CN110330486A - 咔唑类噁二唑共缀物及其制备方法和应用 - Google Patents
咔唑类噁二唑共缀物及其制备方法和应用 Download PDFInfo
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- CN110330486A CN110330486A CN201910695435.5A CN201910695435A CN110330486A CN 110330486 A CN110330486 A CN 110330486A CN 201910695435 A CN201910695435 A CN 201910695435A CN 110330486 A CN110330486 A CN 110330486A
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- carbazole
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- compound
- oxadiazoles
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Abstract
本发明涉及咔唑类噁二唑共缀物及其制备方法和应用,属于化学合成技术领域,咔唑类噁二唑共缀物如通式I所示,该类化合物对革兰阳性菌、革兰阴性菌和真菌中的一种或多种具有一定抑制活性,可以用于制备抗细菌和/或抗真菌药物,从而为临床抗微生物治疗提供更多高效、安全的候选药物,有助于解决日趋严重的耐药性、顽固的致病性微生物以及新出现的有害微生物等临床治疗问题。其制备原料简单,廉价易得,合成路线短,对抗感染方面的应用具有重要意义。
Description
技术领域
本发明属于化学合成技术领域,具体涉及咔唑类噁二唑共缀物及其制备方法和应用。
背景技术
耐药菌株的快速传播严重影响了许多临床抗菌药物的抗菌效率,在过去几十年中,免疫受损人群中受真菌感染人数的显著增加迫使研究人员们不得不加快新型抗菌药物的研发步伐。抗微生物药物,特别是氮唑类药物的产生,开辟了微生物药物治疗的新时代,自从第一个氮唑类抗菌药物克霉唑用于临床以来,氮唑类药物引起广泛关注。同时,随着唑类有药物应用日益广泛,微生物耐药性问题日趋严重,其中,导致微生物耐药性产生的机制主要是微生物细胞摄入/渗入的抗微生物药物量减少,药物作用的靶酶基因突变或过量表达,将药物泵出/转运到细胞外的能力增强,微生物耐药性给抗微生物治疗带来极其严峻的挑战。因此,对现有抗微生物化合物进行结构修饰以降低毒副作用及寻找作用于新靶点的高效低毒抗微生物药物已成为近年来抗微生物药物研究的两大热点。
咔唑霉素和murrayafoline A的成功上市,极大地推动了天然和合成咔唑类化合物在医药领域开发及应用。大量的构效关系研究表明,咔唑的多环、平面和芳香结构,使其可以通过夹层、小沟结合或静电相互作用与DNA碱基对共价结合,致使其可以靶向DNA,此外,咔唑也能破坏细菌膜的完整性,并使必需的膜相关蛋白发生错误定位,而且咔唑衍生物还能干扰DNA依赖性酶,拓扑异构酶I/II和端粒酶,或其他靶标如细胞周期蛋白依赖性激酶和雌激素受体等。这些优点极大地提高了研究人员对咔唑类多靶点抗菌药物的研发积极性。然而由于咔唑的平面刚性结构使得咔唑类化合物的溶解性较差,大大限制了其进一步的应用,因此改善咔唑类化合物的水溶性和亲脂性是有望增强其代谢稳定性和生物活性的关键。
发明内容
有鉴于此,本发明的目的之一在于提供具有高效、低毒、广谱性的咔唑类噁二唑共缀物及其可药用盐;目的之二在于提供咔唑类噁二唑共缀物及其可药用盐的制备方法;目的之三在于提供咔唑类噁二唑共缀物及其可药用盐在制备抗细菌和/或抗真菌药物中的应用;目的之三在于提供含咔唑类噁二唑共缀物及其可药用盐的制剂。
为达到上述目的,本发明提供如下技术方案:
1、咔唑类噁二唑共缀物及其可药用盐,结构如通式I所示:
式中:
R1、R2、R3、R4、R5、R6、R7、R8为氢、卤素、氰基、烷基、硝基、三氟甲基、烯基、炔基、芳基、羟烷基、羧基、酯基、酰基或巯基;
R9为氢、烷基、烯基、炔基、芳基、氰基、羟烷基、羧基、酯基、酰基或杂环基;
n为0-18的整数。
优选地
R1、R4、R5、R7、R8为氢;
R2为氢、溴或氯;
R3、R6为氢或溴;
R9为甲基、乙基、正丁基、正己基、正辛基、芳基、羟乙基、氰基、乙酰基、乙氧基酰基、羧基、乙烯基、烯丙基、乙酸基、丙酸基;
n为0-7的整数。
优选地,为下述化合物中的任一种:
优选地,所述可药用盐为钠盐、硫酸盐、盐酸盐、硝酸盐或醋酸盐。
2、所述的咔唑类噁二唑共缀物及其可药用盐的制备方法,所述方法如下:
a.中间体II-1、II-2、II-3和II-4的制备:以咔唑、2-溴咔唑、2-氯咔唑、3,6-二溴咔唑为起始原料,均以碳酸铯作碱,分别与2-溴乙酸乙酯在N,N-二甲基甲酰胺中反应,制得中间体II-1、II-2、II-3和II-4;
b.中间体III-1、III-2、III-3和III-4的制备:以中间体II-1、II-2、II-3和II-4为起始原料,均以无水乙醇为溶剂,分别滴加水合肼反应,制得中间体III-1、III-2、III-3和III-4;
c.中间体IV-1、IV-2、IV-3和IV-4的制备:以中间体III-1、III-2、III-3和III-4为原料,均以无水乙醇为溶剂,分别与二硫化碳和氢氧化钾反应,制得中间体IV-1、IV-2、IV-3和IV-4;
