CN114426542B - 取代的二芳基胺化合物及其药物组合物、制备方法和用途 - Google Patents
取代的二芳基胺化合物及其药物组合物、制备方法和用途 Download PDFInfo
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Abstract
Description
本申请要求享有2020年10月29日向中国国家知识产权局提交的,专利申请号为202011187029.7,名称为“取代的二芳基胺化合物及其药物组合物、制备方法和用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。
发明领域
本发明属于制药技术领域,具体地涉及取代的二芳基胺化合物及其药物组合物、制备方法和用途。
背景技术
帕金森病(Parkinson’s disease,PD)是一种常见的神经退化性疾病,影响1-2%的老年人群。全基因组关联研究(Genome-wide association studies,GWAS)在非家族性PD的24个位点上关联到28种相关的遗传风险变异。其中,LRRK2(Park8)的突变也在遗传形式中发现,确定了家族性和非家族性PD的共同分子途径驱动发病机制,是引起相关疾病的最常见原因(Simon-Sanchez J,Schulte C,Bras JM,Sharma M,Gibbs JR,et al.Genome-wide association study reveals genetic risk underlying Parkinson'sdisease.Nat Genet,2009,41,1308-1312.)。PD致病性LRRK2突变图谱主要与激酶(G2019S,I2020T)和ROC-COR结构域(R1441C/G/H,Y1699C)有关,这意味着这些酶活性对病情至关重要。致病突变的频率很罕见,约占总体的2%左右,然而,在某些种族人群中,最常见的突变G2019S在高达40%的患者中发现,将该激酶激活二至三倍(West AB,Moore DJ,Biskup S,Bugayenko A,Smith WW,et al.From The Cover:Parkinson's disease-associatedmutations in leucine-rich repeat kinase 2augment kinase activity.Proceedingsof the National Academy of Sciences,2005,102,16842-16847.)。除了致病突变外,LRRK2的普通遗传变异是散发性PD的危险因素(Tan,E.K.Identification of a commongenetic risk variant(LRRK2 Gly2385Arg)in Parkinson's disease.Ann Acad MedSingapore.2006,35,840-842.)。
在2004年,LRRK2被确定为与负责PD遗传的基因,其与PARK8位点相关,并发现其由51个外显子组成,从而产生了一个大的(268kDa)蛋白。随后,鉴定了很多LRRK2一级结构变异体,包括还出现在散发性PD中的与家族性PD分离的显性突变,以及LRRK2基因座处的多态性,所述多态性增加了散发性PD发展的终生风险。
LRRK2是一种核心具有两种酶功能的多域蛋白。GTP酶结构域包含复合蛋白的RAS(Ras of complex protein,ROC),所述ROC终止于一个Roc结构域C端(COR)的间隔结构域,紧接着是属于丝氨酸/苏氨酸激酶的激酶结构域。该酶促核心被蛋白质-蛋白质相互作用结构域所包围,包括Armadillo、锚蛋白和LRRK2的N端富含亮氨酸重复序列(leucine-richrepeat,LRR)结构域。LRRK2的C末端含有WD40结构域,是蛋白质折叠所必需的区域,可控制LRRK2的功能和激酶活性(Rudenko IN,Kaganovich A,Hauser DN,Beylina A,Chia R,etal.The G2385R variant of leucine-rich repeat kinase 2associated withParkinson's disease is a partial loss-of-function mutation.BiochemicalJournal,2012,446,99-111.)。有趣的是,最新描述的显性致病突变发生在LRRK2的酶促核内,表明LRRK2活性的修饰极大地影响PD的发生和进展。
到目前为止,LRRK2突变中近40个单氨基酸替代突变与常染色体显性PD有关。欧洲最普遍的LRRK2突变形式约占家族性PD的6%和散发性PD病例的3%,包括Gly2019的氨基酸替换为Ser残基。Gly2019位于保守DYG-Mg 2+结合基序内,在激酶结构域的亚结构域-VII中。最近的报道表明,这种突变增强了LRRK2的自磷酸化,并且将它磷酸化髓鞘磷脂碱性蛋白的能力提高了2-3倍。在无论是否存在氧化应激的情况下,当细胞系和原代神经元培养中过度表达G2019S-LRRK2时,均观察到细胞毒性和包涵体的形成。这些结果以及LRRK2激酶活性的基因性失活显示出对这种毒性表型的保护作用表明,LRRK2激酶活性的改变可能与LRRK2-PD的神经毒性和致病机制有关。
研究已发现,从LRRK2 G2019S帕金森病患者中诱导的多能干细胞(Inducedpluripotent stem cells,iPSC)表现出突神经突增生缺陷和对鱼藤酮的敏感性增加,这可以通过G2019S突变的基因修正或用LRRK2激酶活性的小分子抑制剂处理细胞来改善(Reinhardt P,Schmid B,Burbulla Lena F,David C,Wagner L,et al.GeneticCorrection of a LRRK2 Mutation in Human iPSCs Links ParkinsonianNeurodegeneration to ERK-Dependent Changes in Gene Expression.Cell Stem Cell,2013,12,354-367.)。在iSPC中与LRRK2 G2019S突变相关的增加的线粒体损伤也被G2019S突变的遗传校正所阻断。
发明内容
为改善上述技术问题,本发明提供一种式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物,药学上可接受的盐、药学上可接受的酯或其前药化合物:
其中:
R1、R2与其连接的原子一起形成无取代或任选被1、2个或更多个Rb取代的3-20元杂环基;
R3、R4相同或不同,彼此独立地选自H、CN、无取代或任选被1、2个或更多个Rc取代的下列基团:C1-40烷基、C3-40环烷基、C6-20芳基、5-20元杂芳基、3-20元杂环基、C1-40烷基氧基、C3-40环烷基氧基、C6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基;且R3、R4不同时为H;
或者,R3、R4与其连接的原子一起形成无取代或任选被1、2个或更多个Rd取代的下列基团:C3-40环烷基、3-20元杂环基;
Ar1选自被1、2个或更多个Re取代的C6-20芳基、5-20元杂芳基;
Ar2选自被1、2个或更多个Rf取代的C6-20芳基、5-20元杂芳基;
每一个Rb、Rc、Rd、Re、Rf相同或不同,彼此独立地选自H、卤素、OH、CN、NO2、氧代(=O)、硫代(=S)、无取代或任选被1、2个或更多个Rg取代的下列基团:C1-40烷基、C2-40烯基、C2-40炔基、C3-40环烷基、C3-40环烯基、C3-40环炔基、C6-20芳基、5-20元杂芳基、3-20元杂环基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-40环烷基氧基、C3-40环烯基氧基、C3-40环炔基氧基、C6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、C1-40烷基硫基、C2-40烯基硫基、C2-40炔基硫基、C3-40环烷基硫基、C3-40环烯基硫基、C3-40环炔基硫基、C6-20芳基硫基、5-20元杂芳基硫基、3-20元杂环基硫基、NH2、-C(O)R11、-C(O)OR12、-OC(O)R13、-S(O)2R14、-S(O)2OR15、-OS(O)2R16;
每一个Rg相同或不同,彼此独立地选自H、卤素、OH、CN、NO2、氧代(=O)、硫代(=S)、C1-40烷基、C2-40烯基、C2-40炔基、C3-40环烷基、C3-40环烯基、C3-40环炔基、C6-20芳基、5-20元杂芳基、3-20元杂环基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-40环烷基氧基、C3-40环烯基氧基、C3-40环炔基氧基、C6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、C1-40烷基硫基、C2-40烯基硫基、C2-40炔基硫基、C3-40环烷基硫基、C3-40环烯基硫基、C3-40环炔基硫基、C6-20芳基硫基、5-20元杂芳基硫基、3-20元杂环基硫基、NH2、-C(O)C1-40烷基、-C(O)NH2、-C(O)NHC1-40烷基、-C(O)-NH-OH、-COOC1-40烷基、-COOH、-OC(O)C1-40烷基、-OC(O)H、-S(O)2C1-40烷基、S(O)2H、-S(O)2OC1-40烷基、-OS(O)2C1-40烷基;
R11、R12、R13、R14、R15、R16相同或不同,彼此独立地选自H、C1-40烷基、C2-40烯基、C2-40炔基、C3-40环烷基、C3-40环烯基、C3-40环炔基、C6-20芳基、5-20元杂芳基、3-20元杂环基、NH2。
