CN116425722A - 一种取代的联吡啶酮-芳(杂)环类化合物及其制备方法与应用 - Google Patents
一种取代的联吡啶酮-芳(杂)环类化合物及其制备方法与应用 Download PDFInfo
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- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- SRDPNDROLKFXRH-UHFFFAOYSA-N thiadiazolo[4,5-c]pyridazine Chemical compound N1=NC=CC2=C1N=NS2 SRDPNDROLKFXRH-UHFFFAOYSA-N 0.000 description 1
- MFWNOJCSZKJNPT-UHFFFAOYSA-N thiadiazolo[4,5-d]pyrimidine Chemical compound C1=NC=C2SN=NC2=N1 MFWNOJCSZKJNPT-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
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- 238000012546 transfer Methods 0.000 description 1
- REDSKZBUUUQMSK-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC REDSKZBUUUQMSK-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
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Abstract
本申请属于化学药物技术领域,涉及一种通式(I)所示的化合物,或其消旋体、或其异构体、或其可药用的盐,
Description
技术领域
本发明属于化学药物技术领域,涉及一种取代的联吡啶酮-芳(杂)环类化合物,或其异构体、或其消旋体、或其可药用的盐,及其制备方法与应用。
背景技术
丝裂原活化蛋白激酶(MAPK)是使用磷酸化级联反应传递和传送外部刺激以产生对环境协调的细胞反应的保守的酶家族。MAPK是调节诸如基因表达、有丝分裂、分化及细胞存活/细胞凋亡的细胞活性的脯氨酸引导的丝氨酸/苏氨酸特异性蛋白激酶。迄今为止,已鉴定了四种不同类别的哺乳动物MAPK:细胞外信号传导激酶(ERK1和ERK2)、c-jun N末端激酶-1(JNK1-3)、p38MAPK(p38α、p38β、p38γ及p38δ)及ERK5。
从生物学、细胞及活体角度进行的这种途径的科学探究主要通过针对p38MAPK的性能良好的、选择性小分子抑制剂的可得性来实现,所述小分子抑制剂靶向p38MAPK的α亚型及较小程度上靶向β亚型。p38αMAPK是参与免疫反应和炎症反应的主要亚型。因此,它的功能对于在诸如巨噬细胞、单核细胞、滑膜细胞及内皮细胞的细胞中多种促炎性细胞因子的产生和活性是关键的,所述促炎性细胞因子包括TNFα、IL-1、IL-6及IL-8。p38MAPK还负责诱导关键的炎症性酶,例如COX2和iNOS,它们分别是炎症位点处类花生酸和一氧化氮的主要来源。此外,p38MAPK途径调节基质金属蛋白酶(MMP)的表达,所述基质金属蛋白酶包括MMP2、MMP9及MMP13。
使用选择性且有效的抑制剂已促进发现p38MAPK底物的若干家族,所述p38MAPK底物包括转录因子、MAPKAP激酶和其他酶。而MAPKAP激酶(MK2、MK-3及PRAK)被p38MAPK选择性磷酸化,而MSK1/2、MNK1/2和RSKb的磷酸化通过p38MAPK和ERK两者催化。尽管由于没有特异性抑制剂,底物的鉴定很困难,但RSKb的激活被认为在细胞存活中起作用。
一旦被p38MAPK磷酸化和激活,MK-2、MK-3和PRAK共有类似的底物特异性。所有的这些激酶能使小热休克蛋白Hsp27磷酸化。研究已表明PRAK-和MK3-缺陷小鼠未对内毒素休克或脂多糖(LPS)诱导的细胞因子产生的降低显示出任何耐受性。相比之下,MK-2-缺陷小鼠对内毒素休克和受损的炎症反应以及诸如TNFα、IFNγ和IL-6的细胞因子产生的显著降低显示出耐受性。因此,p38/MK2轴(axis)对于调节促炎症反应是特别必要和充足的。
利用p38:MK2相互作用以及使用MK2作为p38底物,发现显示出感兴趣性质的新的p38α抑制剂(Davidson等人)。该抑制剂通过防止MK2(Ki app 300nM)的p38α依赖性磷酸化同时保留ATF2(Ki app>20uM)的p38α依赖性磷酸化来显示底物选择性。与阻断所有p38底物的p38依赖性磷酸化的常规p38ATP竞争性抑制剂相比,这种新的抑制剂功能独特。第二个独立研究也描述了具有独特机制性能的p38抑制剂。该工作显示了选择性抑制MK2的p38依赖性磷酸化的新的机制。不同于Davidson等人之前的研究,这些机制独特的化合物与ATP相竞争且使p38/MK2复合物稳定。
