CN116283963A - 一种高效詹纳斯激酶1选择性抑制剂 - Google Patents
一种高效詹纳斯激酶1选择性抑制剂 Download PDFInfo
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Abstract
本发明描述的是吡咯并[2,3‑b]吡啶衍生物、它们作为詹纳斯激酶1(JAK1)选择性抑制剂的用途以及包含他们的药物组合物。
Description
技术领域
本发明提供两种药学活性的吡咯并[2,3-b]吡啶类金刚烷衍生化合物。此类化合物可用于抑制詹纳斯激酶(JAK)，尤其是詹纳斯激酶1(JAK1)。本发明亦涉及包含此类化合物的组合物和制备此类化合物的方法，以及用于治疗和预防由JAK尤其是JAK1介导的病症的方法。
背景技术
JAK-STAT(Janus kinase-signal transducer and activator oftranscription)信号通路是一组脊椎动物中普遍存在的信号通路，许多细胞因子包括：IFN家族(IFN-α、IFN-β、IFN-ω、Limitin、IFN-γ、IL-10、IL-19、IL-20、IL-22)；gp130家族(IL-6、IL-11、OSM、LIF、CNTF、NNT-1/BSF-3、G-CSF、CT-1、Leptin、IL-12、IL-23)；γC家族(IL-2、IL-7、TSLP、IL-9、IL-15、IL-21、IL-4、IL-13)；IL-3家族(IL-3、IL-5、GM-CSF)；单链家族(EPO、GH、PRL、TPO)；受体酪氨酸激酶(PDGF、CSF-1、HGF)等都通过该通路传导信号。JAK-STAT信号通路与多种血液性疾病相关，包括但不限于红细胞增多症、血小板增多症、白血病以及骨髓纤维化等，JAK-STAT信号通路还与多种免疫性疾病相关，包括但不限于类风湿关节炎、强直脊柱炎、红斑狼疮、牛皮癣、过敏性皮炎、溃疡性肠炎、斑秃、脱发、干眼病等。因此，JAK-STAT信号通路成为多种血液性相关疾病和自身免疫相关疾病的重要靶点。此外，JAK-STAT信号通路还与器官移植过程中的排异反应相关。
詹纳斯激酶家族包括：JAK1、JAK2、JAK3和TYK2四种，它们在JAK-STAT信号通路的信号转导中起中枢作用，它们通过互相活化然后对下游的STAT(STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b和STAT6)蛋白进行磷酸化，促使STAT蛋白二聚体的形成，STAT蛋白二聚体可识别特定的DNA序列，并调控特定基因的表达。小分子詹纳斯激酶抑制剂可以有效调节JAK-STAT信号通路，是治疗多种血液性相关疾病、自身免疫相关疾病和器官移植排异反应的潜在药物。
詹纳斯激酶在发挥作用的时候，通常由特定类型的细胞因子与其受体相互作用，然后由两个或者多个JAK组合起来对不同的STAT蛋白进行磷酸化，例如IL-27和IL-35与其受体结合后通过JAK1和JAK2的组合对STAT1、STAT3或STAT4进行磷酸化从而实现信号的传导；IL-2、IL-4、IL-7、IL-9、IL-15和IL-21与其受体结合后通过JAK1和JAK3的组合对STAT1、STAT3、STAT5a、STAT5b或STAT6进行磷酸化，从而实现信号的传导；IL-6、IL-10、IL-11、IL-19、IL-20、IL-22和IL-27与其受体结合后通过JAK1、JAK2和TYK2的组合对STAT1、STAT2、STAT3、STAT4或STAT5a、STAT5b进行磷酸化，从而实现信号的传导。JAK1通过与其它JAK蛋白组合对多种细胞因子(尤其是白介素)的信号进行传导，因此，JAK1与机体的免疫息息相关。JAK2是目前所知唯一的能够与其自身组合进行信号传递的詹纳斯激酶，IL-3、IL-5、GM-CSF、红细胞生成素、血小板生成素、粒细胞集落刺激因子、生长激素和瘦蛋白与其受体结合后通过JAK2和JAK2的组合对STAT1、STAT3、STAT5a、STATb或STAT6进行磷酸化，从而实现信号的传导，因此JAK2与血液细胞、骨髓细胞等息息相关。
