CN109384716B - 一种氘代喹啉化合物及其制备和用途 - Google Patents

一种氘代喹啉化合物及其制备和用途 Download PDF

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CN109384716B
CN109384716B CN201810889771.9A CN201810889771A CN109384716B CN 109384716 B CN109384716 B CN 109384716B CN 201810889771 A CN201810889771 A CN 201810889771A CN 109384716 B CN109384716 B CN 109384716B
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杜武
吕海斌
李海波
耿熙
李兴海
陈元伟
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Abstract

本发明提供了一种氘代喹啉化合物及其制备和用途。具体地，本发明公开了一种式(Ⅰ)所示喹啉衍生物或其立体化学异构体、溶剂合物或药学上可接受的盐。实验结果证明，本发明提供的氘代喹啉化合物具有更好的代谢稳定性和药代动力学，能够用于制备更安全有效的治疗结核病的药物，应用前景优良。

Description

一种氘代喹啉化合物及其制备和用途
技术领域
本发明属于药物化学技术领域，具体涉及一种氘代喹啉化合物及其制备和用途。
背景技术
结核病是由结核杆菌感染引起的慢性传染病。在全球传染病统计中，结核病是仅次于艾滋病额第二致死传染病。尽管目前临床应用的抗结核治疗药物众多，但一线抗结核药物仍为应用了数十年的异烟肼、利福平、吡嗪酰胺和乙胺丁醇。这些药物的长期使用，患者体内的结核杆菌表现出明显的耐药性。
公开号为WO2004011436A1的专利申请公开了通式Ⅰa和Ⅰb所示的二芳基喹啉类衍生物，具有较好的抗结核杆菌活性。
Figure BDA0001756642310000011
在此基础上，已开发出一种新型的抗结核杆菌药物，命名为TMC-207,其结构如下式所示，该药已于2012年被批准上市。但是该药物有严重的毒副作用包括QT延长导致严重心律不齐及致死风险。
Figure BDA0001756642310000012
氘代药物是指将药物分子中的部分氢原子替换为氘。由于氘在药物分子中形状和体积与氢接近，氘代药物一般会保留原来药物的生物活性和选择性。由于C-D键比C-H键更稳定，使得氘代药物在化学反应过程中，C-D键更不容易断裂，其半衰期会延长。
由于生物系统的代谢过程复杂，药物在生物体内的药代动力学性质受到多方面因素影响，也表现出相应的复杂性。与相应的非氘代药物相比，氘代药物药代动力学性质的变化表现出极大的偶然性和不可预测性。某些位点的氘代非但不能延长半衰期，反而可能会使其缩短(Scott L.Harbeson,Roger D.Tung.Deuterium in Drug Discovery andDevelopment，P405-406。)，劣化其药代动力学性质；另一方面，药物分子上某些位置的氢因为空间位阻等原因也不易被氘代，因此，药物的氘代并非随心所欲，可氘代的位点是不可预期的。
本发明人期望通过对TMC-207化合物进行氘代，得到一类抗结核病菌和结核病、药代动力学性质良好、降低有毒副作用的代谢产物的氘代药物。
发明内容
本发明的目的在于提供一种对结核病具有生物活性的喹啉衍生物。
一种式(Ⅰ)所示喹啉衍生物或其立体化学异构体、溶剂合物或药学上可接受的盐：
Figure BDA0001756642310000021
其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12分别独立地选自氢、氘、C1～C10烷基、C3～C10环烷基、C3～C10杂环烷基、C6～C10芳基、C6～C10杂环芳基；其中所述的烷基、环烷基、杂环烷基、芳基、杂芳基中的氢可进一步地被一个或多个氘原子取代；
A为苯基或氘取代的苯基，其结构如式(Ⅱ)所示，其苯环上的R13、R14、R15、R16、R17分别独立地取自H、D；
B为萘基或氘取代的萘基，其结构如式(Ⅲ)所示，R18、R19、R20、R21、R22、R23、R24分别独立地取自H、D；
