CN103664910A - 含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物及其制法与其抗菌活性 - Google Patents
含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物及其制法与其抗菌活性 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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Abstract
Description
技术领域
本发明涉及一类新型含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物及其制备方法与作为抗菌药物的用途。
背景技术
过去的几十年中,多药耐药微生物的问题在全球已经达到令人震惊的程度。因此,寻找高效、低副作用的抗微生物感染的新药物成为一个重要和迫切的任务。
1,4-苯并二噁烷衍生物是许多药物和天然产物中常见的结构单元,并且有着重要的生物活性,它们可以作为临床医疗阻滞剂,在抗高血压、抗高血糖等疗法中扮演着日益重要的角色。并且近年来,有文献报道,1,4-苯并二噁烷衍生物具有一定的抗菌、抗炎、抗肿瘤的活性。
三氮唑是生产酮康唑、伊曲康唑、氟康唑、伏立康唑、沙排康唑等抗真菌药物的重要中间体,由于该类药物具有抗菌谱广、抗真菌活性好、吸收好,尤其适于口服吸收等特点,因此在临床上被广泛使用。因此,对1,4-苯并二噁烷结构进行修饰,形成含1,4-苯并二噁烷的1,2,4-三氮唑结构,能增强其抗菌活性。
发明内容
本发明的目的是提供一类新型的含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物及其制备方法和用途。本发明的技术方案如下:
一类新型的含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物,它具有如下通式:
式中R为:
一种制备权利要求1所述的含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物的方法,其特征是它由下列步骤组成:
步骤1.于50ml乙醇中加入10g 1,4-苯并二噁烷-5-羧酸溶解,缓慢滴入3ml浓硫酸,80℃回流,反应10h。反应结束后,蒸干溶剂,加入20ml乙酸乙酯,饱和氯化钠洗涤3次,无水硫酸钠干燥,快速柱层析,得无色透明油状液体1,4-苯并二噁烷-5-羧酸乙酯。
步骤2.用20ml乙醇溶解1,4-苯并二噁烷-5-羧酸乙酯,然后加入水合肼(85%)30ml,80℃回流,反应24h。反应结束后,冷却至室温后大量白色固体析出,饱和氯化钠溶液洗涤3次,乙醇洗涤3次除去水合肼,在乙醇中重结晶得白色针状固体,过滤,干燥,得1,4-苯并二噁烷-5-羧酸酰肼6g。
步骤3:1.6g KOH溶于20ml乙醇,加入6g上步得到的酰肼,冰浴搅拌, 加入2ml CS2,冰浴反应15h。反应结束后,无水乙醚稀释,抽滤,得白色钾盐6.4g。然后将得到的盐溶于10ml水,加入30ml水合肼(85%),回流6-7h。反应结束后,冷却至室温,100ml水稀释,盐酸调PH至无固体析出。抽滤,水洗,乙醇重结晶得1,4-苯并二噁烷-5-羧酸三氮唑3.6g。
步骤4:用10ml乙醇溶解步骤3所得三氮唑,然后加入几滴冰醋酸,再向反应液中加入等摩尔量的苯甲醛,80℃回流,反应12h。反应结束后,冷却至室温,有大量白色或黄色固体析出,过滤得到产物粗品,将粗品用乙醇重结晶,得到产物,含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物。
实验结果表明,本发明的新型含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物对细菌具有明显的抑制作用。因此本发明的含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物可以应用于制备抗菌药物。
具体实施方式
通过以下实施例进一步详细说明本发明,但本发明的范围并不受这些实施例的任何限制。
实施例1:(E)-5-(2,3-二氢[b][1,4]二噁烷-5-基)-4-((4-氟亚苄基)氨基)-4H-1,2,4-三氮唑-3-巯基的制备
用10ml乙醇溶解步骤3所得三氮唑,然后加入几滴冰醋酸,再向反应液中加入等摩尔量的对氟苯甲醛,80℃回流,反应12h。反应结束后,冷却至室温,有大量白色或黄色固体析出,过滤得到产物粗品,将粗品用乙醇重结晶,得到目标化合物。得到白色或浅黄色粉末,产率89%,mp:201-202℃;1H NMR(300MHz,DMSO-d6,δppm):4.23-4.26(d,J=8.92Hz,2H);4.28-4.29(d,J=3.96Hz,2H);6.82-6.97(m,2H);7.24-7.36(m,3H);7.82(m,2H);9.78(s,1H);13.52(s,1H).MS(ESI):386.40(C17H13FN4O2S,[M+H]+).Anal.Calcd for C17H12FN4O2S:C,57.29;H,3.68;N,15.72%;Found:C,57.22;H,3.61;N,15.69%.
