CN113950478B - 作为nr2b负向调节剂的嘌呤衍生物及其作为药物的用途,特别是用于治疗抑郁病症 - Google Patents
作为nr2b负向调节剂的嘌呤衍生物及其作为药物的用途,特别是用于治疗抑郁病症 Download PDFInfo
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Abstract
本发明为关于新颖的通式A的嘌呤、其制备方法、含有其的药物组合物,及其在疗法中,尤其在治疗或预防与NR2B负向立体异位调节性质相关的病况中的用途。
Description
【技术领域】
本发明为关于新颖的通式A的嘌呤
其制备方法、含有其的药物组合物,及其在疗法中,尤其在治疗或预防与NR2B负向立体异位调节性质相关的病况中的用途。
根据通式A的本发明化合物展示NR2B负向立体异位调节特性。
【背景技术】
过去二十年里的广泛研究已表明,N-甲基-D-天冬氨酸受体(NMDA)在阿尔茨海默氏症(Alzheimer's disease)、帕金森氏病(Parkinson's disease)、运动困难症、中风、运动神经性疾病、精神病、癫痫症、焦虑、精神分裂症及疼痛中发挥相关作用。
非选择性NMDA受体拮抗剂氯胺酮(外消旋以及S对映异构体),即主要用于开始及保持麻醉的药物,在过去几年里已证实在以亚麻醉剂量治疗重度抑郁症(MDD)方面的临床功效(Murrough等人,2013,Am J Psychiatry.170:1134;Singh等人,2016,BiolPsychiatry.80:424)。更确切而言,氯胺酮使功效快速起效,该功效在未充分对标准药物疗法作出反应的MDD患者中持续数天(Berman等人,2000.Biol Psychiatry 47:351,Serafini等人,2014.Curr.Neuropharmacol.12:444)。然而,非选择性NMDA受体拮抗剂具有一定范围的限制其应用的非所要作用。详言之,分裂性及精神性副作用对于诸如氯胺酮的非选择性NMDA受体拮抗剂突出(Krystal等人,1994.Arch.Gen.Psychiatry 51:199)。在1990年代早期,发现存在多种NMDA受体亚型,其含有不同NR2(A-D)次单元(Paoletti等人,2013NatRev.Neurosci 14:383)。近年来,NR2B次型选择性NMDA受体负向立体异位调节剂(NR2BNAM)引起了人们的兴趣且已展示出在大范围临床适应症(诸如注意力、情绪、情感及疼痛)的潜能,以及涉及许多不同的人类病症(Mony等人,2009.Br.J.Pharmacol.157:1301;Chaffey等人,Current Anaesthesia&Critical Care 19,183)。详言之,NR2B NAM亦已证实在早期临床试验中的抗抑郁功效(Preskorn等人,2008.J Clin Psychopharmacol 70:58)。使用NR2B NAM以及应用各种转殖基因小鼠菌株的临床前研究已展示出,含有含NR2B的NMDA受体调节氯胺酮在(例如)强迫游泳实验中的正面效果(Miller等人,2014eLife 3:e03581;Kiselycznyk等人,2015,Behav Brain Res,287:89)。此外,归因于极大减弱的分裂性及拟精神病的副作用,选择性NR2B NAM具有优于非选择性NMDA受体拮抗剂(诸如氯胺酮)的优点(Jimenez-Sanchez等人,2014.Neuropsychopharmacology 39:2673)。迄今为止所描述的NR2B NAM已显现出关于其受体药理学及/或关于在人类药物疗法中的潜在用途受限的其他药物特性的缺点(Taylor等人,2006,Clin Pharmacokinet.45:989;Addy等人,2009J ofClinical Pharmacology 49:856))。
WO2016/29146公开式(I)化合物
其为适用作抗生素的甲硫胺酰基-tRNA合成酶(MetRS)的抑制剂。WO2016/29146中的式(I)涵盖展现苯并咪唑或咪唑并吡啶子结构的特定实施例1734、1744、1745、1757、1758、1785及1790。
出人意料地发现本发明化合物是强力NR2B负向立体异位调节剂(参见表1),而WO2016/29146的特定实施例1734、1744、1745、1757、1758、1785及1790展示NR2B离子通道的相当不佳的负向立体异位调节或完全未展示活性(参见表2)。
此外,本发明的化合物展示良好膜渗透率及低至中等活体外流出(参见表3的MDCK分析MDR1(p-GP))。因此,预期本发明化合物展示有效CNS药物所需的有利的脑穿透。
MDCK分析提供关于化合物穿过血脑屏障的潜能的信息。横跨可渗透过滤器支撑体上所生长的偏振汇合MDCK-MDR1细胞单层的渗透性测量为用作活体外吸收模型:在自顶端至基底(AB)及自基底至顶端(BA)输送方向上(pH 7.4,37℃)测量横跨MDCK-MDR1细胞单层的化合物的表观渗透系数(PE)。AB渗透性(PEAB)表示自血液至大脑中的药物吸收且BA渗透性(PEBA)表示经由被动渗透以及主动输送机制自大脑返回至血液中的药物流出,该等主动输送机制为由在MDCK-MDR1细胞上表达的流出及摄取转运体、主要由过度表达的人类MDR1介导。在两个输送方向上的相同或相似的渗透性指示被动渗透,向量渗透性指向另外的主动输送机制。PEBA高于PEAB(PEBA/PEAB>5)指示涉及由MDR1介导的主动流出,其使目标折衷以达成充分大脑暴露。因此,此分析提供宝贵的支持以供选择适用于另外的活体内测试的化合物。未受到血脑屏障处的流出限制的高渗透性为待用于主要在CNS中起作用的药物的化合物的有利特征。因此,为确保血脑屏障处的高渗透性,极佳的为使MDR1转运体处的流出降至最低(流出<5)。
此外,本发明化合物在人类肝脏微粒体中为代谢稳定的(参见表4,代谢稳定性)。因此,预期本发明化合物在人体内具有有利活体内清除率且因此具有所要作用持续时间。
