CN1880315A - N2-喹啉或异喹啉取代的嘌呤衍生物及其制备方法和其用途 - Google Patents
N2-喹啉或异喹啉取代的嘌呤衍生物及其制备方法和其用途 Download PDFInfo
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- CN1880315A CN1880315A CNA2005100268463A CN200510026846A CN1880315A CN 1880315 A CN1880315 A CN 1880315A CN A2005100268463 A CNA2005100268463 A CN A2005100268463A CN 200510026846 A CN200510026846 A CN 200510026846A CN 1880315 A CN1880315 A CN 1880315A
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Abstract
本发明公开了一种N2-喹啉或异喹啉取代的嘌呤衍生物,以及含有所述化合物的药物组合物。本发明的化合物具有毒性低、抗癌谱广、抗癌活性高、稳定性好等特点。可用于制备抗肿瘤药物,本发明公开了它们的制备方法。
Description
技术领域
本发明涉及药物化学,具体涉及N2-喹啉或异喹啉取代的嘌呤衍生物及其制备方法和应用。
背景技术
癌症是人类健康的一大威胁,人类的大多数肿瘤都是由外界环境因素造成的,全世界每年死于癌症的人数已不少于500万。虽然现在已有一些治疗办法,如外科手术、放疗、化疗等可使病人获愈,治愈率不高。用化学药物预防及治疗癌症,目前是制服肿瘤的最有效方法之一。
嘌呤或嘧啶碱基的某些衍生物已显示出抗病毒和抗肿瘤活性。见EP 173624;EP 253412;EP 353955;WO 9201698;EP 481214等专利文献的相关报道。
天然存在的核苷和人工合成的核苷类似物中,嘧啶或嘌呤或其它杂环取代基都是位于糖环的1位,即相当于含羟基氢化呋喃衍生物的2位。近来,已有这种衍生物作为抗肿瘤或/和抗病毒活性的有效药物的相关报道。
另一类O6-烷基嘌呤衍生物具有衰竭O6-烷基鸟嘌呤-DNA烷基转移酶活性,以增强杀死肿瘤细胞之化疗用烷化剂的功效。虽然O6-甲基鸟嘌呤在ATase缺陷细胞中能杀死细胞的机理尚不清楚,但O6-氯乙基鸟嘌呤杀死细胞的机理被认为是:通过环桥亚乙基鸟嘌呤中间物,在相对链上的胞嘧啶残基上形成DNA链间交联,该环桥亚乙基鸟嘌呤中间物可为通过ATase中介的氯乙基去除或复合物形成所阻断。US5091430和WO9113898都公开了一种衰竭宿主中之肿瘤细胞的O6-烷基鸟嘌呤-DNA烷基转移酶之水平的方法。
在现有技术中也公开了一些N2-取代的嘌呤衍生物,如US4853386公开了一种N6-二取代的嘌呤衍生物,该化合物可用于治疗过敏性疾病;JP 2003-55377 A和JP 2003-119197 A公开了具有抗病毒活性的6-环丙基氨基-9H嘌呤类化合物。J.Org.Chem.(2004年69卷3212-3215页)公开了具有抗炎效果的糖基化的嘌呤类衍生物。J.Med.Chem.(1984年27卷,175-181页)公开了N2-丁基苯基-2’-去氧嘌呤衍生物,该化合物具有真核细胞DNAα聚合酶的活性。TetrahedronLetters(1998年,39卷,1827-1830)公开了2,6,9-三取代的嘌呤衍生物。上述的嘌呤化合物与本申请化合物部分结构相同或相似,但是这些嘌呤化合物不具有较好的抗肿瘤效果。也未见具有较好抑制异常细胞生长、具有抗肿瘤效果的N2-喹啉或异喹啉取代的嘌呤衍生物的相关报道。
因此需要寻找毒性低、抗癌谱广、抗癌活性高、稳定性好的抗肿瘤药物。
发明内容
本发明所要解决的技术问题在于研究设计一种毒性低、抗癌谱广、抗癌活性高、稳定性好的N2-取代的嘌呤化合物。
本发明提供了一种结构式(A)的N2-喹啉或异啉取代的嘌呤化合物或其盐或其水合物:
其中:
W为H或任意取代的C1-C6的直链或支链的烷基或取代的C3-C6的环烷基,所述
取代基为C1-C6的直链或支链的烷基或卤素;
Y为H或药学上可接受的糖,其中糖优选为下式结构:
Z为下列基团:
Q为下列基团:
其中B,E,G,R,T,M为H或C1-C6的直链或支链的烷基或卤代烷基、C3-C6的环烷基、卤素、CN或NH2。
优选W为H或下列基团
较好的W为下列基团:
最好的W为:
所述化合物的Q为下列基团:
尤其是:
所述化合物的取代基B,E,G,R,T,M为H,F,CH3,CF3,CN或NH2;尤其是H。
其中Y为H。
本发明具体提供了以下化合物:
本发明尤其提供下式化合物
本发明的另一目的是提供了一式I→式XVIII化合物的药物组合物,该药物组合物由式I→式XVIII中的任意一项的化合物或其盐、水合物与药用辅料组成的,所述组合物是适用于肠内、局部和肠胃外给药、或通过吸入喷雾向哺乳动物给药的药物组合物。组合物为片剂、胶囊剂、丸剂、口服液体制剂、颗粒剂、散剂、注射剂、植入剂或外用制剂。
本发明的又一目的是提供了一种制备上述化合物或其盐或其水合物的方法,该方法包括以下步骤:
(1)由式(j)化合物
与Q-NH2反应,生成式(b)化合物
在式(j))化合物中,加入有机溶剂及0.8~1.5mol/mol的Q-NH2,加热至50~150℃反应1~72小时,反应液加水,冷却放置;
(2)将式(b)化合物制为式(c)化合物
在式(b)化合物中,加入卤化剂,有机溶剂,在50~150℃下反应1~72小时,冷却,加水,用酸调节pH值至2~5,然后冷却放置;
(3)由式(c)化合物与W-NH2合成下式化合物
在式(c)化合物中,加入0.8~1.5mol/mol的W-NH2,缚酸剂,有机溶剂,在50-150℃下反应1-72小时,蒸去有机溶剂;
