CN104955804B - 增强抗分枝杆菌的活性抗生素活性的饱和的氮和n‑酰化的杂环化合物 - Google Patents

增强抗分枝杆菌的活性抗生素活性的饱和的氮和n‑酰化的杂环化合物 Download PDF

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CN104955804B
CN104955804B CN201380067137.2A CN201380067137A CN104955804B CN 104955804 B CN104955804 B CN 104955804B CN 201380067137 A CN201380067137 A CN 201380067137A CN 104955804 B CN104955804 B CN 104955804B
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N·维兰德
B·德普雷
A·博拉尔
P·布鲁丹
M·弗利波
L·曼戈
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Universite Lille 2 Droit et Sante
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Abstract

本发明涉及通式(I)的化合物：

Description

增强抗分枝杆菌的活性抗生素活性的饱和的氮和N-酰化的杂 环化合物
本发明涉及一种用于治疗细菌和分枝杆菌感染(例如结核、麻风病和非典型分枝杆菌感染)的化合物。
本发明还涉及可用作药物的新化合物，特别是用作治疗细菌和分枝杆菌感染(例如结核、麻风病和非典型分枝杆菌感染)的药物的新化合物。
本发明还涉及药物组合物，所述药物组合物包含作为活性组分的至少一种前述的化合物和任选地具有抗细菌和/或分枝杆菌活性的抗生素，特别是可通过EthA途径激活的抗生素，更特别是选自硫代酰胺家族(例如乙硫异烟胺或丙硫异烟胺)的抗生素。
本发明还涉及产品(试剂盒)，所述产品(试剂盒)含有至少一种前述的化合物和至少一种具有抗细菌和/或分枝杆菌活性的抗生素、特别是可通过EthA途径激活的抗生素，更特别是选自硫代酰胺家族(例如乙硫异烟胺或丙硫异烟胺)的抗生素，作为组合产品，以在结核、麻风病或普通分枝杆菌感染的治疗中同时地、分别地或在时间上分散地使用。
在全世界，结核每年杀死两百万人。AIDS的流行和对抗生素多重耐药的菌株的出现使得加剧了该疾病的影响，国际卫生组织认为这是越来越危险的世界范围内流行病的原因，并且是全球范围内的卫生紧急事件。
目前，越来越大量的结核分枝杆菌(Mycobacterium tuberculosis)菌株对一线抗生素(例如异烟肼(INH)和利福平(RIF))具有多重耐药的特征。这些抗生素因而必须被所述菌株对其不耐药的二线抗生素 (例如乙硫异烟胺(ETH))代替。但是，这些二线抗生素具有低治疗指数(活性组分的治疗指数是治疗剂量与毒性剂量的比值)的缺点。
已经考虑的一种策略包括通过将乙硫异烟胺(ETH)与特定化合物缔合来增强乙硫异烟胺的活性。事实上，ETH是前药，其在体内通过 EthA酶转化为治疗活性形式(参见文章“Activation of the prodrug ethionamide is regulated in mycobacteria”,A.R.Baulard等，Journal of Biological Chemistry,2000,275,28326-28331)。观察到的对ETH的耐药性是由结核分枝杆菌的转录抑制子EthR控制EthA酶的表达并且制约 ETH转化为治疗活性物质而引起。
本发明的一个目的是提供新的化合物，所述化合物很可能显著地增强具有抗结核活性的抗生素的活性，特别是选自硫代酰胺家族，例如乙硫异烟胺或丙硫异烟胺的抗生素的活性。
本发明的另一个目的是提供例如之前提到的化合物，所述化合物与具有抗结核活性的抗生素组合，并且在相同的抗生素剂量下，使得能够获得更大的功效或者使得能够减少前述抗生素的剂量以获得给定的功效，其中所述抗生素选自硫代酰胺家族，特别是乙硫异烟胺和/或丙硫异烟胺。
本发明的另一个目的是提供例如之前提到的化合物，所述化合物简单并且廉价地制备。
本发明的另一个目的是提供例如之前提到的化合物，所述化合物人满意地溶解于生物流体中。
本发明的另一个目的是提供例如之前提到的化合物，所述化合物特别在口服时很可能是活性的并且/或产生较小的副作用。
为了实现至少一种前述的目的，本发明因此提供通式(I)化合物：
