CN108409727A - 一种脂肪酰胺水解酶抑制剂及其制备方法 - Google Patents
一种脂肪酰胺水解酶抑制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种脂肪酰胺水解酶抑制剂及其制备方法，其结构式为其中，X选自C；R1选自H；R2选自H；R3选自H。经过测试的化合物对于人和大鼠脂肪酰胺水解酶具有很好地抑制活性，其hFAAH IC50（nM）为28，rFAAH IC50（nM）为110。说明本发明的化合物可以作为脂肪酰胺水解酶抑制剂用于相关药物的制备的后续研发。
Description
本申请是申请日为2017年10月25日，申请号为2017110102607，发明名称为“一种脂肪酰胺水解酶抑制剂及其制备方法”的专利的分案申请。
技术领域
本发明涉及一种脂肪酰胺水解酶抑制剂及其制备方法，属于药物化学、药物分析、药物制剂和药物活性测试等领域的结合。
背景技术
脂肪酰胺水解酶（Fatty acid amide hydrolase，FAAH）是一种内膜酰胺FAAH信号家族蛋白酶，它是生物体内许多具有生物活性的脂肪酰胺（Fatty acid amide）信使分子的主要催化水解代谢酶。最初发现的脂肪酰胺水解酶是由Schmid和他的同事们在肝脏中发现的N-酰基乙醇胺的氨基水解酶。这种水解酶可以将N-酰基乙醇胺（NAE）水解生成脂肪酸和乙醇胺。1996年，Cravatt等将此酶克隆出来，将其命名为脂肪酰胺水解酶（FAAH）。人体中的脂肪酰胺水解酶酶含有597个氨基酸，分子量为63KDa。脂肪酰胺水解酶主要分布在微粒体及线粒体的膜上。FAAH出现在多种组织中，包括头、肠、肝、睾丸、子宫、肾、眼睛、脾和肺等。在大脑中，FAAH在不同区表达程度也不一样，在苍白球区域和海马区活性最强，而在脑髓中活性最差；在免疫系统中，FAAH活性由淋巴细胞和巨噬细胞表达。FAAH作为内源性大麻素系统的组成成员，对大麻素信号的终止起着重要作用，是神经系统疾病、炎症、代谢性疾病及心血管疾病治疗的潜在靶点。
FAAH的催化中心是Ser241、Ser217和Lysl42构成的催化三联体，并含有多个通道及腔室，包括膜接入通道（membrane access channel，MAC），将活性部位与酶定位膜表面相连；细胞质接入通道，允许亲水性物质退出活性中心（cytosolic access channel）；结合脂肪酸链的疏水区域称为脂肪酸链结合区（acyl chain-binding pocket，ABP），可调节共晶体抑制剂的脂肪酸链。
尽管目前还未有FAAH抑制剂上市，但已有多个药物处于临床及临床前生物活性测试阶段。据Thomson Reuters Cortellis数据库统计，目前有多个药物处于研究阶段。
发明内容
本发明的目的之一在于提供一种脂肪酰胺水解酶抑制剂，其结构式为
其中，X选自C或N；R1选自H或C；R2选自H、C或F；R3选自H、C、F或CH2CH3。
进一步地，其盐或其溶剂化合物。
本发明的另一目的在于提供一种脂肪酰胺水解酶抑制剂的合成路线：
。
本发明的另一目的在于提供一种脂肪酰胺水解酶抑制剂用于治疗、预防或辅助治疗哺乳动物和人中在调节脂肪酰胺水解酶相关疾病中的应用，所述疾病如疼痛，包括急性的和慢性的，如术后痛、慢性痛、癌痛、癌症化疗引起的疼痛、神经痛、伤害感受性痛、炎性痛、背痛、由如以下各种来源的疾病引起的疼痛：糖尿病性神经病、包括人类免疫缺陷病毒的嗜神经型病毒性疾病、带状疱疹引起的疼痛如后疱疹神经痛；多神经病、神经毒性、机械神经损伤、腕管综合症、免疫学机理如多发性硬化症。
进一步地，所述的脂肪酰胺水解酶抑制剂在治疗疼痛的药物中的应用。
本发明的另一目的在于一种组合物，包括权利要求1所述的脂肪酰胺水解酶抑制剂及药学上可接受的辅料。
进一步地，所述组合物中所述的脂肪酰胺水解酶抑制剂作为唯一活性成分。
显然，根据本发明的上述内容，按照本领域的普通技术知识和手段，在不脱离本发明上述基本技术思想前提下，还可以做出其他多种形式的修改、替换或变更。
具体实施方式
中间体一：4-溴-1H-吡咯-2-甲酰氯的合成