人类肝脏微粒体中的稳定性涉及在选择及/或设计具有有利的药物动力学特性的环境中化合物对生体转化的易感性。许多药物的主要代谢部位为肝脏。人类肝脏微粒体含有细胞色素P450(CYP)且因此表示用于研究活体外药物代谢的模型系统。人类肝脏微粒体中的经增强稳定性与若干优点相关,包括增加的生物可用性及足够半衰期,其可实现患者的较低及较不频繁的给药。因此,人类肝脏微粒体中的经增强稳定性为待用于药物的化合物的有利特征。
因此,本发明化合物必须更适合人类使用。
因此,目标技术问题为提供强力NR2B负向立体异位调节剂。
【发明内容】
本发明提供新颖的式A的嘌呤
其中
R1表示任选经1、2或3个选自由以下组成的群的取代基取代的苯基:氟、氯、甲基、乙基、环丙基、F2HC-、FH2C-、F3C-;
R2表示氢、甲基;
或其盐,尤其其药物学上可接受的盐。
在另一实施方案中,在通式A中,R1具有如前述实施方案中任一者定义的相同含义,且
R2表示氢。
在另一实施方案中,在通式A中,R1具有如前述实施方案中任一者定义的相同含义,且
R2表示甲基。
在另一实施方案中,在通式A中,R2具有如前述实施方案中任一者所定义的相同含义,且
R1表示任选经1、2或3个选自由以下组成的群的取代基取代的苯基:氟、氯、甲基、F2HC-。
在另一实施方案中,在通式A中,R2具有如前述实施方案中任一者所定义的相同含义,且
R1表示
本发明提供新颖的通式A的嘌呤,其出乎意料地为强力NR2B负向立体异位调节剂。
本发明的另一方面涉及作为具有适当膜渗透率及低至中等活体外流出的NR2B负向立体异位调节剂的根据式A的化合物。
本发明的另一方面涉及作为具有在人类肝脏微粒体中的高代谢稳定性的NR2B负向立体异位调节剂的根据式A的化合物。
本发明的另一方面涉及作为具有在人类肝脏微粒体中的适当膜渗透率、低至中等活体外流出及高代谢稳定性的NR2B负向立体异位调节剂的根据式A的化合物。
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,任选连同一或多种惰性载剂及/或稀释剂。
本发明的另一方面涉及根据式A的化合物,其用于预防及/或治疗与NR2B负向立体异位调节剂相关的病症。
本发明的另一方面涉及制造本发明化合物的方法。
【实施方式】
制备
以下流程将以实施例的方式大体上说明如何制造根据通式A的化合物及对应中间化合物。若流程的上下文中未另外定义,则缩写的取代基可如上文所定义。
流程1:方法A
流程2:方法B
流程3:方法C
可替代地,可使用外消旋吗啉-2,4-二甲酸4-叔丁酯或4-苄基-吗啉-2-甲酸作为起始材料来进行根据流程1、2及3的合成。
流程1、2及3可成功地用于最终化合物的公克级合成,其以40毫摩尔浓度所需经取代的吗啉(外消旋或S对映异构体)为起始材料,使用过量的所需经取代的苯甲醇、DIPEA(3当量)、所需偶合剂(诸如CDI或双-[1,2,4]三唑-1-基-甲酮)及DMF作为溶剂。可获得具有良好至高对映异构体过量的最终化合物;可替代地,可应用手性分离以获得纯对映异构体。
可使用对应的吗啉(外消旋或S对映异构体;40mmol)、TEA(2.5当量)、略微过量的必需碳酸酰亚胺酯及1/1混合物CH3CN/THF(体积/体积)作为溶剂来进行替代公克级合成。
在流程1、2及3中,所有取代基R1及R2具有如针对通式A,即直接提到通式A的本发明的所有实施方案所定义的含义且特定言之,具有如申请专利范围中所定义的含义。
一般定义
未在本文中特定地定义的术语应被赋予本领域普通技术人员依据本发明及上下文将对其赋予的含义。
在本发明的化合物以化学名称以及化学式形式描述的情况下,若有任何不一致的情况,则应以化学式为准。
星号可在子式中使用以指示连接至核心分子或连接至如所定义的与其键结的取代基的键。
如本文所用的术语“经取代”意谓指定原子上的任何一或多个氢经来自指定基团的选择置换,其限制条件为不超过指定原子的可行价态,且取代后得到稳定化合物。
立体化学:
除非特别指示,否则贯穿本说明书及所附申请专利范围,给定的化学式或名称将涵盖其旋转异构体、互变异构体及所有立体异构体、光学异构体及几何异构体(例如对映异构体、非对映异构体、E/Z异构体等)及外消旋体以及呈不同比例的单独对映异构体的混合物、非对映异构体的混合物或存在此类异构体及对映异构体的前述形式中的任一者的混合物,以及盐,包括其药物学上可接受的盐。
通式A
包含互变异构体A-1及A-2两者:
所有本发明化合物以其互变异构形式A-1及/或A2存在。
盐:
词组“药物学上可接受(pharmaceutically acceptable)”在本文中用于指在合理医学判断范畴内,适用于无过度毒性、刺激、过敏反应或其他问题或并发症,与合理益处/风险比相匹配的那些化合物、材料、组合物及/或剂型。
如本文所使用,“药物学上可接受的盐”是指本发明化合物的衍生物,其中亲本化合物与酸或碱形成盐或错合物。
与含有碱性部分的亲本化合物形成药物学上可接受的盐的酸的实施例包括无机酸或有机酸,诸如苯磺酸、苯甲酸、柠檬酸、乙磺酸、反丁烯二酸、龙胆酸(gentisicacid)、氢溴酸、氢氯酸、顺丁烯二酸、苹果酸、丙二酸、杏仁酸、甲磺酸、4-甲基-苯磺酸、磷酸、柳酸、丁二酸、硫酸或酒石酸。
与含有酸性部分的母体化合物形成药物学上可接受的盐的阳离子及碱的实施例包括Na+、K+、Ca2+、Mg2+、NH4+、L-精氨酸、2,2'-亚胺双乙醇、L-赖氨酸、N-甲基-D-葡萄糖胺或三(羟基甲基)-氨基甲烷。
可通过习知化学方法由含有碱性部分或酸性部分的亲本化合物合成本发明的药物学上可接受的盐。一般而言,可通过使这些化合物的游离酸或游离碱形式与足量适当碱或酸于水中或于有机稀释剂(如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈或其混合物)中反应来制备此盐。除了上述例如适用于纯化或分离本发明化合物者(例如三氟乙酸盐)以外的其他酸的盐亦包含本发明的一部分。
生物分析及资料
缩写清单
DMEM 达尔伯克氏改良伊格尔氏培养基(Dulbecco's Modified Eagle's Medium)
FBS 胎牛血清
