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CN114907353A - 一种前药化合物及其制备方法和用途 - Google Patents

一种前药化合物及其制备方法和用途 Download PDF

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Publication number
CN114907353A
CN114907353A CN202110182307.8A CN202110182307A CN114907353A CN 114907353 A CN114907353 A CN 114907353A CN 202110182307 A CN202110182307 A CN 202110182307A CN 114907353 A CN114907353 A CN 114907353A
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CN
China
Prior art keywords
group
substituted
unsubstituted
compound
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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CN202110182307.8A
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English (en)
Inventor
姚元山
李傲
P·K·贾达夫
陈以乐
曹国庆
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Minghui Pharmaceutical Hangzhou Ltd
Minghui Pharmaceutical Shanghai Ltd
Original Assignee
Minghui Pharmaceutical Hangzhou Ltd
Minghui Pharmaceutical Shanghai Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by Minghui Pharmaceutical Hangzhou Ltd, Minghui Pharmaceutical Shanghai Ltd filed Critical Minghui Pharmaceutical Hangzhou Ltd
Priority to CN202110182307.8A priority Critical patent/CN114907353A/zh
Priority to JP2023548348A priority patent/JP2024506090A/ja
Priority to IL305009A priority patent/IL305009A/en
Priority to AU2022219344A priority patent/AU2022219344A1/en
Priority to US18/276,342 priority patent/US20240139327A1/en
Priority to MX2023009282A priority patent/MX2023009282A/es
Priority to PCT/CN2022/075714 priority patent/WO2022171140A1/zh
Priority to EP22752300.8A priority patent/EP4293020A1/en
Priority to CA3207813A priority patent/CA3207813A1/en
Priority to KR1020237030622A priority patent/KR20230160804A/ko
Priority to CN202280014289.5A priority patent/CN116848104A/zh
Publication of CN114907353A publication Critical patent/CN114907353A/zh
Pending legal-status Critical Current

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Abstract

本发明提供了一种前药化合物及其制备方法和用途，具体地，本发明提供了一种如式(I)所示的化合物，及其制备方法和作为激酶抑制剂前药用于制备透皮给药制剂的用途。

Description

一种前药化合物及其制备方法和用途
技术领域
