CN116003403B - 一种氘代吲唑类化合物、药物组合物及其应用 - Google Patents
一种氘代吲唑类化合物、药物组合物及其应用 Download PDFInfo
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- CN116003403B CN116003403B CN202211451463.0A CN202211451463A CN116003403B CN 116003403 B CN116003403 B CN 116003403B CN 202211451463 A CN202211451463 A CN 202211451463A CN 116003403 B CN116003403 B CN 116003403B
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Abstract
本发明公开了式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物，药物组合物及其应用。本发明提供的式I所示化合物对非胰岛素依赖性糖尿病(2型糖尿病)、肥胖症等具有较好的治疗作用。
Description
技术领域
本发明属于创新药物化学领域，涉及一种氘代吲唑类化合物、药物组合物及应用。
背景技术
2型糖尿病(T2DM)是一种表现为血糖浓度增高的慢性代谢性疾病，具有较高的发病率和死亡率。全球2型糖尿病的患病率正以惊人的速度上升。2019年，超过4.63亿人患有糖尿病，以T2DM为主。肥胖被认为是T2DM的一个重要危险因素，大约85％的T2DM患者超重或肥胖。此外，在超重/肥胖人群中，适度减轻体重可以预防T2DM的发生，并减少已确诊的T2DM患者对抗糖尿病药物的需求。胰高血糖素样肽-1(GLP-1)是当营养素通过消化道时，由小肠L细胞分泌的肠降血糖素，GLP-1通过激活GLP-1受体发挥多种生理作用，包括葡萄糖依赖胰岛素分泌和生物合成，抑制胰高血糖素释放，胰腺β细胞生存，提高胰岛素敏感性，延缓胃功能清空。尽管GLP-1类似物已经应用于临床治疗糖尿病，但是GLP-1类似物必须经过皮下注射给药，病人依从性较差。而开发非多肽类GLP-1受体小分子激动剂，改善病人依从性具有重要意义，并成为糖尿病领域研究热点之一。目前，已经有GLP-1受体激动剂应用于临床治疗T2DM。另外，GLP-1受体激动剂还能诱导饱腹感，并能减轻人的体重。然而，在大多数肥胖患者中，目前批准的GLP-1受体激动剂受剂量依赖的胃肠道副作用的限制，只能达到中等的减肥效果。LY3502970是一种GLP-1受体激动剂，目前处于临床II研究阶段。
氘代药物是指将药物分子中的部分氢原子替换为氘。由于氘在药物分子中形状和体积与氢接近，氘代药物一般会保留原来药物的生物活性和选择性。由于C-D键比C-H键更稳定，使得氘代药物在化学反应过程中，C-D键更不容易断裂，其半衰期会延长。自2000年以来，氘代策略便被广泛应用于药物的研究中。
发明内容
本发明提供了一种如式I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物，其结构如下：
其中，R1为氢或氘，
R2、R3、R4、R5、R6或R7独立地选自CD3或CH3，
当R1为氢时，R2、R3、R4、R5、R6或R7至少有一个为CD3。
在一些实施方案中，所述的R1为氘。
在一些实施方案中，所述的R2为CD3。
在一些实施方案中，所述化合物由以下任一结构式表示：
本发明提供了一种如式I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物在制备GLP-1受体激动剂中的应用。
本发明提供了一种I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物在制备用于非依赖性糖尿病、高血糖、糖耐量降低和胰岛素依赖型糖尿病、肥胖症、糖尿病并发症、高血压、高血脂症、动脉粥样硬化、冠心病、脑梗死、非酒精性脂肪性肝炎、帕金森病或阿尔茨海默病的药物中的应用。
在一些实施方案中，所述的非依赖性糖尿病、高血糖、糖耐量降低和胰岛素依赖型糖尿病、肥胖症、糖尿病并发症、高血压、高血脂症、动脉粥样硬化、冠心病、脑梗死、非酒精性脂肪性肝炎、帕金森病或阿尔茨海默病为与GLP-1受体活性异常相关的非依赖性糖尿病、高血糖、糖耐量降低和胰岛素依赖型糖尿病、肥胖症、糖尿病并发症、高血压、高血脂症、动脉粥样硬化、冠心病、脑梗死、非酒精性脂肪性肝炎、帕金森病或阿尔茨海默病。
本发明提供了一种药物组合物，其含有如式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物，及药学上可接受的载体或辅料。
