CN103396396B - 胺基烷酰克林沙星及其应用 - Google Patents
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Abstract
本发明公开了式I所示的胺基烷酰克林沙星(n为1或2;表示脂肪胺基或杂环胺基),该类化合物在多种常用溶剂中的溶解度较克林沙星明显增大;所有合成化合物对沙门菌、铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌都具有一定的抑制活性,其中近1/3的化合物表现出较好的抑菌效果,6个化合物对部分菌株的抑菌活性与克林沙星相当或更强,此外,部分化合物对耐药大肠杆菌临床分离株、猪源耐喹诺酮类大肠杆菌也有较好的抑菌效果;部分化合物的急性毒性和光毒性低于克林沙星;该类化合物可用于制备抗菌药物,在治疗细菌感染方面具有潜在的应用前景。
Description
技术领域
本发明属于化学领域,涉及一种克林沙星衍生物,还涉及该衍生物在制药领域中的应用。
背景技术
克林沙星(CF)为第四代喹诺酮抗菌药物中的“超广谱”候选分子,在国外已完成Ⅲ期临床评价,但因存在明显的光毒性等原因,最终未申请上市。发明人所在研究室研究发现,CF原药的溶解性较差,水溶液的稳定性不够,这些可能也是影响其成药的重要因素。
对克林沙星的结构改造,最可行的策略就是保留克林沙星的母体结构、将其非药效基团进行结构修饰。通过合理药物设计,引入合理结构单元,有可能获得毒性降低、活性增强、溶解性提高和分子稳定性增加的先导分子。
发明人所在研究室前期研究发现,克林沙星母体7-吡咯环的氨基经天然或非天然氨基酸、简单脂肪或芳香酸修饰,所得衍生物中某些分子的抗菌活性接近或优于克林沙星,毒性低于克林沙星,并且绝大多数分子的溶解性和溶液稳定性优于克林沙星(中国专利申请201010523646x);向克林沙星母体分子中引入脲结构单元,也获得了溶解性和抗菌活性很好的分子(中国专利申请201210483417.9)。但是,克林沙星母体7-吡咯环的氨基经简单脂肪或芳香酸修饰后,氨基的碱性被掩蔽,所得衍生物的整体酸碱性和克林沙星母体分子差别较大。如果引入合理结构单元,得到和克林沙星母体分子相近的整体酸碱性,可能获得抗菌活性、溶解性俱佳而毒性很低的新型分子。
发明内容
有鉴于此,本发明的目的之一在于提供一种克林沙星衍生物,具有和克林沙星母体分子相近的整体酸碱性,抗菌活性、溶解性俱佳而毒性较低;目的之二在于提供所述克林沙星衍生物在制药领域中的应用。
为达到上述目的,经研究,本发明提供如下技术方案:
1.式I所示的胺基烷酰克林沙星及其可药用盐:
式中,n为1或2;表示脂肪胺基或杂环胺基,
所述脂肪胺基为NR1R2,R1为氢或C1-C4烷基,所述C1-C4烷基可以被羟基所取代;R2为C2-C4烷基、C1-C4烷氧基、C2-C4烷酰氧基、羟基、氨基、甲氨基、二甲基氨基、脲基、硫脲基、环丙基、环戊基或环己基,所述C2-C4烷基可以被羟基、氨基、甲氨基或二甲基氨基所取代;
所述杂环胺基为吡咯烷基、哌啶基、吗啉基或哌嗪基,所述哌啶基可以被羟基所取代;所述哌嗪基的另1个氮原子可以被C1-C4烷基、烷氧羰基类氨基保护基、7-(1-乙基-6-氟-1,4-二氢-4-氧代-3-羧基)喹啉基、7-(1-环丙基-6-氟-1,4-二氢-4-氧代-3-羧基)喹啉基或7-(1-(4-氟苯基)-6-氟-1,4-二氢-4-氧代-3-羧基)喹啉基所取代,所述C1-C4烷基可以被羟基取代。
进一步,n为1;表示脂肪胺基或杂环胺基,
所述脂肪胺基为NR1R2,R1为氢、C1-C3烷基或2-羟基乙基;R2为C2-C4烷基、2-羟基乙基、(R)-1-乙基-2-羟基乙基、2-氨基乙基、3-氨基丙基、3-(二甲基氨基)丙基、4-氨基丁基、甲氧基、乙酰氧基、羟基、氨基、甲氨基、二甲基氨基、脲基、硫脲基、环丙基、环戊基或环己基;
所述杂环胺基为吡咯烷基、哌啶基、4-羟基哌啶基、吗啉基、哌嗪基、4-甲基哌嗪基、4-(2-羟基乙基)哌嗪基、4-叔丁氧羰基哌嗪基、4-(7-(1-乙基-6-氟-1,4-二氢-4-氧代-3-羧基)喹啉基)哌嗪基、4-(7-(1-环丙基-6-氟-1,4-二氢-4-氧代-3-羧基)喹啉基)哌嗪基或4-(7-(1-(4-氟苯基)-6-氟-1,4-二氢-4-氧代-3-羧基)喹啉基)哌嗪基。
例如,本发明合成化合物TM1-2~TM1-32、TM1-34、TM1-36~TM1-40。
再进一步,n为1;表示脂肪胺基或杂环胺基,所述脂肪胺基为NR1R2,R1为氢,R2为2-羟基乙基、(R)-1-乙基-2-羟基乙基、2-氨基乙基、3-(二甲基氨基)丙基、乙酰氧基、羟基、氨基、硫脲基或环丙基;或者,R1为甲基,R2为2-羟基乙基或氨基;或者,R1、R2均为2-羟基乙基;所述杂环胺基为4-羟基哌啶基或吗啉基。即本发明合成化合物TM1-9~TM1-13、TM1-15、TM1-17、TM1-22、TM1-23、TM1-28、TM1-29、TM1-32、TM1-34、TM1-36。
更进一步,n为1;表示脂肪胺基,所述脂肪胺基为NR1R2,R1为氢,R2为2-羟基乙基、(R)-1-乙基-2-羟基乙基、2-氨基乙基、羟基、氨基或硫脲基;或者,R1为甲基或2-羟基乙基,R2为2-羟基乙基。即本发明合成化合物TM1-9~TM1-13、TM1-28、TM1-32、TM1-36。
更进一步,n为1;表示脂肪胺基,所述脂肪胺基为NR1R2,R1为甲基或2-羟基乙基,R2为2-羟基乙基;或者,R1为氢,R2为2-羟基乙基、2-氨基乙基、羟基或硫脲基。即本发明合成化合物TM1-10~TM1-13、TM1-32、TM1-36。
更进一步,n为1;表示脂肪胺基,所述脂肪胺基为NR1R2,R1为甲基或2-羟基乙基,R2为2-羟基乙基。即本发明合成化合物TM1-11和TM1-12。
进一步,n为2;表示脂肪胺基,所述脂肪胺基为NR1R2,R1为氢、甲基或2-羟基乙基;R2为2-羟基乙基。即本发明合成化合物TM2-1~TM2-3。
2.式I所示的胺基烷酰克林沙星及其可药用盐在制备抗菌药物中的应用。
进一步,所述抗菌药物为抗沙门菌、铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌中任一种或多种的药物。由于本发明合成化合物TM1-9~TM1-13、TM1-28、TM1-32、TM1-36经试验证实具有抗耐药大肠杆菌(包括猪源耐喹诺酮类大肠杆菌)的作用,因此,所述大肠杆菌不仅包括非耐药大肠杆菌,还包括耐药大肠杆菌。
本发明的有益效果在于:本发明提供了式I所示的胺基烷酰克林沙星,溶解性试验结果显示,该类化合物在多种常用溶剂中的溶解度均较克林沙星明显增大;抑菌试验结果显示,所有合成化合物对沙门菌、铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌都具有一定的抑菌活性,其中TM1-9~TM1-13、TM1-15、TM1-17、TM1-22、TM1-23、TM1-28、TM1-29、TM1-32、TM1-34、TM1-36表现出较好的抑菌效果,尤其TM1-10~TM1-13、TM1-32和TM1-36对部分菌株的抑菌活性与CF相当或更强;此外,TM1-9~TM1-13、TM1-28、TM1-32和TM1-36对耐药大肠杆菌临床分离株和猪源耐喹诺酮类大肠杆菌也都具有抑菌活性,其中TM1-11、TM1-12和TM1-36对耐药大肠杆菌临床分离株的有效抑制数和抑制效果强于CF,TM1-12和TM1-36对猪源耐喹诺酮类大肠杆菌的抑制效果好;毒性试验结果显示,TM1-11和TM1-12的急性毒性远远低于CF,TM1-11的光毒性也小于CF。这些化合物及其可药用盐可用于制备抗菌药物,在治疗细菌感染方面具有潜在的应用前景。
具体实施方式
为了使本发明的目的、技术方案和有益效果更加清楚,下面对本发明的优选实施例进行详细的描述。
优选实施例中使用的检测仪器和主要试剂如下:核磁共振仪(AV-300,Bruker,USA;TMS为内标);高分辨质谱仪(HR ESI-FTICR MS,Varian7.0T,USA);熔点测定仪(X-6,北京福凯仪器有限公司);旋光仪(WZZ-2S,上海精密科学仪器有限公司);克林沙星(>95%,郑州克尔泰生化科技有限公司);诺氟沙星(NF)、环丙沙星、沙拉沙星(>95%,郑州克尔泰生化科技有限公司);胺及其余试剂均为市售化学纯或分析纯产品。
实施例1、中间体IM1的合成
在100mL圆底烧瓶中依次加入原料CF、K2CO3及适量二氯甲烷(DCM),在冰浴下滴加氯乙酰氯的DCM溶液,CF、K2CO3与氯乙酰氯的投料摩尔比为1:2.5:1.5~2.5,滴毕,冰浴下持续搅拌反应,TLC(薄层色谱法)监测反应进程。反应完成后,得到黄绿色浑浊液,抽滤,滤饼用DCM洗涤,洗液与滤液合并,旋蒸得粗品,其纯度满足后续反应需要。将粗品经柱层析纯化得纯品,干燥,称重,计算收率。具体实验条件及结果见表1。
IM17-(3-(2-氯乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色固体,m.p.214.7-216.9℃;1H NMR(300MHz,CDCl3)δ:14.31(s,1H,H-11),8.92(s,1H,H-2),8.05(d,1H,J=11.1Hz,H-5),4.41-4.29(m,1H,H-12),4.14(s,2H,H-20),3.95-3.65(m,4H,H-16,H-17and H-14),3.62-3.46(m,1H,H-14),2.26-1.74(m,2H,H-15),1.35-0.92(m,4H,H-13);13C NMR(75MHz,CDCl3)δ:176.69,169.15,165.72,154.62,152.23,143.77,137.82,124.18,120.51,111.65,108.4,50.79,47.08,42.8,41.43,41.21,40.78,11.49(2×C);HR MS:C19H18Cl2FN3O4[M+Na]+计算值为464.0551,测定值为464.0550.
