CN1870991A - 作为多聚(adp-核糖)聚合酶(parp)抑制剂的被取代的吲哚类化合物 - Google Patents
作为多聚(adp-核糖)聚合酶(parp)抑制剂的被取代的吲哚类化合物 Download PDFInfo
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- CN1870991A CN1870991A CNA2004800307419A CN200480030741A CN1870991A CN 1870991 A CN1870991 A CN 1870991A CN A2004800307419 A CNA2004800307419 A CN A2004800307419A CN 200480030741 A CN200480030741 A CN 200480030741A CN 1870991 A CN1870991 A CN 1870991A
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- Prior art keywords
- indole
- formaldehyde
- piperazine
- phenyl
- alkyl
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- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 title claims description 47
- 239000003112 inhibitor Substances 0.000 title abstract description 8
- 150000002475 indoles Chemical class 0.000 title abstract description 7
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 title description 45
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 title description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 174
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 66
- 238000000034 method Methods 0.000 claims abstract description 56
- 201000010099 disease Diseases 0.000 claims abstract description 51
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 11
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims abstract description 8
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims abstract description 8
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 pyrrole radicals Chemical class 0.000 claims description 169
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 108
- 201000006417 multiple sclerosis Diseases 0.000 claims description 96
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- 230000000694 effects Effects 0.000 claims description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 34
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 33
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 28
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 27
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- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 claims description 19
- 210000002569 neuron Anatomy 0.000 claims description 19
- 125000005936 piperidyl group Chemical group 0.000 claims description 19
- 125000003368 amide group Chemical group 0.000 claims description 18
- 125000004193 piperazinyl group Chemical group 0.000 claims description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 16
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- JYCGXZGGVUKKNQ-UHFFFAOYSA-N tert-butyl formate piperazine Chemical compound C(C)(C)(C)OC=O.N1CCNCC1 JYCGXZGGVUKKNQ-UHFFFAOYSA-N 0.000 claims description 12
- 241001597008 Nomeidae Species 0.000 claims description 11
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- 239000012453 solvate Substances 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
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- GBSBKSABVLLECH-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]-1-phenylindole-3-carbaldehyde Chemical compound C1CN(CCO)CCN1C1=C(C=O)C2=CC=CC=C2N1C1=CC=CC=C1 GBSBKSABVLLECH-UHFFFAOYSA-N 0.000 claims description 9
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
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- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 7
- XELFNCLBKGBNLZ-UHFFFAOYSA-N 1-(4-butylphenyl)-2-piperazin-1-ylindole-3-carbaldehyde Chemical compound C1=CC(CCCC)=CC=C1N1C2=CC=CC=C2C(C=O)=C1N1CCNCC1 XELFNCLBKGBNLZ-UHFFFAOYSA-N 0.000 claims description 6
- NAEKHISYDJUGPG-UHFFFAOYSA-N 1-(4-ethenylphenyl)-2-piperazin-1-ylindole-3-carbaldehyde Chemical compound C1=CC(C=C)=CC=C1N1C2=CC=CC=C2C(C=O)=C1N1CCNCC1 NAEKHISYDJUGPG-UHFFFAOYSA-N 0.000 claims description 6
- OKAYUOHMUAXIGU-UHFFFAOYSA-N 1-(4-ethylphenyl)-2-piperazin-1-ylindole-3-carbaldehyde Chemical compound C1=CC(CC)=CC=C1N1C2=CC=CC=C2C(C=O)=C1N1CCNCC1 OKAYUOHMUAXIGU-UHFFFAOYSA-N 0.000 claims description 6
- VIJVEFJOBUZLLH-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-piperazin-1-ylindole-3-carbaldehyde Chemical compound C1=CC(F)=CC=C1N1C2=CC=CC=C2C(C=O)=C1N1CCNCC1 VIJVEFJOBUZLLH-UHFFFAOYSA-N 0.000 claims description 6
- XVOOCCYPMVCNJO-UHFFFAOYSA-N 1-(4-methyl-3-nitrophenyl)-2-piperazin-1-ylindole-3-carbaldehyde Chemical compound C1=C([N+]([O-])=O)C(C)=CC=C1N1C2=CC=CC=C2C(C=O)=C1N1CCNCC1 XVOOCCYPMVCNJO-UHFFFAOYSA-N 0.000 claims description 6
- YELWFIMFXVYHHI-UHFFFAOYSA-N 1-(4-tert-butylphenyl)-2-[2-(dimethylamino)ethylamino]indole-3-carbaldehyde Chemical compound CN(C)CCNC1=C(C=O)C2=CC=CC=C2N1C1=CC=C(C(C)(C)C)C=C1 YELWFIMFXVYHHI-UHFFFAOYSA-N 0.000 claims description 6
- RIRLLQPWWGOVPZ-UHFFFAOYSA-N 1-(benzenesulfonyl)-2-piperazin-1-ylindole-3-carbaldehyde Chemical compound C=1C=CC=CC=1S(=O)(=O)N1C2=CC=CC=C2C(C=O)=C1N1CCNCC1 RIRLLQPWWGOVPZ-UHFFFAOYSA-N 0.000 claims description 6
- VYYDEFMPUVDYKB-UHFFFAOYSA-N 1-[3-(hydroxymethyl)phenyl]-2-piperazin-1-ylindole-3-carbaldehyde Chemical compound OCC1=CC=CC(N2C3=CC=CC=C3C(C=O)=C2N2CCNCC2)=C1 VYYDEFMPUVDYKB-UHFFFAOYSA-N 0.000 claims description 6
- HVSOWMPVDIZSNW-UHFFFAOYSA-N 2-piperazin-1-yl-1-pyridin-2-ylindole-3-carbaldehyde Chemical compound C=1C=CC=NC=1N1C2=CC=CC=C2C(C=O)=C1N1CCNCC1 HVSOWMPVDIZSNW-UHFFFAOYSA-N 0.000 claims description 6
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- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
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- MWEQTWJABOLLOS-UHFFFAOYSA-L disodium;[[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-oxidophosphoryl] hydrogen phosphate;trihydrate Chemical compound O.O.O.[Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP([O-])(=O)OP(O)([O-])=O)C(O)C1O MWEQTWJABOLLOS-UHFFFAOYSA-L 0.000 claims description 6
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- TUJQMOFASNTKCI-UHFFFAOYSA-N 1-(3-chloro-4-fluorophenyl)-2-piperazin-1-ylindole-3-carbaldehyde Chemical compound C1=C(Cl)C(F)=CC=C1N1C2=CC=CC=C2C(C=O)=C1N1CCNCC1 TUJQMOFASNTKCI-UHFFFAOYSA-N 0.000 claims description 5
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Abstract
本发明涉及一系列如本文所述的式(I)的被取代吲哚衍生物。本发明还涉及制备这类化合物的方法。本发明的化合物是多聚(腺苷5’-磷酸核糖)聚合酶(PARP)抑制剂,因此可用作药物,尤其可用于治疗和/或预防各种疾病,包括与中枢神经系统和心血管紊乱相关的疾病。
Description
发明背景
发明领域
本发明涉及一系列取代的吲哚类化合物。更具体地说,本发明涉及一系列新的N,2,3-取代的吲哚衍生物。本发明还涉及制备这些化合物的方法。本发明的化合物是多聚(腺苷5’-二磷酸核糖)聚合酶(PARP)的抑制剂,因此,可用作药物,尤其是可用于治疗和/或预防各种疾病,包括与中枢神经系统和心血管紊乱相关的疾病。
技术说明
多聚(腺苷5’-二磷酸核糖)聚合酶[多聚(ADP-核糖)聚合酶,PARP,EC2.4.2.30]亦称为多聚(ADP核糖)合成酶(PARS),是真核细胞的与染色质结合的核酶,大约以2×105个分子/细胞核的密度存在。多细胞生物体中PARP高度的进化保守性可被视为多聚(ADP-核糖)基化的生理学重要性的启示。PARP被DNA链断裂活化后,将ADP-核糖单元从NAD+转移到包括组蛋白和PARP本身在内的核蛋白上。该反应产生多聚(ADP)核糖和烟酰胺,后者是PARP的负反馈抑制剂。NAD+在此过程中的作用不同于它在其它酶促过程中作为氧化还原辅因子的作用。如此形成的多聚(ADP-核糖)一般含有200个含有线性和分支连接的核糖单位,大约每25个ADP-核糖单位含有一个分支。通过α-(1”-2’)核糖基-糖苷键实现连接。由于ADP-核糖聚合体的负电荷,多聚(ADP-核糖基化)蛋白失去了对DNA的亲合力,并因此而失活。多聚(ADP-核糖)基化是一种即刻的、共价的、但又是瞬时的翻译后修饰。多聚(ADP-核糖)处于能动状态,它在快速合成后随即发生多聚(ADP)糖苷水解酶(PARG)催化的降解。因此,PARP和其它经修饰的蛋白又回到其原始的状态。关于PARP的综述,可参阅:Liadet.L.,“多聚(腺苷5’-二磷酸)核糖聚合酶的活化-危重疾病代谢功能紊乱的病因之一”,Current Opinions Clin.Nutrition Metabolic Care,
5,175-184(2002);Burkle,A.,“多聚(ADP-核糖)基化的生理学和病理生理学”,BioEssays,
23,795-806(2001);Hageman,G.J.和Stierum,R.H.,“烟酸、多聚(ADP-核糖)聚合酶-1和基因组稳定性”,Mutation Res.,
475,45-56(2001);Smith,S.,“PARP的世界”,TrendsBiochem Sci.,
26,174-179(2001);Tong,W.-M.等人,“多聚(ADP-核糖)聚合酶:保护基因组和抑制肿瘤生成的守护天使”,Biochim.Biophys.Acta,1552,27-37(2001)。
在脑缺血过程中,钙内流进入神经元引起氧化氮合酶的活化,导致氧化氮及随后的反应活性的过氧亚硝酸根离子的产生。过氧亚硝酸根离子造成对DNA的严重损伤并导致PARP的失控性活化。细胞NAD和ATP被迅速耗尽,于是细胞因失去细胞能量的来源而发生坏死性死亡。类似地,在心肌缺血和炎症过程中,DNA也被过氧亚硝酸根离子损伤。
若干项关于PARP-/-动物和各种抑制剂的研究证实了PARP在一系列疾病模型的病理生理学方面的作用。例如,在中风模型中,PARP缺陷动物的梗塞面积与PARP+/+对照动物相比要低80%。例如参阅Eliasson,M.J.L.等人,“多聚(ADP-核糖)聚合酶基因破坏使小鼠产生对脑缺血的抵抗能力”,Nature Med.,
3,1089(1997)。此外,使用多种PARP抑制剂(如3-氨基苯甲酰胺、GPI 6150、PJ-34和烟酰胺)的多项研究表明,中风后治疗的模型因中风引起的梗塞体积和行为缺陷均有所减少。一般参阅Takahashi,K.等人,“用多聚(ADP-核糖)聚合酶抑制剂进行后处理可减轻局灶性缺血所造成的大脑损伤”,Brain Res.,
829,46,(1999);Mokudai,T.等人,“用烟酰胺(维生素B3)进行延迟性治疗可改善Wistar大鼠短暂性局灶性缺血后的神经学输出并减小梗塞体积”,Stroke,
31,1679(2000);Abdelkarim,G.E.等人,“PJ34,一种新型有效的多聚(ADP核糖)聚合酶(PARP)抑制剂,对中风体外模型和体内模型的保护作用”,Int.J.Mol.Med.,
7,255(2000);Ding,Y.等人,“采用行为评估法研究多聚(ADP-核糖)聚合酶的抑制对于大脑中动脉阻塞大鼠的长期神经保护作用”,Brain Res.,
915,210(2001)。
通过采用抑制剂或剔除实验而确定了PARP所起作用的其它疾病模型是链佐星诱导的糖尿病(可参阅Mabley,J.G.等人,“利用基因破环或5-碘-6-氨基-1,2-苯并吡喃酮的抑制作用来抑制多聚(ADP-核糖)合成酶可防止小鼠罹患多次低剂量链佐星诱导的糖尿病”,Br.J.Pharmacol.,
133,909-919(2001);Gale,E.A.等人,“IDDM中β-细胞破坏的分子机理:烟酰胺的作用”,Horm.Res.,
45,39-43(1996);以及Heller,B.等人,“多聚(ADP-核糖)聚合酶基因的失活影响胰岛细胞中氧自由基和氧化氮的毒性”,J.Biol.Chem.,
270,11176-11180(1995)。
PARP还与糖尿病性心肌症有关,参阅Pacher,P.等人,“多聚(ADP-核糖)聚合酶的活化在糖尿病的心肌和内皮功能紊乱发展过程中的作用”,Diabetes,
51,514-521(2002);PARP还与头部外伤有关,参阅LaPlaca,M.C.等人,“对多聚(ADP-核糖)聚合酶的药理学抑制作用在大鼠创伤性脑损伤后具有神经保护作用”,J.Neurotrauma,
18,369-376(2001)。还可参阅Verma,A.,“创伤性脑损伤神经保护的机会”,J.Head Trauma Rehabil.,
15,1149-1161(2000)。
此外,涉及PARP的疾病还包括心肌缺血,一般可参阅Pieper,A.A.等人,“多聚(ADP-核糖)聚合酶-1基因破环可减少心肌缺血后的损伤”,Mol.Med.,
6,271-282(2000)。还可参阅Grupp,I.L.等人,“在缺乏多聚(ADP-核糖)合成酶的情况下对离体工作心脏缺氧再氧合的保护作用”,J.Mol.Cell.Cardio.,
31,297-303(1999)。
其它的疾病包括实验性过敏性脑脊髓炎(EAE),可参阅,例如Scott,G.S.等人,“多聚(ADP-核糖)合成酶的活化在实验性过敏性脑脊髓炎发展过程中的作用”,J.Neuroimmunology,
117,78-86(2001)。
已有报导称,PARP的作用可能会导致癌症,可参阅,如Martin,N.M.,“DNA修复抑制和癌症治疗”,J.Photochem.Photobiol.B,
63,162-170(2001)。最后,与衰老相关的疾病也已经涉及PARP,可参阅Von Zglinicki,T.等人,“紧张、DNA损伤和衰老——一项综合研究”,Exp.Geront.,
36,1049-1062(2001)。还可参阅Rosenthal,D.S.等人,“多聚(ADP-核糖)聚合酶与衰老”,“衰老过程中DNA损伤和修复的作用”,Gilchrist,B.A.和Bohr,V.A.,编辑,Elsevier Science B.V.(2001),第113-133页。
本文所述的所有参考文献均整体引入本文。
本发明的一个目的是提供一系列取代的吲哚衍生物,它们是有效的抑制PARP-1的选择性抑制剂。
本发明的另一目的是提供如本文所公开的取代的吲哚衍生物的制备方法。
本发明的又一目的是提供一系列新的吲哚-3-甲醛类化合物,正如它们在体外试验和全细胞测定中所表现的抑制酶活性所显示的那样,它们是有效的抑制PARP-1酶的抑制剂。
发明概述
因此,按照本发明的实践,提供了一种治疗患者中因多聚(腺苷5’-二磷酸核糖)聚合酶(PARP)的作用而引起的疾病或病症的方法,该方法包括给所述患者施用治疗有效量的化合物,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有式(I)所示的一般结构:
其中
R是氢、羟基、C1-4烷氧基或氨基;
R1是C1-6烷基、C6-12芳基、C6-12芳基C1-4烷基、C6-12芳基磺酰基或杂芳基,且其中的烷基、芳基或杂芳基可任选被一个或数个选自以下的取代基取代:卤素、C1-6烷基、C2-6链烯基、式CnHxFy或OCnHxFy的氟烷基或氟烷氧基(其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1)、C1-4烷氧基、C1-4硫代烷基、羟基、羟基C1-4烷基、C1-4酰氧基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、氨基C1-4烷基、C1-4烷基氨基C1-4烷基、C1-4二烷基氨基C1-4烷基、-CN、-CO2H、-CO2C1-4烷基、-NHCOC1-4烷基、取代或未取代的苯基、取代或未取代的苯氧基、取代或未取代的苄氧基、取代或未取代的吡咯基,以及取代或未取代的吡啶基;
R2和R3相同或不同且分别选自:
氢、C1-4烷基、C1-4二烷基氨基C1-4烷基、吡咯烷基C1-4烷基、咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO以及-CO2C1-4烷基;或
R2和R3与它们所连接的氮原子一起形成咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO、-CO2C1-4烷基、羟基C1-4烷基、环氧乙烷基C1-4烷基、二羟基C1-4烷基、-(CH2)aN-CO2C1-4烷基、羟基,以及-(CH2)aOPO(OC1-4烷基)2,其中a是1至4的整数;
R4是C1-4烷基、式CnHxFy或OCnHxFy的氟烷基或氟烷氧基(其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1)、C1-4烷氧基或C1-4硫代烷基;以及
X和Y相同或不同且分别选自CH或N。
在本发明的另一方面,还提供了一种在患者中产生不通过NMDA毒性介导的神经元活动的方法,该方法包括给所述患者施用治疗有效量的化合物,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有如本文所述的式(I)所示的一般结构。
在本发明的另一方面,提供了一种化合物,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有如本文所述的式(I)所示的一般结构。
通过以下的详细说明,本发明的这些方面以及各种其它方面将是显而易见的。
发明详述
本文所用的术语具有以下含意:
如本文所用的表达“C1-6烷基”包括甲基和乙基以及直链和支链的丙基、丁基、戊基和己基。具体的烷基有甲基、乙基、正丙基、异丙基和叔丁基。衍生的表达,如“C1-4烷氧基”、“C1-4硫代烷基”、“C1-4烷氧基C1-4烷基”、“羟基C1-4烷基”、“C1-4烷基羰基”、“C1-4烷氧羰基C1-4烷基”、“C1-4烷氧羰基”、“氨基C1-4烷基”、“C1-4烷基氨基”、“C1-4烷基氨甲酰基C1-6烷基”、“C1-4二烷基氨甲酰基C1-4烷基”、“单或双-C1-4烷基氨基C1-4烷基”、“氨基C1-4烷基羰基”、“二苯基C1-4烷基”、苯基C1-4烷基”、“苯基羰基C1-4烷基”以及“苯氧基C1-4烷基”等应作同样的理解。
如本文所用的表达“C2-6链烯基”包括乙烯基以及直链或支链的丙烯基、丁烯基、戊烯基和己烯基。类似地,“C2-6炔基”包括乙炔基和丙炔基以及直链或支链的丁炔基、戊炔基和己炔基。
如本文所用的表达“C1-4酰基”将具有与“C1-6烷酰基”同样的含意,其在结构上还可表示为“R-CO-”,其中R是如本文所定义的C1-3烷基。此外,“C1-3烷基羰基”将与C1-4酰基同义。具体地说,“C1-4酰基”意指甲酰基、醋酰基或乙酰基、丙酰基、正丁酰基等。对于衍生的表达例如“C1-4酰氧基”和“C1-4酰氧基烷基”应作同样的理解。
如本文所用的表达“C1-6全氟烷基”意味着该烷基中所有的氢原子被氟原子替换。其示范性实例包括三氟甲基、五氟乙基以及直链或支链的七氟丙基、九氟丁基、十一氟戊基以及十三氟己基。对于衍生的表达“C1-6全氟烷氧基”应作同样的理解。
如本文所用的表达“C6-12芳基”意指取代或未取代的苯基或萘基。取代的苯基或萘基的具体实例包括邻-、对-、间-甲苯基、1,2-、1,3-、1,4-二甲苯基、1-甲基萘基、2-甲基萘基等。“取代的苯基”或“取代的萘基”还包括本文进一步定义的或本领域技术人员已知的任何可能的取代基。对于衍生的表达“C6-12芳基磺酰基”应作同样的理解。
如本文所用的表达“C6-12芳基C1-4烷基“意味着如本文所定义的C6-12芳基进一步与本文所定义的C1-4烷基连接。其代表性实例包括苯甲基、苯基乙基、2-苯基丙基、1-萘基甲基、2-萘基甲基等。
如本文所用的表达“杂芳基”包括所有已知的含有杂原子的芳香族基团。代表性的五元杂芳基包括呋喃基、噻吩基、吡咯基、异吡咯基、吡唑基、咪唑基、唑基、噻唑基、异噻唑基等。代表性的六元杂芳基包括吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等。双环杂芳基的代表性实例包括苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、苯并咪唑基、吲唑基、吡啶并呋喃基、吡啶并噻吩基等。
如本文所用的表达“杂环基”包括所有已知的含有杂原子的还原性环基。代表性的五元杂环基包括四氢呋喃基、四氢噻吩基、吡咯烷基、2-噻唑啉基、四氢噻唑基、四氢唑基等。代表性的六元杂环基包括哌啶基、哌嗪基、吗啉基、硫吗啉基等。各种其它的杂环基包括但不限于吖丙啶基、氮杂环庚基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基,以及三氮杂环辛基等。
“卤素”或“卤代”表示氯、氟、溴及碘。
如本文所用的“患者”表示温血动物,如大鼠、小鼠、狗、猫、豚鼠以及灵长类动物例如人类。
如本文所用的表达“可药用载体”表示无毒的溶剂、分散剂、赋形剂、辅剂或其它与本发明的化合物混合以形成药物组合物、即能施用于患者的剂量形式的物质。此类载体的一个实例是可药用的油,通常用于胃肠道外施用。
