CN1085216A - 具有抑制腺苷再吸收作用的二苯基噁唑、噻唑和咪唑衍生物 - Google Patents
具有抑制腺苷再吸收作用的二苯基噁唑、噻唑和咪唑衍生物 Download PDFInfo
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Abstract
一系列4,5-二苯基-噁唑、噻唑和咪唑的1-哌
嗪基-N-苯基乙酰胺衍生物为新的腺苷转移抑制
剂,它们对CNS组织,尤其是神经元具有有效的抗
局部缺血保护作用。本发明也涉及对由缺氧、局部缺
血、中风等引起的CNS局部缺血进行治疗的方法,
它包括给需要治疗的个体服用这些新化合物。
Description
本申请是1992年7月31日递交且现已放弃的系列号为07/923,399申请的部分继续申请。
本发明涉及具有药物和生物活性的4,5-二苯基-噁唑、噻唑和咪唑的N-哌嗪乙酰胺衍生物以及其制备方法和应用。具体地说,本发明的化合物是新的腺苷再吸收抑制剂,它们在缺氧、局部缺血或中风条件下具有神经保护作用。
从化学结构上讲,以下文献代表了相关的现有技术。
Inoue等人在美国专利4,101,660中公开并要求了一组具有消炎和止痛作用的噁烷化合物(1)
其中R1为苯基,R2为氢,R为羟乙基。在Chom.Abstr.91:56986x中,该组化合物扩大到其二苯基衍生物(R1=R2=苯基),在Chem Abstr.91:56987Y中扩大到其哌啶衍生物(R=哌啶基烷基)。
具有结构(2)的各种N-芳基-哌嗪烷酰胺作为抗局部缺血剂用于心肌组织及用于治疗睡眠疾病已有报导。
Hermans和Schaper的美国专利3,267,104提到哌嗪环可被取代的N-芳基-4-(4,4-二芳基丁基)-1-哌嗪烷酰胺可作为冠状血管舒张剂、局部麻醉剂、CNS刺激剂以及抗角叉胶剂。
Van Daele的美国专利4,776,125公开了一组具有相关结构的化合物,与哌嗪环相连的是不同的X取代基,它们用于治疗心脏组织的局部缺血。
Hiraiwa等人的美国专利4,948,796要求了包括结构(3)化合物在内的一组哌嗪衍生物,它们可保护大脑细胞出现局部缺血。
Marangos和Gruber在NO 91/04032中公开了一种通过利用例如腺苷转移抑制剂增加细胞外腺苷浓度来治疗神经变性疾病的方法。
但是无论是上述文献还是整个现有技术均没有提示本发明新的抗局部缺血的二苯基噁唑、噻唑和咪唑。
本发明涉及4,5-二苯基-噁唑、噻唑和咪唑的1-哌嗪基-N-苯基乙酰胺,它们是新的腺苷转移抑制剂,这些化合物可用于保护CNS组织,尤其是神经元对付由损伤或疾病如中风引起的局部缺血的影响。该方法包括给需要这种治疗的哺乳动物服用本发明新化合物。
从最宽角度讲,本发明包括具有抗局部缺血性质并具有结构式Ⅰ的4,5-二苯基-噁唑、噻唑和咪唑的1-哌嗪-4-基-N-苯基乙酰胺衍生物:
其中
R1和R2独立选自氢、C1-4烷基、C1-4烷氧基、卤原子和三氟甲基;
R3为氢原子、卤素、C1-4烷氧基、硝基或-NR9R10,
R9和R10独立选自氢、C1-4烷基、C1-5烷酰基和
R4为氢或C1-4烷基;
R5和R6各自独立选自氢、-CO2R11(R11为C1-4烷基)、-CONR9R10和氧,或R5和R6共同形成亚甲桥或亚乙桥;
R7和R8共同形成亚丁桥或各自代表
其中R12为氢、三氟甲基、卤素、C1-4烷基或C2-4烷基-N(R4)2;
n为0或整数1-4;且
X是S、O或NH。
本发明还包括式Ⅰ化合物的可作药物的盐和/或溶合物,尤其是水合物,以及在某些式Ⅰ化合物中由于结构的不对称性所产生的立体异构体,如对映体。利用本领域普通技术人员熟悉的各种方法可分离各种异构体。在本说明书的优选实施方案部分给出了这类方法的一个实例。
优选的式Ⅰ化合物包括其中R1和R2为甲基或氯;R5为氨基羰基;R7和R8为取代和未取代苯环的式Ⅰ化合物。一更优选的化合物是2-氨基羰基-4-〔(4,5-二苯基-2-噁唑基)甲基〕-N-(4-氨基-2,6-二氯苯基)-1-哌嗪乙酰胺。
对于医学应用来说,优选的是可作药用的酸加成盐,其阴离子对有机阳离子的毒性或药理活性不产生明显影响的盐。酸加成盐可通过将结构式Ⅰ的有机碱与有机或无机酸反应(优选通过在溶剂中接触)获得,或通过现有技术中所详述的普通方法获得。有用的有机酸是羧酸,如马来酸、乙酸、酒石酸、丙酸、富马酸、羟乙磺酸、琥珀酸、棕榈酸、环己烷氨基磺酸、新戊酸等;有用的无机酸有氢卤酸,如HCl、HBr、HI;硫酸;磷酸等。优选的式Ⅰ化合物的溶合物是水合物。
本发明化合物是具有抗局部缺血作用的有用药理剂。具有腺苷增强作用的该化合物可用作神经保护剂、抗惊厥剂和睡眠改善剂。对选择的代表性化合物进行测试后发现它们能够加强戊巴比妥诱导的睡眠时间。这一药理试验中的活性说明了本发明化合物作为安眠药的镇静作用。
中枢神经系统组织尤其容易受到局部缺血的损伤。脑局部缺血或供氧不足可能由受伤或疾病引起,并可能持续从很短时间至很长时间,如中风。在这方面,式Ⅰ化合物可用于治疗和预防因头部损伤、中风、呼吸停止、心动停止、Rey氏综合症、大脑血栓、栓塞、出血或肿瘤、脑脊髓炎、脊髓损伤、脑积水和手术后脑损伤引起的脑损伤。
已有许多报告认为,在缺氧、局部缺血和/或中风情况下腺苷在中枢神经系统中发挥着保护神经的作用。因此,提高局部缺血组织中腺苷水平的药剂将增强神经保护作用。从药理学角度考虑,通过抑制腺苷再吸收转移系统来增强或维持腺苷水平较为有利。因此,式Ⅰ化合物的抗局部缺血活性首先是通过有效抑制腺苷再吸转移而得以证实。这一抑制作用是通过评估式Ⅰ化合物阻止放射性标记的腺苷吸进鼠皮层突触体的能力而加以测定的,见:Bender,Wu and phillis,The characterization of〔3H〕 adenosine uptake into rat cerebral corticel synaptosomes,35.J.Neurochem.629-640(1980)。
对在腺苷再吸转移抑制检测中测得的其ID50值一般低于10μM的部分式Ⅰ化合物也在体内心搏动模型中进行了测试,例如在沙土鼠模型中保护海马组织因两侧颈动脉闭塞而出现局部缺血细胞丧失,以及在大鼠模型中减少大脑中动脉闭塞(MCAO)后新皮层梗塞量。
本发明涉及的另一个方面是给患有局部缺血症或易患局部缺血症的哺乳动物服用式Ⅰ化合物或其可作药用的盐和/或其溶合物。该化合物一般按每千克体重0.01-30mg的量服用。该剂量下限为非肠道途径给药,上限为口服给药。
式Ⅰ化合物的剂量以及剂量方案必须通过职业判断并考虑受体年龄、体重和状况、给药途径、局部缺血的性质和程度而针对每一具体情况仔细调整。但一般来说,对于人用的日剂量为0.5g-10g,优选1-5g。在某些情况下,在低剂量下能够获得足够的疗效,而在另一些情况下则需要大剂量。包括日剂量在内的式Ⅰ化合物的量可按单剂量或多剂量方式给出,这一点是本领域普通技术人员熟知的。
术语“内吸给药”在这里指通过口腔、舌下、颊、经鼻、经皮直肠、肌内、静脉内、心室内、鞘内和皮下等途径给药。根据良好的临床实践,最好是按产生良好疗效而不引起任何害处或不良副作用的浓度水平服用本发明化合物。
在治疗上,本发明化合物一般是按药物组合物的形式使用,该组合物中包括局部缺血有效保护量的式Ⅰ化合物或其可作药用的酸加成盐和/或其水合物以及可作药用的载体。用于这一治疗的药物组合物含有大量或少量(如95%-0.5%)的至少一种本发明化合物以及一种药物载体,该载体包括一种或多种无毒、无活性并可作药用的固体、半固体或液体稀释剂、填充剂或配药助剂。该药物组合物最好为剂量单位形式,即具体对应于一份或多份计算用于产生所需疗效剂量的预定量药物的物理分散单位。在实际应用中,剂量单位含有单剂量的1、1/2、1/3或更低。单剂量最好含有在按预定剂量方案服用一个或多个剂量单位后足以产生所需疗效的量,通常是按每日一次、两次、三次或多次给药的日剂量、其1/2、1/3或更低。可以想象本发明组合物中也可加入其它治疗制剂。优选每单位剂量产生0.1-1g活性成分的药物组合物,并通常将其制成片剂、锭剂、胶囊、粉剂、水溶性或油性悬液、浆液、酏剂和水溶液。优选的口服组合物是片剂、胶囊,并可含有常规赋形剂,如粘合剂(如糖浆、阿拉伯胶、白明胶、山梨糖醇、黄蓍胶或聚乙烯吡咯烷酮)、填充剂(如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨糖醇或甘氨酸)、润滑剂(如硬脂酸镁、滑石、聚乙二醇或硅石)、崩解剂(如淀粉)和湿润剂(如十二烷基硫酸钠)。对于非肠道组合物使用的是式Ⅰ化合物与常规药物载体形成的溶液或悬浮液,如用于静脉注射的水溶液或用于肌内注射的油状悬液。具有非肠道使用所需澄明度、稳定剂和适应性的该组合物是通过将0.1-10%(重量)式Ⅰ化合物或其一种盐溶于水或一种由多羟基脂肪醇组成的载体而制得,该脂肪醇如甘油、丙二醇和聚乙二醇或其混合物。聚乙二醇由非挥发性、通常为液体的聚乙二醇的混合物组成,它可溶于水和有机液体且其分子量为200-1500。
当打算经鼻给药时,是将式Ⅰ化合物配制成对鼻粘膜的穿透能力增强的药物组合物。该配方通常使用式Ⅰ碱性化合物的脂肪酸盐,其制法和用法是本领域技术人员熟知的。
反应流程Ⅰ概括了制备式Ⅰ化合物的一般步骤。
流程1中,R1-R8、X和n的定义同前,LG是有机合成领域所通常使用类型的合成有机离去机团:在亲核取代型反应中最常用的离去基团是卤化物或磺酸酯基团,如甲苯磺酸酯、对溴苯磺酸酯nosylate和mesylate。合成有机离去基团及其操作是有机合成领域技术人员熟知的,并在有关文献中有详细记载,如见:March,Advanced Organic Chemistry,2d ed.;McGrawflill:New York,pages 325-331;carey and Sundberg,Advaneed Organic Chemistry A:Structure and Reactivity,3d ed.Plenum:New York,pages 270-292。
PG表示常用于“保护”仲胺官能基型合成有机“保护基”,如酰基型保护基,如苄氧羰基(CBZ)或叔丁氧羰基(t-BOC)或三氟乙酰基(TFA)等。用于有机合成的合适“保护”基也是实施者熟知的,并在相关文献中有适当记载。如见:Carey and Sundberg,Advanced Organic Chemistry B:Reactions and Synthesis,3d ed.;Plenum:New York pages 677,686-689。