根据本发明的实施方案,R1、R2与其连接的原子一起形成无取代或任选被1、2个或更多个Rb取代的3-10元杂环基;
根据本发明的实施方案,R3、R4相同或不同,彼此独立地选自H、CN、无取代或任选被1、2个或更多个Rc取代的下列基团:C1-6烷基、C3-8环烷基、C1-6烷基氧基、C3-8环烷基氧基;且R3、R4不同时为H;
或者,R3、R4与其连接的原子一起形成无取代或任选被1、2个或更多个Rd取代的下列基团:C3-8环烷基、3-8元杂环基;
根据本发明的实施方案,Ar1选自被1、2个或更多个Re取代的C6-10芳基、5-10元杂芳基;
根据本发明的实施方案,Ar2选自被1、2个或更多个Rf取代的C6-10芳基、5-10元杂芳基。
根据本发明示例性的实施方案,R3、R4相同或不同,彼此独立地选自H、C1-6烷基、卤代C1-6烷基,如H、甲基、三氟甲基;且R3、R4不同时为H;
或者,R3、R4与其连接的原子一起形成C3-8环烷基,如环丙烷基;
根据本发明示例性的实施方案,Ar1选自被1、2个或更多个Re取代的苯基;
根据本发明的实施方案,式(I)所示的化合物可以具有式(II)所示的结构:
其中,R1、R2、R3、R4、Ar1、Ar2独立地具有上文所述的定义。
根据本发明的实施方案,式(I)所示化合物可选自下列化合物:
根据本发明的实施方案,所述通式涵盖的化合物,例如本发明上下文具体列出的具体化合物可以独立地具有手性的化学结构,故其可以其各种立体异构体形式、立体异构体混合物的形式或消旋体的形式存在。
因此,本发明上下文中的化合物可以作为对映体纯的(+)-对映体或(-)-对映体(即相应的对映体过量(ee)值>99%),或作为具有(+)-对映体过量或(-)-对映体过量的混合物存在。
本领域技术人员可以通过本发明化合物的旋光度[α]D清楚区别不同的对映异构体,所述化合物的立体异构体(如对映异构体形式)可以独立地具有正旋光值或负旋光值。例如,当溶于非手性溶剂时,可以通过它们的旋光度[α]D清楚的区别不同的对映异构体:其中一个对映异构体具有大于0°的旋光度[α]D(又可称为(+)-化合物),另一个对映异构体具有小于0°的旋光度[α]D(又可称为(-)-化合物)。
作为实例,本发明如下化合物的对映异构体分别具有大于0°的旋光度和小于0°的旋光度:
该化合物的对映异构体分别可标记为化合物1和化合物4,其中:
化合物1的旋光度<0°,优选<约-40°,更优选<约-50°,例如在1mg/mL乙醇溶液中的旋光度为约-52.5°;
化合物4的旋光度>0°,优选>约+20°,更优选>约+40°,例如在1mg/mL乙醇溶液中的旋光度为约+43.5°。
或者作为选择,可以通过流动相的保留时间差异区分不同的对映异构体,例如通过超临界流体色谱仪(supercritical fluid chromatography,SFC)分离,采用chiralpak-IC柱,4.6mm×250mm,5μm,CO2-IPA(0.2%DEA)洗脱时,一种对映异构体的保留时间tR低于另一种对映异构体。例如,化合物1的tR<2min,如约1.94min;化合物4的tR>2min,如约2.33min。
本发明还提供式(I-1)所示的化合物:
其中,PG为保护基团;Ar2’为Ar2基团失去一个H后形成的亚结构;
R1、R2、R3、R4、Ar1、Ar2独立地具有上文所述的定义。
本发明还提供式(I-1)所示的化合物在制备式(I)所示化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物,药学上可接受的盐、药学上可接受的酯或其前药化合物中的用途。
本发明还提供式(I)所示化合物的制备方法,
其中,PG、R1、R2、R3、R4、Ar1、Ar2、Ar2’独立地具有上文所述的定义;
根据本发明的实施方案,PG可以选自氨基保护基。其中,适宜的PG可以选自C1-40烷基、C6-20芳基C1-40烷基、C1-40烷基磺酰基、C1-40烷基苯磺酰基,例如4-甲苯磺酰基、叔丁基、异丙基、苄基、叔丁氧基羰基(Boc)、2-联苯基-2-丙氧羰基、苄氧基羰基、芴甲氧羰基(Fmoc)、三氟乙酰基。
根据本发明的实施方案,式(I-1)化合物在脱去保护基团PG的条件下进行反应,得到式(I)化合物。所述脱去保护基团PG的条件是本领域技术人员已知的那些反应条件。
本发明还提供式(I-1)所示化合物的制备方法,包括以式(I-2)化合物和式(I-3)化合物反应得到式(I-1)所示化合物;
其中,PG、R1、R2、R3、R4、Ar1、Ar2、Ar2’独立地具有上文所述的定义。
据本发明的实施方案,所述制备方法可以在溶剂如有机溶剂的存在下进行。例如,所述的有机溶剂可以选自下列的至少一种:醇类,如甲醇、乙醇、异丙醇、正丁醇;醚类,如乙基丙基醚、正丁基醚、苯甲醚、苯***、环己基甲基醚、二甲基醚、二乙基醚、二甲基乙二醇、联苯醚、二丙基醚、二异丙基醚、二正丁基醚、二异丁基醚、二异戊基醚、乙二醇二甲基醚、异丙基乙基醚、甲基叔丁基醚、四氢呋喃、甲基四氢呋喃、二氧六环、二氯二乙基醚、以及环氧乙烷和/或环氧丙烷的聚醚;脂肪族、环脂肪族或芳香族烃类,如戊烷、己烷、庚烷、辛烷、壬烷,以及可能被氟和氯原子取代的类,如亚甲基氯化物、二氯甲烷、三氯甲烷、四氯化碳、氟苯、氯苯或二氯苯;环己烷、甲基环己烷、石油醚、辛烷、苯、甲苯、氯苯、溴苯、二甲苯;酯类如乙酸甲酯、乙酸乙酯、乙酸丁酯、乙酸异丁酯及碳酸二甲酯、碳酸二丁酯或碳酸乙烯酯。
根据本发明的实施方案,所述制备方法可以在催化剂的存在下进行;所述催化剂可以为Pd催化剂,所述Pd催化剂可以选自Pd2(dba)3、Pd(dba)2、Pd(OAc)2、Pd[(PPh)3]4、Pd[(PPh)3]2Cl2或Pd2(dppf)Cl2中的至少一种。所述制备方法还可以加入配体,所述配体可以为有机膦配体,所述有机膦配体可以选自2-双环已基膦-2',6'-二异丙氧基联苯(RuPhos)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(DavePhos)、外消旋或者R构型或者S构型的2,2’-双-二苯基膦烷基-[1,1’]联萘(BINAP)、1,1-双(二苯基膦基)二茂铁(DPPF)、双-(2-二苯基膦基苯基)醚(DPEPhos)中的至少一种。
根据本发明的实施方案,所述制备方法可以在碱作用下进行,所述碱可以为无机碱,所述无机碱选自、碳酸钠、碳酸钾、碳酸氢钾、碳酸氢钠和碳酸铯中的至少一种。
本发明还提供一种药物组合物,其包含治疗有效量的式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物,药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种。
根据本发明的实施方案,所述药物组合物还包括一种或多种药学上可接受的辅料。
根据本发明的实施方案,所述药物组合物还可以进一步含有一种或多种额外的治疗剂。
本发明还提供一种调节LRRK激酶,尤其是LRRK2激酶活性的方法,包括给予患者预防或治疗有效量的式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物,药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种。
根据本发明的实施方案,所述LRRK激酶优选为LRRK2激酶或其突变体或同等型,或它们的组合。
本发明还提供用于与LRRK激酶,尤其是LRRK2激酶活性相关的疾病或病症的式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物,药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种。
根据本发明的实施方案,所述LRRK激酶优选为LRRK2激酶或其突变体或同等型,或它们的组合。
所述与LRRK激酶,尤其是LRRK2激酶活性相关的疾病或病症包括:神经退化性疾病、增殖性疾病、与蛋白激酶相关的疾病、溶酶体疾病、Tau病和多巴胺水平降低引起的疾病,例如癌症(如乳腺癌)、帕金森病、与GBA突变相关的帕金森氏病(PD)、其他α-突触核蛋白病、tau蛋白病、认知损伤或认知障碍、阿尔茨海默病、戈谢病、C型尼曼氏病(NPC)、嗜银颗粒病、皮克病、皮质基底核退化症、进行性核上性瘫痪、痴呆、与17号染色体相关的遗传性额颞叶痴呆、帕金森病(FTDP-17)、颅脑损伤、中风、癫痫、药物成瘾相关的戒断症状/复发、炎性肠病(如克罗恩氏病、溃疡性结肠炎)、麻风病、免疫***疾病等。优选地,所述疾病和病症包括与脑部相关,尤其是与脑部供血或神经相关的疾病或病症,例如认知损伤或认知障碍、阿尔茨海默病、痴呆、与17号染色体相关的遗传性额颞叶痴呆、帕金森病(FTDP-17)、颅脑损伤、中风、癫痫。
在一些实施方案中,所述患者是人。
本发明还提供治疗或预防与LRRK激酶,尤其是LRRK2激酶活性相关的疾病或病症的方法,包括给予患者式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物,药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种。
本发明还提供式(I)所示的化合物、其消旋体、立体异构体、互变异构物、同位素标记物、N-氧化物、水合物、溶剂化物、多晶型物、代谢物,药学上可接受的盐、药学上可接受的酯或其前药化合物中的至少一种在制备药物中的用途。
所述药物可以用于与LRRK激酶,尤其是LRRK2激酶活性相关的疾病或病症。
