CN102295635B - 抗肿瘤药物四氢化萘酰胺类化合物及其药学上可接受的盐及制备方法和应用 - Google Patents
抗肿瘤药物四氢化萘酰胺类化合物及其药学上可接受的盐及制备方法和应用 Download PDFInfo
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Abstract
本发明涉及通式为Ⅰ所示的新的化合物四氢化萘酰胺类化合物,或此类化合物药学上可接受的盐,做为一种抗肿瘤药物。本发明还提供了这类化合物的制备方法,以及含有它们的药物组合物,和体外和体内的抗肿瘤作用结果和急性毒性研究,本发明得到的抗肿瘤药物四氢化萘酰胺类化合物,具有更优良的抗肿瘤活性和安全性,可在治疗白血病、肺癌、结肠癌、卵巢癌及肾癌等肿瘤中的应用,因而治疗窗宽,所以在医药领域中作为抗肿瘤剂是非常有应用价值的。
Description
技术领域
本发明属于医药领域,尤其涉及抑制肿瘤细胞生长、发挥抗肿瘤效果的四氢化萘酰胺类化合物和其药学上可接受的盐及制备方法及用途。
背景技术
伊马替尼竞争性抑制三磷酸腺苷(ATP)与胸苷激酶(TK)受体如KIT的结合位点,阻滞TK磷酸化,从而抑制信号传导,并可抑制与激酶活性相关的KIT突变(引起KIT受体活化)和野生型的KIT。其作用靶位主要有3种:Abelson(ABL)蛋白、KIT蛋白和血小板衍生生长因子(PDGF)受体。伊马替尼可通过功能获得性KIT突变引起不依赖干细胞因子的激活作用,来减少来自GIST的细胞系(GIST882)的激酶磷酸化,当浓度达到1μmol/L时,可完全抑制激酶磷酸化。
伊马替尼,2001年5月被FDA批准用于治疗慢性粒细胞白血病(CML),2003年被FDA批准用于治疗胃肠道间质瘤(GIST)。
其结构为:
伊马替尼有明显的不良反应,多数患者在服用期间会出现一些不良反应,但绝大多数属轻到中度。
在CML的临床试验过程中,因药物相关的不良反应而停药者,在α-干扰素治疗失败的慢性期患者中仅占1%,加速期中约占2%,急变期占5%。
在GIST临床试验中,因药物相关的不良事件而停药者占3.4%。
CML和GIST病人发生的不良反应相似,只有两种例外:GIST病人发生骨髓抑制较少,肿瘤内出血仅在GIST病人中观察到。在CML和GIST病人中,最常见报告的与药物治疗相关的不良事件有轻度恶心(50~60%)、呕吐、腹泻、腹痛、乏力、肌痛、肌痉挛及红斑,这些不良事件均容易处理。
所有研究中,均报告有浮肿和水潴留,发生率分别为47~59%和7~13%,其中严重者分别为1~3%和1~2%。大多数患者的浮肿表现为眶周和下肢浮肿。曾有青光眼的个别报告,与水潴留有关。也有胸水、腹水、肺水肿和体重迅速增加的报告。这些事件通常可采用暂停使用伊马替尼、使用利尿剂或给予其它支持治疗而得以缓解。但是个别患者情况严重,甚至威胁生命。有1例急变期患者因并发胸水、充血性心力衰竭和肾功能衰竭的复杂临床情况而死亡。
当伊马替尼与高剂量的化疗药联合使用时,可发生一过性的肝毒性,如转氨酶升高及高胆红素血症。
发明内容
为解决以上问题,本发明的目的是提供比伊马替尼具有更优良的抗肿瘤活性和安全性,及治疗窗宽的抗肿瘤药物四氢化萘酰胺类化合物和其药学上可接受的盐。
本发明的另一目的是提供抗肿瘤药物四氢化萘酰胺类化合物和其药学上可接受的盐的制备方法及其应用。
本发明中,为改变伊马替尼的上述弱点,我们对其进行结构修饰,合成多种四氢化萘酰胺类化合物和其药学上可接受的盐,对其抗肿瘤活性进行研究,结果发现用下述通式[Ⅰ]和[Ⅱ]表示的化合物具有极其优良的抗肿瘤活性、稳定性和安全性。
本发明涉及用通式[Ⅰ]表示的化合物和其药学上可接受的盐:
[Ⅰ]
式中:
R1是一个饱和环状氨基,所述的饱和环状氨基选自于哌啶基,哌嗪基、咪唑烷基、吡咯烷基、杂氮环丁烷基和吗啉基,或者每个基团可选地被1、2、3或4个R1 a取代,所述的R1 a是氢原子、卤素、氨基、氰基、C1-6烷基、C1-6羟烷基、C1-6卤代烷基或C1-6氰代烷基。
D选自于吡啶基、嘧啶基、吡嗪基、三嗪基、噻唑基、异噻唑基、咪唑基、噁唑基、异噁唑基、三唑基、或吡唑基,或者每个基团可选地被1、2、或3个R,2所取代,所述的R2独立选自于卤素、氰基、氨基、C1-6烷基、C1-6羟烷基、C1-6卤代烷基、或C1-6氰代烷基。
E选自于吡啶基、嘧啶基、吡嗪基、三嗪基、噻唑基、异噻唑基、咪唑基、噁唑基、异噁唑基、三唑基、吡唑基、氮噁唑基、吡咯并吡啶基、吡咯并嘧啶基、吡唑并嘧啶基、喹啉基、异喹啉基、喹唑啉基、哌嗪基或吗啉基,或者每个基团可选地被1、2、或3个R3所取代,所述的R3独立选自于卤素、氰基、氨基、C1-6烷基、C1-6羟烷基、C1-6卤代烷基、或C1-6氰代烷基。
上述的用通式[Ⅰ]表示的化合物和其药学上可接受的盐,优选的,具有如下结构通式[Ⅱ]:
其中:
R4和R5独立地选自于氢原子、氰基、C1-6烷基、C1-6羟烷基、C1-6卤代烷基、C1-6氰代烷基;
R6独立地选自于氢原子、C1-6烷基、C2-6羟烷基、C2-6卤代烷基、C1-6氰代烷基、酰基和羧酸酯;
p是0、1或2。
上述通式[Ⅱ]表示的化合物和其药学上可接受的盐,优选的,D为嘧啶基,E为吡啶基,具有通式[Ⅲ]的结构:
上述通式[Ⅲ]表示的化合物和其药学上可接受的盐,优选的化合物1为:D为嘧啶基,E为吡啶基,R4和R5为氢原子,R6为甲基,p为1,其结构式如下:
上述通式[Ⅱ]表示的化合物和其药学上可接受的盐,优选的,D为嘧啶基,E为嘧啶基,具有通式[Ⅳ]的结构:
上述通式[Ⅳ]表示的化合物和其药学上可接受的盐,优选的化合物2为:D为嘧啶基,E为嘧啶基,R4和R5为氢原子,R6为甲基,p为1,其结构式如下:
上述的化合物及其药学上可接受的盐,作为有效成分在制备治疗肿瘤疾病的药物中的应用。
一种药物组合物,包括上述的化合物及其药学上可接受的盐,和至少一种药学上可接受的载体。
在治疗肿瘤疾病的药物中的应用,包括对:白血病、肺癌、肝癌、结肠癌、神经癌、黑色素瘤、卵巢癌、肾癌前列腺癌和乳腺癌等。
本发明的有益效果是:本发明得到的抗肿瘤药物四氢化萘酰胺类化合物及其药学上可接受的盐,具有更优良的抗肿瘤活性和安全性,可在治疗白血病、肺癌、结肠癌、卵巢癌及肾癌等肿瘤中的应用,抗癌谱广,治疗窗宽,所以在医药领域中作为抗肿瘤剂是非常有应用价值的。
附图说明
图1是本发明通式[Ⅰ]表示的化合物及其药学上可允许的盐的合成机理图。
图2是本发明化合物1的合成工艺路线图。
图3是本发明化合物2的合成工艺路线图。
具体实施方式
以下举出实施例,进一步具体地说明本发明,但本发明不受这些实施例的限制。
下面将详细描述本发明的示例性实施方案。然而,这些实施方案仅为说明目的,并不旨在限制本发明的范围。
本发明化合物还包括药学上可接受的盐。药学上可接受的盐是指把母体化合物中的碱性基团转换成盐的形式。药学上可接受的盐包括,但不限于,碱性基团例如胺(氨)基的无机或有机酸盐。
药学上可接受的盐可以由无机或有机酸制备,无机酸可以包括但不仅限于盐酸、氢溴酸、硫酸、硝酸、磷酸等。有机酸可以包括但不仅限于乙酸、丙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。
本文所用的“药学上可接受的载体”包括任何和全部的药学上的溶剂、分散介质、包衣、等渗和吸收延迟剂等,这样的介质和药剂用于药学活性物质,在本领域是众所周知的,除非任何常规介质或药剂与活性成分不相容,其在治疗组合物中的应用是可以预期的,补充的活性成分也可以并入组合物中。
本发明的药物组合物可口服、注射、喷雾吸入、皮肤外用、直肠用、鼻腔用、阴道用、腹腔用、或通过植入储液囊或透皮贴剂等用途而使用。
本发明重要方面是本发明可用于治疗涉及肿瘤疾病,包括:白血病、肺癌、结肠癌、卵巢癌及肾癌等。
本发明的另一方面涉及制备通式[Ⅰ]化合物的制备方法。如图1所示,通式[Ⅰ]化合物可以使用以下的方法和工艺制备。
6-甲氧基-1-萘满酮在48% HBr溶液中回流,得到中间体1-1,其酚羟基用三氟甲磺酸酐保护得到中间体1-2,1-2在DMF中与CO反应,用钯作为催化剂,如二醋酸钯、1,3-二(苯基磷)丙烷(dppp)或双(三苯基膦)二氯化钯(II)[(PPh3)2PdCl2] 得到中间体1-3,1-3在醇溶剂(例如乙醇)中,被还原剂(例如硼氢化钠)还原得到中间体1-4。1-4的羟基在例如二氯亚砜的试剂作用下氯代,得到中间体1-5,1-5的氯基团被一个环胺基(或环状氨基)取代,用三乙胺或碳酸钾做为碱,从而得到中间体1-6,1-6在三甲基铝甲苯溶液中与6-甲基-N1-[(4-吡啶-3-基)嘧啶-2-基]苯-1,3-二胺反应得到通式[Ⅰ]化合物。也可以由1-6中的酯基水解得到中间体1-7,1-7在氯化亚砜作用下形成酰氯后与醇或氨基反应或在偶联剂例如EDCI(1-乙基-3-(3-二甲胺丙基)碳二亚胺)或DCC(1,3-二环己基碳二亚胺),以DMAP(4,4-二甲氨基吡啶)或HOBT(1-羟基苯并三氮唑)为催化剂条件下直接与醇或氨基反应得到通式[Ⅰ]化合物。
实施例1 化合物1及其药学上可接受的盐的制备
(一)N-{4-甲基-3-[(4-吡啶-3基)嘧啶-2-氨基]苯基}-5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺(化合物1)的制备,化合物1的结构式如下:
步骤A:6-羟基-1-萘满酮的合成
将6-甲氧基-1-萘满酮(17.6克,100毫摩尔)在100毫升48 %溴化氢溶液中100℃下反应24小时后冷却至室温,将反应液加入冰水中搅拌有大量固体析出,过滤出固体并用5%碳酸氢钠水溶液漂洗,再用去离子水洗涤至中性,干燥,粗产物用硅胶柱纯化,用乙酸乙酯:正己烷=1:5洗脱得产物13.9克,产率86.0 %。MS(M+1)=163.14。
步骤B:三氟甲磺酸-5-羰基-5,6,7,8-四氢萘-2-酯的合成
将6-羟基-1-萘满酮(8.1克,50毫摩尔)溶解在50毫升的二氯甲烷中,缓慢加入用20毫升二氯甲烷溶液稀释的三氟甲磺酸酐14.1克,0~5 ℃条件下边搅拌边缓慢滴加用20毫升二氯甲烷稀释的三乙胺5.05克,约10分钟滴加完毕后,缓慢升至室温搅拌2小时后,停止反应,反应液用5%碳酸氢钠水溶液洗2次,盐水洗2次,有机相用无水硫酸钠干燥,过滤后浓缩得产物13.97克,产率95.2% 。MS(M+1)=295.21。
步骤C:5-羰基-5,6,7,8-四氢萘-2-羧酸甲酯的合成
