CN113906033A - 咪唑并吡嗪衍生物及其作为药剂的用途 - Google Patents
咪唑并吡嗪衍生物及其作为药剂的用途 Download PDFInfo
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- CN113906033A CN113906033A CN202080040496.9A CN202080040496A CN113906033A CN 113906033 A CN113906033 A CN 113906033A CN 202080040496 A CN202080040496 A CN 202080040496A CN 113906033 A CN113906033 A CN 113906033A
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Abstract
本发明涉及通式A的新型咪唑并吡嗪、其制备方法、含有它们的药物组合物以及其在疗法中、特别是在与NR2B负别构调节特性有关的病症的治疗或预防中的用途。
Description
本发明涉及通式A的新型咪唑并吡嗪
其制备方法、含有其的药物组合物以及其在疗法中、特别是在与NR2B负别构调节特性有关的病症的治疗或预防中的用途。
根据通式A的本发明化合物显示NR2B负别构调节特性。
过去二十年间的广泛研究已经表明,N-甲基-D-天冬氨酸受体(NMDA)在以下疾病中具有相关作用:阿尔茨海默病、帕金森病、运动障碍、卒中、运动神经元病、精神病、癫痫、焦虑、精神分裂症和疼痛。
非选择性NMDA受体拮抗剂氯胺酮(外消旋以及S对映体),一种主要用于开始和维持麻醉的药物,在过去数年中已经显示在亚麻醉剂量下在治疗严重抑郁障碍(MDD)中的临床功效(Murrough等人2013,Am J Psychiatry.170:1134;Singh等人2016,BiolPsychiatry.80:424)。更精确地,氯胺酮在对标准药物疗法反应不足的MDD患者中引发持续几天的功效的快速发动(Berman等人2000.Biol Psychiatry 47:351;Serafini等人2014.Curr.Neuropharmacol.12:444)。然而,非选择性NMDA受体拮抗剂具有一系列不合意的影响,限制了它们的应用。具体来说,游离性和心因性副作用对于非选择性NMDA受体拮抗剂(如氯胺酮)是显而易见的(Krystal等人1994.Arch.Gen.Psychiatry 51:199)。在1990年代早期,发现存在多个NMDA受体亚型,它们含有不同的NR2(A-D)亚基(Paoletti等人,2013Nat Rev.Neurosci 14:383)。最近,NR2B亚型选择性NMDA受体负别构调节剂(NR2BNAM)已经引起人们的兴趣,并且已经在多种临床适应症(如注意力、情绪、心境和疼痛)中显示潜力,以及参与多种不同的人类障碍(Mony等人2009.Br.J.Pharmacol.157:1301;Chaffey等人,Current Anaesthesia&Critical Care 19,183)。具体来说,NR2B NAM也已经在临床试验的早期阶段显示抗抑郁功效(Preskorn等人2008.J Clin Psychopharmacol70:58)。使用NR2B NAM以及应用各种转基因小鼠品系的临床前研究已经显示,含有NMDA受体的NR2B介导氯胺酮在例如强迫游泳测试中的积极作用(Miller等人2014eLife 3:e03581;Kiselycznyk等人2015,Behav Brain Res,287:89)。此外,由于游离性和致幻觉副作用显著减小,选择性NR2B NAM具有优于非选择性NMDA受体拮抗剂(如氯胺酮)的优点(Jimenez-Sanchez等人2014.Neu ropsychopharmacology 39:2673)。迄今描述的NR2B NAM已经展现关于其受体药理学和/或在人类药物疗法中具有有限潜在用途的其他药物特性的缺点(Taylor等人,2006,Clin Pharmacokinet.45:989;Addy等人2009J of Cli nicalPharmacology 49:856)。
WO 2016/29146披露式(I)的化合物
其是甲硫氨酰-tRNA合成酶(MetRS)的抑制剂,可用作抗生素。WO 2016/29146中的式(I)涵盖具体实施例1734、1744、1745、1757、1758、1785和1790,它们展现苯并咪唑或咪唑并吡啶结构。
