CN1311772A - 新的3－芳基－2－羟基丙酸衍生物i - Google Patents

新的3－芳基－2－羟基丙酸衍生物i Download PDF

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CN1311772A
CN1311772A CN99809340A CN99809340A CN1311772A CN 1311772 A CN1311772 A CN 1311772A CN 99809340 A CN99809340 A CN 99809340A CN 99809340 A CN99809340 A CN 99809340A CN 1311772 A CN1311772 A CN 1311772A
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K·安德松
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AstraZeneca AB
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Abstract

式(Ⅰ)所示新的3－芳基－2－羟基丙酸衍生物、及其可药用盐、溶剂化物和结晶形式,制备所述化合物的方法和中间体,含有所述化合物的药物制剂,和所述化合物在与胰岛素抗性有关的临床病症中的应用。

Description

新的3-芳基-2-羟基丙酸衍生物Ⅰ
                      发明领域
本发明涉及新的3-芳基-2-羟基丙酸衍生物、及制备该化合物的方法和其中间体，所述化合物在与胰岛素抗性有关的临床病症中有用，还涉及用于实施所述化合物治疗应用的方法、以及含有所述化合物的组合物。
                      发明背景
胰岛素抗性被定义为在整个体内或个别组织例如骨骼肌、心肌、脂肪和肝脏中对胰岛素作用的敏感性下降，胰岛素抗性在患有或未患有糖尿病的许多个体中很常见。胰岛素抗性综合征-IRS是指包括伴有下述病症的胰岛素抗性的一组表征：高胰岛素血、可能的非胰岛素依赖型糖尿病(NIDDM)、动脉高血压、中央性(内脏)肥胖、以VLDL(极低密度脂蛋白)浓度增高和HDL(高密度脂蛋白)浓度下降为特征，且表现为脂蛋白水平紊乱的血脂蛋白异常、和纤维蛋白溶解作用降低。
最近的流行病学研究证明，对于患有胰岛素抗性的个体，其心血管发病和死亡的危险性大大增加，其中主要是患有心肌梗塞和中风。在非胰岛素依赖型糖尿病中，与动脉粥样硬化有关的病症引起的死亡占总死亡率高达80％。
在临床医学中，人们仅有限地认识到，对于IRS需要提高胰岛素敏感性，并由此矫正血脂蛋白异常(血脂蛋白异常被认为促进了动脉粥样硬化的进程)。
此外，目前没有任何适用的药物治疗来充分矫正与IRS有关的代谢紊乱。迄今为止，NIDDM的治疗是集中在矫正与该疾病有关的碳水化合物代谢控制混乱上。通过促分泌素，例如磺酰脲来刺激内源性胰岛素分泌，并且需要时施用外源性胰岛素是将血糖调节至正常水平的常用方法，但是如果存在胰岛素抗性的话，这样会进一步增强胰岛素抗性，并且既不能矫正IRS的其他表征，也不能降低心血管疾病发病率和死亡率。此外，这种治疗会带来引起相关并发症的低血糖的高度危险性。
其他治疗措施是集中在葡萄糖代谢和吸收异常上，包括双胍类药物例如乌洛托品(methformin)，或葡萄糖苷酶抑制剂，例如阿卡波糖。虽然这些治疗剂在一定程度上有效，但是它们的副作用使其临床作用很有限。
一种新的治疗措施涉及使用胰岛素致敏化剂，例如噻唑烷二酮类化合物至少部分通过对核受体的激动作用来介导其作用。环格列酮是这类化合物中的原型。在IRS动物模型中，这些化合物看上去能矫正胰岛素抗性和相应的血甘油三酯过多与血胰岛素过多，以及糖尿病高血糖等，这些化合物是通过对脂质转运和代谢施加影响，而改善胰岛素敏感性的，从而增强胰岛素对骨骼肌，肝脏和脂肪组织的作用来实现其矫正功能的。
现有技术中不连续地报道过环格列酮以及下文中描述的噻唑烷二酮类化合物在临床上的发展，这是因为它们具有不可接受的毒性或表现出不足的效力。因此需要具有胰岛素敏化特性的新的且更好的化合物。
                      现有技术
US 5306726和WO 91/19702中公开了下式所示化合物和其某些衍生物：
Figure A9980934000081
和
Figure A9980934000082
并且公开了它们能用作降血糖和降胆固醇剂，US 5232945描述这些化合物可用于治疗高血压。
AU 650429公开了在结构上相关的化合物，但是声称它们具有不同特性：利尿、抗高血压、抗血小板聚集、和抗脂氧合酶特性。
EP 139421公开了能降低血脂和血糖水平的化合物。在这些化合物当中，曲格列酮已作为治疗NIDDM或治疗葡萄糖耐受量下降的药物在市场上销售。
                      本发明描述
现在已经惊奇地发现，式Ⅰ所示新化合物(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸能有效地治疗与胰岛素抗性有关的病症。
Figure A9980934000091
本发明还涉及式Ⅰ化合物的可药用盐、溶剂化物，例如水合物、和结晶形式。
在本说明书中，术语“可药用盐”包括(但不限于)碱金属盐(例如钠盐、锂盐和钾盐)，碱土金属盐(例如钙盐、钡盐和镁盐)，铝盐、锌盐和铋盐，铵盐，与碱性氨基酸，例如精氨酸、赖氨酸等形成的盐，以及与有机胺例如乙醇胺、乙二胺、三乙醇胺、苄基苯乙基胺、二乙胺、氨丁三醇、苯乍生、氯普鲁卡因、胆碱、葡甲胺、普鲁卡因、克立咪唑和哌嗪等形成的盐。
在本申请说明书和权利要求中，给定的化学结构式或命名应当包括其所有可药用盐、结晶形式、和其溶剂化物，例如水合物。制备方法
本发明化合物可依据下述方法A-H中的任一方法制得。然而，本发明不限于这些方法，本发明化合物还可依据现有技术中用于制备结构类似化合物的方法制得。
A．本发明式Ⅰ化合物可通过将式Ⅱ化合物转化来制得，其中A是-ORp，其中Rp是保护基，例如乙基，或者A是手性辅助基团，例如手性胺如(R)-fenyl甘氨醇，手性醇，例如薄荷醇，或手性噁唑烷酮例如(S)-4-苄基-2-噁唑烷酮。该转化可作为水解来进行，可依据本领域技术人员已知的标准方法或如实验部分所述在酸性或碱性条件下进行水解。
B．其中A是手性辅助基团或-ORp且Rp定义同上的式Ⅰ或式Ⅱ化合物可通过将式Ⅲ化合物
Figure A9980934000102
其中X是OH或离去基团，例如磺酸根或卤素，与式Ⅳ化合物反应来制得其中Q是H,A是手性辅助基团、-OH或-ORp，且Rp定义同上。
