CN111132975B - N-(2,2-二氟乙基)-n-[(嘧啶基氨基)丙基]芳基甲酰胺 - Google Patents
N-(2,2-二氟乙基)-n-[(嘧啶基氨基)丙基]芳基甲酰胺 Download PDFInfo
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- CN111132975B CN111132975B CN201880061775.6A CN201880061775A CN111132975B CN 111132975 B CN111132975 B CN 111132975B CN 201880061775 A CN201880061775 A CN 201880061775A CN 111132975 B CN111132975 B CN 111132975B
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Abstract
本发明涉及新型N‑(2,2‑二氟乙基)‑N‑[(嘧啶基氨基)丙基]‑芳基甲酰胺衍生物、用于制备它们的方法、包含它们的药物组合物以及它们在治疗中的用途，特别是在治疗或预防与食欲肽亚型1受体相关的病况中的用途。
Description
技术领域
本发明涉及N-(2,2-二氟乙基)-N-[(嘧啶基氨基)丙基]芳基甲酰胺衍生物、用于制备它们的方法、包含它们的药物组合物以及它们在治疗中的用途，特别是在治疗或预防与食欲肽亚型1受体相关的病况中的用途。
背景技术
食欲肽是下丘脑神经肽，其在调节许多生理行为如唤醒、觉醒、食欲、食物摄入、认知、动机行为、奖赏、情绪和压力中起重要作用。食欲肽A，也称为下丘泌素1，是由33个氨基酸组成的肽，而食欲肽B，也称为下丘泌素2，是由28个氨基酸组成的肽。两者均衍生自称为前食欲肽原的常见前体肽(Sakurai等人，Cell，1998Feb 20；92(4):573-85，和De Lecea等人，Proc.Nat.Acad.Sci.，1998Jan 6；95(1):322-7)。食欲肽结合两个孤儿G蛋白偶联受体，即食欲肽受体1型(OX1R)和食欲肽受体2型(OX2R)，它们广泛分布于中枢神经系统和周围器官，例如肾上腺、性腺和肠道。食欲肽A主要与OX1R结合，而食欲肽B能够与OX1R和OX2R结合。
食欲肽参与多种行为的调节，包括例如情绪和奖赏、认知、冲动控制的调节，自主神经内分泌功能、唤醒、警醒和睡眠-觉醒状态的调节(Muschamp等人，Proc.Natl.Acad.Sci.USA 2014Apr 22；111(16):E1648-55；有关最新综述，请参见Sakurai，Nat.Rev.Neurosci.，2014；Nov；15(11):719-31；Chen等人，Med.Res.Rev.，2015；Jan；35(1):152-97；Gotter等人，Pharmacol.Rev.，2012，64:389-420等)。
小分子对OX1R和OX2R的双重拮抗作用在治疗失眠方面具有临床疗效，为此，药物苏沃雷生[[(7R)-4-(5-氯-1,3-苯并噁唑-2-基)-7-甲基-1,4-二氮杂环庚烷-1-基][5-甲基-2-(2H-1,2,3-三唑-2-基)苯基]甲酮]已获准销售(Kishi等人，PLoS One，2015；10(8):e0136910)。双重食欲肽受体拮抗剂的睡眠诱导作用主要通过OX2R介导(Bonaventure等人，J.Pharmacol.Exp.Ther.，March 2015，352，3，590-601)，而其它生理状态如情绪和奖赏、认知、冲动控制，自主神经内分泌功能、唤醒和警醒的调节则通过OX1R介导。
由于其诱导睡眠的作用，OX1R和OX2R双重拮抗剂不适用于治疗与冲动控制缺陷相关的病症，例如在成瘾症(如物质使用障碍)、人格障碍(如边缘型人格障碍)、进食障碍(如暴食症)或注意力缺陷多动障碍中所见的病症。因此，期望提供一种OX1R选择性拮抗剂用于治疗冲动控制缺陷。
多种结构类型的食欲肽受体拮抗剂综述于Roecker等人(J.Med.Chem.2015，59，504-530)。WO03/051872、WO2013/187466、WO2016/034882、WO2017/129829和Bioorganic&Medicinal Chemistry 2015，23，1260-1275描述食欲肽受体拮抗剂。
具体实施方式
本发明提供N-(2,2-二氟乙基)-N-[(嘧啶基氨基)丙基]芳基甲酰胺衍生物，其出乎意料的是强效的OX1R拮抗剂(测定A)，其进一步特征在于