已经惊人地发现本发明的化合物是有效NR2B负别构调节剂(见表1),而WO 2016/29146的具体实施例1734、1744、1745、1757、1758、1785和1790显示NR2B离子通道的较差负别构调节或者完全没有活性(见表2)。
另外,本发明的化合物显示良好的膜渗透性以及低至中体外外排(MDCK测定MDR1(p-GP)见表3)。因此,预期本发明的化合物会显示有利的脑渗透,这是有效的CNS药剂所需要的。
MDCK测定提供关于化合物跨越血脑屏障的潜力的信息。使用横跨在渗透性过滤器支持物上生长的极化、汇合的MDCK-MDR1细胞单层的渗透性测量作为体外吸收模型:在顶部至基底(AB)和基底至顶部(BA)转运方向上测量化合物跨越MDCK-MDR1细胞单层的表观渗透系数(PE)(pH 7.4,37℃)。AB渗透性(PEAB)代表将药物从血液吸收至脑中,并且BA渗透性(PEBA)代表将药物经由被动渗透性以及由外排和摄取转运蛋白介导的主动转运机制二者从脑外排回至血液中,所述外排和摄取转运蛋白在MDCK-MDR1细胞上表达,主要由过表达的人MDR1表达。渗透性在两个转运方向上相同或类似表明被动渗透,而矢量渗透性指向另外的主动转运机制。PEBA高于PEAB(PEBA/PEAB>5)表明涉及由MDR1介导的主动外排,这可能会影响实现足够脑暴露的目标。因此,此测定为选择适用于进一步体内测试的化合物提供有价值的支持。在血脑屏障处不受限于外排的高渗透性是要用于主要作用于CNS的药物的化合物的有利特征。因此,为了确保在血脑屏障处的高渗透性,将MDR1转运蛋白处的外排最小化(外排<5)是高度优选的。
另外,本发明的化合物在人肝微粒体中代谢稳定(见表4,代谢稳定性)。因此,预期本发明的化合物在人体中具有有利的体内清除,并因此具有所需作用持续时间。
在人肝微粒体主动稳定性是指在选择和/或设计具有有利的药代动力学特性的药物的情况下,化合物对生物转化的敏感性。许多药物的主要代谢部位是肝脏。人肝微粒体含有细胞色素P450(CYP),并因此代表用于在体外研究药物代谢的模型系统。在人肝微粒体中增强的稳定性与几种优点相关,包括增加的生物利用度和足够的半衰期,这可以使得能够对患者以较低剂量和频率给药。因此,在人肝微粒体中增强的稳定性是要用于药物的化合物的有利特征。
因此,本发明的化合物必须对于人使用更加可行。
因此,客观的技术问题是提供有效的NR2B负别构调节剂。
本发明提供式A的新型咪唑并吡嗪
其中
R1表示苯基,所述苯基任选地被选自以下的1至3个取代基取代:氟、氯、甲基、乙基、环丙基、F2HC-、FH2C-、F3C-;
或其盐,特别是其药学上可接受的盐。
在另一实施方案中,在通式A中
R1表示苯基,所述苯基任选地被选自氟、甲基的1或2个取代基取代。
在另一实施方案中,在通式A中
R1表示
本发明提供通式A的新型咪唑并吡嗪,其意外地是有效NR2B负别构调节剂。
本发明的另一方面涉及作为NR2B负别构调节剂的根据式A的化合物,其具有适当的膜渗透性和低至中体外外排。
本发明的另一方面涉及作为NR2B负别构调节剂的根据式A的化合物,其在人肝微粒体中具有高代谢稳定性。
本发明的另一方面涉及作为NR2B负别构调节剂的根据式A的化合物,其具有适当的膜渗透性、低至中体外外排以及在人肝微粒体中的高代谢稳定性。
本发明的另一方面涉及药物组合物,其含有至少一种根据式A的化合物以及任选地一种或多种惰性载体和/或稀释剂。
本发明的另一方面涉及根据式A的化合物,其用于预防和/或治疗与NR2B负别构调节剂相关的障碍。
本发明的另一方面涉及制造本发明的化合物的方法。
制备
以下方案应借助例子大体上说明如何制造根据通式A的化合物和相应的中间化合物。如果在所述方案的上下文内没有另外定义,那么缩写的取代基可以如上文所定义。
方案1:方法A
方案2:方法B
可替代地,合成可以使用外消旋吗啉-2,4-二甲酸4-叔丁酯作为起始材料来进行。
方案1和2可以成功地用于最终化合物的克级合成,其是从40毫摩尔所需取代的吗啉(外消旋或S对映体)开始,使用过量的所需取代的苯甲醇、DIPEA(3当量)、所需偶合剂(如CDI)和作为溶剂的DMF。
替代性克级合成可以使用相应的吗啉(外消旋或S对映体;40mmol)、TEA(2.5当量)、稍微过量的所需亚氨酰碳酸酯和作为溶剂的1/1(体积/体积)CH3CN/THF混合物来进行。可以获得具有良好至高对映体过量的最终化合物;可替代地,可以应用手性分离以获得纯的对映体。
