CN103524509B - 詹纳斯激酶抑制剂(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈的盐 - Google Patents

詹纳斯激酶抑制剂(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈的盐 Download PDF

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CN103524509B
CN103524509B CN201310367212.9A CN201310367212A CN103524509B CN 103524509 B CN103524509 B CN 103524509B CN 201310367212 A CN201310367212 A CN 201310367212A CN 103524509 B CN103524509 B CN 103524509B
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pyrrolo
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jak
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J.D.罗杰斯
H.-Y.李
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Abstract

本发明提供(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈的盐形式，其有用于调节詹纳斯激酶活性，并有用于治疗与詹纳斯激酶活性相关的疾病，包括例如免疫相关疾病、皮肤病、骨髓增生性病症、癌症以及其他疾病。

Description

詹纳斯激酶抑制剂(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈的盐
本申请是申请号为200880102903.3(国际申请号为PCT/US2008/066662)、申请日为2008年6月12日、发明名称为"詹纳斯激酶抑制剂(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈的盐"的中国专利申请的分案申请。
发明领域
本发明提供(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈的盐形式，其有用于调节詹纳斯激酶(Januskinase)活性，有用于治疗与詹纳斯激酶活性相关的疾病，所述疾病包括例如免疫相关疾病、皮肤病、骨髓增生性病症、癌症以及其它疾病。
背景技术
蛋白激酶(PK)是一组调节各种重要的生物学过程的酶，所述过程包括细胞生长、存活和分化；器官形成和形态发生；新血管形成；组织修复和再生等等。蛋白激酶通过催化蛋白质(或底物)的磷酸化并由此调节各种生物学环境(context)中的底物的细胞活性来发挥其生理功能。除了在正常组织/器官中的功能之外，许多蛋白激酶在包括癌症在内的许多人类疾病中还起着专门的作用。蛋白激酶的一个亚组(也被称为致癌蛋白激酶)在异常调节时可引起肿瘤形成和生长，并进一步有助于肿瘤的维持和发展(Blume-JensenP等，Nature2001，411(6835)：355-365)。迄今，致癌蛋白激酶代表用于癌症干涉和药物开发的最大的，最具有吸引力的蛋白质靶标组群之一。
詹纳斯激酶(JAK)家族在涉及免疫应答的细胞增殖和功能的细胞因子依赖性调节中发挥作用。当前，有四种已知的哺乳动物JAK家族成员：JAK1(也称为詹纳斯激酶-1)、JAK2(也称为詹纳斯激酶-2)、JAK3(也称为白细胞詹纳斯激酶；JAKL；L-JAK和詹纳斯激酶-3)和TYK2(也称为蛋白质-酪氨酸激酶2)。JAK蛋白的大小为120-140kDa，并包含7个保守的JAK同源(JH)结构域；其中的一个是功能性催化激酶结构域，另一个是潜在发挥调节功能和/或担当STATs的停靠位点(docMngsite)的假激酶结构域(Scott，Godshall等，2002，前述)。
