CN1568187A - 2h-2,3-二氮杂萘-1-酮和其使用方法 - Google Patents
2h-2,3-二氮杂萘-1-酮和其使用方法 Download PDFInfo
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- CN1568187A CN1568187A CNA028202198A CN02820219A CN1568187A CN 1568187 A CN1568187 A CN 1568187A CN A028202198 A CNA028202198 A CN A028202198A CN 02820219 A CN02820219 A CN 02820219A CN 1568187 A CN1568187 A CN 1568187A
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- HDQBJYWFRWQWLT-UHFFFAOYSA-N methyl 2,2-dimethyl-3-[3-[(4-oxo-3h-phthalazin-1-yl)amino]propylamino]-3-phenylpropanoate Chemical compound N=1NC(=O)C2=CC=CC=C2C=1NCCCNC(C(C)(C)C(=O)OC)C1=CC=CC=C1 HDQBJYWFRWQWLT-UHFFFAOYSA-N 0.000 description 1
- OINKWIOPYXLZJJ-UHFFFAOYSA-N methyl 2-cyano-3-methylbenzoate Chemical compound COC(=O)C1=CC=CC(C)=C1C#N OINKWIOPYXLZJJ-UHFFFAOYSA-N 0.000 description 1
- GYTNVYDEYTWEPO-UHFFFAOYSA-N methyl 3-[3-(1-methylpiperidin-2-yl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C2N(CCCC2)C)=N1 GYTNVYDEYTWEPO-UHFFFAOYSA-N 0.000 description 1
- ITZDGQXPGCJMET-UHFFFAOYSA-N methyl 3-[3-(1-methylpiperidin-3-yl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C2CN(C)CCC2)=N1 ITZDGQXPGCJMET-UHFFFAOYSA-N 0.000 description 1
- OGEOUISYVLXRNA-UHFFFAOYSA-N methyl 3-[3-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C2CCN(C)CC2)=N1 OGEOUISYVLXRNA-UHFFFAOYSA-N 0.000 description 1
- VJYHHHYUJCJOIR-UHFFFAOYSA-N methyl 3-[3-(1-methylpyrrol-2-yl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2N(C=CC=2)C)=N1 VJYHHHYUJCJOIR-UHFFFAOYSA-N 0.000 description 1
- CWGALNNGIBPFHF-UHFFFAOYSA-N methyl 3-[3-(1-methylpyrrolidin-2-yl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C2N(CCC2)C)=N1 CWGALNNGIBPFHF-UHFFFAOYSA-N 0.000 description 1
- IVWRXYQJEQHTTJ-UHFFFAOYSA-N methyl 3-[3-(1H-pyrrol-2-yl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2NC=CC=2)=N1 IVWRXYQJEQHTTJ-UHFFFAOYSA-N 0.000 description 1
- FVQSATVMHHZTLO-UHFFFAOYSA-N methyl 3-[3-(3-ethoxyphenyl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound CCOC1=CC=CC(C=2N=C(CCC(=O)OC)ON=2)=C1 FVQSATVMHHZTLO-UHFFFAOYSA-N 0.000 description 1
- SJZXIWYMUPZAKY-UHFFFAOYSA-N methyl 3-[3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2C=C(OC)C=CC=2)=N1 SJZXIWYMUPZAKY-UHFFFAOYSA-N 0.000 description 1
- WZGKOVSMGRREEB-UHFFFAOYSA-N methyl 3-[3-(3-propoxyphenyl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound CCCOC1=CC=CC(C=2N=C(CCC(=O)OC)ON=2)=C1 WZGKOVSMGRREEB-UHFFFAOYSA-N 0.000 description 1
- CHCLYTZFPLBGDH-UHFFFAOYSA-N methyl 3-[3-(4-ethoxyphenyl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound C1=CC(OCC)=CC=C1C1=NOC(CCC(=O)OC)=N1 CHCLYTZFPLBGDH-UHFFFAOYSA-N 0.000 description 1
- BTILTLZVIUZMSO-UHFFFAOYSA-N methyl 3-[3-(4-propoxyphenyl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound C1=CC(OCCC)=CC=C1C1=NOC(CCC(=O)OC)=N1 BTILTLZVIUZMSO-UHFFFAOYSA-N 0.000 description 1
- RFLDKZVWVQBDRB-UHFFFAOYSA-N methyl 3-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]propanoate Chemical compound COC(=O)CCC1=NC(CCl)=NO1 RFLDKZVWVQBDRB-UHFFFAOYSA-N 0.000 description 1
- YJQBIXZPKQFBEX-UHFFFAOYSA-N methyl 3-[3-[1-methyl-5-[(2-methylpropan-2-yl)oxycarbonylamino]pyrazol-4-yl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C2=C(N(C)N=C2)NC(=O)OC(C)(C)C)=N1 YJQBIXZPKQFBEX-UHFFFAOYSA-N 0.000 description 1
- NHGSWHPSLQRMQO-UHFFFAOYSA-N methyl 3-[3-[3-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2C=C(OCC(F)(F)F)C=CC=2)=N1 NHGSWHPSLQRMQO-UHFFFAOYSA-N 0.000 description 1
- ZOPXDOXBBSTHJF-UHFFFAOYSA-N methyl 3-[3-[3-(difluoromethoxymethyl)phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2C=C(COC(F)F)C=CC=2)=N1 ZOPXDOXBBSTHJF-UHFFFAOYSA-N 0.000 description 1
- VRQOMUXOFNBCBB-UHFFFAOYSA-N methyl 3-[3-[3-(ethoxymethyl)phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound CCOCC1=CC=CC(C=2N=C(CCC(=O)OC)ON=2)=C1 VRQOMUXOFNBCBB-UHFFFAOYSA-N 0.000 description 1
- IKJMHEAISPMRSG-UHFFFAOYSA-N methyl 3-[3-[3-(hydroxymethyl)phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2C=C(CO)C=CC=2)=N1 IKJMHEAISPMRSG-UHFFFAOYSA-N 0.000 description 1
- ZODCLVFDPSMLDQ-UHFFFAOYSA-N methyl 3-[3-[3-[tri(propan-2-yl)silyloxymethyl]phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2C=C(CO[Si](C(C)C)(C(C)C)C(C)C)C=CC=2)=N1 ZODCLVFDPSMLDQ-UHFFFAOYSA-N 0.000 description 1
- MXJSEOUHCGMESG-UHFFFAOYSA-N methyl 3-[3-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2C=CC(OCC(F)(F)F)=CC=2)=N1 MXJSEOUHCGMESG-UHFFFAOYSA-N 0.000 description 1
- FCYWFBWBMIGJQX-UHFFFAOYSA-N methyl 3-[3-[4-(difluoromethoxymethyl)phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2C=CC(COC(F)F)=CC=2)=N1 FCYWFBWBMIGJQX-UHFFFAOYSA-N 0.000 description 1
- ZKZDLQRTZAWXCU-UHFFFAOYSA-N methyl 3-[3-[4-(ethoxymethyl)phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound C1=CC(COCC)=CC=C1C1=NOC(CCC(=O)OC)=N1 ZKZDLQRTZAWXCU-UHFFFAOYSA-N 0.000 description 1
- BTRLZCPYLZCHKI-UHFFFAOYSA-N methyl 3-[3-[4-(hydroxymethyl)phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2C=CC(CO)=CC=2)=N1 BTRLZCPYLZCHKI-UHFFFAOYSA-N 0.000 description 1
- HQYAYDMURLDZFM-UHFFFAOYSA-N methyl 3-[3-[4-(methoxymethyl)phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound C1=CC(COC)=CC=C1C1=NOC(CCC(=O)OC)=N1 HQYAYDMURLDZFM-UHFFFAOYSA-N 0.000 description 1
- WYGWZYPBPVNAND-UHFFFAOYSA-N methyl 3-[3-[4-[tri(propan-2-yl)silyloxymethyl]phenyl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2C=CC(CO[Si](C(C)C)(C(C)C)C(C)C)=CC=2)=N1 WYGWZYPBPVNAND-UHFFFAOYSA-N 0.000 description 1
- TZXAYDVLCAZGAK-UHFFFAOYSA-N methyl 3-[3-[5-(3-methylbutanoylamino)thiophen-3-yl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound O1C(CCC(=O)OC)=NC(C=2C=C(NC(=O)CC(C)C)SC=2)=N1 TZXAYDVLCAZGAK-UHFFFAOYSA-N 0.000 description 1
- CFKPDTUMDZVWFO-UHFFFAOYSA-N methyl 3-[3-[5-(ethoxycarbonylamino)thiophen-3-yl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound S1C(NC(=O)OCC)=CC(C=2N=C(CCC(=O)OC)ON=2)=C1 CFKPDTUMDZVWFO-UHFFFAOYSA-N 0.000 description 1
- CRTFQKFETSWTQB-UHFFFAOYSA-N methyl 3-[3-[5-(ethylsulfonylamino)thiophen-3-yl]-1,2,4-oxadiazol-5-yl]propanoate Chemical compound S1C(NS(=O)(=O)CC)=CC(C=2N=C(CCC(=O)OC)ON=2)=C1 CRTFQKFETSWTQB-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供包含二环芳基片段的化合物,如2H-2,3-二氮杂萘-1-酮或其衍生物,还提供包含该化合物的组合物,其制备和使用方法。具体而言,本发明提供通式I的化合物,或其药学上可接受的盐,水合物,溶剂化物或前药,其中Q1,Q2和Y是在此的定义的那些。
Description
发明领域
本发明涉及2H-2,3-二氮杂萘-1-酮化合物,包含该化合物的组合物,及其制备方法和使用方法。
发明背景
基因功能调节在真核细胞中有数种机理。其中,有基因转录调节、mRNA调节和蛋白质翻译后的修饰。术语“蛋白质的翻译后修饰”包括多种过程,借以使蛋白质结构被修饰,导致细胞、亚细胞定位、稳定性、转运、相互作用特异性、酶活性和许多其他特性的变化。
经广泛研究的翻译后修饰过程包括乙酰化、糖基化和磷酸化。较少描述的过程,涉及ADP-核糖聚合物对蛋白质靶的共价加成。该聚合物称作聚(ADP-核糖),而引起这种活性的酶有各种名称,如称作聚(ADP-核糖)聚合酶(PARP)、聚(ADP-核糖)合成酶(PARS)或ADP-核糖基转移酶(ADPRT),在此称作“PARP”。PARP是一种位于各器官细胞核中的酶,包括肌肉、心脏和脑细胞中。PARP在修复DNA链断裂中发挥生理作用。一旦被受损的DNA碎片激活,PARP催化多达100个ADP-核糖单位附着到多种核蛋白上,包括组蛋白和PARP本身。而PARP功能的确切范围并未完全确定,据认为这种酶发挥了增强DNA修复的作用。一组结构相关的基因产物中至少3个成员已显示能催化聚-ADP-核糖基化。目前,这一基因家族中研究最多的成员是PARP1。PARP1基因产物在细胞核中被高水平表达,并依赖于DNA损伤的活化。不受任何理论的束缚,据信,PARP1通过氨基端DNA结合域联结到DNA的单或双链断裂处。该联结激活了羧基端的催化域,导致在靶分子上形成ADP-核糖聚合物。通过定位于中央的自修饰域,PARP1本身是聚ADP-核糖基化的靶。PARP1核糖基化引起PARP1分子从DNA解离。结合、核糖基化和解离的整个过程进行得很快。已经提出,PARP1暂时结合到DNA损伤位置导致DNA修复机理的募集,或可能为修复机理如募集而起足够长的抑制重组的作用。
PARP反应的ADP-核糖的来源是烟酰胺腺苷二核苷酸(NAD)。NAD在细胞中从细胞储存的ATP合成,因此,高水平的PARP活性的活化可迅速导致细胞能量储存枯竭。已经证实,PARP活性的诱导可导致细胞死亡,这与细胞NAD和ATP库枯竭有关。在许多氧化应激的场合或炎症期间会诱导PARP活性。例如,在缺血组织再灌注期间,产生活性氧化氮,它导致产生其他的活性氧,包括过氧化氢、过硝酸盐和羟基自由基。后面的这些物质可直接损伤DNA,产生的损伤诱导PARP活性的活化。通常,发生的PARP活性的活化,足以使细胞能量储存消耗,细胞死亡。据信,当内皮细胞和致炎细胞合成氧化氮时,在炎症期间有类似的机理,氧化氮导致周围细胞的中氧化性DNA损伤以及随后的PARP活性活化。据信,PARP活化导致的细胞死亡是局部缺血—再灌注损伤或炎症引起的组织损伤程度的主要关键因素。
两类证据认为,PARP活性在这些过程中是关键的因素。第一,已经成功利用PARP活性的化学抑制剂,在局部缺血—再灌注损伤或炎症的动物模型中减少组织损伤。第二,如小鼠中PARP1的两个等位基因被破坏(剔除PARP1的小鼠或PARP1突变型小鼠),对于局部缺血—再灌注损伤的多种形式和炎症的有害作用具有耐受力。
抑制PARP活性对治疗人类癌症还显示潜在的用途。PARP小分子抑制剂使得受处理的肿瘤细胞系对由电离辐射和某些损伤DNA的化疗药物敏感而被杀死。而PARP抑制剂本身一般不具有明显的抗肿瘤效果,当与化学疗法结合时,它们可诱导肿瘤在化疗药本身并无效的浓度时消退。而且,PARP1突变型小鼠和PARP1突变细胞系对辐照以及类似的化疗药物敏感。
目前已知的抑制PARP的化合物并未在临床应用于种种疾病。因此,需要临床上有用的PARP抑制剂。
发明概述
本发明提供二环芳基化合物,如2H-2,3-二氮杂萘-1-酮及其衍生物,包含该化合物的组合物,及其制备和使用方法。具体而言,本发明提供通式I的二环化合物:
其中,Q1和Q2各自独立地选自N或CRa,Ra是氢、卤素、硝基或烷基;
R是氢、烷基或氮保护基;
Y选自下列:
(A)-NR1R2,其中R1是氢或烷基;
R2选自:
(a)-C(=O)-Ar1,其中Ar1是芳基;
(b)杂烷基;
(c)环烷基;
(d)任选取代的芳烷基;
(e)任选取代的环烷基烷基;
(f)烷基;
(g)取代的环烯基烷基;
(h)取代的杂芳烷基;
(i)杂芳烯基;
(j)取代的芳烯基;
(k)烯基;
(l)炔基;
(m)-NR60-[C(=X5)]g-R61,其中R60是氢或烷基,g为0或1,R61是氢、任选取代的芳基或任选取代的芳烷基;
(B)-R3-C(=X1)-Y1,
其中R3是亚烷基;
X1是O或S;
Y1是-NR4R5,其中R4是氢、烷基、芳烷基或杂烷基,R5选自下列:
(a)任选取代的芳烷基;
(b)任选取代的杂烷基;
(c)-NH-[C(=X2)]a-(R6)b-R7,其中a和b各自独立地是0或1,X2是O或S,R6是亚烷基或杂亚烷基,R7是任选取代的芳基、任选取代的杂芳基、烷基、任选取代的芳基氨基、烷氧基或杂环基烷基氨基;
(d)烷基;
(e)任选取代的杂环基;
(f)杂芳基;
(g)任选取代的杂环烷基;
(h)任选取代的杂芳烷基;
(i)环烷基烷基;
(j)任选取代的杂环烷基烷基;
(k)任选取代的环烷基;
(l)杂烷基;
(m)任选取代的杂环烷基;
(n)取代的芳基取代的杂烷基;
(o)-NH-SO2-Ar2,其中Ar2是取代的芳基;
(p)-R8-NHR9-C(=O)-R10,其中R8是亚烷基,R9是氢或烷基,R10是取代的杂芳烷基;
(C)-(亚烷基)x-NR11-R12-NR13-[C(=X3)]c-[NR14]d-[R15]e-[C(=X4)]f-[R16],其中,X为0或1;R11选自氢、烷基和任选取代的杂芳烷基;或R11与其上连接的氮原子以及至少R12的一部分一起形成任选取代的杂环基;
R12选自下列基团:
(a)亚烷基,
(b)环亚烷基,
(c)杂亚烷基,
(d)亚芳烷基,
(e)亚芳基;
c为0、1或2;
d、e和f各自独立地是0或1;
X3和X4各自独立地选自O和S;
R13选自氢、烷基、式-(亚烷基)-[C(=O)NR40]y-Ar4,其中y是0或1,R40是氢或烷基,Ar4是任选取代的芳基或任选取代的杂芳基;或R11和R13与连接在其上的氮原子以及R12一起形成任选取代的杂环基;或R13与连接在其上的氮原子以及R12的至少一部分一起形成任选取代的杂环基,或R13和R16与连接在其上的原子一起形成任选取代的杂环;
R14是氢或烷基;
R15选自:
(a)任选取代的亚烷基;
(b)任选取代的杂亚烷基;
(c)任选取代的亚烯基;
R16选自:
(a)氢;
(b)任选取代的杂芳基;
(c)任选取代的芳基;
(d)任选取代的杂烷基;
(e)烷氧基;
(f)任选取代的环烷基;
(g)任选取代的烷基;
(h)任选取代的芳氧基;
(i)取代的芳烷氧基;
(j)杂环烷基
(k)芳基磺酰基烷基;
(l)-NR50R51,其中,R50是氢或烷基,R51是任选取代的芳基、任选取代的环烷基、任选取代的芳烷基、任选取代的杂芳基、任选取代的杂芳烷基或任选取代的杂烷基;
(m)-NHPO3R17R18,其中R17和R18是烷基;
(n)-NHSO2Ar2,其中Ar2是取代的芳基或芳烯基;
(o)烷基氨基甲酸酯;
(p)-SO2R19,其中,R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基或取代的杂芳基;
(q)烷基磺酰基烷基;
(r)杂环基;
(s)式-(亚烷基)-[C(=O)NR40]y-Ar5的片断,其中y为0或1,R40是氢或烷基,Ar5是任选取代的芳基或任选取代的杂芳基;
(D)-NR11-R12-N=CR20R21;
其中,R11和R12如上定义;
R20选自氢和烷基;
R21选自烷基和取代的杂芳基。
定义
除非特别指出,在说明书和权利要求书中使用术语具有如下含义:
“亚烯基”指有2-20个,较好2-10个,更好2-6个碳原子的并包含至少一个C-C双键的直链或支链的二价烃基。亚烯基可通过含C-C双键的碳原子和/或通过饱和碳原子连接。亚烯基可任选被一个或多个卤素取代基取代。
“烯基”指2-20个,较好2-10个,更好2-6个碳原子的并包含至少一个C-C双键的直链或支链的一价烃基。烯基可通过含C-C双键的碳原子和/或通过饱和碳原子连接。烯基可任选被一个或多个卤素取代基取代。烯基例子包括:乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、戊烯基、5-己烯基、十二碳烯基等。
“烷氧基”、“环烷氧基”、“杂环基氧基”、“杂环烷氧基”、“芳氧基”和″杂芳氧基″指式-ORa部分,其中Ra是烷基、环烷基、杂环基、杂环烷基、芳基和杂芳基,如在此分别定义的。
“烷基”指1-20个,较好1-10个,更好1-6个碳原子的直链或支链的饱和一价烃基。烷基可任选被一个或多个卤素取代基取代。烷基例子包括甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基、己基、十二烷基、氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、碘甲基、溴甲基等。
“烷基氨基甲酸酯”指式-NRa-C(=O)-ORb部分,其中Ra是氢或烷基,Rb是如在此的定义的烷基。
“亚烷基”指有1-20个,较好1-10个,更好1-6个碳原子的直链或支链的饱和二价烃基。亚烷基可任选被一个或多个卤素取代基取代。亚烷基例子包括亚甲基、亚乙基、亚丙基、亚丁基等。
“烷基磺酰基烷基”指式-Ra-SO2-Rb部分,其中,Ra和Rb是在此的定义的烷基。
“炔基”指2-20个,较好2-10个,更好2-6个碳原子的并包含至少一个C-C三键的直链或支链的一价烃基。炔基可通过含C-C三键的碳原子和/或通过饱和碳原子连接。炔基可任选被一个或多个卤素取代基取代。
“亚炔基”指如此定义的二价炔基,如含-C≡C-基团部分。
“氨基”指式-NRhRi部分,其中,Rh和Ri各自是氢、烷基、环烷基、芳基、芳烷基、杂烷基或-C(=O)Rj,其中Rj是烷基、芳烷基、芳基、环烷基、氢或杂烷基。
“芳烯基”指式-RaRb部分,其中Ra是亚烯基,Rb是如在此的定义的芳基。
“芳烷基”指式-RaRb部分,其中Ra是亚烷基,Rb是如在此的定义的芳基。
“芳炔基”指式-RaRb部分,其中Ra是亚炔基,Rb是如在此的定义的芳基。
“芳亚烷基”指式-Ra-Rb-部分,其中Ra是亚烷基,Rb是如在此的定义的亚芳基。
“芳基”指有6-20个,较好6-12个环原子的一价单环、二环或三环芳烃部分。芳基的芳族部分仅含碳原子。芳基例子包括苯基、萘基和芴基。
“亚芳基”指二价单环或二环芳烃部分。
“芳基磺酰基烷基”指式-Ra-SO2-Ar部分,Ra是亚烷基,Ar是如在此的定义的芳基。
“环烷基”指3-10个环原子的饱和或不饱和的非芳族一价单环、二环或三环烃基部分,如环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、十氢萘基、金刚烷基、降冰片基(即二环[2.2.1]庚-5-烯基)等。
“环烷基烷基”指式-RaRb部分,其中Ra是亚烷基,Rb是如在此的定义的环烷基。
“卤化物”或“卤代”在此交替使用,指氟、氯、溴或碘,较好是氟或氯。
“杂烷基”指在此的定义的烷基部分,其中有一个或多个氢原子已被非氢原子或片断取代。较好的,一个或两个碳原子被羰基氧取代,和/或一个或多个(较好是一个、两个或三个)氢原子独立地被选自下列的取代基取代:-ORa、-NRbRc、-C≡N和-S(O)nRd(其中,n是0-2的整数,较好为2),应理解,杂烷基部分通过碳原子连接,其中的Ra是氢、烷基、芳基或芳烷基;Rb和Rc各自独立地是氢、烷基、任选取代的芳基、任选取代的芳烷基、任选取代的杂芳基或任选取代的杂芳烷基;Rd是烷基、任选取代的芳基、任选取代的芳烷基、任选取代的杂芳基或任选取代的杂芳烷基。
“杂亚烷基”指如在此的定义的亚烷基部分,其中有一个或多个氢原子已被非氢原子或片断取代。较好的,一个或两个碳原子被羰基氧取代,和/或一个或多个(较好是一个、两个或三个)氢原子独立地被选自下列的取代基取代:-ORa、-NRbRc、-C≡N和-S(O)nRd(其中,n是0-2的整数,较好为2),应理解,杂亚烷基部分通过碳原子连接,其中的Ra是氢、烷基、芳基或芳烷基;Rb和Rc各自独立地是氢、烷基、任选取代的芳基、任选取代的芳烷基、任选取代的杂芳基或任选取代的杂芳烷基;Rd是烷基、杂烷基、任选取代的芳基、任选取代的芳烷基、任选取代的杂芳基或任选取代的杂芳烷基。
“杂烯基”指如在此的定义的烯基部分,其中有一个或多个氢原子(较好是一个、两个或三个)已被独立地选自下列的取代基取代:-ORa、-NRbRc、-C≡N和-S(O)nRd(其中,n是0-2的整数,较好为2),应理解,杂烷基部分通过碳原子连接,其中的Ra是氢、烷基、芳基或芳烷基;Rb和Rc各自独立地是氢、烷基、任选取代的芳基、任选取代的芳烷基、任选取代的杂芳基或任选取代的杂芳烷基;Rd是烷基、任选取代的芳基、任选取代的芳烷基、任选取代的杂芳基或任选取代的杂芳烷基。
“杂芳烯基”指式-RaRb部分,其中Ra是亚烯基,Rb是如在此的定义的杂芳基。
“杂芳烷基”指式-RaRb部分,其中Ra是亚烷基,Rb是如在此的定义的杂芳基。
“杂芳基”指一价单环、二环或三环的杂芳族片断,如在此的定义的芳基,其中,至少一个芳族碳环原子被O、N、NH或S基团取代。杂芳基通过芳族环系的杂原子或碳原子连接。较好的杂芳基包括:吡啶基、呋喃基、噻吩基、咪唑并[2,1-b]噻唑基、噻唑基、噁二唑基、吡啶基、嘧啶基、三嗪基、呋喃基(furanyl)、噻吩基、噻二唑基、吡咯基、吡唑基、二苯并呋喃基、吡唑并嘧啶基4-氧代-1H-[1,8]二氮杂萘基、3-氧代-二氢-吡唑基、咪唑基、异咪唑基、噁唑基、异噁唑基、三唑基、四唑基、苯并呋喃基、苯并噁二唑基,苯并噻吩基、吲哚基、苯并咪唑基、1H-吲唑基、噁唑烷基、异噁唑烷基、苯并三唑基、苯并异噁唑基,羟吲哚基、苯并噁唑啉基、喹啉基、异喹啉基、4-氧代-3,4-二氢-2,3-二氮杂萘基、四唑基等。更好的杂芳基是噁二唑基、呋喃基、4-氧代-3,4-二氢-2,3-二氮杂萘基、噻吩基、吡啶基、咪唑基、噻唑基、四唑基、吡唑基、吲哚基、苯并[1,2,5]噁二唑基、吡唑并[1,5-a]嘧啶基、异噁唑基、吡嗪基、吡咯基、[1,2,4]噁二唑基、噁唑基、苯并咪唑基、[1,3,4]噻二唑基、异咪唑基、异噁唑基、1,2,3-三唑基、4-氧代-1H-[1,8]二氮杂萘基、1,2-二氢-3-氧代-吡唑基、苯并呋喃基、喹啉基、嘧啶基、苯并噻吩基和二苯并呋喃基。
“杂环烷基”指3-8个环原子的饱和或不饱和非芳烃的单环、二环或三环部分,其中一个或多个环原子是选自下列的杂原子:NRa(其中,Ra是氢、烷基、胺保护基、或式-S(O)mRb部分,其中的m是0-2的整数,Rb是氢或烷基)、O或S(O)n(其中的n是0-2的整数),其余的环原子是C,应理解杂环烷基部分的连接是通过环系的碳原子。或者,此外,杂环烷基部分的一个、两个或三个环碳原子可被羰基氧取代。较好的杂环烷基是:哌啶基、2-氧代-四氢呋喃基、吡咯烷基、哌嗪基、吗啉代、二氮杂环庚烷基、7,7-二甲基-2-氧代-二环[2.2.1]庚基、四氢呋喃基、噻唑烷基、2,3-二氢-4-氧代-1H-吡啶基和噁唑烷基。更好的杂环烷基是:哌啶基、2-氧代-四氢呋喃基、吡咯烷基、7,7-二甲基-2-氧代-二环[2.2.1]庚基、四氢呋喃基、噻唑烷基、2,3-二氢-4-氧代-1H-吡啶基和噁唑烷基。
“杂环烷基烷基”指式-RaRb部分,其中Ra是亚烷基,Rb是如在此的定义的杂环烷基,应理解Rb与Ra通过碳原子,存在氮原子时较好是氮原子连接。
“杂环基”指3-8个环原子的饱和或不饱和非芳族的单环、二环或三环部分,其中一个或多个环原子是选自下列的杂原子:N,NRaO,或S(O)n其中,n是0-2的整数,Ra是氢、烷基、胺保护基、或式-S(O)mRb部分,其中的m是0-2的整数,Rb是氢或烷基,其余的环原子是C,应理解杂环基部分通过环系的杂原子连接,存在氮时较好为氮原子。此外,杂环基部分的一个或多个环碳原子还可被羰基氧取代。较好的杂环基是哌啶基、吡咯烷基,哌嗪基,吗啉代,二氮杂环庚烷基、噻唑烷基,2,3-二氢-4-氧代-1H-吡啶基和噁唑烷基。
“杂环基烷基”指式-RaRb部分,其中Ra是亚烷基,Rb是如在此的定义的杂环基,应理解Rb与Ra通过杂原子,存在氮原子时较好是氮原子连接。
“任选取代的芳烷基”指如在此的定义的芳烷基或取代的芳烷基。
“任选取代的芳基”指如在此的定义的芳基或取代的芳基。
“任选取代的环烷基烷基”指如在此的定义的环烷基烷基或取代的环烷基烷基。
“任选取代的杂烷基”指如在此的定义的杂烷基或取代的杂烷基。
“任选取代的杂芳烷基”指如在此的定义的杂芳烷基或取代的杂芳烷基。
“任选取代的杂芳基”指如在此的定义的杂芳基或取代的杂芳基。
“任选取代的杂环基”指如在此的定义的杂环基或取代的杂环基烷基。
“任选取代的杂环基烷基”指如在此的定义的杂环基烷基或取代的杂环基烷基。
“取代的烷基”“取代的亚烷基”和“取代的烯基”分别指如在此的定义的烷基、亚烷基和烯基,其中,一个或多个(较好是一个或两个)氢原子已被非氢或非卤化物部分取代。较好的,一个或多个,更好是一个或两个氢原子已被下列基团取代:任选取代的芳基、任选取代的杂芳基、任选取代的芳氧基、任选取代的杂芳氧基、任选取代的杂环基、任选取代的杂环烷基或任选取代的环烷基。
“取代的芳烯基”指式-RaRb部分,其中Ra是亚烯基,Rb是如在此的定义的取代芳基。
“取代的芳烷基”指式-RaRb部分,其中Ra是亚烷基,Rb是如在此的定义的芳基。
“取代的芳基”指如在此的定义的芳基部分,其中,芳基部分的一个或多个(较好是一个、两个或三个)氢原子已被非氢部分取代。较好的芳基部分的一个或多个氢原子已被下列基团取代:卤化物、羟基、-NRaRb(其这Ra和Rb独立地是氢、烷基、杂烷基、或-SO2Rc,其中Rc是烷基)、硝基、亚硝基、-C(=O)Ra(其中Ra是烷基、烷氧基或羟基)、任选取代的烷硫醇基(即-SRd,其中Rd是任选取代的烷基),-NReC(=O)Rf(其中Re是氢或烷基,Rf是氢、任选取代的芳基、任选取代的环烷基,或较好是任选取代的烷基或烷氧化物)、任选取代的杂烷基、任选取代的烷基、任选取代的烷氧化物、炔基、任选取代的芳炔基、任选取代的芳烯基、-Xm-(亚烷基)n-Arz(其中X是O或S(O)p,m和n独立地是0或1,p是0,1或2,Arz是任选取代的芳基或任选取代的杂芳基)、任选取代的环烷基、任选取代的环烷基烷基、任选取代的杂环基、-S(O)nRb(其中n是0,1或2,Rb是烷基、杂芳烷基或-NReRf,其中Re和Rf独立地是氢或烷基)、氰基、-OC(=O)NH-Ara(其中,Ara是任选取代的芳基)或杂烯基。此外,“取代的芳基”还包括稠合到一个或多个在此的定义的其他环部分的芳基,如任选取代的杂环烷基、任选取代的杂环基或任选取代的环烷基,应理解系通过芳族碳环原子连接。取代的芳基的例子包括但不限于:氯苯基、氟苯基、二氯苯基、二氟苯基、(2-二乙基氨基乙基)苯基、(2-羟乙基)苯基、氨基苯基、羟基苯基、苯并[1,3]二氧杂环戊烯基、2,3-二氢苯并呋喃基、二苯并呋喃基、其衍生物等。
“取代的环烷基”指如在此的定义的环烷基部分,其中的一个或多个氢原子已被非氢部分取代。较好的,环烷基部分的一个或多个(较好为一个、两个或三个)氢原子已独立地被下列基团取代:氨基、羟基、任选取代的烷氧基、卤化物、任选取代的烷基、任选取代的杂烷基、任选取代的杂环烷基、任选取代的杂环基、任选取代的芳基或任选取代的杂芳基。此外,取代的环烷基包括有一个或多个在此的定义的其他环部分的稠环体系的环烷基,例如任选取代的芳基、任选取代的杂芳基、任选取代的杂环烷基、任选取代的杂环基或任选取代的环烯基等,应理解取代的环烷基通过环烷基部分的碳原子连接。稠合到另一个环系的取代的环烷基的例子包括二环[4.2.0]辛-1,3,5-三烯基、二环[4.3.0]-壬-1,3,5-三烯基(即茚满基(indanyl))。
“取代的环烷基烷基”指式-RaRb部分,其中Ra是亚烷基,Rb是如在此的定义的环烷基。
