CN101031553A - 用作ppar(过氧化物酶体增殖物激活受体)配体来治疗高脂血症和糖尿病的2-{-3,′2-(苯基)-唑-4-基甲氧基-环已基甲氧氧基}-丙酸衍生物 - Google Patents
用作ppar(过氧化物酶体增殖物激活受体)配体来治疗高脂血症和糖尿病的2-{-3,′2-(苯基)-唑-4-基甲氧基-环已基甲氧氧基}-丙酸衍生物 Download PDFInfo
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- CN101031553A CN101031553A CNA2005800271498A CN200580027149A CN101031553A CN 101031553 A CN101031553 A CN 101031553A CN A2005800271498 A CNA2005800271498 A CN A2005800271498A CN 200580027149 A CN200580027149 A CN 200580027149A CN 101031553 A CN101031553 A CN 101031553A
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Abstract
本发明涉及式(I)化合物,其中R1表示H、(C1-C6)烷基;R2表示H、O-(C1-C3)烷基、CF3;或R1和R2与苯基环一起表示稠合萘基;R3表示(C1-C6)烷基;R4表示(C1-C6)烷基、苄基;R5表示H、(C1-C6)烷基。本发明还涉及其生理上相容的盐、溶剂化物和生理功能性衍生物。除其中涉及抗胰岛素性的紊乱外,本发明的化合物还适用于治疗和/或预防脂肪酸代谢紊乱和葡萄糖利用紊乱。
Description
本发明涉及具有环己基甲氧基取代基的乙酸衍生物、其制备方法和其作为药物的用途以及其生理上耐受的盐和生理功能性衍生物。
具有类似结构的化合物已经在本领域被描述为用于治疗高脂血症和糖尿病(WO 2004/076427)。
本发明基于如下目的:发现一种特别有效的化合物,其允许可用于治疗的对脂类和/或碳水化合物代谢的调节并因此适用于预防和/或治疗疾病如2型糖尿病和动脉粥样硬化及其多种后遗症。
这已经通过选择如下文所述的化合物得以实现,该化合物除了显示出特别好的PPARα作用外,还出人意料地显示出相应的好的PPARγ作用。
本发明涉及式I化合物及其生理耐受的盐、溶剂化物和生理功能性衍生物,
其中,
R1为H、(C1-C6)烷基;
R2为H、O-(C1-C3)烷基、CF3;或者
R1和R2与苯基环一起是稠合的萘基;
R3为(C1-C6)烷基;
R4为(C1-C6)烷基、苄基;
R5为H、(C1-C6)烷基。
优选的式I化合物是如下定义的那些:
R1为H、甲基、丙基或丁基;
R2为H、甲氧基、CF3;或者
R1和R2与苯基环一起是稠合的萘基;
R3为甲基、乙基或丙基;
R4为甲基、丙基或苄基;且
R5为H。
特别优选的式I化合物是其中R1或R2为H的那些或其中R4为甲基的那些。
取代基R1、R2、R3、R4和R5中的烷基可以是直链或支链。
式I化合物含有至少两个不对称中心,并且可以含有更多个不对称中心。因此,式I化合物可以以它们的外消旋物、外消旋混合物、纯对映异构体、非对映异构体和非对映异构混合物的形式存在。本发明包括式I化合物的所有这些异构形式。这些异构形式可通过已知方法获得,即使其中一些没有被明确描述。
由于水溶性高于起始或基础化合物,可药用盐特别适于医药应用。这些盐必须具有可药用的阴离子或阳离子。本发明化合物的适宜的可药用酸加成盐为无机酸盐和有机酸盐,所述的无机酸例如是盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸,所述的有机酸例如是乙酸、苯磺酸、苯甲酸、枸橼酸、乙磺酸、富马酸、葡糖酸、乙醇酸、羟乙磺酸、乳酸、乳糖酸、马来酸、苹果酸、甲磺酸、琥珀酸、对甲苯磺酸和酒石酸。适宜的可药用碱性盐为铵盐、碱金属盐(例如钠盐和钾盐)、碱土金属盐(例如镁盐和钙盐)、氨丁三醇(2-氨基-2-羟甲基-1,3-丙二醇)、二乙醇胺、赖氨酸或乙二胺。
作为用于制备或纯化可药用盐和/或用于非治疗应用、例如体外应用的有用中间体的具有不可药用阴离子的盐、例如三氟乙酸盐同样属于本发明的范围。
本文所用的术语“生理功能性衍生物”是指施用于哺乳动物(如人)后能够(直接或间接)生成式I化合物或其活性代谢物的本发明式I化合物的任何生理学上耐受的衍生物,例如酯。
生理功能性衍生物还包括本发明化合物的前体药物,例如如H.Okada等,Chem.Pharm.Bull.1994,42,57-61中所述。这类前体药物可以被体内代谢为本发明的化合物。这些前体药物本身可以具有或不具有活性。
本发明的化合物也可以以不同的多晶型形式存在,例如以无定形和结晶性多晶型形式存在。本发明的化合物的所有多晶型形式均被本发明的范围所涵盖,是本发明的另一方面。
下文所有提及的“式I化合物”均是指以上所述的式I化合物以及本文所述的它们的盐、溶剂化物和生理功能性衍生物。
用途
本发明还涉及式I化合物和它们的药物组合物作为PPAR受体配体的用途。本发明的PPAR受体配体适宜作为PPAR受体活性的调节剂。
过氧化物酶体增殖物激活受体(PPAR)是可以通过配体激活且属于核激素受体类的转录因子。有三种PPAR同型,PPARα、PPARγ和PPARδ,它们由不同基因编码(过氧化物酶体增殖物激活受体(PPAR):结构、激活机理和不同功能。Motojima K,Cell Struct Funct.,1993年10月,18(5),267-77)。
存在两种PPARγ变体,即PPARγ1和PPARγ2,它们是启动子选择使用和差别mRNA剪接的结果(Vidal-Puig等,J.Clin.Invest.,97:2553-2561,1996)。不同的PPAR受体具有不同的组织分布并且调节不同的生理功能。PPAR受体在大量基因调节的各个方面起关键作用,这些基因的产物至关重要地直接或间接参与脂类和碳水化合物代谢。因此,例如,PPARα受体在肝脏中的脂肪酸分解代谢或脂蛋白代谢的调节中起重要作用,而PPARγ至关重要地参与例如脂肪细胞分化的调节。然而,PPAR受体还另外参与多种其它生理过程的调节,包括不直接与碳水化合物或脂类代谢相关联的生理过程。不同PPAR受体的活性可以通过多种脂肪酸、脂肪酸衍生物和合成化合物来不同程度地调节。对于涉及功能、生理作用以及病理生理学的相关综述,参见:Joel Berger等,Annu.Rev.Med.,2002,53,409-435;Timothy Wilson等,J.Med.Chem.,2000,43卷,第4期,527-550;Steven Kliewer等,Recent Prog Horm Res.,2001,56,239-63。
本发明涉及适于调节PPAR受体活性、特别是PPARα和PPARγ的活性的式I化合物。基于调节的特性,式I化合物适宜用于治疗、控制和预防下文所述的适应症以及一系列其它相关的医药应用(例如参见JoelBerger等,Annu.Rev.Med.,2002,53,409-435;Timothy Wilson等,J.Med.Chem.,2000,43卷,第4期,527-550;Steven Kliewer等,Recent Prog HormRes.,2001,56:239-63;Jean-Charles Fruchart,Bart Staels和PatrickDuriez:PPARS,代谢疾病和动脉硬化,Pharmacological Research,44卷,第5期,2001;Sander Kersten,Beatrice Desvergne & Walter Wahli:PPAR在健康和疾病中的作用,Nature,405卷,2000年5月25日;Ines PinedaTorra,Giulia Chinetti,Caroline Duval,Jean-Charles Fruchart和BartStaels:过氧化物酶体增殖物激活受体:从转录控制到临床实践,Curr OpinLipidol 12:2001,245-254)。
此类化合物特别适用于治疗和/或预防:
1.-脂肪酸代谢紊乱和葡萄糖利用紊乱
-其中涉及抗胰岛素性的紊乱
2.-糖尿病,特别是2型糖尿病,包括与之有关的后遗症的预防。
其中的具体方面是:
-高血糖症,
-抗胰岛素性增加,
-葡萄糖耐量增加,
-胰腺β细胞的保护
-大-和微血管紊乱的预防
3.血脂异常症和它们的后遗症,例如动脉粥样硬化、冠心病、脑血管病等,特别是下述一个或多个因素表征的疾病(但不限于此):
-高血浆甘油三酯浓度,高餐后血浆甘油三酯浓度
-低HDL胆固醇浓度
-低ApoA脂蛋白浓度
-高LDL胆固醇浓度
-低密度LDL胆固醇颗粒
-高ApoB脂蛋白浓度
4.与代谢综合征有关的多种其它病症,如:
-肥胖症(超重),包括向心性肥胖
-血栓形成、高凝性和血栓形成前状态(动脉和静脉)
-高血压
-心力衰竭,例如(但不限于此)心肌梗塞、高血压性心脏病或心肌病后的心力衰竭
