CN1211252A - 用作拓扑异构酶抑制剂的甲氧檗因类似物 - Google Patents
用作拓扑异构酶抑制剂的甲氧檗因类似物 Download PDFInfo
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- CN1211252A CN1211252A CN97192211A CN97192211A CN1211252A CN 1211252 A CN1211252 A CN 1211252A CN 97192211 A CN97192211 A CN 97192211A CN 97192211 A CN97192211 A CN 97192211A CN 1211252 A CN1211252 A CN 1211252A
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- topoisomerase
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Abstract
本发明提供了用作抗癌剂的原小檗碱型生物碱衍生物及其使用方法。本发明还提供了用作拓扑异构酶抑制剂的原小檗碱衍生物。本发明还提供了甲氧檗因和光花椒碱衍生物,它们是以拓扑异构酶Ⅰ为靶点的治疗剂,对于喜树碱抗性癌细胞有效,并对CNS肿瘤特别有效。
Description
发明背景
DAN拓扑异构酶是一类特有的核酶,它们通过断裂并再连接DNA的AA磷酸二酯骨架来改变DNA的拓扑状态。哺乳动物的拓扑异构酶Ⅰ能够通过过渡性断裂一个DNA链来改变DNA的拓扑结构,而拓扑异构酶Ⅱ通过引起双链断裂来发生作用。最近认为拓扑异构酶中毒可作为一种有吸引力的药理学靶点用于开发新的癌症化疗药物。曾研究用生物碱和其衍生物作为潜在的抗肿瘤药物,包括喜树碱和小檗碱(Hahn等,抗生素(Antibiotics),Vol.3,Gogglieb等编,Springer:New York,577-584页(1975);Shideman,Bull.Natl.Formulary Committee,18:3(1950);Bhakkuni等,生物碱(The alkaloids);Vol.28,Brossi,A.编,Academic PreSS:New York,95-181页(1986);Suffness等,生物碱(The alkaloids);Vol.XXV,Brossi,A.编;Academic Press:New York,178-197页(1985))。
对喜树碱和其衍生物的大量研究证实细胞拓扑异构酶Ⅰ是抗肿瘤生物碱喜树碱的分子靶点(Hsiang等,癌症研究(Cancer Res).48:1722-1726(1988))。但是有些肿瘤细胞系对喜树碱有抗性。
拓扑异构酶Ⅰ是喜树碱分子靶点的确定促进了进一步鉴定和开发其它以拓扑异构酶Ⅰ为靶点的抗肿瘤化合物(拓扑异构酶Ⅰ毒素)。它们是放线菌素D、吗啉代阿霉素、与DNA小沟结合的顺和反-苯并咪唑、吲哚并咔唑衍生物、bulgarein、茚托利辛、saintopin、吲哚并喹啉二酮、光花椒碱衍生物和小檗碱衍生物。这些化合物中有许多是拓扑异构酶Ⅰ和Ⅱ的双重毒素。尽管新拓扑异构酶Ⅰ毒素的数量迅速增加,但除喜树碱外,尚未证明由新毒素导致的细胞杀死作用与拓扑异构酶Ⅰ中毒有关。同样,也不清楚DNA结合的嵌入方式(已知对于拓扑异构酶Ⅱ中毒是必需的)是否与毒双重毒素使拓扑异构酶Ⅰ中毒有关。
许多研究集中在广泛分布的各类生物碱上,所述生物碱的结构与异喹啉环有关。其中的两类化合物苯并啡啶、光花椒碱以及相关的生物碱花椒路宁在体外诱导拓扑异构酶Ⅰ介导的DNA裂解方面非常有效(Wang等,Chem.Res.Toxicol.6:813-818(1993))。已经表明属于原小檗碱家族的数种化合物(已知其在动物中具有抗肿瘤活性)是拓扑异构酶Ⅰ毒素。小檗碱代表了研究最广泛的一类天然原小檗碱型生物碱,并报道其在小鼠中对P-388白血病有弱抗肿瘤活性(Suffness等,生物碱(The Alkaloids),Vol.XXV,Brossi,A.编,AcademicPress:New York,178-197页(1995))。
甲氧檗因,原小檗碱的生物碱类似物,相对于小檗碱有更显著的抗肿瘤活性,在小鼠体内对L1210和P388白血病有显著的活性(Zee-Cheng等,药物化学杂志(J.Med.Chem.)17:347(1974);Zee-Cheng等,药物化学杂志(J.Med.Chem.)19:882(1976))。尽管尚未确定其抗肿瘤活性的分子基础,但已经发现结合双链和三链DNA的能力可能是产生所述抗白血病活性的原因(WilSon等,药物化学杂志(J.Med.Chem.)19:1261(1976);Lee等,生物化学(Biochemistry)32:5591-5597(1993))。甲氧檗因的抗肿瘤活性以及其相对低的毒性,促进了对许多衍生物合成的研究(Zee-Cheng等,药物化学杂志(J.Med.Chem.)17:347(1974)),已经证实,在甲氧檗因的8位存在甲基取代基和在5,6-位不饱和与其在小鼠中对L1210和P388白血病的抗肿瘤活性密切相关(Messmer等,药学杂志(J.Pharm.Sci.)61:1858-1859(1972);Cushman等,药物化学杂志(J.Med.Chem.)28:1031-1036(1985);Stermitz等,药物化学杂志(J.Med.Chem.)18:708-713(1975);Janin等,药物化学杂志(J.Med.Chem.)36:3686-3692(1993))。
尽管开发了安全有效的治疗药物,但是仍然需要细胞毒性得到改善并且对药物抗性癌细胞有效的抗癌药物。
发明概述
其中R1,R2,R3,R6和R7彼此独立地选自H、OH和(C1-C8)烷氧基,优选-OCH3;R4是H或(C1-C8)烷基,优选-OCH3;R5是H、(C1-C8)烷基,优选-CH3,或不存在;R8和R9是-CH=CH-、-(CH2)2或不存在。
或者,R2和R3一起是-OCH2O-;R1和R2一起是-OCH2O-;R6和R7一起是-OCH2O-。
在一个实施方案中,R2和R3一起是-OCH2O-。根据另一个实施方案,R8是-CH=CH-,R9不存在,R3是H。在另一个实施方案中,R9是-CH=CH-或-(CH2)2,R1或R2是H,R5和R8不存在。在又一个实施方案中,R8和R9均不存在。
与母体化合物相比,式(Ⅰ)化合物显示出改进的对拓扑异构酶Ⅰ的抑制活性,并且还是拓扑异构酶Ⅱ的有效抑制剂。本发明的化合物还是对肿瘤细胞的有效的细胞毒剂,对喜树碱抗性的人肿瘤细胞系具有细胞毒活性。
本发明还提供抑制癌细胞生长的方法,包括向患有癌症的哺乳动物施用抑制所述癌细胞生长有效量的式(Ⅰ)化合物。可将所述化合物或其盐与可药用载体混合进行给药。
发明详述
DAN拓扑异构酶是负责修饰DNA的拓扑学状态的核酶。合成了甲氧檗因类似物并评估了其作为拓扑异构酶Ⅰ和拓扑异构酶Ⅱ毒素的活性。还评估了这些类似物对人成淋巴细胞系RPMI 8402及其喜树碱抗性突变株CPTK-5;表皮癌细胞系KB 3-1;以及胶质母细胞瘤(一种CNS肿瘤)SF-268的细胞毒性。
这些类似物的药理学活性明显取决于取代方式和取代基的性质。还合成了许多1-苄基异喹啉和3-苯基异喹啉类化合物。评估仅掺入了甲氧檗因部分环结构的化合物是否是拓扑异构酶毒素,同时评估其细胞毒性。这些构效研究表明与甲氧檗因环系统有关的结构刚性对于药理学活性可能是很重要的。在这些甲氧檗因类似物上存在的3,4-亚甲二氧基取代基通常伴有作为拓扑异构酶毒素活性的提高。在所评估的甲氧檗因类似物中,5,6-二氢-3,4-亚甲二氧基-10,11-二甲氧基二苯并-[a,g]-喹啉鎓氯化物是最强的拓扑异构酶Ⅰ毒素,与喜树碱的活性相似。该类似物还具有作为拓扑异构酶Ⅱ毒素的意外效力。
根据本发明,通过给患癌症的哺乳动物施用有效量的式(Ⅰ)化合物而使癌细胞受到抑制。文中所用的“有效量”是导致靶癌细胞生长受到抑制的量。如文中所述的,适宜剂量为约0.5-约100mg/kg体重/天。
据信本文所述的组合物对于治疗哺乳动物实体瘤或血液恶性肿瘤是有效的。这些实体瘤包括头和颈、肺,间皮癌,纵膈、食管、胃、胰腺、肝胆管系统、小肠、结肠、直肠、肛门、肾、输尿管、膀胱、前列腺、尿道、阴茎、睾丸、妇科器官、卵巢、乳腺、内分泌系统、皮肤和中枢神经系统的癌症;软组织肉瘤和骨肉瘤;皮和眼内源的黑素瘤。血液恶性肿瘤包括儿童白血病和淋巴瘤、假白血病、淋巴细胞和皮源的淋巴瘤,急性和慢性白血病,浆细胞肿瘤以及与AIDS有关的癌症。治疗的优选哺乳动物种是人和家养动物。
