CN104356082B - 一类取代杂环衍生物及其制备方法 - Google Patents

一类取代杂环衍生物及其制备方法 Download PDF

Info

Publication number
CN104356082B
CN104356082B CN201410603721.1A CN201410603721A CN104356082B CN 104356082 B CN104356082 B CN 104356082B CN 201410603721 A CN201410603721 A CN 201410603721A CN 104356082 B CN104356082 B CN 104356082B
Authority
CN
China
Prior art keywords
cdcl
substituted heterocycle
cnmr
100mhz
hnmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410603721.1A
Other languages
English (en)
Other versions
CN104356082A (zh
Inventor
邱彦
李宇航
任杰
杨隆河
朱程刚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xiamen University
Original Assignee
Xiamen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xiamen University filed Critical Xiamen University
Priority to CN201410603721.1A priority Critical patent/CN104356082B/zh
Publication of CN104356082A publication Critical patent/CN104356082A/zh
Priority to CN201580059446.4A priority patent/CN107074788B/zh
Priority to PCT/CN2015/093140 priority patent/WO2016066115A1/zh
Priority to US15/522,985 priority patent/US10174015B2/en
Application granted granted Critical
Publication of CN104356082B publication Critical patent/CN104356082B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

一类取代杂环衍生物及其制备方法，涉及取代杂环生物。一类取代杂环衍生物的化学结构式如下：

Description

一类取代杂环衍生物及其制备方法
技术领域
本发明涉及取代杂环生物，尤其是涉及可抑制内源性大麻素NAAA和/或FAAH酶活性的一类取代杂环衍生物及其制备方法。
背景技术
四氢大麻酚作用的受体CB1的发现促使科学家对该受体内源性配体进行研究。目前发现N-花生四烯酰乙醇胺(AEA)，O-花生四烯酰乙醇胺(virodhamine，O-arachidonoylethanolamine)和花生四烯酰多巴胺(N-arachidonoyldopamine)等作用于大麻素受体的内源性大麻素。与前列腺素等脂类递质一样，这些内源性大麻素在体内并不蓄积，而是在局部按需合成，并且受到酶和受体的调控，能被其特异性的水解酶代谢成相应的脂肪酸和乙醇胺、甘油等物质，从而降低这类物质在体内的作用。
AEA是第一个被发现的内源性大麻素[1-3]，主要激动CB1受体和CB2受体，可产生与THC等大麻提取物相似的药理学功能。此外有报道，对瞬时电位阳离子通道(子类V，成员1)(transientreceptorpotentialcationchannelsubfamilyVmember1，TRPV1)[4-6]、G蛋白偶联受体55(GPR55)[7-11]、过氧化物酶体增殖物活化受体γ(PPAR-γ)[12-15]也有较弱的激动作用。AEA是研究最为广泛的两个内源性大麻素，目前认为AEA是大麻素受体的部分激动剂。
除此之外，还有一部分脂肪酰基乙醇胺类脂质，例如：油酰乙醇胺(N-Oleoylethanolamide，OEA)、N-棕榈酰乙醇胺(N-palmitoylethanolamide，PEA)虽不作用于大麻素受体，但是与AEA和2-AG有着相似的结构以及在内分泌调节方面有类似的功能，被称之为类内源性大麻素物质。其中PEA和OEA通过作用于PPAR-α产生镇痛抗炎和抑制食欲的作用[16]；N-stearoylethanolamine(SEA)能够促进肿瘤细胞的凋亡[17]以及抑制食欲[18]；油酰胺(Oleamide)具有调节睡眠等作用[19]。
AEA能被特异性的脂肪酰胺水解酶(Fattyacidamidehydrolase，FAAH)水解成花生四烯酸和乙醇胺而失去活性。FAAH在1996年克隆获得，属于酰胺水解酶(amidasesignature)家族，是第一个在哺乳动物中发现的此家族蛋白，存在于细胞内膜，并具有一段跨膜结合的α螺旋。FAAH蛋白由579个氨基酸构成，目前FAAH晶体结构已经获得，水解底物AEA活性中心由典型的Ser-Ser-Lys三个氨基酸构成(Ser241-Ser217-Lys142)。FAAH最佳水解pH偏碱性(pH＝8～9)，在脂肪酸酰基乙醇胺类底物化合物中对AEA水解选择性较高，此外还可水解OEA，PEA，OA等其他多种脂肪酸酰胺[20-21]，但相对水解活性要弱。
在FAAH基因敲除鼠中，AEA水平在中枢和外周组织中显著升高[22]。小分子化合物抑制FAAH活性也能显著提高AEA的水平，但动物表现出僵直、活动度降低、体温降低等大麻样副作用。目前，FAAH抑制剂在抗抑郁、抗焦虑、抗神经病理性疼痛等方面具有一定的作用。有些FAAH抑制剂在治疗抑郁、关节炎性疼痛等方面已经进入临床研究。FAAH抑制剂根据结构可以分为四大类：早期的AEA底物类似物、α-酮杂环类、氨基甲酸酯类和芳香脲类。
PEA的特异性水解酶脂肪酰基乙醇胺水解酶(N-acylethanolamineacidamidase，NAAA)于2005年才被发现与克隆[23]。NatuoUeda课题组于1999年在人成巨核细胞株(CMK)中发现一种具有水解AEA活性的大麻素水解酶[24]。然而，这种酶与已知的AEA水解酶FAAH有很大的不同：(1)这种酶在酸性pH条件下(pH4.5)水解活性最强，而FAAH酶是在碱性条件下水解较强(pH9.0)[25]；(2)这种酶对PEA水解活性远远大于对AEA的水解活性；(3)这种酶对FAAH具有较好抑制作用的丝氨酸抑制剂PMSF和MAFP不敏感。随后，该课题组又在大鼠各个组织中发现NAAA酶在肺中活性最高，在脾、胸腺、小肠等组织中活性逐渐降低，并最终在肺组织中纯化出这种酶[26]。并于2005年，成功从大鼠、小鼠和人源细胞中克隆出这种酶的cDNA序列，并把这种酶命名为N-脂肪酰基乙醇胺水解酶(N-Acylethanolamine-hydrolyzingAcidAmidase，NAAA)[23]。随后的研究发现NAAA主要在溶酶体中表达[27]。NAAA包含362个氨基酸(大鼠和小鼠)及359个氨基酸(人)序列，分子量分别为40.3Kda(大鼠)及40.1kDa(小鼠和人)。这些氨基酸序列中，大鼠和小鼠的同源性达90.1％，大鼠和人的同源性达76.5％，小鼠和人的同源性达76.7％。人的NAAA基因位于4q21.1染色体上。NAAA与FAAH并没有同源性，然而却与酸性神经酰胺水解酶(acidceramidases)具有一定的同源性，归类为胆酰甘氨酸水解酶(choloylglycinehydrolase)家族，对酰胺的水解具有选择性[23]。
由于缺乏晶体结构，NAAA的催化水解域空间组成尚不完全清楚，特异性的抑制剂也较少。有限的研究显示，β-内酰胺类NAAA抑制剂S-OOPP(IC50＝420nM)局部给药能够抑制角叉菜胶诱导的大鼠肉芽肿白细胞及LPS诱导的RAW264.7细胞PEA含量下降，从而抑制白细胞的迁移以及炎性渗出，同时，对大鼠的脊柱损伤模型也表现出较好的治疗作用，该过程经由PPAR-α途径介导[28]。结构类似物ARN077(IC50＝127nM)局部给药可明显抑制角叉菜胶诱导的炎性疼痛和坐骨神经结扎(SNL)引发的神经病理性疼痛。在SNL模型中，ARN077(1％，20μL，表皮给药)比阳性对照药物加巴喷丁(50mg/kg，口服)对促诱发痛的镇痛效果更加明显[29]。该研究首次证明NAAA抑制剂具有镇痛的作用，但是该类结构的主要药效团四元内酯环不但本身结构不稳定，生物稳定性也极差，动物体内半衰期低于1min，使其不能应用于系统性给药。
本发明的目的在于提供新颖的内源性大麻素水解酶抑制剂及其制备方法。
参考文献：