实施例2:(E)-5-(2,3-二氢[b][1,4]二噁烷-5-基)-4-((4-氯亚苄基)氨基)-4H-1,2,4-三氮唑-3-巯基的制备
制备方法同实施例1。以对氯苯甲醛代替对氟苯甲醛,得到目标化合物。白色粉末,产率76%,mp:207-208℃;1H NMR(300MHz,DMSO-d6,δppm):4.21-4.24(d,J=8.22Hz,2H);4.27-4.30(d,J=7.38Hz,2H);6.88-6.94(m,2H);7.23-7.34(m,3H);7.86(m,2H);9.92(s,1H);13.41(s,1H).MS(ESI):372.83(C17H13FN4O2S,[M+H]+).Anal.Calcd for C17H12FN4O2S:C,54.77;H,3.51;N,15.03%;Found:C,54.82;H,3.52;N,15.24%.
实施例3:(E)-5-(2,3-二氢[b][1,4]二噁烷-5-基)-4-((4-溴亚苄基)氨基)-4H-1,2,4-三氮唑-3-巯基的制备
制备方法同实施例1。以对溴苯甲醛代替对氟苯甲醛,得到目标化合物。白色粉末,产率79%,mp:213-215℃;1H NMR(300MHz,DMSO-d6,δppm):4.22-4.24(d,J=5.21Hz,2H);4.25-4.28(d,J=8.51Hz,2H);7.04-7.08(m,2H);7.46-7.51(d,J=14.72Hz,2H);7.58(m,2H);9.98(s,1H);13.29(s,1H).MS(ESI):417.28(C17H13BrN4O2S,[M+H]+).Anal.Calcd for C17H12BrN4O2S:C,48.93;H,3.14;N,13.43%;Found:,C,48.88;H,3.13;N,13.29%.
实施例4:(E)-5-(2,3-二氢[b][1,4]二噁烷-5-基)-4-((4-甲基亚苄基)氨基)-4H-1,2,4- 三氮唑-3-巯基的制备
制备方法同实施例1。以对甲基苯甲醛代替对氟苯甲醛,得到目标化合物。白色粉末,产率86%,mp:203-205℃;1H NMR(300MHz,DMSO-d6,δppm):3.56(s,3H);4.25-4.27(d,J=4.67Hz,2H);4.34-4.37(d,J=7.85Hz,2H);6.85-6.89(m,2H);7.28-7.35(m,3H);7.76(m,2H);9.89(s,1H);13.64(s,1H).MS(ESI):352.41(C18H16N4O2S,[M+H]+).Anal.Calcd for C18H15N4O2S:C,61.35;H,4.58;N,15.90%;Found:C,61.41;H,4.57;N,15.78%.
实施例5:(E)-4-(亚苄基)-5-(2,3-二氢[b][1,4]二噁烷-5-基)-4H-1,2,4-三氮唑-3-巯基的制备
制备方法同实施例1。以无取代苯甲醛代替对氟苯甲醛,得到目标化合物。白色粉末,产率80%,mp:201-202℃;1H NMR(300MHz,DMSO-d6,δppm):4.24-4.28(d,J=9.59Hz,2H);4.32-4.36(d,J=8.32Hz,2H);6.79-6.86(m,2H);7.28-7.35(m,3H);7.84(m,2H);9.92(s,1H);13.61(s,1H).MS(ESI):338.38(C17H13N4O2S,[M+H]+).Anal.Calcd for C17H12N4O2S:C,60.34;H,4.17;N,16.56%;Found:C,62.41;H,4.16;N,16.47%.
实施例6:(E)-5-(2,3-二氢[b][1,4]二噁烷-5-基)-4-((4-甲氧基亚苄基)氨基)-4H-1,2,4-三氮唑-3-巯基的制备
制备方法同实施例1。以对甲氧基苯甲醛代替对氟苯甲醛,得到目标化合物。白色粉末,产率82%,mp:197-199℃;1H NMR(300MHz,DMSO-d6,δppm):3.67(s,3H);4.13-4.16(d,J=10.32Hz,2H);4.31-4.35(d,J=9.23Hz,2H);6.88-6.92(m,2H);7.34-7.39(m,3H);7.81(m,2H);9.72(s,1H);13.49(s,1H).MS(ESI):348.41(C18H16N4O3S,[M+H]+).Anal.Calcd for C18H15N4O3S:C,58.68;H,4.38;N,15.21%;Found:C,58.75;H,4.37;N,15.33%.