在JAK激酶水平上阻断信号转导在人类癌症治疗上持有开发前景。抑制JAK激酶也预期对患有诸如牛皮癣和皮肤致敏之类的皮肤免疫病症的患者具有治疗益处。因此，人们广泛地寻找JAK激酶或相关激酶的抑制剂，几篇出版物报道了有效化合物种类，例如2006年12月12日申请的序列号为11/637,545的美国专利申请中报道了某些JAK抑制剂，其包括下文描述的(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈
因此，持续需要已知詹纳斯激酶抑制剂的新的或改进形式，以用于开发癌症和其它疾病治疗用的新的、改进的、以及更有效的药物制剂。本文描述的盐形式和方法针对这些需求以及其它目标。
发明内容
本发明尤其提供选自以下的盐：
(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈马来酸盐；
(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈硫酸盐；以及
(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈磷酸盐。
本发明进一步提供本发明的盐的制备方法，其包括将(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈与马来酸、硫酸或磷酸化合(combining)。
本发明进一步提供组合物，其包含本发明的盐形式以及至少一种药学上可接受的载体。
本发明进一步提供调节JAK活性的方法，其包括使JAK与本发明的盐接触。
本发明进一步提供在患者中治疗疾病的方法，其中所述疾病与JAK活性相关，所述方法包括对所述患者施用治疗有效量的本发明的盐。
本发明进一步提供在患者中治疗癌症、皮肤病或炎症的方法，所述方法包括对所述患者施用治疗有效量的本发明的盐。
本发明进一步提供本发明的盐，其在通过疗法(therapy)治疗人或动物体的方法中使用。
本发明进一步提供本发明的盐，其用于治疗癌症、皮肤病或炎症。
本发明进一步提供本发明的盐在制备药物中的用途，所述药物用于治疗本文所记载的疾病或病症中的任意种。
具体实施方式
本发明尤其提供JAK抑制剂(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈的盐，所述盐选自马来酸盐、硫酸盐和磷酸盐。这些盐调节一种或多种JAK的活性，且有用于例如治疗与JAK的表达或活性相关的疾病。
相比于游离碱形式和其它的盐形式，本发明的盐具有众多优点。尤其，这些盐是高度结晶的，其易于制备药物制剂，并改进活性成分的一般处理、操作和储存。相比于游离碱形式，本发明的盐还具有优异的水溶性、解离率、化学稳定性(具有较长的货架期)、与赋形剂的相容性、以及再现性。
在一些实施方案中，本发明的盐是基本分离的。“基本分离的”指该盐至少部分地或基本上从其在其中形成或被检测的环境中分离。部分分离可以包括例如富集(enrichedin)本发明的盐的组合物。基本分离可以包括含有至少约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%的所述盐的组合物。
本发明的盐也包括存在于所述盐中的原子的所有同位素。同位素包括原子序数相同但质量数不同的那些原子。例如，氢的同位素包括氚和氘。
可以使用已知技术来制备本发明的盐。常规地，通过以下方式来制备盐形式：在溶液中，使游离碱化合物与含有所需盐形式的阴离子的酸化合，然后从反应溶液中分离(例如通过结晶、沉淀、蒸发等)盐产物固体。也可以使用其它的盐形成技术。
使用方法
本发明的盐可以调节一种或多种詹纳斯激酶(JAKs)的活性。术语“调节”意指提高或降低JAK激酶家族的一种或多种成员的活性的能力。因此，通过使JAK与本文描述的化合物或组合物中的一种或多种接触，而在调节JAK的方法中使用本发明化合物。在一些实施方案中，本发明的盐可以担当一种或多种的JAK的抑制剂。在一些实施方案中，本发明化合物可以起刺激一种或多种的JAK的活性的作用。在其它实施方案中，可以在需要受体调节的个体中通过施用调节量的本发明的盐，将本发明化合物用于调节JAK的活性。
本发明的盐结合和/或调节的JAK包括JAK家族的任何成员。在一些实施方案中，所述JAK为JAK1、JAK2、JAK3或TYK2。在一些实施方案中，所述JAK为JAK1或JAK2。在一些实施方案中，所述JAK是JAK2。在一些实施方案中，所述JAK为JAK3。
