CN1364092A - 联合应用降西沙必利和质子泵抑制剂或h2-受体拮抗剂的方法和组合物 - Google Patents
联合应用降西沙必利和质子泵抑制剂或h2-受体拮抗剂的方法和组合物 Download PDFInfo
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- CN1364092A CN1364092A CN00806999A CN00806999A CN1364092A CN 1364092 A CN1364092 A CN 1364092A CN 00806999 A CN00806999 A CN 00806999A CN 00806999 A CN00806999 A CN 00806999A CN 1364092 A CN1364092 A CN 1364092A
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- optical voidness
- proton pump
- cisapride
- stereoisomer
- pump inhibitor
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Abstract
本发明涉及预防、治疗或控制胃肠道疾病或其症状的方法和组合物,其应用两种或多种试剂或化合物以提供对5-HT3受体、5-HT4受体、和至少一种H2受体和质子泵的三重作用。
Description
1.发明领域
本发明涉及预防、治疗和控制胃肠道疾病或其症状的方法和组合物,其通过服用同时或按顺序作用于5-HT3受体、5-HT4受体和H2受体或质子泵的一种或多种试剂或化合物。
2.发明背景
胃肠道疾病是影响胃肠道即胃和肠的常见疾病。有许多胃肠道疾病,它包括:胃食管反流疾病、呕吐、胃肠道运动性机能障碍、胃肠道溃疡、病理学分泌过多症和胃酸过多症。这些疾病可以通过各种非侵入性方式治疗,例如:给患者服用治疗剂,例如ZANTAC(雷尼替丁)、TRITEC(雷尼替丁)、AXID(尼唑替丁)、TAGAMET(西咪替丁)、PREVACID(兰索拉唑)、PEPCID、PEPCID AC、ACID CONTROLLER TM、MYLANTA AR ACID REDUCER TM(法莫替丁)、PRILOSEC(奥美拉唑)及其它药物。新的药用化合物和制剂正不断被开发。
美国专利US 4,962,115、5,057,525和5,137,896(均为“VanDaele”所发明)公开了N-(3-羟基-4-哌啶烯基)苯甲酰胺类化合物。据说这些化合物能刺激胃肠道***的运动。Van Deale指出:可以通过常规方法独立地得到这些化合物的顺式和反式非对映体外消旋物,这些顺式和反式非对映体外消旋物可以进一步拆分成其光学异构体。这个外消旋体之一为西沙必利,其化学名为顺-4-氨基-5-氯-N-[1-[3-(4-氟苯氧基)丙基]-3-甲氧基-4-哌啶基]-2-甲氧基苯甲酰胺。ScHapira等,Acta Gastroenterolog.Belg.,LIII:446-457(1990)。西沙必利主要被用来治疗胃食管反流疾病(“GERD”),该疾病的特征在于胃中物质反流至食管。西沙必利的市售产品为PROPULSID,其为顺(-)和顺(+)西沙必利非对映体的外消旋混合物。
苯甲酰胺衍生物由于作用于由神经递质血清素调节的神经***从而具有若干显著的药理学作用。据报道:血清素的主要生成和储存部位是胃肠粘膜的肠嗜铬细胞。另外还据报道:血清素提供强大的肠传递和减少吸收时间,并常常并发腹泻。该刺激作用还常常与恶心呕吐有关。
由于能在胃肠道中调节血清素神经***,一些苯甲酰胺衍生物是有效的抗止吐剂,并用于在癌症化疗或放疗期间控制呕吐。Costall等,NeuroPharmacology,26:1321-1326(1987)。该作用是其在特定部位特别是3-型5-羟色胺(5-HT3)受体阻断血清素能力的结果。Clarke等,Trends in Pharmacological Science,10:385-386(1989)。化疗和放疗通过损害胃肠道中肠嗜铬细胞可以引起恶心和呕吐。结果,神经递质血清素被释放出来,在脑部postrema区域的化学受体引发区刺激传入性迷走神经纤维(因此引发呕吐反流)和血清素受体。目前尚不清楚苯甲酰胺衍生物这种作用的解剖部位,也不清楚这种作用是中枢(CNS)作用还是外周作用或其结合。Barnes等,J.Pharm.Pharmacol.,40:586-588(1988)。
某些苯甲酰胺衍生物的第二种明显作用是从食道至近小肠区域增加胃肠道平滑肌活性,从而加速食道和小肠传递以及有助于胃排空和增加下部食管***紧张性。Decktor等,Eur.J.Pharmacol.,147:313-316(1988)。虽然苯甲酰胺衍生物本身不属于胆碱能受体拮抗剂,但前面所述的平滑肌作用可以被毒蕈碱受体阻断剂例如阿托品或神经传递抑制剂例如阻断钠通道的河豚毒素所阻断。Fernandez和Massingham,Zife Sci.,36:1-14(1985)。业已报道对小肠中血清素收缩效果的类似阻断活性。Craig和Clarke,Brit.J.Pharmacol.,96:247P(1989)。有人认为:一些苯甲酰胺衍生物的主要平滑肌作用是对一类称作5-HT4受体的血清素受体激动作用的结果,5-HT4受***于肠壁肠肌丛中间神经元表面。Clarke等,Trends inPharmacological Science,10:385-386(1989)和Dumuis等,N.S.Arch.Pharmacol.,340:403-410(1989)。然后这些受体的活化增加乙酰胆碱从位于周围平滑肌纤维附近的副交感神经末端的释放。正是由于乙酰胆碱与其在平滑肌膜表面的受体结合才真正引起肌肉收缩。
据报道,西沙必利进入中枢神经***,并与5-HT4受体结合。这意味着西沙必利可能具有中枢调节作用。西沙必利是有效的5-HT4受体配体,而该受***于中枢神经***的若干区域。Dumuis等,N.S.Arch.Pharmacol.,340:403-410(1989)。调节血清素能***可能具有多种行为作用。
把外消旋的西沙必利与其它治疗剂联合给药将使肝对西沙必利的代谢产生抑制。例如,酮康唑对西沙必利的动力学具有明显的影响,因为其抑制西沙必利的代谢消除,导致稳态血浆浓度增加8倍。Physician’s Desk Reference,Medical Economics Co.,Inc.,P.1308-1309页,第52版(1998)。外消旋西沙必利和其它治疗剂相互作用还可引起潜在的心血管副作用,例如心脏中毒。当病人体内其它药物干扰西沙必利的代谢从而引起体内外消旋西沙必利积累时,会发生这种潜在的副作用。