5.其中涉及例如炎性反应或细胞分化过的疾病或病症:
-动脉粥样硬化,例如(但不限于此)冠状动脉硬化,包括心绞痛或心肌梗塞、中风。
-血管再狭窄或再闭塞
-慢性炎性肠病,例如节段性回肠炎和溃疡性结肠炎
-胰腺炎
-其它炎性状态
-视网膜病变
-脂肪细胞肿瘤
-脂肪细胞癌,例如脂肉瘤
-实体瘤和赘生物,例如(但不限于此)胃肠道癌、肝癌、胆管癌、胰腺癌、内分泌肿瘤、肺癌、肾癌和泌尿道癌、生殖道癌、前列腺癌等
-急性和慢性骨髓增生性疾病和淋巴瘤
-血管生成
-神经变性疾病
-阿尔茨海默病
-多发性硬化症
-帕金森病
-红斑鳞屑性皮肤病,例如银屑病
-寻常痤疮
-由PPAR调节的其它皮肤病和皮肤病学病症
-湿疹和神经性皮炎
-皮炎,例如脂溢性皮炎或光照性皮炎
-角膜炎和角化病,例如脂溢性角化病、老年角化病、光化性角化病、光诱导性角化病或毛囊角化病
-瘢痕瘤和瘢痕瘤预防
-疣,包括湿疣或尖锐湿疣
-人乳头瘤病毒(HPV)感染,例如性病疣、病毒性疣,例如传染性软疣、粘膜白斑病
-丘疹皮肤病,例如扁平苔癣
-皮肤癌,例如基底细胞癌、黑素瘤或皮肤T-细胞淋巴瘤
-局限性良性表皮瘤,例如角皮病、表皮痣
-冻疮
-高血压
-X综合征
-多囊性卵巢综合征(PCOS)
-哮喘
-骨关节炎
-红斑狼疮(LE)或炎性风湿病,例如类风湿性关节炎
-脉管炎
-消瘦(恶病质)
-痛风
-缺血/再灌注综合征
-急性呼吸窘迫综合征(ARDS)。
制剂
为了达到所需生物学作用而需要的式I化合物的量取决于多种因素,例如所选择的具体化合物、预期用途、施用方式和患者的临床状况。日剂量一般为0.001mg至100mg(通常0.01mg至50mg)/天/千克体重,例如0.1-10mg/kg/天。静脉内剂量可以是例如0.001mg至1.0mg/kg,可以合适地以10ng至100ng/千克/分钟输注施用。适于这些目的的输液可以含有例如0.1ng至10mg、通常1ng至10mg/毫升。单个剂量可以含有例如1mg至10g活性成分。因此,注射用安瓿剂可以含有例如1mg至100mg,可以口服施用的单剂量制剂、例如胶囊剂或片剂可以含有例如0.05至1000mg,通常0.5至600mg。对于上述病症的治疗,式I化合物可以以化合物本身的形式使用,不过它们优选是含可接受载体的药物组合物形式。当然载体必须是可接受的,这意味着它与组合物的其它成分是相容的,并且对患者的健康无害。载体可以是固体或液体或者是固体和液体,优选地与化合物配制成单剂量,例如片剂,所述的单剂量可以含有0.05至95重量%的活性成分。也可以存在包括其它式I化合物在内的其它药学活性物质。本发明的药物组合物可以用已知的制药方法之一制备,所述方法主要包括将活性成分与药理学上可接受的载体和/或赋形剂混合。
本发明的药物组合物是适于口服、直肠、局部、经口(例如舌下)和胃肠道外(例如皮下、肌内、皮内或静脉内)施用的那些,但是在每种情况下最适宜的施用方式取决于所治疗病症的性质和严重程度以及在每种情况下所用的式I化合物的类型。包衣制剂和包衣缓释制剂也被本发明的范围所涵盖。优选耐酸的和耐胃液的制剂。适宜的耐胃液的包衣包括醋酞纤维素、聚醋酸乙烯邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯和甲基丙烯酸与甲基丙烯酸甲酯的阴离子聚合物。
适于口服施用的药物制剂可以是独立的单位形式,例如胶囊剂、扁囊剂、可吮吸片剂(suckable tablet)或片剂,其中每个单位形式含有确定量的式I化合物;散剂或颗粒剂;在水性或非水性液体中的溶液剂或混悬剂;或者水包油型或油包水型乳剂。如已经提及的那样,这些组合物可以通过任何适宜的药学方法制备,所述方法包括使活性成分与载体(其可以含有一种或多种另外的成分)相接触的步骤。一般而言,组合物可以通过以下方法制备:将活性成分与液体和/或微细粉碎的固体载体均匀且均质地混合,如果必要,之后使产品成形。因此,例如,片剂可以通过将化合物、酌情与一种或多种另外的成分的粉末或颗粒进行压制或成形来制备。压制片可以通过在适宜的机器中将酌情与粘合剂、助流剂、惰性稀释剂和/或一种(或多种)表面活性剂/分散剂混合的自由流动形式、例如粉末或颗粒形式的化合物进行压片来制备。成形片可以通过在适宜的机器中将被惰性液体稀释剂润湿的粉状化合物成形来制备。
适于经口(舌下)施用的药物组合物包括含有式I化合物以及矫味剂、通常是蔗糖和阿拉伯胶或西黄蓍胶的可吮吸片剂,和含有在惰性基质如明胶和甘油或蔗糖和阿拉伯胶中的化合物的锭剂。
适于胃肠道外施用的药物组合物优选包括式I化合物的无菌水性制剂,其优选与预期接受者的血液等张。这些制剂优选静脉内施用,但是也可以以注射剂形式皮下、肌内或皮内施用。这些制剂优选可通过将化合物与水混合以及使得到的溶液灭菌并与血液等张来制备。本发明的注射用组合物一般含有0.1至5重量%的活性化合物。
适于直肠施用的药物组合物优选为单剂量栓剂形式。这些组合物可以通过将式I化合物与一种或多种常规的固体载体例如可可脂混合并将所得混合物成形来制备。
适于局部应用于皮肤的药物组合物优选为软膏剂、乳膏剂、洗剂、糊剂、喷雾剂、气雾剂或油形式。可使用的载体有凡士林、羊毛脂、聚乙二醇、醇和两种或多种这些物质的组合。活性成分的浓度一般为组合物重量的0.1至15%,例如0.5至2%。
透皮施用也是可能的。适于透皮应用的药物组合物可以是适宜与患者的表皮长期紧密接触的单个硬膏剂形式。该类硬膏剂适宜地含有活性成分,所述活性成分处于酌情被缓冲的水溶液中、溶解于和/或分散于胶粘剂中或分散于聚合物中。适宜的活性成分浓度为约1%至35%,优选约3%至15%。活性成分可以通过电转运或离子导入法被释放,如例如Pharmaceutical Research,2(6):318(1986)中所述。
式I化合物通过有利地作用于代谢障碍而区别于其它化合物。它们对脂类和碳水化合物代谢具有有利的作用,特别是它们可降低甘油三酯水平,适于预防和治疗II型糖尿病和动脉硬化及其多种后遗症。
与其它药物的组合
本发明的化合物可以单独施用或与一种或多种其它药学活性物质例如能有利地作用于代谢紊乱或常常与之有关的疾病的药学活性物质组合施用。这些药物的实例有:
1.降血糖药、抗糖尿病药,
2.用于治疗血脂异常症的活性成分,
3.抗动脉粥样硬化药,
4.抗肥胖剂,
5.抗炎活性成分,
6.用于治疗恶性肿瘤的活性成分,
7.抗血栓形成的活性成分,
8.用于治疗高血压的活性成分,
9.用于治疗心力衰竭的活性成分以及
10.用于治疗和/或预防由糖尿病引起的或与糖尿病有关的并发症的活性成分。
它们可以与本发明的式I化合物组合使用,特别是用于产生协同增强作用。通过将活性成分分别施用于患者或以其中多种活性成分存在于一种药物制剂中的组合产品的形式可以施用活性成分的组合。
可提及的实例有:
抗糖尿病药
适宜的抗糖尿病药例如在Rote Liste 2001,第12章中或在USPDictionary of USAN and International Drug Names,US Pharmacopeia,Rockville 2001中公开。抗糖尿病药包括所有胰岛素和胰岛素衍生物,例如Lantus(参见www.lantus.com)或Apidra以及其它速效胰岛素(参见US 6,221,633)、GLP-1受体调节剂,如WO 01/04146等中所述,例如在Novo Nordisk A/S的WO 98/08871中公开的那些。
口服有效的降血糖活性成分优选包括磺酰脲类、双胍类、氯茴苯酸类、二唑烷二酮类、噻唑烷二酮类、葡糖苷酶抑制剂、胰高血糖素拮抗剂、口服GLP-1激动剂、DPP-IV抑制剂、钾通道开放剂,例如在WO 97/26265和WO 99/03861中所公开的那些、胰岛素增敏剂、与刺激糖异生和/或糖原分解有关的肝酶的抑制剂、葡萄糖摄取调节剂、改变脂类代谢和导致血液脂类组成改变的化合物、减少食物摄入或食物吸收的化合物、PPAR和PXR调节剂以及作用于β细胞的ATP-依赖性钾通道的活性成分。
在本发明的一个实施方案中,式I化合物与胰岛素组合施用。
在本发明的一个实施方案中,式I化合物与影响肝糖生成的物质如糖原磷酸化酶抑制剂(参见:WO 01/94300、WO 02/096864、WO 03/084923、WO 03/084922、WO 03/104188)组合施用。
在一个实施方案中,式I化合物与磺酰脲类例如甲苯磺丁脲、格列本脲、格列吡嗪或格列美脲组合施用。
在一个实施方案中,式I化合物与作用于β细胞的ATP-依赖性钾通道的活性成分例如甲苯磺丁脲、格列本脲、格列吡嗪、格列美脲或瑞格列奈组合施用。
在一个实施方案中,式I化合物与双胍类例如二甲双胍组合施用。
在另一个实施方案中,式I化合物与氯茴苯酸类例如瑞格列奈组合施用。
在一个实施方案中,式I化合物与噻唑烷二酮类例如环格列酮、吡格列酮、罗格列酮或Dr.Reddy’s Research Foundation的WO 97/41097中所公开的化合物、特别是5-[[4-[(3,4-二氢-3-甲基-4-氧代-2-喹唑啉基)甲氧基]苯基]甲基]-2,4-噻唑烷二酮组合施用。