由于各个JAK的分工不同，JAK1、JAK3和TYK2通常作为免疫相关疾病的作用靶点，而JAK2通常作为血液相关疾病的作用靶点，因此选择性抑制不同的JAK对于治疗特定的JAK-STAT信号通路异常相关疾病尤为重要，例如选择性的抑制JAK1激酶活性可以有效治疗免疫相关疾病或者器官移植排异反应，且同时避免抑制JAK2依赖性的红细胞生成素和血小板生成素的信号传导，从而避免贫血等不良反应的发生。因此开发具有特定JAK的高选择性抑制剂，尤其是JAK1相对于JAK2的高选择性抑制剂有很大的需求。
然而，四种JAK的激酶结构域具有高度的同源性，特别是其活性中心氨基酸残基的同源性非常高，给开发针对特定JAK具有良好选择性的JAK抑制剂带来了极大的挑战。同源对比发现在JAK1激酶结构域的活性中心的966位置的谷氨酸残基分别对应JAK2的939位的天冬氨酸残基、JAK3的912位的天冬氨酸残基以及TYK的988位的天冬氨酸残基，JAK1的966位谷氨酸残基侧链的延伸长度均长于其它JAK对应的天冬氨酸残基。因此，抑制剂可通过正负电荷或氢键与JAK1中的966位谷氨酸残基侧链相互作用并同时不与其它JAK所对应的天冬氨酸侧链发生相互作用从而实现对JAK1的选择性。
发明内容
下述为本文使用的各个术语或符号的定义：
符号
代表连接点。
术语“氘代”指利用氢的同位素氘全部或部分代替化合物中的氢元素。
术语“卤素”指氟、氯、溴或碘。
如果取代基描述为“独立地选自”一组，则每个取代基彼此独立地选择。因此，每个取代基可以与其它取代基相同或不同。
术语“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
术语“可药用的盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
短语“治疗”指减缓与疾病、紊乱或病症有关的症状，或者中止那些症状的进一步发展或恶化。根据患者的疾病和病症，如本文使用的术语“治疗”包括一种或多种治愈性、减缓性和预防性治疗。本发明的化合物也可以与其它药物和治疗剂一起给药。
短语“治疗有效的”指预防或改善疾病的严重性、同时避免了典型地与可替代治疗有关的不良副作用的试剂的能力。短语“治疗有效的”应当理解为相当于短语“用于治疗、预防或改善而言有效的”，两者都旨意于胜任在联合治疗中使用的每种试剂的量，其能够实现改善癌症、心血管疾病或疼痛和炎症的严重性、以及每种试剂本身治疗时发病率的目标，同时避免了典型地与可替代治疗有关的不良副作用。
本发明的化合物，本发明的目的在于提供I、II所示结构的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、及其混合物形式、及其可药用的盐，以及代谢产物和代谢前体或前药。本发明提供I、II所示的化合物结构如下：
或其可药用的盐。
本发明中的化合物的药学上可接受的盐包括含其酸加成盐和碱盐。
合适的酸加成盐是由形成无毒盐的酸形成的。实例包括但不限于：乙酸盐、己二酸盐、天门冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、羟基苯甲酰苯甲酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘化物/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/二氢磷酸盐、焦谷氨酸盐、糖酸盐、硬脂酸盐、琥珀酸盐、丹宁酸盐、酒石酸盐、甲苯磺酸盐、三氟醋酸盐和羟萘甲酸盐等。
合适的碱盐是由形成无毒盐的碱形成的。实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨基丁三醇盐和锌盐。
药物组合：
