CN110563642A - 抗真菌化合物及其应用 - Google Patents
抗真菌化合物及其应用 Download PDFInfo
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- CN110563642A CN110563642A CN201910939689.7A CN201910939689A CN110563642A CN 110563642 A CN110563642 A CN 110563642A CN 201910939689 A CN201910939689 A CN 201910939689A CN 110563642 A CN110563642 A CN 110563642A
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
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Abstract
本发明提供一种抗真菌的化合物及其制备方法和用途。该化合物具有优良的广谱抗真菌活性，对常见真菌，如酿酒酵母菌、构巢曲霉和马尔尼菲青霉菌都有较强的抑制作用，尤其对重要的医学真菌‑白色念珠菌有比较强的抑制效果，可用于治疗或预防真菌引起的感染性疾病，因此具有广阔的临床应用前景。
Description
技术领域
本发明涉及一种化合物，尤其涉及一种抗真菌化合物，此外本发明还涉及该抗真菌化合物的制备方法及其应用。
背景技术
真菌是自然界广泛存在的一种真核微生物。迄今为止，已经发现有200多种真菌能够导致人体疾病或者动植物危害(如危害水稻的稻瘟菌等)。真菌引起的人体疾病分为浅表性感染和深部感染。浅表性真菌感染主要由表皮癣菌属、小孢霉菌属和毛癣菌属引起，表现为头癣、体癣、花斑癣及甲真菌病。深部真菌病的主要病原菌则包括念珠菌、隐球菌、曲霉、孢子丝菌等，主要感染消化道和呼吸系统，其危害性极大，病死率高。随着临床上高效广谱抗生素、肾上腺皮质激素和免疫抑制剂的广泛应用，以及AIDS、器官组织移植和化疗等免疫受损病人的逐渐增多，使得真菌感染日益严重。目前，抗真菌药已成为抗感染类药物中的重要组成部分，在临床和OTC领域均有大量的应用。
常见的抗真菌药物按化学结构可以分为以下几类：1、三唑类、吡咯类抗真菌药，包括：咪唑类和三唑类。咪唑类包括：酮康唑、克霉唑、咪康唑、益康唑和舍他康唑等。目前，多为浅表真菌感染或皮肤黏膜念珠菌感染的局部用药。三唑类包括：氟康唑、伊曲康唑、伏立康唑和处于研究阶段的沙康唑、帕索康唑、雷夫康唑、SCH39304(SM8668)和SDZ89-485，均可用于治疗深部真菌感染。吡咯类药物作用的主要靶酶是14-去甲基酶(14-DM)，利用咪唑环和三唑环上的第3位或第4位氮原子镶嵌在该酶的细胞色素P450蛋白的铁原子上，抑制 14-DM的催化活性，使羊毛甾醇不能转化成14-去甲基羊毛甾醇，进而阻止麦角甾醇合成，使真菌的细胞膜合成受阻，导致真菌细胞破裂死亡。2、多烯类，包括：两性霉素B(AmB)、两性霉素B含脂复合体(ABLC)、两性霉素硫酸胆甾醇酯(ABCD)、两性霉素B脂质体 (L-AmB)以及制霉菌素。此类药物通过与真菌细胞膜磷脂双分子层上的甾醇发生交互作用，导致细胞膜产生水溶性的孔道，使细胞膜的通透性发生改变，最终导致重要的细胞内容物流失而造成菌体死亡。两性霉素B也可通过刺激巨噬细胞调整自体免疫功能产生杀菌作用。制霉菌素脂质体(NYS)能与真菌细胞膜上的麦角醇结合，降低细胞膜稳定性，对多种真菌有活性。3、棘白菌素类，此类化合物作为1,3-β-D-葡聚糖合成酶的非竞争性抑制剂，在抑制其生物活性的同时，不影响核酸和甘露聚糖的生物合成。1,3-β-D-葡聚糖是维持真菌细胞壁完整性的重要物质，但隐球菌缺乏该物质。1,3-β-D-葡聚糖缺乏导致真菌细胞壁通透性增加，细胞溶解，真菌死亡。4、尼可霉素类，尼可霉素类药物的主要成分均是由链霉素属的发酵液中分离出来的，尼可霉素通过抑制真菌专有的几丁质合成酶、阻断真菌细胞壁所必需的几丁质的合成，引起真菌细胞的膨胀和破裂，由于哺乳动物细胞中不存在几丁质合成酶和几丁质，因此，尼可霉素对真菌的作用是选择性的，对哺乳动物的毒性非常低。尼可霉素对敏感的念珠菌、球孢子菌、皮炎芽生菌和组织胞浆菌有强大的杀菌作用，对耐药菌株采用与唑类药物联合用药也有良好活性。