在一个实施方案中,式I化合物与DPPIV抑制剂例如WO 98/19998、WO 99/61431、WO 99/67278、WO 99/67279、WO 01/72290、WO 02/38541、WO 03/040174中所述的那些、特别是P93/01(1-环戊基-3-甲基-1-氧代-2-戊基氯化铵)、P-31/98、LAF237(1-[2-(3-羟基金刚烷-1-基氨基)乙酰基]吡咯烷-2-(S)-甲腈)、TS021((2S,4S)-4-氟-1-[[(2-羟基-1,1-二甲基乙基)氨基]乙酰基]吡咯烷-2-甲腈单苯磺酸盐)组合施用。
在本发明的一个实施方案中,式I化合物与PPARγ激动剂例如罗格列酮、吡格列酮组合施用。
在一个实施方案中,式I化合物与对SGLT-1和/或2有抑制作用的化合物、例如直接或间接在WO 2004/007517、WO 2004/052902和WO2004/052903中公开的那些化合物组合施用。
在一个实施方案中,式I化合物与α-葡糖苷酶抑制剂例如米格列醇或阿卡波糖组合施用。
在一个实施方案中,式I化合物与一种以上的上述化合物、例如与磺酰脲和二甲双胍、磺酰脲和阿卡波糖、瑞格列奈和二甲双胍、胰岛素和磺酰脲、胰岛素和二甲双胍、胰岛素和曲格列酮、胰岛素和洛伐他汀等组合施用。
脂类调节剂
在本发明的一个实施方案中,式I化合物与HMGCoA还原酶抑制剂如洛伐他汀、氟伐他汀、普伐他汀、辛伐他汀、ivastatin、伊伐他汀、阿托伐他汀、罗苏伐他汀组合施用。
在本发明的一个实施方案中,式I化合物与胆酸吸收抑制剂(参见例如US 6,245,744、US 6,221,897、US 6,227,831、EP 0683 773、EP 0683 774)组合施用。
在本发明的一个实施方案中,式I化合物与聚合胆酸吸附剂例如考来烯胺、考来维仑组合施用。
在本发明的一个实施方案中,式I化合物与胆固醇吸收抑制剂例如WO 0250027中所述的那些或依泽替米贝、替奎安、帕马苷组合施用。
本发明的一个实施方案中,式I化合物与LDL受体诱导剂(参见例如US 6,342,512)组合施用。
在一个实施方案中,式I化合物与填充剂、优选不溶性填充剂(参见例如carob/Caromax(Zunft H J;等,用于治疗高胆固醇血症的角豆果肉制品,ADVANCES IN THERAPY(2001年9月-10月),18(5),230-6);Caromax是一种由Nutrinova,Nutrition Specialties & Food Ingredients GmbH,Industiepark Hchst,65926 Frankfur/Main提供的含角豆的产品)组合施用。可能是在一个制剂中或通过分别施用式I化合物和Caromax来实现与Caromax组合。Caromax在本文中也可以以食物产品形式施用,例如以烘烤产品或穆兹利棒形式施用。
在本发明的一个实施方案中,式I化合物与PPARα激动剂组合施用。
在本发明的一个实施方案中,式I化合物与混合型PPARα/γ激动剂、例如AZ 242(Tesaglitazar,(S)-3-(4-[2-(4-甲磺酰氧基苯基)乙氧基]苯基)-2-乙氧基丙酸)、BMS 298585(N-[(4-甲氧基苯氧基)羰基]-N-[[4-[2-(5-甲基-2-苯基-4-唑基)乙氧基]苯基]甲基]甘氨酸)或WO 99/62872、WO 99/62871、WO 01/40171、WO 01/40169、WO 96/38428、WO 01/81327、WO 01/21602、WO 03/020269、WO 00/64888或WO 00/64876中所述的化合物组合施用。
在本发明的一个实施方案中,式I化合物与贝特类例如非诺贝特、吉非贝齐、氯贝特、苯扎贝特组合施用。
在本发明的一个实施方案中,式I化合物与烟酸或尼克酸组合施用。
在本发明的一个实施方案中,式I化合物与CETP抑制剂例如CP-529、414(托切普(torcetrapib))组合施用。
在本发明的一个实施方案中,式I化合物与ACAT抑制剂组合施用。
在本发明的一个实施方案中,式I化合物与MTP抑制剂例如英普他派组合施用。
在本发明的一个实施方案中,式I化合物与抗氧化剂组合施用。
在本发明的一个实施方案中,式I化合物与脂蛋白脂肪酶抑制剂组合施用。
在本发明的一个实施方案中,式I化合物与ATP柠檬酸裂合酶抑制剂组合施用。
在本发明的一个实施方案中,式I化合物与鲨烯合成酶抑制剂组合施用。
在本发明的一个实施方案中,式I化合物与脂蛋白(a)拮抗剂组合施用。
抗肥胖剂
在本发明的一个实施方案中,式I化合物与脂肪酶抑制剂例如奥利司他组合施用。
在一个实施方案中,其它活性成分是芬氟拉明或右旋芬氟拉明。在另一个实施方案中,其它活性成分是西布曲明。
在另一个实施方案中,式I化合物与以下物质组合施用:CART调节剂(参见“可卡因-苯丙胺调节的转录影响小鼠的能量代谢、焦虑和胃排空”Asakawa,A等,M.:Hormone and Metabolic Research(2001),33(9),554-558)、NPY拮抗剂如萘-1-磺酸{4-[(4-氨基喹唑啉-2-基氨基)甲基]环己基甲基}酰胺盐酸盐(CGP 71683A))、MC4激动剂(例如1-氨基-1,2,3,4-四氢萘-2-甲酸[2-(3a-苄基-2-甲基-3-氧代-2,3,3a,4,6,7-六氢吡唑并[4,3-c]吡啶-5-基)-1-(4-氯苯基)-2-氧代乙基]酰胺(WO 01/91752))、食欲素(orexin)拮抗剂(例如1-(2-甲基苯并唑-6-基)-3-[1,5]萘啶-4-基脲盐酸盐(SB-334867-A))、H3激动剂(3-环己基-1-(4,4-二甲基-1,4,6,7-四氢咪唑并[4,5-c]吡啶-5-基)丙-1-酮草酸盐(WO 00/63208))、TNF激动剂、CRF拮抗剂(例如[2-甲基-9-(2,4,6-三甲基苯基)-9H-1,3,9-三氮杂芴-4-基]二丙基胺(WO 00/66585))、CRF BP拮抗剂(例如尿皮质素(urocortin))、尿皮质素激动剂、β3激动剂(例如1-(4-氯-3-甲磺酰基甲基苯基)-2-[2-(2,3-二甲基-1H-吲哚-6-基氧基)乙基氨基]乙醇盐酸盐(WO 01/83451))、MSH(促黑激素)激动剂、CCK-A激动剂(例如{2-[4-(4-氯-2,5-二甲氧基苯基)-5-(2-环己基乙基)噻唑-2-基氨基甲酰基]-5,7-二甲基吲哚-1-基}乙酸三氟乙酸盐(WO 99/15525))、5-羟色胺再摄取抑制剂(例如右旋芬氟拉明)、混合型5-羟色胺能和去甲肾上腺素能化合物(例如WO 00/71549)、5HT激动剂例如1-(3-乙基苯并呋喃-7-基)哌嗪草酸盐(WO 01/09111)、铃蟾肽激动剂、甘丙肽(galanin)拮抗剂、生长激素(例如人生长激素)、生长激素释放化合物(6-苄氧基-1-(2-二异丙氨基乙基氨基甲酰基)-3,4-二氢-1H-异喹啉-2-甲酸叔丁酯(WO 01/85695))、TRH激动剂(参见例如EP 0 462 884)、解偶联蛋白2或3调节剂、瘦素(leptin)激动剂(参见例如Lee,Daniel W.;Leinung,Matthew C.;Rozhavskaya-Arena,Marina;Grasso,Patricia.瘦素激动剂用作治疗肥胖症的潜在手段.Drugs of theFuture(2001),26(9),873-881)、DA激动剂(溴隐亭、Doprexin)、脂肪酶/淀粉酶抑制剂(例如WO 00/40569)、PPAR调节剂(例如WO 00/78312)、RXR调节剂或TR-β激动剂。
在本发明的一个实施方案中,其它的活性成分是瘦素。
在一个实施方案中,其它的活性成分是右旋苯丙胺、苯丙胺、吗吲哚或苯丁胺。
在一个实施方案中,式I化合物与作用于冠脉循环和血管系统的药物例如ACE抑制剂(例如雷米普利)、作用于肾素-血管紧张素系统的药物、钙拮抗剂、β-阻滞剂等组合施用。
在一个实施方案中,式I化合物与具有抗炎作用的药物组合施用。
在一个实施方案中,式I化合物与用于癌症治疗和癌症预防的药物组合施用。
可以理解,本发明的化合物与一种或多种上述化合物以及任选的一种或多种其它药理学活性物质的任何适宜的组合均被认为落入本发明授予保护的范围内。
化合物的活性如下进行测试:
在细胞PPARα试验中PPAR激动剂的EC50值的测定
原理
采用稳定转染的HEK细胞系(HEK=人胚肾)(在本文称为“PPARα报告细胞系”)分析与人PPARα结合并以激动方式激活它的物质的功效。所述细胞包含两个基因元件,即萤光素酶报告元件(pdeltaM-GAL4-Luc-Zeo)和PPARα融合蛋白(GR-GAL4-人PPARα-LBD),PPARα融合蛋白依赖PPARα配体介导萤光素酶报告元件的表达。稳定和组成型表达的融合蛋白GR-GAL4-人PPARα-LBD在PPARα报告细胞系的细胞核中通过GAL4蛋白部分结合到稳定整合进此细胞系基因组中的萤光素酶报告元件的5’-上游GAL4 DNA结合基序。如果在试验中使用脂肪酸耗竭的胎牛血清(cs-FCS),没有PPARα配体加入时,只有极少量萤光素酶报告基因表达。PPARα配体结合并激活PPARα融合蛋白,因而导致萤光素酶报告基因的表达。形成的萤光素酶可以通过借助合适底物的化学发光法检测。