在方案1和2中,取代基R1具有如针对通式A所定义的含义,本发明中直接涉及所述取代基的所有实施方案,以及具体地如权利要求中所定义的含义。
通用定义
在本文中没有明确定义的术语应当被给予如下含义,所述含义将是本领域技术人员根据本公开文本和上下文而给予所述术语的。
如果以化学名称以及式的形式描绘本发明的化合物,则在有任何不一致的情况下,应以所述式为准。
可以在子式中使用星号来指示连接至核心分子或连接至如定义为与其结合的取代基的键。
如本文所用的术语“取代的”意指,指定原子上的任何一个或多个氢被来自所指示组的选择替代,条件是不超过所述指定原子的可行价数,并且所述取代产生稳定化合物。
立体化学:
除非明确指示,否则在整个说明书和所附权利要求书中,给定的化学式或名称应涵盖旋转异构体、互变异构体以及所有立体异构体、光学异构体和几何异构体(例如对映体、非对映体、E/Z异构体等)及其外消旋体,以及单独的对映体的不同比例的混合物、非对映体混合物或者任何前述形式的混合物,其中存在此类异构体和对映体,以及盐,包括其药学上可接受的盐。盐:
短语“药学上可接受的”在本文中用于指代如下的那些化合物、材料、组合物和/或剂型,它们在合理的医学判断范围内适合使用,而没有过度的毒性、刺激、过敏反应或者其他问题或并发症,并且与合理的收益效益/风险比相称。
如本文所用,“药学上可接受的盐”是指所公开的化合物的衍生物,其中母体化合物与酸或碱形成盐或复合物。
与含有碱性部分的母体化合物形成药学上可接受的盐的酸的例子包括无机酸或有机酸,如苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、龙胆酸、氢溴酸、盐酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、4-甲基-苯磺酸、磷酸、水杨酸、琥珀酸、硫酸或酒石酸。
与含有酸性部分的母体化合物形成药学上可接受的盐的阳离子和碱的例子包括Na+、K+、Ca2+、Mg2+、NH4 +、L-精氨酸、2,2'-亚氨基双乙醇、L-赖氨酸、N-甲基-D-谷氨酰胺或三(羟甲基)-氨基甲烷。
本发明的药学上可接受的盐可以通过常规化学方法从含有碱性或酸性部分的母体化合物合成。通常,此类盐可以通过使这些化合物的游离酸或碱形式与足量的适当的碱或酸在水中或在有机稀释剂(如醚、乙酸乙酯、乙醇、异丙醇或乙腈或其混合物)中反应来制备。除上文所提及的那些酸以外的酸的盐也构成本发明的一部分,其例如可用于纯化或分离本发明的化合物(例如三氟乙酸盐)。
生物学测定和数据
缩写列表
DMEM 达尔伯克改良伊格尔培养基
FBS 胎牛血清
FLIPR 荧光成像读板器
HEK293 源自人胚肾细胞的细胞系
HEPES 羟乙基-哌嗪乙磺酸缓冲液
MDCK Madin-Darby犬肾
MDR1 多药耐药蛋白1
p-GP P糖蛋白
体外作用:
体外药理学活性的确定
本发明化合物的活性可以使用以下体外NMDA NR1/NR2b细胞测定来证实:
方法:
使用具有NMDA NR1/NR2B受体的四环素诱导型表达的人HEK293细胞系作为化合物功效和效力的测试系统。所述细胞系购自ChanTest,目录号CT6121。通过在FLIPRtetra系统(Molecular Devices)中测量化合物对由甘氨酸/谷氨酸盐激动作用诱导的细胞内钙浓度的作用来确定化合物活性。
细胞培养:
所述细胞是作为冷冻小瓶中的冷冻细胞而获得,并且储存在-150℃下直至使用。
使细胞在培养基(DMEM/F12、10%FBS、5μg/mL杀稻瘟素、150μg/mL Zeozin、500μg/mL遗传霉素)中生长。重要的是,密度不超过80%汇合。对于传代培养,通过Versene使细胞脱离烧瓶。对于测定,使细胞脱离,用诱导培养基(不含谷氨酰胺的DMEM/F12、10%FBS、2μg/mL四环素、2mM氯胺酮)洗涤两次,并接种至384孔pure coat胺板(BD 359324,50000个细胞/孔,在50μl中),在48h后在诱导培养基中进行测定。
化合物制备
将测试化合物以10mM的浓度溶解于100%DMSO中,并在第一步骤中稀释于DMSO中至5mM浓度,之后在100%DMSO中进行连续稀释步骤。稀释因子和稀释步骤的数量可以根据需求而变化。通常,在所述测定中,以一式两份通过1:5稀释制备8种不同浓度,用水性测定缓冲液(137mM NaCl、4mM KCl、1.8mM CaCl、10mM HEPES、10mM葡萄糖,pH 7.4)(得到高于最终测试浓度3倍的化合物浓度)和2.7%的DMSO(得到0.9%最终DMSO浓度)进行物质的其他中间稀释(1:37.5)。