其中X为Br、X’为Cl,W同权利要求1中的定义。
本申请还提供了另一种制备上述化合物或其盐的方法,所述方法包括以下步骤:
(1)由式(k)化合物
与W-NH2反应,生成式(e)化合物
在式(k)化合物中,加入有机溶剂,加入0.8~1.5mol/mol的W-NH2,缚酸剂,加热至30~120℃,反应1~72小时,蒸去溶剂。
(2)将式(e)与Q-NH2反应生成(f)化合物
在式(e)化合物中,加入0.8~1.5mol/mol的Q-NH2,有机溶剂,缚酸剂,在70~170℃下反应1~72小时,蒸去溶剂。
其中X、X’为Cl,W同权利要求1中的定义。
结构式(A)的化合物的盐包括可药用的盐,例如由无机酸或有机酸得到的酸加合盐,例如盐酸盐、氢溴酸盐、氢碘酸盐、对甲苯磺酸盐、磷酸盐、硫酸盐、高氯酸盐、乙酸盐、三氟乙酸盐、丙酸盐、枸橼酸盐、丙二酸盐、琥珀酸盐、乳酸盐、草酸盐、酒石酸盐和苯甲酸盐。盐还可以是与碱形成的盐,这样的盐包括由无机碱或有机碱得到的盐,例如碱土金属盐如镁盐或钙盐、有机胺盐如吗啉、哌啶、二甲胺或二乙胺盐。
本发明的化合物,优选的合成路线是合成路线A和B。
合成路线A
合成路线B
本发明进一步涉及所述化合物适用于肠内(例如口服或直肠给药)、局部和肠胃外给药、或通过吸入喷雾向哺乳动物(包括人)给药的药物组合物,例如口服、注射、植入、外用等形式。其中口服包括片剂(普通片、含片、舌下片、口腔贴片、咀嚼片、分散片、可溶片、泡腾片、阴道片或阴道泡腾片、缓释片、控释片、肠溶片、口腔速释片等);胶囊剂(硬胶囊、软胶囊、缓释胶囊、控释胶囊、肠溶胶囊等);丸剂(滴丸、糖丸、小丸);口服液体制剂(糖浆剂;口服溶液剂;口服混悬剂;口服乳剂);颗粒剂(混悬颗粒、泡腾颗粒、肠溶颗粒、缓释颗粒、控释颗粒等);散剂。注射剂包括注射液、注射用无菌粉末或无菌块状物(包括采用溶剂结晶法、喷雾干燥法或冷冻干燥法等工艺制备)、注射用浓溶液;植入剂;外用制剂包括:栓剂;气雾剂;粉雾剂;喷雾剂;膜剂;凝胶剂;贴剂等制剂形式。
本发明的药物组合物可根据任何本领域公知的制备药物组合物的方法剂型制备。该组合物可用于抗肿瘤并用于治疗相关的疾病,该组合物单独地、或以与一种或多种其他抗肿瘤药物联合使用。与载体物质组合以制备单一剂型的活性成分的量可以依据所治疗的宿主及具体的给药方式而改变。
本申请还提供了所述化合物在制备药物中的用途。所述化合物用于预防或治疗异常细胞生长,所述异常细胞生长可以表现为肿瘤,所述肿瘤可以是肺癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、黑素瘤、子宫癌、卵巢癌、直肠癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌、软组织肉瘤、尿道癌、前列腺癌、淋巴细胞瘤、膀胱癌、肾或输尿管癌、脊椎肿瘤、脑干神经胶质瘤、垂体腺瘤,尤其是肺癌、肝癌、血癌、胰腺癌和乳腺癌。
通过对本发明化合物的测定发现,在体外抑制肿瘤细胞生长实验中,该化合物对体外培养的人肺癌、肝癌、血癌细胞具有明显的生长抑制作用,并显示剂量-效应关系。较好的式I化合物对人肝癌细胞IC50=11.22μg/ml,对人白血病细胞(血癌)IC50=12.8μg/ml,对人肺癌细胞IC50=10.24μg/ml。本发明所述的药物,腹腔注射时对小鼠LD50为160mg/kg。
对肝癌H22小鼠抑瘤实验80mg/kg,该药物抑瘤率为69%。
该化合物可结合化疗、放疗及生物技术疗法治疗肿瘤,具增效及降低药物副作用。
药理实验部分
以化合物I为例,对化合物的活性进行了测定:
化合物I:
1、IC50值的测定(Lewis肺癌)
a)、取Lewis肺癌细胞,培养于含15%小牛血清DMEM营养液中,接种于96孔培养板,1×104细胞/孔,置于37℃,5%CO2孵箱中,用含有15%小牛血清的DMEM培养液,将该化合物稀释至所需浓度,分别加入96孔板各孔中,每浓度3孔,6孔空白对照。培养72小时,加入MTT液,1小时后加DMSO显色,酶标仪测OD值。计算各浓度药物杀伤率,按座标法求出IC50值。
Lewis肺癌IC50=10.24μg/ml
b)、应用上述试验相同方法,测出化合物I对人肝癌细胞IC50=11.22μg/ml。
c)、应用上述试验相同方法,测出化合物I对人白血病细胞(血癌)IC50=12.8μg/ml,显示该化合物具有抑制非实体瘤细胞功能。
2、具有明显的抗肿瘤作用
a)、取30只体重21~22g昆明种小鼠,雌雄各半,随机分成3组,每组10只,右腹皮下接种肝癌H22细胞悬浮液0.2ml/只。次日,取2组分别腹腔注射此化合物80mg,40mg/kg,每日一次,连续7天,对照组IP DMSO+生理盐水。于停药后次日处死小鼠,称体重,瘤重,计算抑瘤率。该化合物对H22有明显抗肿瘤作用,80mg、40mg/kg给药抑瘤率分别为69%、40%。
表1 化合物I对肝癌抑瘤率
级别 | 体重(g) | 瘤重(g) | 抑瘤率(%) | |
80mg/kg40mg/kg对照 | 前 | 后 | 0.520.991.62 | 6940 |
20.621.921.3 | 21.425.829.7 |
b)、体外癌细胞生长抑制实验
以8μg/ml、16μg/ml化合物I处理人肺癌细胞(Lewis)及白血病细胞,观察细胞动态生长情况4天。两天以内给药组与对照组细胞数差别不大,第三天开始,给药组细胞数急剧下降,而对照组癌细胞继续呈对数生长。随着时间增加,组间差别愈大。
上述药理试验显示本发明所述化合物对肝癌细胞、白血病细胞(实体瘤,非实体瘤)有明显的生长抑制作用,并显示剂量——效应关系。
具体实施方式
以下将结合实施例具体说明本发明,本发明的实施例仅用于说明本发明的技术方案,并非限定本发明。
实施例1-3:式I、II、III化合物的制备
合成路线A
实施例1:制备标题化合物I