d.通式I所示咔唑类噁二唑共缀物及其可药用盐的制备:以中间体IV-1、IV-2、IV-3和IV-4为原料,均以碳酸铯或碳酸钾作碱,乙腈作溶剂,分别与卤代化合物发生取代反应,制得通式I所示咔唑类噁二唑共缀物及其可药用盐。
优选地,
步骤a中,所述咔唑、2-溴咔唑、2-氯咔唑或3,6-二溴咔唑与碱和2-溴乙酸乙酯的摩尔比为1:1.3:1.3;所述反应的温度为85℃;
步骤b中,所述中间体II-1、II-2、II-3或II-4与水合肼的质量体积比为1:20;所述质量体积比的单位为g:mL;所述反应的温度为80℃;
步骤c中,所述中间体III-1、III-2、III-3或III-4与二硫化碳和氢氧化钾的摩尔比为1:1.3:1.3;所述反应的温度为85℃;
步骤d中,所述中间体IV-1、IV-2、IV-3或IV-4与碱和卤代化合物的摩尔比为1:1.3:1.3;所述反应的温度为35℃。
3、所述的咔唑类噁二唑共缀物及其可药用盐在制备抗细菌和/或抗真菌药物中的应用。
优选地,所述细菌为耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC 25923、金黄色葡萄球菌ATCC 29213、克雷白氏肺炎杆菌、鲍曼不动杆菌、大肠杆菌、铜绿假单胞菌ATCC 27853或大肠杆菌ATCC 25922中的一种或多种;所述真菌为白色念珠菌、热带假丝酵母菌、烟曲霉菌或近平滑假丝酵母菌ATCC 20019中的一种或多种。
4、含所述的咔唑类噁二唑共缀物及其可药用盐的制剂。
优选地,所述制剂为片剂、胶囊剂、颗粒剂、注射剂、粉针剂、滴眼剂、搽剂、栓剂、软膏剂或气雾剂中的一种或多种。
本发明的有益效果在于:本发明提供了咔唑类噁二唑共缀物及其制备方法和应用,本发明利用药物设计拼合原理,将1,3,4-噁二唑和咔唑结合在一起,设计合成了一系列新的咔唑类噁二唑共缀物,这些化合物经体外抗微生物活性检测发现对革兰氏阳性菌(耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC 25923、金黄色葡萄球菌ATCC 29213)、革兰氏阴性菌(克雷白氏肺炎杆菌、鲍曼不动杆菌、大肠杆菌、铜绿假单胞菌27853、大肠杆菌25922)和真菌(白色念珠菌、热带假丝酵母菌、烟曲霉菌、近平滑假丝酵母菌20019)都有一定抑制活性,可以用于制备抗细菌和/或抗真菌药物,从而为临床抗微生物治疗提供更多高效、安全的候选药物,有助于解决日趋严重的耐药性、顽固的致病性微生物以及新出现的有害微生物等临床治疗问题。其制备原料简单,廉价易得,合成路线短,对抗感染方面的应用具有重要意义。
本发明的其他优点、目标和特征在某种程度上将在随后的说明书中进行阐述,并且在某种程度上,基于对下文的考察研究对本领域技术人员而言将是显而易见的,或者可以从本发明的实践中得到教导。本发明的目标和其他优点可以通过下面的说明书来实现和获得。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。
实施例1:中间体II-1的制备:
将含有咔唑(1.000g,5.980mmol)和碳酸铯(2.530g,7.780mmol)的N,N-二甲基甲酰胺(100mL)在85℃下搅拌30分钟,稍冷,然后加入2-溴乙酸乙酯(1.300g,7.780mmol),继续在85℃下搅拌反应,通过薄层色谱法跟踪直至反应完成后,将反应混合物倒入冰水中析出固体,抽滤、洗涤并干燥,得到中间体II-1(1.067g),收率:70.5%。
实施例2:中间体II-2的制备:
将含有2-溴咔唑(1.000g,4.063mmol)和碳酸铯(1.721g,5.282mmol)的N,N-二甲基甲酰胺(100mL)在85℃下搅拌30分钟,稍冷,然后加入2-溴乙酸乙酯(0.882g,5.282mmol),继续在85℃下搅拌反应,通过薄层色谱法跟踪直至反应完成后,将反应混合物倒入冰水中析出固体,抽滤、洗涤并干燥,得到中间体II-2(1.017g),收率:75.6%。
实施例3:中间体II-3的制备:
将含有2-氯咔唑(1.000g,4.974mmol)和碳酸铯(2.1071g,6.467mmol)的N,N-二甲基甲酰胺(100mL)在85℃下搅拌30分钟,稍冷,然后加入2-溴乙酸乙酯(1.080g,6.467mmol),继续在85℃下搅拌反应,通过薄层色谱法跟踪直至反应完成后,将反应混合物倒入冰水中析出固体,抽滤、洗涤并干燥,得到中间体II-3(1.104g),收率77.3%。
实施例4:中间体II-4的制备:
将含有3,6-二溴咔唑(1.000g,3.096mmol)和碳酸铯(1.311g,4.026mmol)的N,N-二甲基甲酰胺(100mL)在85℃下搅拌30分钟,稍冷,然后加入2-溴乙酸乙酯(0.672g,4.026mmol),继续在85℃下搅拌反应,通过薄层色谱法跟踪直至反应完成后,将反应混合物倒入冰水中析出固体,抽滤、洗涤并干燥,得到中间体II-4(0.994g),收率78.5%。
实施例5:中间体III-1的制备:
向含有中间体II-1(1.000g,3.950mmol)的乙醇中加入20mL水合肼后,在80℃下回流并通过薄层色谱法跟踪直至反应完成。待反应完成后,减压蒸馏除去乙醇,过滤得到白色固体化合物III-1(0.944g),收率:76.5%。