其中：
n＝0或1；
R1表示选自以下的基团：
直链或支链并且任选取代的C1-C5烷基链；
特别是被至少一个氟原子(F)取代，
被至少一个氟原子(F)取代或被饱和或不饱和的C3-C6环状基团取代的直链或支链C1-C3烷基链；和
基团CH2CF3,(CH2)2CF3,CF2CF3；
X选自N和CH；
R2选自以下基团：苯基、苄基、被至少一个直链或支链的C1-C4烷基链取代的苯基或苄基、被至少一个直链或支链并且被取代的、特别地被至少一个氟原子(F)取代的C1-C4烷基链取代的苯基或苄基，被至少一个选自Cl、F、CF3、OCH3、OCF3、或OH的基团取代的苯基，以及具有6个顶点、饱和或不饱和的，包含一个、两个或三个氮原子的杂环。
有利地，m＝n＝1。所述组分与乙硫异烟胺组合对分枝杆菌、特别是对结核分枝杆菌显示出特别的活性。
R1可以选自以下基团：-CH2-异丙基；环丙基，环丁基，环戊基，-CH2- 环丙基，-CH2-环丁基，和-CH2-环戊基。
有利地，R1是-CH2CF3基团。所述组分表现出对乙硫异烟胺良好的增强活性，特别是针对结核分枝杆菌。
有利地，X＝CH。所述组分已证实与乙硫异烟胺组合更高效，特别是针对细菌结核分枝杆菌。
根据第一种实施方式，R2是苯基。
根据第二种实施方式，R2是苄基。
根据第三种实施方式，R2是被至少一个氟原子取代的苯基。
根据第四种实施方式，R2是在相对于与X所成键的间位被Cl,F,CF3或CH3取代的苯基。
有利地，R2是在相对于与X所成键的对位被氟原子取代的苯基。
根据另一个实施方式，R2是选自以下基团的基团：
本发明化合物可以选自下列化合物：
本发明还涉及将前述化合物用作药物，特别是用于治疗细菌和分枝杆菌感染，尤其是用于治疗结核、麻风病或非典型分枝杆菌感染。
本发明还涉及药物组合物，所述药物组合物包含作为活性组分的至少一种之前提到的通式(I)化合物和一种药学上可接受的赋形剂。
在根据本发明的药物组合物内，用作活性组分使用的一种或多种化合物可以以这样的量使用，所述量使得待给药的单位剂量包含在约 0.3mg和1g之间。在根据本发明的药物组合物中，所述一种或多种具有抗分枝杆菌活性的抗生素当存在时，有利地以这样的量使用，所述量使得给药的单位剂量等于或低于由世界卫生组织(WHO，Treatment oftuberculosis:Guidelines for National Programs.2003； WHO/CDS/TB2003.313.)、国家或非政府卫生组织或有法定资格的药学实验室通常推荐的剂量。
本领域技术人员依据所述药物组合物的给药途径，能够选择一种或几种药学上可接受的赋形剂。本领域技术人员当然会确保这样做使得所用的一种或多种赋形剂与根据本发明的组合物所附属的固有性质相容。而且，所述药物或药物组合物的剂型(例如溶液、悬浮液、乳剂、片剂、胶囊、栓剂等)将取决于选择的给药途径。
因此，从本发明的意义上说，所述药物或药物组合物可以通过任何合适的途径给药，例如口服、直肠、局部(例如外用)、全身、静脉、肌肉或粘膜途径，又或者通过使用药贴，又或者以微脂囊、微粒、微胶囊内的或是固定在微脂囊、微粒、微胶囊上、连接在纳米颗粒或类似物上的包封形式。通过适用于通过口服途径给药的赋形剂的非限制性实例，可以特别地例举滑石、乳糖、淀粉及其衍生物、纤维素及其衍生物、聚乙二醇、丙烯酸聚合物、明胶、硬脂酸镁、动物油脂、植物油脂或合成油脂、石蜡衍生物、二醇类、稳定剂、防腐剂、抗氧化剂、润湿剂、抗粘接剂、分散剂、乳化剂、味觉改性剂、渗透剂、增溶剂等。本文考虑的用于所述药物和药物组合物的制剂和给药技术在本领域是已知的，本领域的技术人员可以特别地参考最新版的Remington's Pharmaceutical Sciences著作。
本发明的目的还在于使用至少一种根据本发明的化合物以制备旨在预防和/或治疗细菌感染，优选分枝杆菌感染，且更优选结核、麻风病或非典型分枝杆菌感染的药物。
有利地，所述药物组合物进一步包含作为活性组分的至少一种具有抗细菌和/或分枝杆菌活性的抗生素，特别是可通过EthA途径激活的抗生素，更特别是尤其选自硫代酰胺家族、特别是选自乙硫异烟胺和丙硫异烟胺的抗生素。
但是，本发明并不限于这些抗生素。
本发明的化合物证实是强化可通过EthA途径激活的抗生素的化合物；然而，本发明的化合物还可以用作抗生素抗菌活性的增强剂，所述抗生素可以通过除前述以外的一种或多种生物激活途径被生物激活。