细胞系的构建
分两个步骤制备PPARα报告细胞系。首先,构建萤光素酶报告元件并且将其稳定地转染进HEK细胞。为此目的,将酵母转录因子GAL4的五个结合位点(每种情况下为5’-CGGAGTACTGTCCTCCGAG-3’)克隆进68bp长的最小的MMTV启动子(Genbank登录号V01175)的5’-上游。最小MMTV启动子部分包含CCAAT盒和TATA元件以便使通过RNA聚合酶II的有效转录成为可能。GAL4-MMTV构建体的克隆和测序可类似于Sambrook J.等的描述(Molecular cloning,Cold Spring HarborLaboratory Press,1989)进行。然后将完整的萤火虫萤光素酶基因(Genbank登录号M15077)克隆进GAL4-MMTV元件的3’-下游。测序后,将由五个GAL4结合位点、MMTV启动子和萤光素酶基因组成的萤光素酶报告元件再克隆进提供zeozin抗性的质粒中以便获得质粒pdeltaM-GAL4-Luc-Zeo。根据Ausubel,F.M.等的描述(Current protocols in molecular biology,1-3卷,John Wiley & Sons,Inc.,1995)将载体转染进HEK细胞中。然后用含有zeozin的培养基(0.5mg/ml)来选择适宜的稳定的细胞克隆,它表现出十分低的萤光素酶基因的基本表达量。
第二步,将PPARα融合蛋白(GR-GAL4-人PPARα-LBD)导入所述稳定细胞克隆中。为此目的,最初,将编码糖皮质激素受体N端76个氨基酸的cDNA(Genbank登录号P04150)连接到编码酵母转录因子GAL4的氨基酸1-147的cDNA部分(Genbank登录号P04386)上。将人PPARα受体的配体结合结构域(氨基酸S167-Y486;Genbank登录号S74349)的cDNA克隆进此GR-GAL4构建体的3’端。将用此方法制备的融合构建体(GR-GAL4-人PPARα-LBD)再克隆进质粒pcDNA3(购自Invitrogen)以便使通过巨细胞病毒启动子进行的组成型表达成为可能。将这个质粒用限制性核酸内切酶线性化并稳定地转染进前述含有萤光素酶报告元件的细胞克隆中。所得到的包含萤光素酶报告元件并组成型表达PPARα融合蛋白(GR-GAL4-人 PPARα-LBD)的PPARα报告细胞系可以通过zeozin(0.5mg/ml)和G418(0.5mg/ml)选择进行分离。
试验方法
PPARα激动剂活性在3天的试验中得以测定,描述如下:
第一天
将PPARα报告细胞系在混合有如下添加物的DMEM培养基(#41965-039,Invirogen)中培养至80%汇合:10% cs-FCS(胎牛血清,#SH-30068.03,Hyclone)、0.5mg/ml的zeocin(#R250-01,Invitrogen)、0.5mg/ml的G418(#10131-027,Invitrogen)、1%的青霉素链霉素溶液(#15140-122,Invitrogen)和2mM的L-谷氨酰胺(#25030-024,Invitrogen)。培养在存在5%CO2时于37℃细胞培养箱中的标准细胞培养瓶(#353112,Becton Dickinson)里进行。80%汇合的细胞用15ml PBS(#14190-094,Invitrogen)洗涤一次,用3ml胰蛋白酶溶液(#25300-054,Invitrogen)在37℃处理2分钟,将其置于5ml上述DMEM培养基中并且在细胞计数器中计数。稀释到500000个细胞/ml后,将35000个细胞接种在具有透明塑料底的96孔微量滴定板(#3610,Corning Costar)的每个孔中。将板在37℃和5%CO2下于细胞培养箱中孵育24小时。
第二天
将待检测的PPARα激动剂溶解于DMSO中,浓度为10mM。将此储备溶液用DMEM培养基(#41965-039,Invitrogen)稀释,在此培养基中混合有5%的cs-FCS(#SH-30068.03,Hyclone)、2mM的L-谷氨酰胺(#25030-024,Invitrogen)以及上述抗生素(zeozin、G418、青霉素和链霉素)。
供试物质在10μM到100pM范围的11种不同浓度下进行检测。较有效的化合物以1μM到10pM或100nM到1pM之间的浓度下进行检测。
通过抽吸将在第一天接种的PPARα报告细胞系的培养基完全除去,并且立刻将在培养基中稀释了的供试物质加入细胞中。使用机器手(Beckman FX)进行此类物质的稀释和添加。在培养基中稀释的供试物质的终体积是每个96-孔微量滴定板孔100μl。在试验中DMSO的浓度低于0.1%v/v以防止溶剂的细胞毒效应。
为了证明本试验在各个单独板中起作用,将同样稀释成11种不同浓度的标准PPARα激动剂加入到各个板中。将检测板于37℃和5%CO2下在培养箱中孵育24小时。
第三天
将用供试物质处理的PPARα报告细胞从培养箱中移出,并且将培养基抽吸掉。通过吸移50μl Bright Glo试剂(来自Promega)进入96-孔微量滴定板的每个孔,将细胞裂解。在暗处室温下孵育10分钟后,在光度计(来自Wallac的Trilux)中测定微量滴定板。微量滴定板的每个孔的测定时间为1秒。
评价
将来自发光计的原始数据导入Microsoft Excel文件中,按照生产商(IDBS)的使用说明用XL.Fit程序计算PPAR激动剂的剂量-效应曲线和EC50值。
在细胞PPARγ试验中PPAR激动剂的EC50值的测定
原理
采用瞬时转染体系来测定PPAR激动剂的细胞PPARγ活性。这基于萤光素酶报告质粒(pGL3basic-5xGAL4-TK)和PPARγ表达质粒(pcDNA3-GAL4-人PPARγ-LBD)的使用。将两种质粒瞬时转染进入人胚肾细胞(HEK细胞)。然后在这些细胞中融合蛋白GAL4-人PPARγLBD表达,所述融合蛋白结合到报告质粒的GAL4结合位点。在存在PPARγ-活性配体时,激活的融合蛋白GAL4-人PPARγLBD诱导萤光素酶报告基因的表达,这可以在加入萤光素酶底物后以化学发光信号的形式被检测。与稳定转染的PPARα报告细胞系不同,在细胞PPARγ试验中两种组分(萤光素酶报告质粒和PPARγ表达质粒)被瞬时转染进HEK细胞中,这是因为PPARγ融合蛋白的稳定和持久表达是有细胞毒作用的。
质粒的构建
萤光素酶报告质粒pGL3basic-5xGAL4-TK是基于来自Promega的载体pGL3basic。报告质粒通过将酵母转录因子GAL4的五个结合位点(每个结合位点具有序列5’-CTCGGAGGACAGTACTCCG-3’)和160bp-长的胸苷激酶启动子部分(Genbank登录号AF027128)5’-上游一起克隆进pGL3basic而被制备。胸苷激酶启动子3’-下游是来自萤火虫(Photinuspyralis)的全长萤光素酶基因(Genbank登录号M15077),此萤光素酶基因已经是所用质粒pGL3basic的一个组分。报告质粒GL3basic-5xGAL4-TK的克隆和测序可类似于Sambrook J.等(Molecular cloging,Cold SpringHarbor Laboratory Press,1989)的描述进行。
PPARγ表达质粒pcDNA3-GAL4-人PPARγLBD通过以下方法制备:首先将编码酵母转录因子GAL4的氨基酸1-147的cDNA(Genbank登录号P04386)克隆进质粒pcDNA3(来自Invitrogen)巨细胞病毒启动子的3’-下游。接着,将人PPARγ受体的配体-结合结构域(LBD)的cDNA(氨基酸I152-Y475;登录号#g1480099)GAL4 DNA结合结构域的3’-下游克隆。PPARγ表达质粒pcDNA3-GAL4-人PPARγ-LBD的克隆和测序同样可类似于Sambrook J.等(Molecular cloning,Cold Spring Harbor LaboratoryPress,1989)的描述进行。除了萤光素酶报告质粒pGL3basic-5xGAL4-TK和PPARγ表达质粒pcDNA3-GAL4-人PPARγ-LBD外,还用于细胞PPARγ试验的是参考质粒pRL-CMV(来自Promega)和来自Stratagene的质粒pBluescript SK(+)。所有四种质粒均用来自Qiagen的质粒制备试剂盒制备,该试剂盒可以确保质粒在转染进入HEK细胞之前具有最小内毒素含量的质量。
试验方法
PPARγ激动剂的活性在如下描述的4天的试验中得以测定。在转染之前,HEK细胞在混合有以下添加物的DMEM(#41965-039,Invitrogen)中培养:10%FCS(#16000-044,Invitrogen)、1%的青霉素链霉素溶液(#15140-122,Invitrogen)和2mM的L-谷氨酰胺(#25030-024,Invitrogen)。