这些相互作用成为应用外消旋西沙必利的显著缺陷;特别是,由于经常在另一种治疗剂之前、同时或紧随之后应用外消旋西沙必利,更存在这种缺陷。另外,给人服用外消旋西沙必利还发现能引起副作用例如心律失常,包括室性心动过速、心室纤维性颤动、QT延长和torsades de pointers、中枢神经***(“CNS”)作用、增加收缩压、与其它药物相互作用,腹泻、腹部痉挛和心脏衰退。
外消旋西沙必利在人体内的代谢途径主要通过哌啶氮原子的氧化N-脱烷基化反应或者通过4-氟苯氧基或苯甲酰胺环上发生芳基羟基化反应。Meuldermans等,Drug Metab.Dispos.,16(3):410-419(1988);和Meuldermans等Drug Metab.Dispos.,16(3):403-409(1988)。降西沙必利(Norcisapride),化学名为4-氨基-5-氯-N-(3-甲氧基-4-哌啶基)-2-甲氧基苯甲酰胺,其为西沙必利的活性代谢物。
近来,有研究者报道:西沙必利代谢物降西沙必利的光学纯(+)立体异构体具有许多有用的特性,而不具有某些外消旋西沙必利的副作用。特别地,美国专利5,739,151公开了应用光学纯(+)降西沙必利产生止吐效果和治疗其它疾病的方法。
已经被研究用于治疗胃肠道疾病的其它试剂或化合物包括质子泵抑制剂和H2受体拮抗剂。质子泵抑制剂通过抑制H+-K+ATP酶从而调节胃液酸度来治疗胃肠道疾病。H2受体拮抗剂抑制组胺与H2受体的结合从而调节胃酸分泌。Goodman & Gilman,The Pharmacological Basisof Therapeutics,第9版,第901-915页(1996年)。
跨细胞膜的胃酸浓度梯度变化较大。体内最大梯度可能存在于分泌盐酸进入胃液的胃内壁细胞质膜两侧。由于胃液中盐酸浓度可高达0.1M,细胞中的H+浓度约10-7M,壁细胞能够在约1百万到1的浓度梯度环境下逆向分泌H+离子。一种称为H+-K+ATP酶的膜结合酶能够有助于H+逆浓度梯度跨膜转运以交换K+从而形成胃盐酸。每分子细胞液ATP水解成ADP和磷酸盐可以把2H+离子从细胞液跨膜转运至胃。Goodman& Gilman,The Pharmacological Basis of Therapeutics,第9版,第901-915页(1996年)。
通过特异性抑制胃壁细胞分泌表面的H+-K+ATP酶***,质子泵抑制剂能抑制酸生成的最后一个步骤-胃酸分泌。质子泵抑制剂包括苯并咪唑化合物,例如奥美拉唑(PRILOSEC)、兰索拉唑(PREVACID)和泮托帕唑。这些质子泵抑制剂含有亚硫酰基,该基团处于取代的苯并咪唑和哌啶环之间。在中性pH环境下,奥美拉唑、兰索拉唑和泮托帕唑是化学稳定的、脂溶性弱碱,没有抑制活性。这些不带电荷的弱碱从血液转运到壁细胞,再分散于分泌小管,药物在此处被质子化从而被捕获。这些质子化物质重排形成次磺酸和亚磺酰胺,后者能与H+-K+ATP酶的巯基相互作用。当每分子酶与两分子抑制剂发生作用时,该酶就被完全抑制住。质子泵抑制剂的作用特异性被认为来源于:a)H+-K+ATP酶的选择性分布;b)催化反应性抑制剂的产生需要酸性环境;和c)在酸性canuliculi环境中和邻近靶酶区域捕获质子化药物和阳离子亚磺酰胺。Goodman & Gilman,The PharmacologfcalBasis of Therapeutics,第9版,第901-915页(1996年)。
H2受体拮抗剂竞争性抑制组胺与H2受体的相互作用。它们是高选择性的,对H1受体几乎没有或没有作用。虽然H2受体存在于许多组织包括血管和支气管平滑肌中,但除影响胃酸分泌外,H2受体拮抗剂几乎完全不干扰生理功能。H2受体拮抗剂包括尼唑替丁(AXID)、雷尼替丁(ZANTAC和TRITEC)、法莫替丁(PEPCIDAC)和西咪替丁(TAGAMET)。Goodman & Gilman,The Pharmacological Basis ofTherapeutics,第9版,第901-915页(1996年)。
H2受体拮抗剂抑制由组胺、其它H2激动剂、胃泌素和毒蕈碱激动剂(程度较低)引起的胃酸分泌。H2受体拮抗剂还抑制基础的和夜间的酸分泌,该效果是其主要临床功效。
虽然已经存在治疗剂,仍然需要对胃肠疾病更有效的广谱治疗。例如,需要有安全有效的方法和组合物用于预防、治疗和控制胃肠道疾病而不产生副作用和有害的药物-药物相互作用。
3.发明概述
本发明包括通过三种不同部位的生物学作用来预防、治疗或控制胃肠道疾病,即对5-HT3受体、5-HT4受体以及H2受体或质子泵的作用。这三重作用的用途被认为提供出人意料的优良治疗特性。与单独作用于三个位点的任意一个位点的用途相比,应用三重作用治疗毒性更低和/或预防、治疗和控制胃肠道疾病的效果更强。
在一个实施方案中,应用三种治疗试剂或化合物,其中之一提供对5-HT3受体的作用、另一种提供对5-HT4受体的作用、第三种为质子泵抑制剂或H2受体拮抗剂。例如,在优选的实施方案中,应用西沙必利、奥丹亚龙以及质子泵抑制剂或H2受体拮抗剂来预防、治疗或控制胃肠道疾病。在一个更优选的实施方案中,应用光学纯的(+)西沙必利或光学纯的(-)西沙必利或其可药用盐、光学纯的R(+)奥丹亚龙或其可药用盐、和质子泵抑制剂或H2受体拮抗剂。
在另一实施方案中,本发明涉及应用两种或多种试剂或化合物协同提供对5-HT3受体、5-HT4受体和H2受体或质子泵的三重作用。在优选的实施方案中,应用两种试剂或化合物,一种提供对5-HT3受体和5-HT4受体的双重作用,另一种提供对H2受体或质子泵的作用。例如,在该优选实施方案中,光学纯(+)降西沙必利或其可药用盐(其兼具5-HT3受体和5-HT4受体活性)和质子泵抑制剂或H2受体拮抗剂被用于预防、治疗或控制胃肠道疾病。
本发明还涉及两种独立分开的药物组合物在预防、治疗或控制患有胃肠道疾病或其症状的病人中的应用,其中之一含有治疗有效量的光学纯(+)降西沙必利或其可药用盐,另一种含有治疗有效量的质子泵抑制剂或H2受体拮抗剂。
另一种可选择的方式是,本发明还包括药物组合物,其含有光学纯的(+)降西沙必利或其可药用盐与一种质子泵抑制剂或H2受体拮抗剂的联合。这样的单一单位剂型含有存在于合适载体中的约0.5mg至约500mg光学纯的(+)降西沙必利或其可药用盐,和约1mg至约200mg质子泵抑制剂或约1mg至约2400mg H2受体拮抗剂。
