CN102093358B - 溴代中氮茚并喹啉二酮类衍生物及其在制备抗菌药物中的应用 - Google Patents
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Abstract
本发明公开了溴代中氮茚并喹啉二酮类衍生物及其在制备抗菌药物中的应用。实验证明，本发明所述的溴代中氮茚并喹啉二酮类衍生物对革兰氏阳性菌，尤其是耐甲氧西林金葡菌有很强的抑制活性，可用于制备有效的抗菌药物。所述的溴代中氮茚并喹啉二酮类衍生物的化学结构式如式I所示，式中R1和R2如说明书所定义。
Description
技术领域
本发明涉及一类溴代中氮茚并喹啉二酮类衍生物及其在制备抗菌药物中的用途。该药对革兰氏阳性菌，尤其是对耐甲氧西林金葡菌有很强的抑制活性。
背景技术
随着抗生素在全球的普及和应用，无论是革兰氏阴性菌或革兰氏阳性菌均已出现多种耐药菌株。其中，革兰氏阳性菌的耐药问题尤为严重。例如，耐甲氧西林金葡菌（MRSA）、耐甲氧西林表皮葡萄球菌、耐青霉素肺炎链球菌以及耐万古霉素肠球菌等在临床上造成严重的问题。目前，对这些耐药菌引起的感染，还缺乏有效的治疗药物，迫切需要研发无交叉耐药性和更有效的、新型的抗菌药物。
在我们前期的研究中，报道了中氮茚并喹啉二酮类衍生物及其在制备抗菌药物中的应用（CN 100441580C）。我们进一步的研究发现，其溴代衍生物具有更强的抗菌活性。
发明内容
本发明的目的是提供一类溴代中氮茚并喹啉二酮类衍生物，以及该类化合物在制备抗菌药物，特别是抗MRSA的药物中的应用。
本发明的溴代中氮茚并喹啉二酮类衍生物如下式I所示：
式I中的R1所代表的基团为：C1-C3烷基、氟取代的C1-C3烷基或胺基取代的C1-C3烷基；
式I中的R2所代表的基团为：-H或甲基。
本发明的溴代中氮茚并喹啉二酮类衍生物可通过化学合成方法获得。通常本发明的溴代中氮茚并喹啉二酮类衍生物可以通过反应式II或者反应式III制备：
上述的溴代中氮茚并喹啉二酮类衍生物可与药学上可接受的辅助剂制成药物。该药物可以制成片剂、丸剂、胶囊剂、悬浮剂、乳剂或注射剂等形式使用。其给药途径可为口服，经皮，静脉或肌肉注射。
与现有技术相比，本发明具有如下有益效果：通过体外抑菌试验表明，与我们之前报道的喹啉二酮衍生物相比，本发明的溴代中氮茚并喹啉二酮类衍生物对革兰氏阳性菌，特别是MRSA具有更强的抑制活性。
具体实施方式：
以下通过实施例对本发明做进一步说明。
实施例1：化合物1的合成
如反应式II，将0.10 mol的6,7-二氯-5,8-喹啉二酮和0.20 mol乙酰乙酸乙酯加入到300 ml乙醇中，在搅拌下加入0.40 mol的3-溴吡啶，回流反应2-15小时。冷却后，减压浓缩溶剂，残余物经过柱层析分离，得到目标化合物1，其结构式与表征如下：
1H NMR (400 MHz, CDCl3) δ: 10.10 (d, J = 0.7 Hz, 1H), 9.05 (dd, J = 4.6, 1.7 Hz, 1H), 8.57 (dd, J = 7.9, 1.7 Hz, 1H), 8.30-8.24 (m, 1H), 7.67 (dd, J = 7.9, 4.7 Hz, 1H), 7.56 (dd, J = 9.6, 1.7 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 178.8, 173.3, 162.7, 154.2, 149.2, 138.1, 135.5, 131.9, 131.0, 128.6, 127.8, 127.2, 122.8, 121.6, 113.5, 107.1, 61.4, 14.3. ESI-MS m/z: 401.0 (100%), 399.0 (88%) [M + H]+.
实施例2：化合物2的合成
如反应式III，将0.10 mol原料M悬浮于100-200 ml氯仿中，搅拌下加入0.12 mol三乙胺和0.11 mol二氯亚砜。该混合液加热回流4-8小时。停止回流，减压去除溶剂和多余的二氯亚砜。残余物溶于100 ml二氯甲烷，并依次加入0.11 mol N,N-二甲基吡啶和0.11 mol 2,2,2-三氟乙醇。加热该混合液至回流5-10小时，减压去除溶剂，残余物经柱层析分离得到化合物2，其结构式与表征如下：
1H NMR (400 MHz, CDCl3) δ: 10.15 (s, br, 1H), 9.07 (d, J = 3.4 Hz, 1H), 8.60 (d, J = 7.0 Hz, 1H), 8.26 (dd, J = 9.6, 0.5 Hz, 1H), 7.71 (dd, J = 7.8, 4.5 Hz, 1H), 7.64 (dd, J = 9.6, 1.7 Hz, 1H), 4.84 (q, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 178.5, 173.5, 160.7, 154.4, 149.0, 138.5, 135.7, 132.9, 130.9, 128.6, 128.5, 127.4, 123.4, 121.3, 113.7, 104.1, 60.8 (q, J = 36.7 Hz, 1C), 29.7. ESI-MS m/z: 453.0 (100%), 455.0 (94%) [M + H]+.
实施例3：化合物3的合成
制备方法A：制备方法同实施例1，所不同的是以0.20 mol乙酰乙酸甲酯代替乙酰乙酸乙酯，得到目标化合物3。
制备方法B：制备方法同实施例2，所不同的是以0.11 mol甲醇代替2,2,2-三氟乙醇，得到目标化合物3，其结构式与表征如下：
1H NMR (400 MHz, CDCl3) δ: 10.08 (s, br, 1H), 9.04 (dd, J = 4.6, 1.6 Hz, 1H), 8.55 (dd, J = 7.9, 1.7 Hz, 1H), 8.26 (dd, J = 9.6, 0.6 Hz, 1H), 7.68 (dd, J = 7.9, 4.7 Hz, 1H), 7.55 (dd, J = 9.6, 1.7 Hz, 1H), 4.04 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 178.8, 173.3, 163.1, 154.3, 149.2, 138.2, 135.5, 132.0, 130.9, 128.3, 127.8, 127.2, 122.9, 121.6, 113.6, 106.5, 52.3. ESI-MS m/z: 384.9 (100%), 386.9 (96%) [M + H]+.
实施例4：化合物4的合成
制备方法同实施例2，所不同的是以0.11 mol 2-氟乙醇代替2,2,2-三氟乙醇，得到目标化合物4，其结构式与表征如下：
1H NMR (400 MHz, CDCl3) δ: 10.11 (s, br, 1H), 9.05 (dd, J = 4.6, 1.7 Hz, 1H), 8.57 (dd, J = 7.9, 1.7 Hz, 1H), 8.28 (dd, J = 9.6, 0.8 Hz, 1H), 7.68 (dd, J = 7.9, 4.7 Hz, 1H), 7.58 (dd, J = 9.6, 1.7 Hz, 1H), 4.92-4.88 (m, 1H), 4.80-4.77 (m, 1H), 4.75-4.72 (m, 1H), 4.68-4.65 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 178.7, 173.4, 162.2, 154.3, 149.2, 138.3, 135.6, 132.3, 131.0, 128.4, 128.1, 127.2, 123.1, 121.6, 113.6, 106.0, 81.3 (d, J = 169 Hz, 1C), 64.0 (d, J = 20 Hz, 1C). ESI-MS m/z: 417.0 (100%), 419.0 (96%) [M + H]+.
实施例5：化合物5的合成
制备方法同实施例2，所不同的是以0.11 mol N,N-二甲胺基乙醇代替2,2,2-三氟乙醇，得到目标化合物5，其结构式与表征如下：
1H NMR (400 MHz, CDCl3) δ: 10.09 (s, 1H), 9.05 (dd, J = 4.6, 1.6 Hz, 1H), 8.56 (dd, J = 7.9, 1.7 Hz, 1H), 8.36 (d, J = 9.6 Hz, 1H), 7.67 (dd, J = 7.9, 4.7 Hz, 1H), 7.55 (dd, J = 9.6, 1.7 Hz, 1H), 4.56 (t, J = 5.8 Hz, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.38 (s, 6H). 13C NMR (100 MHz, CDCl3) δ: 178.8, 173.3, 162.5, 154.3, 149.2, 138.2, 135.5, 131.9, 131.0, 128.3, 127.9, 127.2, 122.8, 121.8, 113.5, 107.0, 62.8, 57.7, 45.7. ESI-MS m/z: 442.0 (100%), 444.0 (98%) [M + H]+.
实施例6：化合物6的合成
制备方法同实施例2，所不同的是以0.11 mol 2-(1-哌啶基)乙醇代替2,2,2-三氟乙醇，得到目标化合物6，其结构式与表征如下：
1H NMR (400 MHz, CDCl3) δ: 10.10-10.08 (m, 1H), 9.04 (dd, J = 4.6, 1.7 Hz, 1H), 8.57 (dd, J = 7.9, 1.7 Hz, 1H), 8.52 (dd, J = 9.6, 0.8 Hz, 1H), 7.67 (dd, J = 7.9, 4.7 Hz, 1H), 7.54 (dd, J = 9.6, 1.7 Hz, 1H), 4.57 (t, J = 5.9 Hz, 2H), 2.82 (t, J = 5.8 Hz, 2H), 2.54 (s, br, 4H), 1.68-1.58 (m, 4H), 1.52-1.44 (m, 2H).13C NMR (100 MHz, CDCl3) δ: 178.8, 173.2, 162.2, 154.2, 149.2, 138.2, 135.5, 131.8, 130.9, 128.2, 127.9, 127.2, 122.9, 122.2, 113.5, 107.2, 62.2, 57.1, 54.7, 26.0, 24.2. ESI-MS m/z: 482.1 (100%), 484.1 (96%) [M + H]+.
实施例7：化合物7的合成
制备方法同实施例2，所不同的是以0.11 mol 2-吗啉基乙醇代替2,2,2-三氟乙醇，得到目标化合物7，其结构式与表征如下：
1H NMR (400 MHz, CDCl3) δ: 10.10 (s, br, 1H), 9.05 (dd, J = 4.6, 1.7 Hz, 1H), 8.56 (dd, J = 7.9, 1.7 Hz, 1H), 8.43 (dd, J = 9.6, 0.7 Hz, 1H), 7.68 (dd, J = 7.9, 4.7 Hz, 1H), 7.55 (dd, J = 9.6, 1.7 Hz, 1H), 4.58 (t, J = 5.8 Hz, 2H), 3.80-3.70 (m, 4H), 2.87 (t, J = 5.8 Hz, 2H), 2.67-2.57 (m, 4H). 13C NMR (100 MHz, CDCl3) δ: 178.8, 173.3, 162.3, 154.3, 149.2, 138.2, 135.5, 131.9, 130.9, 128.3, 127.9, 127.2, 122.9, 121.9, 113.5, 106.9, 67.0, 61.8, 56.9, 53.7. ESI-MS m/z: 486.1 (100%), 484.1 (92%) [M + H]+.
实施例8：化合物8的合成
制备方法同实施例1，所不同的是以0.40 mol 3-氯吡啶代替3-溴吡啶，得到目标化合物8。
1H NMR (400 MHz, CDCl3) δ: 10.01 (s, br, 1H), 9.05 (d, J = 3.6 Hz, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.33 (d, J = 9.6 Hz, 1H), 7.68 (dd, J = 7.8, 4.6 Hz, 1H), 7.46 (dd, J = 9.6, 2.0 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H). ESI-MS m/z: 355.0 (100%),357.0 (34%) [M + H]+.
实施例9：抗菌活性测定
应用琼脂稀释法测定实验化合物的最小抑菌浓度（MIC），测定结果表明，实验化合物对几种革兰氏阳性菌显示出显著的抑制活性，尤其是对临床分离的MRSA（7365）具有良好的抑制活性。化合物1、2、3和4对MRSA的抑制活性是阳性对照药物万古霉素的32-64倍。
溴代中氮茚并喹啉二酮类衍生物的抑菌活性
注: KLT-2的结构见中国发明专利CN 100441580C。
Claims (1)
1.如式I所示的溴代中氮茚并喹啉二酮类衍生物：
式I中的R1所代表的基团为：C1-C3烷基、氟取代的C1-C3烷基或胺基取代的C1-C3烷基；
式I中的R2所代表的基团为：-H或甲基。
2. 权利要求1所述的溴代中氮茚并喹啉二酮类衍生物在制备抗革兰氏阳性菌的药物中的应用。
3. 权利要求1所述的溴代中氮茚并喹啉二酮类衍生物在制备抗耐甲氧西林金葡菌的药物中的应用。
4. 一种用于抗菌的药物，其特征是该药物由权利要求1所述的溴代中氮茚并喹啉二酮类衍生物以及药学上可接受的辅助剂组成。
5. 按照权利要求4所述的药物，其特征是该药物为片剂、丸剂、胶囊剂、悬浮剂、乳剂或注射剂。
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| CN1887884A (zh) * | 2006-07-14 | 2007-01-03 | 中山大学 | 喹啉二酮衍生物及其在制备抗菌药物中的应用 |
| CN101182321A (zh) * | 2007-12-11 | 2008-05-21 | 中山大学 | 中氮茚并氮杂萘醌类衍生物及其制备方法与抗癌应用 |
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| CN1887884A (zh) * | 2006-07-14 | 2007-01-03 | 中山大学 | 喹啉二酮衍生物及其在制备抗菌药物中的应用 |
| CN101182321A (zh) * | 2007-12-11 | 2008-05-21 | 中山大学 | 中氮茚并氮杂萘醌类衍生物及其制备方法与抗癌应用 |
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| Title |
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| 钱立刚，等.喹啉二酮类化合物的合成研究——形成双（二氢喹啉二酮基）甲烷的可能途径.《化学学报》.1985,第43卷463-466. * |
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