CN1323314A - 卡斯帕酶抑制剂 - Google Patents
卡斯帕酶抑制剂 Download PDFInfo
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- CN1323314A CN1323314A CN99805973A CN99805973A CN1323314A CN 1323314 A CN1323314 A CN 1323314A CN 99805973 A CN99805973 A CN 99805973A CN 99805973 A CN99805973 A CN 99805973A CN 1323314 A CN1323314 A CN 1323314A
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- alkyl
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Abstract
本发明涉及新型化合物,它们是卡斯帕酶抑制剂,特别是白介素-1β转化酶(“ICE”)抑制剂。本发明还涉及含这些化合物的药物组合物。本发明的这些化合物和药物组合物特别适于抑制卡斯帕酶活性,并因此可以有利地用作抗白介素-1-(“IL-1”)、编程性细胞死亡、干扰素-γ诱导因子(IGIF)或干扰素-γ(“IFN-γ”)介导的疾病的试剂,这些疾病包括炎性疾病、自身免疫性疾病、骨破坏疾病、增殖疾病、感染性疾病和变性疾病。本发明还涉及抑制卡斯帕酶活性和降低IGIF产生及IFN-γ产生的方法,以及用本发明的化合物和组合物治疗白介素-1、编程性细胞死亡和干扰素-γ介导疾病的方法。本发明还涉及制备本发明化合物的方法。
Description
发明技术领域
本发明涉及作为卡斯帕酶(caspase)抑制剂的新型化合物,具体地讲是白介素-1β转化酶(“ICE”)抑制剂。本发明还涉及含这些化合物的药物组合物。本发明的化合物和药物组合物特别适于抑制卡斯帕酶活性并因而可以有利地用作抗白介素-1(“IL-1”),编程性细胞死亡,干扰素-γ诱导因子(IGIF)或干扰素-γ(“IFN-γ”)介导的疾病的制剂,这些疾病包括炎性疾病、自身免疫性疾病、破坏骨的疾病、增殖性疾病,感染性疾病和变性疾病。本发明还涉及用本发明的化合物和组合物抑制卡斯帕酶活性及降低IGIF产生和IFN-γ产生的方法,以及治疗白介素-1,编程性细胞死亡和干扰素-γ介导的疾病的方法。本发明还涉及制备本发明化合物的方法。
发明背景
白介素1(“IL-1”)是主要的促炎蛋白和免疫调节蛋白,其刺激成纤维细胞分化和增殖,刺激由滑液细胞产生前列腺素、胶原酶和磷脂酶以及软骨细胞、嗜碱细胞和嗜酸性细胞的脱粒和中性白细胞的激活。Oppenheim,J.H.等,Immunology Today,7,pp.45-56(1986)。因此其参与了慢性和急性炎性和自身免疫性疾病的病理过程。例如,在类风湿性关节炎中,IL-1是患病关节中炎症和软骨蛋白聚糖破坏的介体。Wood,D.D.等,Arthritis Rheum.26,975,(1983);Pettipher,E.J.等,Proc.Natl.Acad.Sci.USA 71,295(1986);Arend,W.P.和Dayer,J.M.,Arthritis Rheum.38,151(1995)。IL-1还是高效的骨吸收剂。Jandiski,J.J.,J.Oral Path 17,145(1988);Dewhirst,F.E.等,J.Immunol.8,2562(1985)。在破坏骨的疾病如骨关节炎和多发性骨髓瘤中另将其称为“破骨细胞激活因子”。Bataille,R.等,Int.J.Clin.Lab.Res.21(4),283(1992)。在某些增殖疾病如急性骨髓性白血病和多发性骨髓瘤中,IL-1可以提高肿瘤细胞的生长和粘附。Bani,M.R.,J.Natl.Cancer Inst.83,123(1991);Vidal-Vanaclocha,F.,Cancer Res.54,2667(1994)。在这些疾病中,IL-1还刺激其它细胞因子如IL-6的产生,IL-6可以调整肿瘤的发育(Tartour等,Cancer Res.54,p.6243(1994)。IL-1主要由外周血单核细胞作为炎性反应的一部分产生并存在两种不同形式的激动剂,IL-1α和IL-1β。Mosely,B.S.等,Proc.Nat.Acad.Sci.,84,pp.4572-4576(1987);Lonnemann,G.等,Eur.J.Immunol.,19,pp.1531-1536(1989)。
IL-1β以生理性失活的前体pIL-1β的形式合成。pIL-1β缺乏常规的前导序列且不被信号肽酶处理。March,C.J.,Nature,315,pp.641-647(1985)。相反,pIL-1β被白介素-1β转化酶(“ICE”)在Asp-116和Ala-117之间裂解,产生生物活性C-末端片断,该片断发现于人血清和滑液中。Sleath,P.R.等,J.Biol.Chem.,265,pp.14526-14528(1992);A.D.Howard等,J.Immunol.,147,pp.2964-2969(1991)。ICE是主要位于单核细胞中的半胱氨酸蛋白酶。它将前体IL-1β转变为成熟的形式。Black,R.A.等,FEBS Lett.,247,pp.386-390(1989);Kostura,M.J.等,Proc.Natl.Acad.Sci.U.S.A.,86,pp.5227-5231(1989)。由ICE加工对成熟IL-1β的透细胞膜转运也是必需的。
ICE(或卡斯帕酶-1)是称作卡斯帕酶的一族同源酶的一员。这些同系物在酶活性位点区域具有类似的序列。这些同系物(卡斯帕酶)包括TX(或ICErel-Ⅱ或ICH-2)(卡斯帕酶-4)(Faucheu,等,EMBO J.,14,p.1914(1995);Kamens J.,等,J.Biol.Chem.,270,p.15250(1995);Nicholson等,J.Biol.Chem.,270 15870(1995)),TY(或ICErel-Ⅲ)(卡斯帕酶-5)(Nicholson等,J.Biol.Chem.,270,p.15870(1995);ICH-1(或Nedd-2)(卡斯帕酶-2)(Wang,L.等,Cell,78,p.739(1994),MCH-2(卡斯帕酶-6),(Fernandes-Alnemri,T.等,Cancer Res.,55,p.2737(1995),CPP32(或YAMA或apopain)(卡斯帕酶-3)(Fernandes-Alnemri,T.等,J.Biol.Chem.,269,p.30761(1994);Nicholson,D.W.等,Nature,376,p.37(1995)),CMH-1(或MCH-3)(卡斯帕酶-7)(Lippke等,J.Biol.Chem.,271(4),p1825-1828(1996));Fernandes-Alnemri,T.等,CancerRes.,(1995)),Mch5(卡斯帕酶-8)(Muzio,M.等,Cell 85(6),817-827,(1996),MCH-6(卡斯帕酶-9)(Duan,H.等,J.Biol.Chem.,271(34),p.16720-16724(1996))Mch4(卡斯帕酶-10)(Vincenz,C.等,J.Biol.Chem.,272,p.6578-6583(1997);Fernandes-Alnemri,T.等,Proc.Natl.Acad.Sci.93,p.7464-7469(1996)),Ich-3(卡斯帕酶-11)(Wang,S.等,J.Diol.Chem.,271,p.20580-20587(1996)),mCASP-12(卡斯帕酶-12),(Van de Craen,M.等,FEBS Lett.403,p.61-69(1997);Yuan,Y.和Miura,M.PCT公开号WO95/00160(1995)),ERICE(卡斯帕酶-13),(Humke,E.W.,等,J.Biol.Chem.,273(25)p.15702-15707(1998))及MICE(卡斯帕酶-14)(Hu,S.等,J.Biol.Chem.,273(45)p.29648-29653(1998))。
当在转染细胞系中过度表达时,这些IEC同系物的每个成员以及IEC本身能诱发编程性细胞死亡。用肽基ICE抑制剂Tyr-Val-Ala-Asp-氯甲基酮抑制一种或多种这样的同系物,导致原代细胞或细胞系中编程性细胞死亡的抑制。Lazebnik等,Nature,371,p.346(1994)。
卡斯帕酶似乎还参与编程性细胞死亡的调节。Yuan,J.等,Cell,75,pp.641-652(1993);Miura,M.等,Cell,75,pp.653-660(1993);Nett-Fiordalisi,M.A.等,J.Cell Biochem.,17B,p.117(1993)。特别是,人们认为ICE或ICE同系物与神经变性疾病如早老性痴呆和帕金森氏病中编程性细胞死亡的调节有关。Marx,J.和M.Baringa,science,259,pp.760-762(1993);Gagliardini,V.等,Science,263,pp.826-828(1994)。抑制编程性细胞死亡的治疗应用可包括治疗早老性痴呆、帕金森氏病、中风、心肌梗塞、脊柱萎缩和衰老。
已表明ICE介导某些组织类型中的编程性细胞死亡(programmedcell death)。Steller,H.,Science,267,p.1445(1995);Whyte,M.和Evan,G.,Nature,376,p.17(1995);Martin,S.J.和Green,D.R.,Cell,82,p.349(1995);Alnemri,E.S.,等,J.Biol.Chem.,270,p.4312(1995);Yuan,J.Curr.Opin.Cell Biol.,7,p.211(1995)。一只ICE基因被破坏的转基因小鼠的Fas介导的编程性细胞死亡的水平不足(Kuida,K.等,Science 267,2000(1995))。ICE的此活性与其作为IL-1β原的加工酶的作用不同。可以想象在某些组织类型中,ICE的抑制可能不影响成熟IL-1β的分泌,但是可能抑制编程性细胞死亡。
具有酶活性的ICE以前被描述为杂二聚体,其由两个亚单位组成:p20和p10(分子量分别为20kDa和10kDa)。这些亚单位是经由p30的形式,通过自身催化的活化机理,由45kDa的酶原(p45)产生的。Thornberry,N.A.等,Nature,356,pp.768-774(1992)。此ICE酶原分为若干功能域:功能域原(p14),一个p22/20亚单位,多肽连接剂和p10亚单位。Thornberry等,出处同上;Casano等,Genomics,20,pp.474-481(1994)。
全长p45由其cDNA和氨基酸序列定性。PCT专利申请WO 91/15577和WO 94/00154。p20和p10 cDNA及氨基酸序列也是已知的。Thornberry等,出处同上。小鼠和大鼠ICE也已测序和克隆。它们具有高度类似于人ICE的氨基酸和核酸序列。Miller,D.K.等,Ann.N.Y.Acad.Sci.,696,pp.133-148(1993);Molineaux,S.M.等,Proc.Nat.Acad.Sci.,90,pp.1809-1813(1993)。通过X射线结晶学技术以原子拆分确定了ICE的三维结构。Wilson,K.P.,等,Nature,370,pp.270-275(1994)。此活性酶以两个p20和两个p10亚单位的四聚体的形式存在。
最近,已将ICE及ICE/CED-3族的其它成员与体内IGIF原pro-IGIF向IGIF的转化或IFN-γ的产生相联系(PCT申请PCT/US96/20843,公开号WO97/22619,将其引入本文作为参考)。IGIF是以前体蛋白“IGIF原”的形式在体内合成的。
干扰素-γ诱导因子(IGIF)是约18kDa的多肽,其刺激T细胞产生干扰素-γ(IFN-γ)。IGIF在体内由被激活的Kupffer细胞和巨嗜细胞产生,并由于内毒素刺激而输出。因此,降低IGIF产生的化合物会有利地用作此种T细胞刺激的抑制剂,进而会降低这些细胞产生IFN-γ的水平。
IFN-γ是对多种免疫细胞具有免疫调节作用的细胞因子。具体地讲,IFN-γ参与巨嗜细胞的激活和Th1细胞选择(F.Belardelli,APMIS,103,p.161(1995))。IFN-γ经STAT和IRF路径通过调节基因的表达发挥其部分作用(C.Schindler和J.E.Darnell,Ann.Rev.Biochem.,64,p.621(1995);T.Taniguchi,J.Cancer Res.Clin.Oncol.,121,p.516(1995))。
缺乏IFN-γ或其受体的小鼠在其免疫细胞功能方面具有多种缺陷并抗内毒性休克(S.Huang等,Science,259,p.1742(1993);D.Dalton等,Science,259,p.1739(1993);B.D.Car等,J.Exp.Med.,179,p.1437(1994))。同IL-12一起,IGIF似乎是T细胞产生IFN-γ的有效诱导剂(H.Okamura等,Infection and Immunity,63,p.3966(1995);H.Okamura等,Nature,378,p.88(1995);S.Ushio等,J.Immunol.,156,p.4274(1996))。
IFN-γ显示了与多种炎性疾病、感染性疾病和自身免疫性疾病的病理有关。因此,能降低IFN-γ产生的化合物可用于改善与IFN-γ相关病理的作用。
因此,能调节IGIF原转化为IGIF的组合物和方法可用于降低体内IGIF和IFN-γ的产生,并因此用于改善与人疾病相关的这些蛋白的有害作用。
卡斯帕酶抑制剂代表了一类用于控制炎症或编程性细胞死亡或二者兼而有之的化合物。已有对ICE的肽或肽基抑制剂的描述(PCT专利申请WO 91/15577,WO 93/05071,WO 93/09135,WO 93/12076,WO93/14777,WO 93/16710,WO 95/35308,WO 96/30395,WO 96/33209和WO 98/01133;欧洲专利申请503 561,547 699,618 223,623 592和623 606;以及美国专利5,434,248,5,710,153,5,716,929和5,744,451)。已观察到这种ICE的肽基抑制剂在炎症的小鼠模型中阻断成熟IL-1β的产生(参见下文)并抑制体外白血病细胞的生长(Estrov等,Blood,84,380a(1994))。但是,由于其肽的特性,这些抑制剂一般表现出不需要的药理学性质,如细胞透过性和细胞活性差、口腔吸收性差、不稳定及代谢快。Plattner,J.J.和D.W.Norbeck,Drug Discovery Technoloqies,C.R.Clark and W.H.Moos编辑(EllisHorwood,Chichester,England,1990),pp.92-126。这些性质妨碍了它们发展为有效的药物。
也已报告了非肽基化合物在体外抑制ICE。见PCT专利申请WO95/26958;美国专利5,552,400;Dolle等,J.Med.Chem.,39,pp.2438-2440(1996)。
但是,尚不清楚这些化合物是否具有用于治疗的适当的药学特性。
因此,需要能有效抑制卡斯帕酶并具有有利的体内活性,以用作预防和治疗慢性和急性IL-1、编程性细胞死亡、IGIF或IFN-γ介导的疾病,以及炎症、自身免疫性疾病、骨破坏、增殖疾病、传染病或变性疾病的化合物。
发明概述
本发明提供了新型化合物及其药用衍生物,它们用作卡斯帕酶抑制剂,特别是ICE抑制剂。这些化合物可以单独或与其它治疗或预防制剂如抗生素、免疫调节剂或其它抗炎药联合使用,以治疗或预防IL-1、编程性细胞死亡、IGIF或IFN-γ介导的疾病。按照优选的实施方案,本发明的化合物能结合卡斯帕酶的活性位点并抑制该酶的活性。
本发明的主要目的是提供式Ⅰ表示的、具有有利的体内特性的新型化合物:
其中各个取代基在本文中有述。
本发明的另一个目的是提供药物组合物,包括多组份组合物。本发明还提供了使用和制备本发明化合物及相关化合物的方法。
发明详述
为了使此处所描述的本发明得到充分理解,给出下列详细描述。
下列缩写和定义用于整个申请中。
缩写
Ac2O | 醋酸酐 |
MeCN | 乙腈 |
AMC | 氨基甲基香豆素 |
n-Bu | 正丁基 |
DMF | 二甲基甲酰胺 |
DIEA | N,N-二异丙基乙胺 |
DMA | N,N-二甲基乙酰胺 |
EDC | 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐 |
Et2O | 乙醚 |
EtOAc | 乙酸乙酯 |
Fmoc | 9-芴基甲氧羰基 |
HBTU | O-苯并三唑-1-基-N,N,N,N'-四甲基脲鎓六氟磷酸盐 |
HOBt | 1-羟基苯并三唑水合物 |
MeOH | 甲醇 |
NMP | N-甲基吡咯烷酮 |
TFA | 三氟乙酸 |
pNA | 对硝基苯胺 |
术语“卡斯帕酶”指作为包括ICE的酶系的一员的酶(见H.Hara,Natl.Acad.Sci.,94,pp.2007-2012(1997))。
术语“HBV”、“HCV”和“HGV”分别指乙型肝炎、丙型肝炎和庚型肝炎(hepatitis-G)病毒。
术语“Ki”指化合物对靶酶如ICE活性的抑制作用的数据检测值。Ki的值越低,疗效越高。此Ki值是将实验测定的速率数据代入标准酶动力学方程式得出的(见I.H.Segel,Enzyme Kinetics,Wiley-Interscience,1975)。
术语“干扰素γ诱导因子”或“IGIF”指能刺激IFN-γ内源性产生的因子。
术语“卡斯帕酶抑制剂”指能显示出可检测的对一种或多种卡斯帕酶的抑制作用的化合物。术语“ICE抑制剂”指能显示出对ICE及选择性地对一种或多种其它卡斯帕酶的可检测的抑制作用的化合物。对这些酶的抑制可以用本文中描述的方法及引用的方法测定。
本领域技术人员能意识到在体内的酶抑制剂并不一定是在体外的酶抑制剂。例如,化合物的前药形式一般在体外实验中显示极小活性或没有活性。这种前药形式可以通过患者体内的代谢或其它生化过程改变为体内的ICE抑制剂。
术语“细胞因子”指介导细胞之间相互作用的分子。
术语“病症”指在对象中产生有害生物后果的任何疾病、紊乱或作用。
术语“对象”指动物,或得自动物的一种或多种细胞。优选,此动物是哺乳动物,首选是人。细胞可以是任何形式的,包括但不限于保持在组织、细胞簇、无限增殖化细胞、转染或转化细胞及得自已进行了物理或表型改变的动物的细胞。
术语“患者”在本申请中指任何动物,优选人。
术语“烷基”指含1至6个碳原子的直链或支链饱和脂族烃。
术语“链烯基”指含2至6个碳原子及至少一个双键的直链或支链不饱和烃。
术语“炔基”指含2至6个碳原子和至少一个三键的直链或支链不饱和烃。
术语“环烷基”指单或多环的、非芳族烃环系,其可以选择性地在环系中含不饱和键。实例包括环己基、金刚烷基、降冰片烷基和螺环戊基。
术语“芳基”指含6、10、12或14个碳原子的、环系的至少一个环是芳环的、单或多环环系。本发明的芳基选择性地被R11单或多取代。芳基环系的例子包括苯基、萘基、和四氢萘基。
术语“杂芳基”指含1至15个碳原子和1至4个杂原子,且该环系的至少一个环是芳环的单或多环环系。杂原子是硫原子、氮原子或氧原子。本发明的杂芳基选择性地被R11单或多取代。
术语“杂环”指含1至15个碳原子和1至4个杂原子,且其中单或多环环系可以选择性地含不饱和键但不是芳环的单或多环环系。杂原子独立地选自硫原子、氮原子或氧原子。
术语“烷芳基”指烷基的某个氢原子被芳基代替的烷基。
术语“烷基杂芳基”指烷基的某个氢原子被杂芳基代替的烷基。
术语“氨基酸侧链”指连接天然或非天然氨基酸的α碳上的任何基团。
术语“取代”指用取代基代替化合物中的某个氢原子。
术语“直链”指共价结合的原子的不分支连接的链。该直链可以被取代,但是此取代基不是此直链的一部分。
在化学式中,其中使用的括号表示分子或基团的连接。具体地讲,括号用来表明:1)一个以上的原子或基团键接在特定的原子上;或2)分支点(即恰在左括号前的原子与括号中的原子或基团以及恰在右括号后的原子或基团键接)。第一个应用的实例为“-N(烷基)2”,表示两个烷基键接一个氮原子。第二个应用的实例是“-C(O)NH2”,表示羰基和氨基(“NH2”)都与指定的碳原子键接。“-C(O)NH2”基团可以用其它方式表示,包括下式:
取代基如甲基的多种表示形式在本文中交互使用。
其它定义在说明书的必要处给出。
本发明的化合物
本发明的一个实施方案A的化合物是式Ⅰ的化合物:
其中:
Y是:
X是-C(R3)2-或-N(R3)-;
m是0或1;
R1是H、-C(O)R8、-C(O)C(O)R8、-S(O)2R8、-S(O)R8、-C(O)OR8、-C(O)N(H)R8、-S(O)2N(H)-R8、-S(O)N(H)-R8、-C(O)C(O)N(H)R8、-C(O)CH=CHR8、-C(O)CH2OR8、-C(O)CH2N(H)R8、-C(O)N(R8)2、-S(O)2N(R8)2、-S(O)N(R8)2、-C(O)C(O)N(R8)2、-C(O)CH2N(R8)2、-CH2R8、-CH2-链烯基-R8或-CH2-炔基-R8;
R2是-H而每个R3独立地是-H,氨基酸侧链,-R8,链烯基-R9或炔基-R9,或者R2和一个R3与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R4是-H而每个R5独立地是H,氨基酸侧链,-R8,链烯基-R9或炔基-R9,或者R4和一个R5与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R6是-H;
R7是-OH,-OR8或-N(H)OH;
每个R8独立地是-烷基,-环烷基,-芳基,杂芳基,-杂环基,-烷基环烷基,-烷基芳基,-烷基杂芳基或-烷基杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
每个R9独立地是-芳基,-杂芳基,环烷基或-杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
每个R10独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-全氟代烷基、-O-烷基、-O-芳基、-O-烷基芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷基芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-S-烷基、-S-芳基、-S-烷基芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2、-烷基、-环烷基、-芳基、-杂芳基、-杂环基、-烷基环烷基、-烷基芳基、-烷基杂芳基或-烷基杂环基,其中结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;而
每个R11独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-烷基、-环烷基、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2。
在实施方案A的另一个形式中:
R1是H、-R8、-C(O)R8、-C(O)C(O)R8、-S(O)2R8、-S(O)R8、-C(O)OR8、-C(O)N(H)R8、-S(O)2N(H)-R8、-S(O)N(H)-R8、-C(O)C(O)N(H)R8、-C(O)CH=CHR8、-C(O)CH2OR8、-C(O)CH2N(H)R8、-C(O)N(R8)2、-S(O)2N(R8)2、-S(O)N(R8)2、-C(O)C(O)N(R8)2、-C(O)CH2N(R8)2、-CH2R8、-CH2-链烯基-R8或-CH2-炔基-R8;
R2是-H而每个R3独立地是-H,氨基酸侧链,-R8,链烯基-R9或炔基-R9,或者每个R3与它们连接的原子一起形成3至7元环或杂环环系,或者R2和一个R3与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
每个R10独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-全氟代烷基、-O-烷基、-O-芳基、-O-烷基芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷基芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)O烷基、-N(H)C(O)O芳基、-N(H)C(O)O烷芳基、-N(H)C(O)O杂芳基、-N(H)C(O)O烷基杂芳基、-N(H)C(O)O环烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-N(H)C(O)N(H)芳基、-N(H)C(O)N(H)烷芳基、-N(H)C(O)N(H)杂芳基、-N(H)C(O)N(H)烷基杂芳基、-N(H)C(O)N(H)环烷基、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2、-烷基、-环烷基、-芳基、-杂芳基、-杂环基、-烷基环烷基-烷芳基、-烷基杂芳基或-烷基杂环基,其中结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
其它取代基定义如上。
在任何上述方案中,优选
m是0;
R2是-H;
一个R3是-H而另一个R3是-R8,-链烯基-R9或-炔基-R9;或
R4和一个R5与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替,其中此环系是: 或
在另一个优选的实施方案中,X是C(R3)2或一个R3是氨基酸侧链,-R8链烯基-R9或炔基-R9。
更优选一个R3是-H而另一个R3是-烷基;或
首选一个R3是-H而另一个R3是-C(H)(CH3)2或-C(CH3)3;而
在另一个首选的实施方案中,一个R3是-H而另一个R3是-CH3,-C(H)(CH3)2或-C(CH3)3而R4和R5就定义如上。
按照另一个实施方案B,本发明提供了式Ⅰ的化合物,其中Y是:
R12是-C(O)烷基、-C(O)环烷基、-C(O)链烯基、-C(O)烷芳基、-C(O)烷基杂芳基、-C(O)杂环基或-C(O)烷基杂环基;
R13是-H,-烷基,-芳基,-烷芳基或-烷基杂芳基;
而其它取代基定义如上。
优选在(c),(d),(e)或(f)中,R8是甲基,乙基,正丙基,异丙基,环戊基,苯乙基或苄基。
实施方案B的其它单个组份的优选定义与上述实施方案A中给出的相同。
X是-C(R3)2-
R1是H、-R8、-C(O)R8、-C(O)C(O)R8、-S(O)2R8、-S(O)R8、-C(O)OR8、-C(O)N(H)R8、-S(O)2N(H)-R8、-S(O)N(H)-R8、-C(O)C(O)N(H)R8、-C(O)CH=CHR8、-C(O)CH2OR8、-C(O)CH2N(H)R8、-C(O)N(R8)2、-S(O)2N(R8)2、-S(O)N(R8)2、-C(O)C(O)N(R8)2、-C(O)CH2N(R8)2、-CH2R8、-CH2-链烯基-R8或-CH2-炔基-R8;
R2是-H而每个R3独立地是-H,氨基酸侧链,-R8,链烯基-R9或炔基-R9,或每个R3与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R4是-H而每个R5独立地是-H,氨基酸侧链,-R8,-链烯基-R9或-炔基-R9,或R4和一个R5与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R6是-H;
R7是-OH、-OR8、-N(H)OH或-N(H)S(O)2R8;
每个R8独立地是-烷基、-环烷基、-芳基、-杂芳基、-杂环基、-烷基环烷基、-烷芳基、-烷基杂芳基或-烷基杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
每个R9独立地是-芳基,-杂芳基,环烷基或-杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
每个R10独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)O烷基、-N(H)C(O)O芳基、-N(H)C(O)O烷芳基、-N(H)C(O)O杂芳基、-N(H)C(O)O烷基杂芳基、-N(H)C(O)O环烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-N(H)C(O)N(H)芳基、-N(H)C(O)N(H)烷芳基、-N(H)C(O)N(H)杂芳基、-N(H)C(O)N(H)烷基杂芳基、-N(H)C(O)N(H)环烷基、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2、-烷基、-环烷基、-芳基、-杂芳基、-杂环基、-烷基环烷基、-烷芳基、-烷基杂芳基或-烷基杂环基、其中结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替、结合在任何氮原子上的氢原子选择性地被R1代替;而
每个R11独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-烷基、-环烷基、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2;
条件是如果一个R3是-H,则另-个R3不是-H。
本发明的另一个优选实施方案D提供了式Ⅰ的化合物,其中Y是:
R12是-C(O)烷基、-C(O)环烷基、-C(O)链烯基、-C(O)烷芳基、-C(O)烷基杂芳基、-C(O)杂环基或-C(O)烷基杂环基;
而其它取代基定义如上,不同的是两个R3都可以是H。
在A-D的任何一个实施方案中,优选的化合物中:
R1是-C(O)R8或-C(O)(O)R8;
R2和一个R3都是-H而另一个R3是氨基酸侧链,-R8,链烯基-R9或炔基-R9;或
条件是环系中的每一个选择性地被一个或多个R10取代。
或者,实施方案A-D的优选化合物为其中R3是-H而另一个R3是甲基,异丙基,叔丁基,-CH2SR8,-CH2SO2R8,-CH2CH2SR8,-CH2CH2SO2R8的化合物。
实施方案A-D中更优选的化合物是其中R4和一个R5与它们连接的原子一起形成如下环系统:
而另一个R5是H的化合物;
或者是一个R3是H而另一个R3是甲基的化合物。
另外,实施方案A-D中更优选的化合物是其中R4和一个R5与它们连接的原子一起形成如下环系:
而另一个R5是H的化合物。
在上述另选的实施方案中,R10优选是4-氟或4,4-二氟。
本发明最优选的化合物是其中R3是甲基;而R4和一个R5与它们连接的原子形成如下环系:而另一个R5是H的化合物。此外,实施方案A-D中首选的化合物是其中R3是甲基;而R4和一个R5与它们连接的原子一起形成如下环系:而另一个R5是H;且R10是4-氟或4,4-二氟的化合物。实施方案(B)或(D)的优选化合物中Y是:其中Z表示-OR8而是:CH3O, 或
本发明特定的化合物包括但不限于实施例5a-5bd,7a-7at,9a-9g,15a-15f,16a-16b,17a-17e,18a-18f,20a-20t,23a-23i,24a-24e,25a-25e,26a-26h,27a-27n,28a-28c,29a-29s,32a-32e,34,G1,G2,41,42,45,46,51,52,56,57,60,61,64,65,68,69,72,73,76-93,98a-z,aa-az和ba-bb,101,102a,102b,108a-d,110,111,116a-h,120a和b,121,122 a-v及123 a-c。
本发明的化合物可以存在一个或多个“不对称”碳原子,因此可以以外消旋体和外消旋混合物、单一对映体、非对映异构体混合物及单一非对映异构体的形式存在。每个产生立体构型的碳原子可以是R或S构型。虽然在本说明书中列举的特定化合物和骨架可能以特定的立体化学构型描述,但是就任何给出的手性碳原子而言具有相反立体化学的化合物和骨架或其混合物也是可以想象的。
这些化合物的所有这些立体异构形式及其药用衍生物包括在本发明中。
术语“药用衍生物”指本发明化合物的任何药用盐、酯或这种酯的盐,或给患者使用时能提供(直接或间接)本发明化合物或其活性代谢物或残基的任何其它化合物。
本发明化合物的药用盐包括,例如,得自药用无机酸、有机酸和碱的盐。适宜的酸的实例包括盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、枸橼酸、甲磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸和苯磺酸。其它酸如草酸,虽然其本身不是药用的,可以用于盐的制备,所述用作获得本发明化合物及其药用酸加成盐的中间体。从适当的碱得到的盐包括碱金属(如钠)、碱土金属(如镁)、铵和N-(C1-4烷基)4 +盐。
本发明还包括本文公开的化合物的任何碱性含氮基团的“季铵盐”形式。该碱性氮原子可以用本领域技术人员已知的任何试剂季铵化,例如,包括低级烷基卤化物,如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物,二烷基硫酸酯如二甲基、二乙基、二丁基和二戊基硫酸酯;长链卤化物如癸基、十二烷基、十四烷基和十八烷基氯化物、溴化物和碘化物;及芳烷基卤化物,包括苄基和苯乙基溴。可以通过这种季铵化得到水或油溶性或者分散性产物。
当多取代时,只要取代基的联合产生稳定的化合物,就可以独立于任何其它取代基选择每个取代基。
本发明考虑的取代基及可变因子的联合只是那些导致形成稳定化合物的那些。术语“稳定”在本文中指所具稳定性足以允许制备和通过本领域已知方法给哺乳动物使用的化合物。一般来说,这些化合物在40℃或更低的温度下,在没有潮湿或其它化学反应性条件下至少稳定一周。
口服给药时,本发明的化合物可以容易地通过或者的血流吸收。此口服有效性使这些化合物是口服给药治疗或预防IL-1、编程性细胞死亡、IGIF或IFN-γ介导疾病的优益制剂。
应理解根据包括溶剂、pH及其它本领域技术人员已知的选择条件,本发明的化合物可能存在多种平衡形式。这些化合物的所有这些形式包括在本发明中。具体地讲,很多本发明的化合物,特别是那些在Y基团中含醛或酮基团及羧酸基团的,可以产生半缩醛或水合物的形式。例如,当Y是
时,实施方案A的化合物是半缩醛的形式。
根据溶剂及其它本领域技术人员已知条件的选择,本发明的化合物还可以是水合物、酰氧基缩醛、缩醛和烯醇的形式。例如,当Y是且R8是H时,本发明的化合物是水合物的形式;当Y是时,该化合物是酰氧基缩醛的形式;当Y是而R8不是H时,该化合物是缩醛的形式;当Y是
时,该化合物是烯醇的形式。
此外,应理解本发明化合物的平衡形式可以包括互变异构体形式。这些化合物的所有这些形式包括在本发明范围内。
用常规技术可以合成式Ⅰ的化合物。有利的是,这些化合物由容易得到的起始物方便地合成。
可以用本文中描述的方法制备本发明的化合物。正如本领域技术人员所知,这些方法不是制备此申请中描述并要求保护的化合物的唯一途径。对本领域技术人员来说其它方法是显而易见的。此外,本文中描述的多种合成步骤可以以不同的顺序或次序进行,从而制备所需的化合物。
应理解本发明的化合物可以用适当的官能基修饰以提高生物选择性。这些修饰是本领域技术人员已知的并包括增加对给出的生物系统(例如,血液、淋巴系统、中枢神经系统)的生物透过性、增加口腔利用度、增加注射给药时的溶解度、改变代谢及改变分泌速度的那些。此外,可以将这些化合物转变为前药形式,作为对此前药的代谢或其它生化过程的结果,在患者的体内产生所需的化合物。在体外实验中,这些前药形式一般显示极小的活性或没有活性。前药的实例包括含酮或醛基团化合物的缩酮、缩醛、肟、亚胺、腙形式,特别是在本发明化合物的Y基团中发生。前药的其它实例包括本文中描述的半缩酮、半缩醛、酰氧基缩醛、酰氧基缩酮、缩酮、缩醛和烯醇形式。
组合物和方法
本发明的化合物是卡斯帕酶抑制剂,特别是ICE抑制剂。因此,这些化合物能靶向和抑制IL-1、编程性细胞死亡、IGIF和IFN-γ介导疾病的过程,并因此靶向在炎性疾病、自身免疫性疾病、骨破坏、增殖紊乱、传染病和变性疾病中活力极高的蛋白质。例如,本发明的化合物通过抑制ICE来抑制前体IL-1β向成熟IL-1β转化。因为ICE是产生成熟IL-1所必需的,通过抑制成熟IL-1的产生,抑制此酶,这样有效阻断了IL-1介导的生理作用和症状的发生。因此,通过抑制IL-1β前体活性,本发明化合物是有效的IL-1抑制剂。
本发明化合物还通过抑制ICE来抑制IGIF原向活性、成熟IGIF的转化。因为ICE是产生成熟IGIF所必需的,通过抑制成熟IGIF的产生,对ICE进行抑制,这样有效地阻断了IGIF介导的生理作用和症状的发生。接着,IGIF是产生IFN-γ所必需的。因此,通过抑制成熟IGIF的产生并随之抑制IFN-γ的产生,因此ICE抑制剂有效阻断了IFN-γ介导生理作用和症状的发生。
当与肽基抑制剂,例如描述于EP 618 223,EP 623 592,WO93/09135,WO 93/16710,US专利5,434,248,WO 95/35308或WO96/33209的那些比较时,本发明的化合物具有惊人的生物利用度。
因此,本发明的药物组合物和方法将用于控制体内卡斯帕酶活性。本发明的组合物和方法因此可用于控制体内IL-1、IGIF或IFN-γ的水平并用于治疗或降低IL-1、编程性细胞死亡、IGIF或IFN-γ介导病症(包括疾病、紊乱和影响)的提升、严重和影响。
本发明的药物组合物含式Ⅰ化合物或其药用盐及药用载体。这些组合物可以选择性地包含其它治疗剂。这些治疗剂包括但不限于抗炎剂、基质金属蛋白酶抑制剂、脂氧合酶抑制剂、细胞因子拮抗剂、免疫抑制剂、抗癌剂、抗病毒剂、细胞因子、生长因子、免疫调节剂、前列腺素或抗血管过度增殖化合物。
术语“药用载体”指可以与本发明化合物一起给患者使用,且不破坏其药理学活性的无毒载体。
可以用于本发明药物组合物的药用载体包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘油、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、羊毛脂和自乳化药物转运系统(SEDDS)如α-生育酚、聚琥珀酸乙二醇1000酯或其它类似的聚合转运基质。
在药物组合物中只含实施方案A-D的化合物作为活性组份时,使用这些组合物的方法可再包括给对象使用其它制剂的步骤。这些制剂包括但不限于抗炎剂、基质金属蛋白抑制剂、脂氧合酶抑制剂、细胞因子拮抗剂、免疫抑制剂、抗癌剂、抗病毒剂、细胞因子、生长因子、免疫调节剂、前列腺素或抗血管过度增殖化合物。
术语“药学有效量”指有效治疗或改善患者的IL-1、编程性细胞死亡、IGIF或IFN-γ介导疾病的量。术语“预防有效量”指有效防止或基本减轻患者的IL-1、编程性细胞死亡、IGIF或IFN-γ介导疾病的量。
本发明的化合物可以以常规方式使用来控制体内IGIF和IFN-γ水平并用于治疗IL-1、编程性细胞死亡、IGIF或IFN-γ介导的疾病或降低它们所介导的作用的提升和严重性。这些治疗方法、其剂量水平和要求可以由本领域技术人员用现有的方法和技术加以选择。
例如,本发明的化合物可以与药用辅剂混合,以药学可接受的方式并以减轻疾病严重性的有效量,给IL-1、编程性细胞死亡、IGIF或IFN-γ介导疾病的患者使用。
或者,在延长的时间内,本发明的化合物可以用于组合物和方法中以治疗IL-1、编程性细胞死亡、IGIF或IFN-γ介导疾病或保护个体抗IL-1、编程性细胞死亡、IGIF或IFN-γ介导疾病。这些化合物可以单独或与本发明的其它化合物以与药物组合物中酶抑制剂的常规应用一致的方式使用。例如,本发明的化合物可以与常规用于疫苗中的药用辅剂混合并以预防有效量使用,以便在延长的时间内保护个体抗IL-1、编程性细胞死亡、IGIF或IFN-γ介导疾病。
式Ⅰ的化合物还可以与其它卡斯帕酶或ICE抑制剂一起使用,以增加治疗或预防多种IL-1、编程性细胞死亡、IGIF或IFN-γ介导疾病的作用。
此外,本发明的化合物可以与常规抗炎剂或与基质金属蛋白酶抑制剂、脂氧合酶抑制剂及IL-1β以外的细胞因子拮抗剂联合使用。
本发明的化合物还可以与免疫调节剂(例如溴匹立明、抗人α干扰素抗体、IL-2、GM-CSF、甲硫氨酸、脑啡肽、干扰素-α、二硫代氨基甲酸二乙酯、肿瘤坏死因子、纳曲酮和EPO)、与前列腺素或与抗病毒剂(例如,3TC、多硫酸化多糖、更昔洛韦(ganiclovir)、利巴韦林、阿昔洛韦、α干扰素、三甲曲沙(trimethotrexate)、和泛昔洛韦(fancyclovir))或这些药物的前药或相关化合物联合使用,以防止或抗IL-1介导的疾病症状如炎症。
当本发明的化合物与其它制剂联合治疗时,它们可以给患者依次或并行给药。或者,本发明的药物或预防组合物含式Ⅰ化合物和其它治疗或预防剂的混合形式。
本发明的药物组合物可以口服、非肠道、吸入喷雾、局部、直肠、鼻内、颊部、阴道或通过植入贮库给药。我们优选口服给药。本发明的药物组合物可以含有任何常规无毒药用载体、辅剂或赋形剂。在一些情况下,可以用药用酸、碱或缓冲剂调节此制剂的pH以提高配制化合物或其转运形式的稳定性。本文中术语非肠道包括皮下、皮内、静脉内、肌肉内、关节内、滑膜腔内、胸骨内、鞘内、损伤区域内和颅内注射或输液技术。
这些药物组合物可以是无菌注射制剂的形式,例如,无菌注射水或油混悬剂。此混悬剂可以按照本领域已知技术用适宜的分散剂或湿润剂(如吐温80)和助悬剂配制。此无菌注射制剂也可以是存在于无毒非肠道给药可接受稀释剂或溶剂(如1,3-丁二醇)中的无菌注射溶液剂或混悬剂。在可接受的载体和溶剂中,可以使用的是甘露醇、水、林格氏溶液和等渗氯化钠溶液。此外,无菌不挥发油可常规用作溶剂或悬浮介质。为此,可以使用任何温和的不挥发油,包括合成的单或二甘油酯衍生物。脂肪酸如油酸及其甘油酯衍生物可用于注射剂的制备,如天然药用油如橄榄油或蓖麻油,特别是其聚氧乙基化的形式。这些油溶液或悬浮液还可以含有长链醇稀释剂或分散剂,如描述于瑞士药典(Pharmacopeia Helvetica)中的,或类似的醇。
