CN112384514A - 作为janus激酶抑制剂的新的氨基-咪唑并嘧啶衍生物及其药物用途 - Google Patents
作为janus激酶抑制剂的新的氨基-咪唑并嘧啶衍生物及其药物用途 Download PDFInfo
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Abstract
本发明涉及式(I)化合物或其药学上可接受的盐、水合物或溶剂化物。本发明还涉及用于治疗的所述化合物、包含所述化合物的药物组合物和用于治疗自身免疫疾病的所述化合物。
Description
技术领域
本发明涉及作为Janus激酶抑制剂的化合物及其衍生物、用于治疗的所述化合物以及包含所述化合物的药物组合物。
发明背景
本发明涉及作为蛋白酪氨酸激酶例如Janus激酶(JAK1、JAK2、JAK3和TYK2)、特别是Janus激酶1(JAK1)的抑制剂的新化合物。
蛋白酪氨酸激酶是催化三磷酸腺苷的末端磷酸转移至蛋白质底物中的酪氨酸残基的酶家族。蛋白质底物上的酪氨酸残基的磷酸化导致调节众多过程例如细胞生长分化及活化、代谢、造血、宿主防御及免疫调节的细胞内信号的转导。随着许多炎症性疾病和免疫系统其他疾病(例如自身免疫性疾病)的分子机制的阐明,突出了这些细胞内信号途径的关键作用,调节蛋白酪氨酸激酶的活性似乎是管控炎性疾病的一条有吸引力的途径。已经鉴定出大量的蛋白酪氨酸激酶,它们可以是受体蛋白酪氨酸激酶(例如胰岛素受体)或非受体蛋白酪氨酸激酶。
蛋白酪氨酸激酶JAK1、JAK2、JAK3和TYK2选择性地与多种细胞因子受体链的胞质结构域缔合,且在组织稳态的细胞因子依赖性调节、先天免疫的启动、成形适应性免疫反应及炎性过程中具有至关重要的作用。其在响应其经由通过刺激细胞因子受体的酪氨酸磷酸化的活化进行的信号转导中至关重要。(1)Schindler C.等人,JAK-STAT signaling:frominterferons to cytokines.J.Biol.Chem 2007;282(28):20059;(2)O’SheaJ.J.Targeting the Jak/STAT pathway for immunosuppression;Ann.Rheum.Dis.2004;63Suppl 2:ii67;(3)Schindler C.Series introduction.JAK-STAT signaling in humandisease;J.Clin.Invest.2002;109(9):1133);(4)O’Shea等人,Cell,第109卷,S121-S131,2002;(5)Schwartz D.M.等人,Nat.Rev.Rheumatol.,2016;12(1):25-36;(6)O’Shea等人,New.Eng.J.Med.2013;368(2):161-170。
虽然JAK1、JAK2和TYK2被广泛表达,但JAK3主要在造血细胞中表达。
JAK1在介导生物反应方面发挥关键作用,且JAK1广泛表达并与数种主要的细胞因子受体家族缔合。其通过IL-2受体γ亚基家族(IL-2、IL-4、IL-7R、IL-9R、IL-15R及IL-21R)、IL-4受体家族(IL-4R、IL-13R)、gp130受体家族和包括IL-10受体家族以及I型和II型IFN受体家族的II类细胞因子受体的成员参与信号传导。
JAK2通过数种单链受体(包括Epo-R、GHR、PRL-R)、IL-3受体家族、gp130受体家族、IL-12受体家族(IL-12和IL-23)及一些II类受体细胞因子家族参与信号传导。因此,JAK2在Epo、IL-3、GM-CSF、IL-5和IFNγ的信号转导中起关键作用。JAK2敲除小鼠表现出胚胎致死表型。
JAK3通过采用I型细胞因子受体家族(亦称为IL-2受体家族)(例如IL-2、IL-4、IL-7、IL-9、IL-15及IL-21)的共同γ链的受体参与信号转导。已经鉴定出XSCID患者群体的JAK3蛋白水平降低或具有共同γ链的遗传缺陷,这表明免疫抑制应该是由阻断经JAK3途径的信号传导引起的。动物研究表明,JAK3不仅在B和T淋巴细胞的成熟中起着至关重要的作用,而且JAK3对于维持T细胞功能在组成上是必需的。可证实,通过这种新机制调节免疫活性可用于治疗T细胞增殖性疾病,例如免疫系统疾病,尤其是自身免疫疾病。
TYK2涉及I型干扰素IL-6、IL-10、IL-12和IL-23信号传导。患有TYK2缺失的人类患者已有记载,并且该患者患有原发性免疫缺陷病症,其特征在于高IgE样综合征,并有许多由病毒、细菌及真菌所致的机会性感染。由于已发现IL-23在许多慢性炎性病况中发挥重要作用,所以可设想TYK2抑制剂在治疗受IL-23影响的疾病方面非常有效。
贫血及嗜中性白血球减少症可能分别与EPO及GM-CSF的抑制有关,因为这两种细胞因子的生物效应显然仅取决于JAK2活化。类似地,IL-12及IL-23参与针对病毒、细菌及真菌的先天性及适应性免疫防御。由于这些细胞因子结合在其信号传导级联中募集JAK2及TYK2的受体,所以可以想象,选择性的JAK1抑制剂将不影响它们的生物活性并因此与抑制JAK1、JAK2、JAK3和TYK2的化合物相比具有更安全的性质。
JAK的活化导致STAT分子的活化并因此导致JAK/STAT信号通路的引发,该途径受磷酸化事件高度调节。STAT分子的活化被认为是JAK活性的有效药效学标记,特定JAK分子的活性可以通过优先募集的活性STAT分子的水平进行评估。
具体而言,由免疫细胞表达的IL-4受体由两条不同的链、即配体高亲和性及信号转导分子IL-4Ra和共同γ链组成,其在配体结合时分别活化JAK1和JAK3,这导致STAT6的募集和活化。类似地,IL-6受体是由IL-6高亲和性受体链(IL-6Ra)和JAK1优先缔合的信号转导分子醣蛋白130(gp130)链形成的异二聚体受体。gp130链在配体结合时活化JAK1和STAT3信号通路。因此,为研究JAK1的活性,可在分别用IL-4或IL-6刺激后在免疫细胞中评价活性STAT6或STAT3的水平。