FLIPR测定:
在测定当天,将细胞用测定缓冲液洗涤3x,在洗涤后,孔中保留10μL缓冲液。将10μL Ca试剂盒加载缓冲液(AAT Bioquest)添加至细胞,并且将板在室温下加盖孵育60分钟。将含有60μM甘氨酸(最终20μM)和3μM谷氨酸盐(最终1μM)的20μl测定缓冲液添加至第1列-第23列。在FLIPRtetra装置上读取荧光(指示由于NR1/NR2B离子通道激活所致的钙流入)持续60秒,以监测谷氨酸盐诱导的作用。在2分钟后,将20μL测定缓冲液中的化合物或对照(第1行-第22行)谨慎添加至孔中。在FLIPR tetra装置上读取荧光再持续6分钟,以监测通过激动剂激活后化合物诱导的作用。计算在化合物添加后5分钟和5分10秒的两次测量的平均值,并将其进一步用于IC50计算。每个测定微量滴定板含有如下孔:具有DMSO对照代替化合物作为甘氨酸/谷氨酸盐诱导的荧光的对照(高对照)的孔(在第23列或第24列),以及具有1μM参考NR2b NAM作为低对照(化合物22;参考文献:Layton,Mark E等人,ACS ChemicalNeuroscience 2011,2(7),352-362)的孔。
数据评价和计算:
读取器的输出文件含有孔数量和所测量的平均荧光单位。对于数据评价和计算,将低对照的测量值设为0%对照,并且将高对照的测量值设为100%对照。使用标准4参数逻辑回归公式计算IC50值。计算:[y=(a-d)/(1+(x/c)^b)+d],a=低值,d=高值;x=浓度M;c=IC50 M;b=斜率。
由通用结构A涵盖并展现低IC50值的NR2B负别构调节剂是优选的。
表1如在FLIPR测定中所获得的本发明的化合物的体外亲和力
实施例编号 | IC50[nM] |
1 | 90 |
3 | 725 |
4 | 382 |
5 | 477 |
10 | 735 |
12 | 210 |
表2如在与表1中的化合物相同的FLIPR测定中获得的最接近的现有技术化合物(WO 2016/29146中的实施例1734、1744、1745、1757、1758、
1785和1790)的体外亲和力
MDCK测定MDR-1(p-GP)
在顶部至基底(AB)和基底至顶部(BA)方向上测量化合物跨越MDCK-MDR1单层(用人MDR1 cDNA表达质粒转染的MDCKII细胞)的表观渗透系数(Papp)。
将MDCK-MDR1细胞(6x 105个细胞/cm2)接种在滤芯(filter insert)(Corning,Transwell,聚碳酸酯,0.4μm孔径)上并培养9至10天。用补充有0.25%BSA的HTP-4水性缓冲液(128.13mM NaCl、5.36mM KCl、1mM MgSO4、1.8mM CaCl2、4.17mM NaHCO3、1.19mMNa2HPO4、0.41mM NaH2PO4、15mM HEPES、20mM葡萄糖,pH 7.4)稀释溶解于DMSO储备溶液中的化合物(1-20mM),以制备转运溶液(终浓度:1或10μM,最终DMSO<=0.5%)。将转运溶液分别应用于顶部或基底外侧供给侧,用于测量A-B或B-A渗透性。接受侧含有补充有0.25%BSA的HTP-4缓冲液。在实验开始时和结束时从供给侧收集样品,并且还以不同时间间隔持续长达2小时从接受侧收集样品,用于通过HPLC-MS/MS进行浓度测量。用新鲜的接受溶液更换采样的接受体积。通过用Papp(b-a)值除以Papp(a-b)值来计算外排比率。结果显示于表3中。
表3
上文实验结果显示,本发明的化合物是具有良好膜渗透性和低至中体外外排的有效NR2B NAM。
代谢稳定性
在37℃下用合并的人肝微粒体测定测试化合物的代谢降解。每个时间点60μl的最终孵育体积含有TRIS缓冲液(室温下pH 7.6)(0.1M)、氯化镁(5mM水溶液)、微粒体蛋白(1mg/mL,用于人)和终浓度1μM的测试化合物。在37℃下的短预孵育期后,通过添加还原型β烟酰胺腺嘌呤二核苷酸磷酸(NADPH,1mM)来起始反应,并且在不同时间点后通过将等分样品转移至溶剂中来终止反应。在离心(10000g,5min)后,通过LC-MS/MS测定上清液的等分样品中母体化合物的量。通过浓度-时间曲线的半对数图的斜率来确定半衰期。结果显示于表4中。
表4
