CN108285469B - 一种抗菌类喹诺酮衍生物及其制备方法和应用 - Google Patents
一种抗菌类喹诺酮衍生物及其制备方法和应用 Download PDFInfo
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- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
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Abstract
本发明公开了一种抗菌类喹诺酮衍生物(Ⅱ)及制备方法,属于抗菌药物研究领域。为了寻找优秀的抗菌药物,采用药物化学理论,设计了系列结构新颖的喹诺酮衍生物。本发明设计的喹诺酮衍生物为全新结构,其制备方法为:以亚磷酸酯和喹诺酮中间体为原料,在碱性离子催化条件下,微波合成仪中发生反应,制得(Ⅱ)所示喹诺酮衍生物。该类衍生物呈现出抗菌活性,尤其是对大肠杆菌、耐氟喹诺酮类大肠杆菌有好的抗菌活性,可作为抗菌候选化合物。
Description
技术领域
本发明涉及一种抗菌药物,具体为一种新结构的喹诺酮衍生物及制备方法和抗菌作用的应用。
背景技术
自1962年萘啶酸面市,喹诺酮类药物经历了50多年的发展,一直是抗感染类药物研究的热点领域之一,且不断涌现出新的品种。然而,随着该类药物的广泛应用,尤其是滥用,使其耐药性迅速增加,如:耐氟喹诺酮类药物弯曲杆菌属、耐氟喹诺酮类药物沙门氏菌的相继出现,现已成为抗感染治疗领域的棘手问题之一。如:大肠杆菌已经成为一个令医院“头痛”的常见细菌。据统计,大约有一半的女性在一生中至少有一次尿路感染,而大肠杆菌是大多数尿路感染的原因。如果抗生素能奏效,尿路感染只是一个小麻烦。但如果大肠杆菌对抗生素产生耐药性,那么小麻烦会“升级”,感染从尿路扩散到肾脏和血液,甚至危及性命。而令人担忧的是,在尿路感染的治疗过程中,发现其对一种及以上抗生素产生耐药性的情况越来越多。而在近年新上市的喹诺酮类抗菌剂大多对这些耐药菌不敏感。因此,研究开发安全、广谱、高效、对耐药菌有好治疗效果的抗菌药物意义重大。
基于上述原因,根据现代药物设计理论及有机合成实验技术,本发明设计合成了一系列全新结构的喹诺酮衍生物进行抗菌活性研究。获取抗菌候选化合物,进一步深入研究。
发明内容
为达到上述目的,本发明在前期抗菌药物研究基础上,结合现代药物设计理论及有机合成实验技术,设计合成了系列新型喹诺酮衍生物。采用的合成技术方案为:目标物的结构通式为R为1-5个碳原子的链状取代基或3-6个碳原子的环烷基;R1为1-6个碳原子的链状取代基或3-6个碳原子的环烷基。其合成反应式为:
其制备的具体步骤为:将中间体(Ⅰ)、亚磷酸酯、[Bmim]OH或[Emim]Cl-AlCl3离子液体(按照1:1.1:0.4摩尔比投料)加入三颈瓶中,再加入适量溶剂乙腈于反应瓶中,放入微波合成仪中,在功率500-800W,温度60-80℃的条件下反应60-80min,反应完毕,过滤,减压浓缩,得到粗品,再用柱色谱分离纯化,最后得到目标产物(Ⅱ),收率在75%-86%。
这类结构新颖的喹诺酮衍生物对大肠杆菌、耐氟喹诺酮类大肠杆菌有显著抗菌活性。一些目标物对大肠埃希菌(E.coli)、耐氟喹诺酮类大肠杆菌(MREC-1#,MREC-2#)有显著抗菌作用,优于对照药诺氟沙星,可作为抗菌候选化合物研究。
具体实施方式
下面结合实施例进一步介绍本发明,但本发明不仅限于下述实施例,可以预见本领域技术人员在结合现有技术的情况下,实施情况可能产生种种变化。
实施例1
其制备的具体步骤为:将中间体(Ⅰ)、亚磷酸酯、[Bmim]OH或[Emim]Cl-AlCl3离子液体(按照1:1.1:0.4摩尔比投料)加入三颈瓶中,再加入适量乙腈于反应瓶中,放入微波合成仪中,在功率500-800W,温度60-80℃的条件下反应60-80min,反应完毕,过滤,减压浓缩,得到粗品,再用柱色谱分离纯化,最后得到目标产物(Ⅱ),收率在75%-86%。具体实施方式:
1-乙基-6-氟-1,4-二氢-4-氧代-7-(O,O'-二乙基磷酰基)-3-喹啉羧酸(Ⅱa)的制备
将2.0mmol的中间体Ⅰ(7-氯-1-乙基-6-氟-1,4-二氢-4-氧代-3-喹啉羧酸)、2.2mmol亚磷酸二乙酯、60ml乙腈及0.8mmol[Bmim]OH离子液体加入100ml三颈瓶中,放入微波合成仪中,在功率800W,温度80℃的条件下反应80min,反应完毕,过滤,减压浓缩,得到粗品,再用柱色谱分离纯化,最后得到目标产物,为黄色固体(Ⅱa),收率86.0%。1H NMR(400MHz,CDCl3)δ:0.84~1.22(m,9H,3CH3),3.82~4.19(m,6H,2OCH2+NCH2),7.22(d,1H,8-H),7.66(t,1H,5-H),8.35(s,1H,2-H).13C NMR(100MHz,CDCl3)δ:177.1,165.1,155.4,146.5,134.0,128.2,1224.4,114.0,109.7,63.4,63.3,49.5,16.3,16.2,13.5.IR(KBr)v:3078,3025,2987,2922,1731,1684,1645,1541,1466,1326,1212,1120,1023cm-1.
实施例2
1-环丙基-6-氟-1,4-二氢-4-氧代-7-(O,O'-二乙基磷酰基)-3-喹啉羧酸(Ⅱb)的制备
将2.0mmol的中间体Ⅰ(7-氯-1-环丙基-6-氟-1,4-二氢-4-氧代-3-喹啉羧酸)、2.2mmol亚磷酸二乙酯、60ml乙腈及0.8mmol[Bmim]OH离子液体加入100ml三颈瓶中,放入微波合成仪中,在功率700W,温度80℃的条件下反应80min,反应完毕,过滤,减压浓缩,得到粗品,再用柱色谱分离纯化,最后得到目标产物,为白色固体(Ⅱb),收率78.5%。1H NMR(400MHz,CDCl3)δ:0.73~1.38(m,10H,2CH2,2CH3),3.58(s,1H,NCH),3.82~4.20(m,4H,OCH2),7.33(d,1H,8-H),7.60(d,1H,5-H),8.41(s,1H,2-H).13C NMR(100MHz,CDCl3)δ:177.0 165.3,155.6,146.9,140.6,134.8,121.2,115.5,109.6,68.2,68.1,40.6,16.3,16.2,9.5,9.4.IR(KBr)v:3082,3038,2980,2925,1719,1665,1625,1502,1471,1333,1282,1228,1098,1020cm-1.
实施例3
1-(2,4-二氟苯基)-6-氟-1,4-二氢-4-氧代-7-(O,O'-二正丁基磷酰基)-3-喹啉羧酸(Ⅱc)的制备
将2.0mmol的中间体Ⅰ(7-氯-1-(2,4-二氟苯基)-6-氟-1,4-二氢-4-氧代-3-喹啉羧酸)、2.2mmol亚磷酸二乙酯、60ml乙腈及0.8mmol[Bmim]OH离子液体加入100ml三颈瓶中,放入微波合成仪中,在功率800W,温度70℃的条件下反应80min,反应完毕,过滤,减压浓缩,得到粗品,再用柱色谱分离纯化,最后得到目标产物,为淡黄色固体(Ⅱc),收率77.7%。1HNMR(400MHz,CDCl3)δ:1.12~1.33(m,6H,2CH3),1.41~1.50(m,4H,2CH2),1.75~1.87(m,4H,2CH2),3.82~4.25(m,4H,2OCH2),6.88-7.30(m,4H,ArH),7.60(d,1H,5-H),8.41(s,1H,2-H).13C NMR(100MHz,CDCl3)δ:178.3,166.5,162.0,158.4,155.1,146.7,133.9,124.1,122.1,115.4,111.3,109.2,104.8,67.9,67.8,32.4,32.3,18.9,18.8,13.6,13.5.IR(KBr)v:3089,3021,2984,2852,1724,1677,1556,1462,1328,1237,1120,1008cm-1.