“取代的杂烷基”指如在此的定义的杂烷基部分,其中的一个或多个氢原子已被非氢部分取代。较好的,杂烷基部分的一个或多个(较好为一个、两个或三个)氢原子已独立地被下列基团取代:卤素、任选取代的杂环烷基、任选取代的杂环基、任选取代的芳基,任选取代的杂芳基,任选取代的芳烯基、任选取代的杂环烷氧基、任选取代的芳氧基或任选取代的杂芳氧基。或者,或此外,取代的杂烷基部分的一个、两个或三个碳原子可被羰基氧取代。
“取代的杂芳烯基”指式-RaRb部分,其中Ra是亚烯基,Rb是如在此的定义的取代的杂芳基。
“取代的杂芳烷基”指式-RaRb部分,其中Ra是亚烷基,Rb是如在此的定义的取代的杂芳基。
“取代的杂芳基”指在此的定义的杂芳基部分,其中的一个或多个氢原子已被非氢部分取代。较好的,杂芳基部分的一个或多个(较好为一个、两个或三个)氢原子已被下列基团取代:卤化物、羟基、硝基、亚硝基、氰基、任选取代的烷氧基、任选取代的烷基、任选取代的杂烷基、任选取代的芳烯基、胺、任选取代的芳基、任选取代的芳氧基、任选取代的芳烷基、任选取代的杂芳基,任选取代的环烷基、任选取代的杂环烷基、任选取代的杂环基、-C(=O)Ra(其中Ra是烷基、烷氧基、氨基或羟基)、-S(O)nR(其中n是0、1或2,且R是烷基)、-X-(亚烷基)n-Ar(其中X是O或S,n是0或1,Ar是任选取代的芳基),或它们的组合。此外,取代的杂芳基包括稠合到一个或多个在此的定义的其他环部分的稠环体系的杂芳基,如任选取代的芳基、任选取代的环基、任选取代的杂环烷基、任选取代的杂环基或任选取代的环烯基等。
“取代的杂环烷基”指在此的定义的杂环烷基部分,其中的一个或多个氢原子已被非氢部分取代。较好的,杂环烷基部分的一个或多个(较好为一个、两个或三个)氢原子已被独立选自下列的基团取代:卤素、羟基、任选取代的烷基、氨基、磺酰基、任选取代的杂烷基、任选取代的芳基、任选取代的杂芳基、任选取代的环烷基、任选取代的杂环烷基、任选取代的杂环基、-C(=O)R(其中R是烷基、烷氧基)、-S(O)nR(其中n是0、1或2,R是烷基)、任选取代的芳氧基、任选取代的烷氧基和任选取代的杂芳氧基。
“取代的杂环基”指在此的定义的杂环基,其中的一个或多个氢原子已被非氢部分取代。较好的,杂环基部分的一个或多个(较好为一个、两个或三个)氢原子已被独立选自下列的基团取代;卤化物、羟基、烷基、氨基、磺酰基、任选取代的杂烷基、任选取代的芳基、任选取代的芳烯基、任选取代的杂芳基、任选取代的环烷基、任选取代的杂环烷基、任选取代的杂环基、-C(=O)R(其中R是烷基、烷氧基)、-S(O)nR(其中n是0、1或2,R是烷基)、任选取代的芳氧基、任选取代的烷氧基和任选取代的杂芳氧基。
“取代的杂环基烷基”指式-RaRb部分,其中Ra是亚烷基,Rb是如在此的定义的取代的杂环基。
“保护基”指除烷基外的部分,当其连接在分子的反应基上时能掩蔽、降低或阻止反应活性。保护基例子可参见T.W.Greene和P.G.M.Wuts,Protective Groups inOrganic Synthesis,3rd edition,John Wiley & Sons,New York,1999,和Harrison和Harrison et al.,Compendium of Synthetic Organic Methods,Vols.1-8(John Wiley和Sons,1971-1996),这些文献在此全文引用参考。羟基保护基的代表例包括:酰基、苄基和三苯甲基醚、四氢吡喃基醚、三烷基甲硅烷基醚和烯丙基醚。氨基保护基例子包括:甲酰基、乙酰基、三氟乙酰基、苄基、苄氧基羰基(CBZ)、叔丁氧基羰基(Boc)、三甲基甲硅烷基(TMS)、2-三甲基甲硅烷基-乙磺酰基(SES)、三苯甲基和取代的三苯甲基、烯丙氧基羰基、9-芴基甲氧基羰基(FMOC)、硝基藜芦基氧基羰基(NVOC)等。
“相应保护基”指对应于其连接的杂原子的合适保护基。
“离去基团”具有通常与合成有机化学相关的含义,即,能被亲核试剂取代的原子或基团,包括卤素(如氯、溴和碘)、烷烃磺酰氧基、芳烃磺酰氧基、烷基羰基氧(如乙酸基)、芳基羰基氧、甲磺酰氧基、甲苯磺酰氧基,三氟甲磺酰氧基、芳氧基(如2,4-二硝基苯氧基)、甲氧基、N,O-二甲基羟胺基等。
“药学上可接受的赋形剂”是指可用于制备药物组合物的赋形剂,它们一般安全、无毒性,既不是生物需要的也无不良作用,并且包含对兽医用途以及人类药用能接受的赋形剂。说明书和权利要求书中使用的“药学上可接受的赋形剂”包括一种和一种以上的这样的赋形剂。
一种化合物的“药学上可接受的盐”是指一种药学上可接受并具有母体化合物的所需药物活性的盐。这样的盐包括:(1)酸加成盐,与无机酸如氢氯酸、氢溴酸、硫酸、硝酸、磷酸等形成;或与有机酸如乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、4-甲基二环[2.2.2]-辛-2-烯-1-羧酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡糖酸、谷氨酸、羟基萘酸、水杨酸、硬脂酸、粘康酸等形成;或(2)存在于母体化合物中的酸性质子被金属离子如碱金属离子、碱土金属离子或铝离子取代,或与有机碱如乙醇胺、二乙醇胺、三乙醇胺、三羟甲基氨甲烷、N-甲基葡糖胺等配位形成的盐。
术语“前药”和“前体药物”在此交替使用,前体药物指给予哺乳动物时能在体内释放式I活性母体药物的化合物。通式I化合物的前体药物可如下方式修饰存在于通式I化合物中的一个或多个官能团来制备,即在体内能使修饰裂解,释放母体化合物。前体药物包括通式I的化合物,其中的羟基、氨基或氢硫基被结合到在体内能分解再分别产生游离的羟基、氨基或氢硫基的任一基团。前体药物的例子包括但不限于,通式I化合物中的羟基官能团的酯(如乙酸酯、甲酸酯和苯甲酸酯衍生物),氨基甲酸酯(如N,N-二甲基氨基羰基)等。
疾病的“治疗”包括:(1)防止疾病,即,使哺乳动物疾病的临床症状不出现,所述哺乳动物可能暴露于或存在患病的倾向而尚未经历或显示疾病的症状;(2)抑制疾病,即阻止或减少疾病或其临床症状的发展;或(3)缓解疾病,即使疾病或其临床症状减轻。
“治疗有效量”指,给予哺乳动物用于治疗疾病时的化合物的量足以实现该疾病的治疗。“治疗有效量”随化合物、疾病以及疾病的程度、待治疗的哺乳动物的年龄、体重等变化。
“神经组织”指构成神经系统的各组成,包括但不限于,神经元、神经支持细胞、神经胶质、Schwann细胞、包含在这些结构中并供给这些结构的脉管系统、中枢神经系统、脑、脑干、脊髓、中枢神经系统与外周神经系统的接合、外周神经系统和有关结构。
“缺血”指由于动脉血液流入受阻造成的局部组织贫血。当流入整个脑的血液停止一段时间时发生全脑缺血。全脑缺血产生于心动停止。当脑一部分丧失其正常的血液供应时发生局部缺血。局部缺血产生于大脑血管血栓栓塞、外伤性头颅损伤、水肿或脑肿瘤。全脑缺血和局部缺血都会引起广泛的神经元损伤。尽管神经组织损伤发生在缺血开始后的数小时甚至数天,但在血液停止流入脑后最初几分钟会造成一些永久性神经组织损伤。缺血还发生在心肌梗塞以及其他心血管疾病的心脏,其中,由于动脉硬化症、血栓症或痉挛而使冠状动脉阻塞,或发生在视网膜缺血的眼睛。
“缺血和再灌注损伤造成的神经组织损伤以及神经变性疾病”包括神经中毒,如在血管性卒中以及全脑和局部缺血中所见,以及视网膜缺血。
“神经变性疾病”包括:阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩性侧索硬化症(即ALS)。
“神经损伤”指对神经组织的任何损伤以及由此导致的任何残疾或死亡。神经损伤的原因可以是,代谢性、中毒性、神经毒性、医源性的、受热或化学品的,包括但不限于,缺血、组织缺氧、脑血管意外、外伤、外科、压力、质量作用、出血、辐射、血管痉挛、神经变性疾病、感染、帕金森病、肌萎缩性侧索硬化(ALS)、髓鞘形成/脱髓鞘过程、癫痫症、认知功能紊乱、谷氨酸异常及其次级效应。
“神经保护”指减少、停止或改善神经损伤,和保护、复苏或回生已受损伤的神经组织的作用。
“防止神经变性”包括对诊断有神经变性疾病的患者或者有出现神经变性疾病的危险的人能防止神经变性。该术语还涵盖对已经患有神经变性疾病或有神经变性疾病症状的患者防止进一步的神经变性。
“放射增敏剂”指一种化合物,特别是本发明的化合物,给予患者治疗有效量时,能提高细胞对电磁辐射的敏感性,和/或促进能用电磁辐射治疗的疾病的治疗。能用电磁辐射治疗的疾病包括:肿瘤性疾病、良性和恶性肿瘤、以及癌细胞。在此未列出的能用电磁辐射治疗的其他疾病也在本发明设想之中。
术语“电磁辐射”和“放射”在此交替使用,包括但不限于:波长在10-20至100米的放射。本发明较好实施方案采用如下的电磁辐射:γ-放射(10-11至10-4nm)、x-射线辐射(10-2至100nm)、紫外线(10nm至400nm)、可见光(400nm至700nm)、红外线(700nm至1.0mm)和微波辐射(1mm至30cm)。
“化疗增敏剂”指一种化合物,特别是本发明化合物,给予患者治疗有效量时,能提高细胞对化疗化合物的敏感性和/或促进能用化疗治疗的疾病的治疗。能用化学疗法治疗的疾病包括:瘤形成的疾病、良性和恶性肿瘤、以及癌细胞。在此未列出的能用化学疗法治疗的其他疾病也在本发明设想中。
如在此使用的,涉及变量时,术语“如在此的定义的”、“上面定义的那些”和“在此的定义的那些”,包括变量的广义定义,以及给出的任何较好、更好和最好的定义。
当涉及化学合成时术语“接触”和“反应”在此交替使用,并指在适当条件下加入或混合两种或多种反应试剂,产生指明和/或要求的产物。应理解,产生指明和/或要求的产物的反应未必直接由最初加入的两种试剂的组合产生,即在该混合物中可能产生的一种或多种中间体,最终导致形成指明和/或要求的产物。
发明详细描述
本发明提供二环芳基化合物,包含该化合物的组合物,以及其制备和使用方法。具体而言,本发明提供2H-2,3-二氮杂萘-1-酮及其衍生物,提供如下通式的二环芳基化合物,及其药学上可接受的盐、水合物、溶剂化物或前体药物:
其中,Q1和Q2各自独立地选自N或CRa,Ra是氢、卤素、硝基或烷基;
R是氢、烷基或氮保护基;
Y选自下列:
(A)-NR1R2,其中R1是氢或烷基;
R2选自:
(a)-C(=O)-Ar1,其中Ar1是芳基;
(b)杂烷基;
(c)环烷基;
(d)任选取代的芳烷基;
(e)任选取代的环烷基烷基;
(f)烷基;
(g)取代的环烯基烷基;
(h)取代的杂芳烷基;
(i)杂芳烯基;
(j)取代的芳烯基;
(k)烯基;
(l)炔基;
(m)-NR60-[C(=X5)]g-R61,其中R60是氢或烷基,g为0或1,R61是氢、任选取代的芳基或任选取代的芳烷基;
(B)-R3-C(=X1)-Y1,
其中R3是亚烷基;
X1是O或S;
Y1是-NR4R5,其中R4是氢、烷基、芳烷基或杂烷基,R5选自下列:
(a)任选取代的芳烷基;
(b)任选取代的杂烷基;
(c)-NH-[C(=X2)]a-(R6)b-R7,其中a和b各自独立地是0或1,X2是O或S,R6是亚烷基或杂亚烷基,R7是任选取代的芳基、任选取代的杂芳基、烷基、任选取代的芳基氨基、烷氧基或杂环基烷基氨基;
(d)烷基;
(e)任选取代的杂环基;
(f)杂芳基;
(g)任选取代的杂环基烷基;
(h)任选取代的杂芳烷基;
(i)环烷基烷基;
(j)任选取代的杂环烷基烷基;
(k)任选取代的环烷基;
(l)杂烷基;
(m)任选取代的杂环烷基;
(n)取代的芳基取代的杂烷基;
(o)-NH-SO2-Ar2,其中Ar2是取代的芳基;
(p)-R8-NHR9-C(=O)-R10,其中R8是亚烷基,R9是氢或烷基,R10是取代的杂芳烷基;
(C)-(亚烷基)x-NR11-R12-NR13-[C(=X3)]c-[NR14]d-[R15]e-[C(=X4)]f-[R16],其中,x为0或1;
R11选自氢、烷基和任选取代的杂芳烷基;或R11与其上连接的氮原子以及至少R12的一部分一起形成任选取代的杂环基;
R12选自下列基团:
(a)亚烷基,
(b)环亚烷基,
(c)杂亚烷基,
(d)亚芳烷基,
(e)亚芳基;
c为0、1或2;
d、e和f各自独立地是0或1;
X3和X4独立地选自O和S;
R13选自氢、烷基、式-(亚烷基)-[C(=O)NR40]y-Ar4,其中y是0或1,R40是氢或烷基,Ar4是任选取代的芳基或任选取代的杂芳基;或R11和R13与连接在其上的氮原子以及R12一起形成任选取代的杂环基;或R13与连接在其上的氮原子以及R12的至少一部分一起形成任选取代的杂环基,或R13和R16与连接在其上的原子一起形成任选取代的杂环;
R14是氢或烷基;
R15选自:
(a)任选取代的亚烷基;
(b)任选取代的杂亚烷基;
(c)任选取代的亚烯基;
R16选自:
(a)氢;
(b)任选取代的杂芳基;
(c)任选取代的芳基;
(d)任选取代的杂烷基;
(e)烷氧基;
(f)任选取代的环烷基;
(g)任选取代的烷基;
(h)任选取代的芳氧基;
(i)取代的芳烷氧基;
(j)杂环烷基
(k)芳基磺酰基烷基;
(l)-NR50R51,其中,R50是氢或烷基,R51是任选取代的芳基、任选取代的环烷基、任选取代的芳烷基、任选取代的杂芳基、任选取代的杂芳烷基或任选取代的杂烷基;
(m)-NHPO3R17R18,其中R17和R18是烷基;
(n)-NHSO2Ar2,其中Ar2是取代的芳基或芳烯基;
(o)烷基氨基甲酸酯;
(p)-SO2R19,其中,R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基或取代的杂芳基;
(q)烷基磺酰基烷基;
(r)杂环基;
(s)式-(亚烷基)-[C(=O)NR40]y-Ar5的部分,其中y为0或1,R40是氢或烷基,Ar5是任选取代的芳基或任选取代的杂芳基;
(D)-NR11-R12-N=CR20R21
其中,R11和R12如上定义;
R20选自氢和烷基;
R21选自烷基和取代的杂芳基。
本发明化合物可以非溶剂化形式以及溶剂化形式存在,包括水合物形式。一般,溶剂化形式包括水合物形式等价于非溶剂化形式,并都包含在本发明范围之内。而且,本发明还包括那些化合物的药学上可接受的盐与该化合物的前体药物形式,以及所有立体异构体而无论是纯的手性形式或外消旋混合物或混合物的其他形式。
通式I混合物还能形成药学上可接受的酸加成盐。所有这些形式都在本发明范围之内。
通式I化合物的药学上可接受的酸加成盐包括源自无机酸如氢氯酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚磷酸等的盐,以及源自有机酸如脂族单元酸和二元羧酸、苯基取代的链烷酸、羟基链烷酸、链烷二酸、芳族酸、脂族和芳族磺酸等的盐。这样的盐包括:硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、邻苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、苯基乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐等。还可考虑氨基酸如精氨酸的盐等,以及葡糖酸盐、半乳糖醛酸盐(参见,例如,Berge等,“PharmaceuticalSalts,”J.of Pharmaceutical Science,1977,66,1-19)。
碱性化合物的酸加成盐的制备为,常规方法中使游离碱形式与足够量的所需要的酸接触产生盐。游离碱形式可通过常规方式,使盐形式与碱接触并分离该游离碱来再生。游离碱形式的一些物理性能不同于其相应的盐形式,如在极性溶剂中的溶解度,但对本发明目的,在其他方面盐等价于其相应的游离碱。
药学上可接受的碱加成盐可用金属离子或胺形成,如碱金属和碱土金属离子或有机胺。用作阳离子的金属离子例子包括钠、钾、镁、钙等。合适的胺的例子是N,N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因(参见,例如,Berge等“Pharmaceutical Salts,”J.of Pharmaceutical Science,1977,66,1-19)。
酸性化合物的碱加成盐制备可通过常规方式,使游离酸形式与足够量的所需要的碱接触产生盐。游离酸形式可通过常规方式,使盐形式与酸接触并分离该游离酸来再生。游离酸形式的一些物理性能可能稍不同于其相应的盐形式,如在极性溶剂中的溶解度,但对本发明目的,盐在其他方面等价于其相应的游离酸。
对式I化合物,一个具体实施方案中,x为0。
另一个实施方案中,R12选自:亚烷基、环亚烷基、杂亚烷基、芳亚烷基和亚芳基。较好的,R12选自:亚丙基、2,2-二甲基亚丙基、亚乙基、1,3-环亚己基、2-羟基亚丙基、1,3-亚苯基、亚丁基和亚苄-3-基。
又一实施方案中,R13与其上连接的氮原子以及R12的至少一部分一起形成任选取代的杂环基。较好的,R13与其上连接的氮原子以及R12的至少一部分一起形成哌啶基。
还有一个实施方案中,R11与其上连接的氮原子以及R12的至少一部分一起形成任选取代的杂环基。较好的,R11与其上连接的氮原子以及R12的至少一部分一起形成哌啶基。
另一个实施方案中,R11和R13与它们连接的氮原子以及R12一起形成任选取代的杂环基。较好的,R11和R13与它们连接的氮原子以及R12一起形成哌嗪基或二氮杂环庚烷基。
又一个实施方案中,R11是氢或烷基。较好的,R11是氢或甲基。
还有一个实施方案中,R11是任选取代的杂芳烷基。较好的,R11是(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基)甲基。
另一个实施方案中,R13是氢或烷基。较好的,R13是氢或甲基。
又一个实施方案中,R14是氢。
还有一个实施方案中,c和e是1,d和f是0,即,Y是式-(亚烷基)x-NR11-R12-NR13-C(=X3)-R15-R16的部分,其中,x,R11,R12,R13,X3、R15和R16如在此的定义。
另一个实施方案中,R15是亚乙基或亚丙基。
又一个实施方案中,R16选自氢、任选取代的杂芳基、任选取代的芳基、烷氧基、任选取代的环烷基、任选取代的芳氧基、取代的芳烷氧基、烯基、任选取代的芳烯基、任选取代的杂环烷基、芳基磺酰基烷基,式-NR50R51(其中R50是氢或烷基,R51是任选取代的芳基、任选取代的环烷基、任选取代的杂芳基、杂芳烷基或任选取代的芳烷基)的部分、式-NHPO3R17R18(R17和R18是烷基),式-NHSO2Ar2(其中Ar2是取代的芳基或芳烯基)、烷基氨基甲酸酯。在一特定的实施方案中,R16宜为取代的杂芳基。
一个具体实施方案中,式I化合物是如下式化合物:
其中,Q1、Q2、R、x、X3、R11、R12、R13和R15如上定义;R41是任选取代的芳基、任选取代的芳烷基、任选取代的杂芳基、任选取代的杂环烷基或任选取代的杂环基烷基。较好的,x为0。较好的,R41选自:任选取代的吡咯基;任选取代的噻吩基;任选取代的呋喃基;任选取代的苯基;任选取代的咪唑基;任选取代的噻唑基;任选取代的吡唑基;任选取代的吲哚基;任选取代的苯并[1,2,5]噁二唑基;任选取代的吡啶基;任选取代的哌啶基;任选取代的吡唑并[1,5-a]嘧啶基;任选取代的吡咯烷基;任选取代的(哌啶-1-基)甲基;任选取代的异噁唑基;任选取代的(吗啉-4-基)甲基;任选取代的苄基和任选取代的吡嗪基。
另一个实施方案中,c,d,e和f为0,即,Y是式-(亚烷基)x-NR11-R12-NR13-R16部分。该实施方案中,x宜为0,即,Y是式-NR11-R12-NR13-R16的部分,其中,R16较好选自氢、任选取代的杂芳烷基、-SO2R19(其中R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基或取代的杂芳基)、任选取代的环烷基烷基、烷基、任选取代的杂烷基、烯基、任选取代的芳烷基和任选取代的杂环烷基烷基。更好的,R16选自-SO2R19(其中R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基或取代的杂芳基)、任选取代的环烷基烷基、任选取代的杂烷基、烯基、取代的杂环烷基烷基和任选取代的杂芳烷基。
式I化合物的又一实施方案中,x为0,c和d为1,即,Y=-NR11-R12-NR13-C(=X3)-NR14-[R15]e-[C(=X4)]f-R16。该实施方案中,R16较好选自任选取代的芳基、环烷基烷基、环烷基、杂芳基、杂环烷基烷基、任选取代的芳烷基、杂芳烷基、杂烷基、烷基、烷基磺酰基烷基、杂环烷基、芳烯基、烷氧基和烯基。
式I化合物的还有一个实施方案中,x为0,c和d为1,e和f为0,即Y=-NR11-R12-NR13-C(=X3)-NR14-R16。在此实施方案中,R16宜选自任选取代的芳基、环烷基烷基、环烷基、杂芳基、杂环烷基烷基、任选取代的芳烷基、杂芳基烷基、杂烷基、烷基、烷基磺酰基烷基和杂环烷基。
式I的另一实施方案中,x和e为0,c,d和f为1,即,Y=-NR11-R12-NR13-C(=X3)-NR14-C(=X4)-R16。此实施方案中,R16较好选自取代的芳基、芳烯基和烷氧基。
又一个实施方案中,X3为S。
式I化合物的另一实施方案中,x为0,c,d,e和f为1,即,Y=-NR11-R12-NR13-C(=X3)-NR14-R15-C(=X4)-R16。在此实施方案中,R16宜选自烷氧基和烯基。
式I化合物的又一个实施方案中,x,d和f为0,c和e为1,即,Y=-NR11-R12-NR13-C(=X3)-R15-R16。在此实施方案中,R16是任选取代的杂芳基。
还有一个实施方案中,c,e和f为1,d和x为0,即,Y=-NR11-R12-NR13-C(=X3)-R15-C(=X4)-R16。在此实施方案中,R16宜选自-NR50R51(其中R50是氢或烷基,R51是任选取代的芳基、任选取代的芳烷基、任选取代的杂芳基或任选取代的杂烷基)、芳基、杂芳基、烷氧基和烷基。
另一个实施方案中,X3是O。
又一个实施方案中,Y是-NR1R2。较好的,R1是氢或甲基。较好的,R2选自下列基团:(a)-C(=O)-Ar1,其中Ar1是芳基,(b)杂烷基,(c)环烷基,(d)任选取代的芳烷基,(e)任选取代的环烷基烷基,(F)取代的环烯基烷基,(g)取代的杂芳烷基,(h)杂芳烯基,(i)取代的芳烯基,(J)烯基,(k)炔基和(1)-NR60-[C(=X5)]g-R61,其中,R60是氢或烷基,g为0或1,R61是氢、任选取代的芳基或任选取代的芳烷基。
还有一个实施方案中,Y是-R3-C(=X1)-Y1。较好的,Y1选自下列基团:(a)任选取代的芳烷基;(b)任选取代的杂烷基;(c)-NH-[C(=X2)]a-(R6)b-R7,其中a和b独立地是0或1,X2是O或S,R6是亚烷基或杂亚烷基,R7是任选取代的芳基、任选取代的杂芳基、烷基、任选取代的芳基氨基、烷氧基或杂环基烷基氨基;(d)烷基;(e)任选取代的杂环基;(f)任选取代的杂环基烷基;(g)任选取代的杂芳烷基;(h)环烷基烷基;(i)任选取代的杂环烷基烷基;(j)任选取代的环烷基;(k)杂烷基;(l)任选取代的杂环烷基;(m)取代的芳基取代的杂烷基;(n)-NH-SO2-Ar2,其中,Ar2是取代的芳基和(o)-R8-NHR9-C(=O)-R10,其中,R8是亚烷基,R9是氢或烷基,R10是取代的杂芳烷基。
由上述优选基团的组合也可构成较好的实施方案。例如,在一个优选的实施方案中,x,d和f为0,c和e为1,R11,R13和R14是氢,R12是亚丙基、2-羟基亚丙基或2,2-二甲基亚丙基,X3是O,R15是亚乙基,R16是取代的杂芳基。这样,各种优选的化合物包含在本发明之内。
本发明另一方面是提供一种组合物,包含药学上可接受的赋形剂和式I的化合物。该组合物中优选的式I化合物也是上述的优选化合物,还有下面描述的式I的其他优选化合物。而且,上述式I的优选化合物包括下面描述的组合物中优选的那些化合物。
因此,在一个实施方案中,组合物中的式I化合物是其中x为0的那些。
另一个较好的组合物中,式I化合物的R16是取代的杂芳基。更好的,R16是取代的[1,2,4]-噁二唑基。还更好的,R16是3-(任选取代的苯基)取代的[1,2,4]-噁二唑-5-基或3-(任选取代的杂芳基)取代的[1,2,4]-噁二唑-5-基。
又一实施方案中,式I化合物具有10μM或更小的体外抑制聚(ADP-核糖)聚合酶的IC50。
还有一个实施方案中,式I化合物具有10μM或更小的体内抑制聚(ADP-核糖)聚合酶的IC50。
本发明又一方面提供了抑制PARP活性的方法,该方法包括给予有效量的式I化合物的步骤。
本发明还有一方面提供了使肿瘤细胞对放射敏感的方法,该方法包括给予肿瘤细胞有效量的式I化合物的步骤。
本发明另一方面提供了使肿瘤细胞对化疗敏感的方法,该方法包括给予肿瘤细胞有效量的式I化合物的步骤。
本发明又一方面提供了治疗动物癌症的方法,该方法包括对需要这种治疗的动物给予治疗有效量的式I化合物的步骤。一个实施方案中,这种方法还包括对所述动物给予化疗剂并合用式I化合物。另一个实施方案中,该方法还包括对所述动物给予辐射并合用式I化合物。
本发明的代表性化合物列于下面表1和表2。
表1.式I的代表性化合物。
表2.式I的代表性化合物及其命名
表1和表2的化合物具有约1mM-1nM范围的PARP1 IC50。此外,表1和表2的化合物具有约1mM-1nM范围的PARP2 IC50。较好的,式I化合物的PARP1 IC50活性约小于或等于100μM,更好小于或等于约50μM,更好约小于或等于10μM,更好约小于或小于1μM,更好约小于或等于500nM,最好约小于或小于200nM。或者或此外,式I化合物的PARP2 IC50活性较好约小于或等于100μM,更好约小于或等于10μM,更好约小于或等于1μM,更好约小于或等于500nM,最好约小于或等于150nM。
本发明化合物在细胞测定中具有能增大某些DNA损伤剂的活性的作用。某些DNA损伤剂包括但不限于,烷化剂、电离辐射以及DNA代谢抑制剂,它们临床上作为癌症治疗手段有用。表1和表2中的许多化合物在以细胞为基础的测定中具有作为DNA损伤增敏剂的活性。这种活性可以测定在PARP抑制剂不存在时杀死90%细胞所需的化疗化合物浓度的1/2时,杀死90%细胞所需的PARP抑制剂的浓度。这可称为两倍增敏的有效浓度或ECTFS。较好的,式I化合物对培养的肿瘤细胞系的ECTFS活性约小于或等于50μM,更好的约小于或等于10μM。
在此本发明的形式构成了现有的较好实施方案,但许多其他形式也是可能的。在此并不打算给出本发明所有可能的等价形式或细节。应理解,在此使用的术语仅用于描述,不构成限制,在不偏离本发明精神或范围时可以进行各种变动。
合成式I化合物
可采用各种方法制备本发明的化合物,包括固相、溶液相和组合合成方法。应理解,虽然下面制备式I化合物的过程常标出确切的结构,但本发明方法可广泛用于式I的类似化合物,只要适当考虑采用有机合成领域的标准方法来保护活性官能团和使活性官能团脱保护。例如,为防止不希望的副反应,在该分子的其他位置的化学反应期间羟基有时需转变为醚或酯。然后除去羟基保护基,提供游离羟基。同样,氨基和羧基可衍生化来使它们不发生不希望的副反应。典型的保护基,连接和分解保护基方法完整描述于T.W.Greene和P.G.M.Wuts,Protective Groups in OrganicSynthesis,3rd edition,John Wiley & Sons,New York,1999和Harrison和Harrison等,Compendium of Synthetic Organic Methods,Vols.1-8(John Wiley和Sons,1971-1996)。
本发明一个具体方面提供了制备式I化合物的方法。具体而言,该方法包括使下式胺化合物与式W-[C(=O)]c-[NR14]d-[R15]e-[C(=O)]f-R16的羧酸衍生物在足以制备式I化合物的条件下接触,其中,Q1,Q2,R,R11,R12,R13,R14,R15,R16,c,d,e和f按照在此的定义;W是羧酸活化基或-OR30,其中R30是氢、烷基、环烷基、芳烷基或芳基。
胺化合物可采用许多方法制备,一个具体实施方案中,胺化合物制备方法为:使下式的氰基酸酯芳基化合物
或下式的酐
与式HR11N-R12-NR13H的胺化合物在足以产生中间产物的条件下接触;并使该中间产物与肼在足以产生胺化合物的条件下接触,其中,Q1,Q2,R11,R12和R13按照在此的定义;Rq是烷基、芳基、环烷基或芳烷基。
本发明又一方面提供了制备下式IA的二环芳基化合物的方法,
该方法包括:
(a)使下式的氰基酸酯芳基化合物
或下式的酐
与式H2N-R12-Z1的胺化合物在足以产生中间产物的条件下接触;
(b)使所述中间产物与肼在足以产生二环芳基化合物的条件下接触,
其中
Q1和Q2独立地是N或CRa,其中的Ra是氢、卤素或烷基;
R是烷基;
R12选自下列基团:
(a)亚烷基,
(b)环亚烷基,
(c)杂亚烷基,
(d)芳亚烷基,
Z1选自下列基团:
(a)任选取代的包含至少一个氮原子的杂环烷基;
(b)任选取代的包含至少一个氮原子的杂环基;
(c)-NR28R29,其中,
R28选自氢和烷基;
R29选自氢、烷基和胺保护基;
(d)烷基;
(e)杂烷基;
(F)任选取代的芳基;
(g)环烷基。
较好的,Z1选自下列基团:任选取代的包含至少一个氮原子的杂环烷基;任选取代的包含至少一个氮原子的杂环基;和-NR28R29,其中,R28和R29为上面定义的那些。这种方法对制备包含二胺取代基的式I化合物特别有用。第二个胺部分在反应之前可以受到保护,或者它可为未保护的胺部分。当第二个胺部分是受保护的胺时产生的中间体为下式或它们的混合物:
当使用苯二甲酸酐时,中间体为式IIA(其中,Q1和Q2是CH)。然而,当第二个胺部分是未保护的胺时,产生的中间体通常为下式:
其中,-Z1a-NH2代表-Z1部分。例如,当胺化合物H2N-R12-Z1是乙二胺(H2N-(CH2)2-NH2)时,产生的中间体是下式:
当胺化合物是BOC-保护的(即,氨基甲酸叔丁酯)乙二胺(H2N-(CH2)2-NHBOC)时,产生的中间体为下式:
或它们的混合物,取决于是使用氰基苯甲酸酯还是苯二甲酸酐。
二胺与氰基苯甲酸酯或邻苯二甲酸酐(下面,称作“芳基部分试剂”)之间的反应通常在醇类溶剂或极性非质子溶剂如二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)或二甲基乙酰胺(DMA)中进行。反应温度取决于许多因素,例如,使用的具体溶剂、各试剂的浓度和其他反应因素。通常,当使用极性非质子溶剂如DMF时,反应通常约在60-100℃下进行,一般,反应温度约为80℃。当使用醇类溶剂时,反应温度一般在室温至约80℃的范围,室温是常规的反应温度。
反应时间取决于各种因素,包括但不限于;各反应试剂的浓度,采用的反应温度和溶剂。当反应于室温在作为溶剂的甲醇或乙醇中进行时,反应时间一般在约1.5-20小时范围。虽并不是必需的,可在反应混合物中加入碱以有利于二胺与芳基部分试剂间的偶合反应。当使用醇类溶剂时,加入碱特别有用。相应的醇盐一般用作碱。例如,反应溶剂是甲醇时,使用的碱是甲醇盐,反应溶剂是乙醇时,使用的碱是乙醇盐。
中间体在与肼反应前可以纯化;然而,通常是进行含水操作,浓缩后,不必进一步纯化就可使用。
中间体与肼的反应通常在醇类溶剂如甲醇或乙醇中进行。中间体与肼水合物通常在醇溶剂中混合。然后加热该混合物,一般在约60℃至90℃温度范围加热约3-20小时,产生式IA的2H-2,3-二氮杂萘-1-酮化合物。
式IA的二环芳基化合物可衍生化(即转化)产生下式IB的二环芳基酰胺:
方法为,使式IA的二环芳基化合物与式W-[C(=O)]c-R15-[C(=O)]f-R16的羧酸衍生物在足以产生式IB的二环芳基酰胺的条件下接触,其中,
W是羧酸活性基或-OR30,其中R30是氢、烷基、芳烷基或芳基;
Z2是-NR13-[C(=O)]c-R15-[C(=O)]f-R16,
其中c为1或2;
d,e和f各自独立地是0或1;
X3按照在此的定义;
R13按照在此的定义,较好选自氢和烷基;
R15按照在此的定义,较好是任选取代的亚烷基或任选取代的杂亚烷基;
R16按照在此的定义。
按照在此的定义,“羧酸活性基”指使羧酸对取代反应具有活性的部分。羧酸活性基的例子包括:卤化物如氯化物和溴化物;式R′-C(=O)-O-的酐,其中R′是氢、任选取代的烷基、任选取代的芳基或任选取代的芳烷基。
较好的,R16选自下列基团:任选取代的杂烷基;烷氧基;任选取代的芳氧基;取代的芳烷氧基;烯基;任选取代的芳烯基;杂环烷基;芳基磺酰基烷基;任选取代的芳氨基;任选取代的环烷基氨基;任选取代的芳烷基氨基;-NHPO3R17R18,其中的R17和R18是烷基;-NHSO2Ar2,其中的Ar2是取代的芳基或芳烯基;取代的杂芳基氨基;杂芳烷基氨基;取代的杂烷基氨基;烷基氨基甲酸酯;-SO2R19,其中的R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基或取代的杂芳基;任选取代的环烷基烷基;环烯基烷基;任选取代的杂环烷基烷基;环烯基和烷基磺酰基烷基。
应理解,当-Z1部分包含被保护的氨基时,该方法还需要在衍生化之前脱氨基保护。例如,当-Z1部分包含BOC-保护的氨基时,BOC基通常通过在衍生化之前与酸三氟乙酸接触,释放游离氨基。
通常使用羧酸来偶合式IA的二环芳基(如2H-2,3-二氮杂萘-1-酮)化合物,即,羧酸衍生物的W是-OH。羧酸这样偶合到胺基产生酰胺键为本领域所了解。该反应一般在羧酸活化剂存在下进行,如在三烷基胺如三乙胺或二异丙基乙胺存在下的HOBt/EDC或HATU/HOBt混合物。可以采用较宽的反应温度范围,而偶合反应一般在室温下进行约2-16小时。
式IA的二环芳基化合物还可使式IA的二环芳基化合物与式X3=C=N-R15-[C(=O)]-R16的异氰酸酯化合物在足以产生式IC的二环芳基脲衍生物的条件下接触,转化为下式的二环芳基(如2H-2,3-二氮杂萘-1-酮)脲衍生物:
其中,
X是O或S;
Z3是-NR13-C(=X3)-NH-R15-[C(=O)]f-R16,
其中f为0或1;
X3按照在此的定义;
R15按照在此的定义,较好是任选取代的亚烷基或任选取代的杂亚烷基;
R16按照在此的定义。
式IA的二环芳基化合物和式X3=C=N-R15-[C(=O)]f-R16的异氰酸酯化合物之间的偶合反应一般在室温下进行,反应时间通常约2-16小时。式X3=C=N-R15-[C(=O)]f-R16的许多异氰酸酯化合物可从认可的来源购得。或者,这些化合物可通过Ozaki等在Chemical Reviews,1972,72,457-460所述的方法制备。