本发明的盐可以是选择性的。"选择性的"指与至少一种其它的JAK相比，本发明化合物分别以更大的亲和性或效能结合或抑制JAK。在一些实施方案中，本发明化合物是相对于JAK3和/或TYK2的JAK1或JAK2的选择性抑制剂。在一些实施方案中，本发明的盐是JAK2(例如，相对于JAK1、JAK3和TVK2)的选择性抑制剂。不希望受到理论束缚，由于JAK3的抑制剂可以导致免疫抑制效应，因此，相对于JAK3，对JAK2具有选择性，有用于治疗癌症(例如多发性骨髓瘤)的化合物可提供具有更少免疫抑制副作用的额外优势。选择性可以为至少约5倍、10倍，至少约20倍，至少约50倍，至少约100倍，至少约200倍，至少约500倍或至少约1000倍。可以通过本领域的常规方法来测定选择性。在一些实施方案中，可以根据每一种酶的Km来测试选择性。在一些实施方案中，可以通过细胞ATP浓度来确定本发明的盐相对于JAK3的对JAK2的选择性。
本发明的另一方面涉及在个体(例如患者)中通过对需要这种治疗的个体施用治疗有效量或剂量的本发明的盐或其药物组合物，来治疗JAK相关的疾病或病症的方法。JAK相关的疾病可以包括与JAK的表达或活性(包括超表达和/或异常的活性水平)直接或间接相关的任何疾病、障碍或病症。JAK相关的疾病也可以包括可以通过调节JAK活性来预防、改善或治愈的任何疾病、障碍或病症。
JAK相关的疾病的例子包括涉及免疫***的疾病，其包括例如器官移植排斥(例如，同种异体移植物排斥和移植物抗宿主病)。
JAK相关的疾病的其它例子包括自身免疫性疾病，例如多发性硬化、类风湿性关节炎、幼年性关节炎、I型糖尿病、狼疮、牛皮癣、炎性肠病、溃疡性结肠炎、克罗恩病、重症肌无力、免疫球蛋白肾病、自身免疫性甲状腺病等。在一些实施方案中，自身免疫性疾病为自身免疫性大疱性皮肤病，例如寻常性天疱疮(PV)或大疱性类天疱疮(BP)。
JAK相关的疾病的其它例子包括过敏性病症，例如哮喘、食物过敏、特应性皮炎和鼻炎。JAK相关的疾病的其它例子包括病毒性疾病，例如，埃巴病毒(EBV)、乙型肝炎、丙型肝炎、HIV、HTLV1、水痘-带状疱疹病毒(VZV)和人***状瘤病毒(HPV)。
JAK相关的疾病或病症的其它例子包括皮肤病，例如牛皮癣(例如，寻常性牛皮癣)、特应性皮炎、皮疹、皮肤刺激、皮肤致敏(sensitization)(例如，接触性皮炎或过敏性接触性皮炎)。例如，包括一些药品在内的某些物质在局部施用时可以引起皮肤致敏。在一些实施方案中，将至少一种本发明的JAK抑制剂连同引起有害的致敏的药剂一起施用或按序施用可以有助于治疗此类有害的致敏或皮炎。在一些实施方案中，通过局部施用至少一种本发明的JAK抑制剂来治疗皮肤病。
在其它实施方案中，JAK相关的疾病为癌症，包括表征为实体瘤的那些癌症(例如，***癌、肾癌、肝癌、胰腺癌、胃癌、乳腺癌、肺癌、头和颈部的癌症、甲状腺癌、胶质母细胞瘤、卡波西肉瘤、卡斯尔曼病(Castleman'sdisease)、黑色素瘤等)、血液癌(hematologicalcancers)(例如淋巴瘤；白血病，例如急性成淋巴细胞白血病、急性髓细胞源性白血病(AML)、或多发性骨髓瘤)、以及皮肤癌(例如皮肤T细胞淋巴瘤(CTCL)和皮肤B细胞淋巴瘤)。皮肤T细胞淋巴瘤的例子包括塞泽里综合征(Sezarysyndrome)和蕈样肉芽肿病。
JAK相关的疾病可以进一步包括表征为突变型JAK2的表达的那些疾病，例如在假激酶结构域(例如，JAK2V617F)中具有至少一处突变的那些疾病。
JAK相关的疾病可以进一步包括骨髓增生性病症(MPD)，例如真性红细胞增多(PV)、自发性凝血细胞增多(ET)、伴有骨髓纤维化的骨髓外化生(MMM)、慢性髓细胞源性白血病(CML)、慢性髓单核细胞白血病(CMML)、嗜酸性细胞增多综合征(HES)、***性肥大细胞病(SMCD)等。
其它的JAK相关的疾病包括炎症和炎性疾病。炎性疾病的例子包括眼部的炎性疾病(例如虹膜炎、葡萄膜炎、巩膜炎、结膜炎，或相关疾病)、呼吸道的炎性疾病(例如，包括鼻和鼻窦的上呼吸道炎症，例如鼻炎或鼻窦炎；或者包括支气管炎、慢性阻塞性肺病的下呼吸道炎症等)、诸如心肌炎的炎性肌病、以及其它的炎性疾病。可通过本发明化合物治疗的其它炎性疾病包括***性炎症反应综合征(SIRS)和脓毒性休克。
