CN115772130A - 一种微管解聚剂及其制备方法和用途 - Google Patents
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Abstract
Description
技术领域
本发明涉及医药化学领域,具体涉及一种微管解聚剂及其制备方法和用途。
背景技术
恶性肿瘤是威胁人类健康的重大疾病之一,肿瘤的治疗一直被全世界密切关注。世界卫生组织公布2018年全球新增癌症病例约1810万例,死亡人数达960万,肿瘤新增病例每年持续上升。我国国家癌症中心的数据表明2017年中国恶性癌症新发病例数为380万例。近年来,随着分子生物学技术的不断提高和对肿瘤发病机制从细胞、分子水平的进一步认识,以及组合化学、基于结构的药物设计和计算机科学等技术的迅速发展,肿瘤生物治疗已经有了长足的进步,进入了分子靶向治疗时代。其中,微管靶向药物广泛用于人类肿瘤的治疗,对实体瘤和血液系统恶性肿瘤都有较好的治疗效果。
微管是由α-微管蛋白和β-微管蛋白组成的动态丝状细胞骨架蛋白,是肿瘤治疗的重要靶标。靶向微管的药物,即微管蛋白结合剂,是目前治疗肿瘤非常成功的一类化疗药,通过破坏肿瘤细胞有丝分裂期的微管动力学平衡,影响有丝分裂纺锤体形成,使细胞分裂停止,从而促进肿瘤细胞凋亡。微管蛋白结合剂包括微管蛋白解聚剂和微管蛋白聚合剂。其中,结合于秋水仙碱位点、长春花碱位点、美登素位点和pironetin位点的微管蛋白抑制剂属于微管蛋白解聚剂;结合于紫杉烷位点和laulimalide/pelorusideA位点的微管蛋白抑制剂属于微管蛋白聚合剂。微管蛋白结合剂是目前治疗肿瘤非常成功的一类化疗药,但其毒副作用较大,且有效性受到多药耐药性的影响,因此应用受限。
此外,大多数微管蛋白结合剂都是天然产物或其合成衍生物,分子量大、结构复杂而难以合成及改构修饰。秋水仙碱位点的微管蛋白抑制剂分子量小,更容易对其进行结构修饰,有望改善其耐药性、提高抗肿瘤活性、改善药代动力学性质以及降低毒副作用。迄今为止,尚未见具有异羟肟酸结构的秋水仙碱位点微管蛋白解聚剂被报道。
发明内容
本发明的目的是提供一种具有抗肿瘤活性的秋水仙碱结合位点微管解聚剂,特别是依赖于异羟肟酸的微管解聚剂及其制备方法和用途。
本发明提供了式I所示化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物、或其前药:
其中,
R1、R2分别独立选自氢、C1~C8烷基;
R3、R4分别独立选自氢、C1~C8烷基、5~6元芳基;或者,R3、R4连接形成3~10元环烷基;
R5选自C1~C8烷氧基、羟基、-N(H)R6;
R6选自氢、羟基、氨基;
当R1选自甲基、R2选自甲基、R3和R4同时为氢时,R5不选自C2烷氧基或N(H)OH。
进一步地,
R1、R2分别独立选自氢、C1~C3烷基;
R3、R4分别独立选自氢、C1~C4烷基、苯基;或者,R3、R4连接形成4~6元环烷基;
R5选自C1~C2烷氧基、羟基、-NH2、-N(H)OH、-N(H)NH2;
当R1选自甲基、R2选自甲基、R3和R4同时为氢时,R5不选自C2烷氧基或N(H)OH。
进一步地,所述化合物如式II所示:
其中,
R1选自氢或C1~C3烷基;
R2选自C1~C3烷基;
R3、R4分别独立选自氢、C1~C4烷基、苯基;或者,R3、R4连接形成4~6元环烷基;且R3、R4不同时选自氢。
进一步地,所述化合物如式III所示:
其中,
R3、R4分别独立选自氢、C1~C4烷基、苯基;或者,R3、R4连接形成4~6元环烷基;且R3、R4不同时选自氢。
进一步地,
R3、R4分别独立选自氢、甲基、丙基、丁基、异丙基、苯基;或者,R3、R4连接形成4~6元环烷基;且R3、R4不同时选自氢。
进一步地,所述化合物如式IV所示:
其中,
R3、R4分别独立选自氢、C1~C4烷基、苯基;或者,R3、R4连接形成4~6元环烷基;且R3、R4不同时选自氢。
进一步地,所述化合物为如下化合物之一:
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物、或其前药在制备微管蛋白解聚剂中的用途;
优选地,所述微管蛋白解聚剂为与微管蛋白秋水仙碱位点结合的微管蛋白解聚剂。
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物、或其前药在制备治疗肿瘤和/或具有耐药性的肿瘤的药物中的用途;
优选地,所述肿瘤为卵巢癌、结肠癌、结直肠癌、急性髓系白血病、急性单核细胞白血病、乳腺癌、宫颈癌、肝癌、肾癌、肺癌、髓性单核细胞白血病、外周淋巴瘤。
本发明还提供了一种药物,它是以前述的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物、或其前药为活性成分,加上药学上可接受的辅料或辅助性成分制备而得的制剂。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
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。
本发明中,所述化合物的结构均是指能够稳定存在的结构。
本发明中,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~C8烷基是指包含1~8个碳原子的直链或支链烷基,包括但不限于甲基、乙基、丙基、异丙基、正丁基、正戊基、异戊基、新戊基;C1~C8烷氧基是指包含1~8个碳原子的烷氧基。
本发明提供了一种可作为微管蛋白解聚剂的化合物,该微管蛋白解聚剂是秋水仙碱结合位点的微管蛋白解聚剂,其抗肿瘤活性依赖于异羟肟酸基团;该化合物对多种肿瘤细胞均有良好的抑制作用,具有广谱抗肿瘤作用;并且对于耐药肿瘤细胞同样表现出良好的抑制作用;该可用于制备治疗肿瘤以及耐药肿瘤的药物。同时,该化合物代谢稳定性好、毒副作用小、安全性好。本发明化合物克服了现有微管蛋白解聚剂毒副作用大,对于耐药肿瘤效果较差的缺陷,具有良好的应用前景。
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为化合物7b、paclitaxel和colchicine对A2780S细胞微管形状的影响;A2780S细胞分别用control(DMSO),paclitaxel(100nM),colchicine(100nM)和7b(3,10和30nM)处理16h,图片为×400放大获得。
图2为化合物8b-14b、paclitaxel和colchicine对A2780S细胞微管形状的影响;A2780S细胞分别用control(DMSO),paclitaxel(100nM),colchicine(100nM)和8b-14b(30nM)处理16h,图片为×400放大获得。
图3为化合物11b、12b、14b和紫杉醇对C26移植瘤模型的抗肿瘤活性,化合物11b、12b、14b口服给药,每两天一次;紫杉醇为每周1次,尾静脉注射:A为各组化合物对小鼠肿瘤体积的影响,游标卡尺每两天测一次肿瘤体积,体积mm3=(π/6)×长×宽×宽;B为各组化合物对小鼠肿瘤肿瘤的影响。
图4为化合物12b、paclitaxel和colchicine对A2780S细胞微管形状以及微管聚合的影响。A为A2780S细胞分别用control(DMSO),paclitaxel(100nM),colchicine(100nM),12b(1,3,10和30nM)处理16h,图片为×400放大获得。B为control(DMSO)、colchicine(5μM)和12b(5和10μM)与微管蛋白(3mg/ml)在37℃下共同孵育,每1分钟监测340nm处的吸光度,持续55分钟。
图5为化合物12b(0,0.2,1,5和25μM)、vincristine(5,25μM)和colchicine(5μM)在A2780S细胞上的EBI竞争实验。
图6为化合物12b在A2780S和A2780/T异种移植肿瘤模型的体内抗肿瘤活性。A和D为化合物对A2780S和A2780T肿瘤生长体积的抑制(游标卡尺每两天测一次肿瘤体积,体积(mm3)=(π/6)×长×宽×宽);B和E为治疗过程中,化合物对荷瘤小鼠体重的影响(小鼠体重变化每两天测量一次);C和F为荷瘤小鼠处死后的肿瘤重量,P<0.01**,P<0.001***,P<0.0001****,t test vs Control,t test。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。用于合成的原料、试剂和溶剂均为分析纯,并按使用要求进行预处理或直接使用。0.2mmTLC硅胶板、60-100目硅胶生产产家均为青岛海洋化工厂。
细胞与动物来源:
人卵巢癌细胞A2780S、A2780/T,人结肠癌细胞HCT116,人结直肠腺癌细胞HT29,人急性髓系白血病细胞MOLM-13,人乳腺癌细胞株MCF-7、MCF-7/ADR,人宫颈癌细胞Hela,人肝癌细胞HepG2和Huh-7,人肾透明细胞腺癌细胞786-O,人大细胞肺癌细胞H460,人乳腺癌细胞MDA-MB-231,人急性单核细胞白血病细胞THP-1,人髓性单核细胞白血病细胞MV4-11,人EB病毒感染的套细胞外周淋巴瘤细胞JVM-2和鼠结肠癌细胞C26购自美国典型培养物中心(American Type Culture Collection,ATCC),人B淋巴细胞瘤细胞Ramos购自中国科学院上海生命科学研究院细胞资源中心。上述所有细胞系由四川大学生物治疗国家重点实验室细胞库培养保种,并于2017年鉴定。
SPF级雌性6-7周BALB/c小鼠、无胸腺裸鼠(athymic nude mice)和NOD-SCID小鼠购自北京华阜康生物科技股份有限公司,雌性7-8周SD大鼠购自成都达硕实验动物有限公司。
实施例1、多种可作为微管蛋白解聚剂的化合物的制备
化合物的合成路线如下:
试剂与条件:(a)氯甲基甲醚(MOMCl),NaH,DMF,0℃-rt,3h;(b)N2H4·H2O,Pd/C(10%),N2,MeOH,rt,overnight;(c)(i)(CHO)n,MeONa,MeOH,rt,overnight;(ii)NaBH4,reflux,2h;(d)(i)4-氯-2-甲基喹唑啉,cat.conc HCl/(Me)2CHOH,(Me)2CHOH,rt,4h;(ii)4mol/L HCl/1,4-dioxane,EA,rt,2h;(e)Appropriate bromide,Cs2CO3,DMF,rt(7a-10a,11a and 13a)or 100℃(12a and 14a),overnight;(f)50%(w/w)NH2OH/H2O aq,NaOH,CH2Cl2/MeOH(1:2),0℃-rt,2h;(g)NaOH,EtOH,H2O,DCM,rt,3-4h;(h)NH3·H2O,MeOH,pressure tube,90℃,12h;(i)N2H4·H2O,MeOH,pressure tube,90℃,5h.
1、中间体的合成
(1)Methoxy-2-(methoxymethoxy)-4-nitrobenzene(中间体3)的合成
商业可得的2-甲氧基-5-硝基苯酚(16.9g,100mmol)溶于250mL的DMF中,降温至0℃后,缓慢加入60%NaH(7.7g,200mmol,2eq.)。反应半小时后,向反应体系中缓慢滴加氯甲基甲醚(MOMCl,15.2mL,200mmol,2eq.)。滴加完后,反应转移至室温继续反应。TLC监测反应(PET:EA=2:1,v/v)。反应完全后,将反应液缓慢倒入2.5L水中,析出大量黄色固体,过滤,滤饼用无水乙醇打浆,抽滤,真空干燥,得淡黄色固体产物(中间体3),收率74%。1H NMR(400MHz,DMSO-d6)δ7.97(d,J=8.6Hz,1H),7.91(s,1H),7.23(d,J=8.9Hz,1H),5.30(s,2H),3.93(s,3H),3.42(s,3H).
(2)4-methoxy-3-(methoxymethoxy)aniline(中间体4)的合成
中间体3(14g,66mmol)溶于120mL甲醇,加入10%钯碳(702mg,0.1eq.),水合肼(32mL,10eq.),置换氮气,室温反应过夜。TLC监测反应(DCM:MeOH=20:1,v/v)。反应完全后,硅藻土过滤,减压浓缩,乙酸乙酯和水萃取后,合并有机相,用无水硫酸钠干燥,溶剂旋干,得淡黄色油状产物(中间体4),收率87%。1H NMR(400MHz,DMSO-d6)δ6.68(d,J=8.5Hz,1H),6.37(d,J=2.5Hz,1H),6.16(dd,J=8.5,2.5Hz,1H),5.05(s,2H),4.67(s,2H),3.63(s,3H),3.38(s,3H).
