CN102875480A - 喹唑啉酮类血管抑制剂、其制备方法及其医药用途 - Google Patents
喹唑啉酮类血管抑制剂、其制备方法及其医药用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域,具体涉及通式I和通式II的喹唑啉酮类血管抑制剂、它们的制备方法以及它们的医药用途,特别是作为预防或治疗肿瘤、视网膜病变、风湿性关节炎、糖尿病、红斑狼疮、慢性炎症等血管增殖性疾病药物的用途。
Description
技术领域
本发明涉及药物化学领域,具体涉及一系列喹唑啉酮类血管抑制剂、它们的制备方法以及它们的医药用途,特别是作为预防或治疗肿瘤、视网膜病变、糖尿病、风湿性关节炎、红斑狼疮、慢性炎症反应等血管增殖性疾病药物的用途。
背景技术
血管生成(Angiogenesis)是指在原有血管基础上,内皮细胞通过出芽或者嵌入形式进行增值和迁移形成新血管的过程。血管生成在生理和病理条件下均可发生。正常生理情况下,创伤愈合、胚胎发育和生殖过程中的生理刺激可引起局部的血管生成。然而病理性的血管新生与许多疾病有关,如肿瘤生长侵袭、视网膜病变、糖尿病、风湿性关节炎、红斑狼疮、慢性炎症反应等。
肿瘤的生长和迁移与血管生成密切相关。肿瘤的生长、发展、迁移都必须通过周围肿瘤血管系统持续地提供充足的营养和物质交换。同时,肿瘤细胞会通过肿瘤原发部位的生成血管进入血液循环,从而提高肿瘤转移的速率。血管生成不仅为肿瘤的进一步生长提供了条件,也为肿瘤的侵袭转移的发生提供了很好的机会。以肿瘤血管为靶点,或通过抑制肿瘤的血管生成过程、或通过快速选择性地破坏肿瘤血管功能,从而切断肿瘤营养来源和使肿瘤血供受阻,导致肿瘤“饿死”和“坏死”。肿瘤血管与正常血管的结构差异是靶向作用于肿瘤血管的基础,肿瘤血管系统是快速增生、不成熟的,在形态上复杂、混乱无序,血管的通透性是相对失控、血管持续处于重建状态。因此,肿瘤血管对药物更为敏感,更容易受到破坏。抑制肿瘤血管系统疗法比其他肿瘤治疗方法有许多优势,如很少产生耐药性、副作用小、效率高等。2-甲氧基雌二醇(2-ME2)是一种有很强活性的血管抑制剂。2-甲氧基雌二醇具有广泛的抗肿瘤药理作用,迄今为止至少有55种肿瘤能被2-甲氧基雌二醇所抑制,在肿瘤治疗方面有着很大的潜力。早期进行的I和II期临床试验表明2-甲氧基雌二醇安全性好,联合用药时能协同作用增强抗肿瘤效果。2-甲氧基雌二醇目前用于治疗激素抵抗性前列腺癌,同时FDA已经授予该药物治疗多发性骨髓瘤的罕见药资格。
病理性血管生成可引起视网膜病变和恶化。视网膜病变特别是老年黄斑变性疾病的一大特征是视网膜脉络膜的新血管化,异常血管发生于脉络膜,并向视网膜下视网膜内生长,占据视网膜黄斑处,损坏视觉细胞,造成视网膜下出血及分泌物泄漏、脂质沉积、视网膜色素细胞与脉络膜分离、纤维瘢痕化,甚至失明。
与血管生成过度相关的另一类疾病是风湿性关节炎。风湿性关节炎的病理性改变为持久性滑膜炎及血管翳形成。血管翳具有类似于肿瘤组织的侵蚀性,可侵蚀和破坏关节软骨组织,最终造成不可逆的关节僵直和功能丧失。风湿性关节炎的滑液细胞含有高表达的血管生成刺激因子,临床上风湿性关节炎患者的关节内血管增生与其病情严重程度相关。
此外,病理性血管新生还与糖尿病,红斑狼疮、慢性炎症等疾病存在很大的关系,在这些疾病中存在血管增生情况,血管生成可诱使这些疾病的发展和恶化。
因此,血管抑制剂能治疗肿瘤、视网膜病变、风湿性关节炎、糖尿病、红斑狼疮、慢性炎症,也能用于治疗其他血管增殖疾病。
发明内容
本发明公开了结构为通式I和通式II的二类喹唑啉酮血管抑制剂化合物及其药学上可接受的盐。经药理实验证明该类化合物具有良好的抑制血管活性。
本发明的化合物结构式通式如下:
通式I 通式II
其中R1、R2、R3各自独立表示H、C1~C6的直链烷基或支链烷基,其中R2还可以表示苄基;
R4、R5各自独立地代表H、R’、OR’、COR’、COOR’、CH(OH)R’、卤素或CF3,其中,R’代表H或C1~C6烷基;
n代表1~6的自然数。
R1、R2、R3优选独立表示H、甲基、乙基、丙基、异丙基。
R4、R5优选独立地代表H、CH3、OH、OCH3、COOH、COOCH3、COCH3、CH(OH)CH3、卤素或CF3。
n优选为2、3、4、5。
R1、R2、R3更优选独立表示H、甲基。
R4、R5更优选独立地代表H、CH3、OCH3、COCH3、COOCH3、CH(OH)CH3、OCOCH3、卤素或CF3。
n更优选为3或4。
本发明的化合物还可以以药学上可接受的盐的形式存在,优选的盐是盐酸盐、硫酸盐、 磷酸盐、乙酸盐和马来酸盐等。
本发明的部分化合物的结构如下:
化合物编号 | R1 | R2 | R3 | R4 | R5 |
XHX030 | CH3 | H | H | 4-CH3 | H |
XHX031 | CH3 | H | H | 3-CH3 | H |
XHX032 | CH3 | H | H | 2-CH3 | H |
XHX033 | CH3 | H | H | H | H |
XHX034 | CH3 | H | H | 2-CH3 | 5-CH3 |
XHX035 | CH3 | H | H | 4-OCH3 | H |
XHX036 | CH3 | H | H | 2-0CH3 | H |
XHX037 | CH3 | H | H | 4-Cl | H |
XHX038 | CH3 | H | H | 3-Cl | H |
XHX039 | CH3 | H | H | 2-Cl | H |
XHX040 | CH3 | H | H | 2-Cl | 5-Cl |
XHX041 | CH3 | H | H | 3-CF3 | 5-CF3 |
XHX042 | CH3 | H | H | 2-CH3 | 5-Cl |
XHX043 | CH3 | H | H | 4-F | H |
XHX044 | CH3 | H | H | 2-F | H |
XHX045 | CH3 | H | H | 2-F | 4-F |
XHX046 | CH3 | H | H | 4-OH | H |
XHX047 | CH3 | H | H | 3-OH | H |
XHX048 | CH3 | H | H | 4-COCH3 | H |
XHX049 | CH3 | H | H | 4-CH(OH)CH3 | H |
XHX050 | CH3 | H | H | 4-COCH3 | 2-CH3 |
XHX051 | CH3 | H | H | 4-COOH | 2-CH3 |
XHX054 | CH3 | H | H | 4-OCH3 | 3-OH |
XHX055 | CH3 | CH3 | H | 4-OCH3 | 3-OH3 |
XHX056 | CH3 | H | CH3 | 4-F | H |
XHX057 | CH3 | H | CH3 | 4-OCH3 | H |
XHX058 | CH3 | H | CH3 | 4-OH | H |
XHX059 | CH3 | H | CH3 | 2-OCH3 | H |
化合物编号 | R1 | R2 | R3 | n |
XHX060 | CH3 | H | H | 4 |
XHX061 | CH3 | H | CH3 | 4 |
XHX062 | CH3 | H | H | 3 |
XHX063 | CH3 | CH3 | H | 4 |
药理实验及实施例中化合物的代号等同于以上代号所对应的化合物结构。
本发明通式I和II的化合物可以由以下方法制备:
(a)K2CO3,EtOH,BnCl;(b)HNO3;(c)KMnO4,Acetone/H2O;(d)SOCl2,tol,substituted aniline;(e)Fe/HCl,THF/H2O;(f)HC(OEt)3,THF,TsOH,ref;(g)5%Pd/C,CH3OH/THF.(h)CH3I.
下面是本发明部分化合物的部分药理学试验及结果:
1.细胞划痕试验测定HUVEC细胞迁移抑制
试验方法:取对数期生长的HUVEC细胞以2×104cell/孔接种于24孔板,每组设4个平 行孔,培养至细胞融合度达90%以上后用200μL枪头划痕,PBS冲洗,去除死细胞,按照预设药物梯度浓度(100μmol/L)加药。分别在0、12h、24h拍照,量取中间空白带的宽度,记录。重复实验三次。
结果:结果显示本发明的化合物表现出不同程度的的抑制细胞迁移的能力其中化合物XHX031、XHX041、XHX044、XHX047、XHX048、XHX049、XHX050、XHX054、XHX056、XHX059对内皮细胞的迁移抑制率接近80%。而化合物XHX046、XHX060、XHX054对内皮细胞的迁移抑制率超过80%,与阳性对照药2-甲氧基雌二醇活性相当,抑制活性较好。
化合物编号 | 抑制率(%) | 化合物编号 | 抑制率(%) |
2-甲氧基雌二醇 | 83 | XHX046 | 83 |
XHX030 | 57 | XHX047 | 75 |
XHX031 | 64 | XHX048 | 74 |
XHX032 | 78 | XHX049 | 75 |
XHX033 | 70 | XHX050 | 77 |
XHX034 | 59 | XHX051 | 78 |
XHX035 | 63 | XHX054 | 81 |
XHX036 | 62 | XHX055 | 78 |
XHX037 | 72 | XHX056 | 61 |
XHX038 | 67 | XHX057 | 79 |
XHX039 | 64 | XHX058 | 74 |
XHX040 | 56 | XHX059 | 64 |
XHX041 | 59 | XHX060 | 82 |
XHX042 | 78 | XHX061 | 72 |
XHX043 | 62 | XHX062 | 68 |
XHX044 | 72 | XHX063 | 74 |
XHX045 | 76 |
2.MTT法测试HUVEC细胞增殖试验
测试方法:HUVEC以含10%胎牛血清的1640培养液培养,取对数生长期细胞用于实验。调整细胞密度为2×104个/mL,接种于96孔板,培养24小时后,加入100μl/孔的含药培养基,各个浓度4个复孔,以相同体积的培养基代替测试药物作为对照组,空白组为200μl培养基,混匀后继续培养48小时后,加入20μl/孔MTT(浓度为5mg/ml)。继续培养4h后,弃上清液,每孔加入DMSO 150μl/孔,酶标检测仪于570nm波长处测定每孔吸光度(A)值,按公式计算细胞增殖抑制率:抑制率=(对照组A值-实验组A值)/(对照组A值-空白组A值)×100%,和计算IC50。
结果:本发明的化合物显示出HUVEC抑制活性,XHX044、XHX060的活性较好,结合抗迁移活性实验,说明化合物能同时抑制细胞的迁移与增值。
3.MTT法测试非小细胞癌细胞NIC-H460增殖试验
测试方法同MTT法测试HUVEC细胞增殖试验
结果:本发明化合物能明显抑制非小细胞癌细胞NIC-H460的增殖,其中XHX036、XHX044、XHX054有中等的抑制活性,其中XHX060有超过阳性对照药的活性。
4、鸡胚绒毛尿囊膜试验检测药物的体内抗血管生成作用
取孵育第7天的鸡胚。通过光照找到胚头,用手钻轻轻剥去直径为1cm大小的蛋壳,同时在鸡胚气室处钻一小孔,负压吸引,使得剥去蛋壳的地方形成一个人工气室;小心去除壳膜,暴露绒毛尿囊膜(CAM);加药(10μl/枚)于制备好的无菌甲基纤维素滤纸薄片载体上,对照组加生理盐水,放入鸡胚气室尿囊绒膜上,将鸡胚气室用无菌透明胶带封上,放入恒温箱内培养,培养条件37℃、湿度60%。3d后取出鸡胚,局部采用丙酮和无水乙醇固定10min,剪下放有滤纸盘的CAM,去除滤纸。观察其新生血管分布情况,计数并拍照。重复实验3次。结果:鸡胚绒毛尿囊膜试验显示本发明化合物具有体内抗血管生成的作用。
附图说明
图1是DMSO组鸡胚尿囊膜培养72小时的血管发育情况图;
图2是2ME2组鸡胚尿囊膜培养72小时的血管发育情况图;
图3是以化合物XHX060组为代表示鸡胚尿囊膜培养72小时的血管发育情况图。
具体实施方式(所述实施例只是用来说明本发明,而不是用来限定本发明)
部分化合物的制备实例如下:
熔点用XT4型显微熔点测定仪;核磁共振氢谱仪为Bruker AV 500型(TMS为内标);质谱仪为岛津GCMS-QP2010型质谱仪或Mariner质谱仪;红外光谱仪为Nicolet Impact 410型(KBr压片);元素分析仪为Elementar Vario EL III。
实施例1
3-甲氧基-4-苄氧基苯甲醛(2)的制备
将3-甲氧基-4-羟基苯甲醛1(10g,65.8mmol)溶于120mL乙醇中,加入K2CO3(11.8g,85.5mmol),氯苄(11.4mL,98.7mmol),回流反应5个小时。反应液过滤除去滤渣,浓缩至干,粗品用乙醇重结晶,得到白色固体2(13.6g,85.5%)。m.p.56-57℃(文献m.p.59℃);EI-MSm/z:242(M+).
实施例2
3-甲氧基-4-苄氧基-6-硝基苯甲醛(3)的制备
将3-甲氧基-4-苄氧基苯甲醛2(13.6g,41mmol)于10℃缓慢加入浓硝酸(95mL)中。加完后于15℃搅拌反应两个小时。将反应液倒入冰水中搅拌,过滤得到黄色固体3(12.9g, 80%)。m.p.:127-130℃(文献m.p.131℃).EI-MS m/z:287(M+).
实施例3
3-甲氧基-4-苄氧基-6-硝基苯甲酸(4)的制备
将3-甲氧基-4-苄氧基-6-硝基苯甲醛3(10g,34.8mmol)溶于120ml丙酮与100ml水的混合溶剂中,加热至50℃,分批加入KMnO4(10g,63.3mmol),搅拌反应一个小时。过滤,滤液浓缩除去丙酮,冰浴下,缓慢加入4mol/L的盐酸,直到析出固体完全。得到淡黄色固体4(5.85g,55.4%)。mp:187-191℃(文献mp 192℃);EI-MS m/z:303(M+).
实施例4
3-苯基-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7a)的制备
3-甲氧基-4-苄氧基-6-硝基苯甲酸4(0.6g,2mmol)溶于SOCl2(10mL),回流1.5个小时后冷至室温并浓干溶剂。加入甲苯(20mL)溶解,并加入苯胺的甲苯溶液(0.92mL,10mmol溶于5mL甲苯)室温搅拌8小时后过滤,得到灰白色固体5a(0.64g,85%)。m.p.:202-205℃ 1H-NMR(300MHz,CDCl3):δ=3.98(s,3H,OCH3),5.21(s,2H,PhCH2O),7.00(s,1H,ArH),7.14(t,J=7.5Hz,1H,ArH),7.34-7.50(m,7H,ArH),7.55-7.58(d,J=7.5Hz,2H,ArH),7.69(s,1H,ArH)ppm.
将5a(1.2g,3.2mmol)溶于THF(50mL)和水(30mL)中,加入铁粉(1.8g,32mmol)和3滴浓盐酸,回流3小时后冷至室温,过滤除去固体。滤液用乙酸乙酯(3×20mL)萃取,合并有机相并用水(20mL)和饱和氯化钠溶液(20mL)洗涤一次,无水Na2SO4干燥,旋干。柱层析得黄色粉末6a(1.05g,99%)。m.p.:176-179℃.1H-NMR(300MHz,DMSO-d6):δ=3.75(s,3H,OCH3),5.07(s,2H,PhCH2O),6.48(s,1H,ArH),7.08-7.04(m,1H,ArH),7.26(s,1H,ArH),7.29-7.47(m,7H,ArH),7.64-7.66(m,2H,ArH),9.72(s,1H,CONH),ppm.MS(EI,m/z):348[M]+.
将6a(100mg,0.29mmol)溶于THF(5mL),加入HC(OEt)3(0.48mL,2.9mmol)后回流4h,冷至室温后加入乙酸乙酯(50mL)稀释,用饱和NaHCO3(2×10mL),饱和氯化钠溶液(10mL)洗涤,无水NaSO4干燥。旋干有机相柱层析得黄色粉末7a(收率:98%)。mp 178-181℃.IR(KBr):3428,2359,1677(C=O),1608(C=N),1498,1301,1250,869,756cm-1.1H-NMR(300MHz,CDCl3):δ=3.95(s,3H,OCH3),5.31(s,2H,PhCH2O),7.20(s,1H,quinazolinone-8-H),7.31-7.42(m,5H,ArH),7.48-7.57(m,5H,ArH),7.70(s,1H,quinazolinone-5-H),8.02(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):358[M]+.Anal.Calcd for C22H18N2O3:C,73.73;H,5.06;N,7.82.Found:C,73.46;H,5.29;N,7.54.
实施例5
3-(4-甲基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7b)的制备
具体操作同实施例4,得黄色固体7b,(收率:90%)。IR(KBr):3477,2955,2359,1674(C=O),1606(C=N),1501,1245,1144,1057,863,746cm-1.1H NMR(300MHz,DMSO-d6):δ=2.39(s,3H,CH3),3.90(s,3H,OCH3),5.30(s,2H,PhCH2O),7.30(s,1H,quinazolinone-8-H),7.33-7.40(m,5H,ArH),7.43(d,J=7.0Hz,2H,ArH),7.49(d,J=6.9Hz,2H,ArH),7.52(s,1H,quinazolinone-5-H),8.19(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):372[M]+.Anal.Calcd for C23H20N2O3:C,74.18;H,5.41;N,7.52.Found:C,73.87;H,5.74;N,7.22.
实施例6
3-(3-甲基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7c)的制备
具体操作同实施例4,得淡黄色粉末7c(收率:86%)。m.p.:156-159℃.IR(KBr):3422,2918,1677(C=O),1608(C=N),1507,1303,1139,1065,869,741,699cm-1.1H NMR(300MHz,CDCl3):δ=2.43(s,3H,CH3),4.01(s,3H,OCH3),5.30(s,2H,PhCH2O),7.18(m,2H,ArH),7.20(s,1H,quinazolinone-8-H),7.30-7.50(m,7H,ArH),7.70(s,1H,quinazolinone-5-H),8.01(s,1H,quinazolinone-2-H)ppm.MS(EI,m/z):372[M]+.Anal.Calcd for C23H20N2O3:C,74.18;H,5.41;N,7.52.Found:C,73.98;H,5.55;N,7.52+.
实施例7
3-(2-甲基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7d)的制备
具体操作同实施例4,得淡黄色粉末7d(收率:72%)。mp 198-199℃.IR(KBr):3457,2910,1673(C=O),1609(C=N),1499,1303,1145,868,748cm-1.1H NMR(300MHz,CDCl3):δ=2.19(s,3H,CH3),4.02(s,3H,OCH3),5.32(s,2H,PhCH2O),7.21-7.23(m,2H,ArH),7.24(s,1H,quinazolinone-8-H),7.34-7.42(m,5H,ArH),7.48-7.51(m,2H,ArH),7.70(s,1H,quinazolinone-5-H),7.91(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):372[M]+.Anal.Calcd for C23H20N2O3:C,74.18;H,5.41;N,7.52.Found:C,73.81;H,5.47;N,7.39.
实施例8
3-(2,4-二甲基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7e)的制备
具体操作同实施例4,得淡黄色粉末7e(收率:79%)。mp 99-102℃.IR(KBr):3442,2918,2351,1683(C=O),1608(C=N),1499,1305,1147,1058,876,846,757,696cm-1.1H NMR(300MHz,DMSO-d6):δ=2.03(s,3H,CH3),2.33(s,3H,CH3),3.90(s,3H,OCH3),5.31(s,2H,PhCH2O),7.19(s,1H,quinazolinone-8-H),7.23-7.52(m,8H,ArH),7.53(s,1H,quinazolinone-5-H),8.12(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):386[M]+.Anal.Calcd for C24H22N2O3:C,74.59;H,5.74;N,7.25.Found:C,74.21;H,5.84;N,7.06.
实施例9
3-(4-氯苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7f)的制备
具体操作同实施例4,得黄色粉末7f(收率:89%)。mp 240-241℃.IR(KBr):3436,2926,2363,1666(C=O),1607(C=N),1502,1285,1244,735cm-1.1H NMR(300MHz,CDCl3):δ=4.01(s,3H,OCH3),5.31(s,2H,PhCH2O),7.21(s,1H,quinazolinone-8-H),7.35-7.42(m,5H,ArH),7.48-7.53(m,4H,ArH),7.68(s,1H,quinazolinone-5-H),8.00(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):392/394[M]+.Anal.Calcd for C22H17ClN2O3·0.5H2O:C,65.76;H,4.51;N,6.97.Found:C,66.04;H,4.39;N,6.87.
实施例10
3-(3-氯苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7g)的制备
具体操作同实施例4,得黄色粉末7g(收率:90%)。mp 221-223℃.IR(KBr):3438,3065,1676(C=O),1609(C=N),1503,1299,1143,867,783,735,688cm-1.1H NMR(300MHz,DMSO-d6):δ=3.90(s,3H,OCH3),5.31(s,2H,PhCH2O),7.32(s,1H,quinazolinone-8-H),7.38-7.45(m,3H,ArH),7.49-7.51(m,4H,ArH),7.53-7.58(m,2H,ArH),7.70(s,1H,quinazolinone-5-H),8.24(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):392/394[M]+.Anal.Calcd for C22H17ClN2O3:C,67.26;H,4.36;N,7.13.Found:C,66.93;H,4.59;N,6.92.
实施例11
3-(2-氯苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7h)的制备
具体操作同实施例4,得淡黄色粉末7h(收率:85%)。mp 176-179℃.IR(KBr):3424,2914,1681(C=O),1608(C=N),1501,1309,1145,1047,758,733cm-1.1H NMR(300MHz,DMSO-d6):δ=3.91(s,3H,OCH3),5.32(s,2H,PhCH2O),7.34(s,1H,quinazolinone-8-H),7.36-7.45(m,4H,ArH),7.50(s,1H,quinazolinone-5-H),7.52-7.61(m,4H,ArH),7.66-7.69(m,1H,ArH),7.71-7.75(m,1H,ArH),8.17(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):392/394[M]+.Anal.Calcd for C22H17ClN2O3·0.5H2O:C,65.76;H,4.51;N,6.97.Found:C,65.85;H,4.21;N,6.80.
实施例12
3-(4-氟苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7i)的制备
具体操作同实施例4,得淡黄色粉末7i(收率:80%)。mp 207-209℃.IR(KBr):3420,3066,1677(C=O),1609(C=N),1497,1310,1144,1057,866,845,749,699cm-1.1H NMR(300MHz,DMSO-d6):δ=3.90(s,3H,OCH3),5.31(s,2H,PhCH2O),7.31(s,1H,quinazolinone-8-H),7.36-7.45(m,5H,ArH),7.49-7.55(m,2H,ArH),7.56(s,1H,quinazolinone-5-H),7.58-7.60(m, 2H,ArH),8.21(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):376[M]+.Anal.Calcd for C22H17FN2O3·0.2H2O:C,69.54;H,4.62;N,7.37.Found:C,69.60;H,4.77;N,6.99.
