CN103816158A - 用于治疗fab-相关疾病的嘌呤衍生物 - Google Patents
用于治疗fab-相关疾病的嘌呤衍生物 Download PDFInfo
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- CN103816158A CN103816158A CN201310728644.8A CN201310728644A CN103816158A CN 103816158 A CN103816158 A CN 103816158A CN 201310728644 A CN201310728644 A CN 201310728644A CN 103816158 A CN103816158 A CN 103816158A
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Abstract
本发明涉及尤其适用于创伤愈合,优选地为糖尿病患者的创伤愈合的具体DPP-4抑制剂。
Description
本申请是申请日为2009年8月13日、申请号为200980131654.5(国际申请号为PCT/EP2009/060521)、发明名称为“用于治疗FAB-相关疾病的嘌呤衍生物”的发明专利申请的分案申请。
本发明涉及具体DPP-4抑制剂,其用于改善创伤愈合(wound healing),尤其是糖尿病患者(尤其为II型糖尿病患者)的创伤愈合,以及涉及这些DPP-4抑制剂在治疗或/和预防皮肤病、创伤或/和创伤愈合障碍,特别是与糖尿病有关的这些疾病中的用途。本发明还包括用于创伤愈合,尤其是糖尿病患者的创伤愈合的药物组合物和组合(combination),其包含本文所定义的DPP-4抑制剂任选地与一种或多种其它的活性物质。
创伤愈合对于任何损伤后存活的生物体至关重要。创伤愈合过程中的严重损伤可导致慢性创伤(chronic wounds),并最终引发溃疡。具体地,糖尿病患者伴随有创伤愈合过程障碍,例如创伤及溃疡愈合缓慢,慢性创伤以及,最终成为糖尿病并发溃疡(例如动脉韧带小腿溃疡(ulcus cruris arteriosum)和脂质渐进性坏死(necrobiosis lipoidica))或糖尿病足。糖尿病患者可能面临皮肤溃疡发生,有15%的终生危险会发展为由感染和截肢引发的并发症。健康的皮肤修复过程一般涉及包括免疫细胞浸润、血管生成、上皮再生及重塑的动态组织运动。更进一步地,据证实,创伤发炎是这些过程的关键,并对组织再生至关重要。糖尿病患者的慢性创伤证实金属蛋白酶浓度的升高及生长因子产生减少是创伤闭合所必须的。糖尿病患者还经常患有干扰血液供应及毛细管灌注的外周血管病。另外,这些病人身上的神经病变及知觉缺失可能导致更深的创伤及创伤愈合过程的恶化。因此,控制血糖是糖尿病并发症如创伤愈合受损的主要干预。然而,由于涉及创伤愈合的复杂生理过程数量庞大,多种因素将会导致及影响创伤愈合障碍。
饮食疗法和锻炼疗法对糖尿病的治疗至关重要。当这些疗法不足以控制患者的病症(特别是他们的血糖浓度)时,需要额外使用口服或非口服的抗糖尿病药物治疗糖尿病。常规的抗糖尿病或抗高血糖药物包括但不限于:二甲双胍、磺酰脲类(sulphonylureas)、噻唑烷二酮类(thiazolidinediones)、列奈类(glinides)、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。然而,使用这些常规抗糖尿病和抗高血糖药物可伴随多种副作用。例如,二甲双胍可伴随乳酸性酸中毒或胃肠道副作用;磺酰脲类、列奈类和胰岛素或胰岛素类似物可伴随低血糖和体重增加;噻唑烷二酮类可伴随水肿、骨折、体重增加或心力衰竭/心脏副作用;以及α-糖苷酶阻断剂类和GLP-1或GLP-1类似物可伴随胃肠道副作用(例如,消化不良、肠胃气胀或腹泻、或恶心或呕吐)。
另外,糖尿病及其并发症的管理复杂,且需要解决许多非血糖控制的问题。
因此,仍然存在对能积极影响创伤愈合特别于糖尿病患者身上的创伤愈合的新且高效药物(有利地抗糖尿病)的高且未满足的需求。
酶DPP-4(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、特别是其在代谢疾病(尤其糖尿病)中的用途公开于WO2002/068420、WO2004/018467、WO2004/018468、WO2004/018469、WO2004/041820、WO2004/046148、WO2005/051950、WO2005/082906、WO2005/063750、WO2005/085246、WO2006/027204、WO2006/029769或WO2007/014886中;或公开在WO2004/050658、WO2004/111051、WO2005/058901或WO2005/097798中;或公开在WO2006/068163、WO2007/071738或WO2008/017670中;或公开在WO2007/128721或WO2007/128761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。此类实施方案涉及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WO2005/003135及WO2007/050485中。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,可参考这些文件。
-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WO00/34241的实施例1中。维格列汀的具体盐公开在WO2007/019255中。维格列汀的结晶形式以及维格列汀片剂制剂公开在WO2006/078593中。维格列汀可如WO00/34241或WO2005/067976所述配制。改良释放的维格列汀制剂描述于WO2006/135723中。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,可参考这些文件。
-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-亚甲基丙腈(methanoprolinenitrile),