表1中间体IM1合成结果
实施例2、目标化合物TM1的合成
1、合成方法优化
发明人首先以N-甲基乙醇胺为胺组分,考察了溶剂和碱对反应的影响。
(1)溶剂对反应的影响
IM1与N-甲基乙醇胺的摩尔比为1:1.5,在KI催化、碱存在下,于不同溶剂中,35℃搅拌反应。结果见表2。
表2溶剂对反应的影响
由表2可以看出,IM1在DMF与DMSO中的溶解性不好,但产物溶解性很好,导致后处理时产品损失,反应收率较低(约30%);以MeCN、H2O、CHCl3和DCM作溶剂时,反应收率略高且收率相近,但CHCl3和DCM作溶剂时反应时间相对较长。后期实验进一步发现,反应底物为含羟基胺或二胺时,用H2O作溶剂的反应效果更好;反应底物为环胺时,用CHCl3和DCM作溶剂的反应效果更好。
(2)碱对反应的影响
IM1与N-甲基乙醇胺的摩尔比为1:1.5~3.0,在KI催化、碱存在下,于乙腈中,35℃搅拌反应。结果见表3。
表3碱对反应的影响
由表3可以看出,以Py(吡啶)与Et3N(三乙胺)作为碱时,反应48h也不能观察到产物的生成;不额外加入其它碱,直接将参与反应的胺既作为反应物又作为碱时,结果也不理想;说明该反应不适合用有机碱催化。以无机碱Na2CO3、K2CO3、Cs2CO3、KF、NaH作为碱时,反应都能发生,其中以K2CO3作为碱时收率最高。
2、合成实验
向反应瓶中加入原料胺组分、K2CO3及催化量的KI和适量溶剂,室温搅拌30分钟后,加入IM1;IM1、K2CO3与胺组分的投料摩尔比为1:3:2,室温(10℃-40℃)搅拌反应,TLC监测反应进程。反应结束后,根据具体情况分别按以下几种方式进行后处理:(1)若产物溶于有机溶剂,加水,用2N HCl调pH至6-7,用DCM萃取,收集有机相,旋蒸得粗品,用二氯甲烷-石油醚(DCM-PE)重结晶;(2)若产物溶于水,调pH至中性,静置分层,收集水相,继续调pH至4~5,冷藏析晶,抽滤,滤饼用90%乙醇重结晶;(3)若反应体系有固体产生,抽滤,滤饼加水,用2N HCl调pH至4~5,冷藏析晶;(4)若产物既溶于有机溶剂,又溶于水,先旋蒸除去有机相,再用2N HCl调pH至4~5,冷藏析晶,即得目标化合物TM1。具体实验条件及结果见表4。
表4目标化合物TM1合成结果
化合物TM1的波谱数据如下:
TM1-27-(3-(2-(乙胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:米黄色固体,m.p.168.4-169.3℃;1H NMR(300MHz,DMSO-d6)δ:14.51(s,1H,H-11),9.04(s,1H,H-18),8.85(s,1H,H-2),7.97(d,1H,J=11.7Hz,H-5),4.44-4.35(m,1H,H-12),4.13(s,2H,H-20),3.72-3.56(m,3H,H-16and H-17),3.36-3.31(m,4H,H-14and H-15),2.96-2.94(m,2H,CH 2 CH3),1.18-1.26(m,5H,H-13and CH3),1.03-0.97(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.52,165.46,164.43,(157.52,154.31),153.32,(143.77,143.50),138.27,123.56,120.34,(111.15,110.85),108.07,50.97,48.31,45.54,42.56,42.02,41.39,34.41,22.56,11.30,11.14.HRMS:C21H24ClFN4O4[M+Na]+计算值为437.1362,实测值为437.1358;(c=1.0mg/mL,CHCl3).
TM1-37-(3-(2-(丙胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.230.2-235.7℃;1H NMR(300MHz,DMSO-d6)δ:14.26(s,1H,H-11),8.83(s,1H,H-2),7.96(d,1H,J=9Hz,H-5),4.39-4.37(m,1H,H-12),3.78-3.57(m,5H,H-16、H-17andH-20),3.35-3.29(m,4H,H-14and H-15),2.75-2.65(m,2H,H-22),1.57-1.50(m,2H,H-23),1.19-0.91(m,2H,H-13),0.99-0.91(m,2H,H-13),0.87(t,3H,J=6Hz,H-24);13C NMR(75MHz,DMSO-d6)δ:176.20,166.61,165.42,(156.21,153.54),152.98,(143.72,143.56),138.21,123.29,120.12,(111.05,110.68),108.31,51.43,51.05,49.85,48.40,45.48,42.50,41.91,20.81,20.43,11.66,11.30;HR MS:C22H26ClFN4O4[M+H]+计算值为465.1699,实测值为465.1692; (c=1.0mg/mL,CHCl3).
TM1-47-(3-(2-(丁胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:米白色固体,m.p.132.6-135.7℃;1H NMR(300MHz,CDCl3)δ:14.39(s,1H,H-11),9.09(s,1H,H-2),8.85(d,1H,J=12Hz,H-5),4.39-4.37(m,1H,H-12),4.16-4.13(m,2H,H-20),3.72-3.57(m,3H,H-16and H-17),3.33-3.16(m,4H,H-14and H-15),2.90-2.88(m,2H,H-22),1.67-1.65(m,2H,H-23),1.35-1.33(m,2H,H-13),1.22-1.20(m,2H,H-24),1.02-1.00(m,2H,H-13),0.93-0.90(t,3H,J=9Hz,H-25);13C NMR(75MHz,CDCl3)δ:176.20,166.61,165.34,(157.32,154.42),152.98,(143.72,143.56),138.21,123.29,120.12,(111.05,110.68),108.31,51.05,49.85,48.40,45.48,42.50,41.91,32.03,20.81,20.43,11.76,11.50;HR MS:C23H28ClFN4O4[M+H]+计算值为479.1856,实测值为479.1850;(c=1.0mg/mL,CHCl3).
