CN101611023A - 1-苯基1-硫代-d-山梨醇衍生物 - Google Patents
1-苯基1-硫代-d-山梨醇衍生物 Download PDFInfo
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- CN101611023A CN101611023A CNA2007800464362A CN200780046436A CN101611023A CN 101611023 A CN101611023 A CN 101611023A CN A2007800464362 A CNA2007800464362 A CN A2007800464362A CN 200780046436 A CN200780046436 A CN 200780046436A CN 101611023 A CN101611023 A CN 101611023A
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- phenyl
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- thio
- bromo
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Abstract
式(I)等表示的1-苯基1-硫代-D-山梨醇化合物或其可药用盐或它们的水合物,或者含有其作为有效成分的药物,作为抑制SGLT1和SGLT2两者的活性,同时具有抑制由消化道吸收葡萄糖的作用和尿糖排泄作用的新型糖尿病、糖尿病相关疾病或糖尿病性并发症的预防或治疗剂有用。
Description
技术领域
本发明涉及具有与肾脏中葡萄糖再吸收有关的钠依赖性葡萄糖协同转运蛋白1(SGLT1)和钠依赖性葡萄糖协同转运蛋白2(SGLT2)的抑制活性的药物,特别是糖尿病、糖尿病相关疾病或糖尿病性并发症的预防或治疗剂。
背景技术
如果患有糖尿病,则空腹时的血糖值显示126mg/dL以上。另外,空腹时的血糖值即使正常,但在餐后显示140~200mg/dL的高血糖值时,会被诊断为糖耐量异常(以下称为IGT(impaired glucose tolerance))。近年来,认为推迟从IGT向糖尿病转变,可以降低心血管障碍的危险。例如,1997年在中国进行的大庆IGT和糖尿病研究(Da Qing IGT andDiabetes Study)中,报告了通过控制饮食和运动可以显著抑制从IGT转变成2型糖尿病(参见非专利文献1)。另外,作为药物治疗有效的例子,报告了如果给与抑制糖的水解酶、使小肠对糖的吸收延迟的α-葡糖苷酶抑制剂阿卡波糖,可以抑制从IGT转变成2型糖尿病,而且也可以显著抑制高血压的发病(参见非专利文献2)。
由以上内容可知,对于抑制糖尿病的发病,通过食物疗法、运动和药物疗法控制IGT是重要的。但是,现状是糖尿病患者数量逐年增加,需要对应于各种成因和病状的新型治疗药。
糖尿病治疗的根本是食物疗法和运动疗法,但是难以维持规律的生活习惯时,或者即使采用这些疗法也不能得到充分的效果时,有必要采取药物疗法。
已知在小肠上皮以高频率表达钠依赖性葡萄糖协同转运蛋白1(SGLT1)。该SGLT1在小肠中,依赖于钠,负责葡萄糖或半乳糖的主动运输(参见非专利文献3)。另外,确认在糖尿病模型大鼠中SGLT1的mRNA和蛋白表达量亢进(参见非专利文献4)。近年来,报道了抑制SGLT1活性,抑制吸收来源于食物的葡萄糖,以求改善IGT的吡唑衍生物的合成例(参见专利文献1~6)。
另外,在肾脏中以高频率表达钠依赖性葡萄糖协同转运蛋白2(SGLT2),在肾小球中已经被过滤的葡萄糖通过SGLT2被再吸收(参见非专利文献5)。而且,将SGLT2抑制剂给与糖尿病大鼠,促进糖排泄到尿中,引起血糖降低作用,因而SGLT2特异性抑制剂被认为是新型糖尿病治疗药的目标分子(参见非专利文献6)。在这种背景下,对SGLT2抑制剂进行研究,提供了各种葡萄糖衍生物(参见专利文献7和8)。
因此,考虑如果可以同时抑制SGLT1和SGLT2的活性,则可以提供同时具有基于抑制SGLT1的餐后高血糖抑制作用以及基于抑制SGLT2的随时血糖降低作用的新型糖尿病治疗药。
迄今为止,报道了较强抑制SGLT2的1-硫代-D-山梨醇衍生物(参见专利文献9)。但是,对于强力抑制SGLT1和SGLT2两者的1-苯基1-硫代-D-山梨醇衍生物尚没有报道。
【专利文献1】国际公开第WO2002/098893号说明书
【专利文献2】国际公开第WO2004/014932号说明书
【专利文献3】国际公开第WO2004/018491号说明书
【专利文献4】国际公开第WO2004/019958号说明书
【专利文献5】国际公开第WO2005/121161号说明书
【专利文献6】国际公开第WO2004/050122号说明书
【专利文献7】欧洲专利申请公开第0850948号说明书
【专利文献8】国际公开第WO2001/068660号说明书
【专利文献9】国际公开第WO2006/073197号说明书
【非专利文献1】Pan XR,et al.Diabets Care,第20卷,534页,1997年
【非专利文献2】J.-L.Chiasson,et al.Lancent,第359卷,2072页,2002年
【非专利文献3】W.S.Lee,et al..J.Biol.Chem.第269卷,12032页,1994年
【非专利文献4】Y.Fujita,et al.Diabetologia第41卷,1459页,1998年
【非专利文献5】E.M.Wright,Am.J.Physiol.Renal.Physiol.,第280卷,F10页,2001年
【非专利文献6】G.Toggenburger,et al.Biochem.Biophys.Acta.,第688卷,557页,1982年
发明内容
本发明所要解决的课题在于提供抑制SGLT1和SGLT2两者的活性,同时具有抑制由消化道吸收葡萄糖的作用和尿糖排泄作用的新型糖尿病治疗药。
本发明人等为了解决上述课题,对于1-硫代-D-山梨醇衍生物的糖苷配基的取代基对SGLT抑制活性的效果进行了悉心研究,结果发现通过组合引入某种取代基强力抑制SGLT1和SGLT2两者活性的化合物(I)至化合物(VII),从而完成了本发明。
也就是说,本发明是
(1)式(I)表示的1-苯基1-硫代-D-山梨醇化合物或其可药用盐或它们的水合物,
【化1】
(2)式(II)表示的1-苯基1-硫代-D-山梨醇化合物或其可药用盐或它们的水合物,
【化2】
(3)式(III)表示的1-苯基1-硫代-D-山梨醇化合物或其可药用盐或它们的水合物,
【化3】
(4)式(IV)表示的1-苯基1-硫代-D-山梨醇化合物或其可药用盐或它们的水合物,
【化4】
(5)式(V)表示的1-苯基1-硫代-D-山梨醇化合物或其可药用盐或它们的水合物,
【化5】
(6)式(VI)表示的1-苯基1-硫代-D-山梨醇化合物或其可药用盐或它们的水合物,
【化6】
(7)式(VII)表示的1-苯基1-硫代-D-山梨醇化合物或其可药用盐或它们的水合物。
【化7】
本发明的另一种方式是含有上述式(I)至式(VII)表示的化合物或其可药用盐或它们的水合物作为有效成分的药物。
本发明的另一种方式是含有作为钠依赖性葡萄糖协同转运蛋白1和钠依赖性葡萄糖协同转运蛋白2活性抑制剂的上述式(I)至式(VII)表示的化合物或其可药用盐或它们的水合物作为有效成分的药物。
本发明的另一种方式是一种糖尿病、糖尿病相关疾病或糖尿病性并发症的预防或治疗剂,其特征在于,含有上述式(I)至式(VII)表示的化合物或其可药用盐或它们的水合物作为有效成分。
在1-硫代-D-山梨醇衍生物的糖苷配基上组合引入某种取代基的化合物抑制了SGLT1和SGLT2两者的活性。另外,这些化合物显示了优良的降血糖作用。
具体实施方式
本发明中使用的用语定义如下。
“可药用盐”是指与碱金属类、碱土金属类、铵、烷基铵等形成的盐,与无机酸或有机酸形成的盐,可以例举钠盐、钾盐、钙盐、铵盐、铝盐、三乙基铵盐、醋酸盐、丙酸盐、丁酸盐、甲酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、枸橼酸盐、硬脂酸盐、琥珀酸盐、乙基琥珀酸盐、乳糖酸盐、葡萄糖酸盐、葡庚糖酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、十二烷基硫酸盐、苹果酸盐、天冬氨酸盐、谷氨酸盐、己二酸盐、与半胱氨酸形成的盐、与N-乙酰基半胱氨酸形成的盐、盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、氢碘酸盐、烟酸盐、草酸盐、苦味酸盐、硫氰酸盐、十一烷酸盐、与丙烯酸聚合物形成的盐、与羧基乙烯基聚合物形成的盐等。
“水合物”是指本发明化合物或其盐的可药用的水合物。本发明的化合物或其盐暴露在大气中,或者通过重结晶等,会吸收水分,有时会带有吸附水,有时会形成水合物。本发明的水合物中也包含这种水合物。
以下说明本发明化合物(I)至(VII)的制备方法。
制备方法1
式中,RA表示甲基、乙基、甲氧基或甲硫基,RB表示甲基或氯基,RC表示苯甲基或烯丙基。
【化8】
(1)步骤1
化合物(1A)可以按照国际专利公开第WO2006/073197号说明书进行制备。另外,也可以按照以下所示参考例进行制备。由化合物(1A)使用正丁基锂、仲丁基锂、叔丁基锂等有机金属试剂可以制备锂试剂(2A)。作为这时反应使用的溶剂,可以例举四氢呋喃、乙醚、甲苯等。反应温度为-78℃至室温,优选-78℃~-25℃。或者也可以使用镁粉末制备格氏(Grignard)试剂(2A)。作为这时反应使用的溶剂,可以例举四氢呋喃、乙醚、二甘醇二甲醚等。另外,作为镁的活化剂,有时也使用碘或1,2-二溴乙烷。
接着,通过在化合物(2A)中加入硫代内酯(3A),可以得到化合物(4A)。加入硫代内酯(3A)时的温度,在(2A)为锂试剂的情况下优选-78℃~-25℃,在(2A)为格氏试剂的情况下优选-15℃~25℃。
(2)步骤2(还原)
使化合物(4A)与Et3SiH、i-Pr3SiH、t-BuMe2SiH或Ph2SiHCl在酸的存在下进行反应,可以合成化合物(5A)。作为该反应使用的酸,可以例举BF3·Et2O、CF3COOH、MeSO3H、InCl3等,作为溶剂,可以例举氯仿、二氯甲烷、乙腈或这些溶剂的混合溶剂,优选乙腈-氯仿、乙腈-二氯甲烷等与乙腈的混合溶剂。其中的反应温度为-60℃~25℃,优选-30℃~25℃。
(3)步骤3(脱保护)
上述得到的化合物(5A)中RC为苯甲基时,使用钯活性炭、氢氧化钯、或铂-钯活性炭等催化剂,在氢气环境下催化加氢,进行脱苯甲基化,可以得到发明化合物。其中,优选钯活性炭、氢氧化钯作为催化剂。作为该反应中使用的溶剂,可以例举甲醇、乙醇、异丙醇、乙酸乙酯、乙酸、以及这些溶剂的混合溶剂。反应温度为室温至回流温度,优选室温。
另外,在脱苯甲基化时,也可以使用BCl3、BCl3·Me2S、BBr3、AlCl3、CF3COOH、TfOH等酸。作为该反应中使用的溶剂,可以例举氯仿、二氯甲烷、乙腈、乙醚、四氢呋喃、二甲基硫醚、苯甲醚等。其中,优选在二甲基硫醚中使用CF3COOH、TfOH、乙二硫醇的方法。反应温度可以为-78℃~40℃。
