CN101198334B - 前列腺素化合物和质子泵抑制剂用于治疗肠胃病的联合应用 - Google Patents
前列腺素化合物和质子泵抑制剂用于治疗肠胃病的联合应用 Download PDFInfo
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- CN101198334B CN101198334B CN200680021015XA CN200680021015A CN101198334B CN 101198334 B CN101198334 B CN 101198334B CN 200680021015X A CN200680021015X A CN 200680021015XA CN 200680021015 A CN200680021015 A CN 200680021015A CN 101198334 B CN101198334 B CN 101198334B
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
本发明涉及(a)特定前列腺素(PG)化合物和(b)H+,K+-ATP酶抑制剂用于治疗肠胃病的联合应用。
Description
技术领域
本发明涉及包含特定前列腺素化合物和H+,K+-ATP酶抑制剂的药物组合物和在哺乳动物受治疗者中使用该组合物治疗肠胃病的方法。
背景技术
质子泵抑制剂(PPI)是有效的胃酸分泌抑制剂,其抑制参与壁细胞中氢离子产生的最后步骤的酶-H+,K+-ATP酶,在治疗胃酸相关性疾病中高度有效,胃酸相关性疾病例如有人类的胃溃疡、出血性溃疡、十二指肠溃疡、NSAID诱发性溃疡、消化性溃疡、腐蚀性食管炎、胃食管反流病、幽门螺杆菌感染、佐-艾综合征(Zollinger-Ellisonsyndrome)、NSAID或COX2抑制剂相关预防、消化不良和胃炎。目前有5种可用的不同PPI,包括奥美拉唑(omeprazole)、兰索拉唑(lansoprazole)、雷贝拉唑(rebeprazole)、艾美拉唑(esomeprazole)和泮托拉唑(pantoprazole)。这些药物都为取代苯并咪唑,其抑制胃酸分泌的最后的共同路径。
胃食管反流指胃内容物从胃逆行运动到食道。当这种反流导致症状性病症或组织学改变时,将其称为胃食管反流病(GERD)。胃中物质反流到食道可引起炎症、食管衬层增生、食道溃疡和Barrett食管。GERD通常为慢性复发性病症。美国成年人群中有大约44%至少每月经历一次胃灼烧,18%至少每周经历2次胃灼烧,7%每日经历一次胃灼烧。大约一百万美国人有腐蚀性食管炎,而这些人中有20%发展为并发症,如食管狭窄。对GERD的治疗的目标在于消除患者的症状,降低反流频率和持续时间,使受损的粘膜愈合和防止出现并发症。治疗GERD包括改变生活方式、抑酸治疗和可能的外科手术。生活方式改变包括升高床头、改变饮食、戒烟和减体重。质子泵抑制剂为GERD抑酸疗法的支柱。
消化性溃疡疾病也为慢性疾病,其具有时而恶化时而缓解的典型特征。全体美国人中有约10%在其一生中会出现消化性溃疡。十二指肠溃疡比胃溃疡更常见。十二指肠溃疡通常25-55岁的个体中发生,而胃溃疡最常发生于55-65岁的个体。消化性溃疡从酸分泌、粘膜防御和运动性异常开始发展。幽门螺旋杆菌(Helicobacter pylori)和非甾体类消炎药在溃疡疾病的进展中也起着重要作用。药物治疗消化性溃疡疾病的目标是降低胃液酸度和增强粘膜防御力。
佐-艾综合征(ZES)是胰腺中分泌胃泌素的肿瘤引起的过度分泌酸的状态。ZES在约0.1%的十二指肠溃疡患者中发生。当患者基础酸排出量大于15meq/hr时,诊断为ZES。质子泵抑制剂是选择用于治疗ZES的药物。
质子泵抑制剂为可利用的最有效的抑酸药物。所有五种可利用的药物对治疗GERD、胃溃疡和十二指肠溃疡似乎同样有效。然而,据报道40mg艾美拉唑在控制酸分泌方面比40mg奥美拉唑、40mg泮托拉唑或30mg兰索拉唑更有效(Medical Letter vol.43(W1103B),2001)。因为不能将泮托拉唑和雷贝拉唑片剂压碎或制成混悬液制剂,所以这两种PPI不适于儿科患者或吞咽困难的患者(CIGNAHEALTHCARE COVERAGE POSITION Number 4005)。
前列腺素(下文称为PG)为有机羧酸类的成员,其包含于人类或其它哺乳动物的组织或器官中,表现出广泛的生理活性。自然界发现的PG(原始PG)通常具有前列腺烷酸主链,如式(A)所示:
根据其结构和在5元环上的取代基,将PG分为7种类型,例如:
A系列前列腺素(PGA);
B系列前列腺素(PGB);
C系列前列腺素(PGC);
D系列前列腺素(PGD);
E系列前列腺素(PGE);
F系列前列腺素(PGF);
等等。另外,将其分为含有13,14-双键的PG1;含有5,6-双键和13,14-双键的PG2;和含有5,6-双键、13,14-双键和17,18-双键的PG3。已知PG具有各种药理学和生理学活性,例如血管舒张、诱发炎症、血小板聚集、刺激子宫肌肉、刺激肠肌活性、抗溃疡作用等等。在人类胃肠(GI)系统中产生的主要前列腺素为E、I和F系列的前列腺素(Sellin,Gastrointestinal and Liver Disease:Pathophysiology,Diagnosis andManagement.(WB Saunders Company,1998);Robert,Physiology of theGastrointestinal Tract 1407-1434(Raven,1981);Rampton,Prostaglandins:Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344(Churchill Livingstone,1988);Hawkey等Gastroenterology,89:1162-1188(1985);Eberhart等,Gastroenterology,109:285-301(1995))。