本发明的药物组合物可以以任何口服可接受的剂型口服给药,这些剂型包括但不限于胶囊、片剂和含水混悬剂及溶液剂。对于口服片剂,常用的载体包括乳糖和玉米淀粉。一般还加入润滑剂如硬脂酸镁。对于口服给药的胶囊形式,可利用的稀释剂包括乳糖和干燥的玉米淀粉。当含水混悬剂和溶液剂及丙二醇口服给药时,此活性组份与乳化剂或助悬剂混合。如果需要,可以加入某些甜味剂和/或矫味剂和/或着色剂。
本发明的药物组合物还可以以栓剂的形式直肠给药。可以通过将本发明的化合物与适当的无刺激性赋形剂混合制备,该赋形剂在室温下是固体但在直肠温度下是液体,并因此会在直肠中融化以释放活性组份。这些物质包括但不限于可可脂、蜂蜡和聚乙二醇。
当所需治疗发生在局部施用容易进入的区域或器官中时,本发明药物组合物的局部给药是特别有利的。为了给皮肤局部施用,此药物组合物应与适宜的软膏配制,其中所含活性组份悬浮于或溶解于载体中。本发明化合物局部给药的载体包括但不限于矿物油、液体石蜡、白凡士林、丙二醇、聚氧乙烯聚氧丙烯化合物、乳化蜡和水。或者,此药物组合物可以与适宜的洗剂或霜配制,其中所含活性化合物悬浮于或溶解于载体中。适宜的载体包括但不限于矿物油、脱水山梨醇单硬脂酸酯、聚山梨醇酯六十、鲸蜡基酯蜡、混合十六十八醇(cetearylalcohol)、2-辛基十二烷醇、苄醇和水。本发明的药物组合物还可以通过直肠栓剂或在适当的灌肠剂中给肠道的较下部位局部施用。局部给药透皮贴剂也包括在本发明中。
本发明的药物组合物可以通过鼻内气雾剂或吸入剂的形式给药。按照药物制剂领域熟知的技术制备这些组合物并可以制备为存在于生理盐水中的溶液,使用苄醇或其它适宜的防腐剂、提高生物利用度的吸收促进剂、碳氟化合物和/或其它本领域已知的溶解或分散剂。
在单独治疗中,用于预防和治疗IL-1、编程性细胞死亡、IGIF或IFN-γ介导疾病的此活性组份化合物的剂量水平为约0.01至约100mg/kg体重每天,优选为0.5至约75mg/kg体重每天并首选约1至50mg/kg体重每天,所述疾病包括炎性疾病、自身免疫性疾病、破坏骨的紊乱、增殖紊乱、传染病、变性疾病、坏死性疾病、炎性腹膜炎、骨关节炎、急性胰腺炎、慢性胰腺炎、哮喘、成人呼吸窘迫综合征、肾小球性肾炎、类风湿性关节炎、系统性红斑狼疮、硬皮病、慢性甲状腺炎、Graves病、自身免疫性胃炎、胰岛素依赖性糖尿病(Ⅰ型)、自身免疫性溶血性贫血、自身免疫性中性白细胞减少症、血小板减少症、慢性活动性肝炎、重症肌无力、炎性肠疾病、克罗恩氏病、牛皮癣、特应性皮炎、移植物抗宿主病、骨质疏松、与骨疾病有关的多发性骨髓瘤、白血病及相关疾病、脊髓发育不良综合征、急性骨髓性白血病、慢性骨髓性白血病、转移性黑素瘤、卡波济氏肉瘤、多发性骨髓瘤、脓毒病、脓毒性休克、志贺氏菌病、早老性痴呆、帕金森氏病、脑局部缺血、心肌局部缺血、脊柱肌肉萎缩、多发性硬化、AIDS相关脑炎、HIV相关脑炎、衰老、脱发、中风导致的神经损伤、溃疡性结肠炎、感染性肝炎、青少年糖尿病、扁平苔藓病(lichenplanus)、急性皮肤肌炎、湿疹、原发性肝硬化、眼色素层炎、贝切特氏病、特应性皮肤病、纯红细胞发育不全、再生障碍性贫血、肌萎缩性侧索硬化、肾病综合征和系统性疾病或由过量饮酒或病毒如HBV,HCV,HGV,黄热病毒,登革热病毒和日本脑炎病毒引起的炎症或编程性细胞死亡所影响的肝脏或其它器官的疾病。
一般来说,本发明的药物组合物每天将使用约1至5次,或者以连续输液的形式给药。此给药可以用作慢性或急性治疗。可以与载体混合以制备单位剂型的活性组份的量,将随所治疗的宿主和特定的给药方式变化。典型的制剂含有约5%至约95%的活性化合物(w/w)。优选,这些制剂含约20%至约80%的活性化合物。
当本发明的组合物含式Ⅰ化合物和一种或多种其它治疗剂或预防剂的联合形式时,此化合物及其它制剂的剂量应为单一治疗方案中正常给药量的约10%至80%。
随着患者症状的改善,如果需要,可以使用本发明的化合物、组合物或联合形式的维持剂量。于是,作为症状的函数,可以将给药剂量或频率降低至,或者二者都可以降低至维持改善症状,当症状已减轻至所需的水平时,停止治疗。但是,长时间内在疾病症状的复发时需要间歇的治疗。
正如本领域技术人员意识到的,可能需要比上述更低或更高的剂量。对任何特定患者的特定剂量和治疗方案将依赖于多种因素,包括所用特定化合物的活性、患者的年龄,体重,整体健康状况,性别,饮食,给药时间,分泌速度、药物联合、疾病的严重性和过程及患者对疾病的素因及主治医师的诊断。
可以用本发明化合物治疗或预防的IL-1或编程性细胞死亡介导的疾病,包括但不限于炎性疾病、自身免疫性疾病、增殖疾病、感染性疾病和变性疾病。可以用本发明化合物治疗或预防的疾病包括变性疾病。
IL-1或编程性细胞死亡介导的炎性疾病包括但不限于骨关节炎、急性胰腺炎、慢性胰腺炎、哮喘和成人呼吸窘迫综合征。优选的炎性疾病是骨关节炎或急性胰腺炎。
可以用本发明化合物治疗或预防的IL-1或编程性细胞死亡介导的自身免疫性疾病包括但不限于肾小球性肾炎,类风湿性关节炎,系统性红斑狼疮,硬皮病,慢性甲状腺炎,Graves病,自身免疫性胃炎,胰岛素依赖性糖尿病(Ⅰ型),自身免疫溶血性贫血,自身免疫性中性白细胞减少,血小板减少症,慢性活动性肝炎,重症肌无力,多发性硬化,炎性肠疾病,克罗恩氏病,牛皮癣,特异性皮炎和移植物抗宿主病。优选此自身免疫性疾病是类风湿性关节炎、炎性肠疾病、克罗恩氏病、牛皮癣或特异性皮炎。
可以用本发明化合物治疗或预防的IL-1或编程性细胞死亡介导骨破坏疾病包括但不限于骨质疏松和与多发性骨髓瘤有关的骨疾病。
可以用本发明化合物治疗或预防的IL-1或编程性细胞死亡介导的增殖疾病包括但不限于白血病及相关疾病如脊髓发育不良综合征,急性骨髓性白血病,慢性骨髓性白血病,转移性黑素瘤、卡波济氏肉瘤,和多发性骨髓瘤。
可以用本发明化合物治疗或预防的IL-1或编程性细胞死亡介导的感染性疾病包括但不限于脓毒病,脓毒性休克和志贺氏菌病。
可以用本发明化合物治疗或预防的IL-1或编程性细胞死亡介导的变性或坏死性疾病包括但不限于早老性痴呆、帕金森氏病、脑局部缺血和心肌局部缺血。优选此变性疾病是早老性痴呆。
可以用本发明化合物治疗或预防的IL-1或编程性细胞死亡介导的疾病包括但不限于早老性痴呆,帕金森氏病,脑局部缺血,心肌局部缺血,脊柱肌肉萎缩,多发性硬化,AIDS相关脑炎,HIV相关脑炎,衰老,脱发和中风引起的神经损伤。
可以用本发明化合物治疗或预防具有炎性或编程性细胞死亡因素的其它疾病。这些疾病可以是系统性疾病或局部影响位于肝脏或其它器官的疾病,例如,这些疾病可以由下列原因引起:过量饮酒或病毒如HBV、HCV、HGV、黄热病毒、登革热病毒和日本脑炎病毒。
可以用本发明化合物治疗或预防的IGIF-或IFN-γ-介导的疾病包括但不限于炎性、感染性、自身免疫性、增殖性、神经变性及坏死性病症。
可以用本发明化合物治疗或预防的IGIF-或IFN-γ-介导的炎性疾病包括但不限于骨关节炎、急性胰腺炎、慢性胰腺炎、哮喘、类风湿性关节炎、炎性肠疾病、克罗恩氏病、溃疡性结肠炎、脑局部缺血、心肌局部缺血和成人呼吸窘迫综合征。优选此炎性疾病是类风湿性关节炎、溃疡性结肠炎、克罗恩氏病、肝炎或成人呼吸窘迫综合征。
可以用本发明化合物治疗或预防的IGIF-或IFN-γ-介导的感染性疾病包括但不限于传染性肝炎、脓毒病、脓毒性休克和志贺氏菌病。
可以用本发明化合物治疗或预防的IGIF-或IFN-γ-介导的自身免疫性疾病包括但不限于肾小球性肾炎,系统性红斑狼疮,硬皮病,慢性甲状腺炎,Graves病,自身免疫性胃炎,胰岛素依赖性糖尿病(Ⅰ型),青少年糖尿病,自身免疫溶血性贫血,自身免疫性中性白细胞减少,血小板减少症,重症肌无力,多发性硬化,牛皮癣,扁平苔藓病,移植物抗宿主病,急性皮肤肌炎,湿疹,原发性肝硬化,肝炎,眼色素层炎,贝切特氏病,特异性皮肤病,单纯红细胞发育不全,再生障碍性贫血,肌萎缩性侧索硬化和肾病综合征。优选自身免疫性疾病是肾小球性肾炎、胰岛素依赖性糖尿病(Ⅰ型)、青少年糖尿病、牛皮癣、移植物抗宿主病或肝炎。
可以治疗或预防的更优选的疾病包括类风湿性关节炎、炎性肠疾病包括克罗恩氏病和溃疡性结肠炎、炎性腹膜炎、脓毒性休克、胰腺炎、脑外伤、器官移植排斥、骨关节炎、哮喘、牛皮癣、早老性痴呆、特异性皮炎或白血病及相关疾病如骨髓发育不良性综合征或多发性骨髓瘤。
因此,本发明的一个实施方案提供了治疗或预防患者的IL-1或编程性细胞死亡介导疾病的方法,包括给此患者使用本文中描述的任何化合物、药物组合物或联合形式和药用载体的步骤。
本发明的另一个实施方案提供了治疗或预防患者的IGIF产生的方法,包括给此患者使用本文中描述的任何化合物、药物组合物或联合形式和药用载体的步骤。
本发明的另一个实施方案提供了降低患者的IFN-γ产生的方法,包括给此患者使用本文中描述的任何化合物、药物组合物或联合形式和药用载体的步骤。
虽然本发明的焦点在于本文所述化合物预防和治疗IL-1、编程性细胞死亡、IGIF和IFN-γ介导疾病的用途,但是本发明的化合物也可以用作其它半胱氨酸蛋白酶的抑制剂。
本发明的化合物也是有利的商业试剂,它们有效结合卡斯帕酶或其它半胱氨酸蛋白酶(包括但不限于ICE)。作为商业试剂,在生化或细胞检测ICE和ICE类似物的实验中,本发明的化合物及其衍生物可以用来阻断靶肽的蛋白水解,或可以衍生并与稳定的树脂结合以作为亲和色谱中的固定底物。这些或其它以商业半胱氨酸蛋白酶抑制剂为特征的用途对本领域技术人员来说将是显而易见的。
为了使本发明得到更充分的理解,给出下列实施例。这些实施例只是用来举例说明而不是以任何方式限定本发明的范围。
总方法
分析HPLC条件:
柱:C-18,粒度:5μ,孔径:100埃,
柱规格:4.6×150mm
溶剂A:0.1%TFA/1%MeCN/98.9%水
溶剂B:0.1%TFA/99.9%MeCN
梯度:在20分钟内以流速1mL/分钟从A至B
柱:氰基柱,粒度:5μ,孔径:100埃,
柱规格:4.6×150mm
溶剂A:0.1%TFA/1%MeCN/98.9%水
溶剂B:0.1%TFA/99.9%MeCN
梯度:A/B=99%/1%至50%/50%,在20分钟内,流速为1mL/分钟
HPLC质谱分析
质谱分析:所有质谱数据用Micromass QuattroⅡ三联四极质谱仪(Beverly,MA)收集,其装配有交叉流动电喷射离子化源。将此质谱仪与Hewlett-Packard生产的HPLC系统(HP1100)连接。此系统的自动加样器是Gilson215(Middleton,WI)液体处理器。所有设备由购自Micromass的MassLynx软件包控制。
用液体色谱-MS进行质谱分析以测定纯度并同时确证分子量。对于样品纯度已用其它方法测定的情况,用流动注射分析(FIA)代替完全色谱分析。在所有情况下,收集阳性和阴性的离子图谱。
质谱条件:对所有实验,在装有交叉流动计数器电极的电子喷射态中校准质谱仪。用分流器将自HPLC的流量降低至原流量的40%。入口的温度设定在140℃并将干燥气流设定为最大信号。将质谱仪的分辨率调节至0.65amu FWHM并在质心状态(centroid mode)收集数据。在阳离子状态中,将锥体电压设定为25V,毛细管电压设定为3.8kV。在阴离子状态中,将锥体电压设定为25V,毛细管电压设定为3.5kV。在阳离子和阴离子状态中,获得全部图谱的时间为1秒,在扫描期间转换时间为0.25秒。对于预计分子量小于350amu的分子的扫描质量范围为70-500m/z,而对预计分子量大于350amu的扫描质量与电荷比率为200-1000m/z。
色谱条件:液体色谱用YMC AQ C18柱(150mm×3mm,粒度为5μm而孔径为120埃)进行。对于所有分析,用含0.2%甲酸的MeCN与含0.2%甲酸的水混合形成洗脱液梯度。该梯度的特性为用15%MeCN:水开始,并在10分钟内将MeCN的量线性增加至90%。在回到起始条件前将此浓度保持恒定2分钟。在整个分析中,流速为0.9mL/分钟。
流动注射条件:用水与MeCN(都加入0.2%甲酸)1∶1的混合物获得FIA数据。将流速设定为0.3mL/分钟。
1H NMR
所有1H NMR图谱用Bruker Instruments AMX-500NMR光谱仪在给出的溶剂中获得。
合成方法
制备实施方案C式Ⅰ化合物的一般方法(方案Ⅰ-Ⅵ)
制备类似物5a-5bd的方法
在方案Ⅰ-Ⅷ中,变量LR指交联剂-树脂并定义如上述方案Ⅰ中。
步骤1:将6.7g(0.8mmol/g载样量,5.36mmol)的4-甲基二苯甲胺盐酸盐树脂(方案Ⅰ)用DMF(3×50 mL),10%DIEA/DMF(3×50mL)和N-甲基吡咯烷酮(NMP)(3×50mL)洗涤。向存在于25mL NMP中的洗涤后树脂的悬浮液中依次加入化合物1(1.1eq(当量),3.5g,5.90mmol),DIEA(3.33eq,3.1mL,17.70mmol),1-羟基苯并三唑水合物(HOBt)(1.1eq,797mg,5.90mmol)和0-苯并三唑-N,N,N,N′-四甲基脲鎓六氟磷酸盐(HBTU)(1.1eq,2.24g,5.90mmol)。按照文献A.M.Murphy等,J.Am.Chem.Soc.,114,pp.3156-3157(1992)的方法制备化合物1。混合物用腕臂震动器在室温下旋转过夜。
将所得混合物过滤,并将此树脂用DMF洗涤,然后室温下用12mL 20%的醋酸酐DMF溶液处理30分钟。将此混合物过滤,并用DMF(2×50mL),CH3OH(50mL),1∶1 DMF/CH2Cl2(2×50mL),CH3OH(50mL)和CH2Cl2(3×50mL)依次洗涤。真空干燥后,获得9.0g的树脂2(0.48mmol/g载样量)。
步骤2:向4.5g的树脂2(0.48mmol/g,2.16mmol)中,加入20%的哌啶的DMF溶液。将此悬浮液在室温下转动5分钟并排干。此方法重复20分钟。然后用DMF(2×40mL),CH3OH(40mL),CH2Cl2(2×40mL),CH3OH(40mL)和NMP(40mL)依次洗涤。向树脂在40mL NMP的悬浮液中依次加入2.92g的N-Fmoc-脯氨酸(4eq,8.64mmol),3.0mL的DIEA(8eq,17.28mmol),1.17g的HOBt(4eq,8.64mmol)和3.27g的HBTU(4eq,8.64mmol)。将此混合物室温下旋转过夜并排干。将此偶联方法重复3小时。然后用DMF(2×40mL),CH3OH(40mL),1∶1DMF/CH2Cl2(2×40mL),CH3OH(40mL)和CH2Cl2(3×40mL)依次洗涤此树脂,并简单真空干燥得到树脂3。
步骤3:将树脂3在25mL 20%哌啶的DMF溶液中的悬浮液室温下旋转5分钟。将此悬浮液排干。在20分钟内重复此过程。用DMF(2×40mL),CH3OH(40mL),CH2Cl2(2×40mL),CH3OH(40mL)和NMP(2×40mL)依次洗涤此树脂。向树脂在40mL NMP的悬浮液中依次加入2.93g的N-Fmoc-缬氨酸(4eq,8.64mmol),3.0mL的DIEA(8eq,17.28mmol),1.17g的HOBt(4eq,8.64mmol)和3.27g的HBTU(4eq,8.64mmol)。将此混合物室温下旋转过夜并排干。将此偶联方法重复3小时。然后用DMF(2×40mL),CH3OH(40mL),1∶1 DMF/CH2Cl2(2×40mL),CH3OH(40mL)和CH2Cl2(3×40mL)依次洗涤此树脂,并真空干燥得到树脂4(0.45mmol/g)。
步骤4:向0.05mmol的树脂4中加入2mL的20%哌啶的DMF溶液。将此悬浮液室温下旋转5分钟并排干。在20分钟内重复此方法。将所得树脂用DMF(3×50ml)、甲醇(5ml)和NMP(3×5ml)依次洗涤。然后加入所需的羧酸(4eq,0.2mmol),接着加入0.8mL的0.25M HOBt的NMP溶液,0.14mL的DIEA(8eq,0.4mmol)和0.8mL的0.25M HBTU的NMP溶液。将此混合物室温下旋转过夜并排干。将此树脂用DMF(2×5mL),CH3OH(5mL),1∶1 DMF/CH2Cl2(2×5mL),CH3OH(5mL)和CH2Cl2(3×5mL)依次洗涤,并真空干燥。然后将2mL的TFA在水中的95%溶液加入此树脂中。将此混合物室温下搅拌1小时,并过滤。将此滤液蒸发,并在乙腈-水中回收此残余物并用制备HPLC纯化,得到化合物5a-5bd。
除非另行说明,实施例5a-5bd,7a-7at,9a-9g,15a-15f,16a-16b,17a-17e,18a-18f,20a-20t,23a-23i,24a-24e,25a-25e,26a-26h,27a-27n,28a-28c,29a-29s,32a-32e的产品收率、分析HPLC条件、HPLC保留时间、产品纯度和质谱数据见表1。
表1.所选实施例的物理数据
实施例 | 产率(mg) | HPLC梯度/时间(分钟) | RT (分钟) | 纯度(%) | 质谱(M+H或M+Na) |
5a | 1.0 | 5-45%/10' | 4.66 | 92 | 475.2 |
5b | 1.0 | 5-45%/10' | 6.86 | 85 | 457.2 |
5c | 4.0 | 5-45%/10' | 5.98 | 85 | 469.2 |
5d | 1.5 | 5-45%/10' | 6.82 | 95 | 467.5 |
5e | 1.0 | 5-45%/10' | 5.52 | 95 | 418.2 |
5f | 0.6 | 5-45%/10' | 4.28 | 93 | 434.2 |
5g | 6.4 | 10-60%/10' | 8.57 | 97 | 504.7(+Na) |
5h | 15.6 | 10-60%/10' | 4.51 | 99 | 459.2 |
5i | 6.6 | 5%-90%/10' | 9.34 | 90 | 506.1 |
5j | 5.1 | 5%-90%/10' | 10.04 | 95 | 506.1 |
5k | 10.7 | 5%-90%/10' | 8.64 | 85 | 520.1 |
5l | 6.6 | 5%-90%/10' | 8.72 | 85 | 540.1 |
5m | 6.8 | 5%-90%/10' | 7.89 | 85 | 502.0 |
5n | 1.9 | 5%-0%/10' | 6.46 | 85 | 494.1 |
5o | 3.8 | 5%-90%/10' | 7.04 | 85 | 506.1 |
5p | 6.8 | 5%-90%/10' | 11.62 | 95 | 576.0 |
5q | 2.2 | 5%-90%/10' | 9.72 | 90 | 508.1 |
5r | 3.8 | 5%-90%/10' | 7.27 | 85 | 462.1 |
5s | 4.3 | 5%-90%/10' | 6.46 | 90 | 470.1 |
实施例 | 产率(mg) | HPLC梯度/时间(分钟) | RT (分钟) | 纯度(%) | 质谱(M+H或M+Na) |
5t | 5.9 | 5%-60%/9'60%-90%/2' | 10.27 | 90 | 486.2 |
5u | 3.1 | 5%-60%/9'60%-90%/2' | 9.09 | 80 | 522.1 |
5v | 1.0 | 5%-60%/9'60%-90%/2 ' | 11.63 | 85 | 502.2 |
5w | 10.3 | 5%-60%/9'60%-90%/2' | 8.75 | 95 | 470.2 |
5x | 8.8 | 5%-60%/9'60%-90%/2' | 8.88 | 95 | 565.1 |
5y | 6.6 | 5%-60%/9'60%-90%/2' | 12.32 | 95 | 518.2 |
5z | 10.2 | 5%-60%/9'60%-90%/2' | 12.63 | 95 | 502.2 |
5aa | 2.5 | 5%-60%/9'60%-90%/2' | 9.57 | 95 | 554.1 |
5ab | 7.8 | 5%-60%/9'60%-90%/2' | 10.54 | 85 | 538.2 |
5ac | 1.4 | 5%-60%/9'60%-90%/2' | 9.28 | 95 | 476.2 |
5ad | 5.3 | 5%-60%/9'60%-90%/2' | 6.51 | 85 | 469.2 |
5ae | 4.3 | 5%-60%/9'60%-90%/2' | 9.81 | 95 | 551.1 |
5af | 0.9 | 5%-60%/9'60%-90%/2' | 9.98 | 90 | 547.4 |
5ag | 5.7 | 5%-60%/9'60%-90%/2' | 10.31 | 90 | 526.2 |
5ah | 1.4 | 5%-60%/9'60%-90%/2' | 8.13 | 85 | 542.1 |
5ai | 10.9 | 10%-90%/10' | 5.88 | 85 | 584.2 |
5aj | 4.2 | 10%-90%/10' | 5.89 | 90 | 556.2 |
5ak | 7.8 | 10%-90%/10' | 5.54 | 85 | 568.3 |
5al | 8.4 | 10%-90%/10' | 6.25 | 95 | 516.2 |
5am | 7.6 | 10%-90%/10' | 6.49 | 95 | 474.3 |
5an | 6.2 | 10%-90%/10' | 6.00 | 95 | 500.2 |
5ao | 9.4 | 10%-90%/10' | 6.68 | 95 | 581.3 |
5ap | 6.4 | 10%-90%/10' | 4.30 | 90 | 500.3 |
5aq | 5.2 | 10%-90%/10' | 6.45 | 95 | 559.2 |
5ar | 1.4 | 10%-90%/10' | 5.38 | 90 | 561.3 |
5as | 16.2 | 10%-90%/10' | 4.25 | 95 | 475.2 |
5at | 15.4 | 10%-90%/10' | 6.68 | 95 | 560.3 |
5au | 5.9 | 10%-90%/10' | 6.70 | 90 | 498.3 |
5av | 4.1 | 10%-90%/10' | 5.13 | 85 | 531.2 |
5aw | 5.5 | 10%-90%/10' | 6.53 | 85 | 570.3 |
5ax | 14.0 | 10%-90%/10' | 6.26 | 90 | 557.3 |
实施例 | 产率(mg) | HPLC梯度/时间(分钟) | RT (分钟) | 纯度(%) | 质谱(M+H或M+Na) |
5ay | 10.4 | 10%-90%/10' | 6.52 | 90 | 510.3 |
5az | 9.2 | 10%-90%/10' | 5.96 | 95 | 522.3 |
5ba | 8.5 | 10%-90%/10' | 6.69 | 95 | 562.3 |
5bb | 4.6 | 10%-90%/10' | 6.00 | 85 | 520.2 |
5bc | 8.8 | 10%-90%/10' | 4.96 | 90 | 546.2 |
5bd | 8.2 | 10%-90%/10' | 8.01 | 95 | 536.3 |
7a | 2.1 | 5-45%/10' | 5.28 | 86 | 440.2 |
7b | 1.7 | 5-45%/10' | 4.12 | 94 | 390.2 |
7c | 0.5 | 5-45%/10' | 4.04 | 94 | 434.2 |
7d | 1.1 | 5-45%/10' | 4.29 | 95 | 441.2 |
7e | 1.1 | 5-45%/10' | 3.28 | 98 | 447.2 |
7f | 1.0 | 5-45%/10' | 3.96 | 97 | 420.2 |
7g | 11.0 | 10%-90%/10' | 4.00 | 95 | 483.4 |
7h | 6.0 | 10%-90%/10' | 4.90 | 95 | 439.3 |
7i | 12.0 | 10%-90%/10' | 6.40 | 95 | 474.3 |
7j | 6.6 | 10%-90%/10' | 4.50 | 95 | 461.4 |
7k | 4.0 | 10%-90%/10' | 5.40 | 95 | 480.4 |
7l | 8.6 | 10%-90%/10' | 2.61 | 95 | 435.3 |
7m | 6.0 | 10%-90%/10' | 4.29 | 95 | 438.4 |
7n | 15.4 | 10%-90%/10' | 2.00 | 85 | 433.4 |
7o | 8.4 | 10%-90%/10' | 4.01 | 90 | 470.0 |
7p | 3.0 | 10%-90%/10' | 4.61 | 95 | 434.4 |
7q | 5.7 | 10%-90%/10' | 3.89 | 95 | 434.3 |
7r | 8.8 | 10%-90%/10' | 2.94 | 95 | 425.3 |
7s | 10.5 | 10%-90%/10' | 3.89 | 90 | 433.4 |
7t | 6.9 | 10%-90%/10' | 2.45 | 85 | 419.3 |
7u | 11.6 | 10%-90%/10' | 1.98 | 85 | 433.3 |
7v | 4.6 | 10%-90%/10' | 4.60 | 95 | 489.4 |
7w | 13.8 | 10%-90%/10' | 4.20 | 95 | 453.3 |
7x | 6.0 | 10%-90%/10' | 3.90 | 95 | 483.2 |
7y | 12.0 | 10%-90%/10' | 5.40 | 95 | 489.2 |
7z | 10.0 | 10%-90%/10' | 5.40 | 95 | 517.2 |
7aa | 11.0 | 10%-90%/10' | 5.30 | 95 | 453.8 |
7ab | 10.0 | 10%-90%/10' | 5.60 | 95 | 595.1 |
7ac | 3.9 | 10-60%/10' | 4.59 | 88 | 469.2 |
7ad | 13.0 | 5-45%/10' | 4.48 | 88 | 415.2 |
7ae | 4.9 | 5-45%/10' | 4.37 | 88 | 426.2 |
7af | 20.6 | 5-45%/10' | 4.68 | 86 | 405.3 |
7ag | 14.9 | 5-45%/10' | 4.78 | 82 | 406.3 |
7ah | 9.5 | 5-45%/10' | 7.40 | 91 | 447.3(+Na) |
7ai | 10.8 | 5-45%/10' | 9.21 | 95 | 480.8(+Na) |
7aj | 8.3 | 5-45%/10' | 9.14 | 92 | 481.1(+Na) |
7ak | 13.6 | 5-45%/10' | 8.05 | 96 | 464.8(+Na) |
7al | 8.1 | 5-45%/10' | 7.04 | 91 | 448.8(+Na) |
7am | 7.8 | 5-45%/10' | 8.54 | 90 | 480.4(+Na) |
实施例 | 产率(mg) | HPLC梯度/时间(分钟) | RT (分钟) | 纯度(%) | 质谱(M+H或M+Na) |
7an | 4.3 | 5-45%/10' | 7.48 | 88 | 460.9(+Na) |
7ao | 13.5 | 5-45%/10' | 7.45 | 92 | 460.7(+Na) |
7ap | 2.5 | 5-45%/10' | 6.52 | 93 | 440.3(+Na) |
7aq | 1.4 | 5-45%/10' | 3.30 | 84 | 405.2 |
7ar | 15.10 | 5-45%/10' | 3.79 | 97 | 413.30 |
7as | 15.70 | 5-45%/10' | 5.50 | 88 | 441.30 |
7at | 22.20 | 5-45%/10' | 4.49 | 94 | 415.30 |
9a | 0.5 | 10-60%/10' | 7.08 | 98 | 527.4(+Na) |
9b | 1.2 | 10-60%/10' | 8.31 | 93 | 570.5(+Na) |
9c | 2.5 | 10-60%/10' | 8.46 | 97 | 569.6 |
9d | 1.2 | 10-60%/10' | 7.22 | 85 | 562.1 |
9e | 0.4 | 10-60%/10' | 7.86 | 95 | 543.2(+Na) |
9f | 4.3 | 10-60%/10' | 8.11 | 96 | 542.5 |
9g | 2.1 | 10-60%/10' | 7.18 | 93 | 526.3 |
15a | 1.0 | 10%-60%/10' | 5.76 | 95 | 477.6 |
15b | 3.9 | 10%-60%/10' | 6.32 | 91 | 483.8 |
15c | 2.9 | 10%-90%/10' | 3.30 | 85 | 463.3 |
15d | 1.3 | 10%-90%/10' | 4.26 | 95 | 531 |
15e | 1.0 | 10%-90%/10' | 3.10 | 85 | 482.3 |
15f | 1.2 | 10%-90%/10' | 3.60 | 95 | 484.6 |
16a | 2.5 | 10%-90%/10' | 2.80 | 95 | 456.3 |
16b | 6.0 | 10%-90%/10' | 1.90 | 95 | 454.2 |
17a | 1.0 | 10%-90%/10' | 3.30 | 85 | 496.8 |
17b | 1.1 | 10%-90%/10' | 3.62 | 85 | 498.3 |
17c | 2.3 | 10%-90%/10' | 5.80 | 95 | 573.2 |
17d | 1.6 | 10%-90%/10' | 1.60 | 95 | 525.1 |
17e | 1.5 | 10%-90%/10' | 2.62 | 95 | 526.3 |
18a | 1.0 | 10%-90%/10' | 3.90 | 95 | 528.3 |
18b | 1.2 | 10%-90%/10' | 5.27 | 95 | 562.3 |
18c | 2.2 | 10%-90%/10' | 4.09 | 95 | 499.2 |
18d | 1.5 | 10%-90%/10' | 3.78 | 95 | 498.3 |
18e | 1.2 | 10%-90%/10' | 4.78 | 95 | 541.3 |
18f | 7.1 | 10%-90%/10' | 3.84 | 98 | 526.1 |
20a | 2.0 | 5-45%/10' | 6.95 | 91 | 483.2 |
20b | 1.3 | 5-45%/10' | 7.58 | 99 | 482.2 |
20c | 2.5 | 10%-90%/10' | 5.89 | 85 | 483.3 |
20d | 4.3 | 10%-90%/10' | 4.09 | 90 | 471.3 |
20e | 3.6 | 10%-90%/10' | 4.65 | 95 | 455.3 |
20f | 12.2 | 10%-90%/10' | 3.25 | 95 | 518.3 |
20g | 12.1 | 10%-90%/10' | 5.01 | 90 | 487.2 |
20h | 3.3 | 10%-90%/10' | 4.30 | 90 | 533.2 |
20i | 5.0 | 10%-90%/10' | 4.16 | 90 | 485.2 |
20j | 1.3 | 10%-90%/10' | 3.45 | 85 | 531.2 |
20k | 9.7 | 10%-90%/10' | 5.41 | 90 | 516.2 |
20l | 3.8 | 10%-90%/10' | 3.73 | 85 | 504.2 |
实施例 | 产率(mg) | HPLC梯度/时间(分钟) | RT (分钟) | 纯度(%) | 质谱(M+H或M+Na) |
20m | 6.6 | 10%-90%/10' | 4.52 | 90 | 488.2 |
20n | 1.8 | 10%-90%/10' | 2.85 | 90 | 551.2 |
20o | 7.0 | 10%-90%/10' | 4.70 | 95 | 520.2 |
20p | 1.2 | 10%-90%/10' | 4.00 | 95 | 566.2 |
20q | 2.3 | 10%-90%/10' | 4.93 | 95 | 481.3 |
20r | 3.6 | 10%-90%/10' | 4.45 | 95 | 519.3 |
20s | 3.0 | 10%-90%/10' | 4.18 | 95 | 552.2 |
20t | 6.0 | 10%-90%/10' | 3.80 | 90 | 517.4 |
23a | 21.0 | 10-60%/10' | 8.11 | 99 | 495.4 |
23b | 25.0 | 10-60%/10' | 8.94 | 99 | 539.8(+Na) |
23c | 26.0 | 10-60%/10' | 8.55 | 99 | 539.9(+Na) |
23d | 12.6 | 10%-90%/10' | 3.90 | 85 | 453.3 |
23e | 8.3 | 10%-90%/10' | 5.16 | 85 | 501.3 |
23f | 12.5 | 10%-90%/10' | 3.41 | 80 | 425.3 |
23g | 1.5 | 10%-90%/10' | 3.34 | 85 | 452.3 |
23h | 8.4 | 10%-90%/10' | 3.84 | 90 | 451.3 |
23i | 9.0 | 10%-90%/10' | 3.78 | 85 | 469.4 |
24a | 1.1 | 10-60%/12' | 8.76 | 90 | 480.5 |
24b | 3.1 | 10-60%/10' | 5.14 | 90 | 375.4 |
24c | 7.2 | 10-60%/10' | 10.33 | 96 | 531.0 |
24d | 3.4 | 10-60%/10' | 6.51 | 95 | 426.5(+Na) |
24e | 6.9 | 10-60%/10' | 7.22 | 99 | 455.5 |
25a | 1.9 | 5-45%/10' | 5.38 | 85 | 455.2 |
25b | 1.5 | 5-45%/10' | 6.90 | 97 | 483.2 |
25c | 1.0 | 5-45%/10' | 8.09 | 94 | 497.2 |
25d | 12.8 | 5-45%/10' | 5.75 | 88% | 453.3 |
25e | 9.5 | 5-45%/10' | 7.76 | 90% | 495.2 |
26a | 10.2 | 5-45%/10' | 7.36 | 95 | 455.1(+Na) |
26b | 1.1 | 5-45%/10' | 7.38 | 89 | 476.3 |
26c | 13.8 | 5-45%/10' | 8.13 | 98 | 483.2 |
26d | 2.3 | 5-45%/10' | 10.35 | 99 | 503.0 |
26e | 12.8 | 5-45%/10' | 11.11 | 99 | 523.2 |
26f | 13.2 | 10-60%/10' | 12.11 | 99 | 545.0 |
26g | 0.7 | 10-60%/10' | 10.89 | 87 | 523.2 |
26h | 4.4 | 10-60%/10' | 11.62 | 99 | 545.8 |
27a | 5.0 | 10%-90%/10' | 4.42 | 95 | 475.3 |
27b | 16.4 | 10-60%/10' | 5.20 | 92 | 505.1 |
27c | 2.7 | 5-45%/10' | 7.50 | 82 | 476.6(+Na) |
27d | 1.6 | 5-45%/12' | 8.70 | 90 | 503.2 |
27e | 4.4 | 5-45%/12' | 7.80 | 82 | 489.2 |
27f | 1.2 | 5-45%/12' | 6.95 | 85 | 476.3 |
27g | 2.5 | 5-45%/12' | 6.67 | 82 | 510.1 |
27h | 1.1 | 5-45%/12' | 8.49 | 95 | 524.1 |
27i | 0.9 | 5-45%/12' | 7.34 | 90 | 484.3 |
27j | 4.3 | 5-45%/12' | 5.77 | 82 | 470.3 |
实施例 | 产率(mg) | HPLC梯度/时间(分钟) | RT (分钟) | 纯度(%) | 质谱(M+H或M+Na) |
27k | 1.3 | 5-45%/12′ | 5.33 | 95 | 551.1 |
27l | 16.6 | 5-45%/10′ | 5.90 | 91 | 477.2 |
27m | 7.O | 5-45%/lO′ | 7.70 | 93 | 494.2 |
27n | 15.1 | 5-45%/10′ | 3.99 | 86 | 466.2 |
28a | 1.2 | 5-45%/10′ | 5.91 | 86 | 487.1 |
28b | 0.5 | 5-45%/10′ | 6.86 | 98 | 486.1 |
28c | 1.5 | 5-45%/10′ | 7.47 | 93 | 515.1 |
29a | 4.5 | 5-45%/12′ | 8.21 | 98 | 392 |
29b | 28.0 | 5-45%/12′ | 11.80 | 96 | 443.3 |
29c | 1.7 | 5-45%/10′ | 3.73 | 97 | 415.2 |
29d | 1.7 | 5-45%/10′ | 4.62 | 89 | 414.2 |
29e | 0.6 | 5-45%/10′ | 4.94 | 85 | 436.2 |
29f | 1.1 | 5-45%/10′ | 6.23 | 97 | 442.2 |
29g | 1.7 | 5-45%/10′ | 6.39 | 90 | 457.2 |
29h | 0.7 | 5-45%/10′ | 3.56 | 92 | 408.2 |
29i | 0.7 | 5-45%/10′ | 6.50 | 96 | 431.2 |
29j | 0.4 | 5-45%/10′ | 7.24 | 89 | 445.2 |
29k | 1.6 | 5-45%/10′ | 7.07 | 90 | 456.2 |
29l | 0.9 | 5-45%/10′ | 3.08 | 99 | 408.2 |
29m | 1.5 | 10-60%/10′ | 6.68 | 90 | 406.3 |
29n | 6.4 | 10-60%/10′ | 4.27 | 87% | 422.3 |
29o | 8.4 | 10-60%/10′ | 4.42 | 86% | 422.3 |
29p | 13.2 | 10-60%/10′ | 5.62 | 83% | 450.3 |
29q | 15.1 | 5-45%/10 | 3.79 | 97% | 413.3 |
29r | 15.7 | 5-45%/10′ | 5.50 | 88% | 441.3 |
29s | 19.9 | 5-45%/10′ | 4.3O | 95% | 394.3 |
32a | 7.7 | 5-60%/20′ | 14.2 | 90 | 469.3 |
32b | 4.0 | 5-60%/20′ | 13.4 | 85 | 485.1(+Na) |
32c | 2.5 | 5-60%/20′ | 11.1 | 90 | 459.3 |
32d | 3.0 | 5-60%/20′ | 8.19 | 95 | 471.3 |
32e | 4.9 | 5-60%/20′ | 14.2 | 90 | 486.2 |
类似物7a-7at按照方案Ⅰ所述制备,不同的是在步骤3中用Fmoc-丙氨酸代替Fmoc-缬氨酸(方案Ⅱ)。
步骤3:将树脂3(3.5g,1.75mmol)在20mL 20%哌啶的DMF溶液中的悬浮液室温下旋转5分钟。将此悬浮液排干。在20分钟内重复此过程。用DMF(2×30mL),CH3OH(30mL),CH2Cl2(2×30mL),CH3OH(30mL)和NMP(2×30mL)依次洗涤此树脂。向树脂在30mL NMP的悬浮液中依次加入1.44g的N-Fmoc-丙氨酸(4eq,7.0mmol),2.4mL的DIEA(8eq,14.0mmol),0.95g的HOBt(4eq,7.0mmol)和2.66g的HBTU(4eq,7.00mmol)。将此混合物室温下旋转过夜并排干。将此偶联方法重复3小时。然后用DMF(2×30mL),CH3OH(30mL),1∶1DMF/CH2Cl2(2×30mL),CH3OH(30mL)和CH2Cl2(3×30mL)依次洗涤此树脂,并真空干燥得到树脂6(0.50mmol/g)。
步骤4:向0.125mmol的树脂6中加入5mL的20%哌啶的DMF溶液。将此悬浮液室温下旋转5分钟并排干。在20分钟内重复此方法。将所得树脂用DMF(3×5ml)、甲醇(5ml)和NMP(3×5ml)依次洗涤。然后加入所需的羧酸(4eq,0.6mmol),接着加入2.0mL的0.25M HOBt的NMP溶液,0.35mL的DIEA(8eq,1.0mmol)和2.0mL的0.25M HBTU的NMP溶液。将此混合物室温下旋转过夜并排干。将此树脂用DMF(3×5mL),CH3OH(5mL),1∶1 DMF/CH2Cl2(2×5mL),CH3OH(5mL)和CH2Cl2(3×5mL)依次洗涤,并真空干燥。然后将5mL的TFA在水中的95%溶液加入此树脂中。将此混合物室温下搅拌1小时,并过滤。将此滤液蒸发,并在乙腈-水中溶解此残余物并用制备HPLC纯化,得到化合物7a-7at。
