CN108003177B - 一种苯并噁嗪利福霉素类衍生物及其制备方法和用途 - Google Patents
一种苯并噁嗪利福霉素类衍生物及其制备方法和用途 Download PDFInfo
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- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种苯并噁嗪利福霉素类衍生物,其化学结构式如式<Ⅰ>所示,该苯并噁嗪利福霉素类衍生物具有优秀的抗菌性能,对常见的菌种具有优秀的抗菌效果,同时还能对一些耐药菌具有良好的抗菌作用,弥补了现有相关药物的不足,可为下一步的抗菌药物的研发提供一定的基础。本发明还提供了制备该苯并噁嗪利福霉素类衍生物的方法以及将该苯并噁嗪利福霉素类衍生物在制备抗生素药物方面的用途。
Description
技术领域
本发明属于抗生素技术领域,具体涉及一种苯并噁嗪利福霉素类衍生物及其制备方法和用途。
背景技术
利福霉素类(rifamycins)药物是一类重要的抗生素,其常用于治疗结核病。利福霉素类药物的母核结构如式<Ⅲ>所示,为27个碳的大环内酰胺,环中含一个萘环。萘环上,由一脂肪链分别与C-2和C-12位碳相连接,构成“安莎桥”结构。
目前,美国食品药品管理局(FDA)批准用于TB治疗的利福霉素类药物主要有利福平(rifampicin,RFP)、利福布汀(rifabutin,RBT)、利福喷丁(rifapentine,RPT),这些药物包括利福定(rifandin)已被国家食品药品监督管理局(SFDA)批准用于TB治疗。
不过,现有的利福霉素类药物虽然具有较强的抗菌性,且抗菌谱也较大,但是对一些耐药菌的抗性仍然不足,限制了其进一步的应用。这些耐药菌为:多重耐药结核分枝杆菌临床株(FJ05120)、广泛耐药结核分枝杆菌临床株(FJ05436、FJ05195)。其中,FJ05436对INH、RMP、STR、CPM、OFX、TYPE耐药,FJ05195对INH、RMP、EMB、STR、OFX、KAN、TYPE耐药。
美国专利US20050203085A1中,研究者发现了包括如式<Ⅳ>所示的众多化合物具有很好的抗菌性。不过,经研究,其对于这些耐药菌的抗性仍差强人意。
之后,WO2013086415A1对类似的化合物也进行了大量的研究,其对众多的修饰方式进行了大量的考察。不过,其仍然没有考察可以对这些耐药菌具有显著抗菌性的化合物。
我国的研究人员虽然对此也进行了一些研究,如王建伟等人在《苯并噁嗪利福霉素衍生物的合成及其抗菌活性初探》发现了一些具有抗菌成分的化合物,但是所得化合物的活性均比较低。
综上所述,虽然利福霉素类得到了广泛的研究,但是仍需开发活性更好且对一些耐药菌具有良好抗菌性的相应化合物。
发明内容
针对现有技术的缺点,本发明的目的之一在于提供一种苯并噁嗪利福霉素类衍生物,所述苯并噁嗪利福霉素类衍生物的化学结构式如式<Ⅰ>所示:
如本发明的实验例所示,本发明所得的化合物对于常规革兰阳性菌、屎肠球菌、粪肠球菌和多重耐药结核分枝杆菌临床株(FJ05120)、广泛耐药结核分枝杆菌临床株(FJ05436、FJ05195)均具有很好的抗菌性。虽然在对革兰阴性菌的抗菌性较利福平、利福喷丁和异烟肼弱,但其活性仍然是比较可观的。
本发明的另外一个目的在于提供包含如<Ⅰ>所示衍生物或其药学上可以接受的盐的药物组合物。
本发明所得衍生物既能和碱生成盐,又能和酸生成盐,任何能够与式<Ⅰ>所示的利福霉素衍生物形成盐的碱或酸都可以被采用。与碱成盐的例子是金属盐,特别是碱金属盐或碱土金属盐、铵盐和胺盐,尤其是与甲胺、乙胺、二乙胺、三乙胺、吡咯烷、吗啉、六亚甲基亚胺等所形成的盐。与酸成盐的例子是与无机酸,如硫酸或盐酸所形成的盐,以及与有机酸,例如对甲苯磺酸、三氟乙酸或醋酸所形成的盐。
本发明的还有一个目的在于提供制备上述衍生物的方法,该方法的步骤包括:
将如式<Ⅱ>所示化合物与1-(2-嘧啶基)哌嗪或1-(反式肉桂基)哌嗪置于有机溶剂中,在二氧化锰条件下加热至20~60℃反应1~6小时,然后进行萃取、水洗、盐洗、干燥、过滤、去除溶剂,获得粗品,然后进行纯化,得到深蓝色粉末,即为所述衍生物;
