CN110885331A - 一种新颖的6-氨基-1H-吡唑并[3,4-d]嘧啶类JAK激酶抑制剂的制备与应用 - Google Patents
一种新颖的6-氨基-1H-吡唑并[3,4-d]嘧啶类JAK激酶抑制剂的制备与应用 Download PDFInfo
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- CN110885331A CN110885331A CN201811078582.XA CN201811078582A CN110885331A CN 110885331 A CN110885331 A CN 110885331A CN 201811078582 A CN201811078582 A CN 201811078582A CN 110885331 A CN110885331 A CN 110885331A
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- phenyl
- pyrazolo
- compound
- amino
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Abstract
本发明提供了可用于预防、治疗和/或改善自身免疫疾病(例如,牛皮癣、类风湿性关节炎、炎性肠炎疾病、斯耶格伦氏综合征、白塞氏病、多发性硬化、系统性红斑狼疮等)的药物,其具有优良的JAK激酶(Janus Kinase)抑制活性。本发明还提供包含所述化合物的药学上可接受的组合物和用于制备这些化合物的方法。
Description
技术领域:
本发明涉及具有JAK激酶抑制作用的杂环化合物,用作预防预防、治疗和/或改善自身免疫疾病(例如,牛皮癣(Psoriasis)、类风湿性关节炎(rheumatoid arthritis)、炎性肠炎疾病(inflammatory enteritis disease)、斯耶格伦氏综合征(sjogren′ssyndrome)、白塞氏病(behcet′s disease)、多发性硬化(multiple sclerosis)、系统性红斑狼疮(systemic lupus erythematosus)等)的药物,还涉及含有它的药物组合等。
背景技术:
JAK激酶(janus kinase)和其下游的效应器、信号转导及转录激活蛋白(signaltransducers and activators of transcription proteins,STATs)形成了重要的细胞因子信号传导途径——JAK-STAT通路(Science,1994,264:1415-1421)。该通路是一条与细胞因子密切相关的细胞内信号转导通路,研究发现该通路可由多种细胞因子、生长因子以及受体激活,参与细胞增殖、分化、凋亡、血管生成以及免疫调节等许多重要的生物学过程(World J Gastroenterol,2007,13:6478-6491)。
JAK激酶家族在细胞素依赖性调节与生长和免疫应答相关的细胞的功能方面起重要作用。JAK家族是存在于细胞内的非受体酪氨酸蛋白激酶,在哺乳动物体内,该家族含有4个主要的家族成员:JAK-1(亦称为janus激酶1)、JAK-2(亦称为janus激酶2)、JAK-3(亦称为janus激酶3)和TYK-2(亦称为tyrosine激酶2)。其中,JAK-1,JAK-2以及TYK-2在各种组织细胞中广泛表达,而JAK3则主要在造血细胞中表达。JAK-STAT信号通路是一条由多种细胞因子受体刺激的信号转导通路,JAK激酶介导细胞内大多数细胞因子的信号传导(Prog MedChem,2013,52:153-223),如白介素(IL)类、干扰素(IFN)类、促生长素(GH)、催乳素(PRL)、促血小板生成素(TPO)、血小板衍生因子(PDGF)以及表皮细胞生长因子(EGF)等,而且不同受体可激活不同亚型的JAK激酶,从而表现差异化的生物学功能(Immunol Rev,2008,223:132-142,Nat Immunol,2009,10:356-360)。其中,JAK-3通过与IL-2、IL-4、IL-7、IL-9、IL-15和IL-21等I型细胞因子受体复合物中的γ链(γc)相结合,调节细胞信号传导。JAK3的突变或缺失往往导致严重的后果,如重症联合免疫缺陷(SCID),对遗传性SCID患者的分析表明其中7%~14%的患者携带有JAK-3基因的纯合突变,这些突变可能导致了JAK-3表达或者功能的改变(Blood,1996,88:817-823),表现为T细胞和自然杀伤细胞(natural killercell,NK)细胞减少、B细胞功能丧失等免疫限制的症状(Chin J New Drug,2015,24:39-45)。此外,淋巴细胞分泌的数种白细胞介素具有促炎、抗炎的作用,在软骨组织的损伤修复中具有重要作用,而JAK-3在淋巴细胞中高表达,在JAK-STAT信号传递及淋巴细胞功能调节中具有关键作用,因而JAK3在类风湿性关节炎的发病及治疗中也均是重要的因素。同时,由于JAK-STAT信号通路的广泛调节作用,银屑病、强直性脊柱炎、干眼症、克罗恩病等很多疾病的发生也涉及了JAK-3的作用,由此不难看出JAK-3作为信号传递成员在疾病发生中的关键作用(Journal of Allergy andClinical TmmurmLogy 127,3,701-721.e70(2011),Cytoki ne&Growth Factor Reviews19,41-52(2008),Invest Ophthalmol VisSci.2008Jul;49(7):3058-3064,Ann Rheum Dis.2010Jul;69(7):1325-1328)。由上述可知,JAK激酶抑制剂是各种自身免疫疾病的潜在治疗药物(Front Biosci.2011Jun 1;17:3214-32)。
与本说明书所描述化合物的结构相似的化合物的例子包括下列化合物。
(1)下式代表的化合物:
(非专利文献1)。
(2)下式代表的化合物:
(非专利文献1)。
(3)下式代表的化合物:
(非专利文献2)。
文献列表
非专利文献
[非专利文献1]Tan L,Akahane K,McNally R,et al.Development of selectivecovalent Janus kinase 3inhibitors[J].Journal of medicinal chemistry,2015,58(16):6589-6606.
[非专利文献2]Ge Y,Wang C,Song S,et al.Identification of highly potentBTK and JAK3 dual inhibitors with improved activity for the treatment of B-cell lymphoma[J].European journal of medicinal chemistry,2018,143:1847-1857.
本发明概述:
本发明解决的问题
本发明的一个目标是,提供具有优良的选择性JAK-3抑制作用的预防、治疗和/或改善自身免疫疾病(例如,牛皮癣、类风湿性关节炎、炎性肠疾病、斯耶格伦氏综合征、白塞氏病、多发性硬化、系统性红斑狼疮等)的药物。
解决问题的方法
为了尝试解决上述问题,本发明人进行了深入的研究,并且发现,下式所代表的化合物(I)具有优良的JAK-3抑制作用,从而完成本发明。
相应地,本发明提供了下列内容。
[1]式(I)代表的化合物或其药学上可接受的盐:
其中,
B独立地选自氢原子、卤素、氰基、羟基;
R3、R4、和R5独立地选自氢原子、卤素、氰基、羟基、被取代的或未被取代的C1-6烃基或被取代的或未被取代的C1-6杂烃基或被取代的或未被取代的C3-8环烃基、被取代的或未被取代的C3-8杂环烃基、被取代的或未被取代的5-、6-、7-或8-元芳基、被取代的或未被取代的5-、6-、7-或8-元杂芳基;
R2是苯基、萘基、芳香5至6元杂环基、或芳香9至11元杂双环基、其中环任选被一个或多个R6取代;
每个R6独立的为卤素、CN、C(O)OR7、OR7、C(O)R7、S(O)2R7、S(O)R7、NO2、OC(O)R7、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R8取代;
R7独立的选自H、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R8取代;
R8为卤素、CN、C(O)OR9、OR4、C(O)R9、S(O)2R9、S(O)R9、NO2、OC(O)R9;
R9独立的选自H、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的卤素取代;
[2]上述[1]的化合物或其盐,其中,
R1是
(1)氢原子,
(2)卤素原子,
(3)氰基,
(4)丙烯酰基,
(5)2-氰基乙酰基,
(6)任选被1至3个选自下列的取代基取代的C1-6烷基:(a)氢原子,(b)卤素原子,(c)羟基,(d)C1-6烷氧基,(e)C3-8环烷基,(f)C1-6烷基-羰基单或二取代的氨基,
(7)任选被1至3个选自下列的取代基取代的C2-7烯基:(a)氢原子,(b)卤素原子,(c)任选取代的C1-6烷基,
(8)任选被1至3个选自下列的取代基取代的C2-7炔基:(a)氢原子,(b)卤素原子,(c)任选取代的C1-6烷基,
(9)任选被1至3个选自下列的取代基取代的C3-10环烷基:(a)卤素原子,(b)C1-6烷基;
(10)3至8元单环非芳香杂环基团;
(11)任选被1至3个选自下列的取代基取代的5或6元单环芳香杂环基团:(a)卤素原子,(b)氰基;
[3]上述[1]的化合物或其盐,其中,
R2是苯基、或芳香5至6元杂环基其中环任选被一个或多个R6取代;
