CN104968658A - 哒嗪酮-酰胺衍生物 - Google Patents
哒嗪酮-酰胺衍生物 Download PDFInfo
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- CN104968658A CN104968658A CN201480007676.1A CN201480007676A CN104968658A CN 104968658 A CN104968658 A CN 104968658A CN 201480007676 A CN201480007676 A CN 201480007676A CN 104968658 A CN104968658 A CN 104968658A
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Abstract
本发明涉及式(I)的化合物
Description
本发明提供作为IRAK抑制剂的式(I)的哒嗪酮-酰胺衍生物和它们在癌症及与IRAK过表达有关的其它疾病,如类风湿性关节炎、系统性红斑狼疮或狼疮性肾炎的治疗中的用途。
背景:
激酶催化蛋白质、脂质、糖、核苷和其它细胞代谢物的磷酸化并在真核细胞生理学的所有方面中发挥关键作用。蛋白激酶和脂质激酶尤其参与响应细胞外介体或刺激(如生长因子、细胞因子或趋化因子)控制细胞的活化、生长、分化和存活的信号传导事件。蛋白激酶通常分成两类:优先将酪氨酸残基磷酸化的那些和优先将丝氨酸和/或苏氨酸残基磷酸化的那些。
激酶是用于开发抗炎药的重要治疗靶点(Cohen, 2009. Current Opinion in Cell Biology 21, 1-8),例如参与获得性和先天性免疫应答的编制(orchestration)的激酶。特别有意义的激酶靶点是IRAK家族的成员。
白细胞介素-1受体相关激酶(IRAKs)关键性地参与控制炎症的细胞内信号传导网络的调节(Ringwood和Li, 2008. Cytokine 42, 1-7)。IRAKs在许多细胞类型中表达并可介导来自各种细胞受体,包括toll样受体(TLRs)的信号。IRAK4被认为是在白细胞介素-1(IL-1)受体和除TLR3外的所有toll样受体(TLRs)下游激活的初始蛋白激酶并通过IRAK1的快速激活和IRAK2的较慢激活引发先天免疫系统中的信号传导。首先通过与IL-1 1型受体共免疫沉淀的IL-1依赖性激酶活性的生物化学提纯识别出IRAK1(Cao等人, 1996. Science 271(5252): 1128-31)。通过与IRAKI同源的序列的人表达序列标签(EST)数据库的研究检索识别出IRAK2(Muzio等人, 1997. Science 278(5343): 1612-5)。使用编码与IRAK1具有显著同源性的多肽的鼠EST序列筛选人植物血凝素活化的外周血白细胞(PBL)cDNA库以识别出IRAK3(也称作IRAKM)(Wesche等人, 1999. J. Biol. Chem. 274(27): 19403-10)。通过对通用cDNA库的IRAK类序列和PCR的数据库研究检索识别出IRAK4(Li等人, 2002. Proc. Natl. Acad. Sci. USA 99(8):5567-5572)。
表达IRAK4的无催化活性突变体而非野生型激酶的小鼠完全抵抗由几种TLR激动剂引起的败血性休克并且它们对IL-1的响应受损。由于基因缺陷而缺乏IRAK4活性的儿童被化脓菌反复感染。IRAK-依赖性TLRs和IL-1Rs看起来对儿童抵抗一些化脓菌的免疫力极其重要,但在成年人对大多数感染的保护性免疫方面起到多余的作用。因此IRAK4抑制剂可能可用于治疗成年人的慢性炎性疾病而不会使他们太易受细菌和病毒感染(Cohen, 2009. Current Opinion in Cell Biology 21, 1-8)。已经开发出强效的IRAK4抑制剂(Buckley等人, 2008. Bioorg Med Chem Lett. 18(12):3656-60)。IRAK1对TLR7介导和TLR9介导的IRF7活化和干扰素-α(IFN-α)的生成必不可少,表明IRAK1抑制剂可能可用于治疗系统性红斑狼疮(SLE)。IRAK2在IRAK4下游活化并在促炎细胞因子生成中发挥作用。因此IRAK2抑制剂可能可用于炎性疾病。
发明概述:
根据本发明的一个方面,提供式(I)的化合物。
根据本发明的另一方面,提供适用于治疗和/或预防与IRAK有关的病症的式(I)的化合物。
根据本发明的另一方面,提供能够调节,尤其是抑制哺乳动物,尤其是人类的疾病状态中IRAK的活性或功能的化合物。
根据本发明的另一方面,提供治疗和/或预防选自以下的病症的方法:自身免疫病、炎性病症、心血管疾病、神经退行性病症、细菌和病毒感染、过敏、哮喘、胰腺炎、多器官衰竭、肾病、血小板聚集、癌症、移植、精子活力、红细胞缺乏症、移植排斥、肺损伤、呼吸疾病和缺血病况。
根据另一方面,本发明提供相对于其它亚型对IRAK-4和/或IRAK-1呈选择性的式(I)的化合物。
根据本发明的另一方面,提供一种药盒或套盒,其包含优选与免疫调节剂组合的至少一种式(I)的化合物。该药盒优选由
(a) 有效量的式(I)的化合物和/或其可药用衍生物、溶剂合物、盐、水合物和立体异构体,包括它们所有比率的混合物,和
(b) 有效量的其它药物活性成分
的单独包装构成。
根据本发明的另一方面,提供式(I)和相关式的化合物的合成方法。
发明详述:
在一个实施方案中,本发明提供式(I)的化合物及其可药用衍生物、溶剂合物、互变异构体、盐、水合物和立体异构体,包括它们所有比率的混合物
其中
Z是指基团
其中
X是CH或N,
Y是CH或N,
Ra、Rc、R1各自独立地是指H、Hal或A1,
Rb是H或烷基
A1是具有1至12个C原子的支链或直链烷基,其中一个或多个,如1至7个H原子可以被Hal、ORb、COORb、CN或N(Rb)2替代,且其中一个或多个,优选1至5个CH2基团可以被O、CO、NRb或S、SO、SO2、1,2-、1,3-或1,4-亚苯基、-CH=CH-或-C≡C-替代,
且
Hal是指F、Cl、Br、I。
本发明特别包括互变异构形式(I'):
如果没有另行指明,烷基是指具有1至12个碳原子,优选1至8个碳原子,最优选1至6个碳原子的碳链。烷基非常优选是指甲基、以及乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基、以及戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基。
基团O烷基优选是指甲氧基和乙氧基。
R优选是甲基、乙基、正丙基或正丁基。
Ra优选是H、Hal、ORd或烷基,其中Rd是H、烷基或CORb。
R1优选是指H、烷基、Hal、O烷基、ORd或(CH2)nCONHRb或(CH2)nCOORb,其中n是0、1、2、3、4、5或6且Rb如上定义,且其中Rd是H、烷基或CORb。
Rb优选是H、甲基或乙基。
Z优选是指吡啶基或嘧啶基。
在上下文中,除非明确地另行指定,所有基团和指数具有式(I)下指出的含义。
通常,式I的化合物携带的取代基越优选,它们就越优选。
下面给出式I的优选化合物1至17以及它们的活性(根据实施例18中描述的IRAK 1和IRAK 4酶分析法获得的IC50值):
*: 1μM < IC50 < 5 μM
**: 0.1 μM < IC50 < 1 μM
***: IC50 < 0.1 μM
n.d: 未测定。
下列缩写是指下面使用的缩写:
