CN115400140A - 呋喃核糖基吡啶衍生物用于预防或治疗癫痫或惊厥的用途 - Google Patents
呋喃核糖基吡啶衍生物用于预防或治疗癫痫或惊厥的用途 Download PDFInfo
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- CN115400140A CN115400140A CN202210101550.7A CN202210101550A CN115400140A CN 115400140 A CN115400140 A CN 115400140A CN 202210101550 A CN202210101550 A CN 202210101550A CN 115400140 A CN115400140 A CN 115400140A
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- 125000000217 alkyl group Chemical group 0.000 claims description 31
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
本发明涉及呋喃核糖基吡啶衍生物用于预防或治疗癫痫或惊厥的用途,属于药物领域。本发明的药物能够改善癫痫发作的惊厥情况,并且改善Racine分级评分,为此对于预防或治疗此类疾病或病症具有重要意义。
Description
技术领域
本发明涉及呋喃核糖基吡啶衍生物用于预防或治疗癫痫或惊厥的用途,属于药物领域。
背景技术
癫痫(epilepsy)即俗称的“羊角风”或“羊癫风”,是大脑神经元突发性异常放电,导 致短暂的大脑功能障碍的一种慢性疾病。据中国最新流行病学资料显示,国内癫痫的总体患病 率为7.0‰,年发病率为28.8/10万,1年内有发作的活动性癫痫患病率为4.6‰。据此估计中国约 有900万左右的癫痫患者,其中500~600万是活动性癫痫患者,同时每年新增加癫痫患者约40 万,在中国癫痫已经成为神经科仅次于头痛的第二大常见病。癫痫可见于各个年龄段。儿童癫 痫发病率较成人高,随着年龄的增长,癫痫发病率有所降低。进入老年期(65岁以后)由于脑 血管病、老年痴呆和神经系统退行性病变增多,癫痫发病率又见上升。
目前国内外对于癫痫的治疗主要以药物治疗为主。癫痫患者经过正规的抗癫痫药物治疗, 约70%的患者其发作有望得到控制,其中50%~60%的患者经过2~5年的治疗有望痊愈,甚至 可以和正常人一样地工作和生活。因此,合理、正规的抗癫痫药物治疗是关键,有必要开发更 有效的预防或治疗癫痫的药物。
发明内容
为改善上述技术问题,本发明提供式I所示的化合物,其消旋体、立体异构体、互变异构 体、同位素标记物、溶剂化物或其前药在制备药物中的用途,所述药物用于预防和/或治疗癫 痫或惊厥:
其中,R1、R2、R3相同或不同,彼此独立地选自C1-22烷基或C2-22烯基,优选地,R1、R2、R3中至少一个为C7-22烷基或C7-22烯基,例如C7-12烷基、C20-22烷基、C7-12烯基或C20-22烯基;
A-选自药学上可接受的阴离子,例如R4COO-或卤素阴离子;
R4选自C1-22烷基或C2-22烯基,优选C7-22烷基或C7-22烯基,例如C7-12烷基、C20-22烷基、C7-12烯基或C20-22烯基。
根据本发明的实施方案,式I所示的化合物中的R1、R2、R3相同或不同,彼此独立地选自 C7-22烷基;例如为C7-12烷基或C20-22烷基;优选地,R1、R2、R3中至少一个为C7-12烷基或C20-22烷基;A-选自R4COO-或卤素阴离子,其中R4选自C7-12烷基或C20-22烯基。
根据本发明的实施方案,式I所示的化合物中的R1、R2、R3相同或不同,彼此独立地选自 C7-14烷基,例如庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基或十四烷基。
根据本发明的实施方案,式I所示的化合物中的R1、R2、R3中的至少一个,更优选两个或 三个基团选自癸基。
根据本发明示例性的技术方案,式I所示的化合物中的A-选自R4COO-或Cl-;优选地,R4选 自C7-14烷基,例如庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基或十四烷基。
