CN111606900A - 一种抗感染药物及其制备方法和应用 - Google Patents
一种抗感染药物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了一种抗感染药物,或其立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物、药学上可接受的盐或前药,在抗感染中的应用,该抗感染药物结构为式I所示:
Description
技术领域
本发明涉及一种抗感染药物及其制备方法和应用,属于医药技术领域。
背景技术
抗生素是目前人类治疗细菌感染性疾病的首选药物,但抗生素的过多使用以及滥用,使得细菌耐药问题日益严重。各类抗生素和抗菌药的耐药菌发展迅速,己严重威胁着感染性疾病患者的生命健康,探索新的抗耐药性革兰氏阳性菌的药物己成为国内外医药界的研究热点。噁唑烷酮类抗菌药是近30年来继磺胺类和氟喹诺酮类后开发的一类新型化学全合成抗菌药,能够通过抑制极早阶段的蛋白质合成而杀死革兰氏阳性病原体,具有抑制多重耐药性革兰氏阳性菌的功效。例如耐甲氧西林的金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus,MRSA)、表皮葡萄球菌(Methicillin-resistantStaphylococcus epidermidis,MRSE)、耐青霉素的肺炎链球菌(Penicillin-resistantStreptococcus pneumoniae,PRSP)及耐万古霉素的肠球菌(Vancomycin-resistantEnterococcu,VRE)等,这些耐药菌的出现严重降低了现有药物的疗效,导致患者治疗时间的显著延长和死亡率的提高。
噁唑烷酮类化合物是一类新型的治疗细菌性感染的药物,可抑制蛋白质合成的起始阶段并很少出现交叉耐药性,由于具有独特的作用机制而备受人们关注。第一个噁唑烷酮类抗菌剂利奈唑胺(Linezolid),已于2000年4月在美国批准上市,用于治疗感染多重耐药革兰氏阳性菌引起的疾病。利奈唑胺被证明是治疗革兰氏阳性菌引起的严重感染的一个重要的药物,目前广泛用于治疗由MRSA引起的医院获得性肺炎以及复杂的皮肤和软组织感染。
厌氧菌(anaerobic bacteria)是一类在无氧条件下生长,而不能在空气(含18%氧气)和/或10%二氧化碳浓度下的固体培养基表面生长的细菌。按其对氧的耐受程度的不同,可分为专性厌氧菌、微需氧厌氧菌和兼性厌氧菌。这类细菌缺乏完整的代谢酶体系,其能量代谢以无氧发酵的方式进行。厌氧菌主要包括:革兰氏阳性厌氧球菌(消化链球菌Peptostreptococcus、微单胞菌Finegoldia、厌氧球菌Anaerococcus、嗜胨菌Peptoniphilus、韦永氏球菌Veillonella等),革兰氏阴性厌氧球菌(韦荣球菌Veillonella),革兰氏阳性厌氧杆菌(丙酸杆菌Propionibacterium、乳酸杆菌lactobacillus、放线菌Actinomyces、真细菌Eubacterium、埃格特菌Eggerthella,阿托波菌Atopobium、双歧杆菌Bifidobactrium、动弯杆菌Mobiluncus等),及革兰氏阴性厌氧杆菌(拟杆菌Bacteroides、幽门螺杆菌Helicobactor、卟啉单胞菌Porphyromonas、普雷沃菌Prevotella、梭形杆菌Fusobacterium等)。
奥硝唑及左奥硝唑用于治疗由脆弱拟杆菌、狄氏拟杆菌、卵园拟杆菌、多形拟杆菌、普通拟杆菌、梭状芽胞杆菌、真杆菌、消化球菌和消化链球菌、幽门螺杆菌、黑色素拟杆菌、梭杆菌、CO2噬织维菌、牙龈类杆菌等敏感厌氧菌所引起的多种感染性疾病。对腹部感染、盆腔感染、口腔感染、脑部感染及治疗消化系统严重阿米巴虫病等疗效显著。
