CN115260164B - 新型4(3h)-喹唑啉酮类似物的制备方法、结构组成及其在抗肿瘤药物中的应用 - Google Patents
新型4(3h)-喹唑啉酮类似物的制备方法、结构组成及其在抗肿瘤药物中的应用 Download PDFInfo
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- CN115260164B CN115260164B CN202110486210.6A CN202110486210A CN115260164B CN 115260164 B CN115260164 B CN 115260164B CN 202110486210 A CN202110486210 A CN 202110486210A CN 115260164 B CN115260164 B CN 115260164B
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Abstract
本发明属于生物医药技术领域。报道了新型4(3H)‑喹唑啉酮类似物的结构组成与表征、化学合成方法及其在抗肿瘤药物方面的应用。这些新颖化合物具有显著地抗肿瘤药效,具有抗肿瘤药物应用前景。
Description
技术领域
本发明属于生物医药技术领域,涉及一类4(3H)-喹唑啉酮类似物及其合成方法和在抗肿瘤药物中的应用,包括其在自身免疫疾病、过敏、炎症、骨疾病、糖尿病、骨矿化和软组织钙化疾病、病毒、焦磷酸钙双水化合物沉积症、恶性肿瘤等药物中的广阔应用。
背景技术
美国的癌症协会最新的统计显示,在男性患者中,肺癌、前列腺癌、结直肠癌、膀胱癌以及肝癌成为死亡率最高的肿瘤疾病;而在女性患者中,肺癌、乳腺癌、结直肠癌、胰腺癌和宫颈癌成为死亡率最高的肿瘤疾病。因此寻找能够治愈肿瘤的方法成为了全球科学家竞共同追求的目标。
喹唑啉酮类化合物是一类具有广泛药理活性的含氮杂环化合物。我们报道了新型结构的4(3H)-喹唑啉酮类似物,研究了该类化合物的结构组成、合成与表征方法、及其在抗肿瘤药物方面的应用。该类化合物的研究将为抗肿瘤药物开发提供创新思路和理论依据。
发明内容
本发明提供了一类结构新颖的4(3H)-喹唑啉酮类似物的结构组成、合成方法及其在抗肿瘤等疾病药物中的应用。
1、本发明提供了如结构式1所示的一类4(3H)-喹唑啉酮类似物
其中Z1为
Z2为或者=N-
Z3为
Ra,Rb,Rc,Rd,Re,Rf,Rg,Rh,Ri,Rj可以分别为以下基团的其中一个: -H,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-Rk和-L1-Rl;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Ro基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rp基团取代;Rk可以为以下基团的其中一个:-CN,-NO2, -OH,-SH,-NH2,-C(=W)-WH,-C(=WH)-NH2,-C(=W)-NH-WH,-C=N-OH,-C(=NH)-NH2,-W -C(=W)-WH,-W-C(=W)-NH2,-S(=O)2-NH2,-S(=O)2-NH-W-,-NH-NH2,-NH-WH,NH-C(=W )-NH2,-NH-S(=O)2-NH2,和-NH-C(=NH)-NH2;
L1可以为以下基团的其中一个:-O-, -S-,-S(=O)-,-S(=O)2-,-C(=W)-,-C(=W)-W-,-C(=W)-NRm-,-C(=W)-NRm-W-,-C=N- O-,-C(=NRm)NRm-,-C(NRmRm)=N-,-W-C(=W)-,-W-C(=W)-W-,-W-C(=W)-NRm-, -S(=O)2-NRm-,-S(=O)2-NRm-W-,-NRm-,-N=CRn-,-NRm-W,-NRm-NRm-,-NRm-C(=NRm)NRm-, -NRm-C(NRmRm)=N-,-NRm-C(=W)-,-NRm-C(=W)-W-,-NRm-C(=W)-NRm-,-NRm-S(=O)2-NRm-和-NRm-S(=O)2-;
Rl可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;同时如果L1是-NH-,Rl可以是N的保护基;
Rm可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Ro基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rp基团取代;
Rn可以为以下基团的其中一个:-H,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;
Ro如果取代在碳原子上,可以是下面基团的其中一个:=O,卤素,碳环基,杂环基,芳基,杂芳基,Rk和L2-Rq;Ro如果取代在氮原子上,可以是下面基团的其中一个:碳环基,杂环基,芳基,杂芳基,Rs和L3-Rr;同时碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rp基团取代;
Rp如果取代在碳原子上,可以是下面基团的其中一个:=O,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-Rk和-L2-Rq;Ri如果取代在氮原子上,可以是下面基团的其中一个:烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-Rs和-L3-Rr;
Rq和Rr可以分别为以下基团的其中一个:烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以分别被一个或者多个Rv基团取代;碳环基,杂环基,可以分别被一个或者多个Rw基团取代;而芳基,杂芳基可以分别被一个或者多个Rx基团取代;
Rs可以为以下基团的其中一个: -OH,-SH,-NH2,-C(=W)-WH,-C(=W)-NH2,-C(=WH)-NH2,和-S(=O2)-NH2;
L2可以为以下基团的其中一个:-O-, -S-,-S(=O)2-,-C(=W)-,-C(=W)-W-,-C(=W)-NRt-,-C(=W)-NRt-W-,-C=N-O-,-C(=N Rt)NRt-,-C(NRtRt)=N-,-W-C(=W)-,-W-C(=W)-W-,-W-C(=W)-NRt-,-S(=O)2-NRt-, -S(=O)2-NRt-W-,-NRt-,-N=CRu-,-NRt-W,-NRt-NRt-,-NRt-C(=NRt)NRt-, -NRt-C(NRtRt)=N-,-NRt-C(=W)-,-NRt-C(=W)-W-,-NRt-C(=W)-NRt-,-NRt-S(=O)2-NRt-和-NRt-S(=O)2-;
L3可以为以下基团的其中一个:-O-,-S-,-NRt-,-C(=W)-,-C(=W)-W-, -C(=W)-NRt-,-C(=NRt)NRt-,-C(NRtRt)=N-,-S(=O)2-NRt-,和-S(=O)2-;
Rt可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以分别被一个或者多个 Rv基团取代;碳环基,杂环基,可以分别被一个或者多个Rw基团取代;而芳基,杂芳基可以分别被一个或者多个Rx基团取代;
Ru可以为以下基团的其中一个:-H,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以分别被一个或者多个Rv基团取代;碳环基,杂环基,可以分别被一个或者多个Rw基团取代;而芳基,杂芳基可以分别被一个或者多个Rx基团取代;
Rv可以为以下基团的其中一个:=O,-OH,-SH,-NH2,-CN,C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺,C1-6烷基二胺,N连接的杂环烷基,其中C1-6烷基和C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺和C1-6烷基二胺可以被-OH,-SH,NH2,卤素,C1-6烷氧基,C1-6卤代的烷氧基, C1-6含硫烷基,C1-6卤代的含硫烷基,C1-6含亚砜烷基,C1-6卤代的含亚砜烷基,C1-6含砜烷基,C1-6卤代的含砜烷基,C1-6烷基胺,C1-6烷基二胺和N连接的杂环烷基这些基团一个或者多个进行取代;
Rw可以为以下基团的其中一个:=O,-OH,-SH,-NH2,-CN,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺,C1-6烷基二胺,N连接的杂环烷基,其中C1-6烷基,C2-6烯基,C2-6炔基和C1-6烷氧基, C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺和C1-6烷基二胺可以被 -OH,-SH,NH2,卤素,C1-6烷氧基,C1-6卤代的烷氧基,C1-6含硫烷基,C1-6卤代的含硫烷基,C1-6含亚砜烷基,C1-6卤代的含亚砜烷基,C1-6含砜烷基,C1-6卤代的含砜烷基,C1-6烷基胺,C1-6烷基二胺和N连接的杂环烷基这些基团一个或者多个进行取代;
