CN1556703A - 具有cb1激动活性,cb1部分激动活性或cb1拮抗活性的1h-咪唑衍生物 - Google Patents
具有cb1激动活性,cb1部分激动活性或cb1拮抗活性的1h-咪唑衍生物 Download PDFInfo
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Abstract
本发明涉及新的1H-咪唑衍生物,涉及这些化合物的制备方法,涉及含有一种或几种这些化合物作为活性成分的药物组合物。这些1H-咪唑衍生物是用于治疗精神病和神经病以及涉及大麻素神经传递的其它疾病有效的大麻素-CB1受体激动剂、部分激动剂或拮抗剂。所述化合物具有通式(I),其中R和R1-R4具有说明书中给出的定义。
Description
本发明涉及一组新的1H-咪唑衍生物,涉及这些化合物的制备方法,和涉及含有这些化合物中的一种或几种作为活性成分的药物组合物。这些1H-咪唑衍生物是有效的大麻素(cannabinoid)-CB1受体激动剂,部分激动剂或拮抗剂,用于治疗精神病和神经病,以及涉及大麻素神经传递的其它疾病。
大麻素存在印度hemp Cannabis sativa中,并且几个世纪以来一直被用作药物(Mechoulam,R.和Feigenbaum,J.J.Prog.Med.Chem.1987,24,159)。但是,只是在过去的十年里大麻素领域的研究才揭示关于大麻素受体和它们的(内源)激动剂和拮抗剂的关键信息。大麻素受体两种不同亚型(CB1和CB2)的发现和随后的克隆刺激了对于新的大麻素受体拮抗剂的研究(Munro,S.等,Nature 1993,365,61.Matsuda,L.A.和Bonner,T.I.Cannabinoid Receptors,Pertwee,R.G.编著,1995,117,Academic Press,London)。另外,制药公司开始对开发用于治疗与大麻素体系失调相关的疾病的大麻素药物感兴趣(Consroe,P.Neurobiology of Disease 1998,5,534.Pop,E.Curr.Opin.In CPNS Investigational Drugs 1999,1,587.Greenberg,D.A.Drug News Perspect.1999,12,458.Pertwee,R.G.,Progressin Neurobiology 2001,63,569)。迄今为止,几种CB1受体拮抗剂是已知的。Sanofi公开了二芳基吡唑同类作为选择性CB1受体拮抗剂。代表性例子是SR-141716A(Dutta,A.K.等,Med.Chem.Res.1994,5,54.Lan,R.等,J.Med.Chem.1999,42,769。Nakamura-Palacios,E.M.等,CNS Drug Rev.1999,5,43)。CP-272871是一种吡唑衍生物,象SR141716A,但是与SR141716A相比效力较低并且对CB1受体亚型选择性较低(Meschler,J.P.等,Biochem.Pharmacol.2000,60,1315)。有人公开了氨基烷基吲哚是CB1受体拮抗剂。代表性例子是lodopravadoline(AM-630),它是1995年引入的。AM-630是中度活性CB1受体拮抗剂,在一些测试中表现为弱的部分激动剂(Hosohata,K.等,Life Sci.1997,61,PL115)。来自Eli Lilly的研究者描述芳基-芳酰基取代的苯并呋喃是选择性CB1受体拮抗剂(例如LY-320135)(Felder,C.C.等,J.Pharmacol.Exp.Ther.1998,284,291)。3-烷基-5,5’-二苯基咪唑啉-二酮被描述是大麻素受体配体,指出它是大麻素拮抗剂(Kanyonyo,M.等,Biorg.Med.Chem.Lett.1999,9,2233)。Aventis Pharma要求保护二芳基亚甲基氮杂环丁烷类似物作为CB1受体拮抗剂(Mignani,S.等,专利FR 2783246,2000;Chem.Abstr.2000,132,236982)。Sanofi-Synthelabo要求保护三环吡唑作为CB1拮抗剂(Barth,F.等,专利WO 0132663,2001;Chem.Abstr.2001,134,340504)。令人感兴趣的,据报道很多CB1受体拮抗剂体外行为象逆反的激动剂(Landsman,R.S.等,Eur.J.Pharmacol.1997,334,R1)。还有人报道吡唑大麻素是CB1受体部分激动剂,在体内表现出大麻模拟效果(Wiley,J.L.等,J.Pharmacol.Exp.Ther.2001,296,1013)。很多类别CB1受体激动剂是已知的,例如典型的大麻素(例如Δ9-THC),非典型的大麻素,氨基烷基吲哚和类二十烷(eicosanoids)(例如anandamide)。有综述提供了有关大麻素研究领域很好的综述(Mechoulam,R.等,Prog.Med.Chem.1998,35,199。Lambert,D.M.Curr.Med.Chem.1999,6,635.Mechoulam,R.等,Eur.J.Pharmacol.1998,359,1。Williamson,E.M.和Evans,F.J.Drugs 2000,60,1303.Pertwee,R.G.Addiction Biology2000,5,37。Robson,P.Br.J.Psychiatry 2001,178,107。Pertwee,R.G.Prog.Neurobiol.2001,63,569。Goya,P.和Jagerovic,N.Exp.Opin.Ther.Patents 2000,10,1529。Pertwee,R.G.Gut 2001,48,859)。
现在出人意料地发现式(I)的新的1H-咪唑衍生物,其前体药物和其盐是潜在的大麻素CB1受体的激动剂,部分激动剂或拮抗剂
其中
