CN1901904A - 1,2-二氮杂-二苯并[e,h]薁用于制备治疗和预防中枢神经系统疾病和障碍的药物制剂的用途 - Google Patents
1,2-二氮杂-二苯并[e,h]薁用于制备治疗和预防中枢神经系统疾病和障碍的药物制剂的用途 Download PDFInfo
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- CN1901904A CN1901904A CNA2004800385511A CN200480038551A CN1901904A CN 1901904 A CN1901904 A CN 1901904A CN A2004800385511 A CNA2004800385511 A CN A2004800385511A CN 200480038551 A CN200480038551 A CN 200480038551A CN 1901904 A CN1901904 A CN 1901904A
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- alkyl
- dibenzo
- diaza
- azulene
- amine
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Landscapes
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及1,2-二氮杂-二苯并[e,h]薁类化合物以及它们的药理学上可接受的盐和溶剂化物制备药物制剂的用途,该药物制剂用于治疗和预防由生物胺或其它神经递质神经化学平衡紊乱所导致的中枢神经系统(CNS)疾病、损伤和障碍。
Description
发明的公开
本发明涉及1,2-二氮杂-二苯并[e,h]薁类化合物以及它们的药理学上可接受的盐和溶剂化物用于制备药物制剂的用途,该药物制剂用于治疗和预防由生物胺或其它神经递质神经化学平衡紊乱所导致的中枢神经系统(CNS)疾病、损伤和障碍。
在先技术
作为CNS中中枢神经递质系统一部分的生物胺(5-羟色胺、去甲肾上腺素、多巴胺)和其它神经递质的稳态和它们的受体的不规则可能是各种精神疾病、损伤和障碍的原因(例如抑郁、精神分裂症、躁狂行为和类似表现)。可能发生由神经递质浓度紊乱所导致的CNS中的病理改变的原因是生物胺和/或某些神经递质的合成失衡(过大或过小),贮存、释放、代谢和/或再吸收的不规则。
针对精神障碍发病理解的研究结果已经显示,5-羟色胺平衡在各种疾病中扮演重要角色。单胺缺陷假说是最初的解释之一,其中抑郁的症状与单胺神经传递减少有关,尤其是5-羟色胺(5-HT)和去甲肾上腺素,这也得到了神经化学试验以及用增加单胺能神经传递的物质成功治疗患者的证实(Expert Opin.Investig.Drugs 2003,12,531-543)。除了5-羟色胺能和去甲肾上腺素能系统以外,多巴胺能系统也在CNS功能障碍中扮演非常重要的角色。这些神经递质系统的确切角色和相互作用因大量受体亚型和它们的药理复杂性而难以理解。因而,已经观察到,例如多巴胺能神经传递受到5-HT2A受体的调节(L.G.Spampinato,J.Neurochem.2000,74,693-701),并且因此5-HT2A受体也可能是治疗疾病和障碍中的靶受体,在它们的病理学中多巴胺能系统功能障碍扮演重要角色(精神病和各种成瘾)。
谷氨酸受体在兴奋性突触传递的介导中扮演重要角色,是中枢神经系统(CNS)中主要的兴奋性神经递质之一。普遍接受的是σ1受体配体能够调控由中枢神经递质系统介导的神经传递,包括谷氨酸能/NMDA(F.P.Monnet,G.Debonnel,J.-L.Junien,C.de Montigny,Eur.J.Pharmacol.,1990,179,441-445)。很多药理和生理作用已经归因于σ1受体。它们包括IP3受体的调节和内质网处的钙信号发送,细胞骨架适配蛋白的活动,神经生长因子-诱导的轴突萌芽的调控,神经递质释放和神经元开通(firing)的调控,作为调节性亚单位的钾通道的调控,精神刺激剂-诱导的基因表达的改变,和蔓延性抑郁的阻滞。在行为上,σ1受体参与学习与记忆、精神刺激剂-诱导的敏化、可卡因-诱导的条件性空间偏爱、精神分裂症和疼痛感知。因而,假设σ1受体至少在部分程度上是细胞内放大器,在生物系统中产生信号转导的超敏化状态。