1、2-溴代次黄嘌呤(20g,93mmol)中,加入6-氨基喹啉(13g,90mmol),乙二醇甲醚(60ml)和水(200ml),加热回流,48h后,TLC监测反应完全,混合物倒入冰水中,析出固体。过滤,固体分别用浓氨水(200ml)和甲醇(3×50ml)洗涤,烘干,得粗产物,粗产物经硅胶柱层析,得产物2(14.2g,收率57%)。
2、喹啉产物2(12g,43mmol)中,加入三氯氧磷(150ml)和N,N-二甲基苯氨(15ml),回流30min,冷却至室温,反应液慢慢倾入冰水(2000ml)中,2h后,用醋酸调节pH值到3,过滤得到黄色固体,粗产物经硅胶柱层析,得到氯化物3(11.5g,收率90%)。
3、氯化物3(10g,34mmol)中加入环丙胺(10ml,145mmol),三乙胺(28ml,200mmol),DMF(100ml),100℃反应3h,TLC检测反应完全。蒸出溶剂,残余物用乙二醇二甲醚溶解,过滤,滤液浓缩蒸干,硅胶柱层析得目标化合物I(7g,22mmol,收率65%)。mp>250℃
化合物I:HNMR(DMSO-d6,δ):0.640~0.642(2H,s),0.845~0.860(2H,m),3.045(1H,s),7.0411~7.432(1H,m),7.632(1H,s,加重水消失),7.865~7.888(2H,m),7.997~8.018(1H,m),8.116~8.136(1H,m),8.623~8.682(2H,m),9.242(1H,s,加重水后消失),12.400(1H,s,加重水后消失)。MS(ESI):318(M+H+),340(M+Na+)
实施例2:制备标题化合物II
在无水乙腈(10ml)中,加入实施例1所获得的化合物I(4.76g,15mmol)和双(三甲基硅基)乙酰胺(BSA,6.3ml,25mmol),室温搅拌1小时后,加入四乙酰基呋喃核糖(1.27g,4mmol)溶于乙腈(10ml)的溶液和TMSTF(1.10ml,16mmol),加热回流5h,补加BSA(1.25ml,5mmol)再搅拌24h,TLC监测,已反应完全,减压浓缩。残余物溶于甲醇(20ml),通入氨气2h,减压蒸除溶剂,残余物经硅胶柱层析得到化合物II(4.65g,收率72%)。
化合物II:MS(ESI):450(M+H+),472(M+Na+)
实施例3:制备标题化合物III
在实施例1所获得的化合物2-(6-胺基喹啉基)-6-环丙胺嘌呤,即化合物I(10g,31.5mmol)中,加入60%NaH(1.5g,37.8mmol)和无水乙腈150ml,氮气保护下,搅拌30min。分批加入3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖1-氯(12g,31.5mmol),约20min加完。加完后在室温下反应2h,过滤,将滤液蒸干,得油状物。用柱层析纯化,得2-(6-胺基喹啉基)-6-环丙胺基-9-(3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖)嘌呤(9.8g,收率47%)。
将上述产物,甲醇钠(25mmol)和甲醇(400ml)室温搅拌反应5h,用醋酸调节pH到中性,蒸去溶剂。用柱层析纯化剩余物,得2-(6-胺基喹啉基)-6-环丙基-9-(2-脱氧-β-D-呋喃核糖)嘌呤,即化合物III(5g,收率80%)。
化合物III:MS(ESI):434(M+H+),456(M+Na+)
实施例4:式I化合物的制备
制备与实施例1相同的化合物I,采用以下路线——合成路线B
1、二氯嘌呤4(3.78g,20mmol)中,加入DMF(50ml)溶解,再加入环丙胺(1.4ml,20mmol)和三乙胺(3.08ml,22mmol),加热至80℃,反应5h,TLC分析,反应完全,减压蒸去溶剂,残余物经硅胶柱层析,得环丙物5(3.34g,收率80%)。
2、环丙物5(2.99g,14.3mmol)中,加入6-氨基喹啉(5.1g,36.1mmol),DMF(50ml),三乙胺(2.4ml,17.1mmol),140℃回流,反应72h,TLC分析原料基本反应完全,减压蒸去溶剂,残余物经硅胶柱层析,得化合物I(3.54g,收率78%)。
实施例5-7:式IV、V、VI化合物的制备
实施例5:式IV化合物的制备
1、2-溴代次黄嘌呤(20g,93mmol)中,加入5-氨基喹啉(13g,90mmol),乙二醇甲醚(60ml)和水(200ml),加热回流,48h后,TLC监测反应完全,冷却至室温,混合物倒入冰水中,析出固体。过滤,固体分别用浓氨水(200ml)和甲醇(3×50ml)洗涤,烘干,得粗产物,粗产物经硅胶柱层析,得产物6(8g,收率32%)。
2、喹啉产物6(12g,43mmol)中,加入三氯氧磷(150ml)和N,N-二甲基苯氨(15ml),回流30min,反应液慢慢倾入冰水(2000ml)中,2h后,用醋酸调节pH值到3,过滤得到黄色固体,粗产物经硅胶柱层析,得到氯化物7(12.0g,收率94%)。
3、氯化物7(10g,34mmol)中,加入环丙胺(10ml,145mmol),三乙胺(28ml,200mmol),DMF(100ml),100℃反应3h,TLC分析,反应完全,蒸出溶剂,残余物用乙二醇二甲醚溶解,过滤,滤液浓缩蒸干,硅胶柱层析得化合物IV(9g,收率84)。
化合物IV:MS(ESI):318(M+H+),340(M+Na+)
实施例6:式V化合物的制备
在无水乙腈(10ml)中,加入实施例5所制备得到的化合物IV(4.76g,15mmol)和双(三甲基硅基)乙酰胺(BSA,6.3ml,25mmol),室温搅拌1小时后,加入四乙酰基呋喃核糖(1.27g,4mmol)溶于乙腈(10ml)的溶液和TMSTF(1.10ml,16mmol),加热回流5h,补加BSA(1.25ml,5mmol),再搅拌24h,TLC监测,已反应完全,减压浓缩。残余物溶于甲醇(20ml),通入氨气2h,减压蒸除溶剂,残余物经硅胶柱层析得到化合物V(4.07g,收率63%)。