Rx可以为以下基团的其中一个:卤素,-OH,-SH,-NH2,-CN,-NO2,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺, C1-6烷基二胺,N连接的杂环烷基,其中C1-6烷基,C2-6烯基,C2-6炔基和C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺和C1-6烷基二胺可以被-OH,-SH,NH2,卤素,C1-6烷氧基,C1-6卤代的烷氧基,C1-6含硫烷基,C1-6卤代的含硫烷基,C1-6含亚砜烷基,C1-6卤代的含亚砜烷基,C1-6含砜烷基,C1-6卤代的含砜烷基,C1-6烷基胺,C1-6烷基二胺和N连接的杂环烷基这些基团一个或者多个进行取代;
2、本发明提供了4(3H)-喹唑啉酮衍生物或该类类似物在药学可以接受的盐,其特征在于,所述的4(3H)-喹唑啉酮类似物与酸形成的酸加盐。其中,所述酸包括盐酸、硫酸、氢溴酸、硫酸、磷酸、乙酸、酒石酸、水杨酸、柠檬酸、苹果酸、甲磺酸、对甲苯磺酸、乳酸、丙酮酸、马来酸、琥珀酸。
3、本发明提供了4(3H)-喹唑啉酮类似物或该类衍生物在药学可以接受的盐,其特征在于,所述的4(3H)-喹唑啉酮类似物与碱形成的碱加盐。其中,所述无机碱衍生的盐包括铝、铵、钾、钠、铁、铜、钙、亚铁、酶、锂、锰;从有机无毒碱衍生物的盐包括一级、二级和三级胺盐、取代胺包括天然取代胺、环胺、乙醇胺、N-乙基吗啉、N-乙基哌啶、葡萄胺。
4、本发明提供了一种药物组合物,其特征在于,含有权利1所述的4(3H)-喹唑啉酮类似物或其在药学可以接受的盐,以及其在药学上可接受的载体;所述药物组合物被配置成可注射流体、气雾剂、乳膏、凝胶剂、丸剂、胶囊剂、糖浆剂。
5、本发明提供了4(3H)-喹唑啉酮类似物或其在药学可以接受的盐或其在药学上可接受的制剂载体在自身免疫疾病、过敏、炎症、骨疾病、糖尿病、骨矿化和软组织钙化疾病、病毒、焦磷酸钙双水化合物沉积症、恶性肿瘤(肝癌、肺癌、前列腺癌、皮肤癌、结肠癌、胰腺癌、乳腺癌、白血病、淋巴癌、卵巢癌、胃癌、膀胱癌、肾癌、口腔癌、黑色素癌、食道癌、宫颈癌等)药物中应用。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中,以下所述的实施例是为了更好地阐述本发明,并不是用来限制本发明的范围。
实施例1:4(3H)-喹唑啉酮类似物的制备方法设计
1、中间体1-4的制备
中间体1-4的制备流程如下式所示:
试剂与条件:(a)Fe,NH4Cl,EtOH,H2O,80℃,20min(b)Et3N,acetone,rt,overnight(c)CS2CO3,EtOH,H2O,50℃,2h
中间体4的合成路线如下所述:起始原料4,5-二甲氧基-2-硝基苯甲酰胺(化合物1)中的硝基在铁粉的作用下被还原成氨基,生成化合物2;化合物2与酰氯反生取代反应形成酰胺键,得到化合物3;化合物3在碳酸铯的作用下,关环生成喹唑啉酮,即中间体4。
2、中间体6a-6e的制备方法如下式所示:
中间体6a-6e的制备。试剂与条件:(a)EtOH,97℃,18h(b)EtOH,H2O,100℃,overnight(c)NMP,150℃,overnight
中间体6a-6e的合成路线:此反应为关环反应,如果生成的中间体为吡啶并噁唑,反应条件为a条件;如果生成的中间体为吡啶并咪唑,反应条件为b条件[1];如果生成的中间体为吡啶并噻唑,反应条件为c条件。
3、中间体8a-8u的制备,如下式所示:
中间体8a-8u的制备。试剂与条件:(a)4M HCl/1,4-Dioxane,97℃,overnight 原料7a-7v与氯乙酰氯反应生成中间体喹唑啉酮8a-8v,该中间体是合成目标产物的一个片段。
4、终产物9-64的制备方法如下式所示:
终产物9-64的制备。试剂与条件:(a)NaOH,MeOH,rt,overnight。终产物9-64的合成路线:利用两个中间体片段,在氢氧化钠的作用下常温搅拌过夜,发生取代反应,得到最终的产物9-64。
实施例2:4(3H)-喹唑啉酮类似物制备方法具体实施例
1、2-氨基-4,5-二甲氧基苯甲酰胺(化合物2)
将4,5-二甲氧基-2-硝基-苯甲酰胺(226mg,1mmol)和氯化铵(160mg,3mmol) 加入到乙醇(10mL)和水(2mL)中,加热到80℃,然后向反应体系加入铁粉(280mg,5mmol),反应20min,TLC检测反应完全,趁热利用硅藻土进行抽滤,悬干滤液,得到产物和氯化铵,此时加入一定量的丙酮进行溶解产物,然后抽滤,除去氯化铵,将滤液悬干,得到中间体2为黄色固体180mg(92%)。1H NMR (400MHz,DMSO)δ7.63(s,1H),7.13(s,1H),6.80(s,1H),6.46(s,2H),6.29(s,1H),3.70(s,3H),3.66(s,3H).13C NMR(101MHz,DMSO)δ171.32, 153.34,147.22,139.28,113.36,104.62,100.10,56.98,55.48.
2、2-(2-氯乙烷酰氨基)-4,5-二甲氧基苯甲酰胺(化合物3)
将2-氨基-4,5-二甲氧基-苯甲酰胺(2)(196mg,1mmol)和三乙胺(280μL, 2mmol)加入到丙酮中(10mL),在冰域下,逐滴的加入氯乙酰氯(160μL, 2mmol),滴加完以后常温下搅拌过夜。向反应液中加入1mL乙醇除去剩余的氯乙酰氯,悬干溶剂,得到褐色油状物,向混合物加入一定量的饱和硫酸氢钠溶液来除去三乙胺,然后用10mL的二氯甲烷进行萃取(3次),并用饱和氯化钠溶液对有机相进行洗涤,洗涤的有机相再用无水硫酸镁进行干燥,抽滤,悬干滤液溶剂,得到亮黄色固体3(220mg,81%)1H NMR(400MHz,DMSO)δ12.68(s, 1H),8.26(s,1H),8.21(s,1H),7.60(s,1H),7.37(s,1H),4.36(s,2H),3.79(s,3H),3.77(s,3H).13C NMR(101MHz,DMSO)δ170.72,165.17,151.76, 144.28,134.74,111.99,111.52,103.95,56.33,55.88,43.93.
3、2-(氯甲基)-6,7-二甲氧基喹唑啉-4(3H)-酮(化合物4)
将2-(2-氯乙烷酰氨基)-4,5-二甲氧基苯甲酰胺(3)(82mg,0.3mmol)和碳酸铯(196mg,0.6mmol)加入到乙醇(10mL)和水(2mL)中,在50℃下搅拌2个小时,在冰域下缓慢地滴加浓盐酸,调节PH至3-4之间,继续搅拌半个小时,然后减压悬去溶剂,得到固体混合物,并向其加入20mL的饱和碳酸氢钠溶液,抽滤,得到白色固体4(62mg,82%)。1H NMR(400MHz,DMSO)δ12.44 (s,1H),7.45(s,1H),7.17(s,1H),4.53(s,2H),3.90(d,J=11.1Hz, 6H).13CNMR(101MHz,DMSO)δ161.31,155.14,151.12,149.44,144.75, 114.77,108.64,105.45,56.48,56.22,43.79.
4、恶唑并[4,5-B]吡啶-2(3H)硫酮(6a)
将2-氨基-3-羟基吡啶(5a)(440mg,4mmol)和乙基黄原酸钾(1.28g,8mmol) 加入到乙醇(15mL),反应温度为97℃,搅拌18个小时。将反应液降到室温,悬干溶剂,加入10mL的水进行溶解,然后用醋酸调节PH到5,有黄色固体析出,于是抽滤,并用一定量的水进行洗涤,得到黄棕色固体6a(550mg,90%)。1H NMR(400MHz,DMSO)δ8.21(d,J=4.9Hz,1H),7.86(d,J=8.0Hz, 1H),7.35–7.10(m,1H).13C NMR(101MHz,DMSO)δ181.83,147.52,144.64,142.08,119.56,117.48.
5、6-氯-3H-恶唑并[4,5-B]吡啶-2-硫酮(6b)
将3-氨基-2-羟基-5-氯吡啶(5b)(290mg,2mmol)和乙基黄原酸钾(641mg, 4mmol)加入到乙醇(10mL),反应温度为97℃,搅拌18个小时。将反应液降到室温,悬干溶剂,加入10mL的水进行溶解,然后用醋酸调节PH到5,有黄色固体析出,于是抽滤,并用一定量的水进行洗涤,得到黄棕色固体6b(320mg, 86%)。1H NMR(400MHz,DMSO)δ14.57(s,1H),8.29(s,1H),8.16(s,1H).13C NMR(101MHz,DMSO)δ181.90,146.48,143.31,142.12,126.30,117.87.
6、1H-咪唑并[4,5-B]吡啶-2(3H)-硫酮(6c)
将2,3-二氨基吡啶(5c)(250mg,2.3mmol)和乙基黄原酸钾(553mg,3.45 mmol)加入到乙醇(5mL)和水(1mL)中,反应温度为100℃,搅拌过夜。将反应液降到室温,静置2个小时,有固体析出,于是抽滤,得到针状的褐色固体 6c(100mg,29%)。1H NMR(400MHz,DMSO)δ12.92(s,2H),8.08(dd,J =5.0,1.3Hz,1H),7.54–7.28(m,1H),7.11(dd,J=7.9,5.1Hz,1H).13C NMR(101MHz,DMSO)δ170.26,146.88,142.72,125.88,118.52,116.62.