本发明涉及药物小分子领域，具体地，本发明提供了一类作为激酶抑制剂前药化合物，及其药学上可接受的盐，水合物或溶剂合物，以及含有上述组分的药物组合物(优选为透皮制剂)。
背景技术
JAK-STAT信号通路是近年来发现的一条由细胞因子刺激的信号转导通路，JAK在细胞因子信号传导中起着重要的作用，JAK激酶家族的下游底物包括转录蛋白的信号转导剂和激活剂(STAT)。JAK蛋白是该通路中重要成员，而其活性的异常提高往往导致疾病的发生，很多疾病都与JAK-STAT信号通路异常细胞反应有关，这些疾病包括自身免疫病、炎性病、骨病、代谢病、神经和神经变性病、癌症、心血管病、变态反应和哮喘、阿尔兹海默氏病。
类风湿性关节炎(rheumatoid arthritis,RA)是一种临床常见的慢性自身免疫性疾病，主要表现为关节肿胀、疼痛、僵硬、畸形和功能严重受损等，人群发病率为0.5％-1.0％。由于RA的发病机制尚未明确，因此其病理过程难以控制，致残率高，严重损害患者身心健康，降低患者生存质量。目前用于治疗RA的药物主要有非甾体抗炎药(NSAID)、改善病情抗风湿药(DMARD)、以及抗体类药物。长期以来，治疗RA的一线药物为DMARDs，1988年，第1个DMARD药物甲氨蝶呤(MTX)获FDA批准治疗RA，MTX是RA治疗史上的一个重要里程碑。该药物因其有效性、耐受性、安全性等优势而被广泛应用，但其具有包括恶心、呕吐、胃部不适、肝毒性等不良反应。相比之下，新近发展的抗体类药物对于中重度RA具有较好的疗效和安全性指标，但是因其靶向特定的细胞因子，获益人群受到明显限制，同时治疗费用和注射方式给药也限制了这类药物的推广。
在过去20年的发展历程中，RA治疗已经取得长足进步，患者病情经现有治疗方法已经可以有效控制。尽管如此，RA患者仍经受疾病复发、治疗有效性不理想、长期耐受性差及一些不良反应等问题。更为重要的是，RA患者的生活质量包括关节等器官功能在现有治疗手段并没有得到真正的改善，因此，着眼于恢复患者的正常机能在这一领域仍存在巨大的未满足的临床需求。
研究表明，在RA中起核心治病作用的是RA滑膜组织及细胞中浸润的单核/巨噬细胞、淋巴细胞等通过自分泌的方式产生大量细胞因子，这些细胞因子相互作用，通过不同途径激活JAK/STAT信号通路(Janus kinase/Signal transducer and activators oftranscription signaling pathway)，通过特异性抑制JAK/STAT信号通路，可阻断上述细胞因子的级联放大作用，从而改善RA患者受损关节症状，因此，JAK/STAT信号通路成为治疗RA的潜在靶点。
由于JAK激酶参与体内各种重要的生理过程，对不同亚型的广泛抑制有可能产生不良反应，Tofacitinib用于MTX反应不足或不耐受的中重度RA患者，临床试验观察其伴随一定的不良反应，包括感染、结核、肿瘤、贫血、肝损伤及胆固醇增加等。Tofacitinib对JAK1，JAK2，JAK3亚型均有显著的抑制活性，由于JAK2活性与红细胞分化以及脂代谢过程相关，上述部分不良反应被认为与该药物的非选择性抑制特点相关。因此，寻找选择性JAK1和/或JAK3抑制剂将成为RA药物研究的新方向。目前JAK抑制剂已经被证实可以用于血液系统疾病、肿瘤、类风湿性关节炎及银屑病等治疗药物。然而，本领域可以用于透皮给药的JAK抑制剂组合物仍然非常有限。
发明内容
本发明的目的是提供一种结构新颖的激酶抑制剂前药化合物，优选地为JAK抑制剂前药化合物，进一步优选为透皮制剂。
本发明的第一方面，提供了一种JAK抑制剂的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其具有如下式(I)所示的结构：
Figure BDA0002941763800000021
所述的G取自JAK抑制剂药物分子失去一个H原子形成的基团，且所述的JAK抑制剂药物分子选自下组：Tofacitinib、Ruxolitinib、Baricitinib、Peficitinib、Pacritinib、Delgocitinib、PF-04965842(Abrocitinib)、Upadacitinib、Filgotinib、Itacitinib、Fedratinib、Decernotinib、SHR-0302、Delgocitinib、ASN-002、Cerdulatinib、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、Deuterium-modifiedruxolitinib analog、ATI-501、R-348、NS-018、Jaktinib、KL-130008、Lestaurtinib、Momelotinib、TD-1473、Zotiraciclib、DTRMHS-07、WXSH-0150、TQ05105、WXFL10203614；
所述的R1和R2各自独立地选自下组：H、D、取代或未取代的C1-C6的烷基、取代或未取代的C1-C6的杂烷基、取代或未取代的C3-C8的环烷基、取代或未取代的C3-C8的杂环基、或R1和R2和与其相连的碳原子构成C3-C8的碳环或杂环；