化合物V:MS(ESI):450(M+H+),472(M+Na+)
实施例7:式VI化合物的制备
在2-(5-胺基喹啉基)-6-环丙胺嘌呤,即实施例5所获得的化合物IV(10g,31.5mmol)中,加入60%NaH(1.5g,37.8mmol)和无水乙腈150ml,氮气保护下,搅拌30min。分批加入3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖1-氯(12g,31.5mmol),约20min加完。加完后在室温下反应2h,过滤,将滤液蒸干,得油状物。用柱层析纯化,得2-(5-胺基喹啉基)-6-环丙胺基-9-(3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖)嘌呤(8.0g,收率38%)。
将上述产物,甲醇钠(25mmol)和甲醇(400ml)室温搅拌反应5h,用醋酸调节pH到中性,蒸去溶剂。用柱层析纯化剩余物,得2-(5-胺基喹啉基)-6-环丙基-9-(2-脱氧-β-D-呋喃核糖)嘌呤,即化合物VI(5.75g,收率92%)。
化合物VI:MS(ESI):434(M+H+),456(M+Na+)
实施例8:制备与实施例5相同的化合物IV,采用以下路线制备
环丙物5(2.99g,14.3mmol)中,加入5-氨基喹啉(5.1g,36.1mmol),DMF(50ml),三乙胺(2.4ml,17.1mmol),140℃回流,反应72h,TLC分析,原料基本反应完全,减压蒸去溶剂,残余物经硅胶柱层析,得化合物IV(2.88g,收率63%)。
实施例9-11:式VII,VIII,IX化合物的制备
实施例9:式VII化合物的制备
1、2-溴代次黄嘌呤(20g,93mmol)中,加入8-氨基喹啉(13g,90mmol),乙二醇甲醚(60ml)和水(200ml),加热回流,48h后,TLC监测反应完全,混合物倒入冰水中,析出固体,分别用浓氨水(200ml)和甲醇(3×50ml)洗涤,烘干,得粗产物,粗产物经硅胶柱层析,得产物8(11.4g,收率46%)。
2、喹啉产物8(12g,43mmol)中,加入三氯氧磷(150ml)和N,N-二甲基苯氨(15ml),回流30min,反应液慢慢倾入冰水(2000ml)中,2h后,用醋酸调节pH值到3,过滤得到黄色固体,粗产物经硅胶柱层析,得到氯化物9(10.3g,收率81%)。
3、氯化物9(10g,34mmol)中加入环丙胺(10ml,145mmol),三乙胺(28ml,200mmol),DMF(100ml),100℃反应3h,点板反应完全,蒸出溶剂,残余物用乙二醇二甲醚溶解,过滤,滤液浓缩蒸干,硅胶柱层析得化合物VII(6g,收率56%)。
化合物VII:MS(ESI):318(M+H+),340(M+Na+)
实施例10:式VIII化合物的制备
无水乙腈(10ml)中,加入化合物VII(4.76g,15mmol)和双(三甲基硅基)乙酰胺(BSA,6.3ml,25mmol),室温搅拌1小时后,加入四乙酰基呋喃核糖(1.27g,4mmol)溶于乙腈(10ml)的溶液和TMSTF(1.10ml,16mmol),加热回流5h,补加BSA(1.25ml,5mmol)再搅拌24h,TLC监测,已反应完全,减压浓缩。残余物溶于甲醇(20ml),通入氨气2h,减压蒸除溶剂,残余物经硅胶柱层析得到化合物VIII(4.2g,收率65%)。
化合物VIII:MS(ESI):450(M+H+),472(M+Na+)
实施例11:式IX化合物的制备
在2-(8-胺基喹啉基)-6-环丙胺嘌呤(10g,31.5mmol)中,加入60%NaH(1.5g,37.8mmol)和无水乙腈150ml,氮气保护下,搅拌30min。分批加入3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖1-氯(12g,31.5mmol),约20min加完。加完后在室温下反应2h,过滤,将滤液蒸干,得油状物。用柱层析纯化,得2-(8-胺基喹啉基)-6-环丙胺基-9-(3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖)嘌呤(7.4g,收率35%)。
将上述产物,甲醇钠(25mmol)和甲醇(400ml)室温搅拌反应5h,用醋酸调节pH到中性,蒸去溶剂。用柱层析纯化剩余物,得2-(8-胺基喹啉基)-6-环丙基-9-(2-脱氧-β-D-呋喃核糖)嘌呤,即化合物IX(3.2g,收率51%)。
化合物IX:MS(ESI):434(M+H+),456(M+Na+)
实施例12:制备与实施例9相同的化合物VII,采用以下路线制备
环丙物5(2.99g,14.3mmol)中,加入8-氨基喹啉(51g,36.1mmol),DMF(50ml),三乙胺(2.4ml,17.1mmol),140℃回流,反应72h,TLC分析,原料基本反应完全,减压蒸去溶剂,残余物经硅胶柱层析,得化合物VII(4.10g,收率90%)
实施例13-15:式X、XI、XII化合物的制备
实施例13:式X化合物的制备
1、2-溴代次黄嘌呤(20g,93mmol)中,加入3-氨基喹啉(13g,90mmol),乙二醇甲醚(60ml)和水(200ml),加热回流,48h后,TLC监测反应完全,混合物倒入冰水中,析出固体。过滤,固体分别用浓氨水(200ml)和甲醇(3×50ml)洗涤,烘干,得粗产物,粗产物经硅胶柱层析,得产物10(15.0g,收率60%)。
2、喹啉产物10(12g,43mmol)中,加入三氯氧磷(150ml)和N,N-二甲基苯氨(15ml),回流30min,冷却至室温,反应液慢慢倾入冰水(2000ml)中,2h后,用醋酸调节pH值到3,过滤得到黄色固体,粗产物经硅胶柱层析,得到氯化物11(10.9g,收率85%)。