[1]DevaneWA,HanusL,BreuerA,etal.Isolationandstructureofabrainconstituentthatbindstothecannabinoidreceptor[J].Science,1992,258:1946-1949.
[2]DiMarzoV,DePetrocellisL.Endocannabinoidsasregulatorsoftransientreceptorpotential(TRP)channels:Afurtheropportunitytodevelopnewendocannabinoid-basedtherapeuticdrugs[J].CurrMedChem,2010,17:1430-1449.
[3]GasperiV,DaineseE,OddiS,etal.GPR55anditsinteractionwithmembranelipids:comparisonwithotherendocannabinoid-bindingreceptors[J].CurrMedChem,2013,20:64-78.
[4]BouaboulaM,HilairetS,MarchandJ,etal.AnandamideinducedPPARgammatranscriptionalactivationand3T3-L1preadipocytedifferentiation[J].EurJPharmacol,2005,517:174-181.
[5]MechoulamR,Ben-ShabatS,HanusL,etal.Identificationofanendogenous2-monoglyceride,presentincaninegut,thatbindstocannabinoidreceptors[J].BiochemPharmacol,1995,50:83-90.
[6]SugiuraT,KondoS,SukagawaA,etal.2-Arachidonoylglycerol:apossibleendogenouscannabinoidreceptorligandinbrain[J].BiochemBiophysResCommun,1995,215:89-97.
[7]SugiuraT,WakuK.Cannabinoidreceptorsandtheirendogenousligands[J].JournalofBiochemistry,2002,132:7-12.
[8]SigelE,BaurR,RaczI,etal.ThemajorcentralendocannabinoiddirectlyactsatGABA(A)receptors[J].ProcNatlAcadSciUSA,2011,108:18150-18155.
[9]GuindonJ,HohmannAG.TheEndocannabinoidSystemandPain[J].Cns&NeurologicalDisorders-DrugTargets,2009,8:403-421.
[10]NomuraDK,LongJZ,NiessenS,etal.MonoacylglycerolLipaseRegulatesaFattyAcidNetworkthatPromotesCancerPathogenesis[J].Cell,2010,140:49-61.
[11]FowlerCJ,GustafssonSB,ChungSC,etal.TargetingtheEndocannabinoidSystemfortheTreatmentofCancer-APracticalView[J].CurrentTopicsinMedicinalChemistry,2010,10:814-827.
[12]Arevalo-MartinA,Garcia-OvejeroD,Molina-HolgadoE.Theendocannabinoid2-arachidonoylglycerolreduceslesionexpansionandwhitematterdamageafterspinalcordinjury[J].NeurobiologyofDisease,2010,38:304-312.
[13]ScotterEL,AboodME,GlassM.Theendocannabinoidsystemasatargetforthetreatmentofneurodegenerativedisease[J].BritishJournalofPharmacology,2010,160:480-498.
[14]CobellisG,RicciG,CacciolaG,etal.AGradientof2-ArachidonoylglycerolRegulatesMouseEpididymalSpermCellStart-Up[J].BiologyofReproduction,2010,82:451-458.
[15]GuidaM,LigrestiA,DeFilippisD,etal.TheLevelsoftheEndocannabinoidReceptorCB2andItsLigand2-ArachidonoylglycerolAreElevatedinEndometrialCarcinoma[J].Endocrinology,2010,151:921-928.
[16]FuJ,GaetaniS,OveisiF,etal.OleylethanolamideregulatesfeedingandbodyweightthroughactivationofthenuclearreceptorPPAR-alpha[J].Nature,2003,425:90-93.
[17]MaccarroneM,PauselliR,DiRienzoM,etal.Binding,degradationandapoptoticactivityofstearoylethanolamideinratC6gliomacells[J].BiochemJ,2002,366:137-144.
[18]TerrazzinoS,BertoF,DalleCarbonareM,etal.Stearoylethanolamideexertsanorexiceffectsinmiceviadown-regulationofliverstearoyl-coenzymeAdesaturase-1mRNAexpression[J].FASEBJ,2004,18:1580-1582.
[19]Huitron-ResendizS,GombartL,CravattBF,etal.Effectofoleamideonsleepanditsrelationshiptobloodpressure,bodytemperature,andlocomotoractivityinrats[J].ExpNeurol,2001,172:235-243.
[20]McKinneyMK,CravattBF.Structureandfunctionoffattyacidamidehydrolase[J].AnnuRevBiochem,2005,74:411-432.
[21]FezzaF,DeSimoneC,AmadioD,etal.Fattyacidamidehydrolase:agate-keeperoftheendocannabinoidsystem[J].SubcellBiochem,2008,49:101-132.
[22]CravattBF,DemarestK,PatricelliMP,etal.Supersensitivitytoanandamideandenhancedendogenouscannabinoidsignalinginmicelackingfattyacidamidehydrolase[J].ProcNatlAcadSciUSA,2001,98:9371-9376.
[23]TsuboiK,SunYX,OkamotoY,etal.MolecularcharacterizationofN-acylethanolamine-hydrolyzingacidamidase,anovelmemberofthecholoylglycinehydrolasefamilywithstructuralandfunctionalsimilaritytoacidceramidase[J].JBiolChem,2005,280:11082-11092.
[24]UedaN,YamanakaK,TerasawaY,etal.Anacidamidasehydrolyzinganandamideasanendogenousligandforcannabinoidreceptors[J].FEBSLett,1999,454:267-270.
[25]LinsenbardtDN,BoehmSL,2nd.Agonismoftheendocannabinoidsystemmodulatesbinge-likealcoholintakeinmaleC57BL/6Jmice:involvementoftheposteriorventraltegmentalarea[J].Neuroscience,2009,164:424-434.
