CN101711238A - 1,3-二羟基取代的苯基酰胺葡糖激酶激活剂 - Google Patents
1,3-二羟基取代的苯基酰胺葡糖激酶激活剂 Download PDFInfo
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- CN101711238A CN101711238A CN200880019467A CN200880019467A CN101711238A CN 101711238 A CN101711238 A CN 101711238A CN 200880019467 A CN200880019467 A CN 200880019467A CN 200880019467 A CN200880019467 A CN 200880019467A CN 101711238 A CN101711238 A CN 101711238A
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Abstract
本发明提供为葡糖激酶激活剂并因而用于治疗糖尿病及相关疾病的化合物或其药学上可接受的盐,所述化合物具有以下结构,其中环中的表示一个或两个双键;R1为烷基、芳基、芳基烷基、杂芳基,或杂芳基烷基;R2为烷基、芳基、芳基烷基、杂芳基,或杂芳基烷基;R5如本文所定义;Z为O、S、S(O)、S(O)2或NR5a;X为S、O、N、NR3或CR3;Y为NCR4或NR4;R3、R4和R5如本文所定义;R8为芳基、杂芳基、-PO(OR9)(OR10)、-PO(OR9)R10或-P(O)(R9)R10(其中R9和R10如本文所定义);R6和R7独立为H、卤素或烷基;m是0或1;和n为0-3。本发明还提供采用以上化合物治疗糖尿病和相关疾病的方法。
Description
发明领域
本发明涉及为葡糖激酶激活剂的新的化合物,并因而用于治疗糖尿病,以及涉及使用这样的化合物治疗糖尿病,尤其是II型糖尿病的方法。
发明背景
葡糖激酶(GK)(主要发现于胰腺β-细胞和肝实质细胞中)催化葡萄糖向葡萄糖-6-磷酸的转化,这是葡萄糖代谢的第一步。葡糖激酶也是胰腺β-细胞和肝实质细胞中葡萄糖代谢的速率控制的酶,其在整个身体的葡萄糖体内平衡方面起重要作用。
Liag,Y.et al.(Biochem.J.,309:167-173(1995))报道了这样的发现,即青年II型(成熟-发病)糖尿病(MODY-2)由葡糖激酶基因中的功能突变的丧失引起,这提示葡糖激酶也作为人体中的葡萄糖感受器发挥功能。因此,激活葡糖激酶并因而增加葡糖激酶感受器系统的敏感性,由此引起胰岛素分泌增加的化合物将用于治疗高血糖症和II型糖尿病。
已证实葡糖激酶激活剂有效增强:1)葡萄糖对从离体大鼠和人的胰岛释放的胰岛素的作用,和2)在离体培养的大鼠胰岛中的胰岛葡糖激酶的葡萄糖感应(如,Matschinsky,F.M.et al.,糖尿病,55:1(2006),和Glucokinase and Glycemic Disease,from Basics to NovelTherapeutics,由Karger,Matschinsky,F.M.et al.,eds.,Ch.6,pp.360-378(2004)发表)。在糖尿病动物模型研究中,已证实葡糖激酶激活剂在胰腺夹(clamp)研究中刺激胰岛素释放,增强糖原合成和减少肝葡萄糖产生。重要的是,已证实葡糖激酶激活剂在2型糖尿病的不同的标准动物模型,如ob/ob小鼠、db/db小鼠和Zucker的急性单次剂量研究中,剂量依赖地降低血糖水平并且还在口服葡萄糖耐量试验中有效改善两种正常的C57/BL6J和ob/ob小鼠中的葡萄糖波动(excursion)(如,在Glucokinase and Glycemic Disease,from Basics toNovel Therapeutics,由Karger,Matschinsky,F.M.et al.,eds.,Ch.6,pp.360-378(2004)发表,及Fyfe,M.C.et al.,Diabetologia,50:1277(2007)中)。
也已证实葡糖激酶激活剂在慢性II型糖尿病动物模型中的抗糖尿病的疗效。例如,在ob/ob小鼠的9天研究中,葡糖激酶激活剂改善整个葡萄糖的分布模式,同时在口服葡萄糖耐量试验研究中自始至终显示出可比较的抗高血糖药效(Fyfe,M.C.et al.,Diabetologia,50:1277(2007))。在另一个例子中,在40-周的慢性研究中,葡糖激酶激活剂防止对葡萄糖不耐受的食物-诱导的肥胖小鼠中高血糖症的发展。用葡糖激酶激活剂治疗的食物-诱导的肥胖小鼠在口服葡萄糖耐量试验的研究结束时显示出相对于对照组的葡萄糖波动的显著改进(Glucokinase and Glycemic Disease,from Basics to Novel Therapeutics,由Karger,Matschinsky,F.M.et al.,eds.,Ch.6,pp.360-378(2004)发表)。
发明概述
依据本发明的一个方面,提供具有结构I的化合物、其立体异构体、其前药酯,或其药学上可接受的盐其中环中的表示一个或两个双键;R1选自烷基,芳基,芳基烷基,杂芳基,或杂芳基烷基;R2选自烷基,芳基,芳基烷基,杂芳基,或杂芳基烷基;X选自S,O,N,NR3,或CR3;Y选自N,CR4,或NR4;Z选自O,S,S(O),S(O)2,或NR5a;R3、R4和R5为相同或不同的且独立选自H,卤素,烷基,芳基,杂芳基,芳基烷基,或杂芳基烷基;然而,当X为NR3或Y为NR4时,R3和R4不是卤素;R5a选自H,烷基,或芳基;R6和R7为相同或不同的且独立选自氢,卤素(优选F),或烷基;R8选自芳基,杂芳基,-PO(OR9)(OR10),-PO(OR9)R10,或-PO(R9)R10;R9和R10为相同或不同的且独立选自氢和烷基;m是0或1;n是0、1、2或3;前提是当Z为O、S、S(O)或S(O)2时,则R8必须被选自以下的取代基取代 5)烷氧基;6)四唑基;7)-SO2NRiRj;8)CN;11)卤代(如Cl、F、CF3);13)烷基;其中Rf和Rg独立选自H、烷基和芳基;Rh为烷基或芳基;和Ri和Rj独立选自H、烷基和芳基,前提是Ri和Rj中的至少一个不是H。
应该理解,当Z为NR5a时,R8基团可以被以上1)至15)基团中的任何基团以及本文公开的其它取代基取代。
在本发明的更优选的式I和Ia化合物中R4、R5、R6和R7各自为H;R8为苯基或杂芳基(如2-吡啶基、3-吡啶基,或2,4-嘧啶基),其各自被选自以下的一个或两个基团取代:CN、烷基、-CONRfRg、烷氧基、四唑基和SO2NRiRj,其中Z为O,R8可以如上被取代和/或被CO2H、CO2烷基、卤素或取代;R1为烷氧基烷基、羟基烷基、烷基、杂芳基或卤代杂芳基;R2为芳基、烷基磺酰基芳基、烷基、芳基烷基、杂环基羰基杂芳基或烷基磺酰基杂芳基;和Z为O、S或SO2。
在甚至更优选的本发明化合物中R1为烷氧基烷基、羟基烷基或烷基;R2为或杂环基羰基杂芳基;Z为S、O或SO2;为CH2或键;和R8为杂芳基如2-吡啶基、3-吡啶基或2,4-嘧啶基,或被一个或两个选自以下基团取代:CN、-CONRfRg、烷氧基、四唑基、烷基、卤代、CF3和-SO2NRiRj;其中Z为O,R8可以如上被取代和/或被CO2烷基、CO2H或卤素取代。
在甚至更优选的本发明的式Ia化合物中R1为CH3OCH2CH(CH3)-、HOCH2CH(CH3)-、i-C3H7、CH3、 R2为i-C3H7、CH3、 R3为H;R4为H;R5为H;X为S;Y为C;m为0;Z为O;n是0或1;为CH2或键;和R8为
本发明的化合物激活或增强葡糖激酶的活性。因此,本发明的化合物可用于治疗与葡糖激酶缺乏相关的多发性疾病或紊乱,如糖尿病及相关病症、与糖尿病相关的微血管并发症、与糖尿病相关的大血管并发症、心血管疾病、代谢综合征及其各组分病症(componentconditions),和其它疾病。可依据本发明预防、抑制或治疗与葡糖激酶活性缺乏相关的疾病或紊乱的实例,包括但不限于,糖尿病、高血糖症、受损的葡萄糖耐受性、胰岛素抗性、高胰岛素血症、视网膜病、神经病、肾病、延迟的伤口愈合、动脉粥样硬化及其后遗症、异常的心脏功能、心肌缺血、中风、代谢综合征、高血压、肥胖症、异常血脂症、高酯血症、高甘油三酯血症、高胆固醇血症、低HDL、高LDL、非心脏缺血、感染、癌症、血管再狭窄、胰腺炎、神经退行性疾病、脂质紊乱、认知功能障碍和痴呆、骨病、HIV蛋白酶相关脂质代谢障碍和青光眼。
本发明提供式I化合物、使用这样的化合物的药用组合物,和使用这样的化合物的方法,特别是,本发明提供含有治疗有效量的式I化合物(单独或与药学上可接受的载体组合)的药用组合物。
此外,依据本发明,提供预防、抑制或治疗与葡糖激酶活性缺乏相关的如上文和下文定义的疾病或紊乱的进展或发病,其中治疗有效量的式I化合物被给予哺乳动物,即有需要的人、患者。
本发明化合物可单独、与其它本发明的化合物组合,或与一种或多种其它治疗剂组合使用。
此外,本发明提供预防、抑制或治疗上文和下文定义的疾病的方法,其中式I化合物和另一种式I化合物和/或至少一种其它类型的治疗剂的治疗有效量的组合被给予哺乳动物,即有需要的人、患者。
在另一个实施方案中,本发明的化合物选自在实施例中说明的化合物。
在另一个实施方案中,本发明涉及包含治疗有效量的本发明的化合物(单独或任选与药学上可接受的载体和/或一种或多种其它药物组合)的药用组合物。
在另一个实施方案中,本发明涉及增强葡糖激酶活性的方法,其包括给予有需要的哺乳动物患者,例如,人类患者治疗有效量的本发明化合物(单独或任选与另一种本发明的化合物和/或至少一种其它类型的治疗剂组合)的步骤。
在另一个实施方案中,本发明涉及预防、抑制或治疗与葡糖激酶活性缺乏相关的疾病或紊乱的进展或发病的方法,其包括给予需要预防、抑制或治疗的哺乳动物患者,例如,人类患者治疗有效量的本发明的化合物(单独或任选与另一种本发明的化合物和/或至少一种其它类型的治疗剂组合)的步骤。
可依据本发明预防、抑制或治疗与葡糖激酶活性缺乏相关的疾病或紊乱的实例,包括但不限于上文描述的那些疾病或紊乱。
在另一个实施方案中,本发明涉及预防、抑制或治疗糖尿病、高血糖症、肥胖症、异常血脂症、高血压和认知功能障碍的进展或发病的方法,其包括给予需要预防、抑制或治疗的哺乳动物患者,例如,人类患者治疗有效量的本发明的化合物(单独或任选与另一种本发明的化合物和/或至少一种其它类型的治疗剂组合)的步骤。
在还一个实施方案中,本发明涉及预防、抑制或治疗糖尿病的进展或发病的方法,其包括给予需要预防、抑制或治疗的哺乳动物患者,例如,人类患者治疗有效量的本发明的化合物(单独或任选与另一种本发明的化合物和/或至少一种其它类型的治疗剂组合)的步骤。
在又一个实施方案中,本发明涉及预防、抑制或治疗高血糖症的进展或发病的方法,其包括给予需要预防、抑制或治疗的哺乳动物患者,例如,人类患者治疗有效量的本发明的化合物(单独或任选与另一种本发明的化合物和/或至少一种其它类型的治疗剂组合)的步骤。
在另一个实施方案中,本发明涉及预防、抑制或治疗肥胖症的进展或发病的方法,其包括给予需要预防、抑制或治疗的哺乳动物患者,例如,人类患者治疗有效量的本发明的化合物(单独或任选与另一种本发明的化合物和/或至少一种其它类型的治疗剂组合)的步骤。
在一个实施方案中,本发明涉及预防、抑制或治疗异常血脂症的进展或发病的方法,其包括给予需要预防、抑制或治疗的哺乳动物患者,例如,人类患者治疗有效量的本发明的化合物(单独或任选与另一种本发明的化合物和/或至少一种其它类型的治疗剂组合)的步骤。
发明详述
在此描述的化合物可具有不对称中心。含有不对称取代的原子的本发明的化合物可以以光学活性或外消旋形式分离。本领域熟知如何制备光学活性形式,如通过拆分外消旋形式或从光学活性的起始原料合成。烯烃、C=N双键等的许多几何异构体也可存在于在此描述的化合物中,且所有此类稳定的异构体均包括在本发明中。本发明化合物的顺式和反式几何异构体均被描述且可作为异构体的混合物或作为分离的异构形式被分离。意欲包括所有的手性、非对映体的、外消旋形式和所有的几何异构形式的结构,除非特别指明具体的立体化学或异构形式。
本文所用的术语“取代的”,意指任何指定原子或环上的一个或多个氢被选自指定的具体替代,前提是不超过指定原子的正常化学价,且取代产生稳定的化合物。当取代基为酮基(即,=O)时,则该原子上的2个氢被替代。
当任何变量(如,Ra)在化合物的任何组成或结构式中出现不止一次时,它在每次出现时的定义独立于其在另外每一次出现时的定义。因此,例如,如果表示基团被0-2个Ra取代时,则所述基团可任选被至多两个Ra基团取代,且Ra在每次出现时独立选自Ra的定义。而且,取代基和/或变量的组合只有在这样的组合产生稳定的化合物时才是允许的。
当显示连接取代基的键交叉连接于环中的两个原子的键时,则这样的取代基可以键结在环的任何原子上。当列出一取代基,而未指明该取代基连接于给定结构式的化合物的其余部分所经过的原子时,则这样的取代基可通过该取代基的任何原子连接。取代基和/或变量的组合只有在这样的组合产生稳定的化合物时才是允许的。
除非另外指明,术语“低级烷基”、“烷基”或“烷(alk)”在本文单独或作为另一个基团的一部分使用时,包括在正链上含有1-20个碳,优选1-10个碳,更优选1-8个碳的直链和支链烃二者,如甲基、乙基、丙基、异丙基、丁基、叔-丁基、异丁基、戊基、己基、异己基、庚基、4,4-二甲基戊基、辛基、2,2,4-三甲基-戊基、壬基、癸基、十一烷基、十二烷基、其各种支链异构体等;这样的基团可任选包括1-4个取代基如卤代,例如F、Br、Cl或I,或CF3、烷基、烷氧基、芳基、芳基氧基、芳基(芳基)或二芳基、芳基烷基、芳基烷基氧基、链烯基、环烷基、环烷基烷基、环烷基烷基氧基、氨基、羟基、羟基烷基、酰基、杂芳基、杂芳基氧基、杂芳基烷基、杂芳基烷氧基、芳基氧基烷基、烷硫基、芳基烷硫基、芳基氧基芳基、烷基酰氨基、烷酰基氨基、芳基羰基氨基、硝基、氰基、硫羟基、卤代烷基、三卤代烷基,和/或烷硫基,以及(=O),ORa、SRa、(=S)、-NRaRb、-N(烷基)3 +、-NRaSO2、-NRaSO2Rc、-SO2Rc-SO2NRaRb、-SO2NRaC(=O)Rb、SO3H、-PO(OH)2、-C(=O)Ra、-CO2Ra、-C(=O)NRaRb、-C(=O)(C1-4亚烷基)NRaRb、-C(=O)NRa(SO2)Rb、-CO2(C1-4亚烷基)NRaRb、-NRaC(=O)Rb、-NRaCO2Rb、-NRa(C1-4亚烷基)CO2Rb、=N-OH、=N-O-烷基,其中Ra和Rb为相同或不同的且独立选自氢、烷基、链烯基、CO2H、CO2(烷基)、C3-7环烷基、苯基、苄基、苯基乙基、萘基、4-7元杂环,或5-6元杂芳基,或当连接于相同的氮原子时,可结合形成杂环基或杂芳基,和Rc选自与Ra和Rb相同的基团,但不是氢。每个Ra和Rb基团不是氢,和每个Rc基团任选具有连接于Ra、Rb和/或Rc的任何可利用的碳或氮原子的至多3个另外的取代基时,所述取代基是相同的或不同的且独立选自以下的基团:(C1-6)烷基、(C2-6)链烯基、羟基、卤素,氰基、硝基、CF3、O(C1-6烷基)、OCF3、C(=O)H、C(=O)(C1-6烷基)、CO2H、CO2(C1-6烷基)、NHCO2(C1-6烷基)、-S(C1-6烷基)、-NH2、NH(C1-6烷基)、N(C1-6烷基)2、N(CH3)3 +、SO2(C1-6烷基)、C(=O)(C1-4亚烷基)NH2、C(=O)(C1-4亚烷基)NH(烷基)、C(=O)(C1-4亚烷基)N(C1-4烷基)2、C3-7环烷基、苯基、苄基、苯基乙基、苯基氧基、苄基氧基、萘基、4-7元杂环基,或5-6元杂芳基。当取代的烷基被芳基、杂环基、环烷基,或杂芳基取代时,所述有环系统如在下文中定义并因而可具有0、1、2或3个也如在下文中定义的取代基。
除非另外指明,本文所用的术语“环烷基”单独或作为另一个基团的一部分时,包括饱和的或部分不饱和(含有1或2个双键)的环状烃基,其含有1-3个环,包括单环烷基、双环烷基(或双环烷基)和三环烷基,含有形成环的总共3-20个碳,优选形成环的3-10个碳,且其可与1或2个如对芳基定义的芳族环稠合,所述环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基和环十二烷基、环己烯基、这些基团中的任何一个可任选被1-4个取代基取代,所述取代基为例如卤素、烷基、烷氧基、羟基、芳基、芳基氧基、芳基烷基、环烷基、烷基酰氨基、烷酰基氨基、氧代、酰基、芳基羰基氨基、氨基、硝基、氰基、硫羟基和/或烷硫基,和/或对烷基的任何取代基。
除非另外指明,本文所用的术语“低级链烯基”或“链烯基”自身或作为另一个基团的一部分时,指在正链上具有2-20个碳,优选2-12个碳,和更优选1-8个碳的直链或支链基团,其在正链上包括1-6个双键,如乙烯基、2-丙烯基、3-丁烯基、2-丁烯基、4-戊烯基、3-戊烯基、2-己烯基、3-己烯基、2-庚烯基、3-庚烯基、4-庚烯基、3-辛烯基、3-壬烯基、4-癸烯基、3-十一碳烯基、4-十二碳烯基、4,8,12-十四碳三烯基等,且其可任选被1-4个以下的取代基取代:即,卤素、卤代烷基、烷基、烷氧基、链烯基、炔基、芳基、芳基烷基、环烷基、氨基、羟基、杂芳基、环杂烷基、烷酰基氨基、烷基酰氨基、芳基羰基-氨基、硝基、氰基、硫羟基、烷硫基,和/或本文描述的任何烷基取代基。
除非另外指明,本文所用的术语“低级炔基”或“炔基”自身或作为另一个基团的一部分时,指在正链上具有2-20个碳,优选2-12个碳且更优选2-8个碳的直链或支链基团,其在正链上包括1个三键,如2-丙炔基、3-丁炔基、2-丁炔基、4-戊炔基、3-戊炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基、4-癸炔基、3-十一碳炔基、4-十二碳炔基等,且其可任选被1-4个以下的取代基取代:即,卤素、卤代烷基、烷基、烷氧基、链烯基、炔基、芳基、芳基烷基、环烷基、氨基、杂芳基、环杂烷基、羟基、烷酰基氨基、烷基酰氨基、芳基羰基氨基、硝基、氰基、硫羟基和/或烷硫基,和/或本文描述的任何烷基取代基。