在制备二苯并[a,g]喹啉;衍生物的过程中,使用与文献报道相似的方法(Zee-Cheng等,药学杂志(J.Pharm.Sci.)61:969-971(1972))。在反应方案1中列出了所用的一般合成方法。将适宜取代的二甲氧基苯乙胺与3,4-二甲氧基苯乙酰氯反应得到苯乙酰胺,5a-c,将其在磷酰氯的存在下环化成3,4-二氢-1-苄基异喹啉衍生物中间体6a-c。可用乙酸酐在发烟硫酸的存在下将这些二氢异喹啉中间体直接转变成5,6-二氢二苯并[a,g]喹啉鎓衍生物,7a-c。或者,可在Vilsmeier-Haack条件(Le Quang等,Acad.Sc.,ser.C 1340(1968))下将6a-c转变成8a-c。还可用钯炭将二氢异喹啉中间体6a-c氧化成其1-苄基异喹啉衍生物9a-c。将9a-c用乙酸酐在发烟硫酸的存在下处理得到8-甲基二苯并[a,g]喹啉鎓衍生物,2a-c。在Vil smeier-Haack条件下,将9a-c转变成二苯并[a,g]喹啉鎓氯化物衍生物,10a-c。反应方案1
反应方案2
反应方案2列出了制备1-甲基-3-苯基异喹啉衍生物所采用的合成方法。使用稍微改变的文献方法,将1,2-二甲氧基苯和1,2-(亚甲二氧基)苯用3,4-二甲氧基苯乙酰氯进行Friedel-Crafts酰化反应,分别得到酮中间体11a和11b。将这些酮与乙腈在P2O5的存在下进行反应,转变成6,7-二甲氧基-1-甲基-3-(3,4-二甲氧基苯基)异喹啉,12a,和6,7-亚甲二氧基-1-甲基-3-(3,4-二甲氧基苯基)-异喹啉,12b。
用三溴化硼在氯仿中裂解掉12a的甲氧基得到四羟基衍生物,13。通过用硫酸二甲酯处理,将化合物12a、12b和13分别转变成其2-甲基异喹啉鎓衍生物,14a、14b和15。
实施例中的表1例举了甲氧檗因和相关化合物作为哺乳动物拓扑异构酶抑制剂的相对活性。如该表所示,甲氧檗因及其多种类似物具有显著的哺乳动物拓扑异构酶Ⅰ毒素的活性在某些情况下与喜树碱相当。以前对一系列甲氧檗因衍生物的结构在小鼠中对L1210和P388白血病的影响所进行的研究表明,存在8-烷基取代、平面性和结构刚性是抗肿瘤活性的重要因素。在该研究中,评估了在相当于甲氧檗因的2,3-位(2a,7a,8a,9a,10a)或3,4-位(2b,7b,8b,9b,10b)的位点有甲氧基取代基的类似物。此外,还合成了3,4-亚甲二氧基取代的类似物(2c,7c,8c,9c,10c)并评估了其药理学活性。在这些甲氧檗因类似物3,4-位的亚甲二氧基似乎是与其作为拓扑异构酶毒素的潜力相关的一个共同因素。亚甲二氧基衍生物2c,7c,8c,10c不仅保持了与甲氧檗因相当的拓扑异构酶Ⅰ毒素活性,还具有显著的拓扑异构酶Ⅱ毒素活性。由于没有迹象表明拓扑异构酶Ⅰ中毒的分子机制与拓扑异构酶Ⅱ中毒的分子机制相关,因此,对于这些类似物来说,观察到同时对这两种拓扑异构酶的活性增加是意想不到的。但是,从取代方式和取代基中的这种修饰使这些分子与强拓扑异构酶Ⅰ和Ⅱ毒素光花椒碱上的烷氧基取代方式更相似的事实来看,这些结果是合理的。
在评估一系列甲氧檗因衍生物作为拓扑异构酶毒素的相对强度的过程中,当比较报道的不同甲氧檗因衍生物体内抗肿瘤活性的构效关系时,还注意到在有利于活性的结构条件中有一些差别。特别令人感兴趣的是,在这一系列化合物中,最佳的拓扑异构酶Ⅰ毒素(8c)没有8-烷基取代基,这与小鼠中抗肿瘤活性的构效关系研究不一致。8c的强活性是在存在拓扑异构酶Ⅰ的条件下所观察到的总DNA裂解情况来证明的,所述裂解是在基本相同的8c(0.27μM,0.1μg/mL)和喜树碱(0.29μM,0.1μg/mL)浓度下发生的。
另外,由于其5,6-位被饱和,因此,8c中存在着扭曲而不是一个平面分子。在以前关于甲氧檗因衍生物在小鼠中的抗肿瘤活性的研究中,该位置的不饱和与活性的消失有关。作为拓扑异构酶Ⅰ毒素,所有其它类似取代的分子2c,7c和10c(它们是平面的和/或有一8-甲基取代基)均比8c的活性低10倍。当作为拓扑异构酶Ⅰ毒素在相同的条件下检测时,小檗碱(8c的位置异构体)是无活性的。化合物2b,7b,8b和10b并没有显著的拓扑异构酶Ⅰ毒素活性。因此,就3,4-亚甲二氧基取代基而言,在这些甲氧檗因类似物3,4-位上的二甲氧基取代出人意料地改变了其作为拓扑异构酶Ⅰ毒素的潜能。而8c只表现出中等的拓扑异构酶Ⅱ毒素活性,这些类似物,包括2c和10c确实有强的拓扑异构酶Ⅱ毒素活性(表1)。
除10a外,所有2,3-二甲氧基甲氧檗因衍生物都是选择性的拓扑异构酶Ⅰ毒素,而没有显著的拓扑异构酶Ⅱ毒素活性。与使用2a,7a和8a观察到的结果相反,化合物10a没有拓扑异构酶Ⅰ毒素活性,而有显著的拓扑异构酶Ⅱ毒素活性。与拓扑异构酶毒素10a以及其它2,3-二甲氧基甲氧檗因衍生物的能力有关的这种例外的活性差异的基础目前尚不清楚。
结构刚性可能是该系列化合物保留拓扑异构酶毒素活性的一个重要条件。化合物9a,9b和9c被认为是甲氧檗因的开环类似物,它们没有8-位的碳以及与季铵基相关的正电荷。所有这三个类似物均只有很弱的拓扑异构酶Ⅰ或Ⅱ毒素活性。
可将1-甲基-3-苯基异喹啉衍生物12a和12b以及其N-甲基化的季铵化类似物14a和14b看作是没有甲氧檗因C5-C6部分的开环类似物,它们没有显著的使拓扑异构酶中毒的活性。另外,化合物13和15作为拓扑异构酶Ⅰ或Ⅱ毒素相对无效,这两种化合物分别是化合物12a/12b和14a/14b的多酚羟基(polyphenolic)类似物。
在表1中总结了甲氧檗因和这些类似物对人淋巴母细胞系RPMI8402的细胞毒性。正如用MTA实验确定的,在细胞毒性和作为拓扑异构酶Ⅰ或Ⅱ毒素的潜能之间没有观察到确切的关系。与喜树碱相反,这些衍生物作为阳离子季铵盐化合物存在。在数种这些衍生物抑制拓扑异构酶Ⅰ的内在活性的基础上,与甲氧檗因结构刚性类似物的结构有关的季铵盐功能基可能是限制细胞吸收和降低其细胞毒性的重要因素。已经表明甲氧檗因和小檗碱的稠合的平面阳离子芳香环系统插入了DNA。此外,已经表明甲氧檗因可与DNA三螺旋结合。尚未完全确定这些过程与使拓扑异构酶中毒的相关程度以及阳离子部分在这些分子相互作用中的作用。
在该研究中合成了数种类似物并评估了细胞毒性,这些类似物没有拓扑异构酶毒素活性,但有显著的细胞毒性。具体地说,化合物9c,13,14b和15对RPMI 8402细胞有显著的细胞毒性。在这些情况下,与其细胞毒性相关的具体的药理学靶点还是未知的。
再用喜树碱抗性细胞系CPT-K5评估这些化合物的细胞毒性,所述细胞系含有拓扑异构酶Ⅰ的突变形式。在该研究中,就更强的拓扑异构酶Ⅰ毒素(2a,2c,7a,7c,8a,8c,10c)的细胞毒性而言,在CPT-K5细胞与RPMI 8402细胞的IC50值之间有差异。这些数据可作为一种指标,说明与这些甲氧檗因衍生物的细胞毒性相关的药理学靶点与其拓扑异构酶Ⅰ毒素活性相关。就相似的差异而言(可以在无拓扑异构酶Ⅰ毒素活性的类似物中观察到这些差异),但人们不能将效果方面的这种差异具体地归因于CPT-K5中的拓扑异构酶Ⅰ的突变形式。另外,显然这些细胞系对所评估的化合物之间的细胞毒性方面的任何差异就喜树碱而言是很微小的。
该研究表明甲氧檗因类似物之间的小的结构变异对于其拓扑异构酶Ⅰ或拓扑异构酶Ⅱ毒素会有很大的影响。在3,4-位有亚甲二氧基取代基的那些情况下,甲氧檗因类似物作为拓扑异构酶Ⅰ和Ⅱ毒素的活性有所提高。这些结果与光花椒碱的强拓扑异构酶Ⅱ活性以及光花椒碱与这些甲氧檗因衍生物的空间关系一致。在该研究中,有强拓扑异构酶Ⅰ毒素活性,但几乎没有拓扑异构酶Ⅱ毒性活性的甲氧檗因类似物在2,3-位有甲氧基取代基。这些数据说明,就抑制哺乳动物拓扑异构酶Ⅰ或Ⅱ的潜力而言,类似取代的光花椒碱类似物,即与2,3-亚甲二氧基取代基相反的1,2-二甲氧基衍生物有相似的选择性。
还用成胶质细胞瘤细胞系SF-268检测了化合物7c。在表2中列出了结果。类似物对所述肿瘤细胞的效力和选择性说明可能发生了主动运输。通过鞘内注射施用本发明类似物提供了对CNS肿瘤达到选择性细胞毒性的方法,这种方法几乎没有全身毒性。
同样可将本文描述的生物学活性化合物的可药用盐用于所要求的方法。可用有机或无机碱如NaOH,Na2CO3,NaHCO3,KOH等以及酸如盐酸和磺基乙酸等形成可药用盐。
尽管可将本文所述的化合物和/或其盐以纯化合物的形式给药,但优选将活性成分制成药物组合物。因此本发明还提供了药物组合物的用途,所述药物组合物含有一种或多种化合物和/或其可药用盐,以及一种或多种可药用载体,选择性地,还可含有其它治疗和/或预防性成分。载体必须是在与组合物的其它成分相容并且对其受体无害意义上的“可接受”。
药物组合物包括适用于经口或胃肠外(包括肌肉内、皮下和静脉内)给药的那些。按照需要,可将组合物方便地以分开的单位剂量形式提供并可通过药剂学领域熟知的任何方法制备。所述方法包括将活性化合物与液体载体、固体基质、半固体载体、细的固体载体或其组合混合的步骤,然后如果需要,可将产物制成适用于所需给药系统的形状。
可将适用于经口给药的药物组合物以分开的单位剂量形式提供,例如含有预定量活性成分的硬或软明胶胶囊、锭剂或片剂;粉末或颗粒剂;溶液剂、悬浮剂或乳剂。还可将活性成分以药团、舐剂或膏剂的形式提供。用于经口给药的片剂和胶囊可含有常规的赋形剂如粘合剂、填充剂、润滑剂、崩解剂或湿润剂。可将片剂用例如肠溶包衣通过本领域熟知的方法包衣。
口服液体制剂可以是例如含水或油悬浮剂、溶液剂、乳剂、糖浆或酏剂的形式,或以用于在使用前用水或其它适宜溶媒配制的干燥产品的形式提供。所述液体制剂可含有常规添加剂如悬浮剂、乳化剂、非水载体(可包括食用油)或防腐剂。