3、氯化物11(10g,34mmol)中加入环丙胺(10ml,145mmol),三乙胺(28ml,200mmol),DMF(100ml),100℃反应3h,TLC分析,反应完全,蒸出溶剂,残余物用乙二醇二甲醚溶解,过滤,滤液浓缩蒸干,硅胶柱层析得化合物X(10.1g,收率94%)。
化合物X:MS(ESI):318(M+H+),340(M+Na+)
实施例14:式XI化合物的制备
无水乙腈(10ml)中,加入化合物X(4.76g,15mmol)和双(三甲基硅基)乙酰胺(BSA,6.3ml,25mmol),室温搅拌1小时后,加入四乙酰基呋喃核糖(1.27g,4mmol)溶于乙腈(10ml)的溶液和TMSTF(1.10ml,16mmol),加热回流5h,补加BSA(1.25ml,5mmol)再搅拌24h,TLC监测,已反应完全,减压浓缩。残余物溶于甲醇(20ml),通入氨气2h,减压蒸除溶剂,残余物经硅胶柱层析得到化合物XI(4.97g,收率77%)。
化合物XI:MS(ESI):450(M+H+),472(M+Na+)
实施例15:式XII化合物的制备
在2-(3-胺基喹啉基)-6-环丙胺嘌呤,即化合物X(10g,31.5mmol)中,加入60%NaH(1.5g,37.8mmol)和无水乙腈150ml,氮气保护下,搅拌30min。分批加入3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖1-氯(12g,31.5mmol),约20min加完。加完后在室温下反应2h,过滤,将滤液蒸干,得油状物。用柱层析纯化,得2-(3-胺基喹啉基)-6-环丙胺基-9-(3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖)嘌呤(8.8g,收率42%)。
将上述产物,甲醇钠(25mmol)和甲醇(400ml)室温搅拌反应5h,用醋酸调节pH到中性,蒸去溶剂。用柱层析纯化剩余物,得2-(3-胺基喹啉基)-6-环丙基-9-(2-脱氧-β-D-呋喃核糖)嘌呤,即化合物XII(5.06g,收率81%)。
化合物XII:MS(ESI):434(M+H+),456(M+Na+)
实施例16:制备与实施例9相同的化合物X,采用以下路线制备
环丙物5(2.99g,14.3mmol)中,加入3-氨基喹啉(51g,36.1mmol),DMF(50ml),三乙胺(2.4ml,17.1mmol),140℃回流,反应72h,TLC分析,原料基本反应完全,减压蒸去溶剂,残余物经硅胶柱层析,得化合物X(3.54g,收率78%)
实施例17-19:式XIII、XIV、XV化合物的制备
实施例17:式XIII化合物的制备
1、2-溴代次黄嘌呤(20g,93mmol)中,加入1-胺基异喹啉(13g,90mmol),乙二醇甲醚(60ml)和水(200ml),加热回流,48h后,TLC监测反应完全,混合物倒入冰水中,析出固体。过滤,固体分别用浓氨水(200ml)和甲醇(3×50ml)洗涤,烘干,得粗产物,粗产物经硅胶柱层析,得产物12(14.2g,收率57%)。
2、喹啉产物12(12g,43mmol)中,加入三氯氧磷(150ml)和N,N-二甲基苯氨(15ml),回流30min,冷却至室温,反应液慢慢倾入冰水(2000ml)中,2h后,用醋酸调节pH值到3,过滤得到黄色固体,粗产物经硅胶柱层析,得到氯化物13(11.5g,收率90%)。
3、氯化物13(10g,34mmol)中加入环丙胺(10ml,145mmol),三乙胺(28ml,200mmol),DMF(100ml),100℃反应3h,TLC分析,反应完全。蒸出溶剂,残余物用乙二醇二甲醚溶解,过滤,滤液浓缩蒸干,硅胶柱层析得化合物XIII(4.2g,收率39%)。
化合物XIII:MS(ESI):318(M+H+),340(M+Na+)
实施例18:式XIV化合物的制备
无水乙腈(10ml)中,加入化合物XIII(4.76g,15mmol)和双(三甲基硅基)乙酰胺(BSA,6.3ml,25mmol),室温搅拌1小时后,加入四乙酰基呋喃核糖(1.27g,4mmol)溶于乙腈(10ml)的溶液和TMSTF(1.10ml,16mmol),加热回流5h,补加BSA(1.25ml,5mmol)再搅拌24h,TLC监测,已反应完全,减压浓缩。残余物溶于甲醇(20ml),通入氨气2h,减压蒸除溶剂,残余物经硅胶柱层析得到化合物XIV(4.2g,收率64%)。
化合物XIV:MS(ESI):450(M+H+),472(M+Na+)
实施例19:式XV化合物的制备
在2-(1-胺基异喹啉基)-6-环丙胺嘌呤,即化合物XIII(10g,31.5mmol)中,加入60%NaH(1.5g,37.8mmol)和无水乙腈150ml,氮气保护下,搅拌30min。分批加入3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖1-氯(12g,31.5mmol),约20min加完。加完后在室温下反应2h,过滤,将滤液蒸干,得油状物。用柱层析纯化,得2-(1-胺基异喹啉基)-6-环丙胺基-9-(3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖)嘌呤(7.09g,收率34%)。
将上述产物,甲醇钠(25mmol)和甲醇(400ml)室温搅拌反应5h,用醋酸调节pH到中性,蒸去溶剂。用柱层析纯化剩余物,得2-(1-胺基异喹啉基)-6-环丙基-9-(2-脱氧-β-D-呋喃核糖)嘌呤XV(3.8g,收率60.8%)。
化合物XV:MS(ESI):434(M+H+),456(M+Na+)
实施例20:采用以下路线制备实施例17的式XIII化合物