TM1-57-(3-(2-(异丙胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:黄色固体,m.p.171.3-173.6℃;1H NMR(300MHz,DMSO-d6)δ:14.37(s,1H,H-11),8.85(s,1H,H-2),7.97(d,1H,J=12Hz,H-5),4.43-4.40(m,1H,H-12),4.14-4.10(m,3H,H-16and H-20),3.68-3.70(m,1H,H-22),3.58-3.61(m,2H,H-17),3.33-3.17(m,4H,H-14and H-15),1.26(d,6H,J=6Hz,H-23),1.22-1.19(m,2H,H-13),0.97-0.96(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.46,165.41,164.77,(157.81,154.23),153.16,(143.78,143.59),138.25,123.37,120.22,111.23,108.03,50.93,50.08,45.56,45.02,42.78,41.97,18.98(2×C),11.36,11.29;HR MS:C22H26ClFN4O4[M+H]+计算值为465.1699,实测值为465.1695;(c=1.0mg/mL,CHCl3).
TM1-67-(3-(2-(二甲胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.265.0-267.5℃;1H NMR(300MHz,DMSO-d6)δ:14.49(s,1H,H-11),9.74(s,1H,H-18),8.85(s,1H,H-2),7.97(d,1H,J=11.1Hz,H-5),4.48-4.31(m,3H,H-20andH-12),3.72-3.68(m,3H,H-16and H-17),3.51-3.34(m,4H,H-14and H-15),2.83(s,6H,2CH3,1.18-1.20(m,2H,H-13),1.02-0.97(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.42,165.53,164.12,(157.42,154.31),153.29,143.64,138.29,123.57,120.36,(111.18,110.84),108.07,67.39,48.31,45.54,42.56,42.02,41.39,30.49,22.56,11.53,11.34;HR MS:C21H24ClFN4O4[M+Na]+计算值为473.1362,实测值为437.1360;(c=1.0mg/mL,CHCl3).
TM1-77-(3-(2-(二乙胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:米黄色固体,m.p.173.4-175.8℃;1H NMR(300MHz,DMSO-d6)δ:14.48(s,1H,H-11),8.93(s,1H,H-18),8.84(s,1H,H-2),7.96(d,1H,J=12Hz,H-5),4.40-4.35(m,3H,H-20and H-12),3.71-3.58(m,3H,H-16and H-17),3.50-3.48(m,2H,H-14),3.18-3.15(m,2H,H-15),2.86(s,4H,CH 2 CH3),1.23-0.99(m,10H,H-13and2CH3);13C NMR(75MHz,DMSO-d6)δ:176.49,165.46,164.43,(157.39,154.27),153.17,143.61,138.27,123.56,120.34,(111.15,110.85),108.07,56.74,50.97,48.31,45.54,42.56,42.02,30.41,11.79,11.39;HR MS:C23H28ClFN4O4[M+Na]+计算值为501.1675,实测值为501.1674;(c=1.0mg/mL,CHCl3).
TM1-87-(3-(2-(二异丙基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:米黄色固体,m.p.290.5~292.3℃;1H NMR(300MHz,DMSO-d6)δ:14.50(s,1H,H-11),8.88(s,1H,H-18),8.82(s,1H,H-2),7.95(d,1H,J=12Hz,H-5),4.40-4.35(m,3H,H-20and H-12),3.71-3.58(m,3H,H-16and H-17),3.50-3.48(m,2H,H-14),3.18-3.15(m,2H,H-15),2.34-2.21(m,2H,H-21),1.32-1.30(m,2H,H-13),1.22-1.16(m,12H,H-22),0.97-0.92(m,2H H-13);(c=1.0mg/mL,CHCl3).
TM1-97-(3-(2-((R)-1-羟基丁醇-2-胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色固体,m.p.233.7~235.5℃;1H NMR(300MHz,DMSO-d6)δ:14.52(s,1H,H-11),8.86(s,1H,H-2),8.68(s,1H,CONH),7.99(d,1H,J=11.4Hz,H-5),5.41(s,1H,H-24),4.43-4.39(m,1H,H-12),4.17(s,2H,H-20),3.73-3.60(m,6H,H-16、H-17、H-14and H-23),3.39-3.34(m,3H,H-14and H-15),3.08-3.06(m,1H,H-22),1.69-1.53(m,2H,CH3 CH 2 ),1.20-1.18(m,2H,H-13),1.01-0.91(m,5H,H-13and CH 3 CH2);13C NMR(75MHz,DMSO-d6)δ:176.17,165.14,164.35,(157.30,153.97),152.92,(143.43,143.24),137.92,(123.20,123.09),119.88,(110.81,110.50),107.68,60.60,58.22,50.74,50.38,,45.11,44.70,42.37,41.65,20.28,10.92,9.99;HR MS:C23H28ClFN4O5[M+H]+计算值为495.1805,实测值为495.1809; (c=1.5mg/mL,H2O).
TM1-107-(3-(2-(羟乙基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.239.5-240.2℃;1H NMR(300MHz,DMSO-d6)δ:14.50(s,1H,H-11),8.93(s,1H,H-18),8.84(s,1H,H-2),7.97(d,2H,J=12Hz,H-5),5.26(s,1H,-OH),4.33-4.26(m,1H,H-12),4.15(s,2H,H-20),3.71-3.68(m,3H,H-16and H-17),3.58-3.55(m,2H,H-23),3.38-3.31(m,4H,H-14and H-15),3.01-2.99(m,2H,H-22),2.87-2.78(m,2H,H-21),1.21-1.18(m,2H,H-13),1.03-0.99(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.52,165.46,164.43,(157.42,154.27),153.27,143.61,138.27,123.56,120.34,(111.15,110.85),108.07,50.97,49.16,48.31,45.54,42.56,42.02,30.41,29.37,11.56,11.37;HR MS:C21H24ClFN4O5[M+Na]+计算值为489.1311,实测值为489.1315;(c=1.0mg/mL,CHCl3).
TM1-117-(3-(2-(N-甲基-羟乙基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.130.7-131.4℃;1H NMR(300MHz,DMSO-d6)δ:14.55(s,1H,H-11),9.59(s,1H,H-18),8.88(s,1H,H-2),8.00(d,2H,J=12.0Hz,H-5),5.40(s,1H,-OH),4.50-4.39(m,3H,H-12and H-20),3.88-3.66(m,4H,H-16、H-17and H-14),3.56-3.53(m,2H,H-22),3.42-3.39(m,3H,H-14and H-15),3.25-3.18(m,2H,H-21),2.92(s,3H,CH3),1.22-1.19(m,2H,H-13),1.02-0.93(m,2H,H-13);13C NMR(75MHz,DMSO)δ:176.52,165.46,164.43,(157.43,154.58),153.27,(143.61,143.45),138.27,123.56,120.34,(111.15,110.85),108.07,62.86,61.19,58.34,50.97,49.72,48.31,45.54,42.56,42.02,30.41,11.53,11.34;HR MS:C22H26ClFN4O5[M+Na]+计算值为503.1468,实测值为503.1465;(c=1.0mg/mL,CHCl3).
TM1-127-(3-(2-(二羟乙基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.242.3-242.8℃;1H NMR(300MHz,DMSO-d6)δ:14.48(s,1H,H-11),9.64(s,1H,H-18),8.84(s,1H,H-2),7.98(d,2H,J=12Hz,H-5),5.21(s,2H,OH),4.56-4.40(m,1H,H-12),4.16(s,2H,H-20),3.82-3.74(m,3H,H-16and H-17),3.64(t,4H,J=6.0Hz,H-22),3.59-3.48(m,6H,H-14and H-23),3.00-2.98(m,2H,H-15),1.22-1.19(m,2H,H-13),1.04-1.00(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.04,168.24,164.98,(156.32,154.66),152.82,(143.29,143.20),137.82,(123.02,122.97),(119.71,119.68),(110.62,110.46),107.58,55.12(2×C),54.69(2×C),50.65,50.45,49.79,45.48,41.77,41.46,10.73(2×C);HR MS:C23H28ClFN4O6[M+Na]+计算值为533.1574,实测值为533.1576;(c=1.0mg/mL,CHCl3).
TM1-137-(3-(2-(2-氨乙基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色固体,m.p.241.2~242.3℃;1H NMR(300MHz,DMSO-d6)δ:14.50(s,1H,H-11),8.85(s,1H,H-2),7.97(d,1H,J=11.7Hz,H-5),4.43-4.39(m,1H,H-12),4.27(s,2H,H-20),3.72-3.58(m,4H,H-16、H-17and H-14),3.40-3.27(m,7H,H-14、H-22、H-23and H-15),1.22-1.19(m,2H,H-13),1.02-0.99(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.09,165.08,163.93,(157.26,153.94),152.86,(143.42,143.22),137.89,(123.13,123.03),(119.93,119.86),(110.75,110.44),107.64,50.89,50.60,47.23,45.12,44.16,42.21,41.64,35.00,10.92(2×C);HRMS:C21H25ClFN5O4[M+H]+计算值为466.1652,实测值为466.1658;(c=1.5mg/mL,H2O).
TM1-147-(3-(2-(3-氨基丙胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色固体,m.p.262.8~264.7℃;1H NMR(300MHz,DMSO-d6)δ:14.51(s,1H,H-11),8.85(s,1H,H-2),7.97(d,1H,J=11.7Hz,H-5),4.44-4.40(m,1H,H-12),4.19(s,2H,H-20),3.72-3.58(m,4H,H-16、H-17and H-14),3.37-3.33(m,3H,H-14and H-15),3.04-2.91(m,4H,H-22and H-24),2.09-2.04(m,2H,H-23),1.22-1.19(m,2H,H-13),1.03-1.00(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.11,165.11,164.03,(157.28,153.96),152.89,(143.41,143.22),137.90,(123.19,123.09),119.89,(110.78,110.48),107.67,51.37,50.62,46.92,45.15,44.25,42.23,41.64,36.02,25.01,10.91(2×C);HR MS:C22H27ClFN5O4[M+H]+计算值为480.1808,实测值为480.1816;(c=1.5mg/mL,H2O).
TM1-157-(3-(2-((3-二甲氨基丙基)胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色固体,m.p.181.8~183.6℃;1H NMR(300MHz,DMSO-d6)δ:14.47(s,1H,H-11),8.84(s,1H,H-2),8.64(s,1H,H-18),7.94(d,1H,J=11.7Hz,H-5),4.44-4.39(m,1H,H-12),4.22(s,2H,H-20),3.71-3.61(m,4H,H-16、H-17and H-14),3.42-3.33(m,3H,H-14andH-15),3.21-3.07(m,4H,H-22and H-24),2.89(d,1H,J=7.5Hz,H-21),2.76(s,6H,CH3),2.22-2.18(m,2H,H-23),1.24-1.19(m,2H,H-13),1.04-1.01(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.03,165.06,164.05,(157.20,153.88),152.80,(143.41,143.22),137.86,(123.07,122.96),119.80,(110.71,110.40),107.61,53.37,51.45,50.58,46.86,45.15,44.18,41.91(2×C),41.65,36.11,20.43,10.93(2×C);HR MS:C24H31ClFN5O4[M+H]+计算值为508.2121,实测值为508.2129;(c=1.5mg/mL,H2O).
TM1-167-(3-(2-(4-氨丁基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色固体,m.p.167.3~168.6℃;1H NMR(300MHz,DMSO-d6)δ:14.51(s,1H,H-11),8.86(s,1H,H-2),7.97(d,1H,J=11.7Hz,H-5),4.43-4.39(m,1H,H-12),4.17(s,2H,H-20),3.72-3.58(m,4H,H-16、H-17and H-14),3.39-3.33(m,3H,H-14and H-15),2.94-2.73(m,4H,H-22and H-25),1.77-1.63(m,4H,H-23and H-24),1.22-1.19(m,2H,H-13),1.02-0.99(m,2H,H-13;13CNMR(75MHz,DMSO-d6)δ:176.14,165.14,164.17,(157.28,153.96),152.90,(143.44,143.25),137.92,(123.17,123.07),(119.96,119.89),(110.79,110.48),107.66,50.92,50.67,46.89,46.28,45.15,42.23,41.68,38.08,24.06,22.34,10.96(2×C);HR MS:C23H29ClFN5O4[M+H]+计算值为494.1965,实测值为494.1968;(c=1.5mg/mL,H2O).
TM1-177-(3-(2-(环丙基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色固体,m.p.168.1-168.7℃;1H NMR(300MHz,DMSO-d6)δ:14.51(s,1H,H-11),9.20(s,2H,H-18),8.85(s,1H,H-2),7.97(d,2H,J=12Hz,H-5),4.44-4.36(m,1H,H-12),4.24(s,2H,H-20),3.80-3.70(m,4H,H-16、H-17and H-14),3.49-3.34(m,3H,H-14and H-15),2.75-2.65(m,1H,H-22),1.21-1.15(m,2H,H-23),1.20-0.93(m,4H,H-13),0.88-0.73(m,2H,H-23);13CNMR(75MHz,DMSO-d6)δ:176.52,165.46,164.43,(157.32,154.45),153.27,(143.80,143.61),138.27,123.56,120.34,(111.15,110.85),108.07,50.97,50.21,48.31,45.54,42.56,42.02,30.41,11.35(2×C),3.71(2×C);HR MS:C22H24ClFN4O4[M+Na]+计算值为485.1362,实测值为485.1365;(c=1.0mg/mL,CHCl3).
TM1-187-(3-(2-(环戊基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.150.2~152.1℃;1H NMR(300MHz,DMSO-d6)δ:14.55(s,1H,H-11),9.22(s,2H,H-18),8.86(s,1H,H-2),7.99(d,2H,J=12Hz,H-5),4.44-4.40(m,1H,H-12),4.13(s,2H,H-20),3.71-3.61(m,4H,H-16、H-17and H-14),3.37-3.33(m,3H,H-14and H-15),2.71(s,2H,H-22),1.90-1.85(m,4H,H-23),1.61-1.57(m,4H,H-24),1.21-1.19(m,2H,H-13),1.02-0.99(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.78,168.83,165.94,(157.57,155.16),152.09,(144.08,143.94),137.89,(124.10,124.02),(120.22,120.17),(112.02,111.78),108.68,58.75,52.63,51.55,51.27,46.24,42.31,41.30,33.42(2×C),23.78(2×C),11.46(2×C);HR MS:C24H28ClFN4O4[M+H]+计算值为491.1856,实测值为491.1859;(c=1.0mg/mL,CHCl3).
TM1-197-(3-(2-(环己基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.240.5-243.0℃;1H NMR(300MHz,DMSO-d6)δ:14.50(s,1H,H-11),9.00(s,1H,H-18),8.84(s,1H,H-2),7.97(d,2H,J=11.4Hz,H-5),4.45-4.34(m,1H,H-12);4.15(s,2H,H-20),3.71-3.54(m,4H,H-16、H-17and H-14),3.39-3.33(m,3H,H-14and H-15),2.87(t,1H,J=8.1Hz,H-22),2.73(s,1H,H-21),1.66-1.57(m,4H,H-23),1.22-1.19(m,2H,H-13),1.02-0.99(m,2H,H-13),0.96-0.94(m,2H,H-25),0.87(q,4H,J=7.2Hz,H-24);13C NMR(75MHz,DMSO-d6)δ:176.52,165.46,164.43,(157.64,154.98),153.30,143.72,138.31,123.56,120.34,(111.15,110.85),108.07,51.10,50.77,47.23,45.56,42.61,42.02,29.42(2×C),27.65,19.68(2×C),13.98,11.33,11.21;HR MS:C25H30ClFN4O4[M+H]+计算值为505.2012,实测值为505.2015;(c=1.0mg/mL,CHCl3).
TM1-207-(3-(2-(吡咯烷基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:白色固体,m.p.170.2~171.7℃;1H NMR(600MHz,CDCl3)δ:8.92(s,1H,H-2),8.04(d,1H,J=11.4Hz,H-5),4.38-4.35(m,1H,H-12),3.83-3.80(m,3H,H-16and H-17),3.40(s,2H,H-20),3.38-3.35(m,4H,H-14and H-15),2.64-2.62(m,4H,H-21),1.84-1.80(m,4H,H-22),1.35-1.31(m,2H,H-13),1.00-0.97(m,2H,H-13);13C NMR(101MHz,CDCl3)δ:176.77,168.93,165.94,(157.57,155.06),152.09,(144.08,143.94),137.89,(124.10,124.02),(120.22,120.17),(112.02,111.78),108.68,58.75,53.99(2×C),51.55,51.27,46.24,42.31,41.30,23.78(2×C),11.46(2×C);HR MS:C23H26ClFN4O4[M+H]+计算值为477.1699,实测值为477.1695;(c=2.0mg/mL,DCM).
