CN113768927A - 使用jak抑制剂治疗化脓性汗腺炎 - Google Patents
使用jak抑制剂治疗化脓性汗腺炎 Download PDFInfo
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- CN113768927A CN113768927A CN202110765598.3A CN202110765598A CN113768927A CN 113768927 A CN113768927 A CN 113768927A CN 202110765598 A CN202110765598 A CN 202110765598A CN 113768927 A CN113768927 A CN 113768927A
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- pyrimidin
- pyrrolo
- pyrazol
- methyl
- acetonitrile
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Abstract
本申请提供了治疗有需要的患者的化脓性汗腺炎的方法,所述方法包括向所述患者施用治疗有效量的抑制JAK1和/或JAK2的化合物或其药学上可接受的盐。
Description
本申请为申请号为201980027348.0(申请日:2019年3月29日,发明名称:使用JAK抑制剂治疗化脓性汗腺炎)的中国发明专利申请的分案申请。
本申请要求2018年3月30日提交的美国临时申请No.62/650,600的权益,所述临时申请以引用的方式整体并入本文中。
技术领域
本申请提供了使用调节Janus激酶(JAK)1和/或2的活性的化合物治疗化脓性汗腺炎(HS)的方法。
背景技术
蛋白激酶(Protein kinase,PK)调控各种生物过程,尤其包括细胞生长、存活、分化、器官形成、形态发生、新血管形成、组织修复和再生。蛋白激酶也在包括癌症的许多人类疾病中起专门作用。细胞因子、低分子量多肽或糖蛋白调控许多与宿主对败血症的炎症反应相关的通路。细胞因子影响细胞分化、增殖和活化,并且可调节促炎反应与消炎反应以允许宿主对病原体适当地反应。大量细胞因子的信号传导涉及蛋白酪氨酸激酶的Janus激酶家族(JAK)和信号转导和转录激活因子(STAT)。存在四种已知的哺乳动物JAK:JAK1(Janus激酶-1)、JAK2、JAK3(又称Janus激酶,白血球;JAKL;和L-JAK)和TYK2(蛋白酪氨酸激酶2)。
细胞因子刺激的免疫和炎症反应引起疾病的发病机理:例如严重合并性免疫缺失病(SCID)的病理由免疫系统受到遏制产生,而过度活性或不适当免疫/炎症反应引起自身免疫疾病(例如哮喘、系统性红斑狼疮、甲状腺炎、心肌炎)和例如硬皮病和骨关节炎的疾病的病理(Ortmann,R.A.,T.Cheng等人(2000)Arthritis Res 2(1):16-32)。
JAK表达的缺乏与许多疾病病况有关。举例来说,Jak1-/-小鼠在出生时矮小,无法喂奶并且在围产期死亡(Rodig,S.J.,M.A.Meraz等人,(1998)Cell93(3):373-83)。Jak2-/-小鼠胚胎贫血并且在交配后约12.5天由于缺乏定向型红血球生成而死亡。
相信JAK/STAT通路和尤其所有四种JAK在哮喘反应、慢性阻塞性肺病、支气管炎和下呼吸道的其它相关炎性疾病的发病机理中起作用。通过JAK传导信号的多种细胞因子与上呼吸道的炎性疾病/疾患相关联,例如影响鼻和鼻窦的疾病(例如鼻炎和鼻窦炎),无论是否在传统上为过敏反应。JAK/STAT通路也与眼睛的炎性疾病/疾患和慢性过敏反应相关。
癌症中JAK/STAT可以通过刺激细胞因子(例如IL-6或GM-CSF)或通过减少例如SOCS(细胞因子信号传导的遏制因子)或PIAS(活化STAT的蛋白抑制因子)的JAK信号传导的内源性抑制因子而活化(Boudny,V.和Kovarik,J.,Neoplasm.49:349-355,2002)。STAT信号传导以及JAK下游的其它通路(例如Akt)的活化与许多癌症类型中的不良预后相关(Bowman,T.等人,Oncogene 19:2474-2488,2000)。升高水平的通过JAK/STAT传导信号的循环细胞因子是恶病质和/或慢性疲劳的起因。因而,JAK抑制可因延伸超过潜在抗肿瘤活性的原因而有益于癌症患者。
JAK2酪氨酸激酶可有益于患有骨髓增生性病症,例如真性红血球增多症(PV)、特发性血小板增多症(ET)、伴有骨髓纤维化的髓样化生(MMM)的患者(Levin等人,CancerCell,第7卷,2005:387-397)。JAK2V617F激酶的抑制减少造血细胞的增殖,这表明JAK2为PV、ET和MMM的患者中药理学抑制的潜在标靶。
JAK的抑制可有益于罹患皮肤免疫病症,例如牛皮癣和皮肤敏化的患者。相信除其中多者通过JAK传导信号(Adv Pharmacol.2000;47:113-74)的多种趋化介素和生长因子外,牛皮癣的维持还视许多炎性细胞因子而定(JCI113:1664-1675)。
因此,不断地需要抑制例如JAK的激酶的新颖或改良剂,用于发展旨在加强或抑制免疫和炎症通路,例如治疗化脓性汗腺炎的新颖且更有效的药物。本申请是针对所述需求和其它需求。
发明内容
本申请提供了治疗有需要的患者的化脓性汗腺炎的方法,所述方法包括向所述患者施用治疗有效量的抑制JAK1和/或JAK2的化合物或其药学上可接受的盐。
在一些实施方案中,相比于对JAK3和TYK2的选择性,所述化合物或盐对JAK1和JAK2具选择性。
在一些实施方案中,相比于JAK2、JAK3和TYK2,所述化合物或盐对JAK1具选择性。
在一些实施方案中,化合物为鲁索利替尼(ruxolitinib)或其药学上可接受的盐。
在一些实施方案中,化合物为鲁索利替尼或其药学上可接受的盐,其中一个或多个氢原子被氘原子置换。
在一些实施方案中,盐为鲁索利替尼磷酸盐。
在一些实施方案中,化合物为{1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈或其药学上可接受的盐。
在一些实施方案中,盐为{1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈己二酸盐。
在一些实施方案中,化合物为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺或其药学上可接受的盐。
在一些实施方案中,盐为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺磷酸盐。
在一些实施方案中,化合物或盐以按游离碱计15mg、30mg、60mg或90mg的剂量施用。
在一些实施方案中,化合物为((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈或其药学上可接受的盐。
在一些实施方案中,化合物为((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈单水合物。
在一些实施方案中,所述方法还包括施用其它治疗剂(例如抗生素、类视色素、皮质类固醇、抗TNF-α剂或免疫抑制剂)。
在一些实施方案中,化合物或盐的施用是局部施用。在一些实施方案中,化合物或盐的施用是经口施用。
在一些实施方案中,所述方法使HiSCR(化脓性汗腺炎临床反应)提高10%、20%、30%、40%或50%。
本申请还提供了抑制JAK1和/或JAK2的化合物或其药学上可接受的盐,用于治疗化脓性汗腺炎。
本申请进一步提供了抑制JAK1和/或JAK2的化合物或其药学上可接受的盐的用途,所述化合物用于制备供治疗化脓性汗腺炎用的药剂。
附图说明
图1展示在经TNFα和IFN-γ刺激的角化细胞中在化合物A-D存在/缺乏下每个重复实验的JAK1的个别基因表达值(MFI)。在递增浓度的JAK抑制剂存在或缺乏下角化细胞用TNFα(25ng/mL)和IFNγ(25ng/mL)刺激。数据呈现为每个组的JAK1表达水平。
图2展示在经TNFα和IFN-γ刺激的角化细胞中在化合物A-D存在/缺乏下每个重复实验的JAK2的个别基因表达值(MFI)。在递增浓度的JAK抑制剂存在或缺乏下角化细胞用TNFα(25ng/mL)和IFNγ(25ng/mL)刺激。数据呈现为每个组的JAK2表达水平。
图3展示在经TNFα和IFN-γ刺激的角化细胞中在化合物A-D存在/缺乏下每个重复实验的IL-1α的个别基因表达值(MFI)。在递增浓度的JAK抑制剂存在或缺乏下角化细胞用TNFα(25ng/mL)和IFNγ(25ng/mL)刺激。数据呈现为每个组的IL-1α表达水平。
图4展示在经TNFα和IFN-γ刺激的角化细胞中在化合物A-D存在/缺乏下每个重复实验的IL-6的个别基因表达值(MFI)。在递增浓度的JAK抑制剂存在或缺乏下角化细胞用TNFα(25ng/mL)和IFNγ(25ng/mL)刺激。数据呈现为每个组的IL-6表达水平。
图5展示在经TNFα和IFN-γ刺激的角化细胞中在化合物A-D存在/缺乏下每个重复实验的IL-1α的个别蛋白质浓度(pg/mL)。在递增浓度的JAK抑制剂存在或缺乏下角化细胞用TNFα(25ng/mL)和IFNγ(25ng/mL)刺激。数据呈现为每个组的IL-1α浓度。
图6展示在经TNFα和IFN-γ刺激的角化细胞中在化合物A-D存在/缺乏下每个重复实验的IL-6的个别蛋白质浓度(pg/mL)。在递增浓度的JAK抑制剂存在或缺乏下角化细胞用TNFα(25ng/mL)和IFNγ(25ng/mL)刺激。数据呈现为每个组的IL-6浓度。
图7展示健康对照者和患有化脓性汗腺炎的受试者的皮肤中JAK1、JAK3和TYK2的基因表达(MFI)。数据呈现为每个健康对照者(n=4)和化脓性汗腺炎(n=41)受试者的JAK1、JAK3或TYK2基因表达水平。
图8展示健康对照者和患有化脓性汗腺炎的受试者的皮肤中STAT1、STAT2和STAT3的基因表达(MFI)。数据呈现为每个健康对照者(n=4)和化脓性汗腺炎(n=41)受试者的STAT1、STAT2或STAT3基因表达水平。
图9展示健康对照者和患有化脓性汗腺炎的受试者的皮肤中IRAK1、IRAK2和IRAK4的基因表达(MFI)。数据呈现为每个健康对照者(n=4)和化脓性汗腺炎(n=41)受试者的IRAK1、IRAK2或IRAK4基因表达水平。
具体实施方式
本申请尤其提供了一种治疗有需要的患者的化脓性汗腺炎的方法,所述方法包括施用治疗有效量的抑制JAK1和/或JAK2的化合物或其药学上可接受的盐。
本文所述的方法利用作为JAK1和/或JAK2的抑制剂的化合物或盐。在一些实施方案中,化合物为:
鲁索利替尼;
鲁索利替尼,其中一个或多个氢原子被氘原子置换;
{1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
4-{3-(氰基甲基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-N-[4-氟-2-(三氟甲基)苯基]哌啶-1-甲酰胺;
[3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-1-(1-{[2-(三氟甲基)嘧啶-4-基]羰基}哌啶-4-基)氮杂环丁烷-3-基]乙腈;
4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺;
((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈;
3-[1-(6-氯吡啶-2-基)吡咯烷-3-基]-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈;
3-(1-[1,3]噁唑并[5,4-b]吡啶-2-基吡咯烷-3-基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈;
