |
7.8 | 5 | 95 | 0.5 |
9.5 | 5 | 95 | 0.5 |
10.0 | 60 | 40 | 0.5 |
12.0 | 60 | 40 | 0.5 |
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12 000amu/sec
LCMS-方法8
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:Gemini-NX 3μ C18(4.6x50mm),110A,柱no.OOB-4453-EO,内部柱no.002
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:0.5ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:28min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[ml/min] |
0.0 | 95 | 5 | 0.5 |
4.0 | 95 | 5 | 0.5 |
19.0 | 20 | 80 | 0.5 |
21.0 | 20 | 80 | 0.5 |
24.0 | 95 | 5 | 0.5 |
28.0 | 95 | 5 | 0.5 |
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12 000amu/sec
LCMS-方法9
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:Kinetex XB-C182.6μm(4.6x50mm),100A,柱no.00B-4496-E0,内部柱no.019
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:1.0ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:7min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[ml/min] |
0.0 | 100 | 0 | 1.0 |
1.0 | 95 | 5 | 1.0 |
4.0 | 80 | 20 | 1.0 |
4.75 | 20 | 80 | 1.0 |
5.25 | 20 | 80 | 1.0 |
6.0 | 95 | 5 | 1.0 |
7.0 | 100 | 0 | 1.0 |
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12 000amu/sec
LCMS-方法10
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:Gemini-NX 3μ C18(4.6x50mm),110A,柱no.OOB-4453-EO,内部柱no.002
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:0.5ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:12min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[ml/min] |
0.0 | 70 | 30 | 0.5 |
6.7 | 20 | 80 | 0.5 |
7.5 | 20 | 80 | 0.5 |
7.8 | 5 | 95 | 0.5 |
9.5 | 5 | 95 | 0.5 |
10.0 | 70 | 30 | 0.5 |
12.0 | 70 | 30 | 0.5 |
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12000amu/sec
LCMS-方法11
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:2.6μm XB-C18(4.6x50mm),110A,柱no.00B-4496-E0,内部柱no.019
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:1.0ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:6min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[ml/min] |
0.0 | 30 | 70 | 1.0 |
3.35 | 20 | 80 | 1.0 |
3.75 | 20 | 80 | 1.0 |
3.9 | 5 | 95 | 1.0 |
4.75 | 5 | 95 | 1.0 |
5.0 | 30 | 70 | 1.0 |
6.0 | 30 | 70 | 1.0 |
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12000amu/sec
LCMS-方法12
仪器:具有DAD检测器的Dionex UHPLC Ultimate 3000/Thermo Scientific MSQPlus
柱:Gemini-NX 3μ C18(4.6x50mm),110A,柱no.OOB-4453-EO,内部柱no.002
试剂:-甲酸≥98%,Sigma-Aldrich
-用于HPLC UV的乙腈/梯度级,Baker
-用于LCMS的μQ-水
HPLC条件:-波长范围:(190-340)nm±4nm
-流速:0.5ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:2.0μl
-分析时间:14min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[ml/min] |
0.0 | 100 | 0 | 0.5 |
2.0 | 95 | 5 | 0.5 |
8.0 | 80 | 20 | 0.5 |
9.5 | 20 | 80 | 0.5 |
