CN103965185A - 含有噻唑基和酯基的1,5-苯并二氮杂卓化合物及其应用 - Google Patents
含有噻唑基和酯基的1,5-苯并二氮杂卓化合物及其应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明公开了一种结构通式为(I)名称为含有噻唑基和酯基的1,5-苯并二氮杂卓化合物及其应用。该化合物具有较广谱和较高的抑真菌和抑细菌的活性,体外抑菌活性试验结果证明:该类化合物对两种真菌(新生隐球菌临床株、标准株和白色念珠菌)具有较明显的抑制活性并具有较强杀灭作用,对两种细菌包括阳性菌-金黄色葡萄球菌和阴性菌-大肠杆菌具有很强的抑制活性和杀灭作用,可作为抗菌药物候选分子和先导化合物。通式()化合物的结构如下:
Description
技术领域
本发明涉及一种药物化合物,特别是含有酯基和噻唑官能团的1,5-苯并二氮杂卓类化合物,属于药物化学技术领域。
背景技术
1,5-苯并二氮杂卓(1,5-benzodiazepine)是一类具有重要的药理活性和生理活性的杂环化合物,是新药研发中一类有价值的活性化合物。在对苯并杂卓化合物的研究中人们发现,抑菌活性也是此类化合物的一个共同的特征, 2008年宋化灿课题组报道了2,4位芳基取代的1,5-苯并二氮杂卓化合物对幽门螺旋杆菌部分菌株的抑菌活性与甲硝唑相当, 而对金葡萄球菌、大肠杆菌、绿脓杆菌也有一定的抑制作用。2011年印度化学家Dawane也报道了2位唑环取代的1,5-苯并二氮杂卓类化合物具有很好的抑菌作用,但是,到目前为止所发现的1,5-苯并二氮杂卓衍生物对真菌和细菌的抑菌活性都不高,只有用量较大时,才呈现抑菌性,因此不具备良好的成药前景。
发明内容
本发明的目的在于提供一种含有噻唑基和酯基的1,5-苯并二氮杂卓化合物。
本发明的目的还在于提供该类化合物在抑制真菌和细菌方面的应用。
为了实现本发明之目的,本发明采用如下技术方案:
本发明提供的含有噻唑基和酯基的1,5-苯并二氮杂卓化合物,其结构式如通式( )所示:
通式()如下:
式中:
R1选自取代的噻唑基,是2-取代噻唑基、4-取代噻唑基、5-取代噻唑基其中一种,噻唑环的取代基为G,G是氢、甲基、溴、氯、氟其中一种。
R2选自烷基或芳基,烷基可以是甲基、乙基、丙基其中一种;芳基可以是苯基、氟代苯基、氯代苯基、溴代苯基、甲氧基苯基、甲基苯基、乙基苯基其中一种。
R3选自烷基或卞基,可以是甲基、乙基、丙基、异丙基、正丁基和苄基其中一种。
R3中的酯基经0,1,2,3,4,5,6个碳原子相连。
R4选自氢或卤素或烷基,可以是氢、氟、氯、溴、甲基、乙基其中的一种。
n 为 0、1、2、3、4、5、6。
本发明还给出了制备通式()所示的化合物的方法。
其制备方法是:N-邻氨芳基-β-烯胺酯与噻唑醛反应、环合反应、脱水反应,得到了一系列本发明的目标化合物,即含有酯基、噻唑官能团的1,5-苯并二氮杂卓类化合物。
制备方法具体步骤如下:
溶剂选自无水甲醇、无水乙醇、DMF、DMSO、二氯甲烷、氯仿,取代的噻唑醛与系列N-邻氨芳基-β-烯胺酯反应,控制温度-10~50℃的条件下,反应5~15 小时。停止反应,静置、抽滤得粗产品,重结晶得本发明的系列化合物2-(2-噻唑基)-3-酯基-4-烃基-1, 5-苯并二氮杂卓化合物。
以下是通式()的合成路线:
实验证实,本发明的通式()类化合物对真菌新生隐球菌(临床株和标准株)有很高的抑制作用和强的杀灭作用,对细菌(金黄色葡萄球菌和大肠杆菌等)其它致病菌也有较强的杀菌作用;与标准药物氟康唑和环丙沙星作对比,结果显示:部分化合物对新生隐球菌标准株及其临床株的MIC、MIC80、MFC能力均超过了标准药物氟康唑2-10倍,对大肠杆菌和金黄色葡萄球菌的MIC、MIC80值与标准药物环丙沙星的几乎相当,因此该化合物可作为药物开发的先导化合物,这项工作对于发现具有特殊功能和新的抑菌活性的杂卓类药物将有重要意义。
本发明取得的有益效果是:本发明所涉及的化合物合成方法简单,易操作,产率高。该化合物无论是对真菌还是对细菌都有很好的抑制和杀灭作用,表现出很好的广谱性,由于化合物分子中酯基的存在,提高药物在生物体内的脂溶性, 改善药物的药代动力学性质,在杂卓环引入活性噻唑环,实现了抑菌活性的叠加,得到了抗菌疗效更强的化合物,此类化合物可作为一种极具应用潜力新型抗菌药物的候选分子和先导化合物,继而有希望成为新型的、广谱、高效、毒副作用更小的理想抗菌药物,对抗菌新药的开发具有很重大的意义。
具体实施方式
以下将结合实施例对发明作进一步说明,但并不限制本发明的范围。
本发明涉及到的化合物均为未见文献报道的新化合物,部分化合物的表征数据如下:
2-(噻唑)-3-酯基-4-烃基-1,5-苯并二氮杂卓的制备及表征
实施例1 2-(2-噻唑)-3-乙酯基-4-甲基-1,5-苯并二氮杂卓
50 mL单口烧瓶中,加入N-邻苯氨基-β-烯胺乙酯2 mmol和20 mL无水甲醇,再加入2-噻唑醛2 mmol, 0℃反应8 小时。停止反应,静置,抽滤得固体物,用无水乙醇重结晶得浅黄色固体,m.p:166~168 ℃,产率83.8%,MS[M+H+]: 316;1H NMR (CDCl3, 500MHz) δ(ppm): 6.58-7.64 (5H, m, -C6H3, -C3H2NS), 6.11 (1H, s, -NH), 6.15 (1H, s, -CH), 4.86 (1H, s, -NH), 4.11-4.15 (2H, -COOCH2), 2.60 (3H, s, -CH3), 1.17-1.19 (3H, t, -CH2CH3). IR (KBr cm-1) ν 3321 (N-H), 1680 (C=O), 1632 (C=C)。经测定该固体为2-(2-噻唑)-3-乙酯基-4-甲基-1,5-苯并二氮杂卓。
实施例2 2-(2-噻唑)-3-乙酯基-4-甲基-8-溴-1,5-苯并二氮杂卓的制备
与实施例1相同的方法进行,不同的是取N-(4-溴-2-苯氨基)-β-烯胺乙酯代替N-邻苯氨基-β-烯胺乙酯,而且需在反应完后减压浓缩,剩余物进行柱层析分离,旋转蒸发得浅黄色颗粒状固体物,m.p:168~170 ℃,产率87.8%,MS[M+H+]: 394;1H NMR (CDCl3, 500MHz) δ(ppm): 6.48-7.67 (5H, m, -C6H3, -C4H2NS), 6.12 (1H, s, -CH), 6.11 (1H, s, -NH), 4.91 (1H, s, -NH), 4.11-4.15 (2H, q, -COOCH2), 2.57 (3H, s, -CH3), 1.17-1.20 (3H, t, -CH2CH3). IR (KBr, cm-1) ν 3340 (N-H), 1670 (C=O), 1625 (C=C)。经测定该固体为2-(2-噻唑)-3-乙酯基-4-甲基-8-溴-1,5-苯并二氮杂卓。
实施例3 2-(2-噻唑)-3-乙酯基-4,8-二甲基-1,5-苯并二氮杂卓的制备