当如上定义的烷基具有在两个不同的碳原子上连接于其它基团的单键时,它们被称为“亚烷基”基团且可任选如上对“烷基”的定义那样被取代。
当如上定义的链烯基和当如上定义的炔基分别具有连接在两个不同的碳原子上的的单键时,它们被分别称为“亚链烯基”和“亚炔基”,且可任选如上对“链烯基”和“炔基”的定义那样被取代。
本文所用的术语“卤素”或“卤代”单独或作为另一个基团的一部分时,指氯、溴、氟和碘以及CF3,优选氯或氟。
除非另外指明,本文所用的术语“芳基”单独或作为另一个基团的一部分时,指在环部分含有6-10个碳的单环和双环芳族基团(如苯基、联苯基或萘基,包括1-萘基和2-萘基)且可任选包括1-3个稠合于碳环或杂环(如芳基、环烷基、杂芳基或环杂烷基环)的另外的环例如芳基基团可通过可利用的碳原子任选被1、2或3个取代基取代,所述取代基有例如,氢、卤代、卤代烷基、烷基、卤代烷基、烷氧基、卤代烷氧基、链烯基、三氟甲基、三氟甲氧基、炔基、环烷基-烷基、环烷基、环杂烷基、环杂烷基烷基、芳基、杂芳基、芳基烷基、芳基氧基、芳基氧基烷基、芳基烷氧基、芳硫基、芳基偶氮基、杂芳基烷基、杂芳基链烯基、杂芳基杂芳基、杂芳基氧基、羟基、硝基、氰基、氨基、取代的氨基(其中氨基包括1或2个取代基(所述取代基为烷基、芳基,或在定义中提及的任何其它芳基化合物))、硫羟基、烷硫基、芳硫基、杂芳硫基、芳硫基烷基、烷氧基芳硫基、烷基羰基、芳基羰基、烷基-氨基羰基、芳基氨基羰基、烷氧基羰基、氨基羰基、烷基羰基氧基、芳基羰基氧基、烷基羰基氨基、芳基羰基氨基、芳基亚硫酰基、芳基亚硫酰基烷基、芳基磺酰基氨基,或芳基砜-氨基羰基,ORa、SRa、(=S)、-NRaRb、-N(烷基)3 +、-NRaSO2、-NRaSO2Rc、-SO2Rc、-SO2NRaRb、-SO2NRaC(=O)Rb、SO3H、-PO(OH)2、-C(=O)Ra、-CO2Ra、-C(=O)NRaRb、-C(=O)(C1-4亚烷基)NRaRb、-C(=O)NRa(SO2)Rb、-CO2(C1-4亚烷基)NRaRb、-NRaC(=O)Rb、-NRaCO2Rb、-NRa(C1-4亚烷基)CO2Rb,其中Ra、Rb和Rc如以上对取代的烷基的定义,且还依次如上所述被任选取代。另外,两个连接于芳基,特别是苯基的取代基,可结合形成另外的环如稠环或螺环,如环戊基或环己基,或稠合的杂环基或杂芳基。当芳基被另外的环取代(或具有第二个稠合于其上的环)时,所述环依次被一个或两个以下基团任选取代:(C1-4)烷基、(C2-4)链烯基、卤素、羟基、氰基、硝基、CF3、O(C1-4烷基)、OCF3、C(=O)H、C(=O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、NHCO2(C1-4烷基)、-S(C1-4烷基)、-NH2、NH(C1-4烷基)、N(C1-4烷基)2、N(C1-4烷基)3 +、SO2(C1-4烷基)、C(=O)(C1-4亚烷基)NH2、C(=O)(C1-4亚烷基)NH(烷基)和/或C(=O)(C1-4亚烷基)N(C1-4烷基)2,和/或本文描述的任何烷基取代基。
除非另外指明,本文所用的术语“低级烷氧基”、“烷氧基”、“芳基氧基”或“芳烷氧基”单独或作为另一个基团的一部分时,包括连接于氧原子的任何上述烷基、芳烷基或芳基基团。
除非另外指明,本文所用的术语“氨基”单独或作为另一个基团的一部分时,指可被一个或两个取代基取代的氨基,所述取代基可以是相同的或不同的,如烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、环杂烷基、环杂烷基烷基、环烷基、环烷基烷基、卤代烷基、羟基烷基、烷氧基烷基,或硫代烷基(thioalkyl)。这些取代基可被羧酸和/或任何R3基团或如上对R3定义的取代基进一步取代。此外,氨基取代基可以与它们连接的氮原子结合在一起,形成1-吡咯烷基、1-哌啶基、1-氮杂基、4-吗啉基、4-硫吗啉基、1-哌嗪基、4-烷基-1-哌嗪基、4-芳基烷基-1-哌嗪基、4-二芳基烷基-1-哌嗪基、1-吡咯烷基、1-哌啶基或1-氮杂基,这些基团任选被烷基、烷氧基、烷硫基、卤代、三氟甲基或羟基取代。
除非另外指明,本文所用的术语“低级烷硫基”、“烷硫基”、“芳硫基”或“芳烷硫基”单独或作为另一个基团的一部分时,包括连接于硫原子的任何上述烷基、芳烷基或芳基基团。
除非另外指明,本文所用的术语“低级烷基氨基”、“烷基氨基”、“芳基氨基”或“芳基烷基氨基”单独或作为另一个基团的一部分时,包括连接于氮原子的任何上述烷基、芳基或芳基烷基基团。
术语“酰基”单独或作为另一个基团的一部分时,指连接于有机基团的羰基,更特别基团C(=O)Re,以及是连接于有机基团的二价基团-C(=O)-或-C(=O)Re-。基团Re可选自如在本文定义的烷基、链烯基、炔基、氨基烷基、取代的烷基、取代的链烯基或取代的炔基,或在适当时的相应的二价基团,如亚烷基、亚链烯基等。
术语“杂环”或“杂环基”或“杂环的”或“环杂烷基”指取代的和未取代的非-芳族3-7元单环基团、7-11元双环基团,和10-15元三环基团,其中至少一个环具有至少一个杂原子(O、S或N)(也称为环杂烷基或杂环烷基)。含有杂原子的杂环基团的每个环可含有一个或两个氧或硫原子和/或1-4个氮原子,前提是每个环的杂原子总数为4个或更少,且进一步的前提是所述环含有至少一个碳原子。形成稠合环的二环和三环基团可只含有碳原子且可以是饱和的、部分饱和的或不饱和的。氮和硫原子可任选被氧化和氮原子可任选被季铵化。杂环基团可连接于任何可利用的氮或碳原子上。杂环基环可含有0、1、2或3个取代基,所述取代基选自卤素、三氟甲基、三氟甲氧基、烷基、取代的烷基、链烯基、取代的链烯基、炔基、硝基、氰基、氧代(=O),ORa、SRa、(=S)、-NRaRb、-N(烷基)3 +、-NRaSO2、-NRaSO2Rc、-SO2Rc-SO2NRaRb、-SO2NRaC(=O)Rb、SO3H、-PO(OH)2、-C(=O)Ra、-CO2Ra、-C(=O)NRaRb、-C(=O)(C1-4亚烷基)NRaRb、-C(=O)NRa(SO2)Rb、-CO2(C1-4亚烷基)NRaRb、-NRaC(=O)Rb、-NRaCO2Rb、-NRa(C1-4亚烷基)CO2Rb、=N-OH、=N-O-烷基、芳基、环烷基、杂环基和/或杂芳基,其中Ra、Rb和Rc如以上对取代的烷基的定义,且也依次如上所述任选被取代。当杂环基被另外的环取代时,所述环依次被一个或两个以下基团任选取代:(C1-4)烷基、(C2-4)链烯基、卤素、羟基、氰基、硝基、CF3、O(C1-4烷基)、OCF3、C(=O)H、C(=O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、NHCO2(C1-4烷基)、-S(C1-4烷基)、-NH2、NH(C1-4烷基)、N(C1-4烷基)2、N(C1-4烷基)3 +、SO2(C1-4烷基)、C(=O)(C1-4亚烷基)NH2、C(=O)(C1-4亚烷基)NH(烷基)和/或C(=O)(C1-4亚烷基)N(C1-4烷基)2。
示例性单环基团包括氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、咪唑啉基、噁唑啉基,异噁唑啉基、噻唑烷基,异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、氮杂基、4-哌啶酮基、四氢吡喃基、吗啉基、硫吗啉基、硫吗啉基亚砜、硫吗啉基砜、1,3-二氧戊环和四氢-1,1-二氧代噻吩基等。示例性双环杂环基团包括奎宁环基。
术语“杂芳基”单独或作为另一个基团的一部分时,指取代的和未取代的芳族5或6元单环基团、9或10元双环基团和11-14元三环基团,所述环的至少一个环具有至少一个杂原子(O、S或N)。含有杂原子的杂芳基基团的每个环含有一个或两个氧或硫原子和/或1-4个氮原子,前提是每个环的杂原子总数为4个或更少且每个环具有至少一个碳原子。形成稠合环的二环和三环基团可只含有碳原子且可以是饱和的、部分饱和的或不饱和的,且可包括芳基、环烷基、杂芳基或环杂烷基基团。氮和硫原子可任选被氧化和氮原子可任选被季铵化。为双环或三环的杂芳基必须包含至少一个完全芳族的环,但其它稠合的环可以是芳族或非-芳族的。杂芳基可连接于任何环的任何可利用的氮或碳原子上。杂芳环系统可含有0、1、2或3个取代基,所述取代基可以是对烷基描述的任何取代基且可选自卤素、三氟甲基、三氟甲氧基、烷基、取代的烷基、链烯基、取代的链烯基、炔基、硝基、氰基,ORa、SRa、(=S)、-NRaRb、-N(烷基)3 +、-NRaSO2、-NRaSO2Rc、-SO2Rc-SO2NRaRb、-SO2NRaC(=O)Rb、SO3H、-PO(OH)2、-C(=O)Ra、-CO2Ra、-C(=O)NRaRb、-C(=O)(C1-4亚烷基)NRaRb、-C(=O)NRa(SO2)Rb、-CO2(C1-4亚烷基)NRaRb、-NRaC(=O)Rb、-NRaCO2Rb、-NRa(C1-4亚烷基)CO2Rb、芳基、环烷基、杂环基和/或杂芳基,其中Ra、Rb和Rc如以上对取代的烷基的定义,且也依次如上所述任选被取代。当杂芳基被另外的环取代时,所述环依次被一个或两个以下的基团任选取代:(C1-4)烷基、(C2-4)链烯基、卤素、羟基、氰基、硝基、CF3、O(C1-4烷基)、OCF3、C(=O)H、C(=O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、NHCO2(C1-4烷基)、-S(C1-4烷基)、-NH2、NH(C1-4烷基)、N(C1-4烷基)2、N(C1-4烷基)3 +、SO2(C1-4烷基)、C(=O)(C1-4亚烷基)NH2、C(=O)(C1-4亚烷基)NH(烷基)和/或C(=O)(C1-4亚烷基)N(C1-4烷基)2.
示例性单环杂芳基包括吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基,异噁唑基、噻唑基、噻二唑基,异噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基等。
示例性双环杂芳基包括吲哚基、苯并噻唑基、苯并间二氧杂环戊烯基、苯并噁唑基、苯并噻吩基、喹啉基、四氢异喹啉基,异喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、色酮基、香豆素基(coumarinyl)、苯并吡喃基、肉啉基、喹喔啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基、二氢异吲哚基、四氢喹啉基等。
示例性三环杂芳基基团包括咔唑基、苯并吲哚基、菲咯啉基、吖啶基、菲啶基、呫吨基等。
本文所用的术语“杂环基烷基”或“杂环烷基”或“环杂烷基烷基”单独或作为另一个基团的一部分时,指通过C原子或杂原子连接于烷基链上的如上定义的杂环基。
本文所用的术语“杂芳基烷基”或“杂芳基链烯基”单独或作为另一个基团的一部分时,指通过C原子或杂原子连接于如上定义的烷基链、亚烷基,或亚链烯基上的如上定义的杂芳基。
本文所用的术语“氰基”指-CN基团。
本文所用的术语“硝基”指-NO2基团。
本文所用的术语“羟基”指-OH基团。
除非另外指明,当提及特别指定的芳基(如苯基)、环烷基(如环己基)、杂环基(如吡咯烷基)或杂芳基(如咪唑基)时,除非另外特别指明,所提及的基团意欲包括具有0-3,优选0-2个取代基的环,所述取代基适当地选自以上对芳基、环烷基、杂环基和/或杂芳基描述的那些取代基。
术语“杂原子”应包括氧、硫和氮。
术语“碳环基”意指饱和的或不饱和的单环或双环,其中所有环的所有原子为碳。因此,该术语包括环烷基和芳基环。碳环可以被取代,在该例子中取代基选自以上对环烷基和芳基描述的那些取代基。
当本文所用的术语“不饱和的”涉及环或基团时,所述环或基团可以是完全不饱和的或部分不饱和的。
纵观说明书全文,其基团和取代基可由本领域技术人员选择,以提供稳定的部分和化合物以及用作药学上可接受的化合物和/或用于制备药学上可接受的化合物的中间体化合物的化合物。
短语“药学上可接受的”用于本文指这样的化合物、物质、组合物和/或剂型,它们在合理的医学判断范围内适合用于与人和动物体组织接触,而无过度的毒性、刺激性、过敏性反应或其它问题或并发症,并与合理的利益/风险比相称。
如本文所用的,“药学上可接受的盐”指所公开的化合物的衍生物,其中本发明化合物通过制备其酸或碱盐来修饰。
术语药学上可接受的“盐”和“盐类”可指由无机和有机碱形成的碱性盐。这样的盐包括铵盐;碱金属盐,如锂、钠,及钾盐(其为优选的);碱土金属盐,如钙和镁盐;与有机碱形成的盐,如胺类的盐(如,二环己胺盐、苄星青霉素、N-甲基-D-葡糖胺,和海巴明盐);和与氨基酸如精氨酸、赖氨酸等形成的盐;和两性离子,即所谓的“内盐”。优选无毒的、药学上可接受的盐,虽然其它盐也是有用的,如在分离或纯化产物方面。
术语药学上可接受的“盐”和“盐类”也包括酸加成盐。这些盐由例如强无机酸,如矿物酸,例如硫酸、磷酸或氢卤酸如HCl或HBr形成;由强有机羧酸,如1-4个碳原子的链烷羧酸,其为未取代的或取代的,例如,通过卤素,例如乙酸,如饱和的或不饱和的二羧酸,例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或对苯二甲酸,如羟基羧酸,例如抗坏血酸、羟基乙酸、乳酸、苹果酸、酒石酸或柠檬酸,如氨基酸,(例如天冬氨酸或谷氨酸或赖氨酸或精氨酸)或苯甲酸形成,或由有机磺酸,如(C1-C4)烷基或芳基磺酸,其为未取代的或取代的,例如通过卤素,例如甲磺酸或对-甲苯磺酸形成。
本发明的药学上可接受的盐可由含有碱性或酸性部分的母体化合物,通过常规化学方法合成。一般来说,这样的盐可通过这些化合物的游离酸或碱形式与化学计量的量的适宜碱或酸在水或在有机溶剂中,或在该二者的混合物中反应来制备;一般来说,非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。合适的盐的一览表可在Remington’s Pharmaceutical Sciences,17th ed.,MackPublishing Company,Easton,PA,p.1418(1985)中发现,其公开内容通过引用结合到本文中。
纵观说明书全文,其基团和取代基可由本领域技术人员选择,以提供稳定的部分和化合物以及用作药学上可接受的化合物和/或用于制备药学上可接受的化合物的中间体化合物的化合物。
可在体内转化以提供生物活性剂(即,式I化合物)的任何化合物为本发明的精神和范围内的前药。
术语“前药”指给予患者后,通过代谢或化学过程经历化学转化,得到所述结构式的化合物和/或其盐和/或溶剂合物的化合物。例如,含有羧基的化合物可形成生理学上可水解的酯,其用作在体内经水解,得到式化合物本身的前药。这样的前药优选口服给予,因为在许多情况下,水解主要发生在消化酶的影响下。当酯本身有活性时,或在水解发生在血液中的情况下,可采用胃肠外给药。
本文所用的术语“前药”包括通过采用本领域技术人员已知的方法,使式I化合物的一个或多个羟基与烷基、烷氧基或芳基取代的酰化剂反应所形成的酯和碳酸酯,以生成乙酸酯、新戊酸酯、甲基碳酸酯、苯甲酸酯等。
各种形式的前药是本领域熟知的并描述于:a)医用化学实践(The Practice of Medicinal Chemistry),CamilleG.Wermuth et al.,Ch.31(Academic Press,1996);b)前药的设计(Design of Prodrugs),由H.Bundgaard(Elsevier,1985)编辑;c)药物设计和开发教科书(A Textbook ofDrug Design andDevelopment),P.Krogsgaard-Larson和H.Bundgaard,eds.Ch.5,pp.113-191(Harwood Academic Publishers,1991);和d)药物和前药代谢的水解(Hydrolysis in Drug andProdrugMetabolism),Bernard Testa和Joachim M.Mayer,(Wiley-VCH,2003).所述参考文献通过引用结合到本文中。
式(I)化合物的生理学上可水解的酯的实例包括C1-6烷基苄基、4-甲氧基苄基、茚满基、苯二甲酰基、甲氧基甲基、C1-6烷酰基氧基-C1-6烷基如乙酰氧基甲基、新戊酰氧基甲基或丙酰氧基甲基、C1-6烷氧基羰基氧基-C1-6烷基如甲氧基羰基-氧基甲基或乙氧基羰基氧基甲基、甘氨酰氧基甲基、苯基甘氨酰氧基甲基、(5-甲基-2-氧代-1,3-间二氧杂环戊烯-4-基)-甲基,以及例如用于青霉素和头孢菌素领域的其它熟知的生理学上可水解的酯。这样的酯可通过本领域已知的常规技术制备。
术语“互变异构体”指可以以其互变异构形式存在的式I化合物及其盐,其中氢原子被移位至分子的其它部分,而此后分子的原子之间的化学键被重排。应该理解,所有的互变异构形式,当它们可能存在时,都包括在本发明范围内。
此外,式I化合物,及其随后的制备,优选被分离和纯化以获得含有以重量计等于或大于99%量的式I化合物的组成(“基本纯”的化合物I),然后将其如本文所述的那样使用或配制。这样的“基本纯”的式I化合物也期望包括在本发明中作为本发明的一部分。
本发明化合物的所有立体异构体,无论是作为混合物或作为纯态形式或基本纯的形式,均包括在本发明中。本发明的化合物在任何碳原子包括任何一个R取代基上可具有不对称中心和/或显示出多晶型现象。因此,式I化合物可以以对映体形式或非对映体形式,或作为其混合物的形式存在。制备方法可利用外消旋体,对映体,或非对映体作为起始原料。当制备非对映体或对映体产物时,它们可通过常规方法例如,层析或分级结晶来分离。
“稳定的化合物”和“稳定的结构”意指足够牢固以便经受得住从反应混合物分离至有用的纯度的,并配制为有效的治疗剂的化合物。本发明意欲包括稳定的化合物。
“治疗有效量”意欲包括有效治疗或预防糖尿病和/或肥胖症的单独的本发明化合物的量或要求保护的化合物的组合的量,或本发明的化合物与其它活性剂组合的量。
如本文所用的,“治疗”或“处理”覆盖哺乳动物,尤其是人类的疾病状态的治疗,并包括:(a)预防发生于哺乳动物中的疾病状态,尤其是,当这样的哺乳动物有易患该疾病状态的倾向,但尚未被诊断为患有该疾病时;(b)抑制该疾病状态,即阻止其发展;和/或(c)缓解该疾病状态,即引起该疾病状态的消退。合成