Ac(乙酰基)、BINAP(2,2’-双(双苯基膦基)-1,1’-联萘)、dba(二亚苄基丙酮)、Bu(丁基)、tBu(叔丁基)、DCE(二氯乙烷)、DCM(二氯甲烷)、DIEA(二-异丙基乙胺)、DMA(二甲基乙酰胺)、DMSO(二甲亚砜)、DMF(N,N-二甲基甲酰胺)、Dppf(1,1’-双(二苯膦二茂铁))、EtOAc(乙酸乙酯)、EtOH(乙醇)、g(克)、cHex(环己烷)、HATU(六氟磷酸N-[(二甲基氨基)(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基氧基)亚甲基]-N-甲基甲铵)、HBTU(六氟磷酸N,N,N′,N′-四甲基-O-(1H-苯并三唑-1-基)脲鎓)、HPLC(高效液相色谱法)、hr(小时)、LC(液相色谱法)、LDA(二异丙基氨基锂)、LiHMDS(双(三甲基甲硅烷基)氨基锂)、MHz(兆赫)、MeOH(甲醇)、min(分钟)、mL(毫升)、mmol(毫摩尔)、mM(毫摩尔浓度)、mp(熔点)、MS(质谱法)、MW(微波)、NMM(N-甲基吗啉)、NMP(N-甲基吡咯烷)、NMR(核磁共振)、O/N(整夜)、PBS(磷酸盐缓冲盐水)、PPh3(三苯膦)、RT(室温)、TEA(三乙胺)、TFA(三氟乙酸)、THF(四氢呋喃)、TLC(薄层色谱法)、oTol(邻甲苯基)、T3P(丙基膦酸酐)、UV(紫外线)。
一般而言,本发明的根据式(I)和相关式的化合物可由易得的原材料制备。如果这样的原材料不可购得,它们可通过标准合成技术制备。一般而言,任何独立的式(I)和相关式的化合物的合成途径取决于各分子的具体取代基,此类因素是本领域普通技术人员理解的。下面在实施例中描述的下列通用方法和程序可用于制备式(I)和相关式的化合物。下列方案中描述的反应条件,如温度、溶剂或共试剂仅作为实例给出而不是限制性的。要认识到,在给出典型或优选实验条件(即反应温度、时间、试剂摩尔数、溶剂等)时,除非另行指明,也可以使用其它实验条件。最佳反应条件可随所用的特定反应物或溶剂而变,但本领域技术人员可以使用常规优化程序确定这样的条件。关于所有保护和脱保护方法,参见Philip J. Kocienski, “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994和Theodora W. Greene和Peter G. M. Wuts, “Protective Groups in Organic Synthesis”, Wiley Interscience, 第3版,1999。
根据R1、Ra、Rb、X、Y和Z的性质,可以选择不同合成策略合成式(I)的化合物。在下列方案中例举的方法中,除非另外提到,R1、Ra、Rb、X、Y和Z如说明书上文中定义。
式(I)的化合物可通过如方案1中概述的其中A是H、Li、Na或K的通式(II)的羧酸化合物和其中R1和Rb如上定义的通式(III)的氨基-苯并咪唑的偶联制备。下面在实施例中给出此类反应的通用程序,使用本领域技术人员公知的条件和方法。可以在合适的溶剂,如DMF、乙腈、THF或DCM中在从大约0℃升至50℃的温度下在存在或不存在添加剂,如HOBt和碱,如DIEA、TEA或NMM的情况下使用标准偶联剂,如HBTU、EDC、T3P或氯甲酸异丁酯。或者,可以使用本领域技术人员公知的条件和方法,在碱,如吡啶或DIEA存在下在合适的溶剂,如甲苯、DCM、THF或DMF中在从大约0℃升至RT的温度下,优选在RT下使羧酸衍生物(如酰基氯)与氨基-苯并咪唑偶联几小时。
方案1
可以如方案2中概述在两个步骤中制备其中A是H或Li、Na或K且Ra和Z如上定义的式(II)的化合物:其中L1是卤素或三氟甲磺酸酯基团且R是烷基的通式(VI)的哒嗪酮与其中R是烷基的式(V)的硼酸或酯之间的Suzuki-Miyura偶联反应以产生其中R是烷基的通式(IV)的酯、接着酯(IV)水解成酸或酸式盐(II)。下面在实施例中给出Suzuki-Miyura偶联反应的通用程序,使用本领域技术人员公知的条件和方法进行这种偶联(参见例如Miyaura, N.;Suzuki, A. Chem. Rev. 1995, 95, 2457;Takahiro I.和Toshiaki M., Tetrahedron Lett. 2005, 46, 3573-3577)。在典型程序中,在合适的溶剂,如THF、甲苯、DMF或二氧杂环己烷中,在存在或不存在水作为助溶剂的情况下,在碱,如Cs2CO3、Na2CO3、K2CO3、CsF和适当的催化剂,例如但不限于二氯双(三苯膦)钯(II)、Pd(PPh3)4或1,1'-双(二苯基膦基)二茂铁二氯钯(II)、Pd(OAc)2、Pd2(dba)3、Pd(Cl)2(PPh3)2或Pd/C存在下,在存在或不存在附加配体,例如但不限于P(tBu)3、P(oTol)3、PPh3、BINAP的情况下加热通式(VI)的哒嗪酮和式(V)的硼酸或酯。这种偶联反应可以在大约20℃至大约150℃的温度下,优选在大约120℃下进行几分钟至几小时,可能在微波辐射下。可以例如在水、水/THF、水/THF/乙醇或水/二氧杂环己烷中使用HCl、H2SO4或使用LiOH、NaOH或KOH在0至100℃的温度下进行酯(IV)的水解。根据所选反应处理(碱性或酸性条件)获得酸或盐形式。
方案2
通式(III)的氨基苯并咪唑可获自商业来源或可根据本领域技术人员公知的程序,例如但不限于J. Org. Chem. 1977, 42, 542或Bioorganic & Medicinal Chemistry Letters 2006, 16, 2842–2845中描述的程序合成。
可以如方案3中概述通过用其中R如上定义且L2是离去基,如溴、氯、碘、烷基磺酸酯或本领域技术人员已知的任何其它合适的离去基或OH基团的通式(VII)的化合物将其中Ra和L1如上定义的通式(VIII)的哒嗪酮烷基化来制备其中Ra、L1和R如上定义的式(VI)的化合物。下面在实施例中给出这种转化的通用程序,使用本领域技术人员公知的条件和方法。在典型程序中,在合适的溶剂,如THF、二氧杂环己烷、DMF、DMA中在-20℃至大约150℃的温度下用碱,例如但不限于NaH、K2CO3、Cs2CO3、LDA、LiHMDS,优选NaH和用式(VIII)的哒嗪酮处理其中L2是离去基的式(VII)的化合物几分钟至几小时。或者,可以通过其中L2是OH基团的式(VII)的化合物与式(VIII)的哒嗪酮使用本领域技术人员公知的用于Mitsunobu反应的条件(参见例如Hughes, D. L. Organic Reactions (New York), 1992,42, 335-656;Reynolds, A. J.;Kassiou, M. Current Organic Chemistry, 2009, 13 (16);1610-1632)的反应获得其中Ra、L1和R如上定义的式(VI)的化合物。通常,该反应在膦,例如但不限于P(tBu)3、PPBu3、P(oTol)3、PPh3存在下,在氮杂二羧酸酯,例如但不限于氮杂二羧酸二乙酯、氮杂二羧酸二异丙酯、四甲基偶氮二甲酰胺存在下,在溶剂,如THF、二氧杂环己烷、DCM、DCE中在-20℃至大约150℃的温度下,优选在室温下进行几分钟至几小时。
方案3
或者,可以使用类似的化学步骤,但以如方案4中概述的不同顺序制备通式(I)的化合物。在通式(VI)的化合物水解成通式(X)的酸或酸式盐后,与通式(II)的氨基苯并咪唑的偶联可以提供通式(XI)的哒嗪酮,其最后通过Suzuki-Miyura偶联反应与通式(V)的硼酸或酯反应产生通式(I)的化合物。下面在实施例中给出这种转化的通用程序,使用本领域技术人员公知的条件和方法。这些转化的典型条件与上文描述相同。
方案4
可通过从适当的溶剂中结晶或通过适当溶剂的蒸发来分离与溶剂分子结合的本发明的化合物。