7、噻唑并[4,5-B]吡啶-2(3H)-硫酮(6d)
将3-氯-2-氨基吡啶(5d)(510mg,4mmol)和乙基黄原酸钾(954mg,6mmol) 加入到NMP(7mL)中,反应温度为150℃,搅拌过夜。反应液降到室温,并向反应液中加入1mL乙酸和150mL的水,有大量固体析出,于是抽滤,1:1的水醇混合物,乙醚依次进行洗涤,得到黄棕色固体6d(598mg,90%)。1H NMR(400 MHz,DMSO)δ14.31(s,1H),8.37(d,J=4.7Hz,1H),8.14(d,J=7.9Hz,1H),7.35–7.27(m,1H).13C NMR(101MHz,DMSO)δ191.46,154.18, 147.26,130.98,124.62,120.04.
8、6-氯噻唑并[4,5-B]吡啶-2(3H)-硫酮(6e)
将2-氨基3,5-二氯甲基吡啶(5e)(647mg,4mmol)和乙基黄原酸钾(954mg, 6mmol)加入到NMP(7mL)中,反应温度为150℃,搅拌过夜。反应液降到室温,并向反应液中加入1mL乙酸和150mL的水,有大量固体析出,于是抽滤,1:1的水醇混合物,乙醚依次进行洗涤,得到黄棕色固体6e(703mg,87%)。1H NMR(400MHz,DMSO)δ8.40(d,J=2.3Hz,1H),8.29(d,J=2.3Hz,1H).13C NMR(101MHz,DMSO)δ191.76,152.99,145.68,130.31,126.71,126.03.
9、2-(氯甲基)喹唑啉-4(3H)-酮(8a)
将邻氨基苯甲酸甲酯(7a)(302mg,2mmol)和氯乙腈(127μL,2mmol)加入到4M HCl/二氧六环(5mL)中,反应温度为97℃,反应过夜。后处理反应,将反应液降到室温,然后在冰浴情况下缓慢加20mL的饱和碳酸氢钠溶液析出固体,抽滤,并分别用水,乙醇,乙醚依次洗涤滤饼,得到棕色固体8a(263mg, 66%)。1H NMR(400MHz,DMSO)δ12.58(s,1H),8.13(d,J=7.8Hz,1H), 7.84(t,J=7.6Hz,1H),7.69(d,J=8.1Hz,1H),7.56(t,J=7.5Hz, 1H),4.56(s,2H).13C NMR(101MHz,DMSO)δ161.98,152.81,148.72,135.11, 127.73,126.34,121.74,43.72.
10、中间体8b-8u的制备过程如表1所示
表1.中间体8b-8u的制备过程
11、化合物2-[((1-氢-苯并咪唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物9)
将2-巯基苯并咪唑(75mg,0.5mmol)、化合物4(127mg,0.5mmol)和氢氧化钠(100mg,2.5mmol)溶解在甲醇中(7mL),常温搅拌过夜。后处理反应,减压除去有机溶剂甲醇得到粗品,粗品利用300-400目的硅胶柱进行纯化,得到终产物白色固体9(150mg,81%)。1HNMR(400MHz,DMSO)δ12.75(s,1H), 12.48(s,1H),7.53(s,1H),7.41(s,2H),7.15(d,J=3.0Hz,1H),7.13 (d,J=3.0Hz,1H),7.06(s,1H),4.51(s,2H),3.87(s,3H),3.85(s,3H).13CNMR(101MHz,DMSO)δ161.16,155.03,152.24,150.01,148.97, 144.87,143.71,135.86,122.42,121.87,117.82,114.43,111.03,108.30,105.38,56.37,56.12,35.01.ESI-MS m/zcalcd for C18H16N4O3S+369.1016, found 369.1019[M+H]+.
12、2-[((苯并恶唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物10)
将2-巯基苯并咪唑换成2-巯基苯并恶唑,按制备化合物9的方法制备。1H NMR(400MHz,DMSO)δ12.39(s,1H),7.64(dd,J=8.8,5.5Hz,2H),7.40(s,1H),7.32(p,J=7.1Hz,2H),7.05(s,1H),4.63(s,2H),3.87(s, 3H),3.85(s,3H).13C NMR(101MHz,DMSO)δ164.01,161.10,155.05,151.77, 150.78,149.00,144.69,141.61,125.13,124.87,118.77,114.38,110.71,108.28,105.39,56.40,56.11,35.12.ESI-MS m/z calcd forC18H15N3O4S+370.0856,found 370.0832[M+H]+.
13、2-[((苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物11)
将2-巯基苯并咪唑换成2-巯基苯并噻唑,按制备化合物9的方法制备。1H NMR(400MHz,DMSO)δ12.43(s,1H),8.04(d,J=8.0Hz,1H),7.87(d,J =8.0Hz,1H),7.48(t,J=7.6Hz,1H),7.43(s,1H),7.38(t,J=7.5Hz,1H),7.09(s,1H),4.66(s,2H),3.89(s,3H),3.87(s,3H).13C NMR (101MHz,DMSO)δ166.23,161.19,155.12,153.00,151.21,149.07,144.86,135.34,126.94,125.12,122.40,121.68,114.49,108.40,105.51,56.46, 56.20,36.20.ESI-MS m/z calcd for C18H15N3O3S2+386.0628,found 386.0606 [M+H]+.
14、2-[(6-甲氧基-(苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)- 酮的制备(化合物12)
将2-巯基苯并咪唑换成6-甲氧基-2-巯基苯并噻唑,按制备化合物9的方法制备。1H NMR(400MHz,CDCl3)δ11.77(s,1H),7.97(d,J=8.9Hz,1H),7.62 (s,1H),7.29(s,1H),7.27(s,1H),7.13(s,1H),7.11(s,1H),4.46(s, 2H),4.02(s,6H),3.90(s,3H).13C NMR(101MHz,CDCl3)δ163.87,161.23, 157.76,155.10,151.91,149.35,146.60,144.58,136.86,122.30,115.56,115.00,107.76,105.72,104.33,56.37,56.30,55.89,36.92.ESI-MS m/z calcd for C19H17N3O4S2+416.0733,found 416.0718[M+H]+.
15、2-[(5-甲基-(1-氢-苯并咪唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉 -4(3H)-酮的制备(化合物13)
将2-巯基苯并咪唑换成2-巯基苯并咪唑,按制备化合物9的方法制备。1H NMR(400MHz,DMSO)δ12.56(s,2H),7.41(s,1H),7.35(d,J=7.2Hz,1H), 7.25(s,1H),7.06(s,1H),6.96(d,J=8.2Hz,1H),4.48(s,2H),3.87(s,3H),3.85(s,3H),2.38(s,3H).13C NMR(101MHz,DMSO)δ161.17, 155.02,151.25,149.10,148.59,144.38,135.08,134.75,133.19,126.33,114.43,113.81,113.51,107.95,105.41,56.32,56.16,35.95,21.54.ESI-MS m/z calcd for C19H18N4O3S+383.1172,found 383.1175[M+H]+.
16、2-[(6-二氟甲氧基-(1-氢-苯并咪唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物14)
将2-巯基苯并咪唑换成6-二氟甲氧基-2-巯基苯并咪唑,按制备化合物9的方法制备。1H NMR(400MHz,DMSO)δ12.66(s,2H),7.48(d,J=8.6Hz,1H), 7.41(s,1H),7.28(s,1H),7.17(s,1H),7.06(s,1H),6.99(dd,J=6.5,1.6Hz,1H),4.51(s,2H),3.87(s,3H),3.85(s,3H).13C NMR(101MHz, DMSO)δ161.18,155.01,152.05,151.55,148.95,146.50,144.83,119.90,117.34,114.79,114.46,114.41,108.27,105.36,56.37,56.11,34.98. ESI-MS m/z calcd for C19H16F2N4O4S+435.0933,found 435.0934[M+H]+.
17、2-[(5-氯-(苯并恶唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备。(化合物15)
将2-巯基苯并咪唑换成5-氯2-巯基苯并恶唑,按制备化合物9的方法制备。1H NMR(400MHz,CDCl3)δ11.20(s,1H),7.77(s,1H),7.60(s,1H),7.42 (d,J=8.6Hz,1H),7.31(d,J=8.8Hz,1H),7.16(s,1H),4.49(s,2H), 4.02(s,3H),4.01(s,3H).13C NMR(101MHz,DMSO)δ166.10,161.07,155.07, 150.57,149.02,144.64,142.91,129.43,124.81,118.56,114.39,112.01,108.28,105.41,56.42,56.13,35.18.ESI-MS m/z calcd forC18H14ClN3O4S+404.0466,found 404.0470[M+H]+.
18、2-[((恶唑并[4,5-B]吡啶)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)- 酮的制备。(化合物16)
将2-巯基苯并咪唑换成6a,按制备化合物9的方法制备。1H NMR(400MHz,DMSO) δ12.45(s,1H),8.43(d,J=4.3Hz,1H),8.10(d,J=8.0Hz,1H),7.42(s,1H),7.36(dd,J=7.7,5.1Hz,1H),7.08(s,1H),4.69(s,2H),3.88 (s,3H),3.86(s,3H).13C NMR(101MHz,DMSO)δ168.48,161.09,155.57, 155.09,150.64,149.03,146.33,144.68,144.17,120.19,118.64,114.41,108.30,105.43,56.44,56.14,35.16.ESI-MS m/z calcd forC17H14N4O4S+371.0809,found 371.0808[M+H]+.
