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【发明授权】克林沙星唑烷酰衍生物及其制备方法和应用_西南大学_201610390274.5 

申请/专利权人:西南大学

申请日:2016-06-03

公开(公告)日:2021-02-19

公开(公告)号:CN107459507B

主分类号:C07D401/14(20060101)

分类号:C07D401/14(20060101);C07D417/14(20060101);A61P31/04(20060101);A61P31/06(20060101)

优先权:

专利状态码:有效-授权

法律状态:2021.02.19#授权;2018.01.05#实质审查的生效;2017.12.12#公开

摘要:本发明公开了一种克林沙星唑烷酰衍生物,具有以下结构式,是以克林沙星为底物,保留其基本骨架,在吡咯环3‑氨基处通过Linker引入唑类结构单元而获得,该衍生物是既含有氟喹诺酮母核又引入了唑类结构单元的双药效团分子,经实验证实,其具有较好的抗菌活性,尤其具有较好的抗结核分枝杆菌活性,且毒性较低、水溶性和稳定性良好,可用于制备抗菌药物,在抗菌治疗尤其是结核病治疗药物领域具有潜在的应用前景。

主权项:1.克林沙星唑烷酰衍生物,其特征在于:具有以下结构式: 式中,n为1,Y为1-氢-咪唑-1-基、2-甲基-1-氢-咪唑-1-基、4-甲基-1-氢-咪唑-1-基、1-氢-苯并咪唑-1-基、1-氢-苯并咪唑-2-巯基、1-氢-吡唑-1-基、3,5-二甲基-1-氢-吡唑-1-基、3-氨基-1-氢-吡唑-1-基、1-氢-1,2,4-三唑-1-基、3-氨基-1-氢-1,2,4-三唑-5-巯基、1-氢-1,2,3-三唑-1-基、2-氢-1,2,3-三唑-2-基、1-氢-四唑-1-基、2-氢-四唑-2-基、5-甲基-1-氢-四唑-1-基、5-氨基-2-氢-四唑-2-基;n为2;Y为1-氢-咪唑-1-基、1-氢-吡唑-1-基、、2-氢-1,2,3-三唑-2-基、5-甲基-2-氢-四唑-2-基。

全文数据:克林沙星唑烷酰衍生物及其制备方法和应用技术领域[0001]本发明属于药物合成技术领域,涉及一类新型克林沙星衍生物、其制备方法、以及在制药中的应用。背景技术[0002]喹诺酮类QuinoIones是一类高效、低毒、选择性好且与抗生素无交叉耐药性的药物,长期以来作为一线抗菌药物应用于临床。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。另外,克林沙星的水溶性较差,水溶液的稳定性不够,可能也是影响其成药的重要因素。对克林沙星进行结构改造,通过合理的药物设计,引入合理的结构单元,有可能获得活性增强、毒性降低、水溶性提高、分子稳定性增加的先导分子。[0003]唑类分子具有广泛的生物活性。近年来,单氮唑类如噁唑、咔唑、噻唑;双氮唑类如吡唑、咪唑、苯并咪唑;三氮唑类如三唑、苯并三唑以及四氮唑类如四唑等得到异常广泛的研究并且许多已经应用于医药、农业等领域。发明内容[0004]有鉴于此,本发明的目的在于设计合成一类含有克林沙星及唑环双药效团的新型分子,并对其生物活性进行研究,以期获得具有较好生物活性、较低毒性、较好水溶性和稳定性的先导分子,为药物研究提供新品种。[0005]经研究,本发明提供如下技术方案:[0006]1.克林沙星唑烷酰衍生物,具有以下结构式:[0007][0008]式中,η为1或2;[0009]Y为1-氢-咪唑-1-基、2-甲基-1-氢-咪唑-1-基、4-甲基-1-氢-咪唑-1-基、1-氢-苯并咪唑-1-基、1-氢-苯并咪唑-2-巯基、1-氢-吡唑-1-基、3,5_二甲基-1-氢-吡唑-1-基、3-氨基-1-氢-吡唑-1-基、1-氢-1,2,4-三唑-1-基、3-氨基-1-氢-1,2,4-三唑-5-巯基、1-氢-1,2,3_三唑-1-基、2-氢_1,2,3_三唑-2-基、1-氢-四唑-1-基、2-氢-四唑-2-基、5-甲基-1-氢-四唑-1-基、5-甲基-2-氢-四唑-2-基、5-氨基-2-氢-四唑-2-基、5-甲巯基-2-氢-四唑-2-基、5-氨基_1,3,4_噻二唑-2-巯基、5-甲氧基-1-氢-苯并咪唑-2-巯基或1-氢-苯并三唑-1_基。[0010]优选的,η为I,Υ为1-氢-咪唑-1-基、2-甲基-1-氢-咪唑-1-基、4-甲基-1-氢-咪唑-1-基、1-氢-苯并咪唑-1-基、1-氢-苯并咪唑-2-巯基、1-氢-吡唑-1-基、3,5_二甲基-l-氢-吡唑-1-基、3-氨基-1-氢-吡唑-1-基、1-氢_1,2,4-三唑-1-基、3-氨基-1-氢_1,2,4-三唑-5-巯基、1-氢-I,2,3-三唑-1-基、2-氢-I,2,3-三唑-2-基、1-氢-四唑-1-基、2-氢-四唑-2-基、5-甲基-1-氢-四唑-1-基、5-甲基-2-氢-四唑-2-基、5-氨基-2-氢-四唑-2-基、5-甲巯基-2-氢-四唑-2-基、5-氨基_1,3,4_噻二唑-2-巯基、5-甲氧基-1-氢-苯并咪唑-2-巯基或1-氢-苯并三唑-1-基;[0011]η为2;Y为1-氢-咪唑-1-基、2-甲基-1-氢-咪唑-1-基、4-甲基-1-氢-咪唑-1-基、1-氢-苯并咪唑-1-基、1-氢-吡唑-1-基、3,5-二甲基-1-氢-吡唑-1-基、1-氢-1,2,4-三唑-1-基、卜氢-1,2,3_三唑-1-基、2-氢_1,2,3_三唑-2-基、5-甲基-1-氢-四唑-1-基、5-甲基-2-氢-四唑-2-基、5-氨基-2-氢-四唑-2-基、5-氨基-1,3,4-噻二唑-2-巯基。[0012]2.所述克林沙星唑烷酰衍生物的制备方法,是将化合物頂与唑类化合物YH在溶剂中、碱作用下于25-85Γ反应制得克林沙星唑烷酰衍生物,所述溶剂为二氯甲烷DCM、二甲基甲酰胺DMF、水或二甲基甲酰胺-水混合液,所述碱为碳酸钾K2CO3或氢化钠NaH;化学反应式如下:[0013][0014]化合物頂结构式中η的定义与克林沙星唑烷酰衍生物结构式中η的定义相同;唑类化合物YH结构式中Y的定义与克林沙星唑烷酰衍生物结构式中Y的定义相同。[0015]3.权利要求1或2所述的克林沙星唑烷酰衍生物在制备抗菌药物中的应用。[0016]优选的,所述抗菌药物为抗铜绿假单胞菌、沙门氏菌、金黄色葡萄球菌、大肠埃希菌和结核分枝杆菌中任一种或多种的药物。[0017]本发明的有益效果在于:本发明基于活性片段药物设计思想,以克林沙星为底物,采用“保留克林沙星基本骨架、对吡咯环3-氨基进行衍生”的思路,借助Linker引入唑类结构单元,合成了一类结构新颖的克林沙星唑烷酰衍生物,该衍生物是既含有氟喹诺酮母核又引入了唑类结构单元的双药效团分子,经实验证实,其具有较好的抗菌活性,尤其具有较好的抗结核分枝杆菌活性,且毒性较低、水溶性和稳定性良好,可用于制备抗菌药物,在抗菌治疗尤其是结核病治疗药物领域具有潜在的应用前景。具体实施方式[0018]为了使本发明的目的、技术方案和有益效果更加清楚,下面将对本发明的优选实施例进行详细的描述。[0019]原料化合物IMl和IM2系按照中国专利CN103396396A“胺基烷酰克林沙星及其应用”中所述合成方法制得。[0020]实施例1目标化合物TM3TM4的合成[0021][0022]向IOOmL圆底烧瓶中依次加入唑类化合物YH、溶剂和碱,搅拌30min后,加入化合物頂1或IM2,控温搅拌反应,薄层色谱法TLC监测反应进程。