本发明还涉及试剂盒或产品，所述试剂盒或产品含有至少一种式(I) 的化合物和至少一种具有抗细菌和/或特别是抗分枝杆菌活性的抗生素，特别是可经酶EthA途径激活的抗生素，更特别是选自硫代酰胺家族、更特别是选自乙硫异烟胺和丙硫异烟胺的抗生素，作为组合产品，以在结核、麻风病或普通分枝杆菌感染的治疗中同时地、分别地或在时间上分散地使用。
定义
在本发明的全部范围内，当没有指出一个基团被取代时，无论该基团是什么，该基团未被取代。
在本发明的含义中，取代的苯基被定义为单、双或三取代苯基。当没有指出所述一种或多种取代基的位置时，取代基的位置不受本发明限制。当指出所述一种或多种取代基时，苯基还可以包含一种或若干种与上面提到的那些不同的其它取代基。
优选地，被Cl、CF3和CH3取代的苯基被单取代，并且取代基(Cl、 CF3和CH3)优选在苯环的与X连接的碳的间位。优选地，X是CH。
至于被氟原子取代的苯基，所有被氟原子单、双或三取代的基团包括在本发明中。有利地，被一个或若干个氟原子取代的苯基不被另一个基团或除F以外的另一个原子取代。因此，在本发明的含义内，被至少一个氟原子取代的苯基包括在苯环的与X连接的碳的邻位、间位或对位被氟原子单取代的苯基，被两个氟原子取代的苯基，特别是被位于苯环与X所成键的邻位和对位的两个氟原子取代的苯基，具有三个各自被氟原子取代的碳原子的苯基，特别是被三个氟原子三取代的苯基，其中两个氟原子位于苯环与X所成键的邻位并且一个氟原子位于相对于该键的对位。
非典型分枝杆菌在本文中定义为由除结核分枝杆菌素(M. Tuberculinum)以外的至少一种分枝杆菌引起的分枝杆菌感染，且特别是涉及堪萨斯分枝杆菌(M.Kansasii)的分枝杆菌感染。
根据本发明，术语“治疗”是指前述感染的治愈性治疗和/或预防性治疗。术语“治疗”包括所有的患者状态的改善，特别是存在于患者至少一个感染部位的细菌数量的任何减少。
在本发明的含义内，具有抗细菌和/或分枝杆菌活性的抗生素定义为能够至少在体外限制或减少细菌和/或分枝杆菌(特别是结核分枝杆菌) 增殖的任何试剂。能够至少在体外破坏分枝杆菌(特别是结核分枝杆菌) 的试剂也是本发明含义内的具有抗分枝杆菌活性的抗生素。在具有抗分枝杆菌活性且可经酶EthA途径激活的抗生素中，乙硫异烟胺、丙硫异烟胺、戊氧苯硫脲、氨硫脲和这些抗生素的至少两种的混合物可被提及。
在本发明中，可通过EthA途径激活的抗生素定义为至少在体外与 EthA酶反应以生成具有抗菌活性物质的任何物质。本领域的技术人员例如通过应用以下出版物中描述的方法能够确定抗生素是否可通过 EthA途径激活：“Activation of the prodrugethionamide is regulated in mycobacteria”A.R.Baulard等，Journal of BiologicalChemistry,2000,275, 28326-28331。
在本发明含义范围内的抗生素还可以是可通过除前述途径以外的另一种生物激活途径激活的抗生素。
实验部分
合成方法
核磁共振光谱(NMR)1H和13C在环境温度下在Bruker TM DPX 300 谱仪在300MHz下执行。化学位移用百万分率(ppm)表达。使用1H 和13C一维(1D)或二维(2D)HSQC-COSY实验进行归属。在LCMS Waters Alliance Micromass ZQ 2000系统上执行质谱。商业化试剂和溶剂不经进一步纯化而使用。
哌啶基和吡咯烷基衍生物的合成方法的一般流程式 ：
方案：
将LDA(THF/庚烷/乙苯的2M溶液，3.3mmole，1.1当量)和5mL 无水THF加入提前烘干并置于氮气下的烧瓶中。将所述溶液冷却至 -78℃。滴加溶解于5mL THF中的N-叔丁氧羰基-4-哌啶酮(或N-叔丁氧羰基-3-吡咯烷酮)(3mmol，1当量)，然后将反应介质在-78℃下搅拌20分钟。加入溶解于5mL THF的N-苯基-三氟甲烷磺酰亚胺 (3.3mmol，1.1当量)。将所述溶液在0℃下搅拌2小时并且随后蒸发。将残余物溶解于环己烷/AcOEt 9:1混合物中，并且随后经氧化铝过滤。产物(三氟甲烷磺酸酯)不经纯化用于下一步。
在含有三氟甲烷磺酸酯(1当量)并置于氮气下的烧瓶中，加入硼酸(1.1当量)，LiCl(3当量)，2N Na2CO3溶液(1.4当量)，DME (0.34M)和四(三苯基膦)钯(0.05当量)。将所述溶液在回流下加热1至16小时并随后蒸发。将残余物溶于AcOEt中并且随后用水洗涤一次，并用NaCl饱和溶液洗涤一次。将有机相干燥并蒸发。将残余物溶于AcOEt中，并经烧结玻璃过滤。将溶剂蒸发，然后将产物用硅胶色谱纯化(环己烷/AcOEt)。
