CN109789117A - 治疗急性肾损伤的方法 - Google Patents
治疗急性肾损伤的方法 Download PDFInfo
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- CN109789117A CN109789117A CN201780062021.8A CN201780062021A CN109789117A CN 109789117 A CN109789117 A CN 109789117A CN 201780062021 A CN201780062021 A CN 201780062021A CN 109789117 A CN109789117 A CN 109789117A
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Abstract
本发明涉及治疗患有急性肾损伤的人类患者的方法。
Description
相关申请的交叉引用
本申请主张2016年10月5日申请的美国临时申请第62/404,390号的权益。前述申请的整个教导内容以引用的方式被并入本文中。
技术领域
本发明涉及治疗患有急性肾损伤的人类患者的方法。
背景技术
急性肾损伤(AKI)此前称为急性肾衰竭(ARF),其是特征为数天内肾功能急剧恶化的一种临床综合征。AKI主要特征为肾小球滤过率(GFR)突然下降,导致含氮废物(尿素、肌酐)滞留。在整个世界人口中,每年每百万人口中发生170至200例严重AKI。迄今,对于已确认的AKI尚无特定的治疗。已发现多种药物预防性地改善毒性和缺血性实验AKI,如不同动物模型中较低的血清肌酐水平、减少的组织学损伤和更快的肾功能恢复所证明的。其包括抗氧化剂、钙通道阻滞剂、利尿剂、血管活性物质、生长因子、消炎剂等。然而,已在临床试验中对这些药物进行研究且显示无益处,并且尚未批准其用于临床AKI。一旦AKI发展,则更难以进行治疗。
本文所公开的化合物为过氧化体增殖物激活受体δ(PPARδ)的例示性调节剂。PPARδ是能够调节线粒体生物合成的核受体。已显示调节PPARδ的活性对于治疗疾病而言是有用的。
发明内容
现已发现一种由以下结构式表示的化合物(R)-3-甲基-6-(2-((5-甲基-2-(6-(三氟甲基)吡啶-3-基)-1H-咪唑-1-基)甲基)苯氧基)己酸:
(以下称作“化合物A”)
减少急性肾病的大鼠模型中的肾损伤(参见实施例2)。具体而言,在对实验室大鼠的肾诱发缺血再灌注损伤后,静脉内给药化合物A 4小时时,化合物A显著降低血浆肌酐水平、改善肾功能且减少早期肾损伤生物标记物NGAL。
还已发现由以下结构式表示的化合物B:
(以下称作“化合物B”)减少急性肾病的大鼠模型中的肾损伤(参见实施例3)。具体而言,在对实验室大鼠的肾诱发缺血再灌注损伤后,经口给药化合物B 4小时时,化合物B显著降低血浆肌酐水平且改善肾功能。
基于这些发现,本文公开治疗急性肾损伤的方法。
本发明的一个实施方式为一种治疗患有急性肾损伤的人类患者的方法。该方法包含向患者静脉内给药有效量的化合物A或其药学上可接受的盐。
本发明的另一实施方式为一种治疗患有急性肾损伤的人类患者的方法。该方法包含向患者给药有效量的化合物B或其药学上可接受的盐。在一个实施方式中,化合物B经口给药;在另一实施方式中,其静脉内给药。
本发明的又一实施方式为一种治疗患有急性肾损伤的人类患者的方法。该方法包含向患者给药有效量的化合物C:
(以下称作“化合物C”);
或其药学上可接受的盐。在一个实施方式中,化合物C经口给药;在另一实施方式中,其静脉内给药。
本发明的另一实施方式为化合物A或其药学上可接受的盐,其用于静脉内治疗患有急性肾损伤的人类患者。
