CN1252798A - 5-羟色胺能试剂吲哚唑酰胺化合物 - Google Patents
5-羟色胺能试剂吲哚唑酰胺化合物 Download PDFInfo
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Abstract
通式(Ⅰ)的化合物及其与药用有机和无机酸形成的酸加成盐和其药用季盐,其中R1、R2、R3、R3’、R4、R5和R6定义如说明书。
Description
本发明涉及具有5-羟色胺能作用的吲唑酰胺化合物,其制备方法及其药物组合物。
在众多已知的5-羟色胺能受体中,最近才在泌尿膀胱、平滑肌和心肌及中枢神经系统的特定区域鉴定出5HT4受体。对这类受体具有激动、部分激动和拮抗作用的化合物对胃肠运动紊乱、中枢神经系统紊乱、小便失禁和心率不齐的药物治疗会带来潜在的益处。实际上这些化合物的作用是通过模拟或拮抗5-羟色胺的能力发生的,这些能力包括通过活化肠神经原刺激肠蠕动,调节重要的脑过程,如锻炼、记忆和焦虑,诱导泌尿膀胱松弛和增加动脉收缩的频率。
业已发现一类对5HT4受体具有亲合力并作为5-羟色胺的部分激动剂或拮抗剂发挥作用的吲唑酰胺化合物。
因此,本发明的第一个目的是提供通式如下的吲唑酰胺化合物及其与药用有机和无机酸形成的酸加成盐和其药用季盐:
其中
R1是氢原子;
R2是异丙基;
R3和R3′是氢原子;
R4和R5是氢原子;
R6选自C1-C3烷基、C3-C7环烷基、含1至4个相同或不同且选自N,O和S的杂原子的5至6元杂环、二甲基氨基C1-C3烷基、甲氧基C1-C3烷基、N-苯基酰胺、氨基磺酰基甲基、二羟基C2-C3烷基、芳基、被至少一个选自卤素和羟基的取代基取代的芳基、芳基C1-C3烷基。
芳基的优选实例为苯基、萘基和联苯基。
杂环的优选实例为噻吩基、呋喃基、吡喃基、吡咯基、咪唑基、吡唑基、异噁唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、呋咱基、吡咯啉基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、吗啉基、三嗪基、噻唑基、四唑基和噻二唑基。R6的典型实例为环丙基、环己基、吡啶基、四唑基、吗啉基、甲氧基甲基、甲氧基丙基、苯基、氯代苯基、溴代苯基、羟基苯基、苯乙基、二甲基氨基甲基和氨基磺酰基甲基。
本发明的第二个目的是提供制备式(I)化合物、其与药用有机和无机酸形成的酸加成盐及其药用季盐的方法,该方法包括:
其中R3、R3′、R4和R5定义如上,而
P是适当的保护基;
其中R1和R2定义如上,而
X是卤素,
其中R1、R2、R3、R3′、R4、R5和P定义如上;
其中R1、R2、R3、R3′、R4和R5定义如上;
c)按照下列反应方案用式(VI)的化合物将式(V)的化合物烷基化得到式(I)的化合物:
其中R1、R2、R3、R3′、R4、R5和R6定义如上,
而Y是卤素;
d)视具体情况而定与药用有机或无机酸形成式(I)的吲唑酰胺化合物的酸加成盐,或式(I)的吲唑酰胺化合物的药用季盐。
保护基(P)的典型实例为苄氧羰基、苄基、叔丁氧羰基和三甲基甲硅烷基乙氧羰基。
步骤a)优选地通过使式(II)化合物与其中X是氯的式(III)化合物在适当的稀释剂存在下并在0至140℃反应0.5至20小时来完成。
优选的稀释剂为质子惰性的、极性或非极性物质。更优选地是质子惰性非极性物质。适宜的质子惰性非极性稀释剂的实例为芳烃,如苯、甲苯和二甲苯。适宜的质子惰性极性稀释剂的实例为二甲基甲酰胺和二甲基亚砜。
更优选地该反应在温度为15至40℃进行1至14小时。