4-[(4-{3-氰基-2-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙基}哌嗪-1-基)羰基]-3-氟苯甲腈;
4-[(4-{3-氰基-2-[3-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡咯-1-基]丙基}哌嗪-1-基)羰基]-3-氟苯甲腈;
[反式-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-3-(4-{[2-(三氟甲基)嘧啶-4-基]羰基}哌嗪-1-基)环丁基]乙腈;
{反式-3-(4-{[4-[(3-羟基氮杂环丁烷-1-基)甲基]-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-{[(2S)-2-(羟基甲基)吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-{[(2R)-2-(羟基甲基)吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
4-(4-{3-[(二甲基氨基)甲基]-5-氟苯氧基}哌啶-1-基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丁腈;
5-{3-(氰基甲基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-N-异丙基吡嗪-2-甲酰胺;
4-{3-(氰基甲基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺;
5-{3-(氰基甲基)-3-[4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-N-异丙基吡嗪-2-甲酰胺;
{1-(顺式-4-{[6-(2-羟基乙基)-2-(三氟甲基)嘧啶-4-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-[(乙基氨基)甲基]-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-(1-羟基-1-甲基乙基)-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-{[(3R)-3-羟基吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-{[(3S)-3-羟基吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{反式-3-(4-{[4-({[(1S)-2-羟基-1-甲基乙基]氨基}甲基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-({[(2R)-2-羟基丙基]氨基}甲基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-({[(2S)-2-羟基丙基]氨基}甲基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-(2-羟基乙基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
或上述任一者的药学上可接受的盐。
在一些实施方案中,相比于JAK3和TYK2,所述化合物或盐对JAK1和JAK2具选择性。在一些实施方案中,化合物为3-环戊基-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈或其药学上可接受的盐。在一些实施方案中,化合物为(3R)-3-环戊基-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈(鲁索利替尼)或其药学上可接受的盐。鲁索利替尼在1mM ATP(测定A)下对JAK1和JAK2具有小于10nM的IC50。3-环戊基-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈和鲁索利替尼可以通过2006年12月12日提交的US 7,598,257(实施例67)(其以引用的方式整体并入本文中)中所述的程序制成。在一些实施方案中,JAK1和/或JAK2的抑制剂为(3R)-3-环戊基-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈磷酸盐。所述磷酸盐可如美国专利8,722,693(其以引用的方式整体并入本文中)中所述制成。
在一些实施方案中,化合物或盐为JAK1抑制剂。在一些实施方案中,相比于JAK2、JAK3和TYK2,化合物或盐对JAK1具选择性。举例来说,相比于JAK2、JAK3和TYK2中的一种或多种,本文所述的一些化合物或其药学上可接受的盐优先抑制JAK1。JAK1在失调时可引起或造成疾病病况的许多细胞因子和生长因子信号传导通路中起重要作用。举例来说,在类风湿性关节炎中IL-6水平升高,类风湿性关节炎是一种已表明具有不利影响的疾病(Fonesca等人,Autoimmunity Reviews,8:538-42,2009)。因为IL-6至少部分经由JAK1传导信号,所以IL-6可间接经由抑制JAK1,产生潜在临床益处(Guschin等人,Embo J 14:1421,1995;Smolen等人,Lancet 371:987,2008)。此外,在一些癌症中,JAK1突变,引起组成性不希望的肿瘤细胞生长和存活(Mullighan,Proc Natl Acad Sci U S A.106:9414-8,2009;Flex,J Exp Med.205:751-8,2008)。在其它自身免疫疾病和癌症中,升高的全身水平的活化JAK1的炎性细胞因子也会引起所述疾病和/或相关症状。因此,此类疾病的患者可得益于JAK1抑制。JAK1的选择性抑制剂可为有效的,同时避免抑制其它JAK激酶的不必要和可能不良的作用。
化脓性汗腺炎的特征在于显著皮肤炎症;然而,概述所述炎症的出版物有限(Hoffman等人,PLOS One,2018年9月28日,https://doi.org/10.1371/journal.pone.0203672)。本文中呈现支持以下假设的实施例:炎症很大程度上是由JAK/STAT介导的通路驱动。实施例C、实施例D和实施例E说明与健康皮肤相比HS患者的皮肤中JAK/STAT基因表达水平升高。此外,实施例C、实施例D和实施例E说明已知在HS中升高的促炎性细胞因子(TNF-α和IFN-γ)在培养的角化细胞中诱发JAK/STAT通路并且此诱发可以通过加入JAK抑制剂而减少。因此,HS患者可得益于JAK1抑制。JAK1的选择性抑制剂可为有效的,同时避免抑制其它JAK激酶的不必要和可能不良的作用。
在一些实施方案中,与JAK2相比,化合物或盐优先抑制JAK1(例如JAK2/JAK1 IC50比率>1)。在一些实施方案中,化合物或盐对JAK1的选择性为对JAK2的选择性的约10倍。在一些实施方案中,如通过在1mM ATP下测量IC50(参见实施例A)所计算,化合物或盐对JAK1的选择性为对JAK2的选择性的约3倍、约5倍、约10倍、约15倍或约20倍。
在一些实施方案中,JAK1抑制剂为表1的化合物或其药学上可接受的盐。表1中的化合物为选择性JAK1抑制剂(相比于JAK2、JAK3和TYK2,具选择性)。在1mM ATP下通过实施例A的方法获得的IC50值示于表1中。
表1
+意指<10nM(关于测定条件,参见实施例A)
++意指≤100nM(关于测定条件,参见实施例A)
+++意指≤300nM(关于测定条件,参见实施例A)
a对映异构体1的数据
b对映异构体2的数据
在一些实施方案中,JAK1抑制剂为{1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈或其药学上可接受的盐。
在一些实施方案中,JAK1抑制剂为{1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈己二酸盐。
{1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈和其己二酸盐的合成和制备可见于例如2011年3月9日提交的美国专利公布No.2011/0224190、2012年9月6日提交的美国专利公布No.2013/0060026和2014年3月5日提交的美国专利公布No.2014/0256941,各以引用的方式整体并入本文中。
在一些实施方案中,JAK1抑制剂为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺或其药学上可接受的盐。
在一些实施方案中,JAK1抑制剂为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺磷酸盐。
在一些实施方案中,JAK1为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺盐酸盐。
在一些实施方案中,JAK1为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺氢溴酸盐。
在一些实施方案中,JAK1为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺硫酸盐。
4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺和其磷酸盐的合成和制备可见于例如2014年5月16日提交的美国专利公布No.US 2014/0343030,其以引用的方式整体并入本文中。
在一些实施方案中,JAK1抑制剂为((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈或其药学上可接受的盐。
在一些实施方案中,JAK1抑制剂为((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈单水合物。
((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈的合成和其无水合物和单水合物形式的表征描述于2013年10月31日提交的美国专利公布No.2014/0121198和2015年4月29日提交的美国专利公布No.2015/0344497中,各以引用的方式整体并入本文中。
在一些实施方案中,表1的化合物通过以下中描述的合成程序制备:2011年3月9日提交的美国专利公布No.2011/0224190、2014年5月16日提交的美国专利公布No.2014/0343030、2013年10月31日提交的美国专利公布No.2014/0121198、2010年5月21日提交的美国专利公布No.2010/0298334、2010年8月31日提交的美国专利公布No.2011/0059951、2011年11月18日提交的美国专利公布No.2012/0149681、2011年11月18日提交的美国专利公布No.2012/0149682、2012年6月19日提交的美国专利公布2013/0018034、2012年8月17日提交的美国专利公布No.2013/0045963和2013年5月17日提交的美国专利公布No.2014/0005166,各以引用的方式整体并入本文中。
在一些实施方案中,JAK1抑制剂选自以下中的化合物或其药学上可接受的盐:2011年3月9日提交的美国专利公布No.2011/0224190、2014年5月16日提交的美国专利公布No.2014/0343030、2013年10月31日提交的美国专利公布No.2014/0121198、2010年5月21日提交的美国专利公布No.2010/0298334、2010年8月31日提交的美国专利公布No.2011/0059951、2011年11月18日提交的美国专利公布No.2012/0149681、2011年11月18日提交的美国专利公布No.2012/0149682、2012年6月19日提交的美国专利公布2013/0018034、2012年8月17日提交的美国专利公布No.2013/0045963和2013年5月17日提交的美国专利公布No.2014/0005166,各以引用的方式整体并入本文中。