[26]UedaN,YamanakaK,YamamotoS.PurificationandcharacterizationofanacidamidaseselectiveforN-palmitoylethanolamine,aputativeendogenousanti-inflammatorysubstance[J].JBiolChem,2001,276:35552-35557.
[27]TsuboiK,ZhaoLY,OkamotoY,etal.PredominantexpressionoflysosomalN-acylethanolamine-hydrolyzingacidamidaseinmacrophagesrevealedbyimmunochemicalstudies[J].BiochimBiophysActa,2007,1771:623-632
[28]SolorzanoC,ZhuC,BattistaN,etal.SelectiveN-acylethanolamine-hydrolyzingacidamidaseinhibitionrevealsakeyroleforendogenouspalmitoylethanolamideininflammation[J].ProcNatlAcadSciUSA,2009,106:20966-20971
[29]SassoO,Moreno-SanzG,MartucciC,etal.AntinociceptiveeffectsoftheN-acylethanolamineacidamidaseinhibitorARN077inrodentpainmodels[J].Pain,2013,154:350-360.
发明内容
本发明的目的在于提供一类取代杂环衍生物及其制备方法。
所述一类取代杂环衍生物的化学结构式如下：
其中，X选自：C，N或O；
Y选自：C或N。
A选自：OR6、NR7R8或CR9R10R11；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11独立选自：-H、＝O、＝NOR’、卤素、卤代基、多卤代基、-(CH2)nCN、-(CH2)nNO2、-(CH2)nR’、-(CH2)nCOOR’、-(CH2)nCONR’2、-(CH2)nOR’、-(CH2)nSR’、-(CH2)nSOR’、-(CH2)nSO2R’、-(CH2)nNR’2、-(CH2)nNR’COR’或-(CH2)nNR’SO2R’；其中n＝0～10，各个R’独立为H或选自含有20个C原子以内的各种取代或未取代的：直链烷基、支链烷基、环烷基、环杂烷基、烯基、炔基、直链杂烷基、支链杂烷基、杂环烷基、杂烯基、杂炔基、杂环基或芳香基。
本发明所用术语“烷基”、“烯基”、“炔基”和“环烷基”指的是：未取代时仅含有C和H的直链、支链和环形单价取代基以及这些的组合物。这些基团之一上的任何氢原子可被卤素，尤其是氟、氯、溴及氟代基、氯代基所取代，也可以被其他基团及杂原子所取代。
本发明所用术语“杂烷基”、“杂烯基”、“杂炔基”和“杂环烷基”指的是：“烷基”、“烯基”、“炔基”和“环烷基”中的某个C原子被杂原子N、O或S所取代，这些含杂原子基团至少含有一个C原子和一个杂原子。这些基团之一上的任何氢原子可被卤素，尤其是氟代基、氯代基所取代，也可以被其他基团所取代。
本发明所用术语“亚烷基”、“亚烯基”、“亚炔基”和“亚环烷基”指的是：未取代时仅含有C和H的直链、支链和环形二价或三价取代基以及这些的组合物。由于它们是二价或三价的，所以可以将分子的两部分连接在一起。典型的结构包括：亚甲基、亚乙基、亚丙基、2-丁烯-1,4-二基、1,4-环己二基等。这些基团之一上的任何氢原子可被卤原子，尤其是氟代基、氯代基所取代，也可以被其他基团所取代。
本发明所用术语“亚杂烷基”、“亚杂烯基”、“亚杂炔基”和“亚杂环烷基”指的是：“亚烷基”、“亚烯基”、“亚炔基”和“亚环烷基”中的某个C原子被杂原子N、O或S所取代，这些含杂原子基团至少含有一个C原子和一个杂原子。典型的结构包括：N,3-吡咯烷二基、N,4-哌啶二基、2,4-四氢噻喃二基等。这些基团之一上的任何氢原子可被卤原子，尤其是氟代基、氯代基所取代，也可以被其他基团所取代。
本发明所用术语“芳香基”指的是：对整个环系统的电子分布而言具有芳香特征的任何单环、双环或稠环系统的一价取代基以及这些的组合物。典型的结构包括：苯环、噻吩、呋喃、吡咯、噻唑、吡唑、咪唑、吡啶、吡喃、嘧啶、吡嗪、喹啉、异喹啉、吲哚、嘌呤或上述芳香基团以任何形式稠合等。这些基团之一上的任何氢原子可被卤原子，尤其是氟代基、氯代基所取代，也可以被其他基团所取代。
本发明所用术语“亚芳香基”指的是：对整个环系统的电子分布而言具有芳香特征的任何单环、双环或稠环系统的二价或三价取代基以及这些的组合物。由于它们是二价或三价的，所以可以将分子的两部分连接在一起。典型的结构包括：1,4-苯二基，1,3-苯二基，2,4-吡啶二基，2,5-吡啶二基等。这些基团之一上的任何氢原子可被卤原子，尤其是氟代基、氯代基所取代，也可以被其他基团所取代。
本发明所用术语“卤代基”指的是：氟代基，氯代基，溴代基或碘代基。本领域技术人员将会认识到，不是所有的在本发明化合物中的取代基将能够容忍用于合成该化合物的某些反应条件。这些结构部分可以在合成中的合适时间点上被引入，或根据需要或按照希望来保护和去保护。本领域中技术人员会认识到，可以在本发明的化合物的合成中的任何方便的时间点上除去保护基团。引入和除去氮和氧保护基团的方法是现有技术中公知的。此外，本领域中技术人员认识到，在许多情况下，结构部分引入的顺序并不是关键的。为了生产本发明的化合物所需要的步骤的具体顺序可以取决于所要合成的具体化合物、起始化合物和取代的结构部分的相对不稳定性。
由以下实例进一步例示本发明，所述实例用以阐述本发明化合物的制备。这些实例仅处于阐述的，并不意欲为以任何方式限制本发明。未特别举例的其他化合物，可采用与本文所述方法结合常规方法，予以合成。
所述一类取代杂环衍生物的合成路线之一如下：
(a)n-BuLi,R-COCl,-78℃→0℃；
所述R基团选自：
所述一类取代杂环衍生物的合成路线之二如下：
(a)(i)CbzCl,Et3N,EtOAc,(ii)BnBr,NaH,THF；
(b)DIBAL-H,THF,0℃；
(c)I2,PPh3,0℃
(a)(i)SmI2,THF,-78℃,(ii)DMP,CH2Cl2,0℃；
(b)(i)H2,Pd/C,(ii)CDI或BTC；
(c)n-BuLi,R-COCl,-78℃→0℃,
(d)NaClO2,丙酮/水,
(e)CH3I,Na2CO3,丙酮,
(f)DEPBT,NH2OH·HCl,Et3N,CH2Cl2
所述R基团选自：
所述一类取代杂环衍生物的合成路线之三如下：
(a)(i)NaN3,DMF,(ii)PPh3,THF/H2O,(iii)Boc2O,Et3N；
(b)(i)H2,Pd/C,(ii)CDI或BTC；
(c)n-BuLi,R-COCl,-78℃→0℃；
(d)CH3I,Et3N,THF。
所述R基团为：
具体实施方式
1、化合物合成实施例
通用合成方法1
在–78℃条件下，向含有恶唑烷酮(44mg，0.5mmol)的四氢呋喃(THF)溶液中缓慢滴加正丁基锂溶液(0.55mmol，0.2mLhexane)。在此温度下搅拌10min之后，向反应溶液中滴加酰氯溶液(0.55mmol，1mLTHF)。反应液在–78℃条件下搅拌0.5h，在4h之内缓慢升温到室温，并在室温条件下搅拌1h。反应结束后，往反应液中滴加饱和NH4Cl溶液(5mL)，并用乙酸乙酯萃取水层，合并有机相，无水硫酸钠干燥，减压蒸去有机溶剂，残留物通过硅胶柱层析纯化，可得到相应的化合物。
棕榈酰恶唑烷酮(1)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物1(83mg；产率：51％)。
IR(film)νmax:2914,2846,1765,1699,1386cm–1；1HNMR(400MHz,CDCl3)δ0.88(t,J＝7.2Hz,3H),1.26–1.32(m,24H),1.62–1.69(m,2H),2.91(t,J＝7.6Hz,2H),4.02(t,J＝8.0Hz,2H),4.41(t,J＝8.0Hz,2H)ppm；13CNMR(100MHz,CDCl3)δ14.0,22.6,24.2,29.1,29.3,29.4,29.5,29.6,29.6,31.8,35.0,42.5,61.9,153.5,173.5ppm；MS(ESI,m/z):326(M+H)+；Anal.calcdforC19H35NO3:C,70.11；H,10.84；N,4.30.Found:C,70.13；H,10.86；N,4.32.
苯己酰恶唑烷酮(2)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶4)，反应得到产物2(41mg；产率：31％)。