本发明的又一实施方式为化合物B或其药学上可接受的盐,其用于治疗患有急性肾损伤的人类患者。在一个实施方式中,化合物B用于经口给药;在另一实施方式中,化合物B用于静脉内给药。
本发明的又一实施方式为化合物C或其药学上可接受的盐,其用于治疗患有急性肾损伤的人类患者。在一个实施方式中,化合物C用于经口给药;在另一实施方式中,化合物C用于静脉内给药。
本发明的又一实施方式为化合物A或其药学上可接受的盐用于制造用于静脉内治疗患有急性肾损伤的人类患者的药物的用途。
本发明的又一实施方式为化合物B或其药学上可接受的盐用于制造用于治疗患有急性肾损伤的人类患者的药物的用途。在一个实施方式中,化合物B用于经口给药;在另一实施方式中,化合物B用于静脉内给药。
本发明的又另一实施方式为化合物C或其药学上可接受的盐用于制造用于治疗患有急性肾损伤的人类患者的药物的用途。在一个实施方式中,化合物C用于经口给药;在另一实施方式中,化合物B用于静脉内给药。
附图说明
图1a、b和c为显示急性肾损伤的大鼠模型中静脉内给药化合物A的治疗效果的柱状图。柱状图1a显示肾损伤后24小时的大鼠中以mg/dL为单位的血浆肌酐水平。柱从左至右表示无肾损伤且静脉内给药载体的大鼠中、和患有肾损伤且静脉内给药载体;0.3mpk的化合物A;1mpk的化合物A;和3.0mpk的化合物A的大鼠中的血浆肌酐水平。类似地,柱状图1b显示肾损伤后24小时的肌酐清除量(一种肾功能的评估)或GFR(肾小球滤过率),并且柱状图1c显示肾损伤后48小时的尿中NGAL(中性粒细胞明胶酶相关脂质运载蛋白(Lipocalin))水平。NGAL是临床中常用的早期肾损伤生物标记物。
图2a和2b为显示急性肾损伤的大鼠模型中化合物B的治疗效果的柱状图。柱状图2a显示肾损伤后24小时的大鼠中以mg/dL为单位的血浆肌酐水平。柱从左至右表示给药30mpk载体的假手术大鼠中、给药30mpk载体的患有急性肾损伤大鼠中、和给药30mpk的化合物B的患有急性肾损伤大鼠中的血浆肌酐水平。类似地,柱状图2b显示肌酐清除量(一种肾功能的评估)或GFR(肾小球滤过率)。
具体实施方式
本文提供用于治疗人类患者的急性肾损伤的方法。这样的方法包含向人类患者给药有效量的化合物A、化合物B或化合物C,或者化合物A、化合物B或化合物C的药学上可接受的盐。在一个实施方式中,在人类患者发生急性肾损伤之后,给药化合物A、化合物B或化合物C,或者化合物A、化合物B或化合物C的药学上可接受的盐。化合物A优选静脉内给药。
如本文所使用,术语“急性肾损伤”或“AKI”先前称作“急性肾衰竭”或“ARF”,是指特征为肾功能迅速减退的一种急性临床综合征,其是由许多因素、例如肾血流量降低、肾小球肾炎、使用肾毒性抗生素和抗癌剂引起的。
急性肾损伤定义为肾功能突然下降,且可基于患者呈现出血清肌酐水平、肾小球滤过率或尿排出量中的一种或多种的变化来诊断。例如,急性肾损伤的特征可为至少1.5倍基线的血清肌酐水平,其中基线是指不超过7天前的患者血清肌酐水平。例如,患有急性肾损伤的患者可具有1.5至1.9倍基线、2.0至2.9倍基线、或者3.0或大于3.0倍基线的血清肌酐水平。替代地,急性肾损伤的特征可为至少0.3mg/dL或至少0.4mg/dL的血清肌酐增加。
可替代地,急性肾损伤的特征可为小于90mL/min/1.73m2的肾小球滤过率。例如,患有急性肾损伤的患者可具有60-89mL/min/1.73m2、30-59mL/min/1.73m2、15-29mL/min/1.73m2或小于15mL/min/1.73m2的肾小球滤过率。
可替代地,急性肾损伤的特征可为患者在6小时内尿排出量小于0.5mL/Kg、12小时内尿排出量小于0.5mL/Kg、12小时内尿排出量小于0.3mL/Kg、或者12小时或更多小时无尿。