反应完成后,加入NaCl水溶液10mL,用2NHCl溶液调节pH至6〜7,2〜8°C冷藏,抽滤,滤饼用饱和食盐水充分洗涤后,水洗,干燥,用不同比例的EtOH-H2O溶液重结晶或分散,得粗品或纯品,粗品用柱层析纯化,得目标化合物TM3或TM4。具体制备条件及实验结果见表1。产物结构经物理常数测定、1HNMR、13CNMR、HR-MS表征。[0023]表1目标化合物TM3TM4的制备条件及实验结果[0024][0025][0026][0027]注表示未获得产物。[0028]由于1,2,3-三氮唑、四氮唑化合物本身存在如下互变结构:[0029][0030]因此,以其为反应原料时,均可能生成两种产物:1-取代产物a’和2-取代产物b’。但是随反应物的不同,有的异构体量较少,难于分离提纯。[0031]目标化合物TM3TM4的结构鉴定数据如下:[0032][0033]7-3-2-1-氢-咪唑-1-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)(TM3-1:淡黄色固体,m·p·258·3〜260·1°C;1HNMR300MHz,DMS0-d65:14.52s,lH,H-Il,9.06s,1H,H-21,8.86s,lH,H-2,7.99d,lH,J=11.7Hz,H-5,7.67s,2H,H-22andH-23,5.46s,2H,H-20,4.46-4.38m,1H,H-12,3.71-3.67m,3H,H-16andH-17,3.50-3.43m,2H,H-14,3.38-3.35m,2H,H-15,1.23-1.19m,2H,H-13,1.04-1.00m,2H,H-13;13C匪R75MHz,DMS0-d6S:176.15,165.14,164.34,157.31,153.99,152.96,143.43,143.24,137.94,136.82,123.52,123.24,123.12,119.91,119.63,110.86,110.54,107.69,50.62,50.55,49.78,45.14,42.55,41·66,10·922XC;HRMS:C22H2iC1FN5〇4[M+H]+计算值为474·1344,实测值为474·1346·[0034]7-3-2-2-甲基-1-氢-咪唑-1-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)(TM3-2:淡黄色固体,m·p·269·3〜270·6°C;1HNMR300MHz,DMS0-d65:14.53s,lH,H-ll,8.86s,lH,H-2,7.99d,lH,J=11.7Hz,H-5,7.56d,2H,J=9.9Hz,H-21andH-22,5.41s,2H,H-20,4.45-4.38m,lH,H-12,3.70-3.64m,3H,H-16andH-17,3.50-3.45m,2H,H-14,3.38-3.34m,2H,H-15,2.50s,3H,H-23,1.22-1·18m,2H,H-13,I·03-0·99ιή,2H,H-13;13C匪R75MHz,DMSO-I6δ:176.13,165.12,163.84,157.23,153.90,152.90,145.57,143.48,143.29,137.95,123.27,123.10,123.00,119.83,117.43,110.80,110.49,107.66,50.67,50.62,48·49,45·22,42·57,41·65,10·93,10·332XC;HRMS:C23H23ClFN5〇4[M+H]+计算值为488·1501,实测值为488·1503.[0035]7-3-2-4-甲基-1-氢-咪唑-1-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)(TM3-3:淡黄色固体,m·p·265·5〜266·7°C;1HNMR300MHz,DMS0-d65:14.52s,lH,H-ll,8.97s,lH,H-21,8.86s,lH,H-2,7.99d,lHJ=11.7Hz,H-5,7.37s,lH,H-22,5.40s,2H,H-20,4.46-4.38m,lH,H-12,3.70-3.64m,3H,H-16andH-17,3.49-3.43m,2H,H-14,3.37-3.31m,2H,H-15,2.31s,3H,H-23,I·23-1·19m,2H,H-13,I·03-0·99m,2H,H-13;13C匪R75MHz,DMSO-Cl6δ:176·09,165.12,164.36,157.24,153.85,152.89,143.44,143.26,137.92,135.76,128.78,123.15,123.05,120.12,(119.84,119.67,(110.79,110.48,107.67,50.87,50.58,49·80,45·15,42·57,41·66,10·94,9·65,8·60;HRMS:C23H23ClFN5〇4[M+H]+计算值为488·1501,实测值为488·1503.[0036][0037]7-3-2-1-氢-苯并咪唑-1-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)(TM3-4:乳黄色固体,πκp·272·4〜273·8°C;1H匪R300MHz,DMS0-d65:14.55s,lH,H-ll,8.86s,lH,H-2,8.59s,lH,H-21,7.99d,lHJ=11.7Hz,H-5,7.76-7.68m,2H,H-22,7.39-7.30m,2H,H-23,5.53s,2H,H-20,4.46-4.39m,lH,H-12,3.80-3.69m,3H,H-16andH-17,3.54-3.51m,2H,H-14,3.38-3.34m,2H,H-15,1.24-1.18m,2H,H-13,1.05-1.01m,2H,H-13;13CNMR75MHz,DMS0-d6S:176.16,165.20,165.14,157.25,153.93,152.89,(143.53,143.34,137.94,124.45,123.202XC,122.98,122.64,119.82,118.13,114.79,111.48,110.81,110.50,107·67,50·79,50·69,46·13,45·25,42·45,41·65,10·922XC;HRMS:C26H23ClFN5〇4[M+H]+计算值为524.1501,实测值为524.1505·[0038]7-3-2-1-氢-苯并咪唑-2-巯基)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)(TM3-5:乳黄色固体,πκp·214·7〜216·1°C;1H匪R300MHz,DMS0-d65:14.27s,lH,H-ll,8.75s,lH,H-2,7.95s,lH,H-21,7.99d,lHJ=12.0Hz,H-5,7.47-7.44m,2H,H-22,7.13-7.09m,2H,H-23,4.52s,2H,H-20,4.33-4.26m,lH,H-12,3.75-3.67m,3H,H-16andH-17,3.35-3.33m,2H,H-14,3.28-3.25m,2H,H-15,1.19-1.13m,2H,H-13,0.93-〇.87m,2H,