综上所述,这两个研究清晰地证明了这样的概念:使用小分子抑制剂可实现选择性的p38/MK2轴阻滞。相对于常规的p38MAPK抑制剂,这些p38/MK2抑制剂在疾病的动物模型中或在人体临床环境中应保留或增强效能且显示出改善的安全特性。
发明内容
鉴于现有技术存在的问题,本申请提供一种取代的联吡啶酮-芳(杂)环类化合物,或其异构体、或其消旋体、或其可药用的盐,作为p38/MK2抑制剂,该化合物可以抑制细胞因子TNFα的产生,从而可以调节炎症反应等相关疾病。
第一方面,本申请提供一种通式(I)所示的化合物,或其或其异构体、或其消旋体、或其可药用的盐:
第二方面,本发明还提供一种药物组合物,其包含治疗有效量的上述任一项所述的化合物或其药物可接受的盐和药物可接受的载体。
第三方面,本发明还提供一种治疗有效量的上述所述的化合物或其药物可接受的盐在制备用于治疗病况的药物中的用途,所述疾病是p38/MK2相关疾病,该化合物可以抑制细胞因子TNFα的产生,从而可以调节炎症反应等相关疾病;具体地,所述病况选自慢性炎症性病症、急性炎症性病症、自身炎症性病症。
具体地,本发明通过以下技术方案来实现:
一种通式(I)所示的化合物,或其异构体、或其消旋体、或其可药用的盐,
其中,A环选自芳环、杂芳环,R1选自氢、卤素、烷基、环烷基、杂环烷基、烷基环烷基、烷基杂环烷基、卤代烷基、氰基、烷氧基,p为0、1、2、3、4或5;
R2独立地选自氢、烷基、环烷基、杂环烷基、卤素、-O-烷基、氰基、卤代烷氧基、砜基,m为0、1、2或3;
R3选自氢、烷基、环烷基、-O-烷基、卤代烷基;
R4选自氢、烷基、环烷基、-O-烷基、卤代烷基;
R5选自氢、卤素、氰基、烷基、环烷基、卤代烷基;
B环选自芳环、杂芳环,R6独立地选自氢、卤素、氰基、烷基、环烷基、卤代烷基、-O-烷基、卤代烷氧基、砜基,n为0、1、2、3、4或5;
X为O、CH2或NH,Y为CH或N;
R7、R8独立地选自氢、烷基、环烷基、烷基环烷基、卤代烷基,或R7和R8一起环化成环烷基、杂环烷基。
作为本发明的一种优选技术方案,所述烷基选自C1-6的烷基,所述C1-6的烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、仲戊基、1-乙基丙基、2-甲基丁基、叔戊基、1,2-二甲基丙基、异戊基、新戊基、正己基、异己基、仲己基、叔己基、新己基、2-甲基戊基、1,2-二甲基丁基、1-乙基丁基;
所述烷氧基选自C1-6烷氧基,所述C1-6烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、仲戊氧基、1-乙基丙氧基、2-甲基丁氧基、叔戊氧基、1,2-二甲基丙氧基、异戊氧基、新戊氧基、正己氧基、异己氧基、仲己氧基、叔己氧基、新己氧基、2-甲基戊氧基、1,2-二甲基丁氧基、1-乙基丁氧基;所述烷氧烷基选自C1-4的烷氧C1-4的烷基,进一步选自甲氧甲基、甲氧乙基、甲氧丙基、甲氧丁基、乙氧甲基、乙氧乙基、乙氧丙基、乙氧丁基、丙氧甲基、丙氧乙基、丙氧丙基、丙氧丁基、丁氧甲基、丁氧乙基、丁氧丙基、丁氧丁基。
作为本发明的一种优选技术方案,所述环烷基选自C3-6的环烷,C3-6的环烷选自环丙基、环丁基、环戊基、环己基。
作为本发明的一种优选技术方案,所述芳环选自四元环、含四元环的稠环、五元环、含五元环的稠环、六元环、含六元环的稠环、联苯型芳环;所述杂芳环是指芳环上至少一个碳原子被杂原子取代。
所述芳环包括苯环和萘环;
所述杂芳环包括吲唑、喹啉、异喹啉、喹喔啉、吲哚、异吲哚、噌啉、喹唑啉、酞嗪、嘌呤、萘啶、蝶啶、苯并呋喃、苯并噻吩、苯并噁唑、苯并噻唑、苯并异噁唑、苯并异噻唑、苯并噁二唑、苯并噻二唑、苯并三唑、苯并三嗪、苯并咪唑、吡嗪并吡唑、吡嗪并嘧啶、吡嗪并哒嗪、吡嗪并三嗪、嘧啶并吡唑、嘧啶并咪唑、嘧啶并三唑、嘧啶并三嗪、嘧啶并哒嗪、哒嗪并咪唑、哒嗪并吡唑、哒嗪并三唑、哒嗪并三嗪、三嗪并咪唑、三嗪并吡唑、三嗪并三唑、吡啶并噁唑、吡啶并噻唑、吡啶并异噁唑、吡啶并异噻唑、吡啶并噁二唑、吡啶并噻二唑、吡啶并呋喃、吡啶并吡咯、吡嗪并噁唑、吡嗪并噻唑、吡嗪并异噁唑、吡嗪并异噻唑、吡嗪并噁二唑、吡嗪并噻二唑、吡嗪并呋喃、吡嗪并吡咯、嘧啶并噁唑、嘧啶并噻唑、嘧啶并异噁唑、嘧啶并异噻唑、嘧啶并噁二唑、嘧啶并噻二唑、嘧啶并呋喃、嘧啶并吡咯、哒嗪并噁唑、哒嗪并噻唑、哒嗪并异噁唑、哒嗪并异噻唑、哒嗪并噁二唑、哒嗪并噻二唑、哒嗪并呋喃、哒嗪并吡咯、三嗪并噁唑、三嗪并噻唑、三嗪并异噁唑、三嗪并异噻唑、三嗪并噁二唑、三嗪并噻二唑、三嗪并呋喃、三嗪并吡咯。