每个R6独立的为卤素、CN、C(O)OR7、OR7、C(O)R7、S(O)2R7、S(O)R7、NO2、OC(O)R7、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R8取代;
R7独立的选自H、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R8取代;
R8为卤素、CN、C(O)OR9、OR9、C(O)R9、S(O)2R9、S(O)R9、NO2、OC(O)R9;
R10独立的选自H、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的卤素取代;
[4]上述[1]至[3]中任一项的化合物或其药学上可接受的盐,所述化合物选自:
N-(3-((6-苯胺-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(3-((6-苯胺-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺;
N-(3-((6-((4-吗啉基苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(3-((6-((4-吗啉基苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺;
N-(3-((6-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(3-((6-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺;
N-(3-((6-((1-(2-甲氧基-乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(3-((6-((1-(2-甲氧基-乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺;
N-(3-((6-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(3-((6-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺;
N-(4-((6-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(4-((6-((4-吗啉基苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(4-((6-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺。
[5]权利要求1-4中所述药物,其是JAK抑制剂。
[6]权利要求5中所述药物,其是预防、治疗和/或改善自身免疫疾病的药物。
[7]权利要求6中所述药物,其中自身免疫疾病是牛皮癣、类风湿性关节炎、炎性肠炎疾病、斯耶格伦氏综合征、白塞氏病、多发性硬化或系统性红斑狼疮。
[8]权利要求1的化合物或其盐用于制备药物的用途,该药物用于预防和/或改善自身免疫疾病。
[9]权利要求8的用途,其中自身免疫疾病是牛皮癣、类风湿性关节炎、炎性肠疾病、斯耶格伦氏综合征、白塞氏病、多发性硬化或系统性红斑狼疮。
本发明效果:
化合物(I)具有优良的JAK-3抑制作用,其用作预防、治疗或改善自身免疫疾病(例如,牛皮癣、类风湿性关节炎、炎性肠疾病(例如,克罗恩病、溃疡性结肠炎等等)、斯耶格伦氏综合征、白塞氏病、多发性硬化、系统性红斑狼疮等)的药物。
本发明的详细说明
在本说明书中,“卤素原子”是指氟原子、氯原子、溴原子或碘原子。
在本说明书中,“C1-6烃基(基团)”是指,C1-6烷基,C2-7烯基,C1-6烷氧基,C2-6烯氧基,C1-6烷基-羰基单或二取代的氨基芳基,等等。
在本说明书中,“C1-6烷基(基团)”是指,例如、甲基、乙基、异丙基、丁基、仲丁基、戊基、异戊基、1-乙基丙基、1-甲基丁基、异己基、1,1-二甲基丁基、3,3-二甲基丁基、2-乙基丁基、1-乙基-2-甲基丙基、1,2-二甲丙基,等等。
在本说明书中,“C2-7烯基(基团)”是指,例如,乙烯基、1-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、3-甲基-2-丁烯基、1-戊烯基、4-甲基-3-戊烯基、3-己烯基、5-己烯基,等等。
在本说明书中,“C2-7炔基(基团)”是指,例如,乙炔基、1-丙炔基、2-丙炔基、3-丁炔基、1-戊炔基、1,1-二甲基丙-2-炔-1-基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基,等等。
在本说明书中,“C1-6烷氧基(基团)”是指,例如,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、异戊氧基、新戊氧基、己氧基,等等。
在本说明书中,“C2-6烯氧基(基团)”是指,例如,乙烯氧基、1-丙烯氧基、2-丙烯氧基、2-甲基-1-丙烯氧基、1-丁烯氧基、2-丁烯氧基、4-甲基-3-戊烯氧基、1-己烯氧基、3-己烯氧基、5-己烯氧基,等等。
在本说明书中,“C1-6烷基-羰基单或二取代的氨基芳基(基团)”是指,例如,N,N-二甲基甲酰基,N,N-二甲基乙酰基,等等。
在本说明书中,“C6-14芳基(基团)”是指,例如,苯基、1-萘基、2-萘基,等等。
在本说明书中中,“单环芳香杂环基团”的例子包括5至7元(优选5或6元)单环芳香杂环基团,作为环构成原子,除了碳原子以外,其还含有1至4个选自氧原子、硫原子(任选氧化)和氮原子(任选氧化)的杂原子,例如,呋喃基(例如,2-呋喃基、3-呋喃基)、噻吩基(例如,2-噻吩基、3-噻吩基)、吡啶基(例如,2-吡啶基、3-吡啶基、4-吡啶基)、嘧啶基(例如,2-嘧啶基、4-嘧啶基、5-嘧啶基)、哒嗪基(例如,3-哒嗪基、4-哒嗪基)、吡嗪基(例如,2-吡嗪基)、吡咯基(例如,1-吡咯基、2-吡咯基、3-吡咯基)、咪唑基(例如,1-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)、吡唑基(例如,1-吡唑基、3-吡唑基、4-吡唑基)、噻唑基(例如,2-噻唑基、4-噻唑基、5-噻唑基),等等
在本说明书中,“非芳香杂环基团”是指单环非芳香杂环基团和稠合的非芳香杂环基团。
在本说明书中中,“单环非芳香杂环基团”的例子包括3至8元(优选5或6元)单环非芳香杂环基团,作为环构成原子,除了碳原子以外,其还含有1至4个选自氧原子、硫原子(任选氧化)和氮原子(任选氧化)的杂原子,例如,氮杂环丁烷基(例如,1-氮杂环丁烷基、2-氮杂环丁烷基)、吡咯烷基(例如,1-吡咯烷基、2-吡咯烷基)、哌啶基(例如,哌啶子基、2-哌啶基、3-哌啶基、4-哌啶基),等等。
在本说明书中,“稠合的非芳香杂环基团”的例子包括8至22元稠合的非芳香杂环基团,具体地说,衍生自稠环的基团,其中,相当于上述3至8元单环非芳香杂环基团的环与C6-14芳香烃稠合;衍生自稠环的基团,其中,相当于上述3至8元单环非芳香杂环基团的环是稠合的环;衍生自稠环的基团,其中相当于上述3至8元单环非芳香杂环基团的环与相当于上述5至7元单环芳香杂环基团的环稠合;以及上述基团是部分饱和的基团,例如,二氢吲哚基(例如,2,3-二氢-1H-吲哚-1-基)、二氢异吲哚基(例如,1,3-二氢-2H-异吲哚-2-基)、二氢苯并呋喃基(例如,2,3-二氢-1-苯并呋喃-5-基),等等。
当化合物(I)是盐形式时,其实例包括:金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或酸性氨基酸形成的盐,等等。金属盐的优选例子包括:碱金属盐,例如钠盐、钾盐等等;碱土金属盐,例如钙盐、镁盐、钡盐等等;招盐,等等。与有机碱形成的盐的优选例子包括与下列有机碱形成的盐:三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己基胺、N,N’-二苄基乙二胺,等等。与无机酸形成的盐的优选例子包括:与盐酸、氢溴酸、硝酸、硫酸、磷酸等等形成的盐。与有机酸形成的优选例子包括与下列有机酸形成的盐:甲酸、乙酸、三氟乙酸、苯二酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、苹果酸、甲磺酸、苯磺酸、对甲苯磺酸等等。与碱性氨基酸形成的盐的优选例子包括与精氨酸、赖氨酸、鸟氨酸等等形成的盐。与酸性氨基酸形成的盐的优选例子包括与天冬氨酸、谷氨酸等等形成的盐。
它们当中,优选药用盐。例如,当化合物具有酸性官能团时,其实例包括无机盐,例如,碱金属盐(例如,钠盐、钾盐等等)、碱土金属盐(例如,钙盐、镁盐等等)等等、铵盐等等,当化合物具有碱性官能团时,其实例包括与无机酸形成的盐,例如盐酸、氢溴酸、硝酸、硫酸、磷酸,等等,以及与有机酸形成的盐,例如乙酸、苯二酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲苯磺酸,等等。
制备方法:
下面说明本发明的化合物(I)或其盐的制备方法。
化合物(I)和原料化合物可以按照本身已知的方法制备,例如,下列反应路线中所示的方法,等等。在下列制备方法的每个步骤中,“室温”通常是指5-40℃,除非另作说明,反应路线中所描述的化学式中的每个符号如上所述。在化学式的化合物中,每个化合物包括盐,这种盐的例子包括与化合物(I)的盐相似的盐,等等。
在每个反应中,当原料化合物或中间体具有氨基、羧基或羟基作为取代基时,通常,可以用肽化学等等使用的保护基来保护这些基团。反应之后,根据需要除去保护基,可以获得目标化合物。保护基的引入和除去方法可以按照本身已知的方法来进行,例如,描述在“Protective Groups in Organic Synthesis,4th Ed”,Wiley-Interscience,Inc.(2006)(Theodora W.Greene,Peter G.M.Wuts)中的方法。