19、2-[(6-氟-(苯并恶唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物17)
将2-巯基苯并咪唑换成5-氟-2-巯基苯并恶唑,按制备化合物9的方法制备。1HNMR(400MHz,DMSO)δ12.42(s,1H),7.70(dd,J=8.8,4.3Hz,1H),7.55(dd,J=8.6,2.1Hz,1H),7.42(s,1H),7.18(ddd,J=14.5,10.9,2.2 Hz,1H),7.07(s,1H),4.65(s,2H),3.89(s,3H),3.87(s,3H).13C NMR (101MHz,DMSO)δ166.30,161.12,158.76,155.10,150.65,149.05,148.34,144.69,142.64,142.50,114.42,112.20,111.94,111.52,111.42,108.32,105.70,105.43,56.45,56.16,35.19.ESI-MS m/z calcd for C18H14FN3O4S+388.0762,found 388.0750[M+H]+.
20、2-[(5-氯-(苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物18)
将2-巯基苯并咪唑换成5-氯-2-巯基苯并噻唑,按制备化合物9的方法制备。1HNMR(400MHz,DMSO)δ12.44(s,1H),8.08(d,J=8.5Hz,1H),7.93(s,1H),7.44(d,J=7.1Hz,2H),7.09(s,1H),4.66(s,2H),3.90(s,3H), 3.87(s,3H).13C NMR(101MHz,DMSO)δ161.17,155.14,153.90,151.01, 149.10,144.82,134.13,131.74,125.10,123.86,121.10,114.50,108.40,105.52,56.47,56.21,36.23.ESI-MS m/z calcd for C18H14ClN3O3S2+420.0238, found 420.0236[M+H]+.
将2-巯基苯并咪唑换成6-乙氧基-2-巯基苯并咪唑,按制备化合物9的方法制备。1H NMR(400MHz,DMSO)12.26(s,2H),δ7.40(s,1H),7.27(d,J=8.5 Hz,1H),7.05(s,1H),6.93(s,1H),6.63(d,J=8.6Hz,1H),4.22(s,2H),4.01(q,J=6.5Hz,2H),3.88(s,3H),3.85(s,3H),1.34(t,J= 6.8Hz,3H).13C NMR(101MHz,DMSO)δ165.89,159.56,154.91,154.00,153.43,147.85,146.27,144.31,138.98,115.12,114.81,109.06,107.48,105.70,99.12,63.87,56.13,56.02,37.65,15.44.ESI-MS m/z calcd for C20H20N4O4S+413.1278,found413.1272[M+H]+.
21、2-[(6-氯-(恶唑并[4,5-B]吡啶)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉 -4(3H)-酮的制备(化合物20)
将2-巯基苯并咪唑换成6b,按制备化合物9的方法制备。1H NMR(400MHz,DMSO) δ12.44(s,1H),8.49(s,1H),8.41(s,1H),7.42(s,1H),7.07(s,1H),4.69(s,2H),3.88(s,3H),3.85(s,3H).13C NMR(101MHz,DMSO)δ169.80, 161.05,155.08,154.46,150.44,149.04,144.87,144.62,144.17,126.74,119.12,114.40,108.29,105.42,56.44,56.14,35.30.ESI-MS m/z calcd for C17H13ClN4O4S+405.0419,found 405.0401[M+H]+.
22、2-[((咪唑并[4,5-B]吡啶)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉 -4(3H)-酮的制备(化合物21)
将2-巯基苯并咪唑换成6c,按制备化合物9的方法制备。1H NMR(400MHz,DMSO) δ13.05(s,1H),12.49(s,1H),8.24(s,1H),7.87(d,J=7.1Hz,1H),7.43(s,1H),7.18(s,1H),7.08(s,1H),4.58(s,2H),3.89(s,3H),3.87 (s,3H).13C NMR(101MHz,DMSO)δ161.20,155.10,153.15,151.96,149.03, 144.90,143.16,142.77,118.55,118.02,116.65,114.48,108.36,105.49,56.43,56.19,34.56.ESI-MS m/z calcd for C17H15N5O3S+370.0968,found 370.0954[M+H]+.
23、2-[((噻唑并[4,5-B]吡啶)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉 -4(3H)-酮的制备(化合物22)
将2-巯基苯并咪唑换成6d,按制备化合物9的方法制备。1H NMR(400MHz,DMSO) δ12.41(s,1H),8.57(d,J=4.3Hz,1H),8.49(d,J=7.9Hz,1H),7.42(s,1H),7.37(dd,J=7.4,5.0Hz,1H),7.07(s,1H),4.69(s,2H),3.88 (s,3H),3.85(s,3H).13C NMR(101MHz,DMSO)δ171.32,163.50,161.14, 155.06,150.91,149.02,148.12,144.76,131.72,129.04,119.94,114.42,108.31,105.42,56.41,56.13,35.92.ESI-MS m/z calcd forC17H14N4O3S2+387.0580,found 387.0574[M+H]+.
24、2-[(6-氯-(噻唑并[4,5-B]吡啶)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉 -4(3H)-酮的制备(化合物23)
将2-巯基苯并咪唑换成6e,按制备化合物9的方法制备。1H NMR(400MHz,DMSO) δ12.43(s,1H),8.67(d,J=2.2Hz,1H),8.59(d,J=2.2Hz,1H),7.41(s,1H),7.07(s,1H),4.70(s,2H),3.89(s,3H),3.87(s,3H).13C NMR (101MHz,DMSO)δ172.83,162.08,161.15,155.07,150.76,149.04,146.68,144.73,131.08,130.30,126.62,114.45,108.29,105.43,56.43,56.15, 36.09.ESI-MS m/z calcd for C17H13ClN4O3S2+421.0190,found421.0188[M +H]+.
25、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物24)
将2-巯基苯并咪唑换成5-甲氧基-2-巯基咪唑并[4,5-b]吡啶,按制备化合物9 的方法制备。1H NMR(400MHz,DMSO)δ13.08(s,2H),7.80(d,J=8.5Hz, 1H),7.43(s,1H),7.07(s,1H),6.62(d,J=8.6Hz,1H),4.49(s,2H),3.89(s,3H),3.87(s,3H),3.86(s,3H).13C NMR(101MHz,DMSO)δ161.25, 160.49,155.08,152.31,150.31,149.62,149.01,144.93,127.59,125.67,114.49,108.35,105.49,105.15,56.42,56.19,53.70,35.03.ESI-MS m/zcalcd for C18H17N5O4S+400.1074,found 400.1053[M+H]+.
26、2-[(5-氯-(1-氢-苯并咪唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物25)
将2-巯基苯并咪唑换成5-氯-2-巯基苯并咪唑,按制备化合物9的方法制备。1HNMR(400MHz,CDCl3)δ8.40–8.22(m,1H),7.85(s,1H),7.35(d,J =9.5Hz,1H),7.22(t,J=8.5Hz,1H),6.70(d,J=8.6Hz,1H),4.38(s,2H),3.89(s,3H),3.87(s,3H).13C NMR(101MHz,DMSO)δ160.50, 155.44,152.86,151.09,150.46,149.61,141.19,135.60,133.59,129.61,125.45,115.59,114.01,105.99,105.77,56.49,56.32,34.95.ESI-MS m/z calcd forC18H15ClN4O3S+403.0626,found 403.0629[M+H]+.
27、2-[(5,6-二氯-(1-氢-苯并咪唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉 -4(3H)-酮的制备(化合物26)
将2-巯基苯并咪唑换成5,6-二氯-2-巯基苯并咪唑,按制备化合物9的方法制备。1H NMR(400MHz,DMSO)δ12.35(s,2H),7.74(s,2H),7.42(s,1H),7.06 (s,1H),4.55(s,2H),3.89(s,3H),3.86(s,3H).13C NMR(101MHz,DMSO) δ160.06,155.66,154.51,152.26,149.82,139.44,137.31,126.04,115.79, 113.79,105.92,104.96,56.61,56.38,33.76.ESI-MS m/z calcd for C18H14Cl2N4O3S+437.0236,found 437.0243[M+H]+.
28、2-[(6-乙氧基-(苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)- 酮的制备(化合物27)
将2-巯基苯并咪唑换成6-乙氧基-2-巯基苯并噻唑,按制备化合物9的方法制备。1H NMR(400MHz,DMSO)δ12.35(s,1H),7.74(d,J=8.9Hz,1H),7.60 (s,1H),7.42(s,1H),7.08(s,1H),7.05(d,J=8.9Hz,1H),4.57(s,2H),4.06(d,J=6.9Hz,2H),3.89(s,3H),3.86(s,3H),1.34(t,J= 6.9Hz,3H).13C NMR(101MHz,DMSO)δ161.14,159.93,156.70,155.76,155.09,149.88,147.10,138.95,137.14,122.40,116.22,113.66,105.96,104.61,64.21,56.68,56.41,34.70,14.98.ESI-MS m/z calcd for C19H17N3O4S2+430.0890,found430.0875[M+H]+.