具体,例如所述萘啶选自所述吡啶并咪唑选自/>所述吡嗪并咪唑选自/>所述吡嗪并三唑选自/> 所述嘧啶并吡唑选自/>所述嘧啶并咪唑选自/> 所述嘧啶并三唑选自/>所述哒嗪并咪唑选自/>所述哒嗪并三唑选自/>所述三嗪并咪唑选自/>所述吡啶并哒嗪选自/> 所述吡啶并吡唑选自/> 所述吡啶并嘧啶选自/>所述吡啶并三嗪选自/>所述嘧啶并三嗪选自/>
作为本发明的一种优选技术方案,所述卤素选自氟、氯、溴、碘;
卤代烷基指烷基上至少一个氢原子被卤素取代,卤代烷氧基指烷氧基上至少一个氢原子被卤素取代;
烷基环烷基是指环烷基上至少一个氢原子被烷基取代;
杂环烷基是指环烷基上至少一个碳原子被杂原子取代;烷基杂环烷基是指杂环烷基上至少一个氢原子被烷基取代。
作为本发明的一种优选技术方案,杂原子选自氮、氧、硫,杂原子为一个或者多个。
作为本发明的一种优选技术方案,化合物,或其异构体、消旋体、或其可药用的盐具有式(Ia)或(Ib)的结构:
其中,m为0、1、2或3;n为0、1、2、3、4或5;p为0、1、2、3、4或5;R1、R2、R3、R4、R5、R6、R7、R8、A环和B环如上定义。
R1独立地选自氢或甲基,p为0、1或2;
R2选自氢;
R3选自甲基、乙基;
R4选自甲基;
R5选自氯或溴;
R6选自氟,n为2;
R7、R8为氢。
作为本发明的一种优选技术方案,所述的化合物,或其异构体、或其消旋体、或其可药用的盐选自:
作为本发明的一种优选技术方案,所述药学上可接受的盐是指所述化合物,或其异构体、或其消旋体、或其可药用的盐与药学上可接受的酸或碱制备。
作为本发明的一种优选技术方案,所述化合物,或其异构体、或其消旋体、或其可药用的盐的一个以上的氢原子上被同位素氘取代。
本发明进一步提供了一种药物组合物,包含治疗有效量的所述化合物,或其异构体、或其消旋体、或其可药用的盐和药物可接受的载体。
本发明进一步提供了所述化合物,或其异构体、或其消旋体、或其可药用的盐的医药用途,具体地,在制备用于治疗疾病的药物中的用途,所述疾病为p38/MK2相关疾病,具体选自慢性炎症性病症和急性炎症性病症,其中,慢性炎症性病症优选为类风湿性关节炎。
本发明的化合物相对于现有技术的化合物具有改善的TNFα、和/或p38/MK2活性。
本发明的化合物可以通过以下制备方法制备得到:
本发明化合物可以通过类似合成路线得到,通过R取代的脒试剂与共用中间体通过关环反应构建嘧啶环,得到R取代的目标产物,同时R基团可以进一步转化成R’基团,得到R’取代的目标产物。
进而,通过不同取代基的中间体化合物按照所述制备方法,得到下式结构中R1-R8为不同取代基团的具体化合物,包括但不限于前述化合物1-化合物4。
为清楚起见,本文定义了在化合物的描述中所使用的通用术语。
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与药学上可接受的酸或碱制备。
除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外,前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在,包括水合物形式。一般而言,溶剂化形式与非溶剂化的形式相当,都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,阻转异构体,及其外消旋混合物和其他混合物,所述混合物例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体,以及D和L异构体,阻转异构体等。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明化合物分子的原子是同位素,通过同位素衍生化通常可以延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。并且,包括一个实施方案,其中至少一个原子被具有相同原子数(质子数)和不同质量数(质子和中子和)的原子取代。本发明化合物中包括的同位素的实例包括氢原子、碳原子、氮原子、氧原子、磷原子、硫原子、氟原子、氯原子,其分别包括2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F、36Cl。特别的是,随其衰退而发射辐射的放射性同位素例如3H或14C可用于药物制剂或者体内化合物的局部解剖学检验。稳定的同位素既不随其量衰减或变化,也不具有放射性,因此其可以安全使用。当构成本发明化合物分子的原子是同位素时,通过用包含相应同位素的试剂替代合成中所用的试剂,可以根据通用方法转化同位素。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氘(2H),碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