(3)4-methoxy-3-(methoxymethoxy)-N-methylaniline(中间体5)的合成
将MeONa(14.7g,273mmol,5eq.)溶于150mL甲醇,冰浴冷却至0℃后,加入中间体4(10g,54.6mmol,1eq.)和多聚甲醛(2.3g,76.4mmol,1.4eq.),室温反应过夜。然后向反应体系中加入NaBH4(2.2g,57.3mmol,1.05eq.)。加热回流2h,TLC监测反应(DCM:MeOH=20:1,v/v)。反应完全后,减压浓缩反应液,然后向浓缩后的反应液中加入500mL的NaOH(1mol/L)水溶液,析出大量白色固体。抽滤,真空干燥,获得白色固体粉末(中间体5),收率75%。1H NMR(400MHz,DMSO-d6)δ6.77(d,J=8.6Hz,1H),6.34(d,J=2.6Hz,1H),6.12(dd,J=8.6,2.6Hz,1H),5.24–5.20(m,1H),5.08(s,2H),3.64(s,3H),3.39(s,3H),2.61(d,J=5.2Hz,3H).
(4)2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenol(中间体6)的合成
将中间体5(8.08g,41mmol,1eq.)和4-氯-2-甲基喹唑啉(7.32g,41mmol,1eq.)加入到250mL异丙醇中,然后加入0.5mL的盐酸/异丙醇溶液,室温搅拌,随着反应的进行,有大量淡黄色固体析出,TLC监测(PET:EA=2:1,v/v)反应完全后,抽滤。获得的滤饼用饱和的NaHCO3溶液碱化,得到的溶液用150mL×3的乙酸乙酯萃取,合并有机相。减压浓缩有机相,向浓缩后的有机相中加入15.4mL盐酸/1,4-二氧六环溶液(4mol/L,62mmol,1.5eq.)。随着反应进行,生成大量黄色固体。TLC监测(DCM:MeOH=20:1,v/v),反应完全后,抽滤,滤饼加入到饱和的NaHCO3溶液中,搅拌,有大量白色固体生成,再次抽滤。获得的滤饼用无水乙醇重结晶,真空干燥,得到灰白色固体粉末(中间体6),收率79%。1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),7.64(d,J=8.0Hz,1H),7.59(ddd,J=8.3,6.1,2.0Hz,1H),7.12–7.03(m,2H),6.94(dd,J=7.1,1.9Hz,1H),6.64(dd,J=7.4,2.2Hz,2H),3.79(s,3H),3.47(s,3H),2.58(s,3H).
2、目标化合物的合成
(1)Ethyl 2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)acetate(目标化合物7a)的合成
向100mL的圆底烧瓶中加入1.77g中间体6(6mmol,1eq.)和3.90g的Cs2CO3(12mmol,2eq.)溶于20mL DMF中,室温搅拌0.5h后,向反应体系中滴加1.10g溴乙酸乙酯(合成目标化合物7a,6.6mmol,1.1eq.)。室温搅拌过夜,TLC监测(DCM:MeOH=20:1,v/v)反应完全后,减压旋干。旋干的固体中加入40mL二氯甲烷使产品溶解于二氯甲烷,抽滤,滤液浓缩后Flash柱分离纯化,得到淡黄色固体7a,收率86%。1H NMR(400MHz,DMSO-d6)δ7.64(d,J=7.7Hz,1H),7.61–7.55(m,1H),7.08–7.03(m,1H),7.00(d,J=4.7Hz,1H),6.98(d,J=5.5Hz,1H),6.92(d,J=2.4Hz,1H),6.75(dd,J=8.5,2.4Hz,1H),4.74(s,2H),4.02(q,J=7.1Hz,2H),3.80(s,3H),3.48(s,3H),2.58(s,3H),1.10(t,J=7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ168.88,162.76,161.47,152.15,148.39,148.09,141.39,132.28,127.89,126.16,124.51,119.41,114.73,113.46,112.52,65.86,60.97,56.24,42.72,26.60,14.40.HRMS(ESI,m/z):calcd for C21H23N3O4[M+H]+382.1761,found:382.1767.
(2)2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)acetic acid(目标化合物7c)的合成
向50mL的圆底烧瓶中加入190.7mg化合物7a(0.5mmol,1eq.),溶于10mL二氯甲烷。将197.5mg的NaOH溶于0.5mL的水和2mL的乙醇,所得的NaOH溶液加入圆底烧瓶,室温搅拌3-4h,TLC监测(DCM:MeOH=20:1,v/v)反应完全后,调节pH至6-7,减压旋干,向旋干的固体中加入20mL二氯甲烷使产品溶解于二氯甲烷,抽滤,滤液用细硅胶拌样,通过Flash柱分离纯化,得到淡黄色固体7c,收率72%。1H NMR(400MHz,DMSO-d6)δ7.65(d,J=8.2Hz,1H),7.61–7.56(m,1H),7.09–7.04(m,1H),7.01(d,J=8.7Hz,1H),6.97(d,J=8.0Hz,1H),6.84–6.79(m,2H),4.91(q,J=6.7Hz,1H),3.81(s,3H),3.47(s,3H),3.46(s,3H),2.59(s,3H),1.44(d,J=6.7Hz,3H).13C NMR(100MHz,DMSO-d6)δ170.86,162.76,161.46,152.02,149.09,147.81,141.36,132.28,127.77,126.26,124.49,118.35,114.71,112.84,111.92,67.21,56.15,42.68,26.56.HRMS(ESI,m/z):calcd for C19H19N3O4[M+H]+354.1448,found:354.1456.
(3)N-hydroxy-2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)acetamide(目标化合物7b)的合成
向50mL的圆底烧瓶中加入190.7mg化合物7a(0.5mmol,1eq.),反应瓶中加入9mLDCM:MeOH(v/v,1:2),反应体系冷却至0℃,然后向该体系中加入0.5mL的50%(w/w)NH2OH/H2O溶液(15mmol,30eq.),5分钟后加入0.2g NaOH(10mmol,10eq.)。在该温度下反应2h,TLC监测(DCM:MeOH=20:1,v/v)反应完全后,反应液倒入90mL水中,用冰乙酸调节pH至7-8,40mL×3的乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,溶剂减压旋干,固体用无水乙醇重结晶,真空干燥得到白色固体粉末产物7b,收率85%。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.03(s,1H),7.65(d,J=8.0Hz,1H),7.61–7.56(m,1H),7.10–7.05(m,1H),7.02(dd,J=10.4,5.2Hz,2H),6.96(d,J=8.6Hz,1H),6.72(dd,J=8.5,2.1Hz,1H),4.40(s,2H),3.80(s,3H),3.49(s,3H),2.59(s,3H).13C NMR(100MHz,DMSO-d6)δ164.51,162.80,161.46,152.13,148.83,148.31,141.38,132.34,127.92,126.17,124.57,119.58,114.72,113.33,113.06,67.52,56.22,42.75,26.60.HRMS(ESI,m/z):calcd for C19H20N4O4[M+H]+369.1557,found:369.1560.
(4)2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)acetamide(目标化合物7d)的合成
向35mL的耐压管中加入190.7mg化合物7a(0.5mmol,1eq.),并加入6mL甲醇,1.16mL的NH3·H2O,(7.5mmol,15eq.),90℃加热搅拌12h,TLC监测(DCM:MeOH=20:1,v/v)反应完全后,反应液减压旋干,残留物用Flash柱分离纯化,得到淡黄色固体7d,收率79%。1HNMR(400MHz,DMSO-d6)δ7.64(d,J=7.8Hz,1H),7.61–7.56(m,1H),7.32(d,J=27.6Hz,2H),7.09–7.04(m,1H),6.99(dd,J=10.2,7.9Hz,3H),6.73(dd,J=8.5,2.4Hz,1H),4.39(s,2H),3.81(s,3H),3.49(s,3H),2.58(s,3H).13C NMR(100MHz,DMSO-d6)δ166.89,162.79,161.44,152.13,148.76,148.30,141.39,132.32,127.92,126.17,124.57,119.56,114.72,113.34,113.10,70.56,68.01,56.24,42.75,26.61.HRMS(ESI,m/z):calcd for C19H20N4O3[M+H]+353.1608,found:353.1607.
(5)2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)acetohydrazide(目标化合物7e)的合成
向35mL的耐压管中加入190.7mg化合物7a(0.5mmol,1eq.),加入5mL甲醇,0.98mL的N2H4·H2O,(20mmol,40eq.),90℃加热搅拌5h,TLC监测(DCM:MeOH=20:1,v/v)反应完全后,反应液减压旋干,残留物用Flash柱分离纯化,得到白色固体粉末7e,收率81%。1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),7.64(d,J=7.6Hz,1H),7.61–7.56(m,1H),7.06(dd,J=6.8,1.3Hz,1H),6.99(dd,J=9.7,5.5Hz,3H),6.74(dd,J=8.5,2.4Hz,1H),4.42(s,2H),4.27(s,2H),3.80(s,3H),3.49(s,3H),2.58(s,3H).13C NMR(100MHz,DMSO-d6)δ166.89,162.79,161.44,152.13,148.76,148.30,141.39,132.32,127.92,126.17,124.57,119.56,114.72,113.34,113.10,70.56,68.01,56.24,42.75,26.61.HRMS(ESI,m/z):calcd forC19H21N5O3[M+H]+368.1717,found:368.1717.
(6)目标化合物8a-14a的合成
化合物8a-11a和13a的制备方法和化合物7a的制备方法一致。化合物12a和14a的制备方法与化合物7a的制备方法上略有不同。相比较而言,12a和14a较其它类似化合物需要的温度及当量比更高。具体制备方法如下:
向100mL的圆底烧瓶中加入1.77g化合物6(6mmol,1eq.)和3.90g的Cs2CO3(12mmol,2eq.)溶于20mL DMF中,室温搅拌0.5h后,向反应体系中滴加2.51g 2-溴代异戊酸乙酯(合成12a,12mmol,2eq.)或3.73g乙基1-溴环丁烷甲酸酯(合成14a,18mmol,3eq.)。100℃搅拌过夜,TLC监测(DCM:MeOH=20:1,v/v)反应完全后,减压旋干。向旋干的残留中加入40mL二氯甲烷使产品溶解于二氯甲烷,抽滤,滤液浓缩后Flash柱分离纯化,得到淡黄色固体12a和14a。
Methyl2-(2-methoxy-5-(methyl(2-methyl-6,7-dihydroquinazolin-4-yl)amino)phenoxy)propanoate(目标化合物8a)
白色固体,收率92%。1H NMR(400MHz,DMSO-d6)δ7.67–7.62(m,1H),7.61–7.56(m,1H),7.09–7.04(m,1H),7.01(d,J=8.7Hz,1H),6.97(d,J=8.0Hz,1H),6.84–6.79(m,2H),4.91(q,J=6.7Hz,1H),3.81(s,3H),3.47(s,3H),3.46(s,3H),2.59(s,3H),1.44(d,J=6.7Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.00,162.77,161.42,152.11,148.47,147.74,141.31,132.31,127.87,126.08,124.55,119.78,114.68,113.70,113.64,73.05,56.24,52.24,42.75,26.57,18.48.HRMS(ESI,m/z):calcd for C21H23N3O4[M+H]+382.1761,found:382.1770。
Ethyl2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)pentanoate(目标化合物9a)
淡黄色蜡状固体,收率90%。1H NMR(400MHz,DMSO-d6)δ7.65(d,J=7.8Hz,1H),7.62–7.55(m,1H),7.07–7.00(m,2H),6.98(d,J=7.9Hz,1H),6.84(dd,J=8.6,2.4Hz,1H),6.75(d,J=2.4Hz,1H),4.70(dd,J=7.2,5.4Hz,1H),3.91–3.86(m,1H),3.81(s,3H),3.47(s,3H),2.59(s,3H),1.84–1.70(m,2H),1.45–1.36(m,2H),1.02(t,J=7.1Hz,3H),0.88(t,J=7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ171.13,162.77,161.44,152.17,148.49,148.08,141.37,132.28,127.92,126.05,124.49,119.75,114.70,113.87,113.68,76.83,60.93,56.34,42.73,34.59,26.57,18.25,14.33,13.94.HRMS(ESI,m/z):calcd forC24H29N3O4[M+H]+424.2231,found:424.2240.