10.5 | 20 | 80 | 0.5 |
12.0 | 95 | 5 | 0.5 |
14.0 | 100 | 0 | 0.5 |
流动相A:0.1%v/v甲酸的水溶液
流动相B:0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:20%MeOH
MS条件:-质量范围:100-1000m/z
-离子化:交替
-扫描速度:12 000amu/sec
UPLC-MS
仪器:Shimadzu LCMS-2020单四级液相色谱质谱仪
柱:Acquity UPLC 1.8μm C18(2.1x 50mm),柱no.186003532,内部柱no.PurCC-MS001
试剂:
-甲酸≥98%,Sigma-Aldrich,
-用于HPLC UV的乙腈/梯度级,Baker,
-用于HPLC的纯化水
UPLC条件:
-波长:254nm和280nm
-流速:0.5ml/min
-柱温:25℃
-自动进样器温度:20℃
-进样体积:3μl
-分析时间:6,0min
-洗脱:梯度
时间[min] | 流动相A[%] | 流动相B[%] | 流速[ml/min] |
0.01 | 95 | 5 | 0.5 |
4.00 | 5 | 95 | 0.5 |
5.00 | 5 | 95 | 0.5 |
5.20 | 95 | 5 | 0.5 |
6.00 | 95 | 5 | 0.5 |
流动相A:
0.1%v/v甲酸的水溶液
流动相B:
0.1%v/v甲酸的乙腈溶液
用于注射器清洗的溶液:
100%乙腈
MS条件:
-质量范围:50-1000m/z
-离子化:交替
-扫描速度:7500u/sec
活性筛选
谷氨酰胺酰环化酶测试测定的IC50值和Ki值的计算
在DMSO中制备10mM化合物储备溶液。为了IC50测定,将化合物储备溶液在DMSO中系列稀释(1∶3)。
所有测量均在EnSpire Perkin Elmer多模式酶标仪中,使用谷氨酰胺酰基-7-氨基-4-甲基香豆素(H-Gln-AMC)作为底物以及重组焦谷氨酰氨基肽酶(pGAP)作为辅助酶进行。在环境温度下于黑色96孔半面积微孔板中进行。将各个由1μl测试化合物溶液或溶剂(DMSO)和49μl QC组成的样品在测定缓冲液(50mM Tris/HCl,pH 8.0或者50mM MES缓冲液,pH=6.0)中适当地稀释。在环境温度下预孵育10min后,通过加入50μl测定缓冲液中的Gln-AMC-底物/pGAP混合物启动酶反应。对于在pH 8.0或6.0下的测量,最终底物浓度分别为50和200μM。在380/460nm的激发/发射波长下记录荧光基质(fluorogenic)AMC的释放。通过前10个数据点的线性回归计算(使用Enspire Manager软件)酶反应的初始速率。使用GraphPad Prism软件进行最终评价和IC50的计算。通过根据4-参数逻辑斯谛方程的非线性回归由标准化数据(无抑制剂下的QC活性=100%)计算IC50值。
根据下式计算Ki-值:Ki=IC50/(1+[S]/Km),其中:
[S]反映底物在测试中的浓度(pH6.0下200μM,pH8.0下50μM),并且Km是各自的Michaelis-Menten常数(pH6.0下390μM,pH8.0下62μM)。
MALDI-TOF质谱法
利用具有线性飞行时间分析器的Hewlett-Packard G2025 LD-TOF系统进行基质辅助激光解吸/离子化质谱法。该仪器配有337nm氮激光、电压加速源(5kV)和1.0m飞行管。检测器在正离子模式下操作,并且使用连接至个人电脑的LeCroy 9350M数字存储示波器来记录和过滤信号。将样品(5μl)与等体积的基质溶液混合。对于基质溶液,使用通过将30mg的2′,6′-二羟基苯乙酮(Aldrich)和44mg的柠檬酸氢二铵(Fluka)溶于1ml乙腈/0.1%TFA在水中的溶液(1/1,v/v)制备的DHAP/DAHC。将小体积(≈1μl)的基质-分析物-混合物转移至探针尖并在真空室(Hewlett-Packard G2024A样品制备配件)中立即蒸发以确保快速且均匀的样品结晶。
对于Glu1-环化的长期测试,将Aβ-衍生的肽在100μl 0.1M乙酸钠缓冲液,pH 5.2或0.1M Bis-Tris缓冲液,pH6.5中于30℃下温育。以0.5mM[Aβ(3-11)a]或0.15mM[Aβ(3-21)a]的浓度使用肽,并且整个24小时中加入0.2U QC。在Aβ(3-21)a的情况下,测定包含1%DMSO。在不同时间,从测定管取出样品,按照生产商的建议使用ZipTips(Millipore)提取肽,与基质溶液混合(1∶1v/v),随后记录质谱。阴性对照不含QC或者包含热灭活的酶。对于抑制剂研究,除了加入的抑制化合物(5mM或2mM本发明的测试化合物)之外,样品组成与上述相同。
本发明的化合物和组合可以具有的优点是,例如,它们更具效力,更具选择性,具有更少的副作用,具有更好的配制和稳定性性质,具有更好的药代动力学性质、更好的生物利用度,能够穿过血脑屏障并在哺乳动物的脑中更有效,与其他药物更相容或更有效地组合,或者比现有技术的其他化合物更易于合成。
在整个说明书和所附的权利要求书中,除非上下文另有要求,否则词语“包含(comprise)”及其变体如“包含(comprises)”和“包含(comprising)”应当理解为意指包括所述的整数、步骤、整数的集合或步骤的集合但不排除任何其他整数、步骤、整数的集合或步骤的集合。
本发明的整个说明书中提及的所有专利和专利申请均整体援引加入本文。
本发明包括上述优选和更优选的集合和集合的实施方案的所有组合。
序列表
<110> 前体生物药物股份公司
<120> 新的抑制剂
<130> PBD132WO
<150> GB 1705263.0
<151> 2017-03-31
<160> 20
<170> PatentIn version 3.5
<210> 1
<211> 42
<212> PRT
<213> Homo sapiens
<400> 1
Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys
1 5 10 15
Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile
20 25 30
Gly Leu Met Val Gly Gly Val Val Ile Ala
35 40
<210> 2
<211> 40
<212> PRT
<213> Homo sapiens
<400> 2
Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys
1 5 10 15
Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile
20 25 30
Gly Leu Met Val Gly Gly Val Val
35 40
<210> 3
<211> 40
<212> PRT
<213> Homo sapiens
<400> 3
Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys Leu Val
1 5 10 15
Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu
20 25 30
Met Val Gly Gly Val Val Ile Ala
35 40
<210> 4
<211> 38
<212> PRT
<213> Homo sapiens
<400> 4
Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys Leu Val
1 5 10 15
Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu
20 25 30
Met Val Gly Gly Val Val
35
<210> 5
<211> 17
<212> PRT
<213> Homo sapiens
<220>
<221> MOD_RES
<222> (17)..(17)
<223> AMIDATION
<400> 5
Gln Gly Pro Trp Leu Glu Glu Glu Glu Glu Ala Tyr Gly Trp Met Asp
1 5 10 15
Phe
<210> 6
<211> 13
<212> PRT
<213> Homo sapiens
<400> 6
Gln Leu Tyr Glu Asn Lys Pro Arg Arg Pro Tyr Ile Leu
1 5 10
<210> 7
<211> 10
<212> PRT
<213> Homo sapiens
<220>
<221> MOD_RES
<222> (10)..(10)
<223> AMIDATION
<400> 7
Gln His Trp Ser Tyr Gly Leu Arg Pro Gly
1 5 10
<210> 8
<211> 97
<212> PRT
<213> Homo sapiens
<400> 8
Gln Pro Lys Val Pro Glu Trp Val Asn Thr Pro Ser Thr Cys Cys Leu
1 5 10 15
Lys Tyr Tyr Glu Lys Val Leu Pro Arg Arg Leu Val Val Gly Tyr Arg
20 25 30
Lys Ala Leu Asn Cys His Leu Pro Ala Ile Ile Phe Val Thr Lys Arg
35 40 45
Asn Arg Glu Val Cys Thr Asn Pro Asn Asp Asp Trp Val Gln Glu Tyr
50 55 60
Ile Lys Asp Pro Asn Leu Pro Leu Leu Pro Thr Arg Asn Leu Ser Thr
65 70 75 80
Val Lys Ile Ile Thr Ala Lys Asn Gly Gln Pro Gln Leu Leu Asn Ser
85 90 95
Gln
<210> 9
<211> 76
<212> PRT
<213> Homo sapiens
<400> 9
Gln Pro Asp Ser Val Ser Ile Pro Ile Thr Cys Cys Phe Asn Val Ile
1 5 10 15
Asn Arg Lys Ile Pro Ile Gln Arg Leu Glu Ser Tyr Thr Arg Ile Thr
20 25 30
Asn Ile Gln Cys Pro Lys Glu Ala Val Ile Phe Lys Thr Lys Arg Gly
35 40 45
Lys Glu Val Cys Ala Asp Pro Lys Glu Arg Trp Val Arg Asp Ser Met
50 55 60
Lys His Leu Asp Gln Ile Phe Gln Asn Leu Lys Pro
65 70 75
<210> 10
<211> 76
<212> PRT
<213> Homo sapiens
<400> 10
Gln Pro Asp Ala Ile Asn Ala Pro Val Thr Cys Cys Tyr Asn Phe Thr
1 5 10 15
Asn Arg Lys Ile Ser Val Gln Arg Leu Ala Ser Tyr Arg Arg Ile Thr
20 25 30
Ser Ser Lys Cys Pro Lys Glu Ala Val Ile Phe Lys Thr Ile Val Ala
35 40 45
Lys Glu Ile Cys Ala Asp Pro Lys Gln Lys Trp Val Gln Asp Ser Met
50 55 60
Asp His Leu Asp Lys Gln Thr Gln Thr Pro Lys Thr
65 70 75
<210> 11
<211> 68
<212> PRT
<213> Homo sapiens
<400> 11
Gln Val Gly Thr Asn Lys Glu Leu Cys Cys Leu Val Tyr Thr Ser Trp
1 5 10 15
Gln Ile Pro Gln Lys Phe Ile Val Asp Tyr Ser Glu Thr Ser Pro Gln
