CN1244542C - 具有nos抑制作用的芳香族胺衍生物 - Google Patents
具有nos抑制作用的芳香族胺衍生物 Download PDFInfo
- Publication number
- CN1244542C CN1244542C CNB971805946A CN97180594A CN1244542C CN 1244542 C CN1244542 C CN 1244542C CN B971805946 A CNB971805946 A CN B971805946A CN 97180594 A CN97180594 A CN 97180594A CN 1244542 C CN1244542 C CN 1244542C
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- Prior art keywords
- side chain
- halogen atom
- phenyl
- substituent
- amino
- Prior art date
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- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical group [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- WBJVHQHMOMJQFR-UHFFFAOYSA-N tert-butyl n-[(2-hydroxy-5-methyl-3-nitrophenyl)methyl]carbamate Chemical class CC1=CC(CNC(=O)OC(C)(C)C)=C(O)C([N+]([O-])=O)=C1 WBJVHQHMOMJQFR-UHFFFAOYSA-N 0.000 description 1
- QDLAVSBKFPHNOB-UHFFFAOYSA-N tert-butyl n-[(3-bromo-2-chloro-6-fluoro-5-nitrophenyl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=C(F)C([N+]([O-])=O)=CC(Br)=C1Cl QDLAVSBKFPHNOB-UHFFFAOYSA-N 0.000 description 1
- BSTLUOONERPTSG-UHFFFAOYSA-N tert-butyl n-[[3-[(3-formyl-6-methoxypyridin-2-yl)amino]phenyl]methyl]carbamate Chemical compound COC1=CC=C(C=O)C(NC=2C=C(CNC(=O)OC(C)(C)C)C=CC=2)=N1 BSTLUOONERPTSG-UHFFFAOYSA-N 0.000 description 1
- QKFRSNAOMIKWIX-UHFFFAOYSA-N tert-butyl n-[[3-[(4-methyl-1,3-thiazol-2-yl)amino]phenyl]methyl]carbamate Chemical compound CC1=CSC(NC=2C=C(CNC(=O)OC(C)(C)C)C=CC=2)=N1 QKFRSNAOMIKWIX-UHFFFAOYSA-N 0.000 description 1
- RKOAQSGYRUFBHH-UHFFFAOYSA-N tert-butyl n-[[3-[(4-methylpyridin-2-yl)amino]phenyl]methyl]carbamate Chemical compound CC1=CC=NC(NC=2C=C(CNC(=O)OC(C)(C)C)C=CC=2)=C1 RKOAQSGYRUFBHH-UHFFFAOYSA-N 0.000 description 1
- IASLDRIAHKYZHI-UHFFFAOYSA-N tert-butyl n-[[3-[(5-methyl-1,3-thiazol-2-yl)amino]phenyl]methyl]carbamate Chemical compound S1C(C)=CN=C1NC1=CC=CC(CNC(=O)OC(C)(C)C)=C1 IASLDRIAHKYZHI-UHFFFAOYSA-N 0.000 description 1
- GJTXQUKCHVCMDP-UHFFFAOYSA-N tert-butyl n-[[3-[[3-(hydroxymethyl)-6-methoxypyridin-2-yl]amino]phenyl]methyl]carbamate Chemical compound COC1=CC=C(CO)C(NC=2C=C(CNC(=O)OC(C)(C)C)C=CC=2)=N1 GJTXQUKCHVCMDP-UHFFFAOYSA-N 0.000 description 1
- OHXLTZVLQLPQBW-UHFFFAOYSA-N tert-butyl n-[[3-[[4-(hydroxymethyl)-6-methoxypyridin-2-yl]amino]phenyl]methyl]carbamate Chemical compound COC1=CC(CO)=CC(NC=2C=C(CNC(=O)OC(C)(C)C)C=CC=2)=N1 OHXLTZVLQLPQBW-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005934 tert-pentyloxycarbonyl group Chemical group 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/92—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the nitrogen atom of at least one of the amino groups being further bound to a carbon atom of a six-membered aromatic ring
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- C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
通式(1)所示的化合物具有NOS抑制活性,作为脑血管障碍治疗药等的医药很有用。(式中R1、R2表示氢原子等,R3、R4表示氢原子、低级烷基等,R5表示氢原子等,X1、X2、X3、X4表示氢原子、低级烷氧基等,A表示可具有取代基的吡啶环等,m、n表示0或1的整数。)
Description
技术领域
本发明涉及N取代的苯胺衍生物,更详细地说就是涉及以含有通式(1)所示化合物或其可能的互变异构体、立体异构体、旋光异构体及医药上允许的盐作为有效成分为特征的预防和治疗药物,该通式(1)表示的化合物具有一氧化氮合成酶(nitric oxide synthase,NOS)抑制作用,能够抑制一氧化氮(nitric oxide,NO)生成,对被认为与过剩的NO或NO代谢产物有关的脑血管障碍〔脑出血、蛛网膜下出血、脑梗塞(动脉粥样化血栓性梗塞、腔隙梗塞(Lacunar infarction)、心源性栓塞症)、一过性脑缺血发作(transient ischemic attach)、脑浮肿〕、头部外伤、脊椎损伤、疼痛〔头痛(偏头痛、紧张性头痛、群发性头痛、慢性发作头痛)〕、帕金森氏病、阿茨海默病、痉挛、吗啡耐受和依赖、败血症休克、慢性关节风湿病、变形性关节炎、病毒性或非病毒性感染、糖尿病等有效。
背景技术
本国因脑血管障碍的死亡数随着急性期治疗的发展而以1970年为界开始减少,但其作为成人疾病的死亡原因仍仅次于癌症处于第2位。另一方面,从涉及发病率的很多统计结果来看没有变化,从世界范围来看今后步入老年化社会,患者人数会大大增加。死亡率的下降和老龄化使慢性脑血管障碍增加,这对于患者个人及社会不用说是个很大的问题,而且因长期疗养从医疗经济性方面来看也将是国家的问题。占脑血管障碍中大部分的脑梗塞是因脑动脉栓塞,引起栓塞部位到末梢的供血不足而导致缺血状态。脑梗塞的慢性期症状大致是神经细胞脱落引起的症状,完全这些症状的治疗药或治疗方法的确立是极为困难的。因此,为提高对脑梗塞治疗成绩,如何实施以神经细胞保护为目的的急性期治疗,急性期到何时开始改善症状等问题说它们怎么重要都不夸张。但是,目前临床上所用的治疗药物是抗血小板药、抗凝药、血栓溶解药等,它们不具有直接的神经保护作用〔峰松一夫等,《medicina》(医学书院)32,1995;水泽英洋等,《内科》(南江堂)79,1997〕。所以,作为对于脑血管障碍、特别是脑梗塞的治疗方法,人们期望开发出和以前治疗药物作用机制完全不同的、具有全新作用机制的药物。
NOS的亚型至少有三种的假说目前得到基因分析的有力支持。即,它们是神经细胞中构成性存在的钙依赖性神经元一氧化氮合成酶(neuronal nitric oxide synthase,缩写为nNOS)(类型1)、血管内皮细胞中构成性存在的钙依赖性eNOS(类型3)、还有巨噬细胞和其它多种细胞被细胞因子及机体内微量毒素(lipopolysaccharide,LPS脂多糖)刺激诱导合成的诱导型钙非依赖性的iNOS(类型2)(Nathanet al.,FASEB J.16,3051-3064,1992;Nagafuji et al.,Mol.Chem.Neuropathol.26,107-157,1995)。
作为伴有脑缺血的脑组织障碍的主要机制包括细胞外谷氨酸浓度上升、突触后存在的谷氨酸受体异常活化、细胞内钙浓度上升、钙依赖性酶的活化等一系列通路(Siesjo,J.Cereb.Blood Flow Metab.1,155-185,1981;Siesjo,J.Neurosurg.60,883-908,1984;Choi,TrendsNeurosci.11,465-469,1988;Sies jo and Bengstsson,J.Cereb.BloodFlow Metab.9,127-140,1989)。如上所述,因nNOS是钙依赖性的,如果抑制了此类型NOS亚型的异常活性化,则能发挥NOS抑制剂所致的神经细胞保护作用(Dawson et al.,Annals Neurol.32,297-311,1992)。
事实上,nNOS的mRNA量和含有nNOS的神经细胞数目从大鼠局部脑缺血后的早期开始增加,其经时变化和梗塞病灶的出现是一致的(Zhang et al.,Brain Res.654,85-95,1994)。此外,对于小鼠局部脑缺血模型,在至少能确认梗塞灶缩小作用的NG-硝基-L-精氨酸(L-NA)用量范围内nNOS活性的抑制率和梗塞灶的缩小率相关(Carreau et al.,Eur.J.Pharmacol.256,241-249,1994)。更进一步,有报道说明,对于nNOS敲除小鼠,局部脑缺血后观察到的梗塞灶体积和对照相比显示出有意义的减小(Huang et al.,Science265,1883-1885,1994)。
另一方面,因为NO是内皮衍生舒张因子(endothelium-derivedrelaxing factor,EDRF)至少的一种化学本体,所以认为其参与血管张力和血流量的调节(Moncade et al.,Pharmacol.Rev.43,109-142,1991)。实际上,如对于大鼠给予高剂量的L-NA,可同时观察到剂量依赖性的体血压上升和脑血流量降低(松居辙等,实验医学,11,55-60,1993)。脑具有在一定范围的体血压变动内维持脑血流量不变的机制(一般称之为“自身调节机制”)(佐野圭司主编《脑卒中实验手册》アイピ-シ-,247-249,1990)。松居等的报告提示此“自身调节机制”失去了作用。因此,脑缺血时,特别是eNOS如有一定程度的抑制则使脑血流量降低和体血压上升,微循环状态恶化,最终扩大了缺血病变。此外,对于eNOS敲除小鼠,局部脑缺血后所观察到的梗塞灶与对照相比增大,对其给予L-NA则显示有意义的缩小(Huang et al.,J.Cereb.Bloood Flow Metab.16,981-987,1996)这些报告提示,eNOS来源的NO大概介导血管扩张作用和血小板聚集抑制作用,对脑组织起着保护作用。
到这里,本发明者们发现,作为已知的NOS抑制剂L-NA对实验性脑缺血后产生的脑浮肿、脑梗塞(Nagafuji et al.,Neurosci.Lett.147,159-162,1992;特开平6-192080号公报)、神经细胞坏死(Nagafuji et al.,Eur.J.Pharmacol.Env.Tox.248,325-328,1993)等具有改善作用。另一方面,也有报告表明,较高用量的NOS抑制剂对缺血性脑损伤无效,或使其更加恶化(Iadecola et al.,J.Cereb.Blood Flow Metab.14,175-192,1994;长藤寿昭,松居辙,实验医学,13,127-135,1995;Nagafuji et al.,Mol.Chem.Neuropathol.26,107-157,1995)。但是,对于永久性或暂时性脑缺血模型,报告脑内和血中的NO或NO相关代谢产物变化的论文的结果都是一致地增大(长藤寿昭,松居辙,实验医学,13,127-135,1995;Nagafuji et al.,Mol.Chem.Neuropathol.26,107-157,1995)。
关于NOS抑制剂对脑缺血模型的效果,作为得出相反报告的理由,可能是所使用的NOS抑制剂对nNOS的选择性低。事实上,在以L-NA和NG-硝基-L-精氨酸甲基酯(L-NAME)开始的现存NOS抑制剂中,不存在对特定的NOS亚型具有高选择性一致作用的物质(Nagafuji et al.,Neuroreport6,1541-1545,1995;Nagafujiet al.,Mol.Chem.Neuropathol.26,107-157,1995)。因此,作为缺血性脑血管障碍治疗药物,应该是对nNOS具有选择性抑制作用的物质(Nowicki et al.,Eur.J.Pharmacol.204,339-340,1991;Dawson et al.,Proc.Natl.Acad.Sci.USA88,6368-6371,1991;Iadecola et al.,J.Cereb.Blood Flow Metab.15,52-59,1995;Iadecola et al.,J.Cereb.Blood Flow Metab.15,378-384,1995;长藤寿昭,松居辙,实验医学,13,127-135,1995;Nagafuji et al.,Mol.Chem.Neuropathol.26,107-157,1995)。
还有,nNOS抑制剂还显示出作为头部外伤(Oury et al.,J.Biol.Chem.268,15394-15398,1993;MacKenzie et al.,Neuroreport6,1789-1794,1995;Mesenge et al,J.Neurotrauma.13,11-16,1996;Wallis et al.,Brain Res.,710,169-177,1996)、头痛和疼痛(Moore et al.,Br.J.Pharmacol.102,198-202,1991;Olesen.,Trends Pharmacol.15,149-153,1994)、帕金森氏病(Youdim et al.,Advaces Neurol.60,259-266,1993;SchulZet al.,J.Neurochem.64,936-939,1995;Hantraye et al.,Nature medicine 2,1017-1021,1996)、阿茨海默病(Hu andEI-FaKahany,Neuroreport 4,760-762,1993;Meda et al.,Nature 374,647-650,1995)、痉挛(Rigaud-Monnet et al.,J.Cereb.Blood Flow Metab.14,581-590;1994)、吗啡耐受和依赖(Kolesnikov et al.,Eur.J.Pharmacol.221,399-400,1992;Cappendijk et al.,Neurosci Lett.162,97-100,1993)等的治疗药物的可能性。
另一方面,有些细胞因子和LPS能够在巨噬细胞等免疫细胞及其它细胞中诱导iNOS的合成,其产生的大量NO使血管扩张,可导致致命的血压下降,所以iNOS抑制剂可能对败血症休克有效(Kilbournand Griffith,J.Natl.Cancer Inst.84,827-831,1992;Cobbet al.,Crit.Care Med.21,1261-1263,1993;Lorente et al.,Crit.Care Med.21,1287-1295,1993)。更进一步,iNOS抑制剂可能作为慢性关节风湿病和变形性关节炎(Farrell et al.,Ann.Rheum.Dis.51,1219-1222,1992;Hauselmann et al.,FEBS Lett.352,361-364,1994;Islante et al.,Br.J.Pharmacol.110,701-706,1993)、病毒性或非病毒性感染(Zembvitz and Vane,Proc.Natl.Acad.Sci.USA 89,2051-2055,1992;Koprowski et al.,Proc.Natl.Acad.Sci.USA90,3024-3027,1993)、糖尿病(Kolbet al.,Life Sci.PL213-PL217,1991)等的治疗药物很有用。
到目前,作为nNOS显示出一定程度选择性的NOS抑制剂,已报道有NG-环丙基-L-精氨酸(L-CPA)(Lamberte et al.,Eur.J.Pharmacol.216,131-134,1992)、L-NA(Furfine et al.,Biochem.32,8512-8517,1993)、S-甲基-L-硫代瓜氨酸(L-MIN)(Narayanan and Griffith,J.Med.Chem.37,885-887,1994;Furfine et al.,j.Biol.Chem.37,885-887,1994;Furfine etal.,J.Biol.Chem.269,26677-26683,1994;WO95/09619号公报;Narayahan et al.,J.Biol.Chem.270,11103-11110,1995;Nagafuji et al.,Neuroreport 6,1541-1545,1995)、S-乙基-L-硫代瓜氨酸(L-EIN)(Furfine et al.,J.Biol.Chem.269,26677-26683,1994;WO95/09619号公报;Narayanan et al.,J.Biol.Chem.270,11103-11110,1995)、ARL17477(Gentile etal.,WO95/05363号公报;Zhang et al.,J.Cereb.Blood FlowMetab.,16,599-604,1996)。
另为,作为对iNOS显示某种程度选择性的抑制剂,有如下一些物质:NG-亚氨乙基-L-鸟氨酸(L-NIO)(McCall et al.,Br.J.Pharmacol.102,234-238,1991)、氨基胍(AG)(Griffith et al.,Br.J.Pharmacol.110,963-968,1993;Hasan et al.,Eur.J.Pharmacol,249,101-106,1993)。
发明的公开
本发明的目的在于提供对主要在脑内神经细胞中构成性存在的钙依赖性nNOS、或钙非依赖性的诱导型iNOS具有抑制作用的、作为对脑血管障碍〔脑出血、蛛网膜下出血、脑梗塞(动脉粥样化血栓性梗塞、ラクナ梗塞、心源性栓塞症)、一过性脑缺血发作、脑浮肿〕、头部外伤、脊椎损伤、疼痛〔头痛(偏头痛、紧张性头痛、群发性头痛、慢性发作头痛)〕、帕金森氏病、阿茨海默病、痉挛、吗啡耐受和依赖、败血症休克、慢性关节风湿病、变形性关节炎、病毒性或非病毒性感染、糖尿病等的治疗药物有用的新型化合物。
本发明者们为解决上述课题,进行了深入研究,结果发现,通式(1)所示的芳香族胺衍生物、或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐具有对类型1NOS等的抑制作用,作为脑血管障碍治疗药物(特别是栓塞性脑血管障碍的治疗药物)显示出显著的效果,从而完成了本发明。
(式中R1、R2相同或不同,表示氢原子、可具有取代基的低级烷基、酰基、低级烷氧基羰基,也可一起形成3~8元环。R3、R4相同或不同,表示氢原子、可具有取代基的低级烷基,也可一起形成碳数3~10的单环或稠环。R5表示氢原子、低级烷基、酰基、低级烷氧基羰基。X1、X2、X3、X4相同或不同,表示氢原子、卤素原子、硝基、氰基、羟基、可具有取代基的低级烷基、低级烯基、低级炔基、可具有取代基的低级烷氧基、可具有取代基的低级烷硫基、可被卤素原子和(或)低级烷基取代的苯基、NX5X6、C(=O)X7;在这里,X5、X6相同或不同,表示氢原子、可具有取代基的低级烷基、酰基、可具有取代基的低级烷氧基羰基,也可一起形成3~8元环;X7表示氢原子、羟基、可具有取代基的低级烷基、可具有取代基的低级烷氧基、NX8X9;这里X8、X9相同或不同,表示氢原子、可具有取代基的低级烷基,也可一起形成3~8元环。A表示可具有取代基的苯环、或者可具有取代基、且作为杂原子含有1个以上氮原子的5~6元环芳香族杂环。n、m分别表示0或1的整数。)
更进一步,本发明还提供由反应路线(A)所示的制造通式(1)所示化合物的方法,
反应路线(A)
即,将通式(2)
(式中R1、R2、R3、R4、X1、X2、X3、X4、n、m表示和上述相同意义;R5表示氢原子、可具有取代基的低级烷基。)
所示的取代苯胺和通式(3)
(式中A表示和上述相同的意义;L表示脱去基团。)
所示化合物进行反应,制造通式(1)所示化合物的方法。
此外,本发明还提供反应路线(B)所示的制造方法,
反应路线(B)
即,将通式(9)
(式中R1、R2、R3、R4、X1、X2、X3、X4、L、n、m表示和上述相同的意义。)
所示的取代苯和通式(10)
(式中A、R5表示和上述相同的意义。)
所示的化合物进行反应,制造通式(1)所示化合物的方法。
本发明还提供上述通式(1)所表示的化合物或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐,其中X1、X2、X3、X4相同或不同,为氢原子、卤素原子、硝基、氰基、可具有取代基的低级烷基、低级烯基、低级炔基、可具有取代基的低级烷氧基、可具有取代基的低级烷硫基、可被卤素原子和(或)低级烷基取代的苯基、NX5X6、C(=O)X7;A为可具有取代基的苯环或吡啶环。
本发明还提供上述通式(1)所表示的化合物或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐,其中A为可具有取代基的、且作为杂原子含有1个以上氮原子的5~6元环芳香族杂环,但可具有取代基的吡啶环除外。
本发明还提供上述通式(1)所表示的化合物或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐,其中在通式(1)中R1为氢原子;R2为氢原子、低级烷基、酰基、低级烷氧基羰基;A为可具有取代基的苯环。
本发明还提供上述通式(1)所表示的化合物或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐,其中通式(1)中A为可具有取代基的吡啶环。
本发明还提供上述通式(1)所表示的化合物或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐,其中在通式(1)中,R1、R2为氢原子;R5为氢原子;X1、X2、X3、X4相同或不同,为氢原子、卤素原子、可具有取代基的低级烷基、可具有取代基的低级烷氧基、NX5X6;A为可具有取代基的苯环、可具有取代基的吡啶环、可具有取代基的嘧啶环、可具有取代基的噁唑环、可具有取代基的噻唑环。
本发明还提供上述通式(1)所表示的化合物或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐,其中在通式(1)中,R3、R4相同或不同,表示氢原子、低级烷基,也可一起形成碳数3~10的单环。
本发明还提供上述通式(1)所表示的化合物或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐,其中在通式(1)中,X1、X2、X3、X4相同或不同,为氢原子、卤素原子、低级烷基、可被苯基取代的低级烷氧基、NX5X6;在这里,X5、X6相同或不同,为氢原子、可被苯基取代的低级烷基、酰基,也可一起形成3~8元环。
本发明还提供上述通式(1)所表示的化合物或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐,其中在通式(1)中A为可具有取代基的苯环、可具有取代基的吡啶环,其取代基为硝基、低级烷氧基、低级烷基、低级烷硫基。
本发明还提供上述通式(1)所表示的化合物或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐,其中在通式(1)中,X1、X2、X3、X4相同或不同,为氢原子、卤素原子、低级烷基、低级烷氧基、NX5X6;在这里,X5、X6相同或不同,为氢原子、低级烷基、酰基,也可一起形成3~8元环。
本发明还提供上述通式(1)所表示的化合物或其可能的互变异构体、立体异构体、旋光异构体和它们医药上允许的盐作为有效成分的nNOS抑制剂,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和上述通式(1)中的定义相同的意义。
具体实施方式
在本发明的A中,作为含有1个以上作为杂原子的氮原子的5~6元环芳香族杂环,例如有吡咯环、吡咯-1-氧化物环、吡唑环、吡唑-1-氧化物环、吡唑-2-氧化物环、吡唑-1,2-二氧化物环、咪唑环、咪唑-1-氧化物环、咪唑-3-氧化物环、咪唑-1,3-二氧化物环、异噁唑环、异噁唑-2-氧化物环、噁唑环、噁唑-3-氧化物环、异噻唑环、异噻唑-1-氧化物环、异噻唑-1,1-二氧化物环、异噻唑-1,2-二氧化物环、异噻唑-2-氧化物环、噻唑环、噻唑-1-氧化物环、噻唑-1,1-二氧化物环、噻唑-3-氧化物环、吡啶环、吡啶-N-氧化物环、哒嗪环、哒嗪-1-氧化物环、哒嗪-1,2-二氧化物环、嘧啶环、嘧啶-1-氧化物环、嘧啶-1,3-二氧化物环、吡嗪环、吡嗪-1-氧化物环、吡嗪-1,4-二氧化物环等。
A中的取代基表示羟基、卤素原子、硝基、氰基、三氟甲基、低级烷氧基、低级烷基、烷基烷硫基、NX10X11、C(=O)X12;这里X10、X11相同或不同,表示氢原子、可具有取代基的低级烷基、酰基、可具有取代基的低级烷氧基羰基,此外也可一起形成3~8元环;X12表示氢原子、羟基、可具有取代基的低级烷基、可具有取代基的低级烷氧基、NX13X14;这里X13、X14相同或不同,表示氢原子、可具有取代基的低级烷基,此外也可一起形成3~8元环。
所说的低级烷基表示碳数1~6的直链烷基、碳数3~8的支链或环烷基,例如有甲基、乙基、正丙基、正丁基、正戊基、正己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、新戊基、叔戊基、异己基、环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
所说的烯基表示碳数2~6的直链烯基、碳数3~6的支链烯基,例如有乙烯基、烯丙基、1-丁烯基、1-戊烯基、1-己烯基、2-丁烯基、2-戊烯基、2-己烯基、异丙烯基、2-丁烯基、1-甲基-1-丙烯基等。
所说的低级炔基表示碳数2~6的直链炔基、碳数3~6的支链炔基,例如有乙炔基、1-丙炔基、1-丁炔基、1-戊炔基、1-己炔基、2-丙炔基、2-丁炔基、2-戊炔基、2-己炔基、1-甲基-2-丙炔基、3-甲基-1-丁炔基、1-乙基-2-丙炔基等。
所说的低级烷氧基表示碳数1~6的直链烷氧基、碳数3~8的支链或环状烷氧基,例如有甲氧基、乙氧基、正丙氧基、正丁氧基、正戊氧基、正己氧基、异丙氧基、异丁氧基、仲丁氧基、叔丁氧基、异戊氧基、新戊氧基、叔戊氧基、异己氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基、环庚氧基、环辛氧基等。
所说的低级烷硫基表示碳数1~6的直链烷硫基、碳数3~8的支链或环状烷硫基,例如有甲基硫基、乙基硫基、正丙基硫基、正丁基硫基、正戊基硫基、正己基硫基、异丙基硫基、异丁基硫基、仲丁基硫基、叔丁基硫基、异戊基硫基、新戊基硫基、叔戊基硫基、异己基硫基、环丙基硫基、环丁基硫基、环戊基硫基、环己基硫基、环庚基硫基、环辛基硫基等。
所说的酰基表示除了甲酰基外烷基部分为低级烷基的烷基羰基、芳香基羰基,例如有乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、异戊酰基、三甲基乙酰基、苯甲酰基、邻苯二甲酰基、甲苯酰基等。
所说的低级烷氧基羰基表示烷基部分为低级烷基的烷氧基羰基,例如有甲氧基羰基、乙氧基羰基、正丙氧基羰基、正丁氧基羰基、正戊氧基羰基、正己氧基羰基、异丙氧基羰基、异丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、异戊氧基羰基、新戊氧基羰基、叔戊氧基羰基、异己氧基羰基、环丙氧基羰基、环丁氧基羰基、环戊氧基羰基、环己氧基羰基、环庚氧基羰基、环辛氧基羰基等。
所说的卤素原子表示氟原子、氯原子、溴原子、碘原子。
所说的脱去基团表示卤素原子、三氟甲磺酰氧基、对甲苯磺酰氧基、甲磺酰氧基。
在R1、R2、R3、R4、X1、X2、X3、X4、X5、X6、X7、X8、X9、X10、X11、X12、X13、X14中,作为可具有取代基的低级烷基、可具有取代基的低级烷氧基、可具有取代基的低级烷硫基、可具有取代基的低级烷氧基羰基中的取代基,例如有卤素原子、可被卤素原子或低级烷基取代的苯基、碳数3~8的环烷基。
作为R1和R2一起形成的3~8元环、X5和X6一起形成的3~8元环、X8和X9一起形成的3~8元环、X10和X11一起形成的3~8元环、X13和X14一起形成的3~8元环,表示含有1个以上作为杂原子的氮原子的杂环,例如有吡咯环、吡唑环、咪唑环、三唑环、氮杂环丙烷、氮杂环丁烷、吡咯烷环、哌啶环、哌嗪环、吗啉环、硫代吗啉环、氮杂_环、氮杂环辛烷(azocane)环等。
作为R3和R4一起形成的碳数3~10的单环或稠环,例如有环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、茚满环、萘满环等。
作为NX5X6、NX8X9、NX10X11、NX13X14,例如有氨基、甲基氨基、苄基氨基、乙基氨基、二甲基氨基、乙基甲基氨基、吡咯烷-1-基、哌啶-1-基、吗啉-4-基、乙酰胺基、苯甲酰胺基、N-甲基乙酰胺基、苯甲酰胺基、叔丁氧基羰基氨基、N-甲基-叔丁氧基羰基氨基、吡咯-1-基、吡唑-1-基、咪唑-1-基、三唑-1-基、氮杂环丙烷-1-基、氮杂环丁烷-1-基、吡咯烷-1-基、哌啶-1-基、哌嗪-1-基、吗啉-4-基、硫代吗啉-4-基等。
作为C(=O)X7,例如有甲酰基、羧基、乙酰基、丙酰基、环丁酰基、甲氧基羰基、乙氧基羰基、叔丁氧基羰基、氨基甲酰基、N-甲基氨基甲酰基、N-乙基氨基甲酰基、N,N-二甲基氨基甲酰基、N-乙基-N-甲基氨基甲酰基、吡咯烷羰基、哌啶羰基、吗啉羰基等。
作为R1、R2,优选氢原子。
作为R3、R4,优选氢原子、碳数1~3的低级烷基、碳数3~5的单环,特别优选氢原子、甲基、乙基、环丁基。
作为R5,优选氢原子。
作为X1、X2、X3、X4,优选氢原子、卤素原子、碳数1~3的低级烷基、碳数1~3的低级烷氧基,特别优选氢原子、氟原子、氯原子、甲基、乙基、甲氧基、乙氧基、正丙氧基。
作为A,优选可具有取代基的苯环或吡啶环,其中更优选硝基、碳数1~3的低级烷基、碳数1~3的低级烷氧基、碳数1~3的低级烷硫基取代的苯环或吡啶环,特别优选6-甲氧基-3-硝基苯-2-基、6-甲基-3-硝基吡啶-2-基、6-甲氧基-3-硝基吡啶-2-基、4-甲基吡啶-2-基。
作为m,n,m、n都为0时,X1、X2、X3、X4以外取代基的苯核的取代基优选间位取代,m+n=1时,X1、X2、X3、X4以外取代基的苯核的取代基优选邻位或对位取代。