化合物(5A)中RC为烯丙基(-CH2CH=CH2)时,可以在二甲基亚砜中使叔丁醇钾作用,进行异构化(-CH=CHCH3)后,使用盐酸或HgCl2/HgO除去。或者也可以在乙酸、对甲苯磺酸水合物、N,N’-二甲基巴比土酸等有机酸的存在下,使用Pd(PPh3)4、PdCl2、钯活性炭等除去。作为该反应中使用的溶剂,可以例举乙腈、乙醚、四氢呋喃等,反应温度可以为25℃~100℃。
制备方法2
化合物(5A)也可以按照以下所示的方法制备。其中,式中符号与上述含义相同。
【化9】
(4)步骤4
按照步骤1记载的方法,对中间体化合物(6A)使用正丁基锂、仲丁基锂、叔丁基锂等有机金属试剂,可以配制芳基锂试剂。向其中加入硫代内酯(3AB),可以得到化合物(7A)。作为这时反应中使用的溶剂,可以例举四氢呋喃、乙醚、甲苯等。反应温度为-78℃至室温,优选-78℃~-25℃。
(5)步骤5(酸水解)
使用盐酸、对甲苯磺酸1水合物等将化合物(7A)中的缩醛基水解,可以制备化合物(8A)。作为这时使用的溶剂,优选四氢呋喃、乙醇、甲醇、水、或这些溶剂的混合溶剂。反应温度为4℃至60℃,优选室温。另外,反应时间根据反应温度有所不同,为1小时~24小时。
(6)步骤6
对4-取代甲苯(9A)使用正丁基锂、仲丁基锂、叔丁基锂等,可以制备苯基锂试剂化合物(10A)。作为反应中使用的溶剂,可以例举四氢呋喃、乙醚、甲苯等。反应温度为-78℃至室温,优选-78℃~-25℃。反应时间优选为5分钟至30分钟。另外,也可以使用金属镁制备格氏试剂(10A)。作为反应中使用的溶剂,可以例举四氢呋喃、乙醚、二甘醇二甲醚等。接着,使试剂(10A)与化合物(8A)反应,可以制备化合物(11A)。
(7)步骤7(还原)
对化合物(11A)使Et3SiH、i-Pr3SiH、t-BuMe2SiH或Ph2SiHCl在酸的存在下进行反应,可以合成化合物(5A)。作为该反应使用的酸,可以例举BF3·Et2O、CF3COOH、InCl3等,作为溶剂,可以例举氯仿、二氯甲烷、乙腈或这些溶剂的混合溶剂,优选乙腈-氯仿、乙腈-二氯甲烷等与乙腈的混合溶剂。其中的反应温度为-60℃~25℃,优选-30℃~0℃。
特别优选的方法是下述方法。在乙腈溶剂中,使用约1当量的酸,在反应温度-15℃~-5℃下,进行反应性高的半缩醛部位的还原。接着,反应温度升温至0℃~5℃,再加入约1当量的酸,将苯甲基位的羟基还原。
硫代内酯(3A)的制备
【化10】
化合物(3A)可以参考Yuasa,H.,et al.J.Chem.Soc.Perkin Trans.1,2763页,1990年进行合成。或者也可以按照上述方案进行合成。
(8)步骤8
用在碱性条件下呈耐性,在中性或酸性条件下可以脱保护的保护基,保护化合物(3B)(可以参考国际公开第WO04/106352号说明书进行制备)的1位羟基。例如,使用3,4-二氢-2H-吡喃(3,4-DHP)和对甲苯磺酸1水合物,用四氢吡喃基(THP基)保护,可以合成化合物(3C)。这时的溶剂,优选四氢呋喃、乙醚、氯仿等。
(9)步骤9
乙酰氧基的脱保护可以使用甲醇钠、氢氧化钠、氢氧化锂、碳酸钾、碳酸铯、三乙胺等碱进行,溶剂可以使用甲醇、乙醇、含水甲醇等。接着,使用适当的碱使苯甲基溴、苯甲基氯或烯丙基溴等作用,可以得到化合物(3D)。作为碱,可以例举三乙胺、N-乙基-N,N-二异丙基胺、吡啶、碳酸钾、碳酸钙、碳酸铯、氢氧化钠、氢氧化钾、氢化钠、甲醇钠、叔丁醇钾等,优选碳酸钾、碳酸钙、碳酸铯、氢氧化钠、氢氧化钾、氢化钠。作为该反应中使用的溶剂,可以例举N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、二氧六环、二甲氧基乙烷等,反应温度优选为-20℃~25℃。
(10)步骤10
然后,将1位的保护基脱保护,可以得到化合物(3E)。例如,通过在甲醇或乙醇中用对甲苯磺酸或吡啶鎓对甲苯磺酸处理化合物(3D),可以除去THP基。
(11)步骤11
最后,用适当的氧化剂处理化合物(3E),可以制备硫代内酯(3A)。作为该反应中使用的氧化剂,优选二甲基亚砜-乙酸酐、Dess-Martinperiodinane、IBX等,反应温度为0℃~40℃。
本发明化合物可以抑制SGLT1和SGLT2两者的活性,通过抑制由消化道吸收葡萄糖的作用和尿糖排泄作用,改善IGT,预防或治疗糖尿病。
因此,本发明的化合物可以用作SGLT1或SGLT2抑制剂、或者糖尿病、糖尿病相关疾病和糖尿病并发症的预防或治疗剂的有效成分。
其中,“糖尿病”包括1型糖尿病、2型糖尿病、由特定原因引起的其他类型的糖尿病。
其中,“糖尿病相关疾病”可以例举肥胖、高胰岛素血症、糖代谢异常、高脂血症、高胆固醇血症、高甘油三酯血症、脂质代谢异常、高血压、充血性心力衰竭、浮肿、高尿酸血症、痛风等。
其中,“糖尿病并发症”可以分为急性并发症和慢性并发症。
“急性并发症”可以例举高血糖(酮酸中毒等)、感染症(皮肤、软组织、胆道系统、呼吸系统、尿路感染等)等。
“慢性并发症”可以例举细小血管病(肾病、视网膜病)、动脉硬化(粥样动脉硬化、心肌梗塞、脑梗塞、下肢动脉闭塞等)、神经障碍(感觉神经、运动神经、自律神经等)、足坏疽等。
主要的并发症是糖尿病视网膜病、糖尿病肾病、糖尿病神经障碍。
本发明化合物的给药量根据疾病、症状、体重、年龄、性别、给药途径等有所不同,对于成人为1天0.1~1000mg/kg体重,优选0.1~200mg/kg体重,更优选0.1~10mg/kg体重。可以将其1天1次至分数次给药。
本发明化合物以增强该化合物的作用或者降低该化合物的给药量等为目的,可以与SGLT1和SGLT2活性抑制药以外的作用机理的糖尿病治疗剂、糖尿病性并发症治疗剂、抗高脂血症剂、降压剂、抗肥胖剂、利尿剂、抗血栓剂等药物(以下简称为联用药物)组合使用。这时,本发明化合物与联用药物的给药时间没有限定,可以将这些药物同时给与给药对象,也可以设定时间差给药。而且,本发明化合物与联用药物可以作为含有各自的活性成分的2种制剂给药,也可以作为含有两种活性成分的单一制剂给药。联用药物的给药量可以以临床上使用的用量作为标准适当选择。另外,本发明化合物与联用药物的配比可以根据给药对象、给药途径、对象疾病、症状、组合等适当选择。例如,给药对象为人的情况下,相对于本发明化合物1重量份,可以使用联用药物0.01~100重量份。
另外,作为糖尿病治疗剂,可以例举胰岛素制剂(例如,由牛、猪的胰脏提取的动物胰岛素制剂;使用大肠菌或酵母,利用基因工程学合成的人胰岛素制剂;胰岛素锌;精蛋白锌胰岛素;胰岛素的片段或衍生物(例如INS-1等)、口服胰岛素制剂)、胰岛素抵抗性改善剂(例如,吡格列酮(Pioglitazone)或其盐(优选盐酸盐)、罗格列酮(Rosiglitazone)或其盐(优选马来酸盐)、利格列酮(Rivoglitazone)(CS-011)(R-119702)、西格列酮(Sipoglitazar)(TAK-654)、美格列酮(Metaglidasen)(MBX-102)、Naveglitazar(LY-519818)、MX-6054、巴格列酮(Balaglitazone)(NN-2344)、T-131(AMG131)、PPARγ激动剂、PPARγ拮抗剂、PPARγ/α双重激动剂、α-糖苷酶抑制剂(例如,伏格列波糖(Voglibose)、阿卡波糖(Acarbose)、米格列醇(Miglitol)、Emiglitate)、双胍类药(Biguanides)(例如,苯乙双胍(Phenformin)、二甲双胍(Metformin)、丁双胍(Buformin)或它们的盐(例如,盐酸盐、富马酸盐、琥珀酸盐))、胰岛素分泌促进剂(磺酰脲类药(例如,甲苯磺丁脲(Tolbutamide)、格列本脲(Glibenclamide)、格列齐特(Gliclazide)、氯磺丙脲(Chlorpropamide)、甲磺氮卓脲(Tolazamide)、乙酰磺环己脲(Acetohexamide)、氯磺吡脲(Glyclopyramide)、格列美脲(Glimepiride)、格列吡嗪(Glipizide)、氨磺丁唑(Glybuzole)等)、瑞格列奈(Repaglinide)、色那列奈(Senaglinide)、那格列奈(Nateglinide)、米格列奈(Mitiglinide)或其钙盐水合物)、GPR40激动剂、GPR40拮抗剂、GLP-1受体激动剂(例如,GLP-1、GLP-1MR剂、利拉鲁肽(Liraglutide)(NN-2211)、艾塞那肽(Exenatide)(AC-2993)(exendin-4)、艾塞那肽LAR、BIM-51077、Aib(8,35)hGLP-1(7,37)NH2、CJC-1131、AVE0010、GSK-716155)、胰淀素(Amylin)激动剂(例如,普兰林肽(pramlintide))、磷酸化酪氨酸磷酸酶(Phosphotyrosine phosphatase)抑制剂(例如,钒酸钠)、二肽基肽酶(dipeptidyl peptidase)IV抑制剂(例如,WO02/038541记载的化合物、NVP-DPP-278、PT-100、P32/98、维达列汀(Vildagliptin)(LAF-237)、P93/01、西他列汀(Sitagliptin)(MK-431)、Saxagliptin(BMS-477118)、SYR-322、MP-513、T-6666、GRC-8200等)、β3激动剂(例如,AJ-9677、AZ40140等)、糖异生抑制剂(例如,糖原磷酸化酶抑制剂、葡萄糖-6-磷酸酶抑制剂、胰高血糖素拮抗剂、果糖-1,6-二磷酸酶抑制剂)、SGLT(钠-葡萄糖协同转运蛋白,sodium-glucose cotransporter)抑制剂(例如,WO04/014931、WO04/089967、WO06/073197记载的化合物、T-1095、Sergliflozin(GSK-869682)、GSK-189075、KGT-1251、KGT-1681、KGA-2727、BMS-512148、AVE2268、SAR7226等)、11β-羟化类固醇脱氢酶抑制剂(例如,WO06/051662记载的化合物、BVT-3498、INCB13739)、GPR119激动剂(例如,PSN-632408、APD-668)、脂联素(adiponectin)或其激动剂、IKK抑制剂(例如,AS-2868)、AMPK活化剂、瘦素(leptin)抵抗性改善剂、促生长素抑制素受体激动剂、葡萄糖激酶活化剂(例如,Ro-28-1675)、胰脂肪酶抑制剂(例如,奥利司他(Orlistat)、ATL-962)、DGAT-1抑制剂。
作为糖尿病性并发症治疗剂,可以例举醛糖还原酶抑制剂(例如,托瑞司他(Tolrestat)、依帕司他(Epalrestat)、折那司他(zenarestat)、唑泊司他(zopolrestat)、米那司他(Minalrestat)、菲达司他(fidarestat)、CT-112)、神经营养因子及其增强剂(例如,NGF、NT-3、BDNF、神经营养蛋白产生及分泌促进剂)、神经再生促进剂(例如,Y-128)、PKC抑制剂(例如,鲁伯斯塔甲磺酸盐(ruboxistaurin mesylate;LY-333531))、AGE抑制剂(例如,ALT946、匹马吉定(pimagedine)、pyratoxathine、N-phenacylthiazolium溴化物(ALT766)、ALT-711、EXO-226、Pyridorin、吡多胺(Pyridoxamine))、活性氧清除剂(例如,硫辛酸)、脑血管扩张剂(例如,硫必利(Tiapride)、美西律(Mexiletine))、促生长素抑制素受体激动剂(例如,BIM23190)、细胞凋亡信号调节激酶1(apoptosis signal-regulating kinase-1)(ASK-1)抑制剂。