本发明提供根据式A的化合物,其意外地导致以下关键参数的有利组合:
1)NR2B负别构调节,
2)在人肝微粒体中的有利稳定性,以及
3)MDR1转运蛋白处的中至低体外外排。
药物组合物
用于施用本发明的化合物的合适制剂对于本领域普通技术人员而言将是清楚的,并且包括例如片剂、丸剂、胶囊、栓剂、锭剂、糖锭剂、溶液、糖浆、酏剂、小袋、注射剂、吸入剂、粉末等。一种或多种药物活性化合物的含量可以在作为整体的组合物的0.1wt.-%至95wt.-%(优选地5.0wt.-%至90wt.-%)的范围内变化。
合适的片剂可以例如通过将本发明的化合物与已知的赋形剂混合并且将所得的混合物压制以形成片剂来获得,所述赋形剂例如惰性稀释剂、载体、崩解剂、佐剂、表面活性剂、粘合剂和/或润滑剂。
在治疗中的用途/使用方法
NR2B NAM的人治疗应用已经归纳于以下的综述中:Traynelis等人(Traynelis等人,Pharmacology Reviews,2010,62:405)、Beinat等人(Beinat等人,Current MedicinalChemistry,2010,17:4166)以及Mony等人(Mony等人,British J.Pharmacology,2009,157:1301)。
本发明涉及可用于治疗精神障碍、疾病和病症的化合物,其中对NR2B的负别构调节具有治疗益处,包括:(1)心境障碍和心境情感障碍;(2)精神分裂症谱系障碍;(3)神经症性、应激相关的和躯体形式障碍,包括焦虑障碍;(4)心理发育障碍;(5)与生理紊乱和身体因素相关的行为综合征;(6)物质相关和成瘾障碍;(7)与负价和正价的症状相关的疾病。
鉴于其药理学作用,本发明的化合物适用于选自以下列表的障碍、疾病或病症的治疗:
(1)心境障碍和心境情感障碍的治疗,包括抑郁、轻躁狂、躁狂和混合型双相障碍I;双相障碍II;抑郁障碍,如单次抑郁发作或复发性严重抑郁障碍、轻度抑郁障碍、产后发作型抑郁障碍、具有精神病性症状的抑郁障碍;伴随或不伴随焦虑痛苦、混合特征、忧郁症特征、非典型特征、心境协调的精神病性特征、心境不协调的精神病性特征、畸张症的严重抑郁障碍。
(2)属于精神分裂症谱系和其他精神病性障碍的心境障碍的治疗,包括精神分裂症以及具有相关阴性和认知症状的分裂情感障碍。
(3)属于神经症性、应激相关的和躯体形式障碍的障碍的治疗,包括焦虑障碍、广泛性焦虑障碍、伴有或不伴有广场恐惧症的惊恐障碍、特定恐惧症、社交恐惧症、慢性焦虑障碍;强迫症;对严重应激的反应和适应障碍,如创伤后应激障碍;其他神经症性障碍,如人格解体-现实解体综合症。
(4)心理发育障碍的治疗,包括广泛性发育障碍(包括阿斯伯格综合症和雷特综合征)、孤独性障碍、儿童孤独症和与智力低下和刻板动作相关的多动障碍、运动功能的特定发育障碍、学业技能的特定发育障碍、注意缺陷/多动症。
(5)与生理紊乱和身体因素相关的行为综合征的治疗,包括与产褥期相关的精神和行为障碍,包括产后抑郁(postnatal depression)和产后抑郁(postpartumdepression);进食障碍,包括神经性厌食和神经性贪食,以及其他冲动控制障碍。
(6)物质相关和成瘾性障碍的障碍的治疗,其为由以下诱导的物质使用障碍:酒精、大麻、致幻剂、兴奋剂、催眠药、烟草。
(7)与负价和正价的症状相关的疾病的治疗,包括快感缺失、持续的威胁和损失、自杀意念。
如本文所用,除非另外说明,否则术语“治疗(treating)”、“治疗(treatment)”应包括出于对抗疾病、病症或障碍的目的来管理和照护人受试者或人患者,并且包括施用本发明的化合物以预防症状或并发症的发作,减轻症状或并发症,或者消除所述疾病、病症或障碍。
如本文所用,除非另外说明,否则术语“预防”应包括(a)降低一种或多种症状的频率;(b)降低一种或多种症状的严重程度;(c)延迟或避免另外的症状的发展;和/或(d)延迟或避免障碍或病症的发展。
根据另一方面,本发明提供式A的化合物或其药学上可接受的盐,其用于治疗和/或预防上文所提及的病症。
根据另一方面,本发明提供根据前述方面中的任一方面的式A的化合物,其特征在于,所述式A的化合物是与行为疗法、TMS(经颅磁刺激)、ECT(电休克疗法)和其他疗法一起使用。
组合疗法
根据本发明的化合物可以与本领域中已知与任何适应症的治疗结合使用的其他治疗选择组合,所述适应症的治疗是本发明的关注点。
