CN104000817B - 一类含1,3,4-噁二唑啉的吡唑衍生物在制备治疗、防肿瘤疾病药物中的用途 - Google Patents
一类含1,3,4-噁二唑啉的吡唑衍生物在制备治疗、防肿瘤疾病药物中的用途 Download PDFInfo
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Abstract
一类含1,3,4-噁二唑啉的吡唑衍生物在制备治疗、防肿瘤疾病药物中的用途，由下述通式（I）表示的或其药学上能接受的盐：，其中R1代表芳香基或5~7元杂环基；R2代表C1~C6直链或支链烷烃、脂肪环基、芳香基或5~7元杂环基；R3代表芳香基或5~7元杂环基；R4代表甲基或乙基；所述的芳香基是苯基、取代苯基、萘基或联苯基；其中所述的取代苯基含1~4个取代基，该取代基取自卤素、羟甲基、C1~C6直链或支链烷烃、硝基、腈基、三氟甲基或C1~C4烷氧基。所述的5~7元杂环基含有1~3个选自氮、硫或氧的杂原子，能被苯基合并，并含有一个或多个选自卤素、硝基、氨基、腈基、三氟甲氧基、三氟甲基和芳香基的取代基。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类含1,3,4-噁二唑啉的吡唑衍生物、其制备方法及医药用途，特别是在制备一类含1,3,4-噁二唑啉的吡唑衍生物用于治疗或者预防肿瘤疾病的药物。
背景技术
在杂环化学中，1,3,4-噁二唑啉是一类重要的有机化合物，其具有广泛的生物活性，例如：抗肿瘤、抗菌、免疫抑制和单胺氧化酶抑制等。例如，在2001年，雅培制药发表了关于含有1,3,4-噁二唑啉母核的化合物A-105972及其抗肿瘤活性的研究，其中A-105972是通过对超过60,000个化学实体的高通量筛选而得到的活性小分子，对多种肿瘤细胞均有较好的抑制活性，如乳腺癌、中枢神经系统肿瘤、结肠癌、肝癌、肺癌及前列腺肿癌等，还包括一些多药耐药性的肿瘤细胞，IC50值在20-200nM之间。A-105972对HL-60、HT-1080、MCF-7、HT-29、LNCaP和A549的IC50分别为17nM、46nM、15nM、8nM、6nM和3nM。对肿瘤细胞分裂周期影响的实验表明，在1μM的浓度下，A-105972能够有效地阻滞HCT-116、LNCaP和PC-3肿瘤细胞分裂在G2-M期。体内试验说明其还能有效地抑制移植瘤的生长，延长小鼠的生存时间。同位素标记显示，A-105972能够和微管蛋白很好的结合，IC50为3.6μM。实验还证明，其还能诱导肿瘤细胞凋亡，促进Bcl-2蛋白的磷酸化等（CancerRes.2001,61:1486-1492；J.Med.Chem.,2001,44:4416-4430）。此外，近年来吡唑类氮杂环也是抗肿瘤药物研究领域的热点之一，Vujasinovic和Zhao等人报道了以吡唑结构为母核的3-苯基-1-芳香甲基吡唑类化合物，生物活性实验显示，这些吡唑衍生物具有较强的抗肿瘤活性，其抗肿瘤活性的主要机制为促进肿瘤细胞的凋亡或自噬（Bioorg.Med.Chem.2012,6:2101-2110；Eur.J.Med.Chem.2010,45:5792-5799）。
利用药物化学领域的药效团骨架拼合等原理，将1,3,4-噁二唑啉与3-苯基-1-芳香甲基吡唑类这两种具有抗肿瘤活性的药效团进行拼合，得到了未见文献报道的含1,3,4-噁二唑啉的吡唑衍生物。
发明内容
本发明的目的是公开了一类含1,3,4-噁二唑啉的吡唑衍生物在制备治疗、防肿瘤疾病药物中的用途，一类含1,3,4-噁二唑啉的吡唑衍生物（I）。体外抗增殖测试显示，本发明化合物对人肝癌细胞HepG2具有一定的体外抗增殖活性。因此，本发明的通式（I）化合物，可用于预防和治疗各种细胞异常增殖、形态变化等相关的疾病，尤其是用于治疗或者预防肿瘤疾病的药物。
本发明所述的含1,3,4-噁二唑啉的吡唑衍生物的结构通式如下述通式（I）所示：
其中
R1代表芳香基或5~7元杂环基；
R2代表C1~C6直链或支链烷烃、脂肪环基、芳香基或5~7元杂环基；
R3代表芳香基或5~7元杂环基；
R4代表甲基或乙基；
所述的芳香基是苯基、取代苯基、萘基或联苯基；其中所述的取代苯基含1~4个取代基，该取代基取自卤素、羟甲基、C1~C6直链或支链烷烃、硝基、腈基、三氟甲基或C1~C4烷氧基；
所述的5~7元杂环基含有1~3个选自氮、硫或氧的杂原子，能被苯基合并，并含有一个或多个选自卤素、硝基、氨基、腈基、三氟甲氧基、三氟甲基和芳香基的取代基；
所述的卤素为氟、氯、溴或碘。