作为药物时,可按药物组合物的形式给予本发明化合物。可按药剂领域中熟知的方式制备这些组合物,可通过多种途径给予它们,这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如,透皮、皮肤、眼和粘膜包括鼻内、***和直肠递药)、肺(例如,通过吸入或吹入粉末或气雾剂,包括通过喷雾器;气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药,或可通过例如连续灌注泵给药。局部给予的药用组合物和制剂可包括透皮贴剂、软膏、洗剂、霜剂、凝胶剂、滴剂、栓剂、喷雾剂、液体剂、粉末制剂和散剂。常规药物载体、水、粉末或油性基质、增稠剂等可能是必须的或需要的。
在制备本发明的组合物时,通常将活性成分与赋形剂混合,通过赋形剂稀释或装入例如胶囊、小药囊、纸或其它容器形式的这种载体内。当赋形剂用作稀释剂时,它可以是固体、半固体或液体物质,用作溶媒、载体或活性成分的介质。因此,组合物可以是以下形式:片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒);含例如高达10%重量活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。
适宜的赋形剂的某些实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、***胶、磷酸钙、藻酸盐、黄蓍胶、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。制剂还可含有:润滑剂例如滑石粉、硬脂酸钠、硬脂酸镁、油酸钠、苯甲酸钠、乙酸钠、氯化钠和矿物油;湿润剂;乳化剂和悬浮剂;防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯;甜味剂和矫味剂。可通过使用本领域中已知的方法配制本发明组合物,以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。
可按单位剂型配制组合物,每一剂量含约5~1000mg,更通常约100~500mg活性成分。术语“单位剂型”是指物理上分离的适宜作为用于人患者和其它哺乳动物的单一剂量单位,各单位含有与适宜的药物赋形剂混合的经计算可产生所需疗效的预定量的活性物质。
活性化合物的有效剂量的范围可很大,通常按药用有效量给药。但是,可以理解实际给予的化合物的量通常由医师根据相关情况决定,它们包括所治疗的病症、所选择的给药途径、所给予的实际化合物;患者个体的年龄、重量和反应;患者症状的严重程度等。
对于制备固体组合物例如片剂,将主要的活性成分与药物赋形剂混合,形成含本发明化合物的均匀混合物的固体预制剂组合物。当称这些预制剂组合物为均匀时,是指活性成分通常均匀地分布在整个组合物中,致使该组合物可容易地划分为同等有效的单位剂型例如片剂、丸剂和胶囊剂。然后将该固体预制剂划分为上述类型的含例如约0.1~1000mg本发明活性成分的单位剂型。
可将本发明片剂或丸剂包衣或复合,得到提供长效作用优点的剂型。例如,片剂或丸剂含内剂量和外剂量组分,后者是前者的被膜形式。可通过肠溶层将两种组分隔离,肠溶层用于在胃中阻止崩解,以使内组分完整通过十二指肠或延迟释放。多种物质可用于此类肠溶层或包衣剂,此类物质包括多种高分子酸和高分子酸与此类物质如虫胶、鲸蜡醇和醋酸纤维素的混合物。
其中可掺入本发明化合物和组合物,用于口服或注射给药的液体形式包括水溶液、适当矫味的糖浆剂、水或油混悬液;和用食用油例如棉子油、芝麻油、椰子油或花生油矫味的乳剂;以及酏剂和类似的药用溶媒。
用于吸入或吹入的组合物包括溶于药学上可接受的水或有机溶剂或其混合物的溶液剂和混悬液、散剂。液体或固体组合物可含有如上所述适宜的药学上可接受的赋形剂。在某些实施方案中,通过口服或鼻呼吸途径给予组合物,实现局部或全身作用。可通过使用呈惰性的气体,使组合物成雾化。可直接由雾化装置吸入雾化溶液,或雾化装置可与面罩帷或间歇正压呼吸机连接。可通过口服或由按适当方式递送制剂的装置通过鼻给予溶液、混悬液或粉末组合物。
给予患者的化合物或组合物的量不固定,取决于给予的药物、给药的目的例如预防或治疗;患者的状态、给药的方式等。在治疗应用时,可给予已患疾病的患者足够治愈或至少部分抑制疾病及其并发症症状的量的组合物。有效剂量应取决于所治疗的疾病状态和主治临床医师的判断,该判断取决于例如疾病的严重程度、患者的年龄、体重和一般状况等因素。
给予患者的组合物可以是上述药用组合物形式。可通过常规灭菌技术或可过滤灭菌,将这些组合物灭菌。可将水溶液包装原样使用,或冻干,给药前,将冻干制剂与无菌水性载体混合。化合物制剂的pH通常为3~11,更优选5~9,最优选7~8。可以理解,使用某些前述赋形剂、载体或稳定剂会导致形成药物盐。
本发明化合物的治疗剂量可根据例如以下而定:治疗的具体用途、给予化合物的方式、患者的健康和状态,以及签处方医师的判断。本发明化合物在药用组合物中的比例或浓度可不固定,取决于多种因素,它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1~10%(w/v)该化合物的生理缓冲水溶液提供本发明化合物,用于肠胃外给药。某些典型剂量范围为约1μg/kg~约1g/kg体重/日。在某些实施方案中,剂量范围为约0.01mg/kg~约100mg/kg体重/日。剂量很可能取决于此类变量,如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验***导出的剂量-反应曲线外推,得到有效剂量。
本发明提供式(I)所述的化合物在分析试验中的用途,所述分析试验用于鉴定能够抑制一种或多种激酶的化合物,所述激酶优选LRRK,更优选LRRK2。
优选地,所述分析试验是竞争性结合试验。
更优选地,竞争性结合试验包括将本发明化合物与激酶接触,并检测根据本发明的化合物与激酶之间的相互作用的任何变化。
本发明的另一方面提供了检测本发明化合物与激酶结合的方法,所述方法包括以下步骤:
(i)在激酶和已知底物存在下,将本发明化合物与所述激酶接触;
(ii)检测所述激酶和所述已知底物之间的相互作用的任何变化;
有益效果
本发明提供的化合物具有良好的LRRK2激酶调节/抑制作用,并具有更优异的透脑率,可用于治疗与LRRK2激酶活性相关的病症和疾病,尤其是与透脑率相关的病症和疾病,并制备用于此类病征和疾病的药物。本发明化合物的制备方法简单,具有良好的应用前景。
术语定义与说明
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当被理解为本申请说明书和/或权利要求书记载的范围内。
除非另有说明,本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如,数值范围“1-40”相当于记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10,以及数值范围“11-40”中的每一个整数数值即11、12、13、14、15、......、35、36、37、38、39、40。此外,当某些数值范围被定义为“数”时,应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如,“0~10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数,还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
应当理解,本文在描述1、2个或更多个中,“更多个”应当是指大于2,例如大于等于3的整数,例如3、4、5、6、7、8、9或10。
术语“卤素”表示氟、氯、溴和碘。
术语“C1-40烷基”应理解为表示具有1~40个碳原子的直链或支链饱和一价烃基。例如,“C1-10烷基”表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链和支链烷基,“C1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。
术语“C2-40烯基”应理解为优选表示直链或支链的一价烃基,其包含一个或多个双键并且具有2~40个碳原子,优选“C2-10烯基”。“C2-10烯基”应理解为优选表示直链或支链的一价烃基,其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子,例如,具有2、3、4、5或6个碳原子(即,C2-6烯基),具有2或3个碳原子(即,C2-3烯基)。应理解,在所述烯基包含多于一个双键的情况下,所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C2-40炔基”应理解为表示直链或支链的一价烃基,其包含一个或多个三键并且具有2~40个碳原子,优选“C2-10炔基”。术语“C2-10炔基”应理解为优选表示直链或支链的一价烃基,其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子,,例如,具有2、3、4、5或6个碳原子(即,“C2-6炔基”),具有2或3个碳原子(“C2-3炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地,所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
术语“C3-40环烷基”应理解为表示饱和的一价单环、二环(如稠环、桥环、螺环)烃环或三环烷烃,其具有3~40个碳原子,优选“C3-10环烷基”。术语“C3-10环烷基”应理解为表示饱和的一价单环、双环(如桥环、螺环)烃环或三环烷烃,其具有3、4、5、6、7、8、9或10个碳原子。所述C3-10环烷基可以是单环烃基,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基,或者是双环烃基如龙脑基、吲哚基、六氢吲哚基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基、2,7-二氮杂螺[3,5]壬烷基、2,6-二氮杂螺[3,4]辛烷基,或者是三环烃基如金刚烷基。