根据本发明的实施方案,式I所示的化合物具有下式II所示的结构:
其中,R1、R2、R3、A-彼此独立地具有上文所述的定义。
根据本发明示例性的实施方案,式I所示的化合物具有下式III所示的结构,其在本说明书 中又称为NRTDA:
根据本发明的实施方案,所述药物还可以任选地包含其他活性成分,所述其他活性成分选 自自噬调节剂(Autophagy Modulator或AM)。
根据本发明的实施方案,所述其他活性成分可以选自选择性自噬调节剂(Selective Autophagy Modulator或AM),更优选自噬诱导剂(Autophagy Inducer)或选择性自噬诱导剂 (Selective Autophagy Inducer),例如,所述其他活性成分可以选自下列中的一种或多种,或 其药学上可接受的盐、前药(如药学上可接受的羧酸酯或磷酸酯)、溶剂合物:
ATP合酶抑制剂,例如:α-螺旋碱性肽抑制剂、血管抑素、肠抑素、腾毒素(Tentoxin)、 腾毒素类似物、白灰制菌素类(Leucinostatins)、肽抑制素(Efrapeptin)、芪类、黄酮、异黄 酮、甾族雌二醇、雌激素代谢物、聚酮类抑制剂(例如,大环内酯)、有机锡化合物、α-吡喃 酮及其衍生物等;优选地,所述大环内酯可以选自寡霉素、佩里霉素(Peliomycin)、杀黑星 菌素(Venturicidin)、奥萨霉素(Ossamycin)、Apoptolidin和胞变霉素(Cytovaricin);
TOR抑制剂,例如:雷帕霉素(Rapamycin,本说明书中可简称RAP)、雷帕霉素衍生物(如西罗莫司、替西罗莫司、依维莫司等)、达托里昔布(Dactolisib)、GSK2126458、XL765、AZD8055、INK128/MLN0128.OSI027、RapaLink类等;
AMPK激活剂,例如:间接AMPK激活剂、双胍类(如二甲双胍)、噻唑烷二酮类、多酚、人参皂苷类、α-硫辛酸,直接AMPK激活剂,如5-氨基咪唑-4-甲酰胺核糖核苷酸、噻吩并吡啶酮、苯并咪唑、水杨酸酯、PT-1、MT 63-78、噻吩并吡啶酮及其衍生物、苯并咪唑及其衍生物、5-(5-羟基-异噁唑-3-基)-呋喃-2-膦酸(C-2)等;
不依赖TOR的自噬增强剂,例如:N-烯丙基-6-溴喹唑啉-4-胺(SMER28)、氯喹或3-甲基 腺嘌呤(3-MA)等。
根据本发明的实施方案,所述药物还包括至少一种药学上可接受的辅料。
可按药剂领域中熟知的方式制备这些药物,可通过多种途径给予它们,这取决于是否需要 局部或全身治疗和所治疗的区域。可局部(例如,透皮、皮肤、眼和粘膜包括鼻内、阴道和直 肠递药)、肺(例如,通过吸入或吹入粉末或气雾剂,包括通过喷雾器;气管内、鼻内)、口 服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内 例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药,或可通过例如连续灌注泵给药。局 部给予的药用组合物和制剂可包括透皮贴剂、软膏、洗剂、霜剂、凝胶剂、滴剂、栓剂、喷雾 剂、液体剂、粉末制剂和散剂。常规药物载体、水、粉末或油性基质、增稠剂等可能是必须的 或需要的。
在制备本发明的药物时,通常将活性成分与辅料混合,通过辅料稀释或装入例如胶囊、小 药囊、纸或其它容器形式的这种载体内。当辅料用作稀释剂时,它可以是固体、半固体或液体 物质,用作溶媒、载体或活性成分的介质。因此,所述药物组合物可以是以下形式:片剂、丸 剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或 溶于液体溶媒);含例如高达10%重量式I所示的化合物,其消旋体、立体异构体、互变异构 体、同位素标记物、溶剂化物或其前药的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无 菌包装粉末。
适宜的辅料的某些实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷 酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。所述辅料还可选自:润滑剂例如滑石粉、硬脂酸钠、硬脂酸镁、油酸钠、苯甲酸钠、乙酸钠、氯化钠和矿物油;湿润剂;乳化剂和悬浮剂;防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯;甜味剂和矫味剂。可通过使用本领域中已知的方法配制本发明组合物,以便在给予患 者后提供速释、缓释或延迟释放活性成分的作用。