在正常生理条件下,内源产生的前列腺素在维持GI功能中起着主要作用,包括调节肠运动和转运以及调节粪便粘稠度(Sellin,Gastrointestinal and Liver Disease:Pathophysiology,Diagnosis andManagement.(WB Saunders Company,1998);Robert,Physiology of theGastrointestinal Tract 1407-1434(Raven,1981);Rampton,Prostaglandins:Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344(Churchill Livingstone,1988);Hawkey等,Gastroenterology,89:1162-1188(1985);Eberhart等,Gastroenterology,109:285-301(1995);Robert,Adv Prostaglandin Thromboxane Res,2:507-520(1976);Main等,Postgrad Med J,64 Suppl 1:3-6(1988);Sanders,Am J Physiol,247:G117(1984);Pairet等Am J Physiol.,250(3 pt 1):G302-G308(1986);Gaginella,Textbook of Secretory Diarrhea 15-30(Raven Press,1990))。当以药理学剂量给予时,PGE2和PGF2α二者都表现出刺激肠转运,并引起腹泻(Robert,Physiology of the Gastrointestinal Tract 1407-1434(Raven,1981);Rampton,Prostaglandins:Biology and Chemistry ofProstaglandins and Related Eicosanoids 323-344(Churchill Livingstone,1988);Robert,Adv Prostaglandin Thromboxane Res,2:507-520(1976))。此外,米索前列醇(misoprostol)这种为治疗消化性溃疡疾病开发的PGE1类似物的最常报道的副作用为腹泻(Monk等,Drugs 33(1):1-30(1997))。
PGE或PGF可刺激肠收缩,但清肠(enteropooling)效果差。因此,将PGE或PGF用作泻药是不切实际的,因为有这样的肠收缩引起腹痛的副作用。
据报道,包括改善肠神经反应、改变平滑肌收缩、刺激粘膜分泌、刺激细胞离子分泌(尤其是产电性Cl-转运)和增加肠流液体积在内的多种机制影响前列腺素的GI作用(Robert,Physiology of theGastrointestinal Tract 1407-1434(Raven,1981);Rampton,prostaglandins:Biology and Chemistry of prostaglandins and Related Eicosanoids 323-344(Churchill Livingstone,1988);Hawkey等,Gastroenterology,89:1162-1188(1985);Eberhart等,Gastroenterology,109:285-301(1995);Robert,Adv Prostaglandin Thromboxane Res,2:507-520(1976);Main等,Postgrad Med J,64 Suppl 1:3-6(1988);Sanders,Am J Physiol,247:G117(1984);Pairet等,Am J Physiol,250(3 pt 1):G302-G308(1986);Gaginella,Textbook of Secretory Diarrhea 15-30(Raven Press,1990);Federal Register Vol.50,No.10(GPO,1985);Pierce等Gastroenterology60(1):22-32(1971);Beubler等,Gastroenterology,90:1972(1986);Clarke等,Am J Physiol 259:G62(1990);Hunt等,J Vet Pharmacol Ther,8(2):165-173(1985);Dajani等,Eur J Pharmacol,34(1):105-113(1975);Sellin,Gastrointestinal and Liver Disease:Pathophysiology,Diagnosisand Management 1451-1471(WB Saunders Company,1998))。另外,经证明前列腺素具有细胞保护作用(Sellin,Gastrointestinal and LiverDisease:Pathophysiology,Diagnosis and Management.(WB SaundersCompany,1998);Robert,Physiology of the Gastrointestinal Tract 1407-1434(Raven,1981);Robert,Adv Prostaglandin Thromboxane Res 2:507-520(1976);Wallace等,Aiiment Pharmacol Ther 9:227-235(1995))。
美国专利第5,225,439号、第5,166,174号、第5,284,858号、第5,428,062号、第5,380,709号、第5,886,034号和第6,265,440号阐述了某些前列腺素E化合物有效治疗溃疡,例如十二指肠溃疡和胃溃疡。
Ueno等的美国专利第5,317,032号阐述了前列腺素类似物泻药,包括存在二环互变异构体,而Ueno的美国专利第6,414,016号阐述该二环互变异构体具有作为抗便秘药的显著活性。为了减轻便秘,可使用小剂量的被一个或多个卤素原子取代的二环互变异构体。为了减轻便秘,可使用小剂量的C-16位取代、尤其为氟原子取代的二环互变异构体。
Ueno等的美国专利公开说明书第2003/0130352号阐述了前列腺素化合物打开和激活氯化物通道,尤其是ClC通道,更尤其是ClC-2通道。
Ueno的美国专利公开说明书第2003/0166632号阐述了ClC-2通道开放剂可有效治疗对开放ClC-2通道有反应的疾病或病症。
Ueno等的美国专利公开说明书第2003/0119898号阐述用于治疗和预防便秘的卤化前列腺素类似物的具体组合物。
Ueno等的美国专利公开说明书第2004/0138308号阐述用于治疗腹部不适和治疗功能性肠胃病,例如肠易激综合征和功能性消化不良的氯化物通道开放剂,尤其是前列腺素化合物。