IR(film)νmax:2920,2858,1780,1700,1388,1225,1111,1039cm–1；1HNMR(400MHz,CDCl3)δ1.36–1.44(m,2H),1.61–1.73(m,4H),2.61(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.97(t,J＝8.4Hz,2H),4.36(t,J＝8.4Hz,2H),7.16–7.18(m,3H),7.24–7.28(m,2H)ppm；13CNMR(100MHz,CDCl3)δ24.0,28.6,31.1,34.9,35.6,42.4,61.9,125.5,128.2,128.3,142.4,153.4,173.3ppm；MS(ESI,m/z):262(M+H)+；HRMS(ESI)calcdfor[C15H20NO3]+(M+H+):262.1438；found:262.1451；Anal.calcdforC15H19NO3:C,68.94；H,7.33；N,5.36.Found:C,68.70；H,7.31；N,5.38.
苯庚酰恶唑烷酮(3)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物3(61mg；产率：44％)。
IR(film)νmax:2918,2850,1781,1703,1386,1225,1039cm–1；1HNMR(400MHz,CDCl3)δ1.35–1.42(m,4H),1.58–1.69(m,4H),2.60(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.98(t,J＝8.4Hz,2H),4.36(t,J＝8.4Hz,2H),7.16–7.17(m,3H),7.24–7.28(m,2H)ppm；113CNMR(100MHz,CDCl3)δ24.1,28.9,28.9,31.2,35.0,35.8,42.4,61.9,125.5,128.1,128.3,142.6,153.5,173.4ppm；MS(ESI,m/z):276(M+H)+；Anal.calcdforC16H21NO3:C,69.79；H,7.69；N,5.09.Found:C,69.83；H,7.68；N,5.10.
苯辛酰恶唑烷酮(4)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物4(61mg；产率：44％)。
IR(film)νmax:2920,2848,1780,1703,1386,1225,1020cm–1；1HNMR(400MHz,CDCl3)δ1.35–1.42(m,4H),1.58–1.69(m,4H),2.60(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.98(t,J＝8.4Hz,2H),4.36(t,J＝8.4Hz,2H),7.16–7.17(m,3H),7.24–7.28(m,2H)ppm；113CNMR(100MHz,CDCl3)δ24.1,28.9,28.9,31.2,35.0,35.8,42.4,61.9,125.5,128.1,128.3,142.6,153.5,173.4ppm；MS(ESI,m/z):290(M+H)+；Anal.calcdforC17H23NO3:C,70.56；H,8.01；N,4.84.Found:C,70.61；H,7.99；N,4.85.
3–噻吩戊酰恶唑烷酮(5)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)；反应得到产物5(57mg；产率：43％)。
IR(film)νmax:2917,2849,1777,1697,1386,1222cm–1；1HNMR(400MHz,CDCl3)δ1.36–1.44(m,2H),1.62–1.73(m,4H),2.63(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.98(t,J＝8.0Hz,2H),3.37(t,J＝8.0Hz,2H),6.91–6.92(m,2H),7.21–7.23(m,1H)ppm；13CNMR(100MHz,CDCl3)δ23.9,28.6,29.9,30.1,34.9,42.4,61.9,119.8,125.0,128.1,142.7,153.4,173.3ppm；MS(ESI,m/z):268(M+H)+；Anal.calcdforC13H17NO3S:C,58.40；H,6.41.Found:C,58.57；H,6.40.
环己基戊酰恶唑烷酮(6)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物6(57mg；产率：43％)。
IR(film)νmax:2917,2849,1577,1541,1468,1384,1068,1023cm–1；1HNMR(400MHz,CDCl3)δ0.82–0.90(m,2H),1.15–1.23(m,6H),1.32–1.34(m,4H),1.63–1.70(m,7H),2.92(t,J＝7.6Hz,2H),4.03(t,J＝8.0Hz,2H),4.42(t,J＝8.0Hz,2H)ppm；13CNMR(100MHz,CDCl3)δ24.3,26.4,26.5,26.7,29.4,33.4,25.0,37.3,37.6,42.5,61.9,153.5,173.6ppm；MS(ESI,m/z):268(M+H)+；Anal.calcdforC15H25NO3:C,67.38；H,9.42；N,5.24.Found:C,67.15；H,9.41；N,5.25.
3–呋喃基戊酰恶唑烷酮(7)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物7(6.3mg；产率：5％)。
1HNMR(400MHz,CDCl3)δ1.34–1.43(m,2H),1.52–1.73(m,4H),2.61(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.98(t,J＝8.0Hz,2H),3.37(t,J＝8.0Hz,2H),6.25(br,1H),7.19(br,1H),7.33(t,J＝1.4Hz,1H)ppm；13CNMR(100MHz,CDCl3)δ24.3,24.0,28.6,31.1,34.9,42.4,61.9,110.9,124.8,138.7,142.6,153.4,173.3ppm；MS(ESI,m/z):252(M+H)+
3–氟基苯基戊酰恶唑烷酮(8)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物8(57mg；产率：51％)。
IR(film)νmax:2918,2850,1779,1699,1617,1585,1387,1223,1044cm–1；1HNMR(400MHz,CDCl3)δ1.36–1.44(m,2H),1.61–1.74(m,4H),2.61(t,J＝7.6Hz,2H),2.92(t,J＝7.6Hz,2H),4.00(t,J＝8.4Hz,2H),4.40(t,J＝8.4Hz,2H),6.84–6.88(m,2H),6.94(d,J＝7.5Hz,1H),7.19–7.24(m,1H)ppm；13CNMR(100MHz,CDCl3)δ24.0,28.6,30.8,34.9,35.4,42.5,61.9,112.4,112.6,115.1,115.3,124.0,124.1,145.0,145.1,153.5,161.7,164.1,173.4ppm；MS(ESI,m/z):280(M+H)+；Anal.calcdforC15H18FNO3:C,64.50；H,6.50；N,5.01.Found:C,64.37；H,6.49；N,5.00.
3–氯基苯基戊酰恶唑烷酮(9)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物9(57mg；产率：51％)。
IR(film)νmax:2917,2849,1777,1692,1573,1537,1468,1383,1202,1066,1036cm–1；1HNMR(400MHz,CDCl3)δ1.35–1.43(m,2H),1.60–1.73(m,4H),2.59(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.99(t,J＝8.3Hz,2H),4.39(t,J＝8.3Hz,2H),7.04(d,J＝7.3Hz,1H),7.13–7.20(m,3H)ppm；13CNMR(100MHz,CDCl3)δ23.9,28.5,30.8,34.9,35.3,43.4,61.9,125.7,126.6,128.4,129.4,133.8,144.5,153.5,173.3ppm；MS(ESI,m/z):296(M+H)+；Anal.calcdforC15H18ClNO3:C,60.91；H,6.13；N,4.74.Found:C,60.77；H,6.15；N,4.73.
4–氟基苯基戊酰恶唑烷酮(10)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物10(55mg；产率：49％)。