式IA的二环芳基化合物还可以通过式IA的二环芳基化合物与式R31-C(=O)-R15-[C(=X3)]f-R16的羰基化合物还原剂存在下在足以产生所述式ID的二环芳胺的条件下接触,转化为下式ID的二环芳胺,
其中,
R31是氢或烷基,较好是氢;
Z4是-NR13-CH(R31)-R15-[C(=O)]f-R16
其中
f是0或1;
X3按照在此的定义,较好是O;
R15按照在此的定义,较好是任选取代的亚烷基或任选取代的杂
亚烷基;
R16按照在此的定义。
胺化合物和羰基间这样的胺化反应通常使用各种还原剂,在羧酸如乙酸存在下进行,还原剂包括但不限于:硼氢化物如NaBH4、NaCNBH3、NaBH(OAc)3等。没有还原剂时,产物通常是亚胺化合物,式ID中的Z4部分为式-NR13=CH(R31)-R15-[C(=X3)]f-R16。
其中Y为式-R22-NR23-R24-[NR25]g-[R26]h-[C(=X4)]i-[R27]j-Ar3,x是1的式I化合物,如式IE的4-取代的2H-2,3-二氮杂萘-1-酮化合物,制备方法为:
使式IF的二环芳基化合物与式HNR23-Z5的胺化合物在足以产生式IE的4-取代二环芳基化合物的条件下反应。
其中
Lg是离去基;
R22是亚烷基;
Z5是-R24-[NR25]g-[R26]h-[C(=X4)]i-[R27]j-Ar3
其中
g、h、i和j各自独立地是0或1;
X4选自O和S;
R24和R26各自独立地是亚烷基;
R23选自氢和杂芳烷基;
R25选自氢和烷基;
R27选自-NH-和亚烷基;
Ar3选自任选取代的芳基和取代的杂芳基。
其中R22是亚甲基,Q1和Q2是CH,Lg是氯化物的式IF的二环芳基化合物,可购得,并可用于制备式IF的其他衍生物。取代反应通常在极性非质子溶剂如DMF或DMSO中于室温下进行。
其中Y是R3-C(=X1)-Y1的式I化合物可由下式IG化合物合成:
通过式IG化合物与式-NR4R5的胺化合物在常规酰胺合成条件下接触合成上述式I化合物。其中,R3,R4,R5,X1和Y1按照在此的定义,Za是-OH、卤化物或烷氧化物。其中R3是亚甲基和Za是-OH的式IG的化合物可由各种途径购得。
药物组合物
式I化合物可给予患者,以达到要求的生理效果。较好的,患者是哺乳动物,更好是人。较好的,式I化合物以包含该化合物或其药学上可接受的盐、前药、立体异构体或混合物(下面,称作“式I化合物”)的药物组合物给药。本发明的药物组合物中式I化合物在体外,通常具有小于或等于10μM,较好小于或等于1μM,更好的小于或等于500nM,最好是小于或等于200nM的抑制PARP的IC50。
本发明组合物可以适合于选择的给药途径即口服或肠胃外用各种剂型给药。肠胃外给药包括但不限于通过下列途径的给药:静脉内;肌肉;皮下;眼内;滑膜内;经上皮,包括经皮、眼、舌下和颊;局部,包括眼、皮肤、眼睛、直肠和通过吹入和气雾剂的鼻吸入;腹膜内和直肠系统。
活性化合物可以例如,与惰性稀释剂或与可吸收的可食用载体口服给药,或包封在软或硬明胶胶囊内,或压制成片剂,或直接与食物混合在一起。对口服治疗给药,活性化合物可与赋形剂混合,并以可吸收的片剂、郏含片剂、糖锭、胶囊、锭剂、酏剂、混悬剂、糖浆、薄片等使用。这样的组合物和制剂可含有至少0.1%的活性化合物。当然,组合物和制剂的百分含量可以改变,一般约含0.1-75重量%的活性组分,较好为约1-50重量%,更好为约1-10重量%活性组分。这样的治疗有用的组合物中活性化合物的量可获得合适的剂量。本发明优选组合物和制剂的制备为,口服单位剂型含有约1-1000mg的活性化合物。活性组分可以是粉剂或颗粒形式;在水性液体或非水性液体中的溶液或混悬液形式;或水包油或油包水乳液形式。活性组分还可以是大丸剂、干药糖剂或糊剂形式。
片剂、糖锭、丸剂、胶囊等还可含有下列组分:粘合剂如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂如磷酸二钙;崩解剂如玉米淀粉、土豆淀粉、藻酸等;润滑剂如硬脂酸镁;可加入甜味剂如蔗糖、乳糖或糖精,或调味剂如薄荷、冬青油或樱桃香精。当单位剂型是胶囊时,除上述组分外可含有液体载体。可存在其他各种物质如包衣,或改变剂量单位的物理形态。例如,片剂、丸剂或胶囊可包有虫胶、糖或两者。糖浆或酏剂可含有活性化合物、作为甜味剂的蔗糖、防腐剂对羟基苯甲酸甲酯或丙酯、染料和调味剂如樱桃或桔子香精。当然,制备任一单位剂型中使用的任何物质都应是药学纯的,其使用剂量基本无毒性。此外,活性化合物可加入到缓释制剂和配方中。
该组合物通常配制成单位剂型,如片剂,胶囊,水性悬浮剂或溶液。这样的配方通常包含固体、半固体或液体载体。载体例子包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、矿物油、可可豆脂、可可豆油、藻酸盐、黄蓍胶、明胶、糖浆、甲基纤维素、聚氧乙烯脱水山梨糖醇单月桂酸酯、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、玉米淀粉等。
特别优选的配方包括片剂和明胶胶囊,包含活性组分与(a)稀释剂,如乳糖,葡萄糖,蔗糖,甘露醇,山梨醇,纤维素,干玉米淀粉和甘氨酸;和/或(b)润滑剂,如二氧化硅,滑石,硬脂酸及其镁盐或钙盐,聚乙二醇。
片剂还可包含粘合剂,如硅酸铝镁,淀粉糊,明胶,黄蓍胶,甲基纤维素,羧甲基纤维素钠和聚乙烯基吡咯烷酮;崩解剂,如淀粉,琼脂,藻酸或其钠盐,和泡腾混合物;和/或吸附剂,着色剂,调味剂和甜味剂。本发明组合物可以灭菌和/或含有佐剂,如防腐剂,稳定剂,溶胀剂或乳化剂,促溶剂,调节渗透压的盐和/或缓冲剂。此外,组合物还可含有其他的治疗有用的物质。水性悬浮剂可与活性组分结合含有乳化剂和悬浮剂。所有口服剂型还可含有甜味剂和/或调味剂和/或着色剂。
这些组合物可分别按照常规的混合、造粒、或包衣方法制备。片剂可通过将活性组分任选与一种或多种附加组分压制或模制来制成。压片可通过在合适的设备中,将自由流动态如粉末或颗粒的活性组分任选与粘合剂、润滑剂、惰性稀释剂、表面活性剂或崩解剂混合压制。模制片可将被惰性液体稀释剂润湿的粉状活性组分和合适载体的混合物通过在合适设备中模制来制备。
活性化合物还可以肠胃外给药。活性化合物可制备成游离碱或药学上可接受的盐的溶液,在水中与表面活性剂如羟丙基纤维素适当混合。还可以制备在甘油、液态聚乙二醇以及它们的混合物、和油中的分散液。在常规储存和使用条件下,这些制剂含有防腐剂,防止微生物的生长。
适合注射使用的药物剂型包括灭菌的水溶液或分散液,和用于临时配制灭菌注射溶液或分散液的灭菌的粉末。各种情况下,剂型都必须灭菌,并必须是易于注射的流体。在制备和储存条件下应是稳定的,较好的能在防止微生物如细菌和真菌污染下储存。
当肠胃外给药时,组合物通常是单位剂量、灭菌的可注射剂型(等渗水溶液,悬浮剂或乳液),有药学上可接受的载体。这样的载体较好是非毒性和肠胃外可接受的。载体例子包括但不限于:水;水溶液如盐水(等渗氯化钠溶液),Ringer溶液,葡萄糖溶液和Hanks溶液;乙醇,多元醇(如,甘油,丙二醇,1,3-丁二醇,和液态聚乙二醇等);植物油或固定油(如,玉米,棉籽,花生,芝麻油,以及合成的单或二-甘油酯),油酸乙酯,和肉豆蔻酸异丙酯;以及合适的混合物。
例如,通过使用包衣如卵磷脂,在分散液的情况保持要求的粒度并使用表面活性剂可保持适当的流动性。通过各种抗菌和抗真菌剂,例如对羟基苯甲酸酯类、三氯叔丁醇、苯酚、山梨酸、硫柳汞等可达到防止微生物活动。许多情况下,较好的包含等渗剂,如糖或氯化钠。
灭菌注射溶液通过将需要量的活性化合物与上面列举的各种其他组分加入到适当溶剂中,如果需要,随后过滤灭菌来制备。分散液制备一般是将各种灭菌的活性组分加入到灭菌的赋形剂中,赋形剂含有基本分散介质和上面列举的需要的其他组分。在用于制备灭菌注射溶液的灭菌的粉末的情况,优选的制备方法是真空干燥和冷冻干燥技术,由其灭菌过滤的溶液得到活性组分和任何需要的其它组分的粉末。
油性悬浮剂的配制可按照本领域已知的方法,使用合适的分散或润湿剂和悬浮剂进行。可接受的溶剂或悬浮介质中较好是灭菌的固定油。为此目的,可使用任一刺激性小的固定油。制备注射剂时还可以使用脂肪酸,如油酸及其甘油酯衍生物,包括橄榄油和蓖麻油,尤其是它们的聚氧乙烯化形式。这些油溶液或悬浮剂还可含有长链醇稀释剂或分散剂。
当直肠给药时,组合物一般配制成单位剂量形式,如栓剂或扁囊剂(cachet)。这些组合物的制备可以是,混合化合物与合适的非刺激性赋形剂,赋形剂在室温为固体,而在直肠温度为液体,这样,组合物可以在直肠中熔融而释放该化合物。常规赋形剂包括可可豆脂,蜂蜡和聚乙二醇或其他脂肪乳液或悬浮剂。
式I化合物还可以局部给药,尤其在治疗的情况涉及局部应用易达到的区域或器官,包括眼、皮肤或下肠道的神经障碍时。这样的组合物可包含局部载体。在此使用的术语“局部载体”为本领域技术人员熟知,指一种或多种适合给患者进行活性化合物局部施用的相容的固体或液体填充稀释剂或赋形剂。局部载体可以是高纯度并适合与患者的部位和器官接触的药学上可接受的载体,而无不适当的毒性、不相容性、不稳定性、过敏反应等。
对眼的局部应用或眼科用途,化合物可配制为在等渗、调节了pH的灭菌盐水中的微粉化悬浮剂,或较好为在等渗的调节了pH的灭菌盐水中的溶液,可以有防腐剂如苯扎氯铵(benzylalkonium chloride),或没有。或者,化合物配制成软膏如矿脂。
对本发明有用的局部应用的组合物(即,局部组合物)可制成各种产品类型。包括但不限于,洗剂,霜剂,凝胶剂,粘片,喷雾剂,软膏和糊剂。这些产品类型可包含多种类型的载体体系,包括但不限于,溶液,乳液,凝胶,固体和脂质体。例如,对皮肤局部应用,化合物可配制成合适的软膏,含有悬浮或溶解在例如下面的一种或多种混合物中的化合物:矿物油,液体矿脂,白色矿脂,丙二醇,聚氧乙烯化合物,聚氧丙烯化合物,乳化蜡和水。或者,化合物可配制合适的洗剂或霜剂,含有悬浮或溶解在下面的一种或多种材料的混合物中的活性化合物:矿物油,脱水山梨糖醇单硬脂酸酯,聚山梨酯60,鲸蜡基酯蜡,鲸蜡硬脂混合醇(cetearyl alcohol),2-辛基十二烷醇,苄醇和水。
本发明中配制为溶液载体体系的局部组合物,通常包含药学上可接受的水性或有机溶剂。水是优选的溶剂。合适的有机溶剂例子包括:乙醇,丙二醇,聚乙二醇,聚丙二醇,甘油,1,2,4-丁三醇,山梨醇酯,1,2,6-己三醇,异丙醇,丁二醇以及它们的混合物。
如果对本发明有用的局部组合物配制成气溶胶载体体系并以喷雾剂应用于皮肤,应在溶液组合物中加入推进剂。推进剂例子包括氯化—氟化的低分子烃。其他有用的推进剂在Sagarin,Cosmetics Science and Technology,2nd Ed.,1972,Vol.2,(″Sagarin volume 2″)中讨论,该文献全文包括于此供参考。有用的推进剂披露于pages443-465 of Sagarin,volume2。
本发明的局部组合物可配制成包含润滑剂的溶液载体体系。这样的组合物含有约2-50%的药学上可接受的局部润滑剂。已知有许多合适的润滑剂并可在此使用。
洗剂可由溶液载体体系制成。洗剂包含约1-20%润滑剂,和约50-90%水。
可由溶液载体体系配制的另一种产品类型是霜剂。霜剂通常包含约5-50%的润滑剂,和约45%-85%水。
可由溶液载体体系配制的还有一种产品类型是软膏。软膏可包含简单的动物或植物油,或半固体烃(油质)基质。软膏还可包含吸收软膏基质,它可吸收水形成乳液。软膏载体也可以是水溶的。软膏可包含约2-10%润滑剂和约0.1-2%的增稠剂。
本发明局部应用的组合物还可包含辅助组分。辅助组分的用途是任意的,但较好是提供本发明局部应用组合物额外要求的性能。这些辅助组分包括:增稠组分,防腐组分,脂质—可溶组分以及着色剂。
局部组合物还包含防腐组分,抑制组合物中微生物和霉菌生长。有用的防腐组分包括:丙二醇,苯氧基乙醇,氯苯甘醚,对羟基苯甲酸甲酯,对羟基苯甲酸乙酯对羟基苯甲酸丁酯,对羟基苯甲酸丙酯,以及它们的混合物。
局部应用的组合物还可包含提供额外光滑感的脂质可溶的组分。脂质可溶组分包括但不限于:steareth-2,steareth-21,聚二甲基硅氧烷和支链新戊酸酯,如新戊酸辛基十二烷基酯,新戊酸庚基十二烷基酯,新戊酸壬基十二烷基酯,新戊酸辛基十一烷基酯,新戊酸庚基十一烷基酯,新戊酸壬基十一烷基酯,新戊酸庚基十三烷酯,新戊酸庚基十三烷基酯,和新戊酸壬基十三烷酯。Steareth-2是聚氧乙烯(2)硬脂基醚,加入0.01%丁基化羟基苯甲醚和0.005%柠檬酸作为防腐剂。同样,steareth-21是聚氧乙烯(21)硬脂基醚,加入0.01%丁基化羟基苯甲醚和0.005%柠檬酸作为防腐剂。
对下肠道的局部应用可用是直肠栓剂(参见上述)或灌肠剂配方。
适合鼻或颊部给药的配方(如自推进粉末调制配方),可包含约0.1-5%w/w的活性组分,或例如约1%w/w的活性组分。此外,有些配方可混合成舌下糖锭或锭剂。
这种配方通常为单位剂型,可采用药物领域熟知的任何方法配制。所有的方法都包括这样一个步骤,将活性组分与构成一种或多种辅助组分的载体结合。该配方的制备一般是,使活性组分均匀而密切地与液体载体或细分散的固体载体或两者混合,然后,如果需要,将产品制成要求的配方的形状。
较好的实施方案中,载体是具有适当的时间释放特性和释放动力学的可生物降解的固体聚合物,或可生物降解聚合物的混合物。本发明组合物然后模制成固体植入剂,在长时间内提供有效浓度的本发明化合物,而不需要频繁再给药。本发明组合物可以本领域技术人员已知的任何适当方式加入到可生物降解的聚合物或聚合物混合物中,形成可生物降解聚合物的均匀基体,或以某种方式包裹在聚合物内,或模制成固体植入剂。一个实施方案中,可生物降解的聚合物或聚合物混合物用于形成包含能以可流动液体给药的本发明药物组合物的软“贮库”,例如,通过注射,但它保持足够的粘度,使药物组合物保持在注射部位周围的局部区域。这样形成的贮库的降解时间可以在数天至数年,取决于选择的聚合物及其分子量。通过使用注射形式的聚合物组合物,甚至可以消除切开的要求。在各种场合,柔软或可流动的传递“贮库”可以在对周围组织创伤最小的情况下调节其在体内占据的空间的形状。
本发明组合物的治疗有效的用量取决于所要求的释放特点,增敏效应所需的药物组合物浓度、以及药物组合物进行治疗必须释放的时间长度。医生可以决定最适合治疗的本治疗剂的剂量,并可依据给药形式以及选择的特定化合物改变,也可根据治疗的具体患者进行改变。医生一般希望最初以小剂量治疗,以小剂量增加,直到达到最佳效果。治疗剂量一般约为0.1-1000mg/天,较好约为10-100mg/天,或约为0.1-50mg/Kg体重/天,较好约为0.1-20mg/Kg体重/天,并可以不同剂量单位给药。对口服给药,可要求高剂量,约2X至4X数量级。
本发明组合物宜以胶囊或片剂给药,它们含有单一剂量或分次剂量的化合物,或是灭菌溶液、悬浮剂或乳剂用于一次剂量或分次剂量的肠胃外给药。
本发明化合物在组合物中的用量为治疗有效量。PARP抑制剂的治疗有效量取决于使用的具体化合物。
药物赋形剂或载体能够与本发明组合物的其他组分混合,并且,以没有明显降低常规使用情况下组合物的治疗效果的相互作用相互混合。
本发明治疗化合物可以单独给予患者,或与如上所述的药学上可接受的载体结合,其比例由化合物的溶解度和化学性能,选择的给药途径以及标准药学实践决定。
用途
给予患者,较好是哺乳动物,更好是人以治疗有效量的上述化合物和组合物,以发挥涉及抑制PARP酶的药理活性。这样,本发明化合物可用于治疗或预防各种疾病,包括动物中坏死或细胞调亡所致细胞损伤或死亡,脑缺血和再灌注损伤或神经变性疾病造成的神经组织损伤。此外,通过给予动物有效量的本发明化合物,本发明化合物还可用于治疗动物的心血管疾病。而且,本发明化合物可用于治疗癌症,和使肿瘤细胞对放射敏感或对化疗敏感。
本发明一个具体实施方案中,式I化合物用于刺激受损的神经元,促进神经元再生,防止神经变性和/或治疗神经障碍。因此,本发明还涉及影响患者中神经元活性的方法,该方法包括给予患者有效量的式I化合物。如上面所述,式I化合物抑制PARP活性,因此对治疗神经组织损伤,特别是动物脑缺血以及再灌注损伤或神经变性疾病引起的损伤有用。
本发明化合物可治疗的神经障碍的例子,包括但不限于,三叉神经痛;舌咽神经痛;面瘫;重症肌无力;肌肉营养失调;肌萎缩性侧索硬化;渐进型肌肉萎缩症;渐进型延髓遗传性肌肉萎缩症;突出,破裂或脱出的椎间盘综合征;颈椎关节强直;神经丛疾病;胸腔出口破坏综合征(thoracic outlet destruction syndromes);外周神经病症如铅、氨苯砜、蜱、卟啉症或Guillain-Barre综合征;阿尔茨海默病、亨廷顿病和帕金森病。
本发明化合物尤其对治疗下列神经障碍有用,包括:由物理损伤或疾病引起的外周神经病症;头部外伤如创伤性脑损伤;对脊髓的物理损伤;与脑损伤相关的卒中如与组织缺氧和脑损伤相关的血管性卒中、局部大脑缺血、全大脑缺血和大脑再灌注损伤;脱髓鞘疾病如多发性硬化症;以及与神经变性有关的神经障碍,如阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩性侧索硬化症。
本发明化合物、组合物和方法,通过给予患者有效量的此申请通式的化合物,可用于治疗患者的心血管疾病。
在此,术语“心血管疾病”指由心脏缺血或心脏再灌注引起的疾病。其例子包括但不限于:冠状动脉疾病,心绞痛,心肌梗死,心脏停止引起的心血管组织损伤,心脏旁路引起的心血管组织损伤,心原性休克,和本领域已知的相关疾病,或涉及心脏或脉管系统的功能紊乱或组织损伤,特别是但不限于与PARP活化相关的组织损伤。
本发明化合物对治疗心脏组织损伤,尤其是由患者心脏局部缺血或再灌注损伤引起的损害有用。本发明化合物尤其对治疗下列心血管疾病有用,包括:冠状动脉疾病如动脉粥样硬化;心绞痛;心肌梗死;心肌局部缺血和心脏停止;心脏旁路和心原性休克。
本发明化合物还可用于治疗由于细胞损伤或由于坏死或细胞凋亡所致细胞死亡引起的组织损伤,由于局部缺血和再灌注损伤引起的神经组织损伤,神经障碍和神经变性疾病;防止或治疗管性卒中;治疗或防止心血管疾病;治疗其他症状和/或病症如与年龄有关的黄斑变性,AIDS和其他免疫系统衰老的疾病,关节炎,动脉粥样硬化,恶病质,癌症,骨骼肌肉变性疾病,涉及复制衰老,糖尿病,头部损伤,免疫系统衰老,肠炎症性疾病(如结肠炎和Crohn病),肌肉营养失调,骨关节炎,骨质疏松,慢性阻塞性肺病,慢性和/或急性疼痛(如神经痛),肾衰竭,视网膜局部缺血,败血症性休克(如内毒素性休克),和皮肤老化;延长寿命和细胞增殖能力;改变衰老细胞的基因表述;或使肿瘤细胞对放射敏感。
另一方面,本发明化合物可用于治疗癌症,使肿瘤细胞对放射敏感和/或对化疗敏感。术语“癌”为广义。本发明化合物可以是“抗癌剂”,该术语还包括“抗肿瘤细胞生长剂”和“抗瘤剂”。例如,本发明化合物对治疗癌症以及使癌细胞如产生ACTH的肿瘤,急性淋巴细胞白血病,急性非淋巴细胞白血病,肾上腺皮质癌,膀胱癌,脑癌,乳癌,宫颈癌,慢性淋巴细胞白血病,慢性髓细胞白血病,结直肠癌,皮肤T-细胞淋巴瘤,子宫内膜癌,食道癌,Ewing恶性肿瘤,胆囊癌,毛细胞白血病,头颈部癌,Hodgkin淋巴瘤,Kaposi肉瘤,肾癌,肝癌,肺癌(小细胞和/或非小细胞),恶性腹膜渗出,恶性胸膜渗出,黑素瘤,间皮瘤,多发性骨髓瘤,神经母细胞瘤,非Hodgkin淋巴瘤,骨肉瘤,卵巢癌,卵巢(生殖细胞)癌,前列腺癌,胰腺癌,阴茎癌,视网膜母细胞瘤,软组织肉瘤,鳞状细胞癌,胃癌,睾丸癌,甲状腺癌,绒毛膜上皮癌,子宫癌,阴道癌,外阴癌和Wilm瘤,对放射敏感和/或对化疗敏感。
放射增敏剂已知可提高癌细胞对电磁辐射毒性作用的敏感性。目前许多对癌症治疗方案采用由X-射线的电磁辐射活化的放射增敏剂。X-射线活化的放射增敏剂例子包括但不限于:甲硝哒唑,米索硝唑,脱甲基米索硝唑,pimonidazole,etanidazole,nimorazole,丝裂霉素C,RSU 1069,SR 4233,EO9,RB 6145,烟酰胺,5-溴脱氧尿苷(BUdR),5-碘去氧尿苷(IUdR),溴去氧胞苷,氟去氧尿苷(FudR),羟基脲,顺铂,及其治疗有效的类似物和衍生物。
光动力学治疗(PDT)癌使用可见光作为增敏剂的放射活化剂。光动力学放射增敏剂例子包括但不限于:血卟啉衍生物,Photofrin,苯并卟啉衍生物,NPe6,初卟啉锡SnET2,pheoborbide-α,细菌叶绿素-α,naphthalocyanines,酞菁染料,酞菁染料锌,和其治疗有效的类似物和衍生物。
放射增敏剂可以和治疗有效量的一种或多种其他化合物结合给药,这些化合物包括但不限于:促进放射增敏剂掺入靶细胞的化合物;控制给靶细胞的治疗药物的量、营养物和/或氧的化合物。
同样,也已知化疗增敏剂可提高癌细胞对化疗化合物的毒性作用的敏感性。可与式I化合物结合使用的化疗药例子包括但不限于,阿霉素,喜树碱,达卡巴嗪,卡铂,顺铂,柔红霉素,多西他赛,多柔比星,干扰素(α,β,γ),白介素2,伊立替庚,紫杉醇,链脲霉素,替莫唑胺,拓扑替庚及治疗有效的类似物和衍生物。此外,可以和式I化合物结合使用的其他治疗剂包括但不限于,5-氟尿嘧啶,甲酰四氢叶酸,5’-氨基-5’-脱氧胸苷,氧,carbogen,输红细胞,全氟烃(如,Fluosol-DA),2,3-DPG,BW12C,钙通道阻断药,己酮可可碱,抗血管形成化合物,肼苯哒嗪和L-BSO。
本发明化合物还可用于治疗良性增生性疾病如良性前列腺肥大,动脉增生性疾病或Cushing综合征。
给药
要求的式I化合物的治疗有效的用量取决于诸多因素,如给予的具体化合物,给药方式,治疗的动物以及治疗的具体疾病。对患有或很可能患有在此所述疾病的患者,式I化合物的合适的全身给药剂量通常在约0.1-100mg碱/kg患者体重,较好约1-10mg/kg患者体重。医生可以决定适合治疗的治疗药剂的剂量。
这样的过程中,医生或兽医可以使用静脉推注,随后静脉输注,认为合适的话,重复给药。如上所述,本发明化合物例如可通过吸入喷雾剂,局部,直肠,鼻,经颊,舌下,阴道,脑室内或通过植入的贮库,以含有常规无毒性的药学上可接受的载体、助剂和赋形剂的制剂,经口腔、肠胃外给药。
对作为中枢神经系统靶的有效治疗,本发明方法中使用的化合物,当从周围给药时,应容易透过血—脑屏障。然而,不能透过血—脑屏障的化合物仍可通过脑室内途径有效给药。
对本发明方法,可采用调节给药时间和顺序的任何有效的给药方案。化合物的剂型较好包括包含活性化合物的有效量的单位药物剂型。有效量指足以抑制PARP活性和/或经给予一种或多种单位剂型产生所要求的作用的量。优选实施方案中,该剂量足以防止或降低血管性卒中或其他神经变性疾病。
治疗神经损伤的方法中(尤其是由溺水或头部损伤引起的急性缺血性卒中和全脑缺血),本发明化合物可以和一种或多种其他的治疗剂,较好是能降低卒中风险的药剂(如阿斯匹林),更好是能降低二次缺血事件的危险(如ticlopidine)的药剂,共同给药。
化合物和组合物可与一种或多种治疗药剂以下列方式共同给药:(i)一起在一个制剂中,或(ii)分开在各制剂中,以最佳速率释放各自的活性剂。各制方含有约0.01-99.99重量%,较好约3.5%-60重量%的本发明化合物,以及一种或多种药学上可接受的赋形剂,如润湿剂,乳化剂和pH缓冲剂。当本发明方法中使用的化合物与一种或多种治疗药剂联合给药时,对这些药剂的具体剂量取决于对上述对本发明组合物和方法概述的那些因素。
对本发明方法,可根据进行治疗的需要,采用调节给药时间和给予化合物的顺序的任何给药方案。这样的方案包括,用另外的治疗药剂进行预治疗和/或与之共同给药。为最大程度地保护神经组织免受神经损伤,本发明化合物应可能快地给予受疾病侵袭的细胞。在预期到神经损伤的情况,宜在预期的神经损伤出现之前给予化合物。这些神经损伤可能性增加的情况包括:手术如颈动脉内膜切除术,心脏,脉管,主动脉,矫形手术;血管内手术如动脉导管插入术(颈动脉,椎骨,主动脉,心脏,肾,脊柱,亚当凯维奇动脉);栓塞剂注射;使用螺管或气囊止血;在治疗脑损伤时中止血管供应;和潜在的医学情况如逐渐增强的短暂性缺血性发作,栓塞及引起的卒中。
实施例
本领域技术人员在考察了下列实施例后会理解本发明的另外的目的、优点和新颖性,但是实施例不构成限制。
实施例1:
此实施例说明4-二胺取代的2H-2,3-二氮杂萘-1-酮制备方法。
4-(3-氨基-丙基氢基)-2H-2,3-二氮杂萘-1-酮(R=H)
2升三口圆底烧瓶,配备有机械搅拌器和温度计,该烧瓶中投入1,3-丙二胺(66.0g,0.890mol)和乙醇(450ml)。然后在20分钟内分批加入邻苯二甲酸酐(120g,0.811mol)。发生放热反应,形成粘稠的白色沉淀。搅拌再持续1小时,产生的沉淀真空过滤。滤饼用乙醇(2×100ml)洗涤,提供178g白色固体,可以直接使用。1升三口圆底烧瓶,配备有机械搅拌器和调温器,在其中投入上面的固体(50.0g)和乙二醇(200ml),反应混合物于170℃回流1小时。蒸馏除去挥发物,直到烧瓶内温度达到210℃。取下加热板,烧瓶冷却至室温,将馏出液倒回烧瓶。产生的溶液用肼一水合物(36.1g,0.721mol)处理,该混合物于90℃加热16小时。冷却至室温后,加入水(500ml),产生的黄色沉淀真空过滤并用水(3×100ml)洗涤。将该物质转移到1升配备有磁力搅拌器的烧杯中,加入37%盐酸(15ml)和水(200ml)的混合物,形成清澈溶液。然后通过加入29%氢氧化铵水溶液(75ml),使产物沉淀。产生的固体过滤并在滤器上用水(3×100ml)洗涤。于45℃真空干燥过夜,提供51%产率的为黄色固体的标题化合物。m.p.147-148℃;1H NMR(DMSO-d6)δ(ppm)8.24(d,1H,J=0.9Hz),8.21(d,1H,J=0.9Hz);7.91-7.77(m,4H),6.74(bs,1H),3.29(dd,2H,J=11.8,6.6Hz),2.67(t,2H,J=6.6Hz),1.72(quin,2H,J=6.7Hz);m/z=219(M+H)。
4-(3-氨基-2,2-二甲基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(R=Me)
按照上面的方法由2,2-二甲基-丙-1,3-二胺制备这一化合物,但有如下变动:
邻苯二甲酸酐(10g,67.5mmol)和2,2-二甲基-丙胺(8.5ml,70.8mmol)(R=Me)溶解在40ml乙醇(EtOH)中。反应完成后,混合物真空浓缩。粗产物(5g,0.02mmol)按照Gaozza等所述环化。沉淀的产物过滤并干燥(3.36g,78%)。
在2,2-二甲基-2,3-二氢-1H-4,9a-二氮杂芴-9-酮(1.5g,7.0mmol)在EtOH(17.5ml)中的溶液中加入肼水合物(0.98ml),混合物加热回流31/2小时。结晶提供了0.994g(58%)的4-(3-氨基-2,2-二甲基-丙基氨基)-2H-2,3-二氮杂萘-1-酮。
实施例2
该实施例说明使用氰基苯甲酸酯化合物制备二胺取代的2H-2,3-二氮杂萘-1-酮的方法。
用于I和III的方法:
2-氰基-苯甲酸甲酯(2g,12.4mmol)和丁-1,4-二胺(1.09g,12.4mmol)的混合物于80℃在DMF(10ml)中加热过夜。加入二氯甲烷(即DCM),有机层用饱和NaHCO3、10%柠檬酸和盐水洗涤,在MgSO4上干燥、过滤和浓缩。使用硅胶柱层析纯化(CH2Cl2至CH2Cl2/MeOH的梯度,98/2),提供600mg环化物质(24%产率)。该物质用肼水合物按照实施例1所述处理提供4-(4-氨基-丁基氨基)-2H-2,3-二氮杂萘-1-酮。用于IV和VII(1,3-环己二胺和1,3-二氨基-2-丙醇)的方法:
2-氰基苯甲酸甲酯(322mg,2.00mmol)在DMF(1ml)中的溶液中,加入1,3-环己二胺(285mg,2.50mmol)。反应混合物于85℃加热16小时,冷却,用醚提取并浓缩,得到320mg为淡黄色固体(71%)的环状中间体。该产物用EtOH(2ml)中用肼水合物(2.80mmol)处理,于85℃加热10小时。产物通过过滤分离,用MeOH洗涤,干燥,产生318mg黄色固体。
用于II,V,VI和VIII:(Boc-保护的二胺)的方法
2-氰基苯甲酸酯(322mg,2.00mmol)的DMF(1ml)溶液中加入3-(氨基甲基)-1-N-boc-哌啶(0.96g,4.50mmol)。反应混合物于85℃加热16小时,冷却并提取到DCM中,产生550mg为黄色油状(51%)的环状中间体。该产物在EtOH(2ml)中用肼水合物(1.50mmol)处理,于85℃加热10小时。产物通过快速层析分离(EtOAc/己烷),产生310mg白色固体。该产物悬浮于50%TFA/DCM(5ml),搅拌1小时。真空下除去溶剂,产生223mg黄色油。
实施例3
用于IX,X,XI的方法
该实施例说明使用单保护的二胺化合物制备二胺取代的2H-2,3-二氮杂萘-1-酮的方法
于0℃在5ml MeOH中合并2-氰基-苯甲酸甲酯(0.40g,2.48mmol)和2.48mmol胺((3-氨基甲基-苯基)-氨基甲酸叔丁酯或(3-氨基-丙基)-甲基-氨基甲酸叔丁酯或4-氨基甲基-哌啶-1-羧酸叔丁酯)。加入2.73mmol NaOMe(为0.5M溶液)并于室温搅拌3-18小时。真空除去溶剂并用EtOAc(100ml)和0.5M NaHSO4(2×15ml)然后是盐水(1×15ml)萃取。有机层干燥(MgSO4)和真空浓缩。
在5ml MeOH中合并上面产生的粗的3-烷基亚氨基-2,3-二氢-异吲哚-1-酮(1.22mmol)和肼水合物(3.65mmol),并加热至85℃18小时。过滤的产物用H2O洗涤。
在5ml DCM中合并上面产生的粗的Boc-保护的化合物(1.2mmol)与三氟乙酸(即TFA)(36.1mmol)。室温搅拌2小时。加入甲苯,真空除去溶剂,以利于除去TFA。
实施例4
此实施例说明偶合芳基二胺2H-2,3-二氮杂萘-1-酮的方法以及进一步使产生的4-(氨基-取代的芳基氨基)-2H-2,3-二氮杂萘-1-酮衍生化的方法。
合成3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氢基)-苯基]-丙酰胺
3-亚氨基-2,3-二氢-异吲哚-1-酮(50mg,0.34mmol)和苯-1,3-二胺(110mg,0.102mmol)于200℃加热16小时。产生的混合物溶解于EtOH(600μL),加入肼水合物(200μL)。于80℃加热2小时后,混合物真空浓缩并溶解于1500μL的DMSO,直接用于制备性HPLC,提供4-(3-氨基-苯基氨基)-2H-2,3-二氮杂萘-1-酮。
4-(3-氨基-苯基氨基)-2H-2,3-二氮杂萘-1-酮(13.8mg,0.055mmol)和3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酸(20mg,0.081mmol)溶解于DMA(400μL)。加入HOBt(15mg,0.11mmol)、HATU(42mg,0.11mmol)和二异丙基乙胺(即DIPEA)(39μL,0.22mmol),混合物于室温搅拌过夜。混合物直接用于制备HPLC。由RPLC/MS测定纯度。
实施例5
此实施例说明制备6H-吡啶并[2,3-d]哒嗪-5-酮及其衍生物的方法。
采用与Carpino,L.A.在J.Am.Chem.Soc.,1962,17,2266所述的类似方法制备2-氰基烟酸甲酯。
2-氨基甲酰基烟酸(2.00g,12.04mmol)在吡啶(10ml)和甲醇(3ml)中的溶液冷却至0℃,10分钟内加入甲磺酰基氯(3.00g,26.3mmol)。该溶液缓慢温热至室温并搅拌6小时。反应混合物用水(20ml)处理,真空除去有机溶剂。含水混合物冷却至-10℃。过滤收集沉淀的2-氰基烟酸甲酯(1.70g,10.49mmol)。在2-氰基烟酸甲酯(2.00mmol)、DMF(1ml)和Sc(OTf)3(0.20mmol)的混合物中加入1,3-二氨基丙烷(2.50mmol)。反应混合物于85℃加热1小时,冷却,用乙醚研制,得到260mg环状中间体7,8-二氢-6H-4,5,8a-三氮杂-芴-9-酮的黄色固体(70%)。该产物用肼水合物(2.80mmol)在EtOH(2ml)中处理,于50℃加热10小时。冷却该溶液,过滤分离出化合物8-(3-氨基-丙基氨基)-6H-吡啶并[2,3-d]哒嗪-5-酮,用MeOH洗涤,干燥,得到244mg黄色固体。由RPLC/MS测定纯度(98%)。
此化合物按照与在此所述的2H-2,3-二氮杂萘-1-酮化合物的类似的方式进一步衍生化。
实施例6
此实施例说明制备6H-吡嗪并[2,3-d]哒嗪-5-酮及其衍生物的方法。
2,3-吡嗪二羧酸酐(6.50g,43.3mmol)的乙醇(25ml)溶液中于5分钟内滴加1,3-丙二胺(3.42g,46.0mmol)。该反应于室温搅拌过夜,过滤收集沉淀的产物,得到9.15g3-(3-氨基-丙基氨基甲酰基)-吡嗪-2-羧酸的白色固体(94%)。该中间体(200mg)溶解于DMF(3ml),并在微波反应器中于175℃加热3分钟,产生7,8-二氢-6H-1,4,5,8a-四氮杂-芴-9-酮,该产物不需进一步纯化就可使用。
7,8-二氢-6H-1,4,5,8a-四氮杂-芴-9-酮(0.53mmol)在乙醇(3ml)中用肼水合物(3.0mmol)于室温处理20小时。真空除去乙醇,粗产物通过快速层析纯化(MeOH/DCM/Et3N),得到8-(3-氨基-丙基氨基)-6H-吡嗪并[2,3-d]哒嗪-5-酮。
此化合物按照与在此所述的2H-2,3-二氮杂萘-1-酮化合物类似的方式进一步衍生化。
实施例7
此实施例说明制备5-甲基-2H-2,3-二氮杂萘-1-酮及其衍生物的方法。
2-碘-3-甲基苯甲酸(1.50g,5.70mmol)溶解于DMF(15ml)并用CuCN(0.625g,7.0mmol)处理。该溶液于85℃加热1小时,冷却后倒入水(25ml)中。溶液冷却至0℃,该溶液沉淀的2-氰基-3-甲基苯甲酸经过滤分离,得到0.651mg白色固体(71%)。粗2-氰基-3-甲基苯甲酸(0.50g,3.1mmol)溶解于MeOH(10ml)并冷却至0℃。该溶液用过量的氯化三甲基甲硅烷(5.0mmol)处理,温热至室温,并搅拌5小时。真空除去甲醇,残余物用水(20ml)处理并用乙酸乙酯萃取,浓缩,得到2-氰基-3-甲基苯甲酸甲酯(0.44g,2.52mmol)。该固体中加入DMF(5ml)、Sc(OTf)3(0.01g,0.02mmol)和二氨基丙烷(0.22g,3.0mmol)。产生的混合物于85℃加热0.5小时,冷却,通过用乙醚研制,分离环状中间体5-甲基-2,3-二氢-1H-4,9a-二氮-芴-9-酮。此化合物(0.112g,0.5mmol)溶解于含过量肼水合物(3.0mmol)的乙醇中。该溶液于室温搅拌20小时,4-(3-氨基-丙基氨基)-5-甲基-2H-2,3-二氮杂萘-1-酮通过快速层析(MeOH/DCM/Et3N)分离。