国际公开说明书第WO00/35448号阐述了用于治疗肠胃病的包含质子泵抑制剂和特定抗胃分泌前列腺素类似物的药物制剂。
米索前列醇为一种抗胃分泌前列腺素类似物,据报道其抑制血小板聚集(Jounal of Physiology and Pharmacology 2002,53,4,635-641)。奥诺前列素(ornoprostil)为一种抗胃分泌前列腺素类似物,也报道其具有抗血小板聚集作用,以增强出血,因此在将其给予出血性溃疡患者时应该小心(奥诺前列素药品说明书)。
发明内容
本发明目的是提供用于治疗肠胃病的已知化合物的新组合。换言之,本发明目的是提供用于治疗肠胃病的新组合物。本发明另一目的是提供治疗肠胃病的方法。
本发明涉及药物组合物,其包含:
(a)药学有效量的由式(I)代表的前列腺素(PG)化合物:
其中L、M和N为氢、羟基、卤素、低级烷基、羟基(低级)烷基、低级烷酰氧基或氧代基,其中L和M中至少有一个为除氢以外的基团,5元环可含有至少一个双键;
A为-CH3或-CH2OH、-COCH2OH、-COOH或其功能衍生物;
B为单键、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-;
Z为
其中R4和R5为氢、羟基、卤素、低级烷基、低级烷氧基或羟基(低级)烷基,其中R4和R5不能同时为羟基和低级烷氧基;
R1为饱和或不饱和二价低级或中级脂族烃残基,其为未取代的或被卤素、烷基、羟基、氧代基、芳基或杂环基取代,脂族烃中至少一个碳原子任选被氧、氮或硫取代;和
Ra为饱和或不饱和低级或中级脂族烃残基,其为未取代的或被卤素、氧代基、羟基、低级烷基、低级烷氧基、低级烷酰氧基、环(低级)烷基、环(低级)烷氧基、芳基、芳氧基、杂环基或杂环-氧基取代;低级烷氧基;低级烷酰氧基;环(低级)烷基;环(低级)烷氧基;芳基;芳氧基;杂环基;杂环-氧基,前体条件为Ra被卤素取代和/或Z为C=O,
(b)药学有效量的H+,K+-ATP酶抑制剂,和
药学上合适的赋形剂。该组合物用于治疗肠胃病。
本发明也涉及在哺乳动物受治疗者中治疗肠胃病的方法,其包括将以下物质组合给予需要治疗的受治疗者:
(a)药学有效量的由式(I)代表的前列腺素(PG)化合物
和
(b)药学有效量的H+,K+-ATP酶抑制剂。
本发明进一步涉及(a)由式(I)代表的前列腺素(PG)化合物和(b)H+,K+-ATP酶抑制剂在制备用于治疗哺乳动物受治疗者肠胃病的药物组合物中的联合应用。
附图简述
图1为显示13,14-二氢-15-酮-16,16-二氟-PGE1(化合物1)对大鼠的总酸排出量的作用的图。数值为6只动物的平均值±S.E.。
##通过学生t检验与盐水处理的对照组比较p<0.01。
发明详述
(a)式(I)化合物
本文所用前列腺素化合物的命名法基于上式(A)代表的前列腺烷酸的编号系统。
式(A)显示了C-20碳原子的基本主链,但本发明不限于具有同样碳原子数目的物质。在式(A)中,组成PG化合物的基本主链的碳原子的编号从羧酸开始(编为1),α-链的碳原子向5元环方向编号为2-7,环上的碳原子编号为8-12,ω-链上的碳原子编号为13-20。当α-链上的碳原子数目减少时,从2号位开始顺序删除编号;当α-链上的碳原子数目增加时,化合物命名为在2位具有取代羧基(C-1)的相应取代基的取代化合物。同样地,当ω-链上的碳原子数目减少时,从20号位开始顺序删除编号;当ω-链上的碳原子数目增加时,超过20位的碳原子命名为取代基。除非另外指出,否则该化合物的立体化学与上式(A)一样。
一般而言,术语PGD、PGE和PGF中的每一种代表在9位和/或11位含羟基的PG化合物,但在本说明书中,这些术语也包括含除9和/或11位羟基之外的取代基的PG化合物。这样的化合物称为9-去羟基-9-取代-PG化合物或11-去羟基-11-取代-PG化合物。含取代羟基的氢的PG化合物简单命名为9-或11-脱氧-PG化合物。
如上所述,PG化合物的命名法基于前列腺烷酸主链。然而,在化合物有部分结构与前列腺素相似的情况下,可使用“PG”缩写。因此,α-链延长2个碳原子、即α-链具有9个碳原子的PG化合物,命名为2-脱羧-2-(2-羧乙基)-PG化合物。同样地,α-链具有11个碳原子的PG化合物命名为2-脱羧-2-(4-羧丁基)-PG化合物。另外,ω-链延长2个碳原子、即在ω-链中含有10个碳原子的PG化合物,命名为20-乙基-PG化合物。然而,也可根据IUPAC命名法命名这些化合物。
类似物(包括取代衍生物)或衍生物的实例包括α-链末端的羧基被酯化的PG化合物;α-链延长的化合物;其生理学上可接受盐;在2-3位具双键或在5-6位具三键的化合物,在3、5、6、16、17、18、19和/或20位具取代基的化合物;和在9和/或11位具有取代了羟基的低级烷基或羟基(低级)烷基的化合物。
根据本发明,3、17、18和/或19位的优选取代基包括含1-4个碳原子的烷基,尤其是甲基和乙基。16位的优选取代基包括低级烷基(例如甲基和乙基)、羟基、卤素原子(例如氯和氟)和芳氧基(例如三氟甲基苯氧基)。17位的优选取代基包括低级烷基(例如甲基和乙基)、羟基、卤素原子(例如氯和氟)、芳氧基(例如三氟甲基苯氧基)。20位的优选取代基包括饱和或不饱和低级烷基(例如C1-4烷基)、低级烷氧基(例如C1-4烷氧基)和低级烷氧基烷基(例如C1-4烷氧基-C1-4烷基)。5位的优选取代基包括卤素原子,例如氯和氟。6位的优选取代基包括形成羰基的氧代基。在9位和/或11位具有羟基、低级烷基或羟基(低级)烷基取代基的PG的立体化学可为α、β或其混合物。
另外,上述类似物或衍生物可为在ω-链末端具有烷氧基、环烷基、环烷氧基、苯氧基或苯基的化合物,其中该ω-链比原始PG短。
用于本发明的特定的前列腺素化合物由式(I)代表:
其中L、M和N为氢、羟基、卤素、低级烷基、羟基(低级)烷基、低级烷酰氧基或氧代基,其中L和M中至少一个为除氢之外的基团,而5元环可含有至少一个双键;
A为-CH3或-CH2OH、-COCH2OH、-COOH或其功能衍生物;
B为单键、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-;
Z为
其中R4和R5为氢、羟基、卤素、低级烷基、低级烷氧基或羟基(低级)烷基,其中R4和R5不能同时为羟基和低级烷氧基;
R1为饱和或不饱和二价低级或中级脂族烃残基,其为未取代的或被卤素、烷基、羟基、氧代基、芳基或杂环基取代,脂族烃中至少一个碳原子任选被氧、氮或硫取代;和