沙格列汀具体公开在美国专利6,395,767及WO01/68603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WO2004/052850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WO2004/052850中所公开。沙格列汀的HCl盐及游离碱的结晶形式公开在WO2008/131149中。制备沙格列汀的方法还公开在WO2005/106011及WO2005/115982中。沙格列汀可以片剂形式配制,如WO2005/117841中所述。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,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US2005/261271、EP1586571及WO2005/095381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WO2007/035629中所公开。此类实施方案涉及苯甲酸阿格列汀。苯甲酸阿格列汀的多晶型公开在WO2007/035372中。制备阿格列汀的方法公开在WO2007/112368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WO2007/033266中所述。阿格列汀与二甲双胍或吡格列酮的制剂分别描述于WO2008/093882或WO2009/011451中。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,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WO03/037327中。前一化合物的甲磺酸盐以及其结晶多晶型公开在WO2006/100181中。后一化合物的富马酸盐以及其结晶多晶型公开在WO2007/071576中。这些化合物可以药物组合物形式配制,如WO2007/017423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WO2005/000848中。制备此化合物(尤其是其二盐酸盐)的方法还公开在WO2008/031749、WO2008/031750及WO2008/055814中。此化合物可以药物组合物形式配制,如WO2007/017423中所述。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,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WO2005/116014及US7291618中。
因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,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WO2007/148185及US20070299076中。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,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(还称为米格列汀(melogliptin))或其可药用盐:
该化合物及其制备方法公开在WO2006/040625及WO2008/001195中。具体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、配制或使用方法的详细信息,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WO2005/095381、US2007060530、WO2007/033350、WO2007/035629、WO2007/074884、WO2007/112368、WO2008/114807、WO2008/114800及WO2008/033851中。具体要求保护的盐包括琥珀酸盐(WO2008/067465)、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、配制或使用方法的详细信息,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WO2006/116157及US2006/270701中。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,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WO02/14271中。具体盐公开在WO2006/088129及WO2006/118127中(尤其包括盐酸盐、氢溴酸盐)。使用此化合物的组合疗法描述于WO2006/129785中。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,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WO2005/047297、WO2008/109681及WO2009/009751中。具体盐公开在WO2008/027273中(包括柠檬酸盐、酒石酸盐)。此化合物的制剂描述于WO2008/144730中。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,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WO2005/075421、US2008/146818及WO2008/114857中。因此,例如关于有关该化合物或其盐的制备、配制或使用方法的详细信息,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WO2009/084497及WO2006/068163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在此引入作为参考。