实施例6:中间体III-2的制备:
向含有中间体II-2(1.000g,3.020mmol)的乙醇中加入20mL水合肼后,在80℃下回流并通过薄层色谱法跟踪直至反应完成。待反应完成后,减压蒸馏除去乙醇,过滤得到白色固体化合物III-2(0.700g),收率:73.2%。
实施例7:中间体III-3的制备:
向含有中间体II-3(1.000g,3.483mmol)的乙醇中加入20mL水合肼后,在80℃下回流并通过薄层色谱法跟踪直至反应完成。待反应完成后,减压蒸馏除去乙醇,过滤得到白色固体化合物III-3(0.706g),收率:74.3%。
实施例8:中间体III-4的制备:
向含有中间体II-4(1.000g,2.445mmol)的乙醇中加入20mL水合肼后,在80℃下回流并通过薄层色谱法跟踪直至反应完成。待反应完成后,减压蒸馏除去乙醇,过滤得到白色固体化合物III-4(0.706g),收率:73.2%。
实施例9:中间体IV-1的制备:
向中间体III-1(1.000g,4.182mmol)的乙醇溶液中加入CS2(0.413g,5.436mmol)和KOH(0.304g,5.436mmol)水溶液后,在85℃下回流反应,并通过薄层色谱法跟踪直至反应完成。反应完成后,将混合物冷却至室温,向混合物中加入冰的盐酸水溶液以调节pH=6,得到白色固体,抽滤,并用冷水洗涤三次,干燥,得到化合物IV-1(0.826g),白色固体,收率:70.3%,熔点:>250℃;1H NMR(600MHz,DMSO-d6)δ14.52(SH)(s,1H),8.18(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.0Hz,2H),7.49(carbazole-2-H,carbazole-7-H)(t,J=7.6Hz,2H),7.26(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),5.87(CH2)(s,2H)ppm.
实施例10:中间体IV-2的制备:
向中间体III-2(1.000g,3.154mmol)的乙醇溶液中加入CS2(0.311g,4.100mmol)和KOH(0.229g,4.10mmol)水溶液后,在85℃下回流反应,并通过薄层色谱法跟踪直至反应完成。反应完成后,将混合物冷却至室温,向混合物中加入冰的盐酸水溶液以调节pH=6,得到白色固体,抽滤,并用冷水洗涤三次,干燥,得到化合物IV-2(0.807g),白色固体,收率:71.3%,熔点:>250℃;1H NMR(600MHz,DMSO-d6)δ14.57(SH)(s,1H),8.20(carbazole-5-H)(d,J=7.7Hz,1H),8.15(carbazole-4-H)(d,J=8.2Hz,1H),8.03(carbazole-1-H)(s,1H),7.71(carbazole-8-H)(d,J=8.2Hz,1H),7.52(carbazole-7-H)(t,J=7.7Hz,1H),7.41(carbazole-3-H)(dd,J=8.2,1.4Hz,1H),7.29(carbazole-6-H)(t,J=7.4Hz,1H),5.90(CH2)(s,2H)ppm.
实施例11:中间体IV-3的制备:
向中间体III-3(1.000g,3.662mmol)的乙醇溶液中加入CS2(0.361g,4.760mmol)和KOH(0.266g,4.760mmol)水溶液后,在85℃下回流反应,并通过薄层色谱法跟踪直至反应完成。反应完成后,将混合物冷却至室温,向混合物中加入冰的盐酸水溶液以调节pH=6,得到白色固体,抽滤,并用冷水洗涤三次,干燥,得到化合物IV-3(0.869g),白色固体,收率:75.3%,熔点:>250℃;1H NMR(600MHz,DMSO-d6)δ14.53(SH)(s,1H),8.20(carbazole-4-H,carbazole-5-H)(d,J=8.3Hz,2H),7.89(carbazole-1-H)(s,1H),7.70(carbazole-8-H)(d,J=8.2Hz,1H),7.51(carbazole-7-H)(t,J=7.6Hz,1H),7.29(carbazole-6-H)(t,J=7.2Hz,2H),5.90(CH2)(s,2H)ppm.
实施例12:中间体IV-4的制备:
向中间体III-4(1.000g,2.532mmol)的乙醇溶液中加入CS2(0.250g,3.291mmol)和KOH(0.184g,3.291mmol)水溶液后,在85℃下回流反应,并通过薄层色谱法跟踪直至反应完成。反应完成后,将混合物冷却至室温,向混合物中加入冰的盐酸水溶液以调节pH=6,得到白色固体,抽滤,并用冷水洗涤三次,干燥,得到化合物IV-4(0.846g),白色固体,收率:76.5%,熔点:>250℃;1H NMR(600MHz,DMSO-d6)δ14.52(SH)(s,1H),δ8.52(carbazole-4-H,carbazole-5-H)(d,J=1.5Hz,2H),7.71(carbazole-1-H,carbazole-8-H)(d,J=8.7Hz,2H),7.66(carbazole-2-H,carbazole-7-H)(dd,J=8.7,1.7Hz,2H),5.90(CH2)(s,2H)ppm.