可配制化合物用于胃肠外给药(如通过注射,例如快速浓注或连续输注),并用安瓿、预填充的注射器、快速浓注的小容器或用含防腐剂的多剂量容器以单位剂量形式提供。组合物可以是油或水载体中的悬浮剂、溶液剂或乳剂形式,并可含有辅剂如悬浮剂、稳定剂和/或分散剂。或者,活性成分可以是粉末形式,可通过无菌分离无菌固体或从溶液通过冻干得到,该粉末用于在使用前用适宜的溶媒如无菌、无热原的水配制。
对施用于表皮的局部给药来说,可将化合物配制成软膏、乳膏或洗剂,或作为透皮贴剂的活性成分。在例如Fisher等(美国专利4788603)或Bawas等(美国专利4931279、4668504和4713224)中公开了适宜的透皮传递系统。例如可用水或油基并加入适宜的增稠剂和/或胶凝剂来配制软膏和乳膏。可用水或油基来配制洗剂,并通常可含有一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。还可将活性成分通过例如在美国专利4140122,4383,529或4051842中公开的离子电渗疗法传递活性成分。
适用于在口中局部给药的组合物包括单位剂量形式如在矫味剂基质中,通常是蔗糖和阿拉伯胶或黄蓍胶中含活性成分的锭剂;在惰性基质如明胶和甘油或蔗糖和阿拉伯胶中含活性成分的软锭剂;粘膜粘附凝胶,和在适宜的液体载体中含活性成分的漱口液。
需要时,可将上述组合物加以改变,例如将其与特定的亲水聚合物基质混合,以提供所用活性成分的缓释制剂,所述聚合物基质包括例如天然凝胶、合成聚合物凝胶或其混合物。
本发明组合物还可含有其它辅剂如矫味剂、着色剂、抗微生物剂或防腐剂。
还应理解,治疗中所需使用的化合物或其活性盐或其衍生物的量不仅随所选的特定盐而变化,而且随给药途径、待治疗疾病的性质以及患者的年龄和条件而变化,并最终由医生自行处理。
但通常,适宜的剂量为约0.5-约100mg/kg/天,例如约10-约75mg/kg/天,如3-约50mg/公斤患者体重/天,优选6-90mg/kg/天,最佳为15-60mg/kg/天。
可将化合物方便地以单位剂量形式给药;每单位剂量形式例如含5至1000mg,优选10至750mg,最佳为50-500mg活性成分。
理想的,施用活性成分应使活性化合物达到约0.5-约75μM,优选约1-50μM,最佳为约2-30μM的峰血浆浓度。可通过例如静脉内注射0.05-5%活性成分的溶液,可用盐水,或经口施用含约1-100mg活性成分的药团达到此目的。通过以0.01-5.0mg活性成分/kg/小时进行连续输注或间歇输注含约0.4-15mg/kg活性成分的输注液可保持理想的血液水平。
可以单个剂量或以适当间隔给药的分散剂量如每天两、三、四或多个亚剂量来方便地提供所需的剂量。可将亚剂量本身进一步分成例如数个不连续的、松散间隔的给药剂量;例如从吹药器中多次吸入或在眼中点入多滴。
已参考各种具体而优选的实施方案和技术描述了本发明。但是应理解可进行许多变化和修饰而不超出本发明的实质和范围。
用下列实施例是为了说明而不是限制本发明。
实施例
实施例Ⅰ-总述
熔点用Thomas-Hoover Unimelt毛细熔点装置测定,红外光谱数据(IR)用Perkin-Elmer 1600傅里叶变换分光光度计测得并用cm-1报告。质子(1H NMR)和碳(13C NMR)核磁共振分别用200MHz和50MHz在Varian Gemini-200傅里叶变换波谱仪测得。NMR波谱在CDCl3(除非另有说明)中测得,化学位移用在四甲基硅烷(TMS)低场的δ单位报告。偶合常数用赫兹报告。质谱从华盛顿大学生物医学和生物有机质谱分析库(Washington University Resource for Biomedical and Bio-OrganicMass Spectrometry)得到。柱色谱是指用指定的溶剂系统在SiliTech32-63μm(ICN Biomedical s,Eschwegge,Ger.)上进行的闪式色谱。燃烧分析由Arlantic Microlabs,Inc.,Norcross,GA进行。
实施例Ⅱ-合成8-甲基二苯并[a,g]喹啉鎓乙酰硫酸盐(acetosulfates)(2a-c)的一般方法
将发烟硫酸(20%)(1mL)加入到4mL新蒸乙酸酐中,反应剧烈放热并且混合物的颜色变为酒红色。将该混合物在85-90℃加热10分钟。然后在氮气下向该酒红色硫酸溶液中加入1-苄基异喹啉(9a-c,2.35mmol,在1mL新蒸乙酸酐中的溶液)并将得到的混合物在85-90℃加热30-60分钟。然后将反应混合物冷却至室温,滴加5mL甲醇并搅拌30分钟。然后将混合物在冰浴中冷却并继续搅拌30分钟。滤出形成的固体产物并依次用2mL蒸馏水、2mL甲醇和10mL乙醚各洗涤两次。然后将粗产物用热甲醇重结晶得到黄色结晶状的所需产物,收率为90-95%。
8-甲基-2,3,10,11-四甲氧基二苯并[a,g]喹啉鎓乙酰硫酸盐(2a):从9a制备;mp 280℃;IR1735;
1H NMR(DMSO-d6)δ3.28(s,3H),3.94(s,3H),4.03(s,3H),4.09(s,6H),7.42(s,1H),7.53(s,1H),7.80(d,1H,J=8.0),7.98(s,1H),8.70(d,1H,J=8.0),9.28(s,1H);13C NMR(DMSO-d6)δ17.5,56.2,56.6,57.2,104.1,105.0,107.3,108.1,116.0,119.9,120.8,121.9,123.7,124.7,133.5,134.5,145.4,151.6,152.7,152.9,156.3;
元素分析:C24H25NO9S的计算值:C,57.25,H,5.00,N,2.78;实测值:C,57.07,H,5.17,N,2.72。
8-甲基-3,4,10,11-四甲氧基二苯并[a,g]喹啉鎓乙酰硫酸盐(2b):从9b制备;mp 267-269℃(分解)(文献值14mp 267-269℃(分解));IR(液体石蜡)2762,1702,1642,1595,1546;
1H NMR(DMSO-d6)δ3.40(s,3H),3.43(s,3H),4.00(s,3H),4.09(s,3H),4.13(s,6H),7.77(s,1H),7.85(d,2H,J=8.1),8.01(d,1H,J=8.1),8.75(d,1H,J=8.0),8.88(d,1H,J=8.0),9.67(s,1H);13C NMR(DMSO-d6)δ17.7,56.8.56.9,57.3,61.6,104.9,105.5,115.1,116.3,117.1,119.5,121.3,122.3.122.9,126.9,134.5,135.5,147.2,153.1,153.7,156.9;
元素分析:C24H25NO9S的计算值:C,57.24,H,5.00,N,2.78;实得C,57.08,H,5.35,N,2.75。
8-甲基-3,4-亚甲二氧基-10,11-二甲氧基二苯并[a,g]喹啉鎓乙酰硫酸盐(2c):从9c制备;mp>270℃(分解);IR(液体石蜡)3417,1727,1648,1615,1551;
1H NMR(DMSO-d6)3.41(s,3H),4.13(s,3H),6.46(s,2H),7.70(d,1H,J=8.7),7.76(s,1H),7.81(d,1H,J=8.0),7.89(s,1H),8.58(d,1H,J=8.7),8.84(d,1H,J=8.0),9.64(s,1H);
元素分析:C23H21NO9S·2.25H2O的计算值:C,52.32,H,4.44,N,2.65;实测值:C,52.21,H,4.24,N,2.68。HRMS:C21H18NO4的计算值:384.1236;实测值:348.1237。
实施例Ⅲ-合成苯乙酰胺(5a-c)的一般方法
氮气下,将3,4-二甲氧基苯乙酰氯(4mmol)的氯仿(6mL)溶液在0℃及剧烈搅拌的条件下滴加到适宜取代的苯乙胺(4mmol)、氯仿(6mL)和2M碳酸钠(3mL)的混合物中。在0℃继续搅拌至反应结束(1-3小时)。用2mL氯仿和2mL水将反应混合物转移到分液漏斗中。分出有机相并将水相用5mL氯仿萃取。将合并的氯仿萃取液依次用5mL 0.1NNaOH、5mL 0.1N HCl和5mL饱和氯化钠溶液洗涤。将氯仿萃取液干燥(硫酸钠)并蒸发。将粗产物用甲醇重结晶得到白色针状的纯净酰胺,收率95-100%。
N-(3,4-二甲氧基苯乙基)-2-(3,4-二甲氧基苯基)乙酰胺(5a):从3,4-二甲氧基苯乙胺和3,4-二甲氧基苯乙酰氯制备;mp 125℃(文献值17123-125℃);IR(Kbr)3327,3064,3007,2916,2840,1642,1608,1591;
1H NMRδ2.67(t,2H),3.40-3.47(m,4H),3.83(s,6H),3.86(s,3H),3.88(s,3H),5.30(brs,1H),6.52-6.86(m,6H);13C NMRδ35.6,41.2,43.5,56.3,56.4,70.5,111.7,112.2,115.8,121.1,127.5,127.9,128.5,129.1,131.1,131.6,137.3,148.1,149.5,158.5,171.8.