在本发明的范围内,现已经意外地发现,本文所定义的具体DPP-4抑制剂具有出乎意料且特别有利的特性,这使得它们特别适用于创伤愈合,尤其是是在糖尿病患者(尤其为II型糖尿病患者)中。
因此,本发明提供本文定义的DPP-4抑制剂,其用于糖尿病或非糖尿病的创伤愈合。
本发明还提供本文定义的DPP-4抑制剂,其用于促进或改善糖尿病与非糖尿病患者,尤其为糖尿病患者中的创伤愈合。
本发明还提供本文定义的DPP-4抑制剂,其用于治疗和/或预防(包含阻止或减缓疾病进程或减少发病发生或延迟发病)创伤愈合过程,尤其是糖尿病患者的创伤愈合过程中的创伤愈合缺陷(deficit)或受损(impairment)。
本发明还提供本文定义的DPP-4抑制剂,其用于治疗和/或预防(包括阻止或减缓疾病进程或减少发病发生或延迟发病)皮肤病、创伤和/或创伤愈合障碍(wound healing disturbance),包括但不限于,糖尿病所伴随的这些疾病。
本发明还提供本文定义的DDP-4抑制剂,其用于治疗和/或预防(包括阻止或减缓疾病进展或减少发病发生或延迟发病)慢性皮肤溃疡、创伤或溃烂、破坏性创伤炎症(例如中性白细胞浸润)、创伤愈合或闭合的延迟或受损、受干扰的组织再生、形成或重塑,尤其在糖尿病患者中。
本发明还提供本文定义的DPP-4抑制剂,其用于缩小创伤尺寸和/或改善创伤闭合,尤其为与糖尿病相关创伤的缩小创伤尺寸和/或改善创伤闭合。
本发明还提供本文定义的DPP-4抑制剂,其用于改善创伤上皮形成(wound epithelialization)、创伤形态(wound morphology)和/或组织再生,尤其是糖尿病相关创伤的创伤上皮形成、创伤形态和/或组织再生。
本发明还提供本文定义的DPP-4抑制剂,其用于促进创伤新上皮形成(neo-epithelialization)或上皮再生(re-epithelialization),尤其是糖尿病相关创伤的创伤新上皮形成或上皮再生。
本发明还提供本文定义的DPP-4抑制剂,其用于减少破坏性创伤炎症(destructive wound inflammation),例如减少多形核中性白细胞(polymorphonuclear neutrophils,PMN)的数量,尤其是在糖尿病相关创伤中。
本发明还提供本文定义的DPP-4抑制剂,其用于治疗和/或预防(包括降低病情发展或进展的风险)代谢障碍或疾病,特别是糖尿病(尤其为II型糖尿病),于已患皮肤病或处于皮肤病风险的病人中,创伤和/或创伤愈合障碍或受损(特别是与糖尿病相关的),例如,本文所述的这些疾病(例如慢性皮肤溃疡、创伤或溃烂(sores)、破坏性创伤炎症(例如,中性白细胞浸润)、创伤愈合或闭合的延迟或受损,或受干扰的组织再生、形成或重塑)。
此外,根据本发明的另一方面,本发明提供如本文定义的DPP-4抑制剂在制备药物中的用途,该药物用于一种或多种以下目的:
-预防、减缓代谢疾病或疾病的进展、延迟或治疗该代谢疾病或疾病,例如,I型糖尿病、II型糖尿病、葡萄糖耐受不良(impaired glucose tolerance,IGT)、空腹血糖异常(impaired fasting blood glucose,IFG)、高血糖、餐后高血糖、超重、肥胖症、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/或糖基化血红蛋白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病变,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/或改良和/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;
-降低与常规的抗高血糖药物相关的副作用的风险;和/或
-维持和/或改良胰岛素敏感性和/或治疗或预防高胰岛素血症和/或胰岛素抵抗;
特别对于患有(或存在患病风险)皮肤病、创伤和/或创伤愈合障碍或受损的患者;特别对于与糖尿病有关的疾病,例如,任何本文所论述的创伤和/或皮肤病(例如,慢性皮肤溃疡、创伤或溃烂、破坏性创伤炎症(例如中性白细胞浸润)、创伤愈合或闭合的延迟或受损,或受干扰的组织再生、形成或重塑);
任选地与一种或多种其它活性物质(例如,任何本文所提及的其它活性物质)组合(in combination with)。
本发明还提供药物组合物,其用于创伤愈合,尤其用于糖尿病患者的创伤愈合,所述药物组合物包含本文定义的DPP-4抑制剂以及任选的一种或多种可药用载体和/或稀释剂。
本发明还提供一种固定或非固定的组合(fixed or non-fixedcombination),其包括用于创伤愈合,尤其为糖尿病患者的创伤愈合的试剂盒,所述组合包括本文所定义的DPP-4抑制剂与一种或多种其他活性物质(例如任一于本文所提及的活性物质)。
本发明还提供本文所定义的DPP-4抑制剂任选地与一种或多种其他活性物质(例如,任一本文所提及的活性物质)组合在制备用于创伤愈合,尤其为糖尿病患者的创伤愈合的药物组合物中的用途。
本发明还提供一种药物组合物,其用于创伤愈合,尤其为糖尿病患者的创伤愈合,所述药物组合物包含本文所定义的DPP-4抑制剂以及任选的一种或多种其它活性物质,例如任一本文所提及的活性物质,例如单独(separate)、依次(sequential)、同时(simultaneous)、并行(concurrent)或时间上错开地(chronologically staggered)使用该活性成份。
本发明还提供一种创伤愈合,尤其为糖尿病患者创伤愈合的方法,所述方法包括向有此需要的患者(尤其为人类患者)给药有效量的本文所定义的DPP-4抑制剂,任选地,该抑制剂可单独或组合使用,例如单独地、依序地、同时地、并行地或时间上错开地与一种、两种或多种其它活性物质(例如任一本文所提及的活性物质)组合使用。
根据本发明的DPP-4抑制剂的实施方案是指那些(除其血糖作用外)对于II型糖尿病患者的创伤修复过程直接显示有利(例如额外血糖(extraglycemic))作用的DPP-4抑制剂。除了改善血糖控制之外,这些DPP-4抑制剂还适于对患有皮肤病、创伤和/或创伤愈合障碍或受损或存有该风险的患者提供额外的治疗益处。
