CN117304133A - 一种具有噻唑侧链的截短侧耳素衍生物及其制备方法和应用 - Google Patents
一种具有噻唑侧链的截短侧耳素衍生物及其制备方法和应用 Download PDFInfo
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- CN117304133A CN117304133A CN202311246986.6A CN202311246986A CN117304133A CN 117304133 A CN117304133 A CN 117304133A CN 202311246986 A CN202311246986 A CN 202311246986A CN 117304133 A CN117304133 A CN 117304133A
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- pleuromutilin
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- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical class C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 title claims abstract description 45
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title claims abstract description 22
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- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 claims description 16
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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Abstract
本发明属于药物化学领域,公开了一种具有噻唑侧链的截短侧耳素衍生物及其制备方法和应用。所述衍生物为式2所示结构的化合物或其药学上可接受的盐。本发明提供的截短侧耳素衍生物是未曾报道过的新类型化合物,水溶性好,特别适合作为新型抗菌药物用于防治人或动物细菌感染性疾病,尤其是耐药金黄色葡萄球菌引起的感染性疾病,本发明制得的具有噻唑侧链的截短侧耳素衍生物水溶性好。
Description
技术领域
本发明属于药物化学领域,尤其涉及一种具有噻唑侧链的截短侧耳素衍生物及其制备方法和应用。
背景技术
抗生素一直是临床细菌感染性疾病治疗的主要手段之一,抗生素通常通过抑制细菌细胞的生理功能来帮助机体免疫系统清除外来病原体。随着抗菌药在兽医临床的广泛使用,兽医临床产生动物源细菌耐药性的问题日渐严重。其中,耐甲氧西林金黄色葡萄球菌(MRSA)是耐药细菌中的典型代表。金黄色葡萄球菌(MRSA)是一种典型的人兽共患病原菌,在自然界中广泛存在,除了对许多消毒剂有抵抗力外,还可在体外各种恶劣的环境中生存。金黄色葡萄球菌通常定植在鼻腔、喉咙、腋窝、腹股沟、会阴和胃肠道等较为湿润的部位。金黄色葡萄球菌是细菌败血症的重要病原体,感染后的死亡率高达40%。MRSA感染在世界各地均有报道,并且在社区和医院的流行率持续上升,对全世界的人类健康构成严重威胁。因此,迫切需要开发具有独特抗菌机制的抗MRSA药物来应对MRSA感染带来的潜在危害。
鸡支原体病是由鸡败血性支原体(Mycoplasma gallisepticum,MG)引起的鸡接触性传染性慢性呼吸道病。MG感染的临床症状为咳嗽、流鼻涕和气管啰音;MS感染可引起滑液囊炎,其特征为跗关节肿大腿跛行,雏鸡感染后生长不良,产蛋鸡产蛋率下降等。目前,几乎所有的养殖场都存在支原体感染。当鸡养殖场中出现鸡支原体病是会严重危害养殖业的利润并造成诸多危害;例如,种鸡利用率大幅下降、蛋鸡产蛋率大幅下降、商品鸡的利润大幅下降并严重损害免疫系统且继发感染加剧。所以开发新型的防治鸡毒支原体的药物变得尤为迫切。
