CN103687856B - 用于治疗糖尿病的新的1,2,3,4-四氢喹啉衍生物 - Google Patents
用于治疗糖尿病的新的1,2,3,4-四氢喹啉衍生物 Download PDFInfo
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- CN103687856B CN103687856B CN201280036072.0A CN201280036072A CN103687856B CN 103687856 B CN103687856 B CN 103687856B CN 201280036072 A CN201280036072 A CN 201280036072A CN 103687856 B CN103687856 B CN 103687856B
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
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Abstract
本发明提供下式的化合物或其可药用的盐。本发明还提供采用所述化合物治疗糖尿病的方法以及制备该化合物的方法。
Description
糖尿病是发展中国家面临的严峻健康问题。人们盼望获得安全有效的糖尿病口服治疗方法。某些成功的商业化的II型糖尿病(T2D)口服治疗方法据信是通过过氧化物酶体增殖物-激活的受体(PPAR)γ受体的调节而起作用。这些药品的给药可能导致不受欢迎的副作用,包括低血糖、肝损伤、胃肠道疾病、肥胖或其它可能与PPARγ活性相关的不受欢迎的作用。能够控制T2D的具有更令人满意的安全属性的新的治疗选择应当能够在更多的患者中有效地治疗或预防糖尿病。尤其特别的是,迫切需要具有新作用机理的治疗方法,该机理应当是能够尽可能减少或避免与PPARγ激活相关的作用。
G蛋白-偶合受体40(GPR-40)也称为游离脂肪酸受体1(FFA1或FFAR1),据报道其能够以高浓度在啮齿类动物胰腺β细胞、胰岛素瘤细胞系和人类胰岛中优势表达。该受体可以通过中链和长链脂肪酸激活。胰岛素分泌的葡萄糖依赖性是GPR-40激活的重要特征,这使得该受体成为开发在T2D治疗中使用的具有满意的安全属性的有效疗法的极佳的靶点。与现有疗法(例如胰岛素和磺酰脲类的治疗方法)相比,能够提供疗效和更令人满意的安全属性的化合物是特别值得期待的。
两个最新公开的专利申请US20110092531和WO2011066183公开了具有GPR-40活性的化合物,该化合物具有螺-双环基团。
本发明提供了用于治疗糖尿病、特别是T2D的化合物。本发明的化合物是GPR-40的有效激活剂。本发明提供了与已经商业化的治疗相比具有独特药理学机理的令人满意的新的治疗方案,本发明还提供了能够选择性激活GPR-40(与PPARγ相比)的化合物。作为选择性GPR-40激活剂,本发明化合物的药理学特性特别适合用于治疗T2D。另外,通过避免与PPARγ调节相关的作用,选择性的GPR-40调节在T2D的治疗中提供了特别令人满意的安全属性。
本发明提供了下面式I的化合物或其可药用的盐:
本发明化合物具有一个在上面结构中用星号(*)标识的手性碳。优选的化合物具有上面所示构型,已知为S构型。
本发明也提供了药用组合物,它包含上述式I化合物或其可药用的盐以及一或多种可药用的载体、稀释剂或赋形剂。
本发明也提供了药用组合物,它包含上述式I化合物或其可药用的盐以及一或多种可药用的载体、稀释剂或赋形剂,还任选包含一或多种治疗剂。
本发明也提供了在哺乳动物中治疗糖尿病的方法。该方法包括给予需要治疗的哺乳动物上述式I化合物或其可药用的盐。更优选本发明提供了通过给予哺乳动物上述式I化合物或其可药用的盐从而在需要治疗的哺乳动物中治疗II型糖尿病的方法。优选上述哺乳动物为人类。
本发明还提供了通过给予需要治疗的哺乳动物药用组合物而在哺乳动物中治疗糖尿病的方法,所述药用组合物包含上述式I化合物或其可药用的盐。更优选本发明提供了通过给予哺乳动物药用组合物从而在需要治疗的哺乳动物中治疗II型糖尿病的方法,所述药用组合物包含上述式I化合物或其可药用的盐。优选哺乳动物为人类。
本发明提供了上述式I化合物或其可药用的盐在治疗中的用途。
另一方面,本发明提供了上述式I化合物、其可药用的盐或在需要的哺乳动物中治疗糖尿病所使用的药用组合物。优选所述用途为治疗II型糖尿病,所述哺乳动物为人类。
本发明提供了式I化合物或其可药用的盐在生产用于治疗糖尿病的药物中的用途。优选所述药物用于治疗II型糖尿病并且用于哺乳动物,特别是人类。
另一方面,本发明提供了用于制备式I化合物或其可药用盐的式II的中间体化合物:
其中R选自C1-4烷基、C1-4卤代烷基、C3-6环烷基、C1-4烷基C3-6环烷基、苯基和C1-5烷基苯基。优选R基团包括C1-2烷基、C1-2卤代烷基、苯基和-C1-2烷基苯基。特别优选R基团包括甲基、乙基、苯基和苄基。