但也有越来越普遍的耐药菌产生和药物的毒副作用问题。所以临床上还需要更多更好的抗菌的药物。
发明内容
鉴于上述现有技术存在的缺陷,本发明的目的是提供一种抗感染药物及应用,该抗感染药物能够有效抗菌,安全性更高,进而能够治疗感染性疾病。
本发明的目的通过以下技术方案得以实现:
一种抗感染药物,该抗感染药物的结构通式为I所示:
Ⅰ
式I所示的结构,其中R 1代表哌嗪基、2-甲基哌嗪基、2,4-二甲基哌嗪基、(S,S)-2,8-二氮杂双环[4,3,0]壬烷基、(R,R)-2,8-二氮杂双环[4,3,0]壬烷基、2,8-二氮杂双环[4,3,0]壬烷基;
R3代表卤素、氢基;
式I所示的结构,其中包括如下化合物:
本发明还提供上述的抗感染药物的制备方法,如反应式Ⅱ所示。
式Ⅱ
在反应式Ⅱ中,R1、R3、R4和R5如式I中所定义。R6为环氧丙基、乙醇基。
根据本发明,抗感染药物的制备方法包括:用左奥硝唑环合物或奥硝唑环合物(A)与噁唑烷酮衍生物(B)反应生成噁唑烷酮-硝唑咪唑类化合物(C) (步骤1);
使噁唑烷酮-硝基咪唑类化合物(C)与三氯氧磷反应再经过水解成盐以形成具有抗感染药物 (D)(步骤2);
本发明还提供上述的抗感染药物,或其立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物、药学上可接受的盐或前药,在制备治疗厌氧菌感染引起的疾病的药物的应用。
本发明还提供一种抗感染药物组合物,其联用组分包括上述的抗感染药物(即式I结构的化合物),或其立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物、药学上可接受的盐或前药。
上述具有羟基的抗感染药物与磷酸酯反应形成抗感染药物前体药物。这种前体药物比未形成前体药物的化合物具有更优异的溶解性;前体药物的溶解性大于100mg/ml,前体药物在水溶液中稳定,并通过血液中的酯酶和磷酸酯酶转化成活性成分,由此开发用于注射或口服的制剂。
本发明的组合物可以包括至少一种具有类似于抗感染药物功能的有效成分。
至于配制药物组合物,至少一种式Ⅰ的化合物可以与至少一种药物可接受载体混合。药物可接受载体可以包括生理盐水、无菌水、林格氏溶液(Ringer's solution)、生理盐水缓冲溶液、葡萄糖溶液、麦芽糖糊精溶液、甘油、乙醇等。根据用户需要,药物组合物可以含有常规赋形剂,如抗氧剂、缓冲、清污剂(soil cleaner)等。组合物也与稀释剂、崩解剂(diaintegrant)、表面活性剂、粘合剂、润滑剂、水溶液、悬浮液等混合,形成注射剂、粉剂、胶囊、颗粒、片剂等。优选情况下,根据疾病或组分,制剂通过使用Remington'sPharmaceutical Science(最新版)(Mack Publishing Company,Easton PA等)所述的方法制备。
本发明的化合物可以口服或肠道外给药,例如静脉、皮下、腹内、局部给药等。化合物的剂量可以随使用的具体化合物、给药方式、所要治疗的病症的症状和严重性、以及与治疗个体相关的各种身体因素而变化。当本发明的化合物在需要时以每千克体重约10-25毫克、优选13-20毫克的日剂量对个体给药时,根据本发明的用法可以获得满意的结果。更优选上述日剂量分成每天几次给药。
在急性毒性测试中,抗感染药物的半致死剂量(LD50)显示大于lg/kg,因此发现该抗感染药物是安全的。
本发明的抗感染药物显示对广谱菌具有抑制活性和低毒性。通过具有羟基的化合物与磷酸酯反应制待的前体药物具有高水溶性。