IR(film)νmax:2917,2849,1782,1709,1579,1495,1384,1222,1091,1040cm–1；1HNMR(400MHz,CDCl3)δ1.35–1.42(m,2H),1.59–1.71(m,4H),2.58(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),4.00(t,J＝8.0Hz,2H),4.39(t,J＝8.0Hz,2H),7.09(d,J＝8.2Hz,2H),7.23(d,J＝8.2Hz,2H)ppm；13CNMR(100MHz,CDCl3)δ224.0,24.4,28.5,31.0,34.9,42.4,61.9,128.3,129.7,140.9,153.5,173.4ppm；MS(ESI,m/z):296(M+H)+；Anal.calcdforC15H18ClNO3:C,60.91；H,6.13；N,4.74.Found:C,60.83；H,6.14；N,4.75.
3–甲基苯基戊酰恶唑烷酮(11)
依通用合成方法2、3(纯化溶剂：乙酸乙酯∶石油醚＝1∶3)，反应得到产物11(72mg；产率：52％)。
IR(film)νmax:2955,2917,2849,1776,1701,1571,1541,1465,1384,1069cm–1；1HNMR(400MHz,CDCl3)δ1.36–1.44(m,2H),1.60–1.73(m,4H),2.32(s,1H),2.57(t,J＝7.6Hz,2H),2.91(t,J＝7.6Hz,2H),4.00(t,J＝8.2Hz,2H),4.38(t,J＝8.2Hz,2H),6.95–6.98(m,3H),7.16(dd,J＝7.3,7.3Hz,1H)ppm；13CNMR(100MHz,CDCl3)δ21.4,24.0,28.7,31.2,34.9,35.6,42.5,61.9,125.4,126.3,128.1,129.2,137.7,142.5,153.5,173.4ppm；MS(ESI,m/z):332(M+H)+；Anal.calcdforC19H25NO4。
4–甲基苯基戊酰恶唑烷酮(12)
依通用合成方法2、3(纯化溶剂：乙酸乙酯∶石油醚＝1∶3)，反应得到产物12(76mg；产率：55％)。
IR(film)νmax:2953,2917,2849,1776,1701,1579,1537,1468,1384,1069,1024cm–1；1HNMR(400MHz,CDCl3)δ1.35–1.43(m,2H),1.59–1.73(m,4H),2.31(s,1H),2.57(t,J＝7.7Hz,2H),2.90(t,J＝7.7Hz,2H),4.00(t,J＝7.8Hz,2H),4.38(t,J＝7.8Hz,2H),7.04–7.09(m,4H)ppm；13CNMR(100MHz,CDCl3)δ20.9,24.0,28.7,31.2,34.9,35.2,42.4,61.9,128.2,128.9,134.9,139.4,153.5,173.4ppm；MS(ESI,m/z):332(M+H)+；Anal.calcdforC19H25NO4。
3–联苯甲酰恶唑烷酮(13)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2)，反应得到产物13(81mg；产率：61％)。
IR(film)νmax:2916,2848,1633,1565,1406,1107,1037cm–1；1HNMR(400MHz,CDCl3)δ4.19–4.20(m,2H),4.52(br,2H),7.36–7.38(m,1H),7.44(br,2H),7.50–7.52(m,1H),7.59–7.61(m,3H),7.77–7.78(br,1H),7.87(s,1H)ppm；13CNMR(100MHz,CDCl3)δ43.7,48.0,48.2,48.4,48.6,48.9,62.6,127.0,127.6,128.3,128.7,130.8,140.0,140.9,153.9,170.0ppm；MS(ESI,m/z):268(M+H)+；Anal.calcdforC16H13NO3:C,71.90；H,4.90；N,5.24.Found:C,71.74；H,4.89；N,5.25.
3–联苯乙酰恶唑烷酮(14)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3)，反应得到产物14(63mg；产率：45％)。
IR(film)νmax:2916,2848,1776,1697,1598,1478,1387,1366,1223,1180,1109cm–1；1HNMR(400MHz,CDCl3)δ4.02(t,J＝8.0Hz,2H),4.35(s,2H),4.39(t,J＝8.0Hz,2H),7.31(d,J＝7.2Hz,1H),7.34(d,J＝7.2Hz,1H),7.38–7.44(m,3H),7.50(d,J＝7.6Hz,1H),7.55–7.60(m,1H)ppm；13CNMR(100MHz,CDCl3)δ41.1,42.7,61.9,126.0,127.2,127.3,128.6,128.6,128.7,128.9,134.0,140.8,141.5,153.5,171.2ppm；MS(ESI,m/z):282(M+H)+；Anal.calcdforC17H15NO3:C,72.58；H,5.37；N,4.98.Found:C,72.71；H,5.39；N,4.96.
4–联苯乙酰恶唑烷酮(15)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3)，反应得到产物15(65mg；产率：46％)。
IR(film)νmax:2914,2844,1776,1697,1578,1386,1366,1025cm–1；1HNMR(400MHz,CDCl3)δ4.00(t,J＝8.4Hz,2H),4.31(s,2H),4.36(t,J＝8.4Hz,2H),7.33(t,J＝7.6Hz,1H),7.37–7.44(m,4H),7.54–7.58(m,4H)ppm；13CNMR(100MHz,CDCl3)δ40.7,42.6,61.9,127.0,127.2,128.7,130.1,132.5,140.0,140.7,153.4,171.1ppm；MS(ESI,m/z):282(M+H)+；Anal.calcdforC17H15NO3:C,72.58；H,5.37；N,4.98.Found:C,72.67；H,5.38；N,4.97.
3–苯氧基苯甲酰恶唑烷酮(16)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2)，反应得到产物16(65mg；产率：48％)。
IR(film)νmax:2917,2845,1783,1682,1577,1483,1436,1322,1200cm–1；1HNMR(400MHz,CDCl3)δ4.14(t,J＝8.0Hz,2H),4.46(t,J＝8.0Hz,2H),7.04(dd,J＝8.6,1.0Hz,2H),7.12(dd,J＝7.4,0.9Hz,1H),7.18(dddd,J＝7.2,7.2,2.0,2.0Hz,1H),7.26(br,1H),7.33–7.39(m,4H)ppm；13CNMR(100MHz,CDCl3)δ43.6,62.2,119.1,119.1,122.6,123.6,123.7,129.4,129.9,134.3,153.0,156.6,156.8,169.1ppm；MS(ESI,m/z):284(M+H)+；Anal.calcdforC16H13NO4:C,67.84；H,4.63；N,4.94.Found:C,68.01；H,4.64；N,4.93.
3–苯氧基苯乙酰恶唑烷酮(17)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物17(86mg；产率：53％)。
IR(film)νmax:2914,2844,1777,1701,1583,1486,1387,1366,1269,1246,1211cm–1；1HNMR(400MHz,CDCl3)δ3.99(t,J＝8.0Hz,2H),4.24(s,1H),4.37(t,J＝8.0Hz,2H),6.89(d,J＝7.8Hz,1H),6.96(s,1H),7.01(dd,J＝8.4,8.4Hz,3H),7.09(dd,J＝7.8Hz,1H),7.25(d,J＝7.8Hz,1H),7.31(dd,J＝8.4,8.4Hz,2H)ppm；13CNMR(100MHz,CDCl3)δ40.9,42.6,61.9,117.4,118.9,120.1,123.2,124.5,129.7,135.3,153.4,156.9,157.2,170.8ppm；MS(ESI,m/z):298(M+H)+；Anal.calcdforC17H15NO4:C,68.68；H,5.09；N,4.71.Found:C,68.51；H,5.08；N,4.72.