根据本发明，药学上可接受的盐包括通式（I）化合物与下列酸形成的酸加成盐：盐酸、苯磺酸、氢溴酸、硫酸、乳酸、磷酸、甲磺酸、硝酸或对甲苯磺酸。
本发明所述通式（I）表示的化合物的药学上可接受的溶剂合物非限制性地包括通式（I）表示的化合物与水、乙醚、乙醇、正丁醇、异丙醇或丙酮的溶剂合物。
本发明所述的药物组合物，其中含有效量本发明化合物、其药学上可接受的盐或药学上可接受的溶剂合物，剂型可以是普通片剂、缓释片剂、口服液、栓剂、胶囊剂、混悬剂、注射剂、颗粒剂等制剂学上常规的剂型形式。
本发明部分化合物是：
3-乙酰基-2-(4-乙酰氧基-3,5-二甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-1）
3-乙酰基-2-(4-氯苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-2）
3-乙酰基-2-(3-乙酰氧基-4-甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-3）
3-乙酰基-2-(4-乙酰氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-4）
3-乙酰基-2-(2,4-二氯苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-5）
3-乙酰基-2-(4-硝基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-6）
3-乙酰基-2-(3-硝基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-7）
3-乙酰基-2-(3,4-二甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-8）
3-乙酰基-2-(3-乙酰氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-9）
3-乙酰基-2-(3,4,5-三甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-10）
3-乙酰基-2-(2-呋喃基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-11）
3-乙酰基-2-(3-甲氧基-4-乙酰氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-12）
本发明通式目标化合物（Ⅰ）的制备方法如下：
其中R1、R2、R3和R4的定义同前。
其中a~b代表反应条件：
a：溶剂为乙醇；反应温度为80℃~90℃。
b：反应温度为120℃~170℃。
其中，中间体（Ⅱ）的制备可参照文献（J.Chem.Soc.,DaltonTrans.,1999,9:1461-1466；Chin.J.Org.Chem.,2007,27(12):1542-1546；Bioorg.Med.Chem.,2007,15(22):6893-6899）报道的方法，以乙酮类化合物（IV）为原料，合成方法如下：
药理活性试验证明，本发明的通式（I）化合物能够有效的抑制人肝癌细胞HepG2的增殖。
以下是本发明部分化合物的药理活性测试方法及结果：
MTT法测试体外抗肿瘤活性
阳性药：5-氟尿嘧啶（5-FU）和紫杉醇。
培养基：DMEM培养基，RPMI-1640培养基
实验方法：
将处于对数生长期的肿瘤细胞消化、计数、配制成浓度为3～4×104个/mL的细胞悬液，96孔细胞培养板中每孔加入100μL细胞悬液（每孔3～4×103个细胞）；96孔细胞培养板置于37℃，5%CO2培养箱中培养24小时；用完全培养基稀释药物至所需浓度，每孔加入100μL相应的含药培养基，同时设立阴性对照组，阳性对照组；96孔细胞培养板置于37℃，5%CO2培养箱中培养72小时；将96孔板进行MTT染色，λ=490nm，测定OD值；每孔加入20μLMTT（5mg/mL），在培养箱继续培养4小时；弃去培养基，每孔加入150μLDMSO溶解，摇床10分钟轻轻地混匀；λ=490nm，酶标仪读出每孔的OD值。计算各组别抑制率，抑制率(%)=[(阴性对照组OD值-实验组OD值)/阴性对照组OD值]×100%。用SPSS17.0软件计算出半数抑制浓度（IC50）。
体外抗肿瘤活性测试结果如下：
表1本发明部分化合物对HepG2细胞的体外抗增殖活性