1)相对于OX2受体的选择性高(测定B)，
2)在人肝微粒体中具有中等至高度的稳定性(测定C)，以及
3)无或低MDCK(Madin-Darby犬肾)外排(测定D)。
就以下关键药效和药代动力学参数的组合而言，本发明的化合物优于现有技术中公开的化合物：
1)作为OX1R拮抗剂的功效，
2)相对于OX2受体的选择性，
3)人肝微粒体中的稳定性，
4)MDCK外排，以及
5)分布容量。
人肝微粒体中的稳定性是指在选择和/或设计具有良好药代动力学性质的药物时，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。人肝微粒体包含细胞色素P450(CYP)，因此代表了用于研究体外药物代谢的模型系统。人肝微粒体中的稳定性增强与多个优点相关，包括增加的生物利用度和更长的半衰期，这可使患者给药的频率越来越低。因此，人肝微粒体的增强的稳定性是用于药物的化合物的有利特性。
MDCK测定提供有关化合物通过血脑屏障的潜力的信息。生长在可渗透滤膜支持物上的极化、汇合的MDCK-MDR1细胞单层跨膜的渗透性测量用作体外吸收模型：沿顶部至底部(AB)和底部至顶部(BA)的运输方向，测量跨MDCK-MDR1细胞单层的化合物的表观渗透系数(PE)(pH 7.4、37℃)。AB渗透性(PEAB)表示药物从血液吸收到脑中，而BA渗透性(PEBA)药物通过被动渗透性以及由外排和摄取转运蛋白(在MDCK-MDR1细胞上表达，主要是由过度表达的人MDR1 P-gp表达)介导的主动转运机制从脑回流到血液中。在两个运输方向上相同或相似的渗透性表示被动渗透，矢量渗透性指向其它主动运输机制。PEBA高于PEAB(PEBA/PEAB>5)表明MDR1 P-gp介导的主动外排参与，这可能会损害实现足够的脑暴露的目标。因此，该测定为选择适用于进一步体内测试的化合物提供了有价值的支持。高渗透性不受血脑屏障外流的限制，这是对主要用于中枢神经系统(CNS)药物的化合物的有利特性。
本发明的化合物与WO2016/034882中的实施例84和91(最接近现有技术的化合物)结构上的不同在于，它们含有中心的N-(2,2-二氟乙基)-(丙-2-基)氨基部分以代替N-甲基-[丁-2-基]氨基部分。这些结构差异出乎意料地导致了以下关键药效学和药代动力学参数的优异组合：
1)作为OX1R拮抗剂的效力，
2)相对于OX2受体的选择性，
3)人肝微粒体中的稳定性，
4)MDCK外排，以及
5)分布容量。
由于本发明的化合物在OX1R上的高效力以及相对于OX2R的选择性，因此预期在体内模型中均为有效的，并且在功效和不良作用(如嗜睡或睡眠)之间具有足够的窗口。
由于关键药效学和药代动力学参数(#1-5)的优异组合，预期本发明的化合物表现出足够的脑暴露能力，并具有中等至低的体内清除率，从而具有更长的作用时间和更高的耐受性。因此，本发明的化合物必然更适合人类使用。
一般定义
根据本文的公开内容和上下文，应当给本文未特别定义的术语赋予本领域技术人员将赋予它们的含义。
立体化学：
除非特别指出，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其互变异构体以及所有的立体、光学和几何异构体(例如对映异构体、非对映异构体、E/Z异构体等)及外消旋体，以及以不同比例的单独的对映异构体的混合物、非对映异构体的混合物或存在上述异构体和对映异构体的任何前述形式的混合物以及其盐，包括其药学上可接受的盐。
盐：
本文所用短语“药学上可接受的”是指在合理的医学判断范围内适合与人类和动物组织接触使用的并且没有过度的毒性、刺激、过敏反应或其它问题或并发症、且具有合理的获益/风险比的那些化合物、材料、组合物和/或剂型。
如本文所用，“药学上可接受的盐”是指所公开化合物的衍生物，其中母体化合物与酸形成盐。与含有碱性部分的母体化合物形成药学上可接受盐的酸的实例包括无机酸或有机酸，例如苯磺酸、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。
本发明的药学上可接受的盐可通过常规化学方法由含有碱性或酸性部分的母体化合物合成。通常，可通过使这些化合物的游离酸或碱形式与足量的适当碱或酸在水中或在有机稀释剂例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈或其混合物中反应来制备此类盐。
除了上述提及的那些以外的其它酸的盐，例如可用于提纯或分离本发明的化合物的盐(例如三氟乙酸盐)也构成了本发明的一部分。
生物测定
缩写：
IP1 D-肌醇-1-磷酸酯