4–苯氧基苯乙酰恶唑烷酮(18)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物18(88mg；产率：59％)。
IR(film)νmax:2916,2848,1777,1577,1537,1486,1467,1385,1237,1108,1040cm–1；1HNMR(400MHz,CDCl3)δ4.02(t,J＝8.0Hz,2H),4.25(s,2H),4.39(t,J＝8.0Hz,2H),6.95(d,J＝8.4Hz,2H),7.00(d,J＝7.6Hz,2H),7.09(t,J＝7.6Hz,1H),7.27(d,J＝8.4Hz,2H),7.32(t,J＝7.6Hz,2H)ppm；13CNMR(100MHz,CDCl3)δ40.3,42.6,62.0,118.8,118.9,123.3,128.2,129.7,131.0,153.4,156.4,157.0,171.3ppm；MS(ESI,m/z):298(M+H)+；Anal.calcdforC17H15NO4:C,68.68；H,5.09；N,4.71.Found:C,68.73；H,5.10；N,4.72.
3–苄氧基苯甲酰恶唑烷酮(19)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物19(82mg；产率：55％)。
IR(film)νmax:2916,2849,1785,1679,1634,1579,1436,1383,1325,1244,1217,1196,1145,1098,1037cm–1；1HNMR(400MHz,CDCl3)δ4.16(t,J＝7.6Hz,2H),4.48(t,J＝7.6Hz,2H),5.08(s,2H),7.14–7.44(m,9H)ppm；13CNMR(100MHz,CDCl3)δ43.7,62.2,70.3,115.1,119.3,121.7,127.6,128.1,128.6,129.0,133.9,136.5,153.1,158.3,169.5ppm；MS(ESI,m/z):298(M+H)+；Anal.calcdforC17H15NO4:C,68.68；H,5.09；N,4.71.Found:C,68.81；H,5.11；N,4.71.
3–苄氧基苯乙酰恶唑烷酮(20)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物20(76mg；产率：49％)。
IR(film)νmax:2916,2849,1777,1698,1583,1489,1449,1387,1365,1272,1224,1158,1109,1039cm–1；1HNMR(400MHz,CDCl3)δ3.97(t,J＝8.1Hz,2H),4.25(s,2H),4.35(t,J＝8.1Hz,2H),5.04(s,2H),6.88(d,J＝7.9Hz,1H),6.91(d,J＝7.9Hz,1H),6.96(s,1H),7.22(dd,J＝7.9,7.9Hz,1H),7.30(dd,J＝7.2,7.2Hz,1H),7.37(dd,J＝7.2,7.2Hz,2H),7.42(d,J＝7.2Hz,2H)ppm；13CNMR(100MHz,CDCl3)δ41.0,42.6,61.9,69.9,113.7,116.2,122.3,127.5,127.9,128.5,129.5,135.0,137.0,153.4,158.9,171.0ppm；MS(ESI,m/z):312(M+H)+；Anal.calcdforC18H17NO4:C,69.44；H,5.50；N,4.50.Found:C,69.20；H,5.49；N,4.51.
4–苄氧基苯甲酰恶唑烷酮(21)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物21(108mg；产率：73％)。
IR(film)νmax:2916,2849,1774,1670,1607,1512,1378,1338,1249,1194,1108,1024cm–1；1HNMR(400MHz,CDCl3)δ4.14(t,J＝8.0Hz,2H),4.47(t,J＝8.0Hz,2H),5.11(s,2H),6.99(d,J＝8.8Hz,2H),7.34–7.43(m,5H),7.69(d,J＝8.8Hz,2H)ppm；13CNMR(100MHz,CDCl3)δ43.9,62.2,70.1,114.0,124.7,127.5,128.2,128.6,131.8,136.2,153.5,162.4,169.0ppm；MS(ESI,m/z):298(M+H)+；Anal.calcdforC17H15NO4:C,68.68；H,5.09；N,4.71.Found:C,68.90；H,5.11；N,4.69.
4–苄氧基苯乙酰恶唑烷酮(22)
依通用合成方法(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物22(77mg；产率：50％)。
IR(film)νmax:2916,2849,1777,1698,1607,1511,1387,1365,1240,1177,1111,1040,1016cm–1；1HNMR(400MHz,CDCl3)δ3.96(t,J＝8.0Hz,2H),4.20(s,2H),4.33(t,J＝8.0Hz,2H),5.03(s,2H),6.92(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,2H),7.30(t,J＝7.2Hz,1H),7.35–7.42(m,4H)ppm；13CNMR(100MHz,CDCl3)δ40.1,42.6,61.9,69.9,114.8,125.8,127.4,127.9,128.5,130.7,136.9,153.4,157.9,171.5ppm；MS(ESI,m/z):312(M+H)+；Anal.calcdforC18H17NO4:C,69.44；H,5.50；N,4.50.Found:C,69.65；H,5.51；N,4.50.
4–苯乙氧基苯甲酰恶唑烷酮(23)
依通用合成方法2、6(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物23(84mg；产率：54％)。
IR(film)νmax:2916,2849,1777,1672,1605,1508,1384,1324,1307,1254,1168,1094,1029cm–1；1HNMR(400MHz,CDCl3)δ3.11(t,J＝7.2Hz,2H),4.14(t,J＝8.0Hz,2H),4.22(t,J＝7.2Hz,2H),4.46(t,J＝8.0Hz,2H),6.90(d,J＝8.4Hz,2H),7.23–7.34(m,5H),7.67(d,J＝8.4Hz,2H)ppm；13CNMR(100MHz,CDCl3)δ35.6,43.9,62.2,68.8,113.7,124.4,126.6,128.5,129.0,131.8,137.8,153.5,162.5,169.0ppm；MS(ESI,m/z):312(M+H)+；Anal.calcdforC21H24N2O4:C,68.46；H,6.57；N,7.60；O,17.37；Found:C,68.23；H,6.44；N,7.78；O,17.45.
4–苄基环己酰恶唑烷酮(24)
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5)，反应得到产物24(84mg；产率：54％)。
1HNMR(400MHz,CDCl3)δ1.53-1.68(m,6H),1.77-1.90(m,3H),2.61-2.63(m,2H),3.60-3.66(t,1H),3.99-4.03(t,J＝8.0Hz,2H),4.36-4.40(t,J＝8.0Hz,1H),7.11-7.19(m,3H),7.25-7.28(m,2H)ppm；13CNMR(100MHz,CDCl3)δ25.2,28.6,36.4,39.8,40.1,42.8,61.8,125.6,128.1,129.0,141.3,153.1,176.6ppm；
2、内源性大麻素水解酶活性检测方法
将30μL(1mg/mL)内源性大麻素水解酶加入进样瓶中，再加入2μLDMSO(空白对照组)或不同浓度的化合物于37℃反应10min。再加入含有底物17∶1FAE的缓冲液170μL，17∶1FAE的浓度为5μM，于37℃反应30min，后加入含有内标十七烷酸的甲醇溶液200μL终止反应。液质联用(LC-MS)检测水解产物17∶1FA的产量，用GraphpadPrism5作图。以此测定得到待测化合物对内源性大麻素水解酶的IC50值。
3、化合物抑制内源性大麻素水解酶活性实施例
采用上述方法，检测化合物对NAAA和FAAH的抑制作用，例如表1所示结果。
表1
在表1中，IC50(NAAA)表示抑制NAAA活性至未抑制水平一半时的浓度，IC50(FAAH)表示抑制FAAH活性至未抑制水平一半时的浓度，“>100μM”表示化合物对相应的酶的IC50大于100μM，认为未对该酶有抑制作用。