急性肾损伤可伴随特定肾病(例如急性间质性肾炎、急性肾小球肾炎和血管炎性肾病)、非特定病况(例如缺血、中毒性损伤)以及肾外病变(例如肾前性氮血症和急性肾后梗阻性肾病)而发生。这些病况中的多于一种可在同一患者中共存,且更重要地,流行病学证据支持以下意见:即使轻度可逆的AKI也具有重大临床后果,包括死亡风险增加。进一步,因为不论病因主要在肾内或主要来自对肾的外部应激,AKI的表现和临床后果均可能相当相似(甚至无法区分),所以AKI综合征涵盖对肾的直接损伤与功能急剧减弱两者。
在一些实施方式中,针对AKI进行治疗的患者患有糖尿病、潜在肾功能不全、肾病综合征、动脉粥样硬化病、败血症、低血压、低氧症、肌红蛋白尿-血尿、或肝病。在其他实施方式中,患者是老年人、孕妇、手术患者、或已曝露于肾毒性剂。
在一个特定实施方式中,针对AKI进行治疗的患者是手术患者。因此,在某些实施方式中,化合物在手术之后给药手术患者。
在另一实施方式中,针对AKI进行治疗的患者已曝露于肾毒性剂。肾毒性剂是能够造成AKI的药物或化学物质。能够造成急性肾损伤的药物或化学物质包括但不限于顺铂(cisplatin);庆大霉素(gentamicin);头孢噻啶(cephaloridine);环孢素(cyclosporine);两性霉素(amphotericin);四氯化碳;三氯乙烯;和二氯乙炔。
同样,患有由先前三段所提及的任一病况引起的AKI的患者可根据所公开的方法用化合物A、化合物B或化合物C、或者化合物A、化合物B或化合物C的药学上可接受的盐治疗。
化合物A、化合物B和化合物C的医药上可接受的盐可用于所公开的方法。术语“药学上可接受的盐”是指在合理医学判断范畴内,适用于与人类和低等动物的组织接触使用而无异常毒性、刺激和过敏反应、且与合理益处/风险比相称的药学盐。药学上可接受的盐为本领域公知的。例如,S.M.Berge等人在J.Pharm.Sci.,1977,66,1-19中描述药理学上可接受的盐。盐是通过与酸(例如氢氯酸、氢溴酸、磷酸、硝酸、硫酸、乙酸、苯磺酸、苯甲酸、甲磺酸、对甲苯磺酸和葡甲胺酸)加成而形成的;以及通过与碱加成而形成的,例如铵盐、碱金属盐(例如钠盐和钾盐)、碱土金属盐(例如镁盐和钙盐)和有机碱盐(例如葡甲胺盐和L-赖氨酸盐)。
医药组合物和其给药
化合物A、化合物B或化合物C、或者化合物A、化合物B或化合物C的药学上可接受的盐可与已知对AKI有益的其他药剂组合使用。
用于向个体提供“治疗有效量”的化合物的给药精确量将取决于给药模式、疾病的类型和严重程度而定,且取决于个体的特征,例如一般健康状况、年龄、性别、体重和对药物的耐受性而定。本领域技术人员能够根据这些和其他因素确定适合的剂量。术语“治疗有效量”是指当向个体给药时会产生有利或所需结果(包括临床结果,例如相比于对照组可抑制、减缓或减轻个体的所治疗病况的症状)的量。例如,治疗有效量可为例如每天0.1mg至约50g。
如本文所使用的术语“给药(administer、administering、administration)”等是指可用于实现将组合物递送至所需生物作用位点的方法。这些方法包括但不限于关节内(关节中)、静脉内、肌肉内、肿瘤内、皮内、腹膜内、皮下、经口、局部、鞘内、吸入、经皮、经直肠等。例如,当所治疗的病况为急性肾脏损伤时,常用经口和静脉内给药。可与本文所描述的试剂和方法一起采用的投药技术见于例如Goodman和Gilman,The PharmacologicalBasis of Therapeutics,当前版本;Pergamon;和Remington的Pharmaceutical Sciences(当前版本),Mack Publishing Co.,Easton,Pa。