在一个实施方案中,此处所述的患者,特别是那些患有(或存在患病风险)皮肤病、创伤和/或创伤愈合障碍或受损,特别是与糖尿病有关的疾病的患者,为接受本发明治疗的患者,所述患者包括但不限于,由于不耐受或禁用二甲双胍而不适合二甲双胍治疗的,和/或具有肾脏疾病、肾功能异常、或肾功能不全或受损(包括具有慢性肾功能不全,例如具有轻度、中度或重度肾功能受损或具有晚期肾疾病,和/或具有肾病、微量或大量白蛋白尿(macroalbuminuria)或蛋白尿(proteinuria)的患者)的糖尿病患者。
根据之前及以下的论述,本领域技术人员会理解本发明的其它方面。
在本发明的意义中,DPP-4抑制剂包括但不限于,任一上下文所提及的那些DPP-4抑制剂,优选口服活性的DPP-4抑制剂。
在第一个实施方案(实施方案A)中,在本发明上下文中的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,在本发明上下文中的DPP-4抑制剂选自以下的DPP-4抑制剂:
西他列汀、维格列汀、沙格列汀、阿格列汀,
(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,和
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WO2004/018468,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WO2004/018468,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WO2004/018468,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WO2004/050658,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WO2006/029769,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WO2005/085246,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WO2005/085246,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WO2006/029769,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WO2005/085246,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WO2005/085246,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WO2005/085246,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WO2005/085246,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,因为它们组合了优越效价和长效与有利的药理学特性、受体选择性及有利的副作用性质,或带来意想不到的治疗优点或改善,当与其它药物活性物质组合时。它们的制备公开在所提及的文献中。
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BI1356)。
除非另有说明,否则根据本发明,应当理解上文及下文所提及的活性化合物(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物质。
关于实施方案A,用于合成本发明实施方案A的DPP-4抑制剂的方法对于本领域的技术人员是公知的。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制备。因此,例如,式(I)的嘌呤衍生物可如WO2002/068420、WO2004/018468、WO2005/085246、WO2006/029769或WO2006/048427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)WO2004/050658或WO2005/110999中所述来获得,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)WO2006/068163、WO2007/071738或WO2008/017670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文献中。具体DPP-4抑制剂的多晶形晶体改良及制剂分别公开在WO2007/128721及WO2007/128724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。BI1356/二甲双胍双重组合的典型剂量规格(dosage strength)为2.5/500mg、2.5/850mg及2.5/1000mg。
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献。
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0.001-100mg/千克体重、优选地以0.1-15mg/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本领域技术人员使用如本领域所述可药用制剂的赋形剂来制备。这些赋形剂的实施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、表面活性剂和乳化剂。
在某些实施方案中,本发明的DPP-4抑制剂优选为口服使用,因此其优选为片剂形式。该片剂通常包含该活性成分及一种或多种稀释剂、填充剂和/或载体,以及任选地一种或多种粘合剂、一种或多种润滑剂、一种或多种崩解剂和/或一种或多种助流剂,以及(视需要)薄膜包衣剂。
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,重点在于甘露糖醇、低取代的羟丙基纤维素和预胶化淀粉。
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,优选共聚维酮和预胶化淀粉。