作为抗高脂血症剂,可以例举他汀类化合物(例如,普伐他汀(Pravastatin)、辛伐他汀(Simvastatin)、洛伐他汀(Lovastatin)、阿伐他汀(Atorvastatin)、氟伐他汀(Fluvastatin)、伊伐他汀(Itavastatin)、罗伐他汀(Rosuvastatin)、匹伐他汀(Pitavastatin)或它们的盐(例如,钠盐、钙盐))、角鲨烯合成酶抑制剂(例如,TAK-475)、贝特类化合物(例如,苯扎贝特(Bezafibrate)、氯贝特(Clofibrate)、双贝特(Simfibrate)、克利贝特(Clinofibrate))、ACAT抑制剂(例如,阿伐麦布(Avasimibe)、依鲁麦布(Eflucimibe))、阴离子交换树脂(例如,消胆胺(Cholestyramine))、丙丁酚(Probucol)、烟酸类药物(例如,尼可莫尔(nicomol)、烟酸戊四醇酯(niceritrol))、廿六烷五烯酸乙酯(ethyl icosapentate)、植物甾醇(例如,大豆甾醇(soysterol)、γ-谷维素(γ-oryzanol))、CETP抑制剂(例如,Torcetrapib、JTT-705、JTT-302、FM-VP4等)、胆固醇吸收抑制剂(例如,依泽替米贝(Ezetimibe)等)。
作为降压剂,可以例举血管紧张素转换酶抑制剂(例如,卡托普利(Captopril)、依那普利(Enalapril)、地拉普利(Delapril))、血管紧张素II拮抗剂(例如,坎地沙坦酯(Candesartan cilexetil)、氯沙坦(Losartan)、依普罗沙坦(Eprosartan)、缬沙坦(Valsartan)、替米沙坦(Telmisartan)、厄贝沙坦(Irbesartan)、他索沙坦(tasosartan)、阿齐沙坦(Azilsartan)(TAK-536))、钙拮抗剂(例如,马尼地平(Manidipine)、硝苯地平(Nifedipine)、氨氯地平(Amlodipine)、依福地平(Efonidipine)、尼卡地平(Nicardipine))、钾通道开放剂(例如,左色满卡林(Levcromakalim)、L-27152、AL0671、NIP-121)、可乐定(Clonidine)。
作为抗肥胖剂,可以例举中枢性抗肥胖药(例如,右旋酚氟拉明(Dexfenfluramine)、芬氟拉明(Fenfluramine)、苯叔丁胺(Phentermine)、西布茶明(Sibutramine)、安非拉酮(Amfepramone)、右旋苯丙胺(Dexamfetamine)、氯苯咪吲哚(Mazindol)、苯丙醇胺(Phenylpropanolamine)、氯苄苯丙胺(Clobenzorex);MCH受体拮抗剂(例如,WO06/035967记载的化合物、SB-568849;SNAP-7941、T-226296);神经肽Y拮抗剂(例如,CP-422935);大麻素(cannabinoid)受体拮抗剂(例如,利莫那班(Rimonabant)(SR-141716)、SR-147778);脑肠肽(ghrelin)拮抗剂;11β-羟化类固醇脱氢酶抑制剂(例如,BVT-3498、INCB13739))、胰脂肪酶抑制剂(例如,奥利司他(Orlistat)、ATL-962)、DGAT-1抑制剂、β3激动剂(例如,AJ-9677、AZ40140)、肽性食欲抑制剂(例如,瘦素(Leptin)、CNTF(睫状神经营养因子))、缩胆囊肽(Cholecystokinin)激动剂(例如,林替曲特(Lintitript)、FPL-15849)、摄食抑制剂(例如,P-57)。
作为利尿剂,可以例举黄嘌呤衍生物(例如,可可碱水杨酸钠、可可碱水杨酸钙)、噻嗪类制剂(例如,乙噻嗪(Ethiazide)、环戊噻嗪(Cyclopenthiazide)、三氯噻嗪(Trichlormethiazide)、氢氯噻嗪(Hydrochlorothiazide)、氢氟噻嗪(Hydroflumethiazide)、双环胺氢氯噻嗪(Bentylhydrochlorothiazide)、戊氟噻嗪(Penflutizide)、多噻嗪(Polythiazide)、甲氯噻嗪(Methyclothiazide))、抗醛甾酮制剂(例如,螺内酯(Spironolactone)、氨苯蝶啶(Triamterene))、碳酸脱水酶抑制剂(例如,乙酰唑胺(acetazolamide))、氯苯磺酰胺类制剂(例如,氯噻酮(Chlorthalidone)、美夫西特(Mefruside)、吲达帕胺(Indapamide))、阿佐塞米(Azosemide)、异山梨醇(Isosorbide)、依他尼酸(Ethacrynic acid)、苯吡磺苯酸(Piretanide)、布美他尼(Bumetanide)、呋塞米(Furosemide)。
作为抗血栓剂,可以例举肝素(例如,肝素钠、肝素钙、达肝素钠(dalteparin sodium)、AVE-5026)、华法林(例如,华法林钾等)、抗凝血酶药(例如,阿加曲班(Argatroban)、希美加群(Ximelagatran)、达比加群(Dabigatran)、Odiparcil、来匹卢定(Lepirudin)、比伐卢定(Bivalirudin)、地西卢定(Desirudin)、ART-123、依达肝素(Idraparinux)、SR-123781、AZD-0837、MCC-977、TGN-255、TGN-167、RWJ-58436、LB-30870、MPC-0920、培莫西卢定(Pegmusirudin)、Org-426751等)、血栓溶解药(例如,尿激酶(urokinase)、替来激酶(tisokinase)、阿替普酶(alteplase)、那替普酶(nateplase)、孟替普酶(monteplase)、帕米普酶(pamiteplase)等)、血小板凝集抑制药(例如,盐酸噻氯匹定(ticlepidine hydrochloride)、西洛他唑(cilostazol)、廿六烷五烯酸乙酯(ethyl icosapentate)、贝前列素钠(beraprost sodium)、盐酸沙格雷酯(sarpogrelate hydrochloride)等)、抗Xa抑制剂(例如,磺达肝素(Fondaparinux)、BAY-59-7939、DU-176b、YM-150、SR-126517、阿哌沙班(Apixaban)、雷扎沙班(Razaxaban)、LY-517717、MLN-102、Octaparine、奥米沙班(Otamixaban)、EMD-503982、TC-10、CS-3030、AVE-3247、GSK-813893、KFA-1982等)、血浆中羧肽酶B(或者作为活性型凝血酶可激活纤维蛋白溶解抑制剂(thrombin-activatablefibrinolysis inhibitor[TAFIa])已知的)抑制剂(例如,AZD-9684、EF-6265、MN-462)等。
本发明的化合物可以作为药物全身或局部地口服给药或非口服给药。
本发明化合物作为药物提供时,可以适当选择固体制剂、液体制剂等各种形式的制剂形态。这时,也可以配合制药学允许的载体。作为这种载体的实例,可以例举一般的赋形剂、增量剂、粘结剂、崩解剂、包衣剂、糖衣剂、pH调节剂、溶解剂或者水性或非水性溶剂等。由本发明化合物和这些载体,可以配制片剂、丸剂、胶囊剂、颗粒剂、粉剂、散剂、溶液剂、乳剂、悬浊剂、注射剂等。
实施例
以下结合参考例、实施例和试验例,进一步详细说明本发明。
参考例1
2,3,4,6-四-O-苯甲基-5-硫代-D-葡萄糖酸(glucono)-1,5-内酯(化合物(3AB))的制备
【化11】
(1)四氢-2H-吡喃-2-基2,3,4,6-四-O-乙酰基-5-硫代-D-吡喃葡萄糖的制备
在2,3,4,6-四-O-乙酰基-5-硫代-D-吡喃葡萄糖(2.0g,5.49mmoL)的氯仿(40mL)溶液中,加入3,4-二氢-2H-吡喃(1.5mL,16.5mmoL)和对甲苯磺酸1水合物(104mg,0.549mmoL),在室温下搅拌1小时。向反应液中加入饱和碳酸氢钠水溶液,用氯仿萃取,用饱和食盐水洗涤有机层后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=1∶1)精制得到的残渣,得到淡黄色无定形的标题化合物(2.56g)。
(2)四氢-2H-吡喃-2-基2,3,4,6-四-O-苯甲基-5-硫代-D-吡喃葡萄糖的制备
接着,在四氢-2H-吡喃-2-基2,3,4,6-四-O-乙酰基-5-硫代-D-吡喃葡萄糖(2.5g)的甲醇(40mL)溶液中,加入25wt%甲醇钠的甲醇溶液(0.11mL,0.55mmoL),搅拌3小时。加入少量的干冰,中和反应液后,浓缩反应液。将得到的残渣溶解于N,N-二甲基甲酰胺(20mL)。在冰冷条件下将该溶液滴加到氢化钠(1.3g,32.9mmol;60%oil)和N,N-二甲基甲酰胺(4mL)的悬浊液中。在室温下搅拌反应液20分钟后,冷却至4℃,加入苯甲基溴(5.6g,32.9mmoL)。在室温下搅拌反应液12小时,加入甲醇(5mL),搅拌30分钟。在反应液中加入冰水,用乙酸乙酯萃取,用饱和食盐水洗涤有机层后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=6∶1)精制得到的残渣,得到标题化合物(3.36g,96%;2步)。
(3)2,3,4,6-四-O-苯甲基-5-硫代-D-吡喃葡萄糖的制备
将四氢-2H-吡喃-2-基2,3,4,6-四-O-苯甲基-5-硫代-D-吡喃葡萄糖(3.30g,5.15mmoL)、吡啶鎓对甲苯磺酸(518mg,2.06mmoL)和乙醇(58mL)的混合物在80℃下搅拌2小时。将反应液冷却至室温,浓缩溶剂。将得到的残渣溶解于乙酸乙酯。将该溶液用饱和碳酸氢钠水溶液、饱和食盐水洗涤后,用无水硫酸镁干燥。过滤除去干燥剂后,用硅胶柱色谱法(己烷∶乙酸乙酯=3∶1)精制残渣,得到无色晶体的标题化合物(2.89g,quant.)。
13C NMR(125MHz,氯仿-d)δ41.3,67.8,71.6,73.0,73.2,75.6,76.2,81.9,82.9,84.4,127.5,127.7,127.8,127.9,128.0,128.3,128.4,128.5,137.8,138.3,138.8.
(4)2,3,4,6-四-O-苯甲基-5-硫代-D-葡萄糖酸-1,5-内酯的制备
将2,3,4,6-四-O-苯甲基-5-硫代-D-吡喃葡萄糖(2.82g,5.07mmoL)、二甲基亚砜(47mL)和乙酸酐(39mL)的混合物在室温下搅拌12小时。在反应液中加入冰水,用乙酸乙酯萃取,用水、饱和碳酸氢钠水溶液、饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=6∶1)精制得到的残渣,得到无色油状的标题化合物(2.3g,82%)。
1H NMR(200MHz,氯仿-d)δppm 3.70(d,J=4.8Hz,2H)3.86-4.02(m,2H)4.09-4.22(m,2H)4.40-4.68(m,7H)4.83(d,J=11.4Hz,1H)7.12-7.41(m,20H).
