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CN106554314B - 苯甲酰胺类衍生物 - Google Patents

苯甲酰胺类衍生物 Download PDF

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Publication number
CN106554314B
CN106554314B CN201610872005.2A CN201610872005A CN106554314B CN 106554314 B CN106554314 B CN 106554314B CN 201610872005 A CN201610872005 A CN 201610872005A CN 106554314 B CN106554314 B CN 106554314B
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CN106554314A (zh
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史颖
米毅
杨汉煜
王旭亮
龚登凰
白敏�
陈肖卓
陈玉洁
张雪娇
马玉秀
高清志
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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Abstract

本发明涉及通式I的苯甲酰胺类衍生物、包含其的药物组合物和其作为药物的应用：
Figure DDA0001124829960000011
其中，R1、Z和Q定义如权利要求1所述。

Description

苯甲酰胺类衍生物
技术领域
本发明属于医药技术领域，涉及一类新的苯甲酰胺类衍生物、包含其的药物组合物、其制备方法、及其作为药物的应用。
背景技术
丝裂原活化蛋白激酶(MAPK)属于丝蛋白/苏氨酸激酶，是一类接受受体传递的信号并将其带入细胞核内的重要分子，具有参与基因表达调控、细胞增殖和死亡的重要机制，在多种受体信号传递途径中均具有关键性作用。p38激酶是丝裂原活化蛋白激酶(MAPK)家族中的重要成员，被认为是细胞因子介导的免疫反应机制的一个重要部分，不仅在炎症、应激反应中具有重要作用，还参与细胞的存活、分化和凋亡等过程，被认为是细胞众多信号转导通路的重要蛋白。人们已知，p38激酶可使一些胞内蛋白质磷酸化，该蛋白质包含在酶解步骤的级联中，能够导致细胞因子(如TNF-α和IL-l)的生物合成和释放。研究发现，p38激酶在很多疾病的发生过程中具有明显的调控作用，特别是在炎症反应性疾病的调控中发挥了核心作用。炎症反应本质上是人体自身免疫系统的一个重要组成部分，如果其发生异常则可能导致一系列严重的疾病，如类风湿性关节炎、慢性肺阻塞、心血管疾病、痛风、银屑病、哮喘、肿瘤、糖尿病、动脉硬化、克罗恩病等。
众所周知，细胞因子是由多种细胞(如单细胞和巨噬细胞)产生的，它们能够导致许多生理学作用，这些生理学作用被认为在疾病(如炎症和免疫调节)中非常重要。细胞因子也被认为影响着疾病的产生和发展。
肿瘤坏死因子(TNF-α)和白介素-1(IL-l)是两个重要的促炎性细胞因子，被认为是激活细胞级联反应的主要介质，在全身炎症反应中起着主导作用，详见CharlesA.Dinarello等人的文章《炎性细胞因子；白介素-1和肿瘤坏死因子作为自身免疫疾病的效应分子》(Inflammatory cytokines:interleukin-1and tumor necrosis factor aseffector molecules in autoimmune diseases.Current Opinion in Immunology，1991，3(6)，941-948)。研究表明，使用特定的抑制剂作用于p38激酶时，TNF-α等促炎性细胞因子的表达量显著下降，说明炎症反应中TNF-α等的过度表达与p38激酶的活性密切相关，p38激酶通过控制和调节促炎性细胞因子肿瘤坏死因子(TNF-α)、白介素-1(IL-lβ)以及抗炎因子白介素-10等的合成和释放过程，从而参与炎症反应过程。因此，细胞因子(如TNF-α和IL-l)被认为参与介导许多疾病，人们期望抑制这些细胞因子的生成和/或作用可有利于预防、控制或治疗这些疾病。
非甾体类抗炎药(NSAID)是使用最常见的抗炎药，但许多个体不能耐受长时间治疗该疾病所需的剂量，使用该类药物常引发严重的毒副作用，比如胃肠道、肾脏、肝脏等的损害，有时还引发心血管不良事件。在抗炎细胞因子生物治疗领域，依那西普(Etanercept)、英夫利昔单抗(Infliximab)、阿达木单抗(Adalimumab)和阿那白滞素(Anakinra)等生物制剂，用来治疗那些使用非甾体抗炎药无效或者不方便使用的炎症患者，已取得很大的成功。然而生物制剂作为大分子药物，有研发周期较长，产业化困难，生产成本较高，注射制剂使用不方便等缺点，抗炎治疗领域需要一些使用方便、疗效较好的新型口服抗炎药物。由于p38激酶被认为是关键的抗炎靶点，调控着TNF、IL-l等炎性因子，在调节炎症反应中起着重要生物功能，p38激酶抑制剂作为化学小分子，有可能被开发成为用于治疗炎症疾病的新型小分子药物，但口服生物利用度差和高毒性一直是困扰此类化合物成药的主要问题。
发明内容
在本发明的一个方面中，本发明提供了式I的化合物或其互变异构体、光学异构体、及其药学上可接受的盐：
Figure BDA0001124829950000021
其中：
Q选自
Figure BDA0001124829950000022
Ra-f分别选自H、卤素、羟基、氨基、C1-6烷基和C1-6烷氧基，所述烷基和烷氧基可任意被一个或多个选自卤素、羟基或氨基的取代基所取代，所述氨基可被1或2个C1-6烷基所取代；