此外,促红细胞生成素的受体(EPOR)是由两个相同受体链构成的同二聚体受体。因此,EPOR链同时是高亲和性配体结合和信号转导分子链,且在配体结合时仅活化缔合的JAK2分子,从而导致STAT5的募集和活化。GM-CSF的受体是由GM-CSF高亲和性受体链(GM-CSFRα)和JAK2特异性缔合的信号转导分子链(GM-CSFRβ)构成的异二聚体受体。在配体结合时,α受体链和β受体链的缔合导致JAK2和STAT5信号通路的活化。因此,为研究JAK2的活性,可在利用GM-CSF或促红细胞生成素(EPO)刺激后在免疫细胞中评价活性STAT5的水平。
Janus激酶的抑制剂预期在所述激酶参与其中的炎性及非感染性自身免疫疾病的治疗中显示效用。最近,泛-JAK抑制剂托法替尼(tofacitinib)和鲁索替尼(ruxolitinib)已经上市,分别用于治疗类风湿性关节炎和骨髓纤维化。
因此,JAK抑制剂还可用于治疗与Janus激酶的活性有关的疾病,所述疾病包括例如皮肤病,如银屑病、特应性皮炎、硬皮病、酒渣鼻、皮肤癌、皮炎、疱疹样皮炎、皮肌炎、白癜风、斑秃、接触性皮炎、湿疹、干燥病、鱼鳞癣、荨麻疹和慢性特发性瘙痒症;呼吸系统疾病,如哮喘、慢性阻塞性肺病、肺纤维化、囊性纤维化、鼻炎、细支气管炎、棉屑沉着病、尘肺病、支气管扩张症、过敏性肺炎、肺癌、间皮瘤和结节病;胃肠疾病,如炎性肠病、溃疡性结肠炎、克罗恩病、腹膜后纤维化、乳糜泻和癌症;眼部疾病,如重症肌无力、干燥综合征(syndrome)、结膜炎、巩膜炎、葡萄膜炎、干眼综合征、角膜炎、虹膜炎;全身性适应症,如狼疮、多发性硬化、类风湿性关节炎、I型糖尿病及糖尿病的并发症、癌症、强直性脊柱炎和银屑病关节炎;以及其他需要免疫抑制的自身免疫性疾病和适应症,例如在器官移植中。
WO2013007768公开了三环杂环化合物、组合物及其作为JAK抑制剂的使用方法。
WO2013007765公开了用作Janus激酶抑制剂的稠合三环化合物。
WO2011086053公开了三环杂环化合物、组合物及其使用方法。
仍然需要有效且选择性抑制特定JAK酶的新化合物,特别是相对于JAK2选择性抑制JAK1的抑制剂,以在不影响总体抗炎性效能的情形下减少不良效应。
发明概述
本发明的化合物显示对Janus激酶的抑制活性;具体地讲,本发明的化合物显示对JAK1的抑制活性。因此,本发明的化合物显示JAK激酶抑制选择性;特别是,所述化合物显示相对于JAK2的对JAK1的抑制选择性。因此,本发明的化合物还可显示出相对于STAT5的对STAT6或STAT3的抑制选择性。
因此,本发明涉及式(I)化合物
其中
A代表C6-环烷基;
R1代表C1-烷基,其中所述C1-烷基任选地被一个或多个选自氘的取代基取代;
R2代表C1-烷基,其中所述C1-烷基被选自R5的取代基取代,并且其中所述C1-烷基任选地被一个或多个氘取代;
R3代表C2-烷基,其中所述C2-烷基被选自R6的取代基取代,并且其中所述C2-烷基任选地被一个或多个氘取代;
R4为氢或氘;
R5代表氰基;
R6代表羟基;
或其药学上可接受的盐、水合物或溶剂化物。
另一方面,本发明涉及药物组合物,其包含如本文所定义的通式(I)化合物以及药学上可接受的媒介物或赋形剂或药学上可接受的载体,以及任选的一种或多种其他治疗活性化合物。
又一方面,本发明涉及如本文所定义的通式(I)化合物,其用作药物。
又一方面,本发明涉及如本文所定义的通式(I)化合物,其用于预防和/或治疗免疫系统疾病(例如自身免疫疾病)或与免疫系统失调有关的疾病。
发明详述
定义
术语“(Ca-Cb)烷基”是指当从支链或直链烃中除去一个氢原子时得到的基团。所述烷基包含1-6个、优选1-4个、例如1-3个、例如2-3个或例如1-2个碳原子。该术语包括正烷基、仲烷基和叔烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基和异己基。“烷基”中的碳原子数由前缀“(Ca-Cb)”表示,其中a为烃基中的最小碳数,b为烃基中的最大碳数。因此,例如(C1-C4)烷基表示包含1至4个碳原子的烷基。C1-烷基表示包含1个碳原子的烷基,例如甲基。C2-烷基表示包含2个碳原子的烷基,例如乙基。
术语“氰基”是指通过碳原子与母体分子部分连接的-CN基团。
术语“(Ca-Cb)环烷基”表示饱和的环烷烃基,包括多环基团,例如双环或三环基团,其包含3-8个碳原子,例如5-8个碳原子,例如5-7个碳原子,例如例如5-6个碳原子,例如3-6个碳原子,例如3-5个碳原子,或例如3-4个碳原子,例如6个碳原子,例如环丙基、环丁基、环戊基、环己基或环庚基,金刚烷基和立方烷基(cubanyl)。“环烷基”中的碳原子数由前缀“(Ca-Cb)”表示,其中a为烃基中的最小碳数,b为烃基中的最大碳数。因此,例如(C5-C8)环烷基表示包含5至8个碳原子的环烷基。
术语“卤素”是指元素周期表第7主族的取代基,例如氟、氯、溴和碘。
术语“烃基”是指仅含有氢和碳原子的基团,它可以含有一个或多个碳-碳双键和/或三键,并且它可以包含与支链或直链部分结合的环状部分。所述烃包含1-10个碳原子,优选包含1-4个碳原子,例如1-3个碳原子,例如1-2个碳原子。该术语包括如本文所示的烷基、环烷基和芳基。
烃基(例如烷基和环烷基)中的碳原子数由前缀“(Ca-Cb)”表示,其中a是烃基中的最小碳数,b是烃基中的最大碳数。因此,例如(C1-C4)烷基意指包含1-4个碳原子的烷基,(C5-C8)环烷基意指包含5-8个碳环原子的环烷基。
术语“羟基”意指-OH基团。
术语“羟基(Ca-Cb)烷基”是指被一个或多个羟基取代的如上定义的(Ca-Cb)烷基,例如羟甲基、羟基乙基、羟丙基。
