CN104080781B - 1H-吲唑-3-甲酰胺化合物作为糖原合酶激酶3β抑制剂的用途 - Google Patents
1H-吲唑-3-甲酰胺化合物作为糖原合酶激酶3β抑制剂的用途 Download PDFInfo
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- CN104080781B CN104080781B CN201380007410.2A CN201380007410A CN104080781B CN 104080781 B CN104080781 B CN 104080781B CN 201380007410 A CN201380007410 A CN 201380007410A CN 104080781 B CN104080781 B CN 104080781B
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Abstract
本发明涉及作为糖原合酶激酶3β(GSK-3β)抑制剂的具有下述通式(I)的1H-吲唑-3-甲酰胺化合物的用途及其在治疗GSK-3β-相关疾病中的用途,例如,(i)胰岛素抵抗疾病;(ii)神经变性疾病;(iii)情绪障碍;(iv)精神分裂性障碍;(v)癌性疾病;(vi)炎症;(vii)物质滥用疾病;和(viii)癫痫。
Description
发明领域
本发明涉及作为糖原合酶激酶3β(GSK-3β)抑制剂起作用的1H-吲唑-3-甲酰胺化合物的新用途及其在治疗GSK-3β-相关疾病中的用途,所述疾病例如为(i)胰岛素抵抗疾病;(ii)神经变性疾病;(iii)情绪障碍;(iv)精神分裂性障碍;(v)癌性疾病;(vi)炎症;(vii)物质滥用疾病;和(viii)癫痫。
本领域的状态
蛋白激酶构成结构相关酶的大家族,其将磷酸基团从高能供体分子(例如腺苷三磷酸,ATP)转移至特异性底物,通常是蛋白质。磷酸化后,该底物进行功能改变,通过这种改变激酶可以调节各种生物功能。
一般而言,可以根据被磷酸化底物的不同将蛋白激酶分成几个种类。例如,丝氨酸/苏氨酸激酶使丝氨酸或苏氨酸氨基酸侧链上的羟基磷酸化。
糖原合酶激酶3(GSK-3)是组成型活性多功能酶,其在最近被发现,属于丝氨酸/苏氨酸激酶种类。
人GSK-3被两种不同和独立的基因编码,产生分别具有约51和47kDa分子量的GSK-3α和GSK-3β蛋白质。两种同种型在其激酶结构域中共有几乎相同的序列,而在激酶结构域外部,其序列显著不同(Benedetti等人,NeuroscienceLetters,2004,368,123-126)。GSK-3α是多功能蛋白质丝氨酸激酶而GSK-3β是丝氨酸-苏氨酸激酶。
已经发现GSK-3β广泛地在所有组织中表达,其中广泛的表达在成年人脑中,这启示了在神经元信号传导途径中的基础作用(Grimes和Jope,ProgressinNeurobiology,2001,65,391-426)。对糖原合酶激酶3的关注归因于其在各种生理学途径中的作用,例如,代谢、细胞周期、基因表达、胚胎发育、癌发生和神经保护(Geetha等人,BritishJournalPharmacology,2009,156,885-898)。
GSK-3β最初因其在调节糖原合酶在将葡萄糖转化成糖原中的作用而被鉴定(Embi等人,EurJBiochem,1980,107,519-527)。GSK-3β显示对糖原合酶的高度特异性。
2型糖尿病是牵连GSK-3β的第一种疾病状态,这归因于其在胰岛素信号传导途径的几个方面中的负调节作用。在这种途径中,3-磷酸肌醇-依赖性蛋白激酶1(PDK-1)活化PKB,其进而使GSK-3β失活。这种GSK-3β的失活导致糖原合酶去磷酸化和活化,这有助于糖原合成(Cohen等人,FEBSLett.,1997,410,3-10)。此外,预计GSK-3β选择性抑制剂增强前驱糖尿病胰岛素抵抗大鼠骨骼肌中的胰岛素信号传导,由此使得GSK-3β成为治疗前驱糖尿病状态中骨骼肌胰岛素抵抗的富有吸引力的靶标(Dokken等人,AmJ.Physiol.Endocrinol.Metab.,2005,288,E1188-E1194)。
还发现GSK-3β为因胰岛素抵抗疾病例如X综合征、肥胖症和多囊性卵巢综合征导致的其他病理状态中的潜在药物靶标(RingDB等人,Diabetes,2003,52:588-595)。
已经发现GSK-3β牵连阿尔茨海默病中的病理性tau的异常磷酸化(Hanger等人,Neurosci.Lett.,1992,147,58-62;Mazanetz和Fischer,NatRevDrugDiscov.,2007,6,464-479;Hong和Lee,J.Biol.Chem.,1997,272,19547-19553)。此外,经证实载脂蛋白ApoE4和β-淀粉样蛋白诱导的GSK-3β早期活化可以导致细胞凋亡和tau高度磷酸化(Cedazo-Minguez等人,JournalofNeurochemistry,2003,87,1152-1164)。在阿尔茨海黙病的其他方面中,还报道了GSK-3β在分子水平上活化的相关性(Hernandez和Avila,FEBSLetters,2008,582,3848-3854)。
此外,已经证实GSK-3β牵连与帕金森病相关的神经变性的起源和维持(DukaT.等人,TheFASEBJournal,2009;23,2820-2830)。
根据这些实验观察结果,GSK-3β抑制剂可以应用于治疗与Tau病变相关神经病理学后果和的认知和注意缺陷;阿尔茨海黙病;帕金森病;亨廷顿病(GSK-3β牵连这样的缺陷和疾病公开在MeijerL.等人,TRENDSPharmSci,2004;25,471-480中);痴呆,例如、但不限于血管性痴呆、外伤后痴呆、因脑膜炎导致的痴呆等;急中风;跌打损伤;脑血管意外;脑和脊髓创伤;周围神经病;视网膜病变和青光眼(GSK-3β牵连这样的病症公开在WO2010/109005中)。
还在几种涉及GSK-3β抑制的研究中启示了治疗脊髓神经变性疾病,如肌萎缩性侧索硬化、多发性硬化、脊髓性肌肉萎缩和因脊髓损伤导致的神经变性,例如在CalderóJ.等人,“Lithiumpreventsexcitotoxiccelldeathofmotoneuronsinorganotypicsliceculturesofspinalcord”,Neuroscience.2010年2月17;165(4):1353-69,LégerB.等人,“Atrogin-1,MuRF1andFoXO中;aswellasphosphorylatedGSK-3betaand4E-BP1arereducedinskeletalmuscleofchronicspinalcord-injuredpatients”,MuscleNerve,2009年7月;40(1):69-78和GalimbertiD.等人,“GSK3βgeneticvariabilityinpatientswithMultipleSclerosis”,NeurosciLett.2011年6月15日;497(1):46-8。
此外,GSK-3β与情绪障碍相关,例如双相情感障碍、抑郁症和精神分裂症。
抑制GSK-3β可能是情绪稳定剂的重要治疗靶标且调节GSK-3β可能牵连用于精神病学的其他药物的治疗作用。在情感障碍、双相情感障碍、抑郁症和精神分裂症中失调的GSK-3β可以具有多重作用,其可能影响神经可塑性,例如调节神经元结构、神经发生、基因表达和神经元对应激的潜在致命性情况的响应能力(Jope和Roh,Curr.DrugTargets,2006,7,1421-1434)。
在锂和丙戊酸盐研究中突出显示了GSK-3β在情感障碍中的作用(Chen等人,J.Neurochem.,1999,72,1327-1330;Klein和Melton,Proc.Natl.Acad.Sci.USA,1996,93,8455-8459),它们两者均为GSK-3β抑制剂并且用于治疗情绪障碍。还存在来自遗传观点的报告,它们支持GSK-3β在双相情感障碍的疾病生理学中的作用(Gould,Expert.Opin.Ther.Targets,2006,10,377-392)。
据报道在具有精神分裂症的个体的外周淋巴细胞和脑中AKT1蛋白质水平及其GSK-3β在丝氨酸-9上的磷酸化减少。因此,这一发现支持了AKT1-GSK-3β信号传导中的改变促成了精神分裂症发病机制的提议(Emamian等人,NatGenet,2004,36,131-137)。
另外,GSK-3β在癌症中的作用是一般公认的现象。
已经证实抑制GSK-3β的小分子在一些具体癌症治疗中的潜能(JiaLuo,CancerLetters,2009,273,194-200)。GSK-3β表达和活化与前列腺癌进展相关(Rinnab等人,Neoplasia,2008,10,624-633)且还提出抑制GSK3b作为胰腺癌(Garcea等人,CurrentCancerDrugTargets,2007,7,209-215)和卵巢癌(QiCao等人,CellResearch,2006,16671-677)的特异性靶标。在结肠直肠癌细胞中紧急抑制GSK-3β活化p53-依赖性细胞凋亡并且拮抗肿瘤生长(Ghosh等人,ClinCancerRes2005,11,4580-4588)。
GSK-3β在MLL-相关白血病中的功能作用的鉴定启示GSK-3β抑制可能是富有希望的疗法,其选择性地用于依赖于HOX超表达的转化的细胞(Birch等人,CancerCell,2010,17,529-531)。
GSK-3β牵连大量炎症性信号传导途径,例如,已经证实GSK-3β抑制诱导抗炎细胞因子IL-10分泌等。根据这一发现,GSK-3β抑制剂可以用于调节炎症抑制(G.Klamer等人,CurrentMedicinalChemistry,2010,17(26),2873-2281,Wang等人,Cytokine,2010,53,130-140)。