R1为：
(1)
Figure BDA0001124829950000023
R2和R3分别选自H、C1-6烷基、(CH2)0-3-3～7元(例如，(CH2)0-3-5～7元)的环烷基或包含1或2个杂原子的杂环烷基，且R2和R3不同时为H；所述C1-6烷基可任意被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、(C0-6烷基)(C0-6烷基)氨基、(C0-6烷基)硫基、(C1-6烷基)羰基、和(C1-6烷基)砜基的取代基所取代；所述3～7元(例如，5～7元)环烷基或杂环烷基被1个Rm取代，其中所述Rm选自氢、C1-6烷基、羟基、卤素或氨基，所述杂环烷基中的杂原子选自O、N和S；或者
R2和R3与其各自相连的原子一起形成5、6或7元环，
其中
所述5、6或7元环被1个Rn取代，其中所述Rn选自氢、C1-6烷基、羟基、卤素或氨基；
所述5、6或7元环，除与R2和R3连接的N原子以外，还包括0、1或2个杂原子，所述杂原子选自O、N和S；
(2)
Figure BDA0001124829950000031
R4选自C1-6烷基、-(CH2)0-1-5～7元环烷基、-CO(CH2)0-1-R5、或-CONH-R6；
R5和R6分别选自C1-6烷基，或-(CH2)0-1-5～7元环烷基；
Z为-(CH2)0-3-Y；Y选自3～7元的环烷基或包含1或2个杂原子的杂环烷基、羟基、C1-6烷氧基、卤素、氨基、氰基、硝基、烯基或炔基；所述环烷基、杂环烷基、氨基、烯基或炔基任意被取代，取代基选自C1-6烷基、C1-6烷氧基、卤素、羟基、氨基、氰基或硝基；所述杂环烷基中的杂原子选自N、S或O；
前提是所述式I的化合物不包括：
Figure BDA0001124829950000032
Figure BDA0001124829950000041
Figure BDA0001124829950000051
Figure BDA0001124829950000061
Figure BDA0001124829950000071
Figure BDA0001124829950000081
优选地，Ra-f分别选自H、F、羟基、氨基、甲基和甲氧基。
更优选地，Ra-f分别选自H、氨基、F和甲基。
优选地，Q选自：
Figure BDA0001124829950000082
更优选地，Q选自：
Figure BDA0001124829950000083
进一步优选地，Q选自：
Figure BDA0001124829950000084
更进一步优选地，Q为：
Figure BDA0001124829950000085
优选地，R1为：
Figure BDA0001124829950000091
R2和R3分别选自H、C1-6烷基、(CH2)0-3-3～7元(例如，(CH2)0-3-5～7元)的环烷基或包含1或2个杂原子的杂环烷基，且R2和R3不同时为H；所述C1-6烷基可任意被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、(C0-6烷基)(C0-6烷基)氨基、(C0-6烷基)硫基、(C1-6烷基)羰基、和(C1-6烷基)砜基的取代基所取代；所述3～7元(例如，5～7元)环烷基或杂环烷基被1个Rm取代，其中所述Rm选自氢、C1-6烷基、羟基、卤素或氨基，所述杂环烷基中的杂原子选自O、N和S；或者
R2和R3与其各自相连的原子一起形成5、6或7元环，
其中
所述5、6或7元环被1个Rn取代，其中所述Rn选自氢、C1-6烷基、羟基、卤素或氨基；
所述5、6或7元环，除与R2和R3连接的N原子以外，还包括0、1或2个杂原子，所述杂原子选自O、N和S。
更优选地，R1为：
Figure BDA0001124829950000092
R2和R3分别选自H、C1-6烷基、(CH2)0-3-3～7元(例如，(CH2)0-3-5～7元)的环烷基，且R2和R3不同时为H；所述C1-6烷基可任意被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、(C0-6烷基)(C0-6烷基)氨基、(C0-6烷基)硫基、(C1-6烷基)羰基、和(C1-6烷基)砜基的取代基所取代；所述3～7元(例如，5～7元)环烷基被1个Rm取代，其中所述Rm选自氢、C1-6烷基、羟基、卤素或氨基；或者
R2和R3与其各自相连的原子一起形成5、6或7元环，
其中
所述5、6或7元环被1个Rn取代，其中所述Rn选自氢、C1-6烷基、羟基、卤素或氨基。
进一步优选地，R1为：
Figure BDA0001124829950000093
R2和R3其中之一为H，另一个选自C1-6烷基、(CH2)0-3-3～7元(例如，(CH2)0-3-5～7元)的环烷基；所述C1-6烷基可任意被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、(C0-6烷基)(C0-6烷基)氨基、(C0-6烷基)硫基、(C1-6烷基)羰基、和(C1-6烷基)砜基的取代基所取代；所述3～7元(例如，5～7元)环烷基被1个Rm取代，其中所述Rm选自氢、C1-6烷基、羟基、卤素或氨基。
优选地，R1选自：
Figure BDA0001124829950000101
更优选地，R1选自：
Figure BDA0001124829950000102
优选地，Z选自：
Figure BDA0001124829950000103
更优选地，Z选自：
Figure BDA0001124829950000104
最优选地，Z为：
Figure BDA0001124829950000111
优选地，本发明提供了选自下述的化合物或其互变异构体、光学异构体、及其药学可接受的盐：
Figure BDA0001124829950000112
Figure BDA0001124829950000121