Claims (4)

1.一类取代杂环衍生物，其特征在于其化学结构式如下：
其中，X为O；
Y为N；
R1不存在；
R2、R3、R4为H；
R5为H-、CH3-、CH3C(＝O)CH2-或(CH3)2NCH2-；
A选自：
2.如权利要求1所述一类取代杂环衍生物的合成路线之一如下：
所述R基团选自：
3.如权利要求1所述一类取代杂环衍生物的合成路线之二如下：
其中DIBAL-H为二异丁基氧化铝；THF为四氢呋喃；
其中SmI2为二碘化钐；THF为四氢呋喃；DMP为12-I-53-乙酸基高碘酸盐；Pd/C为钯炭；CDI为羰基二咪唑；BTC为三光气；
所述R基团选自：
4.如权利要求1所述一类取代杂环衍生物的合成路线之三如下：
其中DMF为二甲基甲酰胺；(Boc)2O为二碳酸二叔丁酯；
所述R基团为：
CN201410603721.1A 2014-10-31 2014-10-31 一类取代杂环衍生物及其制备方法 Active CN104356082B (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN201410603721.1A CN104356082B (zh) 2014-10-31 2014-10-31 一类取代杂环衍生物及其制备方法
CN201580059446.4A CN107074788B (zh) 2014-10-31 2015-10-29 取代杂环衍生物、其制备方法和用途
PCT/CN2015/093140 WO2016066115A1 (zh) 2014-10-31 2015-10-29 取代杂环衍生物、其制备方法和用途
US15/522,985 US10174015B2 (en) 2014-10-31 2015-10-29 Substituted heterocyclic derivative, preparation method and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410603721.1A CN104356082B (zh) 2014-10-31 2014-10-31 一类取代杂环衍生物及其制备方法