用于所公开的方法中的医药组合物包括化合物A、化合物B或化合物C、或者化合物A、化合物B或化合物C的药学上可接受的盐,且典型而言包括至少一种额外物质,例如赋形剂、除本公开的那些之外的已知的治疗剂和其组合。
用于所公开方法中的医药组合物被配制以与其预期给药途径相容。在一个实施方式中,组合物是根据常规流程被配制为适合于静脉内、皮下、肌肉内、经口、鼻内或局部给药给人类的药物组合物。
通过静脉内制剂给药治疗剂在药学工业中是公知的。静脉内制剂包含药学活性剂(例如化合物A、化合物B或化合物C、或者化合物A、化合物B或化合物C的药学上可接受的盐),所述药学活性剂溶解于药学上可接受的溶剂或溶液中、例如无菌水、生理盐水溶液、乳酸林格氏液(lactated Ringer's)、或例如林格氏溶液的其他盐溶液中。制剂应当促进该一种或多种活性成分的整体稳定性,并且制剂的制备也应当是具有成本效益的。所有这些因素最终决定静脉内制剂的总体成功和有用性。
经口制剂通常经制备为呈例如片剂或丸剂形式的压缩制剂。片剂可例如含有约5%至10%的活性成分(例如化合物A、化合物B或化合物C、或者化合物A、化合物B或化合物C的药学上可接受的盐);约80%的填充剂、崩解剂、润滑剂、助流剂和粘结剂;和10%的确保片剂在胃或肠道中容易崩解、解离和溶解的化合物。丸剂可涂布有糖、清漆或蜡以掩盖味道。
实施例
实施例1
(R)-3-甲基-6-(2-((5-甲基-2-(6-(三氟甲基)吡啶-3-基)-1H-咪唑-1-基)甲基)苯氧基)己酸(化合物A)的合成
方案:
(R)-6-溴基-3-甲基己酸乙酯的合成:
在1L圆底烧瓶中,在室温(RT)下用PBr3(101.0g,373.56mmol)处理(R)-6-羟基-3-甲基己酸乙酯(65.0g,373.56mmol)在二氯甲烷(650mL)中的溶液。在室温下搅拌反应混合物3小时。在反应完成(通过TLC监测)之后,反应混合物用水(500mL)稀释且用乙醚(3×500mL)萃取。有机萃取物经分离且经无水Na2SO4干燥。在减压下去除溶剂以获得标题化合物(57.12g)。
步骤-1:N-(丙-2-炔-1-基)-6-(三氟甲基)烟酰胺的合成:
在100mL圆底烧瓶中,在室温下在氮气氛围下,用1-[双(二甲胺基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(7.2g,18.84mmol)和三乙胺(3.1mL,23.55mmol)处理经搅拌的6-(三氟甲基)烟酸(3g,15.70mmol)和丙-2-炔-1-胺(1.05g,18.84mmol)在二甲基甲酰胺(DMF:50mL)中的溶液。将所得反应混合物在室温下搅拌3小时。在反应完成之后(通过TLC监测),反应混合物用冷水稀释,且将所沉淀固体过滤、用水洗涤且在减压下干燥,从而得到标题化合物(2.6g,72.6%)。
1H NMR(300MHz,CDCl3):δ9.08(d,J=2.1Hz,1H),8.32(dd,J=8.4,2.4Hz,1H),7.78(d,J=7.8Hz,1H),6.62(brs,1H),4.30-4.28(m,2H),2.33(t,J=2.4Hz,1H)。
LCMS(ESI+,m/z):229.2(M+H)+。
步骤-2:5-(1-(2-甲氧基苯甲基)-5-甲基-1H-咪唑-2-基)-2-(三氟甲基)吡啶的合成:
在50mL可重复密封的试管中,在室温下在氮气氛围下,用三氟甲磺酸锌(0.16g,0.43mmol)处理N-(丙-2-炔-1-基)-6-(三氟甲基)烟酰胺(1.0g,4.38mmol)和2-甲氧基苯基苯甲基胺(1.2g,8.77mmol)在甲苯(10mL)中的溶液。将反应混合物在120℃下加热12小时。在反应完成(通过TLC监测)之后,反应混合物用水稀释且用EtOAc(3×20mL)萃取。有机萃取物用饱和NaHCO3、盐水洗涤且经无水Na2SO4干燥。在减压下浓缩溶液且通过硅胶柱色谱法(洗脱,含25%EtOAc的己烷)提纯所获得的残留物,从而得到标题化合物(0.8g,52.6%)。
1H NMR(400MHz,CDCl3):δ8.79(s,1H),8.07(d,J=8.1Hz,1H),7.68(d,J=8.1Hz,1H),7.31(t,J=8.4Hz,1H),7.09(s,1H),6.94-6.87(m,2H),6.56(d,J=7.5Hz,1H),5.16(s,2H),3.87(s,3H)。LCMS(ESI+,m/z):348.3(M+H)+。
步骤-3:2-((5-甲基-2-(6-(三氟甲基)吡啶-3-基)-1H-咪唑-1-基)甲基)苯酚的合成:
在100mL圆底烧瓶中,在0℃下用BBr3(0.8mL,2.31mmol)逐滴处理5-(1-(2-甲氧基苯甲基)-5-甲基-1H-咪唑-2-基)-2-(三氟甲基)吡啶(0.8g,2.31mmol)在二氯甲烷(300mL)中的溶液。在室温下搅拌反应混合物2小时。在反应完成(通过TLC监测)之后,反应混合物用NaHCO3水溶液碱化(pH~9)且用乙酸乙酯(EtOAc)萃取。有机萃取物经无水Na2SO4干燥且在减压下浓缩,从而提供标题化合物(0.5g,65.1%)。
1H NMR(400MHz,DMSO-d6):δ9.92(s,1H),8.83(s,1H),8.12(d,J=8.1Hz,1H),7.94(d,J=8.1Hz,1H),7.12(d,J=6.9Hz,1H),7.02(s,1H),6.87(d,J=7.8Hz 1H),6.73(t,J=7.2Hz,1H),6.37(d,J=7.2Hz,1H),5.20(s,2H),2.15(s,3H)。
LCMS(ESI+,m/z):334.3(M+H)+。
步骤-4:(R)-3-甲基-6-(2-((5-甲基-2-(6-(三氟甲基)吡啶-3-基)-1H-咪唑-1-基)甲基)苯氧基)己酸乙酯的合成:
在50mL圆底烧瓶中,在室温下在氮气氛围下,用K2CO3(0.41g,3.00mmol)和(R)-6-溴基-3-甲基己酸乙酯(0.710g,3.00mmol)处理经搅拌的2-((5-甲基-2-(6-(三氟甲基)吡啶-3-基)-1H-咪唑-1-基)甲基)苯酚(0.5g,1.50mmol)在DMF(10mL)中的溶液。在60℃下将所得反应混合物加热12小时。在反应完成(通过TLC监测)之后,反应混合物用冰冷水淬灭且用乙酸乙酯萃取(75mL×3)。经合并的有机萃取物用盐水洗涤,经无水Na2SO4干燥且在减压下浓缩。通过硅胶柱色谱法(梯度洗脱,15-30%EtOAc于己烷中)提纯所获得的残留物,从而提供标题化合物(0.45g,61.3%)。
产量:0.45g(61.3%)。
LCMS(ESI+,m/z):491.0(M+H)+。
步骤-5:(R)-3-甲基-6-(2-((5-甲基-2-(6-(三氟甲基)吡啶-3-基)-1H-咪唑-1-基)甲基)苯氧基)己酸(化合物A)的合成:
在250mL圆底烧瓶中,在室温下用单水合氢氧化锂(16.0g,74.33mmol)处理经搅拌的(R)-3-甲基-6-(2-((5-甲基-2-(6-(三氟甲基)吡啶-3-基)-1H-咪唑-1-基)甲基)苯氧基)己酸乙酯(0.45g,0.92mmol)在四氢呋喃(THF:5mL)、乙醇(2.5mL)和水(2.5mL)中的溶液。在室温下搅拌反应混合物12小时。在反应完成(通过TLC监测)之后,反应混合物在减压浓缩。所获得的残留物用EtOAc洗涤,用冷水稀释且用1N HCl酸化(pH~5)。过滤固体且在减压下干燥,从而给出标题化合物(0.166g,39.2%)。