本文所用的术语“可药用盐”表示本发明化合物的盐可用于医药制剂。但是,其它的盐也可用于制备本发明的化合物或其可药用盐。适宜的本发明化合物的可药用盐包括酸加成盐,它可例如通过将本发明化合物的溶液和可药用酸的溶液混合而形成;这类酸例如是盐酸、氢溴酸、硫酸、甲磺酸、2-羟基乙磺酸、对甲苯磺酸、富马酸、马来酸、羟基马来酸、苹果酸、抗坏血酸、琥珀酸、戊二酸、乙酸、水杨酸、肉桂酸、2-苯氧基苯甲酸、羟基苯甲酸、苯乙酸、苯甲酸、草酸、柠檬酸、酒石酸、乙醇酸、乳酸、丙酮酸、丙二酸、碳酸或磷酸。还可形成酸式金属盐,如磷酸一氢钠和硫酸氢钾。同样,按此法而形成的盐可以以单酸盐或二酸盐的形式而存在,亦可以以基本上无水或含水的盐的形式而存在。此外,当本发明的化合物含有酸性基团时,则适宜的可药用盐可包括碱金属盐如钠盐或钾盐;碱土金属盐如钙盐或镁盐;以及与适宜的有机配体形成的盐,如季铵盐。
表达“立体异构体”是个体分子仅在原子空间取向上有区别的所有异构体的总称。通常,它包括往往由于存在至少一个不对称中心而形成的镜像异构体(对映异构体)。当本发明的化合物含有两个或两个以上不对称中心时,它们还可以以非对映异构体存在,同样,某些分子还可以以几何异构体(顺式/反式)的形式而存在。类似地,本发明的某些化合物可以以两种或两种以上结构不同但处于快速平衡的形式的混合物而存在,通常称为互变异构体。互变异构体的代表性实例包括酮-烯醇互变异构体、酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。应该理解,所有这样的异构体及其任何比例的混合物均属于本发明的范围。
广义地说,术语“取代的”意在包括有机化合物所有可允许的取代基。在本文所公开的几个具体实施方案中,术语“取代的”表示被一个或数个分别选自以下的取代基所取代:C1-6烷基、C2-6链烯基、C1-6全氟烷基、苯基、羟基-、-CO2H、酯、酰胺、C1-C6烷氧基、C1-C6硫代烷基、C1-C6全氟烷氧基、-NH2、Cl、Br、I、F、-NH-低级烷基,以及-N(低级烷基)2。但是,本领域技术人员所了解的任何其它适宜的取代基也可用于这些实施方案。
“治疗有效量”指有效治疗指定的疾病、紊乱或病症的化合物的量。
术语“神经组织”指构成神经系统的各种组成,包括但不限于神经元、神经支持细胞、神经胶质、Schwann细胞、包含在这些结构内并供应这些结构的脉管系统、中枢神经系统、脑、脑干、脊髓、中枢神经系统与外周神经系统的连接、外周神经系统,以及有关结构。
术语“缺血”指由于动脉血流入受阻而引起的局部性组织缺血。全面性缺血是在流向整个脑部(或心脏)的血液停止一段时间的情况下发生的。全面性缺血可由心心脏停搏引起。局灶性缺血在脑部的某一部分缺乏正常血液供应的情况下发生。局灶性缺血可由脑血管的血栓栓塞阻塞、创伤性头部损伤、水肿或脑瘤而引起。全面性和局灶性缺血即使是短暂的也会引起广泛的神经元损伤。虽然神经组织损伤在缺血发生后数小时或甚至数天后出现,但是某些永久性神经组织损伤可能在血液停止流入脑后的最初几分钟内就发生了。这些损伤中大多数归结于谷氨酸毒性(心脏内无谷氨酸毒性)和组织再灌注的继发后果,例如所释放的损伤内皮的影响血管的产物,受损组织释放的细胞毒素产物,例如自由基和白三烯。缺血还可发生在出现心肌梗塞和其它心血管紊乱的心脏里,其中的冠状动脉由于动脉粥样硬化、血栓症或痉挛而被阻塞;缺血还可发生在视网膜缺血的眼睛里。
术语“缺血和再灌注损伤以及神经变性疾病所造成的神经组织损伤”包括神经毒性,例如在脉管中风、全面性和局灶性缺血以及视网膜缺血中所观察到的。
术语“神经变性疾病”包括阿尔茨海默氏病、帕金森病和亨廷顿氏病。
术语“神经损伤”指对神经组织的任何损伤和所导致的任何残疾或死亡。神经损伤的原因可能是代谢、毒性、神经毒性、医原性、热或化学的,包括但不限于缺血、低氧、脑血管意外、创伤、手术、压力、质量效应、出血、辐射、血管痉挛、神经变性疾病、感染、帕金森病、肌萎缩性侧索硬化(ALS)、髓鞘形成/脱髓鞘过程、癫痫症、认知障碍、谷氨酸水平异常及其继发效应。
术语“神经保护”指减轻、阻止或改善神经损伤的作用以及保护、恢复或复原已经遭到神经损伤的神经组织的作用。
术语“预防神经变性”包括在已诊断患有神经变性疾病的患者或出现神经变性疾病的处危人群中预防神经变性的能力。此术语还包括预防已经患有神经变性疾病或具有其症状的患者发生进一步的神经变性。
术语“治疗”指:
(i)预防疾病、紊乱或病症在易患该疾病、紊乱和/或病症但尚未被诊断为已患有该疾病、紊乱和/或病症的患者中发生;
(ii)抑制疾病、紊乱或病症,即,阻止其发展;以及
(iii)减轻疾病、紊乱或病症,即,使得疾病、紊乱和/或病症消退。
在本发明的一个方面。公开了一种治疗患者中因多聚(腺苷5’-二磷酸核糖)聚合酶(PARP)的作用而引起的疾病或病症的方法,该方法包括给所述患者施用治疗有效量的化合物,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有式(I)所示的一般结构:
其中
R是氢、羟基、C1-4烷氧基或氨基;
R1是C1-6烷基、C6-12芳基、C6-12芳基C1-4烷基、C6-12芳基磺酰基或杂芳基,且其中的烷基、芳基或杂芳基可任选被一个或数个选自以下的取代基取代:卤素、C1-6烷基、C2-6链烯基、式CnHxFy或OCnHxFy的氟烷基或氟烷氧基(其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1)、C1-4烷氧基、C1-4硫代烷基、羟基、羟基C1-4烷基、C1-4酰氧基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、氨基C1-4烷基、C1-4烷基氨基C1-4烷基、C1-4二烷基氨基C1-4烷基、-CN、-CO2H、-CO2C1-4烷基、-NHCOC1-4烷基、取代或未取代的苯基、取代或未取代的苯氧基、取代或未取代的苄氧基、取代或未取代的吡咯基,以及取代或未取代的吡啶基;
R2和R3相同或不同且分别选自:
氢、C1-4烷基、C1-4二烷基氨基C1-4烷基、吡咯烷基C1-4烷基、咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO以及-CO2C1-4烷基;或
R2和R3与它们所连接的氮原子一起形成咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO、-CO2C1-4烷基、羟基C1-4烷基、环氧乙烷基C1-4烷基、二羟基C1-4烷基、-(CH2)aN-CO2C1-4烷基、羟基,以及-(CH2)aOPO(OC1-4烷基)2,其中a是1至4的整数;
R4是C1-4烷基、式CnHxFy或OCnHxFy的氟烷基或氟烷氧基(其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1)、C1-4烷氧基或C1-4硫代烷基;以及
X和Y相同或不同且分别选自CH或N。
在本发明这一方法的一种实施方案中,公开了如下定义的化合物:其中X和Y是碳原子、R是氢且R1是苯基。在该实施方案中,优选的化合物是其中R2和R3与它们所连接的氮原子一起形成杂环基的化合物。优选的杂环基选自吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基。
属于该实施方案一部分的具体化合物非限制性地包括:
1-苯基-2-(硫吗啉-4-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛,
5-甲基-1-苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
2-(哌啶-1-基)-1-苯基-1H-吲哚-3-甲醛,
2-(氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛,
2-(2,5-二氮杂双环[2.2.1]庚-2-基)-1-苯基-1H-吲哚-3-甲醛,
2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吲哚-3-甲醛,
1-苯基-2-[1,4,7]三氮杂环辛-1-基-1H-吲哚-3-甲醛,以及
2-(吗啉-4-基)-1-苯基-1H-吲哚-3-甲醛。
在本发明该方法的实施方案的另一方面,公开了如下定义的化合物:其中R1是苯基,被一个或数个选自以下的取代基取代:硝基、溴、氯、氟、碘、甲氧基、乙氧基、硫甲基、甲基、乙基、正丁基、叔丁基、乙烯基、羟基甲基、-CHO、-CN、苯基、苯氧基、二甲基氨基、-NHCOCH3以及吡啶基。此外,在该实施方案的化合物中,R2和R3与它们所连接的氮原子一起形成选自哌啶基或哌嗪基的杂环基。
该实施方案范围内的化合物的代表性实例有:
2-(哌嗪-1-基)-1-(3-硝基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-甲氧基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-叔丁基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-溴苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-氯苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-氯-4-氟苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基-1-(3-甲氧基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-硫甲基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-氟苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-甲基苯基)-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基-)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-哌啶-1-基-1H-吲哚-3-甲醛,
1-(3-甲酰基苯基)-2-(哌嗪-2-基)-1H-吲哚-3-甲醛,
1-(联苯-4-基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(4-乙基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(3-溴苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-甲基-3-硝基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-二甲基氨基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-苯氧基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-氟苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(3-氯苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-乙烯基苯基)-1H-吲哚-3-甲醛,
1-(3-羟基甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(3-乙氧基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-丁基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
N-{3-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]苯基}-乙酰胺盐酸盐,
4-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]-苄腈,以及
2-哌嗪-1-基-1-[(4-吡啶-4-基)苯基]-1H-吲哚-3-甲醛。
在该实施方案的另一方面,公开了如下定义的化合物:其中的杂环基进一步被一个或数个选自以下的取代基取代:甲基、羟基乙基、2,3-二羟基丙基、环氧乙烷基甲基、氧代、-(CH2)2NHCO2-叔丁基、-CO2CH3、-CO2-叔丁基、-CHO以及-(CH2)2OPO(OC2H5)2。
该实施方案范围内的化合物的代表性实例可列举如下:
2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛,
2-(4-环氧乙烷基甲基哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛,
{2-[4-(3-甲酰基-1-苯基-2,3-二氢-1H-吲哚-2-基)-哌嗪-1-基]-乙基}-氨基甲酸叔丁酯,
4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-哌嗪-2-甲酸甲酯,
2-(4-甲酰基-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛,
2-[4-(2-羟基乙基)二氮杂环庚-1-基]-1-苯基-1H-吲哚-3-甲醛,
2-(4-环氧乙烷基甲基-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛,
2-[4-(2,3-二羟基丙基)-[1,4]二氮杂环庚-1-基]-1-苯基-1H-吲哚-3-甲醛,
2-(5-氧代-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛,
4-(3-甲酰基-1-苯基-1H-吲哚-2-基)哌嗪-1-甲酸叔丁酯,
2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛盐酸盐,
磷酸二乙基酯2-[4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-哌嗪-1-基]-乙基酯盐酸盐,
2-(3,5-二甲基哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛盐酸盐,以及
5-(3-甲酰基-1-苯基-1H-吲哚-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯。
在本发明该实施方案的另一方面,描述了如下定义的化合物:其中R1是苯基,它可进一步被一个或数个选自以下的取代基取代:叔丁基、碘、氰基苯基以及叔丁氧羰基-1-吡咯基。
该实施方案的具体化合物可选自:
1-(4-叔丁基苯基)-2-[4-(2-羟基乙基)哌嗪-1-基]-1H-吲哚-3-甲醛,
磷酸2-{4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-基}-乙基酯二乙基酯盐酸盐,
1-(4-叔丁基苯基)-2-(4-甲基-哌嗪-1-基)-1H-吲哚-3-甲醛,
4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]哌嗪-1-甲酸叔丁酯,
5-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯,
1-(4-叔丁基-苯基)-2-(2-甲基-吖丙啶-1-基)-1H-吲哚-3-甲醛,
4-[3-甲酰基-1-(4-碘苯基)-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯,
4-[1-(4’-氰基联苯-4-基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯,以及
4-{1-[4-(叔丁氧羰基-1H-吡咯-2-基)-苯基]-3-甲酰基-1H-吲哚-2-基}-哌嗪-1-甲酸叔丁酯。
在本发明方法的另一实施方案中,描述了如下定义的式(I)化合物:其中X是氮且Y是碳,或者X是碳且Y是氮。
该实施方案的具体化合物非限制性地包括:
1-苯基-2-(哌嗪-1-基)-1,3-二氢吡咯并[2,3-b]吡啶-3-甲醛,以及
1-苯基-2-(哌嗪-1-基)-1H-吡咯并[2,3-c]吡啶-3-甲醛。
在本发明方法的另一实施方案中,提供了如下定义的式(I)化合物:其中R2和R3与它们所连接的氮原子一起形成咪唑基。该实施方案的一个实例是2-咪唑-1-基-1-苯基-1H-吲哚-3-甲醛。
在本发明的方法另一实施方案中,公开了如下定义的式(I)化合物:其中R2是氢或甲基,R3是二甲基氨基乙基、吡咯烷基乙基氨基以及哌啶基。
该实施方案的具体化合物选自:
2-(2-二甲基氨基乙基氨基)-1-苯基-1H-吲哚-3-甲醛,
2-[(甲基哌啶-4-基)氨基]-1-苯基-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-[(2-二甲基氨基乙基)-甲基氨基]-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-(2-二甲基氨基乙基氨基)-1H-吲哚-3-甲醛,以及
1-(4-叔丁基苯基)-2-(2-吡咯烷-1-基-乙基氨基)-1H-吲哚-3-甲醛盐酸盐。
在本发明方法的另一实施方案中,提供了如下定义的式(I)化合物:其中R1是甲基、苄基、萘基、噻吩基、吡啶基以及苯磺酰基。该实施方案的
实例包括:
2-(哌嗪-1-基)-1-甲基-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-苄基-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(1-萘基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(噻吩-3-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(吡啶-2-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(吡啶-3-基)-1H-吲哚-3-甲醛,以及
1-苯磺酰基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛。
最后,在本发明方法的另一实施方案中,提供了如下定义的式(I)化合物:其中R是羟基、甲氧基或氨基;R1是苯基,R2和R3与它们所连接的氮原子一起形成哌嗪基,R4是氢且X和Y是碳原子。该实施方案范围内的化合物的代表性实例包括:
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲酸,
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲酰胺,以及
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲酸甲酯。
在该实施方案中,可用本发明的化合物治疗的具体疾病或紊乱或病症包括但不限于:由于坏死或细胞凋亡导致细胞受损或死亡而造成的组织损伤、神经元介导的组织损伤或疾病、由于缺血及再灌注损伤而造成的神经组织损伤、神经紊乱及神经变性疾病、脉管中风、心血管紊乱、年龄相关性黄斑变性、AIDS及其它免疫衰老疾病、关节炎、动脉粥样硬化、恶病质、癌症、涉及复制性衰老的骨胳肌退化性疾病、糖尿病、头部创伤、免疫衰老、炎性肠病、肌营养不良症、骨关节炎、骨质疏松症、慢性疼痛、急性疼痛、神经性疼痛、神经性损伤、外周神经损伤、肾衰竭、视网膜缺血、败血症性休克及衰老。
在该实施方案的另一方面,可用本发明的化合物治疗的具体疾病或紊乱或病症包括但不限于:由于坏死或细胞凋亡导致细胞受损或死亡而造成的组织损伤、神经元介导的组织损伤或疾病、脑缺血、头部创伤、中风、再灌注损伤、神经紊乱及神经变性疾病、脉管中风、心血管紊乱、心肌梗塞、心肌缺血、实验性过敏性脑脊髓炎(EAE)、多发性硬化症(MS)、与心脏手术相关的缺血、年龄相关性黄斑变性、关节炎、动脉粥样硬化、癌症、涉及复制性衰老的骨胳肌退化性疾病、糖尿病及糖尿病心肌病。如本文所用的“与心脏手术相关的缺血”指在开胸及患者可能使用心肺机的其它心脏手术中所发生的任何脑损伤。
本领域技术人员应很容易地理解,本文明确说明的病状及疾病并非意欲限制而是意欲解释说明本发明化合物的功效。因此可以理解,本发明的化合物可用于治疗由PARP的作用而引起的任何疾病。即,本发明的化合物具有PARP抑制活性,可以被有效地施用以改善全部或部分由PARP介导的任何病情。
在本发明的另一实施方案中,提供了一种在患者中产生神经元活动的方法,该方法包括给所述患者施用治疗有效量的化合物,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有如本文所述的式(I)所示的一般结构。本文所述的神经元活动可以由NMDA毒性介导或不由它介导。
在本发明实施方案的这一方面,具体的神经元活动非限制性地列举如下:刺激受损神经元、促进神经元再生、预防神经变性及治疗神经紊乱。一般而言,神经元受损是脑缺血、视网膜缺血或再灌注损伤的结果。因此,本发明的化合物能提高神经元活动,从而减轻缺血的影响。
在该实施方案的另一方面,具体的神经紊乱非限制性地列举如下:由物理损伤或疾病状态引起的外周神经病变、创伤性脑损伤、脊髓的物理损伤、与脑损伤相关的中风、与神经变性有关的神经紊乱。
此外,在该实施方案中,与神经变性有关的具体神经紊乱非限制性地列举如下:阿尔茨海默氏病、帕金森病、亨廷顿氏病和肌萎缩性侧索硬化。
在本发明的另一实施方案中,还提供了治疗患者的心血管紊乱的方法,该方法包括给所述患者施用治疗有效量的化合物,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有如本文所述的式(I)所示的一般结构。
在本发明的该实施方案中,可列举的具体心血管紊乱包括但不限于冠状动脉疾病、心肌梗塞、心绞痛、心源性休克及心血管组织损伤。
本文公开的本发明的方法中所用的化合物的各种实施方案均可用于本文所述的各种疾病状态的治疗方法中。如本文所述,本发明的方法中所用的化合物能抑制PARP的作用,从而减轻因PARP的活性所引起的效应和/或病症。在本发明方法的另一实施方案中,本发明的化合物可通过本领域已知的任何方法施用。具体而言,本发明的化合物可经口、肌内、皮下、直肠、气管内、鼻内、腹膜内或局部途径施用。
用于本发明方法的吲哚衍生物中的一些是已知的。例如,在Becher等人,Synthesis,530-533(1989)中公开了如下定义的化合物:其中R、R2、R3、R4是氢,X和Y是碳,且R1是苯基或甲基。在DE 2707268(1978)中公开了如下定义的化合物:其中R和R4是氢,R2和R3是甲基,X和Y是碳且R1是苯基。最后,在Capperucci等人,J.Org.Chem.,60,2254-2256(1995)中公开了如下定义的化合物:其中R、R2、R3、R4是氢,X和Y是碳,且R1是乙基。美国专利US 4,148,895还公开了一系列吲哚衍生物。本文中所述的所有参考文献均整体引入本文。
但是,本发明化合物中的一些是新的。因此,在本发明的这一方面,提供了一类化合物,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有式(I)所示的一般结构:
其中
R是氢、羟基、C1-4烷氧基或氨基;
R1是萘基、取代的苯基、C6-12芳基C1-4烷基、C6-12芳基磺酰基或杂芳基,且其中的萘基、芳基或杂芳基可任选被一个或数个选自以下的取代基取代:卤素、C1-6烷基、C1-6链烯基、式CnHxFy或OCnHxFy的氟烷基或氟烷氧基(其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1)、C1-4烷氧基、C1-4硫代烷基、羟基、羟基C1-4烷基、C1-4酰氧基、硝基、氨基、C1-4烷基氨基、C1-4二烷基氨基、氨基C1-4烷基、C1-4烷基氨基C1-4烷基、C1-4二烷基氨基C1-4烷基、-CN、-CO2H、-CO2C1-4烷基、-NHCOC1-4烷基、取代或未取代的苯基、取代或未取代的苯氧基、取代或未取代的苄氧基、取代或未取代的吡咯基以及取代或未取代的吡啶基;
R2和R3相同或不同且分别选自:
氢、C1-4烷基、C1-4二烷基氨基C1-4烷基、吡咯烷基C1-4烷基、咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO以及-CO2C1-4烷基;或
R2和R3与它们所连接的氮原子一起形成咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO、-CO2C1-4烷基、羟基C1-4烷基、环氧乙烷基C1-4烷基、二羟基C1-4烷基、-(CH2)aN-CO2C1-4烷基、羟基以及-(CH2)aOPO(OC1-4烷基)2,其中a是1至4的整数;
R4是C1-4烷基、式CnHxFy或OCnHxFy的氟烷基或氟烷氧基(其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1)、C1-4烷氧基或C1-4硫代烷基;以及
X和Y相同或不同且分别选自:CH或N。
属于本发明范围内的一些新的化合物可列举如下:
2-(哌嗪-1-基)-1-(3-硝基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-甲氧基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-叔丁基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-溴苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-氯苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-氯-4-氟苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-甲氧基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-硫甲基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-氟苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-甲基苯基)-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-哌啶-1-基-1H-吲哚-3-甲醛,
1-(3-甲酰基苯基)-2-(哌嗪-2-基)-1H-吲哚-3-甲醛,
1-(联苯-4-基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(4-乙基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(3-溴苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-甲基-3-硝基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-二甲基氨基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-苯氧基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-氟苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(3-氯苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-乙烯基苯基)-1H-吲哚-3-甲醛,
