CN109608447A - 苯并噻唑二唑类衍生物及其制备方法和应用 - Google Patents
苯并噻唑二唑类衍生物及其制备方法和应用 Download PDFInfo
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- CN109608447A CN109608447A CN201910018172.4A CN201910018172A CN109608447A CN 109608447 A CN109608447 A CN 109608447A CN 201910018172 A CN201910018172 A CN 201910018172A CN 109608447 A CN109608447 A CN 109608447A
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- Prior art keywords
- imidazoles
- base
- propyl
- thiazole
- formamide
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Abstract
本发明属于药物合成领域,尤其涉及一种苯并噻唑二唑类衍生物及其制备方法,本发明还涉及二唑类衍生物在制备治疗由于真菌或细菌感染引起的各类疾病的药物中的应用。本发明限定的化合物具有较好的抗真菌和抗细菌活性,与现有的抗菌药物相比,具有结构新颖、高效、广谱等优点,因此本类化合物具有很好的应用前景。
Description
技术领域
本发明属于药物合成领域,尤其涉及一种苯并噻唑二唑类衍生物及其制备方法,本发明还涉及二唑类衍生物在制备治疗由于真菌或细菌感染引起的各类疾病的药物中的应用。
背景技术
真菌感染是一种常见病,可根据感染部位的不同,分为浅部真菌感染和深部真菌感染。其中,浅部真菌感染的发病率较高,可引起皮肤、指甲、粘膜等处的感染,但一般不会导致严重的后果;浅部真菌感染主要致病菌为毛癣菌、表皮癣菌等。深部真菌感染又称为系统性真菌感染,近些年随着免疫抑制剂、广谱抗生素的大量使用、癌症患者的放化疗和艾滋病患者的日益增多,严重损害了人体的正常免疫功能,使得深部真菌感染的发病率越来越高;念珠菌、隐球菌和烟曲霉是导致深部真菌感染的三大主要致病菌;另外,据报道结合菌、镰刀菌和丝孢菌也能够导致深部真菌感染。临床上,治疗浅部真菌感染的药物相对较多,而治疗深部真菌感染药物比较有限,仅有两性霉素B和唑类(氟康唑、伊曲康唑等)抗菌药物。而且,由于真菌细胞与人类细胞同属真核细胞,二者的相似性较高,使得抗真菌药物缺乏对人体细胞的选择性,导致较强的毒副作用,难以满足临床的治疗需求。例如:两性霉素B虽然有着较强的抗真菌活性,但只能静脉注射且肾毒性较大,严重限制了其临床应用;酮康唑作为第一个口服的广谱抗真菌药物,由于较强的肝肾毒性及胃肠道反应,于2015年在中国停止生产销售使用;应用较为广泛的伊曲康唑,能够抑制细胞色素P4503A4,与其他药物同时服药时会产生严重的相互作用;5-氟胞嘧啶抗菌谱较窄,且较易产生耐药性;同样,特比萘芬抗菌谱也较窄,仅用于浅部真菌感染。另外,由于抗真菌药物的广泛使用,导致真菌的耐药性问题也变得日趋严重。因此,亟需寻找安全、高效、低毒、广谱的抗真菌药物已经成为研究的热点。
细菌感染是临床上另一种常见病,通常致病菌侵入血循环中生长繁殖,产生毒素和其他代谢产物所引起的急性全身性感染,临床上以寒战、高热、皮疹、关节痛及肝脾肿大为特征,部分可有感染性休克和迁徙性病灶。临床上部分患者还可出现烦躁、四肢厥冷及紫绀、脉细速、呼吸增快、血压下降等。尤其是老人、儿童、有慢性病或免疫功能低下者、治疗不及时会有并发症者,可发展为败血症或者脓毒血症。细菌是许多疾病的病原体,包括肺结核、淋病、炭疽病、梅毒、鼠疫、砂眼等疾病都是由细菌所引发。例如,几种革兰氏阳性物种造成人类疾病,最常见的生物体包括葡萄球菌属、链球菌属、肠球菌属、梭菌属、杆菌属、棒状杆菌属和李斯特菌属;临床上难治性耐药细菌的实例包括耐甲氧西林金黄色葡萄球菌(MRSA)、耐青霉素肺炎链球菌(PRSP)和耐万古霉素肠球菌(VRE)。虽然,抗生素的使用使人类许多严重的细菌感染性疾病得到有效控制,但抗生素的广泛使用也导致了耐药菌株的增加,降低了现有抗生素的抗菌效率。但是,由于细菌已经对现有抗生素产生耐药性、高毒性菌株的传播和没有可利用的更有效的新型抗菌剂,细菌性传染病的治疗变得更加困难和昂贵。目前认为,最有前景的治疗策略应是不致死病原菌细胞而仅削弱病原菌的致病毒性,该策略不威胁病原菌自身的生存而不会引起耐药性问题。近来的研究发现,病原菌的致病性是由一种密度依赖的群体感应系统(QS)调控,群体感应系统通过介导致病基因的表达以实现其致病性。当致病菌密度达到一定程度时,致病菌自身合成、释放某种信号分子,能够启动相关基因的表达,调控致病菌的多种生物行为,诸如生物发光、产生毒素、形成生物膜、产生抗生素等。