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且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。
适宜的制粒方法为
●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 ganulation);
●流化床制粒;或
●用适宜赋形剂干法制粒(例如,通过滚筒压缩),随后压片或包装成胶囊。
优选用于口服使用(尤其是片剂)的本发明实施方案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,和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。
在另一实施方案中,本发明的DPP-4抑制剂可用于局部使用,因此,例如其可以软膏的形式存在。该局部使用制剂通常包含混有适于局部制剂的载体材料的活性成份,例如,甘油酯、半合成及合成甘油酯、氢化油、液体蜡、液体石蜡、液体脂肪醇、固醇、聚乙二醇和/或纤维素衍生物。
关于本发明DPP-4抑制剂的剂型、制剂及给药的详细信息,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献。
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抑制剂静脉给药时,其通常所需的剂量为0.1mg至10mg、优选0.25mg至5mg,当口服给药时,为0.5mg至100mg、优选2.5mg至50mg或0.5mg至10mg、更优选2.5mg至10mg或1mg至5mg,在每一情形下每天给予1-4次。因此,例如,当口服给药时,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0.5mg至10mg/患者/天、优选2.5mg至10mg或1mg至5mg/患者/天。
使用包含实施方案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0.1-100mg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0.5mg、1mg、2.5mg、5mg和10mg。
关于第二实施方案(实施方案B),在实施方案B中欲给药至哺乳动物(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0.5mg至约350mg、例如约10mg至约250mg、优选20-200mg、更优选20-100mg活性部分/人/天,或约0.5mg至约20mg、优选2.5-10mg/人/天,优选地分成1-4个单个剂量,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和200mg的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25mg与200mg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100mg,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和200mg。西他列汀的具体单位剂量规格(例如每片)为25、50及100mg。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和257mg。将剂量经调节的25mg及50mg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50/500mg及50/1000mg。
DPP-4抑制剂维格列汀的剂量范围通常介于每日10mg与150mg之间、具体而言介于每日25mg与150mg、25mg与100mg或25mg与50mg或50mg与100mg之间。每日口服剂量的具体实施例为25、30、35、45、50、55、60、80、100或150mg。在更具体方面中,维格列汀的日给予量可介于25mg与150mg之间或介于50mg与100mg之间。在另一更具体方面中,维格列汀的日给予量可为50mg或100mg。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50mg或100mg维格列汀。维格列汀/二甲双胍双重组合的典型剂量规格为50/850mg和50/1000mg。
阿格列汀可以如下日剂量给予患者:介于5mg/天与250mg/天之间,任选介于10mg与200mg之间,任选介于10mg与150mg之间,且任选介于10mg与100mg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,可使用的具体剂量包括但不限于每天10mg、12.5mg、20mg、25mg、50mg、75mg和100mg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。
沙格列汀可以如下日剂量给予患者:介于2.5mg/天与100mg/天之间,任选介于2.5mg与50mg之间。可使用的具体剂量包括但不限于每天2.5mg、5mg、10mg、15mg、20mg、30mg、40mg、50mg和100mg沙格列汀。沙格列汀/二甲双胍双重组合的典型剂量规格为2.5/500mg及2.5/1000mg。
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药的DPP-4抑制剂,例如以<100mg或<70mg/患者/天、优选<50mg、更优选<30mg或<20mg、甚至更优选1mg至10mg/患者/天、特别是1mg至5mg(更具体而言为5mg),若需要,分成1-4个单个剂量,特别是1或2个单个剂量,其大小可相同,优选地每天一次口服给药、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,例如可以每日一次的给药方案(即5mg BI1356,每日一次)或每日两次的给药方案(即2.5mg BI1356,每日两次),在每天任何时候,伴随或不伴随食物给予5mg日口服剂量的BI1356。