作为通式(1)所示的化合物,优选2-(3-氨基甲基苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-6-甲基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-6-乙基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-6-乙氧基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-6-甲基硫-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-6-甲基-3-硝基苯、2-(3-氨基甲基苯基氨基)-6-甲氧基-3-硝基苯、2-(3-氨基甲基-2-甲基苯基氨基)-6-甲氧基-3-硝基吡啶、2-(4-氨基乙基苯基氨基)-6-甲氧基-3-硝基吡啶、2-〔3-(1-氨基-1-甲基乙基)苯基氨基〕-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基-2-甲氧基苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基-4-氯苯基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基-4-氟苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基-2-乙氧基苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基-2-氯苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-4-甲基吡啶、2-〔3-(1-氨基-1-甲基乙基)苯基氨基〕-4-甲基吡啶、2-(3-氨基甲基-2-甲基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-4-乙基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-4-乙氧基苯基氨基)-4-甲基吡啶、2-(2-氨基乙基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-氯苯基氨基)-4-甲基吡啶、2-〔3-(1-氨基-环丁基)苯基氨基〕-4-甲基吡啶、2-(4-氨基乙基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-乙氧基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-4-氯苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-正丙氧基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-4-氯-2-乙氧基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-乙氧基-4-甲基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-甲氧基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-异丙氧基苯基氨基)-4-甲基吡啶。
还有,除了通式(1)所示化合物之外,本发明也包括其可能的互变异构体、立体异构体、旋光异构体和它们的化合物。
通式(1)所示的本发明化合物可按以下方法进行合成。
通式(1)所示的化合物,可以通过将通式(2)所示的化合物作为起始原料和通式(3)的化合物反应合成得到。
这里的通式(1)、通式(2)、通式(3)中,R1、R2、R3、R4、R5、X1、X2、X3、X4、X5、X6、X7、X8、X9、A、L、n、m分别表示和上述相同的意义。
即,通式(1)所示的化合物,可以通过将通式(2)所示的化合物和通式(3)所示的化合物,在碳酸钾、三乙基胺、二异丙基乙基胺、叔丁醇钾、叔丁醇钠等碱的存在下,根据需要加入铜、钯、镍等金属催化剂和二苯基磷乙烷、二苯基磷丙烷、二苯基磷二茂铁、2,2’-双(二苯基磷)-1,1’-联二萘等配基,在不影响反应的溶剂中,例如甲醇、乙醇、异丙醇等醇类,或二甲基甲酰胺、四氢呋喃、乙腈、甲苯、1,4-二噁烷中,从室温至反应混合物沸点的温度范围内进行反应合成制得。优选在三乙基胺或二异丙基乙基胺的存在下,在二甲基甲酰胺中,在60℃下进行反应,可以在碳酸钾、叔丁醇钾或叔丁醇钠存在下,加入钯催化剂和二苯基磷二茂铁或2,2’-双(二苯基磷)-1,1’-联二萘等配基,在乙腈或甲苯中,在80℃~反应混合物沸点的温度范围内进行合成反应。
此外,通式(1)所示的化合物可以通过以通式(9)所示化合物为起始原料,和通式(10)的化合物进行反应合成制得。
还有,在通式(1)、通式(9)、通式(10)中,R1、R2、R3、R4、X1、X2、X3、X4、R5、A、L、m、n分别表示和上述相同的意义。
即,通式(1)所示的化合物,可以通过将通式(9)所示的化合物和通式(10)所示的化合物,在碳酸钾、三乙基胺、叔丁醇钾、叔丁醇钠等碱的存在下,根据需要加入铜、钯、镍等金属催化剂和二苯基磷乙烷、二苯基磷丙烷、二苯基磷二茂铁、2,2’-双(二苯基磷)-1,1’-联二萘等配基,优选加入钯催化剂和二苯基磷二茂铁,在不影响反应的溶剂中,例如甲醇、乙醇、异丙醇等醇类,或二甲基甲酰胺、四氢呋喃、乙腈、甲苯、二噁烷中,优选在甲苯中,从室温至反应混合物沸点的温度范围内,优选在80℃下进行反应合成制得。
在通式(1)所示的化合物中,A为可具有取代基的吡啶环,其取代基的一个为低级烷氧基、低级烷硫基、NX10X11的通式(5)所示的化合物可以以结合有脱去基团的通式(4)的化合物为起始原料合成制得。
这里,在通式(4)、通式(5)、通式(12)、通式(13)、通式(14)中,R1、R2、R3、R4、X1、X2、X3、X4、L、m、n分别表示和上述相同的意义;R6表示硝基、氰基、三氟甲基、C(=O)X7等吸电性基团;R7、R8分别表示氢原子、卤素原子、硝基、氰基、三氟甲基、羟基、低级烷氧基、低级烷基、低级烷硫基、NX5X6、C(=O)X7;这里X5、X6、X7分别表示和上述相同的基团;R11表示低级烷氧基、低级烷硫基、NX10X11;R12、X10分别表示低级烷基;X11表示氢原子、低级烷基。
即,式(5)所示的化合物例如可通过将式(4)所示的化合物和与期望相对应的通式(12)、通式(13)或通式(14)所示的化合物在三乙基胺、氢化钠等碱的存在下,在不影响反应的溶剂中、例如二甲基甲酰胺、四氢呋喃、乙腈中,从室温至反应混合物沸点的温度范围内进行反应合成制得。
在通式(1)所示的化合物中,A为可具有取代基的吡啶环,其取代基的一个为低级烷基通式(11)所示的化合物可以用结合有脱去基团的通式(4)的化合物所对应的低级烷基碳酸酯起亲核取代反应所得的化合物脱碳酸制得。
这里,通式(4)、通式(11)中的R1、R2、R3、R4、R6、R7、R8、X1、X2、X3、X4、L、m、n分别表示和上述相同的意义;R14表示低级烷基。
即,通式(11)所示的化合物例如可通过将通式(4)所示的化合物和根据期望相对应的低级烷基二碳酸酯,在氢化钠等碱的存在下,在不影响反应的溶剂中,例如二甲基甲酰胺、四氢呋喃、乙腈中,优选在二甲基甲酰胺中,在室温至反应混合物沸点的温度范围内,优选在室温下进行反应后,在硫酸水溶液中、反应混合物沸点下进行反应合成制得。
这里所说的低级烷基二碳酸酯例如有丙二酸二甲酯、丙二酸二乙酯、甲基丙二酸二乙酯、乙基丙二酸二乙酯、正丙基丙二酸二乙酯、异丙基丙二酸二乙酯、正丁基丙二酸二乙酯、异丁基丙二酸二乙酯、叔丁基丙二酸二乙酯、正戊基丙二酸二乙酯等。
通式(1)中,A为可具有取代基的吡啶环,其取代基的一个为氨基的通式(7)所示的化合物例如可以将所对应的通式(6)的化合物中的硝基还原制得。
还有,通式(6)、通式(7)中的R1、R2、R3、R4、m、n分别表示和上述相同的意义;R6、R7、R8分别表示氢原子、卤素原子、三氟甲基、羟基、低级烷基、低级烷氧基、低级烷硫基、NX5X6、COX7;这里的X5、X6、X7分别表示和上述相同的意义。
即,通式(7)所示的化合物可以通过将通式(6)所示的化合物在乙醇、甲醇、乙酸乙酯、乙酸、1,4-二噁烷等不影响反应的溶剂中,优选在乙醇、甲醇中,在氢气氛围下,从室温至反应混合物沸点的温度内、优选在室温下,用钯碳、阮氏镍或氧化铂作为催化剂进行催化还原,或用氯化镍和硼氢化钠等进行还原反应,还原硝基而制得。
在通式(1)中,A为可具有取代基的吡啶环,其取代基的一个为NR9R10的通式(8)所示的化合物可以用通式(7)的化合物为起始原料进行合成。
这里,在通式(7)、通式(8)、通式(15)、通式(16)、通式(17)中,R1、R2、R3、R4、R6、R7、R8、R12、X1、X2、X3、X4、L、m、n分别表示和上述相同的意义;R9表示氢原子、低级烷基;R10表示低级烷基、酰基、低级烷氧基羰基;R13表示可被苯基取代的低级烷基;X表示卤素原子。
即,通式(8)所示的化合物可以通过将通式(7)所示的化合物和期望相对应的通式(15)、通式(16)或通式(17)所示的化合物,在三乙基胺、碳酸钾等碱的存在下,在不影响反应的溶剂中,从室温至反应混合物沸点的温度内,优选在室温下进行反应合成制得。
合成上述式(1)、式(5)、式(7)、式(8)、式(11)所示的化合物时,在这些合成过程中伯胺基或仲胺基需要保护的情况下,用适当的树脂保护后,或者用Green and Wuts.“PROTECTIVE GROUPSIN ORGANIC SYNTHESIS有机合成中的保护基团”2nd Edition.JohnWiley & Sons Inc.,P.309,1991中记载的适当保护基团保护后,再进行各反应。此外,可根据需要进行脱保护反应。作为氨基的保护基团,例如有叔丁氧基羰基、三氟乙酰基等。
对于氨基的保护反应,例如叔丁氧基羰基化,可以在不影响反应的溶剂中,例如在甲醇、乙醇、异丙醇等醇类、或二氯甲烷、二甲基甲酰胺、1,4-二噁烷中,在三乙基胺、4-二甲基氨基吡啶等有机碱的存在下,与二碳酸二叔丁酯在0℃至室温下进行反应。
此外,用Wang Resin的氨基保护反应,可以在不影响反应的溶剂中,例如在二氯甲烷、二甲基甲酰胺、1,4-二噁烷中,在4-甲基吗啉、三乙基氨基、4-二甲基氨基吡啶等有机碱的存在下,用4-酰基苯氧基羰基-Wang Resin(Tetrahedron Lett.,37,937-940(1996))在0℃至室温下进行反应。
对于氨基的脱保护反应,例如保护基团为叔丁氧基羰基或上述所示的Wang resin时,优选在不影响反应的溶剂中,例在甲醇、乙醇、1,4-二噁烷、二氯甲烷中,或者在无溶剂的情况下,杂0℃至室温下,用三氟乙酸、盐酸、甲磺酸等脱保护剂进行反应,特别优选在无水条件、室温下用三氟乙酸进行反应。
通式(1)所示的本发明化合物中,其结构中具有不对称碳原子,这些纯立体异构体和旋光异构体可以按本领域周知的方法,例如用旋光异构体分离柱的层析法和分别结晶的方法分离得到。
对于通式(1)所示本发明化合物的医药上允许的盐,此医药上允许的盐没有特殊的限定,例如盐酸、硫酸、硝酸、氢溴酸、氢碘酸等无机酸盐,甲酸、乙酸、福马酸、酒石酸等有机酸盐,钠、钾等碱金属盐,钙、镁等碱土金属盐。
本发明化合物或其盐可以加入适当的赋形剂、辅助剂、润滑剂、防腐剂、崩解剂、缓冲剂、粘合剂、稳定剂、润湿剂、乳化剂、着色剂、矫味剂或芳香剂等,以片剂、颗粒剂、细粒剂、散剂、胶囊剂、糖浆剂、酏剂、悬浊剂、乳剂、注射剂等剂型,口服或非口服给药。对于脑血管障碍的超急性期(发作即后)、急性期(发作~2,3天)、亚急性期(发作后2,3天~2周后),主要是肌肉注射或静脉注射给药。更进一步,对于慢性期(发作后第3周以后),可以适当地通过口服给药。
本发明化合物或其盐的给药量可以根据患者体形、年龄、疾病的程度、发病后经过的时间等进行适当的选择,但一般来说口服给药时每天0.5~5毫克/个体,非口服给药时1~10毫克/个体。还有,一般来说即使给予相同用量不同患者的血药浓度也会有很大不同,所以一边监测药物的血中浓度一边调整每个患者的最适用量则更理想。
作为内服药剂制剂化时,作为制剂载体,例如可以使用乳糖、蔗糖、山梨糖醇、甘露糖醇、马铃薯淀粉或玉米淀粉等淀粉或淀粉衍生物、纤维素衍生物或明胶等通常所用的辅助剂,同时也可加入硬脂酸镁、碳蜡或聚乙二醇等润滑剂,可以按常法将此混合物制成颗粒剂、片剂、胶囊剂等。
作为水性制剂制剂化时,例如可以用注射用蒸馏水将有效量的主成分溶解,根据需要加入抗氧化剂、稳定剂、助溶剂、缓冲剂、防腐剂等,完全溶解后,按常法过滤、填充、密封,用高压蒸气灭菌法、干热灭菌法等灭菌,制成注射剂。
作为冷冻干燥制剂制剂化时,可以用注射用蒸馏水溶解了主成分的水溶液按常法冷冻干燥,或根据需要加入使冷冻干燥易于进行的赋形剂,如甘露醇、肌醇、乳糖、麦芽糖、蔗糖等糖类或糖醇类或者甘氨酸等,按常法进行冷冻干燥,制成制剂。
实施例
实施例化合物的一览表如表1~表37所示。
表1
【表1】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
1 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
2 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
3 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
4 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
5 | (2) | CR6 | N | NHMe | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
6 | (2) | CR6 | N | NHMe | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | |
7 | (2) | CR6 | N | NHEt | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
8 | (2) | CR6 | N | NHEt | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
9 | (2) | CR6 | N | H | 2 | 4-H | 5-NO2 | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
10 | (2) | CR6 | N | H | 2 | 4-H | 5-NO2 | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
11 | (2) | CR6 | N | H | 2 | 4-H | 5-NH2 | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
12 | (2) | CR6 | N | H | 2 | 4-H | 5-NH2 | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
13 | (2) | CR6 | N | NO2 | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
14 | (2) | CR6 | N | NO2 | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
15 | (2) | CR6 | N | NO2 | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表2
【表2】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
16 | (2) | CR6 | N | NH2 | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
17 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
18 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
19 | (2) | CR6 | N | NH2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
20 | (2) | CR6 | N | NH2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
21 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-OMe | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
22 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-OMe | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
23 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-Et | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
24 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-Et | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
25 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-Et | 5-H | 6-H | 3 | CO2 tBu | H | 0 | indan-2-yl | 0 | H | ||
26 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-Et | 5-H | 6-H | 3 | H | H | 0 | indan-2-yl | 0 | H | HCl | |
27 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-Cl | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
28 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-Cl | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
29 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-NHMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
30 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-NHMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表3
【表3】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
31 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-NHEt | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
32 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-NHEt | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
33 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-NHnPr | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
34 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-NHnPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
35 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-NMe2 | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
36 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-NMe2 | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
37 | (2) | CR6 | N | CO2H | 2 | 4-H | 5-H | 6-Cl | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
38 | (2) | CR6 | N | CO2H | 2 | 4-H | 5-H | 6-Cl | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
39 | (2) | CR6 | N | H | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
40 | (2) | CR6 | N | H | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
41 | (2) | CR6 | N | CF3 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
42 | (2) | CR6 | N | CF3 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
43 | (2) | CR6 | N | CO2Me | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
44 | (2) | CR6 | N | CO2Me | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
45 | (2) | CR6 | N | CO2H | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表4
【表4】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
46 | (2) | CR6 | N | H | 2 | 4-OBn | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | Ac | H | 0 | H | H | 0 | H | HCl |
47 | (2) | CR6 | N | H | 2 | 4-OBn | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
48 | (2) | CR6 | N | H | 2 | 4-H | 5-H | 6-H | 2-H | 4-cyclobutyl | 5-H | 6-H | 3 | Bz | H | 0 | H | H | 0 | H | HCl |
49 | (2) | CR6 | N | H | 2 | 4-H | 5-H | 6-H | 2-H | 4-cyclopentyl | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
50 | (2) | CR6 | N | H | 2 | 4-H | 5-H | 6-H | 2-H | 4-piperidino | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
51 | (2) | CR6 | N | H | 2 | 4-H | 5-H | 6-H | 2-H | 4-O(CH2)2Ph | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
52 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
53 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
54 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-nPr | 2-H | 4-H | 5-H | 6-H | 3 | Bn | H | 0 | H | H | 0 | H | HCl |
55 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-iPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
56 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OH | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
57 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OEt | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
58 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OnPr | 2-H | 4-H | 5-H | 6-H | 3 | CH2CH2Ph | H | 0 | H | H | 0 | H | HCl |
59 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OiPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
60 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-SH | 2-H | 4-H | 5-H | 6-H | 3 | CH2CH2Cl | CH2CH2Cl | 0 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表5
【表5】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
61 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-SMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
62 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-SEt | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
63 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-SnPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Me | HCl |
64 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-SiPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Et | HCl |
65 | (2) | CR6 | N | H | 2 | 4-NO2 | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
66 | (2) | CR6 | N | H | 2 | 4-NO2 | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
67 | (2) | CR6 | N | H | 2 | 4-H | 5-NO2 | 6-OMe | 2-H | 4-H | 5-NHAc | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
68 | (2) | CR6 | N | H | 2 | 4-H | 5-NO2 | 6-Et | 2-H | 4-NHBn | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
69 | (2) | CR6 | N | CO2H | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-NO2 | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | nPr | HCl |
70 | (2) | CR6 | N | CO2H | 2 | 4-H | 5-H | 6-Et | 2-H | 4-H | 5-NO2 | 6-H | 3 | H | H | 0 | H | H | 0 | Ac | HCl |
71 | (2) | CR6 | N | CO2Me | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Bn | HCl |
72 | (2) | CR6 | N | CO2Me | 2 | 4-H | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
73 | (2) | CR6 | N | CONH2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-F | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
74 | (2) | CR6 | N | CONH2 | 2 | 4-H | 5-H | 6-Et | 2-H | 4-H | 5-Br | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
75 | (2) | CR6 | N | CF3 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-CH2Br | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表6
【表6】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
76 | (2) | CR6 | N | CF3 | 2 | 4-H | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
77 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-Me | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
78 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-nPr | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
79 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-NHMe | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
80 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-NHEt | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
81 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-NMe2 | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
82 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-pyrrolidin-1-yl | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
83 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-OH | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
84 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-OEt | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
85 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-Me | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
86 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-F | 4-H | 5-Et | 6-H | 3 | H | H | 0 | CH2CH2OH | CH2CH2OH | 0 | H | HCl |
87 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-Cl | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
88 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-Me | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
89 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-OH | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
90 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-OMe | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表7
【表7】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
91 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | Me | H | 0 | H | HCl |
92 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-CN | 5-H | 6-H | 3 | H | H | 0 | Et | H | 0 | H | HCl |