将不饱和衍生物(1当量)与PtO2(0.1当量)或Pd/C(0.1当量)溶解于乙醇(0.1M)中。将反应混合物置于氢气下并在环境温度下搅拌直至投入的产物消失。将所述溶液在硅藻土上过滤，然后蒸发。或者：将不饱和衍生物(1当量)与甲酸铵(5当量)和Pd/C(10％质量计)溶解于甲醇中(0.1M)。将反应混合物在回流下加热直至投入的产物消失。将溶液在硅藻土上过滤并且随后蒸发。将保护的胺(1当量)与二噁烷(1M) 加入烧瓶中，然后加入HCl的二噁烷溶液(4N，5当量)。将溶液在环境温度下搅拌1小时，然后蒸发。将残余物加入石油醚，并且然后经烧结玻璃过滤。
使用EDCl(1.3当量)和HOBt(0.4当量)的DMF溶液(0.25M)在 DEIA(4当量)存在下将酸(1.3当量)活化，随后加入胺(1当量)。将所述溶液在环境温度下搅拌3小时，然后蒸干。将残余物溶于AcOEt 中，然后使用饱和NaHCO3洗涤两次，使用1N HCl洗涤两次，并使用饱和NaCl洗涤一次。将有机相用MgSO4干燥，然后蒸发。使用制备型HPLC 纯化残余物。
哌嗪的合成方法的一般流程式 ：
方案：
使用EDCl(1.3当量)和HOBt(0.4当量)的DMF溶液(0.25M) 在DIEA(4当量)存在下将酸(1.3当量)活化，随后加入可商购的哌嗪(1当量)。将所述溶液在环境温度下搅拌3小时，然后蒸发。将残余物溶于AcOEt中，然后使用饱和NaHCO3洗涤两次，使用1N HCl洗涤两次，并使用饱和NaCl洗涤一次。将有机相用MgSO4干燥，然后蒸发。使用制备型HPLC纯化残余物。
BDM_44647
4-苯基哌啶可商购。仅进行了偶联。
1H NMR(CD2Cl2)δ7.36-7.31(m,2H),7.25-7.21(m,3H),4.78-4.71(m, 1H),3.99-3.93(m,1H),3.22-3.12(m,1H),2.84-2.48(m,6H),1.96-1.86(m, 2H),1.72-1.56(m,2H)。MS[M+H]+m/z 286。
BDM_44648
4-苯基哌啶可商购。仅进行了偶联。
1H NMR(CD2Cl2)δ7.36-7.31(m,2H),7.25-7.20(m,3H),4.78-4.72(m, 1H),3.99-3.92(m,1H),3.19-3.09(m,1H),2.81-2.60(m,2H),2.45(t,J＝ 7.0Hz,2H),2.29-2.16(m,2H),1.97-1.87(m,4H),1.70-1.54(m,2H)。MS [M+H]+m/z 300。
BDM_44808
1H NMR(CDCl3)δ7.34-7.28(m,2H),6.97-6.94(m,3H),3.83-3.80(m, 2H),3.67-3.64(m,2H),3.24-3.17(m,4H),2.68-2.49(m,4H)。MS[M+H]+ m/z 287。
BDM_44809
1H NMR(CDCl3)δ7.34-7.28(m,2H),6.97-6.94(m,3H),3.82-3.79(m, 2H),3.65-3.62(m,2H),3.22-3.16(m,4H),2.48(t,J＝7.2 Hz,2H), 2.31-2.15(m,2H),2.03-1.92(m,2H)。MS[M+H]+m/z 301。
BDM_70666
1H NMR(CD2Cl2)δ7.27-7.20(m,2H),7.16-7.03(m,2H),4.79-4.73(m, 1H),3.98-3.93(m,1H),3.24-3.08(m,2H),2.74-2.48(m,5H),1.95-1.86(m, 2H),1.74-1.63(m,2H)。MS[M+H]+m/z 304。
BDM_70531
1H NMR(CD2Cl2)δ7.27-7.20(m,2H),7.16-7.02(m,2H),4.79-4.74(m, 1H),3.99-3.94(m,1H),3.24-3.09(m,2H),2.75-2.49(m,5H),1.95-1.86(m, 2H),1.75-1.59(m,2H)。MS[M+H]+m/z 304。
BDM_44751
1H NMR(CD2Cl2)δ7.33-7.19(m,2H),7.06-7.00(m,2H),4.77-4.72(m, 1H),3.98-3.92(m,1H),3.21-3.11(m,1H),2.83-2.49(m,6H),1.94-1.86(m, 2H),1.68-1.46(m,2H)。
13C NMR(CD2Cl2)δ167.64,161.45(d,J＝244 Hz),141.20,127.42(q, J＝274Hz),128.16(d,J＝8 Hz),115.11(d,J＝21 Hz),45.83,42.40,41.91, 33.81,32.96,29.53(q,J＝29 Hz),25.79。MS[M+H]+m/z 304。