H-13;HRMS:C26H23ClFN5O4S[M+H]+计算值为556.1222,实测值为556.1219·[0039][0040]7-3-2-1-氢-吡唑-1-基)乙酰胺基-1-吡咯烷基-1-环丙基-6-氟-8-氯-I,4-二氢-4-氧代-3-喹啉羧酸)(TM3-6:淡黄色固体,m·p·258·2〜259·1°C;1HNMR300MHz,DMS0-d65:14.54s,lH,H-ll,8.86s,lH,H-2,7.97d,lH,J=11.7Hz,H-5,7.68d,lH,J=2.1Hz,H-21,7.45d,lH,J=1.5Hz,H-23,6.28t,lH,J=1.8Hz,H-22,5.22s,2H,H-20,4.43-4.38m,lH,H-12,3.70-3.66m,3H,H-16andH-17,3.58-3.54m,4H,H-14andH-15,1.22-1·18m,2H,H-13,1.03-0.99m,2H,H-13;13C匪R75MHz,DMS0-d6S:176.18.165.84.165.15,157.27,153.94,152.90,(143.54,143.35,138.64,137.97,131.49,123.09,122.98,119.82,110.81,110.50,107.67,105.41,52.68,50.84,50·68,45·24,42·25,41·65,10·912XC;HRMS:C22H2iClFN5〇4[M+Na]+计算值为496·1164,实测值为496.1162.[0041]7-3-2-3,5-二甲基-1-氢-吡唑-1-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)(TM3-7:淡粉色固体,m.p·290·2〜291·6°C;1HMMR300MHz,DMS0-d6S:14.56s,lH,H-ll,8.86s,lH,H-2,7.99d,lH,J=11.4Hz,H-5,5.81s,lH,H-21,5.04s,2H,H-20,4.44-4.40m,lH,H-12,3.71-3.67m,3H,H-16andH-17,3.40-3.32m,4H,H-14andH-15,2.13s,3H,H-23,2.07s,3H,H-22,1.23-1.19m,2H,H-13,1.03-0.99m,2H,H-13;HRMS:C24H25ClFN5〇4[M+Na]+计算值为524·1477,实测值为524·1476.[0042]7-3-2-3-氨基-1-氢-吡唑-1-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)(TM3-8:橘黄色固体,m·p·155·9〜157·1°C;1HNMR300MHz,DMS0-d65:14.53s,lH,H-ll,8.86s,lH,H-2,7.97d,lH,J=11.7Hz,H-5,7.70d,lH,J=2.4Hz,H-22,5.74d,lH,J=2.7Hz,H-21,4.44-4.37m,lH,H-12,4.11s,2H,H-20,3.68-3.61m,3H,H-16andH-17,3.40-3.32m,4H,H-14andH-15,1.23-1.18m,2H,H-13,1.03-0.99m,2H,H-13;13C匪R75MHz,DMS0-d6δ:176.15,167.73,165.15,157.23,153.40,152.87,143.40,137.94,132.99,122.93,119.76,115.29,HO.78,HO.49,107.66,58.72,50.86,50.77,45.48,42.84,41.67,10.942XC;HRMS:C22H22ClFN6〇4[M+H]+计算值为489.1453,实测值为489.1452·[0043][0044]7-3-2-1-氢-I,2,4-三唑-1-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)(TM3-10:淡黄色固体,m·p·208·6〜209·9°C;1H匪R300MHz,DMS〇-d6S:14.54s,1H,H-11,8.86s,1H,H-2,8.47s,1H,H-21,7.98s,1H,H-22,7.97d,1H,J=11·7Hz,Η-5,5·38s,2H,H-20,4.44-4.38m,lH,H-12,3.72-3.68m,3H,H-16andH-17,3.43-3.41m,2H,H-14,3.36-3.33m,2H,H-15,1.22-1.17m,2H,H-13,1.05-1.00m,2H,H-13;13C匪R75MHz,DMSO-I6δ:176.50,165.84,165.33,157.00,154.30,153.23,151.32,145.97,143.87,142.75,138.27,123.77,123.31,120.19,119.81,111.45,111.13,107.92,51.00,50.89,50.49,45.56,42.69,42.04,11·252XC;HRMS:C2iH2〇C1FN6〇4[M+H]+计算值为475·1297,实测值为475·1296·[0045]7-3-2-3-氨基-1-氢-I,2,4-三唑-5-巯基)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)(TM3-11:淡黄色固体,πκp·268·9〜270·37.97d,lHJ=11.7Hz,H-5,6.11s,2H,H-22,4.43-4.38m,lH,H-12,4.10s,2H,H-20,3.70-3.64m,3H,H-16andH-17,3.37-3.30m,4H,H-HandH-15,1.24-1.18m,2H,H-13,1.03-0.98m,2H,H-13;13C匪R75MHz,DMSO-I6δ:176.16,166.57,165.16,157.23.153.90,152.87,143.54,143.35,137.95,(123.03,122.95,119.76,110.78,110.47,107.66,50.91,50.69,46.44,42.24,41.66,34.25,10.92;HRMS:C2iH2iC1FN7〇4S[M+H]+计算值为522.1127,实测值为522.1122.[0046][0047]7-3-2-1-氢-I,2,3-三唑-1-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)(TM3-12:淡黄色固体,m·p·290·3〜290·5°C;1H匪R300MHz,DMS0-d65:14.53s,lH,H-ll,8.86s,lH,H-2,8.06d,lH,J=0.9Hz,H-22,8.00d,lH,J=12.0Hz,H-5,7.76d,lH,J=0.9Hz,H-21,5.59s,2H,H-20,4.44-4.37m,lH,H-12,3.75-3.69m,3H,H-16andH-17,3.47-3.43m,2H,H-14,3.38-3.33m,2H,H-15,1.22-1·17m,2H,H-13,1.05-1.00m,2H,H-13;13C匪R75MHz,DMS0-d6S:176.20,165.16,164.77,157.27,153.96,152.92,(143.54,143.34,137.98,134.75,126·62,(123·14,123·10,119·76,(110·82,110·51,107·68,55·59,50·82,50·59,45·22,42·24,41·66,10·922XC;HRMS:C2iH2〇ClFN6〇4[M+Na]+计算值为497·1116,实测值为497.1118.