Ra为饱和或不饱和低级或中级脂族烃残基,其为未取代的或被卤素、氧代基、羟基、低级烷基、低级烷氧基、低级烷酰氧基、环(低级)烷基、环(低级)烷氧基、芳基、芳氧基、杂环基或杂环-氧基取代;低级烷氧基;低级烷酰氧基;环(低级)烷基;环(低级)烷氧基;芳基;芳氧基;杂环基;杂环-氧基,前提条件为Ra被卤素取代和/或Z为C=O。
用于本发明的优选化合物由式(II)代表:
其中L和M为氢、羟基、卤素、低级烷基、羟基(低级)烷基、低级烷酰氧基或氧代基,其中L和M中至少一个为除氢之外的基团,而5元环可含有一个或多个双键;
A为-CH3或-CH2OH、-COCH2OH、-COOH或其功能衍生物;
B为单键、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-;
Z为
其中R4和R5为氢、羟基、卤素、低级烷基、低级烷氧基或羟基(低级)烷基,其中R4和R5不能同时为羟基和低级烷氧基;
X1和X2为氢、低级烷基或卤素;
R1为饱和或不饱和二价低级或中级脂族烃残基,其为未取代的或被卤素、烷基、羟基、氧代基、芳基或杂环基取代,脂族烃中至少一个碳原子任选被氧、氮或硫取代;
R2为单键或低级亚烷基;和
R3为低级烷基、低级烷氧基、低级烷酰氧基、环(低级)烷基、环(低级)烷氧基、芳基、芳氧基、杂环基或杂环-氧基,前提条件为X1和X2中有一个被卤素取代和/或Z为C=O。
在上述式中,R1和Ra定义中的术语“不饱和”意欲包括至少一个或多个双键和/或三键,所述双键或三键可孤立、分别或连续存在于主链和/或侧链的碳原子之间。根据常规命名法,两个连续位置之间的不饱和键通过这两个位置中的较低的编号标示来代表,两个远侧位置之间的不饱和碱通过这两个位置的标示来代表。
术语“低级或中级脂族烃”指含1-14个碳原子(对于侧链而言,优选1-3个碳原子)、优选1-10个、尤其是1-8个碳原子的直链或支链烃基。
术语“卤素原子”包括氟、氯、溴和碘。
除非另外指出,否则贯穿整个说明书的术语“低级”意欲包括含1-6个碳原子的基团。
术语“低级烷基”指含有1-6个碳原子的直链或支链饱和烃基,例如包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基和己基。
术语“低级亚烷基”指含有1-6个碳原子的直链或支链二价饱和烃基,包括例如亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚叔丁基、亚戊基和亚己基。
术语“低级烷氧基”指低级烷基-O-基团,其中低级烷基如上所定义。
术语“羟基(低级)烷基”指被至少一个羟基取代的如上所定义的低级烷基,例如羟基甲基、1-羟基乙基、2-羟基乙基和1-甲基-1-羟基乙基。
术语“低级烷酰氧基”指由式RCO-O-代表的基团,其中RCO-为通过如上所定义的低级烷基氧化而形成的酰基,例如乙酰基。
术语“环(低级)烷基”指通过如上所定义的低级烷基环化而形成的环基,但其含有三个或更多个碳原子,包括例如环丙基、环丁基、环戊基和环己基。
术语“环(低级)烷氧基”指环(低级)烷基-O-基团,其中环(低级)烷基如上所定义。
术语“芳基”可包括未取代的或取代的芳香烃环(优选单环基),例如苯基、甲苯基、二甲苯基。取代基实例为卤素原子和卤代(低级)烷基,其中卤素原子和低级烷基如上所定义。
术语“芳氧基”指由式ArO-代表的基团,其中Ar为如上所定义的芳基。
术语“杂环基”可包括单环到三环杂环基,优选单环杂环基,其为5-14元环,优选5-10元环,其含有任选取代的碳原子和1-4个(优选1-3个)1或2种选自氮原子、氧原子和硫原子的杂原子。杂环基实例包括呋喃基、噻吩基、吡咯基、唑基、异唑基、噻唑基、异噻唑基、咪唑基、吡唑基、呋咱基、吡喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、2-吡咯啉基、吡咯烷基、2-咪唑啉基、咪唑烷基、2-吡唑啉基、吡唑烷基、哌啶基、哌嗪基、吗啉基、吲哚基、苯并噻吩基、喹啉基、异喹啉基、嘌呤基、喹唑啉基、咔唑基、吖啶基、菲啶基、苯并咪唑基、苯并咪唑啉基、苯并噻唑基、吩噻嗪基。在这种情况下的取代基实例包括卤素和卤素取代的低级烷基,其中卤素原子和低级烷基如上所述。
术语“杂环-氧基”意即由式HcO-代表的基团,其中Hc为如上所述的杂环基。
术语A的“功能性衍生物”包括盐(优选药学上可接受盐)、醚、酯和酰胺。
合适的“药学上可接受盐”包括常规所用的无毒盐,举例而言,无机碱盐,例如碱金属盐(例如钠盐和钾盐)、碱土金属盐(例如钙盐和镁盐)、铵盐;或有机碱盐,例如胺盐(例如甲胺盐,二甲胺盐、环己胺盐、苄胺盐、哌啶盐、乙二胺盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、三(羟基甲基氨基)乙烷盐、单甲基-单乙醇胺盐、普鲁卡因盐和咖啡因盐)、碱性氨基酸盐(例如精氨酸盐和赖氨酸盐)、四烷基季铵盐等等。通过常规方法例如从相应的酸和碱或通过盐交换可制备这些盐。
醚的实例包括烷基醚,举例而言,低级烷基醚,例如甲基醚、乙基醚、丙基醚、异丙基醚、丁基醚、异丁基醚、叔丁基醚、戊基醚和1-环丙基乙基醚;中级或高级烷基醚,例如辛基醚、二乙基己基醚、月桂基醚和十六烷基醚;不饱和醚,例如油基醚和亚麻基(linolenyl)醚;低级烯基醚,例如乙烯基醚、烯丙基醚;低级炔基醚,例如乙炔基醚和丙炔基醚;羟基(低级)烷基醚,例如羟基乙基醚和羟基异丙基醚;低级烷氧基(低级)烷基醚,例如甲氧基甲基醚和1-甲氧基乙基醚;任选取代芳基醚,例如苯基醚、甲苯基醚、叔丁基苯基醚、水杨基醚、3,4-二-甲氧基苯基醚和苯甲酰氨基苯基醚;和芳基(低级)烷基醚,例如苯甲基醚、三苯甲基醚和二苯甲基醚。
酯的实例包括脂肪族酯类,举例而言,低级烷基酯,例如甲酯、乙酯、丙酯、异丙酯、丁酯、异丁酯、叔丁酯、戊酯和1-环丙基乙酯;低级烯基酯,例如乙烯酯和烯丙酯;低级炔基酯,例如乙炔酯和丙炔酯;羟基(低级)烷基酯,例如羟基乙基酯;低级烷氧基(低级)烷基酯,例如甲氧基甲酯和1-甲氧基乙酯;和任选取代芳基酯,例如苯基酯、甲苯基酯、叔丁基苯酯、水杨基酯、3,4-二-甲氧基苯基酯和苯甲酰氨基苯酯;和芳基(低级)烷基酯,例如苯甲酯、三苯甲酯和二苯甲酯。
A的酰胺意即由式CONR’R”代表的基团,其中R’和R”各自为氢、低级烷基、芳基、烷基磺酰基或芳基磺酰基、低级烯基和低级炔基,举例而言,包括低级烷基酰胺,例如甲基酰胺、乙基酰胺、二甲基酰胺和二乙基酰胺;芳基酰胺,例如苯胺和甲苯胺;和烷基磺酰胺或芳基磺酰胺,例如甲基磺酰胺、乙基磺酰胺和甲苯磺酰胺。