除非另有定义,术语“3-20元杂环基”是指饱和的或不饱和的非芳族的环或环系,例如,其是4-、5-、6-或7-元的单环、7-、8-、9-、10-、11-或12-元的二环(如稠环、桥环、螺环)或者10-、11-、12-、13-、14-或15-元的三环环系,并且含有至少一个,例如1、2、3、4、5个或更多个选自O、S和N的杂原子,其中N和S还可以任选被氧化成各种氧化状态,以形成氮氧化物、-S(O)-或-S(O)2-的状态。优选地,所述杂环基可以选自“3-10元杂环基”。术语“3-10元杂环基”意指饱和的或不饱和的非芳族的环或环系,并且含有至少一个选自O、S和N的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。所述杂环基可以包括稠合的或桥连的环以及螺环的环。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。杂环基可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于二氢呋喃基、二氢吡喃基、2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基。所述3-20元杂环基与其它基团相连构成本发明的化合物时,可以为3-20元杂环基上的碳原子与其它基团相连,也可以为3-20元杂环基环上杂环原子与其它基团相连。例如当3-20元杂环基选自哌嗪基时,可以为哌嗪基上的氮原子与其它基团相连。或当3-20元杂环基选自哌啶基时,可以为哌啶基环上的氮原子和其对位上的碳原子与其它基团相连。
术语“C6-20芳基”应理解为优选表示具有6~20个碳原子的一价芳香性或部分芳香性的单环、二环(如稠环、桥环、螺环)或三环烃环,其可以是单芳族环或稠合在一起的多芳族环,优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”),特别是具有6个碳原子的环(“C6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C13芳基”),例如芴基,或者是具有14个碳原子的环(“C14芳基”),例如蒽基。当所述C6-20芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为邻位、对位或间位取代。
术语“5-20元杂芳基”应理解为包括这样的一价单环、二环(如稠环、桥环、螺环)或三环芳族环系:其具有5~20个环原子且包含1-5个独立选自N、O和S的杂原子,例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5、6、7、8、9、10、11、12、13或14个环原子,特别是5或6或9或10个碳原子,且其包含1-5个,优选1-3各独立选自N、O和S的杂原子并且,另外在每一种情况下可为苯并稠合的。“杂芳基”还指其中杂芳族环与一个或多个芳基、脂环族或杂环基环稠合的基团,其中所述连接的根基或点在杂芳族环上。非限制性实例包括1-、2-、3-、5-、6-、7-或8-吲嗪基、1-、3-、4-、5-、6-或7-异吲哚基、2-、3-、4-、5-、6-或7-吲哚基、2-、3-、4-、5-、6-或7-吲唑基、2-、4-、5-、6-、7-或8-嘌呤基、1-、2-、3-、4-、6-、7-、8-或9-喹嗪基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、1-、4-、5-、6-、7-或8-酞嗪基(phthalazinyl)、2-、3-、4-、5-或6-萘啶基、2-、3-、5-、6-、7-或8-喹唑啉基、3-、4-、5-、6-、7-或8-噌啉基、2-、4-、6-或7-蝶啶基、1-、2-、3-、4-、5-、6-、7-或8-4aH咔唑基、1-、2-、3-、4-、5-、6-、7-或8-咔唑基咔唑基、1-、3-、4-、5-、6-、7-、8-或9-咔啉基、1-、2-、3-、4-、6-、7-、8-、9-或10-菲啶基、1-、2-、3-、4-、5-、6-、7-、8-或9-吖啶基、1-、2-、4-、5-、6-、7-、8-或9-啶基、2-、3-、4-、5-、6-、8-、9-或10-菲咯啉基、1-、2-、3-、4-、6-、7-、8-或9-吩嗪基、1-、2-、3-、4-、6-、7-、8-、9-或10-吩噻嗪基、1-、2-、3-、4-、6-、7-、8-、9-或10-吩嗪基、2-、3-、4-、5-、6-或1-、3-、4-、5-、6-、7-、8-、9-或10-苯并异喹啉基、2-、3-、4-或噻吩并[2,3-b]呋喃基、2-、3-、5-、6-、7-、8-、9-、10-或11-7H-吡嗪并[2,3-c]咔唑基、2-、3-、5-、6-或7-2H-呋喃并[3,2-b]-吡喃基、2-、3-、4-、5-、7-或8-5H-吡啶并[2,3-d]-邻-嗪基、1-、3-或5-1H-吡唑并[4,3-d]-唑基、2-、4-或54H-咪唑并[4,5-d]噻唑基、3-、5-或8-吡嗪并[2,3-d]哒嗪基、2-、3-、5-或6-咪唑并[2,1-b]噻唑基、1-、3-、6-、7-、8-或9-呋喃并[3,4-c]噌啉基、1-、2-、3-、4-、5-、6-、8-、9-、10或11-4H-吡啶并[2,3-c]咔唑基、2-、3-、6-或7-咪唑并[1,2-b][1,2,4]三嗪基、7-苯并[b]噻吩基、2-、4-、5-、6-或7-苯并唑基、2-、4-、5-、6-或7-苯并咪唑基、2-、4-、4-、5-、6-或7-苯并噻唑基、1-、2-、4-、5-、6-、7-、8-或9-苯并氧杂基(benzoxapinyl)、2-、4-、5-、6-、7-或8-苯并嗪基、1-、2-、3-、5-、6-、7-、8-、9-、10-或11-1H-吡咯并[1,2-b][2]苯并氮杂基(benzazapinyl)。典型的稠合杂芳基包括但不限于2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、2-、3-、4-、5-、6-或7-吲哚基、2-、3-、4-、5-、6-或7-苯并[b]噻吩基、2-、4-、5-、6-或7-苯并唑基、2-、4-、5-、6-或7-苯并咪唑基和2-、4-、5-、6-或7-苯并噻唑基。。当所述5-20元杂芳基与其它基团相连构成本发明的化合物时,可以为5-20元杂芳基环上的碳原子与其它基团相连,也可以为5-20元杂芳基环上的杂原子与其它基团相连。当所述5-20元杂芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为杂芳基环上与碳原子相连的氢被取代,或者杂芳基环上与杂原子相连的氢被取代。
术语“螺环”是指两个环共用1个成环原子的环系。
术语“稠环”是指两个环共用2个成环原子的环系。
术语“桥环”是指两个环共用3个以上成环原子的环系。
除非另有说明,杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式,例如其位置异构体。因此,对于一些说明性的非限制性实例,可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-、11-、12-位等(如果存在)中的1、2个或更多个位置上取代或与其他基团键合的形式,包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基;吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。
术语“氧代”是指取代基中的碳原子、氮原子或硫原子被氧化后形成的氧基取代(=O)。
除非另有说明,本文中术语的定义同样适用于包含该术语的基团,例如C1-6烷基的定义也适用于C1-6烷基氧基、C3-8环烷基-C1-6烷基-等。
本领域技术人员可以理解,式(I)所示化合物可以以各种药学上可接受的盐的形式存在。如果这些化合物具有碱性中心,则其可以形成酸加成盐;如果这些化合物具有酸性中心,则其可以形成碱加成盐;如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基),则其还可以形成内盐。
本发明的化合物可以溶剂合物(如水合物)的形式存在,其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂,特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
根据其分子结构,本发明的化合物可以是手性的,因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物涵盖了各手性碳为R或S构型的异构体或其混合物、消旋体。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物,或者以此形式用于合成。在外消旋的胺的情况中,通过与光学活性的拆分试剂反应,从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸,例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物),也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物,例如,己烷/异丙醇/乙腈。
可以根据已知的方法,例如通过萃取、过滤或柱层析来分离相应的稳定异构体。
术语“患者”是指包括哺乳动物在内的任何动物,优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物,最优选人。
