CN1287781C - Kcnq钾通道激动剂在制备诱导或保持膀胱功能的药物的用途 - Google Patents
Kcnq钾通道激动剂在制备诱导或保持膀胱功能的药物的用途 Download PDFInfo
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Abstract
本发明提供利用KCNQ钾通道激动剂在哺乳动物中保持膀胱控制或治疗尿失禁的方法和药物组合物,所述KCNQ钾通道包括单独的或者组合的KCNQ2、KCNQ3、KCNQ4和KCNQ5钾通道。用在这些方法中的化合物包括在U.S.5,384,330(Dieter等)中所述的1,2,4-三氨基-苯衍生物和在U.S.5,565,483(Hewawasam等)中所述的3-苯基羟吲哚化合物。其中,本发明的优选化合物是N-[2-氨基-4-(4-氟苄基氨基)-苯基]氨基甲酸乙酯,也称为瑞替加滨(retigabine)。
Description
本发明涉及利用调节KCNQ族钾通道的化合物来调节膀胱组织的新方法,特别是打开或激(agonize)这些通道的化合物。本发明的方法包括治疗、预防、抑制和减缓欲望性尿失禁,也称为膀胱不稳定性、神经原性膀胱障碍、排泄机能障碍、机能亢进性膀胱障碍或排尿肌过度活跃。本发明的方法还包括预防和治疗混合压迫性和欲望性尿失禁,包括与继发性症状如前列腺肥大相关的尿失禁。
发明背景
U.S.5,384,330(Dieter等)(EP 0554543B)说明了具有以下通式的药物活性的1,2,4-三氨基苯衍生物:
及其作为抗癫痫药、肌肉松弛剂、解热和末梢止痛剂的性质。
U.S.5,565,483(Hewawasam等)(EP 0747354B)说明了具有下式的化合物:
其中,R是氢、羟基或氟基;R1、R2、R3和R4各自独立地是氢、C1-4烷基、卤素、三氟甲基、苯基、对甲基苯基或对三氟甲基苯基;或者R1和R2、R2和R3或者R3和R4结合在一起,形成苯并稠环;R5是氢或C1-4烷基;且R6是氯或三氟甲基;或其无毒的可药用盐、溶剂化物或水合物,其是用于治疗局部缺血、惊厥和哮喘的钾通道的开启物。
文章Modulation of KCNQ2/3 Potassium Channels by the NovelAnticonvulsant Retigabine,Main等,Molecular Pharmacology,58:pp.253-262,2000描述了瑞替加滨(retigabine)(D23129;N-[2-氨基-4-(4-氟苄基氨基)-苯基]氨基甲酸乙酯)以三重方式调节卵母细胞中的KCNQ2/3钾通道中的作用,即retigabine使通道激活的电压依赖性向更大超极化膜电势移动,增大通道激活率和减慢通道失活。文章“KCNQ4 Channel Inactivation by BMS-204352 andRetigabine”R L Schroder等Neuropharmacology
40,888-898(2000)描述了使用retigabine和BMS-204352;(3S)-(+)-(5-氯-2-甲氧基苯基)-1,3-二氢-3-氟-6-(三氟甲基))-2H-吲哚-2-酮以可逆的和浓度相关方式激活KCN Q4通道。
U.S.5,849,789和5,852,053(都是Rostock等人的)说明了使用retigabine治疗神经变性失调,包括与中风有关的那些。
U.S.5,914,425(Meisel等)说明了retigabine的新晶型。
U.S.6,117,900说明了使用retigabine,也称为N-[2-氨基-4-(4-氟苄基氨基)-苯基]氨基甲酸乙酯,来治疗神经性疼痛。
发明详述
本发明包括调节哺乳动物中的膀胱组织的方法,特别是其保持膀胱控制的用途,该方法包括为需要的哺乳动物服用药物有效量的作为KCNQ族钾通道的激动剂或开启剂的化合物,所述KCNQ族钾通道包括单独或组合的KCNQ2,KCNQ3,KCNQ4和KCNQ5钾通道。本发明的一个特定实施方案包括在本文所述的方法中使用一种或多种KCNQ2/3钾通道的激动剂或开启剂。另一系列的本发明方法包括使用一种或多种XCNQ3/5钾通道的激动剂或开启剂。
用于本发明方法中的化合物是在U.S.5,384,330(Dieter等)和EP 0554543B中公开的那些,其内容并入本文作为参考。这些化合物包括具有下式的那些或其可药用盐:
其中:
R1选自氢、C1-C6烷基、C2-C6烷酰基或基团Ar;
R2选自氢或C1-C6烷基;
R3选自C1-C6烷氧基、NH2、C1-C6烷基氨基、C1-C6二烷基氨基、被基团Ar、C1-C6烷基、C2-C6烯基、C2-C6炔基取代的氨基、基团Ar或基团ArO-;
R4选自氢C1-C6烷基或基团Ar;
R5选自氢或C1-C6烷基或基团Ar;
Alk表示具有1-9个碳原子的直链或支链亚烷基,其也可以被基团Ar取代;
Ar是被基团R6、R7和/或R8取代的苯基,其中,这些基团R6、R7和R8是相同或不同的,并且表示H、C1-C6烷基、C3-C7环烷基、羟基、C1-C6烷氧基、C2-C6烷酰氧基、卤素、羟基、C1-C6卤代烷基、-CN、-NH2、-NH-C1-C6烷基、-N(C1-C2烷基)2、-CO2H、-CO-C1-C6烷基、-CO-O-C1-C6烷基、-COAr、-CO-OAr、-CONH2、-CONH-C1-C6烷基、-CON(C1-C6烷基)2、-CONHAr、-NH-CO-C1-C6烷基、-NHCO-Ar、-NHCO-C1-C6烷氧基、-N-H-CO-Ar、-NHCO-NH2、-NHCO-N(-C1-C6烷基)2、-NHCO-NHAr、-NH-SO2-C1-C6烷基、-NH-SO2Ar、-NH-SO2-硝基苯基、-SO2-OH、-SO2-C1-C6烷基、-SO2-Ar、-SO2-C1-C6烷氧基、-SO2-OAr、-SO2-NH2、-SO2-NH-C1-C6烷基、-SO2-N(C1-C6烷基)2、-SO2-NHAr、-SO2-C1-C6烷氧基;
n是0或1。
烷基、卤代烷基、烯基、炔基、烷氧基、烷基氨基、烷酰基氨基、烷酰氧基、和烷酰基一般可以是直链或支链的。如果这些是更复杂基团的组分,例如为单烷基或二烷基氨基、烷酰基氨基、烷氧羰基、烷基羰基和类似的基团形式,则同理可应用于烷基和烷基氧基(=烷氧基)。C3-C7环烷基优选的是环戊基或环己基。C2-C6烯基优选的是烯丙基、C2-C6炔基优选表示炔丙基。
卤原子是氯、溴或氟,特别是氯或氟。烷基和烷氧基本身或作为更复杂基团的组分特别由1-4个碳原子,优选1或2个碳原子组成。烷酰基如烷酰氨基或烷酰氧基特别由2-4,优选2-3个碳原子组成。Alk特别由1-3个,优选1或2个碳原子组成。
该组中的更优选化合物是:
2-氨基-4-(4-氟苄基氨基)-1-乙氧基羰基氨基苯;
2-氨基-4-(4-三氟甲基苄基氨基)-1-乙氧基羰基氨基-苯;
2-氨基-4-苄基氨基-1-乙氧基羰基氨基-苯;
2-氨基-4-(3,5-二氯代苄基氨基)-1-乙氧基羰基氨基-苯;
2-氨基-4-(3,5-二氯代苄基氨基)-1-丙氧基羰基氨基苯;
2-氨基-(2-氯代苄基氨基)-1-(二乙基氨基甲酰基氨基)苯;
2-氨基-4-(2,4-二氯代苄基氨基)-1-(二甲基氨基甲酰基氨基)苯;和
1,2-二乙酰基氨基-4-(4-氟代苄基氨基)苯。
用于本发明方法的最优选化合物是N-[2-氨基-4-(4-氟代苄基氨基)-苯基]氨基甲酸及其可药用盐和酯形式。特别优选的是retigabine,也称为N-[2-氨基-4-(4-氟代苄基氨基)-苯基]氨基甲酸乙酯(CAS Registry No.150812-12-7),具有下式:
用于本发明方法的还有retigabine的代谢物形式,其可以从N-[2-氨基-4-(4-氟代苄基氨基)-苯基]氨基甲酸乙酯接受者的血液、尿或粪便中分离。代谢物包括retigabine的葡糖苷,[4-(4-氟-苄基氨基)-2-(3,4,5-三羟基-6-羟甲基四氢吡喃-2-基氨基)-苯基]-氨基甲酸乙酯,及其两种glucoronide类似物,6-[2-乙氧基羰基氨基-5-(4-氟-苄基氨基)-苯基氨基]-3,4,5-三羟基四氢吡喃-2-甲酸和6-[(3-氨基-4-乙氧基羰基-氨基-苯基)-(4-氟-苄基)-氨基]-3,4,5-三羟基四氢吡喃-2-甲酸。其它代谢物包括N-[2-氨基-4-(4-氟-苄基氨基)-苯基]-乙酰胺,其环化类似物(4-氟-苄基)-2-甲基-1H-苯并咪唑-5-基)胺和N-[2-氨基-4-(4-氟-苄基氨基)-苯基]乙酰胺、6-[(4-乙酰基氨基-3-氨基-苯基)-(4-氟-苄基)-氨基]-3,4,5-三羟基四氢吡喃-2-甲酸和6-[2-乙酰基氨基-5-(4-氟-苄基氨基)-苯基氨基]-3,4,5-三羟基四氢吡喃-2-甲酸的glucoronide类似物。