反应流程1中的起始物是N-苯基乙酰胺衍生物(Ⅴ),如2-卤-N-苯基乙酰胺;和“被保护的”哌嗪(Ⅳ),如1-哌嗪羧醛。该物质或者是市售产品,或者易于制备,例如将溴代乙酰氯与取代苯胺反应可制得Ⅴ;保护基与哌嗪环的一个氮原子相连可产生Ⅳ。将Ⅴ和Ⅳ反应所产生的式Ⅲ中间产物去保护后,得到Ⅱ,再将Ⅱ与合适的二苯基噁唑或噻唑(x)反应就得到所需的式Ⅰ产物,其中x为S或O。
为了制备咪唑产物,可将中间体Ⅱ与酮-酯化合物Ⅷ反应,得到Ⅵ,或将化合物Ⅱ与酯Ⅶ反应,然后将产生的Ⅺ与酮醇Ⅸ反应而得到Ⅵ,Ⅵ可转化成Ⅰ,其中X为NH。
按反应流程Ⅱ可获得式Ⅴ反应中间体。
将1,3-二环己基碳化二亚胺(DCC:0.81g,3.92mmole)一次性加到快速搅拌的4-〔〔〔2,6-二甲基苯基)氨基〕羰基〕甲基〕-1-哌嗪乙酸(1.0g,3.27mmol)、2-羟基-1,2-二-(4-乙基苯基)乙醛(Ⅸ:0.88g,3.27mmol)和二甲基氨基吡啶(DMAP:40mg)和无水二甲基甲酰胺(25ml)的混合物。室温反应2小时后再加入1当量DCC和DMAP。将混合物于室温下继续搅拌22小时,然后加热至70℃ 6小时。冷却后用乙酸乙酯稀释混合物,用饱和碳酸氢钠溶液和盐水洗涤,干燥并浓缩。硅胶闪蒸色谱纯化残余物(用50%乙酸乙酯的己烷溶液及乙酸乙酯进行梯度洗脱)后得到0.50g苯偶姻酯(Ⅵ),为灰白色固体。该酯不经进一步纯化直接用于后续反应。
实施例5
溴乙酸基-1,2-二-(4-乙基苯基)乙醛(Ⅷ)
将溴代乙酰氯(2,00ml,24.2mmol)和无水二氯甲烷(20ml)溶液滴加到2-羟基-1,2-二-(4-乙基苯基)乙醛(Ⅸ:6.5g,24.2mmol)和N-甲基吗啉(NMM:2.7ml,24.2mmol)及无水二氯甲烷(180ml)的冷(0℃)混合物中。该混合物于0℃搅拌1小时后再于室温搅拌2小时,然后加入2-羟基-1,2-二-(4-乙基苯基)乙醛(0.5ml)和NMM(0.6ml)。1小时后,用饱和碳酸氢钠溶液、1N HCl和盐水洗涤混合物。干燥并蒸发溶剂后,在硅胶上闪蒸色谱(先用10%乙酸乙酯的己烷溶液再用25%乙酸乙酯的己烷溶液进行梯度洗脱)纯化残余物,得到6.10g(65%)溴代乙酸基-1,2-二(4-乙基苯基)乙醛的浅黄色油状物,它不经进一步纯化直接用于后续反应。
实施例6
1,2-双〔4-三氟甲基)苯基〕-2-羟基乙醛(Ⅸ)
将50g(0.29mole)三氟甲基苯甲醛和0.7g(0.05当量)氰化钠于400ml 70%乙醇水溶液中的混合物加热回流20小时。冷却反应混合物,浓缩并过滤产物后产生结晶(42g,84%)m.p.77-80℃。
1H NMR(300 MHz,CDCl3)δ7.99(d,J=8.13Hz,2H),7.68(d,J=8.26Hz,2H),7.59(d,J=8.14Hz,2H),7.45(d,J=8.15Hz,2H),6.01(s,1H),4.51(s,1H);13C NMR(75MHz,CDCl3δ197.54,141.80(O),135.82,129.26,127.95,126.19,126.14,126.09,125.85,125.81,75.83,IR(KBr)3436,3074,2940,1696,1680,1618,1514,1420,1332,1250,1174,1132,1114,1098,1070,1018,980,878,856,830,822,700,686,626,600 cm-1;MS(DCI)m/e 349;
Anal.Calc'd for C16H10O2F6:C,55.18;H,2.89;Found:C,55.12;H,2.85;
实施例7
2-溴、氯-N-(2,6-二甲基苯基)乙酰胺(Ⅴ)
将溴代乙酰氯(20.0ml,0.234mol)的无水二氯甲烷(70ml)溶液滴加到2,6-二甲基苯胺(29.5ml,0.234mol)、N-甲基吗啉(28.0ml,0.254mol)及无水二氯甲烷(500ml)的冷(0℃)混合物中,于0℃搅拌1小时,室温搅拌2小时,然后用1N NaOH、1N HCl和盐水洗涤。干燥并蒸发溶剂后,用热的乙醚/乙酸乙酯研磨残余物,抽滤后得到46.75g(83%)式Ⅴ化合物,为灰白色固体,m.p.148-149℃。
1HNMR(300 MHz,CDCl3)δ8.28(br s,1H),7.08-6.97(m,3H),4.14(s,0.5H),3.93(s,1.5H),2.16 and 2.15(2s,6H);13C NMR(75 MHz,CDCl3)ppm 164.96,135.63,133.41,128.44,128.39,127.78,42.92,29.04,18.41;IR(KBr)3440,3212,3042,2974,1644,1534,1476,1308,1218,1120,762 cm-1;MS(DCI)m/z 242.
Anal.Calc'd for 0.75C10H12BrNO°0.25C10H12ClNO:C,51.02;H,5.19;N,5.92.
Found:C,51.27;H,5.10;N,6.06.
实施例8
(4-硝基-2,6-二氯苯基)-2-溴乙酰胺(Ⅴ)
将4-硝基-2,6-二氯苯胺(17g,82mmol)、溴代乙酰氯(25ml,304mmol)、水(0.6ml)、H2SO4(3.0g)、三氟乙酸(150ml)及二氯甲烷(150ml)的混合物于室温下搅拌5天。所得混合物倒入500ml热水中并搅拌45分钟,过滤收集黄色沉淀(23.32g)用水和甲醇洗涤沉淀物,再经二氯甲烷-乙醚研制后得到灰白色固体(11.56g,43%)
m.p.195-197℃;1H NMR(300 MHz,CDCl3)δ4.14(s,2H),8.12(broad s,1H),8.33(s,2H)。
实施例9
N-(叔丁氧羰基)-3-氨基羰基哌嗪(Ⅳ)
于-20℃向2-氨基羰基哌嗪(9.83g,76.2mmol)和三乙胺(10.7ml,76mmol)的200ml DMF溶液中加入二-叔丁基碳酸氢盐(16.6g,76.2mmol),搅拌2小时后加热至室温。真空除去溶剂后得到黄白色固体(19.8g)。经二氯甲烷-乙醚重结晶后得到Ⅳ白色固体(15.46g,89%)。
m.p.103-106℃;1H NMR(300 MHz,CDCl3)δ1.46(s,9H),1.85-2.00(m,1H),2.73-2.82(m,1H),2.87-3.18(m,2H),3.32-3.38(m,1H),3.70-3.85(m,1H),4.01-4.10(m,1H),5.54(broad s,1H),6.70(broad s,1H).
实施例10
N-(2,6-二甲基苯基)-4-甲酰基-1-哌嗪乙酰胺(Ⅲ)
将2-溴-N-(2,6-二甲基苯基)乙酰胺(Ⅴ:24.2g,0.10mol)、无水碳酸钠(15.9g,0.15mol)、碘化钠(0.10g)、1-哌嗪甲醛(Ⅳ:10.3ml,0.10mol)及无水二甲基甲酰胺(200ml)的混合物于85℃加热6小时,然后冷却,抽滤并真空浓缩、残余物溶于微量的热5%甲醇的乙酸乙酯溶液中。室温放置2小时后抽滤混合物,再次浓缩滤液,得到灰色固体,并用乙酸乙酯重结晶,从而分离出式Ⅲ化合物17.95g(65%),为白色固体。
m.p.139-140℃;1H NMR(300 MHz,CDCl3)δ8.50(br s,1H),7.99(s,1H),7.25-7.03(m,3H),3.59-5.56(m,2H),3.42-3.39(m,2H),3.17(s,2H),2.66-2.59(m,4H),2.19(s,6H);13C NMR(75 MHz,CDCl3)ppm 167.96,160.96,135.18,133.67,128.53,127.55,61.89,54.28,53.21,45.69,40.07,18.83;IR(KBr)3432,3274,2958,1672,1506,1446,1436,1148,1020,1008,788 cm-1;MS m/z calc'd for C15H22N3O2276.1712,found 276.1709.
Anal.Calc'd for C15H21N3O2:
C,65.43;H,7.69;N,15.26.
Found:C,65.42;H,7.76;N,15.32.
实施例11
2-(氨基羰基)-N-(4-硝基-2,6-二氯苯基)-4-(叔丁氧羰基)-1-哌嗪乙酰胺(Ⅲ)
将(4-硝基-2,6-二氯苯基)-2-溴乙酰胺(2.57g,7.84mmol)、2-氨基羰基-4-叔丁氧羰基哌嗪(1.80g,7.86mmol)、K2CO3(4.35g)及50ml DMF的混合物于室温下搅拌24小时。所得混合物在乙酸乙酯和水之间分配,并用乙酸乙酯剧烈再萃取水溶性萃取物,真空除去溶剂后,合并乙酸乙酯萃取物,得到2.59g残余物。经二氯甲烷-己烷重结晶后得到式Ⅲ白色固体(1.67g,45%):
m.p.>123℃(dec.);1H NMR(300 MHz,CDCl3)δ1.45(s,9H),2.47-2.55(m,1H),3.05-3.10(m,1H),3.15-3.35(m,4H),3.50-3.56(d,1H),3.83(broad s,1H),4.00-4.04(m,1H),5.59(broad s,1H),6.12(broad s,1H),8.24(s,2H),9.40(broad s,1H);MS(FAB)m/z 476(M+).
实施例12
2-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-4-(叔丁氧羰基)-1-哌嗪乙酰胺(Ⅲ)
将2-(氨基羰基)-N-(4-硝基-2,6-二氯苯基)-4-(叔丁氧羰基)-1-哌嗪乙酰胺(1.0g,2.1mmol)的30ml含甲醇化4%噻吩(0.25ml)甲醇溶液和5%钯碳催化剂(450mg)在parr装置中于50℃和25psi氢化30分钟。冷却并过滤除去催化剂,从滤液中真空除去溶剂,得到式Ⅲ的无定形固体(0.88g,94%)。
实施例13
N-(4-硝基-2,6-二氯苯基)-4-甲酰基-1-哌嗪乙酰胺(Ⅲ)
将N-甲酰基哌嗪(0.41ml,4.0mmol)、(4-硝基-2,6-二氯苯基)-2-溴乙酰胺(1.31g,4.0mmol)、K2CO3(2.2g)和20ml DMF的混合物于室温下搅拌15分钟。混合物在乙酸乙酯和水之间分配,水溶性萃取物用盐水稀释,然后用乙酸乙酯完全萃取。从合并的乙酸乙酯萃取物中真空除去溶剂,得到作为残余物的式Ⅲ产物(1.79g)。
1H NMR(300 MHz,CDCl3)δ2.73-2.78(m,2H),2.85-2.97(m,4H),3.34(s,2H),3.51-3.56(m,1H),3.68-3.72(m,1H),8.30(s,2H),9.14(broad s,1H).