本发明中的化合物的可药用盐可以通过如下三种方法的一种或多种制备：1.化合物与期望的酸或碱反应；2.使用期望的酸或碱，从化合物的合适的前体除去酸或碱不稳定的保护基，或者使合适的环状前体例如内酯或内酰胺开环；3.与合适的酸或碱反应或利用合适的离子交换柱将化合物的一种盐转化成另一种盐。所有这三个反应都通常是在溶液中进行的。所得盐可以沉淀出和过滤收集或者可通过蒸发溶剂回收。得到的盐中的离子化程度可以由完全电离到几乎不电离不等。
本发明还提供用于治疗或改善多种JAK相关疾病的组合物，其可以通过混合一种或多种本文描述的化合物、或其可药用盐或互变异构体，与可药用载体、赋形剂、粘合剂、稀释剂等制备。本发明的药物组合物可以通过本领域众所周知的方法包括但不限于常规的制粒、混合、溶解、包入胶囊、冻干、乳化或研碎等方法来制备。所述组合物包括但不限于颗粒剂、粉剂、片剂、糖浆剂、栓剂、注射剂、乳剂、酏剂、混悬剂或溶液剂的形式。本发明的组合物可以配制用于多种给药途径，例如口服给药、经粘膜给药、直肠给药、局部给药或皮下给药以及鞘内、静脉内、肌内、腹膜内、鼻内、眼内或心室内注射。本发明的化合物还可以局部给药而不是以全身方式给药。
对于口服、口腔和舌下给药，粉剂、混悬剂、颗粒剂、片剂、丸剂和胶囊是可接受的固体剂型。这些可以例如通过混合发明的一种或多种化合物或其可药用盐或互变异构体与至少一种添加剂或赋形剂比如淀粉或其它添加剂来制备。合适的添加剂或赋形剂包括但不限于蔗糖、乳糖、纤维素糖、甘露醇、麦芽糖醇、葡聚糖、山梨醇、淀粉、琼脂、藻酸盐、壳多糖、壳聚糖、果胶、黄蓍胶、阿拉伯胶、明胶、胶原、酪蛋白、白蛋白、合成或半合成高分子化合物或甘油酯、甲基纤维素和羟丙基甲基纤维素等。任选地，口服剂型可以包含有助于给药的其它组分，比如惰性稀释剂，或润滑剂比如硬脂酸镁，或防腐剂比如对羟基苯甲酸或山梨酸，或抗氧剂比如抗坏血酸、生育酚或半胱氨酸、崩解剂、粘合剂、增稠剂、缓冲剂、甜味剂、调味剂或芳香剂。另外，可以加入染料或颜料进行鉴定。可以用领域已知的合适包衣材料进一步处理片剂和丸剂。
用于口服给药的液体剂型包括但不限于乳剂、糖浆剂、酏剂、混悬剂、浆剂和溶液剂的形式，其可以包含惰性稀释剂比如水。可以使用无菌液体，比如但不限于油、水、醇及其组合将药物制剂制备成液体混悬剂或溶液剂。对于口服或肠胃外给药，可以加入药学合适的表面活性剂、助悬剂或乳化剂。
化合物也可以局部、(皮内)皮下或透皮给药至皮肤或粘膜。用于该目的的的制剂包括但不限于凝胶剂、水凝胶、洗剂、溶液剂、乳膏剂、软膏剂、扑粉、敷料、泡沫、膜剂、皮肤贴剂、糯米纸囊剂、植入物、海绵状物、纤维、绑带和微乳剂。也可以使用脂质体。典型的载体包括醇、水、矿物油、液状石蜡、凡士林、甘油、聚乙二醇和丙二醇。
化合物也可以通过鼻腔给药，药物制剂可以是喷雾剂或气雾剂，其包含合适的溶剂和任选地其它化合物，比如但不限于稳定剂、抗微生物剂、抗氧剂、pH调节剂、表面活性剂、生物利用度调节剂及其组合。用于气雾剂的推进剂可以包括压缩空气、氮气、二氧化碳或烃基低沸点溶剂。
可注射的剂型通常包括水性混悬剂或油性混悬剂，其可以使用合适的分散剂或润湿剂和助悬剂来制备。可注射的形式可以在溶液相中，或者是混悬剂的形式，其是用溶剂或稀释剂制备的。可接受的溶剂或赋形剂包括无菌水、林格溶液或等渗的盐水溶液。可选地，无菌油类可以用作溶剂或助悬剂。通常，所述油或脂肪酸是非挥发性的，包括天然的或合成的油、脂肪酸、甘油单酯、甘油二酯或甘油三酯。
对于直肠给药，药物制剂可以是栓剂、软膏剂、灌肠剂、片剂或乳膏剂的形式，其在肠道、乙状结肠曲或直肠释放化合物。直肠栓剂是通过混合一种或多种发明的化合物、或所述化合物的可药用盐或互变异构体，和可接受的赋形剂例如可可脂或聚乙二醇来制备，其在正常贮存温度下为固相，在适于在体内比如在直肠中释放药物的温度下为液相。在制备软明胶类型的制剂和栓剂中也可以采用油类。在制备混悬剂制剂中可以施用水、生理盐水、含水右旋糖和相关糖溶液、和甘油，所述制剂也可以包含助悬剂比如果胶、卡波姆、甲基纤维素、羟丙基纤维素或羧甲基纤维素，以及缓冲剂和防腐剂。