20 25 30
Cys Pro Lys Pro Gly Val Ile Leu Leu Thr Lys Arg Gly Arg Gln Ile
35 40 45
Cys Ala Asp Pro Asn Lys Lys Trp Val Gln Lys Tyr Ile Ser Asp Leu
50 55 60
Lys Leu Asn Ala
65
<210> 12
<211> 373
<212> PRT
<213> Homo sapiens
<400> 12
Gln His His Gly Val Thr Lys Cys Asn Ile Thr Cys Ser Lys Met Thr
1 5 10 15
Ser Lys Ile Pro Val Ala Leu Leu Ile His Tyr Gln Gln Asn Gln Ala
20 25 30
Ser Cys Gly Lys Arg Ala Ile Ile Leu Glu Thr Arg Gln His Arg Leu
35 40 45
Phe Cys Ala Asp Pro Lys Glu Gln Trp Val Lys Asp Ala Met Gln His
50 55 60
Leu Asp Arg Gln Ala Ala Ala Leu Thr Arg Asn Gly Gly Thr Phe Glu
65 70 75 80
Lys Gln Ile Gly Glu Val Lys Pro Arg Thr Thr Pro Ala Ala Gly Gly
85 90 95
Met Asp Glu Ser Val Val Leu Glu Pro Glu Ala Thr Gly Glu Ser Ser
100 105 110
Ser Leu Glu Pro Thr Pro Ser Ser Gln Glu Ala Gln Arg Ala Leu Gly
115 120 125
Thr Ser Pro Glu Leu Pro Thr Gly Val Thr Gly Ser Ser Gly Thr Arg
130 135 140
Leu Pro Pro Thr Pro Lys Ala Gln Asp Gly Gly Pro Val Gly Thr Glu
145 150 155 160
Leu Phe Arg Val Pro Pro Val Ser Thr Ala Ala Thr Trp Gln Ser Ser
165 170 175
Ala Pro His Gln Pro Gly Pro Ser Leu Trp Ala Glu Ala Lys Thr Ser
180 185 190
Glu Ala Pro Ser Thr Gln Asp Pro Ser Thr Gln Ala Ser Thr Ala Ser
195 200 205
Ser Pro Ala Pro Glu Glu Asn Ala Pro Ser Glu Gly Gln Arg Val Trp
210 215 220
Gly Gln Gly Gln Ser Pro Arg Pro Glu Asn Ser Leu Glu Arg Glu Glu
225 230 235 240
Met Gly Pro Val Pro Ala His Thr Asp Ala Phe Gln Asp Trp Gly Pro
245 250 255
Gly Ser Met Ala His Val Ser Val Val Pro Val Ser Ser Glu Gly Thr
260 265 270
Pro Ser Arg Glu Pro Val Ala Ser Gly Ser Trp Thr Pro Lys Ala Glu
275 280 285
Glu Pro Ile His Ala Thr Met Asp Pro Gln Arg Leu Gly Val Leu Ile
290 295 300
Thr Pro Val Pro Asp Ala Gln Ala Ala Thr Arg Arg Gln Ala Val Gly
305 310 315 320
Leu Leu Ala Phe Leu Gly Leu Leu Phe Cys Leu Gly Val Ala Met Phe
325 330 335
Thr Tyr Gln Ser Leu Gln Gly Cys Pro Arg Lys Met Ala Gly Glu Met
340 345 350
Ala Glu Gly Leu Arg Tyr Ile Pro Arg Ser Cys Gly Ser Asn Ser Tyr
355 360 365
Val Leu Val Pro Val
370
<210> 13
<211> 76
<212> PRT
<213> Homo sapiens
<400> 13
Gln Pro Val Gly Ile Asn Thr Ser Thr Thr Cys Cys Tyr Arg Phe Ile
1 5 10 15
Asn Lys Lys Ile Pro Lys Gln Arg Leu Glu Ser Tyr Arg Arg Thr Thr
20 25 30
Ser Ser His Cys Pro Arg Glu Ala Val Ile Phe Lys Thr Lys Leu Asp
35 40 45
Lys Glu Ile Cys Ala Asp Pro Thr Gln Lys Trp Val Gln Asp Phe Met
50 55 60
Lys His Leu Asp Lys Lys Thr Gln Thr Pro Lys Leu
65 70 75
<210> 14
<211> 33
<212> PRT
<213> Homo sapiens
<400> 14
Gln Pro Leu Pro Asp Cys Cys Arg Gln Lys Thr Cys Ser Cys Arg Leu
1 5 10 15
Tyr Glu Leu Leu His Gly Ala Gly Asn His Ala Ala Gly Ile Leu Thr
20 25 30
Leu
<210> 15
<211> 11
<212> PRT