制备类似物9a-9g的方法
步骤1:将10.0g(0.75mmol/g载样量,7.5mmol)AgroPore-氨基甲基树脂(商品目录号800047)用DMF(3×40mL),10%DIEA/DMF(3×40mL),DMF和NMP(3×40mL)洗涤。向上述树脂中依次加入化合物1(0.87eq,3.88g,6.55mmol),HBTU(1.14eq,3.13g,8.25mmol),HOBt(1.14eq,1.26g,8.25mmol)和NMP(40mL)。然后室温下通过烧瓶的底部通入2分钟氮气鼓泡将这些试剂混合。加入N,N-二异丙基乙胺(3.33eq,4.35mL,25mmol)并将所得悬浮液在室温下过夜混合,过滤并用NMP(3×40mL)和DMF(3×40mL)依次洗涤。然后室温下用50mL的20%醋酸酐DMF溶液处理38分钟。将此混合物过滤,并用NMP(3×40mL),二氯甲烷(3×40mL),1∶1甲醇/CH2Cl2(3×40mL)和CH3OH(3×40mL)依次洗涤。真空干燥后,得到13.76g的树脂2(0.35mmol/g载样量)。
步骤2:将7个反应容器中,每个都加入181mg的树脂2(0.48mmol/g,0.063mmol),然后用二氯甲烷(3×1mL)和NMP(3×1mL)洗涤。然后将每个反应器用1mL的25%哌啶的DMF溶液处理并室温下混合(旋转)15分钟。将此方法进行一式三份。然后,用NMP(3×1mL)将每个容器洗涤三次。然后用500μl的0.4M(2S,4R)-Fmoc-4-氨基-1-Boc-吡咯烷-2-甲酸/0.4M HOBt/NMP溶液,500μl的0.4M HBTU/NMP溶液和250μl 1.6M DIEA/NMP溶液处理容器并在室温下混合3小时。混合后,将这些容器排干并重复此过程。
步骤3:将所得树脂用NMP(3×1mL)洗涤并用1mL的25%哌啶的DMF溶液处理并在室温下混合(旋涡)15分钟。将此方法重复一式三份。将所得树脂用NMP(3×1mL)洗涤,然后用醋酸酐、或异丙基异氰酸酯、或甲磺酰氯或氯甲酸甲酯处理。对于醋酸酐:加入300μl 1.6MDIEA/NMP溶液和1mL的0.5M醋酸酐/0.125M DIEA/0.015M HOBt在NMP中的溶液。对于异丙基异氰酸酯:加入300μl的1.6M DIEA/NMP溶液和1mL的1M异丙基异氰酸酯的NMP溶液。对于甲磺酰氯:加入600μl 1M吡啶在二氯甲烷中的溶液和600μl 1M甲磺酰氯的二氯甲烷溶液。对于氯甲酸甲酯:加入500μl的1.6M DIEA/NMP溶液和1ml的0.7M氯甲酸甲酯的二氯甲烷溶液,将所得悬浮液室温下混合6小时,排除溶剂并重复此偶联方法。
步骤4:将所得树脂用NMP(3×1mL)洗涤,然后用TFA/二氯甲烷的1∶1混合物在室温下处理30分钟。然后将所得树脂用二氯甲烷(3×1mL)和NMP(3×1mL)洗涤。然后,用500μl的0.4M Fmoc-缬氨酸-甲酸/0.4M HOBt/NMP溶液,500μl的0.4M HBTU/NMP溶液和250μl的1.6M DIEA/NMP溶液处理,并在室温下混合3小时。混合后,将此容器排干并重复此偶联步骤。
步骤5:将所得树脂用NMP(3×1mL)洗涤并用1mL的25%哌啶的DMF溶液处理并在室温下混合(旋涡)15分钟。将此方法重复一式三份。将所得树脂用NMP(3×1mL)洗涤,然后用500μl的0.4M 1-异喹啉甲酸/0.4M HOBt/NMP溶液或500μl的0.4M对-茴香酸/0.4M HOBt/NMP溶液处理。将所得混合物用500μl的0.4M HBTU/NMP溶液和250μl的1.6M DIEA/NMP溶液处理,然后室温下混合3小时,排除溶剂并重复此步骤。将所得树脂用1.5mL的TFA的95%水溶液处理,并在室温下搅拌1小时并过滤。将此滤液蒸发,并在DMF/乙腈/水的2∶1∶2的混合物中回收此残余物,通过制备HPLC纯化得到化合物9a-9g。
制备类似物15和16(方案Ⅳ):
合成2-(S)-哌嗪-1,2,4-三甲酸4-叔丁基酯1-(9H-芴-9-基甲基)酯
向2-(S)-哌嗪甲酸(Lonza)(3g,15mmol)在1∶1水∶二噁烷(30mL)的溶液中,加入(BOC)2O的二噁烷溶液(3.3g,15mmol,在5mL二噁烷中),同时用1N氢氧化钠维持pH为11。室温下将此pH维持3小时。用1N盐酸将此溶液的pH调节至9.5,冷却至0℃并用Fmoc-Cl(3.87g,15mmol)处理。将pH在9.5维持1小时并将此混合物室温下搅拌过夜。将所得悬浮液过滤并用1N硫酸氢钾处理此滤液至pH2,然后用乙酸乙酯(2×75mL)萃取。用盐水和硫酸镁干燥此有机层,过滤并浓缩得到无色油状物。将此油状物溶解于乙酸乙酯中并加入到己烷中,分离后得到3.5g(51%收率)的白色固体。1H NMR(500MHz,DMSO-d6)δ1.55(s,9H)2.80-3.5(m,3H),3.8-4.9(m,5H),5.7(bs,1H),7.3(m,2H),7.3-7.9ppm(m,8H),LC/MS(ES-)m/e 451.3(M-H)
步骤1:向5g的树脂2(0.375mmol/g,1.82mmol)中,加入25ml20%的哌啶的DMF溶液。将此悬浮液在室温下转动5分钟并排干。此方法重复20分钟。然后用DMF(2×50mL),CH3OH(50mL),CH2Cl2(2×50mL),CH3OH(50mL)和NMP(50mL)依次洗涤树脂。向树脂在25mL NMP的悬浮液中依次加入3.5g的N-Fmoc-Boc哌嗪甲酸(4eq,7.48mmol),1.0mL的DIEA(8eq,14.96mmol),1.01g的HOBt(4eq,7.48mmol)和2.83g的HBTU(4eq,7.48mmol)。将此混合物室温下旋转过夜并排干。将此偶联方法重复3小时。然后用DMF(2×50mL),CH3OH(50mL),1∶1 DMF/CH2Cl2(2×50mL),CH3OH(1×50mL)和CH2Cl2(3×50mL)依次洗涤此树脂,并简单真空干燥得到树脂10。
步骤2:向5g(0.335mmol/g载样量,1.675mmol)的树脂10中加入25mL 20%哌啶的DMF溶液。将此悬浮液室温下旋转5分钟并排干。在20分钟内重复此过程。用DMF(2×50mL),CH3OH(50mL),CH2Cl2(2×50mL),CH3OH(50mL)和NMP(2×50mL)依次洗涤此树脂。向树脂在25mL NMP的悬浮液中依次加入2.08g的N-Fmoc-缬氨酸或N-Fmoc-丙氨酸(4eq,6.7mmol),1.17mL的DIEA(4eq,6.7mmol),0.905g的HOBt(4eq,6.7mmol)和1.38g的HBTU(4eq,3.66mmol)。将此混合物室温下旋转过夜并排干。将此偶联方法重复3小时。然后用DMF(2×50mL),CH3OH(50mL),1∶1 DMF/CH2Cl2(2×50mL),CH3OH(50mL)和CH2Cl2(3×50mL)依次洗涤此树脂,并真空干燥,分别得到树脂11或12(0.35mmol/g,5g)。
步骤3:向1.5g(0.165mmol)的树脂11或12中加入2mL的20%哌啶的DMF溶液。将此悬浮液室温下旋转5分钟并排干。在20分钟内重复此方法。将所得树脂用DMF(3×15ml)、甲醇(15ml)和NMP(3×15ml)依次洗涤。然后加入所需的羧酸(4eq,0.66mmol),接着加入存在于NMP中的0.25g(0.66mmol)的HOBt,0.12mL的DIEA(4eq,0.66mmol)和0.89g(0.66mmol)HBTU。将此混合物室温下旋转过夜并排干。将此树脂用DMF(2×15mL),CH3OH(15mL),1∶1 DMF/CH2Cl2(2×15mL),CH3OH(15mL)和CH2Cl2(3×15mL)依次洗涤,并真空干燥,得到13或14。
合成类似物17和18的方法(见方案Ⅳ):
步骤5:用2mL 25%的TFA/二氯甲烷将树脂13或14处理30分钟,并用DMF(2×5mL),10%DIEA/二氯甲烷(2×5mL),DMF/二氯甲烷(2×5mL),甲醇(5mL)和二氯甲烷(3×5mL)洗涤,并干燥5分钟。将所得树脂用NMP(3×1mL)洗涤,然后用醋酸酐或或甲乙酸(methoxacetic acid)或2-丙磺酰氯或异丙基异氰酸酯或甲磺酰氯或氯甲酸甲酯按照用于制备类似物9的方法(方案Ⅲ)处理。按照化合物15和16步骤4所述获得化合物17和18。
化合物17a和17b通过在步骤4前还原氨化反应用Na(OAc)3BH和HCHO(38%在水中,0.2mL)及CH3COOH(0.02mL)制备,而化合物18c在步骤4前用光气处理,并接着用氨气处理制备。
制备类似物20的方法
按照化合物5描述的方法(方案Ⅰ)制备化合物20a-20t,不同的是在步骤3中用适当的Fmoc-氨基酸代替Fmoc-缬氨酸(方案Ⅴ)。
方案Ⅴ
制备3-({1-[2-(4-氨基-3-氯-苯甲酰基氨基)-3-甲基磺酰基-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(20i)
将0.132mmol树脂3在4mL 20%哌啶的DMF中的混悬液室温下旋转5分钟,并将此混合物排干。将此步骤重复20分钟。将此树脂用DMF(两次),甲醇(一次),二氯甲烷(两次),甲醇(一次)和NMP(两次)依次洗涤。向此树脂在4mL NMP的悬浮液中依次加入189mg的N-Fmoc-甲基半胱氨酸(4eq,0.528mmol),0.185mL的DIEA(8eq,1.056mmol),71mg的HOBt(4eq,0.528mmol)和200mg的HBTU(4eq,0.528mmol)。将此混合物室温下旋转过夜并排干。将此偶联步骤重复3小时。然后将此树脂用DMF(两次),甲醇(一次)和1∶1 DMF/二氯甲烷(两次),甲醇(一次)和二氯甲烷(三次)依次洗涤,并真空干燥。
将100mg此树脂在2mL of 20%的哌啶DMF溶液中的悬浮液室温下旋转5分钟,并排于。在20分钟内重复此步骤。将此树脂用DMF(两次),甲醇(一次),二氯甲烷(两次),甲醇(一次)和NMP(两次)洗涤。向此树脂在2mL的NMP中的悬浮液中,连续加入38mg的4-氨基-3-氯苯甲酸(4eq,0.2mmol),0.140mL的DIEA(8eq,0.4mmol),27mg的HOBt(4eq,0.2mmol)和76mg的HBTU(4eq,0.4mmol)。将此混合物室温下旋转过夜并排干。然后将此树脂用DMF(两次),甲醇(一次)和1∶1 DMF/二氯甲烷(两次),甲醇(一次)和二氯甲烷(三次)依次洗涤,并真空干燥。然后将此树脂用2mL的95%TFA水溶液处理1小时。将此混悬液过滤,并将此滤液真空浓缩并通过制备HPLC纯化得到标题化合物(20i)。
制备3-({1-[2-(3,5-二氯-4-羟基苯甲酰基氨基)-4-甲磺酰基-丁酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(20p)
按照制备20i的方法用N-Fmoc-甲硫氨酸作为第一组份偶联树脂3而3,5二氯-4-羟基苯甲酸作为第二组份制备化合物20p。
制备3-[(1-{2-[(异喹啉-1-羰基}-氨基]-3-甲磺酰基-丙酰基}-吡咯烷-2-羰基}-氨基]4-氧代-丁酸(20r)
用B.M.Trost和D.P.Curran,Tetrahedron Lett..22,pp.1287-190(1981)的方法,将N-Fmoc甲基半胱氨酸氧化为相应的砜。向0.714g(2mmol)的N-Fmoc甲基半胱氨酸在24mL的1∶1甲醇和水的、在0℃下搅拌的溶液中,加入3.68g(3eq,6mmol)的OxoneTM。将此混合物室温下搅拌48小时,用水稀释,用6N盐酸酸化至pH2并用三批100mL的乙酸乙酯萃取。将合并的有机萃取物干燥(硫酸镁)并真空浓缩得到0.700g(89%收率)的砜:1H NMR(DMSO-d6,500MHz)δ 2.97(s,3H),3.49-3.59(m,2H),4.25(m,1H),4.30-4.38(m,2H),4.46(m,1H),7.33(t,2H),7.42(t,2H,),7.70-8.00(m,4H);C19H19NO6S准确的质量理论值m/e 389.09,实测值m/e 390.2。
将0.250mmol的树脂3在10mL的20%哌啶DMF溶液中的悬浮液室温下旋转5分钟并将此混合物排干。将此方法重复20分钟。将此树脂用DMF(两次),甲醇(一次),二氯甲烷(两次),甲醇(一次)和NMP(两次)依次洗涤。向此树脂在6mL的NMP悬浮液中依次加入200mg的N-Fmoc-甲基半胱氨酸砜(4eq,0.50mmol),0.175mL的DIEA(8eq,1.00mmol),70mg的HOBt(4eq,0.50mmol)和188mg的HBTU(4eq,0.50mmol)。将此混合物室温下旋转过夜并排干。将此偶联方法重复3小时。将此树脂用DMF(两次),甲醇(一次),1∶1DMF/二氯甲烷(两次),甲醇(一次)和二氯甲烷(三次)依次洗涤,并真空干燥。
将150mg的此树脂在4mL的20%哌啶的DMF溶液中的悬浮液室温下旋转5分钟并排干。将此步骤重复20分钟。将此树脂用DMF(两次),甲醇(一次),二氯甲烷(两次),甲醇(一次)和NMP(两次)依次洗涤。向此树脂在3mL的NMP的悬浮液中,依次加入52mg的1-异喹啉甲酸(4eq,0.3mmol),0.104mL的DIEA(8eq,0.6mmol),37mg的HOBt(4eq,0.3mmol)和104mg的HBTU(4eq,0.3mmol)。将此混合物室温下旋转过夜并排干。将此树脂用DMF(两次),甲醇(一次)和1∶1 DMF/二氯甲烷(两次),甲醇(一次)和二氯甲烷(三次)依次洗涤,并真空干燥。然后,将此树脂用2mL的95%TFA水溶液处理1小时。将此悬浮液过滤,真空浓缩滤液并通过制备HPLC纯化,得到标题化合物(20r)。
制备3-({1-[2-(3,5-二氯-4-羟基苯甲酰基氨基)-3-甲磺酰基-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(20s)
制备类似物23的方法
按照化合物7所述方法(方案Ⅱ)制备化合物23a-23i,不同的是在步骤2中用适当的Fmoc-氨基酸代替Fmoc脯氨酸(方案Ⅵ)。
制备3-({2-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-4-甲基-3,4-二氢-2H-吡唑-3-羰基}-氨基)-4-氧代-丁酸(23g)
按照化合物7描述的方法制备化合物23g,不同的是在步骤2中用4-甲基-4,5-二氢-吡唑-1,5-二甲酸1-(9H-芴-9-基甲基)酯代替Fmoc-脯氨酸(方案Ⅱ)。
制备4-甲基-4,5-二氢-吡唑-1,5-二甲酸1-(9H-芴-9-基甲基)酯:
向650mg(2mmol)的(10,10-二甲基-3,3-二氧代-λ6-硫杂-4-氮杂-三环[5.2.1.00,0]癸-4-基)-(4-甲基-3,4-二氢-2H-吡唑-3-基)-甲酮(J.Am.Chem.Soc.,119,pp.8379-8380(1997))在6mL水和14mLTHF的、在0℃搅拌的溶液中,加入420mg(10mmol,5eq)的氢氧化锂。将此混合物在0℃下搅拌2小时并在室温下搅拌30分钟,用20mL水稀释,并用乙醚(20mL)洗涤,然后将溶液的pH调节至9并加入519mg(2mmol,1eq)的Fmoc-Cl在3mL二噁烷中的溶液。将此混合物室温下搅拌过夜,用乙醚洗涤,酸化至pH2-3并用3批40-mL乙酸乙酯洗涤。将此合并的有机萃取物用盐水洗涤,干燥(硫酸镁)并真空浓缩得到690mg(98%收率)的无色泡沫,经鉴定为标题化合物。1HNMR(DMSO-d6,500MHz)δ1.2(d,3H),3.2(m,1H),4.2-4.6(m,3H),7.1(s,1H),7.2-7.5(m,5H),7.7-8.0(m,4H)。C20H18N2O4准确的质量理论值m/e 350.13,实测值m/e 351.3。
制备3-({1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-4-甲氧基-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(23i)
按照化合物7所述方法制备化合物23i,不同的是在步骤2中用N-Fmoc-4-甲氧基脯氨酸代替Fmoc-脯氨酸(方案Ⅱ)。
制备N-Fmoc-4-甲氧基脯氨酸:
向在0℃下搅拌的、735mg(3mmol)的N-Boc-4-羟基脯氨酸甲基酯的20mL THF溶液中加入79mg(1.1eq,3.3mmol)的60%存在于矿物油中的氢化钠。将此混合物在0℃搅拌1小时,并加入碘代甲烷(0.56mL,3eq,9mmol)。将此混合物室温下搅拌过夜,通过加入饱和氯化铵溶液停止反应,用水稀释并用三批80mL的乙酸乙酯萃取。用盐水洗涤合并的有机萃取物,干燥(硫酸镁)并真空浓缩得到淡黄色油状物。将此油状物在9mL的甲醇和3mL水中回收,并加入378mg(3eq,9mmol)的氢氧化锂。将此混合物室温下搅拌过夜,用水稀释,酸化至pH3并用3批80mL的乙酸乙酯萃取。用盐水洗涤合并的有机萃取物,干燥(MgSO4)并真空浓缩。将此残余的油状物在10mL的TFA中回收并将此溶液在室温下搅拌2小时并真空浓缩。将此残余的油状物用6mL的10%碳酸钠水溶液和3mL二噁烷稀释,并加入氯甲酸9-芴基甲酯(779mg,1eq,3mmol)的5mL二噁烷溶液。将此混合物室温下搅拌过夜,用水稀释,酸化至pH3并用3批80mL的乙酸乙酯萃取。用盐水洗涤合并的有机萃取物,干燥(MgSO4)并真空浓缩得到油状物,将其用硅胶进行柱色谱,用二氯甲烷/甲醇20∶1洗脱纯化,得到600mg(55%)的N-Fmoc-4-甲氧基脯氨酸:C21H21NO5准确的质量理论值m/e367.14,实测值m/e 368.4。
向0.125mmol的树脂2中加入4mL的20%哌啶的DMF溶液。将此混合物室温下旋转5分钟并排干。在20分钟内重复此方法。将此树脂用DMF(两次),甲醇(一次),二氯甲烷(两次),甲醇(一次)和NMP(两次)依次洗涤。向此树脂的4mL NMP悬浮液中依次加入184mg的N-Fmoc-4-甲氧基脯氨酸(4eq,0.50mmol),0.175mL的DIEA(8eq,1.00mmol),70mg HOBt(4eq,0.50mmol)和188mg的HBTU(4eq,0.50mmol)。将此混合物室温下旋转过夜并排干。在3小时内重复此偶联步骤。将此树脂用DMF(两次),甲醇(一次),1∶1 DMF/二氯甲烷(两次),甲醇(一次)和二氯甲烷(三次)依次洗涤,并真空干燥。
向此树脂中加入4mL的20%哌啶的DMF溶液。将此混合物室温下旋转5分钟并排干。将此步骤在20分钟内重复。将此树脂用DMF(两次),甲醇(一次),二氯甲烷(两次),甲醇(一次)和NMP(两次)依次洗涤。向此树脂的4mL NMP悬浮液中依次加入156mg的N-Fmoc-丙氨酸(4eq,0.50mmol),0.175mL的DIEA(8eq,1.00mmol),70mg的HOBt(4eq,0.50mmol)和188mg的HBTU(4eq,0.50mmol)。将此混合物室温下旋转过夜并排干。将此偶联步骤重复3小时。将此树脂用DMF(两次),甲醇(一次),1∶1 DMF/二氯甲烷(两次),甲醇(一次)和二氯甲烷(三次)依次洗涤,并真空干燥。
向此树脂中加入4mL的20%哌啶的DMF溶液。将此混合物室温下旋转5分钟并排干。将此步骤在20分钟内重复。将此树脂用DMF(两次),甲醇(一次),二氯甲烷(两次),甲醇(一次)和NMP(两次)依次洗涤。向此树脂的4mL NMP悬浮液中依次加入80mg的4-氨基-3-氯苯甲酸(4eq,0.50mmol),0.175mL的DTEA(8eq,1.00mmol),70mg的HOBt(4eq,0.50mmol)和188mg的HBTU(4eq,0.50mmol)。将此混合物室温下旋转过夜并排干。将此树脂用DMF(两次),甲醇(一次),1∶1 DMF/二氯甲烷(两次),甲醇(一次)和二氯甲烷(三次)依次洗涤,并真空干燥。
制备类似物24a-e的方法
按照化合物5所述方法(方案Ⅰ)制备化合物24a-24e,不同的是用Fmoc-氮杂环丁烷甲酸或反式-2-苯基-Fmoc-氮杂环丁烷甲酸代替步骤2中的Fmoc-脯氨酸。
制备类似物25的方法
按照化合物5和7所述方法(方案Ⅰ和方案Ⅱ)制备化合物25a-25e,不同的是在步骤2中用Fmoc-2(S)-哌啶酸代替Fmoc-脯氨酸并在步骤3中偶联Fmoc-缬氨酸或Fmoc-丙氨酸或Fmoc-叔亮氨酸。
制备26a-h的方法
制备类似物27的方法
按照化合物7所述方法(方案Ⅱ)制备化合物27a-27n,不同的是在步骤2中用Fmoc-4,4-二氟脯氨酸代替Fmoc-脯氨酸。
制备N-Boc-4,4-二氟脯氨酸甲酯:在-78℃搅拌下,向9.63mL(7.2mmol)的草酰氯在10.6mL二氯甲烷的溶液中加入0.94mL(13.2mmol)的存在于15ml二氯甲烷中的二甲基亚砜溶液。将此溶液在-78℃下搅拌30分钟。然后滴加1.47g(6mmol)的N-Boc-4-羟基脯氨酸甲酯的19mL二氯甲烷溶液。将此混合物在-78℃搅拌1.5小时,并加入3.34mL(24mmol)的三乙胺。让此溶液升温至室温并搅拌过夜。然后,用100mL的二氯甲烷稀释,用100mL水,100mL的1N HCl和100mL盐水依次洗涤,干燥(MgSO4)并真空浓缩。将此残余物通过柱色谱在硅胶上(用乙酸乙酯/己烷,1∶3洗脱)纯化,得到1.294g(89%收率)的N-Boc-4-氧代-脯氨酸甲酯。1H NMR(500MHz,CDCl3)δ1.45(m,9H),2.60(m,1H),2.95(m,1H),3.75(m,3H),3.90(m,2H),4.80(m,25 1H)。
向808mg(3.33mmol)N-Boc-4-氧代脯氨酸甲酯的13mL二氯甲烷溶液中,在0℃搅拌下加入0.88mL(7.19mmol,2.2eq)的DAST。将此混合物在℃下搅拌2小时,室温下搅拌16小时,并倒入冰水中。将此混合物室温下搅拌2小时。分离有机相,用水洗涤,干燥(硫酸镁)并真空浓缩。将此残余物通过柱色谱在硅胶上(用乙酸乙酯-己烷,1∶8)纯化,得到754mg(79%收率)的二氟代衍生物,为淡黄色油状物。1HNMR(500MHz,CDCl3)δ1.50(M,9H),2.45(m,1H),2.70(m,1H),3.75(m,3H),3.80(m,2H),4.50(m,1H)。
制备N-Fmoc-4,4-二氟脯氨酸:
向754mg(2.85mmol)的N-Boc-4,4-二氟脯氨酸甲酯的5mL的THF溶液中,在0℃搅拌下加入179mg(4.27mmol)的氢氧化锂5mL水溶液。将此溶液在0℃下搅拌3小时,室温下搅拌1小时,用水稀释,用乙醚萃取,酸化至pH2-3并用2批30mL乙酸乙酯萃取。用盐水洗涤合并的有机萃取物,干燥(MgSO4)并真空浓缩得到652mg(91%)的酸,为淡黄色固体。
将652mg(2mmol)的N-Boc-4,4二氟脯氨酸的10mL的1∶1 TFA/二氯甲烷溶液,在0℃下搅拌45分钟并真空浓缩。将此残余物在3mL的二噁烷中回收并加入5ml 10%碳酸钠水溶液,然后加入675mg(1eq)的Fmoc-Cl的5mL二噁烷溶液。将此混合物室温下搅拌16小时,用20mL水稀释,并用2批20mL乙醚萃取,酸化至pH2并用3批30mL乙酸乙酯萃取。合并的有机萃取物用50mL盐水洗涤,干燥(MgSO4)并真空浓缩。将此残余物通过柱色谱在硅胶上(用二氯甲烷/甲醇10∶1洗脱)纯化,得到850mg(88%)的N-Fmoc-4,4-二氟脯氨酸,为褐色固体。1H NMR(500MHz,CDCl3)δ2.55(m,1H),2.95(m,1H),3.80(m,2H),4.20(m,1H),4.30(m,2H),4.55(m,1H),7.32(m,2H),7.45(m,2H),7.70(m,2H),7.90(m,2H)。C20H17F2NO4的准确理论质量m/e373.11,实测值m/e 374.4。
按照化合物5和7所述方法(方案Ⅰ和方案Ⅱ)制备化合物28a-28c,不同的是用Fmoc-二甲基硫代脯氨酸代替步骤2中的Fmoc-脯氨酸。
制备实施方案A式Ⅰ化合物的一般方法(方案Ⅶ-Ⅷ)
实施方案A式Ⅰ的化合物,其中R4=H而一个R5=H:
类似物29的制备方法
类似物32的制备方法
按照化合物5所述方法(方案Ⅰ)制备化合物32a-32e,不同的是用2-(3-叔丁氧羰基氨基-2-氧代吡咯烷-1-基)-4-甲基-戊酸(30)(Neosystem商品目录号BB02101)代替步骤2中的Fmoc-脯氨酸,接着进行步骤4(方案Ⅶ)。
R2和R3与它们连接的原子一起形成5元环的实施方案A式Ⅰ的化合物
其中X=N-CH3的实施方案A式Ⅰ的化合物
制备3-({1-[N-(异喹啉-1-羰基)-N-甲基-肼基羰基}-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(34)
将0.250mmol树脂3(方案Ⅷ)在10mL 20%哌啶的DMF溶液中的悬浮液室温下旋转5分钟并排干。将此方法重复20分钟。将此树脂用DMF(两次),甲醇(一次),1∶1 DMF/二氯甲烷(两次),甲醇(一次)和二氯甲烷(三次)依次洗涤并简单干燥。向此树脂中加入5mL的干燥二氯甲烷,0.128mL的DIEA(3eq,0.75mmol)和0.400mL的20%光气的甲苯溶液(3eq,0.75mmol)。将此混悬液在室温下旋转1.5小时。将此混合物排干并将此树脂用二氯甲烷洗涤几次。向树脂在5mL二氯甲烷的悬浮液中加入0.133mL甲基肼(10eq,2.5mmol)。将此混合物室温下旋转过夜并排干。将此树脂用DMF(两次),甲醇(一次)1∶1DMF/二氯甲烷(两次),甲醇(一次)和二氯甲烷(三次)依次洗涤,并真空干燥。
向存在于3mL NMP中的0.075mmol树脂中依次加入52mg的1-异喹啉甲酸(4eq,0.3mmol),0.19mL的DIEA(8eq,0.6mmol),37mg的HOBt(4eq,0.3mmol)和104mg的HBTU(4eq,0.3mmol)。将此混合物室温下旋转过夜并排干。将此树脂用DMF(两次),甲醇(一次),1∶1 DMF/二氯甲烷(两次),甲醇(一次)和二氯甲烷(三次)依次洗涤,并真空干燥。
将此树脂用4mL 95%TFA的水溶液处理1小时。将此混合物过滤。滤液真空浓缩得到油状物,将其通过HPLC纯化得到标题化合物(34)。
R3=R3=H的实施方案A式Ⅰ的化合物:
3-({1-[(4-氨基-3-氯-苯甲酰基氨基)-乙酰基]吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(G1)
按照化合物7所述制备,不同的是在步骤3中用Fmoc-甘氨酸代替Fmoc-丙氨酸(方案Ⅱ)得到4.3mg的标题化合物。LC-MS(ES+)m/e=425.2(M+H)
3-({1-[(4-氨基-3-氯-苯甲酰基氨基)-乙酰基]-4,4-二氟-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(G2)
按照化合物7和27所述制备,不同的只是用Fmoc-甘氨酸代替步骤3中的Fmoc-丙氨酸(方案Ⅱ)得到10.0mg的标题化合物。LC-MS(ES+)m/e=461.2(M+H)
制备Y=C的实施方案C式Ⅰ和实施方案D式Ⅰ化合物的一般方
法(方案Ⅸ-ⅩⅩⅡ)
所选环系统的来源结构 参考文献
5-叔丁基-3-[2-(9H-芴-9-基甲氧基羰基氨基)-3-甲基丁酰基]-2,3-二氢[1,3,4]噻二唑-2-甲酸乙酯(37)
向搅拌的、聚乙烯基吡啶(2.63g,25mmol)在5-叔丁基-2,3-二氢[1,3,4]噻二唑-2-甲酸乙酯(36)(J.Med.Chem.,34,p.439(1991))(2.16g,10mmol)的干燥甲苯溶液中的悬浮液中,滴加(1-氯羰基-2-甲基-丙基)-氨基甲酸9H-芴-9-基甲酯(4.76g,12.1mmol)的20mL无水甲苯,进行处理。搅拌16小时后,将此悬浮液过滤并用饱和碳酸氢钠水溶液洗涤。分离有机层,用水洗涤,用无水硫酸钠干燥并蒸发得到黄色油状物。通过快速色谱用9/1己烷/乙酸乙酯洗脱纯化,得到2.66g(49%收率)的标题化合物(37),为清澈粘稠油状物。1H NMR(500MHz,CD3OD)δ0.89(d,1.5H),0.93(d,1.5H),1.00(d,1.5H),1.06(d,1.5H),1.22(t,3H),1.28(s,9H),2.12-2.22(m,0.5H),2.32-2.42(m,0.5H),4.18-4.28(m,2H),4.31-4.45(m,2H),4.96-5.01(m,0.5H),5.02-5.10(m,0.5H),5.52(d,0.5H),5.61(d,0.5H),6.10(s,0.5H),6.13(s,0.5H),7.27-7.34(m,2H),7.35-7.42(m,2H),7.56-7.64(m,2H),7.73-7.78(m,2H)。
3-(2-乙酰基氨基-3-甲基丁酰基)-5-叔丁基-2,3-二氢-[1,2,4]噻二唑-2-甲酸乙酯(38)
向化合物(37)(方案Ⅸ)(0.508g,0.94mmol)的CH3CN(10mL)溶液中加入二乙胺(1mL)。将此溶液室温下搅拌2小时,真空除去溶剂并将所得油状物与二氯甲烷(4x)共沸。将粗品油状物溶解于二氯甲烷(5mL)和三乙胺(0.26mL,1.86mmol)并加入乙酰氯(80μl,1.1mmol)。将此溶液在氮气氛下室温搅拌2小时。蒸发溶剂,并将粗品物质溶解于乙酸乙酯中并用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤,并用无水硫酸钠干燥,过滤并蒸发,得到黄色油状物。通过快速柱色谱在硅胶上用己烷/EtOAc(95/5至90/10%)纯化,得到此产物,为黄色油状物(0.301g,89%收率)。1H-NMR(500MHz,CDCl3)δ0.88(dd,3H),0.99(dd,3H),1.16-1.45(m,12H),2.02(s,3H),2.09-2.19(m,0.5H)。2.30-2.40(m,0.5H),4.12-4.29(m,2H),5.20-5.27(m,0.5H),5.30-5.36(m,0.5H),6.60(s,0.5H),6.90(s,0.5H),6.20-6.31(m,1H)。分析HPLC(C18柱),(非对映异构体的混合物)7.77,7.98分钟。LC-MS(ES+)m/e=358.3(M+H)。
3-(2-乙酰基氨基-3-甲基丁酰基)-5-叔丁基-2,3二氢-[1,2,4]噻二唑-2-甲酸(39)
向化合物38(0.301g,0.84mmol)的甲醇(10mL)溶液中加入1N氢氧化钠溶液(1.7mL,1.7mmol)。将此反应液在氮气氛下室温搅拌2小时,蒸发溶剂。并将残余物溶解于乙酸乙酯中并用0.5N硫酸氢钠(2x)和盐水洗涤,并用无水硫酸钠干燥,过滤并蒸发,得到标题化合物,为黄色油状物(0.277g,定量)。
制备2-(苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯(40)
通过改良的Bioorg.Med.Chem.Lett.Vol.2,No.6,pp.613-618,(1992)所述的方法由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯制备化合物40。
向DMSO(27.52g,352mmol)的二氯甲烷(240mL)溶液中,在-78℃加入草酰氯(24.4g,192mmol)。15分钟后,缓慢加入3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯(41.44g,160mmol)的二氯甲烷(100mL)溶液,并将此混合物在-78℃再搅拌1.5小时。加入DIEA(62.0g,480mmol)并让此混合物升温至室温,保持15分钟。将所得溶液用二氯甲烷(300mL)稀释,用0.5N硫酸氢钠(500mL×2),水(300mL×2)和盐水(400mL×2)洗涤。将此有机层用无水硫酸钠干燥,过滤并真空浓缩至体积为200mL。向此溶液中加入苄醇(48g,444mmol),随后加入3埃分子筛(30g)和对甲苯磺酸(0.8g)。将此反应混和物搅拌4天并加入TFA(96mL)。将所得悬浮液搅拌1小时,然后真空蒸发。加入乙酸乙酯(500mL)并将此混合物通过硅藻土板过滤。滤液用饱和碳酸氢钠(500mL×2),水(400mL×2)和盐水(300mL×2)洗涤。有机溶液用无水硫酸钠干燥,过滤和真空蒸发得到90g的淡黄色油状物,将其与己烷(400mL×2)搅拌,由较低层残余物中得到31g的粗品,用乙酸乙酯/己烷(4/96至22/78)进行色谱,得到6.97g的反-2-(苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯(较高Rf),4.53g的顺式非对映异构体和12.97g的非对映异构体混合物(总收率53%)。
1H-NMR(500MHz,CDCl3)反式非对映异构体:δ2.41-2.45(m,H),3.02-3.07(m,H),4.28(br,H),4.50-4.80(m,3H),4.80-5.15(m,2H),5.24-5.32(m,2H),5.48(s,H),5.88-6.00(m,H),7.31-7.56(m,5H);顺式非对映异构体:δ2.49-2.53(m,H),2.83-2.89(m,H),4.57-4.65(m,4H),4.87-4.90(m,H),5.12-5.30(m,3H),5.52-5.53(d,H),5.88-6.00(m,H),7.31-7.39(m,5H);分析HPLC保留时间:反式非对映异构体10.49min和顺式非对映异构体10.37min;LC-MS:m/z 292(M+H+)。
3-(2-乙酰基氨基-3-甲基丁酰基)-5-叔丁基-2,3二氢-[1,2,4]噻二唑-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(41)
向(2-苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯(40)(0.385g,1.32mmol)的DMF(2ml)和二氯甲烷(2ml)溶液中,加入DMBA(0.456g,2.92mmol)和Pd(PPh3)4(0.136g,0.12mmol)并将此溶液室温下搅拌15分钟。加入(39)的二氯甲烷(4.5ml)和DMF(0.5ml)溶液,随后加入HOBt(0.168g,1.24mmol)和EDC(0.256g,1.33mmo1)。在氮气氛下将此反应室温下搅拌18小时。蒸发溶剂。将此粗品溶解于EtOAc并用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤,并用无水硫酸钠干燥,过滤并蒸发得到黄色固体。通过快速柱色谱纯化得到标题化合物(41),为非对映异构体的混合物(374mg,88%收率)。1H-NMR(500MHz,CDCl3)δ0.75-1.05(m,6H),1.19-1.34(m,9H),1.93-2.08(m,3H),2.19-2.50(m,2H),2.80-3.03(m,1H),4.56-4.93(m,3H),5.02-5.20(m,1H)5.46-5.56(m,1H),5.95-6.16(m,2H),6.86-6.95(m,1H),7.20-7.43(m,5H)。分析HPLC(C18柱),(非对映异构体的混合物)8.58分钟。LC-MS(ES+)m/e=519.2(M+H)。
制备3-{[3-(2-乙酰基氨基-3-甲基-丁酰基)5-叔丁基-2,3-二氢-[1,3,4]噻二唑-2-羰基]-氨基}-4-氧代-丁酸(42)
按照方法A(见方案ⅩⅩⅢ)将45mg(0.087mmol)41的样品水解得到17mg(45%收率)的标题化合物。分析HPLC(C18柱):5.15分钟。LC-MS(ES+)m/e=429.3(M+H)
5-叔丁基-3-[2-(4-甲氧基-苯甲酰基氨基)-3-甲基丁酰基]-2,3-二氢-[1,3,4]噻二唑-2-甲酸乙酯(43)
按照化合物38报告的方法用茴香酰氯制备得到216mg(50%)的标题化合物,为无定型固体。1H NMR(500MHz,CDCl3)δ0.92(d,1.5H),0.98(d,1.5H),1.03(d,1.5H),1.07(d,1.5H),1.21(t,3H),1.28(s,(H),2.21-2.28(m,0.5H),2.41-2.48(m,0.5H),3.83(s,-4H),4.15-4.28(m,2H),5.41-5.46(m,0.5H),5.48-5.53(m,0.5H),6.08(s,0.5H),6.13(s,0.5H),6.75(d,0.5H),6.85(d,0.5H),6.91(d,2H),7.59(d,2H)。
5-叔丁基-3-[2-(4-甲氧基-苯甲酰基氨基)-3-甲基丁酰基]-2,3-二氢-[1,3,4]噻二唑-2-甲酸(44)
按照化合物39描述的方法制得180mg(定量)的标题化合物,为白色固体。1H NMR(500MHz,CDCl3)δ0.92(d,1.5H),0.96(d,1.5H),1.03(d,1.5H),1.07(d,1.5H),2.22-2.30(m,0.5H),2.37-2.45(m,0.5H),3.83(s,1.5H)3.84(s,1.5H)5.41-5.48(m,1H),6.14(s,0.5H),6.15(s,0.5H),6.87-6.95(m,2H),7.75-7.83(m,3H)。
5-叔丁基-3-[2-(4-甲氧基-苯甲酰基氨基)-3-甲基-丁酰基]-2,3-二氢-[1,3,4]噻二唑-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(45a和45b)
按照化合物41所述的方法制备得到粗品标题化合物,为4个非对映异构体。将此粗品通过快速色谱纯化,用二氯甲烷至二氯甲烷/乙酸乙酯(6/4)的梯度洗脱,得到31mg的较高Rf组份,为单一非对映异构体(45a)。分析HPLC(Microsorb C18柱)19.87分钟。1H NMR(500MHz,CDCl3)(单一非对映异构体)δ1.04(d,3H),1.14(d,3H),1.28(s,9H),2.77(d,0.5H),2.81(d,0.5H),2.90(d,0.5H),2.95(d,0.5H),3.84(s,3H),4.44-4.49(m,1H),4.53(d,1H),4.85(d,1H),5.02-5.08(m,1H),6.37(s,1H),6.41(d,1H),6.93(d,2H),7.26-7.40(M,5H),7.75(d,2H),7.92-7.96(m,1H)。
较低Rf馏份含185mg的固体,为3∶1∶2的非对映异构体的混合物(45b)。分析HPLC:Microsorb C18柱,19.00,19.26,20.02mins,1H NMR(500MHz,CDCl3)(3种非对映异构体的3∶1∶2混合物)δ0.89(d,2.25H),0.98(d,0.75H),1.02(d,0.5H),1.03(d,1.5H),1.08(d,0.25H),1.10(d,0.75H),1.16(s,0.75H),1.17(s,2.25H),1.23(s,0.375H),1.24(s,1.125H),1.28(s,1.125H),1.29(s,3.375H),2.12-2.18(m,0.33H),2.32-2.42(m,0.67H),2.43-2.51(m,0.5H),2.61-2.67(m,0.5H),2.84-2.92(m,0.5H),2.96-3.07(m,0.5H),3.8S(s,3H),4.58-4.71(m,2H),4.81(d,0.16H)4.86(d,0.32H)4.91(d,0.52H),5.09-5.13(m,0.33H)5.14-5.18(m,0.67H),5.35(dd,1H),5.46(s,0.16H)5.53(d,0.32H)5.58-5.62(d,0.52H),6.17(s,0.52H),6.20(s,0.16H),6.34(s,0.32H),6.50(d,0.32H),6.62(d,0.16H),6.67(d,0.52H),6.86(d,0.33H),6.91(d,0.67H),6.94(d,1.0H),7.24-7.43(m,5H),7.61(d,1H),7.70(d,0.33H),7.71(d,0.67H),7.76(d,1H)。
制备3-({5-叔丁基-3-[2-(4-甲氧基苯甲酰基氨基)-3-甲基-丁酰基]-2,3-二氢[1,3,4]噻二唑-2-羰基}-氨基)-4-氧代-丁酸(46a)
按照方法B(见方案ⅩⅩⅢ)将30mg 45a样品水解得到8mg(30%收率)的所需产物。分析HPLC(Microsorb C-18柱,乙腈/水,用TFA缓冲液)12.85min,1H NMR(500MHz,CD3OD)δ0.98-1.1(m,6H),1.28(s,9H),2.20-2.31(m,1H),2.40-2.48(m,1H),2.6-2.72(m,1H),3.84(s,3H),4.18-4.26(m,1H),4.56-4.62(m,1H),5.25-5.32(m,1H),6.24-6.28(m,1H),6.98(d,2H),7.85(d,2H)。
制备3-({5-叔丁基-3-[2-(4-甲氧基-苯甲酰基氨基)-3-甲基-丁酰基]-2,3-二氢[1,3,4]噻二唑-2-羰基}-氨基)-4-氧代-丁酸(46b)
按照方法B(见方案ⅩⅩⅢ)将30mg的45b样品(3种非对映异构体的混合物)水解,得到22mg(84%收率)的所需产物,为3∶2的非对映异构体混合物。分析HPLC(Microsorb氰基柱)7.08,7.78分钟。1HNMR(500MHz,CD3OD)δ0.98-1.06(m,4H),1.09-1.12(m,2H),1.29& 1.31(2singlets,9H),2.23-2.30(m,0.5H),2.36-2.55(m,1.5H).,2.62-2.72(m,1H),3.85(s,3H),4.18-4.27(m,1H),4.58-4.65(m,1H),5.27-5.33(m,1H)6.23-6.27(m,1H),7.00(d,2 H),7.70-7.88(m,2H).