1-(3-羟基甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(3-乙氧基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-丁基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
N-{3-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]苯基}-乙酰胺盐酸盐,
4-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]-苄腈,以及
2-哌嗪-1-基-1-[(4-吡啶-4-基)苯基]-1H-吲哚-3-甲醛。
以下化合物也是新的:
1-(4-叔丁基苯基)-2-[4-(2-羟基乙基)哌嗪-1-基]-1H-吲哚-3-甲醛,
磷酸2-{4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-基}-乙基酯二乙基酯盐酸盐,
1-(4-叔丁基苯基)-2-(4-甲基-哌嗪-1-基)-1H-吲哚-3-甲醛,
4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]哌嗪-1-甲酸叔丁酯,
5-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-2,5-二氮杂双环[2-2-1]庚烷-2-甲酸叔丁酯,
1-(4-叔丁基-苯基)-2-(2-甲基-吖丙啶-1-基)-1H-吲哚-3-甲醛,
4-[3-甲酰基-1-(4-碘苯基)-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯,
4-[1-(4’-氰基联苯-4-基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯,和
4-{1-[4-(叔丁氧羰基-1H-吡咯-2-基)-苯基]-3-甲酰基-1H-吲哚-2-基}-哌嗪-1-甲酸叔丁酯。
在该实施方案的另一方面,其中X是氮且Y是碳或者X是碳且Y是氮的式(I)化合物是新的。该实施方案范围内的化合物的具体实例可无任何限制地列举如下:
1-苯基-2-(哌嗪-1-基)-1,3-二氢吡咯并[2,3-b]吡啶-3-甲醛,
1-苯基-2-(哌嗪-1-基)-1H-吡咯并[2,3-c]吡啶-3-甲醛,
2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛;三氟乙酸盐,以及
2-哌嗪-1-基-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-3-甲醛;双三氟乙酸盐。
其中R2和R3与它们所连接的氮原子一起形成咪唑基的式(I)化合物也是新的。该实施方案的具体实例无任何限制地包括2-咪唑-1-基-1-苯基-1H-吲哚-3-甲醛。
其中R2是氢或甲基且R3是二甲基氨基乙基、吡咯烷基乙基氨基和哌啶基的式(I)化合物也是新的。该实施方案范围内的化合物的实例无任何限制地包括:
2-(2-二甲基氨基乙基氨基)-1-苯基-1H-吲哚-3-甲醛,
2-[(甲基哌啶-4-基)氨基]-1-苯基-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-[(2-二甲基氨基乙基)-甲基氨基]-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-(2-二甲基氨基乙基氨基)-1H-吲哚-3-甲醛,以及
1-(4-叔丁基苯基)-2-(2-吡咯烷-1-基-乙基氨基)-1H-吲哚-3-甲醛盐酸盐。
最后,其中R1是苄基、萘基、噻吩基、吡啶基和苯磺酰基的式(I)化合物是新的。该实施方案所包含的具体化合物无限制地包括:
2-(哌嗪-1-基)-1-苄基-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(1-萘基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(噻吩-3-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(吡啶-2-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(吡啶-3-基)-1H-吲哚-3-甲醛,以及
1-苯磺酰基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛。
本发明的化合物可以通过本领域技术人员所知的任何方法合成。尤其是,用于制备本发明化合物的若干原料是已知的或本身可从市场购得。本发明的化合物及若干前体化合物还可通过文献中所报导的制备类似化合物的方法以及本文即将描述的方法来制备。
更具体地说,本文所公开的化合物可根据以下流程图1-6中的方法来合成;除非另有说明,其中X、Y、Z、R1、R2、R3和R4如式(I)中定义。
流程图1显示了合成初始羟吲哚(II)的一般步骤。通常,这一途径最适合于其中X和Y是碳且R1是苯基的化合物。如流程图1的步骤1所示,初始中间体羟吲哚(II)可通过两条不同的途径来制备。在一条途径中,在适宜的有机溶剂如甲苯中及在适宜的碱如三乙胺存在时,使取代的苯胺(1)与α-氯乙酰氯(2)反应。所生成的乙酰苯胺衍生物(3)在流程图1的步骤2中于Friedel-Crafts芳基化条件下发生环化,以形成羟吲哚(II)。通常,这类反应在惰性非极性溶剂如1,2-二氯苯中使用路易斯酸如氯化铝进行。然而,也可采用本领域已知的制备这类物质的各种变通方法。
或者,如流程图1的步骤3所示,初始的取代的苯胺1可直接与草酰氯反应,以形成取代的靛红衍生物4。该反应可在适宜的有机溶剂如甲苯中进行。然后,所生成的靛红衍生物4通过在碱性条件下、通常在氢氧化钾存在时在极性溶剂如乙二醇中与肼反应,而转化为羟吲哚中间体(II)。
流程图1
流程图2显示了制备中间体羟吲哚(II)的可选方法。这一途径还适合于其中X和Y是碳的化合物。在流程图2的步骤1A中,取代的靛红衍生物5与适宜的R1-Z反应以形成N-取代的靛红衍生物4,其中Z是适宜的离去基团。该反应尤其适合于那些其中R1是取代或未取代的芳基如苯基或萘基的化合物。该反应通常利用芳基硼酸(如R1=苯基时为苯基硼酸)在催化剂如乙酸酮及有机碱如三乙胺和/或吡啶存在时,在适宜的有机溶剂中进行。靛红衍生物4还可以以类似方式从羟吲哚6开始而制备。在流程图2的步骤2中,如上所述,此靛红衍生物4通过与肼反应而转化为羟吲哚中间体(II)。最后,在流程图2的步骤3中,中间体(II)首先与由磷酰氯与DMF作用而形成的Vilsmeier试剂反应,然后再与所需的胺R2R3NH反应,而转化为其中R是氢的本发明的化合物。
流程图2
流程图3显示了制备本发明化合物的可选方法,其中X和Y是碳且R是氢。在流程图3的步骤1中,取代的羟吲哚7与如上所述的Vilsmeier试剂反应以形成5-取代的-2-氯吲哚-3-甲醛(8)。在流程图3的步骤2中,利用如上所述的所需R1Z,使醛8发生N-取代反应以形成醛中间体(III)。一般而言,这样的取代反应利用硼酸R1B(OH)2在催化剂如乙酸酮和有机碱如三乙胺和吡啶的混合物存在时、在疏质子非极性有机溶剂如二氯甲烷中进行。最后,在流程图3的步骤3中,醛中间体(III)与所需胺R2R3NH反应,以形成其中R是氢的本发明的化合物(I)。
流程图3
流程图4显示了制备中间体羟吲哚(II)的另一途径。这一途径尤其适合于制备其中R1是杂芳基且X和Y是碳的本发明的化合物。在流程图4的步骤1中,5-取代的吲哚(9)首先与其中Z是卤素的式R1-Z的杂芳基化合物反应。这一途径尤其适合于制备其中R1是吡啶基或噻吩基的化合物。
因此,按照这一方法,吲哚9与3-溴吡啶、2-溴噻吩或2-氟吡啶在适宜碱和催化剂存在时发生反应,这取决于所用杂芳基化合物R1-Z的类型。例如,与2-氟吡啶反应时,使用氢化钠作为DMF中的碱。叔丁醇钠、三(二亚苄基丙酮)钯、2-(二叔丁基膦基)联苯的甲苯溶液用于偶合3-溴吡啶。碳酸钾和溴化亚铜的NMP溶液用于偶合2-溴噻吩。然后,如此形成的N-取代的吲哚10在流程图4的步骤2中氧化为羟吲哚II。后一氧化步骤可采用本领域任何已知的方法来实现。通常,这样的氧化反应采用N-氯琥珀酰亚胺的二氯甲烷溶液于环境温度下进行,随后将反应产物在乙酸和磷酸中进行后处理,生成羟吲哚(II),然后按照以上流程图1-3所述的任何方法将羟吲哚(II)转化为所需的本发明化合物。
流程图4
流程图5显示了制备其中Y是氮的本发明化合物的另一方法。在流程图5的步骤1至3中,将适宜的吡啶衍生物11转化为羟吲哚中间体(IIA)。因此,在流程图5的步骤1中,将吡啶衍生物11氧化形成吡啶-N-氧化物(12),将后者在流程图5的步骤2中用适宜的氯化剂氯化。该氯化反应可例如用磷酰氯进行形成2-氯吡啶中间体(13)。在流程图5的步骤3中,将中间体13在适宜的反应条件下环化,形成羟吲哚中间体(IIA),后者可采用流程图1至3或如下所述的流程图6中的任何方法进一步转化为本发明的化合物。
流程图5
最后,流程图6显示了制备其中X是氮的本发明的化合物(I)的另一方法。流程图6的步骤1至4显示了将吡啶衍生物14转化为羟吲哚中间体18的途径。按照流程图6的步骤5至8,将如此形成的羟吲哚18转化为本发明的化合物(IB)。
流程图6
最后,在本发明的另一实施方案中,提供了一种药物组合物,该药物组合物包含可药用载体和化合物,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有如本文所述的式(I)所示的一般结构。
如本文所述,本发明的药物组合物以PARP抑制活性为特征,因此,可用于治疗患者中因PARP作用引起的任何疾病、病症或紊乱。同样,如上所述,所有本文所公开的本发明化合物的优选实施方案均可用于制备如本文所述的药物组合物。
优选本发明的药物组合物采取以下单位剂量形式:片剂、丸剂、胶囊、粉末、颗粒剂、灭菌胃肠道外溶液或混悬液、计量气雾剂或液体喷雾剂、滴剂、安瓿剂、自动注射装置或栓剂;用于经口、胃肠道外、鼻内、舌下或直肠给药,或用于吸入或吹入给药。或者,组合物可以是适于每周一次或每月一次给药的形式;例如,活性化合物的不溶性盐,如癸酸盐,可用于提供肌内射的储库制剂。可以设想采用含有活性成分的可溶蚀性聚合物。制备固体组合物如片剂时,将主要活性成份与药用载体混合,所述的载体例如是常规制片成份如玉米淀粉、乳糖、蔗糖、山梨醇、滑石粉、硬脂酸、硬脂酸镁、磷酸氢钙、胶以及其它药用稀释剂如水,以形成含有本发明的化合物或其可药用盐的均一混合物的固体预制备组合物。当我们说这些预制备组合物为均一的时,指活性成份均匀地分散在组合物中,因此,该组合物可被容易地分为等同有效的单位剂量形式,如片剂,丸剂和胶囊剂。然后将该固体预制备组合物分成上文描述类型的含有0.1至约500毫克本发明活性成份的单位剂量形式。矫味的单位剂量形式含有1到100毫克、例如1、2、5、10、25、50或100毫克的活性成分。这种新组合物的片剂或丸剂可以包衣或以其它方式复合,以便提供具有有利的延时作用的剂量形式。例如,片剂或丸剂可包含内剂量和外剂量部分,外剂量部份为包在内剂量部份外的形式。两个部份可由肠溶层分隔开,肠溶层在胃里不被崩解,从而使内剂量部分完整进入十二指肠或被延迟释放。多种材料都可用作肠溶层或肠溶衣,包括多种聚合酸以及聚合酸与材料如虫胶、十六醇和醋酸纤维的混合物。
其中可包含本发明的新的组合物以口服或注射给药的液体形式包括水溶液、适宜矫味的糖浆、水性或油性混悬液、食用油(如棉籽油、芝麻油、椰子油或花生油)的矫味乳剂,以及酏剂和类似的药用溶媒。适于水性混悬液的分散剂或悬浮剂包括合成和天然胶质如西黄蓍胶、阿拉伯胶、海藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。
本发明的药物组合物可以以本领域已知的任何方式给药。一般来说,本发明的药物组合物可通过口服、肌内、皮下、直肠、气管内、鼻内、腹膜内或局部途径给药。本发明的药物组合物优选通过口服合鼻内途径给药。任何已知的通过口服或鼻内途径给药的方法都可用于施用本发明的组合物。
在治疗如本文所述的各种疾病状态中,适宜的剂量水平为约0.01到250毫克/公斤/日,优选约0.05到100毫克/公斤/日,尤其是约0.05到20毫克/公斤/日。该化合物可按照每日1到4次的给药方案施用。
以下实施例对本发明作了进一步阐述,这些实施例仅出于解释说明的目的,绝非以任何方式限制本发明的范围。
实施例(概述)
反应一般在氮气氛围中进行。溶剂用硫酸镁干燥,并用旋转蒸发仪真空蒸发。TLC分析用EM Science硅胶60 F254板进行,通过紫外线辐射显影。快速色谱法使用Alltech预填充硅胶柱进行。1H NMR波谱通常在Gemini 300或Varian VXR 300分光计上以300MHz进行,在氘代溶剂中测定,除非另有说明,氘代溶剂为DMSO-D6或CDCl3。化学位移值以百万分率(ppm)报告,参考四甲基甲硅烷(TMS)作为内标。LC/MS在Micromass Platform LCZ上进行。
在以下实施例和制备例中,所用的术语将具有以下含意:“kg”指千克,“g”指克,“mg”指毫克,“μg”指微克,“pg”指皮克,“lb”指磅,“oz”指盎司,“mol”指摩尔,“mmol”指毫摩尔,“μmole”指微摩尔,“nmole”指纳摩尔,“L”指升,“mL”或“ml”指毫升,“μL”指微升,“gal”指加仑,“℃”指摄氏度,“Rf”指保留因子,“mp”或“m.p.”指熔点,“dec”指分解,“bp”或“b.p.”指沸点,“mm Hg”指以毫米汞柱计的压力,“cm”指厘米,“nm”指纳米,“abs.”指绝对,“conc.”指浓缩,“c”指以g/ml计的浓度,“THF”指四氢呋喃,“DMF”指二甲基甲酰胺,“NMP”指1-甲基-2-吡咯烷酮,“盐水”指饱和氯化钠水溶液,“M”指摩尔/升,“mM”指毫摩尔/升,“μM”指微摩尔/升,“nM”指纳摩尔/升,“N”指当量浓度,“TLC”指薄层色谱法,“HPLC”指高效液相色谱法,“HRMS”指高分辨率质谱,“L.O.D.”指干燥失重,“μCi”指微居里,“i.p.”指腹膜内,“i.v.”指静脉内,anhyd=无水,aq=水性,min=分钟,hr=小时,d=天,sat.=饱和,s=单峰,d=双峰,t=三重峰,q=四重峰,m=多重峰,dd=双重双峰,br=宽峰,LC=液相色谱法,MS=质谱,ESI/MS=电雾化电离/质谱,RT=保留时间,M=分子离子。
以下实施例描述了用于制备本发明化合物的各种原料的制备方法。
制备例1
1-苯基-1H-吲哚-2-酮
标题化合物按照Latrell,Bartmann,Granzier的DE 2 707 268(1978)中所述步骤如下制备。将二苯胺(40g,237mmol)和三乙胺(66.1mL,474mmol)的甲苯(65mL)溶液滴加至氯乙酰氯(20.7mL,260mmol)的甲苯(40mL)溶液中,同时在冰水浴中冷却。移去冰水浴,将反应混合物于55-65℃加热3小时。用甲苯(100mL)稀释冷却后的反应混合物,过滤并浓缩滤液,得到2-氯-N,N-二苯基乙酰胺(24.4g,42%产率),为浅棕色固体。NMR(CDCl3)7.56-7.19(10H,m),4.01(2H,s)。
将氯化铝(8.0g,60mmol)分两批加入上述酰胺(5.0g,20.4mmol)的1,2-二氯苯(10mL)溶液中。将反应混合物回流加热30min,稍微冷却后倒在冰上(100g),过滤收集生成的固体并用戊烷洗涤。将生成的米黄色固体溶于乙酸乙酯,干燥,过滤并浓缩,得到1-苯基-1H-吲哚-2-酮(2.53g,60%产率),为米黄色固体。
NMR 7.57(2H,t),7.41(3H,m),7.32(1H,d),7.2(1H,t),7.09(1H,t),6.79(1H,d);3.73(2H,d).
制备例2
2-氯-1-苯基-1H-吲哚-3-甲醛
标题化合物可按照Andreani,A.;Bonazzi,D.等人,J.Med.Chem.
20,1344-1346,1977;Latrell,Bartmann,Granzier DE 2 707 268(1978)中所述的方法或按照以下所述的方法合成。
将磷酰氯(50mL,538mmol)缓慢加入DMF(50mL)的二氯甲烷(50mL)溶液中,同时维持温度为5℃。于30min后,加入1-苯基-1H-吲哚-2-酮(25g,120mmol)和吡啶(25mL,309mmol)的氯仿(125mL)溶液,并于室温搅拌该反应物48小时。将反应物倒入冰水(600mL),分出水层并用氯仿萃取(3×200mL)。将所合并的有机层和萃取液干燥、过滤并浓缩。将固体残余物从乙醇中结晶,得到2-氯-1-苯基-1H-吲哚-3-甲醛(12.0g,39.25%产率),为橙色固体。NMR(CDCl3)10.21(1H,s),8.37(1H,d),7.60(3H,m),7.41(2H,m),7.38(1H,t),7.28(1H,m),7.10(1H,d)。浓缩滤液,将残余物用二氯甲烷作为洗脱剂进行色谱法,获得第二批产物(7.5g,24.5%产率)。
制备例3
1-苯基-1H-吲哚-2,3-二酮
标题化合物按照Bryant,N.M.,III等人Syn Commun,
23,1617-25(1993)中的方法如下制备。将二苯胺(26.6g,157mmol)的甲苯(65mL)溶液缓慢加入草酰氯(14.8mL,170mmol)的甲苯(35mL)溶液中,同时在冰水浴中冷却以维持温度低于40℃。将生成的棕色浆液于55-65℃加热1小时。注意:将剧烈放出氯化氢气体。蒸馏除去约100mL溶剂(它含有未反应的草酰氯)并将残余物于118-125℃加热过夜。将反应物冷却后倒入冰水(200mL)中,用乙酸乙酯萃取(4×250mL)。将所合并的萃取液干燥、过滤并浓缩,得到1-苯基-1H-吲哚-2,3-二酮(33.0g,94%产率)。H-NMR 7.70(1H,d),7.58(3H,d),7.43(3H,m),7.19(1H,t),6.90(1H,d)。
制备例4
2-氯-1-苯基-1H-吲哚-3-甲醛
将2-氯-1H-吲哚-3-甲醛(5.00g,27.8mmol)、苯基硼酸(6.79g,55.6mmol)、乙酸铜(10.11g,55.7mmol)、吡啶(4.40g,55.7mmol)、三乙胺(5.63g,55.6mmol)、4分子筛(15.0g)和二氯甲烷(300mL)的混合物于室温搅拌4天。通过Celite垫过滤反应混合物并用水、2N盐酸水溶液、饱和碳酸氢钠水溶液、盐水洗涤滤液,干燥、过滤并浓缩。经色谱法纯化残余物,用二氯甲烷洗脱。将含有产物的级分合并和浓缩,得到2-氯-1-苯基-1H-吲哚-3-甲醛(4.40g,88%产率),为黄色固体。
NMR(CDCl3)12.30(1H,s),8.37(1H,d),7.58-7.70(3H,m),7.43(2H,d),7.23-7.40(2H,m),7.10(1H,d).
制备例5
5-甲基-1-苯基-1H-吲哚-2,3-二酮
将5-甲基-1H-吲哚-2,3-二酮(5-甲基靛红,2.0g,12.41mmol)、苯基硼酸(3.027g,24.82mmol)、无水乙酸铜(4.50g,24.77mmol)、活性4分子筛(6.6g)、三乙胺(3.47mL,24.9mmol)、吡啶(2.01mL,24.9mmol)和二氯甲烷(165mL)的混合物于室温搅拌24小时。通过hyflo垫过滤混合物并蒸发。将残余物与乙酸乙酯一起搅拌,过滤除去不溶的铜盐并蒸发滤液。经快速色谱法纯化残余物,用二氯甲烷洗脱,得到标题化合物(1.91g,65%产率),为橙色固体。MS 238(M+H)。
制备例6
1-(4-吡啶基)-1H-吲哚-2,3-二酮
将1H-吲哚-2,3-二酮(靛红,552mg,3.75mmol)、吡啶-4-硼酸(922mg,7.5mmol)、无水乙酸铜(1.36mg,7.5mmol)、活性4分子筛(2.0g)、三乙胺(1.05mL,7.5mmol)、吡啶(607μL,7.5mmol)和二氯甲烷(50mL)的混合物于室温搅拌24小时。通过hyflo垫过滤混合物并蒸发。将残余物与乙酸乙酯一起搅拌,过滤除去不溶的铜盐并蒸发滤液。经快速色谱法纯化残余物,用戊烷与30至80%乙酸乙酯洗脱,得到标题化合物。
制备例7
1-苯基-1H-吲哚-2-酮
向市售1-苯基-1H-吲哚-2,3-二酮(10.10g,45.7mmol)的乙二醇(125mL)溶液中加入粉末状氢氧化钾(7.4g,112mmol)、水合肼(16.35mL)和水(4mL)。将反应物于160℃加热1.5小时,然后冷却至室温,用浓盐酸调至酸性,用水稀释并过滤收集生成的固体。将该固体用水洗涤后溶于二氯甲烷,干燥并除去溶剂,得到1-苯基-1H-吲哚-2-酮(8.6g,90%产率),为固体。
制备例8
5-甲基-1-苯基-1H-吲哚-2-酮
如上所述,用粉末状氢氧化钾(1.92g,112mmol)、水合肼(16.35mL)和水(4mL)处理1-苯基-1H-吲哚-2,3-二酮(1.908g,11.83mmol)在乙二醇(30mL)中的混悬液。经快速色谱法纯化粗产物,用二氯甲烷洗脱。将含有产物的级分合并、浓缩,将残余物与戊烷一起研磨,得到5-甲基-1-苯基-1H-吲哚-2-酮,为灰白色固体。MS 224(M+1)
制备例9
2-氯-1-甲基-1H-吲哚-3-甲醛
在10min时间内,用60%氢化钠(440mg,11mmol)分批处理2-氯-1H-吲哚-3-甲醛(1.0g,5.5mmol)的DMF(30mL)溶液。搅拌30min后,缓慢加入甲基碘(685μL,11mmol),并将生成的混合物于室温搅拌3小时。小心加入水(5mL)并除去溶剂。将残余物溶于乙酸乙酯并用水、盐水洗涤,过滤并浓缩,得到2-氯-1-甲基-1H-吲哚-3-甲醛(1.16g,105%),熔点94.5-95.5℃,为白色固体。MS 194(M+H)。
制备例10
2-氯-1-苄基-1H-吲哚-3-甲醛
在此制备例中基本重复了制备例9的方法,但采用以下两种原料:2-氯-1H-吲哚-3-甲醛(1.0g,5.5mmol)和苄基溴(1.88g,11mmol),得到标题化合物(77%),为白色固体。MS 270(M+H)。
制备例11
2-氯-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛
步骤1:1-苯基-7-氮杂吲哚:
在N2气氛中,向7-氮杂吲哚(550mg,4.66mmol)、碘化铜(7.4mg,0.038mmol)和磷酸钾(1.74g,8.18mmol)的混合物中加入外消旋反式-1,2-二氨基环己烷(0.046mL,0.38mmol)、碘代苯(0.436mL,3.9mmol),再加入无水二烷(5mL)。将生成的混悬液在油浴中于110℃加热24小时,同时用磁性搅拌器搅拌。将生成的混合物通过短硅胶塞过滤,用乙酸乙酯充分洗涤滤饼。将滤液蒸发至棕色油状。将残余物经快速色谱法在10克硅胶柱上纯化,用庚烷∶乙酸乙酯(4∶1)洗脱。将含有产物的级分合并,蒸发溶剂,并经快速色谱法在10克硅胶柱上进一步纯化,用庚烷∶乙酸乙酯(19∶1)洗脱。将纯净的含有产物的级分合并和蒸发,得到758mg 1-苯基-7-氮杂吲哚为浅棕色油(100%产率)。
1H NMR(300MHz),CDCl3):8.37(1H,dd),7.97(1H,dd),7.76(2H,d),7.56-7.49(3H,m),7.35(1H,t),7.13(1H,dd),6.63(1H,d).
步骤2:3,3-二溴-1-苯基-1,3-二氧-吡咯并[2,3-b]吡啶-2-酮:
在N2气氛中,历经3.5用过溴溴化吡啶(2.15g,6.71mmol)分批处理1-苯基-7-氮杂吲哚(325mg,1.68mm0l)的叔丁醇(12mL)溶液,并偶尔在电热板上轻微加热以避免反应混合物凝固。在添加过程的某个阶段,该混合物粉碎,得到浓橙色混悬液。再搅拌该反应物2.5小时。将反应混合物蒸发并将残余物在水和乙酸乙酯之间分配。分出乙酸乙酯层并再用2份水和1份饱和盐水洗涤,用硫酸镁干燥。过滤并蒸发,得到橙色固体。将粗产物与乙醚一起研磨,分出生成的固体,并在真空中干燥,得到612mg 3,3-二溴-1-苯基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮,为橙色固体(99%产率)。
MS:m/e 367/369/371(M+H),389/391/393(M+Na).1H NMR(300MHz,CDCl3):8.24(1H,dd),7.94(1H,dd),7.51-7.60(4H,m),7.47(1H,m),7.18(1H,dd).
步骤3:1-苯基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮:
将3,3-二溴-1-苯基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮(600mg,1.63mmol)和10%(重量)披钯炭(300mg)悬浮在无水乙醇(60mL)中。将此混合物在常压的氢气气氛中搅拌17小时。将反应混合物通过hyflo垫过滤,用乙醇充分洗涤滤饼。浓缩滤液,得到粗制1-苯基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮,为橙棕色固体。未经进一步纯化使用此物质。MS:m/e 211(M+H),443(2M+Na)。
步骤4:2-氯-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛:
将用冰-丙酮冷却的无水二甲基甲酰胺(0.71mL,9.17mmol)和无水二氯甲烷(1mL)的溶液在N2气氛中用磷酰氯(0.69mL,7.42mmol)以点滴方式处理。将生成的淡黄色混合物继续搅拌30min,得到不透明胶。将固体形式的粗制1-苯基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮历经10min分批加入,形成红色混合物。加入二氯甲烷(1mL),在加入吡啶(0.45mL,5.56mmol),得到深红色混合物。使反应物历经1hr缓慢温热至室温,于室温搅拌38小时。将该红色反应混合物浓缩,用磷酰氯(8mL)处理残余物,混合物于110℃油浴中加热3小时。浓缩该红色混合物后,用冰水和饱和碳酸氢钠水溶液处理残余物直至停止冒泡。用5份二氯甲烷萃取混合物,所合并的萃取液用硫酸镁干燥,过滤并蒸发,得到橙色固体。将残余物经快速色谱法在5克硅胶柱上纯化,用二氯甲烷洗脱。将含有产物的级分合并,蒸发溶剂,在与庚烷一起研磨后,得到220mg 2-氯-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛,为松散粉红色固体(53%产率,以3,3-二溴-1-苯基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮计算)。
MS:m/e 257/259(M+H).1H NMR(300MHz,CDCl3):10.24(1H,s),8.62(1H,dd),8.39(1H,dd),7.68-7.56(3H,m),7.49(2H,d),7.31(1H,dd).
制备例12
2-氯-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-3-甲醛
步骤1:1-吡啶-3-基-7-氮杂吲哚:
在N2气氛中,向7-氮杂吲哚(550mg,4.66mmol)、碘化铜(7.4mg,0.038mmol)和磷酸钾(1.74g,8.18mmol)的混合物中加入外消旋反式-1,2-二氨基环己烷(0.046mL,0.38mmol)、3-溴吡啶(0.376mL,3.9mmol),再加入无水二烷(5mL)。将生成的混悬液在油浴中于110℃加热38小时,同时用磁性搅拌器搅拌。再加入碘化铜(65mg,0.341mmol),并将生成的混合物在油浴中于110℃加热57小时,得到棕色淤泥状混合物。通过短硅胶塞过滤,用乙酸乙酯充分洗涤滤饼,滤液蒸发,得到粗产物,为深棕色油。将残余物经快速色谱法在10克硅胶柱上纯化,用庚烷∶乙酸乙酯∶二氯甲烷(3∶1∶1,增至32∶13∶5和24∶16∶10)洗脱。将含有产物的级分合并和蒸发,得到818mg1-吡啶-3-基-7-氮杂吲哚,为浅棕色油(108%产率)。
MS:m/e 196(M+H).1H NMR(300MHz,CDCl3):9.01(1H,br.s),8.60(1H,br.s),8.39(1H,dd),8.30(1H,d),8.00(1H,dd),7.55(1H,d),7.49(1H,dd),7.18(1H,dd),6.70(1H,d).