本文所描述的JAK抑制剂可以进一步用于治疗缺血性再灌注损伤或与诸如休克或心跳停搏之类的炎性缺血性事件相关的疾病或病症。本文所描述的JAK抑制剂可以进一步用于治疗厌食症、恶病质或疲劳，例如由癌症引起或与癌症相关的那些。本文所描述的JAK抑制剂可以进一步用于治疗再狭窄、硬皮病或纤维化。本文所描述的JAK抑制剂可以进一步用于治疗与缺氧或星形细胞增生相关的病症，例如糖尿病性视网膜病、癌症或神经变性。参见例如，Dudley，A.C.等，Biochem.J.2005，390(部分2)：427-36和Sriram，K.等，J.Biol.Chem.2004，279(19)：19936-47。Epub2004年3月2日。
本文所描述的JAK抑制剂可以进一步用于治疗痛风和由于例如良性***肥大或良性***增生而引起的***尺寸增大。
本文使用的术语"接触"指将所指出的各部分(moieties)在体外***或体内***中聚集在一起(bhngimgtogether)。例如，使JAK与本发明的盐"接触"包括对具有JAK的个体或患者(例如人)施用本发明的盐，以及例如，将本发明的盐引入含有含JAK的细胞制剂或纯化制剂的样本中。
本文使用的术语"个体"或"患者"可以互相换用，指任何动物，包括哺乳动物，优选小鼠、大鼠、其它啮齿类、兔、狗、猫、猪、牛、羊、马或灵长类，最优选人。
本文使用的短语"治疗有效量"指引起研究者、兽医、内科医生或其它临床医生在组织、***、动物、个体或人中所寻求的引起生物学或医学反应的活性盐或药物试剂的量。
本文使用的术语"治疗"指以下中的一种或多种：(1)预防疾病；例如在可能易患某种疾病、病症或障碍，但还没有经历或表现该疾病的病理或症状的个体中预防所述疾病、病症或障碍；(2)抑制疾病；例如，在经历或表现某种疾病、病症或障碍的病理或症状的个体中抑制所述疾病、病症或障碍；以及(3)改善疾病；例如，在经历或表现某种疾病、病症或障碍的病理或症状的个体中改善所述疾病、病症或障碍(即，逆转(reversing)病理和/或症状)，例如降低疾病的严重性。
联合治疗
一种或多种其它药物试剂，例如化疗剂、抗炎剂、类固醇、免疫抑制剂、以及Bcr-Abl、Flt-3、RAF和FAK激酶抑制剂(例如WO2006/056399中所描述的那些抑制剂)，或者其它药剂可以与本发明的盐联合使用，以治疗JAK相关的疾病、障碍或病症。可以同时或按序对患者施用所述一种或多种其它药物试剂。
化疗剂的例子包括蛋白酶体(proteosome)抑制剂(例如硼替佐米)、沙利度胺、来那度胺(revlimid)、以及DNA损害剂(例如美法仑、多柔比星、环磷酰胺、长春新碱、依托泊甙、卡莫司汀等等。
类固醇的例子包括皮质类固醇，例如***或***。
Bcr-Abl抑制剂的例子包括美国专利No.5,521,184、WO04/005281、EP2005/009967、EP2005/010408以及序列号为60/578,491的美国申请中所公开的属(genera)和种(species)的化合物及其药学上可接受的盐。
合适的Flt-3抑制剂的例子包括WO03/037347、WO03/099771和WO04/046120中所公开的化合物及其药学上可接受的盐。
合适的RAF抑制剂的例子包括WO00/09495和WO05/028444中所公开的化合物及其药学上可接受的盐。
合适的FAK抑制剂的例子包括WO04/080980、WO04/056786、WO03/024967、WO01/064655、WO00/053595和WO01/014402中所公开的化合物及其药学上可接受的盐。
在一些实施方案中，本发明的盐形式可以与其他的激酶抑制剂(例如伊马替尼)联合使用，特别用于治疗对伊马替尼或其他激酶有抗性的患者。
在一些实施方案中，一种或多种本发明盐形式可以与化疗剂联合使用，用于治疗癌症(例如多发性骨髓瘤)，且与单独使用化疗剂的反应相比，可以改进治疗反应，而不加剧其毒性影响。用于治疗多发性骨髓瘤的其它药物试剂的例子例如可以非限制性地包括美法仑、美法仑+***(MP)、多柔比星、***和万珂(硼替佐米)。用于治疗多发性骨髓瘤的其它药物试剂包括Bcr-Abl、Flt-3、RAF和FAK激酶抑制剂。将本发明的JAK抑制剂与其他的药剂联合的理想结果是增效或协同的效应。另外，用本发明的JAK抑制剂治疗可以逆转多发性骨髓瘤细胞对例如***之类的药剂的抗性。所述药剂可与本发明化合物以单剂型或连续剂型(singleorcontinuousdosageform)联合，或者所述药剂作为单独的剂型可以同时或按序施用。