IP3 D-肌醇-1,4,5-三磷酸酯
HEPES 4-(2-羟基乙基)-1-哌嗪乙磺酸
HBSS 汉克斯平衡盐溶液
BSA 牛血清白蛋白
DMSO 二甲基亚砜
CHO 中国仓鼠卵巢
细胞系中表达的食欲肽受体的激活导致细胞内IP3浓度增加。IP1是IP3的下游代谢产物，在受体激活后会积聚在细胞中，并且在LiCl存在下稳定。将均相时间分辨荧光技术与Lumi4-Tb穴状化合物(可从Cisbio Bioassay商购)以及适合的荧光板读取器一起使用。如Trinquet等人Anal.Biochem.2006，358，126-135，Degorce等人Curr.Chem.Genomics2009，3，22-32所述，该功能性反应是可检测和可量化的。该技术用于表征食欲肽受体的药理修饰。
通过以下方法确定化合物的生物活性：
A.OX1R效力的体外测试：OX1R IP1
IP1测量在稳定表达全长人食欲肽1受体和水母发光蛋白的CHO-K1细胞中进行。将细胞在含有10％胎牛血清的Ham营养混合物F12培养基中、在37℃、95％湿度和5％CO2孵育箱中培养。CHO-K1/hOx1细胞量扩大到更大的细胞数量。这些细胞以冷冻小瓶中的冷冻细胞形式获得，并在-150℃保存直至使用。解冻后细胞的成活力>90％。在准备测定中，测定前24小时，将细胞在37℃解冻，并立即用细胞培养基稀释。离心后，将细胞沉淀重新悬浮于培养基中，然后以每孔10000细胞/25μL的密度分布到测定板中。将板在室温孵育1小时以减少边缘效应，然后在37℃/5％CO2孵育24小时。化合物是通过在DMSO中进行8点连续稀释并在测定缓冲液(含20mM HEPES、0.1％BSA和50mM LiCl的HBSS，pH 7.4)中进行最终稀释步骤来制备的，以确保在测定中DMSO的最终浓度为1％。在测定当天，用60μL测定缓冲液将板中的细胞洗涤两次(洗涤后孔中保留20μL缓冲液)，然后添加在测定缓冲液中稀释的5μL/孔的化合物。在室温孵育15分钟后，将溶解在测定缓冲液中的食欲肽A肽(最终浓度：0.5nM和/或50nM)5μL/孔溶解于测定板中。将测定板在37℃孵育60分钟。然后添加5μl/孔的抗IP1-穴状化合物Tb溶液以及添加5μl/孔的IP1-d2稀释液，并将板在室温避光孵育另外60分钟。使用EnVision读取器(PerkinElmer)测量615nm和665nm(激发波长：320nm)处的发射。读取器计算出665nm和615处之间的发射比率。
8点四参数非线性曲线拟合和IC50值和Hill斜率的确定是使用常规分析软件例如AssayExplorer(Accelrys)进行的。为了建立激动剂浓度独立性参数，可使用以下公式计算Kb值：IC50/((2+(A/EC50)n)1/n-1)(其中A＝浓度激动剂，EC50＝EC50激动剂，n＝Hill斜率激动剂)(参见P.Leff，I.G.Dougall，Trends Pharmacol.Sci.1993，14(4),110-112)。
B.OX2R效力的体外测试：OX2R IP1
IP1测量在稳定表达全长人食欲肽2受体和水母发光蛋白的CHO-K1细胞中进行。将细胞在含有10％胎牛血清的Ham营养混合物F12培养基中、在37℃、95％湿度和5％CO2孵育箱中培养。CHO-K1/hOx2细胞量扩大到更大的细胞数量。这些细胞以冷冻小瓶中的冷冻细胞形式获得，并在-150℃保存直至使用。解冻后细胞的成活力>90％。在准备测定中，测定前24小时，将细胞在37℃解冻，并立即用细胞培养基稀释。离心后，将细胞沉淀重新悬浮于培养基中，然后以每孔5000个细胞/25μL的密度分布到测定板中。将板在室温孵育1小时以减少边缘效应，然后将它们在37℃/5％CO2孵育24小时。化合物是通过在DMSO中进行8点连续稀释并在测定缓冲液(含20mM HEPES、0.1％BSA和50mM LiCl的HBSS，pH 7.4)中进行最终稀释步骤来制备的，以确保在测定中DMSO的最终浓度为1％。
在测定当天，用60μL测定缓冲液将板中的细胞洗涤两次(洗涤后孔中保留20μL缓冲液)，然后添加5μl/孔在测定缓冲液中稀释的化合物。在室温孵育15分钟后，将溶解在测定缓冲液中的食欲肽A肽(最终浓度：0.5nM)以每孔5μL溶解于测定板中。将测定板在37℃孵育60分钟。然后向板中添加5μl/孔的抗IP1-穴状化合物Tb溶液以及添加5μl/孔的IP1-d2稀释液，并将板在室温避光孵育60分钟。使用EnVision读取器(PerkinElmer)测量615nm和665nm(激发波长：320nm)处的发射。由读取器计算出665nm和615处之间的发射比率。