本发明的药物组合物和方法,特别是那些含有治疗有效量的光学纯(+)降西沙必利或其可药用盐的药物组合物和方法可以用于预防或减轻胃肠道疾病症状,同时能降低或避免由服用常规治疗剂例如常规5-HT3受体拮抗剂、5-HT4受体激动剂或拮抗剂、H2受体拮抗剂和质子泵抑制剂所带来的副作用。而且,本发明的组合物和方法包括治疗、预防或控制胃肠道疾病并同时降低或避免有害的药物-药物相互作用,已知当应用已有的市售产品例如外消旋西沙必利时,会出现这种相互作用。
4.发明详述
本发明包括胃肠道疾病的预防、治疗或控制,其途径是通过在三个不同位点的生物学作用,即作用于5-HT3受体、5-HT4受体,和H2受体或质子泵(例如抑制H+-K+-ATP酶***)。这三重位点作用的应用被认为提供比常规胃肠道疾病的治疗有出人意外的优良治疗特性。与应用单独作用于三个位点的任意一个位点的试剂相比,应用三重作用治疗能更安全和/或更有效地预防、治疗和控制胃肠道疾病。
更具体地说,本发明还涉及至少三种试剂或化合物在预防、治疗或控制胃肠道疾病或其症状中的应用,其中一种作用于5-HT3受体、另一种作用于5-HT4受体,第三种作用于质子泵***或H2受体。优选地,这三种化合物为西沙必利、奥丹亚龙和质子泵抑制剂或H2受体拮抗剂。更优选地,这三种化合物为光学纯的(+)西沙必利或光学纯的(-)西沙必利或其可药用盐、光学纯的R(+)奥丹亚龙或其可药用盐和质子泵抑制剂或H2受体拮抗剂。
本发明还涉及提供作用于5-HT3受体、5-HT4受体和H2受体或质子泵机理的三重作用的至少两种试剂或化合物在预防、治疗或控制胃肠道疾病中的协同应用。优选地,应用两种试剂或化合物,一种提供在5-HT3受体和5-HT4受体处的双重作用,另一种提供在H2受体或质子泵***处的作用。更优选地,这两种试剂或化合物为光学纯的(+)降西沙必利或其可药用盐和H3受体拮抗剂或质子泵抑制剂。
可以用本发明组合物和方法治疗的胃肠道疾病包括但不限于上和下胃肠道***疾病、胃-食道反流疾病(“GERD”)、呕吐、胃肠道运动机能障碍、胃肠道溃疡、病理性分泌过多症和胃酸过多。所述胃肠道疾病还包括但不限于消化不良、胃轻瘫、便秘、手术后肠梗阻、肠道假性阻塞、胃溃疡、十二指肠溃疡、胃灼热、胃酸过多性消化不良、侵蚀性食管炎、胃发酸、胃不适和佐-埃综合症。
在最优选的实施方案中,本发明涉及光学纯(+)降西沙必利或其可药用盐和至少一种质子泵抑制剂或H2受体拮抗剂在预防、治疗或控制胃肠道疾病或其症状中的应用。应该注意:尽管光学纯(+)降西沙必利是优选的,但在本发明的方法和组合物中,可以应用外消旋降西沙必利或其可药用盐代替光学纯(+)降西沙必利。类似地,若适合,作为供选择方案,可以应用质子泵抑制剂或H2拮抗剂的光学纯立体异构体或其活性代谢物以及其可药用盐。本文仅仅以举例说明的方式举出具体的实施例。
不被理论所束缚,据信应用具有5-HT3受体拮抗剂和5-HT4受体激动剂双重活性的试剂或化合物以及质子泵抑制剂或H2受体拮抗剂提供三重作用,这种应用令人意外地产生:更明显的剂量相关性效果、副作用的减少、由协同活性引起的良好治疗和由此所致的高治疗指数。例如,光学纯(+)降西沙必利具有5-HT3受体拮抗剂和5-HT4受体激动剂双重活性,当与质子泵抑制剂或H2受体拮抗剂联合应用时将具有三重作用。因此,与单独应用5-HT3受体拮抗剂、5-HT4受体激动剂、具有5-HT3受体拮抗剂和5-HT4受体激动剂双重活性的试剂或化合物、质子泵抑制剂或H2受体拮抗剂相比,更需要应用本发明的组合物和方法。
根据本发明,联合应用光学纯(+)降西沙必利或其可药用盐和质子泵抑制剂或H2受体拮抗剂预防、治疗或控制胃肠道疾病被认为能降低或避免与已有用于治疗胃肠道疾病的产品例如外消旋西沙必利有关的副作用。另外,还认为该实施方案用于降低或避免与外消旋西沙必利有关的不良的药物-药物相互作用。
本发明还涉及预防、治疗或控制由5-HT3受体、5-HT4受体或质子泵或H2受体机能不良引起的疾病的方法,该方法通过服用治疗有效量的光学纯(+)降西沙必利或其可药用盐和治疗有效量的质子泵抑制剂或H2受体拮抗剂。
本发明还涉及预防、治疗或控制GERD、呕吐、胃肠道运动机能障碍、胃肠道溃疡、病理性分泌过多症或胃酸过多的方法,包括:给患者服用治疗有效量的光学纯(+)降西沙必利或其可药用盐和质子泵抑制剂或H2受体拮抗剂。在具体的实施方案中,本发明还涉及联合应用这些试剂用于预防、治疗或控制侵蚀性食管炎、消化不良、胃轻瘫、便秘、手术后肠梗阻、肠道假性阻塞、胃溃疡、十二指肠溃疡、胃灼热、胃酸过多性消化不良、侵蚀性食管炎、胃发酸、肚子痛和佐-埃综合症。
涉及三重作用治疗应用的本发明还可任选地包括一种或多种另外的已知用于治疗胃肠道疾病的治疗试剂的应用。所述另外的治疗剂的例子包括但不限于羟嗪(ANTARAX)、苯海拉明(BENADRYLPARENTAREL)、丙氯拉嗪(COMPAZINE)、屈***酚(MARINOL)、异丙嗪(PHENERGAN)、美克洛嗪(ANTIVERT)、曲美苄胺(TIGAN)、硫乙拉嗪(TORECAN)、奋乃静(TRILAFON)和硫糖铝(CARAFATE)等,当合适时,还包括其光学纯的立体异构体或其活性代谢物。
本发明方法中所用的两种或多种治疗剂可以同时、连续或联合给药,也就是说,光学纯(+)降西沙必利或其可药用盐和质子泵抑制剂或H2受体拮抗剂以及任选的其它治疗剂可以联合给药、同时但独立地给药或者连续给药。
本发明的方法和组合物被认为能够提供降低或避免与用于治疗胃肠道疾病的现有方法和组合物有关的副作用的优点。参见:Physician’s Desk Reference,Medical Economics Co.,Inc.,第52版(1998和1999)。
本文所用的术语“不利的作用”和“有害的副作用”包括但不限于心律不齐、心脏传导障碍、食欲兴奋、体重增加、镇静、胃肠道痛苦、头痛、口干、便秘、腹泻和药物-药物相互作用。术语“心律不齐”包括但不限于心室性心动过速、torsades de points、QT延长和心室纤维性颤动。
本文所用的术语“胃肠道疾病”包括但不限于胃肠道运动机能障碍、GERD、呕吐、胃肠道溃疡、病理性胃酸分泌过多症、胃酸过多症、侵蚀性食管炎、消化不良、胃轻瘫、便秘、术后肠梗阻、肠假性梗阻、胃溃疡、十二指肠溃疡、胃灼热、胃酸过多性消化不良、侵蚀性食管炎、胃发酸、胃不适和佐-埃综合症。
本文所用的术语“患者”是指哺乳动物特别是人。