在一些实施方案中,JAK1抑制剂为式I化合物
或其药学上可接受的盐,其中:
X为N或CH;
L为C(=O)或C(=O)NH;
A为苯基、吡啶基或嘧啶基,各任选地经1个或2个独立选择的R1基团取代;并且
每个R1独立地为氟或三氟甲基。
在一些实施方案中,式I化合物为{1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈或其药学上可接受的盐。
在一些实施方案中,式I化合物为4-{3-(氰基甲基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-N-[4-氟-2-(三氟甲基)苯基]哌啶-1-甲酰胺或其药学上可接受的盐。
在一些实施方案中,式I化合物为[3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-1-(1-{[2-(三氟甲基)嘧啶-4-基]羰基}哌啶-4-基)氮杂环丁烷-3-基]乙腈或其药学上可接受的盐。
在一些实施方案中,JAK1抑制剂为式II化合物
或其药学上可接受的盐,其中:
R2为C1-6烷基、C1-6卤烷基、C3-6环烷基或C3-6环烷基-C1-3烷基,其中所述C1-6烷基、C3-6环烷基和C3-6环烷基-C1-3烷基各任选地经1个、2个或3个独立选自氟、-CF3和甲基的取代基取代;
R3为H或甲基;
R4为H、F或Cl;
R5为H或F;
R6为H或F;
R7为H或F;
R8为H或甲基;
R9为H或甲基;
R10为H或甲基;并且
R11为H或甲基。
在一些实施方案中,式II化合物为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺或其药学上可接受的盐。
在一些实施方案中,JAK1抑制剂为式III化合物
或其药学上可接受的盐,其中:
Cy4为四氢-2H-吡喃环,其任选地经1个或2个独立地选自CN、OH、F、Cl、C1-3烷基、C1-3卤烷基、CN-C1-3烷基、HO-C1-3烷基、氨基、C1-3烷基氨基和二(C1-3烷基)氨基的基团取代,其中所述C1-3烷基和二(C1-3烷基)氨基任选地经1个、2个或3个独立选自F、Cl、C1-3烷基氨基磺酰基和C1-3烷基磺酰基的取代基取代;并且
R12为-CH2-OH、-CH(CH3)-OH或-CH2-NHSO2CH3。
在一些实施方案中,式III化合物为((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈或其药学上可接受的盐。
在一些实施方案中,JAK1和/或JAK2的抑制剂为巴瑞替尼(barcitinib)、托法替尼(tofacitinib)、奥拉替尼(oclacitinib)、非戈替尼(filgotinib)、甘多替尼(gandotinib)、来他替尼(lestaurtinib)、莫莫替尼(momelotinib)、巴克瑞替尼(bacritinib)、PF-04965842、乌帕替尼(upadacitinib)、培非替尼(peficitinib)、非德替尼(fedratinib)、葫芦素I(cucurbitacin I)、ATI-501(Aclaris)、ATI-502(Aclaris)、JTE052(Leo Pharma和Japan Tobacco)或CHZ868。
在一些实施方案中,JAK1和/或JAK2的抑制剂可为同位素标记化合物或其药学上可接受的盐。“同位素”或“放射性标记”化合物为其中一个或多个原子经原子质量或质量数不同于在自然界中通常发现(即天然存在)的原子质量或质量数的原子置换或取代的本公开化合物。可掺入本公开的化合物中的合适放射性核素包括但不限于2H(氘又写成D)、3H(氚又写成T)、11C、13C、14C、13N、15N、15O、17O、18O、18F、35S、36Cl、82Br、75Br、76Br、77Br、123I、124I、125I和131I。举例来说,本公开的化合物中的一个或多个氢原子可被氘原子置换,例如-CD3取代成-CH3。
本文所述的化合物的一个或多个组成原子可经天然或非天然丰度的原子同位素置换或取代。在一些实施方案中,化合物包括至少一个氘原子。在一些实施方案中,化合物包括两个或更多个氘原子。在一些实施方案中,化合物包括1-2个、1-3个1-4个、1-5个或1-6个氘原子。在一些实施方案中,化合物中的所有氢原子均可被氘原子置换或取代。
用于同位素包括于有机化合物中的合成方法为本领域中已知(DeuteriumLabeling in Organic Chemistry,Alan F.Thomas(New York,N.Y.,Appleton-Century-Crofts,1971;The Renaissance of H/D Exchange,Jens Atzrodt,Volker Derdau,Thorsten Fey和Jochen Zimmermann,Angew.Chem.Int.Ed.2007,7744-7765;The OrganicChemistry of Isotopic Labelling,James R.Hanson,Royal Society of Chemistry,2011)。同位素标记化合物可用于多种研究,例如NMR光谱学、代谢实验和/或分析法。
经例如氘的重同位素取代可提供由更大代谢稳定性产生的某些治疗优点,例如体内半衰期延长或剂量需求减少,由此在一些情况下可为优选。(参见例如A.Kerekes等人J.Med.Chem.2011,54,201-210;R.Xu等人J.Label Compd.Radiopharm.2015,58,308-312)。具体地说,在一个或多个代谢位点处的取代可提供所述治疗优点中的一个或多个。
因此,在一些实施方案中,JAK1和/或JAK2的抑制剂为其中化合物中的一个或多个氢原子被氘原子置换的化合物,或其药学上可接受的盐。
在一些实施方案中,JAK1和/或JAK2的抑制剂为其中一个或多个氢原子被氘原子置换的鲁索利替尼,或其药学上可接受的盐。在一些实施方案中,JAK1和/或JAK2的抑制剂为美国专利9249149(其以引用的方式整体并入本文中)中的任一化合物或其药学上可接受的盐。在一些实施方案中,JAK1和/或JAK2的抑制剂为CTP-543或其药学上可接受的盐。
在一些实施方案中,化合物为式I化合物:
或其药学上可接受的盐,其中:
R1选自H和D;
每个R2独立地选自H和D,条件为连接于共同碳的每个R2相同;
每个R3独立地选自H和D,条件为连接于共同碳的每个R3相同;
R4选自H和D;
每个R5相同且选自H和D;并且
R6、R7和R8各独立地选自H和D;条件为当R1为H,每个R2和每个R3为H,R4为H,并且R6、R7和R8各为H时,每个R5为D。
在一些实施方案中,JAK1和/或JAK2的抑制剂为选自下表中以下化合物100-130的式I化合物(其中R6、R7和R8各为H)或其药学上可接受的盐。在一些实施方案中,JAK1和/或JAK2的抑制剂为选自下表中以下化合物200-231的式I化合物(其中R6、R7和R8各为D)或其药学上可接受的盐。
在一些实施方案中,JAK1和/或JAK2的抑制剂为其中一个或多个氢原子被氘原子置换的巴瑞克替尼,或其药学上可接受的盐。在一些实施方案中,JAK1和/或JAK2的抑制剂为美国专利9540367(其以引用的方式整体并入本文中)中的任一化合物或其药学上可接受的盐。
如本文所用,短语“任选地取代”意指未取代或取代。如本文所用,术语“取代”意指去除氢原子并且被取代基置换。应了解既定原子上的取代受价数限制。
如本文所用,单独或与其它术语组合使用的术语“Cn-m烷基”是指可为直链或支链的具有n至m个碳原子的饱和烃基。在一些实施方案中,烷基含有1至6个或1至3个碳原子。烷基部分的实例包括(但不限于)例如以下的化学基团: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、2-甲基-1-丁基、3-戊基、正己基、1,2,2-三甲基丙基等等。
如本文所用,单独或与其它术语组合使用的术语“亚烷基”是指可为支链或直链的二价烷基连接基团,其中两个取代基可连接在亚烷基连接基团的任何位置。亚烷基的实例包括(但不限于)乙-1,2-二基、丙-1,3-二基、丙-1,2-二基等等。
如本文所用,术语“HO-C1-3烷基”是指式-亚烷基-OH的基团,其中所述亚烷基具有1至3个碳原子。
如本文所用,术语“CN-C1-3烷基”是指被氰基取代的C1-3烷基。
如本文所用,术语“氨基”是指式-NH2的基团。
如本文所用,术语“二(C1-3烷基)氨基”是指式-N(烷基)2的基团,其中两个烷基各独立地具有1至3个碳原子。
如本文所用,术语“C1-3烷基氨基”是指式-NH(烷基)的基团,其中烷基具有1至3个碳原子。
如本文所用,术语“二(C1-3烷基)氨基磺酰基”是指式-S(O)2N(烷基)2的基团,其中各烷基各独立地具有1至3个碳原子。
如本文所用,术语“C1-3烷基磺酰基”是指式-S(O)2-基团的基团,其中烷基具有1至3个碳原子。
如本文所用,单独或与其它术语组合使用的“卤基”或“卤素”包括氟、氯、溴和碘。在一些实施方案中,卤基为氟基或氯基。
如本文所用,单独或与其它术语组合使用的术语“Cn-m卤烷基”是指具有至多{2(n至m)+1}个可相同或不同的卤素原子的Cn-m烷基。在一些实施方案中,卤素原子为氟原子。在一些实施方案中,烷基具有1-6个或1-3个碳原子。卤烷基实例包括CF3、C2F5、CHF2、CCl3、CHCl2、C2Cl5等等。在一些实施方案中,卤烷基为氟烷基。
如本文所用,术语“C1-3氟烷基”是指可部分或完全被氟原子取代的C1-3烷基。
如本文所用,单独或与其它术语组合使用的术语“C3-6环烷基”是指具有3-6个碳原子的非芳香族单环烃部分,其可任选地含有一个或多个亚烯基作为环结构的一部分。环烷基的一个或多个成环碳原子可氧化形成羰基键。例示性C3-6环烷基包括环丙基、环丁基、环戊基、环己基、环戊烯基、环己烯基、环已二烯基等等。在一些实施方案中,环烷基为环丙基、环丁基、环戊基或环己基。
如本文所用,术语“C3-6环烷基-C1-3烷基”是指式-C1-3亚烷基-C3-6环烷基的基团。
本文所述的化合物可为不对称的(例如具有一个或多个立构中心)。除非另外指示,否则意图例如对映异构体和非对映异构体的所有立体异构体。含有经不对称取代的碳原子的化合物可以呈光学活性或消旋形式分离。本领域中已知从光学上不活跃的起始物质制备光学活性形式的方法,例如通过拆分外消旋混合物或通过立体选择性合成。烯烃、C=N双键等等的许多几何异构体也可以存在于本文所述的化合物中,并且本申请中涵盖所有此类稳定异构体。描述本申请化合物的顺式与反式几何异构体并且可以呈异构体混合物或呈分开异构体形式分离。在一些实施方案中,化合物具有(R)-构型。在一些实施方案中,化合物具有(S)-构型。
化合物的外消旋混合物的拆分可以通过本领域中已知的许多方法中的任一种进行。一示例方法包括使用作为光学活性的成盐有机酸的手性拆分酸进行分步结晶。适用于分步结晶法的拆分剂为例如光学活性酸,例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或多种光学活性樟脑磺酸(例如β-樟脑磺酸)的D和L形式。其它适合于分步结晶法的拆分剂包括α-甲基苯甲胺的立体异构纯形式(例如S和R形式,或非对映异构纯形式)、2-苯基甘胺醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1,2-二氨基环己烷等等。
外消旋混合物的拆分还可以通过在填充光学活性拆分剂(例如二硝基苯甲酰基苯基甘氨酸)的柱上洗脱来进行。合适洗脱溶剂组成可由本领域的技术人员决定。