当两个或多个如上定义的术语组合使用时,例如芳基烷基、环烷基烷基等,应理解第一个提及的基团是后一个提及的基团上的取代基,其中与母体分子部分的连接点在后一个基团上。
基团C(O)表示羰基(C=O)。
如果将取代基描述为独立地选自一个组,则每个取代基彼此独立地选择。因此,各取代基可以与其他取代基相同或不同。
术语“任选取代的”是指“未取代或取代的”,因此本文所述的通式涵盖包含指定的任选取代基的化合物以及不包含任选取代基的化合物。
术语“药学上可接受的盐”是指通过使包含碱性部分的式(I)化合物与适宜的无机或有机酸反应所制备的盐,所述无机或有机酸是例如盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、甲酸、乙酸、2,2-二氯乙酸、己二酸、抗坏血酸、L-天冬氨酸、L-谷氨酸、粘酸、乳酸、马来酸、L-苹果酸、邻苯二甲酸、柠檬酸、丙酸、苯甲酸、戊二酸、葡萄糖酸、D-葡萄糖醛酸、甲磺酸、水杨酸、琥珀酸、丙二酸、酒石酸、苯磺酸、乙烷-1,2-二磺酸、2-羟基乙磺酸、甲苯磺酸、氨基磺酸或富马酸。药学上可接受的盐的其他实例列于Berge,S.M.;J.Pharm.Sci.;(1977),66(1),1-19中,其以引用方式并入本文。
术语“溶剂化物”是指通过化合物(例如式(I)化合物)与溶剂(例如醇、甘油或水)之间的相互作用形成的物质,其中所述物质是结晶形式或无定型形式的。当水为溶剂时,所述物质称为水合物。
本文所用的术语“治疗”表示出于对抗疾病、病症或病况的目的管控和照护患者。该术语意欲包括延迟疾病、病症或病况的进展,改善、缓和或缓解症状及并发症和/或治愈或消除疾病、病症或病况。该术语包括病况的预防,其中预防应理解为出于对抗疾病、疾患或病况的目的管控和照护患者,并且包括施用活性化合物以防止症状或并发症的发作。然而,预防(预防性)和治疗性(治愈性)治疗是两个单独的方面。
除非另外指明,本文提供的所有精确值代表相应的近似值,例如,关于特定测量提供的精确示例性值可被认为也提供相应的近似测量值,在适当的情况下用“约”修饰。
本文所引用的所有参考文献(包括出版物、专利申请和专利)均以全文引用的方式并入本文中,并且其并入程度就像将每一参考文献单独且特别指出以引用方式并入一样,不管在本文中是否在其它地方单独提到对特定文献的引用。
本发明的实施方案
本发明的一个实施方案提供了根据上式(I)的化合物,其中
其中
A代表C6-环烷基;
R1代表C1-烷基,其中所述C1-烷基任选地被一个或多个选自氘的取代基取代;R2代表C1-烷基,其中所述C1-烷基被选自R5的取代基取代;
R3代表C2-烷基,其中所述C2-烷基被选自R6的取代基取代;
R4代表氢;
R5代表氰基;
R6代表羟基;
或其药学上可接受的盐、水合物或溶剂化物。
本发明的一个实施方案提供了根据以上式(I)的下式(Ia)的化合物
其中
R1代表C1-烷基,其中所述C1-烷基任选地被一个或多个选自氘的取代基取代;
R2代表C1-烷基,其中所述C1-烷基被选自R5的取代基取代,并且其中所述C1-烷基任选地被一个或多个氘取代;
R4代表氢或氘;
R5代表氰基;
R6代表羟基;
Ra、Rb、Rc和Rd各自独立地选自氢或氘;
或其药学上可接受的盐、水合物或溶剂化物。
在一个实施方案中,本发明提供了通式(I)的化合物;其中式(I)是通式(Ib)
其中R1、R2、R4和R6如上所定义,且其中Ra、Rb、Rc和Rd各自独立地选自氢和氘;或其药学上可接受的盐、水合物或溶剂化物。
在一个实施方案中,本发明提供了通式(I)的化合物;其中式(I)是通式(Ic)
其中R1、R2、R4和R6如上所定义,且其中Ra、Rb、Rc和Rd各自独立地选自氢和氘;或其药学上可接受的盐、水合物或溶剂化物。
在一个实施方案中,本发明提供了通式(I)的化合物;其中式(I)是通式(Id)
其中R1、R2、R4和R6如上所定义,且其中Ra、Rb、Rc和Rd各自独立地选自氢和氘;或其药学上可接受的盐、水合物或溶剂化物。
本发明的一个实施方案提供了式(I)的化合物,所述化合物选自
2-[反式-4-[8-[(1R)-1-羟基乙基]-2-(甲基氨基)嘌呤-9-基]环己基]乙腈,
2-[反式-4-[8-(1-羟基乙基)-2-(甲基氨基)嘌呤-9-基]环己基]乙腈
或其药学上可接受的盐、水合物或溶剂化物。
本发明的一个实施方案提供了式(I)的化合物,所述化合物选自
2-[反式-4-[8-[(1R)-1-羟基乙基]-2-(甲基氨基)嘌呤-9-基]环己基]乙腈,
2-[反式-4-[8-(1-羟基乙基)-2-(甲基氨基)嘌呤-9-基]环己基]乙腈,
2-[反式-4-[8-[(1R)-1-羟基乙基]-2-(三氘代甲基氨基)嘌呤-9-基]环己基]乙腈
或其药学上可接受的盐、水合物或溶剂化物。
本发明的一个实施方案提供了式(I)的化合物,所述化合物选自
2-[反式-4-[8-[(1R)-1-羟基乙基]-2-(甲基氨基)嘌呤-9-基]环己基]乙腈,
或其药学上可接受的盐、水合物或溶剂化物。
本文所述的两个或更多个实施方案的任何组合都被认为在本发明的范围内。
式(I)化合物或其药学上可接受的盐、水合物或溶剂化物可以直接通过从有机溶剂浓缩,或通过从有机溶剂或所述溶剂与共溶剂(可以是有机或无机的,例如水)的混合物中结晶或重结晶以结晶形式获得。晶体可以以基本上无溶剂的形式或溶剂化物(例如水合物)的形式分离。本发明覆盖所有结晶形式(例如多晶形物和假多晶形物)以及其混合物。