29、2-[(6-溴-(苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物28)
将2-巯基苯并咪唑换成6-溴-2-巯基苯并噻唑,按制备化合物9的方法制备。1HNMR(400MHz,CDCl3)δ11.44(s,1H),7.98–7.89(m,2H),7.62(d,J =8.7Hz,1H),7.59(s,1H),7.10(s,1H),4.47(s,2H),4.01(s,3H), 4.00(s,3H).13C NMR(101MHz,DMSO)δ166.52,160.13,155.69,154.36, 151.75,149.80,139.65,137.49,130.09,124.90,123.20,117.76,113.76,105.90,105.03,56.65,56.37,34.65.ESI-MS m/z calcd forC18H14BrN3O3S2+463.9733,found 463.9733[M+H]+.
30、2-[(6-氟-(苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物29)
将2-巯基苯并咪唑换成6-氟-2-巯基苯并噻唑,按制备化合物9的方法制备。1HNMR(400MHz,CDCl3)δ11.80(s,1H),8.02(dd,J=8.7,4.6Hz,1H), 7.60(s,1H),7.50(d,J=7.8Hz,1H),7.29(s,1H),7.18(s,1H),4.54(s,2H),4.02(s,3H),4.01(s,3H).13C NMR(101MHz,DMSO)δ164.98, 160.94,160.03,158.53,155.71,154.63,149.83,149.58,139.34,136.87,136.76,122.96,122.87,115.35,115.11,113.74,109.15,108.87,105.94,104.86,56.66,56.39,34.66.ESI-MS m/z calcd for C18H14FN3O3S2+404.0533, found404.0536[M+H]+.
31、2-[(5-甲氧基-(苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)- 酮的制备(化合物30)
将2-巯基苯并咪唑换成5-甲氧基-2-巯基苯并噻唑,按制备化合物9的方法制备。1H NMR(400MHz,DMSO)δ12.37(s,1H),7.87(s,1H),7.42(d,J=6.9 Hz,2H),7.09(s,1H),7.02(s,1H),4.61(s,2H),3.88(s,3H),3.87(s, 3H),3.83(s,3H).13C NMR(101MHz,DMSO)δ165.96,160.10,159.19,155.69, 154.48,154.03,149.81,139.60,127.14,122.74,114.55,113.78,107.87, 105.94,105.17,56.65,56.39,55.96,34.71.ESI-MS m/z calcdfor C19H17N3O4S2+416.0733,found 416.0735[M+H]+.
32、2-[(5-氟-(苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物31)
将2-巯基苯并咪唑换成5-氟-2-巯基苯并噻唑,按制备化合物9的方法制备。1HNMR(400MHz,CDCl3)δ11.45(s,1H),7.77(d,J=9.1Hz,1H),7.75– 7.69(m,1H),7.60(s,1H),7.17(s,1H),7.11(s,1H),4.49(s,2H),4.01 (s,3H),4.01–3.99(m,3H).13C NMR(101MHz,DMSO)δ167.60,162.88, 160.48,159.49,156.05,155.98,153.44,153.32,150.18,136.84,131.37,123.69,123.59,113.70,113.45,108.14,107.90,106.13,105.03,103.30, 56.71,56.42,33.76.ESI-MS m/z calcd for C18H14FN3O3S2+404.0533,found404.0526[M+H]+.
33、2-[(6-氯(苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物32)
将2-巯基苯并咪唑换成6-氯-2-巯基苯并噻唑,按制备化合物9的方法制备。1HNMR(400MHz,CDCl3)δ11.45(s,1H),7.97(d,J=8.7Hz,1H),7.77(s, 1H),7.59(s,1H),7.48(d,J=8.7Hz,1H),7.10(s,1H),4.47(s,2H), 4.01(s,3H),4.00(s,3H).13C NMR(101MHz,DMSO)δ166.49,160.07,155.67, 154.38,151.50,149.79,139.60,137.07,129.73,127.38,122.82,122.10,113.78,105.92,105.04,56.64,56.38,34.69.ESI-MS m/z calcd forC18H14ClN3O3S2+420.0238,found 420.0229[M+H]+.
34、2-[(4-甲基(苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮的制备(化合物33)
将2-巯基苯并咪唑换成4-甲基-2-巯基苯并噻唑,按制备化合物9的方法制备。1HNMR(400MHz,CDCl3)δ12.42(s,1H),7.63(d,J=7.9Hz,1H),7.62 (s,1H),7.33(s,1H),7.31(d,J=8.0Hz,1H),7.12(s,1H),4.46(s, 2H),4.01(s,3H),3.99(s,3H),2.94(s,3H).13CNMR(101MHz,DMSO)δ 163.35,159.68,156.44,155.91,151.84,150.02,137.94,135.34,131.37,127.39,125.43,119.79,113.45,106.10,103.97,56.71,56.47,34.45,18.20.ESI-MS m/z calcd for C19H17N3O3S2+400.0784,found 400.0780[M+ H]+.
35、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-喹唑啉-4(3H)-酮的制备(化合物34)
将5-甲氧基-2-巯基咪唑并[4,5-b]吡啶(91mg,0.5mmol)、2-(氯甲基)喹唑啉-4(3H)-酮(97mg,0.5mmol)和氢氧化钠(100mg,2.5mmol)溶解在甲醇中(7mL),常温搅拌过夜。后处理反应,减压除去有机溶剂甲醇得到粗品,粗品利用300-400目的硅胶柱进行纯化,得到终产物白色固体34(88mg,52%)。1H NMR(400MHz,CDCl3)δ8.30(d,J=7.9Hz,1H),7.78(t,J=7.3Hz, 2H),7.70(d,J=8.1Hz,1H),7.50(t,J=7.5Hz,1H),6.63(d,J=8.7Hz,1H),4.39(s,2H),3.96(s,3H).13C NMR(101MHz,DMSO)δ162.69, 160.85,155.55,145.78,144.51,143.73,135.86,128.42,126.75,126.21,123.89,121.91,120.93,109.96,54.54,34.77.ESI-MS m/z calcd for C16H13N5O2S+340.0863,found 340.08635[M+H]+.
36、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-6-甲氧基-喹唑啉-4(3H)-酮的制备(化合物35)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8b,按制备化合物34的方法制备。1H NMR(400MHz,CDCl3)δ7.85(d,J=8.4Hz,1H),7.66(s,1H),7.64(d,J =8.9Hz,1H),7.36(d,J=8.3Hz,1H),6.69(d,J=8.6Hz,1H),4.42(s,2H),3.98(s,3H),3.93(s,3H).13C NMR(101MHz,DMSO)δ161.58, 161.15,158.35,151.46,148.72,148.53,142.50,129.36,128.66,126.03,125.88,124.34,122.32,106.55,56.12,53.96,35.20.ESI-MS m/z calcd forC17H15N5O3S+370.0968,found 370.0973[M+H]+.
37、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-8-甲基-喹唑啉 -4(3H)-酮的制备(化合物36)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8c,按制备化合物34的方法制备。1H NMR(400MHz,CDCl3)δ8.16(d,J=7.8Hz,1H),7.78(d,J=8.1Hz,1H), 7.63(d,J=7.4Hz,1H),7.39(t,J=7.6Hz,1H),6.62(d,J=8.7Hz,1H),4.41(s,2H),3.95(s,3H),2.68(s,3H).13CNMR(101MHz,DMSO)δ 162.66,161.88,151.90,148.03,146.07,144.00,135.45,134.81,126.85,125.79,123.97,121.26,121.14,109.77,54.53,35.79,16.89.ESI-MS m/z calcdfor C17H15N5O2S+354.1019,found 354.1028[M+H]+.
38、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-7-甲基-喹唑啉 -4(3H)-酮的制备(化合物37)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8d,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ12.48(s,2H),7.96(d,J=8.0Hz,1H),7.79(d,J =6.1Hz,1H),7.38(s,1H),7.30(d,J=8.1Hz,1H),6.61(d,J=8.5Hz,1H),4.48(s,2H),3.85(d,J=7.2Hz,3H),2.41(s,3H).13C NMR(101 MHz,DMSO)δ162.74,160.42,156.38,147.03,145.29,144.57,142.66,130.02,126.79,126.32,122.53,122.06,118.45,110.05,54.54,34.36,21.83.ESI-MS m/z calcd for C17H15N5O2S+354.1019,found 354.1023[M+ H]+.