Ethyl 2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)hexanoate(目标化合物10a)
淡黄色油状物,收率91%。1H NMR(400MHz,DMSO-d6)δ7.65(d,J=7.5Hz,1H),7.61–7.56(m,1H),7.08–7.00(m,2H),6.97(d,J=8.0Hz,1H),6.84(dd,J=8.6,2.5Hz,1H),6.75(d,J=2.4Hz,1H),4.69(t,J=6.3Hz,1H),3.88(dd,J=10.6,7.1Hz,2H),3.81(s,3H),3.47(s,3H),2.58(s,3H),1.78(dd,J=15.3,7.1Hz,2H),1.35(dd,J=14.4,7.0Hz,2H),1.31–1.23(m,2H),1.02(t,J=7.1Hz,3H),0.85(t,J=7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ171.13,162.78,161.44,152.15,148.49,148.06,141.36,132.32,127.92,126.05,124.51,119.78,114.70,113.89,113.71,77.02,60.94,56.36,42.75,32.19,27.01,26.59,22.13,14.35,14.21.HRMS(ESI,m/z):calcd for C25H31N3O4[M+H]+438.2387,found:438.2386.
Ethyl2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-2-methylpropanoate(目标化合物11a)
淡黄色固体粉末,收率87%。1H NMR(400MHz,DMSO-d6)δ7.66(d,J=7.8Hz,1H),7.62–7.57(m,1H),7.06(dd,J=11.5,4.9Hz,2H),7.04–6.98(m,2H),6.55(d,J=2.4Hz,1H),3.90(q,J=7.1Hz,2H),3.78(s,3H),3.47(s,3H),2.59(s,3H),1.35(s,6H),1.01(t,J=7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ173.22,162.83,161.53,152.18,150.87,145.08,141.18,132.36,127.99,126.13,124.56,121.21,118.91,114.63,114.03,80.35,61.21,56.21,42.67,26.57,24.93,14.14.HRMS(ESI,m/z):calcd for C23H27N3O4[M+H]+410.2074,found:410.2079.
Ethyl2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-3-methylbutanoate(目标化合物12a)
淡黄色蜡状固体,收率85%。1H NMR(400MHz,DMSO-d6)δ7.67–7.63(m,1H),7.61–7.56(m,1H),7.07–7.00(m,2H),6.97(d,J=7.8Hz,1H),6.84(dd,J=8.6,2.5Hz,1H),6.72(d,J=2.5Hz,1H),4.47(d,J=5.6Hz,1H),3.93–3.82(m,2H),3.81(s,3H),3.47(s,3H),2.58(s,3H),2.12(dq,J=13.5,6.8Hz,1H),1.01(t,J=7.1Hz,3H),0.98(d,J=6.8Hz,3H),0.94(d,J=6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ170.50,162.78,161.44,152.15,148.52,148.38,141.41,132.31,127.92,126.04,124.52,119.74,114.70,114.06,113.63,81.84,60.79,56.48,42.75,31.54,26.58,18.57,18.04,14.38.HRMS(ESI,m/z):calcd forC24H29N3O4[M+H]+424.2231,found:424.2235.
Methyl2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-2-phenylacetate(目标化合物13a)
白色固体粉末,收率92%。1H NMR(400MHz,DMSO-d6)δ7.64(d,J=7.7Hz,1H),7.60–7.56(m,1H),7.50–7.44(m,2H),7.38(d,J=4.8Hz,3H),7.00(t,J=9.9Hz,2H),6.94–6.85(m,2H),6.79(dd,J=8.3,1.9Hz,1H),5.95(d,J=21.6Hz,1H),3.82(s,3H),3.46(s,3H),3.44(s,3H),2.58(s,3H).13C NMR(100MHz,DMSO-d6)δ170.08,162.75,161.46,152.12,148.70,147.23,141.34,135.74,132.33,129.43,129.10,127.89,126.01,124.60,120.17,114.68,114.49,113.91,78.39,56.42,52.60,42.73,26.61.HRMS(ESI,m/z):calcd forC26H25N3O4[M+H]+444.1918,found:444.1924.
Ethyl1-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)cyclobutane-1-carboxylate(化合物14a)
透明蜡状固体,收率91%。1H NMR(400MHz,DMSO-d6)δ7.66(d,J=7.9Hz,1H),7.61–7.56(m,1H),7.09–7.01(m,2H),6.96(d,J=8.2Hz,1H),6.86(dd,J=8.6,2.4Hz,1H),6.09(d,J=2.4Hz,1H),3.92(q,J=7.1Hz,2H),3.80(s,3H),3.43(s,3H),2.58(s,3H),2.37(ddd,J=12.9,8.8,3.9Hz,2H),2.24–2.15(m,2H),1.85–1.70(m,2H),1.01(t,J=7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ171.99,162.82,161.50,152.11,148.21,145.50,141.17,132.36,127.92,126.02,124.56,119.06,114.64,113.82,112.68,79.91,61.34,56.18,42.64,31.86,26.53,14.21,13.48.HRMS(ESI,m/z):calcd for C24H27N3O4[M+H]+422.2074,found:422.2037.
(7)目标化合物8c-14c的合成
化合物8c-14c的制备方法和化合物7c的制备方法一致。
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)propanoic acid(目标化合物8c)
淡黄色固体,收率70%。1H NMR(400MHz,DMSO-d6)δ7.84(d,J=8.2Hz,1H),7.76–7.66(m,1H),7.18–7.12(m,1H),7.04(d,J=8.7Hz,1H),7.00(d,J=2.4Hz,1H),6.90(d,J=8.4Hz,1H),6.85(dd,J=8.5,2.4Hz,1H),4.85(q,J=6.7Hz,1H),3.82(s,3H),3.57(s,3H),2.67(s,3H),1.46(d,J=6.7Hz,3H).13C NMR(100MHz,DMSO-d6)δ173.00,161.49,161.14,149.14,148.26,146.78,139.50,133.76,126.62,125.66,123.91,119.38,113.63,113.59,113.18,72.90,56.28,43.41,24.59,18.52.HRMS(ESI,m/z):calcd for C20H21N3O4[M+H]+368.1605,found:368.1603.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)pentanoic acid(目标化合物9c)
淡黄色固体,收率91%。1H NMR(400MHz,DMSO-d6)δ8.05(d,J=8.3Hz,1H),7.85(t,J=7.6Hz,1H),7.26(t,J=7.8Hz,1H),7.14(dd,J=5.3,3.1Hz,2H),7.07(d,J=8.5Hz,1H),6.78(d,J=8.6Hz,1H),4.76(t,1H),3.86(s,3H),3.71(s,3H),2.78(s,3H),1.87–1.75(m,2H),1.42(dd,J=14.7,7.3Hz,2H),0.88(t,J=7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.35,160.84,160.00,150.12,148.77,140.78,137.48,135.45,127.21,126.95,119.50,119.31,113.88,113.11,112.44,76.37,56.45,44.24,34.40,22.31,18.38,13.99.HRMS(ESI,m/z):calcd for C22H25N3O4[M+H]+396.1918,found:396.1922.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)hexanoicacid(目标化合物10c)
浅灰色固体,收率92%。1H NMR(400MHz,DMSO-d6)δ8.04(d,J=8.3Hz,1H),7.85(t,J=7.6Hz,1H),7.26(t,J=7.8Hz,1H),7.14(d,J=7.2Hz,2H),7.06(d,J=8.4Hz,1H),6.79(d,J=8.6Hz,1H),4.75(t,1H),3.86(s,3H),3.71(s,3H),2.77(s,3H),1.87–1.77(m,2H),1.37(dd,J=11.5,5.3Hz,2H),1.29(dd,J=13.4,6.6Hz,2H),0.85(t,J=7.1Hz,3H).13CNMR(100MHz,DMSO-d6)δ172.34,160.84,160.01,150.14,148.76,140.79,137.48,135.47,127.22,126.95,119.52,119.32,113.90,113.17,112.45,76.60,56.47,44.24,32.01,27.18,22.34,22.16,14.26.HRMS(ESI,m/z):calcd for C23H27N3O4[M+H]+410.2074,found:410.2075.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-2-methylpropanoic acid(目标化合物11c)
淡黄色固体,收率85%。1H NMR(400MHz,DMSO-d6)δ7.64(d,J=7.6Hz,1H),7.61–7.55(m,1H),7.07–6.96(m,3H),6.86(dd,J=8.6,2.4Hz,1H),6.71(d,J=2.4Hz,1H),3.77(s,3H),3.46(s,3H),2.58(s,3H),1.34(s,6H).13C NMR(100MHz,DMSO-d6)δ162.79,161.36,152.05,150.55,140.81,132.37,127.85,126.21,124.52,120.00,118.20,114.54,113.63,100.00,80.66,56.17,49.06,42.69,26.55,25.30.HRMS(ESI,m/z):calcd for C21H23N3O4[M+H]+382.1761,found:382.1766.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-3-methylbutanoic acid(目标化合物12c)
淡黄色固体,收率98%。1H NMR(400MHz,DMSO-d6)δ7.64(d,J=7.9Hz,1H),7.61–7.54(m,1H),7.04(t,J=7.1Hz,1H),6.98(d,J=8.1Hz,1H),6.93(d,J=8.6Hz,1H),6.87(d,J=2.3Hz,1H),6.65(dd,J=8.5,2.3Hz,1H),4.40(d,J=4.9Hz,1H),3.79(s,3H),3.46(s,3H),2.58(s,3H),2.16(td,J=13.4,6.7Hz,1H),0.99(t,J=7.0Hz,6H).13C NMR(100MHz,DMSO-d6)δ172.49,162.72,161.40,151.79,149.05,148.49,141.21,132.37,127.61,126.17,124.56,119.02,114.60,113.68,113.37,82.25,56.44,42.69,31.32,26.44,19.03,18.04.HRMS(ESI,m/z):calcd for C22H25N3O4[M+H]+396.1918,found:396.1922.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-2-phenylacetic acid(目标化合物13c)
淡黄色固体,收率94%。1H NMR(400MHz,DMSO-d6)δ7.65(d,J=8.2Hz,1H),7.57(t,J=7.6Hz,1H),7.51(d,J=6.7Hz,2H),7.43–7.31(m,3H),7.03(d,J=2.3Hz,1H),6.96(t,J=7.9Hz,2H),6.85(d,J=8.5Hz,1H),6.66(dd,J=8.5,2.3Hz,1H),5.84(s,1H),3.81(s,3H),3.45(s,3H),2.59(s,3H).13C NMR(100MHz,DMSO-d6)δ171.16,162.56,161.39,151.28,148.79,147.78,141.00,136.62,132.49,129.05,128.91,127.85,127.22,126.13,124.67,119.63,114.47,114.28,113.64,78.77,56.38,42.75,26.29.HRMS(ESI,m/z):calcd forC25H23N3O4[M+H]+430.1761,found:430.1751.
1-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)cyclobutane-1-carb oxylic acid(目标化合物14c)
淡黄色固体,收率94%。1H NMR(400MHz,DMSO-d6)δ7.65(d,J=8.1Hz,1H),7.58(t,J=7.3Hz,1H),7.07(t,J=7.4Hz,1H),6.98(dd,J=12.6,8.7Hz,2H),6.77(d,J=7.8Hz,1H),6.21–6.14(m,1H),3.79(s,3H),3.44(s,3H),2.58(s,3H),2.40–2.32(m,2H),2.19–2.08(m,2H),1.83–1.73(m,2H).13C NMR(100MHz,DMSO-d6)δ173.89,162.75,161.44,151.93,148.12,145.85,140.95,132.41,127.74,126.16,124.64,118.44,114.55,113.54,112.52,79.75,56.12,42.61,31.91,26.50,13.63.HRMS(ESI,m/z):calcd for C22H23N3O4[M+H]+394.1761,found:394.1761.