1H NMR(400MHz,DMSO-d6):δ11.96(brs,1H),8.79(s,1H),8.05(d,J=8.0Hz,1H),7.90(d,J=8.0Hz,1H),7.24(t,J=7.6Hz,1H),7.02(d,J=8.4Hz,1H),7.00(s,1H),6.84(t,J=7.6Hz,1H),6.43(d,J=7.2Hz,1H),5.21(s,2H),3.98(t,J=6.0Hz,2H),2.19-2.14(m,1H),2.13(s,3H),2.03-1.94(m,1H),1.85-1.80(m,1H),1.68-1.66(m,2H),1.38-1.36(m,1H),1.28-1.18(m,1H),0.85(d,J=6.4Hz,3H)。
19F NMR(400MHz,DMSO-d6):δ-66.46
LCMS(ESI+,m/z):462.3(M+H)+。
HPLC:95.11%(210nm)。
化合物A的葡甲胺盐的制备
使用两种独立的方法来产生化合物A的葡甲胺盐。
方法1
在4mL玻璃小瓶中将化合物A(102.7mg)与葡甲胺(43.7mg)和2mL的2-丙醇合并。用盖密封小瓶且使内容物在25℃下经受20分钟超声处理,随后在50℃下搅拌60分钟。接着将小瓶移动至新的搅拌板,且在25℃下搅拌小瓶中的浆料。
方法2
在4mL玻璃小瓶中将化合物A(102.2mg)与葡甲胺(43.2mg)和2mL的乙腈合并。用盖密封小瓶且使内容物在25℃下经受20分钟超声处理,随后在50℃下搅拌60分钟。接着将小瓶移动至新的搅拌板,且在25℃下搅拌小瓶中的浆料。
对于方法1和方法2两者,在25℃下搅拌2天之后,将两个样品离心,弃去上清液,且将固体风干。
化合物A的葡甲胺盐的水合物的制备
在500mL圆底烧瓶中,在0℃下用葡甲胺(8.45g,43.33mmol)处理经搅拌的化合物A(20g,43.33mmol)在THF(100mL)和水(100mL)中的溶液。在室温下将所得反应混合物搅拌6小时。在减压下浓缩反应混合物且在减压下干燥所获得的固体(3小时),从而提供呈白色固体状的标题化合物(28.5g,98.95%)。
1H NMR(400MHz,CD3OD):δ8.75(s,1H),8.02(d,J=8.4Hz,1H),7.82(d,J=8.0Hz1H),7.26(t,J=8.4Hz,1H),7.03(s,1H),6.99(d,J=8Hz,1H),6.85(t,J=7.6Hz,1H),6.50(d,J=7.6Hz,1H),5.25(s,2H),4.09-3.99(m,3H),3.97-3.77(m,2H),3.74-3.61(m,3H),3.29-3.06(m,2H),2.64(s,3H),2.22(s,3H),2.18-2.14(m,1H),1.99-1.94(m,2H),1.83-1.75(m,2H),1.51-1.38(m,1H),1.32-1.22(m,1H),0.86(d,J=6.0Hz,3H)。
19F NMR(400MHz,CD3OD):δ-69.39
元素分析:C31H43F3N4O8.H2O计算值:C,55.18;H,6.72;N,8.30。实验值:C,54.95;H,6.89;N,8.07
水分含量(Karl Fischer):2.33%
实施例2
化合物A在急性肾损伤的动物模型中静脉内给药时减少缺血再灌注损伤