可通过烷基化反应或Mitsunobu反应来进行该反应。
在烷基化反应中，离去基团X可以是磺酸根例如甲磺酸根、对硝基苯磺酸根、对甲苯磺酸根，或卤素，例如溴或碘。在碱例如碳酸钾或碳酸铯存在下，将大约等摩尔量或其中一种化合物过量的式Ⅲ化合物与式Ⅳ化合物，在惰性溶剂，例如异丙醇或乙腈中加热至回流温度。
将该混合物回流所需时间，通常是0.5小时-24小时，后处理操作一般包括过滤以除去固体盐，蒸发，中和(当A=OH时)，和用水与有机溶剂，例如二氯甲烷、乙酸乙酯、或乙醚提取。
如果需要的话，通过例如重结晶或标准色谱法将粗产物纯化。
可依据标准方法，或者如Tsunoda T.,Yamamiaya Y.,Ito S.,《四面体通讯》，34,1639-1642(1993)或Mitsunobu，《合成》，1981,p.1所述进行该Mitsunobu反应。当采用Mitsunobu反应时，A不能是-OH。
在典型Mitsunobu反应中，将大约等摩尔量或其中一种化合物过量的其中X是羟基的式Ⅲ化合物与式Ⅳ化合物，在惰性溶剂，例如氯仿、二氯甲烷、或四氢呋喃中混合。加入轻微摩尔过量的偶氮二羧酸酯(1-4当量)，例如DEAD或ADDP和膦(1-4当量)，例如三丁基膦或三苯基膦，将该反应混合物在足够高的温度下，例如在室温下搅拌足够长时间(1-24小时)，以获得产物，然后可依据文献中记载的标准方法进行后处理，并且如果需要的话通过例如标准色谱法进行纯化。
式Ⅲ化合物可通过本领域技术人员已知的标准方法由市售原料制得，或者可如实验部分所述制得。
其中Q是H,A是手性辅助基团、-OH或-ORp，且Rp定义同上的式Ⅳ化合物，可如实验部分所述制得，或者通过将式Ⅳ化合物转化来制得，其中Q是Rq,Rq是保护基，例如苄基，且A是手性辅助基团、-OH或-ORp，其中Rp定义同上。
C．其中A是手性辅助基团的式Ⅱ化合物，和其中A是手性辅助基团、Q是氢或Rq、且Rq定义同上的式Ⅳ化合物，可通过将式Ⅴ化合物进行非对映异构体分离而制得，
Figure A9980934000121
其中A是手性辅助基团，Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上。可通过结晶或色谱法来分离非对映异构体。可如实验部分所述进行色谱法分离。
其中A是手性辅助基团，Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上的式Ⅴ化合物可通过将式Ⅵ化合物转化来制得，
Figure A9980934000122
其中Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq，且Rx是氢或Rp，其中Rq和Rp定义同上，
例如通过将式Ⅵ化合物与手性胺或手性醇反应来制得。
当A是手性胺时，式Ⅴ化合物可这样制得：依据本领域技术人员众所周知的方法或者如实施例所述，在肽偶合系统(例如EDC、DCC、HBTU、TBTU、PyBop或DMF中的草酰氯)、合适的碱(例如吡啶、DMAP、TEA或DiPEA)和合适的有机溶剂(例如二氯甲烷、乙腈或DMF)存在下，将式Ⅵ化合物与手性胺，例如(R)-苯基甘氨醇反应。
当A是手性醇时，式Ⅴ化合物可由相同方法通过用手性醇例如薄荷醇代替手性胺而制得，或者可通过混合酐法用新戊酰氯和手性醇的锂盐制得。
其中A是手性辅助基团，Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上的式Ⅴ化合物，和其中Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq，且Rx是氢或Rp，其中Rq和Rp定义同上的式Ⅵ化合物可通过将式Ⅶ化合物还原来制得，
Figure A9980934000131
其中A是手性辅助基团、-OH或-ORp,Rp定义同上，Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上，
然后如果需要的话除去保护基。
烯烃的还原可通过多种已知用于还原碳-碳双键的方法进行，例如在适当催化剂存在下进行催化氢化，或使用氢转移试剂，例如2,5-二甲基-1,4-二氢吡啶-3,5-二甲酸二乙酯。
催化氢化可在下述溶剂中进行：醇、溶纤剂、质子极性有机溶剂、醚、低级脂肪酸，尤其是甲醇、乙醇、甲氧基乙醇、二甲基甲酰胺、四氢呋喃、二氧杂环己烷、二甲氧基乙烷、乙酸乙酯或乙酸，这些溶剂可单独使用或以混合物形式使用。所用催化剂的实例包括钯黑、炭载钯、氧化铂、或Wilkinson′s催化剂。根据所要进行的反应的反应性，该反应可在不同温度和压力下进行。
当使用2,5-二甲基-1,4-二氢吡啶-3,5-二甲酸二乙酯进行氢转移反应时，将等摩尔量的反应物混合，并在惰性气氛下或真空下将该混合物加热至熔化(140℃-250℃)。
其中A是手性辅助基团、-OH或-ORp,Rp定义同上，Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上的式Ⅶ化合物可这样制得：将式Ⅷ羰基化合物其中Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上，与式Ⅸ化合物
Figure A9980934000142
其中A是手性辅助基团、-OH或-ORp,Rp定义同上，或与式Ⅹ化合物
Figure A9980934000143
其中A是手性辅助基团或-ORp,Rp定义同上，L1=L2=L3是苯基，或者L1=L2是-O烷基且L3是=O，
进行缩合反应，例如Knoevenagel或Wittig型反应，然后如果需要的话，除去保护基，或者如Cacchi S.,Ciattini P.G.,Morera E.,Ortar G.，《四面体通讯》，28(28)1987,pp 3039-3042所述进行芳基化反应。
在该缩合步骤中，在碱存在下将大约等摩尔量的反应物混合，以获得烯烃化合物。该步骤可在惰性溶剂存在下或不在溶剂存在下于-20℃至混合物熔化点温度下进行。为了获得烯烃化合物，可能需要加入脱水剂。
在典型的该反应中，将式Ⅷ化合物与式Ⅸ化合物在溶剂，例如四氢呋喃中混合。在低温即-20℃缓慢地加入无水叔丁醇钾。用乙酸中止该反应。分离出粗产物，将其再溶于甲苯中，并与对甲苯磺酸在迪安-斯达克分水器中回流。将该溶液冷却，分离出产物，并依据标准方法纯化(参见Groger T.,Waldmann E.,Monatsh Chem 89,1958,p 370)。
该缩合步骤还可以作为Wittig型反应来进行(参见例如《综合有机合成》(Comprehensive Organic Synthesis)vol.1 p.755-781Pergarnon Press)或者如实验部分所述来进行。