TM1-217-(3-(2-(哌啶基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.225.6~226.9℃;1H NMR(600MHz,CDCl3)δ:14.33(s,1H,H-11),8.92(s,1H,H-2),8.05(d,1H,J=17.4Hz,H-5),4.39-4.34(m,1H,H-12),3.87-3.84(m,3H,H-16and H-17),3.40-3.34(m,4H,H-14and H-15),3.22(s,2H,H-20),2.49-2.47(m,4H,H-21),1.64-1.59(m,4H,H-22),1.47-1.42(m,2H,H-24),1.36-1.30(m,2H,H-13),1.01-0.96(m,2H,H-13).13C NMR(101MHz,CDCl3)δ:176.76,168.74,165.93,(157.61,155.10),152.09,(144.11,143.97),137.89,(124.12,124.04),(120.24,120.19),(112.04,111.80),108.70,62.55,54.34(2×C),51.59,51.31,46.46,42.40,41.29,25.96(2×C),23.86,11.47(2×C);HR MS:C24H28ClFN4O4[M+Na]+计算值为513.1675,实测值为513.1675;(c=2.0mg/mL,DCM).
TM1-227-(3-(2-(4-羟基哌啶基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.227.4~228.8℃;1H NMR(600MHz,CDCl3)δ:14.34(s,1H,H-11),8.92(s,1H,H-2),8.05(d,1H,J=11.4Hz,H-5),5.30(s,1H,H-25),4.38-4.35(m,1H,H-12),3.84-3.73(m,3H,H-16and H-17),3.39-3.33(m,4H,H-14and H-15),3.24(s,2H,H-20),2.82-2.80(m,2H,H-21),2.30-2.26(m,2H,H-21),1.95-1.92(m,2H,H-22),1.65-1.59(m,3H,H-22and H-23),1.35-1.31(m,2H,H-13),1.00-0.97(m,2H,H-13).13C NMR(101MHz,CDCl3)δ:176.79,168.64,165.95,(157.63,155.11),152.12,(144.03,143.89),137.88,(124.19,124.11),(120.32,120.27),(112.07,111.83),108.71,67.53,61.68,51.57,51.28,51.09(2×C),46.47,42.42,41.29,34.48(2×C),11.47(2×C);HR MS:C24H28ClFN4O5[M+Na]+计算值为529.1624,实测值为529.1620;(c=1.5mg/mL,DCM).
TM1-237-(3-(2-(吗啉基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:乳白色固体,m.p.213.9~215.3℃;1H NMR(600MHz,CDCl3)δ:14.31(s,1H,H-11),8.92(s,1H,H-2),8.06(d,1H,J=11.4Hz,H-5),4.38-4.34(m,1H,H-12),3.83-3.80(m,3H,H-16and H-17),3.75(t,4H,J=4.8Hz,H-22),3.41-3.34(m,4H,H-14and H-15),3.27(s,2H,H-20),2.57-2.55(m,4H,H-21),1.35-1.31(m,2H,H-13),1.00-0.97(m,2H,H-13).13C NMR(101MHz,CDCl3)δ:176.75,167.90,165.89,(157.63,155.11),152.13,(143.94,143.80),137.86,(124.27,124.19),(120.38,120.33),(112.09,111.86),108.73,66.86(2×C),61.74,53.51(2×C),51.47,51.26,46.40,42.39,41.29,11.48(2×C);HR MS:C23H26ClFN4O5[M+Na]+计算值为515.1468,实测值为515.1472;(c=1.5mg/mL,DCM).
TM1-247-(3-(2-(哌嗪基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色乳状体,m.p.194.3~195.5℃;1H NMR(600MHz,DMSO-d6)δ:14.48(s,1H,H-11),8.85(s,1H,H-2),7.96(d,1H,J=11.4Hz,H-5),4.58(s,2H,H-20),4.43-4.40(m,1H,H-12),3.72-3.69(m,4H,H-16and H-17),3.60-3.57(m,4H,H-22),3.48-3.42(m,8H,H-14、H-21andH-15),1.23-1.19(m,2H,H-13),1.03-1.00(m,2H,H-13);13C NMR(151MHz,DMSO-d6)δ:176.12,165.07,162.96,(156.44,154.78),152.90,(143.32,143.22),137.89,(123.19,123.13),(119.92,119.89),(110.71,110.55),107.68,55.46,50.48(2×C),48.82(4×C),45.25,42.15,41.59,10.87(2×C);HR MS:C23H27ClFN5O4[M+Na]+计算值为514.1628,实测值为514.1630;(c=1.5mg/mL,DMF).
TM1-257-(3-(2-(4-甲基哌嗪基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色晶状体,m.p.232.8~233.6℃;1H NMR(600MHz,D2O)δ:8.64(s,1H,H-2),7.08(d,1H,J=9.6Hz,H-5),4.27-4.24(m,1H,H-12),3.81-3.76(m,7H,H-16、H-17and H-22),3.64-3.61(m,4H,H-21),3.43-3.38(m,4H,H-14and H-15),3.07(s,3H,H-23),1.27-1.25(m,2H,H-13),0.86-0.84(m,2H,H-13);13C NMR(101MHz,D2O)δ:176.65,168.83,164.26,(157.71,155.20),153.56,(145.49,145.35),138.93,(122.62,122.54),(120.30,120.25),(111.16,110.93),107.27,58.59,57.86,51.41(2×C),51.37(2×C),51.02(2×C),46.73,44.09,43.18,11.99(2×C);HRMS:C24H29ClFN5O4[M+Na]+计算值为528.1784,实测值为528.1789;(c=1.5mg/mL,H2O).
TM1-267-(3-(2-(4-(2-羟乙基)哌嗪基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.230.2~231.1℃;1H NMR(600MHz,D2O)δ:8.64(s,1H,H-2),7.03(d,1H,J=9.0Hz,H-5),4.56(s,2H,H-20),4.26-4.23(m,1H,H-12),4.02-4.00(m,2H,H-24),3.88-3.78(m,9H,H-16、H-21and H-22),3.66-3.62(m,2H,H-17),3.54-3.52(m,2H,H-23),3.44-3.38(m,4H,H-14and H-15),1.29-1.27(m,2H,H-13),0.85-0.843(m,2H,H-13).13C NMR(101MHz,D2O)δ:176.65,168.80,164.24,(157.69,155.18),153.58,(145.50,145.36),138.95,(122.62,122.54),120.25,(111.18,110.95),107.32,59.40,58.65,57.95,56.10(2×C),51.52,50.86,49.92(2×C),46.78,44.14,43.21,12.07;HR MS:C25H31ClFN5O5[M+Na]+计算值为558.1890,实测值为558.1894;(c=1.0mg/mL,H2O).
TM1-277-(3-(2-(4-(叔丁氧羰基)哌嗪基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.218.7~219.6℃;1H NMR(600MHz,CDCl3)δ:14.31(s,1H,H-11),8.92(s,1H,H-2),8.06(d,1H,J=11.4Hz,H-5),4.38-4.34(m,1H,H-12),3.82-3.89(m,3H,H-16and H-17),3.52-3.50(m,4H,H-22),3.40-3.34(m,6H,H-20、H-14and H-15),2.60-2.57(m,4H,H-21),1.47(s,9H,H-25),1.35-1.31(m,2H,H-13),1.00-0.97(m,2H,H-13);13CNMR(101MHz,CDCl3)δ:176.75,167.50,165.88,(157.63,155.11),154.63,152.14,(143.88,143.73),137.83,(124.32,124.24),120.38,(112.11,111.87),108.74,79.97,60.90,52.76(4×C),51.43,51.17,46.38,42.41,41.29,28.39(3×C),11.48(2×C);HR MS:C28H35ClFN5O6[M-H]+计算值为590.2187,实测值为590.2192;(c=2.0mg/mL,DCM).
TM1-287-(3-(2-(肼基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:黄色固体,m.p.164.6~166.2℃;1H NMR(600MHz,DMSO-d6)δ:14.51(s,1H,H-11),8.84(s,1H,H-2),7.94(d,1H,J=12.0Hz,H-5),4.43-4.39(m,1H,H-12),3.96(s,2H,H-20),3.73-3.64(m,3H,H-16and H-17),3.58-3.56(m,2H,H-22),3.38-3.33(m,4H,H-14and H-15),1.21-1.19(m,2H,H-13),1.02-0.97(m,2H,H-13);13C NMR(151MHz,DMSO-d6)δ:176.13,165.12(2×C),(156.84,154.34),152.92,(143.43,143.29),137.93,(123.13,123.05),(119.87,119.82),(110.76,110.53),107.67,50.78,50.62,49.45,45.01,42.03,41.64,10.91(2×C);HR MS:C28H35ClFN5O6[M+H]+计算值为438.1339,实测值为438.1340;(c=1.5mg/mL,DMF).