5、氟尿嘧啶类，5-氟尿嘧啶(5-FC)的抗真菌作用机制为抑制胸腺嘧啶合成酶，阻止DNA的合成，从而抑制真菌细胞的生长。6、β-1,3-D-葡聚糖合成酶抑制剂，β-1,3-D-葡聚糖是真菌细胞壁的重要成分，哺乳动物细胞中缺乏该成分，此类药物能特异性作用于真菌特有的细胞壁成分β-1,3-D-葡聚糖合成酶，从而阻断真菌细胞壁的合成。7、甘露糖糖蛋白合成抑制剂，这类药物可与真菌细胞壁甘露糖糖蛋白结合形成钙依赖性三元复合物，该复合物作用于真菌细胞膜导致胞内钾外流从而杀伤真菌。贝那米星A在体外几乎对所有致病真菌都有效，其皮下和静脉注射对白假丝酵母菌、烟曲霉菌、新型隐球菌也均有效。
目前临床抗真菌药物在应用中，容易出现耐药性、半衰期长、不良反应多、患者耐受性不好等确定，因此需要提供更多可以解决上述一个或多个缺点的新型抗真菌药物。
发明内容
鉴于以上所述现有技术的缺点，本发明要解决的技术问题是提供一种具有药用价值的抗真菌化合物，进一步提供一种以上述抗真菌化合物为活性成分的药物组合物，以及在制备治疗真菌引起感染性疾病的药物中的应用。
本发明中化合物结构如式(I)：(I)，其中，R1为取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的杂环，R2为卤素、羟基、氰基、氨基、硝基、C1-C3烷基。
作为优选的，R1为取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基，R2为羟基、卤素、氨基、甲基。
进一步优选，R1为三氟甲基取代的苯基、卤素取代的苯基。
进一步，例举出的最优化合物为
本发明中还包括上述化合物的组合物，其包含治疗有效量的上述化学式为(I)的抗真菌化合物，以及含有一种或多种药学上可接受的载体。上述可接受的载体是无毒的、能辅助施用并且对化学式为(I)的化合物的治疗益处没有不利影响。此类载体可以是本领域的技术人员通常能得到的任何固体赋形剂、液体赋形剂、半固体赋形剂或者在气雾剂组合物中可以是气体赋形剂。固体药物赋形剂包括淀粉、纤维素、滑石、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻米、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、甘油硬脂酰酯、氯化钠、无水脱脂乳等。液体和半固体赋形剂可以选自甘油、丙二醇、水、乙醇和各种油，包括那些源于石油、动物、植物或人工合成的油，例如，花生油、豆油、矿物油、芝麻油等、优选的液体载体，特别是用于可注射溶液的，包括水、盐水、葡萄糖水溶液和甘醇。
本发明的化合物通过以下途径以药物组合物施用：口服、系统性施用(例如，透过皮肤的、鼻内的或者用栓剂)或肠胃外施用(例如，肌肉内、静脉内或皮下)。优选的施用方法是使用方便的日剂量方案的口服，它可以根据疾病程度调节。
本发明药物组合物可制成片剂、胶囊、乳液、输液剂、针剂、喷雾剂等临床常见剂型。各种剂型可以按照药学领域的常规方法制备。例如使该化合物(活性成分)与一种或者多种载体混合，然后将其制成所需的剂型，如片剂、药丸、胶囊、半固体、粉末、缓释剂型、溶液、混悬液、配剂、气雾剂等等。
剂型中化合物的量可以在本领域技术人员所用的全部范围内变动。通常，按重量百分比 (wt％)记，剂型中含有占总剂型约1-99wt％的具有化学式(I)的化合物，并且还有一种或多种合适的药物赋形剂作为平衡物。优选的，化合物以大约20-70wt％的比例存在。
本发明还提供上述抗真菌化合物在制备治疗真菌引起感染性疾病的药物中的应用。
本发明的抗真菌化合物具有优良的广谱抗真菌活性，对常见真菌，如酿酒酵母菌、构巢曲霉和马尔尼菲青霉菌都有较强的抑制作用，尤其对重要的医学真菌-白色念珠菌也有比较强的抑制效果，可用于治疗或预防真菌引起的感染性疾病。
具体实施方式
以下由特定的具体实施例说明本发明的实施方式，熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效。
实施例1制备化合物
将化合物1(500mg)置于50mL干燥的双口瓶，氮气保护下，加入10mL无水DMF，在0℃下1mL/min滴加1mL无水吡啶，然后以0.5mL/min滴加3-氯-4-三氟甲基-苯甲酰率(400mg)，室温反应2-4小时，加水淬灭反应，用二氯甲烷(20×3)萃取，有机相用饱和食盐水洗涤3次，无水硫酸钠干燥，过滤，收集滤液减压浓缩，柱层析，洗脱剂为氯仿：甲醇(V:V)＝30：1，得无色粘稠状液体化合物2。