氨基保护基的例子包括:甲酰基、C1-6烷基-羰基、C1-6烷氧基-羰基、苯甲酰基、C7-10芳烷基-羰基(例如,苄基羰基等)、C7-12芳烷氧基-羰基(例如,苄氧羰基、9-芴基甲氧羰基等)、三苯甲基、邻苯二甲酰基、N,N-二甲基氨基亚甲基、任选被C1-6烷基取代的甲硅烷基(例如,三甲硅烷基、三乙甲硅烷基、二甲基苯基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二乙基甲硅烷基,等)、C2-6烯基(例如,1-烯丙基,等),等等。这些基团任选被1至3个选自卤素原子、C1-6烷氧基和硝基的取代基取代。
羧基保护基的例子包括:C1-6烷基、C7-12芳烷基(例如,苄基等)、苯基、三苯甲基、任选被C1-6烷基取代的甲硅烷基(例如,三甲硅烷基、三乙基甲硅烷基、二甲基苯基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二乙基甲硅烷基等)、C2-6烯基(例如,1-烯丙基,等),等等。
羟基保护基的例子包括:C1-6烷基、苯基、三苯甲基基团、C7-12芳烷基(例如,苄基等)、甲酰基、C1-6烷基-羰基、苯甲酰基、C7-12芳烷氧基-羰基(例如,苄基羰基等)、2-四氢吡喃基、2-四氢呋喃基、任选被C1-6烷基取代的甲硅烷基(例如,三甲硅烷基、三乙基甲硅烷基、二甲基苯基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二乙基甲硅烷基等)、C2-6烯基(例如,1-烯丙基等),等等。
这些基团任选被1至3个选自卤素原子、C1-6烷基、C1-6烷氧基和硝基的取代基取代。
可以按照本身已知的方法除去这些保护基,例如,描述在“Protective GroupsinOrganic Synthesis,4th Ed”,Wiley-Interscience,Inc.(2006)(Theodora W.Greene,Peter G.M.Wuts)等等中的方法。具体地说,可以采用使用酸、碱、紫外线、肼、苯肼、N-甲基二硫代甲氨酸钠、四丁基氟化铵、乙酸钯、三烷基甲硅烷基卤(例如,三甲硅烷基碘、三甲硅烷基溴)等等的方法。
在必要时,还可以使用微波辐射装置等,在微波辐射下进行合成步骤中的反应。
每个步骤所获得的化合物可以以反应混合物或粗品形式直接用于下一步,或可以按照常规方法从反应混合物中分离,并且可以容易地按照分离方法纯化,例如重结晶、蒸馏、色谱等等。
例如,可以按照下列方法A或与其类似的方法,制备化合物(I)。每个方法中的原料化合物可以是商购的产品或还可以按照本身已知的方法或与其类似的方法制备。
在化合物(I)中,式(I-A)所代表的化合物
其中,化学式中的每个符号如上所述,
(在下文中,简写为化合物(I-A))可以按照下列方法A或与其类似的方法制备。在制备方法的每个步骤中,原料化合物可以是盐形式。盐的例子包括与化合物(I)的盐相似的那些盐。
方法A
其中,符号如上所述。
在该方法中,用作起始原料的化合物(II)可以是商购的产品,或还可以按照本身已知的方法或与其类似的方法制备。
步骤A-1
该步骤是化合物(II)与多聚甲醛进行反应、使化合物(II)转化为化合物(III)的步骤。
每1mol化合物(II),多聚甲醛和碱的使用数量为大约1mol-大约100mol,优选大约1mol-大约10mol。
所使用的碱的例子包括:有机胺(例如,三甲胺、三乙胺等等)、碱金属盐(例如,碳酸氢钠等等)、金属氢化物(氢化钾等等)、碱金属醇化物(甲醇钠等等)、碱金属二硅胺化物(例如,二硅胺化锂等等),等等。它们当中,优选碱金属盐(碳酸钠、碳酸钾、碳酸铯等等)。
在该步骤中,对溶剂没有特别限制,可用溶剂也可不用溶剂,只要反应能够进行即可。其实例包括:烃(例如,苯、甲苯、二甲苯、己烷、庚烷等等)、卤代烃(例如,氯仿、二氯甲烷等等)、醚(例如,二乙醚、二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、1,2-二甲氧基乙烷等等)、腈(例如,乙腈等等)、非质子极性溶剂(例如:N,N-二甲基甲酰胺、二甲亚砜、六甲基磷酰胺等等)、质子极性溶剂(例如,水、甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、2-甲基-2-丙醇等等)和其混合物。
在该步骤中,反应温度通常为大约-50℃-大约200℃,优选大约-10℃-大约100℃。在该步骤中,反应时间通常为大约0.1小时-大约100小时。
可以利用已知的分离和纯化方法,例如,浓缩、减压浓缩、溶剂提取、结晶、重结晶、相转移、色谱等等,将由此所获得的化合物(III)分离和纯化。此外,化合物(III)不用纯化就可以直接用于下一个反应。
步骤A-2
该步骤是化合物(III)进行氧化反应、使化合物(III)转化为化合物(IV)的步骤。
每1mol化合物(HI),氧化剂和催化剂使用数量为大约1mol-大约100mol,优选大约1mol-大约30mol。
在该步骤中,对氧化剂没有特别限制,只要反应能够进行即可。其实例包括:过硫酸钾、高锰酸钾,等等。
在该步骤中,对催化剂没有特别限制,可用催化剂也可不用催化剂,只要反应能够进行即可。其实例包括:硝酸银,等等。
在该步骤中,对溶剂没有特别限制,可用溶剂也可不用溶剂,只要反应能够进行即可。其实例包括:烃(例如,苯、甲苯、二甲苯、己烷、庚烷等等)、卤代烃(例如,氯仿、二氯甲烷等等)、醚(例如,二乙醚、二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、1,2-二甲氧基乙烷等等)、腈(例如,乙腈等等)、非质子极性溶剂(例如:N,N-二甲基甲酰胺、二甲亚砜、六甲基磷酰胺等等)、质子极性溶剂(例如,水、甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、2-甲基-2-丙醇等等)和其混合物。
在该步骤中,反应温度通常为大约-50℃-大约200℃,优选大约20℃-大约100℃。在该步骤中,反应时间通常为大约0.1小时-大约100小时。
可以利用已知的分离和纯化方法,例如,浓缩、减压浓缩、溶剂提取、结晶、重结晶、相转移、色谱等等,将由此所获得的化合物(IV)分离和纯化。此外,化合物(IV)不用纯化就可以直接用于下一个反应。
步骤A-3
该步骤是化合物(IV)与卤代试剂进行卤代反应、使化合物(IV)转化为化合物(V)的步骤。
每1mol化合物(IV),卤代试剂的使用数量为大约1mol-大约100mol,优选大约1mol-大约10mol。
所使用的卤代试剂的例子包括:氟、氯、溴、碘、NBS、NIS等等,它们当中优选溴、碘。
在该步骤中,对溶剂没有特别限制,只要反应能够进行即可。其实例包括:烃(例如,苯、甲苯、二甲苯、己烷、庚烷等等)、卤代烃(例如,氯仿、二氯甲烷等等)、醚(例如,二乙醚、二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、1,2-二甲氧基乙烷等等)、腈(例如,乙腈等等)、非质子极性溶剂(例如:N,N-二甲基甲酰胺、二甲亚砜、六甲基磷酰胺等等)、质子极性溶剂(例如,水、甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、2-甲基-2-丙醇等等)和其混合物。
在该步骤中,反应温度通常为大约-50℃-大约200℃,优选大约0℃-大约200℃。在该步骤中,反应时间通常为大约0.1小时-大约100小时。
在该步骤中,反应气体保护没有特别限制,可进行气体保护也可不保护,只要反应能够进行即可。保护气体包括:氮气、氩气等。
可以利用已知的分离和纯化方法,例如,浓缩、减压浓缩、溶剂提取、结晶、重结晶、相转移、色谱、酸溶碱沉等等,将由此所获得的化合物(V)分离和纯化。此外,化合物(V)不用分离就可以直接用于下一个反应。
步骤A-4
该步骤是化合物(V)与取代苄肼试剂进行取代反应、使化合物(V)转化为化合物(VI)的步骤。
每1mol化合物(VI),取代取代苄肼试剂的使用数量为大约1mol-大约100mol,优选大约1mol-大约10mol。
所使用的碱的例子包括:有机胺(例如,三甲胺、三乙胺等等)、碱金属盐(例如,碳酸氢钠等等)、金属氢化物(氢化钾等等)、碱金属醇化物(甲醇钠等等)、碱金属二硅胺化物(例如,二硅胺化锂等等),等等。它们当中,优选碱金属盐(碳酸钠、碳酸钾、碳酸铯等等)。
在该步骤中,对溶剂没有特别限制,只要反应能够进行即可。其实例包括:烃(例如,苯、甲苯、二甲苯、己烷、庚烷等等)、卤代烃(例如,氯仿、二氯甲烷等等)、醚(例如,二乙醚、二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、1,2-二甲氧基乙烷等等)、腈(例如,乙腈等等)、非质子极性溶剂(例如:N,N-二甲基甲酰胺、二甲亚砜、六甲基磷酰胺等等)、质子极性溶剂(例如,水、甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、2-甲基-2-丙醇等等)和其混合物。
在该步骤中,反应温度通常为大约-50℃-大约250℃。在该步骤中,反应时间通常为大约0.1小时-大约100小时。
在该步骤中,反应气体保护没有特别限制,可进行气体保护也可不保护,只要反应能够进行即可。保护气体包括:氮气、氩气等。
可以利用已知的分离和纯化方法,例如,浓缩、减压浓缩、溶剂提取、结晶、重结晶、相转移、色谱、酸溶碱沉等等,将由此所获得的化合物(VI)分离和纯化。此外,化合物(VI)不用分离就可以直接用于下一个反应。
步骤A-5
该步骤是化合物(VI)与取代试剂进行取代反应,使化合物(VI)转化和化合物(VII)的步骤。
每1mol化合物(VI),取代试剂的使用数量为大约1mol-大约100mol,优选大约1mol-大约10mol。