进一步地,本发明的化合物一个或多个氢原子上被同位素氘(2H)取代,本发明化合物氘代后,具有延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。
所述同位素衍生物的制备方法通常包括:相转移催化方法。例如,优选的氘化方法采用相转移催化剂(例如,四烷基铵盐,NBu4HSO4)。使用相转移催化剂交换二苯基甲烷化合物的亚甲基质子,导致比在酸(例如,甲磺酸)存在下用氘化硅烷(例如三乙基氘化甲硅烷)或用路易斯酸如三氯化铝采用氘化硼酸钠还原而引入较高的氘。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂载体或介质,代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息,可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005),该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言,术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型,组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异,取决于受体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”,“活性物质”或“活性剂”是指一种化学实体,它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
本发明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、其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上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发明的实施例。
具体实施方式
下面结合实施例对本申请作进一步详细的描述,但本申请的实施方式不限于此。
实施例1
合成3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-苯基嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮
具体合成路线如下:
步骤A:合成2,2-二甲基-6-(2-氧代丙基)-4H-1,3-二噁-4-酮
室温下,将2,2,6-三甲基-4H-1,3-二噁英-4-酮(30克,211.27毫摩尔)溶于四氢呋喃(100毫升)中,氮气保护,降至零下70摄氏度,滴加双三甲基硅基胺基锂(290毫升,1M)反应2小时,加入二乙基锌(290毫升,1M)反应0.5小时。于1.5小时内缓慢升温至零下20摄氏度,加入1-乙酰基咪唑(28克,253.52毫摩尔)反应3小时。
反应完全后,加入冰水中淬灭,6N的盐酸调节pH至3-4,乙酸乙酯萃取(50毫升×3次),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析纯化(洗脱剂:正己烷/乙酸乙酯=4/1)得到19克黄色固体2,2-二甲基-6-(2-氧代丙基)-4H-1,3-二恶-4-酮(收率:49%)。LC-MS:RT=1.65min,[M+H]+=185.13。
步骤B:合成2′-溴-4-羟基-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮
室温下,将2-溴-5-甲基吡啶-4-胺(5克,26.74毫摩尔)溶于二氧六环(100毫升)中,加入2,2-二甲基-6-(2-氧代丙基)-4H-1,3-二恶-4-酮(5.9克,32.09毫摩尔),升至90摄氏度反应5小时,滴加10N的硫酸直至不再有固体产生,继续反应2小时。
反应完全后,浓缩,加水,搅拌0.5小时,过滤,滤饼水洗两次,收集6克土黄色固体2′--溴-4-羟基-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮(收率:76%)。LC-MS:RT=1.66min,[M+H]+=295.11。
步骤C:合成2′-溴-3-氯-4-羟基-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮
室温下,将2′-溴-4-羟基-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮(200毫克,0.68毫摩尔)溶于异丙醇(5毫升)中,加入NCS(62毫克,0.37毫摩尔)、一滴二氯乙酸,升至60摄氏度反应6小时。
反应完成后,加水淬灭,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析纯化(乙酸乙酯)得到100毫克白色固体产物2′-溴-3-氯-4-羟基-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮(收率:83%)。LC-MS:RT=1.68min,[M+H]+=329.06。
步骤D:合成2′-溴-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮
室温下,向含有2′-溴-3-氯-4-羟基-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮(4克,12.20毫摩尔)的N,N-二甲基甲酰胺(20毫升)中,加入2-(溴甲基)-3,5-二氟吡啶(2.50克,12.20毫摩尔)和碳酸钾(3.36克,24.40毫摩尔),室温反应。
反应结束,加水淬灭,乙酸乙酯萃取(30毫升×3次),合并有机相,饱和食盐水洗涤(30毫升×2次),无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/0),得到2.50克白色固体2′-溴-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮(收率:45%)。LC-MS:RT=1.93min,[M+H]+=456.05。
步骤E:合成2′-乙酰基-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮
室温下,将2′-溴-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮(1克,2.19毫摩尔)、三丁基(1-乙氧基乙烯基)锡(791毫克,2.19毫摩尔)和PdCl2(PPh3)2(158毫克,0.22毫摩尔)溶于1,4-二噁烷(7毫升)中,于100摄氏度微波辐射2小时。过滤,乙酸乙酯淋洗。浓缩,残余物溶于四氢呋喃(2毫升)中,加浓盐酸直到完全水解。浓缩,残余物经硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/0)得到400毫克黄色油状的2′-乙酰基-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮(收率:44%)。LC-MS:RT=1.86min,[M+H]+=420.12。
步骤F:合成3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-苯基嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮
室温下,向含有2′-乙酰基-3-氯-4-(3,5-二氟-吡啶-2-基甲氧基)-5′-甲基-[1,4′]联吡啶基-2-酮(70.0毫克,0.17毫摩尔)的N,N-二甲基甲酰胺(3.0毫升)中,加入N,N-二甲基甲酰胺二甲缩醛(40.0毫克,0.33毫摩尔),升至55摄氏度反应5小时。浓缩反应液至一半体积,加入苯甲脒盐酸盐(79.8毫克,0.51毫摩尔)、碳酸钾(46.0毫克,0.34毫摩尔),升至75摄氏度反应4小时。
反应结束,加水淬灭,乙酸乙酯萃取(20毫升×3次),合并有机相,饱和食盐水洗涤(20毫升×2次),无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/0)。得到41.0毫克白色固体3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-苯基嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮(收率:45.4%)。LC-MS:RT=2.07min,[M+H]+=532.15。
实施例2
合成2′-(2-(1H-吡唑-1-基)嘧啶-4-基)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮
具体合成路线如下:
步骤A:合成2-(甲硫基)-4-(三丁基甲锡烷基)嘧啶
室温下,向含4-碘-2-甲硫基嘧啶(504毫克,2.0毫摩尔)的四氢呋喃(3毫升)溶液中,加入六丁基二锡(2.32克,4.0毫摩尔)、三苯基膦醋酸钯(148毫克,0.2毫摩尔)、四丁基氟化铵(6毫升),氮气保护下反应12小时。
反应结束,浓缩,残余物经柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/8)得到250毫克透明油状液体2-(甲硫基)-4-(三丁基甲锡烷基)嘧啶(收率:30.0%)。LC-MS:RT=3.37min,[M+H]+=417.16。