(8)目标化合物8b-14b的合成
化合物8b-14b的制备方法和化合物7b的制备方法一致。
N-hydroxy-2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)propena mide(目标化合物8b)
白色固体,收率87%。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.97(s,1H),7.65(d,J=8.1Hz,1H),7.58(t,J=7.2Hz,1H),7.07(t,J=7.3Hz,1H),6.97(dd,J=14.1,5.2Hz,3H),6.74(dd,J=8.5,2.3Hz,1H),4.58(q,J=6.4Hz,1H),3.80(s,3H),3.48(s,3H),2.59(s,3H),1.36(d,J=6.5Hz,3H).13C NMR(100MHz,DMSO-d6)δ167.68,162.80,161.47,152.14,148.96,147.75,141.34,132.34,127.92,126.16,124.59,119.95,114.80,114.70,113.59,74.03,56.27,42.73,26.60,18.86.HRMS(ESI,m/z):calcd for C20H22N4O4[M+H]+383.1714,found:383.1715.
N-hydroxy-2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)pentana mide(目标化合物9b)
灰白色固体,收率79%。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.96(s,1H),7.65(d,J=8.1Hz,1H),7.58(t,J=7.3Hz,1H),7.06(t,J=7.5Hz,1H),6.98(dd,J=8.1,6.1Hz,2H),6.92(d,J=2.3Hz,1H),6.74(dd,J=8.6,2.3Hz,1H),4.42(t,J=6.4Hz,1H),3.80(s,3H),3.48(s,3H),2.59(s,3H),1.78–1.63(m,2H),1.39–1.27(m,2H),0.84(t,J=7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ167.03,162.79,161.47,152.14,148.92,148.10,141.33,132.34,127.92,126.15,124.59,119.86,114.68,114.68,113.69,77.67,56.32,42.72,34.78,26.60,18.16,14.01.HRMS(ESI,m/z):calcd for C22H26N4O4[M+H]+411.2027,found:411.2029.
N-hydroxy-2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)hexana mide(目标化合物10b)
淡黄色固体,收率77%。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.94(s,1H),7.65(d,J=7.7Hz,1H),7.61–7.56(m,1H),7.09–7.03(m,1H),6.99(d,J=3.7Hz,1H),6.97(d,J=4.4Hz,1H),6.92(d,J=2.4Hz,1H),6.75(dd,J=8.6,2.4Hz,1H),4.40(t,J=6.4Hz,1H),3.79(s,3H),3.48(s,3H),2.59(s,3H),1.78–1.67(m,2H),1.30–1.22(m,4H),0.83(t,J=7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ167.01,162.77,161.47,152.06,148.96,148.07,141.31,132.37,127.86,126.16,124.61,119.89,114.76,114.67,113.71,77.91,56.33,42.74,32.33,26.94,26.58,22.22,14.29.HRMS(ESI,m/z):calcd for C23H28N4O4[M+H]+425.2183,found:425.2188.
N-hydroxy-2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-2-methylpropanamide(目标化合物11b)
淡黄色固体,收率70%。1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.83(s,1H),7.62(d,J=8.3Hz,1H),7.55(t,J=7.5Hz,1H),7.01(dd,J=13.0,8.1Hz,2H),6.92(dd,J=12.2,5.4Hz,2H),6.79(d,J=2.2Hz,1H),3.76(s,3H),3.44(s,3H),2.55(s,3H),1.23(s,6H).13C NMR(100MHz,DMSO-d6)δ170.65,162.80,161.37,152.11,151.74,144.69,140.99,132.35,127.93,126.21,124.51,121.88,121.04,114.53,113.91,82.09,56.34,42.72,26.58,25.20.HRMS(ESI,m/z):calcd for C21H24N4O4[M+H]+397.1870,found:397.1869.
N-hydroxy-2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-3-methylbutanamide(目标化合物12b)
白色固体粉末,收率71%。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.98(s,1H),7.62(d,J=8.2Hz,1H),7.55(t,J=7.5Hz,1H),7.03(t,J=7.6Hz,1H),6.93(dd,J=11.3,8.7Hz,3H),6.66(dd,J=8.5,1.8Hz,1H),4.07(d,J=6.9Hz,1H),3.76(s,3H),3.44(s,3H),2.55(s,3H),2.07(dq,J=13.3,6.7Hz,1H),0.95(d,J=6.7Hz,3H),0.86(d,J=6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ166.43,162.80,161.47,152.03,148.92,148.60,141.31,132.38,127.83,126.17,124.63,119.85,114.78,114.65,113.73,83.27,56.40,42.73,31.45,26.56,18.63,18.58.HRMS(ESI,m/z):calcd for C22H26N4O4[M+H]+411.2017,found:411.2024.
N-hydroxy-2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-2-phenylacetamide(目标化合物13b)
灰白色固体粉末,收率79%。1H NMR(400MHz,DMSO-d6)δ7.63(d,J=8.0Hz,1H),7.57(t,J=7.3Hz,1H),7.46(d,J=6.7Hz,2H),7.37–7.28(m,3H),7.01–6.92(m,3H),6.86(d,J=8.4Hz,1H),6.67(d,J=7.7Hz,1H),5.59(s,1H),3.81(s,3H),3.43(s,3H),2.58(s,3H).13C NMR(100MHz,DMSO-d6)δ165.55,162.75,161.50,152.07,149.12,147.39,141.32,137.25,132.34,128.80,128.63,127.84,127.61,126.04,124.63,120.24,115.66,114.66,113.76,79.20,56.42,42.66,26.58.HRMS(ESI,m/z):calcd for C25H24N4O4[M+H]+445.1870,found:445.1871.
N-hydroxy-1-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)cyclobutane-1-carboxamide(目标化合物14b)
白色固体粉末,收率77%。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.78(s,1H),7.64(d,J=8.2Hz,1H),7.58(t,J=7.6Hz,1H),7.05(dd,J=16.5,8.0Hz,2H),6.96(d,J=8.5Hz,1H),6.86(dd,J=8.6,2.2Hz,1H),6.22(d,J=2.2Hz,1H),3.79(d,J=5.2Hz,3H),3.46(s,3H),2.58(s,3H),2.24(t,J=9.1Hz,2H),2.00(dd,J=21.8,9.8Hz,2H),1.71–1.56(m,2H).13C NMR(100MHz,DMSO-d6)δ168.69,162.77,161.42,152.13,148.85,145.13,140.98,132.33,127.87,126.22,124.55,119.14,114.53,114.07,113.58,80.76,56.16,42.56,31.50,26.56,19.01,13.44.HRMS(ESI,m/z):calcd for C22H24N4O4[M+H]+409.1870,found:409.1872.
(9)目标化合物8d-14d的合成
化合物8d-14d的制备方法和化合物7d的制备方法一致。
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)propanamide(目标化合物8d)
白色固体,收率81%。1H NMR(400MHz,DMSO-d6)δ7.64(d,J=7.5Hz,1H),7.61–7.56(m,1H),7.34(s,1H),7.21(s,1H),7.08–7.03(m,1H),6.99(d,J=8.6Hz,2H),6.94(d,J=2.5Hz,1H),6.75(dd,J=8.6,2.5Hz,1H),4.55(q,J=6.7Hz,1H),3.81(s,3H),3.47(s,3H),2.58(s,3H),1.36(d,J=6.6Hz,3H).13C NMR(100MHz,DMSO-d6)δ173.57,162.78,161.45,152.15,148.75,147.94,141.37,132.32,127.94,126.12,124.57,119.79,114.71,114.51,113.51,75.57,56.25,42.72,26.60,18.89.HRMS(ESI,m/z):calcd for C20H22N4O3[M+H]+367.1765,found:367.1766.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)pentanamide(目标化合物9d)
灰白色固体,收率72%。1H NMR(400MHz,DMSO-d6)δ7.65(d,J=7.7Hz,1H),7.62–7.55(m,1H),7.36(s,1H),7.22(s,1H),7.08–7.03(m,1H),6.99(d,J=8.6Hz,2H),6.92(d,J=2.4Hz,1H),6.76(dd,J=8.6,2.4Hz,1H),4.43(dd,J=6.9,5.3Hz,1H),3.81(s,3H),3.48(s,3H),2.58(s,3H),1.76–1.62(m,2H),1.38(dq,J=14.5,7.3Hz,2H),0.85(t,J=7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ173.02,162.77,161.44,152.10,148.71,148.31,141.34,132.34,127.91,126.11,124.56,119.67,114.68,114.35,113.60,79.29,56.31,42.71,34.83,26.59,18.27,14.09.HRMS(ESI,m/z):calcd for C22H26N4O3[M+H]+395.2078,found:395.2085.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)hexanamide(目标化合物10d)
淡黄色固体,收率74%。1H NMR(400MHz,DMSO-d6)δ7.65(dd,J=8.3,0.7Hz,1H),7.61–7.56(m,1H),7.36(s,1H),7.22(s,1H),7.08–7.03(m,1H),6.99(d,J=8.6Hz,2H),6.92(d,J=2.5Hz,1H),6.76(dd,J=8.6,2.5Hz,1H),4.43(t,J=6.1Hz,1H),3.81(s,3H),3.48(s,3H),2.58(s,3H),1.73(dt,J=6.9,4.8Hz,2H),1.34(dt,J=15.3,6.7Hz,2H),1.25(dd,J=14.8,7.1Hz,2H),0.83(t,J=7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ173.00,162.77,161.44,152.14,148.74,148.29,141.37,132.32,127.93,126.10,124.55,119.71,114.69,114.46,113.63,79.53,56.32,42.71,32.37,27.06,26.60,22.28,14.29.HRMS(ESI,m/z):calcd for C23H28N4O3[M+H]+409.2234,found:409.2242.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-2-methylpropanamide(目标化合物11d)
淡黄色固体,收率75%。1H NMR(400MHz,DMSO-d6)δ7.65(d,J=8.0Hz,1H),7.62–7.55(m,1H),7.43(s,1H),7.22(s,1H),7.07(d,J=8.6Hz,1H),7.06–7.02(m,1H),7.01–6.93(m,2H),6.80(d,J=2.4Hz,1H),3.80(s,3H),3.48(s,3H),2.58(s,3H),1.24(s,6H).13CNMR(100MHz,DMSO-d6)δ176.36,162.81,161.41,152.19,151.48,144.86,141.07,132.31,128.00,126.19,124.51,121.52,120.37,114.57,113.87,82.27,56.29,42.68,26.60,24.87.HRMS(ESI,m/z):calcd for C21H24N4O3[M+H]+381.1921,found:381.1925.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-3-methylbutanamide(目标化合物12d)
淡黄色固体,收率70%。1H NMR(400MHz,DMSO-d6)δ7.65(d,J=8.0Hz,1H),7.58(t,J=7.1Hz,1H),7.37(s,1H),7.24(s,1H),7.08–7.02(m,1H),6.99(dd,J=8.2,4.5Hz,2H),6.95(d,J=2.0Hz,1H),6.73(dd,J=8.4,2.0Hz,1H),4.20(d,J=5.5Hz,1H),3.82(s,3H),3.48(s,3H),2.59(s,3H),2.11(td,J=12.8,6.3Hz,1H),0.98(d,J=6.7Hz,3H),0.93(d,J=6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.34,162.77,161.44,152.13,148.86,148.71,141.40,132.31,127.93,126.12,124.56,119.62,114.69,114.44,113.67,84.65,56.41,42.70,31.33,26.60,18.94,18.20.HRMS(ESI,m/z):calcd for C22H26N4O3[M+H]+395.2078,found:395.2078.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-2-phenylacetamide(目标化合物13d)
白色固体,收率76%。1H NMR(400MHz,DMSO-d6)δ7.63(d,J=7.6Hz,1H),7.61–7.54(m,2H),7.46(dd,J=7.7,1.4Hz,2H),7.40–7.28(m,4H),7.01–6.93(m,3H),6.86(d,J=8.3Hz,1H),6.70(dd,J=8.6,2.5Hz,1H),5.60(s,1H),3.82(s,3H),3.42(s,3H),2.58(s,3H).13C NMR(100MHz,DMSO-d6)δ171.21,162.74,161.48,152.10,148.98,147.45,141.33,137.35,132.33,128.75,128.67,127.88,127.65,126.02,124.61,120.15,115.44,114.68,113.68,80.65,56.41,42.67,26.60.HRMS(ESI,m/z):calcd for C25H24N4O3[M+H]+429.1921,found:429.1917.