实施例13
3-(4-乙酰苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7j)的制备
具体操作同实施例4,得淡黄色粉末7j(收率:89%)。mp 236-237℃.IR(KBr):3439,1681(C=O),1665(C=O),1607(C=N),1499,1287,1249,1142,1056,865,780,696cm-1.1H NMR(300MHz,CDCl3):δ=2.67(s,3H,CH3),4.02(s,3H,OCH3),5.32(s,2H,PhCH2O),7.26(s,1H,quinazolinone-8-H),7.35-7.43(m,3H,ArH),7.48-7.51(m,2H,ArH),7.55(d,J=8.1Hz,2H,ArH),7.69(s,1H,quinazolinone-5-H),8.08(s,1H,quinazolinone-2-H),8.13(d,J=8.1Hz,2H,ArH),ppm.MS(EI,m/z):400[M]+.Anal.Calcd for C24H20N2O4:C,71.99;H,5.03;N,7.00.Found:C,72.29;H,5.18;N,6.86.
实施例14
3-(4-羟基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7k)的制备
具体操作同实施例4,得白色粉末7k(收率:39%)。mp 243-244℃.IR(KBr):3432,3212,2930,1651(C=O),1609(C=N),1500,1288,1145,1056,865,751cm-1.1H NMR(300MHz,CDCl3):δ=3.99(s,3H,OCH3),5.31(s,2H,PhCH2O),6.42(brs,1H,PhOH),6.85(d,J=8.7Hz,2H,ArH),7.16(s,1H,quinazolinone-8-H),7.20(d,J=6.3Hz,2H,ArH),7.34-7.42(m,3H,ArH),7.48-7.50(m,2H,ArH),7.70(s,1H,quinazolinone-5-H),8.02(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):374[M]+.Anal.Calcd for C22H18N2O4:C,70.58;H,4.85;N,7.48.Found:C,70.26;H,4.92;N,7.36.
实施例15
3-(4-甲氧基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7l)的制备
具体操作同实施例4,得淡黄色粉末7l(收率:80%)。mp 190-191℃.IR(KBr):3436,3053,2930,2840,1673(C=O),1611(C=N),1497,1251,1177,1023,864,843,749,699cm-1.1H NMR(300MHz,DMSO-d6):δ=3.83(s,3H,OCH3),3.90(s,3H,OCH3),5.30(s,2H,PhCH2O),7.10(d,J=9.0Hz,2H,ArH),7.30(s,1H,quinazolinone-8-H),7.36-7.47(m,5H,ArH),7.49(d,J=9.0Hz,2H,ArH),7.53(s,1H,quinazolinone-5-H),8.18(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):388[M]+.Anal.Calcd for C23H20N2O4:C,71.12;H,5.19;N,7.21.Found:C,70.91;H,5.25;N,6.83.
实施例16
3-(2,4-二氟苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7m)的制备
具体操作同实施例4,得淡黄色粉末7m(收率:80%)。mp 155-156℃.IR(KBr):3447,3065,1677(C=O),1607(C=N),1500,1297,1143,1054,867,840,752,700cm-1.1H NMR(300MHz,CDCl3):δ=4.01(s,3H,OCH3),5.31(s,2H,PhCH2O),7.07(t,2H,ArH),7.26(s,1H,quinazolinone-8-H),7.31-7.41(m,4H,ArH),7.43-7.48(m,2H,ArH),7.50(s,1H,quinazolinone-5-H),7.68(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):394[M]+.Anal.Calcd for C22H16F2N2O3:C,67.00;H,4.09;N,7.10.Found:C,66.92;H,4.34;N,6.99
实施例17
3-(2,4-二氯苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7n)的制备
具体操作同实施例4,得淡黄色粉末7n(收率:84%)。mp 84-87℃.IR(KBr):3448,3085,2938,1680(C=O),1607(C=N),1500,1289,1146,1045,867,747,698,597cm-1.1H NMR(300MHz,CDCl3):δ=4.01(s,3H,OCH3),5.31(s,2H,PhCH2O),7.22(s,1H,quinazolinone-8-H),7.31-7.56(m,8H,ArH),7.69(s,1H,quinazolinone-5-H),7.82(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):427/429[M]+.Anal.Calcd for C22H16Cl2N2O3:C,61.84;H,3.77;N,6.56.Found:C,61.42;H,4.11;N,6.18.
实施例18
3-(2-甲基-4-甲氧酰苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7o)的制备
具体操作同实施例4,得淡黄色粉末7o(收率:92%)。mp 209-210℃.IR(KBr):3434,2946,1724(C=O),1678(C=O),1606(C=N),1500,1297,1267,1193,1150,750cm-1.1H NMR(300MHz,CDCl3):δ=2.24(s,3H,CH3),3.96(s,3H,OCH3),4.02(s,3H,OCH3),5.32(s,2H,PhCH2O),7.23(s,1H,quinazolinone-8-H),7.31-7.43(m,4H,ArH),7.48-7.51(m,2H,ArH),7.69(s,1H,quinazolinone-5-H),7.87(s,1H,ArH),8.03(d,J=8.2Hz,1H,ArH),8.09(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):430[M]+.Anal.Calcd for C25H22N2O5:C,69.76;H,5.15;N,6.51.Found:C,69.36;H,5.22;N,6.15.
实施例19
3-(3-甲氧基-4-苯甲氧基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7p)的制备
具体操作同实施例4,得淡黄色粉末7p(收率:76%)。mp 157-159℃.MS(EI,m/z):494[M]+.
实施例20
3-(2-氯-5-甲基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7q)的制备
具体操作同实施例4,得淡黄色粉末7q(收率:78%)。mp 160-162℃.IR(KBr):3444,2930,1668(C=O),1603(C=N),1496,1295,1248,1138cm-1.1H NMR(300MHz,CDCl3):δ=2.20(s, 3H,CH3),4.02(s,3H,OCH3),5.32(s,2H,PhCH2O),7.23(s,1H,quinazolinone-8-H),7.28-7.35(m,3H,ArH),7.35-7.45(m,3H,ArH),7.48-7.51(m,2H,ArH),7.69(s,1H,quinazolinone-5-H),7.75(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):406[M]+.
实施例21
3-(3-氟苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7r)的制备
具体操作同实施例4,得黄色粉末7r(收率:75%)。mp 198-200℃.IR(KBr):3444,2930,1674(C=O),1597(C=N),1507,1292,1249,1133,1001,880,744,698cm-1.1H NMR(300MHz,CDCl3):δ=4.02(s,3H,OCH3),5.31(s,2H,PhCH2O),7.19(s,1H,quinazolinone-8-H),7.26-7.21(m,3H,ArH),7.28-7.40(m,3H,ArH),7.47(s,1H,ArH),7.48-7.55(m,2H,ArH),7.69(s,1H,quinazolinone-5-H),8.00(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):376[M]+.
实施例22
3-(3-羟基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7s)的制备
具体操作同实施例4,得白色粉末7s(收率:35%)。mp 214-216℃.MS(EI,m/z):374[M]+.
实施例23
3-(3,5-二三氟甲基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7t)的制备
具体操作同实施例4,得白色粉末7t(收率:70%)。mp 203-206℃.IR(KBr):3424,3065,1673(C=O),1607(C=N),1505,1281,1180,1143,1126,1001,699cm-1.1H NMR(300MHz,DMSO-d6):δ=4.01(s,3H,OCH3),5.32(s,2H,PhCH2O),7.30(s,1H,quinazolinone-8-H),7.30-7.50(m,5H,ArH),7.67(s,1H,quinazolinone-5-H),7.94(s,2H,ArH),8.01(s,1H,quinazolinone-2-H),8.04(s,1H,ArH),ppm.MS(EI,m/z):494[M]+.
实施例24
3-(2-甲氧基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7u)的制备
具体操作同实施例4,得白色粉末7u(收率:70%)。mp 172-173℃.MS(EI,m/z):388[M]+.