参考例2
2-[4-(苯甲氧基)-5-溴-2-甲基苯基]-1,3-二氧戊环(化合物(6A))的制备
【化12】
(1)1-[4-(苯甲氧基)-2-甲基苯基]乙酮的制备
在4’-羟基-2’-甲基苯乙酮(3.06g,20mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入碳酸钾(3.66g,26.4mmol)、苯甲基溴(2.7mL,22.4mmol)和n-Bu4NI(0.75g,2.03mmol),在室温下搅拌14小时。在冰冷条件下,在反应液中加入饱和氯化铵水溶液,接着,加入水和乙酸乙酯,分离有机层后,用20wt.%硫代硫酸钠水溶液、饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=8∶1→6∶1)精制得到的残渣,得到无色粉末状的标题化合物(5.05g,quant.)。
1H NMR(300MHz,氯仿-d)δppm 2.55(s,3H)2.57(s,3H)5.11(s,2H)6.78-6.86(m,2H)7.30-7.47(m,5H)7.75(dd,J=7.93,1.09Hz,1H).
(2)4-(苯甲氧基)-5-溴-2-甲基苯甲酸的制备
在1-[4-(苯甲氧基)-2-甲基苯基]乙酮(20.9g,87.1mmol)的丙酮(300mL)溶液中加入NaBr(9.86g,95.9mmol)的水溶液(100mL)、水(200mL)和Oxone(注册商标,oxone一过硫酸氯化物,Aldrich)(59.0g,95.9mmol),在室温下搅拌2.5小时。在冰冷条件下,在反应液中加入亚硫酸钠(20g)的水溶液(50mL),接着,加入水和乙酸乙酯,分离有机层。用20wt.%亚硫酸钠水溶液、饱和食盐水洗涤该有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,得到1-[4-(苯甲氧基)-5-溴-2-甲基苯基]乙酮和1-[4-(苯甲氧基)-3-溴-2-甲基苯基]乙酮的混合物(27.2g)。在其中加入5%次氯酸钠溶液(300mL,255mmol)和氢氧化钾(4.80g,85.3mmol)的水溶液(10mL),在120℃下搅拌1小时后,冷却至室温,过滤析出的不溶物。在该不溶物中加入2N盐酸,用乙酸乙酯萃取后,用2N盐酸、饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用甲醇洗涤得到的残渣,得到无色粉末状的标题化合物(16.6g,59%,2步)。
1H NMR(300MHz,DMSO-d6)δppm 2.45-2.57(m,3H)5.28(s,2H)7.18(s,1H)7.31-7.54(m,5H)8.03(s,1H)12.83(brs,1H).
ESI m/z=319(M-H),321(M+2-H).
(3)2-[4-(苯甲氧基)-5-溴-2-甲基苯基]-1,3-二氧戊环的制备
在4-(苯甲氧基)-5-溴-2-甲基苯甲酸(16.6g、51.7mmol)的氯仿(80mL)悬浊液中加入草酰氯(5mL,56.9mmol)和N,N-二甲基甲酰胺(6滴),在室温下搅拌1小时后,浓缩反应液,得到4-(苯甲氧基)-5-溴-2-甲基苯甲酰氯。接着,在N,O-二甲基羟胺盐酸盐(5.55g,56.9mmol)和三乙胺(15mL,103mmol)的氯仿(60mL)悬浊液中,在冰冷条件下,滴加4-(苯甲氧基)-5-溴-2-甲基苯甲酰氯的氯仿(60mL)溶液,在室温下搅拌1小时。在冰冷条件下,加入水和氯仿,分离有机层后,用饱和碳酸氢钠水溶液、饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,得到4-(苯甲氧基)-5-溴-N-甲氧基-N-甲基苯甲酰胺。在其四氢呋喃(150mL)溶液中在-10℃下加入氢化锂铝(1.96g,51.7mmol),在相同温度下搅拌1小时。在反应液中加入1N盐酸,加入乙酸乙酯,分离有机层后,用1N盐酸、饱和碳酸氢钠水溶液、饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,得到4-(苯甲氧基)-5-溴-2-甲基苯甲醛。在其甲苯(120mL)溶液中加入乙二醇(30mL,517mmol)和对甲苯磺酸一水合物(0.50g,2.58mmol),用Dean-Stark装置加热回流1.5小时。在反应液中加入乙酸乙酯,分离有机层后,用水、饱和碳酸氢钠水溶液、饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=5∶1)精制得到的残渣。再用NH型硅胶柱色谱法(氯仿)精制,得到无色粉末状的标题化合物(12.8g,71%,3步)。
1H NMR(300MHz,氯仿-d)δppm 2.34(s,3H)3.92-4.19(m,4H)5.15(s,2H)5.87(s,1H)6.74(s,1H)7.27-7.51(m,5H)7.72(s,1H).
ESI m/z=348.
参考例3
2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-5-(1,3-二氧戊环-2-基)-4-甲基苯基]-5-硫代-D-吡喃葡萄糖(化合物(7A))的制备
【化13】
在2-[4-(苯甲氧基)-5-溴-2-甲基苯基]-1,3-二氧戊环(12.9g,36.9mmol)的四氢呋喃(100mL)溶液中,在氮气环境下,在-78℃滴加2.67M正丁基锂己烷溶液(14.5mL,36.9mmol),在相同温度下搅拌30分钟。接着,滴加2,3,4,6-四-O-苯甲基-5-硫代-D-葡萄糖酸-1,5-内酯(9.77g,17.6mmol)的四氢呋喃(40mL)溶液,在相同温度下搅拌15分钟。在反应液中加入饱和氯化铵水溶液,用乙酸乙酯萃取后,用饱和氯化铵水溶液、饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=3∶1→2∶1)精制得到的残渣,得到无色透明的无定形的标题化合物(10.6g,73%)。
1H NMR(300MHz,氯仿-d)δppm 2.39(s,3H)3.46-3.72(m,2H)3.86-4.22(m,8H)4.43-5.00(m,8H)5.10(s,2H)5.92(s,1H)6.66-6.90(m,3H)7.00-7.38(m,23H)7.57(brs,1H).
ESI m/z=847(M+Na+).
参考例4
2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-5-甲酰基-4-甲基苯基]-5-硫代-D-吡喃葡萄糖(化合物(8A))的制备
【化14】
在2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-5-(1,3-二氧戊环-2-基)-4-甲基苯基]-5-硫代-D-吡喃葡萄糖(11.1g,13.5mmol)的四氢呋喃(100mL)溶液中,在冰冷条件下,加入6N盐酸(100mL),在室温下搅拌12小时。在冰冷条件下,在反应液中加入水,用乙酸乙酯萃取后,用饱和碳酸氢钠水溶液、饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=2∶1)精制得到的残渣,作为淡黄色油状化合物得到标题化合物(10.1g,quant.)。
1H NMR(300MHz,氯仿-d)δppm 2.64(s,3H)3.51-3.70(m,2H)3.84-4.29(m,4H)4.46-4.97(m,8H)5.04-5.24(m,2H)6.62-6.82(m,3H)6.99-7.38(m,23H)7.60(brs,1H)10.05(s,1H).
ESI m/z=803(M+Na+).
参考例5
1-(苯甲氧基)-2-溴-5-甲基-4-(4-甲氧基苯甲基)苯的制备
【化15】
(1)在4-(苯甲氧基)-5-溴-2-甲基苯甲醛(3.0g,9.83mmol)的四氢呋喃(20mL)溶液中,在-18℃下滴加0.5M 4-甲氧基苯基溴化镁的四氢呋喃溶液(29.5mL,14.7mmol),在-15℃下搅拌15分钟。在反应液中加入饱和氯化铵水溶液,用乙酸乙酯萃取后,用饱和氯化铵水溶液、饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=4∶1)精制得到的残渣,得到无色油状物的[1-(苯甲氧基)-2-溴-5-甲基苯基](4-甲氧基苯基)甲醇(4.48g)。
(2)接着,在[1-(苯甲氧基)-2-溴-5-甲基苯基](4-甲氧基苯基)甲醇(4.40g)的乙腈(20mL)和氯仿(20mL)的混合溶液中,在4℃下依次加入Et3SiH(3.1mL,19.7mmol)和BF3·Et2O(1.2mL,9.83mmol)。在相同温度下搅拌30分钟后,加入2M氢氧化钾水溶液(20mL)。用氯仿萃取得到的混合液,用1M盐酸和饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=10∶1)精制得到的残渣,得到无色油状的标题化合物(3.46g,89%)。
1H NMR(300MHz,氯仿-d)δppm 2.17(s,3H)3.79(s,3H)3.82(s,2H)5.12(s,2H)6.77(s,1H)6.82(d,J=8.4Hz,2H)7.02(d,J=8.4Hz,2H)7.19-7.45(m,4H)7.44-7.58(m,2H).
EI m/z=396,398.
参考例6
1-(苯甲氧基)-2-溴-5-甲基-4-(4-甲基苯甲基)苯的制备
【化16】
按照与参考例5同样的方法,用4-甲基苯基溴化镁代替4-甲氧基苯基溴化镁合成标题化合物。
1H NMR(300MHz,氯仿-d)δppm 2.17(s,3H)2.31(s,3H)3.84(s,2H)5.12(s,2H)6.76(s,1H)6.95-7.03(m,2H)7.04-7.14(m,2H)7.22-7.58(m,6H).
EI m/z=380,382.
参考例7
1-(苯甲氧基)-2-溴-4-(4-乙基苯甲基)-5-甲基苯的制备
【化17】
(1)[4-(苯甲氧基)-5-溴-2-甲基苯基](4-乙基苯基)甲醇的制备
在1-溴-4-乙基苯(5.00g,16.4mmol)的四氢呋喃(30mL)溶液中,在-60℃下用5分钟滴加2.66M n-BuLi的己烷溶液(6.47mL,17.2mmol)。在相同温度下搅拌15分钟后,在该溶液中滴加4-(苯甲氧基)-5-溴-2-甲基苯甲醛(3.03g,16.4mmol)的四氢呋喃(15mL)溶液,在相同温度下搅拌15分钟。在反应液中加入饱和氯化铵水溶液,升温至室温,将其用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,得到标题化合物。
(2)1-(苯甲氧基)-2-溴-4-(4-乙基苯甲基)-5-甲基苯的制备
接着,在[4-(苯甲氧基)-5-溴-2-甲基苯基](4-乙基苯基)甲醇的氯仿(80mL)溶液中,在0℃下依次加入Et3SiH(3.93mL,24.6mmol)和BF3·Et2O(2.49mL,19.7mmol),在相同温度下搅拌30分钟。在反应液中加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=98∶2)精制得到的残渣,得到无色油状的标题化合物(5.31g,82%,2步)。
1H NMR(300MHz,氯仿-d)δppm 1.22(t,J=7.62Hz,3H)2.17(s,3H)2.61(q,J=7.62Hz,2H)3.85(s,2H)5.12(s,2H)6.76(s,1H)7.01(d,2H)7.10(d,2H)7.27-7.43(m,4H)7.48(d,2H).
ESI m/z=412,414(M+NH4 +).