L选自下组：无、取代或未取代的C1-C6的亚烷基、取代或未取代的C1-C6的亚杂烷基；
R3选自下组：取代或未取代的C1-C20的烷基、取代或未取代的C3-C20的环烷基、取代或未取代的C1-C20的杂烷基、取代或未取代的3-20元的杂环基、取代或未取代的C6-C14的芳基，或者R3和R1或R2相连，从而形成一个取代或未取代的5-20元的内酯环或杂内酯环；其中，所述的杂内酯环指所述内酯环的环骨架上包括1-3个选自下组的杂原子：N、O或S(O)p；
其中，所述的杂烷基指碳链上的一个或多个碳原子被选自下组的杂原子取代：N、O或S(O)p；
p选自下组：0、1或2；
所述的杂环基包括1-3个选自下组的杂原子：N、O或S(O)p；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、C3-C8杂环基、氧代、-CN、羟基、氨基、羧基、酰胺、磺酰胺、砜基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6烷氧基、＝O。
在另一优选例中，所述的R1和R2各自独立地为H、D、C1-C6的烷基，L选自无或C1-C6的亚烷基，且所述的R3选自下组：C1-C20的烷基，C3-C20的环烷基，C6-C14的芳基。
在另一优选例中，所述的R1和R2各自独立地为H，L选自无，且所述的R3选自下组：C1-C20的烷基。
在另一优选例中，所述的G基团选自下组：
Figure BDA0002941763800000031
在另一优选例中，所述的式(I)化合物具有如下式(II)所示的结构：
Figure BDA0002941763800000032
在另一优选例中，所述的式(I)化合物具有如下式所示的结构：
Figure BDA0002941763800000041
在另一优选例中，所述的R3选自下组：C3-C20的烷基，C3-C20的环烷基。
在另一优选例中，所述的式I化合物具有选自下组的结构：
Figure BDA0002941763800000042
Figure BDA0002941763800000051
在另一优选例中，所述的药学上可接受的盐为盐酸盐。
本发明的第二方面，提供了一种制备如本发明第一方面所述的化合物的方法，其包括步骤：
Figure BDA0002941763800000052
在惰性溶剂中，用式1e化合物与R3C(O)X反应，得到式(I)化合物；其中，所述的X为OH或活化基团(优选为卤素或OC(O)R3)，其余各基团的定义如本发明第一方面中所述。
在另一优选例中，所述的方法还包括步骤：
Figure BDA0002941763800000061
用1c与1d反应，得到化合物1e。
在另一优选例中，所述的方法还包括步骤：
Figure BDA0002941763800000062
用化合物1a和氯甲酸氯甲酯反应，得到化合物1c。
本发明的第三方面，提供了一种如下式1e所示的中间体：
Figure BDA0002941763800000063
本发明的第四方面，提供了一种药物组合物，其含有药学上可接受的载体和本发明第一方面所述的化合物，及其药学上可接受的盐，水合物或溶剂合物。
在另一优选例中，所述的药物组合物为透皮给药制剂。
在另一优选例中，所述的药物组合物还具有皮肤渗透促进剂(如表面活性剂、二甲亚砜、癸基甲基亚砜、氮酮类促进剂、醇类促进剂、挥发油、氨基酸、磷脂、油酸)。
在另一优选例中，所述的药物组合物透皮给药后，所述的式I化合物在体内代谢形成托法替尼。
在另一优选例中，所述的药物组合物用于治疗或预防与JAK激酶的活性或表达量相关的疾病；较佳地，所述的疾病选自下组：癌症、骨髓增殖性疾病、炎症、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病、人或动物自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮癣。
本发明的第五方面，提供了一种如本发明第一方面所述的化合物，或其药学上可接受的盐或水合物的用途，其用于制备治疗或预防与JAK激酶的活性或表达量相关的疾病的药物组合物。
在另一优选例中，所述的疾病选自下组：癌症、骨髓增殖性疾病、炎症、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病、人或动物自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮癣。
本发明的第六方面，提供了一种透皮给药制剂，其包括：
本发明第一方面所述的化合物；
任选的皮肤渗透促进剂，优选地，所述的皮肤渗透促进剂选自下组：表面活性剂、二甲亚砜及其类似物、氮酮类化合物、吡咯酮衍生物、醇类化合物、醚类化合物、脂肪酸类化合物及脂肪酸酯类化合物，或其组合；
任选的支撑层。
