CN102267998A - 新型抗寄生虫吡嗪异喹啉衍生物 - Google Patents

新型抗寄生虫吡嗪异喹啉衍生物 Download PDF

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CN102267998A
CN102267998A CN201110154047XA CN201110154047A CN102267998A CN 102267998 A CN102267998 A CN 102267998A CN 201110154047X A CN201110154047X A CN 201110154047XA CN 201110154047 A CN201110154047 A CN 201110154047A CN 102267998 A CN102267998 A CN 102267998A
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杨越
孙德群
杨春华
罗敏
张凌子
孙丽
张文龙
苟招聘
王锦
胡长燕
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Shandong University Weihai
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    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract

本发明涉及新型通式I的吡嗪异喹啉衍生物,以及其药用上适用于人和动物的各种盐,各种异构体,氮氧化合物。所述化合物具有杀灭人体或动物体内寄生虫,包括血吸虫、绦虫、囊虫、华支睾吸虫、肺吸虫、姜片虫的作用。结构通式I

Description

新型抗寄生虫吡嗪异喹啉衍生物
技术领域本发明涉及一种治疗寄生虫疾病的新型吡喹类衍生物,寄生虫疾病包括但不限于血吸虫、绦虫、囊虫、华支睾吸虫、肺吸虫、姜片虫引起的人畜共患性疾病.
背景技术血吸虫病是由于感染三种主要的血吸虫(曼氏血吸虫,埃及血吸虫,日本血吸虫)而引起的流行病。40年来,吡喹酮仍然是广泛用于防治人和动物各种血吸虫成虫感染的唯一有效药物。由于它的大量和长期使用,目前已经产生药物抗性;而针对血吸虫幼虫感染的血吸虫病至今仍无有效药物治疗。据世界卫生组织披露全球有2亿人感染血吸虫病,有约6亿人受感染威胁,血吸虫病的高发病人数有2千万,每年有至少280000人死于血吸虫病。而卫生部和国家发改委下发的“全国综合治理血吸虫病‘十五’计划”数据表明,我国目前尚未控制血吸虫病传播的108个县集中分布在湖沼地区和大山区,动物宿主众多,钉螺分布广泛,受环境因素影响很大,防治工作特别困难,重复感染依然十分严重,疫情处于很不稳定状态。面对如此众多的血吸虫病感染人群仅吡喹酮一种化学药物是很不相称的,因此亟需研制新的抗血吸虫药物。
发明内容一种通式I的化合物,其药用上适用于人和动物的各种盐,及其各种异构体,氮氧化合物.
结构通式I,
Figure BSA00000514064800021
其中,
A是不饱和环,包括苯环,吡啶环和氮氧偶极吡啶环;
B是饱和氮杂环,包括五元,六元,和七元饱和氮杂环,B环上可以由C1-C4烷基取代,或形成3-5元饱和并环;
C是饱和氮杂环,包括五元,六元,和七元饱和氮杂环,可以是酮或非酮化合物;
D是饱和环,包括三元,四元,五元,六元,和七元饱和环;
A选自如下基闭:
Figure BSA00000514064800022
B+C选自如下基团:
D选自如下基团:
Figure BSA00000514064800031
其中优选的但不限于的化合物为:
Figure BSA00000514064800032
Figure BSA00000514064800041
Figure BSA00000514064800051
药理学
本发明化合物出乎意料地显示适于治疗寄生虫疾病,尤其包括血吸虫、绦虫、囊虫、华支睾吸虫、肺吸虫、姜片虫引起的人畜共患性疾病.本发明也涉及将上文定义的通式I的化合物,将其药学上接受的酸或碱加成盐,包括季盐,立体化学异构形式,N-氧化合物形式用做药,以及下述任何药物组合物在制备用于治疗寄生虫疾病,包括血吸虫、绦虫、囊虫、华支睾吸虫、肺吸虫、姜片虫引起的人畜共患性疾病的药物中的用途。
因此,本发明另一方面提供一种治疗患有寄生虫疾病(包括血吸虫疾病)的方法,该方法包括治疗有效量的本发明化合物或药物组合物给予患者或患蓄。