还证实GSK-3β抑制可以减弱小鼠中可卡因诱导的行为。给用GSK-3β抑制预处理的小鼠施用可卡因显示药理学抑制GSK3减少了对可卡因的急性行为响应和反复可卡因产生的长期神经适应(Cocaine-inducedhyperactivityandsensitizationaredependentonGSK3,MillerJS等人Neuropharmacology.2009年6月;56(8):1116-23,电子版,2009年3月27日)。
在几种研究中证实了GSK-3β在几种形式的癫痫发生中的作用,它们启示抑制GSK-3β可以成为治疗癫痫症的途径(Novelglycogensynthasekinase3andubiquitinationpathwaysinprogressivemyoclonusepilepsy,LohiH等人,HumMolGenet.2005年9月15日;14(18):2727-36和HyperphosphorylationandaggregationofTauinlaforin-deficientmice,ananimalmodelforLaforadisease,PuriR等人,JBiolChem.2009年8月21日;284(34):22657-63)。
GSK-3β抑制与治疗疼痛的相关性已经在MartinsDF等人“TheantinociceptiveeffectsofAR-A014418,aselectiveinhibitorofglycogensynthasekinase-3beta,inmice”,J.Pain,2011年3月;12(3):315-22中得以证实。
有关GSK-3β、其能够、其治疗潜能及其可能的抑制剂的综述如"GSK-3β:roleintherapeuticlandscapeanddevelopmentofmodulators"中所示(S.Phukan等人,BritishJournalofPharmacology(2010),160,1-19)。
WO2004/014864公开了1H-吲唑-3-甲酰胺化合物作为选择性细胞周期蛋白依赖性激酶(CDK)抑制剂。推定这种化合物用于治疗癌症(通过CDK2介导的机制)和神经变性疾病,特别是阿尔茨海黙病(通过CDK5介导的机制)和作为抗病毒药和抗真菌药(通过CDK7、CDK8和CDK9介导的机制)。
细胞周期蛋白依赖性激酶(CDKs)是丝氨酸/苏氨酸激酶,首先发现了它们在调节细胞周期中的作用。CDKs还牵连调节转录、mRNA加工和神经细胞分化。这种激酶仅在其与调节亚单位即细胞周期蛋白发生相互作用和结合之后活化。
此外,将1H-吲唑-3-甲酰胺化合物描述为治疗慢性和神经性疼痛的止痛药(例如,参见WO2004/074275和WO2004/101548)和用于治疗胃肠道病症、中枢神经系统障碍和心血管疾病的5-HT4受体拮抗剂(例如,参见WO1994/10174)。
发明概述
因为直到最近发现GSK-3β为药理学靶标,所以对找到选择性抑制GSK-3β的化合物存在强烈需求。
申请人还令人意外地发现,式(I)的1H-吲唑-3-甲酰胺化合物能够抑制GSK-3β并且在与其他激酶比较时对GSK-3β具有极高亲和力。因此,所述化合物能够选择性地抑制GSK-3β。
因此,用于本发明的化合物能够选择性地抑制GSK-3β活性且由此用于治疗归因于GSK-3β不受控制的活化和/或超表达的病理状态,其选自:(i)胰岛素抵抗疾病,例如2型糖尿病、X综合征、肥胖症和多囊性卵巢综合征;(ii)神经变性疾病,例如帕金森病、阿尔茨海默病、亨廷顿病和脊髓神经变性疾病;(iii)情绪障碍,例如双相情感障碍和抑郁障碍;(iv)精神分裂性障碍;(v)癌性疾病,例如前列腺癌、胰腺癌、卵巢癌和结肠-直肠癌和MLL-相关白血病;(vi)炎症;(vii)物质滥用疾病;和(viii)癫痫。
然后在第一个方面中,本发明涉及具有下述通式(I)的1H-吲唑-3-甲酰胺化合物及其与药学上可接受的有机和无机酸和碱的加成盐在治疗归因于GSK-3β不受控制的活化和/或超表达的疾病中的用途:
其中
Ra和Ra'彼此相同或不同,为氢原子;卤原子;C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基,其任选地被一个或多个选自卤素、羟基、-NH2和C1-C3烷氧基的取代基取代;具有3-12个成员的脂族或芳族碳环或杂环,其任选地被一个或多个选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、-NR1R2、-C(O)OH、-C(O)OR1和-C(O)NR1R2的取代基取代;
Y是价键、C1-C6烷基、C2-C6烯基或C2-C6炔基,其任选地被一个或多个选自卤素、羟基、-NH2和C1-C3烷氧基的取代基取代;
Rb是具有3-12个成员的脂族或芳族碳环或杂环,其任选地被一个或多个选自卤素、羟基、硝基、氰基、-CF3、C1-C6烷氧基、苄基氧基、C1-C4烷基、C2-C4烯基和C2-C4炔基、-NHSO2CH3、-SO2NH2、-Z-C(O)OH、-Z-C(O)OR1和-Z-C(O)NR1R2的取代基取代,其中Z是σ-键或(C1-C3)烷基;
R1和R2独立地为氢原子、C1-C4烷基、C2-C4烯基、C2-C4炔基和苯基;
所述疾病选自:(i)胰岛素抵抗疾病,例如2型糖尿病、X综合征、肥胖症和多囊性卵巢综合征;(ii)神经变性疾病,例如帕金森病、阿尔茨海默病、亨廷顿病和脊髓神经变性疾病;(iii)情绪障碍,例如双相情感障碍和抑郁障碍;(iv)精神分裂性障碍;(v)癌性疾病,例如前列腺癌、胰腺癌、卵巢癌和结肠-直肠癌和MLL-相关白血病;(vi)炎症;(vii)物质滥用疾病;和(viii)癫痫。
在第二个方面中,本发明涉及治疗归因于GSK-3β不受控制的活化和/或超表达的病理状态的方法,所述病理状态选自:(i)胰岛素抵抗疾病,例如2型糖尿病、X综合征、肥胖症和多囊性卵巢综合征;(ii)神经变性疾病,例如帕金森病、阿尔茨海默病、亨廷顿病和脊髓神经变性疾病;(iii)情绪障碍,例如双相情感障碍和抑郁障碍;(iv)精神分裂性障碍;(v)癌性疾病,例如前列腺癌、胰腺癌、卵巢癌和结肠-直肠癌和MLL-相关白血病;(vi)炎症;(vii)物质滥用疾病;和(viii)癫痫,该方法通过对有此需要的人给予有效量的具有下述通式(I)的1H-吲唑-3-甲酰胺及其与药学上可接受的有机和无机酸和碱的加成盐来进行:
其中
Ra和Ra'彼此相同或不同,为氢原子;卤原子;C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基,其任选地被一个或多个选自卤素、羟基、-NH2和C1-C3烷氧基的取代基取代;具有3-12个成员的脂族或芳族碳环或杂环,其任选地被一个或多个选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、-NR1R2、-C(O)OH、-C(O)OR1和-C(O)NR1R2的取代基取代;
Y是价键、C1-C6烷基、C2-C6烯基或C2-C6炔基,其任选地被一个或多个选自卤素、羟基、-NH2和C1-C3烷氧基的取代基取代;
Rb是具有3-12个成员的脂族或芳族碳环或杂环,其任选地被一个或多个选自卤素、羟基、硝基、氰基、-CF3、C1-C6烷氧基、苄基氧基、C1-C4烷基、C2-C4烯基和C2-C4炔基、-NHSO2CH3、-SO2NH2、-Z-C(O)OH、-Z-C(O)OR1和-Z-C(O)NR1R2的取代基取代,其中Z是σ-键或(C1-C3)烷基;
R1和R2独立地为氢原子、C1-C4烷基、C2-C4烯基、C2-C4炔基和苯基。
本发明还包括上述式(I)的化合物的前药、立体异构体和对映异构体。
属于上述式(I)范围内的一些化合物是新的,即在本申请的申请日之前从未在印刷出版物中被公开并举例说明。
因此,在第三个方面中,本发明涉及下式的1H-吲唑-3-甲酰胺化合物:
-N-{[1-(2,4-二氯苄基)哌啶-4-基]甲基}-5-甲氧基-1H-吲唑-3-甲酰胺和
-N-({1-[4-(苄基氧基)苄基]哌啶-4-基}甲基)-5-甲氧基-1H-吲唑-3-甲酰胺。
发明详述
在本说明书和如下权利要求的上下文中,“C1-6烷基”预以表示具有1-6个碳原子的直链或支链烷基,例如甲基、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、3-戊基、异戊基、新戊基、正己基、仲己基和新己基。
在本说明书和如下权利要求的上下文中,“C1-4烷基”预以表示具有1-4个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。
在本说明书和如下权利要求的上下文中,“C1-3烷基”预以表示具有1-3个碳原子的直链或支链烷基,例如甲基、乙基、丙基和异丙基。
在本说明书和如下权利要求的上下文中,“C2-6烯基”预以表示具有2-6个碳原子和至少一个双键的直链或支链烷基,例如乙烯基(乙烯基)、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、丁烯基、戊烯基和己烯基。
在本说明书和如下权利要求的上下文中,“C2-4烯基”预以表示具有2-4个碳原子和至少一个双键的直链或支链烷基,例如乙烯基(乙烯基)、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基和丁烯基。
在本说明书和如下权利要求的上下文中,“C2-6炔基”预以表示具有2-6个碳原子和至少一个三键的直链或支链烷基,例如乙炔基、1-丙炔基、2-丙炔基(炔丙基)、丁炔基、戊炔基和己炔基。
在本说明书和如下权利要求的上下文中,“C2-4炔基”预以表示具有2-4个碳原子和至少一个三键的直链或支链烷,例如乙炔基、1-丙炔基、2-丙炔基(炔丙基)和丁炔基。