接着,步骤b)按照保护基领域技术人员已知的技术进行(Theodora W.Greene and Peter G.M.Wuts,“有机合成中的保护基”,pp.309-406,John Wiley & Sons,Inc.,N.Y.,1991)。对于苄基和苄氧羰基而言,保护基的脱保护优选通过催化加氢进行。适宜的催化剂的实例为钯/活性碳。
此脱保护反应优选在适宜的稀释剂如低级脂肪醇、低级脂肪酸及其混合物存在下进行加氢来完成。优选的稀释剂的实例为乙醇/乙酸混合物。
步骤c)优选借助其中Y是氯或溴的式(VI)化合物在酸的适宜受体如碱金属碳酸盐和碳酸氢盐、低级三烷基胺和适宜的稀释剂如芳烃、二甲基甲酰胺和脂肪族低级醇存在下进行。
用于形成本发明加成盐(步骤d)的优选有机和无机酸的典型实例为草酸、马来酸、酒石酸、甲磺酸、硫酸、磷酸、氢溴酸和盐酸。
甲基碘是形成本发明药用季盐的优选化合物的典型实例。
上述盐的制备包括药用有机或无机酸,或甲基碘向步骤c)获得的式(I)的吲唑酰胺化合物中的加入(步骤d)。
式(IV)和(V)的中间体是新的。因此,他们是本发明的另一个目的。
或者,式(I)吲唑酰胺化合物可通过将适宜的4-氨基甲基哌啶用式(III)化合物酰化制备。
从本发明药物组合物治疗中获益的病理症状的典型例子为对5-HT4受体拮抗剂的治疗产生响应的所有病理情况,例如,与高肠道运动有关的胃肠紊乱,如IBS(应激性肠道综合征)、小便失禁和心率不齐如动脉纤维性颤动。
优选将本发明的药物组合物制备为适宜的剂型,其中含有有效量的至少一种式(I)化合物或其药用加成盐或其季盐以及至少一种药用惰性成分。
适宜的剂型的实例为口服片剂、胶囊、包衣片剂、颗粒剂、溶液剂和糖浆;局部给药霜剂、油膏和含药胶带;直肠给药栓剂及注射、喷雾或眼部给药的无菌溶液剂。
这些剂型中还可含有其它常规组分如稳定剂、防腐剂、表面活性剂、缓冲剂、调节渗透压用盐、乳化剂、甜味剂、着色剂、矫味剂等。
当特殊治疗需要时,本发明的药物组合物可含有其它有利于治疗的可共同添加的药学活性组分。
式(I)化合物或其药用盐的用量可以随一些已知因素在宽范围内变化,例如,所治疗的疾病类型、该疾病的患病程度、患者的体重、剂型、所选择的给药途径、每天用药次数和所选式(I)化合物的药效。但是,本领域技术人员可容易并常规地确定最佳用量。
一般来说,本发明药物组合物中式(I)化合物或其盐的用量应确保给药剂量水平为0.001至50mg/kg每天。
本发明药物组合物的剂型可按照药剂师已知的包括混合、制粒、压制、溶解、灭菌等在内的方法制备。
下列实施例用来举例说明本发明,而不作任何方式的限制。
实施例1
1-异丙基-1H-3-吲唑羰酰氯的制备(III:R1=H,R2=C3H7)
a)2-甲基丙基-1-异丙基-1H-3-吲唑甲酸酯
向2-甲基丙基-1H-3-吲唑甲酸酯(50g,0.24mol)的1,2-二甲氧基-乙烷(300ml)溶液中,加入异丙基溴(27.5ml,0.29mol)的1,2-二甲氧基-乙烷(100ml)溶液和氢氧化钾(13.5g,0.24mol),并将此混合物加热回流8小时。除去溶剂后,将此残余物溶解于甲苯(300ml)中,用1N氢氧化钠(100ml)、水(2×100ml)洗涤并然后干燥,再真空浓缩。通过闪式色谱(洗脱剂,己烷∶乙酸乙酯=95∶5)由此残余物中纯化出2-甲基丙基-2-异丙基-2H-3-吲唑甲酸酯异构体,得到油状标题化合物(23g)。1H NMR(CDCl3,δ):1.07(d,J=7Hz,6H);1.66(d,J=7Hz,6H);1.95-2.48(m,1H);4.26(d,J=7Hz,2H);4.96(七重峰J=7Hz,1H);7.1 5-7.70(m,3H);8.03-8.33(m,1H).