可按单位剂型配制所述药物,每一剂量中的活性成分彼此独立地选自约1~1000mg,更通 常约100~500mg。术语“单位剂型”是指物理上分离的适宜作为用于人患者和其它哺乳动物的 单一剂量单位,各单位含有与适宜的药物赋形剂混合的经计算可产生所需疗效的预定量的活性 物质。
所述活性成分的有效剂量的范围可很大,通常按药用有效量给药。但是,可以理解实际给 予的活性成分的量通常由医师根据相关情况决定,它们包括所治疗的病症、所选择的给药途径、 所给予的实际活性成分;患者个体的年龄、重量和反应;患者症状的严重程度等。
对于制备固体组合物例如片剂,将式I所示的化合物,其消旋体、立体异构体、互变异构 体、同位素标记物、溶剂化物或其前药与药物赋形剂混合,形成含式I所示的化合物,其消旋 体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药的均匀混合物的固体预制剂 组合物。当称这些预制剂组合物为均匀时,是指活性成分通常均匀地分布在整个组合物中,致 使该组合物可容易地划分为同等有效的单位剂型例如片剂、丸剂和胶囊剂。
可将本发明的片剂或丸剂包衣或复合,得到提供长效作用优点的剂型。例如,片剂或丸剂 含内剂量和外剂量组分,后者是前者的被膜形式。可通过肠溶层将两种组分隔离,肠溶层用于 在胃中阻止崩解,以使内组分完整通过十二指肠或延迟释放。多种物质可用于此类肠溶层或包 衣剂,此类物质包括多种高分子酸和高分子酸与此类物质如虫胶、鲸蜡醇和醋酸纤维素的混合 物。
根据本发明的实施方案,可掺入本发明的药物,用于口服或注射给药的液体形式包括水溶 液、适当矫味的糖浆剂、水或油混悬液;和用食用油例如棉子油、芝麻油、椰子油或花生油矫 味的乳剂;以及酏剂和类似的药用溶媒。
用于吸入或吹入的药物包括溶于药学上可接受的水或有机溶剂或其混合物的溶液剂和混 悬液、散剂。液体或固体药物可含有如上所述适宜的药学上可接受的赋形剂。在某些实施方案 中,通过口服或鼻呼吸途径给予所述药物组合物,实现局部或全身作用。可通过使用呈惰性的 气体,使组合物成雾化。可直接由雾化装置吸入雾化溶液,或雾化装置可与面罩帷或间歇正压 呼吸机连接。可通过口服或由按适当方式递送制剂的装置通过鼻给予溶液、混悬液或粉末形式 的药物。
给予患者的药物的量不固定,取决于给予的药物、给药的目的例如预防或治疗;患者的状 态、给药的方式等。在治疗应用时,可给予已患疾病的患者足够治愈或至少部分抑制疾病及其 并发症症状的量的组合物。有效剂量应取决于所治疗的疾病状态和主治临床医师的判断,该判 断取决于例如疾病的严重程度、患者的年龄、体重和一般状况等因素。
给予患者的药物可以是上述药用形式。可通过常规灭菌技术或可过滤灭菌,将这些药物灭 菌。可将水溶液包装原样使用,或冻干,给药前,将冻干制剂与无菌水性载体混合。所述药物 制剂的pH通常为3~11,更优选5~9,最优选7~8。可以理解,使用某些前述赋形剂、载体或 稳定剂会导致形成药物盐。
本发明药物的治疗剂量可根据例如以下而定:治疗的具体用途、给予药物的方式、患者的 健康和状态,以及签处方医师的判断。本发明式I所示的化合物,其消旋体、立体异构体、互 变异构体、同位素标记物、溶剂化物或其前药在药物中的比例或浓度可不固定,取决于多种因 素,它们包括剂量、化学特性(例如疏水性)和给药途径。
本发明还提供治疗和/或预防癫痫或惊厥的方法,包括给予患者治疗或预防有效量的式I所 示的化合物,其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药。
根据本发明的实施方案,所述癫痫选自原发性或继发性癫痫。
术语定义与说明
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的 定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以 彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当被理解为本申 请说明书和/或权利要求书记载的范围内。