FLIPR 荧光成像板读取仪
HEK293 源自人类胚胎肾细胞的细胞株
HEPES 羟基乙基-哌嗪乙烷-磺酸缓冲液
MDCK 马丁-达比(Madin-Darby)犬肾
MDR1 多重抗药性蛋白1
p-GP p-糖蛋白
活体外效应:
活体外药理学活性的测定
可使用以下活体外NMDA NR1/NR2b细胞分析证明本发明的化合物的活性:方法:
将具有四环素可诱导NMDA NR1/NR2B受体表达的人类HEK293细胞株用作化合物功效及效能的测试系统。该细胞株为购自ChanTest,目录号#CT6121。通过在FLIPRtetra系统(Molecular Devices)中测量化合物对甘氨酸/谷氨酸促效作用诱导的胞内钙浓度的影响来测定化合物活性。
细胞培养:
获得在低温小瓶中呈冷冻细胞形式的细胞且将其在-150℃储存至使用为止。
细胞在培养基(DMEM/F12,10%FBS,5μg/mL杀稻瘟菌素(Blasticidin),150μg/mL新霉素(Zeozin),500μg/mL遗传霉素(Geneticin))中生长。重要的是密度不超过80%满度(confluence)。为了继代培养,通过维尔烯(Versene)将细胞与烧瓶分离。为了分析,将细胞分离,用诱导培养基(不含谷酰氨酸的DMEM/F12,10%FBS,2μg/mL四环素,2mM氯胺酮)洗两次,且在诱导培养基中分析的前48小时,接种至384孔纯涂胺板(BD 359324,50μl中50000个细胞/孔)。
化合物制备
将测试化合物以10mM的浓度溶解于100%DMSO中,且在第一步骤中在DMSO中稀释至5mM的浓度,随后为在100%DMSO中的连续稀释步骤。稀释因子及稀释步骤的数目可根据需要而变化。通常,一式两份地制备8种不同浓度的1:5稀释液,利用水性分析缓冲液(137mMNaCl,4mM KCl,1.8mM CaCl,10mM HEPES,10mM葡萄糖,pH 7.4)进行对物质的进一步中间稀释(1:37.5),使化合物浓度比最终测试浓度高3倍及DMSO为2.7%,从而使分析中的最终DMSO浓度为0.9%。
FLIPR分析:
在分析当天,利用分析缓冲液将细胞洗涤3次,在洗涤之后各孔中留下10μL缓冲液。将10μL Ca试剂盒加样缓冲液(AAT Bioquest)添加至细胞中且将培养盘与盖一起在室温下培育60分钟。将20μl含有60μM甘氨酸(最终20μM)及3μM谷氨酸(最终1μM)的分析缓冲液添加至第1-23行。在FLIPRtetra装置上读取荧光(指示作为NR1/NR2B离子通道活化的结果的钙流入)达60秒,以监测谷氨酸诱导的效应。2分钟后,将分析缓冲液中的20μL化合物或对照物(第1-22列)谨慎地添加至孔中。在FLIPR tetra装置上再读取荧光6分钟,以在通过促效剂进行活化之后监测化合物诱导的效应。计算化合物添加后5分钟及5分钟10秒时的2次测量的平均值,且将该平均值进一步用于IC50计算。每一分析微量滴定盘含有具有DMSO对照物而非化合物作为甘氨酸/谷氨酸诱导的荧光的对照(高对照)的孔(在第23或24列中)及具有1μM参考NR2b NAM作为低对照(化合物22;参考:Layton,Mark E等人,ACS ChemicalNeuroscience 2011,2(7),352-362)的孔。
数据评估及计算:
读取仪的输出档案含有孔编号及所测量的平均荧光单元。对于数据评估及计算而言,低对照的测量结果设定为0%对照且高对照的测量结果设定为100%对照。使用标准4参数逻辑回归公式计算IC50值。计算值n:[y=(a-d)/(1+(x/c)^b)+d],a=低值,d=高值;x=浓度M;c=IC50 M;b=斜率。
一般结构A所涵盖且展现低IC50值的NR2B负向立体异位调节剂为优选的。
表1如FLIPR分析中所获得的本发明化合物的活体外亲和力
表2如在与表1中的化合物相同的FLIPR分析中获得的最接近的先前技术化合物的活体外亲和力(WO2016/29146中的实施例1734、1744、1745、1757、1758、1785及1790)
WO2016/29146中的实施例编号 | IC50[nM] |
1734 | >8885 |
1744 | >8889 |
1745 | >8898 |
1757 | >8900 |
1758 | >8884 |
1785 | 6200 |
1790 | >8887 |
MDCK分析MDR-1(p-GP)
在自顶端至基底(AB)及自基底至顶端(BA)方向上测量横跨MDCK-MDR1单层(经人类MDR1 cDNA表达质体转染的MDCKII细胞)的化合物的表观渗透系数(Papp)。
将MDCK-MDR1细胞(6×105个细胞/cm2)接种于过滤器芯(Corning,Transwell,聚碳酸酯,0.4μm微孔尺寸)上且培养9至10天。将溶解于DMSO储备溶液中的化合物(1-20mM)用补充有0.25%BSA的HTP-4水性缓冲液(128.13mM NaCl、5.36mM KCl、1mM MgSO4、1.8mMCaCl2、4.17mM NaHCO3、1.19mM Na2HPO4、0.41mM NaH2PO4、15mM HEPES、20mM葡萄糖,pH7.4)稀释,以制备输送溶液(最终浓度:1或10μM,最终DMSO<=0.5%)。将输送溶液涂覆至顶端或基底外侧供体侧面以用于分别测量A-A或B-A渗透性。接收器侧面含有补充有0.25%BSA的HTP-4缓冲液。在实验开始及结束时自供体收集样品且亦以各种时间间隔自接收器侧收集样品持续多至2小时,以用于通过HPLC-MS/MS进行浓度测量。用新鲜接收器溶液替换取过样的接收器体积。将Papp(b-a)值除以Papp(a-b)值来计算流出比率。结果展示于表3中。
表3
以上实验结果展示本发明化合物为具有良好膜渗透率及低至中等活体外流出的强力NR2B NAM。
代谢稳定性