在典型的该反应中，在1-5倍摩尔过量的碱，例如四甲基胍或碳酸钾存在下，将大约等摩尔量的式Ⅷ和式Ⅹ反应物搅拌。该步骤可在惰性溶剂，例如二氯甲烷或乙腈存在下于适当温度(-10℃至+60℃)进行足够长时间。
其中Q是-CH2CH2Ph-4-OSO2CH3的式Ⅷ化合物可通过将其中X是-OH或离去基团，例如磺酸根或卤素的式Ⅲ化合物与式Ⅺ化合物偶合来制得
Figure A9980934000151
当X是离去基团，例如磺酸根或卤素时，该反应可作为烷基化反应来进行，当X是-OH时，该反应可如上所述作为Mitsunobu反应来进行。
D．其中A是-ORp、且Rp定义同上的式Ⅰ或式Ⅱ化合物，与其中A是-OH或-ORp、且Q是H或Rq、Rp和Rq定义同上的式Ⅳ化合物，可通过将式Ⅴ化合物进行对映异构体分离、例如通过手性色谱法进行对映异构体分离来制得
Figure A9980934000161
其中A是-OH或-ORp,Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq，其中Rp和Rq定义同上。
E．其中A是手性辅助基团或-ORp、且Rp定义同上的式Ⅰ或式Ⅱ化合物，与其中A是手性辅助基团、-OH或-ORp,Rp定义同上，且Q是H或Rq,Rq定义同上的式Ⅳ化合物，可通过将式Ⅶ化合物不对称还原来制得
Figure A9980934000162
其中A是手性辅助基团、-OH或-ORp,Rp定义同上，Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上。
该不对称还原可用多种已知用来还原碳-碳双键的还原方法来进行，例如在适当手性催化剂，例如Rh-BINAP或[Et-DuPHOS-Rh(COD)]存在下进行催化氢化，或者使用用于诱导不对称性的手性辅助基团在适当催化剂，例如炭载钯存在下进行催化氢化。
该催化氢化可在多种溶剂中进行，例如醇、溶纤剂、质子极性有机溶剂、醚、低级脂肪酸，尤其是甲醇、乙醇、甲氧基乙醇、二甲基甲酰胺、四氢呋喃、二氧杂环己烷、二甲氧基乙烷、乙酸乙酯或乙酸，这些溶剂可单独使用或以混合物形式使用。根据所要进行的反应的反应性，该反应可在不同温度和压力下进行。
F．其中A是手性辅助基团或-ORp、且Rp定义同上的式Ⅰ或式Ⅱ化合物，与其中A是手性辅助基团、-OH或-ORp,Rp定义同上，且Q是H或Rq,Rq定义同上的式Ⅳ化合物，可通过将式Ⅻ化合物烷基化、并根据所用反应条件使产物具有所需立体化学来制得其中A是手性辅助基团、-OH或-ORp,Rp定义同上，Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上。
该烷基化可用多种烷基化剂来进行，例如乙基卤化物或硫酸二乙酯(参见例如Benedict D.R.,Bianchi T.A.,Cate L.A.，《合成》(1979),pp.428-429；Barluenga J.,Alonso-Cires L.,Campos P.J.,Asensio G.，《合成》，1983,p.53-55；《日本化学会通报》，1986,59,2481；S.Patai，《醚键化学》，Wiley-Interscience NY,1967,445-498或《有机合成评述》vol 1,Wiley-Interscience 1970,NY,p.285-328)。
其中A是手性辅助基团、-OH或-ORp,Rp定义同上，且Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上的式Ⅻ化合物，可通过将式ⅩⅢ化合物不对称还原来制得，
Figure A9980934000172
其中A是手性辅助基团、-OH或-ORp,Rp定义同上，Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上。
该不对称还原可用多种已知用来以对映选择性方式还原酮的还原方法来进行(参见Flynn G.A.,Beight D.W.，《四面体通讯》，29(4),1988,pp.423-426)。
其中A是手性辅助基团，且Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上的式Ⅻ化合物还可通过将其中A是手性辅助基团，且Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上的式ⅩⅢ化合物进行手性还原来制得(参见Y.B.,Snow K.,Belley M.，《有机化学杂志》，1993,58,pp 993-994)。
其中A是手性辅助基团、-OH或-ORp,Rp定义同上，且Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上的式Ⅻ化合物可通过将式ⅩⅣ化合物转化、并根据所用反应条件使产物具有所需立体化学来制得(参见例如K.Koga,C.C.Wu和S.Yamada，《四面体通讯》，no.25,1971,p 2283-2286；Kunz H.,Lerchen H-G.，《四面体通讯》，28(17)1987,pp.1873-1876)
Figure A9980934000181
其中A是手性辅助基团、-OH或-ORp,Rp定义同上，Q是氢、-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上。
G．其中A是手性辅助基团的式Ⅱ化合物，和其中A是手性辅助基团，且Q是Rq,Rq定义同上的式Ⅳ化合物，可通过将式ⅩⅤ化合物
Figure A9980934000182
其中X是离去基团例如卤素或磺酸根，Q是-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上，与式Ⅸ化合物反应来制得其中A是手性辅助基团。
在该烷基化步骤中，在一种或多种碱，例如碳酸钾、氯化三乙基苄基铵、氢化钠、LDA、丁基锂或LHMDS存在下，将式ⅩⅤ化合物与式Ⅸ化合物在惰性溶剂，例如乙腈、DMF或二氯甲烷中，于合适温度下反应适当时间。该反应可依据文献中记载的已知标准方法来进行(参见例如Pearsson W.H.,Cheng M.C.，《有机化学杂志》，51(19)1986,3746-3748；Myers A.G.,Yang B.H.,Gleason J.L.，《美国化学会志》1994,116,pp 9361-9362；Negrete G.R.,Konopelski J.P.，《四面体非对称性》，2,2,pp.105-108,1991,Davies S.G.,Sanganee H.J.，《四面体非对称性》，6,3,pp.671-674,1995；Hulin B.,Newton L.S.,Lewis D.M.,Genereux P.E.,Gibbs E.M.,Clark D.A.《医药化学杂志》39,3897-3907(1996)和Savignac M.,Durand J-O,Genet J-P，《四面体非对称性》，4,4,pp.717-722,1994)。