流程1描述制备本发明的式IA、IB和IC化合物的方法(本发明的式I化合物的亚组)。5-氰硫基噻唑-2-胺III可通过用硫氰酸钾处理2-氨基-5-溴代噻唑氢溴酸盐II而获得。酰胺V可由胺III与酸IV的反应而获得,例如通过按照在WO 02/46173中的描述的程序,使用合适的酰胺偶合试剂,如DEPBT、BOP、EDAC/HOBT、EDAC/HOAT或PyBOP,或在肽合成实践(The Practice of PeptideSynthesis)(Springer-Verlag,2nd Ed.,Bodanszky,Miklos(1993))中描述的那些试剂。用硼氢化钠还原中间体硫氰酸酯V,接着处理氯化物或溴化物VI(其可经市售获得或通过文献已知的方法或通过本领域技术人员采用的其它方法容易地制备),提供相应的硫化物,其为式IA化合物(式I化合物的亚组)。随后用合适的氧化剂如H2O2/对-甲苯磺酰基咪唑或或本领域技术人员使用的其它试剂氧化化合物IA,提供相应的砜,其为式IB化合物(式I化合物的亚组)。另外,用合适的氧化剂如间-氯过苯甲酸,或本领域技术人员使用的其它试剂氧化化合物IA,提供相应的亚砜,其为式IC化合物(式I化合物的亚组)。流程2
流程2描述制备本发明的式IA化合物(本发明的式I化合物的亚组)的备选方法。用硼氢化钠还原中间体硫氰酸酯III,接着处理氯化物或溴化物VI(其可通过文献已知的方法或通过本领域技术人员采用的其它方法容易地合成),提供中间体硫代烷基噻唑VII。酰胺IA可由胺VII与酸IV的反应而获得,例如通过按照在WO 02/46173中描述的程序,使用合适的酰胺偶合试剂,如DEPBT、BOP、EDAC/HOBT、EDAC/HOAT、PyBOP,或在肽合成实践(The Practiceof Peptide Synthesis)(Springer-Verlag,2nd Ed.,Bodanszky,Miklos(1993))中描述的那些试剂,得到式IA化合物(式I化合物的亚组)。流程3Q=N,CHR15=CO2H,四唑,烷基,烷氧基,卤素,氨基,oH,cN,CO2Ra,CONRaRb,或PO(OEt)2其中Ra和Rb相同或不同且为H或烷基
流程3描述制备本发明的式ID化合物(本发明的式I化合物的亚组)的方法。氨基噻唑中间体VIII可通过用适当取代的羟基苯或羟基杂芳基化合物XXI(其可通过文献已知的方法或通过本领域技术人员采用的其它方法容易地合成),在碱的存在下(例如在回流的丙酮中的碳酸铯;在WO 02/50071中描述的程序)处理2-氨基-5-溴代噻唑一氢溴酸盐II而获得。所需的酰胺ID可通过胺VIII与酰氯或酰氟IX(通过用草酰氯/DMF或氰尿酰氟/吡啶处理相应的酸IV制备)的反应,使用合适的碱,如吡啶、吡啶/DMAP或NaHCO3而获得,得到式ID化合物(式I化合物的亚组)。作为选择,酰胺1D可由胺VIII与相应的羧酸IV的反应,使用合适的酰胺偶合试剂,如BOP、EDAC/HOBT或EDAC/HOAT、PyBOP等而获得。流程4
流程4描述制备本发明的式IE化合物(本发明的式I化合物的亚组)的方法。2-氨基-5-溴代噻唑X可转化为相应的2-硝基-5-溴代噻唑XI(例如,在典型的Sandmeyer型条件下,如,Bioorg.Med.Chem.Lett.,14:5521-5525(2004))。然后可使溴代噻唑XI与各种胺XII(包括伯胺,其中R5a=H和仲胺,其中R5a=烷基)以置换反应方式进行反应,得到5-氨基-2-硝基-噻唑XIII。可通过各种方法,例如氢化或用连二亚硫酸钠,将硝基噻唑XIII还原为相应的氨基噻唑XIV。然后所需的酰胺IE可由氨基噻唑XIV与羧酸IV反应,例如通过按照在WO 2002/46173中描述的程序,使用合适的酰胺偶合试剂,如DEPBT、BOP、EDAC/HOBT、EDAC/HOAT、PyBOP,或在肽合成实践(The Practice of Peptide Synthesis)(Spring-Verlag,2nd Ed.,Bodanszky,Miklos(1993))中描述的那些试剂而获得。作为选择,酰胺IE可由氨基噻唑XIV与从酸IV获得的相应的酰氯IX(通过,如草酰氯)的反应而获得。流程5
羧酸IV可通过下面在流程5中所示的两条路径之一制备。在路径1(当R1=R2)中,酸IV通过2-步骤程序制备,包括:1)用卤化物XVI在碱(如,碳酸铯、碳酸钾等)的存在下,使3,5-二羟基苯甲酸酯XV烷基化,和2)在碱性或酸性条件下水解烷基化羧酸衍生物。在路径2中,当R1不同于R2时,通过用苄基溴在碳酸钾的存在下,使3,5-二羟基苯甲酸酯XV烷基化,如在WO 2005/121110所述,接着通过Mitsunobu反应引入R1基团[关于综述,见:Synthesis,1(1981);Org.React.,42:335(1992)],可实现对苯酚基团之一的选择性一保护(monoprotection)。使苄基醚XVIII去保护,接着烷基化或与卤化物R2-X(XIX)进行Mitsunobu反应,酯水解提供酸IV。流程6Q=N,CHR15=CO2H,四唑,烷基,烷氧基,卤素,氨基,cN,CO2Ra,或CONRaRb其中Ra和Rb相同或不同且为H或烷基
流程6描述制备本发明的式IF化合物(本发明的式I化合物的亚组)的方法。氨基嘧啶中间体XXII可通过用适当取代的羟基苯或羟基杂芳基化合物(XXI)(其可通过文献已知的方法或通过本领域技术人员采用的其它方法容易地合成)在碱的存在下(例如DMF中的碳酸铯,同时加热;如在Bioorg.Med.Chem.Lett.,11:2185-2188(2001)中所述的程序),处理2-氨基-卤代嘧啶XX而获得。所需的酰胺IF可由氨基嘧啶XXII与酸IV的反应,例如通过按照在WO 2002/46173中描述的程序,使用合适的酰胺偶合试剂,如DEPBT、BOP、EDAC/HOBT、EDAC/HOAT、PyBOP,或在肽合成实践(The Practiceof Peptide Synthesis)(Spring-Verlag,2nd Ed.,Bodanszky,Miklos(1993))中描述的那些试剂而获得。作为选择,酰胺IF可由氨基嘧啶XXII与得自酸IV的相应的酰氯IX的反应(通过与例如草酰氯的反应)而获得。流程7
流程7描述制备本发明的式IG化合物(本发明的式I化合物的亚组)的方法。氨基嘧啶中间体XXIV可通过在加热下,用适当取代的醇(XXIII)的醇盐(alkoxide)(该醇盐可由醇与合适的碱的反应来制备,如NaN(TMS)2)处理2-氨基-卤代嘧啶XX而获得;如在J.Chem.Res.,747-749(2005)中所概述的。所需的酰胺IG可由氨基嘧啶XXIV与酸IV的反应,例如通过按照在WO 2002/46173中描述的程序,使用合适的酰胺偶合试剂,如在流程6中所述的DEPBT、BOP、EDAC/HOBT、EDAC/HOAT或PyBOP等而获得。作为选择,酰胺IG可由氨基嘧啶XXIV与得自酸IV的相应的酰氯IX的反应(通过与例如草酰氯反应)而获得。流程8
流程8描述制备本发明的式IH、II和IJ化合物(本发明的式I化合物的亚组)的方法。氨基嘧啶中间体XXVI可通过用硫醇盐(thiolate)(使用合适的碱如NaH或NaN(TMS)2,由取代的硫醇XXV生成)处理2-氨基-卤代嘧啶XX而获得。酰胺1H可得自胺XXVI与酸IV的反应,例如通过按照在WO 02/46173中描述的程序,使用合适的酰胺偶合试剂,如DEPBT、BOP、EDAC/HOBT、EDAC/HOAT或PyB OP,或在肽合成实践(The Practice of Peptide Synthesis)(Spring-Verlag,2nd Ed.,Bodanszky,Miklos(1993))中描述的那些试剂。作为选择,酰胺IH可由胺XXVI与得自酸IV的相应的酰氯IX的反应(通过与例如草酰氯的反应)而获得。随后用合适的氧化剂如或本领域技术人员使用的其它试剂氧化含硫化合物IH,提供相应的砜,其为式II化合物(式I化合物的亚组)。另外,用合适的氧化剂如间-氯过苯甲酸,或本领域技术人员使用的其它试剂氧化化合物IH,提供相应的亚砜,其为式IJ化合物(式I化合物的亚组)。流程9
流程9描述制备本发明的式IK化合物(本发明的式I化合物的亚组)的方法。氨基嘧啶中间体XXVII可通过在叔胺的存在及加热下,用伯胺或仲胺处理2-氨基-卤代嘧啶XX而获得(例如,如在J.Am.Chem.Soc.,124:1594-1596(2002)中所述)。所需的酰胺IK可由氨基嘧啶XXVII与酰氯IX(通过用草酰氯/DMF处理相应的酸IV制备)在合适的碱的存在下的反应而获得。作为选择,酰胺IK可如在流程6中所述,使用合适的酰胺偶合试剂,如BOP、EDAC/HOBT、EDAC/HOAT或PyBOP,由氨基嘧啶XXVII与相应的羧酸IV反应而获得。流程10
流程10描述制备本发明的式IL化合物(本发明的式I化合物的亚组)的方法。氨基嘧啶中间体XXIX可通过用适当取代的苯胺或氨基杂芳基化合物(XXVIII)(其可通过文献已知的方法或通过本领域技术人员采用的其它方法容易地合成)在碱和使用合适的配体(例如碳酸铯和Pd2(dba)3/DPPF,同时加热;如在J.Med Chem.,48:4892-4909(2005)中描述的程序)的钯催化剂的存在下,处理2-氨基-卤代嘧啶XX而获得。所需的酰胺IL可由氨基嘧啶XXIX与得自酸IV的酰氯IX(通过与例如草酰氯的反应)在碱的存在下反应而获得。作为选择,酰胺IL可通过按照来自WO 2002/46173的程序,使用合适的酰胺偶合试剂,如DEPBT、BOP、EDAC/HOBT、EDAC/HOAT或PyBOP,或在肽合成实践(The Practice of Peptide Synthesis)(Spring-Verlag,2nd Ed.,Bodanszky,Miklos(1993)中描述的那些试剂),由氨基嘧啶XXIX与酸IV反应而获得。
本发明的化合物具有作为葡糖激酶活性的增强剂的活性,因而可用于与治疗葡糖激酶活性有关的疾病。
因此,本发明的化合物可给予哺乳动物,优选人,用于治疗各种病症和紊乱包括,但不限于治疗、预防或延缓糖尿病及相关病症、与糖尿病相关的微血管并发症、与糖尿病相关的大血管并发症、心血管疾病、代谢综合征及其各组分病症,和其它疾病的进展。因此,相信本发明的化合物可用于预防、抑制或治疗糖尿病、高血糖症、受损的葡萄糖耐受性、胰岛素抗性、高胰岛素血症、视网膜病、神经病、肾病、延迟的伤口愈合、动脉粥样硬化及其后遗症、异常的心脏功能、心肌缺血、中风、代谢综合征、高血压、肥胖症、异常血脂症、高酯血症、高甘油三酯血症、高胆固醇血症、低HDL、高LDL、非心脏缺血、感染、癌症、血管再狭窄、胰腺炎、神经退行性疾病、脂质紊乱、认知功能障碍和痴呆、骨病、HIV蛋白酶相关脂质代谢障碍和青光眼。
代谢综合征或“综合征X”如在Ford et al.,J.Am.Med.Assoc.,287:356-359(2002)和Arbeeny et al.,Curr.Med.Chem.-Imm.,Endoc.&Metab.Agents,1:1-24(2001)中所述。B.组合
本发明在其范围内包括药用组合物,其含有作为活性组分的治疗有效量的至少一种式I化合物(单独或与药用载体或稀释剂组合)。任选地,本发明的化合物可单独,与其它本发明化合物组合,或与一种或多种其它治疗剂,如抗糖尿病药或其它药用活性物质组合使用。
本发明的化合物可与其它葡糖激酶活性增强剂或一种或多种其它合适的治疗剂组合使用,所述治疗剂用于治疗前述紊乱包括:抗糖尿病药、抗高血糖症药、抗高胰岛素血症药、抗视网膜病药、抗神经病药、抗肾病药、抗动脉粥样硬化药、抗感染药、抗局部缺血药、抗高血压药、抗肥胖症药、抗血脂异常药、抗高脂血症药、抗高甘油三酯血症药、抗高胆固醇血症药、抗局部缺血药、抗癌药、抗细胞毒性剂、抗再狭窄药、抗胰腺药、降脂药、食欲抑制药、记忆增强剂和促智药(cognitive agents)。
与本发明的化合物组合使用的合适的抗糖尿病药的实例包括胰岛素和胰岛素类似物:LysPro胰岛素,含有胰岛素的吸入制剂;胰高血糖素样肽;磺酰脲及类似物:氯磺丙脲、格列本脲、甲苯磺丁脲、妥拉磺脲、醋磺己脲、格列吡嗪、格列本脲、谷胱甘肽、瑞格列奈、美格列奈;双胍类:二甲双胍、苯乙双胍、丁双胍;α2-拮抗剂和咪唑啉:咪格列唑、伊格列哚、德格列哚、咪唑克生、依法克生、氟洛克生;其它胰岛素促分泌剂:利诺格列、促胰岛素药、毒蜥唾液类、BTS-67582、A-4166;噻唑烷二酮(PPARγ激动剂):环格列酮、吡格列酮、曲格列酮、罗西格列酮;非-噻唑烷二酮PPARγ激动剂;选择性PPARγ调节剂(SPPARMs;如,来自Metabolex的美他格列森);PPAR-α激动剂;PPARα/γ双重激动剂;PPARδ激动剂、PPARα/γ/δ全激动剂(pan agonists);SGLT2抑制剂;二肽基肽酶-IV(DPP4)抑制剂;醛糖还原酶抑制剂;RXR激动剂:JTT-501、MX-6054、DRF2593、LG100268;脂肪酸氧化抑制剂:氯莫克舍、乙莫克舍;α-葡萄糖苷酶抑制剂:阿卡波糖片剂、阿卡波糖、米格列醇、乙格列酯、伏格列波糖、MDL-25,637、卡格列波糖、MDL-73,945;β-激动剂:BRL 35135、BRL 37344、Ro 16-8714、ICID7114、CL 316,243、TAK-667、AZ40140;磷酸二酯酶抑制剂、cAMP和cGMP两种类型:西地那非、L686398:L-386,398;支链淀粉拮抗剂:普兰林肽、AC-137;脂氧合酶抑制剂:马索罗酚;促生长素抑制素类似物:BM-23014、司格列肽、奥曲肽;胰高血糖素拮抗剂:BAY 276-9955;胰岛素信号传导激动剂、拟胰岛素,PTP1B抑制剂:L-783281、TER17411、TER17529;糖原异生抑制剂:GP3034;促生长素抑制素类似物和拮抗剂;抗脂肪分解药:烟酸、阿西莫司、WAG 994;葡萄糖转运刺激剂:BM-130795;葡萄糖合酶激酶抑制剂:氯化锂、CT98014、CT98023;和甘丙肽受体激动剂。
其它合适的噻唑烷二酮包括Mitsubishi’s的MCC-555(公开于美国专利号5,594,016)、Glaxo-Wellcome’s的法格列扎(GI-262570)、恩格列酮(CP-68722,Pfizer),或达格列酮(CP-86325,Pfizer)、isaglitazone(MIT/J&J)、JTT-501(JPNT/P&U)、L-895645(Merck)、R-119702(Sankyo/WL)、NN-2344或巴格列酮(Dr.Reddy/NN)或YM-440(Yamanouchi)。
合适的PPARα/γ双重激动剂包括莫格列扎(Bristol-MyersSquibb)、替格列扎(Astra/Zeneca)、那格列扎(Lilly/Ligand);AVE-0847(Sanofi-Aventis);TAK-654(Takeda),以及由Murakami etal.,“一种用作过氧物酶体增殖-激活的受体α(PPARα)和PPARγ的共配体的新的胰岛素增敏剂(A Novel Insulin Sensitizer Acts As aColigand for Peroxisome Proliferation-Activated Receptor Alpha(PPARalpha)and PPAR gamma);PPARα激活对Zucker肥胖大鼠肝中异常脂质代谢的影响(Effect of PPAR alpha Activation on Abnormal LipidMetabolism in Liver of Zucker Fatty Rats)”,糖尿病,47:1841-1847(1998),WO 01/21602和US 6,414,002中公开的那些,其公开内容通过引用结合到本文中,使用其中提出的剂型,其中作为优选的指定化合物优选用于本发明中。合适的PPARδ激动剂包括,例如,GW-501516(Glaxo)。合适的PPARα/γ/δ全激动剂包括,例如,GW-677954(Glaxo)。
合适的α2拮抗剂也包括公开于WO 00/59506中的那些,使用其中描述的剂型。
合适的SGLT2抑制剂包括T-1095、根皮苷、WAY-123783,和在WO 01/27128中描述的那些。
合适的DPP4抑制剂包括沙格列汀(Bristol-Myers Squibb)、维格列汀(Novartis)和西格列汀(Merck)以及公开于WO 99/38501、WO99/46272、WO 99/67279(PROBIODRUG)、WO 99/67278(PROBIODRUG)、WO 99/61431(PROBIODRUG)中的那些,如由Hughes et al.,Biochemistry,38(36):11597-11603(1999)公开的NVP-DPP728A(1-[[[2-[(5-氰基吡啶-2-基)氨基]乙基]氨基]乙酰基]-2-氰基-(S)-吡咯烷)(Novartis),如由Yamada et al.,Bioorg.&Med.Chem.Lett.,8:1537-1540(1998)公开的TSL-225(色氨酰-1,2,3,4-四氢异喹啉-3-羧酸),如由Ashworth et al.,Bioorg.&Med.Chem.Lett.,6(22):1163-1166和2745-2748(1996)公开的2-氰基吡咯烷类化合物(pyrrolidides)和4-氰基吡咯烷类化合物(pyrrolidides),使用以上参考文献中描述的剂型。
合适的醛糖还原酶抑制剂包括公开于WO 99/26659中的那些。
合适的氯茴苯酸类包括那格列奈(Novartis)或KAD 1229(PF/Kissei)。
胰高血糖素样肽-1(GLP-1)的实例包括GLP-1(1-36)酰胺、GLP-1(7-36)酰胺、GLP-1(7-37)(如公开于授权给Habener的美国专利号5,614,492),以及AC2993(Amylin)和LY-315902(Lilly)。
可用于与本发明化合物组合的其它抗糖尿病药包括溴隐亭和D-chiroinositol.