在一些实施方案中，将诸如***之类的皮质类固醇与至少一种JAK抑制剂联合施用于患者，其中间歇施用，而非连续施用***。
在一些其它实施方案中，在骨髓移植或干细胞移植之前、期间和/或之后，将一种或多种本发明的JAK抑制剂与其他的治疗剂联合施用于患者。
药物制剂和剂型
当用作药物时，可以药物组合物的形式施用本发明的盐。这些组合物可以用制药领域众所周知的方式来制备，并可以通过各种途径施用，施用途径取决于希望局部治疗还是全身治疗，以及待治疗的区域。可以局部施用(包括透皮、表皮、眼部以及粘膜施用(包括鼻内、***和直肠递送)；肺部施用(例如通过吸入或吹入粉末或气溶胶，包括通过喷雾器；气管内或鼻内施用)；口服或胃肠外施用。胃肠外施用包括静脉内、动脉内、皮下、腹膜内、肌内施用，或注射或输注；或者颅内施用，例如鞘内施用，或者心室内施用。胃肠外施用可以采取单一大丸剂的形式，或者可以例如通过连续灌注泵施用。局部施用的药物组合物和制剂可以包括透皮贴剂、软膏剂、洗剂、乳膏剂、凝胶、滴剂、栓剂、喷雾剂、液休剂和散剂。常规的药物载体、水性、粉末或油性基质、增稠剂等等可能是必需的或希望的。经涂覆的(coated)避孕套、手套等等也可能是有用的。
本发明还包括药物组合物，其含有上述作为活性成分的一种或多种本发明化合物与一种或多种药学上可接受的载体(赋形剂)的组合。在制备本发明组合物中，活性成分通常与赋形剂混合，被赋形剂稀释或包封在载体中，所述载体为例如胶囊、小药囊、纸或其他容器之类的形式。当赋形剂担当稀释剂时，其可以是固体、半固体或液体材料，作为活性成分的赋形剂、载体或介质。因此，所述组合物可以为以下形式：片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、驰剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(作为固体，或在液体介质中)、含有例如至多10重量%活性化合物的软膏剂、软胶囊或硬胶囊、栓剂、无菌注射溶液以及无菌包装粉末(sterilepackagedpowders)。
在制备制剂时，可以研磨活性化合物，以在与其它成分混合之前提供适当的粒度。如果活性化合物基本上是不可溶的，则可以将其研磨至小于200目的粒度。如果活性化合物基本上是水溶性的，则可以通过研磨调整粒度，以提供在制剂中的基本均匀分布，例如约40目。
可以使用已知的研磨程序(例如湿法研磨)研磨本发明化合物，以获得适合于片剂制剂或其他制剂类型的粒度。可以通过本领域已知的方法(例如参见国际专利申请No.WO2002/000196)来制备本发明化合物的细粒状(纳米微粒)制剂。
合适的赋形剂的一些例子包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉、***树胶、磷酸钙、海藻酸盐、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。所述制剂可以另外包括：润滑剂，例如滑石、硬脂酸镁以及矿物油；湿润剂；乳化及悬浮剂；防腐剂，例如苯甲酸甲酯和苯甲酸丙基羟基酯；甜味剂；以及矫味剂。通过使用本领域已知的程序对本发明组合物进行配制，以便在对患者施用后提供快速释放、持续释放或延迟释放活性成分。
可以将所述组合物配制为单位剂型(unitdosageform)，每一剂量含有约5到约1000mg(1g)(更通常为约100到约500mg)的活性成分。术语"单位剂型"是指适合作为人类对象或其他动物用的单剂量(unitarydosages)的物理离散单位(physicallydiscreteunits)，每一单位含有经计算产生所需治疗效果的预定量活性物质，以及合适的药物赋形剂。
活性化合物可以在宽泛的剂量范围内是有效的，通常以药物有效量进行施用。但应理解，通常由医生根据有关情况来确定化合物的实际施用量，所述情况包括待治疗的病症、所选择的给药途径、实际施用的化合物、个体患者的年龄、体重及反应、患者症状的严重性等。
对于制备诸如片剂等固体组合物，将主要的活性成分与药物赋形剂混合以形成含有本发明化合物的均匀混合物的固体预配制(preformulation)组合物。当提及这些预配制组合物为均匀的时，活性成分通常均匀地分散遍布于组合物中，从而该组合物易于细分成同等有效的单位剂型，例如片剂、丸剂和胶囊。然后将该固体预配制物细分成以上所述类型的单位剂型，所述单位剂型含有例如约0.1至约1000mg本发明的活性成分。