环丙物5(2.99g,14.3mmol)中,加入1-胺基异喹啉(51g,36.1mmol),DMF(50ml),三乙胺(2.4ml,17.1mmol),140℃回流,反应72h,TL℃分析,原料基本反应完全,减压蒸去溶剂,残余物经硅胶柱层析,得化合物XIII(4.16g,收率92%)
实施例21-22:式XVI、XVII、XVIII化合物的制备
实施例21:式XVI化合物的制备
化合物3(10g,34mmol)中,加入环丁胺(10.3g,145mmol),三乙胺(28ml,200mmol),DMF(100ml),100℃反应3h,TLC分析,反应完全,蒸出溶剂,残余物用乙二醇二甲醚溶解,过滤,滤液浓缩蒸干,硅胶柱层析得化合物XVI(6.8g,收率60%)。
化合物XVI:MS(ESI):332(M+H+),354(M+Na+)
实施例22:式XVII化合物的制备
无水乙腈(10ml)中,加入化合物XVI(4.97g,15mmol)和双(三甲基硅基)乙酰胺(BSA,6.3ml,25mmol),室温搅拌1小时后,加入四乙酰基呋喃核糖(1.27g,4mmol)溶于乙腈(10ml)的溶液和TMSTF(1.10ml,16mmol),加热回流5h,补加BSA(1.25ml,5mmol)再搅拌24h,TLC监测,已反应完全,减压浓缩。残余物溶于甲醇(20ml),通氨气2h,减压蒸除溶剂,残余物经硅胶柱层析得到化合物XVII(4.71g,收率71%)。
化合物XVII:MS(ESI):464(M+H+),486(M+Na+)
实施例23:式XVIII化合物的制备
在2-(6-胺基喹啉基)-6-环丁胺嘌呤,即化合物XVI(10g,31.5mmol)中,加入60%NaH(1.5g,37.8mmol)和无水乙腈150ml,氮气保护下,搅拌30min。分批加入3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖1-氯(12g,31.5mmol),约20min加完。加完后在室温下反应2h,过滤,将滤液蒸干,得油状物。用柱层析纯化,得2-(6-胺基喹啉基)-6-环丁胺基-9-(3,5-二对甲苯磺酸酯基-2-脱氧-β-D-呋喃核糖)嘌呤。
将上述产物,甲醇钠(25mmol)和甲醇(400ml)室温搅拌反应5h,用醋酸调节pH到中性,蒸去溶剂。用柱层析纯化剩余物,得2-(6-胺基喹啉基)-6-环丁基-9-(2-脱氧-β-D-呋喃核糖)嘌呤,即化合物XVIII(7g,收率51.8%)。
化合物XVIII:MS(ESI):448(M+H+),470(M+Na+)
实施例24:采用以下合成路线制备式XVI化合物
1、二氯嘌呤4(3.78g,20mmol)加入DMF(50ml)溶解,再加入环丁胺(1.4g,20mmol)和三乙胺(3.08ml,22mmol),加热至80℃,反应5h,TLC分析,反应完全,减压蒸去溶剂,残余物经硅胶柱层析,得环丁物14(4.1g,收率92%)。
2、环丁物14(3.19g,14.3mmol)中,加入6-氨基喹啉(5.1g,36.1mmol),DMF(50ml),三乙胺(2.4ml,17.1mmol),140℃回流,反应72h,TLC分析,原料基本反应完全,减压蒸去溶剂,残余物经硅胶柱层析,得化合物XVI(3.82g,收率81%)。
实施例25:
化合物I盐酸盐及乳酸盐的制备
化合物I盐酸盐的制备:
将化合物I(10g,31.54mmol),乙醇(210ml),H2O(25ml),加热溶解,滴加2mol/L盐酸(0.7ml,37.85mmol),滴加完后再回流反应0.5小时,缓慢冷却至室温,冷却至5℃以下,放置5小时,过滤,干燥,得浅黄色固体粉末10g,收率90%。
熔点:大于270℃。
化合物I乳酸盐的制备:
将化合物I(5g,15.77mmol),95%乙醇(105ml),H2O(12.5ml)加热溶解,滴加10%乳酸乙醇溶液,加完后,再回流反应1小时,缓慢冷却到室温,冷却至5℃以下,放置5小时,过滤,干燥,得黄色固体粉末5.6g,收率87%。
熔点:239-248℃。
实施例26:药物制剂的制备:
包衣片的制备:
片芯处方:
化合物I 50g
微晶纤维素 150g
乳糖 50g
羧甲基淀粉钠 25g
交联羧甲基纤维素钠 15g
微粉硅胶 1.5g
制成 1000片
制备工艺:准确称取处方量的化合物I与乳糖混匀后加入处方量的微粉硅胶助流以增加主药的流动性。再加入其它辅料充分混匀后粉末直接压片,即得。
包衣液的处方:
欧巴代(Opadry)25g,80%乙醇适量包衣。
注射剂的制备:
处方:
化合物I 50g
吐温-80 20g
药用乙醇 30g
注射用水 加至 10000mL
制成 1000瓶
制备工艺:准确称取处方量的化合物I与吐温-80混匀后研磨,加入0.3%药用乙醇溶液加热溶解。0.22μm滤膜无菌过滤,10ml/瓶灌封,100℃流通蒸气灭菌,即得。
Claims (15)
2、根据权利要求1所述的式(A)化合物或其盐、水合物,其特征在于其中所述W为H或为下列基团:
3、根据权利要求1所述的式(A)化合物或其盐、水合物,其特征在于其中所述的Y为H。
4、根据权利要求1所述的式(A)化合物或其盐、水合物,其特征在于其中所述的W为下列基团:
其中B,E,G,R,T,M均为H。
6、根据权利要求5所述的式(A)化合物或其盐、水合物,其特征在于其中所述Q为:
9、一种药物组合物,其特征在于该药物组合物由权利要求1至8中的任意一项的化合物或其盐、水合物与药用辅料组成的。
10、根据权利要求9所述的药物组合物,其特征在于其中所述药物组合物为片剂、胶囊剂、丸剂、口服液体制剂、颗粒剂、散剂、注射剂、植入剂或外用制剂。
11、权利要求1至8中的任意一项的化合物或其盐或水合物的制备方法,其特征在于该方法包括以下步骤:
(1)由式(j)化合物
与Q-NH2反应,生成式(b)化合物
在式(j)化合物中,加入有机溶剂及0.8~1.5mol/mol的Q-NH2,加热至50~150℃反应1~72小时,反应液加水,冷却放置;
