CN109700814A - 对尽管使用口服或非口服抗糖尿病药物治疗但血糖控制仍不足的患者中的糖尿病的治疗 - Google Patents
对尽管使用口服或非口服抗糖尿病药物治疗但血糖控制仍不足的患者中的糖尿病的治疗 Download PDFInfo
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- Proteomics, Peptides & Aminoacids (AREA)
Abstract
本发明涉及具体DPP‑4抑制剂,其适于治疗和/或预防尽管使用口服或非口服抗糖尿病药物治疗但血糖控制仍不足的患者的代谢病,特别是糖尿病。
Description
本申请是申请号为200980141002.X(国际申请号PCT/EP2009/063511),申请日:2009年10月15日,优先权日:2008年10月16日的中国发明专利申请(发明名称:对尽管使用口服或非口服抗糖尿病药物治疗但血糖控制仍不足的患者中的糖尿病的治疗)的分案申请。
技术领域
本发明涉及具体的DPP-4抑制剂,其用于治疗和/或预防尽管使用口服或非口服抗糖尿病药物(特别是胰岛素促泌剂,例如磺酰脲类或格列奈类 (glinide)药物)疗法但血糖控制仍不足的患者的代谢病,特别是糖尿病(尤其是 II型糖尿病)及其相关病症,还涉及这些DPP-4抑制剂在所述治疗和/或预防中的用途。本发明还包括用于治疗和/或预防这些患者的代谢病(特别是糖尿病)的药物组合物,其包含如本文所定义的DPP-4抑制剂以及任选一种或多种其它活性物质。
背景技术
II型糖尿病为涉及胰岛素抵抗和胰岛素分泌受损的双重内分泌作用的复杂病理生理学引起的普遍慢性及进行性疾病。II型糖尿病的治疗通常开始于饮食及锻炼,之后进行口服抗糖尿病药物单一疗法,以及尽管常规的单一疗法最初在一些患者中控制血糖,但是其伴随高继发性失效率。至少在一些患者中且在有限时间内,可通过组合多种口服药物以达成血糖的降低(这在使用单一药物长期疗法是不可能维持的),从而可以克服用于维持血糖控制的单一药物疗法的限制。现有数据支持以下结论:在患有II型糖尿病的大多数患者中,单一疗法将失效且需要多种药物进行治疗。
但是,由于II型糖尿病为进行性疾病,故即使对组合疗法具有良好初始反应的患者最终还会需要增大剂量或用胰岛素进一步治疗,这是因为血糖水平极难长时间维持稳定。因此,尽管现有组合疗法具有增强血糖控制的效力,但其并非没有限制(尤其关于长期功效)。另外,许多结果表明低血糖的风险可随常规组合疗法增大,且对多种药物的需要还可降低患者依从性。另外,服用多种抗高血糖药物可能会增大与患者可能正服用的其它药物发生药代动力学相互作用。
因此,对于许多患者而言,这些现存药物疗法尽管治疗但仍会造成血糖控制的渐进性损害且尤其不能长期充分控制血糖过多,且因此不能达成及维持后期或晚期II型糖尿病(包括尽管使用常规的口服或非口服抗糖尿病药物但血糖控制仍不充分的糖尿病、继发性药物失效和/或必需胰岛素(with indication on)治疗的糖尿病)中的代谢控制。
因此,尽管高血糖的强化治疗可降低慢性损害的发病率,但许多患有II 型糖尿病的患者仍不能得以充分治疗,部分地是由于常规的抗高血糖疗法在长期功效、耐受性及给药不便方面的限制。
此治疗失效的高发率为II型糖尿病患者的高比率长期高血糖-伴随性并发症或慢性损伤(包括微血管及大血管并发症,例如,糖尿病性肾病、视网膜病变或神经病,或心血管并发症)的主要因素。
常规用于治疗(例如,一线或二线,和/或单一或(起始(initial)或追加 (add-on))组合疗法)的口服抗糖尿病药物,包括(但不限于),二甲双胍、磺酰脲类、噻唑烷二酮类、格列奈类及α-葡萄糖苷酶抑制剂。
常规用于治疗(例如,一线或二线,和/或单一或(起始或追加)组合疗法) 的非口服抗糖尿病药物,包括(但不限于),GLP-1或GLP-1类似物,以及胰岛素或胰岛素类似物。
然而,使用这些常规的抗糖尿病或抗高血糖药物可能伴随多种副作用。例如,二甲双胍可能伴随有乳酸性酸中毒或胃肠道副作用;磺酰脲类、格列奈类及胰岛素或胰岛素类似物可能伴随有低血糖及体重增加;噻唑烷二酮类可能伴随有水肿、骨折、体重增加及心力衰竭/对心脏的不利作用;以及α- 葡萄糖苷酶抑制剂及GLP-1或GLP-1类似物可能伴随有胃肠道不良作用(例如,消化不良、胃肠胀气或腹泻、或恶心或呕吐)。
磺酰脲类(SU)以及格列奈类刺激胰岛素以非葡萄糖依赖性方式自胰腺β细胞分泌,且一般及经常用作II型糖尿病(尤其适于非肥胖患者和/或不适用二甲双胍疗法或二甲双胍疗法无效的患者)的一线或二线(单一或组合)治疗。
然而,如上所述,一些患者并非总是对这些常规口服抗糖尿病药物反应良好(尤其在长期治疗方面),且可能显示尽管使用磺酰脲类药物治疗但血糖控制仍不足或恶化(继发性SU失效)。此外,进行长期磺脲疗法的患者会经历胰腺β细胞功能随时间流逝而降低或耗尽。
对于那些处于磺酰脲类单独(单一疗法)不能有效控制血糖水平的情况的患者,取决于疾病阶段可能需要变换为其它口服药物(例如,变换为二甲双胍/噻唑烷二酮类)或SU组合疗法(包括追加及起始双重及三重SU组合疗法)、尤其是磺酰脲类与二甲双胍和/或与噻唑烷二酮类组合,和/或与胰岛素组合或(最终)转变至胰岛素(例如,取决于疾病阶段,每日一次基础胰岛素 (basal insulin)、每日两次预混胰岛素(premix insulin)或每日多次胰岛素)。然而,即使在组合疗法中,尤其随时间流逝,一些患者还可能显示出尽管使用组合治疗但血糖控制仍不足或恶化。
因此,随时间流逝而功效持续性损失是使用包括格列奈类及磺酰脲类 (继发性SU失效)在内的胰岛素促泌剂的主要关注问题。此外,磺酰脲类会增大胰岛素的血浆浓度且可造成低血糖,其为除体重增加外的另一主要副作用,特别是伴随肾损伤和/或在老年患者中。因此,在SU药物疗法中,一方面,就功效而言,有时可需要增大酰脲类药物剂量,而另一方面,就安全/ 耐受性而言,有时可需要降低酰脲类药物剂量,因此在SU药物疗法中通常需要采取令人不满意的折衷方案。
因此,本领域仍需要为患有后期或晚期II型糖尿病的这些患者提供有效、安全且可耐受的抗糖尿病疗法,这些患者包括服用常规口服和/或非口服抗糖尿病药物(例如二甲双胍、磺酰脲类、噻唑烷二酮类、格列奈类和/或α- 葡萄糖苷酶抑制剂类,和/或GLP-1或GLP-1类似物,和/或胰岛素或胰岛素) 但血糖控制仍不充分的患者。
此外,本领域仍需要为继发性口服抗糖尿病药物失效的糖尿病患者提供充分的血糖控制。
此外,本领域仍需要预防继发性口服抗糖尿病药物失效(包括预防或减缓其进展)。
此外,本领域仍需要预防与抗糖尿病疗法相关的副作用或降低其风险。
发明内容
在糖尿病治疗的监测中,HbA1c值(血红蛋白B链非酶促糖基化作用的产物)异常重要。由于其形成基本上依赖于血糖水平和红细胞寿命,故HbA1c 在“血糖记忆”意义上反映前4-12周的平均血糖水平。其HbA1c浓度通过更加强化的糖尿病治疗长期得以良好控制的糖尿病患者(即,在样品中<6.5%的总血红蛋白)明显较好地防止糖尿病性微血管病。糖尿病的现有治疗可在糖尿病患者中产生大约1.0-1.5%HbA1C水平的平均改善。该HbA1C水平降低并不足以在所有糖尿病患者中使其达成<7.0%、优选<6.5%且更优选<6% HbA1c的期望目标范围。
在血糖控制内,除改善HbA1c水平外,对II型糖尿病患者的其它建议治疗目标为改善空腹血糖(FPG)及餐后血糖(PPG)水平至正常或尽可能接近正常。餐前(空腹)血糖的建议期望目标范围为90-130mg/dL(或70-130mg/dL) 或<110mg/dL,且餐后2小时血浆葡萄糖的建议期望目标范围为<180mg/dL 或<140mg/dL。
在本发明范围内,尽管使用口服抗糖尿病药物治疗但血糖控制仍不足的患者包括(但不限于)尽管使用该药物治疗但仍具有7.0%至10%(或7.5%至 11%、或7.5%至10%)的HbA1c值的患者。
附图说明
图1及2显示了5周龄雌性db/db小鼠在用指定化合物治疗54天后的 HbA1c及葡萄糖值。与对照相比,DPP-4抑制剂BI 1356改善HbA1c以及葡萄糖值。不同的是,与对照及BI1356相比,浓度为3mg/kg的磺酰脲类格列本脲损害葡萄糖以及HbA1c值。
图3显示了在OGTT测试期间胰岛素的增加。仅用BI 1356治疗的动物能够响应葡萄糖含量增加而上调胰岛素。
具体实施方式
在本发明范围内,继发性口服抗糖尿病药物失效的糖尿病患者的一个实施方案是指不适用二甲双胍疗法的患者,包括
-禁用二甲双胍疗法的患者,例如,具有一种或多种标签指明的二甲双胍疗法禁忌症的患者,例如具有至少一种选自以下禁忌症的患者:
肾疾病、肾损伤或肾功能障碍(例如,如当局批准的二甲双胍的产品信息所规定),
脱水、
不稳定性或急性充血性心力衰竭、
急性或慢性代谢性酸中毒,及
遗传性半乳糖不耐受;
及
-遭受一种或多种由二甲双胍引起的不耐受副作用、特别是与二甲双胍相关的胃肠道副作用的患者,例如遭受选自以下至少一种胃肠道副作用的患者:
恶心、
呕吐、
腹泻、
肠积气,及
严重腹部不适。
可适用于本发明疗法的患者的实施方案可包括(但不限于):常规二甲双胍疗法不适用的糖尿病患者,例如由于对二甲双胍耐受性降低、不耐受或禁忌,或由于(轻度)受损的/降低的肾功能(包括老年患者,例如≥60-65)而需要降低剂量的二甲双胍疗法的那些糖尿病患者。
此外,由于对副作用的敏感性增加,故老年患者(≥60-70岁)的治疗应当经常伴随有肾功能的谨慎监测。除非肌酸酐清除率的测量证实不会降低肾功能,否则通常不建议在老年个体、特别是≥80岁的个体中使用二甲双胍。因此,不适用二甲双胍疗法的患者还可包括(但不限于)例如≥60-65岁或特别是≥80岁的老年患者。
在本发明范围内,继发性口服抗糖尿病药物失效的糖尿病患者的另一实施方案是指患有肾疾病、肾功能障碍或肾功能不全或损伤(包括轻度、中度及重度肾损伤)的患者,如由(例如)升高的血清肌酸酐水平(例如,血清肌酸酐水平高于其年龄所具有的正常上限,例如,在男性中≥130-150μmol/l、或≥1.5mg/dl(≥136μmol/l),且在女性中≥1.4mg/dl(≥124μmol/l))或异常肌酸酐清除率(例如,肾小球滤过率(GFR)≤30-60ml/min)所示。