本发明化合物显示抗寄生虫疾病,尤其是抗血吸虫、绦虫的活性,该类化合物的作用机制尚未研究清楚,可能与该类化合物作用血吸虫的钙离子通道有关,即迅速引起虫体活动兴奋、虫体肌肉挛缩和皮层的广泛受损,从而导致虫的肝移,影响虫的体表营养吸收、排泌和防御功能以及继发的代谢紊乱,且皮层的损害和剥落则破坏了虫得以在宿主体内存活的伴随免疫机制,其体表抗原决定簇的显露为宿主抗血吸虫特异性抗体的免疫攻击提供了靶部位。
本发明也涉及组合物,其包含药学上可接受的载体和作为活性成分的治疗有效量的本发明化合物。本发明化合物可被调配成用于给药目的的不同药物形式。作为适当组合物的例证的是全身给药药物通常所采用的所有组合物。为制备本发明药物组合物,有效量的特定化合物(任选以加成盐形式)作为活性成分与药物可接受载体紧密组合,取决于给药所需的制剂形式,所述载体可采取多种形式。这些药物组合物宜为特别是适合口服给药或胃肠外注射的单一剂量形式。例如,在制备口服剂型的组合物时,在口服液体制剂如混悬剂,糖浆剂,乳剂和溶液剂的情况下,可以采用任何平常的药物介质,如水,乙二醇,油,醇等;或者在粉末剂,丸剂,胶囊剂和片剂的情况下,采用固体载体例如淀粉,糖,高岭土,稀释剂,粘合剂等。
取决于给药的方式,所述药物组合优选包括0.05-99%重量,更优选0.1-70%重量的活性成分,以及优选1-99.95%重量,更优选30-99.9%重量的药学上可接受的载体,所有百分比均基于总组合物计算。
实施例一典型化合物1-3的制备:
Figure BSA00000514064800071
向装有磁力搅拌的圆底烧瓶中加入1-1(188mg,1mmol),环己甲酸(128mg,1mmol),EDCI(211mg,1.1mmol)和DMAP(139mg,1.1mmol)。室温下搅拌过夜,用1%盐酸水和饱和碳酸钠溶液交替洗涤,最后用水洗。无水硫酸镁干燥后浓缩得白色固体.Mp 132-135(277mg,收率93%)。
Figure BSA00000514064800072
向装有磁力搅拌的圆底烧瓶中加入1-1(188mg,1mmol),环戊甲酸(114mg,1mmol),EDCI(211mg,1.1mmol)和DMAP(139mg,1.1mmol)。室温下搅拌过夜,用1%盐酸水和饱和碳酸钠溶液交替洗涤,最后用水洗。无水硫酸镁干燥后浓缩得白色固体Mp 128-130(256mg,收率90.14%)。
Figure BSA00000514064800073
向装有磁力搅拌的圆底烧瓶中加入1-1(188mg,1mmol),环庚甲酸(142mg,1mmol),EDCI(211mg,1.1mmol)和DMAP(139mg,1.1mmol)。室温下搅拌过夜,用1%盐酸水和饱和碳酸钠溶液交替洗涤,最后用水洗。无水硫酸镁干燥后浓缩得白色固体.Mp 137-139(287mg,收率92%)。
实施例二典型化合物10-12的制备:
Figure BSA00000514064800081
向装有磁力搅拌的圆底烧瓶中加入10-1(232mg,1mmol),环己甲酸(128mg,1mmol),EDCI(211mg,1.1mmol)和DMAP(139mg,1.1mmol)。室温下搅拌过夜,用1%盐酸水和饱和碳酸钠溶液交替洗涤,最后用水洗。无水硫酸镁干燥后浓缩得白色固体.Mp 143-146(324mg,收率95%)。
Figure BSA00000514064800082
向装有磁力搅拌的圆底烧瓶中加入10-1(232mg,1mmol),环庚甲酸(142mg,1mmol),EDCI(211mg,1.1mmol)和DMAP(139mg,1.1mmol)。室温下搅拌过夜,用1%盐酸水和饱和碳酸钠溶液交替洗涤,最后用水洗。无水硫酸镁干燥后浓缩得白色固体.Mp 138--141(295mg,收率90%)。
Figure BSA00000514064800091
向装有磁力搅拌的圆底烧瓶中加入10-1(232mg,1mmol),环庚甲酸(142mg,1mmol),EDCI(211mg,1.1mmol)和DMAP(139mg,1.1mmol)。室温下搅拌过夜,用1%盐酸水和饱和碳酸钠溶液交替洗涤,最后用水洗。无水硫酸镁干燥后浓缩得白色固体.Mp 149-153(316mg,收率89%)。
生物学效应:
测定化合物抗日本血吸虫的体外方法:
成虫体外培养:采集活的雄性成虫置于DMEM培养液(10条/3ml/皿)中,分组加药。每皿分别加入化合物各3ul,终浓度为50(mol/ml,对照组加DMS03(1(参考其他实验组加药最高剂量)。加药后充分摇匀,放入37℃、5%CO:培养箱中。培养过夜(16h)后用生理盐水洗涤虫体3次,加入新鲜培养液,在体视显微镜下观察培养.24h~72h后的血吸虫活力状态,并影像记录。结果见表1,
表1
Figure BSA00000514064800101
表中死亡率等级:A为100-80%