式<Ⅱ>所示化合物为3’-(叔丁基二甲基硅氧基)苯并噁嗪利福霉素,其制备方式可以参考文献[ChemPharmBull,1993,41(1):148-155]和中国专利(ZL91105825.7)。
所述有机溶剂包括氯代烃、醇类溶剂、吡啶类溶剂、芳烃、非质子极性溶剂中的一种;所述氯代烃包括二氯甲烷或氯仿;所述醇类溶剂包括甲醇或乙醇;所述吡啶类溶剂包括吡啶;所述芳烃包括乙腈,苯或甲苯;所述非质子极性溶剂包括二甲基甲酰胺、二甲基乙酰胺或二甲亚砜。
一般情况下,所述式<Ⅱ>所示化合物与1-(2-嘧啶基)哌嗪或1-(反式肉桂基)哌嗪的摩尔比为1:1~3。
所述纯化的方法为:通过柱层析方法进行纯化1~2次,洗脱剂系统为二氯甲烷、乙酸乙酯和甲醇的混合液。作为本发明的一个优选方案,所述洗脱剂系统中二氯甲烷、乙酸乙酯和甲醇的体积比为2.4:1.0:0.12。
本发明的利福霉素衍生物是一种深蓝色的粉末,能以较为容易的方法从反应产物中分离和纯化,即从反应体系中除去反应溶剂得到粗产品,再经重结晶,柱层析等方法被纯化。
优选的,进行所述萃取时,利用氯仿或者与氯仿极性相近的中等极性溶剂进行。
式<Ⅰ>所示的本发明的利福霉素衍生物还可以通过与诸如抗坏血酸、亚硫酸氢钠之类的还原剂发生还原反应而被转化成如式<Ⅴ>所示的利福霉素衍生物。
本发明还有一个目的在于提供上述衍生物或者上述药物组合物在制备抗生素药物方面的用途。
本发明的有益效果:
本发明所得的苯并噁嗪利福霉素类衍生物具有优秀的抗菌性能,对常见的菌种具有优秀的抗菌效果,同时还能对一些耐药菌具有良好的抗菌作用,弥补了现有相关药物的不足,可为下一步的抗菌药物的研发提供一定的基础。
具体实施方式
下面通过实施例对本发明进行具体描述,有必要在此指出的是以下实施例只是用于对本发明进行进一步的说明,不能理解为对本发明保护范围的限制,该领域的技术熟练人员根据上述发明内容所做出的一些非本质的改进和调整,仍属于本发明的保护范围。
实施例1
3’-羟基-5’-[4-(2-嘧啶基)-1-哌嗪基]苯并噁嗪利福霉素的合成
参考文献[中国医药工业杂志,1993,24(2):49-51;化工试剂,2004,18(10):22-24],以2-氨基嘧啶为原料合成1-(2-嘧啶基)哌嗪。
将2.5g(2.7mmol)化合物<Ⅱ>溶于30mLDMSO中,室温下搅拌条件下缓慢加入1-(2-嘧啶基)哌嗪0.53g(3.24mmol),再加入1gMnO2并升温至50℃反应。反应5h后,过滤,将滤液倒入90mL乙酸乙酯中,有机相用水洗(30ml×3),再用饱和食盐水洗涤(30ml×3)。然后以无水硫酸钠干燥有机相0.5h,过滤,滤液用旋转蒸发仪除去溶剂,得到化合物1的粗品为深蓝色粉末。粗品以洗脱剂(二氯甲烷:乙酸乙酯:甲醇=2.4:1.0:0.12)洗脱,进行柱层析分离与纯化,重复两次洗脱,除去溶剂后得到深蓝色粉末1.10g[TLC条件:Rf=0.67(二氯甲烷:乙酸乙酯:甲醇=1.0:1.0:0.2)]。
质谱数据(MS)(m/z):
理论分子量:M=962.4
[M+1]+=963.3[M+1-OCH3]+=931.3
红外波谱数据(IR)(波数cm-1):
3440.5,3262.9,3025.7,2968.3,2933.2,2878.2,2698.7,1733.1,1712.0,1689.9,1660.9,1613.5,1585.3,1488.4,1448.8,1412.0,1369.2,1311.4,1281.5,1252.9,1208.3,1165.5,1141.2,1061.9,1021.7,981.6,950.1,912.7,895.2,812.2,797.5,770.4,754.6,661.7,638.5,554.5,527.5,489.5,454.1,433.1,409.0
核磁共振氢谱(1H-NMR)(δ:ppm)