b)1-异丙基-1H-3-吲唑甲酸
将实施例1a)的化合物(10g,0.04mol)在0.75N氢氧化钠(100ml)中的混悬液加热回流12小时。然后冷却此溶液,用6N盐酸(40ml)酸化,滤出固体沉淀并用1∶1己烷/乙酸乙酯重结晶得到标题化合物(5.5g),m.p.162-3℃(Harada H.et al.,“Chem.Pharm.Bull.”,43(11),1912-1930,1995)。1H NMR(DMSO,δ);1.54(d,J=7Hz,6H);5.13(七重峰J=7Hz,1H);7.20-7.65(m,2H);7.85(d,J=8Hz,1H);8.14(d,J=7Hz,1H);13.08(s宽峰,1H).
c)1-异丙基-1H-3-吲唑羰酰氯
将亚硫酰氯(4ml,0.054mol)加入到搅拌的实施例1b)化合物的溶液中,并将此混合物搅拌回流2小时。真空除去溶剂后,用己烷将此残余物重结晶得到3.5g标题化合物,m.p.63-4℃。元素分析 C H NC11H11ClN2O%实测值: 59.29 5.20 12.76%理论值: 59.33 4.98 12.581H NMR(CDCl3,δ);1.69(d,J=7Hz,6H);5.00(七重峰,J=7Hz,1H);7.20-7.70(m,3H);8.03-8.33(m,1H).
实施例2
N3-{[1-(2-苯乙基)-4-哌啶基]甲基}-1-异丙基-1H-3-吲唑甲酰胺盐酸盐(AFR 306)的制备
(I:R1=R3=R3′=R4=R5=H,R2=C3H7,R6=苯基)
将存在于甲苯(30ml)中的按照EP-A-0343307所述制备的[1-(2-苯乙基)-1-哌啶基]甲基胺(3g,0.014mol)滴加到实施例1c)化合物(3g,0.014mol)的甲苯(30ml)混悬液中。室温3小时后,将此固体过滤,溶解于水中,用6N氢氧化钠溶液碱化并用二氯甲烷(2×200ml)萃取。蒸发除去溶剂,用二氧化硅柱将此残余物纯化(洗脱剂,三氯甲烷∶甲醇=95∶5)并转变为相应的盐酸盐。所得产物(2g)熔点为211-212℃。元素分析 C H N Cl-C25H33ClN4O%实测值: 68.13 7.52 12.78 8.03%理论值: 68.09 7.54 12.70 8.041H NMR(DMSO,δ);1.56(d,J=7Hz,6H);1.50-2.30(m,5H);2.70-3.90(m,1 0H);5.10(七重峰J=7Hz,1H);7.05-7.63(m,7H);7.81(d,J=8Hz,1H);8.21(d,J=8Hz,1H);8.47(t,J=6Hz,1H);11.05(s宽峰,1H).IR(KBr):νco1652cm-1.
实施例3
N3-{[1-(苯基甲基)-4-哌啶基]甲基}-1-异丙基-1H-3-吲唑甲酰胺的制备
(IV:R1=R3=R3′=R4=R5=H,R2=C3H7,P=-CH2C6H5)
向搅拌的1-异丙基-1H-3-吲唑羰酰氯(52g,0.234mol)的甲苯(300ml)溶液中,滴加按照WO94/101 74所述制备的[1-(苯基甲基)-4-哌啶基]甲基胺(47.7g;0.234mol)的甲苯(200ml)溶液。5小时后,减压蒸除溶剂。用2N氢氧化钠处理此反应混合物,用二氯甲烷萃取并真空浓缩。用7∶3己烷/乙酸乙酯将此固体残余物(95g)重结晶得到标题化合物,为白色固体(45g),m.p.72-74℃。元素分析 C H NC24H30N4O%实测值: 73.78 7.87 14.35%理论值: 73.81 7.74 14.351H NMR(CDCl3,δ);1.59(d,J=7Hz,6H);1.10-2.25(m,7H);2.80-3.15(m,2H);3.27-3.60(m,4H);4.86(七重峰J=7Hz,1H);7.00-7.60(m,9H);8.27-8.52(m,1H).IR(KBr):νco1641cm-1.