[0048]7-3-2-2-氢-I,2,3-三唑-2-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)(TM3-13:淡黄色固体,m.p·254·3〜255·2°C;1H匪R300MHz,DMS0-d65:14.54s,lH,H-ll,8.86s,lH,H-2,7.98d,lH,J=11.7Hz,H-5,7.83s,2H,H-21,5.63s,2H,H-20,4.44-4.37m,1H,H-12,3.71-3.65m,3H,H-16andH-17,3.44-3.39m,2H,H-14,3.37-3.33m,2H,H-15,1.22-1.17m,2H,H-13,1.03-0.99m,2H,H-13;13CNMR75MHz,DMS〇-de5:176.11,176.07,165.11,164.76,164.70,157.23.153.91,152.83,143.50,143.31,137.90,133.112XC,123.07,122.96,119.75,110.77,110.46,107.68,50.81,50.74,50.59,45.19,42.37,41.64,10.932XC;HRMS:C2iH2〇ClFN6〇4[M+Na]+计算值为497·1116,实测值为497·1118·[0049][0050]7-3-2-1-氢-四唑-1-基)乙酰胺基-1-吡咯烷基-1-环丙基-6-氟-8-氯-I,4-二氢-4-氧代-3-喹啉羧酸)(了]«3-14:淡黄色固体,1114.289.2〜289.7°:;1!1匪1?300MHz,DMS0-d65:14.54s,lH,H-ll,9.03s,lH,H-21,8.86s,lH,H-2,7.98d,lHJ=12.0Hz,H-5,6.05s,2H,H-20,4.45-4.38m,lH,H-12,3.73-3.68m,3H,H-16andH-17,3.49-3.45m,2H,H-14,3.38-3.34m,2H,H-15,I.23-1.17m,2H,H-13,1.04-1.00m,2H,H-13;13C匪R75MHz,DMSO-I6δ:176.18,165.17,163.53,(157.29,153.96,153·28,152·95,143·31,137·97,123·05,(119·49,119·03,110·84,107·69,53·79,50·66,50·54,45·28,42·38,41·65,10·912XC;HRMS:C2〇Hi9C1FN7〇4[M+H]+计算值为476·1249,实测值为476.1247.[005117-3-2-2-氢-四唑-2-基)乙酰胺基-1-吡咯烷基-1-环丙基-6-氟-8-氯-I,4-二氢-4-氧代-3-喹啉羧酸)(TM3-15:淡黄色晶状体,m·p·290·0〜290·4°C;1HNMR300MHz,DMS0-d65:14.53s,lH,H-ll,9.35s,lH,H-21,8.86s,lH,H-2,7.98d,lHJ=11.7Hz,H-5,5.75s,2H,H-20,4.45-4.38m,lH,H-12,3.73-3.68m,3H,H-16andH-17,3.49-3.45m,2H,H-14,3.38-3.34m,2H,H-15,I.24-1.15m,2H,H-13,1.05-0.99m,2H,H-13;13C匪R75MHz,DMSO-I6δ:176.23,165.18,163.86,(157.32,154.00,152.99,145.42,(143.48,143.30,137.99,(123.23,123.12,119.95,119.88,110.87,110.57,107.71,50.72,50.58,48.91,45.19,42.53,41.66,10-922X0;HRMS:C20Hi9ClFN704[M+Na]+计算值为498·1069,实测值为498·1068·[0052][0053]7-3-2-5-甲基-1-氢-四唑-1-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)(TM3-16:淡黄色晶状体,m.p.272.1〜272.9°C;1HMffi300MHz,DMS0-d6S:14.54s,lH,H-ll,8.86s,lH,H-2,7.98d,lH,J=11.7Hz,H-5,5.92s,2H,H-20,4.45-4.38m,lH,H-12,3.72-3.66m,3H,H-16andH-17,3.48-3.43m,2H,H-14,3.38-3.34m,2H,H-15,2.48s,3H,H-21,1.24-1.17m,2H,H-13,1.04-0.99m,2H,H-13;13C匪R75MHz,DMSO-I6δ:176.19,165.17,163.62,162.18,157.29,153.97,152.96,143.51,137.99,137.96,123.17,123.06,119.88,119.81,HO.85,HO.54,107.70,53.58,50.75,50.59,45.64,42.37,41.66,10.912XC,10.47;HRMS:C2iH2iC1FN7〇4[M+H]+计算值为490·1406,实测值为490·1408.[0054]7-3-2-5-甲基-2-氢-四唑-2-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)(TM3-17:淡黄色固体,πκp·290.2〜290.7°C;1HNMR300MHz,DMS0-d65:14.53s,lH,H-ll,8.86s,lH,H-2,7.98d,lH,J=11.7Hz,H-5,5.69s,2H,H-20,4.45-4.38m,lH,H-12,3.73-3.68m,3H,H-16andH-17,3.51-3.45m,2H,H-14,3.38-3.34m,2H,H-15,2.45s,3H,H-21,1.24-1.17m,2H,H-13,1.04-O·98m,2H,H-13;13CNMR75MHz,DMS0-d6S:176.16,165.13,163.56,157.24,153.92,153.56.152.89,143.51,143.32,137.96,123.09,119.81,110.81,110.50,107.66,50.72,50.65,47.89,45.20,42.46,41.65,10.922XC,8.35;HRMS:C2iH2iC1FN7〇4[M+H]+计算值为490.1406,实测值为490.1404·[0055][0056]7-3-2-5-氨基-2-氢-四唑-2-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)(TM3-18:乳黄色固体,m·p·256·4〜257·6°C;1HNMR300MHz,DMS0-d65:14.54s,lH,H-ll,8.86s,lH,H-2,7.98d,lH,J=12.0Hz,H-5,6.70s,2H,H-21,5.25