-R代表苯基,噻吩基,2-吡啶基,3-吡啶基,4-吡啶基,嘧啶基,哌嗪基,哒嗪基或三嗪基,这些基团可以被1,2,3或4个相同或不同的选自C1-3-烷基或烷氧基,羟基,卤素,三氟甲基,三氟甲硫基,三氟甲氧基,硝基,氨基,一-或二烷基(C1-2)-氨基,一-或二烷基(C1-2)-酰氨基,(C1-3)-烷氧羰基,羧基,氰基,氨基甲酰基和乙酰基的取代基Y取代,或者R代表萘基,前提是当R是4-吡啶基时,R4代表卤原子或氰基,氨基甲酰基,甲酰基,乙酰基,三氟乙酰基,氟代乙酰基,丙酰基,氨磺酰,甲磺酰基,甲基硫烷基或者有支链或没有支链的C1-4-烷基,其中C1-4-烷基可以被1-3个氟原子或溴原子,氯原子,碘原子,氰基或羟基取代,
-R1代表苯基或吡啶基,这些基团可以被1-4个相同或不同的取代基Y取代,其中Y具有上述定义,或者R1代表嘧啶基,哌嗪基,哒嗪基或三嗪基,这些基团可以被1-2个相同或不同的取代基Y取代,或者R1代表具有一个或两个选自N,O,S的杂原子的五元芳香杂环,杂原子可以是相同或不同的,所述五元芳香杂环可以被1-2个相同或不同的取代基Y取代,或者R1代表萘基,
-R2代表H,有支链或没有支链的C1-8-烷基,C3-8-环烷基,C3-8-链烯基,C5-8-环烯基,这些基团可以含有硫,氧或氮原子,
-R3代表有支链或没有支链的C2-8-烷基,C1-8-烷氧基,C5-8-环烷氧基,C3-8-环烷基,C5-10-双环烷基,C6-10-三环烷基,C3-8-链烯基,C5-8-环烯基,这些基团可以任选地含有一个或多个选自N,O,S的杂原子并且这些基团可以被羟基或1-2个C1-3-烷基或1-3个氟原子取代,或者R3代表芳香环可以被1-5个相同和不同的取代基Z取代的苄基或苯乙基,所述取代基Z选自C1-3-烷基或烷氧基,羟基,卤原子,三氟甲基,三氟甲硫基,三氟甲氧基,硝基,氨基,一-或二烷基(C1-2)-氨基,一-或二烷基(C1-2)-酰氨基,(C1-3)-烷基磺酰基,二甲基-磺氨基,(C1-3)-烷氧羰基,羧基,三氟甲基磺酰基,氰基,氨基甲酰基,氨磺酰和乙酰基,或者R3代表苯基或吡啶基,这些基团可以被1-4个取代基Z取代,其中Z具有上述定义,
或者R3代表吡啶基,或者R3代表苯基,前提是R4代表卤原子或氰基,氨基甲酰基,甲酰基,乙酰基,三氟乙酰基,氟代乙酰基,丙酰基,氨磺酰,甲磺酰基,甲基硫烷基或者C1-4-烷基,其中C1-4-烷基可以被1-3个氟原子或溴原子,氯原子,碘原子,氰基或羟基取代,
或者R3代表基团NR5R6,前提是R2代表氢原子或甲基,其中
-R5和R6是相同和不同的,并且代表有支链或没有支链的C1-4-烷基,或者R5和R6和它们键合的氮原子一起形成饱和的或不饱和的具有4-10个环原子的单环或双环杂环基团,杂环含有一个或两个相同和不同的选自N,O,S的杂原子,所述杂环基团可以被C1-3-烷基或羟基取代,
或者R2和R3和它们键合的氮原子一起形成饱和的或不饱和的具有4-10个环原子的杂环基团,杂环含有一个或两个相同和不同的选自N,O,S的杂原子,所述杂环基团可以被C1-3-烷基或羟基取代,
-R4代表氢原子或卤原子或氰基,氨基甲酰基,甲酰基,乙酰基,三氟乙酰基,氟代乙酰基,丙酰基,氨磺酰,甲磺酰基,甲基硫烷基或者有支链或没有支链的C1-4-烷基,其中C1-4-烷基可以被1-3个氟原子或溴原子,氯原子,碘原子,氰基或羟基取代。
由于强的CB1激动剂,部分激动剂或拮抗剂活性,根据本发明的化合物适合用于治疗精神病,例如精神错乱,焦虑,抑郁症,注意力不集中,记忆失调,认知失调,食欲失调,肥胖症,成瘾,欲(appetence),药物依赖性和神经失调,例如神经退行性病变,痴呆,张力失常,肌肉痉挛,颤抖,癫痫,多发性硬化,创伤性脑损伤,中风,帕金森病,早老性痴呆,癫痫症,亨廷顿舞蹈病,图雷特综合征,大脑局部缺血,大脑中风,颅脑损伤,中风,脊索损伤,神经炎症,斑硬化,病毒性脑炎,脱髓鞘相关疾病,以及用于治疗疼痛,包括神经痛,和涉及大麻素神经传递的其它疾病,包括治疗脓毒性休克,青光眼,糖尿病,癌症,呕吐,恶心,肠胃失调,胃溃疡,腹泻和心血管疾病。
使用中国仓鼠卵巢(CHO)细胞的膜制品测定本发明的化合物对于大麻素CB1受体的亲和性,其中人大麻素CB1受体与作为放射配体的[3H]CP-55940结合被稳定转染。新鲜制备的细胞膜制品与[3H]-配体在加入或没有加入本发明的化合物温育之后,通过用玻璃纤维过滤器过滤实现结合的和自由的配体的分离。通过液体闪烁计数测定过滤器上的放射性。
通过使用其中稳定表达人大麻素CB1受体的CHO细胞的功能研究测定本发明的化合物的大麻素CB1拮抗活性。使用毛喉素(forskolin)刺激腺苷环化酶并且通过定量测定积累的环AMP的量来测定。伴随CB1受体激动剂对CB1受体的激活(例如CP-55940或(R)-WIN-55212-2)能以浓度依赖方式减弱毛喉素诱导的cAMP的蓄积。这种CB1受体-介导的应答能被CB1受体拮抗剂例如本发明的化合物拮抗。
根据公开的方法能测定本发明化合物的部分激动剂活性的大麻素激动剂活性,例如评价体内大麻碱模拟作用(Wiley,J.L.等,J.Pharmacol.Exp.Ther.2001,296,1013)。
本发明涉及具有式(I)的消旋体,对映异构体混合物和单独的立体异构体。
应用常规方法,使用辅助物质和/或液体或固体载体材料,能将本发明的化合物制备成适合施用的形式。
下面是用于本发明的化合物的合适的合成途径:
合成途径A
步骤1:其中R7代表有支链或没有支链的(C1-4)烷基或苄基的具有式(II)的化合物的酯水解
该反应给出具有式(III)的化合物
其中R,R1和R4具有上文描述的定义。
根据已知方法能获得其中R7代表有支链或没有支链的(C1-4)烷基或苄基的具有式(II)的中间体,例如:
a)I.K.Khanna等,J.Med.Chem.2000,43,3168-3185
b)N.Kudo等,Chem.Pharm.Bull.1999,47,857-868
c)K.Tsuji等,Chem.Pharm.Bull.1997,45,987-995
d)I.K.Khanna等,J.Med.Chem.1997,40,1634-1647
e)M.Guillemet等,Tetrahedron Lett.1995,36,547-548
步骤2:通过活化或偶联方法例如形成活性酯,或者在偶联剂例如DCC,HBTU,BOP或类似试剂的存在下,使具有式(III)的化合物与其中R2和R3具有如上所述定义的式R2R3NH的化合物反应。该反应得到期望的具有式(I)的1H-咪唑衍生物。