本发明还提供了上述式I的(3S)-3-[4-[[5-[(8-甲氧基-3,4-二氢-2H-喹啉-1-基)甲基]-2-噻吩基]甲氧基]苯基]己-4-炔酸的制备方法。该方法包括将式II的中间体化合物脱保护或脱酯从而制备式I化合物或其可药用的盐。
本领域技术人员应当理解并且能够在无需过度实验的情况下实施脱保护反应。本领域技术人员应当理解,除了羧酸和被保护的羧酸外,其它易于转化为羧酸的官能团可以用于代替所述羧酸和被保护的羧酸。此类官能团、制备以及这些基团向羧酸的转化可以参考“有机转化反应概览:官能团制备指南(Comprehensive Organic Transformations:A Guide toFunctional Group Preparations)”,Larock.R.C,Wiley VCH,1999和“March高级有机化学、反应、机理和结构(March’s Advanced OrganicChemistry,Reactions,Mechanisms and Structure)”,March,J.,Wiley-Interscience,第6版,2007。
本发明化合物,即(3S)-3-[4-[[5-[(8-甲氧基-3,4-二氢-2H-喹啉-1-基)甲基]-2-噻吩基]甲氧基]苯基]己-4-炔酸,可以是可药用的盐。“可药用的盐”是指临床上和/或兽医应用中可以接受的本发明化合物的盐。可药用的盐以及用于其制备的常规方法学在本领域中是众所周知的。参见,例如,P.Stahl等,可药用盐手册:性质、选择和应用(Hand book of PharmaceuticalSalts:Properties,Selection and Use),(VCHA/Wiley-VCH,2002);S.M.Berge等,“可药用的盐”,Journal of Pharmaceutical Sciences,第66卷,第1期,1977年1月。
术语“可药用的载体、稀释剂或赋形剂”是指在药学上与组合物中的其它成分是相容的载体、稀释剂或赋形剂。
为了更为清晰,下面流程中排除了某些取代基,这并非以任何方式限定该流程的启示。另外,单一异构体、对映体或非对映异构体可以在合成式I化合物的任何适当的点通过例如手性色谱的方法分离。此外,下面流程和制备中所述中间体包括多种氮、羟基和酸保护基团,例如酯。可变的保护基团在任何情况下可以是相同的或不同的,这取决于具体的反应条件和实施的具体的转化反应。保护和去保护条件对于本领域技术人员而言是公知的,描述于文献中。参见,例如,Greene和Wuts,有机合成中的保护基团(Protective Groups in Organic Synthesis)(T.Greene和P.Wuts编辑,第2版,1991).
本文中使用的缩写根据Aldrichimica Acta,Vol.17,No.1,1984所定义。其它缩写如下定义:“ADDP”是指1-(偶氮二羰基)二哌啶;“BSA”是指牛血清白蛋白;“DIBAL-H”是指二异丁基氢化铝;“DIPEA”是指二异丙基乙胺;“DMEM”是指杜氏改良的伊戈尔培养基(Dulbecco’s ModifiedEagle’s Medium);“DTT”是指二硫苏糖醇;“ESI”是指电喷雾离子化;“EtOAc”是指乙酸乙酯;“EtOH”是指乙醇;“F12”是指Ham氏F12培养基;“FBS”是指胎牛血清;“HEK”是指人类胚胎肾;“IC50”是指一种药物对于该药物而言产生50%最大抑制响应的浓度;“MeOH”是指甲醇;“NBS”是指N-溴代琥珀酰亚胺;“PPAR”是指过氧化物酶体增殖物激活受体;“PPRE”是指过氧化物酶体增殖物响应元件;“RFU”是指相对荧光单位;“RPMI”是指Roswell Park Memorial Institute;“RT”是指室温;“THF”是指四氢呋喃;“TK”是指胸苷激酶。
本文中使用的术语烷基为直链烷基(例如乙基或正丙基)或支链烷基(例如异丙基或叔丁基)。术语C1-4卤代烷基是指具有1、2、3或更多个与烷基链相连的卤代基团的烷基。如果有2个或更多个卤素,则所述卤素不需要与同一个碳相连。该术语也包括全卤代烷基,其中烷基中所有的氢原子均被卤素代替。
在下面的流程中,除非另有说明,所有的取代基如前所定义。试剂和原料通常是本领域技术人员易于获得的。其它可以通过有机和杂环化学的标准工艺制备,这些技术与已知相似结构的化合物的合成工艺类似,下列在制备和实施例中描述的方法包括任何新的方法。
流程1
流程2
制备和实施例
下面的制备和实施例进一步阐明了本发明,代表了式(I)化合物的典型合成方法。所述化合物根据IUPACNAME ACDLABS或Symyx Draw3.2命名。
制备1
8-甲氧基喹啉
于室温下,将氢氧化钾(435g,7.76mol)加至8-羟基喹啉(250g,1.724mol)的THF(10L)溶液中并搅拌。滴加甲基碘(435g,2.58mol)并搅拌过夜。过滤反应混合物并用THF(2L)洗涤固体。将溶液浓缩至干;加入水;用二氯甲烷(2×3L)萃取;合并有机层;用盐水洗涤。收集有机层,经硫酸钠干燥。过滤除去固体。收集滤液,减压浓缩,获得红色油状物,静置后固化,获得目标化合物(281g,102%),其无需进一步纯化可以直接使用。ESI(m/z)160(M+H)。