在此上下文中,对于更详细实施例而言,轻度肾损伤可由(例如)50-80 ml/min的肌酸酐清除率(大约对应于男性中≤1.7mg/dL,女性中≤1.5mg/dL的血清肌酸浓度)表示;中度肾损伤可由(例如)30-50ml/min的肌酸酐清除率(大约对应于男性中>1.7至≤3.0mg/dL,女性中>1.5至≤2.5mg/dL的血清肌酸浓度)表示;且重度肾损伤可由(例如)<30ml/min的肌酸酐清除率(大约对应于男性中>3.0mg/dL,女性中>2.5mg/dL的血清肌酸浓度)表示。患有晚期肾疾病的患者需要透析。
酶DPP-4(二肽基肽酶IV,还称为CD26)为丝氨酸蛋白酶,已知其可导致二肽自N末端具有脯氨酸或丙氨酸残基的许多蛋白的N-末端解离。由于此特性,DPP-4抑制剂干扰包括肽GLP-1在内的生物活性肽的血浆浓度,且将其视为治疗糖尿病的颇具前景的药物。
例如,DPP-4抑制剂及其用途、特别是其在代谢病(尤其糖尿病)中的用途公开于WO2002/068420、WO 2004/018467、WO 2004/018468、WO 2004/018469、WO 2004/041820、WO2004/046148、WO 2005/051950、WO 2005/082906、WO 2005/063750、WO 2005/085246、WO2006/027204、WO 2006/029769或WO 2007/014886中;或公开在WO 2004/050658、WO 2004/111051、WO 2005/058901或WO 2005/097798中;或公开在WO 2006/068163、WO 2007/071738或WO 2008/017670中;或公开在WO 2007/128721或WO 2007/128761中。
作为其它DPP-4抑制剂,可提及以下化合物:
-西他列汀(Sitagliptin,MK-0431),其具有以下结构式A,其为(3R)-3- 氨基-1-[3-(三氟甲基)-5,6,7,8-四氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7- 基]-4-(2,4,5-三氟苯基)丁-1-酮,还称为(2R)-4-氧代-4-[3-(三氟甲基)-5,6-二氢 [1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]-1-(2,4,5-三氟苯基)丁-2-胺,
在一个实施方案中,西他列汀呈其磷酸二氢盐的形式,即磷酸西他列汀。在另一个实施方案中,磷酸西他列汀呈结晶无水合物或单水合物的形式。此类实施方案指磷酸西他列汀单水合物。西他列汀游离碱及其可药用盐公开在美国专利6,699,871中及公开在WO03/004498的实施例7中。结晶磷酸西他列汀单水合物公开在WO 2005/003135及WO 2007/050485中。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
西他列汀的片剂制剂可以商品名购得。西他列汀/二甲双胍组合的片剂制剂可以商品名购得。
-维格列汀(Vildagliptin,LAF-237),其具有以下结构式B,其为(2S)-{[(3- 羟基金刚烷-1-基)氨基]乙酰基}吡咯烷-2-甲腈,还称为(S)-1-[(3-羟基-1-金刚烷基)氨基]乙酰基-2-氰基-吡咯烷,
维格列汀具体公开在美国专利6,166,063中及公开在WO 00/34241的实施例1中。维格列汀的具体盐公开在WO 2007/019255中。维格列汀的结晶形式以及维格列汀片剂制剂公开在WO 2006/078593中。维格列汀可如WO 00/34241或WO 2005/067976中所述配制。改善释放的维格列汀制剂阐述于 WO 2006/135723中。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
维格列汀的片剂制剂可以商品名购得。维格列汀/二甲双胍组合的片剂制剂可以商品名购得。
-沙格列汀(Saxagliptin,BMS-477118),其具有以下结构式C,其为 (1S,3S,5S)-2-{(2S)-2-氨基-2-(3-羟基金刚烷-1-基)乙酰基}-2-氮杂二环[3.1.0] 己烷-3-甲腈,还称为(S)-3-羟基金刚烷基甘氨酸-L-顺式-4,5-亚甲基吡咯烷-2- 甲腈(methanoprolinenitrile),
沙格列汀具体公开在美国专利6,395,767及WO 01/68603的实施例60 中。
在一个实施方案中,沙格列汀呈其HCl盐或其单苯甲酸盐形式,如WO 2004/052850中所公开。在另一个实施方案中,沙格列汀呈游离碱形式。在另一个实施方案中,沙格列汀呈游离碱的单水合物形式,如WO 2004/052850 中所公开。沙格列汀的HCl盐及游离碱的结晶形式公开在WO 2008/131149 中。制备沙格列汀的方法还公开在WO 2005/106011及WO2005/115982中。沙格列汀可以片剂形式配方,如WO 2005/117841中所述。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-阿格列汀(Alogliptin,SYR-322),其具有以下结构式E,其为 2-({6-[(3R)-3-氨基哌啶-1-基]-3-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基}甲基)苄腈
阿格列汀具体公开在US 2005/261271、EP 1586571及WO 2005/095381 中。
在一个实施方案中,阿格列汀呈其苯甲酸盐、其盐酸盐或其甲苯磺酸盐的形式,各如WO 2007/035629中所公开。此类实施方案指苯甲酸阿格列汀。苯甲酸阿格列汀的多晶型公开在WO 2007/035372中。制备阿格列汀的方法公开在WO 2007/112368中且特别公开在WO2007/035629中。阿格列汀(即其苯甲酸盐)可以片剂形式配制并给予,如WO 2007/033266中所述。阿格列汀与二甲双胍或吡格列酮的制剂分别阐述于WO 2008/093882或WO 2009/011451中。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-(2S)-1-{[2-(5-甲基-2-苯基-唑-4-基)-乙基氨基]-乙酰基}-吡咯烷-2-甲腈或其可药用盐,优选为甲磺酸盐,或
(2S)-1-{[1,1-二甲基-3-(4-吡啶-3-基-咪唑-1-基)-丙基氨基]-乙酰基}-吡咯烷-2-甲腈或其可药用盐:
这些化合物及其制备方法公开在WO 03/037327中。
前一化合物的甲磺酸盐以及其结晶多晶型公开在WO 2006/100181中。后一化合物的富马酸盐以及其结晶多晶型公开在WO 2007/071576中。这些化合物可以药物组合物形式配制,如WO 2007/017423中所述。
因此,例如关于有关这些化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-(S)-1-((2S,3S,11bS)-2-氨基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并 [2,1-a]异喹啉-3-基)-4-氟甲基-吡咯烷-2-酮或其可药用盐:
该化合物及其制备方法公开在WO 2005/000848中。制备此化合物(尤其是其二盐酸盐)的方法还公开在WO 2008/031749、WO 2008/031750及WO 2008/055814中。此化合物可以药物组合物形式配制,如WO 2007/017423 中所述。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-(3,3-二氟吡咯烷-1-基)-((2S,4S)-4-(4-(嘧啶-2-基)哌嗪-1-基)吡咯烷-2-基) 甲酮(还称为戈塞列汀(gosogliptin))或其可药用盐:
该化合物及其制备方法公开在WO 2005/116014及US 7291618中。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-(1((3S,4S)-4-氨基-1-(4-(3,3-二氟吡咯烷-1-基)-1,3,5-三嗪-2-基)吡咯烷-3-基)-5,5-二氟哌啶-2-酮或其可药用盐:
该化合物及其制备方法公开在WO 2007/148185及US 20070299076中。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-(2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-三唑-1-基甲基)环戊基氨基]-乙酰基}-4-氟吡咯烷-2-甲腈(也称为美格列汀(melogliptin))或其可药用盐:
该化合物及其制备方法公开在WO 2006/040625及WO 2008/001195中。明确要求保护的盐包括甲磺酸盐及对甲苯磺酸盐。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-(R)-2-[6-(3-氨基-哌啶-1-基)-3-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基]-4-氟-苄腈或其可药用盐:
该化合物及其制备方法及用途公开在WO 2005/095381、US 2007060530、WO 2007/033350、WO 2007/035629、WO 2007/074884、WO 2007/112368、WO 2008/114807、WO 2008/114800及WO 2008/033851中。具体要求保护的盐包括琥珀酸盐(WO 2008/067465)、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、(R)-扁桃酸盐及盐酸盐。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-5-{(S)-2-[2-((S)-2-氰基-吡咯烷-1-基)-2-氧代-乙基氨基]-丙基}-5-(1H-四唑-5-基)-10,11-二氢-5H-二苯并[a,d]环庚三烯-2,8-二甲酸双-二甲基酰胺或其可药用盐:
该化合物及其制备方法公开在WO 2006/116157及US 2006/270701中。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-3-{(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌嗪-1-基]吡咯烷-2-基羰基}噻唑烷(还称为特力列汀(teneligliptin))或其可药用盐:
该化合物及其制备方法公开在WO 02/14271中。具体盐公开在WO 2006/088129及WO 2006/118127中(尤其包括盐酸盐、氢溴酸盐)。使用此化合物的组合疗法阐述于WO2006/129785中。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-[(2R)-1-{[(3R)-吡咯烷-3-基氨基]乙酰基}吡咯烷-2-基]硼酸(还称为度特列汀(dutogliptin))或其可药用盐:
该化合物及其制备方法公开在WO 2005/047297、WO 2008/109681及 WO 2009/009751中。具体盐公开在WO 2008/027273中(包括柠檬酸盐、酒石酸盐)。此化合物的制剂阐述于WO 2008/144730中。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-(2S,4S)-1-[2-[(4-乙氧基羰基二环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟吡咯烷-2-甲腈或其可药用盐:
该化合物及其制备方法公开在WO 2005/075421、US 2008/146818及 WO 2008/114857中。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
-2-({6-[(3R)-3-氨基-3-甲基哌啶-1-基]-1,3-二甲基-2,4-二氧代-1,2,3,4-四氢-5H-吡咯并[3,2-d]嘧啶-5-基}甲基)-4-氟苄腈或其可药用盐,或6-[(3R)-3- 氨基-哌啶-1-基]-5-(2-氯-5-氟-苄基)-1,3-二甲基-1,5-二氢-吡咯并[3,2-d]嘧啶 -2,4-二酮或其可药用盐:
这些化合物及其制备方法分别公开在WO 2009/084497及WO 2006/068163中。因此,例如关于有关这些化合物或其盐的制备、配制或使用方法的细节,可参考这些文件。
为避免任何疑问,上文所引用各上述文件的公开内容的全文以引用方式明确地在此引入作为参考。
在本发明范围内,现在已令人吃惊地发现,如本文所定义的DPP-4抑制剂具有令人吃惊且特别有利的特性,这些特性使得其特别适于治疗和/或预防(包括预防或减缓进展或延迟发病)后期或晚期II型糖尿病患者(包括尽管使用口服和/或非口服糖尿病药物治疗但血糖控制仍不足的患者和/或必需胰岛素治疗的患者)中的代谢病、特别是糖尿病(II型糖尿病)以及相关病症(例如糖尿病并发症)。
因此,本发明提供如本文所定义的DPP-4抑制剂,其用于治疗尽管使用一种或多种常规口服抗糖尿病药物(选自二甲双胍、磺酰脲类、噻唑烷二酮类、格列奈类及α-葡萄糖苷酶抑制剂)疗法(包括单一、双重或三重药物) 但血糖控制仍不足的患者。
在另一实施方案中,本发明提供如本文所定义的DPP-4抑制剂,其用于治疗尽管使用一种、两种或三种选自以下的常规口服或非口服抗糖尿病药物疗法(包括单一、双重或三重药物)但血糖控制仍不足的患者:二甲双胍、磺酰脲类、噻唑烷二酮类、格列奈类、α-葡萄糖苷酶抑制剂类、GLP-1及 GLP-1类似物、及胰岛素及胰岛素类似物;例如尽管使用二甲双胍、磺酰脲类、吡格列酮或(基础)胰岛素的单一疗法、或尽管使用二甲双胍/吡格列酮、二甲双胍/磺酰脲类、二甲双胍/(基础)胰岛素、磺酰脲类/吡格列酮、磺酰脲类/(基础)胰岛素或吡格列酮/(基础)胰岛素组合的双重组合疗法。
本发明进一步提供如本文所定义的DPP-4抑制剂,其用于治疗尽管使用磺酰脲类单一疗法、或尽管使用二甲双胍/磺酰脲类、磺酰脲类/吡格列酮或磺酰脲类/(基础)胰岛素组合的双重组合治疗但血糖控制仍不足的糖尿病患者。
具体而言,本发明提供如本文所定义的DPP-4抑制剂,其用于治疗尽管使用磺酰脲类药物治疗但血糖控制仍不足的患者。
本发明进一步提供如本文所定义的DPP-4抑制剂,其用于治疗和/或预防尽管使用磺酰脲类药物治疗但血糖控制仍不足的患者的代谢病、特别是II 型糖尿病。
本发明进一步提供如本文所定义的DPP-4抑制剂,其用于治疗和/或预防继发性磺酰脲类药物失效的糖尿病。
本发明进一步提供如本文所定义的DPP-4抑制剂的用途,其用于制备治疗和/或预防尽管使用磺酰脲类药物治疗但血糖控制仍不足的患者的代谢病、特别是II型糖尿病的药物组合物。
本发明进一步提供药物组合物,其用于治疗和/或预防尽管使用磺酰脲类药物治疗但血糖控制仍不足的患者的代谢病、特别是II型糖尿病,所述药物组合物包含如本文所定义的DPP-4抑制剂以及任选一种或多种可药用载体和/或稀释剂。
本发明进一步提供包括试剂盒的固定或不固定组合(fixed or non-fixedcombination),其用于治疗和/或预防尽管使用磺酰脲类药物治疗但血糖控制仍不足的患者的代谢病、特别是II型糖尿病,所述组合包含如本文所定义的 DPP-4抑制剂以及任选一种或多种其它活性物质,例如任何那些本文所提及的活性物质。
本发明进一步提供如本文所定义的DPP-4抑制剂与一种或多种其它活性物质(例如,任何那些本文所提及的活性物质)组合在制备用于治疗和/或预防尽管使用磺酰脲类药物治疗但血糖控制仍不足的患者的代谢病、特别是II 型糖尿病的药物组合物中的用途。
本发明进一步提供药物组合物,其用于治疗和/或预防尽管使用磺酰脲类药物治疗但血糖控制仍不足的患者的代谢病、特别是II型糖尿病,所述药物组合物包含如本文所定义的DPP-4抑制剂以及任选一种或多种其它活性物质,例如,任何那些本文所提及的活性物质,例如以单独(separate)、依次 (sequential)、同时(simultaneous)、并行(concurrent)或按时间顺序交叉(chronologically staggered)使用这些活性成份。
本发明进一步提供一种治疗和/或预防尽管使用磺酰脲类药物治疗但血糖控制仍不足的患者的代谢病、特别是II型糖尿病的方法,该方法包括向有此需要的患者(特别是人类患者)给药有效量的如本文所定义的DPP-4抑制剂,任选地单独给药或与有效量的一种或多种其它活性物质(例如,任何那些本文所提及的活性物质)组合(例如)单独、依次、同时、并行或按时间顺序交叉给药。
另外,本发明提供如本文所定义DPP-4抑制剂,任选地(追加或起始) 与一种或两种选自以下的常规抗高血糖药物组合:二甲双胍、磺酰脲类、噻唑烷二酮类(例如吡格列酮)、格列奈类、α-葡萄糖苷酶抑制剂类、GLP-1或 GLP-1类似物及胰岛素或胰岛素类似物,其用于尽管使用(例如,若适用,尽管使用最大耐受口服剂量的)一种、两种或三种选自以下的常规抗高血糖药物疗法(例如,尽管使用二甲双胍、磺酰脲类、吡格列酮或(基础)胰岛素的单一疗法、或尽管使用二甲双胍/吡格列酮、二甲双胍/磺酰脲类、二甲双胍 /(基础)胰岛素、磺酰脲类/吡格列酮、磺酰脲类/(基础)胰岛素或吡格列酮/(基础)胰岛素组合的双重组合疗法)但血糖控制仍不足的患者:二甲双胍、磺酰脲类、噻唑烷二酮类、格列奈类、α-葡萄糖苷酶抑制剂类、GLP-1或GLP-1 类似物,及胰岛素或胰岛素类似物。
在本发明的另一实施方案中,提供如本文所定义的DPP-4抑制剂,任选地与一种选自以下的常规抗高血糖药物组合:二甲双胍、磺酰脲类、噻唑烷二酮类(例如吡格列酮)、格列奈类、α-葡萄糖苷酶抑制剂类、GLP-1及GLP-1 类似物,及胰岛素及胰岛素类似物,其用于单独服用所述常规抗高血糖药物不能足够控制血糖的II型糖尿病患者的(二线)疗法。
在本发明的另一实施方案中,提供如本文所定义的DPP-4抑制剂,任选地与两种选自以下的常规抗高血糖药物组合:二甲双胍、磺酰脲类、噻唑烷二酮类(例如吡格列酮)、格列奈类、α-葡萄糖苷酶抑制剂类、GLP-1及GLP-1 类似物,及胰岛素及胰岛素类似物,其用于服用所述常规抗高血糖药物的双重组合不能足够控制血糖的II型糖尿病患者的(三线)疗法。
在本发明的另一实施方案中,提供如本文所定义的DPP-4抑制剂与二甲双胍、吡格列酮、磺酰脲类及胰岛素的常规抗高血糖药物的组合;其用于单独服用常规抗高血糖药物但血糖控制不足的II型糖尿病患者的疗法。
在本发明的另一实施方案中,提供如本文所定义的DPP-4抑制剂与两种选自以下的常规抗高血糖药物的组合:二甲双胍及吡格列酮、二甲双胍及磺酰脲类、二甲双胍及胰岛素、磺酰脲类及吡格列酮、磺酰脲类及胰岛素、及吡格列酮及胰岛素;其用于服用两种常规抗高血糖药物但血糖控制不足的 II型糖尿病患者的疗法。
具体而言,本发明提供如本文所定义的DPP-4抑制剂与磺酰脲类药物组合,其用于治疗尽管使用最大耐受剂量的磺酰脲类药物单一疗法但血糖控制仍不足的II型糖尿病患者。
此外,本发明提供如本文所定义的DPP-4抑制剂与磺酰脲类药物以及二甲双胍的组合,其用于治疗尽管使用磺酰脲类药物以及二甲双胍双重组合治疗但血糖控制仍不足的II型糖尿病患者。