实施例4
N3-(4-哌啶基甲基)-1-异丙基-1H-3-吲唑甲酰胺盐酸盐的制备
(V:R1=R3=R3′=R4=R5=H,R2=C3H7)
将实施例3的产物(28g,0.076mol)在乙醇(1500ml)中的混悬液和冰醋酸(66ml)用10%钯碳(13.4g)在35psi下氢化24小时。将此混合物过滤并真空浓缩此滤液。将此残余物溶解于水中,用5N氢氧化钠处理并室温搅拌2小时。滤出所得固体(16.6g)并转变为相应的盐酸盐(9.5g),m.p.211-214℃(分解)。元素分析 C H NC17H25ClN4O.1/2H2O%实测值: 58.82 7.68 16.36%理论值: 59.03 7.58 16.201H NMR(DMSO,δ);1.55(d,J=7Hz,6H);1.31-2.18(m,5H);2.58-3.64(m,7H);5.09(七重峰J=7Hz,1H);7.12-7.60(m,2H);7.80(d,J=8Hz,1H);8.20(d,J=8Hz,1H);8.41(t,J=6Hz,1H);8.82-9.60(m,2H).IR(KBr):νco1658cm-1.
实施例5
N3-{[1-(4-苯基丁基)-4-哌啶基]甲基}-1-异丙基-1H-3-吲唑甲酰胺草酸盐(AFR 603)的制备
(I:R1=R3=R3′=R4=R5=H,R2=C3H7,R6=-CH2CH2C6H5)
向作为游离碱的实施例4的产物(5.27g,15.6mmol)的乙醇(20ml)搅拌混悬液中加入碳酸钾(6.5g,50mmol)和4-苯基溴丁烷(“Braun”,B-44,2872,1911)(3.6g,17.1mmol)。将此反应混合物搅拌回流10小时。除去溶剂后,将此残余物在乙酸乙酯和1N盐酸中分配。用2N氢氧化钠将此水相碱化,用乙酸乙酯萃取并真空浓缩。将此固体转变为相应的草酸盐(2g),m.p.154-155℃。元素分析 C H NC29H38N4O5.1/2H2O%实测值: 65.87 7.47 10.62%理论值: 65.52 7.39 10.541H NMR(DMSO,δ);1.55(d,J=7Hz,6H);1.31-2.18(m,5H);2.30-3.64(m,14H);5.08(七重峰,J=7Hz,1H);7.12-7.60(m,7H);7.80(d,J=8Hz,1H);8.19(d,J=8Hz,1H);8.41(t,J=6Hz,1H).
实施例6
N3-{[1-(2-环己基乙基)-4-哌啶基]甲基}-1-异丙基-1H-3-吲唑甲酰胺盐酸盐(AFR 604)的制备
(I:R1=R3=R3′=R4=R5=H,R2=C3H7,R6=-C6H11)
按照实施例5的方法,用N3-(4-哌啶基甲基)-1-异丙基-1H-3-吲唑甲酰胺(4.42g)和(2-溴乙基)-环己烷(“J.A.C.S.”,48,1089-1093,1926)(4.63g)得到标题化合物(2.5g),m.p.244-246℃(分解)。元素分析 C H N Cl-C25H39N4O.1/2H2O%实测值: 65.51 9.05 12.57 7.89%理论值: 65.83 8.84 12.28 7.771H NMR(DMSO,δ);1.55(d,J=7Hz,6H);0.68-2.18(m,17H);2.63-3.70(m,10H);5.09(七重峰J=7Hz,1H);7.12-7.60(m,2H);7.80(d,J=8Hz,1H);8.20(d,J=8Hz,1H);8.41(t,J=6Hz,1H);10.70(s 宽峰1H).IR(KBr):νco1656cm-1.