发明的组合物也可以包括例如胶束或脂质体或其它包囊形式，或者可以以延长释放形式给药以提供延期储存或递送效应。因此，药物制剂可以压制成颗粒状物或圆柱状物，可以肌内或皮下植入，作为储库型注射剂或作为植入物比如支架。这样的植入物可以采用已知的物质，比如硅酮和可生物降解的聚合物。
所述组合物可以包含例如约0.1％重量到约90％以上重量的活性物质，取决于给药方法。当组合物包括剂量单位时，每个单位可以包含例如约0.1至500mg以上的活性成分。如对于成年人治疗采用的剂量可以为例如约0.1至1000mg/天，取决于给药途径和给药频率。
具体剂量可以根据JAK相关疾病的情况、受试者的年龄、体重、一般健康状况、性别和饮食、给药间隔、给药途经、排泄速率和药物组合来调节。包含有效量的任何上述剂型都在常规实验的范围内，因此，都在本发明的范围之内。通常，总日剂量可以典型地为约1mg/kg/天至约500mg/kg/天，单剂量或分剂量给予。典型地，用于人类的剂量可以为约5mg至约100mg/天，单剂量或多剂量给予。治疗有效剂量或数量可以根据给药途径和剂型变化。
JAK抑制剂的药物制剂，本发明中的化合物或与一种或多种另外的试剂组合，所述另外的试剂可以包括，但不限于环孢素A、雷帕霉素、他克莫司、西罗莫司、依维莫司、硫唑嘌呤、布喹那、脱氧精胍菌素、来氟米特、阿司匹林、扑热息痛、布洛芬、萘普生、吡罗昔康、甲氨蝶呤、抗炎性类固醇(例如泼尼松龙或地塞米松)等。这些组合可以作为同一或独立的剂型给药，经由相同或不同的给药途径，并且符合标准药物实践的相同或不同给药时间表。
治疗方法：
在一个实施方案中，发明提供治疗或预防受试者中与JAK1相关的疾病的方法，其包括向受试者给药有效量的一种或多种本文描述的化合物，所述受试者比如哺乳动物，即人类或非人类哺乳动物。所述JAK相关疾病可以与JAK1相关。可以治疗的合适的非人类受试者包括驯养动物或野生动物、陪伴动物，比如狗和猫等。在一个实施方案中，所述化合物以可药用形式给药，任选地在可药用载体中。
JAK/STAT信号与许多免疫反应异常的调节有关，例如：关节炎、哮喘、脱发、糖尿病、某些眼部疾病、炎症、过敏、肠炎、变态反应或疾病、银屑病、移植排斥。如下更详细地讨论可以从JAK1的抑制得益的疾病。
在一些实施方案中，发明的方法和组合物涵盖治疗结缔组织和关节疾病包括但不限于：关节炎、类风湿关节炎、幼年型关节炎、青少年关节炎、牛皮癣性关节炎、椎关节炎、强直脊柱炎、腱炎和滑囊炎、腰椎关节病等结缔组织或关节疾病。
在一些实施方案中，发明的方法和组合物涵盖治疗皮肤或毛发相关疾病包括但不限于：过敏性皮炎、皮肤瘙痒、痤疮、青春痘、酒渣鼻、红斑狼疮、天疱疮、牛皮癣、脱发、斑秃等。
在一些实施方案中，发明的方法和组合物涵盖治疗疾病包括但不限于：溃疡性肠炎、克罗恩病、溃疡性结肠炎、直肠炎、哮喘、鼻炎、花粉过敏、干眼病、葡萄膜炎、角膜炎、I型糖尿病、多发硬化自身免疫性脑脊髓炎、自身免疫性睾丸炎、古德帕斯彻病、交感性眼炎/以及器官移植排异反应等。
附图说明
图1:以实施例1为例的促进毛发生长实验效果,分别在给药当天、第10天、第20天、第25天和第30天的效果。图中为8周龄的C57小鼠背部剃毛然后将其分组，采用右半身涂抹的方法，对小鼠进行间隔24小时的涂抹给药，药水为含2％的实施例中的化合物的DMSO溶液，空白对照组仅为DMSO溶液，不含任何实施例中的化合物。
具体实施方法
化学合成：
除非在以下实施例中另有说明，否则在以下实施例中使用的试剂、起始材料和溶剂购自商业供应商(例如Aldrich、Fluka、Sigma等)，并且无需另外纯化即可使用。
实施实例：
实施例1：