Claims (7)

1.一种通式I的化合物,其药用上适用于人和动物的各种盐,及其各种异构体,氮氧化合物。
结构通式I,
Figure FSA00000514064700011
其中,
A是不饱和环,包括苯环,吡啶环和氮氧偶极吡啶环;
B是饱和氮杂环,包括五元,六元,和七元饱和氮杂环,B环上可以由C1-C4烷基取代,或形成3-5元饱和并环;
C是饱和氮杂环,包括五元,六元,和七元饱和氮杂环,可以是酮或非酮化合物;
D是饱和环,包括三元,四元,五元,六元,和七元饱和环;
A选自如下基团:
Figure FSA00000514064700012
B+C选自如下基团:
Figure FSA00000514064700013
Figure FSA00000514064700021
D选自如下基团:
Figure FSA00000514064700022
2.如权利要求1所述的化合物,其特征在于所述化合物优选自:
Figure FSA00000514064700023
Figure FSA00000514064700031
Figure FSA00000514064700041
3.如权利要求1-2所述的化合物,其特征在于该类化合物用于杀灭人体或动物体内寄生虫,包括血吸虫、绦虫、囊虫、华支睾吸虫、肺吸虫、姜片虫的作用。
4.如权利要求1-2中的任一项化合物,其特征在于用作药物。
5.一种组合物,所述组合物包含药学上可接受的载体,和如权利要求1-2所述的化合物作为活性成分的治疗有效量。
6.如权利要求1-2所述的化合物,或权利要求5所述的组合物,其特征在于用于治疗血吸虫、绦虫、囊虫、华支睾吸虫、肺吸虫、姜片虫疾病中的药物作用。
7.一种治疗寄生虫,包括血吸虫、绦虫、囊虫、华支睾吸虫、肺吸虫、姜片虫疾病的方法,所述方法包括治疗的有效量的权利要求1-2所述的任一项化合物,或权利要求5所述的组合物给予所述患者或患蓄。 
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Publication number Priority date Publication date Assignee Title
CN102321088A (zh) * 2011-08-03 2012-01-18 威海秀水药物研发有限公司 一种新型抗血吸虫化合物
CN113754666A (zh) * 2021-09-07 2021-12-07 凯美克(上海)医药科技有限公司 一种苯并吡嗪类化合物及其合成方法

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CN1683346A (zh) * 2005-03-01 2005-10-19 江苏工业学院 吡喹酮合成工艺

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Title
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Publication number Priority date Publication date Assignee Title
CN102321088A (zh) * 2011-08-03 2012-01-18 威海秀水药物研发有限公司 一种新型抗血吸虫化合物
CN113754666A (zh) * 2021-09-07 2021-12-07 凯美克(上海)医药科技有限公司 一种苯并吡嗪类化合物及其合成方法

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