术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、***、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量,它包括以下一项或多项:(1)预防疾病:例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病:例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病:例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。治疗有效量最初可以由细胞培养测定来进行估计,也可以从体内数据估计初始剂量。使用这些初步指导,本领域普通技术人员可以确定人类的有效剂量。此外,也可以通过细胞培养物或实验动物中的标准药物程序来确定本文所述化合物的毒性和治疗功效,例如通过测定LD50和ED50。
术语“与LRRK激酶活性相关的疾病或病症”是指以本文定义的不适当所述激酶活性或激酶的过度活性为特征的疾病或病症。不适当活性是指(i)通常不表达所述激酶的细胞中的激酶表达;(ii)增加的激酶表达,导致不希望的细胞增殖、分化和/或生长;或(iii)降低的激酶表达,导致细胞增殖、分化和/或生长不期望的减少。激酶的过度活性是指编码特定激酶的基因的扩增或一定激酶活性水平的产生,其可以与细胞增殖、分化和/或生长紊乱相关(即,随着激酶水平增加,一个或多个的细胞紊乱的症状的严重程度增加)。过度活性也可以是由于突变而导致的与配体无关或组成型激活的结果,所述突变如负责配体结合的激酶的片段缺失。
本发明所述“辅料”的实例见“Handbook of Pharmaceutical Excipients,第2版,1994,由A Wade和PJ Weller编辑”。
本发明所述“载体”或“稀释剂”在制药领域是熟知的,并且在例如Remington'sPharmaceutical Sciences,Mack Publishing Co.(A.R.Gennaro编辑1985)中进行了描述。
药物载体、辅料或稀释剂的选择可以根据预期给药途径和标准药学实践来进行选择。药物组合物可以包含或额外包含作为载体、辅料或稀释剂的任何合适的粘合剂、润滑剂、悬浮剂、包衣剂、增溶剂、缓冲剂、调味剂、表面活性剂、增稠剂、防腐剂(包括抗氧化剂)等,以及为了使得制剂与接受者的血液等渗所包含的物质。
其中载体是固体的适用于口服给药的药物制剂最优选地是单位剂量制剂形式,如各自含有预定量的活性化合物的丸剂、胶囊或片剂。可以通过压制或模制,任选地与一种以上的辅助成分一起制备片剂。可以通过在合适的机器中压制处于自由流动形式(诸如粉末或颗粒)的活性化合物,任选地与粘合剂、润滑剂、惰性稀释剂、润滑物质、表面活性剂或分散剂混合来制备压制片剂。可以通过模制活性化合物和惰性液体稀释剂来制备模制的片剂。可以任选地将片剂包衣,如果不进行包衣的话,可以任选地打印符号。可以通过将活性化合物单独地或与一种以上的辅助成分混合填充到胶囊壳中,然后以常规方式进行密封来制备胶囊。扁囊剂类似于胶囊,其中将活性化合物与任何辅助成分一起密封在米纸膜中。也可以将活性化合物配制成可分散的颗粒,例如可以在给药前将其悬浮于水中,或洒在食物上。可以将颗粒包装在例如小袋中。其中载体可以是液体的适合于口服给药的制剂,可以作为以水性或非水性液体方式的溶液或悬浮液,或作为水包油液体乳剂呈现。
术语“药学上可接受的盐”包括其合适的酸加成盐或碱盐。关于合适的药物盐见JPharm Sci,66,199,1977,Berge等。例如用强无机酸,如矿物酸,例如氢卤酸(如盐酸、氢溴酸和氢碘酸)、硫酸、磷酸硫酸盐、硫酸氢盐、半硫酸盐、硫氰酸盐、过硫酸盐和磺酸;用强有机羧酸,如未取代或取代的(例如,通过卤素)1至4个碳原子的链烷羧酸,如乙酸;用饱和或不饱和二羧酸,例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或四邻苯二甲酸;用羟基羧酸,例如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸;用氨基酸,例如天冬氨酸或谷氨酸;用苯甲酸;或用有机磺酸,如未取代或取代的(例如,通过卤素)(C1-C4)-烷基-或芳基-磺酸,如甲烷-或对甲苯磺酸,来形成盐。
优选的盐包括,例如乙酸盐、三氟乙酸盐、乳酸盐、葡萄糖酸盐、柠檬酸盐、酒石酸盐、马来酸盐、苹果酸盐、泛酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、丁酸盐、二葡糖酸盐、环戊酸盐、葡庚糖酸盐、甘油磷酸盐、草酸盐、庚酸盐、己酸盐、富马酸盐、烟酸盐、棕榈酸酯、果胶酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、酒石酸盐、乳糖酸盐、pivolate、樟脑酸盐、十一酸盐和琥珀酸盐,有机磺酸如甲磺酸盐、乙磺酸盐、2-羟基乙烷磺酸盐、樟脑磺酸盐、2-萘磺酸盐、苯磺酸盐、对氯苯磺酸盐和对甲苯磺酸盐;和无机酸如盐酸、氢溴酸、氢碘酸、硫酸、硫酸氢、半硫酸、硫氰酸、过硫酸、磷酸和磺酸。
术语“药学上可接受的酯”是指使用有机酸或醇/氢氧化物,与本发明化合物结构中可被酯化的官能团形成酯。有机酸包括羧酸,如未取代或取代的(例如,通过卤素)1至12个碳原子的链烷羧酸,如乙酸;用饱和或不饱和二羧酸,例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或四邻苯二甲酸;用羟基羧酸,例如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸;用氨基酸,例如天冬氨酸或谷氨酸;用苯甲酸;或用有机磺酸,如未取代或取代的(例如,通过卤素)(C1-C4)-烷基-或芳基-磺酸,如甲烷-或对甲苯磺酸。合适的氢氧化物包括无机氢氧化物,如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铝。醇包括可以是未取代或取代的(例如,通过卤素)1-12个碳原子的烷醇。
术语“同位素标记物”,表示本发明化合物中至少一个原子被同位素代替。所述同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,如相应的2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F和36Cl。用同位素如氘(即2H)取代可以提供由更大的代谢稳定性,例如增加的体内半衰期或降低的剂量需求产生的某些治疗优势,因此在某些情况下可能是优选的。例如,本发明包括其中任一氢原子被氘原子代替的通式(I)的化合物。
术语“前药化合物”,表示在体内释放根据通式(I)的活性母体药物的共价键合的化合物。这样的前药通常是其中一个以上的适当基团已被修饰,使得在给药至人或哺乳动物受试者后该修饰可能被逆转的本发明化合物。通常通过这类受试者中天然存在的酶来进行逆转,尽管可能将第二药剂与这种前药一起给药以便在体内进行逆转。这类修饰的实例包括上文所述的药学上可接受的酯,其中可以由酯酶等进行这种逆转。
术语“多晶型物”,表示各种结晶形式、多晶形式和水合形式的本发明化合物。在制药工业中已明确,可以通过在这类化合物的合成制备中使用的溶剂的纯化和/或分离的方法而以任何这些形式分离化学化合物。
术语“给药”,表示本发明的药物组合物可适用于直肠、鼻内、支气管内、局部(包括口腔和舌下)、***或肠胃外(包括皮下、肌内、静脉内、动脉内和皮内)、腹膜内或鞘内给药。优选地,所述制剂是口服给药的制剂。制剂可以方便地以单位剂型,即以包含单位剂量或者单位剂量的多个单位或子单位的离散部分的形式呈现。作为实例,制剂可以是以片剂和缓释胶囊的形式,并且可以通过药学领域熟知的任何方法进行制备。
本发明的用于口服给药的制剂可以呈现为:离散单位,如各自含有预定量的活性剂的胶囊、凝胶剂、滴剂、扁囊剂、丸剂或片剂;作为粉末或颗粒;作为水性液体或非水性液体中的活性剂的溶液、乳液或悬浮液;或作为水包油液体乳剂或油包水液体乳剂;或作为团注制剂等。优选地,每剂量的这些组合物含有1至250mg且更优选10-100mg的活性成分。
对于用于口服给药的组合物(例如,片剂和胶囊),还包括溶剂和/或常用辅料,例如粘合剂,例如糖浆、***胶、明胶、山梨糖醇、黄芪胶、聚乙烯吡咯烷酮(聚维酮)、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、蔗糖和淀粉;填料和载体,例如玉米淀粉、明胶、乳糖、蔗糖、微晶纤维素、高岭土、甘露醇、磷酸二钙、氯化钠和海藻酸;和润滑剂,如硬脂酸镁、硬脂酸钠和其它金属硬脂酸酯、甘油硬脂酸、硬脂酸、硅酮流体、滑石蜡、油和胶体二氧化硅。调味剂如薄荷、冬青油、樱桃香料等也可以使用。可能需要添加着色剂以使剂型容易被识别。片剂也可以通过本领域熟知的方法进行包衣。
适用于口服给药的其它制剂包括包含调味基质,通常为蔗糖和***胶或黄芪胶中的活性剂的锭剂;包含惰性基质如明胶和甘油、或蔗糖和***胶中的活性剂的软锭剂;和包含合适液体载体中的活性剂的漱口剂。
其它给药形式包括进行静脉内、动脉内、鞘内、皮下、皮内、腹膜内或肌肉内注射并由无菌或可灭菌溶液制备的溶液或乳剂。可注射形式通常每剂含有10-1000mg,优选10-250mg之间的活性成分。
所述给药的形式还可以为联合给药,即将一种以上的本发明化合物与一种以上的其它活性剂联合给药。在这种情况下,可以将本发化合物与一种以上的其它活性剂连续、同时或序贯给药。
分析试验
本发明的另一方面涉及如上所述的化合物在分析试验中的用途,这种分析试验用于鉴定能够抑制一种或多种激酶、更优选LRRK、甚至更优选LRRK2的其它候选化合物。
优选地,该分析试验是竞争性结合试验。