(2)将式(b)化合物制为式(c)化合物
在式(b)化合物中,加入卤化剂,有机溶剂,在50~150℃下反应1~72小时,冷却,加水,用酸调节pH值至2~5,然后冷却放置;
(3)由式(c)化合物与W-NH2合成下式化合物
在式(c)化合物中,加入0.8~1.5mol/mol的W-NH2,缚酸剂,有机溶剂,在50-150℃下反应1-72小时,蒸去有机溶剂;
其中X为Br、X’为Cl,W同权利要求1中的定义。
12、权利要求1至8中的任意一项的化合物或其盐或水合物的制备方法,其特征在于该方法包括以下步骤:
(1)由式(k)化合物
与W-NH2反应,生成式(e)化合物
在式(k)化合物中,加入有机溶剂,加入0.8~1.5mol/mol的W-NH2,缚酸剂,加热至30~120℃,反应1~72小时,蒸去溶剂。
(2)将式(e)与Q-NH2反应生成(f)化合物
在式(e)化合物中,加入0.8~1.5mol/mol的Q-NH2,有机溶剂,缚酸剂,在70~170℃下反应1~72小时,蒸去溶剂。
其中X、X’为Cl,W同权利要求1中的定义。
13、根据权利要求1所述的化合物,其特征在于其中所述的盐为药学上可接受的盐,该盐可为由有机酸或无机酸得到的酸加合盐,优选为盐酸盐、氢溴酸盐、氢碘酸盐、对甲苯磺酸盐、磷酸盐、硫酸盐、高氯酸盐、乙酸盐、三氟乙酸盐、丙酸盐、枸橼酸盐、丙二酸盐、琥珀酸盐、乳酸盐、草酸盐、酒石酸盐和苯甲酸盐,该盐还可以是与碱形成的盐,包括与无机碱或有机碱得到的盐。
14、权利要求1至8中的任意一项的化合物或其盐、水合物在制备治疗或预防肿瘤疾病药物中的应用。
15、根据权利要求14所述的权利要求1至8中的任意一项的化合物或其盐、水合物在制备治疗或预防肿瘤疾病药物中的应用,其特征在于所述肿瘤疾病为肺癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、黑素瘤、子宫癌、卵巢癌、直肠癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌、软组织肉瘤、尿道癌、前列腺癌、淋巴细胞瘤、膀胱癌、肾或输尿管癌、脊椎肿瘤、脑干神经胶质瘤或垂体腺瘤。
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JP2008516106A JP2008546653A (ja) | 2005-06-16 | 2006-01-23 | N2−キノリン又はイソキノリン置換のプリン誘導体及びその製造方法並びにその用途 |
CA002611865A CA2611865A1 (en) | 2005-06-16 | 2006-01-23 | N2-quinolyl or isoquinolyl substituted purine derivatives, the preparation and uses thereof |
ES06705534.3T ES2529915T3 (es) | 2005-06-16 | 2006-01-23 | Derivados de purina sustituidos con N2-quinolilo o isoquinolilo, su preparación y sus usos |
PCT/CN2006/000113 WO2006133611A1 (fr) | 2005-06-16 | 2006-01-23 | Dérivés de purine substituée par un groupe n2-quinoléyle ou isoquinoléyle, leurs préparations et utilisations |
EP06705534.3A EP1897882B1 (en) | 2005-06-16 | 2006-01-23 | N2-quinolyl or isoquinolyl substituted purine derivatives, the preparation and uses thereof |
BRPI0611564-0A BRPI0611564A2 (pt) | 2005-06-16 | 2006-01-23 | derivados da purina por substituição de n2-quinolina ou isoquinolina e respectivos métodos de preparação e usos |
RU2007148681/04A RU2417230C2 (ru) | 2005-06-16 | 2006-01-23 | N2-хинолил- или изохинолилзамещенные производные пурина, способы их получения и использования |
AU2006257583A AU2006257583B2 (en) | 2005-06-16 | 2006-01-23 | N2-quinolyl or isoquinolyl substituted purine derivatives, the preparation and uses thereof |
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JP (1) | JP2008546653A (zh) |
CN (1) | CN100526315C (zh) |
AU (1) | AU2006257583B2 (zh) |
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CA (1) | CA2611865A1 (zh) |
ES (1) | ES2529915T3 (zh) |