将化合物4-溴-1H-吡咯-2-甲酰胺 (10 mmol)溶于30毫升二氯甲烷，向其中加入5毫升DMF，然后滴加3克二氯亚砜，加热至回流，搅拌5小时，减压蒸出溶剂，向其中加入20毫升甲苯，减压蒸出甲苯同时将残余的二氯亚砜带走，所得产品直接用于下一步反应。1H-NMR(400 MHz, CDCl3) δ: 7.17-7.22(m, 2H), 8.97(s, 1H)。
中间体二：4-溴-N-(3-甲基-1,2,4-噻二唑基-5)-1H-吡咯-2-甲酰胺的合成
将上一步的粗产品4-溴-1H-吡咯-2-酰氯溶于40毫升二氯甲烷溶液，向其中加入10毫升三乙胺，控制温度低于10℃，向体系中滴加入3-甲基-1,2,4-噻二唑-5-胺(12 mmol)的二氯甲烷溶液，，滴加完毕后恢复室温，常温搅拌10小时，然后用50毫升5%的碳酸钠水溶液洗涤反应体系，有机相用无水Na2SO4干燥，蒸干溶剂后，得到的固体快速柱色谱分离，得到2.45g浅黄色固体，两步总产率85%。1H-NMR (400 MHz, CDCl3) δ: 2.18(s, 3H), 6.78(d, 1H),7.16(d, 1H), 8.83(s, 1H)。
实施例1：N-(3-甲基-1,2,4-噻二唑基-5)-4-苯氧基-1H-吡咯基-2-甲酰胺的合成
将4-溴-N-(3-甲基-1,2,4-噻二唑基-5)-1H-吡咯-2-甲酰胺(10 mmol)溶于30 ml甲苯中，向其中加入硫化铜(1 mmol)和碳酸铯(12 mmol)，搅拌半小时，向其中加入苯酚(12mmol)，体系加热至100℃后反应10小时。然后降温至常温，过滤，蒸干溶剂，快速柱色谱分离，可得2.3 g类白色N-(3-甲基-1,2,4-噻二唑基-5)-4-苯氧基-1H-吡咯基-2-甲酰胺固体，产率77%。1H-NMR (400 MHz, CDCl3) δ: 2.18(s, 3H), 6.23(d, 1H), 6.45(d,1H),6.91-7.02(m, 3H), 7.29(m, 2H), 8.64(s, 1H).13C-NMR (75 MHz, CDCl3) δ:17.71,108.26, 119.9, 120.66, 121.66, 124.89, 129.81, 143.43, 153.96, 162.46,167.63, 173.89.LC-MS(ESI, pos, ion) m/z: 301[M+1]。
实施例2：N-(3-甲基-1,2,4-噻二唑基-5)-4-(2-吡啶氧基)-1H-吡咯基-2-甲酰胺的合成
将4-溴-N-(3-甲基-1,2,4-噻二唑基-5)-1H-吡咯-2-甲酰胺(10 mmol)溶于30 ml甲苯中，向其中加入硫化铜(1 mmol)和碳酸铯(12 mmol)，搅拌半小时，向其中加入2-羟基吡啶(12 mmol)，体系加热至100℃后反应10小时。然后降温至常温，过滤，蒸干溶剂，快速柱色谱分离，可得2.4 g淡黄色N-(3-甲基-1,2,4-噻二唑基-5)-4-(2-吡啶氧基)-1H-吡咯基-2-甲酰胺固体，产率80%。1H-NMR (400 MHz, CDCl3) δ: 2.15(s, 3H), 6.00(d, 1H), 6.36-6.38(m, 2H), 6.54(dd, 1H), 7.21(dd, 1H), 7.58(dt, 1H), 8.59(s, 1H).13C-NMR (75MHz, CDCl3) δ: 17.71, 108.26, 116.02, 118.61, 120.82, 121.66, 137.45, 143.09,148.62, 162.36, 162.46, 167.63, 173.89.LC-MS(ESI, pos, ion) m/z: 302[M+1]。
实施例3：N-(3-甲基-1,2,4-噻二唑基-5)-4-(3-氟苯氧基)-1H-吡咯基-2-甲酰胺的合成