步骤B:合成3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(甲硫基)嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮
室温下,向含2′,3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮(206毫克,0.5毫摩尔)的1,4-二氧六环(3毫升)中,加入2-(甲硫基)-4-(三丁基甲锡烷基)嘧啶(208.5毫克,0.5毫摩尔)、四三苯基膦钯(115.5毫克,0.1毫摩尔),氮气保护下,升至110摄氏度反应18小时。/>
反应结束,加水淬灭,乙酸乙酯萃取(20毫升×3次),合并有机相,饱和食盐水(20毫升×2次)洗涤,无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/0)。得到55毫克黄色固体3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(甲硫基)嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮(收率:22.0%)。LC-MS:RT=2.00min,[M+H]+=502.19。
步骤C:合成3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(甲基磺酰基)嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮
室温下,向含3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(甲硫基)嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮(50毫克,0.1毫摩尔)的二氯甲烷(2毫升)中,加入间氯过氧苯甲酸(34.5毫克,0.2毫摩尔)反应2小时。
反应结束,加水淬灭,乙酸乙酯萃取(20毫升×3次),合并有机相,饱和食盐水(20毫升×2次)洗涤,无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/0)。得到15毫克黄色固体3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(甲基磺酰基)嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮(收率:28.1%)。LC-MS:RT=1.98min,[M+H]+=534.14。
步骤D:合成2′-(2-(1H-吡唑-1-基)嘧啶-4-基)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮
室温下,向含3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(甲基磺酰基)嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮(30毫克,0.06毫摩尔)的四氢呋喃(3毫升)中,加入钠氢(13毫克,0.6毫摩尔),搅拌10分钟,加入吡唑(38毫克,0.56毫摩尔),反应0.5小时。
反应完成后,加水淬灭,乙酸乙酯萃取(20毫升×2次),合并有机相,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=10/1)得到9毫克白色固体2′-(2-(1H-吡唑-1-基)嘧啶-4-基)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮(收率:31%)。LC-MS:RT=1.91min,[M+H]+=522.14。
实施例3
合成3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2′-(2-(3,5-二甲基-1H-吡唑-1-基)嘧啶-4-基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮
具体合成路线如下:
步骤A:合成3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2′-(2-(3,5-二甲基-1H-吡唑-1-基)嘧啶-4-基)-5′,6-二甲基-2H-[1,4′-联吡啶]-2-酮
室温下,向含3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(甲基磺酰基)嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮(30毫克,0.06毫摩尔)的四氢呋喃(3毫升)中,加入钠氢(13毫克,0.56毫摩尔),搅拌10分钟,加入3,5-二甲基-1H-吡唑(51毫克,0.56毫摩尔),反应0.5小时。