1-(2-苄氧基羰基氨基-2-甲基-丙酰基)吡咯烷-2-甲酸叔丁基酯(49)
向脯氨酸-叔丁基酯(47)(2.00g,12mmol)的二氯甲烷(15ml)溶液中,加入N-苄氧羰基-2-甲基丙氨酸(3.05g,13mmol),HOBt(2.36g,17mmol)和EDC(3.43g,18mmol)并将此溶液室温下在氮气氛下搅拌48小时。蒸发溶剂,将此粗品溶解于乙酸乙酯中并用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤,用无水硫酸钠干燥,过滤并蒸发得到白色固体(4.68g,100%)。1H-NMR(500MHz,CDCl3)δ1.20-2.15(m,4H),1.43(s,9H),1.59(d,6H),3.21-3.79(m,2H),4.35(br s,1H),4.82-5.19(m,3H),5.74(br s,1H),7.17-7.49(m,5H)。分析HPLC(C18柱)10.66分钟。LC-MS(ES+)m/e=391.3(M+H)。
1-[2-(4-甲氧基-苯甲酰基氨基)-2-甲基-丙酰基]吡咯烷-2-甲酸叔丁基酯(50)
向化合物49(1.00g,2.56mmol)的甲醇(20ml)溶液中,加入10%Pd/C(200mg)并将此混合物在氢气氛中搅拌2小时。将此混合物过滤通过0.45μm PTFE过滤器过滤并真空除去溶剂得到无色油状物。将此油状物溶解于二氯甲烷(25mL)和DIEA(660μl,3.79mmol)中并加入对茴香酰氯(480mg,2.8mmol)。将此溶液在氮气氛下室温搅拌18小时。真空除去溶剂并将此油状物溶解于乙酸乙酯中。将此有机相用0.5N硫酸氢钠(2x),水,饱和碳酸氢钠(2x)和盐水洗涤。将此有机相用硫酸钠干燥,过滤并蒸发得到白色固体,将其通过快速柱色谱纯化,用二氯甲烷/MeOH(99/1至98/2%)洗脱,得到标题化合物,为白色固体(655mg,65%收率)。1H-NMR(500MHz,CDCl3)δ1.47(s,9H),1.68-2.24(m,5H),1.80(d,6H),3.55-3.68(m,1H),3.72-3.93(m,1H),3.84(s,3H),4.43-4.55(m,1H),6.90(d,2H),7.60(br s,1H),7.77(d,2H)。分析HPLC(C18柱)8.98分钟。
1-[2-(4-甲氧基-苯甲酰基氨基)-2-甲基-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(51)
向化合物50(325mg,0.83mmol)的二噁烷(5mL)溶液中,加入三乙胺(463μl,3.32mmol)和TMS三氟甲磺酸盐(642μl,3.32mmol)并将此溶液在100℃下搅拌5小时,然后在室温下搅拌18小时。用水稀释此反应,用饱和碳酸氢钠调节至pH8,并用乙醚萃取,用硫酸钠干燥,过滤并蒸发得到白色固体(230mg,83%收率),将其直接用于下步反应。
向(2-苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯(40)(1.027g,3.5mmol)的二氯甲烷(20ml)溶液中,加入DMBA(543mg,3.48mmol)和Pd(PPh3)4(280mg,0.24mmol)并将此溶液在氮气氛下室温搅拌20分钟。加入1-[2-(4-甲氧基-苯甲酰基氨基)-2-甲基-丙酰基]-吡咯烷-2-甲酸(818mg,2.45mmol)的二氯甲烷(5ml)溶液,接着加入HOBt(0.534g,3.95mmol)和EDC(738mg,3.84mmol)。将此反应在氮气氛下室温下搅拌18小时。蒸发溶剂,将此粗品溶解于乙酸乙酯或者,并用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤,用无水硫酸钠干燥,过滤并蒸发得到黄色固体。通过快速柱色谱纯化,用乙酸乙酯/己烷(20/80至50/50%)洗脱,得到淡黄色固体产物(760mg,61%收率)。1H NMR(500MHz,CD3OD)δ1.53(d,6H),1.65-1.93(m,3H),1.96-2.14(m,1H),2.60(dd,0.1H),2.77(dd,0.85H),2.94(dd,0.85H),3.04-3.11(m,0.2H),3.42-3.52(m,1H),3.57-3.67(m,1H),3.84(s,3H),4.38-4.76(m,3H)4.84(d,1H),5.64-5.70(m,1H),6.96-7.03 2H)7.23-7.43(m,5H),7.78-7.97(m,2H)。分析HPLC(C18柱)13.32,14.37分钟。LC-MS(ES+)m/e=524.3(M+H)。
制备3-({1-[2-(4-甲氧基-苯甲酰基氨基)-2-甲基-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(52)
按照方法C(见方案ⅩⅩⅢ)将61mg(0.14mmol)化合物51的样品水解,得到30mg(60%收率)的标题化合物:分析HPLC(C18柱)6.79分钟。LC-MS(ES+)m/e=434.3(M+H)。
1-[2-(4-甲氧基-苯甲酰基氨基)-3-甲基丁酰基]-吡咯烷-2-甲酸叔丁基酯(54)
向H-val-pro-otBu·HCl(53)(2.011g,7.44mmol)的二氯甲烷(20ml)悬浮液中,加入DIEA(3.2ml,18.4mmol),随后加入4-甲氧基-苯甲酰基氯(1.26g,7.4mmol)的二氯甲烷(5ml)溶液。将此溶液在氮气氛下室温搅拌1小时,然后浓缩。将所得油状物溶解于乙酸乙酯中并用0.5N硫酸氢钾(2x),饱和碳酸氢钠(2x)和盐水洗涤,然后真空浓缩得到标题化合物,为白色固体(2.814g,94%收率)。1H-NMR(500MHz,CDCl3)δ1.05(dd,6H),1.46(s,9H),1.88-2.29(m,5H),3.65-3.74(m,1H),3.81-3.92(m,1H),3.85(s,3H),4.32-4.42(m,1H),4.81-4.91(m,1H),6.79-6.86(m,1H),6.91(d,2 H),7.78(d,2H)。分析HPLC(氰基柱)10.18分钟。
1-[2-(4-甲氧基-苯甲酰基氨基)-3-甲基丁酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)酰胺(56)
将1.079g(2.67mmol)化合物54样品溶解于15%TFA的二氯甲烷(40mL)溶液中并室温搅拌4小时。溶剂真空浓缩得到化合物55,为白色固体(0.93g,100%),将其用于下步反应。
向化合物40(1.796g,6.17mmol)的二氯甲烷(20ml)溶液中,加入DMBA(1.119g,7.17mmol)和Pd(PPh3)4(0.683g,0.59mmol)并将此溶液室温下搅拌20分钟。加入化合物55(0.928g,2.67mmol)的二氯甲烷(17ml)和DMF(2ml)溶液,随后加入HOBt(0.811g,6.01mmol)和EDC(1.16g,6.04mmol)。将此反应室温下在氮气氛下搅拌18小时。蒸发溶剂,将此粗品溶解于EtOAc中并用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤,用无水硫酸钠干燥,过滤并蒸发得到黄色固体。通过快速色谱用乙酸乙酯/二氯甲烷(10/90至40/60%)洗脱纯化得到标题化合物,为淡黄色固体(910mg,63%收率)。1H-NMR(500MHz,CDCl3)δ0.96(dd,6H),1.84-2.19(m,4H),2.25-2.38(m,1H),2.45(dd,1H),2.80-2.98(m,1H),3.60-3.72(m,1H),3.82-3.95(m,1H),3.86(s,3H),4.26-4.9S(m,6H),5.41(s,0.2H),5.53(d,0.8H),6.67-6.77(m,1H),6.88-6.99(d,2H)
7.22-7.57(m,5H),7.71-7.82(d,2H)。
分析HPLC(氰基柱)(2种非对映异构体的混合物)9.21分钟。LC-MS(ES+) m/e=538.3(M+H)。
3-({1-[2-(4-甲氧基-苯甲酰基氨基)-3-甲基-丁酰基]吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(57)
按照方法A(见方案ⅩⅩⅢ),将125mg(0.23mmol)化合物56的样品水解得到60mg(58%收率)的标题化合物:分析HPLC 5.71分钟。LC-MS(ES+)m/e=448.2(M+H)。
制备4-氨基-3-氯-苯甲酸:
将4-氨基-3-氯苄腈(4.82g,31.58mmol)在6N HCl(140ml)中的悬浮液加热至回流。将沉淀加热溶解得到无色溶液。再进一步加热该溶液出现絮状沉淀。9小时后,将此反应冷却至室温。将所得沉淀过滤,然后溶解于THF中并蒸发溶剂。将此残余物再从甲苯中浓缩得到白色固体(3.18g,59%收率)。1H-NMR(500MHz,CD3OD∶CDCl3 1∶4)δ6.80(d,1H),7.75(dd,1H),7.94(d,1H)。分析HPLC(氰基柱)8.73分钟。
[2-(4-氨基-3-氯-苯甲酰基氨基)-3-甲基丁酰基]吡咯烷-2-甲酸叔丁基酯(58)
向化合物53(1.707g,6.31mmol)的二氯甲烷(25ml)悬浮液中,在0℃下加入DIEA(3.2ml,18.4mmol),随后加入4-氨基-3-氯苯甲酸(1.298g,7.56mmol),HOBt(1.005g,7.44mmol)和EDC(1.456g,7.58mmol)的溶液。将所得混合物在0℃下搅拌15分钟,然后让其升温至室温并搅拌18小时。蒸发溶剂并将所得油状物溶解于乙酸乙酯中,用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤,得到白色固体(2.68g)。经快速色谱用MeOH/二氯甲烷(1/99至2/98%)纯化得到2.04g(76%收率)的化合物58,为白色固体。1H-NMR(500MHz,CDCl3)δ1.05(dd,6H)1.47(s,9H),1.86-2.29(m,5H),3.62-3.78(m,1H)3.78-3.94(m,1H),4.39(dd,1H),4.79-4.89(dd,1H),6.73(d,1H),6.78(d,1H),7.52(dd,1H),7.75(d,1H)。分析HPLC(氰基柱)16.18分钟。LC-MS(ES+) M/e=424.3(M+H)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-3-甲基丁酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(60)
将0.632g(1.49mmol)的化合物59样品溶解于50%TFA的二氯甲烷(20mL)溶液中并将此溶液室温下搅拌2小时。通过从二氯甲烷(3x)中反复浓缩除去残留的TFA,得到产物,为白色固体。
通过化合物56使用的方法让385mg(1.04mmol)样品与化合物40反应。标题化合物(60)分离为黄色固体(265mg,45%收率)。1H-NMR(500MHz,CD3OD)δ0.89-1.12(m,6H),1.72-2.26(m,5H),2.49(dd,0.25H),2.60(dd,0.7H),2.80(dd,0.75H),2.96-3.09(m,0.3H),3.64-3.77(m,1H),3.94-4.10(m,1H),4.20-4.74(m,4H),4.76-4.95(m,1H),5.51(s,0.5H),5.61-5.70(m,1.5H),6.79(dd,1H),7.23-7.43(m,5H),7.48-7.61(m,1.4H),7.68-7.81(m,1H),7.99-8.12(m,0.6H)。
分析HPLC(氰基柱)(2种非对映异构体的混合物)14.90,15.20分钟。LC-MS(ES+)m/e=557.2(M+H)。
3-({1-[2-(4-氨基-3-氯-苯甲酰基氨基)-3-甲基丁酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(61)
按照方法A(见方案ⅩⅩⅢ)将45mg(0.08mmol)的化合物60样品水解得到30mg(80%收率)的标题化合物:1H NMR(500MHz,CD3OD)δ1.06(dd,6H),1.78-2.38(m,5H),2.38-2.86(m,2H),3.62-3.83(m,1H),4.12-4.76(m,4H),7.04-7.21(m,1H),7.58-8.01(m,2H);分析HPLC 8.16分钟。LC-MS(ES+) m/e=467.3(M+H)。
方案ⅩⅢ
1-[2-(4-羟基-3,5-二甲基-苯甲酰基氨基)-3-甲基丁酰基]-吡咯烷-2-甲酸叔丁基酯(63)
向化合物62(由化合物53和Fmoc-Cl制备)(600mg,1.22mmol)的无色DMF(10ml)溶液中,加入二乙胺(3ml)。将此溶液在氮气氛下室温搅拌3小时并蒸发溶剂。将所得油状物溶解于二氯甲烷(8ml)中,并加入3,5-二甲基-4-羟基苯甲酸(0.302g,1.82mmol),HOBt(338mg,2.5mmol)和EDC(0.456g,2.43mmol),并将此溶液在氮气氛下室温搅拌18小时。溶剂真空浓缩并将所得油状物溶解于乙酸乙酯中,用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤,得到粗品,为白色固体(0.80g)。快速色谱使用MeOH/二氯甲烷(1/99至2/98%)洗脱,得到380mg(75%收率)的白色固体。1H-NMR(500MHz,CDCl3)δ1.06(dd,6H),1.47(s,9H),1.90-2.32(m,5H)2.24(s,6H),3.65-3.75(m,1H),3.84-3.92(m,1H),4.36-4.42(m,1H),4.82-4.88(m,1H),5.53-5.61(m,1H),6.77-6.85(m,1H),7.42(s,2H)。分析HPLC(氰基柱)17.53分钟。LC-MS(ES+) m/e=419.3(M+H)。
1-[2-(4-羟基-3,5-二甲基-苯甲酰基氨基)-3-甲基丁酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(64)
按照制备化合物56的方法由化合物63和化合物40制得标题化合物(64),为淡黄色固体(352mg,72%收率)。1H-NMR(500MHz,CD3OD)δ0.83-1.28(m,6H),1.66-2.37(m,3H),2.23(s,6H),2.48-2.54(m,0.2H),2.61(ddd,0.8H),2.72(ddd,0.9H),3.01-3.09(m,1H),3.66-3.76(m,1H),3.9 5-4.07(m,1H),4.48-4.73(m,3H),4.75-4.92(m,1H),5.45-15.48(m,0.1H),5.61-5.64(m,0.1H),5.64-5.70(m,0.8H),7.21-7.62(m,6H),7.88-8.04(m,1H)。分析HPLC(氰基柱),(2种非对映异构体的混合物)17.73分钟。LC-MS(ES+)m/e=552.3(M+H).
3-({1-[2-(4-羟基-3,5-二甲基-苯甲酰基氨基)-3-甲基-丁酰基]-吡咯烷-2-羰基}-氨基)-4-氧代丁酸(65)
按照方法A(见方案ⅩⅩⅢ)将160mg(0.29mmol)的化合物64样品水解13.1mg(10%收率)的标题化合物:分析HPLC(氰基柱)10.28分钟。LC-MS(ES+) m/e=462.2(M+H).
1-[2-(2-9H-芴-9-基-乙酰基氨基)-3,3-二甲基丁酰基]-吡咯烷-2-甲酸叔丁基酯(66)
向H-pro-OtBu(53)(1.033g,6.0mmol,Ⅱ,方案5)的二氯甲烷(20ml)和DMF(5ml)溶液中,加入Fmoc-tLeu-OH(2.337g,6.60mmol,Ⅰ,Scheme,5),HOBt(1.63g 12.1mmol)和EDC(2.30g,12.0mmol)并将此溶液在氮气氛下室温搅拌18小时。真空除去溶剂,并将此残余物溶解于乙酸乙酯中,并用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤。将此有机层用无水硫酸钠干燥并蒸发得到淡黄色固体(3.65g)。进行快速色谱用EtOAc/己烷(10/90至20/80%)洗脱,得到标题化合物(66)(2.25g,74%收率)。1H-NMR(500MHz,CDCl3)δ1.09(s,9H),1.47(s,9H),1.79-2.28(m,3H),3.62-3.72(m,1H),3.76-3.83(m,1H),4.18-4.43(m,4H),5.48-5.67(m,1H),7.28-7.44(m,4H),7.55-7.64(m,2H),7.72-7.82(m,2H)。分析HPLC(氰基柱)11.95分钟。LC-MS(ES+) m/e=507.3(M+H)。
1-[2-(4-甲氧基-苯甲酰基氨基)-3,3-二甲基-丁酰基]吡咯烷-2-甲酸叔丁基酯(67)
向化合物66(0.503g,0.99mmol)的DMF(8ml)溶液中,加入二乙胺(2.5ml)并将此溶液室温下搅拌1小时并蒸发溶剂。将所得残余物从二氯甲烷(3x)中反复浓缩。将所得油状物溶解于二氯甲烷(9ml)并加入DIEA(260μl,1.49mmol)和4-甲氧基-苯甲酰基氯(190mg,1.05mmol)。将此溶液在氮气氛下搅拌18小时,并将溶剂真空浓缩。将此残余物溶解于EtOAc中并用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤,然后用无水硫酸钠干燥并蒸发得到白色固体(0.529g)。进行快速色谱在硅胶上用MeOH/二氯甲烷(1/99至2/98%)洗脱,得到标题化合物(2.25g,74%收率)。1H NMR(500MHz,CD3OD)δ1.01(s,1.4H),1.11(s,7.6H),1.73-2.25(m,4H),2.47-2.77(m,1H),2.81(dd,0.7H),2.91-3.11(m,0.3H),3.61-4.03(m,3H),3.84(s,3H),4.2.9-4.4.9(m,1H),4.49-5.00(m,5H),5.46(s,0.15H),5.58-5.73(m,0.85H),6.94-7.04(m,2H),7.27-7.41(m,4H),7.61-7.73(m,1H),7.74-7.84(m,2H)。分析HPLC(氰基柱)13.10分钟。
1-[2-(4-甲氧基-苯甲酰基氨基)-3,3-二甲基-丁酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(68)
向化合物67(0.909,1.74mmol)的二氯甲烷(25ml)溶液中,加入2,6-二甲基吡啶(2.1ml,18.0mmol)和TMS三氟甲磺酸盐(2.3ml,11.9mmol),并将此反应在氮气氛下室温搅拌1.5小时。将所得混合物用二氯甲烷稀释,用10%碳酸氢钠(2x)和盐水洗涤,然后用硫酸钠干燥,过滤并蒸发。将此残余物溶解于二氯甲烷,然后用DIEA(0.6ml,3.5mmol)和4-甲氧基苯甲酰氯(0.355g,2.09mmol)处理,并让其在氮气氛下室温搅拌18小时。将此粗品通过快速色谱纯化,用二氯甲烷/MeOH(99/1)洗脱,得到标题化合物(274mg,28%收率)。1H-NMR(500MHz,CD3OD)δ1.01(s,1.4H),1.11(s,7.6H),1.7-2.25(m,4H),2.47-2.77(m,1H),2.81(dd,0.7H),2.91-3.11(m,0.3H),3.61-4.03(m,3H),3.84(s,3H),4.29-4.49(m,1H),4.49-5.00(m,5H),5.46(s,0.15H),5.58-5.73(m,0.85H),6.-94-7.04(m,2H),7.27-7.41(m,4H),7.61-7.73(m,1H),7.74-7.84(m,2H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)17.03,17.39分钟。LC-MS(ES+) m/e=552.3(M+H)。
3-({1-[2-(4-甲氧基-苯甲酰基氨基)-3,3-二甲基-丁酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(69)
按照方法C(见方案ⅩⅩⅢ)将117mg(0.21mmol)的化合物68样品水解得到40mg(41%收率)的标题化合物:分析HPLC7.16分钟。LC-MS(ES+) m/e=462.3(M+H)。
1-(2-叔丁氧羰基氨基-3,3-二甲基-丁酰基)吡咯烷-2-甲酸苄基酯(70)
向H-pro-OBzl·HCl(2.00g,8.66mmol)的二氯甲烷(20ml)悬浮液中,加入DIEA(2.25ml,12.92mmol)得到无色溶液。加入Boc-tLeu-OH(1.95g,9.52mmol),HOBt(1.76g,13.03mmol)和EDC(2.49g,12.95mmol),并将此溶液在氮气氛下室温搅拌18小时。真空除去溶剂,溶解于乙酸乙酯中,并用水,0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤。用无水硫酸钠干燥并蒸发得到标题化合物(3.57g,99%收率)。1H-NMR(500MHz,CDCl3)δ0.99(s,9H),1.40(s,9H),1.88-2.33(m,4H),3.58-3.90(m,2H),4.21-4.35(d,1H),4.53-4.66(m,1H),5.04-5.38(m,3H),7.14-7.42(m,5H)LC-MS(ES+)m/e=419.4(M+H)。
{1-[2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-羰基]-2,2-二甲基丙基}-氨基甲酸叔丁基酯(71)
将871mg(2.08mmol)的化合物70的样品溶解于甲醇(15mL)中并加入10%Pd/c(200mg)。将此悬浮液在氢气氛下搅拌1小时,通过硅藻土板过滤并蒸发溶剂。按照用于制备化合物56的方法将所得残余物与化合物40反应得到889mg(71%收率)的标题化合物(71)。1H-NMR(500MHz,CDCl3)δ0.93(s,9H)1.44(s,9H),1.78-2.18(m,4H),2.29-2.49(m,2H),2.76-3.04(m,1H),3.50-3.70(m,1H),3.70-3.85(m,1H),4.20-4.37(m,1H),4.49-4.78(m,3H),4.78-4.98(m,1H),5.12-5.26(m,1H),5.40-5.59(m,1H),7.10-7.78(m,5H)。分析HPLC(氰基柱)11.17分钟。LC-MS(ES+)m/e=518.3(M+H)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-3,3-二甲基丁酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(72)
将456mg(0.088mmol)的化合物71的二氯甲烷(20mL)溶液用无水TFA(5mL)处理,然后在氮气氛下室温搅拌1小时并蒸发至干。将此残余物从二氯甲烷(3x)中反复浓缩,然后真空干燥。将所得残余物溶解于二氯甲烷(20ml)中,冷却至0℃,然后用DIEA(1.3ml,8eq,2.46mmol)处理,随后用4-氨基-3-氯-苯甲酸(202mg,1.17mmol),HOBt(183mg,1.35mmol)和EDC(279mg,1.45mmol)处理。将所得混合物升温至室温并搅拌18小时。真空除去溶剂并将此残余物溶解于EtOAc中,然后用蒸馏水(3x),0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤。将此有机层用硫酸钠干燥,过滤并蒸发得到残余物,将其通过快速色谱纯化,用二氯甲烷/MeOH(99/1至97/3%)洗脱,得到285mg(57%收率)的标题化合物(72),为黄色固体。
1H-NMR(500MHz,CD3OD)δ0.91-1.24(m,9H),1.70-2.27(m,4H),2.47-2.85(m,1.5H),2.99-3.13(m,0.5H),3.39-3.53(m,0.5H),3.60-3.78(m,1.5H),3.85-4.04(m,1H),4.24-4.47(m,2H),4.53-4.97(m,4H),5.46(s,0.3H),3.88-4.02(m,0.1H),5.60-5.69(m,0.6H),6.80(d,1H),7.22-7.77(m,7H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)15.90,16.23分钟。LC-MS(ES+)m/e=571.2(M+H)。
3-({1-[2-(4-氨基-3-氯-苯甲酰基氨基)-3,3-二甲基丁酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(73)
按照方法A(方案ⅩⅩⅢ)将40mg(0.07mmol)的化合物72样品水解得到25mg(74%收率)的标题化合物:分析HPLC(氰基柱)10.66分钟。LC-MS(ES+) m/e=481.3(M+H)。
{2-[2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-基]-1-甲基-2-氧代-乙基}氨基甲酸叔丁基酯(75)
向化合物40(6.69g,23.0mmol)的无水二氯甲烷溶液中,加入1,3-二甲基巴比土酸(DMBA)(3.97g,25.4mmol)和Pd(PPh3)4(1.12g,0.97mmol)。将此溶液室温下在氮气氛下搅拌15分钟,冷却至0℃,随后加入Boc-ala-pro-OH(BaChem)(5.087g,17.8mmol),HOBt(3.60g,26.7mmol)和EDC(5.12g,26.7mmol)。让所得溶液温热至室温并在氮气氛下搅拌18小时。将溶剂真空浓缩并将此残余物溶解于EtOAc中,然后用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤。将此有机层用无水硫酸钠干燥并蒸发得到桔黄色油状物(12.23g)。在硅胶上进行快速柱色谱,用二氯甲烷/EtOAc(80/20至60/40)洗脱,得到标题化合物75,为黄色固体(7.28g,86%收率)。1H-NMR(500MHz,CD3OD)δ1.19-1.31(m,3H),1.42(s,9H),1.69-2.29(m,4H),2.45-2.67(m,0.9H),2.71-2.86(m,0.5H),2.99-3.10(m,0.6H),3.49-3.84(m,2H),4.24-4.45(m,2.5H),4.57-4.73(m,1.5H),4.76-4.92(m,1H),5.45(s,0.45H),5.63-5-68(m,0.55H),7.25-7.40(m,5H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)15.99,16.33分钟。LC-MS(ES+) m/e=476.3(M+H)。
1-[2-(4-氨基-3-氯-苯甲酰氨基)-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺](76)
将1.899g(3.99mmol)75样品的二氯甲烷(20ml)溶液用无水TFA(5ml)处理,然后在氮气氛下室温搅拌1小时,并蒸发至干。将此残余物从二氯甲烷(3x)中反复浓缩,然后真空干燥。将所得残余物溶解于二氯甲烷(20ml),冷却至0℃,然后用DIEA(5.6ml,8eq,32.1mmol),4-氨基-3-氯-苯甲酸(0.910g,5.3mmol),HOBt(0.824g,6.1mmol)和EDC(1.197g,6.23mmol)处理。将所得混合物升温至室温并搅拌18小时。真空除去溶剂并将此残余物溶解于乙酸乙酯中,然后用蒸馏水(3x),0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤。将此有机层用硫酸钠干燥,过滤并蒸发得到残余物,将其通过快速色谱纯化,用二氯甲烷/MeOH(99/1至97/3%)洗脱。得到标题化合物,为白色固体(1.221g,58%收率)。1H-NMR(500MHz,CD3OD)δ1.15(d,0.25H),1.29-1.60(m,2.75H),2.41-2.54(m,0.5H),2.55-2.70(m,0.5H),2.77(dd,0.5H)3.03(ddd,0.5H),3.59-3.75(m,1H),3.75-3.98(m,1H)4.26-5.01(m,5H),5.41-5.57(m,1H).5.60-5.76(m,0.5H),6.70-6.92(m,0.5H),7.15-7.48(m,5H),7.48-7.68(m,1H),7.68-7.88(m,1H),8.15-8.34(m,1H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)14.44,14.89分钟。LC-MS(ES+)m/e=529.3(M+H)
[1-[2-(4-甲氧基-3,5-二甲基-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺](77)
由化合物75和3,5-二甲基-4-甲氧基苯甲酸按照制备化合物76的方法合成,得到标题化合物(1.18g,44%收率)。1H-NMR(500MHz,CD3OD)δ1.40(m,3H),1.67-2.41(m,4H),2.28(s,6H),2.48(ddd,0.5H),2.62(dd,0.5H),2.78(ddd,0.5H),3.04(ddd,0.5H),3.62-3.94(m,3H),3.71(s,3H),4.21-4.51(m,2H),4.59-4.85(m,4H),5.46(s,0.25H),5.52(s,0.25H),5.63(d,0.4H),5.67(d,0.1H),7.17-7.45(m,5H),7.45-7.65(m,2H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)15.06,15.39分钟。LC-MS(ES+)m/e=538(M+H)
制备4-乙酰基氨基-3-氯苯甲酸
向4-氨基-3-氯-苯甲酸(10.0g,58.3mmol)的无水THF(100mL)溶液中,加入乙酰氯(20.7ml,291.1mmol),并将此溶液室温下搅拌48小时。蒸发溶剂并从己烷中沉淀产物,然后过滤并干燥得到白色固体(11.73g,94%收率)。1H-NMR(500MHz,CD3OD)δ2.28(s,3H),7.92(dd,1H),7.99-8.16(m,2H)。分析HPLC(氰基柱)7.84分钟。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(78)
按照制备化合物76的方法,由化合物75和4-乙酰基氨基-3-氯-苯甲酸制得标题化合物(146mg,19%收率)。1H-NMR(500MHz,CD3OD)δ1.28-1.52(m,3H),1.68-2.38(m,4H),2.20(s,3H),2.41-2.88(m,1.5H),2.96-3.10(m,0.5H),2.96-3.10(m,0.5H),3.43-3.75(m,1H),3.80-3.96(m,1H),4.25-5.00(m,%H),5.42-5.54(m,0.5H),5.63-5.78(m,0.5H),7.13-7.48(m,0 5H),7.79-8.14(m,2.5H),8.56-8.70(m,0.5H)。分析HPLC(cvano柱)(2种非对映异构体的混合物)8.64分钟。LC-MS(ES+) m/e=571.2(M+H)。
1-[2-(3-异丙氧基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(79)
按照制备化合物76的方法,由化合物75和3-异丙氧基苯甲酸制得标题化合物(120mg,58%收率)。1H-NMR(500MHz,CD3OD)δ1.27(d,6H),1.33-1.52(m,3H),1.69-2.31(m,4H),2.49(dd,0.3H),2.63(dd,0.7H),2.78(dd,0.7H),3.03(dd,0.3H),3.43-3.73(m,1H),3.78-3-94(m,1H),4.27-4.47(m,2H),4.47-4.87(m,4H),5.47(s,0.7H),5.53(d,0.3H),5.64(d,0.BH),5.72(d,0.2H),6.98-7.12(m,1H),7.19-7.47(m,9H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)14.54,14.85分钟。
LC-MS(ES+) m/e=538(M+H)。
喹喔啉-2-甲酸{2-[2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-基]-1-甲基-2-氧代-乙基}-酰胺(80)
按照制备化合物76的方法,由化合物75和2-喹喔啉甲酸制得标题化合物(122mg,60%收率)。1H-NMR(500MHz,CD3OD)δ1.12-1.67(m,3H),1.68-2.34(m,4H),2.35-2.70(m,0.85H),2.70-2.95(m,0.75H),3.06(dd,0.4H),3.41-3.49(m,2H),4.18-5.03(m,6H),5.47(d,0.5H),5.55,(d,2H),5.67(dd,1H),5.71(dd,0.3H),7.03-7.53(m,5H),7.80-8.06(m,2H),8.06-8.34(m,2H),9.43-9.48(m,1H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)9.06分钟。LC-MS(ES+) m/e=532.3(M+H)。1-[2-(3-苄氧基-4-甲氧基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(81)
按照制备化合物76的方法,由化合物75和3-苄氧基-4-甲氧基苯甲酸制得标题化合物(142mg,58%收率)。1H-NMR(500MHz,CD3OD)δ1.14(d,0.3H),1.27-1.52(m,2.7H),1.66-2.30(m,4H),2.47(dd,0.4H),2.59(dd,0.6H),2.77(dd,0.6H),3.02(dd,0.4H),3.41-3.72(m,1H),3.72-3.99(m,2H),3.86(s,3H),4.19-4.86(m,SH),4.99-5.15(m,2H),5.45(m,0.8H),5.65(m,1.2H),6.98(dd,1H),7.11-7.63(m,12H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)12.28,12.44分钟。LC-MS(ES+) m/e=616.3(M+H)
4-烯丙氧-3,5-二甲基-苯甲酸
将4-羟基-3,5-二甲基-苯甲酸(3.32g,20mmol),烯丙基溴(7.26g,60mmol),苄基三乙基氯化铵(455mg,2mmol)和碳酸钾(6.9g,50mmol)在DMF(50mL)中的混合物,室温下搅拌16小时。将此混合物用乙酸乙酯(200mL)稀释,用水,盐水洗涤。将此有机层用硫酸钠干燥,过滤并真空蒸发得到5.3g的酯,为油状物。将此酯与氢氧化钠(5g,125mmol)在水/甲醇(50mL/50mL)中回流6小时。将此混合物真空蒸发除去甲醇,并将所得溶液用水(200mL)稀释,用乙酸乙酯/己烷(30mL/70mL)洗涤。将水层在0℃下用浓盐酸酸化至pH2。过滤收集所得沉淀并用水洗涤,高真空干燥得到3.86g(收率94%)的标题化合物。1H-NMR(500MHz,CDCl3)2.33(s,6H),4.35-4.37(m,2H),5.28-5.30(m,H),5.42-5.46(m,H),6.07-6.15(m,H),7.79(s,2H);分析HPLC保留时间:11.28min;LC-MS:m/z=205(M-H+)
1-[2-(4-烯丙氧-3,5-二氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(82)
按照制备化合物76的方法,由化合物75和4-烯丙氧-3,5-二氯-苯甲酸制得标题化合物(208mg,47%收率)。1H-NMR(500MHz,CDCl3)δ1.05-1.58(m,3H),1.68-3.21(m,7H),3.39-3.90(m,3H),4.05-5.01(m,6H),5.22-5.62(m,3H),6.04-6.25(m,1H),6.94-7.63(m,8H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)9.69,9.89分钟。LC-MS(ES+) m/e=604.2(M+H)。
1-[2-(3,5-二氯-4-羟基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(83)
将化合物82的140mg样品(0.23mmol)溶解于二氯甲烷(4mL)中并用DMBA(35.4mg,0.26mmol)和Pd(PPh3)4(32mg,0.028mmol)处理。将此溶液在0℃下搅拌15分钟,升温至室温,保持2小时,然后用二氯甲烷稀释,并用水(2x)和盐水洗涤。溶剂真空浓缩并将此残余物经快速色谱在硅胶上用MeOH/二氯甲烷(1/99至3/97)洗脱纯化,得到标题化合物(93.2mg,71%收率)。1H-NMR(500MHz,CD3OD)δ1.16(d,0.25H),1.28-1.49(m,2.75H),1.63-2.33(m,4H),2.48(dd,0.4H),3.39-3.59(m,0.2H),3.60-3.73(m,0.8H),3.73-3.96(m,1H),4.24-4.48(m,2H),4.57-4.92(m,7H),5.44(s,0.4H),5.50(d,0.4H),5.64(d,0.8H),5.75(d,0.5H),7.16-7.43(m,5H),7.78-7.89(m,1.6H),8.40-8.63(m,0.4H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)11.57,11.82分钟。LC-MS(ES+)m/e=564.1(M+H)
1-(2-苯甲酰基氨基-丙酰基)-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(84)
按照制备化合物76的方法,由化合物75和苯甲酰氯制得标题化合物,无色油状物(8mg,38%收率)。1H-NMR(500MHz,CD3OD)δ1.35-1.54(m,3H),1.72-2.30(m,4H),2.42-2.70(m,1.3H),2.74-2.84(m,0.5H),3.03(dd,0.2H),3.41-3.75(m,2H),3.81-3.96(m,1H),4.22-4.86(m,4H),5.46(s,0.3H),5.51-5.54(m,0.1H),5.66(d,0.5H),5.72(d,0.1H),7.20-7.57(m,7H),7.77-7.89(m,2H),8.42-8.67(m,1H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)15.23,15.67分钟。
异喹啉-1-甲酸{2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-基}-1-甲基-2-氧代-乙基}-酰胺(85)
按照制备化合物76的方法,由化合物75和1-异喹啉甲酸制备,得到标题化合物(732mg,53%收率)。1H-NMR(500MHz,CD3OD)δ1.22-1.56(m,3H),1.70-2.34(m,4H),2.43-2.71(m,0.9H),2.73-2.89(m,0.5H),3.06(ddd,0.6H),3.42-3.81(m,2H),3.,84-4.01(m,1H),4.29-5.00(m,5H),5.47(d,0.65H),5.55(s,0.3H),5.67(d,0.8H),5.72(d,0.25H),7.21-7.43(m,5H),7.49-7.83(m,2.5H),7.88-8.04(m,1.8H),8.45-8.54(m,0.8H),8.97-9.06(m,0.6H)。分析HPLC(2种非对映异构体的混合物)15.71,16.04分钟。LC-MS(ES+) m/e=531.2(M+H)
1-[2-(4-氨基-5-氯-2-甲氧基-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(86)
按照制备化合物76的方法,由化合物75和4-氨基-5-氯-2-甲氧基苯甲酸制得标题化合物(330mg,61%收率)。1H-NMR(500MHz,CD3OD)δ1.22(d,0.25H),1.29-1.50(m,0.75H),1.68-2.36(m,4H),2.38-2.89(m,1.5H),2-94-3.14(m,0.5H),3.37-3.98(m,6H),4.27-4.98(m,6H),5.44-5.50(m,0.4H),5.53-5.56(s,0.1H),5.60-5-75(m,0.5H),6.50(s,1H),7.17-7.45(m,4H),7.73-7.90(m,1H),8.49-8.70(m,1H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)16.39,16.82分钟。LC-MS(ES+) m/e=559.2(M+H)。