在本说明书和如下权利要求的上下文中,“C1-6烷氧基”预以表示具有1-6个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、仲戊氧基、异戊氧基和正己氧基(n-esiloxy)。
在本说明书和如下权利要求的上下文中,“C1-3烷氧基”预以表示具有1-3个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、正丙氧基和异丙氧基。
根据本发明优选的实施方案,上述式(I)的Ra、Ra'、Rb和Y的含义如下文所述。
优选地,Ra和Ra'彼此相同或不同,为氢原子;卤原子,其选自氯、溴和碘;C1-C6烷基和C1-C6烷氧基,其任选地被一个或多个选自卤素、羟基、-NH2或C1-C3烷氧基的取代基取代;具有4-10个成员的脂族或芳族碳环或杂环,其任选地被一个或多个选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、-NR1R2、-C(O)OH、-C(O)OR1和-C(O)NR1R2的取代基取代。
更优选地,Ra和Ra'彼此相同或不同,为卤原子,其选自氯和溴;羟基;C1-C6烷基;C1-C6烷氧基;或具有5-6个成员的脂族或芳族碳环或杂环,其任选地被一个或多个选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、-NR1R2和-C(O)OH的取代基取代。
有利地,所述具有5或6个成员的脂族或芳族碳环或杂环选自苯基、吡啶、嘧啶、吡嗪、哒嗪、吡咯、呋喃、噻吩、噁唑、异噁唑、噻唑、异噻唑、2H-吡喃、环己基、环戊基、哌啶、哌嗪。
甚至更优选地,Ra和Ra'彼此相同或不同,为溴原子;C1-C3烷氧基;或具有6个成员的芳族碳环或杂环,其任选地被1或2个选自卤素、羟基、C1-C3烷基、C1-C3烷氧基、-NR1R2和-C(O)OH的取代基取代。
在一个优选的实施方案中,所述具有6个成员的脂族或芳族碳环或杂环选自苯基、吡啶、嘧啶、吡嗪、哒嗪、2H-吡喃、环己基、哌啶、哌嗪。
在一个甚至更优选的实施方案中,所述具有6个成员的脂族或芳族碳环或杂环选自苯基、吡啶、嘧啶、2H-吡喃、环己基。
优选地,Y是价键、C1-C6烷基,其任选地被一个或多个选自卤素、羟基、-NH2和C1-C3烷氧基的取代基取代。
更优选地,Y是C1-C6烷基。
甚至更优选地,Y是C1-C3烷基。
优选地,Rb是4-10个成员的脂族或芳族碳环或杂环,其被一个或多个选自卤素、羟基、硝基、氰基、-CF3、C1-C6烷氧基、苄基氧基、C1-C4烷基、-NHSO2CH3、-SO2NH2、-Z-C(O)OH、-Z-C(O)OR1和-Z-C(O)NR1R2的取代基取代,其中Z是σ-键或(C1-C3)烷基。
更优选地,Rb是5-6个成员的脂族或芳族碳环或杂环,其被一个或多个选自卤素、羟基、硝基、-CF3、C1-C6烷氧基、苄基氧基、-NHSO2CH3、-SO2NH2、-Z-C(O)OH和-Z-C(O)OR1的取代基取代,其中Z是σ-键或(C1-C3)烷基。
有利地,所述具有5或6个成员的脂族或芳族碳环或杂环选自苯基、吡啶、嘧啶、吡嗪、哒嗪、吗啉、吡咯、呋喃、噻吩、噁唑、异噁唑、噻唑、异噻唑、1-氧杂-2,4-二唑、2H-吡喃、环己基、环戊基、哌啶、哌嗪。
甚至更优选地,Rb是具有6个成员的芳族碳环,其被1或2个选自卤素、羟基、硝基、-CF3、C1-C3烷氧基和苄基氧基的取代基取代。
在一个优选的实施方案中,所述具有6个成员的脂族或芳族碳环或杂环选自苯基、吡啶、嘧啶、吡嗪、哒嗪、吗啉、2H-吡喃、环己基、哌啶、哌嗪。
在一个甚至更优选的实施方案中,所述具有6个成员的脂族或芳族碳环或杂环选自苯基、吡啶、嘧啶、吗啉、2H-吡喃、环己基。
在一个优选的实施方案中,所述具有5个成员的脂族或芳族碳环或杂环选自呋喃、噻吩、噻唑、噁唑和1-氧杂-2,4-二唑。
优选地,R1和R2独立地为氢原子、C1-C4烷基或苯基。
更优选地,R1和R2独立地为C1-C3烷基。
甚至更优选地,R1和R2均为甲基。
优选地,所述具有5或6个成员的脂族或芳族碳环或杂环选自苯基、环己烷、环戊烷、吡啶、吡嗪、嘧啶、吡嗪、哒嗪、哌啶、哌嗪、呋喃、噻吩、吡咯、吡咯烷、咪唑、吗啉、噻唑、噻唑烷、噻二唑、噻二唑烷、噁唑、噁唑烷、异噁唑、异噁唑烷、吡唑。
更优选地,所述碳环是苯基且所述杂环是吡啶、噁唑、咪唑和吡咯。
用于本发明的化合物优选作为与药学上可接受的有机或无机酸或碱的盐使用。
优选地,所述药学上可接受的有机酸选自草酸、马来酸、甲磺酸、对甲苯磺酸、琥珀酸、柠檬酸、苹果酸、酒石酸、乳酸。
优选地,所述药学上可接受的有机碱选自选自氨丁三醇、赖氨酸、精氨酸、甘氨酸、丙氨酸和乙醇胺。
优选地,所述药学上可接受的无机酸选自盐酸、氢溴酸、磷酸和硫酸。
优选地,所述药学上可接受的无机碱选自碱金属或碱土金属例如钠、钾和钙的氢氧化物或碳酸盐。
本发明还包括上述式(I)的化合物的前药、立体异构体和对映异构体的用途。
本文所用的术语“前药”是指这样的活性剂,其在体内被一些生理化学过程转化成母体药物(例如前药在接触生理性pH时被转化成期望的药物形式)。前药通常是有用的,因为在一些情况中,它们比母体药物易于施用。例如,它们可以通过口服给药得到生物利用,而母体药物不能。前药在药物组合物中还可以具有超过母体药物的改善的溶解度。作为实例,但不限于此,前药可以是本发明的化合物,其中它作为酯(所述的“前药”)施用以有利于通过其中水溶性并非有益的细胞膜输送,然后,一旦进入其中水溶性有益的细胞,则被代谢水解成羧酸。
前药具有许多有用的特性。例如,前药可以比最终的药物更具有水溶性,由此有利于药物的静脉内给药。前药还可以具有高于最终药物的口服生物利用度水平。在施用后,前药被酶或化学裂解以便将最终药物递送至血液或组织内。
特别关注本文公开的化合物的酯前药。酯可以由连接上述式(I)的化合物的羧酸官能团通过与醇或酚反应形成。或者,酯可以由连接上述式(I)的化合物的羟基官能团通过与羧酸或氨基酸反应形成。尽管没有指定限定,但是酯可以是烷基酯、芳基酯或杂芳基酯。术语烷基具有本领域技术人员一般所理解的含义且是指直链、支链或环状烷基部分。C1-6烷基酯类是特别有用的,其中酯的烷基部分具有1-6个碳原子,且包括、但不限于甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基异构体、己基异构体、环丙基、环丁基、环戊基、环己基及其具有1-6个碳原子的组合。
上述式(I)的本发明化合物可以用于治疗归因于GSK-3β不受控制的活化和/或超表达的病理状态,其选自(i)胰岛素抵抗疾病;(ii)神经变性疾病;(iii)情绪障碍;(iv)精神分裂性障碍;(v)癌性疾病;(vi)炎症;(vii)物质滥用疾病;和(viii)癫痫。
有利地,胰岛素抵抗疾病是2型糖尿病、X综合征、肥胖症和多囊性卵巢综合征。
有利地,急性和慢性神经变性疾病是帕金森病、阿尔茨海黙病、亨廷顿病和脊髓神经变性疾病。
优选地,脊髓神经变性疾病是肌萎缩性侧索硬化、多发性硬化、脊髓性肌肉萎缩和因脊髓损伤导致的神经变性。
有利地,情绪障碍是双相情感障碍和抑郁障碍。
优选地,双相情感障碍是I型双相情感障碍、II型双相情感障碍、循环性精神病(cyclothymia)和未有特殊说明的双相情感障碍(BD-NOS)。
优选地,抑郁障碍是重度抑郁障碍(MDD)、非典型抑郁症(AD)、忧郁性抑郁症、精神病性重度抑郁症(PMD)、紧张性抑郁症、产后抑郁症(PPD)、季节性情感障碍(SAD)、心境恶劣障碍和未有特殊说明的抑郁障碍(DD-NOS)。
有利地,精神分裂性障碍是偏执型精神分裂症、混乱型精神分裂症、紧张型精神分裂症、简单型精神分裂症、残留型精神分裂症和未分化型精神分裂症。
有利地,癌性疾病前列腺癌、胰腺癌、卵巢癌和结肠-直肠癌和MLL-相关白血病。
有利地,物质滥用疾病是因精神兴奋药导致的滥用疾病。
典型地,用于本发明的式(I)的1H-吲唑-3-甲酰胺化合物以药物组合物的形式施用。
因此,本发明的另一个方面涉及药物组合物,其包含至少一种如上所述的式(I)的化合物和至少一种惰性的药学上可接受的赋形剂,该药物组合物用于治疗归因于GSK-3β不受控制的活化和/或超表达的病理状态,其选自(i)胰岛素抵抗疾病,例如2型糖尿病、X综合征、肥胖症和多囊性卵巢综合征;(ii)神经变性疾病,例如帕金森病、阿尔茨海默病、亨廷顿病和脊髓神经变性疾病;(iii)情绪障碍,例如双相情感障碍和抑郁障碍;(iv)精神分裂性障碍;(v)癌性疾病,例如前列腺癌、胰腺癌、卵巢癌和结肠-直肠癌和MLL-相关白血病;(vi)炎症;(vii)物质滥用疾病;和(viii)癫痫。
优选地,将本发明的药物组合物制备成剂型,其包含有效量的至少一种如上所述的式(I)的化合物、其与药学上可接受的有机或无机酸或碱的盐或其前药和至少一种惰性的药学上可接受的赋形剂。
适合的剂型的实例是用于口服给药的片剂、胶囊、包衣片剂、颗粒、溶液和糖浆剂;用于局部施用的溶液、香膏剂(pomade)和软膏剂;用于透皮施用的含药贴剂;用于直肠施用的栓剂和可注射无菌溶液。
其他适合的剂型是具有缓释的剂型和基于用于口服、注射或透皮施用的脂质体的那些剂型。
所述剂型还可以包含其他传统的成分,例如:防腐剂、稳定剂、表面活性剂、缓冲剂、用于调节渗透压的盐、乳化剂、甜味剂、着色剂、矫味剂等。
式(I)的1H-吲唑-3-甲酰胺或其药学上可接受的酸加成盐在本发明药物组合物中的量可以在宽范围内根据已知因素的不同而改变,例如,病理状态的类型、疾病的严重性、患者的体重、剂型、所选择的给药途径、每日的给药次数和所选择的式(I)的1H-吲唑-3-甲酰胺化合物的效力。然而,本领域技术人员可以以便利和常规的方式确定最佳用量。
典型地,式(I)的化合物或其药学上可接受的酸加成盐在本发明药物组合物中的量例如可以确保为0.0001-100mg/kg/天的施用水平。优选地,施用水平为0.001-50mg/kg/天且甚至更优选0.01-10mg/kg/天。