步骤2:3,3-二溴-1-吡啶-3-基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮:
在N2气氛中,历经2.75hr用过溴溴化吡啶(4.36g,13.6mmol)分批处理1-吡啶-3-基-7-氮杂吲哚(粗制,800mg,4.10mmol)的叔丁醇(40mL)溶液,并偶尔在电热板上轻微加热以避免反应混合物凝固。在添加过程的某个阶段,该混合物粉碎,得到浓橙色混悬液。搅拌该反应物3小时。将反应混合物蒸发并将残余物在水和乙酸乙酯之间分配。分出乙酸乙酯层,用2份水和1份饱和盐水洗涤,用硫酸镁干燥。过滤并蒸发,得到松脆棕色固体。将粗产物与乙醚一起研磨,分离生成的固体,真空干燥,得到2.12g粗制3,3-二溴-1-吡啶-3-基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮(140%产率)。
MS:m/e 368/370/372(M+H).1H NMR(300MHz,DMSO-d6):9.03(1H,br.s),8.81(1H,m),8.40(1H,m),8.31(1H,d),8.24(1H,d),7.89(1H,dd),7.41(1H,dd).
步骤3:1-吡啶-3-基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮:
将3,3-二溴-1-吡啶-3-基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮(粗制,2.12g)和10%(重量)披钯炭(750mg)悬浮在无水乙醇(85mL)中。将此混合物在常压的氢气气氛中搅拌19小时。将反应混合物通过hiflo垫过滤,用大量的沸腾乙醇充分洗涤滤饼。浓缩滤液,得到粗制1-吡啶-3-基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮,为粘性棕色固体。加入饱和碳酸氢钠水溶液(30mL),并用8份二氯甲烷萃取该混合物。将所合并的萃取液用硫酸镁干燥,过滤并蒸发,得到棕色残余物。将粗产物经快速色谱法在5克硅胶柱上纯化,用二氯甲烷∶甲醇(99∶1)洗脱。将含有产物的级分合并和蒸发,得到380mg1-吡啶-3-基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮(47%产率,以3-溴吡啶计算)。
MS:m/e 212(M+h).1H NMR(300MHz,CDCl3):8.90(1H,d),8.62(1H,dd),8.19(1H,d),7.96(1H,dt),7.61(1H,d),7.47(1H,dd),7.08(1H,dd),3.78(2H,s).
步骤4:2-氯-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-3-甲醛:
将用冰-丙酮冷却的无水二甲基甲酰胺(0.71mL,9.2mmol)和无水二氯甲烷(2mL)的溶液在N2气氛中用磷酰氯(0.93mL,10mmol)以点滴方式处理。将生成的淡黄色混合物继续搅拌40min,得到浑浊混合物。将1-吡啶-3-基-1,3-二氢-吡咯并[2,3-b]吡啶-2-酮(370mg,1.75mmol)和吡啶(0.30mL,3.7mmol)的二氯甲烷(1mL)溶液历经20min分批加入,形成红色混合物。使反应物历经1hr缓慢温热至室温,并于室温搅拌24小时。将该红色反应混合物浓缩,用磷酰氯(10mL)处理残余物并将该混合物在油浴中于110℃加热3小时。浓缩该红色混合物后,用冰水和饱和碳酸氢钠水溶液处理残余物直至停止冒泡。用5份二氯甲烷萃取该混合物,将所合并的萃取液用硫酸镁干燥,过滤并蒸发,得到棕色固体。将残余物经快速色谱法在10克硅胶柱上纯化,用二氯甲烷洗脱。将含有产物的级分合并,蒸发溶剂,将残余物经快速色谱法在10克硅胶柱上纯化,用二氯甲烷洗脱。在与庚烷一起研磨后,得到36mg 2-氯-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-3-甲醛,为松散乳色粉末。经快速色谱法在5克硅胶柱上纯化庚烷上清液,用二氯甲烷∶甲醇(99∶1)增至乙酸乙酯洗脱,又获得11mg产物。总产量,47mg,10%产率。MS:m/e 258/260(M+H)。
实施例1
1-苯基-2-(硫吗啉-4-基)-1H-吲哚-3-甲醛
将2-氯-1-苯基-1H-吲哚-3-甲醛(130mg,0.51mmol)和硫吗啉(105mg,1.02mmol)在二烷(6mL)中的溶液回流10小时。除去溶剂并经色谱法纯化残余物,用二氯甲烷洗脱,得到1-苯基-2-(硫吗啉-4-基)-1H-吲哚-3-甲醛(135mg,82%产率),为黄色固体。
NMR(CDCl3)8.30(1H,d),7.5-7.70(3H,m),7.40(2H,d),7.28(1H,t),7.19(1H,t),6.98(1H,d),3.55(4H,t),2.46(4H,t).
实施例2
2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-2-酮
将2-氯-1-苯基-1H-吲哚-3-甲醛(2.55g,19.6mmol)、4-(2-羟基乙基)-哌嗪(1.00g,3.92mmol)在二烷(13mL)中回流加热过夜。将冷却后的反应物用水稀释并用二氯甲烷萃取。将有机层干燥,过滤并蒸发至半固体,再与乙醚一起研磨,得到2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛,为浅棕色固体。MS 350(M+H)。
实施例3
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛
将2-氯-1-苯基-1H-吲哚-3-甲醛(2.0g,7.83mmol)、哌嗪(6.73g,78.3mmol)和二烷(25mL)的混合物回流加热过夜。冷却至室温后加入水(100mL),于1hr后过滤收集固体,用水洗涤并经快速色谱法纯化,用氯仿-5%甲醇洗脱。将含有产物的级分合并和浓缩,得到2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛(0.87g,36%),为米黄色固体。经快速色谱法纯化样品(熔点175℃)用二氯甲烷-5%甲醇洗脱。
NMR(CDCl3)10.29(1H,s),8.27(1H,d),7.60(2H,m),7.51(1H,t),7.40(2H,d),7.23(1H,m),7.15(1H,t),6.98(1H,d),3.27(4H,m),2.78(4H,m).
实施例4
5-甲基-1-苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛
如实施例2所述,使2-氟-5-甲基-1-苯基-1H-吲哚-3-甲醛与哌嗪反应,得到5-甲基-1-苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,为浅黄色固体(63%产率)。
实施例5
2-(2-二甲基氨基乙基氨基)-1-苯基-1H-吲哚-3-甲醛
如实施例2所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与N,N-二甲基乙二胺反应,得到标题化合物,为米黄色固体(42%产率)。
NMR(CDCl3)10.0(1H,s),7.73(1H,br s),7.59(4H,m),7.42(2H,m),7.18(1H,t),7.0(1H,t),6.77(1H,d),2.98(2H,br),2.38(2H,br t),2.12(6H,s).
实施例6
2-(哌啶-1-基)-1-苯基-1H-吲哚-3-甲醛
如实施例2所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与哌啶反应,经快速色谱法后,得到标题化合物(50%产率)。
NMR(CDCl3)10.23(1H,s),8.29(1H,d),7.59(2H,m),7.50(1H,m),7.40(2H,d),7.22(1H,m),7.11(1H,t),6.98(1H,d),3.25(4H,m),1.53(2H,m),1.42(4H,m).
实施例7
2-(氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛
如实施例2所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与氮杂环庚烷反应,得到标题化合物(42%产率)。
NMR(CDCl3)10.25(1H,s),8.23(1H,d),7.58(2H,m),7.51(1H,m),7.39(2H,d),7.25(1H,m),7.15(1H,t),6.98(1H,d),3.50(4H,m),2.55(4H,m),2.33(3H,s),1.78(2H,m).
实施例8
2-[(甲基哌啶-4-基)氨基]-1-苯基-1H-吲哚-3-甲醛
如实施例2所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与4-甲基氨基-哌啶-1-甲酸叔丁酯反应,得到标题化合物(18%产率)。LC-RT 2.20min.;MS 334(M+H)。
实施例9
2-(哌嗪-1-基)-1-甲基-1H-吲哚-3-甲醛
如实施例2所述,使2-氯-1-甲基-1H-吲哚-3-甲醛(1.0g,5.5mmol)与哌嗪反应,得到标题化合物(24%),为橙棕色固体。MS 244(M+H)。
实施例10
2-(哌嗪-1-基)-1-苄基-1H-吲哚-3-甲醛
如实施例2所述,使2-氯-1-苄基-1H-吲哚-3-甲醛(1.0g,5.5mmol)与哌嗪反应,得到标题化合物(64%),熔点163-165℃,为浅黄色固体。MS 320(M+H)。
实施例11
2-(哌嗪-1-基)-1-芳基-1H-吲哚-3-甲醛
依照如下所述步骤分两步平行合成一系列芳基取代的标题化合物。
步骤A:2-氯-1-芳基-1H-吲哚-3-甲醛:
将2-氯-1H-吲哚-3-甲醛(200mg,1.1mmol)、乙酸铜(400mg,2.2mmol)、4分子筛(587mg)、所需的芳基硼酸(2.2mmol)、二氯甲烷(15mL)、三乙胺(308μL,2.2mmol)以及吡啶(178μL,2.2mmol)置入11支可密封反应试管,将该反应混合物于室温搅拌36小时。用乙醚稀释,通过Hifio过滤并将滤液浓缩。经色谱法纯化残余物,用戊烷-10%乙酸乙酯洗脱,得到对应的2-氯-1-芳基-1H-吲哚-3-甲醛。将这11个实施例各自生成的产物和产率列入表1。
表1
实施例编号 | 产物 | 产率(%) |
实施例11A-1 | 2-氯-1-(3-硝基苯基)-1H-吲哚-3-甲醛 | 78 |
实施例11A-2 | 2-氯-1-(1-萘基)-1H-吲哚-3-甲醛 | 29 |
实施例11A-3 | 2-氯-1-(4-甲氧基苯基)-1H-吲哚-3-甲醛 | 46 |
实施例11A-4 | 2-氯-1-(4-叔丁基苯基)-1H-吲哚-3-甲醛 | 30 |
实施例11A-5 | 2-氯-1-(4-溴苯基)-1H-吲哚-3-甲醛 | 42 |
实施例11A-6 | 2-氯-1-(4-氯苯基)-1H-吲哚-3-甲醛 | 61 |
实施例11A-7 | 2-氯-1-(3-氯-4-氟苯基)-1H-吲哚-3-甲醛 | 66 |
实施例11A-8 | 2-氯-1-(3-甲氧基苯基)-1H-吲哚-3-甲醛 | 35 |
实施例11A-9 | 2-氯-1-(4-硫甲基苯基)-1H-吲哚-3-甲醛 | 16 |
实施例11A-10 | 2-氯-1-(3-氟苯基)-1H-吲哚-3-甲醛 | 67 |
实施例11A-11 | 2-氯-1-(3-甲基苯基)-1H-吲哚-3-甲醛 | 46 |
步骤B:2-(哌嗪-1-基)-1-芳基-1H-吲哚-3-甲醛:
将步骤A所得2-氯-1-芳基-1H-吲哚-3-甲醛、哌嗪(860mg,10mmol)和二烷(10mL)置入11支反应试管,将该溶液回流加热36小时。冷却至室温后加入水,用乙酸乙酯萃取该混合物。用水、盐水洗涤萃取液,干燥、过滤并浓缩。经快速色谱法纯化粗制的2-(哌嗪-1-基)-1-芳基-1H-吲哚-3-甲醛,用二氯甲烷-10%甲醇洗脱。将这11个实施例各自生成的产物和产率列入表2。表中的所有最终产物均显示了特征1H NMR波谱。
表2
实施例编号 | 产物 | 产量(mg) |
实施例11B-1 | 2-(哌嗪-1-基)-1-(3-硝基苯基)-1H-吲哚-3-甲醛 | 25 |
实施例11B-2 | 2-(哌嗪-1-基)-1-(1-萘基)-1H-吲哚-3-甲醛 | 32 |
实施例11B-3 | 2-(哌嗪-1-基)-1-(4-甲氧基苯基)-1H-吲哚-3-甲醛 | 93 |
实施例11B-4 | 2-(哌嗪-1-基)-1-(4-叔丁基苯基)-1H-吲哚-3-甲醛 | 61 |
实施例11B-5 | 2-(哌嗪-1-基)-1-(4-溴苯基)-1H-吲哚-3-甲醛 | 80 |
实施例11B-6 | 2-(哌嗪-1-基)-1-(4-氯苯基)-1H-吲哚-3-甲醛 | 110 |
实施例11B-7 | 2-(哌嗪-1-基)-1-(3-氯-4-氟苯基)-1H-吲哚-3-甲醛 | 35 |
实施例11B-8 | 2-(哌嗪-1-基)-1-(3-甲氧基苯基)-1H-吲哚-3-甲醛 | 55 |
实施例11B-9 | 2-(哌嗪-1-基)-1-(4-硫甲基苯基)-1H-吲哚-3-甲醛 | 32 |
实施例11B-10 | 2-(哌嗪-1-基)-1-(3-氟苯基)-1H-吲哚-3-甲醛 | 88 |
实施例11B-11 | 2-(哌嗪-1-基)-1-(3-甲基苯基)-1H-吲哚-3-甲醛 | 72 |
实施例12
2-(哌嗪-1-基)-1-(噻吩-3-基)-1H-吲哚-3-甲醛
步骤1:1-(噻吩-3-基)-1H-吲哚:
将吲哚(5.64g,48.3mmol)、3-溴噻吩(4.84mL,51.6mmol)、碳酸钾(7.16g,51.6mmol)、溴化亚铜(298mg,2.1mmol)和N-甲基吡咯烷酮(57mL)的混合物在氮气氛围中于180℃搅拌48小时。冷却至室温后,将反应混合物倒入水(300mL)中,然后用乙酸乙酯萃取。将萃取液用水、盐水洗涤,干燥、过滤并浓缩,得到棕色油,经色谱法纯化,用庚烷-10%二氯甲烷洗脱。将含有产物的级分合并和浓缩,得到1-(噻吩-3-基)-1H-吲哚(6.20g,64%产率),为无色油。
步骤2:1-(噻吩-3-基)-1H-吲哚-2-酮:
将上述1-(噻吩-3-基)-1H-吲哚(6.10g,30.6mmol)、N-氯琥珀酰亚胺(4.30g,32.2mmol)和二氯甲烷(230mL)的溶液于室温搅拌2小时。然后除去溶剂,将残余物溶于乙酸(127mL)并加热至70℃。然后加入85%磷酸并将反应混合物在轻微回流条件下加热24小时。冷却至室温后,将反应物浓缩至约原体积,倒入冰水中并用乙酸乙酯萃取。将所合并的萃取液用水、盐水洗涤,干燥、过滤并浓缩。将黑色残余物经色谱法纯化,用二氯甲烷与0至5%甲醇洗脱。将含有产物的级分合并和浓缩,得到1-(噻吩-3-基)-1H-吲哚-2-酮(4.12g,63%产率),为棕色固体。MS 216(M+H)。
步骤3:2-氯-1-(噻吩-3-基)-1H-吲哚-3-甲醛:
将磷酰氯(1.9mL,20.9mmol)缓慢加入冷却至0-5℃的二甲基甲酰胺(2mL)和二氯甲烷(2mL)的搅拌溶液中。于5min后,加入上述1-(噻吩-3-基)-1H-吲哚-2-酮(1.0g,2.65mmol)、吡啶(1mL)和二氯甲烷(4mL)的溶液,将该反应物于室温搅拌48小时。将反应混合物倒入冰/水中并用乙酸乙酯萃取。过滤除去固体并分离有机层,干燥、过滤并浓缩。经色谱法纯化残余物,用戊烷-10%乙酸乙酯洗脱。将含有产物的级分合并和浓缩,得到2-氯-1-(噻吩-3-基)-1H-吲哚-3-甲醛(694mg,57%),为浅橙色固体。MS 262(M+H)。
步骤4:2-(哌嗪-1-基)-1-(噻吩-3-基)-1H-吲哚-3-甲醛:
如实施例3所述,使如上制备的2-氯-1-(噻吩-3-基)-1H-吲哚-3-甲醛与哌嗪反应,得到标题化合物,为浅黄色固体(78%产率)。MS 409(M+H)。
实施例13
2-(哌嗪-1-基)-1-(吡啶-3-基)-1H-吲哚-3-甲醛
步骤1:1-(吡啶-3-基)-1H-吲哚:
在氩气氛围中,将溴吡啶(1.7mL,17.6mmol)的甲苯(15mL)溶液加入吲哚(2.0g,17.1mmol)、三(二亚苄基丙酮)钯(480mg,0.52mmol)、2-(二叔丁基膦基)联苯(5.52mg,0.76mmol)、叔丁醇钠和甲苯(25mL)中,将该混合物于100℃搅拌加热48小时。冷却至室温后,加入乙醚,通过Hi-Flo垫过滤反应混合物并浓缩。经色谱法纯化残余物,用戊烷-25%乙酸乙酯洗脱。将含有产物的级分合并和浓缩,得到1-(吡啶-3-基)-1H-吲哚(485mg,15%),为黄棕色油。
步骤2:1-(吡啶-3-基)-1,3-二氢吲哚-2-酮:
如实施例12所述,使1-(吡啶-3-基)-1H-吲哚与N-氯琥珀酰亚胺反应,得到1-(吡啶-3-基)-1,3-二氢吲哚-2-酮(59%产率),为浅棕色固体。
步骤3:2-氯-1-(吡啶-3-基)-1,3-二氢吲哚-3-甲醛:
将磷酰氯(500μL,5.39mmol)于0-5℃缓慢加入搅拌中的二甲基甲酰胺(516μL)的二氯甲烷(516μL)溶液中。于15min后,加入1-(吡啶-3-基)-1,3-二氢吲哚-2-酮(250mg,1.2mmol)和吡啶(258μL)的二氯甲烷(2mL)溶液。将该反应混合物温热至室温并搅拌24小时。用水稀释该反应物,用氢氧化铵调至碱性,用二氯甲烷萃取并浓缩萃取液。将残余物用磷酰氯(5mL)处理并回流加热2小时。冷却至室温后除去过量磷酰氯,将残余物用冰/水处理,用氢氧化铵调至碱性并用二氯甲烷萃取。将所合并的萃取液用盐水洗涤,干燥、过滤并浓缩。经色谱法纯化残余物,用戊烷-30%乙酸乙酯洗脱。将含有产物的级分合并和浓缩,得到2-氯-1-(吡啶-3-基)-1,3-二氢吲哚-3-甲醛(42mg,14%产率),为黄色固体。MS 257(M+H)。
步骤4:2-(哌嗪-1-基)-1-(吡啶-3-基)-1H-吲哚-3-甲醛:
如实施例2所述,使2-氯-1-(吡啶-3-基)-1,3-二氢吲哚-3-甲醛与哌嗪反应,经快速色谱法纯化后,得到标题化合物(23%产率)。
实施例14
1-苯基-2-(哌嗪-1-基)-1,3-二氢吡咯并[2,3-b]吡啶-3-甲醛
步骤1:(1-羟吡啶-3-基)乙腈:
标题化合物按照[S.Okuda等人,J.Am.Chem.Soc.,
81,740,(1959)]中概述的方法制备。将过乙酸(38%,40mL,0.2mol)加入搅拌中的3-吡啶基乙腈(15.0g,127mmol)的乙酸(75mL)溶液中,将反应物于95℃加热24小时,再于室温搅拌24小时。加入水并除去溶剂。再加入水(100mL)并再次除去。用甲苯和乙醚重复此过程,得到(1-羟吡啶-3-基)乙腈,为乳色固体。
步骤2:(2-氯吡啶-3-基)乙腈:
将(1-羟吡啶-3-基)乙腈(7.5g,35.9mmol)小心加入剧烈搅拌的磷酰氯(100mL)中。历经1.5hr将该混合物缓慢(以5℃增量)加热至80℃(注意:若加热太快,将于约70℃发生剧烈分解)。所有固体皆溶解。将该反应物回流加热3小时。除去过量磷酰氯并用冷水小心处理残余物。加入饱和碳酸氢钠使混合物呈碱性,然后用乙酸乙酯萃取(3次)。将所合并的萃取液用盐水洗涤,干燥、过滤并浓缩。经色谱法纯化残余物,用戊烷与10至100%乙醚洗脱。流出的第二种化合物为所需的(2-氯吡啶-3-基)乙腈(2.35g,42.9%产率),为浅棕色固体。
步骤3:(2-氯吡啶-3-基)乙酸:
将在浓盐酸(15mL)中的(2-氯吡啶-3-基)乙腈(1.0g,6.55mmol)于100℃搅拌2小时。冷却至室温后,用水稀释反应混合物并将该溶液浓缩至干。将残余物溶于水,用氢氧化铵调至碱性,用乙酸重新酸化并用乙酸乙酯萃取。将所合并的萃取液用盐水洗涤,干燥、过滤并浓缩,得到(2-氯吡啶-3-基)乙酸(442mg,39%),为白色固体。
步骤4:1-苯基-1,3-二氢吡咯并[2,3-h]吡啶-2-酮:
标题化合物按照Ting,P.C.等人,J.Med.Chem.,
33,2697(1990)中所述的方法如下合成。将搅拌中的(2-氯吡啶-3-基)乙酸(400mg,2.3mmol)、苯胺(456μL,5.0mmol)、对甲苯磺酸(10mg)和戊醇(5mL)的混合物回流加热24小时。冷却至室温后,加入水(80mL)并用乙酸乙酯-25%二氯甲烷萃取该混合物。分离有机层、干燥、过滤并浓缩。经色谱法纯化残余物,用二氯甲烷与0至5%甲醇洗脱。将含有产物的级分合并和浓缩,得到1-苯基-1,3-二氢吡咯并[2,3-b]吡啶-2-酮(356mg,76%),为浅棕色固体。MS 211(M+H)。
步骤5:3-二甲基氨基亚甲基-1,3-二氢吡咯并[2,3-b]吡啶-2-酮:
将磷酰氯(693μL,7.47mmol)缓慢加入搅拌中的冷却至0-5℃的二甲基甲酰胺(714μL)和二氯甲烷(714μL)的溶液中。于10min后,将上述1-苯基-1,3-二氢吡咯并[2,3-b]吡啶-2-酮(350mg,1.66mmol)、吡啶(357μL)和二氯甲烷(1.43mL)的溶液加入,于室温搅拌该反应物24小时。将反应混合物倒入水中,用氢氧化铵将pH值调至8,并用二氯甲烷萃取(2次)。将所合并的萃取液干燥、过滤并浓缩。经色谱法纯化残余物,用二氯甲烷-2%甲醇洗脱。将含有产物的级分合并和浓缩,得到3-二甲基氨基亚甲基-1,3-二氢吡咯并[2,3-b]吡啶-2-酮(211mg,47.9%产率)。
步骤6:2-氯-1-苯基-1,3-二氢吡咯并[2,3-b]吡啶-3-甲醛:
用磷酰氯(10mL)处理3-二甲基氨基亚甲基-1,3-二氢吡咯并[2,3-b]吡啶-2-酮(210mg,0.79mmol),并于回流温度下搅拌2小时。除去过量磷酰氯,用冰/水处理残余物并用乙酸乙酯萃取。将所合并的萃取液用水、盐水洗涤,干燥、过滤并浓缩,得到2-氯-1-苯基-1,3-二氢吡咯并[2,3-b]吡啶-3-甲醛(231mg)。MS 257(M+H)。
步骤7:1-苯基-2-(哌嗪-1-基)-1,3-二氢吡咯并[2,3-b]吡啶-3-甲醛:
如实施例2所述,使2-氯-1-苯基-1,3-二氢吡咯并[2,3-b]吡啶-3-甲醛与哌嗪反应,得到1-苯基-2-(哌嗪-1-基)-1,3-二氢吡咯并[2,3-b]吡啶-3-甲醛(63%产率)。
实施例15
1-苯基-2-(哌嗪-1-基)-1H-吡咯并[2,3-c]吡啶-3-甲醛
步骤1:4-氯-3-硝基吡啶:
将4-羟基-3-硝基吡啶(10.0g,71.4mmol)于55-60℃分批加入机械搅拌中的五氯化磷(16.32g,78.6mmol)和磷酰氯(16.2mL)的混合物中。添加完毕后,将温度升至130-140℃并维持4小时。冷却至室温后,除去磷酰氯并小心用冰/水处理残余物,用碳酸钠调至碱性并用乙醚萃取。将所合并的萃取液干燥、过滤并浓缩,得到4-氯-3-硝基吡啶(5.1g,45%产率),为浅黄色固体。
步骤2:2-(3-硝基吡啶-4-基)丙二酸二苄酯:
标题化合物按照Daisley,R.W.;Hanbali,J.R.Svnth.Commun.,763,(1981)中所述步骤如下制备。将丙二酸二苄酯(3.47mL,13.9mmol)滴加至搅拌中的60%氢化钠(556g,13.9mmol)的油分散体与甲苯(20mL)的混合物中。于1hr后,用4-氯-3-硝基吡啶(2.0g,12.6mmol)的甲苯(10mL)溶液处理该混合物,然后回流加热2小时。冷却至室温后,将反应物浓缩,用1M盐酸水溶液(6mL)处理残余物并用乙酸乙酯萃取。将所合并的萃取液用盐水洗涤,干燥、过滤并浓缩。经色谱法纯化残余物,用戊烷-20%乙酸乙酯洗脱。将含有产物的级分合并和浓缩,得到2-(3-硝基吡啶-4-基)丙二酸二苄酯(1.72g,33.6%产率),为黄色油。
步骤3:(3-硝基吡啶-4-基)乙酸苄酯:
标题化合物按照WO,00 55159中所述步骤如下制备。将2-(3-硝基吡啶-4-基)丙二酸二苄酯(1.58g,5.6mmol)、氯化锂(250mg,10.6mmol)、二甲基亚砜(35mL)和水(95mL)的溶液回流加热8小时。冷却至室温后,用水稀释该反应物并用乙酸乙酯萃取。将所合并的萃取液用水、盐水萃取,干燥、过滤并浓缩,得到(3-硝基吡啶-4-基)乙酸苄酯(1.13g,99%产率),为黄橙色油。将此产物经色谱法纯化,用戊烷与20至30%乙酸乙酯洗脱,得到粉红色油状的产物。MS 273(M+H)。