s,2H,H-20,4.45-4.38m,1H,H-12,3.69-3.63m,3H,H-16andH-17,3.49-3.43m,2H,H-14,3.38-3.33m,2H,H-15,1.23-1.17m,2H,H-13,1.03-0.95m,2H,H-13;13CNMR75MHz,DMS〇-de5:176.13,165.12,163.91,157.25,153.93,156.46.152.89,(143.53,143.34,137.94,(123.09,122.99,119.81,119.74,110.81,110.50,107.67,50.63,50.57,46.32,45.02,42.35,41.64,10.902XC;HRMS:C21H21ClFN7〇4[M+H]+计算值为491·1358,实测值为491·1359·[0057]7-3-2-5-甲巯基-2-氢-四唑-2-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)(TM3-19:乳黄色固体,m·p·296·3〜297·2°C;HRMS:C2iH2iClFN7〇4S[M+Na]+计算值为544·0946,实测值为544·0945.[0058]7-3-2-5-氨基_1,3,4_噻二唑-2-巯基)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)(TM3-20:乳黄色固体,m·p·277·8〜278·9°C;1HNMR300MHz,DMS0-d6S:14.56s,lH,H-ll,8.85s,lH,H-2,7.96d,lH,J=11.7Hz,H-5,7.33s,2H,H-21,4.43-4.36m,lH,H-12,4.26s,2H,H-20,3.70-3.64m,3H,H-16andH-17,3.37-3.31m,4H,H-14andH-15,1.22-1.17m,2H,H-13,1.02-0.98m,2H,H-13;13C匪R75MHz,DMS0-d6S:176.16,170.05,165.77,165.18,157.23,153.91,152.90,149.36,143.48,143.31,137.96,123.04,(119.79,119.72,111.06,110.82,110.51,50.83,50.67,46.36,42.36,41.62,37.55,10.922XC;HRMSIC2IH2OCIFn6O4S2[M+H]+计算值为539.0738,实测值为539.0736·[0059][0060]7-3-2-5-甲氧基-1-氢-苯并咪唑-2-巯基)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)(TM3-21:浅粉色固体,m.p·193·5〜200·90Ci1HNMR600MHz,DMS0-d65:12.73s,lH,H-ll,8.74s,lH,H-2,7.88d,lH,J=9.6Hz,H-5,7.33-7.31m,lH,H-23,6.99-6.95m,lH,H-22,6.73-6.71m,lH,H-24,4.46s,2H,H-20,4.35-4.29m,lH,H-12,3.77-3.74m,3H,H-16、H-22andH-17,3.34-3.32111,2H,H-14,3.28-3.25m,2H,H-15,1.19-1.13m,2H,H-13,0.94-0.90m,2H,H-13·[006117-3-2-I-氢-苯并三唑-I-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)(TM3-22:乳黄色固体,m·p·270·3〜272·1°C;1H匪R600MHz,DMS0-d65:14.60s,lH,H-ll,8.75s,lH,H-2,8.05d,lH,J=8.4Hz,H-24,7.90d,lH,J=9.6Hz,H-5,7.79d,lH,J=8.4Hz,H-21,7.55t,lH,J=7.8Hz,H-23,7.41t,lHJ=7.8Hz,H-22,5.94s,2H,H-20,4.36-4.30m,lH,H-12,3.83-3.79m,3H,H-16、H-22andH-17,3.48-3.44m,2H,H-14,3.34-3.32m,2H,H-15,1.20-1.15m,2H,H-13,0.95-0.91m,2H,H-13.[0062][0063]7-3-2-1-氢-咪唑-I-基)丙酰胺基-1-吡咯烷基-1-环丙基-6-氟-8-氯-I,4-二氢-4-氧代-3-喹啉羧酸)(了]«4-1:淡黄色乳状体,1114.179.6〜181.1°:;1!1丽1?300MHz,DMS0-d65:14.53s,lH,H-ll,8.85s,lH,H-2,8.58s,lH,H-22,7.95d,lHJ=11.7Hz,H-5,7.58s,lH,H-23,7.36s,lH,H-24,4.43-4.37m,lH,H-12,4.36t,lH,J=6·6Ηζ,H-21,3.63-3.59m,3H,H-16andH-17,3.34-3.31m,2H,H-14,3.29-3.26m,2H,H-15,3.04t,lH,J=6.6Hz,H-20,1.19q,2H,J=6.6Hz,H-13,1.02-0.98m,2H,H-13;13C匪R75MHz,DMS0-d6δ:176.09,168.26,165.05,157.24,153.91,152.83,143.46,143.27,137.91,136.35,123.10,122.99,122.87,121.14,(119.81,119.75,HO.74,HO.43,107.66,50.81,50.58,45.52,43.79,41.82,41.57,33.03,10.842X0.[0064]7-3-2-2-甲基-I-氢-咪唑-I-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)(TM4-2:棕色固体,m·p·235·8〜237·2°C;1H匪R300MHz,DMS0-d65:14.52s,lH,H-ll,8.85s,lH,H-2,7.96d,lH,J=11.7Hz,H-5,7.67d,lH,J=2.1Hz,H-23,7.55d,lH,J=2.1Hz,H-24,4.44-4.37m,1H,H-12,4.31d,IH,J=6.6Hz,H-21,3.63-3.60m,3H,H-16andH-17,3.34-3.27m,2H,H-HandH-15,3.07d,lHJ=6.6Hz,H-20,2.68s,3H,H-22,1.19q,2H,J=6.6Hz,H-13,1.03-0.97m,2H,H-13;13CNMR151MHz,DMS〇-d65:176.05,168.05,164.93,156.41,154.73,152.71,144.28,143.32,143.23,137.82,123.09,121.65,119.83,117.65,110.59,HO.43,107.65,50.73,50.52,45.48,42.76,41.77,41.47,32.02,10.762XC,10.27.