(关于活化和偶联方法的更多信息参见:M.Bodanszky和A.Bodanszky:肽合成实践,Springer-Verlag,纽约,1994;ISBN:0-387-57505-7)。
或者,使具有式(III)的化合物与卤化试剂例如亚硫酰氯(SOCl2)反应。该反应得到相应的酰氯化合物(IV)。
使具有式(IV)的化合物与其中R2和R3具有如上所述定义的式R2R3NH的化合物反应,得到具有式(I)的1H-咪唑衍生物。该反应优选在有机碱例如二异丙基乙基胺(DIPEA)或三乙胺的存在下进行。
或者,使具有式(II)的化合物在酰氨基化反应中与其中R2和R3具有如上所述定义的式R2R3NH的化合物反应,得到具有式(I)的1H-咪唑衍生物。
合成途径B
其中R4代表氢并且其中R,R1和R7具有如上对于化合物(II)的定义的式(II)的化合物与具有通式R4’-X的化合物反应,其中X代表离去基团,R4’代表C1-4烷基,其中烷基可以被1-3个氟原子取代,或者其中R4’代表氰基,甲酰基,乙酰基,三氟乙酰基,氟代乙酰基,甲基烷硫基或丙酰基部分,或者卤原子。该反应在强的非亲核性碱例如二异丙基氨基化锂(LDA)的存在下,优选在无水条件下,在惰性有机溶剂例如四氢呋喃中进行,得到具有式(II)的化合物
其中R,R1和R7具有如上所述定义,R4代表C1-4烷基,其中烷基可以被1-3个氟原子取代,或者其中R4代表氰基,甲酰基,乙酰基,三氟乙酰基,氟代乙酰基,甲基硫烷基或丙酰基,或者卤原子。
与合成途径A,途径A的步骤1或途径A的步骤2中描述的方法相类似(参见上文),能将根据合成途径B获得的通式(II)化合物转化为通式(I)化合物。
合成途径C
通过使具有式(V)的化合物或者其互变异构体
其中R和R1具有上面给出的定义,
与具有式(VI)的化合物反应
其中R4代表有支链或没有支链的C1-4烷基,其中C1-4烷基可以被1-3个氟原子取代,并且R8代表离去基团,例如溴取代基,并且R7代表有支链或没有支链的(C1-4)烷基或苄基,
能合成具有式(II)的化合物
其中R4代表有支链或没有支链的C1-4烷基,其中C1-4烷基可以被1-3个氟原子取代,并且其中R,R1具有上面给出的定义,并且R7代表有支链或没有支链的(C1-4)烷基或苄基。
反应优选在有机溶剂例如在2-丙醇或者在N-甲基-2-吡咯烷酮(NMP)中进行。在反应期间加入一种酸例如三氟乙酸(TFA)可以加强具有式(II)化合物的形成。
(有关离去基团概念的更多信息参见:M.B.Smith和J.March:高等有机化学,275页,第五版,(2001)John Wiley&Sons,纽约,ISBN:0-471-58589-0)。
与合成途径A,途径A的步骤1或途径A的步骤2中描述的方法相类似(参见上文),能将根据合成途径C获得的通式(II)的化合物转化为通式(I)的化合物。
根据已知的方法能获得具有式(VI)的本发明化合物,例如:P.Seifert等,Helv.Chim.Acta,1950,33,725。
合成途径D
在自由基引发剂象二苯甲酰基过氧化物的存在下,使具有式(II)的化合物
其中R4代表甲基,并且其中R,R1具有上面给出的定义,并且R7代表有支链或没有支链的(C1-4)烷基或苄基,与立体选择性溴化化合物例如N-溴-琥珀酰亚胺(NBS)反应,得到式(VII)的化合物:
其中R,R1和R7具有上面给出的定义。具有式(VII)的化合物(类似于W.B.等,J.Label.Compds.Radiopharm,1999,42,589)与例如KCl,KI,KF或KCN反应,得到式(VIII)化合物
其中R,R1和R7具有上面给出的定义并且Nu代表氯,碘,氟或氰基。该反应优选在弱碱例如NaHCO3的存在下或者在冠醚或穴状配体的存在下进行。(有关冠醚或穴状配体的更多的信息参见:M.B.Smith和J.March:高等有机化学,105页,第五版,(2001)John Wiley&Sons,纽约,ISBN:0-471-58589-0)。
与合成途径A,途径A的步骤1或途径A的步骤2中描述的方法相类似(参见上文),能将根据合成途径D获得的通式(VII)或(VIII)化合物转化为通式(I)化合物。
实施例1
A部分:氮气下向1M双(三甲基甲硅烷基)氨基化钠的THF(70毫升)溶液滴加4-氯代苯胺(8.86克,69.5毫摩尔)的无水THF溶液。将混合物搅拌20分钟之后,加入2,4-二氯苄腈(12克,70毫摩尔)的THF溶液。将得到的混合物搅拌过夜,倒入冰水(400毫升)中并且用二氯甲烷萃取,Na2SO4干燥并且真空浓缩,得到黄色油状物(15.7克)。从二氯甲烷/庚烷混合物结晶,接着用甲基-叔丁基醚洗涤,得到N-(4-氯苯基)-2,4-二氯苯甲脒(8.66克,42%产率),为黄色固体。熔点(MP):93-95℃。
类似地制备:
N-(4-溴苯基)-2,4-二氯苯甲脒,MP:117-119℃。
B部分:在回流温度下,将2-丙醇中N-(4-氯苯基)-2,4-二氯苯甲脒(2.00克,6.68毫摩尔),3-溴-2-氧代丙酸乙酯(2.65克,13.6毫摩尔)和NaHCO3(1.12克,13.3毫摩尔)的混合物搅拌20小时。冷却至室温之后,真空浓缩混合物并且将残余物悬浮于二氯甲烷,用水(3×50毫升)和盐水(3×50毫升)洗涤。用二氯甲烷萃取水层。将合并的有机层用Na2SO4干燥并且真空浓缩,得到棕色粗产物(2.0克)。通过柱层析进一步纯化产物(硅胶,庚烷/EtOAc=90/10(v/v))得到1-(4-氯苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸乙酯(0.759克,29%产率),为黄色油状物,其静置时缓慢固化。熔点:150-152℃。
MS:395(MH+).1H-NMR(400MHz,CDCl3):δ7.91(s,1H),7.49(dd,J=8Hz,J=2Hz,1H),7.29-7.36(m,4H),7.07(dt,J=8Hz,J=2Hz,2H),4.44(q,J=7Hz,2H),1.42(t,J=7Hz,3H).