N-(2,3-二甲氧基苯乙基)-2-(3,4-二甲氧基苯基)乙酰胺(5b):从2,3-二甲氧基苯乙胺(Lindemann,Helv.Chim.Acta.1949,32,69-75)和3,4-二甲氧基苯乙酰氯制备;mp 80℃(文献值2979-80℃);IR 3315,2962,2838,1636,1593,1548;
1H NMRδ2.61(t,2H),3.22-3.30(m,4H),3.58(s,3H),3.64(s,6H),3.67(s,3H),6.22(brs,1H),6.44-6.79(m,6H);13C NMRδ30.0,41.0,43.7,55.9,56.2,56.3,60.9,111.2,111.9,112.9,122.0,122.6,124.4,127.9,133.1,147.5,148.5,149.5,153.1,171.9.
N-(2,3-亚甲二氧基苯乙基)-2-(3,4-二甲氧基苯基)乙酰胺(5c):从2,3-亚甲二氧基苯乙胺28和3,4-二甲氧基苯乙酰氯制备;mp 124℃;IR(KBr)3297,3084,2935,1643,1458;
1H NMRδ2.66(t,2H),3.36-3.42(m,4H),3.75(s,3H),3.79(s,3H),5.73(s,2H),5.81(brs,1H),6.61-6.76(m,6H);13C NMRδ29.8,39.7,43.8,56.4,101.0,107.5,111.9,112.9,120.7,122.0,122.1,123.3,127.7,146.0,147.5,148.7,149.6,171.8;
元素分析:C19H21NO5的计算值:C,66.46,H,6.16,N,4.08;实测值:C,66.31,H,6.16,N,4.07。
实施例Ⅳ-合成二氢畀喹啉(6a-C)的一般方法
将乙酰胺(5a-c,2.47mmol)与磷酰氯(5.69mmol)和干燥甲苯(10mL)一起在氮气下回流20-60分钟。然后小心蒸除溶剂并将残余物溶于约5mL甲醇。将溶液倒入约10-15mL冷水中。用10mL乙醚洗涤两次,然后向水层中加入10g冰。向冰冷的水层中鼓入氮气泡的同时,用浓氨水将pH值调至pH10。然后将水层用氯化钠饱和,然后用20mL乙醚萃取5次。将合并的乙醚萃取液用无水碳酸钾干燥,过滤,蒸发得到二氢异喹啉,6a-c。由于这些混合物易于氧化,应避免接触空气。所述二氢异喹啉不经纯化,直接用于制备7a-c、8a-c和9a-c。
实施例Ⅴ-合成5,6-二氢-8-甲基二苯并[a,g]喹啉鎓乙酰硫酸盐(7a-c)的一般方法
将各二氢异喹啉(6a-c,2.35mmol)溶于1.0mL新蒸的乙酸酐中。采用与合成8-甲基二苯并[a,g]喹啉鎓乙酰硫酸盐(2a-c)所用相似的方法。用各二氢异喹啉中间体代替前述方法中所用的相应的1-苄基异喹啉中间体。将得到的产物用沸腾的甲醇重结晶得到亮黄色结晶状产物,收率85-90%。
5,6-二氢-8-甲基-2,3,10,11-四甲氧基二苯并[a,g]喹啉鎓乙酰硫酸盐(7a):从6a制备;mp 278-279℃(文献值13277-279℃);IR(KBr)3450,2946,1725,1611,1567;
1H NMR(DMSO-d6)δ3.18(t,2H),3.23(s,3H),3.40(s,3H),3.89(s,3H),3.94(s,3H),4.08(s,6H),4.75(t,2H),7.13(s,1H),7.63(s,2H),7.80(s,1H),8.74(s,1H);13C NMR(DMSO-d6)δ17.8,26.2,49.8,56.1,56.3,56.8,57.3,106.2,106.4,109.1,110.9,117.5,120.0,122.2,128.6,135.6,139.0,148.9,151.6,152.2,155.4,156.9,167.5.
5,6-二氢-8-甲基-3,4,10,11-四甲氧基二苯并[a,g]喹啉鎓乙酰硫酸盐(7b):从6b制备;mp 255-256℃;IR(KBr)3432,2946,1723,1609,1567,1502,1429;
1H NMR(DMSO-d6)δ3.20(t,2H),3.22(s,3H),3.82(s,3H),3.94(s,3H),4.07(s,6H),4.74(t,2H),7.26(d,1H,J=8.9),7.67(s,1H),7.78(s,1H),7.87(d,1H,J=8.9),8.67(s,1H);13C NMR(DMSO-d6)δ17.7,21.0,49.4,56.3,56.8,57.3,60.7,106.3,112.7,117.6,121.3,122.3,122.9,128.9,135.5,138.9,144.7,152.3,154.6,155.3,156.9,167.6;元素分析:C24H27NO9S·1.25H2O的计算值:C,54.59,H,5.63,N,2.65;实测值:C,54.59,H,5.60,N,2.67;HRMS:C22H24NO4的计算值:366.1705;实测值:366.1706。
5,6-二氢-8-甲基-3,4-亚甲二氧基-10,11-二甲氧基二苯并[a,g]喹啉鎓乙酰硫酸盐(7c):从6c制备;mp>270℃;IR(KBr)3434,2920,1724,1617;1H NMR(DMSO-d6)δ3.16(t,2H),3.23(s,3H),3.40(s,3H),4.08(s,6H),4.76(t,2H),6.23(s,2H),7.17(d,1H,J=8.0),7.67(s,1H),7.70(d,1H,J=8.0),7.81(s,1H),8.69(s,1H);13C NMR(DMSO-d6)17.9,20.8,49.2,56.8,57.3,102.7,106.3,106.5,108.5,116.2,118.1,121.2,122.4,122.7,135.5,139.0,144.2,149.6,152.4,155.6,157.0,167.6;
元素分析:C23H23NO9S·H2O的计算值:C,54.43,H,4.96,N,2.76;实测值:C,54.39,H,4.96,N,2.74;HRMS:C21H20NO4的计算值:350.1392;实测值:350.1384。
实施例Ⅵ-合成5,6-二氢二苯并[a,g]喹啉鎓氯化物(8a-c)的一般方法
将磷酰氯(7.42mmol)于氮气下滴加到冰冷(0℃)的二甲基甲酰胺中。将该混合物于0℃搅拌15分钟。然后滴加各种二氢异喹啉(2.7mmol)在5.5mL二甲基甲酰胺中的溶液并在0℃搅拌1-2小时。然后将反应混合物在100℃加热1-2小时。将反应混合物冷却至室温,然后倒入含有20g冰和10mL 6N HCl的混合物中。滤出所形成的沉淀并依次用5mL冷水和10mL乙醚分别洗涤2次。将得到的各种终产物用甲醇重结晶。
5,6-二氢-2,3,10,11-四甲氧基二苯并[a,g]喹啉鎓氯化物(8a):从6a制备;mp 261-262℃;IR(液体石蜡)1664,1660,1564;
1H NMR(CD3OD)δ3.35(t,3H),3.91(s,3H),4.02(s,3H),4.10(s,3H),4.17(s,3H),5.04(t,2H),7.10(s,1H),7.78(s,1H),8.60(s,1H),9.64(s,1H),10.12(s,1H);13C NMR(CD3OD)δ28.1,56.4,56.7,56.9,57.3,57.8,104.4,106.6,107.5,108.1,108.2,109.0,110.2,112.4,112.5,112.8,115.4,117.7,119.6,130.4,146.5;
元素分析:C21H22NO4Cl·0.75H2O的计算值:C,62.84,H,5.90,N,3.49;实测值:C,62.79,H,5.84,N,3.46;HRMS:C21H22NO4的计算值:352.1549;实测值:352.1549。
5,6-二氢-3,4,10,11-四甲氧基二苯并[a,g]喹啉鎓氯化物(8b):从6b制备;mp 252℃;IR(液体石蜡)3383,1632,1600,1571;
1HNMR(DMSO-d6)δ3.27(t,2H),3.81(s,3H),3.95(s,3H),4.01(s,3H),4.08(s,3H),4.80(t,2H),7.29(d,1H,J= 8.9),7.68(s,1H),7.73(s,1H),7.96(d,1H,J=8.9),8.82(s,1H),9.60(s,1H);13C NMR(DMSO-d6)δ20.9,54.4,56.3,56.6,56.9,60.6,105.7,106.7,112.7,118.4,120.4,122.4,122.6,129.1,136.8,138.5,145.2,145.7,152.5,154.9,157.6;
元素分析:C21H22NO4Cl·1.5H2O的计算值:C,60.79,H,5.71,N,3.38;实测值:C,60.79,H,5.71,N,3.38;HRMS:C20H18NO4的计算值:336.1236;实测值:336.1244。
5,6-二氢-3,4-亚甲二氧基-10,11-二甲氧基二苯并[a,g]喹啉鎓氯化物(8c):从6c制备;mp>280℃;IR(液体石蜡)2725,1622,1574;1H NMR(CD3OD)δ3.27(t,2H),4.07(s,3H),4.13(s,3H),4.62(t,2H),6.16(s,2H),7.03(d,1H,J=8.4),7.60(s,1H),7.63(s,1H),7.75(d,1H,J=8.4),8.60(s,1H),9.34(s,1H);13C NMR(CD3OD)δ22.2,56.0,57.3,57.7,104.3,106.6,107.5,109.6,117.3,120.1,122.3,122.9,124.6,139.2,146.5,146.6,152.0,155.0,160.3
元素分析:C20H18NO4Cl·2H2O的计算值:C,58.89,H,5.43,N,3.43;实测值:C,58.74,H,5.39,N,3.45;HRMS:C20H18NO4的计算值:336.1236;实测值:336.1244。
实施例Ⅶ-合成1-苄基异喹啉(9a-c)的一般方法
将适宜的二氢异喹啉(3.4mmol)与0.3g 10%钯碳一起在5mL 1,2,3,4-四氢化萘(使用前用氮气清洗20分钟)中于220-230℃下回流3-4小时。然后将反应混合物冷却至180℃并用Schlenk型过滤装置(Aldrich Chemical Co.)在氮气下过滤。冷却至室温后,将滤液冷却至0℃并加入氯化氢(1.0M的无水乙醚溶液)将混合物的pH调至pH1.0。析出1-苄基异喹啉的盐酸盐沉淀。滤出沉淀,用10mL无水乙醚洗涤3次,干燥后得到各种1-苄基异喹啉盐酸盐,收率为90-100%。然后将干燥的盐酸盐溶于最少量的甲醇(2-5mL)中并向甲醇中加入10g冰。向该冰冷的含水溶液中加入浓氨水将pH调至10。将水层用氯化钠饱和,然后用氯仿萃取3次,每次10mL。将合并的氯仿萃取液干燥(硫酸钠)并蒸发得到9a-c。