根据另一方面,本发明提供根据前述方面中的任一方面的式A的化合物,其特征在于,所述式A的化合物是与使用选自以下的一种或多种抗抑郁药的治疗一起施用:度洛西汀、依地普仑、安非他酮、文拉法辛、地文拉法辛、舍曲林、帕罗西汀、氟西汀、沃替西汀、米氮平、西酞普兰、维拉佐酮、曲唑酮、阿米替林、氯米帕明、阿戈美拉汀、左旋体米那普仑、锂、多塞平、去甲替林。术语“抗抑郁药”应意指可以用于治疗抑郁或与抑郁性症状相关的疾病的任何药剂或药物。
根据另一方面,本发明提供根据前述方面中的任一方面的式A的化合物,其特征在于所述式A的化合物是与使用选自以下的一种或多种抗精神病药物的治疗一起施用:阿立哌唑、棕榈酸帕潘立酮、鲁拉西酮、喹硫平、利哌立酮、奥氮平、帕潘立酮、依匹哌唑、氯氮平、阿塞那平、氯丙嗪、氟哌啶醇、卡利拉嗪、齐拉西酮、氨磺必利、伊潘立酮、氟奋乃静、布南色林、阿立哌唑十二烷酸酯。术语“抗精神病药物”应意指可以用于治疗与精神病性或抑郁性症状相关的疾病的任何药剂或药物。
根据另一方面,本发明提供根据前述方面中的任一方面的式A的化合物,其特征在于,所述式A的化合物是与使用选自以下的一种或多种精神兴奋剂一起施用:赖右苯丙胺、哌醋甲酯、苯丙胺、右苯丙胺、右哌甲酯、阿莫达非尼、莫达非尼。术语“精神兴奋剂”应意指可以用于治疗像心境障碍或冲动控制障碍的疾病的任何药剂或药物。
根据另一方面,本发明提供根据前述方面中的任一方面的式A的化合物,其特征在于,所述式A的化合物是与使用选自以下的益智药的治疗一起施用:奥拉西坦、吡拉西坦或天然产物圣约翰草(St John's-wort)。
根据另一方面,本发明提供根据前述方面中的任一方面的式A的化合物,其是与使用一种或多种抗抑郁药、抗精神病药物、精神兴奋剂、益智药或天然产物的治疗一起施用,其特征在于,所述式A的化合物与一种或多种抗抑郁药、抗精神病药物、精神兴奋剂、益智药或天然产物的组合是与行为疗法、TMS(经颅磁刺激)、ECT(电休克疗法)和其他疗法一起施用。
实验部分
缩写:
ACN 乙腈
APCI 大气压化学电离
Boc 叔丁氧羰基
CDI 1,1'-羰基二咪唑
CO2 二氧化碳
d 天
DA 二极管阵列
DAD 二极管阵列检测器
DCM 二氯甲烷
DIPE 二异丙醚
DIPEA 二异丙基乙胺
DMF 二甲基甲酰胺
ee、e.e. 对映体过量
ELSD 蒸发光散射检测器
ESI 电喷雾电离(在MS中)
EtOAc 乙酸乙酯
EtOH 乙醇
Exp. 实施例
h 小时
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓-六氟磷酸盐
HPLC 高效液相色谱
HPLC-MS 偶联高效液相色谱-质谱
IPA 异丙醇
M 摩尔浓度(mol/L)
MeOH 甲醇
min 分钟
MS 质谱
MW 分子量
NH3 氨
PSI 磅/平方英寸
rt 室温
Rt 保留时间
scCO2 超临界CO2
Sol 溶剂
solv 溶剂
TBTU O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱
SFC 超临界流体色谱
通用分析
所有反应都是使用商品级试剂和溶剂来进行。在Bruker AVANCE IIIHD 400MHz仪器上使用TopSpin 3.2pl6软件记录NMR谱。化学位移是以从内参三甲基硅烷向低场移动的百万分率(ppm)给出,以δ为单位。选择的数据按以下方式来报告:化学位移、多重性、偶合常数(J)、积分。使用Merck硅胶60F254板进行分析型薄层色谱(TLC)。使用短波UV光将所有化合物可视化为单一斑点。使用液相色谱质谱仪(LCMS)获得低分辨率质谱,所述液相色谱质谱仪由Agilent 1100系列LC与Agilent 6130四极质谱仪(电喷雾正电离)偶联组成。
方法:
对于用于HPLC-MS方法和手性SFC分析方法的溶剂混合物,以相应溶剂的体积百分比给出溶剂%。
HPLC-MS方法:
方法1
方法名称: | Z011_S03 |
装置描述: | Agilent 1200,具有DA检测器和MS检测器 |
柱: | XBridge C18_3.0x 30mm_2.5μm |
柱生产商: | Waters |
描述: |
手性SFC分析方法:
方法2:I_C2_20_MeOH_NH3_001
方法3:I_C2_40_IPA_NH3_001
方法4:I_SA_20_MEOH_NH3_001
中间体的制备:
实施例1a