制备2
8-甲氧基-1,2,3,4-四氢喹啉
将氰基硼氢化钠(505g,8.11mol)的EtOH(1L)溶液加至8-甲氧基喹啉(425g,2.673mol)的EtOH(9L)溶液中并搅拌。将反应混合物冷却至内部温度为0℃,在60分钟内滴加HCl(35%,1.12L,10.962mol),滴加的速度应当使得内部温度不超过20℃。将反应混合物温热至室温,然后加热至回流2.5小时。冷却至室温并搅拌过夜。加入氢氧化铵(25%,1L);用水(15L)稀释;用二氯甲烷(3×10L)萃取混合物。合并有机层并经硫酸钠干燥。过滤除去固体。收集滤液并减压浓缩,获得残留物。残留物经硅胶快速色谱纯化,用乙酸乙酯:己烷(1:10)洗脱,获得目标化合物(357g,82%)。ESI(m/z)164(M+H)。
制备3
5-甲基噻吩-2-甲酸甲酯
于0℃,20分钟内,将亚硫酰氯(153ml,2.1mol)滴加至5-甲基噻吩-2-甲酸(100g,0.703mol)的MeOH(1L)溶液中,搅拌。加入完成后,将反应混合物加热至回流3.5小时。冷却并真空浓缩,获得粘稠的油状物。将该油状物用EtOAc(500ml)稀释,用水(300ml)洗涤,然后用盐水(300ml)洗涤。有机层经硫酸钠干燥。过滤除去固体。收集滤液并减压浓缩,获得目标化合物(106g,97%),其无需进一步纯化可以直接使用。ESI(m/z)156(M+H)。
制备4
5-(溴代甲基)噻吩-2-甲酸甲酯
于室温下,将新结晶的NBS(323.8g,1.81mol)加至5-甲基噻吩-2-甲酸甲酯(258g,1.65mol)的氯仿(2.6L)溶液中并搅拌。加入过氧化苯甲酰(3.99g,0.016mol),将反应混合物加热至回流7小时。将反应混合物冷却至室温,通过硅藻土过滤。用氯仿(250ml)洗涤滤饼。收集有机层,除去溶剂,获得目标化合物(388g,100%),其无需进一步纯化可以直接使用。ESI(m/z)236(M+H)。
制备5
5-[(8-甲氧基-3,4-二氢-2H-喹啉-1-基)甲基]噻吩-2-甲酸甲酯
将5-(溴代乙基)噻吩-2-甲酸甲酯(432.5g,1.84mol)的EtOH(500ml)溶液加至8-甲氧基-1,2,3,4-四氢喹啉(300g,1.84mol)的EtOH(1L)溶液中并搅拌。滴加DIPEA(641ml,3.67mol)并于室温下搅拌过夜。反应完成后,真空除去EtOH,加入水(5L)。用EtOAc(3×3L)萃取水相;合并有机层,经硫酸钠干燥。过滤溶液并减压浓缩,获得残留物。残留物经硅胶快速色谱纯化,采用乙酸乙酯:己烷(6:94)洗脱,获得目标化合物(325g,56%)。ESI(m/z)318(M+H)。
制备6
[5-[(8-甲氧基-3,4-二氢-2H-喹啉-1-基)甲基]-2-噻吩基]甲醇
在1.5h的时间内,于-70℃,通过套管将DIBAL-H(1M的甲苯溶液2.7L,2.66mol)缓慢加至搅拌的5-(8-甲氧基-3,4-二氢喹啉-1(2H)-基)甲基)噻吩-2-甲酸甲酯(281g,0.886mol)的THF(4L)溶液中。通过薄层色谱(TLC)检测反应完成。反应完成后,将反应混合物温热至20℃,加入饱和的氯化铵溶液。加入酒石酸钾钠溶液(1.3Kg在5L水中的溶液),搅拌过夜。分离有机层,用EtOAc(2×5L)萃取水相,然后合并有机层,用硫酸钠干燥合并的有机层,过滤除去固体,减压从滤液中除去溶剂,得到目标化合物,为白色固体(252g,98%)。ESI(m/z)290(M+H)。
制备7
(3S)-3-[4-[[5-[(8-甲氧基-3,4-二氢-2H-喹啉-1-基)甲基]-2-噻吩基]甲氧基]苯基]己-4-炔酸乙基酯
将三丁基膦(50%的EtOAc溶液,543ml,1.34mol)加至ADDP(282.5g,1.5eq)的THF(3L)溶液中,冷却混合物至内部温度为0℃,然后搅拌15分钟,用15min滴加(S)-3-(4-羟基苯基)己-4-炔酸乙基酯(173.5g,0.747mol)的THF(3L)溶液,然后滴加5-((8-甲氧基-3,4-二氢喹啉-1(2H)-基)甲基)噻吩-2-基)甲醇(216g,0747mol)的THF(5L)溶液,使反应混合物温热至室温并搅拌过夜,通过硅藻土过滤反应混合物,用乙酸乙酯(2L)洗涤滤饼,浓缩有机滤液至干,加入水(4L),用乙酸乙酯(3×5L)萃取,合并有机层,经硫酸钠干燥合并的有机层,过滤除去固体,减压浓缩,得到油状物,经硅胶快速色谱纯化残留物,用乙酸乙酯:己烷(6:94)洗脱,得到目标化合物(167g,44%)。ESI(m/z)504(M+H)。
实施例1
(3S)-3-[4-[[5-[(8-甲氧基-3,4-二氢-2H-喹啉-1-基)甲基]-2-噻吩基]甲氧基]苯基]己-4-炔酸