实施例25
2-甲基-3-(4-甲氧基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7v)的制备
3-甲氧基-4-苄氧基-6-硝基苯甲酸4(0.6g,2mmol)溶于SOCl2(10mL),回流1.5个小时后冷至室温并浓干溶剂。加入甲苯(20mL)溶解,并加入对甲氧基苯胺的甲苯溶液(1.23g,10mmol溶于5mL甲苯)室温搅拌8小时后过滤,得到固体5v。
将5v(1.2g,3.2mmol)溶于THF(50mL)和水(30mL)中,加入铁粉(1.8g,32mmol)和3滴浓盐酸,回流3小时后冷至室温,过滤除去固体。滤液用乙酸乙酯(3×20mL)萃取,合并有机相并用水(20mL)和饱和氯化钠溶液(20mL)洗涤一次,无水Na2SO4干燥,旋干,得6v。
将6v溶于THF(5mL),加入CH3C(OEt)3(0.48mL,2.9mmol)后回流4h,冷至室温后加入乙酸乙酯(50mL)稀释,用饱和NaHCO3(2×10mL),饱和氯化钠溶液(10mL)洗涤,无水NaSO4干燥。旋干有机相柱层析得黄色粉末7v(收率:87%)。mp 162-163℃.IR(KBr):3432,3057,2930,2828,1688(C=O),1609(C=N),1499,1392,1247,1026,841,752,740,567cm-1.1HNMR(300MHz,CDCl3):δ=2.22(s,3H,CH3),3.88(s,3H,OCH3),3.98(s,3H,OCH3),5.29(s,2H,PhCH2O),7.06(d,J=8.8Hz,2H,ArH),7.14(s,1H,quinazolinone-8-H),7.17(d,J=8.8Hz,2H,ArH),7.31-7.40(m,3H,ArH),7.49-7.42(m,2H,ArH),7.60(s,1H,quinazolinone-5-H),ppm.MS(EI,m/z):402[M]+.Anal.Calcd for C24H22N2O4:C,71.63;H,5.51;N,6.96.Found:C,71.59;H,5.65;N,6.91.
实施例26
2-甲基-3-(4-羟基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7w)的制备
具体操作同实施例25,得白色粉末7w(收率:40%)。mp 208-210℃.MS(EI,m/z):388[M]+.
实施例27
2-甲基-3-(2-甲氧基苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7x)的制备
具体操作同实施例25,得白色粉末7x(收率:56%)。mp 173-174℃.IR(KBr):3444,2930,2828,1680(C=O),1609(C=N),1496,1464,1394,1264,1181,1023,755cm-1.1H NMR(300MHz,CDCl3):δ=2.18(s,3H,CH3),3.79(s,3H,OCH3),3.98(s,3H,OCH3),5.29(s,2H,PhCH2O),7.07-7.20(m,4H,ArH),7.31-7.40(m,3H,ArH),7.42(s,1H,quinazolinone-8-H),7.42-7.49(m,2H,ArH),7.62(s,1H,quinazolinone-5-H),ppm.MS(EI,m/z):402[M]+.
实施例28
2-甲基-3-(4-氟苯基)-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7y)的制备
具体操作同实施例25,得淡黄色粉末7y(收率:84%)。mp 197-198℃.IR(KBr):3433,3077,1687(C=O),1608(C=N),1499,1391,1282,1027,855,756,700,593cm-1.1H NMR(300MHz,CDCl3):δ=2.26(s,3H,CH3),4.01(s,3H,OCH3),5.30(s,2H,PhCH2O),7.00-7.23(m,4H,ArH),7.24(s,1H,quinazolinone-8-H),7.31-7.40(m,3H,ArH),7.42-7.50(m,2H,ArH),7.58(s,1H,quinazolinone-5-H),ppm.MS(EI,m/z):390[M]+.Anal.Calcd for C23H19FN2O3:C,70.76;H,4.91;N,7.18.Found:C,70.46;H,5.08;N,6.97.
实施例29
3-环己基-6-甲氧基-7-苄氧基-4(3H)-喹唑啉酮(7z)的制备
具体操作同实施例4,得黄色粉末7z(收率:86%)。mp 194-196℃.IR(KBr):3441,2934,1655(C=O),1607(C=N),1505,1287,1104,1001,866,784,757,738,704cm-1.1H NMR(300 MHz,CDCl3):δ=1.24-1.28(m,1H,cyclohexyl),1.50-1.69(m,4H,cyclohexyl),1.77-1.81(m,1H,cyclohexyl),1.92-2.02(m,4H,cyclohexyl),4.01(s,3H,OCH3),4.81(m,1H,cyclohexyl),5.28(s,2H,PhCH2O),7.15(s,1H,quinazolinone-8-H),7.29-7.41(m,3H,ArH),7.46-7.48(m,2H,ArH),7.64(s,1H,quinazolinone-5-H),8.04(s,1H,quinazolinone-2-H),ppm.MS(EI,m/z):364[M]+.Anal.Calcd for C22H24N2O3:C,72.50;H,6.64;N,7.69.Found:C,72.12;H,6.92;N,7.55.
实施例30
3-苯基-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX033)的制备
将7a(297mg,0.83mmol)溶于甲醇(15mL)和THF(25mL),加入5%Pd/C(10mg),通入氢气并在室温下搅拌4个小时。反应完毕后过滤除去Pd/C,将溶剂减压浓缩至干,柱层析(石油醚∶乙酸乙酯=1∶1)得灰白色晶体XHX033(189mg,85%)。m.p.:227-229℃;IR(KBr):3412,3240,1640(C=O),1619(C=N),1498,1455,1434,1289,1263,1209,710cm-1.1H NMR(300MHz,DMSO-d6),δ=3.90(s,3H,OCH3),7.05(s,1H,quinazolinone-8-H),7.38-7.58(m,6H,ArH+quinazolinone-5-H),8.17(s,1H,quinazolinone-2-H),10.44(s,1H,Ph-OH)ppm;MS(EI,m/z):268[M]+.Anal.Calcd for C15H12N2O3·0.25H2O:C,66.05;H,4.62;N,10.27.Found:C,66.33;H,4.66;N,10.19.
实施例31
3-(4-甲基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX030)的制备
具体操作同实施例30,投入7b(240mg,0.65mmol),得到XHX030 165mg(91%)。m.p.:120-122℃;IR(KBr):3428,1679(C=O),1611(C=N),1511,1456,1411,1304,1285,1258,1048cm-1.1H NMR(300MHz,DMSO-d6),δ=2.39(s,3H,PhCH3),3.89(s,3H,OCH3),7.05(s,1H,quinazolinone-8-H),7.35(s,4H,ArH),7.50(s,1H,quinazolinone-5-H),8.13(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):282[M]+.Anal.Calcd.for C16H14N2O3:C,68.07;H,5.00;N,9.92.Found:C,68.00;H,5.02;N,9.93.
实施例32
3-(3-甲基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX031)的制备
具体操作同实施例30,投入7c(330mg,0.9mmol),得到XHX031 233mg(93%)。m.p.:254-256℃;IR(KBr):3069,1677(C=O),1602(C=N),1500,1471,1441,1307,1260,1201,1024cm-1.1H NMR(300MHz,DMSO-d6),δ=2.38(s,3H,PhCH3),3.89(s,3H,OCH3),7.05(s,1H,quinazolinone-8-H),7.26-7.31(m,3H,ArH),7.26-7.31(t,J=8.2Hz,1H,ArH),7.50(s,1H,quinazolinone-5-H),8.14(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):282[M]+.Anal.Calcd.for C16H14N2O3:C,68.07;H,5.00;N,9.92.Found:C,67.94;H,5.01;N,9.84.
实施例33
3-(2-甲基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX032)的制备
具体操作同实施例30,投入7d(180mg,0.5mmol),得到XHX032 95mg(70%)。m.p.:224-225℃;IR(KBr):3436,1682(C=O),1611(C=N),1498,1310,1259,1191,1142cm-1.1H NMR(300MHz,CDCl3),δ=2.19(s,3H,PhCH3),4.04(s,3H,OCH3),6.38(brs,1H,PhOH),7.23(m,1H,ArH),7.29(s,1H,quinazolinone-8-H),7.30-7.42(m,3H,ArH),7.71(s,1H,quinazolinone-5-H),7.93(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):282[M]+.Anal.Calcd.for C16H14N2O3:C,68.07;H,5.00;N,9.92.Found:C,68.13;H,5.09;N,9.99.