在37℃下使用汇聚的人类肝脏微粒体来分析测试化合物的代谢降解。每个时间点60μl的最终培育体积含有室温的TRIS缓冲液pH 7.6(0.1M)、氯化镁(5mM水溶液)、微粒体蛋白(针对人类为1mg/mL)及最终浓度为1μM的测试化合物。在37℃下的短预培育时期之后,反应通过添加呈还原形式的β-烟酰胺腺嘌呤二核苷酸磷酸(NADPH,1mM)开始且通过在不同时间点后将等分试样转移至溶剂中来中止。在离心(10000g,5分钟)之后,通过LC-MS/MS分析上清液的等分试样以获得亲本化合物的量。通过浓度-时间特征曲线的半对数曲线图的斜率来测定半衰期。结果展示于表4中。
表4
本发明提供根据式A的化合物,其出乎意料地产生以下关键参数的有利组合:
1)NR2B负向立体异位调节,
2)在人类肝脏微粒体中的有利稳定性,及
3)在MDR1转运体处的中等至低的活体外流出
药物组合物
用于投与本发明化合物的适合制剂将为一般技术者显而易知且包括例如片剂、丸剂、胶囊、栓剂、口含片、糖衣锭、溶液、糖浆剂、酏剂、药囊、可注射剂、吸入剂及散剂等。药物活性化合物的含量可在整体组合物的0.1至95重量%,优选5.0至90重量%范围内变化。
可例如通过将本发明化合物与已知赋形剂(例如惰性稀释剂、载剂、崩解剂、佐剂、表面活性剂、粘合剂及/或润滑剂)混合及压制所得混合物以形成片剂,获得适合的片剂。
治疗用途/使用方法
NR2B NAM的人类治疗应用已概括于Traynelis等人的综述(Traynelis等人,Pharmacology Reviews,2010,62:405)、Beinat等人的综述(Beinat等人,CurrentMedicinal Chemistry,2010,17:4166)及Mony等人的综述(Mony等人,BritishJ.Pharmacology,2009,157:1301)中。
本发明为关于适用于治疗精神性病症、疾病及病况的化合物,其中NR2B的负向立体异位调节具有治疗益处,该等精神性病症、疾病及病况包括:(1)情绪障碍及情绪情感性障碍;(2)精神分裂症谱障碍;(3)神经性、压力相关及类躯体化症精神障碍,包括焦虑症;(4)心理发展障碍;(5)与生理紊乱及身体因素相关的行为综合征;(6)物质相关及成瘾症;(7)与负向效价及正向效价的症状相关的疾病。
鉴于其药理学效果,本发明化合物适合用于治疗选自由以下组成的清单的病症、疾病或病况:
(1)治疗情绪障碍及情感性情绪障碍,包括I型躁郁症(抑郁、轻躁狂、躁狂及混合形式);II型躁郁症;抑郁症,诸如单次抑郁发作或复发性重度抑郁症、轻微抑郁症、产后发作的抑郁症、具有精神病性症状的抑郁症;重度抑郁症伴有或不伴有焦虑窘迫、混合特征、忧郁型特征、非典型特征、情绪一致型精神病特征、情绪不一致型精神病特征、紧张症。
(2)治疗属于精神分裂症谱的情绪障碍及其他精神病性病症,包括具有相关负向性症状及认知症状的精神分裂症及分裂情感性精神障碍。
(3)治疗属于神经性、压力相关及类躯体化症精神障碍的病症,包括焦虑症、广泛性焦虑症、伴有或不伴有畏旷症的恐慌症、特定恐惧症、社交恐惧症、慢性焦虑症;强迫症;对严重压力及适应障碍的反应,诸如创伤后压力症;其他神经性病症,诸如人格解体-现实感丧失综合征(depersonalisation-derealisation syndrome)。
(4)治疗心理发展障碍,包括综合性发育障碍,包括阿斯伯格氏综合征(Asperger's syndrome)及雷特氏综合征(Rett's syndrome)、自闭性病症、儿童自闭症及与智力迟钝及刻板动作相关的过度活跃症、特定的运动功能发育障碍、特定的学术性技能发育障碍、注意力不足/过动症。
(5)治疗与生理紊乱及身体因素相关的行为综合征,包括与产褥期相关的精神及行为障碍,包括产后及产褥期抑郁症;饮食障碍,包括神经性厌食症及神经性暴食症及其他冲动控制病症。
(6)治疗物质相关病症及成瘾症,其为由酒精、大麻、迷幻剂、刺激剂、催眠剂、烟草诱发的物质使用障碍。
(7)治疗与负向效价及正向效价的症状相关的疾病,包括快感缺乏、持续性威胁及损失、自杀观念。
如本文中所使用,除非另外说明,否则术语“治疗(treating/treatment)”应包括针对对抗疾病、病况或病症目的管理及护理人类个体或人类患者,且包括投与本发明化合物以预防症状或并发症发作,缓解症状或并发症或消除疾病、病况或病症。
如本文中所使用,除非另外说明,否则术语“预防(prevention)”应包括(a)降低一或多种症状的频率;(b)降低一或多种症状的严重程度;(c)延迟或避免额外症状的发展;及/或(d)延迟或避免病症或病况的发展。
根据另一方面,本发明提供式A化合物或其药物学上可接受的盐,其用于治疗及/或预防上述病况。
根据另一方面,本发明提供如前述方面中任一项的式A化合物,其特征在于除行为疗法、TMS(经颅磁刺激)、ECT(电惊厥疗法)及其他疗法之外使用式A化合物。
组合疗法
根据本发明的化合物可与已知用于与任何适应症的治疗有关技术的其他治疗选项组合,该治疗为本发明的重点。
根据另一方面,本发明提供如前述方面中任一项的式A化合物,其特征在于除了用一或多种抗抑郁剂治疗之外投与式A化合物,该一或多种抗抑郁剂选自由以下组成的清单:度洛西汀(duloxetine)、依地普兰(escitalopram)、安非他酮(bupropion)、文拉法辛(venlafaxine)、地文拉法辛(desvenlafaxine)、舍曲林(sertraline)、帕罗西汀(paroxetine)、氟西汀(fluoxetine)、沃替西汀(vortioxetine)、米氮平(mirtazapine)、西它普兰(citalopram)、维拉唑酮(vilazodone)、曲唑酮(trazodone)、阿米曲替林(amitriptyline)、氯米帕明(clomipramine)、阿戈美拉汀(agomelatine)、左旋米那普仑(levomilnacipran)、锂、多塞平(doxepin)、去甲替林(nortriptyline)。术语“抗抑郁剂”应意谓可用于治疗抑郁或与抑郁症状相关疾病的任何药物制剂或药物。