参考例8
1-(苯甲氧基)-2-溴-5-甲基-4-[4-(甲硫基)苯甲基]苯的制备
【化18】
按照与参考例7同样的方法,用4-溴苯硫基甲烷代替4-溴甲苯,得到[4-(苯甲氧基)-5-溴-2-甲基苯基][4-(甲硫基)苯基]甲醇(6.93g,66%)。
1H NMR(300MHz,氯仿-d)δppm 2.05(d,J=3.6Hz,1H)2.16(s,3H)2.47(s,3H)5.13(s,2H)5.86(d,J=3.6Hz,1H)6.73(s,1H)7.22(s,4H)7.28-7.51(m,5H)7.70(s,1H).
ESI m/z=463(M-Cl-).
接着,用[4-(苯甲氧基)-5-溴-2-甲基苯基][4-(甲硫基)苯基]甲醇代替[4-(苯甲氧基)-5-溴-2-甲基苯基](4-乙基苯基)甲醇,得到淡茶色油状的标题化合物(6.28g,94%)。
1H NMR(300MHz,氯仿-d)δppm 2.15(s,3H)2.46(s,3H)3.84(s,2H)5.12(s,2H)6.77(s,1H)6.98-7.06(m,2H)7.14-7.21(m,2H)7.23-7.51(m,6H).
ESI m/z=430(M+NH4 +).
参考例9
5-溴-2-氯-4-甲氧基苯甲醛的制备
【化19】
(1)1-溴-4-氯-2-甲氧基-5-甲基苯的制备
(i)在4-氯-2-甲氧基-5-甲基苯胺(20.2g,117mmol)的丙酮(100mL)溶液中,加入48%溴化氢水溶液(50mL,2.93moL),在冰冷条件下滴加亚硝酸钠(10.1g,146mmol)的水溶液(70mL),升温至室温,搅拌1个半小时。
(ii)在硫酸铜5水合物(87.9g,352mmol)和溴化钠(36.2g,352mmol)的水溶液(160mL)中,用20分钟滴加亚硫酸钠(22.4g,176mmol)的水溶液(70mL),在室温下搅拌30分钟后,在冰冷条件下静置。通过倾析除去上清液,再用水(1L)洗涤得到的沉淀物,上清液的倾析重复4次,得到无色粉末的溴化铜。向其中加入48%溴化氢水溶液(50mL,2.93moL),搅拌,用40分钟在冰冷条件下滴加(i)制备的重氮盐水溶液,在室温下搅拌15小时。减压蒸馏除去反应溶液中的丙酮,用乙酸乙酯萃取得到的沉淀物,用饱和食盐水洗涤有机层后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷)精制得到的残渣,得到无色晶体的标题化合物(23.5g)。
(2)1-溴-(5-溴甲基)-4-氯-2-甲氧基苯的制备
接着,在1-溴-4-氯-2-甲氧基-5-甲基苯(23.2g)的四氯化碳(400mL)溶液中,加入N-溴代琥珀酰亚胺(19.2g)、2,2’-偶氮二(2-甲基丙腈)(1.61g),加热回流1小时。放冷后,在反应液中加入水,用乙酸乙酯萃取,用饱和食盐水洗涤有机层后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,得到无色油状的标题化合物(33.5g)。
(3)(5-溴-2-氯-4-甲氧基苯基)甲醇的制备
在1-溴-(5-溴甲基)-4-氯-2-甲氧基苯(33.4g)的1,4-二氧六环(350mL)溶液中,加入碳酸钠(52.0g)的水溶液(350mL),加热回流1小时。放冷后,在反应液中加入水(350mL),用乙酸乙酯萃取,用饱和食盐水洗涤有机层后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,得到无色粉末的标题化合物(25.8g)。
(4)5-溴-2-氯-4-甲氧基苯甲醛的制备
在(5-溴-2-氯-4-甲氧基苯基)甲醇(25.8g)的氯仿(300mL)溶液中,加入二氧化锰(129g,1.48mol),在室温下搅拌18小时。硅藻土过滤除去不溶物,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=50∶1→30∶1)精制得到的残渣,得到无色粉末的标题化合物(20.0g,82%,4步)。
1H NMR(300MHz,氯仿-d)δppm 3.99(s,3H)6.92(s,1H)8.12(s,1H)10.27(s,1H).
参考例10
5-溴-2-氯-4-羟基苯甲醛的制备
【化20】
在5-溴-2-氯-4-甲氧基苯甲醛(18.6g,74.4mmol)的二甲基亚砜(300mL)溶液中,加入吡啶盐酸盐(43.0g,372mmol),在145℃下搅拌3小时。用冰冷却反应液,加入10%盐酸水溶液,调节至酸性,用乙酸乙酯萃取,用饱和食盐水洗涤有机层后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,得到无色晶体(20.1g)。将其用氯仿重结晶,得到无色晶体的标题化合物(11.7g,67%)。
1H NMR(300MHz,DMSO-d6)δppm 7.07(s,1H)7.96(s,1H)10.08(s,1H)12.05(brs,1H).
参考例11
5-溴-2-氯-4-(丙-2-烯-1-基氧)苯甲醛的制备
【化21】
在5-溴-2-氯-4-羟基苯甲醛(12.0g,51.0mmol)、碘化四丁基铵(941mg,2.55mmol)、碳酸钾(11.3g,81.5mmol)的N,N-二甲基甲酰胺(250mL)溶液中,加入烯丙基溴(5.61mL,66.3mmol),在室温下搅拌16小时。将反应液用冰冷却后,加入10%盐酸水溶液(50mL),再加入水(200mL),将其用乙酸乙酯萃取后,用饱和食盐水洗涤有机层,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,将得到的残渣用乙醇重结晶,得到无色粉末的标题化合物(11.5g、82%)。
1H NMR(300MHz,氯仿-d)δppm 4.70(dt,J=5.0,1.6Hz,2H)5.40(dq,J=10.6,1.4Hz,1H)5.52(dd,J=17.3,1.1Hz,1H)6.04(dd,J=17.0,10.3Hz,1H)6.90(s,1H)8.13(s,1H)10.27(s,1H).
参考例12
1-溴-4-氯-5-(4-甲氧基苯甲基)-2-(丙-2-烯-1-基氧)苯的制备
【化22】
(1)[5-溴-2-氯-4-(丙-2-烯-1-基氧)苯基](4-甲氧基苯基)甲醇的制备
在1-溴-4-甲氧基苯(1.43mL,11.43mmol)的四氢呋喃(100mL)溶液中,在-80℃下用5分钟滴加2.64M n-BuLi的己烷溶液(4.54mL,11.98mmol)。在相同温度下搅拌15分钟后,在该溶液中滴加5-溴-2-氯-4-(丙-2-烯-1-基氧)苯甲醛(3.00g,10.89mmol)的四氢呋喃(50mL)溶液,缓慢升温至室温,在相同温度下搅拌30分钟。在反应液中加入饱和氯化铵水溶液,减压浓缩,蒸馏除去四氢呋喃。将其用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,得到淡黄色油状物的标题化合物(3.79g)。
(2)1-溴-4-氯-5-(4-甲氧基苯甲基)-2-(丙-2-烯-1-基氧)苯的制备
接着,在[5-溴-2-氯-4-(丙-2-烯-1-基氧)苯基](4-甲氧基苯基)甲醇(3.77g,9.83mmol)的氯仿(50mL)溶液中,在0℃下依次加入Et3SiH(2.35mL,14.74mmol)和BF3·Et2O(1.49mL,11.79mmol),在相同温度下搅拌30分钟。在反应液中加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(氯仿∶己烷=1∶4)精制得到的残渣,得到无色油状物的标题化合物(1.56g,39%,2步)。
1H NMR(300MHz,氯仿-d)δppm 3.79(s,3H)3.93(s,2H)4.57(dt,J=5.0,1.6Hz,2H)5.32(dd,J=10.6,1.4Hz,1H)5.50(d,J=1.6Hz,1H)5.91-6.15(m,1H)6.84(d,J=8.7Hz,2H)6.90(s,1H)7.09(d,J=8.7Hz,2H)7.30(s,1H).
EI m/z=366,368.
参考例13
1-溴-4-氯-5-(4-甲基苯甲基)-2-(丙-2-烯-2-基氧)苯的制备
【化23】
(1)[5-溴-2-氯-4-(丙-2-烯-1-基氧)苯基](4-甲基苯基)甲醇的制备
按照与参考例12(1)同样的方法,用4-溴甲苯代替1-溴-4-甲氧基苯进行合成。用硅胶柱色谱法(己烷∶乙酸乙酯=87∶13)精制,得到无色固体的标题化合物(1.04g,38%)。
1H NMR(300MHz,氯仿-d)δppm 2.21(d,J=3.57Hz,1H)2.33(s,3H)4.55-4.61(m,2H)5.33(dq,J=10.57,1.45Hz,1H)5.47(dq,J=17.31,1.59Hz,1H)5.96-6.11(m,2H)6.84(s,1H)7.15(d,2H)7.25(d,2H)7.80(s,1H).
(2)1-溴-4-氯-5-(4-甲基苯甲基)-2-(丙-2-烯-2-基氧)苯的制备
按照与参考例12(2)同样的方法,用[5-溴-2-氯-4-(丙-2-烯-1-基氧)苯基](4-甲基苯基)甲醇代替[5-溴-2-氯-4-(丙-2-烯-1-基氧)苯基](4-甲氧基苯基)甲醇进行合成。用硅胶柱色谱法(己烷∶乙酸乙酯=87∶13)精制,得到无色油状的标题化合物(827mg,83%)。
1H NMR(300MHz,氯仿-d)δppm 2.32(s,3H)3.96(s,2H)4.57(dt,J=5.05,1.59Hz,2H)5.32(dq,J=10.57,1.45Hz,1H)5.48(dq,1H)5.96-6.11(m,J=17.23,10.39,5.15,5.15Hz,1H)6.90(s,1H)7.05(d,2H)7.11(d,2H)7.31(s,1H).
EI m/z=350,352.
参考例14
1-溴-4-氯-5-(4-乙基苯甲基)-2-(丙-2-烯-1-基氧)苯的制备
【化24】
(1)[5-溴-2-氯-4-(丙-2-烯-1-基氧)苯基](4-乙基苯基)甲醇的制备
按照与参考例12(1)同样的方法,用1-溴-4-乙基苯代替1-溴-4-甲氧基苯进行合成。用硅胶柱色谱法(己烷∶乙酸乙酯=87∶13)精制,得到无色固体的标题化合物(1.96g,35%)。
1H NMR(300MHz,氯仿-d)δppm 1.22(t,J=7.54Hz,3H)2.20(d,J=3.57Hz,1H)2.63(q,J=7.67Hz,2H)4.58(dd,J=5.05,0.70Hz,2H)5.33(dq,J=10.59,1.44Hz,1H)5.48(dq,J=17.25,1.71,1.55Hz,1H)5.95-6.15(m,2H)6.85(s,1H)7.17(d,2H)7.28(d,2H)7.82(s,1H).
(2)1-溴-4-氯-5-(4-乙基苯甲基)-2-(丙-2-烯-2-基氧)苯的制备
按照与参考例12(2)同样的方法,用[5-溴-2-氯-4-(丙-2-烯-1-基氧)苯基](4-乙基苯基)甲醇代替[5-溴-2-氯-4-(丙-2-烯-1-基氧)苯基](4-甲氧基苯基)甲醇进行合成。用硅胶柱色谱法(己烷∶乙酸乙酯=87∶13)精制,得到无色油状的标题化合物(1.55g,83%)。
1H NMR(300MHz,氯仿-d)δppm 1.22(t,J=7.54Hz,3H)2.62(q,J=7.77Hz,2H)3.97(s,2H)4.58(dt,J=4.97,1.55Hz,2H)5.32(dq,J=10.57,1.45Hz,1H)5.48(dq,J=17.25,1.66Hz,1H)6.04(dddd,J=17.25,10.41,5.13,4.97Hz,1H)6.90(s,1H)7.08(d,2H)7.13(d,2H)7.33(s,1H).