虽然,临床上已有诸多的抗菌药物可以兼具抗真菌感染、抗细菌感染的作用,但是均存在单一抗菌效果显著的局限问题,例如唑类药物在临床有着不可替代的作用,但该类药物暴露出越来越多的不足,如抗菌谱窄、耐药性、毒副作用、使用剂型单一、药物相互作用等,开发新型的广谱、高效、低毒、给药方式多样化的抗菌药物一直是该领域研究的重要课题。亟待发现一种新型的抗菌药物,既能针对性治疗常见的真菌感染又能很好的抑制细菌感染,并且能够在不抑制致病菌生长的前提下,减弱致病菌毒性的物质,用于治疗真菌性或细菌感染性疾病,避免耐药菌株的增加。
发明内容
针对现有技术存在的问题,本发明提供一种苯并噻唑二唑类衍生物及其制备方法和应用;该苯并噻唑二唑类衍生物经体外抗菌活性测试,表明该类化合物具有较强的抗菌活性,在治疗真菌感染或抗细菌感染疾病中具有较大的研究价值。
为了实现上述目的,本发明提供了通式I所示的苯并噻唑二唑类衍生物如下。
所述通式中的X为C或N,优选C。
所述通式中的M为羰基或亚甲基。
所述通式中的R为氢基、卤素、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)烷基硫基,或被卤素取代的(C1-C6)烷基或(C1-C6)烷氧基.
所述通式中的R优选氢基、卤素、(C1-C6)烷基或(C1-C6)烷氧基;所述卤素为氟、氯、溴或碘代。
所述烷基为直链或支链的烷基。
本发明通式I化合物及其药学上可接受的盐或前药优选以下化合物,但这些化合物并不意味着对本发明的任何限制:
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-氯苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-甲基苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-甲氧基苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-氟苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-溴苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-4-甲基苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-4-氯苯并[d]噻唑-2-甲酰胺;
N-[(苯并[d]噻唑-2-基)甲基]-1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-胺;
N-[(6-氟苯并[d]噻唑-2-基)甲基]-1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-胺;
N-[(6-氯苯并[d]噻唑-2-基)甲基]-1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-胺。
为了实现本发明的另一个目的,本发明的通式I衍生物的制备方法具体如下。
第一种情况,当M为羰基时:
步骤1、中间体苯并噻唑甲酸的合成。
以R取代的苯胺为起始原料,首先与草酸二乙酯缩合得到中间体2,再在劳森试剂作用下发生硫代反应得到中间体3,最后经水解、铁氰酸钾作用下环合得到中间体5,具体合成路线如下。
试剂与条件(a)Diethyl oxalate,150℃,5h;(b)Lawesson’s reagent,toluene,reflux,7h;(c)2N NaOH,rt,2h;(d)K3[Fe(CN)6],H2O,0-25℃,4h.