还用于本发明方法中的是公开于在1996年10月15日授权的U.S.5,565,483(Hewawasam等)和EP 0747354B中的化合物,其内容并入本文作为参考。这些化合物包括取代的3-苯基羟吲哚化合物,具有下式:
其中:
R是氢、羟基或氟;
R1,R2,R3和R4各自独立地是氢、C1-4烷基、卤素、三氟甲基、苯基、对甲基苯基或对三氟甲基苯基;或者R1和R2、R2和R3或R3和R4结合在一起形成苯并稠合环;
R5是氢或C1-4烷基;和
R6是氯或三氟甲基;或者其无毒可药用盐、溶剂化物或水合物,及其光学形式。
用于本发明的一组取代的3-苯基羟吲哚化合物包括其中R是氢的上述那些。这些化合物的另一个分组包括下述的那些:即其中R1、R2、R3和R4各自独立地选自H、C1-C4烷基、卤素或三氟甲基,并且当R1和R4是H时;R2或R3是苯基、对甲氧基苯基或三氟甲基苯基;或者R1和R2、R2和R3或R3和R4结合在一起形成苯并稠合环;R5是H或C1-C4烷基;并且R6是氯或三氟甲基,或其可药用盐形式。
这些取代的3-苯基羟吲哚化合物的非限制性实例是:
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-羟基-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-3-羟基-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-4,6-二氯-1,3-二氢-3-羟基-2-H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-3-羟基-7-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-3-羟基-4-三氟甲基)-2H-吲哚-2-酮;
(±)-1,3-二氢-3-羟基-3-[2-羟基-5-(三氟甲基)苯基]-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-3-羟基-4,6-二(三氟甲基)-2H-吲哚-2-酮;
(-)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-羟基-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-3-羟基-6-(三氟甲基)-2H-吲哚-2-酮;
(-)-3-(5-氯-2-羟基苯基)-1,3-二氢-3-羟基-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-氟-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-3-羟基-2H-苯基[g]吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-6-苯基-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-2H-苯基[g]吲哚-2-酮;
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-氟-6-苯基-2H-吲哚-2-酮;
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-氟-6-碘-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-6-(4-甲基苯基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-氟-7-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-2H-苯基[e]吲哚-2-酮;
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-氟-5-甲基-2H-吲哚-2-酮;