更优选地,竞争性结合试验包括让本发明化合物与激酶,优选LRRK、更优选LRRK2和候选化合物接触,并检测根据本发明的化合物与激酶之间的相互作用的任何变化。
优选地,通过本发明化合物的SAR修饰产生候选化合物。
如本文所使用的,术语“SAR修饰”是指通过化学衍生化来改变给定化合物的标准方法。
因此,在一个方面,所鉴定的化合物可以作为模型(例如,模板),用于开发其它化合物。在这种测试中使用的化合物可以游离于溶液中、固定在固体载体上、承载在细胞表面或位于细胞内。可以测量化合物和待测试药剂之间的活性消除或结合复合物的形成。
本发明的分析试验可以是筛选,因而测试了大量药剂。在一方面,本发明的分析测定方法是高通量筛选。
本发明还考虑了使用竞争性药物筛选试验,其中能够结合化合物的中和抗体与用于结合化合物的测试化合物特异性竞争。
提供了用于筛选的另一技术,用于对物质具有合适结合亲和力的试剂进行高通量筛选(HTS),并且该技术基于WO 84/03564中详细描述的方法。
预期本发明的分析试验方法,将适合于对测试化合物进行小规模筛选和大规模筛选以及适合于定量试验。
优选地,竞争性结合试验包括在激酶的已知底物存在下,让本发明化合物与所述激酶接触,并检测所述激酶和所述已知底物之间相互作用的任何变化。
本发明的另一方面提供了检测配体与激酶结合的方法,所述方法包括以下步骤:
(i)在激酶的已知底物存在下,让配体与所述激酶接触;
(ii)检测所述激酶和所述已知底物之间的相互作用的任何变化;
并且其中所述配体是本发明化合物。
本发明的一个方面涉及一种方法,包括以下步骤:
(a)进行上述测定方法;
(b)鉴定能够与配体结合结构域结合的一种或多种的配体;和
(c)制备一定量的所述一种或多种配体。
本发明的另一方面提供了一种方法,包括以下步骤:
(a)进行上述测定方法;
(b)鉴定能够与配体结合结构域结合的一种或多种配体;和
(c)制备包含所述一种或多种配体的药物组合物。
本发明的另一方面提供了一种方法,包括以下步骤:
(a)进行上述测定方法;
(b)鉴定能够与配体结合结构域结合的一种或多种配体;
(c)修饰能够与配体结合结构域结合的所述一种或多种配体;
(d)进行这种上述测定方法;
(e)任选地制备包含所述一种或多种配体的药物组合物。
本发明还涉及通过上述方法鉴定的配体。
本发明的另一方面涉及包含通过上述方法鉴定的配体的药物组合物。
本发明的另一方面涉及通过上述方法鉴定的配体在制备药物组合物中的用途,该药物组合物用于治疗一种或多种病症。
上述方法可用于筛选可用作一种或多种激酶的抑制剂的配体。
附图说明
图1为实施例5中给药后的小鼠平均血药浓度-时间曲线;
图2为实施例5中给药后的小鼠脑组织药物浓度-时间曲线。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
在整个说明书中使用以下缩写:
AcOH 乙酸
DCM 二氯甲烷
DEA 二乙胺
DMF N,N-二甲基甲酰胺
EA,EtOAc 乙酸乙酯
IPA 异丙醇
NMR 核磁共振
PE 石油醚
SFC 超临界流体色谱
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TMS 三甲基硅烷基
TMSOTf 三氟甲磺酸三甲基硅酯
tR 保留时间
Ts 对甲苯磺酰基
UV 紫外线
色谱法
使用由Agela Technologies制造的设备进行高压液相色谱法,并通过多波长UV检测器进行监测。用于分离过程的典型流动相是PE/EA、DCM/MeOH或水/MeCN。
分析方法
在室温下在所述溶剂中,使用Bruker AV 400光谱仪进行1H核磁共振(NMR)光谱,除非另有说明。在所有情况下,NMR数据与所提出的结构一致。使用用于指定主峰的常规缩写,以份每百万计给出特有的化学位移(δ):例如,s,单峰;d,二重峰;t,三重峰;q,四重峰;dd,双二重峰;br,宽。使用Agilent 1290Infinity/6460triple Quad LCMS记录质谱。当使用薄层色谱(TLC)时,它是指硅胶TLC。
化合物制备
在没有描述制备起始原料的情况下,这些起始原料是可以是通过商业渠道购买的,文献中已知的,或者由本领域技术人员使用标准程序易于可获得的。在说明通过类似于先前的实施例或中间体而制备化合物的情况下,本领域技术人员将理解,可以改变每个特定反应的反应时间、试剂的当量数和温度,并且采用不同的后处理或纯化技术可能是必须的或期望的。
实施例1
步骤1:(3-甲氧基-4-硝基苯基)甲醇(中间体1-1)
在0℃的冰浴中,向3-甲氧基-4-硝基苯甲酸(15.0g,0.0761mol)的THF(50mL)溶液逐滴加入THF(228mL,0.228mol,1M)中的BH3溶液。将所得混合物加热至60℃搅拌4小时。冷却至0℃后,加入MeOH(30mL)来猝灭反应。浓缩所得混合物得到残渣,用硅胶柱色谱(PE/EA=1:1)对所述残渣进行纯化,得到(3-甲氧基-4-硝基苯基)甲醇(1-1,10.0g,71.9%),其为黄色固体。m/z(ESI)+:184[M+H]+。
步骤2:3-甲氧基-4-硝基苯甲醛(中间体1-2)
将中间体1-1(10.0g,54.6mmol)和MnO2(9.48g,109mmol)的混合物在DCM(200mL)中回流过夜。冷却至室温后,将所述混合物通过硅藻土(celite)过滤,滤液浓缩,得到3-甲氧基-4-硝基苯甲醛(1-2,6.67g,67.4%),其为白色固体。1H NMR(300MHz,CDCl3)δ10.05(s,1H),7.92(d,J=8.1Hz,1H),7.60(d,J=1.3Hz,1H),7.54(dd,J=8.1,1.4Hz,1H),4.03(s,3H).m/z(ESI)+:182[M+H]+。
步骤3:4-(3-甲氧基-4-硝基苯亚甲基)吗啉-4-基(中间体1-3)
在0℃下,向中间体1-2(1.00g,5.52mmol)和4-(三甲基硅烷基)吗啉(1.05g,6.60mmol)在DCM(25mL)的溶液中逐滴加入TMSOTf(1.5g,6.60mmol)。在室温下搅拌所得混合物2h,浓缩反应混合液,得到粗中间体1-3,直接用于下一步。
步骤4:4-(2,2,2-三氟-1-(3-甲氧基-4-硝基苯基)乙基)吗啉(中间体1-4)
在0℃下向DMF(20mL)中的粗中间体1-3(约5.5mmol)溶液中顺序加入TMSCF3(1.18g,8.25mmol)和KF(0.50g,8.25mmol)。当反应液变为红色时,使反应体系升温至室温,搅拌过夜。用EtOAc(100mL)稀释反应混合物,用盐水(30mL)洗涤,在无水Na2SO4干燥,过滤和浓缩产生残渣。用硅胶柱色谱(PE/EA=5:1)对残渣进行纯化,得到4-(2,2,2-三氟-1-(3-甲氧基-4-硝基苯基)乙基)吗啉(1-4,1.00g,56%经两步反应),其为白色固体。m/z(ESI)+:321[M+H]+
步骤5:2-甲氧基-4-(2,2,2-三氟-1-吗啉基乙基)苯胺(中间体1-5)
将MeOH(30mL)中的中间体1-4(1.00g,3.12mmol)和10%Pd/C(300mg)的混合物用H2脱气和充气3次。然后将所得混合物在室温下在H2气氛中搅拌过夜。将所得混合物用硅藻土(celite)过滤,将滤液浓缩得到粗2-甲氧基-4-(2,2,2-三氟-1-吗啉基乙基)苯胺(1-5,800mg),其为白色固体。m/z(ESI)+:291[M+H]+.
步骤6:2-氯-4-乙氧基-7H-吡咯[2,3-d]嘧啶(中间体1-6)
2,4-二氯-7H-吡咯[2,3-d]嘧啶(10.0g,0.054mol)的EtOH溶液(300mL)加入EtONa(3.6g,0.054mol)。将得到的混合物在90℃搅拌过夜。将所述反应混合物浓缩,用EtOAc(300mL)稀释,用盐水洗涤。将分离的有机层用无水Na2SO4干燥,过滤并浓缩得到粗产物。使用快柱层析(PE/EA=20:1)纯化剩余物,得到粗2-氯-4-乙氧基-7H-吡咯[2,3-d]嘧啶(1-6,5.0g),其为白色固体。m/z(ESI)+:198[M+H]+.
步骤7:2-氯-4-乙氧基-7-甲苯磺酰基-7H-吡咯[2,3-d]嘧啶(中间体1-7)
在0℃下向DMF(20mL)中的粗中间体1-6(5.0g,25mmol)溶液加入NaH(1.22g,30.4mmol)。将所得混合物在0℃下搅拌0.5h。然后在0℃下加入TsCl(5.80g,30.4mmol)。在室温下将所得混合物搅拌2h。在0℃下加入水来猝灭反应,然后用EtOAc(200mL)稀释。用盐水洗涤有机层,用无水Na2SO4干燥,过滤并浓缩得到粗产物。用快柱层析(PE/EA=20:1)纯化所得剩余物,得到2-氯-4-乙氧基-7-甲苯磺酰基-7H-吡咯[2,3-d]嘧啶(1-7,2.00g,22%经两步反应)。m/z(ESI)+:352[M+H]+.
步骤8:4-乙氧基-N-(2-甲氧基-4-(2,2,2-三氟-1-吗啉基乙基)苯基)-7-甲苯磺酰基-7H-吡咯[2,3-d]嘧啶-2-胺(中间体1-8)
在N2气氛下,向中间体1-7(1.20g,3.42mmol)和中间体1-5(1.00g,3.44mmol)的1,4-二氧六环(10mL)溶液中加入Pd2(dba)3(275mg,0.310mmol)、RuPhos(280mg,0.617mmol)和Cs2CO3(1.95g,5.98mmol)。在微波反应器中在125℃下将所得混合物搅拌1h。冷却至室温后,用EtOAc和水稀释反应混合物。用盐水洗涤分离的有机层,用无水Na2SO4干燥,过滤并浓缩,得到残余。用硅胶柱色谱(EA)纯化所述残余,得到4-乙氧基-N-(2-甲氧基-4-(2,2,2-三氟-1-吗啉基乙基)苯基)-7-甲苯磺酰基-7H-吡咯[2,3-d]嘧啶-2-胺(1-8,900mg,43.6%)。m/z(ESI)+:606[M+H]+.