实施例13:化合物I-1的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入溴乙烷(0.100g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-1(0.100g),白色固体,收率41.7%,熔点:101-102℃;1H NMR(600MHz,DMSO-d6)δ8.18(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.48(carbazole-2-H,carbazole-7-H)(t,J=7.6Hz,2H),7.26(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),5.99(CH2)(s,2H),3.14(CH2CH3)(q,J=7.2Hz,2H),1.30–1.22(CH3)(t,3H)ppm.
实施例14:化合物I-2的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入溴代正丁烷(0.127g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-2(0.110g),无色液体,收率46.0%;1H NMR(600MHz,DMSO-d6)δ8.18(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.48(carbazole-2-H,carbazole-7-H)(t,J=7.6Hz,2H),7.26(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),6.00(CH2)(s,2H),3.09(CH2CH2CH2CH3)(t,J=7.3Hz,2H),1.58–1.51(m,2H)(CH2CH2CH2CH3),1.26(CH2CH2CH2CH3)(dq,J=14.6,7.3Hz,2H),0.79(CH2CH2CH2CH3)(t,J=7.4Hz,3H)ppm.
实施例15:化合物I-3的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入溴代正己烷(0.152g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-3(0.100g),无色液体,收率38.5%;1H NMR(600MHz,DMSO-d6)δ8.18(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.70(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.48(carbazole-2-H,carbazole-7-H)(t,J=7.7Hz,2H),7.26(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),6.00(CH2)(s,2H),3.08(CH2CH2CH2CH2CH2CH3)(t,J=7.3Hz,2H),1.57–1.51(CH2CH2CH2CH2CH2CH3)(m,2H),1.25–1.12(CH2CH2CH2CH2CH2CH3)(m,6H),0.81(CH2CH2CH2CH2CH2CH3)(t,J=7.1Hz,3H)ppm.
实施例16:化合物I-4的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入溴代正辛烷(0.168g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-4(0.110g),无色液体,收率47.8%;1H NMR(600MHz,DMSO-d6)δ8.17(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.48(carbazole-2-H,carbazole-7-H)(t,J=7.7Hz,2H),7.25(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),5.99(CH2)(s,2H),3.08(SCH2CH2(CH2)5CH3)(t,J=7.2Hz,2H),1.59–1.50(SCH2CH2(CH2)5CH3)(m,2H),1.19(SCH2CH2(CH2)5CH3)(d,J=36.1Hz,10H),0.83(SCH2CH2(CH2)5CH3)(t,J=7.1Hz,3H)ppm.
实施例17:化合物I-5的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入2,4-二氟苄溴(0.192g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-5(0.110g),白色固体,收率34.0%,熔点:141-142℃;1H NMR(600MHz,DMSO-d6)δ8.20(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.68(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.49(carbazole-2-H,carbazole-7-H)(t,J=7.7Hz,2H),7.27(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),7.22(1,3-difluorobenzene-6-H)(dd,J=15.4,8.5Hz,1H),7.16–7.11(1,3-difluorobenzene-5-H)(m,1H),6.79(1,3-difluorobenzene-3-H)(t,J=8.4Hz,1H),6.00(CH2)(s,2H),4.36(SCH2)(s,2H)ppm.
实施例18:化合物I-6的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入对氯苄氯(0.150g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-6(0.120g),白色固体,收率41.7%,熔点:147-148℃;1H NMR(600MHz,DMSO-d6)δ8.20(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.68(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.50(carbazole-2-H,carbazole-7-H)(t,J=7.6Hz,2H),7.27(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),7.16(chlorobenzene-H)(s,4H),6.00(CH2)(s,2H),4.31(SCH2)(s,2H)ppm.
实施例19:化合物I-7的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入对氟苄氯(0.133g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-7(0.110g),白色固体,收率39.8%,熔点:146-147℃;1H NMR(600MHz,DMSO-d6)δ8.20(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.50(carbazole-2-H,carbazole-7-H)(t,J=7.7Hz,2H),7.27(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),7.20(fluorobenzene-2-H,fluorobenzene-6-H)(dd,J=8.3,5.6Hz,2H),6.94(fluorobenzene-3-H,fluorobenzene-5-H)(t,J=8.8Hz,2H),6.00(CH2)(s,2H),4.32(SCH2)(s,2H)ppm.
实施例20:化合物I-8的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入对2,4-二氯苄氯(0.180g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-8(0.120g),白色固体,收率38.4%,熔点:135-136℃;1H NMR(600MHz,DMSO-d6)δ8.20(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.68(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.55(2,4-dichloro-benzene-3-H)(d,J=1.9Hz,1H),7.49(carbazole-2-H,carbazole-7-H)(t,J=7.7Hz,2H),7.27(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),7.22(2,4-dichloro-benzene-6-H)(d,J=8.3Hz,1H),7.10(2,4-dichloro-benzene-5-H)(dd,J=8.3,2.0Hz,1H),6.00(CH2)(s,2H),4.39(SCH2)(s,2H)ppm.
实施例21:化合物I-9的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入邻氟苄氯(0.133g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-9(0.110g),白色固体,收率39.8%,熔点:107-108℃;1H NMR(600MHz,DMSO-d6)δ8.19(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.68(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.49(carbazole-2-H,carbazole-7-H)(t,J=7.6Hz,2H),7.26(carbazole-3-H,carbazole-6-H,fluorobenzene-3-H)(dd,J=13.3,6.0Hz,3H),7.15(fluorobenzene-4-H)(t,J=7.5Hz,1H),7.12–7.07(fluorobenzene-6-H)(m,1H),6.91(fluorobenzene-5-H)(t,J=7.5Hz,1H),5.99(CH2)(s,2H),4.37(SCH2)(s,2H)ppm.
实施例22:化合物I-10的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入邻氟苄氯(0.148g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-10(0.110g),白色固体,收率38.2%,熔点:123-124℃;1H NMR(600MHz,DMSO-d6)δ8.19(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.49(carbazole-2-H,carbazole-7-H)(t,J=7.7Hz,2H),7.39(2-chlorobenzene-3-H)(d,J=8.0Hz,1H),7.30–7.22(carbazole-3-H,carbazole-6-H,2-chlorobenzene-4-H)(m,3H),7.19(2-chlorobenzene-6-H)(d,J=7.5Hz,1H),7.04(2-chlorobenzene-6-H)(t,J=7.5Hz,1H),6.01(CH2)(s,2H),4.41(SCH2)(s,2H)ppm.
实施例23:化合物I-11的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入对硝基苄氯(0.200g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-11(0.120g),黄色固体,收率33.8%,熔点:139-140℃;1H NMR(600MHz,DMSO-d6)δ8.19(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.97(4-nitrobenzene-3-H,4-nitrobenzene-5-H)(d,J=8.5Hz,2H),7.66(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.48(carbazole-2-H,carbazole-7-H)(t,J=7.6Hz,2H),7.43(4-nitrobenzene-3-H,4-nitrobenzene-6-H)(d,J=8.5Hz,2H),7.26(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),5.99(CH2)(s,2H),4.46(SCH2)(s,2H)ppm.
实施例24:化合物I-12的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入2-溴乙醇(0.116g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-12(0.100g),白色固体,收率43.3%,熔点:100-101℃;1H NMR(600MHz,DMSO-d6)δ8.18(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.48(carbazole-2-H,carbazole-7-H)(t,J=7.5Hz,2H),7.26(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),5.99(CH2)(s,2H),3.62(CH2CH2OH)(q,J=5.9Hz,2H),3.25(CH2CH2OH)(t,J=6.1Hz,2H)ppm.
实施例25:化合物I-13的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入溴乙腈(0.110g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-13(0.110g),白色固体,收率48.4%,熔点:138-139℃;1H NMR(600MHz,DMSO-d6)δ8.18(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.70(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.49(carbazole-2-H,carbazole-7-H)(t,J=7.6Hz,2H),7.26(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),6.04(CH2)(s,2H),4.39(CH2CN)(s,2H)ppm.
实施例26:化合物I-14的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入氯丙酮(0.086g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-14(0.120g),白色固体,收率50.0%,熔点:136-137℃;1H NMR(600MHz,DMSO-d6)δ8.18(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.68(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.48(carbazole-2-H,carbazole-7-H)(t,J=7.6Hz,2H),7.26(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),5.98(CH2)(s,2H),4.32(CH2COCH3)(s,2H),2.16(CH2COCH3)(s,3H)ppm.
实施例27:化合物I-15的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(300mg,0.920mmol)的乙腈溶液中加入2-溴乙酸乙酯(0.154g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-15(0.120g),无色液体,收率46.0%;1H NMR(600MHz,DMSO-d6)δ8.18(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.68(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.48(carbazole-2-H,carbazole-7-H)(s,2H),7.26(carbazole-3-H,carbazole-6-H)(s,2H),5.99(CH2)(s,2H),4.12(SCH2)(s,2H),4.01(CH2CH3)(q,J=7.1Hz,2H),1.08(CH2CH3)(t,J=7.1Hz,3H)ppm.
实施例28:化合物I-16的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入氯乙酸(0.034g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-16(0.100g),白色固体,收率41.7%,熔点:239-240℃;1H NMR(600MHz,DMSO-d6)δ8.17(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.48(carbazole-2-H,carbazole-7-H)(t,J=7.6Hz,2H),7.25(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),5.96(CH2)(s,2H),3.76(CH2COOH)(s,2H)ppm.
实施例29:化合物I-17的制备:
向含有中间体IV-3(0.200g,0.634mmol)和碳酸钾(0.114g,0.825mmol)的乙腈溶液中加入氯乙酸(0.076g,0.825mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-17(0.100g),白色固体,收率41.7%,熔点:170-171℃;1H NMR(600MHz,DMSO-d6)δ8.19(carbazole-5-H)(d,J=7.7Hz,1H),8.14(carbazole-4-H)(d,J=8.2Hz,1H),8.00(carbazole-1-H)(s,1H),7.68(carbazole-8-H)(d,J=8.2Hz,1H),7.51(carbazole-7-H)(t,J=7.7Hz,1H),7.40(carbazole-3-H)(d,J=8.2Hz,1H),7.28(carbazole-6-H)(t,J=7.5Hz,1H),6.00(CH2)(d,J=10.2Hz,2H),3.93(SCH2)(s,2H)ppm.