将4-溴-N-(3-甲基-1,2,4-噻二唑基-5)-1H-吡咯-2-甲酰胺(10 mmol)溶于30 ml甲苯中，向其中加入硫化铜(1 mmol)和碳酸铯(12 mmol)，搅拌半小时，向其中加入3-氟苯酚(12mmol)，体系加热至100℃后反应10小时。然后降温至常温，过滤，蒸干溶剂，快速柱色谱分离，可得2.6 g淡黄色N-(3-甲基-1,2,4-噻二唑基-5)-4-(3-氟苯氧基)-1H-吡咯基-2-甲酰胺固体，产率84%。1H-NMR (400 MHz, CDCl3) δ: 2.19(s, 3H), 6.07(d, 1H), 6.44(d,1H), 6.68(m, 1H), 7.27(m, 1H), 7.46(m, 1H), 7.60(m, 1H), 8.85(s, 1H).13C-NMR(75 MHz, CDCl3) δ: 17.71, 108.26, 108.49, 111.04, 116.13, 120.66, 121.66,131.17, 143.43, 155.32, 162.46, 163.83, 167.63, 173.89.LC-MS(ESI, pos, ion)m/z:319[M+1]。
实施例4：N-(3-甲基-1,2,4-噻二唑基-5)-4-(对乙基苯氧基)-1H-吡咯基-2-甲酰胺的合成
将4-溴-N-(3-甲基-1,2,4-噻二唑基-5)-1H-吡咯-2-甲酰胺(10 mmol)溶于30 ml甲苯中，向其中加入硫化铜(1 mmol)和碳酸铯(12 mmol)，搅拌半小时，向其中加入对乙基苯酚(12 mmol)，体系加热至100℃后反应10小时。然后降温至常温，过滤，蒸干溶剂，快速柱色谱分离，可得2.8 g N-(3-甲基-1,2,4-噻二唑基-5)-4-(对乙基苯氧基)-1H-吡咯基-2-甲酰胺固体，产率85%。1H-NMR (400 MHz, CDCl3) δ: 1.18(t, 3H), 2.18(s, 3H), 2.72(q.2H). 6.07(d, 1H), 6.41(d, 1H), 7.01(m, 2H), 7.14(m, 2H), 8.62(s, 1H).13C-NMR(75 MHz, CDCl3) δ: 13.19, 17.71, 27.82, 108.26, 120.66, 120.82, 121.66,127.78, 139.92, 143.43, 152.41, 162.46, 167.63, 173.89.LC-MS(ESI, pos, ion)m/z: 329[M+1]。
实施例5：N-(3-甲基-1,2,4-噻二唑基-5)-4-(2,3二甲基苯氧基)-1H-吡咯基-2-甲酰胺的合成
将4-溴-N-(3-甲基-1,2,4-噻二唑基-5)-1H-吡咯-2-甲酰胺(10 mmol)溶于30 ml甲苯中，向其中加入硫化铜(1 mmol)和碳酸铯(12 mmol)，搅拌半小时，向其中加入对乙基苯酚(12 mmol),体系加热至100℃后反应10小时。然后降温至常温，过滤，蒸干溶剂，快速柱色谱分离，可得2.7 g 黄色N-(3-甲基-1,2,4-噻二唑基-5)-4-(2,3二甲基苯氧基)-1H-吡咯基-2-甲酰胺固体，产率82%。1H-NMR (400 MHz, CDCl3) δ: 2.08(s, 3H), 2.18(s, 3H), 2.29(s, 3H), 6.08(d, 1H), 6.35(d, 1H), 6.79-6.89(m, 3H), 8.68(s, 1H). 13C-NMR (75MHz, CDCl3) δ: 13.38, 17.71, 19.79, 108.26, 117.32, 119.41, 121.66, 125.25,125.31, 127.98, 137.11, 143.35, 154.08, 162.46, 167.63, 173.89.LC-MS(ESI,pos, ion) m/z: 329[M+1]。
试验例1：人和大鼠脂肪酰胺水解酶抑制活性
本发明化合物对人和大鼠脂肪酰胺水解酶（FAAH）抑制活性，试验方法同CN103958473B，除非另有说明，否则所有试剂购自Sigma。简述如下：
材料和试剂：