Figure BDA0001124829950000131
Figure BDA0001124829950000141
本发明另一方面还提供了一种药用组合物，其包括如上所述的式Ⅰ化合物、或其互变异构体、光学异构体及其药学可接受的盐。
本发明另一方面还提供了如上所述的式Ⅰ化合物或其互变异构体、光学异构体及其药学可接受的盐，或上述的药物组合物在制备用于治疗预防和/或治疗通过p38激酶活性介导的或通过由p38激酶活性产生的细胞因子介导的病症或疾病的药物中的用途。其中所述的疾病例如选自炎症疾病，例如类风湿性关节炎、慢性肺阻塞、心血管疾病、痛风、银屑病、哮喘、肿瘤、糖尿病、动脉硬化、克罗恩病等。
本发明另一方面还提供了如上所述的式Ⅰ化合物或其互变异构体、光学异构体及其药学可接受的盐的制备方法，包括将式Ⅱ化合物和式Ⅲ化合物进行缩合得到式Ⅰ化合物：
Figure BDA0001124829950000142
Q、Z和R1如前述所定义，X为卤素，优选为F、Cl、Br或I。
具体实施方式
几何异构体可以存在于本化合物中。本发明的化合物可以含有E或Z构型的碳-碳双键或碳-氮双键，其中术语“E”代表碳-碳或碳-氮双键的对侧的更高顺序取代基，术语“Z”代表碳-碳或碳-氮双键的同侧上的更高顺序取代基(利用Cahn-Ingold Prelog优先规则确定)。本发明的化合物还可以以“E”和“Z”异构体的混合物形态存在。将环烷基或杂环烷基周围的取代基称为顺式或反式构型。
本发明的化合物在R或S构型中可以含有不对称取代的碳原子，其中术语“R”和“S”如IUPAC 1974Recommendations for Section E，Fundamental Stereochemistry，PureAppl.Chem.(1976)45，13-10所定义。具有不对称取代的碳原子的化合物(具有相等数量的R和S构型)在那些碳原子处是外消旋的。具有过量的一种构型(相对于另一个)的原子使该构型存在更高数量，优选过量大约85％-90％，更优选过量大约95％-99％，更加优选过量大于大约99％。相应地，本发明包括外消旋混合物、相对和绝对立体异构体和相对与绝对立体异构体的混合物。
含有NH、C(O)OH、OH或SH部分的本发明的化合物可以具有与其连接的形成前体药物的部分。通过代谢过程除去形成前体药物的部分，并且体内释放具有游离羟基、氨基或羧酸的化合物。前体药物可有效用于调节化合物的药物动力学性能，例如，溶解度和/或疏水性，在胃肠道中的吸收，生物利用率，组织渗透性和廓清率。
前体药物是设计的活性药物的衍生物，其可以改善一些确定的、不合需要的物理或生物学性质。物理性能通常是相关的溶解度(过高或不足的脂质或水溶性)或稳定性，而有问题的生物学特性包括代谢太快或生物利用率差，这本身可能与物理化学性质相关。
前体药物通常如下制备：a)形成活性药物的酯、半酯、碳酸酯、硝酸酯、酰胺、异羟肟酸、氨基甲酸酯、亚胺、曼尼希碱、磷酸盐、磷酸酯和烯胺，b)用偶氮、糖苷、肽和醚官能团使药物功能化，c)使用药物的缩醛胺、半缩醛胺、聚合物、盐、复合物、磷酰胺、乙缩醛、半缩醛和缩酮形式。例如，参见Andrejus Korolkovas’s，"Essentials of MedicinalChemistry"，John Wiley-Interscience Publications，John Wiley and Sons，New York(1988)，pp.97-118，本文结合其所有内容作为参考。酯可以利用本领域技术人员已知的一般方法、由含有羟基或羧基的的底物来制备。这些化合物的典型反应是用另一个原子替代一个杂原子的取代。酰胺可以用类似的方式、由含有氨基或羧基的底物来制备。酯还可以与胺或氨反应，形成酰胺。制备酰胺的另一种方式是将羧酸和胺一起加热。
本发明的化合物可以以同位素示踪的或富集形式存在，含有一个或多个原子，这些原子的原子量或质量数不同于自然界中发现的最大量的原子的原子量或质量数。同位素可以是放射性或非放射性的同位素。原子例如氢、碳、磷、硫、氟、氯和碘的同位素包括但不局限于：2H，3H，13C，14C，15N，18O，32P，35S，18F，36Cl和125I。含有这些和/或其它原子的其它同位素的化合物在本发明范围之内。
本文使用的术语“互变异构体”指的是因分子中某一原子在两个位置迅速移动而产生的官能团异构体，它们之间可以互相转变，通常在某一状态下会达到一种平衡状态，以其中某一种形式为主存在，如烯醇式和酮式互变异构体。
本文使用的术语“光学异构体”指的是分子结构完全相同，物理化学性质相近，但旋光性不同的物质。
本文使用的术语“盐”选自：盐酸盐、氢溴酸盐、硫酸盐、亚硫酸盐、磷酸盐、甲磺酸盐、对甲苯磺酸盐、马来酸盐、酒石酸盐、苹果酸盐、富马酸盐、柠檬酸盐等。
在本文中，术语“C1-6烷基”是指含1-6个碳原子的直链或支链饱和烃基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。
在本文中，术语“卤素”是指氟、氯、溴或碘。
在本文中，术语“C1-6烷氧基”是指“C1-6烷基-O-”，其中C1-6烷基是如上所述的。
在本文中，术语“(C0-6烷基)(C0-6烷基)氨基”是指氨基被两个彼此独立的C0-6烷基取代，C0烷基取代意味着没有被取代。
在本文中，术语“(C0-6烷基)硫基”是指硫基被C0-6烷基取代，C0烷基取代意味着没有被取代。
在本文中，术语“(C1-6烷基)羰基”是指羰基被C1-6烷基取代，其中C1-6烷基是如上所述的。
在本文中，术语“(C1-6烷基)砜基”是指砜基被C1-6烷基取代，其中C1-6烷基是如上所述的。
在本文中，术语“3～7元环烷基”是指环丙烷基、环丁烷基、环戊烷基、环己烷基或环庚烷基。
在本文中，术语“5～7元环烷基”是指环戊烷基、环己烷基或环庚烷基。