TM1-297-(3-(2-(1-甲基肼基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:黄色固体,m.p.157.1~158.7℃;1H NMR(300MHz,DMSO-d6)δ:14.52(s,1H,H-11),8.86(s,1H,H-2),7.97(d,1H,J=11.7Hz,H-5),4.43-4.39(m,1H,H-12),3.94(s,2H,H-20),3.68-3.61(m,4H,H-16、H-17and H-14),3.38-3.33(m,3H,H-14and H-15),3.47(s,3H,CH3),1.22-1.19(m,2H,H-13),1.02-0.99(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.09,166.40,165.08,(157.23,153.91),152.84,(143.45,143.26),137.91,(123.08,122.97),119.76,(110.74,110.44),107.65,56.97,50.84,50.57,45.51,43.35,41.90,41.63,10.90(2×C);HR MS:C20H23ClFN5O4[M+H]+计算值为452.1495,实测值为452.1504;(c=1.0mg/mL,DMF).
TM1-307-(3-(2-(1,1-二甲基肼基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色棉状体,m.p.246.5~247.1℃;1H NMR(600MHz,DMSO-d6)δ:14.49(s,1H,H-11),8.85(s,1H,H-2),7.96(d,1H,J=12.0Hz,H-5),4.88(s,2H,H-20),4.43-4.39(m,1H,H-12),3.74-3.61(m,3H,H-16and H-17),3.47(s,6H,H-22),3.42-3.35(m,4H,H-14and H-15),1.23-1.19(m,2H,H-13),1.03-1.00(m,2H,H-13);13C NMR(151MHz,DMSO-d6)δ:176.11,165.05,162.84,(156.41,154.75),152.90,(143.24,143.14),137.88,(123.20,123.14),(119.92,119.88),(110.70,110.55),107.67,64.97,56.09(2×C),51.57,50.42,45.47,42.00,41.59,10.86(2×C);HR MS:C21H25ClFN5O4[M+H]+计算值为466.1652,实测值为466.1657; (c=1.0mg/mL,H2O).
TM1-317-(3-(2-(甲氧胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色固体,m.p.257.3~259.1℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),8.85(s,1H,H-2),7.96(d,1H,J=11.7Hz,H-5),6.76(s,1H,H-18),4.43-4.39(m,1H,H-12),3.72(s,2H,H-20),3.68-3.63(m,3H,H-16and H-17),3.41(s,3H,H-22),3.35-3.30(m,4H,H-14and H-15),1.22-1.19(m,2H,H-13),1.01-0.98(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.77,166.53,165.93,(157.18,155.50),152.16,(143.89,143.80),137.85,(124.30,124.24),(120.41,120.39),(112.06,111.91),108.74,62.29,51.05,50.90,45.33,42.49,41.30,39.70,11.49(2×C);HR MS:C20H22ClFN4O5[M+H]+计算值为453.1336,实测值为453.1340;(c=1.5mg/mL,DMF).
TM1-327-(3-(2-(羟胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色固体,m.p.223.2~224.1℃;1H NMR(600MHz,DMSO-d6)δ:14.50(s,1H,H-11),8.82(s,1H,H-2),7.91(d,1H,J=12.0Hz,H-5),4.41-4.36(m,1H,H-12),3.80-3.58(m,5H,H-16、H-20and H-17),3.38-3.33(m,4H,H-14and H-15),1.21-1.17(m,2H,H-13),1.01-0.98(m,2H,H-13);13C NMR(151MHz,DMSO-d6)δ:176.07,166.73,165.06,(156.30,154.64),152.79,(143.59,143.50),137.95,(122.83,122.78),(119.48,119.45),(110.63,110.47),107.63,62.64,51.05,50.66,45.97,41.94,41.56,10.84(2×C);(c=1.5mg/mL,DMF).
TM1-347-(3-(2-(乙酰氧基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:乳白色固体,m.p.166.2~167.6℃;1H NMR(300MHz,DMSO-d6)δ:14.53(s,1H,H-11),8.85(s,1H,H-2),7.97(d,1H,J=12.0Hz,H-5),4.48(s,2H,H-20),4.42-4.39(m,1H,H-12),3.66-3.62(m,4H,H-16、H-17and H-14),3.38-3.32(m,6H,H-14、CH3and H-15),1.21-1.18(m,2H,H-13),1.03-0.96(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.14,165.10(2×C),164.98,(157.25,153.93,152.84,(143.47,143.28),(137.93,137.90),(123.10,123.00),(119.86,119.79),(110.75,110.44),(107.67,107.65),60.26,50.80,50.59,46.23,42.38,42.04,41.62,10.89(2×C);(c=1.5mg/mL,DCM).
TM1-367-(3-(2-(硫代脲基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:土黄色固体,m.p.287.5~289.2℃;1H NMR(300MHz,DMSO-d6)δ:8.86(s,1H,H-2),8.01(d,1H,J=11.7Hz,H-5),6.01(s,2H,H-20),4.43-4.38(m,1H,H-12),3.56-3.50(m,5H,H-20、H-16and H-17),3.27-3.20(m,4H,H-14and H-17),1.20-1.18(m,2H,H-13),1.03-1.00(m,2H,H-13);(c=1.5mg/mL,H2O).
TM1-377-(3-(2-(脲基胺基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:浅黄色固体,m.p.260.2~264.3℃;1H NMR(300MHz,DMSO-d6)δ:8.84(s,1H,H-2),8.00(d,1H,J=11.7Hz,H-5),6.03(s,2H,H-20),4.42-4.37(m,1H,H-12),3.57-3.52(m,5H,H-20、H-16and H-17),3.29-3.22(m,4H,H-14and H-17),1.20-1.18(m,2H,H-13),1.03-0.99(m,2H,H-13);HR MS:C20H22ClFN6O5[M+K]+计算值为519.0956,实测值为519.0964;(c=1.5mg/mL,DMF).
TM1-387-(3-(2-(4-(3-羧基-1-环丙基-6-氟-4-氧代-1,4-二氢喹啉-7-基)哌嗪基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:m.p.283.5-284.2℃;1H NMR(300MHz,DMSO-d6)δ:15.16(s,1H,H-24),14.47(s,1H,H-11),8.84(s,1H,H-2),8.68(s,1H,H-25),7.99(d,2H,J=11.7Hz,H-5and H-23),7.62(s,1H,H-22),4.55(s,2H,H-19),4.40-4.29(m,1H,H-12andH-26),3.87-3.55(m,12H,H-14,H-17H-20and H-21),1.34-1.00(m,8H,H-13and H-27);HR MS:C36H35ClF2N6O7[M+Na]+计算值为759.2116,实测值为759.2112;(c=1.0mg/mL,DMSO).
TM1-397-(3-(2-(4-(3-羧基-1-乙基-6-氟-4-氧代-1,4-二氢喹啉-7-基)哌嗪基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:黄色固体,m.p.285.1-287.3℃;HR MS:C35H35ClF2N6O7[M+Na]+计算值为747.2116,实测值为747.2114.
TM1-407-(3-(2-(4-(3-羧基-1-(4-氟)-苯基-6-氟-4-氧代-1,4-二氢喹啉-7-基)哌嗪基)乙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:黄色固体,m.p.247.2-248.8℃;HRMS:C39H34ClF3N6O7[M+Na]+计算值为813.2022,实测值为813.2020.
实施例3、中间体IM2的合成
在100mL圆底烧瓶中依次加入原料CF、K2CO3及适量DCM,在冰浴下滴加氯丙酰氯的DCM溶液,CF、K2CO3与氯乙酰氯的投料摩尔比为1:2.5:1.5~2.0,滴毕,冰浴下持续搅拌反应,TLC监测反应进程。反应完成后,得到黄绿色浑浊液,抽滤,滤饼用DCM洗涤,洗液与滤液合并,旋蒸得粗品,用DCM-石油醚(体积比1:3)重结晶,或石油醚-乙醚(体积比1:3)分散,得中间体IM2,干燥,称重,计算收率。产物纯度满足后续反应需要,但分析用样品需经柱层析纯化。具体实验条件及结果见表5。
IM27-(3-(3-氯丙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡黄色固体,m.p.207.1~208.8℃;1H NMR(300MHz,DMSO-d6)δ:14.50(s,1H,H-11),8.85(s,1H,H-2),8.78(s,1H,H-18),7.97(d,1H,J=11.4Hz,H-5),4.43-4.39(m,1H,H-12),3.69-3.62(m,3H,H-16and H-17),3.38-3.31(m,2H,H-14),3.19-3.17(m,2H,H-20),3.05-3.03(m,2H,H-21),2.88-2.90(m,2H,H-15),1.21-1.18(m,2H,H-13),1.03-0.99(m,2H,H-13);13C NMR(75MHz,DMSO-d6)δ:176.14,168.43,165.07,(157.34,154.21),152.87,(143.31,143.17),137.93,(123.16,123.08),(119.85,119.80),(110.75,110.52),107.69,50.80,50.57,45.61,41.88,41.57,28.64,10.83(2×C);HR MS:C20H20Cl2FN3O4[M+H]+计算值为456.0888,实测值为456.0894; (c=2.5mg/mL,DCM).