1-[2-(4-乙酰基氨基-5-氯-2-甲氧基-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(87)
按照制备化合物76的方法,由化合物75和4-乙酰基氨基-5-氯-2-甲氧基苯甲酸制得标题化合物(364mg,64%收率)。1H-NMR(500MHz,CD3OD)δ1.20-1.27(m,0.25),1.35-1.49(m,0.75H),1.72-2.30(m,4H),2.23(s,3H),2.42-2.58(m,0.6H),2.59-2.68(m,0.5H),2.73-2.86(m,0.7H),2.99-3.11(m,0.7H),3.41-4.07(m,5H),4.29-4.97(m,SH),4.79-5.56(m,0.5H),5.65-5.73(m,0.5H),7.18-7.44(m,4.3H),7.90-8.09(m,2H),8.71-8.85(m,0.7H)。
分析HPLC(氰基柱)(2种非对映异构体的混合物)15.61,16.01分钟。LC-MS(ES+) m/e=601.1(M+H)。
吡啶-2-甲酸{2-[2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-基]-1-甲基-2-氧代-乙基}-酰胺(88)
按照制备化合物76的方法,由化合物75和吡啶-2-甲酸制得标题化合物(233mg,42%收率)。1H-NMR(500MHz,CD3OD)δ1.30-1.59(m,3H),1.68-2.36(m,4H),2.39-2.57(m,0.6H),2.57-2.69(m,0.35H),2.71-2.87(m,0.4H),3.05(dd,0.65H),3.39-3-93(m,3H),4.24-4.99(m,5H),5.49-5.55(m,0.8H),5.63-5.77(m,1.2H),7.17-7.46(m,5H),7.49-7.60(m,1H),7.89-7.99(m,1H),8.03-8.12(m,1H),8.58-8.67(m,1H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)8.63分钟。LC-MS(ES+) m/e=481.3(M+H)。
[1-[2-(4-氨基-3,5-二氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺](89)
按照制备化合物76的方法,由化合物75和3,5-二氯-4-氨基苯甲酸制得标题化合物(162mg,70%收率)。1H-NMR(500MHz,CD3OD)δ1.21-1.58(m,3H),1.58-2.37(m,4H),2.37-3.13(m,2H),3.43-3.74(m,1.5H),3.77-3.94(m,1H),4.28-4.51(m,1.5H),4.50-5.01(m,3H),5.41-5.77(m,1H)7.15-7.49(m,5H),7.66-7.88(m,2H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)8.36分钟。LC-MS(ES+) m/e=563.2(M+H)。
1-[2-(4-甲氧基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(90)
按照制备化合物76的方法,由化合物75和4-甲氧基-苯甲酰氯制得标题化合物(404mg,50%)。1H-NMR(500MHz,CD3OD)δ1.19(d,0.3H),1.29-1.58(m,2.7H),1.58-2.38(m,4H),2.43-2.69(m,1H),2.74-2.86(m,0.6H),2.99-3.11(m,0.4H),3.39-3.75(m,1.5H),3.77-3-94(m,1H),3.84(s,3H),4.29-4.94(m,4.5H),5.45-5.55(m,4.5H),5.63-5.71(m,0.5H),5.73(d,0.1H),6.85-7.09(m,2H),7.19-7.44(m,4H),7.73-7.92(m,2H),8.26-8.44(m,1H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)15.18,15.65分钟。LC-MS(ES+) m/e=510.2(M+H)。
1-{2-[(9-氧代-9H-芴-4-羰基)-氨基]-丙酰基}吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(91)
按照制备化合物76的方法,由化合物75和9-氧代-9H-芴-甲酸制得标题化合物(403mg,44%收率)。1H-NMR(500MHz,CDCl3)δ1.38-1.59(m,3H),1.75-2.37(m,4H),2.43-2.59(m,0.65H),2.59-2.72(m,0.35H),2.79-2.89(m,0.35H),3.01-3.11(m,0.65H),3.68-3.86(m,1H),3.92-4.09(m,1H),4.35-5.03(m,7H),5.42-5.90(m,1H),7.06-8.00(m,12H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)12.30分钟。LC-MS(ES+) m/e=582.1(M+H)
1-[2-(3,5-二氯-4-甲氧基-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(92)
按照制备化合物76的方法,由化合物75和3,5-二氯-4-甲氧基-苯甲酸制得标题化合物(364mg,46%收率)。1H-NMR(500MHz,CD3OD)δ1.17(d,0.25H),1.28-1.53(m,2.75H),1.64-2.33(m,4H),2.39-2.94(m,1.5H),2.94-3.12(m,0.5H),3.41-3.74(m,2H),3.74-4.00(m,1H),3.91(s,3H),4.26-5.02(m,5H),5.42-5.81(m,1H),7.08(d,0.4H),7.21-7.43(m,4.6H),7.53-7.69(m,0.5H),7.85-7.97(m,1.2H)分析HPLC(氰基柱)(2种非对映异构体的混合物)10.79分钟。LC-MS(ES+) m/e=578.2(M+H)
喹啉-6-甲酸{2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-基}-1-甲基-2-氧代-乙基}-酰胺(93)
按照制备化合物76的方法,由化合物75和6-喹啉甲酸制得标题化合物(344mg,71%收率)。1H-NMR(500MHz,CD3OD)δ1.11-1.58(m,3H),1.69-2.40(m,4H),2.42-3.15(m,2H),3.80-4.01(m,1H),4.29-4.99(m,5H),5.44-5.54(m,0.5H),5.63-5.73(d,0.4H),5.73-5.79(d,0.1H),7.18-7.43(m,5H),7.56-7.67(m,1H),8.08(d,1H),8.13-8.25(m,1H),8.40-8.56(m,2H),8.88-8.99(m,1H)。分析HPLC(氰基柱)(2种非对映异构体的混合物)10.27,10.50分钟。LC-MS(ES+) m/e=531.2(M+H)。
1-(2-苄氧基羰基氨基-丙酰基)-吡咯烷-2-甲酸叔丁基酯(95)
按照Pierre Chevallet,Patrick Garrouste,BarbaraMalawaska & Jean Martinez在Tetrahedron Letters,Vol.34,pp.7409-7412,(1993)中描述的方法制备。在55℃下Cbz-ala-pro-OH(10.0g,31.2mmol),叔丁基溴(180g,1.31mol),苄基三乙基氯化铵(7.11g,31.2mmol)和碳酸钾(180g,1.30mol)在N,N-二甲基乙酰胺(DMA)(225mL)中的混合物搅拌24小时。将此反应混和物冷却至室温并用1升冰水稀释,用乙酸乙酯(200mL×3)萃取。将此有机层用无水硫酸钠干燥,过滤并真空蒸发得到14g的油状物,将其通过快速色谱用己烷/乙酸乙酯(95/5至50/50)洗脱纯化,得到11.73g(收率99.7%)的标题化合物,为清澈的油状物。1H-NMR(500MHz,CDCl3):δ1.25-1.50(m,12H),1.85-2.25(m,4H),3.42-3.70(m,2H),4.25-4.57(m,2H),5.07-5.11(m,2H),5.69(d,H),7.28-7.38(m,5H);分析HPLC保留时间:11.07min;LC-MS:m/z=377(M+H+)。96a,X=Cl,Y=NH2,Z=H96b,X=Cl,Y=AcNH,Z=H96c,X=Cl,Y=AcNH,Z=CH3O97a,X=Cl,Y=NH2,Z=H97b,X=Cl,Y=AcNH,Z=H97c,X=Cl,Y=AcNH,Z=CH3O
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸叔丁基酯(96a)
向化合物95(10.50g,27.9mmol)的甲醇(100ml)溶液中加入10%Pd/C(5.00g)在EtOAc(50ml)中的悬浮液。将此混合物在氢气氛下搅拌48小时,通过硅藻土板过滤并蒸发溶剂得到蜡状固体。将其溶解于二氯甲烷(100ml)和DMF(50ml)中并将此溶液冷却至0℃。加入4-氨基-3-氯苯甲酸(5.82g,27.2mmol),DIEA(14.58ml,83.7mmol),HOBt(3.77g,27.9mmol)和EDC(6.68g,34.8mmol)并将此溶液在0℃下搅拌15分钟,然后在室温下搅拌24小时。用乙酸乙酯稀释此反应混和物,用硫酸氢钠(2x),10%碳酸氢钠(2x)和盐水洗涤,然后用硫酸镁干燥,过滤并蒸发。将此粗品通过快速柱色谱纯化,用二氯甲烷/MeOH(99/1至97/3%)洗脱,得到标题化合物,为白色固体(7.75g,70%收率)。1H-NMR(500MHz,CD3OD)δ1.27-1.67(m,12H),1.82-2.14(m,4H),3.48-3.85 2H),4.26-4.53(m,3H),4.81-4.98(m,1H),6.71(d,1H),7.15(m,1H),7.50(dd,1H),7.75(d,1H)。分析HPLC 10.83分钟。LC-MS(ES+) m/e=396.3(MH+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(97a)
用TFA/二氯甲烷处理由96a制备。反应完毕后,真空除去溶剂并将此残余物从甲苯中反复浓缩。将所得残余物真空干燥至恒重。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸叔丁基酯(96b)
按照用于化合物96a的方法由化合物95和4-乙酰基氨基-3-氯苯甲酸制得标题化合物,为白色固体(9.18g,77?6收率)。
1H-NMR(500MHz,CD3OD)δ1.30-1.62(m,12H),1.85-2.16(m,3H),2.16-2.44(m,1H),2.27(s,3H),3.47-3.83(m,2H),4.34-4.54(m,1H),4.8.9(m,1H),7.27-7.39(m,1H),7.59-7.71(m,2H),7.83-7.97(m,1H),8.47(d,1H)。分析HPLC 9.43分钟。
1-[2-(4-乙酰氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(97b)
用TFA/二氯甲烷处理由96b制备。反应完毕后,真空除去溶剂并将此残余物从甲苯中反复浓缩。将所得残余物真空干燥至恒重。
4-乙酰基氨基-5-氯-2-甲氧基-苯甲酸
4-乙酰基氨基-5-氯-2-甲氧基-苯甲酸甲酯(2.09g,8.11mmol)溶解于甲醇(110ml)中,并加入氢氧化锂溶液(25.48mmol在30ml 1∶1MeOH∶H2O中),室温下将此溶液搅拌6小时。溶剂真空浓缩,加入EtOAc并用0.5N盐酸洗涤有机相,然后用饱和碳酸氢钠(2x)萃取。将水相用12N盐酸酸化至pH1并将所得沉淀萃取入二氯甲烷中。将合并的萃取物用无水硫酸钠干燥,过滤并蒸发得到标题化合物,为白色固体(0.933g,50%收率)。1H-NMR(500MHz,CDCl3)δ2.31(s,3H),4.10(s,3H),7.78-7.92(br s,1H),8.17(s,1H),8.45(s,1H)。分析HPLC5.62分钟。
1-[2-(4-乙酰基氨基-5-氯-2-甲氧基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸叔丁基酯(96c)
向化合物95(1.534g,4.07mmol)的甲醇(40ml)溶液中,加入10%Pd/C(650mg)并将此混合物在氢气氛下搅拌2小时。将此悬浮液通过硅藻土板过滤并蒸发得到黄色油状物。让其与4-乙酰基-5-氯-2-甲氧基苯甲酸反应,按照用于制备化合物96a的方法,得到标题化合物(497mg,52%收率)。1H-NMR(500MHz,CD3OD)δ1.46(d,3H),1.49(s,9H),1.80-2.01(m,3H),2.19-2.40(m,1H),2.22(s,3H),3.58-3-72(m,1H),3.78-3.89(m,1H),3.98-4.09(s,3H),4.31-4.45(s,1H),4.78-4.95(m,1H),7.89-8.10(m,2H)。分析HPLC11.31分钟。
1-[2-(4-乙酰基氨基-5-氯-2-甲氧基-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸(97c)
用TFA/二氯甲烷处理由化合物96c制备。反应完毕后,真空除去溶剂并将此残余物从甲苯中反复浓缩。将所得残余物真空干燥至恒重。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(5-氧代-2-苯乙氧基-四氢呋喃-3-基)-酰胺(98a)
向(5-氧代-2-苯乙氧基-四氢呋喃-3-基)-氨基甲酸烯丙基酯(194mg,0.54mmol)(如(40)所述用苯乙醇制备)的无水二氯甲烷(5mL)溶液中,在0℃下加入DMBA(196mg,1.26mmol)和Pd(PPh3)4(32mg,0.03mmol)。将此溶液搅拌15分钟,并加入97a(由96a通过在二氯甲烷中用TFA处理制备)(166mg,0.49mmol)和DIEA(680μl,3.90mmol)的二氯甲烷(2mL)溶液,然后加入HOBt(98mg,0.73mmol)和EDC(122mg,0.63mmol)。将此溶液在0℃下搅拌15分钟,然后在室温下搅拌18小时。真空除去溶剂并将此残余物溶解于乙酸乙酯中,然后用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤。用无水硫酸钠干燥并蒸发,得到桔黄色固体,将此通过快速柱色谱纯化,用二氯甲烷/MeOH(99/1至97/3%)洗脱,得到标题化合物,为白色固体(190mg,73%收率)。1H-NMR(500MHz,CD3OD)δ1.29(d,0.6H),1.41(d,2.4H),1.78(m,1H),2.08(m,3H),2.56(m,1H),2.77(dd,1H),
2.94(t,2H),3.53(m,0.3H),3.67(m,0.5H),3.85(m,2H),3.96-4.08(m,1H),4.40(m,2H),4.62(m,1H),4.67-4.79(m,1H),5.57(d,0.7H),5.60(d,0.3H),6.78(dd,1H),7.21(m,5H),7.58(m,1H),7.79(m,1H),8.26(d,1H)。分析HPLC 14.52分钟。LC-MS(ES+)
m/e=543.2(MH+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98b)
由(2-苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯(40)的顺式非对映异构体和97a,按照用于98a的方法制备。分离出的标题化合物为淡黄色固体(720mg,51%收率)。1H-NMR(500MHz,CD3OD)δ1.16(d,0.5H),1.40(d,2.5H),1.64-2.25(m,4H),2.61(dd,1H),2.79(dd,1H),3.37-3.59(m,1H)3.59-3.74(m,1H),3.77-3.92(m,1H),4.29-4.47(m,1H),4.47-5.02 25(m,4H),5.48(s,0.5H),5.66(d,1H)5.68(d,0.5H),6.79(d,1H),7.17-7.52(m,5H),7.48-7.62(m,1H),7.68-7.83(m,1H)。分析HPLC15.98分钟。LC-MS(ES+) m/e=529.2(MH+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98c)
用反式-(2-苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯(40)和97a,按照用于98a的方法制备。标题化合物以白色固体分离(186.6mg,46%收率)。1H-NMR(500MHz,CD3OD)δ1.30-1.52(m,3H),1.76-2.33(m,4H),2.41-2.59(m,1H),2.90(dd,0.15H),3.04(dd,0.85H),3.44-3.75(m,1.5H),3.82-3.95(m,1H),4.27-4.42(m,2H),4.42-4.56(m,0.5H),4.56-4.86(m,4H),5.42-5.55(m,1H),6.79(d,1H),7.21-7.42(m,4.6H),7.54-7.63(m,1.4H),7.76-7.83(m,0.65H),8.60-8.68(m,0.35H)。分析HPLC 15.19分钟。LC-MS(ES+) m/e=529.3(MH+)
2-(乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯如(40)所述用乙醇制备。用己烷/乙酸乙酯(95/5至80/20)进行色谱,得到0.94g的反式-2-(乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯(较高Rf),1.96g的顺式非对映异构体(较低Rf)和8.08g的非对映异构体混合物(总收率60%)。1H-NMR(500MHz,CDCl3),对于反式非对映异构体:δ1.13-1.31(m,3H),2.31-2.45(m,1H),2.92-3.08(m,1H),3.52-3.72(m,1H),3.78-3.92(m,1H),4.10-4.25(m,1H),4.45-4.70(m,2H),5.00(bs,1H),5.12-5.45(m,3H),5.80-5.95(m,1H);对于顺式非对映异构体1.13-1.35(m,3H),2.38-2.50(m,1H),2.75-2.92(m,1H),3.60-3.73(m,1H),3.82-3.95(m,1H),4.40-4.70(m,3H),5.10-5.52(m,4H),5.80-5.94(m,1H);LC-MS:m/z=230(M+H+)对于两种非对映异构体。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(98d)
由(2-乙氧基-5-氧代-四氢呋喃-3-基)氨基甲酸烯丙基酯和97a按照用于98a的方法制备。分离出的标题化合物为白色固体(175mg,77%收率)。1H-NMR(500MHz,CD3OD)δ1.13(t,0.5H),1.23(t,2.5H),1.36(d,0.5H),1.44(d,2.5H),1.75-2.38(m,4H),2.56(dd,1H),2.76(dd,1H),3.45-3.97(m,5H),4.47(dd,1H),4.59-4.67(m,1H),4.74(q,1H),5.55(d,0.2H),5.56(d,0.8H),6.75-6.82(m,1H),7.56(dd,1H),7.77(d,1H),8.3-9(d,1H)。分析HPLC 8.17分钟。LC-MS(ES+) m,/e=467.4(MH+)
(2-环戊基氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯按照化合物40描述的方法,用环戊醇制备得到标题化合物,为非对映异构体的混合物。用己烷/EtOAc(90/10至80/20)进行快速柱色谱得到标题化合物的顺式非对映异构体:顺式非对映异构体1H NMR(500MHz,CDCl3)δ1.5-2.0(m,8H),2.45(dd,1H),2.81(dd,0.9H),3.0(dd,0.1H),4.31(m,1H),4.59(m,4H),5.23(m,1H),5.32(m,1H),5.45(s,0.1H),5.51(s,0.9H),5.92,(m,1H)ppm;反式非对映异构体1H-NMR(500MHz,CDCl3)δ1.50(m,2H),1.67(m,6H),2.36(d,1H),2.8(dd,0.08H),2.96(dd,0.92H),4.13(m,1H),4.25(m,1H),4.55(br,2H),5.20(d,1H),5.30(m,2H),5.43(s,0.92H),5.5(d,0.08H),5.89(s,1H)ppm
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-环戊基氧基-5-氧代-四氢呋喃-3-基)-酰胺(98e)
由(2-环戊基氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯和97a,按照用于98a的方法制得标题化合物(280mg,51%收率)。1H-NMR(500MHz,CD3OD)δ1.38(d,0.5H),1.44(d,2.5H),1.49-2.35(m,12H),2.47(dd,0.7H),2.56(dd,0.3H),2.75(dd,0.3H),2.81-2.88(m,0.1H),2.97(dd,0.6H),3.47-3.76(m,0.2H),3.82-3.96(m,1H),4.10-4.40(m,2H),4.40-4.46(m,1H),5.44(d,0.5H),5.50(d,0.2H),5.65(d,0.3H),6.79(d,1H),7.54-7.64(m,1H),7.78(d,1H),8.21-8.31(m,1H)。
分析HPLC 15.02,15.34分钟。LC-MS(ES+) m/e=507.3(MH+)
(2-环己基氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯
由-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯按照化合物40所述,用环己醇制备,得到标题化合物,为非对映异构体的混合物(淡黄色油状物)(4.62g,85%收率)。用己烷/EtOAc(90/10至80/20)进行快速柱色谱,得到394mg(7%收率)的标题化合物的顺式非对映异构体。1HNMR(500MHz,CDCl3)δ1.11-2.09(m,10H),2.35-2.61(dd,1H),2.72-2.98(dd,1H),3.60-3.83(m,1H),4.32-4.72(m,3H),5.06-5.43(m,2H),5.60(d,1H),5.82-6.03(m,1H)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-环己基氧基-5-氧代-四氢呋喃-3-基)-酰胺(98f)
由顺-(2-环己基氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯和97b按照用于98a的方法制备,得到标题化合物(121mg,33%收率)。1H-NMR(500MHz,CD3OD)δ1.06-1.61(m,9H),1.61-2.37(m,7H),2.22(s,3H),2.52-2.81(m,2H),3.49-3.78(m,2H),3.84-3.97(m,1H),4.42-4.57(m,1H),4.57-4.69(m,1H),5.67-5.81(m,1H)7.72-7.89(m,1H),7.89-8.12(m,2H)分析HPLC 9.84分钟。LC-MS(ES+) m/e=563.3(MH+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-环己基氧基-5-氧代-四氢呋喃-3-基)-酰胺(98g)
由顺-(2-环己基氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯和97a按照用于98a的方法制得标题化合物(153mg,47%收率)。1H-NMR(500MHz,CD3OD)δ1.06-2.38(m,14H),1.42(d,3H),2.50-2.66(m,1H),2.69-2.82(dd,1H),3.06-3.75(m,2H),3.80-3.94(m,1H),4.40-4.52(m,1H),4.57-4.65(m,1H),4.70-4.80(m,1H),5.72(d,1H),6.71(m,1H),7.50-7.63(m,1H),7.78(d,0.6H),8.42(d,0.4H)。分析HPLC 10.30分钟。LC-MS(ES+)m/e=521.2(MH+)
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(98h)
由(2-乙氧基-5-氧代-四氢呋喃-3-基)氨基甲酸烯丙基酯和97a按照用于98a的方法制备。分离出的标题化合物为白色固体(195mg,82%收率)。1H-NMR(500MHz,CD3OD)δ1.32-1.55(m,3H),1.58-1.77(m,3H),1.98-2.54(m,4H),2.68-2.76(d,0.3H),2.79-2.89(m,0.7H),2.96-3.10(m,0.7H),3.18-3.27(dd,0.3H),3.72-4.18(m,4H),4.46-5.12(m,3H),5.60(s,0.4H),5.74-5.84(m,0.6H)7.03(d,0.8H),7.75-7.86(m,1H),8.01(d,0.7H)8.35(d,0.3H),8.74(d,0.2H)。分析HPLC 8.31分钟。LC-MS(ES+) m/e=467.3(MH+)。
[5-氧代-2-(三环[3.3.1.10.0]癸-2-基氧基)-四氢呋喃-3-基]-氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯如化合物40所述用2-金刚醇(6.21g,5当量)制得标题化合物,为淡黄色油状物(1.52g,61%收率)。1H NMR(500MHz,CDCl3)δ1.38-2.22(m,14H),2.40(d,0.2H),2.53(dd,0.7H),2.87(dd,0.7H),2.87(dd,0.8H),3.00-3.12(m,0.3H),3.84-3.97(m,1H),4.40-4.71(m,3H),5.18-5-44(m,2H),5.53-5.69(m,1H),5.82-6.02(m,1H)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸[5-氧代-2-(三环[3.3.1.10.0]癸-2-基氧基)-四氢呋喃-3-基]酰胺(98i)
由[5-氧代-2-(三环[3.3.1.10.0]癸-2-基氧基)-四氢呋喃-3-基]-氨基甲酸烯丙基酯和97a按照用于98a的方法制备。分离出的标题化合物为白色固体(76mg,13%收率)。1H-NMR(500MHz,CD3OD)δ1.38-2.22(m,14H),w.40(d,0.2H),2.53(dd,0.7H),2.87(dd,0.8H),3.00-3.12(m,0.3H),3.84-3.97(m,1H),4.40-4.71(m,3H),5.18-5.44(m,2H),5.53-5.69(m,1H),5.82-6.02(m,1H)。分析HPLC11.89分钟。LC-MS(ES+) m/e=573.2(MH+)。
1-[2-(4-乙酰基氨基-5-氯-2-甲氧基-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸(2-苄氧基5-氧代-四氢呋喃-3-基)-酰胺(98j)
由顺-{2-[2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-基]-1-甲基-2-氧代乙基)-氨基甲酸叔丁基酯和97c,按照用于98a的方法制得标题化合物(222mg,82%收率)。1H-NMR(500MHz,CD3OD)δ1.23(d,0.6H),1.42(d,2.4H),1.72-2.27(m,4H),2.23(s,3H),2.63(dd,1H),2.77-2.88(m,1H),3.43-3.52(m,0.5H),3.56-3.71(m,1.5H),3.74-3.85(m,1H),3.98(s,3H),(m,1.5H),4.51-4.92(m,4.5H),5.63-5.76(m,1H),7.23-7.40(m,5H),7.97(s,1H),8.45(d,1H),8.69-8.80(m,1H)。分析HPLC 11.63分钟,LC-MS(ES+) m/e=601.2(MH+)。
合成1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(98k)
由反-(2-乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯和97a按照用于98a的方法制得175mg的标题化合物(59%)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.10-1.28(m,3H),1.42(d,0.6H),1.46(d,2.4H),1.75-2.45(m,4H),2.45-2.70(m,1H),2.80-3.05(m,1H),3.50-3.95(m,4H),4.20-4.75(m,3H),4.75-4.90(m,1H),5.32(s,0.8H),5.38(s,0.2H),6.80(d,1H),7.55-7.84(m,2H)。分析HPLC:10.47分钟。LC-MS(ES+):m/e=467.3(M+H+)。
合成1-[2-(4-氨基-3,5-二氯-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(981)
由(2-乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯和1-[2-(4-氨基-3,5-二氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-基甲酸叔丁基酯,按照用于98a的方法制备,得到158mg的标题化合物(54%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.08-1.30(m,3H),1.32-1.52(m,3H),1.72-2.44(m,4H),2.40-3.05(m,2H),3.50-3.97(m,4H),4.25-4.70(m,3H),4.70-4.86(m,1H),5.33(s,0.4H),5.47(s,0.1H),5.56(d,0.4H),5.62(d,0.1H),7.50(s,1H),7.80(s,1H)。分析HPLC:10.84分钟。LC-MS(ES+):m/e=501.2(M+H+).
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98m)
按照制备98a的方法用Cbz-Ala-D-pro-OH制备,得到230mg的标题化合物(69%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.30(d,1.2H),1.45(d,1.8H),1.62-2.40(m,4H),2.40-3.10(m,2H),3.30-3.97(m,2H),4.33-4.95(m,5H.),5.30(s,0.5H),5.68(d,0.5H),6.80(d,1H),7.25-7.95(m,7H)。分析HPLC:11.56,11-91分钟。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98n)
由97b和顺-(2-苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯,按照用于制备98a的方法,制得210mg的标题化合物(64%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.33(d,0.6H),1.44(d,2.4H),1.68-2.40(m,4H),2.26(s,3H),2.55-3.05(m,2H),3.40-3.90(m,2H),4.20-4.95(m,5H),5.68(d,0.8H),5.84(d,0.2H)7.15-8.30(m,8H)。分析HPLC:15.67分钟。LC-MS(ES+):m/e=571.1(M+H+)
(2-异丙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯
按照化合物40描述的方法用异丙醇制备,得到3.80g(81%收率)的标题化合物,为无色油状物。1H-NMR(500MHz,CDCl3)δ1.10-1.35(m,6H),2.32-2.60(m,1H),2.82(dd,0.5B),3.02(dd,0.5H),3.82-4.11(m,1H),4.48-4.66(m,3H),5.20-5.36(m,2H),5.54(dd,1H),5.82-6.05(m,1H)。LC-MS(ES+):m/e=244.2(M+H+)
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-异丙氧基-5-氧代-四氢呋喃-3-基)-酰胺(98o)
由97a和(2-异丙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯,按照制备98a的方法制得200mg的标题化合物(66%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.05-1.35(m,6H),1.35-1.50(m,3H),1.70-2.45(m,4H),2.45-3.05(m,2H),3.55-4.10(m,3H),4.15-4.88(m,4H),5.48(s,0.4H),5.58(s,0.1H),5.6 4(d,0.4H),5.70(d,0.1H),6.78(d,1H),7.58(d,1H),7.80(s,1H)。分析HPLC:12.19,12.40分钟。LC-MS(ES+):m/e=581.2(M+H+)。
1-[2-(4-乙酰基氨基-3,5-二氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98p)
由1-[2-(4-乙酰基氨基-3,5-二氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸叔丁基酯和顺-(2-苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯,按照制备98a的方法,制得230mg标题化合物(72%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.36(d,0.6H),1.47(d,2.4H),1.68-2.47(m,4H),2.23(s,3H)2.60-3.15(m,2H),3.40-3.90(m,2H),4.15-4.95(m,5H),5.68(d,0.8H),5.84(d,0.2H),7.20-7.98(m,7H)。分析HPLC:13.07分钟。LC-MS(ES+):m/e=605.1(M+H+)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-环戊基氧基-5-氧代-四氢呋喃-3-基)-酰胺(98g)
由97b和(2-环戊基氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得215mg的标题化合物(69%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.35-1.90(m,11H),1.90-2.35(m,4H)2.24(s,3H),2.40-3.10(m,2H),3.50-3.95(m,3H)4.15-4.90(m,3H),5.44(s,0.55H),5.56(s,0.15H),5.64(d,0.22H),5.71(d,0.08H),7.70-8.25(m,3H)。分析HPLC:12.13分钟。LC-MS(ES+):m/e=549.2(M+H+)
合成1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(98r)
由97b和顺-(2-乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得68mg的标题化合物(24%)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.13(t,0.6H),1.28(t,2.4H),1.38(d,0.6H),1.48(d,2.4H),1.75-2.40(m,4H),2.22(s,3H),2.55-2.88(m,2H),3.50-3.92(m,4H),4.40-4.90(m,3H),5.57(d,0.8H),5.61(d,0.2H),7.60-8.20(m,3H)。分析HPLC:8.64分钟。LC-MS(ES+):m/e=509.2(M+H+)
制备(2-环戊基甲氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯,如化合物40所述,用环戊基甲醇(6.5mL,60mmol)制备,得到2.98g(52%总收率)的标题化合物,为差向异构体的混合物。纯化得到0.97g(17%收率)的4(S),5(R),为无色油状物。1H NMR(500MHz,CDCl3)δ1.19(m,2H),1.54(m,4H),1.71(m,2H),2.16(m,1H),2.44(dd,J=17.2,10.4Hz,1H),2.82(dd,J=17.2,8.4Hz,1H),3.44(dd,J=9.3,7.2Hz,1H),3.71(dd,J=9.3,7.2Hz,1H),4.57(m,3H),5.32(m,3H),5.41(d,J=5.2Hz,1H),5.91(ddt,J=17.1,10.4,5Hz,1H)ppm。LC-MS.(ES+):m/e=284。
还分离了差向异构体混合物(0.66g,11%收率)和4(S),5(S)差向异构体(1.35g,24%收率),为蜡状固体。1H-NMR(500MHz,CDCl3)δ1.20(m,2H),1.54(m,4 H),1.69(m,2H),2.10(m,1H),2.37(d,J=8.1Hz,1H),2.97(dd,J=18.0,7.6HZ,1H),3.42(dd,J=7.3,1.7Hz,1H),3.49(m,2H),3.64(dd,J=9.0,7.3Hz,1H),4.19(br,1H),4.55(m,2H),5.25(m,2H),5.36(s,1H),5.87-(M,1H)ppm.LC-MS(ES+):m/e=284(M+H)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-环戊基甲氧基-5-氧代-四氢呋喃-3-基)-酰胺(98s)
由97a和顺-(2-环戊基甲氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得195mg的标题化合物(51%收率)。1H-NMR 5(500MHz,1∶1 CDCl3∶CD3OD)δ1.15-1.90(m,11H),1.90-2.40(m,5H),2.55-2.78(m,2H),3.50-3.90(m,4H),4.38-4.92(m,3H),5.53(d,0.5H),5.57(d,0.2H),6.78(d,1H),7.50-8.15(m,2H)。分析HPLC:10.48分钟。LC-MS(ES+):m/e=521.2(M+H+)。
(5-氧代-2-(3-苯基-丙氧基)-四氢呋喃-3-基)氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯,按照化合物40所述的方法,用3-苯基丙醇,制备得到1.15g(32%收率)的标题化合物,为无色油状物。1H-NMR(500MHz,CDCl3)δ1.82-2.05(m,2H),2.38(dd,1H),2.68(m,2H),2.82(dd,1H),3.55-3.65(m,1H),3.82-3.92(m,1H),4.48-4.72(m,3H),5.12-5.59(m,3H),5.82-6.03(m,1H),7.11-7.45(m,5H)。分析HPLC:9.08分钟。LC-MS(ES+):m/e=320.2(M+H+).