步骤2、目标化合物的合成。
以组氨醇6为起始原料,与中间体联苯酸5经缩合试剂EDCI和HOBt作用下得到酰胺中间体7,中间体7在CDI作用下与咪唑发生取代反应,得到目标化合物8,具体合成路线如下。
试剂与条件:(a)EDCI,HOBt,DIEA,r.t.,7h;(b)CDI,imidazole,CH3CN,reflux,7h。
第二种情况:当M为-CH2-时。
以R取代的苯胺为起始原料,首先与乙醇酸乙酯缩合得到中间体9,再在劳森试剂作用下发生硫代反应得到中间体10,最后经铁氰酸钾作用下环合得到中间体11,中间体11在戴斯-马丁试剂氧化作用下得到中间体12。
其合成路线如。
试剂与条件(a)Ethyl glycolate,150℃,5h;(b)Lawesson’s reagent,toluene,reflux,7h;(c)K3[Fe(CN)6],H2O,0-25℃,4h;(d)Dess-Martin reagent,DCM,rt,1h.
步骤2、目标化合物的合成。
以组氨醇4为起始原料,与中间体取代的苯并噻唑-2-甲醛12经还原胺化得到中间体13,中间体13在CDI作用下与咪唑发生取代反应得到目标化合物14。具体合成路线如所示。
试剂与条件:(a)Na2SO4,NaBH(OAc)3;(b)CDI,imidazole,CH3CN,reflux,7h。
本发明的显著效果。
本发明人所设计的二唑类化合物经过体外抗真菌活性实验表明,具有较好的抗真菌活性,因此本发明可以用于制备治疗各种抗真菌的药物,如抗假丝酵母菌、白色念珠菌、红色毛癣菌、红色酵母菌、新生隐球菌、石膏样毛发癣菌、根霉菌、烟曲霉等药物。另外,经过体外抗细菌活性研究实验表明,具有较强的抗细菌活性,本化合物准要针对的细菌性传染病由革兰氏阳性细菌造成的葡萄球菌属、链球菌属、肠球菌属、梭菌属、杆菌属、棒状杆菌属和李斯特菌属;临床上可用于治疗细菌性传染病,例如丘疹、脓疱病、骨髓炎脑脓肿、尿路感染、脑膜炎、骨髓炎、心内膜炎、中毒性休克综合征、支气管炎、鼻炎、中耳炎、破伤风、腹泻、假膜性结肠炎、中毒性巨结肠;全身性感染(例如菌血症、败血症);腹内感染及肺感染(例如患有囊肿性纤维变性的患者中的肺感染)等由革兰氏阴性细菌引起的具体感染。
本发明限定的化合物具有较好的抗真菌和抗细菌活性,与现有的抗菌药物相比,具有结构新颖、高效、广谱等优点,因此本类化合物具有很好的应用前景。
具体实施方式
下面结合具体实施例对本发明做详细的说明。
实施例1 N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-苯并[d]噻唑-2-甲酰胺的制备
步骤1 2-氧代-2-苯氨基乙酸乙酯的的制备(中间体2)
在室温下,向20mL的草酸二乙酯中加入苯胺5.00g(53.8mmol),升温至150℃反应5h。TLC监测反应完全。将反应液冷却到室温,然后加入100mL石油醚,搅拌析出大量白色固体,再经过滤、干燥得白色固体8.83g,收率85.1%。MS[M+H]++(m/z):194.1。
步骤2 2-硫代-2-苯氨基乙酸乙酯的制备(中间体3)
将中间体22.00g(10.4mmol)溶于50mL甲苯中,然后加入劳森试剂2.10g(5.2mmol),70℃反应3h,TLC监测反应完成。将反应液减圧浓缩,再经硅胶柱层析纯化,得红色固体产品1.64g,收率75.8%。MS[M+H]+(m/z):210.2。
步骤3 2-硫代-2-苯氨基乙酸的制备(中间体4)
将中间体31.5g(7.2mmol)溶于15mL甲醇中,加入30mL 2N的氢氧化钠溶液,在室温下反应2h,TLC检测反应完成,减压浓缩除去甲醇。
步骤4苯并[d]噻唑-2-甲酸的制备(中间体5)