实施例14
N-(4-氨基-2,6-二氯苯基)-4-甲酰基-1-哌嗪乙酰胺(Ⅲ)
将N-(4-硝基-2,6-二氯苯基)-4-甲酰基-1-哌嗪乙酰胺(1.79g粗品)悬浮于含有4%甲醇化噻吩(0.5ml)和5%钯-碳催化剂(900mg)的甲醇(50ml)中,利用parr装置于50℃和26psi氢化30分钟。经过滤和真空除去溶剂后滤液中产生1.38g粗残余物,于失活硅胶(300g硅胶于含3.4ml浓NH4OH的二氯甲烷中的淤浆)上进行闪蒸色谱,用CH2Cl2∶MeOH∶NH4OH98.8∶1.0∶0.2洗脱产物后得到590mg式Ⅲ灰白色固体。于二氯甲烷-乙醚中研制后得到白色固体(520mg,39%):m.p.>220℃(分解)。
实施例15
N-(2,6-二甲基苯基)-1-哌嗪乙酰胺二盐酸盐水合物(Ⅱ)
于氮气环境下将N-(2,6-二甲基苯基)-4-甲酰基-1-哌嗪乙酰胺(17.70g,64.0mmol)溶于甲醇(500ml)和1N HCl(130ml)的混合物中,回流7小时后,冷却,浓缩并在乙酸乙酯和水之间分配。从有机相中分离出水相,并蒸发干燥,分离得到21.00g(98%)标题化合物,为白色固体。
m.p.185-195℃(sealed tube);1H NMR(300 MHz,D2O)δ7.11-7.01(m,3H),4.31(s,2H),3.65-3.62(m,4H),3.56-3.50(m,4H),2.04(s,6H);13C NMR(75 MHz,D2O)ppm 168.55,140.74,136.95,133.37,133.19,61.89,54.16,45.56,22.24;IR(KBr)3440,2958,1690,1532,1472,1442,1386,1308,1240,964,770 cm-1;MS m/z calc'd forC14H22N3O 248.1763,found 248.1763.
Anal.Calc'd for C14H21N3O°2.0HCl°0.8H2O:
C,50.20;H,7.41;N,12.55;H2O,4.38.
Found:C,50.19;H,7.26;N,12.22;H2O,2.60.
实施例16
4-〔〔〔(2,6-二甲基苯基)氨基〕羰基〕甲基〕-2-哌嗪羧酸乙酯二盐酸盐水合物(Ⅲ)
将2-溴、氯-N-(2,6-二甲基苯基)乙酰胺(15.3g,0.063mol)、无水碳酸钠(6.70g,0.063mol)、碘化钠(0.95g)、2-哌嗪乙酸乙酯(10.0g,0.063mol)和无水二甲基甲酰胺(200ml)的混合物于100℃加热6小时,然后冷却并真空浓缩。残余物在乙酸乙酯和水之间分配并分离出有机相,盐水洗涤,干燥并浓缩。经硅胶闪蒸色谱(其用纯乙酸乙酯再用10%甲醇的乙酸乙酯溶液的梯度洗脱)纯化残余物后,得到11.60g(57%)棕色油状式Ⅱ化合物,其纯度足以使其直接使用,还得到5.15g(16%)作为副产物的1,4-〔双〔〔(2,6-二甲基苯基)氨基〕羰基〕甲基〕-2-哌嗪羧酸乙酯。为进行鉴定用醚的盐酸化物将少部分式Ⅱ化合物转化为其二盐酸盐。分离得到灰白色固体,
m.p.149-159℃(185℃ decomp.pt.,sealed tube);1H NMR(300 MHz,DMSO-d6)d 10.15(br m,1H),9.77(s,1H),7.06(s,3H),4.54-4.51(m,1H),4.21(q,J=7.1 Hz,2H),3.70(m,2H),3.56-3.52(m,1H),3.40-3.02(series of m,5H),2.13(s,6H),1.21(t,J=7.1 Hz,3H);13C NMR(75 MHz,DMSO-d6)ppm 166.15,165.67,135.29,134.61,127.78,126.76,62.40,58.51,53.80,50.42,48.30,41.39,18.32,13.92;IR(KBr)3432,2982,2924,2828,2732,2476,1748,1668,1506,1472,1444,1376,1296,1274,1220,1098,774 cm-1;MS m/z calc'd for C17H25N3O3320.1974,found 320.1982.
Anal.Calc'd for C17H25N3O3°2.0HCl°0.1H2O°0.2Et2O:C,52.28;H,7.20;N,10.28;H2O,0.44.
Found:C,52.46;H,7.58;N,10.34;H2O,5.52。
*使用与2-哌嗪甲酰胺相同的方法。Felder,E.;Maffei,S.;Pietra,S.;Pietre,D.Helv.Chem.Acta.1960,43,888。
实施例17
3-氨基羰基-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺二盐酸化物水合物(Ⅱ)
将2-溴,氯-N-(2,6-二甲基苯基)乙酰胺(9.37g,38.71mmol)、无水碳酸钠(4.10g,38.71mmol)、碘化钠(0.58g)和2-哌嗪甲酰胺叫花5.0g,38.71mmol)及无水二甲基甲酰胺(200ml)的混合物于100℃加热6小时,然后冷却并真空浓缩。残余物在乙酸乙酯和水间分配,分离出有机相,盐水洗涤,干燥并浓缩。经硅胶闪蒸色谱(先用纯乙酸乙酯再用10%甲醇的乙酸乙酯溶液进行梯度洗脱)纯化残余物后,得到4.25g(38%)灰白色泡沫状式Ⅱ化合物及3.15(18%)2-(氨基羰基)N,N′-双(2,6-二甲基苯基)-1,4-哌嗪二乙酰胺副产物。为进行鉴定用甲醇化盐酸化物将少部分标题化合物转化为其二盐酸盐。分离灰白色固体,
m.p.185-222℃(dec.,sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.17(s,1H),10.80-10.20 and 9.80-9.60(2br s,1H),8.38(s,1H),7.88(s,1H),7.08(s,3H),4.29-4.22(m,1H),4.16(br s,2H),3.93-3.90(m,1H),3.58-3.55(m,1H),3.44-3.31(m,4H),2.17(s,6H);13C NMR(75 MHz,DMSO-d6)ppm 167.75,165.24,136.83,135.78,129.47,128.57,58.49,55.13,52.22,49.60,20.01;IR(KBr)3406,3168,3016,2698,2466,1694,1538,1472,1442,1398,774 cm-1;MS m/z calc'd for C15H23N4O2291.1821,found 291.1815.
Anal.Calc'd for C15H22N4O2°2.0HCl°0°2.6H2O:
C,43.93;H,7.18;N,13.66;H2O,11.42.
Found:C,42.43;H,6.15;N,12.82;H2O,10.6.
实施例18
2-氨基羰基)-N-(4-氨基-2,6-二氯苯基)-1-哌嗪乙酰胺三氟乙酸盐(Ⅱ)
将2-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-4-(叔丁氧羰基)-1-哌嗪乙酰胺(0.88g,2.0mmol)的三氟乙酸(10ml)溶液于室温下搅拌20分钟,然后真空蒸发溶剂,得到粘性油状物(2.34g,100%)它为含有部分残余三氟乙酸的(三)-三氟乙酸盐。
实施例19
N-(4-氨基-2,6-二氯苯基)-1-哌嗪乙酰胺(Ⅱ)
将N-(4-氨基-2,6-二氯苯基)-4-甲酰基-1-哌嗪乙酰胺(470mg,1.42mmol)的1N HCl(20ml)溶液回流45分钟,水溶性HCl与正丙醇一起共沸除去。残余物(610mg)在甲醇-二氯甲烷中重结晶后得到505mg灰白色固体。将该物质溶于甲醇并用浓NH4OH碱化。真空除去溶剂,残余物溶于甲醇并过滤。除去溶剂后从滤液中得到作为无定形残余物的式Ⅱ(370mg,86%)。
实施例20
3-氨基羰基-4-〔(4,5-二苯基-2-噁唑基)甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺二盐酸化物水合物(Ⅰ)
将3-氨基羰基-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺(0.50g,1.72mmol)、无水碳酸钠(0.18g,1.72mmol)、碘化钠(26mg)、2-溴甲基-4,5-二苯基噁唑(0.54g,1.72mmol)及无水二甲基甲酰胺(30ml)的混合物于100℃加热3小时,然后冷却并真空浓缩。残余物加至乙酸乙酯中,并用饱和碳酸氢钠溶液和盐水洗涤。干燥并蒸发溶剂后,经硅胶闪蒸色谱(依次用乙酸乙酯和10%甲醇的乙酸乙酯梯度洗脱)纯化残余物,再与醚的氯化氢成盐后得到0.62g(55%)式Ⅰ化合物,为红褐色固体。
m.p.138-176℃(185℃ decomp.pt.,sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.37(s,1H),8.01(br s,1H),7.76(br s,1H),7.64-7.59(m,4H),7.51-7.36(m,6H),7.10(s,3H),5.80-4.40(br s,3H),4.31(s,2H),4.05(m,2H),3.78(m,1H),3.65-3.62(m,1H),3.51-3.27(series of m,4H),3.18-3.08(m,1H),2.18(s,6H);13C NMR(75 MHz,DMSO-d6)ppm 171.38,164.43,160.35,147.31,136.77,136.29,135.57,133.46,130.88,130.72,130.44,130.09,129.91,129.52,129.19,128.66,128.35,66.65,58.03,54.29,52.64,51.47,19.92,16.91;IR(KBr)3402,3176,3022,2558,1694,1602,1540,1508,1474,1444,1410,1378,1224,1158,840,774,582 cm-1;MS m/z calc'd for C31H34N5O3524.2662,found 524.2645.
Anal.Calc'd for C31H33N5O3°2.0HCl°0.35Et2O°1.8H2O:C,59.42;H,6.48;N,10.69;H2O,4.95.Found:C,59.74;H,5.94;N,10.89;H2O,5.5.