于室温将氢氧化钾(49.76g,0.88mol)的水(372ml)溶液加至(S)-3-(4-((5-8-甲氧基-3,4-二氢喹啉-1(2H)-基)甲基)噻吩-2-基)甲氧基)苯基)己-4-炔酸乙酯(149g,0.296mol)的EtOH(1.49L)溶液中,搅拌过夜,浓缩反应混合物至干,加入水(1.3L)中。用EtOAc(2×300ml)萃取得到的溶液并分离。用2N HCl将水层的pH调整至pH=6,收集得到的固体,从热MeOH(298ml,2体积)中重结晶,得到目标化合物(91g,65%)。ESI(m/z)476(M+H)。
GPR40:信息
采用Nagasumi最近报道的在胰岛素II启动子控制下的过度表达人GPR40基因的转基因小鼠进行的研究结果进一步支持了以下观点:GPR40在体内GDIS和血浆葡萄糖水平的调节中发挥了重要的作用,特别是在啮齿动物胰岛素抗性模型中。Nagasumi K等,在正常和糖尿病小鼠胰腺β-细胞中GPR40的过度表达增加了葡萄糖刺激的胰岛素分泌并且提高了葡萄糖耐受性(Overexpression of GPR40in pancreaticβ-cellsaugments glucose-stimulated insulin secretion and improves glucosetolerance in normal and diabetic mice),Diabetes58:1067-1076,2009。也可以参见:Briscoe CP等,中链和长链脂肪酸激活孤儿G蛋白-偶联受体GPR40(The orphan G protein-coupled receptor GPR40is activated bymedium and long chain fatty acids),Journal Biological Chemistry278:11303–11311,2003。这些发现进一步说明,特别期望开发用于治疗T2D的新的GPR40调节剂化合物。
钙通量的初步试验
基本上根据下述方法对实施例1化合物进行试验,其钙通量的初步试验的EC50值低于1μM。
该试验通过测定细胞内钙水平的增加而用于筛选化合物,当配体结合并激活GPR40时,导致细胞内钙水平增加,从而证明了GPR40激动剂的效能和疗效。采用于37℃和5%的CO2环境中在含有F12介质的杜氏改良的伊戈尔培养基中保存的过度表达人GPR40cDNA的HEK293细胞进行研究,该培养基以3:1的比例补充有10%的FBS和800μg/ml新霉素。在0.1%的不含脂肪酸的BSA存在下,在试验缓冲液(1×HBSS(Hank平衡盐溶液)和20mM HEPES(4-(2-羟基乙基)-1-哌嗪乙磺酸)中,采用钙4染料试验试剂盒(Molecular Devices)进行激动剂试验。采用荧光成像读板仪(FLIPR),以细胞内钙的增加测定受体的激活。采用超出基线的最大荧光改变测定激动剂的响应。通过浓度对相对荧光单位(RFUs)的绘图,采用Excel Fit软件(version4;IDBS)计算化合物的EC50(最大响应一半时的有效浓度)值。根据与天然配体亚油酸相比较的化合物所具有的最大响应计算效能百分比。当在该试验中进行测试时,实施例1的试验化合物的EC50为152±52nM,效能百分比为84±24%。这些结果进一步证明作为GPR40激动剂的该化合物具有令人满意的效能和功效。
葡萄糖依赖性胰岛素分泌(GDIS)试验
因为已知GPR40的激活能够导致胰岛素的分泌,该分泌依赖于高葡萄糖浓度,所以开发了两种不同的试验系统(胰岛瘤细胞系和主要啮齿动物胰岛(primary rodent islets))对在上述GPR40初步试验中已知能够增加细胞内钙的化合物进一步定性。
GDIS试验采用小鼠胰岛瘤细胞系Min6进行。Min6细胞于37℃和5%CO2环境中保存在杜氏改良的雅戈尔培养基(DMEM)中,该培养基含有非必要氨基酸、10%FBS、50mM2-巯基乙醇、1%青霉素和链霉素。在试验的当天,将细胞采用不含葡萄糖的200μl预热的Krebs-ringer缓冲液洗涤二次。添加含有2.5mM葡萄糖的200μL预热的Krebs-ringer缓冲液使得细胞挨饿,随后在高浓度葡萄糖(25mM)存在下加入化合物。将板于37℃温育2小时。在2h温育结束时,将上清液轻轻转移至微孔滤器板中,以200g(引力)旋转3分钟。采用Mercodia胰岛素评价试剂盒分析胰岛素。向Min6细胞中加入0.01、0.1、1.0和10.0μM浓度的实施例1化合物和25mM的葡萄糖,导致胰岛素分泌产生剂量依赖性的增加,1.0μM的剂量导致统计学上的显著性(P<0.01)增加(超出了25mM葡萄糖所获得的结果的2.68倍)。