第一天
首先制备溶液A,它是一种包含所有四种上述质粒以及DMEM的转染混合液。下列量用于制备3ml溶液A,在试验中其用于96孔微量滴定板的每个孔:2622μl无抗生素和无血清的DMEM(#41965-039,Invitrogen)、100μl参考质粒pRL-CMV(1ng/μl)、100μl萤光素酶报告质粒pGL3basic-5xGAL4-TK(10ng/μl)、100μl PPARγ表达质粒pcDNA3-GAL4-人PPARγ-LBD(100ng/μl)以及78μl质粒pBluescript SK(+)(500ng/μl)。然后通过混合1.9ml DMEM(#41965-039,Invitrogen)与100μl PolyFect转染试剂(来自Qiagen)为每个96孔微量滴定板制备2ml溶液B。接着,将3ml溶液A和2ml溶液B混合产生5ml溶液C,通过多次抽吸将其充分混合并在室温下孵育10分钟。
将175cm2容量的细胞培养瓶中80%汇合的HEK细胞用15ml的PBS(#14190-094,Invitogen)洗涤一次并用3ml胰蛋白酶溶液(#25300-054,Invitrogen)在37℃下处理2分钟。然后将细胞置于15ml混合有10%FCS(#16000-044,Invitrogen)、1%青霉素链霉素溶液(#15140-122,Invitrogen)和2mM的L-谷氨酰胺(#25030-024,Invitrogen)的DMEM(#41965-039,Invitrogen)中。将细胞混悬液在细胞计数器中计数后,将混悬液稀释至250000个细胞/ml。将15ml该细胞混悬液和5ml溶液C混合以用于一块微量滴定板。将200μl此混悬液接种到具有透明塑料底部的96孔微量滴定板(#3610,Corning Costar)的每个孔中。将此板于37℃和5%CO2下在细胞培养箱中孵育24小时。
第二天
将待检测的PPAR激动剂以10mM的浓度溶解于DMSO中。将该储备溶液用混合有2%Ultroser(#12039-012,Biosepra)、1%青霉素链霉素溶液(#15140-122,Invitrogen)和2mM L-谷氨酰胺(#25030-024,Invitrogen)的DMEM(#41965-039,Invitrogen)稀释。将供试物质在总共11种从10μM到100pM范围内的不同浓度下进行试验。较有效的化合物在1μM到10pM范围内的浓度下进行试验。
将在第一天转染和接种的HEK细胞的培养基通过抽吸完全除去,并将用培养基稀释的供试物质立刻加入细胞中。这些物质的稀释和添加通过机器手(Beckman FX)进行。用培养基稀释的供试物质的最终体积是96孔微量滴定板的每个孔100μl。将每个板装载同样被稀释成11种不同浓度的标准PPARγ激动剂,以便证明每个单独板中的检测功能。将试验板在37℃和5%CO2下于培养箱中孵育48小时。
第四天
通过抽吸将培养基除去后,将50μl Dual-GloTM试剂(Dual-GloTM萤光素酶测试体系;Promega)按照生产商的使用说明加入每个孔中以便裂解细胞并且向细胞中形成的萤火虫萤光素酶(Photinus pyralis)提供底物。在室温下暗处孵育10分钟后,在测量仪器中测量萤火虫萤光素酶介导的化学发光(测量时间/孔为1秒;来自Wallac的Trilux)。然后将50μl Dual-GloTMStop& Glo试剂(Dual-GloTM萤光素酶测试体系;Promega)加入每个孔中以便终止萤火虫萤光素酶的活性并向通过参考质粒pRL-CMV表达的海肾(Renilla)萤光素酶提供底物。在室温下暗处孵育另外10分钟后,再次在测量仪器中以1秒/孔测量通过海肾萤光素酶介导的化学发光。
评价
将来自发光计的原始数据导入Microsoft Excel文件中。对源自微量滴定板每个孔的每次检测值确定萤火虫/海肾萤光素酶活性比率。按照生产商(IDBS)的使用说明通过XL.Fit程序由该比率计算出PPAR激动剂的剂量-效应曲线和EC50值。
本发明的一些式I化合物的活性结果显示在下表I中:
表1
实施例编号 | 结构式 | EC50PPARα[μM] | EC50PPARγ[μM] |
1 | 0,045 | 0,93 | |
2 | 0,0035 | 2,9 | |
3 | 0,019 | 0,67 | |
4 | 0,0020 | 1,1 | |
5 | 0,012 | 1,5 | |
7 | 0,0012 | 2,6 | |
9 | 0,32 | 0,39 | |
10 | 0,054 | 0,13 | |
11 | 0,0041 | 0,87 | |
12 | 0,012 | 0,075 | |
13 | 0,0066 | 0,13 | |
14 | 0,00038 | 0,22 | |
14 | 0,00053 | 0,056 | |
15 | 0,00039 | 0,16 | |
16 | 0,017 | 0,40 | |
17 | 0,00016 | 0,51 | |
18 | 0,0026 | 0,15 | |
19 | 0,00038 | 0,54 | |
20 | 0,00054 | 0,17 | |
21 | 0,0058 | 0,60 |
*WO 2004/076427的实施例8a。
**WO 2004/076427的实施例10。
表1显然表明:与临床上使用的贝特类类似(例如参见J.-Ch.Fruchard等人:PPARS,代谢病和动脉粥样硬化,Pharmacological Research,第44卷,第5期,2001;S.Kersten等人:PPAR在健康和疾病中的作用,NATURE,第405卷,2000年5月25日;I.Pineda等人:过氧化物酶体增殖物激活受体:从转录控制到临床实践,Curr Opin Lipidol 12:2001,245-254),本发明的式I化合物激活PPARα受体和PPARγ受体并因此例如引起体内甘油三酯水平降低。
以下详述的实施例用于说明本发明但并非限制于此。
表II
EX | R1 | R2 | R3 | R4 | R5 |
1 | H | 3-OCH3 | C2H5 | CH3 | H |
2 | 4-CH3 | H | C2H5 | CH3 | H |
3 | 4-i-C4H9 | H | C2H5 | CH3 | H |
4 | 2-萘基 | C2H5 | CH3 | H | |
5 | H | 3-CF3 | C2H5 | CH3 | H |
6 | 4-i-C3H7 | H | C2H5 | CH3 | H |
7 | 2-萘基 | CH3 | CH3 | H | |
8a | H | 3-OCH3 | i-C3H7 | CH3 | H |
9 | H | 3-OCH3 | i-C3H7 | CH3 | H |
10 | H | 3-OCH3 | C2H5 | n-C3H7 | H |
11 | 4-CH3 | H | C2H5 | n-C3H7 | H |
12 | 4-i-C4H9 | H | C2H5 | n-C3H7 | H |
13 | 2-萘基 | C2H5 | n-C3H7 | H | |
14 | 4-i-C3H7 | H | C2H5 | n-C3H7 | H |
15 | 2-萘基 | CH3 | n-C3H7 | H | |
16 | H | 3-OCH3 | C2H5 | CH2Ph | H |
17 | 4-CH3 | H | C2H5 | CH2Ph | H |
18 | 4-i-C4H9 | H | C2H5 | CH2Ph | H |
19 | 2-萘基 | C2H5 | CH2Ph | H | |
20 | 4-i-C3H7 | H | C2H5 | CH2Ph | H |
21 | 2-萘基 | CH3 | CH2Ph | H |
a外消旋
方法
本发明的式I化合物可按照下述反应流程获得:
化合物A-1在仲羟基上被保护(例如对PG=TBDPS而言,通过与TBDPSCl和咪唑在DMF中于室温搅拌;或对PG=THP而言,通过与二氢吡喃和甲苯磺酸在二氯甲烷中于室温搅拌),得到化合物A-2,其中R6具有上文所述的含义。在醚溶剂中用氢化铝锂使A-2被还原为化合物A-3。使化合物A-3与化合物A-4(2-卤代乙酸和醇R6-OH的酯,其中R6具有上文所述的含义,且卤素可以是氯、溴或碘)反应,得到化合物A-5。化合物A-5与碱氨基锂(例如二异丙基氨基锂或锂-2,2,5,5-四甲基pyrrolidide)和通式R4X的烷基卤(其中R4具有上文所述的含义且卤素可以是氯、溴或碘)在醚溶剂于降低温度下反应。然后将以这种方法获得的化合物与碱氨基锂(例如二异丙基氨基锂或锂-2,2,5,5-四甲基pyrrolidide)和通式R5X的烷基卤(其中R5具有上文所述的含义且卤素可以是氯、溴或碘)在醚溶剂于降低温度下反应,得到化合物A-6。从A-6消除保护基(当PG=TBDPS时用四丁基氟化铵的THF溶液,或者当PG=THP时用甲苯磺酸的甲醇溶液),得到通式A-7化合物。使化合物A-7与碱(例如氢化钠或叔丁醇钾)和化合物A-8(参见方法A,其中R1、R2和R3具有上文所述的含义)在醚溶剂中反应,得到化合物A-9。使化合物A-9水解为酸A-10:当R6为伯或仲烷基时使用碱在甲醇中进行,或者当R6为叔烷基时使用无水酸在惰性溶剂中进行(例如使用氯化氢在二烷中进行或使用三氟乙酸在二氯甲烷中进行)。