在冰浴条件下将浓缩液冷却到0℃,然后缓慢滴加铁氰化钾7.08g(21.6mmol)的水溶液,将反应液升至室温继续反应3h,然后用2N的盐酸调节pH至1-2,出现大量白色固体,经过滤、干燥得0.98g目标产物,收率77.0%。。MS[M+H]+(m/z):180.1。
步骤5中间体7的制备。
将中间体5(2g,11.2mmol)、EDC·HCl 2.35g(12.3mmol)和HOBt 1.66g(12.3mmol)溶于40mL DMF中,室温下搅拌1h后,加入组氨醇盐酸盐2.01g(12.28mmol)和DIEA3.61g(27.9mmol),室温下搅拌8h,TLC监测反应完全,加入30mL水,乙酸乙酯萃取,饱和食盐水洗涤有机层,Na2SO4干燥过夜。滤除干燥剂,减压浓缩得到棕色油状物2.60g,收率77.1%。ESI-MS[M+H]+(m/z):303.3.
步骤6 N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-苯并[d]噻唑-2-甲酰胺的制备。
将中间体5(1.00g,3.31mmol)、CDI 0.81g(4.96mmol)和咪唑0.45g(6.61mmol)溶解于25mL乙腈中,在70℃下反应5h,TLC监测反应完全。加压浓缩反应液,将残留物溶于乙酸乙酯,水洗,饱和食盐水洗涤,Na2SO4干燥过夜。滤除干燥剂,减压浓缩得到红棕色油状物,柱层析得到类白色固体0.71g,收率60.9%。
LC-MS m/z[M+H]+353.2.1H-NMR(CDCl3,400MHz):δ:13.13(s,1H),8.75(s,1H),8.16(d,J=7.24hz,1H),8.11(d,J=7.84HZ,1H),7.98-7.97(m,1H),7.76(s,1H),7.73(s,1H),7.56-7.51(m,2H),7.10(s,1H),6.95(s,1H),5.17-5.05(m,1H),4.66-4.54(m,2H),2.94-2.64(m,2H).
按照实施例1的方法,分别使用取代的联苯酸为原料,经缩合、关环、水解、酯化等过程制备得到实施例2-8。
实施例2 N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-氯苯并[d]噻唑-2-甲酰胺
LC-MS m/z[M+H]+387.1.1H-NMR(400MHz,DMSO-d6)δ13.19(s,1H),9.69(d,J=8.4Hz,1H),8.73(s,1H),8.38(d,J=2.1Hz,1H),8.18(d,J=8.8Hz,1H),7.79(s,1H),7.69(dd,J=8.8,2.2Hz,1H),7.63(s,1H),7.22(s,1H),6.81(s,1H),5.01-4.93(m,1H),4.58(dd,J=14.1,4.6Hz,1H),4.48(dd,J=14.1,9.9Hz,1H),2.95-2.64(m,2H).
实施例3 N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-甲基苯并[d]噻唑-2-甲酰胺
LC-MS m/z[M+H]+367.1.1H-NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.59(d,J=8.5Hz,1H),8.74(s,1H),8.04(d,J=8.4Hz,1H),8.03(s,1H),7.77(s,1H),7.62(s,1H),7.49(dd,J=8.5,1.3Hz,1H),7.20(s,1H),6.83(s,1H),5.01-4.94(m,1H),4.57(dd,J=14.1,4.6Hz,1H),4.47(dd,J=14.1,9.9Hz,1H),2.94-2.64(m,2H),2.48(s,3H).