采用Langerhans主要啮齿动物胰岛的GDIS试验也可以用于对示例化合物进行定性。通过胶原酶消化和Histopaque密度梯度分离(Histopaque density gradient separation)自雄性SD(Sprague Dawley)大鼠分离胰岛。将该胰岛在含有GlutaMAXn(L-谷氨酰胺的稳定的二肽形式(Invitrogen catalog#61870-010))的RPMI-1640介质中温育过夜,从而有助于通过分离过程回收。在48-孔板中,在EBSS(Earle平衡盐溶液)缓冲液中温育90分钟,测定胰岛素分泌。简单地说,将胰岛先在含有2.8mM葡萄糖的EBSS中预温育30分钟,然后将其转移至含有150μl2.8mM萄萄糖的48-孔板(4个胰岛/孔)中,在试验化合物存在或不存在下,用含有2.8或11.2mM葡萄糖的150μl的EBSS温育90分钟。在温育结束时除去孔中的缓冲液,采用大鼠胰岛素ELISA试剂盒(Mercodia)分析胰岛素水平。在该试验系统中,与采用11.2mM葡萄糖所获得的结果相比,1、3和10μM浓度的实施例1化合物与胰岛和11.2mM葡萄糖的温育产生了统计学上显著性(P<0.05)的胰岛素增加3.0uM(2.1倍)。因此,实施例1化合物在该试验条件下诱导了胰岛素的产生。
选择性试验:
过氧化物酶体增殖物-激活的受体(PPAR)α、δ和γ结合和功能试验:
因为已知GPR40能够通过配体与PPARγ的结合而激活,所以在PPARα、PPARδ和PPARγ的结合和功能试验中对示例化合物进行测试以确定实施例1化合物对GPR40的选择性。实施例1化合物与PPAR的结合基本上根据下述方法进行测试,10μM浓度的试验化合物的结合值大于1000nM,因此认为其对于PPAR活性是阴性的。
采用闪烁亲近分析(SPA)技术评价化合物与PPARα、δ和γ受体的结合亲和力。采用生物素化的低聚核苷酸正向重复序列2(direct repeat)(DR2)使得受体与硅酸钇链霉亲和素包被的SPA珠结合。将PPARα、δ、γ和维甲酸X受体(RXR)α在HEK293细胞中过度表达,在各个试验中采用含有特定受体的细胞裂解物。在含有10mM HEPES pH7.8、80mMKCl、0.5mM MgCl2、1mM DTT、0.5%3[(3-胆酰胺基丙基)二甲基铵基(ammonio)]-丙磺酸(CHAPS)和4.4%牛血清的结合缓冲液中,使得DR2在30分钟的时间内与SPA珠连接。将细胞裂解物在含有11个浓度的化合物之一的各个孔中温育,对于α和δ受体试验而言,每个孔中还含有放射标记的(~0.033.8μCi3H)PPARα/δ双重激动剂参比化合物(丁酸,2-[4-[2-[[[(2,4-二氟苯基)氨基]羰基]庚基氨基]乙基]苯氧基]-2-甲基,参见Burris T.P.等,molecular Pharmacology2005,67,(3)948-954);对于γ受体试验而言,每个孔中还含有放射标记的(~0.037.3μCi3H)PPARγ激动剂参比化合物(丙酸,2-甲基-2-[4-[3-[丙基[[5-(2-吡啶基)-2-噻吩基]磺酰基]氨基]丙基]苯氧基],参见Burris T.P.等,molecular Pharmacology2005,67,(3)948-954),在上述结合缓冲液中还含有110.3μg的钇SPA链霉亲和素包被的珠、0.126nM HD Oligo DR2和0.3μg PPARα与0.5μg RXRα、0.5μg PPARδ与0.5μg RXRα或1.25μg PPARγ与3.03μg RXRα以及14%甘油和5μg剪切的鲑鱼精子DNA。对于α和δ受体试验而言,在10,000nM未标记的PPARα/δ双重激动剂参比化合物存在下,对于γ受体试验而言,在PPARγ激动剂参比化合物存在下,测定非特异性结合。将结合反应物(在96孔[Costar3632]板中,每孔100μl)温育10h,采用Wallac Microbeta计数每分钟的分解(dpm)。采用4-参数逻辑方程,通过拟合11个点的浓度-响应曲线,测定化合物的受体结合亲和力(IC50)。采用Cheng-Prussoff方程自IC50测定Ki,通过饱和结合测定Kd。对于实施例1化合物,在三种PPAR结合试验中,即使采用高达10μM的浓度也未测定到结合。因此,本文中所述试验证明,实施例1化合物能够选择性地激活GPR40,同时避免了不希望出现的PPAR活性。但当采用高达30μM的浓度进行试验时,示例化合物对于PPAR同工型的相对IC50大于10μM,这支持了示例的化合物在避免PPAR的活性同时提供了希望的GPR40激活。