在另一优选例中，所述的药物以单一相或者多相，溶液或者混悬存在。
在另一优选例中，所述的制剂以溶液、混悬剂、凝胶剂、乳剂、膏剂、泡沫剂等形式给药。
在另一优选例中，所述的支撑层是膜聚合物或骨架聚合物。
在另一优选例中，所述的支撑层选自下组：压敏胶材料、背衬材料、防粘材料、药库材料。
在另一优选例中，所述的透皮给药制剂还包括剥离层。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，开发了一种如式(I)所示的化合物。所述的化合物对调节细胞因子和/或干扰素具有出乎意料的活性，可用于治疗由细胞因子和/或干扰素介导的疾病。基于上述发现，发明人完成了本发明。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C1-C6烷基表示具有1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等，“C1-C20烷基”具有类似的含义。术语“亚烷基”指失去一个氢原子的烷基，例如C1-C6亚烷基表示具有1-6个碳原子的直链或支链的亚烷基。术语“杂烷基”指碳链上的一个或多个碳原子被选自下组的杂原子取代的烷基：O、S、NH、C(O)或C(NH)，术语“亚杂烷基”具有类似的含义。
如本文所用，术语“C3-C8环烷基”指具有3-8个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环、并环或螺环形式，“C3-C20的环烷基”具有类似的定义。
如本文所用，术语“C6-C14芳基”是指具有6-14个碳原子的芳基，例如，苯基或萘基等类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
如本文所用，术语“3-20元杂环基”是指具有3-20个环原子，且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、具体实施方式与其他化学合成方法的结合所形成的实施方式、以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请所使用的溶剂可以经市售获得。本申请采用的缩略词如：aq代表水溶液；HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐；EDCI代表N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；Cbz代表苄氧羰基，一种氨基保护基；Boc代表叔丁基氧羰基，一种氨基保护基；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；THF代表四氢呋喃；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；Boc2O代表二-叔丁基二碳酸酯；LDA代表二异丙基氨基锂。
化合物经人工或者
Figure BDA0002941763800000081
软件命名，市售化合物采用供应商目录名称。
药物组合物和施用方法
由于本发明化合物在透皮给药后能够在体内代谢形成治疗活性成分，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)癌症、骨髓增殖性疾病、炎症、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病等在内的多种自身免疫及炎症相关疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有1-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure BDA0002941763800000092
Figure BDA0002941763800000091
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的前药化合物可方便地配制成包含一种或多种本发明化合物和药用载体的药学组合物。参见Remington：The Science and Practice of Pharmacy第19版(宾夕法尼亚州Easton，Mack Publishing Co.，1995)，该书公开了典型的载体和制备药学组合物的常用方法，所述方法可按叙述使用或经改良，制成含有本发明化合物的药剂。如前所述，本发明的化合物还可以药用盐等形式施用。