就病理性CNS障碍的治疗、并特别是精神障碍疗法而言,最频繁应用的药物根据它们的结构为多环化合物(苯并二氮杂、三环和四环抗抑郁剂、单胺氧化酶(MAO)抑制剂、5-羟色胺再吸收的选择性抑制剂等)。
通过引入新颖的四环抗抑郁剂米安色林,开辟了新的药物疗法领域(Claghorn,J.;Lesem,M.D.Prog.Drug Res.1996,46,243-262;Sperling,W.;Demling,J.Drugs Today 1997,33,95-102)。该文献公开了大量在CNS神经化学平衡紊乱的治疗中显示药理作用的四环衍生物。WO 99/19317、WO 97/38991和US 6,511,976描述了含有四氢呋喃环的四环衍生物的制备及其作为具有抗精神病、心血管和胃动力作用的物质的用途。US 4,145,434公开了二苯并(环庚三烯并-,氧杂并-,硫杂并-)吡咯烷和二苯并吡咯烷子基氮杂衍生物的制备及其作为具有潜在CNS作用的物质的用途。也公开过一些四环异唑烷衍生物的制备和潜在抗焦虑作用(Drugs Fut.2002,27,Suppl.A:C41;Drugs Fut.2002,27,Suppl.A:P182,WO 96/14320,WO96/14321)。向含有氧杂环的四环结构引入哌啶环导致显示抗抑郁作用的分子Org-4428的形成(Sperling,W.;Demling,J.Drugs Today1997,33,95-102)。分子Org-5222含有与氧杂核稠合的吡咯烷环,并被描述为潜在的抗焦虑剂和抗精神病剂(Sperling,W.;Demling,J.Drugs Today 1997,33,95-102)。作为一类新颖的具有抗炎作用的化合物,一些1,3-二氮杂-二苯并[e,h]薁衍生物及其盐也是已知的(US 3,711,489,US 4,198,421和CA 967,573)。
已知的还有具有取代基的四氢吡唑类2-取代的二苯并薁,所述取代基例如酰基烷氧基羰基、苯基或取代的苯基(Gansser C.et al.,Ann.Pharm.1984,41:465-471;或Olivera R.et al.,TetrahedronLetters,2000,41:4353-43564357-4360)。进而,已知有吡唑类二苯并氮杂的实例,其在2-位被烷基(Kawashiha K Takeda KenkysushoHo 1978,37:6-11,Fishou D et al.,Tetrahedron 1984,40.5121-5133)、苯基或取代的苯基(FR 2,504,140,EP 0063525)取代。
不过,本领域已知的用在病理性CNS障碍疗法、并特别是精神障碍疗法中的药物与广泛的副作用有关。因而需要CNS疾病和障碍的安全有效治疗。
在我们的早期国际公报WO 03/099822中(全文结合在此作为参考,并且如随27.08.2004的信的修改)我们公开过1,2-二氮杂-二苯并[e,h]薁类化合物、它们药学上可接受的盐和溶剂化物、用于其制备的方法和中间体以及它们的抗炎效果,尤其抑制肿瘤坏死因子-α(TNF-α)产生和抑制白介素-1(IL-1)产生以及它们的止痛作用。
我们现已惊人地发现,上述说明书所述1,2-二氮杂-二苯并[e,h]薁类化合物在CNS疾病和障碍的治疗中是有效的。这些化合物区别于本领域已知的作用于CNS的四环化合物(WO 99/19317,WO 97/38991;Sperling,W.;Demling,J.Drugs Today 1997,33,95 102,OliveraR.et al.,Tetrahedron Letters,2000,41:4353-43564357-4360,Kawashiha K Takeda Kenkysusho Ho 1978,37:6-11,EP 0063525)之处在于有价值的药理学和物理化学性质。