[0065]7-3-2-4-甲基-I-氢-咪唑-I-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)(TM4-3:黄色固体,πκp·175·9〜176·8°C;1H匪R300MHz,DMS0-d65:14.53s,lH,H-ll,9.08s,lH,H-22,8.85s,lH,H-2,7.97d,lHJ=11.7Hz,H-5,7.43s,lH,H-23,4.44-4.37m,lH,H-12,4.37-4.33m,2H,H-21,3.64-3.60m,3H,H-16andH-17,3.42-3.39m,2H,H-14,3.30-3.26m,2H,H-15,3.09d,2HJ=6.3Hz,H-20,2.28s,3H,H-24,1.23-1.17m,2H,H-13,1.03-0.97m,2H,H-13;13C匪R151MHz,DMS〇-d6δ:176.03,168.01,164.94,(156.39,154.73,152.71,(143.34,143.24,137.83,134.51,130.46,123.04,119.80,118.63,110.58,110.42,107.64,50.74,50.49,45.46,44.60,41.76,41.48,32.46,10.762XC,9.46.[0066][0067]7-3-2-0-氢-苯并咪唑-基)丙酰胺基)-丨-吡咯烷基-卜环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸)(TM4-4:灰白色固体,m·p·259·2〜261·7°C;1H匪R300MHz,DMS0-d65:14.53s,lH,H-ll,8.84s,lH,H-2,8.24s,lH,H-22,7.94d,lHJ=11.7Hz,H-5,7.64d,2H,J=7.5Hz,H-23,7.29-7.17m,2H,H-24,4.52t,2H,J=5.7Hz,H-21,4.42-4.35m,lH,H-12,3.63-3.53m,3H,H-16andH-17,3.24-3.16m,4H,H-14andH-15,3.09t,2H,J=5.7Hz,H-20,1.21-1.15m,2H,H-13,I.01-0.96m,2H,H-13;13C匪R75MHz,DMSO-I6δ:176.08,168.69,165.03,157.15,153.83,152.79,144.28,143.37,143.18,137.85,133.68,123.13,123.01,122.15,121.352XC,119.71,119.64,119.322XC,110.70,110.44,110.39,50.73,50.47,45.49,41.76,41.46,40.46,32.49,10.782XC.[0068]7-3-2-1-氢-吡唑-I-基)丙酰胺基-1-吡咯烷基-1-环丙基-6-氟-8-氯-I,4-二氢-4-氧代-3-喹啉羧酸)(TM4-6:淡粉色固体,m·p·211·8〜220·1°C;1HNMR300MHz,DMS0-d65:14.54s,lH,H-ll,8.85s,lH,H-2,7.96d,lH,J=11.7Hz,H-5,7.73s,lH,H-22,7.44s,lH,H-24,6.22s,lH,H-23,4.41-4.38m,lH,H-12,4.37t,2H,J=6.6Hz,H-21,3.61-3.66m,3H,H-16andH-17,3.31-3.27m,4H,H-14andH-15,2.96t,2H,J=6.6Hz,H-20,1.19q,2H,J=6.3Hz,H-13,1.02-0.98m,2H,H-13;13CNMR75MHz,DMS0-de5:176.18,168.62,165.08,157.24,153.92,152.87,143.49,143.30,138.52,137.93,130.10,123.11,123.10,119.72,110.77,110.46,107.67,104.84,50.89,50.64,47.41,45.57,41.79,41.56,33.02,10.822X0.[0069]7-3-2-3,5-二甲基-I-氢-吡唑-I-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)(TM4-7:白色乳状体,πκρ·212·1〜213.91:;¾Mffi300MHz,DMS0-d6S:14.54s,lH,H-ll,8.85s,lH,H-2,7.96d,lH,J=12.0Hz,H-5,5.76s,lH,H-23,4.43-4.36m,lH,H-12,4.14t,2H,J=6.3Hz,H-21,3.63-3.56m,3H,H-16andH-17,3.28-3.22m,4H,H-HandH-15,2.88t,2H,J=6.6Hz,H-20,2.23s,3H,H-22,2.08s,3H,H-24,1.23-1.16m,2H,H-13,1.03-0.97m,2H,H-13;13CNMR151MHz,DMS0-de5:176.06,168.81,164.92,156.36,154.71,152.68,145.72,143.37,143.27,138.61,137.84,123.02,119.72,110.57,110.42,107.64,104.27,50.72,50.53,45.62,43.95,41.72,41.45,32.56,13.25,10.732XC,10.38.[0070][0071]7-3-2-1-氢-I,2,4_三唑-1-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)(TM4-10:淡黄色乳状体,m.p·229·5〜231·2°C;1HNMR300MHz,DMSO-I6S:14.54s,lH,H-ll,8.85s,lH,H-2,8.51s,1H,H-22,7.96s,1H,H-23,7.96d,lHJ=11.7Hz,H-5,4.44t,2H,J=6.6Hz,H-21,4.43-4.37m,lH,H-12,3.64-3.58m,3H,H-16andH-17,3.31-3.27m,4H,H-14andH-15,1·19q,2H,J=6.3Hz,H-13,1.03-0.97m,2H,H-13;13CNMR75MHz,DMS〇-de5:176.14,168.26,165.06,157.22,153.93,152.87,151.22,144.28,143.48,143.26,137.92,122.46,119.59,HO.99,107.68,50.82,50.56,45.48,44.93,41.79,41.55,32.22,10.8K2XC.[0072]7-3-2-2-氢-I,2,3-三唑-2-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)(TM4-12:淡黄色固体,πκp·185·7〜187·2°C;1H匪R300MHz,CDCl3S:14.30s,1H,H-11,8.92s,lH,H-2,7.981,1H,J=11·4Ηζ,H-5,7.62s,2H,H-22,4.86t,2H,J=7.2Hz,H-21,4.39-4.32m,lH,H-12,3.85-3.64m,3H,H-16andH-17,3.37-3·32m,4H,H-14andH-15,3.11t,2H,J=7.2Hz,H-20,I.32q,2H,J=6.9Hz,H-13,1.n-0.95m,2H,H-13;13C匪R151MHz,CDC13S:176.78,168.42,165.81,157.32,155.64,152.17,143.88,143.79,137.91,137.90,134.262XC,124.37,124.32,120.63,120.60,111.98,111.82,108.73,51.10,51.07,50.75,46.22,42,42,41.41,32.69,11.522X0.