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(5-氧代-2-(3-苯基丙氧基)-四氢呋喃-3-基)-酰胺(98t)
由97b和顺-(5-氧代-2-(3-苯基-丙氧基)-四氢呋喃-3-基)氨基甲酸烯丙基酯,按照制备98a使用的方法制得200mg标题化合物(57%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.34(d,0.6H),1.44(d,2.4H),1.75-2.40(m,6H),2.50-2.95(m,4H),3.47-3.95(m,4H),4.38-4.82(m,3H),5.52(d,0.5H),5.56(d,0.2H),6.75-8.25(m,8H)。分析HPLC:10.79分钟。
LC-MS(ES+):m/e 557.2(M+H+)。
合成1-[2-(4-乙酰基氨基-3-氯苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-环戊基甲氧基-5-氧代-四氢呋喃-3-基)酰胺(98u)
由97b和顺-(2-环戊基甲氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得215mg的标题化合物(67%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.38(d,0.6H)1.47(d,2.4H),1.11-1.88(m,5H),1.92-2.40(m,5H),2.24(s,3H),2.53-2.86(m,2H),3.30-3.90(m,4H),4.38-4.89(m,3H),5.53(d,0.8H),5.60(d,0.2H),7.68-8.22(m,3H)。分析HPLC:9.90分钟。LC-MS(ES+):m/e 563.3(M+H+)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(5-氧代-2-(3-苯基丙氧基1)-四氢呋喃-3-基)-酰胺(98v)
由1-(2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸叔丁基酯和顺-(5-氧代-2-(3-苯基-丙氧基)四氢呋喃-3-基)-氨基甲酸烯丙基酯,按照用于制备98a的方法制得238mg的标题化合物(75%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.33(d,0.6H),1.56(d,2.4H),1.78-2.45(m,6H),2.27(s,3H),2.53-2.97(m,4H),3.53-3.94(m,4H),4.47-4.86(m,3H),5.53(d,0.8H),5.62(d,0.2H),7.11-8.26(m,8H)。分析HPLC:10.27分钟。LC-MS(ES+):m/e=599.2(M+H+)。
1-[2-(4-氨基-3-三氟甲基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98w)
由{2-[2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-基]-1-甲基-2-氧代-乙基}-氨基甲酸叔丁基酯和4-氨基-3-三氟甲基-苯甲酸按照用于制备98a的方法制得56mg的标题化合物(48%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.20-1.55(m,3H),1.75-2.50(m,4H),2.50-3.10(m,2H),3.50-4.00(m,2H),4.30-5.00(m,5H),5.42(s,0.4H),5.51(s,0.2H),5.62(d,0.3H),5.78(d,0.1H),6.84(d,1H),7.20-8.15(m,7H)。分析HPLC:14.90,15.20分钟。LC-MS(ES+):m/e=563.2(M+H+)。
1-[2-(3-氯-4-二甲基氨基-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98x)
由{2-[2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-基]-1-甲基-2-氧代-乙基}-氨基甲酸叔丁基酯和3-氯-4-二甲基氨基-苯甲酸,按照制备98a的方法制备,得到82mg的标题化合物(44%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.18-1.53(m,3H),1.70-2.40(m,4H),2.55-3.10(m,2H),2.84(s,6H),3.45-3.94(m,2H),4.25-4.95(m,5H),5.46(s,0.3H),5.51(s,0.2H),5.63(d,0.4H),5.73(d,0.1H),7.05(d,1H),7.15-7.95(m,7H)。分析HPLC:11.85,12.19分钟。LC-MS(ES+):m/e=557.3(M+H+)。
1-[2-(4-二甲基氨基-3,5-二氟-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98y)
由{2-[2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-基]-1-甲基-2-氧代-乙基}-氨基甲酸叔丁基酯和4-二甲基氨基-3,5-二氯-苯甲酸,按照制备98a的方法制得106mg的标题化合物(65%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.10-1.55(m,3H),1.75-2.30(m,4H)2.45-3.15(m,2H),2.84(s,6H),3.40-3.95(m,2H),4.15-4.95(m,5H),5.47(s,0.35H),5.54(s,0.15H),
1-[2-(4-氨基-2,3,5,6-四氟-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸(2-苄氧基5-氧代-四氢呋喃-3-基)-酰胺(98z)
由{2-(2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-吡咯烷-1-基]-1-甲基-2-氧代-乙基}-氨基甲酸叔丁基酯和4-氨基2,3,5,6-四氟-苯甲酸按照用于制备98a的方法制得58mg的标题化合物(73%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.30-1.50(m,3H),1.62-2.35(m,4H),2.45-3.12(m,2H),3.50-3.90(m,2H),4.20-4.95(m,5H),5.42(s,0.4H),5.52(s,0.1H),5.64(d,0.4H),5.82(d,0.1H),7.25-7.65(m,5H)。分析HPLC:16.56,16.90分钟。LC-MS(ES+):m/e 567.2(M+H+)。
1-{2-[3-氯-4-(2,2-二甲基丙酰基氨基)-苯甲酰基氨基]-丙酰基}-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98aa)
向98b(100mg,0.19mmol)和聚(4-乙烯基吡啶)(200mg)的悬浮液中,加入新戊酰氯(70μl,0.57mmol)。将所得悬浮液室温下搅拌过夜,过滤并用乙酸乙酯(25mL)稀释。将此有机层用10%碳酸氢钠(2×25mL),饱和氯化钠(1×25mL)洗涤,干燥(MgSO4)并蒸发至干,进行色谱纯化后得到98mg的标题化合物(85%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.10-1.55(m,3H),1.38(s,9H),1.65-2.40(m,4H),2.60-3.10(m,2H),3.46-3.88(m,2H),4.20-4.95(m,5H),5.62(d,0.5H),5.78(d,0.2H),7.15-8.30(m,8H)。分析HPLC:11.82分钟。LC-MS(ES+):m/e=613.2(M+H+)
1-[2-(3-氯-4-丙酰基氨基)-苯甲酰基氨基]丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98ab)
由98b和丙酰氯按照用于制备98aa的方法制得104mg标题化合物(95%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.16(t,0.6H),1.18(d,0.6H),1.27(t,2.4H),1.38(d,2.4H),1.72-2.35(m,4H),2.45-2.58(m,2H),2.58-3.05(m,2H),3.45-3.85(m,2H),4.20-4.88(m,5H),5.64(d,0.5H),5.76(d,0.2H),7.20-8.35(m,8H)。分析HPLC:9.89分钟。LC-MS(ES+):m/e=585.2(M+H+)。
1-[2-(3-氯-4-苯基乙酰基氨基)-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基5-氧代-四氢呋喃-3-基)-酰胺(98ac)
由98b和苯基乙酰氯按照用于制备98aa的方法制得85mg的标题化合物(77%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.18(d,0.6H),1.40(d,2.4H),1.72-2.38(m,4H),2.58-3.05(m,2H),3.46-3.78(m,2H),3.85(s,2H),4.18-4.92(m,5H),5.63(d,0.5H),5.75(d,0.2H),7.15-8.34(m,13H)。分析HPLC:11.63分钟。LC-MS(ES+):m/e=647.2(M+H+)
1-[2-(3-氯-4-甲基-丁酰基氨基)-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98ad)
由98b和异戊酰氯按照用于制备98aa的方法制得60mg的标题化合物(58%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.07(d,5H),1.15(d,0.8H),1.27(d,1H),1.45(d,2.2H),1.67-2.30(m,5H),2.34(d,2H),2.58-3.05(m,2H),3.48-3.88(m,2H),4.10-4.98(m,5H),5.68(d,0.7H),5.78(m,0.3H),7.18-8.33(m,8H)。分析HPLC:10.74分钟。LC-MS(ES+):m/e=613.2(M+H+)。
1-[2-(4-甲氧基-3,5-二甲基-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(98ae)
由1-[2-(4-甲氧基-3,5-二甲基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸叔丁基酯和顺-(2-乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得174mg(81%收率)的标题化合物。1H-NMR(500MHz,CDCl3):δ1.04(t,0.45H),1.27(t,2.55H),1.34-1.45(m,3H),1.95-2.45(m,10H),2.78-2.84(m,H),3.60-3.90(m,8H),4.50-4.70(m,2H),4.90-4.94(m,H),5.45(d,0.85H),5.61(d,0.15H),6.99(d,H),7.15(d,H),7.45(s,2H);分析HPLC保留时间:10.09min;LC-MS:M/z=476(M+H+)。
1-[2-(4-甲氧基-3,5-二甲基-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(98af)
由1-[2-(4-甲氧基-3,5-二甲基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸叔丁基酯和反-(2-乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得168mg(77%收率)的标题化合物。1H-NMR(500MHz,CDCl3):δ1.10-1.35(m,3H),1.35-1.60(m,3H),1.90-2.45(m,10H),2.60-3.00(m,H),3.55-3.95(m,5H),4.15-4.60(m,2H),4.83-5.00(m,H),5.29(s,H),6.95-7.06(m,H),7.50(s,2H),7.92(d,H);分析HPLC的保留时间:10.14min;LC-MS:m/z=476(M+H+)。
1-[2-(4-甲氧基-3,5-二甲基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98ag)
由1-[2-(4-甲氧基-3,5-二甲基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸叔丁基酯和顺-(2-苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯(40),按照制备98a的方法,制得406mg(收率71%)的标题化合物。1H-NMR(500MHz,CDCl3):δ1.09(d,0.6H),1.35(m,2.4H),1.90-2.20(m,3H),2.22-2.50(m,10H),2.84-2.90(m,H),3.52-3.62(m,1.6H),3.65-3.80(m,3.4H),4.10-4.40(m,H),4.50-4.75(m,3H),4.82-4.95(m,2H),5.54(d,0.8H),5.80(d,0.2H),6.87(d,H),7.10-7.40(m,6H),7.45(s,2H);分析HPLC保留时间:16.71分钟1;LC-MS:m/z=538(M+H+)
1-[2-(4-烯丙氧-3,5-二甲基-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98ah)
由1-[2-(-4-烯丙氧-3,5-二甲基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸叔丁基酯和化合物40按照用于制备98a的方法制得264mg(收率46%)的标题化合物。1H-NMR(500MHz,CDCl3):δ1.09-1.43(m,3H),1.90-2.20(m,3H),2.20-2.38(m,7H),2.38-2.52(m,H),2.80-2.95(m,H),3.52-3.67(m,H),3.70-3.80(m,H),4.10-4.40(m,2H),4.40-4.95(m,5H),5.26-5.55(m,3H),6.00-6.14(m,H),6.87(d,H),7.10-7.70(m,8H);分析HPLC保留时间:18.56和18.92min;LC-MS:m/z=564(M+H+)
{2-[1R-(2S-异丙基-5R-甲基-环己基氧基)]-5-氧代-四氢呋喃-3-基}-氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯如化合物40所述用(1R,2S,5R)-(-)-薄荷醇制备,得到0.32g标题化合物的顺式非对映异构体(较低Rf)和4.25g的反式/顺式非对映异构体的混合物(总收率67%)。1H-NMR(500MHz,CDCl3)混合物:δ0.70-1.05(m,13H),1.20-1.47(m,2H),1.60-1.80(m,2H),1.94-2.20(m,2H),2.35-2.50(m,H),2.82-3.04(m,H),3.40-3.61(m,H),4.43-4.70(m,3H),5.15-5.35(m,2H),5.48-5.61(m,H),5.90-5.94(m,H);顺式非对映异构体0.70-1.05(m,13H),1.20-1.47(m,2H),1.60-1.80(m,2H),1.94-2.18(m,2H),2.40-2.50(m,H),2.82-2.92(m,H),3.54-3.61(m,H),4.45-4.70(m,3H),5.18-5.35(m,2H),5.58-5.61(m,H),5.90-5.93(m,H);反式/顺式非对映异构体混合物的LC-MS:m/z=340(M+H+)。
4-苄氧基-3,5-二甲基-苯甲酸
通过合成4-烯丙氧-3,5-二甲基-苯甲酸的方法制备,得到2.43g(收率56%)的标题化合物。1H-NMR(500MHz,CDCl3):δ4.87(s,2H),7.36-7.48(m,5H),7.92(s,2H);LC-MS:m/z=255(M-H+)。
1-[2-(4-苄氧基-3,5-二甲基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-[1R-(2S-异丙基-5R-甲基-环己基氧基)]-5-氧代-四氢呋喃-3-基)-酰胺(98ai)
由1-[2-(4-苄氧基-3,5-二甲基苯甲酰基氨基)-丙酰基)-吡咯烷-2-甲酸叔丁基酯{2-[1R-(2S-异丙基-5R-甲基环己基氧基)]-5-氧代-四氢呋喃-3-基}-氨基甲酸烯丙基酯,按照制备98a的方法制得130mg(收率39%)的标题化合物。1H-NMR(500MHz,CDCl3):δ0.45-1.10(m,12H),1.15-1.90(m,8H),1.90-2.45(m,12H),2.80-2.84(m,H),3.50-3.85(m,3H),4.45-4.70(m,2H),4.80-4.95(m,3H),5.62(d,H),7.05(d,H),7.17(d,H),7.30-7.60(m,7H),7.62-7.75(m,H);分析HPLC的保留时间:15.90和16.08min;LC-MS:m/z=662(M+H+)。
1-[2-(4-羟基-3,5-二甲基-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸{2-[1R-(2S-异丙基-5R-甲基-环己基氧基)]-5-氧代-四氢呋喃-3-基)-酰胺(98aj)
将1-[2-(4-苄氧基-3,5-二甲基苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-[1R-(2S-异丙基-5R-甲基-环己基氧基)]-5-氧代-四氢呋喃-3-基)-酰胺(110mg,0.17mmol)的乙酸乙酯(2mL)溶液,在钯碳(20mg)上在氢气氛下搅拌24小时,然后通过硅藻土板过滤并真空蒸发。将所得残余物通过色谱用二氯甲烷/甲醇(99/1至96/4)纯化,得到58mg标题化合物。1H-NMR(500MHz,CDCl3):δ0.70-1.00(m,10H),1.20-1.80(m,10H),1.90-2.40(m,11H),2.82-2.86(m,H),3.57-3.78(m,3H),4.55-4.67(m,2H),4.90-4.94(m,H),5.29(s,H),5.62(d,H),6.90(d,H),7.14(d,H),7.42(s,2H);分析HPLC保留时间:12.84和13.05min;LC-MS:m/z=572(M+H+)。
1-[2-(4-羟基-3,5-二甲基-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98ak)
将98ah(230mg,0.41mmol)的二氯甲烷(10mL)溶液,用DMBA(65mg,0.42mmol)和Pd(PPh3)4(50mg)室温下处理20小时。将此混合物真空蒸发至干,并通过快速色谱用二氯甲烷/甲醇(99.5/0.5至97/3)洗脱纯化,得到181mg的标题化合物。1H-NMR(500MHz,CDCl3):δ1.08(d,0.75H),1.20-1.35(m,2.25H),1.70-2.50(m,12H),2.80-2.90(m,H),3.50-3.65(m,H),3.70-3.80(m,H),4.10-4.25(m,H),4.35-4.98(m,3H),5.53(d,0.75H),5.85(d,0.25H),6.81(d,H),7.13-7.60(m,8H);分析HPLC保留时间:10.38和10.56分钟;LC-MS:m/z 524(M+H+)。
1-[2-(4-二甲基氨基-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98al)
由1-[2-(4-二甲基氨基-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸叔丁基酯和顺-(2-苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得60mg(45%收率)。1H-NMR(500MHz,CDCl3):δ1.04(d,0.75H),1.35(d,2.25H),1.80-2.50(m,5H),2.75-3.20(m,BH),3.45-3.75(m,2H),4.05-4.20(m,0.5H),4.30-4.80(m,3.5H),4.80-4.95(m,1.5H),5.52(d,H),5.75-6.00(m,0.5H),6.60-6.90(m,3H),7.10-7.50(m,4H),7.50-7.80(m,2H);分析HPLC保留时间:10.46分钟;LC-MS:m/z=523(M+H+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸{2R-[1R-(2S-异丙基-5R-甲基-环己基氧基)]-5-氧代-四氢呋喃-3-基}酰胺(98am)
由1-[2-(4-氨基-3-氯-苯甲酰基氨基)丙酰基]-吡咯烷-2-甲酸叔丁基酯(97a)和顺-{2-[1R-(2S-异丙基-5R-甲基环己基氧基)]-5-氧代-四氢呋喃-3-基}-氨基甲酸烯丙基酯按照用于制备98a的方法制得103mg(收率67%)的标题化合物。1H-NMR(500MHz,CDCl3)δ0.70-1.10(m,12H),1.20-1.50(m,5H),1.50-1.85(m,2H),1.90-2.30(m,5H),2.75-2.85(m,H),3.50-3.70(m,2H),3.70-3.82(m,H),4.20-4.65(m,4H),4.80-4.95(m,H),5.61(d,H),6.70-6.73(m,H),6.95(d,H),7.15(d,H),7.49-7.51(m,H),7.73(s,H);分析HPLC的保留时间:12.88min;LC-MS:m/z=577(M+H+)。
{2-[1S-(2R-异丙基-5S-甲基-环己基氧基)]-5-氧代-四氢呋喃-3-基}-氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯,如化合物40所述,用(1S,2R,5S)-(+)-薄荷醇制备,得到855mg标题化合物的反式非对映异构体(较高Rf),503mg的顺式非对映异构体(较低Rf)和459mg的反/顺非对映异构体混合物(总收率66%)。1H-NMR(500MHz,CDCl3)反式非对映异构体:δ0.74-1.00(m,12H),1.20-1.45(m,2H),1.58-1.72(m,2H),1.98-2.12(m,2H),2.18-2.40(m,H),2.98-3.03(m,H),3.49-3.54(m,H),4.17(br,H),4.59(br,2H),4.97(br,H),5.22-5.33(m,2H),5.58(s,H),5.87-5.93(m,H);顺式非对映异构体0.75-1.02(m,12H),1.25-1.45(m,2H),1.57-1.70(m,2H),2.00-2.16(m,2H),2.40-2.52(m,H),2.78-2.90(m,H),3.40-3.50(m,H),4.58(br,2H),5.24-5.35(m,2H),5.51-5.52(d,H),5.85-5.98(m,H);两种非对映异构体的LC-MS:m/z=340(M+H+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸{2R-[1S-(2R-异丙基-5S-甲基-环己基氧基)]-5-氧代-四氢呋喃-3-基}酰胺(98an)
由97a和顺-{2-[1S-(2R-异丙基-5S-甲基-环己基氧基)]-5-氧代-四氢呋喃-3-基}氨基甲酸烯丙基酯按照用于制备98a的方法制得88mg(50%收率)的标题化合物。1H-NMR(500MHz,CDCl3):δ0.70-1.10(m,12H),1.20-1.50(m,14H),1.50-1.70(br,2H),1.90-2.25(m,4H),2.27-2.37(m,H),2.40-2.50(m,H),2.75-2.79(m,H),3.35-3.80(m,3H),4.20-4.57(m,3H),4.60-4.70(m,H),4.88-4.92(m,H),5.53(d,H),6.71-6.75(m,H),6.90(d,H),7.20(d,H),7.50-7.53(m,H),7.75(d,H);分析HPLC保留时间:13.20分钟;LC-MS:m/z=577(M+H+)。
(2-环己基甲氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯,按照化合物40所述,用环己基甲醇制备,得到1.04g(较高Rf)(35%收率)标题化合物的反式非对映异构体和1.295g(较低Rf)(44%收率)的顺式非对映异构体。1H-NMR(500MHz,CDCl3)反式非对映异构体:δ0.90-0.96(m,2H),1.10-1.30(m,3H),1.55-1.85(m,6H),2.37-2.41(d,H),2.97-3.03(m,H),3.34-3.38(m,H),3.58-3.62(m,H),4.55-4.70(m,2H),4.70-4-73(m,H),5.03(bs,H),5.22-5.37(m,3H),5.87-5.93(m,H);顺式非对映异构体0.91-0.97(m,2H),1.10-1.31(m,3H),1.56-1.90(m,7H),2.44-2.48(m,H),2.81-2.87(m,H),3.35-3.39(m,H),3.63-3.67(m,H),4.53-4.70(m,3H),5.20-5.50(m,3H),5.89-5.95(m,H);两种非对映异构体的LC-MS:M/z=298(M+H+)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-环己基甲氧基-5-氧代-四氢呋喃-3-基)-酰胺(98ao)
由97b和顺-(2-环己基甲氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯,按照制备98a使用的方法制备,得到212mg(64%收率)的标题化合物。1H-NMR(500MHz,CDCl3):δ0.70-1.30(m,5H),1.30-1.85(m,9H),1.85-2.60(m,8H),2.75-3.00(m,H),3.10-3.80(m,4H),4.30-4.95(m,3H),5.42(d,0.85H),5.62(d,0.15H),6.87(d,0.15H),7.08(d,0.85H),7.25(d,H),7.60-7.90(m,3H),8.08(d,0.15H),8.50(d,0.85H);分析HPLC保留时间:11.81min;LC-MS:m/z=577(M+H+)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸{2R-[1S-(2R-异丙基-5S-甲基-环己基氧基)]-5-氧代-四氢呋喃-3-基}酰胺(98ap)
由97b和顺-{2-[1S-(2R-异丙基-5S-甲基-环己基氧基)]-5-氧代-四氢呋喃-3-基}氨基甲酸烯丙基酯按照用于制备98a的方法制得223mg(63%收率)的标题化合物。1H-NMR(500MHz,CDCl3):δ0.70-1.15(m,12H),1.20-1.85(m,8H),1.85-2.60(m,9H),2.74-2.88(m,H),3.35-3.85(m,3H),4.40-4.55(m,H),4.65-4.78(m,H),4.88-4.91(m,H),5.53(d,H),7.00-7.25(m,2H),7.60-7.90(m,3H),8.50(d,H);分析HPLC的保留时间:13.31min;LC-MS:m/z=619(M+H+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-环己基甲氧基-5-氧代-四氢呋喃-3-基)-酰胺(98aq)
由97a和顺-(2-环己基甲氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得113mg(56%收率)的标题化合物。1H-NMR(500MHz,CDCl3):δ0.70-1.39(m,5H),i.-Ac;-J..go(m,8H),1.90-2.20(m,3H),2.30-2.60H),2.80-3.00(m,H),3.15-3.80(m,4H),4.28-4.75(m,4H),4.89-4.93(m,H),5.42(d,H),6.74(d,H),6.87(d,H),7.30(d,H),7.51-7.53(m,H),7.74(d,H);分析HPLC保留时间:12.02min;LC-MS:m/z=535(M+H+)
(2-丁氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯,如化合物40所述,用正丁醇制备,得到878mg(29%收率)的标题化合物(313mg的反式非对映异构体,260mg的顺式非对映异构体和305mg的混合物)。1H-NMR(500MHz,CDCl3)反式非对映异构体:δ(较高Rf)0.89-0.96(t,3H),1.32-1.40(m,2H),1.54-1.63(m,2H),2.37-2.41(d,H),2.98-3.04(q,H),3.55-3.60(m,H),3.77-3.82(m,H),4.19-4.22(m,H),4.58(br,2H),5.03(br,H),5.23-5.40(m,3H),5.87-5.93(m,H),顺式非对映异构体(较低Rf)0.91-0.95(t,3H),1.34-1.39(m,2H),1.56-1.63(m,2H),2.42-2.50(m,H),2.83-2.87(m,H),4.07-4.11(t,H),4.45-4.50(m,0.5H),4.51-4.70(m,2.5H),5.23-5.35(m,2H),5.42-5.43(d,H),5.80-5.95(m,H);两种非对映异构体的LC-MS:m/z=258(M+H+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-丁氧基-5-氧代-四氢呋喃-3-基)-酰胺(98ar)
由97a和顺-(2-丁氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得118mg(48%收率)的标题化合物,为顺式非对映异构体。
1H-NMR(500MHz,CDCl3):δ0.80-1.02(m,2H),1.35-1.51(m,5H),1.51-1.70(m,2H),1.90-2.27(m,3H),2.30-2.46(m,H),2.80-2.90(m,H),3.55-3-94(m,4H),4.30-4.75(m,4H),4.90-5-00(m,H),5.44-5.46(m,H),6.73-6.80(m,H),6.80-6.93(m,H),7.16-7.25(m,H),7.49-7.60(m,H),7.70-7.84(m,H);分析HPLC保留时间:9.71min;LC-MS:m/z495(M+H+)
(2-异丁氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯,如化合物40所述,用异丁醇制得190mg(收率7.3%)的标题化合物,为反式非对映异构体和290mg(收率11%)的顺式非对映异构体:1H-NMR(500MHz,CDCl3)反式非对映异构体:δ(较高Rf)0.85-1.05(m,6H),1.82-1.98(m,H),2.37-2.42(d,H),2.98-3.04(m,-H),3.31-3.35(m,H),3.55-3.58(m,H),4.20-4.30(t,H),4.58(br,2H),5.07(br,H),5.22-5.43(m,3H),5.84-5.96(m,H),顺式非对映异构体(较低Rf)0.85-1.05(m,6H),1.88-1.95(m,H),2.40-2.51(m,H),2.83-2.90(m,H),3.33-3.36(m,H),3.61-3.65(m,H),3.87-3.88(d,H),4.40-4.68(m,3H),5.20-5.40(m,2H),5.42-5.43(d,H),5.80-5.97(m,H);两种非对映异构体的LC-MS:m/z=258(M+H+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-异丁氧基-5-氧代-四氢呋喃-3-基)-酰胺(98as)
由97a和顺-(2-异丁氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得93mg(38%收率)的标题化合物。1H-NMR(500MHz,CDCl3)δ0.74-0.76(t,0.6H),0.80-1.00(m,5.4H),1.40-1.50(m,3H),1.90-2.22(m,3H),2.33-2.45(m,H),2.80-2.90(m,H),3.32-3.38(m,H),3.55-3.80(m,3H),4.38(br,H),4.50-4.60(m,H),4.70-4.80(m,H),4.90-5.00(m,H),5.42-5.45(m,H),6.74-6.76(d,H),6.86-6.88(d,H),7.31-7.33(d,H),7.51-7.53(m,H),7.74-7.75(d,H);分析HPLC的保留时间:9.63 & 9.80分钟;LC-MS:m/z=495(M+H+)。
[2-(茚-2-基)氧基-5-氧代-四氢呋喃-3-基]-氨基甲酸烯丙基酯
由3-烯丙基氧基羰基氨基-4-羟基-丁酸叔丁基酯(5.2g,20mmol)如化合物40所述,用2-茚醇(8.05g,60mmol)制备,得到4.10g(65%收率)的标题化合物,为差向异构体的混合物。经纯化得到1.76g(28%收率)的4(S),5(R)差向异构体,为黄色油状物。1H NMR(500MHz,CDCl3)δ 2.42(dd,J=17.2,10.5Hz,JH),2.79(dd,J=17.2,8.4Hz,1H),2.99(dd,J=16.7,4.1Hz,1H),3.04(dd,J=16.7,4.1Hz,1H),3.22(dd,J=17.2,6.6Hz,1H),3.26(dd,J=17.2,6.6Hz,1H),4.53(m,3H),4.70(m,1H),5.20(m,2H),5.60(d,J=5.3Hz,1H),5.87(m,1H),7.17(m,4H)ppm。LC-MS(ES+):m/e=318(M+H)。分析HPLC(C18柱):17.094分钟。
还分离出差向异构体混合物(0.75g,12%收率)和4(S),5(S)差向异构体(1.59g,25%),为白色固体。1H-NMR(500MHz,CDCl3)δ2.38(d,J=17.9Hz,1H),3.0(m,3H),3.22(m,2H),4.13(m,1H),4.58(m,2H),4.68(m,2H),4.98(br s,1H),5.26(m,1H),5.57(s,1H),5.88(ddt,J=18.0,11.1,5.4Hz,1H),7.20(m,4H)ppm。LC-MS(ES+):m/e=318(M+H)。分析HPLC(C18柱):17.025(5.5%),17.325(94.5%)分钟。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸[2-(茚-2-基氧基)-5-氧代-四氢呋喃-3-基]-酰胺(98at)
由97a和[2-(茚醇-2-基]氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得标题化合物,为差向异构体的71∶29的混合物,为米色固体(0.20g,58%收率)。1H-NMR(500MHz,CDCl3)δ1.0-1.5(m,3H),1.6-2.3(m,4H),2.42(m,1H),2.6-3.4(m,6H),3.5-4.1(m,3H),4.2-4.9(m,4H),5.65(d,J=5.OHz,0.80H),5.8(m,0.07H),5.85(d,J=5.0Hz,0.13H),6.8-7.3(m,6E),7.4-7.9(m,3H)ppm。分析HPLC(C18柱)16.035(71.4%),16.476(28.6%)分钟。LC-MS(ES+):m/e=555(M+H)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸[2-(茚-2-基氧基)-5-氧代-四氢呋喃-3-基]-酰胺(98au)
由97b和[2-(茚醇-2-基)氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得标题化合物为76∶24的差向异构体混合物,为米色固体(0.22g,57%收率)。1H-NMR(500MHz,CDCl3)δ1.08(d,J=6.9Hz,0.4H),1.26(d,7=6.9Hz,0.6H),1.35(d,J=6.9Hz,2H),1.8-2.3(m,3H),2.28(s,2H),2.29(s,1H)2.4(m,1H),2.8(m,1H),3.10(m,2H),3.27(m,2H)3.58(m,2H),3.69(m,1H),4.5-4.9(m,4H),5.65(d,J=5.3Hz,0.68H),5.84(d,J=5.3Hz,0.18H),6.38(br,0.14H),6.9-7.7(m,6H),7.6-7.9(m,3H),8.33(brd,J=6.8Hz,0.18H),8.51(br d,J=8.0Hz,0.82H)ppm。分析HPLC(C18柱)15.596(76.2%),15.932(23.8%)分钟。LC-MS(ES+):m/e=597(M+H)
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-环戊基氧基-5-氧代-四氢呋喃-3-基)-酰胺(98av)
由97a和顺-(2-环戊基氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯按照用于制备98a的方法制得标题化合物,为米色固体(0.19g,59%收率)。1H-NMR(500MHz,CDCl3)δ1.2-2.4(m,15H),2.4-3.1(m,2H),3.6-3.9(m,2H),4.2-4.4(m,2H),4.5-5.0(m,4B),5.40(d,J=5.0Hz,0.35H),5.55(d,J=5.0Hz,0.65H),6.8-8.2(m,5H)ppm。分析HPLC(C18柱)14.065分钟。LC-MS(ES+):m/e=507(M+H)。
1-[2-(3,5-二氯-4-羟基-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(98aw)
由1-[2-(4-烯丙氧-3,5-二甲基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸叔丁基酯和顺-40化合物按照用于制备化合物98a的方法制得标题化合物,为淡黄色固体(1.087g,64%收率)。1H-NMR(500MHz,CDCl3)δ1.09(d,J=6.9Hz,0.6H),1.33(d,J=6.9Hz,2.4H),1.96(m,1H),2.03(m,1H),2.10(m,1H),2.28(m,0.8H),2.40(dd,J=17.3,10.2Hz,0.BH),2.56(m,0.2H),2.85(dd,J=17.3,B.5Hz,0.8H),3.09(dd,J=17.7,10.2Hz,0.2H),3.57(m,1H),3.73(dt,J=9.2,7.9Hz,0.5H),4.09(m,0.2H),4.21(d,J=7.9Hz,0.2H),4.44(d,J=9.8Hz,0.2H),4.55(dd,J=8.0,3.0Hz,0.8H),4.62(d,J=11.6Hz,1H),4.70(m,1H),4.80(m,1H),4.89(d,J=11.6Hz,0.5H),5.52(d,J=5.2Hz,0.8H),5.82(d,J=5.2Hz,0.2H),6.51(br,0.2H),6.62(br,0.8H),7.0-7.4(m.7H),7.43(s,0.4H),7.66(d,J=1.0Hz,1.6H)ppm。分析HPLC(C18柱)10.135分钟。LC-MS(ES+):m/e=564,566(6∶4)(M+H)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-环戊基氧基-5-氧代-四氢呋喃-3-基)-酰胺(98ax)
按照用于制备(98av)的方法,用反-(2-环戊基氧基-5-氧代-四氢呋喃-3-基)-酰胺制备,得到标题化合物,为米色固体(0.24g,74%收率)。1H-NMR(500MHz,CDCl3)δ1.41(d,J=6.5Hz,3H),1.7(m,7H),1.98(br,2H),2.13(br,2H),2.27(m,1H),2.69(m,1H),2.86(dd,J=18.0,6.8Hz,0.7H),2.98(dd,J=18.3,8.2Hz,0.3H),3.60(br,1.4H),3.77(br,0.6H),4.1-4.6(m,5H),4.82(m,1H),5.27(m,0.65H),5.51(d,J=5.3Hz,0.05H),5.59(br s,0.3H),6.76(br,1H),7.00(br,1H),7.49(br,1H),7.74(br,1H),7.89(br,1H)ppm。分析HPLC(C18柱)9.756分钟。LC-MS(ES+):m/e=507(M+H)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(98ay)
由(2-乙氧基-5-氧代-四氢呋喃-3-基)氨基甲酸烯丙基酯和97b按照用于98a的方法制备。分离出的标题化合物为白色固体(51mg,18%收率)。1H-NMR(500MHz,1∶1 CDCl3∶CD3OD)δ1.08-1.35(m,3H),1.35-1.55(m,3H),1.75-2.44(m,4H),2.26(s,3H),2.44-3.07(m,2H),3.48-3.97(m,2H),4.18-4.92(m,5H),5.32(d,0.4H),5.47(d,0.1H),5.58(d,0.4H),5.64(d,0.1H),7.70-8.35(m,3H)。分析HPLC 10.37,10.54分钟。LC-MS(ES+)m/e=509.2(M+H+)。
[2-(2-氯-乙氧基)-5-氧代-四氢呋喃-3-基]氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯(5.2g,20mmol),如化合物40所述,用氯乙醇(4.05mL,60mmol)制备,得到1.84g(35%收率)的标题化合物,为差向异构体的混合物。对于反式非对映异构体:1H-NMR(500MHz,CDCl3)δ2.42(dd,J=18.1Hz,1H),3.00(dd,J=18.1,7.8Hz,1H),3.63(m,2H),3.85(m,1H),4.02(m,1H),4.23(m,1H),4.57(br s,2H),5.17(br s,1H),5.22(d,H=11.5Hz,1H),5.29(d,J=16.8Hz,1H),5.44(s,1H),5.89(m,1H)ppm;LC-MS(ES+)m/e=264(M+H)。顺-非对映异构体:1H-NMR(500MHz,CDCl3)δ2.47(dd,J=17.3,10.7Hz,1H),2.83(dd,J=17.3,8.4Hz,1H),3.65(m,2H),3.83(m,1H),4.11(m,1H),4.57(m,3H),5.22(d,H=10.4Hz,1H),5.30(d,J=17.2Hz,1H),5.33,(m,I.H),5.47(d,J=5.2Hz,1H),5.89(ddt,J=17.1,11.0,5.4Hz,1H)ppm;LC-MS(ES+) m/e=264(M+H)。
[2-(2-吗啉-4-基-乙氧基)-5-氧代-四氢呋喃-3-基]-氨基甲酸烯丙基酯
由[2-(2-氯-乙氧基)-5-氧代-四氢呋喃-3-基]-氨基甲酸烯丙基酯,通过与吗啉(2eq)和KI(1eq)在DMF中反应制备。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸[2-(2-吗啉-4-基乙氧基)-5-氧代-四氢呋喃-3-基]-酰胺(98az)
[2-(4-氯-苄氧基)-5-氧代-四氢呋喃-3-基]-氨基甲酸烯丙基酯
由3-烯丙氧羰基氨基-4-羟基-丁酸叔丁基酯,如化合物40所述,用4氯苄醇制备,得到标题化合物为白色固体。反式非对映异构体:HPLC(C18柱)10.924min;1H-NMR(500MHz,CDCl3)δ2.41(d,J=5.0Hz,1H),3.02(dd,J=18.1,7.8Hz,1H),4.25(br,1H),4.56(m,2H),4.58(d,J=11.7Hz,1E),4.79(d,J=11.7Hz,1H),4.99(br,1H),5.22(dd,J=10.4,1.1Hz,1H),5.28(dd,J=17.2,1.3Hz,1H),5.44(s,1H),5.86(m,1H),7.25(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,2H)ppm;LC-MS(ES+) m/e=326(M+H);顺-非对映异构体:HPLC(C18柱)10.780min;1H-NMR(500MHz,CDCl3)δ2.47(dd,J=17.3,10.5Hz,1H),2.85(dd,J=17.3,8.4Hz,1H),4.55(m,3H),4.58(d,J=11.7Hz,1H),4.84(d,J=11.7Hz,1H),5.23(dd,H=10.4,I.1Hz,1H),5.30(d,J=16.6Hz,1H),5.49(d,J=5.0Hz,1H),5.89(ddt,J=17.1,11.0,5.4Hz,1H),7.23(d,J=8.3Hz,2H),7.31(d,J=8.3Hz,2H)ppm;LC-MS(ES+) m/e=326(M+H)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸[2-(4-氯-苄氧基)-5-氧代-四氢呋喃-3-基]-酰胺(98ba)
由97a和顺-[2-(4-氯-苄氧基)-5-氧代-四氢呋喃-3-基]-氨基甲酸烯丙基酯按照用于98a的方法制得154mg(65%收率)的标题化合物,为淡粉色固体。HPLC(C18柱)10.597min;1H-NMR(500MHz,CDCl3)δ1.14(d,J=6.8Hz,0.75H),1.34,(d,J=6.8Hz,2.25H),1.6(br,0.25H),1.91(m,1H),2.03(m,1H),2.10(m,1H),2.29(m,0.75H),2.40(dd,J=17.3,10.3Hz,0.75H),2.51(m,0.25H),2.82(dd,J=17.3,B.5Hz,0.75H),3.08(dd,J=17.9,10.9Hz,0.25H),3.58(m,1H),3.72(dd,J=16.5,8.7Hz,0.75H),4.10(m,0.25H),4.22(d,J=5.0Hz,0.25H),4.39(d,J=10.5Hz,0.25H),4.54(dd,J=9.1,2.9Hz,0.75H),4.60(d,J=11.9Hz,0.75H),4.68(m,1H),4.85(d,J=11.7Hz,0.75H),4.86(m,1H),5.49(d,J=5.2Hz,0.75H),5.81(d,J=5.2Hz,0.25H),6.2(br,0.25H),6.74(m,2H),7.05(d,J=S.5Hz,0.5H),7.17(d,J=8.4Hz,0.5H),7.30(m,3.25H),7.48(dd,J=8.4,2.0Hz,0.75H),7.56(d,J=1.9Hz,0.25H),7.73(d,J=1.9Hz,0.75H),8.42(d,J=5.7Hz,0.25H)ppm;LC-MS(ES+) m/e=563,565(M+H)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸[2-(4-氯-苄氧基)-5-氧代-四氢呋喃-3-基]-酰胺(98bb)
由97b和顺-[2-(4-氯-苄氧基)-5-氧代-四氢呋喃-3-基]-氨基甲酸烯丙基酯按照用于制备98a的方法制得165mg(64%收率)的标题化合物,为淡黄色固体。HPLC(C18柱)10.491min;1H-NMR(500MHz,CDCl3)δ1.16(d,J=6.8Hz,0.6H),1.35,(d,J=6.8Hz,2.4H),1.94(m,1H),2.04(m,1H),2.10(m,1H),2.25(s,3H),2.28(m,1H),2.40(dd,J=17.3,10.4Hz,0.8H),2.53(m,0.2H),2.84(dd,J=17.3,8.5Hz,0.8H),3.02(dd,J=17.5,10.5Hz,0.2H),3.58(m,1H),3.72(ddd,J=17.2,8.3,8.3Hz,0.8H),4.13(m,0.2H),4.22(d,J=8.2Hz,0.2H),4.40(d,J=10.9Hz,0.2H),4.54(dd,J=8.1,3.0Hz,0.8H),4.60(d,J=11.8Hz,0.8H),4.69(m,1H),4.85(d,J=11.8Hz,0.8H),4.87(m,1H),5.49(d,J=5.2Hz,0.8H),5.80(d,J=5.2Hz,0.2H),6.47(br,0.2H),6.95(d,J=8.3Hz,0.8H),7.05(d,J=8.3Hz,0.4H),7.18(d,J=8.3Hz,0.4H),7.29(m,3.2H),7.49(dd,J=8.6,1.9Hz,0.2H),7.63(dd,J=8.6,1.9Hz,0.8H),7.74(d,J=1.9Hz,1H),7.85(d,J=1.9Hz,0.8H),8.25(d,J=6.4Hz,0.2H),8.51(m,0.8H)ppm;LC-MS(ES+) m/e=605,607(M+H)。