进一步地,本发明的衍生物可以显示对包括革兰氏阳性菌如葡萄球菌、肠道球菌和链球菌,厌氧微生物如类菌体和梭菌体以及耐酸微生物如结核分支菌、鸟分支菌在内的人和动物病原体的有力抗菌活性。
因此,将含有该抗感染药物的组合物用于抗生素中。
具体实施方式
上述的抗厌氧菌的药物联用组合物可以包括式I所示的抗感染药物,式I所示的抗感染药物结构的立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物和药学上可接受的盐或前药中的至少一种与本领域己知的抗菌药物的联用。
本发明还提供上述的药物组合物在制备治疗人体厌氧菌感染引起的疾病的药物中的应用。
本发明的突出效果为:
本发明的抗感染药物,或其立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物、药学上可接受的盐或前药,能够有效抗厌氧菌,进而治疗厌氧菌感染性疾病。
具体实施方式
为了对本发明的技术特征、目的和有益效果有更加清楚的理解,现对本发明的技术方案进行以下详细说明,但不能理解为对本发明的可实施范围的限定。下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
实施例1:2-甲基-5-硝基-1-(((S)-环氧乙烷-2-基)甲基)1H-咪唑的制备
称取左奥硝唑100g加入500ml二氯甲烷中搅拌溶解,降温至-10~-15℃;称取氢氧化钠36.5g加入500ml水搅拌溶解放冷,慢慢滴加到二氯甲烷中,控制温度不得过-10℃,加毕后0~5℃保温反应2小时,分出二氯甲烷层,水层用100ml二氯甲烷萃取,合并二氯甲烷层,二氯甲烷层加入100ml水洗涤2次,加入适量无水硫酸钠干燥,过滤,滤液减压浓缩,得棕色油状物75.7g。
实施例2:2-甲基-5-硝基-1-(((R)-环氧乙烷-2-基)甲基)1H-咪唑的制备
称取右奥硝唑100g加入500ml二氯甲烷中搅拌溶解,降温至-10~-15℃;称取氢氧化钠36.5g加入500ml水搅拌溶解放冷,慢慢滴加到二氯甲烷中,控制温度不得过-10℃,加毕后0~5℃保温反应2小时,分出二氯甲烷层,水层用100ml二氯甲烷萃取,合并二氯甲烷层,二氯甲烷层加入100ml水洗涤2次,加入适量无水硫酸钠干燥,过滤,滤液减压浓缩,得棕色油状物72.5g。
实施例3:2-甲基-5-硝基-1-((环氧乙烷-2-基)甲基)1H-咪唑的制备
称取奥硝唑100g加入500ml二氯甲烷中搅拌溶解,降温至-10~-15℃;称取氢氧化钠36.5g加入500ml水搅拌溶解放冷,慢慢滴加到二氯甲烷中,控制温度不得过-10℃,加毕后0~5℃保温反应2小时,分出二氯甲烷层,水层用100ml二氯甲烷萃取,合并二氯甲烷层,二氯甲烷层加入100ml水洗涤2次,加入适量无水硫酸钠干燥,过滤,滤液减压浓缩,得棕色油状物76.3g。
实施例4:化合物1制备
取利奈唑胺衍生物1 10g无水乙醇50ml加入反应瓶中搅拌溶液,升温至60℃慢慢加入2-甲基-5-硝基-1-(((S)-环氧乙烷-2-基)甲基)1H-咪唑2g,加毕后保温反应6~8小时,降温至室温,有大量固体析出,搅拌析晶2小时,过滤,滤饼用适量无水乙醇洗涤,干燥,得化合物1固体10.1g。
实施例5:化合物2制备
取利奈唑胺衍生物1 10g无水乙醇50ml加入反应瓶中搅拌溶液,升温至60℃慢慢加入氘代奥硝唑2g,加毕后保温反应6~8小时,降温至室温,有大量固体析出,搅拌析晶2小时,过滤,滤饼用适量无水乙醇洗涤,干燥,得化合物2固体9.8g。
实施例6:化合物3制备