本文所用的术语“外消旋”是指以比例约1∶1存在的(+)和(-)对映异构体混合物。
本文所用的术语“光学纯”指基于活性成分总重含有约90%重量以上的所需立体异构体的混合物,其中所需立体异构体优选大于约95%重量、更优选大于约99%重量,例如当用西沙必利时,所述活性成分总重指(+)西沙必利。本文所用的术语“基本上不含有”指小于约10%重量、优选小于约5%重量、更优选小于约1%重量的非所需要的立体异构体,例如(-)降西沙必利。
本文所用的术语“5-HT3受体拮抗剂”指能够可逆性结合到3-型5-羟色胺受体的化合物。5-HT3受体拮抗剂包括但不限于格兰西龙(KYTRIL)、甲氧氯普胺(REGLAN)、奥丹亚龙(ZOFRAN)、renzapride、扎考必利和托比色创,合适时可以为上述物质的光学纯立体异构体或其活性代谢物。
本文所用的术语“5-HT4受体激动剂”指能可逆性结合于4-型5-羟色胺受体的化合物。5-HT4受体激动剂包括但不限于降西沙必利和西沙必利,当合适时为其光学纯立体异构体或其活性代谢物。
本文所用的术语“质子泵”指H+-K+-ATP酶,一种膜结合的酶,其有助于H+逆浓度梯度跨膜的主动转运。
本文所用的术语“质子泵抑制剂”指任何通过在胃上皮细胞分泌腺的表面抑制H+-K+-ATP酶***来抑制或遏抑胃酸分泌的试剂或化合物。质子泵抑制剂包括但不限于拉唑类(prazole)衍生物例如奥美拉唑、兰索拉唑、泮托帕唑、拉比拉唑(rabeprazole),当合适时,可以是其光学纯立体异构体例如光学纯(+)兰索拉唑、光学纯(-)兰索拉唑、光学纯(+)奥美拉唑、光学纯(-)奥美拉唑、光学纯(+)拉比拉唑、光学纯(-)拉比拉唑、光学纯(+)泮托帕唑和光学纯(-)泮托帕唑,或其活性代谢物。适合用于本发明的质子泵抑制剂的活性代谢物包括但不限于羟基奥美拉唑、羟基兰索拉唑、奥美拉唑的羧酸衍生物和脱甲基泮托帕唑,合适时,可以应用其光学纯的立体异构体。例如,可以按照本领域普通技术人员公知的合成方法,尤其是根据US 4,544,750、4,620,008、4,620,008、4,758,579、5,045,552、5,374,730、5,386,032、5,470,983和5,502,195制备奥美拉唑、兰索拉唑、泮托帕唑和拉比拉唑,这些专利公开的内容在此引入作为参考。
本文所用的术语“H2受体拮抗剂”指能竞争性抑制组胺与H2受体相互作用的任意试剂或化合物。H2受体拮抗剂包括但不限于西咪替丁、法莫替丁、雷尼替丁、尼唑替丁,合适时可以为其光学纯立体异构体或其活性代谢物。H2受体拮抗剂的活性代谢物包括但不限于N2-单脱甲基尼唑替丁,和合适时可以是其光学活性立体异构体。
尼唑替丁可以按照本领域普通技术人员已知的合成方法,特别是可以采用US 5,541,335和US 5,700,945中公开的方法制备,其公开的内容在此引入作为参考。雷尼替丁可以按照本领域普通技术人员已知的方法合成,特别是可以采用US 5,118,813公开的方法制备,其公开的内容在此引入作为参考。西咪替丁可以按照本领域普通技术人员已知的方法制备,特别是可以采用US 4,413,129、US4,855,439、US4,886,910、US 4,886,912和US 5,118,813公开的方法,其公开的内容在此引入作为参考。另外,法莫替丁可以按照本领域普通技术人员已知的合成方法制备,例如按照Guimaraens等ContactDermatitis,31(4):259(1994)中描述的方法制备。
本发明预防、治疗或控制的疾病可以参见Stedman’s MedicalDictionary第26版,Williams和Wilkins(1995)。
本文所用的术语“胃-食道反流症”或“GRED”被定义为以胃中内容物反流入食道为特征的疾病。
本文所用的术语“胃肠道溃疡”被定义为以胃肠道壁表面有损害为特征的疾病,其由表面组织损失所引起,通常伴有炎症。胃肠道溃疡包括但不限于十二指肠溃疡和胃溃疡。
本文所用的术语“侵蚀性食道炎”被定义为由酸性胃内容物反流引起的以食道下部炎症为特征的疾病,其通常由下部食道***机能障碍所引起。
本文所用的术语“消化不良”被定义为以消化功能或机能损害为特征的疾病,其可表现为原发性胃肠道机能障碍症状或由其它疾病例如阑尾炎、胆囊失调或营养不良所引起的综合症。
本文所用的术语“胃轻瘫”被定义为胃麻痹,其由胃运动异常所引起,或者其被定义为一些疾病例如糖尿病、全身进行性硬化症、神经性厌食或肌强直性营养不良的并发症。
本文所用的术语“便秘”被定义为以不经常或难以排便为特征的疾病,其由一些疾病例如肠肌肉紧张缺乏或肠痉挛状态所引起。
本文所用的术语“术后肠梗阻”被定义为由手术后肌肉紧张破裂所引起的肠内阻塞。
本文所用的术语“预防”和“防止”被分别定义为阻止或阻碍和阻止或阻碍患者疾病或病症的发生,其中所述的患者具有患这样的疾病或病症的危险性,所述患者包括但不限于患有应激状态(stress)的患者。
本文所用的术语“肠假性梗阻”被定义为以便秘、绞痛和呕吐但没有物理性阻塞为特征的疾病。
本文所用的术语“胃酸过多症”被定义为以胃液中酸度异常高为特征的疾病。
本文所用的术语“治疗有效量”被定义为治疗剂单独应用或与其它药物联合应用以提供预防、治疗或控制胃肠道疾病治疗效果的治疗剂的量,其中所述胃肠道疾病包括但不限于胃肠道运动机能障碍、GERD、呕吐、胃肠道溃疡、病理性胃酸分泌过多症、胃酸过多症或其症状。对于各种疾病可以应用不同的治疗有效量,如同本领域普通技术人员容易知道的。
光学纯(+)降西沙必利可以由西沙必利外消旋混合物得到,其化学合成可以按照1983年4月13日公开的欧洲专利申请0,076,530A2记载的方法进行,或者按照US 4,962,115、5,057,525或5,137,896记载的方法进行,这些文献公开的内容在此引入作为参考。还可参见:Van Daele,等Drug Development Res.,8:225-232(1986)。在Meuldermans,W等Drug Metab.Dispos.,16(3):410-419(1988)和Meuldermans,W.,等Drug Metab.Dispos.,16(3):403-409(1988)中记载了西沙必利代谢为降西沙必利。本领域普通技术人员也知道外消旋降西沙必利的制备方法,特别是可以参见Van Daele的EP0,076,530A2和US 5,137,896,这些专利所公开的内容在此引入作为参考。也可以应用常规方式例如应用光学活性拆分酸通过拆分对映异构体从外消旋混合物制备得到本文所讨论的手性化合物的光学纯立体异构体。本领域普通技术人员也知道外消旋化合物的拆分方法,尤其可以参免:Jacques,J.等Enantimers,Racemates and Resolutions,Wiley-Interscience纽约(1981);Wilen,S.H.,等Tetrahedron,33:2725(1977);Eliel,E.L.StereochemisTry of Carbon Compounds,McGraw-Hill,NY,(1962);Wilen,S.H.Tables of Resolving Agentsand Optical Resolutions,E.L.Eliel,编辑Univ.of Notre DamePress,Notre Dame,IN,第268页(1972)。