动物、手术和给药:在这些实验中使用大约280至300g Sprague-Dawley雄性大鼠,其自由采食标准饲料和水。将大鼠(n=8/组)用异氟烷麻醉且将其腹侧置放于温度受控的加热的手术台上。在背侧表面上切开皮肤,经由侧切口暴露两个肾。将血管夹施加至两个肾蒂且闭塞持续45分钟。45分钟之后,将夹移除,针对成功再灌注对肾进行监测,且随后缝合手术位点。假处理组(n=4只大鼠)除不施加闭塞夹具之外,经受类似手术流程。化合物A被配制为每天新制的化合物A(1.5摩尔当量化合物A)的葡甲胺盐水合物在5%右旋糖中的澄清溶液。在动物从手术醒来4小时后,经由尾静脉以3mg/kg、1mg/kg或0.3mg/kg静脉内给与化合物A,且类似地向假手术和IRI对照动物给与载体。
血液采集:再灌注二十四(24)小时之后,在轻度异氟烷麻醉下通过从所有组进行眼球后取血,将血液采集于K2EDTA管中。在4℃下,通过以3000rpm离心10分钟来分离血浆。
尿液采集:在手术恢复之后立即将所有研究动物组置放于代谢笼中,且采集尿液24或48小时。仔细测量尿液体积,且随后在4℃下以3000rpm离心10分钟来移除沉淀物。
血浆和尿肌酐使用完全自动的临床生物化学分析器(SiemensPlus Integrated Chemistry System)来分析。UrinaryNGAL使用BioPorto ELISA试剂盒来分析。肌酐清除率计算如下:
资料分析和统计分析:
GraphPad Prism软件第6.05版用于绘图和统计检验。经由D'Agostino Pearson综合正态性检验和Shapiro-Wilk正态性检验来检验所有组中肌酐的正态性分布。统计显著性(p<0.05)通过普通单因子方差分析(One-way ANOVA)、接着通过将IRI处理组用作对照组进行邓尼特多重比较(Dunnett's multiple comparison)来确定。对比IR-载体,**p<0.01,***p<0.001,且****p<0.0001。
结果:数据显示于图1中。在缺血4小时后静脉内给与的化合物A减少肾损伤。化合物A在以0.3mg/kg、1mg/kg或3mg/kg给与时,显著降低血浆肌酐、改善肾功能且减少早期肾损伤生物标记物NGAL。
实施例3
化合物B在急性肾损伤的动物模型中静脉内给药时减少缺血再灌注损伤
动物、手术和给药:在这些实验中使用大约280至300g Sprague-Dawley雄性大鼠,其自由采食标准饲料和水。将大鼠(n=8/组)用异氟烷麻醉且将其腹侧置放于温度受控的加热的手术台上。在背侧表面上切开皮肤,经由侧切口暴露两个肾。将血管夹施加至两个肾蒂且闭塞持续45分钟。45分钟之后,将夹移除,针对成功再灌注对肾进行监测,且缝合手术位点。假处理组(n=4只大鼠)除不施加闭塞夹具之外,经受类似手术流程。化合物B被配制为每天新制的在含0.25%羧甲基纤维素钠、0.25%Tween-80的纯化水中的悬浮液。在动物从手术醒来4小时后,以30mg/kg经口给与化合物B,且类似地向假手术和IRI对照动物给与载体。
血液采集:再灌注二十四(24)小时之后,在轻度异氟烷麻醉下通过自所有组进行眼球后取血,将血液采集于K2EDTA管中。在4℃下,通过以3000rpm离心10分钟来分离血浆。
尿液采集:在手术恢复之后立即将所有研究动物组置放于代谢笼中,且采集尿液24小时。仔细测量尿液体积,且随后在4℃下以3000rpm离心10分钟来移除沉淀物。
血浆和尿肌酐使用完全自动的临床生物化学分析器(SiemensPlus Integrated Chemistry System)来分析。肌酐清除率计算如下:
资料分析和统计分析:
GraphPad Prism软件第6.05版用于绘图和统计检验。经由D'Agostino Pearson综合正态性检验和Shapiro-Wilk正态性检验来检验所有组中的数据正态性分布。正态性分布的数据经受未配对双尾t检验。非正态性分布的数据经受Mann-Whitney检验(非参数)。通过IRI载体组相比于化合物处理组为p<0.05来确定统计显著性。对比IR-载体,**p<0.01,且***p<0.001。