可以通过与药物化学家熟知的技术制备本发明药物组合物的剂型且包含混合、制粒、压制、溶解、灭菌等。
用于本发明的式(I)的化合物的非限制性实例是下表1的那些。
表1
实验部分
1H-NMR光谱法:内标=四甲基硅烷;DMSO-d6=氘代二甲亚砜;(s)=单峰;(d)=二重峰;(t)=三重峰;(br)=宽峰;(dd)=双二重峰;(dt)=双三重峰;(ddd)=双双二重峰;(dtd)=双三重二重峰;(m)=多重峰;J=偶合常数;δ=化学位移(以ppm计)。
式(I)的化合物的制备
可以通过本领域技术人员公知的方法,例如通过下列方法A-D得到式(I)的化合物。
方法A
在0℃将1-羟基苯并三唑(HOBt,7.40g,54.8mmol)和N,N'-二环己基碳二亚胺(DCC,11g,53.3mmol)加入到适当取代的1H-吲唑-3-甲酸(化合物i,12g,49.8mmol)在DMF(200ml)中的溶液中。1小时后,在相同温度加入适当1-取代的[哌啶-4-基]甲胺(化合物ii,10g,58.1mmol)在DMF(100ml)中的溶液,将该混合物在0℃搅拌2小时,然后静置在过夜过程中达到室温。用AcOEt稀释该混合物,通过过滤除去固体。用盐酸(HCl)2N将该溶液萃取3次。用5NNaOH使酸性相的pH增加(约13),用二氯甲烷(DCM)将该溶液萃取3次。用无水Na2SO4干燥有机相。
过滤溶剂,减压蒸发,使残余物充分纯化。
可以将下列中间体化合物(a-d)用作上述合成途径中的化合物(ii):
a)1-{1-[2-(4-甲氧基苯基)乙基]哌啶-4-基}-甲胺
向搅拌的如WO2004/101548中所述制备的N-[苯基亚甲基]-1-(哌啶-4-基)甲胺(化合物iii;0.158mol;31.9g)在无水乙醇(70ml)中的溶液中加入1-(2-溴乙基)-4-甲氧基苯(化合物iv;0.237mol;32.7g)和碳酸钾。
将该溶液回流8小时,然后冷却,通过减压蒸发溶剂浓缩。用3NHCl稀释该反应混合物,在室温搅拌3小时。然后用二氯甲烷洗涤酸性溶液,使其呈碱性。用3部分二氯甲烷萃取水相,再合并,用Na2SO4干燥。
通过减压蒸发除去溶剂,将由此得到的产物(v)照此不经任何纯化使用。
1HNMR(300MHz,DMSO-d6)。δ7.00-7.19(m,2H),6.76-6.89(m,2H),3.71(s,3H),2.91(d,J=11.56Hz,2H),2.55-2.72(m,4H),2.37-2.47(m,2H),1.90(dt,J=1.98,11.56Hz,2H),1.70(d,J=11.89Hz,2H),1.52(ddd,J=3.96,7.27,10.90Hz,1H),1.15(dtd,J=3.80,12.01,12.14Hz,2H)。
[M.M.+H+]计算值249.1961;[M.M.+H+]测定值249.1950
b)1-[1-(2,4-二氯苄基)哌啶-4-基]甲胺
通过对制备中间体(v)所述相同的方法、使用2,4-二氯-1-(氯甲基)苯(化合物vi)作为原料试剂制备中间体(vii)。
用快速色谱法(SiO2,CHCl3/MeOH=9/1)纯化产物(vii)。
c)1-{1-[4-(三氟甲基)苄基]哌啶-4-基}甲胺
通过对制备中间体(v)所述相同的方法、使用1-(溴甲基)-4-(三氟甲基)苯(化合物viii)作为原料试剂制备中间体(ix)。
用快速色谱法(SiO2,CHCl3/MeOH=9/1)纯化产物(ix)。
d)1-{1-[4-(苄基氧基)苄基]哌啶-4-基}甲胺
通过对制备中间体(v)所述相同的方法、使用1-(苄基氧基)-4-(氯甲基)苯(化合物x)作为原料试剂制备中间体(xi)。
将由此得到的产物(xi)照此不经任何进一步纯化使用。
例如,可以根据如下所述的方法A制备化合物(5)和(6)。
化合物(5):
可以使用化合物(xii)和(xi)作为原料、按照上述公开的方法A制备化合物(5)。
化合物(6):
在使用CartCartPd/C10%作为柱的微型反应器连续流动系统(H-Cube)中氢化化合物(5)(0.6mmol)。将H-Cube的关键参数设定如下:温度80℃;压力1巴;流速1ml/分钟。
通过减压蒸发除去溶剂,如表2中所述纯化化合物(6)。
方法B
第一步:
向适合的化合物(xiii)(2.13g;0.0061mol)在甲苯(50ml)中的混悬液中滴加如WO94/10174中所述制备的1-(1-苄基哌啶-4-基)甲胺(化合物xiv;2,52g;0.012mol)和三乙胺(TEA;3.2ml;0.023mol)的甲苯(10ml)溶液。将该反应混合物回流12小时,然后过滤。通过减压蒸发除去溶剂,将残余物溶于乙酸乙酯。将有机相转入分液漏斗,用饱和NaHCO3溶液和水洗涤,析出,用Na2SO4干燥。
使得到的产物(xv)充分结晶。
第二步:
将适合的N-[(1-苄基哌啶-4-基)甲基]-1H-吲唑-3-甲酰胺(化合物xv;0.506g;1.34mmol)在无水乙醇(8ml)和冰醋酸(0.8ml)中的溶液在使用CartCartPd/C10%作为柱的微型反应器连续流动系统(H-Cube)中氢化。将H-Cube的关键参数设定如下:温度80°;压力10巴;流速1ml/分钟。
3小时后,减压浓缩该溶液,用水稀释,转入分液漏斗。然后用乙酸乙酯洗涤水相,用1NNaOH使呈碱性,用乙酸乙酯萃取。收集有机层,用Na2SO4干燥,通过减压蒸发除去溶剂。
将由此得到的固体在真空炉中干燥,得到0.27g期望的取代的N-(哌啶-4-基甲基)-1H-吲唑-3-甲酰胺(xvi),将其不经任何的进一步纯化使用。
第三步:
向在85℃搅拌的化合物(xvi)(0.75mmol;215mg)在甲基-乙基-酮(MEK;9ml)中的溶液中滴加适合的卤代化合物(xvii;1.05Eq)和三乙胺(TEA;210μl;2Eq)。将该反应混合物回流8小时,然后冷却,用乙酸乙酯稀释。用饱和NH4Cl溶液和水洗涤有机层。使有机相析出,用Na2SO4干燥。
通过减压蒸发除去溶剂,如表2中所述纯化产物(I)。
方法C
第一步:
将亚硫酰氯(SOCl2;9,3ml;0.128mol)加入到适当取代的1H-吲唑-3-甲酸(化合物i;2,36g;0.0123mol)在甲苯(77ml)中的混悬液中,将该反应混合物回流4小时。通过减压蒸发除去溶剂,将残余物溶于甲苯2次,得到2.13g期望的产物(xiii)2,10-取代的7H,14H-吡唑并[1,2-b:4,5-b']二-吲唑-7,14-二酮。
第二步:
向(xiii)(5,2mmol)在甲苯(40ml)中的混悬液中滴加适合的胺(化合物ii;2,1Eq)和三乙胺(TEA;3,6Eq;2.6ml)的溶液。将该反应混合物回流8小时,然后冷却,在2NHCl(20ml)中搅拌8小时。将该混悬液转入分液漏斗,分离出水相,用1NNaOH使呈碱性。
通过减压蒸发除去溶剂,如下所述纯化产物(I)。
例如,可以按照下述方法C制备化合物(3)。
化合物(3):
将亚硫酰氯(SOCl2;9,3ml;0.128mol)加入到5-甲氧基-1H-吲唑-3-甲酸(化合物xii;2,36g;0.0123mol)在甲苯(77ml)中的混悬液中,将该反应混合物回流4小时。通过减压蒸发除去溶剂,将残余物溶于甲苯2次,得到2.13g期望的产物2,10-二甲氧基-7H,14H-吡唑并[1,2-b:4,5-b']二-吲唑-7,14-二酮(xviii)。
1HNMR(300MHz,氯仿-d):δ8.53(dd,J=0.58,9.17Hz,2H),7.64(d,J=1.98Hz,2H),7.35(dd,J=2.48,9.08Hz,2H),3.97(s,6H)。
[M.M.+H+]计算值349.0937;[M.M.+H+]测定值349.0922。
向化合物(xviii)(2.13g;0.0061mol)在甲苯(50ml)中的混悬液中滴加如方法A中所述制备的中间体化合物(vii)(2,52g;0.012mol)和三乙胺(TEA;3.2ml;0.023mol)在甲苯(10ml)中的溶液。将该反应混合物回流12小时,然后过滤。通过减压蒸发除去溶剂,用乙酸乙酯溶解残余物。将有机相转入分液漏斗,用饱和NaHCO3溶液和水洗涤,析出,用Na2SO4干燥。
如下表2中所公开的使由此得到的化合物(3)结晶。
1HNMR(300MHz,DMSO-d6):δ13.39(br.s.,1H),8.25(t,J=6.04Hz,1H),7.56(d,J=2.01Hz,1H),7.50(dd,J=0.55,8.96Hz,1H),7.17-7.36(m,5H),7.05(dd,J=2.47,9.06Hz,1H),3.80(s,3H),3.43(s,2H),3.20(t,J=6.13Hz,2H),2.79(d,J=11.16Hz,2H),1.89(t,J=10.61Hz,2H),1.46-1.74(m,3H),1.07-1.34(m,2H)。
[M.M.+H+]计算值379.2134;[M.M.+H+]测定值379.2129
方法D
将产物(xix)、适当取代的芳基硼酸(化合物xx)、[1,1'-双(二苯基膦基)二茂铁]-二氯-钯(II)[Pd(dppf)Cl2]、碳酸铯在1,4-二噁烷和水(3:1之比)中的溶液进行微波照射。
程序设定如下:
-3';T1=160℃,T2=130℃;最大功率300W
-45';T1=160℃,T2=130℃;最大功率300W
-5';T1=20℃,T2=15℃。
在1个微波照射周期后,减压蒸发除去溶剂,用2:1之比的氯仿和甲醇溶液稀释该反应混合物,过滤。
如下所述纯化由此得到的产物(I)。
纯化方法
根据方法A-D之一得到的式(I)的化合物可以使用如下技术(a)-(c)之一纯化。
(a)硅胶快速色谱法
使用20-45μM硅胶柱的BiotageFlashMasterPersonal系统或使用40μM硅胶柱的GraceReveleris快速色谱系统进行快速色谱。
流速=60ml/min.