可以以常规方式制备含有碱性中心的式(I)的化合物的可药用阴离子盐。例如,可以用合适的酸(纯的或在合适的溶液中)处理游离碱的溶液,并通过过滤或通过在真空下蒸发反应溶剂分离所得盐。
可以以常规方式制备含有酸性中心的式(I)的化合物的可药用阳离子盐。例如,可以用合适的碱(纯的或在合适的溶液中)处理游离酸的溶液,并通过过滤或通过在真空下蒸发反应溶剂分离所得盐。在一些情况下,可通过将酸的溶液与碱金属或碱土金属盐(如乙基己酸钠、油酸镁)的溶液(使用式(I)的化合物的所需碱金属或碱土金属盐在其中沉淀的溶剂)混合制备盐,或可另外通过浓缩和添加非溶剂分离盐。
这两种类型的盐都可以使用离子交换树脂技术形成或相互转化。
根据所用条件,反应时间通常为几分钟至14天。反应温度为大约-30℃至大约140℃,通常-10℃至90℃,特别是大约0℃至70℃。
式(I)和相关的式还包括这些化合物的旋光形式(立体异构体)、对映体、外消旋物、非对映体和水合物和溶剂合物。术语“该化合物的溶剂合物”是指惰性溶剂分子加合到该化合物上,这由于它们的相互吸引力形成。溶剂合物是例如单水合物或二水合物或醇化物。
术语“可药用衍生物”是指例如式I的化合物的盐和所谓的前药化合物。
术语“前药衍生物”是指已用例如烷基或酰基、糖或寡肽改性并在生物体中快速裂解形成活性化合物的式I的化合物。式I的化合物的“前药”优选是指在体内快速转化(例如通过在血液中水解)以产生式I的母体化合物的衍生化合物。T. Higuchi和V. Stella在"Pro-drugs as Novel Delivery Systems", Vol 14, A.C.S. Symposium Series, American Chemical Society (1975)中提供了前药概念的深入论述。可用作含羧基化合物的前药的酯的实例可见于E. B. Roche编辑的"Bioreversible Carriers in Drug Design: Theory and Application", Pergamon Press: New York (1987)的第14-21页。这些参考资料和本说明书通篇引用的任何其它参考资料意在并入本文作为参考。
这些还包括如例如Int. J. Pharm. 115, 61-67 (1995)中所述的本发明的化合物的可生物降解的聚合物衍生物。
式(I)和相关的式还包括式I的化合物的混合物,例如两种非对映体例如在1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000比率下的混合物。
这些特别优选是立体异构化合物的混合物。
药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。这种单位可根据治疗的疾病状况、给药方法和患者的年龄、体重和状况包含例如0.5毫克至1克,优选1毫克至700毫克,特别优选5毫克至100毫克的本发明的化合物,或药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。优选剂量单位制剂是包含如上指示的日剂量或分剂量或其相应分数的活性成分的那些。此外,可以使用制药领域中公知的方法制备这种类型的药物制剂。
药物制剂可适于通过任何所需的合适方法给药,例如通过经口(包括口腔或舌下)、直肠、经鼻、局部(包括口腔、舌下或经皮)、阴道或肠道外(包括皮下、肌内、静脉内或皮内)方法给药。可以使用制药领域中已知的所有方法通过例如将活性成分与赋形剂或辅助剂合并来制备这样的制剂。
适合口服给药的药物制剂可作为独立单位,例如胶囊或片剂;粉剂或颗粒剂;在水性或非水液体中的溶液或悬浮液;可食用泡沫或泡沫食品;或水包油液体乳剂或油包水液体乳剂给药。
因此,例如,在以片剂或胶囊形式口服给药的情况下,可以将活性成分组分与口服、无毒和可药用的惰性赋形剂,例如乙醇、甘油、水等合并。通过将该化合物研碎至合适的细粒度并将其与以类似方式研碎的药物赋形剂,例如可食用的碳水化合物,例如淀粉或甘露醇混合,制备粉剂。还可能存在香料、防腐剂、分散剂和染料。
通过如上所述制备粉末混合物并用其填充成形明胶壳,制备胶囊。在填充操作之前可以将助流剂和润滑剂,例如固体形式的高分散硅酸、滑石、硬脂酸镁、硬脂酸钙或聚乙二醇添加到该粉末混合物中。也可以添加崩解剂或增溶剂,例如琼脂、碳酸钙或碳酸钠以改进服用胶囊后药物的利用率。
此外,如果需要或必要,也可以将合适的粘合剂、润滑剂和崩解剂以及染料掺入该混合物中。合适的粘合剂包括淀粉、明胶、天然糖,例如葡萄糖或β-乳糖,由玉米制成的甜味剂、天然和合成橡胶,例如阿拉伯树胶、黄蓍胶或藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。这些剂型中所用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括,但不限于,淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。例如通过制备粉末混合物、粒化或干压该混合物、添加润滑剂和崩解剂并将整个混合物压成片剂来配制片剂。通过将以合适方式粉碎的化合物与如上所述的稀释剂或基料和任选与粘合剂,例如羧甲基纤维素、藻酸盐、明胶或聚乙烯基吡咯烷酮,溶出阻滞剂,例如石蜡,吸收促进剂,例如季铵盐,和/或吸收剂,例如膨润土、高岭土或磷酸二钙混合,制备粉末混合物。可通过用粘合剂,例如糖浆、淀粉糊、acadia mucilage、或纤维素或聚合物材料的溶液润湿并将其压过筛子来粒化该粉末混合物。代替粒化,可以使该粉末混合物经过压片机,以产生形状不均匀的团块,将其打碎形成颗粒。可以通过添加硬脂酸、硬脂酸盐、滑石或矿物油来润滑颗粒以防止粘着到铸片模具上。然后将润滑的混合物压成片剂。也可以将活性成分与自由流动的惰性赋形剂合并,然后在不进行粒化或干压步骤的情况下直接压成片剂。可能存在由虫胶密封层、糖或聚合物材料层和蜡光泽层构成的透明或不透明保护层。可以将染料添加到这些涂层中以便能区分不同的剂量单位。
口服液,例如溶液、糖浆和酏剂可以以剂量单位形式制备以使所给的量包含预定量的化合物。可以通过将该化合物溶解在含有合适香料的水溶液中来制备糖浆,而酏剂使用无毒醇类媒介物制备。可以通过将该化合物分散在无毒媒介物中来配制悬浮液。也可以加入增溶剂和乳化剂,例如乙氧基化异硬脂醇和聚氧乙烯山梨糖醇醚,防腐剂、香料添加剂,例如薄荷油,或天然甜味剂或糖精,或其它人工甜味剂等。
如果需要,用于口服给药的剂量单位制剂可包封在微囊中。也可以以延长或延迟释放的方式制备该制剂,例如通过将微粒材料包衣或包埋在聚合物、蜡等中。
式(I)和相关式的化合物及其盐、溶剂合物和生理功能衍生物和其它活性成分也可以以脂质体递送体系,例如小单层囊泡、大单层囊泡和多层囊泡的形式给药。脂质体可以由各种磷脂,例如胆固醇、十八烷基胺或磷脂酰胆碱形成。
式(I)和相关式的化合物及其盐、溶剂合物和生理功能衍生物和其它活性成分也可以使用单克隆抗体作为独立载体(该化合物分子偶联到其上)递送。该化合物也可以偶联到作为靶向药物载体的可溶聚合物上。这样的聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺基酚、聚羟乙基天冬酰胺基酚或聚环氧乙烷聚赖氨酸,其被棕榈酰基取代。该化合物还可偶联到适合实现药物控释的一类可生物降解的聚合物,例如聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯、和水凝胶的交联或两亲嵌段共聚物上。
适合经皮给药的药物制剂可作为独立的膏药给药以与接受者的表皮长时间密切接触。因此,例如,可以一般而言如Pharmaceutical Research, 3(6), 318 (1986)中所述通过离子电渗从膏药递送活性成分。