C部分:1-(4-氯苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸乙酯(0.810克,2.06毫摩尔)和LiOH(0.173克,7.20毫摩尔)溶解于H2O/THF(20毫升/20毫升)混合物中并且在50℃下搅拌16小时。真空浓缩混合物,得到1-(4-氯苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸。加入亚硫酰氯(60毫升)并且将混合物在回流温度下搅拌1小时并且真空浓缩,得到粗产物1-(4-氯苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-酰基氯。
D部分:将粗产物1-(4-氯苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-酰基氯(919毫克,大约2.39毫摩尔),1-氨基哌啶(0.469克,4.69毫摩尔)和三乙胺(0.363克,3.59毫摩尔)溶解于二氯甲烷并且在室温下搅拌1小时。混合物用饱和的NaHCO3水溶液(3×20毫升)洗涤,硫酸钠干燥并且真空浓缩,通过柱层析进一步纯化(乙酸乙酯,硅胶)得到1-(4-氯苯基)-2-(2,4-二氯苯基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺(356毫克,26%产率(以1-(4-氯苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸乙酯为基础)),质谱(MS):449。
类似地制备:
2.1-(4-氯苯基)-2-(2,4-二氯苯基)-N-(吡咯烷-1-基)-1H-咪唑-4-甲酰胺;MS:435。
3.N-(叔丁氧基)-1-(4-氯苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酰胺;MS:438。
4.1-(4-氯苯基)-2-(2,4-二氯苯基)-N-苯基-1H-咪唑-4-甲酰胺;MS:442。
5.1-(4-氯苯基)-N-环己基-2-(2,4-二氯苯基)-1H-咪唑-4-甲酰胺;MS:448。
6.N-(苄基)-1-(4-氯苯基)-2-(2,4-二氯苯基)-N-甲基-1H-咪唑-4-甲酰胺;MS:470。
7.1-[1-(4-氯苯基)-2-(2,4-二氯苯基)-4-(1H-咪唑)羰基]-六氢-1H-吖庚因;MS:448。
8.2-(4-氯苯基)-1-(2,4-二氯苯基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺(从2,4-二氯苯胺和4-氯苄腈制备);MS:449。
9.N-(叔丁氧基)-2-(4-氯苯基)-1-(2,4-二氯苯基)-1H-咪唑-4-甲酰胺(从2,4-二氯苯胺和4-氯苄腈制备);MS:438。
实施例10
A部分:0℃氮气下向无水THF(100毫升)滴加二异丙基胺(2.30克,22.8毫摩尔)。滴加正丁基锂(7.34毫升,2.5M己烷溶液,18.4毫摩尔)。将得到的溶液冷却到-78℃。滴加2-(4-氯苯基)-1-(2,4-二氯苯基)-1H-咪唑-4-甲酸乙酯(6.0克,15.2毫摩尔)的无水THF溶液。混合物的颜色由黄色变为紫棕色。将搅拌的混合物温热至-40℃并且冷却到-78℃,并且静置30分钟。滴加碘甲烷(6.44克,45.4毫摩尔),并且将得到的溶液在-78℃下搅拌30分钟,然后保持室温。用氯化铵水溶液将得到的溶液淬火,加入二乙醚,用硫酸镁干燥有机层,过滤并且真空浓缩,得到油状物(6.4克)。通过柱层析进一步纯化油状物(甲苯/EtOAc=10/2(v/v),硅胶)得到纯的2-(4-氯苯基)-1-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酸乙酯(5.3克,85%产率),为黄色油状物。
B部分:2-(4-氯苯基)-1-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酸乙酯(0.250克,0.61毫摩尔)和LiOH(0.052克,2.17毫摩尔)溶解于H2O/THF(1/1(v/v);50毫升),并且在50℃下搅拌1小时。浓缩混合物,得到粗产物2-(4-氯苯基)-1-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酸。向该混合物加入亚硫酰氯(50毫升)并且将得到的混合物在回流温度下搅拌1小时。浓缩混合物,得到2-(4-氯苯基)-1-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-酰基氯。
C部分:将2-(4-氯苯基)-1-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-酰基氯(1.5克,3.75毫摩尔),1-氨基哌啶(0.725克,7.25毫摩尔)和三乙胺(0.549克,5.44毫摩尔)溶解于二氯甲烷并且在室温下搅拌1小时。混合物用饱和的NaHCO3水溶液洗涤,硫酸钠干燥并且真空浓缩,通过柱层析进一步纯化(庚烷/乙酸乙酯=1/1(v/v),硅胶)得到2-(4-氯苯基)-1-(2,4-二氯苯基)-5-甲基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺(0.220克,13%产率),为白色泡沫状物质。MS:463。
类似地制备:
11.N-(叔丁氧基)-2-(4-氯苯基)-1-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酰胺;MS:452。
12.1-(4-氯苯基)-2-(2,4-二氯苯基)-5-甲基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺;MS:463;熔点:165-167℃。
13.N-(叔丁氧基)-2-(2,4-二氯苯基)-1-(4-氯苯基)-5-甲基-1H-咪唑-4-甲酰胺;MS:452。
14.N-(叔丁氧基)-1-(4-氯苯基)-2-(2,4-二氯苯基)-5-乙基-1H-咪唑-4-甲酰胺;无定形,MS:468。
15.1-(4-氯苯基)-2-(2,4-二氯苯基)-5-乙基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺;MS:477。
16.1-(4-溴苯基)-N-(叔丁氧基)-2-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酰胺;无定形。
17.1-(4-溴苯基)-2-(2,4-二氯苯基)-5-甲基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺;MP:>204℃。TLC(硅胶,EtOAc)Rf=0.3。
18.1-(4-溴苯基)-N-(叔丁氧基)-2-(2,4-二氯苯基)-5-乙基-1H-咪唑-4-甲酰胺;无定形。TLC(硅胶,CH2Cl2/丙酮=9/1(v/v))Rf=0.45。
19.1-(4-溴苯基)-2-(2,4-二氯苯基)-5-乙基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺;MP:>140℃。TLC(硅胶,EtOAc)Rf=0.4。
20.1-(4-溴苯基)-N-环己基-2-(2,4-二氯苯基)-5-乙基-1H-咪唑-4-甲酰胺;MP:>135-140℃。
21.1-(4-溴苯基)-2-(2,4-二氯苯基)-5-乙基-N-(正戊基)-1H-咪唑-4-甲酰胺;浆状物。TLC(硅胶,CH2Cl2/丙酮=19/1(v/v))Rf=0.4。
实施例22
A部分:向搅拌的1-(4-溴苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸乙酯(6.10克,0.0139摩尔)的THF(70毫升)溶液加入LiOH(0.67克,0.0278摩尔)和水(70毫升)。得到的混合物在50℃下搅拌16小时。冷却至室温之后,加入HCl(1N溶液,28mL),得到油状沉淀物,持续搅拌并且加入水(70毫升)时完全固化。过滤收集沉淀,用水洗涤并且真空干燥,得到1-(4-溴苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸(4.92克,86%产率)。熔点:138-142℃。