实施例21
N-(2,6-二甲基苯基)-4-〔4,5-二苯基-2-噁唑基〕-1-哌嗪乙酰胺二盐酸化物(Ⅰ)
在氮气环境下将2-氯-4,5-二苯基噁唑*(1.52g 5.97mmol)、无水碳酸钠(1.89g,17.91mmol)、N-(2,6-二甲基苯基)-1-哌嗪乙酰胺二盐酸化物水合物(2.0g,5.97mmol)及二甲苯/无水二甲基甲酰胺(25ml/10ml)的混合物加热回流6小时,然后冷却并真空浓缩。残余物加到乙酸乙酯中,并用盐水洗涤。干燥并蒸发溶剂后,经硅胶闪蒸色谱(用50%乙酸乙酯的己烷溶液洗脱)纯化残余物,得到不很纯的白色固体,将其用乙酸乙酯重结晶,与甲醇化的氯化氢成盐后得到1.27g(40%)式Ⅰ化合物,为白色固体。
m.p.190-209℃(dec.,sealed tube);1H NMR(300 MHz,DMSO-d6)d10.94(m,0.5H),10.46(s,1H),7.58-7.54(m,2H),7.50-7.45(m,2H),7.43-7.28(m,6H),7.09(s,3H),4.41(s,2H),4.18(m,2H),3.63-3.50(2m,6H),2.18(s,6H);13C NMR(75 MHz,DMSO-d6)ppm 162.62,158.63,139.57,135.08,134.40,133.83,132.17,128.85,128.62,128.30,127.92,127.83,127.51,126.98,125.42,56.11,50.55,42.44,18.23;IR(KBr)3422,3182,3022,2562,1690,1602,1592,1540,1474,1444,1404,1348,1288,1238,960,766,694 cm-1;MS(DCI)m/z 467。
Anal.Calc'd for C29H30N4O2°1.7HCl°0.3H2O:
C,65.23;H,6.10;N,10.49;Cl,11.29;H2O,1.01;
Found:C,65.28;H,6.10;N,10.34;Cl,0.00;H2O,1.24。
实施例22
N-(2,6-二甲基苯基)-4-〔2-(4,5-二苯基-2-噁唑基)乙基〕-1-哌嗪乙酰胺二盐酸化物水合物(Ⅰ)
向4,5-二苯基-2-噁唑乙酸乙酯(CA:956963 october 29,1974)(3.0g,9.76mmol)的无水四氢呋喃(150ml)冷溶液(-10℃)中加入氢化铝锂(0.37g,9.76mmol)。0.5小时后,另加0.5当量LAH(0.37g),混合物于-10℃搅拌3小时,然后用1N HCl终止反应。用乙酸乙酯稀释混合物,并用1N HCl、饱和碳酸氢钠溶液和盐水洗涤。干燥并蒸发溶剂后,将残余物溶于无水二氯甲烷(10ml),并于0℃用三乙胺(0.4)ml,3.39mmol)和甲磺酰氯(0.26ml 3.39mmol)处理。0℃ 0.5小时后,用二氯甲烷稀释混合物,并用饱和碳酸氢钠溶液和盐水洗涤,然后干燥并蒸发溶剂。在前面所说的标准烷基化条件下用N-(2,6-二甲基苯基)-1-哌嗪乙酰胺二盐酸化物水合物(1.14g,3.39mmol)处理甲磺酸盐。分离得到0.24g(12%)式1化合物,为浅黄色固体,
m.p.193-203℃(sealed tube);1H NMR(300 MHz,D2O/DMSO-d6)δ10.16(br s,1H),7.55-7.50(m,4H),7.45-7.30(m,6H),7.05(s,3H),4.26(br s,2H),3.68-3.43(2m,10H),2.13(s,6H);13C NMR(75 MHz,D2O/DMSO-d6)ppm167.51,160.63,147.14,136.72,135.61,134.35,132.36,130.78,130.40,130.29,129.38,128.97,128.91,127.74,59.11,53.83,51.33,50.67,24.04,19.01;IR(KBr)3422,3178,2974,2394,1684,1538,1502,1474,1444,1378,1286,962,766,696 cm-1;MS(DCI)m/z 495。
Anal.Calc'd for C31H34N4O2°2.0HCl°1.7H2O°0.1Et2O:
C,62.28;H,6.73;N,9.25;H2O,5.06.
Found:C,62.51;H,6.48;N,8.99;H2O,5.12.
实施例23
4-〔〔4,5-双(4-乙基苯基)-2-咪唑基〕甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺三盐酸化物水合物和4-〔〔4,5-双(4-乙基苯基)-2-噁唑基〕甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺二盐酸化物水合物
(方法A):
将1,3-二环己基碳化二亚胺(DCC,0.81g,3.92mmol)一次性加到4-〔〔〔2,6-二甲基苯基)氨基〕羰基〕甲基〕-1-哌嗪乙酸(1.0g,3.27mmol)、2-羟基-1,2-二-(4-乙基苯基)乙醛(Ⅸ:0.88g,3.27mmol)、二甲基氨基吡啶(DMAP;40mg)和无水二甲基甲酰胺(25ml)的快速搅拌混合物中。室温反应2小时后,再加入1当量DCC和DMAP于室温下继续搅拌22小时,然后于70℃加热6小时。冷却后用乙酸乙酯稀释混合物,用饱和碳酸氢钠溶液和盐水洗涤,干燥,浓缩。经硅胶闪蒸色谱(依次用50%乙酸乙酯的己烷溶液和乙酸乙酯梯度洗脱)纯化残余物后得到0.50g苯偶姻酯(Ⅵ),为灰白色固体。将该酯溶于冰醋酸(15ml)并加入固体乙酸铵(0.17g)。回流0.5小时后,再加入乙酸铵(0.17g),将混合物加热2小时,然后冷却并真空浓缩。经硅胶闪蒸色谱(依次用纯乙酸乙酯和10%甲醇的乙酸乙酯溶液梯度洗脱)纯化残余物并用HCl的甲醇溶液酸化后,得到0.14g(3.8%两步)噁唑产物(褐色固体)和0.15g(3.9%,两步)咪唑产物(灰白色固体)。
对于式Ⅰ噁唑:
m.p.223-227℃(dec.,sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.10(s,1H),7.54-7.50(m,4H),7.34-7.26(m,4H),7.10(s,3H),4.25(br s,2H),4.13(br s,2H),3.60-2.8(br m,7H),2.69-2.60(m,4H),2.16(s,6H),1.21(t,J=7.6Hz,6H);13C NMR(75 MHz,DMSO-d6)ppm 164.57,157.96,147.63,146.83,145.76,136.79,136.03,135.54,130.70,130.11,129.82,129.53,129.07,128.68,128.38,127.24,57.81,53.14,51.98,49.95,29.70,29.66,19.91,17.09,17.00;IR(KBr)3430,2964,2930,2872,1684,1538,1522,1444,1060,966,836 cm-1;MS m/z calc'd for C34H41N4O2537.3229,found 537.3223.
对于式Ⅰ咪唑:
m.p.208-215℃(dec.,sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.28(s,1H),7.44(d,J=8.2 Hz,4H),7.32(d,J=8.3 Hz,4H),7.10(s,3H),4.32(s,2H),4.14(s,2H),3.85(br s,12H),3.53(br s,2H),3.37(br s,2H),3.15(br s,2H),2.65(q,J=7.6 Hz,4H),2.17(s,6H),1.20(t,J=7.5Hz,6H);13C NMR(75 MHz,DMSO-d6)ppm164.46,146.98,136.74,135.48,130.16,129.90,129.57,128.74,126.51,57.58,53.04,51.64,50.36,29.64,19.89,17.01;IR(KBr)3422,2964,2932,2544,1688,1640,1532,1444,1416,1384,836,770 cm-1;MS m/z calc'd for C34H42N5O 536.3389,found 536.3391.
实施例24
4-〔〔4,5-双(4-乙基苯基)-2-咪唑基〕甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺三盐酸化物水合物和4-〔〔4,5-双(4-乙基苯基)-2-噁唑基〕甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺二盐酸化物水合物
(方法B):
将溴乙酰氯(2.00ml,24.2mmol)的无水二氯甲烷(20ml)溶液滴加到2-羟基-1,2-二-(4-乙基苯基)乙醛(Ⅸ:6.5g,24.2mmol)、N-甲基吗啉(NMM:2.7ml,24.2mmol)和无水二氯甲烷(180ml)的冷混合物(0℃)中。于0℃搅拌1小时,再于室温搅拌2小时,然后加入2-羟基-1,2-二-(4-乙基苯基)乙醛(0.5ml)和NMM(0.6ml)。1小时后,用饱和碳酸氢钠溶液、1N HCl和盐水洗涤混合物。干燥并蒸发溶剂,残余物在硅胶上通过闪蒸色谱(用依次用10%乙酸乙酯的己烷溶液和25%乙酸乙酯的己烷溶液梯度洗脱)纯化,得到6.10g(65%)淡黄色油状溴乙酸基-1,2-二-(4-乙基苯基)乙醛。用无水碳酸钠(0.86g,8.09mmol)、碘化钠(0.12g)及N-(2,6-二甲基苯基)-1-哌嗪乙酰胺(2.0g,8.09mmol)的无水乙腈(120ml)溶液处理部分溴乙酸基-1,2-二-(4-乙基苯基)乙醛(3.15g,8.09mmol),所得混合物于80℃加热5小时,然后冷却并真空浓缩。利用纯乙酸乙酯于硅胶上闪蒸色谱纯化残余物,得到3.40g(76%)淡黄色泡沫状的2-氧代-1,2-二-(4-乙基苯基)乙基4-〔〔〔26-二甲基苯基)氨基〕羰基〕-甲基〕-1-哌嗪乙酸酯、将部分2-氧代-1,2-二-(4-乙基苯基)乙基4-〔〔〔2,6-二甲基苯基)氨基〕羰基〕-甲基〕-1-哌嗪乙酸酯(2.50g,4.50mmol)溶于冰醋酸(75ml),并加入乙酸铵(1.65g,22.5mmol),混合物于氮气环境下温和回流6小时,真空除去溶剂。残余物在乙酸乙酯和1N氢氧化钠溶液间分配(至碱性),分离出有机相,用盐水洗浇,干燥并浓缩。残余物通过硅胶闪蒸色谱(依次用乙酸乙酯和10%甲醇的乙酸乙酯溶液梯度洗脱)纯化,在与醚的盐酸成盐后得到0.61g(22%)噁唑产物Ⅰ的白色固体和0.85g(30%)咪唑产物Ⅰ的白色固体,
对于噁唑:
m.p.134-156℃(sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.43(s,1H),7.44(d,J=7.9Hz,4H),7.28(d,J=8.0 Hz,4H),7.06(s,3H),4.33(s,2H),4.20(s,2H),3.52-2.90(series of m,8H),2.65-2.58(m,4H),2.14(s,6H),1.17(t,J=7.5 Hz,6H);13C NMR(75 MHz,DMSO-d6/D2O)ppm 162.51,145.97,142.13,135.18,132.39,128.45,128.01,127.94,127.71,123.86,55.97,51.84,50.05,48.46,27.73,17.47,14.85;IR(KBr)3422,3176,2964,2932,2354,1688,1538,1522,1498,1474,1456,1444,1414,1374,1298,1060,964,836,772 cm-1;MS(DCI)m/z 537。
Anal.Calc'd for C34H40N4O2°1.6HCl°0.5H2O:
C,67.61;H,7.11;N,9.28;Cl,9.39;
H2O,1.49;
Found:C,67.59;H,7.03;N,9.11;Cl,9.35;
H2O,1.68.
对于咪唑:
m.p.185-195℃(sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.32(s,1H),7.50(d,J=7.9 Hz,4H),7.29(d,J=8.3 Hz,2H),7.24(d,J=8.3 Hz,2H),4.32-4.30(m,4H),3.58-3.07(series of m,8H),2.66-2.57(m,4H),2.15(s,6H),1.17(t,J=7.5 Hz,6H);13C NMR(75 MHz,DMSO-d6/D2O)ppm 163.09,157.00,146.08,145.59,144.60,135.16,133.88,132.72,128.27,128.09,127.91,127.54,127.35,126.43,124.96,56.32,51.75,51.07,48.55,27.81,27.77,17.63,15.02;IR(KBr)3422,3176,2966,2932,2872,2560,1690,1636,1530,1496,1456,1416,1374,1304,1240,836,772 cm-1;
Anal.Calc'd for C34H41N5O°2.3HCl°0.6H2O:
C,64.78;H,7.12;N,11.11;Cl,12.94;
Found:C,64.48;H,7.03;N,10.83;Cl,13.05.