实施例4
目标化合物的抗菌活性测试
以诺氟沙星(norfloxacin)为对照药物,采用微量稀释法测定目标物的MIC,测定目标化合物对金黄色葡萄球菌(S.aureus)、大肠埃希菌(E.coli)、耐氟喹诺酮类大肠杆菌(MREC-1#,MREC-2#)的抗菌活性。
如:目标物1-(2,4-二氟苯基)-6-氟-1,4-二氢-4-氧代-7-(O,O'-二正丁基磷酰基)-3-喹啉羧酸对E.coli、MREC-1#、MREC-2#的MIC分别为0.32mg/mL、2.7mg/mL、3.0mg/mL;目标物1-(2,4-二氟苯基)-6-氟-1,4-二氢-4-氧代-7-(O,O'-二异丁基磷酰基)-3-喹啉羧酸对E.coli、MREC-1#、MREC-2#的MIC分别为0.35mg/mL、2.2mg/mL、2.7mg/mL,优于对照药。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (4)
3.根据权利要求1所述的抗菌类喹诺酮衍生物的制备方法,其特征在于,其步骤为:将中间体(Ⅰ)、亚磷酸酯、[Bmim]OH或[Emim]Cl-AlCl3离子液体(按照1:1.1:0.4摩尔比投料)加入三颈瓶中,再加入适量溶剂乙腈于反应瓶中,放入微波合成仪中,在功率500-800W,温度60-80℃的条件下反应60-80min,反应完毕,过滤,减压浓缩,得到粗品,再用柱色谱分离纯化,最后得到目标产物抗菌类喹诺酮衍生物(II)。
4.根据权利要求1所述抗菌类喹诺酮衍生物应用于制备抗大肠杆菌、耐氟喹诺酮类大肠杆菌活性药物的应用。
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CN1105799A (zh) * | 1993-03-18 | 1995-07-26 | 大制药株式会社 | 作为基质金属蛋白酶抑制剂的喹诺酮衍生物 |
CN1430617A (zh) * | 1999-11-24 | 2003-07-16 | 大塚制药株式会社 | 奎诺酮衍生物的生产方法 |
CN104447537A (zh) * | 2014-11-17 | 2015-03-25 | 河南大学 | 一种含乙基喹啉环的3,3′-亚甲基-双氟喹诺酮衍生物及其制备方法和应用 |
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CN1948306A (zh) * | 2005-10-10 | 2007-04-18 | 上海医药工业研究院 | 氟喹诺酮-噁唑烷酮衍生物及制备方法和应用 |
CN101565428B (zh) * | 2009-06-02 | 2011-06-29 | 重庆科瑞制药有限责任公司 | 普卢利沙星的制备方法 |
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CN1105799A (zh) * | 1993-03-18 | 1995-07-26 | 大制药株式会社 | 作为基质金属蛋白酶抑制剂的喹诺酮衍生物 |
CN1430617A (zh) * | 1999-11-24 | 2003-07-16 | 大塚制药株式会社 | 奎诺酮衍生物的生产方法 |
CN1171886C (zh) * | 1999-11-24 | 2004-10-20 | 大塚制药株式会社 | 喹诺酮衍生物的生产方法 |
CN104447537A (zh) * | 2014-11-17 | 2015-03-25 | 河南大学 | 一种含乙基喹啉环的3,3′-亚甲基-双氟喹诺酮衍生物及其制备方法和应用 |
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