5,6-二甲氧基-1-(3,4-二甲氧基苄基)异喹啉盐酸盐(9b):从6b制备;mp 206-208℃(文献值14206-208℃);IR(液体石蜡)2676,1630,1625,1588;
1H NMR(CD3OD)δ3.76(s,3H),3.81(s,3H),4.03(s,3H),4.15(s,3H),4.87(s,2H),6.86(t,2H),7.07(s,1H),7.92(d,1H,J=1),8.31(d,2H,J=5.7),8.55(d,1H,J=1);13C NMR(CD3OD)δ38.1,56.9,57.1,58.1,62.5,113.7,114.2,119.2,120.8,122.5,122.8,127.7,129.1,131.2,135.9,143.5,150.5,151.3,158.5,160.2
5,6-亚甲二氧基-1-(3,4-二甲氧基苄基)异喹啉盐酸盐(9c):从6c制备;mp 111℃;IR(KBr)3429,3064,3003,2930;
1H NMR(CD3OD)δ2.93(s,3H),4.03(s,3H),4.04(s,3H),6.01(s,2H),6.91(d,1H,J=8.8)7.07(s,1H),7.25(s,1H),7.60(m,2H),7.68(s,1H)13C NMRδ(CD3OD)23.2,56.5,76.9,77.4,78.2,101.6,104.4,106.0,107.8,109.9,114.1,121.0,122.5,134.0,135.2,148.1,149.2,150.1,153.1,156.2;
元素分析:C19H17O4的计算值:C,70.58,H,5.30,N,4.33;实测值:C,70.85,H,5.51,N,4.31。
实施例Ⅷ-合成二苯并[a,g]喹啉鎓氯化物(10a-c)的一般方法
采用与合成5,6-二氢二苯并[a,g]喹啉鎓氯化物(8a-c)所用相似的方法。用1-苄基异喹啉中间体代替前述方法中相应的二氢异喹啉中间体。将所得产物用1∶1冰乙酸和6N HCl的混合物结晶得到黄色结晶状产物10a-c,收率为92-98%。
2,3,10,11-四甲氧基二苯并[a,g]喹啉鎓氯化物(10a):从9a制备;mp、1H NMR、13C NMR如前所报道。12
3,4,10,11-四甲氧基二苯并[a,g]喹啉鎓氯化物(10b):从9b制备;mp 223-225℃(分解);IR(KBr)3394,2947,2843,1626,1598,1561,1503,1433;1H NMR(使用同轴管,外管中为溶于三氟乙酸的9b,内管中为氧化氘) δ4.51(s,3H),4.55(s,6H),4.61(s,3H),7.94(s,1H),7.96(s,1H),8.06(d,1H,J=9.2),8.46(d,1H,J=7.3),8.78(d,1H,J=7.3),9.01(d,1H,J=9.2),9.56(s,1H),9.83(s,1H);
13C NMR(使用同轴管,外管中为溶于三氟乙酸的9b,内管中为氧化氘)
δ58.4,58.8,59.1,64.7,107.0,107.2,118.9,119.2,119.7,121.6,125.0,126.8,127.2,132.0,139.4,139.5,140.0,145.1,156.6,157.9,161.1
元素分析:C21H20NO4Cl·1.25H2O的计算值:C,61.76,H,5.55,N,3.43;实测值:C,60.67,H,5.37,N,3.43;HRMS:C21H20NO4的计算值:350.1392;实测值:350.1392。
3,4-亚甲二氧基-10,11-二甲氧基二苯并[a,g]喹啉;氯化物(10c):从9c制备;mp>270℃(分解);IR(KBr)3414,3015,2928,1620,1564,1488;1H NMR(使用同轴管,外管中为溶于三氟乙酸的化合物,内管中为氧化氘) δ4.55(S,3H),4.60(s,3H),6.67(s,2H),7.81(d,1H,J=8.5),7.92(s,2H),8.18(d,1H,J=7.7),8.68(t,2H),9.47(s,1H),9.77(s,1H);
13C NMR(使用同轴管,外管中为溶于三氟乙酸的化合物,内管中为氧化氘)δ58.8,59.1,106.7,107.0,107.1,115.2,115.7,118.4,119.8,121.7,121.8.126.6,131.1,139.5,139.9,140.3,147.1,153.6,156.4,161.1;
元素分析:C20H16NO4Cl·1.75H2O的计算值:C,59.86,H,4.90,N,3.49;实测值:C,59.72,H,4.93,N,3.48;HRMS:C20H16NO4的计算值:334.1079;实测值:334.1075。
实施例Ⅸ-3,4,3’,4′-四甲氧基脱氧苯偶姻(11a)
将无水氯化铝粉末(0.78g)缓慢加入到搅拌中的1,2-二甲氧基苯(0.64g,4.66mmol)和3,4-二甲氧基苯乙酰氯(1.0g,4.66mmol)的混合物的10mL新蒸无水二氯甲烷溶液中。发生放热反应。将混合物回流时,橙色溶液变为棕色。将反应混合物继续加热回流2小时,然后冷却至室温。将冷却的溶液倒入含有5g碎冰和5.5mL 7.5N HCl的混合物中。分出有机相并将水相用10mL二氯甲烷萃取3次。将合并的二氯甲烷萃取液干燥(硫酸钠)、过滤并蒸发得到白色固体,将其用乙醇结晶得到纯净的白色针状的11a,收率98%;mp 105-107℃(文献值30mp104-106℃) 1H NMRδ3.85(s,6H),3.91(s,3H),3.94(s,3H),4.18(s,2H),6.81(m,2H),6.91(m,2H),7.56(d,1H,J=2.0),7.66(dd,1H,J=8.4,2.0);13C NMRδ45.2,56.3,56.4,56.5,110.4,111.1,111.8,112.8,121.3,121.9,123.9,127.9,130.2,148.4,149.5,153.8,197.0.
实施例Ⅹ-3,4-二甲氧基-3’,4’-亚甲二氧基脱氧苯偶姻(11b)
将3,4-二甲氧基苯乙酰氯(3.25g,15mmol)在15mL新蒸无水二氯甲烷中的溶液于-10℃下滴加到搅拌中的苯并1,3-二氧杂环戊烯(1.83g,15mmol)和氯化锡(Ⅳ)(4.6g,17.6mmol)的混合物的15mL二氯甲烷溶液中。然后将该混合物升至室温并继续搅拌2小时。将反应混合物倒入25mL 6N HCl中并搅拌16小时。分出有机相,将水相用二氯甲烷萃取3次,每次20mL。将合并的二氯甲烷萃取液依次用20mL 0.1N氢氧化钠和20mL蒸馏水洗涤。然后将二氯甲烷萃取液干燥(硫酸钠)、过滤并蒸发得到奶油色固体。将粗产物用乙醇结晶得到3.0g白色针状的11b,收率66%;mp 110-111℃;IR(液体石蜡)2725,1675,1589,1519;1H NMRδ3.80(s,3H),3.81(s,3H),4.09(s,2H),5.96(s,2H),6.76(m,4H),7.42(d,1H,J=1.5),7.58(dd,1H,J=6.4,1.5);13C NMRδ45.3,56.3,102.3,108.3,108.7,111.8,112.7,112.9,121.9,125.4,127.7.131.8,148.4,148.6,149.4,152.2,196.4;
元素分析:C17H16O5的计算值:C,67.99,H,5.37;实测值:C,67.98,H,5.32。
实施例Ⅺ-合成1-甲基-3-苯基异喹啉(12a,12b)的一般方法
将五氧化二磷(4mmol)分三次加入到10mL各种脱氧苯偶姻的乙腈溶液(100mM)中。将反应混合物在氮气下搅拌18-20小时。加入10mL水终止反应。将得到的悬浮液用10%氢氧化钠中和并用二氯甲烷萃取3次,每次10mL。将合并的有机相干燥(硫酸钠)、过滤并蒸发得到奶油色残余物。将该残余物进行硅胶色谱,用95∶5二氯甲烷和乙酸乙酯的混合物洗脱得到相应的1-甲基-3-苯基异喹啉12a和12b,收率75-85%。
6,7-二甲氧基-1-甲基-3-(3,4-二甲氧基苯基)异喹啉(12a):从11a制备;mp 168-169℃(文献值31168-170℃);IR(液体石蜡)2725,1621,1573,1508;
1H NMRδ2.95(s,3H),3.93(s,3H),4.02(s,9H),6.96(d,1H,J=8.4),7.08(s,1H),7.25(s,1H),7.60(dd,1H,J=8.4,2.0),7.71(s,2H);13CNMRδ23.2,56.4,104.3,105.9,110.4,111.7,113.9,119.5,122.4,133.6,133.9,149.2,149.6,149.7,150.0,1531,156.2
6,7-二甲氧基-1-甲基-3-(3,4-亚甲二氧基苯基)异喹啉(12b):从11b制备;mp 174℃;IR(液体石蜡)2727,1622,1573,1504;
1HNMRδ2.93(s,3H),4.03(s,3H),4.04(s,3H),6.00(s,2H),6.91(1H,d,J=8.8),7.07(s,1H),7.25(s,1H),7.60(m,2H),7.67(s,1H);13C NMRδ23.2,56.5,101.6,104.4,106.0,107.8,108.9,114.1,121.0,122.5,133.9,135.2,148.1,148.6,149.2,150.1,153.1,156.2;
元素分析:C19H17NO4的计算值:C,70.58,H,5.30,N,4.33;实测值:C,70.55,H,5.28,N,4.30。
实施例Ⅻ-6,7-二羟基-1-甲基-3-(3,4-二羟基苯基)异喹啉(13)
将化合物12a(250mg,0.74mmol)溶于5mL氯仿并用干冰和丙酮的混合物将其冷却至-50℃。向该混合物中滴加7.4mL 1.0M三溴化硼的二氯甲烷溶液。使反应混合物在4小时的时间内升至室温。滤出沉淀并用乙醚洗涤两次,每次2mL。将该粗产物用乙醇重结晶得到白色针状的13,收率98%;mp>280℃(分解);IR(液体石蜡)3326,1602,1531;
1H NMR(CD3OD)δ3.08(s,3H),6.98(d,1H,J=8.1),7.19(dd,1H,J=8.1,1.9),7.24(s,1H),7.37(s,1H),7.61 (s,1H),7.94(s,1H);13C NMR(CD3OD)δ17.8,109.6,110.6,116.1,117.3,119.6,121.2,122.8,125.6,138.4,142.5,147.7,149.5,152.0,154.3,158.3;
HRMS:C16H13NO4的计算值:283.0844;实测值:283.0839.