实施例4 N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-甲氧基苯并[d]噻唑-2-甲酰胺
LC-MS m/z[M+H]+383.2.1H-NMR(600MHz,DMSO-d6)δ13.24(s,1H),9.48(d,J=8.3Hz,1H),8.76(s,1H),8.05(d,J=9.0Hz,1H),7.78(d,J=2.5Hz,1H),7.77(s,1H),7.64(s,1H),7.25(dd,J=9.0,2.6Hz,1H),7.22(s,1H),6.85(s,1H),4.98-4.94(m,1H),4.88-4.84(m,1H),4.47(dd,J=14.1,9.6Hz,1H),3.86(s,3H),2.91-2.71(m,2H).
实施例5 N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-氟苯并[d]噻唑-2-甲酰胺
LC-MS m/z[M+H]+371.1.1H-NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.61(d,J=8.3Hz,1H),8.73(s,1H),8.22(dd,J=9.1,4.9Hz,1H),8.14(dd,J=8.7,2.6Hz,1H),7.76(s,1H),7.61(s,1H),7.52(td,J=9.1,2.7Hz,1H),7.22(s,1H),6.82(s,1H),5.00-4.93(m,1H),4.91-4.84(m,1H),4.45(dd,J=14.1,9.7Hz,1H)2.94-2.62(m,2H).
实施例6 N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-溴苯并[d]噻唑-2-甲酰胺
LC-MS m/z[M+H]+331.1.1H-NMR(400MHz,DMSO-d6)δ13.23(s,1H),9.66(d,J=8.3Hz,1H),8.76(s,1H),8.55(d,J=2.0Hz,1H),8.13(d,J=8.8Hz,1H),7.82(dd,J=8.4,2.0Hz,1H),7.77(s,1H),7.64(s,1H),7.24(s,1H),6.81(s,1H),5.00-4.93(m,1H),4.93-4.86(m,1H),4.49(dd,J=14.0,9.7Hz,1H),2.84-2.67(m,2H).
实施例7 N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-4-甲基苯并[d]噻唑-2-甲酰胺
LC-MS m/z[M+H]+367.2.1H-NMR(400MHz,DMSO-d6)δ13.31(s,1H),9.41(d,J=8.4Hz,1H),8.74(s,1H),8.03(d,J=7.3Hz,1H),7.79(s,1H),7.65(s,1H),7.52-7.44(m,2H),7.23(s,1H),6.85(s,1H),4.98-4.95(m,1H),4.63(dd,J=14.1,5.1Hz,1H),4.55(dd,J=14.1,9.5Hz,1H),2.94-2.69(m,5H).
实施例8 N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-4-氯苯并[d]噻唑-2-甲酰胺
LC-MS m/z[M+H]+387.2.1H-NMR(400MHz,DMSO-d6)δ13.24(s,1H),9.36(d,J=8.4Hz,1H),8.74(s,1H),8.57(d,J=8.2Hz,1H),8.04(d,J=7.5Hz,1H),7.78-7.76(m,2H),7.62(s,1H),7.21(s,1H),6.84(s,1H),5.05–4.97(m,1H),4.64–4.54(m,2H),2.93-2.67(m,2H).