实施例25
2-(氨基羰基)-N-〔4-氨基-2,6-二氯苯基)-4-〔(4,5-二苯基噁唑基)甲基〕-1-哌嗪乙酰胺(Ⅰ)
将2-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-1-哌嗪乙酰胺三氟乙酸酯(1.38g,2.0mmol)、4,5-二苯基-2-溴甲基噁唑(72%,875mg,2.0mmol)、K2CO3(4.0g)和20ml DMF的混合物于室温下搅拌15分钟。所得混合物在乙酸乙酯-己烷和水之间分配,干燥有机萃取物,真空除去溶剂,得到1.27g粗残余物。将其在失活硅胶(300g硅胶于含3.4ml浓NH4OH的二氯甲烷中的淤浆)上闪蒸色谱。用CH2Cl2∶MeOH∶NH4OH 97.4∶2.0∶0.6洗脱产物,得到970mg残余物,再于甲醇-乙醚中研制后得到白色固体(638mg55%):
m.p.137-139℃;1H NMR(300 MHz,DMSO-d6)δ2.83-3.27(m,7H),3.32(s,2H),3.81(s,2H),5.67(s,2H),6.64(s,2H),7.28(s,2H),7.40-7.49(m,6H),7.55-7.63(m,4H),9.44(s,1H);MS(FAB)m/z 579(M+);
Anal.calc'd for C29H28N6O3Cl2°H2O:
C,58.30;H,5.06;N,14.07;
Found:C,58.06;H,4.92;N,13.87;
实施例26
N-(4-氨基-2,6-二氯苯基)-4-〔(4,5-二苯基噁唑基)甲基〕-1-哌嗪乙酰胺
将N-(4-氨基-2,6-二氯苯基)-1-哌嗪甲酰胺(370mg,1.22mmol)、4,5-二苯基-2-溴乙基噁唑(72%,530mg,1.22mmol)、K2CO3(700mg)和20ml DMF的混合物于室温下搅拌15分钟,然后在乙酸乙酯和水之间分配。经干燥乙酸乙酯萃取物并真空除去溶剂后得到900mg粗残余物。再于二氯甲烷-乙醚中重结晶后得到白色固体(312mg,48%)
m.p.>203℃(dec.);1H NMR(300 MHz,DMSO-d6)δ2.50-2.65(m,8H),3.05(s,2H),3.75(s,2H),5.63-5.64(s,2H),6.60(s,2H),7.34-7.47(m,6H),7.52-7.58(m,4H),9.14(s,1H);MS(DCI)m/z 536(M+);
Anal.calc'd for C28H27N5O2Cl2°0.25H2O:
C,62.17,H,5.12,N,12.95,
Found:C,62.13,H,5.05,N,12.89.
适当改动上述方法可产生其它式Ⅰ产物。这些改动是本领域技术人员熟知的。下面给出了按这类方法制备的其它式Ⅰ化合物。
实施例27
2-氨基羰基-N-(2,6-二甲基苯基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-1-哌嗪乙酰胺二盐酸盐水合物(Ⅰ)
得到0.78g(55%)淡黄色晶状固体:
m.p.166-176℃(sealed tube);1H NMR(300 MHz,DMSO-d6)δ9.94(br s,1H),8.23(br s,1H),7.81(br s,1H),7.61-7.58(m,4H),7.51-7.36(m,6H),7.08(s,3H),4.34(m,2H),4.14(m,1H),3.87(m,2H),3.54-3.21(3m,5H),2.15(s,6H);13C NMR(75 MHz,DMSO-d6)ppm 174.59,169.63,161.45,147.06,137.01,136.56,136.14,133.55,130.75,130.43,130.01,129.38,129.14,128.26,67.60,60.59,56.53,55.14,53.11,52.84,19.87;IR(KBr)3414,3020,2466,1688,1504,1476,1444,1378,1072,1026,964,766,696 cm-1;MS(DCI)m/z 524.
Anal.Calc'd for C31H33N5O3°2.0HCl°1.0H2O°0.3Et2O:
C,60.73;H,6.33;N,11.00;H2O,2.83.
Found:C,60.41;H,5.93;N,11.08;H2O,2.57.
实施例28
N-(2,6-二甲基苯基)-4-〔(4,5-二苯基-2-噻唑基)甲基〕-1-哌嗪乙酰胺二盐酸化物水合物(Ⅰ)
得到0.80g(58%)灰白色固体
m.p.149-166℃(decomp.pt.195℃,sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.37(s,1H),7.47-7.44(m,2H),7.39-7.37(m,3H),7.35-7.29(m,5H),7.07(s,3H),4.47(br s,2H),4.33(s,2H),3.60(br s,4H),3.39-3.32(m,4H),2.16(s,6H);13C NMR(75 MHz,DMSO-d6/D2O)ppm 163.22,161.95,149.24,135.19,134.60,133.51,132.74,130.59,129.12,128.98,128.84,128.55,128.46,128.37,127.92,127.55,56.39,55.83,50.70,48.81,17.64;IR(KBr)3422,2966,2362,1684,1538,1498,1474,1440,760,698 cm-1;MS m/z
Anal.Calc'd for C30H33N4OS:497.2375,found 497.2364.
Anal.Calc'd for C30H32N4OS°1.7HCl°0.2H2O:
C,64.09;H,6.11;N,9.97;H2O,0.64;
Found:C,64.12;H,6.07;N,9.92;H2O,0.60.
实施例29
4-〔(2-苯并咪唑基)甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺三盐酸化物水合物(Ⅰ)
得到0.78g(53%)
m.p.200-230℃(sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.47(s,1H),7.82-7.79(m,2H),7.53-7.50(m,2H),7.07(s,3H),4.34(s,2H),4.27(s,2H),3.52(br m,8H),3.11(m,2H),2.89(m,2H),2.16(s,6H);13C NMR(75 MHz,DMSO-d6/D2O)ppm 162.43,150.18,135.19,132.53,130.37,127.96,127.68,126.18,113.76,55.97,51.89,51.07,48.78,17.57;IR(KBr)3422,3176,2966,2856,1688,1622,1538,1474,1460,1442,1388,1340,1292,990,752,622 cm-1;MS m/z calc'd for C22H28N5O:378.2294,found 378.2290。
Anal.Calc'd for C22H27N5O°2.5HCl°0.7H2O°0.14Et2O:
C,55.12;H,6.62;N,14.25;H2O,2.57;
Found:C,55.36;H,6.44;N,14.09;H2O,2.34.
实施例30
M-(2,6-二甲基苯基)-4-〔(4,5-二苯基-2-咪唑基)甲基〕-1-哌嗪乙酰胺二盐酸化物水合物
得到0.26g(32%)灰白色固体,
m.p.195-210℃(dec.,sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.41(s,1H),7.52-7.51(m,4H),7.44-7.43(m,6H),7.06(s,3H),4.30(s,2H),4.17(s,2H),3.51(m,2H),3.34(m,2H),3.18(m,2H),2.86(m,2H),2.14(s,6H);13C NMR(75 MHz,DMSO-d6/D2O)ppm 162.49,142.59,135.17,132.62,129.74,129.13,128.24,128.08,127.95,127.62,126.65,56.01,51.79,50.15,48.50,17.61;IR(KBr)3422,3176,2956,2836,2682,2562,1690,1638,1602,1538,1476,1444,1368,1284,766,696 cm-1;MS m/z calc'd for C30H34N5O1:
480.2763,found 480.2753.
Anal.Calc'd for C30H33N5O°2.1HCl°0.8H2O:
C,63.15;H,6.48;N,12.27;H2O,2.53;
Found:C,63.30;H,6.36;N,12.26;H2O,2.35.
实施例31
2,6-(二甲基苯基)-4-〔4,5-双(4-甲氧苯基)-2-噁唑基)甲基〕-1-哌嗪乙酰胺二盐酸化物
得到0.31g(9%)白色固体
m.p.229-235℃(dec.,sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.33(s,1H),7.54-7.49(m,4H),7.07(s,3H),7.05-6.96(m,4H),4.43(br s,2H),4.34(br s,2H),3.79(s,3H),3.77(s,3H),3.69-3.65(m,4H),3.54-3.37(m,4H),2.16(s,3H);13C NMR(75 MHz,DMSO-d6)ppm 162.70,159.83,159.19,154.72,145.63,135.08,133.85,133.59,128.64,128.31,127.80,126.94,123.82,120.38,114.50,114.18,55.91,55.34,55.21,50.87,49.60,47.95,18.23;IR(KBr)3422,3258,3228,2940,2352,1704,1610,1540,1520,1498,1446,1304,1248,1176,1022,956,826 cm-1;MS m/z calc'd for C32H37N4O4:541.2815,found 541.281.
通过对上述合成方法进行改进所合成的另一些式Ⅰ化合物总结于表Ⅰ中。
*1 盐酸盐
2 马来酸盐
3 游离碱
4 (2∶1)2-氧代和3-氧代哌嗪衍生物的混合物
制备并试验了部分其它式Ⅰ化合物,且已发现它们具有前面所述的药理活性,因此可用作抗局部缺血剂。在以下的实施例和表Ⅱ中对这些化合物作了更详细的叙述,它们是通过对前面的合成方法进行适当改动而制备的。
为了提供某些立体异构的式Ⅰ化合物的单一对映体,也已开发出一种手性合成法。反应流程Ⅲ说明了该方法。这一方法产生在哌嗪环中具有手性中心的式Ⅰ化合物。利用这一方法可分离单一对映体,得到该组中优选的化合物:R-(+)-和S-(-)-2-(氨基羰基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-N-(4-氨基-2,6-二氯苯基)-1-哌嗪乙酰胺。这两种对映体均具有神经保护作用,但S-(-)对映体的活性是R-(+)-对映体活性的30倍。
反应流程Ⅳ显示了特定哌嗪起始物的单一对映体的制备方法。
实施例49
R-(+)-哌嗪-2-甲酰胺(10)
A.N,N′-二(苯基甲基)-哌嗪-2-羧酸乙酯(3)
于40℃机械搅拌下向10(N,N′-二苄基乙二胺(76.8g,0。296mol)的甲苯(240ml)溶液中滴加2(2,3-二溴丙酸乙酯,71.0g,0.296mol)和三乙胺(84ml,0.60mol)的75ml甲苯溶液中,温度保持在80℃以下。于80℃搅拌2.5小时后冷却,过滤所得混合物,滤液用200ml水分配,用Na2SO4干燥有机萃取物,并真空除去溶剂后,得到琥珀色油(3,105g,100%)。该物质用于后续步骤,因此未得到分析结果。
将3(94.25g,0。264mol)、L-
醇(53.6g,0.343mol)、NaH(2.0g,60%的矿物油悬液)及150ml甲苯混合物蒸馏,并根据需要逐步加入甲苯,这一操作持续1。5小时。然后将母液与2NHCl(170ml)和乙醚(800ml)的混合物一起搅拌30分钟。过滤收集沉淀,依次用乙醚和1NHCl洗涤,得到白色固体(83.0g)。过夜放置后第一批产物结晶(12.6g)。将第一产物在400ml乙醇和240ml0.2NHCl中分级重结晶,并每次加入80ml 0.2NHCl至母液中以进一步进行重结晶。利用这一方法收集六次产物。利用旋光度测定相应于文献值的光学纯度。
4.先三次的产物主要由R-异物体组成,将其合并。
得到:白色固体(40.0g,30%)
m.p.152-167℃;1H NMR(300 MHz,DMSO-d6):δ0.56-0.59(d,j=6.9Hz,3H),0.74-0.76(d,j=6.9 Hz,3H),0.83-0.86(d,j=6.3 Hz,3H),0.93-1.04(q,j=11.7Hz,3H),1.31-1.43(m,2H),1.57-1.62(m,3H),1.87-1.90(d,j=11.7Hz,1H),2.66-2.72(m,2H),3.03-3.24(m,4H),3.40(s,3H),3.70-3.82(dd,j=14.4,10.2 Hz,2H),4.43-4.48(m,2H),4.61-4.67(dt,j=6.9,3.6 Hz,1H),7.26-7.32(m,5H),7.43(s,3H),7.61(s,2H);13C NMR(75 MHz,DMSO-d6):δ15.45,20.49,21.80,22.41,25.44,30.82,33.53,46.06,46.42,49.93,50.77,57.77,58.57,61.94,75.10,127.46,128.32,128.72,128.83,129.46,131.50,136.66,168.69;IR(KBr):1730,1275,755,700 cm-1;MS(DCI):m/z 449;[α]D20+18.73(c=1.0,CHCl3);analysis calc'd.for C29H40N2O2·HCl·H2O:C,69.23;H,8.61;N,5.57;found:C,69.51;H,8.57;N,5.56.