此外,本发明提供如本文所定义的DPP-4抑制剂与磺酰脲类药物以及吡格列酮的组合,其用于治疗尽管使用磺酰脲类药物以及吡格列酮双重组合治疗但血糖控制仍不足的II型糖尿病患者。
此外,本发明提供如本文所定义的DPP-4抑制剂与磺酰脲类药物以及胰岛素的组合,其用于治疗尽管使用磺酰脲类药物以及胰岛素双重组合治疗但血糖控制仍不足的II型糖尿病患者。
此外,如本文定义的DPP-4抑制剂可用于在下述糖尿病患者中一种或多种以下方法:
-预防代谢病、减缓代谢病的进展、延迟或治疗代谢病;
-改善血糖控制和/或减少空腹血糖、餐后血糖和/或糖化血红蛋白 HbA1c;
-预防选自糖尿病并发症的病况或病症、减缓该病况或病症的进展、延迟或治疗该病况或病症;
-减轻体重或防止体重增加或促进体重减轻;
-预防或治疗胰腺β细胞变性和/或改善和/或恢复胰腺β细胞功能和/或刺激和/或恢复胰腺胰岛素分泌功能;和/或
-维持和/或改善胰岛素敏感性和/或治疗或预防高胰岛素血症和/或胰岛素抵抗;
所述糖尿病患者尽管使用口服抗糖尿病药物,尤其是磺酰脲类药物治疗但血糖控制仍不足(继发性SU失效)。
在继发性口服抗糖尿病药物失效的患者中,可通过本发明疗法改善这些代谢病或病症的实例,包括(但不限于),I型糖尿病、II型糖尿病、葡萄糖耐受不良、胰岛素抵抗、高血糖、高血脂、高胆固醇血症、血脂异常、代谢综合征X、肥胖、高血压、慢性全身性炎症、视网膜病变、神经病、肾病、动脉粥样硬化、内皮功能障碍及骨质疏松症。
本发明进一步提供如本文定义的DPP-4抑制剂的用途,其任选地与其一种或多种其它活性物质(例如,任何那些本文所提及者)组合,其用于制备一种或多种以下目的的药物:
-预防、减缓代谢病或疾病的进展、延迟或治疗该代谢病或疾病,例如, I型糖尿病、II型糖尿病、葡萄糖耐受不良(IGT)、空腹血糖异常(IFG)、高血糖、餐后高血糖、超重、肥胖、血脂异常、高血脂、高胆固醇血症、高血压、动脉粥样硬化、内皮功能障碍、骨质疏松症、慢性全身性炎症、视网膜病变、神经病、肾病和/或代谢综合征;
-改善血糖控制和/或减少空腹血糖、餐后血糖和/或糖化血红蛋白 HbA1c;
-预防、减缓、延迟或逆转葡萄糖耐受不良(IGT)、空腹血糖异常(IFG)、胰岛素抵抗和/或自代谢综合征至II型糖尿病的进展;
-预防糖尿病并发症、降低其风险、减缓其进展、延迟或治疗该糖尿病并发症,例如微血管及大血管疾病,例如肾病、微量或大量蛋白尿 (macroalbuminuria)、蛋白尿(proteinuria)、视网膜病变、白内障、神经病、学习或记忆损伤、神经变性或认知障碍、心血管或脑血管疾病、组织缺血、糖尿病足或溃疡、动脉粥样硬化、、高血压、内皮功能障碍、心肌梗塞、急性冠状动脉综合症、不稳定型心绞痛、稳定型心绞痛、外周动脉闭塞性疾病、心肌病、心力衰竭、心率失调、血管狭窄、和/或中风;
-减轻体重或防止体重增加或促进体重减轻;
-预防、减缓、延迟或治疗胰腺β细胞变性和/或胰腺β细胞功能衰退和 /或改善和/或恢复胰腺β细胞功能和/或刺激和/或恢复胰腺胰岛素分泌功能;
-预防、减缓、延迟或治疗非酒精性脂肪肝疾病(NAFLD),包括肝脏脂肪变性、非酒精性脂肝炎(NASH)和/或肝纤维化;
-预防第一次或第二次常规(口服)抗高血糖单一或组合疗法无效的II型糖尿病、减缓其进展、延迟或治疗所述疾病;
-达成充足治疗效果所需的常规的抗高血糖药物的剂量减少;
-降低与常规抗高血糖药物相关的副作用的风险;和/或
-维持和/或改善胰岛素敏感性和/或治疗或预防高胰岛素血症和/或胰岛素抵抗;
特别是在尽管使用常规口服或非口服抗糖尿病药物的单一或双重或三重组合治疗但血糖控制仍不足的患者,所述药物选自二甲双胍、磺酰脲类、噻唑烷二酮类(例如吡格列酮)、格列奈类、α-葡萄糖苷酶抑制剂类、GLP-1 及GLP-1类似物、及胰岛素及胰岛素类似物。
本发明的具体实施方案涉及如本文所定义的DPP-4抑制剂,其用于达到和/或维持继发性磺酰脲类药物失效的II型糖尿病患者的血糖控制。
本发明的另一具体实施方案涉及如本文所定义的DPP-4抑制剂,其用于预防(包括预防或减缓加剧)继发性SU失效的糖尿病。
本发明的另一具体实施方案涉及如本文所定义的DPP-4抑制剂,其用于预防与SU抗糖尿病疗法相关的副作用(例如,低血糖和/或体重增加)或降低其风险(或甚至用于减肥)。
本发明的另一具体实施方案涉及如本文所定义的DPP-4抑制剂,其用于治疗继发性磺酰脲类药物失效的糖尿病,其中所述DPP-4抑制剂用于与磺酰脲类药物单一或双重药物的追加或起始组合的疗法(例如,作为对使用或不使用二甲双胍的SU药物疗法的追加疗法)、或用作磺酰脲类药物的替代物,任选地与一种或多种其它治疗剂(例如,二甲双胍和/或噻唑烷二酮类(例如吡格列酮))组合。
本发明的另一具体实施方案涉及如本文所定义的DPP-4抑制剂,其在尽管使用磺酰脲类药物(例如,格列本脲、格列吡嗪或格列美脲,使用或不使用二甲双胍)治疗但血糖控制仍不足(例如,具有7.5%至10%或7.5%至11%的HbA1c)的患者中用于改善(例如,自基线平均降低)HbA1c和/或FPG、降低葡萄糖波动和/或改善胰岛素分泌。
本领域技术人员根据上下文说明将容易理解本发明的其它方面。
在本发明范围内,DPP-4抑制剂包括(但不限于)上下文所提及的那些 DPP-4抑制剂中的任一种、优选口服活性的DPP-4抑制剂。
本发明的一个实施方案涉及DPP-4抑制剂,其用于治疗和/或预防继发性口服抗糖尿病药物失效的II型糖尿病患者的代谢病(特别是II型糖尿病),其中所述患者还遭受肾疾病、肾功能障碍或肾损伤,尤其特征在于所述DPP-4 抑制剂以与具有正常肾功能的患者相同的剂量给药至这些患者,因此,例如,该DPP-4抑制剂不需针对肾功能损伤下调剂量。
本发明的另一实施方案涉及DPP-4抑制剂,其用于治疗和/或预防继发性口服抗糖尿病药物失效的II型糖尿病患者的代谢病(特别是II型糖尿病),其中这些患者由于对二甲双胍不耐受或禁忌(例如,任何那些上文或下文所定义不耐受或禁忌症)而对二甲双胍疗法失效或不适用二甲双胍疗法或需要降低二甲双胍剂量。
出于本发明前述目的建议的DPP-4抑制剂(尤其对于患有肾功能不良的患者)为下列口服DPP-4抑制剂,该DPP-4抑制剂及其活性代谢物优选具有相对较宽(例如,约>100倍)的治疗窗,和/或尤其其主要经肝脏代谢或胆分泌消除。
更详细地,特别适合本发明前述目的的DPP-4抑制剂(尤其对于患有肾功能不良的患者)可为下列口服给药的DPP-4抑制剂,其具有相对较宽(例如,>100倍)的治疗窗和/或其满足一种或多种以下药代动力学特性(优选在其治疗口服剂水平):
-该DPP-4抑制剂基本上或主要经肝排泄(例如,>80%或甚至>90%所给予的口服剂量),和/或其中肾排泄实质上不代表消除途径或仅代表次要消除途径(例如,<10%、优选<7%所给予的口服剂量,例如根据放射性标记碳(14C) 物质口服剂量的消除测量);
-该DPP-4抑制剂主要以母体药物无变化方式排泄(例如,在口服服用放射性标记碳(14C)物质后,尿及粪便中所排泄放射性平均为>70%、或>80%、或优选90%),和/或其非实质地或仅有一小部分(例如,<30%、或<20%、或优选10%)经新陈代谢消除;
-该DPP-4抑制剂的(主要)代谢产物在药理上无活性。例如,主要代谢产物不结合至目标酶DPP-4或不抑制其活性,且任选,与母体化合物相比,其快速消除(例如,终末半衰期≤20h、或优选≤约16h,例如15.9h)。
对本发明前述目的具有吸引力的DPP-4抑制剂的其它特性可为以下的一种或多种:快速达到稳态(例如,在用治疗口服剂量治疗的第二天与第五天间达到稳态血浆浓度(>90%的稳态血浆浓度))、较少累积(例如,在治疗口服剂量下平均累积比RA,AUC≤1.4),和/或优选在每天使用一次时保持DPP-4 抑制的长效作用(例如,在治疗口服剂量水平具有几乎完全(>90%)DPP-4抑制、在每天一次摄取治疗口服药物剂量后经24h时间间隔有>80%抑制)、在治疗剂量水平餐后2小时血糖波动显著降低达≥80%(在治疗的第一天时即已达到此降低),且在第一天尿中所排泄无变化母体化合物的累积量低于所给予剂量的1%且在稳态下增加至不超过约3-6%。
因此,本发明还涉及DPP-4抑制剂,其用于治疗和/或预防由于对二甲双胍不耐受或禁忌而不适合二甲双胍疗法的患者(更具体而言,患有肾疾病、肾功能障碍或肾损伤的患者)的代谢病(尤其II型糖尿病),其特征在于该 DPP-4抑制剂非实质或仅有一小部分(例如,<10%、优选<7%的所给予的口服剂量)经肾排泄(例如根据放射性标记碳(14C)物质口服剂量的消除测量)。
此外,本发明涉及DPP-4抑制剂,其用于治疗和/或预防由于对二甲双胍不耐受或禁忌而不适合二甲双胍疗法的患者(更具体而言,患有肾疾病、肾功能障碍或肾损伤的患者)的代谢病(尤其II型糖尿病),其特征在于该 DPP-4抑制剂基本上或主要经肝排泄(例如根据放射性标记碳(14C)物质口服剂量的消除测量)。
此外,本发明涉及DPP-4抑制剂,其用于治疗和/或预防代谢病(尤其由于对二甲双胍不耐受或禁忌而不适合二甲双胍疗法的患者,更具体而言,患有肾疾病、肾功能障碍或肾损伤的患者的II型糖尿病),其特征在于该DPP-4 抑制剂主要以母体药物无变化方式排泄(例如,在口服给予放射性标记碳(14C) 物质后,尿及粪便中所排泄放射性平均为>70%、或>80%、或优选90%),该 DPP-4抑制剂非实质或仅有一小部分经新陈代谢消除,和/或该DPP-4抑制剂的主要代谢产物在药理上无活性或具有相对较宽治疗窗。
在第一个实施方案(实施方案A)中,在本发明上下文中DPP-4抑制剂为以下DPP-4抑制剂中的任一种:
式(I)
或式(II)
或式(III)
或式(IV)
其中R1表示([1,5]二氮杂萘-2-基)甲基、(喹唑啉-2-基)甲基、(喹喔啉-6- 基)甲基、(4-甲基-喹唑啉-2-基)甲基、2-氰基-苄基、(3-氰基-喹啉-2-基)甲基、 (3-氰基-吡啶-2-基)甲基、(4-甲基-嘧啶-2-基)甲基或(4,6-二甲基-嘧啶-2-基)甲基,且R2表示3-(R)-氨基-哌啶-1-基、(2-氨基-2-甲基-丙基)-甲基氨基或(2-(S)- 氨基-丙基)-甲基氨基,或其可药用盐。