式(I)化合物可包含或不包含不对称取代的(手性)碳原子,其导致异构形式(例如对映异构体以及可能的非对映异构体)的存在。本发明涉及所有这些异构体,无论是光学纯形式还是其混合物形式(例如外消旋混合物或部分纯化的光学混合物)。本发明的化合物及中间体的纯的立体异构形式可通过本领域已知的方法获得。不同异构形式可通过物理分离方法例如选择性结晶及色谱技术(例如使用手性固定相的高压液相色谱)分离。对映异构体可以通过其非对映异构体盐的选择性结晶而彼此分离,所述非对映异构体盐可以与旋光性胺如l-麻黄碱或旋光性酸形成。光学纯化的化合物随后可从所述纯化的非对映异构盐中释放。对映异构体也可以通过形成非对映异构体衍生物来拆分。或者,对映异构体可通过使用手性固定相的色谱技术分离。纯的立体异构形式也可以衍生自适当的起始原料的相应的纯的立体异构形式。如果需要特定的立体异构体,则可以通过立体选择性或立体特异性的制备方法和/或通过使用手性纯起始原料来合成所述化合物。此外,当分子中存在双键或完全或部分饱和的环系统时,可以形成几何异构体。意欲将任何几何异构体,如分离的、纯的或部分纯化的几何异构体或其混合物包括在本发明的范围内。
在通式(I)的化合物中,原子可以表现其天然同位素丰度,或可以人工方式使一种或多种原子富集具有相同原子序数但原子质量或质量数不同于在自然界中发现的原子质量或质量数的特定同位素。本发明旨在包括通式(I)化合物的所有适宜同位素变化形式。例如,氢的不同同位素形式包括1H、2H和3H,碳的不同同位素形式包括12C、13C和14C,氮的不同同位素形式包括14N和15N。富集氘(2H)可例如延长体内半衰期或减少剂量方案,或可提供可用作表征生物样品的标准化合物。同位素富集的通式(I)化合物可通过本领域技术人员熟知的常规技术或通过与本文一般方法及实施例中所述那些类似的方法使用适当同位素富集的试剂和/或中间体来制备。
在本发明的一个或多个实施方案中,如上文所定义的式I化合物可用于治疗,特别是用于治疗例如皮肤病如增殖性和炎性皮肤病症、银屑病、特应性皮炎、硬皮病、酒渣鼻、皮肤癌、皮炎、疱疹样皮炎、皮肌炎、白癜风、斑秃、接触性皮炎、湿疹、干燥病、鱼鳞癣、荨麻疹和慢性特发性瘙痒症;呼吸系统疾病,如哮喘、慢性阻塞性肺病、肺纤维化、囊性纤维化、鼻炎、细支气管炎、棉屑沉着病、尘肺病、支气管扩张症、过敏性肺炎、肺癌、间皮瘤和结节病;胃肠疾病,如炎性肠病、溃疡性结肠炎、克罗恩病、腹膜后纤维化、乳糜泻和癌症;眼部疾病,如重症肌无力、干燥综合征、结膜炎、巩膜炎、葡萄膜炎、干眼综合征、角膜炎、虹膜炎;全身性适应症,如狼疮、多发性硬化、类风湿性关节炎、I型糖尿病及糖尿病的并发症、癌症、强直性脊柱炎和银屑病关节炎;以及其他需要免疫抑制的自身免疫性疾病和适应症,例如在器官移植中。
在一个实施方案中,本发明提供如上文所定义的式I化合物,其用于预防和/或治疗银屑病或特应性皮炎。
在一个实施方案中,本发明提供预防、治疗或改善免疫系统疾病(例如自身免疫疾病)的方法,所述方法包括向患有至少一种所述疾病的人施用有效量的一种或多种上述通式I化合物,任选地与药学上可接受的载体或一种或多种赋形剂一起施用,任选地与其它治疗活性化合物组合施用。
在一个实施方案中,本发明提供预防、治疗或改善银屑病或特应性皮炎的方法,所述方法包括向患有至少一种所述疾病的人施用有效量的一种或多种上述通式I化合物,任选地与药学上可接受的载体或一种或多种赋形剂一起施用,任选地与其它治疗活性化合物组合施用。
在一个实施方案中,本发明提供式I的化合物,其用于制备用于预防和/或治疗免疫系统疾病例如自身免疫疾病(例如银屑病或特应性皮炎)的药物。
在本发明的一个或多个实施方案中,如上文所定义的式I化合物可用作抗炎剂,其能够调节蛋白酪氨酸激酶的JAK家族的蛋白酪氨酸激酶(例如JAK1、JAK2、JAK3或TYK2蛋白酪氨酸激酶)的活性。
在一个或多个实施方案中,本发明提供用于治疗疾病的通式(I)化合物,所述疾病对JAK1激酶活性的抑制有响应。
除可用于人类治疗外,本发明的化合物还可用于动物的兽医治疗,所述动物包括哺乳动物,例如马、牛、绵羊、猪、狗和猫。
本发明的药物组合物
对于在治疗中使用,本发明的化合物通常为药物组合物形式。因此,本发明涉及包含式(I)化合物、任选的一种或多种其他治疗活性化合物以及药学上可接受的赋形剂、媒介物或载体的药物组合物。赋形剂在与组合物的其他成分相容并且对其接受者无害的意义上必须是“可接受的”。
适宜地,活性成分占制剂重量的0.0001%-99.9%。
剂量单位形式的化合物可以以适当的间隔一天施用一次或多次,但这通常取决于患者的情况并根据从业医师所开的处方。适宜地,制剂的剂量单位含有0.001mg至1000mg、优选0.01mg至100mg、例如0.1至50mg的式(I)化合物。
本发明化合物的适宜剂量将(尤其)取决于患者的年龄及情况、欲治疗疾病的严重程度以及从业医师所熟知的其他因素。化合物可根据不同给药时间表(例如每天、每周或以每月间隔)以口服、胃肠外、局部、经皮或皮内及其他途径施用。一般而言,单一剂量将在0.001mg/kg体重至400mg/kg体重的范围内。化合物可以推注形式(即一次施用全部日剂量)或以分开剂量一天两次或更多次施用。
在局部治疗的上下文中,更合适的是指“使用单位”,其表示能够施用于患者并且可以容易地处理和包装的单一剂量,其保持为物理上及化学上稳定的单位剂量,包含活性材料本身或其与固体、半固体或液体药物稀释剂或载体的混合物。
与局部使用相关的术语“使用单位”是指单位的,即单一剂量,其能够以每平方厘米治疗面积0.001微克至1mg、优选0.05微克至0.5mg所述活性成分的施用形式局部施用于患者。
还设想在某些治疗方案中,以较长的间隔,例如每隔一天、每周或甚至以更长间隔施用可能是有益的。
如果治疗涉及施用其他治疗活性化合物,则建议在Goodman&Gilman’s ThePharmacological Basis of Therapeutics,第9版,J.G.Hardman和L.E.Limbird(编辑),McGraw-Hill 1995中查阅所述化合物的可用剂量。
可同时或依序施用本发明的化合物与一种或多种其他活性化合物。