根据另一方面,本发明提供如前述方面中任一项的式A化合物,其特征在于除了用一或多种抗精神病药治疗之外投与式A化合物,该一或多种抗精神病药选自由以下组成的清单:阿立哌唑(aripiprazole)、棕榈酸帕潘立酮(paliperidone palmitate)、鲁拉西酮(lurasidone)、喹硫平(quetiapine)、利培酮(risperidone)、奥氮平(olanzapine)、帕潘立酮(paliperidone)、布瑞哌唑(brexpiprazole)、氯氮平(clozapine)、阿塞那平(asenapine)、氯丙嗪(chlorpromazine)、氟哌啶醇(haloperidol)、卡利拉嗪(cariprazine)、齐拉西酮(ziprasidone)、胺磺必利(amisulpride)、伊潘立酮(iloperidone)、氟非那嗪(fluphenazine)、布南色林(blonanserin)、阿立哌唑十二烷酸酯(aripiprazole lauroxil)。术语“抗精神病药”应意谓可用于治疗与精神病性或抑郁性症状相关的疾病的任何药物制剂或药物。
根据另一方面,本发明提供如前述方面中任一项的式A化合物,其特征在于除了用一或多种精神兴奋药治疗之外投与式A化合物,该一或多种精神兴奋药选自由以下组成的清单:赖氨酸右旋安非他明(lisdexamfetamine)、哌醋甲酯(methylphenidate)、安非他明(amfetamine)、右旋安非他明(dexamfetamine)、右哌甲酯(dexmethylphenidate)、阿莫达非尼(armodafinil)、莫达非尼(modafinil)。术语“精神兴奋药”应意谓可用于治疗如情绪障碍或冲动控制病症的疾病的任何药物制剂或药物。
根据另一方面,本发明提供如前述方面中任一项的式A化合物,其特征在于除了用益智药治疗之外投与式A化合物,该益智药选自由以下组成的清单:奥拉西坦(oxiracetam)、吡拉西坦(piracetam)或天然产品金丝桃草(St John's-wort)。
根据另一方面,本发明提供如前述方面中任一项的除了用一或多种抗抑郁剂、抗精神病药、精神兴奋药、益智药或天然产品治疗之外投与的式A化合物,其特征在于除了行为疗法、TMS(经颅磁刺激)、ECT(电惊厥疗法)及其他疗法之外使用式A化合物与一或多种抗抑郁剂、抗精神病药、精神兴奋药、益智药或天然产品的组合。
实验部分
缩写:
ACN 乙腈
Alox B 氧化铝,碱性
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 天数
DA 二极管数组
DAD 二极管数组检测器
DCM 二氯甲烷
DIPE 二异丙基醚
DIPEA 二异丙基乙胺
DMF 二甲基甲酰胺
ee,e.e. 对映异构体过量
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'-四甲脲鎓-六氟磷酸盐
HPLC 高效液相层析
HPLC-MS 耦合高效液相层析-质谱法
IPA 异丙醇
M 摩尔浓度(mol/L)
MeOH 甲醇
min 分钟
MS 质谱法
MW 分子量
NH3 氨
NMP N-甲基-2-吡咯啶酮
PSI 磅/平方吋
QDa 四极杆道尔顿
rt 室温
Rt 滞留时间
scCO2 超临界CO2
Sol 溶剂
soln 溶液
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 薄层层析法
SFC 超临界流体层析
一般分析
所有反应为使用商品级试剂及溶剂进行。使用TopSpin 3.2pl6软件将NMR频谱记录于Bruker AVANCE IIIHD 400MHz仪器上。化学位移为在δ单元中的内部参考三甲基硅烷低场以百万分率(ppm)形式给出。所选择数据为按以下方式报告:化学位移、多重性、偶合常数(J)、积分。使用Merck硅胶60F254板进行分析型薄层层析(TLC)。使用短波UV光将所有化合物以单点形式可视化。使用由耦合至Agilent 6130四极质谱仪(电喷雾正电离)的Agilent 1100系列LC组成的液相层析质谱仪(LCMS)获得低分辨率质谱。
方法:
对于用于HPLC-MS方法及手性SFC分析方法的溶剂混合物,以对应溶剂的体积百分比给出%溶剂。
HPLC-MS方法:
方法1
方法名称: | Z003_S05 |
装置描述: | 具有DA-及MS-检测器的Agilent 1200 |
管柱: | XBridge C18_3.0×30mm_2.5μm |
管柱制造商: | Waters |
描述: |
方法2
方法名称: | Z011_S03 |
装置描述: | 具有DA-及MS-检测器的Agilent 1200 |
管柱: | XBridge C18_3.0×30mm_2.5μm |
管柱制造商: | Waters |
描述: |
方法3
方法名称: | Z018_S04 |
装置描述: | 具有DA-及MS-检测器的Agilent 1200 |
管柱: | Sunfire C18_3.0×30mm_2.5μm |
管柱制造商: | Waters |
描述: |
方法5
方法名称: | 004_CA02 |
装置描述: | Waters Acquity,QDa检测器 |
管柱: | XBridge C18_3.0×30mm_2.5μm |
管柱制造商: | Waters |
描述: |
方法6
方法名称: | 004_CA11 |
装置描述: | Waters Acquity,QDa检测器 |
管柱: | XBridge C18_3.0×30mm_2.5μm |
管柱制造商: | Waters |
描述: |
方法7
方法名称: | 003_CA11 |
装置描述: | Waters Acquity,QDa检测器 |
管柱: | Sunfire C18_3.0×30mm_2.5μm |
管柱制造商: | Waters |
描述: |
手性SFC分析方法:
方法8:
IC420MeOHNH3001
方法9:I_C4_25_MEOH_NH3_001
/>
方法10:I_IB_25_IPA_NH3_001
方法11:I_IC_25_MEOH_NH3_001
方法12:I_IG_35_MEOH_NH3_001
方法13:I_SA_20_MEOH_NH3_001
/>