优选L和M实例包括氢、羟基和氧代基,尤其是M为羟基而L为氧代基,其具有所谓的PGE型5元环结构。
优选A的实例为-COOH、其药学上可接受盐、酯或酰胺。
优选的X1和X2实例为二者都是卤素原子,更优选氟原子,即所谓16,16-二氟型。
优选的R1为含有1-10个碳原子(优选6-10个碳原子)的烃残基。另外,该脂族烃中至少一个碳原子任选被氧、氮或硫取代。举例而言,R1实例包括以下基团;
-CH2-CH2-CH2-CH2-CH2-CH2-、
-CH2-CH=CH-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-CH=CH-、
-CH2-C≡C-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-O-CH2-、
-CH2-CH=CH-CH2-O-CH2-、
-CH2-C≡C-CH2-O-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、
-CH2-CH=CH-CH2-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH=CH-、
-CH2-C≡C-CH2-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、
-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、
-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH2-CH=CH-、
-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-和
-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-。
优选的Ra为含有1-10个碳原子(更优选含1-8个碳原子)的烃。Ra可具有一个或两个含一个碳原子的侧链。
最优选的实施方案是前列腺素化合物为13,14-二氢-15-酮-16,16-二氟-前列腺素E1化合物或13,14-二氢-15-酮-16,16-二氟-18-甲基-前列腺素E1化合物。
在上式(I)和(II)中的环和α链和/或ω链的构象可与原始PG相同或不同。然而,本发明也包括具有原始型构象的化合物和具有非原始型构象的化合物的混合物。
在本发明中,13和14位之间为二氢和15位为酮基(=O)的PG化合物,通过在11位羟基和15位酮基之间形成半缩醛可呈酮基-半缩醛平衡。
举例而言,当X1和X2二者都为卤素原子(尤其是氟原子)时,业已显示该化合物含有互变异构体、二环化合物。
若上述互变异构体存在,则两种互变异构体的比例随着分子其余部分的结构或所存在的取代基的种类而变化。有时一种异构体可能比另一种占优势存在。然而,应该理解本发明包括两种异构体。
另外,本发明所用的15-酮-PG化合物包括所述二环化合物和其类似物或衍生物。
所述二环化合物由式(III)代表
其中,A为-CH3或-CH2OH、-COCH2OH、-COOH或其功能衍生物;
X1’和X2’为氢、低级烷基或卤素;
Y为
其中R4’和R5’为氢、羟基、卤素、低级烷基、低级烷氧基或羟基(低级)烷基,其中R4’和R5’不能同时为羟基和低级烷氧基。
R1为饱和或不饱和二价低级或中级脂族烃残基,其为未取代的或被卤素、烷基、羟基、氧代基、芳基或杂环基取代,脂族烃中至少一个碳原子任选被氧、氮或硫取代;和
R2’为饱和或不饱和低级或中级脂族烃残基,其为未取代的或被卤素、氧代基、羟基、低级烷基、低级烷氧基、低级烷酰氧基、环(低级)烷基、环(低级)烷氧基、芳基、芳氧基、杂环基或杂环-氧基取代;低级烷氧基;低级烷酰氧基;环(低级)烷基;环(低级)烷氧基;芳基;芳氧基;杂环基;杂环-氧基。
R3’为氢、低级烷基、环(低级)烷基、芳基或杂环基。
此外,虽然不管是否存在异构体,本发明所用化合物都可由基于酮型的结构式或命名表示,但应该注意这样的结构或名称并非意欲排除半缩醛型化合物。
在本发明中,在同一的目的中可使用任何异构体,例如个别互变异构体、其混合物或光学异构体、其混合物、外消旋混合物和其它立体异构体。
通过以下美国专利所公开的方法可制备本发明所用的某些化合物:美国专利第5,073,569号、第5,166,174号、第5,221,763号、第5,212,324号、第5,739,161号和第6,242,485号(这些引用的参考文献在此引作参考)。
(b)H+,K+-ATP酶抑制剂
本发明所用的H+,K+-ATP酶抑制剂即质子泵抑制剂,包括但不限于通式(II)化合物、其碱盐(alkaline salt)、其单对映体中的一种或对映体中一种的碱盐:
Het1为
其中Rb、Rc和Rd相同或不同,并选自氢、烷基、任选被氟取代的烷氧基、烷硫基、烷氧基烷氧基、二烷氨基、哌啶基、吗啉基、卤素、苯基和苯基烷氧基,
Re和Rf相同或不同,并选自氢、烷基和芳基烷基,和
Rg为氢、卤素、三氟甲基、烷基或烷氧基;
Het2为
处于苯并咪唑部分的苯环中心的N指任选被Rh-Rk取代的环碳原子中的一个,可被交换为氮原子而无任何取代基;和
X为
其中R1为氢或与Rd一起形成亚烷基链,和
Rm和Rn相同或不同,并选自氢、卤素或烷基。
具体优选的式II化合物实例为
艾美拉唑
本文所用化合物可以中性形式使用,或以碱盐形式,例如Mg2+、Ca2+、Na+或K+盐使用。所述化合物也可以其一种单对映体或单对映体碱盐形式使用。
本文所用的优选的质子泵抑制剂化合物为奥美拉唑、兰索拉唑、泮托拉唑、艾美拉唑、雷贝拉唑或其药学上可接受盐、其一种单对映体或其药学上可接受盐,尤其是奥美拉唑、兰索拉唑和艾美拉唑镁盐,更优选奥美拉唑和兰索拉唑。
药学上合适的赋形剂
根据本发明,组合物可调配为任何形式。因此,可视组合物所期需的形式来选择药学上合适的赋形剂。根据本发明,“药学上合适的赋形剂”意即惰性物质,其适于所述形式且与本发明活性成分联合。
举例而言,本发明口服给药用固态组合物可包括片剂、制剂、颗粒剂等等。在这样的固态组合物中,一种或多种活性成分可与至少一种惰性稀释剂混合,所述惰性稀释剂例如乳糖、甘露醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯基吡咯烷酮、硅酸铝镁(magnesium aluminate metasilicate)等等。按照常规的后处理(work-up),所述组合物可含有除惰性稀释剂之外的添加剂,举例而言,润滑剂,例如硬脂酸镁;崩解剂,例如纤维葡萄糖酸钙;稳定剂,例如环糊精,举例而言,α,β-环糊精或γ-环糊精;醚化环糊精,例如二甲基-α-环糊精、二甲基-β-环糊精、三甲基-β-环糊精或羟丙基-β-环糊精;支链环糊精,例如葡萄糖基-环糊精、麦芽糖基-环糊精;甲酰化环糊精、含硫环糊精;磷脂等等。当使用上述环糊精时,有时可形成具有环糊精的包合物以提高稳定性。或者,有时可使用磷脂形成脂质体,导致提高稳定性。