步骤4:(3-氨基吡啶-4-基)乙酸苄酯:
标题化合物按照WO,00 55159中所述步骤如下制备。将(3-硝基吡啶-4-基)乙酸苄酯(1.10g,5.23mmol)、10%披钯炭(200mg)和变性酒精(100mL)的混合物在氢气氛围中搅拌6小时。通过Hi-Flo垫过滤除去催化剂并浓缩滤液,得到(3-氨基吡啶-4-基)乙酸苄酯(0.92g,98%产率),为黄棕色油。MS 181(M+H)。
步骤5:1,3-二氢吡咯并[2,3-c]吡啶-2-酮盐酸盐:
标题化合物按照WO,00 55159中所述步骤如下制备。将(3-硝基吡啶-4-基)乙酸苄酯(0.92g,5.1mmol)、乙醚(45mL)和10%盐酸水溶液(2.5mL)的混合物剧烈搅拌18小时。分离有机层并用水(15mL)洗涤。将所合并的水层和洗涤液浓缩,得到1,3-二氢吡咯并[2,3-b]吡啶-2-酮盐酸盐(又称为6-氮杂-1,3-二氢吲哚-2-酮)(790mg,91%产率),为浅黄色固体。MS 135(M+H)。
步骤6:3-二甲基氨基亚甲基-1,3-二氢吡咯并[2,3-c]吡啶-2-酮:
将磷酰氯(1.93mL,3.17mmol)缓慢加入搅拌中的冷却至0-5℃的二甲基甲酰胺(1.99mL)和二氯甲烷(3mL)的溶液中。于10min后,历经5min将上述1,3-二氢吡咯并[2,3-b]吡啶-2-酮盐酸盐(6-氮杂-1,3-二氢吲哚-2-酮)(790mg,4.63mmol)、吡啶(1.5mL)和二氯甲烷(5mL)的溶液加入,并将反应物于室温搅拌18小时。除去溶剂,得到粗制3-二甲基氨基亚甲基-1,3-二氢吡咯并[2,3-b]吡啶-2-酮。
步骤7:2-氯-1H-吡咯并[2,3-c]吡啶-3-甲醛:
用磷酰氯(10mL)处理上述粗制3-二甲基氨基亚甲基-1,3-二氢吡咯并[2,3-b]吡啶-2-酮,并于回流温度下搅拌3小时。除去过量磷酰氯并用冰/水处理残余物,用氢氧化铵调至碱性并用二氯甲烷萃取。浓缩水层,将残余物溶于少量水中,用氯化钠饱和并用乙酸乙酯连续萃取过夜。将有机萃取液浓缩,经色谱法纯化残余物,用二氯甲烷-5%甲醇洗脱,得到2-氯-1H-吡咯并[2,3-b]吡啶-3-甲醛(75mg,9%产率),为浅黄色固体。LC-MS:1.02min;181(M+H)。
步骤8:2-氯-1-苯基-1H-吡咯并[2,3-c]吡啶-3-甲醛:
将2-氯-1H-吡咯并[2,3-b]吡啶-3-甲醛(70mg,0.39mmol)、乙酸铜(140mg,0.77mmol)、苯基硼酸(93mg,0.76mmol),4分子筛(200mg)、三乙胺(106μL)、吡啶(61μL)和二氯甲烷(5.5mL)的混合物于室温剧烈搅拌48小时。通过Hi-Flo垫过滤除去固体并浓缩滤液。经色谱法纯化残余物,用二氯甲烷-2%甲醇洗脱。将含有产物的级分合并和浓缩,得到2-氯-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛(25mg,25%产率),为浅黄色油。
步骤9:1-苯基-2-(哌嗪-1-基)-1H-吡咯并[2,3-c]吡啶-3-甲醛:
如实施例2所述,使2-氯-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛与哌嗪反应,得到标题化合物,为浅棕色油(29.4%产率)。LC-MS 0.4min;307(M+H)。
实施例16
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲酰胺
步骤1:2-氯-1-苯基-1H-吲哚-2-甲酸:
于25℃,历经30min将亚氯酸钠(7.8g,86mmol)和水合磷酸二氢钠(7.8g,56mmol)的水(40mL)溶液滴加至剧烈搅拌中的2-氯-1-苯基-1H-吲哚-3-甲醛(4.0g,15.6mmol)、2M 2-甲基-2-丁烯(74mL,148mmol)在二烷(58mL)中的溶液中。于2.5hr后,再加入亚氯酸钠(1.92g,21.2mmol)和水合磷酸二氢钠(1.92g)。再过2.5hr后,又加入亚氯酸钠(0.96g,10.6mmol)和水合磷酸二氢钠(0.96g)。在反应总共6.5小时后,加入乙酸乙酯(100mL)并继续搅拌45min。分出水层并用乙酸乙酯萃取(2×60mL)。将所合并的乙酸乙酯层和萃取液浓缩至约80mL,然后用1%氢氧化钠水溶液萃取(3×150mL)。将所合并的水萃取液用浓盐酸调至酸性。过滤收集生成的固体,用水洗涤并从2-丙醇中结晶,得到2-氯-1-苯基-1H-吲哚-2-甲酸(3.28g,77.5%产率),为浅黄色固体。
NMR(CDCl3)8.30(1H,d),7.60(3H,m),7.41(2H,d),7.38(1H,t),7.23(1H,m),7.10(1H,d).
步骤2:2-氯-1-苯基-1H-吲哚-2-甲酰胺:
标题化合物按照J.Heterocyclic Chem.
25,1519,(1988)中所述方法如下制备。将2-氯-1-苯基-1H-吲哚-2-甲酸(500mg,1.85mmol)的亚硫酰氯(3.6mL)溶液回流6小时。除去未反应的亚硫酰氯,用浓氢氧化铵处理残余物,并于室温搅拌过夜。过滤收集固体并从乙醇中结晶,得到2-氯-1-苯基-1H-吲哚-2-甲酰胺(300mg,60%产率)。
NMR(CDCl3)8.39(1H,d),7.6(3H,m),7.40(2H,d),7.35-7.10(2H,m),7.05(1H,d),6.43(1H,br s),5.62(1H,br s).
步骤3:2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲酰胺:
如实施例2所述,使2-氯-1-苯基-1H-吲哚-2-甲酰胺与哌嗪反应,得到标题化合物(59%产率),为白色固体。
NMR(CDCl3)8.39(1H,d),7.95(1H,br s),7.59(3H,m),7.4(2H,m),7.22(1H,m),7.11(1H,t),6.8(1H,d),5.45(1H,br s),3.01(4H,m),2.83(4H,m).
实施例17
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲酸甲酯
步骤1:2-氯-1-苯基-1H-吲哚-2-甲酸甲酯:
将2-氯-1-苯基-1H-吲哚-2-甲酸(500mg,1.85mmol)的亚硫酰氯(3.6mL)溶液回流6小时。除去未反应的亚硫酰氯,用甲醇(15mL)处理残余物,并于室温搅拌过夜。除去甲醇并将残余物溶于二氯甲烷,用水洗涤,干燥、过滤并浓缩,得到2-氯-1-苯基-1H-吲哚-2-甲酸甲酯(450mg,85%产率),为琥珀色油。
NMR(CDCl3)8.20(1H,d),7.60(3H,m),7.40(2H,d),7.31(1H,t),7.21(1H,m),7.02(1H,d),4.0(3H,s).
步骤2:2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲酸甲酯:
如实施例2所述,使2-氯-1-苯基-1H-吲哚-2-甲酸甲酯与哌嗪反应,得到标题化合物(69%产率),为乳色固体。
NMR(CDCl3)8.08(1H,d),7.58(2H,m),7.50(1H,m),7.36(2H,d),7.22(1H,t),7.11(1H,t),6.99(1H,d),3.98(3H,s),3.14(4H,m),2.70(4H,m).
实施例18
2-(4-环氧乙烷基甲基哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛
将搅拌中的1-苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛(438mg,1.37mmol)、表溴醇(188mg,1.37mmol)、碳酸钾(758mg,5.49mmol)和乙腈(20mL)的混合物回流加热2.5小时。将反应物冷却并过滤除去固体。浓缩滤液并经色谱法纯化残余物,用二氯甲烷与1-5%甲醇洗脱。将含有所需产物的级分合并和浓缩,得到2-(4-环氧乙烷基甲基哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛(41%产率),为黄色固体。LC/MS:MS 376(M+H);RT 2.65min;
NMR(CDCl3):10.28(1H,s),8.26(1H,d),7.43-7.65(3H,m),7.17-7.42(3H,m),7.13(1H,t),6.96(1H,d),3.49(4H,m),3.03(1H,m),2.56-2.86(4H,m),2.30-2.50(2H,m),1.74(2H,m),1.56(2H,s).
实施例19
{2-[4-(3-甲酰基-1-苯基-2,3-二氢-1H-吲哚-2-基)-哌嗪-1-基]-乙基}-氨基甲酸
叔丁酯
如实施例1所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与2-(哌嗪-1-基-乙基)氨基甲酸叔丁酯反应,得到标题化合物(35%产率),为黄色固体。LC/MS:449(M+H);RT 2.77 min;
NMR(CDCl3):10.28(1H,s),8.26(1H,d),7.48-7.65(3H,m),7.38(2H,d),7.22-7.26(1H,m),7.14(1H,t),6.96(1H,d),3.15-3.50(8H,m),2.30-2.50(4H,m),1.45(9H,s).
实施例20
4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-哌嗪-2-甲酸甲酯
如实施例1所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与哌嗪-2-甲酸甲酯反应,得到4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-哌嗪-2-甲酸甲酯(9%产率),为黄色固体。
LC/MS:MS 364(M+H);RT 2.54 min;NMR(CDCl3):10.29(1H,s),8.26(1H,d),7.07-7.65(m,buried),6.98(1H,d),3.60-4.10(4H,m),2.60-3.55(6H,m).
实施例21
2-(2,5-二氮杂双环[2.2.1]庚-2-基)-1-苯基-1H-吲哚-3-甲醛
将5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(275mg,0.66mmol)和三氟乙酸(2mL)在二氯甲烷(1mL)中的溶液于室温搅拌过夜。将溶剂蒸发并将残余物溶于二氯甲烷(10mL),用5%碳酸钠水溶液、水、盐水洗涤,干燥、过滤并浓缩,得到2-(2,5-二氮杂双环[2.2.1]庚-2-基)-1-苯基-1H-吲哚-3-甲醛(180mg,87%产率),为白色固体。
MS:319(M+H);NMR(CDCl3):10.30(1H,s),8.28(1H,d),7.45-7.63(3H,m),7.40(2H,d),7.23(1H,d),7.14(1H,t),6.96(1H,d),3.20-3.37(4H,m),2.70-2.80(4H,m).
实施例22
2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吲哚-3-甲醛
步骤1:4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-[1,4]二氮杂环庚烷-1-甲酸叔丁酯:
如实施例1所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与[1,4]二氮杂环庚烷-1-甲酸叔丁酯反应,得到4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-[1,4]二氮杂环庚烷-1-甲酸叔丁酯(87%产率),为黄色固体。
LC/MS MS 420(M+H);RT 3.55 min;NMR(CDCl3):10.25(1H,s),8.27(1H,d),7.46-7.66(3H,m),7.37(2H,d),7.22-7.30(1H,t),7.16(1H,T),6.96(1H,d),3.25-3.45(8H,m),1.56(2H,m),1.44(9H,s).
步骤2:2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吲哚-3-甲醛:
将4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-[1,4]二氮杂环庚烷-1-甲酸叔丁酯(1.06g,2.53mmol)和三氟乙酸(10mL)在二氯甲烷(4mL)中的溶液于室温搅拌过夜。将溶剂蒸发并将残余物溶于二氯甲烷(10mL),用5%碳酸钠水溶液、水、盐水洗涤,干燥、过滤并浓缩。经色谱法纯化残余物,用二氯甲烷与5至10%甲醇洗脱。将含有产物的级分合并和浓缩,得到2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吲哚-3-甲醛(86%产率),为白色固体。
LC/MS:MS 320(M+H);2.5min;NMR(CDCl3)10.30(1H,s),8.25(1H,d),7.03-7.70(7H,m),6.97(1H,d),3.20-3.46(4H,m),2.84(4H,m)1.62(2H,m).
实施例23
2-(4-甲酰基-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛
如实施例1所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与[1,4]二氮杂环庚烷-1-甲醛反应,得到2-(4-甲酰基-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛(97%产率),为黄色固体。
LC/MS:MS 348(M+H);RT2.77min;(CDCl3):10.26(1H,d),8.22(1H,d),8.00(0.5H,s),7.86(0.5H,s),7.47-7.69(3H,m),7.23-7.38(3H,m),7.17(1H,t),6.97(1H,d),3.25-3.70(8H,m),1.50-1.73(2H,m).
实施例24
2-[4-(2-羟基乙基)二氮杂环庚-1-基]-1-苯基-1H-吲哚-3-甲醛
如实施例1所述,使2-氯-1-苯基-1H-吲哚-3-甲醛溶液与2-[1,4]二氮杂环庚-1-基-乙醇反应,得到2-[4-(2-羟基乙基)二氮杂环庚-1-基]-1-苯基-1H-吲哚-3-甲醛(20%产率),为白色固体。
LC/MS:346(M+H);RT 2.77min;NMR(CDCl3):7.66(1H,d),7.38-7.60(5H,m),7.00-7.18(3H,m),6.36(1H,s),3.96(2H,s),3.84(2H,m),3.61(2H,m),3.10(2H,m),2.60(2H,m),1.56-2.20(4H,m).
实施例25
2-(4-环氧乙烷基甲基-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛
将2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吲哚-3-甲醛(438mg,1.37mmol)、表溴醇(188mg,1.37mmol)和碳酸钾(758mg,5.49mmol)在乙腈(20mL)中的溶液回流2.5小时。将反应混合物冷却,除去溶剂并经色谱法纯化残余物,用二氯甲烷与1至5%甲醇洗脱。将含有产物的级分合并和浓缩,得到2-(4-环氧乙烷基甲基-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛(41%产率),为黄色固体。
LC/MS:376(M+H),RT 2.65 min;NMR(CDCl3):10.28(1H,s),8.26(1H,d),7.43-7.65(3H,m),7.17-7.42(3H,m),7.13(1H,t),6.96(1H,d),3.49(4H,m),3.03(1H,m),2.56-2.86(4H,m),2.30-2.50(2H,m),1.74(2H,m),1.56(2H,s).
实施例26
2-(5-氧代-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛
如实施例1所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与[1,4]二氮杂环庚烷-5-酮反应,得到2-(5-氧代-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛(35%产率),为黄色固体。
LC/MS:MS 334(M+H);RT 2.64min;NMR(CDCl3):10.26(1H,d),8.21(1H,d),7.52-7.69(3H,m),7.37(2H,m),7.28(1H,t),7.17(1H,t),6.98(1H,d),3.41(4H,m),3.20(2H,m),2.45(2H,m).
实施例27
2-咪唑-1-基-1-苯基-1H-吲哚-3-甲醛
如实施例1所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与咪唑反应,得到2-咪唑-1-基-1-苯基-1H-吲哚-3-甲醛(12%产率),为白色固体。
LC/MS:288(M+H);RT 2.55min;NMR(CDCl3):9.94(1H,s),8.45(1H,d),7.63(1H,s),7.35-7.54(6H,m),7.17-7.29(2H,m),7.12(1H,s),7.03(1H,s).
实施例28
1-苯基-2-[1,4,7]三氮杂环辛-1-基-1H-吲哚-3-甲醛
如实施例1所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与[1,4,7]三氮杂环辛烷反应,得到1-苯基-2-[1,4,7]三氮杂环辛-1-基-1H-吲哚-3-甲醛(37%产率),为黄色固体。
LC/MS:321(M+H-H2O);RT 2.96min;NMR(CDCl3):7.37(1H,d),7.18-7.30(3H,m),7.13(1H,t),6.97(2H,d),6.90(1H,t),6.79(1H,t),2.76-3.10(12H,m).
实施例29
1-(4-叔丁基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛
步骤1:1-(4-叔丁基-苯基)-2-氯-1H-吲哚-3-甲醛:
将2-氯-1H-吲哚-3-甲醛(2.2g,12.25mmol)、4-叔丁基苯基硼酸(4.36g,24.49mmol)、乙酸酮(4.45g,24.50mmol)、4分子筛(2.5g)、吡啶(3.0mL)和二氯甲烷(40mL)的混合物于室温搅拌过夜。用二氯甲烷(100mL)稀释该反应混合物,用水(50mL)、3N盐酸水溶液(10mL)洗涤,过滤除去沉淀,再次用水(50mL)、碳酸氢钠水溶液、盐水洗涤二氯甲烷层,干燥并过滤。浓缩滤液,得到固体。将该粗产物从二氯甲烷-甲醇中结晶,得到1-(4-叔丁基苯基)-2-氯-1H-吲哚-3-甲醛(3.09g,81%产率),为黄色固体。TLC(硅胶,20%乙酸乙酯/庚烷)
Rf=0.50;ESI/MS 312(M+H),RT 4.32min;NMR:10.12(1H,s);8.20(1H,d,J=6Hz);7.71(2H,d);7.53(2H,d);7.38(2H,m);7.11(1H,d);1.38(9H,s).
步骤2:1-(4-叔丁基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛:
将1-(4-叔丁基苯基)-2-氯-1H-吲哚-3-甲醛(2.95g,9.46mmol)、哌嗪(10.60g,123mmol)在二烷(50mL)中的混合物于110℃加热过夜。加入水并用乙酸乙酯萃取该反应混合物。将所合并的乙酸乙酯层用盐水洗涤,干燥并浓缩。经色谱法纯化该粗产物,用二氯甲烷-5%甲醇洗脱。将含有产物的级分合并和浓缩,得到1-(4-叔丁基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛(2.4g,70%产率),为浅乳色固体。TLC(硅胶,二氯甲烷-10%甲醇)
Rf=0.27;ESI/MS 362(M+H),RT 3.27min;NMR 10.14(1H,s);8.12(1H,d,J=3Hz);8.09(2H,d);7.68(2H,d);7.47(2H,m);6.91(1H,d,J=6Hz);3.20(4H,m);2.53(4H,m);2.25(1H,br s);1.36(9H,s).
实施例30
1-(4-叔丁基苯基)-2-[4-(2-羟基乙基)哌嗪-1-基]-1H-吲哚-3-甲醛
将1-[(4-叔丁基苯基)-2-哌嗪-1-基]-1H-吲哚-3-甲醛(1.3g,3.60mmol)、2-溴乙醇(600mg,4.80mmol)、碳酸钾(2.0g,14.50mmol)和乙腈(30mL)的混合物回流60小时。再加入2-溴乙醇(0.5mL)并继续回流25小时。将冷却后的反应混合物溶于水并用乙酸乙酯萃取(3次)。将所合并的乙酸乙酯层用盐水洗涤,干燥和浓缩。经色谱法纯化残余物,用乙酸乙酯与5%至10%甲醇洗脱。将含有产物的级分合并和浓缩,得到1-(4-叔丁基苯基)-2-[4-(2-羟基乙基)哌嗪-1-基]-1H-吲哚-3-甲醛(1.2g,82%产率),为浅黄色固体。TLC(硅胶,二氯甲烷-10%甲醇)
Rf=0.23;ESI/MS 406(M+H),RT=3.22min;1H NMR 10.13(1H,s);8.11(1H,d,J=6Hz);7.66(2H,d,J=9Hz);7.44(2H,d,J=6Hz);7.19(2H,m);6.91(1H,d,6Hz);4.39(1H,t);3.47(2H,q);3.26(4H,br t);2.34(6H,br m);1.36(9H,s).13C NMR 183.17;156.49;151.24;135.68;134.03;127.34;126.58;125.16;122.56;119.97;109.63;105.70;60.18;58.35;52.75;51.50;34.56;31.08.
实施例31
磷酸2-{4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-基}-乙基
酯二乙基酯盐酸盐
步骤1:磷酸2-{4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-基}-乙基酯二乙基酯:
将氯代磷酸二乙酯(0.22mL,1.52mmol)加入1-(4-叔丁基苯基)-2-[4-(2-羟基乙基)哌嗪-1-基]-1H-吲哚-3-甲醛(510mg,1.26mmol)和三乙胺(0.35mL,2.49mmol)在四氢呋喃(5mL)中的溶液中。将生成的橙色溶液于室温搅拌过夜。加入水并用乙酸乙酯萃取该混合物。将所合并的乙酸乙酯层用水、盐水洗涤,干燥和浓缩,得到油状产物,经色谱法纯化,用乙酸乙酯和乙酸乙酯-5%甲醇洗脱,得到磷酸2-{4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-基}-乙基酯二乙基酯(280mg,68%产率),为白色粉末。
ESI/MS 542(M+H)Rt=3.52min;1H NMR 10.13(1H,s);8.11(1H,d,J=6Hz);7.66(2H,d,J=6Hz);7.46(2H,d,J=9Hz);7.19(2H,m);6.92(1H,d,9Hz);4.04(6H,m);3.33(2H,br s);3.26(4H,br s);2.49(4H,br s);1.36(9H,s);1.30(6H,t).