与实施例1相同的方法进行,不同的是取N-(4-甲基-2-苯氨基)-β-烯胺乙酯代替N-邻苯氨基-β-烯胺乙酯,产物为浅黄色颗粒状固体,m.p:162~164 ℃,产率90.1%。MS[M+H+]: 330;1H NMR (CDCl3, 500MHz) δ(ppm): 6.40-7.65 (5H, m, -C6H3, -C3H2NS), 6.16 (1H, s, -NH), 6.12 (1H, s, -CH), 4.81 (1H, s, -NH), 4.10-4.14 (2H, q, -COOCH2), 2.57 (3H, s, -CH3), 2.12 (3H, s, -CH3), 1.16-1.18 (3H, t, -CH2CH3). IR (KBr, cm-1) ν 3317 (N-H), 1674 (C=O), 1621 (C=C)。经测定该固体为2-(2-噻唑)-3-乙酯基-4-甲基-8-甲基-1,5-苯并二氮杂卓
实施例4 2-(2-噻唑)-3-丙酯基-4甲基-1,5-苯并二氮杂卓
与实施例1相同的方法进行,不同的是取N-邻苯氨基-β-烯胺丙酯代替N-邻苯氨基-β-烯胺乙酯,产品为白色粉末状固体,m.p:154~156 ℃,产率82.6%。 MS[M+H+]: 330;1H NMR (CDCl3, 500MHz) δ(ppm): 6.56-7.64 (6H, m, -C6H4, -C3H2NS), 6.22 (1H, s, -NH), 6.14-6.15 (1H, d, -CH), 4.90-4.92 (1H, d, -NH), 4.00-4.03 (2H, t, -CH2CH2CH3), 2.59 (3H, s, -CH3), 1.52-1.60 (2H, m, -CH2CH2CH3), 0.79-0.82 (3H, t, -CH2CH2CH3). IR (KBr,cm-1) ν3304 (N-H), 1734 (C=O), 1668 (C=C)。,经测定该固体为2-(2-噻唑)-3-丙酯基-4甲基-1,5-苯并二氮杂卓。2-(2-噻唑)-3-丙酯基-4-甲基-1,5-苯并二氮杂卓
实施例5 2-(2-噻唑)-3-异丙酯基-4甲基-1,5-苯并二氮杂卓
与实施例1相同的方法进行,不同的是取N-邻苯氨基-β-烯胺异丙酯代替N-邻苯氨基-β-烯胺乙酯,产品为白色粉末状固体,m.p:168~170 ℃,产率86.4%, MS[M+H+]: 330;1H NMR (CDCl3, 500MHz) δ(ppm): 6.58-7.63 (6H, m, -C6H4, -C3H2NS), 6.19 (1H, s, -CH), 6.13 (1H, s, -NH), 4.99-5.01 (1H, t, -CH(CH3)2), 4.90 (1H, s, -NH), 2.58 (3H, s, -CH3),1.21-1.22 (3H, d, J=5.0Hz, -CH(CH3)2), 1.06-1.07( 3H, d, -CH(CH3)2). IR (KBr, cm-1) ν 3326 (N-H), 1730 (C=O), 1669 (C=C)。经测定该固体为2-(2-噻唑)-3-异丙酯基-4甲基-1,5-苯并二氮杂卓。2-(2-噻唑)-3-异丙酯基-4-甲基-1,5-苯并二氮杂卓,白色粉末状固体,m.p:168~170 ℃,产率86.4%,
实验例6 抑菌活性实验
(1) 将试验样品用DMSO配成不同浓度的溶液,用微量加样器将其加到滤纸片上,使每片含样品量分别为200、100、50、25、12.5 μg,室温放置至DMSO挥发后备用。将对照药物氟康唑用生理盐水配成不同浓度溶液,用微量加样器将其加到滤纸片上,使每片含药量分别为10、5、2.5、1.5、0.250、0.125、0.0625 μg。