在本文中，术语“3～7元(例如，5～7元)的包含1或2个杂原子的杂环烷基”是指环丙烷、环丁烷、环戊烷、环己烷或环庚烷上的1或2个C原子被O、N或S杂原子取代，例如可为氧杂环丙烷基、氮杂环丙烷基、氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧六环基、环氧己烷基、氮杂环庚烷基、四氢噻吩基或硫化环戊烷基。
在本文中，术语“-(CH2)0-1-”是指亚甲基或键，即，-(CH2)1-是指亚甲基，-(CH2)0-是指键。
在本文中，术语“-(CH2)0-3-”是指键、亚甲基、或连续2或3个亚甲基。在本文中，术语“-(CH2)0-1-5～7元环烷基”是指5～7元环烷基与亚甲基或键相连，所述5～7元环烷基是如上所述的。
在本文中，术语“5-7元环”是指含5、6或7个环原子的环，所述环至少包含一个氮原子作为环原子，并且除该氮原子以外，所述的5、6或7元环还可以包含0、1或2个选自O、N和S的杂原子；所述的5、6或7元环包括但不限于吡咯烷、哌啶、哌嗪、吗啉、硫代吗啉、氮杂环庚烷等。
在本文中，术语“Q”中的连接键的标注含义为：键1与苯环端连接，键2与R1端连接。
在本发明的又一方面中，本发明提供了一种药用组合物，其包括本发明所述的化合物、或其互变异构体、光学异构体及其药学可接受的盐。
本发明的药物组合物可以适用于口服施用形式如颗粒剂、片剂或胶囊，非肠道注射包括静脉、皮下注射、肌内注射、鞘内注射、或输液的形式如无菌溶液、悬浮液或乳液，局部施用形式如软膏剂或霜剂，直肠施用形式如栓剂，或为呼吸道施用形式如吸入剂，一般地，上述组合物可以采用常规赋形剂通过常规方法制备。
在本发明的又一方面中，本发明提供一种本发明所述的化合物或其互变异构体、光学异构体及其药学可接受的盐，或所述的药物组合物在制备用于治疗预防和/或治疗通过p38激酶活性介导的或通过由p38激酶活性产生的细胞因子介导的病症或疾病的药物中的用途。其中所述的疾病例选自炎症疾病，例如类风湿性关节炎、慢性肺阻塞、心血管疾病、痛风、银屑病、哮喘、肿瘤、糖尿病、动脉硬化、克罗恩病等。
本发明另一方面还提供了如上所述的式I化合物或其互变异构体、光学异构体及其药学可接受的盐的制备方法，包括将式Ⅱ化合物和式Ⅲ化合物进行缩合得到式Ⅰ化合物：
Figure BDA0001124829950000171
Q、Z和R1如权利要求1定义，X为卤素，优选为F、Cl、Br或I。
优选地，所述缩合反应的反应溶剂为异丙醇。
优选地，所述缩合反应中式Ⅱ化合物与式Ⅲ化合物的摩尔比为0.8～1.2:1，优选为1:1。
优选地，所述缩合反应在碱性条件下进行，所述碱优选为碳酸氢钠。
优选地，所述缩合反应在催化条件下进行，所用催化剂优选为四(三苯基膦)钯。
优选地，所述缩合反应的反应温度为80～100℃。
本发明的化合物具有良好的生物活性，且生物利用度高，安全性好。这些效果可以由以下的实验研究证实。
I.体外细胞水平测定
试验材料：
细胞：人单核细胞白血病THP-1细胞(中科院上海细胞库)
脂多糖：Lipopolysaccharides from Escherichia coli O55:B5，L2880(Sigma公司产品)
试剂盒：人TNFα的Elisa试剂盒(Human TNF-αElisa MAX Deluxe Set，430206，Biolegend公司产品)
试验方法：人单核细胞白血病THP-1细胞接种96孔板，密度为5*105/孔，细胞过夜贴壁培养，加入用培养基稀释的不同浓度的化合物孵育2h，加入LPS(脂多糖)10μg/ml刺激2h，离心取上清液，上清液采用人TNFα的Elisa试剂盒测定TNFα浓度。求得各化合物的IC50值。
对本发明化合物进行了上述活性测定试验，试验结果表明，本发明化合物均具有较强的的TNFα抑制活性，IC50值均小于0.5μM，优选为小于0.1μM，更优选为小于20nM，进一步优选为小于10nM，最优选为小于5nM。
实施例编号 IC<sub>50</sub>值(nM) 实施例编号 IC<sub>50</sub>值(nM)
3 B 28 B
4 A 30 A
5 A 31 A
9 B 32 A
10 A 33 A
14 B 41 A
15 A 42 B
16 A 44 A
17 A 47 B
20 B 50 A
22 A 51 A
23 B 52 B
24 B 54 B
25 A 55 B
26 B 56 B
对比例 C
实施例编号 IC<sub>50</sub>值(nM) 实施例编号 IC<sub>50</sub>值(nM)
57 A 62 B
58 A 79 B
59 A 80 B
60 B 81 B
61 A 对比例 C
A：小于5nM；
B：小于10nM且大于等于5nM；
C：小于20nM且大于等于10nM；
D：小于0.1μM且大于等于20nM；
E：小于0.5μM且大于等于0.1μM。
Ⅱ.p38激酶活性测定
试验方法：p38α40nM，加入到反应缓冲液中，其中包括20mM HEPES(4-羟乙基哌嗪乙磺酸)，5mM MgCl2，1mM DTT(二硫苏糖醇)，pH 7.4。加入40μM磷酸化肽底物，加入不同浓度的药物，加入100μM ATP(三磷酸腺苷)。黑暗中反应90min，激发和发射波长分别为544和590nM处测定荧光值。根据荧光值求得各化合物的IC50值。
对本发明化合物进行了上述活性测定试验，试验结果表明，本发明化合物均具有较强的的p38激酶抑制活性，IC50值均小于0.5μM，优选为小于0.1μM，更优选为小于20nM，进一步优选为小于10nM，最优选为小于5nM。
实施例编号 IC<sub>50</sub>值(nM) 实施例编号 IC<sub>50</sub>值(nM)
3 A 52 B
4 A 55 B
5 A 56 B
9 B 57 A
15 A 58 A
16 A 59 A
25 B 60 A
30 A 61 A
31 A 62 A
32 A 79 A
44 B 80 A
51 B 对比例 C
A：小于5nM；
B：小于10nM且大于等于5nM；