对映异构纯的化合物以对映异构纯的酯A-1为原料进行合成。
实施例1至21可通过这种方法合成。
所用的缩略语表示:
Ac 乙酰基
Bn 苄基
Bu 丁基
iBu 异丁基
tBu 叔丁基
BuLi 正丁基锂
Bz 苯甲酰基
Cy 环己基
DCI 直接化学电离(MS中)
DCM 二氯甲烷
DHP 2,3-二氢吡喃
DMAP 4-N,N-二甲基氨基吡啶
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
EA 乙酸乙酯
EDC N′-(3-二甲氨基丙基)-N-乙基碳二亚胺×HCl
EI 电子碰撞电离(MS中)
equiv. 当量
ESI 电喷雾电离(MS中)
Et 乙基
h 小时
HATU 六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲
HOBt 1-羟基-1H-苯并三唑×H2O
HPLC 高压、高效液相色谱法
LC-MS 联用液相色谱法-质谱法
Me 甲基
MS 质谱法
MsCl 甲磺酰氯
MTBE 叔丁基甲基醚
NMR 核磁共振光谱法
Pd/C 披钯炭
Ph 苯基
iPr 异丙基
nPr 正丙基
Rf 保留比(TLC中)
RT 室温
sat. 饱和
TBAF 四丁基氟化铵
TBAI 四丁基碘化铵
TBDPSCl 叔丁基二苯基甲硅烷基氯
TBDMSCl 叔丁基二甲基甲硅烷基氯
TFA 三氟乙酸
THF 四氢呋喃
THP 四氢吡喃基
TLC 薄层色谱法
Tr 三苯甲基
TsOH 甲苯磺酸
其它化合物可以按照上述方法制备。
通式A-8的化合物的结构单元的合成:
使二乙酮与亚硝酸异戊酯和HCl在乙醚中反应,产生戊烷-2,3-二酮-2-肟(G.Buechi,J.Galindo,J.Org.Chem.(1991)56(8),2605-2606)。使后者与对甲基苯甲醛和HCl在乙酸中反应,得到5-乙基-4-甲基-2-对甲苯基唑-3-氧化物(P.M.Weintraub,J.Med.Chem.(1972)15(4),419-420)。使该化合物与磷酰氯在氯仿中沸腾,产生4-氯甲基-5-乙基-2-对甲苯基唑(M.S.Malamas,R.P.Carlson,D.Grimes,R.Howell,K.Glaser,I.Gunawan,J.A.Nelson,M.Kanzelberger,U.Shah,D.A.Hartman,J.Med.Chem.(1996)39(1),237-245)。将该化合物与碘化钠在丙酮中加热回流,产生5-乙基-4-碘甲基-2-对甲苯基唑(A.,Zlatkov,P.,Peikov,J.,Rodriguez-Alvarez,N.,Danchev,I.,Nikolova,J.,Mitkov,Eur.J.Med.Chem.Chim.Ther.(2000)35(10),941-948)。
按照类似的合成方法由表III中所述的前体得到以下结构单元:
表III:
实施例1
2-{(1R,3S)-3-[5-乙基-2-(4-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸
(1R,3S)-3-(四氢吡喃-2-基氧基)环己烷甲酸异丙酯
将20.0g(1R,3S)-3-羟基环己烷甲酸异丙酯和9.94g二氢吡喃溶于100ml二氯甲烷中,于室温(RT)加入甲苯磺酸一水合物。将溶液于室温静置过夜,然后加入饱和碳酸氢钠溶液。分离出有机相,用饱和碳酸氢钠溶液洗涤一次,然后用水洗涤,经硫酸镁干燥,浓缩,得到28.0g(1R,3S)-3-(四氢吡喃-2-基氧基)-环己烷甲酸异丙酯,为棕色油。
(1R,3S)-3-羟基环己烷甲酸异丙酯的合成在L.Fonteneau,S.Rosa,D.Buisson,Tetrahedron:Asymmetry(2002),13(6),579-585中有描述。
1H-NMR(500MHz,DMSO):δ=4,82-4,92(m,1H);4,61-4,64和4,68-4,72(m,1H,THP-CH(OR)2);3,70-3,80(m 1H);3,49-3,58(m,1H);3,35-3,46(m,1H);2,20-2,36(m1H);2,04-2,16(m,1H),0,97-2,0(m,13H);1,15-1,19(2d,6H).
[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基]-甲醇
将47g(1R,3S)-3-(四氢吡喃-2-基氧基)-环己烷甲酸异丙酯于0℃滴加至13.2g氢化锂铝在THF中的混悬液中。将混合物于室温搅拌1小时,然后于0℃加入68ml乙酸乙酯,随后加入溶于62.6ml水中的55.6g氢氧化钠。然后加入50ml甲醇,将混合物搅拌至沉淀为白色。向混悬液中加入50g硫酸镁,然后过滤。将滤液浓缩,此时硫酸镁进一步被沉淀出;用MTBE使其完全被沉淀出,然后滤除。蒸馏除去溶剂,得到34g[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基]-甲醇,为浅黄色油。
1H-NMR(500MHz,DMSO):δ=4,67-4,72(m,1H);4,36-4,42(m,1H);3,73-3,81(m1H);3,44-3,52(m,1H);3,37-3,44(m,1H);3,16-3,27(m,2H);1,84-2,04(m 2H);1,66-1,75(m,2H),1,54-1,64(m,2H);1,32-1,51(m,4H);1,08-1,30(m,2H);0,67-1,02(m,3H).
[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-乙酸叔丁酯
将34g[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基]-甲醇、100g溴代乙酸叔丁酯、16.2g叔丁基硫酸氢铵和5.9g叔丁基碘化铵溶于250ml甲苯中,于10℃(冰水浴)加入63.5g氢氧化钠在80ml水中的溶液,将混合物于10℃剧烈搅拌8小时(KPG桨搅拌器)。然后加入MTBE和水,分离各相。将水相用MTBE萃取两次,所合并的有机相用饱和氯化钠溶液洗涤,经硫酸镁干燥,浓缩。将残余物进行硅胶色谱法(庚烷/乙酸乙酯梯度)。得到36.4g[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-乙酸叔丁酯和6.8g[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基]-甲醇,为浅黄色油。C18H32O5(328.22);MS(Cl+):329(3)[MH+],245.2(100)[MH+-C5H8O],189.2(50)[MH+-C5H8O-C4H8]
2-甲基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-丙酸叔丁酯
于-78℃将100ml二异丙基氨基锂溶液(2M THF溶液)加入30g[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-乙酸叔丁酯在250ml THF中的溶液,在此期间温度应当不高于-55℃。将溶液于此温度搅拌10分钟,然后温热至-10℃并于此温度另外搅拌15分钟,然后再次将溶液冷却至-78℃,滴加17.1ml甲基碘。将溶液温热至-10℃,然后加入饱和氯化铵溶液和MTBE。分离各相,有机相用饱和氯化铵溶液洗涤,所合并的水相再用MTBE萃取一次,然后将所合并的有机相用饱和氯化钠溶液洗涤,经硫酸镁干燥,浓缩。
于-78℃将87ml二异丙基氨基锂溶液(2M THF溶液)加入以这种方法获得的残余物在217ml THF中的溶液中,在此期间温度应当不高于-55℃。将溶液于此温度搅拌10分钟,然后温热至-10℃并于此温度另外搅拌15分钟,然后再次将溶液冷却至-78℃,滴加14.7ml甲基碘。将溶液温热至-10℃,然后加入饱和氯化铵溶液和MTBE。分离各相,有机相用饱和氯化铵溶液洗涤,所合并的水相再用MTBE萃取一次,然后将所合并的有机相用饱和氯化钠溶液洗涤,经硫酸镁干燥,浓缩,得到29g 2-甲基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-丙酸-叔丁酯,为黄色油。
1H-NMR(500MHz,DMSO):δ=4,68-4,72(m,1H);3,74-3,80(m,1H);3,44-3,53(m,1H);3,38-3,44(m,1H);3,13-3,17(m,1H);3,06-3,12(m,1H);1,70-2,06(m,2H);0,73-1,76(m,13H);1,42(s,9H),1,27(s,6H).