实施例30:化合物I-18的制备:
向含有中间体IV-2(0.200g,0.557mmol)和碳酸钾(0.100g,0.724mmol)的乙腈溶液中加入氯乙酸(0.068g,0.724mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-18(0.100g),白色固体,收率41.7%,熔点:220-221℃;1H NMR(600MHz,DMSO-d6)δ8.19(carbazole-4-H,carbazole-5-H)(dd,J=7.9,2.9Hz,2H),7.85(carbazole-1-H)(s,1H),7.68(carbazole-8-H)(d,J=8.2Hz,1H),7.50(carbazole-7-H)(t,J=7.6Hz,1H),7.28(carbazole-6-H)(t,J=7.2Hz,2H),5.99(CH2)(s,2H),3.93(SCH2)(s,2H)ppm.
实施例31:化合物I-19的制备:
向含有中间体IV-4(0.200g,0.457mmol)和碳酸钾(0.083g,0.595mmol)的乙腈溶液中加入氯乙酸(0.055g,0.595mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-19(0.100g),白色固体,收率41.7%,熔点:>250℃;1H NMR(600MHz,DMSO-d6)δ8.51(carbazole-4-H,carbazole-5-H)(d,J=1.5Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.7Hz,2H),7.66(carbazole-2-H,carbazole-7-H)(d,J=1.6Hz,2H),5.98(CH2)(s,2H),3.75(SCH2)(s,2H)ppm.
实施例32:化合物I-20的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸钾(0.063g,0.920mmol)的乙腈溶液中加入溴丙烯(0.110g,0.920mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-20(0.120g),白色固体,收率58.3%,熔点:100-101℃;1H NMR(600MHz,DMSO-d6)δ8.18(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.49(carbazole-2-H,carbazole-7-H)(t,J=7.6Hz,2H),7.26(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),6.00(CH2)(s,2H),5.80(CH2CHCH2)(m,J=17.0,7.1Hz,1H),5.02(CH2CHCH2)(d,J=16.9Hz,1H),4.94(CH2CHCH2)(d,J=10.0Hz,1H),3.75(CH2CHCH2)(d,J=6.9Hz,2H)ppm.
实施例33:化合物I-21的制备:
向含有中间体IV-1(0.200g,0.711mmol)和碳酸铯(0.300g,0.920mmol)的乙腈溶液中加入氯丙酸(0.100g,0.925mmol),在35℃下搅拌反应并通过薄层色谱跟踪至反应结束。反应完成后,减压蒸馏除去乙腈。粗品经过柱色谱(以二氯甲烷为洗脱剂)纯化,得化合物I-21(0.100g),白色固体,收率39.8%,熔点:212-213℃;1H NMR(600MHz,DMSO-d6)δ8.17(carbazole-4-H,carbazole-5-H)(d,J=7.7Hz,2H),7.69(carbazole-1-H,carbazole-8-H)(d,J=8.2Hz,2H),7.51–7.45(carbazole-2-H,carbazole-7-H)(t,2H),7.25(carbazole-3-H,carbazole-6-H)(t,J=7.4Hz,2H),5.97(CH2)(s,2H),3.20(CH2CH2)(t,J=6.9Hz,2H),2.18(CH2CH2)(t,J=6.9Hz,2H).其中,DMSO-d6为氘代二甲亚砜。
实施例34:咔唑类噁二唑共缀物的体外抗微生物活性
采用符合1993年美国国家委员会制定的临床实验标准(National Committee forClinical Laboratory Standards,NCCLS)的96孔微量稀释法,检测实施例13–33制得的咔唑类噁二唑共缀物及实施例9-11制备的中间体对革兰氏阳性菌(耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC 25923、金黄色葡萄球菌ATCC29213)、革兰氏阴性菌(克雷白氏肺炎杆菌、鲍曼不动杆菌、大肠杆菌、铜绿假单胞菌27853、大肠杆菌25922)和真菌(白色念珠菌、热带假丝酵母菌、烟曲霉菌、近平滑假丝酵母菌20019)的最低抑制浓度(MIC),将待测化合物用少量二甲亚砜溶解,再加水稀释制成浓度为1.28mg/mL的溶液,再用培养液稀释至128μg/mL,35℃下培养24-72小时,将培养板至振荡器上充分摇匀后,在波长490nm处测定MIC,结果见表1-3。