B部分:向无水乙腈(40毫升)中1-(4-溴苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸(1.23克,2.99毫摩尔)的悬浮液连续加入二异丙基乙胺(DIPEA)(1.15毫升,6.6毫摩尔),O-苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓(uronium)六氟磷酸盐(HBTU)(1.36克,3.6毫摩尔)和1-氨基哌啶(0.39毫升,3.6毫摩尔)。搅拌16小时之后,真空浓缩得到的混合物。残余物溶解于乙酸乙酯并且加入NaHCO3水溶液。收集乙酸乙酯层,用水和盐水洗涤,Na2SO4干燥,过滤并且真空浓缩,得到粗产物固体。通过用乙腈重结晶进一步纯化固体,得到1-(4-溴苯基)-2-(2,4-二氯苯基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺(830毫克,56%产率)。熔点:219-221℃。
类似地制备:
23.N-(叔丁氧基)-1-(4-溴苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酰胺。无定形。TLC(硅胶,Et2O)Rf=0.3。
24.1-(4-溴苯基)-2-(2,4-二氯苯基)-N-(吡咯烷-1-基)-1H-咪唑-4-甲酰胺。熔点:238-240℃。
25.N-(Azepan-1-基)-1-(4-溴苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酰胺。熔点:201-204℃。
26.1-(4-氯苯基)-2-(2,4-二氯苯基)-N-(六氢环戊[c]吡咯2(1H)-基)-1H-咪唑-4-甲酰胺。MS:475。
27.1-(4-氯苯基)-2-(2,4-二氯苯基)-N-(4-氟代苄基)-1H-咪唑-4-甲酰胺。MS:474。
28.1-(4-氯苯基)-2-(2-甲氧基-4-氯苯基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺;熔点:220℃。
29.1-(4-氯苯基)-N-环己基-2-(2-甲氧基-4-氯苯基)-1H-咪唑-4-甲酰胺;熔点:177-179℃。
30.1-(4-氯苯基)-2-(2-氟-4-氯苯基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺;熔点:217-218℃。
31.2-(2,4-二氯苯基)-1-(4-氯苯基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺;熔点:175-176℃。
32.N-环己基-2-(2,4-二氯苯基)-1-(4-氟苯基)-1H-咪唑-4-甲酰胺;熔点:184-185℃。
33.N-环己基-2-(2-氟-4-氯苯基)-1-(4-氯苯基)-1H-咪唑-4-甲酰胺;熔点:157-159℃。
34.1-(4-氯苯基)-2-(2-甲氧基-4-氯苯基)-N-(正戊基)-1H-咪唑-4-甲酰胺;熔点:115℃。
35.2-(2,4-二氯苯基)-1-(4-甲氧基苯基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺;熔点:178-179℃。
36.N-环己基-2-(2,4-二氯苯基)-1-(4-甲氧基苯基)-1H-咪唑-4-甲酰胺;熔点:175-176℃。
37.1-(4-氯苯基)-2-(2,4-二氯苯基)-N,N-二乙基-1H-咪唑-4-甲酰胺。熔点:177-179℃。
38.1-(4-氯苯基)-N-环己基-2-(2-三氟甲基-4-氯苯基)-1H-咪唑-4-甲酰胺;熔点:172℃。
39.1-(4-氯苯基)-N-(哌啶-1-基)-2-(2-三氟甲基-4-氯苯基)-1H-咪唑-4-甲酰胺;熔点:219℃。
40.N-(1-金刚烷基)-1-(4-氯苯基)-2-(2-三氟甲基-4-氯苯基)-1H-咪唑-4-甲酰胺;熔点:288℃。
41.1-(4-氯苯基)-N-(2,2,2-三氟乙基)-2-(2-三氟甲基-4-氯苯基)-1H-咪唑-4-甲酰胺;熔点:149℃。
42.2-(2,4-二氯苯基)-1-(吡啶-3-基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺;熔点:165-170℃。
43.N-环己基-2-(2,4-二氯苯基)-1-(吡啶-3-基)-1H-咪唑-4-甲酰胺;熔点:195℃。
44.2-(2,4-二氯苯基)-1-(吡啶-3-基)-N-(正戊基)-1H-咪唑-4-甲酰胺;熔点:117℃。
实施例45
A部分:将2,4-二氯苯甲酰氯(40.0g,0.19mol)溶解于四氢呋喃(1L)。向得到的搅拌的溶液依次加入二异丙基乙胺(DIPEA)(73.4mL,2.2摩尔当量)和4-(三氟甲基)苯胺(30.7g,0.19mol)。1小时之后真空浓缩混合物,得到油状物。这种油状物从乙醇中结晶,得到纯的2,4-二氯-N-(4-(三氟甲基)苯基)苯甲酰胺(53.2g,83%产率)。1H-NMR(200MHz,DMSO-d6):δ10.90(br s,1H),7.91(br d,J=8Hz,2H),7.63-7.77(m,4H),7.57(dt,J=8Hz,J=2Hz,1H)。
B部分:将2,4-二氯-N-(4-(三氟甲基)苯基)苯甲酰胺(19.0g,0.057mol)溶解于苯(150mL)并且加入PCl5(13.0g,1.1摩尔当量)。将得到的混合物在回流温度下加热2小时,让保持室温并且真空浓缩,得到残余物。残余物溶解于无水THF,冷却至0℃并且转移到高压釜中。从演示瓶中快速加入过量的NH3并且将混合物在室温下搅拌50小时。加入乙酸乙酯和NaHCO3水溶液的混合物。收集乙酸乙酯层,Na2SO4干燥,过滤并且真空浓缩。通过柱色谱法纯化得到的油状物(二乙醚/石油醚=1/1(v/v),硅胶),得到纯的2,4-二氯-N-(4-(三氟甲基)苯基)苯甲脒(16.9g,89%产率)。熔点:108-109℃。
C部分:将2,4-二氯-N-(4-(三氟甲基)苯基)苯甲脒(15.0g,0.0450mol)溶解于2-丙醇并且依次加入3-溴-2-氧代丁酸乙酯(20.8g,2摩尔当量)和NaHCO3。得到的混合物在回流温度下加热40小时并且使之保持室温。真空去除2-丙醇,向残余物加入乙酸乙酯并且用NaHCO3(5%水溶液)洗涤得到的有机层。收集乙酸乙酯层,Na2SO4干燥,过滤并且真空浓缩。通过柱色谱法纯化得到的油状物(二乙醚/石油醚=1/3(v/v),硅胶)并且通过用环己烷结晶进一步纯化,得到2-(2,4-二氯苯基)-5-甲基-1-(4-(三氟甲基)苯基)-1H-咪唑-4-甲酸乙酯(10.45g,52%产率),为黄色固体,熔点:160-162℃。
D部分:将生成的2-(2,4-二氯苯基)-5-甲基-1-(4-(三氟甲基)苯基)-1H-咪唑-4-甲酸乙酯转化为2-(2,4-二氯苯基)-5-甲基-1-(4-(三氟甲基)苯基)-1H-咪唑-4-甲酸(熔点:224-226℃),根据上面实施例22描述的方法,将该羧酸转化为2-(2,4-二氯苯基)-5-甲基-N-(哌啶-1-基)-1-(4-(三氟甲基)苯基)-1H-咪唑-4-甲酰胺(熔点:173-174℃)。
类似地制备:
46.2-(2,4-二氯苯基)-N-(哌啶-1-基)-1-(4-(三氟甲基)苯基)-1H-咪唑-4-甲酰胺。熔点:>200℃(分解)。
47.N-环已基-2-(2,4-二氯苯基)-5-甲基-1-(4-(三氟甲基)苯基)-1H-咪唑-4-甲酰胺。熔点:178-179℃。
48.N-环己基-2-(2,4-二氯苯基)-1-(4-(三氟甲基)苯基)-1H-咪唑-4-甲酰胺。熔点:199-200℃。
实施例49
A部分:N-(4-甲氧基苯基)-2,4-二氯苯甲脒(15.0克,50.8毫摩尔)溶解于2-丙醇并且依次加入3-溴-2-氧代丁酸乙酯(23.5克,2摩尔当量)和NaHCO3(8.5克,2摩尔当量)。得到的混合物在回流温度下加热40小时之后保持室温。真空去除2-丙醇,向残余物加入乙酸乙酯,得到的有机层用NaHCO3(5%水溶液)洗涤。收集乙酸乙酯层,用Na2SO4干燥,过滤并且真空浓缩。得到的油状物用柱色谱法纯化(二乙醚/石油醚=1/3(v/v),硅胶),得到2-(2,4-二氯苯基)-5-甲基-1-(4-甲氧基-苯基)-1H-咪唑-4-甲酸乙酯(8.61克,42%产率),为固体。1H-NMR(200MHz,CDCl3):δ7.33(d,J=8Hz,1H),7.27(d,J=2Hz,1H),7.18(dd,J=8Hz,J=2Hz,1H),7.03(dt,J=8Hz,J=2Hz,2H),6.85(dt,J=8Hz,J=2Hz,2H),4.42(q,J=7Hz,2H),3.80(s,3H),2.43(s,3H),1.43(t,J=7Hz,3H)。