EI m/z=364,366.
实施例1
(1-A)
2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-4-甲基-5-(4-甲基苯甲基)苯基]-5-硫代-D-吡喃葡萄糖的制备
【化25】
在1-(苯甲氧基)-2-溴-5-甲基-4-(4-甲基苯甲基)苯(3.01g,7.89mmol)的四氢呋喃(15mL)溶液中,在-60℃下用4分钟滴加2.6Mn-BuLi的己烷溶液(3.3mL,8.68mmol)。在相同温度下搅拌30分钟后,在该溶液中滴加2,3,4,6-四-O-苯甲基-5-硫代-D-葡萄糖酸-1,5-内酯(2.91g,5.26mmol)的四氢呋喃(10mL)溶液,在相同温度下搅拌15分钟。在反应液中加入饱和氯化铵水溶液,升温至室温,将其用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=5∶1)精制得到的残渣,得到淡黄色胶状的标题化合物(2.44g,54%)。
1H NMR(300MHz,氯仿-d)δppm 2.20(s,3H)2.27(s,3H)3.46-3.59(m,1H)3.65(dd,J=9.6,2.4Hz,1H)3.78-4.16(m,5H)4.43-4.70(m,5H)4.75-4.97(m,4H)5.09(s,2H)6.70-7.42(m,31H).
(1-B)
(1S)-1,5-脱水-2,3,4,6-四-O-苯甲基-1-[2-(苯甲氧基)-4-甲基-5-(4-甲基苯甲基)苯基]-1-硫代-D-山梨醇的制备
【化26】
在2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-4-甲基-5-(4-甲基苯甲基)苯基]-5-硫代-D-吡喃葡萄糖(2.44g,2.85mmol)的氯仿(5.0mL)和乙腈(12.0mL)的混合溶液中,在-15℃下依次加入Et3SiH(0.91mL,5.69mmol)和BF3·Et2O(0.43mL,3.42mmol),搅拌1小时。在反应液中加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=8∶1)精制得到的残渣,得到无色粉末的标题化合物(2.1g,88%)。
1H NMR(300MHz,氯仿-d)δppm 2.17(s,3H)2.25(s,3H)3.01-3.19(m,1H)3.49-3.60(m,1H)3.64-3.75(m,1H)3.77-3.97(m,5H)3.98-4.11(m,1H)4.48-4.66(m,5H)4.85(s,2H)4.90(d,J=10.7Hz,1H)4.97-5.11(m,2H)6.66-7.52(m,31H).
ESI m/z=858(M+NH4 +).
实施例2
(2-A)
2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-5-(4-甲氧基苯甲基)-4-甲基苯基]-5-硫代-D-吡喃葡萄糖的制备
【化27】
在1-(苯甲氧基)-2-溴-4-(4-甲氧基苯甲基)-5-甲基苯(3.46g,8.71mmol)的四氢呋喃(17mL)溶液中,在-50℃下用5分钟滴加2.6Mn-BuLi的己烷溶液(3.7mL,9.58mmol)。在-60℃下搅拌30分钟后,在该溶液中滴加2,3,4,6-四-O-苯甲基-5-硫代-D-葡萄糖酸-1,5-内酯(3.22g,5.81mmol)的四氢呋喃(10mL)溶液,在相同温度下搅拌15分钟。在反应液中加入饱和氯化铵水溶液,升温至室温,将其用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=5∶1)精制得到的残渣,得到淡黄色胶状的标题化合物(2.22g,44%)。
1H NMR(300MHz,氯仿-d)δppm 2.20(s,3H)3.47-4.03(m,10H)4.02-4.21(m,2H)4.51(s,2H)4.63(d,J=10.7Hz,1H)4.73-4.98(m,4H)5.10(s,2H)6.48-7.76(m,31H).
ESI m/z=895(M+Na+).
(2-B)
(1S)-1,5-脱水-2,3,4,6-四-O-苯甲基-1-[2-(苯甲氧基)-5-(4-甲氧基苯甲基)-4-甲基苯基]-1-硫代-D-山梨醇的制备
【化28】
在2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-5-(4-甲氧基苯甲基)-4-甲基苯基]-5-硫代-D-吡喃葡萄糖(2.20g,2.52mmol)的氯仿(6.0mL)和乙腈(12.0mL)的混合溶液中,在-15℃下依次加入Et3SiH(0.80mL,5.04mmol)和BF3·Et2O(0.38mL,3.02mmol),搅拌1小时。在反应液中加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=5∶1)精制得到的残渣,得到无色粉末的标题化合物(2.15g,99%)。
1H NMR(300MHz,氯仿-d)δppm 2.17(s,3H)3.00-3.23(m,1H)3.55(t,J=10.8Hz,1H)3.66-4.16(m,10H)4.45-4.65(m,5H)4.85(s,2H)4.90(d,J=10.7Hz,1H)4.96-5.13(m,2H)6.51-7.46(m,31H).
ESI m/z=879(M+Na).
实施例3
(3-A)
2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-5-[(4-甲氧基苯基)(羟基)甲基]-4-甲基苯基]-5-硫代-D-吡喃葡萄糖的制备
【化29】
在1-溴-4-甲氧基苯(520mg,2.78mmol)和四氢呋喃(3mL)的混合物中,在-78℃下加入2.6M n-BuLi的己烷溶液(1.01mL,2.69mmol)。紧接着加入2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-5-甲酰基-4-甲基苯基]-5-硫代-D-吡喃葡萄糖(700mg,0.896mmol)的四氢呋喃(3mL)溶液,再搅拌30分钟,将反应液升温至室温。在反应液中加入水,用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=2∶1)精制得到的残渣,得到无色无定形的标题化合物(570mg,72%)。
1H NMR(300MHz,氯仿-d)δppm 2.03-2.24(m,3H)3.51-4.02(m,9H)4.49-5.16(m,10H)5.87(brs,1H)6.73-7.36(m,31H).
ESI m/z=911(M+Na+),887(M-H).
(3-B)
(1S)-1,5-脱水-2,3,4,6-四-O-苯甲基-1-[2-(苯甲氧基)-5-(4-甲氧基苯甲基)-4-甲基苯基]-1-硫代-D-山梨醇的制备
【化30】
在2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-5-[(4-甲氧基苯基)(羟基)甲基]-4-甲基苯基]-5-硫代-D-吡喃葡萄糖(570mg,0.641mmol)的乙腈(6.0mL)溶液中,在-10℃下依次加入Et3SiH(0.308mL,1.93mmol)和BF3·Et2O(0.090mL,1.41mmol),搅拌10分钟。在反应液中加入氯仿(3.0mL),接着在0℃下加入BF3·Et2O(0.090mL,1.41mmol)。将反应混合物在5℃下搅拌30分钟后,加入饱和碳酸氢钠水溶液,用氯仿萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(己烷∶乙酸乙酯=5∶1)精制得到的残渣,得到无色粉末的标题化合物(440mg,80%)。光谱数据与实施例2一致。
实施例4
(1S)-1,5-脱水-1-[4-甲基-5-(4-甲基苯甲基)-2-羟基苯基]-1-硫代-D-山梨醇的制备(化合物(I))
【化31】
将(1S)-1,5-脱水-2,3,4,6-四-O-苯甲基-1-[2-(苯甲氧基)-4-甲基-5-(4-甲基苯甲基)苯基]-1-硫代-D-山梨醇(2.1g,2.50mmol)、20%氢氧化钯活性炭(2.06g)和乙酸乙酯(20mL)-乙醇(20mL)的混合物在氢气环境中,在室温下搅拌50小时。通过硅藻土过滤反应液中的不溶物,浓缩其滤液。用硅胶柱色谱法(氯仿∶甲醇=10∶1)精制得到的残渣,得到无色粉末的标题化合物(340mg,35%)。
1H NMR(300MHz,甲醇-d4)δppm 2.07(s,3H)2.27(s,3H)2.92-3.04(m,1H)3.58(dd,J=10.3,9.0Hz,1H)3.73(dd,J=11.5,6.6Hz,1H)3.78-3.88(m,3H)3.94(dd,J=11.5,3.8Hz,1H)4.29(d,J=10.6Hz,1H)6.60(s,1H)6.94-6.98(m,2H)7.01-7.04(m,2H)7.05(s,1H).
ESI m/z=408M+NH4 +),389(M-H).
元素分析计算值 C21H26O5S·H2O:C,61.72;H,6.92.实测值:C,61.85;H,6.78.
实施例5
(1S)-1,5-脱水-1-[5-(4-甲氧基苯甲基)-4-甲基-2-羟基苯基]-1-硫代-D-山梨醇的制备(化合物(II))
【化32】
将(1S)-1,5-脱水-2,3,4,6-四-O-苯甲基-1-[2-(苯甲氧基)-5-(4-甲氧基苯甲基)-4-甲基苯基]-1-硫代-D-山梨醇(2.11g,2.46mmol)、20%氢氧化钯活性炭(2.1g)和乙酸乙酯(20mL)-乙醇(20mL)的混合物在氢气环境中,在室温下搅拌24小时。通过硅藻土过滤反应液中的不溶物,浓缩其滤液。用硅胶柱色谱法(氯仿∶甲醇=10∶1)精制得到的残渣,得到无色粉末的标题化合物(690mg,69%)。
1H NMR(300MHz,甲醇-d4)δppm 2.08(s,3H)2.91-3.06(m,1H)3.26(t,1H)3.59(dd,J=10.3,8.9Hz,1H)3.68-3.78(m,1H)3.74(s,3H)3.81(s,2H)3.82-3.88(m,1H)3.94(dd,J=11.3,3.7Hz,1H)4.29(d,J=10.6Hz,1H)6.60(s,1H)6.69-6.82(m,2H)6.96-7.03(m,2H)7.04(s,1H).
ESI m/z=429(M+Na+)
元素分析计算值 C21H26O6S·H2O:C,59.27;H,6.65.实测值:C,59.32;H,6.40.
实施例6
(1S)-1,5-脱水-2,3,4,6-四-O-苯甲基-1-[2-(苯甲氧基)-5-(4-乙基苯甲基)-4-甲基苯基]-1-硫代-D-山梨醇的制备
【化33】
在1-(苯甲氧基)-2-溴-4-(4-乙基苯甲基)-5-甲基苯(5.31g,13.4mmol)的四氢呋喃(50mL)溶液中,在-60℃下用5分钟滴加2.66Mn-BuLi的己烷溶液(5.05mL,13.4mmol)。在相同温度下搅拌15分钟后,在该溶液中滴加2,3,4,6-四-O-苯甲基-5-硫代-D-葡萄糖酸-1,5-内酯(6.76g,12.2mmol)的四氢呋喃(25mL)溶液,在相同温度下搅拌2小时。在反应液中加入饱和氯化铵水溶液,升温至室温。将其用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,得到2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-5-(4-乙基苯甲基)-4-甲基苯基]-5-硫代-D-吡喃葡萄糖。将其溶解于氯仿(30mL)和乙腈(30mL)的混合溶液中,冷却至0℃。接着,依次加入Et3SiH(2.92mL,18.3mmol)和BF3·Et2O(1.86mL,14.6mmol),搅拌1小时。在反应液中加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用NH型硅胶柱色谱法(己烷∶乙酸乙酯=4∶1)和硅胶柱色谱法(己烷∶乙酸乙酯=87∶13)精制得到的残渣,得到淡黄色胶状的标题化合物(3.41g,33%,2步)。
1H NMR(300MHz,氯仿-d)δppm 1.16(t,J=8.16Hz,3H)2.18(s,3H)2.48-2.61(m,2H)3.06-3.17(m,1H)3.54(t,J=8.70Hz,1H)3.70(d,J=10.26Hz,1H)3.76-3.98(m,5H)4.05(d,J=11.81Hz,1H)4.50-4.64(m,5H)4.82-4.93(m,3H)5.00-5.10(m,2H)6.73(s,1H)6.78(d,J=6.06Hz,2H)6.94(br.s.,3H)7.09-7.19(m,5H)7.22-7.34(m,18H)7.35-7.44(m,2H).