将4(21.8g,0.0434mo)、10%Pd/C(2.6g)及200ml乙醇的混合物于Parr装置中于40-50Psi氢化18小时。过滤除去催化剂,真空浓缩滤液。向残余物中加入1NHCl的乙醚溶液(25ml)和50ml乙醇。剧烈搅拌混合物30分钟,过滤收集白色固体(12.7g,86%);
m.p.>225℃(dec.);1H NMR(300 MHz,DMSO-d6):δ0.67-0.70(d,j=6.9 Hz,3H),0.84-0.88(dd,j=5.7,0.9 Hz,6H),1.03-1.10(m,2H),1.38-1.45(t,j=11.4 Hz,2H),1.61-1.65(d,j=10.5 Hz,2H),1.78-1.89(dsept,j=6.9,2.7 Hz,1H),1.91-1.95(m,1H),3.19-3.50(m,6H),3.65-3.71(dd,j=9.9,3.3 Hz,1H),4.58-4.63(dd,j=8.4,3.6 Hz,1H),4.67-4.76(dt,j=6.6,4.5 Hz,1H),10.29(br s,3H);13C NMR(75 MHz,DMSO-d6):δ15.78,20.73,21.11,21.83,22.40,25.26,30.75,33.49,40.57,46.07,51.89,76.63,164.56;IR(KBr):3600-2300,1745,1370,1250 cm-1;MS(DCI):m/z 269;[α]D20-50.34(c=1.1H2O);analysis calc'd.for C15H28N2O2·2.3HCl:C,51.15;H,8.67;N,7.95;found:C,51.07;H,8.70;N,7.59.
D.R-(+)-哌嗪-2-羧酸二盐酸化物(8)
将6(12。7g,0.0372mol)的100ml 6NHCl溶液回流6小时,冷却后加入200ml乙醚。搅拌所得混合物,过滤收集到白色固体(6.53g,86%);
m.p.>255℃(dec.);1H NMR(300 MHz,D2O):δ3.29-3.47(m,3H),3.59-3.71(m,2H),3.85-3.90(m,1H),4.25-4.30(m,1H);13C NMR(75 MHz,D2O):δ42.14,42.48,44.63,56.00,170.18;IR(KBr):3100-2400,1760,1216,926 cm-1;MS(DCI):m/z 131;[α]D20+3.89(c=1.2,2N HCl);analysiscalc'd.for C5H10N2O2·2 HCl:C,29.57;H,5.96;N,13.80;found:C,29.74;H,5.94;N,13.80.
E.R-(+)-哌嗪-2-甲酰胺(10)
用50W-X8 200目H+型阳离子交换树脂(42g,92meq)回流含30%氨水(4.6ml,0.069mol)的8(6.98g,0。0344mol)的200ml甲醇溶液24小时。过滤收集树脂,并重悬浮在200ml甲醇中。然后冷却悬浮液至0℃,向溶液(9。50g,0。560mol)中通入NH3,封瓶,于室温下搅拌3天。过滤收集树脂,放入柱中,并用150ml 2N氨水洗脱。合并滤液和洗脱液,真空除去溶剂,剩余的水与正丙醇一起共沸除去。残余物在Amberlite CG-400,200目氢氧根型阴离子交换树脂上纯化,用水洗脱10,用1NHCl洗脱未反应的8。将溶剂与正丙醇一起共沸除去后得到白色固体(3。23g,73%);
m.p.140-148°;1H NMR(300 MHz,DMSO-d6):δ2.37-2.60(m,4H),2.69-2.75(m,1H),2.83-2.88(m,1H),2.98-3.02(m,1H),6.96(br s,1H),7.10(br s,1H);IR(KBr):3600-2700,1680,1600 cm-1;MS(DCI)m/z 130;[α]D20+27.27(c=1.35,EtOH);Analysis calc'd.for C5H11N3O:C,46.49;H,8.58;N,32.53;found:C,46.26;H,8.59;N,32.18.
实施例50
S-(-)-哌嗪-2-甲酰胺(11)
利用实施例49步骤A的残余物重复实例49的步骤B-E。
后三次收获物主要由S-异物体组成,将其与原始的第二次收获物合并,得到白色固体(36.0g,26%)
m.p.165-171℃;1H NMR(300 MHz,DMSO-d6)δ0.65-0.67(d,j=6.6 Hz,3H),0.84-0.86(d,j=6.0 Hz,6H),0.93-1.18(q,j=8.7 Hz,3H),1.41-1.45(m,2H),1.60-1.64(d,j=10.5 Hz,2H),1.82-1.86(m,2H),2.64-2.71(m,1H),2.98-3.26(m,4H),3.39-3.46(m,1H),3.77-3.80(m,3H),4.29-4.34(m,2H),4.65-4.68(m,1H),7.29-7.31(m,5H),7.42(s,3H),7.59-7.61(m,2H);13C NMR(75 MHz,DMSO-d6)δ15.75,20.56,21.84,22.60,25.71,30.80,33.56,46.15,46.30,49.11,50.97,57.49,58.38,62.17,75.13,127.54,128.35,128.70,128.98,129.52,131.66,168.59;IR(KBr)1735,1200,750,700 cm-1;[α]D20-104.45(c=1.0,CHCl3);HRMS(FAB):m/z calc'd for C29H41N2O2:449.3168;found:449.3183.
m.p.249-251°(dec.,sealed tube);1H NMR(300 MHz,DMSO-d6)δ10.26(br s,3H),4.76-4.68(m,1H),4.63-4.58(m,1H),3.65-3.60(m,1H),3.51-3.21(series of m,7H),1.92-1.83(m,2H),1.64-1.60(m,2H),1.43-1.36(m,2H),1.09-0.98(m,3H),0.85(t,J=6.6 Hz,6H),0.69(d,J=6.9 Hz,3H);13C NMR(75 MHz,DMSO-d6)δ164.77,76.50,55.99,51.93,46.14,40.77,33.48,30.75,25.36,22.66,21.82,20.62,18.56,16.14,15.78;IR(KBr)3440,2956,2872,2742,2696,2588,1744,1454,1388,1370,1354,1282,1066,984,964,944,932 cm-1;MS(DCI)m/z 269;[α]D20-56.08°(c=1.2,2N HCl);analysis calc'd for C15H28N2O2·2HCl·0.6H2O:C,51.17.H,8.93.N,7.96.Cl,20.14.H2O,3.07.Found:C,51.06;H,8.68;N,7.83;Cl,20.32.
C。S-(-)-哌嗪-2-羧酸二盐酸化物(9)
白色固体,8。68g(94%),
m.p.274-276°(dec.,sealed tube);1H NMR(300 MHz,D2O)δ10.37(v br m,3H),4.39(dd,J=11.6,3.8 Hz,1H),3.65(dd,J=13.3,3.7 Hz,1H),3.49-3.35(m,2H),3.33-3.14(series of m,3H);13C NMR(75 MHz,DMSO-d6)δ166.54,52.04,41.11;IR(KBr)3026,2982,2806,1758,1552,1532,1434,1408,1392,1244,1216,1098,1056,940,926,830,636,536 cm-1;MS(DCI)m/z 131;[α]D20-3.17°(c=1.0,2N HCl);analysis calc'd for C5H10N2O2·2HCl:C,29.57.H,5.96.N,13.80.Cl,34.92.Found:C,29.60;H,5.84;N,13.71;Cl,35.11.
D。S-(-)-哌嗪-2-甲酰胺(11)
白色固体,3。18g(59%)
m.p.138-141°;1H NMR(300 MHz,DMSO-d6)δ7.14(br s,1H),7.00(br s,1H),3.03(dd,J=9.3,3.1 Hz,1H),2.91-2.87(m,1H),2.77-2.40(series of m,7H);13C NMR(75 MHz,DMSO-d6)δ174.24,59.12,49.42,46.02,45.28;IR(KBr)3352,3312,3192,2972,2948,2910,2830,1678,1616,1414,1310,1138,1120,912,842 cm-1;MS(DCI)m/z 130;[α]D20-21.73°(c=1.8,EtOH);analysis calc'd for C5H11N3O:C,46.50.H,8.58.N,32.53.Found:C,46.13;H,8.51;N,32.15.
实施例51
A。R-(-)-(1,1-二甲基乙氧羰基)-2-哌嗪甲酰胺(ⅩⅣ-对映体)
在逐步加入二碳酸二叔丁酯(12。5g,0。0574mol)的情况下,将10(由实例49制得;7.40g,0。574mol)的150ml甲醇溶液于室温下搅拌1小时。真空除去溶剂,残余物通过硅胶塞,用CH2Cl2∶MeOH 95∶5-85∶15洗脱。真空除去溶剂后得到t-BOC衍生物,为白色固体(11.4g,87%);
m.p.125-130°;1H NMR(DMSO-d6):δ1.39(s,9H),2.57-2.64(m,1H),2.84-2.93(m,3H),3.20-3.23(m,1H),3.30-3.35(m,1H),3.65-3.69(m,1H),3.90-3.95(m,1H),7.27(br s,1H),7.47(br s,1H);IR(KBr):34-,1690,1650,1370,1270,1150;MS(DCI):m/z 230;[α]D20-19.40(c=1.0,EtOH);analysis calc'd for C10H19N3O3·0.25 H2O:C,51.38;H,8.41;N,17.97;found:C,51.36;H,8.11;N,17.83.
B.S-(+)-(1,1-二甲基乙氧羰基)-2-哌嗪甲酰胺(XIV-对映体)
按类似方法制备t-BOC衍生物11(实施例50)
白色固体,4。55g(89%);
m.p.134-136°;1H NMR(300 MHz,DMSO-d6)δ7.27(br s,1H),7.12(br s,1H),3.83(m,1H),3.63-3.59(m,1H),3.06-3.01(m,1H),2.84-2.72(m,3H),2.54-2.49(m,2H),1.39(s,9H);13C NMR(75 MHz,DMSO-d6)δ172.82,153.87,78.81,57.78,46.37,43.89,28.07;IR(KBr)3366,3252,3002,2990,2976,2940,2924,2862,1686,1646,1406,1368,1270,1222,1172,1154,890 cm-1;MS(DCI)m/z 230;[α]D20+22.88°(c=1.2,EtOH);analysis calc'd for C10H19N3O3:C,52.39.H,8.35.N,18.33.Found:C,52.19;H,8.27;N,18.25.
实施例52
A.R-(+)-2-(氨基羰基)-N-(4-硝基-2,6-二氯苯基)-4-(1,1-二甲基乙氧羰基)-1-哌嗪乙酰胺(Ⅲ)
将R-(-)-对映体(实例51-A制备的ⅩⅣ,4.7g,0。0205mol)、N-(4-硝基-2,6-二氯苯基)-2-溴乙酰胺(6。8g,0.0207mol)及三乙胺(3.2ml,0.023mol)的100ml DMF溶液于室温下搅拌4小时。将该溶液加至900ml乙酸乙酯中,过滤,滤液用pH5苯二甲酸氢盐0.5M(2×400ml)及水(2×400ml)分配,有机萃取物置Na2SO4上干燥,并真空除去溶剂。残余物溶于CH2Cl2,用硅胶塞过滤,用CH2Cl2洗脱未反应的起始溴乙酰胺,用CH2Cl2∶MeoH 90∶10洗脱15。真空除去溶剂后得到浅褐色固体(7。50g,77%);
m.p.115-120°;1H NMR(300 MHz,CDCl3):δ1.47(s,9H),2.50-2.60(m,1H),3.05-3.40(m,5H),3.56-3.61(m,1H),3.82-3.87(m,1H),4.05-4.10(m,1H),5.80(br s,1H),6.35(br s,1H),8.26(s,2H);IR(KBr):1700,1675,1535,1345,1250 cm-1;MS(DCI):m/z 476;[α]D20+32.19(c=1.0,CHCl3);Chiral HPLC:78% ee;Analysis calc'd for C18H23N5O6Cl2:C,45.39;H,4.87;N,14.70;found:C,45.27;H,4.89;N,14.53.