将三氟甲磺酸-5-羰基-5,6,7,8-四氢萘-2-酯(11.8克,40毫摩尔)溶解在50毫升甲醇中,加入DMF 5毫升、DIEA(N,N-二异丙基乙胺)5毫升、二醋酸钯4克、1,3-双(二苯基膦)丙烷4克,密闭反应体系,抽真空,加入氮气,再抽真空后,通入一氧化碳气囊,在65℃下搅拌反应22小时,反应液加硅藻土过滤,硅藻土固体用乙醇洗净后合并滤液相,浓缩后用200毫升乙酸乙酯溶解,用食盐水洗(200、200、100)后有机相加入无水硫酸钠干燥,过滤,滤液减压蒸馏浓缩后硅胶柱纯化,在乙酸乙酯:正己烷=1:2流动相条件下分离得产物5.3克,产率65 %。MS(M+1)=205.34。
步骤 D:5-羟基-5,6,7,8-四氢萘-2-羧酸甲酯的合成
把5-羰基-5,6,7,8-四氢萘-2-羧酸甲酯(4.08克,20毫摩尔)溶解在50毫升的乙醇溶液中,慢慢加入硼氢化钠(0.76克,20毫摩尔),室温下搅拌3小时,将反应液减压浓缩后加入乙酸乙酯50毫升,用盐水洗2次,无水硫酸钠干燥,过滤浓缩后得到4.1克产物,产率99.5% 。MS(M+1)=207.12。
步骤E:5-氯-5,6,7,8-四氢萘-2-羧酸甲酯的合成
把5-羟基-5,6,7,8-四氢萘-2-羧酸甲酯(3.09克,15毫摩尔)溶解在20毫升的二氯甲烷溶液中,0-5℃下慢慢滴加含有氯化亚砜(7.08克,60毫摩尔)的10毫升二氯甲烷溶液。滴加完毕后升至室温下反应6小时,将反应液减压浓缩后加入乙酸乙酯50毫升,用盐水洗2次(50毫升),无水硫酸钠干燥,过滤浓缩后得到3.18克产物,产率94.5% 。MS(M+1)=225.21。
步骤 F:5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-羧酸甲酯的合成
把5-氯-5,6,7,8-四氢萘-2-羧酸甲酯(2.41克,10毫摩尔)溶解在20毫升DMF溶剂中,加入碳酸钾(2.78克,20毫摩尔),N-甲基哌嗪(2克,20毫摩尔),50℃下反应5小时后,将反应液加入乙酸乙酯80毫升,用稀盐酸水溶液调PH值至中性后,分出乙酸乙酯相并用饱和食盐水洗涤(80×3),无水硫酸钠干燥,过滤,滤液减压旋出有机溶剂后硅胶柱层析分离,甲醇:二氯甲烷=30:1条件下得到产物2.12克,产率73.9 % ,MS(M+1)=289.31。
步骤 G:5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-羧酸的合成
把5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-羧酸甲酯(2.88克,10毫摩尔)溶解到30毫升甲醇及20毫升四氢呋喃溶液中,加入含2N的NaOH(10毫升,20毫摩尔),室温下反应16小时,用2N盐酸水溶液调PH=4后,减压旋出有机溶剂,加入乙酸乙酯60毫升并用饱和食盐水洗涤(60×3),乙酸乙酯相用无水硫酸钠干燥,过滤,滤液减压旋出有机溶剂后硅胶柱层析分离,甲醇:二氯甲烷:冰乙酸=20:1:5滴的条件下分离得到产物2.16克,产率78.8% ,MS(M+1)=275.18。
步骤 H:N-{4-甲基-3-[(4-吡啶-3基)嘧啶-2-氨基]苯基}-5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺(化合物1)的合成
方法一:
将5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-羧酸甲酯(2.88克,10毫摩尔)和6-甲基-N1-[(4-吡啶-3-基)嘧啶-2-基]苯-1,3-二胺 (3.32克,12毫摩尔)悬浮在30毫升的甲苯中,加入2M的三甲基铝甲苯溶液(5毫升,10毫摩尔),混合物100℃下反应6小时,溶液冷却。在搅拌下加入酒石酸钾钠水溶液(50毫升)。其溶液用乙酸乙酯提取3次(100、100、50毫升),合并后的提取液用碳酸氢钠洗(100毫升)和盐水洗(100、100、50毫升),无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱纯化在50%乙酸乙酯/二氯甲烷/1%三乙胺流动相条件下分离得到产物,即化合物1,2.32克,产率43.5%。
方法二:
将5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-羧酸(1.37克,5毫摩尔)、6-甲基-N1-[(4-吡啶-3-基)嘧啶-2-基]苯-1,3-二胺 (1.83克,5.5毫摩尔)、 EDCI(1-乙基-3-(3-二甲胺丙基)碳二亚胺)(1.15克,6毫摩尔)、DMAP(4,4-甲氨基吡啶)(0.31克,2.5毫摩尔)加入到30毫升的四氢呋喃与10毫升DMF混合液中,室温下反应4小时后,将反应液减压旋出四氢呋喃,加入乙酸乙酯50毫升,并用食盐水洗涤3次(60、60、30毫升),乙酸乙酯相用无水硫酸钠干燥,过滤,滤液减压旋出溶剂,硅胶柱层析在50%乙酸乙酯/二氯甲烷/1%三乙胺流动相条件下分离得到目标产物,即化合物1 ,1.65克,产率61.8%。
MS(M+1)=534.21。1H-NMR (DMSO-d 6 ppm): δ 9.98 (s, 1H); 9.07 (s, 1H); 8.67(s,1H); 8.61(d, J = 4.8 Hz, 1H); 8.54(d, J = 4.8 Hz, 1H); 8.47(d, J = 9.0 Hz, 1H); 7.89(s,1H); 7.76(s,1H); 7.71(d, J = 9.0 Hz, 1H); 7.54(dd, J = 8.0 Hz, 4.8 Hz, 1H); 7.37(d, J = 8.0 Hz, 1H); 7.33(d, J = 4.8 Hz, 1H); 7.17(d, J = 9.0 Hz, 1H); 6.97 (d, J = 9.0 Hz, 1H); 4.34(t, J = 9.0 Hz, 1H); 2.41-2.83(m, 10H); 2.05(s, 3H); 2.00(s, 3H); 1.92(m, 2H); 1.76(m, 2H)。