在第二实施方案(实施方案B)中,在本发明上下文中DPP-4抑制剂选自以下的DPP-4抑制剂:西他列汀、维格列汀、萨格列汀、阿格列汀,
(2S)-1-{[2-(5-甲基-2-苯基-唑-4-基)-乙基氨基]-乙酰基}-吡咯烷-2-甲腈,
(2S)-1-{[1,1-二甲基-3-(4-吡啶-3-基-咪唑-1-基)-丙基氨基]-乙酰基}-吡咯烷-2-甲腈,
(S)-1-((2S,3S,11bS)-2-氨基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-3-基)-4-氟甲基-吡咯烷-2-酮,
(3,3-二氟吡咯烷-1-基)-((2S,4S)-4-(4-(嘧啶-2-基)哌嗪-1-基)吡咯烷-2-基)甲酮,
(1((3S,4S)-4-氨基-1-(4-(3,3-二氟吡咯烷-1-基)-1,3,5-三嗪-2-基)吡咯烷-3- 基)-5,5-二氟哌啶-2-酮,
(2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-三唑-1-基甲基)环戊基氨基]-乙酰基}-4-氟吡咯烷-2-甲腈,
(R)-2-[6-(3-氨基-哌啶-1-基)-3-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基]-4-氟-苄腈,
5-{(S)-2-[2-((S)-2-氰基-吡咯烷-1-基)-2-氧代-乙基氨基]-丙基}-5-(1H-四唑-5-基)-10,11-二氢-5H-二苯并[a,d]环庚三烯-2,8-二甲酸双-二甲基酰胺,
3-{(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌嗪-1-基]吡咯烷-2-基羰基}噻唑烷,
[(2R)-1-{[(3R)-吡咯烷-3-基氨基]乙酰基}吡咯烷-2-基]硼酸,
(2S,4S)-1-[2-[(4-乙氧基羰基二环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟吡咯烷-2-甲腈,
2-({6-[(3R)-3-氨基-3-甲基哌啶-1-基]-1,3-二甲基-2,4-二氧代-1,2,3,4-四氢-5H-吡咯并[3,2-d]嘧啶-5-基}甲基)-4-氟苄腈,及
6-[(3R)-3-氨基-哌啶-1-基]-5-(2-氯-5-氟-苄基)-1,3-二甲基-1,5-二氢-吡咯并[3,2-d]嘧啶-2,4-二酮,
或其可药用盐。
关于第一个实施方案(实施方案A),优选的DPP-4抑制剂为以下化合物中的任一种或全部及其可药用盐:
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(参照WO 2004/018468,实施例2(142)):
·1-[([1,5]二氮杂萘-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参照WO 2004/018468,实施例2(252)):
·1-[(喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参照WO 2004/018468,实施例2(80)):
·2-((R)-3-氨基-哌啶-1-基)-3-(丁-2-炔基)-5-(4-甲基-喹唑啉-2-基甲基)-3,5-二氢-咪唑并[4,5-d]哒嗪-4-酮(参照WO 2004/050658,实施例136):
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(2-氨基-2-甲基-丙基)-甲基氨基]-黄嘌呤(参照WO 2006/029769,实施例2(1)):
·1-[(3-氰基-喹啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶 -1-基)-黄嘌呤(参照WO 2005/085246,实施例1(30)):
·1-(2-氰基-苄基)-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参照WO 2005/085246,实施例1(39)):
·1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-(2-氨基-丙基)-甲基氨基]-黄嘌呤(参照WO 2006/029769,实施例2(4)):
·1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶 -1-基)-黄嘌呤(参照WO 2005/085246,实施例1(52)):
·1-[(4-甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参照WO 2005/085246,实施例1(81)):
·1-[(4,6-二甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基- 哌啶-1-基)-黄嘌呤(参照WO 2005/085246,实施例1(82)):
·1-[(喹喔啉-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤(参照WO 2005/085246,实施例1(83)):
这些DPP-4抑制剂不同于结构上相当的DPP-4抑制剂,因为当与其它医药活性物质组合时,其将优越效能及持久效应与有利的药理学特性、受体选择性及有利的副作用性质组合或带来意想不到的治疗优点或改善。其制备公开在所提及的公开文件中。
在本发明实施方案A的上述DPP-4抑制剂中,更优选的DPP-4抑制剂为1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶 -1-基)-黄嘌呤,特别是其游离碱(其还称为BI 1356)。
除非另有说明,否则根据本发明,应当理解上下文所提及活性化合物(包括DPP-4抑制剂)的定义还包含其可药用盐以及其水合物、溶合物及多晶型形式。关于其盐、水合物及多晶型形式,特别提及的为那些在本文中所提及的。
关于实施方案A,用于合成本发明实施方案A的DPP-4抑制剂的方法已为技术人员所已知。有利地,本发明实施方案A的DPP-4抑制剂可使用如文献中所述的合成方法来制备。因此,例如,式(I)的嘌呤衍生物可如WO 2002/068420、WO 2004/018468、WO 2005/085246、WO 2006/029769或WO 2006/048427中所述来获得,其公开内容在此引入作为参考。式(II)的嘌呤衍生物可如(例如)WO 2004/050658或WO 2005/110999中所述获得,其公开内容在此引入作为参考。式(III)及(IV)的嘌呤衍生物可如(例如)WO 2006/068163、WO 2007/071738或WO 2008/017670中所述获得,其公开内容在此引入作为参考。上文特别提及的那些DPP-4抑制剂的制备公开在与本发明相关的所提及的公开文件中。具体DPP-4抑制剂的多晶形晶体改善及制剂分别公开在WO 2007/128721及WO 2007/128724中,其公开内容在此引入作为参考。具体DPP-4抑制剂与二甲双胍或其它组合药物的制剂阐述于 PCT/EP2009053978中,其公开内容在此引入作为参考。BI 1356/二甲双胍双重组合的典型剂量规格(dosagestrengths)为2.5/500毫克、2.5/850毫克及 2.5/1000毫克。
关于实施方案B,用于合成实施方案B的DPP-4抑制剂的方法阐述于科学文献中和/或公开专利文件、特别是那些本文所引用的文件。
对于在温血脊椎动物(特别是人类)中的医药应用而言,本发明化合物通常以0.001-100毫克/千克体重、优选地以0.1-15毫克/千克的剂量使用,在每一情形下每天使用1-4次。出于此目的,任选与其它活性物质组合的化合物可与一种或多种惰性常规的载体和/或稀释剂一起掺入,例如与玉米淀粉、乳糖、葡萄糖、微晶纤维素、硬脂酸镁、聚乙烯吡咯烷酮、柠檬酸、酒石酸、水、水/乙醇、水/甘油、水/山梨糖醇、水/聚乙二醇、丙二醇、十六烷基硬脂醇、羧甲基纤维素或脂肪物质(例如,硬脂肪)或其适宜混合物一起掺入到常规的盖仑制剂(例如,素片或包衣片、胶囊、粉剂、悬浮液或栓剂)中。
因此,包含如本文所定义DPP-4抑制剂的本发明药物组合物由技术人员使用如本领域所述可药用的制剂赋形剂制备。这些赋形剂的实例包括但不限于稀释剂、粘合剂、载体、填充剂、润滑剂、流动促进剂、结晶延缓剂、崩解剂、增溶剂、着色剂、pH调节剂、表面活性剂及乳化剂。
用于实施方案A化合物的适宜稀释剂的实例包括纤维素粉末、磷酸氢钙、赤藻糖醇、低取代的羟丙基纤维素、甘露糖醇、预胶化淀粉或木糖醇。在那些稀释剂中,优选甘露糖醇、低取代的羟丙基纤维素及预胶化淀粉。
用于实施方案A化合物的适宜润滑剂的实例包括滑石粉、聚乙二醇、山嵛酸钙、硬脂酸钙、氢化蓖麻油或硬脂酸镁。在那些润滑剂中,优选硬脂酸镁。
用于实施方案A化合物的适宜粘合剂的实例包括共聚维酮(乙烯基吡咯烷酮与其它乙烯基衍生物的共聚物)、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、聚乙烯基吡咯烷酮(聚维酮)、预胶化淀粉,或低取代的羟丙基纤维素(L-HPC)。在那些粘合剂中,优选共聚维酮及预胶化淀粉。
用于实施方案A化合物的适宜崩解剂的实例包括玉米淀粉或交聚维酮。在那些崩解剂中,优选玉米淀粉。
制备本发明实施方案A的DPP-4抑制剂的药物制剂的适宜方法为:
·将与适宜压片赋形剂呈粉末混合物形式的活性物质直接压片;
·用适宜赋形剂制粒,随后与适宜赋形剂混合,随后压片以及薄膜包衣;或
·将粉末混合物或颗粒包装成胶囊。
适宜制粒方法为:
·在强力混合器中湿法制粒,随后通过流化床干燥;
·一罐式制粒(one-pot granulation);
·流化床制粒;或