根据我们的认识,迄今尚未公开或提示过公开在我们的早期国际公报WO 03/099822中的1,2-二氮杂-二苯并[e,h]薁和它们药学上可接受的盐和溶剂化物用于制备药物制剂的用途,所述的药物制剂可用于治疗和预防由神经化学稳态紊乱所导致的中枢神经系统疾病、损伤和障碍。
技术问题的解决方案
本发明解决了有效治疗和预防由生物胺平衡紊乱所导致的中枢神经系统疾病、损伤和障碍的问题。因此,本发明涉及通式I的1,2-二氮杂-二苯并[e,h]薁类化合物和它们药学上可接受的盐和溶剂化物用于制备药物制剂的用途,
其中
X表示CH2或者选自O、S、S(=O)、S(=O)2和NRa的杂原子,其中Ra是氢或者选自C1-C3-烷基、C1-C3-烷酰基、C1-C7-烷氧基羰基、C7-C10-芳基烷氧基羰基、C7-C10-芳酰基、C7-C10-芳基烷基、C3-C7-烷基甲硅烷基和C5-C10-烷基甲硅烷基烷氧基烷基的取代基;
Y和Z彼此独立地表示一个或多个相同或不同的连接于任意可用碳原子的取代基,选自氢、卤素、C1-C4-烷基、C2-C4-烯基、C2-C4-炔基、卤代-C1-C4-烷基、羟基、C1-C4-烷氧基、三氟甲氧基、C1-C4-烷酰基、氨基、氨基-C1-C4-烷基、N-(C1-C4-烷基)氨基、N,N-二(C1-C4-烷基)氨基、巯基、C1-C4-烷硫基、磺酰基、C1-C4-烷基磺酰基、亚磺酰基、C1-C4-烷基亚磺酰基、羧基、C1-C4-烷氧基羰基、氰基、硝基;
R1表示CHO、CH2OH或式II取代基:
其中
R3和R4同时或彼此独立地具有下列含义:氢;C1-C4-烷基;具有芳族环以及稠合芳族环含义的芳基,含有一个具有至少6个碳原子的环或两个具有总计10个碳原子的环,并且在碳原子之间具有交替的双键;或者与N一起具有杂环或杂芳基的含义,其中杂环涉及五元或六元完全饱和或部分不饱和的杂环基团,含有至少一个选自O、S和N的杂原子,其中所述杂环可以任选地被一个或两个取代基取代,所述取代基选自卤素、C1-C4烷基、氰基、硝基、羟基、C1-C4烷氧基、巯基、C1-C4烷硫基、氨基、N-(C1-C4-烷基)氨基、N,N-二(C1-C4-烷基)氨基、磺酰基、C1-C4烷基磺酰基、亚磺酰基、C1-C4烷基亚磺酰基;其中杂芳基涉及单环或双环的芳族和部分芳族基团,具有4至12个碳原子,并且它们中的至少一个是选自O、S和N的杂原子,并且其中所述杂芳基可以任选地被一个或两个取代基取代,所述取代基选自卤素、C1-C4烷基、氰基、硝基、羟基、C1-C4烷氧基、巯基、C1-C4烷硫基、氨基、N-(C1-C4)烷基氨基、N,N-二(C1-C4-烷基)-氨基、磺酰基、C1-C4烷基磺酰基、亚磺酰基、C1-C4烷基亚磺酰基;
m代表整数1至3;
n代表整数0至3;
Q1和Q2彼此独立地具有氧、硫或下列基团的含义:
其中取代基
y1和y2彼此独立地具有下列含义:氢;卤素;C1-C4-烷基,任选地被一个、两个、三个或更多个取代基取代,所述取代基选自卤原子、羟基、C1-C4烷氧基、巯基、C1-C4烷硫基、氨基、N-(C1-C4)烷基氨基、N,N-二(C1-C4-烷基)-氨基、磺酰基、C1-C4烷基磺酰基、亚磺酰基和C1-C4烷基亚磺酰基;芳基,其任选地被一个、两个、三个或更多个取代基取代,所述取代基选自卤原子、羟基、C1-C4烷氧基、巯基、C1-C4烷硫基、氨基、N-(C1-C4)烷基氨基、N,N-二(C1-C4-烷基)-氨基、磺酰基、C1-C4烷基磺酰基、亚磺酰基和C1-C4烷基亚磺酰基,其中芳基具有如上所定义的含义;羟基;C1-C4-烷氧基;C1-C4-烷酰基;巯基;C1-C4-烷硫基;磺酰基;C1-C4-烷基磺酰基;亚磺酰基;C1-C4-烷基亚磺酰基;氰基;硝基;或者一起构成羰基或亚氨基;或者
R1具有氢的含义,条件是R2同时具有CH2OCH2CH2Si(CH3)3、CH2CH2C6H5、CH2CH2OH或式II取代基的含义;
R2表示氢、CH2OCH2CH2Si(CH3)3、CH2CH2C6H5、CH2CH2OH或式II取代基,其中式II具有如上所定义的含义;