0.76(H-34,3H),0.80(H-33,3H),0.91(H-31,3H),0.96(H-32,3H),1.68(H-26,1H),1.84(H-22,1H),1.95(H-24,1H;H-36,3H)(两峰重叠),1.89(H-13,3H),2.16(H-30,3H;H-20,1H)(两峰重叠),2.31(H-14,3H),2.93(H-37,3H),3.01(H-23,1H),3.27(H-27,1H),3.42(H-21,1H),3.93~4.15[H-2”(6”),4H;H-3”(5”),4H](哌嗪环上两峰重叠),4.92(H-25,1H),5.14(H-28,1H),5.33(H-19,1H),5.76(H-17,1H),5.98(H-29,1H),6.09~6.13(H-4’,1H;H-6’,1H)(两峰重叠),6.63(-N=CH-CH=CH-N=,1H),7.19(H-18,1H),8.34(-N=CH-CH=CH-N=,2H)
实施例2
3’-羟基-5’-(4-反式肉桂基-1-哌嗪基)苯并噁嗪利福霉素
将2.5g(2.7mmol)化合物III溶于40mLDMSO中,室温下搅拌条件下缓慢加入1-(反式肉桂基)哌嗪0.82g(4.05mmol),再加入1.5gMnO2并升温至45℃反应。反应4h后,过滤,将滤液倒入100mL乙酸乙酯中,有机相用水洗(35mL×3),再用饱和食盐水洗涤(30mL×3)。然后以无水硫酸钠干燥有机相0.5小时,过滤,滤液用旋转蒸发仪除去溶剂,得到化合物2的粗品为深蓝色粉末。粗品以洗脱剂(二氯甲烷:乙酸乙酯:甲醇=4:1:0.05)洗脱,进行柱层析分离与纯化,重复两次洗脱,除去溶剂后得到深蓝色粉末1.44g[TLC条件:Rf=0.61(二氯甲烷:乙酸乙酯:甲醇=2.0:1.0:0.1)]。
波谱数据:
MS数据(m/z):
理论分子量:M=1000.45
[M+1]+=1001.2[M+1-OCH3]+=969.2
红外波谱数据(IR)(波数cm-1):
3448.2,3259.8,3025.1,2967.3,2933.8,2881.8,2817.5,2696.3,1733.3,1712.2,1690.1,1660.6,1612.4,1586.7,1566.2,1489.1,1413.4,1370.7,1312.6,1280.8,1253.3,1210.2,1166.0,1141.7,1100.9,1084.4,1078.8,1062.6,1017.8,996.6,970.2,946.6,912.8,895.9,812.4,794.8,770.3,753.4,741.1,693.3,661.8,548.0,528.8,490.0,445.9,436.3
核磁共振氢谱(1H-NMR)(δ:ppm)
0.65(H-34,3H),0.78(H-33,3H),0.93(H-31,3H),0.97(H-32,3H),1.63(H-26,1H),1.73(H-22,1H),1.97(H-24,1H;H-36,3H)(两峰重叠),1.86(H-13,3H),2.09(H-30,3H),2.18(H-20,1H),2.28(H-14,3H),2.64[2反式肉桂基-N-CH 2-CH2,4H],2.94(H-37,3H),2.97~3.10(H-23,1H),3.13(-CH 2-CH=CH-Ph,2H)3.25(H-27,1H),3.39(H-21,1H),3.83[2反式肉桂基-N-CH2-CH 2-,4H],4.78(H-25,1H),4.92(H-28,1H),5.32(H-19,1H),5.60(H-17,1H),5.95(H-29,1H),6.02(H-4’,1H;H-6’,1H)(两峰重叠),6.31(-CH2-CH=CH-Ph,1H),6.60(-CH2-CH=CH-Ph,1H),7.09(H-18,1H),7.15~7.45(-CH2-CH=CH-Ph,5H)
实验例1
选择化合物A、化合物B、利福平、利福喷丁和异烟肼为对照品,进行体外抗菌活性试验。