结果表明，目标化合物对人肝癌细胞HepG2具有不同程度的体外抑制作用，其中化合物I-1的活性最强，其IC50值为28.04μM，优于阳性对照药5-FU（37.57μM），但弱于阳性药紫杉醇（0.0012μM）。这说明我们设计合成的含1,3,4-噁二唑啉的吡唑衍生物具有一定的抗肿瘤活性，具有进一步研究的价值。
具体实施方式
仪器与试剂
本发明所制得的含1,3,4-噁二唑的吡唑类化合物（I）的熔点用Mel-TEMP熔点仪测定，温度计未经校正；1HNMR用BruckAV-300型核磁共振仪测定，所用溶剂为DMSO-d6，内标TMS；红外光谱仪为NicoletImpact410型，KBr压片；ESI-MS用HP1100LC/MSD质谱仪测定。
下面的实施例用于具体说明本发明物（I）的制备，但本发明并不局限于下列实施例。
实施例1
3-乙酰基-2-(4-乙酰氧基-3,5-二甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-1）的制备：
将0.322g(1mmol)1-芳甲基-3-(4-甲氧基苯基)吡唑-5-甲酰肼（II-1）和1mmol4-羟基-3,5-二甲氧基苯甲醛加入到5mL乙醇中，加热至回流（80℃~90℃），搅拌反应5h，TLC检测反应完全后，冷却，抽滤，滤饼用冰乙醇洗涤三次，真空干燥。将上一步得到的固体（III-1）加入到5mL醋酐中，N2保护下，加热至回流（120℃~170℃），搅拌反应3~4h，TLC检测反应完全后，冷却至室温，倾入冰水混合物中，剧烈搅拌至油状物固化，过滤，滤饼水洗至中性，干燥，粗品用硅胶柱层析分离得浅黄白色固体3-乙酰基-2-(4-乙酰氧基-3,5-二甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率66%。
m.p.:141-143°C;1HNMR(300MHz,DMSO-d6)δ:2.25(s,3H,COCH3),2.29(s,3H,COCH3),3.72(s,3H,OCH3),3.77(s,3H,OCH3),3.85(s,3H,OCH3),5.77~5.79(dd,J=21.5Hz,2H,CH2Ph),6.79(s,2H,ArH),6.96(d,J=8.7Hz,2H,ArH),7.11(s,1H,inpyrazolemoiety),7.23~7.36(m,6H,ArH),7.80(d,J=8.7Hz,2H,ArH);ESI-MSm/z:571.2[M+H]+;IR(KBr,v):3451,3126,2922,2850,1767,1671,1609,1469,1436,1402,1364,1291,1251,1201,1173,1129,1055,953cm-1。
实施例2
3-乙酰基-2-(4-氯苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-2）的制备：
用4-氯苯甲醛替代4-羟基-3,5-二甲氧基苯甲醛，按实施例1所述的方法，其余所需原料、试剂同实施例1，得浅黄白色固体3-乙酰基-2-(4-氯苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率75%。
m.p.:122-124°C;1HNMR(300MHz,DMSO-d6)δ:2.21(s,3H,COCH3),3.77(s,3H,OCH3),5.70(dd,J=22.7Hz,2H,CH2Ph),6.96(d,J=8.7Hz,2H,ArH),7.17(s,1H,inpyrazolemoiety),7.23~7.51(m,10H,ArH),7.80(d,J=8.7Hz,2H,ArH);ESI-MSm/z:487.1[M+H]+;IR(KBr,v):3446,3132,2921,2851,2359,2336,1667,1612,1597,1542,1469,1437,1405,1300,1246,1182,1088,1050,1031,977cm-1。
实施例3
3-乙酰基-2-(3-乙酰氧基-4-甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-3）的制备：
用3-羟基-4-甲氧基苯甲醛替代4-羟基-3,5-二甲氧基苯甲醛，按实施例1所述的方法，其余所需原料、试剂同实施例1，得白色固体3-乙酰基-2-(3-乙酰氧基-4-甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率72%。