需要时片剂或丸剂可用在胃中或肠中可溶的膜来包衣,例如用糖、凝胶、羟丙基纤维素或羟丙基甲基纤维素邻苯二甲酸酯包衣。另外,用吸收性物质例如明胶可使其形成胶囊。优选将组合物调配为软明胶胶囊,其含有特定前列腺素化合物和中链脂肪酸甘油三酯的液态内容物。本发明所用中链脂肪酸甘油三酯实例包括含6-14个碳原子的饱和或不饱和脂肪酸甘油三酯,其可具有支链。优选的脂肪酸为直链饱和脂肪酸,例如己酸(C6)、辛酸(C8)、癸酸(C10)、月桂酸(C12)和豆蔻酸(C14)。另外,可联合使用两种或多种中链脂肪酸甘油三酯。其它合适的赋形剂公开于美国专利第6,583,174号中。
口服给药用液态组合物可为药学上可接受的乳剂、溶液剂、混悬剂、糖浆剂或酏剂,以及常用的惰性稀释剂。除惰性稀释剂之外,这样的组合物可含有辅助剂,例如润滑剂和助悬剂、甜味剂、矫味剂、防腐剂、增溶剂、抗氧化剂等等。添加剂的详细资料可从在药学领域的任何综合教科书中阐述的那些中选择。这样的液态组合物可直接包封在软胶囊中。本发明胃肠外给药用溶液剂,例如栓剂、灌肠剂等等,包括无菌水性或非水溶液剂、混悬剂、乳剂、清洁剂等等。水性溶液剂和混悬剂包括例如蒸馏水、生理盐水和Ringer氏溶液。
非水溶液剂和混悬剂包括例如丙二醇、聚乙二醇、脂肪酸甘油三酯和植物油(如橄榄油)、醇类(例如乙醇)、聚山梨醇酯等等。这样的组合物可含有辅助剂,例如防腐剂、湿润剂、乳化剂、分散剂、抗氧化剂等等。
本发明胃肠外给药用的可注射组合物实例包括无菌水性或非水溶液剂、混悬剂和乳剂。用于水性溶液剂或混悬剂的稀释剂可包括例如注射用蒸馏水、生理盐水和Ringer氏溶液。
用于溶液剂和混悬剂的非水稀释剂包括例如丙二醇、聚乙二醇、植物油例如橄榄油、醇类例如乙醇和聚山梨醇酯。该组合物可进一步包含添加剂,例如防腐剂、湿润剂、乳化剂、分散剂等等。它们可通过过滤(例如通过阻留细菌过滤器)、与灭菌器结合来除菌,或借助气体或放射性同位素照射灭菌。也可以经灭菌的粉末组合物来提供可注射的组合物,在使用前将其溶入经灭菌的注射用溶剂。
本发明组合物另外的形式为栓剂或阴道栓剂,其可通过使活性成分混入常规基质(例如在体温时软化的可可脂)来制备,具有合适的软化温度的非离子表面活性剂可用于改善可吸收性。
按照本发明方法,可借助口服给药或胃肠外给药全身或局部给予本发明组合物,包括栓剂、灌肠剂等等。可给予单种或多种组合物以达到所期需的剂量。
根据本发明,通过给予本发明指定的化合物组合,本发明可治疗哺乳动物受治疗者。哺乳动物受治疗者可为包括人类在内的任何受治疗者。可全身或局部施予所述化合物。通常可通过口服给药、静脉注射(包括输注)、皮下注射、直肠内给药、阴道内给药、透皮给药等等来给予所述化合物。剂量可视动物品系、年龄、体重、待治疗的症状、所期需的治疗效果、给药途径、治疗期限等等而变化。举例而言,通过每天1-6次(优选1-4次)全身给药,或连续给予以下药物组合,可达到满意的效果:每一剂0.001-100000μg(优选0.01-10000μg,更优选0.1-1000μg,尤其是1-100μg)特定前列腺素化合物和1-200mg(更优选1-60mg)H+,K+-ATP酶抑制剂。
本文所用术语“联合”意即特定前列腺素化合物和PPI这两种活性成分以单一实体或剂量形式同时给予患者,或将二者以分开实体同时或无特定时间限制序贯给予患者,其中这样的给药在体内提供这两种组分的治疗有效水平,优选在同一时间提供。
本文所用术语“治疗”包括任何控制手段,例如预防、护理、减轻病症、缓解病症和阻止病程进展。
本文所用的特定前列腺素化合物具有显著的抗溃疡活性和细胞保护活性,包括诱导胃肠道恢复屏障功能的活性,并基本上不影响胃酸排出量和ATP诱导的血小板聚集。这些事实提示:特定前列腺素化合物的抗溃疡活性并非源于抑制胃酸分泌,其不同于H+,K+-ATP酶抑制剂的作用机理。因此,通过含有组分(a)和(b),该组合具有优势,即其对肠胃病具有更好的效果,因此,可以降低剂量和/或减轻副作用。
举例而言,本文所用“肠胃病”包括但不限于胃溃疡、出血性溃疡、十二指肠溃疡、NSAID诱导性溃疡、消化性溃疡、腐蚀性食管炎、胃食管反流病、幽门螺杆菌感染、佐-艾综合征、NSAID或COX2抑制剂相关预防、消化不良、胃炎、消化道出血、食道溃疡和Barrett食管。
参考试验例将领会本发明的更详细情况,然而,其并非意欲限制本发明。
实施例1
所用的每组试验动物由10只雄性Crj:Wistar品系的大鼠组成。在经口给予化合物1(13,14-二氢-15-酮-16,16-二氟-PGE1、)或溶媒之前,让动物禁食24小时。口服给予试验样品或溶媒10分钟后,所有大鼠接受20mg/kg的口服剂量的吲哚美辛。6小时后对动物实施安乐死。取出胃,测量各处胃溃疡的最长轴的长度。用各单个溃疡长度总和来计算溃疡指数。
如表1所示,化合物1(13,14-二氢-15-酮-16,16-二氟-PGE1)经证明提供显著的抗吲哚美辛诱导性溃疡形成的保护作用。
表1化合物1对吲哚美辛诱导性大鼠胃溃疡的作用
a各单个溃疡长度总和
b平均值±SE;*与溶媒处理的对照组比较,p<0.05(学生t检定)
实施例2
所用的每组试验动物由9或10只雄性Crj:Wistar品系的大鼠组成。在经口给予试验样品之前让动物禁食24小时。口服给予各种剂量的化合物1(13,14-二氢-15-酮-16,16-二氟-PGE1)或溶媒10分钟后,将每只动物放入窄笼中,浸入水(23℃)中最高点到剑突达6小时。然后对动物实施安乐死。取出胃,测量各处胃溃疡的最长轴的最大长度。用各单个溃疡长度总和来计算溃疡指数。
如表2所示,化合物1显示出提供显著的抗应激诱导性溃疡形成的保护作用。
表2化合物1对应激诱导性大鼠胃溃疡的作用
a各单一溃疡长度总和
b平均值±SE;**与溶媒处理的对照组比较,p<0.01(Dunnett检定)
实施例3