合适的抗局部缺血药包括,包括但不限于,在临床医师案头参考书(Physicians’Desk Reference)中描述的那些和NHE抑制剂,包括公开于WO 99/43663中的那些。
合适的抗感染药的实例为抗生素药物包括,但不限于临床医师案头参考书(Physicians’DeskReference)中描述的那些。
用于与本发明化合物组合的合适降脂药的实例包括一种或多种MTP抑制剂、HMG CoA还原酶抑制剂、角鲨烯合成酶抑制剂、贝特酸(fibric acid)衍生物、ACAT抑制剂、脂氧合酶抑制剂、胆固醇吸收抑制剂、回肠Na+/胆酸共转运蛋白(cotransporter)抑制剂、LDL受体活性上调剂(upregulators)、胆酸螯合剂、胆固醇酯转移蛋白抑制剂(如,托塞匹布(Pfizer))和/或烟酸及其衍生物。
可如上所述使用的MTP抑制剂包括公开于美国专利号5,595,872、美国专利号5,739,135、美国专利号5,712,279、美国专利号5,760,246、美国专利号5,827,875、美国专利号5,885,983和美国专利号5,962,440中的那些。
可以与一种或多种式I化合物组合使用的HMG CoA还原酶抑制剂包括如公开于美国专利号3,983,140中的美伐他汀及相关化合物、如公开于美国专利号4,231,938中的洛伐他汀(美维诺林)和相关化合物,和如公开于美国专利号4,346,227中的普伐他汀和相关化合物,如公开于美国专利号4,448,784和4,450,171中的辛伐他汀和相关化合物。可用于本发明中的其它HMG CoA还原酶抑制剂包括,包括但不限于,公开于美国专利号5,354,772中的氟伐他汀;如公开于美国专利号5,006,530和5,177,080中的西立伐他汀;如公开于美国专利号4,681,893、5,273,995、5,385,929和5,686,104中的阿托伐他汀;如公开于美国专利号5,011,930中的atavastatin(Nissan/Sankyo’s nisvastatin(NK-104));如公开于美国专利号5,260,440中的visastatin(Shionogi-Astra/Zeneca(ZD-4522));和公开于美国专利号5,753,675中的相关他汀类化合物;如公开于美国专利号4,613,610中的甲羟戊基内酯(mevalonolactone)衍生物的吡唑类似物;如公开于PCT申请WO86/03488中的甲羟戊基内酯(mevalonolactone)衍生物的茚类似物;如公开于美国专利号4,647,576中的6-[2-(取代的-吡咯-1-基)烷基)吡喃-2-酮及其衍生物;Searle’s的SC-45355(3-取代的戊二酸衍生物)二氯代乙酸酯;如公开于PCT申请WO 86/07054中的甲羟戊基内酯(mevalonolactone)的咪唑类似物;如公开于法国专利号2,596,393中的3-羧基-2-羟基-丙烷-膦酸衍生物;如公开于欧洲专利申请号0221025中的2,3-二取代的吡咯、呋喃和噻吩衍生物;如公开于美国专利号4,686,237中的甲羟戊基内酯(mevalonolactone)的萘基类似物;如公开于美国专利号4,499,289中的八氢萘;如公开于欧洲专利申请号0142146A2中的美维诺林(洛伐他汀)的酮基类似物;以及如公开于美国专利号5,506,219和5,691,322中的喹啉和吡啶衍生物。
优选的降血脂药为普伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、氟伐他汀、西立伐他汀、atavastatin和ZD-4522。
此外,用于抑制HMG CoA还原酶的次膦酸化合物,如公开于GB 2205837中的那些,适合用于与本发明的化合物的组合中。
适合用于本发明的角鲨烯合成酶抑制剂包括,包括但不限于,公开于美国专利号5,712,396中的α-膦酰基-磺酸酯、由Biller et al.,J.Med.Chem.,31(10):1869-1871(1988)公开的那些,包括类异戊二烯(氧膦基-甲基)膦酸酯,以及其它已知的角鲨烯合成酶抑制剂,例如,如在美国专利号4,871,721和4,924,024以及在Biller,S.A.et al.,当代药物设计(Current Pharmaceutical Design),2:1-40(1996)中所公开的。
此外,适合用于本发明的其它角鲨烯合成酶抑制剂包括由Ortiz de Montellano,P.et al.,J.Med.Chem.,20:243-249(1977)公开的焦磷酸萜类化合物,如由Corey et al.,J.Am.Chem.Soc.,98:1291-1293(1976)公开的法呢基二磷酸酯类似物A和焦磷酸前角鲨烯(presqualene)(PSQ-PP)类似物,由McClard,R.W.et al.,J.Am.Chem.Soc.,109:5544(1987)报道的氧膦基膦酸酯和由Capson,T.L.,Ph.D.dissertation,June,1987,Dept.Med.Chem.U of Utah,Abstract,Table of Contents,pp.16,17,40-43,48-51,Summary报道的环丙烷类。
可以与一种或多种式I化合物组合使用的贝特酸(firic acid)衍生物包括非诺贝特、吉非贝特、氯贝丁酯、苯扎贝特、环丙贝特、克利贝特等、普罗布考,以及如公开于美国专利号3,674,836中的相关化合物(优选普罗布考和吉非贝齐)、胆酸螯合剂如考来烯胺、考来替泊和DEAE-Sephadex(交联葡聚糖)以及卵磷脂抽脂针(Rhone-Poulenc),Eisai E-5050(N-取代的乙醇胺衍生物)、伊马昔尔(HOE-402),tetrahydrolipstatin(THL)、istigmastanyl磷酸胆碱(SPC,Roche)、氨基环糊精(Tanabe Seiyoku)、Ajinomoto AJ-814(甘菊环衍生物)、亚油甲氨(melinamide)(Sumitomo)、Sandoz 58-035、American Cyanamid CL-277,082和CL-283,546(二取代的脲衍生物)、烟酸、阿西莫司、阿昔呋喃、新霉素、p-氨基水杨酸、阿司匹林、如公开于美国专利号4,759,923中的聚(联丙烯甲基胺)衍生物、如公开于美国专利号4,027,009中的季胺聚(联丙烯二甲基铵氯化物)和紫罗烯,和其它已知的降血清胆固醇药。
可以与一种或多种式I化合物组合使用的ACAT抑制剂包括公开于未来的药物(Drugs of the Future),24:9-15(1999)(Avasimibe)中的那些;Nicolosi et al.,“ACAT抑制剂,Cl-1011有效预防和减少人主动脉脂肪斑块面积(The ACAT inhibitor,Cl-1011is effective in theprevention and regression of aortic fatty streak area in hamsters)”,Atherosclerosis(Shannon,Irel.),137(1):77-85(1998);Ghiselli,G.,“FCE27677的药理学模式:一种具有由选择性抑制肝分泌的含ApoB100的组蛋白极大的强效降血脂活性的新的ACAT抑制剂(Thepharmacological profile of FCE 27677:a novel ACAT inhibitor withpotent hypolipidemic activity mediated by selective suppression of thehepatic secretion of ApoB 100-containing lipoprotein”,Cardiovasc.DrugRev.,16(1):16-30(1998);Smith,C.et al.,“RP 73163:一种可生物利用的烷基亚硫酰基-二苯基咪唑ACAT抑制剂(RP 73163:a bioavailablealkylsulfinyl-diphenylimidazoleACAT inhibitor”,Bioorg.Med.Chem.Lett.,6(1):47-50(1996);Krause,B.R.et al.,第6章:“ACAT抑制剂:在试验动物中的降血脂和抗动脉粥样硬化活性的生理学机制(ACATinhibitor:Physiologic Mechanisms for Hypolipidemic andAnti-Atherosclerotic Activities in Experimental Animals”,Inflammation:Mediators and Pathways,CRC Press,Inc.,publ.,Ruffolo,Jr.,R.R.et al.,eds.,pp.173-198(1995);Sliskovic et al.,“ACAT抑制剂:有效的抗动脉粥样硬化药(ACAT inhibitor:potential anti-atherosclerotic agents”,Curr.Med.Chem.,1(3):204-225(1994);Stout et al.,“酰基-CoA抑制剂:作为降胆固醇血症药的胆固醇O-酰基转移酶(ACAT)(Inhibitors ofacyl-CoA:cholesterol O-acyl transferase(ACAT)as hypocholesterolemicagents。6.具有脂质调节活性的第一种水溶性ACAT抑制剂(The firstwater-soluble ACAT inhibitor with lipid-regulating activity。酰基-CoA抑制剂:胆固醇酰基转移酶(Inhibitors of acyl-CoA:cholesterolacyltransferase)(ACAT)。7.具有增强的降胆固醇血症活性的一系列取代的N-苯基-N’-[(1-苯基环戊基)甲基]脲的开发(Development of aseries of substituted N-phenyl-N’-[(1-phenylcyclopentyl)methyl]ureaswith enhanced hypocholesterolemic activity”,Chemtracts:Org.Chem.,8(6):359-362(1995),或TS-962(Taisho Pharmaceutical Co.Ltd.)。
降血脂药可以是LD2受体活性的上调剂(upregulator),如MD-700(Taisho Pharmaceutical Co.Ltd)和LY295427(Eli Lilly)。
适用于与本发明化合物组合的合适胆固醇吸收抑制剂的实例包括SCH48461(Schering-Plough),以及公开于Atherosclerosis,115:45-63(1995)和J.Med.Chem.,41:973(1998)中的那些。
用于与本发明化合物组合的合适回肠Na+/胆酸共转运蛋白抑制剂的实例包括如公开于Drugs of the Future,24:425-430(1999)中的化合物。
可以与一种或多种式I化合物组合使用的脂氧合酶抑制剂包括15-脂氧合酶(15-LO)抑制剂,如公开于WO 97/12615中的苯并咪唑衍生物、如公开于WO 97/12613中的15-LO抑制剂、如公开于WO96/38144中的异噻唑酮,和由Sendobry et al.,“用缺乏明显的抗氧化剂特性的高度选择性15-脂氧合酶抑制剂减轻兔的食物诱导的动脉粥样硬化(Attenuation of diet-induced atherosclerosis in rabbits with highlyselective 15-lipoxygenase inhibitor lacking significant antioxidantproperties)”,Brit.J.Pharmacology,120:1199-1206(1997),和Cornicelliet al.,“15-脂氧合酶及其抑制作用:针对血管病的新的治疗靶(15-lipoxygenase and its Inhibition:A Novel Therapeutic Target for VascularDisease)”,当代药物设计(Current Pharmaceutical Design),5:11-20(1999)公开的15-LO抑制剂。
用于与本发明化合物组合的合适抗高血压药的实例包括β肾上腺素能阻滞剂、钙通道阻滞剂(L-型和T-型;如,地尔硫维拉帕米、硝苯地平、氨氯地平和mybefradil)、利尿剂(如氯噻嗪、双氢氯噻嗪、氟甲噻嗪、氢氟甲噻嗪、苄氟噻嗪、甲基氯噻嗪、三氯噻嗪、泊利噻嗪、苄噻嗪、利尿酸tricrynafen、氯噻酮、呋喃苯胺酸、musolimine、布美他尼、氨苯蝶啶、阿米洛利、安体舒通)、肾素抑制剂、ACE抑制剂(如,卡托普利、佐芬普利、福辛普利、伊拉普利、ceranopril、西拉普利、地拉普利、喷托普利、喹普利拉、雷米普利、赖诺普利)、AT-1受体拮抗剂(如,氯沙坦、厄贝沙坦、缬沙坦)、ET受体拮抗剂(如,西他生坦、atrsentan,以及公开于美国专利号5,612,359和6,043,265中的化合物)、ET/AII双重拮抗剂(如,公开于WO 00/01389中的化合物)、中枢肽键内切酶(NEP)抑制剂、血管肽酶抑制剂(NEP-ACE双重抑制剂)(如,奥马曲拉和gemopatrilat),和硝酸酯。
用于与本发明化合物组合的合适抗肥胖症药物的实例包括大麻素类受体1拮抗剂或反相激动剂、β3肾上腺素能激动剂、脂酶抑制剂、血清素(和多巴胺)重摄取抑制剂、甲状腺受体β药和/或食欲抑制剂。
可任选与本发明化合物组合使用的大麻素类受体1拮抗剂和反相激动剂包括重组体,SLV 319,和在Hertzog,D.L.,Expert Opin.Ther.Patents,14:1435-1452(2004)中讨论的那些。
可任选与本发明化合物组合使用的β3肾上腺素能激动剂包括AJ9677(Takeda/Dainippon)、L750355(Merck),或CP331648(Pfizer)或如公开于美国专利号5,541,204、5,770,615、5,491,134、5,776,983和5,488,064中的其它已知的β3激动剂,以及AJ9677、L750,355,优选CP331648。
可任选与式I化合物组合使用的脂酶抑制剂的实例包括奥利司他或ATL-962(Alizyme),优选奥利司他。
可任选与式I化合物组合使用的血清素(和多巴胺)重摄取抑制剂可以是西布曲明、托吡酯(Johnson&Johnson),或axokine(Regeneron),优选西布曲明和托吡酯。
可任选与本发明化合物组合使用的甲状腺受体β化合物的实例包括甲状腺受体配体,如公开于WO 97/21993(U.Cal SF)、WO99/00353(KaroBio)和WO 00/039077(KaroBio)中公开的那些,优选KaroBio申请中的化合物。
可任选与本发明化合物组合使用的食欲抑制剂包括右旋安非他明、苯丁胺、苯基丙醇胺或马吲哚,优选右旋安非他明。
可与本发明的化合物组合使用的其它化合物包括CCK受体激动剂(如,SR-27895B);甘丙肽受体拮抗剂;MCR-4拮抗剂(如,HP-228);瘦素(leptin)或拟似物;11-β-羟基甾体脱氢酶1型抑制剂;尿皮质素(urocortin)拟似物、CRF拮抗剂,和CRF结合蛋白(如,RU-486、尿皮质素(urocortin))。
此外,本发明的化合物可与抗癌药和细胞毒性剂组合使用,这些药物包括但不限于烷化剂如氮芥、烷基磺酸酯、亚硝基脲、氮杂环丙烷和三氮烯;抗代谢剂如叶酸拮抗剂、嘌呤类似物,和嘧啶类似物;抗生素如蒽环霉素、博来霉素、丝裂霉素、放线菌素和普卡霉素;酶如L-天门冬酰胺酶;法呢基-蛋白转移酶抑制剂;5α还原酶抑制剂;17β-羟基甾体脱氢酶3型的抑制剂;激素药物如糖皮质激素、雌激素/抗雌激素药、雄激素/抗雄激素药、黄体酮,和黄体激素-释放激素拮抗剂、乙酸奥曲肽;微血管-破坏剂(disruptor agents),如海鞘素或其类似物和衍生物;微血管-稳定剂如紫杉烷类,例如,紫杉醇多西他赛及其类似物,和大环内酯类抗肿瘤药,如大环内酯A-F及其类似物;来自植物的产品,如长春花属生物碱、表鬼臼脂素、紫杉烷类;和拓扑异构酶抑制剂;异戊二烯基-蛋白转移酶抑制剂;和其它药物如羟基脲、丙卡巴肼、米托坦、六甲蜜胺、铂配体络合物如顺铂和卡铂;和用作抗癌药和细胞毒性剂的其它药物如生物反应修饰剂、生长因子;免疫调节剂;和单克隆抗体。另外的抗癌药公开于EP 1177791中。本发明化合物也可与放射疗法联合使用。