93 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-CN | 5-H | 6-H | 3 | H | H | 0 | nPr | H | 0 | H | HCl |
94 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-cyclobutylthio | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | Me | Me | 0 | H | HCl |
95 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-cyclopentylthio | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | -(CH2)2- | 0 | H | HCl | |
96 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-cyclohexylthio | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | -(CH2)3- | 0 | H | HCl | |
97 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | -(CH2)4- | 0 | H | HCl | |
98 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | Me | H | 0 | H | H | 0 | H | HCl |
99 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | Et | H | 0 | H | H | 0 | H | HCl |
100 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-OMe | 4-H | 5-H | 6-H | 3 | Me | Me | 0 | H | H | 0 | H | HCl |
101 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-OMe | 4-H | 5-H | 6-H | 3 | -(CH2)3- | 0 | H | H | 0 | H | HCl | |
102 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | -(CH2)4- | 0 | H | H | 0 | H | HCl | |
103 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | -(CH2)6- | 0 | H | H | 0 | H | HCl | |
104 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | CH2OH | H | 0 | H | HCl |
105 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | CH2CH2OH | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式的取代位置。
*2:数字表示苯环上的取代位置。
表8
【表8】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
106 | (2) | CR6 | N | H | 2 | 4-OMe | 5-H | 6-NO2 | 2-H | 4-Ph | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
107 | (2) | CR6 | N | OH | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
108 | (2) | CR6 | N | CHO | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
109 | (2) | CR6 | N | CO2H | 4 | 2-H | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
110 | (2) | CR6 | N | CONH2 | 4 | 2-H | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
111 | (2) | CR6 | N | CO2Me | 4 | 2-H | 5-H | 6-OMe | 2-H | 4-H | 5-Me | 6-Me | 3 | H | H | 0 | H | H | 0 | H | HCl |
112 | (2) | CR6 | N | CN | 4 | 2-H | 5-H | 6-Et | 2-Me | 4-Me | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
113 | (2) | CR6 | N | CF3 | 5 | 2-Me | 4-H | 6-H | 2-H | 4-H | 5-Br | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
114 | (2) | CR6 | N | NO2 | 4 | 2-H | 5-OEt | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
115 | (2) | CR6 | N | H | 5 | 2-H | 4-NO2 | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
116 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Me | HCl |
117 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Et | HCl |
118 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | nPr | HCl |
119 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OEt | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Ac | HCl |
120 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Bz | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表9
【表9】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
121 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-SMe | 2-H | 4-H | 5-H | 6-H | 2 | H | H | 0 | H | H | 0 | CO2Me | HCl |
122 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-SEt | 2-H | 4-H | 5-H | 6-H | 2 | H | H | 0 | H | H | 0 | CO2Et | HCl |
123 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-Ph | 6-H | 2 | H | H | 0 | Me | Me | 0 | H | HCl |
124 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-CONH2 | 5-H | 6-H | 2 | H | H | 0 | CH2OH | H | 0 | H | HCl |
125 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-Me | 4-H | 5-H | 6-H | 2 | H | H | 0 | CH2Br | H | 0 | H | HCl |
126 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-Me | 4-H | 5-H | 6-H | 2 | H | H | 0 | H | H | 0 | H | HCl |
127 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-CH2OH | 4-H | 5-H | 6-H | 2 | H | H | 0 | H | H | 0 | H | HCl |
128 | (2) | CR6 | N | CO2H | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 2 | H | H | 0 | Bn | H | 0 | H | HCl |
129 | (2) | CR6 | N | CO2H | 2 | 4-H | 5-H | 6-Me | 2-Me | 4-H | 5-H | 6-H | 2 | H | H | 0 | CH2CH2Ph | H | 0 | H | HCl |
130 | (2) | CR6 | N | CO2H | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 2 | H | H | 0 | CH2OH | H | 0 | H | HCl |
131 | (2) | CR6 | N | CO2Me | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-NO2 | 2 | H | H | 0 | H | H | 0 | H | HCl |
132 | (2) | CR6 | N | CO2Me | 2 | 4-H | 5-H | 6-Me | 2-Cl | 4-OMe | 5-H | 6-H | 2 | H | H | 0 | H | H | 0 | H | HCl |
133 | (2) | CR6 | N | CO2Me | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-NHAc | 5-H | 6-H | 2 | H | H | 0 | H | H | 0 | H | HCl |
134 | (2) | CR6 | N | CO2Me | 2 | 4-H | 5-H | 6-Et | 2-Me | 4-H | 5-H | 6-H | 2 | H | H | 0 | H | H | 0 | H | HCl |
135 | (2) | CR6 | N | CO2Me | 2 | 4-H | 5-H | 6-Et | 2-H | 4-CONH2 | 5-H | 6-H | 2 | CH2CH2F | H | 0 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表10
【表10】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
136 | (2) | CR6 | N | H | 4 | 2-CONMe2 | 5-H | 6-OMe | 3-H | 4-H | 5-H | 6-H | 2 | H | H | 1 | H | H | 0 | H | 2HCl |
137 | (2) | CR6 | N | H | 4 | 2-CONHMe | 5-H | 6-Et | 3-H | 4-H | 5-H | 6-H | 2 | H | H | 1 | H | H | 0 | H | 2HCl |
138 | (2) | CR6 | N | H | 4 | 2-NHAc | 5-H | 6-H | 3-H | 4-H | 5-H | 6-H | 2 | H | H | 1 | H | H | 0 | H | 2HCl |
139 | (2) | CR6 | N | H | 4 | 2-NHCO2Me | 5-H | 6-H | 3-H | 4-H | 5-H | 6-H | 2 | H | H | 1 | H | H | 0 | H | 2HCl |
140 | (2) | CR6 | N | H | 4 | 2-NHBz | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 2 | H | H | 1 | H | H | 0 | H | 2HCl |
141 | (2) | CR6 | N | NO2 | 5 | 2-H | 4-H | 6-F | 2-H | 4-H | 5-H | 6-H | 2 | H | H | 1 | H | H | 0 | H | HCl |
142 | (2) | CR6 | N | NO2 | 5 | 2-H | 4-H | 6-Br | 2-H | 3-H | 5-H | 6-H | 4 | H | H | 0 | H | H | 1 | H | HCl |
143 | (2) | CR6 | N | NO2 | 5 | 2-H | 4-H | 6-H | 2-CO2H | 3-H | 5-H | 6-H | 4 | H | H | 0 | H | H | 1 | H | HCl |
144 | (2) | CR6 | N | NO2 | 5 | 2-H | 4-H | 6-H | 2-H | 3-CO2Me | 5-H | 6-H | 4 | H | H | 0 | H | H | 1 | H | HCl |
145 | (2) | CR6 | N | NO2 | 5 | 2-H | 4-H | 6-H | 2-H | 3-CONHMe | 5-H | 6-H | 4 | H | H | 0 | H | H | 1 | H | HCl |
146 | (2) | CR6 | N | NO2 | 5 | 2-H | 4-H | 6-H | 2-H | 3-H | 5-CHO | 6-H | 4 | H | H | 0 | H | H | 1 | H | HCl |
147 | (2) | CR6 | N | H | 2 | 3-H | 4-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | CHO | HCl |
148 | (2) | CR6 | N→O | H | 2 | 3-H | 4-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
149 | (2) | CR6 | N→O | H | 2 | 3-H | 4-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
150 | (2) | CR6 | N→O | H | 2 | 3-H | 4-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表11
【表11】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
151 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
152 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
153 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
154 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-NHMe | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CH2CH2F | CH2CH2F | 0 | H | H | 0 | H | 2HCl |
155 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-NMe2 | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CH2CH2Cl | CH2CH2Cl | 0 | H | H | 0 | H | 2HCl |
156 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-NHEt | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CH2CH2Br | CH2CH2Br | 0 | H | H | 0 | H | 2HCl |
157 | (2) | CR6 | CH | NO2 | 2 | 4-SMe | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
158 | (2) | CR6 | CH | NO2 | 2 | 4-SEt | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
159 | (2) | CR6 | CH | NO2 | 2 | 4-SnP r | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
160 | (2) | CR6 | CH | CO2H | 2 | 4-H | 5-H | 6-Me | 2-Me | 4-H | 5-H | 6-H | 3 | H | H | 0 | -(CH2)2- | 0 | H | HCl | |
161 | (2) | CR6 | CH | CO2H | 2 | 4-H | 5-H | 6-nPr | 2-H | 4-Et | 5-H | 6-H | 3 | H | H | 0 | -(CH2)3- | 0 | H | HCl | |
162 | (2) | CR6 | CH | CO2H | 2 | 4-H | 5-H | 6-NHnPr | 2-H | 4-H | 5-nPr | 6-H | 3 | H | H | 0 | -(CH2)4- | 0 | H | 2HCl | |
163 | (2) | CR6 | CH | CO2H | 2 | 4-H | 5-H | 6-F | 2-NHBn | 4-H | 5-H | 6-H | 3 | -(CH2)2- | 0 | H | H | 0 | H | 2HCl | |
164 | (2) | CR6 | CH | CO2H | 2 | 4-H | 5-H | 6-Cl | 2-H | 4-NHEt | 5-H | 6-H | 3 | -(CH2)3- | 0 | H | H | 0 | H | 2HCl | |
165 | (2) | CR6 | CH | CO2H | 2 | 4-H | 5-H | 6-Br | 2-H | 4-H | 5-H | 6-SEt | 3 | -(CH2)4- | 0 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表12
【表12】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
166 | (2) | CR6 | CH | CO2Me | 2 | 4-H | 5-H | 6-Me | 2-H | 4-pyrrolidin-1-yl | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
167 | (2) | CR6 | CH | CO2Me | 2 | 4-H | 5-H | 6-Et | 2-H | 4-pyrrolidin-1-yl | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
168 | (2) | CR6 | CH | CO2Me | 2 | 4-H | 5-H | 6-OMe | 2-OMe | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
169 | (2) | CR6 | CH | H | 2 | 4-H | 5-CONH2 | 6-Me | 2-OEt | 4-H | 5-H | 6-H | 3 | Bn | H | 0 | H | H | 0 | H | HCl |
170 | (2) | CR6 | CH | H | 2 | 4-H | 5-CONH2 | 6-Me | 2-H | 4-OBn | 5-H | 6-H | 3 | CH2CH2Ph | H | 0 | H | H | 0 | H | HCl |
171 | (2) | CR6 | CH | H | 2 | 4-H | 5-CONMe2 | 6-Me | 2-F | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
172 | (2) | CR6 | CH | H | 2 | 4-H | 5-CONMe2 | 6-Me | 2-Cl | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
173 | (2) | CR6 | CH | H | 2 | 4-NHAc | 5-H | 6-Me | 2-Br | 4-H | 5-H | 6-H | 3 | Ac | H | 0 | H | H | 0 | H | |
174 | (2) | CR6 | CH | H | 2 | 4-NHAc | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
175 | (2) | CR6 | CH | H | 2 | 4-NHAc | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
176 | (2) | CR6 | CH | H | 2 | 4-NHBn | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | Me | H | 0 | H | HCl |
177 | (2) | CR6 | CH | H | 2 | 4-NHBn | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | Me | Me | 0 | H | HCl |
178 | (2) | CR6 | CH | H | 2 | 4-NHBz | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | Bz | H | 0 | Me | Et | 0 | H | |
179 | (2) | CR6 | CH | CF3 | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | Bn | H | 0 | H | HCl |
180 | (2) | CR6 | CH | CF3 | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | CH2OH | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表13
【表13】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
181 | (2) | CR6 | CH | CN | 2 | 4-H | 5-H | 6-cyclobutyl | 2-H | 4-OH | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
182 | (2) | CR6 | CH | CN | 2 | 4-H | 5-H | 6-cyclopentyl | 2-H | 4-H | 5-CN | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
183 | (2) | CR6 | CH | CN | 2 | 4-H | 5-H | 6-cyclohexyl | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
184 | (2) | CR6 | CH | OH | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | CH2CH2OH | CH2CH2OH | 0 | H | 2HCl |
185 | (2) | CR6 | CH | OH | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-OH | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
186 | (2) | CR6 | CH | NH2 | 2 | 4-H | 5-NHCOMe | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
187 | (2) | CR6 | CH | NH2 | 2 | 4-H | 5-NHCO2Me | 6-H | 2-H | 4-CH2Ph | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
188 | (2) | CR6 | CH | NH2 | 2 | 4-H | 5-CHO | 6-H | 2-H | 4-CH2OH | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
189 | (2) | CR6 | CH | NH2 | 2 | 4-H | 5-H | 6-H | 2-CH2OH | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
190 | (2) | CR6 | CMe | CHO | 2 | 4-H | 5-H | 6-cyclobutylthio | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
191 | (2) | CR6 | CH | CHO | 2 | 4-H | 5-H | 6-cyclopentylthio | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
192 | (2) | CR6 | CH | CHO | 2 | 4-H | 5-H | 6-cyclohexylthio | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
193 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-H | 2-OH | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
194 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-H | 2-CN | 4-H | 5-H | 6-H | 3 | Me | H | 0 | H | H | 0 | H | HCl |
195 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-NO2 | 3 | Me | Me | 0 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表14
【表14】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
196 | (2) | CR6 | CH | H | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | Me | 0 | Me | H | 0 | H | HCl |
197 | (2) | CR6 | CH | H | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-NO2 | 3 | Me | Me | 0 | H | H | 0 | H | HCl |
198 | (2) | CR6 | CEt | H | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | H | H | 0 | H | HCl |
199 | (2) | CR6 | CH | H | 2 | 4-H | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | H | H | 0 | H | HCl |
200 | (2) | CR6 | CH | H | 2 | 4-H | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | H | H | 0 | Ac | HCl |
201 | (2) | CR6 | CH | H | 2 | 4-H | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | H | H | 0 | Me | HCl |
202 | (2) | CR6 | CH | H | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | H | H | 0 | Ac | HCl |
203 | (2) | CR6 | CH | H | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | H | H | 0 | nPr | HCl |
204 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-Me | 2-H | 3-H | 5-H | 6-H | 4 | H | H | 0 | H | H | 1 | CO2Me | HCl |
205 | (2) | CR6 | CnPr | NO2 | 2 | 4-H | 5-H | 6-Me | 2-H | 3-H | 5-H | 6-H | 4 | H | H | 0 | H | H | 1 | CO2Et | HCl |
206 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-Me | 2-H | 3-H | 5-H | 6-H | 4 | H | H | 0 | CH2OH | H | 1 | H | HCl |
207 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-Me | 2-H | 3-H | 5-H | 6-H | 4 | H | H | 0 | CH2Ph | H | 1 | H | HCl |
208 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 3-H | 4-H | 6-H | 5 | H | H | 1 | H | H | 0 | H | HCl |
209 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 3-H | 4-H | 6-H | 5 | H | H | 1 | CH2CH2Ph | H | 0 | H | HCl |
210 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 3-H | 4-H | 6-H | 5 | H | H | 1 | CH2Ph | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表15
【表15】
实施例序号 | A | Y | Z | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
211 | (2) | N | N | 2 | 4-NO2 | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
212 | (2) | N | N | 2 | 4-NO2 | 5-H | 6-Et | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
213 | (2) | N | N | 2 | 4-NO2 | 5-H | 6-nPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
214 | (2) | N | N | 2 | 4-NO2 | 5-H | 6-iPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
215 | (2) | N | N | 2 | 4-CO2H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
216 | (2) | N | N | 2 | 4-CO2H | 5-H | 6-OEt | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
217 | (2) | N | N | 2 | 4-CO2H | 5-H | 6-OnPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
218 | (2) | N | N | 2 | 4-CO2H | 5-H | 6-OiPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
