CN1784233A - 用于治疗神经变性的甘氨酸/nmda拮抗剂和速激肽nk－1受体拮抗剂的组合 - Google Patents
用于治疗神经变性的甘氨酸/nmda拮抗剂和速激肽nk－1受体拮抗剂的组合 Download PDFInfo
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Abstract
本发明涉及药物制剂，该制剂包含与速激肽NK－1受体拮抗剂联用的化合物，该化合物用作N－甲基－D－天冬氨酸(NMDA)受体的马钱子碱不敏感的甘氨酸调控位点的拮抗剂，用于治疗神经变性尤其是中风或脑局部缺血引起的神经变性。
Description
本发明涉及药用组合物，该组合物包含活性成分的组合。更详细地说，本发明涉及药物制剂，该制剂包含与速激肽NK-1受体拮抗剂联用的化合物，该化合物用作N-甲基-D-天冬氨酸(NMDA)受体的马钱子碱不敏感的甘氨酸调制位点的拮抗剂(在下文中称为“甘氨酸/NMDA拮抗剂”)，用于治疗神经变性尤其是中风或脑局部缺血引起的神经变性。
甘氨酸/NMDA拮抗剂因有利于治疗急性神经变性疾病而闻名于本领域，该疾病由多种原因引起，例如中风、瞬时局部缺血发作、手术期间的局部缺血、全面的局部缺血(继发性心脏骤停)和损害到脑或脊髓的头部外伤。另外，甘氨酸/NMDA拮抗剂也可用于治疗某些慢性神经学疾病例如老年痴呆、帕金森氏病和阿尔茨海默病。也可在外周神经功能受损的情况下，如视网膜变性和斑点变性时有实用性。
此外，据报道甘氨酸/NMDA拮抗剂有利于治疗癫痫；焦虑症；物质滥用和/或成瘾如酗酒；疼痛；听觉紊乱如耳鸣；偏头痛和精神障碍如精神分裂症。然而，有报道在临床试验期间给予某些甘氨酸/NMDA拮抗剂后会产生基于机理的副作用，主要包括恶心和呕吐。
P物质(SP；神经激肽-1；NK-1)的神经肽受体广泛分布于哺乳动物的神经系统(尤其是脑和脊神经节)、循环系统和外周组织(尤其是十二指肠和空肠)，并参与调控各种生物学过程。这些过程包括嗅觉、视觉、听觉和痛觉；运动控制；胃动力；血管舒张；唾液分泌和排尿。
P物质是天然存在的十一肽，属于多肽的速激肽家族，后者由于它们使血管外平滑肌组织迅速收缩而得名。除P物质外，已知的哺乳动物的速激肽包括神经激肽A和神经激肽B。当前的命名法将P物质受体、神经激肽A受体和神经激肽B受体分别命名为神经激肽-1、神经激肽-2和神经激肽-3。
正在开发速激肽神经激肽-1(NK-1；P物质)受体拮抗剂，用以治疗大量与速激肽(尤其是SP)的过量或不平衡相关的生理紊乱。这种病症的实例包括中枢神经系统障碍包括焦虑、抑郁和精神病。近来，美国食品药品监督管理局(FDA)已批准使用速激肽NK-1受体拮抗剂阿瑞吡坦(aprepitant)[2-(R)-(1-(R)-(3，5-双(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟苯基)-4-(3-(5-氧代-1H，4H-1，2，4-三唑基)甲基)吗啉]用于预防伴随癌症化疗药包括高剂量的顺铂而产生的急性和迟延的恶心和呕吐。
现在发现，在治疗神经变性尤其中风或脑局部缺血造成的神经变性中，甘氨酸/NDMA拮抗剂与速激肽NK-1受体拮抗剂联用提供有益的治疗结果。
于是本发明提供治疗神经变性的方法，包括对需要这种治疗的患者同时给予、分开给予或者按顺序给予甘氨酸/NMDA拮抗剂和速激肽NK-1受体拮抗剂组合。
本发明也提供了甘氨酸/NMDA拮抗剂和速激肽NK-1受体拮抗剂组合在制备治疗神经变性的药物上的用途。
另一方面，本发明提供了药用组合物，该组合物包含甘氨酸/NMDA拮抗剂和速激肽NK-1受体拮抗剂以及与之结合的药学上可接受的载体。
又一方面，本发明提供了包含甘氨酸/NMDA拮抗剂和速激肽NK-1受体拮抗剂产品，该产品作为同时使用、分开使用或按顺序使用的治疗神经变性的联合制剂。
在本发明的普通实践中，常常在一个合理的时间期间，其典型地高至约间隔一个小时，给予患者甘氨酸/NMDA拮抗剂和速激肽NK-1受体拮抗剂。本化合物可在同一药用载体中并因此可同时给药。它们可在分离的药用载体中，并通过临给药前混和上述材料而同时给予。它们也可以不同的剂型同时或者按顺序给药。
例如，用于本发明的典型的甘氨酸/NMDA拮抗剂如EP-A-0481676所述。优选的用于本发明的甘氨酸/NMDA拮抗剂包括UK-240，455和UK-333，747，已各自在WO 96/09295[实施例80(d)]和WO 98/38186(源自WO 97/32873)公开，它们的化学结构如下：
用于本发明的速激肽NK-1受体拮抗剂的性质可为肽类或非肽类。但是，优选使用非肽类速激肽NK-1受体拮抗剂。在一个优选实施方案中，速激肽NK--1受体拮抗剂是中枢神经系统(CNS)透过性速激肽NK-1受体拮抗剂。另外，为方便起见，优选使用口服有效的速激肽NK-1受体拮抗剂。为方便给药，还优选作用时间长的速激肽NK-1受体拮抗剂。用于本发明的特别优选的速激肽NK-1受体拮抗剂类别包含口服有效和作用时间长的化合物。
已对用于本发明的速激肽NK-1受体拮抗剂做了完整的描述，例如，美国专利：5,162,339、5,232,929、5,242,930、5,373,003、5,387,595、5,459,270、5,494,926、5,496,833和5,637,699；欧洲专利公开号：EP0360390、0394989、0428434、0429366、0430771、0436334、0443132、0482539、0498069、0499313、0512901、0512902、0514273、0514274、0514275、0514276、0515681、0517589、0520555、0522808、0528495、0532456、0533280、0536817、0545478、0558156、0577394、0585913、0590152、0599538、0610793、0634402、0686629、0693489、0694535、0699655、0699674、0707006、0708101、0709375、0709376、0714891、0723959、0733632