除非另有说明,本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体 的整数数值。例如,数值范围“1-100”相当于记载了数值范围“1-100”中的每一个整数数值即1、 2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20……、90、91、92、93、94、95、96、97、98、99和100,以及介于上述整数之间的至少以0.1间隔的每个小数值。
除非另有说明,当本说明书上下文中提及“活性成分”时,其意指式I所示的化合物,其 消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物或其前药。
术语“卤素”表示氟、氯、溴和碘。
术语“C1-22烷基”应理解为表示具有1~20个碳原子的直链或支链饱和一价烃基,其也可称为 “直链或支链的C1-22烷基”。例如,表示具有1、2、3、4、5、6、7、8、9、10、11、1、13、14、15、16、17、18、19、20、21或22个碳原子的直链和支链烷基。“C8-12烷基”表示具有8、9、10、11或12个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六 烷基、十七烷基、十八烷基、十九烷基、二十烷基、异丙基、异丁基、仲丁基、叔丁基、异戊 基、2-甲基壬基、1-甲基壬基、1-乙基辛基、1,2-二甲基辛基、新戊基、1,1-二甲基辛基、4-甲 基壬基、3-甲基壬基、2-乙基辛基、3,3-二甲基辛基、2,2-二甲基辛基、2,3-二甲基辛基或1,3-二甲基辛基等或它们的异构体。
术语“C2-22烯基”应理解为优选表示直链或支链的一价烃基,其包含一个或多个双键并且具 有2~22个碳原子,优选“C2-10烯基”。“C2-10烯基”应理解为优选表示直链或支链的一价烃基,其 包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子,例如,具有2、3、4、5 或6个碳原子(即,C2-6烯基),具有2或3个碳原子(即,C2-3烯基)。应理解,在所述烯基包含 多于一个双键的情况下,所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2- 甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、 戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)- 戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2- 烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2- 烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基 丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、 (E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2- 甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基 丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
本发明的活性成分可以溶剂合物(如水合物)的形式存在,其中本发明的活性成分包含作 为所述化合物晶格的结构要素的极性溶剂,特别是例如水、甲醇或乙醇。极性溶剂特别是水的 量可以化学计量比或非化学计量比存在。
根据其分子结构,本发明的活性成分可以是手性的,因此可能存在各种对映异构体形式。 因而这些活性成分可以以消旋体形式或光学活性形式存在。本发明的活性成分涵盖了各手性碳 为R或S构型的异构体或其混合物、消旋体。本发明的活性成分可以通过本领域技术人员公知 的化学或物理方法分离为对映异构体化合物,或者以此形式用于合成。在外消旋的胺的情况中, 通过与光学活性的拆分试剂反应,从混合物制得非对映异构体。适当的拆分试剂的示例是光学 活性的酸,例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳 酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑 磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤 维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物),也可有利地进行色谱对 映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物,例如,己烷/异丙醇/乙腈。 可以根据已知的方法,例如通过萃取、过滤或柱层析来分离相应的稳定异构体。
术语“药学上可接受的阴离子”包括其合适的酸根或阴离子,例如选自下列酸的酸根或阴离 子:无机酸,如矿物酸,例如氢卤酸(如盐酸、氢溴酸和氢碘酸)、硫酸、磷酸硫酸盐、硫酸 氢盐、半硫酸盐、硫氰酸盐、过硫酸盐和磺酸;有机羧酸,如具有取代(例如,被卤素取代) 或未取代的1至22个碳原子的直链或支链烷基的羧酸,如乙酸、丙酸、丁酸、戊酸、己酸、 辛酸、壬酸、癸酸、十一烷酸、十二烷酸、十三烷酸、十四烷酸或十五烷酸;具有取代(例如, 被卤素取代)或未取代的2至22个碳原子的直链或支链烯基的羧酸,如丙烯酸、丁烯酸、戊 烯酸、己烯酸、辛烯酸、壬烯酸、癸烯酸、十一烯酸、十二烯酸、十三烯酸、十四烯酸或十五烯酸;饱和或不饱和二羧酸,例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或四邻苯二甲酸;羟基羧酸,例如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸;用氨基酸,例如天冬氨酸或谷氨酸;苯甲酸;或有机磺酸,如取代(例如,通过卤素取代)或未取代的(C1-C4)-烷基-或芳基-磺酸,如甲烷-或对甲苯磺酸。
优选的酸根或阴离子可以选自下列酸的酸根或阴离子:例如乙酸、、丙酸、丁酸、戊酸、 己酸、辛酸、壬酸、癸酸、十一烷酸、十二烷酸、十三烷酸、十四烷酸或十五烷酸、三氟乙酸、 乳酸、葡萄糖酸、柠檬酸、酒石酸、马来酸、苹果酸、泛酸、己二酸、藻酸、天冬氨酸、苯甲酸、丁酸、二葡糖酸、环戊酸、葡庚糖酸、甘油磷酸、草酸、庚酸、己酸、富马酸、烟酸、棕 榈酸酯、果胶酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、酒石酸、乳糖酸、pivolate、樟脑酸和 琥珀酸,有机磺酸如甲磺酸、乙磺酸、2-羟基乙烷磺酸、樟脑磺酸、2-萘磺酸、苯磺酸、对氯 苯磺酸和对甲苯磺酸;和无机酸如酸、氢溴酸、氢碘酸、硫酸、硫酸氢、半硫酸、硫氰酸、过 硫酸、磷酸和磺酸。
术语“药学上可接受的盐”包括其合适的酸加成盐或碱盐。关于合适的药物盐见JPharm Sci,66,199,1977,Berge等。例如用强无机酸,如矿物酸,例如氢卤酸(如盐酸、氢溴酸 和氢碘酸)、硫酸、磷酸硫酸盐、硫酸氢盐、半硫酸盐、硫氰酸盐、过硫酸盐和磺酸;用强有机羧酸,如未取代或取代的(例如,通过卤素)1至4个碳原子的链烷羧酸,如乙酸;用饱和 或不饱和二羧酸,例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或四邻苯二甲酸;用羟基羧酸,例如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸;用氨基酸,例如天冬氨酸或谷氨酸;用苯甲酸;或用有机磺酸,如未取代或取代的(例如,通过卤素)(C1-C4)-烷基-或芳基-磺酸,如甲烷-或对甲苯磺酸,来形成盐。
优选的盐包括,例如乙酸盐、三氟乙酸盐、乳酸盐、葡萄糖酸盐、柠檬酸盐、酒石酸盐、 马来酸盐、苹果酸盐、泛酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、丁酸盐、二葡糖 酸盐、环戊酸盐、葡庚糖酸盐、甘油磷酸盐、草酸盐、庚酸盐、己酸盐、富马酸盐、烟酸盐、棕榈酸酯、果胶酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、酒石酸盐、乳糖酸盐、pivolate、樟脑酸盐、十一酸盐和琥珀酸盐,有机磺酸如甲磺酸盐、乙磺酸盐、2-羟基乙烷磺酸 盐、樟脑磺酸盐、2-萘磺酸盐、苯磺酸盐、对氯苯磺酸盐和对甲苯磺酸盐;和无机酸如盐酸、 氢溴酸、氢碘酸、硫酸、硫酸氢、半硫酸、硫氰酸、过硫酸、磷酸和磺酸。
术语“前药化合物”,表示在体内释放所述活性成分的共价键合的化合物。这样的前药通 常是其中一个以上的适当基团已被修饰,使得在给药至人或哺乳动物受试者后该修饰可能被逆 转的本发明化合物。通常通过这类受试者中天然存在的酶来进行逆转,尽管可能将第二药剂与 这种前药一起给药以便在体内进行逆转。这类修饰的实例包括上文所述的药学上可接受的酯, 其中可以由酯酶等进行这种逆转。
术语“药学上可接受的酯”是指使用有机酸或醇/氢氧化物,与本发明化合物结构中可被酯 化的官能团形成酯。有机酸包括羧酸,如未取代或取代的(例如,通过卤素)1至12个碳原 子的链烷羧酸,如乙酸;用饱和或不饱和二羧酸,例如草酸、丙二酸、琥珀酸、马来酸、富马 酸、邻苯二甲酸或四邻苯二甲酸;用羟基羧酸,例如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石 酸或柠檬酸;用氨基酸,例如天冬氨酸或谷氨酸;用苯甲酸;或用有机磺酸,如未取代或取代 的(例如,通过卤素)(C1-C4)-烷基-或芳基-磺酸,如甲烷-或对甲苯磺酸。合适的氢氧化物包 括无机氢氧化物,如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铝。醇包括可以是未取代或取代 的(例如,通过卤素)1-12个碳原子的烷醇。
术语“同位素标记物”,表示本发明化合物中至少一个原子被同位素代替。所述同位素的实 例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,如相应的2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F和36Cl。用同位素如氘(即2H)取代可以提供由更大的代谢稳定性, 例如增加的体内半衰期或降低的剂量需求产生的某些治疗优势,因此在某些情况下可能是优选的。例如,本发明包括其中任一氢原子被氘原子代替的式I化合物。
术语“患者”是指包括哺乳动物在内的任何动物,优选小鼠、大鼠、其它啮齿类动物、兔、 狗、猫、猪、牛、羊、马或灵长类动物,最优选人。
术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个 体或人中寻找的引起生物学或医学反应的活性成分或药物组合的量,它包括以下一项或多项: (1)预防疾病:例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中 预防疾病、紊乱或病症。(2)抑制疾病:例如在正经历或出现疾病、紊乱或病症的病理或症 状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病: 例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转 病理和/或症状)。治疗有效量最初可以由细胞培养测定来进行估计,也可以从体内数据估计初 始剂量。使用这些初步指导,本领域普通技术人员可以确定人类的有效剂量。此外,也可以通 过细胞培养物或实验动物中的标准药物程序来确定本文所述化合物的毒性和治疗功效,例如通 过测定LD50和ED50。
有益效果
发明人出人意料地发现,式I所示的化合物,其消旋体、立体异构体、互变异构体、同位 素标记物、溶剂化物或其前药能够改善癫痫发作的惊厥情况,并且改善Racine分级评分,为此 对于预防或治疗此类疾病或病症具有重要意义。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施 例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明 上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制 备。
实施例1:1-((2R,3R,4S,5R)-3,4-二癸酰氧基-5-(癸酰氧甲基)四氢呋喃-2-基)-3-氨甲酰基吡 啶-1-鎓氯化物(NRTDA)的制备
在10~15℃将癸酰氧(150g,786.54mmol,163.22mL,3.27eq)滴加到烟酰胺核糖氯化物 (化合物NR,70g,240.80mmol,1eq)的吡啶(1L)溶液中。然后室温搅拌4小时,反应液直接 过滤,减压浓缩。得到的残留物用快速硅胶柱层析法(洗脱剂:0-5%的甲醇/二氯甲烷)分离纯 化,得到1-((2R,3R,4S,5R)-3,4-二癸酰氧基-5-(癸酰氧甲基)四氢呋喃-2-基)-3-氨甲酰基吡啶-1- 鎓氯化物(化合物NRTDA,32g,41.52mmol,收率17.24%,纯度97.77%)呈橙黄的固体。
MS m/z(ESI):717.7;
1H NMR:EB5107-1-P1A(400MHz,DMSO-d6)δ9.62(s,1H),9.18-9.37(m,2H),9.02(s,1H), 8.37-8.49(m,1H),8.24(s,1H),6.69(d,J=3.38Hz,1H),5.67(dd,J=3.75,5.50Hz,1H),5.47(t, J=5.88Hz,1H),4.63-4.72(m,1H),4.39-4.57(m,2H),2.23-2.46(m,6H),1.49-1.58(m,6H), 1.15-1.35(m,36H),0.80-0.91(m,9H)。
实施例2:本发明药物组合对大鼠癫痫治疗作用的实验研究
1.供试品
NRTDA,由实施例1制备,使用吐温80增加溶解。
2.阳性对照品
名称:丙戊酸(VPA),商品名:德巴金,生产单位:赛诺菲制药有限公司,批号:BHG0505, 规格:0.5g/片,保存条件:密封,25℃以下干燥保存,有效期:2024年1月,配制:使用超纯 水配制。
3.实验动物
雄性Wistar大鼠,分组时体重范围为180~200g,由河南省实验动物中心提供,在IVC环境 的饲养室饲养,参考标准GB 14925-2001,每日上午给鼠料一次,自由摄取,自由饮水。
4.实验动物的分组和识别方法
4.1动物识别方法
检疫期:用黑色油性笔标记区分动物(1/2/3/4号)。
给药观察期:用于给药的大鼠,用苦味酸进行标记,各笼动物(4只)分别以头、背、尾、 白顺序区分。
实验动物分组:检疫期结束,将所用大鼠按拟定计划进行造模、给药,按模型分为戊四唑 (PTZ)模型实验组。每种模型组又分别分为:
(1)模型组
(2)阳性药组(丙戊酸)
(3)NRTDA组(200mg)
4.2供试品和对照品的给药方法、频率、剂量和用药期限
给药方法:生理盐水、阳性药丙戊酸钠、受试物均为经口灌胃给药。
用药期限:戊四唑(PTZ)模型实验组于造模当天开始给药,前3天每天给药一次,后改 为隔天给药一次。给药28天。
给药频率:NRTDA组每天给药两次,上下午各一次。
4.3供试品和对照品的剂量设计
阳性药组:丙戊酸钠(100mg·kg-1·d-1)
供试品组:NRTDA组(200mg)。
每周称一次体重,给药量根据最新体重计算。
给药溶剂:均为1ml/200g。
5.实验方法
5.1戊四唑(PTZ)模型将24只大鼠(180±20g),随机分为模型组、阳性药组、治疗组, 共3组。各组前三天给予药物:模型组经口灌胃生理盐水5ml·kg-1d-1,阳性药组经口灌胃丙戊 酸钠5ml·kg-1d-1(100mg·kg-1d-1),治疗组按拟定剂量经口灌胃受试物,第四天给药30分钟后, 开始给予造模剂:正常组腹腔注射生理盐水3ml·kg-1d-1,其余组分别腹腔注射戊四唑 35mg·kg-1d-1(浓度1%),之后根据Racine[1]分级评分法每7天对大鼠惊厥进行评价。干预药物 共用药4周(时间参考模型组大鼠行为评级),造模剂用药3周,于第4周末次给予戊四唑点 燃测试后,参照Racine分级评分法对大鼠惊厥进行评价。之后处死大鼠,取脑,采用免疫组 化SP两步法测定大鼠脑组织中c-fos、c-jun蛋白阳性细胞数[2]。
5.2检测指标:大鼠体重及一般状态;Racine分级评分法对大鼠惊厥进行评分,c-fos、c-jun 蛋白阳性细胞数及脑组织神经元活性。
6.数据统计处理方法
7.实验结果
7.1体重及一般情况
试验期间各组大鼠体重均有所增加,NRTDA组大鼠体重增长缓慢,实验结束时二组大鼠 体重与模型组大鼠有显著性差异,P<0.05;实验期间各组大鼠一般状态无显著差异,结果见 表1。
表1各组大鼠体重
组别 | 检疫期体重 | 第一周体重 | 第二周体重 | 第三周体重 | 第四周体重 |
模型组 | 203.4±5.28 | 206.5±23.54 | 220.2±30.01 | 304±11.31 | 343.8±12.46 |
阳性组 | 216.3±7.4 | 257.2±9.33 | 274.5±11.5 | 325.5±15.5 | 349.5±11.5 |
NRDTA(200mg) | 201.8±7.46 | 218.8±4.15 | 251.3±10.06 | 282.3±11.30 | 299±9.41* |
*与当日模型组比,P<0.05。
7.2癫痫发作潜伏期、发作持续时间
各组大鼠给与戊四唑后,均于3min内出现癫痫症状,发作持续3-5min,组间未观察到显 著性差异。
7.3Racine分级评分法对各组大鼠进行评分
Racine分级评分法:0级,正常行为状态,无任何发作;Ⅰ级(1级),面肌抽动,咀嚼;Ⅱ级(2级),前肢阵挛,但无直立位;Ⅲ级(3级),前肢阵挛,伴直立位;Ⅳ级(4级), 全身强直-阵挛发作;V级(5级),全身强直-阵挛发作,伴跌倒。有效点燃标准:凡连续5 次达到2级以上惊厥,或2次5级以上惊厥者,为达到点燃标准。
实验结果见表2。
表2各组大鼠Racine分级评分结果
*与当日模型组比,P<0.05。
结果表明:NRDTA组的大鼠痫性发作较模型组大鼠症状要轻(Racine评分低),P<0.05。
以上对本发明的实施方式进行了示例性的说明。但是,本发明的保护范围不拘囿于上述示 例性的实施方式。应当理解,凡在本发明的精神和原则之内,本领域技术人员所做的任何修改、 等同替换、改进等,均应包含在本申请权利要求书的保护范围之内。
Claims (9)
2.如权利要求1所述的用途,其特征在于,R1、R2、R3相同或不同,彼此独立地选自C7-22烷基;例如为C7-12烷基或C20-22烷基;优选地,R1、R2、R3中至少一个为C7-12烷基或C20-22烷基;A-选自R4COO-或卤素阴离子,其中R4选自C7-12烷基或C20-22烯基。
3.如权利要求1或2所述的用途,其特征在于,R1、R2、R3相同或不同,彼此独立地选自C7-14烷基,例如庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基或十四烷基。
4.如权利要求1或2所述的用途,其特征在于,R1、R2、R3中的至少一个,更优选两个或三个基团选自癸基。
5.如权利要求1-4任一项所述的用途,其特征在于,A-选自R4COO-或Cl-;
优选地,R4选自C7-14烷基,例如庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基或十四烷基。
8.如权利要求1-7任一项所述的用途,其特征在于,所述药物还任选地包含其他活性成分,所述其他活性成分包括但不限于自噬调节剂;
优选地,所述其他活性成分选自选择性自噬调节剂,更优选自噬诱导剂或选择性自噬诱导剂,例如,所述其他活性成分可以选自下列中的一种或多种,或其药学上可接受的盐、前药(如药学上可接受的羧酸酯或磷酸酯)、溶剂合物:
ATP合酶抑制剂,例如:α-螺旋碱性肽抑制剂、血管抑素、肠抑素、腾毒素(Tentoxin)、腾毒素类似物、白灰制菌素类(Leucinostatins)、肽抑制素(Efrapeptin)、芪类、黄酮、异黄酮、甾族雌二醇、雌激素代谢物、聚酮类抑制剂(例如,大环内酯)、有机锡化合物、α-吡喃酮及其衍生物等;优选地,所述大环内酯可以选自寡霉素、佩里霉素(Peliomycin)、杀黑星菌素(Venturicidin)、奥萨霉素(Ossamycin)、Apoptolidin和胞变霉素(Cytovaricin);
TOR抑制剂,例如:雷帕霉素(Rapamycin,本说明书中可简称RAP)、雷帕霉素衍生物(如西罗莫司、替西罗莫司、依维莫司等)、达托里昔布(Dactolisib)、GSK2126458、XL765、AZD8055、INK128/MLN0128.OSI027、RapaLink类等;
AMPK激活剂,例如:间接AMPK激活剂、双胍类(如二甲双胍)、噻唑烷二酮类、多酚、人参皂苷类、α-硫辛酸,直接AMPK激活剂,如5-氨基咪唑-4-甲酰胺核糖核苷酸、噻吩并吡啶酮、苯并咪唑、水杨酸酯、PT-1、MT 63-78、噻吩并吡啶酮及其衍生物、苯并咪唑及其衍生物、5-(5-羟基-异噁唑-3-基)-呋喃-2-膦酸(C-2)等;
不依赖TOR的自噬增强剂,例如:N-烯丙基-6-溴喹唑啉-4-胺(SMER28)、氯喹或3-甲基腺嘌呤(3-MA)等。
9.如权利要求1-8任一项所述的用途,其特征在于所述癫痫选自原发性或继发性癫痫。
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