用作洗脱液的溶剂是如下表2中所示。
(b)结晶
根据所纯化的化合物的不同使用不同的结晶溶剂。溶剂如下表2中所示。
(c)制备型LC/MS系统
LC/MS系统由Waters2767样品控制器、Waters2478双λ吸收检测器和使用电喷雾(ESI)电离源的WatersMicromassZQ单一四极质谱仪组成,所用的柱为使用19x10mm(Waters)前置柱的X-BridgePrepC185μm。级分采集可利用系统软件MassLynxTMv.4.1。将检测波长设定在230nm并且将温度设定在25℃。
将样品(50mg/ml)溶于1:1之比的DMSO/CH3CN。流动相为:
通道A=CH3CN+0.1%甲酸(洗脱液A)
通道B=H2O+0.1%甲酸(洗脱液B)
流速=40ml/min
梯度=在15分钟内达到的洗脱液A的最小和最大百分比分别为2-20和25-55。
下表2显示了如表1中所列式(I)的每种化合物的制备和纯化方法和每种化合物的单一同位素质量。
表2
MM:单一同位素质量
CHCl3:氯仿
EtOHabs:无水乙醇
AcOEt:乙酸乙酯
Hex:己烷
MeOH:甲醇
THF:四氢呋喃
表3
DMSO:二甲亚砜
如下文所述制备化合物7-31。
化合物7的合成-2-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噻唑-4-甲酸甲酯
7a)4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-甲酸叔丁酯
在0℃将1-羟基苯并三唑(HOBt,24.3g,142mmol)和N,N'-二环己基碳二亚胺(DCC,29.3g,142mmol)加入到5-甲氧基-1H-吲唑-3-甲酸(30g,129mmol)在DMF(400mL)中的溶液中。1小时后,在相同稳定加入[4-(氨基甲基)哌啶-1-基]乙酸乙酯(26g,129mmol)在DMF(250mL)中的溶液。将该混合物在0℃搅拌2小时,然后静置达到室温过夜。用EtOAc稀释该混合物,通过过滤除去固体。用盐酸(HCl)2N将该溶液萃取3次。用5NNaOH增加酸相的pH(约13),用二氯甲烷(DCM)将该溶液萃取3次。用无水Na2SO4干燥有机相,过滤溶剂,减压蒸发,得到4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-甲酸叔丁酯7a(96%收率)。
MS:389m/z(M+H)+。
7b)5-甲氧基-N-(哌啶-4-基甲基)-1H-吲唑-3-甲酰胺盐酸盐
将2MHCl的Et2O溶液(1.8L)加入到化合物7a(92.8g,0.24mol)在MeOH(500mL)中的溶液中。将该混合物在室温搅拌3小时,然后过滤得到的固体,干燥,得到5-甲氧基-N-(哌啶-4-基甲基)-1H-吲唑-3-甲酰胺盐酸盐7b(61.1g,89%收率)。
MS:289m/z(M+H)+。
最终,将化合物7b(637mg,1.96mmol)和碳酸钾(813mg,5.88mmol)在乙腈(5mL)中的混合物回流加热1小时,然后滴加2-(氯甲基)-1,3-噻唑-4-甲酸甲酯(500mg,2.6mmol)在乙腈(5mL)中的溶液,将该混合物回流过夜,然后冷却,用EtOAc稀释,过滤。用水洗涤得到的固体,干燥,通过快速色谱法纯化(硅胶,CHCl3-CHCl3:MeOH9:1),得到280mg(32%收率)2-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噻唑-4-甲酸甲酯7。
1HNMR(300MHz,DMSO-d6)δ=13.41(s,1H),8.46(s,1H),8.29(t,J=6.0Hz,1H),7.55(d,J=2.2Hz,1H),7.50(d,J=9.1Hz,1H),7.05(dd,J=2.4,9.0Hz,1H),3.81(s,3H),3.80(s,5H),3.21(t,J=6.2Hz,2H),2.89(d,J=11.3Hz,2H),2.13(t,J=10.8Hz,2H),1.78-1.54(m,3H),1.37-1.14(m,2H)
MS:444m/z(M+H)+。
化合物8的合成-2-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噻唑-4-甲酸
向化合物7(1.85mmol)在MeOH(10mL)中的溶液中加入1MNaOH水溶液(3.7mL)。将该溶液回流过夜,然后真空除去有机溶剂,用H2O稀释残余物,通过添加1MHCl将pH调整至5。将该混合物保持在4℃过夜,然后过滤得到的固体,用新鲜水洗涤,真空干燥,得到2-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噻唑-4-甲酸8(43%收率)。
1HNMR(300MHz,DMSO-d6)δ=13.42(br.s.,1H),12.91(br.s.,1H),8.34(s,1H),8.29(t,J=6.0Hz,1H),7.56(d,J=2.2Hz,1H),7.51(d,J=9.1Hz,1H),7.05(dd,J=2.6,9.1Hz,1H),3.87-3.69(m,5H),3.22(t,J=6.2Hz,2H),2.89(d,J=11.3Hz,2H),2.12(t,J=10.6Hz,2H),1.81-1.50(m,3H),1.37-1.11(m,2H)
MS:430m/z(M+H)+。
化合物9的合成-2-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噁唑-4-甲酸甲酯
根据对化合物7所述的方法、使用2-(氯甲基)-1,3-噁唑-4-甲酸甲酯制备2-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噁唑-4-甲酸甲酯9。收率:410mg,45%。
1HNMR(300MHz,DMSO-d6)δ=13.40(br.s.,1H),8.80(s,1H),8.26(t,J=6.2Hz,1H),7.55(d,J=2.6Hz,1H),7.51(d,J=9.1Hz,1H),7.05(dd,J=2.4,9.0Hz,1H),3.80(s,6H),3.67(s,2H),3.18(t,J=6.2Hz,2H),2.82(d,J=11.3Hz,2H),2.14-1.93(m,2H),1.74-1.45(m,3H),1.29-1.10(m,2H)
MS:428m/z(M+H)+。
化合物10的合成-2-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噁唑-4-甲酸水合物
根据对化合物8所述的方法、以化合物9为原料制备2-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噁唑-4-甲酸水合物10。收率:238mg,82%。
1HNMR(300MHz,DMSO-d6)δ=13.40(s,1H),12.99(br.s.,1H),8.67(s,1H),8.26(t,J=6.0Hz,1H),7.55(d,J=2.2Hz,1H),7.50(d,J=9.5Hz,1H),7.04(dd,J=2.6,9.1Hz,1H),3.80(s,3H),3.66(s,2H),3.18(t,J=6.4Hz,2H),2.82(d,J=11.0Hz,2H),2.05(t,J=10.4Hz,2H),1.76-1.44(m,3H),1.33-1.05(m,2H)
MS:414m/z(M+H)+。
化合物11的合成-2-{[4-({[(5-溴-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噁唑-4-甲酸甲酯
11a)4-({[(5-溴-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-甲酸叔丁酯
根据化合物7对所述的方法、由5-溴-1H-吲唑-3-甲酸和4-(氨基甲基)哌啶-1-甲酸叔丁酯制备4-({[(5-溴-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-甲酸叔丁酯11a。收率:40.6g,87%
MS:437m/z(M+H)+。
11b)5-溴-N-(哌啶-4-基甲基)-1H-吲唑-3-甲酰胺盐酸盐
将2MHCl的Et2O溶液(1.8L)加入到化合物4-(氨基甲基)哌啶-1-甲酸叔丁酯11a(0.24mol)在MeOH(500mL)中的溶液中。将该混合物在室温搅拌3小时,然后过滤得到的固体,干燥,得到5-溴-N-(哌啶-4-基甲基)-1H-吲唑-3-甲酰胺盐酸盐11b(76%收率)。
MS:337m/z(M+H)+。
最终,根据对化合物7所述的方法、由11b和2-(氯甲基)-1,3-噁唑-4-甲酸甲酯制备2-{[4-({[(5-溴-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噁唑-4-甲酸甲酯11。收率:166mg,16%。
1HNMR(300MHz,DMSO-d6)δ=13.73(br.s.,1H),8.80(s,1H),8.42(t,J=6.0Hz,1H),8.31(dd,J=0.8,1.8Hz,1H),7.60(dd,J=0.8,8.8Hz,1H),7.52(dd,J=1.8,8.8Hz,1H),3.80(s,3H),3.67(s,2H),3.18(t,J=6.4Hz,2H),2.81(d,J=11.3Hz,2H),2.13-1.95(m,2H),1.74-1.44(m,3H),1.32-1.06(m,2H)
MS:428m/z(M+H)+。
化合物12的合成-2-({4-[({[5-(2,3-二氟苯基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)-1,3-噁唑-4-甲酸水合物
将化合物11(0.44mmol)、(2,3-二氟苯基)硼酸(1.77mmol)、[1,1'-双(二苯基膦基)二茂铁]-二氯-钯(II)[Pd(dppf)Cl2](81mg,0.11mmol)和碳酸铯(575mg,1.76mmol)在1,4-二噁烷和水(3:1之比,8mL)中的溶液如下进行微波照射:
时间期限=3';T1=160℃,T2=130℃;最大功率300W
时间期限=45';T1=160℃,T2=130℃;最大功率300W
时间期限=5';T1=20℃,T2=15℃。
在1个循环的微波照射后,通过减压蒸发除去溶剂,用甲醇溶液(20mL)稀释该反应混合物,用C盐过滤,真空干燥。用硅胶柱过滤粗产物,用1:1之比的氯仿和甲醇洗涤。将得到的固体溶于DMSO,通过制备型HPLC纯化(通道A=CH3CN+0.1%甲酸;通道B=H2O+0.1%甲酸:流速=40ml/min;梯度=15%-50%洗脱液A,15分钟),得到2-({4-[({[5-(2,3-二氟苯基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)-1,3-噁唑-4-甲酸水合物12(6%收率)。
1HNMR(300MHz,DMSO-d6)δ=13.70(s,1H),12.99(br.s.,1H),8.57(s,1H),8.42(t,J=6.0Hz,1H),8.34(d,J=0.7Hz,1H),7.73(dd,J=0.8,8.8Hz,1H),7.61(td,J=1.8,8.7Hz,1H),7.52-7.21(m,3H),3.64(s,2H),3.20(t,J=6.2Hz,2H),2.82(d,J=11.0Hz,2H),2.04(t,J=10.6Hz,2H),1.73-1.45(m,3H),1.33-1.09(m,2H)
MS:496m/z(M+H)+。
化合物13的合成-4-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噻唑-2-甲酸乙酯
根据对化合物7所述的方法、使用4-(氯甲基)-1,3-噻唑-2-甲酸乙酯制备4-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}-1,3-噻唑-2-甲酸乙酯13。收率:45mg,11%。
1HNMR(300MHz,DMSO-d6)δ=13.39(s,1H),8.26(t,J=6.0Hz,1H),7.86(s,1H),7.55(d,J=2.2Hz,1H),7.50(d,J=8.8Hz,1H),7.04(dd,J=2.2,8.8Hz,1H),4.37(q,J=7.0Hz,2H),3.80(s,3H),3.64(s,2H),3.19(t,J=6.2Hz,2H),2.85(d,J=11.3Hz,2H),1.98(t,J=10.6Hz,2H),1.79-1.45(m,3H),1.33(t,J=7.1Hz,3H),1.29-0.96(m,2H)
