CN115466246B - 吡咯酰哌啶胺类化合物及其用途 - Google Patents
吡咯酰哌啶胺类化合物及其用途 Download PDFInfo
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- CN115466246B CN115466246B CN202110656714.8A CN202110656714A CN115466246B CN 115466246 B CN115466246 B CN 115466246B CN 202110656714 A CN202110656714 A CN 202110656714A CN 115466246 B CN115466246 B CN 115466246B
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- -1 Pyrrole amide piperidine amine compound Chemical class 0.000 title claims abstract description 53
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- 241000204031 Mycoplasma Species 0.000 claims description 7
- 241000193163 Clostridioides difficile Species 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
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- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Abstract
本发明属于抗菌药物技术领域,公开了吡咯酰哌啶胺类化合物及其用途。具体涉及吡咯酰哌啶胺类化合物与其药学上可接受的盐及其在制备抗菌、抗支原体或者抗衣原体感染药物中的用途。所述化合物具有如下通式所示的结构:
Description
技术领域
本发明属于抗菌药物技术领域,具体涉及吡咯酰哌啶胺类化合物与其药学上可接受的盐及其作为抗菌、支原体或者衣原体感染药物的用途。
背景技术
细菌感染是致病菌或条件致病菌侵入体内生长繁殖,产生毒素和其他代谢产物所引起的感染。细菌感染是危害人类健康的主要因素之一,而近年来不断出现的细菌耐药性使得全球公共卫生面临的挑战更为严峻。目前超级耐药细菌“ESCAPE”包括:屎肠球菌(Enterococcus faecium),金黄色葡萄球菌(Staphylococcus aureus),艰难梭菌(Clostridium difficile),鲍曼不动杆菌(Acinetobacter baumannii),绿脓杆菌(Pseudomonas aeruginosa)和肠杆菌(Enterobacteriaceae)已对人类的健康造成了严重的威胁。而随着抗生素滥用以及细菌本身的进化,临床上针对这些超级细菌已逐渐面临无药可用的境地。因此,研究和开发新作用机制的抗菌药物已迫在眉睫。
DNA回旋酶Gyr B亚基和拓扑异构酶IV Par E亚基的Gyr B/Par E双靶点抑制剂在抗菌药物研发方面具有如下的优势:(1)可同时抑制细菌的两个靶点,耐药的风险比较低;(2)具有杀菌机理;(3)Gyr B/Par E抑制剂新生霉素的抗菌作用经过历史临床验证。因此针对此靶点开发抗菌药物具有一定的可行性。但此类Gyr B/Par E抑制剂作为抗菌药物的研发也存在一定的问题:1、多数化合物抑制酶活性较好,但无体外抗菌活性;2、多数化合物未显示出体内抗菌活性,或者药代动力学性质较差;3、绝大多数化合物只能抑制革兰氏阳性菌的生长,但对革兰氏阴性菌没有作用或者作用比较差。正是因为上述原因,除了新生霉素外(上市后被撤市),目前还没有Gyr B/Par E双靶点抑制剂药物成功上市。而对目前在研的Gyr B/Par E抑制剂进行结构优化或者开发新结构类型的Gyr B/Par E抑制剂,有望提高这个靶点的成药潜力。