BDM_71148
1H NMR(CD2Cl2)δ6.69(t,J＝8.7 Hz,2H),4.78-4.72(m,1H), 3.98-3.92(m,1H),3.27-3.10(m,2H),2.68-2.48(m,5H),2.07-1.90(m,2H), 1.82-1.74(m,2H)。MS[M+H]+m/z340。
BDM_44819
1H NMR(CD2Cl2)δ7.04-6.98(m,2H),6.95-6.90(m,2H),3.79-3.75(m, 2H),3.64-3.61(m,2H),3.14-3.07(m,4H),2.61-2.46(m,4H)。MS[M+H]+ m/z 305。
BDM_44820
1H NMR(CD2Cl2)δ7.04-6.98(m,2H),6.94-6.89(m,2H),3.77-3.74(m, 2H),3.62-3.59(m,2H),3.12-3.06(m,4H),2.45(t,J＝7.2 Hz,2H),
2.25-2.15(m,2H),1.97-1.87(m,2H)。MS[M+H]+m/z 319。
BDM_70669
1H NMR(CD2Cl2)δ6.99-6.82(m,3H),3.79-3.76(m,2H),3.64-3.61(m, 2H),3.05-2.99(m,4H),2.67-2.48(m,4H)。MS[M+H]+m/z 323。
BDM_70534
1H NMR(CD2Cl2)δ7.41-7.39(m,1H),7.32-7.17(m,3H),4.80-4.75(m, 1H),3.99-3.94(m,1H),3.35-3.17(m,2H),2.76-2.49(m,5H),1.99-1.89(m, 2H),1.66-1.53(m,2H)。MS[M+H]+m/z 320。
BDM_70668
1H NMR(CD2Cl2)δ7.32-7.21(m,3H),7.15-7.13(m,1H),4.78-4.72(m, 1H),3.98-3.93(m,1H),3.21-3.11(m,1H),2.83-2.48(m,6H),1.95-1.87(m, 2H),1.69-1.52(m,2H)。MS[M+H]+m/z 320。
BDM_70535
1H NMR(CD2Cl2)δ7.33-7.30(m,2H),7.20-7.17(m,2H),4.78-4.71(m, 1H),3.99-3.92(m,1H),3.21-3.11(m,1H),2.82-2.48(m,6H),1.94-1.86(m, 2H),1.67-1.51(m,2H)。MS[M+H]+m/z 320。
BDM_44811
1H NMR(CD2Cl2)δ7.28-7.23(m,2H),6.91-6.86(m,2H),3.78-3.75(m, 2H),3.64-3.61(m,2H),3.20-3.13(m,4H),2.67-2.46(m,4H)。MS[M+H]+ m/z 321。
BDM_44812
1H NMR(CD2Cl2)δ7.27-7.22(m,2H),6.91-6.86(m,2H),3.77-3.74(m, 2H),3.62-3.59(m,2H),3.18-3.12(m,4H),2.45(t,J＝7.2 Hz,2H), 2.31-2.15(m,2H),1.97-1.87(m,2H)。MS[M+H]+m/z 335。
BDM_70716
1H NMR(CDCl3)δ7.39(d,J＝8.3 Hz,1H),7.29(d,J＝2.0 Hz,1H), 7.04(dd,J＝8.3 Hz,J＝2.0 Hz,1H),4.82-4.77(m,1H),4.00-3.94(m,1H), 3.21-3.12(m,1H),2.79-2.48(m,6H),1.96-1.88(m,2H),1.67-1.51(m, 2H)。
13C NMR(CDCl3)δ167.99,145.10,132.60,130.58,128.84,127.11(q,J ＝275Hz),126.11,45.74,42.40,41.90,33.48,32.53,29.69(q,J＝29 Hz), 25.95。MS[M+H]+m/z354。
BDM_70536