步骤2:磷酸2-{4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-基}-乙基酯二乙基酯盐酸盐:
将磷酸2-{4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-基}-乙基酯二乙基酯(90mg,0.166mmol)溶于甲醇并用1M含醚盐酸处理。将溶剂除去一半并与乙醚一起研磨,得到磷酸2-{4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-基}-乙基酯二乙基酯盐酸盐(85mg,89%产率),为固体。
ESI/MS 542(M+H),RT=3.52min;1H NMR 10.06(1H,s);8.11(1H,d,J=6Hz);7.69(2H,d,J=9Hz);7.51(2H,d,J=6Hz);7.24(2H,m);6.96(1H,d,J=6Hz);4.33(2H,br s);4.10(4H,q);3.68(2H,br s);3.39(6H,br s);3.03(2H,br s);1.37(9H,s);1.27(6H,t);13C NMR 229.09;209.60;197.36;184.62;183.17;154.06;151.49;135.32;133.45;127.20;126.81;124.98;122.94;119.71;113.77;109.99;109.53;106.00;63.72;63.65;51.36;48.00;34.59;31.06;15.97;15.88.
实施例32
1-(4-叔丁基苯基)-2-(4-甲基-哌嗪-1-基)-1H-吲哚-3-甲醛
如实施例29的步骤2所述,使1-(4-叔丁基苯基)-2-氯-1H-吲哚-3-甲醛与1-甲基哌嗪反应,得到1-(4-叔丁基苯基)-2-(4-甲基-哌嗪-1-基)-1H-吲哚-3-甲醛为浅棕色固体。TLC(硅胶,乙酸乙酯-16.5%甲醇-0.8% 7N 甲醇铵);
Rf=0.23;ESI/MS 376(M+H),RT=3.4min;NMR 10.14(1H,s);8.12(1H,d,J=9Hz);7.67(2H,d);7.45(2H,d);7.19(2H,m);6.92(1H,d,J=6Hz);3.26(4H,m);2.18(7H,m);1.37(9H,s).
实施例33
1-(4-叔丁基苯基)-2-哌啶-1-基-1H-吲哚-3-甲醛
如实施例29的步骤2所述,使1-(4-叔丁基苯基)-2-氯-1H-吲哚-3-甲醛与哌啶反应,得到1-(4-叔丁基苯基)-2-哌啶-1-基-1H-吲哚-3-甲醛(87%产率),为灰白色固体。TLC(硅胶,庚烷-30% 乙酸乙酯);
Rf=0.23;ESI/MS 361(M+H);RT=4.48min;NMR 10.14(1H,s);8.11(1H,d,J=6Hz);7.66(2H,d);7.46(2H,d);7.16(2H,m);6.91(1H,d,J=9Hz);3.27(4H,m);1.46(6H,m);1.36(9H,s).
实施例34
1-(4-叔丁基苯基)-2-[(2-二甲基氨基乙基)-甲基氨基]-1H-吲哚-3-甲醛
如实施例29的步骤2所述,使1-(4-叔丁基苯基)-2-氯-1H-吲哚-3-甲醛与N,N,N’-三甲基乙二胺反应,得到1-(4-叔丁基苯基)-2-[(2-二甲基氨基乙基)-甲基氨基]-1H-吲哚-3-甲醛(42%产率),为浅褐色固体。TLC(硅胶,7NNH3的甲醇/MeOH/乙酸乙酯(0.1∶2∶10mL)溶液)Rf=0.29。ESI/MS 378(M+H);
RT=3.43min.NMR10.18(1H,s);8.10(1H,d,J=9Hz);7.66(2H,d);7.48(2H,d);7.17(1H,t);7.08(1H,t);6.88(1H,d,J=9Hz);3.21(2H,t);3.02(3H,s);2.18(2H,t);2.00(6H,t);1.36(9H,s).
实施例35
1-(4-叔丁基苯基)-2-(2-二甲基氨基乙基氨基)-1H-吲哚-3-甲醛
如实施例29的步骤2所述,使1-(4-叔丁基苯基)-2-氯-1H-吲哚-3-甲醛与N,N-二甲基乙二胺反应,得到1-(4-叔丁基苯基)-2-(2-二甲基氨基乙基氨基)-1H-吲哚-3-甲醛(26%产率),为浅褐色固体。
ESI/MS 364(M+H);RT=3.39min.NMR 9.94(1H,s);7.84(1H,br s);7.67(2H,d);7.48(2H,d,J=9Hz);7.10(1H,t);6.98(1H,t);6.66(1H,d,J=9Hz);3.05(2H,brs);2.30(2H,BR t);2.03(6H,S);1.36(9H,s).
实施例36
4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]哌嗪-1-甲酸叔丁酯
如实施例29的步骤2所述,使1-(4-叔丁基苯基)-2-氯-1H-吲哚-3-甲醛与1-叔丁氧羰基哌嗪反应,得到4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]哌嗪-1-甲酸叔丁酯(70%产率),为浅黄色固体。TLC(庚烷-30%乙酸乙酯)
Rf=0.19;ESI/MS 462(M+H);RT=4.42min.;NMR10.13(1H,s);8.13(1H,d,J=9Hz);7.68(2H,d);7.49(2H,d);7.21(2H,m);6.95(1H,d,J=9Hz);3.20(8H,m);1.37(18H,s).
实施例37
5-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-2,5-二氮杂双环[2.2.1]庚
烷-2-甲酸叔丁酯
如实施例29的步骤2所述,使1-(4-叔丁基苯基)-2-氯-1H-吲哚-3-甲醛与(1S,4S)-2-叔丁氧羰基-2,5-二氮杂双环[2.2.1]庚烷反应,得到5-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(66%产率),为绿色固体。TLC(庚烷-30%乙酸乙酯)
Rf=0.07.ESI/MS 418(M-C(CH3)3),474(M+H);RT=4.16min;NMR 10.02(1H,s);8.18(1H,d,J=6Hz);7.63(4H,br m);7.13(2H,m);6.66(1H,d,J=9Hz);4.75(1H,br s);4.30(1H,br s);3.28(2H,br m);3.08(2H,brm);1.99(2H,br s);1.35(18H,2峰重叠).
实施例38
1-(4-叔丁基-苯基)-2-(2-甲基-吖丙啶-1-基)-1H-吲哚-3-甲醛
在氮气氛围中将1-(4-叔丁基苯基)-2-氯-1H-吲哚-3-甲醛(100mg,0.321mmol)、Pd2(dba)3(15mg,0.016mmol)、2,2’-双(二苯基膦基)-1,1’-联萘(BINAP)(20mg,0.032mmol)和叔丁醇钠(46mg,0.479mmol)加入侧管试管中。在其中加入甲苯(3.0mL)、2-甲基氮丙啶(37mg,0.678mmol)的甲苯(1.0mL)溶液,将生成的混合物于80℃搅拌过夜。将反应物冷却,加入水并用乙酸乙酯萃取该混合物。将所合并的乙酸乙酯层用水、盐水洗涤,以硫酸钠干燥,过滤并将溶剂浓缩,得到油状产物,经色谱法纯化,用庚烷与5至30%乙酸乙酯洗脱。将含有产物的级分合并和浓缩,得到1-(4-叔丁基-苯基)-2-(2-甲基-吖丙啶-1-基)-1H-吲哚-3-甲醛(70mg,66%产率),为黄色固体。TLC(庚烷-30%乙酸乙酯)
Rf=0.20;ESI/MS 333(M+H);RT=4.15min;NMR 10.16(1H,s);8.08(1H,d,J=6Hz);7.70(2H,d,J=9Hz);7.49(2H,d,9Hz);7.21(2H,m);6.91(1H,d,J=9Hz);2.43(2H,m);2.28(1H,d);1.38(9H,s);0.79(3H,d,J=6Hz).
实施例39
1-(4-叔丁基苯基)-2-(2-吡咯烷-1-基-乙基氨基)-1H-吲哚-3-甲醛盐酸盐
如实施例29的步骤2所述,使1-(4-叔丁基苯基)-2-氯-1H-吲哚-3-甲醛与1-(2-氨基乙基)吡咯烷反应得到油。将此油溶于少量甲醇并用1M含醚盐酸处理。除去溶剂并将残余物与乙醚一起研磨,得到1-(4-叔丁基苯基)-2-(2-吡咯烷-1-基-乙基氨基)-1H-吲哚-3-甲醛盐酸盐(20%产率),为浅米黄色固体。
ESI/MS 390(M+H);RT=3.42min.NMR 10.68(1H,s);7.95(1H,d,J=9Hz);7.67(2H,d,J=9Hz);7.47(2H,d,J=9Hz);7.10(2H,m);6.63(1H,d,J=9Hz);3.54(2H,m);3.40(2H,m);3.21(2H,m);2.83(2H,m);1.91(4H,m);1.35(9H,s).
实施例40
4-(3-甲酰基-1-苯基-1H-吲哚-2-基)哌嗪-1-甲酸叔丁酯
如实施例29的步骤2所述,使2-氯-1H-吲哚-3-甲醛与叔丁基-1-哌嗪甲酸酯反应,得到4-(3-甲酰基-1-苯基-1H-吲哚-2-基)哌嗪-1-甲酸叔丁酯(43%产率),为黄色固体。
ESI/MS 300(M),306[M-CO2C(CH3)3],350[M-C(CH3)3],406(M+H);RT=3.89min;NMR 10.15(1H,s);8.14(1H,d,J=9Hz);7.69(5H,m);7.22(2H,m);6.94(1H,d,J=9Hz);3.22(8H,2brm);1.37(9H,s).
实施例41
2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛盐酸盐
步骤1:2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛:
如实施例30所述,使1-苯基-2-哌嗪-1-基-1H-吲哚-3-甲醛与溴乙醇反应,得到2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛(87%产率),为黄色固体。TLC(乙酸乙酯-10%甲醇)
Rf=0.13;ESI/MS 350(M+H);RT=2.67min;NMR 10.16(1H,s);8.13(1H,d,J=6Hz);7.68(5H,m);7.20(2H,m);6.91(1H,d,J=6Hz);4.39(1H,t);3.47(2H,q);3.2(4H,m);2.34(6H,m).
步骤2:2-[4-(2-羟基乙基)-哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛盐酸盐:
将2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛溶于甲醇并用1M含醚盐酸处理。搅拌30min后,除去溶剂并将残余物溶于少量甲醇,用乙醚处理,沉淀出2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛盐酸盐(85%产率),为乳色固体。
ESI/MS 350(M+H);RT=2.32min;NMR 10.15(1H,s);8.13(1H,d,9Hz);7.70(5H,m);7.25(2H,m);6.96(1H,d,J=6Hz);5.31(1H,br s);3.73(2H,br s);3.56(6H,br m);3.17(2H,br s);2.97(2H,br s).
实施例42
磷酸2-[4-(3-甲酰基-1-苯基-1H-吲哚-2-基)哌嗪-1-基]乙基酯二乙基酯
盐酸盐
步骤1:磷酸二乙基酯2-[4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-哌嗪-1-基]-乙基酯:
如实施例31的步骤1所述,使2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛与氯代磷酸二乙酯反应,得到磷酸二乙基酯2-[4-(3-甲酰基-1-苯基-1H-吲哚-2-基)哌嗪-1-基]乙基酯(71%产率),为黄色固体。
ESI/MS 486(M+H);RT=2.94min;NMR 10.15(1H,s);8.13(1H,d,J=9Hz);7.68(5H,m);7.20(2H,m);6.91(1H,d,J=6Hz),4.04(6H,m);3.28(6H,m);2.49(4H,br s);1.23(6H,t).
步骤2:磷酸二乙基酯2-[4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-哌嗪-1-基]-乙基酯盐酸盐:
如实施例31的步骤2所述,用1M含醚盐酸处理磷酸二乙基酯2-[4-(3-甲酰基-1-苯基-1H-吲哚-2-基)哌嗪-1-基]乙基酯,得到磷酸二乙基酯2-[4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-哌嗪-1-基]-乙基酯盐酸盐(54%产率),为粉红色粉末。
ESI/MS 486(M+H);RT=2.52min:NMR 10.15(1H,s);8.13(1H,d,J=6Hz);7.70(5H,m);7.24(2H,m);6.96(1H,d,J=9Hz);4.30(2H,br s);4.07(6H,m);3.59(8H,br m);1.27(6H,t).
实施例43
2-(吗啉-4-基)-1-苯基-1H-吲哚-3-甲醛
如实施例29的步骤2所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与吗啉反应,得到2-(吗啉-4-基)-1-苯基-1H-吲哚-3-甲醛(88%产率),为松散乳色固体。
ESI/MS 307(M+H);RT=2.99min;NMR 10.15(1H,s);8.14(1H,d,J=6Hz);7.69(5H,m);7.22(2H,m);6.94(1H,d,J=9Hz);3.45(4H,m);3.28(4H,m).
实施例44
2-(3,5-二甲基哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛盐酸盐
如实施例29的步骤2所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与2,6-二甲基哌嗪反应,得到2-(3,5-二甲基哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛,为固体。将该固体溶于甲醇,用1M含醚盐酸处理并浓缩。将残余物与乙醚一起研磨,得到2-(3,5-二甲基哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛盐酸盐(74%产率),为紫色固体。ESI/MS 334(M+H);RT=2.52min.
实施例45
5-(3-甲酰基-1-苯基-1H-吲哚-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸
叔丁酯
如实施例29的步骤2所述,使2-氯-1-苯基-1H-吲哚-3-甲醛与(1S,4S)-2-叔丁氧羰基-2,5-二氮杂双环[2.2.1]庚烷反应,得到5-(3-甲酰基-1-苯基-1H-吲哚-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(98%产率),为紫色固体。TLC(庚烷-50%乙酸乙酯)
Rf=0.46;NMR 10.27(1H,s);8.26(1H,d,J=9Hz);7.62(3H,m);7.41(2H,d);7.24(1H,m);7.18(1H,t);6.99(1H,d,J=9Hz);3.32(8H,2broad s peaks);1.44(9H,s).
实施例46
1-(3-甲酰基苯基)-2-(哌嗪-2-基)-1H-吲哚-3-甲醛
步骤1:2-氯-1-(3-甲酰基苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与3-甲酰基苯基硼酸反应,得到2-氯-1-(3-甲酰基苯基)-1H-吲哚-3-甲醛(99%产率),为白色固体。
ESI/MS 284(M+H);RT=3.37min;NMR10.15(1H,s);10.12(1H,s);8.23(3H,m);7.98(2H,m);7.41(2H,m);7.18(1H,d,J=9Hz).
步骤2:1-(3-甲酰基苯基)-2-(哌嗪-2-基)-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使2-氯-1-(3-甲酰基苯基)-1H-吲哚-3-甲醛与哌嗪反应,得到1-(3-甲酰基苯基)-2-(哌嗪-2-基)-1H-吲哚-3-甲醛(59%产率),为乳色固体。ESI/MS 334(M+H);RT=2.29min.
实施例47
1-(联苯-4-基)-2-哌嗪-1-基-1H-吲哚-3-甲醛盐酸盐
步骤1:1-联苯-4-基-2-氯-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与4-联苯基硼酸反应,得到1-联苯-4-基-2-氯-1H-吲哚-3-甲醛(52%产率),为黄色固体。
ESI/MS 332(M+H),RT=4.14min;NMR10.15(1H,s);8.23(1H,d,J=9Hz);7.99(2H,d,J=9Hz);7.82(2H,d,J=9Hz);7.69(7H,m);7.54(1H,m).
步骤2:1-(联苯-4-基)-2-哌嗪-1-基-1H-吲哚-3-甲醛盐酸盐:
如实施例29的步骤2所述,使1-(联苯-4-基)-2-氯-1H-吲哚-3-甲醛与哌嗪反应,随后如实施例44所述用盐酸处理,得到1-(联苯-4-基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐(44%产率),为乳色固体。ESI/MS 382(M+H),RT=2.87min.
实施例48
1-(4-乙基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐
步骤1:2-氯-1-(4-乙基苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与4-乙基苯基硼酸反应,得到2-氯-1-(4-乙基-苯基)-1H-吲哚-3-甲醛(73%产率),为浅黄色固体。
ESI/MS 284(M+H);RT=4.04min;NMR 10.12(1H,s);8.20(1H,d,J=9Hz);7.54(4H,m);7.38(2H,m);7.28(1H,d);2.77(2H,q);1.28(3H,t).
步骤2:1-(4-乙基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐:
如实施例29的步骤2所述,使2-氯-1-(4-乙基苯基)-1H-吲哚-3-甲醛与哌嗪反应,随后如实施例44所述用盐酸处理,得到1-(4-乙基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐(39%产率),为乳色固体。
ESI/MS 334(M+H);RT=2.67min;NMR 10.13(1H,s);8.11(1H,d,J=6Hz);7.50(4H,s);7.24(2H,m);6.94(1H,d,J=6Hz);3.42(4H,m);2.95(4H,m);2.76(2H,q);1.30(3H,t).
实施例49
1-(3-溴苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛
步骤1:1-(3-溴苯基)-2-氯-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与3-溴苯基硼酸反应,得到1-(3-溴苯基)-2-氯-1H-吲哚-3-甲醛(87%产率),为乳色固体。ESI/MS 334(M),375[(M+2+CH3CN)加合物];RT=3.59min.
步骤2:1-(3-溴苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使1-(3-溴-苯基)-2-氯-1H-吲哚-3-甲醛与哌嗪反应,得到1-(3-溴苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛(31%产率)。
ESI/MS 384(M),386(M+2);RT=2.70min;NMR(CDCl3)10.31(1H,s);8.28(1H,d,J=9Hz);7.67(2H,m);7.63-7.16(5H,m);7.01(1H,d,J=9Hz);3.31(4H,m);2.82(4H,m).
实施例50
1-(4-甲基-3-硝基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛
步骤1:2-氯-1-(4-甲基-3-硝基苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与4-甲基-3-硝基苯基硼酸反应,得到2-氯-1-(4-甲基-3-硝基苯基)-1H-吲哚-3-甲醛(35%产率),为浅乳色固体。ESI/MS 315(M+H);356[(M+1+CH3CN)加合物];RT=3.35min.
步骤2:1-(4-甲基-3-硝基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使2-氯-1-(4-甲基-3-硝基苯基)-1H-吲哚-3-甲醛与哌嗪反应,得到1-(4-甲基-3-硝基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛(68%产率)。
ESI/MS 365(M+H);RT=2.65min;NMR(CDCl3)10.35(1H,s);8.31(1H,d,J=9Hz);8.11(1H,s);7.61(2H);7.31(2H);7.01(1H,d,J=9Hz);3.31(4H,m);2.88(4H,m);2.74(3H,s).
实施例51
1-(4-二甲基氨基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛
步骤1:2-氯-1-(4-二甲基氨基-苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与(4-二甲基氨基)-苯基硼酸反应,得到2-氯-1-(4-二甲基氨基-苯基)-1H-吲哚-3-甲醛(80%产率),为浅米黄色固体。ESI/MS 299(M+H);RT=3.37min.
步骤2:1-(4-二甲基氨基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使2-氯-1-(4-二甲基氨基苯基)-1H-吲哚-3-甲醛与哌嗪反应,得到1-(4-二甲基氨基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛(51%产率)。
ESI/MS 349(M+H);RT=2.44min;NMR(CDCl3)10.24(1H,s);8.25(1H,d,J=9Hz);7.20(3H,m);7.10(1H,m);6.97(1H,d,J=9Hz);6.83(2H,d);3.29(4H,m);3.05(6H,s);2.82(4H,m).
实施例52
1-(4-苯氧基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛
步骤1:2-氯-1-(4-苯氧基-苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与4-苯氧基苯基硼酸反应,得到2-氯-1-(4-苯氧基苯基)-1H-吲哚-3-甲醛(34%产率),为乳色固体。ESI/MS 348(M+H),389[(M+1+CH3CN)加合物],RT=3.74min.
步骤2:1-(4-苯氧基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使2-氯-1-(4-苯氧基苯基)-1H-吲哚-3-甲醛与哌嗪反应,得到1-(4-苯氧基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛(40%产率)。
ESI/MS 398(M+H);RT=2.95min;NMR(CDCl3)10.28(1H,s);8.28(1H,d,J=9Hz);7.46-7.10(11H,m);7.00(1H,d,J=9Hz);3.31(4H,m);2.81(4H,m).
实施例53
1-(4-甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛
步骤1:2-氯-1-对甲苯基-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与4-甲苯基硼酸反应,得到2-氯-1-(4-甲基苯基)-1H-吲哚-3-甲醛(48%产率),为乳色固体。
ESI/MS 270(M+H),311[(M+1+CH3CN)加合物]:RT=3.55min.
步骤2:1-(4-甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使2-氯-1-(4-甲基苯基)-1H-吲哚-3-甲醛与哌嗪反应,得到1-(4-甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛(29%产率)。
ESI/MS 320(M+H);RT=2.64min;NMR(CDCl3)10.27(1H,s);8.27(1H,d,J=9Hz);7.38-7.15(6H,m);6.96(1H,d,J=6Hz);3.26(4H,m);2.81(4H,m);2.47(3H,s).
实施例54
1-(4-氟苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐
步骤1:2-氯-1-(4-氟苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与4-氟苯基硼酸反应,得到2-氯-1-(4-氟苯基)-1H-吲哚-3-甲醛(84%产率),为乳色固体。
ESI/MS 274(M+H);RT=3.64min;NMR10.12(1H,s);8.20(1H,d,J=6Hz);7.72(2H,m);7.58(2H,m);7.39(2H,m);7.12(1H,d,J=9Hz).
步骤2:1-(4-氟苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐
如实施例29的步骤2所述,使2-氯-1-(4-氟苯基)-1H-吲哚-3-甲醛与哌嗪反应,随后如实施例44所述用盐酸处理,得到1-(4-氟苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐(40%产率),为乳色固体。
ESI/MS 324(M+H);RT=2.44min;NMR 10.15(1H,s);8.13(1H,d,J=9Hz);7.71(2H,m);7.54(2H,m);7.23(2H,m);6.95(1H,d,J=9Hz);3.33(4H,br s);2.95(4H,br s).
实施例55
1-(3-氯苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛
步骤1:2-氯-1-(3-氯苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与3-氯苯基硼酸反应,得到2-氯-1-(3-氯苯基)-1H-吲哚-3-甲醛(70%产率),为乳色固体。
ESI/MS 290(M+H);RT=3.55min;NMR10.13(1H,s);8.21(1H,d);7.84(1H,d);7.74(3H,m);7.38(2H,m);7.16(1H,d,J=9Hz).
步骤2:1-(3-氯苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使2-氯-1-(3-氯苯基)-1H-吲哚-3-甲醛与哌嗪反应,得到1-(3-氯苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛(64%产率),为乳色固体。ESI/MS 340(M+H);RT=2.66min.
实施例56
2-(哌嗪-1-基)-1-(4-乙烯基苯基)-1H-吲哚-3-甲醛
步骤1:2-氯-1-(4-乙烯基苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与4-乙烯基苯基硼酸反应,得到2-氯-1-(4-乙烯基苯基)-1H-吲哚-3-甲醛(28%产率),为灰白色固体。
ESI/MS 282(M+H);RT=3.59min;NMR10.22(1H,s);8.36(1H,d,J=6Hz);7.65(2H,d);7.37(5H,m);6.87(1H,dd);5.92(1H,d,J=18Hz);5.45(1H,d,J=12Hz).