39、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-6-甲基-喹唑啉 -4(3H)-酮的制备(化合物38)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8e,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ12.28(s,2H),δ7.89(s,1H),7.83(d,J=8.6Hz, 1H),7.60(d,J=8.3Hz,1H),7.46(d,J=8.3Hz,1H),6.66(d,J=8.6Hz,1H),4.50(s,2H),3.85(s,3H),2.42(s,3H).13C NMR(101MHz,DMSO) δ161.55,161.53,153.20,148.32,147.50,145.21,137.40,136.47,126.25, 126.05,125.78,124.63,121.02,107.44,54.12,35.20,21.20.ESI-MS m/z calcd for C17H15N5O2S+354.1019,found 354.1023[M+H]+.
40、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-6-氟-喹唑啉 -4(3H)-酮的制备(化合物39)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8f,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ13.18(s,1H),12.75(s,1H),7.77(d,J=8.1Hz,2H), 7.66(d,J=6.0Hz,2H),6.61(d,J=8.6Hz,1H),4.49(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ161.69,161.27,161.24,161.17,159.24, 153.06,148.57,148.28,145.35,130.08,130.00,125.98,125.56,123.48,123.24,122.78,122.70,111.10,110.87,106.67,53.95,35.31.ESI-MS m/z calcd for C16H12FN5O2S+358.0768,found 358.0761[M+H]+.
41、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-6-氯-喹唑啉 -4(3H)-酮的制备(化合物40)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8g,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ12.84(s,2H),8.01(s,1H),7.78(d,J=8.5Hz,2H), 7.59(d,J=8.6Hz,1H),6.60(d,J=8.4Hz,1H),4.49(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ162.58,160.59,154.02,147.13,145.72, 144.40,135.28,131.85,128.44,125.97,125.40,122.66,121.62,109.67,54.52,35.70.ESI-MS m/z calcd for C16H12ClN5O2S+374.0473,found 374.0460 [M+H]+.
42、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-6-溴-喹唑啉 -4(3H)-酮的制备(化合物41)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8h,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ13.20(s,1H),12.78(s,1H),8.15(s,1H),7.90(d, J=8.6Hz,1H),7.79(s,1H),7.51(d,J=8.6Hz,1H),6.60(d,J=8.5Hz,1H),4.49(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ162.46, 160.52,154.07,147.38,146.32,144.75,137.95,128.79,128.47,125.95,123.05,121.93,119.94,109.39,54.47,35.75.ESI-MS m/z calcd forC16H12BrN5O2S+419.9948,found 419.9942[M+H]+.
43、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-8-氟-喹唑啉 -4(3H)-酮的制备(化合物42)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8i,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ13.15(s,1H),12.82(s,1H),7.90(d,J=7.9Hz,1H),7.78(s,1H),7.72–7.59(m,1H),7.55–7.41(m,1H),6.61(d,J= 8.6Hz,1H),4.52(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ162.56, 160.91,160.88,157.66,155.14,153.53,147.61,144.37,137.52,137.40,127.61,127.54,125.85,123.53,122.04,121.52,120.50,120.31,109.58,54.50,36.11.ESI-MS m/z calcd for C16H12FN5O2S+358.0768,found 358.0779 [M+H]+.
44、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-8-氯-喹唑啉 -4(3H)-酮的制备(化合物43)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8j,按制备化合物34的方法制备。1H NMR(400MHz,CDCl3)δ8.23(d,J=7.8Hz,1H),7.86(t,J=6.9Hz,2H), 7.42(t,J=7.6Hz,1H),6.72(d,J=8.7Hz,1H),4.48(s,2H),3.98 (s,3H).13C NMR(101MHz,DMSO)δ162.71,161.26,153.78,147.80,144.69, 143.84,134.96,130.53,127.62,125.79,125.42,123.18,121.05,109.88,54.55,35.93.ESI-MS m/z calcd for C16H12ClN5O2S+374.0473,found374.0464 [M+H]+.
45、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-8-溴-喹唑啉 -4(3H)-酮的制备(化合物44)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8k,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ13.22(s,1H),12.85(s,1H),8.08(d,J=7.7Hz,2H), 8.00–7.67(m,1H),7.39(t,J=7.7Hz,1H),6.61(d,J=8.5Hz,1H),4.50(s,2H),3.80(d,J=32.1Hz,3H).13CNMR(101MHz,DMSO)δ162.67, 161.32,153.70,147.97,145.76,143.92,138.28,128.13,126.14,125.80,123.13,121.52,121.13,109.79,54.55,35.86.ESI-MS m/z calcd forC16H12BrN5O2S+419.9948,found 419.9933[M+H]+.
46、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-7-三氟甲基-喹唑啉-4(3H)-酮的制备(化合物45)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8l,按制备化合物34的方法制备。1H NMR(400MHz,CDCl3)δ8.42(d,J=8.2Hz,1H),7.98(s,1H),7.88(s,1H), 7.71(d,J=8.0Hz,1H),6.73(d,J=8.7Hz,1H),4.42(s,2H),3.99 (s,3H).13C NMR(101MHz,DMSO)δ162.66,161.05,154.87,147.94,147.29, 144.45,134.71,134.39,128.24,126.00,125.14,124.42,123.80,123.14,122.42,121.69,109.68,54.51,36.20.ESI-MS m/z calcd forC17H12F3N5O2S+408.0737,found 408.0739[M+H]+.
47、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-5-氟-喹唑啉-4(3H)-酮的制备(化合物46)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8m,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ13.20(s,1H),12.62(s,1H),7.76(dd,J=13.9,7.8 Hz,2H),7.39(d,J=8.1Hz,1H),7.34–7.15(m,1H),6.63(d,J=8.5Hz,1H),4.48(s,2H),3.86(s,3H).13C NMR(101MHz,DMSO)δ162.61, 162.18,159.56,158.77,154.74,148.81,147.10,144.62,136.10,136.00,126.03,122.11,121.84,114.23,114.03,110.91,110.84,109.63,54.54,35.44.ESI-MS m/z calcd for C16H12FN5O2S+358.0768,found 358.0754[M+ H]+.
48、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-7-氯-喹唑啉 -4(3H)-酮的制备(化合物47)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8n,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ12.81(s,2H),8.10(d,J=8.5Hz,1H),7.79(s,1H), 7.64(s,1H),7.54(d,J=8.5Hz,1H),6.63(d,J=8.6Hz,1H),4.51(s,2H),3.86(s,3H).13C NMR(101MHz,DMSO)δ162.65,161.03,154.97, 148.40,147.25,144.47,139.70,128.54,127.82,126.03,125.55,121.70, 120.30,109.69,54.56,35.87.ESI-MS m/z calcd for C16H12ClN5O2S+374.0473, found 374.0489[M+H]+.
49、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-7-溴-喹唑啉 -4(3H)-酮的制备(化合物48)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8o,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ13.18(s,1H),12.77(s,1H),8.01(d,J=8.4Hz,1H),7.78(s,2H),7.67(d,J=8.5Hz,1H),6.63(d,J=8.6Hz,1H),4.51 (s,2H),3.86(s,3H).13C NMR(101MHz,DMSO)δ162.67,161.15,154.93, 148.32,147.16,144.42,130.60,128.67,128.52,126.04,121.67,120.57,109.76,54.57,35.88.ESI-MS m/z calcd for C16H12BrN5O2S+419.9948,found 419.9940[M+H]+.
50、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-6-三氟甲基-喹唑啉-4(3H)-酮的制备(化合物49)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8p,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ13.21(s,1H),12.91(s,1H),8.34(s,1H),8.08(d, J=8.5Hz,1H),7.77(d,J=8.3Hz,2H),6.62(d,J=8.5Hz,1H),4.54(s,2H),3.85(s,3H).13C NMR(101MHz,DMSO)δ162.58,161.14,155.76, 150.31,147.48,144.62,131.12,128.30,127.47,127.14,125.97,125.49,123.71,122.78,121.79,121.66,120.07,119.74,109.54,54.52,36.03.ESI-MS m/z calcd for C17H12F3N5O2S+408.0737,found 408.0739[M+H]+.
51、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-6,7-二氟-喹唑啉 -4(3H)-酮的制备(化合物50)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8q,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ12.86(s,2H),8.00(t,J=9.4Hz,1H),7.79(d,J =7.2Hz,1H),7.73–7.56(m,1H),6.62(d,J=8.5Hz,1H),4.50(s,2H),3.86(s,3H).13C NMR(101MHz,DMSO)δ162.51,160.54,155.55,155.41, 154.03,153.02,152.88,150.36,150.21,147.88,147.69,146.16,146.04,144.73,125.94,121.88,118.91,118.86,115.23,115.05,114.08,113.89,109.38,54.50,35.96.ESI-MS m/z calcd for C16H11F2N5O2S+376.0674,found 376.0676[M+H]+.
52、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-5-甲基-喹唑啉 -4(3H)-酮的制备(化合物51)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8r,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ13.22(s,1H),12.35(s,1H),7.83(s,1H),7.59(t, J=7.7Hz,1H),7.38(d,J=7.3Hz,1H),7.22(d,J=7.3Hz,1H),6.63(d,J=8.4Hz,1H),4.47(d,J=13.5Hz,2H),3.86(s,3H),2.76(s, 3H).13C NMR(101MHz,DMSO)δ162.65,161.02,156.49,145.25,145.06, 143.24,141.52,135.27,131.11,126.38,122.56,120.50,118.98,109.82,54.52,33.76,22.45.ESI-MS m/z calcd for C17H15N5O2S+354.1019,found 354.1011[M+H]+.