方案ⅩⅧ
2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)哌啶-1-甲酸-叔丁基酯(100)
由哌啶-1,2-二甲酸1-叔丁基酯(99)和化合物40,按照用于制备化合物75的方法制备,得到标题化合物,为黄色固体(2.63g,57%收率)。1H-NMR(500MHz,CDCl3)δ1.15-1.79(rn,15H),2.12-2.50(m,2H),2.56-2.83(m,1H),2.89(dd,0.5H),3.05(dd,0.5H),3.81-4.15(br s,1H),4.36-4.97(m,3H),5.37-5.61(m,1H),6.42-6.89(br s,1H),7.17-7.51(m,5H)。LC-MS(ES+)m/e=419.4(MH+)。
{2-[2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-哌啶-1-基]-1-甲基-2-氧代-乙基}氨基甲酸叔丁基酯(101)
将2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-哌啶-1-甲酸叔丁基酯(100)溶解于20%TFA的二氯甲烷(25mL)溶液中并室温下搅拌50分钟。蒸发溶剂并将残余的酸与二氯甲烷(4x)共沸。将所得油状物溶解于二氯甲烷(20mL)和DMF(5mL)中,冷却至0℃,并用DIEA(4.7mL,27.0mmol),Boc-丙氨酸(970mg,5.1mmol),HOBt(924mg,6.8mmol)和EDC(1.31g,6.8mmol)处理,将此溶液在氮气氛下搅拌18小时。溶剂真空浓缩,然后溶解于EtOAc中,并用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤。将此有机层用无水硫酸钠干燥并蒸发得到桔黄色固体,将其溶解于二氯甲烷并滴加至乙醚中,得到白色沉淀。此标题化合物为白色固体(1.21g,73%收率)。1H-NMR(500MHz,CDCl3)δ1.10-1.79(m,18H),1.98-2.19(m,0.5H),2.28-2.88(m,3H),2.89-3.13(m,0.5H),3.78-3.95(m,0.5H),4.21-5.16(m,5.5H),5.38-5.59(m,0.3H),5.66-(d,0.4H),5.80(d,0.3H),7.24-7.40(m,5H)。LC-MS(ES+) m/e=490.3(MH+)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]哌啶-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)酰胺(102a)
由{2-[2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-哌啶-1-基]-1-甲基-2-氧代-乙基}氨基甲酸-叔丁基酯和4-乙酰基氨基-3-氯苯甲酸,按照用于制备98a的方法制备,得到标题化合物(71mg,47%收率)。1H-NMR(500MHz,CDCl3)δ1.10-1.97(m,10H),2.10-2.68(m,5H),2.73-3.24(m,2H),3.62-3.92(m,1H),4.24-5.27(m,5H),5.48-5.59(m,0.5H),5.75-5.85(m,0.5H),6.51-6.61.(d,1H),7.05-7.45(m,4H),7.52-8.12(m,4H)。分析HPLC 8.30分钟。LC-MS(ES+) m/e=585.3(MH+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-哌啶-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(102b)
如102a所述制备,得到标题化合物(0.06g,27%收率),为黄色固体。1H-NMR(500MHz,CDCl3)δ1.2-1.8(m,7H)2.1-2.6(m,2H),2.7-3.2(m,4H),3.6-4.0(m,1H),4.3-4.9(m,7H),5.0-5.8(m,2H),6.5-7.0(m,2H),7.2-7.8(m,5H)ppm。分析HPLC(氰基柱)14.559(39.6%),15.198(60.4%)。LC-MS:(ES+):m/e=543(M+H)
4-羟基-吡咯烷-1,2-二甲酸1-苄基酯2-叔丁基酯(104)
按照用于制备化合物95的方法制备化合物104。
在55℃下,将Cbz-Hyp-OH(4.854g,18mmol)的DMA(135ml)悬浮液,苄基三乙基氯化铵(4.105g,18mmol),碳酸钾(64g,46mmol)和2-溴-2-甲基丙烷(99ml,859mmol)搅拌18小时。用冰水稀释此混合物并用EtOAc(3x)萃取,将此有机相用水,0.5N硫酸氢钠溶液和盐水洗涤,干燥并真空除去溶剂,得到标题化合物,为黄色油状物(5.368g,98%收率)。1H-NMR(500MHz,CDCl3)δ1.33(s,5H),1.47(s,4H),2.01-2.14(m,1B),2.22-2.38(m,1H),3.50-3.72(m,2H),4.34-4.45(m,1H),4.45-4.53(m,1H),5.04-5.20(m,2H),7.22-7.42(m,5H)。分析HPLC 10.14分钟。LC-MS(ES+) m/e=322.2(MH+)。
4-氟-吡咯烷-1,2-二甲酸1-苄基酯2-叔丁基酯(105)
在-78℃下,将化合物104(4.262g,13.96mmol)的二氯甲烷(100mL)溶液用DAST(1.80ml,13.6mmol)处理,搅拌10分钟,然后升温至室温并在氮气氛下搅拌60小时。将此混合物倒入到冰冷的碳酸氢钠(10%溶液,350ml)中并用二氯甲烷(2x)萃取,将此有机相用水、盐水洗涤,用无水硫酸钠干燥并浓缩得到棕色油状物(4.299g),将其通过快速柱色谱在硅胶上用己烷/EtOAc(90/10至80/20%)洗脱纯化。获得的标题化合物为黄色油状物(2.805g,64%收率)。1H-NMR(500MHz,CDCl3)δ1.37(s,4.5H),1.45(s,4.5H),2.20-2.55(m,2H),3.61-3.93(m,2H),4.41(d,0.5H),4.49(d,0.5H),5.03-5.21(m,3H),7.23-7-44(m,5H)。分析HPLC 12.15分钟。LC-MS(ES+)m/e=324.2(MH+)。
1-(2-苄氧基羰基氨基-丙酰基)-4-氟-吡咯烷-1,2-二甲酸1-苄基酯2-叔丁基酯(106)
将化合物105(2.72g,8.42mmol)的甲醇(50ml)溶液和10%Pd/C(1.27g)在氢气氛下搅拌2小时,然后通过硅藻土板过滤,并蒸发溶剂得到黄色油状物(1.526g)。将此油状物溶解于二氯甲烷(30ml)并用DIEA(1.5ml,8.6mmol),Cbz-ala-OH(2.34g,10.5mmol)和EDC(2.32g,12mmol)在0℃下处理。将此混合物在0℃下再搅拌10分钟,然后升温至室温,并搅拌18小时。溶剂真空浓缩并将此残余物溶解于EtOAc,然后用0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤。将此有机层用无水硫酸钠干燥并蒸发得到白色固体,将其通过快速柱色谱,用己烷/EtOAc(80/20至60/40%)洗脱纯化。分离出的标题化合物为白色固体(286g,86%,由4-氟吡咯烷-1,2-二甲酸1-苄基酯2-叔丁基酯)。1H-NMR(500MHz,CD3OD)δ1.26-1.59(m,12H),2.20-2.67(m,.2H),3.45-4-13(m,2H),4.25-4.47(m,1H),4.58-4.71(m,1H),4.96-5,.17(m,2H),5.19-5.45(m,1H),7.23-7.48(m,5H)。分析HPLC 16.36分钟。LC-MS(ES+)m/e=395.3(MH+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-4-氟-吡咯烷-2-甲酸-叔丁基酯(107)
将化合物106(2.65g,6.72mmol)的甲醇(40ml)悬浮液和10%Pd/C(1.32g)在氢气氛下搅拌1.5小时,通过硅藻土板过滤并浓缩得到蜡状固体(1.694g)。将此固体溶解于二氯甲烷(25ml)并用DIEA(3.4ml,19.5mmol),4-氨基-3-氯苯甲酸(1.362g,7.9mmol),HOBt(1.164g,8.62mmol)和EDC(1.645g,8.57mmol)在0℃下在氮气氛下处理。让此混合物升温至室温并搅拌18小时。溶剂真空浓缩。将此残余物溶解于EtOAc,用水(4x),0.5N硫酸氢钠(2x),饱和碳酸氢钠(2x)和盐水洗涤。将此有机层用无水硫酸钠干燥并蒸发得到白色固体,将其通过快速柱色谱用二氯甲烷/MeOH(99/1至98/2%)洗脱纯化。得到的产物为白色固体(2.705g,97%)。1H-NMR(500MHz,CD3OD)δ1.33(s,9H),1.48(d,3H),2.31-2.55(m,2H),3.93(d,d,1H),4.02-4.21(m,1H),4.59-4.76(m,IE),5.31(br s,0.5H),5.41(brs,0.5H),6.78(d,1H),7.57(d,d,1H),7.78(s,1H),8.31(d,1H)。分析HPLC 14.14分钟。LC-MS(ES+) m/e=414.2(MH+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-4-氟-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(108a)
由顺-(2-苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯和107a,按照合成98a的方法制备。分离出的标题化合物为白色固体(41mg,15%收率)。1H-NMR(500MHz,CD3OD)δ0.94(d,0.3H),1.07(d,1H),1.40(m,1.7H),2.21-2.65(m,2.2H),2.70-2.85(m,1.4H),2.96-3.08(m,1.4H),2.96-3.08(dd,0.4H),3.57-4.24(m,3H),4.41-4.93(m,4H),5.14-5.45(m,1H),5.60-5.67(m,0.6H),5.77(d,0.4H),6.77(dd,1H),7.15-7.41(m,5H),7.51-7.62(m,1H),7.77(dd,1H)。分析HPLC 12.83分钟。LC-MS(ES+) m/e=547.1(MH+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-4-氟-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(108b)
由(2-苄氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯107a,按照用于合成98a的方法制备。分离出的标题化合物为白色固体(654mg,54%收率)。1H-NMR(500MHz,CD3OD))δ1.07(d,0.5H),1.25-1-56(m,2.5H),2.21-2.65(m,2.3H),2.68-2.89(m,1H),2.91-3.10(m,0.7H),3.57-4.23(m,2H),4.32-4.95(m,5H),5.16-5.52(m,1H),5.45-5.50(m,0.3H),5.54-5.58(m,0.2H),5.61-5.67(m,0.3H),5.77(d,0.2H),6.72-6.84(m,1H),7.16-7.41(m,5H),7.50-7.65(m,1H),7.71-7.87(m,1H)。分析HPLC12.83分钟。LC-MS(ES+) m/e=547.1(MH+)
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-4-氟-吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(108c)
由顺-(2-乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯和107a按照合成98a的方法制得标题化合物(100.3mg,38%收率)。1H-NMR(500MHz,CD3OD)δ1.09(t,1.2H),1.25(t,1.8H),1.40(d,1H),1.49(d,2H),2.33-2.61(m,2H),2.65-2.95(m,2H),3.44-4.30(m,4H),4.47-4.79(m,3H),5.18-5.25(m,0.2H),5.275.36(m,0.5H),5.39-5.46(m,0.3H),5.56(m,1H),6.72-6.94(m,0.5H),7.54-7.69(m,0.5H),7.79(d,0.55H),8.06(d,0.SSH),9.00(d,0.3H)。分析HPLC 8.46分钟。LC-MS(ES+) m/e=485.2(MH+)。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-4-氟-吡咯烷-2-甲酸[2-(2-异丙基-5-甲基-环己基)-5-氧代-四氢呋喃-3-基]-酰胺(108d)
由{2-[1R-(2S-异丙基-5R-甲基环己基氧基)]-5-氧代-四氢呋喃-3-基}-氨基甲酸烯丙基酯和107a按照合成98a的方法制得标题化合物(95mg,31%收率)。1H-NMR(500MHz,CD3OD)δ0.42(d,2H),0.57(d,2H),0.60-1-10(m,10H),1.22-1.76(m,6H),1.96-2.17(m,1H),2.29-2.60(m,2H),2.61-2.88(m,1.5H),3.02-3.23(dd,0.5H),3.37-3.47(m,0.5H),3.50-3.61(m,0.5H),3.63-4.24(m,2H),4.48-4.62(m,3H),5.18-5.48(m,1H),5.72(d,0.4H),5.82(d,0.6H),6.77-6.84(m,1H),7.53-7.67(m,1H),7.78(d,0.4H),7.84(d,1H)/分析HPLC 8.34分钟。LC-MS(ES+) m/e=595(MH+)。
方案ⅩⅩ
{2-[2-(2-乙氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)吡咯烷-1-基]-1-甲基-2-氧代-乙基}氨基甲酸叔丁基酯(109)
由(2-乙氧基-5-氧代-四氢呋喃-3-基)氨基甲酸烯丙基酯74,按照用于合成化合物75的方法制备,得到标题化合物,为淡黄色固体(660mg,73%收率)。1H-NMR(500MHz,CD3 OD)δ1.14-1.36(m,6H),1.42(s,9H),1.75-2.29(m,4H),2.48(dd,0.5H),2.58(dd,0.5H),2.72-2.85(m,0.5H),2.99(dd,0.5H),3.43-3.91(m,4H),4.07-4.52(m,2.5H),4.53-4.72(m,0.5H),5.37(s,0.5H),5.57(d,0.5H)。分析HPLC(2种非对映异构体的混合物)7.92,8.14分钟。LC-MS(ES+) m/e=414.3(MH+)。
1-[2-(4-烯丙基氧基-3,5-二氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(110)
由化合物109和4-烯丙氧-3,5-二氯-苯甲酸,按照用于合成化合物82的方法制备,得到标题化合物为s白色固体(228mg,65%)。1H-NMR(500MHz,CD3OD)δ1.10-1.30(m,4H),1.32-1.52(m,3H),1.63-2.31(m,4H),2.41-2.50(d,0.5H),2.52-2.61(dd,0.5H),2.67-2.81(m,0.5H),2.94-3.05(dd,0.5H),3.47-3.96(m,4H),4.21-4.81(m,5H),5.22-5.32(m,1H),5.35-5.49(m,1.5H),5.55-5.63(m,0.5H),6.06-6.21(m,1H),7.90(s,2H)。分析HPLC(2种非对映异构体的混合物)12.56分钟。LC-MS(ES+) m/e=542.3(MH+)。
1-[2-(3,5-二氯-4-羟基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(111)
在0℃下,向化合物110(194mg,0.36mmol)的二氯甲烷(5ml)溶液中,加入DMBA(70.7mg,0.45mmol)和Pd(PPh3)4(50.3mg,0.044mmol)。15分钟后将此溶液升温至室温,搅拌2小时,用二氯甲烷稀释,然后用水(2x)和盐水洗涤。将此有机层用无水硫酸钠干燥并蒸发得到粗品。进行快速色谱用二氯甲烷/甲醇(99/1至95/5%)洗脱,得到标题化合物(138.6mg,77%收率)。1H-NMR(500MHz,CD3OD)δ1.13-1.31(m,3H),1.35-1.49(m,3H),1.84-2.35(m,4H),2.43-3.05(m,2H),3.48-3.93(m,4H),4.22-4.80(m,3H),5.38(d,0.4H),5.46(s,0.1H),5.55-5.61(m,0.5H),7.76-7.94(m,2H)。分析HPLC 8.70分钟。LC-MS(ES+) m/e=502.2(MH+)。
方案ⅩⅪ
化合物116a-116h按照化合物98所述制备,不同的只是用1-(2-苄氧基羰基氨基-丙酰基)-4,4-二氟吡咯烷-2-甲酸叔丁基酯(114)代替1-(2-苄氧基羰基氨基-丙酰基)-吡咯烷-2-甲酸叔丁基酯(95)。
制备1-(2-苄氧基羰基氨基-丙酰基)-4,4-二氟-吡咯烷-2-甲酸叔丁基酯(114)
将4,4-二氟-吡咯烷-1,2-二甲酸-1-苄基酯-2-叔丁基酯(113)(Karanewsky,等,J.Med.Chem.33,pp.1459-1469(1990))(0.42g,1.23mmol)和10%钯碳(0.22g)在甲醇(6mL)中的溶液,在1个大气压的氢气压下搅拌3小时。将此混合物通过硅藻土板过滤并蒸发。将此残余物溶解于二氯甲烷(4mL)和DMF(2mL),并冷却至0℃。加入2-苄氧基羰基氨基-丙酸(0.30g,1.35mmol),EDC(0.30,1.54mmol),DIEA(0.65mL)和HOBt(0.17g,1.23mmol)并将此反应在0℃搅拌0.5小时,然后在氮气氛下室温搅拌16小时。真空除去溶剂并将此残余物溶解于乙酸乙酯,然后用10%硫酸氢钠、饱和碳酸氢钠、水和盐水洗涤,用硫酸钠干燥并蒸发。通过快速色谱在硅胶上用25∶75乙酸乙酯∶己烷洗脱纯化,得到1-(2-苄氧基羰基氨基丙酰基)-4,4-二氟-吡咯烷-2-甲酸叔丁基酯(0.39g,77%收率),为无色油状物。1H-NMR(500MHz,CDCl3)δ1.3-1.6(m,12H),2.5(m,0.5H),2.7(m,1.2H),3.9(m,1H),4.1(m,1H),4.4(m,1H),4.7(m,1H),5.1(m,2H),5.59(br d,J=7.7Hz,0.8H),5.7(br d,J=7.7Hz,0.2H),7.35(m,5H)ppm。分析HPLC(氰基柱)17.069分钟。LC-MS(ES+) m/e=413(M+H),357(M+H-叔丁基),313[M+H-(CO2叔丁基)]。
1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-4,4-二氟-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(116a)
由化合物115a和顺-40化合物制得标题化合物,为米色固体(0.14g,73%收率)。1HNMR(500MHz,CD3OD)δ1.0-1.5(m,3H),2.0-3.5(m,4H+CH3OH),3.5-5.5(M,6H+H2O),5.6-5.8(M,1H),6.7-6.8(m,1H),7.1-7.8(m,8H),8.2-8.6(m,1H)ppm。分析HPLC(氰基柱)13.744分钟。LC-MS(ES+) m/e=565(M+H)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-4,4-二氟-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(116b)
由115b和顺-40得到标题化合物,为米色固体(0.08g,38%收率)。1H-NMR(500MHz,CDCl3)δ1.03(d,J=6.9Hz,0.4H),1.30(d,J=6.9Hz,0.6H),2.25(d,J=2.9Hz,3H),2.4-3.2(m,4H),3.6-4.4(m,4H),4.6-4.9(m 3H),5.52(d,J=5.2Hz,0.6H),5.78(d,J=5.2Hz,0.4H),6.6(br s,1H),6.9-7.9(m,8H),8.39(d,J=5.1Hz,0.4H),8.44(d,J=8.3Hz,0.6H),8.74(d,J=6.8Hz,1H)ppm。分析HPLC(氰基柱)11.830分钟。LC-MS(ES+):m/e=607(M+H)
1-[2-(4-乙酰基氨基-5-氯-2-甲氧基-苯甲酰基氨基)-丙酰基]-4,4-二氟-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(116c)
由115c和顺-40得到标题化合物,为米色(0.07g,29%收率)。1H-NMR(500MHz,CDCl3)δ0.99(d,J=6.9Hz,1.35H),1.32(d,J=6.9Hz,1.65H),2.25(s,1.5H),2.26(s,1.5H),2.3-3.2(m,4H),3.95(s,0.55H),3.98(s,0.45H),3.7-4.1(m,2.5H),4.2-4.5(m,1.5H),4.6-4.9(m,3H),5.52(d,J=5.3Hz,0.55H),5.80(d,J=5.3Hz,0.45H),7.0-7.4(m,4H),7.7-7.9(m,2H),8.0-8.4(m,2H),8.49(d,J=6.5Hz,1H),8.93(d,J=6.7Hz,1H)ppm。分析HPLC(氰基柱)12.959分钟。LC-MS(ES+):m/e=637(M+H)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-4,4-二氟-吡咯烷-2-甲酸(2-乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(116d)
由115b和顺-(2-乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯得到标题化合物,为92∶8的差向异构体混合物。米色固体(0.27g,66%收率)。1H-NMR(500MHz,CDCl3)δ1.0-1.5(m,6H),2.25(s,1.5H),2.26(s,1.2H),2.3-3.1(m,4H),3.3-4.3(m,4H),4.5-4.9(m,3H),5.45(d,J=5.3Hz,0.75H),5.59(d,J=5.2Hz,0.25H),6.7-7.1(m,2H),7.62(dd,J=8.7,2.0Hz,1H),7.76(m,1H),7.85(d,J=2.0Hz,1H),8.48(m,1H)ppm。分析HPLC(C18柱)13.300(91.8%),14.046(8.2%)分钟。LC-MS(ES+):m/e=545(M+H)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-4,4-二氟-吡咯烷-2-甲酸(2-环已基氧基-5-氧代-四氢呋喃-3-基)-酰胺(116e)
由115b和顺-(2-环己基氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯制得标题化合物,为93∶7的差向异构体的混合物。1H-NMR(500MHz,CDCl3)δ1.0-2.0(m,13H),2.25(s,2H),2.26(s,1H),2.40(dd,J=17.3,10.1Hz,1H),2.84(dd,J=17.3,5.5Hz,.1H),2.5-3.0(m,2H),3.5-4.3(m,3.5H),4.5-4.9(m,2.5H),5.59(d,J=5.3Hz,0.75H),5.76(d,J=5.2Hz,0.25H),6.74(br d,J=5.7Hz,0.25H),6.93(br d,J=7.1Hz,1H),7.06(br d,J=7.8Hz,0.75H),7.62(dd,J=8.6,2.0Hz,1H),7.78(m,1H),7.85(d,J=2.0Hz,1H),8.35(br d,J=6.6Hz,0.25H),8.50(br d,J=8.2Hz,0.75H)ppm。分析HPLC(C18柱)17.112(93%),17.433(7%)分钟。LC-MS(ES+):m/e=599(M+H)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-4,4-二氟-吡咯烷-2-甲酸[2-(茚醇-2-基)氧基-5-氧代-四氢呋喃-3-基]-酰胺(116f)
由115b和[2-(茚醇-2-基)氧基-5-氧代-四氢呋喃-3-基]氨基甲酸烯丙基酯制得标题化合物,为62∶38差向异构体的混合物。米色固体(0.34g,71%收率)。1H-NMR(500MHz,CDCl3)δ1.09(d,J=6.9Hz,0.6H),1.21(d,J=6.9Hz,0.9H),1.33(d,J=6.9Hz,0.9H),1.42(d,J=6.9Hz,0.6H),2.28(s,2H),2.29(s,1H),2.40(dd,J=17.4,10.3Hz,1H),2.4-3.3(m,7H),3.6-4.2(m,2H),4.5-4.8(m,4H),5.66(m,0.6H),5.84(d,J=4.3Hz,0.2H),6.22(m,0.2H),6.7-7.0(m,2H),7.2-7.3(m,4H),7.5-7.7(m,1H),7.8-8.0(m,2H),8.52(m,0.6H),8.62(br d,J=6.5Hz,0.4H)ppm。分析HPLC(C18柱)16.556(62.0%),16.824(38.0%)分钟。LC-MS(ES+):m/e=633(M+H)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-4,4-二氟-吡咯烷-2-甲酸(2-环戊基甲氧基-5-氧代-四氢呋喃-3-基)-酰胺(116g)
由115b和顺-(2-环戊基甲氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸烯丙基酯制得标题化合物,为米色固体(0.20g,44%收率)。1H-NMR(500MHz,CDCl3)δ1.0-1.8(M,11H)1.9-3.0(m,5H),2.26(s,3H),3.29(m,0.25H),3.47(m,0.75H),3.58(m,0.25H),3.74(m,0.75H),3.8(m,0.75H),4.1(m,0.25H),4.25(m,1H),4.4-4.8(m,3H),5.44(d,7=5.2Hz,0.75H),5.62(d,J=5.2Hz,0.25H),6.7(br,0.25H),6.91(d,J=7.1Hz,1H),7.1(m,0.75H),7.59(d,J=8.5Hz,0.25H),7.63(dd,J=5.5,2.5Hz,0.75H),7.75(m,1H),7.86(d,J=1.5Hz,1H),8.33(brd,J=6.5Hz,0.25H),8.49(br d,J=8.4Hz,0.75H)ppm。分析HPLC(C18柱)17.705分钟。LC-MS(ES+):m/e=599(M+H)。
1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-4,4-二氟-吡咯烷-2-甲酸(2-苯基乙氧基-5-氧代-四氢呋喃-3-基)-酰胺(116h)
由115b和顺-(5-氧代-2-苯乙基氧基四氢呋喃-3-基)-氨基甲酸烯丙基酯制得标题化合物,为米色固体(0.15g,24%收率)。1H-NMR(500MHz,CDCl3)δ1.29(d,J=6.9Hz,0.75H),1.40(d,L7=6.9Hz,2.25H),2.25(s,2.25H),2.26(s,0.75H),2.3-3.0(m,6H),3.7-4.8(m,7H),5.38(d,J=5.3Hz,0.75H),5.67(d,J=5.1Hz,0.25H),6.65(m,1H),6.90(d,J=7.0Hz,0.75H),7.06(d,J=7.6Hz,0.25H),7.1-7.3(m,5H),7.57(d,J=8.6Hz,0.25H),7.63(d,J=8.6Hz,0.75H),7.75(m,1H),7.86(d,J=1.8Hz,1H),8.35(d,J=6.2Hz,0.25H),8.49(d,J=8.3Hz,0.75H)ppm。分析HPLC(C18柱)17.265分钟。LC-MS(ES+):m/e=621(M+H)。
2-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)吡咯烷-1-甲酸叔丁基酯(118)
由化合物40(1.16g,4.0mmol)和Boc-Pro-OH按照制备化合物100的方法(方案ⅩⅧ)制得1.53g(94%收率)的标题化合物,为白色固体。1H-NMR(500MHz,CDCl3):δ1.61(br,9H),1.88(br,2H),2.00-2.50(m,3H),2.80-3.10(m,H),3.20-3.60(m,2H),4.05-4.45(m,1.5H),4.58-4.80(m,1.5H),4.83-4.98(m,H),5.43-5.53(m,H),7.26-7.45(m,5H),7.60-7.80(d,H);分析HPLC:11.32min;LC-MS:m/e=405(M+H+)。
2-苯基氨基丙酸(119)
将丙氨酸(356mg,4.0mmol),碘代苯(816mg,4.0mmol),反-二氯双(三-o-甲苯基膦)钯(Ⅱ){Pd[P(o-Tol)3]2Cl2}(160mg,0.2mmol),碘化铜(Ⅰ)(40mg,0.2mmol),碳酸钾(552mg,4.0mmol),苄基三乙基氯化铵(160mg,0.8mmol),三乙胺(1.6mL)和水(0.8mL)在DMF(8mL)中的混合物,在氮气氛下在100℃下搅拌20小时。将此混合物冷却至室温,用乙酸乙酯(50mL)和水(50mL)稀释,用6N HCl酸化至pH=2至3。用乙酸乙酯(50mL×4)萃取水层。将合并的有机层用水、盐水洗涤,用无水硫酸钠干燥,过滤和真空蒸发得到红色油状物。进行快速色谱己烷/乙酸乙酯/乙酸(95/5/0.5至80/20/0.5)洗脱得到300mg(45%收率)的标题化合物,为粉红色固体。1H-NMR(500MHz,CDCl3/CD3OD=0.5ml/3滴)δ1.45(d,3H),4.02-4.15(m,H),6.57-6.70(m,3H),7.11-7.25(m,2H);分析HPLC:6.10分钟。LC-MS:m/e=166(M+H+)。
1-(2-苯基氨基-丙酰基)-吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺(120a和120b)
将化合物118(405mg,1.0mmol)在二氯甲烷(2mL)中的溶液用TFA(2mL)处理1小时。将反应溶液真空蒸发并与二氯甲烷共沸4次,得到吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺,为淡黄色固体。1H-NMR(500MHz,CDCl3):δ1.87-2.15(m,4H),2.30-2.70(m,2H),2.80-3.08(m,H),3.45(br,2H)4.35-4.98(m,3H),5.30-5.56(m,H),7.10-7.60(m,5H)分析HPLC:7.78/8.20分钟;LC-MS:m/e=305(M+H+)。
2-苯基氨基丙酸(119)(300mg,1.8mmol)在二氯甲烷(10mL)中用HOBt(270mg,2.0mmol)和EDC(2.1g,11mmol)在0℃处理10分钟。加入二异丙基乙胺(2mL),随后加入吡咯烷-2-甲酸(2-苄氧基-5-氧代-四氢呋喃-3-基)-酰胺的二氯甲烷(10mL)溶液。将此混合物室温下搅拌4小时,用二氯甲烷(40mL)稀释,用水、然后用盐水洗涤。将此有机层用无水硫酸钠干燥,过滤和真空蒸发得到淡黄色固体。进行快速色谱用二氯甲烷/甲醇(99/1至98/2)洗脱,得到151mg(33%收率)的标题化合物的反式非对映异构体(120a)和129mg(29%收率)的顺式非对映异构体(120b),为白色固体。1H-NMR(500MHz,CDCl3)反式非对映异构体:δ1.37-1.41(m,3H),1.50-2.45(m,4H),2.60-2.70(m,0.3H),2.89-2.94(m,0.7H),3.40-3.80(m,2H),4.10-4.50(m,3H),4.50-4.90(m,3H),5.26(s,0.3H),5.38(s,0.7H),6.45-6.60(m,2.3H),6.65-6.80(m,H),7.10-7.20(m,2.5H),7.25-7.50(m,4.5H),7.53-7.70(m,0.7H),7.82(d,H)。顺式非对映异构体:δ0.86-0.89(m,H),1.20-1.40(m,4E),1.80-2.45(m,4H),2.80-2.86(m,H),3.58-3.65(m,2H),-4.20-4.40(m,H),4.50-4.75(m,2H),4.90(d,H),5.52(d,H),6.45-6.70(m,3H),6.75-6.85(m,H),7.10-7.20(m,2.3H),7.30-7.50(m,5.7H);分析HPLC:反式非对映异构体10.55分钟,而顺式非对映异构体10.62分钟;两种非对映异构体LC/MS:m/e=452(M+H+)。
4-氧代-3-{[1-(2-苯基氨基-丙酰基)-吡咯烷-2-羰基]-氨基)-丁酸(121)
由化合物120(151mg,0.33mmol)用方法A水解得到101mg(83%收率)的标题化合物,为白色固体。1H-NMR(500MHz,CDCl3/CD3OD=1/1):δ1.20-1.65(m,2H),1.65-2.35(m,3H),2.40-3.00(m,H),3.20-3.80(m,2H),3.90-4.90(m,7H),7.25-7.80(m,5H);分析HPLC:6.38分钟;LC-MS:m/e=362(M+H+)。
制备实施方案C式Ⅰ化合物的一般方法(方案ⅩⅩⅢ-ⅩⅩⅤ)
水解方法A:
将烷基半缩醛的0.005-50mmol样品溶解于2.5NHCl/CH3CN(10/1),并在室温下搅拌直到反应完毕。将所得水层用乙醚(2×20mL)洗涤并冻干得到产物。
水解方法B:
将烷基半缩醛的0.005-50mmol样品加到纯甲酸中并室温下搅拌过夜。将此混合物用3∶1的己烷/乙醚混合物研磨,得到沉淀。倾析溶剂并用乙醚洗涤此沉淀,得到产物。
水解方法C:
将烷基半缩醛的0.005-50mmol样品溶解于甲醇和20%Pd(OH)2/C中,并在氢气氛下搅拌直到反应完毕。将所得悬浮液过滤并真空浓缩此溶液,然后用3∶1的己烷/乙醚混合物研磨,得到沉淀。倾析溶剂并用乙醚洗涤此沉淀,得到产物。
水解方法D:
将存在于CH3CN/水(1/2)中的烷基半缩醛的0.005-50mmol样品与酸性树脂(Dowex 50w×2,H+型)摇动,直到反应完毕。将此溶液过滤并用CH3CN/水(1/4)洗涤此树脂。将所得水层用乙醚洗涤,真空浓缩至较小的体积,然后冻干得到产物。
4-氧代-3-[(1-(2-[9-氧代-9H-芴-4-羰基}-氨基]丙酰基}-吡咯烷-2-羰基)-氨基)-丁酸(122a)
将化合物91的109.0mg(0.19mmol)样品按照方法A水解得到88mg(96%收率)的标题化合物:分析HPLC 7.15分钟。LC-MS(ES+)m/e=492.2(M+H)。
3-({1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122b)
将化合物76的51.0mg(0.096mmol)样品按照方法A水解得到43.0mg(100%收率)的标题化合物:1H-NMR(500MHz,CD3OD/D2O:0.5mL/10滴):δ1.37-1.52(m,3H),1.80-2.20(m,3H),2.20-2.37(m,H),2.49-2.60(m,H),2.60-2.75(m,H),3.70-3.80(m,E),3.80-3.95(m,H),4.20-4.35(m,H),4.40-4.50(m,H),4.50-4.70(m,H),4.70-4.85(m,H),6.85-6.67(d,H),7.58-7.60(m,H),7.77(s,H);分析HPLC保留时间:6.54min;LC-MS:m/z=439(M+H+)。
3-({1-[2-(3,5-二氯-4-甲氧基-苯甲酰基氨基)丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122c)
3-({1-[2-(4-甲氧基-3,5-二甲基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122d)
将化合物77的55.0mg(0.102mmol)样品按照方法A水解得到44.0mg(96%收率)的标题化合物:分析HPLC(C18)8.70分钟,1H-NMR(CDCl3,500Mhz)δ1.23-1.70(m,3H),1.80-2.70(m,10H),2.70-3.15(m,2H),3.58-4.20(m,5H),4.32-5.50(m,3H),5.60-6.00(m,H),6.80-7.90(m,4H);LC-MS(ES+) m/e=448.2(M+H)。
4-氧代-3-[(1-{2-[(吡啶-2-羰基)-氨基]-丙酰基}吡咯烷-2-羰基)-氨基]-丁酸(122e)
3-({1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122f)
将化合物78的52mg(0.091mmol)样品按照方法A水解得到40mg(91%收率)的标题化合物:1H NMR(500MHz,CD3OD)δ1.08-1.61(m,3H),3.77-2.41(m,3H),2.21(s,3H),2.41-2.77(m,2H),3.43-3.63(m,0.3H),3.65-3.76(m,1H),3.81-3.94(m,1H),4.18-4.34(m,1H),4.42-4.64(m,1.7H),4.77(q,1H),7.79(dd,1H);分析HPLC 4.97分钟。LC-MS(ES+) m/e=481.3(M+H)。
3-({1-[2-(4-氨基-3,5-二氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122g)
将化合物89的44.3mg(0.079mmol)样品按照方法A水解得到30mg(81%收率)的标题化合物:分析HPLC 5.40分钟。LC-MS(ES+)m/e=473.2(M+H)。
3-({1-[2-(3-异丙氧基-苯甲酰基氨基)-丙酰基]吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122h)
将化合物79的52.0mg(0.097mmol)样品按照方法A水解得到30.0mg(69%收率)的标题化合物:分析HPLC 8.92分钟。LC-MS(ES+)m/e=448.3(M+H)。
3-({1-[2-(3-苄氧基-4-甲氧基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122i)
将化合物81的50.8mg(0.082mmol)样品按照方法A水解得到22.4mg(52%收率)的标题化合物:分析HPLC 6.72分钟。LC-MS(ES+)m/e=526.3(M+H)。
4-氧代-3-[(1-{2-[(喹喔啉-2-羰基)-氨基]-丙酰基}-吡咯烷-2-羰基)-氨基]-丁酸(122j)
3-({1-[2-(3,5-二氯-4-羟基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122k)
将化合物83的35mg(0.060mmol)样品按照方法A水解得到29.4mg(75%收率)的标题化合物:分析HPLC 7.91分钟。1H-NMR(500MHz,CD3OD)δ1.47(m,3H).1.8-2.3(m,4H),2.49(m,1H),2.61(m,1H),3.5(br m,0.2H),3.69(br m,0.9H),3.84(br m,0.9H),4.27(m,1H),4.46(m,1H),4.57(m,1H),4.73(m,1H),7.83(m,2H)ppm,LC-MS(ES+) m/e=474.1(M+H)。
3-({1-[2-(4-氨基-3-三氟甲基-苯甲酰基氨基)丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(1221)
3-({1-[2-(3-氯-4-二甲基氨基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122m)
3-({1-[2-(4-二甲基氨基-3,5-二氟-苯甲酰基氨基)-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122n)
3-({1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122o)
将化合物98m的20.0mg(0.046mmol)样品按照方法A水解得到16.7mg(100%收率)的标题化合物:分析HPLC 8.47分钟。LC-MS(ES+)m/e=439.2(M+H)。
3-({1-[2-(4-氨基-2,3,5,6-四氟-苯甲酰基氨基)丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122p)
4-氧代-3-[(1-{2-[(喹啉-6-羰基)-氨基]丙酰基}-吡咯烷-2-羰基)-氨基]-丁酸(122q)
将化合物93的44mg(0.080mmol)样品按照方法A水解得到41mg(100%收率)的标题化合物:1H NMR(500MHz,CD3OD)δ1.24-1.69(m,3H)1.75-2.37(m,4H),2.39-2.87(m,2H),3.46-4.04(m,2H),4.11-4.77(m,3H),8.19(dd,1H),8.33(d,1H)8.56-8.58(m,1H),8.85(s,1H),9.27-9.39(m,2H);分析HPLC 4.91分钟。LC-MS(ES+) m/e=441.2(M+H)。
3-({1-[2-(4-乙酰基氨基-5-氯-2-甲氧基-苯甲酰基氨基)-丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122r)
3-[(1-{2-[3-氯-4-(2,2-二甲基-丙酰基氨基)苯甲酰基氨基]-丙酰基}-吡咯烷-2-羰基)氨基]-4-氧代-丁酸(122s)
将98aa的19.0mg(0.036mmol)样品按照方法A水解得到14.5mg(90%收率)的标题化合物:分析HPLC 7.28分钟。LC-MS(ES+)m/e=523.3(M+H)。
3-({1-[2-(3-氯-4-丙酰基氨基-苯甲酰基氨基)丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122t)
3-({1-[2-(3-氯-4-苯基乙酰基氨基-苯甲酰基氨基)丙酰基]-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(122u)
将98ac的10.0mg(0.017mmol)样品按照方法A水解得到7.9mg(85%收率)的标题化合物:分析HPLC 7.52分钟。LC-MS(ES+)m/e=557.2(M+H)。
3-[(1-{2-[3-氯-4-(3-甲基-丁酰基氨基)苯甲酰基氨基]-丙酰基}-吡咯烷-2-羰基}-氨基]-4-氧代-丁酸(122v)
将98ad的8.0mg(0.015mmol)样品按照方法A水解得到6.5mg(96%收率)的标题化合物:分析HPLC 6.92分钟。LC-MS(ES+)m/e=523.2(M+H)。
方案ⅩⅩⅤ108a,X=Cl,Y=NH2,Z=H,Q1=F,Q2=H116b,X=Cl,Y=AcNH,Z=H,Q1=Q2=F116c,X=Cl,Y=AcNH,Z=CH3O,Q1=Q2=F123a,X=Cl,Y=NH2,Z=H,Q1=F,Q2=H123b,X=Cl,Y=AcNH,Z=H,Q1=Q2=F123c,X=Cl,Y=AcNH,Z=CH3O,Q1=Q2=F
3-({1-[2-(4-氨基-3-氯-苯甲酰基氨基)-丙酰基]-4-氟-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(123a)
将108b的12.4mg(0.022mmol)样品按照方法A水解得到9.6mg(93%收率)的标题化合物:分析HPLC 6.99分钟。LC-MS(ES+)m/e=473.2(M+H)。
3-({1-[2-(4-乙酰基氨基-3-氯-苯甲酰基氨基)丙酰基]-4,4-二氟-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(123b)
将116b的26.2mg(0.043mmol)样品按照方法A水解得到10.8mg(49%收率)的标题化合物:分析HPLC 9.89分钟。LC-MS(ES+)m/e=517.2。
3-({1-[2-(4-乙酰基氨基-3-氯-2-甲氧基苯甲酰基氨基)-丙酰基]-4,4-二氟-吡咯烷-2-羰基}-氨基)-4-氧代-丁酸(123c)
将116c的23.1mg(0.036mmol)样品按照方法A水解得到1.8mg(9%收率)的标题化合物:分析HPLC 11.87分钟。LC-MS(ES+)m/e=547.1(M+H)。
生物学方法
用下述方法获得选择的本发明混合物的体外、离体和体内数据。结果见表2-8。符号“ND”表示此混合物在所述实验中没有检测。
在ICE卡斯帕酶实验中,“A”项表示<10nM的抑制。“B”项表示10-1000nM的抑制。“C”项表示>1000nM的抑制。见表2和3。
在PBMC检测中,“A”项表示<500nM的抑制。“B”项表示500-1000nM的抑制。“C”项表示1001-2000nM的抑制。“D”项表示>2000nM的抑制。见表4。
在全血实验中,“A”项表示<2500nM的抑制。“B”项表示2500-7500nM的抑制。“C”项表示>7500nM的抑制。见表5。
在原位代谢实验中,[f(g)×f(h)]值描述如下:“A”项表示<0.25。“B”项表示0.25-0.49。“C”项表示0.5-0.75。“D”项表示>0.75。胆汁分泌检测中,“A”项表示<5%。“B”项表示5-10%。“C”项表示>10%。见表6。
在静脉清除实验中,数值报告如下:“A”项表示<50。“B”向表示50-80。“C”项表示>80。见表7。
在生物利用度实验中,Cmax值(μg/ml)描述如下:“A”项表示<2.5。“B”项表示2.5-5.0。“C”项表示>5.0。AUC值(μg×hr/ml)描述如下:“A”项表示<2.5。“B”项表示2.5-5.0。“C”项表示>5.0。半衰期(小时)范围描述如下:“A”项表示<1.5。“B”项表示1.5-2.0。“C”项表示>2.0。F值(%)描述如下:“A”项表示<33。“B”项表示33-67。“C”项表示>67。见表8。
体外实验
酶抑制
通过Margolin等(J.Biol.Chem.,272pp.7223-7228(1997))的方法获得被测化合物对不同卡斯帕酶的Ki值。在37℃,检测在10mM Tris(Sigma Corp,St Louis MO)pH 7.5,1mM二硫苏糖醇(DTT,Research organic INC,Cleveland,OH)和0.1%CHAPS(Pierce,Rockford IL)中检测。对于卡斯帕酶-3,将8%甘油加入到检测缓冲液中,以改善酶稳定性。将65μL等份的检测缓冲液和5μL等份的适当稀释度的存在于DMSO中的抑制剂加入到96孔板中,用10μL卡斯帕酶处理,然后在实验缓冲液中稀释(由活性位点滴定测定的0.5-40nM活性蛋白)。对于每个测定包括含DMSO但不含化合物的对照。然后在加入适当的底物(20μL,最终浓度1-4XKM,最终实验体积100μL)前,将板在37℃温育15分钟以引发反应。在37℃下检测反应速度,该检测是通过在405nM(对于pNA底物)的吸收值随时间的增加或荧光(Ex,390,Em460)(对于AMC底物)随时间的增加。将所得速度相对于抑制剂的浓度绘制曲线,而地此数据符合竞争抑制剂的Morrison紧密结合方程(Morrison,J.F.,Biochem.Biophys.Acta,185pp.269-286(1969))。用于每个实验的底物如下:
卡斯帕酶-1 Suc-YVAD-pNA(Bachem,King of Prussia,PA)(实验中最终浓度80μM),
卡斯帕酶-3 Ac-DEVD-pNA(Bachem,-King of Prussia,PA)(实验中的最终浓度,60μM),