m.p.:158-160°C;1HNMR(300MHz,DMSO-d6)δ:2.21(s,3H,COCH3),2.25(s,3H,COCH3),3.77(s,3H,OCH3),3.78(s,3H,OCH3),5.70~5.83(dd,J=25.1Hz,2H,CH2Ph),6.96(d,J=8.7Hz,2H,ArH),7.10(s,1H,inpyrazolemoiety),7.14(d,J=8.3Hz,2H,ArH),7.24~7.37(m,7H,ArH),7.80(d,J=8.7Hz,2H,ArH);ESI-MSm/z:541.2[M+H]+;IR(KBr,v):3486,3131,2924,2851,2035,1890,1763,1673,1611,1516,1471,1443,1403,1362,1298,1273,1250,1201,1125,1051,1022cm-1。
实施例4
3-乙酰基-2-(4-乙酰氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-4）的制备：
用4-羟基苯甲醛替代4-羟基-3,5-二甲氧基苯甲醛，按实施例1所述的方法，其余所需原料、试剂同实施例1，得白色固体3-乙酰基-2-(4-乙酰氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率70%。
m.p.:128-131°C;1HNMR(300MHz,DMSO-d6)δ:2.22(s,3H,COCH3),2.27(s,3H,COCH3),3.77(s,3H,COCH3),5.71~5.83(dd,J=22.1Hz,2H,CH2Ph),6.95(d,J=8.7Hz,2H,ArH),7.17~7.37(m,9H,ArH),7.43(d,J=8.4Hz,2H,ArH),7.80(d,J=8.7Hz,2H,ArH);ESI-MSm/z:511.2[M+H]+;IR(KBr,v):3492,3061,3026,2923,2853,1759,1669,1611,1512,1470,1437,1400,1368,1302,1249,1220,1167,1052,1027,913cm-1。
实施例5
3-乙酰基-2-(2,4-二氯苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-5）的制备：
用2,4-二氯苯甲醛替代4-羟基-3,5-二甲氧基苯甲醛，按实施例1所述的方法，其余所需原料、试剂同实施例1，得白色固体3-乙酰基-2-(2,4-二氯苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率69%。
m.p.:149-151°C;1HNMR(300MHz,DMSO-d6)δ:2.23(s,3H,COCH3),3.77(s,3H,OCH3),5.76(s,2H,CH2Ph),6.95(d,J=8.6Hz,2H,ArH),7.21~7.36(m,7H,ArH),7.42~7.51(m,2H,ArH),7.74(s,1H,ArH),7.80(d,J=8.6Hz,2H,ArH);ESI-MSm/z:521.1[M+H]+;IR(KBr,v):3421,3125,3089,3072,3031,3003,2938,2837,2360,2342,1665,1610,1589,1419,1435,1404,1351,1299,1245,1175,1103,1047,1030,976cm-1。
实施例6
3-乙酰基-2-(4-硝基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-6）的制备：
用4-硝基苯甲醛替代4-羟基-3,5-二甲氧基苯甲醛，按实施例1所述的方法，其余所需原料、试剂同实施例1，得黄白色固体3-乙酰基-2-(4-硝基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率72%。
m.p.:156-157°C;1HNMR(300MHz,DMSO-d6)δ:2.23(s,3H,COCH3),3.78(s,3H,OCH3),5.71~5.84(dd,J=23.7Hz,2H,CH2Ph),6.96(d,J=8.7Hz,2H,ArH),7.25~7.38(m,7H,ArH),7.70(d,J=8.6Hz,2H,ArH),7.81(d,J=8.6Hz,2H,ArH),8.26(d,J=8.6Hz,2H,ArH);ESI-MSm/z:498.2[M+H]+;IR(KBr,v):3423,3121,3073,3030,3004,2946,2837,1666,1613,1531,1470,1450,1437,1396,1348,1289,1249,1214,1176,1111,1048,1029,978cm-1。