219 | (2) | N | N | 2 | 4-CO2Me | 5-H | 6-NHMe | 2-H | 4-H | 5-H | 6-H | 3 | Bn | H | 0 | H | H | 0 | H | HCl |
220 | (2) | N | N | 2 | 4-CO2Me | 5-H | 6-NMe2 | 2-H | 4-H | 5-H | 6-H | 3 | CH2CH2Ph | H | 0 | H | H | 0 | H | HCl |
221 | (2) | N | N | 2 | 4-CO2Et | 5-H | 6-NHEt | 2-H | 4-H | 5-H | 6-H | 3 | CH2(CH2)2Ph | H | 0 | H | H | 0 | H | HCl |
222 | (2) | N | N | 2 | 4-CO2Et | 5-H | 6-NHnPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
223 | (2) | N | N | 2 | 4-CO2Et | 5-H | 6-H | 2-Me | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
224 | (2) | N | N | 2 | 4-CO2 nPr | 5-H | 6-H | 2-Et | 4-H | 5-H | 6-H | 3 | H | H | 0 | Bn | H | 0 | H | HCl |
225 | (2) | N | N | 2 | 4-CO2 nPr | 5-H | 6-H | 2-nPr | 4-H | 5-H | 6-H | 3 | H | H | 0 | CH2CH2Ph | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表16
【表16】
实施例序号 | A | Y | Z | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
226 | (2) | N | N | 4 | 2-CF3 | 5-H | 6-H | 2-H | 4-OMe | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
227 | (2) | N | N | 4 | 2-CF3 | 5-H | 6-H | 2-H | 4-OEt | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
228 | (2) | N | N | 4 | 2-CF3 | 5-H | 6-H | 2-H | 4-OnPr | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
229 | (2) | N | N | 4 | 2-H | 5-CN | 6-H | 2-H | 3-H | 5-NHMe | 6-H | 4 | Ac | H | 1 | H | H | 0 | H | HCl |
230 | (2) | N | N | 4 | 2-H | 5-CN | 6-H | 2-H | 3-H | 5-NHEt | 6-H | 4 | Bz | H | 1 | H | H | 0 | H | HCl |
231 | (2) | N | N | 4 | 2-H | 5-CN | 6-H | 2-H | 3-H | 5-NHnPr | 6-H | 4 | CO2 tBu | H | 1 | H | H | 0 | H | |
232 | (2) | N | N | 4 | 2-H | 5-H | 6-CONH2 | 2-H | 3-H | 5-H | 6-SMe | 4 | H | H | 1 | H | H | 0 | H | 2HCl |
233 | (2) | N | N | 4 | 2-H | 5-H | 6-CONH2 | 2-H | 3-H | 5-H | 6-SEt | 4 | H | H | 1 | H | H | 0 | H | 2HCl |
234 | (2) | N | N | 4 | 2-H | 5-H | 6-CONH2 | 2-H | 3-H | 5-H | 6-SnPr | 4 | H | H | 1 | H | H | 0 | H | 2HCl |
235 | (2) | N | N | 5 | 2-OMe | 4-H | 6-H | 3-H | 4-H | 5-H | 6-NO2 | 2 | Me | H | 1 | H | H | 0 | H | 2HCl |
236 | (2) | N | N | 5 | 2-OEt | 4-H | 6-H | 3-H | 4-H | 5-H | 6-NO2 | 2 | Me | Me | 1 | H | H | 0 | H | 2HCl |
237 | (2) | N | N | 5 | 2-H | 4-cyclopropyl | 6-H | 3-H | 4-H | 5-H | 6-NO2 | 2 | Et | H | 1 | H | H | 0 | H | 2HCl |
238 | (2) | N | N | 5 | 2-H | 4-cyclobutyl | 6-H | 3-H | 4-H | 5-H | 6-NO2 | 2 | Et | Et | 1 | H | H | 0 | H | 2HCl |
239 | (2) | N | N | 5 | 2-H | 4-cyclopentyl | 6-H | 3-H | 4-H | 5-H | 6-CO2H | 2 | CH2CH2Cl | CH2CH2Cl | 1 | H | H | 0 | H | 2HCl |
240 | (2) | N | N | 5 | 2-H | 4-cyclohexyl | 6-H | 3-H | 4-H | 5-H | 6-CO2H | 2 | CH2CH2Br | CH2CH2Br | 1 | H | H | 0 | H | 2HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表17
【表17】
实施例序号 | A | Y | Z | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
241 | (2) | N | N | 2 | 4-CHO | 5-H | 6-H | 2-H | 4-NHAc | 5-H | 6-H | 3 | -CH2CH2- | 0 | H | H | 0 | H | HCl | |
242 | (2) | N | N | 2 | 4-CHO | 5-H | 6-H | 2-H | 4-NHBz | 5-H | 6-H | 3 | -CH2CH2CH2- | 0 | H | H | 0 | H | HCl | |
243 | (2) | N | N | 2 | 4-NH2 | 5-H | 6-H | 2-H | 4-H | 5-CONH2 | 6-H | 3 | -CH2(CH2)2CH2- | 0 | H | H | 0 | H | 2HCl | |
244 | (2) | N | N | 2 | 4-NH2 | 5-H | 6-H | 2-H | 4-H | 5-CONHMe | 6-H | 3 | H | H | 0 | Me | H | 0 | Me | 2HCl |
245 | (2) | N | N | 2 | 4-NH2 | 5-H | 6-H | 2-H | 4-H | 5-CONHEt | 6-H | 3 | H | H | 0 | Me | Me | 0 | Et | 2HCl |
246 | (2) | N | N | 2 | 4-H | 5-OH | 6-H | 2-H | 4-H | 5-H | 6-CO2Me | 3 | H | H | 0 | Et | H | 0 | nPr | 2HCl |
247 | (2) | N | N | 2 | 4-H | 5-OH | 6-H | 2-H | 4-H | 5-H | 6-CO2Et | 3 | H | H | 0 | Et | Et | 0 | CHO | HCl |
248 | (2) | N | N | 2 | 4-H | 5-H | 6-pyrrolidin-1-yl | 2-H | 4-H | 5-H | 6-CO2 nPr | 3 | H | H | 0 | -CH2CH2- | 0 | Ac | 2HCl | |
249 | (2) | N | N | 2 | 4-H | 5-H | 6-piperidino | 2-H | 4-CH2OH | 5-H | 6-H | 3 | H | H | 0 | -CH2CH2CH2- | 0 | Bz | 2HCl | |
250 | (2) | N | N | 2 | 4-H | 5-H | 6-H | 2-H | 4-F | 5-H | 6-H | 3 | H | H | 0 | -CH2(CH2)2CH2- | 0 | CO2Et | HCl | |
251 | (2) | N | N | 2 | 4-H | 5-H | 6-H | 2-H | 4-Cl | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | CO2 nPr | HCl |
252 | (2) | N | N | 2 | 4-H | 5-H | 6-H | 2-H | 4-Br | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | CO2 tBu | HCl |
253 | (2) | N→O | N→O | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-CH2Br | 6-H | 3 | H | H | 0 | CH2CH2F | CH2CH2F | 0 | H | HCl |
254 | (2) | N→O | N→O | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-CN | 6-H | 3 | H | H | 0 | CH2CH2Cl | CH2CH2Cl | 0 | H | HCl |
255 | (2) | N→O | N→O | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-CF3 | 6-H | 3 | H | H | 0 | CH2CH2Br | CH2CH2Br | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表18
【表18】
实施例序号 | A | T | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
256 | (5) | CR6 | NO2 | 2 | 4-H | 5-Me | H | 2-H | 4-OMe | 5-H | 6-H | 3 | Me | H | 0 | H | H | 0 | Me | HCl |
257 | (5) | CR6 | NO2 | 2 | 4-H | 5-Et | H | 2-H | 4-OEt | 5-H | 6-H | 3 | H | H | 0 | Me | H | 0 | H | HCl |
258 | (5) | CR6 | NO2 | 2 | 4-H | 5-nPr | Me | 2-H | 4-OnPr | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Et | HCl |
259 | (5) | CR6 | NO2 | 2 | 4-H | 5-iPr | H | 2-H | 4-OiPr | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
260 | (5) | CR6 | CO2H | 2 | 4-H | 5-OMe | H | 2-Me | 4-H | 5-H | 6-H | 3 | Et | H | 0 | H | H | 0 | H | HCl |
261 | (5) | CR6 | CO2H | 2 | 4-H | 5-OEt | H | 2-Et | 4-H | 5-H | 6-H | 3 | H | H | 0 | Et | H | 0 | nPr | HCl |
262 | (5) | CR6 | CO2H | 2 | 4-H | 5-OnPr | Et | 2-nPr | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | iPr | HCl |
263 | (5) | CR6 | CO2Me | 2 | 4-H | 5-SMe | H | 2-H | 4-H | 5-NO2 | 6-H | 3 | nPr | H | 0 | H | H | 0 | H | HCl |
264 | (5) | CR6 | CO2Et | 2 | 4-H | 5-SEt | H | 2-H | 4-H | 5-NO2 | 6-H | 3 | H | H | 0 | nPr | H | 0 | H | HCl |
265 | (5) | CR6 | CO2 nPr | 2 | 4-H | 5-SnPr | nPr | 2-H | 4-H | 5-NO2 | 6-H | 3 | H | H | 0 | H | H | 0 | Ac | HCl |
266 | (5) | CR6 | CN | 2 | 4-H | 5-H | H | 2-H | 4-H | 5-H | 6-CO2H | 3 | -CH2CH2- | 0 | H | H | 0 | H | HCl | |
267 | (5) | CR6 | CN | 2 | 4-H | 5-H | H | 2-H | 4-H | 5-H | 6-CO2Me | 3 | H | H | 0 | -CH2CH2- | 0 | H | HCl | |
268 | (5) | CR6 | CN | 2 | 4-H | 5-H | H | 2-H | 4-H | 5-H | 6-CO2Et | 3 | H | H | 0 | H | H | 0 | Bz | HCl |
269 | (5) | CR6 | CF3 | 2 | 4-H | 5-H | H | 2-H | 4-NH2 | 5-H | 6-H | 3 | CH2CH2F | H | 0 | H | H | 0 | H | 2HCl |
270 | (5) | CR6 | CF3 | 2 | 4-H | 5-H | H | 2-H | 4-CONH2 | 5-H | 6-H | 3 | H | H | 0 | CH2CH2F | H | 0 | CHO | 2HCl |
*1:数字表示所用的(2)-(7)结构上的取代位置。
*2:数字表示苯环上的取代位置。
表19
【表19】
实施例序号 | A | T | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
271 | (5) | CR6 | H | 4 | 2-CHO | 5-H | H | 2-F | 3-H | 5-H | 6-H | 4 | H | H | 1 | H | H | 0 | CO2Me | HCl |
272 | (5) | CR6 | H | 4 | 2-CHO | 5-H | H | 2-Cl | 3-H | 5-H | 6-H | 4 | H | H | 1 | H | H | 0 | CO2Et | HCl |
273 | (5) | CR6 | H | 4 | 2-H | 5-NHAc | Ac | 2-Br | 3-H | 5-H | 6-H | 4 | Ac | H | 1 | H | H | 0 | H | |
274 | (5) | CR6 | H | 4 | 2-H | 5-NHBz | H | 2-H | 3-H | 5-H | 6-H | 4 | Bz | H | 1 | H | H | 0 | H | |
275 | (5) | CR6 | H | 4 | 2-CONH2 | 5-H | H | 2-H | 3-H | 5-H | 6-H | 4 | Me | Me | 1 | H | H | 0 | H | 2HCl |
276 | (5) | CR6 | H | 4 | 2-CONHMe | 5-H | Bz | 2-H | 3-H | 5-H | 6-H | 4 | H | H | 1 | Me | Me | 0 | H | 2HCl |
277 | (5) | CR6 | H | 4 | 2-H | 5-CONHEt | H | 2-H | 3-H | 4-H | 5-H | 6 | CO2Et | H | 0 | H | H | 1 | H | |
278 | (5) | CR6 | H | 4 | 2-H | 5-CONHnPr | H | 2-H | 3-H | 4-H | 5-H | 6 | H | H | 0 | H | H | 1 | H | 2HCl |
279 | (5) | CR6 | H | 4 | 2-F | 5-H | CO2Me | 2-H | 3-NHAc | 4-H | 5-H | 6 | CO2 tBu | H | 0 | H | H | 1 | H | |
280 | (5) | CR6 | H | 4 | 2-Cl | 5-H | H | 2-H | 3-NHBz | 4-H | 5-H | 6 | H | H | 0 | H | H | 1 | H | 2HCl |
281 | (5) | CR6 | H | 4 | 2-Br | 5-H | H | 2-H | 2-CONHMe | 4-H | 5-H | 6 | H | H | 0 | H | H | 1 | H | 2HC |
282 | (5) | CR6 | NHMe | 4 | 2-H | 5-H | CO2Et | 2-H | 3-H | 4-H | 5-H | 6 | CH2CH2Cl | CH2CH2Cl | 0 | H | H | 1 | H | HCl |
283 | (5) | CR6 | NHEt | 4 | 2-H | 5-H | H | 2-H | 3-H | 4-H | 5-H | 6 | H | H | 0 | CH2CH2Br | CH2CH2Br | 1 | H | 2HCl |
284 | (5) | CR6 | NHnPr | 4 | 2-H | 5-H | H | 2-H | 3-H | 4-H | 5-H | 6 | H | H | 0 | H | H | 1 | H | 2HCl |
285 | (5) | CR6 | H | 4 | 2-OH | 5-H | CO2 tBu | 2-H | 3-H | 4-H | 5-H | 6 | H | H | 0 | H | H | 1 | H | 2HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表20
【表20】
实施例序号 | A | T | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
286 | (5) | N | 2 | 4-NO2 | 5-H | Me | 2-Me | 4-H | 5-H | 6-H | 3 | H | H | 0 | Me | H | 0 | H | HCl |
287 | (5) | N | 2 | 4-NO2 | 5-H | H | 2-Et | 4-H | 5-H | 6-H | 3 | Me | H | 0 | H | H | 0 | Me | HCl |
288 | (5) | N | 2 | 4-CO2H | 5-H | H | 2-H | 4-nPr | 5-H | 6-H | 3 | H | H | 0 | Et | H | 0 | H | HCl |
289 | (5) | N | 2 | 4-CO2H | 5-H | Et | 2-H | 4-iPr | 5-H | 6-H | 3 | Et | H | 0 | H | H | 0 | Et | HCl |
290 | (5) | N | 2 | 4-CF3 | 5-H | H | 2-H | 4-H | 5-OMe | 6-H | 3 | H | H | 0 | nPr | H | 0 | H | 2HCl |
291 | (5) | N | 2 | 4-CF3 | 5-H | H | 2-H | 4-H | 5-OEt | 6-H | 3 | nPr | H | 0 | H | H | 0 | Ac | HCl |
292 | (5) | N | 2 | 4-CO2Me | 5-H | nPr | 2-H | 4-H | 5-H | 6-NHMe | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
293 | (5) | N | 2 | 4-CO2Me | 5-H | H | 2-H | 4-H | 5-H | 6-NHEt | 3 | -CH2CH2- | 0 | H | H | 0 | Bz | HCl | |
294 | (5) | N | 2 | 4-CO2Et | 5-H | H | 2-SMe | 4-H | 5-H | 6-H | 3 | H | H | 0 | -CH2CH2- | 0 | H | HCl | |
295 | (5) | N | 2 | 4-CO2Et | 5-H | iPr | 2-SEt | 4-H | 5-H | 6-H | 3 | Ac | H | 0 | H | H | 0 | H | |
296 | (5) | N | 2 | 4-CN | 5-H | H | 2-H | 4-OH | 5-H | 6-H | 3 | H | H | 0 | CH2CH2F | H | 0 | H | HCl |
297 | (5) | N | 2 | 4-CN | 5-H | H | 2-H | 4-F | 5-H | 6-H | 3 | Bz | H | 0 | H | H | 0 | H | |
298 | (5) | N | 2 | 4-NH2 | 5-H | Ac | 2-H | 4-H | 5-Cl | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
299 | (5) | N | 2 | 4-NHAc | 5-H | H | 2-H | 4-H | 5-Br | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
300 | (5) | N | 2 | 4-NHMe | 5-H | H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | CH2CH22Cl | H | 0 | H | 2HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表21
【表21】
实施例序号 | A | T | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
301 | (5) | N | 2 | 4-H | 5-NMe2 | Bz | 2-H | 4-H | 5-H | 6-NO2 | 3 | CH2CH2Cl | CH2CH2Cl | 0 | H | H | 0 | H | 2HCl |
302 | (5) | N | 2 | 4-H | 5-NHEt | H | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
303 | (5) | N | 2 | 4-H | 5-NHnPr | H | 2-H | 4-H | 5-CO2H | 6-H | 3 | CH2CH2Br | CH2CH2Br | 0 | H | H | 0 | H | 2HCl |
304 | (5) | N | 2 | 4-H | 5-OH | H | 2-H | 3-CO2Me | 5-H | 6-H | 4 | H | H | 1 | Me | Me | 0 | CHO | HCl |
305 | (5) | N | 2 | 4-H | 5-OMe | H | 2-H | 3-CO2Et | 5-H | 6-H | 4 | H | H | 1 | Et | Et | 0 | CO2Me | HCl |
306 | (5) | N | 2 | 4-H | 5-OEt | CO2Me | 2-H | 3-H | 5-CN | 6-H | 4 | H | H | 0 | H | H | 1 | CO2Et | HCl |
307 | (5) | N | 2 | 4-H | 5-Me | H | 2-H | 3-H | 5-H | 6-CHO | 4 | H | H | 0 | H | H | 1 | H | 2HCl |
308 | (5) | N | 4 | 2-Me | 5-H | H | 3-CONH2 | 4-H | 5-H | 6-H | 2 | CO2 tBu | CO2 tBu | 1 | H | H | 0 | H | |
309 | (5) | N | 4 | 2-Et | 5-H | H | 3-H | 4-CONHMe | 5-H | 6-H | 2 | H | H | 1 | H | H | 0 | H | 2HCl |
310 | (5) | N | 4 | 2-nPr | 5-H | CO2Et | 3-CH2OH | 4-H | 5-H | 6-H | 2 | Me | Me | 0 | H | H | 1 | H | 2HCl |
311 | (5) | N | 4 | 2-H | 5-SMe | H | 3-H | 4-CH2Cl | 5-H | 6-H | 2 | H | H | 0 | CH2CH2OH | CH2CH2OH | 1 | H | 2HCl |
312 | (5) | N | 4 | 2-H | 5-SEt | H | 3-H | 4-H | 5-H | 6-H | 2 | H | H | 0 | H | H | 1 | H | 2HCl |
313 | (5) | N→O | 2 | 4-Me | 5-H | H | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | H | H | 0 | H | HCl |
314 | (5) | N→O | 2 | 4-Et | 5-H | CO2 tBu | 2-H | 4-H | 5-H | 6-CHO | 3 | H | H | 0 | H | H | 0 | H | HCl |
315 | (5) | N→O | 2 | 4-nPt | 5-H | H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表22
【表22】
实施例序号 | A | U | W | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
316 | (4) | N | N | 3 | 2-NO2 | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
317 | (4) | N | N | 3 | 2-NO2 | 5-H | 6-H | 2-Me | 4-H | 5-H | 6-H | 3 | H | Me | 0 | H | H | 0 | H | HCl |
318 | (4) | N | N | 3 | 2-CO2H | 5-H | 6-Et | 2-H | 4-OMe | 5-H | 6-H | 3 | Ac | H | 0 | H | H | 0 | H | |
319 | (4) | N | N | 3 | 2-CO2H | 5-H | 6-H | 2-Et | 4-H | 5-H | 6-H | 3 | H | Et | 0 | H | H | 0 | H | HCl |
320 | (4) | N | N | 3 | 2-CO2Me | 5-H | 6-nPr | 2-H | 4-OEt | 5-H | 6-H | 3 | Bz | H | 0 | H | H | 0 | H | |
321 | (4) | N | N | 3 | 2-CO2Et | 5-H | 6-H | 2-nPr | 4-H | 5-H | 6-H | 3 | H | nPr | 0 | H | H | 0 | H | HCl |
322 | (4) | N | N | 3 | 2-CO2 nPr | 5-H | 6-nBu | 2-H | 4-OnPr | 5-H | 6-H | 3 | H | H | 0 | Me | H | 0 | H | HCl |
323 | (4) | N | N | 3 | 2-CN | 5-H | 6-OH | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
324 | (4) | N | N | 3 | 2-CN | 5-H | 6-H | 2-H | 4-H | 5-NH2 | 6-H | 3 | H | H | 0 | Et | H | 0 | H | 2HCl |
325 | (4) | N | N | 3 | 2-H | 5-NH2 | 6-H | 2-H | 4-H | 5-NHMe | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
326 | (4) | N | N | 3 | 2-H | 5-NHAc | 6-H | 2-H | 4-H | 5-NHEt | 6-H | 3 | H | H | 0 | CH2CH2Cl | CH2CH2Cl | 0 | H | 2HCl |
327 | (4) | N | N | 3 | 2-H | 5-NHBz | 6-H | 2-H | 4-SMe | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
328 | (4) | N | N | 3 | 2-CONH2 | 5-H | 6-H | 2-H | 4-SEt | 5-H | 6-H | 3 | CO2Me | H | 0 | H | H | 0 | H | |
329 | (4) | N | N | 3 | 2-CONHMe | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CH2CH2Br | CH2CH2Br | 0 | H | H | 0 | H | 2HCl |
330 | (4) | N | N | 3 | 2-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | CH2OH | H | 0 | H | 2HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表23
【表23】
实施例序号 | A | U | W | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
331 | (4) | N | N | 3 | 2-H | 5-H | 6-Et | 2-H | 3-H | 5-H | 6-CO2H | 4 | Me | Me | 1 | H | H | 0 | Me | 2HCl |
332 | (4) | N | N | 3 | 2-H | 5-H | 6-nPr | 2-H | 3-H | 5-H | 6-CO2Me | 4 | H | H | 1 | H | H | 0 | H | 2HCl |
333 | (4) | N | N | 3 | 2-H | 5-H | 6-nBu | 2-H | 3-H | 5-H | 6-CO2Et | 4 | H | H | 1 | H | H | 0 | Et | 2HCl |
334 | (4) | N | N | 3 | 2-H | 5-OH | 6-H | 2-H | 3-H | 5-CN | 6-H | 4 | H | H | 0 | Me | Me | 1 | H | 2HCl |
335 | (4) | N | N | 3 | 2-H | 5-OMe | 6-H | 2-H | 3-H | 5-F | 6-H | 4 | H | H | 0 | H | H | 1 | nPr | 2HCl |
336 | (4) | N | N | 3 | 2-H | 5-OEt | 6-H | 2-H | 3-H | 5-H | 6-CO2NH2 | 4 | H | H | 0 | H | H | 1 | H | 2HCl |
337 | (4) | N | N | 3 | 2-SMe | 5-H | 6-H | 2-Cl | 3-H | 4-H | 5-H | 6 | H | H | 0 | H | H | 1 | Ac | HCl |
338 | (4) | N | N | 3 | 2-Et | 5-H | 6-H | 2-CH2OH | 3-H | 4-H | 5-H | 6 | H | H | 0 | H | H | 1 | H | 2HCl |
339 | (4) | N | N | 3 | 2-CF3 | 5-H | 6-H | 2-H | 3-H | 4-H | 5-CO2NHMe | 6 | H | H | 0 | H | H | 1 | Bz | HCl |
340 | (4) | N | N | 3 | 2-CF3 | 5-H | 6-H | 2-H | 3-H | 4-H | 5-cyclopentyl | 6 | H | H | 1 | H | H | 0 | H | 2HCl |
341 | (4) | N | N | 3 | 2-H | 5-H | 6-pyrrolidin-1-yl | 2-H | 3-H | 4-H | 5-H | 6 | H | H | 1 | H | H | 0 | CO2 tBu | |