本文所述的化合物包括互变异构形式。互变异构形式由单键与相邻双键交换同时伴随质子迁移产生。互变异构形式包括质子转移互变异构体,其为具有相同经验式和总电荷的异构质子化状态。质子转移互变异构体实例包括酮-烯醇对、酰胺-亚氨酸对、内酰胺-内酰亚胺对、烯胺-亚胺对和其中质子可占据杂环系统的两个或更多个位置的环状形式,例如1H-咪唑和3H-咪唑、1H-1,2,4-三唑、2H-1,2,4-三唑和4H-1,2,4-三唑、1H-异吲哚和2H-异吲哚以及1H-吡唑和2H-吡唑。互变异构形式可处于平衡或通过适当取代而在空间上锁定成一种形式。举例来说,将认识到以下吡唑环可形成两种互变异构体:
意图权利要求书涵盖两种互变异构体。
可发现所有化合物和其药学上可接受的盐与例如水和溶剂的其它物质(例如水合物和溶剂化物)一起,或可分离。
在一些实施方案中,本文所述的化合物或其盐基本上分离。“基本上分离”意指化合物至少部分或基本上与形成或检测到其的环境分离。部分分离可包括例如富集本文所述的化合物的组合物。基本上分离可包括含有至少约50重量%、至少约60重量%、至少约70重量%、至少约80重量%、至少约90重量%、至少约95重量%、至少约97重量%或至少约99重量%本文所述的化合物或其盐的组合物。用于分离化合物和其盐的方法是本领域中常规的。
本文中短语“药学上可接受”用以指在合理医学判断范围内,适合与人类和动物的组织接触使用,无过度毒性、刺激、过敏反应或其它问题或并发症,与合理利益/风险比相称的那些化合物、物质、组合物和/或剂型。
如本文所用的表述“周围温度”和“室温”为本领域中所了解,并且一般是指温度,例如反应温度约为进行反应的房间的温度,例如约20℃至约30℃。
本申请还包括本文所述的化合物的药学上可接受的盐。如本文所用,“药学上可接受的盐”是指所公开化合物的衍生物,其中母体化合物通过将所存在的酸或碱部分转变成其盐形式而改性。药学上可接受的盐的实例包括(但不限于)例如胺的碱性残余物的无机酸盐或有机酸盐;例如羧酸的酸性残余物的碱盐或有机盐;等等。本申请的药学上可接受的盐包括例如由无毒无机酸或有机酸形成的母体化合物的常规无毒盐。本申请的药学上可接受的盐可以通过常规化学方法由含有碱性或酸性部分的母体化合物合成。一般来说,此类盐可以通过使这些化合物的游离酸或游离碱形式与化学计算量的适当碱或酸在水中或有机溶剂中或两者的混合物中反应来制备;一般来说,非水性介质,如乙醚、乙酸乙酯、醇(例如甲醇、乙醇、异丙醇或丁醇)或乙腈(ACN)是优选的。合适盐的清单见于Remington'sPharmaceutical Sciences,第17版,Mack Publishing Company,Easton,Pa.,1985,第1418页和Journal of Pharmaceutical Science,66,2(1977),各以引用的方式整体并入本文中。
如本文所用,术语“接触”是指在体外系统或体内系统中使所指示部分在一起。举例来说,JAK与本发明的化合物“接触”包括向例如人类的具有JAK的个体或患者施用本申请的化合物,以及例如将本发明的化合物引入含有含JAK的细胞或纯化制剂的样品中。
如本文所用,术语“受试者”、“个体”或“患者”可互换使用,是指任何动物,包括哺乳动物,优选为小鼠、大鼠、其它啮齿动物、兔、犬、猫、猪、牛、羊、马或灵长类动物,并且最优选为人类。在一些实施方案中,“受试者”、“个体”或“患者”需要所述治疗。
在一些实施方案中,抑制剂以治疗有效量施用。如本文所用,短语“治疗有效量”是指活性化合物或药剂引起由研究员、兽医、医学博士或其它临床医师在组织、系统、动物、个体或人类中所寻求的生物或医学反应的量。
如本文所用,术语“治疗(treating)”或“治疗(treatment)”是指以下中一种或多种:(1)抑制疾病;例如抑制正经历或展示疾病、疾患或病症的病变或症状的个体中的疾病、疾患或病症(即阻止病变和/或症状进一步发展);(2)改善疾病;例如,改善正经历或展示疾病、疾患或病症的病变或症状的个体中的疾病、疾患或病症(即逆转病变和/或症状),例如降低疾病的严重度;或(3)预防易患所述疾病、疾患或病症但尚未经历或显示疾病的病变或症状的个体中的疾病、疾患或病症。在一些实施方案中,治疗是指抑制或改善疾病。在一些实施方案中,治疗是预防疾病。
组合疗法
本文所述的方法还可包括施用一种或多种其它治疗剂。一种或多种其它治疗剂可同时或依次施用于患者。
在一些实施方案中,其它治疗剂为抗生素。在一些实施方案中,所述抗生素为克林霉素(clindamycin)、强力霉素(doxycycline)、米诺环素(minocycline)、甲氧苄啶(trimethoprim)-磺胺甲异噁唑(sulfamethoxazole)、红霉素(erythromycin)、甲硝唑(metronidazole)、利福平(rifampin)、莫西沙星(moxifloxacin)、达普松(dapsone)或它们的组合。在一些实施方案中,抗生素为克林霉素、强力霉素、米诺环素、甲氧苄啶-磺胺甲基异噁唑或红霉素与甲硝唑组合。在一些实施方案中,抗生素为利福平、莫西沙星和甲硝唑的组合。在一些实施方案中,抗生素为莫西沙星与利福平的组合。
在一些实施方案中,其它治疗剂为类视色素。在一些实施方案中,所述类视色素为阿维A酯(etretinate)、阿维A(acitretin)或异维A酸(isotretinoin)。
在一些实施方案中,其它治疗剂为类固醇。在一些实施方案中,其它治疗剂为皮质类固醇。在一些实施方案中,所述类固醇为例如去炎松(triamcinolone)、地塞米松(dexamethasone)、氟轻松(fluocinolone)、可的松(cortisone)、泼尼松(prednisone)、泼尼松龙(prednisolone)或氟米龙(flumetholone)。
在一些实施方案中,其它治疗剂为抗TNF-α剂。在一些实施方案中,所述抗TNF-α剂为抗TNF-α抗体。在一些实施方案中,抗TNF-α剂为英夫利昔单抗(infliximab)或依那西普(etanercept)或阿达木单抗(adalimumab)。
在一些实施方案中,其它治疗剂为免疫抑制剂。在一些实施方案中,所述免疫抑制剂为甲氨蝶呤(methotrexate)或环孢菌素A。在一些实施方案中,免疫抑制剂为霉酚酸酯(mycophenolate mofetil)或霉酚酸钠(mycophenolate sodium)。
在一些实施方案中,其它治疗剂为非那雄胺(finasteride)、二甲双胍(metformin)、阿达帕林(adapalene)或杜鹃花酸(azelaic acid)。
在一些实施方案中,所述方法还包括施用选自IMiD、抗IL-6剂、降低甲基化剂和生物反应调节剂(BRM)的其它治疗剂。
一般地,BRM为由活生物体制成用于治疗疾病的物质,其在体内天然存在,或可在实验室中制成。BRM的实例包括IL-2、干扰素、各种类型的集落刺激因子(CSF、GM-CSF、G-CSF)、单克隆抗体(例如阿昔单抗(abciximab)、依那西普、英夫利昔单抗、利妥昔单抗、曲妥珠单抗(trasturzumab))和高剂量抗坏血酸。
在一些实施方案中,降低甲基化剂为DNA甲基转移酶抑制剂。在一些实施方案中,DNA甲基转移酶抑制剂选自5-氮杂胞苷(5azacytidine)和地西他滨(decitabine)。
一般地,IMiD作为免疫调节剂。在一些实施方案中,IMiD选自沙利度胺(thalidomide)、来那度胺(lenalidomide)、泊马度胺(pomalidomide)、CC-11006和CC-10015。
在一些实施方案中,所述方法还包括施用选自以下的其它治疗剂:抗胸腺细胞球蛋白、重组人类粒细胞集落刺激因子(G CSF)、粒细胞-单核细胞CSF(GM-CSF)、红血球生成刺激剂(ESA)和环孢霉素(cyclosporine)。
在一些实施方案中,所述方法还包括向患者施用其它JAK抑制剂。在一些实施方案中,其它JAK抑制剂为巴瑞替尼、托法替尼、奥拉替尼、非戈替尼、甘多替尼、来他替尼、莫莫替尼、巴克瑞替尼、PF-04965842、乌帕替尼、培非替尼、非德替尼、葫芦素I或CHZ868。
一种或多种其它医药,例如消炎剂、免疫抑制剂以及PI3Kδ、mTor、Bcr-Abl、Flt-3、RAF和FAK激酶抑制剂,例如WO 2006/056399(其以引用的方式整体并入本文中)中所述的那些抑制剂,或其它剂,可与本文所述的化合物组合使用,用于治疗JAK相关的疾病、病症或疾患。一种或多种其它医药可同时或依次施用患者。
Bcr-Abl抑制剂的实例包括美国专利No.5,521,184、WO 04/005281和美国序列号60/578,491(均以引用的方式整体并入本文中)中公开的种类的化合物和其药学上可接受的盐。
合适Flt-3抑制剂的实例包括如WO 03/037347、WO 03/099771和WO 04/046120(均以引用的方式整体并入本文中)中公开的化合物和其药学上可接受的盐。
合适RAF抑制剂的实例包括如WO 00/09495和WO 05/028444(均以引用的方式整体并入本文中)中公开的化合物和其药学上可接受的盐。
合适FAK抑制剂的实例包括如WO 04/080980、WO 04/056786、WO 03/024967、WO01/064655、WO 00/053595和WO 01/014402(均以引用的方式整体并入本文中)中公开的化合物和其药学上可接受的盐。
在一些实施方案中,一种或多种本发明的化合物可与一种或多种其它激酶抑制剂,包括伊马替尼(imatinib)组合使用,特别用于治疗对伊马替尼或其它激酶抑制剂有抗性的患者。
在一些实施方案中,其它治疗剂选自DehydrexTM(Holles Labs)、西韦酰胺(Civamide)(Opko)、透明质酸钠(Vismed,Lantibio/TRB Chemedia)、环孢霉素(ST-603,Sirion Therapeutics)、ARG101(T)(睾丸激素,Argentis)、AGR1012(P)(Argentis)、依卡倍特钠(ecabet sodium)(Senju-Ista)、吉法酯(gefarnate)(Santen)、15-(s)-羟基二十碳四烯酸(15(S)-HETE)、西维美林(cevilemine)、强力霉素(ALTY-0501,Alacrity)、米诺环素、iDestrinTM(NP50301,Nascent Pharmaceuticals)、环孢霉素A(Nova22007,Novagali)、氧四环素(耐久霉素,MOLI1901,Lantibio)、CF101(2S,3S,4R,5R)-3,4-二羟基-5-[6-[(3-碘苯基)甲基氨基]嘌呤-9-基]-N-甲基-氧杂环戊烷-2-氨甲酰基,Can-Fite Biopharma)、伏环孢素(voclosporin)(LX212或LX214,Lux Biosciences)、ARG103(Agentis)、RX-10045(合成消退素类似物,Resolvyx)、DYN15(Dyanmis Therapeutics)、利格列酮(rivoglitazone)(DE011,Daiichi Sanko)、TB4(RegeneRx)、OPH-01(Ophtalmis Monaco)、PCS101(PericorScience)、REV1-31(Evolutec)、催泪蛋白(Lacritin)(Senju)、瑞巴帕特(rebamipide)(Otsuka-Novartis)、OT-551(Othera)、PAI-2(University of Pennsylvania and TempleUniversity)、匹鲁卡品(pilocarpine)、他克莫司(tacrolimus)、吡美莫司(pimecrolimus)(AMS981,Novartis)、依碳酸氯替泼诺(loteprednol etabonate)、利妥昔单抗、地夸磷索四钠(diquafosol tetrasodium)(INS365,Inspire)、KLS-0611(Kissei Pharmaceuticals)、去氢表雄甾酮、阿那白滞素(anakinra)、依法珠单抗(efalizumab)、霉酚酸钠、依那西普羟氯奎、NGX267(TorreyPines Therapeutics)、雅美罗(actemra)、吉西他滨(gemcitabine)、奥沙利铂(oxaliplatin)、L-天冬酰胺酶或沙利度胺。