实施例34
3-(2,4-二甲基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX034)的制备
具体操作同实施例30,投入7e(240mg,0.62mmol),得到XHX034 170mg(92%)。m.p.:227-230℃;IR(KBr):3061,1685(C=O),1604(C=N),1499,1310,1261,1201,1145,1004cm-1. 1H NMR(300MHz,DMSO-d6),δ=2.02(s,3H,PhCH3),2.33(s,3H,PhCH3),3.90(s,3H,OCH3),7.06(s,1H,quinazolinone-8-H),7.18(s,1H,ArH),7.20-7.27(d,J=8.2Hz,1H,ArH),7.29-7.38(d,J=8.1Hz,1H,ArH),7.50(s,1H,quinazolinone-5-H),8.05(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):296[M]+.Anal.Calcd.for C17H13N2O3·0.25H2O:C,67.88;H,5.53;N,9.31.Found:C,67.77;H,5.24;N,9.12.
实施例35
3-(4-甲氧基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX035)的制备
具体操作同实施例30,投入7l(180mg,0.46mmol),得到XHX035 120mg(87%)。m.p.:218-220℃;IR(KBr):3373,1678(C=O),1615(C=N),1501,1307,1250,1203,1141,1020,820cm-1.1H NMR(300MHz,DMSO-d6),δ=3.83(s,3H,OCH3),3.89(s,3H,OCH3),7.04(s,1H,quinazolinone-8-H),7.06-7.10(d,J=8.9Hz,2H,ArH),7.39-7.42(d,J=8.9Hz,2H,ArH),7.49(s,1H,quinazolinone-5-H),8.12(s,1H,quinazolinone-2-H),10.40(s,1H,PhOH)ppm;MS(EI,m/z):298[M]+.Anal.Calcd.for C16H14N2O4:C,64.42;H,4.73;N,9.39.Found:C,64.44;H,4.94;N,9.22.
实施例36
3-(2-甲氧基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX036)的制备
具体操作同实施例30,投入7u(250mg,0.64mmol),得到XHX036 156mg(81%)。m.p.:215-216℃;IR(KBr):3077,1693(C=O),1614(C=N),1500,1261,1209,1138cm-1.1H NMR(300MHz,d6-DMSO),δ=3.76(s,3H,OCH3),δ=3.89(s,3H,OCH3),7.03(s,1H, quinazolinone-8-H),7.10(m,1H,ArH),7.25(d,J=6Hz,1H,ArH),7.41(d,J=6Hz,1H,ArH),7.48(s,1H,quinazolinone-5-H),7.48(m,1H,ArH),8.01(s,1H,quinazolinone-2-H),10.44(brs,1H,PhOH)ppm;MS(EI,m/z):298[M]+.Anal.Calcd.for C16H14N2O4·0.25H2O:C,63.47;H,4.83;N,9.25.Found:C,63.32;H,4.76;N,9.02.
实施例37
3-(4-氯苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX037)的制备
具体操作同实施例30,投入7f(130mg,0.33mmol),得到XHX037 92mg(92%)。m.p.:221-223℃;IR(KBr):3061,1686(C=O),1611(C=N),1587,1499,1309,1253,1212,1143,1048cm-1.1H NMR(300MHz,DMSO-d6),δ=3.89(s,3H,OCH3),7.04(s,1H,quinazolinone-8-H),7.49(s,2H,ArH),7.57(s,2H,ArH),7.69(s,1H,quinazolinone-5-H),8.18(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):302/304[M]+.Anal.Calcd.for C15H11ClN2O3:C,59.52;H,3.66;N,9.25.Found:C,59.52;H,3.87;N,9.07.
实施例38
3-(3-氯苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX038)的制备
具体操作同实施例30,投入7g(200mg,0.51mmol),得到XHX038 100mg(65%)。m.p.:261-263℃;IR(KBr):3053,1677(C=O),1611(C=N),1590,1498,1310,1263,1210,1142,1053,755,697cm-1.1H NMR(300MHz,CDCl3),δ=4.04(s,3H,OCH3),6.32(s,1H,PhOH),7.41(s,1H,ArH),7.43(s,1H,quinazolinone-8-H),7.45-7.57(m,3H,ArH),7.71(s,1H,quinazolinone-5-H),8.06(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):302/304[M]+.Anal.Calcd.for C15H11ClN2O3:C,59.52;H,3.66;N,9.25.Found:C,59.23;H,3.92;N,9.11.
实施例39
3-(2-氯苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX039)的制备
具体操作同实施例30,投入7h(150mg,0.38mmol),得到XHX039 108mg(93%)。m.p.:218-221℃;IR(KBr):3069,1687(C=O),1610(C=N),1498,1309,1261,1211cm-1.1H NMR(300MHz,CDCl3),δ=4.04(s,3H,OCH3),6.42(s,1H,PhOH),7.30(s,1H,quinazolinone-8-H),7.40-7.60(m,4H,ArH),7.72(s,1H,quinazolinone-5-H),7.90(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):302/304[M]+.Anal.Calcd.for C15H11ClN2O3:C,59.52;H,3.66;N,9.25.Found:C,59.40;H,4.09;N,9.17.
实施例40
3-(2,4-二氯苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX040)的制备
具体操作同实施例30,投入7n(210mg,0.50mmol),得到XHX040 110mg(66%)。m.p.: 244-246℃;IR(KBr):3057,1681(C=O),1610(C=N),1498,1309,1262,1204,1138cm-1.1HNMR(300MHz,CDCl3),δ=4.04(s,3H,OCH3),6.37(s,1H,PhOH),7.41(s,1H,quinazolinone-8-H),7.43-7.46(m,1H,ArH),7.49-7.60(m,2H,ArH),7.71(s,1H,quinazolinone-5-H),8.05(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):304[M]+.
实施例41
3-(3,5-二(三氟甲基)苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX041)的制备
具体操作同实施例30,投入7t(220mg,0.45mmol),得到XHX041 120mg(67%)。m.p.:215-216℃;IR(KBr):3395,1673(C=O),1620(C=N),1498,1383,1280,1182,1134cm-1.1HNMR(300MHz,CDCl3),δ=4.06(s,3H,OCH3),6.40(brs,1H,PhOH),7.31(s,1H,quinazolinone-8-H),7.70(s,1H,quinazolinone-5-H),7.95(s,1H,ArH),8.02(s,1H,ArH),8.07(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):404[M]+.Anal.Calcd.for C17H10F2N2O3:C,50.51;H,2.49;N,6.93.Found:C,50.30;H,2.48;N,6.55.
实施例42
3-(2-氯-3-甲基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX042)的制备
具体操作同实施例30,投入7q(240mg,0.60mmol),得到XHX042 140mg(74%)。m.p.:163-165℃;IR(KBr):3428,1685(C=O),1610(C=N),1499,1309,1260,1210cm-1.1H NMR(300MHz,CDCl3),δ=2.21(s,3H,CH3),4.04(s,3H,OCH3),6.40(brs,1H,PhOH),7.29(s,1H,quinazolinone-8-H),7.30-7.45(m,2H,ArH),7.71-7.74(d,J=7.9Hz,1H,ArH),7.77(s,1H,quinazolinone-5-H),7.93(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):316[M]+.Anal.Calcd.for C16H13ClN2O3:C,60.67;H,4.14;N,8.84.Found:C,60.20;H,3.96;N,8.69.
实施例43
3-(4-氟苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX043)的制备
具体操作同实施例30,投入7i(240mg,0.61mmol),得到XHX043 174mg(95%)。m.p.:235-236℃;IR(KBr):3069,1695(C=O),1613(C=N),1501,1309,1250,1227,1205,840cm-1. 1H NMR(300MHz,DMSO-d6),δ=3.89(s,3H,OCH3),7.05(s,1H,quinazolinone-8-H),7.32-7.42(m,2H,ArH),7.50(s,1H,quinazolinone-5-H),7.52-7.62(m,2H,ArH),8.16(s,1H,quinazolinone-2-H),10.44(s,1H,PhOH)ppm;MS(EI,m/z):286[M]+.Anal.Calcd.forC15H11FN2O3·0.25H2O:C,61.96;H,3.99;N,9.63.Found:C,61.74;H,4.11;N,9.21.