B部分:向搅拌的2-(2,4-二氯苯基)-5-甲基-1-(4-甲氧基-苯基)-1H-咪唑-4-甲酸乙酯(8.00克,0.0198摩尔)的THF(80毫升)溶液加入LiOH(0.59克,2摩尔当量)和水(80毫升)。得到的混合物在80℃下搅拌16小时。冷却至室温之后,加入HCl(2N溶液,12.3mL),得到油状沉淀物,加入水并且用乙酸乙酯萃取。收集乙酸乙酯层,Na2SO4干燥,过滤并且真空浓缩。残余物用二异丙基醚结晶并且干燥,得到2-(2,4-二氯苯基)-5-甲基-1-(4-甲氧基-苯基)-1H-咪唑-4-甲酸(4.04克,87%产率),为浅灰色固体。熔点:189-191℃。
C部分:向无水乙腈(25毫升)中的2-(2,4-二氯苯基)-5-甲基-1-(4-甲氧基-苯基)-1H-咪唑-4-甲酸(1.00克,2.65毫摩尔)连续加入二异丙基乙胺(DIPEA)(1.02毫升,2.2摩尔当量),O-苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(HBTU)(1.21克,1.2摩尔当量),并且将得到的溶液搅拌15分钟。加入环己胺(0.36毫升,1.2摩尔当量)。搅拌50小时之后,真空浓缩得到的混合物。残余物溶解于二氯甲烷并且加入NaHCO3水溶液。收集二氯甲烷层,用Na2SO4干燥,过滤并且真空浓缩。残余物通过柱色谱法进一步纯化(梯度:二氯甲烷=>二氯甲烷/甲醇=99/1(v/v),硅胶),得到N-(1-环己基)-2-(2,4-二氯苯基)-5-甲基-1-(4-甲氧基-苯基)-1H-咪唑-4-甲酰胺(1.03克,85%产率)。熔点:160-161℃。
类似地制备:
50.1-(4-甲氧基-苯基)-2-(2,4-二氯苯基)-N,N,5-三甲基-1H-咪唑-4-甲酰胺。熔点:101-104℃。
51.1-(4-氯代吡啶-2-基)-2-(2,4-二氯苯基)-5-甲基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。MS:464(MH+)。
52.1-(4-氯代吡啶-2-基)-2-(2,4-二氯苯基)-5-甲基-N-(4-吗啉基)-1H-咪唑-4-甲酰胺。MS:466(MH+)。
53.N-(1-Azepanyl)-1-(4-氯代吡啶-2-基)-2-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酰胺。MS:478(MH+)。
54.1-(4-氯代吡啶-2-基)-N-环己基-2-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酰胺。MS:463。
55.1-(4-氯代吡啶-2-基)-2-(2,4-二氯苯基)-5-甲基-N-(正戊基)-1H-咪唑-4-甲酰胺。MS:463。
56.1-(4-氯代吡啶-2-基)-2-(2,4-二氯苯基)-N-(4-氟代苄基)-5-甲基-1H-咪唑-4-甲酰胺。MS:489。熔点:123-126℃。
57.1-(4-氯代苯基)-N-环己基-5-甲基-2-(2-三氟甲基-4-氯苯基)-1H-咪唑-4-甲酰胺。熔点:212℃。
58.1-(4-氯代苯基)-5-甲基-N-(哌啶-1-基)-2-(2-三氟甲基-4-氯苯基)-1H-咪唑-4-甲酰胺。熔点:165℃。
59.1-(4-氯代苯基)-2-(2-甲氧基-4-氯苯基)-5-甲基-N-(正戊基)-1H-咪唑-4-甲酰胺。熔点:131℃。
60.1-(4-氯代苯基)-2-(2-甲氧基-4-氯苯基)-5-甲基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。熔点:>256℃。
61.N-环己基-1-(4-氯代苯基)-2-(2-甲氧基-4-氯苯基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:201℃。
62.2-(2,4-二氯苯基)-1-(4-氟代苯基)-5-甲基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。熔点:223-224℃。
63.2-(2,4-二氯苯基)-5-甲基-1-(4-甲氧基苯基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。熔点:>90℃。(分解)。
64.N-环己基-1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:229-230℃。
65.1-(4-氯代苯基)-5-甲基-N-(正戊基)-2-(2-三氟甲基-4-氯代苯基)-1H-咪唑-4-甲酰胺。无定形。
66.1-(4-氯代苯基)-2-(2-氟-4-氯代苯基)-5-甲基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。熔点:195℃。
67.1-(4-氯代苯基)-2-(2-氟-4-氯代苯基)-5-甲基-N-(正戊基)-1H-咪唑-4-甲酰胺。熔点:115℃。
68.1-(4-氯代苯基)-N-(环己基)-2-(2-氟-4-氯代苯基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:188℃。
69.1-(4-氯代苯基)-N-(环己基)-2-(1,5-二甲基-1H-吡咯-2-基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:188-189℃。
70.1-(4-氯代苯基)-2-(1,5-二甲基-1H-吡咯-2-基)-5-甲基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。熔点:208-210℃。
71.2-(2-氯代苯基)-1-(3-氟代苯基)-5-甲基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。熔点:236-238℃。
72.2-(2-氯代苯基)-1-(3-氟代苯基)-5-甲基-N-(正戊基)-1H-咪唑-4-甲酰胺。熔点:97-102℃。
73.2-(2-氯代苯基)-N-环己基-1-(3-氟代苯基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:180-182.5℃。
74.2-(2-氯代苯基)-1-(3-氟代苯基)-N-(2-(4-氟代苯基)乙基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:123.5-126℃。
75.1-(4-氯代吡啶-2-基)-2-(2,4-二氯苯基)-5-乙基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。熔点:146℃。
76.1-(4-氯代吡啶-2-基)-2-(2,4-二氯苯基)-5-乙基-N-(4-吗啉基)-1H-咪唑-4-甲酰胺。熔点:223℃。
77.N-(1-氮杂环庚烷基(Azepanyl))-1-(4-氯代吡啶-2-基)-2-(2,4-二氯苯基)-5-乙基-1H-咪唑-4-甲酰胺。熔点:177℃。
78.1-(4-氯代吡啶-2-基)-N-环己基-2-(2,4-二氯苯基)-5-乙基-1H-咪唑-4-甲酰胺。熔点:149℃。
79.1-(4-氯代吡啶-2-基)-2-(2,4-二氯苯基)-5-乙基-N-(正戊基)-1H-咪唑-4-甲酰胺。熔点:油状物。
80.1-(4-氯代吡啶-2-基)-2-(2,4-二氯苯基)-5-乙基-N-(4-氟代苯基甲基)-1H-咪唑-4-甲酰胺。MP:无定形。
81.1-(4-氯代苯基)-2-(2,4-二氯苯基)-N-(六氢环戊-[c]吡咯-2(1H)-基)-5-甲基-1H咪唑-4-甲酰胺。MP:143-146℃。
82.1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-N-苯基-1H咪唑-4-甲酰胺。熔点:91-95℃。
83.1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-N-(四氢-2H-吡喃-2-基氧)-1H-咪唑-4-甲酰胺。熔点:128-133℃。