此化合物按照与在此所述的2H-2,3-二氮杂萘-1-酮类似的方式进一步衍生化。
实施例8
此实施例说明制备5-甲基-2H-2,3-二氮杂萘-1-酮及其衍生物的方法。
采用对6H-吡啶并[2,3-d]哒嗪-5-酮衍生物(实施例5)所述的类似方法,3-氨基甲酰基吡啶甲酸(1.5mmol)与过量MsCl(4.0mmol)反应,产生3-氰基吡啶甲酸甲酯(1.2mmol)。合并3-氰基吡啶甲酸甲酯(1.2mmol)、Sc(OTf)3(0.02mmol)和二氨基丙烷(3.0mmol),于80℃加热1小时,产生7,8-二氢-6H-1,5,8a-三氮杂-芴-9-酮,用在EtOH中的过量肼水合物(5.0mmol)于室温处理,得到化合物5-(3-氨基-丙基氨基)-7H-吡啶并[2,3-d]哒嗪-8-酮(0.75mmol)的黄色固体。
此化合物按照与在此所述的2H-2,3-二氮杂萘-1-酮类似的方式进一步衍生化。
实施例9
此实施例说明二胺取代的2H-2,3-二氮杂萘-1-酮化合物的各种衍生化方法。
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-取代的酰胺
合成酰胺的通法A:
在原料胺(10mg,0.046mmol)的DMA(300μL)溶液中加入DIPEA(8.8μL,0.51mmol),随后加入酰氯如苯甲酰氯(6.4μL,0.055mmol)。混合物于室温搅拌过夜。加入DMSO(300μL),如果有沉淀,过滤混合物。粗混合物进行质谱指导的制备性LC/MS,提供需要的物质。
合成酰胺的通法B:
在胺如4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(8.5mg,0.039mmol)和酸(0.039mmol)在DMA(400μL)的溶液中加入,HOBt(5.8mg,0.043mmol)、EDC(8.1mg,0.043mmol)和DIPEA(7.7μL,0.043mmol)。混合物于室温搅拌过夜。加入DMSO(400μL),如有必要进行过滤。粗混合物进行质谱指导的制备性LC/MS,提供需要的物质。
合成酰胺通法C:
合并0.05mmol of 4-(3-氨基-苄基氨基)-2H-2,3-二氮杂萘-1-酮和0.075mmol羧酸、HATU(13.5mg,0.10mmol)、HOBt(17mg,0.125mmol)、DIEA(36μl,0.20mmol)在800μlDMA中的溶液。室温搅拌18小时。粗混合物进行质谱指导的制备性LC/MS,提供需要的物质。
实施例10
此实施例说明合成包含任选取代的杂芳基部分的羧酸化合物的方法。
其中,Ar是任选取代的芳基或任选取代的杂芳基。
合成脒肟:
按照Swain,C.J.et al.,J.Med.Chem.1991,34,140-151的改进方法制备脒肟衍生物。简而言之,将羟胺盐酸盐(0.15g,2.1mmol)和Na2CO3(0.11g,1.05mmol)溶解在20%EtOH水溶液中,随后加入腈化合物(2.1mmol)。混合物加热回流4-18小时。除去溶剂后,如果需要,脒肟通过硅胶柱纯化(0-5%MeOH/CH2Cl2)。
合成相应的酸:
按照R.M.Srivastava等在J.Het.Chem,1984,21,1193-1195所述的方法制备相应的酸。
简而言之,等摩尔量的酐和脒肟于120℃加热3小时。反应混合物冷却至室温,直接用于与模板胺偶合,不需进一步纯化。
实施例11
此实施例说明合成包含任选取代的杂芳基部分的羧酸的另一种方法以及其进一步衍生化或偶合于2H-2,3-二氮杂萘-1-酮化合物或其衍生物的方法。
6-氯-N-羟基-烟脒:
羟胺盐酸盐(0.50g,7.22mmol)和Na2CO3(0.38g,3.61mmol)溶解在2.5ml水中。加入6-氯烟腈(cloronicotinonitrile)(1.00g,7.22mmol)的20ml甲醇溶液,该混合溶液室温搅拌48小时。过滤沉淀并干燥,得到0.668g(54%)无色固体产物。
3-[3-(6-氯-吡啶-3-基)-[1,2,4]噁二唑-5-基]-丙酸:
琥珀酸酐(0.39g,3.89mmol)和6-氯-N-羟基-烟脒(0.67g,3.89mmol)溶解在2mlDMF中,于120℃加热2小时。过滤冷的溶液,用水洗涤沉淀,并干燥,得到0.70g(71%)的无色固体产物,该产物无需进一步纯化就可使用。
用胺亲核试剂取代氯基,合成3-[3-(6-甲基氨基-吡啶-3-基)-[1,2,4]噁二唑-5-基]-丙酸
甲胺(2M,1.5ml,3.0mmol)与2ml乙醇中的3-[3-(6-氯-吡啶-3-基)-[1,2,4]噁二唑-5-基]-丙酸(76mg,0.3mmol)合并,该溶液在封管中加热至100℃过夜。冷却后,除去溶剂,残余物通过RP-HPLC纯化。
用甲醇钠取代,如合成3-[3-(6-甲氧基-吡啶-3-基)-[1,2,4]噁二唑-5-基]-丙酸
甲醇钠(0.5M,3.94ml,1.97mmol)与3-[3-(6-氯-吡啶-3-基)-[1,2,4]噁二唑-5-基]-丙酸(100mg,0.394mmol)合并,该溶液在封管内加热至85℃1小时。冷却后,除去溶剂,残余物用乙酸乙酯和NaHSO4萃取。从有机层除去溶剂后,分离出为无色固体的产物,该产物无需进一步纯化就可使用。
按照在此所述的方法,将偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮。
实施例12
此实施例说明合成3-(3-氨基-苯基)-[1,2,4]噁二唑方法和将其偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮的方法。
合成(3-氰基-苯基)-氨基甲酸叔丁酯:
3-氨基-苄腈(118mg,1.00mmol)和Boc2O(871mg,4.00mmol)在2.5ml THF中的溶液在N2下于60℃搅拌24小时。除去溶剂后,残余物用二乙醚和NaHSO4萃取。有机层在MgSO4上干燥,蒸发得到(3-氰基-苯基)-氨基甲酸叔丁酯(175mg,80%),该产物无需进一步纯化就可使用。
合成[3-(N-羟基氨基甲亚胺酰)-苯基]-氨基甲酸叔丁酯:
羟胺盐酸盐(179mg,2.60mmol)和Na2CO3(138mg,1.30mmol)溶解于1ml水中。加入(3-氰基-苯基)-氨基甲酸叔丁酯(560mg,2.60mmol)的10ml甲醇溶液,该混合溶液回流搅拌过夜。除去溶剂,产生的沉淀用水和乙酸乙酯萃取,产生[3-(N-羟基氨基甲亚胺酰)-苯基]-氨基甲酸叔丁酯,该产物无需进一步纯化就可使用。
合成3-[3-(3-叔丁氧基羰基氨基-苯基)-[1,2,4]噁二唑-5-基]-丙酸:
琥珀酸酐(14mg,0.14mmol)和[3-(N-羟基氨基甲亚胺酰)-苯基]-氨基甲酸叔丁酯(35mg,0.14mmol)溶解在0.25ml DMF中并于120℃加热2小时。将冷溶液蒸发并干燥,得到3-[3-(3-叔丁氧基羰基氨基-苯基)-[1,2,4]噁二唑-5-基]-丙酸,该产物无需进一步纯化就可使用。
按照在此所述的方法,将酸偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮。
实施例13
此实施例说明合成3-[3-(4-甲硫基-苯基)-[1,2,4]噁二唑-5-基]-丙酸和3-[3-(4-甲磺酰基-苯基)-[1,2,4]噁二唑-5-基]-丙酸的方法和将其偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮的方法。
合成N-羟基-4-甲硫基-苄脒:
羟胺盐酸盐(104mg,1.5mmol)和Na2CO3(80mg,0.75mmol)溶解在0.5ml水中。加入4-甲硫基-苄腈(223mg,1.5mmol)的4ml甲醇溶液,该混合溶液于室温搅拌约48小时。除去溶剂后,沉淀用水洗涤,过滤和干燥后,得到N-羟基-4-甲硫基-苄脒(203mg,75%),该产物无需进一步纯化就可使用。
合成3-[3-(4-甲硫基-苯基)-[1,2,4]噁二唑-5-基]-丙酸:
琥珀酸酐(112mg,1.12mmol)和N-羟基-4-甲硫基-苄脒(203mg,1.12mmol)溶解在2.0ml DMF中,于120℃加热过夜。将冷溶液蒸发和干燥,得到3-[3-(4-甲硫基-苯基)-[1,2,4]噁二唑-5-基]-丙酸,该产物无需进一步纯化就可使用。
合成4-甲磺酰基-苄腈:
4-甲硫基-苄腈(250mg,1.68mmol)溶解于12ml HOAc。加入高锰酸钾(531mg,3.36mmol)的水溶液(7-8ml)。室温下搅拌30分钟后,搅拌下加入NaHSO3,直到溶液的棕色消失。将混合物浓缩,用水稀释。过滤该沉淀,真空干燥,得到4-甲磺酰基-苄腈(250mg,82%),该产物无需进一步纯化就可使用。
合成N-羟基-4-甲磺酰基-苄脒:
羟胺盐酸盐(100mg,1.44mmol)和Na2CO3(76mg,0.72mmol)溶解在0.5ml水中。加入4-甲磺酰-苄腈(260mg,1.44mmol)的4ml甲醇溶液,该混合溶液室温下搅拌约48小时。除去溶剂后,沉淀用水洗涤,过滤和干燥,得到N-羟基-4-甲磺酰基-苄脒(180mg,59%),该产物无需进一步纯化就可使用。
合成3-[3-(4-甲磺酰基-苯基)-[1,2,4]噁二唑-5-基]-丙酸:
琥珀酸酐(85mg,0.85mmol)和N-羟基-4-甲磺酰基-苄脒(180mg,0.85mmol)溶解在2.0ml DMF,于120℃加热过夜。冷溶液蒸发和干燥,得到3-[3-(4-甲磺酰基-苯基)-[1,2,4]噁二唑-5-基]-丙酸,该产物无需进一步纯化就可使用。
采用在此所述的方法,将酸偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮。
实施例14
此实施例说明合成2-[5-芳基-1,3,4-噁二唑-2-基]丙酸和其偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮的方法
方法A
方法B
方法A
合成N-苯甲酰琥珀酰肼:
琥珀酸酐(70mg,0.7mmol)溶解于3ml含DMA(183μL,1.05mmol)的DIEA。加入苯甲酰肼(95mg,0.7mmol),溶液室温搅拌过夜。真空除去溶剂,得到N-苯甲酰琥珀酰肼,该产物无需进一步纯化就可使用。
合成2-[5-苯苯-1,3,4-噁二唑-2-基]丙酸:
粗的苯甲酰琥珀酰肼(50mg,0.21mmol)溶解于1ml浓H2SO4,于80℃加热30分钟。混合物加入到碎冰中,用DCM萃取。有机层在MgSO4上干燥,蒸发,得到2-[5-苯基-1,3,4-噁二唑-2-基]丙酸(40mg,87%),该产物无需进一步纯化就可使用。
对某些噁二唑,该产物不必萃取,而只要由水溶液过滤和干燥。对许多产物,该序列反应产生不需要的邻苯二甲酰亚胺产物。这种情况下,可采用下述方法B,得到需要的噁二唑。
方法B
合成N-(4-氯苯甲酰)-甲基琥珀酰肼:
合并琥珀酸单甲酯(79mg,0.6mmol)与3ml DMF中的EDC(134mg,0.7mmol)、HOBt(108mg,0.8mmol)和DIEA(261μL,1.5mmol)。加入4-氯苯甲酰肼(85mg,0.5mmol),室温搅拌过夜。真空除去溶剂,产生的残余物用EtOAc、NaHCO3、NaHSO4和盐水萃取。有机层在MgSO4上干燥,蒸发后得到粗N-(4-氯苯甲酰)-甲基琥珀酰肼(139mg,98%),该产物无需进一步纯化就可使用。
合成2-[5-(4-氯苯基-1,3,4-噁二唑-2-基)丙酸甲酯:
N-(4-氯苯甲酰)-甲基琥珀酰肼(57mg,0.2mmol)与POCl3(186μL,2.0mmol)合并于85℃加热2小时。真空除去溶剂,产生的甲酯和游离酸的混合物无需进一步纯化就可使用。
合成2-[5-(4-氯苯基-1,3,4-噁二唑-2-基)丙酸:
于0℃,将上面的粗的混合物用1N NaOH(300μL,0.3mmol)在2ml of 10%H2O/二噁烷处理,直到消耗了所有的酯(1-3小时)。除去溶剂和产生的残余物用10%NaHSO4酸化,用EtOAc萃取。有机层在MgSO4上干燥,蒸发得到粗产物(48mg,95%),该产物无需进一步纯化就可使用。
方法A和方法B产生的酸按照在此所述的方法(如EDC/HOBt偶合方法)偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮。
实施例15
此实施例说明合成3-(5-芳基-2-四唑基)丙酸的方法和其偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮的方法。
采用R.T.Buckler,S.Hayao,O.J.Lorenzetti,L.F.Sancilio,H.E.Hartzler,W.G.Strycker,J.Med.Chem.,1970,13,725的改进方法,由腈化合物合成四唑。
合成5-p-甲苯基四唑:
甲苯基氰(103mg,1.0mmol)与NH4Cl(70mg,1.3mmol)和NaN3(85mg,1.3mmol)的3ml DMF溶液回流过夜。产生的5-p-甲苯基四唑通过RP-HPLC纯化。
合成3-(5-p-甲苯基-2-四唑基)丙酸乙酯:
乙醇钠(21%,173μL,0.536mmol)与5-p-甲苯基四唑(65.9mg,0.412mmol)回流下溶解于650μL无水乙醇。回流下加入3-溴-丙酸乙酯(69μL,0.536mmol),混合物保持回流过夜。过滤粗混合物,浓缩,用二乙醚和饱和NaHCO3萃取。有机层干燥,蒸发。需要时,进一步通过RP-HPLC纯化,提供3-(5-p-甲苯基-2-四唑基)丙酸乙酯。
合成3-(5-p-甲苯基-2-四唑基)丙酸:
3-(5-p-甲苯基-2-四唑基)丙酸乙酯(11.5mg,0.044mmol)溶解于120μL浓HCl和120μL冰醋酸,于85℃加热过夜。通过用水稀释沉淀出纯的酸,然后过滤和干燥,得到10mg(97%)无色固体。
然后采用在此所述的方法,使四唑酸偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮。
实施例16
此实施例说明合成1-(3-芳基-1,2,4-噁二唑-5-基)乙酰胺方法和和其偶合到4-(3-氨基-丙氨基)-2H-2,3-二氮杂萘-1-酮的方法。
合成1-[3-(4-甲氧基苯基)-1,2,4-噁二唑-5-基]乙酸乙酯:
乙基丙二酰氯(77μL,0.60mmol)、DIEA(209μL,1.2mmol)和p-甲氧基-苄脒肟(100mg,0.60mmol)在5ml THF中的溶液于室温搅拌1.5小时。再加入77μL乙基丙二酰氯,搅拌该混合物1小时。除去溶剂,残余物真空下于110℃加热30分钟,真空下室温过夜。要求的产物以RP-HPLC纯化,得到46mg(30%)无色油。
合成1-[3-(4-甲氧基苯基)-1,2,4-噁二唑-5-基]乙酸:
1-[3-(4-甲氧基苯基)-1,2,4-噁二唑-5-基]乙酸乙酯(46mg,0.17mmol)在2ml二噁烷和0.2ml水中的溶液冷却至0℃。加入氢氧化钠(1N,210μL,0.21mmol),混合物于0℃搅拌2小时。该溶液用10%NaHSO4中和,浓缩,然后用EtOAc和10%NaHSO4萃取。有机层在MgSO4上干燥,蒸发,得到为无色固体的产物(30mg,75%),该产物无需进一步纯化就可使用。
按照在此所述的方法,该酸偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮。
实施例16
此实施例说明合成3-(5-芳基-[1,2,4]噁二唑-3-基)-丙酸衍生物的方法和其偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮的方法。
采用和Diaz-Ortiz,A.;Diez-Barra,E.;De La Hoz,A.;Moreno,A.;Gomez-Escalonilla,M.J.;Loupy,A.;Heterocycles,1996,43(5),1021-1030所述类似的方法,制备噁二唑部分。
4-硝基丁酸甲酯(200mg,1.36mmol)和6-氯烟腈(226mg,1.63mmol)溶解在二噁烷(3ml)中,并用1,4-苯二异氰酸酯(435mg,2.72mmol)和三乙胺(2.0mg,0.02mmol)处理。反应混合物在微波反应器中于175℃加热4分钟。过滤反应混合物,滤液浓缩。3-[5-(6-甲氧基-吡啶-3-基)-[1,2,4]噁二唑-3-基]-丙酸甲酯用甲醇(3ml)中的过量NaOMe(5mmol)处理,室温搅拌5小时。真空除去甲醇,残余物溶解于二噁烷(5ml),滴加浓缩HCl进行处理,直到形成沉淀。过滤收集生成的3-[5-(6-甲氧基-吡啶-3-基)-[1,2,4]噁二唑-3-基]-丙酸,通过RPLC测定纯度(95%)。
该酸(125mg,0.50mmol)和4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(100mg,0.46mmol)溶解于DMF(2ml),用EDC(95mg,0.50mmol)和三乙胺(76mg,0.75mmol)处理。通过制备性RPLC分离化合物3-[5-(6-甲氧基-吡啶-3-基)-[1,2,4]噁二唑-3-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺。
实施例17
此实施例说明合成3-(4-芳基-[1,2,3]三唑-1-基)-丙酸衍生物的方法和其偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮的方法。
4-叠氮丁酸甲酯(200mg,1.40mmol)和1-乙炔基-4-甲氧基苯(277mg,2.10mmol)溶解在二噁烷(3ml),在微波反应器中于175℃加热5分钟。反应混合物过滤,滤液真空浓缩。化合物3-[4-(4-甲氧基-苯基)-[1,2,3]三唑-1-基]-丙酸甲酯在THF(3ml)中用含水的2M NaOH(5ml)处理,室温搅拌5小时。真空除去甲醇,残余物溶解于二噁烷(5ml),并且滴加浓HCl处理,直到形成沉淀。过滤收集产生的酸,通过RPLC测定纯度(78%)。化合物3-[4-(4-甲氧基-苯基)-[1,2,3]三唑-1-基]-丙酸(125mg,0.50mmol)和4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(100mg,0.46mmol)溶解于DMF(2ml),用EDC(95mg,0.50mmol)和三乙胺(76mg,0.75mmol)处理。通过制备性RPLC分离3-[4-(4-甲氧基-苯基)-[1,2,3]三唑-1-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺。
实施例18
此实施例说明合成3-(5-芳基-异噁唑-3-基)-丙酸衍生物的方法和其偶合到4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮的方法。
采用与Dondoni,A.;Barbaro,G.;J.Chem.Soc.Perkins 2,1974,1591所述类似的方法,制备异噁唑部分。
4-硝基丁酸甲酯(200mg,1.36mmol)和1-乙炔基-4-甲氧基苯(264mg,2.00mmol)溶解在二噁烷(3ml),用1,4-苯二异氰酸酯(435mg,2.72mmol)和三乙胺(2.0mg,0.02mmol)处理。反应混合物在微波反应器中于185℃加热5分钟。将反应混合物过滤,滤液真空浓缩。
在甲醇(3ml)中将3-[5-(4-甲氧基-苯基)-异噁唑-3-基]-丙酸甲酯用过量的4MNaOH处理,室温搅拌5小时。真空除去甲醇和水,残余物溶解于二噁烷(5ml),滴加浓HCl进行处理直到形成沉淀。过滤收集产生的3-[5-(4-甲氧基-苯基)-异噁唑-3-基]-丙酸,通过RPLC测定纯度(91%)。
3-[5-(4-甲氧基-苯基)-异噁唑-3-基]-丙酸(124mg,0.50mmol)和4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(100mg,0.46mmol)溶解于DMF(2ml),用氢氯化1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺(95mg,0.50mmol)和三乙胺(76mg,0.75mmol)处理。通过制备性RPLC将3-[5-(4-甲氧基-苯基)-异噁唑-3-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺分离。
实施例19
此实施例说明包含二芳基取代基的式I化合物的制备方法。
合并4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(678mg,3.11mmol)与50mlDMA中的6.21mmol酸、EDC(1.42g,7.46mmol)、HOBt(1.26g,9.33mmol)和DIEA(2.2ml,12.4mmol)。室温搅拌18小时。除去溶剂并用150ml EtOAc和50ml10%NaHSO4萃取。过滤萃取时形成的沉淀。该物质无需进一步纯化就可以使用。在300mlDMA、300ml MeOH和150ml of 1M Na2CO3中合并0.05mmol芳基溴、0.10mmolLiCl、1mg Pd(OAc)2、16mg PPh3和0.06mmol芳基硼酸。密封反应小瓶,加热至85℃18小时。粗混合物进行质谱指导的制备性LC/MS,提供需要的物质。
实施例20
此实施例说明包含(硫)脲部分的式I化合物制备方法。
在原料胺如4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(17.5mg,0.08mmol)的DMA(400μL)溶液中加入DIPEA(17μL,0.095mmol),随后加入异(硫)氰酸酯,如2-异氰酸根-1,4-二甲氧基-苯(17.2mg,0.096mmol)。混合物于室温搅拌过夜。加入DMSO(400μL),必要时过滤。粗混合物进行质谱指导的制备性LC/MS,提供需要的物质。
实施例21
此实施例说明包含磺酰胺部分的式I化合物的制备方法。
合成N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-取代的磺酰胺:
原料胺(10mg,0.046mmol)的DMA(300μL)溶液中加入DIPEA(8.8μL,0.51mmol),随后加入磺酰氯如苯甲酰磺酰氯(7μL,0.055mmol)。混合物于室温搅拌过夜。加入DMSO(300μL),必要时进行过滤。粗混合物进行质谱指导的制备性LC/MS,提供需要的物质。
实施例22
此实施例说明采用还原胺化法将羰基化合物偶合到式I化合物的二胺衍生物的方法。
合成4-(3-苄基氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮:
4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(22mg,0.10mmol)、DMF(1ml)和AcOH(0.01ml)的混合物中加入苯甲醛(11mg,0.10mmol)和NaCNBH3(12mg,0.20mmol)。反应混合物室温搅拌15小时,过滤,用质谱指导的制备性LC/MS纯化。
实施例23
此实施例说明偶合包含亚胺部分的式I化合物的方法。
合成4-{3-[(1,5-二甲基-3-氧代-2-苯基-2,3-二氢-1H-吡唑-4-基亚甲基)-氨基]-丙基氨基}-2H-2,3-二氮杂萘-1-酮:
在4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(22mg,0.10mmol)、DMF(1ml)和AcOH(0.01ml)的混合物中加入4-安替比林甲醛(22mg,0.10mmol)。反应混合物室温搅拌15小时,过滤,通过质谱指导的制备性LC/MS分离。由RPLC/MS测定纯度(95%)。
实施例24
此实施例说明制备4-[3-(4-氧代-2-苯基-3,4-二氢-2H-吡啶-1-基)-丙基氨基]-2H-2,3-二氮杂萘-1-酮的方法。
4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(22mg,0.10mmol)、乙腈(即ACN)(1ml)、Sc(OTf)3(5mg,0.01mmol)和(3-甲氧基-1-亚甲基-烯丙基氧)-三甲基硅烷(17mg,0.10mmol)的混合物中加入苯甲醛(11mg,0.10mmol)。反应混合物室温搅拌20小时,过滤,通过质谱指导的制备性LC/MS纯化。
实施例24
此实施例说明制备2,2-二甲基-3-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基]-3-苯基-丙酸甲酯的方法。
4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(22mg,0.10mmol)、ACN(1ml),Sc(OTf)3(5mg,0.01mmol)和(1-甲氧基-2-甲基-丙烯氧基)-三甲基硅烷(17mg,0.10mmol)混合物中加入苯甲醛(11mg,0.10mmol)。反应混合物室温搅拌20小时,过滤并通过质谱指导的制备性LC/MS纯化。通过RLPC/MS测定纯度(95%)。
实施例25
此实施例说明4-氨基-2,3-二氮杂萘酮还原烷基化制备各种氨基衍生物的方法。
合并4-氨基二氮杂萘酮(0.0085g,0.05mmol)和200μL DMA中的50μL乙酸。加入醛或酮(0.10mmol),室温振荡1小时。加入200ml DMA中的NaBH3CN(0.0079g,0.75mmol),室温振荡18小时。粗混合物进行质谱指导的制备性LC/MS,提供需要的物质。由RPLC/MS测定纯度。
实施例26
此实施例说明4-氨基-2,3-二氮杂萘酮衍生物烷基化方法。
4-(3-氨基-丙基氨基)-2H-2,3-二氮杂萘-1-酮(15mg,0.07mmol)的DMA(500μL)溶液中加入氯乙酰胺或溴乙酰胺,如2-氯-N-(5-甲基-1-苯基-1H-吡唑-3-基)-乙酰胺(17.5mg,0.07mmol)和DIPEA(15μL,0.084mmol)。混合物搅拌并加热至80℃过夜,用DMSO(400μL)稀释,通过制备性HPLC纯化。分离单烷基化和二烷基化产物。由RPLC/MS测定纯度。
实施例27
此实施例说明合成4烷基氨基甲基-2H-2,3-二氮杂萘-1-酮及其衍生物的方法。
合成(2-{3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-乙基)-氨基甲酸叔丁酯
3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酸(100mg,0.40mmol)和(2-氨基-乙基)-氨基甲酸叔丁酯(71.4mg,0.41mmol)溶解于DMF(1ml)。加入HOBt(59mg,0.44mmol)、EDC(84mg,0.44mmol)和DIPEA(78μL,0.44mmol)。混合物室温搅拌过夜。加入CH2Cl2,有机层用饱和NaHCO3、10%柠檬酸和盐水洗涤。干燥(MgSO4)和真空浓缩。产生的产物以硅胶柱层析纯化(CH2Cl2至CH2Cl2/MeOH 95/5的梯度)。产率68%。
合成N-(2-氨基-乙基)-3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酰胺
(2-{3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酰基氨基}-乙基)-氨基甲酸叔丁酯的Boc基通过用CH2Cl2/TFA(1/1)室温处理1小时除去,随后真空浓缩。残余物溶解于MeOH/水(5/1),加入Dowex OH-直到pH约为8。过滤除去离子交换树脂,残余物真空浓缩。
合成3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-{2-[(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基甲基)-氨基]-乙基}-丙酰胺
4-氯甲基-2H-2,3-二氮杂萘-1-酮(9.7mg,0.05mmol)的DMF(200μL)溶液中加入N-(2-氨基-乙基)-3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酰胺(14.4mg,0.05mmol)和DIPEA(9μL,0.05mmol)。混合物于室温搅拌过夜,直接用于制备性HPLC。
由RPLC/MS测定纯度。
实施例28
此实施例说明合成4烷基氨基甲基-2H-2,3-二氮杂萘-1-酮及其衍生物的另一种方法。
合成4-(4-{3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酰基}-哌嗪-1-基甲基)-2H-2,3-二氮杂萘-1-酮
4-氯甲基-2H-2,3-二氮杂萘-1-酮(40mg,0.21mmol)的DMA(800μL)溶液中加入哌嗪-1-羧酸叔丁酯(39mg,0.21mmol)和DIPEA(37μL,0.21mmol)。混合物于室温搅拌过夜并真空浓缩。加入TFA(1ml),混合物室温搅拌1小时。真空除去溶剂,随后与二噁烷一起蒸发。在400μL残余物在DMA中的储备溶液(0.25mM)中,加入3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酸(26mg,0.11mmol)、EDC(22mg,0.12mmol)、HOBt(16mg,0.12mmol)。随后加入DIPEA直到中性pH。混合物于室温搅拌过夜和直接用于制备性HPLC。由RPLC/MS测定纯度。
实施例29
此实施例说明合成4-烷基氨基甲基-2H-2,3-二氮杂萘-1-酮及其衍生物的另一种方法。
4-氯甲基-2H-2,3-二氮杂萘-1-酮(13mg,0.067mmol)的DMA(400μL)溶液中加入胺(如N-(2-氨基-乙基)-乙酰胺(8mg,0.08mmol))和DIPEA(14.3μL,0.08mmol)。混合物于室温搅拌过夜,用DMSO(400μL)稀释,通过制备性HPLC纯化,产生4-[(2-氨基-乙基氨基)-甲基]-2H-2,3-二氮杂萘-1-酮和二烷基化化合物。由RPLC/MS测定纯度。
实施例30
此实施例说明制备N-取代的-2-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基)-乙酰胺的方法。
(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基)-乙酸(购得)(10.2mg,0.05mmol)和胺或酰肼,如丁酰肼(5.6mg,0.055mmol)溶解在DMF(300μL)中。加入HOBt(7.43mg,0.055mmol),EDC(10.8mg,0.055mmol)和DIPEA(9.8μL,0.055mmol),反应物室温搅拌过夜。粗混合物进行质谱指导的制备性LC/MS,提供需要的物质。
实施例31
此实施例说明制备8-(顺式-3-氨基环己基-氨基)-6H-吡啶并[2,3-d]哒嗪-5-酮和5-(顺式-3-氨基环己基氨基)-7H-吡啶并[2,3-d]哒嗪-8-酮的方法。
500ml的四口圆底烧瓶,配备有磁力搅拌器,加料漏斗,温度计和蒸馏冷凝管,在其中投入2,3-吡啶二羧酸酐(26.1g,175mmol)和乙醇(90ml)。30分钟内,该悬浮液中滴加1,3-环己二胺(顺式-和反式-异构体混合物,21.0g,184mmol)的乙醇(10ml)溶液。观察到一放热反应,加料期间反应混合物温和回流。室温搅拌2.5小时后,反应混合物加热回流,然后回流下再搅拌1小时。反应混合物冷却至室温,然后蒸发至干。产生的残余物加热至210℃。于210℃搅拌1.5小时后,反应混合物冷却至室温,通过柱层析纯化。提供50%产率的6,10-亚甲基-7,8,9,10-四氢-6H-1,5,10a-三氮杂环辛四烯并[a]茚-11-酮和6,10-亚甲基-7,8,9,10-四氢-6H-4,5,10a-三氮杂环辛四烯并[a]茚-11-酮的混合物。主要异构体:白色固体;m.p.141-143℃,1H NMR(CDCl3)δ(ppm)8.79(dd,1H,J=1.3,4.9Hz),8.04(dd,1H,J=1.3,7.6Hz),7.45(dd,1H,J=4.9,7.6Hz),4.48(bs,1H),4.25(bs,1H),1.16-1.99(m,8H)。次要异构体:淡黄色固体;m.p.165-167℃,1H NMR(CDCl3)δ(ppm)8.78(dd,1H,J=1.2,4.8Hz),8.10(dd,1H,J=1.2,7.7Hz),7.49(dd,1H,J=4.8,7.7Hz),4.49(bs,1H),4.15(bs,1H),1.13-1.95(m,8H)。
50ml圆底烧瓶配备有磁力搅拌器,其中投入异构体的混合物(2.50g,11.0mmol)、肼一水合物(1.49g,29.8mmol)和1-丁醇(5ml)。反应混合物加热至回流并于回流下搅拌13.5小时。冷却至室温后,反应混合物蒸发至干,残余物通过柱层析纯化,得到68%产率的8-(顺式-3-氨基环己基氨基)-6H-吡啶并[2,3-d]哒嗪-5-酮和23%产率的5-(顺式-3-氨基环己基氨基)-7H-吡啶并[2,3-d]哒嗪-8-酮。
8-(顺式-3-氨基环己基氨基)-6H-吡啶并[2,3-d]哒嗪-5-酮,黄色固体;1H NMR(CD3OD)δ(ppm)9.01(dd,1H,J=1.6,4.6Hz),8.60(dd,1H,J=1.6,8.1Hz),7.80(dd,1H,J=4.6,8.1Hz),3.76(tt,1H,J=3.7,11.4Hz),2.78(tt,1H,J=3.7,11.2Hz),2.37(bd,1H,J=11.8Hz),2.13(bd,1H,J=11.8Hz),1.80-2.03(m,2H),1.42(ddt,1H,J=3.3,13.2,26.4Hz),1.06-1.27(m,3H);m/z=260(M+H).