步骤2:2-(哌嗪-1-基)-1-(4-乙烯基苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使2-氯-1-(4-乙烯基苯基)-1H-吲哚-3-甲醛与哌嗪反应,得到2-(哌嗪-1-基)-1-(4-乙烯基苯基)-1H-吲哚-3-甲醛(44%产率),为黄色固体。
ESI/MS 332(M+H),RT=2.57min;NMR(CDCl3)10.29(1H,s);8.28(1H,d,J=6Hz);7.62(2H,d,J=6Hz);7.38(4H,m);7.00(1H,d,J=9Hz);6.85(1H,dd);5.89(1H,d,J=15Hz);5.42(1H,d,J=18Hz);3.38(4H,m);2.77(4H,m).
实施例57
1-(3-羟基甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛
步骤1:2-氯-1-(3-羟基甲基苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与3-(羟基甲基)-苯基硼酸反应,得到2-氯-1-(3-羟基甲基苯基)-1H-吲哚-3-甲醛(17%产率),为粉红色固体。ESI/MS 286(M+H);RT=2.85min.
步骤2:1-(3-羟基甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛
如实施例29的步骤2所述,使2-氯-1-(3-羟基甲基苯基)-1H-吲哚-3-甲醛与哌嗪反应,得到1-(3-羟基甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛(32%产率),为红色固体。ESI/MS 336(M+H);RT=2.37min.
实施例58
1-(3-乙氧基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛
步骤1:2-氯-1-(3-乙氧基苯基)-1H-吲哚-3-甲醛:
如实施例29的步骤1所述,使2-氯-1H-吲哚-3-甲醛与4-乙氧基苯基硼酸反应,得到2-氯-1-(4-乙氧基苯基)-1H-吲哚-3-甲醛(37%产率),为灰白色固体。ESI/MS 300(M+H);RT=3.56min.
步骤2:1-(3-乙氧基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使2-氯-1-(3-乙氧基苯基)-1H-吲哚-3-甲醛与哌嗪反应,得到1-(3-乙氧基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛(37%产率),为浅黄色固体。
ESI/MS 350(M+H);RT=2.69min;NMR(CDCl3)10.26(1H,s);8.26(1H,d,J=6Hz);7.28(3H,m);7.21(3H,m);6.95(1H,d,J=9Hz);4.15(2H,q);3.29(4H,m);2.79(4H,m);1.49(3H,t).
实施例59
1-苯磺酰基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛
步骤1:1-苯磺酰基-2-氯-1H-吲哚-3-甲醛:
标题化合物按照O.Olton等人,Tetrahedron,54(1998),13915-13928中所述步骤如下制备。将氢氧化钠加入搅拌中的2-氯-1H-吲哚-3-甲醛(239mg,1.33mmol)的乙醇(10mL)溶液中。于2hr后,除去溶剂,将固体残余物溶于丙酮并用苯磺酰氯(0.25mL,1.96mmol)处理。不久沉淀出固体。于室温搅拌1.5hr后,将反应混合物回流加热1.5小时。冷却后,加入水并用二氯甲烷萃取反应物。将所合并的二氯甲烷层用盐水洗涤,用硫酸钠干燥并浓缩至油状物,经色谱法纯化,用庚烷与0至10%乙酸乙酯洗脱。将含有产物的级分合并和浓缩,得到1-苯磺酰基-2-氯-1H-吲哚-3-甲醛(70mg,17%产率),为黄色固体。
MS 320(M+H);NMR 10.09(1H,s);8.26(1H,d,J=9Hz);8.15(3H,m);7.85(3H,M);7.56(2H,m).
步骤2:1-苯磺酰基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使1-苯磺酰基-2-氯-1H-吲哚-3-甲醛与哌嗪反应,得到1-苯磺酰基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛(45%产率)。
ESI/MS 370(M+H);RT=2.59min.
实施例60
2-(哌嗪-1-基)-1-(吡啶-2-基)-1H-吲哚-3-甲醛
步骤1:2-氯-1-吡啶-2-基-1H-吲哚-3-甲醛:
标题化合物按照Andreani,A.等人,J.Med.Chem.
20,(1977)1344-1346中所述步骤如下制备。于0℃向二甲基甲酰胺(0.50mL)和二氯甲烷(0.50mL)的混合物中加入磷酰氯(0.50mL)。搅拌15min后,加入1-(吡啶-2-基)-1,3-二氢吲哚-2-酮(Le Baunt,G.等人,EP 0580502)(250mg,1.2mmol)在二氯甲烷(2.0mL)和吡啶(0.25mL)中的溶液,将生成的深红色溶液搅拌36小时。将反应混合物倒入冰水中并用二氯甲烷萃取。将所合并的有机层用水、饱和碳酸氢钠、盐水洗涤,用硫酸钠干燥,过滤并浓缩。将深色残余物经色谱法纯化,用二氯甲烷与0至3%甲醇洗脱。将含有产物的级分合并和浓缩,得到2-氯-1-(吡啶-2-基)-1H-吲哚-3-甲醛(70mg,23%产率),为米黄色固体。TLC(二氯甲烷)Rf=0.18;
ESI/MS 257(M+H);RT=2.99min;NMR 10.16(1H,s);8.79(1H,d);8.25(2H,m);7.84(1H,d,J=9Hz);7.73(1H,m);7.40(3H,m).
步骤2:2-(哌嗪-1-基)-1-(吡啶-2-基)-1H-吲哚-3-甲醛:
如实施例29的步骤2所述,使2-氯-1-(吡啶-2-基)-1H-吲哚-3-甲醛与哌嗪反应,得到2-(哌嗪-1-基)-1-(吡啶-2-基)-1H-吲哚-3-甲醛(72%产率),为橙色固体。
ESI/MS 307(M+H);RT=2.23min;NMR10.30(1H,s);8.75(1H,m);8.26(1H,d,J=9Hz);7.98(1H,m);7.46(5H,m);3.30(4H,m);2.81(4H,m).
实施例61
1-(4-丁基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐
如实施例29的步骤2所述,使1-(4-丁基苯基)-2-氯-1H-吲哚-3-甲醛与哌嗪反应,随后如实施例44所述用盐酸处理,得到1-(4-丁基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐(46%产率),为乳色固体。
ESI/MS 362(M+H);RT=3.02min;NMR 10.13(1H,s);8.12(1H,d,J=9Hz);7.48(4H,s);7.21(2H,m);6.94(1H,d,J=9Hz);3.41(4H,br m);2.97(4H,br m);2.74(2H,t);1.64(2H,p);137(2H,m);0.97(3H,t).
实施例62
N-{3-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]苯基}-乙酰胺盐酸盐
如实施例29的步骤2所述,使N-[3-(2-氯-3-甲酰基-吲哚-1-基)苯基]-乙酰胺与哌嗪反应,随后如实施例44所述用盐酸处理,得到N-{3-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]苯基}-乙酰胺盐酸盐(37%产率),为乳色固体。ESI/MS 363(M+H);RT=2.2min.
实施例63
4-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]-苄腈
如实施例29的步骤2所述,使4-(2-氯-3-甲酰基吲哚-1-基)-苄腈与哌嗪反应,得到4-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]-苄腈,为浅褐色固体。
ESI/MS 331(M+H);NMR(CDCl3)10.35(1H,s);8.31(1H,d,J=9Hz);7.92(2H,d);7.60(2H,d);7.31(3H,m);6.99(1H,d,J=9Hz);3.28(4H,m);2.79(4H,m).
实施例64
4-[3-甲酰基-1-(4-碘苯基)-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯
如实施例29的步骤2所述,使2-氯-1-(4-碘苯基)-1H-吲哚-3-甲醛与哌嗪反应,得到4-[3-甲酰基-1-(4-碘苯基)-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯(33%产率),为浅褐色固体。TLC(庚烷-30%乙酸乙酯)Rf=0.25
;NMR(CDCl3)10.28(1H,s);8.26(1H,d,J=9Hz);7.92(2H,d,J=9Hz);7.26(4H,m);6.98(1H,d,J=9Hz);3.36(4H,m);3.25(4H,m);1.46(9H,s).
实施例65
4-[1-(4’-氰基联苯-4-基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯
将4-[3-甲酰基-1-(4-碘苯基)-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯(294mg,0.553mmol)和Pd(PPh3)4(32mg,0.0277mmol)的混合物置入侧管试管并通入N2。加入四氢呋喃(6.0mL)和1M碳酸钾水溶液(0.6mL),再加入4-氰基苯硼酸(122mg,0.830mmol)的THF(2.0mL)溶液。于70℃搅拌8hr后,将反应物冷却,再溶于乙酸乙酯,用水(2×10mL)、盐水洗涤,用硫酸钠干燥,过滤并浓缩。经色谱法纯化残余物,用庚烷与10至40%乙酸乙酯洗脱。将含有产物的级分合并和浓缩,得到4-[1-(4’-氰基联苯-4-基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯,为黄色固体。TLC(庚烷-30%乙酸乙酯);RT=0.13
;ESI/MS 451[M-C(CH3)3];NMR(CDCl3)10.30(1H,s);8.28(1H,d,J=9Hz);7.84(6H,m);7.55(2H,d);7.29(3H,m);3.34(8H,m);1.44(9H,s).
实施例66
4-{1-[4-(叔丁氧羰基-1H-吡咯-2-基)-苯基]-3-甲酰基-1H-吲哚-2-基}-哌嗪-1-
甲酸叔丁酯
如实施例66所述,使4-[3-甲酰基-1-(4-碘苯基)-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯与1-(叔丁氧羰基)吡咯-2-硼酸反应,得到4-{1-[4-(叔丁氧羰基-1H-吡咯-2-基)-苯基]-3-甲酰基-1H-吲哚-2-基}-哌嗪-1-甲酸叔丁酯,为米黄色固体(56%产率)。
ESI/MS 571(M+1),515[M-C(CH3)3];NMR(CDCl3)10.28(1H,s);8.27(1H,d,J=6Hz);7.59(2H,d);7.41(6H,m);6.32(2H,m);3.36(8H,m);1.46(9H,s);1.44(9H,s).
实施例67
2-哌嗪-1-基-1-[(4-吡啶-4-基)苯基]-1H-吲哚-3-甲醛
步骤1:4-[3-甲酰基-1-[(4-吡啶-4-基)-苯基]-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯:
如实施例65所述,使4-[3-甲酰基-1-(4-碘苯基)-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯与4-吡啶基硼酸反应,得到4-[3-甲酰基-1-[(4-吡啶-4-基)-苯基]-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯(70%产率),为黄色固体。
ESI/MS 483(M+1);NMR(CDCl3)10.30(1H,s);8.76(2H,d);8.28(1H,d,J=6Hz);7.89(2H,d,J=9Hz);7.64(5H,m);7.20(2H,m);3.36(8H,m);1.58(9H,s).
步骤2:2-哌嗪-1-基-1-[(4-吡啶-4-基)苯基]-1H-吲哚-3-甲醛:
将4-[3-甲酰基-1-[(4-吡啶-4-基)苯基]-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯(68mg,0.141mmol)溶于二氯甲烷(1mL),用三氟乙酸(2mL)处理并于室温搅拌2小时。除去溶剂,将生成的油溶于水,用20%氢氧化钠水溶液调节为碱性pH约为7~8,并用二氯甲烷萃取。将所合并的有机层用盐水洗涤并用硫酸钠干燥,过滤并浓缩。经色谱法纯化残余物,用二氯甲烷与0至10%甲醇洗脱,得到2-哌嗪-1-基-1-[(4-吡啶-4-基)苯基]-1H-吲哚-3-甲醛(46mg,85%),为浅褐色固体。ESI/MS 383(M+1)。
实施例68
2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛;三氟乙酸盐
步骤1:4-(3-甲酰基-1-苯基-1H-吡咯并[2,3-b]吡啶-2-基)-[1,4]二氮杂环庚烷-1-甲酸叔丁酯:
用[1,4]二氮杂环庚烷-1-甲酸叔丁酯(0.80mL,4.11mmol)处理2-氟-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛(210mg,0.818mmol)在1,4-二烷(10mL)中的溶液,将生成的黄色溶液在回流冷凝器下于110℃加热19.5小时。将反应混合物蒸发,得到橙色油。将残余物经快速色谱法在10克硅胶柱上纯化,用二氯甲烷增至用二氯甲烷∶甲醇(99∶1)洗脱。将含有产物的级分合并,将溶剂蒸发,得到342mg 4-(3-甲酰基-1-苯基-1H-吡咯并[2,3-b]吡啶-2-基)-[1,4]二氮杂环庚烷-1-甲酸叔丁酯,为黄橙色玻璃状(99.5%产率)。
MS:m/e 421(M+H),443(M+Na),365(M-C4H8+H),343(M-C5H8O2+Na),321(M-C5H8O2+H).1H NMR(300MHz,CDCl3):10.23(1H,s),8.49(1H,d),8.22(1H,dd),7.64-7.48(3H,m),7.42(2H,d),7.19(1H,dd),3.50-3.29(8H,m),1.65-1.52(2H,m),1.44(9H,s).
步骤2:2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛;三氟乙酸盐:
用三氟乙酸(0.60mL,6.04mmol)处理4-(3-甲酰基-1-苯基-1H-吡咯并[2,3-b]吡啶-2-基)-[1,4]二氮杂环庚烷-1-甲酸叔丁酯(330mg,0.786mmol)的二氯甲烷(20mL)溶液。将生成的溶液于室温搅拌22小时,再用等分试样的三氟乙酸(0.60mL,6.04mmol)处理该反应物。再搅拌18hr后,将反应混合物蒸发,得到胶粘状红色油。将粗产物盐与乙腈和乙醚一起研磨,得到285mg 2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛的三氟乙酸盐,为粉红色固体(84%产率)。LC/MS:保留时间2.25min,
m/e 321(M+H).1H NMR(300MHz,DMSO-d6):10.15(1H,s),8.60(2H,br.s),8.36(1H,dd),8.08(1H,dd),7.63-7.48(5H,m),7.22(1H,dd),3.63-3.48(4H,m),3.11-2.95(4H,m),1.81(2H,m).
实施例69
2-哌嗪-1-基-1-吡啶-3-基-1H-吡咯并[2,3-h]吡啶-3-甲醛;双三氟乙酸盐
步骤1:4-(3-甲酰基-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-2-基)-哌嗪-1-甲酸叔丁酯:
用哌嗪-1-甲酸叔丁酯(157mg,0.843mmol)处理2-氯-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-3-甲醛(46mg,0.179mmol)在1,4-二烷(4mL)中的溶液,将生成的黄色溶液在回流冷凝器下于95℃加热29小时。将反应混合物蒸发,得到红色油。将残余物经快速色谱法在5克硅胶柱上纯化,用二氯甲烷∶乙酸乙酯(3∶1,增至2∶1至1∶1)洗脱。将含有产物的级分合并,将溶剂蒸发,得到62mg 4-(3-甲酰基-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-2-基)-哌嗪-1-甲酸叔丁酯,为橙色蜡状固体(85%产率)。
MS:m/e 408(M+H),430(M+Na).1H NMR(300MHz,CDCl3):10.29(1H,s),8.78(1H,d),8.74(1H,dd),8.50(1H,d),8.20(1H,dd),7.94(1H,dm),7.59(1H,dd),7.22(1H,dd),3.39-3.28(8H,m),1.46(9H,s).
步骤2:2-哌嗪-1-基-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-3-甲醛;双三氟乙酸盐:
用三氟乙酸(0.18mL,0.18mmol)处理4-(3-甲酰基-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-2-基)-哌嗪-1-甲酸叔丁酯(60mg,0.15mmol)的二氯甲烷(6mL)溶液。将生成的溶液于室温搅拌4天,形成乳状混悬液,再用等分试样的三氟乙酸(0.20mL,2.0mmol)处理该反应物,得到橙色溶液。再搅拌20hr后,将反应混合物蒸发,得到橙色油。将粗产物与乙腈和乙醚一起研磨,得到54mg 2-哌嗪-1-基-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-3-甲醛的双三氟乙酸盐,为褐色固体(68%产率)。LC/MS:保留时间1.72min,
m/e 308(M+H).1H NMR(300MHz,DMSO-d6):10.16(1H,s),8.86(1H,d),8.78(2H,br.s),8.74(1H,d),8.41(1H,d),8.17-8.13(2H,m),7.70(1H,dd),7.30(1H,dd),3.50-3.46(4H,m),3.06-3.00(4H,m).
生物学实施例
实施例70
此实施例说明本发明的化合物在抑制PARP作用方面的生物学功效。
重组人PARP的克隆、表达及部分纯化:
全长人PARP(PARP1)是由人脑cDNA库的克隆和两个Incyte克隆的PCR片段组装而成。PARP基因(3046bp)被亚克隆到pFastBac-HTb载体内以形成PARP-pFastBac-HTb,此克隆的序列进行了验证。使用Gibco-BRL公司的Bac-to-Bac表达方案,表达PARP-pFastBac-HTb以获取蛋白质。所产生的重组病毒被用于放大供纯化的材料。
将从表达PARP的细胞的培养液中所获得的细胞沉淀用混合蛋白酶抑制剂合剂处理,并反复冻融4次使之溶解。将此材料悬浮于10mMHEPES/0.1M NaCl/pH 7.2中,搅拌后再离心处理。从上清液获取以40%-70%硫酸铵沉淀的蛋白质。将沉淀物溶解于10mM HEPES/pH7.2中并离心处理。通过透析或使用脱盐柱,将上清缓冲液更换为10mMHEPES/pH 7.2/0.1M NaCl/25%甘油。将此酶制剂于-20℃储存备用。
然后,采用如下所述的放射性酶测定法或“ELISA”酶活性测定法用这种酶制剂来测定本发明的化合物:
放射性酶测定法:
测定被标记NAD的放射性在酸沉淀蛋白中的掺入率。反应混合物(体积100μL或50μL,在试管或96孔板中)含有100μg/mL小牛胸腺DNA(经超声处理)、100μg/mL组蛋白、100mM Tris(pH 8.0)、1.0mM DTT、10mMMgCl2、NAD(200μM,0.65微居里/mL)以及不同量的酶。将该反应物于37℃培养10min或于室温培养60min。添加冰冷的三氯乙酸(TCA;10%或20%w/v水溶液)使反应终止并使蛋白质沉淀。在短暂于冰上或4℃下储存2小时后,经玻璃纤维过滤器(2.5cm滤片或96孔滤板)真空过滤反应混合物。用TCA和乙醇洗涤此过滤器后,将其干燥,加入闪烁液后测定氚CPM值。在使用滤片过滤的100μL试样中,用6mL EcoLume闪烁液(ICN公司)计数,10μL约含20mg/mL蛋白质的典型酶制剂的CPM值为10,000到20,000。用野生型病毒感染的昆虫细胞则没有活性。NAD的Km值被确定为111μM(文献报道为50μM至100μM)。将抑制作用待测的本发明化合物溶于水或DMSO中,加入试样中获得一系列浓度的溶液。从若干被测的参照化合物得出以下结果:3-氨基苯甲酰胺抑制上述反应的IC50为140μM,烟酰胺的IC50约为400μM,1,5-异喹啉二醇的IC50为1μM。另一文献的标准DPQ得出的IC50为11μM。本发明化合物的结果归纳于表3。
“ELISA”酶测定法:
测定生物素标记的NAD(生物素-NAD)在包被培养板的组蛋白中的掺入率。用组蛋白包被96孔蛋白结合酶标(EIA)板,并用牛血清清蛋白封闭。反应混合物(50μL)含有DNA、缓冲液、酶、(试验化合物)以及250μM NAD和5μL生物素-NAD(Trevigen公司)。于室温反应后,洗涤培养孔并用Extravidin(Sigma公司)处理。培养并洗涤后,用过氧化物酶底物TMB(Sigma)显色。用2M硫酸终止TMB反应,于450nm读取吸光度。
按照这一方法测定的本发明化合物的IC50值(溶液中化合物的半数抑制浓度,以微摩尔(μM)浓度表示)归纳于表3中。
表3
实施例编号 | IC50(μM) |
实施例1 | 15.1 |
实施例2 | 4.6 |
实施例3 | 2.5 |
实施例9 | 27.5 |
实施例11B-1 | 2.5 |
实施例11B-2 | 4.0 |
实施例11B-3 | 4.5 |
实施例11B-4 | 10.0 |
实施例11B-5 | 3.0 |
实施例11B-6 | 4.0 |
实施例11B-7 | 4.0 |
实施例11B-8 | 5.5 |
实施例11B-9 | 4.0 |
实施例11B-10 | 2.5 |
实施例11B-11 | 3.0 |
实施例12 | 2.0 |
实施例13 | 3.0 |
实施例19 | 8.8 |
实施例21 | 5.1 |
实施例22 | 4.5 |
实施例41 | 43.1 |
实施例43 | 11.4 |
实施例45 | 5.1 |
实施例46 | 0.85 |
实施例47 | 6.9 |
实施例48 | 15.5 |
实施例49 | 1.9 |
实施例50 | 1.4 |
实施例51 | 26.0 |
实施例52 | 42.2 |
实施例53 | 19.9 |
实施例54 | 3.1 |
实施例55 | 4.1 |
实施例56 | 1.5 |
实施例57 | 1.4 |
实施例58 | 0.85 |
实施例61 | 2.7 |
实施例62 | 0.99 |
实施例63 | 2.3 |
实施例71
以下实施例说明本发明的化合物在以细胞为基础的分析中在抑制PARP作用方面的功效。
以细胞为基础的分析:
采用标准方法在添加10%胎牛血清(FCS)的RPMI 1640+Glutamax培养基中培育和维持HL-60(人白血病)细胞。为进行测定,将细胞以50万个细胞/mL的密度悬浮在添加了0.1%FCS的培养基中,并接种于96孔培养板(100μL/孔)上。预培养3hr后,用化合物处理细胞1小时,然后将AlamarBlue指示剂(Serotec)加入细胞中。进一步培养24hr后,测量荧光值(激发560nm,发射590nm)。与对照细胞相比(10μM有效PARP抑制剂)的荧光值减少是细胞死亡的一种量度。试验化合物存在时的荧光值增加表明避免了由去血清导致的细胞死亡。为了检测多聚ADP-核糖基化,将细胞分别在化合物存在和不存在的条件下去血清。将细胞溶解并将蛋白质在SDS-PAGE凝胶上跑板。用多聚ADP-核糖抗体(Alexis或Calbiochem)检测多聚ADP-核糖基化蛋白。
从该研究中获得的结果以每种试验化合物的EC50(试验化合物有效预防细胞死亡的半数有效浓度,以微摩尔浓度(μM)表示)表示并归纳于表4。
表4
实施例编号 | EC50(μM) |
实施例2 | 3.4 |
实施例3 | 1.9 |
实施例9 | 8.0 |
实施例12 | 3.0 |
实施例72
以下动物模型用于显示本发明的化合物在治疗中风患者方面的功效。
将雄性Fisher 344大鼠麻醉。分离并结扎右颈动脉,右颈静脉插管以便给予化合物。通过颅骨切开术暴露大脑中动脉(MCA),电凝结MCA及其右支和豆核纹状体动脉。切断动脉以免血管再通。MCA阻塞后,用本发明的化合物(或标准DPQ)进行静脉内给药15min。化合物以10mg/kg推注给药,然后以5mg/kg/hr输注6hr(总剂量40mg/kg)。
MCA阻塞48hr后,处死大鼠,取出鼠脑并作2mm冠状切片。将切片用氯三苯四唑培养以显示梗塞区域,通过图像分析验证并定量梗塞区域的程度和位置。
在此动物模型上试验的实施例3化合物给出以下结果。如上所述推注并输注总剂量为40mg/kg的2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛(实施例3)。在此剂量时,实施例3化合物的试验显示梗塞体积显著(40-50%)减小。
实施例73
本实施例说明本发明的化合物在治疗心肌缺血患者方面的功效。
将雄性Sprague-Dawley大鼠麻醉并打开胸腔。取一根细丝线置于冠状动脉左前降支周围。将丝线穿过塑料管并闭合胸腔。待血液动力学稳定后,拉紧穿过塑料管的丝线使冠状动脉闭塞。通过收缩压下降和心电图(EGC)改变可确认闭塞成功。放松结扎处开始再灌注。
为测定实施例3的化合物在本动物模型中的功效,将动物分成3组。一组在比赛前10min按10mg/kg剂量静脉内施用实施例3的化合物。第二组在再灌注前5min接受相同剂量的实施例3的化合物。第三组作为空白对照。闭塞时间是20min,随后再灌注60min。处死大鼠后,通过用氯三苯四唑进行心脏组织切片染色来测定梗塞面积,以处危面积百分比(%)表示。
采用参比标准卡立泊来德进行类似研究。结果表明,当在缺血之前给药时,两种化合物均显示出显著的保护作用。但是,当在再灌注之前给药时,卡立泊来德未显示出作用,实施例3的化合物显示出小但显著的作用。
虽然本发明已经通过前述的某些实施例进行了说明,但不应理解为本发明受其限制;而应该理解为本发明涵盖了如上文公开的一般范围。可以进行各种变通和具体化而不背离本发明的宗旨和范围。
Claims (23)
1.式(I)化合物在制备用于治疗因多聚(腺苷5’-二磷酸核糖)聚合酶(PARP)的作用而引起的疾病或病症的药物中的用途,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有式(I)所示的一般结构:
其中
R是氢、羟基、C1-4烷氧基或氨基;
R1是C1-6烷基、C6-12芳基、C6-12芳基C1-4烷基、C6-12芳基磺酰基或杂芳基,且其中的烷基、芳基或杂芳基可任选被一个或数个选自以下的取代基取代:卤素;C1-6烷基;C2-6链烯基;式CnHxFy或OCnHxFy的氟烷基或氟烷氧基,其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1;C1-4烷氧基;C1-4硫代烷基;羟基;羟基C1-4烷基;C1-4酰氧基;硝基;氨基;C1-4烷基氨基;C1-4二烷基氨基;氨基C1-4烷基;C1-4烷基氨基C1-4烷基;C1-4二烷基氨基C1-4烷基;-CN;-CO2H;-CO2C1-4烷基;-NHCOC1-4烷基;取代或未取代的苯基;取代或未取代的苯氧基;取代或未取代的苄氧基;取代或未取代的吡咯基;以及取代或未取代的吡啶基;
R2和R3相同或不同且分别选自:
氢、C1-4烷基、C1-4二烷基氨基C1-4烷基、吡咯烷基C1-4烷基、咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO以及-CO2C1-4烷基;或
R2和R3与它们所连接的氮原子一起形成咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO、-CO2C1-4烷基、羟基C1-4烷基、环氧乙烷基C1-4烷基、二羟基C1-4烷基、-(CH2)aN-CO2C1-4烷基、羟基,以及-(CH2)aOPO(OC1-4烷基)2,其中a是1至4的整数;
R4是C1-4烷基;式CnHxFy或OCnHxFy的氟烷基或氟烷氧基,其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1;C1-4烷氧基;或C1-4硫代烷基;以及