方法14:I_SA_25_MEOH_NH3_001
中间体制备:
实施例1b
将S-吗啉-2,4-二甲酸4-叔丁酯(13.00g,56.4mmol)及6-甲基嘧啶-4,5-二胺(10g,含量70%;56.4mmol)溶解于EtOAc(200ml)中;使温度降低至0℃,随后逐滴添加TEA(19.65ml;140.97mmol),随后历经1小时逐滴添加1-丙烷膦酸(于EtOAc中的50%溶液;39.87ml;67.66mmol)。在处理之前在室温下搅拌反应混合物1.5小时:添加400ml DCM,随后添加100ml NaHCO3(5%水溶液);分离各相且经Na2SO4干燥有机相;使用混合物EtOAc/MeOH80/20通过急骤层析纯化蒸发溶剂之后获得的粗产物。获得5.78g所需化合物。
HPLC-MS;方法:Z011_S03;Rt[分钟]:0.76 | MS:338(M+H)+ |
手性SFC;方法:I_C4_20_MEOH_NH3_001; | Rt[分钟]:3.31分钟;e.e.100% |
实施例1c
将S-吗啉-2,4-二甲酸4-叔丁酯(25.0g,108mmol)溶解于THF(400ml)中。接着添加TBTU(38.2g,119mmol),随后添加嘧啶-4,5-二胺盐酸盐(15.9g,108mmol,CAS编号97846-32-7)及TEA(30.1ml,216mmol)。在处理之前在室温下搅拌反应混合物20小时:过滤反应混合物且在真空中浓缩滤液。用150mL H2O处理残余物且搅拌30分钟。将所获得的沉淀物滤出,用H2O洗涤且在烘箱中在55℃下干燥。
获得34.3g所需产物。
实施例1f
将嘧啶-4,5-二胺盐酸盐(5.00g,34.1mmol)及(S)-4-苄基-吗啉-2-甲酸(7.75g,35.0mmol)溶解于DMF(150ml)及DIPEA(15ml,87.8mmol)中。接着添加HATU(13.3g,35.0mmol)且在室温下搅拌反应混合物历经一个周末。处理:用25ml K2CO3溶液(2M水溶液)稀释反应混合物,经Alox B过滤且用DMF/MeOH的混合物洗涤。经由管柱层析法(洗脱剂:DCM/MeOH/NH3 9/1/0.1,体积/体积/体积)分离粗产物。获得8.81g所需产物。
实施例2b-方法A(根据流程1)
在80℃下搅拌实施例1b(4.30g,12.75mmol)、碳酸钾(1.76g,12.75mmol)及异丙醇(300ml)的混合物持续22小时。滤出沉淀物,用异丙醇洗涤且在真空中浓缩滤液。将残余物干燥隔夜。获得4.06g所需化合物,按原样用于下一步骤中。
实施例2b-方法B(根据流程2)
在90℃下加热实施例1b(4.14g;12.27mmol)及溴化锂(2.13g;24.5mmol)于1-丙醇(80ml)中的混合物历经14天。反应混合物吸附于硅胶上且通过急骤层析纯化;洗脱剂:EtOAc/MeOH/NH4OH(9/1/0.1至8/2/0.2;体积/体积/体积)。获得3g所需化合物。
实施例2c
在80℃下搅拌实施例1c(5.00g,15.5mmol)、碳酸钾(2.14g,15.5mmol)及异丙醇(50ml)的混合物持续35小时。滤出沉淀物,用异丙醇洗涤且在真空中浓缩滤液。将残余物干燥隔夜。获得5.00g所需产物。
实施例3b
将实施例2b(3.50g,11.0mmol)溶解于DCM(120ml)中,在冰冷却下逐滴添加含HCl的二噁烷(4M,13.7ml,55.0mmol)。将反应混合物在室温下搅拌2小时。在35℃下在真空中浓缩反应混合物。
获得3.20g所需化合物作为盐,其原样用于下一步骤中。
实施例3c
向实施例2c(9.40g,30.8mmol)于DCM(1200ml)中的混合物中逐滴添加含HCl的二噁烷(4M,35.0ml,140mmol)且在室温下搅拌反应混合物隔夜。在真空中蒸发溶剂且残余物与甲苯一起再蒸发2次。获得8.60g呈盐形式的所需产物。
实施例5a-方法C(根据流程3)
在120℃下搅拌实施例1f(8.80g,28.1mmol)、LiBr(3.50g,40.3mmol)、MeOH(100ml)及NMP(5ml)的混合物1.5天。
经由管柱层析法(DCM/MeOH/NH3 9/1/0.1;体积/体积/体积)随后通过制备型HPLC及最终手性SFC来分离粗产物。获得650mg所需产物。
实施例6a-方法C(根据流程3)
将实施例5a(650mg,2.20mmol)溶解于MeOH(30ml)中且添加Pd(OH)2(150mg)且在50℃及3巴(bar)H2压力下搅拌反应混合物3天。过滤反应混合物且在真空中浓缩滤液。
获得432mg所需产物。
例示性实施方案
实施例2
将(2,4-二氟苯基)甲醇(229μl;2.05mmol;CAS编号56456-47-4)、TEA(0.43ml,3.08mmol)及双[1,2,4]三唑-1-基-甲酮(337mg;2.05mmol)在DMF(6ml)中混合在一起;在50℃下加热反应混合物持续1小时。接着添加实施例3b(300mg;1.03mmol)且在50℃下搅拌反应混合物隔夜。在冷却下来之后,用MeOH稀释反应混合物,随后过滤且经由半制备型HPLC分离。获得52.5mg所需化合物。
实施例6
将(2-氟-4-甲基苯基)甲醇(864mg,6.16mmol;CAS编号252004-38-9)及双[1,2,4]三唑-1-基-甲酮(1.01g;6.16mmol)在DMF(18ml)中混合在一起;在50℃下加热反应混合物持续1小时。接着添加实施例3b(900mg;3.08mmol)及TEA(1.29ml,9.24mmol)且在50℃下搅拌反应混合物隔夜。在冷却下来之后,在真空中浓缩反应混合物。用H2O稀释残余物且用EtOAc萃取。经Na2SO4干燥有机层,过滤且在真空中浓缩。将粗产物溶解于THF中,随后过滤且经半制备型HPLC分离。获得180mg所需化合物,其含有16.5%R对映异构体;因此,对混合物进行手性SFC纯化,得到130mg所需S对映异构体。
实施例7