2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯
将29g 2-甲基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-丙酸-叔丁酯溶于150ml异丙醇中,加入2.3g甲苯磺酸一水合物。待甲苯磺酸完全溶解后,将溶液静置4天,然后与饱和碳酸氢钠溶液混合,部分浓缩。将残余物加入MTBE/水中,分离各相,水相用MTBE萃取,所合并的有机相经硫酸镁干燥,浓缩。将残余物用庚烷/乙酸乙酯3∶1进行硅胶色谱法,得到13.8g 2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯,为黄色油。C15H28O4(272.20);MS(Cl+):273.4(24)[MH+],217.2(100)[MH+-C4H8],199(18),5 113(19)
2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸-叔丁酯
将200mg 2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯的MTBE溶液滴加至65mg氢化钠(60%重量,在矿物油中)在10ml MTBE中的混悬液中。待气体放出停止后,加入503mg 4-碘甲基-5-乙基-2-(3-甲氧基苯基)-唑的MTBE溶液,将混悬液回流加热过夜。向反应混合物中加入乙酸乙酯(还可以采用MTBE),将混合物用水和饱和氯化钠溶液洗涤,经硫酸镁干燥,浓缩。将残余物进行硅胶色谱法(庚烷/乙酸乙酯梯度),得到323mg 2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-丙酸-叔丁酯,为黄色油。C28H41NO6(487.64):LCMS(ESI):488.41[MH+]
2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸
将300mg 2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-丙酸-叔丁酯在1ml三氟乙酸中于室温静置过夜。将溶液完全蒸发,向残余物中加入水,用碳酸氢钠溶液调节pH至3。将溶液用乙酸乙酯萃取,将有机相用水洗涤两次,经硫酸镁干燥,浓缩。将残余物进行硅胶色谱法(二氯甲烷/甲醇梯度),得到256mg 2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸,为黄色树脂状。C24H33NO6(431.53):LCMS(ESI):432.1[MH+]
实施例2
2-[(1R,3S)-3-(5-乙基-2-对甲苯基唑-4-基甲氧基)-环己基甲氧基]-2-甲基丙酸
类似于实施例1,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯和4-碘甲基-5-乙基-2-对甲苯基-唑获得2-[(1R,3S)-3-(5-乙基-2-对甲苯基唑-4-基甲氧基)-环己基甲氧基]-2-甲基-丙酸。C24H33NO5(415.24):LCMS(ESI):416.39[MH+]
实施例3
2-{(1R,3S)-3-[5-乙基-2-(4-异丁基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸
类似于实施例1,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯和4-碘甲基-5-乙基-2-(4-异丁基苯基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(4-异丁基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸。C27H39NO5(457.28):LCMS(ESI):458.43[MH+]
实施例4
2-{(1R,3S)-3-[5-乙基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸
类似于实施例1,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯和5-乙基-4-碘甲基-2-(萘基-2-基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸。C27H33NO5(451.24):LCMS(ESI):452.19[MH+]
实施例5
2-{(1R,3S)-3-[5-乙基-2-(3-三氟甲基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸
类似于实施例1,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯和5-乙基-4-碘甲基-2-(3-三氟甲基-苯基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(3-三氟甲基-苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸。C24H30F3NO5(469.21):LCMS(ESI):470.20[MH+]
实施例6
2-{(1R,3S)-3-[5-乙基-2-(4-异丙基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸
类似于实施例1,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯和5-乙基-4-碘甲基-2-(4-异丙基苯基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(4-异丙基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸。C26H37NO5(443.27):LCMS(ESI):488.72[M+HCOO]
实施例7
2-甲基-2-{(1R,3S)-3-[5-甲基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-丙酸
类似于实施例1,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯和5-甲基-4-碘甲基-2-(萘-2-基)-唑获得2-甲基-2-{(1R,3S)-3-[5-甲基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-丙酸。C26H31NO5(437.22):LCMS(ESI):438.17[MH+]
实施例8
2-{顺式-3-[5-异丙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸
类似于实施例1,由外消旋的2-(顺式-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯和4-碘甲基-2-(3-甲氧基苯基)-5-异丙基唑,获得外消旋的2-{顺式-3-[5-异丙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸。C25H35NO6(445.25):LCMS(ESI):446.27[MH+]
实施例9
2-{(1R,3S)-3-[5-异丙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸
类似于实施例1,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯和4-碘甲基-2-(3-甲氧基苯基)-5-异丙基唑获得2-{(1R,3S)-3-[5-异丙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸。C25H35NO6(445.25):LCMS(ESI):446.27[MH+]
实施例10
2-甲基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-戊-4-烯酸叔丁酯
类似于实施例1中2-甲基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-丙酸-叔丁酯的合成,由[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-乙酸叔丁酯、甲基碘、烯丙基溴和二异丙基氨基锂获得2-甲基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-戊-4-烯酸-叔丁酯,为两种非对映异构体的混合物。
1H-NMR(500MHz,DMSO):δ=5,65-5,76(m,1H),5,04-5,13(m,2H),4,68-4,72(m,1H);3,73-3,80(m,1H);3,44-3,53(m,1H);3,38-3,44(m,1H);3,06-3,23(m,2H);2,55-2,63(m,1H);2,32-2,45(m,2H);1,70-2,06(m,2H);0,73-1,76(m,12H);1,42(s,9H);1,22(s,3H).
2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基戊-4-烯酸-叔丁酯
类似于实施例1中2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯的合成,由2-甲基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-戊-4-烯酸-叔丁酯和甲苯磺酸一水合物获得2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基戊-4-烯酸-叔丁酯,为两种非对映异构体的混合物。
1H-NMR(500MHz,DMSO):δ=5,65-5,76(m,1H),5,04-5,13(m,2H),4,45-4,48(m,1H);3,29-3,36(m,1H);3,06-3,20(m,2H);2,31-2,44(m,2H);1,65-1,93(m,2H);1,55-1,70(m,2H);1,07-1,52(m,2H);0,95-1,06(m,1H),0,71-0,86(m,2H);1,41(s,9H);1,22(s,3H).