在该步骤中,对溶剂没有特别限制,只要反应能够进行即可。其实例包括:烃(例如,苯、甲苯、二甲苯、己烷、庚烷等等)、卤代烃(例如,氯仿、二氯甲烷等等)、醚(例如,二乙醚、二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、1,2-二甲氧基乙烷等等)、腈(例如,乙腈等等)、非质子极性溶剂(例如:N,N-二甲基甲酰胺、二甲亚砜、六甲基磷酰胺等等)、质子极性溶剂(例如,水、甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、2-甲基-2-丙醇等等)和其混合物。
在该步骤中,反应温度通常为大约-50℃-大约250℃。在该步骤中,反应时间通常为大约0.1小时-大约100小时。
在该步骤中,反应气体保护没有特别限制,可进行气体保护也可不保护,只要反应能够进行即可。保护气体包括:氮气、氩气等。
可以利用已知的分离和纯化方法,例如,浓缩、减压浓缩、溶剂提取、结晶、重结晶、相转移、色谱、酸溶碱沉等等,将由此所获得的化合物(VII)分离和纯化。此外,化合物(VII)不用分离就可以直接用于下一个反应。
步骤A-6
该步骤是化合物(VII)进行还原反应,使化合物(VII)转化和化合物(VIII)的步骤。
每1mol化合物(VII),还原试剂或催化剂的使用数量为大约1mol-大约100mol,优选大约1mol-大约10mol。
在该步骤中,对溶剂没有特别限制,只要反应能够进行即可。其实例包括:烃(例如,苯、甲苯、二甲苯、己烷、庚烷等等)、卤代烃(例如,氯仿、二氯甲烷等等)、醚(例如,二乙醚、二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、1,2-二甲氧基乙烷等等)、腈(例如,乙腈等等)、非质子极性溶剂(例如:N,N-二甲基甲酰胺、二甲亚砜、六甲基磷酰胺等等)、质子极性溶剂(例如,水、甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、2-甲基-2-丙醇等等)和其混合物。
所使用的催化剂的例子包括:钯碳、铁粉、锌粉、镍、铂、硼烷催化剂、镧系金属氯化物,等等。
在该步骤中,反应温度通常为大约-50℃-大约250℃。在该步骤中,反应时间通常为大约0.1小时-大约100小时。
在该步骤中,反应气体保护没有特别限制,可进行气体保护也可不保护,只要反应能够进行即可。保护气体包括:氮气、氩气等。
可以利用已知的分离和纯化方法,例如,浓缩、减压浓缩、溶剂提取、结晶、重结晶、相转移、色谱、酸溶碱沉等等,将由此所获得的化合物(VIII)分离和纯化。此外,化合物(VIII)不用分离就可以直接用于下一个反应。
步骤A-7
该步骤是化合物(VIII)与酰氯进行反应、使化合物(VIII)转化为化合物(I-A)的步骤。
每1mol化合物(III),酰氯的使用数量为大约1mol-大约100mol,优选大约1mol-大约30mol。
所使用的酰胺的例子包括:丙烯酰胺、丁烯酰胺等等,它们当中优选丙烯酰胺和丁烯酰胺。
在该步骤中,对碱没有特别限制,可用碱也可不用碱,只要反应能够进行即可。所使用的碱的例子包括:有机胺(例如,三甲胺、三乙胺等等)、碱金属盐(例如,碳酸氢钠等等)、金属氢化物(氢化钾等等)、碱金属醇化物(甲醇钠等等)、碱金属二硅胺化物(例如,二硅胺化锂等等),等等。它们当中,优选碱金属盐(碳酸钠、碳酸钾、碳酸铯等等)。
在该步骤中,对溶剂没有特别限制,可用溶剂也可不用溶剂,只要反应能够进行即可。其实例包括:烃(例如,苯、甲苯、二甲苯、己烷、庚烷等等)、卤代烃(例如,氯仿、二氯甲烷等等)、醚(例如,二乙醚、二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、1,2-二甲氧基乙烷等等)、腈(例如,乙腈等等)、非质子极性溶剂(例如:N,N-二甲基甲酰胺、二甲亚砜、六甲基磷酰胺等等)、质子极性溶剂(例如,水、甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、2-甲基-2-丙醇等等)和其混合物。
在该步骤中,反应温度通常为大约-50℃-大约250℃,优选大约-10℃-大约250℃。在该步骤中,反应时间通常为大约0.1小时-大约100小时。
在该步骤中,反应气体保护没有特别限制,可进行气体保护也可不保护,只要反应能够进行即可。保护气体包括:氮气、氩气等。
可以利用已知的分离和纯化方法,例如,浓缩、减压浓缩、溶剂提取、结晶、重结晶、相转移、色谱等等,将由此所获得的化合物(I-A)分离和纯化。
当化合物(I)具有旋光异构体、立体异构体、区域异构体或旋转异构体时,这些异构体也包括在化合物(I)范围内,并且可以按照本身已知的合成法和分离方法(例如,浓缩、溶剂提取、柱色谱、重结晶等等),获得单一产物形式。例如,当化合物(I)具有旋光异构体时,由该化合物拆分的旋光异构体也具有在化合物(I)范围内。
可以按照本身已知的方法来制备旋光异构体。具体地说,使用光学活性的合成中间体,或按照已知的方法对消旋的最终产物进行光学拆分,获得旋光异构体。
光学拆分方法可以是本身已知的方法,例如,分级重结晶方法、手性柱方法、非对映体方法,等等。
1)分级重结晶方法
在这种方法中,与旋光性化合物(例如,(+)-扁桃酸、(-)-扁桃酸、(+)-酒石酸、(-)-酒石酸、(+)-1-苯乙胺、(-)-1-苯乙胺、辛可宁、(-)-辛可尼定、番木鳖碱,等等)形成消旋体的盐,利用分级重结晶方法将其分离,如果需要的话,通过中和步骤获得游离的旋光异构体。
2)手性柱方法
在这种方法中,将消旋体或其盐施加于分离旋光异构体的柱(手性柱)上,进行分离。例如,在液相色谱的情况下,将旋光异构体的混合物施加到手性柱上,例如,CHIRA1系列(Daicel Chemical Industries,1td.制造)等等,并用单独的水、各种缓冲剂(例如,磷酸盐缓冲剂,等等)和有机溶剂(例如,乙醇、甲醇、异丙醇、乙腈、三氟乙酸、三乙胺等等)或其混合物作为洗脱液进行展开,使旋光异构体分离。例如,在气相色谱的情况下,使用手性柱进行分离。
3)非对应异构体方法
在这种方法中,利用消旋混合物与光学活性试剂的化学反应,将消旋混合物制备为非对映体的混合物,通过典型的分离方法(例如,分级重结晶方法、色谱方法,等等),将其转变为单一物质,并进行化学处理,例如水解等等,分离光学活性试剂部分,由此获得旋光异构体。例如,当化合物(I)在分子中含有羟基或伯或仲氨基时,使化合物和光学活性的有机酸(例如,MTPA[α-甲氧基-α-(三氟甲基)苯乙酸]、(-)-薄荷基氧基(menthoxy)乙酸,等等)进行缩合反应,分别得到酯化合物或酰胺化合物的非对映体。当化合物(I)带有羧基时,使该化合物和光学活性的胺或光学活性的醇试剂进行缩合反应,分别得到酰胺化合物或酯化合物的非对映体。通过酸水解或碱水解,分离的非对映体转变为原始化合物的旋光异构体。
化合物(I)可以是晶体。
化合物(I)的晶体可以按照本身已知的结晶方法来制备。
结晶方法的例子包括:溶液结晶方法、蒸汽结晶方法、熔融结晶方法,等等。
“溶液结晶方法”通常是非饱和状态转变为过饱和状态的方法,这种方法改变与化合物的溶解度有关的因素(溶剂组合物、pH值、温度、离子强度、氧化还原态,等等)或改变溶剂的数量。其具体实例包括:浓缩法、缓慢冷却法、反应法(扩散法、电解法)、水热生长法、熔盐法,等等。所使用的溶剂的例子包括:芳香烃(例如,甲苯、二甲苯,等等)、卤代烃(例如,二氯甲烷、氯仿,等等)、饱和烃(例如,己烷、环己烷,等等)、醚(例如,二乙醚、二异丙醚、四氢呋喃,等等)、腈(例如,乙腈,等等)、酮(例如,丙酮,等等)、亚砜(例如,二甲亚砜,等等)、酰胺(例如,N,N-二甲基甲酰胺,等等)、酯(例如,乙酸甲酯、乙酸乙酯,等等)、醇(例如,甲醇、乙醇、异丙醇,等等)、水,等等。这些溶剂可单独使用,或合适比例(例如,1∶1至1∶100(体积比))的两种或多种溶剂组合使用。在必要时,可以使用晶种。
“蒸汽结晶方法”是,例如,汽化方法(密封管方法、气流方法)、气相反应方法、化学迁移方法等等。
“熔融结晶方法”是,例如,正常冷凝方法(单晶控制法、温度梯度法、布里兹曼法)、区域熔融法(区域平衡法、悬浮区域法)、特定生长法(V1S方法、液相外延方法),等等。
结晶方法的优选例子包括下列方法:在-20℃至120℃,将化合物(I)溶解在合适的溶剂(例如,醇,例如乙醇、异丙醇,等等)中,并将获得的溶液冷却至低于溶解温度的温度(例如,-10-50℃,优选-10-20℃),等等。
可以将由此获得的本发明的晶体分离,例如,过滤,等等。
所获得的晶体的分析方法通常是利用粉末X射线衍射的晶体分析方法。作为测定晶体取向的方法,还可以使用机械法或光学法,等等。
上述制备方法所获得的化合物(I)的晶体(下文简写为“本发明的晶体”)具有高纯度、高质量和高稳定性,甚至在一般条件下长期保存之后,也不会变性。此外,它在生物学特性(例如,药物动力学(吸收、分布、代谢、排出)、效果表达等等)方面也具有优越性,尤其用作药物。
在本说明书中,比旋光度([α]D)是指使用旋光计测定的比旋光度。
在本说明书中,熔点是指,例如,使用显微熔点测定装置、DSC(差示扫描量热法)装置等所测定的熔点。
可以使用前体药物形式的化合物(I)。化合物(I)的前体药物是指,在生物体内的生理条件下,由于酶、胃酸等等所造成的反应而能够转变为化合物(I)的化合物,也就是说,通过酶致氧化、还原、水解反应等等而转变为化合物(I)的化合物;通过水解反应等等(由于胃酸)而转变为化合物(I)的化合物,等等。
化合物(I)的前体药物的例子包括:
(1)使化合物(I)的氨基进行酰化、烷基化或磷酸化所获得的化合物(例如,使化合物(I)的氨基进行二十酰基化、丙氨酰化、戊胺基羰基化、(5-甲基2-氧代-1,3-二氧杂环戊烯-4-基)甲氧羰基化、四氢呋喃基化、吡咯烷基甲基化、新戊酰氧基甲基化、叔丁化、乙氧羰基化、叔丁氧羰基化、乙酰化或环丙基羰基化等等所获得的化合物);
