CN108815167A - 一种新化合物在制备治疗肿瘤的药物中的用途 - Google Patents
一种新化合物在制备治疗肿瘤的药物中的用途 Download PDFInfo
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- CN108815167A CN108815167A CN201810506868.7A CN201810506868A CN108815167A CN 108815167 A CN108815167 A CN 108815167A CN 201810506868 A CN201810506868 A CN 201810506868A CN 108815167 A CN108815167 A CN 108815167A
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Abstract
式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物在制备治疗肿瘤的药物中的用途:其中,R1选自R2、R3分别独立地选自H、卤素、烷基、或者R2和R3与其相连的碳原子组成含1~2个杂原子的1取代或多取代六元芳香杂环;R4、R5、R6分别表示苯环上的0~3取代,R4、R5、R6分别独立选自H,卤素原子,C1~6烷基,C1~6烷氧基,羟基,氨基,羧基,硝基,CH3O(CH2)nCH2O‑,其中n为1~6的整数。本发明化合物治疗治疗肿瘤,药效明确。
Description
技术领域
本发明属药物合成领域,具体涉及一种化合物及用途。
背景技术
近年来,随着生活节奏的加快,人们压力的进一步增大。精神分裂症和癌症已经成为当今社会不能忽视的疾病,严重影响到了社会的正常发展和正常的公共秩序。20世纪起,感染癌症的人数日益增加。世界上每年死于癌症的患者数以百万,并且癌症患者大多数为低收入和中等收入人群。目前癌症的治疗可以经过中药治疗、手术切除、化疗、放射性治疗、免疫治疗以及单克隆抗体治疗或者其他治疗方法,但很少有彻底治愈的病例。如何能够最大程度的降低癌症患者的疼痛,达到好的预防和治疗效果是当前很多研究人员迫切需要解决的问题。
发明内容
本发明的目的在于提供治疗肿瘤的新化合物。
本发明提供了式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物在制备治疗肿瘤的药物中的用途,
其中,R1选自
R2、R3分别独立地选自H、卤素、烷基、或者R2和R3与其相连的碳原子组成含1~2个杂原子的1取代或多取代六元芳香杂环;
R4、R5、R6分别表示苯环上的0~3取代,R4、R5、R6分别独立选自H,卤素原子, C1~6烷基,C1~6烷氧基,羟基,氨基,羧基,硝基,CH3O(CH2)nCH2O-,其中n为1~6的整数。
进一步地,所述的药物是治疗结肠癌、纤维肉瘤、表皮癌、乳腺癌的药物。
本发明还提供了式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物在制备对受体酪氨酸激酶(EGFR)抑制活性的药物中的用途,
其中,R1选自
R2、R3分别独立地选自H、卤素、烷基、或者R2和R3与其相连的碳原子组成含1~2个杂原子的1取代或多取代六元芳香杂环;
R4、R5、R6分别表示苯环上的0~3取代,R4、R5、R6分别独立选自H,卤素原子, C1~6烷基,C1~6烷氧基,羟基,氨基,羧基,硝基,CH3O(CH2)nCH2O-,其中n为1~6的整数。
本发明还提供了式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物在制备抑制新生血管的药物中的用途,
其中,R1选自
R2、R3分别独立地选自H、卤素、烷基、或者R2和R3与其相连的碳原子组成含1~2个杂原子的1取代或多取代六元芳香杂环;
R4、R5、R6分别表示苯环上的0~3取代,R4、R5、R6分别独立选自H,卤素原子, C1~6烷基,C1~6烷氧基,羟基,氨基,羧基,硝基,CH3O(CH2)nCH2O-,其中n为1~6的整数。
进一步地,所述R4、R5、R6分别独立选自H,卤素原子,C1~6烷基,C1~6烷氧基, CH3O(CH2)nCH2O-,其中n为1~6的整数。
进一步地,所述R4、R5、R6分别独立选自H,F,甲基,甲氧基,CH3OCH2CH2O-,
进一步地,所述R4、R5、R6表示苯环上的无取代或一取代。
进一步地,所述R1选自
进一步地,所述的六元芳香杂环为
其中R7选自
进一步地,所述化合物为下列化合物之一:
进一步地,所述化合物的制备方法如下:
(一)化合物1~14的合成:
(1)中间体h的合成:
(2A)化合物1~7的合成:
(2B)化合物8~14的合成:
(二)化合物15-21的合成:
(三)化合物22-43的合成:
本发明通过药物化学基本原理,设计、合成了5个系列共43个化合物。通过MTT 法,初步测试了化合物cpd1-cpd21在10μM浓度下抑制结肠癌HT-29和表皮癌A431的活性。其中,化合物cpd9和另外5个先导化合物表现出良好的抑制活性,其中化合物cpd9 对HT-29和表皮癌的抑制率分别达89.4%和84.2%。
进一步对化合物cpd9进行了活性及机理研究。利用MTT法,测定了cpd9在不同的浓度(0.3125、0.625、1.25、2.5、5.0、12.5和25μM)下对结肠癌HT-29和表皮癌A431 细胞增殖的抑制率,并计算了其IC50,分别为2.9μM和6.8μM。结肠癌细胞HT-29经2.5 μM的cpd9处理16小时,发生了明显的细胞凋亡现象。
本发明测定了化合物cpd1-cpd43在10μM浓度下对受体酪氨酸激酶(EGFR)的抑制活性,其中化合物cpd9和cpd37对EGFR的抑制率分别为92.9%和91.3%。继续测定了cpd9和cpd37在不同浓度下(0.3125、0.625、1.25、2.5、5.0、12.5和25μM)对EGFR的抑制活性,并计算出其IC50,分别为3.3μM和3.9μM。
利用斑马鱼胚胎测定了cpd9在1μM、10μM和20μM浓度下,抑制新生血管的能力。
综上,本发明化合物具有优异的抗肿瘤活性和抑制新生血管的能力,应用前景优良。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀(Ca~Cb)烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,(C1~C4)烷基是指包含1~4个碳原子的烷基。
所述C1~C6烷基是指C1、C2、C3、C4、C5、C6的烷基,即具有1~6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等等。C1-C6的烷氧基也具有与其基团相应的含义。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1:化合物cpd1-cpd21对HT-29细胞系的生长抑制率
图2:化合物cpd1-cpd21对A431细胞系的生长抑制率
图3:cpd9对HT-29和A431细胞生长抑制曲线
图4:cpd9诱导HT-29细胞凋亡
图5:cpd9对斑马鱼胚胎体节间血管的影响,A为阴性(空白)对照;B为给药cpd9 10μM的斑马鱼胚胎新生血管发育情况;C为给药cpd9 20μM的斑马鱼胚胎新生血管发育情况;D为阳性对照,即给药Gefitinib 10μM的斑马鱼胚胎新生血管发育情况。
具体实施方式
本发明使用的原料和仪器均可通过市场购买得到。
实施例1、化合物1的合成
合成路线:
制备方法:
(1)将化合物a(10g,1.0eq)和二氯甲烷(100ml)加到三口瓶中,氮气保护下,降温至-78℃,加入三溴化硼(10eq)的二氯甲烷溶液(1g/3ml)。加毕,保温反应1h,升温到25℃体系反应4-6h,反应结束后,用10ml水洗,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到6.97g化合物b,收率:80.5%。
(2)将化合物b(5g,1.0eq)和吡啶(50ml)加到三口瓶中,氮气保护下,控制温度小于20℃加入醋酸酐(2.5eq)。加毕,保温反应1h,升温到25℃体系反应4-6h,反应结束后,将反应液倾入冰水中,3N盐酸调PH 6-7,用DCM萃取,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到6.14g化合物c,收率:83.4%。
(3)将化合物c(6g,1.0eq)和三氯氧磷(50ml)加到三口瓶中,氮气保护下,加入N,N-二甲基苯胺(2.5eq)。加毕,升温至回流反应4-6h,反应结束,蒸掉过量的三氯氧磷后,将反应液倾入冰水中,用DCM萃取,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到4.19g化合物d,收率:65.3%。
(4)将化合物d(4g,1.0eq),三乙胺(1.2eq)和二氯甲烷(50ml)加到三口瓶中,冰浴降温至0℃,加入化合物e(1eq)的二氯甲烷溶液(1g/2mL)。加毕,升温至25℃反应4-6h,反应结束,用10ml水洗,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到 4.50g化合物f,收率:81%。
(5)将化合物f(4g,1.0eq),氢氧化锂(2.0eq),乙醇(20ml)和水(30ml)加到三口瓶中,冰浴降温至0℃,加入Boc2O(1.2eq)。加毕,升温至25℃反应4-6h,反应结束,再补加氢氧化钠(3eq),升温至50℃反应5-6h,反应完毕,将反应液倾入冰水中, 2N盐酸水调PH 6-7,用DCM萃取,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到3.75g化合物g,收率:90%。
(6)将化合物g(3g,1.0eq),对甲苯磺酸(0.01eq),4-哌啶酮(1.2eq)和甲苯(50ml)加到三口瓶中,升温至回流分水。反应结束,50℃减压移除溶剂,过快速柱,得到3.21g 化合物h,收率:89%。
(7)将化合物h(3g,1.0eq),三乙胺(1.2eq)和二氯甲烷(50ml)加到三口瓶中,冰浴降温至0℃,加入苯甲酰氯(1eq)的二氯甲烷溶液(1g/2mL)。加毕,升温至25℃反应4-6h,反应结束,用10ml水洗,无水硫酸钠干燥,浓缩有机相至干,加乙酸乙酯(20ml) 溶解完全后,降温至0℃以下,通入干燥的氯化氢气体至饱和后,保温搅拌1-2h,有大量固体析出,过滤出固体,加至50ml水中,饱和碳酸钠调PH8-9,DCM萃取,无水硫酸钠干燥后,浓缩有机相至干,过快速柱,得到目标化合物3.13g,收率:75%。
1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38(m,4H,CH2),3.29-3.39(m, 4H,CH2),4.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH), 7.41(s,1H,CH),7.63(s,2H,CH),7.70(s,1H,CH).8.03(s,2H,CH),8.49(s,1H,CH)。
分子式:C26H20ClFN4O3,相对分子质量:490.91。
实施例2、化合物2的合成
将实施例1步骤(7)中的苯甲酰氯替换为2-氟苯甲酰氯,采用与实施例1相同的制备方法,即可制备得到化合物2,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38(m, 4H,CH2),3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s, 1H,CH)7.29(s,1H,CH),7.40(s,1H,CH).7.41(s,1H,CH)7.42(s,1H,CH),8.00(s,1H, CH),8.01(s,1H,CH)8.49(s,1H,CH)。分子式:C26H19ClF2N4O3,相对分子质量:508.9。
实施例3、化合物3的合成
将实施例1步骤(7)中的苯甲酰氯替换对氟苯甲酰氯,采用与实施例1相同的制备方法,即可制备得到化合物3,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38(m, 4H,CH2),3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s, 1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.42(s,2H,CH),.8.12(s,2H,CH),8.49(s,1H, CH)。分子式:C26H19ClF2N4O3,相对分子质量:508.9。
实施例4、化合物4的合成
将实施例1步骤(7)中的苯甲酰氯替换为4-甲基苯甲酰氯,采用与实施例1相同的制备方法,即可制备得到化合物4,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.34(m, 3H,CH3)2.13-2.38(m,4H,CH2),3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.79(s,1H,CH), 7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.41(s,2H,CH),.7.91(s, 2H,CH),8.49(s,1H,CH)。分子式:C27H22ClFN4O3,相对分子质量:504.94。
实施例5、化合物5的合成
将实施例1步骤(7)中的苯甲酰氯替换为对甲氧基苯甲酰氯,采用与实施例1相同的制备方法,即可制备得到化合物5,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38 (m,4H,CH2),3.29-3.39(m,4H,CH2),3.83(m,3H,CH3)4.0(s,1H,NH)6.79(s,1H,CH), 7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.17(s,2H,CH),.7.92(s, 2H,CH),8.49(s,1H,CH)。分子式:C27H22ClFN4O4,相对分子质量:520.94。
实施例6、化合物6的合成
将实施例1步骤(7)中的苯甲酰氯替换为4-(2-甲氧基乙氧基)苯甲酰氯,采用与实施例1相同的制备方法,即可制备得到化合物6,1H NMR(300MHz,CDCl3,25℃,TMS): δ=2.13-2.38(m,4H,CH2),3.29-3.39(m,4H,CH2),3.30(m,3H,CH3)3.79 (d,J=7.1,2H,CH2),4.0(s,1H,NH)4.31(d,J=7.1,2H,CH2)6.79(s,1H,CH),7.16(s, 1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.17(s,2H,CH),.7.92(s,2H, CH),8.49(s,1H,CH)。分子式:C29H26ClFN4O5,相对分子质量:564.99。
实施例7、化合物7的合成
将实施例1步骤(7)中的苯甲酰氯替换为4-((4-甲基哌嗪-1-烷基)甲基)苯甲酰氯,采用与实施例1相同的制备方法,即可制备得到化合物7,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38(m,4H,CH2),2.26(m,3H,CH3)2.35(m,4H,CH2)2.48(m, 4H,CH2)3.29-3.39(m,4H,CH2),)4.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s, 1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.41(s,2H,CH),.7.91(s,2H,CH),8.49(s,1H, CH)。分子式:C32H32ClFN6O3,相对分子质量:603.09。
实施例8、化合物8的合成
合成路线:
步骤(1)-(6)与实施例1中完全相同;
步骤(7)如下:将化合物h(3g,1.0eq)和二氯甲烷(40ml)加到三口瓶中,氮气保护下,冰浴降温至0℃,加入异氰酸苯酯(1.0eq)的二氯甲烷溶液(1g/2mL)。加毕,保温反应30min后,升温至25℃反应2-3h,反应结束,浓缩有机相至干,加乙酸乙酯(20ml) 溶解完全后,降温至0℃以下,通入干燥的氯化氢气体至饱和后,保温搅拌1-2h,有大量固体析出,过滤出固体,加至50ml水中,饱和碳酸钠调PH8-9,DCM萃取,无水硫酸钠干燥后,浓缩有机相至干,过快速柱,得到目标化合物2.05g,收率:66%。
1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38(m,4H,CH2),3.29-3.39(m, 4H,CH2),4.0(s,1H,NH)6.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.19(s, 1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.43(s,2H,CH),.7.61(s,2H, CH),8.49(s,1H,CH)。分子式:C26H21ClFN5O3,相对分子质量:505.93。
实施例9、化合物9的合成
将实施例8步骤(7)中的异氰酸苯酯替换为2-氟异氰酸苯酯,采用与实施例8相同的制备方法,即可制备得到化合物9,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38 (m,4H,CH2),3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.0(s,1H,NH)6.79(s,1H,CH),7.01(s, 1H,CH)7.16(s,1H,CH)7.20(s,1H,CH)7.22(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH), 7.41(s,1H,CH),7.96(s,1H,CH),8.49(s,1H,CH)。
分子式:C26H20ClF2N5O3,相对分子质量:523.92。
实施例10、化合物10的合成
将实施例8步骤(7)中的异氰酸苯酯替换为4-氟异氰酸苯酯,采用与实施例8相同的制备方法,即可制备得到化合物10,1H NMR(300MHz,CDCl3,25℃,TMS):δ= 2.13-2.38(m,4H,CH2),3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.0(s,1H,NH)6.79(s, 1H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.22(s, 2H,CH),.7.60(s,2H,CH),8.49(s,1H,CH)。
分子式:C26H20ClF2N5O3,相对分子质量:523.92。
实施例11、化合物11的合成
将实施例8步骤(7)中的异氰酸苯酯替换为4-甲基异氰酸苯酯,采用与实施例8相同的制备方法,即可制备得到化合物11,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38(m,4H,CH2),2.34(s,3H CH3)3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.0(s,1H, NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH), 7.21(s,2H,CH),.7.56(s,2H,CH),8.49(s,1H,CH)。
分子式:C27H23ClFN5O3,相对分子质量:519.95。
实施例12、化合物12的合成
将实施例8步骤(7)中的异氰酸苯酯替换4-甲氧基异氰酸苯酯,采用与实施例8相同的制备方法,即可制备得到化合物12,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38(m,4H,CH2),3.29-3.39(m,4H,CH2),3.38(s,3H CH3),4.0(s,1H,NH)6.0(s,1H, NH)6.79(s,1H,CH),6.97(s,2H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH), 7.41(s,1H,CH),7.51(s,2H,CH),8.49(s,1H,CH)。
分子式:C27H23ClFN5O4,相对分子质量:535.95。
实施例13、化合物13的合成
将实施例8步骤(7)中的异氰酸苯酯替换为4-(2-甲氧基乙氧基)异氰酸苯酯,采用与实施例8相同的制备方法,即可制备得到化合物13,1H NMR(300MHz,CDCl3,25℃, TMS):δ=2.13-2.38(m,4H,CH2),2.26(m,3H,CH3)2.35(m,4H,CH2)2.48(m, 4H,CH2)3.29-3.39(m,4H,CH2),)4.0(s,1H,NH)6.0(s,1H,NH)6.79(s,1H,CH),6.97(s, 2H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),.7.51(s,2H, CH),8.49(s,1H,CH)。分子式:C29H27ClFN5O5,相对分子质量:580.01。
实施例14、化合物13的合成
将实施例8步骤(7)中的异氰酸苯酯替换为4-((4-甲基哌嗪-1-烷基)甲基)异氰酸苯酯,采用与实施例8相同的制备方法,即可制备得到化合物14,1H NMR(300MHz,CDCl3, 25℃,TMS):δ=2.13-2.38(m,4H,CH2),2.26(m,3H,CH3)2.35(m,4H,CH2)2.48(m, 4H,CH2)3.29-3.39(m,4H,CH2),)4.0(s,1H,NH)6.0(s,1H,NH)6.79(s,1H,CH),7.16(s, 1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.21(s,2H,CH),.7.56(s,2H, CH),8.49(s,1H,CH),。分子式:C32H33ClFN7O3,相对分子质量:618.10。
实施例15、化合物15的合成
合成路线:
制备方法:
(1)将叔丁醇钾(1.0eq),三甲基碘化亚砜(1.1eq)和DMSO(50ml)加到三口瓶中,室温下(25℃)搅拌反应30min后,加入化合物i(10g,1.0eq)。加毕,室温反应过夜,反应结束后,加入200ml水和200ml乙酸乙酯,充分搅拌后,分出有机相,水相再用200ml乙酸乙酯萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到8.03g化合物j,收率:75%。
(2)将化合物j(8g,1.0eq),化合物k(1.5eq),高氯酸锂(1.7eq)和乙腈(50ml) 加到三口瓶中,加热至80℃搅拌反应12-18h,反应结束后,降温至室温,加入200ml乙酸乙酯稀释,饱和食盐水洗,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到9.06g 化合物l,收率:63%。
(3)将化合物l(8g,1.0eq),碳酸铯(1.5eq)和乙腈(50ml)加到三口瓶中,加热至60℃搅拌反应6-8h,反应结束后,降温至室温,加入200ml乙酸乙酯稀释,饱和食盐水洗,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到6.37g化合物m,收率:84%。
(4)将吗啉(2.2eq)和无水四氢呋喃(10ml)加到三口瓶中,氮气保护下,降温至 -5℃,加入DIBALH(2.0eq),滴毕,保温反应3h,然后将将化合物m(6g,1.0eq)的四氢呋喃溶液(1g/3ml)加至反应体系中,加入过程中,控制内温小于0℃,加完后,保温反应30min,再加入DIBALH(1.1eq),保温反应1h,1N盐酸淬灭,饱和食盐水洗,水相用乙酸乙酯反萃,合并有机相,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到 4.79g化合物n,收率:87%。
(5)将化合物n(4g,1.0eq),化合物o和乙醇(50ml)加到三口瓶中,再滴加10mg 哌啶,升温至回流4-6h,反应结束,用10ml水洗,无水硫酸钠干燥,浓缩有机相至干,加乙酸乙酯(20ml)溶解完全后,降温至0℃以下,通入干燥的氯化氢气体至饱和后,保温搅拌1-2h,有大量固体析出,过滤出固体,加至50ml水中,饱和碳酸钠调PH8-9,DCM 萃取,无水硫酸钠干燥后,浓缩有机相至干,过快速柱,得到3.65g化合物p,收率:83%。
(6)将化合物p(3g,1.0eq)和THF(50ml)加到三口瓶中,氮气保护下,降温至 0℃,加入氢化钠(1.5eq),加毕,保温搅拌30min,再加入苄氯(1.1eq),保温反应1h 后,升温至室温反应4-6h,反应结束后,加水淬灭,水相用乙酸乙酯反萃,合并有机相,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到2.39g目标化合物,收率:64%
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97(m,4H),2.51(m,4H),3.66(s,2H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
分子式:C28H25FN2O3,相对分子质量:456.51。
实施例16、化合物16的合成
将实施例15步骤(6)中的苄氯替换为2-氟苄氯,采用与实施例15相同的制备方法,即可制备得到化合物16。分子式:C28H24F2N2O3,相对分子质量:474.50。
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97(m,4H),2.51(m,4H),3.66(s,2H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
实施例17、化合物17的合成
将实施例15步骤(6)中的苄氯替换为4-氟苄氯,采用与实施例15相同的制备方法,即可制备得到化合物17。分子式:C28H24F2N2O3,相对分子质量:474.50。
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97(m,4H),2.51(m,4H),3.66(s,2H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
实施例18、化合物18的合成
将实施例15步骤(6)中的苄氯替换为4-甲基苄氯,采用与实施例15相同的制备方法,即可制备得到化合物18。分子式:C29H27FN2O3,相对分子质量:470.53。
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97(m,4H),2.34(s,3H),2.51(m,4H),3.66(s,2H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
实施例19、化合物19的合成
将实施例15步骤(6)中的苄氯替换为4-甲氧基苄氯,采用与实施例15相同的制备方法,即可制备得到化合物19。分子式:C29H27FN2O4,相对分子质量:486.53。
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97(m,4H),2.51(m,4H),3.66(s,2H),3.83(s,3H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
实施例20、化合物20的合成
将实施例15步骤(6)中的苄氯替换为4-(2-甲氧基乙氧基)苄氯,采用与实施例15相同的制备方法,即可制备得到化合物20。
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97(m,4H),2.51(m,4H),3.30(s,3H),3.66(s,2H),3.79(t,J=7.1Hz,2H),4.28(s.2H),4.31(t,J=7.1Hz,2H),7.05(m,6H),7.33(m,4H),7.56(s,1 H),7.79(m,1H),8.0(s,1H,NH)。分子式:C31H31FN2O5,相对分子质量:530.59。
实施例21、化合物21的合成
将实施例15步骤(6)中的苄氯替换为4-((4-甲基哌嗪-1-烷基)甲基)苄氯,采用与实施例15相同的制备方法,即可制备得到化合物21。
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97(m,4H),2.26(s,3H),2.35-2.48(m,8H), 3.66(s,2H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
分子式:C34H37FN4O3,相对分子质量:568.68。
实施例22、化合物22的合成
合成路线:
制备方法:
(1)将化合物d(10g,1.0eq),和6N盐酸(50ml)加到三口瓶中,升温至50℃反应4-6h,反应结束,降至室温,用DCM萃取,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到5.95g化合物q,收率:85%。
(2)将化合物q(5g,1.0eq),对甲苯磺酸(0.01eq),4-哌啶酮(1.2eq)和甲苯(50ml)加到三口瓶中,升温至回流分水。反应结束,50℃减压移除溶剂,过快速柱,得到6.14g 化合物r,收率:87%。
(3)将化合物r(5g,1.0eq)和THF(50ml)加到三口瓶中,氮气保护下,降温至0℃,加入氢化钠(1.5eq),加毕,保温搅拌30min,再加入2-氟苯甲酰氯(1.1eq),保温反应1h后,升温至室温反应4-6h,反应结束后,加水淬灭,水相用乙酸乙酯反萃,合并有机相,无水硫酸钠干燥,浓缩有机相至干,过快速柱,得到5.18g化合物raw20,收率: 72%
(4)将化合物raw20(2g,1.0eq),化合物raw21(1.5eq),DIPEA(1.0eq)和异丙醇(50ml)加到三口瓶中,加热升温至90℃反应4-6h,反应结束后,直接浓缩至干,过快速柱,得到1.45g目标化合物,收率:55%。1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.38 (m,4H),2.82(s,3H),3.39(m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41 (m,3H),7.50(d,J=7.5Hz,1H),8.00(m,2H),8.49(s,1H)。
分子式:C28H22FN5O3S,相对分子质量:527.57。
实施例23、化合物23的合成
将实施例22中的raw21替换为raw22,采用与实施例22相同的制备方法,即可制备得到化合物23,1H NMR(300MHz,CDCl3,25℃,TMS):δ=0.90(t,J=8.0Hz,3H),1.65(m,2H),2.38(m,4H),2.86(m,2H),3.39(m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H), 7.41(m,3H),7.50(d,J=7.5Hz,1H),8.00(m,2H),8.49(s,1H)。
分子式:C30H26FN5O3S,相对分子质量:555.62。
实施例24、化合物24的合成
将实施例22中的raw21替换为raw23,采用与实施例22相同的制备方法,即可制备得到化合物24,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.38(m,4H),2.86(m,2H),3.39 (m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50(m,3H),8.00(m,4H),8.49(s,1H)。分子式:C33H24FN5O3S,相对分子质量:589.64。
实施例25、化合物25的合成
将实施例22中的raw21替换为raw24,采用与实施例22相同的制备方法,即可制备得到化合物25,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.34(s,3H),2.38(m,4H),2.86 (m,2H),3.39(m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50(m,3H),8.00(m,4H),8.49(s,1H)。分子式:C34H26FN5O3S,相对分子质量:603.67。
实施例26、化合物26的合成
将实施例22中的raw21替换为raw25,采用与实施例22相同的制备方法,即可制备得到化合物26,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.38(m,4H),2.86(m,2H),3.39 (m,4H),4.0(s,1H,NH),5.35(s,1H,OH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50(m,3H),8.00(m,4H),8.49(s,1H)。分子式:C33H24FN5O4S,相对分子质量:605.64。
实施例27、化合物27的合成
将实施例22中的raw21替换为raw26,采用与实施例22相同的制备方法,即可制备得到化合物27,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.38(m,4H),2.86(m,2H),3.39 (m,4H),3.83(s.3H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50(m,3H),8.00(m,4H),8.49(s,1H)。分子式:C34H26FN5O4S,相对分子质量:619.66。
实施例28、化合物28的合成
将实施例22中的raw21替换为raw27,采用与实施例22相同的制备方法,即可制备得到化合物28,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.34(s,3H),2.38(m,4H),2.86 (m,2H),3.39(m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50(m,3H),8.00(m,4H),8.49(s,1H)。分子式:C34H26FN5O3S,相对分子质量:603.67。
实施例29、化合物29的合成
将实施例22中的raw21替换为raw28,采用与实施例22相同的制备方法,即可制备得到化合物29,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.26(t,2H,J=7.1Hz,CH2), 2.26(t,2H,J=7.1,CH2),3.39(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),4.1(s, 1H,NH),5.35(s,1H,OH),6.73(d,1H,J=7.5Hz,CH),6.91(d,1H,J=7.5Hz,CH),7.02(s, 1H,J=1.5Hz,CH),7.24(s,1H,CH),7.32(s,1H,CH),7.34(dd,1H,J=7.5,7.5Hz,CH), 7.40(dd,1H,J=7.5,7.5Hz,CH),7.41(s,1H,CH),7.42(dd,1H,J=7.5,8.0Hz,CH),7.50(d, 1H,J=7.5Hz,CH),7.59(d,1H,J=7.5Hz,CH),8.00(dd,1H,J=7.5Hz,CH),8.01(d,1H,J =5.0,7.5Hz,CH),8.49(s,1H,CH)。分子式:C33H24FN5O4S,相对分子质量:605.64。
实施例30、化合物30的合成
将实施例22中的raw21替换为raw29,采用与实施例22相同的制备方法,即可制备得到化合物30,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.40(t,2H,J=7.1Hz,CH2), 2.40(t,2H,J=7.1Hz,CH2),3.37(t,2H,J=7.1Hz,CH2),3.37(t,2H,J=7.1Hz,CH2),4.1 (s,1H,NH),6.70(d,1H,J=7.5Hz,CH),7.02(s,1H,CH),7.24(s,1H,CH),7.39(dd,1H, CH),7.41(s,1H,CH),7.44(d,1H,J=7.5,8.0Hz,CH),7.45(d,1H,J=7.5Hz,CH),7.46(dd, 1H,J=7.5,7.5Hz,CH),7.50(d,1H,J=7.5Hz,CH),7.89(d,1H,J=7.5Hz,CH),8.00(dd, 1H,J=7.5,7.5Hz,CH),8.01(d,1H,J=5.0,7.5Hz,CH),8.01(s,1H,CH),8.51(s,1H,CH)。
分子式:C33H23ClFN5O3S,相对分子质量:624.08。
实施例31、化合物31的合成
将实施例22中的raw21替换为raw30,采用与实施例22相同的制备方法,即可制备得到化合物31,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.44(t,2H,J=7.1Hz,CH2), 2.44(t,2H,J=7.1Hz,CH2),3.34(t,2H,J=7.1Hz,CH2),3.34(t,2H,J=7.1Hz,CH2),4.0 (s,1H,NH),6.73(d,1H,J=7.5Hz,CH),7.02(2,1H,CH),7.24(s,1H,CH),7.40(dd,1H,J= 7.5,7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J=7.5,8.0Hz,CH),7.50(d,1H,J=7.5Hz, CH),7.77(dd,1H,J=7.5,7.5Hz,CH),8.00(dd,1H,CH),8.01(d,1H,J=5.0,7.5Hz,CH), 8.22(d,1H,J=5.0,7.5,7.5Hz,CH),8.42(d,1H,J=7.5Hz,CH),8.49(s,1H,CH),8.65(s, 1H,CH)。分子式:C33H23FN6O5S,相对分子质量:634.64。
实施例32、化合物32的合成
将实施例22中的raw21替换为raw31,采用与实施例22相同的制备方法,即可制备得到化合物32,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.33(t,2H,J=7.1Hz,CH2), 2.33(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),3.9 (s,1H,NH),6.73(s,1H,J=7.5Hz,CH),7.02(s,1H,CH),7.24(s,1H,CH),7.24(d,1H,J= 7.5,8.0Hz,CH),7.40(dd,1H,J=7.5,7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J=7.5,8.0 Hz,CH),7.50(d,1H,J=7.5Hz,CH),7.65(d,1H,J=5.0,7.5Hz,CH),7.99(s,1H,CH),8.00 (dd,1H,J=5.0,7.5,7.5Hz,CH),8.01(d,1H,J=5.0,7.5Hz,CH),8.51(s,1H,CH)。
分子式:C33H22ClF2N5O3S,相对分子质量:642.07。
实施例33、化合物33的合成
将实施例22中的raw21替换为raw32,采用与实施例22相同的制备方法,即可制备得到化合物33,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.38(t,2H,J=7.1Hz,CH2), 2.38(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),4.1(s, 1H,NH),6.73(d,1H,J=7.5Hz,CH),7.04(s,1H,CH),7.24(s,1H,CH),7.30(d,1H,J=7.5,8.0Hz,CH),7.30(d,1H,J=7.5,8.0Hz,CH),7.41(d,1H,J=7.5,7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J=7.5,8.0Hz,CH),7.50(d,1H,J=7.5Hz,CH),7.77(d,1H,J=5.0,7.5Hz,CH),7.77(d,1H,J=5.0,7.5Hz,CH),8.01(dd,1H,J=5.0,7.5,7.5Hz,CH),8.03(d,1H,J=5.0,7.5Hz,CH),8.49(s,1H,CH)。分子式:C33H23F2N5O3S,相对分子质量:607.63。
实施例34、化合物34的合成
将实施例22中的raw21替换为raw33,采用与实施例22相同的制备方法,即可制备得到化合物34,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.24(s,3H,CH3),2.37(t,2H, CH2),2.38(t,2H,CH2),3.09(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),3.39(t, 2H,J=7.1Hz,CH2),4.0(s,1H,NH),4.27(t,2H,J=7.1Hz,CH2),6.28(d,1H,J=10.9Hz, CH),6.68(d,1H,J=7.5Hz,CH),6.70(s,1H,CH),7.24(s,1H,CH),7.40(dd,1H,J=7.5,7.5 Hz,CH),7.41(s,1H,CH),7.42(d,1H,J=7.5,8.0Hz,CH),7.43(d,1H,J=7.5Hz,CH),8.00 (dd,1H,J=5.0,7.5,7.5Hz,CH),8.01(d,1H,J=5.0,7.5Hz,CH),8.49(s,1H,CH),8.82(d, 1H,J=10.9Hz,CH),16.55(OH)。分子式:C34H29ClFN5O6,相对分子质量:658.08。
实施例35、化合物35的合成
将实施例22中的raw21替换为raw34,采用与实施例22相同的制备方法,即可制备得到化合物35,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.36(s,3H,CH3),2.38(t,2H,J =7.1Hz,CH2),2.38(t,2H,J=7.1Hz,CH2),3.09(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),4.0(s,1H,NH),4.27(t,2H,J=7.1Hz,CH2), 6.28(d,1H,J=10.0Hz,CH),6.46(s,1H,J=8.0Hz,CH),6.72(d,1H,J=5.0,7.5Hz,CH), 7.24(s,1H,CH),7.32(d,1H,J=7.5Hz,CH),7.40(dd,1H,J=7.5,7.5Hz,CH),7.41(s,1H, CH),7.42(d,1H,J=7.5,8.0Hz,CH),8.00(dd,1H,J=5.0,7.5,7.5Hz,CH),8.01(d,1H,J= 5.0,7.5Hz,CH),8.49(s,1H,CH),8.82(d,1H,J=10.0Hz,CH),16.77(OH)。
分子式:C34H29F2N5O6,相对分子质量:641.62。
实施例36、化合物36的合成
将实施例22中的raw21替换为raw35,采用与实施例22相同的制备方法,即可制备得到化合物36,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.30(s,3H,CH3),2.38(t,2H,J =7.1Hz,CH2),2.38(t,2H,J=7.1Hz,CH2),3.09(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),4.1(s,1H,NH),4.27(t,2H,J=7.1Hz,CH2),6.28(d,1H,J=10.3Hz,CH),7.00(d,1H,J=7.5Hz,CH),7.24(s,1H,CH),7.40(dd,1H,J=7.5,7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J=7.5,8.0Hz,CH),7.45(s,1H,CH),7.94(d,1H, J=7.6Hz,CH),8.00(dd,1H,J=5.0,7.5,7.5Hz,CH),8.01(d,1H,J=5.0,7.5Hz,CH),8.49(s,1H,CH),8.82(d,1H,J=10.3Hz,CH),16.77(OH)。
分子式:C34H29FN6O8,相对分子质量:668.63。
实施例37、化合物37的合成
将实施例22中的raw21替换为raw36,采用与实施例22相同的制备方法,即可制备得到化合物37,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.27(s,3H,CH3),2.38(t,2H,J =7.1Hz,CH2),2.38(t,2H,J=7.1Hz,CH2),3.09(t,2H,J=7.1Hz,CH2),3.40(t,2H,J=7.1Hz,CH2),3.40(t,2H,J=7.1Hz,CH2),4.1(s,1H,NH),4.27(t,2H,J=7.1Hz,CH2),6.12(s,1H,CH),6.28(d,1H,J=10.6Hz,CH),7.13(d,1H,J=7.5Hz,CH),7.22(d,1H,J=7.5 Hz,CH),7.24(s,1H,CH),7.40(dd,1H,J=7.5,7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J =7.5,8.0Hz,CH),8.00(dd,1H,J=5.0,7.5,7.5Hz,CH),8.01(d,1H,J=5.0,7.5Hz,CH),8.49(s,1H,CH),8.82(d,1H,J=10.6Hz,CH),16.60(OH)。
分子式:C34H29ClFN5O6,相对分子质量:658.08。
实施例38、化合物38的合成