(二)N-{4-甲基-3-[(4-吡啶-3基)嘧啶-2-氨基]苯基} -5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺甲磺酸盐(环苯替尼)的合成,其结构式如下:
将反应瓶加入化合物1 (5.33克,10毫摩尔),无水甲醇100毫升,甲烷磺酸(1.01克,10.5毫摩尔),70℃下回流反应1小时后,加入药用脱色炭2克,再回流1小时后,抽滤,滤液减压浓缩后加入异丙醇100毫升搅拌结晶。过滤,烘干得产物N-{4-甲基-3-[(4-吡啶-3基)嘧啶-2-氨基]苯基} -5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺甲磺酸盐5.94克,产率94.5% 。熔点:191~193℃。元素分析:C33H39N7O4S
计算值:C, 62.94; H, 6.24; N, 15.57; 测试值:C 62.82;H 6.44;N 15.31。
实施例2 4-{6-[({4-甲基-3-[(4-吡啶-3-基嘧啶-2-基)氨基]苯基}氨基)羰基]-1,2,3,4-四氢萘-1-基}哌嗪-1-羧酸叔丁酯的制备
其结构式如下:
步骤A: 4-[6-(甲氧基羰基)-1,2,3,4-四氢萘-1-基]哌嗪-1基-羧酸叔丁基酯的合成
将5-氯-5,6,7,8-四氢萘-2-羧酸甲酯(22.4克,100豪摩尔)、碳酸钾(27.8克,200毫摩尔)、哌嗪-1-羧酸叔丁基酯(20.5克,110毫摩尔)加入到300毫升DMF中,40℃下搅拌5小时,过滤不溶物,滤液加入到乙酸乙酯800毫升中,用盐水(3×800毫升)洗,有机相加入无水硫酸钠干燥,过滤,滤液减压浓缩后硅胶柱层析在乙酸乙酯:正己烷=1:1条件下洗脱得到产物在100毫升48 %溴化氢溶液中100℃下反应24小时后冷却至室温,将反应液加入冰水中搅拌有大量固体析出,过滤出固体并用5%碳酸氢钠水溶液漂洗,再用去离子水洗涤至中性,干燥,粗产物用硅胶柱纯化,用乙酸乙酯:正己烷=1:5洗脱得产物30.7克,产率82.0 % 。MS(M+1)=375.35。
步骤B: 5-(4-叔丁氧羰基-哌嗪-1-基)-5,6,7,8-四氢萘-2-羧酸的合成
把4-[6-(甲氧基羰基)-1,2,3,4-四氢萘-1-基]哌嗪-1基-羧酸叔丁基酯(3.74克,10毫摩尔)溶解到80毫升甲醇及20毫升四氢呋喃溶液中,加入含2N的NaOH(10毫升,20毫摩尔),室温下反应12小时,用2N盐酸水溶液调PH=5~6后,减压旋出有机溶剂,加入乙酸乙酯100毫升并用饱和食盐水洗涤(3×100毫升),乙酸乙酯相用无水硫酸钠干燥,过滤,滤液减压旋出有机溶剂后硅胶柱层析分离,甲醇:二氯甲烷:冰乙酸=20:1:5滴的条件下分离得到产物3.07克,产率85.3% ,MS(M+1)=361.27。
步骤C:4-{6-[({4-甲基-3-[(4-吡啶-3-基嘧啶-2-基)氨基]苯基}氨基)羰基]-1,2,3,4-四氢萘-1-基}哌嗪-1-羧酸叔丁酯的合成
将5-(4-叔丁氧羰基-哌嗪-1-基)-5,6,7,8-四氢萘-2-羧酸(1.8克,5毫摩尔)、6-甲基-N1-[(4-吡啶-3-基)嘧啶-2-基]苯-1,3-二胺 (1.83克,5.5毫摩尔)、 EDCI(1-乙基-3-(3-二甲胺丙基)碳二亚胺)(1.15克,6毫摩尔)、DMAP(4,4-甲氨基吡啶)(0.31克,2.5毫摩尔)加入到30毫升的四氢呋喃与10毫升DMF混合液中,室温下反应6小时后,将反应液减压旋出四氢呋喃,加入乙酸乙酯50毫升,并用食盐水洗涤3次(60、60、30毫升),乙酸乙酯相用无水硫酸钠干燥,过滤,滤液减压旋出溶剂,硅胶柱层析在50%乙酸乙酯/二氯甲烷/1%三乙胺流动相条件下分离得到目标产物2.76克,产率89.2%。
MS(M+1)=620.43。1H-NMR (DMSO-d 6 ppm): δ 10.01 (s, H); 9.23 (s, 1H); 8.94 (s, 1H); 8.61(d, J = 4.8 Hz, 1H); 8.51(d, J = 5.2 Hz, 1H); 8.45(d, J = 8.4 Hz, 1H); 7.98(s,1H); 7.74(s,1H); 7.72(d, J = 8.0 Hz, 1H); 7.55(dd, J = 8.0 Hz, 4.8 Hz, 1H); 7.47(d, J = 8.4 Hz, 1H); 7.44(d, J = 5.2 Hz, 1H); 7.19(d, J = 7.6 Hz, 1H); 7.03 (d, J = 9.0 Hz, 1H); 4.32(t, J = 8.0 Hz, 1H); 3.12-3.31(m, 4H); 2.51-2.83(m, 4H); 2.45(m, 2H); 2.35(m, 2H); 2.31(m, 2H); 2.08 (s, 3H); 1.95(m, 2H); 1.77(m, 2H); 1.46(s, 9H)。