(2)使化合物(I)的羟基进行酰化、烷基化、磷酸化或硼化所获得的化合物(例如,使化合物(I)的羟基乙酰化、棕榈酰化、丙酰化、新戊酰化、琥珀酰化、延胡索酰化、丙氨酰化或二甲基氨基甲基羰基化等等所获得的化合物);
(3)使化合物(I)的羧基进行酯化或酰胺化所获得的化合物(例如,使化合物(I)的羧基进行乙基酯化、苯基酯化、羧甲基酯化、二甲基氨基甲基酯化、新戊酰氧基甲基酯化、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基酯化、环己基氧基羰基乙基酯化或甲酰胺化等等所获得的化合物),等等。这些化合物可以按照本身已知的方法、由化合物(I)来制备。
化合物(I)的前体药物也可以是在生理条件下能够转变为化合物(I)的化合物,如下列文献所述:“IYAKUHIN no KAIHATSU(Development of Pharmaceuticals)”,Vol.7,Design of Molecules,p 163-198,Published by HIROKAWA SHOTEN(1990)。
在本说明书中,化合物(I)和化合物(I)的前体药物有时共同简写为“本发明的化合物”。
化合物(I)可以是水合物、非水合物、溶剂化物或非溶剂化物。
化合物(I)也包括同位素(例如,3H、14C、35S、125I等等)等等标记的化合物。
化合物(I)还包括氘转化形式,其中中转变为2H(D)。
化合物(I)也包括其互变异构体。
化合物(I)可以是药用共晶体或其盐。共晶体或其盐是指晶体物质,其在室温下由两种或多种具体固体构成,每种固体具有不同的物理性能(例如,结构、熔点、熔化热、吸湿性、溶解度和稳定性,等等)。共晶体或其盐可以按照本身已知的共结晶方法来制备。
化合物(I)也可以用作PET示踪剂。
由于本发明的化合物具有优良的JAK抑制活性,所以,基于这种作用,它们也用作安全药物。
例如,含有本发明化合物的本发明的药物可以用于哺乳动物(例如,小鼠、大鼠、仓鼠、兔子、猫、狗、牛、羊、猴子、人等等),作为JAK相关的疾病的预防或治疗剂,更具体地说,下面(1)-(4)(尤其是(2))所描述的疾病。
(1)炎性疾病(例如,急性胰炎、慢性胰腺炎、哮喘、成人呼吸窘迫综合征、慢性阻塞性肺病(COPD)、炎性骨疾病、炎性肺病、炎性肠疾病、乳糜泻、肝炎、系统炎性响应综合症(SIRS)、手术后或外伤后的炎症、肺炎、肾炎、脑膜炎、膀胱炎、咽喉炎、胃粘膜损伤、脑膜炎、脊椎炎、关节炎、皮炎、慢性肺炎、支气管炎、肺梗塞形成、矽肺、肺结节病等等),
(2)自身免疫疾病(例如,牛皮癣、类风湿性关节炎、炎性肠疾病(例如,克罗恩病、溃疡性结肠炎等等)、斯耶格伦氏综合征、白塞氏病、多发性硬化、系统性红斑狼疮、关节强硬性椎关节炎、多肌炎、皮肤肌炎(DM)、结节性动脉周围炎(PN)、混合结缔组织病(MCTD)、硬皮病、深红斑狼疮、慢性甲状腺炎、Graves’疾病、自身免疫性胃炎、I型和II型糖尿病、自身免疫性溶血性贫血、自身免疫性中性白细胞减少、血小板减少、特异性皮炎、慢性活动型肝炎、重症肌无力、移植物抗宿主疾病、艾迪生病、异常免疫应答、关节炎、皮炎、放射性皮炎等等)(尤其是牛皮癣、类风湿性关节炎、炎性肠疾病、斯耶格伦氏综合征、白塞氏病、多发性硬化和系统性红斑狼疮),
(3)骨关节变性疾病(例如,类风湿性关节炎、骨质疏松症、骨关节炎等等)
(3)肿瘤疾病[例如,恶性肿瘤、血管生成性青光眼、幼儿血管瘤、多发性骨髓瘤、急性髓母细胞性白血病、慢性肉瘤、多发性骨髓瘤、慢性粒性白血病、转移病变性黑素瘤、卡波氏肉瘤、血管增殖、恶病体质、乳腺癌的转移病变、肺癌(例如,非小细胞肺癌、小细胞肺癌、恶性间皮瘤等等)、间皮瘤、胰腺癌(例如,胰管癌等等)、胃癌(例如,粘液腺癌、腺鳞癌等等)、乳头状腺癌、乳腺癌(例如,侵入性导管癌、导管原位癌、炎性乳腺癌等等)、卵巢癌(例如,卵巢上皮癌、性腺外生殖细胞肿瘤、卵巢生殖细胞肿瘤、卵巢低恶性潜在肿瘤等等)、前列腺癌(例如,激素依赖性前列腺癌、非激素依赖性前列腺癌等等)、肝癌(例如,原发性肝癌、肝外胆管癌等等)、甲状腺癌(例如,甲状腺髓样癌等等)、肾脏癌(例如,肾脏细胞癌、肾脏和尿管的转移细胞癌,等等)、子宫癌、脑肿瘤(例如,松果体的星形细胞瘤、纤维性星形细胞瘤、弥漫性星形细胞瘤、间变性星形细胞瘤,等等)、黑素瘤、肉瘤、膀胱癌、血癌等等,包括多发性骨髓瘤、垂体腺瘤、胶质瘤、听神经瘤、成视网膜细胞瘤、咽癌、喉癌、舌癌、胸腺瘤、食道癌、十二指肠癌、结肠直肠癌、直肠癌、肝癌、胰腺内分泌肿瘤、胆管癌、胆囊癌、阴茎癌、尿管癌、睾丸肿瘤、外阴癌、宫颈癌、子宫内膜癌、子宫肉瘤、绒膜疾病、阴道癌、皮肤癌、真菌霉菌病、基底细胞瘤、软组织肉瘤、恶性淋巴瘤、霍奇金疾病、脊髓发育不良综合症、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、成年T细胞白血病、慢性骨髓增殖疾病、卡波济氏肉瘤、巨大淋巴结增生症、淋巴瘤、白血病多发性骨髓瘤、真性红细胞增多症、原发性血小板增多症、原发性骨髓纤维化症、慢性粒性白血病、慢性单核细胞性白血病、嗜酸性白细胞增多综合征、特发性骨髓纤维化、系统性肥大细胞病、胰腺内分泌肿瘤、纤维组织细胞瘤、平滑肌肉瘤、横纹肌肉瘤、未知的原发性癌]。
优选,本发明的药物可以用作预防、治疗和/或改善自身免疫疾病(例如,牛皮癣、类风湿性关节炎、炎性肠疾病、斯耶格伦氏综合征、白塞氏病、多发性硬化、系统性红斑狼疮等等)、炎性疾病、骨关节变性疾病或肿瘤病的药物,特别优选牛皮癣、类风湿性关节炎、炎性肠疾病(优选克罗恩病或溃疡性结肠炎)、斯耶格伦氏综合征、白塞氏病、多发性硬化、系统性红斑狼疮、淋巴瘤、白血病多发性骨髓瘤、真性红细胞增多症、原发性血小板增多症、原发性骨髓纤维化症、慢性粒性白血病、慢性单核细胞性白血病、嗜酸性白细胞增多综合征、特发性骨髓纤维化、系统性肥大细胞病。
本文中,上述“预防”疾病是指,例如,给予患者含有本发明化合物的药物,这种患者由于一些与疾病有关的因素而处于发病的高风险状态,但还没有形成疾病,或已经形成疾病但没有自觉症状的患者,或给予治疗疾病之后害怕疾病复发的患者含有本发明化合物的药物。
本发明的药物显示了优良的药物动力学(例如,药物在血浆中的半衰期)、低毒(例如,HERG抑制、CYP抑制、CYP诱导)、低的药物相互作用特性。本发明的化合物可以直接用作药物,或利用本身已知的方法和通常使用的药物制剂的制备方法,将本发明的化合物与药用载体混合,制备药物组合物,作为本发明的药物。可以口服或胃肠外安全地给予哺乳动物(例如,人、猴子、牛、马、猪、小鼠、大鼠、仓鼠、兔子、猫、狗、羊和山羊)本发明的药物。
可以安全地单独给予含有本发明化合物的药物,或按照本身已知的方法作为药物制剂的制备方法,与药理学可接受的载体混合,并且利用下列形式给药:例如,片剂(包括糖衣片剂、膜包衣片剂、舌下片剂、口腔崩解片、口腔片剂等等)、丸剂、粉剂、颗粒剂、胶囊剂(包括软胶囊、微囊)、锭剂、糖浆剂、液剂、乳剂、混悬剂、控制释放制剂(例如,瞬时释放制剂、缓释制剂、缓释微囊)、气雾剂、膜剂(例如,口服崩解膜剂、口腔粘膜-粘附膜剂)、注射剂(例如,皮下注射、静脉注射、肌内注射、腹膜内注射)、静脉输液、透皮吸收式制剂、乳膏剂、软膏剂、洗剂、粘附剂、栓剂(例如,直肠栓剂、阴道栓剂)、小药丸、鼻部制剂、肺制剂(吸入剂)、眼睛滴剂等等,口服或胃肠外(例如,静脉内、肌内、皮下、器官内、鼻内、滴剂、脑内、直肠内、阴道内、腹膜内和瘤体内给药,给予至肿瘤附近,以及直接给予至病变处)。
本发明化合物在本发明药物中的含量大约为全部药物的0.01至100%重量。剂量根据给药的患者、给药途径、疾病等等而改变。例如,对于口服给予患有牛皮癣、类风湿性关节炎、炎性肠疾病、斯耶格伦氏综合征、白塞氏病、多发性硬化或系统性红斑狼疮的患者(体重大约60kg),每天可以给予一至几份大约0.01mg/kg体重-大约500mg/kg体重的活性成份(化合物(I)),优选大约0.1mg/kg体重-大约50mg/kg体重,更优选大约1mg/kg体重-大约30mg/kg体重。
可以用于制备本发明药物的药用载体,可以列举出传统上用作制剂物质的各种有机或无机载体物质,对于固体制剂而言,例如,赋形剂、润滑剂、粘合剂和崩解剂;或对于液体药物而言,溶剂、增溶剂、悬浮剂、等渗剂、缓冲剂、抚慰剂等等。此外,必要时,视情况而定,也可以使用合适数量的普通添加剂,例如防腐剂、抗氧化剂、着色剂、甜味剂、吸附剂、湿润剂等等。
赋形剂的例子包括乳糖、白糖、D-甘露醇、淀粉、玉米淀粉、结晶纤维素、轻质无水硅酸等等。
润滑剂的例子包括:硬脂酸镁、硬脂酸钙、滑石粉、胶态二氧化硅,等等。
粘合剂的例子包括结晶纤维素、白糖、D-甘露醇、糊精、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、淀粉、蔗糖、凝胶、甲基纤维素、羧甲基纤维素钠等等。
崩解剂的例子包括淀粉、羧甲纤维素、羧甲纤维素钙、羧甲淀粉钠、1-羟丙基纤维素等等。
溶剂的例子包括注射用水、醇、丙二醇、聚乙二醇、芝麻油、玉米油、橄榄油等等。
增溶剂的例子包括聚乙二醇、丙二醇、D-甘露醇、苯甲酸苄酯、乙醇、三氨基甲烷、胆固醇、三乙醇胺、碳酸钠、柠檬酸钠等等。
悬浮剂的例子包括:表面活性剂,例如硬脂酰三乙醇胺、月桂基磺酸钠、月桂基丙氨酸、卵磷脂、苯扎氯铵、苄索氯铵、单硬脂酸甘油酯等等;亲水性聚合物,例如聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素等。
等渗剂的例子包括葡萄糖、山梨糖醇、氯化钠、丙三醇、D-甘露醇等等。
缓冲剂的例子包括:缓冲溶液,例如磷酸盐、乙酸盐、碳酸盐、柠檬酸盐等等。
抚慰剂的例子包括苯甲醇,等等。
防腐剂的例子包括:对羟基苯甲酸酯、氯丁醇、苯甲醇、苯乙醇、脱氢乙酸、山梨酸,等等。
抗氧化剂的例子包括:亚硫酸盐、抗环血酸、α-生育酚等等。
为了预防或治疗各种疾病,本发明的化合物还可以与其它药物一起使用。在下面,当本发明的化合物与其它药物一起使用的药物被称为“本发明的组合药物”。