可以对本发明的片剂或丸剂进行包衣或其他形式的复合，以提供具有延长作用的优点的剂型。例如，片剂或丸剂可以包含内剂量组分和外剂量组分，后者是前者的包膜(envelope)形式。可以通过肠溶层(entericlayer)将该两种组分分开，所述肠溶层用于在胃中抵抗崩解，使内组分完整进入十二指肠或被延迟释放。可以使用各种材料用于此类肠溶层或包衣，此类材料包括许多高分子酸，以及高分子酸与诸如虫胶、鲸蜡醇和醋酸纤维素等的混合物。
用于口服或注射给药的其中可掺混本发明的化合物和组合物的液体形式包括水溶液、适当矫味的糖浆、水性混悬液或油性混悬液、用食用油(例如棉籽油、芝麻油、椰油或花生油)矫味的乳液、以及酏剂和类似的药物载体。
用于吸入或吹入的组合物包括药学上可接受的水溶剂或有机溶剂或其混合物中的溶液和混悬液，以及粉末。液体或固体组合物可以含有上文所描述的合适的药学上可接受的赋形剂。在一些实施方案中，经口或经鼻呼吸道途径施用所述组合物，以获得局部或全身效果。可通过使用惰性气体对组合物进行雾化。可以从雾化装置直接吸入雾化溶液，或者可将雾化装置与面罩(facemaskstent)或间歇正压呼吸机(intermittentpositivepressurebreathingmachine)连接。可通过以适当方式递送所述制剂的装置经口或经鼻施用溶液、混悬液或粉末组合物。
施用于患者的盐或组合物的量将根据所施用的物质、施用目的(例如预防或治疗)、患者的状况、给药方式等而变化。在治疗性应用中，可以对已经罹患某一疾病的患者施用足以治愈或至少部分消除该疾病及其并发症的症状的量的组合物。有效剂量取决于所治疗的疾病状况以及主治医生根据以下因素的判断：例如疾病严重性、患者的年龄、体重和一般状况等。
对患者施用的组合物可以是以上所述的药物组合物形式。可以通过常规灭菌技术对这些组合物进行灭菌，或者将这些组合物无菌过滤。可以将水溶液包装，以直接使用，或者将其冻干，在施用前，将冻干制剂与无菌水性载体混合。化合物制剂的pH通常在3-11之间，更优选为5-9，最优选为7-8。应理解，使用某种前述的赋形剂、载体或稳定剂将导致形成药用盐。
本发明的盐的治疗剂量可以根据例如以下因素而变化：进行治疗的具体用途、化合物的给药方式，患者的健康或状况、以及开处方医生的判断。本发明的盐在药物组合物中的比例或浓度可以根据许多因素而变化，所述因素包括剂量、化学特征(例如疏水性)和给药途径。例如本发明的盐可以提供于生理缓冲剂水溶液中，用于胃肠外施用，所述生理缓冲剂水溶液含有约0.1至10%w/v的本发明化合物。一些典型的剂量范围为约1μg/kg体重/天至约1g/kg体重/天。在一些实施方案中，剂量范围为约0.01mg/kg体重/天至约100mg/kg体重/天。剂量可能取决于以下变量：例如疾病或病症的类型和进展程度、具体患者的总体健康状况、所选择的化合物的相对生物学功效、赋形剂的配方，以及其给药途径。可以由得自体外或动物模型测试***的剂量-反应曲线推断有效剂量。
本发明的组合物可以进一步包括一种或多种另外的药物试剂，例如化疗剂、类固醇、抗炎化合物或免疫抑制剂，上文中列举了它们的例子。
标记的化合物和分析方法
本发明的另一方面涉及标记的本发明盐(放射性标记、荧光标记等)，其不仅在成像技术中有用，还在分析中有用，既在体外以及体内用于对包括人的组织样本中的JAK进行定位或定量，以及用于通过抑制标记化合物的结合来鉴定JAK配体。因此，本发明包括含有此类标记化合物的JAK分析。
本发明进一步包括同位素标记的本发明的盐。"同位素标记的"或"放射性标记的"化合物是其中一个或多个原子被原子质量或质量数不同于通常在自然中发现的(即天然存在)的原子质量或质量数的原子替换或取代的本发明的盐。可以并入本发明化合物的合适的放射性核素包括但不限于2H(也写作D，代表氘)、3H(也写作T，代表氚)、11C、13C、14C、13N、15N、15O、17O、18O、18F、35S、36Cl、82Br、75Br、76Br、77Br、123I、124I、125I和131I。并入本发明放射性标记的化合物的放射性核素将取决于该放射性标记的化合物的具体应用。例如，对于体外金属蛋白酶标记和竞争分析，掺有3H、14C、82Br、125I、131I、35S或的化合物通常最有用。对于放射性成像应用，11C、18F、125I、123I、124I、131I、75Br、76B，或77Br通常最有用。