和0776893；PCT国际专利公开号：WO90/05525、90/05729、91/09844、91/18899、92/01688、92/06079、92/12151、92/15585、92/17449、92/20661、92/20676、92/21677、92/22569、93/00330、93/00331、93/01159、93/01165、93/01169、93/01170、93/06099、93/09116、93/10073、93/14084、93/14113、93/18023、93/19064、93/21155、93/21181、93/23380、93/24465、94/00440、94/01402、94/02461、94/02595、94/03429、94/03445、94/04494、94/04496、94/05625、94/07843、94/08997、94/10165、94/10167、94/10168、94/10170、94/11368、94/13639、94/13663、94/14767、94/15903、94/19320、94/19323、94/20500、94/26735、94/26740、94/29309、95/02595、95/04040、95/04042、95/06645、95/07886、95/07908、95/08549、95/11880、95/14017、95/15311、95/16679、95/17382、95/18124、95/18129、95/19344、95/20575、95/21819、95/22525、95/23798、95/26338、95/28418、95/30674、95/30687、95/33744、96/05181、96/05193、96/05203、96/06094、96/07649、96/10562、96/16939、96/18643、96/20197、96/21661、96/29304、96/29317、96/29326、96/29328、96/31214、96/32385、96/37489、97/01553、97/01554、97/03066、97/08144、97/14671、97/17362、97/18206、97/19084、97/19942、97/21702和97/49710；和英国专利公开序号：2 266 529、2 268 931、2 269 170、2 269 590、2 271 774、2 292 144、2 293 168、2 293 169和2 302 689。
优选的用于本发明的速激肽NK-1受体拮抗剂是阿瑞吡坦(同上)，公布于WO 95/16679。
在本发明的一个优选实施方案中，如文中所述，UK-240,455或UK 333,747可与阿瑞吡坦一同给予。
可以方便地使本发明的药用组合物适应口服给药、直肠给药或者胃肠外给药。口服给药，制剂可以片剂、丸剂、胶囊剂、散剂或颗粒剂形式存在；胃肠外给药，可以方便地使用无菌的肠胃外的溶液剂或混悬剂；直肠给药，制剂可以方便地以栓剂形式给予。适当地，本发明药用组合物可以制成适应同时给药、分开给药或按顺序给药的各部分药盒的形式。
本组合物可用药学领域熟知的常规方法配制，例如，Remington：The Science and Practice of Pharmacy(药学的科学和实践)，MackPublishing Company，第19版，1995。
对于联合给药，甘氨酸/NMDA拮抗剂和速激肽NK-1受体拮抗剂可以与显示出所需效应相一致的比例存在。尤其是，甘氨酸/NMDA拮抗剂与速激肽NK-1受体拮抗剂的适宜摩尔比会是约1∶1。优选的，此比率在0.001∶1-1000∶1之间。更优选的是0.01∶1-100∶1。
与速激肽NK-1受体拮抗剂共用治疗神经变性时，甘氨酸/NMDA拮抗剂以每日剂量约0.001-250毫克/千克适当给予，典型的约0.005-100毫克/千克，优选的约0.01-50毫克/千克，更优选约0.05-10毫克/千克。在与甘氨酸/NMDA拮抗剂共用治疗神经变性时，速激肽NK-1受体拮抗剂以每日剂量约0.001到250毫克/千克适当给予，典型的约0.005到100毫克/千克，优选的约0.01到50毫克/千克，更优选约0.05到10毫克/千克。典型的活性组分的共同给药方案是一日1-4次。
以下述非限制性实施例为例说明本发明。
实施例1至4
片剂制备
按下述制备含有UK-240，455和阿瑞吡坦，或UK-333，747和阿瑞吡坦片剂：
| 实施例1 | 实施例2 | |
| UK240，455阿瑞吡坦微晶纤维素改良食物玉米淀粉硬脂酸镁 | 5.0mg10.0mg42.0mg42.0mg1.0mg | 10.0mg10.0mg39.5mg39.5mg1.0mg |
| 实施例3 | 实施例4 | |
| UK333，747阿瑞吡坦微晶纤维素改良食物玉米淀粉硬脂酸镁 | 5.0mg10.0mg42.0mg42.0mg1.0mg | 10.0mg10.0mg39.5mg39.5mg1.0mg |
将所有活性成分、纤维素和一部分玉米淀粉混合，并粒化成10％玉米淀粉糊。所得粒经过筛、干燥并与剩余的玉米淀粉和硬脂酸镁混合。然后将所得粒压制成片剂。
Claims (8)
1.一种甘氨酸/NMDA拮抗剂和速激肽NK-1受体拮抗剂的组合，所述组合在治疗神经变性中同时、分开或按顺序使用。
2.权利要求1定义的组合，其中甘氨酸/NMDA拮抗剂是：
或
3.权利要求2定义的组合，其中甘氨酸/NMDA拮抗剂是UK-240,455。
4.权利要求2定义的组合，其中甘氨酸/NMDA拮抗剂是UK-333,747。
5.前述权利要求中任一项定义的组合，其中速激肽NK-1受体拮抗剂是阿瑞吡坦[2-(R)-(1-(R)-(3，5-双(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟苯基)-4-(3-(5-氧代-1H，4H-1，2，4-三唑基)甲基)吗啉]。
6.一种药用组合物，所述组合物包含前述权利要求中任一项定义的组合以及药学上可接受的载体。
7.权利要求1-5中任一项定义的组合在制备治疗神经变性的药物上的用途。