1H NMR(CD2Cl2)δ7.68(d,J＝4.5 Hz,1H),7.58(t,J＝4.5 Hz,1H), 7.46(d,J＝4.5 Hz,1H),7.37(t,J＝4.5 Hz,1H),4.81-4.77(m,1H), 4.00-3.97(m,1H),3.23-3.17(m,2H),2.73-2.52(m,5H),1.92-1.85(m,2H), 1.75-1.68(m,2H)。MS[M+H]+m/z 354。
BDM_70546
1H NMR(CD2Cl2)δ7.51-7.46(m,4H),4.80-4.75(m,1H),4.01-3.95(m, 1H),3.23-3.14(m,1H),2.93-2.82(m,1H),2.74-2.50(m,5H),1.99-1.90(m, 2H),1.74-1.57(m,2H)。
13C NMR(CD2Cl2)δ167.72,146.30,130.56(q,J＝32 Hz),130.37, 129.09,127.44(q,J＝275 Hz),124.35(q,J＝275 Hz),123.51(q,J＝4 Hz), 123.25(q,J＝4 Hz),45.73,42.48,42.29,33.46,32.63,29.52(q,J＝28 Hz), 25.83。MS[M+H]+m/z 354。
BDM_70667
1H NMR(CD2Cl2)δ7.61(d,J＝8.4 Hz,2H),7.37(d,J＝8.4 Hz,2H), 4.80-4.74(m,1H),4.01-3.95(m,1H),3.23-3.13(m,1H),2.92-2.82(m,1H), 2.73-2.48(m,5H),1.98-1.89(m,2H),1.73-1.61(m,2H)。MS[M+H]+m/z 354。
BDM_70665
1H NMR(CD2Cl2)δ7.19-7.09(m,4H),4.80-4.74(m,1H),4.00-3.94(m, 1H),3.23-3.14(m,1H),3.06-2.95(m,1H),2.74-2.47(m,5H),2.38(s,3H), 1.88-1.80(m,2H),1.71-1.54(m,2H)。MS[M+H]+m/z 300。
BDM_70664
1H NMR(CD2Cl2)δ7.23-7.20(m,1H),7.06-7.01(m,3H),4.77-4.71(m, 1H),3.98-3.92(m,1H),3.20-3.11(m,1H),2.79-2.46(m,6H),2.33(s,3H), 1.94-1.85(m,2H),1.71-1.53(m,2H)。MS[M+H]+m/z 300。
BDM_70663
1H NMR(CD2Cl2)δ7.16-7.10(m,4H),4.77-4.70(m,1H),3.97-3.91(m, 1H),3.20-3.10(m,1H),3.06-2.95(m,1H),2.77-2.47(m,5H),2.33(s,3H), 1.93-1.85(m,2H),1.69-1.51(m,2H)。MS[M+H]+m/z 300。
BDM_70540
1H NMR(CD2Cl2)δ7.25-7.15(m,2H),6.98-6.91(m,2H),4.78-4.72(m, 1H),3.97-3.92(m,1H),3.86(s,3H),3.28-3.14(m,2H),2.75-2.47(m,5H), 1.94-1.84(m,2H),1.69-1.54(m,2H)。
13C NMR(CD2Cl2)δ167.59,156.89,133.37,127.49(q,J＝275 Hz), 127.18,126.35,120.56,110.44,55.23,46.16,42.73,35.54,32.31,31.48, 29.59(q,J＝29 Hz),25.81。MS[M+H]+m/z 316。
BDM_70538
1H NMR(CD2Cl2)δ7.27-7.22(m,1H),6.83-6.76(m,3H),4.78-4.71(m, 1H),3.99-3.92(m,1H),3.80(s,3H),3.20-3.11(m,1H),2.81-2.47(m,6H), 1.95-1.87(m,2H),1.71-1.54(m,2H)。MS[M+H]+m/z 316
BDM_70537
1H NMR(CD2Cl2)δ7.17-7.14(m,2H),6.89-6.86(m,2H),4.76-4.71(m, 1H),3.97-3.92(m,1H),3.79(s,3H),3.20-3.11(m,1H),2.74-2.50(m,6H), 1.93-1.86(m,2H),1.63-1.55(m,2H)。