MS:458m/z(M+H)+。
化合物14的合成-2-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}呋喃-3-甲酸甲酯
根据化合物7对所述的方法、使用2-(氯甲基)呋喃-3-甲酸甲酯制备2-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}呋喃-3-甲酸甲酯14。收率:120mg,13%。
1HNMR(300MHz,DMSO-d6)δ=13.39(s,1H),8.23(t,J=6.0Hz,1H),7.70(d,J=2.2Hz,1H),7.54(d,J=2.6Hz,1H),7.50(d,J=8.4Hz,1H),7.04(dd,J=2.4,9.0Hz,1H),6.70(d,J=2.2Hz,1H),3.83(s,2H),3.80(s,3H),3.76(s,3H),3.17(t,J=6.4Hz,2H),2.80(d,J=11.3Hz,2H),2.10-1.88(m,2H),1.70-1.42(m,3H),1.31-1.02(m,2H)
MS:427m/z(M+H)+。
化合物15的合成-5-{[4-({[(5-溴-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}呋喃-2-甲酸乙酯
根据对所述的方法化合物7、由11b和5-(氯甲基)呋喃-2-甲酸乙酯制备5-{[4-({[(5-溴-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}呋喃-2-甲酸乙酯15。收率:300mg,62%。
1HNMR(300MHz,DMSO-d6)δ=13.73(br.s.,1H),8.41(t,J=6.04Hz,1H),8.32(dd,J=0.73,1.83Hz,1H),7.57-7.65(m,1H),7.45-7.56(m,1H),7.21(d,J=3.66Hz,1H),6.48(d,J=3.66Hz,1H),4.27(q,J=7.32Hz,2H),3.53(s,2H),3.19(t,J=6.40Hz,2H),2.81(d,J=11.34Hz,2H),1.82-2.09(m,2H),1.64(d,J=12.44Hz,3H),1.02-1.36(m,5H)
MS:489m/z(M+H)+。
化合物16的合成-5-({4-[({[5-(2-甲氧基吡啶-3-基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸水合物
根据对化合物12所述的方法、由化合物15和(2-甲氧基吡啶-3-基)硼酸、并且使用下列用于纯化的制备型HPLC参数制备5-({4-[({[5-(2-甲氧基吡啶-3-基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸水合物16:通道A=CH3CN+0.1%甲酸;通道B=H2O+0.1%甲酸:流速=40ml/min;梯度=10%-45%洗脱液A,15分钟。收率:14mg,5%。
1HNMR(300MHz,DMSO-d6)δ13.62(br.s.,1H),8.36(t,J=6.04Hz,1H),8.28(s,1H),8.19(dd,J=1.83,5.12Hz,1H),7.77(dd,J=2.20,7.32Hz,1H),7.65(dd,J=0.80,8.80Hz,1H),7.58(dd,J=1.80,8.80Hz,1H),7.11(dd,J=5.12,7.32Hz,1H),6.84(br.s.,1H),6.31(d,J=2.93Hz,1H),3.89(s,3H),3.47(s,2H),3.19(t,J=6.22Hz,2H),2.99(s,1H),2.82(d,J=10.98Hz,2H),1.83-2.04(m,2H),1.41-1.75(m,3H),1.06-1.34(m,2H)
MS:490m/z(M+H)+。
化合物17的合成-5-({4-[({[5-(6-甲氧基吡啶-3-基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸水合物
根据对化合物12所述的方法、由化合物15(6-甲氧基吡啶-3-基)硼酸、并且使用下列用于纯化的制备型HPLC参数制备5-({4-[({[5-(6-甲氧基吡啶-3-基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸水合物17:通道A=CH3CN+0.1%甲酸;通道B=H2O+0.1%甲酸:流速=40ml/min;梯度=10%-45%洗脱液A,15分钟。收率:23mg,8%。
1HNMR(300MHz,DMSO-d6)δ13.65(br.s.,1H),8.48(d,J=2.02Hz,1H),8.39(t,J=6.06Hz,1H),8.34(s,1H),7.96-8.07(m,1H),7.70(d,J=1.21Hz,2H),7.03(d,J=3.23Hz,1H),6.94(d,J=8.07Hz,1H),6.40(d,J=3.23Hz,1H),3.92(s,3H),3.51(s,2H),3.21(t,J=6.26Hz,2H),2.83(d,J=10.90Hz,2H),1.98(t,J=10.90Hz,2H),1.48-1.78(m,3H),1.07-1.34(m,2H)
MS:490m/z(M+H)+。
化合物18的合成-5-({4-[({[5-(4-甲氧基苯基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸水合物
根据对化合物12所述的方法、由化合物15和(4-甲氧基苯基)硼酸、并且使用下列用于纯化的制备型HPLC参数制备5-({4-[({[5-(4-甲氧基苯基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸水合物18:通道A=CH3CN+0.1%甲酸;通道B=H2O+0.1%甲酸:流速=40ml/min;梯度=15%-50%洗脱液A,15分钟。收率:14mg,5%。
1HNMR(300MHz,DMSO-d6)δ13.55(s,1H),8.27-8.41(m,2H),7.64-7.72(m,2H),7.61(d,J=8.88Hz,2H),7.05(d,J=8.88Hz,2H),6.96(br.s.,1H),6.37(d,J=3.23Hz,1H),3.81(s,3H),3.49(s,2H),3.20(t,J=6.26Hz,2H),2.82(d,J=10.90Hz,2H),1.86-2.05(m,2H),1.66(d,J=12.11Hz,3H),1.09-1.33(m,2H)
MS:489m/z(M+H)+。
化合物19的合成-5-({4-[({[5-(2,3-二氟苯基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸
根据对化合物12所述的方法、由化合物15和(2,3-二氟苯基)硼酸、并且使用下列用于纯化的制备型HPLC参数制备5-({4-[({[5-(2,3-二氟苯基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸19:通道A=CH3CN+0.1%甲酸;通道B=H2O+0.1%甲酸:流速=40ml/min;梯度=15%-50%洗脱液A,15分钟。收率:32mg,11%。
1HNMR(300MHz,DMSO-d6)δ13.74(br.s.,1H),8.42(t,J=5.65Hz,1H),8.35(s,1H),7.69-7.80(m,1H),7.55-7.67(m,1H),7.21-7.54(m,3H),7.05(d,J=3.23Hz,1H),6.41(d,J=3.23Hz,1H),3.52(s,2H),3.20(t,J=6.06Hz,2H),2.83(d,J=10.50Hz,2H),1.98(t,J=10.70Hz,2H),1.42-1.79(m,3H),1.04-1.35(m,2H)
MS:495m/z(M+H)+。
化合物20的合成-5-({4-[({[5-(2-氟苯基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸水合物
根据对化合物12所述的方法、由化合物15和(2-氟苯基)硼酸、并且使用下列用于纯化的制备型HPLC参数制备5-({4-[({[5-(2-氟苯基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸水合物20:通道A=CH3CN+0.1%甲酸;通道B=H2O+0.1%甲酸:流速=40ml/min;梯度=10%-45%洗脱液A,15分钟。收率:20mg,7%。
1HNMR(300MHz,DMSO-d6)δ13.66(br.s.,1H),8.39(t,J=6.04Hz,1H),8.32(s,1H),7.65-7.76(m,1H),7.50-7.63(m,2H),7.38-7.50(m,1H),7.23-7.38(m,2H),7.08(d,J=3.29Hz,1H),6.43(d,J=3.29Hz,1H),3.52(s,2H),3.20(t,J=6.22Hz,2H),2.82(d,J=10.98Hz,2H),1.98(t,J=10.79Hz,2H),1.44-1.79(m,3H),1.02-1.38(m,2H)
MS:477m/z(M+H)+。
化合物21的合成-5-({4-[({[5-(4-甲氧基吡啶-3-基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸甲酸盐
根据对化合物12所述的方法、由化合物15和(4-甲氧基吡啶-3-基)硼酸、并且使用下列用于纯化的制备型HPLC参数制备5-({4-[({[5-(4-甲氧基吡啶-3-基)-1H-吲唑-3-基]羰基}氨基)甲基]哌啶-1-基}甲基)呋喃-2-甲酸甲酸盐21:通道A=CH3CN+0.1%甲酸;通道B=H2O+0.1%甲酸:流速=40ml/min;梯度=2%-40%洗脱液A,15分钟。收率:40mg,14%。
1HNMR(300MHz,DMSO-d6)δ13.61(br.s.,1H),8.47(d,J=5.85Hz,1H),8.31-8.43(m,2H),8.24(s,1H),7.66(d,J=8.78Hz,1H),7.53(dd,J=1.46,8.42Hz,1H),7.18(d,J=5.49Hz,1H),7.09(d,J=3.29Hz,1H),6.43(d,J=3.29Hz,1H),3.86(s,3H),3.54(s,2H),3.19(t,J=6.04Hz,2H),2.83(d,J=10.98Hz,2H),1.99(t,J=10.79Hz,2H),1.44-1.79(m,3H),0.98-1.36(m,2H)
MS:490m/z(M+H)+。
化合物22的合成-5-{[4-({[(5-溴-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}呋喃-2-甲酸
根据对化合物8所述的方法、由化合物15并且使用EtOH作为溶剂制备5-{[4-({[(5-溴-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}呋喃-2-甲酸22。收率:264mg,98%。
1HNMR(300MHz,DMSO-d6)δ13.78(br.s.,1H),8.43(t,J=5.85Hz,1H),8.32(d,J=1.21Hz,1H),7.61(d,J=8.80Hz,1H),7.53(dd,J=2.00,8.80Hz,1H),7.11(d,J=3.63Hz,1H),6.45(d,J=3.23Hz,1H),3.57(s,2H),3.19(t,J=6.26Hz,2H),2.85(d,J=11.30Hz,2H),2.02(t,J=10.90Hz,2H),1.45-1.77(m,3H),1.08-1.37(m,2H)
MS:461m/z(M+H)+。
化合物23的合成-5-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}呋喃-2-甲酸乙酯
根据对化合物7所述的方法、由5-(氯甲基)呋喃-2-甲酸乙酯制备5-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}呋喃-2-甲酸乙酯23。收率:290mg,71%。