C：小于20nM且大于等于10nM；
D：小于0.1μM且大于等于20nM；
E：小于0.5μM且大于等于0.1μM。
Ⅲ.CYP450酶抑制试验
试验方法：采用人肝微粒体(Xenotech公司产品)，加入CYP450,2C9酶的底物4-羟基双氯芬酸和不同剂量的化合物，加入NADPH(还原型辅酶Ⅱ，Chem-impex international公司产品)混合，37℃水浴反应，到终止时间时加入终止液(200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔，以乙腈为溶剂)终止反应，采用甲醇或乙醇沉淀蛋白，用LC-MS/MS法测定底物的代谢产物浓度，求出化合物对CYP450,2C9酶抑制的IC50值。
对本发明化合物进行了上述CYP450酶抑制试验，试验结果表明，本发明化合物对CYP450,2C9酶抑制活性低，安全性更高。
Figure BDA0001124829950000191
Figure BDA0001124829950000201
Ⅳ药代动力学试验
试验方法：SD大鼠口服给予化合物，于给药后的不同时间点(0.25、0.5、1、2、4、6、8、24、48h)，由大鼠眼眶采血，所采集全血经EDTA(乙二胺四乙酸钠)抗凝，3000g离心分离得到大鼠血浆样品，采用甲醇或乙醇沉淀蛋白，用LC-MS/MS法测定药后大鼠血浆中的药物浓度，绘制药-时曲线并计算药代动力学参数，通过非房室模型统计矩参数描述化合物给药后大鼠体内的药代动力学行为。
对本发明化合物进行了上述药代动力学试验，试验结果表明，本发明化合物的口服生物利用度高。
实施例编号 AUC<sub>0-t</sub>(ng·h/mL)
57 22097
59 11319
61 12190
对比例 9633
实施例
在以下的实施例部分中，举例说明本发明化合物的制备方法。原料化合物是通过本文中所述的方法合成的或者是市售可得的，并且购自以下厂家：百灵威、北京伊诺凯科技有限公司、阿拉丁试剂、阿法爱莎、韶远化学科技(上海)有限公司。
在以下的实施例部分中，所使用的缩写具有下述含义。
DMF N,N-二甲基甲酰胺
Pd(dppf)Cl2 [1,1'-双(二苯基膦基)二茂铁]二氯化钯
Pd(PPh3)4 四(三苯基膦)钯
制备例：
(1)按照下述流程，制备化合物Ⅱ。
流程一：
Figure BDA0001124829950000211
步骤(1)：N-环丙基-3-氟-5-碘-4-甲基苯甲酰胺(化合物Ⅱ-b)的制备
在反应瓶中，加入3-氟-5-碘-4-甲基苯甲酸(化合物Ⅱ-a，36mmol)和氯化亚砜(50mL)，80℃回流6小时，减压蒸出过量的氯化亚砜，得淡黄色油状物，向其中加入二氯甲烷(30mL)，待用。
在反应瓶中，将环丙胺(38.6mmol)溶于二氯甲烷(50mL)中，加入碳酸钠(71.7mmol)，于0～5℃下，滴入上述酰氯的二氯甲烷溶液，滴毕室温反应1小时。反应完全后，加入水(50mL)，搅拌，分相。有机相分别用5％盐酸溶液(50mL)和饱和碳酸钠溶液(50mL)洗涤，无水硫酸钠干燥。过滤，浓缩，得11.25克白色固体(收率，98.0％)，即化合物Ⅱ-b。
步骤(2)：N-环丙基-5-氟-4-甲基-3-(4,4,5,5-四甲基-[1,3,2]-二氧杂硼烷-2-基)-苯甲酰胺(化合物(Ⅱ-1))的制备
在反应瓶中，将化合物Ⅱ-b(35.1mmol)、双联频哪醇基二硼烷(52.9mmol)、乙酸钾(176.4mmol)、Pd(dppf)Cl2(0.36mmol)加到无水DMF(100mL)中，在80℃下搅拌反应12小时。反应完毕后过滤，滤液中加入水(100mL)，加乙酸乙酯(50mL)萃取3次。有机相合并后干燥、减压浓缩至干，残留物用环己烷重结晶得6.2g白色固体(收率55.4％)，即化合物Ⅱ-1。
流程二：
Figure BDA0001124829950000212
步骤(1)：3-氟-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酸(化合物Ⅱ-c)的制备
将II-a(14.0g，50.0mmol)和双联频哪醇基二硼烷(19.0g，75.0mmol)悬浮于300mLDMF中，然后分别加入乙酸钾(14.7g，150mmol)和Pd(dppf)Cl2(3.65g，5.0mmol)，100℃反应18小时。反应完毕，冷却至室温，过滤，加入500mL纯化水，乙酸乙酯萃取(300mL×3)，合并有机相，有机相用1N稀盐酸洗涤(200mL×2)，减压浓缩，剩余物用100mL异丙醚重结晶，得到白色固体Ⅱ-c(9.87g，收率70.5％)。
步骤(2)：N-(1-苄基氮杂环丁烷-3-基)-3-氟-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(化合物Ⅱ-e)的制备
将II-c(2.80g，10.0mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.11g，11.0mmol)和1-羟基苯并三唑(1.49g，11.0mmol)悬浮于100mL二氯甲烷中，室温搅拌30分钟，加入II-d(1.78g，11.0mmol)，继续反应8小时。反应完毕，加入100mL 1N稀盐酸，分相后有机相减压浓缩，剩余物经柱层析纯化(石油醚:乙酸乙酯＝5～1:1)，得到白色固体Ⅱ-e(4.02g，收率94.8％)。
步骤(3)：N-(氮杂环丁烷-3-基)-3-氟-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(化合物(Ⅱ-2))的制备
将Ⅱ-e(3.99g，9.4mmol)和10％Pd/C(0.40g)悬浮于100mL甲醇中，室温常压下氢化5小时，过滤，有机相减压浓缩，剩余物经柱层析纯化(石油醚:乙酸乙酯＝5～1:1)，得到白色固体Ⅱ-2(2.30g，收率73.2％)。
流程三：.