在一些实施方案中,其它治疗剂为抗血管生成剂、胆碱能激动剂、TRP-1受体调节剂、钙通道阻断剂、粘蛋白促分泌素、MUC1刺激剂、钙调磷酸酶抑制剂、皮质类固醇、P2Y2受体激动剂、蕈毒受体激动剂、mTOR抑制剂、另一JAK抑制剂、Bcr-Abl激酶抑制剂、Flt-3激酶抑制剂、RAF激酶抑制剂和FAK激酶抑制剂,例如以引用的方式整体并入本文中的WO 2006/056399中所述的那些抑制剂。在一些实施方案中,其它治疗剂为四环素衍生物(例如米诺环素或强力霉素)。在一些实施方案中,其它治疗剂结合于FKBP12。
在一些实施方案中,其它治疗剂为烷基化剂或DNA交联剂;抗代谢物/去甲基剂(例如5-氟尿嘧啶(5-flurouracil)、卡培他滨(capecitabine)或阿扎胞苷(azacitidine));抗激素疗法(例如激素受体拮抗剂、SERM或芳香酶抑制剂);有丝分裂抑制剂(例如长春新碱(vincristine)或太平洋紫杉醇(paclitaxel));拓扑异构酶(I或II)抑制剂(例如米托蒽醌(mitoxantrone)和伊立替康(irinotecan));细胞凋亡诱导剂(例如ABT-737);核酸疗法(例如反义或RNAi);核受体配体(例如激动剂和/或拮抗剂:所有反式视黄酸或贝沙罗汀(bexarotene));表观遗传靶向剂,例如组蛋白去乙酰酶抑制剂(例如伏瑞斯特(vorinostat))、降低甲基化剂(例如地西他滨);蛋白质稳定性调节剂,例如Hsp90抑制剂、泛素和/或类泛素结合或解聚分子;或EGFR抑制剂(埃罗替尼(erlotinib))。
在一些实施方案中,其它治疗剂包括抗生素、抗病毒剂、抗真菌剂、麻醉剂、消炎剂(包括类固醇和非类固醇消炎剂)和抗过敏剂。合适药剂的实例包括氨基糖苷类,例如阿米卡星(amikacin)、庆大霉素(gentamycin)、托普霉素(tobramycin)、链霉素(streptomycin)、奈替米星(netilmycin)和卡那霉素(kanamycin);喹诺酮类,例如环丙沙星(ciprofloxacin)、诺氟沙星(norfloxacin)、氧氟沙星(ofloxacin)、曲氟沙星(trovafloxacin)、洛美沙星(lomefloxacin)、左氧氟沙星(levofloxacin)和依诺沙星(enoxacin);萘啶;磺酰胺;多粘菌素(polymyxin);氯霉素(chloramphenicol);新霉素(neomycin);巴龙霉素(paramomycin);甲磺酸粘菌素(colistimethate);杆菌肽(bacitracin);万古霉素(vancomycin);四环素;利福平和其衍生物(“利福平类”);环丝氨酸;β-内酰胺;头孢菌素(cephalosporin);两性霉素(amphotericin);氟康唑(fluconazole);氟胞嘧啶(flucytosine);游霉素(natamycin);霉康唑(miconazole);酮康唑(ketoconazole);皮质类固醇;双氯芬酸(diclofenac);氟比洛芬(flurbiprofen);酮洛酸(ketorolac);舒洛芬(suprofen);色甘酸(cromolyn);洛度沙胺(lodoxamide);左卡巴斯汀(levocabastin);萘唑啉;安他唑啉(antazoline);非尼拉敏(pheniramine);或氮杂内酯(azalide)抗生素。
药物制剂和剂型
当用作药物时,本发明的化合物可以呈药物组合物形式施用。这些组合物可以用制药领域众所周知的方式制备,并且可以通过多种途径施用,取决于需要局部还是全身治疗和待治疗的区域。施用可以是局部(包括经皮、表皮、经眼和粘膜,包括鼻内、阴道和直肠递送)、肺(例如通过吸入或吹入粉末或气雾剂,包括通过喷雾器;气管内或鼻内)、经口或不经肠。不经肠施用包括静脉内、动脉内、皮下、腹膜内、肌肉内施用或注射或输注;或颅内,例如鞘内或心室内施用。不经肠施用可以呈单次推注剂量形式,或可以例如通过连续灌注泵。用于局部施用的药物组合物和制剂可以包括经皮贴片、软膏、洗剂、乳膏、凝胶、滴剂、栓剂、喷雾、液体和粉剂。常规药物载体、水性、粉末或油性基剂、增稠剂等等可为需要或合乎需要的。
在一些实施方案中,施用是局部施用。在一些实施方案中,施用是局部施用至皮肤。
在一些实施方案中,施用是经口施用。
本发明还包括药物组合物,其含有本发明的化合物或其药学上可接受的盐作为活性成分,以及一种或多种药学上可接受的载体(赋形剂)。在一些实施方案中,组合物适合于局部施用。在制造本发明的组合物时,活性成分通常与赋形剂混合,被赋形剂稀释,或装入此类载体内,呈例如胶囊、药囊、纸剂或其它容器形式。当赋形剂充当稀释剂时,其可以是固体、半固体或液体物质,充当活性成分的媒介物、载体或介质。因此,组合物可以呈含有例如至多10重量%的活性化合物的片剂、丸剂、粉剂、糖锭、药囊、扁囊剂、酏剂、悬浮液、乳液、溶液、糖浆、气雾剂(呈固体形式或于液体介质中)、软膏、软和硬明胶胶囊、栓剂、无菌可注射溶液和无菌包装粉剂的形式。
在制备制剂时,活性化合物在与其它成分组合前可被研磨,以提供适当的粒度。如果活性化合物基本上不溶,那么其可以研磨至小于200目的粒度。如果活性化合物基本上溶于水,那么粒度可以通过研磨来调整以在制剂中基本上均匀分布,例如约40目。
本发明的化合物可以使用已知的研磨程序,例如湿磨来研磨,以获得适合于片剂形成和其它制剂类型的粒度。本发明化合物的细粉状(纳米颗粒)制剂可以通过本领域中已知的方法制备,例如参见国际申请No.WO 2002/000196。
合适赋形剂的一些实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、褐藻酸盐、黄芪胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。制剂可另外包括:润滑剂,例如滑石、硬脂酸镁和矿物油;润湿剂;乳化剂和悬浮剂;防腐剂,例如甲基-和丙基羟基-苯甲酸酯;甜味剂;和调味剂。通过采用本领域中已知的程序,本发明的组合物可以被配制成使活性成分在施用患者之后快速、持续或延迟释放。
在一些实施方案中,药物组合物包含硅化微晶纤维素(SMCC)和至少一种本文所述的化合物或其药学上可接受的盐。在一些实施方案中,硅化微晶纤维素包含约98%微晶纤维素和约2%二氧化硅w/w。
在一些实施方案中,组合物为包含至少一种本文所述的化合物或其药学上可接受的盐和至少一种药学上可接受的载体的持续释放组合物。在一些实施方案中,组合物包含至少一种本文所述的化合物或其药学上可接受的盐和至少一种选自微晶纤维素、乳糖单水合物、羟丙基甲基纤维素和聚氧化乙烯的组分。在一些实施方案中,组合物包含至少一种本文所述的化合物或其药学上可接受的盐和微晶纤维素、乳糖单水合物和羟丙基甲基纤维素。在一些实施方案中,组合物包含至少一种本文所述的化合物或其药学上可接受的盐和微晶纤维素、乳糖单水合物和聚氧化乙烯。在一些实施方案中,组合物还包含硬脂酸镁或二氧化硅。在一些实施方案中,微晶纤维素为Avicel PH102TM。在一些实施方案中,乳糖单水合物为Fast-flo 316TM。在一些实施方案中,羟丙基甲基纤维素为羟丙基甲基纤维素2208K4M(例如Methocel K4 MPremierTM)和/或羟丙基甲基纤维素2208K100LV(例如MethocelK00LVTM)。在一些实施方案中,聚氧化乙烯为聚氧化乙烯WSR 1105(例如Polyox WSR1105TM)。
在一些实施方案中,湿式造粒工艺用于产生组合物。在一些实施方案中,干式造粒工艺用于产生组合物。
组合物可以呈单位剂型配制,每个剂量含有约1至约1,000mg、约1mg至约100mg、约1mg至约50mg和约1mg至10mg活性成分。优选地,剂量为约1mg至约50mg或约1mg至约10mg活性成分。在一些实施方案中,每个剂量含有约10mg活性成分。在一些实施方案中,每个剂量含有约50mg活性成分。在一些实施方案中,每个剂量含有约25mg活性成分。术语“单位剂型”是指适合呈单一剂量用于人类受试者和其它哺乳动物的物理离散单元,每个单元含有经计算以产生所需治疗效果的预定量的活性物质以及合适药物赋形剂。
在一些实施方案中,组合物包含约1至约1,000mg、约1mg至约100mg、1mg至约50mg和约1mg至10mg活性成分。优选地,组合物包含约1mg至约50mg或约1mg至约10mg活性成分。本领域的一般技术人员将了解此具体化为含有约1mg至约10mg、约1mg至约20mg、约1mg至约25mg、约1mg至约50mg活性成分的化合物或组合物。
在一些实施方案中,化合物或其药学上可接受的盐的剂量为以游离碱计15mg、30mg、60mg或90mg。在一些实施方案中,化合物4或其药学上可接受的盐的剂量为以游离碱计15mg、30mg、60mg或90mg。在一些实施方案中,化合物或其药学上可接受的盐的剂量为以游离碱计15mg。在一些实施方案中,化合物或其药学上可接受的盐的剂量为以游离碱计30mg。在一些实施方案中,化合物或其药学上可接受的盐的剂量为以游离碱计60mg。在一些实施方案中,化合物或其药学上可接受的盐的剂量为以游离碱计90mg。
活性化合物可在宽剂量范围内有效,并且一般以药学上有效量施用。然而,应了解,化合物事实上施用的量通常将由医师根据有关环境来决定,包括待治疗的疾患、所选施用途径、实际施用的化合物、个别患者的年龄、体重和反应、患者症状的严重度等等。
为了制备例如片剂的固体组合物,主要活性成分与药物赋形剂混合,形成含有本申请化合物的均匀混合物的固体预配制组合物。当称这些预配制组合物为均质时,活性成分通常均匀分散在组合物中,以便组合物容易再分成同等有效的单位剂型,例如片剂、丸剂和胶囊。接着此固体预配制剂再分成含有例如约0.1mg至约1000mg本申请的活性成分的上述类型的单位剂型。
本申请的片剂或丸剂可以包覆包衣或以另外方式混配,得到提供长期作用的益处的剂型。举例来说,片剂或丸剂可以包含内部配药组分和外部配药组分,后者呈在前者上的包膜形式。两种组分可以被肠层隔开,所述肠层用于对抗在胃中崩解,并且允许内部组分完整地进入十二指肠或延迟释放。多种物质可用于此类肠层或包衣,此类物质包括许多聚合酸和聚合酸与例如虫胶、鲸蜡醇和乙酸纤维素的混合物。
可并入本申请的化合物和组合物以经口施用或注射的液体形式包括水溶液、经适当调味的糖浆、水性或油性悬浮液和经食用油(例如棉籽油、芝麻油、椰子油或花生油)调味的乳液,以及酏剂和类似药物媒介物。
用于吸入或吹入的组合物包括药学上可接受的水性或有机溶剂中的溶液和悬浮液或其混合物,以及粉剂。液体或固体组合物可以含有如上所述的合适药学上可接受的赋形剂。在一些实施方案中,组合物通过经口或经鼻呼吸途径施用以实现局部或全身作用。组合物可以通过使用惰性气体喷雾。喷雾溶液可以直接从喷雾装置呼吸,或者喷雾装置可以附连至面罩、帐或间歇性正压呼吸机。溶液、悬浮液或粉剂组合物可以经口或经鼻从以适当方式递送制剂的装置施用。
局部制剂可以含有一种或多种常规载体。在一些实施方案中,软膏可以含有水和一种或多种选自例如液体石蜡、聚氧乙烯烷基醚、丙二醇、白凡士林等等的疏水性载体。乳膏的载体组合物可基于水与甘油和一种或多种其它组分(例如单硬脂酸甘油酯、PEG-单硬脂酸甘油酯和鲸蜡硬脂醇)组合。凝胶可使用异丙醇和水,适当地与例如甘油、羟乙基纤维素等等的其它组分组合来配制。在一些实施方案中,局部制剂含有至少约0.1wt%、至少约0.25wt%、至少约0.5wt%、至少约1wt%、至少约2wt%或至少约5wt%的本发明化合物。局部制剂可例如以100g适当包装在管内,管任选地与关于治疗例如牛皮癣或其它皮肤疾患的所选适应症的说明书相联。
化合物或组合物施用至患者的量将视所施用的物品、施用目的(例如预防或治疗)、患者状态、施用方式等等而变。在治疗应用中,组合物可以足够治愈或至少部分阻止疾病和其并发症的症状的量施用至已罹患疾病的患者。有效剂量将视所治疗的疾病疾患以及主治医师视例如疾病严重度、患者年龄、体重和整体状况等因素进行判断而定。