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BI1356)。BI1356显示高效力、24小时持续作用以及宽的治疗窗。在每日一次服用1、2.5、5或10mg BI1356的多个口服剂量达12天的II型糖尿患者中,BI1356显示出有利的药效学和药代动力学性质(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药浓度(大于在第13天时给药前血浆浓度的90%))、较少累积(例如,在高于1mg剂量下平均累积比RA,AUC≤1.4)以及保持DPP-4抑制的长效(例如,在5mg及10mg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和97.3%抑制,及在摄取药物后经24小时间隔有>80%抑制)、以及以≥2.5mg的剂量餐后2小时血糖偏移显著降低达≥80%(在第一天时即已达到此降低),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/分钟,例如对于5mg剂量,肾清除率为约70ml/分钟)。在患有II型糖尿病人群中,BI1356显示出与安慰剂相似的安全性及耐受性。使用约≥5mg的低剂量,BI1356可作为每日一次的可靠口服药物,DPP-4抑制可持续整个24小时。在治疗口服剂量水平,BI1356主要经肝排泄,仅有一小部分(约<7%的口服给药剂量)经肾排泄。BI1356主要经胆无变化地排泄。经肾消除的BI1356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BI1356的剂量。非肾消除的BI1356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)BI1356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,可获得改良的治疗结果,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浓度或脂浓度、升高血液中HDL浓度、降低血压或治疗动脉粥样硬化或肥胖症所需的活性物质。
另外,在本发明的意义内,任选添加至其它组合药物中,DPP-4抑制剂可与一种或多种常规用于治疗(慢性)创伤的药物组合。
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组合使用,借此可获得改良的治疗结果。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。为此所需组合药物的药物制剂可以药物组合物购得或者可通过本领域技术人员使用常规的方法来配制。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federalassociation of the pharmaceutical industry的“Rote ”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 ofmanufacturers’information on prescription drugs)(称为“Physician’s DeskReference)中。
抗糖尿病组合药物的实施例为二甲双胍;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、格列波脲和格列齐特;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GI262570;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和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-葡糖苷酶阻断剂,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(insulinglusilin)、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(50mg至600mg),例如PDGF-受体-激酶(参见,EP-A-564409、WO98/35958、US5093330、WO2004/005281,和WO2006/041976);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II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)、YM178、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AS3201、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WO2009/035969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。
二甲双胍通常以每日约250mg至3000mg的剂量范围,特别地约500mg至2000mg高达2500mg的剂量范围给予,使用多种剂量方案,例如约100mg至500mg或200mg至850mg,每日1-3次,或约300mg至1000mg,每日1或2次,或给予缓释二甲双胍,其剂量约为100mg至1000mg或优选500mg至1000mg,每日1或2次,或约500mg至2000mg,每日1次。盐酸二甲双胍的具体剂量规格可为250、500、625、750、850与1000mg。
吡格列酮的剂量通常为约1-10mg、15mg、30mg或45mg,每天一次。
罗格列酮通常以4mg至8mg剂量给予,每天一次(或分成两次)(典型剂量规格为2、4和8mg)。
格列本脲通常以2.5至20mg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和5mg),或微粉化格列本脲以0.75至12mg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和6mg)。