53、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-7-甲酸甲酯-喹唑啉 -4(3H)-酮的制备(化合物52)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8s,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ13.45(s,1H),12.82(s,1H),8.20(d,J=8.2Hz,1H),8.03(s,1H),7.96(d,J=8.2Hz,1H),7.79(d,J=8.4Hz,1H),6.62 (d,J=8.6Hz,1H),4.53(s,2H),3.90(s,3H),3.85(s,3H).13C NMR(101 MHz,DMSO)δ166.55,165.62,162.67,161.10,154.71,147.13,146.92,144.48,136.80,135.33,127.32,127.07,126.03,124.57,121.75,109.74, 54.53,53.19,35.81.ESI-MS m/z calcd for C18H15N5O4S+398.0918,found 398.0921[M+H]+.
54、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-6–碘-喹唑啉 -4(3H)-酮的制备(化合物53)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8t,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ12.88(s,2H),8.36(s,1H),8.06(d,J=8.6Hz,1H), 7.79(d,J=8.6Hz,1H),7.37(d,J=8.5Hz,1H),6.62(d,J=8.6Hz,1H),4.49(s,2H),3.85(s,3H).13C NMR(101MHz,DMSO)δ162.66,160.50, 153.81,147.37,146.94,144.70,143.52,134.64,128.83,126.23,123.23,121.92,109.68,92.51,54.57,36.07.ESI-MS m/z calcd forC16H12IN5O2S+465.9829,found 465.9830[M+H]+.
55、2-[(5-甲氧基-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-7–氟-喹唑啉 -4(3H)-酮的制备(化合物54)
将2-(氯甲基)喹唑啉-4(3H)-酮换成8u,按制备化合物34的方法制备。1H NMR(400MHz,DMSO)δ13.22(s,1H),12.69(s,1H),8.22–8.10(m,1H),7.83(s,1H),7.38(t,J=8.5Hz,2H),6.63(d,J=8.6Hz,1H),4.51 (s,2H),3.86(s,3H).13C NMR(101MHz,DMSO)δ167.35,164.84,162.59, 161.10,154.45,150.11,149.98,147.43,144.67,129.54,129.43,126.20,121.88,118.44,116.05,115.82,112.21,111.99,109.60,54.52,36.00.ESI-MS m/z calcd for C16H12FN5O2S+358.0768,found 358.0762[M+H]+.
56、2-[(5-氯-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-7-甲酸甲酯-喹唑啉 -4(3H)-酮的制备(化合物55)
将5-氯-2-巯基苯并咪唑(92mg,0.5mmol)、2-(氯甲基)-7-甲酸甲酯喹唑啉 -4(3H)-酮(126mg,0.5mmol)和氢氧化钠(100mg,2.5mmol)溶解在甲醇中(7mL),常温搅拌过夜。后处理反应,减压除去有机溶剂甲醇得到粗品,粗品利用300-400目的硅胶柱进行纯化,得到终产物白色固体55(132mg,66%)。1H NMR(400MHz,DMSO)δ12.88(s,2H),8.19(d,J=8.2Hz,1H),8.04 (d,J=1.4Hz,1H),7.96(dd,J=8.2,1.6Hz,1H),7.51(s,1H),7.45(d,J=5.5Hz,1H),7.15(dd,J=8.5,2.0Hz,1H),4.56(s,2H),3.89 (s,3H).13C NMR(101MHz,DMSO)δ165.72,161.31,154.06,151.10,147.89, 135.92,135.27,133.84,129.13,127.85,127.20,126.83,124.99,124.59,115.30,113.77,53.14,35.46.ESI-MS m/z calcd forC18H13ClN4O3S+401.0470, found 401.0467[M+H]+.
57、2-[(5,6-二氯-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-7-甲酸甲酯-喹唑啉-4(3H)-酮(化合物56)
将5-氯-2-巯基苯并咪唑换成5,6-二氯-2-巯基苯并咪唑,按制备化合物55的方法制备。1H NMR(400MHz,DMSO)δ12.90(s,2H),8.20(d,J=8.2Hz,1H), 8.04(d,J=1.3Hz,1H),7.97(dd,J=8.2,1.6Hz,1H),7.72(s,2H),4.59(s,2H),3.90(s,3H).13C NMR(101MHz,DMSO)δ165.79,161.31,154.72, 153.03,148.00,137.98,135.35,127.92,127.22,126.80,125.44,124.59,115.61,53.17,34.98.ESI-MS m/z calcd for C18H12Cl2N4O3S+435.0080,found 435.0063[M+H]+.
58、2-[(5-甲氧基-(噻唑并[4,5-B]吡啶)-2-硫代)甲基]-7-甲酸甲酯-喹唑啉-4(3H)-酮的制备(化合物57)
将5-氯-2-巯基苯并咪唑换成5-甲氧基-2-巯基苯并噻唑,按制备化合物55的方法制备。1H NMR(400MHz,DMSO)δ12.75(s,1H),8.20(d,J=8.2Hz,1H), 8.07(s,1H),7.97(d,J=8.2Hz,1H),7.88(d,J=8.8Hz,1H),7.38 (d,J=2.0Hz,1H),7.00(dd,J=8.8,2.2Hz,1H),4.64(s,2H),3.89(s,3H),3.81(s,3H).13C NMR(101MHz,DMSO)δ166.76,165.78,161.32, 159.11,154.62,154.13,147.81,135.38,127.81,127.25,126.91,126.86,124.47,122.63,114.39,104.98,55.94,53.16,35.99.ESI-MS m/z calcd forC19H15N3O4S2+414.0577,found 414.0571[M+H]+.
59、2-[(6-氯-(噻唑并[4,5-B]吡啶)-2-硫代)甲基]-7-甲酸甲酯-喹唑啉 -4(3H)-酮的制备(化合物58)
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将5-氯-2-巯基苯并咪唑换成6-氯-2-巯基苯并噻唑,按制备化合物55的方法制备。1H NMR(400MHz,DMSO)δ12.75(s,1H),8.23(s,1H),8.20(d,J= 1.6Hz,1H),8.08(d,J=1.3Hz,1H),7.98(dd,J=8.2,1.6Hz,1H), 7.83(d,J=8.7Hz,1H),7.50(dd,J=8.7,2.2Hz,1H),4.68(s,2H),3.91(s,3H).13C NMR(101MHz,DMSO)δ167.30,165.83,161.34,154.49,151.68,147.99,136.92,135.43,129.60,127.95,127.35,127.28,126.87,124.57,122.76,122.05,53.19,36.09.ESI-MS m/z calcd for C18H12ClN3O3S2+418.0081,found418.0071[M+H]+.
60、2-[(4-甲基-(噻唑并[4,5-B]吡啶)-2-硫代)甲基]-7-甲酸甲酯-喹唑啉 -4(3H)-酮的制备(化合物59)
将5-氯-2-巯基苯并咪唑换成4-甲基-2-巯基苯并噻唑,按制备化合物55的方法制备。1H NMR(400MHz,DMSO)δ12.77(s,1H),8.22(d,J=7.6Hz,1H), 8.08(s,1H),7.98(d,J=7.6Hz,1H),7.82(s,1H),7.26(s,2H),4.64(s,2H),3.91(s,3H),2.57(s,3H).13C NMR(101MHz,DMSO)δ165.77, 164.36,161.26,155.37,151.97,147.81,135.41,135.12,131.25,127.71,127.30,127.27,126.81,125.17,124.43,119.66,53.17,36.06,18.24.ESI-MS m/z calcd for C19H15N3O3S2+398.0628,found 398.0619[M+H]+.
61、2-[(5-氯-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-7–氟-喹唑啉-4(3H)- 酮的制备(化合物60)
将5-氯-2-巯基苯并咪唑(92mg,0.5mmol)、2-氨基-4-氟苯甲酸甲酯(106mg,0.5mmol)和氢氧化钠(100mg,2.5mmol)溶解在甲醇中(7mL),常温搅拌过夜。后处理反应,减压除去有机溶剂甲醇得到粗品,粗品利用300-400目的硅胶柱进行纯化,得到终产物白色固体60(96mg,53%)。1H NMR(400MHz,DMSO) δ12.94(s,1H),12.68(s,1H),8.16(dd,J=8.7,6.3Hz,1H),7.54(s,1H),7.47(s,1H),7.42–7.31(m,2H),7.17(dd,J=8.5,2.0Hz,1H),4.56(s,2H).13C NMR(101MHz,DMSO)δ167.36,164.86,161.08,154.68, 151.30,150.51,150.37,137.23,135.04,129.51,129.40,128.41,124.24,118.46,115.95,115.71,115.32,113.92,112.44,112.22,35.29.ESI-MS m/z calcd for C16H10ClFN4OS+361.0321,found361.0321[M+H]+.