用于分析的人和大鼠脂肪酰胺水解酶（FAAH）基因已由Patricelli等（Biochemistry.1998，37（43），15177-87）描述。跨膜域删除的脂肪酰胺水解酶（FAAH）基因克隆至pET15b（Novagen，#69661）（人FAAH）/pET28a（Novagen，#69864-3）（大鼠FAAH基因）质粒中并在大肠杆菌（Ecoli）BL21DE3中表达。pGR07质粒（Takara Bio Inc，日本）中的伴侣蛋白groEL-groES与脂肪酰胺水解酶（FAAH）共表达，从而改善大肠杆菌中表达的蛋白质的溶解度。如Mileni等（Proc NatlAcad Sci USA.2008，105（35），12820-4）中所记载，来表达并富集蛋白质。简言之，室温下用阿拉伯糖（2mM）和异丙基β-D-1-硫代半乳糖苷（IPTG）（1mM）诱导LB培养基（Luria Broth）（2L）中的细菌培养物20h。将培养物在1200×g下离心10min，并将细胞团（cell pellet）重悬在100mL含20mM NaPi（pH7.4）、100mM NaCl、核酸酶（500u）、抑肽酶（1μg/mL）和亮抑酶肽（1μg/mL）的缓冲液中。通过声波法（Amp 20％、脉冲15s×15，冰上）裂解细胞，并通过5000×g下离心20min来除去细胞碎片。悬浮液经100,000×g下超速离心1h富集，并将细胞团重悬在16mL含20mM NaPi（pH7.8）、500mM NaCl、1％曲拉通X-100的缓冲液中。悬浮的细胞提取物在100,000×g下进行超速离心1h，并将富集的悬浮液用于体外分析。所有蛋白质提取步骤在冰上或4℃下进行。
体外分析：
化合物的生物活性使用基于荧光的分析来评价，从而定量花生四烯基7-氨基、4甲基香豆素酰胺（AAMCA）、脂肪酰胺水解酶（FAAH）的荧光底物的水解（Anal Biochem.2005、343(1)：143-51）。在96孔黑色聚苯乙烯板（Greiner Bio-one，Germany）中以200μL体积进行分析。各反应由含50mM HEPES、1mM EDTA和0.1％BSA（PH7.4）的分析缓冲液中的人脂肪酰胺水解酶（FAAH）蛋白和10μM AAMCA构成。在DMSO中用2μL不同浓度的抑制剂（DMSO的终浓度1％）在振荡的同时温育反应1min并在50min内监控动力学模式中荧光的增加。在激发波长355nm下和在460nm发射下，使用Flexstation III酶标仪（Molecular Devices，Sunnyvale，CA）测量荧光的增加。使用作为抑制剂浓度的函数的反应速率来测定抑制剂的IC50。使用GraphPadPrism（Graph Pad Software Inc.，San Diego，CA）分析数据。如上所述利用大鼠脂肪酰胺水解酶（FAAH）蛋白和10μM AAMCA底物评价化合物对大鼠脂肪酰胺水解酶（FAAH）的活性。
,表1本发明化合物对人和大鼠FAAH抑制活性。
| hFAAH IC50（nM） | rFAAH IC50（nM） | |
| 实施例1 | 28 | 110 |
| 实施例2 | 6 | 127 |
| 实施例3 | 2 | 73 |
| 实施例4 | 17 | 82 |
| 实施例5 | 22 | 86 |
| OL-135 | 10 | 79 |
结果表明，经过测试的化合物对于人和大鼠脂肪酰胺水解酶具有很好地抑制活性，其IC50值在2nM至127nM范围内，实施例3的IC50值为2nM。阳性对照OL-135对人和大鼠脂肪酰胺水解酶的抑制活性IC50值分别为10nM和79nM。说明本发明的化合物可以作为脂肪酰胺水解酶抑制剂用于相关药物的制备的后续研发。
Claims (6)
1.一种脂肪酰胺水解酶抑制剂，其结构式为
其中，X选自C；R1选自H；R2选自H；R3选自H。
2.如权利要求1所述的脂肪酰胺水解酶抑制剂的合成路线为
。
3.如权利要求1所述的脂肪酰胺水解酶抑制剂用于治疗、预防或辅助治疗哺乳动物和人中在调节脂肪酰胺水解酶相关疾病中的应用。
4.如权利要求1所述的脂肪酰胺水解酶抑制剂在治疗疼痛的药物中的应用。
5.一种组合物，其特征在于，包括权利要求1所述的脂肪酰胺水解酶抑制剂及药学上可接受的辅料。
6.如权利要求4所述的组合物，其特征在于，权利要求1所述的脂肪酰胺水解酶抑制剂作为唯一活性成分。
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