其中X是离去基团，例如卤素或磺酸根，Q是-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上的式ⅩⅤ化合物，可依据本领域技术人员已知的标准方法由式ⅩⅥ化合物制得其中Q是-CH2CH2Ph-4-OSO2CH3或Rq,Rq定义同上。
其中Q是-CH2CH2Ph-4-OSO2CH3或Rq、Rq定义同上的式ⅩⅥ化合物，可依据本领域技术人员已知的标准方法，将其中Q是-CH2CH2Ph-4-OSO2CH3或Rq、Rq定义同上的式Ⅷ化合物还原来制得。
H．其中A是-OH，且Q是氢或Rq,Rq定义同上的本发明式Ⅰ化合物和式Ⅳ化合物可通过将其外消旋体拆分、然后如果需要的话进行中和来制得。
该拆分可通过将本发明式Ⅰ化合物或式Ⅳ化合物的外消旋体与手性碱，例如奎宁形成的盐，在惰性溶剂，例如乙酸乙酯或甲苯中分离结晶来进行(参见例如Duhamel L.,Danvy D.,Plaquevent J.C.,GirosB.,Gros C.,Schwartz J.C.,Lecomte J.M.,的US 5136076,StephaniR.,Cesare V.，《化学教育杂志》，10,1997,p.1266和Yamamoto M.,Hayashi M.,Masaki M.,Nohira H.，《四面体非对称性》，2,6,pp.403-406,1991)。
可用常规技术将本发明化合物从其反应混合物中分离出来。
本领域技术人员应当理解，为了以其它方法、并且在某些情况下以更方便的方式获得本发明化合物，在整个路线中上述各处理步骤可以以不同顺序进行，和/或各反应可以在不同阶段进行(即通过不同中间体进行化学转化，以生成上文所述的与特定反应有关的物质)。
在任一上述制备方法A-H中，当需要时，可用如Green和Wuts的标准教科书“有机合成中的保护基”，第2版(1991)中描述的保护基Rp或Rq，将羟基、氨基或其它反应活性基团保护。保护基Rp或Rq可以是树脂，例如Wang树脂或2-氯三苯甲基氯树脂。官能团的保护和脱保护可在上述任一反应步骤之前或之后进行。可依据本领域技术人员众所周知的技术除去保护基。
术语“惰性溶剂”是指不与原料、反应物、中间体或产物以对所需产物的收率造成不利影响的方式进行反应的溶剂。
除非另外指出或注明，否则术语“手性辅助基团”是指手性基团，例如手性醇或胺，如(-)-薄荷醇、(+)-异薄荷醇、(-)-降新醇(norneol)、(R)-2-苯基甘氨醇、(S)-2-苯基甘氨醇、(R)-4-苯基-2-噁烷酮、或(S)-4-苄基-2-噁唑烷酮，当与羰基连接时，可容易地将这些手性基团分裂以形成相应的酸。中间体
当制备本发明式Ⅰ化合物时，式Ⅳ中间体特别有用，其中Q是氢，A是-OH或-ORp,Rp是保护基，例如乙基，或者A是手性基团，例如手性胺，如(R)-fenyl甘氨醇，或手性醇。如薄荷醇，或手性噁唑烷酮，如(S)-4-苄基-2-噁唑烷酮。式Ⅳ中间体的制备如上所述。在该标题下，描述了其作为用于制备本发明最终化合物的中间体的应用。药物制剂
本发明化合物一般可通过口服、非胃肠道、静脉内、颊内、直肠、阴道、透皮和/或经鼻途径和/或通过吸入途径，以包含其游离酸、或可药用有机或无机碱加成盐作为活性组分的药物制剂的形式，以可药用剂型给药。根据欲治疗的病症和患者具体情况以及给药途径，本发明组合物可以以不同剂量给药。
本发明化合物还可以与可用于治疗与动脉粥样硬化的发展和病变有关的病症，例如高血压、高血脂、血脂蛋白异常、糖尿病和肥胖症等其它治疗剂联合使用。
在人的治疗中，本发明化合物的合适日剂量为约0.005-5mg/kg体重，优选0.01-0.5mg/kg体重。
另一方面，本发明提供了包含本发明化合物或其可药用衍生物、并任选包含可药用辅料、稀释剂和/或载体的药物制剂。药理特征
本发明式(Ⅰ)化合物适于预防和/或治疗与胰岛素敏感性降低(胰岛素抗性)和相应代谢障碍有关的临床病症。这些临床病症包括但不限于表现出胰岛素抗性特征的腹部肥胖、动脉高血压、高胰岛素血、高血糖(非胰岛素依赖型糖尿病(NIDDM))、和血脂蛋白异常(血浆脂蛋白失调)。血脂蛋白异常也称为B表型致动脉粥样化性脂蛋白特性，其特征是非酯化脂肪酸中度增加、极低密度脂蛋白(VLDL)甘油三酯增加、高密度脂蛋白(HDL)减少、并且存在小而浓厚的低密度脂蛋白(LDL)。预计用本发明化合物进行治疗可降低与动脉粥样硬化有关的心血管疾病发病率和死亡率。这些心血管疾病包括引起心肌梗塞的大血管病变、脑血管病变和下肢外周动脉机能不全。因为具有胰岛素敏化作用，所以预计式(Ⅰ)化合物还能减缓糖尿病中与慢性高血糖有关的临床病症的进程，例如引起肾病和视网膜损伤的大血管病变的进程。此外，本发明化合物还可用于治疗与胰岛素抗性有关的心血管系统以外的多种病症，例如多囊卵巢综合征。本发明化合物是没有毒性的胰岛素敏化剂，其具有令人惊奇的良好治疗作用和药动学特征，并且不引起不良的体重增加。
常规实验程序
1H NMR和13C NMR测定是用BRUKER ACP 300和Varian UNITY加400和500分光光度计进行的，分别在300、400和500MHz的1H频率，与75、100、和125MHz的13C频率下进行操作。
除非另外指出，否则化学位移是以ppm作为单位给出，使用溶剂作为内标。
                    制备实施例
实施例1．
(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸
a)2-(4-甲磺酰氧基苯基)乙基甲磺酸酯
将对羟基苯乙醇(15g；0.108mol)溶于二氯甲烷中。在0℃加入三乙胺(27.3g；0.27mol)，然后加入甲磺酰氯(27.2g；0.239mol)在二氯甲烷中的溶液。将该反应混合物升至室温，然后在室温搅拌，之后进行TLC检查。将该反应混合物过滤，用水洗涤滤液。将有机相用硫酸钠干燥，然后真空蒸发，获得28g(产率为88％)2-(4-甲磺酰氧基苯基)乙基甲磺酸酯。
1H-NMR(400MHz；CDCl3): δ2.85(s,3H),3.05(t,2H),3.15(s,3H),4.35(s,2H),7.2(dm,2H),7.25(dm,2H).13C-NMR(100MHz；CDCl3):δ34.8,37,27,37,31,69.6,122.2,130.5,135.8,148.1.