除了应用上述分离技术外,也可以应用本领域普通技术人员公知的方法,通过立体专一性合成制备光学纯的化合物。手性合成可以产生高对映异构体纯度的产品。然而,在某些情况下,产品的对映异构体纯度不够高。本领域技术人员理解:可以应用上述分离方法对通过手性合成得到的活性立体异构体拆分进一步提高其对映异构体纯度。
例如,也可以通过酶生物催化拆分从外消旋降西沙必利中混合物制备光学纯的(+)降西沙必利。这种合成对本领域普通技术人员来说是已知的,尤其可以参见US 5,057,427和5,077,217,这些专利公开的内容在此引入作为参考。
在本文所述疾病和症状的急性或慢性控制中,所述活性成分(例如(+)降西沙必利、5-HT3拮抗剂、5-HT4激动剂或拮抗剂、质子泵抑制剂或H2受体拮抗剂)的预防剂量或治疗剂量大小可以根据所预防、治疗或控制的疾病的性质和严重程度和给药途径变化。例如,可以采用口服、粘膜(包括直肠)、胃肠外(包括皮下、肌肉内、弹丸注射和静脉注射)、舌下、经皮、鼻内和***等方式给药。所用的剂型包括片剂、胶囊、锭剂、糖锭、分散体、混悬剂、栓剂、溶液剂、胶囊、软弹性明胶胶囊和贴剂等。所用剂量和甚至给药频率也可按照年龄、体重和各个患者的反应进行调整。本领域技术人员考虑上述因素后容易选择合适的给药方案。
通常来说,用于治疗所述疾病的5-HT3受体拮抗剂、5-HT4受体激动剂或提供5-HT3受体和5-HT4受体双重作用的治疗剂的每日总剂量为约0.5mg-约500mg、优选约1mg-约350mg、更优选约2mg-约250mg。
本领域技术人员容易确定质子泵抑制剂合适的每日剂量。通常来说,治疗所述疾病的质子泵抑制剂(例如兰索拉唑、泮托帕唑、拉比拉唑、奥美拉唑或其光学纯立体异构体或其活性代谢物)的每日总剂量范围是约1mg-约200mg、优选约5mg-约150mg、更优选约10mg-约100mg。
另外,本领域技术人员容易确定H2受体拮抗剂的合适的每日剂量范围。目前所用的已知的H2受体拮抗剂合适剂量可以参见例如Physician’s Desk Reference,Medical Economics Co.,Inc.,第52版(1999年)。例如,雷尼替丁所用的口服每日剂量范围约1mg-约800mg、优选约100mg-约600mg、更优选约250mg-约500mg。西咪替丁的口服每日剂量范围是约1mg-约2400mg、优选约400mg-约1600mg、更优选约600mg-约1000mg。法莫替丁的口服每日剂量范围是约1mg-约200mg、优选约10mg-约80mg、更优选约15mg-约50mg。尼唑替丁的口服每日剂量范围是约1mg-约600mg、优选约50mg-约500mg、更优选约250mg-约350mg。
在控制患者症状时,在治疗开始可以按较低剂量例如给药约0.5mg-约10mg(+)降西沙必利和约1mg-约5mg质子泵抑制剂或约1mg-约5mg H2受体拮抗剂,然后根据患者的综合反应再增加至高达推荐的每日剂量或更高剂量。另外,对于儿童、65岁以上的年老患者和那些肝肾功能不全的患者,开始时推荐使用低剂量,然后应根据个体反应和血液含量进行滴定。在某些情况下,可能还需要采用此处所述范围之外的各个活性成分剂量,这对于本领域技术人员来说是显而易见的。另外,需要注意:根据各个患者的反应,临床医师或主治大夫知道如何以及何时中断、调整或终止治疗。
用于本发明的药物组合物可以含有5-HT3受体拮抗剂和5-HT4受体激动剂或提供5-HT3受体和5-HT4受体双重作用的治疗剂以及含有质子泵抑制剂或H2受体拮抗剂作为活性成分,所述组合物可能还含有可药用载体和任选的其它治疗成分。
在一个实施方案中,所述药物组合物含有三种治疗剂:5-HT3受体拮抗剂和5-HT4受体激动剂以及质子泵抑制剂或H2受体拮抗剂,还可以含有可药用载体和任选的其它治疗成分。在优选的实施方案中,该药物组合物含有两种治疗剂,一种提供5-HT3受体和5-HT4受体的双重作用,另一种为质子泵抑制剂或H2受体拮抗剂。
本文所用的术语“可药用盐”指由可药用非毒性酸制备得到的盐,这些酸包括但不限于无机酸、有机酸、溶剂化物、水合物或包合物。所述无机酸的例子为盐酸、氢溴酸、氢碘酸、硝酸、硫酸和磷酸。合适的有机酸可以选自,例如,脂肪羧酸、芳香羧酸和有机磺酸类,其具体例子为甲酸、乙酸、丙酸、琥珀酸、苯甲酸、樟脑磺酸、柠檬酸、富马酸、葡糖酸、羟乙磺酸、乳酸、苹果酸、半乳糖二酸、酒石酸、对甲基苯磺酸、羟基乙酸、葡糖醛酸、马来酸、糠酸、谷氨酸、苯甲酸、邻氨基苯甲酸、水杨酸、苯乙酸、杏仁酸、扑酸(双羟萘酸)、甲磺酸、乙磺酸、泛酸、苯磺酸、硬脂酸、磺胺酸、海藻酸和半乳糖醛酸等。特别优选的酸为氢溴酸、盐酸、磷酸和硫酸。在一个实施方案中,5-HT3受体拮抗剂、5-HT4受体激动剂或提供5-HT3受体拮抗剂和5-HT4受体激动剂双重作用的治疗剂以游离碱形式或水合物形式给药。例如,光学纯的(+)降西沙必利以游离碱或水合物形式给药。
本发明还涉及酸性的活性化合物或试剂的用途,其中的盐可以用可药用的非毒性碱制备,所用的碱包括有机碱、无机碱、溶剂化物、水合物或其包合物。所述无机碱包括但不限于铝、钙、锂、镁、钾、钠和锌的金属盐。合适的有机碱包括但不限于N,N-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)、赖氨酸和普鲁卡因。
在实际应用中,本发明药物组合物中的活性试剂可以作为活性成分按照常规药物混合技术与可药用载体充分混合。所述载体可以是多种形式并根据所需给药的剂型含有多种成分。本发明的组合物包括但不限于混悬剂、溶液剂和酏剂;气溶胶;或赋形剂包括但不限于淀粉、糖类、微晶纤维素、稀释剂、制粒剂、润滑剂、粘合剂和崩解剂等。优选地,药物组合物为口服剂型。由于易于给药,片剂和胶囊剂为优选的剂型,其代表最有利的口服单位剂型,其中应用固体药物辅料。如果需要,可以用标准水或非水溶液技术对片剂进行包衣。