适合局部给药的药物化合物可配制为软膏、乳膏、混悬剂、洗剂、粉剂、溶液、糊剂、凝胶、喷雾剂、气雾剂或油。
为了治疗眼睛或其它外部组织,例如口腔和皮肤,该制剂优选以局部软膏或乳膏的形式施用。在配制成软膏的情况下,活性成分可以与石蜡族或水混溶性膏基一起使用。或者,活性成分可以与水包油膏基或油包水膏基一起配制成乳膏。
适合局部施用于眼睛的药物制剂包括滴眼液,其中将活性成分溶解或悬浮在合适的载体,特别是水性溶剂中。
适合局部施用于口腔的药物制剂包括锭剂、软锭剂和漱口液。
适合直肠给药的药物制剂可以以栓剂或灌肠剂的形式给药。
其中载体物质是固体的适合经鼻给药的药物制剂包括粒度为例如20-500微米的粗粉,其以鼻吸的方式给药,即通过经鼻腔通道从靠近鼻子放置的含有粉剂的容器中快速吸入。以液体作为载体物质的适合作为鼻喷剂或鼻滴剂给药的制剂包括在水或油中的活性成分溶液。
适合通过吸入给药的药物制剂包含可由各种类型的含气雾剂的加压分配器、喷雾器或吹入器生成的细粒状粉或雾。
适合阴道给药的药物制剂可作为子宫托、棉条、乳膏、凝胶、糊剂、泡沫或喷雾制剂给药。
适合肠道外给药的药物制剂包括包含抗氧化剂、缓冲剂、抑菌剂和溶质的水性和非水无菌注射液,借此使该制剂与被治疗的接受者的血液等渗;和可包含悬浮介质和增稠剂的水性和非水无菌悬浮液。该制剂可以在单剂或多剂容器,例如密封安瓿和管瓶中给药并以冷冻干燥(冻干)状态储存,以致只需在临使用前添加无菌载液,例如注射用水。
可以由无菌粉剂、颗粒剂和片剂根据配方制备注射溶液和悬浮液。
无需说,除上文特别提到的成分外,该制剂还可包含本领域中根据制剂的特定类型常见的其它试剂;因此,例如,适合口服给药的制剂可包含香料。
式(I)和相关式的化合物和其它活性成分的治疗有效量取决于许多因素,包括例如动物的年龄和体重、需要治疗的确切疾病状况及其严重程度、制剂的性质和给药方法,并最终由治疗医生或兽医决定。但是,化合物的有效量通常为0.1至100毫克/公斤接受者(哺乳动物)体重/天,特别通常为1至10毫克/公斤体重/天。因此,体重70公斤的成年哺乳动物每天的实际量通常为70至700毫克,其中这种量可以以每天单剂给药或通常以每天一系列分剂量(例如2、3、4、5或6)给药,以使总日剂量相同。可作为该化合物本身的有效量的分数确定其盐或溶剂合物或生理功能衍生物的有效量。
本发明还涉及治疗患有IRAK相关病症的对象的方法,其包括给予所述对象有效量的式I和相关式的化合物。本发明优选涉及一种方法,其中该IRAK相关病症是与过度活跃的免疫应答或癌症有关的自身免疫病或病况。本发明还涉及治疗患有免疫调节异常的对象的方法,其包括给予所述对象有效治疗所述免疫调节异常的量的式(I)和相关式的化合物。本发明优选涉及一种方法,其中所述免疫调节异常是自身免疫或慢性炎性疾病,其选自:过敏性疾病、肌萎缩侧索硬化(ALS)、系统性红斑狼疮、慢性类风湿性关节炎、I型糖尿病、炎性肠病、胆汁性肝硬变、葡萄膜炎、多发性硬化症、克罗恩氏病、溃疡性结肠炎、大疱性类天疱疮、肉状瘤病、牛皮癣、自身免疫性肌炎、韦格纳肉芽肿病、鱼鳞病、格雷夫斯眼病和哮喘。本发明还涉及一种方法,其中所述免疫调节异常是骨髓或器官移植排斥或移植物抗宿主疾病。本发明还涉及一种方法,其中所述免疫调节异常选自:器官或组织的移植、由移植引起的移植物抗宿主疾病、自身免疫综合征,包括类风湿性关节炎、系统性红斑狼疮、桥本氏甲状腺炎、多发性硬化症、系统性硬化症、重症肌无力、I型糖尿病、葡萄膜炎、后葡萄膜炎、变应性脑脊髓炎、肾小球肾炎、感染后自身免疫病,包括风湿热和感染后肾小球肾炎、炎性和过度增殖性皮肤病、牛皮癣、特应性皮炎、接触性皮炎、湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、大疱性类天疱疮、大疱性表皮松解、荨麻疹、血管性水肿、血管炎、红斑、皮肤嗜酸粒细胞增多症、红斑狼疮、痤疮、斑秃、角膜结膜炎、春季结膜炎、与白塞氏病有关的葡萄膜炎、角膜炎、疱疹性角膜炎、圆锥形角膜、角膜上皮营养不良、角膜白斑、眼天疱疮、蚕蚀性角膜溃疡、巩膜炎、格雷夫斯眼病、Vogt-Koyanagi-Harada综合征、肉状瘤病、花粉过敏、可逆阻塞性气道疾病、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、粉尘性哮喘、慢性或顽固性哮喘、迟发型哮喘和气道高反应性、支气管炎、胃溃疡、由缺血性疾病和血栓症造成的血管损伤、缺血性肠病、炎性肠病、坏死性小肠结肠炎、与热灼伤有关的肠损伤、乳糜泻、直肠炎、嗜酸细胞性胃肠炎、肥大细胞增多症、克罗恩氏病、溃疡性结肠炎、偏头痛、鼻炎、湿疹、间质性肾炎、肺出血肾炎综合征、溶血性尿毒症综合征、糖尿病性肾病、多发性肌炎、格林-巴利综合征、美尼尔氏病、多神经炎、多发性神经炎、单神经炎、神经根病、甲状腺机能亢进、巴塞多氏病、纯红细胞再生障碍、再生障碍性贫血、再生不良性贫血、特发性血小板减少性紫癜、自身免疫性溶血性贫血、粒细胞缺乏症、恶性贫血、巨幼红细胞性贫血、红细胞发生不能、骨质疏松症、肉状瘤病、纤维化肺、特发性间质性肺炎、皮肌炎、寻常性白斑病、寻常性鱼鳞病、光过敏、皮肤T细胞淋巴瘤、慢性淋巴细胞性白血病、动脉硬化、动脉粥样硬化、主动脉炎综合征、结节性多动脉炎、心肌病、硬皮病、韦格纳肉芽肿、Sjogren's综合征、肥胖症、嗜酸性筋膜炎(eosinophilic fascitis)、牙龈损伤、牙周组织损伤、牙槽骨损伤、substantia ossea dentis、肾小球肾炎、男性型脱发或老年性脱发(通过防止毛发脱落或提供毛发萌发和/或促进毛发生成和毛发生长)、肌肉萎缩症、脓皮病和Sezary's综合征、阿狄森氏病、在保存(preservation)、移植或缺血性疾病时发生的器官的缺血再灌注损伤、内毒素休克、假膜性结肠炎、药物或辐射造成的结肠炎、缺血性急性肾功能不全、慢性肾功能不全、肺氧或药物造成的毒素病、肺癌、肺气肿、白内障、铁质沉着病、视网膜色素变性、老年性黄斑变性、玻璃体瘢痕(vitreal scarring)、角膜碱烧伤、多形性红斑性皮炎、线性IgA大疱性皮炎(linear IgA ballous dermatitis)和水泥皮炎(cement dermatitis)、牙龈炎、牙周炎、脓毒症、胰腺炎、由环境污染、老化、癌变、癌转移和低气压病造成的疾病、由组胺或白三烯-C4释放造成的疾病、白塞氏病、自身免疫性肝炎、原发性胆汁性肝硬化、硬化性胆管炎、肝部分切除、急性肝坏死、由毒素、病毒性肝炎、休克或缺氧造成的坏死、乙肝病毒肝炎、非甲非乙型肝炎、肝硬变、酒精性肝硬变、肝衰竭、暴发性肝衰竭、迟发性肝衰竭、“慢加急性”肝衰竭、化疗效果增强、巨细胞病毒感染、HCMV感染、AIDS、癌症、老年性痴呆、帕金森病、外伤和慢性细菌感染。
与IRAK有关的病症优选选自类风湿性关节炎、银屑病关节炎、骨关节炎、系统性红斑狼疮、狼疮性肾炎、强直性脊柱炎、骨质疏松症、系统性硬化症、多发性硬化症、牛皮癣、I型糖尿病、II型糖尿病、炎性肠病(克罗恩氏病和溃疡性结肠炎)、高免疫球蛋白D(Hyperimmunoglobulinemia D)和周期性发热综合征、冷吡啉(cryopyrin)相关的周期性综合征、Schnitzler's综合征、全身型幼年特发性关节炎、成人斯蒂尔病、痛风、假性痛风、SAPHO综合征、卡斯尔曼病、脓毒症、中风、动脉粥样硬化、乳糜泻、DIRA(IL-1受体拮抗剂缺乏症)、阿尔茨海默氏病、帕金森氏病、癌症。
式(I)和相关式的优选化合物表现出小于大约5 μM,优选小于大约1 μM,更优选小于大约0.100 μM的与IRAK结合的IC50。
实验部分
下面借助一些实施例例示本发明,它们不应被视为限制本发明的范围。
概述:
下述实施例中提供的HPLC数据如下获得:
方法A: 柱Waters XbridgeTM C8 50 mm x 4.6 mm,流速2 mL/min;8分钟梯度H2O:CH3CN:TFA,从100:0:0.1%到0:100:0.05%,
UV检测: max plot或指定波长。
下述实施例中提供的LC/MS数据如下获得:
LC:
方法A: 柱Waters XbridgeTM C8 50 mm x 4.6 mm,流速2 mL/min;8分钟梯度H2O:CH3CN:TFA,从100:0:0.1%到0:100:0.05%。
方法B: 柱Waters XbridgeTM C8 50 mm x 4.6 mm,流速1 mL/min;8分钟梯度H2O:CH3CN:NH4HCO3,从100:0:0.1%到0:100:0.05%。
UV检测: max plot或指定波长。
质谱: MS Waters ZMD (ESI)。
使用Bruker AV-400 MHz获得下述实施例中提供的NMR数据。
本发明的化合物根据程序Autonom中使用的标准命名。
可以由易得的原材料通过几种合成方法、使用溶液相和固相化学程序或混合溶液和固相程序制备根据式(I)的化合物。下面在实施例中描述合成途径的实例。除非另行指明,可以分离作为外消旋混合物获得的式(I)和相关式的化合物以提供对映体富集的混合物或纯对映体。
除非另行报道,下列实验描述中使用的市售原材料购自Aldrich或Sigma或ABCR。
中间体1: 3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸锂
步骤1: 3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸甲酯的形成
在0℃下将三溴化磷(1.7克,6.6毫摩尔)添加到3-羟甲基-苯甲酸甲酯(1克,6.0毫摩尔)在乙醚(20毫升)中的溶液中。使反应混合物升温至RT并搅拌2小时。其随后用水处理。水相用饱和NaHCO3溶液(15毫升)碱化并用二氯甲烷萃取。合并的有机相经无水Na2SO4干燥,过滤并浓缩以产生3-溴甲基-苯甲酸甲酯,将其溶解在NMP中。然后将6-吡啶-3-基-2H-哒嗪-3-酮(1.1克,6.5毫摩尔)和碳酸铯(2.1克,6.5毫摩尔)添加到这种溶液中并将反应混合物在RT下搅拌12小时。其用水处理,水相用乙酸乙酯(3 × 15毫升)萃取,合并的有机相经无水Na2SO4干燥,过滤并在减压下浓缩。通过硅胶上的快速色谱法提纯以提供黄色固体状的标题产物(0.8克,57%)。
步骤2: 3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸锂的形成
将一水合氢氧化锂(0.35克,8.7毫摩尔)和3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸甲酯(1.4克,4.35毫摩尔)在THF:水(1:2, 10毫升)中的溶液在RT下搅拌12小时。将反应混合物浓缩并与甲苯共沸以提供黄色固体状的标题化合物(0.5克,52%)。
中间体2: 3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酸甲酯
根据对中间体1,步骤1描述的程序由3-羟甲基-苯甲酸甲酯和6-氯-3-基-2H-哒嗪-3-酮获得灰白色固体状的标题化合物(9.8克,94%)。
中间体3: 3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酸
将一水合氢氧化锂(0.307克,7.5毫摩尔)和3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酸甲酯(1.2克,4.30毫摩尔)在THF: 水(2:1, 30毫升)中的溶液在RT下搅拌12小时。然后将反应混合物浓缩,用饱和柠檬酸溶液(15毫升)酸化并用二氯甲烷(3 × 10毫升)萃取。合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并浓缩以提供灰白色固体状的标题化合物(1.5克,83%)。
中间体4: 2-(2-氨基-1H-苯并[d]咪唑-5-基)-N,N-二甲基乙酰胺
步骤1: 2-(苯并[c][1,2,5]噻二唑-5-基)-N,N-二甲基乙酰胺的形成
在0℃下向苯并[1,2,5]噻二唑-5-基-乙酸(如Bioorg.Med.Chem.Lett. (1998) p 17-22中所述制备,5克,25.7毫摩尔)在THF中的溶液中加入N,N-二甲胺(15.4毫升,30.8毫摩尔)和三乙胺(0.1毫升,0.8毫摩尔)。向这种反应混合物中加入T3P(在乙酸乙酯中的50% w/v溶液,49毫升,77.2毫摩尔)并在室温下搅拌12小时。该反应混合物用10%碳酸氢钠(15毫升)洗涤并用二氯甲烷(3 ×10毫升)萃取。合并的有机相用10%柠檬酸溶液洗涤,经无水Na2SO4干燥,过滤并浓缩以提供黄色固体状的标题化合物(3克,53%)。
步骤2: 2-(3,4-二氨基苯基)-N,N-二甲基乙酰胺的形成
将雷尼镍(9克,40.5毫摩尔)添加到2-(苯并[c][1,2,5]噻二唑-5-基)-N,N-二甲基乙酰胺(3克,13.5毫摩尔)在甲醇(100毫升)中的溶液中。然后在高压釜中将反应混合物在45℃下加热12小时。其随后经硅藻土垫过滤,将滤液在减压下浓缩以提供棕色固体状的标题化合物(2.0克,76%)。
步骤3: 2-(2-氨基-1H-苯并[d]咪唑-5-基)-N,N-二甲基乙酰胺的形成
将2-(3,4-二氨基苯基)-N,N-二甲基乙酰胺(3.0克,15.5毫摩尔)在乙醇(15毫升)中的溶液经30分钟添加到溴化氰(1.8克,17.0毫摩尔)在水(100毫升)中的搅拌溶液中。将反应混合物在RT下搅拌20小时。在减压下除去乙醇。所得水相用饱和NaHCO3溶液碱化并用乙酸乙酯萃取。合并的有机相经无水Na2SO4干燥,过滤并浓缩以提供棕色固体状的标题化合物(1.0克,45%)。
中间体5: 3-[3-(6-羟甲基-吡啶-3-基)-6-氧代-6H-哒嗪-1-基甲基]-苯甲酸
步骤1: 3-[3-(6-羟甲基-吡啶-3-基)-6-氧代-6H-哒嗪-1-基甲基]-苯甲酸甲酯的形成
将3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酸甲酯(0.5克,1.79毫摩尔)和[5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2-吡啶基]甲醇(0.831克,3.53毫摩尔)在DMF/H2O(9毫升/1毫升)中的混合物在氮气气氛下脱气10分钟,将Na2CO3(2.6毫升,2M溶液,5.39毫摩尔)添加到上述材料中,接着添加双(三苯膦)二氯化钯(II)(0.063克,0.089毫摩尔)。然后将反应混合物在100℃下加热3小时,用水稀释并用EtOAc萃取。合并的有机层然后用水、盐水洗涤,经无水Na2SO4干燥,过滤并浓缩。粗产物通过硅胶上的快速色谱法(正己烷: EtOAc, 80:20)提纯以提供黄色固体状的标题化合物(380毫克,52%)。
步骤2: 3-[3-(6-羟甲基-吡啶-3-基)-6-氧代-6H-哒嗪-1-基甲基]-苯甲酸的形成
根据对中间体3描述的程序由3-[3-(6-羟甲基-吡啶-3-基)-6-氧代-6H-哒嗪-1-基甲基]-苯甲酸甲酯获得灰白色固体状的标题化合物(230毫克,63%)。
中间体6: N-(1H-苯并咪唑-2-基)-3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酰胺