342 | (4) | N | N | 3 | 2-H | 5-H | 6-piperidino | 2-H | 3-H | 4-H | 5-H | 6 | H | H | 1 | H | H | 0 | H | 2HCl |
343 | (4) | N→t | N→t | 3 | 2-H | 5-H | 6-cyclobutyl | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
344 | (4) | N→t | N→t | 3 | 2-H | 5-H | 6-H | 2-H | 3-H | 5-H | 6-cyclohexylthio | 4 | H | H | 1 | H | H | 0 | H | 2HCl |
345 | (4) | N→t | N→t | 3 | 2-H | 5-H | 6-H | 2-H | 3-H | 4-Bn | 5-H | 6 | H | H | 0 | H | H | 1 | H | 2HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表24
【表24】
实施例序号 | A | U | W | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
346 | (3) | N | N | 3 | 4-NO2 | 5-H | 6-H | 2-Me | 4-H | 5-H | 6-H | 3 | Me | H | 0 | H | H | 0 | H | HCl |
347 | (3) | N | N | 3 | 4-NO2 | 5-H | 6-H | 2-Et | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Me | HCl |
348 | (3) | N | N | 3 | 4-H | 5-CO2H | 6-H | 2-H | 4-nBu | 5-H | 6-H | 3 | Et | H | 0 | H | H | 0 | H | HCl |
349 | (3) | N | N | 3 | 4-H | 5-CO2Me | 6-H | 2-H | 4-Bn | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Et | HCl |
350 | (3) | N | N | 3 | 4-H | 5-H | 6-CONH2 | 2-H | 4-H | 5-NH2 | 6-H | 3 | Bn | H | 0 | H | H | 0 | H | |
351 | (3) | N | N | 3 | 4-H | 5-H | 6-CONHMe | 2-H | 4-H | 5-NHMe | 6-H | 3 | H | H | 0 | H | H | 0 | Ac | HCl |
352 | (3) | N | N | 3 | 4-CF3 | 5-H | 6-H | 2-F | 4-H | 5-H | 6-H | 3 | H | H | 0 | Me | Me | 0 | H | 2HCl |
353 | (3) | N | N | 3 | 4-CF3 | 5-H | 6-H | 2-H | 4-Br | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
354 | (3) | N | N | 3 | 4-H | 5-CN | 6-H | 2-Cl | 4-H | 5-H | 6-H | 3 | H | H | 0 | Me | H | 0 | H | HCl |
355 | (3) | N | N | 3 | 4-H | 5-CN | 6-H | 2-H | 4-NHBn | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
356 | (3) | N | N | 3 | 4-NH2 | 5-H | 6-H | 2-H | 4-OMe | 5-H | 6-H | 3 | Ac | H | 0 | H | H | 0 | H | |
357 | (3) | N | N | 3 | 4-H | 5-NHMe | 6-H | 2-H | 4-H | 5-OEt | 6-H | 3 | H | H | 0 | H | H | 0 | Bz | 2HCl |
358 | (3) | N | N | 3 | 4-H | 5-H | 6-NHBn | 2-nPr | 4-H | 5-H | 6-H | 3 | CO2Me | H | 0 | H | H | 0 | H | |
359 | (3) | N | N | 3 | 4-nPr | 5-H | 6-H | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
360 | (3) | N | N | 3 | 4-H | 5-Et | 6-H | 2-H | 4-H | 5-H | 6-CHO | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
*1:数字表示所用的(2)-(7)结构式的取代位置。
*2:数字表示苯环上的取代位置。
表25
【表25】
实施例序号 | A | U | W | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
361 | (3) | N | N | 3 | 4-Me | 5-H | 6-H | 2-H | 4-CO2H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
362 | (3) | N | N | 3 | 4-SMe | 5-H | 6-H | 2-H | 4-H | 5-CO2Et | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | CO2 tBu | |
363 | (3) | N | N | 3 | 4-H | 5-SEt | 6-H | 2-H | 4-H | 5-H | 6-CONH2 | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
364 | (3) | N | N | 3 | 4-H | 5-H | 6-SnPr | 2-H | 4-H | 5-CONHMe | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
365 | (3) | N | N | 3 | 4-F | 5-H | 6-H | 2-CN | 3-H | 5-pyrrolidin-1-yl | 6-H | 4 | H | H | 1 | H | H | 0 | Me | 2HCl |
366 | (3) | N | N | 3 | 4-H | 5-Br | 6-H | 2-H | 3-H | 5-piperidino | 6-H | 4 | H | H | 0 | H | H | 1 | H | 2HCl |
367 | (3) | N→O | N→O | 3 | 4-H | 5-H | 6-Me | 2-H | 3-H | 5-H | 6-H | 4 | H | H | 1 | H | H | 0 | H | HCl |
368 | (3) | N→O | N→O | 3 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
369 | (3) | N | N | 4 | 3-OMe | 5-H | 6-H | 2-F | 4-H | 5-H | 6-H | 3 | Et | H | 0 | H | H | 0 | H | 2HCl |
370 | (3) | N | N | 4 | 3-H | 5-OEt | 6-H | 2-H | 3-Cl | 5-H | 6-H | 3 | H | H | 0 | Et | H | 0 | H | 2HCl |
371 | (3) | N | N | 4 | 3-H | 5-H | 6-OnPr | 2-H | 3-H | 5-Br | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
372 | (3) | N | N | 4 | 3-NO2 | 5-H | 6-OMe | 2-H | 3-H | 4-CH2CH2Ph | 5-H | 6 | H | H | 1 | H | H | 0 | H | HCl |
373 | (3) | N | N | 4 | 3-H | 5-H | 6-H | 2-H | 3-H | 4-CH2(CH2)2Ph | 5-H | 6 | H | H | 1 | CH2OH | H | 0 | H | 2HCl |
374 | (3) | N→O | N→O | 4 | 3-H | 5-H | 6-NHMe | 2-H | 3-H | 4-H | 5-H | 6 | H | H | 0 | H | H | 1 | CO2Et | 2HCl |
375 | (3) | N→O | N→O | 4 | 3-H | 5-H | 6-NHEt | 2-H | 3-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 1 | H | 2HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表26
【表26】
实施例序号 | A | T | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
376 | (6) | N | 3 | 4-NO2 | 5-H | H | 2-H | 4-Me | 5-H | 6-H | 3 | Me | H | 0 | H | H | 0 | Me | 2HCl |
377 | (6) | N | 3 | 4-NO2 | 5-H | Me | 2-H | 4-Et | 5-H | 6-H | 3 | H | H | 0 | Me | Me | 0 | H | 2HCl |
378 | (6) | N | 3 | 4-CF3 | 5-H | H | 2-H | 4-nPr | 5-H | 6-H | 3 | H | H | 0 | Me | H | 0 | H | HCl |
379 | (6) | N | 3 | 4-CF3 | 5-H | Et | 2-CH2OH | 4-H | 5-H | 6-H | 3 | Et | H | 0 | H | H | 0 | H | HCl |
380 | (6) | N | 3 | 4-H | 5-CO2H | H | 2-CH2CH2OH | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Et | HCl |
381 | (6) | N | 3 | 4-H | 5-CO2Me | nPr | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | Et | H | 0 | H | HCl |
382 | (6) | N | 3 | 4-H | 5-CO2Et | H | 2-H | 4-H | 5-NH2 | 6-H | 3 | nPr | H | 0 | H | H | 0 | H | 2HCl |
383 | (6) | N | 3 | 4-CN | 5-H | H | 2-H | 4-H | 5-H | 6-NHMe | 3 | H | H | 0 | H | H | 0 | Ac | 2HCl |
384 | (6) | N | 3 | 4-CONH2 | 5-H | H | 2-NHEt | 4-H | 5-H | 6-H | 3 | H | H | 0 | CH2OH | H | 0 | H | 2HCl |
385 | (6) | N | 3 | 4-CONHMe | 5-H | H | 2-H | 4-H | 5-H | 6-H | 3 | Ac | H | 0 | H | H | 0 | H | |
386 | (6) | N | 3 | 4-H | 5-H | Ac | 2-Cl | 4-H | 5-H | 6-H | 3 | H | H | 0 | CH2CH2OH | CH2CH2OH | 0 | H | HCl |
387 | (6) | N | 3 | 4-H | 5-H | Bn | 2-Br | 4-H | 5-H | 6-H | 3 | H | H | 0 | Et | Et | 0 | H | HCl |
388 | (6) | N | 3 | 4-H | 5-H | CO2Me | 2-OMe | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | Bn | HCl |
389 | (6) | N | 3 | 4-H | 5-H | CO2Et | 2-H | 4-OEt | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
390 | (6) | N | 3 | 4-H | 5-H | CO2 nPr | 2-H | 4-OBn | 5-H | 6-H | 3 | H | H | 0 | Bn | H | 0 | Bz | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表27
【表27】
实施例序号 | A | T | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
391 | (6) | N | 3 | 4-OMe | 5-H | Bz | 2-H | 4-H | 5-H | 6-NO2 | 3 | H | H | 0 | H | H | 0 | H | HCl |
392 | (6) | N | 3 | 4-OEt | 5-H | H | 2-H | 4-H | 5-H | 6-CO2Me | 3 | Me | Me | 0 | H | H | 0 | H | 2HCl |
393 | (6) | N | 3 | 4-OnPr | 5-H | H | 2-H | 4-H | 5-H | 6-CO2Et | 3 | H | H | 0 | H | H | 0 | CO2Me | 2HCl |
394 | (6) | N | 3 | 4-H | 5-SMe | H | 2-H | 3-H | 5-CONH2 | 6-H | 4 | H | H | 1 | H | H | 0 | H | 2HCl |
395 | (6) | N | 3 | 4-H | 5-SEt | H | 2-H | 3-H | 5-CONHMe | 6-H | 4 | H | H | 1 | H | H | 0 | H | 2HCl |
396 | (6) | N | 4 | 3-H | 5-SnBu | H | 2-H | 3-H | 5-CONHEt | 6-H | 4 | H | H | 0 | Me | H | 1 | H | 2HCl |
397 | (6) | N | 4 | 3-F | 5-H | H | 2-H | 3-H | 5-H | 6-H | 4 | CH2CH2Br | CH2CH2Br | 0 | H | H | 1 | H | 2HCl |
398 | (6) | N | 4 | 3-Cl | 5-H | H | 2-H | 4-SMe | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
399 | (6) | N | 4 | 3-Br | 5-H | H | 2-H | 4-SEt | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
400 | (6) | N | 4 | 3-NH2 | 5-H | H | 2-H | 3-H | 4-H | 5-CHO | 6 | H | H | 1 | H | H | 0 | H | 2HCl |
401 | (6) | N | 4 | 3-NHMe | 5-H | H | 2-H | 3-H | 4-NHCO2Me | 5-H | 6 | H | H | 1 | H | H | 0 | H | 2HCl |
402 | (6) | N→O | 4 | 3-H | 5-Me | H | 2-H | 3-OBn | 4-H | 5-H | 6 | -CH2(CH2)2CH2- | 1 | H | H | 0 | H | HCl | |
403 | (6) | N→O | 4 | 3-H | 5-Et | H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 1 | -CH2(CH2)3CH2- | 0 | H | HCl | |
404 | (6) | N→O | 3 | 4-H | 5-OMe | H | 2-H | 4-NHBn | 5-H | 6-H | 3 | H | H | 1 | H | H | 0 | H | 2HCl |
405 | (6) | N→O | 3 | 4-H | 5-OEt | H | 2-H | 3-H | 5-H | 6-H | 4 | H | H | 1 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表28
【表28】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 |
406 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-Me | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
407 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-pyrrolidin-1-yl | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
408 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 3-H | 5-H | 6-H | 4 | CO2 tBu | H | 1 | H | H | 0 | H |
409 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-OMe | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
410 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | Me | Me | 0 | H |
411 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-Me | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
412 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 3-H | 4-H | 5-H | 6-H | 2 | CO2 tBu | H | 1 | H | H | 0 | H |
413 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-OMe | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
414 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-Cl | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
415 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-Me | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
416 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-F | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
417 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-OEt | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
418 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
419 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
420 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-OMe | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表29
【表29】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 |
421 | (2) | CR6 | N | H | 2 | 4-H | 5-NO2 | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
422 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
423 | (2) | CR6 | N | H | 2 | 4-CO2Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
424 | (2) | CR6 | N | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
425 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OEt | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
426 | (2) | CR6 | N | CF3 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
427 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-OMe | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
428 | (2) | CR6 | CMe | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
429 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | Me | Me | 0 | H |
430 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | Et | H | 0 | H |
431 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-Me | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
432 | (2) | CR6 | N | H | 4-Me | 5-H | 6-H | 2-H | 4-Et | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
433 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-OEt | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
434 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 3-H | 4-H | 5-H | 6-H | 2 | CO2 tBu | H | 1 | H | H | 0 | H |
435 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-Cl | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表30
【表30】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 |
436 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | -CH2CH2CH2- | 0 | H | |
437 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 3-H | 5-H | 6-H | 4 | CO2 tBu | H | 1 | H | H | 0 | H |
438 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OEt | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
439 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-Cl | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
440 | (2) | CR6 | N | CN | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
441 | (2) | CR6 | N | Cl | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
442 | (2) | CR6 | N | CO2Me | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
443 | (2) | CR6 | N | H | 2 | 4-CO2H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
444 | (2) | CR6 | N | H | 2 | 4-CH2OH | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
445 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
446 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-CH(CO2Me)2 | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
447 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-CMe(CO2Et)2 | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
448 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-SMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
449 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
450 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表31
【表31】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
451 | (2) | CR6 | N | H | 2 | 4-Et | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
452 | (2) | CR6 | N | CO2H | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
453 | (2) | CR6 | N | CONH2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
454 | (2) | CR6 | N | CH2OH | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
455 | (2) | CR6 | N | Me | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
456 | (2) | CR6 | N | CHO | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | CO2 t8u | H | 0 | H | H | 0 | H | |
457 | (2) | CR6 | N | H | 2 | 4-H | 5-NO2 | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
458 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-Me | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
459 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-pyrrolidin-1-yl | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
460 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 3-H | 5-H | 6-H | 4 | H | H | 1 | H | H | 0 | H | HCl |
461 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-OMe | 3 | H | H | 0 | H | H | 0 | H | HCl |
462 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | Me | Me | 0 | H | HCl |
463 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-Me | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
464 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 3-H | 4-H | 5-H | 6-H | 2 | H | H | 1 | H | H | 0 | H | HCl |
465 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-OMe | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表32
【表32】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
466 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-Cl | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
467 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-F | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
468 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-OEt | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
469 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-Cl | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
470 | (2) | CR6 | N | H | 2 | 4-CO2Me | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
471 | (2) | CR6 | N | H | 2 | 4-CO2H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
472 | (2) | CR6 | N | H | 2 | 4-CH2OH | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
473 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
474 | (2) | N | N | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl | |
475 | (2) | CR6 | N | CF3 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
476 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-OMe | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