X和Y相同或不同且分别选自CH或N。
2.如权利要求1所述的用途,其中
X和Y是碳;
R是氢;
R1是甲基、苄基、萘基、噻吩基、吡啶基、苯磺酰基、苯基或被一个或数个选自以下的取代基取代的苯基:硝基、溴、氯、氟、碘、甲氧基、乙氧基、硫甲基、甲基、乙基、正丁基、叔丁基、乙烯基、羟基甲基、-CHO、-CN、苯基、苯氧基、二甲基氨基、-NHCOCH3、吡啶基、氰苯基,以及叔丁氧羰基-1-吡咯基;
R2和R3与它们所连接的氮原子一起形成咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基和三氮杂环辛基;且其中的杂环基进一步被一个或数个选自以下的取代基取代:甲基、羟基乙基、2,3-二羟基丙基、环氧乙烷基甲基、氧代、-(CH2)2NHCO2-叔丁基、-CO2CH3、-CO2-叔丁基、-CHO,以及-(CH2)2OPO(OC2H5)2。
3.如权利要求2所述的用途,其中该化合物选自:
1-苯基-2-(硫吗啉-4-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛,
5-甲基-1-苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
2-(哌啶-1-基)-1-苯基-1H-吲哚-3-甲醛,
2-(氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛,
2-(2,5-二氮杂双环[2.2.1]庚-2-基)-1-苯基-1H-吲哚-3-甲醛,
2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吲哚-3-甲醛,
1-苯基-2-[1,4,7]三氮杂环辛-1-基-1H-吲哚-3-甲醛,
2-(吗啉-4-基)-1-苯基-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-硝基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-甲氧基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-叔丁基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-溴苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-氯苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-氯-4-氟苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-甲氧基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-硫甲基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-氟苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-甲基苯基)-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-哌啶-1-基-1H-吲哚-3-甲醛,
1-(3-甲酰基苯基)-2-(哌嗪-2-基)-1H-吲哚-3-甲醛,
1-(联苯-4-基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(4-乙基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(3-溴苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-甲基-3-硝基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-二甲基氨基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-苯氧基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-氟苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(3-氯苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-乙烯基苯基)-1H-吲哚-3-甲醛,
1-(3-羟基甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(3-乙氧基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-丁基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
N-{3-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]苯基}-乙酰胺盐酸盐,
4-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]-苄腈,
2-哌嗪-1-基-1-[(4-吡啶-4-基)苯基]-1H-吲哚-3-甲醛,
2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛,
2-(4-环氧乙烷基甲基哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛,
{2-[4-(3-甲酰基-1-苯基-2,3-二氢-1H-吲哚-2-基)-哌嗪-1-基]-乙基}-氨基甲酸叔丁酯,
4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-哌嗪-2-甲酸甲酯,
2-(4-甲酰基-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛,
2-[4-(2-羟基乙基)二氮杂环庚-1-基]-1-苯基-1H-吲哚-3-甲醛,
2-(4-环氧乙烷基甲基-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛,
2-[4-(2,3-二羟基丙基)-[1,4]二氮杂环庚-1-基]-1-苯基-1H-吲哚-3-甲醛,
2-(5-氧代-[1,4]二氮杂环庚-1-基)-1-苯基-1H-吲哚-3-甲醛,
4-(3-甲酰基-1-苯基-1H-吲哚-2-基)哌嗪-1-甲酸叔丁酯,
2-[4-(2-羟基乙基)哌嗪-1-基]-1-苯基-1H-吲哚-3-甲醛盐酸盐,
磷酸二乙基酯2-[4-(3-甲酰基-1-苯基-1H-吲哚-2-基)-哌嗪-1-基]-乙基酯盐酸盐,
2-(3,5-二甲基哌嗪-1-基)-1-苯基-1H-吲哚-3-甲醛盐酸盐,
5-(3-甲酰基-1-苯基-1H-吲哚-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯,
1-(4-叔丁基苯基)-2-[4-(2-羟基乙基)哌嗪-1-基]-1H-吲哚-3-甲醛,
磷酸2-{4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-基}-乙基酯二乙基酯盐酸盐,
1-(4-叔丁基苯基)-2-(4-甲基-哌嗪-1-基)-1H-吲哚-3-甲醛,
4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]哌嗪-1-甲酸叔丁酯,
5-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯,
1-(4-叔丁基-苯基)-2-(2-甲基-吖丙啶-1-基)-1H-吲哚-3-甲醛,
4-[3-甲酰基-1-(4-碘苯基)-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯,
4-[1-(4’-氰基联苯-4-基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯,
4-{1-[4-(叔丁氧羰基-1H-吡咯-2-基)-苯基]-3-甲酰基-1H-吲哚-2-基}-哌嗪-1-甲酸叔丁酯,
2-咪唑-1-基-1-苯基-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-甲基-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-苄基-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(1-萘基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(噻吩-3-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(吡啶-2-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(吡啶-3-基)-1H-吲哚-3-甲醛,以及
1-苯磺酰基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛。
4.如权利要求1所述的用途,其中X是氮且Y是CH,或者X是CH且Y是氮。
5.如权利要求4所述的用途,其中该化合物选自:
1-苯基-2-(哌嗪-1-基)-1,3-二氢吡咯并[2,3-b]吡啶-3-甲醛,
1-苯基-2-(哌嗪-1-基)-1H-吡咯并[2,3-c]吡啶-3-甲醛,
2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛;三氟乙酸盐,以及
2-哌嗪-1-基-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-3-甲醛;双三氟乙酸盐。
6.如权利要求1所述的用途,其中R2是氢或甲基,且R3是二甲基氨基乙基、吡咯烷基乙基氨基和哌啶基。
7.如权利要求6所述的用途,其中该化合物选自:
2-(2-二甲基氨基乙基氨基)-1-苯基-1H-吲哚-3-甲醛,
2-[(甲基哌啶-4-基)氨基]-1-苯基-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-[(2-二甲基氨基乙基)-甲基氨基]-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-(2-二甲基氨基乙基氨基)-1H-吲哚-3-甲醛,以及
1-(4-叔丁基苯基)-2-(2-吡咯烷-1-基-乙基氨基)-1H-吲哚-3-甲醛盐酸盐。
8.如权利要求1所述的用途,其中R是羟基、甲氧基或氨基;R1是苯基,R2和R3与它们所连接的氮原子一起形成哌嗪基,R4是氢,且X和Y是碳。
9.如权利要求8所述的用途,其中该化合物选自:
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲酸,
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲酰胺,以及
2-(哌嗪-1-基)-1-苯基-1H-吲哚-3-甲酸甲酯。
10.如权利要求1所述的用途,其中该化合物通过口服、肌内、皮下、直肠、气管内、鼻内、腹膜内或局部途径给药。
11.如权利要求1所述的用途,其中该疾病或病症选自:由于坏死或细胞凋亡导致细胞受损或死亡而造成的组织损伤、神经元介导的组织损伤或疾病、由于缺血及再灌注损伤而造成的神经组织损伤、神经紊乱及神经变性疾病、脉管中风、心血管紊乱、年龄相关性黄斑变性、AIDS及其它免疫衰老疾病、关节炎、动脉粥样硬化、恶病质、癌症、涉及复制性衰老的骨胳肌退化性疾病、糖尿病、头部创伤、免疫衰老、炎性肠病、肌营养不良症、骨关节炎、骨质疏松症、慢性疼痛、急性疼痛、神经性疼痛、神经性损伤、外周神经损伤、肾衰竭、视网膜缺血、败血症性休克及衰老。
12.如权利要求1所述的用途,其中该疾病或病症选自:由于坏死或细胞凋亡导致细胞受损或死亡而造成的组织损伤、神经元介导的组织损伤或疾病、脑缺血、头部创伤、中风、再灌注损伤、神经紊乱及神经变性疾病、脉管中风、心血管紊乱、心肌梗塞、心肌缺血、实验性过敏性脑脊髓炎(EAE)、多发性硬化症(MS)、与心脏手术相关的缺血、年龄相关性黄斑变性、关节炎、动脉粥样硬化、癌症、涉及复制性衰老的骨胳肌退化性疾病、糖尿病及糖尿病心肌病。
13.如权利要求1所述的式(I)化合物在产生神经元活动中的用途。
14.如权利要求13所述的用途,其中的神经元活动选自:刺激受损神经元、促进神经元再生、预防神经变性及治疗神经紊乱。
15.如权利要求14所述的用途,其中神经元受损是脑缺血、视网膜缺血或再灌注损伤的结果。
16.如权利要求14所述的用途,其中神经紊乱选自:由物理损伤或疾病状态引起的外周神经病变、创伤性脑损伤、脊髓的物理损伤、与脑损伤相关的中风、与神经变性有关的神经紊乱。
17.如权利要求16所述的用途,其中与神经变性有关的神经紊乱选自:阿尔茨海默氏病、帕金森病、亨廷顿氏病和肌萎缩性侧索硬化。
18.如权利要求13所述的用途,其中神经元活动由NMDA毒性介导。
19.如权利要求13所述的方法,其中神经元活动不通过NMDA毒性介导。
20.式(I)化合物在制备用于治疗心血管紊乱的药物中的用途,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有式(I)所示的一般结构:
其中
R是氢、羟基、C1-4烷氧基或氨基;
R1是C1-6烷基、C6-12芳基、C6-12芳基C1-4烷基、C6-12芳基磺酰基或杂芳基,且其中的烷基、芳基或杂芳基可任选被一个或数个选自以下的取代基取代:卤素;C1-6烷基;C2-6链烯基;式CnHxFy或OCnHxFy的氟烷基或氟烷氧基,其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1;C1-4烷氧基;C1-4硫代烷基;羟基;羟基C1-4烷基;C1-4酰氧基;硝基;氨基;C1-4烷基氨基;C1-4二烷基氨基;氨基C1-4烷基;C1-4烷基氨基C1-4烷基;C1-4二烷基氨基C1-4烷基;-CN;-CO2H;-CO2C1-4烷基;-NHCOC1-4烷基;取代或未取代的苯基;取代或未取代的苯氧基;取代或未取代的苄氧基;取代或未取代的吡咯基;以及取代或未取代的吡啶基;
R2和R3相同或不同且分别选自:
氢、C1-4烷基、C1-4二烷基氨基C1-4烷基、吡咯烷基C1-4烷基、咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO以及-CO2C1-4烷基;或
R2和R3与它们所连接的氮原子一起形成咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO、-CO2C1-4烷基、羟基C1-4烷基、环氧乙烷基C1-4烷基、二羟基C1-4烷基、-(CH2)aN-CO2C1-4烷基、羟基,以及-(CH2)aOPO(OC1-4烷基)2,其中a是1至4的整数;
R4是C1-4烷基;式CnHxFy或OCnHxFy的氟烷基或氟烷氧基,其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1;C1-4烷氧基;或C1-4硫代烷基;以及
X和Y相同或不同且分别选自CH或N。
21.如权利要求20所述的用途,其中心血管紊乱是冠状动脉疾病、心肌梗塞、心绞痛、心源性休克及心血管组织损伤。
22.化合物,包括该化合物的对映异构体、立体异构体和互变异构体及它们可药用的盐、溶剂化物或衍生物,该化合物具有式(I)所示的一般结构:
其中
R是氢、羟基、C1-4烷氧基或氨基;
R1是萘基、取代的苯基、C6-12芳基C1-4烷基、C6-12芳基磺酰基或杂芳基,且其中的萘基、芳基或杂芳基可任选被一个或数个选自以下的取代基取代:卤素;C1-6烷基;C1-6链烯基;式CnHxFy或OCnHxFy的氟烷基或氟烷氧基,其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1;C1-4烷氧基;C1-4硫代烷基;羟基;羟基C1-4烷基;C1-4酰氧基;硝基;氨基;C1-4烷基氨基;C1-4二烷基氨基;氨基C1-4烷基;C1-4烷基氨基C1-4烷基;C1-4二烷基氨基C1-4烷基;-CN;-CO2H;-CO2C1-4烷基;-NHCOC1-4烷基;取代或未取代的苯基;取代或未取代的苯氧基;取代或未取代的苄氧基;取代或未取代的吡咯基;以及取代或未取代的吡啶基;
R2和R3相同或不同且分别选自:
氢、C1-4烷基、C1-4二烷基氨基C1-4烷基、吡咯烷基C1-4烷基、咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO以及-CO2C1-4烷基;或
R2和R3与它们所连接的氮原子一起形成咪唑基或选自以下的杂环基:吗啉基、硫吗啉基、吖丙啶基、吡咯烷基、哌啶基、氮杂环庚基、哌嗪基、二氮杂环庚基、二氮杂双环[2.2.1]庚-2-基以及三氮杂环辛基;且其中的杂环基可任选被一个或数个选自以下的取代基取代:C1-4烷基、氧代、-CHO、-CO2C1-4烷基、羟基C1-4烷基、环氧乙烷基C1-4烷基、二羟基C1-4烷基、-(CH2)aN-CO2C1-4烷基、羟基以及-(CH2)aOPO(OC1-4烷基)2,其中a是1至4的整数;
R4是C1-4烷基;式CnHxFy或OCnHxFy的氟烷基或氟烷氧基,其中n是1至4的整数、x是0至8的整数、y是1至9的整数且x与y的和为2n+1;C1-4烷氧基;或C1-4硫代烷基;以及
X和Y相同或不同且分别选自:CH或N。
23.如权利要求22所述的化合物,选自:
2-(哌嗪-1-基)-1-(3-硝基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-甲氧基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-叔丁基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-溴苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-氯苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-氯-4-氟苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-甲氧基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-硫甲基苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-氟苯基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(3-甲基苯基)-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-哌啶-1-基-1H-吲哚-3-甲醛,
1-(3-甲酰基苯基)-2-(哌嗪-2-基)-1H-吲哚-3-甲醛,
1-(联苯-4-基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(4-乙基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(3-溴苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-甲基-3-硝基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-二甲基氨基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-苯氧基苯基)-2-哌嗪-1-基-1H-吲哚-3-甲醛,
1-(4-甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-氟苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
1-(3-氯苯基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(4-乙烯基苯基)-1H-吲哚-3-甲醛,
1-(3-羟基甲基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(3-乙氧基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛,
1-(4-丁基苯基)-2-(哌嗪-1-基)-1H-吲哚-3-甲醛盐酸盐,
N-{3-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]苯基}-乙酰胺盐酸盐,
4-[3-甲酰基-2-(哌嗪-1-基)-吲哚-1-基]-苄腈,
2-哌嗪-1-基-1-[(4-吡啶-4-基)苯基]-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-[4-(2-羟基乙基)哌嗪-1-基]-1H-吲哚-3-甲醛,
磷酸2-{4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-基}-乙基酯二乙基酯盐酸盐,
1-(4-叔丁基苯基)-2-(4-甲基-哌嗪-1-基)-1H-吲哚-3-甲醛,
4-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]哌嗪-1-甲酸叔丁酯,
5-[1-(4-叔丁基苯基)-3-甲酰基-1H-吲哚-2-基]-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯,
1-(4-叔丁基-苯基)-2-(2-甲基-吖丙啶-1-基)-1H-吲哚-3-甲醛,
4-[3-甲酰基-1-(4-碘苯基)-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯,
4-[1-(4’-氰基联苯-4-基)-3-甲酰基-1H-吲哚-2-基]-哌嗪-1-甲酸叔丁酯,
4-{1-[4-(叔丁氧羰基-1H-吡咯-2-基)-苯基]-3-甲酰基-1H-吲哚-2-基}-哌嗪-1-甲酸叔丁酯,
1-苯基-2-(哌嗪-1-基)-1,3-二氢吡咯并[2,3-b]吡啶-3-甲醛,
1-苯基-2-(哌嗪-1-基)-1H-吡咯并[2,3-c]吡啶-3-甲醛,
2-[1,4]二氮杂环庚-1-基-1-苯基-1H-吡咯并[2,3-b]吡啶-3-甲醛;三氟乙酸盐,
2-哌嗪-1-基-1-吡啶-3-基-1H-吡咯并[2,3-b]吡啶-3-甲醛;双三氟乙酸盐,
2-咪唑-1-基-1-苯基-1H-吲哚-3-甲醛,
2-(2-二甲基氨基乙基氨基)-1-苯基-1H-吲哚-3-甲醛,
2-[(甲基哌啶-4-基)氨基]-1-苯基-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-[(2-二甲基氨基乙基)-甲基氨基]-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-(2-二甲基氨基乙基氨基)-1H-吲哚-3-甲醛,
1-(4-叔丁基苯基)-2-(2-吡咯烷-1-基-乙基氨基)-1H-吲哚-3-甲醛盐酸盐,
2-(哌嗪-1-基)-1-苄基-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(1-萘基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(噻吩-3-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(吡啶-2-基)-1H-吲哚-3-甲醛,
2-(哌嗪-1-基)-1-(吡啶-3-基)-1H-吲哚-3-甲醛,以及
1-苯磺酰基-2-(哌嗪-1-基)-1H-吲哚-3-甲醛。
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EP (1) | EP1663202A1 (zh) |
JP (1) | JP2007504238A (zh) |
KR (1) | KR20060088102A (zh) |
CN (1) | CN1870991A (zh) |
AU (1) | AU2004270187A1 (zh) |
BR (1) | BRPI0414136A (zh) |
CA (1) | CA2537097A1 (zh) |
IL (1) | IL173917A0 (zh) |
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- 2004-09-01 BR BRPI0414136-9A patent/BRPI0414136A/pt not_active IP Right Cessation
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- 2004-09-01 EP EP04782937A patent/EP1663202A1/en not_active Withdrawn
- 2004-09-01 MX MXPA06002499A patent/MXPA06002499A/es not_active Application Discontinuation
- 2004-09-01 CN CNA2004800307419A patent/CN1870991A/zh active Pending
- 2004-09-01 US US10/933,098 patent/US7405300B2/en not_active Expired - Fee Related
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CN102786460A (zh) * | 2012-09-04 | 2012-11-21 | 苏州楚凯药业有限公司 | 3-吲哚甲醛类化合物的合成方法 |
CN102786460B (zh) * | 2012-09-04 | 2014-10-22 | 苏州楚凯药业有限公司 | 3-吲哚甲醛类化合物的合成方法 |
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CN105189494B (zh) * | 2013-03-13 | 2017-04-26 | 普罗克西梅根有限公司 | 作为ssao抑制剂的咪唑并[4,5‑c]吡啶和吡咯并[2,3‑c]吡啶衍生物 |
CN104876851A (zh) * | 2015-05-15 | 2015-09-02 | 南京大学 | 一类含吲哚-3羧酸骨架的哌嗪类衍生物的制备方法及在抗癌药物中的应用 |
WO2018228474A1 (zh) * | 2017-06-14 | 2018-12-20 | 上海时莱生物技术有限公司 | 聚(adp-核糖)聚合酶抑制剂、制备方法及用途 |
US11072596B2 (en) | 2017-06-14 | 2021-07-27 | Selection Bioscience Llc | Poly(ADP-ribose) polymerase inhibitor, preparation method and use |
CN108484473A (zh) * | 2018-03-01 | 2018-09-04 | 上海优合生物科技有限公司 | 一种n-苯基吲哚酮的制备方法 |
CN113365998A (zh) * | 2019-02-02 | 2021-09-07 | 正大天晴药业集团股份有限公司 | 用于parp抑制剂的吲哚并七元酰肟类似物 |
CN113365998B (zh) * | 2019-02-02 | 2023-04-14 | 正大天晴药业集团股份有限公司 | 用于parp抑制剂的吲哚并七元酰肟类似物 |
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US20050054631A1 (en) | 2005-03-10 |
US7405300B2 (en) | 2008-07-29 |
WO2005023246A1 (en) | 2005-03-17 |
US20080255350A1 (en) | 2008-10-16 |
JP2007504238A (ja) | 2007-03-01 |
AU2004270187A1 (en) | 2005-03-17 |
EP1663202A1 (en) | 2006-06-07 |
US8008491B2 (en) | 2011-08-30 |
KR20060088102A (ko) | 2006-08-03 |
BRPI0414136A (pt) | 2006-10-31 |
MXPA06002499A (es) | 2006-06-20 |
IL173917A0 (en) | 2006-07-05 |
CA2537097A1 (en) | 2005-03-17 |
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