5-(顺式-3-氨基环己基氨基)-7H-吡啶并[2,3-d]哒嗪-8-酮,黄色固体;1H NMR(CD3OD)δ(ppm)9.02(dd,1H,J=1.5,4.5Hz),8.55(dd,1H,J=1.5,8.4Hz),7.86(dd,1H,J=4.5,8.4Hz),3.78(tt,1H,J=3.7,11.4Hz),2.79(tt,1H,J=3.7,11.3Hz),1.79-2.38(m,4H),1.10-1.43(m,4H);m/z=260(M+H)。
采用这种方法制备的其他胺如下。观察到产率为9-87%:
4-(3-氨基丙基氨基)-5,8-二氟-2H-2,3-二氮杂萘-1-酮;
4-(3-氨基丙基氨基)-5-硝基-2H-2,3-二氮杂萘-1-酮;
4-(3-氨基-2,2-二甲基丙基氨基)-2H-2,3-二氮杂萘-1-酮;
4-(3-氨基-2-羟基丙基氨基)-2H-2,3-二氮杂萘-1-酮;
4-(顺式-3-氨基环己基氨基)-2H-2,3-二氮杂萘-1-酮。
实施例32
此实施例说明制备4-(2-二甲基氨基乙氧基)-苄腈的方法。
采用如下US专利No.2,970,149的改良法制备该物质。
1-升三口圆底烧瓶配备有磁力搅拌器,温度计和蒸馏冷凝管,在其中投入4-氰基苯酚(23.8g,0.200mol)和甲苯(230ml)。该悬浮液中加入25%甲醇钠的甲醇溶液(4.38M,68ml,0.300mol)。将反应物加热,蒸馏甲醇和甲苯的共沸物,直到内温度达到100℃。然后反应冷却至室温。在第二个配备有磁力搅拌器的1-升一口圆底烧瓶中,2-二甲基氨基乙基氯盐酸盐(13.2g,0.300mol)在甲苯(200ml)中制浆,加入饱和碳酸钾水溶液(400ml)。混合物冷却至-5℃,搅拌4小时,分离有机层,转移到置于冰水浴中的1-升烧瓶中。2-二甲基氨基乙基氯的甲苯溶液通过套管在45分钟内从该烧瓶缓慢转移到上面的4-氰基苯酚钠的甲苯悬浮液中,反应温度保持在15-20℃。添加完毕后,混合物回流65小时。反应混合物然后冷却至室温,真空过滤除去无机盐,滤液用水洗涤,在硫酸钠上干燥。滤液蒸发至干,提供83%产率的为黄色油的标题化合物。1H NMR(DMSO-d6)δ(ppm)7.65(d,2H,J=8.8 Hz),7.09(d,2H,J=8.8Hz),4.18(t,2H,J=5.4Hz),2.79(t,2H,J=5.4Hz),2.34(s,6H);m/z=191(M+H)。
采用这种方法制备的其他苄腈如下。观察到产率为59-93%:
3-(2-二甲基氨基乙氧基)苄腈4-[2-(4-吗啉基)乙氧基]苄腈
实施例33
此实施例说明制备4-二甲基氨基甲基-苄腈的方法。
A500-ml的三口圆底烧瓶配备有磁力搅拌器,加料漏斗,温度计和回流冷凝器,在其中投入4-溴甲基苄腈(7.84g,40.0mmol)和THF(50ml)。室温下,10分钟内滴加2M二甲基胺的THF溶液(60ml,120mmol)。观察到放热反应,室温搅拌24小时后,反应混合物分配在1N盐酸(150ml)和二乙醚(200ml)之间。分离醚层,水相用饱和碳酸钾水溶液碱化至pH9。产生的混合物用二乙醚萃取(3×100ml)。合并的有机相在硫酸钠上干燥,过滤。滤液蒸发至干,得到97%产率为褐色油的标题化合物。1H NMR(CDCl3)δ(ppm)7.60(d,2H,J=8.2Hz),7.44(d,2H,J=8.2Hz),3.47(s,2H),2.24(s,6H);m/z=161(M+H)。
3-二甲基氨基甲基苄腈也采用该方法制备,产率为94%。
实施例34
此实施例说明制备5-二-叔丁氧基羰基-氨基-1-甲基-1H-吡唑-4-甲腈的方法。
配备有磁力搅拌器的500-ml一口圆底烧瓶中投入5-氨基-1-甲基-1H-吡唑-4-甲腈(2.00g,16.4mmol)、三乙胺(5.02g,49.1mmol),DMAP(0.20g,1.64mmol)和THF(100ml)。产生的混合物中加入焦碳酸二-叔丁酯(7.87g,36.1mmol)。室温搅拌4小时后,反应混合物分配在饱和氯化铵水溶液(100ml)和二氯甲烷(200ml)之间。有机相分离,于硫酸钠上干燥,过滤。滤液浓缩,随后柱层析,得到100%产率的淡黄色油的标题化合物。1H NMR(CDCl3)δ(ppm)7.75(s,1H),3.72(s,3H),1.47(s,18H)。
采用这种方法制备的其他要保护的胺如下;观察到产率为41-100%:
3-二-叔丁氧基羰基氨基苄腈;
4-二-叔丁氧基羰基氨基-2-甲硫基噻唑-5-甲腈;
5-二-叔丁氧基羰基氨基噻吩-3-甲腈;
4-二-叔丁氧基羰基氨基-5-氰基咪唑-1-羧酸叔丁酯;
5-二-叔丁氧基羰基氨基-4-氰基咪唑-1-羧酸叔丁酯;
5-二-叔丁氧基羰基氨基-3-甲基异噁唑-4-甲腈;
5-二-叔丁氧基羰基氨基噻吩-2-甲腈;
3-二-叔丁氧基羰基氨基-4-氰基吡唑-1-羧酸叔丁酯
实施例35
此实施例说明制备(4-氰基-1H-吡唑-3-基)氨基甲酸叔丁酯的方法。
配备有磁力搅拌器和回流冷凝器的500-ml一口圆底烧瓶中投入3-二-叔丁氧基羰基氨基-4-氰基吡唑-1-羧酸叔丁酯(25.5g,62.4mmol)、碳酸钾(19.2g,137mmol)、乙醇(200ml)和水(190ml)。然后反应加热回流5小时。此后,反应冷却至室温,减压下除去乙醇。产生的混合物中加入乙酸乙酯(200ml),将两层分离。水层用乙酸乙酯萃取(2×200ml),合并的有机萃取液用饱和氯化钠溶液洗涤(2×150ml),在硫酸钠上干燥。过滤并减压下浓缩,提供粗固体。该产物从乙酸乙酯重结晶,提供60%产率为白色固体的标题化合物。m.p.167-170℃;1H NMR(DMSO),δ(ppm)=13.30(bs,1H),9.50(bs,1H),8.43(bs,1H),1.40(s,9H)。
也采用这种方法制备(5-氰基-1H-咪唑-4-基)氨基甲酸叔丁酯和(4-氰基-1H-咪唑-5-基)氨基甲酸叔丁酯的混合物,产率49%。
实施例36
此实施例说明制备[4-氰基-1-(2-三甲基甲硅烷基乙氧基甲基)-1H-吡唑-3-基]氨基甲酸叔丁酯的方法。
配备有磁力搅拌器和数字温度计的200-ml一口圆底烧瓶中投入(4-氰基-1H-吡唑-3-基)氨基甲酸叔丁酯(196mg,0.94mmol)和无水THF(10ml)。反应混合物冷却至-25℃,一次加入1M六甲基二硅氮烷钠(sodium hexamethyldisilazide)的THF(1.0ml,1.0mmol)溶液。搅拌20分钟后,使反应温热至室温。一次加入2-氯甲氧基乙基三甲基硅烷(0.2ml,1.1mmol),继续搅拌1小时。然后在反应混合物中加入乙酸乙酯(15ml)和水(10ml)。将两层分离,水层用乙酸乙酯萃取(2×10ml)。合并的有机萃取液用饱和氯化钠溶液(2×15ml)洗涤,硫酸钠上干燥,过滤并减压浓缩。产生的残余物通过柱层析纯化,提供100%产率(318mg)为无色油的标题化合物。1H NMR(CDCl3),δ(ppm)=6.72(bs,1H),5.33(s,2H),3.60(t,2H,J=8.2Hz),1.54(s,9H),0.93(t,2H,J=8.2Hz),0.00(s,9H)。
也采用这种方法制备[5-氰基-1-(2-三甲基甲硅烷基乙氧基甲基)-1H-咪唑-4-基]氨基甲酸叔丁酯和[4-氰基-1-(2-三甲基甲硅烷基乙氧基甲基)-1H-咪唑-5-基]氨基甲酸叔丁酯的混合物,产率为75%,使用碳酸钾为碱,二甲基甲酰胺为溶剂。
实施例37
此实施例说明制备2-乙磺酰基噻吩-5-甲腈的方法。
配备有磁力搅拌器和数字温度计的100ml一口圆底烧瓶中投入5-氨基噻吩-3-甲腈(300mg,2.42mmol)、吡啶(0.28g,3.59mmol)和二氯甲烷(10ml)。然后在氮气下于0℃,在5分钟内滴加乙磺酰氯(0.34g,2.64mmol)的二氯甲烷(5ml)溶液。于0℃搅拌1小时后,反应混合物温热至室温,然后在室温再搅拌20小时。反应混合物用二氯甲烷(50ml)稀释,然后用1N盐酸(2×20ml)和饱和氯化钠溶液(20ml)洗涤。有机相在硫酸钠上干燥,过滤。滤液浓缩,随后通过柱层析,提供75%产率的为棕色固体的标题化合物。1H NMR(CDCl3)δ(ppm)7.83(bs,1H),7.68(d,1H,J=1.5Hz),7.02(d,1H,J=1.5Hz),3.19(q,2H,J=7.4Hz),1.42(t,3H,J=7.4Hz)。
实施例38
此实施例说明制备1-(4-氰基噻吩-2-基)-3-异丁基脲的方法。
配备有磁力搅拌器的500-ml一口圆底烧瓶中投入异丁基氨基甲酰基甲酸钾(2.75g,15.0mmol)、过硫酸铵(5.13g,22.5mmol)、硝酸银(255mg,1.50mmol),乙酸铜(II)(27mg,0.15mmol)、二氯甲烷(90ml)和水(90ml)。混合物加热至40℃,然后于40℃搅拌3小时。此时之后,反应混合物冷却至室温。分离有机相,用硫酸钠干燥,过滤并浓缩至一半体积。在产生的溶液中加入5-氨基噻吩-3-甲腈(500mg,4.03mmol)。室温下搅拌24小时后,反应混合物加热至40℃,然后于该温度下再搅拌14小时。反应混合物浓缩,随后通过柱层析,提供50%产率为淡黄色固体的标题化合物。1HNMR(CDCl3)δ(ppm)7.86(bs,1H),7.40(d,1H,J=1.4Hz),6.54(d,1H,J=1.5Hz),5.24(t,1H,J=5.6Hz),3.10(t,2H,J=6.3Hz),1.79(m,1H),0.92(d,6H,J=6.7Hz)。
实施例39
此实施例说明制备2,6-二甲氧基-4-甲基烟腈的方法。
配备有磁力搅拌器的2升一口圆底烧瓶中投入2,6-二羟基-4-甲基烟腈(4.50g,30.0mmol)、二甲基甲酰胺(180ml)、氧化银(9.73g,42.0mmol)和碘甲烷(14.9g,105mmol),混合物于室温搅拌18小时。然后加入二氯甲烷(400ml)和甲醇(400ml),产生的悬浮液通过硅藻土521垫过滤。滤液减压下蒸发至干,残余物通过柱层析纯化,提供45%产率的为白色固体的标题化合物。m.p.92-94℃;1H NMR(DMSO-d6)δ(ppm)6.23(s,1H),4.02(s,3H),3.95(s,3H),2.42(s,3H);m/z=179(M+H)。
实施例40
此实施例说明制备4-(三异丙基甲硅烷氧基-甲基)苄腈的方法。
配备有磁力搅拌器和数字温度计的250ml三口圆底烧瓶中投入4-羟基甲基苄腈(10.0g,75.2mmol)、二氯甲烷(80ml)和咪唑(7.20g,106mmol),反应混合物冷却至0℃。15分钟内滴加三异丙基氯硅烷(15.9g,82.4mmol),混合物于室温搅拌1小时。然后该混合物加入到水(100ml)中,分离有机层,然后用10%柠檬酸水溶液洗涤(100ml)。在硫酸钠上干燥,过滤和减压浓缩,提供定量产率为无色油的标题化合物。该物质无需进一步纯化就可以使用。1H NMR(CDCl3)δ(ppm)7.62(d,2H,J=8.3Hz),7.46(d,2H,J=8.4Hz),4.88(s,2H),1.03-1.28(m,21H);m/z=290(M+H)。
采用这种方法也以定量产率制备3-(三异丙基甲硅烷氧基甲基)苄腈。
实施例41
此实施例说明制备2-甲基噻吩-3-甲腈的方法。
配备有磁力搅拌器和数字温度计的100-ml三口圆底烧瓶中用氮气清洗,投入噻吩-3-甲腈(2.91g,26.7mmol)和无水四氢呋喃(15ml)。溶液冷却至-73℃,滴加2M二异丙基胺基锂在庚烷/四氢呋喃中的溶液(14.8ml,29.6mmol),温度保持在-73℃至-65℃。加料完成后,于-73℃搅拌30分钟。然后滴加碘甲烷(4.10g,28.9mmol),温度还保持在-73℃至-65℃。然后混合物缓慢温热至室温。反应混合物中加入25%氯化铵水溶液(5ml),产生的悬浮液过滤并蒸发至干。为分离无机杂质,残余物用甲基叔丁基醚研制(150ml)和过滤。滤液减压浓缩,提供为棕色油的标题化合物,产率为90%。1H NMR(DMSO-d6)δ(ppm)7.54(d,1H,J=5.4Hz),7.31(d,1H,J=5.4Hz),2.61(s,3H);m/z=124(M+H)。
采用这种方法还制备2-乙基噻吩-3-甲腈,产率为47%。
实施例42
此实施例说明制备1-(2-二甲基氨基乙基)-1H-吡咯-2-甲腈的方法。
该物质采用如下US专利No.2,970,149的改良法制备。
配备有磁力搅拌器,温度计和回流冷凝器的250-ml三口圆底烧瓶用氮气清洗,并投入吡咯-2-甲腈(1.84g,20.0mmol)和无水二甲基甲酰胺(20ml)。产生的溶液冷却至0℃,于0-5℃分批加入矿物油中的60%氢化钠(1.20g,30.0mmol)。一旦添加完毕,反应于0-5℃再搅拌40分钟。
在第二个配备有磁力搅拌器的100-ml一口圆底烧瓶中,2-二甲基氨基乙基氯盐酸盐(4.32g,30.0mmol)在甲苯(20ml)中制浆,加入饱和碳酸钾水溶液(35ml)。混合物冷却至0℃,搅拌1.5小时,分离有机层,在碳酸钾上干燥,并转移到置于冰水浴中的100-ml烧瓶。该2-二甲基氨基乙基氯的甲苯溶液通过套管转移到上述吡咯-2-甲腈的钠盐溶液中,反应温度保持在0-5℃。添加完全后,混合物于110℃加热18小时。反应混合物然后冷却至室温,减压蒸发至干,加入二氯甲烷(50ml)。真空过滤除去无机盐,滤液用水洗涤(3×20ml),在硫酸钠上干燥。滤液蒸发至干,提供定量产率的为黄色油的1-(2-二甲基氨基乙基)-1H-吡咯-2-甲腈。该物质无需进一步纯化就可以使用。1H NMR(CDCl3)δ(ppm)6.91(t,1H,J=2.2Hz),6.78(dd,1H,J=3.9,1.5Hz),6.16(dd,1H,J=2.8,3.9Hz),4.11(t,2H,J=6.6),2.67(t,2H,J=6.6Hz),2.27(s,6H);m/z=164(M+H)。
实施例43
此实施例说明制备4-(2-二甲基氨基乙氧基)-N-羟基苄脒的方法。
配备有磁力搅拌器和回流冷凝器的500-ml一口圆底烧瓶中投入4-(2-二甲基氨基乙氧基)苄腈(31.5g,0.17mol)、乙醇(200ml)、羟胺盐酸盐(17.2g,0.25mol)和碳酸钾(34.8g,0.25mol)。产生的混合物回流18小时。冷却至室温后,反应混合物过滤,滤液浓缩至干,提供49%产率的为棕色油的标题化合物。1H NMR(CD30D)δ(ppm)7.87(d,2H,J=8.9Hz),7.04(d,2H,J=8.9Hz),4.36(t,2H,J=5.1Hz),3.37(t,2H,J=5.1Hz),2.79(s,6H);m/z=224(M+H)。
上述方法中,乙酸钠可取代碳酸钾。采用这种方法制备的其他羟基脒如下。观察到产率为25-99%。
N-羟基苄脒;4-氯-N-羟基苄脒;4-溴-N-羟基苄脒;4-氟-N-羟基苄脒;4-三氟甲氧基-N-羟基苄脒;4-羟基-N-羟基苄脒;3-羟基-N-羟基苄脒;3-硝基-N-羟基苄脒;4-甲基-N-羟基苄脒;3-甲基-N-羟基苄脒;3-乙基-N-羟基苄脒;2,3-二氯-N-羟基苄脒;3,4-二氟-N-羟基苄脒;N-羟基-4-三异丙基甲硅烷氧基甲基苄脒;N-羟基-3-三异丙基甲硅烷氧基甲基苄脒;3-氯-2-氟-N-羟基苄脒;3-氯-4-甲基-N-羟基苄脒;4-甲硫基-N-羟基苄脒;4-二甲基氨基甲基-N-羟基苄脒;3-二甲基氨基甲基-N-羟基苄脒;4-[2-(4-吗啉基)乙氧基]-N-羟基苄脒;6-甲氧基-N-羟基烟脒;3-(2-二甲基氨基乙氧基)-N-羟基苄脒;4-甲氧基-N-羟基苄脒;2,4-二甲氧基-N-羟基苄脒;3,5-二甲氧基-N-羟基苄脒;2,3-二甲氧基-N-羟基苄脒;2,5-二甲氧基-N-羟基苄脒;2,6-二甲氧基-N-羟基苄脒;2-氯-N-羟基烟脒;2,6-二甲氧基-4-甲基-N-羟基烟脒;N-羟基-1H-吡咯-2-甲脒;1-(2-二甲基氨基乙基)-N-羟基-1H-吡咯-2-甲脒;1-甲基-N-羟基-1H-吡咯-2-甲脒;4-二氟甲氧基-N-羟基苄脒;2-硝基-N-羟基噻吩-4-甲脒;3,4-亚甲基二氧-N-羟基苄脒;1,5-二甲基-N-羟基-1H-吡咯-2-甲脒;N-羟基噻吩-2-甲脒;N-羟基噻吩-3-甲脒;N-羟基-2,3-二氢苯并呋喃-5-甲脒;N-羟基-2-甲基噻唑-4-甲脒;[5-(N-羟基氨基甲亚胺酰)噻吩-2-基]氨基甲酸叔丁酯;[4-(N-羟基氨基甲亚胺酰)噻吩-2-基]氨基甲酸叔丁酯;4-(N-羟基氨基甲亚胺酰)哌啶-1-羧酸叔丁酯;3-(N-羟基氨基甲亚胺酰)哌啶-1-羧酸叔丁酯;2-(N-羟基氨基甲亚胺酰)哌啶-1-羧酸叔丁酯;和2-(N-羟基氨基甲亚胺酰)吡咯烷-1-羧酸叔丁酯。
实施例44
此实施例说明制备[4-(N-羟基氨基甲亚胺酰)-1-(2-三甲基甲硅烷基-乙氧基甲基)-1H-吡唑-3-基]氨基甲酸叔丁酯的方法。
配备有磁力搅拌器的25-ml一口圆底烧瓶中投入[4-氰基-1-(2-三甲基甲硅烷基乙氧基甲基)-1H-吡唑-3-基]氨基甲酸叔丁酯(203mg,0.6mmol)、甲醇(10ml)和50%羟胺水溶液(0.2ml)。反应混合物于室温搅拌18小时。混合物然后浓缩为粘性的油。该油在高真空下干燥,提供94%产率的白色固体标题化合物。m.p.157-158℃;1H NMR(DMSO-d6)δ(ppm)9.47(s,1H),9.03(s,1H),8.10(s,1H),5.85(bs,2H),5.27(s,2H),3.53(t,2H,J=8.0Hz),1.43(s,9H),0.84(t,2H,J=8.0Hz),-0.07(s,9H);m/z=372(M+H)。
乙醇可取代甲醇,得类似的产率。采用这种方法制备的其他羟基脒如下,观察到产率在32-99%范围。
5-叔丁氧基羰基氨基-N-羟基-1-甲基-1H-吡唑-4-甲脒;[4-(N-羟基氨基甲亚胺酰)噻吩-2-基]氨基甲酸叔丁酯;[5-(N-羟基氨基甲亚胺酰)-1-(2-三甲基甲硅烷基乙氧基甲基)-1H-咪唑-4-基]氨基甲酸叔丁酯;[4-(N-羟基氨基甲亚胺酰)-1-(2-三甲基甲硅烷基乙氧基甲基)-1H-咪唑-5-基]氨基甲酸叔丁酯;[4-(N-羟基氨基甲亚胺酰)-3-甲基异噁唑-5-基]氨基甲酸叔丁酯;[3-(N-羟基氨基甲亚胺酰)苯基]氨基甲酸叔丁酯;3-氟-N-羟基-4-甲基苄脒;2-甲基-N-羟基噻吩-3-甲脒;2-乙基-N-羟基噻吩-3-甲脒;5-乙磺酰基氨基-N-羟基噻吩-3-甲脒;3-[4-(N-羟基氨基甲亚胺酰)噻吩-2-基]-1-异丁基脲;[5-(N-羟基氨基甲亚胺酰)-2-甲硫基噻唑-4-基]氨基甲酸叔丁酯和2-氯-N-羟基乙脒。
实施例45
此实施例说明制备3-{3-[4-(2-二甲基氨基乙氧基)苯基]-1,2,4-噁二唑-5-基}丙酸的方法。
配备有磁力搅拌器的100-ml一口圆底烧瓶中投入4-(2-二甲基氨基乙氧基)-N-羟基苄脒(18.0g,81.0mmol)和琥珀酸酐(20.0g,200mmol),该烧瓶用氮气清洗。然后,反应在油浴中加热至120℃,3小时。冷却至室温后,加入水(50ml),混合物回流10分钟,以分解过量的琥珀酸酐。产生的溶液然后冷却至室温,用29%氢氧化铵碱化至pH5,减压蒸发至干。残余物溶解于甲醇,并通过硅胶柱,用甲醇洗脱。合并含纯物质的部份,减压蒸发至干,提供40%产率的为白色固体的标题酸。m.p.81-84℃;1H NMR(CD3OD)δ(ppm)7.98(d,2H,J=8.9Hz),7.06(d,2H,J=8.9Hz),4.38(t,2H,J=5.1Hz),3.49(t,2H,J=5.1Hz),3.18(t,2H,J=7.1Hz),2.88(s,6H),2.82(t,2H,J=7.1Hz);m/z=306(M+H)。
采用这种方法制备的其他噁二唑基丙酸如下。观察到产率在14-85%范围。
3-(3-苯基-1,2,4-噁二唑-5-基)丙酸;3-[3-(4-氯苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(4-溴苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(4-氟苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(3-硝基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(4-三氟甲氧基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(4-二氟甲氧基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(4-羟基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(3-羟基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(4-甲基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(3-甲基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(3-乙基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(4-二甲基氨基甲基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(3-二甲基氨基甲基苯基-1,2,4-噁二唑-5-基)]丙酸;3-{3-[3-(2-二甲基氨基乙氧基)苯基]-1,2,4-噁二唑-5-基}丙酸;3-{3-[4-(2-吗啉-4-基乙氧基)苯基]-1,2,4-噁二唑-5-基}丙酸;3-[3-(2,3-二氯苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(3,4-二氟苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(3-氯-4-甲基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(3-氟-4-甲基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(4-氯-3-氟苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(3,4-亚甲基二氧苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(4-甲硫基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(4-甲氧基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(2,3-二甲氧基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(2,4-二甲氧基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(2,5-二甲氧基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(2,6-二甲氧基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(3,5-二甲氧基苯基-1,2,4-噁二唑-5-基)]丙酸;3-[3-(噻吩-2-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(噻吩-3-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(2,3-二氢苯并呋喃-5-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(2-甲基噻唑-4-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(6-甲氧基吡啶-3-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(6-羟基吡啶-3-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(5-硝基噻吩-3-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(2-甲基噻吩-3-基)-1,2,4-噁二唑-5-基]丙酸;和3-[3-(2-乙基噻吩-3-基)-1,2,4-噁二唑-5-基]丙酸。
实施例46
此实施例说明制备3-[3-(5-叔丁氧基羰基氨基噻吩-3-基)-1,2,4-噁二唑-5-基]丙酸的方法。
配备有磁力搅拌器和回流冷凝器的100-ml三口圆底烧瓶用氮气清洗并投入5-叔丁氧基羰基氨基-N-羟基噻吩-3-甲脒(2.96g,11.5mmol)、琥珀酸酐(1.16g,11.6mmol)、无水1,2-二甲氧基乙烷(17ml)和N,N-二异丙基乙胺(1.62g,12.6mmol)。产生的溶液室温下搅拌30分钟,然后回流18小时。反应混合物真空蒸发至干后,在残余物中加入碳酸钾(5.0g,36.2mmol)的水溶液(85ml)。产生的悬浮液(pH=10)搅拌30分钟,通过硅藻土521垫过滤,滤液用2N盐酸酸化至pH3。混合物用二氯甲烷萃取(100ml),萃取液在硫酸钠上干燥。过滤并减压浓缩,提供26%产率为棕色固体的标题化合物。m.p.104-110℃;1H NMR(DMSO-d6)δ(ppm)12.51(1H,bs),10.67(s,1H),7.59(s,1H),6.92(s,1H),3.14(t,2H,J=6.9),2.81(t,2H,J=6.8Hz),1.49(s,9H);m/z=338(M-H)。
采用这种方法制备的其他噁二唑基丙酸如下。观察到产率在28-67%范围。
3-[3-(2,6-二甲氧基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(1-甲基-1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(1,5-二甲基-1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸;3-{3-[1-(2-二甲基氨基乙基)-1H-吡咯-2-基]-1,2,4-噁二唑-5-基}丙酸;3-[3-(2-氯吡啶-3-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(2,6-二甲氧基-4-甲基吡啶-3-基)-1,2,4-噁二唑-5-基]丙酸和3-[3-(4-叔丁氧基羰基氨基-2-甲硫基噻唑-5-基)-1,2,4-噁二唑-5-基]丙酸。
实施例47
此实施例说明制备3-叔丁氧基羰基氨基-N-(3-甲酯基丙酰氧基)苄脒的方法。
配备有磁力搅拌器和数字温度计的50-ml一口圆底烧瓶中投入[3-(N-羟基氨基甲亚胺酰)-苯基]氨基甲酸叔丁酯(5.56g,22.1mmol)、二异丙基乙胺(4.29g,33.2mmol)和THF(25ml)。反应混合物然后在冰/盐浴中冷却至0℃。3-甲酯基丙酰氯(3.99g,26.6mmol)然后被滴加到反应混合物中。一旦滴加完毕,取下冷却浴,混合物于室温再搅拌3小时。然后,反应物减压浓缩,残余物溶解于乙酸乙酯(60ml),产生的溶液用2M碳酸钾水溶液洗涤(2×60ml)。在硫酸钠上干燥,过滤并减压蒸发,提供定量产率的为白色固体的3-叔丁氧基羰基氨基-N-(3-甲酯基丙酰氧基)苄脒,该固体可直接使用。1H NMR(CDCl3)δ(ppm)7.71(s,1H),7.50(m,2H),7.33(m,2H),6.58(bs,1H),5.19(bs,2H),3.71(s,3H),2.83(m,2H),2.75(m,2H),1.52(s,9H).
采用这种方法制备的其他N-(3-甲酯基丙酰氧基)脒如下,观察到的产率在80%至定量范围。
4-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]哌啶-1-羧酸叔丁酯;3-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]-哌啶-1-羧酸叔丁酯;2-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]哌啶-1-羧酸叔丁酯;2-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]吡咯烷-1-羧酸叔丁酯;4-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]噻吩-2-基氨基甲酸叔丁酯;5-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]噻吩-2-基氨基甲酸叔丁酯;5-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]噻吩-2-基氨基甲酸叔丁酯;4-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]-2-甲基-2H-吡唑-3-基氨基甲酸叔丁酯;5-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]-1-(2-三甲基甲硅烷基)乙氧基甲基-1H-咪唑-4-基氨基甲酸叔丁酯;4-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]-1-(2-三甲基甲硅烷基)-乙氧基甲基-1H-咪唑-5-基氨基甲酸叔丁酯;N-(3-甲酯基丙酰氧基)-1H-吡咯-2-甲脒;N-(3-甲酯基丙酰氧基)-1-甲基-1H-吡咯-2-甲脒;4-[N-(3-甲酯基丙酰氧基)氨基甲亚胺酰]-1-(2-三甲基甲硅烷基)乙氧基甲基-1H-吡唑-3-基氨基甲酸叔丁酯;N-(3-甲酯基-丙酰氧基)-3-三异丙基甲硅烷氧基甲基苄脒;N-(3-甲酯基-丙酰氧基)-4-三异丙基甲硅烷氧基甲基苄脒;3-{4-[N-(3-甲酯基-丙酰氧基)氨基甲亚胺酰]噻吩-2-基}-1-异丁基脲.;5-乙磺酰基-氨基-N-(3-甲酯基丙酰氧基)噻吩-3-甲脒;2-氯-N-(3-甲酯基丙酰氧基)乙脒和[4-(N-(3-甲酯基-丙酰氧基)氨基甲亚胺酰)-3-甲基异噁唑-5-基]氨基甲酸叔丁酯。
实施例48
此实施例说明制备3-[3-(3-叔丁氧基羰基氨基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯的方法。
将3-叔丁氧基羰基氨基-N-(3-甲酯基丙酰氧基)苄脒(8.25g,22.6mmol)在甲苯(120ml)中的悬浮液加入到配备有磁力搅拌器和回流冷凝器的250-ml圆底烧瓶中,内容物加热至回流5小时。然后反应物冷却,产生的溶液真空浓缩。提供定量产率的为黄色固体的3-[3-(3-叔丁氧基羰基氨基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯。m.p.90-91℃;1H NMR(CDCl3)δ(ppm)7.97(s,1H),7.72(d,1H,J=7.6Hz),7.61(d,1H,J=7.6Hz),7.39(m,2H),6.57(bs,1H),3.73(s,3H),3.26(t,2H,J=7.3Hz),2.94(t,2H,J=7.3Hz),1.53(s,9H);m/z=346(M-H)。
1,2-二甲氧基乙烷可取代甲苯。采用这种方法制备的其他噁二唑酯如下。观察到的产率在54%至定量范围。
3-[3-(1-叔丁氧基羰基哌啶-4-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(1-叔丁氧基羰基哌啶-3-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(1-叔丁氧基羰基哌啶-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(1-叔丁氧基羰基吡咯烷-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(2-叔丁氧基羰基氨基噻吩-4-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(2-叔丁氧基羰基氨基噻吩-5-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(3-叔丁氧基羰基氨基-2-甲基-2H-吡唑-4-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(3-叔丁氧基羰基氨基-1-(2-三甲基甲硅烷基)乙氧基甲基-1H-吡唑-4-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(4-叔丁氧基羰基氨基-1-(2-三甲基甲硅烷基)乙氧基甲基-1H-咪唑-5-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(5-叔丁氧基羰基氨基-1-(2-三甲基甲硅烷基)乙氧基甲基-1H-咪唑-4-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(1-甲基-1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(3-三异丙基甲硅烷氧基甲基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(4-三异丙基甲硅烷氧基甲基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-{4-[(5-(2-甲酯基)乙基)-1,2,4-噁二唑-3-基]噻吩-2-基}-1-异丁基脲;3-(2-乙磺酰基氨基噻吩-4-基-1,2,4-噁二唑-5-基)丙酸甲酯;3-(3-氯甲基-1,2,4-噁二唑-5-基)丙酸甲酯和3-[3-(5-叔丁氧基羰基氨基-3-甲基异噁唑-4-基)-1,2,4-噁二唑-5-基]丙酸甲酯。
实施例49
此实施例说明制备3-[3-(4-羟基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯的方法。
配备有磁力搅拌器的100-ml一口圆底烧瓶中投入3-[3-(4-羟基苯基)-1,2,4-噁二唑-5-基]丙酸(7.62g,32.4mmol)和无水甲醇(130ml)。反应混合物冷却至0℃,15分钟内滴加亚硫酰氯(13.3g,112mmol)。取下冰浴,于室温继续搅拌16小时。减压除去溶剂。残余物溶解于乙酸乙酯(60ml),该溶液用水(2×40ml)、10%碳酸氢钠水溶液(2×40ml)和饱和氯化钠溶液(20ml)洗涤。有机层在硫酸钠上干燥,过滤和减压下浓缩。粗产物通过柱层析纯化,提供91%产率的白色固体的标题化合物。m.p.90-92℃;1H NMR(DMSO-d6),δ(ppm)=10.1(s,1H),7.81(d,2H,J=9.6Hz),6.90(d,2H,J=8.6Hz,),3.62(s,3H),3.20(t,2H,J=7.0Hz,),2.91(t,2H,J=7.0Hz);m/z=249(M+H)。
采用这种方法还制备3-[3-(3-羟基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯。产率为83%。
实施例50
此实施例说明制备3-[3-(4-异丙氧基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯的方法。
配备有磁力搅拌器的500-ml一口圆底烧瓶中投入3-[3-(4-羟基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯(768mg,3.09mmol)、碳酸钾(560mg,4.0mmol)和无水DMF(130ml)。反应物于室温搅拌20分钟。一次加入2-溴丙烷(455mg,3.70mmol),持续搅拌18小时。减压除去溶剂,残余物中加入水(20ml)。混合物用1∶1的乙酸乙酯和己烷的混合物萃取(3×20ml)。合并的有机萃取液用水(2×20ml)和饱和氯化钠溶液(20ml)洗涤,硫酸钠上干燥。过滤并真空浓缩,提供92%产率为无色油的标题化合物。1H NMR(CDCl3),(ppm)=7.97(d,2H,J=7.0Hz),6.94(d,2H,J=7.0Hz),4.83(hept,1H,J=6.1Hz),3.73(s,3H),3.25(t,2H,J=7.3Hz),2.94(t,2H,J=7.5Hz),1.36(d,6H,J=6.1Hz);m/z=291(M+H)。
上述方法中,烷基碘可取代烷基溴。
采用这种方法制备的其他4-烷氧基苯基噁二唑-5-基丙酸甲酯如下。观察到的产率在58-98%范围。
3-[3-(3-甲氧基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(4-乙氧基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(3-乙氧基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(4-丙氧基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(3-丙氧基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(3-异丙氧基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯和3-[3-(4-环丙基甲氧基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯。
3-{3-[4-(2,2,2-三氟乙氧基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯和3-{3-[3-(2,2,2-三氟乙氧基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯可以类似的方式,使用2,2,2-三氟乙醇的对-甲苯磺酸酯于100℃制备。
实施例51
此实施例说明制备3-[3-(5-二甲基氨基甲基-1-甲基-1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯的方法。
配备有磁力搅拌器和回流冷凝器的250-ml三口圆底烧瓶中投入3-[3-(1-甲基-1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯(2.14g,9.10mmol)、氢氯化二甲胺(2.20g,27.0mmol),低聚甲醛(0.82g,27.0mmol)和正-丁醇(80ml)。混合物加热至100℃16小时。之后,再加入氢氯化二甲胺(1.10g,13.5mmol)和低聚甲醛(0.41g,13.5mmol),继续加热8小时。反应物冷却至室温,减压除去丁醇。在残余物中加入乙酸乙酯(80ml)和2M碳酸钾水溶液(80ml),两相混合物于室温搅拌15分钟。将两层分离。水层用乙酸乙酯萃取(2×50ml),合并的有机萃取液用饱和氯化钠溶液洗涤(2×50ml),在硫酸钠上干燥,过滤,真空浓缩。产生的残余物通过柱层析纯化,提供71%产率为黄色油的标题化合物。1H NMR(CDCl3),δ(ppm)=6.77(d,1H,J=3.8Hz),6.01(d,1H,J=3.8Hz),3.88(s,3H),3.65(s,3H),3.31(s,2H),3.14(t,2H,J=7.3Hz),2.84(t,2H,J=7.4Hz),2.14(s,6H)。
实施例51
此实施例说明制备3-{3-[1-(2-乙氧基乙基)-1H-吡咯-2-基]-1,2,4-噁二唑-5-基}丙酸甲酯的方法。
配备有磁力搅拌器的50-ml一口圆底烧瓶中投入3-[3-(1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯(700mg,3.16mmol)和无水DMF(10ml)。反应混合物冷却至-40℃,一次加入1M六甲基二硅氮烷钠的THF溶液(3.80ml,3.80mmol)。在此温度下搅拌20分钟后,混合物温热至室温。一次加入1-溴-2-乙氧基乙烷(735mg,4.80mmol),继续搅拌16小时。减压除去溶剂。残余物中加入乙酸乙酯(40ml)和水(30ml)。分离有机层,水层用乙酸乙酯萃取(2×25ml)。合并的有机萃取液用饱和氯化钠溶液洗涤(2×30ml),硫酸钠上干燥,过滤,减压浓缩。产生的残余物通过柱层析纯化,提供61%产率的黄色半固体的标题化合物。1H NMR(CDCl3),(ppm)=6.94(d,1H,J=3.3Hz),6.21(t,1H,J=3.3Hz),4.50(t,2H,J=5.7Hz),3.73(s,3H),3.71(d,2H,J=5.4Hz),3.44(qt,2H,J=7.0Hz),3.22(t,2H,J=7.2Hz),2.91(t,2H,J=7.5Hz),1.14(t,3H,J=7.0Hz)。
上述方法中,氢化钠可取代六甲基二硅氮烷钠。采用这种方法制备的其他N-烷基吡咯酯如下。观察到的产率在72-39%范围。
3-[3-(1-乙基-1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯和3-[3-甲基(1-三异丙基甲硅烷氧基甲基-1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯。
实施例52
此实施例说明制备3-{3-[4-(羟基甲基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯的方法。
在配备有磁力搅拌器的500-ml一口圆底烧瓶中,将3-{3-[4-(三异丙基甲硅烷氧基甲基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯(17.0g,40.6mmol)溶解于四氢呋喃(250ml)。加入氟化四丁基铵三水合物(30.5g,117mmol),反应混合物于室温搅拌17小时。混合物减压蒸发至干,通过硅胶柱层析纯化,提供75%产率为黄色固体的标题化合物。m.p.56-57℃;1H NMR(DMSO-d6)7.94(d,2H,J=8.0Hz),7.49(d,2H,J=8.0Hz),5.35(t,1H,J=5.7Hz),4.57(d,2H,J=5.7Hz),2.93(t,2H,J=6.9Hz),3.62(s,3H),3.24(t,2H,J=7.1Hz);m/z=245(M-OH)。
采用这种方法还制备了3-{3-[3-(羟基甲基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯。产率为66%。
实施例53
此实施例说明制备3-{3-[4-(甲氧基甲基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯的方法。
配备有磁力搅拌器的25-ml一口圆底烧瓶中投入3-{3-[4-(羟基甲基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯(262mg,1.00mmol)、二甲基甲酰胺(2ml)、氧化银(464mg,2.00mmol)和碘甲烷(284mg,2.00mmol)。反应混合物于室温搅拌17小时,然后用甲醇稀释(2ml),通过硅藻土521垫过滤。滤液减压下蒸发至干,提供油状物,可通过硅胶柱层析纯化。提供42%产率为白色固体的标题化合物。m.p.38-39℃;1H NMR(CDCl3)8.04(d,2H,J=8.3Hz),7.44(d,2H,J=8.1Hz),4.52(s,2H),3.74(s,3H),3.42(s,3H),3.27(t,2H,J=7.4Hz),2.95(t,2H,J=7.4Hz);m/z=245(M-OCH3)。
采用这种方法还制备3-{3-[4-(乙氧基甲基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯和3-{3-[3-(乙氧基甲基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯。产率分别为22和23%。
实施例54
此实施例说明制备3-{3-[4-(二氟甲氧基甲基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯的方法。