抗菌活性采取美国国家临床实验室标准化委员会(Clinicaland LaboratoryStandardsInstituteCLSI,即原NCCLs)推荐的琼脂二倍稀释法:抗微生物药物敏感性试验标准操作规程(PerformanceStandards forAntimicrobialSusceptibilityTesting)和中华人民共和国药效局颁布的新药(西药)临床前研究指导原则汇编(药学、药理学、毒理学)中抗菌药物药效学指导原则测定各试验药物对试验菌株的最低抑菌浓度(MIC)。
化合物A的化学结构式除了R为α-萘甲基之外,其余与式<Ⅰ>一致;化合物B的化学结构式除了R为苯乙基之外,其余与式<Ⅰ>一致。
如表1所示,本发明的化合物(实施例1、实施例2)对所试革兰阳性菌具有强抗菌作用。对所试甲氧西林敏感金黄色葡萄球菌MSSA、甲氧西林敏感表皮葡萄球菌MSSE的MIC(最低抑菌浓度)值为<0.008---0.25μg/mL。本发明的化合物对上述菌株的抗菌作用与利福平、利福喷丁基本相同,强于异烟肼。本发明的化合物对于屎肠球菌、粪肠球菌、链球菌属也具有可观的抗菌作用。
表1
注:
金葡球菌MSSA:Methicin–susceptibility(甲氧西林敏感株),其中10-12至10-14分别代表采集到的不同的菌株,编号为自命名
金葡球菌MRSA:Methicllin–resistant(甲氧西林耐药株),其中10-11和10-12分别代表采集到的不同的菌株,编号为自命名
表葡球菌MSSE:Methicin–susceptibility(甲氧西林敏感株),其中10-10至10-14分别代表采集到的不同的菌株,编号为自命名
表葡球菌MRSE:Methicllin–resistant(甲氧西林耐药株),其中,10-11和10-15分别代表采集到的不同的菌株,编号为自命名
屎肠球菌10-1和屎肠球菌10-2为自命名,为采集到的2种屎肠球菌
粪肠球菌10-1和粪肠球菌10-2为自命名,为采集到的2种粪肠球菌
链球菌属10-3至链球菌属10-5为自命名,为采集到的3种链球菌
如表2所示,本发明的化合物(实施例1、实施例2)对于标准质控菌也有着较为良好的抗菌作用。
表2
如表1和表2的结果可知,本发明的化合物对于常见菌的抗菌作用与现有的抗菌药物利福平、利福喷丁和异烟肼较为接近,且在某些方面优于上述抗菌药物。
实验例2
选择化合物A、化合物B、化合物C进行对耐药菌株的抗菌性能的实验,结果如表3所示。FJ05120、FJ05436和FJ05195由中国疾病预防与控制中心提供。FJ05436对INH、RMP、STR、CPM、OFX、TYPE耐药,FJ05195对INH、RMP、EMB、STR、OFX、KAN、TYPE耐药。
化合物A的化学结构式除了R为α-萘甲基之外,其余与式<Ⅰ>一致;化合物B的化学结构式除了R为苯乙基之外,其余与式<Ⅰ>一致;化合物C的化学结构式如式<Ⅵ>所示:
如表3可知,本发明的化合物对于耐药菌FJ05120、FJ05436和FJ05195均具有十分优秀的抗菌作用。
表3
综上实验结果可知,本发明的化合物不仅对常见菌具有良好的抗菌效果,且对传统结核菌耐药的耐药菌株也有着优异的抗菌效果。
Claims (7)
2.根据权利要求1所述的制备方法,其特征在于,所述有机溶剂包括氯代烃、醇类溶剂、吡啶类溶剂、芳烃、非质子极性溶剂中的一种;所述氯代烃包括二氯甲烷或氯仿;所述醇类溶剂包括甲醇或乙醇;所述吡啶类溶剂包括吡啶;所述芳烃包括乙腈,苯或甲苯;所述非质子极性溶剂包括二甲基甲酰胺、二甲基乙酰胺或二甲亚砜。
3.根据权利要求1所述的方法,其特征在于,进行所述萃取时,利用氯仿或者与氯仿极性相近的溶剂进行。
4.根据权利要求1-3任一项所述方法制备得到的苯并噁嗪利福霉素类衍生物。
5.一种药物组合物,其包含权利要求4所述的衍生物或其药学上可以接受的盐,还包括药学上可以接受的辅料、载体或者赋形剂。
6.根据权利要求5所述的药物组合物,其特征在于,所述盐包括碱金属盐或碱土金属盐、铵盐、胺盐、硫酸盐、盐酸盐、对甲苯磺酸盐中的任意一种。
7.权利要求4所述衍生物在制备抗生素药物方面的用途。
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