8点四参数非线性曲线拟合和IC50值和Hill斜率的确定是使用常规分析软件进行的，例如AssayExplorer(Accelrys)。为了建立激动剂浓度独立性参数，可使用以下公式计算Kb值：IC50/((2+(A/EC50)n)1/n-1)(其中A＝浓度激动剂，EC50＝EC50激动剂，n＝Hill斜率激动剂)(参见P.Leff，I.G.Dougall，Trends Pharmacol.Sci.1993，14(4),110-112)。
然后，测定A(OX1R)和测定B(OX2R)的Kb值可以提供与激动剂(食欲肽A)浓度无关的选择性比率。
C.人肝微粒体(人类MST)的代谢稳定性评估
根据本发明所述的化合物的代谢稳定性可如下进行研究：
在37℃，用合并的人肝微粒体测定试验化合物的代谢降解。每个时间点的最终孵育体积为100μL，其包含室温pH 7.6的TRIS缓冲液(0.1M)、MgCl2(5mM)、微粒体蛋白(1mg/mL)和最终浓度为1μM的测试化合物。在37℃短暂的预温育期后，通过添加β-烟酰胺腺嘌呤二核苷酸磷酸盐(还原形式(NADPH，1mM))引发反应，并在不同时间点将等分试样转移至溶剂中终止反应。离心(10000g，5分钟)后，通过LC-MS/MS分析上清液的等分试样中母体化合物的量。半衰期(t1/2)由浓度-时间曲线的半对数图的斜率确定。
D.评估人MDR1基因转染的Madin-Darby犬肾(MDCK)细胞的外排
测量了化合物沿MDCK-MDR1细胞单层在顶部至底部(AB)和底部至顶部(BA)的运输方向的表观渗透性系数(PE)(pH 7.4，37℃)。AB渗透性(PEAB)表示药物从血液吸收到大脑中，而BA渗透性(PEBA)药物通过被动渗透性以及由外排和摄取转运蛋白(在MDCK-MDR1细胞上表达，主要是由过度表达的人MDR1 P-gp表达)介导的主动转运机制从脑中回流到血液。通过将AB渗透性与参考化合物(在人体内具有已知的体外渗透性和口服吸收性)的AB渗透性进行比较，将这些化合物划分为渗透性/吸收性类别。在两个传输方向上相同或相似的渗透率表示被动渗透，矢量渗透性指向其它主动传输机制。高于PEAB的PEBA表示参与MDR1 P-gp介导的主动外排。主动转运是浓度依赖性可饱和的。
将MDCK-MDR1细胞(1-2x 10e5细胞/1cm2面积)接种在滤芯(Costar Transwell聚碳酸酯或PET滤芯，孔径0.4μm)上，并培养(DMEM)7天。随后，通过在完全培养基中与5mM丁酸钠一起培养细胞2天来增强MDR1表达。将化合物溶解在适当的溶剂(例如DMSO，1 -20mM储备溶液)中。用HTP-4缓冲液(128.13mM NaCl、5.36mM KCl、1mM MgSO4、1.8mM CaCl2、4.17mMNaHCO3、1.19mM Na2HPO4 x 7H2O、0.41mM NaH2PO4xH2O、15mM HEPES、20mM葡萄糖、0.25％BSA，pH 7.4)稀释储备溶液，以制备转运溶液(0.1-300μM化合物，最终DMSO<＝0.5％)。将转运溶液(TL)应用于顶端或基底外侧供体侧，分别测量A-B或B-A的渗透性(3个过滤器重复)。接收方包含与供体相同的缓冲液。在实验开始和结束时，从供体处以及在不同的时间间隔(最多2小时)也从接收方收集样品，以通过HPLC-MS/MS或闪烁计数进行浓度测量。采样的接收器体积将替换为新的接收器溶液。
生物学数据
表1：WO2016/034882中在结构上最接近的现有技术化合物(实施例91和84)的体外效力，如其中所报道：
本发明的化合物
表1中分别显示所有本发明的化合物与WO2016/034882中相应的最接近的现有技术化合物的关键生物学特性(包括OX1R和OX2R效力、在人肝微粒体中的稳定性和MDCK外排)的完整和详细比较。
表2.本发明的化合物与WO2016/034882中最接近的现有技术化合物的生物学数据的比较
本发明的实施例1和2与WO2016/034882中的实施例91即最接近的现有技术化合物在结构上的不同在于它含有中心N-(2,2-二氟乙基)-(丙-2-基)氨基部分以替代N-甲基-[丁-2-基]氨基部分。此外，实施例1在苯环上包含两个具有不同取代模式的氟原子，而实施例2在苯环上包含一个在不同位置上的氟原子。与WO2016/034882中的实施例91相比，这些结构差异出乎意料地导致实施例1和2对OX1R更有效并更具选择性，在人肝微粒体中具有相当的代谢稳定性和MDCK外排。