(2)将对数生长期的菌种用MH液体培养基稀释成106 CFU/mL,用无菌棉签蘸取菌液,均匀涂布在MH琼脂平板上,然后将含药纸片贴在培养基上,于37 ℃培养48小时观察结果。
(3)实验重复三次,抗菌结果取平均值。
用以上方法对本发明的部分化合物进行活性测定其结果如下:
实验例7 本实施例的抑菌活性数据如表1所示:
表1 本发明实施例抑菌活性数据
注:抑菌活性可以划分为高度敏感(>14mm)、中度敏感(10-14mm)、轻度敏感(6-10mm)和不敏感(<6mm)四个不同的程度。
实验例8 本发明的化合物与标准药物氟康唑抑菌性能对比情况如表2所示:
表2 化合物与氟康唑对新生隐球菌及其临床株的MIC、MIC80和MFC值
由表2可知,实施例1中的化合物对新生隐球菌的MIC值为2.0μg/mL、MIC80为1.0μg/mL、MFC为10.0μg/mL,与标准药物氟康唑相比较(MIC为>128.0μg/mL、MIC80为1.0μg/mL、MFC为>128.0μg/mL)杀菌能力要好很多,其中MIC80与标准药物持平,而MIC和MFC作用至少为标准的54倍和12.8倍;对新生隐球菌临床株MIC及MFC值都要比氟康唑好很多,MIC及MFC的作用能力至少为标准药物的21.3倍和9.1倍。实施例3中的化合物对新生隐球菌的MIC、MIC80、MFC分别为4.0μg/mL、3.0μg/mL、14.0μg/mL,抑菌和杀菌能力分别为标准药物的32倍、0.7倍、9.1倍;对新生隐球菌临床株的MIC、MIC80、MFC分别为3.0μg/mL、1.5μg/mL、12.0μg/mL,其MIC能力约为标准药物的42.7倍,MIC80能力约为标准药物的1.3倍,MFC能力至少约为标准药物的10.7倍。
实施例7和8抑菌及杀菌活性数据验证了本发明的通式()类化合物对真菌新生隐球菌(临床株和标准株)有很高的抑制作用和强的杀灭作用,对细菌(金黄色葡萄球菌和大肠杆菌等)其它致病菌也有较强的杀菌作用。证实了该化合物可用于药物开发的先导化合物。
Claims (9)
1.一种含有噻唑基和酯基的1,5-苯并二氮杂卓化合物,其特征在于其结构如通式( )所示,通式()如下:
通式()中,R1选自取代的噻唑基,是2-取代噻唑基、4-取代噻唑基、5-取代噻唑基其中一种;
R2选自烷基或芳基;
R3选自烷基或卞基;
R4选自氢或卤素或烷基;
n 为 0、1、2、3、4、5、6。
2.根据权利要求1所述的化合物,其特征在于R1噻唑环的取代基为G,G是氢、甲基、溴、氯、氟其中一种。
3.根据权利要求1所述的化合物,其特征在于R2中的烷基是甲基、乙基、丙基其中一种。
4.根据权利要求1所述的化合物,其特征在于R2中的芳基是苯基、氟代苯基、氯代苯基、溴代苯基、甲氧基苯基、甲基苯基、乙基苯基其中一种。
5.根据权利要求1所述的化合物,其特征在于R3中的烷基是甲基、乙基、丙基、异丙基、正丁基其中一种。
6.根据权利要求1所述的化合物,其特征在于R3中的酯基经0,1,2,3,4,5,6个碳原子相连。
7.根据权利要求1所述的化合物,其特征在于卤素是氟、氯和溴其中一种。
8.根据权利要求1所述的化合物,其特征在于R4 中的烷基是甲基、乙基其中的一种。
9.一种如权利要求1所述的通式为()的化合物的应用,其特征在于作为抗菌药物候选分子和先导化合物。
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