DS2969为日本第一三共制药研发的Gyr B/Par E双靶点抑制剂,具有较好的抗菌活性和成药性,目前正处于临床一期研究,主要用于治疗艰难梭菌引起的感染(WO2017056012)。但是,其还存在一定的不足,比如体外抗阳性菌活性还需进一步提高(金黄色葡萄球菌ATCC 29213,MIC=0.2ug/mL),而且其对革兰氏阴性菌活性比较弱(大肠杆菌ATCC25922,MIC=32ug/mL)。除此之外,阿斯利康研发的AZD5099(J.Med.Chem.57,6060-6082)也曾进入临床研究,但其体内暴露量变异系数较高,同时存在线粒体损伤风险,而且对革兰氏阴性菌的活性也比较弱(大肠杆菌ATCC25922,MIC=32ug/mL)。
发明内容
本发明的目的是为了克服现有技术中Gyr B/Par E抑制剂的缺点,提供一类具有更强抗菌、抗支原体或者抗衣原体活性,同时成药性更好的广谱吡咯酰哌啶胺类化合物及其药学上可接受的盐以及其作为抗菌/抗支原体/抗衣原体感染药物的用途。
本发明提供如下技术方案:
本发明第一方面提供了一种吡咯酰哌啶胺类化合物及其药学上可接受的盐或立体异构体,具有通式I所示结构,
其中,R1、R5、R6各自独立地选自H、卤素、羟基、氨基、硝基、氰基、羧基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、二(C1-6烷基)氨基、羟基C1-6烷基、氨基C1-6烷基、卤代C1-6烷基或卤代C1-6烷氧基;
R2选自H、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、C1-6烷基氨基、二(C1-6烷基)氨基、氨基C1-6烷氧基、氨基C1-6环烷氧基;
R3和R4分别独立地选自H、C1-6烷基、卤代C1-6烷基;或者R3和R4连同它们连接的碳原子一起组成C3-8环烷基或C3-8杂环烷基;
A选自任选被1-4个Q1取代的苯基或5-8元杂芳基;
Q1选自H、卤素、羟基、氨基、硝基、氰基、羧基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二(C1-6烷基)氨基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基或卤代C1-6烷硫基。
进一步地,所述吡咯酰哌啶胺类化合物及其药学上可接受的盐或立体异构体,具有通式IA所示结构,
其中,R1、R5、R6各自独立地选自H、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基;
R2选自H、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、C1-6烷基氨基、二(C1-6烷基)氨基、氨基C1-6烷氧基、氨基C1-6环烷氧基;
R3和R4分别独立地选自H、C1-6烷基、卤代C1-6烷基;或者R3和R4连同它们连接的碳原子一起组成C3-6环烷基或C3-6杂环烷基;
A选自任选被1-3个Q1取代的5-6元杂芳基;
Q1选自H、卤素、羟基、氨基、硝基、氰基、羧基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二(C1-6烷基)氨基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基或卤代C1-6烷硫基。
更进一步地,A选自噻唑、呋喃、噻吩、吡唑、咪唑、噁唑、噻二唑、吡啶、吡嗪、嘧啶或哒嗪;
再进一步地,R1、R5、R6各自独立地选自H、氟、氯、溴、羟基、氨基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、三氟乙基、三氟丙基、三氟甲氧基或三氟乙氧基;
R2选自H、氟、氯、溴、羟基、氨基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、三氟甲基、三氟乙基、三氟丙基、三氟甲氧基、三氟乙氧基、三氟甲硫基或三氟乙硫基、甲基氨基、二甲基氨基、氨基乙氧基、氨基丙氧基、氨基环戊烷氧基;
R3和R4分别独立地选自H、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、三氟甲基、三氟乙基或三氟丙基;
或者,R3和R4连同它们连接的碳原子一起组成环丙基、环丁基、环戊基、环己基、环庚基、环辛基、氧杂环丙基、氧杂环丁基、氮杂环丙基、氮杂环丁基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、四氢呋喃基、四氢吡咯烷基、四氢吡唑烷基、四氢咪唑烷基、四氢噻吩基、四氢噻唑烷基、四氢吡喃基、四氢噻喃基、哌啶基、六氢吡啶基、哌嗪基或吗啉基;