·用适宜赋形剂干法制粒(例如,通过滚筒压缩)且随后压片或包装成胶囊。
本发明实施方案A的DPP-4抑制剂的示例性组合物包含第一稀释剂甘露糖醇、具有额外粘合剂特性的作为第二稀释剂的预胶化淀粉、粘合剂聚维酮、崩解剂玉米淀粉,以及作为润滑剂的硬脂酸镁,其中聚维酮和/或玉米淀粉为可选的。
关于本发明DPP-4抑制剂的剂型、制剂及给药细节,可参考科学文献和/或公开的专利文件、特别是那些本文所引用的文件。
关于第一个实施方案(实施方案A),当实施方案A中本文所提及的 DPP-4抑制剂经静脉内给予时,其通常所需的剂量为0.1毫克至10毫克、优选0.25毫克至5毫克,且当口服给予时,为0.5毫克至100毫克、优选2.5 毫克至50毫克或0.5毫克至10毫克、更优选2.5毫克至10毫克或1毫克至 5毫克,在每一情形下每天给予1-4次。因此,例如,当口服给予时,1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤的剂量为0.5毫克至10毫克/患者/天、优选2.5毫克至10毫克或1毫克至5毫克/患者/天。
用包含实施方案A中本文所提及的DPP-4抑制剂的药物组合物所制备的剂型以0.1-100毫克的剂量范围含有活性成份。因此,例如,1-[(4-甲基- 喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤的具体剂量规格为0.5毫克、1毫克、2.5毫克、5毫克及10毫克。
关于第二实施方案(实施方案B),在实施方案B中欲给予哺乳动物(例如人类,例如约70千克体重)的本文所提及DPP-4抑制剂的剂量通常可为约0.5 毫克至约350毫克、例如约10毫克至约250毫克、优选20-200毫克、更优选20-100毫克活性部分/人/天,或约0.5毫克至约20毫克、优选2.5-10毫克 /人/天,优选地分成1-4个单独剂量,这些剂量的(例如)大小可相同。单独剂量规格包含(例如)10、25、40、50、75、100、150及200毫克DPP-4抑制剂活性部分。
DPP-4抑制剂西他列汀的剂量规格通常介于25毫克与200毫克活性部分之间。西他列汀的推荐剂量针对活性部分(游离碱无水物)计算为100毫克,每天一次。西他列汀游离碱无水物(活性部分)的单位剂量规格为25、50、75、 100、150及200毫克。西他列汀的具体单位剂量规格(例如每片)为25、50 及100毫克。药物组合物中使用等量的磷酸西他列汀单水合物与西他列汀游离碱无水物,即分别为32.13、64.25、96.38、128.5、192.75、及257毫克。将剂量经调节的25毫克及50毫克西他列汀用于肾衰竭患者。西他列汀/二甲双胍双重组合的典型剂量规格为50/500毫克及50/1000毫克。
DPP-4抑制剂维格列汀的剂量范围通常介于每日10毫克与150毫克之间、具体而言介于每日25毫克与150毫克、25毫克与100毫克或25毫克与 50毫克或50毫克与100毫克之间。每日口服剂量的特定实例为25、30、35、 45、50、55、60、80、100或150毫克。在更具体方面中,维格列汀的日给予量可介于25毫克与150毫克之间或介于50毫克与100毫克之间。在另一更具体方面中,维格列汀的日给予量可为50毫克或100毫克。活性成份的施用每天可至多发生三次、优选地每天一次或两次。具体剂量规格为50毫克或100毫克维格列汀。维格列汀/二甲双胍双重组合的典型剂量规格为 50/850毫克及50/1000毫克。
阿格列汀可以如下日剂量给予患者:介于5毫克/天与250毫克/天之间,任选介于10毫克与200毫克之间,任选介于10毫克与150毫克之间,且任选介于10毫克与100毫克阿格列汀之间(在每一情形下皆基于阿格列汀的游离碱形式的分子量)。因此,可使用的特定剂量包括但不限于每天10毫克、 12.5毫克、20毫克、25毫克、50毫克、75毫克及100毫克阿格列汀。阿格列汀可以其游离碱形式或可药用盐形式给予。
萨格列汀可以如下日剂量给予患者:介于2.5毫克/天与100毫克/天之间,任选介于2.5毫克与50毫克之间。可使用的特定剂量包括但不限于每天 2.5毫克、5毫克、10毫克、15毫克、20毫克、30毫克、40毫克、50毫克及100毫克萨格列汀。萨格列汀/二甲双胍双重组合的典型剂量规格为2.5/500 毫克及2.5/1000毫克。
本发明DPP-4抑制剂的具体实施方案指那些以低剂量治疗有效的口服给予的DPP-4抑制剂,例如以<100毫克或<70毫克/患者/天、优选<50毫克、更优选<30毫克或<20毫克、甚至更优选1毫克至10毫克/患者/天(若需要,分成1-4个单独剂量,特别是1或2个单独剂量,其大小可相同)、特别是1 毫克至5毫克(更具体而言为5毫克),优选地每天一次口服给予、更优选地在一天中任何时间在伴随或不伴随食物情况下给予。因此,例如日口服剂量为5mg的BI 1356可以每日一次给药方案(即每日一次5mg的BI 1356)或以每日两次给药方案(即每日两次2.5mg的BI 1356),在任何时候伴随或不伴随食物给予。
在本发明范围内欲强调的特别优选的DPP-4抑制剂为1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤(还称为BI 1356)。BI 1356呈现高效能、24小时持续作用及宽治疗窗。在每日一次服用1、2.5、5或10毫克BI1356的多个口服剂量达12天的II型糖尿病患者中,BI 1356显示出有利的药效学及药代动力学性质(例如,参见下表1):快速达到稳态(例如,在所有剂量组中,在治疗第二天与第五天间达到稳态血浆浓度(>90%的在第13天时给药前血浆浓度))、较少累积(例如,在高于1毫克剂量下平均累积比RA,AUC≤1.4)及保持DPP-4抑制的持久效应(例如,在 5毫克及10毫克剂量水平具有几乎完全(>90%)DPP-4抑制,即在稳态下分别为92.3及97.3%抑制,及在摄取药物后经24h时间间隔有>80%抑制)、以及以≥2.5毫克的剂量餐后2小时血糖波动显著降低达≥80%(在第一天时即已达到此降低),且其中在第一天尿中所排泄无变化母体化合物的累积量低于所给予剂量的1%且在第12天时增加至不超过约3-6%(对于所给予的口服剂量,肾清除率CLR,ss为约14-约70mL/min,例如对于5毫克剂量,肾清除率为约70ml/min)。在患有II型糖尿病人群中,BI 1356显示出与安慰剂相似的安全性及耐受性。使用约≥5毫克的低剂量,BI 1356可作为每日一次的可靠口服药物,且DPP-4抑制可持续整个24h。在治疗口服剂量水平,BI 1356 主要经肝排泄且仅有一小部分(约<7%的口服给予剂量)经肾排泄。BI 1356主要经胆无变化排泄。经肾消除的BI 1356部分随时间及剂量的增加仅略有增加,因此根据患者的肾功能可能无需改变BI 1356的剂量。非肾消除的BI 1356由于其低累积可能性及宽安全边际量可对肾功能不全及糖尿病性肾患者病率较高的患者人群具有明显益处。
表1:于稳态下(第12天)BI 1356的药代动力学参数的几何平均值 (gMean)及几何变异系数(gCV)
*中值及范围[最小值-最大值]
NC由于大部分值低于定量下限而未计算
由于不同代谢功能病症通常同时发生,因此经常需要使多种不同活性成份相互组合。因此,视所诊断的功能病症而定,若使DPP-4抑制剂与常规用于各个病症的活性物质组合,可获得经改善的治疗结果,这些活性物质为(例如)一种或多种选自其它抗糖尿病物质中的活性物质,尤其降低血液中血糖水平或脂浓度、升高血液中HDL浓度、降低血压或治疗动脉粥样硬化或肥胖所需的活性物质。
上述DPP-4抑制剂除其用于单一治疗外还可与其它活性物质结合使用,借此可获得经改善的治疗结果。此组合治疗可作为这些物质的自由组合或以固定组合(例如以片剂或胶囊)的形式给予。为此所需组合配伍药物的药物制剂可以药物组合物购得或者可通过技术人员使用常规的方法来配方。可以药物组合物购得的活性物质在现有技术的许多地方皆有阐述,例如federal association of the pharmaceutical industry的每年出版的药物目录中,或每年更新的关于处方药的制造商信息汇编(compilation of manufacturers’information on prescription drugs)(称为“医生案头参考”(Physician’s Desk Reference))中。
抗糖尿病组合药物的实例为二甲双胍;磺酰脲类,例如格列本脲、甲苯磺丁脲、格列美脲、格列吡嗪、格列喹酮、格列波脲及格列齐特;那格列奈;瑞格列奈;噻唑烷二酮类,例如罗格列酮及吡格列酮;PPARγ调节剂,例如美塔格列生(metaglidase);PPAR-γ激动剂,例如GI 262570;PPAR-γ拮抗剂;PPAR-γ/α调节剂,例如替格列扎(tesaglitazar)、莫格他唑(muraglitazar)、阿格列扎(aleglitazar)、及indeglitazar、AVE0897及KRP297;PPAR-γ/α/δ调节剂; AMPK-激活剂,例如AICAR;乙酰基-CoA羧化酶(ACC1及ACC2)抑制剂;二酰甘油-乙酰基转移酶(DGAT)抑制剂;胰腺β细胞GCRP激动剂,例如 SMT3-受体-激动剂及GPR119;11β-HSD-抑制剂;FGF19激动剂或类似物;α-葡萄糖苷酶抑制剂,例如阿卡波糖、伏格列波糖及米格列醇;α2-拮抗剂;胰岛素及胰岛素类似物,例如人胰岛素、赖脯胰岛素、谷赖胰岛素(insulin glusilin)、r-DNA-门冬胰岛素(insulinaspart)、NPH胰岛素、地特胰岛素、锌胰岛素悬浮液及甘精胰岛素(insulin glargin);肠抑胃肽(GIP);普兰林肽、达瓦林肽(davalintide);白糊精及白糊精类似物或GLP-1及GLP-1类似物,例如Exendin-4,例如艾塞那肽(exenatide)、艾塞那肽LAR、利拉鲁肽(liraglutide)、他司鲁肽(taspoglutide)、AVE-0010、LY-2428757、LY-2189265、塞马鲁肽 (semaglutide)或阿必鲁肽(albiglutide);SGLT2-抑制剂,例如KGT-1251;蛋白酪氨酸磷酸酶的抑制剂(例如,trodusquemine);葡萄糖-6-磷酸酶的抑制剂;果糖-1,6-双磷酸酶调节剂;糖原磷酸化酶调节剂;胰高血糖素受体拮抗剂;磷酸烯醇丙酮酸羧激酶(PEPCK)抑制剂;丙酮酸脱氢酶激酶(PDK)抑制剂;酪氨酸激酶抑制剂(50毫克至600毫克),例如PDGF-受体-激酶(参见, EP-A-564409、WO 98/35958、US5093330、WO 2004/005281、及WO 2006/041976);葡糖激酶/调节蛋白调节剂,包括葡糖激酶激活剂;糖原合酶激酶抑制剂;含有SH2结构域肌醇5-磷酸酶2型(SHIP2)的抑制剂;IKK抑制剂,例如高剂量水杨酸酯;JNK1抑制剂;蛋白激酶C-θ抑制剂;β3激动剂,例如利托贝隆(ritobegron)、YM 178、索拉贝隆(solabegron)、他利贝隆 (talibegron)、N-5984、GRC-1087、雷法贝隆(rafabegron)、FMP825;醛糖还原酶抑制剂,例如AS 3201、折那司他、非达司他、依帕司他、然尼司他 (ranirestat)、NZ-314、CP-744809及CT-112;SGLT-1或SGLT-2抑制剂,例如达格列净(dapagliflozin)、舍格列净(sergliflozin)、atigliflozin、larnagliflozin 或canagliflozin(或来自WO 2009/035969的式(I-S)或(I-K)化合物);KV1.3 通道抑制剂;GPR40调节剂;SCD-1抑制剂;CCR-2拮抗剂;多巴胺受体激动剂(甲磺酸溴隐亭(bromocriptine mesylate)/Cycloset);及其它DPP IV抑制剂。
二甲双胍通常以约500mg至2000mg高达2500mg/天变化的剂量、使用约100mg至500mg或200mg至850mg(每天1-3次)、或约300mg至 1000mg(每天一次或两次)的各种给药方案给予,或以约100mg至1000mg 或优选500mg至1000mg(每天一次或两次)或约500mg至2000mg(每天一次)的剂量给予缓释二甲双胍。具体剂量规格可为250、500、625、750、850 及1000mg盐酸二甲双胍。
吡格列酮的剂量通常为约1-10毫克、15毫克、30毫克或45毫克,每天一次。
罗格列酮通常以4毫克至8毫克剂量给予,每天一次(或分成两次)(典型剂量规格为2、4及8毫克)。
格列本脲通常以2.5-5至20毫克的剂量给予,每天一次(或分成两次)(典型剂量规格为1.25、2.5及5毫克),或微粉化格列本脲以0.75-3至12毫克的剂量给予,每天一次(或分成两次)(典型剂量规格为1.5、3、4.5及6毫克)。
格列吡嗪通常以2.5至10-20毫克的剂量每天给予一次(高达40毫克,分两次)(典型剂量规格为5毫克及10毫克),或延长释放的格列吡嗪以5-10 毫克(高达20毫克)的剂量每天给予一次(典型剂量规格为2.5、5及10毫克)。
格列美脲通常以1-2至4毫克(高达8毫克)的剂量给予,每天一次(典型剂量规格为1、2及4毫克)。
格列本脲/二甲双胍双重组合物通常以1.25/250毫克(每日一次)至 10/1000毫克(每日两次)的剂量给予(典型剂量规格为1.25/250、2.5/500及 5/500毫克)。
格列吡嗪/二甲双胍双重组合通常以2.5/250至10/1000毫克的剂量给予,每日两次(典型剂量规格为2.5/250、2.5/500及5/500毫克)。
格列美脲/二甲双胍双重组合通常以1/250至4/1000毫克的剂量给予,每日两次。
罗格列酮/格列美脲双重组合通常以4/1毫克(每日一次或两次)至4/2毫克(每日两次)的剂量给予(典型剂量规格为4/1、4/2、4/4、8/2及8/4毫克)。
吡格列酮/格列美脲双重组合通常以30/2至30/4毫克(每日一次)的剂量给予(典型剂量规格为30/4及45/4毫克)。
罗格列酮/二甲双胍双重组合通常以1/500至4/1000毫克(每日两次)的剂量给予(典型剂量规格为1/500、2/500、4/500、2/1000及4/1000毫克)。
吡格列酮/二甲双胍双重组合通常以15/500毫克(每日一次或两次)至 15/850毫克(每日三次)的剂量给予(典型剂量规格为15/500及15/850毫克)。
非磺酰脲类胰岛素促分泌那格列奈通常以60至120毫克的剂量伴餐给予(高达360毫克/天,典型剂量规格为60及120毫克);瑞格列奈通常以0.5 至4毫克的剂量伴餐给予(高达16毫克/天,典型剂量规格为0.5、1及2毫克)。瑞格列奈/二甲双胍双重组合可以1/500及2/850毫克的剂量规格使用。
阿卡波糖通常以25至100毫克的剂量伴餐给予(高达300毫克/天,典型剂量规格为25、50及100毫克)。米格列醇通常以25至100毫克的剂量伴餐给予(高达300毫克/天,典型剂量规格为25、50及100毫克)。
典型用于单一或双重或三重(追加或起始)组合疗法的常规抗糖尿病和抗高血糖药物可包括但不限于,二甲双胍、磺酰脲类、噻唑烷二酮类、格列奈类、α-糖苷酶阻断剂类、GLP-1和GLP-1类似物,及胰岛素和胰岛素类似物,例如此处通过实例方式指明的药物,包括其组合。
降低血液中脂浓度的组合药物实例为HMG-CoA-还原酶抑制剂,例如辛伐他汀、阿托伐他汀、洛伐他汀、氟伐他汀、普伐他汀、匹伐他汀及罗苏伐他汀;贝特类,例如苯扎贝特、非诺贝特、氯贝丁酯、吉非贝齐、依托贝特及益多酯(etofyllinclofibrate);烟酸及其衍生物,例如阿昔莫司;PPAR-α激动剂;PPAR-δ激动剂;乙酰-辅酶A:胆固醇酰基转移酶(ACAT;EC2.3.1.26) 的抑制剂,例如阿伐麦布;胆固醇吸收抑制剂,例如依折麦布(ezetimib);结合至胆汁酸的物质,例如考来烯胺、考来替泊及考来维仑;胆汁酸转运抑制剂;HDL调节活性物质,例如D4F、反向D4F(reverse D4F)、LXR调节活性物质及FXR调节活性物质;CETP抑制剂,例如托彻普(torcetrapib)、JTT-705/达彻普(dalcetrapib)或来自WO 2007/005572的化合物12 (anacetrapib);LDL受体调节剂;及ApoB100反义RNA。
阿托伐他汀的剂量通常为1毫克至40毫克或10毫克至80毫克,每天一次。
降低血压的组合药物的实例为β-阻断剂,例如阿替洛尔、比索洛尔、塞利洛尔、美托洛尔及卡维地洛;利尿剂,例如氢氯噻嗪、氯噻酮、希帕胺、呋塞米、吡咯他尼、托拉塞米、螺内酯、依普利酮、阿米洛利及氨苯蝶啶;钙通道阻断剂,例如氨氯地平、硝苯地平、尼群地平、尼索地平、尼卡地平、非洛地平、拉西地平、乐卡地平(lercanipidine)、马尼地平、伊拉地平、尼伐地平、维拉帕米、戈洛帕米及地尔硫卓;ACE抑制剂,例如雷米普利、赖诺普利、西拉普利、喹那普利、卡托普利、依那普利、贝那普利、培哚普利、福辛普利及群多普利;以及血管紧张素II受体阻断剂(ARB),例如替米沙坦、坎地沙坦、缬沙坦、氯沙坦、厄贝沙坦、奥美沙坦及依普罗沙坦。
替米沙坦的剂量通常为每天20毫克至320毫克、或40毫克至160毫克。
升高血液中HDL浓度的组合药物实例为胆固醇酯转运蛋白(CETP)抑制剂;内皮脂酶抑制剂;ABC1调节剂;LXRα拮抗剂;LXRβ激动剂;PPAR-δ激动剂;LXRα/β调节剂及增加载脂蛋白A-I的表达和/或血浆浓度的物质。
用于治疗肥胖的组合药物实例为西布曲明;四氢尼泊司他汀(tetrahydrolipstatin)(奥利司他);西替利司他(cetilistat)、阿利茨默(alizyme);右芬氟拉明;阿索开(axokine);大麻素受体1拮抗剂,例如CB1拮抗剂利莫纳班(rimonobant);MCH-1受体拮抗剂;MC4受体激动剂;NPY5以及NPY2 拮抗剂;β3-AR激动剂,例如SB-418790及AD-9677;5HT2c受体激动剂,例如APD 356/氯卡色林(lorcaserin);筒箭毒碱抑制剂;Acrp30及脂连素;硬脂酰基CoA去饱和酶(SCD1)抑制剂;脂肪酸合酶(FAS)抑制剂;CCK受体激动剂;多肽格那啉(Ghrelin)受体调节剂;Pyy 3-36;阿立新受体拮抗剂;及特索芬辛(tesofensine);以及布普品(bupropion)/纳曲酮,布普品/唑尼沙胺,托吡酯/芬特明和普兰林肽/美曲普汀的双重组合。
治疗动脉粥样硬化的组合药物实例为磷脂酶A2抑制剂;酪氨酸激酶抑制剂(50毫克至600毫克),例如PDGF-受体-激酶(参见EP-A-564409、WO 98/35958、US 5093330、WO2004/005281、及WO 2006/041976);oxLDL抗体及oxLDL疫苗;apoA-1Milano;ASA;及VCAM-1抑制剂。
本发明的范围并不限于本文所述的具体实施方案。除本文所述的那些以外,那些技术人员由本发明公开内容应可明了本发明的各种修改。这些修改意欲包括于随附的权利要求的范围内。
本文所引用的所有专利申请案的全文均在此引入作为参考。
由以下实施例可明了本发明其它实施方案、特征及优点。以下实施例用于以实施例方式示例性地说明本发明的原理,而非对其加以限制。
实施例
动物模型:
酰脲类药物(SU)例如格列本脲为糖尿病治疗中最常用的药物之一。长期用SU治疗会造成基础胰岛素分泌升高和葡萄糖刺激胰岛素分泌降低。这些特征可对低血糖及继发性药物失效的发生起重要作用。Db/db小鼠用作证实胰岛素抵抗及血糖高含量的II型糖尿病的动物模型。另外,与动物年龄有关,衰老db/db小鼠的胰腺β细胞不能用增强的胰岛素分泌补偿高葡萄糖波动。因此,此模型适用于研究与DPP-4抑制剂(例如BI 1356)相比,格列本脲诱发的继发性药物失效。
方法
动物及圈养