应当理解，"放射性标记的"或"标记的化合物"是并有至少一种放射性核素的盐。在一些实施方案中，放射性核素选自3H、14C、125I、35S和82Br。
本发明可以进一步包括将放射性同位素并入本发明化合物的合成方法。将放射性同位素并入有机化合物的合成方法在本领域是众所周知的，本领域普通技术人员将容易地认识到可应用于本发明化合物的方法。
本发明的标记盐可以用于筛选分析，以鉴定/评价化合物。例如，将标记的新近合成或鉴定的化合物(即，测试化合物)与JAK接触，通过跟踪标记，监测其浓度变化，可以评价其结合JAK的能力。例如，可以评价测试化合物(被标记)降低另一种已知与JAK结合的化合物(即标准化合物)的结合的能力。因此，测试化合物与标准化合物竞争结合JAK的能力与其结合亲和性直接相关。相反地，在一些其他的筛选分析中，将标准化合物标记而不将测试化合物标记。因此，为了评价标准化合物和测试化合物之间的竞争，对标记的标准化合物的浓度进行监测，从而确定测试化合物的相对结合亲和性。
试剂盒
本发明还包括药物试剂盒，其有用于例如治疗或预防JAK相关的疾病或病症，例如癌症、炎症或皮肤病，所述药物试剂盒包括一个或多个容纳包含治疗有效量的本发明的盐的药物组合物的容器。如果需要的话，此类试剂盒可以进一步包括一种或多种不同的常规药物试剂盒组分，例如含有一种或多种药学上可接受的载体的容器，其它的容器等，这些对于本领域技术人员将是显而易见的。在试剂盒中还可以包括说明书(插页或标签形式)，说明待施用的各组分的量、给药指南、和/或混合组分的指南。
通过具体实施例对本发明进行更为详细的描述。以下给出的实施例仅用于描述的目的，并无意在以任何方式限制本发明。本领域技术人员将容易地认识到各种非关键的参数，可以改变或修改这些参数以产生基本相同的结果。
实施例
实施例1：(R)-3-(4-(7H-吡咯并[2，3，d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈马来酸盐的制备
向试管中加入(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈(153.7mg，0.5mmol)和马来酸(61.7mg)，然后加入异丙醇(IPA)(4mL)。将所得混合物加热至清澈，冷却至室温，之后搅拌另外2.5小时。通过过滤收集沉淀物，用0.8mL的冷IPA洗涤滤饼。真空干燥滤饼至恒重，得到最终的盐产物(173mg)。
该马来酸盐经H1NMR显示为1：1的盐，通过X射线粉末衍射(XRPD)证实结晶度。差示扫描量热法(DSC)显示在约175.96℃(开始于175.67℃)处有一个尖锐的熔融峰。产物通过热重分析(TGA)显示在高达150℃下仅有轻微的重量损失。
实施例2：(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈磷酸盐的制备
在试管中加入(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈(153.5mg)和磷酸(56.6mg)，然后加入异丙醇(IPA)(5.75mL)。将所得混合物加热至清澈，冷却至室温，之后搅拌另外2小时。通过过滤收集沉淀物，用0.6mL的冷IPA洗涤滤饼。真空干燥滤饼至恒重，得到最终的盐产物(171.7mg)。
该磷酸盐经H1NMR显示为1：1的盐，通过X射线粉末衍射(MRPD)证实结晶度。差示扫描量热法(DSC)显示在约198.66℃处有一个尖锐的熔融峰。产物通过TGA显示在高达200℃下几乎没有(little)重量损失。
实施例3：(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈硫酸盐的制备
在测试管中加入(R)-3-(4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈(153.0mg)和硫酸(56.1mg)，之后加入乙腈(7.0mL)。将所得混合物加热至清澈，冷却至室温，之后搅拌另外2小时。通过过滤收集沉淀物，用0.8mL的冷乙腈洗涤滤饼。真空干燥滤饼至恒重，得到最终的盐产物(180mg)。
该硫酸盐经H1NMR显示为1：1的盐，通过X射线粉末衍射(XRPD)证实结晶度。差示扫描量热法(DSC)显示在约186.78℃处有一个尖锐的熔融峰。产物通过TGA显示在高达175℃下几乎没有重量损失。
实施例A