13C NMR(CD2Cl2)δ168.38,158.58,138.06,127.49(q,J＝275 Hz), 127.56,113.81,55.16,45.97,42.53,41.76,34.06,33.12,29.56(q,J＝29 Hz),25.80。MS[M+H]+m/z 316。
BDM_70539
1H NMR(MeOD)δ7.08(dd,J＝7.6Hz,J＝1.5Hz,1H),7.00(td,J＝ 7.6Hz,J＝1.7Hz,1H),6.80-6.74(m,2H),4.71-4.64(m,1H),4.09-4.02(m, 1H),3.27-3.15(m,2H),2.80-2.70(m,3H),2.58-2.47(m,2H),1.96-1.83(m, 2H),1.74-1.53(m,2H)。MS[M+H]+m/z302。
BDM_45572
1H NMR(MeOD)δ7.04(d,J＝8.7Hz,2H),6.72(d,J＝8.7Hz,2H), 4.67-4.61(m,1H),4.04-3.98(m,1H),3.21-3.12(m,1H),2.75-2.66(m,4H), 2.58-2.46(m,2H),1.89-1.79(m,2H),1.67-1.44(m,2H)。MS[M+H]+m/z 302。
BDM_70542
1H NMR(CD2Cl2)δ8.52(d,J＝6.1Hz,2H),7.16(d,J＝6.1Hz,2H), 4.80-4.73(m,1H),4.01-3.93(m,1H),3.22-3.13(m,1H),2.84-2.48(m,6H), 1.98-1.89(m,2H),1.71-1.54(m,2H)。MS[M+H]+m/z 287。
BDM_70670
4-苄基哌啶可商购。仅进行了偶联。
1H NMR(CD2Cl2)δ7.33-7.28(m,2H),7.24-7.16(m,3H),4.59-4.51(m, 1H),3.82-3.77(m,1H),3.02-2.92(m,1H),2.59-2.47(m,7H),1.85-1.67(m, 3H),1.24-1.07(m,2H)。MS[M+H]+m/z 300.
BDM_70719
1H NMR(CD2Cl2)δ7.35-7.26(m,5H),3.61(t,J＝5.1 Hz,2H),3.54(s, 2H),3.45(t,J＝5.1 Hz,2H),2.61-2.41(m,8H)。MS[M+H]+m/z 301。
BDM_70717
1H NMR(CDCl3)δ7.24-7.18(m,2H),7.07-7.00(m,2H),4-09-3.99(m, 0.5H),3.91-3.81(m,1H),3.72-3.64(m,0.5H),3.60-3.31(m,3H),2.61-2.50 (m,4H),2.46-2.27(m,1H),2.16-1.95(m,1H)。MS[M+H]+m/z 290。
BDM_44810
1H NMR(CDCl3)δ7.34-7.28(m,2H),6.97-6.90(m,3H),3.80(t,J＝5.1 Hz,2H),3.66(t,J＝5.1 Hz,2H),3.22-3.15(m,4H),2.42-2.37(m,2H), 1.70-1.53(m,3H),0.95(d,J＝6.3Hz,6H)。MS[M+H]+m/z 261。
BDM_44813
1H NMR(CDCl3)δ7.26-7.22(m,2H),6.91-6.86(m,2H),3.74(t,J＝5.1 Hz,2H),3.63(t,J＝5.1Hz,2H),3.18-3.11(m,4H),2.39-2.34(m,2H), 1.67-1.49(m,3H),0.95(d,J＝6.3Hz,6H)。MS[M+H]+m/z 295。
BDM_44821
1H NMR(CDCl3)δ7.04-6.98(m,2H),6.94-6.90(m,2H),3.74(t,J＝5.1 Hz,2H),3.63(t,J＝5.1Hz,2H),3.12-3.05(m,4H),2.39-2.34(m,2H), 1.64-1.49(m,3H),0.95(d,J＝6.6Hz,6H)。MS[M+H]+m/z 279。
BDM_44649
4-苯基哌啶可商购。仅进行了偶联。
1H NMR(CD2Cl2)δ7.36-7.31(m,2H),7.25-7.20(m,3H),4.77-4.73(m, 1H),4.02-3.98(m,1H),3.18-3.09(m,1H),2.81-2.71(m,1H),2.66-2.57(m, 1H),2.39-2.34(m,2H),1.94-1.85(m,2H),1.69-1.51(m,5H),0.95(d,J＝ 6.4Hz,6H)。MS[M+H]+m/z 260。