例如,当本发明的化合物用作JAK-1和/或JAK-3抑制剂时,它可以与下列药物组合使用。
(1)非甾体抗炎药(NSAID):包括:①传统的NSAID,②环加氧酶抑制剂(COX-1选择性抑制剂、COX-2选择性抑制剂,等等),③一氧化氮-释放NSAID,④JAK抑制剂等等;
(2)改善疾病的抗风湿药(DMARD):
①青霉胺,②氨基水杨酸药物③嘧啶合成抑制剂,等等;
除了上述以外,其它并用药物还包括,例如,抗菌剂、抗真菌剂、抗原生动物的药物、抗生素、镇咳药和祛痰剂、镇静剂、麻醉剂、抗溃疡药物、抗心律失常药物、降血压利尿药物、抗凝血剂、安神药、抗精神病药、抗肿瘤药物、促血清脂质减少的药物、肌肉松弛药、抗癫痫药物、抗抑郁剂、抗过敏药物、心脏兴奋剂、心律失常的治疗药物、血管扩张剂、血管收缩剂、糖尿病的治疗药物、抗麻醉药、维生素、维生素衍生物、止喘药、频尿/尿失禁的治疗剂、止痒药、特异性皮炎的治疗剂、过敏性鼻炎的治疗剂、血压增高剂、内毒素-拮抗剂或-抗体、信号转导抑制剂、炎症介质活性的抑制剂、抑制炎症介质活性的抗体、抗炎症的介质活性的抑制剂、抑制抗炎症介质活性的抗体,等等。
对于组合使用而言,对本发明化合物和并用药物的给予时间没有限制,本发明化合物或并用药物可以同时给予患者,或可以在不同的时间给予患者。可以按照临床上使用的剂量,确定“并用药物”的剂量,并且可以根据给药患者、给药途径、疾病、并用药物等等来合适地选择剂量。
对组合使用的给药形式没有特别限制,只要本发明化合物和并用药物能够组合使用即可。这种给药模式的例子包括下列模式:
(1)给予同时加工本发明化合物和并用药物所获得的单一制剂,(2)通过相同给药途径同时给予分别制备的本发明化合物和并用药物的两种制剂,(3)通过相同给药途径以交错方式给予分别制备的本发明化合物和并用药物的两种制剂,(4)通过不同给药途径同时给予分别制备的本发明化合物和并用药物的两种制剂,(5)通过不同给药途径以交错方式给予分别制备的本发明化合物和并用药物的两种制剂(例如,按照本发明的化合物和并用药物的顺序进行给药,或以反顺序给药),等等。
在本发明的组合药物中,可以恰当地根据给药患者、给药途径、疾病等等来选择本发明化合物和并用药物的混合比例。
例如,尽管本发明化合物在本发明组合药物中的含量根据制剂形式而变化,但通常为整个制剂的大约0.01-100wt%,优选大约0.1-50wt%,更优选大约0.5-20wt%。
在本发明的组合药物中,并用药物的含量根据制剂形式而改变,通常为整个制剂的大约0.01-100%重量,优选大约0.1至50%重量。
同时,添加剂(例如载体等)在本发明组合药物中的含量根据制剂形式而变化,基于该制剂,通常为大约1-99.99wt%重量,优选大约10-90wt%重量。
当单独制备本发明的化合物和并用药物时,可以采用相同含量。组合药物的剂量根据本发明化合物的种类、给药途径、症状、患者的年龄等等而变化。例如,对于口服给予患有类风湿性关节炎的患者(体重大约60kg),化合物(I)的剂量为大约0.1mg/kg体重-大约30mg/kg体重,优选大约1mg/kg体重-20mg/kg体重,可以每天给予一次至几次。
可以采用任何数量的并用药物,只要副作用不会产生问题即可。当给予本发明的组合药物时,可以同时给予本发明的化合物和并用药物,或可以以交错方式给药。当以一定时间间隔给药时,间隔时间根据有效成份、剂型和给药方法而变化,例如,当首先给予并用药物时,下列给药方法是一个实例:给予并用药物之后,在1分钟至3天的时间范围之内给予本发明的化合物,优选10分钟至1天,更优选15分钟至1小时。当首先给予本发明的化合物时,下列给药方法是一个实例:给予本发明的化合物之后,在1分钟至1天的时间范围之内,给予并用药物,优选10分钟至6小时,更优选15分钟至1小时。
实施例:
在下文中,参照参比实施例、实施例、实验实施例和制剂实施例来更详细地解释本发明,但这些实施例不限制本发明,并且可以在本发明范围内进行改变。
在下面的实施例中,“室温”通常是指大约10℃至大约35℃。混合溶剂表示的比例是体积混合比例,除非另作说明。除非另作说明,否则,%是指wt%。
在硅胶柱色谱中,碱性硅胶是指使用氨基丙基硅烷结合的硅胶。在高效液相色谱(HPLC)中,C18是指使用十八烷基结合的硅胶。洗脱溶剂的比例是体积混合比例,除非另作说明。
在下面实施例和实验实施例中,使用下列缩写。
THF:四氢呋喃,
DIEA:N,N-二异丙基乙胺
M:摩尔浓度。
利用Fourier变换类型NMR,测定1H-NMR(质子核磁共振波谱)。对于分析,使用ACD/SpecManager等。不描述很轻的质子(例如羟基、氨基等等)的峰。
利用1C/MS(液相色谱质谱仪)测定MS(质谱)。作为电离法,使用ESI(电喷射离子化)方法等。数据表示那些实测值。通常,观察分子离子峰。在盐的情况下,通常观察到游离形式的分子离子峰或碎片离子峰。
参考实施例1
3-硝基苄肼盐酸盐
于500mL三口瓶中,加入160mL乙醇溶解的85%水合肼(62g),加热至回流,然后缓慢向其中滴加72mL乙醇溶解的3-硝基氯化苄(20g),逐滴滴加,加入时间约1h,加料完毕后,回流温度下,搅拌反应3h。点板监控反应。反应结束,冷却至室温,减压干燥,残渣用300mLEA溶解。加入100mL饱和食盐水洗涤2次,水层再用200mL EA萃取,合并有机相,加入无水Na2SO4干燥,减压旋干,残渣加入150mL EA溶解,于0℃以下,向溶液中加入HCl甲醇溶液产品成盐析出,抽滤,得白色至淡黄色粉末。
MS(ESI+):[M+H]+168.1。
参考实施例2
4-硝基苄肼盐酸盐
利用与参考实施例1一样的方法,由4-硝基氯化苄和水合肼获得标题化合物。
MS(ESI+):[M+H]+168.1。
参考实施例3
1-(2-甲氧基乙基)-4-硝基-1H-吡唑
向100mL的茄形瓶中加入4-硝基吡唑(5g),K2CO3(9.17g),2-溴乙基甲基醚(7.38g),KI(1.47g)和63mL CH3CN,回流过夜。反应结束,减压旋干,加入H2O 75mL,EA 50mL×3,合并有机层,饱和食盐水洗涤,有机相加入无水Na2SO4干燥,减压干燥,得油状产物。
MS(ESI+):[M+H]+172.2。
参考实施例4
1-甲基-4-硝基-1H-吡唑
利用与参考实施例3一样的方法,由4-硝基吡唑和碘甲烷获得标题化合物。
MS(ESI+):[M+H]+128.2。
参考实施例5
2-(4-硝基-1H-吡唑-1-基)乙醇
利用与参考实施例3一样的方法,由4-硝基吡唑、KI和2-溴乙醇获得标题化合物。
MS(ESI+):[M+H]+158.2。
参考实施例6
4-(4-硝基苯基)吗啉
于单口瓶中加入4-氟硝基苯(1g),K2CO3(1.08g)和6mL DMSO,于室温搅拌反应30min,滴加入吗啡啉(0.62g),加热120℃搅拌反应2h,点板监测。混合物倒入醇和水混合液(1∶1)中,黄色沉淀过滤得产物。
MS(ESI+):[M+H]+209.2。
参考实施例7
1-甲基-4-(4-硝基苯基)哌啶
利用与参考实施例6一样的方法,由4-氟硝基苯和N-甲基哌啶获得标题化合物。
MS(ESI+):[M+H]+222.2。
参考实施例8
1-(2-甲氧基乙基)-1H-吡唑-4-氨基
于单口瓶中加入1-(2-甲氧基乙基)-4-硝基-1H-吡唑(5g),Pd/C(1g)和50mL乙醇,于氢气球置换空气,室温反应约24h。反应结束,硅藻土减压抽滤,减压干燥。得产物。
MS(ESI+):[M+H]+142.2。
参考实施例9
1-甲基-1H-吡唑-4-氨基
利用与参考实施例8一样的方法,由1-甲基-4-硝基-1H-吡唑和Pd/C获得标题化合物。
MS(ESI+):[M+H]+98.1。
参考实施例10
2-(4-氨基-1H-吡唑-1-基)乙醇
利用与参考实施例8一样的方法,由1-甲基-4-硝基-1H-吡唑和Pd/C获得标题化合物。
MS(ESI+):[M+H]+128.2。
参考实施例11
4-吗啉苯胺
利用与参考实施例8一样的方法,由4-(4-硝基苯基)吗啉和Pd/C获得标题化合物。
MS(ESI+):[M+H]+179.2。
参考实施例12
4-(4-甲基哌嗪-1-基)苯胺
利用与参考实施例8一样的方法,由1-甲基-4-(4-硝基苯基)哌啶和Pd/C获得标题化合物。
MS(ESI+):[M+H]+192.2。
实施例1
N-(3-((6-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺
A)6-氯-1-(3-硝基苄基)-1H-吡唑并[3,4-d]嘧啶
于500mL三口瓶中,加入4,6-二氯-嘧啶-5-甲醛(8.4g)和240mL THF,0℃下加入NEt3(14.56g),温度不超过0℃,滴加完毕,搅拌10min,然后,缓慢加入3-硝基苄肼盐酸盐(9.74g),加入过程中控制温度不超过0℃,投料完毕,搅拌反应1-2h,反应结束,减压干燥,得粗品,拌样,经硅胶柱色谱分离纯化,得标题化合物。
MS(ESI+):[M+H]+290.2。
B)N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1-(3-硝基苄基)-1H-吡唑并[3,4-d]嘧啶-6-氨基
向25mL的茄形瓶中加入6-氯-1-(3-硝基苄基)-1H-吡唑并[3,4-d]嘧啶(0.1g),1-(2-甲氧基乙基)-1H-吡唑-4-胺基盐酸盐(0.05g),DIEA(0.12g)和10mL IPA,回流反应6h。反应结束,降至室温,析出晶体,减压抽滤,得标题化合物。
MS(ESI+):[M+H]+395.2。
C)1-(3-氨基苄基)-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-6-氨基