表1、化合物I-1至I-21及中间体IV-1至IV-3的体外抗革兰阳性菌活性数据(MIC,μmol/mL)
从表1可以看出,本发明中化合物I-21,对所测试的革兰阳性菌表现出一定的抑制作用,中间体IV-4对所测试革兰阳性菌的显示很强的抑制活性,特别是对耐甲氧西林金黄色葡萄球菌(MRSA)的MIC值为0.0006μmol/mL,是诺氟沙星活性的83倍。
表2、化合物I-1至I-21及中间体IV-1至IV-3的体外抗革兰阴性菌活性数据(MIC,μmol/mL)
从表2可以看出,本发明中部分化合物对所测试的革兰阴性菌表现出良好的抑制作用,特别的,化合物IV-4对铜绿假单胞菌27853的MIC值为0.0006μmol/mL,是诺氟沙星活性的35.7倍。
表3、化合物I-1至I-21及中间体IV-1至IV-3的体外抗真菌活性数据(MIC,μmol/mL)
从表3可以看出,本发明化合物I-1至I-21及中间体IV-1至IV-3,对所测试的真菌均表现出一定的抑制作用,特别是中间体IV-2对白色念珠菌表现出较高的抗菌活性,MIC值为0.0028μmol/mL,是临床药物氟康唑的4.6倍。
实施例35:咔唑类噁二唑共缀物的制药用途
根据上述抗微生物活性检测结果,本发明的咔唑类噁二唑共缀物具有较好的抗细菌、抗真菌活性,可以制成抗细菌、抗真菌药物供临床使用。这些药物既可以是单方制剂,例如由一种结构的咔唑类噁二唑共缀物与药学上可接受的辅料制成;也可以是复方制剂,例如由一种结构的咔唑类噁二唑共缀物与已有抗细菌、抗真菌活性成分(如诺氟沙星、环丙沙星、磺胺甲噁唑、氟康唑、磷氟康唑、伊曲康唑等)以及药学上可接受的辅料制成,或者由不同结构的几种咔唑类噁二唑共缀物与药学上可接受的辅料制成。所述制剂类型包括但不限于片剂、胶囊剂、散剂、颗粒剂、滴丸剂、注射剂、粉针剂、溶液剂、混悬剂、乳剂、栓剂、软膏剂、凝胶剂、膜剂、气雾剂、透皮吸收贴剂等剂型,以及各种缓释、控释制剂和纳米制剂。
1、化合物I-3片剂的制备
处方:化合物I-3 10g,乳糖187g,玉米淀粉50g,硬脂酸镁3.0g,体积百分浓度为70%的乙醇溶液适量,共制成1000片。
制法:将玉米淀粉于105℃下干燥5小时备用;将化合物I-3与乳糖、玉米淀粉混合均匀,用70%的乙醇溶液制软材,过筛制湿颗粒,再加入硬脂酸镁,压片,即得;每片重250mg,活性成分含量为10mg。
2、化合物I-4胶囊剂的制备
处方:化合物I-4 25g,改性淀粉(120目)12.5g,微晶纤维素(100目)7.5g,低取代羟丙纤维素(100目)2.5g,滑石粉(100目)2g,甜味剂1.25g,橘子香精0.25g,色素适量,水适量,制成1000粒。
制法:将处方量的化合物I-4微粉化粉碎成极细粉末后,与处方量的改性淀粉、微晶纤维素、低取代羟丙纤维素、滑石粉、甜味剂、橘子香精和色素混匀,用水制软材,12-14目筛制粒,40-50℃下干燥,过筛整粒,装入空胶囊,即得;每片重50mg,活性成分含量为25mg。
3、化合物I-5颗粒剂的制备
处方:化合物I-5 26g,糊精120g,蔗糖280g。
制法:将化合物I-5、糊精、蔗糖混合均匀,湿法制粒,60℃干燥,分装,即得。
4、化合物I-6注射剂的制备
处方:化合物I-6 10g,丙二醇500mL,注射用水500mL,共制成1000mL。
制法:称取化合物I-6、加入丙二醇和注射水,搅拌溶解,再加入1g活性炭,充分搅拌后静置15分钟,用5μm钛棒过滤脱炭,再依次用孔径为0.45μm和0.22μm的微孔滤膜精滤,最后灌封于10mL安瓿中,100℃流通蒸气灭菌45分钟,即得。
5、化合物I-2粉针剂的制备
制法:化合物I-2无菌粉末在无菌条件下分装,即得。
6、化合物I-8滴眼剂的制备
处方:化合物I-8 3.78g,氯化钠0.9g,硼酸缓冲溶液适量,蒸馏水加至1000mL。
制法:称取化合物I-8、氯化钠加至500mL蒸馏水中,溶解完全后用硼酸缓冲溶液调节pH至6.5,加蒸馏水至1000mL,搅拌均匀,微孔滤膜过滤,灌装,密封,100℃流通蒸气灭菌1小时,即得。
7、化合物I-10搽剂的制备
处方:化合物I-10 4g,钾肥皂7.5g,樟脑5g,蒸馏水加至100mL。
制法:将樟脑用体积百分浓度为95%的乙醇溶液溶解,备用;将钾肥皂加热液化,备用,称取化合物I-10,在不断搅拌下加入钾肥皂液和樟脑乙醇溶液,再逐渐加入蒸馏水,乳化完全后再加入蒸馏水至全量,即得。
8、化合物I-12栓剂的制备
处方:化合物I-12 4g,明胶14g,甘油70g,蒸馏水加至100mL,公制100枚。
制法:称取明胶和甘油,加蒸馏水至100mL,水浴60℃加热熔化呈糊状时加入化合物I-12,搅拌均匀,近凝固时倒入阴道栓模具中,冷却凝固,即得。
9、化合物I-13软膏剂的制备