截短侧耳素(Pleuromutilin,式1)是有骈合5-6-8三环的二萜类天然产物,于20世纪50年代由Kavanagh等从Pleurotus mutilu和Pleurotus passeckerianus的培养物中分离纯化后得到。截短侧耳素相对分子量为378.51,分子式C22H34O5,熔点为167℃~168℃,乳白色晶体,易溶于乙醇和丙酮,微溶于水。
研究表明,截短侧耳素类及其衍生物对多数革兰氏阳性菌、部分革兰氏阴性菌以及支原体均有较强的抑菌活性,且有别与临床广泛应用的其他抗菌药物。截短侧耳素及其衍生物可通过与细菌50s核糖体亚基23s RNA的肽基转移酶中心(PTC)的V区结合而抑制细菌蛋白质的合成。由于独特的作用机理,截短侧耳素及其衍生物不易与其他药物产生交叉耐药性。同时,药物化学工作者通过在三环骨架的多个位点进行化学修饰,对截短侧耳素进行生物转化以及全合成,以期改善截短侧耳素类化合物成药性。目前多数修饰主要集中于截短侧耳素的C14侧链,通常为取代末端羟基或整个侧链而产生两种主要类型的半合成截短侧耳素。通过对其母核C-14位的侧链进行结构修饰后,能够得到抗菌效果好、水溶性较强的截短侧耳素衍生物。
到目前为止,通过改造其C14侧链,成功上市的抗菌药物已有兽用抗菌药泰妙菌素(Tiamulin)、沃尼妙林(Valnemulin),人皮肤外用药瑞它妙林(Retapamulin)以及于2019年通过美国FDA审批上市,用于治疗社区获得性细菌性肺炎(CABP)的人用药乐福妙林(Lefamulin)共四款。与基于同一母核开发成功的药物,如青霉素、头孢菌素、沙星类抗菌药动辄数十种相比,截短侧耳素仅成功开发四种抗菌药,且针对截短侧耳素类抗菌药的耐药菌尚不多见。因此,开发更多截短侧耳素类抗菌药十分必要。
发明内容
为了克服现有技术中存在的不足和缺点,本发明的首要目的在于提供一种具有噻唑侧链的截短侧耳素衍生物,此类截短侧耳素衍生物具有良好的抗菌活性,特别适合制备新型抗菌药物用于动物或人全身系统感染。
本发明的另一目的在于提供上述具有噻唑侧链的截短侧耳素衍生物的制备方法。
本发明的再一目的在于提供上述具有噻唑侧链的截短侧耳素衍生物在制备治疗感染性疾病特别是经耐药金黄色葡萄球菌、或多药耐药菌、或支原体引起的感染性疾病的药物中的用途。
本发明目的通过以下技术方案实现:
一种具有噻唑侧链的截短侧耳素衍生物,所述衍生物为式2所示结构的化合物或其药学上可接受的盐:
其中,R为环丙基、环丁基、环戊基、环己基、
上述优选结构的化合物的具体基团归纳如表1所示:
表1化合物编号及具体基团
所述的药学上可接受的盐为式2化合物与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐;
所述的药学上可接受的盐优选具有如下结构式:
上述具有噻唑侧链的截短侧耳素衍生物的制备方法,包含如下步骤:
(1)将截短侧耳素与对甲基苯磺酰氯反应,得到如式3所示结构的中间体I;
(2)将步骤(1)制得的中间体I与碘化钠反应,得到如式4所示结构的中间体II;
(3)将氨基乙腈盐酸盐作为原料,与CS2进行反应,得到如式5所示结构的中间体III;
(4)将步骤(2)制得的中间体II与步骤(3)制得的中间体III反应,得到如式6所示结构的中间体IV;
(5)将步骤(4)制得的中间体IV和各种酰氯反应得到如式2所示结构的具有噻唑侧链的截短侧耳素衍生物;
所述的中间体Ⅰ、中间体II、中间体Ⅲ和中间体Ⅳ分别具有式3~6结构式:
步骤(1)中所述的对甲苯磺酰氯与截短侧耳素摩尔比优选为1.1:1;
步骤(2)中所述的反应优选采用无水甲醇作为溶剂,中间体Ⅰ与碘化钠的摩尔比优选为1:1,反应条件优选为75℃反应2~3h;
步骤(3)中所述的氨基乙腈盐酸盐与CS2的摩尔比优选为1:1.1;
步骤(4)中所述的反应的具体操作为:在冰浴下向中间体III中加入中间体II,再加入甲醇钠,甲醇钠与中间体II的摩尔比优选为1:1;
步骤(5)中所述的反应的具体操作为:在常温条件下,在中间体IV中滴加酰氯,中间体IV和酰氯摩尔比优选为1:1.1,在反应溶液中滴入三乙胺作为催化剂,反应时间优选为2~4h。