实施例ⅩⅢ-合成1,2-二甲基-3-苯基异喹啉鎓衍生物(14a,14b,15)的一般方法
将各种1-甲基-3-苯基异喹啉衍生物(0.67mmol)加入1mL硫酸二甲酯中。然后将该反应混合物于100℃加热20-60分钟,然后冷却至室温。向冷却的反应混合物中加入无水乙醚(8mL)并将形成的悬浮液搅拌5分钟。滤出沉淀并用甲醇重结晶得到95-100%相应的N-甲基异喹啉鎓盐。
6,7-二甲氧基-1,2-二甲基-3-(3,4-二甲氧基苯基)异喹啉鎓甲硫酸盐(methosulfate)(14a):从12a制备;mp 224-226℃;IR(液体石蜡)3508,1640,1613,1548,1506;
1H NMR(CD3OD)δ3.21(s,3H),3.67(s,3H),3.94(s,3H),3.98(s,3H),4.11(s,3H),4.12(s,1H),7.20(d,1H,J=8.6),7.48(m,2H),7.62(s,1H),7.66(s,1H),8.24(s,1H);13C NMR(CD3OD)δ18.0,56.9,57.1,57.3,57.6,106.0,107.5,112.8,113.5,120.7,122.7,123.2,126.4,139.1,151.5,170.4,170.9,171.3;
元素分析:C22H27NO8S·1.5H2O的计算值:C,53.65,H,5.83,N,2.84;实测值:C,53.35,H,5.52,N,2.91。
6,7-二甲氧基-1,2-二甲基-3-(3,4-亚甲二氧基苯基)异喹啉鎓甲硫酸盐(14b):从12b制备;mp 235-237℃;IR(液体石蜡)3479,1612,1568;
1H NMR(DMSO-d6)δ3.22(s,3H),3.38(s,3H),4.06(s,6H),6.20(s,2H),7.14(m,2H),7.23(m,1H),7.70(s,1H),7.86(s,1H),8.09(s,1H);13CNMR(DMSO-d6)δ18.2,43.5,56.8,56.9,102.2,106.2,106.3,109.1,110.0,122.9,123.2,124.1,127.7,134.7,144.9,147.9,149.0,152.5,156.9,157.1;
元素分析:C21H23NO8S的计算值:C,53.11,H,5.15,N,3.11;实测值:C,53.03,H,5.19,N,2.95。
6,7-二羟基-1,2-二甲基-3-(3,4-二羟基苯基)异喹啉鎓甲硫酸盐(15):从13制备;mp 118-120℃;IR(KBr)3249,1614,1528,1454;
1H NMR(CD3OD)δ3.08(s,3H),3.68(s,3H),6.98(d,1H,J=8.2),7.21(m,2H),7.37(s,1H),7.61(s,1H),7.94(s,1H);13C NMR(CD3OD)δ17.8,109.6,110.6,116.1,117.3,119.6,121.2,122.8,125.6,138.4,142.6,147.7,149.5,152.0,154.3,158.3;
元素分析:C18H19NO8S的计算值:C,52.81,H,4.68,N,3.42;实测值:C,52.79,H,4.65,N,3.40。
实施例ⅩⅣ-材料
从Novagen购实用于酶表达的质粒pET11a和大肠杆菌菌株BL21(DE3)。从Sigma购买IPTG。从Amersham(UK)购买用于细菌溶解产物的Western印迹分析的ECL系统。所有限制酶和Vent聚合酶均来自New England Biolabs。按照公开的方法(Halligan等,J.Biol.Chem.260:2475-2482(1985))从牛胸腺分离哺乳动物拓扑异构酶Ⅰ。在JN2-134酵母菌株中表达各种拓扑异构酶Ⅰ基因的单拷贝酵母质粒YCpGALl由M-A Bjornsti博士(Thomas Jefferson University,Philadelphia,PA)赠送。所有细菌和酵母培养基均来自Difco(Detroit,MI),而细胞培养基是从Gibco-BRL(Gaithersburg,MD)购买的。
实施例ⅩⅤ-在大肠杆菌中表达拓扑异构酶Ⅰ
为了得到大量的人拓扑异构酶Ⅰ,将人拓扑异构酶ⅠcDNA克隆到pET-11a载体中,其中cDNA的转录在可诱导T7启动子(Studier等,Methods in Enzymol.,Vol.185:60-89,San Diego:AcademicPress(1990))的控制下。总之,通过在BamHⅠ和EcoRⅠ位点进行切割,从质粒YCpGAL1-hTOP1(Bjornsti等,Cancer Res.49:6318-6323(1989))中分离3.4 kb DNA片段,该片段含有人拓扑异构酶的完整编码区和终止密码子下游的约1kb非翻译区。用相同的限制酶切割载体pET-11a,去磷酸化,然后在载体克隆位点的适当阅读框架下游与插入片段相连。用连接混合物转化大肠杆菌,分离正确克隆pET1B(参见图2A的图谱),然后通过限制图谱确定其一致性。由于pET中的翻译启始位点位于上游NdeⅠ位点,因此,表达的拓扑异构酶Ⅰ在其N末端有15个氨基酸的融合。然后将pET1B转化到大肠杆菌BL21(DE3)中,用0.4mM IPTG诱导1小时后,用10%SDS-PAGE分析细菌溶解产物。用抗人拓扑异构酶Ⅰ的兔抗体,通过Western印迹来确定表达。用简单的方法分离表达的蛋白质。总之,通过重复的声脉冲来溶解大肠杆菌细胞。用1M NaCl和6%聚乙二醇(PEG)处理声提取物以除去核酸。将PEG上清液直接在羟磷灰石柱上进行色谱。表达的人DNA拓扑异构酶Ⅰ在0.6M磷酸钾的步骤中洗脱。将洗脱的酶用50%甘油、30mM磷酸钾(pH7.0)、1mM二硫苏糖醇(DTT)和0.1mM EDTA透析,然后在-20℃贮存。纯化酶的松弛活性具有比活性比牛胸腺拓扑异构酶Ⅰ低约2个数量级的比活性。
实施例ⅩⅥ-在大肠杆菌中表达喜树碱-抗性(CPT-K5)拓扑异构酶Ⅰ
合成两个互补寡核苷酸,所述寡核苷酸含有使CPT-K5产生抗性表型的点突变CAG(Asp533)->CGG(Gly),然后用连续PCR方法(CurrentProtocols in Molecular Biology,Ausubel等编,Vol.1,8.5.7.页Boston:Wiley Interscience(1991))将所述寡核苷酸加工成拓扑异构酶Ⅰ编码序列。两个寡核苷酸是5’-CTTCCTCGGGAAGGGCTCCATCAGATAC-3’(引物X1),和5’-GTATCTGATGGAGCCCTTCCCGAGGAAG-3’(引物X2),其中下划线的序列代表突变的密码子。在不同的PCR中使用各个寡核苷酸以扩增与突变位点相邻的两个DNA片段,用寡核苷酸5’-ACTGTGATCCTAGGG-3’(“A”)和5’-TTCATCGACAAGCTTGCTCTGAG-3’(“H”)分别作为X1和X2的相应引物对。“A”和“H”与特有限制位点AvrⅡ和HindⅢ周围的人拓扑异构酶Ⅰ序列互补。第一轮PCR后,将两个扩增的产物X1-H和X2-A变性,然后由于寡核苷酸X1和X2的重叠而通过其15个碱基对的互补序列退火。然后将双链DNA片段的短区在72℃用Vent聚合酶延伸2分钟以得到推测的748个碱基对的全长产物A-H。然后用两个外引物“A”和“H”扩增含突变的拓扑异构酶Ⅰ片段的全长DNA片段。然后用AvrⅡ和HindⅢ消化扩增的突变拓扑异构酶Ⅰ cDNA,通过取代拓扑异构酶Ⅰ cDNA序列中的相应AvrⅡ/HindⅢ片段而克隆到pET1B中。将质粒pET1B-CPTK5转化到大肠杆菌BL21(DE3)中进行表达,该质粒含有代替了野生型人拓扑异构酶Ⅰ cDNA的突变CPT-K5拓扑异构酶Ⅰ cDNA。用IPTG诱导后,用Western印迹分析溶解产物中的蛋白质。然后按用于野生型酶的方法从细菌溶解产物中纯化CPT-K5拓扑异构酶Ⅰ。
实施例ⅩⅦ-拓扑异构酶Ⅰ和拓扑异构酶Ⅱ裂解试验
按文献记载的内容(Liu等,J.Biol.Chem.258:15365-15370(1983))进行重组拓扑异构酶Ⅰ和牛胸腺拓扑异构酶Ⅰ和Ⅱ的裂解试验。制备用于裂解试验的质粒YEpG DNA并用公开的方法在其3’末端进行标记。
实施例ⅩⅧ-酵母细胞毒性试验
已经确定,当消除了拓扑异构酶Ⅰ的功能时,酵母是可以存活的,而且拓扑异构酶Ⅰ毒素只能杀死有功能性拓扑异构酶的细胞(Biornsti等,Cancer Res.49:6318-6323(1989))。因此,将存在各种药物下的各试验菌株的相对生长程度与对照平板减药物进行比较,表明1)药物对酵母是否有细胞毒性作用,2)细胞毒性是否是拓扑异构酶Ⅰ特异性的和3)与人拓扑异构酶Ⅰ相比,药物对酵母是否有任何不同的特异性。