将S-吗啉-2,4-二甲酸4-叔丁酯(1.26g,5.45mmol)溶解于DMF(20ml)中。然后添加HATU(2.28g,5.99mmol),之后添加吡嗪-2,3-二胺(600mg,5.45mmol,CAS编号13134-31-1)和TEA(1.52ml,10.9mmol)。将反应混合物在室温下搅拌20h,之后进行处理:用玻璃过滤器过滤反应混合物,并在真空中浓缩滤液。将残余物用40mL H2O处理并搅拌2h。过滤出所获得的沉淀并在空气中干燥。获得1.60g所需产物。
HPLC-MS;方法:Z011_S03;R<sub>t</sub>[min]:0.76 | MS:324(M+H)<sup>+</sup> |
实施例2a-方法A(根据方案1)
将实施例1a(1.60g,4.95mmol)、碳酸钾(2.74g,19.8mmol)与异丙醇(50ml)的混合物在80℃下搅拌6h。过滤出沉淀,用异丙醇洗涤,并在真空中浓缩滤液。将残余物干燥过夜。获得1.50g所需产物。
HPLC-MS;方法:Z011_S03;R<sub>t</sub>[min]:0.58 | MS:306(M+H)<sup>+</sup> |
实施例2a-方法B(直接环化,根据方案2)
将S-吗啉-2,4-二甲酸4-叔丁酯(3.15g,13.62mmol)溶解于DMF(30ml)中。然后添加HATU(5.7g,15mmol),之后添加吡嗪-2,3-二胺(1.5g,13.62mmol,CAS编号13134-31-1)和TEA(3.8ml,27.2mmol)。将反应混合物在室温下搅拌7h,之后进行处理:用玻璃过滤器过滤反应混合物,并在真空中浓缩滤液。将残余物用100mL H2O处理并搅拌12h。过滤出所获得的沉淀并在空气中干燥。获得2.0g所需环化产物。
实施例3a
将实施例2a(2g,6.55mmol)溶解于DCM(120ml)中,添加二噁烷中的HCl(4M,9.83ml,39.3mmol),并将反应混合物在室温下搅拌3.5h。在真空中蒸发溶剂,并将所获得的残余物原样用于下一步骤中。获得1.8g作为盐的所需产物。
示例性实施方案
实施例1
将(2-氟-4-甲基苯基)甲醇(151mg;1.08mmol,CAS编号252004-38-9)与CDI(175mg;1.08mmol)在DMF(3ml)中混合在一起;将反应混合物在50℃下加热30分钟。然后按顺序添加实施例3a(150mg;0.54mmol)和DIPEA(0.28ml;1.62mmol),并将反应混合物在室温下搅拌2小时。将反应混合物用3ml的MeOH/水(1/1;体积/体积)混合物稀释,之后进行过滤并经由半制备型HPLC分离。将残余物与3mL DIPE一起研磨,过滤并在空气中干燥。获得157mg所需化合物。
实施例3
将(2-氟-3-甲基苯基)甲醇(151mg;1.08mmol,CAS编号307975-03-7)与CDI(175mg;1.08mmol)在DMF(3ml)中混合在一起;将反应混合物在50℃下加热30分钟。然后按顺序添加实施例3a(150mg;0.54mmol)和DIPEA(0.28ml;1.62mmol),并将反应混合物在室温下搅拌16小时。将反应混合物用3ml的MeOH/水(1/1;体积/体积)混合物稀释,之后进行过滤并经由半制备型HPLC分离。获得80mg所需化合物。
实施例4
将(2-氟苯基)甲醇(116μl;1.08mmol,CAS编号446-51-5)与CDI(175mg;1.08mmol)在DMF(3ml)中混合在一起;将反应混合物在50℃下加热30分钟。然后按顺序添加实施例3a(150mg;0.54mmol)和DIPEA(0.28ml;1.62mmol),并将反应混合物在室温下搅拌3小时。将反应混合物用3ml的MeOH/水(1/1;体积/体积)混合物稀释,之后进行过滤并经由半制备型HPLC分离。获得98mg所需化合物。
实施例5
与实施例4类似地合成实施例5。起始材料:实施例3a(150mg,0.54mmol)和(2,4-二氟苯基)甲醇(121μl,1.08mmol,CAS编号56456-47-4)。经由半制备型HPLC纯化粗制品。获得112mg所需化合物。
实施例10
将(4-氟苯基)甲醇(157μl,1.44mmol,CAS编号459-56-3)溶解于DMF(6ml)中;添加TEA(0.3ml;2.16mmol),之后添加双-[1,2,4]三唑-1-基-甲酮(236mg,1.44mmol)和实施例3a(200mg,0.72mmol)。将反应混合物在50℃下搅拌2h,之后用H2O/MeOH(4ml;1/1;体积/体积混合物)稀释,过滤并用半制备型HPLC纯化。