将实施例22中的raw21替换为raw37,采用与实施例22相同的制备方法,即可制备得到化合物38,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.27(s,3H,CH3),2.39(t,2H,J =7.1Hz,CH2),2.39(t,2H,J=7.1Hz,CH2),3.09(t,2H,J=7.1Hz,CH2),3.36(t,2H,J=7.1Hz,CH2),3.36(t,2H,J=7.1Hz,CH2),4.0(s,1H,NH),4.29(t,2H,J=7.1Hz,CH2), 6.28(d,1H,J=10.9Hz,CH),6.44(CH),6.45(CH),7.24(s,1H,CH),7.40(dd,1H,J=7.5, 7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J=7.5,8.0Hz,CH),7.72(CH),8.00(dd,1H,J= 5.0,7.5,7.5Hz,CH),8.01(d,1H,J=5.0,7.5Hz,CH),8.49(s,1H,CH),8.82(d,1H,J=10.9 Hz,CH),16.77(OH)。分子式:C34H29F2N5O6,相对分子质量:641.62。
实施例39、化合物39的合成
将实施例22中的raw21替换为raw38,采用与实施例22相同的制备方法,即可制备得到化合物39,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.27(s,3H,CH3),2.40(t,2H,J =7.1Hz,CH2),2.40(t,2H,J=7.1Hz,CH2),3.09(t,2H,J=7.1Hz,CH),3.41(t,2H,J=7.1Hz,CH2),3.41(t,2H,J=7.1Hz,CH2),4.2(s,1H,NH),4.27(t,2H,J=7.1Hz,CH2),6.16(J=5.0Hz,CH),6.28(d,1H,J=10.5Hz,CH),6.88(dd,1H,J=7.5,8.0Hz,CH),6.97(J=5.0,7.5Hz,CH),7.24(s,1H,CH),7.40(dd,1H,J=7.5,7.5Hz,CH),7.41(s,1H,J=7.5,8.0Hz,CH),7.42(d,1H,J=7.5,8.0Hz,CH),7.72(d,1H,J=7.5Hz,CH),8.00(dd,1H,J=5.0,7.5,7.5Hz,CH),8.01(d,1H,J=5.0,7.5Hz,CH),8.49(s,1H,CH),8.82(d,1H,J=10.5Hz,CH),16.77(OH)。分子式:C34H29FN6O8,相对分子质量:668.63。
实施例40、化合物40的合成
将实施例22中的raw21替换为raw39,采用与实施例22相同的制备方法,即可制备得到化合物40,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.26(s,3H,CH3),2.40(t,2H,J =7.1Hz,CH2),2.40(t,2H,J=7.1Hz,CH2),3.09(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),3.39(t,2H,J=7.1Hz,CH2),4.0(s,1H,NH),4.28(t,2H,J=7.1Hz,CH2), 6.18(s,1H,CH),6.28(d,1H,J=10.3Hz,CH),6.36(d,1H,J=7.5Hz,CH),7.09(dd,1H,J= 7.5,7.5Hz,CH),7.19(d,1H,J=7.5Hz,CH),7.24(s,1H,CH),7.40(dd,1H,J=7.5,7.5Hz, CH),7.41(s,1H,CH),7.42(d,1H,J=7.5,8.0Hz,CH),8.00(dd,1H,J=5.0,7.5,7.5Hz,CH),8.01(d,1H,J=5.0,7.5Hz,CH),8.49(s,1H,CH),8.83(d,1H,J=10.3Hz,CH),16.77(OH)。分子式:C34H30FN5O6,相对分子质量:623.63。
实施例41、化合物41的合成
将实施例22中的raw21替换为raw40,采用与实施例22相同的制备方法,即可制备得到化合物41,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.17(s,3H,CH3),2.28(s,3H, CH3),2.39(t,2H,J=7.1Hz,CH2),2.39(t,2H,J=7.1Hz,CH2),3.10(t,2H,J=7.1Hz, CH2),3.40(t,2H,J=7.1Hz,CH2),3.40(t,2H,J=7.1Hz,CH2),4.1(s,1H,NH),4.25(t,2H, J=7.1Hz,CH2),6.06(s,1H,J=1.5Hz,CH),6.28(d,1H,J=10.8Hz,CH),6.87(d,1H,J= 7.5Hz,CH),6.89(d,1H,J=7.5Hz,CH),7.24(s,1H,CH),7.40(dd,1H,J=7.5,7.5Hz,CH), 7.41(CH),7.42(d,1H,J=7.5,8.0Hz,CH),8.00(dd,1H,J=5.0,7.5,7.5Hz,CH),8.01(d, 1H,J=5.0,7.5Hz,CH),8.49(s,1H,CH),8.82(d,1H,J=10.8Hz,CH),16.77(OH)。分子式: C35H32FN5O6,相对分子质量:637.66。
实施例42、化合物42的合成
将实施例22中的raw21替换为raw41,采用与实施例22相同的制备方法,即可制备得到化合物42,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.28(s,3H,CH3),2.39(t,2H,J =7.1Hz,CH2),2.39(t,2H,J=7.1Hz,CH2),3.10(t,2H,J=7.1Hz,CH2),3.40(t,2H,J=7.1Hz,CH2),3.40(t,2H,J=7.1Hz,CH2),3.9(s,1H,NH),4.28(t,2H,J=7.1Hz,CH2),6.28(d,1H,J=10.5Hz,CH),6.74(d,J=7.5Hz,CH),6.74(d,J=7.5Hz,CH),7.24(s,1H,CH),7.40(dd,1H,J=7.5,7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J=7.5,8.0Hz,CH),7.55(dd,1H,J=7.5Hz,CH),7.55(dd,1H,J=7.5Hz,CH),8.00(dd,J=5.0,7.5,7.5Hz,CH),8.01(d,J=5.0,7.5Hz,CH),8.50(s,1H,CH),8.82(d,1H,J=10.4Hz,CH),16.79(OH).分子式:C34H30FN5O6,相对分子质量:623.63。
实施例43、化合物43的合成
将实施例22中的raw21替换为raw42,采用与实施例22相同的制备方法,即可制备得到化合物43,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.16(s,3H,CH3),2.30(s,3H, CH3),2.39(t,2H,J=7.1Hz,CH2),2.39(t,2H,J=7.1Hz,CH2),3.10(t,2H,J=7.1Hz, CH2),3.40(t,2H,J=7.3Hz,CH2),3.40(t,2H,J=7.3Hz,CH2),4.1(s,1H,NH),4.28(t,2H, J=7.1Hz,CH2),6.30(d,1H,J=10.5Hz,CH),6.45(s,1H,CH),6.63(d,1H,J=7.5Hz,CH), 7.24(d,1H,CH),7.37(d,1H,J=7.5Hz,CH),7.40(dd,1H,J=7.5,7.5Hz,CH),7.41(s,1H, CH),7.42(d,1H,J=7.5,8.0Hz,CH),8.00(dd,1H,J=5.0,7.5,7.5Hz,CH),8.01(d,1H,J= 5.0,7.5Hz,CH),8.49(s,1H,CH),8.82(d,1H,J=10.5Hz,CH),16.77(OH)。分子式: C35H32FN5O6,相对分子质量:637.66。