B.S-(-)-2-(氨基羰基)-N-(4-硝基-2,6-二氯苯基)4-(1,1-二甲基乙氧羰基)-1-哌嗪乙酰胺(Ⅲ)
同样,利用得自实例51-B的ⅩⅣ中间体可制备S-(-)-对映体化合物。
淡黄色泡沫,8.20g(90%),
m.p.102-105°;1H NMR(300 MHz,DMSO-d6)δ10.16(s,1H),8.40(s,2H),7.64(s,1H),7.34(s,1H),3.69-3.65(m,2H),3.33(s,1(?)),3.23-2.99(m,5H),2.42-2.36(m,1H),1.39(s,9H);13C NMR(75 MHz,DMSO-d6)δ172.08,168.48,153.55,146.27,139.24,134.27,123.57,79.12,64.23,59.77,58.32(?),54.92,50.20,45.56,41.69,28.01;IR(KBr)3268,3096,2978,2934,1698,1538,1482,1428,1390,1366,1346,1268,1246,1168,1148,1126,812,758,742 cm-1;MS(DCI)m/z 476;[α]D20-23.09°(c=1.6,EtOH);analysis calc'd for C18H23Cl2N5O6·0.35EtOAc·0.08CH3CN·0.11CH2Cl2·0.10H2O:C,45.30.H,5.11.N,13.64.H2O,0.35.Found:C,44.95;H,4.96;N,13.44;H2O.
实施例53
A.R-(+)-2-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-4-(1,1-二甲基乙氧羰基)-1-哌嗪乙酰胺(Ⅲ)
将实例52A产物(7.35g,0.0154mol)、5%Pt/C(3.25g)、4%甲醇化的噻吩(1.5ml)及150ml甲醇的混合物于50℃、50Psi的Parr装置中氢化2小时。过滤除去催化剂,从滤液中真空除去溶剂,得到一白色固体(6。73g,93%);
m.p.>135(dec.);1H NMR(300 MHz,DMSO-d6):δ1.40(s,9H),2.28-2.34(m,1H),2.89-3.32(m,6H),3.66-3.76(m,2H),5.68(s,2H),6.65(s,2H),7.63(s,1H),7.95(s,1H),9.46(s,1H);IR(KBr):3400-3300,1700,1670,1370,1260 cm-1;MS(DCI):m/z 446;[α]D20+30.33(c=1.2,EtOH);Analysis calc'd for C18H25N5O4Cl2·0.5H2O·0.5CH4O:C,47.14;H,5.99;N,14.86;found:C,47.08;H,5.53;N,14.77.
B。S-(-)-2-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-4-(1,1-二甲基乙氧羰基)-1-哌嗪乙酰胺(Ⅲ)
按类似方式氢化实施例52B产物后得到灰白色泡沫,7。0g(93%)
m.p.155-160°;1H NMR(300 MHz,DMSO-d6)δ9.47(s,1H),7.64(s,1H),7.32(s,1H),6.64(s,2H),5.68(s,2H),3.70-3.65(m,2H),3.26-2.88(series of m,6H),2.32-2.26(m,1H),1.39(s,9H);13C NMR(75 MHz,DMSO-d6)δ172.22,168.76,153.53,149.31,133.88,119.44,112.47,79.12,64.84,58.29,50.23,45.35,28.02;IR(KBr)3448,3350,2978,2932,1684,1598,1504,1462,1426,1366,1270,1246,1168,1126,802 cm-1;MS(DCI)m/z 446;[α]D20-26.99°(c=0.95,EtOH);Analysis calc'd for C18H25Cl2N5O4·0.10H2O:C,48.25.H,5.67.N,15.63.H2O,0.40.Found:C,47.96;H,5.57;N,15.24;H2O.
实施例54
A。R-(+)-2-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-1-哌嗪乙酰胺三盐酸化物(Ⅱ)
将实例53A制备的被保护的乙酰胺中间体(6。55g,0。0147mol)于20ml甲醇及80ml乙酸乙酯中的溶液与200ml 1N HCl的乙醚溶液合并。所得混合物于室温下搅拌2小时,真空减少溶剂至50ml,加入50ml乙醚。过滤收集所得沉淀,于甲醇∶乙腈(1∶3)中重结晶后,得到白色固体(5。3g,79%);
m.p.190-215(dec.);1H NMR(300 MHZ,DMSO-d6):δ2.90-2.95(m,1H),3.10-3.47(m,7H),3.62-3.64(m,1H),6.84(s,2H),7.66(s,1H),7.98(s,1H),9.24(br s,1H),9.64(br s,1H),9.75(s,1H);IR(KBr):3700-3200,1690,1600,1530 cm-1;MS(DCI):m/z 346;[α]D20+17.94(c=1.0,H2O);analysis calc'd for C13H17N5O2Cl2·3 HCl:C,34.27;H,4.43;N,15.37;found:C,34.31;H,4.69;N,15.34.
B.S-(-)-2-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-1-哌嗪乙酰胺三盐酸化物(Ⅱ)
按类似方式,使S-对映体去保护,得到灰白色固体,5。88g(87%),
m.p.222-226°(dec.,sealed tube);1H NMR(300 MHz,D2O)δ7.51(s,2H),3.72(dd,J=8.4,3.5 Hz,1H),3.66-3.23(series of m,7H),3.00-2.90(m,1H);13C NMR(75 MHz,D2O)δ175.00,174.10,137.71,134.54,133.97,126.08,62.83,59.52,49.68,46.67,44.86;IR(KBr)3378,3268,3136,2916,2810,2592,1706,1542,1470,1416,1376,968,810,596 cm-1;MS(DCI)m/z 346;[α]D20-3.67°(c=1.1,H2O);analysis calc'd for C13H17Cl2N5O2·2.95HCl·1.5H2O:C,32.48.H,4.81.N,14.57.Cl,36.50.H2O,5.62.Found:C,32.64;H,4.55;N,14.57;Cl,36.60;H2O,12.57.
实施例55
A。R-(+)-2-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-1-哌嗪乙酰胺三盐酸化物-水合物(Ⅰ)
将实例54A制备的化合物Ⅱ(5。0g,0。011mol)于100ml含三乙胺(6.4ml,0.046mol)的乙腈中的混合物于室温下搅拌至完全溶解。向其中加入2-溴甲基-4,5-二苯基噁唑(3.46g,0.011mol),所得混合物于室温搅拌4小时。真空除去溶剂,残余物在CH2Cl2(100ml)和NaHCO3饱和水溶液(75ml)间分配。水洗(2×50ml)有机萃取物,Na2SO4干燥并真空除去溶剂。闪蒸色谱残余物,产物用CH2Cl2∶MeOH∶NH4OH 98.8∶1.0∶0.2-98.2∶1.5∶0。3洗脱,得到浅黄色固体(3。17g,50%)。通过手性HPLC测得光学纯度为74%ee。于无水乙醇中分级重结晶导致母液中R-对映体的浓缩。从浓缩母液中真空除去溶剂,残余物在MeOH∶H2O 70∶30(100ml和CH2Cl2(5×10ml)之间分配,除去大部分有色杂质。从水-甲醇苯取物中真空除去溶剂,按前述条件闪蒸色谱残余物,得到灰白色固体(1。10g)。将其溶于CH2Cl2和甲醇的混合物中,向其中加入1N HCl的乙醚溶液(6。0ml)。真空除去溶剂,得到灰白色固体(100%ee,1.15g,15%);
m.p.>185(dec.);1H NMR(300 MHz,DMSO-d6):δ3.15-3.25(m,2H),3.35-3.45(m,3H),3.49-3.54(m,1H),3.70(br s,2H),3.97-4.02(m,1H),4.40(br s,2H),5.75(s,1H),6.76(s,2H),7.33-7.51(m,6H),7.57-7.60(m,4H),7.77(s,1H),8.10(s,1H),9.89(br s,1H);13C NMR(75 MHz,DMSO-d6):48.36,51.43,54.95,113.74,126.71,127.42,127.87,128.56,128.82,129.09,129.44,131.37,133.73,134.85,146.26,147.61;IR(KBr):3700-1900,1700,770,700 cm-1;MS(DCI):m/z 579;[α]D20+15.80(c=0.9,EtOH);analysis calc'd for C29H28N6O3Cl2·3HCl·H2O:C,49.28;H,4.71;N,11.89;found:C,49.29;H,4.66;N,11.76.
B.S-(-)-2-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-1-哌嗪乙酰胺三盐酸化物(Ⅰ)
按类似方式制得S-对映体产物,为白色固体(100%ee,99.6%),1.50g(17%),
m.p.200-210°br m,8H),7.03(s,2H),4.47(s,2H),4.04-4.02(m,1H),3.75-3.56(2m,3H),3.42-3.25(m,5H);13C NMR(75 MHz,DMSO-d6/D2O)δ169.97,168.21,153.79,146.96,144.26,134.93,133.91,130.69,129.74,129.04,128.87,127.48,127.22,126.60,122.36,115.60,60.99,55.79,51.29,50.81,49.25,47.42;IR(KBr)3394,3160,2956,2842,2570,1698,1604,1526,1504,1470,1444,1414,1384,1358,766,696 cm-1;MS(DCI)m/z 579;[α]D20-18.68°(c=1.0,EtOH);analysis calc'd for C29H28N6O3Cl2·1.6HCl·0.9H2O:C,53.26;H,4.84;N,12.85;Cl,19.52;H2O,2.48.Found:C,53.22;H,4.74;N,12.80;Cl,19.50;H2O,2.34.
实施例56
4-〔2-苯并咪唑基)甲基)-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺三盐酸化物水合物醚合物(Ⅰ)
利用2-苯并咪唑基甲基溴作为化合物X起始物,得到0。78g(33%)标题化合物,为淡黄色固体,
m.p.200-230℃(sealed tube);1H NMR(300 MHz,DMSO-d6δ10.47(s,1H),7.82-7.79(m,2H),7.53-7.50(m,2H),7.07(s,3H),4.34(s,2H),4.27(s,2H),3.52(br m,8H),3.11(m,2H),2.89(m,2H),2.16(s,6H);13C NMR(75 MHz DMSO-d6/D2O)ppm 162.43,150.18,135.19,132.53,130.37,127.96,127.68,126.18,113.76,55.97,51.89,51.07,48.78,17.59;IR(KBr)3422,3176,2966,2856,1688,1622,1538,1474,1460,1442,1388,1340,1292,990,752,622 cm-1;MS m/c calc'd for C22H28N5O:378.2294,found 378.2290.Anal. Calc'd for C22H27N5O·2.5HCl·0.7H2O·0.14Et2O:C,55.12;H,6.62;N,14.25;H2O,2.57.Found C,55.36;H,6.44;N,14.09;H2O,2.34.