在所述的药物组合物中，所述的如式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物用量为治疗有效量。
本发明提供了一种药物组合物在制备中GLP-1受体激动剂中的应用。
本发明提供了一种药物组合物在制备用于非依赖性糖尿病、高血糖、糖耐量降低和胰岛素依赖型糖尿病、肥胖症、糖尿病并发症、高血压、高血脂症、动脉粥样硬化、冠心病、脑梗死、非酒精性脂肪性肝炎、帕金森病或阿尔茨海默病的药物中的应用。
在一些实施方案中，所述的非依赖性糖尿病、高血糖、糖耐量降低和胰岛素依赖型糖尿病、肥胖症、糖尿病并发症、高血压、高血脂症、动脉粥样硬化、冠心病、脑梗死、非酒精性脂肪性肝炎、帕金森病或阿尔茨海默病为与GLP-1受体活性异常相关的非依赖性糖尿病、高血糖、糖耐量降低和胰岛素依赖型糖尿病、肥胖症、糖尿病并发症、高血压、高血脂症、动脉粥样硬化、冠心病、脑梗死、非酒精性脂肪性肝炎、帕金森病或阿尔茨海默病。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的游离体形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的游离体形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸(形成碳酸盐或碳酸氢盐)、磷酸(形成磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸(形成硫酸盐或硫酸氢盐)、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；有机酸盐还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的游离体形式。化合物的游离体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本发明的“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
术语“异构体”是指具有相同化学式而有不同的原子排列的化合物。
术语“代谢产物”是指式I所示化合物或其盐通过体内代谢产生的药学活性产物。这种产物可以从例如所给药的化合物的氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯、葡糖醛酸化、酶促裂解等产生。因此，本发明包括本发明的化合物的代谢产物，包括使本发明的化合物与哺乳动物接触足够得到其代谢产物的一段时间的方法而产生的化合物。
代谢产物的鉴定典型地通过制备本发明化合物的放射性标记的同位素、将其以可检测的剂量(例如，大于约0.5mg/kg)非肠道给予动物，例如大鼠、小鼠、豚鼠、猴、或人，允许充分的时间以发生代谢(典型地约30秒到30小时)和从尿、血液或其它生物样本分离其转化产物。这些产物容易分离，因为它们是被标记的(其它通过利用能够结合存在于代谢物中的抗原表位的抗体分离)。以常规的方式确定代谢物结构，例如，通过MS，LC/MS或NMR分析。通常，代谢物的分析是以与本领域技术人员公知的常规药物代谢研究相同的方法进行的。只要代谢物产物不是以其它方式在体内不能被发现，否则它们可用于本发明化合物的治疗剂量给药的检定测定法。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。可在体内转化以提供生物活性物质(即式I所示化合物)的任何化合物是在本发明的范围和主旨内的前药。例如，含有羧基的化合物可形成生理上可水解的酯，其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药，这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时，可使用肠胃外给药。
本发明的积极进步效果在于：
(1)本发明化合物对GLP-1受体具有显著的激动活性。
(2)本发明化合物药代动力学性质显著提高，半衰期延长，具有很好的口服生物利用度较高，
(3)本发明化合物对2型糖尿病和肥胖症具有良好的治疗作用。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1：化合物I-1的合成
步骤一：化合物b的合成
0℃下，向化合物a(2.13g，10mmol)的DMF(15mL)溶液中加入NaH(12mmol，480mg，60％)，室温下搅拌10min，然后向反应液中滴加氘代碘甲烷(1.7g，12mmol)。室温下搅拌反应2h。待反应完成后，加入饱和氯化铵淬灭反应。减压去掉溶剂，乙酸乙酯萃取(10mL×3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化制得化合物b(1.5g，63％)。MS(ESI,m/z):231(M++1).