配备有磁力搅拌器和数字温度计的100-ml一口圆底烧瓶中投入3-{3-[4-(羟基甲基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯(2.50g,9.54mmol)、乙腈(20ml)、2-(氟磺酰基)二氟乙酸(2.04g,11.4mmol)和4分子筛(2g)。混合物在氮气氛中于室温搅拌1小时。反应混合物冷却至0℃,滴加三乙胺(3.45g,34.2mmol)。于0-5℃继续搅拌2小时。温热至室温后,将混合物注入水中(20ml),用二氯甲烷萃取(3×20ml)。有机萃取液合并,用水洗涤,在硫酸钠上干燥,减压蒸发至干。产生的物质通过硅胶柱层析纯化,提供10%产率为白色固体的标题化合物。m.p.34-35℃;1H NMR(CDCl3)8.08(d,2H,J=8.3Hz),7.47(d,2H,J=8.2Hz),6.34(t,1H,J=74.0Hz),4.95(s,2H),3.73(s,3H),3.27(t,2H,J=7.4Hz),2.95(t,2H,J=7.3Hz);m/z=313(M+H)。
采用这种方法还制备了3-{3-[3-(二氟甲氧基甲基)苯基]-1,2,4-噁二唑-5-基}丙酸甲酯。产率为4%。
实施例55
此实施例说明制备3-[3-(1-甲基哌啶-4-基)-1,2,4-噁二唑-5-基]丙酸甲酯的方法。
配备有磁力搅拌器的25-ml圆底烧瓶中投入4-[5-(2-甲氧基羰基乙基)-1,2,4-噁二唑-3-基]哌啶-1-羧酸叔丁酯(620mg,1.83mmol)和4M氯化氢的1,4-二噁烷溶液(6ml)。室温搅拌1.5小时,将反应混合物倒入10%碳酸钾水溶液(50ml)。产生的混合物用二氯甲烷萃取(3×30ml)。合并的有机相用水洗涤,硫酸钠上干燥并过滤。滤液蒸发至干,得到淡黄色油,将其直接加入到配备有磁力搅拌器的50-ml圆底烧瓶中,该烧瓶中含有四氟硼酸甲基三甲氧基磷鎓(402mg,1.78mmol)的二氯甲烷(8ml)溶液。产生的反应混合物于室温搅拌16小时,然后加甲醇(5ml)终止反应。再搅拌30分钟后,反应混合物分配在二氯甲烷(20ml)和10%碳酸钾水溶液(20ml)之间。合并的有机相用硫酸钠干燥并过滤。滤液浓缩,随后通过柱层析,得到35%产率为淡黄色油的标题化合物;1H NMR(DMSO-d6)δ(ppm)3.71(s,3H),3.18(t,2H,J=7.2Hz),2.67-2.93(m,5H),2.30(s,3H),1.82-2.12(m,6H);m/z=254(M+H)。
采用这种方法制备的其他噁二唑酯如下。观察到的产率在38-56%范围。
3-[3-(1-甲基哌啶-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(1-甲基哌啶-3-基)-1,2,4-噁二唑-5-基]丙酸甲酯和3-[3-(1-甲基吡咯烷-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯。
实施例56
此实施例说明制备3-[3-(5-苄氧基羰基氨基噻吩-2-基)-1,2,4-噁二唑-5-基]丙酸甲酯的方法。
配备有磁力搅拌器的50-ml圆底烧瓶中投入3-[3-(5-叔丁氧基羰基氨基噻吩-2-基)-[1,2,4]噁二唑-5-基]丙酸甲酯(0.20g,0.57mmol)、三乙胺(0.47g,4.52mmol),DMAP(0.061g,0.50mmol)和THF(6ml)。室温下加入氯甲酸苄酯(0.39g,2.28mmol)在THF(1ml)中的溶液。搅拌3小时后,反应混合物分配在饱和氯化铵水溶液(20ml)和二氯甲烷(20ml)之间。分离出有机相,在硫酸钠上干燥,过滤。滤液浓缩至干,产生的物质溶解于二氯甲烷(4ml)和三氟乙酸(2ml)的混合物中。室温搅拌0.5小时后,在反应混合物中加入甲苯(5ml)。浓缩并通过柱层析纯化,得到83%产率为淡黄色固体的标题化合物;m.p.146-148℃;1H NMR(DMSO-d6)δ(ppm)11.28(s,1H),7.49(d,1H,J=4.0Hz),7.33-7.45(m,5H),6.62(d,1H,J=4.0Hz),5.22(s,2H),3.62(s,3H),3.19(t,2H,J=7.0Hz),2.90(t,2H,J=6.9Hz)。
采用这种方法制备的其他丙酸甲酯如下。观察到的产率在93-100%范围。
3-[3-(5-乙氧基羰基氨基噻吩-3-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-[3-(5-丙酰基氨基噻吩-3-基)-1,2,4-噁二唑-5-基]丙酸甲酯;3-{3-[5-(3-甲基丁酰基氨基)噻吩-3-基]-1,2,4-噁二唑-5-基}丙酸甲酯和3-[3-(5-苄氧基羰基氨基噻吩-3-基)-1,2,4-噁二唑-5-基]丙酸甲酯。
实施例57
此实施例说明制备3-[3-(3-叔丁氧基羰基氨基苯基)-1,2,4-噁二唑-5-基]丙酸的方法。
100-ml圆底烧瓶中投入3-[3-(3-叔丁氧基羰基氨基苯基)-1,2,4-噁二唑-5-基]丙酸甲酯(4.04g,11.6mmol)、氢氧化锂(1.39g,58.2mmol)、甲醇(15ml)、水(15ml)和THF(15ml)。产生的溶液室温搅拌2小时。减压除去溶剂,残余物溶解于水中(60ml)。产生的溶液冷却至0℃,通过加入2N盐酸,酸化至pH5。混合物用乙酸乙酯萃取(4×50ml),合并的萃取液在硫酸钠上干燥。过滤和减压浓缩,提供83%产率为白色固体的3-[3-(3-叔丁氧基羰基氨基苯基)-1,2,4-噁二唑-5-基]丙酸。m.p.143-144℃;1HNMR(DMSO-d6)δ(ppm)12.42(bs,1H),9.60(s,1H),8.24(s,1H),7.57(m,2H),7.42(t,1H,J=7.9Hz),3.26(t,2H,J=6.9Hz),2.84(t,2H,J=6.9Hz),1.49(s,9H);m/z=332(M-H)。
采用这种方法制备的其他噁二唑基丙酸如下。观察到的产率在55-99%范围。
3-[3-(1-叔丁氧基羰基哌啶-4-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(1-叔丁氧基羰基哌啶-3-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(1-叔丁氧基羰基哌啶-2-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(1-叔丁氧基羰基吡咯烷-2-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(2-丙酰基氨基噻吩-4-基)-1,2,4-噁二唑-5-基]丙酸;3-{3-[2-(3-甲基丁酰基氨基)噻吩-4-基]-1,2,4-噁二唑-5-基}丙酸;3-[3-(2-苄氧基羰基氨基噻吩-5-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(2-苄氧基羰基氨基噻吩-4-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(3-叔丁氧基羰基氨基-2-甲基-2H-吡唑-4-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(3-叔丁氧基羰基氨基-1-(2-三甲基甲硅烷基)乙氧基-甲基-1H-吡唑-4-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(4-叔丁氧基羰基氨基-1-(2-三甲基甲硅烷基)乙氧基甲基-1H-咪唑-5-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(5-叔丁氧基羰基氨基-1-(2-三甲基甲硅烷基)乙氧基甲基-1H-咪唑-4-基)-1,2,4-噁二唑-5-基]丙酸;3-[(3-甲基-1-三异丙基甲硅烷氧基甲基-1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸;3-{3-[1-(2-乙氧基乙基)-1H-吡咯-2-基]-1,2,4-噁二唑-5-基}丙酸;3-[3-(3-二氟甲氧基甲基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(4-二氟甲氧基甲基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(4-乙氧基甲基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(3-乙氧基甲基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(4-甲氧基甲基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(3-甲氧基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(4-异丙氧基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(3-异丙氧基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(4-丙氧基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(3-丙氧基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(3-乙氧基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(4-乙氧基苯基)-1,2,4-噁二唑-5-基]丙酸;3-{3-[4-(2,2,2-三氟乙氧基)苯基]-1,2,4-噁二唑-5-基}丙酸;3-{3-[3-(2,2,2-三氟乙氧基)苯基]-1,2,4-噁二唑-5-基}丙酸;3-[3-(4-环丙基甲氧基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(1-乙基-1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(5-乙氧基羰基氨基噻吩-3-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(2-叔丁氧基羰基氨基噻吩-5-基)-1,2,4-噁二唑-5-基]丙酸;3-{4-[(5-(2-羧基)乙基)-1,2,4-噁二唑-3-基]噻吩-2-基}-1-异丁基脲;3-(2-乙磺酰基氨基噻吩-4-基-1,2,4-噁二唑-5-基)丙酸;3-(3-氯甲基-1,2,4-噁二唑-5-基)丙酸;3-[3-(5-叔丁氧基羰基氨基-3-甲基异噁唑-4-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(5-二甲基氨基甲基-1-甲基-1H-吡咯-2-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(1-甲基哌啶-2-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(1-甲基哌啶-3-基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(1-甲基吡咯烷-2-基)-1,2,4-噁二唑-5-基]丙酸和3-[3-(1-甲基哌啶-4-基)-1,2,4-噁二唑-5-基]丙酸。
实施例58
此实施例说明制备3-[3-(2,4-二羟基苯基)-1,2,4-噁二唑-5-基]丙酸的方法。
配备有磁力搅拌器和数字温度计的50-ml一口圆底烧瓶中投入3-[3-(2,4-二甲氧基苯基)-1,2,4-噁二唑-5-基]丙酸(835mg,3.00mmol),,该烧瓶用氮气清洗,然后加入无水二氯甲烷(10ml)。产生的溶液冷却至-70℃后,加入1M三溴化硼的二氯甲烷溶液(9.0ml,9.0mmol),反应混合物缓慢温热至室温。室温下再搅拌1小时后,混合物加水停止反应(50ml),加热至回流。产生的悬浮液然后冷却至室温,过滤固体。滤饼用水研制(20ml),以除去硼酸,于45℃减压下干燥过夜,提供71%产率为棕色固体的标题化合物。m.p.177-179℃;1H NMR(DMSO-d6)(ppm)12.40(bs,1H),9.95(s,1H),9.75(s,1H),7.65(d,1H,J=9.2Hz),6.38(m,2H),3.16(t,2H,J=7.0Hz),2.82(t,2H,J=6.8Hz);m/z=249(M-H)。
采用这种方法制备的其他取代的丙酸如下。观察到的产率在29-100%范围。
3-[3-(2,3-二羟基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(3,5-二羟基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(2,5-二羟基苯基)-1,2,4-噁二唑-5-基]丙酸;3-[3-(2,6-二羟基苯基)-1,2,4-噁二唑-5-基]丙酸和3-[3-(2-羟基-6-甲氧基-4-甲基吡啶-3-基)-1,2,4-噁二唑-5-基]丙酸。
实施例59
此实施例说明制备3-[3-(3,4-二羟基苯基)-1,2,4-噁二唑-5-基]丙酸的方法。
配备有磁力搅拌器的500-ml一口圆底烧瓶中投入3-[3-(3,4-亚甲基二氧苯基-1,2,4-噁二唑-5-基)]丙酸(2.74g,10.4mmol),该烧瓶用氮气清洗,然后加入无水二氯甲烷(110ml)和1M三氯化硼的二氯甲烷溶液(31ml,31mmol)。室温下2小时后,反应混合物加水中止反应(20ml),加热至回流。反应混合物冷却至室温,真空蒸发二氯甲烷。产生的水性悬浮液过滤;滤饼用水洗涤(20ml),然后减压下于45℃干燥6小时。得到71%产率为棕色固体的标题化合物。m.p.151-155℃;1H NMR(DMSO-d6)δ(ppm)12.3(bs,1H),9.4(bs,2H),7.38(s,1H),7.29(d,1H,J=8.2Hz),6.85(d,1H,J=8.2Hz),3.14(t,2H,J=6.8Hz),2.81(t,2H,J=6.8Hz);m/z=149(M-H)。
实施例60
此实施例说明制备3-{3-[2-(4-甲基哌嗪-1-基)-吡啶-3-基]-1,2,4-噁二唑-5-基}丙酸的方法。
配备有磁力搅拌器的25-ml一口圆底烧瓶中投入3-[3-(2-氯吡啶-3-基)-1,2,4-噁二唑-5-基]丙酸(500mg,2.00mmol)、1-甲基哌嗪(220mg,2.20mmol)、二甲基甲酰胺(7ml)和碳酸钾(690mg,5.00mmol)。该烧瓶用氮气清洗,于100℃加热27小时。反应混合物真空蒸发至干,产生的固体通过硅胶柱层析纯化,提供59%产率为棕色油的标题化合物。1H NMR(CDCl3)δ(ppm)8.22(dd,1H,J=4.6,1.6Hz),7.93(dd,1H,dd,J=7.6,1.7Hz),6.76(dd,1H,J=7.4,4.8Hz),3.20-3.30(m,4H),3.04(t,2H,J=7.3 Hz),2.48(t,2H,J=6.7),2.35-2.45(m,4H),2.21(s,3H);m/z=316(M-H)。
实施例61
此实施例说明制备3-[3-(吗啉-4-基甲基)-1,2,4-噁二唑-5-基]丙酸钠的方法。
配备有磁力搅拌器的25-ml一口圆底烧瓶中投入3-(3-氯甲基-1,2,4-噁二唑-5-基)丙酸(1.48g,7.77mmol)、二甲基甲酰胺(4ml)和吗啉(2.0g,22.9mmol)。反应混合物于室温搅拌4小时。产生的悬浮液过滤,滤饼用乙醚洗涤并干燥,提供2.52g粗产物。该产物一部分(1.49g)溶解于甲醇(6ml),用氢氧化钠处理(399mg,9.98mmol)。1小时后,反应混合物真空浓缩至干,然后用乙酸乙酯研制。沉淀物过滤和减压干燥,提供68%产率的3-[3-(吗啉-4-基甲基)-1,2,4-噁二唑-5-基]丙酸钠,它被少量乙酸钠污染,为白色固体。该物质可直接使用。m.p.155-161℃(dec.);1H NMR (DMSO-d6)δ(ppm)3.56(m,6H),2.98(t,2H,J=7.2Hz),2.46(t,4H,J=4.3Hz),2.36(t,2H,J=7.2Hz);m/z=263(M-Na)。
实施例62
此实施例说明制备N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-p-甲苯基-[1,2,4]噁二唑-5-基)-丙酰胺的盐酸盐的方法。
配备有磁力搅拌器的10-ml圆底烧瓶用氮气清洗,投入4-(3-氨基丙基氨基)-2H-2,3-二氮杂萘-1-酮(152mg,0.65mmol)、3-{3-[4-甲基苯基]-1,2,4-噁二唑-5-基}丙酸(163mg,0.65mmol)、无水DMF(4ml),氢氯化1-(3-二甲基氨基-丙基)-3-乙基碳化二亚胺(150mg,0.78mmol),1-羟基苯并三唑(84mg,0.78mmol)和二异丙基乙胺(85mg,0.78mmol)。室温下搅拌22小时后,混合物过滤,滤液减压浓缩至干。残余物通过柱层析纯化,通过用1当量的1M氯化氢的二噁烷溶液处理该游离碱的甲醇(2ml)悬浮液,转化为相应的盐酸盐。产生的溶液减压下浓缩,并在高真空下干燥,得到54%产率为白色固体的标题化合物。m.p.194-196℃;1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),8.21(d,1H,J=7.7Hz),8.10(m,1H),7.80-7.91(m,4H),7.30(d,2H,J=8.0Hz),3.13-3.24(m,6H),2.69(t,2H,J=7.2Hz),2.33(s,3H),1.71-1.80(m,2H);m/z=433(M+H)。
1M氯化氢的二乙醚溶液可取代1M氯化氢的二噁烷溶液。采用这种方法制备的实例,包括观察的产率和分析数据列于下面。
3-[3-(4-氯-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,84%,白色固体;m.p.198-200℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.20(d,1H,J=6.9Hz),8.10(m,2H),7.96(d,2H,J=8.4Hz),7.85(m,2H),7.59(d,2H,J=8.5Hz),3.10-3.30(m,7H),2.70(t,2H,J=7.2Hz),1.76(m,2H);m/z=453(M+H);
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-苯基-[1,2,4]噁二唑-5-基)-丙酰胺盐酸盐,62%,白色固体;m.p.179-181℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.20(d,1H,J=7.5Hz),8.10(m,2H),7.97(m,2H),7.84(m,2H),7.53(m,3H),3.10-3.30(m,7H),2.70(t,2H,J=7.2Hz),1.76(m,2H);m/z=419(M+H);
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-p-甲苯基-[1,2,4]噁二唑-5-基)-丙酰胺盐酸盐,53%,白色固体;m.p.194-196℃;1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),8.21(d,1H,J=7.7Hz),8.10(m,1H),7.80-7.91(m,4H),7.30(d,2H,J=8.0Hz),3.13-3.24(m,6H),2.69(t,2H,J=7.2Hz),2.33(s,3H),1.75(m,2H);m/z=433(M+H);
3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-环己基]-丙酰胺盐酸盐,79%,灰白色固体;m.p.155℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.52(s,1H),8.18(m,2H),8.00(d,1H,J=9.0Hz),7.85(m,2H),7.05(d,2H,J=9.0Hz),3.79(s,3H),3.60(m,2H),3.16(m,2H),2.64(t,2H,J=6.9Hz),2.21(d,1H,J=11.1Hz),1.97(d,1H,J=9.3Hz),1.75(d,2H,J=10.3Hz),1.30-1.40(m,5H);m/z=489(M+H);
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂-1-基氨基)-丙基]-3-[3-(4-三氟甲氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酰胺盐酸盐,25%,白色固体;m.p.176-179℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.22(d,1H,J=7.0Hz),8.08-8.10(m,4H),7.88(t,1H,J=7.0Hz),7.80(t,1H,J=7.5Hz),7.51(d,2H,J=8.3Hz),3.13-3.26(m,6H),2.71(t,2H,J=7.1Hz),1.72-1.81(m,2H);m/z=503(M+H);
3-[3-(4-氟-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,30%,白色固体;m.p.284-287℃;1H NMR(DMSO-d6)δ(ppm)8.24(d,1H,J=7.1Hz),7.82-8.05(m,5H),7.30(t,2H,J=8.8Hz),3.16-3.25(m,6H),2.70(t,2H,J=6.9Hz),1.78(m,2H);m/z=437(M+H);
3-[3-(2,3-二氢-苯并呋喃-5-基)-[1,2,4]噁二唑-5-基]-N-[2,2-二甲基-3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨)-丙基]-丙酰胺盐酸盐,82%,白色固体;m.p.115-118℃;1H NMR(CDCl3)δ(ppm)9.28(bs,1H),8.42(m,2H),8.02(m,2H),7.58(m,2H),6.70(d,1H,J=8.2Hz,4.54(t,2H,J=8.7Hz),3.67(m,2H),3.18-3.31(m,8H),1.18(s,6H);m/z=489(M+H);
2-羟基-N-[2-羟基-3-(4-氧代-3,4-二氢-2,3-二氮杂-1-基氨基)-丙基]-4-甲硫基丁酰胺盐酸盐,66%,白色固体;m.p.165-170℃;1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),8.22(dd,1H,J=0.9,7.7Hz),8.11(d,1H,J=8.1Hz),7.91(dt,1H,J=1.2,7.1Hz),7.82(t,1H,J=7.4Hz),7.72(bs,1H),6.58(t,1H,J=5.4Hz),5.70(dd,1H,J=1.9,5.5Hz),5.08(dd,1H,J=3.3,4.9Hz),3.94(m,2H),3.28(m,1H),3.24(t,2H,J=5.6Hz),3.12(m,1H),2.01(s,3H),1.79(m,2H);m/z=367(M+H);
3-(3-苯并[1,3]二氧杂环戊烯-5-基-[1,2,4]噁二唑-5-基)-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,69%,白色固体;m.p.236-242℃;1H NMR(DMSO-d6)δ(ppm)11.53(s,1H),8.21(d,1H,J=7.1Hz),8.03-8.09(m,2H),7.90(t,1H,J=7.0Hz),7.79(t,1H,J=7.4Hz),7.52(d,1H,J=8.1Hz),7.39(s,1H),7.02(d,1H,J=8.1Hz),6.52(t,1H,J=5.2Hz),6.10(s,2H),3.14-3.62(m,6H),2.68(t,2H,J=7.0Hz),1.71-1.80(m,2H);m/z=463(M+H)
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-噻吩-2-基-[1,2,4]噁二唑-5-基)-丙酰胺盐酸盐,83%,褐色固体;m.p.193-196℃;1H NMR(DMSO-d6)δ(ppm)11.57(s,1H),8.20(d,1H,J=7.8Hz),8.06(m,2H),7.68-7.95(m,4H),7.23(m,1H),3.08-3.30(m,7H),2.68(t,2H,J=7.2Hz),1.76(m,2H);m/z=425(M+H);
3-[3-(2,3-二氯-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,79%,灰白色固体;m.p.178-184℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.21(d,1H,J=6.6Hz),8.10(m,2H),7.80-7.91(m,4H),7.51(t,1H,J=8.0Hz),3.08-3.25(m,6H),2.70(t,2H,J=7.0Hz),1.75(m,2H);m/z=487(M+H);
3-[3-(4-甲硫基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,77%,白色固体;m.p.190-191℃;1H NMR(CD3OD)δ(ppm)8.28(m,2H),8.02(m,2H),7.77(d,2H,J=8.5Hz),7.08(d,2H,J=8.4Hz),3.36(m,2H),2.85(t,2H,J=6.4Hz),2.38(m,3H),1.98(m,2H);m/z=465(M+H);
3-[3-(2,3-二氢-苯并呋喃-5-基)-[1,2,4]噁二唑-5-基]-N-[2-羟基-3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,33%,白色固体;m.p.174-177℃;1HNMR(DMSO-d6)δ(ppm)11.55(s,1H),8.21(dd,1H,J=1.3,7.7Hz),8.07(m,2H),7.88(dt,1H,J=1.4,7.3Hz),7.80(m,2H),7.71(dd,1H,J=1.8,8.3Hz),6.85(d,1H,J=8.3Hz),6.46(t,1H,J=5.6Hz),4.99(d,1H,J=5.0Hz),4.59(t,2H,J=8.8Hz),3.84(m,1H),3.09-3.28(m,8H),2.72(t,2H,J=7.3Hz);m/z=477(M+H);
3-[3-(6-甲氧基-吡啶-3-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,49%,桃红色固体;m.p.150℃(dec.);1H NMR(CD3OD)δ(ppm)8.68(d,1H,J=2.2Hz),8.46(d,1H,J=8.1Hz),8.28(m,2H),8.06(m,2H),6.93(d,1H,J=8.8Hz),3.92(s,3H),3.28-3.48(m,6H),2.88(t,2H,J=6.9Hz),2.03(m,2H);m/z=450(M+H);
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂-1-基氨基)-丙基]-3-(3-噻吩-3-基-[1,2,4]噁二唑-5-基)-丙酰胺盐酸盐,64%,白色固体;m.p.195-198℃;1H NMR(DMSO-d6)δ(ppm)11.57(s,1H),8.23(m,2H),8.09(m,2H),7.88(t,1H,J=8.1Hz),7.80(t,1H,J=7.8Hz),7.73(dd,1H,J=5.1,3.0Hz),7.54(dd,1H,J=5.1,1.2Hz),6.56(t,1H,J=5.3Hz),3.10-3.30(m,6H),2.68(t,2H,J=8.7Hz),1.77(m,2H);m/z=425(M+H);
3-{3-[4-(2-二甲基氨基-乙氧基)-苯基]-[1,2,4]噁二唑-5-基}-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,17%,白色固体;m.p.65-67℃;1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),10.10(s,1H),8.21(dd,1H,J=7.8,1.2Hz),8.10(m,2H),7.93(d,2H,J=8.8Hz),7.83(m,2H),7.12(d,2H,J=8.8Hz),4.40(t,2H,J=5.0Hz),3.57(m,2H),3.10-3.30(m,6H),2.87(s,3H),2.86(s,3H),2.69(t,2H,J=7.1Hz),1.78(m,2H);m/z=506(M+H);
3-[3-(4-羟基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(5-氧代-5,6-二氢-吡啶并[2,3-d]哒嗪-8-基氨基)-环己基]-丙酰胺盐酸盐,14%,黄色固体;m.p.74℃(dec.);1H NMR(CD3OD)δ(ppm)9.02(dd,1H,J=1.6,4.6Hz),8.60(dd,1H,J=1.6,8.1Hz),7.77-7.84(m,3H),6.79(m,2H),3.79(m,2H),3.23(m,2H),2.76(t,2H,J=7.0 Hz),2.37(bd,1H,J=11.7Hz),2.11(bd,1H,J=10.8Hz),1.88(m,2H),1.15-1.53(m,4H);m/z=476(M+H);
3-[3-(4-二氟甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,49%,灰白色固体;m.p.189-196℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.30-7.70(m,7H),7.60-7.49(m,3H),3.26-3.13(m,6H),2.70(m,2H),1.76(m,2H);m/z=485(M+H);
3-[3-(4-溴-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,24%,白色固体;m.p.188-195℃;1H NMR(DMSO-d6)δ(ppm)11.57(bs,1H),8.08-8.34(m,3H),7.88-7.95(m,4H),7.78(m,2H),3.14-3.27(m,6H),2.71(m,2H),1.77(t,2H,J=6.8Hz);m/z=497(M+H);
N-[3-(5,8-二氟-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酰胺盐酸盐,14%,淡黄色固体;m.p.174-176℃;1H NMR(DMSO-d6)δ(ppm)11.66(s,1H),8.10(t,1H,J=5.6Hz),7.89(d,2H,J=8.8Hz),7.77(m,1H),7.61(dt,1H,J=3.9,10.4Hz),7.05(d,2H,J=8.8Hz),6.07(bs,1H),3.81(s,3H),3.11-3.22(m,6H),2.69(t,2H,J=7.0Hz),1.70(m,2H);m/z=485(M+H);
3-{3-[3-(2-二甲基氨基-乙氧基)-苯基]-[1,2,4]噁二唑-5-基}-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,32%,白色固体;m.p.68-70℃;1H NMR(DMSO-d6)δ(ppm)11.57(s,1H),10.32(s,1H),8.10(m,3H),7.88(t,1H,J=7.0Hz),7.80(t,1H,J=7.2Hz),7.61(d,1H,J=7.7Hz),7.54(m,1H),7.48(t,1H,J=7.8Hz),7.20(d,1H,J=8.2Hz),4.42(t,2H,J=4.9Hz),3.10-3.26(m,7H),2.86(s,3H),2.84(s,3H),2.70(t,2H,J=7.1Hz),1.75(m,2H);m/z=506(M+H);
3-[3-(4-二甲基氨基甲基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,55%,白色固体;m.p.98℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),11.26(s,1H),8.21-8.26(m,3H),8.03(d,2H,J=7.9Hz),7.69-7.89(m,4H),4.35(d,2H,J=4.6Hz),3.17-3.40(m,6H),2.70-2.76(m,8H),1.78(m,2H);m/z=476(M+H);
3-[3-(3-二甲基氨基甲基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,24%,白色固体;m.p.90℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),10.74(s,1H),7.61-8.18(m,9H),4.38(bs,2H),3.19-3.21(m,6H),2.71(bs,8H),1.77(bs,2H);m/z=476(M+H);
3-[3-(3-羟基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,31%,白色固体;m.p.250-251℃;1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),8.21(d,1H,J=6.6Hz),8.20(bs,2H),7.80-7.90(m,2H),7.29-7.42(m,3H),6.95(m,1H),3.13-3.25(m,6H),2.69(t,2H,J=7.2Hz),1.77(m,2H);m/z=435(M+H);
3-[3-(3,4-二氟-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,55%,灰白色固体;m.p.195-200℃;1H NMR(DMSO-d6)δ(ppm)11.53(s,1H),8.20(d,1H,J=6.7Hz),8.06(m,2H),7.80-7.92(m,4H),7.56-7.60(m,1H),3.15-3.23(m,6H),2.70(t,2H,J=7.1Hz),1.75(m,2H);m/z=455(M+H);
3-[3-(3,4-二羟基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,45%,浅棕色固体;m.p.178-185℃;1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),8.20(d,1H,J=6.6Hz),8.05(m,2H),7.88(t,1H,J=10.6Hz),7.77(t,1H,J=12.3Hz),7.37(d,1H,J=2.0Hz),7.28(dd,1H,J=9.9,8.2Hz),6.84(d,1H,J=8.2Hz),3.24(t,2H,J=7.1Hz),3.11-3.19(m,5H),2.66(t,2H,J=7.3Hz);m/z=451(M+H);
3-[3-(3,5-二羟基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,39%,灰白色固体;m.p.189-195℃;1H NMR(DMSO-d6)δ(ppm)11.52(s,1H),8.22(d,1H,J=9.4Hz),8.19(d,1H,J=1.3Hz),8.08(t,1H,J=6.7Hz),7.88(t,1H,J=7.2Hz),7.82(t,1H,J=7.2Hz),6.96(s,2H),6.37(s,1H),3.13-3.24(m,6H),2.70(t,2H,J=7.3Hz),1.82(m,2H);m/z=451(M+H);
3-[3-(2,3-二羟基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,41%,灰白色固体;m.p.178-182℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.20(d,1H,J=7.1Hz),8.10(d,2H,J=7.5Hz),7.88(t,1H,J=7.4Hz),7.80(t,1H,J=7.4Hz),7.24(d,1H,J=6.4Hz),6.95(d,1H,J=1.2Hz),6.76(t,1H,J=7.9Hz),3.15-3.27(m,6H),2.70(t,2H,J=7.2 Hz),1.74-1.79(m,2H);m/z=451(M+H);
3-[3-(2,5-二羟基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,60%,白色固体;m.p.200-206℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.21(d,1H,J=6.8Hz),8.09(bs,2H),7.88(t,1H,J=7.3Hz),7.82(t,1H,J=3.6Hz),7.22(d,1H,J=1.1Hz),6.84(s,2H),3.13-3.26(m,6H),2.70(t,2H,J=7.2Hz),1.77(m,2H);m/z=451(M+H);
3-[3-(2,4-二羟基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,28%,白色固体;m.p.202℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.57(s,1H),8.10-8.20(m,3H),7.83(m,2H),7.64(d,1H,J=9.3Hz),6.40(m,2H),3.27(m,2H),3.10-3.21(m,6H),2.68(t,2H,J=7.2Hz),1.75(m,2H);m/z=451(M+H);
3-[3-(2,6-二羟基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,57%,白色固体;m.p.170-172℃;1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),10.82(s,1H),10.20(s,1H),8.21(d,1H,J=7.7Hz),7.81-8.15(m,4H),7.41(t,1H,J=8.1Hz),7.05(d,1H,J=8.4Hz),6.68(d,1H,J=7.8Hz),3.25(m,2H),3.16(m,2H),2.72(t,2H,J=6.9Hz),2.46(t,2H,J=7.2Hz),1.71-1.80(m,2H);m/z=451(M+H);
3-[3-(1-甲基-1H-吡咯-2-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,74%,黄色固体;m.p.173-177℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.56(bs,1H),8.10-8.20(m,3H),7.87(m,2H),7.03(t,2.1Hz),6.75(dd,1H,3.8,1.8Hz),6.11(dd,1H,J=3.8,2.7Hz),3.87(s,3H),3.09-3.26(m,6H),2.67(t,2H,J=7.1Hz),1.77(m,2H);m/z=422(M+H);
3-{3-[4-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]噁二唑-5-基}-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂基-1-基氨基)-丙基]-丙酰胺盐酸盐,63%,褐色固体;m.p.114-116℃;1HNMR(CD3OD)δ(ppm)7.84-8.29(m,6H),6.94(d,2H,J=8.9Hz),4.38(t,2H,J=4.5Hz),4.09(d,2H,J=11.7Hz),3.89(t,2H,J=12.6Hz),3.61-3.69(m,4H),3.25-3.39(m,8H),2.84(t,2H,J=6.9Hz),1.90(m,2H);m/z=548(M+H);
3-[3-(6-羟基-吡啶-3-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,41%,褐色固体;m.p.153℃(dec.);1H NMR(DMSO-d6)δ(ppm)8.15-8.23(m,3H),7.97(d,1H,J=2.3Hz),7.84-7.93(m,3H),6.47(d,1H,J=9.6Hz),6.23(bs,1H),5.75(s,1H),3.12-3.29(m,6H),2.68(t,2H,J=7.0Hz),1.77(m,2H);m/z=436(M+H);
3-[3-(2,3-二甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,45%,白色固体;m.p.137-144℃;1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),8.08(t,2H,J=9.0Hz),7.88(t,1H,J=7.4Hz),7.80(t,1H,J=7.2Hz),7.33(dd,1H,J=7.2,2.0Hz),7.18(m,2H),3.85(s,3H),3.75(s,3H),3.13-3.24(m,6H),2.69(t,2H,J=7.2Hz),1.77(m,2H);m/z=479(M+H);
3-[3-(2,4-二甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,58%,白色固体;m.p.120℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.21(d,1H,J=7.5Hz),7.97(m,1H),7.86(m,2H),7.76(d,1H,J=8.7Hz),6.69(d,1H,J=2.3Hz),6.62(dd,1H,J=9.0,2.3Hz),3.84(s,3H),3.81(s,3H),3.10-3.35(m,7H),2.67(t,2H,J=7.2Hz),1.76(m,2H);m/z=479(M+H);
3-[3-(2,5-二甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸,66%,灰白色固体;m.p.198-201℃;1H NMR(DMSO-d6)δ(ppm)11.61(s,1H),8.20(d,1H,J=7.8Hz),8.06(m,2H),7.86(t,1H,J=7.7Hz),7.80(t,1H,J=7.2Hz),7.33(d,1H,J=2.8Hz),7.11(m,2H),3.79(s,3H),3.74(s,3H),3.13-3.26(m,6H),2.68(t,1H,J=7.2Hz),1.76(m,2H);m/z=479(M+H);
3-[3-(2,6-二甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,39%,灰白色固体;m.p.171-176℃;1H NMR(DMSO-d6)δ(ppm)11.71(s,1H),8.20(d,1H,J=1.3Hz),8.11(bs,2H),7.46(t,1H,J=8.4 Hz),6.76(d,2H,J=8.5Hz),3.16-3.25(m,6H),2.65(t,2H,J=7.3Hz),2.51(s,3H),1.76(m,2H);m/z=479(M+H);
3-[3-(2,6-二甲氧基-4-甲基-吡啶-3-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,49%,白色固体;m.p.105℃(dec.);1HNMR(DMSO-d6)δ(ppm)11.55(s,1H),8.21(d,1H,J=7.8Hz),8.05-8.12(m,2H),7.78-7.91(m,2H),6.37(s,1H),3.88(s,3H),3.81(s,3H),3.14-3.23(m,7H),2.66(t,2H,J=7.2Hz),2.07(s,3H),1.75(m,2H);m/z=494(M+H);