步骤a：氮气保护下，在100ml圆底烧瓶中加入1(1.0g,2.6mmol)，4-氨基金刚烷醇(2.57g，26mmol)加热至180℃反应2小时，随后冷却至室温加水淬灭，水层用二氯甲烷萃取。将合并的有机物用水和盐水洗涤，并随后用无水硫酸钠干燥，过滤并浓缩，将得到的残余物经硅胶色谱用甲醇/二氯甲烷(1:50)纯化，得到2.2g(84％，纯度>98％)的白色固体3。1HNMR(500MHz,Chloroform-d)δ8.19(s,1H),8.03(d,J＝8.0Hz,2H),7.56-7.48(m,1H),7.26(d,J＝8.0Hz,2H),6.51-6.46(m,1H),5.41–5.32(m,1H),4.06(d,J＝7.5Hz,1H),2.37(s,3H),2.32(s,1H),2.27–2.17(m,2H),1.94–1.67(m,9H),1.65-1.61(m,1H),1.55-1.49(m,1H).13CNMR(126MHz,Chloroform-d)δ147.85,146.20,146.14,145.14,143.56,143.43,135.13,129.55,128.15,123.46,123.33,108.62,108.57,104.04,103.93,102.38,102.33,67.34,67.22,60.43,56.17,55.67,45.09,45.00,44.05,39.08,35.42,35.17,34.08,29.81,29.43,29.38,21.66。
步骤b：氮气保护下，在50ml圆底烧瓶中依次将3(0.9g,2mmol)，吡唑频哪醇硼酯(0.78g,4mmol)，碳酸钾(1.1g,8mmol)及四三苯基膦钯(0.11g,0.1mmol)加入1，4-二氧六环(20ml)在120℃下搅拌24小时。随后冷却至室温，加水淬灭，用二氯甲烷萃取。将合并的有机物用水和盐水洗涤，并随后用无水硫酸钠干燥，过滤并浓缩，将得到的残余物经硅胶色谱用甲醇/二氯甲烷(1:20)纯化，得到0.35g(80％，纯度>98％)的白色固体4。1H NMR(500MHz,DMSO-d6)δ13.19(s,1H),8.00-7.93(m,3H),7.81(s,1H),7.69–7.61(m,2H),7.41(d,J＝8.0Hz,2H),6.69(d,J＝4.0Hz,1H),5.23(d,J＝7.5Hz,1H),4.52(s,1H),3.98(d,J＝7.5Hz,1H),2.35(s,3H),2.04(s,2H),1.95(s,1H),1.79(d,J＝11.5Hz,2H),1.65–1.56(m,4H),1.43(d,J＝13.0Hz,2H),1.33(d,J＝13.0Hz,2H).13C NMR(126MHz,DMSO-d6)δ147.42,144.65,144.54,143.85,137.64,134.19,129.25,127.06,122.48,113.54,108.77,106.36,104.54,64.79,54.66,44.48,42.99,32.79,29.04,28.19,20.47。
步骤c:氮气保护下，在20ml圆底烧瓶中将4(1g,2.3mmol)和氢氧化钾(0.16g，2.9mmol)溶于甲醇(5ml)在45℃下搅拌5小时。随后冷却至室温，过滤，用少量冷甲醇及冰水洗涤，得到0.58g(89％，纯度>99％)的白色固体5。1HNMR(500MHz,DMSO-d6)δ13.11(s,1H),11.29(s,1H),7.94(s,1H),7.74(s,1H),7.67(s,1H),7.19(d,J＝3.0Hz,1H),6.38(d,J＝3.0Hz,1H),5.08(d,J＝8.0Hz,1H),4.52(s,1H),4.09(d,J＝7.5Hz,1H),2.11(s,2H),1.97(s,1H),1.80(d,J＝11.5Hz,2H),1.69–1.58(m,4H),1.49(d,J＝12.5Hz,2H),1.35(d,J＝12.5Hz,2H).13C NMR(126MHz,DMSO-d6)δ150.19,144.54,144.38,138.88,127.77,122.95,116.08,105.88,105.72,99.64,65.98,55.96,45.63,44.39,34.21,30.23,29.37.HPLC tR＝2.61min,purity 96.3％.HRMS(ESI)m/z:[M+H]+Calcd for C20H24N5O 350.1903；Found350.1910。