反应完成后,加水淬灭,乙酸乙酯萃取(20毫升×2次),合并有机相,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=10/1)得到5毫克白色固体3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(3,5-二甲基-1H-吡唑-1-基)嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮(收率:16%)。LC-MS:RT=1.95min,[M+H]+=550.20。
实施例4
合成3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(4-甲基-1N-吡唑-1-基)嘧啶-4-基)-2N-[1,4′-联吡啶]-2-酮
具体合成路线如下:
步骤A:合成3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(4-甲基-1N-吡唑-1-基)嘧啶-4-基)-2N-[1,4′-联吡啶]-2-酮
室温下,向含3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(甲基磺酰基)嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮(30毫克,0.06毫摩尔)的四氢呋喃(3毫升)中,加入钠氢(13毫克,0.56毫摩尔),搅拌10分钟,加入4-甲基-1H-吡唑(50毫克,0.56毫摩尔),反应0.5小时。
反应完成后,加水淬灭,乙酸乙酯萃取(20毫升×2次),合并有机相,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=10/1)得到13毫克白色固体3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5′,6-二甲基-2′-(2-(4-甲基-1H-吡唑-1-基)嘧啶-4-基)-2H-[1,4′-联吡啶]-2-酮(收率:40%)。LC-MS:RT=1.93min,[M+H]+=536.21。
实施例5-32
化合物编号为5-32的化合物的合成路线具体参见实施例1-4的化合物的合成路线,所不同的是中间体的取代基略有不同,根据目标化合物确定。
对比例1
化合物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2’-(2-(2-羟基丙-2-基)嘧啶-4-基)-5’,6-二甲基-2H-[1,4’-联吡啶]-2-酮的结构为:
对比例1的化合物合成路线参见中国专利号为CN201480032278.5的说明书编号为49的化合物的合成路线。
实施例33:LPS诱导U937释放TNFα实验
人单核细胞中的细胞因子调节:已显示p38途径是包括TNFα、IL-1β和IL-6在内的多种促炎细胞因子的生物合成的关键。因此,p38 MAPK途径的抑制通过减少促炎细胞因子的生物合成来降低炎症反应。本研究显示了抑制TNFα(促炎细胞因子)的生物合成所需的本发明化合物的半量。这是本发明化合物有助于降低炎症的效果的反映,该效果有助于治疗许多疾病,包括慢性炎症性病症、急性炎症性病症、自身炎症性病症。使用人U937细胞系对p38抑制剂阻断细胞因子产生的效能和功效进行了评价。
试剂与仪器:
1640培养基,货号A10491-01,Gibco。青链霉素,货号15140-122,Gibco。胎牛血清,货号10099-141C,Gibco。PBS,货号10010-031,Gibco。LPS,货号L2880,Sigma。PMA,货号P1585,Sigma。二甲基亚砜,货号D8418-1L,Sigma。TNFα试剂盒,货号K151QWD-4,MSD。
96孔板,货号3599,康宁。振板器,货号QB-9002,QILINBEIER。离心机,货号5810R,Eppendorf。二氧化碳培养箱,货号371,Thermo。计数器,货号C10281,Gibco。显微镜,货号CKX41,OLYMPUS。MSD读板机,1201MESO SECTOR 600,MSD。
实验细胞:
U937,ATCC,货号CRL-1593.2。
药物配制:
称取一定的药物约2mg的药物,用DMSO配制成10mM(以游离碱计算)的母液,10倍稀释母液至1mM,然后依次4倍稀释至250μM,62.5μM,15.6μM,3.9μM,0.97μM,0.24μM,0.061μM。而后将上述稀释的一系列DMSO的药物,用培养基稀释20倍作为工作液。