该药物制剂用于治疗和预防由生物胺或其它神经递质神经化学平衡紊乱所导致的中枢神经系统疾病、损伤和障碍。
术语“卤代”、“卤”或“卤素”涉及卤原子,它可以是氟、氯、溴或碘(最优选氯或溴)。
术语“烷基”涉及具有从烷烃衍生的原子团含义的烷基,该原子团可以是直链、支链或环状的,或者直链与环状的组合和支链与环状的组合。优选的直链或支链烷基例如有甲基、乙基、丙基、异丙基、丁基、仲丁基和叔丁基。优选的环状烷基例如有环戊基或环己基。
术语“卤代烷基”涉及必须被至少一个卤原子取代的烷基。最常见的卤代烷基例如有氯甲基、二氯甲基、三氟甲基或1,2-二氯丙基。
术语“烯基”涉及具有烃原子团含义的烯基,它可以是直链、支链或环状的,或者是直链与环状或支链与环状的组合,但是具有至少一个碳-碳双键。最常见的烯基有乙烯基、丙烯基、丁烯基或环己烯基。
术语“炔基”涉及具有烃原子团含义的炔基,它是直链或支链的,含有至少一条、至多两个碳-碳叁键。最常见的炔基例如有乙炔基、丙炔基或丁炔基。
术语“烷氧基”涉及直链或支链烷氧基。这类基团的实例有甲氧基、丙氧基、丙-2-氧基、丁氧基、丁-2-氧基或甲基丙-2-氧基。
术语“芳基”涉及具有芳族环含义的基团,例如苯基,以及稠合芳族环。芳基含有一个具有至少6个碳原子的环或两个具有总计10个碳原子的环,并且在碳原子之间具有交替的双(共振)键。最常用的芳基例如有苯基或萘基。一般而言,芳基可以经由直接的键或者经由C1-C4亚烷基、例如亚甲基或亚乙基借助任意可用的碳原子连接于分子的其余部分。
术语“杂芳基”涉及具有单环或双环芳族和部分芳族基团含义的基团,具有4至12个碳原子,至少一个是杂原子,例如O、S或N,并且可用的氮原子或碳原子是该基团经由直接的键或者经由如前所定义的C1-C4亚烷基与分子其余部分键合的位置。这种类型的实例有噻吩基、吡咯基、咪唑基、吡啶基、唑基、噻唑基、吡唑基、四唑基、嘧啶基、吡嗪基、喹啉基或三嗪基。
术语“杂环”涉及五元或六元完全饱和或部分不饱和的杂环基团,含有至少一个杂原子,例如O、S或N,并且可用的氮原子或碳原子是该基团经由直接的键或者经由如前所定义的C1-C4亚烷基与分子其余部分键合的位置。最常见的实例有吗啉基、哌啶基、哌嗪基、吡咯烷基、吡嗪基或咪唑基。
术语“烷酰基”涉及直链酰基,例如甲酰基、乙酰基或丙酰基。
术语“芳酰基”涉及芳族酰基,例如苯甲酰基。
术语“任选被取代的烷基”涉及可以任选地另外被一个、两个、三个或多个取代基取代的烷基。这类取代基可以是卤原子(优选氟或氯)、羟基、C1-C4烷氧基(优选甲氧基或乙氧基)、巯基、C1-C4烷硫基(优选甲硫基或乙硫基)、氨基、N-(C1-C4)烷基氨基(优选N-甲基氨基或N-乙基氨基)、N,N-二(C1-C4-烷基)-氨基(优选二甲氨基或二乙氨基)、磺酰基、C1-C4烷基磺酰基(优选甲磺酰基或乙磺酰基)、亚磺酰基、C1-C4烷基亚磺酰基(优选甲亚磺酰基)。
术语“任选被取代的烯基”涉及任选地另外被一个、两个或三个卤原子取代的烯基。这类取代基例如可以是2-氯乙烯基、1,2-二氯乙烯基或2-溴丙烯-1-基。
术语“任选被取代的芳基、杂芳基或杂环”涉及可以任选地另外被一个或两个取代基取代的芳基、杂芳基或杂环基团。取代基可以是卤原子(优选氯或氟)、C1-C4烷基(优选甲基、乙基或异丙基)、氰基、硝基、羟基、C1-C4烷氧基(优选甲氧基或乙氧基)、巯基、C1-C4烷硫基(优选甲硫基或乙硫基)、氨基、N-(C1-C4)烷基氨基(优选N-甲基氨基或N-乙基氨基)、N,N-二(C1-C4-烷基)-氨基(优选N,N-二甲氨基或N,N-二乙氨基)、磺酰基、C1-C4烷基磺酰基(优选甲磺酰基或乙磺酰基)、亚磺酰基、C1-C4烷基亚磺酰基(优选甲亚磺酰基)。
若X具有NRa的含义,Ra涉及氢或者选自C1-C3-烷基(优选甲基或乙基)、C1-C3-烷酰基(优选甲酰基或乙酰基)、C1-C7-烷氧基羰基(优选甲氧羰基或叔丁氧羰基)、C7-C10-芳基烷氧基羰基(优选苄氧羰基)、C7-C10-芳酰基(优选苯甲酰基)、C7-C10-芳基烷基(优选苄基)、C3-C7-烷基甲硅烷基(优选三甲基甲硅烷基)或C5-C10-烷基甲硅烷基烷氧基烷基(优选三甲基甲硅烷基乙氧基甲基)的基团。