1HNMR(300MHz,DMSO-d6)δ13.37(br.s.,1H),8.25(t,J=6.04Hz,1H),7.42-7.60(m,2H),7.21(d,J=3.29Hz,1H),6.97-7.12(m,1H),6.48(d,J=3.29Hz,1H),4.26(q,J=7.32Hz,2H),3.80(s,3H),3.53(s,2H),3.18(t,J=6.22Hz,2H),2.81(d,J=11.34Hz,2H),1.87-2.05(m,2H),1.46-1.73(m,3H),1.28(t,J=6.95Hz,3H),1.01-1.41(m,2H)
MS:441m/z(M+H)+。
化合物24的合成-5-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}呋喃-2-甲酸
根据对化合物8所述的方法、由化合物23并且使用EtOH作为溶剂制备5-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}呋喃-2-甲酸24。收率:64mg,84%。
1HNMR(300MHz,DMSO-d6)δ12.78-14.43(m,1H),8.26(t,J=6.04Hz,1H),7.55(d,J=2.56Hz,1H),7.52(d,J=9.15Hz,1H),7.04(dd,J=2.60,9.10Hz,1H),6.91(d,J=3.29Hz,1H),6.35(d,J=3.29Hz,1H),4.04(br.s.,1H),3.80(s,3H),3.50(s,2H),3.18(t,J=6.22Hz,2H),2.83(d,J=11.34Hz,2H),1.97(t,J=10.79Hz,2H),1.47-1.73(m,3H),1.04-1.33(m,2H)
MS:413m/z(M+H)+。
化合物25的合成-N-[(1-{2-[(2R,6S)-2,6-二甲基吗啉-4-基]乙基}哌啶-4-基)甲基]-5-甲氧基-1H-吲唑-3-甲酰胺
将化合物7b(8g,24.6mmol)和碳酸钾(17g,123mmol)在丙酮(250mL)中的混合物回流1小时,然后滴加(2R,6S)-4-(2-氯乙基)-2,6-二甲基吗啉(25.9mmol)。将该混合物回流过夜,然后冷却,过滤。干燥得到的固体,通过制备型HPLC纯化(通道A=CH3CN+0.1%甲酸;通道B=H2O+0.1%甲酸:流速=40ml/min;梯度=10%-45%洗脱液A,15分钟),得到N-[(1-{2-[(2R,6S)-2,6-二甲基吗啉-4-基]乙基}哌啶-4-基)甲基]-5-甲氧基-1H-吲唑-3-甲酰胺25(48.3%收率)
1HNMR(300MHz,DMSO-d6)δ=13.40(s,1H),8.30-8.14(t,J=6.11Hz,1H),7.58-7.53(d,J=1.98Hz,1H),7.53-7.46(dd,J=8.92,0.66Hz,1H),7.11-6.96(dd,J=8.92,2.31Hz,1H),3.80(s,3H),3.57-3.43(m,2H),3.21-3.11(t,J=6.28Hz,2H),2.92-2.77(d,J=11.23Hz,2H),2.76-2.63(d,J=10.24Hz,2H),2.44-2.26(m,4H),1.97-1.77(t,J=10,90Hz,2H),1.71-1.46(t,J=10.73Hz,4H),1.27-1.07(m,3H),1.06-0.94(d,J=6.28Hz,6H)
LC-MS:430.28(MH+)
化合物26的合成-N-[(1-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙基}哌啶-4-基)甲基]-5-甲氧基-1H-吲唑-3-甲酰胺
根据对化合物25所述的方法、使用(2R,6S)-4-(3-氯苯基)-2,6-二甲基吗啉和作为溶剂的甲醇制备N-[(1-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙基}哌啶-4-基)甲基]-5-甲氧基-1H-吲唑-3-甲酰胺26。收率=91mg(59.1%)。
1HNMR(300MHz,DMSO-d6)δ=12.12(s,1H),7.80-7.62(d,J=2.20Hz,1H),7.40-7.32(d,J=9.15,1H),7.27-7.18(t,J=6.04Hz,1H),7.07-6.99(dd,J=9.15,2.20Hz,1H),3.89-3.78(s,3H),3.76-3.53(m,2H),3.47-3.30(t,J=6.22Hz,2H),3.07-2.93(m,2H),2.75-2.68(d,J=10.98Hz,2H),2.45-2.24(m,4H),2.07-1.88(t,J=10.79Hz,2H),1.83-1.59(m,7H),1.53-1.35(m,2H),1.18-1.05(d,J=6.22Hz,6H)
LC-MS:444.30(MH+)
化合物27的合成-5-甲氧基-N-({1-[2-(3-甲基环己基)乙基]哌啶-4-基}甲基)-1H-吲唑-3-甲酰胺
将化合物11b(420mg,1.46mmol)在DMF(45ml)和三乙胺(0.61ml,4.4mmol)中的溶液在80℃搅拌1h,然后用1-(2-溴乙基)-3-甲基环己烷(300mg,1.46mmol)处理。将该混合物在相同温度搅拌过夜,然后将该反应体系冷却至室温,通过减压蒸发除去溶剂。通过硅胶快速色谱法纯化粗5-甲氧基-N-({1-[2-(3-甲基环己基)乙基]哌啶-4-基}甲基)-1H-吲唑-3-甲酰胺27,使用9/1的CH3Cl/CH3OH混合物作为洗脱液。收率=45mg(18.0%)。
1HNMR(300MHz,DMSO-d6)δ=13.41(s,1H),8.30-8.20(t,J=6.11Hz,1H),7.58-7.53(d,J=2.31Hz,1H),7.53-7.47(d,J=8.59Hz,1H),7.08-7.02(dd,J=8.92,2.32Hz,1H),3.80(s,3H),3.23-3.13(t,J=6.28Hz,2H),2.90-2.78(d,J=10.57Hz,2H),2.35-2.20(m,2H),1.97-1.05(m,17H),0.90-0.45(m,5H)
LC-MS:413.29(MH+)
化合物28的合成-4-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}吡啶-2-甲酸
根据对化合物25所述的方法、使用4-(氯甲基)吡啶-2-甲酸甲酯作为试剂和CH3CN作为溶剂制备4-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}吡啶-2-甲酸28。收率=335mg(16%)。
1HNMR(300MHz,DMSO-d6)δ=13.25(s,1H),8.54(d,J=4.8Hz,1H),8.27(t,J=6.0Hz,1H),7.93(s,1H),7.56(d,J=2.2Hz,1H),7.51(d,J=9.5Hz,1H),7.43(d,J=4.0Hz,1H),7.04(dd,J=2.2,9.5Hz,1H),3.80(s,3H),3.53(s,2H),3.20(t,J=6.0Hz,2H),2.78(d,J=11.0Hz,2H),1.96(t,J=10.6Hz,2H),1.75-1.45(m,3H),1.35-1.16(m,2H)
化合物29的合成-5-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}吡啶-2-甲酸钠
29a)5-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}吡啶-2-甲酸甲酯
根据对化合物25所述的方法、使用5-(氯甲基)吡啶-2-甲酸甲酯作为试剂和CH3CN作为溶剂制备5-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}吡啶-2-甲酸甲酯29a,不经进一步纯化用于随后的步骤。
然后用NaOH(0.22g,5.5mmol)的水(10ml)溶液在回流状态下将粗5-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}吡啶-2-甲酸甲酯29a(1.2g,2.7mmol)在乙醇(10ml)中的溶液处理3h。将该混合物冷却至室温,减压蒸发溶剂。用乙醇/乙酸乙酯的混合物(1.09g,91%)结晶5-{[4-({[(5-甲氧基-1H-吲唑-3-基)羰基]氨基}甲基)哌啶-1-基]甲基}吡啶-2-甲酸钠29。
1HNMR(300MHz,DMSO-d6)δ=13.86(br.s.,1H),8.37(d,J=1.2Hz,1H),8.24(t,J=6.1Hz,1H),7.91(d,J=8.1Hz,1H),7.65(dd,J=2.0,8.1Hz,1H),7.61-7.48(m,2H),7.01(dd,J=2.5,8.8Hz,1H),3.79(s,3H),3.47(s,2H),3.19(t,J=6.1Hz,2H),2.77(d,J=10.9Hz,2H),1.91(t,J=10.9Hz,2H),1.65(s,3H),1.35-1.07(m,2H)
化合物30的合成-N-({1-[(5-氨基甲酰基-1,2,4-噁二唑-3-基)甲基]哌啶-4-基}甲基)-5-甲氧基-1H-吲唑-3-甲酰胺
根据对化合物25所述的方法、使用3-(氯甲基)-1,2,4-噁二唑-5-甲酸乙酯作为试剂和CH3CN作为溶剂制备N-({1-[(5-氨基甲酰基-1,2,4-噁二唑-3-基)甲基]哌啶-4-基}甲基)-5-甲氧基-1H-吲唑-3-甲酰胺30。收率=80mg(4%)。
1HNMR(300MHz,DMSO-d6)δ=13.18(br.s.,1H),8.70(br.s.,1H),8.32(br.s.,1H),8.26(t,J=6.2Hz,1H),7.55(d,J=1.8Hz,1H),7.50(dd,J=0.7,9.1Hz,1H),7.05(dd,J=1.8,9.1Hz,1H),3.80(s,3H),3.69(s,2H),3.19(t,J=6.2Hz,2H),2.86(d,J=11.0Hz,2H),2.19-1.93(m,2H),1.82-1.39(m,3H),1.33-1.07(m,2H)
化合物31的合成-N-({1-[2-(4-硝基苯基)乙基]哌啶-4-基}甲基)-1H-吲唑-3-甲酰胺盐酸盐
将7H,14H-吡唑并[1,2-b:4,5-b']二吲唑-7,14-二酮(8.2g,28.5mmol)、1-{1-[2-(4-硝基苯基)乙基]哌啶-4-基}甲胺(15g,57mmol)在甲苯(300ml)中的混合物在室温搅拌过夜。过滤由此得到的固体,用2NHCl(100ml溶解,用乙醚(3x150ml)洗涤。用NaOH碱化酸相,用DCM(3x200ml)萃取。真空除去溶剂,然后将残余物倾入THF(30ml),用1.25MHCl的MeOH溶液处理。过滤由此得到的粗固体N-({1-[2-(4-硝基苯基)乙基]哌啶-4-基}甲基)-1H-吲唑-3-甲酰胺盐酸盐31,使其从EtOH中结晶。
1HNMR(300MHz,DMSO-d6)δ=13.70(s,1H),10.82(br.s.,1H),8.55(t,J=6.1Hz,1H),8.30-8.10(m,3H),7.67-7.52(m,3H),7.41(ddd,J=1.2,7.0,8.4Hz,1H),7.24(ddd,J=0.8,7.0,8.0Hz,1H),3.57(d,J=11.7Hz,2H),3.48-3.15(m,6H),3.04-2.83(m,2H),1.90(d,J=11.5Hz,3H),1.75-1.50(m,2H)
下表1A概括了上述化合物7-31的化学名和结构。
表1A
药理学特性
用于本发明的式(I)的化合物的药理学特性通过如下部分中所述的方法评价。
试验I-对人GSK-3β的活性(体外试验)
使用下列方法评价对人GSK-3β的活性(根据Meijer等人,Chem.Biol.,2003-10:1255-1266)。
在第一种筛选试验中,一式两份测试10μM浓度的化合物。
将人重组酶GSK-3β在22℃在化合物或媒介物的存在下在反应缓冲液中温育90分钟,所述反应缓冲液包含ATP+100nM未磷酸化特异性底物肽(Ulight-CFFKNIVTPRTPPPSQGK-酰胺)。通过LANCE技术测定底物磷酸化(PerkinElmer,CT,USA)。
将下表4中报道的结果表示为在测试化合物存在下得到的对照比活性(controlspecificactivity)的抑制百分比(为10μM时的%抑制)。
在第二种试验中,在100μM-10nM的10-倍稀释的5种浓度下一式两份测定相同化合物。使用相同的第一种试验测试化合物1-7、9、11和13-26,在另一种试验中,基于647标记的ATP-竞争性激酶抑制剂骨架的结合和替代、使用LanthaScreenTMTR-FRET技术EuKinase测定包、根据制造商的说明(LifeTechnologies,Italy)测试化合物8、10、12和27-31。两种测定的结果相差无几
