CN108558858A - 硝基呋喃类抗结核化合物 - Google Patents
硝基呋喃类抗结核化合物 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种硝基呋喃类抗结核化合物，该化合物结构为或或
Description
技术领域
本发明属于化学药物领域，具体涉及一种硝基呋喃类抗结核化合物。
背景技术
结核病是一种由结核分枝杆菌引起的慢性呼吸道传染性疾病，也是全世界十大疾病死因之一。据世界卫生组织（WHO）2015年统计，全球有1040万人患有结核病，180万人因此病而死亡。全球每年都有结核病新增病例，其中亚洲发生的新发结核病病例最多，占全球新发病例的61%。
结核分枝杆菌的致病机制是通过寄宿宿主细胞，引发一系列炎症、产生毒性的菌体成分及代谢物、造成免疫损伤而致病，严重威胁着人们的健康。
结核病与其它一些细菌感染疾病相比较难治，其原因是多方面的。一是繁殖懒惰性。结核分枝杆菌生长较为缓慢，18个小时才分裂一次，这种惰性繁殖常给临床治疗带来困难。二是顽固性，其细胞壁上的多糖荚膜组织能保护细菌，防止有害物质入侵，与一般细菌相比较难杀死；三是潜伏性，结核分枝杆菌产生硫酸脑苷脂的脂质，在吞噬细胞中潜伏；四是耐药性，由于目前药物种类缺乏、传统耐药性药物长期使用，使得现有疗效降低。五是TB/HIV双重感染。结核病患者或者携带者同时感染艾滋病（HIV），致使潜在性结核转变为活性结核，为结核病的治疗带来意想不到的困难。
迄今为止，抗结核的主要药物仍然是使用上个世纪50年代至60年代开发的异烟肼、吡嗪酰胺、利福平、卷曲霉素、链霉素等化疗药物。多数情况下，采用多药联合的方法对抗大部分结核分枝杆菌。由于耐药的迅速产生和新药的缺乏，使得开发新的抗结核药物显得迫切需要。
硝基芳香环类化合物在治疗肿瘤、神经性疾病和广谱抗菌领域均有广泛应用。随着结核病占全球的病例高，逐渐被开发应用于抗结核分枝杆菌。硝基芳香环类化合物作为抗结核药物在其结构上具有特有的特点及优势：如强吸电性，极性大，基团小，有H键作用；硝基在生物体内能被各种还原酶（I、Ⅱ型硝基还原酶，NTR）还原，生成N-烃基取代羟胺、亚硝基化合物和胺的活性物质；硝基在生物体内可以发生脱硝基化反应，成为NO供体。正是如此，在很多情况下，通常硝基类的化合物是某些药物的前药。
对于硝基类化合物在抗结核领域的应用，主要分为硝基咪唑、硝基苯环和硝基呋喃三大类。
最早的硝基咪唑类抗结核化合物是甲硝哒唑（Metronidazole），因在厌氧条件下有抗菌作用，而被用于治疗潜伏性的结核感染，但在体内的不稳定性导致其没被开发成抗结核药。随后，研究发现肿瘤化疗药物中，并环的硝基咪唑系列化合物具有抗结核活性，活性最好的化合物是CGI-17341，但由于其致突变性也没被继续研究。令人惊喜地是，CGI-17341的构效关系分析发现，在并环的2位引入支链可以克服致突变的副作用，据此开发了两个系列化合物——硝基咪唑[2,1-b]并嗪类和硝基咪唑[2,1-b]并恶唑类，代表性化合物分别是PA-824和OPC67683。
OPC67683是PA-824的同系物，它们对多重耐药菌和潜伏菌均有效，与当前抗结核药物相比没有交叉耐药现象，但OPC67683活性更高，是PA-824的16倍。而且在免疫缺陷的小鼠模型中保持抗结核活性，这表明OPC67683可被用于共感TB/HIV的病人。OPC67683在2014年4月被欧洲食品药品监督管理局（EMA）批准上市，治疗MDR-TB。
TBA-354是该系列中最新的化合物，结构与PA-824非常相似，在急性感染模型中的活性、代谢稳定性和ADME（吸收、分布、代谢和排泄）都明显优于PA-824，最新报道已进入临床Ⅰ期。
苯并噻嗪酮类和硝基苯甲酰胺类化合物同属硝基苯环化合物，对结核分枝杆菌，包括耐多药和广泛耐药结核分枝杆菌都展现出良好的活性，其中活性最好的化合物BTZ043体外对结核分枝杆菌标准株最低抑菌浓度达到1 ng/mL，比一线抗结核药物异烟肼低20倍，巨噬细胞内抗结核MIC ＜ 0.01 μg/mL，明显优于抗结核一线药物异烟肼和利福平，是目前多重耐药结核（MDR-TB）和广泛耐药结核病(XDR-TB)的临床前候选药物。
据文献报道，十异戊二烯磷酰-β-D-核糖2′-差向异构酶（DprE1）易成为硝基芳香类化合物抗结核的靶点。比如二硝基苯甲酰胺类化合物DBN1，苯并喹喔啉类VI-9376]以及硝基三氮唑化合物377790都对DprE1酶有一定作用。
最初，作为广谱抗生素的硝基呋喃类化合物，通过作用微生物酶系统，抑制乙酰辅酶A，干扰微生物糖代谢，因其杀菌能力强、抗菌谱广、不易产生耐药等，在临床上得到广泛应用。但因为硝基呋喃类药物的严重致癌和致畸胎等毒副作用，被欧盟、美国、中国等国家在20世纪初明令禁止使用。最近几年，由于结核多重耐药现象猖獗，具有强效抗耐药结核的硝基呋喃类化合物又重新进入人们视野，被开发研究。
Lee等在研究硝基呋喃类化合物抗结核研究中发现了多个活性化合物。他们从高通量筛选得到的5-硝基呋喃-2-酰胺类化合物（H37Rv，MIC=0.6μM）入手，在苯环的对位引入哌嗪支链得到Lee-562，活性提高到MIC= 0.014 μM，然后将中间的酰胺基团生物电子等排替换为恶唑环，得到这类化合物中活性最高的化合物Lee-878(MIC = 0.0001 μM)，但Lee-878的水溶解低(0.55 μM)，药代数据不理想。因此通过优化支链合成了Lee-1106，溶解度提升了10倍，活性基本保持（MIC= 0.046 μM），且与利福平、PA-824有协同效应，小鼠慢性感染模型中，给药9天，肺和脾脏中结核杆菌降低90%。
发明内容
本发明所要解决的技术问题为：如何提供一种高效、低毒的新型抗结核化学药物及其制备方法。
本发明的技术方案为：化合物，具有式1或式2或式3所示的结构，
式1或式2或式3所示的化合物或其药学上可接受的盐在制备抗结核药物中的应用。
式1或式2或式3所示的化合物或其药学上可接受的盐非治疗目的在体外用于抑制分枝杆菌的用途。
与现有技术相比，本发明具有以下有益效果：
本发明的化合物具有很高的抗结核活性，其中式1的化合物在1μM和0.1μM浓度下分别达到99.6%和93.4%，式2的化合物在1μM和0.1μM浓度下分别达到100.03%和80.7%，式3的化合物在1μM和0.1μM浓度下分别达到94.3%和83.7%，可作为抗结核候选药物。
具体实施方式
本发明设计了一种具有新的结构的化合物，其具有以下结构的通式：
在该通式的基础上，以Ciprofloxacin（环丙沙星）为阳性对照，测试了该通式下R5为不同取代基时，在1 μM和0.1 μM两个浓度下，对结核分枝杆菌（H37Ra）的抑制率（Inh%）。
测试方法为：分别测试浓度1μM、0.1μM下对细菌的抑制率%Inh。化合物测试中所使用的菌株来自美国国家菌种保藏中心（ATCC），结核分枝杆菌H37Ra (ATCC 25177)由上海睿智化学有限公司保存和测试。最低抑菌浓度MIC定义为抑制对照组90%以上菌株生长的最低药物浓度。
操作过程如下：
待测菌株于罗氏培养基37 °C培养3周后，再于Middlebrook 7H9 培养基培养10天，直到细菌密度达到1个麦氏单位浊度，备用。选择抗结核药物环丙沙星作为阳性对照，待测试化合物以及阳性对照用DMSO配制成10mM溶液备用。
细菌液用1:25的Middlebrook 7H9 培养基稀释（4×105 CFU/mL)，取100 μL加入到96微孔板中，微孔板事先加入100 μL连续稀释的待测药物（100μM~0.1μM，或0.1μM~0.00001μM）。37 °C培养6天后，加入25 μL 1:1 的Alamar Blue和10% Tween 80，在492nm下测其背景荧光，记录数据，并将96孔板放回孵化箱中再培养24小时。24小时后再次在492nm下测定每孔的荧光，记录数据计算抑制率。
表1 R5为不同取代基时结核杆菌抑制率
由表1可知，在苯环的对位接上Cl取代，得到化合物6b，在1μM浓度下，抑制率为100.03%。进一步改变Cl取代基的位置，发现间位取代的6c和邻位取代的6d在1 μM浓度下活性下降，其中邻位取代的化合物6d活性消失。因为6b化合物的活性较好，我们在化合物6b的基础上，将苯环对位的Cl替换为Br，得到化合物6e，1μM抑制率为99.1%，0.1μM抑制率为62.6%，活性略低于6b（0.1 μM，Inh% = 80.7%）。与此同时，我们在苯环上的不同取代位置引入-CF3、-NO2、-CH3和-OCH3，对比的抑制率可知，-CF3对位取代的化合物6f活性较好，在1 μM和0.1 μM浓度下，抑制率分别达到99.6%和93.4%，而-CF3邻位取代的化合物6g活性消失；抑制率为故推测苯环上对位的卤素取代有利于活性。-NO2对位取代的化合物6h比间位取代的化合物6i活性高，0.1 μM浓度下，6h保持64.2%的抑制率，6i无活性；-CH3取代的化合物，只有对位取代的6j在1 μM浓度下，保持90.2%的抑制率，间位6k活性消失；-OCH3对、间位取代的化合物6l和 6m抑制率都较低，只有甲氧基二取代的化合物6n活性较好，在1 μM浓度下，抑制率为95.0%。
综上活性初步分析，我们可以明显发现苯环上取代基的位置对活性的影响有一定共性，取代基处于对位的活性普遍比在间位和邻位的活性好。-Cl：对位>间位>邻位；–CF3：对位>邻位；-NO2：对位>间位；-CH3：对位>邻位；-OCH3：对位>间位。同时，对比苯环上对位取代基-Cl、-Br、-CF3、-NO2、 -CH3和-OCH3，发现吸电子基团活性普遍优于供电子基团活性：-Cl、-Br、-CF3、-NO2>-CH3、-OCH3，在吸电子基团中，-CF3对位取代6f活性最高，在1 μM和0.1μM浓度下，抑制率分别为99.6%和93.4%。
实施例1
化合物4-(4-chlorophenyl)-2-(1-((5-nitrofuran-2-yl)methyl)piperidin-4-yl)thiazole的合成
合成方法：以4-三氟甲基溴代苯乙酮(A)与N-Boc-哌啶4-硫代酰胺(B)在质子性溶剂乙醇中发生Hantasch缩合反应生成噻唑环中间体(C)；然后在强酸TFA条件下脱掉Boc基团，得到化合物(D)最后与5-硝基糠醛(C)发生还原胺化反应，制得最终产物F
核磁共振检测：
1H NMR (400 MHz, DMSO-d 6 ) δ: 8.05 (s, 1H), 8.01 – 7.92 (m, 2H), 7.67 (d,J = 3.7 Hz, 1H), 7.56 – 7.44 (m, 2H), 6.79 (d, J = 3.7 Hz, 1H), 3.69 (s, 2H),3.03 (tt, J = 11.4, 3.8 Hz, 1H), 2.98 – 2.90(m, 2H), 2.30 – 2.20 (m, 2H),2.12 – 2.04 (m, 2H), 1.77 (qd, J = 12.3, 3.6 Hz, 2H).
13C NMR (101 MHz, DMSO-d 6 ) δ : 175.31, 157.57, 152.86, 151.79, 133.56,132.85, 129.21, 128.15, 114.42, 114.24, 113.36, 54.43, 52.76, 39.84, 32.65.
ESI-MS:HRMS Calcd for C19H18ClN3O3S [M+H]+ 404.0757, Found 404.0833。
实施例2
化合物2-(1-((5-nitrofuran-2-yl)methyl)piperidin-4-yl)-4-(4-(trifluoromethyl)phenyl)thiazole合成
合成方法：以4-氯溴代苯乙酮(A)与N-Boc-哌啶4-硫代酰胺(B)在质子性溶剂乙醇中发生Hantasch缩合反应生成噻唑环中间体(C)；然后在强酸TFA条件下脱掉Boc基团，得到化合物(D)最后与5-硝基糠醛(C)发生还原胺化反应，制得最终产物F
核磁共振检测：
1H NMR (400 MHz, DMSO-d 6 ) δ: 8.22 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.79(d, J = 8.2 Hz, 2H), 7.68 (d, J = 3.7 Hz, 1H), 6.79 (d, J = 3.6 Hz, 1H), 3.70(s, 2H), 3.10 –3.01 (m, 1H), 2.96 (d, J = 11.4 Hz, 2H), 2.25 (t, J = 10.7 Hz,2H), 2.09 (d, J = 11.6 Hz, 2H), 1.79 (qd, J = 12.4, 3.3 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ: 180.38, 162.29, 157.26, 143.11, 133.36,133.04, 131.74, 130.89, 120.88, 119.15, 118.10, 59.17, 57.49, 37.37, 28.95.
ESI-MS:HRMS Calcd for C20H18F3N3O3S [M+H]+438.1021, Found438.1098。
实施例3
化合物N-(3-(2-(1-((5-nitrofuran-2-yl)methyl)piperidin-4-yl)thiazol-4-yl)phenyl)benzamide合成
合成方法：以3-苯酰胺溴代苯乙酮(A)（其中3-苯酰胺溴代苯乙酮类化合物A1，由酰胺苯乙酮与四丁基三溴化胺TBA-Br3发生α-溴代反应制得）与N-Boc-哌啶4-硫代酰胺(B)在质子性溶剂乙醇中发生Hantasch缩合反应生成噻唑环中间体C；然后在强酸TFA条件下脱掉Boc基团,得到化合物(D); 最后与5-硝基糠醛(E)发生还原胺化反应，制得最终产物F
核磁共振检测：
1H NMR (400 MHz, DMSO-d 6 ) δ: 10.35 (s, 1H), 8.37 (s, 1H), 8.01 (d, J =7.3 Hz, 2H), 7.91 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.69 – 7.64(m, 2H), 7.63– 7.57 (m, 1H), 7.54 (t, J = 7.3 Hz, 2H), 7.41 (t, J = 7.9 Hz, 1H), 6.78 (d,J = 3.6 Hz, 1H), 3.69 (s, 2H), 3.10 – 3.00 (m, 1H), 2.96 (d, J = 11.3 Hz,2H), 2.25 (t, J = 10.8 Hz, 2H), 2.09 (d, J = 11.6 Hz, 2H), 1.87 – 1.70 (m,2H), 1.32 – 1.14 (m, 2H).
13C NMR (101 MHz, CDCl3) δ: 179.80, 170.83, 162.31, 158.84, 156.53,144.80, 140.05, 139.88, 136.82, 134.20, 133.59, 132.91, 126.59, 125.25,123.54, 119.17, 118.36, 118.09, 59.21, 57.58, 37.48, 27.32.
ESI-MS:HRMS Calcd for C26H24N4O4S [M+H]+489.1518, Found489.1590。
Claims (3)
1.化合物，具有式1或式2或式3所示的结构，
式1
式2
式3。
2.根据权利要求1所述的化合物或其药学上可接受的盐在制备抗结核药物中的应用。
3.根据权利要求1所述的化合物或其药学上可接受的盐非治疗目的在体外用于抑制分枝杆菌的用途。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86102565A (zh) * | 1985-04-11 | 1986-11-12 | 合成实验室公司 | 硝基呋喃衍生物的制备方法及其在医疗上的应用 |
| CN1909907A (zh) * | 2004-01-23 | 2007-02-07 | 詹森药业有限公司 | 喹啉衍生物及其作为分枝杆菌抑制剂的用途 |
| CN101516876A (zh) * | 2006-07-04 | 2009-08-26 | 里尔巴斯德研究所 | 具有乙硫异烟胺活性增强作用的化合物及其用途 |
| CN102656164A (zh) * | 2009-08-14 | 2012-09-05 | 沃泰克斯药物股份有限公司 | 作为结核病抑制剂的嘧啶化合物 |
| CN104211708A (zh) * | 2013-05-29 | 2014-12-17 | 中国医学科学院药物研究所 | 苯并噁嗪酮衍生物及其作为抗菌剂的应用 |
-
2018
- 2018-05-23 CN CN201810501479.5A patent/CN108558858A/zh active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86102565A (zh) * | 1985-04-11 | 1986-11-12 | 合成实验室公司 | 硝基呋喃衍生物的制备方法及其在医疗上的应用 |
| CN1909907A (zh) * | 2004-01-23 | 2007-02-07 | 詹森药业有限公司 | 喹啉衍生物及其作为分枝杆菌抑制剂的用途 |
| CN101516876A (zh) * | 2006-07-04 | 2009-08-26 | 里尔巴斯德研究所 | 具有乙硫异烟胺活性增强作用的化合物及其用途 |
| CN102656164A (zh) * | 2009-08-14 | 2012-09-05 | 沃泰克斯药物股份有限公司 | 作为结核病抑制剂的嘧啶化合物 |
| CN104211708A (zh) * | 2013-05-29 | 2014-12-17 | 中国医学科学院药物研究所 | 苯并噁嗪酮衍生物及其作为抗菌剂的应用 |
Non-Patent Citations (2)
| Title |
|---|
| 郑梅琴等: "Alamar blue 法检测药物细胞内抗结核活性的研究", 《中国抗生素杂志》 * |
| 陆宇等: "应用Alamar Blue 和MTT 测定抗结核药物最低抑菌浓度的研究", 《中国防痨杂志》 * |
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