制剂包括例如适于口服、直肠、胃肠外(包括皮下、腹膜内、肌内、关节内和静脉内)、经皮、皮内、经眼、局部、经鼻、舌下或经颊施用的那些形式。
制剂可适宜地以剂量单位形式存在,并可通过但不局限于医药业内所熟知的任一方法制备,例如如Remington,The Science and Practice of Pharmacy,第21版,2005中所公开的那些。所有方法均包括使活性成分与构成一种或多种辅助成分的载体结合的步骤。通常,通过将活性成分与液体载体、半固体载体或细分的固体载体或它们的组合均匀且紧密地结合在一起,然后如果需要,将产品成型为所需制剂来制备制剂。
适于口服和经颊施用的本发明制剂可呈以下形式:各自含有预定量活性成分的离散单位形式,如胶囊、小药囊、片剂、口香糖或锭剂;散剂、颗粒剂或丸剂形式;水性液体或非水性液体中的溶液剂或混悬剂形式;或凝胶剂、纳米乳剂或微乳剂、水包油乳剂、油包水乳剂或其他分散系统形式。用于水性混悬剂的适宜分散剂或助悬剂包括合成或天然表面活性剂和增粘剂。活性成分还可以以推注、舐剂(electuary)或糊剂形式施用。
片剂可通过将活性成分任选与一种或多种辅助成分压制、模制或冻干来制得。压制片剂可通过在适宜机器中压制呈自由流动形式的活性成分(例如粉末或颗粒)来制备,所述活性成分任选与粘合剂和/或填充剂;润滑剂;崩解剂或分散剂混合。模制片剂可通过在适宜机器中模制经惰性液体稀释剂润湿的粉末状活性成分及适宜载体的混合物来制得。冻干片剂可在冻干机中从原料药的溶液形成。可包含适宜的填充剂。
用于直肠施用的制剂可呈栓剂形式,其中本发明的化合物与低熔点、水溶性或不可溶固体混合。
适于胃肠外施用的制剂适宜地包含活性成分的无菌油性或水性制剂,其优选与接受者的血液等渗,例如等渗盐水、等渗葡萄糖溶液或缓冲溶液。此外,制剂可含有共溶剂、增溶剂和/或复合剂。制剂可适宜地通过例如经细菌截留过滤器过滤、向制剂中添加灭菌剂、辐照制剂或加热制剂来灭菌。在例如Encyclopedia of Pharmaceutical Technology,第9卷,1994中所公开的脂质体制剂也适于胃肠外施用。
或者,式(I)化合物可以以无菌固体制剂形式存在,例如在临用前可轻易溶解于无菌溶剂中的冻干粉末。
经皮制剂可呈硬膏剂、贴片、微针、脂质体或纳米颗粒递送系统或应用于皮肤的其他皮肤制剂的形式。
适于经眼施用的制剂可呈活性成分(可为微晶形式的)的无菌水性制剂的形式,例如呈水性微晶混悬液的形式。亦可使用例如如Encyclopedia of PharmaceuticalTechnology,第2卷,1989中所公开的脂质体制剂或生物可降解聚合物系统来提供用于经眼施用的活性成分。
适于局部(例如皮肤、真皮内或经眼)施用的制剂包括液体或半固体制剂,例如擦剂、洗剂、凝胶剂、涂抹剂(applicants)、喷雾剂、泡沫剂、成膜系统、微针、微乳剂或纳米乳剂、水包油或油包水乳剂,例如乳膏、软膏剂或糊剂;或溶液剂或混悬剂,例如滴剂。
对于局部施用,式(I)化合物通常以组合物的0.001重量%至20重量%的量存在,例如0.01%至约10%,但也可以高达组合物的约100%的量存在。
适于经鼻或经颊施用的制剂包括粉末剂、自抛射和喷雾制剂,例如气雾剂和雾化剂。此类制剂更详细地公开于例如Modern Pharmaceutics,第2版,G.S.Banker和C.T.Rhodes(编辑),第427-432页,Marcel Dekker,New York;Modern Pharmaceutics,第3版,G.S.Banker和C.T.Rhodes(编辑),第618-619页和第718-721页,Marcel Dekker,NewYork and Encyclopedia of Pharmaceutical Technology,第10卷,J.Swarbrick和J.C.Boylan(编辑),第191-221页,Marcel Dekker,New York。
除上文所提及的成分以外,式(I)化合物的制剂可包含一种或多种额外成分,例如稀释剂、缓冲剂、矫味剂、着色剂、表面活性剂、增稠剂、渗透增强剂、增溶剂、防腐剂(例如羟基苯甲酸甲酯(包括抗氧化剂))、乳化剂等。
制备方法
本发明化合物可以通过合成领域技术人员熟知的多种方式来制备。举例而言,式(I)化合物可使用下文所概述的反应和技术以及合成有机化学领域内已知的方法或如本领域技术人员所了解的其变化形式来制备。优选方法包括但不限于下文所述的那些。反应在适合所采用的试剂及材料且适于所实现的转变的溶剂中进行。另外,在下文所述的合成方法中,应理解所有提出的反应条件(包括溶剂的选择、反应气氛、反应温度、实验的持续时间及后处理程序)均选择为所述反应的标准条件,所述标准条件是本领域技术人员易于了解的。并非落在给定类别中的所有化合物均可与一些所述方法中需要的一些反应条件相容。对与反应条件相容的取代基的限制对于本领域技术人员将是显而易见的并可使用替代方法。若需要,可使用合成有机化学家所熟知的标准方法来纯化本发明的化合物或任何中间体,例如“Purification of Laboratory Chemicals”,第6版.2009,W.Amarego和C.Chai,Butterworth-Heinemann中所述的方法。起始材料是可商业购得的已知化合物,或可通过本领域技术人员熟知的常规合成方法来制备。
一般方法、制备例和实施例
起始材料可商业购得或在文献中已知。试剂和溶剂可商业购得且未经纯化即使用,除非另有说明。色谱纯化使用具有预填充二氧化硅快速柱的Grace系统或Teledyne IscoRf系统进行或使用硅胶60手动进行。以300MHz、400MHz或600MHz在Bruker仪器上记录1H NMR光谱,以四甲基硅烷(δ=0.00ppm)作为内标。
通篇使用以下缩写:
AcOH 乙酸
DCM 二氯甲烷
DIPEA N,N-二异丙基乙胺