处方:化合物I-13 0.5-2g,十六醇6-8g,白凡士林8-10g,液体石蜡8-19g,单甘脂2-5g,聚氧乙烯(40)硬脂酸脂2-5g,甘油5-10g,尼泊金乙酯0.1g,蒸馏水加至100g。
制法:将十六醇、白凡士林、液体石蜡、单甘脂和聚氧乙烯(40)硬脂酸脂加热完全溶化后混匀,保温80℃,作为油相备用;将尼泊金乙酯加入甘油和蒸馏水中,加热至85℃溶解,再在不断搅拌下加入油相,乳化后加入化合物I-13,搅拌冷却,即得。
10、化合物I-14与氟康唑复方粉针剂的制备
处方:化合物I-14 50g,氟康唑50g,苯甲酸钠1g,共制成100瓶。
制法:取处方量的化合物V-14、氟康唑和苯甲酸钠,在无菌状态下混合均匀,分装100瓶,即得。
11、化合物I-15气雾剂的制备
处方:化合物I-15 2.5g,Span20 3g,滑石粉(100目)4g,三氯一氟甲烷加至适量。
制法:将化合物I-15、Span20和滑石粉分别置真空干燥箱内干燥数小时,置干燥器内冷却至室温,用气流粉碎机粉碎成微粉,再按处方量混匀,灌入密闭容器内,加入三氯一氟甲烷至规定量,即得。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (10)
1.咔唑类噁二唑共缀物及其可药用盐,其特征在于,结构如通式I所示:
式中:
R1、R2、R3、R4、R5、R6、R7、R8为氢、卤素、氰基、烷基、硝基、三氟甲基、烯基、炔基、芳基、羟烷基、羧基、酯基、酰基或巯基;
R9为氢、烷基、烯基、炔基、芳基、氰基、羟烷基、羧基、酯基、酰基或杂环基;
n为0-18的整数。
2.如权利要求1所述的咔唑类噁二唑共缀物及其可药用盐,其特征在于,
R1、R4、R5、R7、R8为氢;
R2为氢、溴或氯;
R3、R6为氢或溴;
R9为甲基、乙基、正丁基、正己基、正辛基、芳基、羟乙基、氰基、乙酰基、乙氧基酰基、羧基、乙烯基、烯丙基、乙酸基、丙酸基;
n为0-7的整数。
3.如权利要求1所述的咔唑类噁二唑共缀物及其可药用盐,其特征在于,为下述化合物中的任一种:
4.如权利要求1所述的咔唑类噁二唑共缀物及其可药用盐,其特征在于,所述可药用盐为钠盐、硫酸盐、盐酸盐、硝酸盐或醋酸盐。
5.权利要求1-4任一项所述的咔唑类噁二唑共缀物及其可药用盐的制备方法,其特征在于,所述方法如下:
a.中间体II-1、II-2、II-3和II-4的制备:以咔唑、2-溴咔唑、2-氯咔唑、3,6-二溴咔唑为起始原料,均以碳酸铯作碱,分别与2-溴乙酸乙酯在N,N-二甲基甲酰胺中反应,制得中间体II-1、II-2、II-3和II-4;
b.中间体III-1、III-2、III-3和III-4的制备:以中间体II-1、II-2、II-3和II-4为起始原料,均以无水乙醇为溶剂,分别滴加水合肼反应,制得中间体III-1、III-2、III-3和III-4;
c.中间体IV-1、IV-2、IV-3和IV-4的制备:以中间体III-1、III-2、III-3和III-4为原料,均以无水乙醇为溶剂,分别与二硫化碳和氢氧化钾反应,制得中间体IV-1、IV-2、IV-3和IV-4;
d.通式I所示咔唑类噁二唑共缀物及其可药用盐的制备:以中间体IV-1、IV-2、IV-3和IV-4为原料,均以碳酸铯或碳酸钾作碱,乙腈作溶剂,分别与卤代化合物发生取代反应,制得通式I所示咔唑类噁二唑共缀物及其可药用盐。
6.如权利要求5所述的方法,其特征在于,
步骤a中,所述咔唑、2-溴咔唑、2-氯咔唑或3,6-二溴咔唑与碱和2-溴乙酸乙酯的摩尔比为1:1.3:1.3;所述反应的温度为85℃;
步骤b中,所述中间体II-1、II-2、II-3或II-4与水合肼的质量体积比为1:20;所述质量体积比的单位为g:mL;所述反应的温度为80℃;
步骤c中,所述中间体III-1、III-2、III-3或III-4与二硫化碳和氢氧化钾的摩尔比为1:1.3:1.3;所述反应的温度为85℃;
步骤d中,所述中间体IV-1、IV-2、IV-3或IV-4与碱和卤代化合物的摩尔比为1:1.3:1.3;所述反应的温度为35℃。
7.权利要求1-4任一项所述的咔唑类噁二唑共缀物及其可药用盐在制备抗细菌和/或抗真菌药物中的应用。
8.如权利要求7所述的应用,其特征在于,所述细菌为耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC 25923、金黄色葡萄球菌ATCC 29213、克雷白氏肺炎杆菌、鲍曼不动杆菌、大肠杆菌、铜绿假单胞菌ATCC 27853或大肠杆菌ATCC 25922中的一种或多种;所述真菌为白色念珠菌、热带假丝酵母菌、烟曲霉菌或近平滑假丝酵母菌ATCC 20019中的一种或多种。
9.含权利要求1-4任一项所述的咔唑类噁二唑共缀物及其可药用盐的制剂。
10.如权利要求9所述的制剂,其特征在于,所述制剂为片剂、胶囊剂、颗粒剂、注射剂、粉针剂、滴眼剂、搽剂、栓剂、软膏剂或气雾剂中的一种或多种。
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