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-氟-4,6-二(三氟甲基)-2H-吲哚-2-酮;
(±)-5-溴-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-氟-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-6-[4-(三氟甲基)苯基]-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-2H-吲哚-2-酮;
(±)-5-溴-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-羟基-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-4,6-二氯-1,3-二氢-2H-吲哚-2-酮;
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-羟基-6-碘-2H-吲哚-2-酮;
(±)-3-(5-氯-羟基苯基)-1,3-二氢-6-碘-2H-吲哚-2-酮;
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-羟基-2H-苯基[f]吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-3-羟基-2H-苯基[f]吲哚-2-酮;和
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-2H-苯基[f]吲哚-2-酮;
及其可药用盐形式。
该组中更优选的化合物是:
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-3-羟基-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-氟-6-(三氟甲基)-2H-吲哚-2-酮;
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-3-羟基-2H-苯基[g]吲哚-2-酮;
(+)-3-(5-氯-2-羟基苯基)-1,3-二氢-6-苯基-2H-吲哚-2-酮;和
(±)-3-(5-氯-2-羟基苯基)-1,3-二氢-2H-苯基[f]吲哚-2-酮。
这些取代的3-苯基羟吲哚化合物的可药用盐形式包括按照碱加成反应所形成的那些,包括使用合适的无机碱所形成的那些,如碱金属和碱土金属碱,如钠、钾、镁和钙金属阳离子。这些化合物可以按照U.S.5,565,483中所述的进行服用。在哺乳动物(包括人)中的药物有效量可以为约0.1μg/kg-约100mg/kg体重。肠道外的服药可以按约1μg/kg-10mg/kg体重的有效剂量进行。
本发明的方法用于遭受或易于产生膀胱不稳定性或尿失禁的哺乳动物中诱导、促进或维持希望的膀胱控制。这些方法包括预防、治疗或抑制与膀胱相关的泌尿病症和膀胱不稳定性,包括夜遗尿、夜尿症、排泄机能障碍和尿失禁。还可以用本发明的方法治疗或预防前列腺肥大继发的膀胱不稳定性。本文所述化合物还用于在希望时促进泌尿的暂时延迟。本发明的化合物还可以用来稳定膀胱并治疗或预防哺乳动物中的失禁,包括欲望性泌尿失禁、压迫性尿失禁或欲望性和压迫性尿失禁的组合,后者也成为混合欲望性和压迫性尿失禁。这些方法包括帮助预防或治疗与继发性症状如前列腺肥大相关的尿失禁。
这些方法可以用来允许接受者控制排尿的急迫性和频度。本发明的方法包括治疗、预防、抑制和减缓急性尿失禁(也称为膀胱不稳定)、神经原性膀胱功能障碍、排泄机能障碍、活动过强的膀胱、排尿肌活动过度、排尿肌反射亢进或无抑制膀胱。
如上所述,本发明的方法包括治疗、预防、抑制或减缓活动过强或不稳定膀胱、神经原性膀胱功能障碍或反射亢进性膀胱。这些用途包括但不限于用于其中尿急与前列腺炎、前列腺肥大、间质性膀胱炎、尿路感染或阴道炎有关的膀胱活动性和不稳定性的那些。本发明的方法还可以用来帮助抑制或校正Frequency-Urgency Syndrome(尿频尿急综合症)的症状,和迟钝的膀胱,其也称为罕见排尿综合症。