体外JAK激酶分析
可以按照以下描述于Park等，AnalyticalBiochemistry(分析生物化学)1999，269，94-104中的体外分析来测试试验化合物对JAK靶标的抑制活性。使用杆状病毒在昆虫细胞中表达具有N末端的组氨酸标签的人JAK1(a.a.837-1142)、Jak2(a.a.828-1132和Jak3(a.a.781-1124)的催化结构域，并进行纯化。通过测量生物素化肤的磷酸化来分析JAK1、JAK2或JAK3的催化活性。通过均相时间分辨荧光(HTRF)检测磷酸化的肤。测定化合物对反应液中的每一种激酶的IC50，所述反应液在50mMTris(PH7.8)缓冲液中含有酶、ATP和500nM肤，所述缓冲液含有100mMNaCl、5mMDTT和0.1mg/mL(0.01%。)的BSA。反应液中的ATP浓度对于Jak1为90μM，对于Jak2为30μM，对于Jak3为3μM。在室温下进行反应1小时，之后用分析缓冲液(PerkinElmer，波士顿，MA)中的20μL45mMEDTA、300nMSA-APC、6nMEu-Py20终止反应。与铕标记的抗体结合40分钟，在Fusion读板仪(PerkinElmer，波士顿，MA)上测定HTRF信号。发现本发明的磷酸盐和相应的游离碱化合物针对JAK1、JAK2和JAK3中的每一种的IC50值都小于50nM。
除本文所描述的那些内容，从前述说明书对本发明作出的各种修改对本领域技术人员而言是显而易见的。此类修改也有意落入所附权利要求书的保护范围内。本申请所引用的每一参考文献通过引用全文并入本文中。

Claims (12)

1.盐，其选自：
(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈磷酸盐；
(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈硫酸盐；和
(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈马来酸盐；
其中所述盐为结晶的。
2.根据权利要求1所述的结晶盐，其为(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈磷酸盐。
3.根据权利要求1所述的结晶盐，其为(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈硫酸盐。
4.根据权利要求1所述的结晶盐，其为(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈马来酸盐。
5.根据权利要求2所述的结晶盐，其中所述结晶盐是1:1(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈:磷酸所形成的盐。
6.根据权利要求3所述的结晶盐，其中所述结晶盐是1:1(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈:硫酸所形成的盐。
7.根据权利要求4所述的结晶盐，其中所述结晶盐是1:1(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈:马来酸所形成的盐。
8.药物制剂，其包含权利要求1-7中任一项所述的结晶盐以及药学上可接受的载体。
9.单位剂型，其包含选自以下的活性成分：
(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈磷酸盐；
(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈硫酸盐；和
(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈马来酸盐，
其中每一剂量含有5到1000mg的活性成分。
10.单位剂型，其包含根据权利要求8所述的药物制剂，其中权利要求1-7中任一项所述的结晶盐为活性成分，且其中每一剂量含有5到1000mg的活性成分。
11.根据权利要求9或10所述的单位剂型，其中所述单位剂型适合于口服施用。
12.根据权利要求11所述的单位剂型，其中所述单位剂型为片剂。
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