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
Et 乙基
EtOAc 乙酸乙酯
EtOH 乙醇
HPLC 高效液相色谱
HRMS 高分辨率质谱
MeCN 乙腈
MeOH 甲醇
min 分钟
MS 质谱
NMR 核磁共振波谱
rt 室温,即18-30℃,通常为20℃
THF 四氢呋喃
TLC 薄层色谱
tR 保留时间
UPLC 超高效液相色谱法
UV 紫外线
分析型LC-MS
方法A
使用具有2.1×50mm AcquityHSS T3 1.8μm柱和以正离子化电喷射模式操作的Acquity SQ检测器的Waters Acquity UPLC系统进行UPLC-MS分析。流动相由缓冲液A(0.1%甲酸在10mM乙酸铵水溶液中的溶液)和缓冲液B(0.1%甲酸的乙腈溶液)组成。使用二元梯度(在1.4分钟内A:B 95:5→5:95),流速为1.2mL/min,柱温为60℃。
方法B
使用具有254nm UV检测的Waters Acquity UPLC系统和以正离子化电喷雾模式操作的Waters LCT Premier XE高分辨率TOF质谱仪进行高分辨率质谱的UPLC-MS分析。使用与方法A中相同的柱和流动相A和B,但梯度较慢(在4.8分钟内A:B 99:1→1:9;0.7mL/min;柱温40℃)。
分析手性固定相HPLC
使用具有PDA检测器和装备有Phenomenex3μm Cellulose-2(250×4.6mm)柱的Waters LCT Premier XE质谱仪的Waters Acquity UPLC仪器进行手性固定相HPLC分析。采用等度条件,流动相由10mM碳酸氢铵水溶液:MeCN 70:30组成,流速为1mL/min。将柱子保持在室温。
中间体
中间体1
2-[反式-4-[(5-氨基-2-氯-嘧啶-4-基)氨基]环己基]乙腈
将2,4-二氯-5-硝基嘧啶(5.0g,26mmol)的DMF(30mL)溶液在冰浴中冷却,加入三氟乙酸反式-4-(氰基甲基)环己基铵(Li,Y.-L.等人,US-20140121198)(6.5g,26mmol)和DIPEA(5.5mL,31mmol)。将混合物在0℃下搅拌2小时,然后在室温下搅拌过夜。蒸发挥发物,将残余物在EtOAc(200mL)和饱和碳酸氢钠水溶液(200mL)之间分配。分离各层,水层用EtOAc萃取三次。将合并的有机层用MgSO4干燥,过滤并蒸发。将残余物溶于乙酸(5mL)中,在10分钟内分批加入铁粉(14g,260mmol)。将混合物在室温搅拌2小时,之后将其过滤并蒸发挥发物。将残余物通过色谱纯化(120g预填充硅胶柱,用DCM:MeOH 100:0至50:50梯度洗脱)得到标题化合物(1.2g),其纯度足以用于随后的步骤。
UPLC-MS(方法A):tR=0.53分钟,m/z=266.1(M+H+)。
实施例
实施例1
2-[反式-4-[8-[(1R)-1-羟基乙基]-2-(甲基氨基)嘌呤-9-基]环己基]乙腈(化合
物1)
步骤1
2-[反式-4-[2-氯-8-[(1R)-1-羟基乙基]嘌呤-9-基]环己基]乙腈
在氩气下,向三乙基氧鎓四氟硼酸盐(4.3g,23mmol)的THF(20mL)溶液中加入(R)-乳酰胺(2.0g,23mmol)。将所得溶液在室温搅拌2小时,然后加入到中间体1(1.2g,4.5mmol)的无水乙醇(40mL)溶液中。将混合物在80℃搅拌过夜。为了实现完全转化,在氩气下将第二部分三乙基氧鎓四氟硼酸(2.6g,14mmol)溶于THF(15mL)中并加入(R)-乳酰胺(1.2g,14mmol)。将所得溶液在室温搅拌2小时并加入到上述反应混合物中。将混合物在80℃下再搅拌过夜,蒸发挥发物,残余物经色谱纯化(80g预填充的硅胶柱,用DCM:MeOH 100:0至90:10梯度洗脱)得到不纯的产物(1.9g)。将其用乙醚研磨,得到棕色固体状标题化合物(308mg,21%)。
UPLC-MS(方法A):tR=0.56分钟,m/z=320.2(M+H+)。
1H NMR(600MHz,DMSO-d6)δ9.01(s,1H),5.92(d,J=6.9Hz,1H),5.13(p,J=6.6Hz,1H),4.66(tt,J=12.3,3.7Hz,1H),2.55(d,J=6.2Hz,2H),2.53–2.38(m,2H),2.02–1.88(m,4H),1.85–1.74(m,1H),1.59(d,J=6.5Hz,3H),1.36–1.25(m,2H)。
步骤2
2-[反式-4-[8-[(1R)-1-羟基乙基]-2-(甲基氨基)嘌呤-9-基]环己基]乙腈
向螺旋帽小瓶中加入步骤1的产物(300mg,0.94mmol)和33%甲胺的乙醇溶液(5mL)并将混合物在70℃下振荡3小时。蒸发挥发物,残余物通过色谱法纯化(24g预填充的硅胶柱,用DCM:MeOH 100:0至90:10梯度洗脱)得到标题化合物(200mg,68%)。
UPLC-MS(方法B):tR=1.79分钟,m/z=315.1811(M+H+)。
分析手性固定相HPLC:tR=10.1分钟。没有检测到其它峰。预期(S)对映异构体为tR=11.0分钟,参见实施例2。
1H NMR(600MHz,DMSO-d6)δ8.52(s,1H),6.83(br s,1H),5.63(d,J=6.7Hz,1H),4.95(p,J=6.5Hz,1H),4.48(tt,J=12.0,4.0Hz,1H),2.82(d,J=4.7Hz,3H),2.69–2.56(m,2H),2.54(d,J=6.3Hz,2H),1.95–1.80(m,4H),1.76–1.67(m,1H),1.53(d,J=6.5Hz,3H),1.32–1.21(m,2H)。
实施例2
2-[反式-4-[8-(1-羟基乙基)-2-(甲基氨基)嘌呤-9-基]环己基]乙腈(化合物2)
按照实施例1制备,但是从外消旋乳酰胺开始。