合成路线如下式所示:
上述的具有噻唑侧链的截短侧耳素衍生物在制备抗菌产品中的应用。
所述的抗菌产品优选为治疗感染性疾病的药物。
所述的感染性疾病为人或动物经耐药金黄色葡萄球菌或多药耐药菌感染引起的感染性疾病。
所述的药物含有一种或多种药学上可接受的载体、赋形剂或稀释剂。
所述的药物的制剂包括多种临床药物剂型,如片剂、注射液、脂质体纳米粒、控释剂等;
一种抗生素药物,含有有效量的具有噻唑侧链的截短侧耳素衍生物,余量为药用辅料或其它可配伍的药物;
所述药用辅料是指常规的药用赋形剂,如溶剂、崩解剂、矫味剂、防腐剂、着色剂和粘合剂等;
所述其它可配伍的药物,指的是以有效剂量的具有噻唑侧链的截短侧耳素衍生物为药物原料,再配伍其它天然药物或化学药品;
与现有技术相比,本发明具有如下优点及有益效果:
(1)本发明提供的截短侧耳素衍生物是未曾报道过的新类型化合物。
(2)本发明经过广泛而深入的研究,合成了大量全新结构的具有噻唑侧链的截短侧耳素衍生物,并进行了广泛的抗菌活性筛选,首次发现该类化合物不仅具有良好的体外抗菌活性,还具有较沃尼妙林(Valnemulin)及瑞它莫林(Retapamulin)制备成本低的优势,因而特别适合作为新型抗菌药物用于防治人或动物细菌感染性疾病,尤其是耐药金黄色葡萄球菌引起的感染性疾病。
(3)本发明制得的具有噻唑侧链的截短侧耳素衍生物水溶性好。
附图说明
图1是化合物2的核磁图谱图。
图2是化合物3的核磁图谱图。
图3是化合物4的核磁图谱图。
图4是化合物10的核磁图谱图。
图5是化合物19的核磁图谱图。
图6为一部分化合物的毒性实验结果。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
在以下实施例中,噻唑中的R基团具体见表1,均为市购,其他试剂也均为市购。
实施例1
(1)中间体Ⅰ制备:将10.0g(26.5mmol)截短侧耳素溶于20ml吡啶并置于冰浴;将5.6g(29.2mmol)对甲基苯磺酰氯溶于10ml吡啶,然后缓慢加入上述的截短侧耳素吡啶溶液,冰浴搅拌该混合液3h后,依次加入冰水与三氯甲烷各50ml,再转移至分液漏斗中振摇,静置待其分层;取有机相,依次用100ml的硫酸(4mol/L)、100ml饱和碳酸氢钠溶液、100ml去离子水洗涤;洗涤后有机相减压蒸发有机溶液,往剩余固体中加入20ml异丙醇,加热溶解后再放冷,析出大量白色粉末,抽滤,并用异丙醇洗涤滤渣,烘干,得到如式3所示结构的中间体Ⅰ,产率81%;
(2)中间体II制备:将11.7g中间体Ⅰ(80mmol)和3.29g甲醇钠(80mmol)加入到无水甲醇中,75℃下搅拌2小时;得到如式4所示结构的中间体II,产率84.21%;
(3)中间体III制备:将10g氨基乙腈(108mmol)溶于无水甲醇中,并在反应液中缓慢滴加9.05g二硫化碳(118mmol),在冰盐浴下反应1小时,析出大量固体,抽滤得到黄色固体中间体III,产量45.17%;
(4)中间体IV制备:将11.7g中间体III(80mmol)和11.9g甲醇钠(80mmol)加入到中间体II(80mmol)中,冰盐浴下反应2小时后将反应液旋转蒸干,用二氯甲烷复溶反应物,并将反应液倒入分液漏斗中,依次加入蒸馏水与二氯甲烷各50ml,振摇后静置待其分层,取其有机相再用蒸馏水洗涤两次并用无水硫酸钠干燥,取有机相;所得有机相旋转蒸干得混合物经二氯甲烷复溶,加入100~200目硅胶10g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析进行纯化(100~200目硅胶粉为固定相,二氯甲烷:甲醇=200:1(V:V)为流动相),得到中间体IV,产率为45.65%。
实施例2 22-((5-(环丙甲酰氨基)噻唑-2-基)-硫)-脱氧截短侧耳素(化合物1)的制备