2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基戊酸-叔丁酯
将2.4g 24(1R,3S)-3-羟基环己基甲氧基)-2-甲基-戊-4-烯酸-叔丁酯溶于15ml乙酸乙酯中,在高压釜中在氩气氛围下,加入一刮勺尖的Pd/C(10%)。然后向高压釜中充入氢气,将溶液于室温在3巴氢气压力下搅拌过夜。然后经硅藻土滤除催化剂,浓缩滤液,得到2.3g 2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基戊酸-叔丁酯,为两种非对映异构体的混合物,为浅黄色油状物。C17H32O4(300.44);MS(CI+):301.5(24)[MH+],245.4(100)[MH+-C4H8],227(18),113(58)
2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基戊酸-叔丁酯
类似于实施例1中2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-丙酸-叔丁酯的合成,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基-戊酸-叔丁酯和4-碘甲基-5-乙基-2-(3-甲氧基苯基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基-苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-戊酸叔丁酯,为两种非对映异构体的混合物。C30H45NO6(515.32):LCMS(ESI):516.41[MH+]
2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基戊酸
类似于实施例1中2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸的合成,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基戊酸-叔丁酯和三氟乙酸获得2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基-苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基戊酸,为两种非对映异构体的混合物。C26H37NO6(459.26):LCMS(ESI):459.58[MH+]
实施例11
2-[(1R,3S)-3-(5-乙基-2-对甲苯基唑-4-基甲氧基)-环己基甲氧基]-2-甲基戊酸
类似于实施例10,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基戊酸-叔丁酯和4-碘甲基-5-乙基-2-对甲苯基唑获得2-[(1R,3S)-3-(5-乙基-2-对甲苯基唑-4-基甲氧基)-环己基甲氧基]-2-甲基戊酸,为两种非对映异构体的混合物。C26H37NO5(443.27):LCMS(ESI):488.53[M+HCOO]
实施例12
2-{(1R,3S)-3-[5-乙基-2-(4-异丁基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基戊酸
类似于实施例10,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基戊酸-叔丁酯和4-碘甲基-5-乙基-2-(4-异丁基苯基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(4-异丁基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基戊酸,为两种非对映异构体的混合物。C29H43NO5(485.31):LCMS(ESI):485.49[MH+]
实施例13
2-{(1R,3S)-3-[5-乙基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基戊酸
类似于实施例10,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基戊酸-叔丁酯和5-乙基-4-碘甲基-2-(萘-2-基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基戊酸,为两种非对映异构体的混合物。C29H37NO5(479.27):LCMS(ESI):524.52[M+HCOO]
实施例14
2-{(1R,3S)-3-[5-乙基-2-(4-异丙基苯基)-唑-4-基甲氧基)-环己基甲氧基]-2-甲基戊酸
类似于实施例10,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基戊酸-叔丁酯和5-乙基-4-碘甲基-2-(4-异丙基苯基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(4-异丙基苯基)-唑-4-基甲氧基)-环己基甲氧基]-2-甲基戊酸,为两种非对映异构体的混合物。C29H37NO5(479.27):LCMS(ESI):524.52[M+HCOO]
实施例15
2-甲基-2-{(1R,3S)-3-[5-甲基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-戊酸
类似于实施例10,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基戊酸-叔丁酯和5-甲基-4-碘甲基-2-(萘-2-基)-唑获得2-甲基-2-{(1R,3S)-3-[5-甲基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-戊酸,为两种非对映异构体的混合物。C28H35NO5(465.25):LCMS(ESI):510.57[M+HCOO]
实施例16
2-甲基-3-苯基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-丙酸-叔丁酯
类似于实施例1中2-甲基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-丙酸-叔丁酯的合成,由[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-乙酸叔丁酯、甲基碘、苄基溴和二异丙基氨基锂获得2-甲基-3-苯基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-丙酸-叔丁酯,为两种非对映异构体的混合物。C26H40O5(432.29):LCMS(ESI):450.34(13)[M++H2O];349.25(22)[M-C5H8O];293.17(100)[M-C5H8O-C4H8]
2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基-3-苯基丙酸-叔丁酯
类似于实施例1中2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基丙酸-叔丁酯的合成,由2-甲基-3-苯基-2-[(1R,3S)-3-(四氢吡喃-2-基氧基)-环己基甲氧基]-丙酸-叔丁酯和甲苯磺酸一水合物获得2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基-3-苯基丙酸-叔丁酯,为两种非对映异构体的混合物。C21H32O4(348.23);MS(Cl+):349.6(38)[MH+],293.4(100)[MH+-C4H8],247.4(18),113.4(19)
2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-3-苯基丙酸-叔丁酯
类似于实施例1中2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸-叔丁酯的合成,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基-3-苯基丙酸-叔丁酯和4-碘甲基-5-乙基-2-(3-甲氧基苯基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-3-苯基丙酸-叔丁酯,为两种非对映异构体的混合物。C34H45NO6(563.32):LCMS(ESI):564.46[MH+]
2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-3-苯基丙酸
类似于实施例1中2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基丙酸的合成,由2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-3-苯基丙酸-叔丁酯和三氟乙酸获得2-{(1R,3S)-3-[5-乙基-2-(3-甲氧基-苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-3-苯基丙酸,为两种非对映异构体的混合物。C30H37NO6(507.26):LCMS(ESI):508.40[MH+]
实施例17
2-[(1R,3S)-3-(5-乙基-2-对甲苯基唑-4-基甲氧基)-环己基甲氧基]-2-甲基-3-苯基丙酸
类似于实施例10,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基-3-苯基丙酸-叔丁酯和4-碘甲基-5-乙基-2-对甲苯基-唑获得2-[(1R,3S)-3-(5-乙基-2-对甲苯基-唑-4-基甲氧基)-环己基甲氧基]-2-甲基-3-苯基丙酸,为两种非对映异构体的混合物。C30H37NO5(491.27):LCMS(ESI):492.40[MH+]
实施例18
2-{(1R,3S)-3-[5-乙基-2-(4-异丁基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-3-苯基丙酸
类似于实施例10,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基-3-苯基丙酸-叔丁酯和4-碘甲基-5-乙基-2-(4-异丁基苯基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(4-异丁基-苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-3-苯基丙酸,为两种非对映异构体的混合物。C33H43NO5(533.31):LCMS(ESI):534.45[MH+]
实施例19
2-{(1R,3S)-3-[5-乙基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-3-苯基丙酸
类似于实施例10,由2-((1R,3S)-3-羟基-环己基甲氧基)-2-甲基-3-苯基丙酸-叔丁酯和5-乙基-4-碘甲基-2-(萘-2-基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(萘基-2-基)唑-4-基甲氧基]-环己基甲氧基}-2-甲基3-苯基丙酸,为两种非对映异构体的混合物。C33H37NO5(527.27):LCMS(ESI):528.40[MH+]
实施例20
2-{(1R,3S)-3-[5-乙基-2-(4-异丙基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-3-苯基丙酸
类似于实施例10,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基-3-苯基丙酸-叔丁酯和5-乙基-4-碘甲基-2-(4-异丙基苯基)-唑获得2-{(1R,3S)-3-[5-乙基-2-(4-异丙基苯基)-唑-4-基甲氧基]-环己基甲氧基}-2-甲基-3-苯基丙酸,为两种非对映异构体的混合物。C32H41NO5(519.30):LCMS(ESI):564.59[M+HCOO]
实施例21
2-甲基-2-{(1R,3S)-3-[5-甲基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-3-苯基丙酸
类似于实施例10,由2-((1R,3S)-3-羟基环己基甲氧基)-2-甲基-3-苯基丙酸-叔丁酯和5-甲基-4-碘甲基-2-(萘-2-基)-唑获得2-甲基-2-{(1R,3S)-3-[5-甲基-2-(萘-2-基)-唑-4-基甲氧基]-环己基甲氧基}-3-苯基丙酸,为两种非对映异构体的混合物。C32H35NO5(513.25):LCMS(ESI):514.38[MH+]
Claims (16)
1.式I化合物及其生理耐受的盐、溶剂化物和生理功能性衍生物,
其中,
R1为H、(C1-C6)烷基;
R2为H、O-(C1-C3)烷基、CF3;或者
R1和R2与苯基环一起是稠合的萘基;
R3为(C1-C6)烷基;
R4为(C1-C6)烷基、苄基;
R5为H、(C1-C6)烷基。
2.如权利要求1所要求的化合物,其中
R1为H、甲基、丙基或丁基;
R2为H、甲氧基、CF3;或者
R1和R2与苯基环一起是稠合的萘基;
R3为甲基、乙基或丙基;
R4为甲基、丙基或苄基;且
R5为H。
3.如权利要求1或2所要求的式I化合物,其中R1或R2为H。
4.如权利要求1至3中一项或多项所要求的式I化合物,其中R4为甲基。
5.药物,包含一种或多种如权利要求1至4中一项或多项所要求的式I化合物。
6.药物,包含一种或多种如权利要求1至4中一项或多项所要求的式I化合物以及一种或多种对代谢紊乱或与之有关的紊乱具有有益作用的活性成分。
7.药物,包含一种或多种如权利要求1至4中一项或多项所要求的式I化合物以及一种或多种抗糖尿病剂。
8.药物,包含一种或多种如权利要求1至4中一项或多项所要求的式I化合物以及一种或多种脂类调节剂。
9.如权利要求1至4中一项或多项所要求的式I化合物在治疗和/或预防脂肪酸代谢紊乱和葡萄糖利用紊乱中的用途。
10.如权利要求1至4中一项或多项所要求的式I化合物在治疗和/或预防其中涉及抗胰岛素性的紊乱中的用途。
11.如权利要求1至4中一项或多项所要求的式I化合物在治疗和/或预防糖尿病和与之有关的后遗症中的用途。
12.如权利要求1至4中一项或多项所要求的式I化合物在治疗和/或预防血脂异常症及其后遗症中的用途。
13.如权利要求1至4中一项或多项所要求的式I化合物在治疗和/或预防与代谢综合征有关的病症中的用途。
14.如权利要求1至4中一项或多项所要求的化合物与至少一种其它活性成分组合在治疗和/或预防脂肪酸代谢紊乱和葡萄糖利用紊乱中的用途。
15.如权利要求1至4中一项或多项所要求的化合物与至少一种其它活性成分组合在治疗和/或预防其中涉及抗胰岛素性的紊乱中的用途。
16.制备包含一种或多种如权利要求1至4中一项或多项所要求的化合物的药物的方法,该方法包括将活性成分与可药用载体混合并将该混合物转化为适于施用的形式。
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DE102004039532A DE102004039532B4 (de) | 2004-08-14 | 2004-08-14 | Cyclohexyl-methyloxy substituierte Essigsäurederivate, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel |
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CA2576545A1 (en) | 2006-02-23 |
AU2005274492A1 (en) | 2006-02-23 |
UY29063A1 (es) | 2006-02-24 |
EP1778655A1 (de) | 2007-05-02 |
US7956077B2 (en) | 2011-06-07 |
DK1778655T3 (da) | 2009-08-24 |
TW200619211A (en) | 2006-06-16 |
IL181010A0 (en) | 2007-07-04 |
BRPI0513999A (pt) | 2008-05-20 |
PT1778655E (pt) | 2009-07-13 |
DE102004039532A1 (de) | 2006-03-02 |
EP1778655B1 (de) | 2009-05-06 |
AR050290A1 (es) | 2006-10-11 |
DE502005007249D1 (de) | 2009-06-18 |
MX2007000913A (es) | 2007-04-16 |
DE102004039532B4 (de) | 2006-09-21 |
SV2006002191A (es) | 2006-07-07 |
KR20070040813A (ko) | 2007-04-17 |
US20070197613A1 (en) | 2007-08-23 |
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ATE430739T1 (de) | 2009-05-15 |
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