Gal4PPARα、Gal4PPARδ和PPARγ报告子功能试验也可以用于监测示例的化合物的选择性。源自非洲绿猴肾组织的CV1细胞采用多种受体转染,报告子质粒采用Fugene。对于Gal4PPARα和PPARδ试验,将含有酵母转录蛋白Gal4响应元件的5个串联副本的报告子质粒(通过腺病毒的主要晚期启动子驱动的克隆的萤火虫荧光素酶基因上游)与SimianVirus40(SV40)驱动的质粒一起转染,后者构成性地表达含有Gal4DNA结合域(DBD)和PPARα或PPARδ配体结合的杂交蛋白。对于PPARγ试验,编码PPARγ和RXRα(均通过巨细胞病毒(CMV)启动子驱动)的质粒与含有荧光素酶报告子cDNA(通过TK启动子驱动)的质粒和受体响应元件(2X PPRE)一起转染。将细胞在T225cm2细胞培养烧瓶中在含有5%的活性炭处理的FBS的DMEM介质中转染。温育过夜后,将转染细胞用胰蛋白酶消化;在含有5%的活性炭处理的FBS的DMEM介质中涂布在不透明的96孔盘中(15,000个细胞/孔),温育4h;将其暴露于以半对数稀释的0.17ηM-10μM的试验化合物或参比化合物中。与所述化合物一起温育24小时后,将细胞裂解,通过发光测定受体激活从而测定荧光素酶活性。将数据拟合为4参数-拟合对数模型以确定EC50值。通过相对于10μM适当的PPAR激动剂参比化合物所获得的最大刺激确定最大刺激百分比。在上述特定PPAR共转染(CTF)/功能试验中,当采用高达10μM浓度进行测定时,采用实施例1化合物没有测定到PPARα、PPARδ或PPARγ的功能激活。因此,该试验证明示例的化合物如希望的那样避免了PPAR激动剂活性。
体内疗效:腹膜内葡萄糖耐量试验(IPGTT)
为了测试示例的化合物在体内激活GPR40从而产生抗糖尿病疗效(即降低血浆葡萄糖水平)的能力,完成了4天腹膜内葡萄糖耐量试验(ipGTT)研究,试验化合物的数据如下所示。
雄性Balb/c(Albino小鼠)小鼠(8-9周龄)单个饲养,喂食常规啮齿类动物食物并随意饮水。将动物称重;根据体重随机分组;记录它们每天的体重。每天一次共三天,口服给予动物含有甲基纤维素和吐温-80的制剂。在第4天的前夜,动物禁食过夜。在第4天早上,在葡萄糖耐量试验(葡萄糖2g/kg,i.p.)之前单独口服给予动物化合物或载体。于葡萄糖负荷后0、3、7、15、30和60分钟,自尾部取血测定血糖水平。自t=0至t=60分钟的血糖波动曲线用于整合每次治疗的曲线下的面积(AUC)。通过相对于载体组的AUC的化合物的AUC数据计算血糖降低百分比。试验化合物以0.3、1.0、3.0、10或30mg/kg的剂量给药,阳性对照(3-[4-(2-甲基-苄基氧基)-苯基]-己-4-炔酸,参见WO2005086661.)以10mg/kg的剂量给药。与载体对照所获得的数据相比,实施例1化合物以3、10和30mg/kg剂量给药的15分钟时间点以及1.0、3.0、10和30mg/kg剂量给药的30分钟和60分钟时间点的葡萄糖水平显著降低。阳性对照的15、30和60分钟点的葡萄糖水平均有所降低。基于AUC计算的降低葡萄糖的该化合物的ED50为1.0mg/kg。该研究结果证明,实施例1化合物通过对GPR40的激活产生体内抗糖尿病疗效。
本发明的示例化合物可以根据本领域已知的习惯方法容易地配制成药用组合物,例如可以参考“雷明顿制药科学(Remington’s PharmaceuticalSciences)”,Gennaro编辑,Mack Publishing Co.Easton Pa.1990,例如片剂、固体或凝胶填充胶囊剂、散剂、悬浮液或溶液剂。所述组合物也可以包含一或多种可药用的载体、赋形剂和稀释剂。适合于此类制剂的可药用的载体、赋形剂和稀释剂的非限定性示例包括下列:淀粉、糖、甘露醇和二氧化硅衍生物;粘合剂,如羧甲基纤维素和其他纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;保湿剂,如甘油;崩解剂,如碳酸钙和碳酸氢钠;用于延迟溶出的成分,如石蜡;吸收促进剂,如季铵化合物;表面活性剂,如鲸蜡醇、单硬脂酸甘油酯;吸附载体,如高岭土和膨润土;润滑剂,如滑石粉、硬脂酸钙和硬脂酸镁以及固体聚乙二醇。
优选的药用组合物包括配制为用于口服给药的片剂或胶囊的那些组合物。这些片剂或胶囊可以包括有效量的用于治疗糖尿病、特别是II型糖尿病的本发明化合物。
将所述药用组合物以有效量给予患者以治疗糖尿病,更具体而言,为II型糖尿病。可以由健康顾问给予有效治疗患者的适当的量或剂量。
Claims (5)
1.化合物或其可药用的盐,该化合物为
2.药用组合物,该药用组合物含有权利要求1的化合物或其可药用的盐以及至少一种可药用的载体、稀释剂或赋形剂。
3.权利要求1的化合物或其可药用的盐在生产用于治疗糖尿病的药物中的用途。
4.式II的化合物:
其中R选自:C1-4烷基、C1-4卤代烷基、C3-6环烷基、C1-4烷基-C3-6环烷基、苯基和C1-5烷基苯基。
5.制备(3S)-3-[4-[[5-[(8-甲氧基-3,4-二氢-2H-喹啉-1-基)甲基]-2-噻吩基]甲氧基]苯基]己-4-炔酸或其可药用的盐的方法,该方法包括使式II的化合物脱酯:
其中:R选自:C1-4烷基、C1-4卤代烷基、C3-6环烷基、C1-4烷基-C3-6环烷基、苯基和C1-5烷基苯基,从而得到式I的化合物或其可药用的盐:
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Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10011609B2 (en) | 2013-11-14 | 2018-07-03 | Cadila Healthcare Limited | Heterocyclic compounds |