实施例9 N-[(苯并[d]噻唑-2-基)甲基]-1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-胺
步骤1中间体11的制备
按照实施例1的合成中间体5的方法以取代的苯胺和乙醇酸乙酯为起始原料经缩合、硫代和环化反应得到中间体11。
步骤2中间体12的制备
将中间体11(2.0g,12.11mmol)溶于二氯甲烷中,加入戴斯-马丁试剂(6.2g,14.53mmol),室温下反应1h,TLC检测反应完成,然后在向反应体系中加入饱和碳酸氢钠20mL和饱和硫代硫酸钠20mL,继续室温反应1h,然后用二氯甲烷萃取,饱和食盐水洗涤有机层,Na2SO4干燥过夜。滤除干燥剂,减压浓缩得到红棕色油状物,柱层析得到类白色固体1.13g,收率57.2。ESI-MS[M+H]+(m/z):164.2。
步骤3中间体13的制备
将中间体12(2.5g,15.3mmol)和组氨醇盐酸盐2.51g(15.3mmol)溶于无水乙醇中,再加入无水硫酸钠(3.65g,30.64mmol),室温下搅拌2个小时,然后在向反应体系中加入三乙酰基硼氢化钠(3.90g,18.38mmol)继续室温反应8h,TLC监测反应完全,加入饱和氯化铵中止反应,用乙酸乙酯萃取,饱和食盐水洗涤有机层,Na2SO4干燥过夜。滤除干燥剂,减压浓缩得到2.96g,收率67.1%。ESI-MS[M+H]+(m/z):289.4。
步骤4 N-[(苯并[d]噻唑-2-基)甲基]-1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-胺的制备
将中间体13(1.50g,5.20mmol)、CDI 1.27g(7.80mmol)和咪唑0.71g(10.4mmol)溶解于30mL乙腈中,在70℃下反应5h,TLC监测反应完全。加压浓缩反应液,将残留物溶于乙酸乙酯,水洗,饱和食盐水洗涤涤,Na2SO4干燥过夜。滤除干燥剂,减压浓缩得到红棕色油状物,柱层析得到类白色固体1.20g,收率68.2%。LC-MS m/z[M+H]+339.4.1H-NMR(CDCl3,400MHz):δ:13.11(s,1H),8.76(s,1H),8.14(d,J=7.44Hz,1H),8.13(d,J=7.84Hz,1H),7.74(s,1H),7.72(s,1H),7.54-7.50(m,2H),7.14(s,1H),6.98(s,1H),5.18-5.06(m,1H),4.65-4.51(m,2H),4.15(m,1H),3.83-3.76(m,2H),2.94-2.64(m,2H).
按照实施例9的方法,分别使用取代的联苯醛为原料,经偶联、还原胺化、取代反应等过程制备得到实施例10和11。
实施例10 N-[(6-氟苯并[d]噻唑-2-基)甲基]-1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-胺
LC-MS m/z[M+H]+357.2.1H-NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.61(d,J=8.3Hz,1H),8.73(s,1H),8.22(dd,J=9.1,4.9Hz,1H),8.14(dd,J=8.7,2.6Hz,1H),7.76(s,1H),7.61(s,1H),7.52(td,J=9.1,2.7Hz,1H),7.22(s,1H),6.82(s,1H),4.91-4.84(m,1H),4.45-4.35(m,1H),4.20-4.15(m,1H),3.84-3.76(m,2H),2.84-2.56(m,2H).
实施例11 N-[(6-氯苯并[d]噻唑-2-基)甲基]-1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-胺
LC-MS m/z[M+H]+373.2.1H-NMR(400MHz,DMSO-d6)δ13.15(s,1H),9.69(d,J=8.4Hz,1H),8.73(s,1H),8.38(d,J=2.1Hz,1H),8.18(d,J=8.8Hz,1H),7.79(s,1H),7.69(dd,J=8.8,2.2Hz,1H),7.63(s,1H),7.22(s,1H),6.81(s,1H),4.58(dd,J=14.1,4.6Hz,1H),4.48-4.31(m,1H),4.20-4.15(m,1H),3.83-3.77(m,2H),2.95-2.63(m,2H).