优选地,本发明的口服药物组合物按单次或多次给药,每天1-4次。所述口服剂型方便地可以为单位剂型,并可以按照制药领域公知的任意方法制备。
适合口服给药的本发明药物组合物可以是分散的药物单位剂型,例如胶囊、扁囊剂、软弹性明胶胶囊、片剂、胶囊或气溶胶喷雾剂,各个剂型含有预定量的活性成分,或者为粉剂或粒剂、或在水或非水液体中的溶液剂或混悬剂、水包油乳剂或油包水液体乳剂。所述组合物可以按照制药领域公知的任意方法制备,但所有方法包括把一种或多种活性成分与载体混合的步骤。通常来说,所述组合物制备如下:把活性成分和液体载体或微细的固体载体或这两者均匀地充分混合,然后,如果需要,把所述产品制成需要的形状。口服固体制剂比口服液体制剂更优选。一种优选的口服固体制剂为胶囊,但最优选的口服固体制剂为片剂。
例如,可以通过任选地与一种或多种辅料压制或模印制备得到片剂。压制片可以这样制备:在合适的机器中,把自由流动形式例如粉状或粒状的活性成分任选地与粘合剂、润滑剂、惰性稀释剂、制粒剂、表面活性剂或分散剂等压片。模印片可以这样制备:在合适的机器中,把用惰性液体稀释剂弄湿的粉末化合物的混合物模印。优选地,每个片剂、扁囊剂、caplet或胶囊含有约0.5mg至约500mg光学纯(+)降西沙必利、更优选约1mg至约350mg,并含有约1mg至约200mg质子泵抑制剂或约1mg至约2400mg H2受体拮抗剂。
可以应用本领域公知的常规方法把适于口服的本发明药物组合物制备成软弹性明胶胶囊单位剂型的药物组合物,参见:例如Ebert,Pharm.Tech,1(5):44-50(1977)。软弹性明胶胶囊具有一个软的球形明胶壳,比硬明胶胶囊的壳略厚些,通过加入增塑剂例如甘油、山梨醇或类似的多元醇使明胶增塑。通过改变所用明胶的类型以及水和增塑剂的用量可以改变明胶壳的硬度。软明胶壳可以含有防腐剂例如对羟基苯甲酸甲酯和丙酯和山梨酸,以防止真菌的生长。所述活性成分可以溶解或悬浮于液体载体或辅料中,其中所述的载体或辅料例如植物油或矿物油、二醇类例如聚乙二醇和丙二醇、甘油三酯、表面活性剂例如聚山梨醇酯或其混合物。
除上面所用的常规剂型外,本发明的化合物还可以通过控释方式或释放设备给药,这些方式为本领域普通技术人员熟知的方式,例如公开于US 3,845,770;3,916,899;3,536,809;3,598,123;和4,008,719、5,674,553、5,059,595、5,591,767、5,120,548、5,073,543、5,639,476、5,354,556和5,733,566中,这些公开的内容在此引入作为参考。这些药物组合物使一种或多种活性成分控释或缓释,其中应用辅料例如羟丙甲基纤维素、其它聚合物基质、凝胶、可渗透膜、渗透***、多层包衣、微粒、脂质体或微球等或者以不同比例应用所述物质的混合物来提供所需要的释放特性。可容易地选择本领域普通技术人员已知的合适控释制剂(包括本文描述的制剂)用于本发明的药物组合物。因此,本发明包括适合控制释放的口服单个单位剂型例如片剂、胶囊、gelcaps和caplets等。
所有控释药物产品具有共同的目标即提供比相应非控释产品更好的药物治疗效果。作为理想地情况,在药物治疗中应用最佳设计的控释制剂的特征在于:在最短的时间内应用最少量的药物治疗或控制病症。控释制剂的优点包括:1)延长药物的治疗活性;2)降低用药频率;和3)增强病人顺从性。
大多数控释制剂被设计成起初释放迅速产生所需治疗效果的药物量,在逐渐和持续释放其余量的药物以在较长时间内维持该治疗效果的水平。为了使体内维持恒定的药物浓度,药物必须以等同于体内代谢和***药物量的速率释放。
可以通过各种引诱剂刺激活性成分的控制释放例如pH、温度、酶、水或其它生理条件或化合物。在本发明上下文中,术语“控释组份”被定义为有助于活性成分控制释放的化合物或化合物的混合物,所述化合物包括但不限于聚合物、聚合物基质、凝胶、可渗透膜、脂质体、微球等。
本发明药物组合物还可以制备成经注射给药(皮下、弹丸注射、肌肉内注射或静脉注射)的胃肠外给药剂型,并可以分散于单位剂型中例如多剂量容器或安瓿中。这样的胃肠外给药组合物可以是处于水性或油性载体中的悬浮剂、溶液剂或乳剂等,除活性成分外,其还可含有一种或多种配方剂例如分散剂、悬浮剂、稳定剂和防腐剂等。
另一种给药途径为透皮释放,例如经腹部皮肤贴片给药。
本发明还通过下列实施例解释,详细描述本发明的化合物和组合物的制备及其应用。显然,对本领域技术人员来说,可以在不偏离本发明的目的和权利的前提下对本发明的材料和方法作出许多改进。
5.实施例
5.1实施例1:受体结合
5-HT3受体
测试了外消旋降西沙必利、外消旋西沙必利以及它们的(+)和(-)立体异构体与来源于N1E-115细胞的5-HT3受体亚型的结合(Cerep,Celle l′Evescault,法国)。
在与适当的配体一起培养后,在真空下用GF/B玻璃纤维过滤器快速过滤该制品,然后通过Brandel或Packard细胞收集器应用冰冷缓冲液洗涤。应用液体闪烁鸡尾酒剂(制剂989)通过液体闪烁计数(LS6000,Beckman)测定结合放射活性。
与受体的特异性放射配体结合被定义为总结合与在过量未标记配体存在下测定的非特异性结合之差。把结果表示为在所述化合物存在下获得的特异性结合的百分抑制率。应用3×10-10M至10-5M的浓度范围以获得完整竞争曲线来确定IC50值,该值经非线性回归分析计算出来。其结果如下面表3和4所示。
应用上述方法还能测试其它活性成分例如格兰西龙、甲氧氯普胺、奥丹亚龙、renzapride、扎考必利和托比色创等。
5-HT4受体
测试了外消旋降西沙必利、外消旋西沙必利以及它们的(+)和(-)立体异构体与来源于豚鼠striata的5-HT4受体亚型的结合(Cerep,Celle l′Evescault,法国)。
在与适当的配体一起培养后,在真空下用GF/B玻璃纤维过滤器快速过滤该制品,然后通过Brandel或Packard细胞收集器应用冰冷缓冲液洗涤。应用液体闪烁鸡尾酒剂(制剂989)通过液体闪烁计数(LS6000,Beckman)确定结合放射活性。
与受体的特异性放射配体结合被定义为总结合与在过量未标记配体存在下测定的非特异性结合之差。把结果表示为在所述化合物存在下获得的特异性结合的百分抑制率。应用3×10-10M至10-5M的浓度范围以获得完整竞争曲线来确定IC50值,该值经非线性回归分析计算出来。其结果如下面表3和4所示。
应用上述方法还能测试其它活性成分例如西沙必利等物质。