<213> Homo sapiens
<400> 15
Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met
1 5 10
<210> 16
<211> 32
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic peptide
<400> 16
Glu Val His His Gln Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser
1 5 10 15
Asn Lys Gly Ala Ile Ile Gly Leu Met Val Gly Gly Val Val Ile Ala
20 25 30
<210> 17
<211> 30
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic peptide
<400> 17
Glu Val His His Gln Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser
1 5 10 15
Asn Lys Gly Ala Ile Ile Gly Leu Met Val Gly Gly Val Val
20 25 30
<210> 18
<211> 34
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic peptide
<400> 18
Glu Ala Ser Asn Cys Phe Ala Ile Arg His Phe Glu Asn Lys Phe Ala
1 5 10 15
Val Glu Thr Leu Ile Cys Ser Arg Thr Val Lys Lys Asn Ile Ile Glu
20 25 30
Glu Asn
<210> 19
<211> 34
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic peptide
<400> 19
Glu Ala Ser Asn Cys Phe Ala Ile Arg His Phe Glu Asn Lys Phe Ala
1 5 10 15
Val Glu Thr Leu Ile Cys Phe Asn Leu Phe Leu Asn Ser Gln Glu Lys
20 25 30
His Tyr
<210> 20
<211> 5
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic peptide
<400> 20
Gln Tyr Asn Ala Asp
1 5
Claims (12)
1.式I的化合物:
A-B-D-E (I)
或者其药学可接受的盐,其中:
A为:
B为C1-12烷基;
D选自
以及
其中
R为氢;
R2为氢或C1-12烷基;
E为:
其中
Y5为C并且Y6-Y10独立地选自C和N,并且
R3、R4和R7为氢;
R5选自卤素、C1-12烷基、O-C1-12烷基、O-苯基和O-C3-10环烷基;并且
R6选自氢、C1-12烷基和O-C1-12烷基。
2.权利要求1的化合物,其中B选自甲基、乙基、丙基、丁基、戊基、己基、庚基和辛基。
3.权利要求1的化合物,其为式(XVI)的化合物:
其中
R5选自卤素、C1-12烷基和O-C1-12烷基;并且
R6选自氢、C1-12烷基和O-C1-12烷基。
4.权利要求1的化合物,其为式(XVII)的化合物:
其中
R2为C1-12烷基;
R5选自卤素、C1-12烷基和O-C1-12烷基;并且
R6选自氢、C1-12烷基和O-C1-12烷基。
5.化合物,其选自:
N-[(1H-1,3-苯并二唑-5-基)甲基]-4′-氟-[1,1′-联苯]-2-胺;
N-[(1H-1,3-苯并二唑-5-基)甲基]-3′,4′-二甲氧基-[1,1′-联苯]-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)吡啶-3-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡啶-4-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-4-(4-甲氧基苯基)吡啶-3-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-5-(4-甲氧基苯基)嘧啶-4-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-甲氧基苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-4-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(3,4-二甲氧基苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-氟苯基)吡啶-3-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-氟苯基)吡啶-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-(4-氟苯基)吡嗪-2-胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-苯氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-[4-(环己基氧基)苯基]苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-丙氧基苯基)苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-[4-(丙-2-基氧基)苯基]苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-甲氧基苯基)-3-甲基苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-甲基苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(4-氯苯基)-3-氟苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-2-(3,4-二甲氧基苯基)-3-氟苯胺;