1-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)cyclobutane-1-carb oxamide(目标化合物14d)
白色固体,收率75%。1H NMR(400MHz,DMSO-d6)δ7.64(dd,J=8.3,0.8Hz,1H),7.61–7.55(m,1H),7.21(s,1H),7.12(s,1H),7.09–7.01(m,2H),6.96(d,J=8.4Hz,1H),6.85(dd,J=8.6,2.5Hz,1H),6.21(d,J=2.5Hz,1H),3.81(s,3H),3.45(s,3H),2.58(s,3H),2.25(ddd,J=12.8,8.8,3.9Hz,2H),2.05–1.95(m,2H),1.71–1.57(m,2H).13C NMR(100MHz,DMSO-d6)δ174.23,162.77,161.44,152.13,148.70,145.26,141.03,132.33,127.91,126.15,124.58,119.02,114.58,113.73,113.56,81.26,56.13,42.59,31.23,26.58,13.46.HRMS(ESI,m/z):calcd for C22H24N4O3[M+H]+393.1921,found:393.1924.
(10)目标化合物8e-14e的合成
化合物8e-14e的制备方法和化合物7e的制备方法一致。
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)propanehydrazide(目标化合物8e)
白色固体,收率86%。1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.65(d,J=7.6Hz,1H),7.62–7.55(m,1H),7.09–7.04(m,1H),6.98(dd,J=8.1,5.9Hz,2H),6.92(d,J=2.4Hz,1H),4.63(q,J=6.5Hz,1H),4.17(s,2H),3.81(s,3H),3.48(s,3H),2.59(s,3H),1.35(d,J=6.6Hz,3H).13C NMR(100MHz,DMSO-d6)δ170.17,162.79,161.41,152.15,148.84,147.78,141.33,132.30,127.94,126.14,124.56,119.85,114.69,114.54,113.59,74.50,56.27,42.76,26.61,18.90.HRMS(ESI,m/z):calcd for C20H23N5O3[M+H]+382.1874,found:382.1878.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)pentanehydrazide(目标化合物9e)
白色固体,收率64%。1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.65(d,J=8.0Hz,1H),7.59(t,J=7.4Hz,1H),7.08–7.03(m,1H),6.98(t,J=8.9Hz,2H),6.88(d,J=2.2Hz,1H),6.79(dd,J=8.5,2.2Hz,1H),4.49(t,J=6.3Hz,1H),4.11(s,2H),3.81(s,3H),3.48(s,3H),2.59(s,3H),1.76–1.65(m,2H),1.37–1.27(m,2H),0.83(t,J=7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.62,162.77,161.39,152.13,148.79,148.14,141.32,132.29,127.91,126.12,124.53,119.72,114.67,114.36,113.70,78.13,56.33,42.75,34.84,26.59,18.17,14.03.HRMS(ESI,m/z):calcd for C22H27N5O3[M+H]+410.2187,found:410.2197.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)hexanehydrazide(目标化合物10e)
淡黄色固体,收率69%。1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.65(d,J=8.2Hz,1H),7.59(t,J=7.5Hz,1H),7.06(t,J=7.6Hz,1H),6.98(t,J=9.2Hz,2H),6.89(d,J=2.3Hz,1H),6.79(dd,J=8.6,2.3Hz,1H),4.48(t,J=6.3Hz,1H),4.13(s,2H),3.81(s,3H),3.48(s,3H),2.59(s,3H),1.77–1.64(m,2H),1.31–1.19(m,4H),0.83(t,J=6.9Hz,3H).13CNMR(100MHz,DMSO-d6)δ169.58,162.78,161.40,152.16,148.82,148.12,141.34,132.29,127.93,126.11,124.52,119.76,114.68,114.46,113.72,78.39,56.34,42.75,32.40,26.95,26.60,22.24,14.26.HRMS(ESI,m/z):calcd for C23H29N5O3[M+H]+424.2343,found:424.2349.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-2-methylpropanehydrazide(目标化合物11e)
灰色固体,收率61%。1H NMR(400MHz,DMSO)δ9.12(s,1H),7.65(d,J=8.0Hz,1H),7.59(t,J=7.4Hz,1H),7.08–7.02(m,2H),6.97(dd,J=8.7,2.9Hz,2H),6.82(d,J=2.5Hz,1H),4.24(s,2H),3.81(s,3H),3.49(s,3H),2.58(s,3H),1.26(s,6H).13C NMR(100MHz,DMSO-d6)δ172.87,162.68,161.34,151.85,144.64,140.87,132.50,127.53,126.27,124.63,121.95,121.14,114.44,113.91,108.17,82.28,56.40,42.79,26.40,25.16.HRMS(ESI,m/z):calcd for C21H25N5O3[M+H]+396.2030,found:396.2029.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-3-methylbutanehydrazide(目标化合物12e)
淡黄色固体,收率67%。1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.65(d,J=7.7Hz,1H),7.59(t,J=7.5Hz,1H),7.08–7.03(m,1H),6.97(t,J=9.7Hz,2H),6.89(d,J=2.4Hz,1H),6.76(dd,J=8.6,2.4Hz,1H),4.19(d,J=6.6Hz,1H),4.10(s,2H),3.81(s,3H),3.48(s,3H),2.59(s,3H),2.08(dq,J=13.4,6.7Hz,1H),0.96(d,J=6.7Hz,3H),0.87(d,J=6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.00,162.77,161.39,152.16,148.77,148.64,141.35,132.28,127.94,126.13,124.53,119.65,114.69,114.37,113.77,83.57,56.43,42.76,31.44,26.62,18.68,18.53.HRMS(ESI,m/z):calcd for C22H27N5O3[M+H]+410.2187,found:410.2188.
2-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)-2-phenylacetohydrazide(目标化合物13e)
灰白色固体,收率67%。1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),7.64(d,J=8.3Hz,1H),7.57(t,J=7.5Hz,1H),7.46(d,J=7.2Hz,2H),7.36–7.28(m,3H),6.96(dd,J=15.5,8.2Hz,3H),6.85(d,J=8.5Hz,1H),6.74(d,J=8.5Hz,1H),5.65(s,1H),4.22(s,2H),3.83(s,3H),3.43(s,3H),2.58(s,3H).13C NMR(100MHz,DMSO-d6)δ168.15,162.75,161.44,152.11,149.04,147.36,141.31,137.18,132.31,128.80,128.66,127.89,127.62,126.02,124.61,120.20,115.34,114.66,113.81,79.64,56.43,42.73,26.60.HRMS(ESI,m/z):calcd for C25H25N5O3[M+H]+444.2030,found:444.2028.
1-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)cyclobutane-1-carb ohydrazide(目标化合物14e)
淡黄色固体,收率70%。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),7.64(d,J=8.1Hz,1H),7.58(t,J=7.4Hz,1H),7.05(dd,J=13.1,8.2Hz,2H),6.94(d,J=8.4Hz,1H),6.90–6.83(m,1H),6.23(d,J=1.8Hz,1H),4.13(s,2H),3.81(s,3H),3.46(s,3H),2.58(s,3H),2.28(t,J=8.7Hz,2H),2.04(dd,J=23.4,12.1Hz,2H),1.64(dt,J=18.4,9.7Hz,2H).13CNMR(100MHz,DMSO-d6)δ170.93,162.75,161.36,152.16,148.93,145.18,140.97,132.29,127.92,126.16,124.52,119.28,114.55,114.20,113.63,80.96,56.19,42.63,31.51,26.60,13.43.HRMS(ESI,m/z):calcd for C22H25N5O3[M+H]+408.2030,found:408.2037.
实施例2、具有异羟肟酸结构的化合物的制备
化合物的合成路线如下:
试剂与条件:(a)(i)4-氯-2-甲基喹唑啉,cat.conc HCl/(Me)2CHOH,(Me)2CHOH,rt,4h;(ii)4mol/L HCl/1,4-dioxane,EA,rt,2h;(b)Appropriate bromide,Cs2CO3,DMF,rt(16)or 100℃(17 and 18),overnight;(c)50%(w/w)NH2OH/H2O aq,NaOH,CH2Cl2/MeOH(1:2,v/v),0℃-rt,2h.
1、中间体的合成
(1)2-methoxy-5-((2-methylquinazolin-4-yl)amino)phenol(中间体15)的合成
中间体15的制备方法与中间体6的制备方法类似。将中间体4(3.66g,20mmol,1eq.)和4-氯-2-甲基喹唑啉(3.57g,20mmol,1eq.)加入到150mL异丙醇中,然后加入0.25mL的盐酸/异丙醇溶液,室温搅拌,随着反应得进行,有大量淡黄色固体析出,TLC监测(PET:EA=2:1,v/v)反应完全后,抽滤。获得的滤饼用饱和的NaHCO3溶液碱化,得到的溶液用100mL×3的乙酸乙酯萃取,合并有机相。减压浓缩有机相,向浓缩后的有机相中加入盐酸/1,4-二氧六环溶液(4mol/L,7.51mL,1.5eq.)。随着反应进行,生成大量黄色固体。TLC监测反(DCM:MeOH=20:1,v/v)反应完全后,抽滤,滤饼加入到饱和的NaHCO3溶液中,搅拌,有大量白色固体生成,再次抽滤。获得的滤饼用无水乙醇重结晶,真空干燥,得到灰白色固体粉末的中间体15,收率74%。1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.02(s,1H),8.48(d,J=8.0Hz,1H),7.79–7.74(m,1H),7.66(d,J=7.7Hz,1H),7.53–7.48(m,1H),7.44(d,J=2.5Hz,1H),7.27(dd,J=8.7,2.5Hz,1H),6.93(d,J=8.8Hz,1H),3.78(s,3H),2.49(s,3H).
2、目标化合物19-21的合成
化合物19-21的制备方法与7b的制备方法类似。向100mL的圆底烧瓶中加入562.6mg中间体15(2mmol,1eq.)和1.30g的Cs2CO3(4mmol,2eq.)溶于10mL DMF中,室温搅拌0.5h后,向反应体系中滴加429mg 2-溴-2-甲基丙酸乙酯(合成中间体16,2.2mmol,1.1eq.)或1.25g 2-溴代异戊酸乙酯(合成中间体17,6mmol,3eq.)或1.24g乙基1-溴环丁烷甲酸酯(合成中间体18,6mmol,3eq.)。室温(中间体16)或100℃加热(中间体17和18)搅拌过夜,TLC监测(DCM:MeOH=20:1,v/v)反应完全后,减压旋干。向旋干的残留物中加入20mL二氯甲烷使产品溶解于二氯甲烷,抽滤,滤液浓缩后Flash柱分离纯化,得到淡黄色固体中间体16-18,收率85%-96%。然后分别称取191mg中间体16(0.5mmol,1eq.)、205mg中间体17(0.5mmol,1eq.)和204mg中间体18于3个50mL反应瓶中,各反应瓶中加入9mL DCM:MeOH(1:2,v/v),反应体系冷却至0℃,然后向该体系中加入0.5mL的50%(w/w)NH2OH/H2O溶液(15mmol,30eq.),5分钟后加入0.2g NaOH(10mmol,10eq.)。在该温度下反应2h,TLC监测(DCM:MeOH=20:1,v/v)反应完全后,反应液倒入90mL水中,用冰乙酸调节pH至7-8,40mL×3的乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤掉硫酸钠后减压旋干,固体用无水乙醇重结晶,获得目标化合物19-21。
N-hydroxy-2-(2-methoxy-5-((2-methylquinazolin-4-yl)amino)phenoxy)-2-methylpropanamide(目标化合物19)
淡黄色固体,收率70%。1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),9.58(s,1H),8.78(s,1H),8.46(d,J=8.1Hz,1H),7.78(t,J=7.2Hz,1H),7.67(d,J=8.1Hz,1H),7.64(d,J=2.4Hz,1H),7.52(t,J=7.5Hz,1H),7.37(dd,J=8.7,2.4Hz,1H),7.03(d,J=8.8Hz,1H),3.79(s,3H),2.49(s,3H),1.49(s,6H).13C NMR(100MHz,DMSO-d6)δ170.90,163.50,157.98,150.69,148.86,143.25,133.17,132.52,127.64,125.56,123.17,117.71,117.49,113.68,112.75,81.60,56.41,26.60,25.55.HRMS(ESI,m/z):calcd for C20H22N4O4[M+H]+383.1714,found:383.1716.
N-hydroxy-2-(2-methoxy-5-((2-methylquinazolin-4-yl)amino)phenoxy)-3-methylbutanamide(目标化合物20)
白色固体,收率77%。1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),9.61(s,1H),8.95(s,1H),8.46(d,J=8.1Hz,1H),7.77(t,J=7.3Hz,1H),7.67(d,J=8.0Hz,1H),7.60(s,1H),7.52(t,J=7.2Hz,1H),7.41(d,J=8.1Hz,1H),7.01(d,J=8.6Hz,1H),4.16(d,J=5.8Hz,1H),3.81(s,3H),2.50(s,3H),2.19(dd,J=12.7,6.3Hz,1H),1.02(dd,J=21.5,6.4Hz,6H).13C NMR(100MHz,DMSO-d6)δ166.84,163.50,157.91,150.51,147.43,146.58,133.14,132.97,127.51,125.55,123.10,116.47,113.57,112.86,112.28,84.17,56.47,31.69,26.60,18.96,18.38.HRMS(ESI,m/z):calcd for C21H24N4O4[M+H]+397.1870,found:397.1868.
N-hydroxy-1-(2-methoxy-5-((2-methylquinazolin-4-yl)amino)phenoxy)cyclobutane-1-carboxamide(目标化合物21)
白色固体,收率69%。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),9.65(s,1H),8.69(s,1H),8.48(d,J=8.1Hz,1H),7.79(t,J=7.5Hz,1H),7.67(d,J=8.2Hz,1H),7.53(t,J=7.4Hz,1H),7.30(d,J=2.0Hz,1H),7.22(dd,J=8.7,2.1Hz,1H),7.00(d,J=8.7Hz,1H),3.80(s,3H),2.75–2.67(m,2H),2.52(s,3H),2.36–2.26(m,2H),1.83(dt,J=17.2,6.9Hz,2H).13C NMR(100MHz,DMSO-d6)δ169.17,163.55,157.89,146.55,143.90,133.28,132.52,127.33,125.64,123.26,115.40,113.62,112.53,111.44,80.56,56.23,32.09,26.52,13.86.HRMS(ESI,m/z):calcd for C21H22N4O4[M+H]+395.1714,found:395.1714.
实施例3、具有异羟肟酸结构的化合物的制备
化合物的合成路线如下:
试剂与条件:(a)tri-methoxymethane,ammonium acetate,MeOH,120℃,autoclave,5h;(b)(i)DIPEA,PhMe,reflux,1h;(ii)POCl3,80℃,2h;(c)(i)4-methoxy-3-(methoxymethoxy)-N-methylaniline,cat.conc HCl/(Me)2CHOH,(Me)2CHOH,rt,4h;(ii)4mol/L HCl/1,4-dioxane,EA,rt,2h;(d)Appropriate bromide,Cs2CO3,DMF,rt(26)or 100℃(27 and 28),overnight;(e)50%(w/w)NH2OH/H2O aq,NaOH,CH2Cl2/MeOH(1:2),0℃-rt,2h.
1、中间体的合成
(1)quinazolin-4(3H)-one(中间体23)的合成
高压釜中加入991mg 2-氨基苯甲酸乙酯(6mmol,1eq.)、1.27g原甲酸三甲酯(12mmol,2eq.)和924mg醋酸铵(12mmol,2eq.),然后加入10mL甲醇溶解,120℃搅拌反应5h。待温度冷却至室温后,打开耐压釜,有大量白色固体生成。TLC监测(PET:EA=2:1,v/v)反应完全,用甲醇将固体溶解,转移至圆底烧瓶,溶剂旋干,加100mL×3的乙酸乙酯和水萃取,合并有机相并用饱和食盐水洗一次,有机相用无水硫酸钠干燥,减压旋干溶剂,得白色纯的中间体23,收率95%。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.14(dd,J=7.9,1.0Hz,1H),8.10(s,1H),7.86–7.79(m,1H),7.68(d,J=8.1Hz,1H),7.54(t,J=7.5Hz,1H).
(2)4-chloroquinazoline(中间体24)的合成
100mL的圆底烧瓶中加入584mg喹唑啉酮(4mmol,1eq.)、1.05mL DIPEA(6mmol,1.5eq.)和15mL甲苯回流1h。回流后,温度降至80℃,缓慢滴加560μL三氯氧磷(6mmol,1.5eq.),80℃加热搅拌过夜。TLC监测(PET:EA=2:1,v/v)反应完全后,减压蒸去剩余的三氯氧磷,反应液倾入冰水。100mL×3的二氯甲烷和水萃取,合并有机相并用饱和食盐水洗,有机相用无水硫酸钠干燥,减压旋干,固体用无水乙醇重结晶,得到淡黄色固体为中间体24,收率60%。1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.19(dd,J=8.0,1.1Hz,1H),8.01–7.95(m,1H),7.90(d,J=8.1Hz,1H),7.72–7.66(m,1H).
(3)2-methoxy-5-(methyl(quinazolin-4-yl)amino)phenol(中间体25)的合成
中间体25的制备方法与中间体6一致,收率78%。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.72(d,J=8.2Hz,1H),7.63(ddd,J=8.3,6.6,1.6Hz,1H),7.13(dtd,J=9.7,8.5,1.2Hz,2H),6.92(d,J=8.5Hz,1H),6.68(d,J=2.6Hz,1H),6.61(dd,J=8.5,2.6Hz,1H),3.78(s,3H),3.47(s,3H).
2、目标化合物29-31的合成
化合物29-31的制备方法与化合物11b、12b和14b的制备方法一致。向100mL的圆底烧瓶中加入562.6mg中间体15(2mmol,1eq.)和1.30g的Cs2CO3(4mmol,2eq.)溶于10mL DMF中,室温搅拌0.5h后,向反应体系中滴加429mg 2-溴-2-甲基丙酸乙酯(合成中间体26,2.2mmol,1.1eq.)或1.25g 2-溴代异戊酸乙酯(合成中间体27,6mmol,3eq.)或1.24g乙基1-溴环丁烷甲酸酯(合成中间体28,6mmol,3eq.)。室温(中间体26)或100℃加热(中间体27和28)搅拌过夜,TLC监测(DCM:MeOH=20:1,v/v)反应完全后,减压旋干。向旋干的残留物中加入20mL二氯甲烷使产品溶解于二氯甲烷,抽滤,滤液浓缩后Flash柱分离纯化,得到淡黄色固体中间体26-28,收率分别为87.5%、92.1%和90.8%。然后分别称取191mg中间体26(0.5mmol,1eq.)、205mg中间体27(0.5mmol,1eq.)和204mg中间体28于3个50mL反应瓶中,各反应瓶中加入9mL DCM:MeOH(v/v,1:2),反应体系冷却至0℃,然后向该体系中加入0.5mL的50%(w/w)NH2OH/H2O溶液(15mmol,30eq.),5分钟后加入0.2g NaOH(10mmol,10eq.)。在该温度下反应2h,TLC监测(DCM:MeOH=20:1,v/v)反应完全后,反应液倒入90mL水中,用冰乙酸调节pH至7-8,40mL×3的乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤掉硫酸钠后减压旋干,固体用无水乙醇重结晶,获得目标化合物29-31。
N-hydroxy-2-(2-methoxy-5-(methyl(quinazolin-4-yl)amino)phenoxy)-2-methylpropanamide(目标化合物29)
淡黄色固体,收率66%。1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.71(s,1H),7.74(d,J=7.7Hz,1H),7.68–7.62(m,1H),7.16–7.10(m,1H),7.08(d,J=8.7Hz,1H),7.02(d,J=8.5Hz,1H),6.97(dd,J=8.6,2.6Hz,1H),6.85(d,J=2.5Hz,1H),3.81(s,3H),3.50(s,3H),1.27(s,6H).13C NMR(100MHz,DMSO-d6)δ170.54,161.28,154.47,151.87,151.54,144.76,140.83,132.50,128.55,126.29,125.42,121.92,121.04,116.39,113.95,82.11,56.36,42.84,25.20.HRMS(ESI,m/z):calcd for C20H22N4O4[M+H]+383.1714,found:383.1720.
N-hydroxy-2-(2-methoxy-5-(methyl(quinazolin-4-yl)amino)phenoxy)-3-methylbutanamide(目标化合物30)
淡黄色固体,收率71%。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.96(s,1H),8.71(s,1H),7.74(d,J=8.2Hz,1H),7.65(t,J=7.3Hz,1H),7.15(t,J=7.4Hz,1H),7.03(d,J=8.4Hz,1H),6.97(dd,J=5.5,3.0Hz,2H),6.73(dd,J=8.6,2.3Hz,1H),4.11(d,J=6.9Hz,1H),3.80(s,3H),3.50(s,3H),0.98(d,J=6.7Hz,3H),0.89(d,J=6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ166.33,161.35,154.45,151.49,149.04,148.65,141.14,132.51,128.48,126.26,125.53,119.84,116.52,114.75,113.71,83.22,56.40,42.88,31.45,18.64,18.60.HRMS(ESI,m/z):calcd for C21H24N4O4[M+H]+397.1870,found:397.1868.
N-hydroxy-1-(2-methoxy-5-(methyl(quinazolin-4-yl)amino)phenoxy)cyclobutane-1-carboxamide(目标化合物31)
淡黄色固体,收率69%。1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.74(d,J=28.5Hz,2H),7.74(d,J=8.0Hz,1H),7.65(t,J=7.3Hz,1H),7.19–7.11(m,1H),7.03(dd,J=13.9,8.6Hz,2H),6.88(d,J=7.7Hz,1H),6.25(s,1H),3.81(s,3H),3.48(s,3H),2.25(dd,2H),2.01(dd,J=19.6,9.7Hz,2H),1.72–1.56(m,2H).13C NMR(100MHz,DMSO-d6)δ168.69,161.37,154.43,151.52,149.00,145.19,140.83,132.52,128.48,126.30,125.51,119.21,116.41,114.09,113.63,80.79,56.19,55.37,42.72,31.49,13.43.HRMS(ESI,m/z):calcd for C21H22N4O4[M+H]+395.1714,found:395.1720.