一、体外抗真菌活性试验。
实验方法如下:阳性对照药:氟康唑和伊曲康唑;供试菌种:供试真菌分别为:热带假丝酵母菌、白色念珠菌、红色毛癣菌、红色酵母菌、新生隐球菌、石膏样毛发癣菌、根霉菌、烟色曲霉菌。
1、产孢丝状真菌药敏试验方法(参照美国国家临床实验室标准化委员会(NCCLS)公布的2003年版产孢丝状真菌药敏试验方案,培养及稀释用培养基均用PDA培养基)。
(1)抗真菌药物稀释液的制备:使用一次性使用的无菌96孔板进行药敏检测;对于每种受试真菌,使用不含抗真菌药物的马铃薯葡萄糖琼脂(PDA)培养基孔作为生长对照孔;首先吸取所用的稀释剂,在第一管中加入药物的储存液,依次进行2倍比稀释。
(2)真菌接种液的制备:大多数真菌必须在35℃用马铃薯葡萄糖琼脂(PDA)培养基活化7天,在孵育7天的菌落上加入含有0.01ml吐温20的0.85%盐水1ml,制备悬液。用分光光度计调整菌悬液浓度;曲霉菌的A值(光密度值)调整至0.10;根霉菌A值(光密度值)调整至0.15;50倍比稀释后得到2倍终浓度的接种悬液。
(3)培养:96孔板在35℃有氧环境中静置孵育24-72小时,观察结果。
2、酵母样真菌药敏试验方法(参照美国国家临床实验室标准化委员会(NCCLS)公布的酵母菌药敏试验方案,培养及稀释用培养基均用SDA培养基)。
(1)抗真菌药物稀释液的制备:用13×100mm的无菌试管进行试验;对照管内只含有沙保罗葡萄糖琼脂(SDA)培养基液体培养基和受试菌株而不含抗真菌药物。
(2)菌接种液的制备:所有受试菌株至少应在沙保罗葡萄糖琼脂(SDA)液体培养基上转种2次,以确保其纯度和生长力,培养温度自始至终应为35℃。应选择经24小时培养的念珠菌的直径大于1mm的菌落5个,将其用0.85%的盐水制成悬液。将其浓度调至1×106-5×106细胞/mL。接种时将其用沙保罗葡萄糖琼脂(SDA)培养基,培养基稀释2000倍,其最终菌浓度为1.0×103-2.0×103细胞/mL。
(3)液体培养基的接种:将0.1mL的抗真菌药物的梯度稀释液分装在已编号的试管中,在生长对照管中,仅加入0.1mL的稀释液而不含药物;在调好菌接种液之后,将0.9mL的菌接种液加入相应的试管内并将其摇匀,使每一梯度的抗真菌药物稀释10倍,培养基被稀释1.11倍。
(4)培养:将试管在35℃有氧环境中培养24-72小时,观测结果。
实验结果见表1。
表1本发明实施例中化合物的抗真菌活性测试结果。
本发明实施例所限定的衍生物1-11对所测试的真菌均表现出不同程度的体外抑制活性,其中有部分化合物对部分测真菌的体外抑制活性与好于阳性对照药(伊曲康唑、氟康唑)或与其相当。
二、体外抗细菌活性试验
试验菌株:金黄色葡萄球菌、大肠杆菌、肺炎链球菌。
(1)通过肉汤微量稀释法测试本发明的化合物对金黄色葡萄球菌、大肠杆菌、肺炎链球菌的抗菌活性。
无菌条件下打开灭好菌的96孔板,第1孔加入200μL含药物的M-H肉汤,终浓度为32μg/mL。剩余11孔均加入100μL空白培养基。用移液枪从第1孔精确吸取100μL加入第二孔,吹打混匀,然后再从第2孔吸取100μL到第3孔,依此类推,直到第10孔,混匀后吸100μL弃去。此时每孔的药物浓度为64、32、16、8、4、2、1、0.5μg/mL。最后2孔不含药物,一个作为细菌生长对照,一个作为阴性对照。
在上述96孔板中,前11孔均加入108CFU/mL的菌悬液0.5μL,使最终接种量约为105CFU/mL。加菌速度要尽量快,以免时间过长,造成每孔细菌生长时间不一致而影响结果判断。每个菌株同时做3个平行试验。整个过程在灭菌后的超净工作台酒精灯旁完成。小心操作,防止污染。将接种好的96孔板放入37℃恒温培养箱培养16-20h,然后观察和记录结果。
培养完成后,将96孔板从恒温箱中取出,观察孔内细菌生长情况。在判定结果之前,要确定生长对照孔的细菌正常生长、阴性对照孔无细菌生长时结果才有意义。将肉眼观察没有细菌生长的孔中的药物浓度作为该药物对该细菌的MIC。如果出现跳孔现象,则需重复试验进行验证。抑菌活性测试结果见表2。
表2本发明化合物抗常规细菌活性测试结果(MIC,μg/mL)。
化合物 | 金黄色葡萄球菌 | 大肠杆菌 | 肺炎链球菌 |
1 | 4 | 2 | 4 |
2 | 2 | 8 | 2 |
3 | 8 | 2 | 4 |
4 | 16 | 8 | 8 |
5 | 2 | 8 | 8 |
6 | 4 | 8 | 4 |
7 | 8 | 4 | 4 |
8 | 4 | 8 | 8 |
9 | 8 | 8 | 4 |
10 | 8 | 8 | 4 |
11 | 8 | 4 | 4 |
环丙沙星 | 16 | 0.5 | 0.5 |
三、小鼠亚急性毒性实验。
将本发明实施例1-11的任一化合物以10ml/kg的浓度悬浮于含0.5%甲基纤维素的水性基料中,并用于亚急性毒性实验,所述实验中对ICR小鼠(雄性,四周大,体重为25g左右),用化合物浓度为10mg/kg至50mg/kg的悬浊液通过装有探测器的1mL注射器予以灌胃,每天一次,连续灌胃两周;直至最小口服剂量10mg/kg时,观察两周内存活情况和内脏器官、肝脏酶和肝脏重量变化等指标,没有检测到毒性症状。由此可见,本发明限定的化合物毒副作用很低。