将化合物2(250mg)置于单口反应瓶中，用50mL甲醇溶解，加入100mg10％Pd/C，抽真空，反应体系在氢气保护下室温反应过夜；反应完毕后，反应液用硅藻土助滤，收集滤液减压浓缩得粗产物，粗产物用乙醇/乙酸乙酯重结晶，得化合物3(70mg)。
1H NMR(300MHz,DMSO-d6)2.46(s，3H，CH3)，3.86(s，2H，CH2)，8.1(1H， NH)，7.88,7.56,7.75(s，1H，CH)，
13C NMR(75MHz,DMSO-d6)75.2，175.9，159.3，102.1，187.1，30.0，50.7。
另外，化合物均按照上述反应流程进行合成制备。
实施例2(抗真菌活性试验)
1.实验菌株：白色念珠菌(CMCC98001)。
2.培养基：白色念珠菌选用沙氏培养基。
培养基具体配方如下：沙氏培养基：蛋白胨10g，葡萄糖40g，加水配成1升溶液。
3.菌悬液的制备：
菌株保存于斜面半固体培养基上，保持菌落的纯化和活性(4℃冰箱保藏)。使用时将菌落接种于液体培养基中，27℃摇床培养24～48小时，用血细胞计数器将菌悬液的浓度控制在1～5×108个/ml之间。
4.抗菌化合物的配制：
将化合物 依次编号为化合物a、b、c，将化合物a、b、c溶解在(二甲基亚砜)DMSO中，配制成10mg/ml，0.2μm微孔滤膜过滤，加样量均为10μl。
5.最小抑制真菌浓度的测定方法：
白色念珠菌参考NCCLS方案。化合物浓度减半稀释观察菌液的生长情况。NCCLS方案将完全不生长的前一管判定为终点，有拖尾现象时采用80％抑制判定法，将生长对照管内的培养物进行1∶4稀释，将与其浓度近似的培养管判定为终点。
所有数据都在真菌生长48h后测定。
6.抗真菌药效测定结果：
| 白色念珠菌MIC(mg/ml) | |
| 化合物a | 27.3 |
| 化合物b | 26.5 |
| 化合物c | 30.2 |
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。
Claims (8)
1.一种抗真菌的化合物，其特征在于，所述化合物结构如式(I)：其中，R1为取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的杂环，R2为卤素、羟基、氰基、氨基、硝基、C1-C3烷基。
2.根据权利要求1所述的抗真菌的化合物，其特征在于：R1为取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基，R2为羟基、卤素、氨基、甲基。
3.根据权利要求1或2所述的抗真菌的化合物，其特征在于：R1为三氟甲基取代的苯基、卤素取代的苯基。
4.根据权利要求1所述的抗真菌的化合物，其特征在于：所述化合物为
5.权利要求1所述的抗真菌化合物的应用，其特征在于：该化合物用于制备抗真菌药物。
6.根据权利要求5所述的抗真菌化合物的应用，其特征在于：所述真菌为白色念珠菌。
7.一种包括权利要求1所述的化合物的组合物，其特征在于：组合物中包括填充剂、润滑剂、赋型剂等辅料。
8.根据权利要求7所述的组合物，其特征在于：该组合物可制成片剂、胶囊、乳液、输液剂、针剂、喷雾剂等剂型。
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| CN1772743A (zh) * | 2005-11-03 | 2006-05-17 | 上海人类基因组研究中心 | 抗真菌化合物及其制备方法和应用 |
| WO2011080265A1 (en) * | 2009-12-29 | 2011-07-07 | Polichem S.A. | Secondary 8-hydroxyquinoline-7-carboxamide derivatives for use as antifungal agents |
| CN103360308A (zh) * | 2012-03-28 | 2013-10-23 | 孙伟新 | 1,4-二羟基-6-甲基-2-吡啶酮类化合物及其制备方法和用途 |
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