b)4-[2-(4-甲酰基苯氧基)乙基]苯基甲磺酸酯
将2-(4-甲磺酰氧基苯基)乙基甲磺酸酯(30g；0.102mol)溶于乙腈中，并缓慢地加到对羟基苯甲醛(31.1g；0.255mol)和碳酸钾(41.46g；0.3mol)在乙腈内的混合物中。将所得混合物回流直至2-(4-甲磺酰氧基苯基)乙基甲磺酸酯反应完全。滤除盐，将溶剂真空蒸发，加入二氯甲烷，将有机相用水洗涤。将溶剂蒸发后，通过硅胶色谱法纯化，用二氯甲烷洗脱，获得21.6g(产率为66％)4-[2-(4-甲酰基苯氧基)乙基]苯基甲磺酸酯。
1H-NMR(400MHz；CDCl3):δ3.05-3.15(t,2H+s,3H),4.2(t,2H),6.95(dm,2H),7.2(dm,2H),7.3(dm,2H),7.8(dm,2H),9.8(s,1H).13C-NMR(100MHz；CDCl3): 837.3,38.3,63.4,116.1,122.1,129.2,130.6, 32.6,138.1,147.7,162.6,191.7.
c)2-乙氧基-3-{4-[2-(4-甲磺酰氧基苯基)乙氧基]苯基}丙烯酸乙酯
在0℃，将四甲基胍(9g；78mol)缓慢地加到4-[2-(4-甲酰基苯氧基)乙基]苯基甲磺酸酯(27g；84.2mmol)和氯化(1,2-二乙氧基-2-氧基乙基)三苯基鏻(30g；72mmol)在氯仿(300ml)内的溶液中。在室温搅拌过夜后，将溶剂真空蒸发。将乙醚加到残余物中，滤除不溶物。再加入乙醚，将该混合物再次过滤。用碳酸氢钠溶液洗涤滤液。将有机相干燥(硫酸镁)，把溶剂蒸发。将残余物在乙醇中重结晶，获得20.2g(产率为64.6％)2-乙氧基-3-{4-[2-(4-甲磺酰氧基苯基)乙氧基]苯基}丙烯酸乙酯。
1H-NMR(500MHz；CDCl3):δ1.34-1.38(2t,2x6H,J=7Hz对二者而言),3.11(t,2H,J=6Hz),3.13(s,3H),3.98(q,2H,J=7Hz),4.2(t,2H,J=6.8Hz),4.28(q,2H,J=7Hz),6.87(dm,2H,J=9Hz，未拆分的),6.95(s,1H),7.23(dm,2H,J=9Hz,未拆分的),7.33(dm,2H,J=9Hz，未拆分的),7.73(dm,2H,J=9Hz，未拆分的).13C-NMR(125MHz；CDCl3):δ14.3,15.5,35.0,37.3,61.0,67.5,68.1,114.4,122.0,123.8,126.6,130.5,131.7,137.7,143.1,147.9,159.0,164.9.
d)2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸乙酯
使用Pd/C(5％；0.75g)作为催化剂，将2-乙氧基-3-{4-[2-(4-甲磺酰氧基苯基)乙氧基]苯基}丙烯酸乙酯(1.47g；3.38mmol)在乙酸乙酯(50ml)中于大气压下氢化3小时。将该反应混合物经由硅藻土过滤并干燥(硫酸镁)。将溶剂真空蒸发，获得(1.44g；产率为98％)2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸乙酯。
1H-NMR(500MHz；CDCl3):δ1.16(t,3H,J=7Hz),1.23(t,3H,J=7Hz),2.92-2.96(m,2H),3.09(t,2H,J=6.6),3.13(s,3H),3.31-3.38(m,1H),3.56-3.63(m,1H),3.94-3.98(m,1H),4.12-4.19(m,4H),6.8(dm,2H,J=8.8Hz，未拆分的),7.14(dm,2H,J=8.9Hz,未拆分的),7.22(dm,2H,J=8.9Hz，未拆分的),7.33(dm,2H,J=8.6Hz，未拆分的).13C-NMR(125MHz；CDCl3):δ14.2,15.0,35.1,37.2,38.4,60.7,66.1,68.1,80.3,114.3,121.9,129.5,130.4,130.5,138.0,147.8,157.4,172.5.
e)2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸
将溶于水(10ml)中的氢氧化锂水合物(0.12g；2.82mmol)缓慢地加到2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸乙酯(1.12g；2.56mmol)在四氢呋喃(30ml)内的溶液中。在室温搅拌3小时后，加入水(50ml)，通过真空蒸发除去四氢呋喃。用盐酸(2M)将水残余物酸化，并用乙酸乙酯萃取3次。将有机相干燥(硫酸镁)，过滤，将溶剂真空蒸发，获得1g(产率为96％)2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸。
1H-NMR(500MHz；CDCl3):δ1.17(t,3H,J=7Hz),2.91-2.99(m,1H),3.03-3.11(m,3H),3.12(s,3H),339-3.47(m,1H),3.57-3.64(m,1H),4.01-4.06(m,1H),4.14(t,2H,J=6.7Hz),6.81(dm,2H,J=8.6Hz，未拆分的),7.15(dm,2H,J=8.6Hz，未拆分的),7.22(dm,2H,J=8.6Hz，未拆分的),7.33(dm,2H,J=8.6Hz，未拆分的).13C-NMR(125MHz；CDCl3):δ15.0,35.1,37.2,37.8,66.8,68.1,79.7,114.4,121.9,128.8,130.49,130.52,137.9,147.8,157.5,169.1.f)(S)-2-乙氧基-N-(2-羟基-(R)-1-苯基乙基)-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酰胺
将2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸(10.5g；25.7mmol)在无水二氯甲烷(150ml)中的溶液在冰浴中冷却，加入EDC(5.42g；28.3mmol)、二异丙基乙胺(4.8ml；28.3mmol)和HOBt×H2O(3.82g；28.3mmol)。20分钟后，移去冰浴，加入(R)-苯基甘氨醇(3.88g；28.3mmol)。在室温搅拌过夜后，加入二氯甲烷(100ml)、柠檬酸(60ml,10％)和乙酸乙酯，分离各相。将有机相依次用柠檬酸(60ml)、碳酸氢钠(2×60ml)和盐水(60ml)洗涤，干燥(硫酸钠)，过滤，将溶剂真空蒸发。将粗产物在乙酸乙酯/庚烷中结晶2次，获得4.43g(R)-2-乙氧基-N-(2-羟基-(R)-1-苯基乙基)-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酰胺。将母液合并，把溶剂真空蒸发，通过硅胶色谱法将残余物纯化，用乙酸乙酯∶庚烷(梯度为25-100％乙酸乙酯)洗脱，获得了5.14g(产率为38％)(S)-2-乙氧基-N-(2-羟基-(R)-1-苯基乙基)-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酰胺和0.51g(总共4.94g，产率为36％)(R)-2-乙氧基-N-(2-羟基-(R)-1-苯基乙基)-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酰胺。
1H-NMR(600MHz；DMSO-d6):δ1.04(t,3H,J=7.0Hz),2.74(dd,1H,J=13.9和7.6Hz),2.84(dd,1H,J=13.9和5.3Hz),3.05(t,2H,J=6.7Hz),3.30(m,1H),3.34(s,3H),3.44(m,1H),3.55(t,2H,J=5.8Hz),3.88(dd,1H,J=7.3和5.5Hz),4.15(t,2H,J=6.7Hz),4.83(m,1H),4.85(t,1 OH,J=5.4Hz),6.80(d,2H,J=8.4Hz),7.09(d,2H,J=8.4Hz),7.17(m,3H),7.23(m,2H),7.28(d,2H,J=8.3Hz),7.43(d,2H,J=8.3Hz),8.06(d,1NH,J=8.2Hz).13C-NMR(150MHz；DMSO-d6):δ15.2,34.4,37.5,38.0,54.6,64.5,65.1,67.9,81.1,114.2,122.2,126.8,127.0,128.1,129.8,130.4,130.7,138.1,141.2,147.8,157.0,171.1.