实施例7
N3-({1-[3-(二甲基氨基)丙基]-4-哌啶基}甲基)-1-异丙基-1H-3-吲唑甲酰胺二马来酸盐(AFR 606)的制备
(I:R1=R3=R3′=R4=R5=H,R2=C3H7,R6=-CH2NC2H6)
按照实施例5的方法,用N3-(4-哌啶基甲基)-1-异丙基-1H-3-吲唑甲酰胺(3g)和N-(3-氯丙基)-N,N-二甲基胺盐酸盐(508mg)得到标题化合物(950mg),m.p.155-156℃。元素分析 C H NC30H43N5O9.1/2H2O%实测值: 57.83 7.01 11.11%理论值: 57.50 7.08 11.181H NMR(DMSO,δ);1.55(d,J=7Hz,6H);1.68-2.28(m,7H);2.81(s,6H);2.75-3.75(m,11H);5.09(七重峰J=7Hz,1H);6.09(s,4H);7.12-7.60(m,2H);7.81(d,J=8Hz,1H);8.20(d,J=8Hz,1H);8.45(t,J=6Hz,1H).
实施例8
N3-({1-[2-(4-吗啉基)乙基]-4-哌啶基}甲基)-1-异丙基-1H-3-吲唑甲酰胺二盐酸盐(AFR 607)的制备
(I:R1=R3=R3′=R4=R5=H,R2=C3H7,R6=C4H4NO)
按照实施例5的方法,用N3-(4-哌啶基甲基)-1-异丙基-1H-3-吲唑甲酰胺(3g)和4-(2-氯乙基)-吗啉(3.42g)得到标题化合物(3.2g),m.p.266-267℃(分解)。元素分析 C H N Cl-C23H37Cl2N5O2.1/2H2O%实测值: 55.74 7.61 13.96 14.12%理论值: 55.75 7.73 14.13 14.311H NMR(DMSO,δ);1.55(d,J=7Hz,6H);1.30-2.25(m,5H);2.75-4.30(m,19H);5.09(七重峰J=7Hz,1H);7.12-7.60(m,2H);7.81(d,J=8Hz,1H);8.20(d,J=8Hz,1H);8.45(t,J=6Hz,1H);10.80(s宽峰1H);10.60(s宽峰,1H).IR(KBr):νco1652cm-1.
实施例9
N3-[(1-{2-[(甲基磺酰基)氨基]乙基}4-哌啶基)甲基]-1-异丙基-1H-3-吲唑甲酰胺盐酸盐(AFR 703)的制备
(I:R1=R3=R3′=R4=R5=H,R2=C3H7,R6=CH3SO2NH-)
按照实施例5的方法,用N3-(4-哌啶基甲基)-1-异丙基-1H-3-吲唑甲酰胺(5g)和N-(3-溴乙基)-甲基磺酰胺(WO93/18036)(3g)得到标题化合物(1.5g),m.p.186-187℃(分解)。元素分析 C H N S Cl-C20H32ClN5O3S%实测值: 52.15 7.22 15.30 6.98 7.77%理论值: 52.45 7.04 15.29 7.00 7.741H NMR(DMSO,δ);1.55(d,J=7Hz,6H);1.40-2.30(m,5H);3.00(s,3H);2.75-3.80(m,10H);5.09(七重峰J=7Hz,1H);7.12-7.70(m,3H);7.80(d,J=8Hz,1H);8.20(d,J=8Hz,1H);8.45(t,J=6Hz,1H);10.73(s宽峰,1H).IR(KBr):νco1651cm-1.