拓扑异构酶Ⅰ特异性的体内细胞毒性试验改编自Knab等(Knab等,J.Biol.Chem.268:22322-22330(1993))。在该系统中,在啤酒酵母的JN2-134菌株中,于GAL1启动子的控制下,表达克隆到单拷贝酵母质粒载体YCpGAL1(Knab等J.Biol.Chem.268:22322-22330(1993))中的各种拓扑异构酶Ⅰ基因(MATa、rad52::LEU2、trp1、ade2-1、his7、ura3-52、ise1、top1-1、leu2)(Bjornsti等,CancerRes.49:6318-6323(1989))。在载体中,拓扑异构酶Ⅰ构建体分别是野生型酵母拓扑异构酶Ⅰ(YCpGAL-ScTOP1)、其中活性位点酪氨酸-727突变为苯丙氨酸(YCpGAL1-Sctop1Y727F)的非功能性酵母拓扑异构酶Ⅰ(Knab等,,J.Biol.Chem.268:22322-22330(1993)),以及野生型人拓扑异构酶Ⅰ(YCpGAL-hTOP1)(Bjornsti等,Cancer Res.49:6318-6323(1989))。为了定性检测药物的细胞毒性和拓扑异构酶Ⅰ特异性,系列稀释(5倍)含具体质粒的酵母细胞,使其在用尿嘧啶和2%半乳糖补充的释放(dropout)培养基中生长。另外,平板含有:A:对照,平板中无药物;B:喜树碱(CPT),0.5μM;C:甲氧檗因,1uM;D:亚甲二氧基-二氢-二甲基-甲氧檗因(MDD-甲氧檗因),1μM和E:光花椒碱,1μM。使平板在30℃生长3天以评估不同化合物对在啤酒酵母中表达的各种拓扑异构酶Ⅰ和的致死作用并对药物进行了检测。
实施例ⅩⅨ-细胞毒性试验
用MTT-微滴定板四唑细胞毒性试验(MTA)(Mosmann,T.,J.Immunol.Methods 65:55-63(1983);Denizot等,J.Immunol.Methods 89:271-277(1986))确定试验药物的IC50。人淋巴母细胞RPMI8402细胞和其喜树碱抗性CPT-K5细胞(Andoh等,Proc.Natl.Acad.Sci.,USA84:5565-5569(1987))是由Toshiwo Andoh博士(Aichi Cancer CenterResearch Institute,Nagoya,Japan)慷慨赠送的。细胞系A2780和其喜树碱抗性衍生物CPT-2000是Jaulang Hwand(Institute ofMolecular Biology,Academia sinica,Taiwan)博士慷慨提供的。使细胞(2000细胞/孔,接种在200ml生长培养基中)在37℃5%CO2中,于悬浮液中生长,然后在用10%热失活胎牛血清、L-谷胺酰胺(2mM)、青霉素(100U/ml)和链霉素(0.1mg/ml)补充的RPMI培养基中通过规则传代来保持。将细胞与不同浓度的药物连续接触4天,在第4天末进行检测。在6个复制孔中,将各浓度和不含药物的对照至少重复2次。将结果作图并测定IC50。药物敏感性的人表皮样癌KB3-1细胞系和其长春花碱选择的多药物抗性变异体KB-V1细胞(Akiyama等,Genetics 11:117-126(1985))是由Michael Gottesmann博士(National Cancer Institute)善意提供的。37℃5%CO2中使这些细胞生长至单层,然后在用10%热失活的胎牛血清补充的Dulbecco’s基本培养基中通过规则传代来保持。在存在1mg/ml长春花碱的条件下保持KB-V1细胞。
表1甲氧檗因衍生物和相关化合物的拓扑异构酶Ⅰ和拓扑异构酶Ⅱ介导的DNA裂解
细胞毒性IC50 a
(μM)
拓扑异构酶Ⅰ介 拓扑异构酶Ⅱ 细胞系化合物 导的DNA裂解b 介导的DNA裂解c RPMI CPT-K5
2a | 10 | >1000 | 4.9 | 20 |
2b | >1000 | 100 | 0.4 | 2.0 |
2c | 10 | 10 | 2.0 | 41 |
7a | 5 | >1000 | 5.9 | >20d |
7b | 1000 | 1000 | 6.9 | 14 |
7c | 10 | 30 | 0.6 | 6.1 |
8a | 20 | >1000 | 10 | 18 |
8b | >1000 | 1000 | 9.0 | 6.4 |
8c | 1 | 50 | 8.1 | 27 |
9a | >1000 | 1000 | 24 | 29 |
9b | >1000 | 1000 | 15 | 15 |
9c | >1000 | >1000 | 9.3 | 15 |
10a | 1000 | 10 | 13 | >32d |
10b | >1000 | 100 | 2.6 | 5.2 |
10c | 10 | 2 | 0.8 | 6.8 |
12a | >1000 | >1000 | 13 | 24 |
12b | 1000 | >1000 | 22 | 31 |
13 | >1000 | >1000 | 7.1 | 99 |
14a | >1000 | >1000 | 43 | 39 |
14b | 1000 | 1000 | 6.7 | 11 |
15 | 1000 | >1000 | 7.3 | 122d |
CPT | 1 | >1000 | 0.004 | >10d |
VM-26 | >1000 | 1 | 0.3 | 0.5 |
a)在与药物连续接触4天后,计算IC50。
b)将拓扑异构酶Ⅰ裂解值报道为REC(相对有效浓度),即在存在人拓扑异构酶Ⅰ的条件下,对质粒DNA产生相同裂解的、相对于喜树碱(CPT,将其值人为地定为1)的浓度。
c)将拓扑异构酶Ⅱ裂解值报道为REC(相对有效浓度),即在存在牛胸腺拓扑异构酶Ⅱ的条件下,对质粒DNA产生相同裂解的、相对于VM-26(将其值人为地定为1)的浓度。
d)将没有细胞毒性迹象认为是IC50值基本大于最大检测剂量的标志。
检测甲氧檗因类似物7c对成胶质细胞瘤细胞的效力。所用的试验与上述用于RPMI-8402细胞系的相似。结果列于下列表2,其中比较了化合物7c对白血病细胞系(RPMI 8402)、表皮癌(KB3-1)和成胶质细胞瘤(SF-268)的作用:
表2
细胞毒性(ug/ml) | |||
化合物 | RPMI 8402 | KB3-1 | SF-268 |
甲氧檗因 | 3.0 | 0.9 | 0.1 |
化合物7c | 0.3 | 0.06 | 0.008 |
阿霉素 | 0.8 | 0.1 | 0.8 |
喜树碱 | 0.003 | 0.004 | 0.005 |
实施例ⅩⅩ-结果
为了确定人DNA拓扑异构酶Ⅰ是否是甲氧檗因和其衍生物的细胞毒性靶点,在T7表达系统中表达人拓扑异构酶Ⅰ cDNA。通过一步色谱纯化表达的人DNA拓扑异构酶Ⅰ。用重组人DNA拓扑异构酶评估甲氧檗因和其衍生物的活性。重组人DNA拓扑异构酶Ⅰ和从牛胸腺纯化的拓扑异构酶Ⅰ有类似的裂解活性,而且在存在喜树碱和甲氧檗因的条件下,产生相似的裂解图谱。
存在甲氧檗因或喜树碱的条件下,重组人DNA拓扑异构酶Ⅰ诱导的延伸的DNA在YEpG DNA断裂。通过下列标准,这些DNA断裂反映了拓扑异构酶Ⅰ可裂解复合物的形成:(1)如果在上样到中性琼脂糖凝胶之前未将反应物变性,由于未观察到断裂,因此它们代表了单链断裂;(2)表明断裂是蛋白质-连接的,而且在加热到65℃时是可逆的,这是拓扑异构酶Ⅰ可裂解复合物的标志。由甲氧檗因诱导的裂解图谱与喜树碱的相似(如果说不同的话),这表明两种药物对拓扑异构酶Ⅰ的作用模式相似。
为了检测甲氧檗因是否是双重毒性的,评估了甲氧檗因对牛胸腺DNA拓扑异构酶Ⅱ的活性。测得甲氧檗因对纯化的牛胸腺DNA拓扑异构酶Ⅱ基本没有活性。将光花椒碱和VM-26均用作对照进行比较。光花椒碱,与VM-26一样(但与甲氧檗因不同),是很强的拓扑异构酶Ⅱ毒素。
甲氧檗因是相当特异性的拓扑异构酶Ⅰ毒素的事实使得可以评估拓扑异构酶Ⅰ是否可作为细胞中甲氧檗因细胞毒性靶点。已将表达人DNA拓扑异构酶Ⅰ的酵母topl缺失菌株用于证明人DNA拓扑异构酶Ⅰ作为酵母细胞中喜树碱唯一的细胞毒性靶点。尽管甲氧檗因对表达人拓扑异构酶Ⅰ或非功能性酵母拓扑异构酶Ⅰ的酵母菌株没有细胞毒性,但有些甲氧檗因衍生物对表达人拓扑异构酶Ⅰ的酵母细胞有很高的毒性。MDD-甲氧檗因对表达人DNA拓扑异构酶Ⅰ的酵母细胞有很高的毒性,但对表达功能性或非功能性酵母拓扑异构酶Ⅰ的酵母细胞没有细胞毒性。该结果表明MDD-甲氧檗因的细胞毒性靶点是酵母系统中的人拓扑异构酶Ⅰ。令人惊奇的是表达功能性酵母拓扑异构酶Ⅰ的酵母细胞是甲氧檗因抗性的,但它们对喜树碱很敏感。由于光花椒碱与MDD-甲氧檗因的结构相似,因此又评估了其在酵母系统中的作用。光花椒碱,与MDD-甲氧檗因一样,对表达人拓扑异构酶Ⅰ的酵母细胞有很高的细胞毒性,但对表达功能性或非功能性酵母拓扑异构酶Ⅰ的酵母细胞没有细胞毒性。该结果再次表明,人拓扑异构酶Ⅰ是光花椒碱的细胞毒性靶点,而且酵母拓扑异构酶Ⅰ是光花椒碱抗性的。
为了评估人细胞中拓扑异构酶Ⅰ作为细胞毒性靶点的可能的作用,检测甲氧檗因衍生物对两对喜树碱抗性细胞系(RPMI8402/CPT-KS和A2780/CPT2000)的作用。在两对细胞系中,认为对喜树碱的抗性是由于人拓扑异构酶Ⅰ结构基因内的突变而产生喜树碱抗性人拓扑异构酶Ⅰ所引起的(Tamura等,Nucl.Acids Res.19:69-75(1991))。如表1中所示,尽管喜树碱的抗性指数在1000-10000的范围内,但甲氧檗因衍生物和光花椒碱的抗性指数在1-9之间。