A选自呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或1,2,4,5-四嗪基。
优选地,所述化合物具有通式IAa所示结构,
其中,R2选自H、氟、氯、溴、羟基、氨基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、三氟甲基、三氟乙基、三氟丙基、三氟甲氧基、三氟乙氧基、三氟甲硫基或三氟乙硫基、甲基氨基、二甲基氨基、氨基乙氧基、氨基丙氧基、氨基环戊烷氧基;
R3和R4分别独立地选自H、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、三氟甲基、三氟乙基或三氟丙基;
或者,R3和R4连同它们连接的碳原子一起组成环丙基、环丁基、环戊基、环己基;
A选自呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,3,4-噁二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基或1,2,4,5-四嗪基。
最优选地,所述化合物具有如下结构:
本发明的第二方面提供了一种药物组合物,所述的药物组合物包含第一方面所述的吡咯酰哌啶胺类化合物及其药学上可接受的盐以及药学上可接受的载体或赋形剂,进一步的所述的药物组合物还包含一种或多种其他活性组分。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助溶剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明化合物的每天的合适剂量范围为0.1-50mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及选自运用其它治疗手段的给药方案。本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明的第三方面提供了所述的吡咯酰哌啶胺类化合物及其药学上可接受的盐、立体异构体、药物制剂和药物组合物在制备抗菌、抗支原体或者抗衣原体药物中的应用。所述的敏感或耐药革兰氏阳性菌选自枯草芽孢杆菌、金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌、艰难梭菌、链球菌、肺炎双球菌、炭疽杆菌、白喉杆菌、破伤风杆菌,所述的敏感或耐药革兰氏阴性菌选自大肠杆菌、鲍曼不动杆菌、铜绿假单胞菌、肺炎克雷伯菌、痢疾杆菌、伤寒杆菌、变形杆菌、霍乱弧菌、奈瑟氏菌、志贺菌属、肺炎杆菌、布氏杆菌、百日咳杆菌、流感杆菌,所述的分支杆菌选自结核分枝杆菌、牛分枝杆菌、麻风分枝杆菌,所述的支原体选自肺炎支原体、溶脲脲原体、人型支原体、生殖器支原体,所述的衣原体选自肺炎衣原体、鹦鹉热衣原体、沙眼衣原体和牛衣原体。
本发明的第四方面提供制备第一方面所述吡咯酰哌啶胺类化合物及其药学上可接受的盐、立体异构体的方法。使用吡咯酸a作为起始原料,首先和叔丁氧羰酰基保护的4-氨基哌啶(b)缩合,然后脱除保护基得到中间体d。中间体再与溴代杂环(e)进行偶连得到中间体f,最后通过格式反应等转化得到目标产物。对于立体异构体的合成,可采用手性的化合物b片段进行制备。
术语:
本发明中,术语“烷基”是指具有指定数目碳原子数的由碳氢原子组成的基团,其可以为直链或支链的烷基,“氨基烷基”是指被氨基取代的烷基,“卤代烷基”是指被卤素取代的烷基。“烷氧基”是指烷基和氧原子相连组成的基团。“烷基氨基”是指烷基和氮原子相连组成的基团,“二烷基氨基”指两个烷基分别与氮原子相连组成的基团。“烷硫基”是指烷基和硫原子相连组成的基团。
有益技术效果:本发明提供了一种吡咯酰哌啶胺类化合物,其对革兰氏阳性菌和阴性菌、分枝杆菌、支原体和衣原体都具有很好的抑制作用。相比DS2969,化合物对革兰氏阳性菌、阴性菌、分枝杆菌、支原体和衣原体的抑制活性均有明显提升,对金黄色葡萄球菌活性、表皮球菌和大肠杆菌提高了10倍以上,对铜绿假单胞菌活性提高了至少8倍以上,对鲍曼不动杆菌和肺炎克雷伯菌活性提高了至少4倍以上。
附图说明
图1小鼠体内药效生存曲线
图2小鼠灌胃给药药时曲线
图3小鼠急性毒性试验生存曲线
具体实施方式
通过下面的实施例可以对本发明进行进一步的描述,然而,本发明的范围并不限于下述实施例。本领域的专业人员能够理解,在不背离本发明的精神和范围的前提下,可以对本发明进行各种变化和修饰。
实施例1:3,4-二氯-N-{(3S,4R)-1-[6-(2-羟基丙烷-2-基)哒嗪-3-基]-3-甲氧基哌啶-4-基}-5-甲基-1H-吡咯-2-羧酰胺的合成
3,4-二氯-5-甲基-1H-吡咯-2-羧酸(1g,5.2mmol)溶于约6ml DMSO,加入HATU(3g,7.7mmol)和DIPEA(1.3ml,7.7mmol),室温搅拌30min,加入(3S,4R)-4-氨基-3-甲氧基哌啶-1-羧酸叔丁酯(1.4g,6.2mmol),室温搅拌。液质监测,待反应完全后,向反应液中加入适量水,有沉淀析出,过滤,用0.1M HCl溶液、饱和NaHCO3溶液依次洗涤滤饼,得到化合物(3S,4R)-4-(3,4-二氯-5-甲基-1H-吡咯-2-羧酰胺基)-3-甲氧基哌啶-1-甲酸叔丁酯,为白色固体(产率85%)。
化合物(3S,4R)-4-(3,4-二氯-5-甲基-1H-吡咯-2-羧酰胺基)-3-甲氧基哌啶-1-甲酸叔丁酯(1g,2.5mmol)溶于1,4-二氧六环(12ml),加入6ml 4MHCl/1,4-Dioxane溶液,50℃搅拌,液质监测,待反应完全后,减压蒸出反应溶剂,得到化合物3,4-二氯-N-((3S,4R)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺,直接用于下一步。
化合物3,4-二氯-N-((3S,4R)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺(800mg,2.7mmol)溶于DMF(8ml),加入化合物6-溴哒嗪-3-羧酸甲酯(700mg,3.2mmol)和DIPEA(1.1ml,6.8mmol),60℃搅拌。液质监测,待反应完全后,向反应液中加入适量水,有沉淀析出,过滤,干燥,得到化合物6-((3S,4R)-4-(3,4-二氯-5-甲基-1H-吡咯-2-羧酰胺基)-3-甲氧基哌啶-1-基)哒嗪-3-羧酸甲酯,为浅棕色固体(产率71%)。
化合物6-((3S,4R)-4-(3,4-二氯-5-甲基-1H-吡咯-2-羧酰胺基)-3-甲氧基哌啶-1-基)哒嗪-3-羧酸甲酯(400mg,0.91mmol)溶于超干四氢呋喃(5ml),氮气保护,于-5℃下逐滴加入CH3BrMg(3M)乙醚溶液(1.7ml,4.6mmol),滴加完毕后,放置室温搅拌。待反应完全后,用饱和氯化铵溶液淬灭,反应液用乙酸乙酯萃取三次,合并EA层,饱和食盐水洗涤,无水硫酸钠干燥,减压蒸干,柱层析(二氯甲烷:甲醇=20:1),得到化合物3,4-二氯-N-{(3S,4R)-1-[6-(2-羟基丙烷-2-基)哒嗪-3-基]-3-甲氧基哌啶-4-基}-5-甲基-1H-吡咯-2-羧酰胺,为白色固体(产率46%)。
ESI-MS(m/z):442.13[M+H]+.1H NMR(500MHz,Chloroform-d)δ9.58(s,1H),7.36(d,J=9.6Hz,1H),6.99(d,J=9.6Hz,1H),4.91(dd,J=15.0,2.8Hz,1H),4.35(dq,J=6.4,3.1Hz,2H),4.20(d,J=13.6Hz,1H),3.60–3.54(m,1H),3.44(s,3H),3.18–3.08(m,2H),2.28(s,3H),2.00–1.90(m,2H),1.57(s,6H).
实施例2:3,4-二氯-N-((3S,4R)-1-(5-(2-羟基丙烷-2-基)-1,3,4-噻二唑-2-基)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺
按照实施例1类似的方法,化合物3,4-二氯-N-((3S,4R)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺(实施例1)与5-溴-噻二唑-2甲酸酯反应,然后再与CH3BrMg进行格式反应,纯化后得到目标产物,收率70%。
ESI-MS(m/z):448.36[M+H]+.1H NMR(400MHz,Chloroform-d)δ9.87(s,1H),4.43(ddd,J=14.5,3.2,2.1Hz,1H),4.36–4.23(m,1H),3.83(d,J=13.5Hz,1H),3.52(q,J=3.2Hz,1H),3.47(s,3H),3.29(ddd,J=13.4,12.1,3.1Hz,1H),3.19(dd,J=14.4,1.7Hz,1H),2.88(s,1H),2.28(s,3H),2.12–1.96(m,1H),1.94–1.83(m,1H),1.67(s,6H).
实施例3:3,4-二氯-N-((3S,4R)-1-(5-(2-羟基丙烷-2-基)嘧啶-2-基)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺
按照实施例1类似的方法,化合物3,4-二氯-N-((3S,4R)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺(实施例1)与2-溴-嘧啶-2甲酸酯反应,然后再与CH3BrMg进行格式反应,纯化后得到目标产物,收率62%。
ESI-MS(m/z):442.34[M+H]+.1H NMR(500MHz,Chloroform-d)δ9.92(s,1H),8.43(s,2H),7.28(d,J=8.2Hz,1H),5.16(d,J=14.8Hz,1H),4.77(d,J=14.9Hz,1H),4.32(d,J=8.2Hz,1H),3.48(s,1H),3.43(s,3H),3.01(d,J=13.9Hz,2H),2.28(s,3H),1.86(d,J=9.5Hz,2H),1.57(s,6H).
实施例4:3,4-二氯-N-((3S,4R)-1-(5-(2-羟基丙烷-2-基)吡嗪-2-基)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺
按照实施例1类似的方法,化合物3,4-二氯-N-((3S,4R)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺(实施例1)与5-溴-吡嗪-2甲酸酯反应,然后再与CH3BrMg进行格式反应,纯化后得到目标产物,收率65%。
ESI-MS(m/z):442.34[M+H]+.1H NMR(500MHz,Chloroform-d)δ9.57(s,1H),8.20(s,1H),8.06(s,1H),4.83–4.69(m,1H),4.33(s,1H),4.22(d,J=13.5Hz,1H),3.57–3.48(m,1H),3.43(s,3H),3.09(d,J=10.3Hz,1H),3.03(d,J=15.4Hz,1H),2.28(s,3H),1.93(d,J=13.0Hz,2H).
实施例5:3,4-二氯-N-((3S,4R)-1-(5-(2-羟基丙烷-2-基)噁唑-2-基)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺
按照实施例1类似的方法,化合物3,4-二氯-N-((3S,4R)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺(实施例1)与2-溴-噁唑-5-甲酸酯反应,然后再与CH3BrMg进行格式反应,纯化后得到目标产物,收率52%。
ESI-MS(m/z):431.31[M+H]+.1H NMR(400MHz,Chloroform-d)δ9.35(s,1H),7.22(d,J=8.7Hz,1H),6.99(s,1H),4.41(d,J=14.3Hz,1H),4.32–4.20(m,1H),4.10(d,J=13.1Hz,1H),3.45(s,4H),3.14–2.98(m,2H),2.28(s,3H),1.94(qd,J=12.3,11.7,4.5Hz,1H),1.82(dd,J=13.0,4.5Hz,1H),1.50(s,6H).
实施例6:3,4-二氯-N-((3S,4R)-1-(5-(2-羟基丙烷-2-基)噻唑-2-基)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺
按照实施例1类似的方法,化合物3,4-二氯-N-((3S,4R)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺(实施例1)与2-溴-噻唑--5-甲酸酯反应,然后再与CH3BrMg进行格式反应,纯化后得到目标产物,收率50%。
ESI-MS(m/z):447.38[M+H]+.1H NMR(500MHz,Chloroform-d)δ10.03–9.97(m,1H),7.28(s,1H),4.94(s,1H),4.80(s,1H),4.39(dd,J=27.6,13.9Hz,1H),4.29(s,1H),3.90(t,J=16.0Hz,1H),3.51(s,1H),3.46(s,3H),3.15(dt,J=24.3,13.8Hz,2H),2.28(s,3H),2.11–1.95(m,3H),1.91–1.81(m,1H),1.28(d,J=31.3Hz,3H).
实施例7:3,4-二氯-N-((3S,4R)-1-(6-(1-羟基环戊基)哒嗪-3-基)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺
化合物3,4-二氯-N-((3S,4R)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺(实施例1)与3,6-二溴-哒嗪反应,然后在正丁基锂条件下与环戊酮反应,纯化后得到目标产物,收率54%。
ESI-MS(m/z):468.38[M+H]+.1H NMR(500MHz,Chloroform-d)δ9.80(s,1H),8.68–8.40(m,1H),7.24–7.18(m,1H),6.94(d,J=10.2Hz,1H),5.07–4.93(m,1H),4.34(d,J=11.3Hz,1H),4.25–4.13(m,1H),3.55(s,1H),3.43(s,3H),3.19–3.03(m,2H),2.28(s,3H),1.85(d,J=74.1Hz,4H),1.25(s,4H).
实施例8:3,4-二氯-N-((3S,4R)-1-(6-(1-羟基环己基)哒嗪-3-基)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺
按照实施例7类似的方法,化合物3,4-二氯-N-((3S,4R)-3-甲氧基哌啶-4-基)-5-甲基-1H-吡咯-2-羧酰胺(实施例1)与3,6-二溴-哒嗪反应,然后在正丁基锂条件下与环己酮反应,纯化后得到目标产物,收率64%。
ESI-MS(m/z):482.41[M+H]+.1H NMR(500MHz,Chloroform-d)δ10.11(s,1H),7.30(d,J=8.2Hz,1H),7.08(d,J=9.3Hz,1H),6.90(d,J=9.3Hz,1H),4.93(dt,J=14.5,2.9Hz,1H),4.33(ddt,J=11.7,8.6,4.2Hz,1H),4.16–4.07(m,1H),3.53(s,1H),3.43(s,3H),3.15–3.03(m,2H),2.82(dd,J=8.5,6.7Hz,2H),2.28(s,3H),2.04–1.87(m,2H),1.70(p,J=7.7Hz,2H),1.40(dd,J=15.1,7.6Hz,2H).
实验例1体外抗菌活性评价
测试方法:采用微量肉汤稀释法评价化合物对敏感/耐药型菌株的体外抗菌活性,测试化合物对不同菌株的体外抗菌活性,具体操作步骤如下:将灭菌的96孔板置于超净台,第一列加入稀释后的菌液200μL,从第二列起每列均加入菌液100μL。将溶解于DMSO中浓度为5mg/mL的供试品溶液取4μL依次加入第一列的各孔,同时设置空白对照组(不加样)和阳性药组(浓度为5mg/mL的左氧氟沙星),每个样品重复三次。加样结束后,使用8道微量移液器依次从前一列取128μL样品加入到后一列进行2倍梯度稀释,加样至最后一孔时,加样混匀后再将液体吸取100μL,稀释后各孔中的化合物浓度分别为128、64、32、16、8、4、2、1、0.5、0.25、0.125、0.06、0.03、0.015、0.008μg/mL。将96孔板置于37℃培养箱培养18h,观察各孔中细菌的生长状况。对于每个化合物,从加样的孔向后数,第一个未见细菌生长的孔对应的化合物浓度即该化合物的最低抑菌浓度(Minimal Inhibitory Concentration,MIC)。
结果:见下表1和表2,化合物显示出很强的体外抗菌活性,其中化合物1和2对革兰氏阳性菌的活性比DS2969提高了60倍以上,同时强于对照药左氧氟沙星;对革兰氏阴性菌的活性比DS2969和AZD5099至少提高了4倍,最高可达到32倍;对艰难梭菌的活性强于DS2969和阳性对照药万古霉素。
表1化合物的体外抗菌活性测试(MIC,μg/mL)
表2化合物的体外抗菌活性测试(MIC,μg/mL)
实验例2小鼠体内抗菌活性评价
实验动物:北京维通利华实验动物技术有限公司,ICR小鼠,体重在20-22g之间,体重均一,雌雄各半。
模型:金黄色葡萄球菌(MRSA,ATCC 43300)感染的败血症模型造模方法:使用2×107-8×106CFU/mL(用5%灭菌酵母液进行稀释配制)金黄色葡萄球菌(MRSA,ATCC 43300)对小鼠进行感染,使得小鼠形成败血症模型(每只小鼠腹腔注射0.5mL菌液)。
实验方案:化合物与阳性药首先溶解于DMSO后再用其他溶剂稀释,使得溶剂比例为生理盐水:吐温80:DMSO=9:0.5:0.5。小鼠分为5组,每组4只小鼠,雌雄各半,给药组于造模后1h分别静脉注射、皮下注射和灌胃给药2.5mg/mL的化合物溶液0.4mL,剂量为50mg/kg,阴性对照组造模后注射空白溶剂0.4mL,阳性对照组造模后皮下注射阳性药DS2969,给药剂量与化合物组相同,观察小鼠14天存活率。
结果:见附图1,化合物1具有显著的体内抗菌活性,并且显示出比DS2969更好或者相当的抗菌活性。
实验例3小鼠体内药代动力学试验
实验动物:北京维通利华实验动物技术有限公司,ICR小鼠,体重在20-22g之间,体重均一,雌雄各半。
实验方案:化合物1给药剂量150mg/kg(溶剂为生理盐水:吐温80:DMSO=9:0.5:0.5),采用灌胃给药方式,分别于给药后10min、20min、30min、1h、3h、5h、8h、24h、36h、48h眼眶采血或摘眼球采血方式采样,用UPLC测定血药浓度,绘制药时曲线并计算关键药代动力学参数。
结果:药时曲线见附图2,关键药代动力学参数见表3,半衰期为9.2h,生物利用度为86%,表明化合物1在体内的血药浓度可以维持较长时间,并且化合物1在体内可以得到很好的吸收,对于治疗效果提供了很好的支撑。
表3化合物1灌胃给药药代动力学参数
实验例4小鼠体内急毒试验
实验动物:北京维通利华实验动物技术有限公司,ICR小鼠,体重在20-22g之间,体重均一,雌雄各半。
实验方案:两组,每组4只,雌雄各半。化合物1给药剂量200mg/kg(溶剂为生理盐水:吐温80:DMSO=9:0.5:0.5),采用腹腔给药和灌胃给药的方式,给药体积0.3mL,观察小鼠14天存活率。
结果:见附图3,两组不同方式给药后小鼠活动正常,未见死亡。
Claims (7)
1.一种吡咯酰哌啶胺类化合物及其药学上可接受的盐,其特征在于,具有通式IAa所示结构,
其中,R2选自氟、氯、溴、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基三氟甲氧基、三氟乙氧基、三氟甲硫基或三氟乙硫基;
R3和R4分别独立地选自甲基、乙基;
或者,R3和R4连同它们连接的碳原子一起组成环丙基、环丁基、环戊基、环己基;
A选自呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,3,4-噁二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基。
2.一种吡咯酰哌啶胺类化合物及其药学上可接受的盐,其特征在于,所述化合物具有如下结构:
。
3.一种药物组合物,其特征在于,所述的药物组合物包含权利要求1-2任一项所述的吡咯酰哌啶胺类化合物及其药学上可接受的盐或立体异构体,以及一种或多种药学上可接受的载体或赋形剂。
4.根据权利要求3的药物组合物,其特征在于,所述的药物组合物还包含一种或多种其他药理活性组分。
5.权利要求1-2任一项所述的吡咯酰哌啶胺类化合物及其药学上可接受的盐或立体异构体、权利要求3-4任一项所述的药物组合物在制备用于治疗细菌、支原体或者衣原体感染的药物中的应用。
6.根据权利要求5的应用,其特征在于,所述的细菌选自敏感或耐药的革兰氏阳性菌、革兰氏阴性菌及分支杆菌,所述的支原体选自敏感或耐药的支原体,所述的衣原体选自敏感或耐药的衣原体。
7.根据权利要求6所述的应用,其特征在于,所述的革兰氏阳性菌选自枯草芽孢杆菌、金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌、艰难梭菌、链球菌、肺炎双球菌、炭疽杆菌、白喉杆菌、破伤风杆菌,所述的革兰氏阴性菌选自大肠杆菌、鲍曼不动杆菌、铜绿假单胞菌、肺炎克雷伯菌、痢疾杆菌、伤寒杆菌、变形杆菌、霍乱弧菌、奈瑟氏菌、志贺菌属、肺炎杆菌、布氏杆菌、百日咳杆菌、流感杆菌,所述的分支杆菌选自结核分枝杆菌、牛分枝杆菌、麻风分枝杆菌,所述的支原体选自肺炎支原体、溶脲脲原体、人型支原体、生殖器支原体,所述的衣原体选自肺炎衣原体、鹦鹉热衣原体、沙眼衣原体和牛衣原体。
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