3-{3-[1-(2-二甲基氨基-乙基)-1H-吡咯-2-基]-[1,2,4]噁二唑-5-基}-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,77%,白色固体;m.p.110-111℃;1H NMR(CD3OD)δ(ppm)8.31(d,1H,J=7.6Hz),8.00(d,1H,J=7.7Hz),7.85(m,2H),7.03(dd,1H,J=2.6,1.8Hz),6.91(dd,1H,J=3.9,1.7Hz),6.17(dd,1H,J=3.8,2.7Hz),4.81(s,6H),4.70(t,2H,J=7.2Hz),3.53(t,2H,J=6.9Hz),3.28-3.45(m,6H),3.24(t,2H,J=6.6Hz),2.82(t,2H,J=7.2Hz),1.88(m,2H);m/z=479(M+H);
3-[3-(2-羟基-6-甲氧基-4-甲基-吡啶-3-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺的CF3CO2H盐,19%,黄色固体;m.p.86℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),8.21(dd,1H,J=7.8,1.4Hz),8.08(d,1H,J=8.1Hz),8.02(t,1H,J=5.7Hz),7.88(t,1H,J=8.1Hz),7.80(t,1H,J=7.1Hz),6.14(s,1H),3.83(s,3H),3.12-3.26(m,7H),2.66(t,2H,J=7.2Hz),2.07(s,3H),1.76(m,2H);m/z=480(M+H)(该样品通过制备性HPLC纯化,获得为三氟乙酸盐);
3-(3-吗啉-4-基-[1,2,4]噁二唑-5-基)-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺·1.5 CF3COOH盐,11%,白色固体;m.p.80-85℃;1H NMR(CD3OD)δ(ppm)8.33(d,1H,J=6.7Hz),8.03(d,1H,J=7.8Hz),7.91(t,1H,J=7.8Hz),7.84(t,1H,J=8.8Hz),4.50(s,2H),3.88(t,4H,J=4.5Hz),3.22-3.43(m,10H),2.83(t,2H,J=7.0Hz),1.88(m,2H);m/z=442(M+H).元素分析:计算值C,47.06%;H,4.69%;N,16.01%;测定值C,47.02%;H,4.95%;N,16.30%。(该样品通过制备性HPLC纯化,获得为1.5三氟乙酸盐)。
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-哌啶-4-基-[1,2,4]噁二唑-5-基)-丙酰胺盐酸盐,80%,白色固体;m.p.107-109℃;1H NMR(CD3OD)δ(ppm)8.32(dd,1H,J=1.4,8.0Hz),8.13(bs,1H),7.92(m,2H),3.59(m,2H),3.43(t,2H,J=6.4Hz),3.05-3.32(m,7H),2.75-2.89(m,5H),1.85-2.39(m,6H);m/z=440(M+H);
3-[3-(5-二甲基氨基甲基-1-甲基-1H-吡咯-2-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,33%,橙色固体;m.p.87-91(dec.);1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),8.21(d,1H,J=7.7Hz),8.12(m,2H),7.84(m,2H),6.78(d,2H,J=3.8Hz),6.62(t,1H,J=5.2Hz),6.38(bs,1H),3.94(s,3H),3.12-3.32(m,6H),2.67(t,2H,J=7.0Hz),2.54(bs,2H),1.76(t,2H,J=6.9Hz);m/z=479(M+H);
3-{3-[2-(4-甲基-哌嗪-1-基)-吡啶-3-基]-[1,2,4]噁二唑-5-基}-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂基-1-基氨基)-丙基]-丙酰胺盐酸盐,65%,黄色固体;m.p.75℃(dec.);1HNMR(CD3OD)δ(ppm)8.26-8.33(m,3H),7.81-7.97(m,3H),7.06(dd,1H,J=7.6,4.9Hz),3.20-3.80(m,14H),2.92(s,3H),2.85(t,2H,J=6.6Hz),1.85(m,2H);m/z=518(M+H);
3-[3-(1-甲基-哌啶-2-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,59%,黄色固体;m.p.125℃(dec.);1H NMR(CD3OD)δ(ppm)8.33(d,1H,J=7.5Hz),8.03(d,1H,J=7.5Hz),7.88(m,2H),4.49(d,1H,J=8.7 Hz),3.55(d,1H,J=7.2Hz),3.10-3.42(m,7H),2.82(t,2H,J=6.8Hz),2.70(s,3H),2.20-1.60(m,8H);m/z=440(M+H);
3-[3-(1-甲基-吡咯烷-2-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,10%,白色固体;m.p.65-67℃;1H NMR(CD3OD)δ(ppm)8.30(m,2H),7.97(m,2H),3.86(bs,1H),3.49(t,2H,J=6.7Hz),3.30-3.42(m,4H),3.27(t,2H,J=7.0Hz),3.07(s,3H),2.84(t,2H,J=7.0Hz),2.60-2.69(m,1H),2.23-2.46(m,3H),1.95(m,2H);m/z=426(M+H);
3-[3-(1-甲基-哌啶-3-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,20%,黄色固体;m.p.135℃(dec.);1H NMR(CD3OD)δ(ppm)8.33(d,1H,J=7.7Hz),8.03(d,1H,J=7.7Hz),7.80-7.95(m,2H),3.77(d,1H,J=11Hz),3.53(d,1H,J=12Hz),2.95-3.45(m,9H),2.91(s,3H);2.77(t,2H,J=6.6Hz),2.05(d,1H,J=13.4Hz),1.48-2.12(m,5H);m/z=440(M+H);
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-{3-[3-(2,2,2-三氟-乙氧基)-苯基]-[1,2,4]噁二唑-5-基}-丙酰胺盐酸盐,84%,灰白色固体;m.p.152-158℃;1HNMR(DMSO-d6)δ(ppm)11.55(s,1H),8.22(d,1H,J=1.2Hz),8.10(m,2H),8.77(m,2H),7.65(d,1H,J=7.7Hz),7.57(s,1H),7.50(t,1H,J=8.1Hz),7.25(m,1H),4.85(q,2H,J=8.9Hz),3.20(m,6H),2.71(t,2H,J=8.9Hz),1.76(q,2H,J=6.9Hz);m/z=517(M+H);
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-{3-[4-(2,2,2-三氟-乙氧基)-苯基]-[1,2,4]噁二唑-5-基}-丙酰胺盐酸盐,67%,灰白色固体;m.p.192-196℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),8.20(d,1H,J=7.8Hz),8.12(m,2H),7.81-7.92(m,4H),7.19(d,2H,J=8.8Hz),4.83(q,2H,J=8.8Hz),3.13-3.25(m,6H),2.69(t,2H,J=7.0Hz),1.76(t,2H,J=6.8Hz);m/z=517(M+H);
3-[3-(3-氟-4-甲基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,46%,灰白色固体;m.p.185-190℃;1H NMR(DMSO-d6)δ(ppm)11.54(bs,1H),8.22-8.17(m,3H),7.87(m,2H),7.71(d,1H,J=1.3Hz),7.62(d,1H,J=10.3Hz),7.39(t,1H J=7.9Hz),6.98(bs,2H),3.25-3.13(m,6H),2.70(t,2H,J=7.0Hz),2.26(s,3H),1.77(quin.,2H,J=6.9Hz);m/z=451(M+H);
3-[3-(4-异丙氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,87%,灰白色固体;m.p.183-186℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.56(bs,1H),8.21(d,1H,J=7.7Hz),8.10(m,2H),7.81-7.91(m,4H),7.01(d,2H,J=8.8Hz),4.65(hep,1H,J=6.1Hz),3.14-3.27(m,6H),2.68(t,2H,J=7.0Hz),1.77(t,2H,J=6.9Hz),1.27(d,6H,J=6.0Hz);m/z=477(M+H);
3-[3-(4-环丙基甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,97%,灰白色固体;m.p.178-180℃(dec.);1HNMR(DMSO-d6)δ(ppm)11.56(bs,1H),8.14-8.22(m,3H),7.82-7.95(m,4H),7.02(d,2H,J=8.7Hz),3.84(d,2H,J=7.0Hz),3.14-3.83(m,6H),2.69(t,2H,J=7.1Hz),1.77(t,2H,J=6.7Hz),1.23(m,1H),0.57(m,2H),0.33(m,2H);m/z=489(M+H);
3-[3-(3-异丙氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,86%,灰白色固体;m.p.135-141℃;1H NMR(DMSO-d6)δ(ppm)8.30-8.19(m,3H),7.86(m,2H),7.59-7.39(m,3H),7.10(m,1H),4.65(m,1H),3.28-3.16(m,6H),2.71(t,2H,J=7.1Hz),1.78(p,2H,J=6.8Hz),1.27(d,6H,J=6.0Hz);m/z=477(M+H);
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-[3-(5-丙酰基氨基-噻吩-3-基)-[1,2,4]噁二唑-5-基]-丙酰胺盐酸盐,71%,灰白色固体;m.p.112-114℃;1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),11.33(s,1H),8.21(dd,1H,J=1.2,7.8Hz),8.10(m,2H),7.88(t,1H,J=7.5Hz),7.80(t,1H,J=7.7Hz),7.59(d,1H,J=1.4Hz),7.02(d,1H,J=1.6Hz),3.24(t,2H,J=6.9Hz),3.12-3.19(m,4H),2.67(t,2H,J=7.1Hz),2.37(q,2H,J=7.5Hz),1.74-1.81(m,2H),1.10(t,3H,J=7.5Hz);m/z=496(M+H);
3-甲基-N-[4-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-噻吩-2-基]-丁酰胺盐酸盐,66%,白色固体;m.p.137-139℃;1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),11.34(s,1H),8.21(dd,1H,J=1.3,7.7Hz),8.08(m,2H),7.88(t,1H,J=7.7Hz),7.80(t,1H,J=8.0Hz),7.59(d,1H,J=1.5Hz),7.03(d,1H,J=1.6Hz),3.24(t,2H,J=6.7Hz),3.12-3.19(m,4H),2.68(t,2H,J=7.1Hz),2.24(d,2H,J=7.1Hz),2.01-2.15(m,1H),1.77(m,2H),0.93(d,6H,J=6.6Hz);m/z=524(M+H);
3-[3-(4-甲氧基甲基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,73%,白色固体;m.p.183℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.55(s,1H)8.21(d,1H,J=7.5Hz),8.07(m,2H),7.94(d,2H,J=8.1Hz),7.88(t,1H,J=6.0Hz),7.80(t,1H,J=7.8Hz),4.40(d,2H,J=8.1Hz),4.45(s,2H),3.31(s,3H),3.07-3.26(m,6H),2.66(t,2H,J=7.2Hz),1.76(m,2H);m/z=463(M+H);
3-[3-(3-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,62%,灰白色固体;m.p.166-172℃;1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),8.21(d,1H,J=6.5Hz),8.13(bs,2H),7.85(m,2H),7.55(d,1H,J=7.7Hz),7.45(t,2H,J=4.5Hz),7.12(d,1H,J=5.9Hz),3.81(s,3H),3.13-3.25(m,6H),2.71(t,2H,J=7.2Hz),1.77(m,2H);m/z=449(M+H);
3-[3-(3-乙氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氨-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,54%,灰白色固体;m.p.166-171℃;1H NMR(DMSO-d6)δ(ppm)11.55(bs,1H),8.21(d,1H,J=6.4Hz),8.15(bs,1H),7.88(m,2H),7.54(d,1H,J=7.7Hz),7.42(m,2H),7.11(d,1H,J=5.6Hz),4.07(m,2H),3.16-3.22(m,6H),2.71(t,2H,J=7.2Hz),1.77(m,2H),1.33(t,3H,J=7.0Hz);m/z=463(M+H);
3-[3-(3-氯-4-甲基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,49%,黄色固体;m.p.185-187℃;1H NMR(DMSO-d6)δ(ppm)11.53(s,1H),8.20(d,1H,J=7.7Hz),8.07(m,3H),7.80-7.90(m,4H),7.47(d,1H,J=8.1Hz),3.12-3.25(m,7H),2.69(t,2H,J=7.2Hz),2.35(s,3H),1.75(m,2H);m/z=467(M+H);
3-[3-(1-乙基-1H-吡咯-2-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,57%,灰白色固体;m.p.148-150(dec.);1H NMR(DMSO-d6)δ(ppm)11.55(bs,1H),8.21(d,1H,J=7.8Hz),8.12(m,2H),7.81-7.92(m,4H),7.19(d,2H,J=8.8Hz),4.83(q,2H,J=8.8Hz),3.13-3.25(m,6H),2.69(t,2H,J=7.0 Hz),1.76(t,2H,J=6.8Hz);m/z=436(M+H);
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-[3-(3-丙氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酰胺盐酸盐,64%,灰白色固体;m.p.141-149(dec.);1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.22(d,1H,J=1.3Hz),8.09(m,2H),8.7.88(m,2H),7.55-7.40(m,3H),7.10(m,1H),3.97(t,2H,J=6.5Hz),3.24-3.12(m,6H),2.70(t,2H,J=7.2Hz),1.77-1.72(m,4H),0.98(t,3H,J=7.4Hz);m/z=477(M+H);
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-[3-(4-丙氧基-苯基)-[1,2,4]噁二唑-5-基]-丙酰胺盐酸盐,87%,灰白色固体;m.p.193-196℃(dec.),1H NMR(DMSO-d6)δ(ppm)11.56(bs,1H),8.21(d,1H,J=7.7Hz),8.13(m,2H),7.82-7.89(m,4H),7.03(d,2H,J=8.9Hz),3.95(t,2H,J=7.0Hz),3.14-3.25(m,6H),2.69(t,2H,J=7.0Hz),1.72-1.80(m,4H),0.98(t,3H,J=7.44Hz);m/z=477(M+H);
3-[3-(4-乙氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,45%,灰白色固体;m.p.196-199℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.55(bs,1H),8.20(d,1H,J=7.7Hz),8.12(m,2H),7.81-7.89(m,4H),7.02(d,2H,J=8.8Hz),4.02(q,2H,J=7.0Hz),3.14-3.25(m,6H),2.68(t,2H,J=7.0 Hz),1.77(t,2H,J=6.9Hz),1.33(t,2H,J=7.0Hz);m/z=463(M+H);
3-[3-(3-氯-2-氟-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,60%,灰白色固体;m.p.195-198℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.55(bs,1H),8.20(d,1H,J=7.8Hz),8.10(m,2H),7.38-7.94(m,4H),7.38(t,1H,J=7.8Hz),3.13-3.25(m,6H),2.71(t,2H,J=7.0Hz),1.76(t,2H,J=6.8 Hz);m/z=471(M+H);
3-[3-(2-乙基-噻吩-3-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,69%,灰白色固体;m.p.156-160℃;1H NMR(DMSO-d6)δ(ppm)11.57(bs,1H),8.21(d,1H,J=7.8Hz),8.11(m,2H),7.87(m,2H),7.45(d,1H,J=5.3Hz),7.39(d,1H,J=5.3Hz),3.12-3.19(m,6H),2.68(t,2H,J=7.1Hz),1.77(m,2H),1.24(t,3HJ=7.4Hz);m/z=453(M+H);
3-[3-(3-乙氧基甲基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,61%,白色固体;m.p.155-157℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.21(d,1H,J=8.4Hz),8.11(m,2H),7.81-7.93(m,4H),7.49(d,2H,J=5.5Hz),4.51(s,2H),3.40-3.60(m,3H),3.13-3.25(m,6H),2.71(t,2H,J=7.1Hz),1.76(m,2H),1.16(t,3H,J=6.9 Hz);m/z=477(M+H);
3-{3-[1-(2-乙氧基-乙基)-1H-吡咯-2-基]-[1,2,4]噁二唑-5-基}-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,54%,灰白色固体;m.p.139-143℃(dec.);1H NMR(DMSO-d6)δ(ppm)8.18-8.23(m,3H),7.92(m,2H),7.07(m,1H),6.77(m,1H),6.13(m,1H),4.43(t,1H,J=5.6Hz),3.60(t,1H,J=5.6Hz),3.30-3.40(m,4H),3.11-3.18(m,4H),2.67(t,2H,J=7.0Hz),1.78(t,2H,J=6.8Hz),1.02(t,3H,J=7.0Hz);m/z=480(M+H);
3-[3-(3-乙基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,23%,灰白色固体;m.p.168-170℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.21(dd,1H,J=1.3,7.7Hz),8.09-8.11(m,2H),7.76-7.91(m,4H),7.42(m,2H),3.13-3.24(m,6H),2.63-2.73(m,4H),1.77(m,2H),1.19(t,3H,J=7.6Hz);m/z 447(M+H);
3-[3-(5-乙磺酰基氨基-噻吩-3-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,64%,白色固体;m.p.161℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),10.57(s,1H),8.21(dd,1H,J=1.2,7.6Hz),8.10(m,2H),7.78-7.91(m,3H),7.08(d,1H,J=1.6Hz),3.24(t,2H,J=6.5Hz),3.09-3.17(m,6H),2.68(t,2H,J=7.1Hz),1.76(m,2H),1.23(t,3H,J=7.3Hz);m/z=532(M+H);
3-{3-[5-(3-异丁基-脲基)-噻吩-3-基]-[1,2,4]噁二唑-5-基}-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,60%,灰白色固体;m.p.143-145℃;1HNMR(DMSO-d6)δ(ppm)11.57(bs,1H),9.89(s,1H),8.21(dd,1H,J=1.2,7.7Hz),8.10(m,2H),7.85(m,2H),7.43(d,1H,J=1.5Hz),6.77(d,1H,J=1.6Hz),6.57(bs,1H),3.12-3.26(m,6H),2.93(d,2H,J=5.5Hz),2.67(t,2H,J=7.1Hz),1.66-1.81(m,3H),0.86(d,6H,J=6.7Hz);m/z=539(M+H)。
实施例63
此实施例说明制备3-{3-[1-(2-羟基-乙基)-1H-吡咯-2-基]-[1,2,4]噁二唑-5-基}-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐的方法。
配备有磁力搅拌器的50-ml一口圆底烧瓶中投入N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)丙基]-3-{3-[1-(2-三异丙基甲硅烷氧基乙基)-1H-吡咯-2-基]-1,2,4-噁二唑-5-基}丙酰胺(243mg,0.40mmol)和无水THF(25ml)。一次加入1M TBAF的THF溶液(1.2ml,1.2mmol),于室温持续搅拌2小时。反应混合物通过二氧化硅垫过滤,用1∶1二氯甲烷和甲醇的混合物洗脱。减压除去溶剂,产生的固体通过柱层析纯化。产生的物质悬浮于甲醇(5ml),通过用1当量的1M氯化氢的二乙醚溶液处理转化为相应的盐酸盐。产生的溶液减压下浓缩,并在高真空下干燥,提供97%产率为白色固体的标题化合物。m.p.115-119℃(dec.);1H NMR(DMSO-d6),δ(ppm)=11.54(s,1H),8.21(d,1H,J=7.7Hz),8.08(m,2H),7.83(m,2H).7.06(t,2H,J=5.4Hz),6.76(m,1H),6.54(t,1H,J=5.4Hz),6.11(m,1H),4.33(t,2H,J=5.8Hz),3.10-3.41(m,6H),2.66(t,2H,J=7.1Hz),2.23(t,2H,J=7.5Hz),1.63(m,2H);m/z=452(M+H)。
实施例64
此实施例说明制备[3-甲基-4-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-异噁唑-5-基]-氨基甲酸叔丁酯的方法。
配备有磁力搅拌器25-ml圆底烧瓶用氮气清洗,投入4-(3-氨基丙基氨基)-2H-2,3-二氮杂萘-1-酮(451mg,2.07mmol)、3-[3-(5-叔丁氧基羰基氨基-3-甲基异噁唑-4-基)-1,2,4-噁二唑-5-基]丙酸(699mg,2.07mmol)、无水DMF(7ml)、氢氯化1-(3-二甲基氨基-丙基)-3-乙基碳化二亚胺(595mg,3.10mmol)、1-羟基苯并三唑(221mg,2.07mmol)和二异丙基乙胺(320mg,2.48mmol)。室温搅拌17小时,混合物过滤,滤液真空浓缩至干。残余物通过柱层析纯化,提供53%产率为白色固体的标题化合物。m.p.135-142℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),10.27(s,1H),8.22(d,1H,J=1.3Hz),8.07(m,2H),7.85(m,2H),6.54(m,1H),3.24-3.13(m,6H),2.65(t,2H,J=7.2Hz),2.35(s,3H),1.76(m,2H),1.38(s,9H);m/z=539(M+H)。
下面列出采用这种方法使用合适试剂制备的其他化合物,包括观察到的产率和分析数据。
3-[3-(3-硝基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺,81%,黄色固体;m.p.205-208℃;1H NMR(DMSO-d6)δ(ppm)11.50(s,1H),8.65(s,1H),8.37(d,2H,J=6.4Hz),8.19(d,1H,J=6.6Hz),8.07(m,2H),7.76-7.88(m,3H),6.48(t,1H,J=5.3Hz),3.14-3.26(m,6H),2.73(t,2H,J=7.1Hz),1.76(m,2H);m/z=464(M+H)。
3-[3-(2-甲基-噻唑-4-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺,88%,白色固体;m.p.183-187℃;1H NMR(DMSO-d6)δ(ppm)11.59(s,1H),8.22(m,2H),8.09(m,2H),7.85(m,2H),6.58(t,1H,J=5.2Hz),3.30-3.10(m,6H),2.77-2.68(m,5H),1.76(quin.,3H,J=5.2Hz);m/z=440(M+H)。
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-m-甲苯基-[1,2,4]噁二唑-5-基)-丙酰胺,89%,白色固体;m.p.170-178℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.22(d,1H,J=6.7Hz),8.19(bs,1H),7.77-7.91(m,4H),7.40(t,1H,J=7.6Hz),7.33(t,1H,J=11.9Hz),3.13-3.24(m,6H),2.70(t,2H,J=7.2Hz),2.36(s,3H),1.76(m,2H);m/z=433(M+H)。
3-[3-(1,5-二甲基-1H-吡咯-2-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺,81%,褐色固体.m.p.168-170℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.59(s,1H),8.21(dd,1H,J=7.8,1.2Hz),8.06(m,2H),7.81(m,2H),6.65(d,1H,J=3.7Hz),6.53(t,1H,J=5.1Hz),5.91(d,1H,J=3.6Hz),3.76(s,3H),3.08-3.40(m,6H),2.65(t,2H,J=7.2Hz),2.22(s,3H),1.76(m,2H);m/z=436(M+H)。
3-[3-(4-羟基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺,13%,褐色固体;m.p.266-269℃;1H NMR(DMSO-d6)δ(ppm)11.66(s,1H),10.08(s,1H),8.21(d,1H,J=7.7Hz),8.07(m,2H),7.88(t,1H,J=7.5Hz),7.75-7.85(m,3H),6.88(d,2H,J=6.8Hz),6.55(t,1H,J=5.3Hz),3.12-3.29(m,6H),2.68(t,2H,J=7.2Hz),1.76(m,2H);m/z=435(M+H)。
3-[3-(5-硝基-噻吩-3-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺,79%,灰白色固体;m.p.240-245℃;1H NMR(DMSO-d6)δ(ppm)11.52(s,1H),8.56(d,1H,J=1.9Hz),8.31(d,1H,J=1.9Hz),8.07(t,1H,J=4.5Hz),8.06(t,1H,J=4.5Hz),7.85(t,1H,J=5.1Hz),7.79(t,1H,J=6.9Hz),6.49(t,1H,J=5.3Hz),3.12-3.24(m,6H),2.67(t,2H,J=7.2Hz),1.75(m,2H);m/z=470(M+H)。
3-[3-(4-甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(8-硝基-4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺,45%,黄色固体;m.p.171-173℃;1H NMR(DMSO-d6)δ(ppm)12.17(s,1H),8.49(dd,1H,J=1.3,8.0Hz),8.28(dd,1H,J=1.3,7.8Hz),7.88-8.03(m,4H),7.05(m,2H),4.92(t,1H,J=5.1Hz),3.80(s,3H),3.05-3.19(m,6H),2.67(t,2H,J=7.1Hz),1.65(m,2H);m/z=494(M+H)。
3-[3-(3,5-二甲氧基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺,72%,灰白色固体;m.p.189-197℃;1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),8.19(d,1H,J=7.6Hz),8.05(m,2H),7.85(t,1H,J=1.4Hz),7.79(t,1H,J=7.6Hz),7.08(d,2H,J=2.3Hz),6.67(t,1H,J=2.3Hz),6.55(t,1H,J=5.3Hz),3.79(s,6H),3.13-3.26(m,6H),2.69(t,2H,J=7.2Hz),1.76(m,2H);m/z=479(M+H)。
[4-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-噻吩-2-基]-氨基甲酸叔丁酯,55%,灰白色固体;m.p.112-118℃;1H NMR(DMSO-d6)δ(ppm)10.63(s,1H),11.53(s,1H),8.21(dd,1H,J=1.4,1.4Hz),8.08(d,1H,J=7.8Hz),8.02(t,1H,J=5.6Hz),7.87(t,1H,J=7.3Hz),7.79(t,1H,J=7.2Hz),7.55(d,1H,J=1.6Hz),6.90(d,1H,J=1.6Hz),6.53(t,1H,J=5.2Hz),3.11-3.30(m,6H),2.67(t,2H,J=7.3Hz),1.74(m,2H),1.49(s,1H);m/z=540(M+H)。
[2-甲硫基-5-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-噻唑-4-基]-氨基甲酸叔丁酯,29%,白色固体;m.p.144-146℃;1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),9.41(s,1H),8.21(d,1H,J=7.7Hz),8.08(d,1H,J=8.0Hz),8.03(t,1H,J=5.5Hz),7.88(t,1H,J=7.3Hz),7.80(t,1H,J=7.7Hz),6.53(t,1H,J=5.3Hz),3.11-3.26(m,6H),2.71(s,3H),2.65(t,2H,J=7.1Hz),1.77(m,2H),1.38(s,9H);m/z 587(M+H)。
4-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-哌啶-1-羧酸叔丁酯,90%,白色固体;m.p.86-88℃;1H NMR(CD3OD)δ(ppm)8.33(dd,1H,J=1.5,7.6Hz),8.02(dd,1H,J=0.8,7.4Hz),7.90(dt,1H,J=1.5,7.3Hz),7.82(dt,1H,J=1.3,7.8Hz),4.03(t,1H,J=3.3Hz),3.99(t,1H,J=3.1Hz),3.29(t,2H,J=6.7Hz),3.32(m,2H),3.18(t,2H,J=7.0Hz),2.89-3.00(m,3H),2.75(t,2H,J=7.0Hz),1.81-1.95(m,4H),1.64(m,2H),1.44(s,9H);m/z 526(M+H)。
2-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-哌啶-1-羟酸叔丁酯,91%,黄色固体;m.p.70-72℃;1H NMR(CD3OD)δ(ppm)8.33(d,1H,J=7.7Hz),7.80-8.04(m,3H),5.48(s,1H),5.37(d,1H,J=4.2Hz),3.94(d,1H,J=13.2Hz),3.39(t,2H,J=6.7Hz),3.20(t,2H,J=6.9Hz),2.93(m,2H),2.75(t,2H,J=7.2Hz),2.20(d,1H,J=13.5Hz),1.75-1.90(m,3H),1.58(d,2H,J=12.8Hz),1.20-1.55(m,11H);m/z=526(M+H)。
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-{3-[1-(2-三异丙基甲硅烷氧基-乙基)-1H-吡咯-2-基]-[1,2,4]噁二唑-5-基}-丙酰胺,77%,灰白色固体;m.p.137-145℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.20(d,1H,J=7.7Hz),8.07(m,2H),7.85(m,2H),7.05(m,1H),6.76(m,1H),6.55(m,1H),6.12(m,1H),4.41(t,2H,J=5.4Hz),3.88(t,1H,J=5.30Hz),3.09-3.24(m,6H),2.65(t,2H,J=7.2Hz),1.76(t,2H,J=7.1Hz),0.88-0.94(m,21H);m/z=608(M+H)。
2-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-吡咯烷-1-羧酸叔丁酯,80%,白色固体;m.p.82-84℃;1H NMR(CDCl3)δ(ppm)10.25(bs,1H),8.43(d,1H,J=7.6Hz),7.73-7.83(m,3H),6.74(t,1H,J=6.1Hz),5.65(bs,1H),4.97(m,1H),3.22-3.57(m,9H),2.75(m,2H),1.82-2.23(m,5H),1.28-1.44(m,9H);m/z=512(M+H)。
3-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-哌啶-1-羧酯叔丁酯,98%,白色固体;m.p.95℃(dec.);1H NMR(CD3OD)δ(ppm)8.32(dd,1H,J=7.8,1.4Hz),8.02(d,1H,J=7.8Hz),7.80-7.93(m,2H),4.11(m,1H),3.85(d,1H,J=12.3Hz),3.39(t,2H,J=6.6Hz),3.25-3.35(m,2H),3.19(t,2H,J=7.1Hz),2.80-3.10(m,2H),2.75(t,2H,J=6.9Hz),2.00-2.15(m,1H),1.61-1.91(m,4H),1.35-1.60(m,11H);m/z=526=(M+H)。
[2-甲基-4-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-2H-吡唑-3-基]-氨基甲酸叔丁酯,90%,白色固体;m.p.106-108℃;1H NMR(CD3OD)δ(ppm)8.32(dt,1H,J=0.8,7.9Hz),8.00(d,1H,J=7.8Hz),7.79-7.91(m,3H),3.73(s,3H),3.34-3.39(m,4H),3.23(t,2H,J=7.0Hz),2.79(t,2H,J=7.0Hz),1.85(m,2H),1.46(s,9H);m/z 538=(M+H)。
[5-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-噻吩-2-基]-氨基甲酸叔丁酯,81%,灰白色固体;m.p.177℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),10.86(s,1H),8.20(d,1H,J=6.6Hz),8.07(m,2H),7.88(t,1H,J=7.3Hz),7.79(t,1H,J=7.4Hz),7.44(d,1H,J=4.0Hz),6.55(m,2H),3.10-3.24(m,7H),2.66(t,2H,J=7.4Hz),1.76(m,2H),1.48(s,9H);m/z=540(M+H)。
[4-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-噻吩-2-基]-氨基甲酸苄酯,74%,白色固体;m.p.138-140℃;1HNMR(DMSO-d6)δ(ppm)11.56(s,1H),11.03(s,1H),8.20(d,1H,J=7.8Hz),8.07(m,2H),7.88(t,1H,J=7.2Hz),7.79(t,1H,J=7.4Hz),7.61(s,1H),7.35-7.45(m,5H),6.93(d,1H,J=1.4Hz),6.55(t,1H,J=5.1Hz),5.20(s,2H),3.12-3.27(m,6H),2.67(t,2H,J=7.0Hz),1.76(m,2H);m/z 574=(M+H)。
[5-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-噻吩-2-基]-氨基甲酸苄酯,65%,白色固体;m.p.158-160℃;1HNMR(DMSO-d6)δ(ppm)11.55(s,1H),11.25(s,1H),8.20(d,1H,J=6.6Hz),8.03-8.10(m,2H),7.88(t,1H,J=7.2Hz),7.79(t,1H,J=7.4Hz),7.34-7.48(m,6H),6.59(d,1H,J=4.0Hz),6.54(t,1H,J=5.2Hz),5.21(s,2H),3.10-3.27(m,6H),2.67(t,2H,J=7.2Hz),1.76(m,2H);m/z=574(M+H)。
3-[3-(4-二氟甲氧基甲基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺,88%,白色固体;m.p.193-195℃;1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),8.20(s,1H,J=6.3Hz),8.04(s,1H),8.07(d,1H,J=7.2Hz),7.98(d,1H,J=8.4Hz),7.79(t,1H,J=6.0Hz),7.88(t,1H,J=6.0Hz),7.51(d,2H,J=8.4Hz),6.82(t,1H,J=75.0Hz),6.53(t,1H,J=5.4Hz),4.96(s,2H),3.10-3.26(m,6H),2.70(t,2H,J=7.2Hz),1.76(m,2H);m/z=499(M+H)。
[4-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-噻吩-2-基]-氨基甲酸乙酯,87%,白色固体;m.p.184-186℃;1HNMR(DMSO-d6)δ(ppm)11.55(s,1H),10.87(s,1H),8.21(dd,1H,J=1.2,7.7Hz),8.02-8.10(m,2H),7.88(dt,1H,J=1.4,7.4Hz),7.80(t,1H,J=7.2Hz),7.59(d,1H,J=1.6Hz),6.93(d,1H,J=1.7Hz),6.55(t,1H,J=5.1Hz),4.17(q,2H,J=7.1Hz),3.12-3.27(m,6H),2.67(t,2H,J=7.1Hz),1.78(m,2H),1.26(t,3H,J=7.1Hz);m/z=512(M+H)。
3-[3-(3-二氟甲氧基甲基-苯基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺,31%,白色固体;m.p.155-157℃;1H NMR(DMSO-d6)δ(ppm)11.54(s,1H),7.77-8.22(m,7H),7.62(m,2H),6.83(t,1H,J=75.4Hz),6.53(t,1H,J=8.2Hz),5.00(s,2H),3.10-3.25(m,6H),2.71(t,2H,J=7.3Hz),1.76(m,2H);m/z=499(M+H)。
[4-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-1-(2-三甲基甲硅烷基-乙氧基甲基)-1H-吡唑-3-基]-氨基甲酸叔丁酯,73%,白色固体;m.p.102-105℃;1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),8.88(s,1H),8.84(s,1H),8.20(d,1H,J=7.8Hz),8.09(d,1H,J=8.0Hz),8.03(m,2H),7.78-7.90(m,4H),6.55(t,1H,J=5.4Hz),5.36(s,2H),3.55(m,2H),3.11-3.28(m,6H),2.65(t,2H,J=7.0Hz),1.79(t,2H,J=6.9Hz),1.33(s,9H),0.81-0.87(m,2H),-0.03(s,9H);m/z=654(M+H)。
[3-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基氨基甲酰基]-乙基}-[1,2,4]噁二唑-3-基)-苯基]-氨基甲酸叔丁酯,85%,白色固体;m.p.199-202℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.59(s,1H),9.62(s,1H),8.27(s,1H),8.20(d,1H,J=7.7Hz),8.09(m,2H),7.85(m,2H),7.56(t,2H,J=7.8Hz),7.39(t,2H,J=7.9Hz),6.57(t,1H,J=5.2Hz),3.14-3.30(m,6H),2.71(t,2H,J=7.5Hz),1.78(t,2H,J=6.9Hz),1.49(s,9H);m/z=534(M+H)。