本发明的实施例3、4和5与WO2016/034882中的实施例84即最接近的现有技术化合物在结构上的不同在于它们含有中心N-(2,2-二氟乙基)-(丙-2-基)氨基部分以替代N-甲基-[丁-2-基]氨基部分。此外，它们包含以不同方式被氟原子取代的苯环而不是被甲基取代的吡啶环。与WO2016/034882中的实施例84相比，这些结构差异出乎意料地导致实施例3、4和5表现出更高的效力和提高的选择性，以及在人肝微粒体中显著更好的稳定性和相当的MDCK外排。
这些结果表明，与WO2016/034882中公开的结构最相似的实施例(最接近的现有技术化合物)分别相比，本发明的化合物出乎意料地为更有效的OX1R拮抗剂，其具有相当或更高的微粒体稳定性，并对OX2受体更具选择性。
在使用治疗/方法中的用途
本发明涉及用于治疗其中OX1R的拮抗作用具有治疗益处的疾病、病症和病状的化合物，包括但不限于与冲动控制缺陷有关的精神和神经病况的治疗和/或预防。这种冲动控制缺陷见于包括以下在内的成瘾中：物质使用障碍；人格障碍，如边缘人格障碍；饮食障碍，例如暴饮暴食障碍；或注意力缺乏多动症。根据本发明的另一方面，本发明的化合物可用于治疗在唤醒/清醒、食欲/食物摄入、认知、动机行为/奖赏、情绪和压力方面与OX1R相关的病理生理失调。
考虑其药理作用，本发明的化合物适合用于治疗选自以下列表的疾病或病况：
(1)治疗或预防物质滥用/依赖性/寻求或成瘾以及预防复发(包括但不限于药物，例如可卡因、阿片类药物(吗啡、巴比妥酸盐、苯二氮
类、安非他命、尼古丁/烟草和其它精神刺激药))、酗酒和与酒精有关的病症、药物滥用或成瘾或复发、对麻醉品的耐受性或戒除麻醉品，
(2)饮食障碍，例如暴饮暴食，神经性暴食症、神经性厌食症、其它特定的进食或饮食障碍、肥胖症、超重、恶病质、食欲/味觉失调、呕吐、恶心、普拉德-威利综合征(Prader-Willi-Syndrome)、食欲亢进、食欲/味觉失调，
(3)注意力缺陷多动症、行为障碍、注意力问题及相关障碍、睡眠障碍、焦虑症(如广泛性焦虑症)、恐慌症、恐惧症、创伤后应激障碍、精神分裂症、阿尔茨海默氏病、帕金森氏病、亨廷顿病和多发性抽动与秽语综合征(Gilles de la Tourette’s syndrome)、多动腿综合征、痴呆、运动障碍、严重智力低下、神经退行性疾病，包括诸如去抑制-痴呆-帕金森-肌萎缩复合体、苍白球-脑桥-黑质变性的疾病学实体，
(4)精神或神经病症中的认知功能障碍、与精神分裂症相关的认知损伤、阿尔茨海默病以及其它神经和精神病症，
(5)情绪障碍、双相障碍、躁狂症、抑郁症、躁狂抑郁症、交际型人格障碍、反社会人格障碍、侵略性(例如冲动攻击性、自杀性)、额颞痴呆、强迫症、谵妄、情感神经症/病症、抑郁性神经症/病症、焦虑神经症、运动障碍，
(6)性障碍、性功能障碍、性心理障碍，
(7)冲动控制病症，例如病理性赌博、拔毛发癖、间歇性暴发障碍、盗窃癖、纵火癖、强迫性购物、网络成瘾、性强迫，
(8)睡眠障碍，例如发作性睡病、时差、睡眠呼吸暂停、失眠、异睡症、生物学和昼夜节律紊乱、与精神和神经病症有关的睡眠障碍，
(9)在任何精神病和/或神经病学情况下对冲动和/或冲动控制缺陷和/或行为抑制解除的治疗、预防和复发控制，
(10)人格障碍，例如交际型人格障碍、反社会人格障碍、偏执型人格障碍、精神分裂症和分裂型人格障碍、组织型人格障碍、自恋型人格障碍、回避型人格障碍、依赖型人格障碍、其它特定和未指定的人格障碍
(11)神经系统疾病，例如脑水肿和血管性水肿、脑痴呆，例如帕金森氏病和阿尔茨海默病、老年痴呆；多发性硬化症、癫痫、颞叶癫痫、耐药性癫痫、癫痫发作、中风、重症肌无力、脑和脑膜感染，如脑脊髓炎、脑膜炎，HIV以及精神分裂症、妄想症、自闭症、情感障碍和抽动症。
本发明的化合物的适用日剂量可以在0.1至2000mg之间变化。
实际的药物有效量或治疗剂量将取决于本领域技术人员已知的因素，例如患者的年龄和体重、给药途径和疾病的严重程度。在任何情况下，药物的剂量和方式均应以使药物有效量适合患者的病情给药。
药物组合物
用于给药本发明化合物的适合制剂对本领域普通技术人员将是明显的，包括例如片剂、丸剂、胶囊剂、栓剂、锭剂、糖锭剂、溶液剂，糖浆剂、酏剂、药囊、注射剂、吸入剂、粉剂等，药物活性化合物的含量可以在整个组合物的0.1至95重量％，优选5.0至90重量％的范围内变化。
例如，适合的片剂可通过将本发明的化合物与已知的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/或润滑剂混合并将所得混合物压制成片剂而获得。
组合疗法
可将根据本发明的化合物与本领域已知的其它治疗选项、同时与本发明所关注的任何治疗适应症的治疗结合使用。