以下通过具体试验例证明本发明的有益效果。
试验例1、本发明化合物抗肿瘤活性研究
1、实验方法
(1)MTT测定化合物的抗肿瘤增殖活性
细胞常规培养于含10%胎牛血清、100U/mL青霉素和100mg/L链霉素的RPMI-1640或DMEM培养液中,置饱和湿度、37℃、5%CO2孵箱中培养。待细胞状态良好,800-1200rpm(或300g)离心3min收集细胞(贴壁细胞需用0.25%胰蛋白酶消化,轻轻吹落)。加完全培养基悬浮,进行计数。96孔板按每孔贴壁细胞3000~5000个细胞,悬浮细胞15000~25000个细胞100μL的细胞悬液接种,置于CO2孵箱中培养过夜。实验组添加100μL含有不同浓度待测化合物(或阳性对照)的培养基,空白对照组则添加等体积含与药物最高实验浓度等量DMSO的新鲜培养基,每组设置3个平行孔,37℃、5%CO2孵箱中培养72h。
药物作用72h后,每孔加入20μL 5mg/mL浓度的MTT工作液,37℃培养箱中继续培养1~4小时,终止培养,小心吸取孔内培养上清液(悬浮细胞则先离心再弃上清液),加入150μL DMSO,置于小型水平摇床振荡5分钟,使结晶物充分溶解混匀后,在酶标仪上检测570nm波长吸光值。按抑制率=(空白对照-给药)/空白对照*100%,计算各实验组抑制率。将化合物处理浓度与其对应的抑制率用Graphpad prism软件拟合剂量-响应曲线,拟合IC50值。
(2)化合物的肝微粒体代谢稳定性研究
孵育体系体积为100μL,体系包括0.1M pH 7.4的PBS,NADPH发生系统(1mM NADP,5mM的6-磷酸葡萄糖,1U/mL 6-磷酸葡萄糖脱氢酶,3.3mM的MgCl2);加入1μL 1mg/mL待测化合物甲醇溶液(浓度100μM/L),采用37℃水浴预孵育5min,加入2.5μL各种属肝微粒体溶液,继续37℃分别孵育0、5、15、30、45和60min后,取出,加入200μL的含内标SAHA 10ng/mL的预冷甲醇终止反应。涡旋混匀3min,13000rpm离心15min,取上清液,进行UFLC-MS/MS测定。
以孵育0min时间点的待测化合物的浓度作为100%,其它孵育时间点的浓度与其相比得剩余百分量。以各时间点的剩余百分量的自然对数和孵育时间作线性回归,求斜率k,根据以下公式计算获得半衰期T1/2和清除率CLint。
T1/2=-0.693/k;
CLint(μL/min/mg)=Ln(2)*1000/T1/2/C肝微粒体
(3)免疫荧光染色实验
生长状态良好的A2780S细胞铺到具有爬片(盖玻片)的6孔板上,继续培养24h。细胞完全贴壁,加入不同浓度的待测化合物(DMSO、本发明化合物、paclitaxel、colchicine)继续孵育16h,弃去上清液,37℃预热的PBS洗一次后用50%甲醇/50%丙酮溶液固定膜2min,再用PBS洗一次,加入溶于3%的BSA溶液的α-tubulin抗体,孵育4h。PBS洗三次,每次5min,用荧光二抗和稀释10倍的DAPI共同孵育40min后,再用PBS洗三次,封片,免疫荧光显微镜镜下观察,获取图片。
(4)微管动力学实验
PEM缓冲液配制:80mM PIPES(调节pH 6.9),2mM MgCl2,0.5mM EGTA;
实验当天配制100mM的GTP储备液;
设置酶标仪程序:37℃预热,kinetic模式动态读数,340nM波长,测吸光值,1min测1次,共60min,384孔板预热;
将100mM的GTP在冰上解冻,用PEM缓冲液稀释为1mM的GTP溶液放冰上备用。待测化合物10mM本发明化合物和秋水仙碱冰上解冻,分别用PEM缓冲液(含1mM GTP)将待测化合物配制为10和20μM两个浓度,秋水仙碱配制为10μM。从仪器中取出预热的384孔板,往不同的小孔中分别加入10μL的control、10μM待测化合物、20μM待测化合物和10μM Colchicine,再往各小孔中快速加入10μL微管蛋白(3mg/mL),快速放入酶标仪测定。实验完成后将数据用Graphpad prism软件作图。
(5)EBI竞争实验
将A2780细胞与待测化合物(本发明化合物、vincristine、colchicine、空白对照DMSO)孵育2h,将EBI(100μM)添加到细胞中,再孵育2h。用免疫沉淀裂解缓冲液裂解总蛋白,然后对β-微管蛋白进行蛋白质印迹分析,以β-actin为实验对照。
(6)流式细胞术检测细胞周期
本发明待测化合物按0、1、3和10nM浓度处理A2780S细胞24h。收集细胞培养液,用胰酶消化收集细胞,与收集的细胞培养液一起500G离心5min。PBS重悬细胞洗2次,用预冷的75%乙醇固定细胞,置于-20℃保存,上机检测前用PBS洗细胞2次,加PI避光染色约10min,进行流式检测。流式结果用modfit软件进行细胞群体比例分析。
(7)流式细胞术检测细胞凋亡
本发明待测化合物按0、2.5、5和10nM浓度处理A2780S细胞48h。收集细胞培养液,用胰酶消化收集细胞,与收集的细胞培养液一起500G离心5min。收集的细胞用PBS洗一遍,再用1×Binding buffer洗一次,将细胞用1×Binding buffer重悬至密度1~5*106/mL的密度。加入5μL荧光标记的Annexin V至100μL的细胞悬液中进行染色,室温避光染色15min后,用1×Binding buffer洗一次后再用200μL 1×Binding buffer重悬细胞,上机之前加入5μL的PI轻轻混匀,1h内完成流式检测。
(8)化合物的药代动力学性质研究
待测本发明化合物溶于DMSO,用生理盐水稀释至2mg/mL。先采集SD大鼠空白血0.2mL,用于“0min”时间点,再称体重,以10mg/kg剂量分别进行灌胃和静脉给药。给药后分别在5min、15min、30min、1h、2h、4h、6h、8h、10h和24h采集0.2mL血,将收集的血3500rpm离心15min,收集上清血浆,-20℃冻存待测。
采集的血浆样品经室温解冻后,涡旋混合均匀,与配制的标准曲线通过蛋白沉淀处理后,同时用LC-MS/MS检测化合物浓度。通过DAS 2.0软件拟合各药代动力学参数,并计算化合物的口服生物利用度,计算公式如下:
口服生物利用度F%=口服等量药物后AUC(0-24h)/静脉等量药物后AUC(0-24h)*100%
(9)化合物在多种皮下肿瘤模型体内抗肿瘤效果研究
为研究优选化合物的体内抗肿瘤效果,建立了C26、A2780S和A2780/T移植瘤小鼠模型。收集对数生长期细胞C26细胞,将单细胞悬液用PBS缓冲液稀释至一定浓度备用。接种时取单细胞悬液0.1mL,107个细胞接种于6-7周龄的雌性BALB/c小鼠。将5×106的A2780S和A2780T细胞分别皮下接种到6-7周龄雌性BALB/c裸鼠和NOD/SCID小鼠中,建立A2780S和A2780/T异种移植模型。然后,将A2780/T肿瘤块剥离并切成小块,接种到新一批NOD/SCID小鼠体内进行药效学研究。当C26、A2780S和A2780/T模型小鼠的肿瘤体积长至100mm3左右时,随机分组,每组6只小鼠。分别用空白对照(含2.5%Tween-80的生理盐水)、本发明化合物、PTX或Cisplatin治疗动物。游标卡尺每两天测量一次肿瘤体积(肿瘤体积(mm3)=π/6×长×宽×宽)。小鼠体重每两天测一次,并观察毒性。实验终止当天,处死小鼠,剥离实体肿瘤进行称重,根据公式:肿瘤抑制剂=(1-治疗组平均肿瘤重量/溶剂对照组平均肿瘤重量)×100%,评价化合物的抗肿瘤活性。本实验根据《实验动物的护理和使用机构指南》进行研究,所有涉及小鼠的实验方案均经过四川大学动物保护和使用委员会(中国四川成都)的批准。
2、实验结果
(1)化合物7a-7e的性能研究
本发明通过MTT法考察化合物7a-7e对人结肠癌细胞HCT116、人卵巢癌细胞A2780S以及人急性髓性白血病细胞MOLM-13的体外抗增殖活性。实验以紫杉醇(Paclitaxel)和秋水仙碱(Colchicine)为阳性对照。结果如表1所示。
表1.化合物7a-7e的体外抗肿瘤细胞增殖活性
a当肿瘤细胞增殖达到50%抑制时化合物的浓度。数据表示为来自三个独立实验的mean±SD。
由表1可知,具有异羟肟酸结构的化合物7b抗肿瘤细胞增殖活性最优,对三种癌细胞增殖均有良好的抑制活性。
将化合物7b对多种肿瘤细胞的抗肿瘤细胞增殖活性与已知HDAC6选择性抑制剂SKLB-23bb比较,并且对化合物7b进行HDAC抑制活性筛选、免疫荧光实验观察。结果如表2、表3和图1所示。
表2.化合物7b与SKLB-23bb对多种肿瘤细胞系的抗增殖活性
表3.化合物7b与SKLB-23bb对HDAC1和HDAC6的抑制活性
研究结果表明将SKLB-23bb的Linker由三个亚甲基缩短为一个亚甲基后,获得的化合物7b,其对18种肿瘤细胞的抗增殖活性IC50在0.954-9.87nM范围,而SKLB-23bb的抗肿瘤细胞增殖活性IC50为20.1–963nM。因此,7b的抗肿瘤细胞增殖活性显著优于SKLB-23bb。更重要的是,化合物7b对HDAC抑制活性消失。因此,上述结果表明,化合物7b虽然具有异羟肟酸基团,但并不是HDAC靶标的小分子抑制剂。
如图1所示,空白对照组A2780S细胞中微管网呈正常丝状,经微管聚合剂紫杉醇处理16h的A2780S细胞纺锤体的微管网明显发生聚集凝结,绿色荧光变亮,并向细胞核靠拢。与秋水仙碱相似,暴露在100nM化合物7b中的A2780S细胞形状从纺锤形变为圆形或不规则形,微管解聚。实验结果证实化合物7b为微管解聚剂。
然而,体外代谢稳定性研究发现,化合物7b在小鼠肝微粒体代谢稳定,而在人肝微粒体中代谢不稳定、相对较快(表4)。因此,为获得药代性质优、抗肿瘤活性好的微管解聚剂,以7b为先导化合物,进行结构优化,并进一步考察异羟肟酸基团的重要性。
表4.化合物7b在小鼠和人肝微粒体中的代谢稳定性
(2)化合物8a-14e的性能研究
本发明通过MTT法考察化合物8a-14e对人结肠癌细胞HCT116、人卵巢癌细胞A2780S以及人急性髓性白血病细胞MOLM-13的体外抗增殖活性。实验以紫杉醇(Paclitaxel)和秋水仙碱(Colchicine)为阳性对照。结果如表5所示。
表5.化合物8a-14e的体外抗肿瘤细胞增殖活性
由表5可知:异羟肟酸类化合物(8b、9b、10b、11b、12b、13b和14b,下面简写为8b-14b)的IC50为亚纳摩尔或几个纳摩尔,而酯(8a、9a、10a、11a、12a、13a和14a)、羧酸(8c、9c、10c、11c、12c、13c和14c)、酰胺(8d、9d、10d、11d、12d、13d和14d)和酰肼(8e、9e、10e、11e、12e、13e和14e)类化合物的IC50值是异羟肟酸类化合物的100倍以上,异羟肟酸类化合物的IC50显著低于其他类型的化合物。说明异羟肟酸类化合物具有优良的抗肿瘤细胞增殖活性,异羟肟酸基团是目标化合物的重要药效团。
将A2780S细胞用8b-14b处理16h,然后通过免疫荧光检测化合物对细胞微管网络的影响。如图2所示,A2780S细胞中的微管网络在没有药物处理的情况下表现出正常的排列和组织。PTX(微管聚合剂)处理导致微管纤维聚合在细胞核附近。相反,暴露于8b-14b的细胞状态与暴露于秋水仙碱(微管解聚剂)的细胞状态相同,微管纺锤体形成明显异常,并且微管网络在30nM的浓度下显著解聚。上述结果表明异羟肟酸化合物8b-14b的抗增殖活性不是由于抑制HDACs,而是来源于对微管的影响。化合物8b-14b是一种微管蛋白解聚剂。
利用体外代谢稳定性筛选化合物,是确定化合物是否具有继续研究价值的重要手段。将上述体外抗肿瘤细胞增殖活性好的异羟肟酸类化合物8b-14b进行体外代谢稳定性考察。一定浓度的化合物8b-14b分别用小鼠和人肝微粒体孵育,UFLC-MS/MS测定孵育指定时间点后的原药剩余浓度,计算获得目标化合物在不同种属肝微粒体中的半衰期和清除率如表6所示。结果表明化合物9b、10b和13b被快速代谢,而化合物8b、11b、12b和14b在小鼠和人肝微粒体中代谢稳定,其在人肝微粒体中代谢稳定性优于化合物7b。