ESI m/z=872(M+NH4 +),889(M+Cl-).
实施例7
(1S)-1,5-脱水-1-[5-(4-乙基苯甲基)-2-羟基-4-甲基苯基]-1-硫代-D-山梨醇的制备(化合物(III))
【化34】
按照与实施例4同样的方法,用(1S)-1,5-脱水-2,3,4,6-四-O-苯甲基-1-[2-(苯甲氧基)-5-(4-乙基苯甲基)-4-甲基苯基]-1-硫代-D-山梨醇代替(1S)-1,5-脱水-2,3,4,6-四-O-苯甲基-1-[2-(苯甲氧基)-4-甲基-5-(4-甲基苯甲基)苯基]-1-硫代-D-山梨醇进行合成,在硅胶柱色谱法之后用乙醇重结晶,得到无色粉末的标题化合物(392mg,24%)。
1H NMR(300MHz,甲醇-d4)δppm 1.19(t,J=7.62Hz,3H)2.08(s,3H)2.58(q,J=7.56Hz,2H)2.99(ddd,J=10.22,6.41,3.73Hz,1H)3.25(t,1H)3.59(dd,J=9.71,8.47Hz,1H)3.74(dd,J=11.50,6.37Hz,1H)3.85(t,J=9.64Hz,3H)3.95(dd,J=11.42,3.81Hz,1H)4.30(d,J=10.41Hz,1H)6.61(s,1H)6.96-7.09(m,5H).
ESI m/z=422(M+NH4 +),403(M-H),439(M+Cl-).
实施例8
(1S)-1,5-脱水-2,3,4,6-四-O-苯甲基-1-[2-(苯甲氧基)-4-甲基-5-[4-(甲硫基)苯甲基]苯基]-1-硫代-D-山梨醇的制备
【化35】
按照与实施例6同样的方法,用1-(苯甲氧基)-2-溴-5-甲基-4-[4-(甲硫基)苯甲基]苯代替1-(苯甲氧基)-2-溴-4-(4-乙基苯甲基)-5-甲基苯,得到淡黄色胶状的标题化合物(3.27g,27%,2步)。
1H NMR(300MHz,氯仿-d)δppm 2.16(s,3H)2.39(s,3H)3.07-3.16(m,1H)3.49-3.60(m,1H)3.63-3.75(m,1H)3.76-4.10(m,6H)4.42-4.66(m,5H)4.85(s,2H)4.90(d,J=10.6Hz,1H)4.97-5.11(m,2H)6.69-7.48(m,31H).
实施例9
(1S)-1,5-脱水-1-[2-羟基-4-甲基-5-[4-(甲硫基)苯甲基]苯基]-1-硫代-D-山梨醇的制备(化合物IV))
【化36】
在(1S)-1,5-脱水-2,3,4,6-四-O-苯甲基-1-[2-(苯甲氧基)-4-甲基-5-[4-(甲硫基)苯甲基]苯基]-1-硫代-D-山梨醇(1.09g,1.25mmol)、甲硫醚(4.5mL)、间甲酚(1.2mL)、三氟乙酸(7.5mL)、1,2-乙烷二硫醇(0.3mL)的混合溶液中,在-20℃下滴加三氟甲磺酸(1.5mL)。在相同温度下搅拌40分钟后,将反应液注入到饱和碳酸钠水溶液和冰的混合物中。用乙酸乙酯萃取,用饱和碳酸钠水溶液、饱和食盐水依次洗涤有机相后,用无水硫酸镁干燥。在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(氯仿∶甲醇=50∶1→10∶1)精制得到的残渣,再用乙醇重结晶,得到无色粉末的标题化合物(166mg,31%)。
1H NMR(300MHz,甲醇-d4)δppm 2.08(s,3H)2.43(s,3H)2.99(ddd,J=10.2,6.4,3.7Hz,1H)3.22-3.31(m,1H)3.59(dd,J=10.3,9.0Hz,1H)3.74(dd,J=11.5,6.4Hz,1H)3.80-3.88(m,3H)3.95(dd,J=11.5,3.7Hz,1H)4.30(d,J=10.4Hz,1H)6.61(s,1H)6.99-7.08(m,3H)7.11-7.18(m,2H).
ESI m/z=440(M+NH4 +),445(M+Na+),421(M-H),457(M+Cl-).
实施例10
(10-A)
1-C-[4-氯-5-(4-甲基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-5-硫代-D-吡喃葡萄糖的制备
【化37】
按照与实施例1(1-A)同样的方法,用1-溴-4-氯-5-(4-甲基苯甲基)-2-(丙-2-烯-2-基氧)苯代替1-(苯甲氧基)-2-溴-5-甲基-4-(4-甲基苯甲基)苯,用2,3,4,6-四-O-丙-2-烯-1-基-5-硫代-D-葡萄糖酸-1,5-内酯代替2,3,4,6-四-O-苯甲基-5-硫代-D-葡萄糖酸-1,5-内酯,得到无色油状的标题化合物(426mg,29%)。
1H NMR(300MHz,氯仿-d)δppm 2.29(s,3H)3.34-3.47(m,1H)3.47-4.31(m,14H)4.37(dd,J=12.43,5.75Hz,1H)4.60(d,J=4.82Hz,2H)4.88(s,1H)4.94(d,J=1.55Hz,1H)5.08-5.38(m,7H)5.42-5.59(m,2H)5.78-6.15(m,4H)6.93(s,1H)6.98-7.08(m,4H)7.24(br.s.,1H).
ESI m/z=644(M+NH4 +),625(M-H),661(M+Cl-).
(10-B)
(1S)-1,5-脱水-1-[4-氯-5-(4-甲基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-1-硫代-D-山梨醇的制备
【化38】
按照与实施例1(1-B)同样的方法,用1-C-[4-氯-5-(4-甲基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-5-硫代-D-吡喃葡萄糖代替2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-4-甲基-5-(4-甲基苯甲基)苯基]-5-硫代-D-吡喃葡萄糖,得到无色固体的标题化合物(271mg,65%)。
1H NMR(300MHz,氯仿-d)δppm 2.29(s,3H)2.94-3.04(m,1H)3.25(t,J=9.09Hz,1H)3.38-4.20(m,11H)4.28(d,J=5.60Hz,2H)4.36(dd,J=12.05,5.98Hz,2H)4.54(dt,J=4.97,1.63Hz,2H)4.81-4.92(m,2H)5.09-5.32(m,7H)5.33-5.51(m,2H)5.80-6.10(m,4H)6.86(s,1H)7.02(td,2H)7.03(d,2H)7.22(s,1H).
ESI m/z=628(M+NH4 +),633(M+Na+),645(M+Cl-).
实施例11
(1S)-1,5-脱水-1-[4-氯-2-羟基-5-(4-甲基苯甲基)苯基]-1-硫代-D-山梨醇的制备(化合物(V))
【化39】
在(1S)-1,5-脱水-1-[4-氯-5-(4-甲基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-1-硫代-D-山梨醇(242mg,0.396mmol)的四氢呋喃(8mL)溶液中,加入N,N-二甲基巴比土酸(618mg,3.96mmol)和四(三苯基膦)钯(91.5mg,0.0792mmol),在90℃下搅拌3小时。将反应液冷却至室温,加入水,用乙酸乙酯萃取,用饱和食盐水洗涤有机相后,用无水硫酸镁干燥。过滤除去干燥剂后,在减压条件下蒸馏除去溶剂,用硅胶柱色谱法(氯仿∶甲醇=9∶1)精制得到的残渣,再用己烷∶乙酸乙酯∶乙醇进行重结晶,得到淡红色粉末的标题化合物(64.2mg,39%)。
1H NMR(600MHz,甲醇-d4)δppm 2.26(s,3H)2.95(ddd,J=10.09,6.42,3.67Hz,1H)3.22(t,J=8.71Hz,1H)3.53(t,1H)3.67-3.79(m,2H)3.84-3.96(m,3H)4.25(d,J=10.55Hz,1H)6.80(s,1H)7.01(d,2H)7.03(d,2H)7.12(s,1H).
ESI m/z=428(M+NH4 +),433(M+Na+),409(M-H),445(M+Cl-).
实施例12
(12-A)
1-C-[4-氯-5-(4-乙基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-5-硫代-D-吡喃葡萄糖的制备
【化40】
按照与实施例1(1-A)同样的方法,用1-溴-4-氯-5-(4-乙基苯甲基)-2-(丙-2-烯-2-基氧)苯代替1-(苯甲氧基)-2-溴-5-甲基-4-(4-甲基苯甲基)苯,用2,3,4,6-四-O-丙-2-烯-1-基-5-硫代-D-葡萄糖酸-1,5-内酯代替2,3,4,6-四-O-苯甲基-5-硫代-D-葡萄糖酸-1,5-内酯,得到无色油状的标题化合物(1.00g,39%)。
1H NMR(300MHz,氯仿-d)δppm 1.20(t,J=7.62Hz,3H)2.59(q,J=7.51Hz,2H)3.37-3.46(m,1H)3.47-4.42(m,15H)4.60(d,J=4.35Hz,2H)4.87(s,1H)4.92(d,J=3.89Hz,1H)5.08-5.37(m,7H)5.41-5.58(m,2H)5.79-6.14(m,4H)6.93(s,1H)7.06(d,2H)7.07(d,2H)7.26(br.s.,1H).
ESI m/z=639(M-H),675(M+Cl-).
(12-B)
(1S)-1,5-脱水-1-[4-氯-5-(4-乙基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-1-硫代-D-山梨醇的制备
【化41】
按照与实施例1(1-B)同样的方法,用1-C-[4-氯-5-(4-乙基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-5-硫代-D-吡喃葡萄糖代替2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-4-甲基-5-(4-甲基苯甲基)苯基]-5-硫代-D-吡喃葡萄糖,得到无色固体的标题化合物(564mg,65%)。
1H NMR(300MHz,氯仿-d)δppm 1.20(t,J=7.54Hz,3H)2.59(q,J=7.82Hz,2H)2.95-3.04(m,1H)3.25(t,J=8.55Hz,1H)3.36-3.94(m,7H)3.99(d,J=5.60Hz,2H)4.03-4.19(m,2H)4.27(d,J=5.75Hz,2H)4.36(dd,J=12.43,5.44Hz,2H)4.54(dt,J=4.82,1.63Hz,2H)4.85(dd,J=15.85,2.64Hz,2H)5.06-5.32(m,7H)5.32-5.48(m,2H)5.80-6.10(m,4H)6.86(s,1H)7.06(d,J=3.26Hz,4H)7.22(br.s.,1H).
ESI m/z=642(M+NH4 +),647(M+Na+),659(M+Cl-).
实施例13
(1S)-1,5-脱水-1-[4-氯-2-羟基-5-(4-乙基苯甲基)苯基]-1-硫代-D-山梨醇的制备(化合物(VI))
【化42】
按照与实施例11同样的方法,用(1S)-1,5-脱水-1-[4-氯-5-(4-乙基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-1-硫代-D-山梨醇代替(1S)-1,5-脱水-1-[4-氯-5-(4-甲基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-1-硫代-D-山梨醇,得到淡红色粉末的标题化合物(97.8mg,29%)。
1H NMR(600MHz,甲醇-d4)δppm 1.18(t,J=7.57Hz,3H)2.57(q,J=7.64Hz,2H)2.96(ddd,J=10.20,6.53,3.44Hz,1H)3.22(t,J=8.94Hz,1H)3.54(dd,J=10.32,8.94Hz,1H)3.71(dd,J=11.69,6.65Hz,1H)3.76(dd,J=10.32,8.94Hz,1H)3.86-3.96(m,3H)4.25(d,J=10.55Hz,1H)6.80(s,1H)7.01-7.07(m,4H)7.14(s,1H).