477 | (2) | CR6 | CMe | NO2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
478 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
479 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | Me | Me | 0 | H | 2HCl |
480 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | Et | H | 0 | H | 2HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表33
【表33】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
481 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-Me | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
482 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-Et | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
483 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-OEt | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
484 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 3-H | 4-H | 5-H | 6-H | 2 | H | H | 1 | H | H | 0 | H | 2HCl |
485 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-Cl | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
486 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
487 | (2) | CR6 | N | H | 2 | 4-Et | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
488 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | -CH2CH2CH2- | 0 | H | 2HCl | |
489 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 3-H | 5-H | 6-H | 4 | H | H | 1 | H | H | 0 | H | 2HCl |
490 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OEt | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
491 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-Cl | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
492 | (2) | CR6 | N | CN | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
493 | (2) | CR6 | N | Cl | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
494 | (2) | CR6 | N | CONH2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
495 | (2) | CR6 | N | Me | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表34
【表34】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
496 | (2) | CR6 | CH | NO2 | 2 | 4-H | 5-H | 6-OMe | 2-H | 4-OMe | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | HCl |
497 | (2) | CR6 | N | H | 2 | 4-H | 5-Me | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
498 | (2) | CR6 | N | Me | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
499 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-OMe | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
500 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-pyrazol-1-yl | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
501 | (2) | CR6 | N | H | 2 | 4-H | 5-Me | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
502 | (2) | CR6 | N | Me | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
503 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-OMe | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
504 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-H | 4-pyrazol-1-yl | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
505 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OnPr | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
506 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OnPr | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
实施例序号 | A | T | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
507 | (7) | S | - | - | 2 | 4-H | 5-Me | - | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
508 | (7) | S | - | - | 2 | 4-H | 5-Me | - | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | |
509 | (7) | S | - | - | 2 | 4-Me | 5-H | - | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
510 | (7) | S | - | - | 2 | 4-Me | 5-H | - | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表35
【表35】
实施例序号 | A | T | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
511 | (7) | O | - | - | 2 | 4-H | 5-Me | - | 2-H | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
512 | (7) | O | - | - | 2 | 4-H | 5-Me | - | 2-OEt | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
513 | (7) | O | - | - | 2 | 4-H | 5-Me | - | 2-Me | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
514 | (7) | O | - | - | 2 | 4-H | 5-Me | - | 2-H | 4-OMe | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
515 | (7) | O | - | - | 2 | 4-H | 5-Me | - | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | CF3CO2H |
516 | (7) | O | - | - | 2 | 4-H | 5-Me | - | 2-OEt | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | CF3CO2H |
517 | (7) | O | - | - | 2 | 4-H | 5-Me | - | 2-Me | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | CF3CO2H |
518 | (7) | O | - | - | 2 | 4-H | 5-Me | - | 2-H | 4-OMe | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | CF3CO2H |
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
519 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OEt | 4-Cl | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
520 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OEt | 4-Me | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
521 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OEt | 4-Cl | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
522 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OEt | 4-Me | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
523 | (2) | CR6 | N | NO2 | 2 | 4-H | 5-NO2 | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | |
524 | (2) | CR6 | N | CN | 2 | 4-Me | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | |
525 | (2) | CR6 | N | H | 2 | 4-CN | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表36
【表36】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 |
526 | (2) | CR6 | N | H | 2 | 4-H | 5-CN | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
527 | (2) | CR6 | N | CN | 2 | 4-CO2Et | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
528 | (2) | CR6 | N | H | 2 | 4-CO2H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
529 | (2) | CR6 | N | H | 2 | 4-H | 5-CO2H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
530 | (2) | CR6 | N | Cl | 2 | 4-H | 5-CO2H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
531 | (2) | CR6 | N | H | 2 | 4-CO2H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
532 | (2) | CR6 | N | H | 2 | 4-H | 5-H | 6-CO2H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
533 | (2) | CR6 | N | CONH2 | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
534 | (2) | CR6 | N | CONH2 | 2 | 4-H | 5-Cl | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
535 | (2) | CR6 | N | H | 2 | 4-CONH2 | 5-H | 6-OMe | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
536 | (2) | CR6 | N | CONH2 | 2 | 4-H | 5-H | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
537 | (2) | CR6 | N | H | 2 | 4-H | 5-Br | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
538 | (2) | CR6 | N | Cl | 2 | 4-H | 5-Cl | 6-H | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
539 | (2) | CR6 | N | H | 2 | 4-H | 5-H | 6-Me | 2-H | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H |
540 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OMe | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
表37
【表37】
实施例序号 | A | Y | Z | R6 | A的取代位置 | R7 *1 | R8 *1 | R9 *1 | X1 *2 | X2 *2 | X3 *2 | X4 *2 | W*的取代位置 | R1 | R2 | n | R3 | R4 | m | R5 | 盐 |
541 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OMe | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
542 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OiPr | 4-H | 5-H | 6-H | 3 | CO2 tBu | CO2 tBu | 0 | H | H | 0 | H | |
543 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OiPr | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
544 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OnBu | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
545 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OnBu | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
546 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OtBu | 4-H | 5-H | 6-H | 3 | CO2 tBu | H | 0 | H | H | 0 | H | |
547 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OtBu | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
548 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OCH2Ph | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
549 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OCH2CH2Ph | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
550 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-Et | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
551 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-CH2Ph | 4-H | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
552 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OMe | 4-Me | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
553 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OiPr | 4-Me | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
554 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OnBu | 4-Me | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
555 | (2) | CR6 | N | H | 2 | 4-Me | 5-H | 6-H | 2-OtBu | 4-Me | 5-H | 6-H | 3 | H | H | 0 | H | H | 0 | H | 2HCl |
*1:数字表示所用的(2)-(7)结构式上的取代位置。
*2:数字表示苯环上的取代位置。
实施例1
2-〔3-(二-(叔丁氧基羰基)氨基甲基)苯基氨基〕-3-硝基吡啶的合成
将3-〔二-(叔丁氧基羰基)氨基甲基〕苯胺(1.50克)、三乙基胺(2.0毫升)、2-氯-3-硝基吡啶(1.10克)和无水二甲基甲酰胺(15毫升)的混合物在60℃下搅拌20小时后,加入乙酸乙酯和水。将有机层用饱和食盐水洗涤后,用无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为正己烷∶乙酸乙酯=3∶1)进行精制,得到标题化合物1.42克(收率69%)。
1H-NMR(CDCl3)
δ:1.47(18H,s),4.81(2H,s),6.83(1H,dd,J=8.3,4.3Hz),7.11(1H,d,J=7.9Hz),7.34(1H,dd,J=7.9,7.9Hz),7.55-7.63(2H,m),8.47(1H,dd,J=4.3,1.7Hz),8.53(1H,dd,J=8.3,1.7Hz),10.11(1H,brs)
和实施例1一样,使用相当的苯胺衍生物或相当的卤素衍生物,得到表38~表43所示的化合物。〔表中反应条件中的碱:(1)表示三乙基胺、(2)表示二异丙基乙基胺。〕
表38
【表38】
表39
【表39】
表40
【表40】
表41
【表41】
表42
【表42】
表43
【表43】
实施例2
2-(3-氨基甲基苯基氨基)-3-硝基吡啶·盐酸盐的合成
将实施例1所得化合物(95.2毫克)和三氟乙酸(2毫升)的混合物在室温下搅拌1小时后,减压浓缩。所得残渣溶于甲醇(3毫升),在室温下加入氯化氢的1,4-二噁烷溶液(4N,0.5毫升),减压浓缩。进一步将所得残渣用乙醇-乙酸乙酯重结晶,得到标题化合物56.7毫克(收率94%)。
1H-NMR(DMSO-d6)
δ:4.03(2H,q,J=5.6Hz),7.03(1H,dd,J=8.2,4.3Hz),7.28(1H,d,J=7.6Hz),7.42(1H,dd,J=7.6,7.6Hz),7.74(1H,s),7.75(1H,d,J=7.6Hz),8.46(3H,brs),8.50-8.60(2H,m),10.00(1H,s)
和实施例2一样,使用相应的反应试剂得到表44~表62所示的化合物。
表44
【表44】
表45
【表45】
表46
【表46】
表47
【表47】
表48
【表48】
表49
【表49】
表50
【表50】
表51
【表51】
表52
【表52】
表53
【表53】
表54
【表54】
表55
【表55】
表56
【表56】
表57
【表57】
表58
【表58】
表59
【表59】
表60
【表60】
表61
【表61】
表62
【表62】
实施例3
3-氨基-2-〔3-(二-(叔丁氧基羰基)氨基甲基)苯基氨基〕吡啶的合成
将实施例1所得化合物(1.41克)、10%钯碳(170毫克)、甲醇(60毫升)和乙酸乙酯(30毫升)的混合物在氢气氛围、室温下搅拌1天。将反应混合物过滤后,将滤液减压浓缩。所得残渣用硅胶柱层析(展开剂为正己烷∶乙酸乙酯=2∶1)进行精制,得到标题化合物1.15克(收率88%)。1H-NMR(CDCl3)
δ:1.45(18H,s),3.40(2H,brs),4.75(2H,s),6.20(1H,brs),6.77(1H,dd,J=7.6,5.0Hz),6.84-6.90(1H,m),7.00(1H,dd,J=7.6,1.3Hz),7.13(1H,s),7.19-7.23(2H,m),7.82(1H,dd,J=5.0,1.3Hz)
和实施例3一样,使用相应的反应试剂得到表63所示的化合物。
表63
【表63】
实施例5
3-甲基氨基-2-〔3-(二-(叔丁氧基羰基)氨基甲基)苯基氨基〕吡啶的合成
往实施例3所得化合物(88.5毫克)、碘甲烷(15微升)和二甲基甲酰胺(2毫升)的混合物中加入氢化钠(含量60%,10毫克),在室温下搅拌4天。往反应混合物中加入乙酸乙酯和饱和碳酸氢钠水溶液。有机层用饱和食盐水洗涤后,用无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为正己烷∶乙酸乙酯=2∶3)进行精制,得到标题化合物19.3毫克(收率21%)。
1H-NMR(CDCl3)
δ:1.44(18H,s),2.85(3H,s),3.48(1H,brs),4.74(2H,s),6.02(1H,s),6.82-6.95(3H,m),7.03(1H,s),7.09(1H,d,J=8.0Hz),7.20(1H,dd,J=8.0,8.0Hz),7.75(1H,dd,J=4.3,1.7Hz)
实施例6
3-甲基氨基-2-(3-氨基甲基苯基氨基)吡啶的合成
以实施例5所得化合物为起始原料,进行和实施例2相同的反应后,将反应混合液减压浓缩。所得残渣用碱性硅胶柱层析(展开剂为氯仿∶甲醇=10∶1)进行精制,得到定量的标题化合物。
1H-NMR(CDCl3)
δ:1.69(2H,brs),2.85(3H,s),3.53(1H,brs),3.81(2H,s),6.08(1H,brs),6.84-6.94(3H,m),7.05(1H,d,J=7.6Hz),7.12(1H,s),7.22(1H,dd,J=7.6,7.6Hz),7.76(1H,dd,J=4.6,2.0Hz)
实施例7
3-乙基氨基-2-〔3-(二-(叔丁氧基羰基)氨基甲基)苯基氨基〕
吡啶的合成
以实施例3所得化合物为起始原料,作为反应试剂使用碘乙烷,和实施例5一样得到标题化合物(收率54%)。
1H-NMR(CDCl3)
δ:1.28(3H,t,J=7.3Hz),1.45(18H,s),3.15(2H,q,J=7.3Hz),3.30(1H,brs),4.74(2H,s),6.05(1H,s),6.82-6.96(3H,m),7.07(1H,s),7.12-7.18(1H,m),7.18(1H,dd,J=7.3,7.3Hz),7.75(1H,dd,J=4.6,1.3Hz)
实施例29
2-〔3-(二-(叔丁氧基羰基)氨基甲基)苯基氨基〕-6-甲基氨基-3-硝基吡啶的合成
将实施例27所得的化合物(77.0毫克)、碳酸钾(89毫克)、甲基胺·盐酸盐(22.0毫克)和乙腈(2毫升)的混合物在60℃下搅拌6小时后,将反应混合物减压浓缩。往所得残渣中加入乙酸乙酯和水。有机层用饱和食盐水洗涤后,以无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为正己烷∶乙酸乙酯=2∶1)进行精制,得到标题化合物71.0毫克(收率93%)。
1H-NMR(CDCl3)
δ:1.43(18H,s),3.03(3H,d,J=4.3Hz),4.81(2H,s),5.93(1H,d,J=8.9Hz),6.98-7.80(5H,m),8.20-8.42(1H,m),10.81(1H,brs)
和实施例29一样,使用相应的胺衍生物得到表64所示的化合物。
表64
【表64】
实施例37
6-氯-2-〔3-(叔丁氧基羰基氨基甲基)苯基氨基〕烟酸的合成
将3-〔二-(叔丁氧基羰基)氨基甲基〕苯胺(81毫克)、2,6-二氯烟酸(90%,53毫克)、二-异丙基乙基胺(64毫克)和1,4-二噁烷(1毫升)的混合液加热回流3天后,减压浓缩。所得残渣用硅胶柱层析(展开剂为二氯甲烷∶甲醇=20∶1)进行精制,得到标题化合物24毫克(收率25%)。
1H-NMR(DMSO-d6)
δ:1.44(9H,s),4.14-4.26(2H,m),6.72(1H,d、J=7.9Hz),6.89(1H,d,J=7.6Hz),7.09(1H.brt),7.26(1H,dd,J=7.6,7.6Hz),7.51(1H,s),7.71(1H,d,J=7.6Hz),8.22(1H,d,J=7.9Hz)
实施例39
2-〔3-(二-(叔丁氧基羰基)氨基甲基)苯基氨基〕-6-甲氧基吡啶的合成
将3-〔二-(叔丁氧基羰基)氨基甲基〕苯胺(50毫克)、四三苯基磷钯(18毫克)、碳酸钾(24毫克)、2-氯-6-甲氧基吡啶(25毫克)和甲苯(3毫升)的混合物在氮气气流下加热回流16小时后,加入乙酸乙酯和水。有机层用饱和食盐水洗涤后,用无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶己烷=1∶4)进行精制,得到标题化合物54.5毫克(收率82%)。
1H-NMR(CDCl3)
δ:1.45(18H,s),3.91(3H,s),4.77(2H,s),6.19(1H,d,J=7.9Hz),6.36(1H,brs),6.39(1H,d,J=7.9Hz),6.93(1H,d,J=6.9Hz),7.23-7.30(3H,m),7.39(1H,dd,J=7.9,7.9Hz)
和实施例39一样,使用相应的苯胺衍生物和卤素衍生物,得到表65~表73所示的化合物。〔表中反应条件中,钯(Pd)表示(1)四三苯基磷钯、(2)三(二苄叉丙酮)二钯;碱表示(1)叔丁醇钾、(2)叔丁醇钠、(3)碳酸钾;配基(ligand)表示(1)二苯基磷二茂铁、(2)2,2’-双(二苯基磷)-1,1’-联二萘。〕
表65
【表65】
表66
【表66】
表67
【表67】
表68
【表68】
表69
【表69】
表70
【表70】
表71
【表71】
表72
【表72】
表73
【表73】
实施例45
2-(3-氨基甲基苯基氨基)-6-甲氧基烟酸·盐酸盐的合成
将实施例43所得化合物(37毫克)、氢氧化钾(96毫克)、水(2毫升)和1,4-二噁烷(2毫升)的混合物在60℃下加热搅拌2小时。将反应混合物冷却后,加入2N盐酸成酸性,用二氯甲烷萃取。有机层用无水硫酸钠干燥后,减压浓缩。将所得残渣和实施例2一样处理,得到定量的标题化合物。
1H-NMR(DMSO-d6)
δ:3.95(3H,s),4.01(2H,brs),6.27(1H,d,J=8.6Hz),7.14(1H,d,J=7.6Hz),7.39(1H,dd,J=8.3,7.6Hz),7.71(1H,s),7.90(1H,d,J=8.3Hz),8.14(1H,d,J=8.6Hz),8.30(3H,brs),10.75(1H,s),13.06(1H,brs)
实施例52
2-(3-氨基甲基苯基氨基)-6-甲基-3-硝基吡啶·盐酸盐的合成
将实施例446所得化合物(118毫克)、浓硫酸(1毫升)和水(2毫升)的混合液在120℃下加热搅拌4小时。将反应混合物注入冰水中,用饱和碳酸氢钠水溶液调pH=8后,用乙酸乙酯萃取。有机层用饱和食盐水洗涤后,用无水硫酸钠干燥,减压浓缩。所得残渣溶于甲醇(2毫升),在室温下加入氯化氢的1,4-二噁烷溶液(4N,0.5毫升),将反应混合物减压浓缩。残渣用甲醇-乙酸乙酯重结晶,得到标题化合物37.1毫克(61%)。
1H-NMR(DMSO-d6)
δ:2.49(3H,s),4.03(2H,q,J=5.6Hz),6.90(1H,d,J=8.6Hz),7.27(1H,d,J=7.9Hz),7.42(1H,dd,J=7.9,7.9Hz),7.77(1H,s),7.86(1H,d,J=7.9Hz),8.31(3H,brs),8.45(1H,d,J=8.6Hz),10.09(1H,s)
实施例53
2-(3-氨基甲基苯基氨基)-6-乙基-3-硝基吡啶·盐酸盐的合成
以实施例447所得混合物作为起始原料,和实施例52一样,得到标题化合物(收率85%)。
1H-NMR(DMSO-d6)
δ:1.24(3H,t,J=7.3Hz),2.79(2H,q,J=7.3Hz),4.02(2H,q,J=5.0Hz),6.92(1H,d,J=8.6Hz),7.26(1H,d,J=7.6Hz),7.43(1H,dd,J=7.6,7.6Hz),7.75(1H,s),7.90(1H,d,J=7.6Hz),8.41(3H,brs),8.48(1H,d,J=8.6Hz),10.10(1H,s)
实施例443
2-〔3-(叔丁氧基羰基氨基甲基)苯基氨基〕-6-甲氧基异烟酸的合成
往实施例423所得化合物(53.8毫克)和甲醇(3毫升)的混合物中加入2N氢氧化钠水溶液(1毫升)。将反应混合物在室温下搅拌4小时后,减压浓缩。往所得残渣中加入乙酸乙酯,用水萃取。水层用2N盐酸调pH=1后,用乙酸乙酯萃取。有机层用饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩,得到标题化合物47.3毫克(收率90%)。
1H-NMR(CDCl3)
δ:7.49(1H,d,J=7.9Hz),7.45(1H,s),7.28(1H,dd,J=7.9,7.3Hz),6.98(1H,s),6.93(1H,d,J=7.3Hz),6.76(1H,s),4.92(1H,brs),4.31(2H,d,J=5.6Hz),3.95(3H,s),1.4(s ‘H6)9
实施例444
2-〔3-(叔丁氧基羰基氨基甲基)苯基氨基〕-4-羟基甲基-6-甲氧基吡啶的合成
往实施例423所得化合物(155.3毫克)、四氢呋喃(4毫升)和甲醇(2毫升)的混合物中加入硼氢化锂(13毫克)。将反应混合物在室温下搅拌1周后,加入水,减压浓缩。往所得残渣中加入水,用乙酸乙酯萃取。有机层用饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶1)进行精制,得到标题化合物86.1毫克(收率60%)。
1H-NMR(CDCl3)
δ:7.37(1H,s),7.18-7.12(2H,m),6.93-6.88(1H,m),6.42(1H,s),6,42(1H,s),6.18(1H,s),4.88(1H,brs),4.59(2H,s),4.29(2H,d,J=5.6Hz),3.90(3H,s),1.45(9H,s)
实施例446