用于与本发明化合物组合的合适记忆增强剂、抗痴呆药,或促智药的实例包括,包括但不限于,多奈哌齐、利伐斯的明、加兰他敏、美卢君、他克林、美曲膦酯、蕈毒碱、呫诺美林、得普尼林和毒扁豆碱。
上述专利和专利申请通过引用结合到本文中。
以上其它治疗剂,当与本发明的化合物组合使用时,可以以例如在临床医师案头教科书(Physicians’Desk Reference),如在以上提及的专利申请的指定的那些量使用,或者由本领域普通技术人员另外确定。制剂和剂量
式I化合物可以以任何合适的方式给予本文描述的任何使用者,例如,口服,如以片剂、胶囊、颗粒剂或散剂的形式;舌下给药;颊下给药;胃肠外,如经皮下、静脉内、肌内或胸骨内注射,或输注技术(如,作为无菌可注射水性溶液或非-水性溶液或悬浮液);经鼻给药,包括给药至鼻粘膜,如通过吸入喷雾剂;局部给药,如以霜剂或软膏剂的形式;或直肠给药如以栓剂的形式;以含有非-毒性的药学上可接受的溶媒或稀释剂的剂量单位制剂给药。
在实施本发明的治疗糖尿病和相关疾病的方法时,将使用含有与药用溶媒或稀释剂组合的式I化合物(有或无其它抗糖尿病药和/或抗高脂血症药和/或其它类型的治疗剂)的药用组合物。可使用常规固体或液体溶媒或稀释剂和适合所需给药模式的类型的药用添加剂,如药学上可接受的载体、赋形剂。粘合剂等,配制药用组合物。可通过口服途径,例如,以片剂、胶囊、珠粒、颗粒剂或散剂的形式给予哺乳动物患者,包括人、猴、狗等所述化合物。对于成人的剂量在0.2-2,000mg每日,优选0.25-250mg每日之间,其可以以单次剂量或以每日1-4次的分剂量的形式给予。
用于口服给予的典型胶囊含有结构I的化合物(25mg)、乳糖(75mg)和硬脂酸镁(15mg)。将该混合物通过60目筛并装入1号明胶胶囊中。
通过将25mg结构I的化合物经无菌操作放置于管制瓶中,无菌冷冻干燥和密封,制备典型的注射制剂。为使用,将管制瓶中的内容物与2mL生理盐水混合,以制备注射制剂。
缩写
在实施例和本文的其它地方使用下面的缩写:Ph=苯基Bn=苄基t-Bu=叔丁基i-Bu=异-丁基Me=甲基Et=乙基Pr=丙基iPr=异丙基Bu=丁基AIBN=2,2’-偶氮二异丁腈TMS=三甲基甲硅烷基TMSCHN2=(三甲基甲硅烷基)重氮甲烷TMSN3=三甲基甲硅烷基叠氮化物TBS=叔-丁基二甲基甲硅烷基FMOC=芴基甲氧基羰基Boc或BOC=叔-丁氧基羰基Cbz=苄氧基羰基或苄氧羰基或苄基氧基羰基THF=四氢呋喃Et2O=乙醚hex=己烷EtOAc=乙酸乙酯DMF=二甲基甲酰胺MeOH=甲醇EtOH=乙醇DCM=二氯甲烷i-PrOH=异丙醇DMSO=二甲亚砜DME=1,2-二甲氧基乙烷DMA=N,N-二甲基乙酰基酰胺DCE=1,2-二氯乙烷HMPA=六甲基磷酰三胺HOAc或AcOH=乙酸TFA=三氟乙酸DIEA或DIPEA或i-Pr2NEt或Hunig’s碱=二异丙基乙胺TEA或Et3N=三乙胺NMM=N-甲基吗啉NBS=N-溴代琥珀酰亚胺NCS=N-氯代琥珀酰亚胺DMAP=4-二甲基氨基吡啶DEPBT=3-二乙氧基磷酰氧基-1,2,3-苯并三嗪-4[3H]-酮mCPBA=3-氯过氧苯甲酸NaBH4=硼氢化钠NaBH(OAc)3=三乙酰氧基硼氢化钠NaN3=钠叠氮化物DIBALH=二异丁基氢化铝LiAlH4=氢化锂铝n-BuLi=正-丁基锂Pd/C=披钯碳PXPd2=二氯(氯代二-叔-丁基膦)钯(II)二聚体或[PdCl2(t-Bu)2PCl]2PtO2=氧化铂KOH=氢氧化钾NaOH=氢氧化钠LiOH=氢氧化锂LiOH.H2O=氢氧化锂一水合物HCl=盐酸H2SO4=硫酸H2O2=过氧化氢Al2O3=氧化铝K2CO3=碳酸钾Cs2CO3=碳酸铯NaHCO3=碳酸氢钠ZnBr2=溴化锌MgSO4=硫酸镁Na2SO4=硫酸钠KSCN=硫氰酸钾NH4Cl=氯化铵DBU=1,8-二氮杂双环[5.4.0]十一碳-7-烯EDC(或EDC.HCl)或EDCI或EDCI.HCl)或EDAC=3-乙基-3’-(二甲基氨基)丙基-碳二亚胺盐酸盐(或1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐)HOBT或HOBT.H2O=1-羟基苯并三唑水合物HOAT=1-羟基-7-氮杂苯并三唑PyBOP试剂或BOP试剂=苯并三唑-1-基氧基-三(二甲基氨基)六氟磷酸鏻NaN(TMS)2=六甲基二甲硅烷基氨基钠或双(三甲基甲硅烷基)氨化钠Ph3P=三苯膦Pd(OAc)2=乙酸钯(Ph3P)4Pdo=四(三苯膦)钯Pd2(dba)3=三(二苄基丙酮)二钯DPPF=1,1’-双(二苯基膦基)二茂铁HATU=2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐,2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基异脲鎓六氟磷酸盐(V)DEAD=偶氮二羧酸二乙酯DIAD=偶氮二羧酸二异丙基酯Cbz-Cl=氯代甲酸苄基酯CAN=硝酸高铈铵SAX=强阴离子交换剂SCX=强阳离子交换剂H2=氢Ar=氩N2=氮Equiv=当量min=分钟h或hr=小时L=升mL=毫升μL=微升g=克mg=毫克mol=摩尔mmol=毫摩尔meq=毫当量RT或R.T.=室温AT=环境温度sat或sat’d=饱和的aq.=含水的TLC=薄层层析HPLC=高效液相层析HPLC Rt=HPLC保留时间LC/MS=高效液相层析/质谱MS或Mass Spec=质谱法NMR=核磁共振NMR光谱数据:s=单峰;d=双峰;m=多重峰;br=宽峰;t=三重峰mp=熔点
实施例
下面的实施例是优选的本发明化合物的示例。实施例1
向3-羟基苄腈(137mg,1.15mmol)的丙酮(3mL)溶液中,加入5-溴代噻唑-2-胺氢溴酸盐(300mg,1.15mmol)和Cs2CO3(749mg,2.30mmol)。将反应混合物于55℃搅拌12小时,然后冷却至RT。过滤该混合物并用丙酮洗涤。真空浓缩合并的滤液,然后分配于EtOAc和H2O之间。有机相用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna 5u C18 21.2x100mm柱;于220nm检测;流速=20mL/min;连续梯度从0%B至100%B,经8min+7min保留时间(hold time)(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分A化合物(70mg,28%收率),为固体。
向部分B酸(250mg,0.66mmol)的CH2Cl2(4mL)溶液中加入草酰氯(723μL,1.45mmol,2M在CH2Cl2中)和DMF(10drops)。将得到的混合物于RT下搅拌1h,然后真空浓缩。使残留物溶于THF(2mL),并缓慢加入到部分A化合物(313mg,1.45mmol)和NaHCO3(166mg,1.97mmol)的THF∶H2O(1∶1,4mL)溶液中。将该反应混合物于RT下搅拌3小时,然后分配于EtOAc和H2O之间。有机相用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(240mg,63%收率),为白色固体。[M+H]+=580.2,1H NMR(400MHz,DMSO-d6):δ7.95(d,J=9.23Hz,2H),7.66-7.70(m,1H),7.57-7.66(m,2H),7.54-7.58(m,1H),7.48-7.54(m,1H),7.43(s,1H),7.32-7.38(m,1H),7.26(d,J=8.79Hz,2H),7.02(t,J=2.20Hz,1H),4.72-4.85(m,1H),3.43-3.57(m,2H),3.29(s,3H),3.22(s,3H),1.25(d,J=6.15Hz,3H).实施例2
向实施例1部分C化合物(53mg,0.092mmol)的水(3mL)溶液中加入NaN3(18mg,0.28mmol)和ZnBr2(62mg,0.28mmol)。搅拌下,将反应物于100℃回流46小时,然后冷却至RT。加入1N HCl水溶液(2mL)和EtOAc(5mL);将含水层调节至pH 1。剧烈搅拌30min后,含水层用EtOAc(6mL)洗涤。真空浓缩合并的有机提取物,残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从40%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(24mg,42%收率),为白色固体。[M+H]+=623.4,1H NMR(400MHz,DMSO-d6)δ7.94(d,J=8.79Hz,2H),7.83(d,J=7.91Hz,1H),7.75(t,J=2.64Hz,1H),7.64(t,J=8.13Hz,1H),7.56(s,1H),7.44(s,1H),7.39(dd,J=8.35,2.20Hz,1H),7.36(s,1H),7.25(d,J=8.79Hz,2H),6.97-7.05(m,1H),4.71-4.85(m,1H),3.44-3.55(m,2H),3.28(s,3H),3.21(s,3H),1.24(d,J=6.15Hz,2H).实施例3
向实施例1部分C化合物(65mg,0.11mmol)的THF(2mL)溶液中加入1N NaOH水溶液(1mL)。搅拌下,将反应物于70℃加热94h。然后使反应物冷却至RT,用EtOAc稀释,并用1NHCl水溶液中和。有机层用H2O和盐水洗涤,干燥(MgSO4),过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(13mg,19%收率),为白色固体。[M+H]+=598.2,1HNMR(400MHz,CD3OD)δ7.96(d,J=9.23Hz,2H),7.60-7.68(m,2H),7.43-7.51(m,2H),7.27-7.34(m,2H),7.22(d,J=8.79Hz,2H),7.19(s,1H),6.96(t,J=2.20Hz,1H),4.64-4.77(m,1H),3.48-3.63(m,2H),3.38(s,3H),3.12(s,3H),1.31(d,J=6.15Hz,3H).实施例4
向5-溴代噻唑-2-胺氢溴酸盐(1.4g,5.3mmol)的丙酮(26mL)的RT溶液中加入3-羟基苯甲酸甲基酯(888mg,5.8mmol)和Cs2CO3(3.8g,11.7mmol)。将该反应混合物于55℃搅拌5小时,然后冷却至RT,并于RT下搅拌另外10h。过滤该混合物并用丙酮洗涤。真空浓缩合并的滤液,使残留物分配于EtOAc和H2O之间。干燥(MgSO4)有机相,过滤,并真空浓缩。使残留物分配于EtOAc和1N NaOH水溶液之间;有机相用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩,得到粗品部分A化合物,为油状物(445mg,34%)。
向部分B化合物(51mg,0.13mmol)的CH2Cl2(1.5mL)溶液中加入草酰氯(147μL,0.30mmol,2M在CH2Cl2中)和DMF(4滴)。将得到的混合物于RT下搅拌1h,然后真空浓缩。使残留物溶于THF(1mL),然后缓慢加入到部分A化合物(50mg,0.20mmol)和NaHCO3(34mg,0.40mmol)的THF∶H2O(1∶1,2mL)溶液中。将反应混合物于RT下搅拌2小时,然后分配于EtOAc和H2O之间。有机相用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩。残留物无须进一步纯化而用于下一步骤。
向粗品部分B化合物(0.13mmol)的THF∶H2O(2∶1,1.5mL)溶液中加入LiO H.H2O(28.1mg,0.67mmol)。将反应物于RT下搅拌40小时,然后用EtOAc稀释,用1N HCl水溶液酸化至pH 1~2,用H2O和盐水洗涤,干燥(MgSO4),过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(15mg,19%收率,经两步),为白色固体。[M+H]+=599.2,1HNMR(400MHz,DMSO-d6)δ7.94(d,J=8.79Hz,2H),7.72(d,J=7.91Hz,1H),7.54-7.59(m,2H),7.51-7.54(m,1H),7.43(dd,J=7.47,2.64Hz,1H),7.41(s,1H),7.33-7.37(m,1H),7.25(d,J=8.79Hz,2H),7.00(t,J=2.20Hz,1H),4.72-4.85(m,1H),3.42-3.57(m,2H),3.28(s,3H),3.20(s,3H),1.24(d,J=6.15Hz,3H).实施例5
按照用于制备实施例4的相同的通用程序,由4-羟基苯甲酸甲基酯制备标题化合物,得到标题化合物(13mg,16%收率),为白色固体。[M+H]+=599.2,1H NMR(400MHz,DMSO-d6)δppm7.89-8.00(m,4H),7.51-7.60(m,1H),7.43(s,1H),7.32-7.38(m,1H),7.25(d,J=9.23Hz,2H),7.21(d,J=8.79Hz,2H),7.01(t,J=2.20Hz,1H),4.71-4.86(m,1H),3.47-3.55(m,2H),3.28(s,3H),3.21(s,3H),1.24(d,J=6.15Hz,3H).实施例6
向5-溴代噻唑-2-胺氢溴酸盐(300mg,1.15mmol)的丙酮(3mL)溶液中,加入4-羟基苯甲酸甲基酯(175mg,1.15mmol)和Cs2CO3(749mg,2.30mmol)。将该反应混合物于55℃搅拌12小时,然后冷却至RT。过滤该混合物并用丙酮洗涤。真空浓缩合并的滤液,然后分配于EtOAc和H2O之间。有机相用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna 5uC1821.2x 100mm柱;于220nm检测;流速=20mL/min;连续梯度从0%B至100%B,经8min+7min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分A化合物(62mg,22%收率),为固体。
经15min,向部分B(i)化合物(3.7g,0.012mol)、(R)-(-)-1-苄基氧基-2-丙醇(2.5g,0.015mol)和Ph3P树脂(30g,0.031mol)的THF(150mL)的0℃溶液中滴加入DIAD(3.5g,0.017mol)。将该反应混合物于0℃搅拌30min,然后使之升温至RT,并于RT下搅拌3h。过滤反应物,并真空浓缩滤液。残留物用EtOAc/己烷(1∶1,10mL)稀释,滤除固体,并真空浓缩滤液。残留物用EtOAc/己烷(1∶1,10mL)再稀释1次,滤除固体,并真空浓缩滤液。残留物经层析(SiO2;EtOAc/Hex,1∶2),得到部分B(ii)化合物,为无色油状物(6.0g)。
将部分B(ii)的化合物(6.0g,0.013mol)和LiOH.H2O(1.6g,0.065mol)在MeOH/THF/H2O(3/3/5,110mL)中的溶液于RT下搅拌3h。真空浓缩反应物,残留物用H2O洗涤,用浓HCl调节至pH 4,然后用EtOAc提取。有机层用H2O洗涤,干燥(Na2SO4),过滤,并真空浓缩,得到部分B(iii)化合物,为白色固体(5.0g).iv.
向部分B(iii)化合物(1.0g,2.3mmol)的EtOAc(5mL)溶液中加入10%Pd/C(100mg)。使用气囊引入H2(g)气氛,将反应物于RT下搅拌72h。过滤该反应混合物,并用MeOH洗涤催化剂。真空浓缩滤液,得到部分B(iv)化合物,为无色油状物(0.82g)。
向叔-丁基二甲基甲硅烷基氯(1.0g,6.7mmol)和部分B(iv)化合物(0.82g,2.2mmol)的DMF(6mL)溶液中加入咪唑(0.91g,13.4mmol)。将反应物于RT下搅拌1小时,然后在冰箱中贮存过夜。第二天,使反应物升温至RT并分配于EtOAc和饱和的NH4Cl水溶液之间。分离有机相,用饱和的NH4Cl水溶液和盐水洗涤,干燥(MgSO4),过滤,并真空浓缩。残留物经层析(SiO2;EtOAc∶己烷,从0%-100%,经14min),得到部分B(v)化合物(725mg,68%收率),为白色泡沫状物。C.