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CN101497615B (zh) * | 2008-01-29 | 2010-12-15 | 浙江医药股份有限公司新昌制药厂 | 取代嘌呤,其制备方法及在医学中的应用 |
WO2015027667A1 (zh) | 2013-08-30 | 2015-03-05 | 浙江医药股份有限公司新昌制药厂 | 2,6-二含氮取代的嘌呤衍生物及其制备方法和其药物组合物与应用 |
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- 2005-06-16 CN CNB2005100268463A patent/CN100526315C/zh not_active Expired - Fee Related
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2006
- 2006-01-23 ES ES06705534.3T patent/ES2529915T3/es active Active
- 2006-01-23 EP EP06705534.3A patent/EP1897882B1/en not_active Not-in-force
- 2006-01-23 AU AU2006257583A patent/AU2006257583B2/en not_active Ceased
- 2006-01-23 WO PCT/CN2006/000113 patent/WO2006133611A1/zh active Application Filing
- 2006-01-23 RU RU2007148681/04A patent/RU2417230C2/ru not_active IP Right Cessation
- 2006-01-23 JP JP2008516106A patent/JP2008546653A/ja active Pending
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2008128428A1 (fr) * | 2007-04-20 | 2008-10-30 | Zhe Jiang Medicine Co., Ltd Xinchang Pharmaceutical Factory | Dérivés de purine substitués contenant 2, 6 diazote, préparation et utilisations de ceux-ci |
EP2149574A1 (en) * | 2007-04-20 | 2010-02-03 | ZheJiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory | 2, 6-dinitrogen-containing substituted purine derivatives, the preparation and uses thereof |
EP2149574A4 (en) * | 2007-04-20 | 2011-06-15 | Zhejiang Med Xinchang Pharm | 2, 6-NITROGENIC SUBSTITUTED PURINE DERIVATIVES, THEIR PREPARATION AND USE |
CN101497615B (zh) * | 2008-01-29 | 2010-12-15 | 浙江医药股份有限公司新昌制药厂 | 取代嘌呤,其制备方法及在医学中的应用 |
WO2015027667A1 (zh) | 2013-08-30 | 2015-03-05 | 浙江医药股份有限公司新昌制药厂 | 2,6-二含氮取代的嘌呤衍生物及其制备方法和其药物组合物与应用 |
CN104418858A (zh) * | 2013-08-30 | 2015-03-18 | 浙江医药股份有限公司新昌制药厂 | 2,6-二含氮取代的嘌呤衍生物及其制备方法和其药物组合物与应用 |
CN104418858B (zh) * | 2013-08-30 | 2018-12-11 | 浙江医药股份有限公司新昌制药厂 | 2,6-二含氮取代的嘌呤衍生物及其制备方法和其药物组合物与应用 |
Also Published As
Publication number | Publication date |
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US20060293274A1 (en) | 2006-12-28 |
AU2006257583B2 (en) | 2013-01-24 |
RU2007148681A (ru) | 2009-07-27 |
EP1897882A4 (en) | 2009-12-23 |
RU2417230C2 (ru) | 2011-04-27 |
CN100526315C (zh) | 2009-08-12 |
CA2611865A1 (en) | 2006-12-21 |
WO2006133611A1 (fr) | 2006-12-21 |
EP1897882B1 (en) | 2014-12-10 |
AU2006257583A1 (en) | 2006-12-21 |
US7399754B2 (en) | 2008-07-15 |
ES2529915T3 (es) | 2015-02-25 |
JP2008546653A (ja) | 2008-12-25 |
EP1897882A1 (en) | 2008-03-12 |
BRPI0611564A2 (pt) | 2010-09-21 |
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