实施例3 N-{4-甲基-3-[(4-吡啶-3基)嘧啶-2-氨基]苯基}-5-(哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺的制备
其结构式如下:
将4-{6-[({4-甲基-3-[(4-吡啶-3-基嘧啶-2-基)氨基]苯基}氨基)羰基]-1,2,3,4-四氢萘-1-基}哌嗪-1-羧酸叔丁酯(1.86克,3毫摩尔)溶解在10毫升三氟乙酸:二氯甲烷=1:4的混合溶液中。在常温下搅拌半小时后,加入碳酸钠水溶液20毫升调节PH至弱碱性,有机相加入无水硫酸钠干燥,过滤,滤液减压浓缩,得产物1.48克,产率95.1%。
MS(M+1)=520.22。1H-NMR (DMSO-d 6 ppm): δ 10.03 (s, 1H); 9.22 (s, 1H); 8.96(s,1H); 8.64(d, J=4.8 Hz, 1H); 8.52(d, J=5.2 Hz, 1H); 8.36(d, J=8.0 Hz, 1H); 8.02(s,1H); 7.76(s,1H); 7.77(d, J=8.0 Hz, 1H); 7.55(dd, J=8.0 Hz, 4.8 Hz, 1H); 7.46(d, J=8.2 Hz, 1H); 7.35(d, J=5.2 Hz, 1H); 7.33(d, J=8.0 Hz, 1H); 7.15(d, J=8.8 Hz, 1H); 4.26(t, J=6.8 Hz, 1H); 2.87(m, 2H); 2.66(m, 4H); 2.38(m, 2H); 2.28(m,2H); 2.22(s,3H); 1.86(m,2H); 1.75(m,2H)。
实施例4 N-{4-甲基-3-[(4-吡啶-3基)嘧啶-2-氨基]苯基}-5-[4-(2-氯乙酰)哌嗪-1-基] -5,6,7,8-四氢萘-2-酰胺的制备
其结构式如下:
将N-[4-甲基-3-(4-吡啶-3-基嘧啶-2-氨基)苯基]-5-(哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺(0.52克,1毫摩尔)溶解在乙腈(10毫升)中,加入氯代乙酰氯(0.14克,1.2毫摩尔),滴加三乙胺(121毫克,1.2毫摩尔),室温下搅拌1小时后将反应液减压浓缩,加入甲苯20毫升,析出白色固体,固体用甲苯洗,过滤,固体干燥得产物0.54克。产率90.8%。
MS(M+1)=596.21。1H-NMR (DMSO-d 6 ppm): δ 10.14 (s, 1H); 9.25 (s, 1H); 8.98(s,1H); 8.67(d, J=4.8 Hz, 1H); 8.49(d, J=5.2 Hz, 1H); 8.46(d, J=8.4 Hz, 1H); 8.05(s,1H); 7.77(s,1H); 7.75(d, J=8.8 Hz, 1H); 7.50(dd, J=8.0 Hz, 4.8 Hz, 1H); 7.46(d, J=8.2 Hz, 1H); 7.41(d, J=5.2 Hz, 1H); 7.35(d, J=7.6 Hz, 1H); 7.17(d, J=8.8 Hz, 1H); 4.31(t, J=6.8 Hz, 1H); 2.2-3.0(m, 12H); 2.20(s, 3H); 2.03(m, 2H)。
实施例5 N-{4-甲基-3-[(4-吡啶-3基)嘧啶-2-氨基]苯基} -5-[(4-氰甲基)哌嗪-1-基] -5,6,7,8-四氢萘-2-酰胺的制备
其结构式如下:
将N-[4-甲基-3-(4-吡啶-3-基嘧啶-2-氨基)苯基]-5-(哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺(0.52克,1毫摩尔)溶解在乙腈(10毫升)中,加入氯乙腈(0.9克,1.2毫摩尔),滴加三乙胺(121毫克,1.2毫摩尔),室温下搅拌1小时后将反应液减压浓缩,加入甲苯20毫升,析出白色固体,固体用甲苯洗,过滤,固体干燥得产物0.54克。产率90.8%。
MS(M+1)=559.32。1H-NMR (DMSO-d 6 ppm): δ 10.10 (s, 1H); 9.33 (s, 1H); 8.96(s,1H); 8.77(d, J=4.8 Hz, 1H); 8.48(d, J=5.2 Hz, 1H); 8.43(d, J=8.4 Hz, 1H); 8.11(s,1H); 7.78(s,1H); 7.74(d, J=8.8 Hz, 1H); 7.52(dd, J=8.0 Hz, 4.8 Hz, 1H); 7.47(d, J=8.2 Hz, 1H); 7.44(d, J=5.2 Hz, 1H); 7.28(d, J=7.6 Hz, 1H); 7.15(d, J=8.8 Hz, 1H); 4.33(t, J=6.8 Hz, 1H); 3.48(s, 2H); 2.3-3.1(m, 10H); 2.18(s, 3H); 2.14(m, 2H); 1.84 (m, 2H)。
实施例6 化合物2及其药学上可接受的盐的制备
(一)N-{4-甲基-3-[(4-嘧啶-5基)嘧啶-2-氨基]苯基}-5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺(化合物2)的制备,其结构式如下:
步骤A:5-乙酰基嘧啶的合成