向部分A化合物(60mg,0.24mmol)、HOBT(43mg,0.31mmol)和Et3N(0.05mL,0.36mmol)的CH2Cl2(6mL)溶液中加入部分B(v)化合物(116mg,0.24mmol)。将该反应混合物于RT下搅拌10min,加入EDC(60mg,0.31mmol)。将反应物于RT下搅拌12小时,然后真空浓缩,残留物经制备型HPLC纯化(Phenomenex Luna AXIA5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分C化合物(10mg,6%收率),为橙色固体。
向部分C化合物(10mg,0.02mmol)的THF∶H2O(2∶1,3mL)溶液中加入LiOH(2mg,0.08mmol)。将反应物于RT下搅拌12h。反应混合物用EtOAc稀释并用1NHCl水溶液酸化至pH 2。混合物用H2O和盐水洗涤。干燥(MgSO4)有机层,过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomencx Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(4mg,41%收率),为白色固体。[M[+H]+=585.2,1H NMR(400MHz,CD3OD)δ8.05-6.98(m,12H),3.72(m,2H),3.70(m,1H),3.29(s,3H),1.31(m,3H).实施例7
向实施例6部分B(v)化合物(200mg,0.42mmol)的CH2Cl2(5mL)的-10℃溶液中加入吡啶(0.04mL,0.5mmol)和氰尿酰氟(0.11mL,1.25mmol)。将反应物于-10℃搅拌30min,然后升温至RT并搅拌90min。将反应混合物倾入冰水中并用CH2Cl2提取。干燥(MgSO4)有机层,过滤,并真空浓缩。使酰氟残留物溶于THF(3mL)并加入到实施例1部分A化合物(99mg,0.46mmol)和吡啶(0.14mL,1.67mmol)在THF(6mL)中的混合物中。将反应物于RT下搅拌72小时,然后真空浓缩,残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5uC1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间于100%B,其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA)。在浓缩含有TFA的流分期间裂解TBS基团,以使醇残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(2.7mg,1%收率),为白色固体。[M+H]+=566.1,1H NMR(400MHz,CD3OD)δ7.97-6.98(m,12H),3.68(m,2H),3.49(m,1H),3.12(s,3H),1.30(m,3H).实施例8
向实施例7化合物(58mg,0.10mmol)的THF(3mL)溶液中加入1N NaOH水溶液(1mL)。将反应物于70℃搅拌48小时,然后冷却至RT并搅拌72h。真空浓缩反应混合物,残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(2mg,4%收率),为白色冻干物(lyophilate)。[M+H]+=585.1,1H NMR(400MHz,CDCl3)δ8.03-6.98(m,12H),3.95(m,1H),3.79(m,2H),3.22(s,3H),1.18(m,3H).实施例9
向实施例6部分B(v)化合物(44mg,0.09mmol)的CH2Cl2(3mL)的-10℃溶液中加入吡啶(0.01mL,0.11mmol)和氰尿酰氟(0.03mL,0.28mmol)。将反应物于-10℃搅拌30min,然后升温至RT并搅拌90min。将反应混合物倾入冰水中并用CH2Cl2提取。干燥(MgSO4)有机层,过滤,并真空浓缩。使酰氟残留物溶于THF(1mL)并加入到实施例4部分A化合物(25mg,0.10mmol)和吡啶(0.03mL,0.37mmol)在THF(3mL)的混合物中。将反应物于RT下搅拌72小时,然后真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA)。在浓缩含有TFA的流分期间裂解TBS基团,以使醇残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分A化合物(25mg,50%收率),为白色固体。
向部分A化合物(25mg,0.04mmol)的THF∶H2O(2∶1,3mL)溶液中加入LiOH.H2O(5mg,0.21mmol)。将反应物于RT下搅拌12h。用EtOAc稀释反应物,用1N HCl水溶液酸化至pH 2,用H2O和盐水洗涤。干燥(MgSO4)有机层,过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(3.9mg,16%收率),为白色冻干物。[M+H]+=585.2,1H NMR(400MHz,CD3OD)δ8.01(m,2H),7.81(m,1H),7.72(s,1H),7.45(m,2H),7.33(m,2H),7.24(m,3H),7.03(s,1H),4.62(broad s,OH),3.72(m,2H),3.21(s,3H),2.98(s,1H),1.31(m,3H).实施例10
向6-氟代吡啶-3-醇(43.5mg,0.385mmol)和5-溴代噻唑-2-胺氢溴酸盐(100mg,0.385mmol)的丙酮(5mL)溶液中加入Cs2CO3(276mg,0.846mmol)。将反应物于55℃搅拌16小时,然后冷却至RT。过滤该混合物并用丙酮洗涤。真空浓缩合并的滤液,然后分配于EtOAc和水之间。有机层用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C 1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从10%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分A化合物(45mg,55%收率),为白色固体。
向实施例1部分B化合物(75mg,0.197mmol)、部分A化合物(54.1mg,0.256mmol)和HOAT(33.5mg,0.246mmol)在DMF(2mL)的混合物中加入Hunig’s碱(0.045mL,0.256mmol)和EDC(47.2mg,0.246mmol)。将反应物于RT下搅拌16小时,然后分配于EtOAc和水之间。有机层用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5μm C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(25mg,22%收率),为黄色泡沫状固体。[M+H]+=574.2,1HNMR(400MHz,DMSO-d6)δ8.16(s,1H),7.95(m,2H),7.85(m,1H),7.55(s,1H),7.39(m,2H),7.25(m,3H),7.01(s,1H),4.78(m,1H),3.48(m,2H),3.28(s,3H),3.20(s,3H),1.23(s,3H).实施例11
向3,5-二羟基苯甲酸甲基酯(1.5g,8.9mmol)的MeCN(20mL)溶液中加入异丙基溴(4.2mL,44.6mmol)和Cs2CO3(8.7g,26.7mmol)。将反应物于回流(85℃)下搅拌12h,然后冷却至RT。用H2O猝灭反应并用EtOAc(3x)提取。有机层用H2O和盐水洗涤,干燥(MgSO4),过滤,并真空浓缩,得到部分A化合物(2.0g,93%收率),为黄色油状物。
向部分A化合物(2.0g,7.9mmol)的THF∶H2O(5∶1,60mL)溶液中加入LiOH.H2O(732mg,17.4mmol)。将反应物于45℃搅拌12小时,然后冷却至RT。真空除去挥发物,水层用Et2O提取。然后用1N HCl水溶液酸化含水层,直至形成混浊的沉淀。然后用EtOAc提取含水层。干燥(MgSO4)合并的有机层,过滤,并真空浓缩,得到部分B化合物(1.8g,100%收率),为灰白色固体。
向部分B化合物(50mg,0.21mmol)、实施例4部分A化合物(75mg,0.30mmol)和HOAT(36mg,0.26mmol)的DMF(0.5mL)溶液中加入iPr2NEt(0.05mL,0.27mmol),接着加入EDC.HCl(50mg,0.26mmol)。将反应物于RT下搅拌72小时,然后分配于EtOAc和H2O之间。有机层用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩,得到粗品部分C化合物,为橙色/棕色油状物。
向部分C化合物的THF∶H2O(2∶1,3mL)溶液中加入LiOH.H2O(25mg,1.04mmol)。将反应物于RT下搅拌12h。加入另一份LiOH.H2O(25mg,1.04mmol),将反应物于RT下搅拌12h。反应混合物用EtOAc稀释,用1NHCl水溶液酸化至pH 2,并用H2O和盐水洗涤。干燥(MgSO4)有机层,过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(7.5mg,8%收率),为灰白色固体。[M+H]+=457.1,1HNMR(400MHz,DMSO-d6)δ7.73(m,1H),7.58(m,2H),7.42(m,1H),7.40(s,1H),7.19(s,2H),6.65(m,1H),4.70(s,2H),1.27(m,12H).实施例12
按照与用于制备实施例11的相同的通用程序,从3,5-二甲氧基苯甲酸制备标题化合物,得到标题化合物(3.0mg,3%收率),为灰白色固体。[M+H]+=401.0,1H NMR(400MHz,DMSO-d6)δ7.75(m,1H),7.55(m,3H),7.45(m,1H),7.40(s,1H),7.25(s,2H),6.780(m,1H),3.81(s,6H).实施例13
按照与用于制备实施例11的相同的通用程序,从实施例6部分A化合物制备标题化合物,得到标题化合物(8.0mg,8%收率),为白色固体。[M[+H]+=457.1,1HNMR(400MHz,CDCl3)δ8.15-6.64(m,8H),4.44(s,2H),1.37(m,12H).实施例14
向实施例11部分B化合物(100mg,0.42mmol)、实施例1部分A化合物(118mg,0.55mmol)和HOAT(71mg,0.52mmol)在DMF(1.0mL)中的混合物中加入iPr2NEt(0.10mL,0.55mmol),接着加入EDC.HCl(101mg,0.52mmol)。将反应物于RT下搅拌48h。使反应混合物分配于EtOAc和H2O之间。有机相用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩,得到粗品部分A化合物,为棕色油状物。
向部分A化合物(91.5mg,0.21mmol)的THF(3mL)溶液中加入1NNaOH水溶液(1mL)。将反应物于70℃搅拌12h。加入另一份1NNaOH水溶液(1mL),并于70℃继续搅拌12h。使反应物冷却至RT并搅拌48h。真空浓缩反应物,残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(6mg,6%收率),为白色固体。[M+H]+=456.1,1H NMR(400MHz,DMSO-d6)δ8.07(broad,NH2),7.65(m,1H),7.59(m,1H),7.49(m,1H),7.37(s,1H),7.31(m,1H),7.18(s,1H),6.64(m,2H),4.69(s,2H),1.26(m,12H).实施例15
向实施例14部分A化合物(91.5mg,0.21mmol)的H2O(4mL)溶液中加入NaN3(41mg,0.63mmol)和ZnBr2(141mg,0.63mmol)。将反应混合物加热至回流(105℃)72h。使反应物冷却至RT并加入1N含水HCl(3mL)和EtOAc(6mL)中。将反应物剧烈搅拌30min,直至含水层达到pH 1。分离有机层,含水层用EtOAc提取。干燥(MgSO4)合并的有机层,过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(40mg,40%收率),为浅橙色固体。[M+H]+=481.1,1HNMR(400MHz,DMSO-d6)δ7.88(m,1H),7.76(m,1H),7.64(m,1H),7.45(s,1H),7.40(m,1H),7.19(s,2H),6.64(s,1H),4.69(s,2H),1.26(m,12H).实施例16
向5-溴代噻唑-2-胺氢溴酸盐(305mg,1.17mmol)的丙酮(7.8mL)溶液中,加入3-氯代苯酚(124μL,1.17mmol)和Cs2CO3(841mg,2.58mmol)。将反应混合物于55℃搅拌68小时,然后冷却至RT。过滤该混合物并用丙酮洗涤。真空浓缩合并的滤液,然后使残留物分配于EtOAc和H2O之间。有机相用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩,得到粗品部分A化合物,为棕色油状物。
向实施例11部分B化合物(40mg,0.17mmol)的CH2Cl2(1.5mL)溶液中加入草酰氯(0.2mL,0.38mmol)和DMF(4滴)。将反应物于RT下搅拌1h并真空浓缩。使残留物溶于THF并加入到部分A化合物(过量)和NaHCO3(43mg,0.50mmol)的THF∶H2O(1∶1,3mL)溶液中。将反应物于RT下搅拌12小时,然后用EtOAc稀释。真空浓缩有机层,残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(5.0mg,7%收率),为褐色冻干物。[M+H]+=447.0,1HNMR(400MHz,DMSO-d6)δ7.42-6.63(m,8H),4.69(s,2H),1.27(m,12H).实施例17-27
向2,4,5-三氟-3-羟基苯甲酸(100mg,0.521mmol)的MeOH(2mL)溶液中加入H2SO4(0.014mL,0.260mmol)。密封反应容器,然后震荡下,于70℃加热至回流18h。使反应物冷却至RT并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分A化合物(85mg,79%收率),为白色固体。
向部分A化合物(85mg,0.412mmol)和5-溴代噻唑-2-胺氢溴酸盐(107mg,0.412mmol)的丙酮(5mL)溶液中加入Cs2CO3(296mg,0.907mmol)。将反应物于55℃搅拌16h,过滤并真空浓缩,得到粗品部分B化合物,其无须进一步纯化或鉴定而用于随后的反应。
向实施例1部分B化合物(104mg,0.274mmol)的CH2Cl2(1mL)溶液中加入草酰氯(2M在CH2Cl2中)(0.315mL,0.630mmol)和DMF(0.1mL)。将反应物于25℃搅拌1小时,然后真空浓缩,得到粗品酰氯。使部分B(125mg,0.411mmol)和NaHCO3(69.0mg,0.822mmol)溶于THF(1.000mL)和H2O(1.000mL)中。将粗品酰氯的THF(1mL)溶液加入到反应混合物中。将反应物于RT下搅拌16小时,然后真空浓缩,得到粗品部分C化合物,其无须进一步纯化而用于随后的反应。
使粗品部分C化合物(157mg,0.236mmol)溶于MeOH(2mL)和H2O(2mL)中。加入LiOH.H2O(56.4mg,2.355mmol),将反应物于RT下搅拌16h。真空浓缩反应物,残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(1.6mg,1%收率,经三步),为灰白色固体。[M+H]+=653.1,1H MR(400MHz,DMSO-d6)δ7.95-7.01(m,9H),4.78(m,1H),3.49(m,2H),3.33(s,3H),3.38(s,3H),1.24(m,3H).实施例29
按照与用于制备实施例28的相同的通用程序,从4-氟代-3-羟基苯甲酸制备标题化合物,得到标题化合物(15mg,10%收率,经4步),为褐色固体。[M+H]+=617.1,1H NMR(400MHz,DMSO-d6)δ7.95(m,2H),7.75(m,1H),7.65(m,1H),7.56-7.46(m,3H),7.35(s,1H),7.25(m,2H),7.01(s,1H),4.77(m,1H),3.49(m,2H),3.28(s,3H),3.21(s,3H),1.24(d,J=6.16Hz,3H).实施例30
向装配有回流冷凝器和磁力搅拌棒的圆底烧瓶中装入Pd(OAc)2(22.45mg,0.100mmol)和Ph3P(79mg,0.300mmol)。使反应容器抽空并用氮气吹洗。随后,通过注射器加入EtOH(20mL)、4-溴代苯酚(865mg,5.00mmol)、iPr2NEt(1.310mL,7.50mmol)和亚磷酸二乙酯(0.772mL,6.00mmol)。将反应混合物于76℃回流下搅拌16小时,然后冷却至RT。反应用EtOAc稀释并用1NHCl水溶液、饱和NaHCO3水溶液和盐水洗涤。干燥(MgSO4)有机层,过滤,并真空浓缩。残留物经层析(80g SiO2,连续梯度从20%EtOAc至100%EtOAc,经20min,然后保留15min))。分离部分A化合物(250mg,22%收率),为无色油状物并无须进一步纯化而用于随后的反应。B.