取利奈唑胺衍生物2 10g、无水乙醇50ml加入反应瓶中搅拌溶液,升温至60℃慢慢加入2-甲基-5-硝基-1-((环氧乙烷-2-基)甲基)1H-咪唑2g,加毕后保温反应6~8小时,降温至室温,有大量固体析出,搅拌析晶2小时,过滤,滤饼用适量无水乙醇洗涤,干燥,得化合物3固体10.8g。
实施例7:化合物8制备
取利奈唑胺衍生物3 10g、无水乙醇50ml加入反应瓶中搅拌溶液,升温至60℃慢慢加入2-甲基-5-硝基-1-(((S)-环氧乙烷-2-基)甲基)1H-咪唑2.8g,加毕后保温反应6~8小时,降温至室温,有大量固体析出,搅拌析晶2小时,过滤,滤饼用适量无水乙醇洗涤,干燥,得化合物8固体11.2g。
实施例8:化合物11制备
取化合物1 20g、二氯甲烷100ml加入反应瓶中搅拌溶解,降温至0℃慢慢加入三氯氧磷4.2g,保温反应6~8小时,反应结束后慢慢加入5ml水进行水解,水解完成后,用盐酸调节pH至4.0,有大量固体析出,搅拌析晶2小时,过滤,滤饼用适量丙酮洗涤,干燥,得化合物11 固体9.9g。
实施例9:化合物13制备
取利奈唑胺衍生物3 10g、无水乙醇50ml加入反应瓶中搅拌溶液,升温至60℃慢慢加入2-三氟甲基-5-硝基-1-(((S)-环氧乙烷-2-基)甲基)1H-咪唑2.8g,加毕后保温反应6~8小时,降温至室温,有大量固体析出,搅拌析晶2小时,过滤,滤饼用适量无水乙醇洗涤,干燥,得化合物13固体10.5g。
实施例10:化合物15制备
同化合物11制备方法,将化合物1换为化合物8,得化合物15。
实验实施例l
本实施例中,分别对化合物1-18和对比化合物1、对比化合物2的体外抗菌活性测试,以说明其一般的抗菌的能力。
本实施例先使用对8株标准菌株的体外抗菌活性测试,冻存于-80℃低温冰箱,使用需要提前2天复苏。用无菌接种环刮取少许冻存的细菌在合适的固体培养基平皿上划线接种,放入合适的气体培养环境中35±2℃培养20-48小时。标准菌株的分类编号如表l所示。作为对比,选用了如下化合物:利奈唑胺、左奥硝唑和盐酸莫西沙星。化合物溶于DMSO中,在测试当天配成40倍浓度的储存液。
表l
细菌种属 | 革兰氏染色分类 | 菌株编号 |
金黄色葡萄球菌 | G+ | ATCC29213 |
粪肠球菌 | G+ | ATCC700221 |
艰难梭菌 | G+ | ATCC43255 |
产气荚膜梭菌 | G+ | ATCC13124 |
铜绿假单胞菌 | G- | ATCC27853 |
大肠杆菌 | G- | ATCC25922 |
肺炎克雷伯杆菌 | G- | ATCC43816 |
鲍曼不动杆菌 | G- | ATCC19606 |
本实施例中的培养基包括如下:胰酶大豆琼脂(Trypticase soy agar,TSA)(BDBBL211043)、TSA+5%绵羊血(TSA II)、离子校正的马一欣二氏肉汤(Cation-adjustedMueller Hinton broth,CAMHB) (BD BBL 212322)、布鲁氏肉汤(Brucellabroth,BB) (BDBBL 211088)、布鲁氏琼脂(Brucella agar,BA) (BD BBL 211086)、绵羊血(Quad Five 630-500)。
本实施例的体外抗菌活性测试测定化合物的最低抑菌浓度(MinimumInhibitoryConcentration,MIC)。方法如下:
按美国临床和实验室标准研究所(Clinical and Laboratory Standards
Institute,CLSI)推荐的标准方法进行。化合物l-18、对比化合物1、对比化合物2、利奈唑胺和左奥硝唑最高测试浓度为64ug/ml,2倍倍比稀释。盐酸莫西沙星最高测试浓度16ug/ml,2倍倍比稀释。