于两口瓶中加入N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1-(3-硝基苄基)-1H-吡唑并[3,4-d]嘧啶-6-氨基(0.2g),0.04g Pd/C和10mL EtOH,N2保护下,加热至回流,在30min内缓慢滴加85%水合肼(0.57g),滴加完毕反应2h。反应结束,降至室温,经硅藻土减压过滤,减压干燥,得标题化合物。
MS(ESI+):[M+H]+365.2。
D)N-(3-((6-((1-(2-甲氧基-乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺
于两口瓶中加入1-(3-氨基苄基)-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-6-氨基(0.03g)和10mL干燥THF,N2保护下,于-5℃条件下,缓慢滴加2mL干燥THF稀释的丙烯酰氯(0.008g),滴加完毕0℃条件下反应2h,反应结束,加入饱和NaHCO3溶液,调节PH成碱性,加入EA 50mI×3,合并有机层,饱和食盐水洗涤,有机相加入无水Na2SO4干燥,减压干燥,得标题化合物。
MS(ESI+):[M+H]+419.2。
实施例2至7
在实施例2至7中,利用与实施例1一样的方法,由实施例1的步骤A获得的6-氯-1-(3-硝基苄基)-1H-吡唑并[3,4-d]嘧啶和任选被1至3个选自卤素原子、氰基、氨基、2-氰基乙酰基、C1-6醇、C1-6醇醚、C1-6的烷基、C2-8的环烷基烷基、C2-6的烯基和C2-6的炔基等等的取代基取代的苯基、或芳香5至6元杂环基(例如,吡唑、取代苯环等)(与实施例2至7的化合物对应),获得标题化合物。该表中的MS是指实测值。
表1
实施例8
N-(3-((6-((1-(2-甲氧基-乙基)-1H-吡唑4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺
A)6-氯-1-(3-硝基苄基)-1H-吡唑并[3,4-d]嘧啶
于500mL三口瓶中,加入4,6-二氯-嘧啶-5-甲醛(8.4g)和240mL THF,0℃下加入NEt3(14.56g),温度不超过0℃,滴加完毕,搅拌10min,然后,缓慢加入3-硝基苄肼盐酸盐(9.74g),加入过程中控制温度不超过0℃,投料完毕,搅拌反应1-2h,反应结束,减压干燥,得粗品,拌样,经硅胶柱色谱分离纯化,得标题化合物。
MS(ESI+):[M+H]+290.2。
B)N-(1-(2-甲氧基乙基)-1H-吡唑4-基)-1-(3-硝基苄基)-1H-吡唑并[3,4-d]嘧啶-6-氨基
向25mL的茄形瓶中加入6-氯-1-(3-硝基苄基)-1H-吡唑并[3,4-d]嘧啶(0.1g),1-(2-甲氧基乙基)-1H-吡唑-4-胺基盐酸盐(0.05g),DIEA(0.12g)和10mL IPA,回流反应6h。反应结束,降至室温,析出晶体,减压抽滤,得标题化合物。
MS(ESI+):[M+H]+395.2。
C)1-(3-氨基苄基)-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-6-氨基
于两口瓶中加入N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1-(3-硝基苄基)-1H-吡唑并[3,4-d]嘧啶-6-氨基(0.2g),0.04g Pd/C和10mL EtOH,N2保护下,加热至回流,在30min内缓慢滴加85%水合肼(0.57g),滴加完毕反应2h。反应结束,降至室温,经硅藻土减压过滤,减压干燥,得标题化合物。
MS(ESI+):[M+H]+365.2。
D)N-(3-((6-((1-(2-甲氧基-乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺
于两口瓶中加入1-(3-氨基苄基)-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-6-氨基(0.03g)和10mL干燥THF,N2保护下,于-5℃条件下,缓慢滴加2mL干燥THF稀释的丁烯酰氯(0.009g),滴加完毕0℃条件下反应2h,反应结束,加入饱和NaHCO3溶液,调节PH成碱性,加入EA 50mL×3,合并有机层,饱和食盐水洗涤,有机相加入无水Na2SO4干燥,减压干燥,得标题化合物。
MS(ESI+):[M+H]+433.3。
实施例9至14
在实施例9至14中,利用与实施例8一样的方法,由实施例8的步骤A获得的6-氯-1-(3-硝基苄基)-1H-吡唑并[3,4-d]嘧啶和任选被1至3个选自卤素原子、氰基、氨基、2-氰基乙酰基、C1-6醇、C1-6醇醚、C1-6的烷基、C2-8的环烷基烷基、C2-6的烯基和C2-6的炔基等等的取代基取代的苯基、或芳香5至6元杂环基(例如,吡唑、取代苯环等)(与实施例9至14的化合物对应),获得标题化合物。该表中的MS是指实测值。
表2
实施例15
N-(4-((6-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺
A)6-氯-1-(4-硝基苄基)-1H-吡唑并[3,4-d]嘧啶
于500mL三口瓶中,加入4,6-二氯-嘧啶-5-甲醛(8.4g)和240mL THF,0℃下加入NEt3(14.56g),温度不超过0℃,滴加完毕,搅拌10min,然后,缓慢加入4-硝基苄肼盐酸盐(9.74g),加入过程中控制温度不超过0℃,投料完毕,搅拌反应1-2h,反应结束,减压干燥,得粗品,拌样,经硅胶柱色谱分离纯化,得标题化合物。
MS(ESI+):[M+H]+290.2。
B)N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1-(4-硝基苄基)-1H-吡唑并[3,4-d]嘧啶-6-氨基
向25mL的茄形瓶中加入6-氯-1-(4-硝基苄基)-1H-吡唑并[3,4-d]嘧啶(0.1g),1-(2-甲氧基乙基)-1H-吡唑-4-胺基盐酸盐(0.05g),DIEA(0.12g)和10mL IPA,回流反应6h。反应结束,降至室温,析出晶体,减压抽滤,得标题化合物。
MS(ESI+):[M+H]+395.2。
C)1-(4-氨基苄基)-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-6-氨基
于两口瓶中加入N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1-(4-硝基苄基)-1H-吡唑并[3,4-d]嘧啶-6-氨基(0.2g),0.04g Pd/C和10mL EtOH,N2保护下,加热至回流,在30min内缓慢滴加85%水合肼(0.57g),滴加完毕反应2h。反应结束,降至室温,经硅藻土减压过滤,减压干燥,得标题化合物。
MS(ESI+):[M+H]+365.2。
D)N-(4-((6-((1-(2-甲氧基-乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺
于两口瓶中加入1-(4-氨基苄基)-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-6-氨基(0.03g)和10mL干燥THF,N2保护下,于-5℃条件下,缓慢滴加2mL干燥THF稀释的丙烯酰氯(0.008g),滴加完毕0℃条件下反应2h,反应结束,加入饱和NaHCO3溶液,调节PH成碱性,加入EA 50mL×3,合并有机层,饱和食盐水洗涤,有机相加入无水Na2SO4干燥,减压干燥,得标题化合物。
MS(ESI+):[M+H]+419.2。
实施例16至21
在实施例16至21中,利用与实施例15一样的方法,由实施例15的步骤A获得的6-氯-1-(4-硝基苄基)-1H-吡唑并[3,4-d]嘧啶和任选被1至3个选自卤素原子、氰基、氨基、2-氰基乙酰基、C1-6醇、C1-6醇醚、C1-6的烷基、C2-8的环烷基烷基、C2-6的烯基和C2-6的炔基等等的取代基取代的苯基、或芳香5至6元杂环基(例如,吡唑、取代苯环等)(与实施例16至21的化合物对应),获得标题化合物。该表中的MS是指实测值。
表3
实施例22
N-(4-((6-((1-(2-甲氧基-乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺
A)6-氯-1-(4-硝基苄基)-1H-吡唑并[3,4-d]嘧啶
于500mL三口瓶中,加入4,6-二氯-嘧啶-5-甲醛(8.4g)和240mL THF,0℃下加入NEt3(14.56g),温度不超过0℃,滴加完毕,搅拌10min,然后,缓慢加入4-硝基苄肼盐酸盐(9.74g),加入过程中控制温度不超过0℃,投料完毕,搅拌反应1-2h,反应结束,减压干燥,得粗品,拌样,经硅胶柱色谱分离纯化,得标题化合物。
MS(ESI+):[M+H]+290.2。
B)N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1-(4-硝基苄基)-1H-吡唑并[3,4-d]嘧啶-6-氨基
向25mL的茄形瓶中加入6-氯-1-(4-硝基苄基)-1H-吡唑并[3,4-d]嘧啶(0.1g),1-(2-甲氧基乙基)-1H-吡唑-4-胺基盐酸盐(0.05g),DIEA(0.12g)和10mL IPA,回流反应6h。反应结束,降至室温,析出晶体,减压抽滤,得标题化合物。
MS(ESI+):[M+H]+395.2。
C)1-(4-氨基苄基)-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-6-氨基
于两口瓶中加入N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1-(4-硝基苄基)-1H-吡唑并[3,4-d]嘧啶-6-氨基(0.2g),0.04g Pd/C和10mL EtOH,N2保护下,加热至回流,在30min内缓慢滴加85%水合肼(0.57g),滴加完毕反应2h。反应结束,降至室温,经硅藻土减压过滤,减压干燥,得标题化合物。