实施例44
3-(3-氟苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX044)的制备
具体操作同实施例30,投入7r(230mg,0.61mmol),得到XHX044 110mg(67%)。m.p.: 234-236℃;IR(KBr):3061,1680(C=O),1601(C=N),1499,1313,1271,1201,1201,875cm-1. 1H NMR(300MHz,CDCl3),δ=4.05(s,3H,OCH3),6.37(brs,1H,PhOH),7.10-7.23(m,4H,3*ArH+quinazolinone-8-H),7.42-7.60(m,1H,ArH),7.70(s,1H,quinazolinone-5-H),8.02(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):286[M]+.Anal.Calcd.for C15H11FN2O3:C,62.94;H,3.87;N,9.79.Found:C,62.64;H,3.92;N,9.53.
实施例45
3-(2,4-二氟苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX045)的制备
具体操作同实施例30,投入7m(320mg,0.80mmol),得到XHX045 235mg(95%)。m.p.:110-112℃;IR(KBr):3064,1685(C=O),1615(C=N),1499,1327,1267,1207,1145,1106cm-1. 1H NMR(300MHz,DMSO-d6),δ=3.90(s,3H,OCH3),7.06(s,1H,quinazolinone-8-H),7.20-7.35(t,1H,ArH),7.50(s,1H,quinazolinone-5-H),7.52-7.61(t,1H,ArH),7.70-7.78(m,1H,ArH),8.18(s,1H,quinazolinone-2-H),10.55(s,1H,PhOH)ppm;MS(EI,m/z):304[M]+.Anal.Calcd.for C15H10F2N2O3·0.25H2O:C,58.35;H,3.43;N,9.07.Found:C,58.42;H,3.74;N,8.93.
实施例46
3-(4-羟基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX046)的制备
具体操作同实施例30,投入7k(160mg,0.43mmol),得到XHX046 110mg(92%)。m.p.:239-240℃;IR(KBr):3404,1657(C=O),1614(C=N),1499,1318,1261,1217cm-1.1H NMR(300MHz,DMSO-d6),δ=3.89(s,3H,OCH3),6.87-6.90(d,J=8.4Hz,2H,ArH),7.04(s,1H,quinazolinone-8-H),7.25-7.28(d,J=8.4Hz,2H,ArH),7.49(s,1H,quinazolinone-5-H),8.10(s,1H,quinazolinone-2-H),9.82(s,1H,PhOH),10.42(s,1H,PhOH)ppm;MS(EI,m/z):284[M]+.Anal.Calcd.for C15H12N2O4·H2O:C,59.60;H,4.67;N,9.26.Found:C,59.59;H,4.56;N,8.87.
实施例47
3-(3-羟基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX047)的制备
具体操作同实施例30,投入7s(170mg,0.45mmol),得到XHX047 75mg(58%)。m.p.:268-270℃;IR(KBr):3383,1669(C=O),1609(C=N),1507,1297,1262,1200,1057,877cm-1. 1H NMR(300MHz,DMSO-d6),δ=3.89(s,3H,OCH3),6.80-6.90(m,3H,ArH),7.04(s,1H,quinazolinone-8-H),7.30-7.37(t,J=8.0Hz,1H,ArH),7.50(s,1H,quinazolinone-5-H),8.13(s,1H,quinazolinone-2-H),9.87(s,1H,PhOH),10.44(s,1H,PhOH)ppm;MS(EI,m/z):284[M]+.Anal.Calcd.for C15H12N2O4·H2O:C,59.60;H,4.67;N,9.27.Found:C,59.19;H,4.36;N,8.81.
实施例48
3-(4-乙酰基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX048)和3-(4-(1-羟基乙基)苯基)-6- 甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX049)的制备
具体操作同实施例30,投入7j(210mg,0.52mmol),得到XHX048 35mg(21%)和XHX04953mg(33%)。
XHX048 m.p.:289-290℃;IR(KBr):3269,1670(C=O),1596(C=N),1503,1322,1297cm-1. 1H NMR(300MHz,DMSO-d6),δ=2.65(s,3H,COCH3),3.90(s,3H,OCH3),7.07(s,1H,quinazolinone-8-H),7.51(s,1H,quinazolinone-5-H),7.67-7.70(d,J=7.9Hz,2H,ArH),8.10-8.13(d,J=7.9Hz,2H,ArH),8.22(s,1H,quinazolinone-2-H),10.51(s,1H,PhOH)ppm;MS(EI,m/z):310[M]+.Anal.Calcd.for C17H14N2O4.CH3OH:C,63.15;H,5.30;N,8.18.Found:C,63.23;H,5.07;N,7.76.
XHX049 m.p.:282-283℃;IR(KBr):3366,1680(C=O),1599(C=N),1496,1317,1297,1258cm-1.1H NMR(300MHz,DMSO-d6),δ=1.36-1.38(d,3H,CHCH 3 ),3.90(s,3H,OCH3),1.36-1.38(d,3H,CHCH3),7.05(s,1H,quinazolinone-8-H),7.41-7.44(d,J=7.8Hz,2H,ArH),7.48-7.55(m,3H,2*ArH+quinazolinone-5-H),8.16(s,1H,quinazolinone-2-H),10.45(s,1H,PhOH)ppm;MS(EI,m/z):312[M]+.Anal.Calcd.for C17H16N2O4·0.5H2O:C,63.54;H,5.33;N,8.72.Found:C,63.65;H,5.25;N,8.71.
实施例49
3-(2-甲基-4-甲氧甲酰苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX050)的制备
具体操作同实施例30,投入7o(350mg,0.80mmol),得到XHX050 260mg(93%)。m.p.:116-119℃;IR(KBr):3408,1723(C=O),1677(C=O),1600(C=N),1497,1439,1307,1264,1196,1044,750cm-1.1H NMR(300MHz,DMSO-d6),δ=2.16(s,3H,PhCH3),3.90(s,6H,2*OCH3),7.07(s,1H,quinazolinone-8-H),7.51(s,1H,quinazolinone-5-H),7.52-7.60(d,J=8.1Hz,1H,ArH),7.92-7.97(d,J=8.1Hz,1H,ArH),8.03(s,1H,ArH),8.11(s,1H,quinazolinone-2-H),10.51(s,1H,PhOH)ppm;MS(EI,m/z):340[M]+.Anal.Calcd.for C18H16N2O5·0.5H2O:C,61.89;H,4.90;N,8.02.Found:C,62.27;H,4.99;N,7.94.
实施例50
3-(2-甲基-4-羧基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX051)的制备
将XHX050(190mg,0.54mmol)溶于甲醇(10mL)和水(1mL)的混合溶剂中,冰浴冷至0℃,加入NaOH(110mg,2.8mmol)室温搅拌反应2.5小时。反应完毕后加入1N HCl调pH至2,用乙酸乙酯萃取(10mL×3)。有机层用无水硫酸钠干燥后减压浓缩至干,乙酸乙酯重结晶得白色固体XHX051(132mg,73%)。m.p.:302-305℃;IR(KBr):3503,1703(C=O),1642(C=O),1612(C=N),1500,1448,1316,1261,1191,865cm-1.1H NMR(300MHz,DMSO-d6),δ= 2.15(s,3H,PhCH3),3.90(s,3H,OCH3),7.09(s,1H,quinazolinone-8-H),7.51(s,1H,quinazolinone-5-H),7.51-7.54(d,J=7.9Hz,1H,ArH),7.90-7.93(d,J=8.6Hz,1H,ArH),8.00(s,1H,ArH),8.13(s,1H,quinazolinone-2-H),10.55(s,1H,PhOH)ppm;MS(EI,m/z):326[M]+.Anal.Calcd.for C17H14N2O5·CH3OH:C,60.33;H,5.06;N,7.82.Found:C,60.51;H,4.93;N,7.34.