向患者施用的组合物可以呈上述药物组合物形式。这些组合物可以通过常规灭菌技术来灭菌,或可无菌过滤。水溶液可以包装成原样使用,或冻干,冻干制剂在施用前与无菌水性载体组合。化合物制剂的pH值通常将在3与11之间,更优选5至9且最优选7至8。应了解某些上述赋形剂、载体或稳定剂的使用将形成药物盐。
本申请化合物的治疗剂量可根据例如具体的治疗用途、化合物的施用方式、患者的健康和状况和处方医师的判断变化。药物组合物中本发明化合物的比例或浓度可以视包括剂量、化学特性(例如疏水性)和施用途径的许多因素而变化。举例来说,本发明的化合物可提供于含有约0.1%w/v至约10%w/v化合物的水性生理缓冲溶液中,以不经肠施用。一些典型剂量范围为每日每公斤体重约1μg至约1g。在一些实施方案中,剂量范围为每日每公斤体重约0.01mg至约100mg。剂量很可能视例如疾病或病症的类型和进展程度、具体患者的整体健康状态、所选化合物的相对生物效力、赋形剂的配制和其施用途径的变量而定。可从来源于体外或动物模型测试系统的剂量反应曲线外推有效剂量。
本发明的组合物还可以包括一种或多种其它药物,所述药物的实例列于上文中。
药盒
本申请还包括药盒,其可用于例如治疗和/或预防细胞因子相关的疾病或病症,例如CRS,所述药盒包括一个或多个含有包含治疗有效量的本文所述的化合物的药物组合物的容器。必要时,此类药盒还可以包括多种常规药盒组件中的一种或多种,例如具有一种或多种药学上可接受的载体的容器、额外容器等,如本领域技术人员显而易知。药盒中还可以包括作为插页或作为标签的说明书,所述说明书指示组分的施用量、施用准则和/或组分混合准则。
实施例
本发明将通过特定的实施例更详细地描述。提供以下实施例以达成说明的目的,并且不意图以任何方式限制本发明。本领域的技术人员将容易识别多个非关键参数,这些参数可以变化或修改,结果基本上相同。
实施例A:体外JAK激酶测定
根据Park等人,Analytical Biochemistry 1999,269,94-104中描述的以下体外测定,测试可用于治疗细胞因子相关的疾病或病症的JAK1抑制剂对JAK标靶的抑制活性。在昆虫细胞中使用杆状病毒表达具有N端His标签的人类JAK1(a.a.837-1142)、JAK2(a.a.828-1132)和JAK3(a.a.781-1124)的催化结构域且纯化。通过测量生物素化肽的磷酸化来测定JAK1、JAK2或JAK3的催化活性。磷酸化肽通过均相时间分辨荧光(HTRF)检测。在40μL反应物中测量化合物对每种激酶的IC50,所述反应物在具有100mM NaCl、5mM DTT和0.1mg/mL(0.01%)BSA的50mM Tris(pH 7.8)缓冲液中含有所述酶、ATP和500nM肽。对于1mMIC50测量,反应物中的ATP浓度为1mM。反应在室温下进行1小时,接着在测定缓冲液(PerkinElmer,Boston,MA)中用20μL 45mM EDTA、300nM SA-APC、6nM Eu-Py20终止。与铕标记的抗体的结合进行40分钟,并且在Fusion板式读数器(Perkin Elmer,Boston,MA)上测量HTRF信号。在此测定中测试表1中的化合物并显示具有表1中的IC50值。
实施例B:JAK1和/或JAK2抑制剂在患有中度至重度化脓性汗腺炎的受试者中的安全性和功效研究
在年龄为18-75岁的患有中度(赫尔利(Hurley)II期)至重度(赫尔利III期)化脓性汗腺炎的男性和女性中进行随机化、双盲、安慰剂对照的多中心研究,历时至少6个月。赫尔利I期与脓肿形成(单个或多个)相关,无窦道和瘢痕形成。赫尔利II期与复发性脓肿有关,形成窦道和形成瘢痕;单处或多处广泛分开的损害。赫尔利III期与整个区域上弥漫性或近弥漫性受累或多个互连窦道和脓肿有关。研究参与者随机化成5组(每组约50个参与者)并且用15mg、30mg、60mg或90mg JAK1和/或JAK2的抑制剂(例如鲁索利替尼、化合物4或化合物5或其药学上可接受的盐)或者安慰剂处理。在第16周(主要终点),安慰剂组中的参与者同等地再随机化至主动处理组,历时8周。维持盲法。主要终点为第16周实现化脓性汗腺炎临床反应(HiSCR)的受试者的比例。
次要终点包括:(1)每次就诊时患有HiSCR的受试者相比于基线的比例;(2)每次就诊时获得0至2的脓肿和炎性结节(AN)计数的受试者的比例;(3)每次就诊时HS疼痛数字等级量表1)中相对于基线的平均变化;(4)第16周和第24周修改版赛多利斯量表(Sartoriusscale)的变化;(5)每次就诊时排液瘘管计数的数目的变化;(6)至第24周需要损害拯救处理的受试者的比例;(7)至第24周损害拯救处理的事件的数目;(8)JAK1和/或JAK2的抑制剂的群体PK(例如表观清除、表观分布容积);(9)通过监测AE的频率、持续时间和严重度、身体检查、生命征象以及血液学、血清化学和尿分析的实验室数据评定的安全性和可耐受性;(10)皮肤病生活质量指数(DLQI)评定的变化;(11)每次就诊时如通过IHS43评分所评定的疾病严重度相对于基线的变化;(12)每次就诊时化脓性汗腺炎生活质量(HiSQOL)评定相比于基线的变化;以及(13)在治疗期期间就功效和安全性终点来说剂量/暴露反应相对于基线的变化百分比的评定。
HiSCR被定义为在第16周时,相对于基线,脓肿和炎性结节(AN)计数减少至少50%,脓肿计数未增加并且排液瘘管计数未增加。疼痛数字等级量表用于评定由HS引起的最坏皮肤和平均皮肤疼痛。2个项目的评级在0(皮肤无疼痛)至10(皮肤疼痛至你能想象得那么剧烈)范围内。通过参与者,在其上床前并且基于“之前24小时”的回忆期,在日记上记录评定。修改版赛多利斯量表用于定量HS严重度。分数给与12个身体区域(左和右腋窝、左和右乳腺下/乳房下区域、乳房间区域、左和右臀部、、左和右腹股沟皱襞、肛周、会阴和其它)分数:分数给与结节(各2分);脓肿(4分);瘘管(4分);疤痕(1分);和两个损害之间的最长距离(2-6分,如果没有损害,那么为0);和损害是否由正常皮肤分开(是-0分;否-6分)。总赛多利斯量表为12个区域分数的和。损害拯救处理:如果急剧疼痛的损害需要立即介入,那么医师选择进行拯救介入。只允许两类介入:(1)损害内注射去炎松缩酮(triamcinoloneacetonide)悬浮液(同一次就诊时总计至多30mg)和/或(2)切开并且排脓。介入可以在同一次就诊时最大两个不同损害上或在两次不同研究就诊时同一损害上进行。在同一次就诊时同一损害不可处理两次。如果在第16周前受试者需要超过两次介入,那么其中止研究。国际化脓性汗腺炎严重度评分系统(IHS4):IH4(分)=(结节数目×1)+(脓肿数目×2)+(排泄道[瘘管/窦]数目×4)。轻度HS:≤3分;中度HS:4-10分;重度HS:≥11分。
研究处理1(活性剂)包括含有15mg 4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺的口服片剂。给药水平包括15mg(1个片剂)、30mg(2个片剂)、60mg(4个片剂)和90mg(6个片剂)。研究处理2(安慰剂)包括口服片剂安慰剂。
至少在第2周、第12周、第16周、第20周和第24周在施用研究药物前后在给药前、给药后1小时和给药后2-5小时的时间点取用于测量JAK1和/或JAK2的抑制剂的血浆浓度的血液样品。如果在第8周前受试者中止,那么在过早中止就诊时,收集谷PK样品(可行的话)。还记录前一次剂量施用的日期/时间。
使用霍赫伯格程序(Hochberg procedure),在总体2侧α=0.05水平下,进行JAK1和/或JAK2的抑制剂在90mg、60mg、30mg和15mg下与安慰剂相比的优势测试。用逻辑回归进行在第16周每个活性剂组与安慰剂之间的比较。在所有剂量水平下,优势测试为显著的(例如HiSCR(化脓性汗腺炎临床反应)提高10%、20%、30%、40%或50%)且证明JAK1和/或JAK2的抑制剂治疗HS的功效。测试展示与安慰剂相比结节减少和无劣势/优势。
使用描述统计学评估所有次要和探索性功效量度。使用描述统计学分析临床安全性数据(生命征象、常规实验室测试和AE)。确定血浆JAK1和/或JAK2抑制剂PK暴露与功效/安全性数据之间的暴露-反应(E-R)关系。当至少一半随机化受试者到达第16周时,进行中期分析以估计治疗反应和推动未来研究计划。
实施例C.角化细胞中干扰素-γ和肿瘤坏死-α诱发的Janus激酶表达和随后炎性介质的产生
转化人类角化细胞(HaCaT)购自AddexBio(目录号T0020001)并且在补充有10%胎牛血清(Hyclone,目录号16140-071)和1x青霉素(Penicillin)/链霉素(Streptomycin)(Gibco,目录号15140-122)的优化达尔伯克改良伊格尔培养基(Optimized Dulbecco’sModified Eagle’s Medium)(AddexBio,目录号C0003-02)中培养。当细胞达到80%-90%汇合时,将其用1x DPBS洗涤,接着通过与0.25%胰蛋白酶(Gibco,目录号25200-056)一起在37℃/5%CO2下孵育3-5分钟,从组织培养烧瓶分离。将细胞培养基加入至经过胰蛋白酶处理的细胞,接着将细胞悬浮液转移至无菌15mL离心管,在1300rpm下短暂离心10分钟。从细胞团块吸出含有胰蛋白酶的培养基,接着使团粒再悬浮在10mL细胞培养基中。使用Countess II自动化细胞计数器计数细胞,并且以4×104个细胞/毫升的浓度接种至经过组织培养基处理的24孔板,并且在37℃/5%CO2下孵育48小时。48小时之后,去除培养基并且替换为500uL细胞培养基或者重组人类干扰素γ(R&D Systems,目录号285-IF-100)与重组人类肿瘤坏死因子α(R&DSystems,目录号210-TA-020)的组合刺激。用组合细胞因子刺激处理的HaCaT细胞以10ng/mL、25ng/mL、50ng/mL或100ng/mL每种细胞因子的最终浓度处理。通过和缓搅动将经过处理的板混合30秒,接着在37℃/5%CO2下孵育24小时。在24小时孵育结束时,立即从每个盘去除培养基。
使用QuantiGene Plex测定试剂和方案(Affymetrix,目录号QGP-232-M18042302)从HaCaT细胞分离RNA。将细胞用1x DPBS洗涤,接着通过与所提供的QuantiGene溶解缓冲液一起在50-55℃下孵育30分钟而溶解。将细胞溶解产物与被设计成与来自所关注的标靶的mRNA特异性杂交的捕获珠粒和探针组一起在55℃下孵育18-24小时。这组32个所关注的标靶包括用于将结果归一化的看家基因。孵育18-24小时之后,利用支链DNA法,根据制造商的程序(Affymetrix,目录号QGP-232-M18042302),放大信号。在杂交和洗涤步骤之后,在Luminex 200上读取测定板并且数据可以表示为净中值荧光强度。接着数据相对于看家基因HPRT1的净中值荧光强度归一化(表2)。
表2.用TNFα和IFNγ刺激人类角化细胞诱发JAK/STAT通路和促炎性细胞因子
使用ProCarta Multiplex免疫测定试剂和方案(Invitrogen,目录号EPX450-12171-901)检测和定量培养基中所关注的标靶蛋白。将培养基与抗体共轭的珠粒一起孵育,所述抗体共轭的珠粒被设计成结合于特异性标靶蛋白的表位并且通过珠粒特殊的光谱图鉴定结合的蛋白。将生物素化的检测抗体和抗生蛋白链菌素-PE加入至测定板中以定量标靶蛋白的量,所述生物素化的检测抗体被设计成结合于相同标靶蛋白的不同表位。在Luminex 200上读取测定板并且数据可以表示为净中值荧光强度。将根据制造商的程序(Invitrogen,目录号EPX450-12171-901)制备的抗原标准曲线的净中值荧光强度值相对于每种标准的预期浓度绘图。从抗原标准曲线推断每种蛋白质的浓度并且浓度可以表示为pg/mL(表3)。
表3.用TNFα和IFNγ刺激人类角化细胞诱发促炎性细胞因子产生
实施例D.Janus激酶抑制剂干扰角化细胞中干扰素-γ和肿瘤坏死-α介导的炎症