MS(ESI+):[M+H]+365.2。
D)N-(4-((6-((1-(2-甲氧基-乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺
于两口瓶中加入1-(4-氨基苄基)-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-6-氨基(0.03g)和10mL干燥THF,N2保护下,于-5℃条件下,缓慢滴加2mL干燥THF稀释的丁烯酰氯(0.009g),滴加完毕0℃条件下反应2h,反应结束,加入饱和NaHCO3溶液,调节PH成碱性,加入EA 50mL×3,合并有机层,饱和食盐水洗涤,有机相加入无水Na2SO4干燥,减压干燥,得标题化合物。
MS(ESI+):[M+H]+433.3。
实施例23至28
在实施例23至28中,利用与实施例22一样的方法,由实施例22的步骤A获得的6-氯-1-(4-硝基苄基)-1H-吡唑并[3,4-d]嘧啶和任选被1至3个选自卤素原子、氰基、氨基、2-氰基乙酰基、C1-6醇、C1-6醇醚、C1-6的烷基、C2-8的环烷基烷基、C2-6的烯基和C2-6的炔基等等的取代基取代的苯基、或芳香5至6元杂环基(例如,吡唑、取代苯环等)(与实施例23至28的化合物对应),获得标题化合物。该表中的MS是指实测值。
表4
实验实施例(JAK-1、JAK-2和JAK-3酶抑制试验)
实验目的:
评价化合物对JAK-1、JAK-2和JAK-3激酶的抑制作用。
实验原理:
基于荧光共振能量转移技术(FRET)偶联蛋白水解酶对特定磷酸化与非磷酸化多肽底物不同的蛋白水解作用。多肽底物两端分别标记为FRET能量供体香豆素和能量受体荧光素,此时供、受体距离较近激发供体可以发生能量转移。
激酶反应(Kinase Reaction)中,JAK-1、JAK-2或JAK-3可以将ATP中的γ-磷酸转移到多肽底物的单个酪氨酸残基上,如果体系中存在JAK-1、JAK-2或JAK-3抑制剂,则ATP上的γ-磷酸基团不会被转移到底物多肽上,磷酸化反应不能发生。基于此原理设计了激酶抑制剂的评价实验,底物多肽设计有激酶磷酸化位点,同时也是蛋白酶切位点,两端分别接2种荧光基团,分别为供体和受体,反应体系中如果激酶活性保持,γ-磷酸基团则被转移到底物的酶切位点,从而不会被蛋白酶切割而分离成两段,在特定波长激光激发下,一段荧光的能量会被转移到另一端的荧光基团而发射能量。否则,及酶活性被抑制后,磷酸基团不能被转移,底物酶切位点会被体系中的酶切割,底物分离成两段,则不会发生荧光的能量转移。基于此评价激酶的活性。
实验步骤:
本实验选择10μl激酶反应体系,首先每体系中加入2.5μl激酶(浓度1nM),2.5μl多肽底物(浓度2μM),2.5μl ATP(浓度10μM)和2.5μl化合物,于室温下反应1h,后加入5μl检测液,室温反应1h,再加入5μl终止液。利用酶标仪(Synergy H1,BioTek,USA),测定荧光强度(在400nm激发下,检测445nm下香豆素的发射和520nm下荧光素的发射强度)。计算每个化合物的抑制活性,其中,认为不含酶的孔的荧光强度是100%抑制。
表5
制剂实施例1(制备片剂)
将全部数量的(1)、(2)、(3)和(4)30g与水一起搅拌,真空干燥,并筛分。将筛分的粉末与(4)14g和(5)1g混合,并用压片机冲压该混合物,由此,获得1000个片剂,每片含有30mg的实施例1的化合物。
制剂实施例2(制备胶囊剂)
将(1)、(2)、(3)和(4)混合,并装填在胶囊中。
本发明的化合物具有优良的选择性JAK-3抑制作用,其用作预防、治疗或改善自身免疫疾病(例如,牛皮癣、类风湿性关节炎、炎性肠疾病、斯耶格伦氏综合征、白塞氏病、多发性硬化、系统性红斑狼疮等)等的药物。
Claims (9)
1.式(I)代表的化合物或其药学上可接受的盐:
其中,
B独立地选自氢原子、卤素、氰基、羟基;
R3、R4、和R5独立地选自氢原子、卤素、氰基、羟基、被取代的或未被取代的C1-6烃基或被取代的或未被取代的C1-6杂烃基或被取代的或未被取代的C3-8环烃基、被取代的或未被取代的C3-8杂环烃基、被取代的或未被取代的5-、6-、7-或8-元芳基、被取代的或未被取代的5-、6-、7-或8-元杂芳基;
R2是苯基、萘基、芳香5至6元杂环基、或芳香9至11元杂双环基、其中环任选被一个或多个R6取代;
每个R6独立的为卤素、CN、C(O)OR7、OR7、C(O)R7、S(O)2R7、S(O)R7、NO2、OC(O)R7、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R8取代;
R7独立的选自H、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R8取代;
R8为卤素、CN、C(O)OR9、OR4、C(O)R9、S(O)2R9、S(O)R9、NO2、OC(O)R9;
R9独立的选自H、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的卤素取代。
2.权利要求1的化合物或其盐,其中,
R1是
(1)氢原子,
(2)卤素原子,
(3)氰基,
(4)丙烯酰基,
(5)2-氰基乙酰基,
(6)任选被1至3个选自下列的取代基取代的C1-6烷基:(a)氢原子,(b)卤素原子,(c)羟基,(d)C1-6烷氧基,(e)C3-8环烷基,(f)C1-6烷基-羰基单或二取代的氨基,
(7)任选被1至3个选自下列的取代基取代的C2-7烯基:(a)氢原子,(b)卤素原子,(c)任选取代的C1-6烷基,
(8)任选被1至3个选自下列的取代基取代的C2-7炔基:(a)氢原子,(b)卤素原子,(c)任选取代的C1-6烷基,
(9)任选被1至3个选自下列的取代基取代的C3-10环烷基:(a)卤素原子,(b)C1-6烷基;
(10)3至8元单环非芳香杂环基团;
(11)任选被1至3个选自下列的取代基取代的5或6元单环芳香杂环基团:(a)卤素原子,(b)氰基。
3.根据权利要求1-2中任一项所述的用途,其中
R2是苯基、或芳香5至6元杂环基其中环任选被一个或多个R6取代;
每个R6独立的为卤素、CN、C(O)OR7、OR7、C(O)R7、S(O)2R7、S(O)R7、NO2、OC(O)R7、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R8取代;
R7独立的选自H、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的R8取代;
R8为卤素、CN、C(O)OR9、OR9、C(O)R9、S(O)2R9、S(O)R9、NO2、OC(O)R9;
R10独立的选自H、C1-6烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C2-6烯基和C2-6炔基任选被一个或多个相同或不同的卤素取代。
4.权利要求1至3任一项的化合物或其药学上可接受的盐,所述化合物选自:
N-(3-((6-苯胺-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(3-((6-苯胺-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺;
N-(3-((6-((4-吗啉基苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(3-((6-((4-吗啉基苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺;
N-(3-((6-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(3-((6-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺;
N-(3-((6-((1-(2-甲氧基-乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(3-((6-((1-(2-甲氧基-乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺;
N-(3-((6-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(3-((6-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丁-2-烯酰胺;
N-(4-((6-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(4-((6-((4-吗啉基苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺;
N-(4-((6-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)苯基)丙烯酰胺。
5.权利要求1-4中所述药物,其是JAK抑制剂。
6.权利要求5中所述药物,其是预防、治疗和/或改善自身免疫疾病的药物。
7.权利要求6中所述药物,其中自身免疫疾病是牛皮癣、类风湿性关节炎、炎性肠炎疾病、斯耶格伦氏综合征、白塞氏病、多发性硬化或系统性红斑狼疮。
8.权利要求1的化合物或其盐用于制备药物的用途,该药物用于预防和/或改善自身免疫疾病。
9.权利要求8的用途,其中自身免疫疾病是牛皮癣、类风湿性关节炎、炎性肠疾病、斯耶格伦氏综合征、白塞氏病、多发性硬化或系统性红斑狼疮。
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