5周龄雌性db/db小鼠自Germany的Charles River获得。将动物以5-6 只动物为一组在12:12L/D循环(在04:00AM开灯,且在04:00PM关灯)下圈养于温度及湿度控制室中。所有动物均可随意地自由获得常规啮齿动物饲料(Altromin standard 1324号饲料,Denmark)及水。
体内实验
在实验第0-59天每日08.00AM通过口服管饲法使用连接至3ml注射器的胃管(luer-lockTM,Becton)给予化合物溶液。使用含有12只动物的组:媒介,0.5%水溶性羟乙基纤维素(Natrosol);BI 1356 3mg/kg;格列本脲3mg/kg。在前两周每日记录一次体重食物摄取及水摄取,且其余时期每周记录两次。在实验第54天时测定处于半饲喂状态的血糖及HbA1c值,在第59天实施 OGTT(2g/kg)。
HbA1c、胰岛素及血糖监测
在第54天10.00AM时,测定血样的“饲喂”级血糖及HbA1c。在血液取样前2小时,将动物转移至无食物的清洁笼子中,之后进行血液取样。在第59天时,实施OGTT(2g/kg),之后使动物禁食过夜并以t=15min检测胰岛素。
血糖:对于各数据点,将来自尾部尖端的10μl血液吸入微毛细管中,并使用BiosenS线葡萄糖分析仪测量。
胰岛素:对于各数据点,自尾部静脉吸收100μl血液,收集于EDTA 管中。使用小鼠内分泌免疫测定板(LINCOplexTM,使用Luminexl00TM系统分析;LincoResearch,Missouri,USA)测量胰岛素。
HbA1c:使用全自动分析仪上的标准酶分析试剂盒(Bayer)测量。
结论
因此,在代表β细胞及SU诱发的继发性药物失效的动物模型中,关于胰岛素分泌及降低HbA1c及葡萄糖,DPP-4抑制剂BI 1356优于格列本脲。
临床:
可使用临床试验测试本发明DPP-4抑制剂对于本发明目的的可用性:
例如,在随机、双盲、安慰剂对照、平行组试验中,在尽管使用一种或两种常规抗高血糖药物(例如,磺酰脲类药物)治疗但血糖控制仍不足(HbA1c 为7.0%至10%或7.5%至10%或11%)的II型糖尿病患者中测试本发明DPP-4 抑制剂(例如,每日一次口服给予的5mg BI 1356)的安全性及功效。
在用磺酰脲类药物的研究中,研究本发明DPP-4抑制剂相对添加至磺酰脲类背景疗法的安慰剂的功效及安全性(2周安慰剂运行期;18周双盲治疗、之后在研究药物终止后随访1周;在贯穿整个试验持续期内以无变化剂量给予用磺酰脲类药物的背景疗法,包括安慰剂运行期)。
通过测定HbA1c值、通过与初始值和/或安慰剂组的值比较,测试治疗是否成功。与初始值和/或安慰剂值相比,HbA1c值显著变化证实DPP-4抑制剂的治疗功效。还可通过测定空腹血糖值、通过与初始值和/或安慰剂组的值比较测试治疗是否成功。空腹葡萄糖含量显著降低证实治疗有效。此外,出现治疗达标响应(即,在治疗下HbA1c<7%)证实治疗有效。
通过评定患者的病况及偏离基线的相关变化(例如副反应(例如,低血糖发作等)的发病率及强度或重量增加)研究治疗的安全性及耐受性。
Claims (27)
1.DPP-4抑制剂,其为:
式(I)
或式(II)
或式(III)
或式(IV)
其中R1表示([1,5]二氮杂萘-2-基)甲基、(喹唑啉-2-基)甲基、(喹喔啉-6-基)甲基、(4-甲基-喹唑啉-2-基)甲基、2-氰基-苄基、(3-氰基-喹啉-2-基)甲基、(3-氰基-吡啶-2-基)甲基、(4-甲基-嘧啶-2-基)甲基或(4,6-二甲基-嘧啶-2-基)甲基,且R2表示3-(R)-氨基-哌啶-1-基、(2-氨基-2-甲基-丙基)-甲基氨基或(2-(S)-氨基-丙基)-甲基氨基,
或其可药用盐;
其用于治疗和/或预防尽管使用一种或多种选自以下的常规口服或非口服抗糖尿病药物治疗但血糖控制仍不足的患者的代谢病:二甲双胍、磺酰脲、噻唑烷二酮、格列奈、α-葡萄糖苷酶抑制剂、GLP-1或GLP-1类似物,及胰岛素或胰岛素类似物。
2.权利要求1的DPP-4抑制剂,其用于治疗和/或预防尽管使用一种或多种选自以下的口服抗糖尿病药物治疗但血糖控制仍不足的患者的代谢病:二甲双胍、磺酰脲、噻唑烷二酮、格列奈及α-葡萄糖苷酶抑制剂。
3.权利要求1或2的DPP-4抑制剂,其用于治疗和/或预防尽管使用磺酰脲药物治疗但血糖控制仍不足的患者的代谢病。
4.权利要求1或2的DPP-4抑制剂,其用于治疗和/或预防尽管单独使用磺酰脲药物治疗但血糖控制仍不足的患者的代谢病。
5.权利要求1或2的DPP-4抑制剂,其用于治疗和/或预防尽管使用磺酰脲药物与二甲双胍组合治疗但血糖控制仍不足的患者的代谢病。
6.权利要求1-5中任一项的DPP-4抑制剂,其用于达成和/或维持继发性磺酰脲失效的II型糖尿病患者的血糖控制。
7.权利要求1-6中任一项的DPP-4抑制剂,其中所述DPP-4抑制剂与所述的常规抗糖尿病药物组合使用。
8.权利要求1-7中任一项的DPP-4抑制剂,其中所述DPP-4抑制剂与所述磺酰脲组合使用,且任选与一种或多种其它治疗剂例如二甲双胍和/或噻唑烷二酮(例如,吡格列酮)组合。
9.权利要求1-6中任一项的DPP-4抑制剂,其中所述DPP-4抑制剂用作所述磺酰脲的替代物,且任选与一种或多种其它治疗剂例如二甲双胍和/或噻唑烷二酮(例如,吡格列酮)组合。
10.权利要求1-9中任一项的DPP-4抑制剂,其中所述磺酰脲选自格列本脲、格列吡嗪及格列美脲。
11.权利要求1-8中任一项的DPP-4抑制剂,其中所述DPP-4抑制剂以与所述磺酰脲且使用或不使用二甲双胍的追加或起始组合疗法使用,该磺酰脲选自格列本脲、格列吡嗪及格列美脲。
12.权利要求1-11中任一项的DPP-4抑制剂,其用于在所述患者中改善HbA1c、FPG和/或PPG、降低葡萄糖波动和/或改善胰岛素分泌。
13.权利要求1-12中任一项的DPP-4抑制剂,其用于治疗必需一线或二线磺酰脲治疗的患者的糖尿病,例如,用于降低HbA1c及改善胰岛素分泌。
14.权利要求1-12中任一项的DPP-4抑制剂,其用于治疗必需双重磺酰脲组合疗法例如磺酰脲加二甲双胍、或磺酰脲加噻唑烷二酮、或磺酰脲加胰岛素的患者的糖尿病。
15.权利要求1-12中任一项的DPP-4抑制剂,其用于治疗必需二甲双胍、磺酰脲及噻唑烷二酮,或二甲双胍、磺酰脲及胰岛素,或磺酰脲、噻唑烷二酮及胰岛素的三重组合疗法的患者的糖尿病。
16.权利要求1-12中任一项的DPP-4抑制剂,其用于治疗必需胰岛素疗法的患者的糖尿病。
17.权利要求1-16中任一项的DPP-4抑制剂,其中所述患者尽管使用磺酰脲药物治疗但仍具有7.5%至11%或7.0%至10%或7.5%至10%的不合适的HbA1c值。
18.权利要求1-17中任一项的DPP-4抑制剂,其用于在所述患者中预防与SU抗糖尿病疗法相关的副作用或降低其风险,例如低血糖和/或重量增加。
19.权利要求1-18中任一项的DPP-4抑制剂,其用于在所述患者中预防继发性SU失效的糖尿病或减缓其进展。
20.权利要求1-19中任一项的DPP-4抑制剂,其中所述患者由于对二甲双胍不耐受或禁忌例如肾损伤和/或老年患者,而不适用二甲双胍疗法或需要降低剂量的二甲双胍疗法。
21.权利要求1-20中任一项的DPP-4抑制剂,其与吡格列酮或二甲双胍组合使用。
22.权利要求1-21中任一项的DPP-4抑制剂,其中所述DPP-4抑制剂选自:
1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤,
1-[([1,5]二氮杂萘-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤,
1-[(喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤,
2-((R)-3-氨基-哌啶-1-基)-3-(丁-2-炔基)-5-(4-甲基-喹唑啉-2-基甲基)-3,5-二氢-咪唑并[4,5-d]哒嗪-4-酮,
1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(2-氨基-2-甲基-丙基)-甲基氨基]-黄嘌呤,
1-[(3-氰基-喹啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤,
1-(2-氰基-苄基)-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤,
1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-(2-氨基-丙基)-甲基氨基]-黄嘌呤,
1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤,
1-[(4-甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤,
1-[(4,6-二甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤,和
1-[(喹喔啉-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤,
或其可药用盐。
23.权利要求1-22中任一项的DPP-4抑制剂,其中所述DPP-4抑制剂为1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤。
24.用于口服治疗糖尿病患者的DPP-4抑制剂,其特征在于<10%、优选≤7%的所给予口服剂量经肾排泄。
25.权利要求24的DPP-4抑制剂,其特征在于其主要经胆无变化地排泄。
26.权利要求24或25中任一项的DPP-4抑制剂,其特征在于>80%、优选≥90%的所给予口服剂量以母体药物无变化地排泄。
27.权利要求24-26中任一项的DPP-4抑制剂,其特征在于其主要代谢产物在药理上无活性。
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