表5IM2合成结果
实施例4、目标化合物TM2的合成
向反应瓶中加入原料胺组分、K2CO3和氯仿适量,搅拌30分钟,加入IM2,胺组分、K2CO3与IM2的投料摩尔比为2:3:1,控温(35~40℃)搅拌反应,TLC监测反应进程。反应结束后,加水,冰浴下用2N HCl调至中性,静置分层,弃去有机相,水相继续调pH至4~5,逐渐变为黄色乳状物,冰箱静置,析出固体,抽滤,用90%乙醇重结晶,即得目标化合物TM2。具体实验条件及结果见表6。
表6目标化合物TM2合成结果
化合物TM2的波谱数据如下:
TM2-17-(3-(3-(羟乙基胺基)丙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:乳白色固体,m.p.260.2~261.3℃;1H NMR(600MHz,DMSO-d6)δ:14.51(s,1H,H-11),8.85(s,1H,H-2),8.76(s,1H,H-18),7.97(d,1H,J=11.4Hz,H-5),5.29(s,1H,OH),4.43-4.39(m,1H,H-12),3.69-3.62(m,5H,H-16、H-24and H-17),3.38-3.31(m,4H,H-14and H-23),3.19-3.17(m,2H,H-20),3.05-3.03(m,2H,H-21),2.88-2.90(m,2H,H-15),1.21-1.18(m,2H,H-13),1.03-0.99(m,2H,H-13);13C NMR(101MHz,DMSO-d6)δ:176.14,168.43,165.07,(156.84,154.35),152.90,(143.41,143.27),137.93,(123.16,123.08),(119.85,119.80),(110.75,110.52),107.69,56.29,50.80,50.57,48.98,45.61,43.08,41.88,41.57,28.64,10.83(2×C);HR MS:C22H26ClFN4O5[M+Na]+计算值为503.1468,实测值为503.1477;(c=1.5mg/mL,H2O).
TM2-27-(3-(3-(N-甲基-羟乙基胺基)丙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:淡绿色固体,m.p.243.1~244.9℃;1H NMR(600MHz,DMSO-d6)δ:14.51(s,1H,H-11),10.21(s,1H,H-18),8.85(s,1H,H-2),7.96(d,1H,J=12.0Hz,H-5),5.40(s,1H,OH),4.43-4.39(m,1H,H-12),3.69-3.62(m,5H,H-16、H-21and H-23),3.45-3.14(m,8H,H-17、H-14、H-22and H-20),3.01-2.98(m,2H,H-15),2.81(s,3H,-CH3),1.22-1.18(m,2H,H-13),1.02-0.99(m,2H,H-13);13C NMR(101MHz,DMSO-d6)δ:176.16,168.09,165.14,(156.85,154.35),152.94,(143.49,143.35),137.97,(123.10,123.02),(119.79,119.74),(110.77,110.54),107.68,57.01,55.28,51.85,50.84,50.65,45.62,41.90,41.63,27.05,10.89(2×C);HR MS:C23H28ClFN4O5[M+Na]+计算值为517.1624,实测值为517.1622;(c=1.5mg/mL,H2O).
TM2-37-(3-(3-(二羟乙基胺基)丙酰胺基)-1-吡咯烷基)-1-环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸:乳白色固体,m.p.241.2~242.8℃;1H NMR(600MHz,DMSO-d6)δ:14.52(s,1H,H-11),9.46(s,1H,H-18),8.86(s,1H,H-2),7.98(d,1H,J=12.0Hz,H-5),5.35(s,2H,OH),4.43-4.39(m,1H,H-12),3.78-3.65(m,9H,H-16、H-21、H-23and H-17),3.48-3.33(m,8H,H-14、H-22and H-20),3.00-2.98(m,2H,H-15),1.22-1.19(m,2H,H-13),1.04-1.00(m,2H,H-13);13C NMR(151MHz,DMSO-d6)δ:176.04,168.24,164.98,(156.32,154.66),152.82,(143.29,143.20),137.82,(123.02,122.97),(119.71,119.68),(110.62,110.46),107.58,55.12(2×C),54.69(2×C),50.65,50.45,49.79,45.48,41.77,41.46,26.51,10.73(2×C);HR MS:C24H30ClFN4O6[M+Na]+计算值为547.1730,实测值为547.1732;(c=1.5mg/mL,H2O).
实施例5、合成化合物的溶解性试验
对中间体IM1、IM2和目标化合物TM1、TM2在多种常用溶剂中的溶解性进行了考察。结果见表7。
表7合成化合物在不同溶剂中的溶解性
实施例6、合成化合物的琼脂扩散抑菌试验
融化普通琼脂培养基,冷却至55~60℃,加入1.0×106FU/mL的试验用细菌悬液(沙门菌SR96-1、铜绿假单胞菌ATCC27853、金黄色葡萄球菌ATCC29213、大肠杆菌临床分离株、鸭源大肠杆菌)1.0mL,倾倒至直径为90mm的平皿中,凝固后打孔备用。向上述琼脂孔中加入含有待测化合物的磷酸盐缓冲液(100mmol/L,pH=7.2),待测化合物的加入量为2μg/孔,加毕,37℃培养24小时,测定抑菌圈直径。以克林沙星(CF)和诺氟沙星(NF)作为阳性对照。结果见表8和表9。
表8合成化合物的琼脂扩散抑菌试验结果(抑菌圈直径:mm)
注:N表示未测定。
表9合成化合物的琼脂扩散抑菌试验结果(抑菌圈直径:mm)
由表8和表9可以看出,所有测试化合物都显示出一定的抑菌活性,其中化合物TM1-9~TM1-13、TM1-15、TM1-17、TM1-22、TM1-23、TM1-28、TM1-29、TM1-32、TM1-34和TM1-36表现出较好的抑菌效果,尤其化合物TM1-10~TM1-12、TM1-32和TM1-36对部分菌株的抑菌活性与CF相当或更强。
实施例7、部分合成化合物对耐药大肠杆菌临床分离株的琼脂扩散抑菌试验
取实施例6琼脂扩散抑菌试验筛选出的具有较好抑菌效果的合成化合物,采用实施例6所述方法检测这些化合物对27株临床分离的耐药大肠杆菌的抑菌效果,待测化合物的加入量分别为4μg/孔和8μg/孔。以CF作为阳性对照。结果见表10和表11。
表10部分合成化合物对耐药大肠杆菌的琼脂扩散抑菌试验结果(化合物加入量为4μg)
表11部分合成化合物对耐药大肠杆菌的琼脂扩散抑菌试验结果(化合物加入量为8μg)
由表10和表11可以看出,当化合物剂量为4μg时,CF对26%的耐药大肠杆菌有效,其中对73号耐药菌株的抑菌效果最好,抑菌圈达到2.13cm;化合物TM1-22、TM1-23、TM1-29只对73号耐药菌株有抑菌效果;TM1-9、TM1-10、TM1-13、TM1-15、TM1-28、TM1-32、TM1-36对约18%的耐药大肠杆菌有效,比CF略差;TM1-11对26%的耐药大肠杆菌有效,与CF相当;TM1-12对48%的耐药大肠杆菌有效,强于CF。当化合物剂量为8μg时,CF对33%的耐药大肠杆菌有效;化合物TM1-11和TM1-36对52%的耐药菌株有效,TM1-12对59%的耐药菌株有效,明显强于CF;其它化合物对耐药菌株的抑菌效果随剂量增加未见明显变化。总体来看,化合物TM1-11、TM1-12和TM1-36对耐药大肠杆菌的有效抑制效果强于CF。