本发明的化合物可以含有常用的非毒性药用载体、辅剂和赋形剂的药剂的形式，经口给药、肠胃外给药、透皮给药、直肠给药、经鼻给药、口含给药、阴道给药或通过植入的贮器给药。优选地，本发明的化合物可用常用的透皮给药系统通过皮肤或粘膜组织进行给药，其中，药剂含于多层结构中，所述多层结构固定在皮肤上，起给药装置的作用。在这样的结构中，药物组合物含于上部的背衬层之下的一层亦即“贮器”层中。多层结构可含有单个贮器，也可含有多个贮器。在一个实例中，贮器包含药用压合式粘合物质的高分子基质，所述粘合物质起着在给药过程中将系统固定于皮肤的作用。合适的皮肤压合式粘合物质包括但不限于聚乙烯、聚硅氧烷、聚异丁烯、聚丙烯酸酯、聚氨酯等。或者，含有药物的贮器和皮肤压合式粘合剂可作为分开的和不同的层存在，在这种情况下，粘合剂在贮器之下，而贮器可以是上述高分子基质，也可以是液体或水凝胶贮器，或者是其他形式。
在这些多层中，作为装置上表面的背衬层起着多层结构的主要结构元素的作用，为装置提供了许多柔韧性。所选的用作背衬材料的物质应基本上不会被活性物质和存在的其他任何物质透过；背衬最好由柔软的弹性材料片或膜制成。适合用作背衬层的聚合物的例子包括聚乙烯、聚丙烯、聚酯等。
在贮存过程中和使用之前，多层结构包括剥离层。在临用之前，将该层从装置上除去，将其底面或药物贮器或单独的压合式粘合剂层露出，使系统可固定在皮肤上。剥离层应由不会被药物/赋形剂透过的材料制成。
透皮给药装置可用本领域已知的常用技术制作，例如，在背衬层上浇注粘合剂、药物和赋形剂的流体混合物，然后层压剥离层。类似地，可将粘合剂混合物浇注在剥离层上，然后层压背衬层。或者，可在没有药物或赋形剂的情况下制作药物贮器，然后通过浸泡装入药物/赋形剂混合物。
多层的透皮给药系统还可含有皮肤渗透促进剂。即，由于皮肤对某些药物的固有的渗透性可能太小，无法使治疗水平的药物透过相当大小的未破皮肤，需要将皮肤渗透促进剂与这些药物一起施用。合适的促进剂是本领域周知的，例如包括二甲亚砜(DMSO)、二甲基甲酰胺(DMF)、N，N-二甲基乙酰胺(DMA)、癸基甲基亚砜(C10MSO)、C2-C6链烷二醇和1-取代的氮杂环庚-2-酮、醇等。
本发明化合物可以单独给药，或者与其他药学上可接受的治疗剂联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的治疗剂。该其他药学上可接受的治疗剂中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗细胞因子和/或干扰素介导的疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选1～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例
实施例1
Figure BDA0002941763800000101
Figure BDA0002941763800000111
第一步
在氮气保护和0℃条件下，向化合物1a(4.00g，34.13mmol)和吡啶(5.40g，68.26mmol)的50mL二氯甲烷溶液中加入氯甲酸氯甲酯(4.90g，38.00mmol)。滴加完毕，反应液自然升至室温并继续反应4小时。反应结束，反应液减压浓缩得到1c粗品(12.00g)。
第二步
氮气保护下，将1c粗品(12.00g，34.13mmol)，化合物1d(5.00g，16.01mmol)和碳酸钾(6.60g，47.75mmol)的50mL N,N-二甲基甲酰胺溶液置于60℃反应过夜。反应结束，冷却，反应液直接经反相柱层析(乙腈：水＝0-100％)纯化得到1e(3.00g)，收率：55％。
MS-ESI计算值[M+1]+343，实测值343。
第三步
在氮气保护和0℃条件下，向化合物1e(1.10g，3.21mmol)和三乙胺(650mg，6.42mmol)30mL二氯甲烷溶液中加入辛酰氯(750mg，4.61mmol)，加完后继续反应0.5小时。反应结束，反应液用二氯甲烷(30mL)稀释，用水(50mL x 1)洗涤，有机相经无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物经制备HPLC(乙腈：水＝0-100％)纯化得到1f(600mg)，收率：40％。
MS-ESI计算值[M+1]+469，实测值469。
第四步
在氮气保护下，向化合物1f(600mg，1.28mmol)的30mL乙酸乙酯溶液中,缓慢滴加氯化氢乙酸乙酯溶液(5M，0.30mL，1.50mmol)。滴加完毕，继续搅拌1小时，然后维持温度低于20℃减压浓缩得到固体，将固体溶于乙腈(10mL)和水(100mL)的溶液中冻干得到1(620mg)，收率：96％。
1H NMR(400MHz,DMSO-d6)δ8.29-8.26(m,1H),7.40-7.40(m,1H),6.77(brs,1H),6.15-6.14(m,2H),4.77(brs,1H),4.16-3.94(m,3H),3.88-3.65(m,2H),3.42-3.41(m,1H),3.29(s,3H),2.41-2.33(m,1H),2.29(t,J＝7.6Hz,2H),1.89-1.74(m,1H),1.62-1.56(m,1H),1.51-1.44(m,3H),1.24-1.16(m,8H),1.04-1.01(m,3H),0.83-0.80(m,3H).