被认为适合与本发明的治疗组合的治疗选项包括：
-抗抑郁药
-情绪稳定剂
-抗精神病药
-抗焦虑药
-镇痫剂
-睡眠剂
-认知增强剂
-兴奋剂
-用于注意力缺陷多动症的非刺激性药物
-其它精神活性药物。
实验部分
缩写列表
RT 室温
ESI-MS 电喷雾电离质谱
aq. 水性
MS 质谱
MeOH 甲醇
PE 石油醚
EA 乙酸乙酯
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
DCM 二氯甲烷
DMA N,N-二甲基乙酰胺
TEA 三乙胺
THF 四氢呋喃
TBME 叔丁基甲基醚
DIPEA N,N-二异丙基乙胺
DIAD 偶氮二羧酸二异丙基酯
CIP 2-氯-4,5-二氢-1,3-二甲基-1H-咪唑鎓六氟磷酸盐
Rt 保留时间
h 小时
min 分钟
ACN 乙腈
TFA 三氟乙酸
M 摩尔浓度
N 当量浓度
HPLC 高效液相色谱
NMP N-甲基-2-吡咯烷酮
TLC 薄层色谱
HPLC-方法：
方法名称：A
柱：BEH C18 1.7μm2.1x 50mm
柱供应商：Waters
方法名称：B
柱：Xselect CSH，2.5μm，4.6x 50mm
柱供应商：Waters
方法名称：C
柱：Xselect CSH Phenyl-Hexyl，4.6x 50mm，2.5μm，柱供应商：Waters
方法名称：D
柱：Venusil，2.1x 50mm，5μm
柱供应商：Agilent Technoligies
方法名称：E
柱：Venusil，2.1x 50mm，5μm
柱供应商：Agilent Technoligies
制备中间体
酸性中间体
2-氟-6-嘧啶-2-基-苯甲酸A-4
类似于上述程序制备A-4。ESI-MS:219[M+H]+；HPLC(Rt)：0.93min(方法E)。
5-氟-2-嘧啶-2-基-苯甲酸A-5：
步骤1：在氮气气氛下，将A-5.1(20.0g，81.5mmol)、A-5.2(25.0g，93.5mmol)，PdCl2(dppf)(3.7g，4.3mmol)和KOAc(32.8g，317.4mmol)在二噁烷中的混合物在100℃搅拌2小时。通过硅藻土过滤反应混合物，并用EA萃取。将有机相用H2O洗涤，干燥并蒸发。粗产物在硅胶上通过快速柱色谱提纯(使用环己烷/EA 100/0至80/20)，得到22g的A-5.3。TLC(Rf)：0.3(硅胶；环己烷/EA 9/1)。
步骤2：在氮气气氛下，将A-5.3(12.0g，38.6mmol)、A-5.4(5.4g，46.3mmol)、PdCl2(dppf)(1.37g，1.66mmol)和Na2CO3(13.3g，124.4mmol)在2-甲基-THF和H2O的混合物中的混合物在80℃搅拌过夜。将反应混合物用TBME和H2O处理，并通过硅藻土过滤。分离有机相，干燥并蒸发。粗产物在硅胶上通过快速柱色谱提纯(使用PE/EA 3/1)，得到7.0g的A-5.5。TLC(Rf)：0.3(硅胶；环己烷/EA 6/4)。
步骤3：向A-5.5(3.5g，16.6mmol)在2-甲基-THF与H2O的3:1混合物(50mL)中的混合物中添加NaOH(1.5g，36.6mmol)并在70℃搅拌2小时。分离有机相并用TBME萃取水相。将水相用HCl(36％水溶液)酸化至pH 1并滤去沉淀物。粗产物在硅胶上通过快速柱色谱提纯(使用DCM/MeOH 20/1)，得到2.1g的A-5。ESI-MS:219[M+H]+；HPLC(Rt):3.42min(方法D)。
合成胺中间体
N-((S)-2-氨基-1-甲基-乙基)-N-(2,2-二氟乙基)-3-氟-2-嘧啶-2-基-苯甲酰胺B-1：
步骤1：在搅拌下，将TEA(11.1mL；79.9mmol)的无水DCM(15.0mL)溶液滴加至B-1.1(3.0g，39.9mmol)和B-1.2(6.0g，39.9mmol)的无水DCM(15.0mL)溶液中。将反应混合物在室温搅拌过夜。向反应混合物中添加NH4Cl饱和水溶液(15.0mL)并用DCM萃取。分离有机相，干燥并蒸发，得到7.0g的B-1.3。ESI-MS：189[M+H]+；HPLC(Rt):0.86min(方法A)。
步骤2：在氮气气氛下，向A-2(2.1g，9.6mmol)、B-1.3(2.0g，10.6mmol)和DIPEA(3.6mL，21.0mmol)在无水DMA和无水ACN中的混合物中添加B-1.4(4.7g，16.9mmol)，并将反应混合物在室温搅拌5小时。将反应混合物倒入冷的H2O中并用EA萃取。将有机相用稀释的柠檬酸洗涤，干燥并浓缩。粗产物在硅胶上通过快速柱色谱提纯(使用EA/正己烷/MeOH 80/20/1)，得到600mg的B-1.5。ESI-MS:389[M+H]+；HPLC(Rt):1.30min(方法A)。