[0073]7-3-2-1-氢-I,2,3-三唑-I-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)(TM4-13:淡黄色固体,m·p·206·3〜208·1°C;1H匪R300MHz,DMS0-d65:14.53s,lH,H-ll,8.85s,lH,H-2,8.13s,lH,H-23,7.95d,lHJ=11.7Hz,H-5,7.71s,lH,H-22,4.63t,2H,J=6.6Hz,H-21,4.43-4.37m,lH,H-12,3.64-3.58m,3H,H-16andH-17,3.32-3.27m,4H,H-14andH-15,3.08t,2H,J=6.6Hz,H-20,1.19q,2H,J=6.6Hz,H-13,1.03-0.97111,2H,H-13;13C匪R75MHz,DMS0-d6S:176.06,168.19,165.09,157.19,153.88,152.84,(143.44,143.26,137.89,133.04,125.14,123.15,123.Ol,I19.75,119.68,I10.74,HO.43,50.88,50.66,45.502XC,41.84,41.54,32.80,10.852XC.[0074][0075]7-3-2-5-甲基-2-氢-四唑-2-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)(TM4-16:淡黄色固体,m·p·203·4〜204·9°C;1HNMR300MHz,CDC13S:14.29s,1H,H-11,8.93s,lH,H-2,7.981,1H,J=11·4Ηζ,H-5,4.96t,2H,J=7.2Hz,H-21,4.40-4.32m,lH,H-12,3.85-3.66m,3H,H-16andH-17,3.38-3.34m,4H,H-14andH-15,3.17t,2H,J=7.2Hz,H-20,2.55s,3H,H-22,1.33q,2H,J=7.2Hz,H-13,1.01-0.96m,2H,H-13;13CNMR75MHz,CDC13S:176.83,167.58,165.92,163.04,(158.13,154.78,152.25,(143.86,143.66,(137.90,137.88,(124.46,124.36,120.66,120.59,112.16,111.85,108.74,51.15,51.08,48.83,46.18,42.45,41·43,32·23,11·57,10·972XC·[0076]7-3-2-5-甲基-丨-氢-四唑-丨-基)丙酰胺基-i-吡咯烷基-卜环丙基-6-氟_8-氯-1,4-二氢-4-氧代-3-喹啉羧酸)(TM4-17:淡黄色晶状体,m.p·207·3〜208·7°C;1HNMR300MHz,αχη3δ:14.33s,1H,H-11,8.92s,1Η,Η-2,8.051,IHJ=11·4Ηζ,H-5,4.60t,2H,J=6.3Hz,H-21,4.40-4.33m,lH,H-12,3.76-3·65m,3H,H-16andH-17,3.37-3.35m,2H,H-14,3.32-3.30m,2H,H-15,3.16t,2H,J=6.3Hz,H-20,2.55s,3H,H-22,1.33q,2H,J=6.9Hz,H-13,1.01-0.96111,2H,H-13;13C匪R75MHz,CDCl3δ:176.86,167.63,166.15,158.18,154.81,152.52,152.31,143.83,143.64,137.90,124.54,124.46,120.75,120.70,112.21,111.90,108.74,51.15,50.99,46.18,42.80,42.56,41.48,32.58,11.60,9.08,9.05·[0077]7-3-2-5-氨基-2-氢-四唑-2-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)(TM4-18:淡黄色乳状体,m·p·300°C;1HNMR300MHz,DMS0-d65:14.51s,lH,H-ll,8.85s,lH,H-2,7.97d,lH,J=11.7Hz,H-5,6.69s,2H,H-22,4.44-4.38m,lH,H-12,4.30t,2H,J=6.9Hz,H-21,3.65-3.60m,3H,H-16andH-17,3.33-3.28m,2H,H-HandH-15,2.99t,2H,J=6.9Hz,H-20,1.19q,2H,J=6.6Hz,H-13,1.03-0.97m,2H,H-13;13CNMR151MHz,DMS〇-de5:176.09,168.28,164.95,155.42,156.40,154.73,152.73,143.35,137.85,123.10,123.04,119.80,119.77,110.61,110.45,107.65,50.74,50.50,45.49,41.81,41.46,40.89,31.56,10.732XC.[0078][0079]7-3-2-5-氨基-u,4-噻二唑-2-巯基丙酰胺基-i-吡咯烷基-卜环丙基-6-氟-8-氯-1,4-二氢-4-氧代-3-喹啉羧酸)(TM4-20:淡黄色乳状体,m.p.260.9〜262.3cCNMR300MHz,DMS0-d6S:14.53s,lH,H-ll,8.85s,lH,H-2,7.97d,lH,J=12·OHz,H-5,7.28s,2H,H-22,4.42-4.37m,lH,H-12,4.26s,2H,H-20,3.66-3.61m,3H,H-16andH-17,3.33-3·26m,6H,H-21、H-14andH-15,2.84t,2H,J=6.6Hz,H-20,1.20q,2H,J=6.6Hz,H-13,1.02-0.97m,2H,H-13;13CNMR75MHz,DMS〇-de5:176.15,169.39,168.98,165.12,163.98,157.28,153.92,152.87,143.53,137.96,123.12,119·68,(110·75,110·48,107·70,50·92,50·61,45·53,41·89,41·52,32·78,29·96,10·852XC.[0080]实施例2目标化合物TM3TM4对部分革兰菌的琼脂抑菌活性试验[0081]本试验以金黄色葡萄球菌六了0:29213、铜绿假单胞菌?31.0050、沙门氏菌31.1152和鸭源大肠埃希菌临床分离株作为指示菌,采用琼脂扩散法中的打孔法对目标化合物TM3TM4进行抗菌活性检测。利用药物在琼脂培养基中的扩散原理,通过比较供试样品与克林沙星对指示菌产生的抑菌圈的大小,来检测供试样品对该指示菌的抑菌效果。[0082]具体试验方法如下:将供试样品用二甲基亚砜DMSO或无菌水溶解制成2mgmL的母液,临用前用无菌水或IM的磷酸盐缓冲液pH7.2稀释制成2yg25yL的供试样品溶液。