加入98ul相应的细菌接种物至试验板中(无菌对照孔除外)。对于艰难梭菌ATCC43255,先加入98ul的50℃的预配制布鲁氏琼脂(含有5ug/ml的氯化血红素和lOug/ml的维生素K1)至试验板中,混合均匀待其冷却凝固后,再加入5ul的艰难梭菌ATCC 43255细菌接种物在琼脂表面。体系加完后用无菌盖盖住试验板,放入离心机800rpm离心30秒,再在振板机上400rpm振1分钟混匀后放入普通培养箱或厌氧罐(艰难梭菌ATCC 43255和产气荚膜梭菌ATCC13124)中35±2℃培养20小时。通过肉眼观察记录不同稀释度细菌接种物在TSA平皿的菌落数。
测试结果下表2所示:
化合物 | 金黄色葡萄球菌 | 粪肠球菌 | 艰难梭菌 | 产气荚膜梭菌 | 铜绿假单胞菌 | 大肠杆菌 | 肺炎克雷伯杆菌 | 鲍曼不动杆菌 |
化合物1 | 8 | 4 | <0.063 | <0.063 | 16 | 8 | 6 | 16 |
化合物2 | 4 | 4 | 0.125 | 0.125 | 32 | 32 | 32 | 16 |
化合物3 | 8 | 8 | <0.063 | <0.063 | 16 | 32 | 32 | 32 |
化合物4 | 8 | 4 | <0.063 | 0.125 | 16 | 8 | 32 | 32 |
化合物5 | 8 | 8 | <0.063 | <0.063 | 16 | 8 | 16 | 16 |
化合物6 | 4 | 2 | <0.063 | 0.125 | 16 | 8 | 32 | 32 |
化合物7 | 4 | 2 | <0.063 | 0.125 | 16 | 8 | 32 | 32 |
化合物8 | 8 | 8 | 0.125 | <0.063 | 16 | 32 | 32 | 32 |
化合物9 | 8 | 4 | 0.125 | 0.125 | 32 | 16 | 16 | 32 |
化合物10 | 8 | 4 | <0.063 | <0.063 | 32 | 32 | 32 | 16 |
化合物11 | 8 | 4 | <0.063 | <0.063 | 16 | 8 | 6 | 16 |
化合物12 | 8 | 8 | 0.125 | <0.063 | 16 | 32 | 32 | 32 |
化合物13 | 8 | 4 | 0.125 | 0.125 | 32 | 32 | 32 | 32 |
化合物14 | 4 | 8 | 0.125 | 0.063 | 16 | 32 | 16 | 32 |
化合物15 | 8 | 8 | 0.125 | <0.063 | 16 | 32 | 32 | 32 |
化合物16 | 8 | 4 | 0.125 | 0.125 | 32 | 32 | 32 | 32 |
化合物17 | 4 | 2 | <0.063 | <0.063 | 32 | 32 | 16 | 32 |
化合物18 | 4 | 2 | <0.063 | <0.063 | 32 | 32 | 16 | 16 |
利奈唑胺 | 4 | 4 | 4 | 2 | 32 | 32 | 16 | 32 |
左奥硝唑 | 32 | 32 | 0.25 | 0.25 | 32 | 32 | 16 | 32 |
盐酸莫西沙星 | 0.25 | 8 | 4 | 0.125 | 0.063 | 0.125 | 0.125 | 0.125 |
对比化合物1 | 32 | 32 | 0.125 | 0.25 | >64 | >64 | >64 | >64 |
对比化合物2 | 16 | 8 | <0.063 | <0.063 | >64 | >64 | >64 | >64 |