格列吡嗪通常以2.5至40mg的剂量每天给予一次(分成两次)(典型剂量规格为5mg和10mg),或延长释放的格列吡嗪以5至20mg的剂量每天给予一次(典型剂量规格为2.5、5和10mg)。
格列美脲通常以1至8mg的剂量给予,每天一次(典型剂量规格为1、2合4mg)。
格列本脲/二甲双胍双重组合物通常以1.25/250mg(每日一次)至10/1000mg(每日两次)的剂量给予(典型剂量规格为1.25/250、2.5/500和5/500mg)。
格列吡嗪/二甲双胍双重组合通常以2.5/250至10/1000mg的剂量给予,每日两次(典型剂量规格为2.5/250、2.5/500和5/500mg)。
格列美脲/二甲双胍双重组合通常以1/250至4/1000mg的剂量给予,每日两次。
罗格列酮/格列美脲双重组合通常以4/1mg(每日一次或两次)至4/2mg(每日两次)的剂量给予(典型剂量规格为4/1、4/2、4/4、8/2和8/4mg)。
吡格列酮/格列美脲双重组合通常以30/2至30/4mg(每日一次)的剂量给予(典型剂量规格为30/4和45/4mg)。
罗格列酮/二甲双胍双重组合通常以1/500至4/1000mg(每日两次)的剂量给予(典型剂量规格为1/500、2/500、4/500、2/1000和4/1000mg)。
吡格列酮/二甲双胍双重组合通常以15/500mg(每日一次或两次)至15/850mg(每日三次)的剂量给予(典型剂量规格为15/500和15/850mg)。
非磺酰脲胰岛素促分泌那格列奈通常以60至120mg的剂量伴餐给予(高达360mg/天,典型剂量规格为60和120mg);瑞格列奈通常以0.5至4mg的剂量伴餐给予(高达16mg/天,典型剂量规格为0.5、1和2mg)。瑞格列奈/二甲双胍双重组合可以1/500和2/850mg的剂量规格使用。
阿卡波糖通常以25至100mg的剂量伴餐给予(高达300mg/天,典型剂量规格为25、50和100mg)。米格列醇通常以25至100mg的剂量伴餐给予(高达300mg/天,典型剂量规格为25、50和100mg)。
典型用于单一或双重或三重(追加(add-on)或起始(initial))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、列奈类、α-糖苷酶阻断剂类、GLP-1和GLP-1类似物,以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,包括它们的组合。
降低血液中脂质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);组合至胆汁酸的物质,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WO2007/005572的化合物12(anacetrapib);LDL受体调节剂;和ApoB100反义RNA。
托伐他汀的剂量通常为1mg至40mg或10mg至80mg,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。
组合药物替米沙坦的剂量通常为每天20mg至320mg、或40mg至160mg。
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。
用于治疗肥胖症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APD356/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;Pyy3-36;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施例为磷脂酶A2抑制剂;酪氨酸激酶抑制剂(50mg至600mg),例如PDGF-受体-激酶(参见EP-A-564409、WO98/35958、US5093330、WO2004/005281和WO2006/041976);oxLDL抗体及oxLDL疫苗;apoA-1Milano;ASA;和VCAM-1抑制剂。
典型用于治疗(慢性)创伤的药物的实例包括但不限于:口服与局部应用药剂,例如己酮可可碱、伊洛前列素、抗菌剂(例如含碘制剂、银释放剂、在数个水平靶向细菌的抗菌剂、全身性抗生素等)、三硝酸甘油酯(一氧化氮供体)、钙离子拮抗剂(如地尔硫卓与硝苯地平)、系统性皮质类固醇、锌(局部或口服应用)、苯妥英钠(局部应用)、类视黄醇、和/或止痛药。
本发明的范围并不限于本文所述具体实施方案。除本文所述的那些以外,那些本领域技术人员由本发明公开内容应可明了本发明的各种修改。这些修改意欲属于随附的权利要求的范围内。
本文所引用的所有专利申请的全文在此引入作为参考。
由以下实施例可明了本发明其它实施方案、特征及优点。以下实施例用于以示例性方式说明本发明的原理,而非对其加以限制。
实施例
使用ob/ob小鼠并作为研究糖尿病-创伤愈合受损的试验模型。这些动物患有严重糖尿病及肥胖综合征,其显示与人状况(例如肥胖,胰岛素抵抗)特征类似的特征。胰岛素与饮食在肥胖小鼠中降低高血糖(正如在肥胖和糖尿病患者中的显示的那样),但在这些动物中没有改善治愈(如最近结果所示)。
使用BI1356治疗12天的ob/ob小鼠在治疗过程中表现出创伤上皮再形成的显著改善,创伤边缘上皮之间的距离呈现显著减小(BI1356组:0.74±0.90mm;对照组:2.02±1.07mm,A,B)。与改善的创伤上皮形成所一致,在对照组受损创伤上观察到PMN的完全积累,但在BI1356组ob/ob小鼠中却未观察到此现象。口服糖耐量测试后,BI1356治疗的动物(C)的葡萄糖波动(glucose excursion)降低了25%(绝对AUC)。
总之,BI1356显示出在ob/ob小鼠中惊人的创伤愈合加速作用,以及与其相关的降低葡萄糖波动的作用。此作用可以(至少)部份地归因于它的血糖降低能力。因此,DPP-4抑制剂BI1356可用于与创伤愈合相关的其他糖尿病并发症如糖尿病足。
方法