Figure BDA0001756642310000022
且所述喹啉衍生物中至少含有一个D原子。
进一步地，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12分别独立地选自氢、氘、C1～C5烷基、C3～C5环烷基、C3～C5杂环烷基、C6～C8芳基、C6～C8杂环芳基；其中所述的烷基、环烷基、杂环烷基、芳基、杂芳基中的氢可进一步地被一个或多个氘原子取代。
进一步地，R1、R2、R3分别独立地选自H、D、CH3、CD3；R4、R5、R6、R7、R8、R9、R10、R11、R12分别独立地选自氢、氘、C1～C3烷基，其中所述的烷基中的氢可进一步被一个或多个氘原子取代。
进一步地，R1、R2、R3分别独立地选自H、D、CH3、CD3，R4、R5、R6、R7、R8、R9、R10、R11、R12分别独立地选自氢或者氘。
进一步地，R1、R2全部为CD3，R3选自CH3或CD3，R8选自H或者D，R4、R5、R6、R7、R9、R10、R11、R12全部为氢。
进一步地，R1、R2、R3全部为CD3，R8选自H或者D，R4、R5、R6、R7、R9、R10、R11、R12全部为氢。
进一步地，所述的立体化学异构体为(1R,2S)。
进一步地，所述的药学上可接受的盐为盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐；优选为富马酸盐。
进一步地，所述的喹啉衍生物结构为
Figure BDA0001756642310000031
本发明还提供了上述的喹啉衍生物或其立体化学异构体、溶剂合物或药学上可接受的盐在制备抗肺结核病的药物中的用途。
一种药物组合物，它是以上述的喹啉衍生物或其立体化学异构体、溶剂合物或药学上可接受的盐为活性成分，加上药学上可接受的辅料制备而成的制剂。
本发明中，“治疗”也包括复发性(relapse)预防或阶段性(phase)预防，以及急性或慢性体征、症状和/或功能失常的治疗。治疗可以是对症治疗，例如抑制症状。它可以在短期内实现，在中期内调整，或者可以说是长期治疗，例如在维持疗法里面。
所述“预防”包括延迟和/或阻止病症、疾病或病况和/或其伴发症状的发作；防止对象染上病症、疾病或病况；或降低对象染上病症、疾病或病况的风险的方法。
本发明中，“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
本发明中，“盐”是将化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀(Ca～Cb)烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，(C1～C6)烷基是指包含1～6个碳原子的烷基。
所述C1～C5烷基是指C1、C2、C3、C4、C5的烷基，即具有1～5个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基等等。
同理，“Ca～Cb杂环烷基”是指所有含a～b个碳原子的含杂原子的环烷基。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
除特别标注的外，本发明所用试剂和测试设备均为常规的市售试剂和设备。
实施例1、合成(1R,2S)-1-(6-溴-2-三氘代甲氧基喹啉-3-基)-4-(二(三氘代甲基)氨基)-2-(奈-1-基)-1-苯基丁-2-醇(3)
Figure BDA0001756642310000051
第一步：合成3-苯甲基-6-溴-2-三氘代甲氧基喹啉(3-2)
3-苄基-6-溴-2-氯喹啉(3-1)购自天津格莱德斯兰德医药有限公司。取3-苄基-6-溴-2-氯喹啉6.64g(20mmol,1.0eq)，氘代甲醇钠4.6g(80mmol,4.0eq)加入到70mL乙腈中，加热至回流搅拌12小时。TLC监控反应，原料消失后，自然冷却至室温，减压蒸馏除去溶剂，加入乙酸乙酯50mL萃取，水洗(3×30mL)，有机相用无水硫酸钠干燥、过滤、浓缩，制得无色油状液体，室温下放置慢慢形成白色固体6.6g，收率：98％。1H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.97(s,1H),7.73-7.68(m,2H),7.32-7.19(m,5H),4.00(s,2H)；ESI-MS(m/z):331.2[M+H]+。