62、2-[(5,6-二氯-(咪唑并[4,5-B]吡啶)-2-硫代)甲基]-7–氟-喹唑啉-4(3H)-酮的制备(化合物61)
将5-氯-2-巯基苯并咪唑换成5,6-二氯-2-巯基苯并咪唑,按制备化合物60的方法制备。1H NMR(400MHz,DMSO)δ13.02(s,1H),12.67(s,1H),8.15(dd, J=8.7,6.3Hz,1H),7.73(s,2H),7.37(ddd,J=13.4,8.6,4.3Hz,2H),4.56(s,2H).13C NMR(101MHz,DMSO)δ167.39,164.88,161.03,154.92, 152.78,149.83,149.70,136.59,129.59,129.48,126.15,118.22,116.15,115.91,115.48,112.07,111.85,34.87.ESI-MS m/z calcd forC16H9Cl2FN4OS+394.9931,found 394.9920[M+H]+.
63、2-[(5–甲氧基-(噻唑并[4,5-B]吡啶)-2-硫代)甲基]-7–氟-喹唑啉 -4(3H)-酮的制备(化合物62)
将5-氯-2-巯基苯并咪唑换成5-甲氧基-2-巯基苯并噻唑,按制备化合物60的方法制备。1H NMR(400MHz,DMSO)δ12.65(s,1H),8.17(dd,J=8.7,6.3 Hz,1H),7.89(d,J=8.8Hz,1H),7.47–7.29(m,3H),7.02(dd,J=8.8,2.5Hz,1H),4.64(s,2H),3.83(s,3H).13CNMR(101MHz,DMSO)δ 167.44,166.71,164.93,161.09,159.10,155.04,154.09,150.10,149.98,129.61,129.51,126.90,122.63,118.25,116.11,115.88,114.40,112.20,111.98,104.97,55.95,35.91.ESI-MS m/z calcd for C17H12FN3O2S2+374.0428, found374.0438[M+H]+.
64、2-[(6–氯-(噻唑并[4,5-B]吡啶)-2-硫代)甲基]-7–氟-喹唑啉-4(3H)- 酮的制备(化合物63)
将5-氯-2-巯基苯并咪唑换成6-氯-2-巯基苯并噻唑,按制备化合物60的方法制备。1H NMR(400MHz,DMSO)δ12.65(s,1H),8.19(d,J=2.1Hz,1H), 8.16(dd,J=8.8,6.4Hz,1H),7.83(d,J=8.7Hz,1H),7.50(dd,J=8.7,2.2Hz,1H),7.44–7.33(m,2H),4.67(s,2H).13C NMR(101MHz, DMSO)δ167.47,167.25,164.97,161.10,154.81,151.66,150.40,150.27,136.91,129.61,129.50,127.35,122.75,122.03,118.40,116.06,115.82,112.39,112.17,36.05.ESI-MS m/z calcd for C16H9ClFN3OS2+377.9932,found377.9933[M+H]+.
65、2-[(4–甲基-(噻唑并[4,5-B]吡啶)-2-硫代)甲基]-7–氟-喹唑啉 -4(3H)-酮的制备(化合物64)
将5-氯-2-巯基苯并咪唑换成4-甲基-2-巯基苯并噻唑,按制备化合物60的方法制备。1H NMR(400MHz,DMSO)δ12.66(s,1H),8.17(dd,J=8.7,6.4Hz, 1H),7.82(dd,J=6.0,3.2Hz,1H),7.38(ddd,J=11.2,9.5,2.5Hz, 2H),7.30–7.21(m,2H),4.62(s,2H),2.58(s,3H).13C NMR(101MHz, DMSO)δ167.49,164.99,164.22,161.02,156.09,151.93,149.73,149.60,135.16,131.33,129.72,129.61,127.36,125.28,119.64,118.14,116.19,115.96,111.87,111.65,35.95,18.23.ESI-MS m/z calcd for C17H12FN3OS2+358.0479,found 358.0488[M+H]+.
实施例3:
采用荷瘤鼠模型检测新型4(3H)-喹唑啉酮类似物抗肿瘤效果
实验动物:
BALB/C普通小鼠、C57BL/6普通小鼠,雄性,体重20-22g,7-8周龄,SPF级,购买自上海斯莱克动物公司。
饲养条件:
所有小鼠均自由觅食和饮水,在室温(23±2)℃下饲养。饲料及水均经高压灭菌处理,全部实验饲养过程为SPF级。
剂量设置:
腹腔注射小鼠,化合物均设置1个剂量组:5mg/kg
试验对照:
阴性对照:生理盐水溶液
给药方法:
给药途径:腹腔注射给药
给药体积:200微升/只
给药次数:每天1次,连续21天
每组动物数:10只
肿瘤细胞株
小鼠结直肠癌细胞株CT26,小鼠乳腺癌细胞株4T1,均购自中国科学院细胞库。
试验主要步骤
肿瘤模型鼠的建立与干预
细胞培养,传代,在细胞对数期收集细胞,做成浓度为(1.0×107)每毫升的细胞悬液,小鼠右前肢腋下注射0.2ml细胞悬液(细胞数目为2.0×106个/只),8天左右致瘤成功,随机均分为11组。11组分别为1:阴性对照组(生理盐水组)、 2-11组,分别随机选择10种新型4(3H)-喹唑啉酮类似物化合物给药组(剂量 5mg/kg)。每天给药1次,腹腔注射给药,连续给药21天。21天后,处死小鼠并称瘤体重量,抑瘤率=[1-实验组平均瘤重/阴性对照组平均瘤重]]×100%。
分别制备小鼠结直肠癌细胞株CT26,移植到BalB/C普通小鼠,小鼠乳腺癌细胞株4T1,移植到BalB/C普通小鼠,观察不同新型4(3H)-喹唑啉酮类似物化合物分别抑制小鼠肿瘤效果。
统计分析
数据用x±s表示,利用SPSS10.0软件进行处理,采用单因素方差分析 (one-wayANOVA)检验比较各组瘤重差异的显著性,显著性水平a=0.05。
实验结果
小鼠皮下接种肿瘤细胞后制备成功皮下移植瘤模型,新型4(3H)-喹唑啉酮衍生物均可明显抑制小鼠CT26和4T1肿瘤生长,给药21天后的瘤重均显著低于阴性对照组,表明新型4(3H)-喹唑啉酮类似物药物具有显著抗肿瘤作用。具体结果见下表2-3。
表2.新型4(3H)-喹唑啉酮类似物对鼠结直肠癌CT26皮下移植瘤的抑制作用 (n=10,mean±SD)
表3.新型4(3H)-喹唑啉酮类似物对鼠4T1乳腺癌皮下移植瘤的抑制作用(n=10,mean±SD)
实施例4新型4(3H)-喹唑啉酮类似物的急性毒性研究
实验材料
BALB/C普通小鼠,雄性,体重20-22g,7-8周龄,SPF级,购买自上海斯莱克动物公司。动物以颗粒饲料喂养,自由摄食和饮水。
实验方法
小鼠按体重分别单次尾静脉注射2g/kg的新型4(3H)-喹唑啉酮类似物药物(选择代表化合物55、61、64),观察给药后小鼠14天内的毒性反应及死亡情况。结果发现,小鼠单次尾静脉注射给药后,小鼠活动正常。给药后14天内,小鼠未出现死亡,第15天,全部小鼠处死,解剖,肉眼检查各脏器,均未见明显病变。
实验结果
上述急性毒性实验结果表明,静脉注射给药最大耐受量MTD不低于2g/Kg,说明新型4(3H)-喹唑啉酮类似物药物的急性毒性低。
Claims (6)
1.一种4(3H)-喹唑啉酮衍生物及其盐,其特征在于,所述4(3H)-喹唑啉酮衍生物结构式为:
2.基于权利要求1所述的4(3H)-喹唑啉酮衍生物及其盐,其特征在于,所述的盐为4(3H)-喹唑啉酮衍生物与酸形成的酸加盐或与碱形成的碱加盐,所述酸包括盐酸、硫酸、氢溴酸、磷酸、乙酸、酒石酸、水杨酸、柠檬酸、苹果酸、甲磺酸、对甲苯磺酸、乳酸、丙酮酸、马来酸、琥珀酸。
3.一种药物组合物,其特征在于,含有权利要求1所述4(3H)-喹唑啉酮衍生物或其盐。
4.权利要求1或2所述的4(3H)-喹唑啉酮衍生物及其盐、权利要求3所述药物组合物在制备抗肿瘤药物中的应用。
5.基于权利要求4所述应用,其特征在于,所述肿瘤为结肠癌、乳腺癌。
6.化合物2-[(6-乙氧基-(苯并噻唑)-2-硫代)甲基]-6,7-二甲氧基-喹唑啉-4(3H)-酮及其药学可以接受的盐在制备抗肿瘤药物中的应用,所述肿瘤为结肠癌、乳腺癌,所述化合物结构式如下:
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