2-〔2-(3-(二-(叔丁氧基羰基)氨基甲基)苯基氨基)-3-硝基吡啶-6-基〕丙二酸二甲酯的合成
往实施例27所得化合物(150毫克)、丙二酸二甲酯(50毫克)和二甲基甲酰胺(3毫升)的混合液中加入氢化钠(含量60%、15毫克)。反应混合物在室温下搅拌3小时后,加入乙酸乙酯和水。有机层用饱和食盐水洗涤后,用无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为正己烷∶乙酸乙酯=2∶1)进行精制,得到标题化合物123毫克(收率68%)。
1H-NMR(CDCl3)
δ:1.47(18H,s),3.76(6H,s),4.81(2H,s),4.91(1H,s),6.95(1H,d,J=8.6Hz),7.08(1H,d,J=7.9Hz),7.32(1H,dd,J=7.9,7.9Hz),7.44(1H,s),7.68(1H,d,J=7.9Hz),8.54(1H,d,J=8.6Hz),10.18(1H,brs)
和实施例446一样,用相应的氯衍生物和相应的反应试剂得到表74所示的化合物。
表74
【表74】
实施例449
2-〔3-(叔丁氧基羰基氨基甲基)苯基氨基〕-4-甲基吡啶的合成
将3-〔二-(叔丁氧基羰基)氨基甲基〕溴苯(260毫克)、三(二苄叉丙酮)二钯(42毫克)、二苯基磷二茂铁(50毫克)、叔丁醇钾(102毫克)、2-氨基-4-甲基吡啶(108毫克)和甲苯(10毫升)的混合物在氮气气流、80℃下加热搅拌22小时。往反应混合物中加入乙酸乙酯、水。有机层用饱和食盐水洗涤后,以无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶1)进行精制,得到标题化合物29.2毫克(收率10%)。
1H-NMR(CDCl3)
δ:1.46(9H,s),2.26(3H,s),4.30(2H,d,J=5.9Hz),4.90(1H,brt),6.59(1H,d,J=5.0Hz),6.60(1H,s),6.68(1H,s),6.94(1H,d,J=6.3Hz),7.21-7.31(3H,m),8.06(1H,d,J=5.0Hz)
和实施例449一样,使用相应的胺衍生物得到表75所示的化合物。
表75
【表75】
实施例452
2-〔3-(叔丁氧基羰基氨基甲基)苯基氨基〕-6-甲氧基烟酸的合成
以实施例442所得化合物为起始原料,和实施例45一样,得到标题化合物(收率92%)。
1H-NMR(CDCl3-CD3OD)
δ:1.46(9H,s),3.99(3H,s),4.30(2H,s),6.16(1H,d,J=8.6Hz),6.94(1H,d,J=7.8Hz),7.28(1H,dd,J=7.8,7.8Hz),7.58(1H,d,J=7.8Hz),7.73(1H,s),8.16(1H,d,J=8.6Hz)
实施例453
2-〔3-(叔丁氧基羰基氨基甲基)苯基氨基〕-6-甲氧基烟酰胺的合成
在室温下往实施例452所得化合物(44毫克)、三乙基胺(18毫克)和四氢呋喃(2毫升)的混合物中加入氯碳酸乙酯(14.3毫克),在室温下搅拌15分钟。在室温下往反应混合物中吹入氨气,在室温下搅拌5分钟后,减压浓缩。往所得残渣中加入饱和碳酸氢钠水溶液,用二氯甲烷萃取。有机层用饱和食盐水洗涤后,以无水硫酸钠干燥,减压浓缩。所得残渣用制备性薄层层析(展开剂为甲醇∶二氯甲烷=1∶20)进行精制,得到标题化合物10毫克(收率11%)。
1H-NMR(DMSO-d6)
δ:1.39(9H,s),3.92(3H,s),4.12(2H,d,J=5.9Hz),6.20(1H,d,J=8.6Hz),6.85(1H,d,J=7.6Hz),7.24(1H,dd,J=7.6,7.6Hz),7.32-7.40(2H,m),7.51(1H,d,J=7.6Hz),7.61(1H,s),8.01(1H,brs),8.10(1H,d,J=8.6Hz)
实施例454
2-〔3-(叔丁氧基羰基氨基甲基)苯基氨基〕-3-羟基甲基-6-甲氧基吡啶的合成
在冰冷却下往实施例452所得化合物(300毫克)、三乙基胺(101毫克)和四氢呋喃(8毫升)的混合物中加入氯碳酸乙酯(109毫克)的四氢呋喃溶液(1毫升),在0℃下搅拌15分钟。将反应混合物过滤后,在冰冷却下往滤液中加入硼氢化锂的四氢呋喃溶液(2M,0.8毫升)。反应混合物在0℃下搅拌30分钟后,在冰冷却下加入1N氢氧化钠水溶液。进一步将反应混合物在0℃下搅拌5分钟后,加入乙醚和水。有机层用饱和食盐水洗涤后,以无水硫酸镁干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶二氯甲烷=1∶10)进行精制,得到标题化合物199毫克(收率69%)。
1H-NMR(CDCl3)
δ:1.46(9H,s),3.93(3H,s),4.31(2H,d,J=5.6Hz),4.67(2H,d,J=5.6Hz),4.79(1H,brt),6.15(1H,d,J=7.9Hz),6.89(1H,d,J=7.6Hz),7.21-7.31(3H,m),7.48(1H,d,J=7.6Hz),7.64(1H,brs),7.70(1H,brs)
实施例456
2-〔3-(叔丁氧基羰基氨基甲基)苯基氨基〕-6-甲氧基吡啶-3-甲醛的合成
将实施例454所得化合物(24毫克)、四氧化锰(40毫克)和苯(8毫升)的混合物在室温下搅拌2天。将反应混合物过滤后,将滤液减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶二氯甲烷=1∶20)进行精制,得到标题化合物14毫克(收率59%)。
1H-NMR(CDCl3)
δ:1.47(9H,s),4.01(3H,s),4.33(2H,d,J=5.6Hz),4.82(1H,brt),6.24(1H,d,J=8.3Hz),7.00(1H,d,J=7.6Hz),7.30(1H,dd,J=7.6,7.6Hz),7.61(1H,d,J=7.6Hz),7.71(1H,d,J=8.3Hz),7.72(1H,s),9.67(1H,s),10.95(1H,s)
实施例472
2-(3-氨基甲基苯基氨基)-4-羟基甲基-6-甲氧基吡啶·二盐酸盐的合成
往实施例423所得化合物(109.5毫克)、四氢呋喃(4毫升)和甲醇(1毫升)的混合物中加入硼氢化锂(19毫克)。将反应混合物在室温下搅拌44小时后,加入2N盐酸,减压浓缩。所得残渣用碱性硅胶柱层析(展开剂为甲醇∶二氯甲烷=1∶19)精制。往所得精制物和甲醇(3毫升)的混合物中加入氯化氢的1,4-二噁烷溶液(4N,0.3毫升),减压浓缩。所得残渣用甲醇-乙酸乙酯重结晶,得到标题化合物48毫克(收率58%)。
1H-NMR(DMSO-d6)
δ:9.18(1H,brs),8.39(3H,brs),7.78(1H,s),7.61(1H,d,J=7.9Hz),7.29(1H,dd,J=7.9,7.3Hz),7.08(1H,brs),7.02(1H,d,J=7.3Hz),6.47(1H,s),6.11(1H,s),4.42(2H,s),3.94(2H,q,J=5.6Hz),3.87(3H,s)
实施例507
2-〔3-(叔丁氧基羰基氨基甲基)苯基氨基〕-5-甲基噻唑的合成
往丙醛(72微升)、氯仿(1毫升)和1,4-二噁烷(1毫升)的混合物中加入溴(52微升)。将反应混合物在室温下搅拌30分钟后,加入N-〔3-(叔丁氧基羰基氨基甲基)苯基〕硫脲(262毫克)、丙酮(2毫升)和三乙基胺(0.14毫升)。将反应混合物加热回流3.5小时后,减压浓缩。往所得残渣中加入水,用乙酸乙酯萃取。有机层用饱和食盐水洗涤,用无水硫酸钠干燥后,减压浓缩。所得残渣用碱性硅胶柱层析(展开剂为二氯甲烷∶甲醇=99∶1)进行精制,得到标题化合物79.2毫克(收率27%)。
1H-NMR(CDCl3)
δ:7.30-7.22(4H,m),7.17(1H,d,J=7.6Hz),6.91(1H,d,J=1.0Hz),4.94(1H,brs),4.30(2H,d,J=5.6Hz),2.34(3H,d,J=1.0Hz),1.47(9H,s)
实施例508
2-(3-氨基甲基苯基氨基)-5-甲基噻唑的合成
将实施例507所得化合物(73毫克)和三氟乙酸(5毫升)的混合物在室温下搅拌1小时后,减压浓缩。所得残渣用碱性硅胶柱层析(展开剂为二氯甲烷∶甲醇=95∶5)进行精制后,得到标题化合物34.5毫克(收率67%)。
1H-NMR(CDCl3)
δ:7.32-7.28(3H,m),7.19(1H,d,J=7.3Hz),6.97(1H,d,J=7.3Hz),6.92(1H,d,J=1.0Hz),3.87(2H,s),2.35(3H,d,J=1.0Hz),1.76(2H,brs)
实施例509
2-〔3-(叔丁氧基羰基氨基甲基)苯基氨基〕-4-甲基噻唑的合成
实施例511
2-〔3-(二-(叔丁氧基羰基)氨基甲基)苯基氨基〕-5-甲基噁唑的合成
在冰冷却下往3-〔二-(叔丁氧基羰基)氨基甲基〕苯胺(200毫克)、二甲基氨基吡啶(166毫克)和二氯甲烷(10毫升)的混合物中加入硫光气(45微升),在室温下搅拌5小时。将反应混合物减压浓缩后,所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶3)进行精制,得到N-〔3-(二-(叔丁氧基羰基)氨基甲基)苯基〕异硫氰酸酯。
将所得化合物(193毫克)、1-迭氮基-丙烷-2-酮(81毫克)、三苯基磷(217毫克)和二氯甲烷(5毫升)的混合物在室温下搅拌15小时后,在室温下加入草酸(115毫克)。将反应混合物在60℃下加热搅拌30分钟后,减压浓缩。往所得残渣中加入乙酸乙酯和2N氢氧化钠水溶液。有机层用饱和食盐水洗涤后,以无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶10)进行精制,得到标题化合物78毫克(收率33%)。
1H-NMR(CDCl3)
δ:1.45(18H,s),2.25(3H,d,J=1.0Hz),4.77(2H,s),6.51(1H,d,J=1.0Hz),6.91(1H,d,J=7.6Hz),7.15(1H,brs),7.22-7.26(1H,m),7.25(1H,dd,J=7.6,7.6Hz),7.40(1H,d,J=7.6Hz)
和实施例511一样,用相应的反应试剂得到表76所示的化合物。
表76
【表76】
实施例515
2-(3-氨基甲基)苯基氨基-5-甲基噁唑·三氟乙酸盐的合成
将实施例511所得化合物(292毫克)和三氟乙酸(2毫升)的混合物在室温下搅拌2小时后,减压浓缩。所得残渣用乙醇-乙酸乙酯-正己烷重结晶,得到标题化合物119毫克(收率38%)。
1H-NMR(DMSO-d6)
δ:2.24(3H,s),3.98(2H,q,J=5.6Hz),6.59(1H,s),7.00(1H,d,J=7.3Hz),7.32(1H,dd,J=7.3,7.3Hz),7.53(1H,d,J=7.3Hz),7.67(1H,s),8.16(3H,brs),10.08(1H,s)
和实施例515同样,用相应的反应试剂得到表77所示化合物
表77
【表77】
实施例523
2-(3-氨基甲基苯基氨基)-3,5-二硝基吡啶的合成
将3-氨基苄基胺(696毫克)、二甲基氨基吡啶(674毫克)、3-硝基苯氧基羰基-Wang Resin(2.85克、Tetraheron Lett.,Vol.37,937(1996))和四氢呋喃(60毫升)的混合物在室温下搅拌24小时后,过滤。所得树脂用二甲基甲酰胺、水、甲醇、二氯甲烷依次洗涤后,减压干燥,得到3-氨基苄基氨基羰基-Wang Resin。
将所得树脂(100毫克、0.071mol)、碳酸钾(100毫克)、2-氯-3,5-二硝基吡啶(72毫克)、乙酸钯(II)(16毫克)、二苯基磷二茂铁(79毫克)和乙腈(9毫升)的混合物在氮气氛围、80℃下搅拌后,过滤。所得树脂用二甲基甲酰胺、水、甲醇、二氯甲烷依次洗涤后,减压干燥,加入三氟乙酸,在室温下搅拌1小时。将反应混合物过滤后,将滤液减压浓缩。往所得残渣中加入水和乙酸乙酯。水层用乙酸乙酯洗涤,减压浓缩。所得残渣用Sep-PaKR Plus C18Cartridges(Waters制造)进行精制,得到标题化合物1.7毫克(收率8%)。
1H-NMR(CD3OD)
δ:4.16(2H,s),7.35(1H,d,J=7.9Hz),7.53(1H,dd,J=7.9,7.9Hz),7.75(1H,d,J=7.9Hz),7.80(1H,s),9.25(1H,d,J=2.4Hz),9.30(1H,d,J=2.4Hz)
和实施例523一样,使用相应的氯衍生物得到表78~表80所示的化合物
表78
【表78】
表79
【表79】
表80
【表80】
更进一步,至此所示反应所用的化合物中,作为新型化合物的实施例25e、实施例417e、实施例500b、实施例519e、实施例520d、实施例538e和实施例542a的合成方法如下所示。
实施例25e
2-(5-氨基-2-乙基苯基)-2-叔丁氧基羰基氨基茚满的合成
实施例25a
3-氰基甲基-4-乙基硝基苯的合成
往3-氯甲基-4-乙基硝基苯(4.0克)和二甲基亚砜(50毫升)的混合物中加入氰化钠(982毫克)。将反应混合物在室温下搅拌3小时后,加入乙酸乙酯、正己烷和水。有机层有能够饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩,得到定量的标题化合物。
1H-NMR(CDCl3)
δ:1.33(3H,t,J=7.6Hz),2.78(2H,q,J=7.6Hz),3.80(2H,s),7.44(1H,d,J=8.6Hz),8.18(1H,dd,J=8.6,2.3Hz),8.35(1H,d,J=2.3Hz)
实施例25b
2-氰基-2-(2-乙基-5-硝基苯基)茚满的合成
往实施例25a所得化合物(3.0克)、α,α’-二氯-o-二甲苯(4.15克)和二甲基亚砜(200毫升)的混合物中加入叔丁醇钾(3.55克),在室温下搅拌3小时后,加入乙酸乙酯和水。有机层用饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩,得到标题化合物(1.36克)(收率29%)。
1H-NMR(CDCl3)
δ:1.45(3H,t,J=7.6Hz),3.11(2H,q,J=7.6Hz)、3.61(2H,d,J=15.5Hz),3.91(2H,d,J=15.5Hz),7.25-7.33(4H,m),7.53(1H,d,J=9.2Hz),8.12-8.16(2H,m)
实施例25c
2-(2-乙基-5-硝基苯基)-2-茚满酰胺的合成。
往实施例25b所得化合物(1.16克)和乙酸(10毫升)的混合物中依次加入水(2毫升)、浓硫酸(20毫升)。将反应混合物加热回流13小时后,冷却,注入冰水,用乙酸乙酯萃取。有机层用饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩,得到标题化合物(870毫克)(收率71%)。
1H-NMR(CDCl3)
δ:1.35(3H,t,J=7.6Hz),2.82(2H,q,J=7.6Hz),3.36(2H,d,J=15.9Hz),3.95(2H,d,J=15.9Hz),5.13(1H,brs),5.43(1H,brs),7.15-7.25(4H,m),7.49(1H,d,J=8.3Hz),8.08(1H,dd,J=8.3,2.3Hz),8.17(1H,d,J=2.3Hz)
实施例25d
2-叔丁氧基羰基氨基-2-(2-乙基-5-硝基苯基)茚满的合成
往实施例25c所得化合物(815毫克)和叔丁醇(12毫升)的混合液中加入四乙酸铅(1.40克)。将反应混合物加热回流3小时,冷却后,加入水,用乙酸乙酯-乙二醇萃取。有机层用水洗涤后,以无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为氯仿)进行精制,得到标题化合物(620毫克)(收率62%)。
1H-NMR(CDCl3)
δ:1.30(3H,t,J=7.6Hz),1.31(9H,s),2.93(2H,q,J=7.6Hz),3.55(2H,d,J=15.9Hz),3.63(2H,d,J=15.9Hz),5.18(1H,s),7.20-7.29(4H,m),7.40(1H,d,J=8.6Hz),8.05(1H,dd,J=8.6,2.3Hz),8.32(2H,d,J=2.3Hz)
实施例25e
2-(5-氨基-2-乙基苯基)-2-叔丁氧基羰基氨基茚满的合成
以实施例25d所得化合物为起始原料,和实施例3一样,得到标题化合物(收率97%)。
1H-NMR(CDCl3)
δ:1.23(3H,t,J=7.6Hz),1.30(9H,s),2.74(2H,q,J=7.6Hz),3.48-3.67(6H,m),5.02(1H,s),6.56(1H,dd,J=8.3,2.3Hz),6.74(1H,d,J=2.3Hz),7.03(1H,d,J=8.3Hz),7.15-7.24(4H,m)
实施例417e
N-(3-氨基-2-乙氧基苯基甲基)亚氨二羧酸二叔丁酯的合成
实施例417a
2-乙氧基-3-硝基苯甲酸乙酯的合成
往3-硝基水杨酸(5.0克)、碘乙烷(11毫升)和二甲基甲酰胺(200毫升)的混合物中加入碳酸钾(9.4克)。将反应混合物在60℃下搅拌4.5小时后,加入水,用乙酸乙酯萃取。有机层用饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶1)进行精制,得到标题化合物5.66克(收率88%)。
1H-NMR(CDCl3)
δ:8.01(1H,dd,J=7.9,1.7Hz),7.89(1H,dd,J=7.9,1.7Hz),7.26(1H,dd,J=7.9,7.9Hz),4.42(2H,q,J=7.3Hz),4.18(2H,q,J=6.9Hz),1.43(3H,t,J=6.9Hz),1.42(3H,t,J=7.3Hz)
实施例417b
2-乙氧基-3-硝基苄醇的合成
往实施例417a所得化合物(117毫克)、四氢呋喃(5毫升)和甲醇(2毫升)的混合物中加入硼氢化锂(10.7毫克)。将反应混合物在室温下搅拌15小时后,加入水,减压浓缩。往所得残渣中加入2N盐酸,用乙酸乙酯萃取。有机层用饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶2)进行精制,得到定量的标题化合物。
1H-NMR(CDCl3)
δ:7.77(1H,d,J=7.9Hz),7.67(1H,d,J=7.3Hz),7.22(1H,dd,J=7.9,7.3Hz),4.80(2H,s),4.08(2H,q,J=6.8Hz),2.10(1H,brs),1.44(3H,t,J=6.8Hz)
实施例417c
2-乙氧基-3-硝基苄基溴的合成
在冰冷却下往实施例417b所得化合物(3.13克)、四溴化碳(5.26克)和二氯甲烷(100毫升)的混合物中加入三苯基磷(4.16克)。将反应混合物在冰冷却下搅拌30分钟后,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶9)进行精制,得到标题化合物3.59克(收率87%)。
1H-NMR(CDCl3)
δ:7.78(1H,dd,J=7.9,1.7Hz),7.65(1H,dd,J=7.6,1.7Hz),7.20(1H,dd,J=7.9,7.6Hz),4.57(2H,s),4.17(2H,q,J=6.9Hz),1.49(3H,t,J=6.9Hz)
实施例417d
N-(2-乙氧基-3-硝基苯基甲基)亚氨二羧酸二叔丁酯的合成
将亚氨二羧酸二叔丁酯(3.23克)、二甲基甲酰胺(50毫升)和氢化钠(0.57克)的混合物在冰冷却下搅拌1小时后,在冰冷却下加入实施例417c所得化合物(3.51克)和二甲基甲酰胺(20毫升)的混合物。将反应混合物在室温下搅拌14小时后,加入2N盐酸,用乙酸乙酯萃取。有机层用饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶9)进行精制,得到标题化合物5.09克(收率95%)。
1H-NMR(CDCl3)
δ:7.72(1H,dd,J=7.9,1.3Hz),7.38(1H,dd,J=7.3,1.3Hz),7.17(1H,dd,J=7.9,7.3Hz),4.91(2H,s),4.06(2H,q,J=6.9Hz),1.45(18H,s),1.44(3H,t,J=6.9Hz)
实施例417e
N-(3-氨基-2-乙氧基苯基甲基)亚氨二羧酸二叔丁酯的合成
往实施例417d所得化合物(5.09克)、氯化镍·6水合物(61毫克)和甲醇(130毫升)的混合物中加入硼氢化钠(1.46克)。将反应混合物在室温下搅拌20分钟后,加入2N盐酸,接着用饱和碳酸氢钠水溶液调pH=8后,减压浓缩。往所得残渣中加入水,用乙酸乙酯萃取。有机层用饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶4)进行精制,得到标题化合物(收率85%)。
1H-NMR(CDCl3)
δ:6.86(1H,dd,J=7.9,7.6Hz),6.63(1H,dd,J=7.6,1.0Hz),6.53(1H,dd,J=7.9,1.0Hz),4.85(2H,s),3.90(2H,q,J=6.9Hz),3.74(2H,brs),1.43(18H,s),1.41(3H,t,J=6.9Hz)
实施例500b
N-〔5-氨基-2-(吡唑-1-基)苯基甲基〕氨基甲酸叔丁酯的合成
实施例500a
N-〔5-硝基-2-(吡唑-1-基)苯基甲基〕亚氨二羧酸二叔丁酯的合成
在冰冷却下往吡唑(1.0克)和二甲基亚砜(50毫升)的混合物中加入氢化钠(0.54克)。将反应混合物在冰冷却下搅拌1小时后,加入N-(2-氟-5-硝基苯基甲基)亚氨二羧酸二叔丁酯(5.0克)的二甲基亚砜(50毫升)溶液。将反应混合物在室温下搅拌15小时后,加入水,用乙酸乙酯萃取。有机层用饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶4)进行精制,得到标题化合物(收率73%)。
1H-NMR(CDCl3)
δ:8.22-8.19(2H,m),7.79-7.78(2H,m),7.50(1H,d,J=9.6Hz),6.53(1H,dd,J=2.3,2.0Hz),4.95(2H,s),1.46(18H,s)
实施例500b
N-〔5-氨基-2-(吡唑-1-基)苯基甲基〕氨基甲酸叔丁酯的合成
往实施例500a所得化合物(4.15克)、氯化镍·6水合物(0.183克)和甲醇(300毫升)的混合物中加入硼氢化钠(2.43克)。将反应混合物在室温下搅拌55分钟后,加入2N盐酸是反应液呈酸性,接着加入饱和碳酸氢钠水溶液使反应液呈碱性,减压浓缩。往所得残渣中加入水,用乙酸乙酯萃取。有机层用饱和食盐水洗涤,以无水硫酸钠干燥后,减压浓缩。所得残渣用乙酸乙酯-正己烷重结晶,得到标题化合物(收率89%)。
1H-NMR(CDCl3)
δ:7.69(1H,d,J=1.3Hz),7.57(1H,d,J=2.0Hz),7.06(1H,d,J=8.3Hz),6.86-6.83(1H,m),6.60(1H,dd,J=8.3,2.3Hz),6.41(1H,dd,J=2.0,1.3Hz),5.62(1H,brs),4.01(2H,d,J=6.6Hz),3.82(2H,brs),1.43(9H,s)
实施例519e
3-(叔丁氧基羰基氨基甲基)-4-氯-2-乙氧基苯胺的合成
实施例519a
5-溴-4-氯-2-氟硝基苯的合成
在冰冷却下往4-氯-2-氟硝基苯(1.00克)、硫酸银(1.95克)和浓硫酸(5毫升)的混合物中加入溴(0.32毫升),在0℃下搅拌30分钟后,在室温下搅拌1小时。将反应混合物注入冰水中,用乙醚萃取。有机层用水、饱和碳酸氢钠水溶液、饱和食盐水依次洗涤,以无水硫酸钠干燥后,减压浓缩,得到标题化合物1.38克(收率95%)。
1H-NMR(CDCl3)
δ:7.47(1H,d,J=9.9Hz),8.37(1H,d,J=7.3Hz)
实施例519b
5-溴-4-氯-2-氟-3-(三氟甲基羰基氨基甲基)硝基苯的合成
将实施例519a所得化合物(204毫克)、N-羟基甲基-2,2,2-三氟乙酰胺(115毫克)和10%发烟硫酸(1.6毫升)的混合物在80℃下搅拌10小时。将反应混合物冷却后,注入冰水中,用乙醚萃取。有机层依次用水、饱和食盐水洗涤后,以无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶3)进行精制,得到标题化合物85.1毫克(收率28%)。
1H-NMR(CDCl3)
δ:4.86(2H,d,J=4.0Hz),6.73(1H,brt),8.39(1H,d,J=7.3Hz)
实施例519c
5-溴-3-(叔丁氧基羰基氨基甲基)-4-氯-2-氟硝基苯的合成
将实施例519所得化合物(601毫克)、浓硫酸(3毫升)和甲醇(12毫升)的化合物加热回流1小时。将反应混合物减压浓缩后,加入2N氢氧化钠水溶液调成碱性,用二氯甲烷萃取(20毫升)。在室温下往有机层中加入二碳酸二叔丁酯(414毫克)和2N氢氧化钠水溶液(10毫升),在室温下搅拌2小时。有机层依次用水、饱和食盐水洗涤后,以无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为氯仿)进行精制,得到标题化合物402毫克(收率66%)。
1H-NMR(CDCl3)
δ:1.44(9H,s),4.57-4.66(2H,m),5.01(1H,brt),8.31(1H,d,J=7.6Hz)
实施例519d
5-溴-3-(叔丁氧基羰基氨基甲基)-4-氯-2-乙氧基硝基苯的合成
在冰冷却下往实施例519c所得化合物(200毫克)、乙醇(36微升)和四氢呋喃(5毫升)的混合物中加入氢化钠(含量60%、25毫克)。将反应混合物在0℃下搅拌2小时后,加入水和乙醚。有机层依次用水、饱和食盐水洗涤后,以无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=1∶4)进行精制,得到标题化合物197毫克(收率92%)。
1H-NMR(CDCl3)
δ:1.45(9H,s),1.47(3H,t,J=6.9Hz),4.08(2H,q,J=6.9Hz),4.62(2H,d,J=5.9Hz),4.93(1H,brt),8.10(1H,s)
实施例519e
3-(叔丁氧基羰基氨基甲基)-4-氯-2-乙氧基苯胺的合成
以实施例519d所得化合物为起始原料,和实施例3一样得到标题化合物(86%)。
1H-NMR(CDCl3)
δ:1.44(3H,t,J=7.3Hz),1.45(9H,s),3.78(2H,brs),3.92(2H,q,J=7.3Hz),4.47(2H,d,J=5.3Hz),4.91(1H,brt),6.63(1H,d,J=8.3Hz),6.94(1H,d,J=8.3Hz)
实施例520d
3-(叔丁氧基羰基氨基甲基)-2-乙氧基-6-甲基苯胺的合成
实施例520a
3-甲基-6-硝基-2-(三氟甲基羰基氨基甲基)苯酚的合成
以5-甲基-2-硝基苯酚为起始原料,和实施例545b一样得到标题化合物(收率16%)。
1H-NMR(CDCl3)
δ:2.57(3H,s),4.67(2H,d,J=6.3Hz),6.89(1H,d,J=8.6Hz),7.00(1H,brs),8.00(1H,d,J=8.6Hz),11.23(1H,s)
实施例520b
2-(叔丁氧基羰基氨基甲基)-4-甲基-6-硝基苯酚的合成
将实施例520a所得化合物(100毫克)、碳酸钾(99.4毫克)、水(1.0毫升)和甲醇(6.0毫升)的混合物在室温下搅拌3小时后,加入二碳酸二叔丁酯(157毫克)。将反应混合物在室温下搅拌30分钟后,减压浓缩。往所得残渣中加入饱和食盐水,用乙酸乙酯萃取。有机层用无水硫酸钠干燥后,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=3∶17)进行精制,得到标题化合物(收率70%)。
1H-NMR(CDCl3)
δ:1.43(9H,s),2.55(3H,s),4.44(2H,d,J=6.3Hz),5.17(1H,brs),6.82(1H,d,J=8.6Hz),7.94(1H,d,J=8.6Hz),11.11(1H,s)
实施例520c
3-(叔丁氧基羰基氨基甲基)-2-乙氧基-4-甲基硝基苯的合成
将实施例520b所得化合物(350毫克)、碳酸铯(404毫克)、二甲基甲酰胺(15毫升)和碘乙烷(0.4毫升)的混合物在60℃下搅拌2小时。往反应混合物中加入乙酸乙酯和水。有机层用饱和食盐水洗涤后,以无水硫酸钠干燥,减压浓缩。所得残渣用硅胶柱层析(展开剂为乙酸乙酯∶正己烷=2∶8)进行精制,定量地得到标题化合物。
1H-NMR(CDCl3)
δ:1.44(9H,s),1.48(3H,t,J=6.9Hz),2.49(3H,s),4.03(2H,q,J=6.9Hz),4.41(2H,d,J=5.6Hz),4.86(1H,brs),7.03(1H,d,J=8.6Hz),7.72(1H,d,J=8.6Hz)
实施例520d
3-(叔丁氧基羰基氨基甲基)-2-乙氧基-4-甲基苯胺
以实施例520c所得化合物为起始原料,和实施例3一样得到标题化合物(92%)。
1H-NMR(CDCl3)
δ:1.43(3H,t,J=6.9Hz),1.44(9H,s),2.26(3H,s),3.61(2H,brs),3.89(2H,q,J=6.9Hz),4.34(2H,d,J=5.3Hz),4.70(1H,brs),6.61(1H,d,J=7.9Hz),6.75(1H,d,J=7.9Hz)
实施例538e
N-〔3-氨基-2-(正丙氧基)苯基甲基〕亚胺二羧酸二叔丁酯的合成
实施例538a
3-硝基-2-(正丙氧基)苯甲酸正丙酯的合成
以3-硝基水杨酸为起始原料,使用正碘丙烷作为反应试剂,和实施例417a一样,得到标题化合物(收率29%)。
1H-NMR(CDCl3)
δ:7.98(1H,dd,J=7.6,1.7Hz),7.87(1H,dd,J=7.9,1.7Hz),7.24(1H,dd,J=7.9,7.6Hz),4.31(2H,t,J=6.9Hz),4.05(2H,t,J=6.9Hz)1.90-1.71(4H,m),1.08-0.97(6H,m)
实施例538b
3-硝基-2-(正丙氧基)苄醇的合成
以实施例538a所得化合物为起始原料,和实施例417b一样,得到标题化合物(收率70%)。
1H-NMR(CDCl3)
δ:7.76(1H,dd,J=8.3,1.3Hz),7.68(1H,dd,J=7.3,1.3Hz),7.21(1H,dd,J=8.3,7.3Hz),4.80(2H,s),3.96(2H,t,J=6.9Hz),2.13(1H,brs),1.91-1.77(2H,m),1.04(3H,t,J=7.3Hz)
实施例538c
3-硝基-2-(正丙氧基)苄基溴的合成
以实施例538b所得化合物为起始原料,和实施例417c一样,得到标题化合物(收率95%)。
1H-NMR(CDCl3)
δ:7.77(1H,dd,J=7.9,1.3Hz),7.64(1H,dd,J=7.9,1.3Hz),7.19(1H,dd,J=7.9,7.9Hz),4.57(2H,s),4.05(2H,t,J=6.6Hz),1.96-1.83(2H,m),1.07(3H,t,J=7.3Hz)
实施例538d
N-〔3-硝基-2-(正丙氧基)苯基甲基〕亚氨二羧酸二叔丁酯的合成
以实施例538c所得化合物为起始原料,和实施例417d一样,得到标题化合物(收率62%)。
1H-NMR(CDCl3)
δ:7.70(1H,dd,J=7.9,1.3Hz),7.37(1H,dd,J=7.9,1.3Hz),7.16(1H,dd,J=7.9,7.9Hz),4.91(2H,s),3.94(2H,t,J=6.6Hz),1.91-1.80(2H,m),1.45(18H,s),1.05(3H,t,J=7.3Hz)
实施例538e
N-〔3-氨基-2-(正丙氧基)苯基甲基〕亚氨二羧酸二叔丁酯的合成
以实施例538d所得化合物为起始原料,和实施例417e一样,定量地得到标题化合物。
1H-NMR(CDCl3)
δ:6.86(1H,dd,J=7.9,7.6Hz),6.63(1H,d,J=7.9Hz),6.52(1H,d,J=7.6Hz),4.85(2H,s),3.78(2H,t,J=6.6Hz),3.74(2H,brs),1.89-1.75(2H,m),1.43(18H,s),1.07(3H,t,J=7.3Hz)
实施例542a
N-〔3-氨基-2-(异丙氧基)苯基甲基〕亚氨二羧酸二叔丁酯的合成
以3-硝基水杨酸为起始原料,使用异碘丙烷作为反应试剂,和实施例417a~实施例417e一样,得到标题化合物。
1H-NMR(CDCl3)
δ:6.85(1H,dd,J=7.9,7.6Hz),6.62(1H,d,J=7.6Hz),6.53(1H,d,J=7.9Hz),4.83(2H,s),4.26-4.15(1H,m),3.69(2H,brs),1.42(18H,s),1.31(6H,d,J=6.3Hz)
实验例
实验例1
就本发明化合物对目前为止已知的3种NOS亚型的抑制作用进行研究。
按以下顺序调制各酶样品(Nagafuji et al.,Neuroreport 6,1541-1545,1995)。
nNOS的酶样品按以下顺序调制。将无处置的Sprague Dawley(SD)系大鼠(体重300-400克)断头,马上取出全脑,在冰上分取大脑皮质。接着,加入5倍量的50mM Tris-HCl,1mM DTT(pH7.4)溶液,匀浆3分钟,将其以1000×g离心10分钟。所得上清以100,000×g离心60分钟,最终所得的上清的可溶性细胞质部分作为nNOS的酶样品。
iNOS的酶样品按以下顺序调制。大鼠腹腔给予LPS(10毫克/千克),6小时后经心脏灌流含有10单位/毫升肝素的生理盐水后,取出肺。接着,加入5倍容量的50mM Tris-HCl,1mM DTT(pH7.4)溶液,匀浆3分钟,将其以1000×g离心10分钟。所得上清以100,000×g离心60分钟,最终所得的上清的可溶性细胞质部分作为iNOS的酶样品。
eNOS的酶样品按以下顺序调制。