化合物活性的评价
乙硫异烟胺增强作用的细胞试验
使用的试验使得可以确认这些化合物能够增强乙硫异烟胺对于结核分枝杆菌本身的杀菌活性成为可能。所述试验是一种“高内涵筛选” (HCS)或密集(dense)内涵筛选试验。HCS试验在细胞培养基上进行，所述培养基能够研究给定环境中的微生物(例如细菌)的某种表型特征。观察到的表型改变可以是从某种标记蛋白的产生的增加(或减少) 到所关注的微生物形态学的改变。所述方法在以下出版物中描述：“Ethionamide Boosters:Synthesis,Biological Activity,and Structure-Activity Relationships of aSeries of 1,2,4-Oxadiazole EthR Inhibitors”,M.Flipo等,Journal of MedicinalChemistry,2011,54(8), 2994-3010”。
所述试验目的在于确定将乙硫异烟胺(ETH)的活性增强10倍所需要的配体浓度。
为了测量将ETH的活性增强10倍所需要的配体浓度，选择乙硫异烟胺的恒定浓度(0.1μg/mL，相当于其CMI99的十分之一)。通过改变配体浓度，可以确定抑制50％的细菌生长所需要的浓度，即将乙硫异烟胺的活性增强10倍所需要的浓度。该浓度将表示为EC50。
溶解度的测量
将样品在DMSO中的40μL(10mM)溶液加入至1.96mL的MeOH 或pH为7.4的PBS中。然后将样品在室温下搅拌24小时，离心5分钟，然后在0.45μm尺寸的过滤器上过滤。然后将20μL的每份溶液加至 180μL的MeOH，然后用LC-MS分析。溶解度确定为PBS/MeOH质谱信号的表面比值。
测量的细胞活性
下面的表I至III总结了受试的本发明的化合物的结构式以及根据前述方案实验性地测量的EC50值。
表I
根据表I的结果，CH2CF3基团提供乙硫异烟胺更大的增强活性，而没有负面地影响该化合物的溶解度。
结果显示对于相同的R1基团和相同的R2基团来说，当n＝1时，本发明的化合物的增强活性得到改善。
表II
下面的表III总结了所有受试的本发明化合物的表达为EC50的活性。表III

Claims (18)

1.通式(I)的化合物：
其中
n＝0或1；
R1选自：-CH2CF3、-CH2CH2CF3；和-CH2-异丙基；
X是N和CH；
R2选自：苯基、苄基、被直链或支链的C1-C4烷基取代的苯基；由被氟取代的直链或支链的C1-C4烷基取代的苯基；被一个或多个选自Cl、F、CF3、OCH3和OH的取代基取代的苯基,和包含一个或两个氮原子的六元杂环基，所述杂环基选自：
条件是当R1是-CH2-异丙基时，n为1且R2选自苯基、被直链或支链的C1-C4烷基取代的苯基；由被氟取代的直链或支链的C1-C4烷基取代的苯基；被一个或多个选自Cl、F、CF3的取代基取代的苯基。
2.根据权利要求1所述的化合物，其中n是1。
3.根据权利要求1或2所述的化合物，其中R1是-CH2CF3。
4.根据权利要求1所述的化合物，其中X是CH。
5.根据权利要求1所述的化合物，其中R1是-CH2-异丙基。
6.根据权利要求1所述的化合物，其中R2是苯基或苄基。
7.根据权利要求1所述的化合物，其中R2是在相对于与X所成键的间位被选自Cl,F,CF3和OCH3的取代基取代的苯基。
8.根据权利要求1所述的化合物，其中R2是被氟取代的苯基。
9.根据权利要求1所述的化合物，其中R2是在相对于与X所成键的对位被氟取代的苯基。
10.根据权利要求1所述的化合物，其选自：
11.根据权利要求1所述的化合物在制备用于治疗分枝杆菌感染的药物中的用途。
12.根据权利要求1所述的化合物在制备用于治疗结核、麻风病和非典型分枝杆菌感染的药物中的用途。
13.药物组合物，其包含作为活性组分的根据权利要求1至10任一项所述的化合物和药学上可接受的载体。
14.根据权利要求13所述的药物组合物，其进一步包含具有抗细菌和/或分枝杆菌活性的抗生素。
15.根据权利要求13所述的药物组合物，其进一步包含可通过EthA途径激活的抗生素。
16.根据权利要求13所述的药物组合物，其进一步包含选自硫代酰胺家族的抗生素。
17.根据权利要求13所述的药物组合物，其进一步包含乙硫异烟胺或丙硫异烟胺。
18.根据权利要求1至10任一项所述的化合物和可通过EthA途径激活的抗生素的组合，其用于制备治疗结核、麻风病和非典型分枝杆菌感染的药物。
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