步骤二：化合物d的合成
将化合物c(542mg，1mmol)溶于氘代DMSO(2mL)中，氮气保护，向上述溶液中加入叔丁醇钾(40mol％,22mg)，升温至35℃搅拌6h。反应完成后，加入水，乙酸乙酯萃取(5mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化制得化合物d(247mg，45％)。MS(ESI,m/z):548(M++1).
步骤三：化合物1的合成
将化合物d(548mg，1mmol)溶于乙酸乙酯(5mL)中，向上述溶液中加入EA/HCl(4M，4mmol，1mL)，室温下搅拌反应4h。待反应完成后，抽滤，收集滤饼，真空干燥制得化合物1(295mg，85％)。MS(ESI,m/z):348(M++1).
步骤四：化合物3的合成
向化合物1(347mg，1mmol)和化合物2(411mg，1mmol)的DMF(3mL)溶液中加入HATU(575mg，1.5mmol)和DIPEA(0.53mL，3mmol)，室温下搅拌反应6h。待反应完成后，向上述溶液中加水淬灭反应，乙酸乙酯萃取(5mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化制得化合物3(481mg，65％)。MS(ESI,m/z):741(M++1).
步骤五：化合物I-1的合成
向化合物b(13mg，0.056mmmol)、化合物3(21mg，0.028mmol)、(1S,2S)-1-N,2-N-二甲基环己烷-1,2-二胺(1.6mg，0.011mmol)和碳酸钾(12mg，0.085mmol)的NMP(0.2mL)溶液中加入碘化亚铜(1.1mg，0.0056mmol)。氮气保护，反应液升温至130℃，搅拌反应3h。冷却至室温，HPLC制备制得化合物I-5(19mg，77％)。1H NMR(500MHz,DMSO-d6)δ9.09(s,1H),7.78(s,1H),7.76(dd,J＝8.4,4.9Hz,1H),7.55–7.46(m,2H),7.29(d,J＝5.0Hz,2H),7.21–7.12(m,2H),6.80(d,J＝7.0Hz,1H),6.62(d,J＝7.1Hz,1H),5.35(q,J＝7.0Hz,1H),3.68(ddd,J＝12.1,5.9,4.7Hz,1H),3.65–3.54(m,1H),3.56–3.47(m,2H),3.15(dddd,J＝7.5,6.4,5.1,4.2Hz,1H),2.93–2.82(m,2H),2.60(dd,J＝6.9,2.8Hz,1H),2.44(dp,J＝6.8,5.2Hz,2H),2.36(dd,J＝5.3,2.8Hz,2H),2.07–1.96(m,2H),1.93–1.83(m,2H),1.55(s,3H),1.25(s,3H),1.20(s,2H),1.01(d,J＝5.2Hz,3H).MS(ESI,m/z):892(M++1).
实施例2：化合物I-2的合成
步骤一：化合物e的合成
向化合物b(107mg,0.47mmol)的N,N-二甲基甲酰胺(15mL)溶液中加入氢氧化钾(105.5mg,1.88mmol)和碘单质(239mg,0.94mmol)，室温反应3小时，TLC监测反应完全，加入亚硫酸钠饱和溶液淬灭反应，水相用乙酸乙酯(10mL×2)萃取，水(20mL×2)洗，饱和食盐(20mL)水洗无水硫酸钠干燥，浓缩柱层析分离纯化制得化合物e(67mg，40％)。MS(ESI,m/z):357(M++1).
步骤二：化合物f的合成
向化合物e(127mg,0.36mmol)的氘代醋酸溶液(8mL)中加入醋酸钠(97.9mg,0.72mmol)，2小时滴完，室温反应24小时，TLC检测反应完全，减压浓缩，柱层析分离纯化制得化合物3(70mg,85％)。MS(ESI,m/z):232(M++1).