向5-溴代噻唑-2-胺氢溴酸盐(141mg,0.543mmol)和部分A化合物(125mg,0.543mmol)的丙酮(5mL)溶液中加入Cs2CO3(389mg,1.195mmol)。将反应物在震荡器中加热至60℃16h。使反应物冷却至RT并真空浓缩。使残留物溶于MeOH。过滤并真空浓缩,得到部分B化合物(155mg,43%收率),为橙色/棕色固体。
向实施例1部分B化合物(100mg,0.263mmol)、部分B化合物(112mg,0.342mmol)和HOAt(44.7mg,0.329mmol)的DMF(2.0mL)溶液中,加入iPr2NEt(0.060mL,0.342mmol)和EDAC(63.0mg,0.329mmol)。将反应物于RT下搅拌48h,然后分配于EtOAc和水之间。有机层用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩。使残留物溶于MeOH并经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(35mg,20%收率),为褐色固体。[M+H]+=691.1,1HNMR(400MHz,DMSO-d6)δ7.95(m,2H),7.73(m,2H),7.55(s,1H),7.44(s,1H),7.35(s,1H),7.25(m,4H),7.01(s,1H),4.78(m,1H),3.98(m,4H),3.49(m,2H),3.28(s,3H),3.21(s,3H),1.21(m,9H).实施例31
于室温、Ar(g)气氛下,向3,5-二羟基甲基苯甲酸酯(10.0g,59.5mmol)的DMF(60.0mL)溶液中加入K2CO3(12.4g,89.7mmol)。经10min缓慢加入苄基溴(10.0mL,84.2mmol;使用前通过碱性Al2O3过滤)。将反应混合物于RT下搅拌12h,小心地用饱和的含水NH4Cl(50mL)猝灭,接着用H2O(350mL)猝灭。用CH2Cl2(1x30mL,2x50mL)提取水性悬浮液。合并的提取物用H2O(100mL)和盐水洗涤,干燥(MgSO4),过滤,并真空浓缩,得到粗产物(27.0g),为金色油状物。粗品物质经层析(在阶式梯度液(10-50%EtOAc/己烷的30%EtOAc/己烷部分)中洗脱产物,得到部分A(i)化合物(4.6g,30%收率),为乳白色粉末。
向部分A(i)化合物(1.0g,3.9mmol)的THF(16.8mL)的0℃溶液中加入(R)-(-)-1-甲氧基-2-丙醇(0.5g,5.8mmol)。然后加入Ph3P(1.5g,5.8mmol),接着缓慢加入DIAD(1.1mL,5.8mmol)。使反应混合物升温至RT并搅拌2天。反应混合物用H2O稀释并用Et2O提取。干燥(MgSO4)有机层,过滤,并真空浓缩,得到粗产物,为稠厚的、淡黄色油状物。粗品物质经层析(在10-30%EtOAc/己烷的阶式梯度液的10%EtOAc/己烷部分洗脱产物),得到部分A(ii)化合物(1.1g,85%收率),为无色油状物。
将含有部分A(ii)化合物(1.2g,3.6mmol)的MeOH(45.4mL)溶液的烧瓶抽空并用Ar(g)吹洗。以1份加入10%Pd/C(0.38g,0.36mmol)。抽空烧瓶,通过三通管用氢气囊填充并于RT下搅拌12h。通过过滤反应混合物,并用EtOAc洗涤。真空浓缩滤液,得到部分A(iii)化合物(0.81g,93%收率),为黄色油状物。
在Ar(g)气氛下,向部分A(iii)化合物(0.14g,0.59mmol)的THF(2.9mL)的0℃溶液中加入Ph3P(0.4g,1.3mmol)和(R)-1-苯基丙-2-醇(0.2g,1.3mmol)。将反应混合物搅拌5min,然后滴加入DIAD(0.3mL,1.3mmol)。将反应混合物于RT下搅拌12h。混合物用H2O稀释并用EtOAc提取。合并的有机层用1N NaOH水溶液和盐水洗涤,干燥(MgSO4),过滤,并真空浓缩,得到粗品化合物(1.0g),为淡黄色油状物。粗品物质经层析(从5-20%EtOAc/己烷的阶式梯度液的10%EtOAc/己烷部分洗脱产物),得到部分A(iv)化合物(0.17g,81%收率),为几乎无色的油状物。
于RT下,向部分A(iv)化合物在THF(1.8mL)和H2O(0.6mL)中的溶液中加入LiOH.H2O(0.02g,0.52mmol)。将反应混合物于45℃搅拌1h;加入另一份LiOH.H2O,并于45℃继续搅拌。6h后起始原被消耗。真空除去溶剂,剩余的含水层用0.5NHCl水溶液酸化至pH2,然后用EtOAc(3x)提取之。合并的有机层用盐水洗涤,干燥(MgSO4),过滤,并真空浓缩,得到粗品部分A(v)化合物(0.16g,86%收率),为淡黄色油状物。
向部分A(v)化合物(24mg,0.070mmol)、实施例10部分A化合物(19.13mg,0.091mmol)和HOAT(11.86mg,0.087mmol)的DMF(2mL)溶液中,加入iPr2NEt(0.016mL,0.091mmol)和EDC(16.70mg,0.087mmol)。将反应物于RT下搅拌48小时,然后真空浓缩。使残留物溶于MeOH,经制备型HPLC纯化(Phenomenex LunaAXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(6.5mg,18%收率),为无色油状物。[M+H]+=538.1,1H MR(400MHz,DMSO-d6)δ7.98-6.60(m,12H),4.63(m,2H),3.58(m,2H),3.22(s,3H),2.83(m,2H),1.20(m,3H).实施例32
按照与用于制备实施例4化合物的相同的通用程序,从实施例31部分A化合物和实施例4部分A化合物制备标题化合物,得到标题化合物(6mg,15%收率),为白色固体。[M+H]+=563.1,1H NMR(400MHz,DMSO-d6)δ7.75-6.64(m,13H),4.68(m,2H),3.52(m,2H),3.26(s,3H),2.85(m,2H),1.24(m,3H).实施例33
向实施例4化合物(25mg,0.042mmol)、氮杂环丁烷盐酸盐(5.08mg,0.054mmol)和HOAT(7.11mg,0.052mmol)的DMF(2mL)溶液中加入Hunig’s碱(0.019mL,0.109mmol)和EDC(10.01mg,0.052mmol)。将反应物于25℃搅拌18h并真空浓缩。残留物使用制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(15.65mg,59%收率),为白色固体冻干物。[M+H]+=638.4,1HNMR(500MHz,CD3OD)δ7.97-6.95(m,12H),4.72(m,1H),4.35(m,2H),4.18(m,2H),3.57(m,2H),3.39(s,3H),3.12(s,3H),2.35(m,2H),1.32(m,3H).实施例34
向实施例4化合物(25mg,0.042mmol)、3-羟基氮杂环丁烷盐酸盐(5.95mg,0.054mmol)和HOAT(7.11mg,0.052mmol)的DMF(2mL)溶液中加入Hunig’s碱(0.019mL,0.109mmol)和EDC(10.01mg,0.052mmol)。将反应物于25℃搅拌18小时,然后真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(8.1mg,30%收率),为白色固体冻干物。[M+H]+=654.1,1H NMR(500MHz,CD3OD)δ7.97-6.97(m,12H),4.71(m,1H),4.18(m,2H),3.95(m,2H),3.58(m,2H),3.39(s,3H),3.12(s,3H),1.32(m,3H).实施例35
将实施例10化合物(50mg,0.087mmol)的1NNaOH水溶液(523μL,0.523mmol)在微波炉中于140℃加热7min,然后冷却至RT。经制备型HPLC纯化反应物(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(8.5mg,17%收率),为灰白色冻干物。[M+H]+=572.3,1HNMR(500MHz,DMSO-d6)δppm 7.86-6.34(m,11H),4.68(m,1H),3.40(m,2H),3.19(s,3H),3.12(s,3H),1.15(m,3H).实施例36
向5-羟基烟酸(200mg,1.438mmol)的MeOH(2mL)溶液中加入浓H2SO4(0.077mL,1.438mmol)。将密封的反应容器放置于震荡器中并于70℃加热至回流18小时,然后冷却至RT。真空除去挥发物,残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从0%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分A甲基酯(180mg,82%收率),为白色固体。
向部分A化合物(180mg,1.175mmol)的丙酮(5mL)溶液中加入2-氨基-5-溴代噻唑一氢溴酸盐(611mg,2.351mmol)和Cs2CO3(957mg,2.94mmol)。将该混合物于回流(55℃)下搅拌18小时,然后冷却至RT并过滤。真空浓缩滤液。使残留物溶于EtOAc并用H2O和盐水洗涤,然后干燥(MgSO4),过滤,并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分B化合物(200mg,67%收率),为黄色固体。
向实施例1部分B化合物(114mg,0.298mmol)、部分B化合物(50mg,0.199mmol)和HOAT(54.2mg,0.398mmol)的DMF(1mL)溶液中加入Hunig’s碱(0.069mL,0.398mmol)和EDC(76mg,0.398mmol)。将反应物于25℃搅拌18h。加入另一份部分B化合物(25mg,0.10mmol),将反应物于25℃搅拌48小时,然后真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分C化合物(11mg,9%收率),为黄色固体冻干物。
在Ar(g)气氛下,向部分C化合物(11mg,0.018mmol)在THF(2mL)∶水(1mL)中的溶液中加入LiOH.H2O(4.29mg,0.179mmol)。将反应物于RT下搅拌18h。用1NHCl水溶液将反应混合物的pH调节至pH~7。真空浓缩反应混合物,残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1 H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(8mg,74%收率),为淡黄色固体冻干物。[M+H]+=600.3,1H NMR(500MHz,DMSO-d6)δ8.76-6.89(m,11H),4.68(m,1H),3.40(m,2H),3.23(s,3H),3.15(s,3H),1.18(m,3H).实施例37
向2-氨基-5-溴代噻唑一氢溴酸盐(495mg,1.904mmol)的丙酮(9.5mL)溶液中加入间苯二酚(315mg,2.86mmol)和碳酸铯(1203mg,3.69mmol)。将反应混合物在回流下搅拌14h。过滤混合物并用丙酮洗涤。真空浓缩滤液。残留物用EtOAc稀释,用盐水洗涤,干燥(MgSO4),过滤并真空浓缩。残留物经制备型HPLC纯化(PhenomenexLuna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从10%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分A化合物(45mg,11%),为棕色油状物。
向实施例1部分B化合物(82mg,0.216mmol)的DMF(1mL)溶液中加入部分A化合物(45mg,0.216mmol)、EDC(83mg,0.432mmol)、HOBT(66.2mg,0.432mmol)和Hunig’s碱(0.113mL,0.648mmol)。将反应混合物于RT下搅拌3天。反应混合物直接经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(6mg,5%收率),为棕色油状物。[M+H]+=571.3,1H NMR(500MHz,CDCl3)δ7.89-7.96(2H,m),7.63(1H,d,J=25.29Hz),7.44(1H,d,J=16.50Hz),7.24(1H,t,J=8.25Hz),7.16(2H,dd,J=9.35,2.20Hz),7.12(1H,s),6.92-6.97(1H,m),6.74-6.88(1H,m),6.61-6.72(1H,m),4.59-4.93(1H,m),3.51-3.67(2H,m),3.43(3H,d,J=4.95Hz),3.08(3H,d,J=6.05Hz),1.36(3H,dd,J=6.05,2.20Hz).实施例38
向部分A化合物(11mg,0.012mmol)的THF(1mL)溶液中,加入1N NaOH水溶液(0.3mL,0.300mmol)。将得到的混合物于RT下搅拌1h。混合物用EtOAc(3mL)稀释,用1NHCl水溶液(0.4mL)酸化。有机层用盐水洗涤,干燥(MgSO4)并真空浓缩,得到粗品部分B化合物(10mg,149%收率),为棕色油状物,其无须进一步纯化而用于下一步骤。
向粗品部分B化合物(10mg,0.018mmol)在CH2Cl2(1mL)中的混合物中,加入异氰酸甲酯(10.00mg,0.175mmol)。将得到的混合物于RT下搅拌18h。真空浓缩反应混合物,残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(4.0mg,54%收率),为黄色油状物。[M+H]+=628.3,1H NMR(500MHz,CDCl3)7.93(2H,d,J=8.80Hz),7.68(1H,s),7.44(1H,s),7.35-7.41(1H,m),7.16(3H,d,J=8.80Hz),6.96-7.05(3H,m),6.93-6.96(1H,m),5.01(1H,d,J=4.40Hz),4.87-4.96(1H,m),3.56-3.63(2H,m),3.43(3H,s),3.08(3H,s),2.91(3H,d,J=4.95Hz),1.36(3H,d,J=6.05Hz).实施例39
向实施例6部分B(i)化合物(150mg,0.465mmol)的DMF(1mL)溶液中加入2-氯代吡啶(0.088ml,0.931mmol)和K2CO3(193mg,1.396mmol)。将反应物加热至120℃并于120℃搅拌2天,然后冷却至RT。将LiCl(59.2mg,1.396mmol)加入到反应混合物中,将其加热至120℃并于120℃再搅拌另外3天。使反应物冷却至RT并过滤。真空浓缩滤液,经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分A化合物(38mg,21%),为白色固体。[M+H]+=386.3.
向部分A化合物(38mg,0.099mmol)的DMF(1mL)溶液中加入实施例4部分A化合物(49.4mg,0.197mmol)、EDC(37.8mg,0.197mmol)、HOBT(30.2mg,0.197mmol)和Hunig’s碱(0.052mL,0.296mmol)。将反应物于RT下搅拌4天。直接经制备型HPLC纯化反应物(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从15%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分B化合物(15mg,25%),为黄色固体。[M+H]+=618.4.
向部分B化合物(15mg,0.024mmol)的THF(1.5mL)溶液中加入1NNaOH水溶液(0.486mL,0.486mmol)。将混合物于RT下搅拌20小时,然后用EtOAc(6mL)稀释并用1NHCl水溶液(1.0mL)酸化。有机层用盐水洗涤,干燥(MgSO4)并真空浓缩,得到粗产物,将其经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从15%B-100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(4.5mg,31%),,为白色固体。[M+H]+=604.4.1HNMR(400MHz,CDCl3)δ8.28(1H,d,J=4.39Hz),7.94(2H,d,J=7.91Hz),7.91(1H,d,J=7.47Hz),7.85(1H,t,J=7.69Hz),7.79(2H,br.s.),7.70(1H,s),7.51(1H,t,J=7.91Hz),7.39(1H,dd,J=8.35,2.64Hz),7.24(1H,s),7.21(2H,br.s.),7.13-7.19(2H,m),7.09(1H,d,J=8.35Hz),3.07(3H,s).实施例40-42
在Ar(g)气氛下,将3-羟基-5-异丙氧基苯甲酸甲基酯(Bioorg.Med.Chem.Lett,15:2103(2005))(609mg,2.90mmol)、5-氯代吡嗪-2-羧酸甲基酯(500mg,2.90mmol)和K2CO3(1.20mg,8.69mmol)的CH3CN(20mL)溶液加热至80℃2h。使反应物冷却至RT,用CH2Cl2(50mL)稀释并过滤。真空浓缩滤液,残留物经层析(SiO2;40g;连续梯度从100%己烷至100%EtOAc,经40min),得到部分A化合物(1.005g,100%收率),为无色油状物。[M+H]+=347.B.
将部分B化合物(1.005g,2.9mmol)、氮杂环丁烷盐酸盐(326mg,3.48mmol)、Et3N(0.485mL,3.48mmol)和MgCl2的混合物(332mg,3.48mmol)于RT下搅拌5h。加入另一份氮杂环丁烷盐酸盐(326mg,3.48mmol)、Et3N(0.485mL,3.48mmol)和MgCl2(332mg,3.48mmol)。将反应物于RT下搅拌30min,然后于0℃贮存过夜。用CH2Cl2(50mL)稀释反应物,并过滤。真空浓缩滤液,残留物经层析(SiO2;40g;连续梯度从100%己烷至100%EtOAc,经40min),得到部分B化合物(267mg,25%收率),为无色油状物。[M+H]+=372.
将部分B化合物(267mg,0.72mmol)和LiOH.H2O(90mg,2.16mmol)的THF(4mL)/H2O(4mL)溶液于RT下搅拌5h。用1NHCl水溶液将反应物酸化至pH 2,然后用EtOAc(3x 10mL)提取。合并的有机提取物用盐水洗涤(10mL),干燥(MgSO4),过滤,并真空浓缩,得到部分C化合物(200mg,78%收率),为白色固体。[M+H]+=358.D.
向部分C化合物(50mg,0.140mmol)的DCM(1mL)溶液中加入1-氯-N,N,2-三甲基丙-1-烯-1-胺(0.022mL,0.168mmol)。将反应物于25℃搅拌30min。当所有的酸转化为酰氯时,加入实施例4部分A化合物(42.0mg,0.168mmol)和2,6-二甲基吡啶(0.041mL,0.350mmol)。将反应物于25℃搅拌18h。加入另一份实施例4部分A化合物(42.0mg,0.168mmol),接着加入吡啶(0.023mL,0.280mmol)。将反应物于25℃搅拌48h。真空浓缩反应物,残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分D化合物(20mg,24%收率),为褐色固体。[M+H]+=590.5.
向部分D化合物(20mg,0.034mmol)的THF(1mL)溶液中加入1NNaOH水溶液(0.051mL,0.051mmol)。将反应物于25℃搅拌数小时。加入另一份1N NaOH水溶液(0.025mL),将反应物于25℃搅拌18h。用1N HCl水溶液中和反应物并经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(5mg,26%收率),为固体褐色冻干物。[M+H]+=576.5.1H NMR(400MHz,MeOH-d3)δ8.72(s,1H),8.48(s,1H),7.92(m,1H),7.87(s,1H),7.79(m,1H),7.72(s,1H),7.45(m,1H),7.40(s,1H),7.18(m,1H),7.05(s,1H),4.22(m,2H),4.15(m,1H),3.55(m,2H),2.41(m,2H),1.35(m,6H).实施例44
向实施例6部分B(i)化合物(2.00g;6.2mmol)在THF(31.0mL)中的0℃溶液中加入丙-2-醇(0.82g,13.7mmol)和Ph3P(3.6g;13.7mmol),接着滴加入DIAD(2.7mL;13.7mmol)。在Ar(g)气氛下,将反应物于25℃搅拌16h。用H2O稀释反应物并用EtOAc(3x)提取。合并的有机提取物用1N NaOH水溶液和盐水洗涤,干燥(MgSO4)并真空浓缩。粗品残留物经层析(SiO2;从10-20至40%溶剂B的阶式梯度液,其中溶剂A=己烷和溶剂B=EtOAc),得到部分A化合物(2.4g;100%)。
向部分A化合物(2.3g;6.33mmol)在THF(52.3mL)和H2O(5.23mL)中的溶液中加入LiOH·H2O(0.61g;25.3mmol)。将在密封小瓶中的反应物于45℃搅拌1h,然后冷却至RT。由于起始原料只有少量转化为产物,因此加入另外一当量的LiOH·H2O。将反应物于50℃搅拌16h。真空除去溶剂,剩余的含水溶液用0.5N HCl水溶液酸化至pH<2。含水层用EtOAc(3x)提取。合并的有机提取物用盐水洗涤,干燥(MgSO4)并真空浓缩,得到部分B化合物(2.07g;88%)。
向部分B化合物(50mg,0.143mmol)的DCM(1mL)溶液中加入1-氯-N,N,2-三甲基丙-1-烯-1-胺(0.023mL,0.171mmol)。将反应物于25℃搅拌30min。当所有的酸已被转化为酰氯时,加入实施例4部分A化合物(42.9mg,0.171mmol)和2,6-二甲基吡啶(0.042mL,0.357mmol)。将反应物于25℃搅拌18h,此后加入更多的实施例4部分A化合物(42.9mg,0.171mmol),接着加入吡啶(0.023mL,0.285mmol)。将反应物于25℃搅拌48h,然后真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分C化合物(20mg,25%收率),为油状物。[M+H]+=583.5.
向部分C化合物(20mg,0.034mmol)的THF(1mL)溶液中加入1N NaOH水溶液(0.051mL,0.051mmol)。将反应物于25℃搅拌18h。经2天的时间加入另外2.5当量的1N NaOH水溶液。当反应完成时,用1NHCl水溶液中和该混合物并用EtOAc提取。干燥(MgSO4)有机层并真空浓缩。残留物经制备型HPLC纯化(Phenomenex LunaAXIA 5u C18 30x100mm柱;于220nm检测;流速=40mL/min;连续梯度从50%B至100%B,经10min+2min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(19.6mg,定量收率),为白色固体冻干物。[M+H]+=569.5;1H NMR(500MHz,CDCl3)δ7.92(d,J=10Hz,2H),7.82(d,1H),7.76(s,1H),7.45(m,2H),7.31(m,2H),7.15(m,3H),6.83(s,1H),4.68(m,1H),3.07(s,3H),1.37(m,6H).实施例45
经30min向3,5-二羟基苯甲酸甲基酯(5g,29.7mmol)和K2CO3(6.16g,44.6mmol)在DMF(15mL)中的搅拌的悬浮液中加入苄基溴(4.95mL,41.6mmol)。将反应物于25℃搅拌18小时,然后过滤。用DCM稀释滤液并用1N HCl水溶液、饱和的含水NH4Cl和盐水洗涤。干燥(MgSO4)有机层并真空浓缩。粗品(白色固体)残留物经层析(粗产物溶于少量的DCM中并装载到330g SiO2柱中,该柱用从0至60%EtOAc/己烷的80min梯度液洗脱),得到部分A化合物(2.10g,27%收率),为白色固体。[M+H]+=259.1.
将5-溴代-2-(甲硫基)吡啶(300mg,1.470mmol)和(2078mg,3.38mmol)在iPrOH(20mL)和H2O(10mL)中的溶液于RT下搅拌过夜。滤除固体。真空浓缩滤液,然后再溶解于EtOAc(100mL)中,并用H2O(2x20mL)和盐水(10mL)洗涤。干燥(MgSO4)有机层并真空浓缩,得到部分B化合物(349.2mg,1.479mmol,101%收率),为白色固体。[M+H]+=236/238.
向部分A化合物(1g,3.87mmol)和部分B化合物(0.914g,3.87mmol)在DMF(5mL)中的搅拌溶液中加入K2CO3(0.803g,5.81mmol)。将反应物于80℃搅拌24h,加入更多的K2CO3(0.5eq,250mg),将反应物于120℃搅拌18h。使反应物冷却至RT,用EtOAc稀释并用H2O和盐水洗涤。干燥(Na2SO4)有机层并真空浓缩.粗品残留物经层析(粗产物溶于少量DCM中并装载到120g SiO2柱中,该柱用从0至100%EtOAc/己烷的50min的梯度液洗脱,接着于100%EtOAc经20min洗脱),得到部分C化合物(1.26g,79%收率),为灰白色固体。[M+H]+=414.1.