将1H-苯并咪唑-2-基胺(0.55克,4.17毫摩尔)、3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酸(0.85克,3.21毫摩尔)、N-甲基吗啉(0.4毫升,3.38毫摩尔)、1-羟基苯并三唑(47毫克,3.53毫摩尔)和HBTU(1.4克,3.69毫摩尔)在DMF(5毫升)中的溶液在RT下搅拌12小时。该反应混合物随后用水淬灭并减压浓缩。粗产物通过硅胶上的快速色谱法提纯以产生黄色固体状的标题化合物(0.7克,58%)。
中间体7: 3-(3-氯-4-甲基-6-氧代-6H-哒嗪-1-基甲基)-苯甲酸甲酯
将3-溴甲基-苯甲酸甲酯(3.0克,13.1毫摩尔)、6-氯-5-甲基-2H-哒嗪-3-酮(1.9克,13.1毫摩尔)和碳酸铯(4.25克,13.1毫摩尔)在N-甲基吡咯烷(15毫升)中的混合物在RT下搅拌14小时。然后将反应混合物倒入冰中并用DCM萃取(3次)。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤并浓缩。在硅胶上的快速柱色谱法提纯提供棕色固体状的标题化合物(1.5克,39%)。
中间体8: 3-(4-甲基-6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸锂
步骤1: 3-(4-甲基-6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸甲酯的形成
3-(3-氯-4-甲基-6-氧代-6H-哒嗪-1-基甲基)-苯甲酸甲酯(1.5克,5.13毫摩尔)和吡啶3-硼酸(0.94克,7.7毫摩尔)在DMF/H2O(9:1;30毫升)中的混合物在氮气气氛下脱气10分钟,将Na2CO3(7.7毫升,15.4毫摩尔)添加到上述材料中,接着添加双(三苯膦)二氯化钯(II)(0.18克,0.25毫摩尔)。然后将反应混合物在100℃下加热4小时并经硅藻土垫过滤。硅藻土垫用二氯甲烷/甲醇洗涤并将滤液在减压下浓缩。粗产物通过硅胶上的快速色谱法提纯以提供棕色固体状的标题化合物(1克,59%)。
步骤2: 3-(4-甲基-6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸锂的形成
根据对中间体1,步骤2描述的程序由3-(4-甲基-6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸甲酯获得棕色固体状的标题化合物(0.5克,65%)。
中间体9: 二甲基-[5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-吡啶-2-基甲基]-胺
(5-溴-吡啶-2-基甲基)-二甲基-胺(购自rare Chemicals, 3克,13.94毫摩尔)和联硼酸频哪醇酯(3.9克,15.34毫摩尔)在二氧杂环己烷(40毫升)中的混合物在氮气气氛下脱气10分钟,将乙酸钾(2.8克,27.89毫摩尔)添加到上述材料中,接着添加1,1′-双(二苯基膦基)二茂铁]二氯钯(II).CH2Cl2(0.50克,0.69毫摩尔)。然后将反应混合物在60℃下加热14小时并经硅藻土垫过滤。硅藻土垫用二氯甲烷/甲醇洗涤,并将滤液在减压下浓缩以提供棕色胶状的标题化合物(1.5克,41%)。
实施例1: 2,2-二甲基-丙酸2-[3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酰基氨基]-1H-苯并咪唑-5-基酯
将2,2-二甲基-丙酸2-氨基-1H-苯并咪唑-5-基酯(购自Ambinter Stock Screening Collection, 0.15克,0.6毫摩尔)、3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)苯甲酸锂(0.1克,0.3毫摩尔)、N-甲基吗啉(0.1毫升,0.9毫摩尔)、1-羟基苯并三唑(80毫克,0.6毫摩尔)和HBTU(200毫克,0.6毫摩尔)在DMF(5毫升)中的溶液在室温下搅拌12小时。该反应混合物然后用10%碳酸氢钠溶液(15毫升)稀释并用二氯甲烷(3 ×10毫升)萃取。合并的有机相用10%柠檬酸溶液洗涤,经无水Na2SO4干燥,过滤并浓缩。所得固体用甲醇(5毫升)搅拌,过滤并在真空下干燥以产生棕色固体状的标题化合物(29毫克,10%)。
实施例2: N-(1H-苯并咪唑-2-基)-3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酰胺
根据对实施例1描述的程序由3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸锂和1H-苯并咪唑-2-胺获得棕色固体状的标题化合物(135毫克,12%)。
实施例3: N-(1-甲基-1H-苯并咪唑-2-基)-3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酰胺
根据对实施例1描述的程序由3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸锂和1-甲基苯并咪唑-2-胺获得灰白色固体状的标题化合物(11毫克,18%)。
实施例4: 2-[3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酰基氨基]-1H-苯并咪唑-5-甲酸甲酯
根据对实施例1描述的程序由3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸锂和2-氨基-1H-苯并咪唑-5-甲酸甲酯(购自PharmaCore inc.)获得棕色固体状的标题化合物(13毫克,19%)。
实施例5: N-(5-羟甲基-1H-苯并咪唑-2-基)-3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酰胺
根据对实施例1描述的程序由3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸锂和(2-氨基-1H-苯并咪唑-5-基)甲醇(购自FCH Group Reagents for Synthesis)获得黄色固体状的标题化合物(6毫克,11%)。
实施例6: N-(5-二甲基氨基甲酰基甲基-1H-苯并咪唑-2-基)-3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酰胺
根据对实施例1描述的程序由3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸锂和2-(2-氨基-1H-苯并[d]咪唑-5-基)-N,N-二甲基乙酰胺获得灰白色固体状的标题化合物(49毫克,19%)。
实施例7: N-(1H-苯并咪唑-2-基)-3-[3-(6-羟甲基-吡啶-3-基)-6-氧代-6H-哒嗪-1-基甲基]-苯甲酰胺
根据对实施例1描述的程序由3-[3-(6-羟甲基-吡啶-3-基)-6-氧代-6H-哒嗪-1-基甲基]-苯甲酸和1H-苯并咪唑-2-胺获得灰白色固体状的标题化合物(28毫克,12%)。
实施例8: N-(1H-苯并咪唑-2-基)-3-(6-氧代-3-嘧啶-5-基-6H-哒嗪-1-基甲基)-苯甲酰胺
根据对中间体5,步骤1描述的程序由 N-(1H-苯并咪唑-2-基)-3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酰胺和 5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)嘧啶获得灰白色固体状的标题化合物(12毫克,9%)。