EP3076959B1 (en) | 2013-12-04 | 2018-07-04 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
WO2015119899A1 (en) | 2014-02-06 | 2015-08-13 | Merck Sharp & Dohme Corp. | Antidiabetic compounds |
CN109666027A (zh) * | 2017-10-17 | 2019-04-23 | 中国科学院上海药物研究所 | 一类酰胺结构的gpr40激动剂化合物及其用途 |
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PL3752501T3 (pl) | 2018-02-13 | 2023-08-21 | Gilead Sciences, Inc. | Inhibitory pd-1/pd-l1 |
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TWI751585B (zh) * | 2019-06-28 | 2022-01-01 | 美商美國禮來大藥廠 | 類升糖素肽1受體促效劑 |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1318058A (zh) * | 1998-09-17 | 2001-10-17 | 辉瑞产品公司 | 用作cetp抑制剂的4-羧基氨基-2-取代的-1,2,3,4-四氢喹啉 |
CN1318057A (zh) * | 1998-09-17 | 2001-10-17 | 辉瑞产品公司 | 用作cetp抑制剂的4-氨基取代的-2-取代的-1,2,3,4-四氢喹啉 |
CN1494542A (zh) * | 2001-03-27 | 2004-05-05 | ������˹ҩƷ��˾ | 作为尾加压素ii受体拮抗剂的1,2,3,4-四氢异喹啉的衍生物 |
US20060004012A1 (en) * | 2004-02-27 | 2006-01-05 | Michelle Akerman | Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders |
US20110092531A1 (en) * | 2009-10-15 | 2011-04-21 | Eli Lilly And Company | Novel Spiropiperidine Compounds |
WO2011066183A1 (en) * | 2009-11-30 | 2011-06-03 | Eli Lilly And Company | Novel spiropiperidine compounds |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2560111A1 (en) * | 2004-03-15 | 2005-09-22 | Takeda Pharmaceutical Company Limited | Aminophenylpropanoic acid derivative |
US7517910B2 (en) * | 2004-03-30 | 2009-04-14 | Takeda Pharmaceutical Company Limited | Alkoxyphenylpropanoic acid derivatives |
-
2012
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- 2012-08-09 SG SG11201401793PA patent/SG11201401793PA/en unknown
- 2012-08-09 KR KR1020147003634A patent/KR101570624B1/ko not_active IP Right Cessation
- 2012-08-09 CA CA2843474A patent/CA2843474C/en not_active Expired - Fee Related
- 2012-08-09 EA EA201490269A patent/EA022165B1/ru not_active IP Right Cessation
- 2012-08-09 PE PE2014000218A patent/PE20140831A1/es not_active Application Discontinuation
- 2012-08-09 MX MX2014001832A patent/MX2014001832A/es unknown