同样的,测定了8b-14b对HDAC的抑制活性。如表6所示,HDAC抑制剂LBH589对HDAC1和HDAC6的IC50分别为0.5nM和5.6nM。化合物8b-10b和13b对HDAC1的抑制活性IC50均高于1.0μM,化合物11b、12b和14b对HDAC1的抑制活性IC50均大于10μM,化合物8b-14b对HDAC6的抑制活性IC50均大于10μM,可见本发明化合物11b、12b和14b对HDAC1和HDAC6几乎无抑制活性。
表6.化合物8b-14b对HDAC1和HDAC6的抑制活性以及在小鼠和人肝微粒体中的代谢稳定性
(3)化合物19-21和29-31的性能研究
基于化合物11b、12b和14b,还考察了喹唑啉4-位氨基的N-甲基取代和喹唑啉2-位的甲基取代对化合物抗肿瘤活性的影响。化合物对肿瘤细胞的抗增殖结果如表7所示。实验结果表明,喹唑啉4-位氨基的N-甲基取代至关重要,化合物11b、12b和14b的IC50均在几个纳摩尔或亚纳摩尔,而甲基替换为H时,化合物19-21的IC50均大于1μM。另外,喹唑啉2-位的甲基替换为H时,化合物29-31对各种肿瘤细胞的抑制活性都降低2-10倍左右。因此,喹唑啉4-位氨基的N-甲基取代和喹唑啉2-位的甲基取代对于保持化合物抗肿瘤活性都非常重要。
本发明通过MTT法考察化合物19-21和29-31对人结肠癌细胞HCT116、人卵巢癌细胞A2780S以及人急性髓性白血病细胞MOLM-13的体外抗增殖活性。实验以紫杉醇(Paclitaxel)和秋水仙碱(Colchicine)为阳性对照。结果如表7所示。
表7.化合物19-21和29-31的体外抗肿瘤细胞增殖活性
(4)异羟肟酸类化合物在体内结肠癌C26小鼠模型抗肿瘤活性
经上述体外肿瘤细胞的抗增殖活性及代谢稳定性筛选,获得体外活性好、代谢稳定的微管化合物11b、12b和14b。为进一步筛选体内活性优的化合物,用BALB/c小鼠建立结肠癌C26小鼠模型,对化合物进行进一步筛选。C26小鼠模型通过小鼠右侧背部皮下注射107个C26肿瘤细胞。当肿瘤体积达100mm3时,荷瘤鼠随机分组(每组6只)。11b和12b均为25mg/kg,14b为50mg/kg剂量灌胃给药,每两天一次给药。紫杉醇为阳性对照,每周30mg/kg腹腔给药一次。实验结果如图3所示。
实验结果表明,上述化合物中,化合物11b在C26小鼠模型的体内抗肿瘤效果较差,化合物12b和14b对C26小鼠模型的抑瘤率分别为56.7%和43.8%,而阳性药紫杉醇对C26小鼠模型的抑瘤率为30.0%。因此,化合物12b为最优化合物。
(5)化合物12的微管蛋白解聚活性
①对HDACs的抑制活性
异羟肟酸官能团是HDAC抑制剂的重要药效团。为确证化合物12b是否仍具有对HDAC抑制活性,除前面已经测定的HDAC1和HDAC6外,进一步将化合物12b进行HDAC2-5和HDAC7-11亚型的抑制活性测定,以Purinostat Mesylate为阳性对照。结果如表8所示,化合物12b对HDAC2-5、HDAC9和HDAC10的抑制活性IC50均大于10μM,对HDAC8和HDAC11的抑制活性IC50均大于5μM。因此,化合物12b的抗肿瘤效果并不是来自于对HDACs的抑制。化合物12b不具有HDACs的抑制活性。
表8.化合物12b对HDAC2-5和HDAC7-11的抑制活性。
a Purinostat Mesylate是一种HDAC抑制剂(Yang L,et al.PurinostatMesylate Is a Uniquely Potent and Selective Inhibitor of HDACs for theTreatment of BCR-ABL-Induced B-Cell Acute Lymphoblastic Leukemia.Clinicalcancer research:an official journal of the American Association for CancerResearch 2019 Dec 15;25(24):7527-7539.),处于I期临床研究中,此处用作测定HDAC酶抑制活性的阳性对照。
②对微管抑制的类型研究
由微管聚合或解聚引起的微管网形态变化可以通过免疫荧光实验直观观察。因此,实验以紫杉醇和秋水仙碱为阳性对照,探讨化合物12b的抗肿瘤细胞增殖活性是否由于其对微管的作用而产生,并确定其属于微管聚合剂还是微管解聚剂。
如图4A所示,空白对照组A2780S细胞中微管网呈正常丝状,经微管聚合剂紫杉醇处理16h的A2780S细胞纺锤体的微管网明显发生聚集凝结,绿色荧光变亮,并向细胞核靠拢。与秋水仙碱相似,暴露在化合物12b中的A2780S细胞形状从纺锤形变为圆形或不规则形,浓度依赖的发生微管解聚。实验结果证实化合物12b为微管解聚剂。
为了进一步研究其抑制微管聚合的能力,以5μM浓度的秋水仙碱为阳性对照,分别以5和10μM的12b考察其对体外微管动力学的影响。实验结果如图4B所示,与阳性对照秋水仙碱一样,12b可以抑制微管蛋白的聚合,10μM的12b抑制微管聚合的能力高于5μM。该研究结果进一步证实化合物12b为微管解聚剂。
③与微管蛋白的结合位点研究
为了探讨化合物12b与微管蛋白的结合位点,进行EBI竞争实验。EBI可与β-tubulin秋水仙碱位点的Cys239和Cys354交联,形成EBI和β-tubulin加合物,在WB中比β-tubulin迁移快。而结合于秋水仙碱位点的药物可以抑制加合物的形成。
实验结果如图5所示,EBI导致加合物的形成,长春新碱不与秋水仙碱位点结合,作为阴性对照。长春新碱5和25μM以及100μM EBI处理的A2780S细胞,只能检测到移动较快的EBI和β-tubulin加和物条带。用5μM的秋水仙碱以及100μM EBI处理过的A2780S细胞只检测到移动较慢的β-tubulin native条带。而化合物12b剂量依赖性减少加合物的形成,增加β-tubulin native的形成,与秋水仙碱的作用一致。因此,EBI实验确证化合物12b是与β-tubulin的秋水仙碱位点结合。
④对多种肿瘤细胞包括耐药细胞株的抗肿瘤活性
化合物12b对多种肿瘤细胞的抗增殖活性结果如表9所示,化合物12b对多种实体和血液肿瘤细胞均具有很好的抗肿瘤细胞增殖活性,并且在同种肿瘤细胞中,其抗肿瘤活性显著优于SKLB-23bb。
表9.化合物12b对多种肿瘤细胞系的抗增殖活性
克服肿瘤细胞的天然或获得性耐药是治疗肿瘤的关键问题。临床前或临床研究已经表明P-gp可介导肿瘤细胞对多种抗肿瘤药物耐药,如P-gp过表达的MCF-7/ADR对阿霉素耐药,P-gp过表达的A549/T细胞系对紫杉醇耐药。β-Ⅲ型微管蛋白的表达改变与紫杉醇的耐药密切相关。例如,β-Ⅲ型微管蛋白在紫杉醇耐药细胞株(A2780/T)中过表达。为了研究化合物12b是否克服耐药,选择了3对细胞系,分别是人卵巢癌细胞株A2780S(敏感)、A2780/T(对紫杉醇耐受)、人肺癌细胞株A549(敏感)和A549/T(对紫杉醇耐受)、乳腺癌细胞株MCF-7(敏感)和MCF-7/ADR(对阿霉素耐受),对比化合物12b在这些敏感细胞株和耐药细胞株的活性。结果如表10所示,化合物12b对这些耐药细胞都表现出很好的抗增殖活性。与紫杉醇和阿霉素相比,它们具有极小的耐药指数。上述结果表明,化合物12b对多种肿瘤细胞表现出良好的抗增殖活性,并且可以克服因P-gp和β-Ⅲ微管蛋白过表达导致的耐药。
表10.化合物12b对耐药细胞株的体外抗增殖活性
⑤药代动力学性质研究
化合物12b是结合于秋水仙碱位点的微管解聚剂,体外活性好、代谢稳定。为了更好的研究其体内抗肿瘤效果,考察了化合物12b的药代动力学性质,确定12b的给药方式及给药频率。结果如表11所示,化合物12b的暴露量AUC0-24h和Cmax相对较大,治疗荷瘤小鼠的给药剂量可以为10mg/kg。化合物12b的口服生物利用度F为64.8%,可以通过口服给药用于肿瘤治疗。另外,12b的口服半衰期T1/2分别为8.91±5.82h,因此,可以初步确定为两天一次给药。
表11.化合物12b的体内药代动力学性质
⑥化合物12b的体内抗肿瘤活性研究
建立人源卵巢癌A2780S和紫杉醇耐药的A2780T异种移植小鼠模型。
在人源卵巢癌A2780S异种移植模型中,当肿瘤体积长至100mm3时,进行随机分组,每组6只。以紫杉醇和顺铂为阳性对照,空白对照组给同体积的生理盐水,所有药物给药方案和给药途径如表12所示。高剂量组的12b(30mg/kg)口服给药,以及12b(15mg/kg)静脉给药对A2780S的肿瘤抑制率均为70%以上,与紫杉醇和顺铂阳性对照药效相当,并且12b的低剂量组口服给药也体现出显著的抗肿瘤效果(表12和图6)。另外,在治疗过程中,顺铂的阳性对照组出现2只小鼠死亡,平均体重下降15.8%,体现出明显的毒性,而紫杉醇和化合物各治疗组体重下降5%以内,没有表现出明显毒性。结果表明化合物12b在A2780S异种移植模型中具有较好的抗肿瘤效果,并且可以口服给药。
在紫杉醇耐药的A2780/T异种移植模型中,当肿瘤体积长至100mm3时,进行随机分组,每组6只。以紫杉醇为阳性对照,空白对照组给同体积的生理盐水,所有药物给药方案和给药途径如表12所示,实验结果如表12和图6所示。PTX治疗组的抑瘤率仅为35.3%,而12b(10mg/kg i.v.隔日)的抑瘤率为75.1%。由于长期给药近1个月,NOD/SCID小鼠的耐受性较BALB/c裸鼠较差,在治疗后期,12b治疗组出现轻度体重减轻。而PTX组的小鼠不仅体重严重下降,而且在治疗过程中有2/6的小鼠死亡,表明12b的毒性明显低于PTX。上述结果表明12b在PTX敏感性和耐药的异种移植小鼠模型中均具有较好的治疗效果。
表12.化合物12b对A2780S和A2780/T异种移植肿瘤模型的体内抗肿瘤活性。
a Q2D,每两天;Q4D,每四天.
综上,本发明提供了一种可作为微管蛋白解聚剂的化合物,该微管蛋白解聚剂是秋水仙碱结合位点的微管蛋白解聚剂,其抗肿瘤活性依赖于异羟肟酸基团;该化合物对多种肿瘤细胞均有良好的抑制作用,具有广谱抗肿瘤作用;并且对于耐药肿瘤细胞同样表现出良好的抑制作用;该可用于制备治疗肿瘤以及耐药肿瘤的药物。同时,该化合物代谢稳定性好、毒副作用小、安全性好。本发明化合物克服了现有微管蛋白解聚剂毒副作用大,对于耐药肿瘤效果较差的缺陷,具有良好的应用前景。
Claims (10)
2.根据权利要求1所述的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物、或其前药,其特征在于:
R1、R2分别独立选自氢、C1~C3烷基;
R3、R4分别独立选自氢、C1~C4烷基、苯基;或者,R3、R4连接形成4~6元环烷基;
R5选自C1~C2烷氧基、羟基、-NH2、-N(H)OH、-N(H)NH2;
当R1选自甲基、R2选自甲基、R3和R4同时为氢时,R5不选自C2烷氧基或N(H)OH。
5.根据权利要求1所述的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物、或其前药,其特征在于:
R3、R4分别独立选自氢、甲基、丙基、丁基、异丙基、苯基;或者,R3、R4连接形成4~6元环烷基;且R3、R4不同时选自氢。
8.权利要求1~7任一项所述的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物、或其前药在制备微管蛋白解聚剂中的用途;
优选地,所述微管蛋白解聚剂为与微管蛋白秋水仙碱位点结合的微管蛋白解聚剂。
9.权利要求1~7任一项所述的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物、或其前药在制备治疗肿瘤和/或具有耐药性的肿瘤的药物中的用途;
优选地,所述肿瘤为卵巢癌、结肠癌、结直肠癌、急性髓系白血病、急性单核细胞白血病、乳腺癌、宫颈癌、肝癌、肾癌、肺癌、髓性单核细胞白血病、外周淋巴瘤。
10.一种药物,其特征在于:它是以权利要求1~7任一项所述的化合物、或其盐、或其立体异构体、或其水合物、或其溶剂合物、或其前药为活性成分,加上药学上可接受的辅料或辅助性成分制备而得的制剂。
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