本发明的方法还可以用来治疗、预防、抑制或限制与伴随其它药物服用或由于其它药物服用产生的尿失禁、泌尿不稳定或尿急,包括利尿剂、抗利尿激素拮抗剂、抗胆碱药、镇静剂或催眠剂、麻醉剂、α-肾上腺素能激动剂、α-肾上腺素能拮抗剂、或钙通道阻断剂。
本发明的方法用于诱导或帮助膀胱控制或在需要这种缓解的人中治疗本文所述的疾病,包括在成人和儿科的使用。但是,它们还可以用于兽医用途,特别是包括犬和猫膀胱控制方法。如果希望,本文中的方法还可以用于家畜如羊、牛、猪和马的饲养。
这些应用可以利用传统的口服给药、直肠给药、肠道外给药或静脉内给药方法,如在兽医实践中通常利用的。在家庭用于宠物的大多数情况下最优选的是口服片剂或胶囊或纯化合物或粉末状或颗粒状药剂,它们可以与可咀嚼或液体兽医药剂或所述动物可接受的食物或液体混合。
本文所用的术语“药物有效量”或“治疗有效量”是指药物组合物或方法的每种活性成分的总量,其足以表现出显著的对病人的益处,即治疗、预防或减缓尿失禁或过度或不希望的排尿欲望,或者降低尿失禁的发生频度。当对个体施用活性成分时,术语单独给药是指单独施用该成分。当组合施用时,该术语是指产生治疗效果的这些活性成分的组合量,而不管是组合给药、还是系列或同时给药。
由U.S.5,384,330可知,本发明的方法可以用约0.1mg/kg-约10mg/kg的上述活性化合物的日剂量进行。该剂量可以按一次服用法给药,如仅仅在就寝前或在旅行前给药,或者在全天分成两个或多个剂量的连续服用法给药。人的给药可以按约10mg BID-约1000mgBID,优选约50mg BID-约500mg BID,更优选约100mg BID-约300mg BID的剂量进行。
本发明的KCNQ钾通道激动剂也可以用本发明的方法结合用于膀胱控制或尿失禁的治疗或抑制的药物有效量的其它药剂一起给药。例如,这些化合物可以与去氨加压素乙酸盐(desmopressin acetate),可以以DDAVPNasal Spray和DDAVP片剂得自AventisPharmaceuticals,以及得自Ferring Pharmaceuticals Inc.的去氨加压素乙酸盐鼻管给药。其它组合产品包括tolterodine酒石酸盐(可以以DETROLTM片剂得自Pharmacia & Upjohn)、羟丁宁(oxybutinin)氯化物(可以以DITROPAN片剂和糖浆形式和DITROPAN XL缓释片剂形式得自ALZA Pharmaceuticals)、溴化普洛盘舍啉(propanthalinebromide)(可以以片剂形式从Roxane Laboratories,Inc.获得)、茛菪碱和茛菪碱硫酸盐(分别可以以CYSTOPAZ片剂和CYSTOPAZ-M时控释放胶囊得自PolyMedica Pharmaceuticals(U.S.A.),Inc.)、茛菪碱氢溴酸盐、盐酸黄酮哌酯(可以以URISPAS100mg片剂得自ALZA Pharmaceuticals)、盐酸丙咪嗪(可以以10mg、25mg和50mg片剂得自Geneva Pharmaceuticals,Inc.)、苯基丙醇胺、盐酸甲氧胺福林(可以以2.5mg和5mg PROAMATINE片剂得自Shire USInc.)、盐酸苯氧苯扎明(可以以DIBENZYLINE胶囊得自WellSpringPharmaceuticals Corporation)、和盐酸哌唑嗪(可以以MINIPRESS胶囊得自Pfizer Inc.)。这些药物的每一种可以按药物有效量和本领域已知的服用方法给药,包括在Physicians′Desk Reference,第55版,2001中所列出的那些,该书由Medical Economics Company,Inc.at Monvale,NJ 07645-1742出版,其相关部分并入本文作为参考。本发明的钾通道激动剂还可以与一种或多种作为后叶加压素激动剂的化合物结合使用,所述化合物包括但不限于在U.S.6,194,407(Failli等)、U.S.6,090,803(Failli等)、U.S.6,096,736(Ogawa等)和U.S.6,096,735(Ogawa等)中所述的那些。