ESI m/z=442(M+NH4 +),423(M-H),459(M+Cl-).
实施例14
(14-A)
1-C-[4-氯-5-(4-甲氧基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-5-硫代-D-吡喃葡萄糖的制备
【化43】
按照与实施例1(1-A)同样的方法,用1-溴-4-氯-5-(4-甲氧基苯甲基)-2-(丙-2-烯-1-基氧)苯代替1-(苯甲氧基)-2-溴-5-甲基-4-(4-甲基苯甲基)苯,用2,3,4,6-四-O-丙-2-烯-1-基-5-硫代-D-葡萄糖酸-1,5-内酯代替2,3,4,6-四-O-苯甲基-5-硫代-D-葡萄糖酸-1,5-内酯,得到无色油状的标题化合物(1.35g,54%)。
1H NMR(300MHz,氯仿-d)δppm 3.35-3.47(m,1H)3.49-3.63(m,2H)3.69(t,2H)3.77(s,3H)3.80-4.42(m,10H)4.60(d,J=5.0Hz,2H)4.82-4.99(m,2H)5.05-5.38(m,8H)5.41-5.60(m,2H)5.76-6.17(m,4H)6.73-6.84(m,2H)6.92(s,1H)6.99-7.11(m,2H)7.34(brs.,1H).
ESI m/z=660(M+NH4 +),641(M-H).
(14-B)
(1S)-1,5-脱水-1-[4-氯-5-(4-甲氧基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-1-硫代-D-山梨醇的制备
【化44】
按照与实施例1(1-B)同样的方法,用1-C-[4-氯-5-(4-甲氧基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-5-硫代-D-吡喃葡萄糖代替2,3,4,6-四-O-苯甲基-1-C-[2-(苯甲氧基)-4-甲基-5-(4-甲基苯甲基)苯基]-5-硫代-D-吡喃葡萄糖,得到无色固体的标题化合物(750mg,56%)。
1H NMR(300MHz,氯仿-d)δppm 2.88-3.08(m,1H)3.25(t,J=9.0Hz,1H)3.35-4.66(m,20H)4.73-4.99(m,2H)5.06-5.33(m,7H)5.33-5.55(m,2H)5.72-6.18(m,4H)6.74-6.83(m,2H)6.86(s,1H)7.04(d,J=8.7Hz,2H)7.21(s,1H).
ESI m/z=649(M+Na+),644(M+NH4 +),625(M-H).
实施例15
(1S)-1,5-脱水-1-[4-氯-2-羟基-5-(4-甲氧基苯甲基)苯基]-1-硫代-D-山梨醇的制备(化合物(VII))
【化45】
按照与实施例11同样的方法,用(1S)-1,5-脱水-1-[4-氯-5-(4-甲氧基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-1-硫代-D-山梨醇代替(1S)-1,5-脱水-1-[4-氯-5-(4-甲基苯甲基)-2-(丙-2-烯-1-基氧)苯基]-2,3,4,6-四-O-丙-2-烯-1-基-1-硫代-D-山梨醇进行合成,在硅胶柱色谱法之后用活性炭(粉末)脱色,用乙酸乙酯重结晶,得到无色粉末的标题化合物(180mg,38%)。
1H NMR(300MHz,甲醇-d4)δppm 2.91-3.05(m,1H)3.24(t,J=8.9Hz,1H)3.29-3.35(m,2H)3.57(t,J=9.6Hz,1H)3.66-3.87(m,4H)3.87-4.00(m,3H)4.27(d,J=10.4Hz,1H)6.74-6.87(m,3H)7.01-7.11(m,2H)7.14(s,1H).
ESI m/z=449(M+Na+),444(M+NH4 +),425(M-H).
制剂实施例
【表1】
制造方法
将药物与乳糖一水合物、结晶纤维素、羧甲基纤维素钙和羟丙基纤维素混合,用粉碎机粉碎该混合物。将粉碎的混合物用搅拌造粒机混合1分钟,然后,用水造粒4~8分钟。在70℃下干燥得到的造粒物40分钟。将造粒干燥粉末用500μm的筛过筛。将过筛后的造粒干燥粉末与硬脂酸镁用V型混合机以30rpm混合3分钟。用旋转式压片机将得到的压片用颗粒压缩成型,如表2所示制成片剂。
【表2】
试验例1
(1)人SGLT1或人SGLT2的克隆以及导入表达载体
由来源于人小肠的mRNA将人SGLT1序列(NM_000343)逆转录后扩增,导入pCMV-tag5A(Stratagene公司)。另外,人SGLT2序列(NM_003041)由来源于人肾的mRNA按照同样的方法配制,导入pcDNA3.1+hygro(Invitrogen公司)。确认各克隆的序列与报道的序列一致。
(2)稳定表达人SGLT1或人SGLT2的CHO-k1细胞的制作
将人SGLT1和人SGLT2表达载体用脂转染胺2000(lipofectamine2000)(Invitrogen公司)转染至CHO-K1细胞。SGLT表达细胞在500μg/mL的浓度的遗传霉素(Geneticin)(SGLT1)或潮霉素B(Hygromycin B)(SGLT2)存在下进行培养,选择耐受菌株,通过下述系统获得糖摄取比活性作为指标。
(3)细胞的钠依赖性糖摄取抑制试验
将稳定表达人SGLT1或人SGLT2的细胞用于钠依赖性糖摄取活性抑制试验。
将细胞在预处理用缓冲液(140mM氯化胆碱、2mM KCl、1mMCaCl2、1mM MgCl2、10mM HEPES/5mM Tris、pH7.4)1mL中温育20分钟。除去预处理用缓冲液,加入含有试验化合物的摄取用缓冲液(含有[14C]甲基α-D-吡喃葡糖苷的甲基α-D-吡喃葡糖苷(抑制SGLT1用0.1mM,抑制SGLT2用1mM)、140mM NaCl、2mM KCl、1mM CaCl2、1mM MgCl2、10mM HEPES/5mM Tris、pH7.4)200μL,在37℃下进行摄取反应30分钟(SGLT1)或1小时(SGLT2)。反应后用洗涤用缓冲液(10mM甲基α-D-吡喃葡糖苷、140mM氯化胆碱、2mM KCl、1mMCaCl2、1mM MgCl2、10mM HEPES/5mM Tris、pH7.4)1mL洗涤细胞2次,溶于0.2M NaOH溶液400μL中。加入Aquazol 2(Perkin Elmer公司),充分混合后,用液体闪烁计数器(Beckman Coulter公司)测定放射活性,计算出糖摄取量。作为对照组,配制不含试验化合物的摄取用缓冲液。另外,作为基础摄取用缓冲液,配制含有氯化胆碱代替NaCl的摄取用缓冲液。
使用适当的6种浓度的试验化合物,测定糖摄取量,计算出以对照组的糖摄取量为100%时,其摄取量50%被抑制的试验化合物浓度作为IC50值。
(4)结果
表3显示化合物(I)~化合物(VII)和化合物98(公开于专利文献9中)的SGLT抑制活性。可以得知将化合物98的乙氧基替换为甲基、乙基、甲氧基或者甲硫基的化合物(I)~(VII)意外地保持了SGLT2抑制活性,并且显示比化合物98强3~6倍的SGLT1抑制活性。
【表3】
(5)试验例2
db/db小鼠的血糖降低作用确认试验
使用db/db小鼠(日本CLEA,雄性,7周龄)作为实验动物。试验物质悬浊于0.5%羧甲基纤维素(CMC)水溶液,配制成1mg/10mL的浓度。试验当日按照下述采血法和血糖值测定法,分组使之与db/db小鼠的血糖值平均值在方差上尽可能没有差异,每组的只数为6只。测定小鼠的体重后,用小鼠口服给药用饲管按10mL/kg的容量强制口服给予配制好的试验物质悬浊液,对于对照组仅给予0.5%CMC水溶液。采血在试验物质给药前(0time)以及口服给药0.5、1、2、4、6、8、24小时后共计8个点实施。另外,试验在自由摄食、摄水的条件下进行。
采血在乙醚麻醉下使用肝素涂覆采血管由病态动物的眶静脉窦(orbital venous sinus)进行,血糖值使用葡萄糖CII试验和光(GlucoseCII-Test Wako)(和光纯药株式会社)进行测定。血糖降低作用强度(%)由各试验物质给药组的0至8小时的随时血糖值采用梯形法计算出血糖值-时间曲线下面积(AUC),用相对于对照组的降低比例表示。
(6)结果
【表4】
化合物 | 血糖降低作用强度(%) |
I | 48.5 |
II | 49.7 |
化合物98(文献9公开) | 35.0 |
工业实用性
按照本发明,可以期待提供含有抑制在小肠上皮表达的SGLT1(钠依赖性葡萄糖协同转运蛋白1)和在肾脏表达的SGLT2(钠依赖性葡萄糖协同转运蛋白2),同时具有抑制由消化道吸收葡萄糖的作用和尿糖排泄作用的1-苯基1-硫代-D-山梨醇化合物作为有效成分的糖尿病的预防或治疗剂。
Claims (10)
8.一种药物,含有权利要求1~7中任意一项所述的1-苯基1-硫代-D-山梨醇化合物或其可药用盐或它们的水合物作为有效成分。
9.如权利要求8的药物,是钠依赖性葡萄糖协同转运蛋白1和钠依赖性葡萄糖协同转运蛋白2活性抑制剂。
10.一种糖尿病、糖尿病相关疾病或糖尿病性并发症的预防或治疗剂,其特征在于,含有权利要求1至7中任意一项所述的1-苯基1-硫代-D-山梨醇化合物或其可药用盐或它们的水合物作为有效成分。
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TW200637839A (en) * | 2005-01-07 | 2006-11-01 | Taisho Pharmaceutical Co Ltd | 1-thio-d-glucitol derivatives |
-
2007
- 2007-12-14 AU AU2007332476A patent/AU2007332476A1/en not_active Abandoned
- 2007-12-14 EP EP07850604A patent/EP2103607A4/en not_active Withdrawn
- 2007-12-14 CA CA002672176A patent/CA2672176A1/en not_active Abandoned
- 2007-12-14 WO PCT/JP2007/074100 patent/WO2008072726A1/ja active Application Filing
- 2007-12-14 US US12/516,758 patent/US20100069460A1/en not_active Abandoned
- 2007-12-14 CN CNA2007800464362A patent/CN101611023A/zh active Pending
- 2007-12-14 RU RU2009126767/04A patent/RU2009126767A/ru not_active Application Discontinuation
- 2007-12-14 JP JP2008549372A patent/JPWO2008072726A1/ja active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107311992A (zh) * | 2013-09-09 | 2017-11-03 | 上海研健新药研发有限公司 | C‑芳基葡糖苷衍生物、其制备方法及其在医药上的应用 |
CN107311992B (zh) * | 2013-09-09 | 2020-08-18 | 上海研健新药研发有限公司 | C-芳基葡糖苷衍生物、其制备方法及其在医药上的应用 |
Also Published As
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US20100069460A1 (en) | 2010-03-18 |
EP2103607A4 (en) | 2011-01-05 |
JPWO2008072726A1 (ja) | 2010-04-02 |
WO2008072726A1 (ja) | 2008-06-19 |
CA2672176A1 (en) | 2008-06-19 |
EP2103607A1 (en) | 2009-09-23 |
RU2009126767A (ru) | 2011-01-20 |
AU2007332476A1 (en) | 2008-06-19 |
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