表3
结合到5-HT3和5-HT4位点的IC50(nM)值化合物 5-HT3 5-HT4 5-HT3/5-HT4比(±)降西沙必利 8.2 686 0.012(+)降西沙必利 4.5 331 0.014(-)降西沙必利 30.4 1350 0.023
表4
结合到5-HT3和5-HT4位点的IC50(nM)值化合物 5-HT3 5-HT4 5-HT3/5-HT4比(±)西沙必利 365 169 2.2(+)西沙必利 310 340 0.9(-)西沙必利 2790 199 14.0
应用基于活性化合物增加在组织培养物中生长的小鼠胚胎colloculi神经元中环AMP生成能力的分析也可以测定5-HT4受***点的激动活性(参见Dumuis等,N.S.Arch.Pharmacol.,340:403-410(1989))。
5.2实施例2:口服制剂片剂配方 每片含量(mg)
A B C活性成分 5.0 10.0 25.0(+)降西沙必利兰索拉唑 5.0 15.0 30.0乳糖BP 57.0 92.0 107.0淀粉BP 20.0 20.0 25.0微晶纤维素 10.0 10.0 10.0氢化植物油 1.5 1.5 1.5聚乙烯基吡咯烷酮 1.5 1.5 1.5压片重 100.0 150.0 200.0
用合适的筛子把活性成分(+)降西沙必利和兰索拉唑过筛,然后将其与乳糖混合直至形成均匀的混合物。加入合适体积的水,然后把粉末制粒。干燥后,过筛颗粒,将其与其余的辅料混合。然后把得到的颗粒压制成所需形状的片剂。通过改变活性成分与辅料的比例或改变压片重量可以制备其它强度的片剂。
5.3实施例3:口服制剂片剂配方 每片含量(mg)
A B C活性成分 5.0 10.0 25.0(+)降西沙必利法莫替丁 10.0 20.0 40.0乳糖BP 38.5 73.5 43.5淀粉BP 30.0 30.0 60.0预胶化玉米淀粉BP 15.0 15.0 30.0硬脂酸镁BP 1.5 1.5 1.5压片重 100.0 150.0 540.0
用合适的筛子把活性成分(+)降西沙必利和法莫替丁过筛,然后将其与乳糖、淀粉和预胶化玉米淀粉混合直至形成均匀的混合物。加入合适体积的水,然后把粉末制粒。干燥后,过筛颗粒,将其与其余的辅料混合。然后把得到的颗粒压制成所需形状的片剂。通过改变活性成分与辅料的比例或改变压片重量可以制备其它强度的片剂。
5.4实施例4:服制剂片剂配方 每片含量(mg)
A B C活性成分 5.0 10.0 25.0(+)降西沙必利乳糖BP 48.5 43.5 78.5淀粉BP 30.0 30.0 30.0预胶化玉米淀粉BP 15.0 15.0 15.0硬脂酸镁BP 1.5 1.5 1.5压片重 100.0 100.0 150.0
用合适的筛子把活性成分(+)降西沙必利过筛,然后将其与乳糖、淀粉和预胶化玉米淀粉混合直至形成均匀的混合物。加入合适体积的水,然后把粉末制粒。干燥后,过筛颗粒,将其与其余的辅料混合。然后把得到的颗粒压制成所需形状的片剂。通过改变活性成分与辅料的比例或改变压片重量可以制备其它强度的片剂。
现已通过具体的实施方案描述了本发明,显然,对本领域技术人员来说,可以在不偏离权利要求中所述的本发明的范围和精神的前提下对本发明作出各种变化和修饰。这些修饰也落于本申请权利要求的范围之内。
Claims (56)
1.治疗患者胃肠道疾病的方法,它包括:服用治疗有效量的一种或多种试剂或化合物或其光学纯立体异构体或其活性代谢物或其可药用盐,其中所述试剂或化合物同时或按顺序作用于5-HT3受体、5-HT4受体、和质子泵或H2受体。
2.治疗患者胃肠道疾病的方法,它包括:服用治疗有效量的拮抗5-HT3受体并激动5-HT4受体的试剂或化合物和治疗有效量的至少一种质子泵抑制剂或H2受体拮抗剂,或这些化合物或试剂的光学纯立体异构体或其活性代谢物或其可药用盐。
3.治疗患者胃肠道疾病的方法,它包括:给患者服用治疗有效量的、基本上不含(-)立体异构体的(+)降西沙必利或其可药用盐,和治疗有效量的至少一种质子泵抑制剂、H2受体拮抗剂,或其光学纯立体异构体或其活性代谢物或其可药用盐。
4.权利要求3的方法,其中所述患者为人。
5.权利要求3的方法,其中胃肠道疾病为胃肠道运动机能障碍。
6.权利要求5的方法,其中胃肠道运动机能障碍选自消化不良、胃轻瘫、便秘、术后肠梗阻和肠假性梗阻。
7.权利要求3的方法,其中胃肠道疾病为胃-食道反流疾病、呕吐、胃肠道溃疡、病理性分泌过多症和胃酸过多症。
8.权利要求7的方法,其中病理性分泌过多症为佐-埃综合症。
9.权利要求7的方法,其中胃酸过多症选自:胃灼热、胃酸过多性消化不良、胃发酸、侵蚀性食道炎和胃不适。
10.权利要求3的方法,其中(+)降西沙必利的服用量为约0.5mg-约500mg。
11.权利要求10的方法,其中(+)降西沙必利的服用量为约1mg-约350mg。
12.权利要求3的方法,其中服用质子泵抑制剂,所述质子泵抑制剂选自:奥美拉唑、兰索拉唑、拉比拉唑、泮托帕唑、羟基奥美拉唑、脱甲基泮托帕唑、羟基兰索拉唑及其光学纯立体异构体。
13.权利要求12的方法,其中质子泵抑制剂的用量为约1mg-约200mg。
14.权利要求13的方法,其中质子泵抑制剂的用量为约5mg-约150mg。
15.权利要求3的方法,其中服用H2受体拮抗剂,所述H2受体拮抗剂选自西咪替丁、雷尼替丁、法莫替丁、尼唑替丁及其光学纯立体异构体或其活性代谢物。
16.权利要求15的方法,其中H2受体拮抗剂的用量为约1mg-约2400mg。
17.权利要求3的方法,其中口服服用(+)降西沙必利和质子泵抑制剂中的至少一种。
18.权利要求17的方法,其中以片剂或胶囊形式口服服用(+)降西沙必利和质子泵。
19.权利要求3的方法,其中口服服用(+)降西沙必利和H2受体拮抗剂中的至少一种。
20.权利要求3的方法,其中把质子泵抑制剂或H2受体拮抗剂与(+)降西沙必利一起通过胃肠外、经皮、直肠或舌下服用。
21.权利要求3的方法,它包括:把质子泵抑制剂或H2受体拮抗剂与(+)降西沙必利同时或按顺序服用。
22.治疗患者胃肠道运动机能障碍的方法,它包括:对所述患者服用治疗有效量的基本上不含(-)立体异构体的(+)降西沙必利或其可药用盐,和治疗有效量的至少一种质子泵抑制剂、H2受体拮抗剂,或其光学纯立体异构体或其活性代谢物或其可药用盐。
23.治疗患者呕吐的方法,它包括:给所述需要这种预防、治疗或控制的患者服用治疗有效量的基本上不含(-)立体异构体的(+)降西沙必利或其可药用盐,和治疗有效量的至少一种质子泵抑制剂、H2受体拮抗剂,或其光学纯立体异构体或其活性代谢物或其可药用盐。