如U.S.5,384,330中所述的化合物,包括retigabine,可以使用传统的药物赋形剂或载体口服给药,优选的是糖衣的或者包含在硬或软明胶胶囊中。在硬明胶胶囊中包含的口服药剂的实例可以包括其中活性化合物占该药剂的约45重量%-50重量%的那些。
微晶纤维素占约43%-约47%,聚烯吡酮占约3%-4%,二氧化硅和硬脂酸镁各占约0.3-0.7%,每个量按重量计。含有50mg、100mg和200mg的胶囊的具体实例可以利用以下列出的成分配制。50mg Retigabine胶囊
成分 | 用量/胶囊 |
Retigabine | 50.0mg |
微晶纤维素,NF | 45.5mg |
聚烯吡酮,USP | 3.5mg |
二氧化硅,胶体,无水,NF | 0.5mg |
硬脂酸镁,EP | 0.5mg |
理论填充重量 | 100.0mg |
100mg Retigabine胶囊
成分 | 用量/胶囊 |
Retigabine | 100.0mg |
微晶纤维素,NF | 91.0mg |
聚烯吡酮,USP | 7.0mg |
二氧化硅,胶体,无水,NF | 1.0mg |
硬脂酸镁,EP | 1.0mg |
理论填充重量 | 200.0mg |
200mg Retigabine胶囊
成分 | 用量/胶囊 |
Retigabine | 200.0mg |
微晶纤维素,NF | 182.0mg |
聚烯吡酮,USP | 14.0mg |
二氧化硅,胶体,无水,NF | 2.0mg |
硬脂酸镁,EP | 2.0mg |
理论填充重量 | 400.0mg |
在以上药剂中的成分可以使用以下步骤制备。
1)分别称重活性组分(retigabine),其优选通过800微米筛,和微晶纤维素成分。
2)通过把聚烯吡酮、USP溶于纯水中来制备造粒溶液。
3)把来自步骤1的组分放入合适的混合机中并充分混合。
4)使来自步骤3的混合物通过1000微米筛,并把过筛的混合物放入流化床造粒机的容器中。
5)把流化床造粒机中的组分加热到最高27℃的产物温度并混合。
6)向流化床中加入来自步骤2的造粒溶液。
7)干燥流化床中的颗粒。
8)称量胶体二氧化硅成分,优选通过1000微米筛,和硬脂酸镁成分,优选通过600微米筛。
9)向含有来自步骤7的干燥颗粒的流化床造粒机容器中加入二氧化硅和硬脂酸镁成分并充分混合这些成分。
10)筛分来自步骤9的混合成分,优选通过800微米筛。
11)把最终筛分过的成分移到合适的混合机中并充分混合。
来自步骤11的最终成分混合物然后可以根据要求涂糖衣、装胶囊或利用传统的片剂赋形剂或载体压制成片剂。应当理解,在本发明范围内的口服剂型可以使用以上所列的成分制备,这些成分各自的用量根据特定药剂中的活性成分的剂量而定。对于兽医用途,步骤11的最终混合物可以纯净地给药或混合到所述动物可接受的食物中。此外,这些混合物可以配制成片剂、胶囊或糖衣制品,如上所述,或者与传统的兽药或食品结合在一起。
对于静脉内给药,可以用传统的低压升华干燥药剂方式制备和保持本文所述的来自U.S.5,384,330中的化合物,并且在用静脉可接受的盐水溶液给药前重新构成,所述盐水溶液如0.9%盐水溶液。静脉处方的pH值可以用静脉和可药用酸(如甲磺酸)按需要调节。
在大鼠膀胱中的KNCQ1、3和5表达和M-电流活动
使用定量的rtPCR,在大鼠膀胱中鉴定KCNQ1,KCNQ3和KCNQ5钾通道的表达。在KCNQ5(0.2±0.1ng KCNQ5 mRNA/GAPDH mRNA)中发现最高量的表达。为了进一步查明膀胱中的M-电流活动,使用标准膜片钳技术,在分离的膀胱平滑肌细胞中测试retigabine(10μM,M-电流激动剂)。对retigabine的暴露显著增大向外的电流,其对iberiotoxin不敏感,并且伴有17.8±3.0mV(n=5)的薄膜超极化。这种超极化通过向组织浴中加入利诺吡啶(linopirine)(50μM,一种M-电流拮抗剂)而颠倒。Retigabine松驰了所分离的氨甲酰胆碱收增过的大鼠膀胱带,其IC50为3.5±0.9μM(n=14)。这种松弛通过M-电流阻断剂linopirdine和XE-991倒转。
Claims (19)
1.KCNQ钾通道激动剂在制备诱导或保持哺乳动物中的膀胱控制的药物中的用途,其中所述KCNQ钾通道激动剂是式(I)的化合物或其可药用盐:
其中:
R1选自氢、C1-C6烷基或C2-C6烷酰基;