类似于实施例6来合成实施例7。起始材料:实施例3b(300mg,1.03mmol)及(2-氟苯基)甲醇(221μl,2.05mmol,CAS编号446-51-5)。经制备型HPLC纯化反应混合物。获得55.0mg所需化合物。
实施例8
将(2-氟-3-甲基苯基)甲醇(189mg;1.35mmol;CAS编号307975-03-7)、TEA(0.38ml,2.70mmol)及双[1,2,4]三唑-1-基-甲酮(295mg;1.80mmol)在DMF(6ml)中混合在一起;在50℃下加热反应混合物持续1小时。接着添加实施例3c(250mg;0.90mmol)且在50℃下搅拌反应混合物持续2小时。用4ml MeOH/水混合物稀释反应混合物,随后过滤且经半制备型HPLC分离。获得178mg所需化合物。
实施例9
类似于实施例2来合成实施例9。起始材料:实施例3c(250mg,0.90mmol)及(3-氟-2-甲基苯基)甲醇(252mg,1.80mmol,CAS编号500912-13-0)。经制备型HPLC纯化反应混合物。获得113mg所需化合物。
实施例10
类似于实施例6来合成实施例10。起始材料:实施例3c(350mg;1.44mmol)及(4-甲基苯基)甲醇353.8mg(2.88mmol)。获得230mg含有约20%R对映异构体的产物;因此经手性SFC分离混合物,得到143mg所需S对映异构体。
实施例11
类似于实施例2来合成实施例11。起始材料:实施例3b(250mg;0.86mmol)及(4-氟苯基)甲醇(187μl,1.71mmol,CAS编号459-56-3)。经制备型HPLC纯化反应混合物。获得43mg所需化合物。
实施例13
将(4-氟苯基)甲醇(194μl;1.80mmol;CAS编号459-56-3)、DIPEA(548μl,3.15mmol)及双[1,2,4]三唑-1-基-甲酮(295mg;1.80mmol)在DMF(5ml)中混合在一起;在50℃下加热反应混合物持续1小时。接着添加实施例3c(250mg;0.90mmol)且在50℃下搅拌反应混合物隔夜。在冷却下来之后,用H2O稀释反应混合物且用EtOAc萃取。经Na2SO4干燥有机层,过滤且在真空中移除溶剂。用DIPE湿磨残余物,过滤所得沉淀物,将其溶解于MeOH/DMF中且经半制备型HPLC分离。获得105mg所需化合物。
实施例14
类似于实施例2来合成实施例14。起始材料:实施例3c(250mg;0.90mmol)及(2,4-二氟苯基)甲醇(0.20mL,1.80mmol,CAS编号56456-47-4)。经制备型HPLC纯化反应混合物。获得154mg所需化合物。
实施例16
类似于实施例2来合成实施例16。起始材料:实施例3c(200mg;0.72mmol)及(3-氟苯基)甲醇(156μl,1.44mmol,CAS编号456-47-3)。经制备型HPLC纯化反应混合物。获得131mg所需化合物。
实施例17
将(2-氟苯基)甲醇(155μl;1.44mmol;CAS编号446-51-5)、DIPEA(438μl,2.52mmol)及双[1,2,4]三唑-1-基-甲酮(236mg;1.44mmol)在DMF(5ml)中混合在一起;在50℃下加热反应混合物持续1.5小时。接着添加实施例3c(200mg;0.72mmol)且在50℃下搅拌反应混合物隔夜。在冷却下来之后,用H2O稀释反应混合物且用EtOAc萃取。经Na2SO4干燥有机层,过滤且在真空中移除溶剂。将残余物溶解于MeOH中,过滤且经半制备型HPLC分离。获得98.3mg所需化合物。
实施例18
将(2,3-二氟苯基)甲醇(162μl;1.44mmol;CAS编号75853-18-8)、DIPEA(438μl,2.52mmol)及双[1,2,4]三唑-1-基-甲酮(236mg;1.44mmol)在DMF(5ml)中混合在一起;在50℃下加热反应混合物持续1.5小时。接着添加实施例3c(200mg;0.72mmol)且在50℃下搅拌反应混合物隔夜。在真空中移除有机溶剂。用H2O稀释残余物且滤出所获得的沉淀物。用DIPE湿磨沉淀物2次,滤出且干燥。获得138mg所需化合物。
实施例19
将(2,6-二氟苯基)甲醇(159μl;1.44mmol;CAS编号19064-18-7)、DIPEA(438μl,2.52mmol)及双[1,2,4]三唑-1-基-甲酮(236mg;1.44mmol)在DMF(5ml)中混合在一起;在50℃下加热反应混合物持续1.5小时。接着添加实施例3c(200mg;0.72mmol)且在50℃下搅拌反应混合物隔夜。用H2O稀释残余物且在室温下搅拌隔夜。在真空中移除溶剂。用H2O稀释残余物,滤出所获得的沉淀物且干燥。获得68.9mg所需化合物。
实施例20
将(4-氟-2-甲基苯基)甲醇(202mg;1.44mmol;CAS编号80141-91-9)、DIPEA(0.38ml,2.16mmol)及双[1,2,4]三唑-1-基-甲酮(236mg;1.44mmol)在DMF(6ml)中混合在一起;在50℃下加热反应混合物持续1小时。接着添加实施例3c(200mg;0.72mmol)且在50℃下搅拌反应混合物隔夜。在冷却下来之后,用H2O/MeOH稀释反应混合物,随后过滤且经半制备型HPLC分离。获得86.0mg所需化合物。
实施例21
类似于实施例8来合成实施例21。起始材料:实施例3b(250mg;0.86mmol)及(4-甲基苯基)甲醇(209mg,1.71mmol,CAS编号589-18-4)。经制备型HPLC纯化反应混合物。获得50.0mg所需化合物。
实施例24
将[4-(二氟甲基)苯基]甲醇(24.0mg,0.15mmol;CAS编号444915-77-9)及CDI(23.0mg;0.14mmol)在DMF(0.5ml)中混合在一起;在40℃下加热反应混合物持续45分钟。接着依序添加实施例3c(24.0mg;0.10mmol)、DIPEA(17.0μl;0.10mmol)及DMF(0.5ml),且在40℃下搅拌反应混合物隔夜。用ACN/H2O/MeOH稀释反应混合物,过滤且经半制备型HPLC分离。获得20.9mg所需化合物。
实施例25