实施例10
N3-({1-[2-(2-哌啶基)乙基]-4-哌啶基}甲基)-1-异丙基-1H-3-吲唑甲酰胺盐酸盐(AFR 605)的制备
(I:R1=R3=R3′=R4=R5=H,R2=C3H7,R6=C5H4N)
向作为游离碱的实施例4产物(10g,33.3mmol)的搅拌的混悬液中,加入2-乙烯基哌啶(3.6g,34mmol)、冰醋酸(2ml)和水(2.5ml)。在95℃16小时后,用2N氢氧化钠将此反应混合物碱化,用乙酸乙酯萃取并真空浓缩。将此残余物通过闪式硅胶色谱用三氯甲烷∶甲醇=97∶3作为洗脱剂纯化得到固体,然后将此固体转变为盐酸盐(5g),m.p.122-123℃(分解)。元素分析 C H N Cl-C24H32ClN5O.H2O%实测值: 62.80 7.42 15.18 7.78%理论值: 62.66 7.45 15.22 7.711H NMR(DMSO,δ);1.55(d,J=7Hz,6H);1.68-2.30(m,5H);2.80-3.78(m,12H);5.10(七重峰J=7Hz,1H);7.12-7.60(m,4H);7.68-8.00(m,2H);8.21(d,J=7Hz,1H);8.33-8.70(m,2H);11.05(s宽峰,1H).IR(KBr):νco1644cm-1.
试验1
对5-HT4受体的拮抗作用
通过试验化合物(I)对5-羟色胺引起的鼠食管膜松弛产生的影响评估该化合物的拮抗作用,其中所述膜用卡巴胆碱进行了预收缩。见J.D.Gale等,在“Br.J.Pharmacol.”,111,332-338(1994)中描述的方法。
所有被测的本发明化合物的pA2>8。AFR603、AFR604、AFR605和AFR306的特定值见下表1。
表1化合物 pA2 s.e.AFR 603 9.12 1.42AFR 604 8.19 0.99AFR 605 10.8 1.90AFR 306 9.36 0.38s.e.=标准误差
Claims (23)
2.权利要求1的化合物,其中芳基选自苯基、萘基和联苯基。
3.权利要求1的化合物,其中杂环为噻吩基、呋喃基、吡喃基、吡咯基、咪唑基、吡唑基、异噁唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、呋咱基、吡咯啉基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、吗啉基、三嗪基、噻唑基、四唑基和噻二唑基。
4.权利要求1的化合物,其中R6选自环丙基、环己基、吡啶基、四唑基、吗啉基、甲氧基甲基、甲氧基丙基、苯基、氯代苯基、溴代苯基、羟基苯基、苯乙基、二甲基氨基甲基和氨基磺酰基甲基。
5.权利要求1的化合物,其中R1、R3、R3′、R4和R5为氢原子,R2是异丙基而R6是苯基。
6.权利要求1的化合物,其中R1、R3、R3′、R4和R5为氢原子,R2是异丙基而R6是苯乙基。
7.权利要求1的化合物,其中R1、R3、R3′、R4和R5为氢原子,R2是异丙基而R6是环己基。
8.权利要求1的化合物,其中R1、R3、R3′、R4和R5为氢原子,R2是异丙基而R6是吡啶基。
9.权利要求1的化合物,其中R1、R3、R3′、R4和R5为氢原子,R2是异丙基而R6是二甲基氨基甲基。
10.权利要求1的化合物,其中R1、R3、R3′、R4和R5为氢原子,R2是异丙基而R6是吗啉基。
11.权利要求1的化合物,其中R1、R3、R3′、R4和R5为氢原子,R2是异丙基而R6是氨基磺酰基甲基。
12.制备式(I)化合物、其与药用有机和无机酸形成的酸加成盐及其药用季盐的方法,该方法包括:
a)将下式的4-氨基甲基哌啶酰化:
其中R3、R3′、R4和R5定义如上,而
P是适当的保护基;
其中R1和R2定义如上,而
X是卤素,
其中R1、R2、R3、R3′、R4、R5和P定义如上;
其中R1、R2、R3、R3′、R4和R5定义如上;
其中R1、R2、R3、R3′、R4、R5和R6定义如上,
而Y是卤素;
d)视具体情况而定与药用有机或无机酸形成式(I)吲唑酰胺化合物的酸加成盐,或式(I)吲唑酰胺化合物的药用季盐。
13.权利要求12的方法,其中P选自苄氧羰基、苄基、叔丁氧羰基和三甲基甲硅烷基乙氧羰基。
14.权利要求12或13的方法,其中通过使式(II)化合物与其中X是氯的式(III)化合物在适当稀释剂存在下并在0至140℃反应0.5至20小时进行步骤a)。
15.权利要求13的方法,其中当P是苄基或苄氧羰基时,步骤b)通过催化氢化进行。
16.权利要求12至14中任一项的方法,其中当式(VI)化合物中的Y是氯或溴时,步骤c)在酸受体和稀释剂存在下进行。
17.权利要求12的方法,其中甲基碘形成步骤d)中式(I)的药用季盐。
19.权利要求18的化合物,其中P选自苄氧羰基、苄基、叔丁氧羰基和三甲基甲硅烷基乙氧羰基。