8.一种治疗神经变性的方法，所述方法包括给予需要这种治疗的患者权利要求1定义的组合。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0310881.8 | 2003-05-12 | ||
| GBGB0310881.8A GB0310881D0 (en) | 2003-05-12 | 2003-05-12 | Pharmaceutical formulation |
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| US (1) | US20070032491A1 (zh) |
| EP (1) | EP1624872A2 (zh) |
| JP (1) | JP2006525983A (zh) |
| CN (1) | CN1784233A (zh) |
| AU (1) | AU2004237127A1 (zh) |
| CA (1) | CA2524904A1 (zh) |
| GB (1) | GB0310881D0 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110730662A (zh) * | 2017-04-10 | 2020-01-24 | 才思治疗公司 | 用于治疗共核蛋白病的nk1-拮抗剂组合和方法 |
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| IL111960A (en) * | 1993-12-17 | 1999-12-22 | Merck & Co Inc | Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them |
| GB9419318D0 (en) * | 1994-09-24 | 1994-11-09 | Pfizer Ltd | Therapeutic agents |
| NZ336842A (en) * | 1997-02-27 | 2000-05-26 | Pfizer | Process of making quinoxalinediones to produce antagonistic effect at NMDA receptors |
| JO2355B1 (en) * | 2003-04-15 | 2006-12-12 | ميرك شارب اند دوم كوربوريشن | Hereditary calcitonin polypeptide receptor antagonists |
| US7494979B2 (en) * | 2003-06-13 | 2009-02-24 | Ironwood Pharmaceuticals, Inc. | Method for treating congestive heart failure and other disorders |
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2003
- 2003-05-12 GB GBGB0310881.8A patent/GB0310881D0/en not_active Ceased
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2004
- 2004-05-04 CA CA002524904A patent/CA2524904A1/en not_active Abandoned
- 2004-05-04 JP JP2006506217A patent/JP2006525983A/ja not_active Withdrawn
- 2004-05-04 WO PCT/GB2004/001926 patent/WO2004098579A2/en not_active Application Discontinuation
- 2004-05-04 US US10/555,711 patent/US20070032491A1/en not_active Abandoned
- 2004-05-04 AU AU2004237127A patent/AU2004237127A1/en not_active Abandoned
- 2004-05-04 CN CNA2004800124780A patent/CN1784233A/zh active Pending
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110730662A (zh) * | 2017-04-10 | 2020-01-24 | 才思治疗公司 | 用于治疗共核蛋白病的nk1-拮抗剂组合和方法 |
| TWI803488B (zh) * | 2017-04-10 | 2023-06-01 | 美商查斯治療公司 | Nk-1拮抗劑組合及治療突觸核蛋白病症之方法 |
Also Published As
| Publication number | Publication date |
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| EP1624872A2 (en) | 2006-02-15 |
| JP2006525983A (ja) | 2006-11-16 |
| CA2524904A1 (en) | 2004-11-18 |
| GB0310881D0 (en) | 2003-06-18 |
| WO2004098579A2 (en) | 2004-11-18 |
| AU2004237127A1 (en) | 2004-11-18 |
| US20070032491A1 (en) | 2007-02-08 |
| WO2004098579A3 (en) | 2005-01-27 |
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