84.N-(外-双环[2.2.1]庚-2-基)-1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:194-195℃。
85.1-(4-氯代苯基)-2-(2,4-二氯苯基)-N-(2-氟乙基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:128-133℃。
86.1-(4-氯代苯基)-2-(2,4-二氯苯基)-N-(反式-4-羟基环己基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:160℃(分解)。
87.1-{[1-(4-氯苯基)-2-(2,4-二氯苯基)-5-甲基-IH-咪唑-4-基]羰基}-4-羟基哌啶。熔点:无定形。
88.1-{[1-(4-氯苯基)-2-(2,4-二氯苯基)-5-甲基-IH-咪唑-4-基]羰基}-1,2,3,4-四氢异喹啉。熔点:143-146℃。
89.N-(内-双环[2.2.1]庚-2-基)-1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:194-195℃。
90.1-(4-氯代苯基)-2-(2,4-二氯苯基)-N-(4-氟代苄基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:165-166℃。
91.1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-N-(正戊基)-1H-咪唑-4-甲酰胺。油状物。
92.N-(氮杂环庚烷-1-基)-1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:147-149℃。
93.1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-N-(吡咯烷-1-基)-1H-咪唑-4-甲酰胺。熔点:205-206℃。
94.1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-N-(吗啉-4-基)-1H-咪唑-4-甲酰胺。熔点:225℃。(分解)。
95.2-(2,5-二氯苯基)-5-甲基-1-苯基-N-(哌啶-1-基)-1H-咪唑-4甲酰胺。熔点:227℃。
96.N-环己基-2-(2,5-二氯苯基)-5-甲基-1-苯基-1H-咪唑-4-甲酰胺。熔点:236℃。
97.N-环己基-2-(2,4-二氯苯基)-1-(2,5-二氟苯基)-5-乙基-1H-咪唑-4-甲酰胺。熔点:144-146℃。
98.N-环己基-2-(2,4-二氯苯基)-1-(2,5-二氟苯基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:206-208℃。
99.N-环己基-2-(1,5-二甲基-1H-吡咯-2-基)-5-乙基-1-苯基-1H-咪唑-4-甲酰胺。熔点:195-196℃。
100.N-环己基-2-(2,5-二氯苯基)-5-乙基-1-苯基-1H-咪唑-4-甲酰胺。熔点:198-199℃。
101.2-(2,5-二氯苯基)-5-乙基-1-苯基-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。熔点:207-208℃。
102.1-(4-氯代苯基)-5-甲基-2-(3-甲基吡啶-2-基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。熔点:211-213℃。
103.1-(4-氯代苯基)-N-环己基-5-甲基-2-(3-甲基吡啶-2-基)-1H-咪唑-4-甲酰胺。熔点:188-190℃。
104.1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-N-(3-(三氟甲基)苯基)-1H-咪唑-4-甲酰胺。熔点:177℃。
105.1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-N-(3-(三氟甲基)苄基)-1H-咪唑-4-甲酰胺。熔点:138-140℃。
106.1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-N-(4-(三氟甲基)苄基)-1H-咪唑-4-甲酰胺。熔点:232℃。
107.1-(4-氯代苯基)-N-环戊基-2-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:172℃。
108.1-(4-氯代苯基)-N-环庚基-2-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酰胺。熔点:154-156℃。
实施例109
A部分:类似于公开的方法(N.Kudo等,Chem.Pharm.Bull.1999,47,857-868),使用二氯乙烷中过量的SO2Cl2在回流温度下反应50小时,将1-(4-溴代苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸乙酯转化为1-(4-溴代苯基)-5-氯-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸乙酯。
B部分:类似于上面实施例22描述的方法,将1-(4-溴代苯基)-5-氯-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸乙酯转化为1-(4-溴代苯基)-5-氯-2-(2,4-二氯苯基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺(熔点:大于150℃);Rf(硅胶,EtOAc)~0.35)。1H-NMR(400MHz,CDCl3):δ7.85(br s,1H),7.52(dt,J=8Hz,J=2Hz,2H),7.26-7.36(m,3H),7.01(dt,J=8Hz,J=2Hz,2H),2.85-2.92(m,4H),1.72-1.80(m,4H),1.40-1.44(m,2H)。
实施例110
A部分:氮气下向搅拌的1-(4-氯代苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸(18.38克,50毫摩尔)的甲苯(200mL)溶液加入N,N-二甲基甲酰胺二叔丁基缩醛(50mL),并且将得到的混合物在80℃下加热4小时。冷却至室温之后浓缩反应混合物并且加入二乙醚。将得到的溶液用水洗涤两次,MgSO4干燥,过滤并且真空浓缩。残余物用二异丙基醚结晶,得到纯的1-(4-氯代苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸叔丁酯(10.35克,49%产率)。熔点:179-181℃。
B部分:
氮气下向冷却的(-70℃)1-(4-氯代苯基)-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸丁酯(4.24克,0.010摩尔)的无水THF(80mL)溶液滴加二异丙基氨基化锂(LDA)(5.25mL,2M的THF溶液,0.0105摩尔),并且将得到的混合物搅拌1小时。滴加对甲苯磺酰氰化物(1.88克,0.011摩尔)的无水THF(20mL)溶液,并且将得到的红色溶液在-70℃下搅拌1小时并且使之保持室温。加入二乙基醚,并且用水将得到的溶液淬火,经hyflo过滤。收集有机层并且用水洗涤,MgSO4干燥,过滤并且真空浓缩,得到油状物。该油状物通过柱色谱法纯化(二氯甲烷,硅胶),得到3.4克的1-(4-氯代苯基)-5-氰基-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸叔丁酯。用二异丙基醚重结晶,得到1-(4-氯代苯基)-5-氰基-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸叔丁酯结晶(2.57克,57%产率)。熔点:210-212℃。
类似地制备:
-1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-甲基-1H-咪唑-4-甲酸叔丁酯。1H-NMR(400MHz,CDCl3):δ7.38(d,J=8Hz,1H),7.34(dt,J=8Hz,J=2Hz,2H),7.27(d,J=2Hz,1H),7.22(dd,J=8Hz,J=2Hz,1H),7.03(dt,J=8Hz,J=2Hz,2H),2.40(s,3H),1.63(s,9H)。