20.权利要求18的方法,其中R1、R3、R3′、R4和R5是氢原子,R2是异丙基而P是苄基。
22.权利要求17的化合物,其中R1、R3、R3′、R4和R5是氢原子,R2是异丙基。
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TWI351282B (en) | 2004-04-07 | 2011-11-01 | Theravance Inc | Quinolinone-carboxamide compounds as 5-ht4 recepto |
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ES2327142T3 (es) * | 2004-11-05 | 2009-10-26 | Theravance, Inc. | Compuestos de quinolinona-carboxamida. |
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JP2008530225A (ja) * | 2005-02-17 | 2008-08-07 | セラヴァンス, インコーポレーテッド | インダゾール−カルボキサミド化合物の結晶型 |
NZ560828A (en) * | 2005-03-02 | 2011-01-28 | Theravance Inc | Quinolinone compounds as 5-HT4 receptor agonists |
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- 1998-04-15 AR ARP980101721A patent/AR012426A1/es active IP Right Grant
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2000
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100364988C (zh) * | 2003-05-15 | 2008-01-30 | 方济各安吉利克化学联合股份有限公司 | 具有止痛活性的吲唑 |
CN100427089C (zh) * | 2003-07-18 | 2008-10-22 | 方济各安吉利克化学联合股份有限公司 | 吲唑衍生物用于制备治疗神经病性疼痛药物的用途 |
CN101558057B (zh) * | 2006-11-22 | 2013-05-01 | 方济各安吉利克化学联合股份有限公司 | 用于治疗某些cns-相关病症的2-烷基-吲唑化合物 |
CN102695506A (zh) * | 2008-06-02 | 2012-09-26 | 扎里卡斯药品有限公司 | 作为钙通道阻断剂的n-哌啶基乙酰胺衍生物 |
US8569344B2 (en) | 2008-06-02 | 2013-10-29 | Zalicus Pharmaceuticals Ltd. | N-piperidinyl acetamide derivatives as calcium channel blockers |
CN102695506B (zh) * | 2008-06-02 | 2015-07-22 | 扎里卡斯药品有限公司 | 作为钙通道阻断剂的n-哌啶基乙酰胺衍生物 |
US9096522B2 (en) | 2008-06-02 | 2015-08-04 | Zalicus Pharmaceuticals, Ltd. | N-piperidinyl acetamide derivatives as calcium channel blockers |
US10208023B2 (en) | 2013-03-01 | 2019-02-19 | Mark G. DeGiacomo | Heterocyclic inhibitors of the sodium channel |
US11427540B2 (en) | 2019-07-11 | 2022-08-30 | Praxis Precision Medicines, Inc. | Formulations of T-type calcium channel modulators and methods of use thereof |
US11649207B2 (en) | 2019-07-11 | 2023-05-16 | Praxis Precision Medicines, Inc. | Formulations of T-type calcium channel modulators and methods of use thereof |
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