第二步：合成3-(二(三氘代甲基)氨基)-1-(奈-1-基)丙-1-酮(3-3)
Figure BDA0001756642310000052
将1-乙酰基萘1.70g(10mmol,1.0eq)、多聚甲醛0.39g(13mmol,1.3eq)和氘代二甲胺盐酸盐1.14g(13mmol,1.3eq)依次加入到25mL乙醇溶液中，加入盐酸0.1mL，反应液加热回流搅拌过夜。自然冷却至室温，减压蒸馏除去溶剂，加30mL水溶解，用乙酸乙酯萃取(2×20mL)除去未反应完全的原料1-乙酰基萘。将水相用碳酸钠调碱，用乙酸乙酯萃取(3×30mL)有机相合并、无水硫酸钠干燥、减压浓缩制得黄色油状液体530mg，收率：22.7％。1HNMR(400MHz,DMSO-d6)δ8.44-8.41(m,1H),8.14-8.11(m,1H),8.08-8.06(m,1H),8.02-7.99(m,1H),7.63-7.58(m,3H),3.25-3.22(t,J＝6.8Hz,2H),2.69-2.65(t,J＝6.8Hz,2H),；ESI-MS(m/z):234.2[M+H]+。
第三步：合成(1R,2S)-1-(6-溴-2-三氘代甲氧基喹啉-3-基)-4-(二(三氘代甲基)氨基)-2-(奈-1-基)-1-苯基丁-2-醇(3)
氮气保护下，向三口瓶中加入15mL无水四氢呋喃，用干冰/丙酮浴降温至-65℃以下，加入LDA(2N，15mL，30mmol,2.0eq)于反应体系中，加入3-苄基-6-溴-2-三氘代甲氧基喹啉(3-2)4.9g(15mmol,1.0eq)的50mL四氢呋喃溶液，加完后，升温至-40±5℃，保温搅拌反应1小时,颜色显示为深黑色。重新降温至-65℃以下，加入3-氘代二甲氨基-1-(萘-5-基)丙酮(3-3)3.8g(16.5mmol,1.1eq)的40mL四氢呋喃溶液，加完后维持体系在-65℃以下保温搅拌反应30分钟。滴加氯化铵饱和溶液于反应体系中淬灭反应，撤去外浴，自然升至室温。加入乙酸乙酯萃取(3×100mL)有机相合并、减压浓缩，过柱纯化，PE/EA＝9/1洗脱，制得1.22g外消旋化合物A。手性柱(IC-3)拆分，收集正向柱保留时间2.873分钟的组分，制得370mg目标化合物D9-贝达喹啉A1，收率：4.4％。1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.59(d,J＝8.4Hz,1H),7.97(s,1H),7.87(d,J＝7.6Hz,2H),7.73-7.59(m,5H),7.49(t,J＝6.8Hz,1H),7.30(t,J＝7.6Hz,1H),7.11(s,2H),6.89-6.87(m,3H),5.89(s,1H),2.51(s,1H),2.04-1.97(m,3H),；ESI-MS(m/z):564.2[M+H]+。
实施例2、合成(1R,2S)-1-(6-溴-2-三氘代甲氧基喹啉-3-基)-4-(二(三氘代甲基)氨基)-1-氘-2-(奈-1-基)-1-苯基丁-2-醇(1)
Figure BDA0001756642310000061
第一步：合成6-溴-3-(苯基(二氘代甲基))-2-三氘代甲氧基喹啉(1-1)
取金属钠2.53g(11mmol,1.1eq)加入到20mL的氘代甲醇溶液中，0-10℃下搅拌30分钟，制成氘代甲醇钠的氘代甲醇溶液，然后加入化合物3-1(3-苄基-6-溴-2-氯喹啉)3.33g(10mmol,1.0eq)，加热至回流搅拌12小时。TLC监控反应，原料消失后，自然冷却至室温，减压蒸馏除去溶剂，加入乙酸乙酯50mL萃取，水洗(3×30mL)，有机相用无水硫酸钠干燥、过滤、浓缩，制得无色油状液体，室温下放置慢慢形成白色固体3.28g，收率：99.1％。1HNMR(400MHz,DMSO-d6)δ8.07(s,1H),7.97(s,1H),7.73-7.68(m,2H),7.32-7.19(m,5H)；LCMS(ESI,m/z):C17H9D5BrNO[M+H]+333.1。
第二步：合成(1R,2S)-1-(6-溴-2-三氘代甲氧基喹啉-3-基)-4-(二(三氘代甲基)氨基)-1-氘-2-(奈-1-基)-1-苯基丁-2-醇(1)
用类似于实施例1的方法，以化合物1-1为原料制备得到目标化合物1.
1H NMR(400MHz,CDCl3)δ1.91-1.95(m,1H),1.99-2.10(m,2H),2.51(d,J＝14.1Hz,1H),6.87-6.89(m,3H),7.10-7.15(m,2H),7.31(t,J＝7.6Hz,2H),7.47(t,J＝8.5Hz,1H),7.61(t,J＝8.5Hz,1H),7.63-7.67(m,2H),7.71(d,J＝8.9Hz,1H),7.87(d,J＝8.5Hz,1H),7.91(d,J＝8.5Hz,1H),7.96(d,J＝2.2Hz,1H),8.60(d,J＝8.5Hz,1H),8.89(s,1H)；LCMS(ESI,m/z):C32H21D10BrN2O2[M+H]+565.2。
实施例3、合成1-(6-溴-2-三氘代甲氧基喹啉-3-基)-4-(三氘代甲氨基)-2-(萘-1-基)-1-苯基-2-丁醇(4)
Figure BDA0001756642310000071
第一步：制备叔丁基三氘代甲基[3-(萘-1-基)-3-氧代丙基]氨基甲酸酯(4-1)：
Figure BDA0001756642310000072
将1-乙酰基萘8.5g(50.0mmol,1.0eq)、多聚甲醛1.5g(50.0mmol,1.0eq)和氘代甲胺盐酸盐7.05g(100.0mmol,2.0eq)依次加入到15mL乙醇溶液中，加入对甲苯磺酸0.86g(5.0mmol,0.1eq)，反应液加热回流搅拌过夜。自然冷却至室温，减压蒸馏除去溶剂，加入乙酸乙酯(200mL)打浆，过滤，得到粘稠状固体。将上述固体，二氯甲烷(50mL)加入到反应瓶中，冰浴下，加入三乙胺(10mL)，滴加Boc酸酐(9.7mL)，缓慢升至室温，搅拌过夜。反应液依次用水(25mL)，0.5N HCl(25mL)，水(25mL)萃洗，无水硫酸钠干燥，过滤浓缩拌样过柱纯化，PE/EA＝4/1洗脱，得到黄色油状物4.8g，收率：30.3％。1H NMR(400MHz,CDCl3)δ8.65(d,J＝8.6Hz,1H),8.00(d,J＝8.2Hz,1H),7.95–7.84(m,2H),7.64–7.45(m,3H),3.70(t,J＝6.9Hz,2H),3.32(s,2H),1.44(s,9H).ESI-MS(m/z):217.4[M+H-Boc]+。
第二步：制备1-(6-溴-2-三氘代甲氧基喹啉-3-基)-4-(三氘代甲氨基)-2-(萘-1-基)-1-苯基-2-丁醇(4)
氮气保护下，向三口瓶中加入7mL干燥的四氢呋喃，用干冰/丙酮浴降温至-65℃以下，加入LDA(2N)13.6mL(27.3mmol,2.0eq)于反应体系中，缓慢滴加3-苄基-6-溴-2-氘代甲氧基喹啉4.5g(13.6mmol,1.0eq)的5mL四氢呋喃溶液，加完后，升温至-40±5℃，保温搅拌反应1小时,颜色显示为深黑色。重新降温至-65℃以下，加入叔丁基氘代甲基[3-(萘-1-基)-3-氧代丙基]氨基甲酸酯4.3g(13.6mmol,1.0eq)的5mL四氢呋喃溶液，加完后维持体系在-65℃以下保温搅拌反应30分钟。滴加氯化铵饱和溶液于反应体系中淬灭反应，。加入乙酸乙酯萃取(2×100mL)合并有机相、减压浓缩，PE/EA＝25/1洗脱，得黄色油状物1.9g。
将上述油状物溶于DCM(50mL)中，滴加三氟乙酸(11mL)，室温下反应3～5小时。向反应液加入饱和碳酸钠水溶液(50mL)萃洗，分层，水层再用DCM(50mL)萃取一次，合并DCM相，水洗至中性，浓缩拌样。柱层析纯化，PE/EA＝1/1洗脱，得白色固体162mg，收率：2.4％。1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.54(d,J＝6.6Hz,1H),7.90(d,J＝2.1Hz,1H),7.87(d,J＝6.3Hz,1H),7.78(d,J＝7.9Hz,1H),7.63(d,J＝8.8Hz,1H),7.60–7.48(m,3H),7.40(t,J＝7.2Hz,1H),7.23(t,J＝7.7Hz,1H),7.10(dd,J＝6.4,2.8Hz,2H),6.85–6.75(m,3H),5.81(s,1H),2.61(d,J＝13.3Hz,1H),2.43(d,J＝12.0Hz,1H),2.10–1.86(m,2H).ESI-MS(m/z):546.8[M+H]+。
实施例4、制备1-(6-溴-2-甲氧基喹啉-3-基)-4-(二(三氘代甲基)氨基)-1-氘-2-(奈-1-基)-1-苯基丁-2-醇(7)
Figure BDA0001756642310000081
第一步：制备3-氘代苄基-6-溴-2-甲氧基喹啉(7-1)
取3-苄基-6-溴-2-甲氧基喹啉938mg(2.85mmol,1.0eq)，叔丁醇钾800mg(7.30mmol,2.5eq)加入到盛有10mL氘代甲醇的25mL封管中，加热至80度，搅拌过夜，TLC监控反应，原料消失后，自然冷却至室温，减压蒸馏除去溶剂，加入乙酸乙酯30mL萃取，水洗(3×20mL)，有机相用无水硫酸钠干燥、过滤、浓缩，制得无色油状液体，室温下放置慢慢形成白色固体923mg，收率：98％。1H NMR(400MHz,CDCl3)δ7.74(d,J＝2.0Hz,1H),7.69(d,J＝9.2Hz,1H),7.60(dd,J＝2.0,9.2Hz,1H),7.49(s,1H),7.32(m,2H),7.26-7.22(m,3H),4.08(s,3H)；ESI-MS(m/z):330.2[M+H]+。
第二步：制备1-(6-溴-2-甲氧基喹啉-3-基)-4-(二(三氘代甲基)氨基)-1-氘-2-(奈-1-基)-1-苯基丁-2-醇(7)
以化合物7-1为原料，用类似于实施例1的方法制得化合物7(38mg收率3.4％)。1HNMR(400MHz,CDCl3)δ8.87(s,1H),8.60(d,J＝8.8Hz,1H),7.97(d,J＝1.8Hz,1H),7.88(t,J＝6.6Hz,2H),7.71(d,J＝8.8Hz,1H),7.64(td,J＝7.7,5.7Hz,3H),7.52–7.46(m,1H),7.30(t,J＝7.7Hz,1H),7.12(d,J＝3.2Hz,2H),6.91–6.85(m,3H),4.21(s,3H),2.58(s,1H),2.13(s,2H),1.96(s,1H).MS(ESI+)m/z:562.3[M+H]+。
本发明的其他化合物可用类似的方法制备得到。
以下通过试验例的方式来说明本发明的有益效果。
试验例1、本发明化合物的肝微粒体代谢稳定性实验
(1)准备母溶液：高纯水，磷酸盐缓冲液(100mM),MgCl2溶液(5mM)；
(2)向孵化实验中加还原型辅酶Ⅱ(NADPH)和肝微粒体；
(3)向对照试验中加入阳性对照物Verapamil，向测试实验中加入测试化合物，测试化合物的最终浓度为2μM；
(4)在0,15,30,45和60分钟的时间点由反应溶液中取样，经处理后再离心处理。取上层清液加高纯水稀释后用LC-MS/MS分析；
(5)数据分析：从提取的离子色谱图确定峰面积。斜率值k通过母体药物的剩余百分比与孵育时间曲线的自然对数的线性回归来确定。
体外半衰期(体外t1/2)由斜率值确定：in vitro t1/2＝﹣(0.693/k)
体外内在清除率(in vitro CLint，以μL/min/mg为单位)使用以下等式(重复测定的平均值)由体外半衰期t1/2(分钟)换算：
Figure BDA0001756642310000091
放大内在清除率(Scale up CLint，以mL/min/kg为单位)通过使用以下式(重复测定的平均值)由体外t1/2(分钟)换算：
Figure BDA0001756642310000092
犬，猴和人肝微粒体代谢稳定性实验结果见表1：
表1、犬，猴和人肝微粒体代谢稳定性实验结果
Figure BDA0001756642310000093
如上表所示，实施例1和实施例2制备的化合物在犬，猴和人的肝微粒体中的半衰期都比贝达喹啉的半衰期长，显示了本发明的氘代化合物的代谢稳定性都比非氘代化合物贝达喹啉好，表明本发明化合物有更好的药代动力学，具有更好的安全性和有效性。
试验例2、本发明化合物的大鼠药代动力学
1)实验材料及仪器：
LC-20AD高效液相色谱系统，购自日本SHIMADZU(岛津)公司
API4000三重四极杆质谱仪，购自美国Applied Biosystem公司
PhenixWinnolin药动学软件(Version 6.3)，购自美国Certara公司
高速冷冻离心机，购自Thermo Fisher Scientific
分析天平，购自赛多利斯，SECURA225D-1CN
SD大鼠，购自成都达硕实验动物有限公司
N,N-二甲基乙酰胺(DMA)(Sigma)
2)实验方法及结果
精密称取适量药物(相当于原形药物25mg/kg)，用DMA/HP-β-CD/水为溶媒，超声、涡漩混匀。取配制的终溶液0.2ml，于-20℃保存，用于浓度测定。健康成年雄性SD大鼠3只(180-250g)，禁食过夜(自由饮水)后，灌胃给药；于给药前及给药后0.5,1,2,4,6,8,12,24h由眼眶后静脉丛采血0.1ml，4℃离心5min分离血浆，于-20℃保存待测。然后采用LC/MS/MS法测定血浆中的待测化合物浓度。
表2、本发明化合物的大鼠药代动力学参数
Figure BDA0001756642310000101
从表2可以看出本发明化合物的暴露量(AUC)显著高于贝达喹啉，显示了更好的药代动力学。预期在临床上可以减小使用剂量，成为更安全,病人依从性更好的抗结核病药物。
综上，本发明提供的氘代喹啉化合物具有更好的代谢稳定性和药代动力学，能够用于制备更安全有效的治疗结核病的药物。应用前景优良。

Claims (3)

1.以下喹啉衍生物或其药学上可接受的盐：
Figure FDF0000011508320000011
2.权利要求1所述的喹啉衍生物或其药学上可接受的盐在制备抗肺结核病菌和抗结核病的药物中的用途。
3.一种药物组合物，其特征在于：它是以权利要求1所述的喹啉衍生物或其药学上可接受的盐为活性成分，加上药学上可接受的辅料制备而成的制剂。
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