Figure BDA0001124829950000221
步骤(1)：3-氟-N-(2-羟基乙基)-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(化合物(Ⅱ-3))的制备
将II-c(2.80g，10.0mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.11g，11.0mmol)和1-羟基苯并三唑(1.49g，11.0mmol)悬浮于100mL二氯甲烷中，室温搅拌30分钟，加入乙醇胺(0.67g，11.0mmol)，继续反应8小时。反应完毕，加入100mL 1N稀盐酸，分相后有机相减压浓缩，剩余物经柱层析纯化(石油醚:乙酸乙酯＝5～1:1)，得到白色固体Ⅱ-3(2.89g，收率89.5％)。
流程四：
Figure BDA0001124829950000231
步骤(1)：N-烯丙基-3-氟-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酰胺(化合物(Ⅱ-4))的制备
将II-c(2.80g，10.0mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.11g，11.0mmol)和1-羟基苯并三唑(1.49g，11.0mmol)悬浮于100mL二氯甲烷中，室温搅拌30分钟，加入烯丙胺(0.63g，11.0mmol)，继续反应8小时。反应完毕，加入100mL 1N稀盐酸，分相后有机相减压浓缩，剩余物经柱层析纯化(石油醚:乙酸乙酯＝5～1:1)，得到白色固体Ⅱ-4(2.17g，收率67.9％)。
(2)化合物Ⅲ的制备：按照下述方法一至方法六，制备下述化合物Ⅲ，即化合物Ⅲ-1～Ⅲ-81。
R1-Q-X
Ⅲ
方法一：R1为
Figure BDA0001124829950000232
Figure BDA0001124829950000233
Ⅲ与Ⅲ-a代表化合物相同；R1、Q、X定义及反应所用原料A和G见下表。
Figure BDA0001124829950000234
Figure BDA0001124829950000241
Figure BDA0001124829950000251
Figure BDA0001124829950000261
Figure BDA0001124829950000262
Figure BDA0001124829950000271
Figure BDA0001124829950000281
制备方法：
将化合物A(例如6.3mmol)加入氯化亚砜(例如5mL)中，回流反应6小时，减压蒸除过量的氯化亚砜，即得化合物B，向其中加入二氯甲烷(例如30mL)，待用。
将化合物G(例如6.8mmol)溶于二氯甲烷(例如30mL)中，于0～5℃下，滴入化合物B的二氯甲烷溶液，滴毕，室温反应1小时。反应完全后，依次用5％盐酸溶液(例如50mL)和5％氢氧化钠溶液(例如50mL)洗涤，有机相干燥，浓缩，即得化合物Ⅲ，收率＞90％。
方法二：R1为
Figure BDA0001124829950000282
Figure BDA0001124829950000283
R1、Q、X定义及反应所用原料G见下表。
Figure BDA0001124829950000284
制备方法：
将化合物C(例如4.6mmol)和三光气(例如4.6mmol)加入四氢呋喃(例如30mL)中，加热回流4小时，冷却至室温，加入5％氢氧化钠溶液(例如50毫升)和乙酸乙酯(例如30毫升)，分离有机相，干燥，减压浓缩，即得化合物D。
将化合物D(例如4.1mmol)、4-二甲胺基吡啶(例如0.41mmol)和化合物G(例如6.2mmol)溶于DMF(例如30mL)中，室温反应6小时，加入水(例如50mL)和乙酸乙酯(例如30mL)，分离有机相，干燥，浓缩，即得化合物Ⅲ(收率约为80％)。
方法三：R1为
Figure BDA0001124829950000291
R4为-CONH-R6。
Figure BDA0001124829950000292
R1、X、Q定义及反应所用原料M见下表。
Figure BDA0001124829950000293
制备方法：
将化合物E(例如4.3mmol)加入乙酸乙酯(例如30mL)中，再加入水(例如30mL)和氢氧化钠(例如4.8mmol)待用。
0-5℃下，向上述反应液中滴入2,2,2-三氯乙基氯甲酯(例如4.7mmol)，滴毕，室温反应1小时，分相，有机相干燥，减压浓缩，得化合物F，收率＞95％。
将化合物F(例如3.0mmol)，化合物M(例如6.0mmol)和N,N-二异丙基乙胺(例如6.0mmol)溶于二甲亚砜(例如30mL)中，80℃反应10小时，加入水(例如50mL)和乙酸乙酯(例如50mL)分相，有机相干燥，减压浓缩，即得化合物Ⅲ。
方法四：R1为H2N-R7，R7为C1-6烷基或5-7元环烷基。
Figure BDA0001124829950000294
R1、X、Q定义及反应所用原料W见下表。
Figure BDA0001124829950000301
制备方法：
将化合物H(例如3.0mmol)，化合物W(例如6.0mmol)和N,N-二异丙基乙胺(例如6.0mmol)加入二甲亚砜(例如30mL)中，80℃反应10小时，加入水(例如50mL)和乙酸乙酯(例如50mL)分相，有机相干燥，减压浓缩，即得化合物Ⅲ。
方法五：Ⅲ-47的制备
Figure BDA0001124829950000302
制备方法：
将环己甲酸(9.3mmol)悬浮于氯化亚砜(5mL)中，80℃回流6小时，减压蒸出过量的氯化亚砜，得淡黄色固体，向其中加入二氯甲烷(30mL)，待用。
将2-氟-4-碘苯胺(8.4mmol)溶于二氯甲烷(30mL)中，于0～5℃下，滴入上述酰氯的二氯甲烷溶液，滴毕室温反应1小时。反应完全后，依次用5％盐酸溶液(50mL)和5％氢氧化钠溶液(50mL)洗涤，有机相干燥，浓缩，得2.9g淡黄色固体，即化合物Ⅲ-47，收率99.5％。
方法六：Ⅲ-48的制备
Figure BDA0001124829950000303
Figure BDA0001124829950000311
制备方法：