实施例9: 3-[3-(6-氨基-吡啶-3-基)-6-氧代-6H-哒嗪-1-基甲基]-N-(1H-苯并咪唑-2-基)-苯甲酰胺
根据对中间体5,步骤1描述的程序由N-(1H-苯并咪唑-2-基)-3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酰胺和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-胺获得黄色固体状的标题化合物(55毫克,36%)。
实施例10: N-(1H-苯并[d]咪唑-2-基)-3-(2-氰基-5-(吡啶-3-基)苯氧基)苯甲酰胺
根据对实施例1描述的程序由3-(4-甲基-6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)-苯甲酸锂和1H-苯并咪唑-2-胺在附加提纯步骤(通过在硅胶上的快速色谱法)下获得灰白色固体状的标题化合物(26毫克,20%)。
实施例11: N-(1H-苯并[d]咪唑-2-基)-3-((3-(6-((二甲基氨基)甲基)吡啶-3-基)-6-氧代哒嗪-1(6H)-基)甲基)苯甲酰胺
根据对中间体5,步骤1描述的程序由N-(1H-苯并咪唑-2-基)-3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酰胺和二甲基-[5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-吡啶-2-基甲基]-胺获得灰白色固体状的标题化合物(103毫克,32%)。
实施例12: N-(1H-苯并[d]咪唑-2-基)-3-((3-(4-甲基吡啶-3-基)-6-氧代哒嗪-1(6H)-基)甲基)苯甲酰胺
根据对中间体5,步骤1描述的程序由N-(1H-苯并咪唑-2-基)-3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酰胺和4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶(购自Boron Molecular)获得米色固体状的标题化合物(12毫克,5%)。
实施例13: N-(1H-苯并[d]咪唑-2-基)-3-((3-(6-甲基哒嗪-4-基)-6-氧代哒嗪-1(6H)-基)甲基)苯甲酰胺
根据对中间体5,步骤1描述的程序由N-(1H-苯并咪唑-2-基)-3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酰胺和3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)哒嗪(购自Combi-Blocks)获得白色固体状的标题化合物(35毫克,12%)。
实施例14: N-(1H-苯并[d]咪唑-2-基)-3-((3-(5-((二甲基氨基)甲基)吡啶-3-基)-6-氧代哒嗪-1(6H)-基)甲基)苯甲酰胺
根据对中间体5,步骤1描述的程序由N-(1H-苯并咪唑-2-基)-3-(3-氯-6-氧代-6H-哒嗪-1-基甲基)-苯甲酰胺和二甲基-[5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-吡啶-3-基甲基]-胺(购自Small Molecules, inc.)获得白色固体状的标题化合物( 94毫克,32%)。
实施例15: N-(5,6-二甲氧基-1H-苯并[d]咪唑-2-基)-3-((6-氧代-3-(吡啶-3-基)哒嗪-1(6H)-基)甲基)苯甲酰胺
根据对中间体6描述的程序由5,6-二甲氧基-1H-苯并咪唑-2-基胺(购自Enamine)和3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)苯甲酸锂获得黄色固体状的标题化合物(46毫克,8%)。
实施例16: N-(5-甲氧基-1H-苯并[d]咪唑-2-基)-3-((6-氧代-3-(吡啶-3-基)哒嗪-1(6H)-基)甲基)苯甲酰胺
根据对中间体6描述的程序由5-甲氧基-1H-苯并咪唑-2-基胺(购自Anichem)和3-(6-氧代-3-吡啶-3-基-6H-哒嗪-1-基甲基)苯甲酸锂获得黄色固体状的标题化合物(101毫克,11%)。
实施例17: N-(1H-苯并咪唑-2-基)-3-[3-(5-羟甲基-吡啶-3-基)-6-氧代-6H-哒嗪-1-基甲基]-苯甲酰胺
根据对实施例1描述的程序由3-[3-(5-羟甲基-吡啶-3-基)-6-氧代-6H-哒嗪-1-基甲基]-苯甲酸锂和1H-苯并咪唑-2-胺获得灰白色固体状的标题化合物(119毫克,41%)。
实施例18: IRAK1和IRAK4酶分析法
IRAK1酶分析法:
IRAK1是人纯化重组酶(His-TEV-IRAK1 (194-712))
在此分析中,IRAK-1水解ATP并自磷酸化。
在链霉亲和素涂布的384孔FlashPlate(PerkinElmer #SMP410A)中进行IRAK-1抑制的测量。
His-TEV-IRAK-1(15ng/孔)、ATP(1 μM, [33P]ATP 0.25μCi/孔)和在DMSO中的化合物(20μM至1nM的浓度范围)或对照物(2%DMSO)在测定缓冲液:Hepes pH7.0 50mM, 无脂肪酸的BSA 0.1%, 二硫苏糖醇DTT 2mM, MgCl2 10mM, EGTA 0.5mM, Triton-X-100 0.01%中在30℃下孵育3小时。通过添加EDTA终止激酶反应。弃置上清液,板用150 mM NaCl洗涤三次,然后在Microbeta Trilux读板仪中测量放射性。
IRAK4酶分析法:
IRAK4是人纯化重组酶(His-TEV-IRAK1 (194-712))
IRAK4水解ATP,自磷酸化并将丝氨酸/苏氨酸通用肽底物(STK: 61ST1BLC,来自总部在Bagnols/Cèze FR的CisBio International)磷酸化。
在链霉亲和素涂布的384孔FlashPlate(PerkinElmer #SMP410A)中进行IRAK-4抑制的测量。His-TEV-IRAK4(20ng/孔)、ATP(2μM, [33P]ATP 0.25μCi/孔)、STK1-生物素肽(300nM)和在DMSO中的化合物(20μM至1nM的浓度范围)或对照物(2%DMSO)在测定缓冲液:Hepes pH7.0 50mM, 无脂肪酸的BSA 0.1%, 二硫苏糖醇DTT 2mM, MgCl2 10mM, EGTA 0.5mM, Tween-20 0.01%, MnCl2 5mM中在30℃下孵育3小时。
通过添加EDTA终止激酶反应。弃置上清液,板用150 mM NaCl洗涤三次,然后在Microbeta Trilux读板仪中测量放射性。
实施例19: 药物制剂的制备
制剂1 - 片剂
式(I)的化合物作为干粉与干明胶粘合剂以大约1:2重量比混合。加入次要量的硬脂酸镁作为润滑剂。在压片机中将该混合物成型为240-270毫克片剂(每片80-90毫克本发明的活性化合物)。
制剂2 - 胶囊
式(I)的化合物作为干粉与淀粉稀释剂以大约1:1重量比混合。将该混合物填充到250毫克胶囊中(每个胶囊125毫克本发明的活性化合物)。
制剂3 - 液体
掺合式(I)的化合物(1250毫克)、蔗糖(1.75克)和黄原胶(4毫克),通过No. 10 目 U.S.筛子,然后与微晶纤维素和羧甲基纤维素钠(11:89,50毫克)在水中的预制溶液混合。将苯甲酸钠(10毫克)、香料和色素用水稀释并在搅拌下加入。然后加入足量的水以产生5毫升总体积。
制剂4 - 片剂