类似于实施例24来合成实施例25。起始材料:实施例3c(24.0mg;0.10mmol)及(4-氯苯基)甲醇(21.0mL,0.15mmol,CAS编号873-76-7)。经制备型HPLC纯化反应混合物。获得16.8mg所需化合物。
实施例26
将实施例3c(25.0mg;0.10mmol)及DIPEA(20.0μl,0.12mmol)溶解于二噁烷(1ml)中,接着在冰冷却下逐滴添加氯甲酸苯甲酯(40.0μl,0.12mmol,含量50%,CAS编号501-53-1),且在室温下搅拌反应混合物隔夜。
在真空中浓缩反应混合物,将其溶解于DMF中且经制备型HPLC纯化。获得14.0mg所需化合物。
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实施例28
将(2-氯苯基)甲醇(21.4mg,0.15mmol;CAS编号17849-38-6)及CDI(0.14mmol)在DMF(1ml)中混合在一起;在室温下搅拌反应混合物持续1.5小时。接着添加溶解于DMF(1ml)中的实施例6a(20.5mg,0.10mmol),且在室温下搅拌反应混合物隔夜。经半制备型HPLC分离反应混合物。获得7.1mg所需化合物。
实施例29
类似于实施例28来合成实施例29。起始材料:实施例6a(20.5mg;0.10mmol)及(3-甲基苯基)甲醇(18.3mg,0.15mmol,CAS编号587-03-1)。经制备型HPLC纯化反应混合物。获得3.4mg所需化合物。
实施例30
类似于实施例28来合成实施例30。起始材料:实施例6a(20.5mg;0.10mmol)及(4-氯-3-氟苯基)甲醇(24.1mg,0.15mmol,CAS编号202925-10-8)。经制备型HPLC纯化反应混合物。获得8.2mg所需化合物。
实施例31
类似于实施例28来合成实施例31。起始材料:实施例6a(20.5mg;0.10mmol)及(3,4-二氟苯基)甲醇(21.6mg,0.15mmol,CAS编号85118-05-4)。经制备型HPLC纯化反应混合物。获得5.4mg所需化合物。
实施例32
类似于实施例28来合成实施例32。起始材料:实施例6a(20.5mg;0.10mmol)及(2-氯-4-氟苯基)甲醇(24.1mg,0.15mmol,CAS编号208186-84-9)。经制备型HPLC纯化反应混合物。获得8.1mg所需化合物。
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实施例34
类似于实施例28来合成实施例34。起始材料:实施例6a(20.5mg;0.10mmol)及(3-氟-4-甲基苯基)甲醇(21.0mg,0.15mmol,CAS编号192702-79-7)。经制备型HPLC纯化反应混合物。获得6.2mg所需化合物。
实施例36
类似于实施例28来合成实施例36。起始材料:实施例6a(20.5mg;0.10mmol)及(2-氟-4-甲基苯基)甲醇(21.0mg,0.15mmol,CAS编号252004-38-9)。经制备型HPLC纯化反应混合物。获得6.0mg所需化合物。
实施例37
类似于实施例28来合成实施例37。起始材料:实施例6a(20.5mg;0.10mmol)及(2-氟-6-甲基苯基)甲醇(21.0mg,0.15mmol,CAS编号478163-35-8)。经制备型HPLC纯化反应混合物。获得5.7mg所需化合物。
实施例38
类似于实施例28来合成实施例38。起始材料:实施例6a(20.5mg;0.10mmol)及(2,4,6-三氟苯基)甲醇(24.3mg,0.15mmol,CAS编号118289-07-9)。经制备型HPLC纯化反应混合物。获得9.1mg所需化合物。
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Claims (15)
1.一种式A化合物
其中
R1表示任选经1、2或3个选自由以下组成的群的取代基取代的苯基:氟、氯、甲基、乙基、环丙基、F2HC-、FH2C-、F3C-;
R2表示氢或甲基。
2.如权利要求1的化合物,其中
R2表示氢。
3.如权利要求1的化合物,其中
R2表示甲基。
4.如权利要求1至3中任一项的化合物,其中
R1表示任选经1、2或3个选自由以下组成的群的取代基取代的苯基:氟、氯、甲基、F2HC-。
5.如权利要求1至4中任一项的化合物,其中
R1表示
6.如权利要求1至5中任一项的化合物,其是一种(S)-对映体,即选自由以下组成的群的化合物:
7.一种如权利要求1至6中任一项的化合物的药物学上可接受的盐。
8.如权利要求1至6中任一项的化合物或权利要求7的药物学上可接受的盐在用于制备NR2B负向立体异位调节剂中的用途。
9.如权利要求1至6中任一项的化合物或权利要求7的药物学上可接受的盐在制备用于治疗及/或预防以下的疾病的药物中的用途:I型躁郁症;II型躁郁症;抑郁症。
10.根据权利要求9所述的用途,其中所述I型躁郁症为抑郁、轻躁狂、躁狂或混合形式。
11.根据权利要求9所述的用途,其中所述抑郁症选自重度抑郁症,其伴有或不伴有焦虑窘迫、混合特征、忧郁型特征、非典型特征、情绪一致型精神病特征、情绪不一致型精神病性特征或紧张症。
12.根据权利要求9所述的用途,其中所述抑郁症选自由单次抑郁发作或复发性重度抑郁症、轻微抑郁症、产后发作的抑郁症、具有精神病症状的抑郁症组成的群。
13.如权利要求8至12中任一项用途,其特征在于投与如权利要求1至6中任一项的化合物或权利要求7的药物学上可接受的盐,此外还投与另一抗抑郁药物治疗。
14.如权利要求8至12中任一项的用途,其特征在于投与如权利要求1至6中任一项的化合物或权利要求7的药物学上可接受的盐,此外还给予行为疗法。
15.一种药物组合物,其包含如权利要求1至6中任一项的化合物或权利要求7的药物学上可接受的盐与药物学上可接受的佐剂、稀释剂及/或载剂混合。
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