MS-ESI计算值[M+1]+469，实测值469。
实施例2
Figure BDA0002941763800000121
第一步
参照实施例1合成方法由化合物1e经两步反应得到化合物2(500mg)，两步收率：39％。
1H NMR(400MHz,DMSO-d6)δ8.40-8.36(m,1H),7.53(brs,1H),6.87(brs,1H),6.20-6.18(m,2H),4.67(brs,1H),4.19-3.73(m,5H),3.43-3.41(m,1H),3.33(s,3H),2.56-2.51(m,1H),2.41-2.40(m,1H),1.88-1.76(m,1H),1.61-1.58(m,1H),1.12-1.10(m,9H).
MS-ESI计算值[M+1]+413，实测值413。
实施例3
Figure BDA0002941763800000122
Figure BDA0002941763800000131
参照实施例1合成方法由化合物1e经两步反应得到化合物3(500mg)，两步收率：37％。
1H NMR(400MHz,DMSO-d6)δ8.38-8.34(m,1H),7.50(brs,1H),6.85(brs,1H),6.19-6.17(m,2H),4.68(brs,1H),4.19-3.74(m,4H),3.43-3.32(m,5H),2.42-2.39(m,1H),2.29(t,J＝7.6Hz,2H),1.89-1.78(m,1H),1.57-1.46(m,3H),1.24-1.16(m,4H),1.07-1.02(m,3H),0.82-0.78(m,3H).
MS-ESI计算值[M+1]+441，实测值441。
实施例4
Figure BDA0002941763800000132
参照实施例1合成方法由化合物1e经两步反应得到化合物4(4.47g)，两步收率：64％。
1H NMR(400MHz,DMSO-d6)δ8.38-8.34(m,1H),7.52-7.50(m,1H),6.86-6.85(m,1H),6.20-6.18(m,2H),4.69(brs,1H),4.19-3.74(m,5H),3.43-3.41(m,1H),3.33(s,3H),2.44-2.41(m,1H),2.28(t,J＝7.6Hz,1H),1.91-1.80(m,1H),1.62-1.57(m,1H),1.46-1.44(m,2H),1.20-1.02(m,12H),0.84-0.80(m,3H),0.76-0.72(m,3H).
MS-ESI计算值[M+1]+497，实测值497。
实施例5
Figure BDA0002941763800000141
参照实施例1合成方法由化合物1e经两步反应得到化合物5(815mg)，两步收率：42％。
1H NMR(400MHz,DMSO-d6)δ8.27-8.26(m,1H),7.40-7.39(m,1H),6.76-6.75(m,1H),6.15-6.14(m,2H),4.77(brs,1H),4.17-3.70(m,5H),3.43-3.20(m,5H),2.41-2.33(m,1H),2.28(t,J＝7.6Hz,2H),1.89-1.74(m,1H),1.59-1.45(m,3H),1.28-1.17(m,16H),1.04-1.01(m,3H),0.87-0.83(m,3H).
MS-ESI计算值[M+1]+525，实测值525。
实施例6
Figure BDA0002941763800000142
Figure BDA0002941763800000151
参照实施例1合成方法由化合物1e经两步反应得到化合物6(510mg)，两步收率：35％。
1H NMR(400MHz,DMSO-d6)δ8.30-8.27(m,1H),7.42-7.41(m,1H),6.78-6.77(m,1H),6.16-6.15(m,2H),4.73(brs,1H),4.17-3.70(m,5H),3.42-3.40(m,1H),3.29(s,3H),2.40-2.38(m,1H),2.28(t,J＝7.6Hz,2H),1.89-1.76(m,1H),1.62-1.45(m,3H),1.27-1.17(m,24H),1.05-1.01(m,3H),0.87-0.83(m,3H).
MS-ESI计算值[M+1]+581，实测值581。
实施例7
Figure BDA0002941763800000152
参照实施例1合成方法由化合物1e经两步反应得到化合物7(350mg)，两步收率：33％。
1H NMR(400MHz,DMSO-d6)δ8.37-8.37(m,1H),7.52-7.49(m,1H),6.85(brs,1H),6.19-6.17(m,2H),4.70(brs,1H),4.18-3.71(m,5H),3.42-3.40(m,1H),3.32(s,3H),2.42-2.37(m,1H),2.29(t,J＝7.6Hz,2H),1.90-1.86(m,1H),1.62-1.46(m,3H),1.24-1.17(m,10H),1.07-1.02(m,3H),0.83-0.82(m,3H).
MS-ESI计算值[M+1]+483，实测值483。
实施例8
Figure BDA0002941763800000161
参照实施例1合成方法由化合物1e经两步反应得到化合物8(350mg)，两步收率：36％。
1H NMR(400MHz,DMSO-d6)δ8.38-8.34(m,1H),7.52-7.50(m,1H),6.85(brs,1H),6.18-6.17(m,2H),4.69(brs,1H),4.18-3.68(m，5H),3.42-3.40(m,1H),3.32(s,3H),2.42-2.37(m,1H),2.29(t,J＝7.2Hz,2H),1.92-1.83(m,1H),1.62-1.46(m,3H),1.24-1.18(m,12H),1.07-0.98(m,3H),0.86-0.83(m,3H).
MS-ESI计算值[M+1]+497，实测值497。
实施例9 Skin-Pampa分析方法
1.去大鼠腹部皮肤，小心剔除皮下脂肪、血管等，保留毛囊，减至适宜大小，pH7.4PBS冲洗干净，用滤纸吸附多余水分，备用。
2.将待测化合物配置于30％乙醇中，得1mg/mL和10mg/mL样品溶液。
3.分别量取各浓度样品溶液1mL，均匀涂抹在备好的大鼠皮肤表面，置于透皮溶出仪上。
4.以温度32℃孵育8h后，取供给室和接收室溶液，于15000rpm离心10min，取上清150μL，加入150μL的50％乙腈，涡旋混合，进行HPLC含量检测。
5.根据下公式计算Skin-Pampa参数
Figure BDA0002941763800000162
Figure BDA0002941763800000163
Pe–有效渗透系数(effective permeability coefficient)
VA–接收孔体积(ml)；
VD–供给孔体积(ml)；
A–膜面积(cm2)；
t–孵化时间(s)；
tLAG–膜平衡时间(s)；
CD(t)–在t时供给孔的浓度；
CA(t)–在t时接收孔的浓度；
CD(0)–供给孔起始的浓度.
表6.Skin PAMPA测试结果汇总
LogPe Pe(10<sup>-6</sup>cm/s)
吡罗昔康(对照化合物) -5.73±0.06 1.84±0.24
Tofacitinib -6.45±0.14 0.36±0.12
实施例1 -5.80±0.11 1.57±0.50
实施例4 -5.50±0.17 3.13±1.15
实施例5 -5.56±0.16 2.78±1.13
实施例7 -5.53±0.08 2.98±0.56
实施例8 -5.66±0.08 2.19±0.35
结论：本发明合成的化合物在大鼠透皮实验中具有优良的透皮特性，适合用于制备透皮给药制剂。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

1.一种JAK抑制剂的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，具有如下式(I)所示的结构：
Figure FDA0002941763790000011
所述的G取自JAK抑制剂药物分子失去一个H原子形成的基团，且所述的JAK抑制剂药物分子选自下组：Tofacitinib、Ruxolitinib、Baricitinib、Peficitinib、Pacritinib、Delgocitinib、Abrocitinib、Upadacitinib、Filgotinib、Itacitinib、Fedratinib、Decernotinib、SHR-0302、Delgocitinib、ASN-002、Cerdulatinib、BMS-986165、PF-06700841、INCB-52793、ATI-502、PF-06651600、AZD-4205、Deuterium-modifiedruxolitinib analog、ATI-501、R-348、NS-018、Jaktinib、KL-130008、Lestaurtinib、Momelotinib、TD-1473、Zotiraciclib、DTRMHS-07、WXSH-0150、TQ05105、WXFL10203614；
所述的R1和R2各自独立地选自下组：H、D、取代或未取代的C1-C6的烷基、取代或未取代的C1-C6的杂烷基、取代或未取代的C3-C8的环烷基、取代或未取代的3-8元的杂环基、或R1和R2和与其相连的碳原子构成C3-C8的碳环或杂环；
L选自下组：无、取代或未取代的C1-C6的亚烷基、取代或未取代的C1-C6的亚杂烷基；
R3选自下组：取代或未取代的C1-C20的烷基、取代或未取代的C3-C20的环烷基、取代或未取代的C1-C20的杂烷基、取代或未取代的3-20元的杂环基、取代或未取代的C6-C14的芳基，或者R3和R1或R2相连，从而形成一个取代或未取代的5-20元的内酯环或杂内酯环；其中，所述的杂内酯环指所述内酯环的环骨架上包括1-3个选自下组的杂原子：N、O或S(O)p；
p选自下组：0、1或2；
其中，所述的杂烷基指碳链上的一个或多个碳原子被选自下组的杂原子取代：N、O或S(O)p；
所述的杂环基包括1-3个选自下组的杂原子：N、O或S(O)p；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、C3-C8杂环基、氧代、-CN、羟基、氨基、羧基、酰胺、磺酰胺、砜基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6烷氧基、＝O。
2.如权利要求1所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的R1和R2各自独立地为H、D、或C1-C6的烷基，L选自无或C1-C6的亚烷基，且所述的R3选自下组：C1-C20的烷基，C3-C20的环烷基，C6-C14的芳基。
3.如权利要求1-2任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的R1和R2各自独立地为H，L选自无，且所述的R3选自下组：C1-C20的烷基。
4.如权利要求1-3任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的G基团选自下组：
Figure FDA0002941763790000021
5.如权利要求1-4任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的式(I)化合物具有如下式(II)所示的结构：
Figure FDA0002941763790000022
6.如权利要求1-5任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的式(I)化合物具有如下式所示的结构：
Figure FDA0002941763790000031
7.如权利要求1-6任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的式I化合物具有选自下组的结构：
Figure FDA0002941763790000032
Figure FDA0002941763790000041
8.一种制备如权利要求2所述的化合物的方法，其特征在于，包括步骤：
Figure FDA0002941763790000042
在惰性溶剂中，用式1e化合物与R3C(O)X反应，得到式(I)化合物；其中，所述的X为OH或活化基团(优选为卤素或OC(O)R3)，其余各基团的定义如权利要求1中所述。
9.一种如下式1e所示的中间体：
Figure FDA0002941763790000051
10.一种药物组合物，其特征在于，它含有药学上可接受的载体和权利要求1-7任一所述的化合物，及其药学上可接受的盐，水合物或溶剂合物。
11.一种权利要求1-7任一所述的化合物，或其药学上可接受的盐或水合物的用途，其特征在于，用于制备治疗或预防与JAK激酶的活性或表达量相关的疾病的药物组合物。
12.一种透皮给药制剂，其特征在于，包括：
权利要求1-7任一所述的化合物；
任选的皮肤渗透促进剂，优选地，所述的皮肤渗透促进剂选自下组：表面活性剂、二甲亚砜及其类似物、氮酮类化合物、吡咯酮衍生物、醇类化合物、醚类化合物、脂肪酸类化合物及脂肪酸酯类化合物，或其组合；
任选的支撑层；
较佳地，药物以单一相或者多相，溶液或者混悬存在；制剂以溶液、混悬剂、凝胶剂、乳剂、膏剂或泡沫剂形式给药。
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