式(I)的化合物作为干粉与干明胶粘合剂以大约1:2重量比混合。加入次要量的硬脂酸镁作为润滑剂。在压片机中将该混合物成型为450-900毫克片剂(150-300毫克本发明的活性化合物)。
制剂5 - 注射液
将式(I)的化合物溶解在缓冲无菌盐水可注射水性介质中至大约5 mg/mL的浓度。
Claims (15)
1.式(I)的化合物及其可药用衍生物、溶剂合物、盐和立体异构体,包括它们所有比率的混合物
其中
Z是指基团
其中
X是CH或N,
Y是CH或N,
Ra、Rc、R1各自独立地是指H、Hal或A1,
Rb是H或烷基
A1是具有1至12个C原子的支链或直链烷基,其中一个或多个,如1至7个H原子可以被Hal、ORb、COORb、CN或N(Rb)2替代,且其中一个或多个,优选1至5个CH2基团可以被O、CO、NRb或S、SO、SO2、1,2-、1,3-或1,4-亚苯基、-CH=CH-或-C≡C-替代,
且
Hal是指F、Cl、Br、I。
2.根据权利要求1的式(I)的化合物,其中Ra是Hal、ORd或烷基,其中Rd是H、烷基或COH或CO烷基。
3.根据权利要求1或2的式(I)的化合物,其中R1是指H、烷基、Hal、O烷基、ORd或(CH2)nCONHRb或(CH2)nCOORb,其中n是0、1、2、3、4、5或6且Rb如上定义,且其中Rd是H、烷基或CORb。
4.根据权利要求1、2或3的式(I)的化合物,其中Z是吡啶基或嘧啶基。
5.式(I)的化合物,其选自:
及其可药用衍生物、溶剂合物、盐和立体异构体,包括它们所有比率的混合物。
6.根据前述权利要求的式(I)的化合物及其可药用衍生物、溶剂合物、互变异构体、盐、水合物和立体异构体,包括它们所有比率的混合物,用作药物。
7.根据权利要求6的化合物,用于治疗或预防炎性疾病、自身免疫病、癌症或多发性硬化症和相关病症。
8.根据权利要求7的化合物,其中所述自身免疫病选自哮喘、类风湿性关节炎、急性播散性脑脊髓炎(ADEM)、阿狄森氏病、斑秃、强直性脊柱炎、抗磷脂抗体综合征(APS)、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳病、大疱性类天疱疮、白塞氏病、乳糜泻、抗-转谷氨酰胺酶、查加斯病、慢性阻塞性肺病、克罗恩氏病、皮肌炎、1型糖尿病、子宫内膜异位症、肺出血肾炎综合征、格雷夫斯病、格林-巴利综合征(GBS)、桥本氏病、化脓性汗腺炎、川崎病、IgA肾病、特发性血小板减少性紫癜、间质性膀胱炎、红斑狼疮、混合性结缔组织病、硬斑病、多发性硬化症(MS)、重症肌无力、发作性睡病、神经性肌强直、寻常天疱疮、恶性贫血、牛皮癣、银屑病关节炎、多肌炎、原发性胆汁性肝硬化、类风湿性关节炎、精神分裂症、硬皮病、Sj?gren's综合征、僵人综合征、系统性硬化症、颞动脉炎、溃疡性结肠炎、血管炎、白癫风、韦格纳肉芽肿病。
9.权利要求7的化合物,其中所述疾病选自类风湿性关节炎、银屑病关节炎、骨关节炎、系统性红斑狼疮、狼疮性肾炎、强直性脊柱炎、骨质疏松症、系统性硬化症、多发性硬化症、牛皮癣、I型糖尿病、II型糖尿病、炎性肠病(克罗恩氏病和溃疡性结肠炎)、高免疫球蛋白D和周期性发热综合征、冷吡啉相关的周期性综合征、Schnitzler's综合征、全身型幼年特发性关节炎、成人斯蒂尔病、痛风、假性痛风、SAPHO综合征、卡斯尔曼病、脓毒症、中风、动脉粥样硬化、乳糜泻、DIRA(IL-1受体拮抗剂缺乏症)、阿尔茨海默氏病、帕金森氏病、癌症。
10.权利要求6的化合物,其中所述疾病选自类风湿性关节炎、狼疮性肾炎、系统性红斑狼疮。
11.根据权利要求1的式(I)的化合物,其用于预防和/或治疗与IRAK过表达有关的疾病。
12.药盒,其由:
(a) 有效量的式(I)的化合物和/或其可药用衍生物、溶剂合物、盐、水合物和立体异构体,包括它们所有比率的混合物,和
(b) 有效量的其它药物活性成分
的单独包装构成。
13.药物组合物,含有至少一种根据权利要求1至5任一项的式(I)的化合物和/或其任何可药用衍生物、溶剂合物、盐和立体异构体,包括它们所有比率的混合物。
14.根据权利要求13的药物组合物,其另外含有至少一种用于治疗炎性疾病或免疫病症的其它药物。
15.根据权利要求14的药物组合物,其另外含有至少一种其它免疫调节剂。
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CN113272291A (zh) * | 2018-11-06 | 2021-08-17 | 艾知怀斯治疗学公司 | 哒嗪酮化合物及其用途 |
CN113272280A (zh) * | 2018-11-06 | 2021-08-17 | 艾知怀斯治疗学公司 | 哒嗪酮化合物及其用途 |
CN114957132A (zh) * | 2021-02-20 | 2022-08-30 | 中国科学院上海药物研究所 | 含s构型的氨基苯甲酰胺基哒嗪酮类化合物、其制备方法、药物组合物及应用 |
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KR20150118981A (ko) | 2015-10-23 |
RU2666899C2 (ru) | 2018-09-13 |
RU2015137757A (ru) | 2017-03-13 |
US20170071936A1 (en) | 2017-03-16 |
ES2634627T3 (es) | 2017-09-28 |
IL240290B (en) | 2019-06-30 |
EP2953944B1 (en) | 2017-04-26 |
AU2014214321B2 (en) | 2018-04-19 |
DK2953944T3 (en) | 2017-07-10 |
HK1215708A1 (zh) | 2016-09-09 |
US20150376167A1 (en) | 2015-12-31 |
AU2014214321A1 (en) | 2015-09-17 |
CA2900431C (en) | 2021-05-04 |
CA2900431A1 (en) | 2014-08-14 |
CN104968658B (zh) | 2017-08-01 |
JP6483624B2 (ja) | 2019-03-13 |
HRP20171076T1 (hr) | 2017-10-06 |
SI2953944T1 (sl) | 2017-08-31 |
RS56331B1 (sr) | 2017-12-29 |
HUE032863T2 (en) | 2017-11-28 |
BR112015018663A2 (pt) | 2017-07-18 |
PL2953944T3 (pl) | 2017-09-29 |
PT2953944T (pt) | 2017-08-01 |
MX364486B (es) | 2019-04-29 |
IL240290A0 (en) | 2015-09-24 |
EP2953944A1 (en) | 2015-12-16 |
KR102293952B1 (ko) | 2021-08-26 |
LT2953944T (lt) | 2017-07-10 |
WO2014121931A1 (en) | 2014-08-14 |
SG11201506100XA (en) | 2015-09-29 |
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JP2016508505A (ja) | 2016-03-22 |
US9567320B2 (en) | 2017-02-14 |
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