g)(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸
将(S)-2-乙氧基-N-(2-羟基-(R)-1-苯基乙基)-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酰胺(4.49g；8.59mmol)、浓硫酸(12.5ml)、二氧杂环己烷(50ml)和水(50ml)在80℃搅拌6小时。冷却后，加入水(100ml)，用二氯甲烷(2×100ml)萃取产物。合并有机相，用盐水(60ml)洗涤，干燥(硫酸钠)，过滤并真空蒸发。通过硅胶色谱法纯化，用庚烷∶乙酸乙酯∶乙酸(10∶10∶1)进行梯度洗脱，与甲苯共沸蒸馏，获得2.78g(产率为79％)(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸。
1H-NMR(600MHz；DMSO-d6):δ1.02(t,3H,J=7.0Hz),2.78(dd,1H,J=13.9和8.0Hz),2.86(dd,1H,J=13.9和5.2Hz),3.04(t,2H,J=6.8Hz),3.28(dq,1H,J=9.1和7.0Hz),3.35(s,3H),3.49(dq,1H,J=9.1和7.0Hz),3.92(dd,1H,J=5.2和7.7Hz),4.15(t,2H,J=6.8Hz),6.82(d,2H,J=8.7Hz),7.11(d,2H,J=8.7Hz),7.27(d,2H,J=8.5Hz),7.42(d,2H,J=8.5Hz),12.59(s,br,1 OH).13C-NMR(150MHz；DMSO-d6):δ15.2,34.4,37.5,37.7,65.0,67.9,79.4,114.2,122.2,129.6,130.4,130.7,138.0,147.8,157.1,173.4.
实施例2。
(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸
a)3-(4-苄氧基苯基)-2-乙氧基丙烯酸乙酯
在0℃，将四甲基胍(33g；0.286mol)加到4-苄氧基苯甲醛(59.1g；0.278mol)和氯化(1,2-二乙氧基-2-氧基乙基)(三苯基)磷(101.8g；72mol)在二氯甲烷(600ml)内的溶液中。在室温搅拌过夜后，将溶剂真空蒸发。将残余物溶于乙醚中，滤除不溶物，将滤液蒸发。把残余物与亚硫酸氢钠(饱和水溶液)和乙醚搅拌过夜。滤除固体物质，将滤液用乙醚萃取，干燥(硫酸镁)，把溶剂真空蒸发。通过快速色谱法纯化粗产物，并在异丙醇中结晶，获得66.8g(产率为86.3％)3-(4-苄氧基苯基)-2-乙氧基丙烯酸乙酯。
13C-NMR(125MHz；CDCl3):δ14.4,15.6,61.0,67.5,70.0,114.8,124.0,126.7,127.5,128.1,128.6,131.7,136.7,143.1,159.2,165.0.b)3-(4-苄氧基苯基)-2-乙氧基丙酸乙酯使用以炭作为载体的铑(5％,50mg)作为催化剂，将3-(4-苄氧基苯基)-2-乙氧基丙烯酸乙酯(0.5g；1.5mmol)在甲醇(20ml)中于大气压下氢化。通过色谱法纯化粗产物，用庚烷∶乙酸乙酯(5∶1)洗脱，获得50mg(产率为10％)3-(4-苄氧基苯基)-2-乙氧基丙酸乙酯。
1H NMR(300MHz；CDCl3):δ7.47-7.30(m,5H),7.17(d,J=8.8,2H),6.91(d,J=8.8Hz,2H),5.06(s,2H),4.17(q,J=7.2Hz,2H),3.98(t,J=6.6Hz,1H),3.61(dq,J=8.9和6.8Hz,1H),3.36(dq,J=8.9和6.8Hz,1H),2.97(d,J=6.6Hz,2H),1.22(t,J=7.2Hz,3H),1.18(t,J=6.8Hz,3H).13C NMR(75MHz；CDCl3):δ172.6,157.6,137.1,130.4,129.5,128.6,127.9,127.5,114.6,80.4,70.0,66.2,60.8,38.5,15.1,14.2.
c)3-(4-苄氧基苯基)-2-乙氧基丙酸
将溶于水(150ml)中的氢氧化锂水合物(7.4g；177mmol)加到3-(4-苄氧基苯基)-2-乙氧基丙酸乙酯(23.25g；70.8mmol)在二氧杂环己烷(150ml)内的溶液中。在室温搅拌过夜后，将二氧杂环己烷真空蒸发，加入水，将该混合物用乙醚洗涤。用盐酸(1M)将水相酸化，并用乙酸乙酯萃取。将有机相用水和盐水洗涤，干燥，将溶剂真空蒸发，获得21.1g(产率为99.2％)3-(4-苄氧基苯基)-2-乙氧基丙酸。
1H NMR(300MHz；CDCl3):δ1.15(t,3H),2.9-3.1(m,2H),3.35-3.45(m,1H),3.6-3.7(m,1H),3.95-3.41(m,1H),5.05(s,2H),6.95(d,2H),7.2 d,2H),7.25-7.5(m,5H).13C NMR(75MHz；CDCl3):δ15.0,38.1,66.6,70.0,79.9,114.7,127.5,128.0,128.6,129.3,130.5,137.1,157.7,176.3.