实施例51
3-环己基-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX060)的制备
具体操作同实施例30,投入7z(100mg,0.30mmol),得到XHX060 53mg(71%)。m.p.:158-160℃;IR(KBr):3411,2930,1649(C=O),1620(C=N),1497,1295,1141,1109cm-1.1HNMR(300MHz,CDCl3),δ=1.18-2.02(m,10H,cyclohexyl),4.03(s,3H,-OCH3),4.83(m,1H,-NCH-),6.42(brs,1H,Ph-OH),7.21(s,1H,quinazolinone-8-H),7.65(s,1H,quinazolinone-5-H),8.10(s,1H,quinazolinone-2-H).ppm;MS(EI,m/z):274[M]+.Anal.Calcd.for C15H18N2O3·0.25H2O:C,64.41;H,6.70;N,10.01.Found:C,64.09;H,6.77;N,9.87.
实施例52
3-(3-甲氧基-4-羟基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX054)的制备
具体操作同实施例30,投入7p(510mg,1mmol),得到XHX054 162mg(50%)。m.p.:162-165℃;IR(KBr):3428,1665(C=O),1617(C=N),1500,1468,1300,1259,1228,1027cm-1.1H NMR(300MHz,CDCl3),δ=3.96(s,3H,OCH3),4.03(s,3H,OCH3),5.93(brs,1H,PhOH),6.42(brs,1H,PhOH),6.80-6.92(dd,J1=8.5Hz and J2=2.2Hz,1H,C6’-ArH),6.92-7.02(d,J=8.1Hz,2H,C5’-ArH+C2’-ArH),7.24(s,1H,quinazolinone-8-H),7.71(s,1H,quinazolinone-5-H),8.01(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):314[M]+.Anal.Calcd.for C16H14N2O5·0.25H2O:C,60.28;H,4.58;N,8.79.Found:C,60.34;H,4.54;N,8.53.
实施例53
3-(3,4-二甲氧基苯基)-6,7-二甲氧基-4(3H)-喹唑啉酮(XHX055)的制备
将XHX054(100mg,0.32mmol)溶于丙酮(15mL),加入K2CO3(110mg,0.8mmol)和CH3I(114mg,0.8mmol),回流4个小时。反应液过滤除去不溶物后减压浓干丙酮,残留物柱层析(CH2Cl2/MeOH,50∶1)得到灰白色晶体XHX055 92mg(84%)。m.p.:205-207℃;IR(KBr):3432,1683(C=O),1611(C=N),1500,1453,1304,1255,1139,1031cm-1.1H NMR(300MHz,CDCl3),δ=3.91(s,3H,OCH3),3.96(s,3H,OCH3),4.02(s,3H,OCH3),4.04(s,3H,OCH3),6.90-7.05(m,3H,ArH),7.21(s,1H,quinazolinone-8-H),7.68(s,1H,quinazolinone-5-H),8.12(s,1H,quinazolinone-2-H)ppm;MS(EI,m/z):342[M]+.Anal.Calcd.for C18H18N2O5:C,63.15;H,5.30;N,8.18.Found:C,62.92;H,5.46;N,7.77.
实施例54
2-甲基-3-(4-氟苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX056)的制备
具体操作同实施例30,投入7y(180mg,0.46mmol),得到XHX056 131mg(95%)。m.p.:225-226℃;IR(KBr):3285,1661(C=O),1607(C=N),1509,1408,1290,1269,1212,1163cm-1. 1H NMR(300MHz,CDCl3),δ=2.21(s,3H,CH3),4.00(s,3H,OCH3),6.50(s,1H,Ph-OH),7.16(s,1H,quinazolinone-8-H),7.23(s,2H,ArH),7.25(s,2H,ArH),7.59(s,1H,quinazolinone-5-H)ppm;MS(EI,m/z):300[M]+.Anal.Calcd.for C16H13FN2O3:C,64.00;H,4.36;N,9.33.Found:C,63.93;H,4.43;N,9.05.
实施例55
2-甲基-3-(4-甲氧基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX057)的制备
具体操作同实施例30,投入7v(300mg,0.75mmol),得到XHX057 220mg(94%)。m.p.:231-233℃;IR(KBr):3432,1681(C=O),1610(C=N),1510,1408,1272,1253cm-1.1H NMR(300MHz,DMSO-d6),δ=2.07(s,3H,CH3),3.83(s,3H,OCH3),3.86(s,3H,OCH3),6.96(s,1H,quinazolinone-8-H),7.06-7.09(d,J=8.7Hz,2H,ArH),7.34(d,J=8.7Hz,2H,ArH),7.39(s,1H,quinazolinone-5-H),10.32(s,1H,Ph-OH)ppm;MS(EI,m/z):312[M]+.Anal.Calcd.for C17H16N2O4:C,65.38;H,5.16;N,8.97.Found:C,65.24;H,5.22;N,8.67.
实施例56
2-甲基-3-(4-羟基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX058)的制备
具体操作同实施例30,投入7w(200mg,0.51mmol),得到XHX058 72mg(47%)。m.p.:255-257℃;IR(KBr):3319,1648(C=O),1613(C=N),1511,1407,1287,1263,1240,1170,1024cm-1.1H NMR(300MHz,DMSO-d6),δ=2.06(s,3H,CH3),3.86(s,3H,OCH3),6.82-6.90(d,J=8.4Hz,2H,ArH),6.94(s,1H,quinazolinone-8-H),7.12-7.16(d,J=8.4Hz,2H,ArH),7.38(s,1H,quinazolinone-5-H),9.80(s,1H,Ph-OH),10.31(s,1H,Ph-OH)ppm;MS(EI,m/z):298[M]+.Anal.Calcd.for C16H14N2O4:C,64.42;H,4.73;N,9.39.Found:C,64.14;H,4.72;N,9.08.
实施例57
2-甲基-3-(2-甲氧基苯基)-6-甲氧基-7-羟基-4(3H)-喹唑啉酮(XHX059)的制备
具体操作同实施例30,投入7x(250mg,0.62mmol),得到XHX059 175mg(90%)。m.p.:255-256℃;IR(KBr):2942,1681(C=O),1609(C=N),1518,1498,1455,1416,1388,1271,1030,756cm-1.1H NMR(300MHz,CDCl3),δ=2.20(s,3H,CH3),3.80(s,3H,OCH3),3.99(s,3H,OCH3),6.65(s,1H,Ph-OH),7.00-7.15(m,2H,ArH),7.20(s,1H,quinazolinone-8-H),7.21-7.25(m,1H,ArH),7.41-7.50(t,J1=7.5Hz,J2=7.1Hz 1H,ArH),7.62(s,1H,quinazolinone-5-H)ppm; MS(EI,m/z):312[M]+.Anal.Calcd.for C17H16N2O4:C,65.38;H,5.16;N,8.97.Found:C,65.05;H,5.04;N,9.06.
实施例58
取实施例30中所得化合物0.5g,淀粉2g,糊精1g混合,用适量30%乙醇作为润湿剂,制粒,压片。
Claims (10)
2.权利要求1的化合物或其药学上可接受的盐,其中R1、R2、R3各自独立表示H、甲基、乙基、丙基、异丙基。
3.权利要求1的化合物或其药学上可接受的盐,其中R4、R5各自独立地代表H、CH3、CH2CH3、OCH3、OCH2CH3、COCH3、COOH、COOCH3、CH(OH)CH3、CF3或卤素。
4.权利要求1的化合物或其药学上可接受的盐,其中n代表4的自然数。
5.权利要求2的化合物或其药学上可接受的盐,其中R1、R2、R3各自独立表示H、甲基。
6.权利要求3的化合物或其药学上可接受的盐,其中R4R5各自独立地代表H、CH3、OCH3、COCH3、COOH、COOCH3、CH(OH)CH3、CF3、Cl或F。
8.权利要求1的化合物或其药学上可接受的盐,其中药学上可接受的盐是盐酸盐、硫酸盐、磷酸盐、乙酸盐和马来酸盐等。
9.血管抑制剂的药物组合物,其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
10.权利要求1至6中任一项的化合物用于制备预防或治疗肿瘤、视网膜病变、风湿性关节炎、糖尿病、红斑狼疮、慢性炎症的用途。
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JPH10259176A (ja) * | 1997-03-17 | 1998-09-29 | Japan Tobacco Inc | 血管新生阻害作用を有する新規アミド誘導体及びその用途 |
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US11234982B2 (en) | 2019-02-15 | 2022-02-01 | Novartis Ag | Methods for treating ocular surface pain |
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