接种指示菌于普通液体培养基(牛肉膏0.3%,蛋白胨1%,氯化钠0.5%,调节pH至7.0〜7.2中,37°C恒温摇床活化培养24小时,用生理盐水稀释制成IO8CFUAiL的菌悬液。将牛肉膏蛋白胨培养基加热熔化后,55°C水浴恒温,按1%体积比加入菌悬液接种量约为IO6CFUAiL,摇匀,取25mL置无菌培养皿中制备菌平板,静置,待平板冷却凝固后,用直径4mm的打孔管在平板上均匀打孔,然后向孔中加入供试样品溶液25yL相当于每孔含药2yg,37°C培养18小时,测量抑菌圈的直径。每个供试样品对每个指示菌做3个平行对照,同时做克林沙星和溶剂的对照。[0083]目标化合物TM3对指示菌的抑菌圈直径mm见表2,可见TM3系列化合物对金黄色葡萄球菌、沙门氏菌、铜绿假单胞菌和大肠埃希菌均有一定的抑菌活性。[0084]表2目标化合物TM3对部分革兰菌的抑菌圈直径mm[0085][0086][0087]目标化合物TM4对指示菌的抑菌圈直径mm见表3,TM4系列化合物的水溶性较TM3系列化合物更好,但随着Linker碳链的增长,该系列化合物对沙门氏菌和大肠埃希菌的抑菌效果不明显。[0088]表3目标化合物TM4对部分革兰菌的抑菌圈直径mm[0089][0090]注:-表示阴性。[0091]实施例3目标化合物TM3对部分革兰菌的最低抑菌浓度MIC试验[0092]本试验以金黄色葡萄球菌ATCC29213、铜绿假单胞菌PSl.0050、沙门氏菌Sl.1152和鸭源大肠埃希菌临床分离株作为指示菌,采用NCCLS推荐的微量肉汤稀释法,检测目标化合物TM3的MIC,并与诺氟沙星和克林沙星进行比较。[0093]具体试验方法如下:在96孔板中,第1孔加入含32mgL供试样品的M-H肉汤200yL,其余11孔均加入空白培养基IOOyL;从第1孔吸取IOOyL加至第2孔,混匀后再从第2孔吸取IOOyL加至第3孔,依此类推,直到第10孔,混勾后吸取IOOyL弃去,则第1孔至第10孔的样品浓度依次为32、16、8、4、2、1、0.5、0.25、0.125、0.062511^1;第11孔和第12孔不加入供试样品,分别作为细菌生长对照和阴性对照。然后第1孔至第11孔分别加入IO8CFUAiL的菌悬液〇.5yL接种量约为105CFUmL,37°C培养16-20小时,肉眼观察孔内细菌生长情况,无细菌生长孔的最低样品浓度即为该样品对该细菌的MIC。每个菌株同时做3个平行试验。试验用的供试样品是用无菌水溶解不溶于水或难溶于水的样品用适量DMSO助溶),室温避光保存120天的溶液。[0094]结果见表4,TM3系列化合物溶解120天后,对金黄色葡萄球菌、铜绿假单胞菌和沙门氏菌仍有不同程度的抑菌活性,说明其水溶液稳定性较好。[0095]表4目标化合物TM3对部分革兰菌的MICygmL[0096][0097][0098]实施例4目标化合物TM3对结核分枝杆菌的抑制活性测试[0099]对目标化合物TM3进行了结核分枝杆菌H37Rv标准菌株)的抑制活性测试。测试工作由美国礼来制药集团(EliLillyandCompany的创新药物开放平台计划(OpenInnovationDrugDiscovery,0IDD以及美国传染病研究中心(InfectiousDiseaseResearchInstitute,IDRI研究团队完成。分别进行了单浓度SP抑制活性测试20μΜ的抑制率)和多浓度(CRC抑制活性测试MIC,并采用CellTiter-G丨〇、?LuminescentCellViabiIityAssayCeimter-Glot发光法细胞活力检测试剂盒测试了供试样品对Hela细胞的细胞毒性20μΜ的百分抑制率,半数抑制浓度IC50。[0100]具体结果见表5。[0101]表5目标化合物ΤΜ3和ΤΜ4抗结核活性测试结果[0102][0103][0104]注:表示未测定。[0105]从表5看出,20μΜ单浓度测试时,所有化合物对结核分枝杆菌H37Rv的抑制能力都很强;14个化合物的MIC值低于2yM;Hela细胞活力测试表明,在20μΜ检测浓度下,所有化合物的细胞毒性都很低。由此表明,ΤΜ3和ΤΜ4系列化合物具有较强的抗结核分枝杆菌活性和较低的细胞毒性。[0106]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。

权利要求:1.克林沙星唑烷酰衍生物,其特征在于:具有以下结构式:式中,η为1或2;Y为1-氢-咪唑-1-基、2-甲基-1-氢-咪唑-1-基、4-甲基-1-氢-咪唑-1-基、1-氢-苯并咪唑-1-基、1-氢-苯并咪唑-2-巯基、1-氢-吡唑-1-基、3,5_二甲基-1-氢-吡唑-1-基、3-氨基-1-氢-吡唑-1-基、1-氢-1,2,4-三唑-1-基、3-氨基-1-氢-1,2,4-三唑-5-巯基、1-氢-1,2,3-三唑-1-基、2-氢-1,2,3-三唑-2-基、1-氢-四唑-1-基、2-氢-四唑-2-基、5-甲基-1-氢-四唑-1-基、5-甲基-2-氢-四唑-2-基、5-氨基-2-氢-四唑-2-基、5-甲巯基-2-氢-四唑-2-基、5-氨基-1,3,4_噻二唑-2-巯基、5-甲氧基-1-氢-苯并咪唑-2-巯基或1-氢-苯并三唑-1-基。2.如权利要求1所述的克林沙星唑烷酰衍生物,其特征在于:η为1,Υ为1-氢-咪唑-1-基、2-甲基-1-氢-咪唑-1-基、4-甲基-1-氢-咪唑-1-基、1-氢-苯并咪唑-1-基、1-氢-苯并咪唑-2-巯基、1-氢-吡唑-1-基、3,5-二甲基-1-氢-吡唑-1-基、3-氨基-1-氢-吡唑-1-基、1-氢-1,2,4-三唑-1-基、3-氨基-1-氢-1,2,4-三唑-5-巯基、1-氢-1,2,3-三唑-1-基、2-氢-1,2,3-三唑-2-基、1-氢-四唑-1-基、2-氢-四唑-2-基、5-甲基-1-氢-四唑-1-基、5-甲基-2-氢-四唑-2-基、5-氨基-2-氢-四唑-2-基、5-甲巯基-2-氢-四唑-2-基、5-氨基-1,3,4-噻二唑-2-巯基、5-甲氧基-1-氢-苯并咪唑-2-巯基或1-氢-苯并三唑-1-基;η为2;Y为1-氢-咪唑-1-基、2-甲基-1-氢-咪唑-1-基、4-甲基-1-氢-咪唑-1-基、l-氢-苯并咪唑-1-基、1-氢-吡唑-1-基、3,5-二甲基-1-氢-吡唑-1-基、1-氢_1,2,4-三唑-1-基、1-氢-1,2,3_三唑-1-基、2-氢-1,2,3_三唑-2-基、5-甲基-1-氢-四唑-1-基、5-甲基-2-氢-四唑-2-基、5-氨基-2-氢-四唑-2-基、5-氨基-1,3,4-噻二唑-2-巯基。3.权利要求1或2所述的克林沙星唑烷酰衍生物的制备方法,其特征在于:将化合物IM与唑类化合物YH在溶剂中、碱作用下于25-85°C反应制得克林沙星唑烷酰衍生物,所述溶剂为二氯甲烷、二甲基甲酰胺、水或二甲基甲酰胺-水混合液,所述碱为碳酸钾或氢化钠;化学反应式如下:化合物IM结构式中η的定义与克林沙星唑烷酰衍生物结构式中η的定义相同;唑类化合物YH结构式中Y的定义与克林沙星唑烷酰衍生物结构式中Y的定义相同。4.权利要求1或2所述的克林沙星唑烷酰衍生物在制备抗菌药物中的应用。5.如权利要求4所述的克林沙星唑烷酰衍生物在制备抗菌药物中的应用,其特征在于,所述抗菌药物为抗铜绿假单胞菌、沙门氏菌、金黄色葡萄球菌、大肠埃希菌和结核分枝杆菌中任一种或多种的药物。

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