Publications (2)

Publication Number Publication Date
CN104356082A CN104356082A (zh) 2015-02-18
CN104356082B true CN104356082B (zh) 2016-07-13

Family

ID=52523419

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410603721.1A Active CN104356082B (zh) 2014-10-31 2014-10-31 一类取代杂环衍生物及其制备方法

Country Status (1)

Country Link
CN (1) CN104356082B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107074788B (zh) * 2014-10-31 2019-09-20 厦门大学 取代杂环衍生物、其制备方法和用途

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2866888B1 (fr) * 2004-02-26 2006-05-05 Sanofi Synthelabo Derives de alkylpiperazine- et alkylhomopiperazine- carboxylates, leur preparation et leur application en therapeutique
TWI530489B (zh) * 2011-03-22 2016-04-21 必治妥美雅史谷比公司 雙（氟烷基）－１，４－苯二氮呯酮化合物
CN102349917A (zh) * 2011-08-16 2012-02-15 厦门大学 一种雷公藤红素的用途及制备方法
ES2405435B1 (es) * 2011-11-25 2014-05-12 Centro De Investigación Biomédica En Red Fisiopatología De La Obesidad Y Nutrición (Ciberobn) Uso del enantiómero (-)-c75 como antitumoral
CN106986863B (zh) * 2012-04-24 2019-12-31 沃泰克斯药物股份有限公司 Dna-pk抑制剂

Also Published As

Publication number Publication date
CN104356082A (zh) 2015-02-18

Similar Documents

Publication Publication Date Title
Chabaud et al. Total synthesis of hyacinthacine A1 and 3-epi-hyacinthacine A1
JP4857332B2 (ja) アルキル、アルケニルおよびアルキニルカルバメート誘導体、この製剤および治療上の使用
US4080337A (en) Multioxymacrocycle compounds containing pyridyl rings as part of the macrocycle
FR2915198A1 (fr) Derives de triazolopyridine-carboxamides et triazolopyridine -carboxamides, leur preparation et leur application en therapeutique.
JP4164645B2 (ja) Ｄｇａｔ阻害剤
CA2542370A1 (fr) Derives de n-[heteroaryl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
WO2008145839A1 (fr) Dérivés de triazolopyridine-carboxamides et triazolopyrimidine-carboxamides, leur préparation et leur application en thérapeutique
WO2007088276A2 (fr) Derives de sulfonamides, leur preparation et leur application en therapeutique
Lee et al. Total synthesis of (−)-kopsinine and ent-(+)-kopsinine
CN104356082B (zh) 一类取代杂环衍生物及其制备方法
Scott et al. Amido, ureido and urethano neighbouring group participation
EP1567150B1 (fr) Derives d indole-3-carboxamide, leur preparation et leur application en therapeutique
Singh et al. Structure–activity relationship study of a series of novel oxazolidinone derivatives as IL-6 signaling blockers
FR2381736A1 (fr) Complexe mixte d'halogenure de magnesium de certains acides 2-aryl-propioniques et procede pour leur preparation
Churches et al. Stereoselectivity of the Petasis reaction with various chiral amines and styrenylboronic acids
CN112574056B (zh) 一种α,α-二氟-γ-羟基乙酰胺衍生物的合成方法
Harada et al. Stereoselective acetalization of 1, 3-alkanediols controlled by intramolecular van der Waals attractive interactions and its application to an enantiodifferentiating transformation of. sigma.-symmetric 1, 3, 5-pentanetriols
Jiang et al. A convenient stereoselective synthesis of trifluoromethyl-substituted polyfunctionalized cyclopropane: synthesis of (±)-trans-trifluoronorcoronamic acid
Yuan et al. Synthesis, Structure Analysis, and Antitumor Activity of (R)‐2, 4‐Dioxo‐5‐fluoro‐1‐[1‐(methoxycarbonyl) Ethylaminocarbonylmethyl]‐1, 2, 3, 4‐tetrahydropyrimidine
WO2020017624A1 (ja) 抗がん剤
CN109608454A (zh) 一种合成6氢-吡啶[1,2-c]喹唑啉-6-酮类化合物的新方法
WO2007020631A2 (en) Tetracyclic benzofuran derivatives with therapeutic activities
US5801271A (en) 7-(n-substituted amino)-2-phenylheptanoic acid derivative and process for manufacturing the same
Xu et al. Synthesis of N-(1, 2, 3, 6-tetrahydropyridylidene)-fluoroalkanesulfonylamides from reactions of per (poly) fluoroalkanesulfonyl azides with 1, 2-dihydropyridines
Jellimann et al. Melatonergic Properties of the (+)-and (−)-Enantiomers of N-(4-Methoxy-2, 3-dihydro-1 H-phenalen-2-yl) amide Derivatives

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant