CN117327028A - 吩噻嗪类衍生物、药物组合物及其在治疗棘球蚴病中的用途 - Google Patents
吩噻嗪类衍生物、药物组合物及其在治疗棘球蚴病中的用途 Download PDFInfo
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- CN117327028A CN117327028A CN202311246278.2A CN202311246278A CN117327028A CN 117327028 A CN117327028 A CN 117327028A CN 202311246278 A CN202311246278 A CN 202311246278A CN 117327028 A CN117327028 A CN 117327028A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
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Abstract
本发明提供了吩噻嗪类衍生物、药物组合物及其在治疗棘球蚴病中的用途,具体地,本发明提供了一种吩噻嗪类衍生物,其光学异构体、药学上可接受的盐或溶剂合物可用于治疗和/或预防棘球蚴寄生相关疾病,其中吩噻嗪类衍生物具有式A所示的结构,X、Y、R1和R2的定义如权利要求所述。本发明的吩噻嗪类衍生物对细粒棘球蚴和多房棘球蚴的原头蚴和包囊具有很强的体外杀灭效果,对细粒棘球蚴病和多房棘球蚴病小鼠具有良好的治疗效果。
Description
技术领域
本发明属于药物化学领域,具体地涉及吩噻嗪类衍生物及药物组合物在治疗棘球蚴病中的用途。
背景技术
棘球蚴病(又称包虫病)是一种严重危害人体健康、妨碍畜牧业生产发展的人畜共患寄生虫病。棘球蚴病呈全球分布,尤以畜牧业为主的国家和地区多见,是当今世界一项重要的公共卫生问题。对人类医学和公共卫生意义重大的两种最重要的形式是细粒棘球蚴病和多房棘球蚴病。
目前尚无有效的棘球蚴病疫苗,药物治疗是当前应用最广泛的治疗手段。阿苯达唑是世界卫生组织唯一推荐的抗棘球蚴病药物,但其口服生物利用度低,给药剂量大,疗程长,疗效不理想,临床治愈率仅为30%左右。尽管多种药物在临床前研究和动物模型中被探索,但仍然缺乏进入临床试验的有效候选药物。本领域迫切需要开发能有效治疗棘球蚴病的具有新的结构特征的新型化合物,该领域具有广阔的市场以及临床需求。
发明内容
本发明的目的是提供一种有效治疗棘球蚴病的新型化合物。
本发明的第一方面,提供了一种下式A所示的化合物、其光学异构体、药学上可接受的盐或溶剂合物在制备治疗和/或预防棘球蚴寄生相关疾病的药物中的用途:
式中:
表示与手性碳连接的基团的构型为R或S;
X选自下组:氢或卤素;
Y选自下组:氢或卤素;
R1和R2各自独立地为氢或任选被1~5个选自卤素、C1-C3卤代烷基、C1-C3烷氧基、羟基和氨基的取代基取代的C1-C12烷基。
本发明第二方面提供一种药物组合物,所述药物组合物含有:
(a)式A化合物,其光学异构体、药学上可接受的盐或溶剂合物;和
(b)药学上可接受的载体;
所述载体选自植物油、豆油、玉米油、色拉油、阿拉伯树胶、黄原胶、西黄蓍胶、山梨酸、苯甲酸、香兰素、甜葡糖、胶体二氧化硅、淀粉、羟丙纤维素、乳糖、硬脂酸镁、微晶纤维素、聚乙二醇、聚维酮K-30、聚乙烯吡咯烷酮、糖精钠、十二烷基硫酸钠、乙醇酸淀粉钠、滑石粉和二氧化钛中的一种或多种;
所述式A化合物如下式所示:
式中,
表示与手性碳连接的基团的构型为R或S;
X选自下组:氢或卤素;
Y选自下组:氢或卤素;
R1和R2各自独立地为氢或任选被1~5个选自卤素、C1-C3卤代烷基、C1-C3烷氧基、羟基和氨基的取代基取代的C1-C12烷基。
本发明第三方面提供下式A所示的化合物、其光学异构体、药学上可接受的盐或溶剂合物,以及含有下式A所示的化合物、其光学异构体、药学上可接受的盐或溶剂合物的药物组合物:
式中:
表示与手性碳连接的基团的构型为R或S;
X和Y各自独立地选自:氢和卤素;且X或Y中至少一个不为氢;
R1和R2各自独立地为氢或任选被1~5个选自卤素、C1-C3卤代烷基、C1-C3烷氧基、羟基和氨基的取代基取代的C1-C12烷基。
附图说明
图1是化合物III-4对细粒棘球蚴病和多房棘球蚴病小鼠的治疗效果图。
具体实施方式
应理解,在本发明范围中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成优选的技术方案。
如本文所用,“烷基”是指直链或支链单价饱和烃基,具体的烷基是具有1至20个碳原子的那些烷基(“C1-C20烷基”),通常含有1-12个碳原子(C1-C12烷基),优选含有1-6个碳原子(C1-C6烷基),更优选含有1-4个碳原子(C1-C4烷基)。烷基的例子包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基、正庚基、正辛基等。
如本文所用,“烷氧基”是指烷基-O-,优选的烷氧基是C1-C10烷氧基,例如C1-C6烷氧基、C1-C4烷氧基、C1-C3烷氧基,其包括,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基、1,2-二甲基丁氧基等。
如本文所用,“卤代”或者“卤素”是指原子序数为9至85的第17族的元素。“卤素”或“卤原子”指F、Cl、Br、和I。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
如本文所用,术语“卤代烷基”是指烷基中的至少一个氢原子被卤素原子。卤代烷基的实例包括C1-C6-卤代烷基、C1-C3-卤代烷基,但不限于其中一个或多个氢原子被Cl、F、Br或I原子取代的甲基、乙基、异丙基、异丁基、仲丁基、叔丁基、戊基或正己基,以及通过下面的实例给出示例性说明的卤代烷基。其中,优选的卤代烷基是单氟-、二氟-或三氟-甲基、单氯-、二氯-或三氯-乙基或单溴-、二溴-或三溴-丙基,例如3,3,3-三氟甲基、2-氯乙基、2,2,2-三溴乙基、氟甲基、三氯甲基等。
本发明的吩噻嗪类衍生物
本发明的吩噻嗪类衍生物具有式A所示的结构:
其中:
表示与手性碳连接的基团的构型为R或S;
X选自下组:氢、氟、氯、溴、碘;
Y选自下组:氢、氟、氯、溴、碘;
R1和R2各自独立地为氢、未取代或取代的C1-C12烷基。
在一些实施方案中,X选自下组:氢、氯和溴。
在一些实施方案中,Y选自下组:氢、氯和溴。
在一些实施方案中,R1和R2上的取代基各自独立选自:卤素、C1-C3卤代烷基、C1-C3烷氧基、羟基或氨基。在一些实施方案中,取代基的数量可以是1、2、3、4或5个。
在一些实施方案中,R1和R2各自独立地被1~3个选自下组的取代基取代:卤素或C1-C3卤代烷基。
在一些实施方案中,R1和R2各自独立地为氢或C1-C12烷基。优选地,R1和R2各自独立地为氢或C1-C8烷基。更优地,R1和R2各自独立地为氢或C1-C6烷基。在一些实施方案中,R1为H,R2为C1-C6烷基。
在一些实施方案中,X位于式A化合物的吩噻嗪环的2位或3位,Y位于7位或8位。在一些实施方案中,X和Y各自独立地为H或氯。
在一些实施方案中,式A化合物具有下式所示的结构:
其中:
表示与手性碳连接的基团的构型为R或S;
X和Y各自独立地选自:氢、氟、氯、溴或碘;且X和Y中至少一个不为氢;
R1和R2各自独立地为氢、未取代或取代的C1-C12烷基。
在一些实施方案中,X和Y各自独立地选自:氢、氟、氯或溴,X位于环中的2位或3位,Y位于环中的7位或8位,且X和Y中至少一个不为氢。优选地,X和Y各自独立地选自:氢、氟、氯或溴,X位于环中的2位或3位,Y位于环中的7位或8位,且X和Y中至少一个不为氢。
在一些实施方案中,X和Y为氯,且X位于环中的2位或3位,Y位于环中的7位或8位。
在一些实施方案中,式A化合物选自下组:
本发明也包括式A化合物的光学异构体、药学上可接受的盐或溶剂合物。本文中,“药学上可接受的盐”指这样一种盐,其保留亲本化合物的期望生物学活性且不产生任何不利的毒物学效果(参见例如,Berge,S.M等人.,1977,J.Pharm.Sci.66:1-19)。此类盐的例子包括酸加成盐和碱加成盐。酸加成盐包括衍生自无毒无机酸,诸如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚磷酸等的盐,以及衍生自无毒有机酸,诸如脂肪族单羧酸和二羧酸、苯基取代的链烷酸、羟基链烷酸、芳香族酸、脂肪族和芳香族磺酸等的盐。碱加成盐包括衍生自碱土金属(诸如钠、钾、镁、钙等)的盐,以及衍生自无毒有机胺的盐,诸如N,N'-二苄乙二胺、N-甲基葡糖胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、普鲁卡因等。
如本文所用,术语“光学异构体”是指具有旋转平面偏振光的能力且具有手性原子的化合物,并且这些化合物通常使用常规R/S构型表示。术语“光学异构体”包括对映异构体和非对映异构体,以及可通过(D)和(L)的名称彼此区别的化合物。除特别说明之处,本发明的所有化合物之中,各手性碳原子(手性中心)可以任选地为R构型或S构型,或R构型和S构型的混合物。
如本文所用,“溶剂化物”或“溶剂合物”是溶剂分子以一定比率组合作为化合物的晶体结构的组成部分的化合物形式。
本发明吩噻嗪类衍生物的制备方法
本发明公开了一种吩噻嗪类衍生物的制备方法,包括步骤:
(a)在非质子溶剂中,在碱存在下,式I化合物与环氧氯丙烷反应得到化合物(II);
(b)在质子溶剂中,化合物(II)与HNR1R2反应得到式A化合物;
X、Y、R1和R2的定义如前文所述。
在步骤(a)中,非质子溶剂可以选自下组:乙腈、丙酮、四氢呋喃、二甲基亚砜、二甲基甲酰胺,或其组合。在一些实施方案中,非质子溶剂可以为四氢呋喃。式I化合物被碱拔除质子后的物种能够在该非质子溶剂中稳定存在。碱可以选自下组:三乙胺、二乙胺、吡啶、碳酸铯、氢化钠、氢氧化锂、氢氧化钾、氢氧化钠,或其组合。在一些实施方案中,碱可为氢化钠。步骤(a)中使用的碱的碱性能够将式I化合物中的活泼氢拔除。碱与式I化合物的摩尔比可为1~5:1,优选为2~4:1,例如3:1。环氧氯丙烷与式I化合物的摩尔比为1~3:1,优选为2:1。反应温度为-20~40℃,优选为0~30℃,更优为10~20℃。反应可进行10分钟~10小时,优选为30分钟~5小时,更优为1~3小时。反应应在无水环境下进行。反应优选在惰性气体保护下进行。惰性气体可选自氮气、氩气,或其组合。在一些实施方案中,反应在氩气保护下进行。
在步骤(b)中,质子溶剂可选自下组:水、甲醇、乙醇、丙醇,或其组合。在一些实施方案中,质子溶剂为乙醇。HNR1R2与化合物(II)的摩尔比可为5~25:1,优选为10~22:1,更优为15~20:1。反应温度可为60~120℃,优选为70~110℃;更优为80~100℃。反应可进行5~24小时,例如7~22小时、10~18小时。
药物组合物和施用方法
本发明还提供了一种药物组合物,其包含药学上可接受的载体和一种或多种本发明式A化合物、其光学异构体、药学上可接受的盐或溶剂合物。
由于本发明式A化合物(“活性化合物”或“活性成分”)具有优异的治疗和/或预防棘球蚴寄生相关疾病的活性,因此,本发明式A化合物、其光学异构体、药学上可接受的盐或溶剂合物,以及含有本发明式A化合物为主要活性成分的药物组合物可用于治疗和/或预防与棘球蚴寄生相关的疾病。
本文中,“药学上可以接受的载体”指一种或多种相容性固体或液体填料或凝胶物质,它们适合于给予动物,而且必须有足够的纯度和对动物足够低的毒性。因此,本文所述的“药物组合物”是包括人在内的动物用的药物组合物。
本文中,“相容性”在此指的是组合物中各组份能和本发明式A化合物相互掺和,而不明显降低式A化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、玉米油、色拉油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温、阿拉伯树胶、黄原胶、西黄蓍胶)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂(如香兰素、甜葡糖)、稳定剂、抗氧化剂、防腐剂(如山梨酸、苯甲酸)、无热原水等。在一些实施方案中,载体选自植物油、豆油、玉米油、色拉油、阿拉伯树胶、黄原胶、西黄蓍胶、山梨酸、苯甲酸、香兰素、甜葡糖、胶体二氧化硅、淀粉、羟丙纤维素、乳糖、硬脂酸镁、微晶纤维素、聚乙二醇、聚维酮K-30、聚乙烯吡咯烷酮、糖精钠、十二烷基硫酸钠、乙醇酸淀粉钠、滑石粉和二氧化钛中的一种或多种。
在一些实施方案中,载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、佐剂、及其组合。另外,这些载体中还可能存在辅助性的物质,如润湿剂或乳化剂、pH缓冲物质等。
可根据不同的给药途径和剂型选择合适的载体。例如,对于固体剂型,合适的载体包括:淀粉、乳糖、磷酸二钙、微晶纤维素、蔗糖和白陶土等。适用于液体剂型的载体包括:无菌水、聚乙二醇、非离子型表面活性剂、食用油(如玉米油、豆油、色拉油、花生油和芝麻油)、乳化剂(如阿拉伯树胶、黄原胶、西黄蓍胶)。在一些实施方案中,该液体剂型含有防腐剂(如山梨酸、苯甲酸)。优选地,该液体剂型还含有调味剂(如香兰素、甜葡糖)。
可将本发明的药物组合物制备成合适的剂型,包括但不限于注射剂、囊剂、乳剂、片剂、丸剂、散剂和颗粒剂。
本发明对化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括但并不限于:口服、肠胃外(静脉内、肌肉内或皮下)和局部给药等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂等。在这些固体剂型中,式A化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
在一些实施方案中,本发明药物组合物为片剂。在一些实施方案中,除本文所述的式A化合物、其光学异构体、药学上可接受的盐或溶剂合物外,所述片剂还可含有胶体二氧化硅、淀粉、羟丙纤维素、乳糖、硬脂酸镁、微晶纤维素、聚乙二醇、聚维酮K-30、聚乙烯吡咯烷酮、糖精钠、十二烷基硫酸钠、乙醇酸淀粉钠、滑石粉和二氧化钛。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。在一些实施方案中,本发明药物组合物为乳剂。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂和喷射剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
在一些实施方案中,本文所述的药物组合物为口服乳剂,除本文所述的式A化合物、其光学异构体、药学上可接受的盐或溶剂合物外,所述乳剂还可含有可食用油脂、乳化剂、防腐剂、调味剂和水等。示例性的乳剂的辅料可如CN 99113446.X所述,本文将其全部内容纳入本文。
本发明的药物组合物中还可含有其它活性成分,或可将本发明的药物组合物与其它能够治疗寄生虫感染,尤其是抗棘球蚴病的药物联合给药。其它能够治疗寄生虫感染,尤其是抗棘球蚴病的药物包括但不限于:抗棘球蚴病药物、抗纤维化药物、免疫调节剂,或其组合。在一些实施方案中,抗棘球蚴病药物为阿苯达唑。在一些实施方案中,抗纤维化药物为吡非尼酮。
在一些实施方案中,本发明的药物组合物还含有第二活性成分。在一些实施方案中,所述第二活性成分选自抗棘球蚴病药物、抗纤维化药物、免疫调节剂,或其组合。
在一些实施方案中,第二活性成分可以选自阿苯达唑和吡非尼酮中的一种或多种。
阿苯达唑为苯并咪唑类化合物之一,具有强大的杀灭寄生虫作用,且驱虫谱较广。对于不愿接受手术治疗、失去手术机会或身体状态差而无法耐受手术的多房棘球蚴病患者,使用阿苯达唑药物治疗可一定程度上延缓疾病进展。
当两种或两种以上的药物联合给药时,一般具有优于两种药物分别单独给药的效果。优选地,联合施用的药物或其它制剂不干扰本发明式A化合物,或其光学异构体、药学上可接受的盐或溶剂合物的治疗活性。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
所用的活性成分的有效剂量可随所用的化合物、给药的模式和待治疗的疾病的严重程度而变化。然而,通常当本发明的化合物每天以约1-300mg/kg动物体重的剂量给予时,能得到令人满意的效果,较佳地每天以1-3次分开的剂量给予,或以缓释形式给药。对大部分大型哺乳动物而言,每天的总剂量约为5-2000mg,较佳地约为50-1500mg。适用于内服的剂量形式,包含与固态或液态药学上可接受的载体密切混合的约50-1500mg的活性化合物。可调节此剂量方案以提供最佳治疗应答。例如,由治疗状况的迫切要求,可每天给予若干次分开的剂量,或将剂量按比例地减少。
用途
本发明的式A化合物,其光学异构体、药学上可接受的盐或溶剂合物可用于制备治疗和/或预防棘球蚴寄生相关疾病的药物组合物。
所述棘球蚴寄生相关疾病为棘球蚴病,更优选为细粒棘球蚴病和/或多房棘球蚴病。
本发明的式A化合物,其光学异构体、药学上可接受的盐或溶剂合物和/或本发明的药物组合物可以杀灭原头蚴和棘球蚴包囊。本发明的式A化合物,其光学异构体、药学上可接受的盐或溶剂合物和本发明药物组合物通过杀灭原头蚴和/或棘球蚴包囊来治疗和/或预防棘球蚴寄生相关疾病。在一些实施方案中,原头蚴为细粒棘球蚴的原头蚴和/或多房棘球蚴的原头蚴。在一些实施方案中,棘球蚴包囊为细粒棘球蚴包囊和/或多房棘球蚴包囊。
与棘球蚴寄生相关的疾病为与畜牧业相关的人畜共患病。优选的给药对象包括但不限于鼠、兔、猫、狗、牛、羊、猪、马、骆驼、人、狼和狐狸中的一种或多种。在一些实施方案中,兔为鼠兔。
本发明的优点包括:
(1)本发明提供了一种新颖的治疗棘球蚴病的化合物。
(2)本发明的化合物可以在体外有效的杀灭细粒棘球蚴和多房棘球蚴的原头蚴及棘球蚴包囊。
(3)本发明的化合物可以体内有效治疗细粒棘球蚴病和多房棘球蚴病。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1.中间体II-1的合成
氢化钠(60%,2.56g,64mmol)在氩气保护下加入史莱克管内,加入四氢呋喃(30mL)并于冰浴下搅拌,随后加入吩噻嗪(3.98g,20mmol),将氩气气流调大,史莱克管开口2min直至气泡减少后塞上保护塞,室温下搅拌30min。缓慢滴加环氧氯丙烷(40mmol)至反应液中,高效液相监测反应进程。待反应结束后,加水淬灭,乙酸乙酯萃取得有机相,无水硫酸钠干燥,过滤,减压浓缩,粗产物经柱层析(石油醚:乙酸乙酯=10:1)纯化得白色固体3.06g,收率70%。ESI-MS:m/z=256[M+H]+。
实施例2.中间体II-2的合成
重复实施例1的合成步骤,用3-氯-吩噻嗪代替吩噻嗪,得白色固体,收率59%。ESI-MS:m/z=290[M+H]+。
实施例3.中间体II-3的合成
重复实施例1的合成步骤,用3,7-二氯-吩噻嗪代替吩噻嗪,得白色固体,收率54%。ESI-MS:m/z=324[M+H]+。
实施例4.中间体II-4的合成
重复实施例1的合成步骤,用2-氯-吩噻嗪代替吩噻嗪,得白色固体,收率67%。ESI-MS:m/z=290[M+H]+。
实施例5.中间体II-5的合成
重复实施例1的合成步骤,用2,8-二氯-吩噻嗪代替吩噻嗪,得白色固体,收率61%。ESI-MS:m/z=324[M+H]+。
实施例6.目标化合物III-1的合成
中间体化合物II-1(510mg,2mmol)溶于无水乙醇(20mL)中,加入丙胺(40mmol),加热回流过夜,高效液相监测反应过程。待反应结束后,加水淬灭,乙酸乙酯萃取得有机相,无水硫酸钠干燥,过滤,高温减压浓缩,粗产物经柱层析纯化(二氯甲烷:甲醇=30:1)得白色固体446mg,收率51%。1HNMR(400MHz,DMSO)δ7.25–7.12(m,4H,Ar-H),7.09(d,J=7.8Hz,2H,Ar-H),6.95(t,J=7.4Hz,2H,Ar-H),3.99–3.81(m,3H,CH2,CH),2.78–2.32(m,4H,2CH2),1.45–1.25(m,2H,CH2),0.79(t,J=7.4Hz,3H,CH3).13C NMR(100MHz,DMSO)δ145.66,127.98,127.65,124.61,123.01,116.63,66.56,53.95,51.75,51.63,22.94,12.13.HRMS:m/z=315.1515[M+H]+.
实施例7.目标化合物III-2的合成
重复实施例6的合成步骤,用正丁胺代替丙胺,得白色固体,收率48%。1H NMR(400MHz,DMSO)δ7.23–7.13(m,4H,Ar-H),7.09(d,J=7.9Hz,2H,Ar-H),6.95(t,J=7.0Hz,2H,Ar-H),4.89(br,1H,OH),3.99–3.79(m,3H,CH2,CH),2.75–2.34(m,4H,2CH2),1.37–1.12(m,4H,2CH2),0.81(t,J=7.2Hz,3H,CH3).13C NMR(100MHz,DMSO)δ145.67,127.97,127.63,124.60,122.99,116.62,66.66,54.06,51.59,49.59,32.17,20.36,14.39.HRMS:m/z=329.1668[M+H]+.
实施例8.目标化合物III-3的合成
重复实施例6的合成步骤,用正戊胺代替丙胺,得白色固体,收率65%。1H NMR(400MHz,DMSO)δ7.23–7.13(m,4H,Ar-H),7.09(d,J=7.8Hz,2H,Ar-H),6.94(t,J=7.4Hz,2H,Ar-H),4.89(br,1H,OH),4.06–3.70(m,3H,CH2,CH),2.79–2.31(m,4H,2CH2),1.43–1.08(m,6H,3CH2),0.82(t,J=6.9Hz,3H,CH3).13C NMR(100MHz,DMSO)δ145.67,127.96,127.63,124.60,122.99,116.62,66.68,54.05,51.59,49.91,29.68,29.49,22.56,14.43.HRMS:m/z=343.1824[M+H]+.
实施例9.目标化合物III-4的合成
重复实施例6的合成步骤,用正己胺代替丙胺,得白色固体,收率72%。1H NMR(400MHz,DMSO)δ7.24–7.12(m,4H,Ar-H),7.09(d,J=8.0Hz,2H,Ar-H),6.94(t,J=7.2Hz,2H,Ar-H),4.89(br,1H,OH),4.05–3.71(m,3H,CH2,CH),2.77–2.30(m,4H,2CH2),1.38–1.05(m,8H,4CH2),0.83(t,J=6.9Hz,3H,CH3).13C NMR(101MHz,DMSO)δ145.67,127.95,127.63,124.60,122.98,116.61,66.65,54.03,51.58,49.92,31.74,29.94,26.92,22.57,14.41.HRMS:m/z=357.1917[M+H]+.
实施例10.目标化合物III-5的合成
重复实施例6的合成步骤,用中间体II-2代替II-1,用正己胺代替丙胺,得白色固体,收率42%。1H NMR(400MHz,DMSO)δ7.24–7.18(m,3H,Ar-H),7.15(dd,J=7.7,1.5Hz,1H,Ar-H),7.09(td,J=7.7,1.9Hz,2H,Ar-H),6.96(td,J=7.4,1.2Hz,1H,Ar-H),4.96(br,1H,OH),4.06–3.55(m,3H,CH2,CH),2.71–2.51(m,2H,CH2),2.46–2.34(m,2H,CH2),1.41–1.07(m,8H,4CH2),0.83(t,J=6.9Hz,3H,CH3).
实施例11.目标化合物III-6的合成
重复实施例6的合成步骤,用中间体II-3代替II-1,用正己胺代替丙胺,得白色固体,收率49%。1H NMR(400MHz,DMSO)δ7.26–7.22(m,2H,Ar-H),7.21–7.08(m,3H,Ar-H),7.01(dd,J=8.2,2.1Hz,1H,Ar-H),4.97(br,1H,OH),4.06–3.67(m,3H,CH2,CH),2.71–2.51(m,2H,CH2),2.48–2.30(m,2H,CH2),1.45–1.16(m,8H,4CH2),0.84(t,J=6.8Hz,3H,CH3).
实施例12.目标化合物III-7的合成
重复实施例6的合成步骤,用中间体II-4代替II-1,用正己胺代替丙胺,得白色固体,收率39%。1H NMR(400MHz,DMSO)δ7.23–7.10(m,5H,Ar-H),7.03–6.93(m,2H,Ar-H),4.95(br,1H,OH),4.04–3.71(m,3H,CH2,CH),2.72–2.51(m,2H,CH2),2.46–2.41(m,2H,CH2),1.39–1.27(m,2H,CH2),1.28–1.11(m,6H,3CH2),0.84(t,J=6.7Hz,3H,CH3).
实施例13.目标化合物III-8的合成
重复实施例6的合成步骤,用中间体II-5代替II-1,用正己胺代替丙胺,得白色固体,收率50%。1H NMR(400MHz,DMSO)δ7.28–7.07(m,5H,Ar-H),7.01(dd,J=8.2,2.0Hz,1H,Ar-H),4.97(br,1H,OH),4.04–3.71(m,3H,CH2,CH),2.72–2.52(m,2H,CH2),2.47–2.34(m,2H,CH2),1.35–1.06(m,8H,4CH2),0.84(t,J=6.8Hz,3H,CH3).
实施例14.目标化合物III-9和III-10的合成
以III-3为原料,通过手性柱拆分得到化合物III-9和III-10。
实施例15.目标化合物III-11和III-12的合成
以III-4为原料,通过手性柱拆分得到化合物III-11和III-12。
实施例16.对原头蚴(节)和棘球蚴包囊的体外杀灭效果测定
细粒棘球蚴的原头蚴从自然感染的绵羊肝脏中的棘球蚴包囊的囊液中采集,多房棘球蚴的原头蚴从人工传代保种的昆明鼠体内采集。将采集到的原头蚴在体外培养体系中培养。药物杀灭原头蚴测试在96孔微孔板中测定,200个原头蚴/孔,每孔加入不同浓度的本发明化合物,每浓度设置3个复孔,将微孔板置于5%CO2培养箱中37℃培养24h。亚甲基蓝染色法评估原头蚴的活力,计算原头蚴死亡率,实验结果参见表1。
细粒棘球蚴和多房棘球蚴原头蚴置于添加20%胎牛血清和抗生素的RPMI1640培养基的培养瓶中,在5%CO2培养箱中37℃条件下进行体外培养,每5天更换一次培养基,待发育完全为棘球蚴包囊时(直径:4-6mm),进行体外杀包囊测试。药物杀灭包囊测试在24孔微孔板中测定,4-7个包囊/孔,每孔加入不同浓度的本发明化合物,将微孔板置于5%CO2培养箱中37℃培养24h。显微镜下评估棘球蚴包囊存活情况,若包囊生发层塌陷并明显与皮层剥离则判定为死亡,计算棘球蚴包囊死亡率,实验结果参见表1。
表1.吩噻嗪类衍生物体外杀灭原头蚴和棘球蚴包囊的效果
从表1结果可知,本发明化合物具有显著的体外杀灭细粒棘球蚴和多房棘球蚴的原头蚴和棘球蚴包囊的效果,明显优于阿苯达唑。本发明化合物起效迅速,24h内即可观察到显著杀虫效果,而阿苯达唑在24h内对原头蚴和棘球蚴包囊无效。吩噻嗪环的硫原子易被氧化为亚砜或被进一步氧化为砜,环上2、3、7、8位为其羟基化代谢位点。氯取代吩噻嗪类衍生物在环上引入氯原子可封闭羟基化代谢位点,且氯原子吸电子基团的引入,可降低环上硫原子的电子给予能力,使其不易被氧化为亚砜或砜。氯取代的结构优化能够有效地提高吩噻嗪类衍生物的稳定性,增强了化合物的杀虫活性。在同等的杀灭多房棘球蚴包囊的效果下,氯取代吩噻嗪类衍生物所需的剂量(20μM)较无取代吩噻嗪类衍生物(30μM)更低。此外,氯取代吩噻嗪类衍生物相较于无取代吩噻嗪类衍生物,脂溶性亦有所提高,可让化合物容易被虫体吸收,更有利于杀灭寄生虫,在低剂量(20μM)下,表现出了更强的杀灭棘球蚴包囊的能力,明显优于无取代吩噻嗪类化合物。
实施例17.本发明化合物对细粒棘球蚴病和多房棘球蚴病小鼠的治疗作用
为验证本发明化合物的体内抗棘球蚴活性,选取化合物III-4对细粒棘球蚴病和多房棘球蚴病小鼠进行了抗棘球蚴治疗效果测试。
精确称量化合物III-4和阳性对照药物阿苯达唑(ABZ),溶解于0.5% CMC-Na水溶液中,制成所需浓度的均匀混悬液。
C57BL/6J小鼠经肝门静脉分别注射接种细粒棘球蚴和多房棘球蚴的原头蚴,200个原头蚴/鼠,感染后3个月,通过B超检测确定细粒棘球蚴病和多房棘球蚴病小鼠模型造模成功即可开始实验。将实验动物随机分为溶媒对照组、阳性药物阿苯达唑高、低剂量组和化合物III-4高、低剂量组,分别每日灌胃给予0.5% CMC-Na水溶液、阿苯达唑80mg/kg和50mg/kg、化合物III-4 80mg/kg和50mg/kg,每天一次,连续给药30天。给药结束后1个月后,小鼠安乐死后解剖,计数棘球蚴包囊数量,测算棘球蚴包囊尺寸。
实验结果参见图1,其中,*p<0.05,**p<0.01,***p<0.001,***p<0.0001。从图1结果可知,化合物III-4对小鼠细粒棘球蚴病和多房棘球蚴病具有显著的治疗效果,显著优于溶媒对照组,且呈剂量依赖性。在同等剂量下,化合物III-4对小鼠多房棘球蚴包囊数量及尺寸有明显的抑制效果,较阿苯达唑提高50%以上,可见化合物III-4的治疗效果显著优于阳性对照药物阿苯达唑,提示将本发明化合物应用到患有棘球蚴病的人或其他动物有期望获得更好的治疗效果或使用更低的给药剂量。
Claims (10)
1.下式A所示的化合物、其光学异构体、药学上可接受的盐或溶剂合物在制备治疗和/或预防棘球蚴寄生相关疾病的药物中的用途:
式中:
表示与手性碳连接的基团的构型为R或S;
X选自下组:氢或卤素;
Y选自下组:氢或卤素;
R1和R2各自独立地为氢或任选被1~5个选自卤素、C1-C3卤代烷基、C1-C3烷氧基、羟基和氨基的取代基取代的C1-C12烷基。
2.如权利要求1所述的用途,其特征在于,式A中,
X选自下组:氢、氯或溴;
Y选自下组:氢、氯或溴;
R1和R2各自独立地为氢或C1-C12烷基;优选地,R1和R2各自独立地为氢或C1-C8烷基;更优地,R1和R2各自独立地为氢或C1-C6烷基。
3.如权利要求1所述的用途,其特征在于,X位于吩噻嗪环的2位或3位,Y位于7位或8位;
优选地,X和Y均为氢,或X和Y中一个为H、另一个为卤素,优选该卤素为氯。
4.如权利要求1所述的用途,其特征在于,式A化合物选自下组:
5.如权利要求1所述的用途,其特征在于,所述疾病为棘球蚴病;优选地,所述疾病为细粒棘球蚴病和/或多房棘球蚴病。
6.一种药物组合物,其特征在于,所述药物组合物含有:
(a)式A化合物,其光学异构体、药学上可接受的盐或溶剂合物;和
(b)药学上可接受的载体;
所述载体选自植物油、豆油、玉米油、色拉油、阿拉伯树胶、黄原胶、西黄蓍胶、山梨酸、苯甲酸、香兰素、甜葡糖、胶体二氧化硅、淀粉、羟丙纤维素、乳糖、硬脂酸镁、微晶纤维素、聚乙二醇、聚维酮K-30、聚乙烯吡咯烷酮、糖精钠、十二烷基硫酸钠、乙醇酸淀粉钠、滑石粉和二氧化钛中的一种或多种;
所述式A化合物如下式所示:
式中,
表示与手性碳连接的基团的构型为R或S;
X选自下组:氢或卤素;
Y选自下组:氢或卤素;
R1和R2各自独立地为氢或任选被1~5个选自卤素、C1-C3卤代烷基、C1-C3烷氧基、羟基和氨基的取代基取代的C1-C12烷基。
7.如权利要求6所述的药物组合物,其特征在于,所述药物组合物任选的包括第二活性成分,所述第二活性成分选自抗棘球蚴病药物、抗纤维化药物、免疫调节剂,或其组合;优选地,所述第二活性成分选自阿苯达唑和吡非尼酮中的一种或多种。
8.下式A所示的化合物、其光学异构体、药学上可接受的盐或溶剂合物:
式中:
表示与手性碳连接的基团的构型为R或S;
X和Y各自独立地选自:氢和卤素;且X或Y中至少一个不为氢;
R1和R2各自独立地为氢或任选被1~5个选自卤素、C1-C3卤代烷基、C1-C3烷氧基、羟基和氨基的取代基取代的C1-C12烷基。
9.如权利要求8所述的式A化合物,其特征在于,
X和Y各自独立地选自:氢、氟、氯或溴,X位于环中的2位或3位,Y位于环中的7位或8位,且X和Y中至少一个不为氢;优选地,X和Y各自独立为H或氯,X位于环中的2位或3位,Y位于环中的7位或8位,且X和Y中至少一个为氯;
R1和R2各自独立地为氢或C1-C12烷基;优选地,R1和R2各自独立地为氢或C1-C8烷基;更优地,R1和R2各自独立地为氢或C1-C6烷基。
10.如权利要求8所述的式A化合物,其特征在于,所述式A化合物选自下组:
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