将1-(嘧啶-5-基)乙醇(2.48克,20毫摩尔)溶解在50毫升二氯甲烷中,加入活性二氧化锰(3克),室温下反应3小时,过滤,滤液减压浓缩柱层析分离得到产物1克,产率45%,MS(M+1)=123.11。
步骤B:(2E)-3-(二甲氨基)-1-(嘧啶-5-基)丙-2-烯-1-酮的合成
将5-乙酰基嘧啶(1克,8.2毫摩尔)和N,N-二甲基甲酰胺二甲基缩醛(1.3克,11毫摩尔)溶解在20毫升的异丙醇中,回流搅拌24小时。冷却到室温,其溶液在减压下浓缩。其残留物加入乙醚。在冰水浴里冷却几小时后,其固体过滤收集,并用冷乙醚洗。干燥得产物1.05克,产率61.9%,MS(M+1)=178.34。
步骤C:N-(2-甲基-5-硝基苯基)-4,5ˊ-二嘧啶-2-胺的合成
将(2E)-3-(二甲氨基)-1-(嘧啶-5-基)丙-2-烯-1-酮(1克,5.6毫摩尔)和N-(2-甲基-5-硝基苯)胍硝酸盐(1.44克,5.6毫摩尔)悬浮在20毫升异丙醇中。加入氢氧化钠(0.28克,7毫摩尔)。混合液在回流搅拌8小时冷却到室温。过滤收集固体,并用异丙醇和乙醚洗涤。过滤收集固体,真空干燥后得到产物1.26克,产率73.5%,MS(M+1)=309.21。
步骤D:N
1
-([4,5ˊ-二嘧啶]-2-基)-6-甲基苯-1,3-二胺的合成
将氯化亚锡二水化物(3.6克,16毫摩尔)溶于10毫升浓盐酸中,在强烈搅拌下将此溶液加至N-(2-甲基-5-硝基苯基)-4,5ˊ-二嘧啶-2-胺里,搅拌2小时后,将混合液浇到冰水里,其混合物用碳酸钾中和至PH值=8,然后用乙酸乙酯提取3次,合并后的提取液用盐水洗涤,无水硫酸钠干燥,然后再减压下浓缩,得到产物0.68克,产率63.0%。MS(M+1)=279.33。
步骤E:N-{4-甲基-3-[(4-嘧啶-5基)嘧啶-2-氨基]苯基}-5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺(化合物2)的合成
将5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-羧酸(1.37克,5毫摩尔)、N1-([4,5ˊ-二嘧啶]-2-基)-6-甲基苯-1,3-二胺(1.53克,5.5毫摩尔)、 EDCI(1-乙基-3-(3-二甲胺丙基)碳二亚胺)(1.15克,6毫摩尔)、DMAP(4,4-甲氨基吡啶)(0.31克,2.5毫摩尔)加入到30毫升的四氢呋喃与10毫升DMF混合液中,室温下反应4小时后,将反应液减压旋出四氢呋喃,加入乙酸乙酯50毫升,并用食盐水洗涤3次(60、60、30毫升),乙酸乙酯相用无水硫酸钠干燥,过滤,滤液减压旋出溶剂,硅胶柱层析在50%乙酸乙酯/二氯甲烷/1%三乙胺流动相条件下分离得到目标产物,即化合物2,1.57克,产率58.8%。
MS(M+1)=535.54。1H-NMR (DMSO-d 6 ppm): δ 10.04 (s, 1H); 9.45 (s, 2H); 9.32(s,1H); 9.11(s,1H); 8.57(d, J=6.0 Hz, 1H); 8.14(s, 1H); 7.75(s, 1H); 7.73(d, J=9.0 Hz, 1H); 7.49(d, J=6.0 Hz, 1H); 7.45(d, J=9.0 Hz, 1H); 7.34(d, J=9.0 Hz, 1H); 7.17(d, J=9.0 Hz, 1H); 4.31(t, J=6.0 Hz, 1H); 2.3-3.0(m, 10H); 2.16(s, 3H); 2.08(s, 3H); 1.98(m, 2H); 1.88 (m, 2H)。
(二)N-{4-甲基-3-[(4-嘧啶-5基)嘧啶-2-氨基]苯基}-5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺甲磺酸盐(胺苯替尼)的合成
其结构式如下:
将反应瓶加入化合物2 (5.34克,10毫摩尔),无水甲醇100毫升,甲烷磺酸(1.01克,10.5毫摩尔),70℃下回流反应1小时后,加入药用脱色炭2克,再回流1小时后,抽滤,滤液减压浓缩后加入异丙醇100毫升搅拌结晶。过滤,烘干得产物N-{4-甲基-3-[(4-吡啶-3基)嘧啶-2-氨基]苯基} -5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺甲磺酸盐5.72克,产率90.8% 。熔点:201~203℃。元素分析:C32H38N8O4S计算值:C 60.93;H 6.07;N17.76;测试值:C 60.81;H 6.32;N17.48。
实施例7 N-{ 4-甲基-3-[(4-吡啶-3基)嘧啶-2-氨基]苯基}-5-(3-甲基咪唑烷-1-基)-5,6,7,8-四氢萘-2-酰胺的合成
其结构式如下:
步骤 A:1-甲基咪唑烷的合成
N-甲基乙二胺(1克,13.5毫摩尔)加入到甲醛(0.4克,13.5毫摩尔)、碳酸钾(6.4克,47.2毫摩尔)、硫酸镁(5.6克,47.2毫摩尔)的25毫升氯仿悬浮液中,室温下搅拌18小时,过滤,滤液减压浓缩,中性氧化铝柱层析在二氯甲烷:甲醇=9:1条件下提纯得产物1-甲基咪唑烷0.81克,产率70%,MS(M+1)=87.11。
步骤 B:5-(3-甲基咪唑烷-1-基)-5,6,7,8-四氢萘-2-羧酸甲酯的合成