按照Wong等(Pharmacol.Soc.32:49-56,1989)所述方法来实施该研究。所用每组试验动物由6只雄性Crj:Wistar品系的大鼠组成。让动物禁食24小时,自由入水。在结扎幽门之前30分钟,经口给予各种剂量的化合物1(13,14-二氢-15-酮-16,16-二氟-PGE1)、盐水和中链脂肪酸甘油三酯(MCT)的制剂。作为阳性对照,动物皮下接受2000μg/kg的五肽促胃酸激素,这是一种已知的胃酸刺激剂。在乙醚的麻醉下,通过中线切口打开腹部,用3-0丝线结扎幽门,关闭腹部。此后不给动物饮食和水。幽门结扎后4小时,通过颈脱位对动物实施安乐死,打开腹部。将胃内容物收集入无菌离心管中,以3000rpm离心10分钟以除去固态物质。收集上清液,测量体积。用0.01N氢氧化钠用自动滴定仪(COMTITE-900,Hiranuma Sangyo,Co.,Ltd.,Japan)将各个胃液样品的1mL等份样滴定到pH7.0,以测定酸度(mEqH+/mL)。计算4小时的胃酸总排出量。
结果
结果示于图1中。在盐水和MCT处理组之间总酸排出量无显著差异。与此相反,与盐水处理对照组比较,皮下给予用作阳性对照的2000μg/kg五肽促胃酸激素诱导总酸排出量显著提高(p<0.01)。与溶媒处理的对照组比较,试验化合物不影响总酸排出量。
实施例4
收集JW/CSK品系的兔子的血液,以9体积血液比1体积3.8%柠檬酸钠溶液的比率,通过与柠檬酸钠混合来使其柠檬酸化。通过以1000rpm(168xg)将柠檬酸化的血液离心10分钟,得到富含血小板的血浆(PRP,platelet-rich plsama)。收集PRP后,进一步将残留的血液以3000rpm(1670xg)离心15分钟,将上清液用作缺乏血小板的血浆(PPP,platelet-poor plsama)。在让PRP(200μL)于37℃与各种试验溶液(25μL)预温育1分钟后,加入25μL血小板聚集剂(ADP25μM)。用血小板聚集仪(HEMATRACER PAT-4A,Niko Bioscience,Inc.)测量血小板聚集。用3种不同动物来源的血小板以双份重复的方式检查各个试验溶液。通过与盐水处理组的最大聚集比较,计算抑制百分率。
如表3所示,化合物1(13,14-二氢-15-酮-16,16-二氟-PGE1)对血小板聚集无影响。另一方面,前列腺素E1(PGE1)显著抑制血小板聚集。
表3.化合物1和PGE1对ADP诱导的兔血小板聚集的作用
a平均值±SE,
**与溶媒对照组比较p<0.01(学生t检定)
实施例5
(方法)
在自由入水过夜禁食后,使用Wistar大鼠。将化合物1(13,14-二氢-15-酮-16,16-二氟-PGE1)或化合物2(13,14-二氢-15-酮-16,16-二氟-18(s)甲基-PGE1)经口给予动物。当评估用化合物1和质子泵抑制剂(兰索拉唑或奥美拉唑)联合治疗的效果时,同时经口给予化合物1和质子泵抑制剂。对照组接受同样体积的溶媒。给药10分钟后,将动物置于应激反应笼(stress cage)中,垂直浸入维持在23℃的水浴中至剑突。5小时后,从笼中取出各个动物,通过CO2窒息处死动物。在结扎胃的心脏区和十二指肠上部后取出胃。用4mL生理盐水溶液填充胃,在1%福尔马林溶液中固定30分钟。沿着较大的胃弯打开胃。测量单个溃疡的长度(mm),用每个胃所有溃疡长度的总和来表示溃疡指数。
(结果)
如表4所示,化合物1和2以剂量依赖性方式抑制胃溃疡。如表5所示,用化合物1和兰索拉唑联合治疗比单用兰索拉唑治疗更有效抑制胃溃疡。此外,用化合物1和奥美拉唑联合治疗也比单用奥美拉唑治疗更有效抑制胃溃疡。
结果证明,用特定前列腺素化合物和质子泵抑制剂联合治疗对抑制胃溃疡具有加性和/或协同作用。
表4化合物1和2对通过浸水应激诱导的大鼠胃溃疡的作用
表5用化合物1和质子泵抑制剂联合治疗通过浸水应激诱导的大鼠胃溃疡的效果
Claims (13)
1.下列物质的组合与药学上可接受赋形剂结合用于制备药物组合物的用途:
(a)由式(II)代表的13,14-二氢-15-酮-16-单或二氟-前列腺素E化合物:
其中L为氧代基,M为氢或羟基;
A为-COOH或其盐、醚、酯或酰胺;
B为-CH2-CH2-;
Z为
X1和X2为氢或氟,条件是X1和X2中至少一个为氟;
R1为饱和或不饱和二价直链或支链C1-C14脂族烃残基;和
R2为单键或直链或支链C1-C6亚烷基;和
R3为直链或支链C1-C6烷基;
和
(b)H+,K+-ATP酶抑制剂,其中所述H+,K+-ATP酶抑制剂为奥美拉唑、兰索拉唑、泮托拉唑、艾美拉唑、雷贝拉唑、帕瑞拉唑、来明拉唑、或其药学上可接受盐、其一种单一对映体或其药学上可接受盐。
2.权利要求1的用途,其中所述13,14-二氢-15-酮-16-单或二氟-前列腺素E化合物为13,14-二氢-15-酮-16,16-二氟-前列腺素E1化合物或13,14-二氢-15-酮-16,16-二氟-18-甲基-前列腺素E1化合物。
3.权利要求1的用途,其中所述13,14-二氢-15-酮-16-单或二氟-前列腺素E化合物为13,14-二氢-15-酮-16,16-二氟-前列腺素E1或13,14-二氢-15-酮-16,16-二氟-18-甲基-前列腺素E1。
4.权利要求1的用途,其中所述H+,K+-ATP酶抑制剂为奥美拉唑、兰索拉唑、泮托拉唑、艾美拉唑、雷贝拉唑或其药学上可接受盐、其一种单一对映体或其药学上可接受盐。
5.权利要求1的用途,其中所述H+,K+-ATP酶抑制剂为奥美拉唑、兰索拉唑、艾美拉唑或其药学上可接受盐、其一种单一对映体或其药学上可接受盐。
6.权要求1的用途,其中所述H+,K+-ATP酶抑制剂为奥美拉唑、兰索拉唑或其药学上可接受盐、其一种单一对映体或其药学上可接受盐。
7.权利要求1的用途,其中所述H+,K+-ATP酶抑制剂为奥美拉唑或其药学上可接受盐、其一种单一对映体或其药学上可接受盐。
8.权利要求1的用途,其中所述H+,K+-ATP酶抑制剂为兰索拉唑或其药学上可接受盐、其一种单一对映体或其药学上可接受盐。
9.权利要求1的用途,其中所述药学上可接受赋形剂为用于口服给药的赋形剂。
10.权利要求1-9中任一项的用途,其中所述药物组合物用于治疗肠胃病。
11.权利要求10的用途,其中所述肠胃病选自胃溃疡、出血性溃疡、十二指肠溃疡、NSAID诱导性溃疡、消化性溃疡、腐蚀性食管炎、胃食管反流、幽门螺杆菌感染、佐-艾综合征、NSAID或COX2抑制剂相关预防、消化不良、胃炎、消化道出血、食道溃疡和Barrett食管。
12.权利要求1的用途,其中组分(a)和(b)同时或序贯给予。
13.一种药物组合物,其包含:
(a)药学有效量的由式(II)代表的13,14-二氢-15-酮-16-单或二氟-前列腺素E化合物:
其中L为氧代基,M为氢或羟基;
A为-COOH或其盐、醚、酯或酰胺;