结果:在缺血4小时后给与的化合物B减少肾损伤。化合物B(图2)在经口给药时降低血浆肌酐且改善肾功能。柱状图a显示肾损伤24小时后的大鼠中以mg/dL为单位的血浆肌酐水平,当经口给药时,血浆肌酐降低。柱从左至右表示给与载体的假手术大鼠;给与载体的患有急性肾损伤大鼠;和给与30mpk的化合物B的患有急性肾损伤大鼠的血浆肌酐水平(图2a)。类似地,柱状图b显示肌酐清除量(一种肾功能的评估)或GFR(肾小球滤过率)(图2b)。
Claims (24)
1.一种治疗患有急性肾损伤的人类患者的方法,其包含向患者静脉内给药有效量的由以下结构式表示的化合物:
或其药学上可接受的盐。
2.如权利要求1的方法,其包括将有效量的所述化合物的葡甲胺盐向所述患者静脉内给药。
3.一种治疗患有急性肾损伤的人类患者的方法,其包含向患者给药有效量的由以下结构式表示的化合物:
或其药学上可接受的盐。
4.一种治疗患有急性肾损伤的人类患者的方法,其包含向患者给药有效量的由以下结构式表示的化合物:
或其药学上可接受的盐。
5.如权利要求3或4的方法,其中,将所述化合物静脉内给药。
6.如权利要求3或4的方法,其中,将所述化合物经口给药。
7.如权利要求1至6中任一项的方法,其中,对所述患者治疗由急性间质性肾炎引起的急性肾损伤。
8.如权利要求1至6中任一项的方法,其中,对所述患者治疗由肾小球肾病引起的急性肾损伤。
9.如权利要求1至6中任一项的方法,其中,对所述患者治疗由急性血管炎性肾病引起的急性肾损伤。
10.如权利要求1至6中任一项的方法,其中,对所述患者治疗由缺血引起的急性肾损伤。
11.如权利要求1至6中任一项的方法,其中,对所述患者治疗由中毒性损伤引起的急性肾损伤。
12.如权利要求1至6中任一项的方法,其中,对所述患者治疗由肾前性氮血症引起的急性肾损伤。
13.如权利要求1至6中任一项的方法,其中,对所述患者治疗由急性肾后破坏性肾病引起的急性肾损伤。
14.如权利要求1至6中任一项的方法,其中,对所述患者治疗由糖尿病、潜在肾功能不全、肾病综合征、动脉粥样硬化病、败血症、低血压、低氧症、肌红蛋白尿-血尿或肝病引起的急性肾损伤。
15.如权利要求1至6中任一项的方法,其中,对所述患者治疗急性肾损伤,或者所述患者是老年人、孕妇、手术患者、或已曝露于肾毒性剂。
16.如权利要求15的方法,其中,所述患者是手术患者。
17.如权利要求15的方法,其中,所述患者已曝露于肾毒性剂且所述肾毒性剂是能够造成急性肾损伤的药物或化学物质。
18.如权利要求17的方法,其中所述药物或化学物质为选自顺铂、庆大霉素、头孢噻啶、环孢素、两性霉素、四氯化碳、三氯乙烯和二氯乙炔中的一种或多种化合物。
19.一种由以下结构式表示的化合物:
或其药学上可接受的盐,其用于静脉内治疗患有急性肾损伤的人类患者。
20.一种由以下结构式表示的化合物:
或其药学上可接受的盐,其用于治疗患有急性肾损伤的人类患者。
21.一种由以下结构式表示的化合物:
或其药学上可接受的盐,其用于治疗患有急性肾损伤的人类患者。
22.由以下结构式表示的化合物:
或其药学上可接受的盐用于制造用于静脉内治疗患有急性肾损伤的人类患者的药物的用途。
23.由以下结构式表示的化合物:
或其药学上可接受的盐用于制造用于治疗患有急性肾损伤的人类患者的药物的用途。
24.由以下结构式表示的化合物:
或其药学上可接受的盐用于制造用于治疗患有急性肾损伤的人类患者的药物的用途。
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