步骤三：化合物I-2的合成
化合物4的合成参考实施例1化合物3的合成方法。
向化合物f(13mg，0.056mmol)、化合物4(21mg，0.028mmol)、(1S,2S)-1-N,2-N-二甲基环己烷-1,2-二胺(1.6mg，0.011mmol)和碳酸钾(12mg，0.085mmol)的NMP(0.2mL)溶液中加入碘化亚铜(1.1mg，0.0056mmol)。氮气保护，反应液升温至130℃，搅拌反应3h。冷却至室温，HPLC制备制得化合物I-2(17mg，67％)。1H NMR(500MHz,DMSO-d6)δ7.78(s,1H),7.76(dd,J＝8.4,4.9Hz,1H),7.55–7.46(m,2H),7.29(d,J＝5.0Hz,2H),7.21–7.12(m,2H),6.80(d,J＝7.0Hz,1H),6.62(d,J＝7.1Hz,1H),5.35(q,J＝7.0Hz,1H),3.68(ddd,J＝12.1,5.9,4.7Hz,1H),3.65–3.54(m,1H),3.56–3.47(m,2H),3.15(dddd,J＝7.5,6.4,5.1,4.2Hz,1H),2.93–2.82(m,2H),2.60(dd,J＝6.9,2.8Hz,1H),2.44(dp,J＝6.8,5.2Hz,2H),2.36(dd,J＝5.3,2.8Hz,2H),2.07–1.96(m,2H),2.01(s,3H),1.99(s,3H),1.93–1.83(m,2H),1.55(s,3H),1.25(s,3H),1.20(s,2H),1.01(d,J＝5.2Hz,3H).MS(ESI,m/z):887(M++1).
实施例3：化合物I-3的合成
化合物i的合成：合成方法如实施例2，只需将原料化合物b替换成化合物g即可。
化合物I-3的合成：合成方法如实施例1，只需将原料更换为即可。1H NMR(500MHz,DMSO-d6)δ7.78(s,1H),7.76(dd,J＝8.4,4.9Hz,1H),7.55–7.46(m,2H),7.29(d,J＝5.0Hz,2H),7.21–7.12(m,2H),6.80(d,J＝7.0Hz,1H),6.62(d,J＝7.1Hz,1H),5.35(q,J＝7.0Hz,1H),3.68(ddd,J＝12.1,5.9,4.7Hz,1H),3.65–3.54(m,1H),3.56–3.47(m,2H),3.15(dddd,J＝7.5,6.4,5.1,4.2Hz,1H),2.93–2.82(m,2H),2.77(s,3H),2.60(dd,J＝6.9,2.8Hz,1H),2.44(dp,J＝6.8,5.2Hz,2H),2.36(dd,J＝5.3,2.8Hz,2H),2.07–1.96(m,2H),1.93–1.83(m,2H),1.55(s,3H),1.25(s,3H),1.20(s,2H),1.01(d,J＝5.2Hz,3H)..MS(ESI,m/z):890(M++1).
实施例4：化合物I-4的合成
合成方法如实施例2，只需将更换为即可。1H NMR(500MHz,DMSO-d6)δ9.09(s,1H),7.78(s,1H),7.76(dd,J＝8.4,4.9Hz,1H),7.55–7.46(m,2H),7.29(d,J＝5.0Hz,2H),7.21–7.12(m,2H),6.80(d,J＝7.0Hz,1H),6.62(d,J＝7.1Hz,1H),5.35(q,J＝7.0Hz,1H),3.68(ddd,J＝12.1,5.9,4.7Hz,1H),3.65–3.54(m,1H),3.56–3.47(m,2H),3.15(dddd,J＝7.5,6.4,5.1,4.2Hz,1H),2.93–2.82(m,2H),2.60(dd,J＝6.9,2.8Hz,1H),2.44(dp,J＝6.8,5.2Hz,2H),2.36(dd,J＝5.3,2.8Hz,2H),2.07–1.96(m,2H),2.01(s,3H),1.99(s,3H),1.93–1.83(m,2H),1.55(s,3H),1.25(s,3H),1.20(s,2H),1.01(d,J＝5.2Hz,3H).MS(ESI,m/z):886(M++1).