B为-CH2-CH2-,
Z为
X1和X2为氢或氟,条件是X1和X2中至少一个为氟;
R1为饱和或不饱和二价直链或支链C1-C14脂族烃残基;
R2为单键或直链或支链C1-C6亚烷基;和
R3为直链或支链C1-C6烷基;
(b)药学有效量的H+,K+-ATP酶抑制剂,其中所述H+,K+-ATP酶抑制剂为奥美拉唑、兰索拉唑、泮托拉唑、艾美拉唑、雷贝拉唑、帕瑞拉唑、来明拉唑、或其药学上可接受盐、其一种单一对映体或其药学上可接受盐;
和药学上合适的赋形剂。
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US67023805P | 2005-04-12 | 2005-04-12 | |
US60/670,238 | 2005-04-12 | ||
PCT/JP2006/308001 WO2006109881A1 (en) | 2005-04-12 | 2006-04-11 | Combined use of prostaglandin compound and proton pump inhibitor for the treatment of gastrointestinal disorders |
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ES2379652T3 (es) * | 2002-10-23 | 2012-04-30 | Sucampo Ag | Compuestos de prostaglandina para el tratamiento de obesidad |
EP2059247A1 (en) * | 2006-09-06 | 2009-05-20 | Sucampo AG | Method and composition for promoting gastrointestinal bicarbonate secretion |
US20090012165A1 (en) * | 2007-07-03 | 2009-01-08 | Sucampo Ag | Pharmaceutical combination of nsaid and prostaglandin compound |
WO2009157397A1 (ja) * | 2008-06-23 | 2009-12-30 | 日本新薬株式会社 | 非ステロイド性抗炎症剤投与に伴う腸管傷害治療剤 |
US20110034424A1 (en) * | 2009-06-30 | 2011-02-10 | Sucampo Ag | Method for the long term nsaid use |
US20120270945A1 (en) * | 2011-04-19 | 2012-10-25 | Sucampo Ag | Method for modulating cytokine activity |
WO2014159679A1 (en) | 2013-03-12 | 2014-10-02 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Methods for using lubiprostone to absorb fluid from the subretinal space |
KR20160015100A (ko) | 2014-07-30 | 2016-02-12 | 미래파인켐 주식회사 | 프로스타글란딘 중간체의 제조방법 |
KR20170025682A (ko) | 2015-08-31 | 2017-03-08 | 미래파인켐 주식회사 | 프로스타글란딘 유도체의 신규한 제조방법 |
CN107582556A (zh) * | 2017-09-15 | 2018-01-16 | 成都泠汐尚品科技有限公司 | 一种治疗消化性溃疡的药物复方制剂 |
CN108051553A (zh) * | 2017-12-29 | 2018-05-18 | 武汉轻工大学 | 一种仔猪肠道功能保护剂的筛选方法 |
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US20070276006A1 (en) | 2007-11-29 |
WO2006109881A1 (en) | 2006-10-19 |
DK1871380T3 (da) | 2011-11-21 |
KR101466980B1 (ko) | 2014-12-01 |
NO20075764L (no) | 2008-01-14 |
RU2468800C2 (ru) | 2012-12-10 |
IL186374A (en) | 2013-05-30 |
KR20070119753A (ko) | 2007-12-20 |
KR20140069182A (ko) | 2014-06-09 |
CA2602812A1 (en) | 2006-10-19 |
JP2008535774A (ja) | 2008-09-04 |
AU2006234632A1 (en) | 2006-10-19 |
PL1871380T3 (pl) | 2012-03-30 |
ZA200709072B (en) | 2008-11-26 |
EP1871380A1 (en) | 2008-01-02 |
ES2371658T3 (es) | 2012-01-05 |
US8962688B2 (en) | 2015-02-24 |
BRPI0610557A2 (pt) | 2010-06-29 |
EP1871380B1 (en) | 2011-10-19 |
CA2602812C (en) | 2014-11-18 |
NZ562763A (en) | 2010-12-24 |
RU2007141655A (ru) | 2009-05-20 |
JP5711442B2 (ja) | 2015-04-30 |
CN101198334A (zh) | 2008-06-11 |
AU2006234632B2 (en) | 2011-10-27 |
IL186374A0 (en) | 2008-03-20 |
PT1871380E (pt) | 2011-11-21 |
JP2013121972A (ja) | 2013-06-20 |
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