C部分:
向1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-氰基-1H-咪唑-4-甲酸叔丁酯(2.57克,5.73毫摩尔)的二氯甲烷(40mL)溶液加入三氟乙酸,并且将得到的溶液在室温下搅拌20小时并且真空浓缩。残余物用二异丙基醚结晶,得到纯的1-(4-氯代苯基)-5-氰基-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸(1.95克,87%产率)。熔点:200-202℃(分解)。
D部分:类似于这里实施例22中B部分描述的方法,将1-(4-氯代苯基)-5-氰基-2-(2,4-二氯苯基)-1H-咪唑-4-甲酸转化为1-(4-氯代苯基)-5-氰基-2-(2,4-二氯苯基)-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺,60%产率。熔点:231-233.5℃。
类似地制备:
111.1-(4-氯代苯基)-2-(2,4-二氯苯基)-5-碘-N-(哌啶-1-基)-1H-咪唑-4-甲酰胺。熔点:196-201℃。
112.1-(4-氯代苯基)-N-环己基-2-(2,4-二氯苯基)-5-碘-1H-咪唑-4-甲酰胺。熔点:226-230℃。
113.1-(4-氯代苯基)-5-氰基-N-环己基-2-(2,4-二氯苯基)-1H-咪唑-4-甲酰胺。熔点:157-158℃。
Claims (10)
1.式(I)的化合物以及它们的前体药物、立体异构体和盐,
其中
-R代表苯基,噻吩基,2-吡啶基,3-吡啶基,4-吡啶基,嘧啶基,哌嗪基,哒嗪基或三嗪基,这些基团可以被1,2,3或4个相同或不同的选自C1-3-烷基或烷氧基,羟基,卤素,三氟甲基,三氟甲硫基,三氟甲氧基,硝基,氨基,一-或二烷基(C1-2)-氨基,一-或二烷基(C1-2)-酰氨基,(C1-3)-烷氧羰基,羧基,氰基,氨基甲酰基和乙酰基的取代基Y取代,或者R代表萘基,前提是当R是4-吡啶基时,R4代表卤原子或氰基,氨基甲酰基,甲酰基,乙酰基,三氟乙酰基,氟代乙酰基,丙酰基,氨磺酰,甲磺酰基,甲基硫烷基或者有支链或没有支链的C1-4-烷基,其中 C1-4-烷基可以被1-3个氟原子或溴原子,氯原子,碘原子,氰基或羟基取代,
-R1代表苯基或吡啶基,这些基团可以被1-4个相同或不同的取代基Y取代,其中Y具有上述定义,或者R1代表嘧啶基,哌嗪基,哒嗪基或三嗪基,这些基团可以被1-2个相同或不同的取代基Y取代,或者R1代表具有一个或两个选自N,O,S的杂原子的五元芳香杂环,所述杂原子可以是相同或不同,所述五元芳香杂环可以被1-2个相同或不同的取代基Y取代,或者R1代表萘基,
-R2代表H,有支链或没有支链的C1-8烷基,C3-8环烷基,C3-8链烯基,C5-8环烯基,这些基团可以含有硫,氧或氮原子,
-R3代表有支链或没有支链的C2-8烷基,C1-8烷氧基,C5-8环烷氧基,C3-8环烷基,C5-10双环烷基,C6-10三环烷基,C3-8链烯基,C5-8环烯基,这些基团可以任选地含有一个或多个选自N,O,S的杂原子并且这些基团可以被羟基或1-2个C1-3烷基或1-3个氟原子取代,或者R3代表芳香环可以被1-5个相同和不同的取代基Z取代的苄基或苯乙基,所述取代基Z选自C1-3-烷基或烷氧基,羟基,卤素,三氟甲基,三氟甲硫基,三氟甲氧基,硝基,氨基,一-或二烷基(C1-2)-氨基,一-或二烷基(C1-2)-酰氨基,(C1-3)-烷基磺酰基,二甲基-磺氨基,(C1-3)-烷氧羰基,羧基,三氟甲基磺酰基,氰基,氨基甲酰基,氨磺酰基和乙酰基,或者R3代表苯基或吡啶基,这些基团可以被1-4个取代基Z取代,其中Z具有上述定义,
或者R3代表吡啶基,或者R3代表苯基,前提是R4代表卤原子或氰基,氨基甲酰基,甲酰基,乙酰基,三氟乙酰基,氟代乙酰基,丙酰基,氨磺酰,甲磺酰基,甲基硫烷基或者C1-4烷基,其中C1-4烷基可以被1-3个氟原子或溴原子,氯原子,碘原子,氰基或羟基取代,
或者R3代表基团NR5R6,前提是R2代表氢原子或甲基,其中
-R5和R6是相同和不同的,并且代表有支链或没有支链的C1-4烷基,或者R5和R6和它们键合的氮原子一起形成饱和的或不饱和的具有4-10个环原子的单环或双环杂环基团,所述杂环基团含有一个或两个相同和不同的选自N,O,S的杂原子,所述杂环基团可以被C1-3烷基或羟基取代,或者R2和R3和它们键合的氮原子一起形成饱和的或不饱和的具有4-10个环原子的杂环基团,所述杂环基团含有一个或两个相同和不同的选自N,O,S的杂原子,所述杂环基团可以被C1-3烷基或羟基取代,
-R4代表氢原子或卤原子或氰基,氨基甲酰基,甲酰基,乙酰基,三氟乙酰基,氟代乙酰基,丙酰基,氨磺酰,甲磺酰基,甲基硫烷基或者有支链或没有支链的C1-4烷基,其中C1-4烷基可以被1-3个氟原子或溴原子,氯原子,碘原子,氰基或羟基取代。
2.含有药学活性量的至少一种权利要求1的化合物作为活性成分的药物组合物。
3.制备权利要求2要求的药物组合物的方法,其特征在于将权利要求1要求的化合物制成适合给药的形式。
4.制备式(I)化合物的方法,其特征在于通过使式(II)、(III)或(IV)的化合物与式R2R3NH化合物反应制备其中R,R1-R3具有权利要求1给出的定义并且R4代表氢原子或卤原子或氰基,氨基甲酰基,甲酰基,乙酰基,三氟乙酰基,丙酰基,氨磺酰,甲磺酰基,甲基硫烷基或者可以被1-3个氟原子取代的C1-4烷基的化合物。
7.式(IX)的化合物
其中R和R4具有权利要求1给出的定义并且其中R1代表苯基或吡啶基,这些基团被1-4个相同和不同的取代基Y取代,或者R1代表嘧啶基,吡嗪基,哒嗪基或三嗪基,这些基团被1-2个相同和不同的取代基Y取代,或者R1代表具有一个或两个选自N,O,S的杂原子的五元芳香杂环部分,所述杂原子可以是相同或不同的,所述五元芳香杂环部分可以被1-2个相同或不同的取代基Y取代,或者R1代表萘基,并且R9代表羟基,有支链或没有支链的C1-4烷氧基,苄氧基或氯取代基。
9.权利要求1要求的化合物用于制备用于治疗涉及大麻素神经传递疾病的药物组合物的用途。
10.权利要求9要求的用途,其特征在于所述疾病是精神病,例如精神错乱,焦虑,抑郁症,注意力不集中,记忆失调,认知失调,食欲失调,肥胖症,成瘾,欲,药物依赖性和神经失调,例如神经退行性病变,痴呆,张力失常,肌肉痉挛,颤抖,癫痫,多发性硬化,创伤性脑损伤,中风,帕金森病,早老性痴呆,癫痫症,亨廷顿舞蹈病,图雷特综合征,大脑局部缺血,大脑中风,颅脑损伤,中风,脊索损伤,神经炎症,斑硬化,病毒性脑炎,脱髓鞘相关疾病,以及用于治疗疼痛,包括神经痛和涉及大麻素神经传递的其它疾病,包括治疗脓毒性休克,青光眼,癌症,糖尿病,呕吐,恶心,哮喘,呼吸疾病,肠胃失调,胃溃疡,腹泻和心血管疾病。
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CN109790151B (zh) * | 2016-10-12 | 2022-03-29 | 三角研究所 | 杂环爱帕琳肽受体(apj)激动剂及其用途 |
US11926612B2 (en) | 2016-10-12 | 2024-03-12 | Research Triangle Institute | Heterocyclic apelin receptor (APJ) agonists and uses thereof |
WO2020103856A1 (en) * | 2018-11-20 | 2020-05-28 | Shanghaitech University | Mmpl3 inhibitors, compositions and uses thereof |
CN113166068A (zh) * | 2018-11-20 | 2021-07-23 | 上海科技大学 | MmpL3抑制剂、组合物及其用途 |
US11655238B2 (en) | 2018-11-20 | 2023-05-23 | Shanghaitech University | MMPL3 inhibitors, compositions and uses thereof |
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