将N-(2-氟-4-碘苯基)环己基甲酰胺(5.0mmol)和硼氢化钠(15.0mmol)悬浮于四氢呋喃(30mL)中，于0-5℃下滴入三氟化硼乙醚溶液(20.0mmol)，滴毕室温反应1小时，继续升温至40～50℃反应2～3小时，缓慢加入水和盐酸，调节pH至2～3，搅拌30分钟。加入乙酸乙酯(50mL)，分离有机相，干燥，减压浓缩，得1.3g淡黄色固体，即Ⅲ-48，收率78.0％。
实施例1-56：化合物I-1～I-56的制备，
合成路线：
Figure BDA0001124829950000312
其中，R1、Q和X具有下表中的含义。
制备方法：
将化合物Ⅲ(例如1.5mmol)和化合物Ⅱ(例如1.5mmol)加入异丙醇中(例如30mL)，加1M碳酸氢钠(例如1.9mL)水溶液和Pd(PPh3)4(例如0.016mmol)，90℃回流10小时，反应完毕，反应液减压浓缩。柱层析纯化(石油醚:乙酸乙酯＝5～1:1)，即得目标化合物。
Figure BDA0001124829950000313
Figure BDA0001124829950000321
Figure BDA0001124829950000331
Figure BDA0001124829950000341
Figure BDA0001124829950000351
Figure BDA0001124829950000361
Figure BDA0001124829950000371
具体物理表征结果：
Figure BDA0001124829950000372
Figure BDA0001124829950000381
Figure BDA0001124829950000391
Figure BDA0001124829950000401
Figure BDA0001124829950000411
Figure BDA0001124829950000421
Figure BDA0001124829950000431
实施例57-81：化合物I-57～I-81的制备
合成路线：
Figure BDA0001124829950000432
其中，R1、Z、Q和X具有下表中的含义。
制备方法：
将化合物Ⅲ(例如1.5mmol)和化合物Ⅱ(例如1.5mmol)加入异丙醇中(例如30mL)，加1M碳酸氢钠(例如1.9mL)水溶液和Pd(PPh3)4(例如0.016mmol)，90℃回流10小时，反应完毕，反应液减压浓缩。柱层析纯化(石油醚:乙酸乙酯＝5～1:1)，即得目标化合物。
Figure BDA0001124829950000441
Figure BDA0001124829950000451
Figure BDA0001124829950000461
Figure BDA0001124829950000471
具体物理表征结果：
Figure BDA0001124829950000472
Figure BDA0001124829950000481
Figure BDA0001124829950000491
Figure BDA0001124829950000501
Figure BDA0001124829950000511
Figure BDA0001124829950000521
备注：*表示：若无特别注明，所用溶剂为DMSO-d6。
#表示：若无特别注明，为[M+H]+。
对比例：6-(5-(环丙基氨甲酰基)-3-氟-2-甲基苯基)-N-新戊基烟酰胺的制备
Figure BDA0001124829950000522
将化合物Ⅲ-72(0.34g,1.5mmol)和化合物Ⅱ(0.479g,1.5mmol)加入异丙醇中(30mL)，加1M碳酸氢钠(1.9mL)水溶液和Pd(PPh3)4(19mg,0.016mmol)，90℃回流10小时，反应完毕，反应液减压浓缩。柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到白色固体即为标题化合物(115mg，20％)。
LC-MS(m/z)：384.2[M+H]+
1HNMR(600MHz,DMSO-d6)δ:0.582-0.587(m,2H),0.683-0.715(m,2H),0.933(s,9H),2.258(d,3H),2.822-2.905(m,1H),3.164(d,2H),7.733-7.681(m,2H),7.762(s,1H),8.335(dd,1H),8.566(d,1H),8.632(t,1H),9.113(d,1H).

Claims (16)

1.式I的化合物及其药学上可接受的盐：
Figure FDA0003030601460000011
其中：
Q选自
Figure FDA0003030601460000012
Rc选自H、卤素、羟基、氨基、C1-6烷基、和C1-6烷氧基，所述烷基和烷氧基可任意被一个或多个选自卤素、羟基或氨基的取代基所取代，所述氨基可被1或2个C1-6烷基所取代；
R1为：
(1)
Figure FDA0003030601460000013
R2和R3分别选自H、C1-6烷基、(CH2)0-3-3～7元的环烷基或3～7元的包含1或2个杂原子的杂环烷基，且R2和R3不同时为H；所述C1-6烷基可任意被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、(C0-6烷基)(C0-6烷基)氨基、(C0-6烷基)硫基、(C1-6烷基)羰基和(C1-6烷基)砜基的取代基所取代；所述3～7元环烷基或杂环烷基被1个Rm取代，其中所述Rm选自氢、C1-6烷基、羟基、卤素或氨基，所述杂环烷基中的杂原子选自O、N和S；或者
R2和R3与其各自相连的原子一起形成5、6或7元环，
其中
所述5、6或7元环被1个Rn取代，其中所述Rn选自氢、C1-6烷基、羟基、卤素或氨基；
所述5、6或7元环，除与R2和R3连接的N原子以外，还包括0、1或2个杂原子，所述杂原子选自O、N和S；
(2)
Figure FDA0003030601460000021
R4选自C1-6烷基、-(CH2)0-1-5～7元环烷基、-CO(CH2)0-1-R5、或-CONH-R6，
R5和R6分别选自C1-6烷基，或-(CH2)0-1-5～7元环烷基；
Z为
Figure FDA0003030601460000022
或(CH2)0-3-Y；Y选自3～7元的环烷基或3～7元的包含1或2个杂原子的杂环烷基、羟基、C1-6烷氧基、卤素、氨基、氰基、硝基；所述环烷基、杂环烷基、氨基任意被取代，取代基选自C1-6烷基、C1-6烷氧基、卤素、羟基、氨基、氰基或硝基；所述杂环烷基中的杂原子选自N、S或O。
2.如权利要求1所述的式I的化合物及其药学可接受的盐，其特征在于：
Z选自：
Figure FDA0003030601460000023
3.如权利要求1所述的式I的化合物及其药学可接受的盐，其特征在于：
Z选自：
Figure FDA0003030601460000024
4.如权利要求1所述的式I的化合物及其药学可接受的盐，其特征在于：
Z为：
Figure FDA0003030601460000025
5.式I的化合物及其药学可接受的盐，
Figure FDA0003030601460000031
其中：
Q选自
Figure FDA0003030601460000032
R1为：
(1)
Figure FDA0003030601460000033
R2和R3分别选自H、C1-6烷基、(CH2)0-3-3～7元的环烷基或3～7元的包含1或2个杂原子的杂环烷基，且R2和R3不同时为H；所述C1-6烷基可任意被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、(C0-6烷基)(C0-6烷基)氨基、(C0-6烷基)硫基、(C1-6烷基)羰基和(C1-6烷基)砜基的取代基所取代；所述3～7元环烷基或杂环烷基被1个Rm取代，其中所述Rm选自氢、C1-6烷基、羟基、卤素或氨基，所述杂环烷基中的杂原子选自O、N和S；或者
R2和R3与其各自相连的原子一起形成5、6或7元环，
其中
所述5、6或7元环被1个Rn取代，其中所述Rn选自氢、C1-6烷基、羟基、卤素或氨基；
所述5、6或7元环，除与R2和R3连接的N原子以外，还包括0、1或2个杂原子，所述杂原子选自O、N和S；
(2)
Figure FDA0003030601460000034
R4选自C1-6烷基、-(CH2)0-1-5～7元环烷基、-CO(CH2)0-1-R5、或-CONH-R6，
R5和R6分别选自C1-6烷基，或-(CH2)0-1-5～7元环烷基；
Z为
Figure FDA0003030601460000035
或(CH2)0-3-Y；Y选自3～7元的环烷基或3～7元的包含1或2个杂原子的杂环烷基、羟基、C1-6烷氧基、卤素、氨基、氰基、硝基；所述环烷基、杂环烷基、氨基任意被取代，取代基选自C1-6烷基、C1-6烷氧基、卤素、羟基、氨基、氰基或硝基；所述杂环烷基中的杂原子选自N、S或O。
6.如权利要求1或5所述的式I的化合物及其药学可接受的盐，其特征在于：
R1为：
Figure FDA0003030601460000041
R2和R3分别选自H、C1-6烷基、(CH2)0-3-3～7元的环烷基或3～7元的包含1或2个杂原子的杂环烷基，且R2和R3不同时为H；所述C1-6烷基可任意被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、(C0-6烷基)(C0-6烷基)氨基、(C0-6烷基)硫基、(C1-6烷基)羰基、和(C1-6烷基)砜基的取代基所取代；所述3～7元环烷基或杂环烷基被1个Rm取代，其中所述Rm选自氢、C1-6烷基、羟基、卤素或氨基，所述杂环烷基中的杂原子选自O、N和S；或者
R2和R3与其各自相连的原子一起形成5、6或7元环，
其中
所述5、6或7元环被1个Rn取代，其中所述Rn选自氢、C1-6烷基、羟基、卤素或氨基；
所述5、6或7元环，除与R2和R3连接的N原子以外，还包括0、1或2个杂原子，所述杂原子选自O、N和S。
7.如权利要求1或5所述的式I的化合物及其药学可接受的盐，其特征在于：
R1为：
Figure FDA0003030601460000042
R2和R3分别选自H、C1-6烷基、(CH2)0-3-3～7元的环烷基，且R2和R3不同时为H；所述C1-6烷基可任意被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、(C0-6烷基)(C0-6烷基)氨基、(C0-6烷基)硫基、(C1-6烷基)羰基、和(C1-6烷基)砜基的取代基所取代；所述3～7元环烷基被1个Rm取代，其中所述Rm选自氢、C1-6烷基、羟基、卤素或氨基；或者
R2和R3与其各自相连的原子一起形成5、6或7元环，
其中
所述5、6或7元环被1个Rn取代，其中所述Rn选自氢、C1-6烷基、羟基、卤素或氨基。
8.如权利要求1或5所述的式I的化合物及其药学可接受的盐，其特征在于：
R1为：
Figure FDA0003030601460000051
R2和R3其中之一为H，另一个选自C1-6烷基、(CH2)0-3-3～7元的环烷基；所述C1-6烷基可任意被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、(C0-6烷基)(C0-6烷基)氨基、(C0-6烷基)硫基、(C1-6烷基)羰基、和(C1-6烷基)砜基的取代基所取代；所述3～7元环烷基被1个Rm取代，其中所述Rm选自氢、C1-6烷基、羟基、卤素或氨基。
9.如权利要求1或5所述的式I的化合物及其药学可接受的盐，其特征在于：
R1选自：
Figure FDA0003030601460000052
10.如权利要求1或5所述的式I的化合物及其药学可接受的盐，其特征在于：
R1选自：
Figure FDA0003030601460000061
11.选自下述的化合物及其药学可接受的盐：
Figure FDA0003030601460000062
Figure FDA0003030601460000071
12.一种药物组合物，其包括权利要求1-11任一项所述的化合物及其药学可接受的盐。
13.权利要求1-11任一项所述的化合物及其药学可接受的盐，或权利要求12所述的药物组合物在制备用于治疗预防和/或治疗通过p38激酶活性介导的或通过由p38激酶活性产生的细胞因子介导的病症或疾病的药物中的用途。
14.如权利要求13所述的用途，其中所述的疾病选自炎症疾病。
15.如权利要求13所述的用途，其中所述的疾病选自类风湿性关节炎、慢性肺阻塞、心血管疾病、痛风、银屑病、哮喘、肿瘤、糖尿病、动脉硬化、克罗恩病。
16.一种如权利要求1或5所述的化合物及其药学可接受的盐的制备方法，包括将式II化合物和式III化合物进行缩合得到式I化合物：
Figure FDA0003030601460000081
Q、Z和R1如权利要求1或5定义，X为卤素。
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