N-(1H-1,3-苯并二唑-5-基甲基)-3-氟-2-(4-氟苯基)苯胺;
N-[(1H-1,3-苯并二唑-5-基)甲基]-4-氟苯-1-磺酰胺;和
[(1H-1,3-苯并二唑-5-基)甲基][(4-氟苯基)(甲基)氧代-λω-硫酮]胺;
或者其药学可接受的盐。
6.权利要求1-5中任一项的式I的化合物在制备用作谷氨酰胺酰环化酶抑制剂的药物中的用途。
7.药物组合物,其包含权利要求1-5中任一项的化合物,所述化合物任选地与一种或多种治疗可接受的稀释剂或载体组合。
8.权利要求7的药物组合物,其还包含至少一种选自以下的化合物:神经保护剂、抗震颤麻痹药、淀粉样蛋白沉积抑制剂、β淀粉样蛋白合成抑制剂、抗抑郁药、抗焦虑药、抗精神病药以及抗多发性硬化药。
9.权利要求7或8的药物组合物,其还包含至少一种选自以下的化合物:PEP-抑制剂、LiCl、DP IV或DP IV样酶抑制剂的抑制剂、乙酰胆碱脂酶(ACE)抑制剂、PIMT增强剂、β分泌酶抑制剂、γ分泌酶抑制剂、中性内肽酶抑制剂、磷酸二酯酶-4(PDE-4)抑制剂、TNFα抑制剂、毒蕈碱M1受体拮抗剂、NMDA受体拮抗剂、σ-1受体抑制剂、组胺H3拮抗剂、免疫调节剂、免疫抑制剂,或者选自antegren(那他珠单抗)、Neurelan(氨吡啶缓释片)、campath(阿仑珠单抗)、IR 208、NBI 5788/MSP 771(替利莫肽)、紫杉醇、Anergix.MS(AG284)、SH636、达芙文(CD 271、阿达帕林)、BAY 361677(白介素-4)、基质金属蛋白酶-抑制剂、干扰素-τ(滋养层素)和SAIK-MS的药剂。
10.权利要求1-5中任一项的化合物或者权利要求7-9中任一项的药物组合物在制备用于治疗或预防选自以下的疾病的药物中的用途:肯尼迪病、溃疡病、有或无幽门螺杆菌感染的十二指肠癌、结直肠癌、佐-埃综合征、有或无幽门螺杆菌感染的胃癌、致病性精神病症、精神分裂症、不育、瘤形成、炎性宿主反应、癌症、恶性转移、黑素瘤、银屑病、体液和细胞介导的免疫应答受损、内皮中的白细胞粘附和迁移过程、食物摄取受损、睡眠-觉醒受损、能量代谢的稳态调节受损、自主神经功能受损、激素平衡受损或者体液调节受损、多发性硬化、格-巴二氏综合征以及慢性炎性脱髓鞘多发性神经根神经病。
11.权利要求1-5中任一项的化合物或者权利要求7-9中任一项的药物组合物在制备用于治疗或预防选自以下的疾病的药物中的用途:轻度认知障碍、阿尔茨海默病、家族性英国型痴呆、家族性丹麦型痴呆、唐氏综合征中的神经变性以及亨廷顿病。
12.权利要求1-5中任一项的化合物或者权利要求7-9中任一项的药物组合物在制备用于治疗或预防选自以下的疾病的药物中的用途:类风湿性关节炎、动脉粥样硬化、胰腺炎和再狭窄。
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-
2017
- 2017-03-31 GB GBGB1705263.0A patent/GB201705263D0/en not_active Ceased
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2018
- 2018-04-03 IL IL269196A patent/IL269196B2/en unknown
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- 2018-04-03 EP EP18718725.7A patent/EP3601269A1/en active Pending
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IL307911A (en) | 2023-12-01 |
AU2018246382A1 (en) | 2019-10-17 |
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IL269196B2 (en) | 2024-04-01 |
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AU2022246405A1 (en) | 2022-10-27 |
JP2022110130A (ja) | 2022-07-28 |
AU2018246382B2 (en) | 2022-06-16 |
IL269196A (en) | 2019-11-28 |
US20200377493A1 (en) | 2020-12-03 |
ZA201905811B (en) | 2020-06-24 |
CA3221839A1 (en) | 2018-10-04 |
IL297534A (en) | 2022-12-01 |
JP2020512373A (ja) | 2020-04-23 |
CA3057783A1 (en) | 2018-10-04 |
US20220274977A1 (en) | 2022-09-01 |
CN110719910A (zh) | 2020-01-21 |
KR20190136005A (ko) | 2019-12-09 |
MX2019011544A (es) | 2019-12-16 |
CN117024352A (zh) | 2023-11-10 |
US11339152B2 (en) | 2022-05-24 |
EP3601269A1 (en) | 2020-02-05 |
WO2018178384A1 (en) | 2018-10-04 |
BR112019019553A2 (pt) | 2020-04-22 |
NZ757601A (en) | 2023-02-24 |
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