转化人类角化细胞(HaCaT)购自AddexBio(目录号T0020001)并且如实施例C中所概述来培养。将四种化合物A-D(A:鲁索利替尼,B:伊它替尼(itacitinib)({1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈),C:4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺,D:((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈)在DMSO中复原,接着将每种化合物用细胞培养基连续稀释至400nM、200nM、100nM和50nM浓度。48小时之后,从24孔板去除细胞培养基并且替换为250uL含有连续稀释的药物的培养基,接着在37℃/5%CO2下孵育15分钟。药物孵育之后,将250uL含有重组人类干扰素γ(R&D Systems,目录号285-IF-100)与重组人类肿瘤坏死因子α(R&D Systems,目录号210-TA-020)的组合刺激加入至平板中。重组人类干扰素γ和重组人类肿瘤坏死因子α的最终浓度为25ng/mL每种细胞因子。加入至含有药物的孔中的细胞因子刺激使每种药物处理的最终浓度为25nM、50nM、100nM和200nM。通过和缓搅动将经过处理的平板混合30秒,接着在37℃/5%CO2下孵育24小时。在24小时孵育结束时,立即从每个平板去除培养基。
使用QuantiGene Plex测定试剂和方案(Affymetrix,目录号QGP-232-M18042302),根据制造商的指南,从HaCaT细胞分离RNA。将细胞用1x DPBS洗涤,接着通过与所提供的QuantiGene溶解缓冲液一起在50-55℃下孵育30分钟而溶解。将细胞溶解产物与被设计成与来自所关注的标靶的mRNA特异性杂交的捕获珠粒和探针组一起在55℃下孵育18-24小时。基因包括用于将结果归一化的看家基因(例如HPRT1、GAPDH)。孵育18-24小时之后,利用支链DNA法,根据制造商的程序(Affymetrix,目录号QGP-232-M18042302),放大信号。在杂交和洗涤步骤之后,在Luminex 200上读取测定板并且数据可以表示为净中值荧光强度。接着数据相对于看家基因HPRT1的净中值荧光强度归一化(表4)。
表4.在JAK抑制剂存在/缺乏下用TNFα和IFNγ刺激的人类角化细胞中标靶基因的归一化表达
图1-4分别说明在用TNFα和IFN-γ刺激的角化细胞中在JAK抑制剂存在/缺乏下每个重复实验的JAK1、JAK2、IL-1α和IL-6的单独的基因表达值(MFI)。
使用ProCarta Multiplex免疫测定试剂和方案(Invitrogen,目录号EPX450-12171-901)检测和定量培养基中所关注的标靶蛋白。将培养基与抗体共轭的珠粒一起孵育,所述抗体共轭的珠粒被设计成结合于特异性标靶蛋白的表位并且通过珠粒特殊的光谱图鉴定结合蛋白。将生物素化的检测抗体和抗生蛋白链菌素-PE加入至测定板中以定量标靶蛋白的量,所述生物素化的检测抗体被设计成结合于相同标靶蛋白的不同表位。在Luminex 200上读取测定板并且数据可以表示为净中值荧光强度。将根据制造商的程序(Invitrogen,目录号EPX450-12171-901)制备的抗原标准曲线的净中值荧光值相对于每种标准的预期浓度绘图。从抗原标准曲线推断每种蛋白质的浓度并且浓度可以表示为pg/mL(表5)。
表5.在JAK抑制剂存在/缺乏下由用TNFα和IFNγ刺激的人类角化细胞产生的炎性介质的浓度
图5和图6分别说明在用TNFα和IFN-γ刺激的角化细胞中在JAK抑制剂存在/缺乏下每个重复实验的IL-1α和IL-6的单独的蛋白质浓度(pg/mL)。
实施例E:化脓性汗腺炎皮肤活检的特征是增加的Janus激酶表达来自3个单一供体的健康对照皮肤总RNA购自Amsbio(目录号HR101和R1234218-50)。来自一池供体的健康对照皮肤总RNA购自Life Technologies公司(目录号QS0639)。化脓性汗腺炎皮肤活检(41个供体)购自Discovery Life Sciences,其呈福尔马林固定-石蜡包埋的(FFPE)块,从中纯化总RNA。
针对表6中所概述的基因,使用QuantiGene Plex测定试剂和方案(LifeTechnologies公司,目录号QGP-277-M19012402)测量健康对照(n=4)和化脓性汗腺炎(n=41)皮肤总RNA样品的基因表达。使用在50ng至500ng的推荐测定范围内的纯化RNA,并且与被设计成与来自所选基因(表6)的mRNA特异性杂交的捕获珠粒一起孵育过夜。这组标靶包括用于将结果归一化的几种看家基因。在孵育过夜之后,使用支链DNA法,根据制造商的程序(Life Technologies公司)放大信号。在Luminex 200上读取测定板并且数据可以表示为净中值荧光强度(净MFI)。数据相对于看家基因ACTB和GAPDH的净MFI的几何平均值归一化。图7-9示出健康对照者和患有化脓性汗腺炎的受试者的皮肤中JAK1、JAK3、TYK2、STAT1、STAT2、STAT3、IRAK1、IRAK2和IRAK4的基因表达。
表6.标靶基因
除本文中描述的内容外,本领域的技术人员从以上描述将显而易见本发明的多种修改。意图此类修改也在随附权利要求书的范围内。本申请中引用的每篇参考文献,包括所有专利、专利申请和公布,均以引用的方式整体并入本文中。
综上所述,本发明包括但不限于以下技术项:
1.一种治疗有需要的患者的化脓性汗腺炎的方法,所述方法包括向所述患者施用治疗有效量的抑制JAK1和/或JAK2的化合物或其药学上可接受的盐,其中所述化合物为:
鲁索利替尼;
鲁索利替尼,其中一个或多个氢原子被氘原子置换;
{1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
4-{3-(氰基甲基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-N-[4-氟-2-(三氟甲基)苯基]哌啶-1-甲酰胺;
[3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-1-(1-{[2-(三氟甲基)嘧啶-4-基]羰基}哌啶-4-基)氮杂环丁烷-3-基]乙腈;
4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺;
((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈;
3-[1-(6-氯吡啶-2-基)吡咯烷-3-基]-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈;
3-(1-[1,3]噁唑并[5,4-b]吡啶-2-基吡咯烷-3-基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈;
4-[(4-{3-氰基-2-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙基}哌嗪-1-基)羰基]-3-氟苯甲腈;
4-[(4-{3-氰基-2-[3-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡咯-1-基]丙基}哌嗪-1-基)羰基]-3-氟苯甲腈;
[反式-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-3-(4-{[2-(三氟甲基)嘧啶-4-基]羰基}哌嗪-1-基)环丁基]乙腈;
{反式-3-(4-{[4-[(3-羟基氮杂环丁烷-1-基)甲基]-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-{[(2S)-2-(羟基甲基)吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-{[(2R)-2-(羟基甲基)吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
4-(4-{3-[(二甲基氨基)甲基]-5-氟苯氧基}哌啶-1-基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丁腈;
5-{3-(氰基甲基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-N-异丙基吡嗪-2-甲酰胺;
4-{3-(氰基甲基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺;
5-{3-(氰基甲基)-3-[4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-N-异丙基吡嗪-2-甲酰胺;
{1-(顺式-4-{[6-(2-羟基乙基)-2-(三氟甲基)嘧啶-4-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-[(乙基氨基)甲基]-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-(1-羟基-1-甲基乙基)-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-{[(3R)-3-羟基吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-{[(3S)-3-羟基吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{反式-3-(4-{[4-({[(1S)-2-羟基-1-甲基乙基]氨基}甲基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-({[(2R)-2-羟基丙基]氨基}甲基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-({[(2S)-2-羟基丙基]氨基}甲基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-(2-羟基乙基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
或上述任一化合物的药学上可接受的盐。
2.如技术项1所述的方法,其中相比于JAK3和TYK2,所述化合物或盐对JAK1和JAK2具选择性。
3.如技术项2所述的方法,其中所述化合物为鲁索利替尼或其药学上可接受的盐。
4.如技术项3所述的方法,其中所述化合物为鲁索利替尼或其药学上可接受的盐,其中一个或多个氢原子被氘原子置换。
5.如技术项3所述的方法,其中所述盐为鲁索利替尼磷酸盐。
6.如技术项1所述的方法,其中相比于JAK2、JAK3和TYK2,所述化合物或盐对JAK1具选择性。
7.如技术项6所述的方法,其中所述化合物为{1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈或其药学上可接受的盐。
8.如技术项7所述的方法,其中所述盐为{1-{1-[3-氟-2-(三氟甲基)异烟酰基]哌啶-4-基}-3[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈己二酸盐。
9.如技术项6所述的方法,其中所述化合物为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺或其药学上可接受的盐。
10.如技术项9所述的方法,其中所述盐为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺磷酸盐。
11.如技术项6所述的方法,其中所述化合物为((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈或其药学上可接受的盐。