结果表明,化合物l-18对革兰氏阴性细菌克雷伯杆菌ATCC 43816、鲍曼不动杆菌ATCC19606、铜绿假单胞菌ATCC 27853和大肠杆菌ATCC 25922的均有抑菌效果(MIC小于32ug/mL);对革兰氏阳性细菌而言,厌氧艰难梭菌ATCC 43255对17个测试化合物最敏感,MIC值在<0.063-0.125ug/mL之间;厌氧产气荚膜梭菌ATCC 13124相对敏感,其MIC值在<0.063-0.25ug/mL 之间;对粪肠球菌ATCC 700221表现出轻微抑制作用,MIC值在2-8ug/mL左右;化合物1-18对金黄色葡萄球菌ATCC 29213抑菌能力相近,MIC值为4-8ug/mL。对比化合物1和2对革兰氏阳性细菌有一定的抑菌作用,但没有本发明的化合物抑菌效果显著。
实验实施例2:本发明化合物对小鼠静脉给药的急性毒性测试
为测试本发明化合物和对比化合物的急性毒性,进行下述实验。
化合物1-18溶解到水中,对5只ICR小鼠给药(5周大,雄性,体重20克±2克的小鼠)。静脉给药以确定半数致死量(LD50,mg/ml)。使用利奈唑胺、左奥硝唑、奥硝唑作为对照。结果如表3所示。
表3
化合物 | 半数致死量(LD<sub>50</sub>,mg/kg) |
利奈唑胺 | 500 |
左奥硝唑 | 520 |
奥硝唑 | 550 |
化合物1 | >1000 |
化合物2 | >1000 |
化合物3 | >1000 |
化合物4 | >1000 |
化合物5 | >1000 |
化合物6 | >1000 |
化合物7 | >1000 |
化合物8 | >1000 |
化合物9 | >1000 |
化合物10 | >1000 |
化合物11 | >1000 |
化合物12 | >1000 |
化合物13 | >1000 |
化合物14 | >1000 |
化合物15 | >1000 |
化合物16 | >1000 |
化合物17 | >1000 |
化合物18 | >1000 |
对比化合物1 | 450 |
对比化合物2 | 450 |
根据表3,本发明的化合物的毒性小于对照药物,表明本发明化合物具有优异的低毒性,安全性更高。
实施例配方:药物组合物的制备
l、粉剂的制备
抗感染药物 2克
乳糖 l克
将上述物料混合,然后将混合物填充到密封包装中,以制备粉剂。
2、片剂的制备
抗感染药物 500毫克
玉米淀粉 100毫克
乳糖 1 00毫克
硬脂酸镁 2毫克
将上述物料混合,然后将混合物用己知方法压片制成片剂。
3、胶囊的制备
抗感染药物 500毫克
玉米淀粉 100毫克
乳糖 100毫克
硬脂酸镁 2毫克
将上述物料混合并通过己知方法将混合物填充到明胶胶囊中制成胶囊。
4、注射剂的制备
抗感染药物 20克
pH调节剂 保持pH为4.0-9.0
葡萄糖 赋形剂
水 溶剂
将抗感染药物、葡糖糖加水溶解,用pH调节剂调节pH至4.0-9.0置冷冻干燥箱冷冻干燥,干燥完加塞,轧盖。
Claims (6)
2.根据权利要求l所述的抗感染药物,其特征在于:抗感染药物包括其立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物、药学上可接受的盐或前药。
5.一种抗感染药物组合物,其特征在于:组分包括权利要求l所述的抗感染药物,或其立体异构体、水合物、氘代物、酯、溶剂化物、晶型、代谢产物,药学上可接受的盐或前药。
6.权利要求5所述的药物组合物在制备治疗人体感染引起的疾病的药物中的应用。
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