步骤3：在0℃，向在无水DMF(9.0mL)中的B-1.5(670mg，3.66mmol)添加NaH(110mg，2.75mmol)。30分钟后，在0℃添加B-1.6(710mg，1.82mmol)。将反应混合物温热至室温并搅拌16小时。将反应混合物倒入冷的NH4Cl溶液中，并用EA萃取。分离有机相，干燥并蒸发。粗产物在硅胶上通过快速柱色谱提纯(使用正己烷/EA 80/20)，得到670mg的B-1.7。ESI-MS:453[M+H]+；HPLC(Rt):1.59min(方法A)。
步骤4：在0℃，在搅拌下，向在无水THF(9.0mL)中的B-1.7(660mg，1.46mmol)添加B-1.8(1.6mL，1.60mmol)。将反应混合物在0℃搅拌1小时。蒸发溶剂，且粗产物在硅胶上通过快速柱色谱提纯(使用DCM/MeOH 97/3)，得到450mg的B-1.9。ESI-MS:339[M+H]+；HPLC(Rt):0.76min(方法A)。
步骤5：在氮气气氛下，向在无水THF(3.6mL)中的B-1.9(370mg，7.09mmol)和B-1.10(330μL，2.21mmol)逐滴添加B-1.11(350μL，1.62mmol)。将反应混合物在室温搅拌16小时。蒸发溶剂，且粗产物在硅胶上通过快速柱色谱提纯(使用EA/正己烷/MeOH 40/60/1)，得到270mg的B-1.12。ESI-MS:364[M+H]+；HPLC(Rt):1.03min(方法A)。
步骤6：在氮气气氛下，向在THF(15.0mL)和H2O(0.8mL)中的B-1.12(260mg，0.71mmol)添加B-1.13(500mg，1.91mmol)，并将反应混合物在室温搅拌16小时。蒸发反应混合物，并用HCl(1M，水溶液)处理残余物，并用EA萃取。分离有机相。将水相用NH4OH碱化至pH10-11，并用DCM萃取。干燥并蒸发有机相，得到240mg的B-1。ESI-MS:338[M+H]+；HPLC(Rt):0.62min(方法A)。
(S)-N*2*-(二氟乙基)-N*1*(5-三氟甲基-嘧啶-2-基)-丙-1,2-二胺B-2：
步骤1：在0℃、在N2气氛下，向B-2.1(2.0g，11.4mmol)、B-2.2(2.2g，14.9mmol)和PPh3(3.9g，14.9mmol)在无水THF(180mL)的混合物中逐滴添加DIAD(3.0mL，16.6mmol)。将反应混合物温热至室温并搅拌16小时。浓缩反应混合物，并将残余物用水处理并用EA萃取。分离有机层，干燥并浓缩。残余物在硅胶上通过快速柱色谱提纯(使用正己烷/EA 70/30的溶剂混合物)，得到3.4g的B-2.3。ESI-MS:304[M+H]+；HPLC(Rt):1.06min(方法A)。
步骤2：在0℃和在氮气气氛下，向在无水DMF中的B-2.3(2.3g，7.56mmol)和B-1.6(1.2mL，8.97mmol)添加NaH(60％，340mg，8.50mmol)。将反应混合物在室温搅拌16小时。将反应混合物倒入冷的NH4Cl(水溶液)中并用EA萃取。将有机相用H2O洗涤，干燥并蒸发。残余物在硅胶上通过快速柱色谱提纯(使用正己烷/EA 80/20的溶剂混合物)，得到1.6g的B-2.4。ESI-MS:368；TLC(Rf):0.6(硅胶；PE/EA 5/1)。
步骤3：将B-2.4(13.5g，36.5mmol)和水合肼(9.30g，182.7mmol)在EtOH(150mL)中的混合物在室温搅拌20小时。将反应混合物过滤并蒸发滤液。将残余物溶于H2O，并用EA萃取。将水相用HCl(0.05M，水溶液)酸化至pH 6并过滤。将滤液冻干，得到8.5g的B-2.5。ESI-MS:239；TLC(Rf):0.5(硅胶；PE/EA5/1)。
步骤4：向在无水NMP(25.0mL)中的B-2.5(4.0g，14.6mmol)和DIPEA(2.74mL，16.0mmol)添加B-2.6(2.7g，14.6mmol)并将反应混合物在微波中、在100℃搅拌1小时。将反应混合物倒入H2O中，并用EA萃取。有机相用稀释的柠檬酸(水溶液)洗涤，干燥并蒸发。残余物在硅胶上通过快速柱色谱提纯(使用环己烷/EA 95/5–60/40的溶剂混合物)，得到2.9g的B-2.7。ESI-MS:384[M+H]+；HPLC(Rt):1.32min(方法A)。