卡斯帕酶-4 AC-WERD-AMC(Synpep,Dublin,CA)(实验中的最终浓度为20μM),
卡斯帕酶-7 AC-DEVD-AMC(Bachem,King of Prussia,PA)(实验中的最终浓度50μM),
卡斯帕酶-8 Ac-DEVD-pNA(Bachem,King of Prussia,PA)(实验中的最终浓度80μM)。
表2.卡斯帕酶-1抑制数据
实施例 | 卡斯帕酶-1 Ki(nM) |
5a | A |
5b | A |
5c | A |
5d | A |
5e | B |
5f | B |
实施例 | 卡斯帕酶-1 Ki(nM) |
5g | B |
5h | A |
5i | A |
5j | A |
5k | A |
5l | B |
5m | A |
5n | A |
5o | B |
5p | B |
5q | B |
5r | B |
5s | B |
5t | C |
5u | B |
5v | B |
5w | B |
5x | A |
5y | A |
5z | A |
5aa | A |
5ab | B |
5ac | A |
5ad | A |
5ae | B |
5af | B |
5ag | A |
5ah | B |
5ai | A |
5aj | B |
5ak | B |
实施例 | 卡斯帕酶-1 Ki(nM) |
5al | A |
5am | A |
5an | B |
5ao | B |
5ap | B |
5aq | B |
5ar | A |
5as | A |
5at | B |
5au | B |
5av | B |
5aw | A |
5ax | A |
5ay | A |
5az | A |
5ba | A |
5bb | A |
5bc | B |
5bd | A |
7a | A |
7b | B |
7c | A |
7d | A |
7e | B |
7f | B |
7g | A |
7h | B |
7i | B |
7j | C |
7k | B |
7l | B |
实施例 | 卡斯帕酶-1 Ki(nM) |
7m | B |
7n | B |
7o | A |
7p | A |
7q | B |
7r | B |
7s | B |
7t | B |
7u | B |
7v | B |
7w | A |
7x | B |
7y | B |
7z | B |
7aa | A |
7ab | B |
7ac | B |
7ad | B |
7ae | B |
7af | B |
7ag | B |
7ah | A |
7ai | A |
7aj | A |
7ak | A |
7al | B |
7am | A |
7an | A |
7ao | B |
7ap | B |
7aq | B |
实施例 | 卡斯帕酶-1 Ki(nM) |
7ar | A |
7as | A |
7at | A |
9a | B |
9b | A |
9c | A |
9d | A |
9e | A |
9f | A |
9g | A |
15a | A |
15b | A |
15c | A |
15d | B |
15e | B |
15f | B |
16a | B |
16b | A |
17a | B |
17b | B |
17c | A |
17d | B |
17e | B |
18a | B |
18b | A |
18c | B |
18d | B |
18e | A |
18f | B |
20a | A |
20b | A |
实施例 | 卡斯帕酶-1 Ki(nM) |
20c | A |
20d | B |
20e | A |
20f | A |
20g | A |
20h | A |
20i | B |
20j | B |
20k | A |
20l | A |
20m | A |
20n | A |
20o | A |
20p | A |
20q | B |
20r | B |
20s | A |
20t | B |
23a | A |
23b | B |
23c | A |
23d | A |
23e | A |
23f | B |
23g | A |
23h | A |
23i | B |
24a | A |
24b | C |
24c | A |
24d | B |
实施例 | 卡斯帕酶-1 Ki(nM) |
24e | B |
25a | A |
25b | A |
25c | A |
25d | A |
25e | A |
26a | A |
26b | A |
26c | A |
26d | A |
26e | A |
26f | A |
26g | A |
26h | A |
27a | B |
27b | B |
27c | B |
27d | A |
27e | B |
27f | B |
27g | A |
27h | B |
27i | B |
27j | B |
27k | B |
27l | B |
27m | B |
27n | B |
28a | A |
28b | A |
28c | A |
实施例 | 卡斯帕酶-1 Ki(nM) |
29a | A |
29b | A |
29c | A |
29d | A |
29e | A |
29f | A |
29g | A |
29h | A |
29i | A |
29j | A |
29k | A |
29l | B |
29m | A |
29n | B |
29o | B |
29p | A |
29q | A |
29r | A |
29s | B |
32a | C |
32b | C |
32c | C |
32d | C |
32e | B |
34 | C |
G1 | C |
G2 | B |
42 | B |
46b | A |
46a | C |
57 | A |
实施例 | 卡斯帕酶-1 Ki(nM) |
65 | A |
61 | A |
69 | A |
73 | A |
121 | C |
122a | A |
122b | A |
122c | A |
122d | A |
122e | B |
122f | A |
122g | A |
122h | B |
122i | A |
122j | B |
122k | A |
122l | B |
122m | B |
122n | B |
122o | C |
122p | A |
122q | B |
122r | B |
122s | B |
122t | B |
122u | A |
122v | B |
123a | B |
123b | B |
123c | B |
表3.卡斯帕酶-3,卡斯帕酶-4和卡斯帕酶-8抑制数据
实施例 | 卡斯帕酶-3 Ki(nM) | 卡斯帕酶-4 Ki(nM) | 卡斯帕酶-8 Ki(nM) |
7c | C | ND | C |
7d | C | ND | B |
7f | C | ND | C |
24a | C | ND | ND |
29a | C | ND | ND |
29b | C | ND | ND |
32d | B | ND | ND |
46b | B | ND | ND |
69 | C | ND | B |
122b | C | A | B |
122d | C | A | C |
122f | C | ND | B |
122k | C | ND | B |
PBMC细胞实验
用人外周学单核细胞(PBMC)或富含粘着单核细胞的混合群落进行的IL-1β实验
用多种细胞来源检测细胞培养物中ICE加工原-IL-1β的情况。人PBMC得自健康的供者,该供者提供了淋巴细胞亚型和单核细胞的混合群落,该群落产生细胞介素和细胞因子对很多类型的生理刺激因子的反应谱。得自PBMC的粘着单核细胞提供了正常单核细胞的丰富来源,该细胞被用于选择研究被激活细胞的细胞因子的产生。
实验方法:
制备被测化合物在DMSO或乙醇中的起始稀释系列,再随后用RPMI-10%FBS介质稀释(含2mM L-谷氨酰胺,10mM HEPES,50 U和50μg/ml pen/strep)分别至以最终实验浓度的4倍得到药物浓度,其中含0.4%DMSO或0.4%乙醇。对于所有药物的稀释度DMSO的最终浓度是0.1%。在ICE抑制实验中检测的滴定浓度,其在括号中表示被测化合物的表观Ki,一般用于主要化合物筛选。
一般来说,检测5-6化合物稀释度且该实验的细胞组份以双份进行,包括对每个细胞培养物上清液的双份ELISA检测。
PBMC分离和IL-1实验:
由一个品脱人血中分离的血沉棕黄色层细胞(最终得到40-45ml最终体积的血浆加细胞),用介质稀释至80mL,且每个LeukoPREP分离试管(Becton Dickinson)中都用10ml细胞悬浮液覆盖。以1500-1800xg离心15分钟后,将血浆/介质层吸出,然后用Pasteur吸量管收集单核细胞层,并转移至15ml圆锥离心管(Corning)中。加入介质使体积达到15ml,通过翻转小心混合细胞并以300xg离心15分钟。将PBMC沉淀再悬浮于小体积的介质中,计数细胞并调节至6×106细胞/ml。
对于细胞检测,将1.0ml的细胞悬浮液加至24孔平底组织培养板(Corning)的每个孔中,加入0.5ml被测化合物稀释液和0.5mlLPS溶液(Sigma #L-3012;20ng/ml溶液,在完全RPMI介质中制备;最终LPS浓度5ng/ml)。加入0.5ml被测化合物而LPS一般足以混合孔中的内容物。每个实验进行3个对照,其为单独的LPS、溶剂载体对照和/或其它调节最终培养体积至2.0ml的介质。将细胞培养物在37℃下5%二氧化碳存在下温育16-18小时。
在温育期后,收获细胞并将其转移至15ml圆锥型离心管中。以200xg离心10分钟后,收集上清液并转移至1.5ml Eppendorf管中。注意可以在胞质溶质提取物中通过Western印迹或ELISA用原-IL-1β特异性抗血清,可以用细胞沉淀进行原-IL-1β和/或成熟IL-1β含量的生物评价。
分离粘着单核细胞:
分离PBMC并如上所述制备。先将介质(1.0ml)加入到孔中,随后加入0.5ml的PBMC悬浮液。温育1小时后,将板轻轻摇动并从每个孔中吸出非粘着细胞。然后用1.0ml介质将孔轻轻洗涤3次,并最后悬浮于1.0ml介质。浓集粘附细胞一般得到2.5-3.0×105细胞/每孔。被测化合物的加入、LPS、细胞温育条件和上清液的处理方法如上所述。
ELISA:
Quantikine试剂盒(R & D Systems)可以用于检测成熟IL-1β。按照制造商的说明进行检测。在PBMC和粘着单核细胞阳性对照中观察到成熟IL-1β浓度为约1-3ng/ml。对LPS阳性对照的1∶5、1∶10和1∶20稀释度的上清液进行ELISA检测以选择实验组中的上清液的最佳稀释度。
化合物的抑制效果可以由IC50值表示,该值是与阳性对照比较上清液中检测到50%成熟IL-1β的抑制剂浓度。
熟练的操作者意识到在细胞实验中得到的值可能依赖于多种因素。这些值可能不需要表示精细定量的结果。
表4.PBMC细胞检测数据
实施例 | PBMC IC50(nM) |
5a | D |
5b | B |
5c | B |
5d | B |
5e | B |
5f | C |
5g | C |
5h | A |
实施例 | PBMC IC50(nM) |
5i | C |
5j | D |
5k | D |
5l | A |
5m | A |
5n | B |
5r | D |
5s | B |
5u | C |
5v | D |
5w | B |
5x | B |
5y | B |
5z | B |
5aa | B |
5ab | B |
5ac | A |
5ad | A |
5ag | B |
5ai | A |
5aj | B |
5ak | B |
5al | D |
5am | D |
5ao | D |
5aq | D |
5ar | D |
5as | D |
5at | D |
5au | D |
5av | D |
实施例 | PBMC IC50(nM) |
5aw | C |
5ax | B |
5ay | B |
5az | B |
5ba | C |
5bb | B |
5bd | C |
7a | D |
7b | B |
7c | A |
7d | A |
7e | D |
7f | D |
7g | A |
7h | B |
7k | B |
7l | B |
7m | B |
7n | B |
7o | A |
7p | D |
7q | D |
7s | B |
7t | D |
7u | D |
7v | D |
7w | C |
7x | D |
7y | D |
7z | C |
9a | B |
实施例 | PBMC IC50(nM) |
9b | B |
9c | A |
9d | B |
9e | C |
9f | B |
9g | C |
15a | D |
15b | C |
15c | B |
15d | C |
15e | D |
15f | D |
16a | A |
16b | C |
17b | C |
17c | D |
17d | D |
17e | B |
18a | B |
18b | B |
18c | B |
18d | B |
18e | C |
18f | D |
20a | B |
20b | B |
20c | C |
20d | D |
20e | C |
20f | B |
20g | A |
实施例 | PBMC IC50(nM) |
20h | A |
20i | B |
20j | D |
20k | A |
20l | B |
20m | B |
20n | B |
20o | A |
20p | A |
20q | B |
20r | B |
20s | C |
20t | B |
23a | C |
23b | B |
23c | C |
23d | B |
23e | B |
23f | C |
23g | C |
23h | C |
23i | A |
24a | B |
24b | D |
24c | A |
24d | B |
24e | C |
25a | A |
25b | B |
25c | B |
26a | C |
实施例 | PBMC IC50(nM) |
26b | B |
26c | B |
26d | B |
26e | A |
26f | A |
26g | A |
26h | A |
27a | A |
28a | B |
28b | B |
28c | B |
29a | A |
29b | C |
29c | B |
29d | B |
29e | A |
29g | B |
29h | A |
29i | A |
29j | B |
29k | A |
29l | B |
29m | B |
42 | D |
46b | D |
57 | B |
65 | B |
61 | B |
69 | A |
73 | B |
122a | D |
实施例 | PBMC IC50(nM) |
122b | B |
122c | D |
122d | B |
122e | C |
122f | B |
122g | B |
122h | C |
122i | C |
122j | D |
122k | A |
122l | B |
IL-1β产生的全血实验
本发明化合物的全血检测IC50值用如下方法获得:
目的:
全血检测是检测IL-1β(或其它细胞因子)产生和潜在抑制剂活性的简单方法。此检测系统的复杂性、其淋巴和炎性细胞类型的完全补体、血浆蛋白的谱和红细胞是表示人体内生理条件的理想体外指标。
材料:
无热原注射器(约30cc)
无热原灭菌真空管,含冻干的Na2EDTA(4.5mg/10ml试管)
人全血样品(约30-50cc)
1.5ml Eppendorf管
被测化合物贮存液(约25mM,在DMSO或其它溶剂中)
无内毒素氯化钠溶液(0.9%)和HBSS
脂多糖(Sigma;Cat.#L-3012)贮存液,1mg/ml在HBSS中
IL-1β ELISA试剂盒(R & D Systems;Cat # DLB50)
TNFαELISA试剂盒(R & D Systems;Cat # DTA50)
水浴或温育器
全血检测实验方法:
将温育器或水浴设定在30℃。将0.25ml等份的血液加入1.5ml Eppendorf管。注意:在每加两个等份的血液后确保将全血样品管倒转。如果细胞沉淀没有均匀悬浮则可能在重复实验中产生不同的结果。用阳性移液管可能也会减少重复等份之间的差异。
在灭菌的、无热原盐水中通过系列稀释制备药物的倍比稀释液。在ICE抑制检测中测定的被测化合物的系列稀释度(其中在括号中表明了表观Ki)一般用于主要化合物的筛选。对于极度疏水化合物,在由相同的血液供者获得的新鲜血浆或在含5%PBS的DMSO中,制备化合物的稀释液以提高溶解度。
加入25μl被测化合物的稀释液或载体对照并轻轻混合样品。然后加入5.0μl LPS溶液(250ng/ml由贮存液制备的新鲜溶液:LPS最终浓度为5.0ng/ml),并再次混合。在30℃下在水浴中温育此试管16-18小时,不时混合。或者,可以将此试管置于摇床中,在相同的温育时期设置为4rpm。用下列对照可以将此实验进行一式两份或一式三份:阴性对照(无LPS);阳性对照(无被测抑制剂);载体对照(最高浓度的DMSO或用于此实验的化合物溶剂)。向所有对照管中再加入盐水以校准对照和实验全血被测样本的体积。
温育期后,将全血在约2000rpm下在小型离心机中离心,如果需要将血浆转移至小型离心管中并在1000xg离心以沉淀残余的血小板。在通过ELISA检测细胞因子水平前,血浆样品可以在-70℃冷冻保存。
ELISA:
可以用R & D Systems(614 McKinley Place N.E.Minneapolis,MN 55413)Quantikine试剂盒检测IL-1β和TNF-α。按照制造商的说明进行这些检测。在个体范围中在阳性对照内可以观察到约1-5ng/ml水平的IL-1β。对于所有样品血浆1∶200的稀释度通常足以用于实验,使ELISA的结果符合ELISA标准曲线的线性范围。如果在全血检测中观察到不同结果,可能需要将标准稀释度最佳化。Nerad,J.L.等,J.Leukocyte Biol.,52,pp.687-692(1992)。
表5.全血检测数据
实施例 | 全血 IC50(nM) |
5a | A |
5b | A |
5c | A |
5d | B |
5e | A |
5f | B |
5h | A |
5i | C |
5j | C |
5k | B |
5l | C |
5m | A |
5n | B |
5r | C |
5s | C |
5u | A |
5w | A |
5x | A |
5y | B |
5z | C |
5aa | A |
5ab | B |
5ac | A |
5ad | A |
5ag | B |
5ai | C |
5aj | C |
5ak | C |
5ax | B |
5ay | B |
实施例 | 全血 IC50(nM) |
5az | A |
5bb | B |
7a | B |
7b | A |
7c | A |
7d | B |
7e | C |
7f | B |
7g | B |
7h | A |
7k | A |
7l | A |
7m | B |
7n | A |
7o | A |
7p | B |
7q | A |
7s | B |
7t | B |
7u | B |
7v | A |
7w | A |
7x | C |
7y | C |
7z | A |
7aa | B |
7ab | A |
7ac | B |
7ad | B |
7ah | B |
7ai | B |
实施例 | 全血 IC50(nM) |
7aj | C |
7ak | B |
7am | B |
7an | B |
7ao | B |
7ap | C |
9a | B |
9b | B |
9c | A |
9d | A |
9e | B |
9f | A |
9g | B |
15a | B |
15b | B |
15c | A |
16b | A |
18a | A |
18b | A |
18c | A |
18d | A |
18e | A |
18f | B |
20a | A |
20b | C |
20c | B |
20d | B |
20e | B |
20f | A |
20g | A |
20h | A |
实施例 | 全血 IC50(nM) |
20i | A |
20k | A |
20l | A |
20m | A |
20n | A |
20o | A |
20p | A |
20q | C |
20r | B |
20s | A |
20t | A |
23a | B |
23b | B |
23c | B |
23d | A |
23e | B |
23f | A |
23g | A |
23h | A |
23i | B |
24a | B |
24c | B |
24d | B |
24e | B |
25a | B |
25b | B |
25c | B |
25d | A |
25e | C |
26c | B |
26d | A |
实施例 | 全血 IC50(nM) |
26e | A |
26f | B |
26g | B |
26h | A |
27a | A |
27b | A |
27d | A |
27e | A |
27f | B |
27g | B |
27h | B |
27i | B |
27l | B |
27m | B |
27n | A |
28a | B |
28b | B |
28c | C |
29a | A |
29c | A |
29d | A |
29e | A |
29g | A |
29h | A |
29i | A |
29j | A |
29k | A |
29l | A |
29n | B |
29o | A |
29p | A |
实施例 | 全血 IC50(nM) |
29q | A |
29r | A |
29s | A |
G2 | B |
42 | B |
46b | B |
57 | C |
65 | A |
61 | A |
69 | A |
73 | A |
122a | A |
122b | A |
122c | B |
122d | A |
122e | B |
122f | A |
122g | A |
122h | A |
122i | A |
122j | B |
122k | A |
122l | A |
122m | B |
122p | B |
122q | B |
122r | B |
122s | B |
123a | A |
123b | B |
离体检测
代谢和分泌
进行大鼠的一过性灌注研究以评价胃肠道(GI)壁代谢(f(g)),干代谢(f(h))和胆汁分泌。所用方法描述于Pang,C.S.,J.Pharmacol.Exp.Therapeutics,333,pp.788-798(1984)。
表6.代谢和分泌数据
实施例 | f(g)×f(h) | 胆汁分泌 |
5c | A | C |
5k | B | A |
5m | B | C |
7d | D | A |
7f | C | A |
7ac | C | C |
18f | D | A |
20f | B | C |
20g | B | A |
23b | B | B |
24a | C | A |
24c | A | C |
24e | A | C |
25d | C | C |
25e | C | B |
26c | A | C |
26e | B | B |
26f | A | C |
27a | C | A |
27b | B | A |
29b | A | B |
实施例 | f(g)×f(h) | 胆汁分泌 |
29g | B | B |
29n | C | A |
29o | C | A |
29p | B | C |
29q | C | A |
29r | C | B |
46b | B | C |
57 | B | B |
65 | B | C |
69 | C | A |
122a | B | A |
122b | C | A |
122c | C | B |
122d | C | A |
122r | B | A |
体内检测
体内大鼠清除检测-清除率
本发明化合物在大鼠中的清除率(ml/min/kg),可以用如下方法得到:
典型方法
在药代动力学实验前,在麻醉下给大鼠进行颈静脉和颈动脉插管。M.J.Free,R.A.Jaffee;“收集血液和其它体液的插管技术”:Animal Models;p.480-495;N.J.Alexander编辑;Academic Press,(1978)。通过颈静脉给药(10mg/ml)的载体通常组成为:丙二醇/盐水,含100mM碳酸氢钠,比率为1∶1。以10-20mg药物/kg给动物用药,并在0,2,5,7,10,15,20,30,60和90分钟从深处的颈动脉中采集血样。将此血样离心得到血浆并在-20℃下保存以备分析。通过非线性回归法用标准软件如Rstrip(MicroMath Software,UT)和/或Pcnonlin(SCI Software,NC)进行数据的药动学分析以得到清除率数值。
典型分析:
用等体积的乙腈(含0.1%TFA)提取鼠血浆。然后将样本在约1000xg离心,并通过梯度HPLC分析上清液。典型的分析方法描述如下。
用200μL的0.1%三氟乙酸(TFA)的乙腈溶液和10μL的50%氯化锌水溶液将200μL血浆沉淀,旋摇,然后以约1000xg离心,并收集上清液并通过HPLC分析。
HPLC方法:
柱:Zorbax SB-CN(4.6×150mm),(5μ粒度)
柱温度:50℃
流速:1.0mL/min
注射体积:75μL.
流动相:A=0.1%TFA在水中和B=100%乙腈
所用梯度:100%A至30%A(在15.5分钟内),0%A(在16分钟),100%A(在19.2分钟)
波长:214nm
在20,10,5,2和1μg/mL浓度绘制标准曲线。
表7.清除率数据
实施例 | 大鼠静脉清除(ml/min/kg) |
7d | A |
7f | B |
20h | B |
20m | A |
65 | C |
122b | B |
122c | C |
122d | B |
122f | A |
生物利用度
口服药动学研究
通过肌肉内注射氯胺酮/甲苯噻嗪混合物来麻醉雄性Sprague-Dawley大鼠(Harlan,Indianapolis,IN,300-350g)。将PE-50插管插入右颈动脉以备采集动脉血样。在用于此实验前让大鼠从手术过夜恢复(≥16小时)。在25%Cremophor EL/水(w/w)或100%丙二醇(PG)中,以给药体积10mL/kg口服被测化合物。给药后在0.25,0.50,1.0,1.5,2,3,4,6和8小时采集血样(约0.30mL),通过离心分离出血浆并在-20℃保存以备分析。用梯度HPLC/MS/MS或酶方法进行血浆样本的定量分析:
在大鼠血浆中定量测定ICE抑制剂的HPLC/MS/MS方法
样本的制备
·将50μl的血浆等份加入Eppendorf离心管。
·向此血浆中加入等体积的乙腈以沉淀血浆蛋白。
·将样品翻转5分钟,并以14,000rpm离心5分钟。
·将75μL的上清液加入到12mm HPLC液体样本小瓶中。
·注射50μL样本通过质谱仪进行分析。
HPLC仪器参数
HPLC:Hewlett Packard HP1100二元溶剂转运系统。
HPLC梯度体积
A=水0.2%甲酸
B=乙腈0.2%甲酸
流动相
时间 %A %B
0 100 0
2 100 0
5 0 100
11 0 100
11.5 100 0
17 100 0
HPLC分析柱:Keystone Phenyl-2 Hypersil 2.0×100mm,5μ120埃孔径,P/N# 105-39-2
注射体积:50μl
流速:0.20mL/分钟。
质谱仪器参数
仪器:P E Sciex API-365 Tandem质谱仪
离子化技术:Turbo-Ionspray(ESI)
极性:正
存在时间:300msec
暂停时间:5msec
扫描时间:0.9sec
扫描状态:MRM(多反应监控)
用于大鼠血浆中ICE抑制剂定量检测的ICE酶检测
用150μL乙腈提取50μL血浆,超声波处理,旋转,以10000xg离心,并将180μL上清液在Sorvall旋转蒸发器中室温下干燥。超声波处理下,将样本再溶解于100μL缓冲液(10mM tris-HCl,pH7.5,含0.1%CHAPS,1mM DTT)中。将10μL每个样本与10μL ICE(1.1mg/mL)在微量滴定板中与60μL缓冲液混合。将样本室温下温育15分钟,然后加入20μL Succ YVAD-pNA(400μM,预温至37℃),并用SpectraMax读数器在405nm监控此板20分钟。此数据符合用符合SpectraMax软件的4个参数绘制的标准曲线。此检测从0.15至2.0-3.0μg/mL醛是线性的。
药代动力学参数
用非分隔法进行这些血浆浓度数据的药代动力学分析。从0至最近检测时间点用线性梯形规则估计曲线下的面积(AUC(0-t))。通过对数线性回归由血浆浓度时间曲线的最终相估计清除速率(Ke)。在曲线尾部的面积估价为最近检测浓度与Ke的比例。从时间0至无穷大曲线下面积(AUC(0-∝))是通过加上尾部至AUC(0-t)面积获得的。清除半衰期估计为0.693/ke。记录观察到的峰值血浆浓度(Cmax)值。对前药的研究:醛利用度(生物利用度)计算为:(AUC醛/前药p.o.)/(AUC醛/醛i.v.)×(醛的给药量,醛i.v./前药的给药量,前药p.o.)×(MW前药/MW醛)。
表8.生物利用度数据
实施例 | Cmax(μg/mL) | AUC(μg×h/mL) | t 1/2(hrs) | F(%) |
56 | A | B | A | |
45 | A | B | ||
90 | C | C | A | C |
85 | A | B | B | A |
68 | A | C | B | |
76 | C | C | C | |
77 | B | B | A | A |
7B | A | A | B | A |
89 | B | C | C | |
83 | A | C | C | |
98d | A | A | B | |
98h | A | C | B | |
98e | C | C | B | |
98c | B | C | C | |
98k | B | C | B | |
98ae | A | A | B | |
98af | A | A | B | |
98b | C | C | B | |
111 | A | A | C | |
98o | A | A | B | |
108a | A | A | B | |
98ag | C | C | B | C |
98a | B | B | C | |
98am | A | A | B | |
116a | C | C | B | |
98an | A | A | B | |
116g | A | A | C | |
116h | A | A | B | |
116e | A | A | B | |
108b | A | A | B |
抗病毒检测
本发明化合物治疗或预防抗病毒相关疾病、紊乱或病症的效果,可在多种体外和体内实验中评价。例如,可以进行实验以测定这些化合物抑制与病毒感染有关的炎性反应的能力。体外实验可以使用全细胞或分离的细胞组份。体内实验包括病毒疾病的动物模型。这些动物模型的实例包括但不限于HBV或HCV感染的啮齿类动物模型,HBV感染的土拨鼠模型和HCV感染的黑猩猩模型。
本发明的化合物也可以在动物模型中评价治疗酒精引起的疾病的结果。
可以用于评价本发明化合物的其它实验公开于PCT申请PCT/US96/20843(公开于1997年6月26日),公开号WO 97/22619。这些实验包括在小鼠中的体内药代动力学研究,抑制ICE类似物,抑制编程性细胞死亡,体内抗炎性效果的急性实验,检测药物的血液浓度,IGIF实验,小鼠角叉菜胶腹膜炎实验和Ⅱ型胶原诱发的关节炎。
本发明化合物在体外能抑制卡斯帕酶,特别是ICE,并还可以给哺乳动物口服给药,它们对治疗IL-1、编程性细胞死亡、IGIF和IFN-γ介导疾病具有明显的临床用途。
虽然我们已描述了一些本发明的实施方案,但是显然我们的基础内容是可以改变的,这样可以提供其它实施方案,这些方案用于本发明的产物和方法。
Claims (26)
X是-C(R3)2-或-N(R3)-;
m是0或1;
R1是H、-R8、-C(O)R8、-C(O)C(O)R8、-S(O)2R8、-S(O)R8、-C(O)OR8、-C(O)N(H)R8、-S(O)2N(H)-R8、-S(O)N(H)-R8、-C(O)C(O)N(H)R8、-C(O)CH=CHR8、-C(O)CH2OR8、-C(O)CH2N(H)R8、-C(O)N(R8)2、-S(O)2N(R8)2、-S(O)N(R8)2、-C(O)C(O)N(R8)2、-C(O)CH2N(R8)2、-CH2R8、-CH2-链烯基-R8或-CH2-炔基-R8;
R2是-H而每个R3独立地是-H,氨基酸侧链,-R8,链烯基-R9或炔基-R9,或者每个R3与和它连接的原子一起形成3至7元环或杂环环系,或者R2和一个R3与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R4是-H而每个R5独立地是H,氨基酸侧链,-R8,链烯基-R9或炔基-R9,或者R4和一个R5与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R6是-H;
R7是-OH,-OR8或-N(H)OH;
每个R8独立地是-烷基,-环烷基,-芳基,-杂芳基,-杂环基,-烷基环烷基-烷基芳基,-烷基杂芳基或-烷基杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;
每个R9独立地是-芳基,-杂芳基,环烷基或-杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;
每个R10独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)O烷基、-N(H)C(O)O芳基、-N(H)C(O)O烷芳基、-N(H)C(O)O杂芳基、-N(H)C(O)O烷基杂芳基、-N(H)C(O)O环烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-N(H)C(O)N(H)芳基、-N(H)C(O)N(H)烷芳基、-N(H)C(O)N(H)杂芳基、-N(H)C(O)N(H)烷基杂芳基、-N(H)C(O)N(H)环烷基、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2、-烷基、-环烷基、-芳基、-杂芳基、-杂环基、-烷基环烷基、-烷芳基、-烷基杂芳基或-烷基杂环基,其中结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;而
每个R11独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-烷基、-环烷基、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2。
X是-C(R3)2-或-N(R3)-;
m是0或1;
R1是H、-R8,-C(O)R8、-C(O)C(O)R8、-S(O)2R8、-S(O)R8、-C(O)OR8、-C(O)N(H)R8、-S(O)2N(H)-R8、-S(O)N(H)-R8、-C(O)C(O)N(H)R8、-C(O)CH=CHR8、-C(O)CH2OR8、-C(O)CH2N(H)R8、-C(O)N(R8)2、-S(O)2N(R8)2、-S(O)N(R8)2、-C(O)C(O)N(R8)2、-C(O)CH2N(R8)2、-CH2R8、-CH2-链烯基-R8或-CH2-炔基-R8;
R2是-H而每个R3独立地是-H,氨基酸侧链,-R8,链烯基-R9或炔基-R9,或者每个R3与和它连接的原子一起形成3至7个元环或杂环环系,或者R2和一个R3与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R4是-H而每个R5独立地是H,氨基酸侧链,-R8,链烯基-R9或炔基-R9,或者R4和一个R5与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R6是-H;
每个R8独立地是-烷基,-环烷基,-芳基,-杂芳基,-杂环基,-烷基环烷基-烷基芳基,-烷基杂芳基或-烷基杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;
每个R9独立地是-芳基,-杂芳基,环烷基或-杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;
每个R10独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)O烷基、-N(H)C(O)O芳基、-N(H)C(O)O烷芳基、-N(H)C(O)O杂芳基、-N(H)C(O)O烷基杂芳基、-N(H)C(O)O环烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-N(H)C(O)N(H)芳基、-N(H)C(O)N(H)烷芳基、-N(H)C(O)N(H)杂芳基、-N(H)C(O)N(H)烷基杂芳基、-N(H)C(O)N(H)环烷基、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2、-烷基、-环烷基、-芳基、-杂芳基、-杂环基、-烷基环烷基、-烷芳基、-烷基杂芳基或-烷基杂环基,其中结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;而
每个R11独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-烷基、-环烷基、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2H2、-CH2N(H)烷基或-CH2N(烷基)2;
R12是-C(O)烷基、-C(O)环烷基、-C(O)链烯基、-C(O)烷芳基、-C(O)烷基杂芳基、-C(O)杂环基或-C(O)烷基杂环基;而
R13是-H,-烷基,-芳基,-烷芳基或-烷基杂芳基。
m是0或1;
X是-C(R3)2-;
R1是H、-R8、-C(O)R8、-C(O)C(O)R8、-S(O)2R8、-S(O)R8、-C(O)OR8、-C(O)N(H)R8、-S(O)2N(H)-R8、-S(O)N(H)-R8、-C(O)C(O)N(H)R8、-C(O)CH=CHR8、-C(O)CH2OR8、-C(O)CH2N(H)R8、-C(O)N(R8)2、-S(O)2N(R8)2、-S(O)N(R8)2、-C(O)C(O)N(R8)2、-C(O)CH2N(R8)2、-CH2R8、-CH2-链烯基-R8或-CH2-炔基-R8;
R2是-H而每个R3独立地是-H,氨基酸侧链,-R8,链烯基-R9或炔基-R9,或每个R3与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R4是-H而每个R5独立地是-H,氨基酸侧链,-R8,-链烯基-R9或-炔基-R9,或R4和一个R5与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R6是-H;
R7是-OH、-OR8、-N(H)OH或-N(H)S(O)2R8;
每个R8独立地是-烷基、-环烷基、-芳基、-杂芳基、-杂环基、-烷基环烷基、-烷芳基、-烷基杂芳基或-烷基杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;
每个R9独立地是-芳基,-杂芳基,环烷基或-杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;
每个R10独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)O烷基、-N(H)C(O)O芳基、-N(H)C(O)O烷芳基、-N(H)C(O)O杂芳基、-N(H)C(O)O烷基杂芳基、-N(H)C(O)O环烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-N(H)C(O)N(H)芳基、-N(H)C(O)N(H)烷芳基、-N(H)C(O)N(H)杂芳基、-N(H)C(O)N(H)烷基杂芳基、-N(H)C(O)N(H)环烷基、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2、-烷基、-环烷基、-芳基、-杂芳基、-杂环基、-烷基环烷基、-烷芳基、-烷基杂芳基或-烷基杂环基,其中结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;而
每个R11独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-烷基、-环烷基、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2;
条件是如果一个R3是-H,则另一个R3不是-H。
4.式Ⅰ表示的化合物,其中Y是:
m是0或1;
X是-C(R3)2-;
R1是H、-R8、-C(O)R8、-C(O)C(O)R8、-S(O)2R8、-S(O)R8、-C(O)OR8、-C(O)N(H)R8、-S(O)2N(H)-R8、-S(O)N(H)-R8、-C(O)C(O)N(H)R8、-C(O)CH=CHR8、-C(O)CH2OR8、-C(O)CH2N(H)R8、-C(O)N(R8)2、-S(O)2N(R8)2、-S(O)N(R8)2、-C(O)C(O)N(R8)2、-C(O)CH2N(R8)2、-CH2R8、-CH2-链烯基-R8或-CH2-炔基-R8;
R2是-H而每个R3独立地是-H,氨基酸侧链,-R8,链烯基-R9或炔基-R9,或每个R3与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R4是-H而每个R5独立地是-H,氨基酸侧链,-R8,-链烯基-R9或-炔基-R9,或R4和一个R5与它们连接的原子一起形成3至7元环或杂环系统,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在此环系的任何氮原子上的氢原子选择性地被R1代替;
R6是-H;
每个R8独立地是-烷基、-环烷基、-芳基、-杂芳基、-杂环基、-烷基环烷基、-烷芳基、-烷基杂芳基或-烷基杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;
每个R9独立地是-芳基,-杂芳基,环烷基或-杂环基,其中结合在任何烷基或环烷基碳原子上的氢原子选择性地被R10代替,结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;
每个R10独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)O烷基、-N(H)C(O)O芳基、-N(H)C(O)O烷芳基、-N(H)C(O)O杂芳基、-N(H)C(O)O烷基杂芳基、-N(H)C(O)O环烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-N(H)C(O)N(H)芳基、-N(H)C(O)N(H)烷芳基、-N(H)C(O)N(H)杂芳基、-N(H)C(O)N(H)烷基杂芳基、-N(H)C(O)N(H)环烷基、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2、-烷基、-环烷基、-芳基、-杂芳基、-杂环基、-烷基环烷基、-烷芳基、-烷基杂芳基或-烷基杂环基,其中结合在任何芳基或杂芳基碳原子上的氢原子选择性地被R11代替,结合在任何氮原子上的氢原子选择性地被R1代替;而
每个R11独立地是-OH、-SH、-F、-Cl、-Br、-I、-NO2、-CN、-NH2、-CO2H、-C(O)NH2、-N(H)C(O)H、-N(H)C(O)NH2、-烷基、-环烷基、-全氟代烷基、-O-烷基、-O-芳基、-O-烷芳基、-N(H)烷基、-N(H)芳基、-N(H)-烷芳基、-N(烷基)2、-C(O)N(H)烷基、-C(O)N(烷基)2、-N(H)C(O)烷基、-N(H)C(O)N(H)烷基、-N(H)C(O)N(烷基)2、-S-烷基、-S-芳基、-S-烷芳基、-S(O)2烷基、-S(O)烷基、-C(O)烷基、-CH2NH2、-CH2N(H)烷基或-CH2N(烷基)2;
R12是-C(O)烷基、-C(O)环烷基、-C(O)链烯基、-C(O)烷芳基、-C(O)烷基杂芳基、-C(O)杂环基或-C(O)烷基杂环基。
7.权利要求6的化合物,其中一个R3是-H,而另一个R3是甲基、异丙基、叔丁基、-CH2SR8、-CH2SO2R8、-CH2CH2SR8或-CH2CH2SO2R8。
8.权利要求7的化合物,其中一个R3是-H,而另一个R3是甲基。
9.权利要求8的化合物,其中R1是-C(O)R8或-C(O)C(O)R8。
11.权利要求10的化合物,其中一个R3是-H而另一个R3是甲基。
12.权利要求11的化合物,其中R1是-C(O)R8或-C(O)C(O)R8。
13.权利要求10的化合物,其中R10是4-氟或4,4-二氟。
14.权利要求13的化合物,其中一个R3是-H而另一个R3是甲基。
15.权利要求14的化合物,其中R1是-C(O)R8或-C(O)C(O)R8。
16.权利要求1或3的化合物,选自5a-5bd,7a-7at,9a-9g,15a-15f,16a-16b,17a-17e,18a-18f,20a-20t,23a-23i,24a-24e,25a-25e,26a-26h,27a-27n,28a-28c,29a-29s,32a-32e,34,42,46,52,56,57,61,65,69,73,121,122 a-v及123 a-c。
17.权利要求4的化合物,选自41,45,51,56,60,64,68,72,76-93,98a-z,aa-az和ba-bb,101,102a,102b,108a-d,110,111,116a-h及120a和b。
18.药物组合物,其中含有:
a)权利要求1-17任一项的化合物;和
b)药用载体、辅剂或载体。
19.治疗或预防患者中选自如下疾病的方法,该方法包括给所述患者使用权利要求1-17任一项的化合物或权利要求18的药物组合物的步骤:
IL-1介导的疾病、编程性细胞死亡介导的疾病、炎性疾病、自身免疫性疾病、破坏骨的紊乱、增殖紊乱、传染病、变性疾病、坏死性疾病、酗酒引起的疾病、病毒介导的疾病、炎性腹膜炎、骨关节炎、胰腺炎、哮喘、成人呼吸窘迫综合征、肾小球性肾炎、类风湿性关节炎、系统性红斑狼疮、硬皮病、慢性甲状腺炎、Graves病、自身免疫性胃炎、胰岛素依赖性糖尿病(Ⅰ型)、自身免疫性溶血性贫血、自身免疫性中性白细胞减少症、血小板减少症、慢性活动性肝炎、重症肌无力、炎性肠疾病、克罗恩氏病、牛皮癣、特应性皮炎、移植物抗宿主病、骨质疏松、白血病及相关疾病、脊髓发育不良综合征、与多发性骨髓瘤相关的骨疾病、急性骨髓性白血病、慢性骨髓性白血病、转移性黑素瘤、卡波济氏肉瘤、多发性骨髓瘤、脓毒病、脓毒性休克、志贺氏菌病、早老性痴呆、帕金森氏病、脑局部缺血、心肌局部缺血、脊柱肌肉萎缩、多发性硬化、AIDS相关脑炎、HIV相关脑炎、衰老、脱发、中风导致的神经损伤、溃疡性结肠炎、脑外伤、器官移植排斥、乙型肝炎、丙型肝炎、G型肝炎、黄热病、登革热病和日本脑炎。
20.权利要求19的方法,其中疾病是类风湿性关节炎、炎性肠疾病、克罗恩氏病、溃疡性结肠炎、炎性腹膜炎、脓毒性休克、胰腺炎、脑外伤、器官移植排斥、骨关节炎、哮喘、牛皮癣、早老性痴呆、特应性皮炎、白血病和相关疾病、骨髓发育不良综合征或多发性骨髓瘤。
21.抑制患者中ICE介导的功能的方法,包括给所述患者使用权利要求1-17任一项的化合物或权利要求18的药物组合物的步骤。
22.降低患者中IGIF或IFN-γ产生的方法,包括给患者使用权利要求1-17任一项的化合物或权利要求18的药物组合物的步骤。
23.权利要求1-17任一项所述化合物或权利要求18的药物组合物在制备治疗或预防患者的如下疾病的药物中的用途:
IL-1介导的疾病、编程性细胞死亡介导的疾病、炎性疾病、自身免疫性疾病、破坏骨的紊乱、增殖紊乱、传染病、变性疾病、坏死性疾病、酗酒引起的疾病、病毒介导的疾病、炎性腹膜炎、骨关节炎、胰腺炎、哮喘、成人呼吸窘迫综合征、肾小球性肾炎、类风湿性关节炎、系统性红斑狼疮、硬皮病、慢性甲状腺炎、Graves病、自身免疫性胃炎、胰岛素依赖性糖尿病(Ⅰ型)、自身免疫性溶血性贫血、自身免疫性中性白细胞减少症、血小板减少症、慢性活动性肝炎、重症肌无力、炎性肠疾病、克罗恩氏病、牛皮癣、特应性皮炎、移植物抗宿主病、骨质疏松、白血病及相关疾病、脊髓发育不良综合征、与多发性骨髓瘤相关的骨疾病、急性骨髓性白血病、慢性骨髓性白血病、转移性黑素瘤、卡波济氏肉瘤、多发性骨髓瘤、脓毒病、脓毒性休克、志贺氏菌病、早老性痴呆、帕金森氏病、脑局部缺血、心肌局部缺血、脊柱肌肉萎缩、多发性硬化、AIDS相关脑炎、HIV相关脑炎、衰老、脱发、中风导致的神经损伤、溃疡性结肠炎、脑外伤、器官移植排斥、乙型肝炎、丙型肝炎、G型肝炎、黄热病、登革热病和日本脑炎。
24.权利要求23的用途,其中疾病是类风湿性关节炎、炎性肠疾病、克罗恩氏病、溃疡性结肠炎、炎性腹膜炎、脓毒性休克、胰腺炎、脑外伤、器官移植排斥、骨关节炎、哮喘、牛皮癣、早老性痴呆、特应性皮炎、白血病和相关疾病、骨髓发育不良综合征或多发性骨髓瘤。
25.权利要求1-17任一项所述化合物或权利要求18的药物组合物在制备抑制患者ICE介导的功能的药物中的用途。
26.权利要求1-17任一项所述化合物或权利要求18的药物组合物在制备降低患者的IGIF或IFN-γ产生的药物中的用途。
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CN102161656B (zh) * | 2004-02-27 | 2013-02-20 | 沃泰克斯药物股份有限公司 | 天冬氨酸特异性半胱氨酸蛋白酶抑制剂及其用途 |
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