UPLC-MS(方法B):tR=1.79分钟,m/z=315.1894(M+H+)。
分析手性固定相HPLC:(R)对映异构体tR=10.2分钟;(S)对映异构体tR=11.0分钟。绝对构型通过与由对映体富集的(R)-乳酰胺制备的(R)对映异构体样品(tR=10.1分钟,参见实施例1)比较来确定。
实施例3
2-[反式-4-[8-[(1R)-1-羟基乙基]-2-(三氘代甲基氨基)嘌呤-9-基]环己基]乙
腈(化合物3)
将装有2-[反式-4-[2-氯-8-[(1R)-1-羟基乙基]嘌呤-9-基]环己基]乙腈(10mg,31μmol)、甲基-3D-胺盐酸盐(22mg,313μmol)、DIPEA(56μL,313μmol)和异丙醇(0.2mL)的螺旋帽小瓶在120℃下振荡过夜。酸制备型HPLC纯化,随后冷冻干燥得到标题化合物。
UPLC-MS(方法B):tR=1.79分钟,m/z=318.214(M+H+)。
1H NMR(600MHz,DMSO-d6)δ8.52(s,1H),6.80(br s,1H),5.64(br s,1H),4.99–4.92(m,1H),4.48(tt,J=12.1,4.1Hz,1H),2.71–2.56(m,2H),2.54(d,J=6.3Hz,2H),1.96–1.80(m,4H),1.76–1.67(m,1H),1.53(d,J=6.5Hz,3H),1.26(qt,J=4.3,12.8Hz,2H)。
JAK激酶分析
从Carna Biosciences,Inc购买人类杆状病毒表达的Janus激酶(JAK)1、2、3和酪氨酸激酶(TYK)2(编号分别为08-144、-045、-046、-147)。全部四种纯化的酶均仅含有催化结构域。JAK1(aa 850-1154)和TYK2(aa 871-1187)被表达有N-末端融合的GST-标签,JAK2和JAK3具有N-末端融合的His-标签。在基于HTRF的分析(CisBio编号62TK0PEC)中测量合成肽的磷酸化抑制。首先,使用Labcyte ECHO 550液体处理器,将75nL测试化合物溶液(100%DMSO)添加至白色浅384孔板(NUNC编号264706)中。此后,添加1μL化合物稀释缓冲液(50mMHEPES,0.05%牛血清白蛋白)和2μL TK溶液(在激酶缓冲液[来自HTRFKinEASE TK试剂盒的1×酶缓冲液,1mM DTT]中的TK底物-生物素)。然后,将5μL激酶-ATP混合物(在激酶缓冲液中制备)添加至孔并将板在RT下培育20分钟(JAK2、JAK3和TYK2)至40分钟(JAK1)。对于全部四种激酶均使用对应于ATP的Km的ATP浓度。缓冲液、底物、激酶和ATP的最终浓度为:JAK1:50mM Hepes缓冲液(pH 7.0)、0.01%BSA、10mM MgCl2、1mM DTT、7μM ATP、50nM SEB、1μM TK底物-生物素和5ng JAK1;JAK2:50mM Hepes缓冲液(pH 7.0)、0.01%BSA、5mM MgCl2、1mMDTT、4μM ATP、1μM TK底物-生物素和0.1ng JAK2;JAK3:50mM Hepes缓冲液(pH 7.0)、0.01%BSA、5mM MgCl2、1mM DTT、2μM ATP、1μM TK底物-生物素和0.3ng JAK3;TYK2:50mMHepes缓冲液(pH 7.0)、0.01%BSA、5mM MgCl2、1mM DTT、13μM ATP、50nM SEB、1μM TK底物-生物素和0.8ng TYK2。然后,通过添加4μL检测混合物(最终浓度:50mM Hepes缓冲液(pH7.0)、0.01%BSA、0.8M KF、20mM EDTA、42nM链霉抗生物素蛋白-XL665和1:400STK AbCryptate)使激酶反应停止并将板在黑暗中培育过夜。使用PerkinElmer Envision读取器使用以下滤光器来量化HTRF信号:320nm激发滤光器、665nm发射滤光器及615nm第2发射滤光器。计算每个孔的比值((665/615)×104)。
STAT6分析
以30-40,000个细胞/孔的密度将25μL STAT6 bla-RA1(Invitrogen编号K1243)细胞悬浮液接种于具有透明底部的384孔Black View板(PerkinElmer编号6007460)中的含有550ng/mL CD40配体(Invitrogen编号PHP0025)的分析培养基(Opti-MEM(Invitrogen编号11058-021)+0.5%热灭活的胎牛血清(Invitrogen编号10082-147)+1%非必需氨基酸(Invitrogen编号11140-050)+1%丙酮酸钠(Invitrogen编号11360-070)+1%青霉素/链霉素(Invitrogen编号15140-122))中。将细胞板在加湿37℃空气/CO2(95%/5%)培育器中培育过夜。次日,使用Labcyte Echo 550液体处理器将125nL测试化合物和参照化合物的溶液转移至细胞板中。然后将板在加湿37℃空气/CO2(95%/5%)培育器中培育1小时。然后,用Labcyte Echo 550将重组人类白介素4(Invitrogen编号PHC0045)添加至板中,直至最终浓度为10ng/mL。然后将细胞在加湿37℃空气/CO2(95%/5%)培育器中培育41/2-5小时。然后,将8μL LiveBLAzer底物混合物(Invitrogen编号K1095)添加至分析板,将其在RT下培育过夜。然后测量荧光:激发:405nm;发射:460nm(绿色通道)、发射:535nm(蓝色通道)。在两个发射通道中减去背景并计算每个孔的比值460/535nm。
STAT5分析