实施例57
4-〔(2-苯并噁唑基)甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺马来酸盐(1∶2。75)
将1。45g实例15的中间体哌嗪乙酰胺的乙腈(30ml)溶液、3g K2CO3、催化量KI和1当量(0.95g,4。53mmol)溴甲基苯并噁唑的混合物搅拌24小时,过滤,蒸发溶剂,残余物溶于MeOH,用马来酸酸化并让其结晶,过滤得到1.67g产物(53%)
mp163-165℃;1HNMR(300 MHz DMSO-d6)δ9.81(s,1H),7.74(m,2H)7.41(m,2H),7.07(m,3H),4.09(s,2H),4.02(s,2H),3.28(s,4H),2.90(s,4H),2.13(s,6H);13C NMR(75 MHz DMSO-d6)δ166.96(0),162.41(0),150.30(0),140.49(0),135.05(0),133.80(0),133.36(+),127.85(+),127.00(+),125.40(+),124.59(+),119.76(+),110.89(+),56.64(-),53.17(-),51.80(-),48.95(-),18.07(+);IR(KBr)3392,1696,1620,1574,1518,1468,1454,1428,1356,1218,1082,990,868;MS(DCI)m/e379;Analysis calc'd for C22H26N4O2·2.75C4H4O4:C,56.81 H,5.35 N,8.03;found:C,56.52 H,5.34 N,8.39.
实施例58
(1S,4S)N-(2,6-二甲基苯基)-5-〔(3,4-二苯基-2-噁唑基)甲基〕-2,5-二氮杂二环〔2。2。1〕庚烷-2-乙酰胺二盐酸化物
以K2CO3为碱用实例7中间体2-溴-N-(2,6-二甲基苯基)乙酰胺的20ml DMF液烷化2,5-二氮杂二环〔2.2.1〕庚烷(2mmol,按WO88/02627制备)。通过柱色谱纯化所需单烷基化产物,并以K2CO3为碱用2-溴甲基-4,5-二苯基噁唑进一步烷基化。分离产物,通过柱色谱纯化。利用盐酸的乙醚溶液制备相应的二盐酸盐。m.p.(165-170℃)。
实施例59
N-(2,6-二甲基苯基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-1,4-二氮杂二环〔2.2.1〕辛烷-1-乙酰胺
按与上面类似的方法,将1,4-二氮杂二环〔2.2.1〕辛烷(见J.Het.Chem.11,449(1974)转化成标题化合物。m。p.154-185°(HCl盐)。
Claims (10)
2、根据权利要求1的化合物,其中R1和R2选自甲基和氯;R5为氨基羰基;R7和R8为苯基;n为1。
3、根据权利要求1的化合物,它选自N-(2,6-二甲基苯基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-1-哌嗪乙酰胺;N-(2,6-二氯苯基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-1-哌嗪乙酰胺;4-〔(4,5-双(4-乙基苯基)-2-噁唑基〕甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺;4-〔〔4,5-双(4-氟苯基)-2-噁唑基〕甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺;4-〔〔4,5-双〔4-(三氟甲基)-苯基〕-2-噁唑基〕甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺;4-〔〔4,5-双(3-氯苯基)-2-噁唑基〕甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺;4-〔〔4,5-二苯基-2-噁唑基〕乙基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺;N-(2,6-二甲基苯基)-4-〔4-(4,5-二苯基-2-噁唑基)丙基〕-1-哌嗪乙酰胺;N-(2,6-二甲基苯基)-4-〔4-(4,5-二苯基-2-噁唑基)丁基〕-1-哌嗪乙酰胺;N-(4-氨基-2,6-二氯苯基)-4-〔(4,5-二苯基噁唑基)甲基〕-1-哌嗪乙酰胺;4-〔(4,5-二苯基-2-噁唑基)甲基〕-N-苯基-1-哌嗪乙酰胺;N-(4-氯苯基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-1-哌嗪乙酰胺;4-〔(4,5-二苯基-2-噁唑基)甲基〕-N-(4-氟苯基)-1-哌嗪乙酰胺;4-〔(4,5-二苯基-2-噁唑基)-甲基〕-N-(4-甲氧苯基)-1-哌嗪乙酰胺;4-〔(4,5-二苯基-2-噁唑基)甲基〕-N-(4-甲基苯基)-1-哌嗪乙酰胺;N-(2,6-二氯苯基-4-〔(4,5-二苯基-2-噁唑基甲基〕-1-哌嗪乙酰胺;2,6-二甲基苯基-4-〔〔4,5-(4-甲氧苯基)-2-噁唑基〕甲基〕-1-哌嗪乙酰胺。
4、根据权利要求1的化合物,它选自4-〔〔4,5-双(4-乙基苯基)-2-咪唑基〕甲基-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺;N-(2,6-二甲基苯基)-4-〔(4,5-二苯基-2-咪唑基)甲基〕-1-哌嗪乙酰胺;N-(2,6-二甲基苯基)-4-〔4-(4,5-二苯基-2-噻唑基)丁基〕-1-哌嗪乙酰胺;N-(2,6-二甲基苯基)-4-〔(4,5-二苯基-2-噻唑基)甲基〕-1-哌嗪乙酰胺;N-(2,6-二甲基苯基-4-〔〔5-〔4-(二甲基氨基)苯基〕〕-〔5-苯基-2-咪唑基〕甲基〕-1-哌嗪乙酰胺。
5、根据权利要求1的化合物,它选自乙基-4-〔〔〔(2,6-二甲基苯基)氨基〕羧甲基〕-1-〔(4,5-二苯基-2-噁唑基)甲基)-2-哌嗪羧酸酯;2-氨基羰基-4-〔(4,5-二苯基-2-噁唑基〕甲基〕-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺;(1S,4S)N-(2,6-二甲基苯基)-5-〔(4,5-二苯基-2-噁唑基)甲基〕-2,5-二氮杂二环〔2,2,1〕庚烷-2-乙酰胺;2-氨基羰基-N-(2,6-二甲基苯基)-4-〔〔4,5-二苯基-2-噁唑基)甲基〕-1-哌嗪乙酰胺;3-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-4-〔(4,5-二苯基-2-噁唑基)甲基-1-哌嗪乙酰胺;2-氨基羰基-N-(4-氨基-2,6-二氯苯基-4-〔〔(4,5-二苯基噁唑基)甲基-1-哌嗪乙酰胺;2-氨基羰基-4-〔(4,5-二苯基-2-噁唑基)甲基-N-(4-氨基-2,6-二氯苯基)-1-哌嗪乙酰胺;5-〔〔3,5-二氯-4-〔〔〔4-〔2-(氨基羰基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-1-哌嗪基〕乙酰基〕氨基〕苯基〕氨基〕-S-氧代戊酸甲酯;2-(氨基羰基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-N-(2,6-二氯苯基)-1-哌嗪乙酰胺;1-〔〔〔〔2,6-二甲基苯基)氨基〕羰基〕甲基〕-4-〔(4,5-二苯基-2-噁唑基)甲基〕-2-哌嗪羧酸甲酯;2-(氨基羰基)-N-(4-氨基-2,6-二氯苯基)-4-〔(4,5-双(4-氟苯基)-2-噁唑基〕甲基〕-1-哌嗪乙酰胺;2-((氨基羰基)-N-(2,6-二氯-4-硝基苯基)-4-〔(4,5-二苯基-2-噁唑基)甲基〕-1-哌嗪乙酰胺。
6、根据权利要求5的化合物,它为2-氨基羰基-4-〔(4,5-二苯基-2-噁唑基)甲基〕-N-(4-氨基-2,6-二氯苯基)-1-哌嗪乙酰胺。
7、根据权利要求1-6任一项的化合物,它用作抗局部缺血剂。
8、一种药物配方,它包括作为活性成分的权利要求1-6中任一项所述的化合物以及一种或多种可作药用的载体、赋形剂或稀释剂。
9、根据权利要求8的药物配方,其中该配方为单位剂量形式。
10、制备权利要求1-6中任一项所述的方法,它包括将式Ⅱ化合物
其中
R1和R2独立选自氢、C1-4烷基、C1-4烷氧基、卤素和三氟甲基;
R3为氢、卤素、C1-4烷氧基、硝基或-NR9R10,
R9和R10独立选自氢、C1-4烷基、烷酰基和
R11为C1-4烷基,n为0或1-4;
R4为氢或C1-4烷基;
R5和R6独立选自氢、-CO2R11、-CONR9R10和氧代,或R5和R6一起形成亚甲桥或亚乙桥;
a)与式Ⅹ化合物反应;
其中R7和R8共同形成亚丁桥或各自为
R12为氢、卤素、三氟甲基、C1-4烷基或
C2-4烷基-N(R4)2;
X为S或O;
LG为合成的有机离去基团;
产生其中X为O或S的式Ⅰ产物;或将式Ⅱ与
b)式Ⅶ化合物EtO2C-(CH2)n-LG反应后再与式Ⅸ化合物
反应,产生式Ⅵ中间体
然后再与NH4OAC/HOAC反应,得到其中X为O或NH的式Ⅰ产物;或将式Ⅱ化合物与
c)式Ⅶ化合物反应,
得到中间体Ⅵ,将其与NH4OAC/HOAC反应后得到其中X为O或NH的式Ⅰ产物。
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US92339992A | 1992-07-31 | 1992-07-31 | |
US07/923,399 | 1992-07-31 | ||
US4833893A | 1993-04-15 | 1993-04-15 | |
US08/048,338 | 1993-04-15 |
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Publication Number | Publication Date |
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CN1085216A true CN1085216A (zh) | 1994-04-13 |
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CN93109303A Pending CN1085216A (zh) | 1992-07-31 | 1993-07-29 | 具有抑制腺苷再吸收作用的二苯基噁唑、噻唑和咪唑衍生物 |
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US (1) | US5382584A (zh) |
EP (1) | EP0582164B1 (zh) |
JP (1) | JP3478852B2 (zh) |
KR (1) | KR940005614A (zh) |
CN (1) | CN1085216A (zh) |
AT (1) | ATE174913T1 (zh) |
AU (1) | AU670953B2 (zh) |
CA (1) | CA2101311A1 (zh) |
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DK (1) | DK0582164T3 (zh) |
ES (1) | ES2125285T3 (zh) |
FI (1) | FI933398A (zh) |
GR (1) | GR3029778T3 (zh) |
HK (1) | HK1014714A1 (zh) |
HU (1) | HUT67460A (zh) |
IL (1) | IL106490A0 (zh) |
MX (1) | MX9304547A (zh) |
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- 1993-07-26 DE DE69322707T patent/DE69322707T2/de not_active Expired - Fee Related
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CN109456285A (zh) * | 2018-10-29 | 2019-03-12 | 安徽省庆云医药股份有限公司 | 一种雷诺嗪的制备方法 |
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KR940005614A (ko) | 1994-03-21 |
AU4423293A (en) | 1994-02-03 |
FI933398A (fi) | 1994-02-01 |
US5382584A (en) | 1995-01-17 |
JPH06157472A (ja) | 1994-06-03 |
EP0582164B1 (en) | 1998-12-23 |
NO932694D0 (no) | 1993-07-27 |
AU670953B2 (en) | 1996-08-08 |
DE69322707D1 (de) | 1999-02-04 |
IL106490A0 (en) | 1993-11-15 |
FI933398A0 (fi) | 1993-07-29 |
DK0582164T3 (da) | 1999-08-23 |
ATE174913T1 (de) | 1999-01-15 |
PL299888A1 (en) | 1994-04-18 |
MX9304547A (es) | 1994-02-28 |
CA2101311A1 (en) | 1994-02-01 |
ES2125285T3 (es) | 1999-03-01 |
EP0582164A1 (en) | 1994-02-09 |
JP3478852B2 (ja) | 2003-12-15 |
HK1014714A1 (en) | 1999-09-30 |
DE69322707T2 (de) | 1999-08-19 |
HUT67460A (en) | 1995-04-28 |
GR3029778T3 (en) | 1999-06-30 |
NO932694L (no) | 1994-02-01 |
TW224096B (zh) | 1994-05-21 |
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