12.如技术项6所述的方法,其中所述化合物为((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈单水合物。
13.如技术项7-12中任一项所述的方法,其中所述化合物或盐以按游离碱计15mg、30mg、60mg或90mg的剂量施用。
14.如技术项1-13中任一项所述的方法,所述方法还包括施用其它治疗剂。
15.如技术项14所述的方法,其中所述其它治疗剂为抗生素、类视色素、皮质类固醇、抗TNF-α剂或免疫抑制剂。
16.如技术项15所述的方法,其中所述抗生素为克林霉素、强力霉素、米诺环素、甲氧苄啶-磺胺甲异噁唑、红霉素、甲硝唑、利福平、莫西沙星、达普松或它们的组合。
17.如技术项15所述的方法,其中所述类视色素为阿维A酯、阿维A或异维A酸。
18.如技术项15所述的方法,其中所述皮质类固醇为去炎松、地塞米松、氟轻松、可的松、泼尼松、泼尼松龙或氟米龙。
19.如技术项15所述的方法,其中所述抗TNF-α剂为英夫利昔单抗、依那西普或阿达木单抗。
20.如技术项15所述的方法,其中所述免疫抑制剂为甲氨蝶呤、环孢菌素A、霉酚酸酯或霉酚酸钠。
21.如技术项14所述的方法,其中所述其它治疗剂为非那雄胺、二甲双胍、阿达帕林或杜鹃花酸。
22.如技术项1-21中任一项所述的方法,其中所述化合物或盐的所述施用是局部施用。
23.如技术项1-21中任一项所述的方法,其中所述化合物或盐的所述施用是经口施用。
24.如技术项1-23中任一项所述的方法,其中所述方法使HiSCR(化脓性汗腺炎临床反应)提高10%、20%、30%、40%或50%。
Claims (22)
1.一种治疗有需要的患者的化脓性汗腺炎的方法,所述方法包括向所述患者施用治疗有效量的抑制JAK1的化合物或其药学上可接受的盐,其中所述化合物为:
R2为C1-6烷基、C1-6卤烷基、C3-6环烷基或C3-6环烷基-C1-3烷基,其中所述C1-6烷基、C3-6环烷基和C3-6环烷基-C1-3烷基各任选地经1个、2个或3个独立选自氟、-CF3和甲基的取代基取代;
R3为H或甲基;
R4为H、F或Cl;
R5为H或F;
R6为H或F;
R7为H或F;
R8为H或甲基;
R9为H或甲基;
R10为H或甲基;并且
R11为H或甲基;
((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈;
3-[1-(6-氯吡啶-2-基)吡咯烷-3-基]-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈;
3-(1-[1,3]噁唑并[5,4-b]吡啶-2-基吡咯烷-3-基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈;
4-[(4-{3-氰基-2-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙基}哌嗪-1-基)羰基]-3-氟苯甲腈;
4-[(4-{3-氰基-2-[3-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡咯-1-基]丙基}哌嗪-1-基)羰基]-3-氟苯甲腈;
[反式-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-3-(4-{[2-(三氟甲基)嘧啶-4-基]羰基}哌嗪-1-基)环丁基]乙腈;
{反式-3-(4-{[4-[(3-羟基氮杂环丁烷-1-基)甲基]-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-{[(2S)-2-(羟基甲基)吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-{[(2R)-2-(羟基甲基)吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
4-(4-{3-[(二甲基氨基)甲基]-5-氟苯氧基}哌啶-1-基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丁腈;
5-{3-(氰基甲基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-N-异丙基吡嗪-2-甲酰胺;
4-{3-(氰基甲基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺;
5-{3-(氰基甲基)-3-[4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-1-基}-N-异丙基吡嗪-2-甲酰胺;
{1-(顺式-4-{[6-(2-羟基乙基)-2-(三氟甲基)嘧啶-4-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-[(乙基氨基)甲基]-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-(1-羟基-1-甲基乙基)-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-{[(3R)-3-羟基吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{1-(顺式-4-{[4-{[(3S)-3-羟基吡咯烷-1-基]甲基}-6-(三氟甲基)吡啶-2-基]氧基}环己基)-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈;
{反式-3-(4-{[4-({[(1S)-2-羟基-1-甲基乙基]氨基}甲基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-({[(2R)-2-羟基丙基]氨基}甲基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-({[(2S)-2-羟基丙基]氨基}甲基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
{反式-3-(4-{[4-(2-羟基乙基)-6-(三氟甲基)吡啶-2-基]氧基}哌啶-1-基)-1-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]环丁基}乙腈;
或上述任一化合物的药学上可接受的盐。
2.根据权利要求1所述的方法,其中相对于JAK2、JAK3和TYK2,所述化合物或盐对JAK1具有选择性。
4.根据权利要求3所述的方法,其中所述化合物为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺或其药学上可接受的盐。
5.根据权利要求3所述的方法,其中所述盐为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺磷酸盐。
6.根据权利要求3所述的方法,其中所述盐为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺盐酸盐。
7.根据权利要求3所述的方法,其中所述盐为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺氢溴酸盐。
8.根据权利要求3所述的方法,其中所述盐为4-[3-(氰基甲基)-3-(3',5'-二甲基-1H,1'H-4,4'-联吡唑-1-基)氮杂环丁烷-1-基]-2,5-二氟-N-[(1S)-2,2,2-三氟-1-甲基乙基]苯甲酰胺硫酸盐。
9.根据权利要求1所述的方法,其中所述化合物为((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈或其药学上可接受的盐。
10.根据权利要求1所述的方法,其中所述化合物为((2R,5S)-5-{2-[(1R)-1-羟基乙基]-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-1-基}四氢-2H-吡喃-2-基)乙腈单水合物。
11.根据权利要求1所述的方法,其中所述化合物或盐以按游离碱计15mg、30mg、60mg或90mg的剂量施用。
12.根据权利要求1所述的方法,所述方法还包括施用其它治疗剂。
13.根据权利要求12所述的方法,其中所述其它治疗剂为抗生素、类视色素、皮质类固醇、抗TNF-α剂或免疫抑制剂。
14.根据权利要求13所述的方法,其中所述抗生素为克林霉素、强力霉素、米诺环素、甲氧苄啶-磺胺甲异噁唑、红霉素、甲硝唑、利福平、莫西沙星、达普松或它们的组合。
15.根据权利要求13所述的方法,其中所述类视色素为阿维A酯、阿维A或异维A酸。
16.根据权利要求13所述的方法,其中所述皮质类固醇为去炎松、地塞米松、氟轻松、可的松、泼尼松、泼尼松龙或氟米龙。
17.根据权利要求13所述的方法,其中所述抗TNF-α剂为英夫利昔单抗、依那西普或阿达木单抗。
18.根据权利要求13所述的方法,其中所述免疫抑制剂为甲氨蝶呤、环孢菌素A、霉酚酸酯或霉酚酸钠。
19.根据权利要求12所述的方法,其中所述其它治疗剂为非那雄胺、二甲双胍、阿达帕林或杜鹃花酸。
20.根据权利要求1-19中任一项所述的方法,其中所述化合物或盐的所述施用是局部施用。
21.根据权利要求1-19中任一项所述的方法,其中所述化合物或盐的所述施用是经口施用。
22.根据权利要求1-19中任一项所述的方法,其中所述方法使HiSCR(化脓性汗腺炎临床反应)提高10%、20%、30%、40%或50%。
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CO2020013600A2 (es) | 2021-01-18 |
CN113768934A (zh) | 2021-12-10 |
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JP2021519775A (ja) | 2021-08-12 |
CN112423759A (zh) | 2021-02-26 |
TW202310843A (zh) | 2023-03-16 |
AU2019245420A1 (en) | 2020-11-12 |
MA52219A (fr) | 2021-02-17 |
TW202002967A (zh) | 2020-01-16 |
IL302865A (en) | 2023-07-01 |
PE20210402A1 (es) | 2021-03-02 |
BR112020019814A2 (pt) | 2021-01-05 |
IL277538A (en) | 2020-11-30 |
WO2019191684A1 (en) | 2019-10-03 |
PH12020551597A1 (en) | 2021-08-16 |
MX2020010322A (es) | 2022-11-30 |
JP2024026074A (ja) | 2024-02-28 |
US11304949B2 (en) | 2022-04-19 |
US20220241286A1 (en) | 2022-08-04 |
EP3773593A1 (en) | 2021-02-17 |
UA127925C2 (uk) | 2024-02-14 |
KR20210018203A (ko) | 2021-02-17 |
EA202092343A1 (ru) | 2021-01-20 |
CA3095487A1 (en) | 2019-10-03 |
ECSP20069416A (es) | 2020-12-31 |
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CL2020002512A1 (es) | 2021-01-29 |
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