把5-氯-5,6,7,8-四氢萘-2-羧酸甲酯(2.41克,10毫摩尔)溶解在20毫升DMF溶剂中,加入碳酸钾(2.78克,20毫摩尔),1-甲基咪唑烷(1.72克,20毫摩尔),50℃下反应5小时后,将反应液加入乙酸乙酯80毫升,用稀盐酸水溶液调PH值至中性后,分出乙酸乙酯相并用饱和食盐水洗涤(3×80毫升),无水硫酸钠干燥,过滤,滤液减压旋出有机溶剂后硅胶柱层析分离,甲醇:二氯甲烷=20:1条件下得到产物2.03克,产率74.1 % ,MS(M+1)=275.28。
步骤 C:5-(3-甲基咪唑烷-1-基)-5,6,7,8-四氢萘-2-羧酸的合成
把5-(3-甲基咪唑烷-1-基)-5,6,7,8-四氢萘-2-羧酸甲酯(2.6克,10毫摩尔)溶解到30毫升甲醇及20毫升四氢呋喃溶液中,加入含2N的NaOH(10毫升,20毫摩尔),室温下反应10小时,用2N盐酸水溶液调PH=3~4后,减压旋出有机溶剂,加入乙酸乙酯60毫升并用饱和食盐水洗涤(3×60毫升),乙酸乙酯相用无水硫酸钠干燥,过滤,滤液减压旋出有机溶剂后硅胶柱层析分离,甲醇:二氯甲烷:冰乙酸=25:1:5滴的条件下分离得到产物2.21克,产率85.0% ,MS(M+1)=261.33。
步骤D:5-(3-甲基咪唑烷-1-基)-1,2,3,4-四氢萘-5-酰氯盐酸盐的合成
反应瓶中加入SOCl2(200毫升),加入5-(3-甲基咪唑烷-1-基)-5,6,7,8-四氢萘-2-羧酸(26克),回流6小时后,降至室温,减压旋出SOCl2,再加入甲苯溶液(50毫升),冷却至0℃有大量白色固体析出,抽滤,将固体干燥得产物(约34.8克,产率99.5%)。
步骤 E:N-{4-甲基-3-[(4-吡啶-3基)嘧啶-2-氨基]-苯基} -5-(4-甲基哌嗪-1-基)-5,6,7,8-四氢萘-2-酰胺的合成
将6-甲基-N1-[(4-吡啶-3-基)嘧啶-2-基]苯-1,3-二胺(2.77克,10毫摩尔)溶解在吡啶(30毫升)中。0~5℃搅拌下慢慢分批加入5-(3-甲基咪唑烷-1-基)-1,2,3,4-四氢萘-5-酰氯盐酸盐(2.78克,10毫摩尔)。约30分钟内加完。升至室温下搅拌4小时。在搅拌下将反应液加入2N氢氧化钠水溶液中(50毫升),随即加入二氯甲烷(50毫升)。搅拌一会儿后,分离二氯甲烷相,水相用二氯甲烷提取(2×50毫升)。合并有机相,无水硫酸镁干燥,过滤,减压浓缩。硅胶柱层析分离,在5%甲醇/二氯甲烷/1%三乙胺条件下洗脱得产物4.68克,产率90.2%。
MS(M+1)=520.16。 δ 9.99 (s, 1H); 9.11 (s, 1H); 8.85(s,1H); 8.66(d, J=4.8 Hz, 1H); 8.52(d, J=4.8 Hz, 1H); 8.47(d, J=9.0 Hz, 1H); 8.02(s,1H); 7.74(s,1H); 7.72(d, J=9.0 Hz, 1H); 7.43(dd, J=8.0 Hz, 4.8 Hz, 1H); 7.38(d, J=8.0 Hz, 1H); 7.34(d, J=4.8 Hz, 1H); 7.27(d, J=9.0 Hz, 1H); 7.16(d, J=9.0 Hz, 1H); 4.22(t, J=9.0 Hz, 1H); 3.46 (s, 2H); 2.2-2.7(m, 6H); 2.11(s, 3H); 2.03(s, 3H); 2.0(m,2H); 1.86(m, 2H)。
实施例8 环苯替尼和胺苯替尼的药效学试验
以实施例1和实施例6提供的环苯替尼和胺苯替尼为受试样品,表示了如以下药效学试验所示的优良抗肿瘤作用。
(1)对于各种癌细胞的抑制生长活性(GI50)测定方法:
肿瘤细胞经胰蛋白酶消化后,分散成单个细胞,并使其悬浮在含青霉素(25 U/ m1)和链霉素(25 μg/ml)的RPMI1640培养基中。将细胞接种于96孔培养板(Corning Incorporated),在37℃,含5%CO2的空气,相对湿度100%条件下培养24小时后,弃去培养液,加入含一系列浓度受试样品的培养液,每一浓度设平行孔,培养24小时后,弃去含受试样品的培养液,加入常规培养液培养48小时后,弃去培养液,再代之以含噻唑蓝(MTT,美国Sigma公司产品)培养液,MTT终浓度为0.5g/L,继续温育4小时后加二甲基亚砜溶解液,1小时后紫色结晶完全溶解,在SK601型酶标仪(日本国Seikagaku公司产品)检测570 nm/630 nm的光密度(OD)。按下式计算受试样品对肿瘤细的半数生长抑制率:
(T-T0)/(C-T0)×100%
注:C表示对照组细胞的OD值
T表示加受试样品组细胞的OD值
T0表示加受试样品时对照平板细胞的OD值
受试样品对于各种癌细胞的抑制作用,结果见表1。
表1 化合物1和化合物2对肿瘤细胞的抑制作用
(2)对人癌移植性小鼠白血病K-562的抑制作用
取生长旺盛期的瘤组织剪切成1.5 mm3左右,在无菌条件下,接种于裸小鼠右侧腋窝皮下。裸小鼠移植瘤用游标卡尺测量移植瘤直径,待肿瘤生长至100~300mm3后将动物随机分组。使用测量瘤径的方法,动态观察被试物抗肿瘤的效应。肿瘤直径的测量次数为每周2次,每次测量时同时称鼠重。实验组每周静脉给药3次,阳性对照组每周静脉给药3次,阴性对照组同时给等量生理盐水。肿瘤体积(tumor volume,TV)的计算公式为:
TV=1/2×a×b2