Claims (9)
1.苯并噻唑二唑类衍生物,其特征在于,所述二唑类衍生物如通式I所示
所述通式中的X为C和N;
所述通式中的M为碳基或亚甲基;
所述通式中的R为氢基、卤素、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)烷基硫基,或被卤素取代的(C1-C6)烷基或(C1-C6)烷氧基。
2.如权利要求1所述的苯并噻唑二唑类衍生物,其特征在于,所述通式中的X优选C。
3.如权利要求1所述的苯并噻唑二唑类衍生物,其特征在于,所述通式中R优选氢基、卤素、(C1-C6)烷基或(C1-C6)烷氧基。
4.如权利要求1所述的苯并噻唑二唑类衍生物,其特征在于,所述卤素为氟、氯、溴或碘代;所述烷基为直链或支链的烷基。
5.如权利要求1所述的苯并噻唑二唑类衍生物,其特征在于,所述的衍生物选自:
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-苯并[d]噻唑-2-甲酰胺。
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-氯苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-甲基苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-甲氧基苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-氟苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-6-溴苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-4-甲基苯并[d]噻唑-2-甲酰胺;
N-[1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-基]-4-氯苯并[d]噻唑-2-甲酰胺;
N-[(苯并[d]噻唑-2-基)甲基]-1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-胺;
N-[(6-氟苯并[d]噻唑-2-基)甲基]-1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-胺;
N-[(6-氯苯并[d]噻唑-2-基)甲基]-1-(1H-咪唑-1基)-3-(1H-咪唑-4基)丙-2-胺。
6.如权利要求1-5所述的苯并噻唑二唑类衍生物用于制备抗真菌和抗细菌药物。
7.如权利要求6所述的应用,其特征在于,所述的真菌包括假丝酵母菌、白色念珠菌、红色毛癣菌、红色酵母菌、新生隐球菌、石膏样毛发癣菌、根霉菌或烟曲霉。
8.如权利要求7所述的应用,其特征在于,所述的细菌为革兰氏阳性细菌。
9.如权利要求8所述的应用,其特征在于,所述革兰氏阳性细菌为金黄色葡萄球菌、大肠杆菌、肺炎链球菌。
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Citations (1)
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CN103724360A (zh) * | 2012-10-10 | 2014-04-16 | 上海医药工业研究院 | 吡啶(或苯)并噻唑化合物及其中间体、制备方法和应用 |
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Non-Patent Citations (2)
Title |
---|
BIN SUN,等: "Design, synthesis, and biological evaluation of amide imidazole derivatives as novel metabolic enzyme CYP26A1 inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
SHIZHEN ZHAO,等: "Design, synthesis, and structure-activity relationship studies of benzothiazole derivatives as antifungal agents", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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