以约10,000个细胞/孔的密度将25μL STAT5 irf1-bla TF1(Invitrogen编号K1219)细胞悬浮液接种于具有透明底部的384孔Black View板(PerkinElmer编号6007460)中的分析培养基(Opti-MEM(Invitrogen编号11058-021)+0.5%热灭活的胎牛血清(Invitrogen编号10082-147)+1%非必需氨基酸(Invitrogen编号11140-050)+1%丙酮酸钠(Invitrogen编号11360-070)+1%青霉素/链霉素(Invitrogen编号15140-122))中。将细胞板在加湿37℃空气/CO2(95%/5%)培育器中培育过夜。次日,用Labcyte Echo 550液体处理器将125nL测试化合物和参照化合物的溶液转移至细胞板中。然后将板在加湿37℃空气/CO2(95%/5%)培育器中培育1小时。然后,使用Labcyte Echo 550将重组人类促红细胞生成素(EPO)(Invitrogen编号PHC9634)添加至板中,直至最终浓度为10ng/mL。然后将细胞在加湿37℃空气/CO2(95%/5%)培育器中培育41/2-5小时。然后将8μL LiveBLAzer底物混合物(Invitrogen编号K1095)添加至分析板,然后将其在RT下培育过夜。然后测量荧光:激发:405nm;发射:460nm(绿色通道)、发射:535nm(蓝色通道)。在两个发射通道中减去背景并计算每个孔的比值460/535nm。
在JAK激酶分析、STAT5和STAT6分析中测试本发明的化合物。结果列于表1中。
表1
Claims (9)
2.根据权利要求1所述的化合物,选自
2-[反式-4-[8-[(1R)-1-羟基乙基]-2-(甲基氨基)嘌呤-9-基]环己基]乙腈,
2-[反式-4-[8-(1-羟基乙基)-2-(甲基氨基)嘌呤-9-基]环己基]乙腈,
2-[反式-4-[8-[(1R)-1-羟基乙基]-2-(三氘代甲基氨基)嘌呤-9-基]环己基]乙腈或其药学上可接受的盐、水合物或溶剂化物。
3.根据权利要求1-2中任一项所述的化合物,其用作药物。
4.根据权利要求1-2中任一项所述的化合物,其用于预防和/或治疗免疫系统疾病如自身免疫性疾病或与免疫系统失调有关的疾病。
5.根据权利要求4使用的化合物,其用于预防和/或治疗选自银屑病和特应性皮炎的疾病。
6.一种药物组合物,其包含根据权利要求1-2中任一项所述的化合物以及药学上可接受的媒介物或赋形剂或药学上可接受的载体。
7.根据权利要求6所述的药物组合物,其还包含一种或多种其它治疗活性化合物。
8.根据权利要求1-2中任一项所述的化合物,其用于治疗疾病,所述疾病对抑制JAK1激酶活性有响应。
9.一种预防、治疗或改善免疫系统疾病如自身免疫性疾病的方法,所述方法包括向患有至少一种所述疾病的人施用有效量的一种或多种根据权利要求1-2中任一项所述的化合物,任选地与药学上可接受的载体或一种或多种赋形剂一起施用,任选地与其它治疗活性化合物组合施用。
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WO2012146667A1 (en) * | 2011-04-29 | 2012-11-01 | Almirall, S.A. | Imidazopyridine derivatives as pi3k inhibitors |
CN103649089A (zh) * | 2011-04-29 | 2014-03-19 | 阿尔米雷尔有限公司 | 作为pi3k抑制剂的吡咯并三嗪酮 |
CN104936959A (zh) * | 2013-03-08 | 2015-09-23 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 2,6,9-三取代嘌呤衍生物及其制备方法与应用 |
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WO2013007768A1 (en) | 2011-07-13 | 2013-01-17 | F. Hoffmann-La Roche Ag | Tricyclic heterocyclic compounds, compositions and methods of use thereof as jak inhibitors |
WO2013007765A1 (en) | 2011-07-13 | 2013-01-17 | F. Hoffmann-La Roche Ag | Fused tricyclic compounds for use as inhibitors of janus kinases |
KR20150074193A (ko) | 2012-11-01 | 2015-07-01 | 인사이트 코포레이션 | Jak 억제제로서 트리사이클릭 융합된 티오펜 유도체 |
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WO2012146667A1 (en) * | 2011-04-29 | 2012-11-01 | Almirall, S.A. | Imidazopyridine derivatives as pi3k inhibitors |
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CN104936959A (zh) * | 2013-03-08 | 2015-09-23 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 2,6,9-三取代嘌呤衍生物及其制备方法与应用 |
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