d)3-(4-苄氧基苯基)-(S)-2-乙氧基-N-(2-羟基-(R)-1-苯基乙基)丙酰胺
将3-(4-苄氧基苯基)-2-乙氧基丙酸(2.92g；9.74mmol)在无水二氯甲烷(30ml)中的溶液在冰浴中冷却，加入EDC(2.03g；10.61mmol)、二异丙基乙胺(1.84ml；10.61mmol)和HOBt×H2O(1.43g；10.61mmol)。30分钟后，移去冰浴，加入(R)-苯基甘氨醇(1.46g；10.61mmol)。在室温搅拌过夜后，加入乙酸乙酯(100ml)，将该混合物依次用硫酸氢钾(1M)、饱和碳酸氢钠溶液、碳酸钠溶液和盐水洗涤，将有机相干燥(硫酸钠)，过滤，将溶剂真空蒸发。将粗产物通过硅胶色谱法纯化，用乙酸乙酯∶庚烷洗脱，获得1.5g(产率为37％)3-(4-苄氧基苯基)-(S)-2-乙氧基-N-(2-羟基-(R)-1-苯基乙基)丙酰胺和1.25g(产率为31％)3-(4-苄氧基苯基)-(R)-2-乙氧基-N-(2-羟基-(R)-1-苯基乙基)丙酰胺。
1H NMR(400MHz；CDCl3):δ7.43-7.27(m,8H),7.22(d,J=8.3Hz,4H),7.13(d,NH,J=7.8Hz,1H),6.96(d,J=8.3Hz,1H),5.08(s,2H),5.01(m,1H),3.99(dd,J=6.8和3.9Hz,1H),3.69(m,2H),3.50(q,J=6.8Hz,2H),3.15(dd,J=14.2和3.9Hz,1H),2.97(dd,J=14.2和6.8Hz,1H),2.94(m,OH,1H),1.16(t,J=6.8Hz,3H).13C NMR(100MHz；CDCl3):δ172.3,157.5,138.9,137.0,130.7,129.4,128.6,128.4,127.7,127.6,127.3,126.5,114.4,81.0,69.8,66.3,66.0,55.3,37.8,15.1.
e)3-(4-苄氧基苯基)-(S)-2-乙氧基丙酸
在水(104ml)和二氧杂环己烷(104ml)中用浓硫酸(27ml)将3-(4-苄氧基苯基)-(S)-2-乙氧基-N-(2-羟基-(R)-1-苯基乙基)丙酰胺(8.9g；21.22mmol)于90℃水解5小时。将该反应混合物倒入水(220ml)中，并用乙酸乙酯萃取。将有机相用盐水洗涤，干燥(硫酸钠)，将溶剂真空蒸发，获得6.85g 3-(4-苄氧基苯基)-2-(S)-乙氧基丙酸与(S)-2-乙氧基-3-(4-羟基苯基)丙酸的混合物，不进一步纯化直接使用。
1H NMR(400MHz；CDCl3):δ7.47-7.30(m,5H),7.19(d,J=8.8,2H),6.93(d,J=8.8Hz,2H),5.10(s,2H),4.06(dd,J=7.8和4.4Hz,1H),3.64(dq,J=9.8和6.8Hz,1H),3.44(dq,J=9.8和6.8Hz,1H),3.09(dd,J=14.2和4.4Hz,1H),2.98(dd,J=14.2和7.8Hz,1H),1.19(t,J=6.8Hz,3H).
f)3-(4-苄氧基苯基)-(S)-2-乙氧基丙酸乙酯
向3-(4-苄氧基苯基)-2-(S)-乙氧基丙酸(6.85g)在乙醇(400ml)内的溶液中通入氯化氢(g)。缓慢地加入亚硫酰氯(2ml,27.4mmol)，将该反应混合物回流2小时。将溶剂真空蒸发，获得8g 3-(4-苄氧基苯基)-(S)-2-乙氧基丙酸乙酯与(S)-2-乙氧基-3-(4-羟基苯基)丙酸乙酯的混合物，不进一步纯化直接使用。
1H NMR(300MHz；CDCl3):δ7.47-7.30(m,5H),7.17(d,J=8.8,2H),6.91(d,J=8.8Hz,2H),5.06(s,2H),4.17(q,J=7.2Hz,2H),3.98(t,J=6.6Hz,1H),3.61(dq,J=8.9和6.8Hz,1H),3.36(dq,J=8.9和6.8Hz,1H),2.97(d,J=6.6Hz,2H),1.22(t,J=7.2Hz,3H),1.18(t,J=6.8Hz,3H).13C NMR(75MHz；CDCl3):δ172.6,157.6,137.1,130.4,129.5,128.6,127.9,127.5,114.6,80.4,70.0,66.2,60.8,38.5,15.1,14.2.
g)(S)-2-乙氧基-3-(4-羟基苯基)丙酸乙酯
使用Pd/C作为催化剂，将3-(4-苄氧基苯基)-(S)-2-乙氧基丙酸乙酯在乙酸乙酯中于大气压下氢化2小时。通过硅胶色谱法纯化，用甲苯∶乙酸乙酯洗脱，获得3.83g(3步的产率为76％)(S)-2-乙氧基-3-(4-羟基苯基)丙酸乙酯。
1H-NMR(400MHz；CDCl3):δ1.18(t,3H,J=6.8Hz),1.24(t,3H,J=7Hz),2.96(d,2H,J=6.5Hz),3.34-3.43(m,1H),3.57-3.66(m,1H),4.00(t,1H,6.5Hz),4.18(q,2H,J=7Hz),5.30(s,1OH),6.74(dm,2H,J=8.5Hz,未拆分的),7.10(dm,2H,J=8.5Hz，未拆分的).13C-NMR(100MHz；CDCl3):δ14.2,15.0,38.4,60.9,66.2,80.4,115.1,129.0,130.5,154.5,172.7.
h)(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸乙酯
将2-(4-甲磺酰氧基苯基)乙基甲磺酸酯(实施例1a)(2.41g；8.14mmol)在乙腈(11.8ml)中的溶液加到(S)-2-乙氧基-3-(4-羟基苯基)丙酸乙酯(1.3g；5.46mmol)、碳酸钾(2.26g；16.4mmol)和硫酸镁(1g)在乙腈(50ml)内的混合物中。将该反应混合物回流19小时。再加入2-(4-甲磺酰氧基苯基)乙基甲磺酸酯(0.8g；2.73mmol)，将该反应混合物再回流25小时。滤除固体物质，把溶剂真空蒸发，获得3.6g(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸乙酯。
i)(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸
在5℃，将溶于水(6ml)中的氢氧化锂水合物(0.299g；5.45mmol)缓慢地加到(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸乙酯(2.29g；5.24mmol)在四氢呋喃(50ml)和水(10ml)内的混合物中。将该反应混合物在5℃搅拌2.5小时，在20℃搅拌3小时，在0℃搅拌15小时，再在20℃搅拌3.5小时。在10℃再加入溶于水(1ml)中的氢氧化锂水合物(44mg；1.05mmol)。在10℃搅拌21.5小时后，再加入溶于水(1ml)中的氢氧化锂水合物(44mg；1.05mmol)。将该反应混合物在25℃搅拌3小时，然后在2℃保持67小时。将四氢呋喃真空蒸发，然后加入水和乙酸乙酯。滤除不溶物，分离滤液相。将水相用乙酸乙酯洗涤2次，用盐酸(2M；3.2ml)酸化，并用乙酸乙酯(30ml)萃取。将有机相用水洗涤2次，干燥(硫酸镁)，过滤，并将溶剂真空蒸发，获得1.9g(2步的产率为72％)(S)-2-乙氧基-3-[4-(2-{4-甲磺酰氧基苯基}乙氧基)苯基]丙酸。
1H-NMR(600MHz；DMSO-d6):δ1.02(t,3H,J=7.0Hz),2.78(dd,1H,J=13.9和8.0Hz),2.86(dd,1H,J=13.9和5.2Hz),3.04(t,2H,J=6.8Hz),3.28(dq,1H,J=9.1和7.0Hz),3.35(s,3H),3.49(dq,1H,J=9.1和7.0Hz),3.92(dd,1H,J=5.2和7.7Hz),4.15(t,2H,J=6.8Hz),6.82(d,2H,J=8.7Hz),7.11(d,2H,J=8.7Hz),7.27(d,2H,J=8.5Hz),7.42(d,2H,J=8.5Hz),12.59(s,br,1OH).13C-NMR(150MHz；DMSO-d6):δ15.2,34.4,37.5,37.7,65.0,67.9,79.4,114.2,122.2,129.6,130.4,130.7,138.0,147.8,157.1,173.4.