使用8-9周龄的雌性C57BI/6J-ob/ob小鼠(Charles River,Sulzfeld)。氯胺酮麻醉后在每个动物个体的背部设置6处切除创伤(包括肉膜(panniculuscarnosus))。这些动物每日使用3mg/kg的BI1356或甲基纤维素(1-2%)治疗。在第10天,在尾巴尖(取样点为0、30、60、90、120与180分钟)进行口服葡萄糖耐量试验(2g/kg)。动物在异氟烷麻醉下通过颈椎脱位方法处死,并对其创伤进行组织学分析。血清用于检测DPP-4活性。组织学试验在6-8μm石蜡包覆以及多聚甲醛固定的经伊红-苏木素染色的切片上进行。另外,通过Ly6G的免疫组织学染色鉴定多形核中性白细胞(PMN),作为创伤发炎的可靠指示(readout)。(参考S.Frank,Methods in Molecular Medicine2003,Kampfer,Diabetes2006)。
结果
A)使用与不使用BI1356治疗的创伤的组织学
如图1所示,创伤组织的组织学分析表明在BI1356治疗的动物中,创伤形态与创伤上皮再生得到了显著改善。
此外,如图1所示,通过Ly6G的免疫组织学分析(由图1的三角形符号表示,借此反映炎症状态)评估了多形核中性白细胞(PMN),作为创伤发炎的可靠指示。中性白细胞为创伤中的第一道防御细胞;但在慢性创伤中,被延长的中性白细胞浸润作用加重了炎症和创伤闭合受损。与改善的创伤上皮形成所一致,观察到接受BI1356治疗的ob/ob小鼠中的PMN积累量的总体降低,但在对照组动物中却未观察到。
B)在BI1356治疗和未治疗的ob/ob小鼠中的创伤尺寸的总结
如图2所示,对ob/ob小鼠给药BI1356后,创伤边缘上皮之间的距离的量化值表明BI1356治疗的动物的创伤尺寸显著减小。
C)使用BI1356或载体治疗的ob/ob小鼠中葡萄糖的体内平衡
如图3所示,对ob/ob小鼠给药BI1356后,葡萄糖波动降低。
与葡萄糖波动降低所一致,使用剂量为3mg/kg/d的BI1356治疗12天后,ob/ob小鼠中的DPP-4活性显著地(p<0.0001)降低至80%。
在正常C57BI/6小鼠(每组n=10)中,通过14天30mg/kg/d的最高剂量的治疗,获得95%的全DPP-4抑制作用(p<0.0001)。在这些动物中,BI1356治疗也显示出改善创伤愈合的趋势。创伤闭合的估计半周期(即50%创伤面积闭合的时间)经计算对照组(n=10)为7.7天,而BI1356治疗的动物为6.8天,尽管不具有统计学显著性。
附图说明
图1显示对照组(a)与BI1356(b)治疗的ob/ob小鼠的创伤组织。箭头与线指示上皮边缘,三角形指示经染色的中性白细胞。gt:肉芽组织,he:过度增生上皮;ne:新生上皮。比例尺=300μm。
图2显示BI1356或对照组(10天,n=9)治疗的ob/ob小鼠的创伤尺寸。
图3显示BI1356或对照组治疗10天的ob/ob小鼠(n=9,在第10天进行OGTT)在口服糖耐量试验后的葡萄糖AUC。
Claims (17)
1.DPP-4抑制剂,其用于创伤愈合,其中所述DPP-4抑制剂
在第一个实施方案(实施方案A)中,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;
或者,在第二实施方案(实施方案B)中,选自:
西他列汀、维格列汀、沙格列汀、阿格列汀、
(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,和
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。
2.权利要求1的DPP-4抑制剂,其用于创伤愈合,优选用于糖尿病患者的创伤愈合,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。
3.权利要求1的DPP-4抑制剂,其用于创伤愈合,优选用于糖尿病患者的创伤愈合,其中所述DPP-4抑制剂选自:
西他列汀、维格列汀、沙格列汀、阿格列汀、
(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,和
(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。
4.权利要求1或2的DPP-4抑制剂,其用于创伤愈合,优选用于糖尿病患者的创伤愈合,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。
5.权利要求1至4中任一项的DPP-4抑制剂,其用于创伤愈合,优选用于糖尿病患者的创伤愈合,其中所述DPP-4抑制剂为口服给药。
6.权利要求1至4中任一项的DPP-4抑制剂,其用于创伤愈合,优选用于糖尿病患者的创伤愈合,其中所述DPP-4抑制剂为局部给药。
7.权利要求1至6中任一项的DPP-4抑制剂,其用于改善创伤上皮形成,尤其是糖尿病相关创伤的创伤上皮形成。
8.权利要求1至7中任一项的DPP-4抑制剂,其用于促进新上皮形成,尤其是糖尿病相关创伤的新上皮形成。
9.权利要求1至8中任一项的DPP-4抑制剂,其用于促进组织再生,尤其是糖尿病相关创伤的组织再生。
10.权利要求1至9中任一项的DPP-4抑制剂,其用于减小创伤尺寸,尤其是糖尿病相关创伤的创伤尺寸。
11.权利要求1至10中任一项的DPP-4抑制剂,其用于减少破坏性创伤炎症,尤其是糖尿病相关创伤的破坏性创伤炎症,例如减少多形核中性白细胞(PMN)的数量。
12.权利要求1至11中任一项的DPP-4抑制剂,其用于治疗和/或预防创伤愈合过程中的创伤愈合缺陷或受损,优选于糖尿病患者中。
13.药物组合物,其用于创伤愈合,优选用于糖尿病患者的创伤愈合,所述药物组合物包含权利要求1至6中任一项的DPP-4抑制剂。
14.片剂,其口服用于创伤愈合,优选口服用于糖尿病患者的创伤愈合,所述片剂包含权利要求1至5中任一项的DPP-4抑制剂。
15.权利要求1至6中任一项的DPP-4抑制剂在制备用于糖尿病患者的创伤愈合的药物组合物中的用途。
16.权利要求1至12中任一项的DPP-4抑制剂与一种或多种其它治疗活性剂组合,以单独、依次、同时、并行或于时间上错开的方式用于创伤愈合。
17.权利要求1至12中任一项的DPP-4抑制剂与一种或多种选自二甲双胍、吡格列酮和替米沙坦的其它治疗活性剂组合,以单独、依次、同时、并行或于时间上错开的方式用于创伤愈合。
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