步骤5：向在无水1,4-二噁烷(5.0mL)中的B-2.7(2.9g，7.52mmol)中添加HCl(4M，在二噁烷中，10.0mL，40.0mmol)并将反应混合物在室温搅拌过夜。减压除去溶剂，用H2O和NH4OH处理残余物，并用DCM萃取。干燥并蒸发有机相，得到2.1g的B-2。ESI-MS:284[M+H]+；HPLC(Rt):1.01min(方法A)。
制备本发明的化合物
实施例2：
将CIP(65mg，0.23mmol)添加至搅拌中的A-1(50mg，0.24mmol)、B-2(65mg，0.20mmol)和DIPEA(110μL，0.64mmol)在无水ACN(2.0mL)的混合物中，并将反应混合物在室温搅拌过夜。将反应混合物过滤，并通过制备型LCMS提纯(使用含NH4OH的H2O/ACN溶剂梯度)，得到50mg的化合物实施例2。ESI-MS:474[M+H]+；HPLC(Rt):3.59min(方法B)。
实施例3：
在室温在氮气气氛下，向搅拌中的B-1(730mg，2.16mmol)和B-2.6(510mg，2.79mmol)在NMP(10mL)中的混合物中添加DIPEA(520μL，3.04mmol)。将反应在100℃加热1小时。冷却后，将反应倒入水中，并用EA萃取。分离有机层，用柠檬酸(稀释的水溶液)洗涤，干燥并浓缩。残余物在硅胶上通过快速柱色谱提纯(使用DCM/MeOH 97/3的溶剂混合物)，得到820mg的实施例3。ESI-MS:484[M+H]+；HPLC(Rt):3.25min(方法C)。
实施例4：
在室温，将DIPEA(120μL，0.70mmol)添加至搅拌中的A-5(100mg，0.35mmol)和B-2(90mg，0.41mmol)在无水DMA中的混合物中。20分钟后，添加CIP(130mg，0.47mmol)并将反应混合物在50℃搅拌5小时，然后冷却至室温并使其搅拌过夜。用H2O处理混合物并用EA萃取。将有机相用H2O洗涤，干燥并蒸发。残余物经制备型LCMS提纯(使用含NH4OH的H2O/ACN溶剂梯度)，得到60mg的化合物实施例4。ESI-MS:485[M+H]+；HPLC(Rt):3.53min(方法C)。
使用如前所述的相应的酸(参见酸性中间体)和胺(参见胺中间体)，类似于上述程序制备以下实施例。对于实施例1：在室温反应过夜。
Claims (4)
1.化合物，其选自
2.根据权利要求1所述的化合物的药学上可接受的盐。
3.一种药物组合物，其包含根据权利要求1或2所述的化合物与药学上可接受的佐剂、稀释剂和/或载体的掺合物。
4.根据权利要求1或2所述的化合物在制备用于治疗与冲动控制缺陷相关的精神或神经病况的药物中的用途。
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- 2018-09-26 WO PCT/EP2018/076108 patent/WO2019063605A1/en unknown
- 2018-09-26 US US16/650,903 patent/US11324724B2/en active Active
- 2018-09-26 JP JP2020517933A patent/JP6874217B2/ja active Active
- 2018-09-26 EP EP18778475.6A patent/EP3668864B1/en active Active
- 2018-09-26 CN CN201880061775.6A patent/CN111132975B/zh active Active
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| US11324724B2 (en) | 2022-05-10 |
| JP6874217B2 (ja) | 2021-05-19 |
| JP2020535191A (ja) | 2020-12-03 |
| EP3668864A1 (en) | 2020-06-24 |
| CN111132975A (zh) | 2020-05-08 |
| EP3668864B1 (en) | 2021-07-21 |
| WO2019063605A1 (en) | 2019-04-04 |
| US20200283418A1 (en) | 2020-09-10 |
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