24.治疗患者胃-食道反流疾病的方法,它包括:服用治疗有效量的基本上不含(-)立体异构体的(+)降西沙必利或其可药用盐,和治疗有效量的至少一种质子泵抑制剂、H2受体拮抗剂,或其光学纯立体异构体或其活性代谢物或其可药用盐。
25.治疗患者胃-食道反流疾病的方法,它包括给需要这种治疗的患者服用治疗有效量的:(a)西沙必利或其可药用盐或其光学纯立体异构体;(b)奥丹亚龙或其可药用盐或其光学纯立体异构体;和(c)治疗有效量的至少一种质子泵抑制剂、H2受体拮抗剂或其光学纯立体异构体或其活性代谢物或其可药用盐。
26.权利要求25的方法,其中服用光学纯(+)西沙必利或光学纯(-)西沙必利或其可药用盐。
27.权利要求25或26的方法,其中服用光学纯R(+)奥丹亚龙。
28.权利要求25的方法,其中所服用的质子泵抑制剂选自奥美拉唑、兰索拉唑、泮托帕唑、拉比拉唑、羟基-奥美拉唑、羟基兰索拉唑、奥美拉唑的羧酸衍生物和脱甲基泮托帕唑。
29.权利要求25的方法,其中质子泵抑制剂的服用量为约1mg至约200mg。
30.权利要求25的方法,其中所服用的H2受体拮抗剂选自西咪替丁、法莫替丁、雷尼替丁、尼唑替丁和N2-脱甲基尼唑替丁。
31.权利要求25的方法,其中H2受体拮抗剂的服用量为约1mg-约2400mg。
32.权利要求25的方法,其中口服服用光学纯(+)西沙必利、光学纯(-)西沙必利、光学纯R(+)奥丹亚龙和质子泵抑制剂中的至少一种。
33.权利要求25的方法,其中口服服用西沙必利、光学纯R(+)奥丹亚龙和H2受体拮抗剂中的至少一种。
34.预防或控制患者胃肠道疾病的方法,它包括:给需要预防或控制的患者服用治疗有效量的5-HT3受体拮抗剂,5-HT4受体激动剂、和H2受体拮抗剂或质子泵抑制剂中的至少一种、或其光学纯立体异构体或其活性代谢物或其可药用盐。
35.预防或控制患者胃肠道疾病的方法,它包括:服用治疗有效量的作用于5-HT3受体和5-HT4受体的试剂或化合物、和治疗有效量的H2受体或质子泵中的至少一种、或其光学纯立体异构体或其活性代谢物或其可药用盐。
36.预防或控制患者胃肠道疾病的方法,它包括:给所述患者服用治疗有效量的基本上不含有(-)立体异构体的(+)降西沙必利、或其可药用盐,和治疗有效量的质子泵抑制剂、H2受体拮抗剂中的至少一种或其光学纯立体异构体或其活性代谢物或其可药用盐。
37.预防或控制患者胃肠道运动机能障碍的方法,它包括:给所述患者服用治疗有效量的基本上不含有(-)立体异构体的(+)降西沙必利、或其可药用盐,和治疗有效量的质子泵抑制剂、H2受体拮抗剂或其光学纯立体异构体或其活性代谢物或其可药用盐中的至少一种。
38.预防或控制患者呕吐的方法,它包括:给需要这种预防、治疗或控制的所述患者服用治疗有效量的基本上不含有(-)立体异构体的(+)降西沙必利或其可药用盐,和治疗有效量的质子泵抑制剂、H2受体拮抗剂中的至少一种或其光学纯立体异构体或其活性代谢物或其可药用盐。
39.预防或控制患者胃-食道反流疾病的方法,它包括:给所述患者服用治疗有效量的基本上不含有(-)立体异构体的(+)降西沙必利、或其可药用盐,和治疗有效量的质子泵抑制剂、H2受体拮抗剂中的至少一种或其光学纯立体异构体或其活性代谢物或其可药用盐。
40.预防或控制患者胃-食道反流疾病的方法,它包括;给需要这种预防或控制的患者服用治疗有效量的(a):西沙必利或其光学纯立体异构体或其可药用盐;(b)奥丹亚龙或其可药用盐或其光学纯立体异构体;和(c)治疗有效量的质子泵抑制剂、H2受体拮抗剂中的至少一种或其光学纯立体异构体或其活性代谢物或其可药用盐。
41.权利要求40的方法,其中服用光学纯(+)西沙必利或光学纯(-)西沙必利或其可药用盐。
42.权利要求40的方法,其中服用光学纯R(+)奥丹亚龙或其可药用盐。
43.权利要求40的方法,其中所服用的质子泵抑制剂选自:奥美拉唑、兰索拉唑、泮托帕唑、拉比拉唑、羟基奥美拉唑、羟基兰索拉唑、奥美拉唑的羧酸衍生物和脱甲基泮托帕唑。
44.权利要求40的方法,其中质子泵抑制剂的服用量为约1mg-约200mg。
45.权利要求40的方法,其中所服用的H2受体拮抗剂选自西咪替丁、法莫替丁、雷尼替丁、尼唑替丁和N2-脱甲基尼唑替丁。
46.权利要求40的方法,其中H2受体拮抗剂的服用量为约1mg-约2400mg。
47.权利要求40的方法,其中口服服用西沙必利、R(+)奥丹亚龙和质子泵抑制剂中的至少一种。
48.权利要求40的方法,其中口服服用西沙必利、R(+)奥丹亚龙和H2受体拮抗剂中的至少一种。
49.适用于治疗胃肠道疾病患者的药物组合物,它包括:治疗有效量的基本上不含有(-)立体异构体的(+)降西沙必利、或其可药用盐;和治疗有效量的质子泵抑制剂、H2受体拮抗剂中的至少一种、或其光学纯立体异构体或其活性代谢物,或其可药用盐。
50.权利要求49的药物组合物,其中含有质子泵抑制剂,其选自奥美拉唑、泮托帕唑、拉比拉唑、兰索拉唑、羟基奥美拉唑、羟基兰索拉唑、奥美拉唑羧酸衍生物和脱甲基泮托帕唑。
51.权利要求49的药物组合物,其中含有H2受体拮抗剂,其选自西咪替丁、雷尼替丁、法莫替丁、尼唑替丁和N2-脱甲基尼唑替丁。
52.适用于治疗胃肠道疾病患者的药物组合物,它包括:(a)治疗有效量的西沙必利光学纯立体异构体或其可药用盐;(b)治疗有效量的光学纯R(+)奥丹亚龙或其可药用盐;和(c)治疗有效量的质子泵抑制剂、H2受体拮抗剂中的至少一种、或其光学纯立体异构体或其活性代谢物、或其可药用盐。
53.权利要求52的药物组合物,其中含有质子泵抑制剂,其选自奥美拉唑、泮托帕唑、拉比拉唑、兰索拉唑、羟基奥美拉唑、羟基兰索拉唑、奥美拉唑的羧酸衍生物和脱甲基泮托帕唑。
54.权利要求52的药物组合物,其中含有H2质子泵抑制剂,其选自西咪替丁、雷尼替丁、法莫替丁、尼唑替丁和N2-脱甲基尼唑替丁。
55.权利要求12的方法,其中质子泵抑制剂为:光学纯(+)泮托帕唑、光学纯(-)泮托帕唑、光学纯(+)拉比拉唑、光学纯(-)拉比拉唑、光学纯(+)兰索拉唑、光学纯(-)兰索拉唑、光学纯(+)奥美拉唑或光学纯(-)奥美拉唑。
56.权利要求50或53的药物组合物,其中质子泵抑制剂为:(+)泮托帕唑、光学纯(-)泮托帕唑、光学纯(+)拉比拉唑、光学纯(-)拉比拉唑、光学纯(+)兰索拉唑、光学纯(-)兰索拉唑、光学纯(+)奥美拉唑或光学纯(-)奥美拉唑。
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