步骤9:4-乙氧基-N-(2-甲氧基-4-(2,2,2-三氟-1-吗啉基乙基)苯基)-7H-吡咯[2,3-d]嘧啶-2-胺(对映异构体1,化合物1)和4-乙氧基-N-(2-甲氧基-4-(2,2,2-三氟-1-吗啉基乙基)苯基)-7H-吡咯[2,3-d]嘧啶-2-胺(对映异构体2,化合物4)的合成
向EtOH/H2O(10mL/1mL)中的中间体1-8(900mg,1.49mmol)溶液加入NaOH(297mg,7.43mmol)。在50℃下将得到的混合物搅拌2h。浓缩所述混合物得到残余。用快柱层析(EA:PE=1:1)纯化所述残余得到4-乙氧基-N-(2-甲氧基-4-(2,2,2-三氟-1-吗啉基乙基)苯基)-7H-吡咯[2,3-d]嘧啶-2-胺(800mg)的对映异构体混合物,通过超临界流体色谱仪(supercritical fluid chromatography,SFC)分离(chiralpak-IC柱,4.6mm×250mm,5μm,CO2-IPA(0.2%DEA)洗脱)得到化合物1(对映异构体1,310mg,38.8%)和化合物4(对映异构体2,300mg,37.5%),均为白色固体。
化合物1:1H NMR(400MHz,CD3OD)δ8.66(d,J=8.3Hz,1H),7.24-6.89(m,3H),6.38(d,J=3.5Hz,1H),4.59(q,J=7.1Hz,2H),4.22-4.07(m,1H),3.98(s,3H),3.70(t,J=4.7Hz,4H),2.67-2.58(m,4H),1.50(t,J=7.1Hz,3H);19F-NMR(400MHz,CD3OD)δ68.40ppm;m/z(ESI)+:452[M+H]+.tR=1.94min,旋光度:-52.5°(1mg/mL乙醇溶液);
化合物4:1H NMR(400MHz,CD3OD)δ8.66(d,J=8.3Hz,1H),7.24-6.89(m,3H),6.38(d,J=3.5Hz,1H),4.59(q,J=7.1Hz,2H),4.22-4.07(m,1H),3.98(s,3H),3.70(t,J=4.7Hz,4H),2.67-2.58(m,4H),1.50(t,J=7.1Hz,3H);19F-NMR(400MHz,CD3OD)δ68.40ppm;m/z(ESI)+:452[M+H]+,tR=2.33min,旋光度:+43.5°(1mg/mL乙醇溶液)。
参照实施例1,使用步骤1、3或6中的合适的起始物料和试剂,可以制备表1所示化合物5-34。
表1
a:SFC,chiralpak-IC柱,4.6mm×250mm,5μm,用CO 2-IPA(0.2%DEA)洗脱。
bOD-H柱,20mm×250mm,5μm,用正己烷/IPA(0.2%NH4OH)=80:20洗脱。
实施例2
步骤1:3-甲氧基-4-硝基苯甲酰氯(中间体2-1)
向DCM(100mL)中的3-甲氧基-4-硝基苯甲酸(5.00g,25.4mmol)的溶液中滴加几滴DMF。然后在0℃冰浴下逐滴滴入DCM(20mL)中的草酰氯溶液(6.50g,51.0mmol)。得到的混合物加热到室温,并搅拌2小时。将混合物浓缩,得到3-甲氧基-4-硝基苯甲酰氯(2-1,5.40g,98.8%),为黄色固体,无需进一步纯化用于下一步。
步骤2:2-(3-甲氧基-4-硝基苯甲酰)丙二酸二乙酯(中间体2-2)
在室温下,用TEA(6.10g,60.2mmol)和丙二酸二乙酯(4.80g,30.1mmol)处理悬浮于甲苯(50mL)的MgCl2(1.67g,17.6mmol)的悬浮液。混合物在室温下搅拌1.5h。然后分批加入中间体2-1(5.40g,25.1mmol),再搅拌1h。在反应混合物中搅拌加入1.0MHCl(10mL),然后用EtOAc(100mL*2)萃取。合并的有机层用盐水洗涤,用无水Na2SO4干燥,过滤和浓缩得到粗2-(3-甲氧基-4-硝基苯甲酰)丙二酸酯(2-2,10.5g),为黄色固体。m/z(ESI)+:340[M+H]+。
步骤3:1-(3-甲氧基-4-硝基苯基)乙烷-1-酮(中间体2-3)
将乙酸(50mL)中的粗中间体2-2(ca 25.1mmol)的溶液和3M H2SO4(aq.,50mL)加热至120℃,搅拌过夜。将所得溶液冷却至室温并用EtOAc(200mL)稀释。用盐水清洗分离的有机相,用无水Na2SO4干燥,过滤并浓缩,得到残余物。用硅胶柱色谱纯化(PE/EA=3:2)所述残余物,得到1-(3-甲氧基-4-硝基苯基)乙烷-1-酮(2-3,3.60g,两步72%),为灰白色固体。m/z(ESI)+:196[M+H]+.
步骤4:4-(1-(3-甲氧基-4-硝基苯基)乙烯基)吗啉(中间体2-4)
在0℃和N2保护下,在吗啉(1.34g,15.4mmol)的己烷(20mL)溶液中加入TiCl4在DCM溶液(1M,2.3mL,2.3mmol)。然后滴加中间体2-3(500mg,2.56mmol)在甲苯(10mL)中的溶液,将所得混合物加热至70℃搅拌20分钟。将混合物冷却至室温,通过硅藻土(celite)过滤。滤液浓缩得到粗4-(1-(3-甲氧基-4硝基苯基)乙烯基)吗啉(2-4,670mg),为黄色油状物。1HNMR(300MHz,CDCl3)δ7.85(d,J=8.1Hz,1H),7.19(s,1H),6.14(d,J=8.4Hz,1H),4.46(d,J=6.6Hz,2H),3.98(s,3H),3.79-3.76(m,4H),2.84-2.80(m,4H)。
步骤5:4-(1,1,1-三氟-2-(3-甲氧基-4-硝基苯基)丙-2-基)吗啉(中间体2-5)
在0℃、N2气氛中,向粗中间体2-4(570mg,2.15mmol)和KHF2(168mg,2.15mmol)的MeCN(30mL)溶液加入TFA(368mg,4.30mmol),然后加入TMSCF3(610mg,8.25mmol)。然后反应混合物升温至室温,搅拌过夜。用Na2CO3(aq.,20mL)猝灭反应混合物,用EA(50mL)萃取。使用盐水(30mL)清洗分离的有机相,用无水Na2SO4干燥,过滤并浓缩得到残余物。用硅胶柱层析(PE/EA=7:3)纯化所述残余物,得到4-(1,1,1-三氟-2-(3-甲氧基-4-硝基苯基)丙-2-基)吗啉(2-5,200mg,27%),为黄色固体。m/z(ESI)+:335[M+H]+。
步骤6:2-甲氧基-4-(1,1,1-三氟-2-吗啉基丙-2-基)苯胺(中间体2-6)
将MeOH(30mL)中的中间体5(200mg,0.60mmol)和10%Pd/C(100mg)的混合物脱气并用H2充气3次。然后在H2气氛中在室温下将所得混合物搅拌过夜。用硅藻土过滤所得混合物,然后浓缩得到粗2-甲氧基-4-(1,1,1-三氟-2-吗啉基丙-2-基)苯胺(6,150mg),为白色固体。m/z(ESI)+:305[M+H]+。
步骤7:4-乙氧基-N-(2-甲氧基-4-(1,1,1-三氟-2吗啉基丙-2-基)苯基)-7H-吡咯[2,3-d]嘧啶-2-胺(对映异构体1,化合物2)和4-乙氧基-N-(2-甲氧基-4-(1,1,1-三氟-2吗啉基丙-2-基)苯基)-7H-吡咯[2,3-d]嘧啶-2-胺(对映异构体2,化合物35)
类似于实施例1中步骤8-9,从中间体2-6来合成化合物2:4-乙氧基-N-(2-甲氧基-4-(1,1,1-三氟-2-吗啉基丙-2-基)苯基)-7H-吡咯[2,3-d]嘧啶-2-胺(对映异构体1,tR=1.63min)和化合物35:4-乙氧基-N-(2-甲氧基-4-(1,1,1-三氟-2-吗啉基丙-2-基)苯基)-7H-吡咯[2,3-d]嘧啶-2-胺(对映异构体2,tR=2.11min)。化合物2:1H NMR(400MHz,CD3OD)δ8.58(d,J=8.6Hz,1H),7.32(s,1H),7.15(d,J=8.6Hz,1H),6.92(d,J=3.5Hz,1H),6.36(d,J=3.5Hz,1H),4.56(q,J=7.1Hz,2H),3.95(s,3H),3.68(t,J=4.4Hz,4H),2.75-2.58(m,4H),1.60(s,3H),1.47(t,J=7.1Hz,3H);19F-NMR(400MHz,CD3OD)δ68.97ppm;m/z(ESI)+:466[M+H]+.化合物35:1HNMR(400MHz,CD3OD)δ8.62-8.52(m,1H),7.32(s,1H),7.15(d,J=8.7Hz,1H),6.92(d,J=3.5Hz,1H),6.36(d,J=3.5Hz,1H),4.56(q,J=7.1Hz,2H),3.95(s,3H),3.68(t,J=4.4Hz,4H),2.75-2.58(m,4H),1.60(s,3H),1.47(t,J=7.1Hz,3H);19F-NMR(400MHz,CD3OD)δ68.97ppm;m/z(ESI)+:466[M+H]+.
实施例3
步骤1:4-(1-(3-甲氧基-4-硝基苯基)环丙基)吗啉(中间体3-1)
在0℃,N2中,向粗中间体2-4(500mg,1.89mmol)在DCM(50mL)中的溶液和CH2I2(1.01g,3.77mmol)的混合物逐滴加入ZnEt2的己烷溶液(1M,2.8mL,2.80mmol)。在该温度下搅拌所述混合物3h。向反应混合物加入NH4Cl(aq.,10mL)。将分离的有机层使用无水Na2SO4干燥、过滤并浓缩给出残余物。使用硅胶柱层析(PE/EA=1:1)纯化所述残余物,得到4-(1-(3-甲氧基-4-硝基苯基)环丙基)吗啉(3-1,500mg,95%),为黄色固体。m/z(ESI)+:279[M+H]+。
步骤2:2-甲氧基-4-(1-吗啉环丙基)苯胺(中间体3-2)
类似于实施例2步骤6,从中间体3-1中制备2-甲氧基-4-(1-吗啉环丙基)苯胺(中间体3-2)。m/z(ESI)+:249[M+H]+。
步骤3:4-乙氧基-N-(2-甲氧基-4-(1-吗啉基环丙基)苯基)-7H-吡咯[2,3-d]嘧啶-2-胺(化合物3)
类似于实施例1中步骤8-9,从中间体3-2合成4-乙氧基-N-(2-甲氧基-4-(1-吗啉基环丙基)苯基)-7H-吡咯[2,3-d]嘧啶-2-胺(化合物3)。1H NMR(400MHz,CD3OD)δ8.53(d,J=8.7Hz,1H),6.91-6.89(m,3H),6.35(d,J=3.5Hz,1H),4.56(q,J=7.1Hz,2H),3.95(s,3H),3.61(t,J=4.8Hz,4H),2.67-2.58(m,4H),1.47(t,J=7.1Hz,3H),0.96-0.93(m,2H),0.84-0.81(m,2H);m/z(ESI)+:410[M+H]+.