生物活性
在Umea ob/ob种患肥胖性糖尿病小鼠中测试本发明化合物的生物活性。将各组小鼠通过管饲法接受本发明化合物，每天给药一次，给药7天。在实验的最后一天，给药2小时后，将处于未进食状态的小鼠麻醉，并从切开的动脉中采集血液。分析血浆中葡萄糖、胰岛素和甘油三酯的浓度。将一组相同大小的未治疗的患肥胖性糖尿病小鼠用作对照。在实验前和实验后测定小鼠体重，将治疗小鼠的体重增加与对照小鼠的体重增加进行比较。关于治疗组小鼠葡萄糖、胰岛素和甘油三酯水平的各个值以相当于对照组相应值的百分比表示。
所希望的“治疗作用”计算表达为与对照动物相比，葡萄糖、胰岛素和甘油三酯这三个变量的平均下降百分比。将所测试的本发明化合物的治疗作用与现有技术化合物曲格列酮(以100μmol/kg的口服剂量通过管饲法给药，给药7天)的治疗作用比较。
与以相同口服剂量给药的曲格列酮相比，所测试的本发明化合物具有更优作用，这证实了本发明所要求保护的化合物效能和效力均提高。
                      缩写
NIDDM    非胰岛素依赖型糖尿病
VLDL     极低密度脂蛋白
HDL      高密度脂蛋白
IRS      胰岛素抗性综合征
PPAR     过氧物酶体增殖子激活受体
DEAD     偶氮二甲酸二乙酯
ADDP     偶氮二羰基二哌啶
EDC      1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺
EDC×HCl 1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐
DCC      环己基碳化二亚胺
HBTU     O-苯并三唑-1-基-N,N,N′,N′-四甲基脲鎓六氟磷酸盐
TBTU     O-苯并三唑-1-基-N,N,N′,N′-四甲基脲鎓四氟硼酸盐
PyBop    六氟磷酸苯并三唑-1-基氧基三吡咯烷基鏻
DMF      甲基甲酰胺
DMAP     4-二甲基氨基吡啶
TEA      三乙胺
DiPEA    异丙基乙胺
BINAP    2,2′-二(二苯基膦基)-1,1′-二萘基
COD       环辛二烯
LDA       异丙基氨化锂
LHMDS     甲基二甲硅烷基氨化锂
TLC       薄层色谱
THF       氢呋喃
Pd/C      炭载钯
HOBt×H2O1-羟基苯并三唑水合物
m         多重峰
t         三重峰
s         单峰
d         双重峰
q         四重峰
qvint     五重峰
br        宽峰
dm        多双峰
rac       消旋体

Claims (11)

1．式Ⅰ化合物，及其可药用盐、溶剂化物、和结晶形式。
2．制备权利要求1的化合物的方法，其特征在于，
a)将式Ⅱ化合物转化，其中A是手性基团或-ORp，其中Rp是保护基，
或者
b)将式Ⅲ化合物与式Ⅳ化合物反应，式中A是-OH、手性辅助基团、或-ORp，且Rp是保护基，X是-OH或离去基团，Q是H，然后如果需要的话，将所得化合物水解，或者
c)将式Ⅴ化合物进行非对映异构体分离，
Figure A9980934000032
其中Q是-CH2CH2Ph-4-OSO2CH3，且A是手性辅助基团，然后将所得化合物水解，或者
d)将式Ⅴ化合物进行对映异构体分离，
Figure A9980934000033
其中Q是-CH2CH2Ph-4-OSO2CH3，且A是-OH或-ORp,Rp是保护基，然后如果需要的话，将所得化合物水解，或者
e)将式Ⅶ化合物不对称还原，
Figure A9980934000041
其中Q是-CH2CH2Ph-4-OSO2CH3，且A是-OH、手性辅助基团或-ORp,Rp是保护基，然后如果需要的话，将所得化合物水解，或者
f)将式Ⅻ化合物烷基化，
Figure A9980934000042
其中Q是-CH2CH2Ph-4-OSO2CH3，且A是-OH、手性辅助基团或-ORp,Rp是保护基，然后如果需要的话，将所得化合物水解，或者
g)将式ⅩⅤ化合物
Figure A9980934000043
与式Ⅸ化合物反应，式中Ⅹ是离去基团，Q是-CH2CH2Ph-4-OSO2CH3，且A是用于在产物中诱导手性的手性辅助基团，然后将所得化合物水解，或者
h)将式Ⅰrac外消旋体拆分，
Figure A9980934000051
然后如果需要的话，将依据方法a)-h)中任一方法制得的化合物转化成其可药用盐、和/或溶剂化物，例如其水合物。
3．式Ⅳ化合物，
Figure A9980934000052
其中Q是氢，且A是-OH、手性辅助基团或-ORp,Rp是保护基。
4．权利要求3的化合物，其中在式Ⅳ中，A是-OH或具有1-3个碳原子的烷氧基。
5．于治疗上应用的权利要求1的化合物。
6．含有权利要求1的化合物作为活性组分、并且任选含有可药用载体、辅料和/或稀释剂的药物制剂。
7．权利要求1的化合物在制备用于预防和/或治疗与胰岛素抗性有关的临床病症的药物中的应用。
8．预防和/或治疗与胰岛素抗性有关的临床病症的方法，其中将治疗活性量的权利要求1的化合物对需要这种预防和/或治疗的哺乳动物给药。
9．权利要求8的方法，其中所述预防和/或治疗与胰岛素抗性有关的临床病症，是预防和/或治疗这类病症中的血脂蛋白异常。
10．权利要求8的方法，其中所述预防和/或治疗与胰岛素抗性有关的临床病症，是预防和/或治疗非胰岛素依赖型糖尿病中的高血糖症。
11．用于预防和/或治疗与胰岛素抗性有关的临床病症的药物制剂，其中所述药物制剂中的活性组分是权利要求1的化合物。
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