通过使用平均重复值生成的抑制曲线的非线性回归分析、使用希尔方程曲线拟合测定表4中报道的IC50值(导致对照比活性的半数最大抑制的浓度)。
表4
化合物N° | %抑制[10μM] | IC50[μM] |
1 | 94 | 0.35 |
2 | 91 | 0.56 |
3 | 0.31 | |
4 | 0.64 | |
5 | 0.35 |
6 | 0.40 | |
7 | 0.13 | |
8 | 0.17 | |
9 | 0.21 | |
10 | 0.31 | |
11 | 0.36 | |
12 | 0.01 | |
13 | 0.95 | |
14 | 0.23 | |
15 | 0.26 | |
16 | 0.36 | |
17 | 0.02 | |
18 | 0.30 | |
19 | 0.01 | |
20 | 0.02 | |
21 | 0.01 | |
22 | 0.2132 --> | |
23 | 0.33 | |
24 | 0.40 | |
25 | 1.40 | |
26 | 2.10 | |
27 | 0.31 | |
28 | 0.45 | |
29 | 0.32 | |
30 | 0.31 | |
31 | 7.20 |
结果显示本发明的化合物1和2在该试验中具有良好的抑制活性:在10μM时,%抑制大于90%且使用每种化合物得到小于0.60μM的IC50。
本发明大部分化合物3-31显示小于1.00μM的IC50值。它们中的一些在最低测定浓度(10nM)下显示IC50值。使用化合物25、26和31得到的大于的1.00μM的IC50值仍然是可接受的。
试验II-对GSK-3β的选择性(体外试验)
(a)对一组60种激酶测试化合物1,以便评价其选择性。根据对测定家族的多样性的考量选择试验。
测试的激酶以如下激酶亚组为代表:
-蛋白质-丝氨酸/苏氨酸激酶;
-蛋白质-酪氨酸激酶;
-其他激酶;和
-非典型激酶。
将人重组激酶在22℃在特异性肽底物+ATP的存在下温育不同时间(10、15、30、60或90分钟)。通过LANCE或HTRF技术(CISBIO,MA,USA)检测磷酸化底物。
一式两份测试10μM的化合物1。
将结果表示为在测试化合物1的存在下得到的对照比活性的抑制百分比并且报道在下表5中。
表5
还测试了化合物1以测定与Gsk3β相比3种不同激酶(PCTAIRE1、DYRK1a和CDK2)的IC50值。使用与上述试验I的第二种测定法相同的方法进行测定。将结果概括在下表5A中。
表5A
结果证实化合物1对GSK-3β具有抑制活性并且与其他激酶相比具有更高的对GSK-3β的亲和力,从而显示了良好的选择性。实际上,表5a的IC50值显示化合物1对Gsk3β的选择性由于对PCTAIRE1、DYRK1a和CDK2激酶。
(b)在与上述对化合物1所述相同的条件下对相同的一组60种激酶测试了化合物7、12、21和24。
将结果表示为在测试化合物存在下对照比活性抑制的百分比并且报道在下表6中。
表6
结果证实化合物7和24对GSK-3β也具有抑制活性并且对GSK-3β比对所有其他激酶具有更高的亲和力,从而显示了良好的选择性,且化合物12和21对GSK-3β具有抑制活性并且与大部分其他同一家族的激酶和不同家族的激酶相比对GSK-3β具有良好的亲和力。
Claims (11)
1.具有下述通式(I)的1H-吲唑-3-甲酰胺化合物及其与药学上可接受的有机和无机酸和碱的加成盐在制备治疗疾病的药物中的用途:
其中
Ra和Ra'彼此相同或不同,为氢原子;卤原子;C1-C6烷基、C2-C6烯基、C2-C6炔基和C1-C6烷氧基,其任选地被一个或多个选自卤素、羟基、-NH2和C1-C3烷氧基的取代基取代;具有3-12个成员的脂族或芳族碳环或杂环,其任选地被一个或多个选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、-NR1R2、-C(O)OH、-C(O)OR1和-C(O)NR1R2的取代基取代;
Y是价键、C1-C6烷基、C2-C6烯基或C2-C6炔基,其任选地被一个或多个选自卤素、羟基、-NH2和C1-C3烷氧基的取代基取代;
Rb是具有3-12个成员的脂族或芳族碳环或杂环,其被一个或多个选自卤素、羟基、硝基、氰基、-CF3、C1-C6烷氧基、苄基氧基、C1-C4烷基、C2-C4烯基和C2-C4炔基、-NHSO2CH3、-SO2NH2、-Z-C(O)OH、-Z-C(O)OR1和-Z-C(O)NR1R2的取代基取代,其中Z是σ-键或(C1-C3)烷基;
R1和R2独立地为氢原子、C1-C4烷基、C2-C4烯基、C2-C4炔基和苯基;
所述疾病归因于GSK-3β不受控制的活化和/或超表达,其选自:(i)胰岛素抵抗疾病;(ii)神经变性疾病;(iii)情绪障碍;(iv)精神分裂性障碍;(v)癌性疾病;(vi)炎症;(vii)物质滥用疾病;和(viii)癫痫。
2.权利要求1的1H-吲唑-3-甲酰胺的用途,其中所述胰岛素抵抗疾病选自2型糖尿病、X综合征、肥胖症和多囊性卵巢综合征。
3.权利要求1的1H-吲唑-3-甲酰胺的用途,其中所述神经变性疾病选自帕金森病、阿尔茨海默病、亨廷顿病和脊髓神经变性疾病。
4.权利要求3的1H-吲唑-3-甲酰胺的用途,其中所述脊髓神经变性疾病选自肌萎缩性侧索硬化、多发性硬化、脊髓性肌肉萎缩和因脊髓损伤导致的神经变性。
5.权利要求1的1H-吲唑-3-甲酰胺的用途,其中所述情绪障碍疾病选自双相情感障碍和抑郁障碍。
6.权利要求5的1H-吲唑-3-甲酰胺的用途,其中所述双相情感障碍选自I型双相情感障碍、II型双相情感障碍、循环性精神病和未有特殊说明的双相情感障碍(BD-NOS)。
7.权利要求5的1H-吲唑-3-甲酰胺的用途,其中所述抑郁障碍选自重度抑郁障碍(MDD)、非典型抑郁症(AD)、忧郁性抑郁症、精神病性重度抑郁症(PMD)、紧张性抑郁症、产后抑郁症(PPD)、季节性情感障碍(SAD)、心境恶劣障碍和未有特殊说明的抑郁障碍(DD-NOS)。
8.权利要求1的1H-吲唑-3-甲酰胺的用途,其中所述物质滥用疾病选自因精神兴奋药导致的滥用疾病。
9.权利要求1的1H-吲唑-3-甲酰胺的用途,其中所述精神分裂性障碍是偏执型精神分裂症、混乱型精神分裂症、紧张型精神分裂症、简单型精神分裂症、残留型精神分裂症和未分化型精神分裂症。
10.权利要求1的1H-吲唑-3-甲酰胺的用途,其中所述癌性疾病选自前列腺癌、胰腺癌、卵巢癌和结肠-直肠癌和MLL-相关白血病。
11.具有下式的1H-吲唑-3-甲酰胺化合物:
N-{[1-(2,4-二氯苄基)哌啶-4-基]甲基}-5-甲氧基-1H-吲唑-3-甲酰胺;和
N-({1-[4-(苄基氧基)苄基]哌啶-4-基}甲基)-5-甲氧基-1H-吲唑-3-甲酰胺。
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KR102101702B1 (ko) * | 2012-02-21 | 2020-04-20 | 아지엔드 키미쉐 리유나이트 안젤리니 프란체스코 에이.씨.알.에이.에프. 에스.피.에이 | 글리코겐 합성효소 키나아제 3 베타 억제제로서 1h-인다졸-3-카복사미드 화합물의 용도 |
US10954240B2 (en) | 2014-09-03 | 2021-03-23 | Merck Sharp & Dohme Corp. | Compounds inhibiting leucine-rich repeat kinase enzyme activity |
US10464896B2 (en) | 2015-06-11 | 2019-11-05 | Basilea Pharmaceutica International AG | Efflux-pump inhibitors and therapeutic uses thereof |
WO2017093157A1 (en) * | 2015-11-30 | 2017-06-08 | Basilea Pharmaceutica Ag | Piperidine, pyrrolidine and 2-oxo-1,3-oxazinane derivatives as inhibitors of bacterial efflux-pumps for the treatment of microbial infections |
EP3468960B1 (en) | 2016-06-08 | 2022-03-23 | GlaxoSmithKline Intellectual Property Development Limited | Chemical compounds as atf4 pathway inhibitors |
RS63255B1 (sr) * | 2018-05-07 | 2022-06-30 | Acraf | 1h-indazol-3-karboksamid jedinjenja kao inhibitori glikogen sintaza kinaze 3 beta |
CN117186027B (zh) * | 2023-09-11 | 2024-04-19 | 上海蓝木化工有限公司 | 一种糖原合酶激酶-3抑制剂及其制备方法 |
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EP0667867A1 (en) | 1992-11-05 | 1995-08-23 | Smithkline Beecham Plc | Piperidine derivatives as 5-ht4 receptor antagonists |
CA2222532A1 (en) | 1995-05-31 | 1996-12-05 | Nisshin Flour Milling Co., Ltd. | Indazole derivatives having monocyclic amine |
IT1291569B1 (it) * | 1997-04-15 | 1999-01-11 | Angelini Ricerche Spa | Indazolammidi come agenti serotoninergici |
GB0218625D0 (en) | 2002-08-10 | 2002-09-18 | Astex Technology Ltd | Pharmaceutical compounds |
ITMI20030287A1 (it) * | 2003-02-18 | 2004-08-19 | Acraf | Indazolammidi dotate di attivita' analgesica metodo, per |
ITMI20030972A1 (it) | 2003-05-15 | 2004-11-16 | Acraf | Indazolo dotato di attivita' analgesica, metodo per prepararlo e composizione farmaceutica che lo comprende. |
UA99927C2 (uk) | 2007-11-12 | 2012-10-25 | Ацьенде Кимике Риуните Анджелини Франческо А.Чи.Р.А.Ф. С.П.А. | Медикамент, який є активним при невропатичному болі |
TW201040191A (en) | 2009-03-27 | 2010-11-16 | Abbott Gmbh & Co Kg | Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors |
US7947728B1 (en) * | 2009-11-11 | 2011-05-24 | Hoffmann-La Roche Inc. | Indole and indazole analogs as glycogen synthase activators |
CN104093712B (zh) * | 2012-02-21 | 2016-11-09 | 方济各安吉利克化学联合股份有限公司 | 作为糖原合酶激酶3β抑制剂的1H-吲唑-3-甲酰胺化合物 |
KR102101702B1 (ko) * | 2012-02-21 | 2020-04-20 | 아지엔드 키미쉐 리유나이트 안젤리니 프란체스코 에이.씨.알.에이.에프. 에스.피.에이 | 글리코겐 합성효소 키나아제 3 베타 억제제로서 1h-인다졸-3-카복사미드 화합물의 용도 |
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