实施例7:含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物抗菌活性研究
1.实验材料和方法
1.1药品与试剂
Mueller-Hinton培养基(牛肉浸粉5g,酪蛋白水解物17.5g,淀粉1.5g,琼脂12.5g,加入1000mL蒸馏水中)、卡那霉素、青霉素、DMSO、MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,商品名为噻唑蓝)、异丙醇、盐酸、均为分析纯试剂、合成的化合物1-6、PBS缓冲液(磷酸盐缓冲液0.01mol/L,pH7.4,Na2HPO4.12H2O 2.9g,KH2PO4 0.2g,NaCl 8.0g,KCl 0.2g,蒸馏水1000mL)。
1.2菌种
大肠杆菌(E.coli)、金黄色葡萄球菌(S.aureus)、枯草芽孢杆菌(B.subtilis)、铜绿假单胞菌(P.aeruginosa)
1.3实验方法
1.3.1培养基的配制
取牛肉浸粉5g,酪蛋白水解物17.5g,淀粉1.5g,琼脂12.5g,加入1000mL蒸馏水中,加热煮沸溶解,分装,121℃高压灭菌15分钟备用。
1.3.2试验菌的培养
在无菌室内,取大肠杆菌,金黄色葡萄球菌,枯草芽孢杆菌和铜绿假单胞菌四种试验菌株,于酒精灯下用接种针分别在四种试验菌株斜面上,刮取少量斜面菌苔,用一定量的无菌水制成菌悬液,然后取一定量加到已融化又冷却至50℃左右的MH培养基中,摇匀,即刻倒入无菌培养皿中,待充分冷凝后用胶塞密封后,于37℃培养18-24小时备用。吸取菌液1mL,用MH培养基按1∶1000稀释,使菌液浓度约为105cfu/mL。
1.3.3抗菌实验:
将待测药品溶于DMSO中配制成2mg/mL的溶液,然后用二倍稀释法将药品稀释成一定浓度梯度(50μg/mL,25μg/mL,12.5μg/mL,3.125μg/mL)与DMSO中。于灭菌微量滴定板第一条中分别加入100μL的培养基,第二条为阳性对照,加入100μL菌悬液。其余的孔中加入90μL的菌悬液和10μL的药物溶液。每个药物溶液浓度平行3次。在微量滴定板底部标明细菌名称。将处理完的培养皿于37℃培养24h,观察。
1.3.4 MIC的测定
在每个微量滴定板都可以直观的测定其MIC值之后,在板的每个孔中加入50μL PBS缓冲液(磷酸盐缓冲液0.01mol/L,pH7.4,Na2HPO4.2H2O 2.9g,KH2PO4 0.2g,NaCl 8.0g,KCl 0.2g,蒸馏水1000mL),其中包含2mg MTT/mL。在室温下继续孵育4-5h。将孔中的物质移出并加入100μL含有5%1mol/L HCl的异丙醇来萃取染料。继续在室温下孵育12h,用酶标仪测定各孔光吸收(OD值),测定波长550nm。根据各孔OD值计算药物对细菌生长的最小抑制浓度。
最小抑制浓度(minimum inhibitory concentration,MIC):在特定环境下孵育24小时,可抑制某种微生物出现明显增长的最低药物浓度即最小抑制浓度,根据测定的光密度(OD值),制作细菌生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的MIC见表1所示。
2.实验结果
表1本发明所列含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物对细菌的抑制MIC值(μg/mL)
Kanamycin;Penicillin:阳性对照。
Claims (3)
2.一种制备权利要求1所述的含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物的方法,其特征是它由下列步骤组成:
步骤1.于50ml乙醇中加入10g 1,4-苯并二噁烷-5-羧酸溶解,缓慢滴入3ml浓硫酸,80℃回流,反应10h。反应结束后,蒸干溶剂,加入20ml乙酸乙酯,饱和氯化钠洗涤3次,无水硫酸钠干燥,快速柱层析,得无色透明油状液体1,4-苯并二噁烷-5-羧酸乙酯。
步骤2.用20ml乙醇溶解1,4-苯并二噁烷-5-羧酸乙酯,然后加入水合肼(85%)30ml,80℃回流,反应24h。反应结束后,冷却至室温后大量白色固体析出,饱和氯化钠溶液洗涤3次,乙醇洗涤3次除去水合肼,在乙醇中重结晶得白色针状固体,过滤,干燥,得1,4-苯并二噁烷-5-羧酸酰肼6g。
步骤3:1.6g KOH溶于20ml乙醇,加入6g上步得到的酰肼,冰浴搅拌,加入2ml CS2,冰浴反应15h。反应结束后,无水乙醚稀释,抽滤,得白色钾盐6.4g。然后将得到的盐溶于10ml水,加入30ml水合肼(85%),回流6-7h。反应结束后,冷却至室温,100ml水稀释,盐酸调PH至无固体析出。抽滤,水洗,乙醇重结晶得1,4-苯并二噁烷-5-羧酸三氮唑3.6g。
步骤4:用10ml乙醇溶解步骤3所得三氮唑,然后加入几滴冰醋酸,再向反应液中加入等摩尔量的苯甲醛,80℃回流,反应12h。反应结束后,冷却至室温,有大量白色或黄色固体析出,过滤得到产物粗品,将粗品用乙醇重结晶,得到产物,含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物。
3.根据权利要求1所述的含1,4-苯并二噁烷的1,2,4-三氮唑类衍生物在制备抗菌药物中的应用。
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