获得150mg所需化合物。
实施例12
与实施例10类似地合成实施例12。起始材料:实施例3a(200mg,0.72mmol)和(4-甲基苯基)甲醇(176mg,1.44mmol,CAS编号589-18-4)。经由半制备型HPLC纯化反应混合物。获得117mg所需化合物。
Claims (10)
2.根据权利要求1所述的化合物,其中
R1表示苯基,所述苯基任选地被选自氟、甲基的1或2个取代基取代。
5.一种根据权利要求1至4中任一项所述的化合物的盐,特别是药学上可接受的盐。
6.根据权利要求1至5中任一项所述的化合物,其用作药剂。
7.根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐,其用于治疗和/或预防抑郁、轻躁狂、躁狂和混合型双相障碍I;双相障碍II;抑郁障碍,如单次抑郁发作或复发性严重抑郁障碍、轻度抑郁障碍、产后发作型抑郁障碍、具有精神病性症状的抑郁障碍;伴随或不伴随焦虑痛苦、混合特征、忧郁症特征、非典型特征、心境协调的精神病性特征、心境不协调的精神病性特征、畸张症的严重抑郁障碍。
8.根据权利要求6至7中任一项所述的用于所述用途的化合物,其特征在于所述化合物是与使用另一抗抑郁药物的治疗一起施用。
9.根据权利要求6至7中任一项所述的用于所述用途的化合物,其特征在于所述化合物是与行为疗法一起施用。
10.一种药物组合物,其包含根据权利要求1至5中任一项所述的化合物与药学上可接受的佐剂、稀释剂和/或载体的混合物。
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Publication number | Priority date | Publication date | Assignee | Title |
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US20020055519A1 (en) * | 1999-10-29 | 2002-05-09 | Thompson Wayne I. | 2-cyclohexyl imidazopyridine NMDA/NR2B antagonists |
WO2016029146A1 (en) * | 2014-08-22 | 2016-02-25 | University Of Washington | Specific inhibitors of methionyl-trna synthetase |
CN106795163A (zh) * | 2014-06-04 | 2017-05-31 | 卢郡控股(开曼)有限公司 | 作为nr2b nmda受体拮抗剂的二氟乙基吡啶衍生物 |
CN111344291A (zh) * | 2017-12-08 | 2020-06-26 | 勃林格殷格翰国际有限公司 | 咪唑并吡啶衍生物及其作为药剂的用途 |
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Publication number | Priority date | Publication date | Assignee | Title |
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US20020055519A1 (en) * | 1999-10-29 | 2002-05-09 | Thompson Wayne I. | 2-cyclohexyl imidazopyridine NMDA/NR2B antagonists |
CN106795163A (zh) * | 2014-06-04 | 2017-05-31 | 卢郡控股(开曼)有限公司 | 作为nr2b nmda受体拮抗剂的二氟乙基吡啶衍生物 |
WO2016029146A1 (en) * | 2014-08-22 | 2016-02-25 | University Of Washington | Specific inhibitors of methionyl-trna synthetase |
CN111344291A (zh) * | 2017-12-08 | 2020-06-26 | 勃林格殷格翰国际有限公司 | 咪唑并吡啶衍生物及其作为药剂的用途 |
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