- 2012-08-09 WO PCT/US2012/050051 patent/WO2013025424A1/en active Application Filing
- 2012-08-09 JP JP2014526078A patent/JP5903162B2/ja active Active
- 2012-08-09 BR BR112014003079A patent/BR112014003079A2/pt not_active IP Right Cessation
- 2012-08-09 EP EP12748334.5A patent/EP2744806B1/en active Active
- 2012-08-09 CN CN201280036072.0A patent/CN103687856B/zh not_active Expired - Fee Related
- 2012-08-09 UA UAA201401073A patent/UA110983C2/uk unknown
- 2012-08-09 ES ES12748334.5T patent/ES2578165T3/es active Active
- 2012-08-09 AU AU2012295372A patent/AU2012295372A1/en not_active Abandoned
-
2013
- 2013-01-30 CR CR20140052A patent/CR20140052A/es unknown
-
2014
- 2014-01-23 IL IL230635A patent/IL230635A/en not_active IP Right Cessation
- 2014-01-28 DO DO2014000018A patent/DOP2014000018A/es unknown
- 2014-01-29 ZA ZA2014/00705A patent/ZA201400705B/en unknown
- 2014-01-30 IN IN191MUN2014 patent/IN2014MN00191A/en unknown
- 2014-02-10 TN TNP2014000058A patent/TN2014000058A1/en unknown
- 2014-02-13 CL CL2014000357A patent/CL2014000357A1/es unknown
- 2014-02-13 GT GT201400022A patent/GT201400022A/es unknown
- 2014-02-13 MA MA36755A patent/MA35351B1/fr unknown
- 2014-02-14 CO CO14032116A patent/CO6880069A2/es active IP Right Grant
- 2014-02-17 EC ECSP14013211 patent/ECSP14013211A/es unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1318058A (zh) * | 1998-09-17 | 2001-10-17 | 辉瑞产品公司 | 用作cetp抑制剂的4-羧基氨基-2-取代的-1,2,3,4-四氢喹啉 |
CN1318057A (zh) * | 1998-09-17 | 2001-10-17 | 辉瑞产品公司 | 用作cetp抑制剂的4-氨基取代的-2-取代的-1,2,3,4-四氢喹啉 |
CN1494542A (zh) * | 2001-03-27 | 2004-05-05 | ������˹ҩƷ��˾ | 作为尾加压素ii受体拮抗剂的1,2,3,4-四氢异喹啉的衍生物 |
US20060004012A1 (en) * | 2004-02-27 | 2006-01-05 | Michelle Akerman | Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders |
US20110092531A1 (en) * | 2009-10-15 | 2011-04-21 | Eli Lilly And Company | Novel Spiropiperidine Compounds |
WO2011066183A1 (en) * | 2009-11-30 | 2011-06-03 | Eli Lilly And Company | Novel spiropiperidine compounds |
Non-Patent Citations (1)
Title |
---|
柴茜,等.基于四氢喹啉酸骈环戊烯骨架的蛋白酪氨酸磷酸酶1B抑制剂的设计、合成及构效关系.《高等学校化学学报》.2011,第32卷(第2期), * |
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