N-[3-(4-氧代-3,4-二氢二氮杂萘-1-基氨基)丙基]-3-(3-氯甲基-1,2,4-噁二唑-5-基)丙酰胺,32%黄色油,1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),8.20(d,1H,J=8.4Hz),8.06(m,2H),7.90(t,1H,J=7.1Hz),7.80(t,1H,J=7.1Hz),6.55(t,1H,J=5.4Hz),5.77(s,2H),3.12-3.26(m,6H),2.61(t,2H,J=7.2Hz),1.76(m,2H)。
实施例65
此实施例说明制备4-(N,N′-二环己基-氨基甲亚胺酰氧基)-4-氧代-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丁酰胺的方法。
配备有磁力搅拌器的3-ml反应瓶(vial)中投入N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)丙基]-3-(3-氯甲基-1,2,4-噁二唑-5-基)丙酰胺(300mg,0.77mol),用氮气清洗。加入无水二甲基甲酰胺(1ml)和吡咯烷(170mg,2.40mmol),反应混合物室温下搅拌15小时。产物然后通过将反应混合物直接加到制备性HPLC柱(25cm×2.18cm,Luna 5mm,C18(2)柱)上进行纯化,用83%的0.2%三氟乙酸水溶液和17%的乙腈的混合物以15ml/min的流速洗脱。含所需产物的部份合并,用10%碳酸钾水溶液处理,减压蒸发至干。残余物进一步通过硅胶柱层析纯化,提供为灰白色固体的游离碱。该固体溶解于甲醇(3ml),通过用1当量1M氯化氢的乙醚溶液处理转化为相应的盐酸盐,产生的溶液浓缩至干。提供6%产率为白色固体的标题化合物。m.p.98-103℃;1H NMR(DMSO-d6)δ(ppm)11.59(s,1H),10.7(bs,1H),8.20(d,1H,J=7.9Hz),8.10(m,2H),7.88(t,1H,J=7.5Hz),7.80(t,1H,J=7.3Hz),6.62(bs,1H),4.64(s,2H),3.30-3.70(m,3H),3.11-3.39(m,6H),2.65(t,2H,J=7.0Hz),1.73-2.49(m,6H);m/z=426(M+H)。
按照类似的方法,还制备N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-哌啶-1-基-[1,2,4]噁二唑-5-基)-丙酰胺,CF3CO2H盐水合物,但按照上面所述仅由制备性HPLC纯化,产率为23%,为白色固体。m.p.92-98℃;1H NMR(DMSO-d6)δ(ppm)10.54(s,1H),8.22(d,1H,J=6.4Hz),8.12(d,1H,J=7.6Hz),7.86(t,1H,J=8.1Hz),7.80(t,1H,J=6.9Hz),4.51(s,1H),3.43(bs,2H),3.11-3.26(m,6H),2.98(bs,2H),2.68(t,2H,J=7.1Hz),1.73-1.78(m,3H);m/z=440(M+H);元素分析:计算的C,49.04%;H,5.80%;N,16.68%;发现的C,48.91%;H,5.62%;N,16.68%。
实施例66
此实施例说明制备N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-哌啶-4-基-[1,2,4]噁二唑-5-基)-丙酰胺盐酸盐的方法。
配备有磁力搅拌器的50-ml圆底烧瓶中投入4-(5-{2-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)丙基氨基甲酰基]乙基}-1,2,4-噁二唑-3-基)哌啶-1-羧酸叔丁酯(457mg,0.87mmol)、三氟乙酸(2ml)和二氯甲烷(4ml)。室温搅拌1小时后,在反应混合物中加入甲苯(5ml),溶液蒸发至干。产生的固体用10%碳酸钾水溶液碱化,混合物再蒸发至干。残余物通过柱层析纯化,通过用1当量的1M氯化氢的二乙醚溶液处理该游离碱的甲醇(5ml)溶液,转化为相应的盐酸盐。产生的溶液浓缩并于高真空下干燥,得到100%产率为白色固体的标题化合物;m.p.56-58℃;1H NMR(CD3OD)δ(ppm)8.32(d,1H,J=7.6Hz),8.10(m,1H),7.92(t,1H,J=7.3Hz),7.85(t,1H,J=7.2Hz),3.39-3.43(m,4H),3.28-3.35(m,3H),3.10-3.22(m,5H),2.77(t,2H,J=7.0Hz),1.85-2.26(m,6H);m/z=426(M+H)。
下面列出采用类似方法制备的其他化合物,包括观察到的产率和分析数据。
3-[3-(4-氨基-2-甲硫基-噻唑-5-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,99%,淡黄色固体;m.p.141℃(dec.);1HNMR(DMSO-d6)δ(ppm)11.61(bs,1H),8.18-8.23(m,3H),7.87(m,2H),3.10-3.29(m,6H),2.60-2.76(m,5H),1.77(m,2H);m/z=487(M+H)。
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-哌啶-2-基-[1,2,4]噁二唑-5-基)-丙酰胺盐酸盐,71%,黄色固体;m.p.130℃(dec.),1H NMR(CD3OD)δ(ppm)8.33(d,1H,J=7.4Hz),7.80-8.10(m,3H),4.55(dd,1H,J=10.9,3.3Hz),3.12-3.50(m,8H),2.80(t,2H,J=7.0Hz),2.30(d,1H,J=12.0Hz),1.65-2.00(m,7H);m/z=426(M+H)。
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-吡咯烷-2-基-[1,2,4]噁二唑-5-基)-丙酰胺盐酸盐,99%,白色固体;m.p.73-75℃;1H NMR(CD3OD)δ(ppm)8.33(dd,1H,J=1.1,7.9Hz),8.06(d,1H,J=8.0Hz),7.91(dt,1H,J=1.3,7.2Hz),7.84(t,1H,J=7.5Hz),4.90(t,1H,J=7.4Hz),3.39-3.53(m,4H),3.28-3.33(m,3H),3.24(t,2H,J=7.0Hz),2.81(t,2H,J=7.0Hz),2.50(m,1H),2.10-2.33(m,3H),1.89(m,2H);m/z=412(M+H)。
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-3-(3-哌啶-3-基-[1,2,4]噁二唑-5-基)-丙酰胺盐酸盐,89%,黄色固体;m.p.157℃(dec.),1H NMR(CD3OD)δ(ppm)7.92-8.40(m,4H),3.25-3.65(m,8H),3.23(t,2H,J=6.9Hz),3.20(m,1H),2.78(t,2H,J=7.2Hz),2.19(m,1H),1.75-2.05(m,5H);m/z=426(M+H)。
3-[3-(5-氨基-1-甲基-1H-吡唑-4-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,88%,白色固体;m.p.173℃(dec.);1HNMR(DMSO-d6)δ(ppm)11.53(bs,1H),8.16-8.23(m,3H),7.84-7.91(m,2H),7.61(s,1H),3.61(s,3H),3.10-3.28(m,6H),2.67(t,2H,J=7.0Hz),1.77(m,2H);m/z=438(M+H)。
按照类似方式合成3-[3-(5-氨基-3H-咪唑-4-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺盐酸盐,但使用等体积的4N盐酸和甲醇,46%,白色固体;m.p.170℃(dec.);1H NMR(DMSO-d6)δ(ppm)11.56(s,1H),8.28(s,1H),8.20(d,1H,J=7.5Hz),8.10(m,2H),7.88(t,1H,J=7.8Hz),7.80(t,1H,J=7.8Hz),6.57(s,1H),3.08-3.25(m,6H),2.69(t,2H,J=7.1Hz),1.71-1.80(m,2H);m/z=424(M+H)。
3-[3-(5-氨基-3-甲基-异噁唑-4-基)-[1,2,4]噁二唑-5-基]-N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-丙基]-丙酰胺(游离碱),8%,白色固体。m.p.110-118℃;1H NMR(DMSO-d6)δ(ppm)11.55(s,1H),8.19(m,1H),8.07(m,2H),7.84(m,2H),7.39(s,2H),6.56(m,1H),3.24-3.11(m,6H),2.67(m,2H),2.27(s,3H),1.76(m,2H);m/z=439(M+H)。
实施例67
此实施例说明制备N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-环己基]-乙酰胺的方法。
配备有磁力搅拌器的25-ml一口圆底烧瓶中投入4-(顺式-3-氨基环己基氨基)-2H-2,3-二氮杂萘-1-酮(150mg,0.58mmol),烧瓶用氮气清洗。然后加入无水二甲基甲酰胺(4.5ml)、三乙胺(117mg,1.16mmol)和乙酸酐(71mg,0.70mmol)。室温搅拌15分钟后,混合物减压蒸发至干。产生的残余物用水研制(20ml),过滤。滤饼在高真空下干燥18小时,提供88%产率为白色固体的标题化合物.m.p.312-315℃;1H NMR(DMSO-d6)δ(ppm)8.20(m,2H),7.90-7.75(m,3H),6.30(d,1H,J=7.4Hz),3.48(m,2H),2.10(m,2H),1.78(s,3H),1.28-1.0(m,4H);m/z=301(M+H)。
下面列出采用这种方法由相应酸酐或酰氯制备的其他化合物包括观察到的产率和分析数据。按照上面所述,由相应游离碱获得以盐酸盐分离的化合物。
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-环己基]-草酰胺酸乙酯盐酸盐,62%,白色固体;m.p.178-182℃;1H NMR(CD3OD)δ(ppm)8.65(d,1H,J=8.1Hz),8.31(d,1H,J=7.7Hz),8.09(m,2H),4.32(q,2H,J=7.1Hz),3.91(m,2H),2.32(bd,1H,J=11.4Hz),2.12(bs,1H),1.95(m,2H),1.45-1.71(m,4H),1.35(t,3H,J=7.1Hz);m/z=359(M+H)。
N-[3-(5-氧代-5,6-二氢-吡啶并[2,3-d]哒嗪-8-基氨基)-环己基]-乙酰胺,78%,黄色固体;m.p.258-259℃;1H NMR(CD3OD/CDCl3,1∶1,v/v)δ(ppm)9.01(dd,1H,J=1.7,4.6Hz),8.65(dd,1H,J=1.7,8.1Hz),7.79(dd,1H,J=4.6,8.1Hz),3.83(m,2H),2.44(bd,1H,J=10.0Hz),2.19(bd,1H,J=12.1Hz),1.85-1.97(m,5H),1.49(m,1H),1.17-1.29(m,3H);m/z=302(M+H)。
N-[3-(5-氧代-5,6-二氢-吡啶并[2,3-d]哒嗪-8-基氨基)-环己基]-丙酰胺,91%,黄色固体;m.p.260-261℃;1H NMR(CD3OD/CDCl3,1∶1,v/v)δ(ppm)9.01(dd,1H,J=1.4,4.5Hz),8.65(dd,1H,J=1.4,8.1Hz),7.78(dd,1H,J=4.5,8.1Hz),3.84(m,2H),2.44(bd,1H,J=11.7Hz),2.16-2.23(m,3H),1.92(m,2H),1.50(m,1H),1.21-1.28(m,3H),1.14(t,3H,J=7.6Hz);m/z=316(M+H)。
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-环己基]-丙烯酰胺,37%,灰白色固体;m.p.161-167℃;1H NMR(DMSO-d6)δ(ppm)8.19(m,2H),7.80(t,1H,J=7.3Hz),6.20(dd,1H J=17.3,10.0Hz),6.07(dd,1H,J=17.3,2.6Hz),6.31(dd,1H,J=9.7,2.4Hz),3.10(m,1H),2.23(d,1H,J=11.8Hz),1.99(d,1H,J=11.7Hz),1.80(bs,1H),1.13-1.39(m,4H);m/z=313(M+H)。
N-[3-(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基氨基)-环己基]-丙酰胺盐酸盐,48%,灰白色固体;m.p.197-201℃;1H NMR(DMSO-d6)δ(ppm)8.25-7.70(m,4H)3.60(m,2H),2.18(m,1H),2.10-1.90(m,4H),1.77(m,2H),1.45-1.05(m,6H),1.01(t,3H,J=7.5Hz);m/z=315(M+H)。
N-[3-(8-氧代-7,8-二氢-吡啶并[2,3-d]哒嗪-5-基氨基)-环己基]-乙酰胺,70%,黄色固体;m.p.176℃(dec.);1H NMR(CD3OD/CDCl3,1∶1,v/v)δ(ppm)9.05(bs,1H),8.43(d,1H,J=8.3Hz),7.81(dd,1H,J=4.0,7.9Hz),7.5(s,1H),3.82(m,2H),2.40(bd,1H,J=12.0Hz),2.16(bd,1H,J=11.1Hz),1.85-1.95(m,5H),1.44-1.50(m,4H);m/z=302(M+H)。
N-[3-(8-氧代-7,8-二氢-吡啶并[2,3-d]哒嗪-5-基氨基)-环己基]-丙酰胺,71%,黄色固体;m.p.182℃(dec.);1H NMR(CD3OD/CDCl3,1∶1,v/v)δ(ppm)9.04(bs,1H),8.47(d,1H,J=8.2Hz),7.88(dd,1H,J=4.3,8.1Hz),3.77-3.89(m,2H),2.40(bd,1H,J=10.8Hz),2.15-2.22(m,3H),1.91(m,2H),1.20-1.50(m,4H),1.14(t,3H,J=7.6Hz);m/z=316(M+H)。
实施例68
此实施例说明制备5-(3-溴丙基)-3-(4-羟基苯基)-1,2,4-噁二唑的方法。
配备有磁力搅拌器的50-ml一口圆底烧瓶中投入4-羟基-N-羟基苄脒(614mg,4.04mmol)和二环己基碳化二亚胺(930mg,4.51mmol),烧瓶用氮气清洗。加入无水二甘醇二甲醚(10ml)和4-溴丁酸(420μL,668mg,4.00mmol),反应混合物于室温搅拌1小时,然后在90℃油浴中加热18小时。之后,反应物冷却,减压除去溶剂。产生的固体通过硅胶柱层析纯化,提供72%产率为黄色油的标题化合物。1H NMR(DMSO-d6)δ 10.15(s,1H),7.84(d,2H,J=7.7Hz),6.91(d,2H,J=7.7Hz),3.67(t,2H,J=6.7Hz),3.11(t,2H,J=7.2Hz),2.32(m,2H)。
实施例69
此实施例说明制备4-(3-{3-[3-(4-羟基-苯基)-[1,2,4]噁二唑-5-基]-丙基氨基}-丙基氨基)-2H-2,3-二氮杂萘-1-酮的方法。
配备有磁力搅拌器的25-ml一口圆底烧瓶中投入4-(3-氨基丙基氨基)-2H-2,3-二氮杂萘-1-酮(350mg,1.61mmol)、5-(3-溴丙基)-3-(4-羟基苯基)-1,2,4-噁二唑(346mg,1.23mmol)、二甲基甲酰胺(2.4ml)和三乙胺(137mg,1.32mmol)。反应混合物室温搅拌48小时,然后将其直接加到制备性HPLC柱(25cm×2.18cm,Luna 5mm,C18(2)柱)上纯化,20分钟用10%乙腈/90%的0.1%三氟乙酸水溶液至100%乙腈的梯度以15ml/min流速洗脱。合并含需要的产物的部份,并冷冻干燥,提供51%产率为白色固体的标题化合物的三氟乙酸盐一水合物。m.p.164-167℃(dec.);1H NMR(CD3OD)δ(ppm)8.34(d,2H,J=7.2Hz),7.99(d,2H,J=7.7Hz),7.81-7.93(m,4H),6.86(d,2H,J=9.0Hz),3.53(t,2H,J=6.5Hz),3.16-3.26(m,4H),3.10(t,2H,J=7.3Hz),2.27(m,2H),2.11(m,2H);m/z=421(M+H);元素分析:计算的C,52.17%;H,4.93%;N,15.21%;发现的C,52.35%;H,4.91%;N,15.13%。
实施例70
此实施例说明测定式I化合物的PARP抑制活性的酶试验。
PARP-1酶系采用常规的色谱方法,由Hela细胞提取液纯化。在适当浓度的抑制剂存在下该酶与32P-NAD(Amersham Inc.或New England Nuclear)和剪切的大肠杆菌DNA(Sigma)一起培养。试验平板通常于室温培养30分钟。蛋白质包括经自核糖基化的PARP通过加入饱和硫酸铵沉淀,收集在Immobilon膜上(Millipore Inc.)。掺入蛋白质的放射活性由该滤膜的闪烁计数测定。酶活性的百分抑制率作为抑制剂浓度的函数绘图,确定50%抑制所需要的抑制剂浓度(IC50)。
遵循类似的方法测定对PARP-2的抑制活性。重组人PARP-2酶由昆虫细胞裂解液提纯,所述裂解液由能表达被偶联到编码附加表位的寡核苷酸序列的全长PARP-2的杆状病毒所感染以促进纯化。
实施例71
此实施例说明确定式I化合物PARP抑制活性的以细胞为基础的试验。
以人结肠癌HCT116细胞系(American Type Culture Collection,Manassas,VA)试验PARP抑制剂增加烷化剂链脲霉素(ICN Pharmaceuticals,Cost Mesa,CA)细胞毒性的能力。该试验在96孔板(Corning Incorporated,Corning,NY)上进行,每一试验孔含有100μl的104细胞/ml的浓度的HCT116细胞,含50μl链脲霉素和50μlPARP抑制剂或稀释剂(DMSO)对照。培养基由90%RPMI1640(Gibco BRL/LifeTechnologies,Rockville,MD)、10%胎牛血清(HyClone,Logan,UT)、100单位青霉素/ml和100μg链霉素/ml(Gibco BRL/Life Technologies)组成。简而言之,用培养基稀释适当浓度的各PARP抑制剂或DMSO对照。将每一PARP抑制剂或稀释剂对照100μL置于五块96孔板每一块的第二排,且每一样品用培养基连续稀释。培养基中有0μM,475μM,950μM,1900μM,或3800μM链脲霉素的50μL的样品加到这五块96-孔板上(每块板上为一个链脲霉素浓度)。通过胰蛋白酶消化(Gibco BRL/LifeTechnologies),从100mm培养平板(Corning Incorporated)获取生长到50-80%铺满的HCT116细胞,并再悬浮于10ml培养基。将细胞计数,用培养基稀释到1×104细胞/ml。在五块板的所有试验孔中加入100μL细胞稀释液。这些板置于37℃,5%CO2培养箱中培养4天。4天结束时,在各试验孔中加入稀释在20μL培养基中的1μL[甲基-3H]-胸苷(1mCi/ml;NEN,Boston,MA)。这些板于37℃,5%CO2再培养24小时,在-80℃冷冻,随后于37℃融化。使用Filtermate 196细胞收集器(Packard),经玻璃纤维滤器过滤(Packard,Meriden,CT)收集标记的DNA。滤器用蒸馏水洗涤四次,用甲醇(EM Science,Gibbstown,NJ)洗涤一次,使之干燥。使用Matrix 96 Direct Beta计数器(Packard)测定掺入的3H。比较在没有PARP抑制剂下抑制90%细胞生长所需的链脲霉素量与在PARP抑制剂存在下抑制90%细胞生长所需的链脲霉素量,来确定相对生长抑制。抑制90%生长所需链脲霉素剂量减半时PARP抑制剂浓度定义为ECtfs(两倍增敏的有效浓度)。
上述对本发明的讨论用于说明。不构成对本发明的限制。虽然本发明的描述已经包括对一个或多个实施方案以及某些变动和修改,但在理解了本发明说明书后,还有其他的变动和修改在本发明范围之内,它们在本领域的知识范围内。打算获得包括在允许程度内的可供选择的实施方案的权利,包括对要求的那些权利的可选择的、可互换的和/或等价的结构、功能、范围或步骤,而无论是否在此披露了这样的可选择的、可互换的和/或等价的结构、功能、范围和步骤,并不打算公开奉献任何可申请专利的题材。在此列举的所有出版物、专利、专利申请在此全部引用作为参考。
Claims (75)
1.通式I化合物:
其药学上可接受的盐、水合物、溶剂化物或前药;
其中
Q1和Q2各自独立是N或CRa,其中Ra是氢、卤素、硝基或烷基;
R是氢、烷基、或氮保护基;
Y选自:
(A)-NR1R2
其中
R1是氢或烷基;
R2选自:
(a)-C(=O)-Ar1,其中Ar1是芳基;
(b)杂烷基;
(c)环烷基;
(d)任选取代的芳烷基;
(e)任选取代的环烷基烷基;
(f)烷基;
(g)取代的环烯基烷基;
(h)取代的杂芳烷基;
(i)杂芳烯基;
(j)取代的芳烯基;
(k)烯基;
(l)炔基;
(m)-NR60-[C(=X5)]g-R61,其中R60是氢或烷基,g是0或1,R61是氢,任选取代的芳基或任选取代的芳烷基;
(B)-R3-C(=X1)-Y1,
其中
R3是亚烷基,
X1是O或S,
Y1是-NR4R5,其中R4是氢,烷基,芳烷基、或杂烷基,R5选自:
(a)任选取代的芳烷基,
(b)任选取代的杂烷基,
(c)-NH-[C(=X2)]a-(R6)b-R7,其中a和b独立地是0或1,X2是O或S,R6是亚烷基或杂亚烷基,R7是任选取代的芳基、任选取代的杂芳基、烷基、任选取代的芳氨基、烷氧基或杂环基烷基氨基,
(d)烷基,
(e)任选取代的杂环基,
(f)杂芳基,
(g)任选取代的杂环基烷基,
(h)任选取代的杂芳烷基,
(i)环烷基烷基,
(j)任选取代的杂环烷基烷基,
(k)任选取代的环烷基,
(l)杂烷基,
(m)任选取代的杂环烷基,
(n)取代的芳基取代的杂烷基,
(o)-NH-SO2-Ar2,其中Ar2是取代的芳基,
(p)-R8-NHR9-C(=O)-R10,其中R8是亚烷基、R9是氢或烷基,R10是取代的杂芳烷基,
(C)-(亚烷基)x-NR11-R12-NR13-[C(=X3)]c-[NR14]d-[R15]e-[C(=X4)]f-R16,
其中
x是0或1;
R11选自氢、烷基和任选取代的杂芳烷基;或R11与其连接的氮原子和R12的至少一部分一起形成任选取代的杂环基;
R12选自:
(a)亚烷基,
(b)环亚烷基,
(c)杂亚烷基,
(d)芳亚烷基,
(e)亚芳基;
c是0,1,或2;
d,e,和f各自独立地是0或1;
X3和X4各自独立地选自O和S;
R13选自氢、烷基、式-(亚烷基)-[C(=O)NR40]y-Ar4的片断,其中y是0或1,R40是氢或烷基,Ar4是任选取代的芳基或任选取代的杂芳基;或R11和R13与它们连接的氮原子以及R12一起形成任选取代的杂环基;或R13与其连接的氮原子和R12的至少一部分一起形成任选取代的杂环基;或R13和R16与它们连接的原子一起形成任选取代的杂环;
R14是氢或烷基;
R15选自:
(a)任选取代的亚烷基,
(b)任选取代的杂亚烷基,
(c)任选取代的亚烯基,
R16选自:
(a)氢
(b)任选取代的杂芳基,
(c)任选取代的芳基,
(d)任选取代的杂烷基,
(e)烷氧基,
(f)任选取代的环烷基,
(g)任选取代的烷基,
(h)任选取代的芳氧基,
(i)取代的芳烷氧基,
(j)杂环烷基,
(k)芳基磺酰基烷基,
(l)-NR50R51,其中R50是氢或烷基,R51是任选取代的芳基、任选取代的环烷基、任选取代的芳烷基、任选取代的杂芳基、任选取代的杂芳烷基、或任选取代的杂烷基,
(m)-NHPO3R17R18,其中R17和R18是烷基,
(n)-NHSO2Ar2,其中Ar2是取代的芳基或芳烯基,
(o)烷基氨基甲酸酯;
(p)-SO2R19,其中R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基、或取代的杂芳基,
(q)烷基磺酰基烷基,
(r)杂环基,
(s)式-(亚烷基)-[C(=O)NR40]y-Ar5的片断,其中y是0或1,R40是氢或烷基,Ar5是任选取代的芳基或任选取代的杂芳基;
(D)-NR11-R12-N=CR20R21;
其中
R11和R12是上面定义的那些;
R20选自氢和烷基;
R21选自烷基和取代的杂芳基。
2.如权利要求1所述的化合物,其特征在于R是氢。
3.如权利要求1所述的化合物,其特征在于x是0。
4.如权利要求1所述的化合物,其特征在于,R12选自亚烷基、环亚烷基、杂亚烷基、芳亚烷基和亚芳基。
5.如权利要求4所述的化合物,其特征在于R12选自亚丙基、2,2-二甲基亚丙基、亚乙基、1,3-亚环己基、2-羟基亚丙基、1,3-亚苯基、亚丁基和亚苄-3-基。
6.如权利要求1所述的化合物,其特征在于R13与其连接的氮原子以及R12的至少一部分一起形成任选取代的杂环基。
7.如权利要求6所述的化合物,其特征在于R13与其连接氮原子以及R12至少一部分一起形成哌啶基。
8.如权利要求1所述的化合物,其特征在于R11与其连接氮原子以及R12至少一部分一起形成任选取代的杂环基。
9.如权利要求8所述的化合物,其特征在于R11与其连接氮原子以及R12至少一部分一起形成哌啶基。
10.如权利要求1所述的化合物,其特征在于R11和R13与它们连接的氮原子以及R12一起形成任选取代的杂环基。
11.如权利要求10所述的化合物,其特征在于R11和R13与它们连接的氮原子以及R12一起形成哌嗪基或二氮杂环庚烷基。
12.如权利要求1所述的化合物,其特征在于R11是氢或烷基。
13.如权利要求12所述的化合物,其特征在于R11是氢或甲基。
14.如权利要求1所述的化合物,其特征在于R11是任选取代的杂芳烷基。
15.如权利要求14所述的化合物,其特征在于R11是(4-氧代-3,4-二氢-2,3-二氮杂萘-1-基)甲基。
16.如权利要求1所述的化合物,其特征在于R13是氢或烷基。
17.如权利要求16所述的化合物,其特征在于R13是氢或甲基。
18.如权利要求1所述的化合物,其特征在于R14是氢。
19.如权利要求1所述的化合物,其特征在于c和e是1,d和f是0。
20.如权利要求19所述的化合物,其特征在于R15是亚乙基或亚丙基。
21.如权利要求19所述的化合物,其特征在于R16选自:
(a)氢,
(b)任选取代的杂芳基,
(c)任选取代的芳基,
(d)烷氧基,
(e)任选取代的环烷基,
(f)任选取代的芳氧基,
(g)取代的芳烷氧基,
(h)烯基,
(i)任选取代的芳烯基,
(j)任选取代的杂环烷基,
(k)芳基磺酰基烷基,
(l)-NR50R51,其中R50是氢或烷基,R51是任选取代的芳基、任选取代的环烷基、任选取代的杂芳基、杂芳烷基、或任选取代的芳烷基,
(m)-NHPO3R17R18,其中R17和R18是烷基,
(n)-NHSO2Ar2,其中Ar2是取代的芳基或芳烯基,
(o)烷基氨基甲酸酯。
22.如权利要求21所述的化合物,其特征在于R16是取代的杂芳基。
24.如权利要求23所述的化合物,其特征在于x是0。
25.如权利要求23所述的化合物,其特征在于R41选自:
(a)任选取代的吡咯基;
(b)任选取代的噻吩基;
(c)任选取代的呋喃基;
(d)任选取代的苯基;
(e)任选取代的咪唑基;
(f)任选取代的噻唑基;
(g)任选取代的吡唑基;
(h)任选取代的吲哚基;
(i)任选取代的苯并[1,2,5]噁二唑基;
(j)任选取代的吡啶基;
(k)任选取代的哌啶基;
(l)任选取代的吡唑并[1,5-a]嘧啶基;
(m)任选取代的吡咯烷基;
(n)任选取代的(哌啶-1-基)甲基;
(o)任选取代的异噁唑基;
(p)任选取代的(吗啉-4-基)甲基;
(q)任选取代的苄基;
(r)任选取代的吡嗪基。
26.如权利要求1所述的化合物,其特征在于c,d,e和f是0。
27.如权利要求26所述的化合物,其特征在于x是0。
28.如权利要求26所述的化合物,其特征在于R16选自:
(a)氢,
(b)任选取代的杂芳烷基,
(c)-SO2R19,其中R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基或取代的杂芳基,
(d)任选取代的环烷基烷基,
(e)烷基,
(f)任选取代的杂烷基,
(g)烯基,
(h)任选取代的芳烷基,
(i)任选取代的杂环烷基烷基。
29.如权利要求28所述的化合物,其特征在于R16选自:
(a)-SO2R19,其中R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基或取代的杂芳基,
(b)任选取代的环烷基烷基,
(c)任选取代的杂烷基,
(d)烯基,
(e)取代的杂环烷基烷基,
(f)任选取代的杂芳烷基。
30.如权利要求3所述的化合物,其特征在于c和d是1。
31.如权利要求30所述的化合物,其特征在于R16选自:
(a)任选取代的芳基,
(b)环烷基烷基,
(c)环烷基,
(d)杂芳基,
(e)杂环烷基烷基,
(f)任选取代的芳烷基,
(g)杂芳烷基,
(h)杂烷基,
(i)烷基,
(j)烷基磺酰基烷基,
(k)杂环烷基,
(l)芳烯基,
(m)烷氧基,
(n)烯基.
32.如权利要求30所述的化合物,其特征在于e和f是0。
33.如权利要求32所述的化合物,其特征在于R16选自:
(a)任选取代的芳基,
(b)环烷基烷基,
(c)环烷基,
(d)杂芳基,
(e)杂环烷基烷基,
(f)任选取代的芳烷基,
(g)杂芳基烷基,
(h)杂烷基,
(i)烷基,
(j)烷基磺酰基烷基,
(k)杂环烷基。
34.如权利要求30所述的化合物,其特征在于e是0,f是1。
35.如权利要求34所述的化合物,其特征在于R16选自:
(a)取代的芳基,
(b)芳烯基,
(c)烷氧基。
36.如权利要求35所述的化合物,其特征在于X3是S。
37.如权利要求30所述的化合物,其特征在于e和f是1。
38.如权利要求37所述的化合物,其特征在于R16选自:
(a)烷氧基,
(b)烯基。
39.如权利要求3所述的化合物,其特征在于c和e是1,d和f是0。
40.如权利要求39所述的化合物,其特征在于R16是任选取代的杂芳基。
41.如权利要求3所述的化合物,其特征在于c,e,和f是1,d是0。
42.如权利要求41所述的化合物,其特征在于R16选自:
(a)-NR50R51,其中R50是氢或烷基,R51是任选取代的芳基、任选取代的芳烷基、任选取代的杂芳基或任选取代的杂烷基,
(b)芳基,
(c)杂芳基,
(d)烷氧基,
(e)烷基。
43.如权利要求42所述的化合物,其特征在于X3是O。
44.如权利要求1所述的化合物,其特征在于Y是-NR1R2。
45.如权利要求44所述的化合物,其特征在于R2选自:
(a)-C(=O)-Ar1,其中Ar1是芳基,
(b)杂烷基,
(c)环烷基,
(d)任选取代的芳烷基,
(e)任选取代的环烷基烷基,
(f)取代的环烯基烷基,
(g)取代的杂芳烷基,
(h)杂芳烯基,
(i)取代的芳烯基,
(j)烯基,
(k)炔基,
(m)-NR60-[C(=X5)]g-R61,其中R60是氢或烷基,g是0或1,R61是氢、任选取代的芳基或任选取代的芳烷基。
46.如权利要求1所述的化合物,其特征在于Y是-R3-C(=X1)-Y1。
47.如权利要求46所述的化合物,其特征在于Y1选自:
(a)任选取代的芳烷基;
(b)任选取代的杂烷基;
(c)-NH-[C(=X2)]a-(R6)b-R7,其中a和b独立地是0或1,X2是O或S,R6是亚烷基或杂亚烷基,R7是任选取代的芳基、任选取代的杂芳基、烷基、任选取代的芳氨基、烷氧基或杂环基烷基氨基;
(d)烷基;
(e)任选取代的杂环基;
(f)任选取代的杂环基烷基;
(g)任选取代的杂芳烷基;
(h)环烷基烷基;
(i)任选取代的杂环烷基烷基;
(j)任选取代的环烷基;
(k)杂烷基;
(l)任选取代的杂环烷基;
(m)取代的芳基取代的杂烷基;
(n)-NH-SO2-Ar2,其中Ar2是取代的芳基;
(o)-R8-NHR9-C(=O)-R10,其中R8是亚烷基,R9是氢或烷基,R10是取代的杂芳烷基。
48.一种组合物,包含:
(i)药学上可接受的赋形剂;
(ii)权利要求1所述的化合物。
49.如权利要求48所述的组合物,其特征在于x是0。
50.如权利要求49所述的化合物,其特征在于R16是取代的杂芳基。
51.如权利要求50所述的化合物,其特征在于R16是取代的[1,2,4]噁二唑基。
52.如权利要求51所述的化合物,其特征在于R16是3-(任选取代的苯基)-取代的[1,2,4]噁二唑-5-基或3-(任选取代的杂芳基)-取代的[1,2,4]-噁二唑-5-基。
53.如权利要求48所述的组合物,其特征在于所述化合物抑制聚(ADP-核糖)聚合酶具有体外小于或等于10μM的IC50。
54.如权利要求48所述的组合物,其特征在于,所述化合物抑制聚(ADP-核糖)聚合酶具有体内小于或等于10μM的IC50。
55.一种抑制PARP活性的方法,包括给予有效量的权利要求1所述的化合物的步骤。
56.一种使肿瘤细胞对辐射敏感的方法,包括给予肿瘤细胞有效量的权利要求1所述的化合物的步骤。
57.一种使肿瘤细胞对化疗敏感的方法,包括给予肿瘤细胞有效量的权利要求1所述的化合物的步骤。
58.一种治疗动物癌症的方法,包括给予需要这样治疗的动物治疗有效量的权利要求1的化合物。
59.如权利要求58所述的方法,其特征在于所述方法还包括给予所述动物化疗药,并合用权利要求1所述的化合物的步骤。
60.如权利要求58所述的方法,其特征在于所述方法还包括给予所述动物辐射,并合用权利要求1所述的化合物。
63.制备下式二环芳基化合物的方法:
所述方法包括下列步骤:
(a)使下式的氰基酸酯芳基化合物:
或下式的酐:
与式H2N-R12-Z1的胺化合物在足以产生中间体产物的条件下接触;
(b)所述中间体产物与肼在足以产生所述二环芳基化合物的条件下接触,其中
Q1和Q2各自独立地是N或CRa,其中Ra是氢、卤素或烷基;
R是烷基;
R12选自:
(a)亚烷基,
(b)环亚烷基,
(c)杂亚烷基,
(d)芳亚烷基
Z1选自:
(a)包含至少一个氮原子的任选取代的杂环烷基;
(b)包含至少一个氮原子的任选取代的杂环基;
(c)-NR28R29,
其中
R28选自氢和烷基;
R29选自氢、烷基、胺保护基;
(d)烷基;
(e)杂烷基;
(f)任选取代的芳基;
(g)环烷基。
64.权利要求61所述的方法,其特征在于Z1选自:
(a)包含至少一个氮原子的任选取代的杂环烷基;
(b)包含至少一个氮原子的任选取代的杂环基;
(c)-NR28R29,其中R28和R29是如权利要求61定义的那些。
65.权利要求64所述的方法,其特征在于所述方法还包括使式IA的二环芳基化合物衍生化,产生下式IB的二环芳基酰胺:
所述衍生化步骤包括,使所述式IA的二环芳基化合物与式W-[C(=O)]c-R15-[C(=O)]f-R16的羧酸衍生物在足以产生式IB的二环芳基酰胺的条件下接触,
其中
Q1,Q2和R12是如权利要求61定义的那些;
W是羧酸活化基或-OR30,其中R30是氢、烷基、芳烷基、或芳基;
Z2是-NR13-[C(=O)]c-R15-[C(=O)]f-R16
其中
c是1或2;
d,e和f各自独立地是0或1;
X3各自独立地选自O和S;
R13独立地选自氢和烷基;
R15选自:
(a)任选取代的亚烷基,
(b)任选取代的杂亚烷基;
R16选自:
(a)氢
(b)任选取代的杂芳基,
(c)任选取代的芳基,
(d)任选取代的杂烷基,
(e)烷氧基,
(f)任选取代的环烷基,
(g)任选取代的烷基,
(h)任选取代的芳氧基,
(i)取代的芳烷氧基,
(j)杂环烷基,
(k)芳基磺酰基烷基,
(l)-NR50R51,其中R50是氢或烷基,R51是任选取代的芳基、任选取代的环烷基、任选取代的芳烷基、任选取代的杂芳基、任选取代的杂芳烷基、或任选取代的杂烷基,
(m)-NHPO3R17R18,其中R17和R18是烷基,
(n)-NHSO2Ar2,其中Ar2是取代的芳基或芳烯基,
(o)烷基氨基甲酸酯,
(p)-SO2R19,其中R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基、或取代的杂芳基,
(q)烷基磺酰基烷基,
(r)杂环基,
(s)式-(亚烷基)-[C(=O)NR40]y-Ar5的片断,其中y是0或1,R40是氢或烷基,Ar5是任选取代的芳基或任选取代的杂芳基。
66.权利要求65所述的方法,其特征在于R16选自:
(a)任选取代的杂烷基,
(b)烷氧基,
(c)任选取代的芳氧基,
(d)取代的芳烷氧基,
(e)烯基,
(f)任选取代的芳烯基,
(g)任选取代的杂环烷基,
(h)芳基磺酰基烷基,
(i)-NR50R51,其中R50是氢或烷基,R51是任选取代的芳基、任选取代的环烷基或任选取代的芳烷基、任选取代的杂芳基、任选取代的杂芳烷基或任选取代的杂烷基,
(j)-NHPO3R17R18,其中R17和R18是烷基,
(k)-NHSO2Ar2,其中Ar2是取代的芳基或芳烯基,
(l)烷基氨基甲酸酯;
(m)-SO2R19,其中R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基或取代的杂芳基,
(n)任选取代的环烷基烷基,
(o)环烯基,
(p)烷基磺酰基烷基。
67.权利要求65所述的方法,其特征在于W是-OR3,其中R3是按照权利要求65定义的那些。
68.权利要求67所述的方法,其特征在于R3是氢,所述制备式IB二环芳基酰胺的条件包括使所述羧酸衍生物与羧酸活化剂接触。
69.权利要求64所述的方法,其特征在于所述方法还包括使所述式IA的二环芳基化合物衍生化,产生下式IC的二环芳基脲衍生物:
所述衍生化步骤包括;使式IA的二环芳基化合物与式X3=C=N-R15-[C(=O)]f-R16的异氰酸酯化合物在足以产生式IC的二环芳基脲衍生物的条件下接触,
其中
Q1,Q2和R12是按照权利要求61定义的那些;
X是O或S;
Z3是-NR13-C(=X3)-NH-R15-[C(=O)]f-R16
其中
f是0或1;
X3选自O和S;
R15选自:
(a)任选取代的亚烷基,
(b)任选取代的杂亚烷基;
R16选自:
(a)氢,
(b)任选取代的杂芳基,
(c)任选取代的芳基,
(d)任选取代的杂烷基,
(e)烷氧基,
(f)任选取代的环烷基,
(g)任选取代的烷基,
(h)任选取代的芳氧基,
(i)取代的芳烷氧基,
(j)杂环烷基,
(k)芳基磺酰基烷基,
(l)-NR50R51,其中R50是氢或烷基,R51是任选取代的芳基、任选取代的环烷基、任选取代的芳烷基、任选取代的杂芳基、任选取代的杂芳烷基、或任选取代的杂烷基,
(m)-NHPO3R17R18,其中R17和R18是烷基,
(n)-NHSO2Ar2,其中Ar2是取代的芳基或芳烯基,
(o)烷基氨基甲酸酯;
(p)-SO2R19,其中R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基或取代的杂芳基,
(q)烷基磺酰基烷基,
(r)杂环基,
(s)式-(亚烷基)-[C(=O)NR40]y-Ar5的片断,,其中y是0或1,R40是氢或烷基,Ar5是任选取代的芳基或任选取代的杂芳基。
70.权利要求64所述的方法,其特征在于所述方法还包括使式IA的二环芳基化合物衍生化,制备式ID的二环芳胺:
所述衍生化步骤包括:使所述式IA的二环芳基化合物与式R31-C(=O)-R15-[C(=O)]f-R16的羰基化合物在还原剂存在下,在足以产生式ID二环芳胺条件下接触,
其中,
Q1,Q2和R12是如权利要求61中定义的那些;
Z4是-NR13-CH(R31)-R15-[C(=O)]f-R16
其中
f是0或1;
X3选自O和S;
R15选自:
(a)任选取代的亚烷基,
(b)任选取代的杂亚烷基;
R16选自:
(a)氢
(b)任选取代的杂芳基,
(c)任选取代的芳基,
(d)任选取代的杂烷基,
(e)烷氧基,
(f)任选取代的环烷基,
(g)任选取代的烷基,
(h)任选取代的芳氧基,
(i)取代的芳烷氧基,
(j)杂环烷基,
(k)芳基磺酰基烷基,
(l)-NR50R51,其中R50是氢或烷基,R51是任选取代的芳基、任选取代的环烷基、任选取代的芳烷基、任选取代的杂芳基、任选取代的杂芳烷基、或任选取代的杂烷基,
(m)-NHPO3R17R18,其中R17和R18是烷基,
(n)-NHSO2Ar2,其中Ar2是取代的芳基或芳烯基,
(o)烷基氨基甲酸酯,
(p)-SO2R19,其中R19是任选取代的芳基、取代的杂芳基、任选取代的杂芳烷基、烷基、芳烯基、取代的杂环烷基烷基、或取代的杂芳基,
(q)烷基磺酰基烷基,
(r)杂环基,
(s)式-(亚烷基)-[C(=O)NR40]y-Ar5的片段,其中y是0或1,R40是氢或烷基,Ar5是任选取代的芳基或任选取代的杂芳基。
71.制备通式IE的4-取代的二环芳基化合物方法:
所述方法包括:使式IF的二环芳基化合物:
与式H2N-Z5的胺化合物在足以产生所述式IE的4-取代的二环芳基化合物的条件下接触,
其中
Q1和Q2各自独立地是N或CRa,其中Ra是氢、卤素或烷基;
Lg是离去基;
R22是亚烷基;
Z5是-R24-[NR25]g-[R26]h-[C(=X4)]i-[R27]j-Ar3
其中
g,h,i和j各自独立地是0或1;
X4选自O和S;
R24和R26各自独立地是亚烷基;
R23选自氢和杂芳烷基;
R25选自氢和烷基;
R27选自-NH-和亚烷基;
Ar3选自任选取代的芳基、稠合芳基环烷基和取代的杂芳基。
72.权利要求71所述的方法,其特征在于R22是亚甲基。
73.权利要求72所述的方法,其特征在于Ar3是取代的杂芳基。
74.权利要求73所述的方法,其特征在于Ar3是取代的[1,2,4]-噁二唑基。
75.权利要求74所述的方法,其特征在于Ar3是3-(任选取代的苯基)-取代的[1,2,4]-噁二唑-5-基。
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EP (1) | EP1423120A4 (zh) |
JP (1) | JP2005501848A (zh) |
KR (2) | KR100955015B1 (zh) |
CN (1) | CN1568187A (zh) |
AU (1) | AU2002331621B2 (zh) |
CA (1) | CA2456985A1 (zh) |
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CN103130723B (zh) * | 2011-11-30 | 2015-01-14 | 成都地奥制药集团有限公司 | 一种多聚(adp-核糖)聚合酶抑制剂 |
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CN111481551B (zh) * | 2013-04-09 | 2023-06-09 | 伊利诺伊大学董事会 | 肿瘤选择性联合疗法 |
WO2022170952A1 (zh) * | 2021-02-09 | 2022-08-18 | 苏州阿尔脉生物科技有限公司 | 一种作为sos1抑制剂的多环哒嗪酮类衍生物、其制备方法及用途 |
CN115057829A (zh) * | 2022-05-31 | 2022-09-16 | 甘肃联凯生物科技有限公司 | 一种高纯度唑丙酸的合成方法 |
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AU2002331621B2 (en) | 2008-06-05 |
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NZ531245A (en) | 2005-09-30 |
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