取1g实施例1制备得到的中间体IV(2mmol)溶解在二氯甲烷中,将环丙基酰氯(2.2mmol)滴加到反应物中在室温下反应3小时。将反应液倒入分液漏斗中,依次加入蒸馏水与二氯甲烷各50ml,振摇后静置待其分层,取其有机相再用蒸馏水洗涤两次并用无水硫酸钠干燥,取有机相;所得有机相旋转蒸干得混合物经二氯甲烷复溶,加入100~200目硅胶1g充分混合,待溶剂挥发完后,将上述粗产物-硅胶粉混合物用柱层析进行纯化(100~200目硅胶粉为固定相,二氯甲烷:甲醇=60:1(V:V)为流动相),得到如式2所示结构的化合物1,如表1所示,R为化合物1的产率48.0%。
实施例3化合物2~24的制备
按照实施例2相同的方法(各反应物摩尔量、反应条件、纯化等均与实施例2相同),得到相应的式2所示产物,编号依次为2~24。其中,图1~6是化合物2、4、10、18和23的核磁图谱图。
上述化合物制备产率归纳如表2所示。
表2化合物编号及产率
效果实施例
(1)体外抑菌实验
实验采用的是肉汤稀释法。实验对照药物选用泰妙菌素。泰妙菌素为截短侧耳素类抗生素,是世界十大兽用抗生素之一。
实验中所用的菌株为耐甲氧西林金黄色葡萄球菌ATCC43300、金黄色葡萄球菌ATCC29213、临床金黄色葡萄球菌(Staphylococcus aureus)AD3、临床金黄色葡萄球菌(S.aureus)144。
目标化合物储备液配制:分别精密称取6.4mg目标化合物置于5mL容量瓶中,用0.25mLDMSO和0.25mL吐温80溶解,再加入4.5mL蒸馏水定容,充分摇匀,得到储备液(1280μg/mL),用0.22μm滤膜过除菌,小管分装,-20℃保存。对照药物泰妙菌素同样按照上述方法配制。
菌液的配制:取出在-20℃下保存完好的菌株接种在新MH平板上,37℃培养24h后挑取单菌落接种在MH培养基中再次培养24h;选取单菌落转移到无菌的生理盐水中并调整其浊度为0.6McF,此时菌液浓度为106CFU/mL。
MIC板制备:取无菌96孔板,第1孔加入180μLMH肉汤培养基,第2至12孔分别加入100μLMH肉汤培养基,往第1孔加入20μL浓度为1280μg/mL的目标化合物溶液,混匀后取100μL加入第2孔,混匀,再吸取100μL至第3孔,依次类推,第12孔吸取100μL弃去。此时各孔药物浓度依次为:128、64、32、16、8、4、2、1、0.5、0.25、0.125、0.06μg/mL,每个浓度药物做三组平行。
接种菌液:在1至12孔各加入100μL菌液,使每孔最终菌液浓度约为5×105CFU/mL,第1孔至第12孔药物浓度分别为64、32、16、8、4、2、1、0.5、0.25、0.125、0.06、0.03μg/mL。接种好的96孔板置于37℃培养箱进行培养,24h观察菌液生长情况。对照药物泰妙菌素同法测定以在小孔内完全抑制细菌生长的最低药物浓度为MIC,阳性对照孔(即不含药物)内细菌需明显生长。当在微量肉汤稀释法出现单一跳孔时,记录抑制细菌的最高药物浓度,如出现多处跳孔则需重复试验。
目标化合物的对测试菌种的MIC结果见表3。
表3目标化合物对四株耐药金黄色葡萄球菌的药敏结果
从表3中的数据可见,本发明大部分化合物对金黄色葡萄球菌表现出较好的抗菌活性,多数化合物对金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌抗菌活性接近或优于临床上广泛使用的泰妙菌素(tiamulin),其中化合物3和4的整体抗菌效果最好。
(2)体外支原体活性抑制实验
实验采用的是肉汤稀释法。实验对照药物选用泰妙菌素。泰妙菌素为截短侧耳素类抗生素,主要用于防止猪支原体肺炎等,对支原体的作用强于大环内酯。
实验中采用菌株为鸡毒支原体352,耐泰妙支原体352,鸡毒支原体M47。
目标化合物储备液配制:化合物用1mLDMSO溶解,再250mL容量瓶定容充分摇匀,得到储备液(5120μg/mL)。
将储备液以倍比稀释法稀释在培养皿中,每个培养皿含药液2m1,稀释至20ml,使化合物的终浓度分别为64,32,16,8,4,2,1,0.5,0.25,0.125,0.0625,0.0313,0.0152,0.00075,0.0004μg/mL。
每排放无菌的2mL EP管15个,将液体培养基在第一管中加入0.9mL,其余各管加入0.5mL,取配好的药液0.1mL加入第一管中充分混合后,取0.5mL加入第二管中,依次类推,最后吸出的0.5mL弃去,然后每管中加入稀释好的菌液0.5mL,盖好盖子,另作空白对照,37℃培养,观察支原体的生长情况