实施例2：
以吡咯频哪醇硼酯代替吡唑频哪醇硼酯,步骤b,c操作与实例1同，得到0.51g(91％，纯度>99％)的白色固体6。1HNMR(500MHz,DMSO-d6)δ11.20(s,1H),8.04(s,1H),7.10(d,J＝3.0Hz,1H),6.71(d,J＝3.0Hz,1H),6.56–6.53(m,1H),6.50(d,J＝3.6Hz,1H),6.16(dd,J＝2.4,1.6Hz,1H),4.52(s,1H),4.09(d,J＝7.5Hz,1H),2.11(s,2H),1.97(s,1H),1.80(d,J＝11.5Hz,2H),1.69–1.58(m,4H),1.49(d,J＝12.5Hz,2H),1.35(d,J＝12.5Hz,2H).13C NMR(126MHz,DMSO-d6)δ149.3,144.5,144.0,124.8,123.4,121.7,120.2,113.2,106.6,103.4,100.3,98.2,98.165.98,55.96,45.63,44.39,34.21,30.23,29.37.HPLC tR＝2.61min,purity 96.3％.HRMS(ESI)m/z:[M+H]+Calcd for C21H25N4O 349.1903；Found349.1906。
以下为实施例3-4的结构、制备方法和质谱表征数据：
| 实施例号 | 通式 | R基团 | 制备方法 | m/zESI+(M+H)+ |
| 3 | IVA1 | -苄基 | b,c,d | 350.1911 |
| 4 | IVA2 | -苄基 | b,c,d | 349.1905. |
IC50的测定：
采用Lance Ultra的方法来检测激酶的活性。在检测板中，将JAK1/JAK2激酶、Ulight标记的多肽底物、ATP以及检测化合物混合，并孵育反应。反应后，加入EDTA终止反应，并同时加入Eu标记的抗体，能够特异性的识别多肽链上的磷酸位点。检测板使用多功能酶标仪Envision进行分析，数据分别用荧光信号665nm/615nm的读数来表示。其中高比值表示活性较高，而低比值则表示活性受到抑制。结果显示实施例1对JAK1和JAK2抑制的IC50分别为：24nm和423nm；实施例2对JAK1和JAK2抑制的IC50分别为21nm和451nm；。说明实施例1和实施例2均对JAK1有很好的抑制作用和选择性。
关节炎模型
选择8周龄的雄性DBA/1小鼠，通过尾部皮下免疫接种在完全弗氏佐剂中乳化的50微克的II型鸡胶原，21天后追加在不完全弗氏佐剂中乳化的50微克的II型鸡胶原。从第42天开始观察记录。采用计分法：1分，正常；2分，1个关节肿胀；3分，超过一个关节肿胀，但未累积全部关节；4分，整个爪子严重肿胀或强直。每只爪子的评分相加即得到小鼠关节炎的总评分。在模型建立成功以后，采用5mg/kg的剂量的化合物或生理盐水给小鼠进行灌胃，早晚相隔12小时各一次，给药两周后对小鼠的关节炎评分，结果显示本发明中的化合物对小鼠关节炎有明显的治疗作用。
| 化合物组别 | 关节炎评分 |
| 空白对照组 | 1 |
| 生理盐水对照组 | 3.7 |
| 实施例1 | 2.1 |
| 实施例2 | 2.1 |
| 实施例3 | 2.4 |
| 实施例4 | 2.7 |
促进毛发生长实验：
将发明中的化合物配成含2％化合物的DMSO溶液，空白对照为纯DMSO溶液，选取8周龄的C57小鼠背部剃毛然后将其分组，采用右半身涂抹的方法，对小鼠进行间隔24小时的涂抹给药，然后观察各组小鼠平均皮肤出现黑斑点时间，半边毛长全时间。结果表明给药组小鼠在大约8天的时候涂药部分会出现黑色斑块并伴随少量的毛发长出，黑色斑块随着时间蔓延扩大并有更多的毛发长出，小鼠平均在31天左右的时候右半身涂药部分毛发长全，而左半身未涂药部分未发生变化，与给药组相比空白对照组在36天左右背部出现黑色斑块，并在过后的三个周整个背部毛发长全，结果表明本发明中的化合物有明显的毛发促进生长作用。