实施例7
3-乙酰基-2-(3-硝基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-7）的制备：
用3-硝基苯甲醛替代4-羟基-3,5-二甲氧基苯甲醛，按实施例1所述的方法，其余所需原料、试剂同实施例1，得淡黄白色固体3-乙酰基-2-(3-硝基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率73%。
m.p.:167-168°C;1HNMR(300MHz,DMSO-d6)δ:2.23(s,3H,COCH3),3.78(s,3H,OCH3),5.71~5.84(dd,J=24.4Hz,2H,CH2Ph),6.96(d,J=8.6Hz,2H,ArH),7.24~7.35(m,7H,ArH),7.71~7.87(m,4H,ArH),8.29(d,J=7.7Hz,2H,ArH);ESI-MSm/z:498.2[M+H]+;IR(KBr,v):3493,3158,3082,3002,2938,2837,1734,1662,1613,1526,1477,1452,1436,1419,1407,1351,1295,1250,1174,1051,1031,956cm-1。
实施例8
3-乙酰基-2-(3,4-二甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-8）的制备：
用3,4-二甲氧基苯甲醛替代4-羟基-3,5-二甲氧基苯甲醛，按实施例1所述的方法，其余所需原料、试剂同实施例1，得淡黄白色固体3-乙酰基-2-(3,4-二甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率68%。
m.p.:125-127°C;1HNMR(300MHz,DMSO-d6)δ:2.23(s,3H,COCH3),3.70(s,3H,OCH3),3.76(s,3H,OCH3),3.77(s,3H,OCH3),5.71~5.83(dd,J=19.2Hz,2H,CH2Ph),6.90~6.99(m,5H,ArH),7.09(s,1H,inpyrazolemoiety),7.23~7.36(m,6H,ArH),7.80(d,J=8.6Hz,2H,ArH);ESI-MSm/z:513.3[M+H]+;IR(KBr,v):2998,2923,2850,1734,1658,1611,1510,1477,1442,1402,1368,1243,1202,1178,1147,1116,1051,1033,1023,980cm-1。
实施例9
3-乙酰基-2-(3-乙酰氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-9）的制备：
用3-羟基苯甲醛替代4-羟基-3,5-二甲氧基苯甲醛，按实施例1所述的方法，其余所需原料、试剂同实施例1，得淡黄色固体3-乙酰基-2-(3-乙酰氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率66%。
m.p.:158-159°C;1HNMR(300MHz,DMSO-d6)δ:2.22(s,3H,COCH3),2.27(s,3H,COCH3),3.77(s,3H,OCH3),5.70~5.83(dd,J=24.0Hz,2H,CH2Ph),6.96(d,J=8.5Hz,2H,ArH),7.17~7.49(m,11H,ArH),7.80(d,J=8.5Hz,2H,ArH);ESI-MSm/z:511.3[M+H]+;IR(KBr,v):3421,3132,2923,2825,2359,1760,1661,1613,1471,1446,1412,1365,1302,1248,1212,1178,1052,1026,942cm-1。
实施例10
3-乙酰基-2-(3,4,5-三甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-10）的制备：
用3,4,5-三甲氧基苯甲醛替代4-羟基-3,5-二甲氧基苯甲醛，按实施例1所述的方法，其余所需原料、试剂同实施例1，得黄白色固体3-乙酰基-2-(3,4,5-三甲氧基苯基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率70%。
m.p.:160-161°C;1HNMR(300MHz,DMSO-d6)δ:2.25(s,3H,COCH3),3.66(s,3H,OCH3),3.72(s,3H,OCH3),3.77(s,3H,OCH3),5.77(s,2H,CH2Ph),6.70(s,2H,ArH),6.96(d,J=8.8Hz,2H,ArH),7.07(s,1H,inpyrazolemoiety),7.22~7.35(m,6H,ArH),7.80(d,J=8.7Hz,2H,ArH);ESI-MSm/z:543.3[M+H]+;IR(KBr,v):3415,2997,2923,2852,2041,1885,1600,1598,1540,1510,1463,1434,1402,1334,1299,1248,1175,1132,1053,1024,998cm-1。
实施例11
3-乙酰基-2-(2-呋喃基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉（I-11）的制备：
用2-呋喃甲醛替代4-羟基-3,5-二甲氧基苯甲醛，按实施例1所述的方法，其余所需原料、试剂同实施例1，得黄白色固体3-乙酰基-2-(2-呋喃基)-5-[3-(4-甲氧基苯基)-1-苯甲基-吡唑-5-基]噁二唑啉，收率73%。
m.p.:148-150°C;1HNMR(300MHz,DMSO-d6)δ:2.21(s,3H,COCH3),3.77(s,3H,OCH3),5.69~5.81(dd,J=21.2Hz,2H,CH2Ph),6.51~6.53(m,1H,ArH),6.76(d,J=3.2Hz,1H,ArH),6.96(d,J=8.8Hz,2H,ArH),7.24~7.38(m,7H,ArH),7.73(s,1H,ArH),7.81(d,J=8.7Hz,2H,ArH);ESI-MSm/z:443.2[M+H]+;IR(KBr,v):3463,3132,2923,2851,2365,2053,1670,1612,1476,1440,1402,1354,1297,1248,1174,1056,1033,1014,921cm-1。
Claims (2)
1.一类含1,3,4-噁二唑啉的吡唑衍生物在制备治疗、防肿瘤疾病药物中的用途，其特征在于：所述的吡唑衍生物为下述通式（I）表示的或其药学上能接受的盐：
其中
R1代表芳香基或5~7元杂环基；
R2代表C1~C6直链或支链烷烃、脂肪环基、芳香基或5~7元杂环基；
R3代表芳香基或5~7元杂环基；
R4代表甲基或乙基；
所述的芳香基是苯基、取代苯基、萘基或联苯基；其中所述的取代苯基含1~4个取代基，该取代基取自卤素、羟甲基、C1~C6直链或支链烷烃、硝基、腈基、三氟甲基或C1~C4烷氧基；
所述的5~7元杂环基含有1~3个选自氮、硫或氧的杂原子，能被苯基合并，并含有一个或多个选自卤素、硝基、氨基、腈基、三氟甲氧基、三氟甲基和芳香基的取代基；
所述的卤素为氟、氯、溴或碘；本通式目标化合物（Ⅰ）的制备方法如下：
其中R1、R2、R3和R4的定义同前；
其中a~b代表反应条件：
a：溶剂为乙醇；反应温度为80℃~90℃；
b：反应温度为120℃~170℃。
2.按权利要求1所述的一类含1,3,4-噁二唑啉的吡唑衍生物在制备治疗、防肿瘤疾病药物中的用途，其特征在于：所述的化合物或其药学上能接受的盐，所述的盐为上述通式（I）化合物与下列酸形成的酸加成盐：盐酸、苯磺酸、氢溴酸、硫酸、乳酸、磷酸、甲磺酸、硝酸或对甲苯磺酸。
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| Design, synthesis and biological evaluation of a novel series of 1,3,4-oxadiazole bearing N-methyl-4-(trifluoromethyl)phenyl pyrazole moiety as cytotoxic agents;Pushpan Puthiyapurayil,et al.;《European Journal of Medicinal Chemistry》;20120406;第53卷;第203-210页 * |
| Synthesis and cytotoxic activity of novel 3-(1H-indol-3-yl)-1H-pyrazole-5-carbohydrazide derivatives;Datong Zhang,et al.;《European Journal of Medicinal Chemistry》;20111001;第46卷;第5868-5877页 * |
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