从由喜树碱和甲氧檗因衍生物(以及光花椒碱)产生的相似的裂解图谱看,令人惊奇的是喜树碱抗性细胞系对甲氧檗因衍生物和光花椒碱没有显著的交叉抗性。这可能说明这些药物有另外的细胞毒性靶点。或者,在抗性细胞中的喜树碱抗性拓扑异构酶Ⅰ由于没有重叠受体位点而不能对甲氧檗因衍生物和光花椒碱产生抗性。为了区别这两种可能性,从CPT-K5细胞中分离喜树碱抗性拓扑异构酶Ⅰ并检测对甲氧檗因衍生物和光花椒碱的抗性/敏感性。不幸的是,从CPT-K5细胞中纯化的CPT-K5拓扑异构酶Ⅰ没有足够的活性可以得出结论性的结果。为了克服该问题,进行体外定点诱变以便在人拓扑异构酶ⅠcDNA的核苷酸位置1809产生A到G的过渡性突变。已经表明在氨基酸序列中导致Asp到Gly(a.a.#533)改变的突变造成了喜树碱抗性(Tamura等,Nucl.Acids Res.19:69-75(1991))。将突变加工到pET1B上的人拓扑异构酶Ⅰ cDNA中。用所得质粒pET1B/CPT-K5过表达CPT-K5拓扑异构酶Ⅰ。部分纯化过表达的重组CPT-K5拓扑异构酶Ⅰ,表明与用相似方法表达和纯化的野生型人拓扑异构酶Ⅰ有相同的比活性。表明重组CPT-K5拓扑异构酶Ⅰ对喜树碱有很高的抗性(超过1000倍)。但是,重组CPT-K5拓扑异构酶Ⅰ对光花椒碱只有有限的抗性(不到10倍),对D-甲氧檗因有中等抗性(约30倍)。令人惊奇的是,按照用裂解试验确定的,重组CPT-K5拓扑异构酶Ⅰ对甲氧檗因有很高的抗性。
如表2中所示,化合物7c对成胶质细胞瘤细胞有突出的细胞毒性,对该CNS肿瘤细胞的细胞毒性比白血病或表皮癌细胞系更大。其对SF-268细胞的效力表明该化合物可能是选择性吸收的。
这些研究表明,甲氧檗因类似物具有增强的拓扑异构酶Ⅰ和/或拓扑异构酶Ⅱ毒素的活性。这些数据表明,就哺乳动物拓扑异构酶Ⅰ或Ⅱ的抑制作用而言,光花椒碱的相似取代的类似物具有相似的选择性。
Claims (35)
2.权利要求1的化合物,其中R8是-CH=CH-。
3.权利要求2的化合物,其中R6和R7是-OCH3。
4.权利要求3的化合物,其中R1是-OCH3。
5.权利要求3的化合物,其中R2是-OCH3。
6.权利要求1的化合物,其中R9是-CH=CH-或-(CH2)2-。
7.权利要求6的化合物,其中R6和R7是-OCH3。
8.权利要求7的化合物,其中R4是CH3。
9.权利要求8的化合物,其中R1是H,R2和R3是-OCH3。
10.权利要求8的化合物,其中R1是H,R2和R3是-OCH2O-。
11.权利要求7的化合物,其中R4是H。
12.权利要求11的化合物,其中R1是H,R2和R3是-OCH3。
13.权利要求11的化合物,其中R1是H,R2和R3是-OCH2O-。
14.权利要求1的化合物,其中R8和R9不存在。
15.权利要求14的化合物,其中R6和R7是OH。
16.权利要求15的化合物,其中R4是CH3。
17.权利要求16的化合物,其中R5是CH3。
18.权利要求17的化合物,其中R1是H,R2和R3是OH。
19.权利要求14的化合物,其中R6和R7是-OCH3。
20.权利要求19的化合物,其中R4是CH3。
21.权利要求20的化合物,其中R5是CH3。
22.权利要求21的化合物,其中R1是H,R2和R3是-OCH3。
23.权利要求22的化合物,其中R2和R3是-OCH2O-。
24.抑制癌细胞生长的治疗方法,包括向患有癌症的哺乳动物施用一定量的权利要求1的化合物。
25.权利要求24的方法,其中的癌细胞位于中枢神经系统(CNS)。
26.使用权利要求1的化合物制备能够有效抑制患有癌症的哺乳动物中肿瘤细胞生长的药物的方法。
27.权利要求26的方法,其中的哺乳动物是人。
28.权利要求26的方法,其中的癌症是白血病或黑素瘤。
29.权利要求26的方法,其中的癌症是实体瘤。
30.权利要求29的方法,其中的肿瘤是乳腺、肺、结肠或卵巢肿瘤。
31.权利要求26的方法,其中的癌细胞位于中枢神经系统(CNS)。
32.权利要求26的方法,其中的化合物与可药用载体一起施用。
33.权利要求32的方法,其中的载体是液体载体。
34.权利要求32的方法,其中的载体是适于胃肠外给药的载体。
35.权利要求32的方法,其中的载体是片剂或胶囊。
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CN1093129C (zh) * | 1999-08-19 | 2002-10-23 | 广州市海科生物技术有限公司 | 一种具有抗肿瘤生理活性的尖叶唐松草阿原碱及其提取方法 |
CN102746292A (zh) * | 2011-04-18 | 2012-10-24 | 中国医学科学院医药生物技术研究所 | 环化的小檗碱衍生物及其制备方法和用途 |
CN102746292B (zh) * | 2011-04-18 | 2015-03-18 | 中国医学科学院医药生物技术研究所 | 环化的小檗碱衍生物及其制备方法和用途 |
US10653701B2 (en) | 2013-08-23 | 2020-05-19 | Neupharma, Inc. | Substituted quinazolines for inhibiting kinase activity |
US11304957B2 (en) | 2013-08-23 | 2022-04-19 | Neupharma, Inc. | Substituted quinazolines for inhibiting kinase activity |
US11865120B2 (en) | 2013-08-23 | 2024-01-09 | Neupharma, Inc. | Substituted quinazolines for inhibiting kinase activity |
CN107613769A (zh) * | 2015-02-17 | 2018-01-19 | 润新生物公司 | 某些化学实体、组合物和方法 |
US10947201B2 (en) | 2015-02-17 | 2021-03-16 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
CN105541714A (zh) * | 2015-12-16 | 2016-05-04 | 浙江普洛康裕制药有限公司 | 一种罂粟碱及盐酸罂粟碱的制备方法 |
US11208388B2 (en) | 2016-08-15 | 2021-12-28 | Neupharma, Inc | Certain chemical entities, compositions, and methods |
CN110759963A (zh) * | 2018-07-25 | 2020-02-07 | 中山大学 | 一种稠环类化合物及其制备方法和用途 |
Also Published As
Publication number | Publication date |
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HUP9900413A3 (en) | 2002-02-28 |
PL328402A1 (en) | 1999-01-18 |
CN1067070C (zh) | 2001-06-13 |
TR199801555T2 (xx) | 1998-11-23 |
CZ254498A3 (cs) | 1998-12-16 |
DE69705112T2 (de) | 2002-03-21 |
NO983669L (no) | 1998-09-23 |
HUP9900413A2 (hu) | 1999-05-28 |
IL124803A0 (en) | 1999-01-26 |
PT888346E (pt) | 2001-10-31 |
AU710070B2 (en) | 1999-09-16 |
CA2241551A1 (en) | 1997-08-14 |
EP0888346A1 (en) | 1999-01-07 |
AU2115597A (en) | 1997-08-28 |
WO1997029106A1 (en) | 1997-08-14 |
AU710070C (en) | 2001-08-30 |
ES2161442T3 (es) | 2001-12-01 |
BR9707425A (pt) | 1999-07-20 |
NZ330705A (en) | 2000-03-27 |
EP0888346B1 (en) | 2001-06-06 |
JP2000504687A (ja) | 2000-04-18 |
NO983669D0 (no) | 1998-08-11 |
KR19990082488A (ko) | 1999-11-25 |
DE69705112D1 (en) | 2001-07-12 |
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