以下通过化合物活性试验证明本发明的有益效果。
试验例1、本发明化合物对肿瘤细胞HT-29及A431抑制作用
在96孔板中接种HT-29和A431细胞,每孔接种3000个,设3个复孔。接种48h 后加药(阳性对照物为辉瑞舒尼替尼SU-11248),化合物浓度10μM(将化合物溶于0.1% DMSO配制),加药后继续培养72h。处理完毕后,每孔加入5mg/ml浓度的MTT20μl,于37℃孵育4h;37℃孵育4h后移去培养基,加入180μlDMSO,37℃至少静置30min,使蓝紫色甲赞颗粒充分溶解。预热酶标仪20min,在酶标仪上读取OD值,检测波长 490nm,最后计算肿瘤细胞生长抑制率。结果如图1和图2所示。取化合物9,检测其在其余浓度下对肿瘤细胞存活率的影响,结果如图3所示。
试验例2、cpd9诱导HT-29细胞的凋亡试验
HT-29细胞经2.5μM的cpd9处理16小时,提取基因组DNA,经4%的多聚甲醛固定细胞、Hoechst染色,结果如图4所示。我们发现经cpd9处理后的细胞出现了明显的DNAladder,提示已经发生了凋亡(图4A)。同时,显微镜观察发现药物处理后的细胞出现皱缩、变圆、脱落,与DNA特异性结合的活性染料Hoechst染色后发现药物处理后的细胞核裂解为碎块从而产生凋亡(图4B)。
试验例3化合物cpd1-cpd43体外对受体酪氨酸激酶抑制活性测试
酶联免疫洗釜测定(ELISA)
(1)酶反应底物Poly(Glu,Tyr)4/1用无钾离子的PBS(10mM磷酸钠缓冲液,150mMNaCl,pH 7.2-7.4)稀释成20μg/ml,125μL/空包被酶标板,于37摄氏度下反应12-15 小时后,弃去空中液体,用200μL/孔的T-PBS(含0.1%的Tween-20的无钾离子的PBS) 洗板3次,每次7分钟,再将酶标板于37摄氏度下干燥约2小时。
(2)每孔加入用反应缓冲液(50mM的HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mM Na3VO4,1mM DTT)稀释的ATP溶液49μL,每孔中加入1μL待测化合物,再加入50μL用反应缓冲液稀释的EGFR激酶域重组蛋白启动反应,每次实验需设无ATP 对照孔两孔。放置37摄氏度摇床(100rpm)反应1小时后,弃去孔中液体,T-PBS洗板三次。
(3)加入抗体PY99 100μL/孔(抗体用含BSA 5mg/ml的T-PBS 1/500稀释),置37 摄氏度下摇床反应半小时后,弃去孔中液体,用T-PBS洗板三次。
(4)加入辣根过氧化物酶标记的羊抗鼠二抗100μL/孔(抗体用含BSA 5mg/ml的 T-PBS 1/2000稀释),置37摄氏度摇床反应半小时后,弃去孔中液体,T-PBS洗板三次。
(5)加入2mg/ml的OPD显色液100μL/孔(用含0.03%H2O2的0.1M柠檬酸-柠檬酸钠缓冲液稀释),25摄氏度下避光反应5分钟。
(6)加入2M H2SO4 50μL/孔终止反应,用可调波长湿微孔板酶标仪VERSAmax读数,波长为490nm。
结果分析:样品的抑制率(%)=[1-(化合物OD值-无酶对照孔OD值)/(阴性对照孔OD 值-无酶对照孔OD值)]*100%。
表1 化合物cpd1-cpd43体外对受体酪氨酸激酶抑制活性测试结果
试验例4、斑马鱼实验
(1)斑马鱼胚胎的处理
筛选前一天,挑选tgflil:eGFP(+/+)装基因斑马鱼纯合子和AB野生型斑马鱼放于交配盒中,第二天早晨光照刺激产卵,收集半小时内的胚胎放于盛有胚胎培养液的培养皿中,置于28.5摄氏度孵化箱培养。当胚胎发育自10hpf时,转移至盛有胚胎培养液的24孔板中,每个孔中放入10个胚胎备用。胚胎发育自12hpf时,将配制好的药液依次加入24孔板中,实验重复三次。
(2)胚胎发育至48hpf,用OLYMPUS MVX10体式荧光显微镜观察。挑选抗血管生成有效的胚胎指标如下:①与同时期野生型AB斑马鱼胚胎相比大体形态发育正常;②flil 基因荧光表达强度减弱、缺失或者血管荧光分布紊乱表达异常的胚胎;
(3)血管生成抑制的分析
将各组胚胎取出,置于含有麻醉剂的培养液中,采用OLYMPUS MVX10体式荧光显微镜拍照,利用FV10-ASW 1.7 Viewer软件对斑马鱼体节间血管(yolk之后的10条体节间血管)进行长度测定,比例尺10mm。
(4)cpd9抗斑马鱼胚胎体节间血管筛选结果
当cpd9的药液浓度为10μM和20μM时,其抑制血管的程度逐渐增加,但整个胚胎发育正常,80%以上发生不同程度的新生血管抑制作用,如图5所示。
综上,本发明化合物具有优异的抗肿瘤活性和抑制新生血管的能力,应用前景优良。
Claims (11)
1.式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物在制备治疗肿瘤的药物中的用途,
其中,R1选自
R2、R3分别独立地选自H、卤素、烷基、或者R2和R3与其相连的碳原子组成含1~2个杂原子的1取代或多取代六元芳香杂环;
R4、R5、R6分别表示苯环上的0~3取代,R4、R5、R6分别独立选自H,卤素原子,C1~6烷基,C1~6烷氧基,羟基,氨基,羧基,硝基,CH3O(CH2)nCH2O-,其中n为1~6的整数。
2.根据权利要求1所述的用途,其特征在于,所述的药物是治疗结肠癌、纤维肉瘤、表皮癌、乳腺癌的药物。
3.式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物在制备对受体酪氨酸激酶(EGFR)抑制活性的药物中的用途,
其中,R1选自
R2、R3分别独立地选自H、卤素、烷基、或者R2和R3与其相连的碳原子组成含1~2个杂原子的1取代或多取代六元芳香杂环;
R4、R5、R6分别表示苯环上的0~3取代,R4、R5、R6分别独立选自H,卤素原子,C1~6烷基,C1~6烷氧基,羟基,氨基,羧基,硝基,CH3O(CH2)nCH2O-,其中n为1~6的整数。
4.式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物在制备抑制新生血管的药物中的用途,
其中,R1选自
R2、R3分别独立地选自H、卤素、烷基、或者R2和R3与其相连的碳原子组成含1~2个杂原子的1取代或多取代六元芳香杂环;
R4、R5、R6分别表示苯环上的0~3取代,R4、R5、R6分别独立选自H,卤素原子,C1~6烷基,C1~6烷氧基,羟基,氨基,羧基,硝基,CH3O(CH2)nCH2O-,其中n为1~6的整数。
5.根据权利要求1~4任一项所述的用途,其特征在于,所述R4、R5、R6分别独立选自H,卤素原子,C1~6烷基,C1~6烷氧基,CH3O(CH2)nCH2O-,其中n为1~6的整数。
6.根据权利要求5所述的用途,其特征在于,所述R4、R5、R6分别独立选自H,F,甲基,甲氧基,CH3OCH2CH2O-,
7.根据权利要求6所述的用途,其特征在于,所述R4、R5、R6表示苯环上的无取代或一取代。
8.根据权利要求1~4任一项所述的用途,其特征在于,所述R1选自
9.根据权利要求1~4任一项所述的用途,其特征在于:所述的六元芳香杂环为其中R7选自
10.根据权利要求1~4任一项所述的用途,其特征在于:所述化合物为下列化合物之一
11.根据权利要求10所述的用途,其特征在于:所述化合物的制备方法如下:
(一)化合物1~14的合成:
(1)中间体h的合成:
(2A)化合物1~7的合成:
(2B)化合物8~14的合成:
(二)化合物15-21的合成:
(三)化合物22-43的合成:
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