| 化合物组别 | 平均出现黑色斑块时间(天) | 平均长全半边毛时间(天) |
| 空白对照 | 36.5 | |
| 实施例1 | 8.3 | 29 |
| 实施例2 | 8.5 | 31 |
| 实施例3 | 8.5 | 32 |
| 实施例4 | 9 | 31 |
需要说明的是，对于上述方法实施例而言，为了简单描述，但是本领域技术人员应该知悉，本申请并不受所描述的顺序限制，因为依据本申请，某些步骤可以采用其他顺序或者同时进行。其次，本领域技术人员也应该知悉，说明书中所描述的实施例均属于优选实施例。
最后应说明的是：以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (6)
1.一种结构如I、II、III、IV所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、及其混合物形式、及其可药用的盐：
2.一种药物或兽医组合物，其包括权利要求1中任意一种化合物或其药学上可接受的盐和药学上可接受的载体。
3.一种用于治疗受试者詹纳斯激酶介导的疾病的方法，其中所述方法包括向受试者给药一定量的如权利要求1中任意一种化合物或其可药用盐，其中所述化合物的量对于治疗詹纳斯激酶介导的疾病是有效的。
4.根据权利要求3所述的一种用于治疗受试者詹纳斯激酶介导的疾病的方法，其中所述詹纳斯激酶介导的关节或结缔组织相关疾病包括但不限于：关节炎、类风湿关节炎、幼年型关节炎、青少年关节炎、牛皮癣性关节炎、椎关节炎、强直脊柱炎、腱炎和滑囊炎、腰椎关节病等。
5.根据权利要求3所述的一种用于治疗受试者詹纳斯激酶介导的疾病的方法，其中所述詹纳斯激酶介导的皮肤或毛发相关疾病包括但不限于：过敏性皮炎、皮肤瘙痒、痤疮、青春痘、酒渣鼻、红斑狼疮、天胞疮、牛皮癣、脱发、斑秃等。
6.根据权利要求3所述的一种用于治疗受试者詹纳斯激酶介导的疾病的方法，其中所述詹纳斯激酶介导的其它疾病包括但不限于：溃疡性肠炎、克罗恩病、溃疡性结肠炎、直肠炎、哮喘、鼻炎、花粉过敏、干眼病、葡萄膜炎、角膜炎、I型糖尿病、多发硬化、自身免疫性脑脊髓炎、自身免疫性睾丸炎、古德帕斯彻病、交感性眼炎以及器官移植排异反应等。
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| CN101351466A (zh) * | 2005-12-28 | 2009-01-21 | 安斯泰来制药株式会社 | Janus激酶3的杂环抑制剂 |
| AU2015207857A1 (en) * | 2005-06-22 | 2015-08-20 | Plexxikon Inc. | Pyrrolo [2,3-B] pyridine derivatives as protein kinase inhibitors |
| CN112174951A (zh) * | 2019-07-02 | 2021-01-05 | 深圳美莹基因科技有限公司 | 作为詹纳斯激酶1选择抑制剂的吡咯并[2，3-b]吡啶衍生物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2015207857A1 (en) * | 2005-06-22 | 2015-08-20 | Plexxikon Inc. | Pyrrolo [2,3-B] pyridine derivatives as protein kinase inhibitors |
| CN101351466A (zh) * | 2005-12-28 | 2009-01-21 | 安斯泰来制药株式会社 | Janus激酶3的杂环抑制剂 |
| CN112174951A (zh) * | 2019-07-02 | 2021-01-05 | 深圳美莹基因科技有限公司 | 作为詹纳斯激酶1选择抑制剂的吡咯并[2，3-b]吡啶衍生物 |
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