部分目标化合物的对鸡毒支原体的MIC结果表4。
表4体外抑菌数据
由上表可知,本发明大部分衍生物具有较好的鸡毒支原体抑制活性。
(3)细胞毒性实验
实验采用的是MTT法。
实验中所用的细胞株为小鼠单核巨噬细胞(RAW264.7)。
目标化合物储备液配制:分别精密称取8mg目标化合物,用1mLDMSO溶解,充分摇匀,得到储备液(8mg/mL),用0.22μm滤膜过除菌,-20℃保存。
MTT孵育及OD值测定:将生长状态良好的细胞收集,96孔板中加入100μL每孔约5×105个/mL密度的细胞进行种板。将96孔板放置5% CO2的恒温培养箱静置过夜。弃掉完全培养液,加入终浓度为4μg/mL的待测化合物(溶于DMSO配置4mg/mL母液),置于5% CO2的恒温培养箱中孵育24h。弃去上清,加入新鲜配置的0.5mg/mL浓度的MTT(溶于DMEM配置5mg/mL母液,-20℃分装保存)避光孵育4h。弃掉上清,加入150μL DMSO后置于室温下下振荡器70r/min振荡10min。酶标仪490nm处测定吸光度值,计算细胞存活率。实验进行三次独立重复。公式如下:
细胞存活率(%)=OD药物组/OD对照组×100%
图6为一部分化合物的毒性实验结果,可知目标化合物在8μg/mL下对选用细胞株不具有毒性,并且有一定的促生长作用,适合作为新型抗菌药物用于防治人或动物或耐药金葡或多药耐药菌引起的感染性疾病。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.一种具有噻唑侧链的截短侧耳素衍生物,其特征在于:所述衍生物为式2所示结构的化合物或其药学上可接受的盐:
其中,R环丙基、环丁基、环戊基、环己基、
2.根据权利要求1所述的具有噻唑侧链的截短侧耳素衍生物,其特征在于:
所述的药学上可接受的盐为式2化合物与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
3.根据权利要求2所述的具有噻唑侧链的截短侧耳素衍生物,其特征在于:所述的药学上可接受的盐具有如下结构式:
4.根据权利要求1~3任一项所述的具有噻唑侧链的截短侧耳素衍生物的制备方法,其特征在于包含如下步骤:
(1)将截短侧耳素与对甲基苯磺酰氯反应,得到如式3所示结构的中间体I;
(2)将步骤(1)制得的中间体I与碘化钠反应,得到如式4所示结构的中间体II;
(3)将氨基乙腈盐酸盐作为原料,与CS2进行反应,得到如式5所示结构的中间体III;
(4)将步骤(2)制得的中间体II与步骤(3)制得的中间体III反应,得到如式6所示结构的中间体IV;
(5)将步骤(4)制得的中间体IV和各种酰氯反应得到如式2所示结构的具有噻唑侧链的截短侧耳素衍生物。
5.根据权利要求4所述的制备方法,其特征在于:
所述的中间体Ⅰ、中间体Ⅱ、中间体Ⅲ和中间体Ⅳ分别具有式3~6结构式:
6.根据权利要求4所述的制备方法,其特征在于:
步骤(1)中所述的对甲苯磺酰氯与截短侧耳素摩尔比为1.1:1;
步骤(2)中所述的反应优选采用无水甲醇作为溶剂,中间体Ⅰ与碘化钠的摩尔比为1:1,反应条件为75℃反应2~3h;
步骤(3)中所述的氨基乙腈盐酸盐与CS2的摩尔比为1:1.1;
步骤(4)中所述的反应的具体操作为:在冰浴下向中间体III中加入中间体II,再加入甲醇钠,甲醇钠与中间体II的摩尔比为1:1;
步骤(5)中所述的反应的具体操作为:在常温条件下,在中间体IV中滴加酰氯,中间体IV和酰氯摩尔比为1:1.1,在反应溶液中滴入三乙胺作为催化剂,反应时间为2~4h。
7.根据权利要求1~3任一项所述的具有噻唑侧链的截短侧耳素衍生物在制备抗菌产品中的应用。
8.根据权利要求7所述的应用,其特征在于:所述的抗菌产品为治疗感染性疾病的药物。
9.根据权利要求7所述的应用,其特征在于:所述的感染性疾病为人或动物经耐药金黄色葡萄球菌或多药耐药菌感染引起的感染性疾病。
10.根据权利要求7所述的应用,其特征在于:所述的药物含有一种或多种药学上可接受的载体、赋形剂或稀释剂。
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