其中a、b分别表示长宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为:RTV=Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为相对肿瘤增殖率T/C(%),计算公式如下:
TRTV:实验组RTV; CRTV: 阴性对照组RTV。
受试样品对人白血病K-562的抑制作用,结果见表2。
表2 化合物1和化合物2对异种移植于裸鼠人白血病K-562的抑制作用
(3)对人癌移植性小鼠白血病P388的抑制作用
无菌条件下, 取接种于小鼠7天的P388白血病腹水, 按1:15稀释, 调整白血病细胞数为1×107 /mL, 每鼠接种0.2 mL, 次日随机分为6组。化合物1和化合物2各剂量组、辅料组每天腹腔给药1次, 连续给药10d, 伊马替尼组隔日腹腔给药1次, 共5次, 对照组给予相同体积生理盐水。每日观察记录动物死亡情况, 超过30天以30天计算。按公式计算生命延长率: 生命延长率(% ) = (药物组平均生存天数- 对照组平均生存天数) /对照组平均生存天数×100%。
受试样品对人白血病P388的抑制作用,结果见表3。
表3 环苯替尼和胺苯替尼对异种移植于裸鼠人白血病P388的抑制作用
本发明提供的化合物1和化合物2,与对照化合物伊马替尼相比较,显示了如上述药理试验结果所示的更优良对肿瘤的抑制作用。
实施例9 环苯替尼和胺苯替尼的安全性试验(急性毒性)
环苯替尼和胺苯替尼通过小鼠尾静脉给药结果显示,环苯替尼和胺苯替尼均对循环系统有一定毒性,大剂量组动物在给药后0.5~2小时出现惊跳,随后可见精神不振,体颤,少动部分小鼠排稀粪,肛门周围有浅黄色稀粪污染。死亡发生在给药后5~12小时内,对死亡小鼠进行解剖,肉眼观察小鼠肠道膨胀,剖开可见水样内容物,肝脏变白,其余脏器未见异常,肝脏病理组织学检查显示肝细胞点状坏死。对各组存活小鼠连续观察14天,摄食、饮水、一般状态及活动情况均未见异常,观察期结束后处死小鼠,肉眼观察肝脏及主要器官均未见异常。
环苯替尼对呼吸系统有一定的毒性,给药后造成小鼠呼吸衰竭死亡,其LD50为420.6mg/kg,95%的可信限为340.3 mg/kg ~ 500.9 mg/kg,毒性靶器官主要为肝脏。
胺苯替尼对呼吸系统有一定的毒性,给药后造成小鼠呼吸衰竭死亡,其LD50为463.5mg/kg,95%的可信限为370.9 mg/kg ~ 556.1 mg/kg,毒性靶器官主要为肺脏。
如上述药理试验结果表明,本发明化合物显示了优良的抗肿瘤作用,作为抗肿瘤剂,对于预防、治疗疾病,特别是处置癌是有效的。将本发明的化合物用于这样的用途时,可制成含有本发明化合物的有效量和药学容许的载体或赋形剂的制剂。
作为抗肿瘤剂使用本发明化合物的给药形态,可选择各种形态,例如可举出片剂、胶囊剂、粉剂、颗粒剂或液剂等的经口制剂、或例如溶液或悬浮液等的杀菌了的液状非经口制剂、注射剂、栓剂、软膏剂等。
固体的制剂可直接以片剂、胶囊剂、颗粒剂或粉末的形态进行制造,但也可使用适当的添加剂制造。作为这样的添加剂,例如可举出乳糖或葡萄糖等的糖类,例如玉米、小麦或米等的淀粉类,例如硬脂酸等的脂肪酸、例如偏硅酸铝酸镁或无水磷酸钙等的无机盐、例如聚乙烯吡咯烷酮或聚亚烷基二醇等的合成高分子,例如硬酯酸钙或硬质酸镁等的脂肪酸盐、例如十八烷醇或苄醇等的醇类,例如甲基纤维素、羧甲基纤维素、乙基纤维素或羟丙基甲基纤维素等的合成纤维素衍生物,其他,明胶、滑石、植物油、阿拉伯树胶等通常可使用的添加物。
这些片剂、胶囊剂、颗粒剂和粉末等的固形制剂,通常可含有0.1~99%(w/w),优选的是0.1~50%(w/w)的有效成分。
液状制剂,可在水、醇类或例如大豆油、花生油、芝麻油等植物油的液状制剂中,使用通常所用的适当添加物、以悬浮液、糖浆剂、注射剂、点滴剂等形态制造。
特别是作为以非经口的肌肉注射、静脉注射或皮下注射的形式给药时的适当溶剂,例如可举出注射用蒸馏水、生理食盐水、葡萄糖水溶液、乙醇、聚乙二醇、静脉注射用液体(例如柠檬酸和柠檬酸钠等的水溶液)或电解质溶液(点滴静脉注射和静脉注射用)等,或这些的混合溶液。
除了这些预先溶解的注射剂之外,也可作成加有粉末或适当的添加剂的在使用时溶解的形态。这些注射液通常可含有0.1~20%(w/w)、优选的是0.5~5%(w/w)的有效成分。
另外,经口给药用的悬浮剂、糖浆剂等的剂型,通常可含0.5~10%(w/w)的有效成分。
本发明化合物优选的给药量,可根据使用的化合物的种类、配合的组合物种类、适用频度和应该治疗的特定部位、病情的轻重、患者的年龄、医生的诊断、肿瘤的种类等而变化,但作为大致目标,例如每天每1个成人的给药量,在经口给药时,可在1~300mg范围内,另外,在非经口给药时,在静脉注射时,优选的是每天在1~150mg范围内。另外,给药次数,根据给药方法和症状而不同,但1天是1~3次。另外,也可使用隔日给药、隔二日给药等间歇给药等给药方法。
Claims (8)
7.权利要求1、2、3、4、5或6所述的化合物及其药学上可接受的盐作为有效成分在制备抗肿瘤药物上的应用。
8.一种药物组合物,其特征在于:包括权利要求1-6任何一项所述的化合物及其药学上可接受的盐,和至少一种药学上可接受的载体。
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