将牛肺动脉血管内皮细胞株(CPAE)在含有20%FBS的MEM培养基上培养。几天后,将其用0.25%胰蛋白酶trypsin,1mM EDTA溶液从烧瓶上剥离,加入适量FBS后,以1000rpm离心10分钟。往沉淀的细胞中加入适量不含钙和镁的磷酸缓冲液(pH7.4),以1000rpm离心10分钟。重复相同操作,洗净细胞后,加入含有1%TritonX-100和1mM DTT的50mM Tris-HCl(pH7.4),在冰中放置1小时。接着匀浆3分钟后,一边搅拌一边在冰中放置30分钟。最终以100,000×g离心60分钟所得上清作为eNOS的酶样品。
NOS活性的测定基本上按照本发明者们报告的方法,定量从底物L-[3H]精氨酸到反应产物L-[3H]瓜氨酸的转化量(Naga fuji et al.,in Brain Edema IX(Ito et al.,eds.)60,pp.285-288,1994;Nagafuji et al.,Neuroreport 6,1541-1545,1995)。
反应液由100nM L-[3H]精氨酸、酶样品(10-30微克/毫升蛋白)、1.25mM CaCl2、1mM EDTA、10微克/毫升钙调素、1mM NADPH、100μM四氢生物喋呤、10μM FAD、10μM FMN、50mM Tris-HCl(pH7.4),往其中加入本发明的化合物或对照化合物。
加入L-[3H]精氨酸开始反应,在37℃下孵育10分钟后,加入2毫升50mM Tris-HCl(pH5.5)、1mM EDTA,置于冰水中停止反应。将反应溶液通过阳离子交换树脂柱(Dowex AG50WX-8,Na+form,3.2毫升),分离残留的底物L-[3H]精氨酸和反应产物L-[3H]citrulline。将此溶出液和一定量蒸馏水通过交换柱所得的溶出液装入小玻璃瓶,回收L-[3H]citrulline。在这之后,加入闪烁剂,用液体闪烁计数器计测放射性,定量L-[3H]citrulline。
对于nNOS和eNOS的活性,求出CaCl2和钙调素存在时检测的活性和CaCl2和钙调素不存在时检测的活性的差值。在CaCl2和钙调素不存在时测出iNOS的活性。酶样品中的蛋白浓度用バイオラット公司制造的微测定装置(マイクロアッセイキット)测得。实验都设平行实验。
表81显示实验化合物对各NOS亚型的IC50值(抑制50%活性所需的浓度)和作为选择性指标的各IC50值的比。
表81
【表81】
实验化合物对三种NOS亚型的抑制作用和选择性
实施例序号或对照化合物 | 抑制作用 | 选择性 | ||||
IC50(nM) | iNOS/nNOS | eNOS/nNOS | eNOS/iNOS | |||
nNOS | iNOS | eNOS | ||||
1852535761151153458460462465466467468469478479481482483484485488489490491506521522541543L-NA | 22.679.886.170.8126.0126.229.820.8111.716.431.235.519.656.340.061.666.978.150.565.469.254.439.922.118.145.829.119.519.725.912.516.9 | 916.7N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.1774.9N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.N.D.3464.3 | 322.41476.76624.3947.41614.9679.3586.1403.11244.3257.21000.0421.0274.62481.0994.0447.5802.01984.51348.6711.01264.22882.4297.9N.D.347.51768.01292.7485.2398.4712.6249.868.2 | 41--------------------32---------205.0 | 1419771313520191116321214442571225271118538-193945252028204.0 | 0.14--------------------1.6---------0.02 |
(注)〖N.D.〗表示没有测定,〖-〗表示不能算出。
产业上的利用可能性
本发明化合物显示出优良的nNOS抑制活性或iNOS抑制活性,作为对脑血管障碍〔脑出血、蛛网膜下出血、脑梗塞(动脉粥样化血栓性梗塞、ラクナ梗塞、心源性栓塞症)、一过性脑缺血发作、脑浮肿〕、头部外伤、脊椎损伤、疼痛〔头痛(偏头痛、紧张性头痛、群发性头痛、慢性发作头痛)〕、帕金森氏病、阿茨海默病、痉挛、吗啡耐受和依赖、败血症休克、慢性关节风温病、变形性关节炎、病毒性或非病毒性感染、糖尿病等的治疗药物很有用。
Claims (42)
1.通式(1)所示的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,
式中R1、R2相同或不同,表示氢原子,
可具有取代基的C1-C6直链烷基、或C3-C8支链或环状烷基,所述的取代基是卤素原子,C3-C8的环烷基,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,
乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、异戊酰基、三甲基乙酰基、苯甲酰基、邻苯二甲酰基、甲苯酰基,
烷基部分为C1-C6直链烷基或者C3-C8支链或环状烷基的烷氧基羰基,
也可一起形成至少含有1个氮原子作为杂原子的3-8元杂环;
R3、R4相同或不同,表示氢原子,可具有取代基的C1-C6直链烷基、或C3-C8支链或环状烷基,所述的取代基是卤素原子,C3-C8的环烷基,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,
也可一起形成碳数3~10的单环或稠环;
R5表示氢原子,
C1-C6直链烷基、或C3-C8支链或环状烷基,
乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、异戊酰基、三甲基乙酰基、苯甲酰基、邻苯二甲酰基、甲苯酰基,
烷基部分为C1-C6直链烷基或者C3-C8支链或环状烷基的烷氧基羰基;
X1、X2、X3、X4相同或不同,表示氢原子,
卤素原子,
硝基,
氰基,
羟基,
可具有取代基的C1-C6直链烷基、或C3-C8支链或环状烷基,所述的取代基是卤素原子,C3-C8的环烷基,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,
C2-C6直链烯基或者C3-C6支链烯基,
C2-C6直链炔基或者C3-C6支链炔基,
可具有取代基的C1-C6直链烷氧基或者C3-C8支链或环状烷氧基,所述的取代基是卤素原子,C3-C8的环烷基,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,
可具有取代基的C1-C6直链烷硫基或者C3-C8支链或环状烷硫基,所述的取代基是卤素原子,C3-C8的环烷基,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,
可被卤素原子、和/或、C1-C6直链烷基或者C3-C8支链或环状烷基取代的苯基,
NX5X6,
C(=O)X7;
在这里,X5、X6相同或不同,表示氢原子,
可具有取代基的C1-C6直链烷基或者C3-C8支链或环状烷基,所述的取代基是卤素原子,C3-C8的环烷基,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,
乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、异戊酰基、三甲基乙酰基、苯甲酰基、邻苯二甲酰基、甲苯酰基,
可具有取代基的烷基部分为C1-C6直链烷基或者C3-C8支链或环状烷基的烷氧基羰基,所述的取代基是卤素原子,C3-C8的环烷基,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,
也可一起形成至少含有1个氮原子作为杂原子的3~8元杂环;
X7表示氢原子,
羟基,
可具有取代基的C1-C6直链烷基或者C3-C8支链或环状烷基,所述的取代基是卤素原子,C3-C8的环烷基,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,
可具有取代基的C1-C6直链烷氧基或者C3-C8支链或环状烷氧基,所述的取代基是卤素原子,C3-C8的环烷基,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,
NX8X9;
这里X8、X9相同或不同,表示氢原子,
可具有取代基的C1-C6直链烷基或者C3-C8支链或环状烷基,所述的取代基是卤素原子,C3-C8的环烷基,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,
也可一起形成至少含有1个氮原子作为杂原子的3~8元杂环;
A表示具有取代基的苯环,或者可具有取代基、且作为杂原子含有1个以上氮原子的5~6元环芳香族杂环;A中的取代基表示羟基,卤素原子,硝基,氰基,三氟甲基,C1-C6直链烷氧基,C3-C8支链或环状烷氧基,C1-C6直链烷基,C3-C8支链或环状烷基,C1-C6直链烷硫基,C3-C8支链或环状烷硫基,
NX10X11或者C(=O)X12;
其中X10和X11相同或不同,
表示氢原子,
可以具有取代基的C1-C6直链烷基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
可以具有取代基的C3-C8的支链或环状烷基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、异戊酰基、三甲基乙酰基、苯甲酰基、邻苯二甲酰基、甲苯酰基,
在烷基部分具有取代基的C1-C6直链烷氧基羰基,在烷基部分的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
在烷基部分具有取代基的C3-C8的支链或环状的烷氧基羰基,所述的烷基部分的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
X10与X11可以结合在一起形成至少含有1个氮原子作为杂原子的3-8元杂环;
X12是卤素原子,
羟基,
可以具有取代基的C1-C6直链烷基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
可以具有取代基的C3-C8的支链或环状烷基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
可以具有取代基的C1-C6直链烷氧基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
可以具有取代基的C3-C8的支链或环状烷氧基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
或者NX13X14,这里X13和X14相同或不同,表示氢原子,
可以具有取代基的C1-C6直链烷基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
可以具有取代基的C3-C8的支链或环状烷基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
X13与X14可以结合在一起形成至少含有1个氮原子作为杂原子的3-8元杂环;
n、m分别表示0或1的整数,但是,A为具有取代基的苯环,其取代基为硝基、氨基或羧基时,R1或R2中任一个要为氢原子;此外,A为具有取代基的苯环时,其取代基不是二-(2-氯乙基)氨基;此外,A为以硝基为取代基的吡啶环时,X1、X2、X3和X4任何一个都不是羟基。
2.根据权利要求1记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中X1、X2、X3、X4相同或不同,为氢原子,
卤素原子,
硝基,
氰基,
可具有取代基的C1-C6直链烷基或者C3-C8支链或环状烷基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C 3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
C2-C6直链烯基,
C3-C6支链烯基,
C2-C6直链炔基,
C3-C6支链炔基,
可具有取代基的C1-C6直链烷氧基、C3-C8支链或环状烷氧基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
可具有取代基的C1-C6直链烷硫基、C3-C8支链或环状烷硫基,所述的取代基是卤素原子,可以被卤素原子、C1-C6直链烷基、C3-C8支链或环状的烷基取代的苯基,C3-C8的环烷基,
可被卤素原子、和/或、C1-C6直链烷基或者C3-C8支链或环状烷基取代的苯基,
NX5X6,C(=O)X7;
A为具有取代基的苯环或可具有取代基的吡啶环,A中的取代基表示和权利要求1中的定义相同。
3.根据权利要求1记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中A为可具有取代基的、且作为杂原子含有1个以上氮原子的5~6元环芳香族杂环,但可具有取代基的吡啶环除外。
4.根据权利要求1记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中在通式(1)中R1为氢原子;R2为氢原子、C1-C6直链烷基、或C3-C8支链或环状烷基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、异戊酰基、三甲基乙酰基、苯甲酰基、邻苯二甲酰基、甲苯酰基,烷基部分为C1-C6直链烷基、或C3-C8支链或环状烷基的烷氧基羰基;A为具有取代基的苯环。
5.根据权利要求2记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中通式(1)中A为可具有取代基的吡啶环。
6.根据权利要求1记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中在通式(1)中,R1、R2为氢原子;R5为氢原子;X1、X2、X3、X4相同或不同,为氢原子、卤素原子、可具有取代基的C1-C6直链烷基或者C3-C8支链或环状烷基、可具有取代基的C1-C6直链烷氧基、或C3-C8支链或环状烷氧基、NX5X6;A为具有取代基的苯环、可具有取代基的吡啶环、可具有取代基的嘧啶环、可具有取代基的噁唑环、可具有取代基的噻唑环。
7.根据权利要求6记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中在通式(1)中,A为具有取代基的苯环、可具有取代基的吡啶环。
8.根据权利要求1~7的任一项记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中在通式(1)中,R3、R4相同或不同,表示氢原子、C1-C6直链烷基、或C3-C8支链或环状烷基,也可一起形成碳数3~10的单环。
9.根据权利要求1~7的任一项记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中在通式(1)中,X1、X2、X3、X4相同或不同,为氢原子,卤素原子,C1-C6直链烷基,C3-C8支链或环状烷基、可被苯基取代的C1-C6直链烷氧基,C3-C8支链或环状烷氧基,NX5X6;在这里,X5、X6相同或不同,为氢原子、可被苯基取代的C1-C6直链烷基或者C3-C8支链或环状烷基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、异戊酰基、三甲基乙酰基、苯甲酰基、邻苯二甲酰基、甲苯酰基,也可一起形成至少含有1个氮原子作为杂原子的3-8元杂环。
10.根据权利要求1~7的任一项记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中在通式(1)中A为具有取代基的苯环、可具有取代基的吡啶环,其取代基为硝基、C1-C6直链烷氧基、C3-C8支链或环状烷氧基、C1-C6直链烷基、C3-C8支链或环状烷基、C1-C6直链烷硫基、C3-C8支链或环状烷硫基。
11.根据权利要求1~7的任一项记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中在通式(1)中,X1、X2、X3、X4相同或不同,为氢原子、卤素原子、C1-C6直链烷基、C3-C8支链或环状烷基、C1-C6直链烷氧基、C3-C8支链或环状烷氧基、NX5X6;在这里,X5、X6相同或不同,为氢原子、C1-C6直链烷基、C3-C8支链或环状烷基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、异戊酰基、三甲基乙酰基、苯甲酰基、邻苯二甲酰基、甲苯酰基,也可一起形成至少含有1个氮原子作为杂原子的3-8元杂环。
12.根据权利要求1~7的任一项记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中在通式(1)中,m、n为0;X1、X2、X3、X4以外的苯环上取代基为间位取代。
13.根据权利要求1~7的任一项记载的化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐,其中在通式(1)中m+n=1;X1、X2、X3、X4以外的苯环上取代基为邻位或对位取代。
14.根据权利要求1记载的化合物或其可能的互变异构体、立体异构体和它们医药上允许的盐,选自通式(1)表示的下列化合物组:2-(3-氨基甲基苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-6-甲基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-6-乙基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-6-乙氧基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-6-甲硫基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-6-甲基-3-硝基苯、2-(3-氨基甲基苯基氨基)-6-甲氧基-3-硝基苯、2-(3-氨基甲基-2-甲基苯基氨基)-6-甲氧基-3-硝基吡啶、2-(4-氨基乙基苯基氨基)-6-甲氧基-3-硝基吡啶、2-〔3-(1-氨基-1-甲基乙基)苯基氨基〕-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基-2-甲氧基苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基-4-氯苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基-4-氟苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基-2-乙氧基苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基-2-氯苯基氨基)-6-甲氧基-3-硝基吡啶、2-(3-氨基甲基苯基氨基)-4-甲基吡啶、2-〔3-(1-氨基-1-甲基乙基)苯基氨基〕-4-甲基吡啶、2-(3-氨基甲基-2-甲基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-4-乙基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-4-乙氧基苯基氨基)-4-甲基吡啶、2-(2-氨基乙基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-氯苯基氨基)-4-甲基吡啶、2-〔3-(1-氨基-环丁基)苯基氨基〕-4-甲基吡啶、2-(4-氨基乙基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-乙氧基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-4-氯苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-正丙氧基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-4-氯-2-乙氧基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-乙氧基-4-甲基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-甲氧基苯基氨基)-4-甲基吡啶、2-(3-氨基甲基-2-异丙氧基苯基氨基)-4-甲基吡啶。
15.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的神经元一氧化氮合成酶抑制剂,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4,、n、m、A表示和权利要求1中相同的意义。
16.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的脑血管障碍治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
17.根据权利要求16记载的治疗药,其中脑血管障碍的病型为脑出血。
18.根据权利要求16记载的治疗药,其中脑血管障碍的病型为蛛网膜出血。
19.根据权利要求16记载的治疗药,其中脑血管障碍的病型为脑梗塞。
20.根据权利要求19记载的治疗药,其中脑梗塞的亚病型为动脉粥样化血栓性梗塞。
21.根据权利要求19记载的治疗药,其中脑梗塞的亚病型为腔隙梗塞。
22.根据权利要求19记载的治疗药,其中脑梗塞的亚病型为心源性栓塞。
23.根据权利要求16记载的治疗药,其中脑血管障碍的病型为一过性脑缺血发作。
24.根据权利要求16记载的治疗药,其中脑血管障碍的病型为脑浮肿。
25.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的头部外伤治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
26.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的脊椎损伤治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
27.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的镇痛药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
28.根据权利要求27记载的治疗药,其中疼痛的病型为头痛。
29.根据权利要求28记载的治疗药,其中头痛的亚病型为偏头痛。
30.根据权利要求28记载的治疗药,其中头痛的亚病型为紧张性头痛。
31.根据权利要求28记载的治疗药,其中头痛的亚病型为群发性头痛和慢性发作性头痛。
32.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的帕金森氏病治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
33.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的阿茨海默病治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
34.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的抗痉挛药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
35.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的对吗啡耐受和依赖的治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
36.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的败血症休克治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
37.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的慢性关节风湿病治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
38.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的变形性关节炎治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
39.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的病毒性或非病毒性感染治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
40.含有以通式(1)所示化合物或其可能的互变异构体、立体异构体、和它们医药上允许的盐作为有效成分的糖尿病治疗药,
式中R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1中相同的意义。
42.根据权利要求1记载的化合物的制备方法,由反应路线(B)表示,
在通式(1)、(9)或(10)中,R1、R2、R3、R4、R5、X1、X2、X3、X4、n、m、A表示和权利要求1相同的意义;L表示脱去基团,所述脱去基团表示卤素原子、三氟甲磺酰氧基、对甲苯碘酰氧基、甲磺酰氧基。
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FR1579474A (zh) * | 1967-10-24 | 1969-08-29 | ||
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JPS5618969A (en) * | 1979-07-24 | 1981-02-23 | Toyama Chem Co Ltd | Novel 1-(4-aminobenzyl)-2,3-dioxopiperazine derivative, its acid addition salt, and their preparation |
DE3330547A1 (de) * | 1983-08-24 | 1985-03-21 | Bayer Ag, 5090 Leverkusen | Benzthiazinophenoxazin-farbstoffe |
NZ224714A (en) * | 1987-06-01 | 1990-03-27 | Janssen Pharmaceutica Nv | Substituted benzotriazole derivatives and pharmaceutical compositions |
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JPH0273071A (ja) * | 1988-09-09 | 1990-03-13 | Sumitomo Chem Co Ltd | ベンズイミダゾール誘導体、その製造法およびそれを有効成分とする殺虫、殺ダニ剤 |
JPH04249551A (ja) * | 1991-01-07 | 1992-09-04 | Sumitomo Chem Co Ltd | ゴム組成物 |
FR2677984B1 (fr) * | 1991-06-21 | 1994-02-25 | Elf Sanofi | Derives d'imidazoline n-substitues, leur preparation, les compositions pharmaceutiques en contenant. |
JPH0558998A (ja) * | 1991-09-06 | 1993-03-09 | Taisho Pharmaceut Co Ltd | カルバゾール誘導体 |
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JPH06192080A (ja) | 1992-09-25 | 1994-07-12 | Chugai Pharmaceut Co Ltd | 脳浮腫の予防および治療剤 |
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ATE174593T1 (de) * | 1993-04-30 | 1999-01-15 | Yamanouchi Pharma Co Ltd | Neue bisoxadiazolidinderivate |
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AU7705694A (en) | 1993-10-04 | 1995-05-01 | Glaxo Wellcome House | Substituted urea and isothiourea derivatives as no synthase inhibitors |
WO1995012572A1 (en) * | 1993-11-04 | 1995-05-11 | Abbott Laboratories | Cyclobutane derivatives as inhibitors of squalene synthetase and protein farnesyltransferase |
IT1275433B (it) * | 1995-05-19 | 1997-08-07 | Smithkline Beecham Farma | Derivati di diarildiammine |
AU2978197A (en) * | 1996-06-04 | 1998-01-05 | Chugai Seiyaku Kabushiki Kaisha | Substituted benzenes having nos inhibitory effects |
-
1997
- 1997-12-24 US US09/331,733 patent/US6331553B1/en not_active Expired - Fee Related
- 1997-12-24 PL PL97334304A patent/PL334304A1/xx unknown
- 1997-12-24 KR KR1019997005674A patent/KR100559816B1/ko not_active IP Right Cessation
- 1997-12-24 CN CNB971805946A patent/CN1244542C/zh not_active Expired - Fee Related
- 1997-12-24 EP EP97950368A patent/EP0949242A4/en not_active Withdrawn
- 1997-12-24 HU HU0000321A patent/HUP0000321A3/hu unknown
- 1997-12-24 RU RU99116598/04A patent/RU2193554C2/ru not_active IP Right Cessation
- 1997-12-24 CA CA002275933A patent/CA2275933A1/en not_active Abandoned
- 1997-12-24 AU AU53394/98A patent/AU742388B2/en not_active Ceased
- 1997-12-24 TW TW086119687A patent/TW584622B/zh not_active IP Right Cessation
- 1997-12-24 WO PCT/JP1997/004762 patent/WO1998028257A1/ja not_active Application Discontinuation
-
1999
- 1999-06-22 NO NO993109A patent/NO993109L/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
US6331553B1 (en) | 2001-12-18 |
WO1998028257A1 (fr) | 1998-07-02 |
RU2193554C2 (ru) | 2002-11-27 |
NO993109D0 (no) | 1999-06-22 |
TW584622B (en) | 2004-04-21 |
NO993109L (no) | 1999-08-24 |
AU742388B2 (en) | 2002-01-03 |
HUP0000321A2 (hu) | 2000-08-28 |
EP0949242A4 (en) | 2004-09-08 |
KR100559816B1 (ko) | 2006-03-10 |
KR20000062280A (ko) | 2000-10-25 |
AU5339498A (en) | 1998-07-17 |
EP0949242A1 (en) | 1999-10-13 |
PL334304A1 (en) | 2000-02-14 |
HUP0000321A3 (en) | 2000-09-28 |
CN1240419A (zh) | 2000-01-05 |
CA2275933A1 (en) | 1998-07-02 |
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