参照实施例1和3,使用合适的起始物料或试剂,以合适的步骤可以合成表2中的化合物36-38。
表2
实施例4激酶抑制测定
材料
在AdaptaTM激酶测定法(LRRK2_IC50测定)中:激酶反应缓冲液含有5×激酶缓冲液S(Life Technologies,PV5213)和2mM DTT(Life Technologies,P2325)。激酶LRRK2G2019S蛋白(PV4881)和ERM(LRRKtide,PV5093)源自Life Technologies。AdaptaTM通用激酶测定试剂盒(Life Technologies,PV5099)包含以下组分:AdaptaTMEu-抗-ADP抗体(PV5097;4μg);10μMADP示踪剂(PV5098;200pmol);TR-FRET稀释缓冲液(PV3574;100mL);激酶淬灭缓冲液(P2825;1mL);10mM ATP(PV3227;500μl);和10mM ADP(PV5096;500μL)。LRRK2-IN-1(1234480-84-2,HY-10875)源自MedChem Express。
AdaptaTM激酶试验方法
通用激酶测定法是一种用于检测ADP的均匀的基于荧光的免疫测定法。与ATP消耗测定法相反,/>测定法对ADP形成非常敏感,大多数信号改变发生在初始10-20%的ATP转化为ADP时。这使得/>通用激酶测定法非常适合用于低活性激酶。
在室温(~21℃)下进行所有测定,并且在所用条件下该测定与时间和酶浓度呈线性关系。由5×激酶缓冲液S储存液(以上列出的)制备1×激酶反应缓冲液溶液,通过向8mLH2O中加入2mL 5×储存液来制备10mL的1×激酶反应缓冲液。将20μL的1M DTT加入至此1×激酶反应缓冲液中。
在低容量384孔板中以10μL体积进行激酶反应。通常,使用Greiner板(目录#3674#,低容量,白壁,784075)。未经测试的其它未经处理的测定板也可能是合适的。这种测定中的底物浓度为100μM,且1×激酶反应缓冲液由50mM Tris-HCl pH 8.5、10mM MgCl2、1mM EGTA、0.01%Brij-35和2mM DTT,以及任何其它的可能是特定激酶所必需的添加剂组成。让激酶反应在室温下进行1小时,随后添加5μL的TR-FRET稀释缓冲液中的激酶淬灭缓冲液(EDTA;30mM)、Eu标记的抗体(6nM)和示踪剂(18.9nM)的制剂。测定孔中的抗体的最终浓度为2nM,示踪剂为6.3nM且EDTA为10mM。让板在室温下平衡至少30分钟,随后在配置用于AdaptaTM TR-FRET的平板读取仪上读取。
使用BMG LABTECH PHERAstar平板读取仪,使用用于AdaptaTM的适当滤波器和仪器设置产生本文档中提供的数据。在孔中以1%DMSO(最终)筛选测试化合物。对于8点滴定,从起始浓度进行5倍连续稀释。
结果
本发明实施例化合物对LRRK2 G2019S抑制的IC50值如下表3所示。
表3
实施例5药物组织分布测试供试品:化合物4,纯度99%
供试品配制称取22.73mg的化合物4置于研钵中(按照纯度99%折算),加入少量0.5%CMC-Na充分研磨,转移至容器中,再洗涤研钵4次,洗涤液转移至容器,并加0.5%CMC-Na至30mL,配制成0.75mg/mL浓度的供试品混悬液。分析取样及给药前用磁力搅拌器以1200rpm的转速搅拌至少15min,现配现用。
给药方式:口服灌胃给药
给药频率和剂量:单次给药30mg/kg(40mL/kg)
给药后,各组动物分别在相应的时间点0.25、0.5、1、2、4、6、8、24h,心脏取血0.4mL,腹腔注射50mg/kg的舒泰麻醉,然后放血至安乐死取脑、肺、肾,用生理盐水清洗后滤纸吸干水分,放入冻存管中,暂存干冰中,12h内放-60℃以下保存。
采集的血液,EDTA-K2抗凝,暂置湿冰中,2h内以4℃、2600g离心10min,取血浆暂存干冰中,14h内放-60℃以下冰箱保存。
分析方法:采用以下LC-MS/MS法分别检测血浆和脑组织中的药物浓度。
仪器:Shimadzu LC-MS/MS(Model:LCMS-8060);
色谱柱:GL Sciences Inc.,InertSustain,C18,3um,2.1*50mm
检测离子:正离子模式,m/z 453.10/338.05
流动相A:含0.1%TFA的水溶液;流动相B:含0.1%TFA的甲醇溶液;
流速:0.4mL·min-1
药动学参数评价指标:采用WinNonlin6.4程序,以非房室模型计算药动学参数。
结果及结论:
图1为实施例5中给药后的小鼠平均血药浓度-时间曲线,其药动力学参数(PK)汇总于下表4:
表4:血浆药代动力学参数
图2为实施例5中给药后的小鼠脑组织药物浓度-时间曲线,其药动力学参数汇总于下表5:
表5:脑组织药代动力学参数
药代动力学参数 | 单位 | |
Tmax | h | 1.00 |
Cmax | ng·g-1 | 1898 |
AUC0-t | ng·h·g-1 | 6457 |
AUC0-∞ | ng·h·g-1 | 7409 |
实验结果表明,本化合物具有优异的透脑率。其中,1h时的透脑率C脑/C血可达约3.2,而AUC脑/AUC血浆则可达约2.0。因此,本发明实施例化合物能够更迅速和有效地穿过血脑屏障,达到治疗位点从而发挥药效。
以上实施例对本发明的实施方式进行了示例性的说明。但是,本申请的保护范围不应拘囿于上述示例性的实施方式。凡在本发明的精神和原则之内,本领域技术人员所作出的任何修改、等同替换、改进等,均应包含在本申请权利要求的保护范围之内。
Claims (17)
1.一种式(I)所示的化合物、立体异构体或其药学上可接受的盐:
其中:
R3、R4相同或不同,彼此独立地选自H、C1-6烷基、卤代C1-6烷基;且R3、R4不同时为H;
或者,R3、R4与其连接的原子一起形成无取代或任选被1、2个或更多个Rd取代的C3-8环烷基;
Ar1选自被1、2个或更多个Re取代的苯基;
每一个Rb相同或不同,彼此独立地选自H、卤素、OH、CN、NO2、氧代(=O)、C1-6烷基、C1-6烷基氧基;
每一个Rd相同或不同,彼此独立地选自H、卤素、OH、CN、NO2、氧代(=O)、C1-6烷基、C1-6烷基氧基;
每一个Re相同或不同,彼此独立地选自H、卤素、OH、CN、NO2、C1-6烷基、C1-6烷基氧基;
每一个Rf相同或不同,彼此独立地选自H、卤素、OH、CN、NO2、无取代或任选被1、2个或更多个Rg取代的下列基团:C1-6烷基、C1-6烷基氧基、NH2;
每一个Rg相同或不同,彼此独立地选自H、卤素、OH、CN、NO2、氧代(=O)、C1-6烷基、C1-6烷基氧基。
2.根据权利要求1所述的化合物、立体异构体或其药学上可接受的盐,其特征在于,R3、R4相同或不同,彼此独立地选自H、甲基、三氟甲基;且R3、R4不同时为H;
或者,R3、R4与其连接的原子一起形成环丙烷基。
7.一种药物组合物,其包含治疗有效量的权利要求1-4任一项所述化合物、立体异构体或其药学上可接受的盐中的至少一种。
8.权利要求1-4任一项所述化合物、立体异构体或其药学上可接受的盐中的至少一种在制备药物中的用途;
所述药物用于治疗或预防与LRRK激酶活性相关的疾病或病症;
所述LRRK激酶为LRRK2激酶或其突变体或同等型,或它们的组合。
9.根据权利要求8所述的用途,其特征在于,所述与LRRK激酶活性相关的疾病或病症为:神经退行性疾病、增殖性疾病、与蛋白激酶相关的疾病、溶酶体疾病、Tau病和多巴胺水平降低引起的疾病、癌症、其他α-突触核蛋白病、tau蛋白病、认知损伤或认知障碍、戈谢病、C型尼曼氏病、嗜银颗粒病、皮克病、皮质基底核退化症、进行性核上性瘫痪、痴呆、颅脑损伤、中风、癫痫、药物成瘾相关的戒断症状/复发、炎性肠病、麻风病、免疫***疾病。
10.根据权利要求9所述的用途,其特征在于,所述神经退行性疾病为帕金森病或阿尔茨海默病。
11.根据权利要求10所述的用途,其特征在于,所述帕金森病为与GBA突变相关的帕金森氏病。
12.根据权利要求9所述的用途,其特征在于,所述痴呆为与17号染色体相关的遗传性额颞叶痴呆。
13.根据权利要求9所述的用途,其特征在于,所述癌症为乳腺癌;所述炎性肠病为克罗恩氏病或溃疡性结肠炎。
14.根据权利要求8所述的用途,其特征在于,所述疾病和病症为与脑部相关的疾病。
15.根据权利要求8所述的用途,其特征在于,所述疾病和病症为与脑部供血或神经相关的疾病或病症。
16.根据权利要求8所述的用途,其特征在于,所述疾病和病症为认知损伤或认知障碍、阿尔茨海默病、痴呆、帕金森病、颅脑损伤、中风、癫痫。
17.根据权利要求16所述的用途,其特征在于,所述痴呆为与17号染色体相关的遗传性额颞叶痴呆。
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