实验方法:
Day0:接种10000/孔,用20ng/ml的PMA刺激48h,37℃,5%CO2培养;
Day2:1、将分化的U937去除上清,PBS清洗一次,加入96μl的1640培养基;
2、加入2μl含有(终浓度0.1%DMSO)的化合物,37℃,5%CO2培养30min;
3、加入2μl LPS(终浓度100ng/ml),刺激细胞,37℃,5%CO2培养4h;
4、离心,取上清,ELISA测定上清中TNFα中含量。
统计方法:
使用试剂盒中的标准曲线计算出每个孔对应的TNFα的含量;
使用GraphPad非线性拟合公式计算化合物IC50,实验结果参见表1。
表1本发明化合物抑制TNFα生成IC50值
化合物编号 | IC50(nM) |
3 | 2.98 |
对比例1 | 16.4(n=6) |
由上表1的实验结果可知,本发明化合物对TNFα生成具有明显抑制活性,可以调节炎症反应等相关疾病。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (12)
1.一种通式(I)所示的化合物,或其异构体、或其消旋体、或其可药用的盐,其特征在于:
其中,A环选自芳环、杂芳环,R1选自氢、卤素、烷基、环烷基、杂环烷基、烷基环烷基、烷基杂环烷基、卤代烷基、氰基、烷氧基,p为0、1、2、3、4或5;
R2独立地选自氢、烷基、环烷基、杂环烷基、卤素、-O-烷基、氰基、卤代烷氧基、砜基,m为0、1、2或3;
R3选自氢、烷基、环烷基、-O-烷基、卤代烷基;
R4选自氢、烷基、环烷基、-O-烷基、卤代烷基;
R5选自氢、卤素、氰基、烷基、环烷基、卤代烷基;
B环选自芳环、杂芳环,R6独立地选自氢、卤素、氰基、烷基、环烷基、卤代烷基、-O-烷基、卤代烷氧基、砜基,n为0、1、2、3、4或5;
X为O、CH2或NH,Y为CH或N;
R7、R8独立地选自氢、烷基、环烷基、烷基环烷基、卤代烷基,或R7和R8一起环化成环烷基、杂环烷基。
2.根据权利要求1所述的化合物,或其异构体、或其消旋体、或其可药用的盐,其特征在于,
所述烷基选自C1-6的烷基,所述C1-6的烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、仲戊基、1-乙基丙基、2-甲基丁基、叔戊基、1,2-二甲基丙基、异戊基、新戊基、正己基、异己基、仲己基、叔己基、新己基、2-甲基戊基、1,2-二甲基丁基、1-乙基丁基;
所述烷氧基选自C1-6烷氧基,所述C1-6烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、仲戊氧基、1-乙基丙氧基、2-甲基丁氧基、叔戊氧基、1,2-二甲基丙氧基、异戊氧基、新戊氧基、正己氧基、异己氧基、仲己氧基、叔己氧基、新己氧基、2-甲基戊氧基、1,2-二甲基丁氧基、1-乙基丁氧基;所述烷氧烷基选自C1-4的烷氧C1-4的烷基,进一步选自甲氧甲基、甲氧乙基、甲氧丙基、甲氧丁基、乙氧甲基、乙氧乙基、乙氧丙基、乙氧丁基、丙氧甲基、丙氧乙基、丙氧丙基、丙氧丁基、丁氧甲基、丁氧乙基、丁氧丙基、丁氧丁基。
3.根据权利要求1所述的化合物,或其异构体、或其消旋体、或其可药用的盐,其特征在于,所述环烷基选自C3-6的环烷,所述C3-6的环烷选自环丙基、环丁基、环戊基、环己基;杂环烷基。
4.根据权利要求1所述的化合物,或其异构体、或其消旋体、或其可药用的盐,其特征在于,所述芳环选自四元环、含四元环的稠环、五元环、含五元环的稠环、六元环、含六元环的稠环、联苯型芳环;所述杂芳环是指芳环上至少一个碳原子被杂原子取代。
5.根据权利要求1所述的化合物,或其异构体、或其消旋体、或其可药用的盐,其特征在于,所述卤素选自氟、氯、溴、碘;卤代烷基指烷基上至少一个氢原子被卤素取代,卤代烷氧基指烷氧基上至少一个氢原子被卤素取代,杂环烷基是指环烷基上至少一个碳原子被杂原子取代。
6.根据权利要求1所述的化合物,或其异构体、或其消旋体、或其可药用的盐,其特征在于,杂原子选自氮、氧、硫,所述杂原子为一个或者多个。
10.根据权利要求1所述化合物,或其异构体、或其消旋体、或其可药用的盐,其特征在于,所述药学上可接受的盐是指化合物,或其异构体、或其消旋体、或其可药用的盐与药学上可接受的酸或碱制备。
11.一种药物组合物,其特征在于,包含治疗有效量的权利要求1-10任一项所述化合物,或其异构体、或其消旋体、或其可药用的盐和药物可接受的载体。
12.权利要求1-10任一项所述化合物,或其异构体、或其消旋体、或其可药用的盐的医药用途,具体地,在制备用于治疗疾病的药物中的用途,所述疾病为p38/MK2相关疾病,具体选自慢性炎症性病症和急性炎症性病症,其中,慢性炎症性病症优选为类风湿性关节炎。
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