向部分C化合物(1.26g,3.05mmol)的EtOAc(20mL)和EtOH(20mL)溶液中加入10%Pd/C(湿)(3.24g,3.05mmol)。在H2(g)气囊及25℃下搅拌反应物18h。过滤除去Pd/C,用EtOAc(3x)洗涤滤饼。真空浓缩滤液,得到部分D化合物(975mg,99%收率),为无色油状物。[M+H]+=324.0.
向部分D化合物(160mg,0.495mmol)和2-碘代丙烷(168mg,0.990mmol)的DMF(2mL)溶液中加入K2CO3(205mg,1.485mmol)。将反应物于120℃搅拌48h。加入更多的K2CO3(205mg,1.485mmol),将反应物于120℃搅拌18h。重复该过程3次,直至反应完成。使反应物冷却至RT并过滤。残留物经制备型HPLC纯化(PhenomenexLuna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到所需的部分E化合物(72.6mg,41.8%收率),为黄色油状物。[M+H]+=352.1.
向部分E化合物(72.6mg,0.207mmol)和Hunig’s碱(0.108mL,0.620mmol)在DCM(2mL)和DMF(.025mL)中的溶液中加入EDC(79mg,0.413mmol),接着加入HOBt一水合物(63.3mg,0.413mmol)。将反应混合物于25℃搅拌5min,然后加入实施例4部分A化合物(78mg,0.310mmol)。将反应物于25℃搅拌48小时,然后真空浓缩。使残留物溶于MeOH,过滤除去固体杂质,并经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;从30%B至100%B的连续梯度,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分F化合物(65.3mg,54%收率),为橙色油状物。[M+H]+=584.0.
向部分F化合物(65.3mg,0.112mmol)的THF(2mL)溶液中加入1N NaOH水溶液(0.201mL,0.201mmol)。将反应物于25℃搅拌数小时。加入另一份1N NaOH水溶液(0.201mL,0.201mmol),将反应物于25℃搅拌18h。加入更多的1N NaOH水溶液(0.1mL,0.1mmol),将反应物于25℃搅拌数小时。用1NHCl水溶液中和反应物并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5uC1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(46.5mg,73%收率),为白色固体冻干物。[M+H]+=570.0;1H NMR(400MHz,MeOH-d4)δ8.82(s,2H),8.10(m,2H),7.80(m,1H),7.72(s,1H),7.64(m,1H),7.50(m,1H),7.35(m,1H),7.20(s,1H),7.02(s,1H),4.73(m,1H),3.40(m,3H),1.35(m,6H).实施例46
向实施例45部分A化合物(250mg,0.968mmol)和部分A化合物(233mg,0.968mmol)在DMF(2mL)中的搅拌溶液中加入K2CO3(201mg,1.452mmol)。将反应物于80℃搅拌24小时,然后于120℃搅拌18h。加入另一份K2CO3(0.5eq,67mg),将反应物于120℃搅拌18h。使反应物冷却至RT,过滤,并用MeOH稀释。所得溶液经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分B化合物(100mg,25%收率),为棕色油状物。[M+H]+=419.1.
向部分B化合物(100mg,0.239mmol)在EtOAc(2mL)和EtOH(2.000mL)中的溶液中加入10%Pd/C(wet)(127mg,0.119mmol)。将反应物在H2(g)气囊下于25℃搅拌18h。滤除Pd/C,并真空浓缩滤液,得到部分C化合物(65mg,83%收率),为白色固体。[M+H]+=329.1.
向部分C化合物(65mg,0.198mmol)和2-碘代丙烷(67.3mg,0.396mmol)的DMF(2mL)溶液中加入K2CO3(82mg,0.594mmol)。将反应物于120℃搅拌数小时。使反应物冷却至80℃并搅拌18h。例如另一份LiCl(16.79mg,0.396mmol),将反应物于120℃搅拌24h。加入更多的LiCl(16.79mg,0.396mmol),将反应物于120℃搅拌18小时,然后冷却至RT,过滤并用MeOH稀释。混合物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分D化合物(27.4mg,38.8%收率),为带棕色的油状物。[M+H]+=357.1.
向部分D化合物(27.4mg,0.077mmol)和Hunig’s碱(0.040mL,0.231mmol)在DCM(2mL)和DMF(0.025mL)中的溶液中加入EDC(29.5mg,0.154mmol),接着加入HOBt一水合物(23.55mg,0.154mmol)。将反应混合物于25℃搅拌5min,然后加入实施例4部分A化合物(28.9mg,0.115mmol)。将反应物于25℃搅拌48小时,然后真空浓缩。使残留物溶于MeOH,过滤,并经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B至100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分E化合物(14mg,31%收率),为混浊油状物。[M+H]+=589.0.F.
向部分E化合物(14mg,0.024mmol)的THF(1mL)溶液中加入1N NaOH水溶液(0.036mL,0.036mmol)。将反应物于25℃搅拌数小时。加入更多的1N NaOH水溶液(0.036mL,0.036mmol),将反应物于25℃搅拌18h。加入更多的1NNaOH水溶液(0.036mL,0.036mmol),将反应物于25℃搅拌数小时。将反应物直接经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(5.9mg,43%收率),为灰白色固体冻干物。[M+H]+=575.0;1H NMR(500MHz,CDCl3)δ8.27(s,1H),7.97(m,1H),7.73(m,1H),7.67(s,1H),7.34(m,2H),7.30(s,1H),7.25(m,1H),7.17(s,1H),6.71(s,1H),4.64(m,2H),4.55(m,1H),4.16(m,2H),2.29(m,2H),1.28(m,6H).实施例47
向实施例45部分E化合物(130mg,0.370mmol)和实施例36部分B化合物(139mg,0.555mmol)的DCM(5mL)溶液中加入PyBOP(385mg,0.740mmol)和Hunig’s碱(0.258mL,1.480mmol)。将反应物于25℃搅拌18小时,然后真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x 100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到部分C化合物(36mg,16%收率),为棕色油状物。[M+H]+=585.5g/mol.
使部分A化合物(36mg)溶于THF(3mL)和H2O(0.3mL)中,并加入LiOH.H2O(13.29mg,0.555mmol)。将反应物于25℃搅拌数小时,然后用1N HCl水溶液中和并真空浓缩。残留物经制备型HPLC纯化(Phenomenex Luna AXIA 5u C1830x100mm柱;于220nm检测;流速=40mL/min;连续梯度从30%B-100%B,经10min+5min保留时间(于100%B中),其中A=90∶10∶0.1H2O∶MeOH∶TFA和B=90∶10∶0.1MeOH∶H2O∶TFA),得到标题化合物(10.5mg,30%收率),为灰白色固体冻干物。[M+H]+=570.9;1HNMR(400MHz,CDCl3)δ8.97(s,1H),8.63(s,1H),8.50(m,1H),8.08(d,J=8.8Hz,1H),7.99(m,1H),7.52(m,1H),7.43(s,1H),7.29(s,1H),7.19(s,1H),6.84(m,1H),4.66(m,1H),3.39(s,3H),1.38(m,6H).测定和生物学数据
本发明的式I化合物,包括在其实施例中描述的化合物,已在下面的测定法中进行测试并显示为葡糖激酶的激活剂。一般来说,本发明的化合物,如公开于下面的实施例中的具体化合物,在相当于(或更大于)100μM,优选10μM,更优选1μM的浓度时已被确定能提高葡糖激酶的活性,从而证实本发明的化合物为特别有效的葡糖激酶活性增强剂。效力可以被计算并表示为EC50(达到完全激活的50%的浓度)和/或以上背景值的最大激活百分数,和指采用下述测定系统测定的活性。
本发明的式I化合物,包括在其实施例中描述的化合物,已在下面的测定法中进行测试并显示为葡糖激酶的激活剂。葡糖激酶串联酶的测定
人葡糖激酶(GK)的酶促活性通过将GK、ATP和葡萄糖温育一离散的时间段,接着用EDTA(乙二胺四-乙酸)猝灭来测定。然后产物葡萄糖-6-磷酸(G6P)的相对量通过使用G6P脱氢酶进行检测测定并测定在405nm的波长下硫代NAD(硫代-烟酰胺腺嘌呤二核苷酸)向硫代NADH(硫代-二氢烟酰胺腺嘌呤二核苷酸)的转化。这种‘去偶’的酶促反应被指定为GK‘串联’测定。化合物激活GK可使用这种测定进行评价。下述的GK串联测定方案使用从0至100μM的一系列范围的激活剂化合物浓度在5和12mM葡萄糖的存在下进行。将人全长葡糖激酶(GK,15nM)与5或12mM葡萄糖在一384孔黑色透明底的微量滴定板中一起温育。为启动GK反应,将镁-ATP(3mM终浓度)加入到在缓冲液(25mM HEPES缓冲液的最终缓冲液条件,pH 7.1,含有1mM二硫苏糖醇和5%DMSO)中的GK中。总反应提及为20μL。使反应进行10分钟,然后用5μL EDTA猝灭;终浓度45mM)。然后将检测反应的组分,硫代NAD和G6PDH(葡萄糖-6-磷酸脱氢酶)(终浓度分别为650μM和3.33单位)以25μL的体积加在一起(得到总体积50μL)。吸光度测量在Spectramax Plus 384吸光度板式读出仪(Molecular Devices)于405nm处进行。读出吸光度,减去背景葡萄糖-6-磷酸水平,然后将激活率计算为对照活性的百分比。对照活性采用在媒介物(DMSO)的存在下的GK,减去背景葡萄糖-6-磷酸来测定。背景葡萄糖-6-磷酸通过在用ATP启动反应前,用EDTA预猝灭GK测定。人GK的表达和纯化
如Mookhtiar et al(1)所述,于25℃,在BL21STAR(DE3)pLysS细胞(Invitrogen)中表达全长人肝GK(未标记的)。基本如Lange(2)所述(稍作修改)纯化蛋白。简言之,通过3个冷冻和融化循环溶解细胞,以15000g离心以便澄清,并用40-65%(NH4)2SO4沉淀。使得到的沉淀再悬浮于缓冲液中,渗析,并直接施加于Q-Sepharose(Sigma)柱上,接着用线性100-600mM KCl的梯度液洗脱。汇集含有GK的流分,相对于25mM Hepes pH 7.2/1mM MgCl2/1mM EDTA/0.1M KCl/1mM DTT渗析过夜,然后用含有加入了10%的甘油的相同缓冲液再次渗析。参考文献1.Mookhtiar,K.A.et al.,“大鼠肝葡糖激酶调节蛋白的异种表达和鉴定(Heterologous expression and characterization of rat liverglucokinase regulatory protein”,Diabetes,45:1670-1677(1996).2.Lange,A.J.et al.,“肝葡糖激酶的表达和定向位点突变(Expression and site-directed mutagenesis of hepatic glucokinase”,Biochem.J.,277:159-163(1991).
对测试的实施例化合物的生物学数据示于下表中。
实施例号 | 人葡糖激酶的EC50(nM)@12mM葡萄糖 |
33 | 6 |
3 | 13 |
34 | 16 |
45 | 34 |
4 | 47 |
42 | 170 |
11 | 171 |
17 | 179 |
对于其它实施例,EC50values could not be calculated from theactivation curves,so the maximal activation data(expressed,为%ofbasal activation)for the实施例化合物tested are shown in the tablebelow.
体内研究:口服葡萄糖耐量试验(OGTT)
实施例号 | 最大激活(%)人葡糖激酶@12mM葡萄糖 |
32 | 118% |
38 | 144% |
46 | 124% |
口服葡萄糖耐量试验在雄性DIO(食物诱导的肥胖)C57BL/6J小鼠中进行,这些大鼠在实验前用高脂肪食物(来自脂肪的60%kcal)喂食26周。在用于实验前将小鼠进食过夜。在以2g/kg体重的剂量口服给予葡萄糖溶液(口服葡萄糖耐量试验;OGTT)之前60min口服给予试验化合物或媒介物(10%二甲基乙酰胺+10%乙醇+10%Cremophore+70%水)。在给予葡萄糖(2小时的时程)之前和之后的不同时间点,从采集的尾血样本测定血糖水平。生成血糖的时间曲线并计算从0至120min期间的曲线下的基线面积的变化(ΔAUC)(给予葡萄糖的时间为零时间)。
下表中的实施例化合物在如上所述的DIO小鼠的OGTT试验中减少葡萄糖AUC水平。
实施例号 | 葡萄糖的减少30mg/kg剂量的AUC |
4 | 37% |
Claims (17)
1.具有以下结构的化合物,其立体异构体、其前药酯,或其药学上可接受的盐:
其中
R1选自
烷基,
芳基,
芳基烷基,
杂芳基,或
杂芳基烷基;
R2选自
烷基,
芳基,
芳基烷基,
杂芳基,或
杂芳基烷基;
X选自以下的基团
S,
O,
N,
NR3,或
CR3;
Y选自以下的基团
N,
CR4,或
NR4;
Z选自以下的基团
O,
S,
S(O),
S(O)2,或
NR5a;
R3、R4和R5为相同或不同的且独立选自以下的基团
H,
卤素,
烷基,
芳基,
杂芳基,
芳基烷基,或
杂芳基烷基;
然而,当X为NR3或Y为NR4时,R3和R4不是卤素;
R5a选自以下的基团
H,
烷基,或
芳基;
R6和R7为相同或不同的且独立选自以下的基团
H,
卤素,或
烷基;
R8选自以下的基团
芳基,
杂芳基,
-PO(OR9)(OR10),
-PO(OR9)R10,或
-PO(R9)R10;
R9和R10为相同或不同的且独立选自氢和烷基;
m是0或1;
n是0、1、2或3;
前提是
当Z为O、S、S(O)或S(O)2时,则R8必须被选自以下的取代基取代
5)烷氧基;
6)四唑基;
7)-SO2NRiRj;
8)CN;
11)卤代(如Cl、F、CF3);
13)烷基;
14)和
其中Rf和Rg独立选自H、烷基和芳基;
Rh为烷基或芳基;和
Ri和Rj独立选自H、烷基和芳基;
前提是Ri和Rj中的至少一个不是H。
3.权利要求1定义的化合物,其中X为S,Y为CH和m为0。
6.权利要求1定义的化合物,其中Z为O或NR5a。
7.权利要求6定义的化合物,其中Z为O。
8.权利要求5定义的化合物,其中
R1为烷氧基烷基、羟基烷基、烷基、杂芳基或卤代杂芳基;
R2为芳基、烷基磺酰基芳基、烷基、芳基烷基、杂环基羰基杂芳基或烷基磺酰基杂芳基;
R5为氢;
Z为O,S或SO2;
n是0或1;
R6和R7各自为氢;和
R8为苯基或杂芳基、
其中R8被-C(O)NRfRg、-C(O)ORh、烷氧基、四唑基、烷基、卤代、CF3或-SO2NRiRj取代。
12.药用组合物,其含有权利要求1定义的化合物及其药学上可接受的载体。
13.药用组合物,其含有权利要求1定义的化合物和另一种治疗剂,所述治疗剂为抗糖尿病药、抗高血糖症药、抗高胰岛素血症药、抗视网膜病药、抗神经病药、抗肾病药、抗动脉粥样硬化药、抗感染药、抗局部缺血药、抗高血压药、抗肥胖症药、抗血脂异常药、抗高脂血症药、抗高甘油三酯血症药、抗高胆固醇血症药、抗局部缺血药、抗癌药、抗细胞毒性剂、抗再狭窄药、抗胰腺药、降脂药、食欲抑制药、记忆增强剂或促智药。
14.一种治疗、预防或延缓需要葡糖激酶激活剂治疗的疾病的进展的方法,该方法包括给予需要治疗的哺乳动物患者治疗有效量的权利要求1定义的式I化合物。
15.权利要求14定义的方法,其中所述疾病为糖尿病、高血糖症、受损的葡萄糖耐受性、胰岛素抗性、高胰岛素血症、视网膜病、神经病、肾病、延迟的伤口愈合、动脉粥样硬化及其后遗症、异常的心脏功能、心肌缺血、中风、代谢综合征、高血压、肥胖症、异常血脂症、高酯血症、高甘油三酯血症、高胆固醇血症、低HDL、高LDL、非心脏缺血、感染、癌症、血管再狭窄、胰腺炎、神经退行性疾病、脂质紊乱、认知功能障碍和痴呆、骨病、HIV蛋白酶相关脂质代谢障碍,和青光眼。
16.一种激活葡糖激酶的方法,该方法包括给予需要治疗的哺乳动物患者治疗有效量的权利要求1定义的式I化合物。
17.一种治疗II型糖尿病的方法,该方法包括给予需要治疗的患者权利要求1定义的化合物。
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- 2008-06-11 JP JP2010512313A patent/JP2010529203A/ja not_active Withdrawn
- 2008-06-11 EP EP08770668A patent/EP2170852A1/en not_active Withdrawn
- 2008-06-11 US US12/663,807 patent/US8222285B2/en active Active
- 2008-06-11 CN CN200880019467A patent/CN101711238A/zh active Pending
Cited By (4)
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WO2016112863A1 (zh) * | 2015-01-14 | 2016-07-21 | 中国科学院上海药物研究所 | N-取代-3,5-二取代苯甲酰胺类化合物及其制备方法和应用 |
CN105837599A (zh) * | 2015-01-14 | 2016-08-10 | 中国科学院上海药物研究所 | N-取代-3,5-二取代苯甲酰胺类化合物及其制备方法和应用 |
CN107108656A (zh) * | 2015-01-14 | 2017-08-29 | 中国科学院上海药物研究所 | N‑取代‑3,5‑二取代苯甲酰胺类化合物及其制备方法和应用 |
CN107108656B (zh) * | 2015-01-14 | 2019-11-05 | 中国科学院上海药物研究所 | N-取代-3,5-二取代苯甲酰胺类化合物及其制备方法和应用 |
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US20100179121A1 (en) | 2010-07-15 |
JP2010529203A (ja) | 2010-08-26 |
WO2008154563A1 (en) | 2008-12-18 |
US8222285B2 (en) | 2012-07-17 |
EP2170852A1 (en) | 2010-04-07 |
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