实施例5：化合物I-5的合成
合成方法如实施例1，只需将原料替换成即可。1HNMR(500MHz,DMSO-d6)δ7.78(s,1H),7.76(dd,J＝8.4,4.9Hz,1H),7.55–7.46(m,2H),7.29(d,J＝5.0Hz,2H),7.21–7.12(m,2H),6.80(d,J＝7.0Hz,1H),6.62(d,J＝7.1Hz,1H),5.35(q,J＝7.0Hz,1H),3.68(ddd,J＝12.1,5.9,4.7Hz,1H),3.65–3.54(m,1H),3.56–3.47(m,2H),3.15(dddd,J＝7.5,6.4,5.1,4.2Hz,1H),2.93–2.82(m,2H),2.60(dd,J＝6.9,2.8Hz,1H),2.44(dp,J＝6.8,5.2Hz,2H),2.36(dd,J＝5.3,2.8Hz,2H),2.07–1.96(m,2H),1.93–1.83(m,2H),1.55(s,3H),1.25(s,3H),1.20(s,2H),1.01(d,J＝5.2Hz,3H)..MS(ESI,m/z):893(M++1).
实施例7：化合物在细胞中对cAMP信号活化程度的检测
本实验在稳定表达人GLP1R的细胞系hGLP1R-HEK293中进行。在包含的潮湿气氛下，hGLP1R-HEK293细胞采用DMEM培养基，该培养基包含10％胎牛血清、100单位/mL青霉素G和100μg/mL硫酸链霉素和500μg/mL遗传霉素。5％CO2、37℃下培养。以2.0×104个细胞/孔，将hGLP1R-HEK293接种于96孔板中，培养过夜。次日，将培养细胞的培养基转换成50μL培养基A(DMEM，20mM HEPES，0.05％BSA，0.5mM 3-异丁基-1-甲基黄嘌呤)，并且在37℃下温育30分钟。然后，加入包含GLP-1的50μL培养基B(DMEM，20mM HEPES，0.05％BSA，0.5mM 3-异丁基-1-甲基黄嘌呤)或化合物，并且在37℃下再温育30分钟。然后，加入100μL分析裂解缓冲液，在37℃下温育30分钟。应用cAMP HiRange试剂盒，将cAMP浓度定量。通过设定cAMP浓度，当将人GLP-1(7-37)以1nM至100％的浓度置于作用下时，各孔的cAMP浓度转化为反应速率(％)。通过应用经XL fit的4参数逻辑回归分析，创建待测化合物的剂量-响应曲线，并且计算半数最大(50％)有效浓度(EC50)。
表1待测化合物对hGLP1R-HEK293细胞cAMP信号活化程度(EC50 nM)
| 名称 | cAMP信号活化 |
| I-1 | 1.85 |
| I-2 | 1.80 |
| I-3 | 1.90 |
| I-4 | 1.83 |
| I-5 | 1.84 |
| LY3502970 | 4.55 |
如表1所示，化合物I-1～I-6显著增加了hGLP1R-HEK293细胞中cAMP的累积，且效果优于阳性对照LY3502970。
实施例8：待测化合物药代动力学性质检测
选用雄性SD大鼠，口服(10mg/kg)或静脉注射(2mg/kg)给药，于给药后5min，15min，30min，1h，2h，4h，8h，10h，24h，从眼底静脉丛连续取血置于含有肝素的EP管中，离心、取上层血浆进行LC-MS/MS分析，根据测试所得的血药浓度-时间数据，采用WinNonlin软件计算药代动力学参数，计算口服生物利用度。
研究结果表明，LY3502970在大鼠中的口服生物利用度为15％，半衰期1.2h；化合物I-1口服生物利用度提高至42％，半衰期延长至3.7h，这说明可以降低化合物I-1的单次给药剂量。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (3)
1.化合物或其药学上可接受的盐在制备GLP-1受体激动剂中的应用，所述化合物为如下任一种：。
2.一种药物组合物，其特征在于，所述药物组合物含有治疗有效量的如权利要求1所述化合物或其药学上可接受的盐，及药学上可接受的载体或辅料。
3.如权利要求1所述化合物或其药学上可接受的盐在制备GLP-1受体激动剂中的应用，其特征在于与GLP-1受体活性异常相关的疾病为非依赖性糖尿病、高血糖、糖耐量降低和胰岛素依赖型糖尿病、肥胖症、糖尿病并发症、高血压、高血脂症、动脉粥样硬化、冠心病、脑梗死、非酒精性脂肪性肝炎、帕金森病或痴呆。
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