实施例8、部分合成化合物的最低抑菌浓度(MIC)测定
取实施例6抑菌试验筛选出的具有较好抑菌效果的合成化合物,采用美国国家临床实验室标准化委员会(NCCLS)推荐的微量稀释法,测定这些化合物对金黄色葡萄球菌ATCC29213、铜绿假单胞菌ATCC27853、沙门菌SR96-1和大肠杆菌临床分离株的MIC:将待测化合物的水溶液用M-H肉汤培养基(Mueller-Hinton Broth)以二倍稀释法稀释备用;在96孔板中加入上述待测化合物的稀释液,待测化合物的加入量分别为16、8.0、4.0、2.0、1.0、0.5、0.25、0.125μg/孔,然后每孔加入1.0×106CFU/mL的试验用细菌悬液0.5μL,37℃培养16小时,测得MIC,结果用琼脂平板抑菌法进行验证。以CF作为阳性对照。结果见表12。
表12部分合成化合物的MIC(μg/mL)
由表12可以看出,除化合物TM1-22、TM1-23和TM1-28的抑菌活性相对较差以外,其它9个化合物整体上都表现出良好的抑菌活性,其中化合物TM1-10~TM1-13、TM1-32、TM1-36的抑菌效果最好,与琼脂扩散抑菌实验的结果基本一致。从抑菌菌种上来看,上述大部分化合物对大肠杆菌和沙门菌的抑菌效果最好,对铜绿假单胞菌也表现出较好的抑菌活性,而除了个别化合物TM1-13和TM1-36外,其他化合物对金黄色葡萄球菌只表现出中等抑菌活性。
实施例9、部分合成化合物对猪源耐喹诺酮类大肠杆菌的MIC测定
取实施例7筛选出的对耐药大肠杆菌临床分离株具有较好抑菌效果的合成化合物,采用微量稀释法,测定这些化合物对27株猪源耐喹诺酮类大肠杆菌(分离自重庆市北碚区、合川区、璧山县多个养猪场,对环丙沙星、氧氟沙星、诺氟沙星等喹诺酮类药物具有耐药性)的MIC:将菌株接种于LB培养基中,37℃摇床活化培养17小时,活化后用M-H肉汤培养基分别稀释成108CFU/mL的菌悬液备用;将待测化合物的水溶液用MH液体培养基以二倍稀释法稀释备用;在96孔板中加入上述待测化合物的稀释液,待测化合物的加入量分别为64、32、16、8.0、4.0、2.0、1.0、0.5μg/孔,然后每孔加入1.0×106CFU/mL的试验用细菌悬液0.5μL,37℃培养16-20小时,肉眼观察孔内细菌生长情况,没有细菌生长的孔中的药物浓度即为该药物对该细菌的MIC。以CF作为阳性对照。结果见表13。
表13部分合成化合物对猪源耐喹诺酮类大肠杆菌的MIC(μg/mL)
由表13可以看出,大部分化合物对猪源耐喹诺酮类大肠杆菌的抑制效果弱于CF,少数化合物对60、67、69、74、75、76号菌株的抑制效果与CF相当或强于CF。总体上,化合物TM1-12和TM1-36对猪源耐喹诺酮类大肠杆菌的抑制效果最好。
实施例10、部分合成化合物的急性毒性试验
根据实施例6-9的试验结果,选择化合物TM1-11和TM1-12作为高活性的克林沙星衍生物,进行体内急性毒性试验。将50只小鼠随机分成5组,每组10只,雌雄各半,试验前禁食不禁水24小时;通过预实验找出待测化合物对小鼠的最大耐受剂量(MTD)和绝对致死剂量(Dm),按照等比数列设计5个剂量组(表14);将5组小鼠分别按设计剂量腹腔注射给予待测化合物,注射体积按0.2mL/10g计算,观察并记录小鼠的毒性反应、中毒发生时间、持续时间和恢复时间以及各组动物的死亡情况和死亡时间,连续观察7天,统计小鼠死亡数,计算死亡率,结果见表15。按孙氏改良寇氏法计算半数致死量(LD50)。
表14剂量分组
表15部分合成化合物的急性毒性试验结果
试验结果显示:CF起效慢,在给药1小时后,Dm组出现呼吸困难、缩瞳、躁动不安等症状,30分钟后出现死亡,死亡前出现强直性抽搐、惊厥、运动困难等症状,将死亡小鼠全部解剖,肉眼观察,小鼠的各内脏器官未见明显异常改变;次日未死亡小鼠逐渐恢复正常,之后几天无异常现象发生。TM1-11和TM1-12的Dm组在给药后40分钟出现腹式呼吸、强直性抽搐、缩瞳、喘息等症状,几分钟后小鼠出现死亡,死亡小鼠全身发紫,将死亡小鼠全部解剖,肉眼观察,小鼠的各内脏器官未见明显异常改变;存活小鼠在给药后5小时逐渐恢复正常,之后几天无异常现象发生。上述结果说明CF与TM1-11、TM1-12的急性毒性反应可能涉及肺心功能不全、呼吸衰竭、神经肌肉、自主神经、肋间肌麻痹、胆碱能神经麻痹等。
按孙氏改良寇氏法计算,CF的LD50为73.19mg/kg±5mg/kg;TM1-11的LD50为412.80mg/kg±5mg/kg;TM1-12的LD50=392.30mg/kg±5mg/kg;TM1-11和TM1-12的毒性都远远低于CF。
实施例11、部分合成化合物的光毒性试验
根据实施例10的急性毒性试验结果,选择毒性最小的化合物TM1-11,进一步开展光毒性实验。将80只小鼠称重后随机分成8组,每组10只,雌雄各半;通过预试验结果:小鼠灌胃给药七天后进行紫外光照射,24小时后小鼠耳部出现充血、水肿,以氯丙嗪(30mg/kg/d)为参照,按照等差数列(公差取40mg/kg/d)设计3个剂量组:120mg/kg/d组、80mg/kg/d组和40mg/kg/d组;将8组小鼠分别给予氯丙嗪、生理盐水、上述3种不同剂量的CF和TM1-11,连续灌胃给药7天,每天1次,给药期间保证小鼠饮食与饮水;于第七天灌胃给药15分钟后,将小鼠放入烧杯中,于小鼠背部垂直距离10-12cm进行紫外光照射,紫外线强度为10~22μW/cm2,以纸板遮住整个光照装置以隔绝外界光线,光照期间断绝小鼠食物与饮水,单给予苹果;光照24小时后,检查小鼠耳、尾、背的变化,连续观察5天,每天检查1次。结果见表16。
表16部分合成化合物的光毒性试验结果
*CF高剂量组小鼠意外死亡2只,TM1-11低剂量组小鼠失踪1只。
由表16可以看出,氯丙嗪组的光毒性最大,所有小鼠都显示出不同程度的光毒性,其中有60%的小鼠达到3级光毒性,小鼠耳部出现很明显的充血、水肿;其次是CF,有1只小鼠达到3级光毒性,有29%的小鼠达到2级光毒性,46%的小鼠达到1级光毒性;TM1-11高、中、低剂量组均无小鼠达到2级和3级光毒性,有31%的小鼠达到1级光毒性,有29%的小鼠无光毒性反应。光毒性达到1级的小鼠数目,TM1-11组比CF组少4只;无光毒性反应的小鼠数目,TM1-11组比CF组多3倍。CF和TM1-11高、中、低三个剂量组对光毒性反应有一定规律,随着化合物剂量增大,显示出的光毒性就越强,说明试验数据可靠。总的来看,光毒性趋势为:生理盐水<TM1-11<CF<氯丙嗪。由此可得出,TM1-11光毒性比CF小,对克林沙星吡咯环进行修饰能降低光毒性。
最后说明的是,以上优选实施例仅用以说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (4)
1.式I所示的胺基烷酰克林沙星及其可药用盐:
式中,n为1; 表示脂肪胺基,
所述脂肪胺基为NR1R2,R1为氢,R2为2-羟基乙基、(R)-1-乙基-2-羟基乙基、2-氨基乙基、乙酰氧基、羟基、硫脲基;或者,R1为甲基或2-羟基乙基,R2为2-羟基乙基。
2.根据权利要求1所述的式I所示的胺基烷酰克林沙星及其可药用盐,其特征在于,n为1;表示脂肪胺基,所述脂肪胺基为NR1R2,R1为氢,R2为2-羟基乙基、2-氨基乙基、羟基或硫脲基;或者,R1为甲基或2-羟基乙基,R2为2-羟基乙基。
3.根据权利要求2所述的式I所示的胺基烷酰克林沙星及其可药用盐,其特征在于,n为1;表示脂肪胺基,所述脂肪胺基为NR1R2,R1为甲基或2-羟基乙基,R2为2-羟基乙基。
4.权利要求1至3任意一项所述的式I所示的胺基烷酰克林沙星及其可药用盐在制备抗菌药物中的应用,其特征在于,所述抗菌药物为抗沙门菌、铜绿假单胞菌、金黄色葡萄球菌、大肠杆菌中任一种或多种的药物。
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