R2选自氢或C1-C6烷基;
R3选自C1-C6烷氧基或甲基;
R4选自氢或C1-C6烷基;
R5选自氢或C1-C6烷基;
Alk表示具有1-3个碳原子的直链或支链亚烷基;
Ar是被基团R6、R7和/或R8取代的苯基,其中,R6、R7和R8这些基团是相同或不同的,并且表示H、C1-C6烷基、羟基、C1-C6烷氧基、C2-C6烷酰氧基、卤素、C1-C6卤烷基、-CN、-NH2、-NH-C1-C6烷基、-N(C1-C6烷基)2、-CO2H、-CO-C1-C6烷基、-CO-O-C1-C6烷基、-CONH2、-CONH-C1-C6烷基、-CON(C1-C6烷基)2、-NH-CO-C1-C6烷基、-NHCO-C1-C6烷氧基、-NHCO-NH2、-NHCO-N(-C1-C6烷基)2;
n是0或1。
2.根据权利要求1的用途,其中,哺乳动物是人。
3.根据权利要求1的用途,其中,哺乳动物是猫或犬。
4.根据权利要求1的用途,其中,式I的化合物选自:
2-氨基-4-(4-氟苄基氨基)-1-乙氧基羰基氨基苯;
2-氨基-4-(4-三氟甲基苄基氨基)-1-乙氧基羰基氨基-苯;
2-氨基-4-苄基氨基-1-乙氧基羰基氨基-苯;
2-氨基-4-(3,5-二氯苄基氨基)-1-乙氧基羰基氨基-苯;或
2-氨基-4-(3,5-二氯苄基氨基)-1-丙氧基羰基氨基苯;
或其可药用盐。
5.根据权利要求1的用途,其中,式I的化合物是N-[2-氨基-4-(4-氟苄基氨基)-苯基]氨基甲酸或其可药用盐或酯形式。
6.根据权利要求5的用途,其中,可药用酯形式是N-[2-氨基-4-(4-氟苄基氨基)-苯基]氨基甲酸乙酯。
7.根据权利要求5的用途,其中,药物有效量为0.1mg/kg-10mg/kg。
8.根据权利要求5的用途,其中,药物有效量为10mg BID-1000mg BID。
9.根据权利要求5的用途,其中,药物有效量为50mg BID-500mg BID。
10.根据权利要求5的用途,其中,药物有效量为100mg BID-300mg BID。
11.KCNQ钾通道激动剂在制备治疗或预防哺乳动物中的尿失禁的药物中的用途,其中所述KCNQ钾通道激动剂是式(I)的化合物或其可药用盐:
其中:
R1选自氢、C1-C6烷基或C2-C6烷酰基;
R2选自氢或C1-C6烷基;
R3选自C1-C6烷氧基或甲基;
R4选自氢或C1-C6烷基;
R5选自氢或C1-C6烷基;
Alk表示具有1-3个碳原子的直链或支链亚烷基;
Ar是被基团R6、R7和/或R8取代的苯基,其中,R6、R7和R8这些基团是相同或不同的,并且表示H、C1-C6烷基、羟基、C1-C6烷氧基、C2-C6烷酰氧基、卤素、C1-C6卤烷基、-CN、-NH2、-NH-C1-C6烷基、-N(C1-C6烷基)2、-CO2H、-CO-C1-C6烷基、-CO-O-C1-C6烷基、-CONH2、-CONH-C1-C6烷基、-CON(C1-C6烷基)2、-NH-CO-C1-C6烷基、-NHCO-C1-C6烷氧基、-NHCO-NH2、-NHCO-N(-C1-C6烷基)2;
n是0或1。
12.根据权利要求11的用途,其中,尿失禁是欲望性尿失禁。
13.根据权利要求11的用途,其中,尿失禁是前列腺肥大继发的。
14.根据权利要求11的用途,其中,尿失禁是混合的欲望性和压迫性尿失禁。
15.根据权利要求11的用途,其中,哺乳动物是人。
16.根据权利要求11的用途,其中,哺乳动物是猫或犬。
17.根据权利要求11的用途,其中,式I的化合物选自:
2-氨基-4-(4-氟苄基氨基)-1-乙氧基羰基氨基苯;
2-氨基-4-(4-三氟甲基苄基氨基)-1-乙氧基羰基氨基-苯;
2-氨基-4-苄基氨基-1-乙氧基羰基氨基-苯;
2-氨基-4-(3,5-二氯苄基氨基)-1-乙氧基羰基氨基-苯;或
2-氨基-4-(3,5-二氯苄基氨基)-1-丙氧基羰基氨基苯;
或其可药用盐。
18.根据权利要求11的用途,其中,式I的化合物是N-[2-氨基-4-(4-氟苄基氨基)-苯基]氨基甲酸或其可药用盐或酯形式。
19.根据权利要求18的用途,其中,可药用酯形式是N-[2-氨基-4-(4-氟苄基氨基)-苯基]氨基甲酸乙酯。
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