当R3和R4与N一起具有杂芳基或杂环的含义时,这意味着这类杂芳基或杂环有至少一个碳原子被氮原子代替,该基团通过它连接于分子其余部分。这类基团的实例有吗啉-4-基、哌啶-1-基、吡咯烷-1-基、咪唑-1-基或哌嗪-1-基。
根据特定取代基的属性,式I化合物可能具有几何异构体和一个或多个手性中心,因此可能存在对映体或非对映异构体。本发明也涉及这类异构体及其混合物、包括外消旋物的用途。
本发明还涉及特定式I化合物的所有可能的互变异构形式。
无论下文何时使用,术语“式I化合物”或“本发明化合物”意味着也包括药学上可接受的加成盐和溶剂化物。
在本发明的一种实施方式中,优选的式I化合物是这样的,其中X代表O、S或NRa,其中Ra是氢或者选自C1-C3-烷基(优选甲基、乙基、丙基或异丙基)、C1-C3-烷酰基(甲酰基或乙酰基)、C7-C10-芳酰基(优选苯甲酰基)和C7-C10-芳基烷基(优选苄基)的取代基。
在本发明的另一种实施方式中,优选的式I化合物是这样的,其中Y和Z彼此独立地表示一个或多个相同或不同的连接于任意可用碳原子的取代基,选自氢、氟、氯、溴、C1-C4-烷基(优选甲基、乙基、丙基或异丙基)、卤代-C1-C4-烷基(优选三氟甲基)、羟基、C1-C4-烷氧基(优选甲氧基)、三氟甲氧基、C1-C4-烷酰基(优选甲酰基或乙酰基)、氨基、氨基-C1-C4-烷基(优选氨基甲基)、N-(C1-C4-烷基)氨基(优选N-甲基或N-乙基)、N,N-二(C1-C4-烷基)氨基(优选二甲氨基或二乙氨基)、巯基、C1-C4-烷硫基(优选甲硫基)、氰基和硝基。
在本发明的另一种实施方式中,优选的式I化合物是这样的,其中R1具有CHO、CH2OH或式II取代基的含义:
其中
R3和R4同时或彼此独立地具有下列含义:氢;C1-C4-烷基(优选甲基、乙基、丙基或异丙基);芳基,其中芳基具有如上所定义的含义;或者与N一起具有杂环或杂芳基的含义,选自吗啉-4-基、哌啶-1-基、吡咯烷-1-基、咪唑-1-基和哌嗪-1-基;
m代表整数1至3;
n代表整数0至3;
Q1和Q2彼此独立地具有氧或CH2基团的含义;或者
R1具有氢的含义,条件是R2同时具有CH2OCH2CH2Si(CH3)3、CH2CH2C6H5、CH2CH2OH或式II取代基的含义。
在本发明的另一种实施方式中,具体优选的式I化合物是:
2-(8-氧杂-1,2-二氮杂-二苯并[e,h]薁-1-基)-乙醇;
2-(8-氧杂-1,2-二氮杂-二苯并[e,h]薁-2-基)-乙醇;
2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-1-基)-乙醇;
2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-2-基)-乙醇;
(2-苯乙基-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基)-甲醇;
(2-苯乙基-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基)-甲醇;
[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基]-甲醇;
[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基]-甲醇;
[11-氯-2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基]-甲醇;
二甲基-{2-[2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-1-基)-乙氧基]-乙基}-胺;
二甲基-{3-[2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-1-基)-乙氧基]-丙基}-胺;
二甲基-{2-[2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-2-基)-乙氧基]-乙基}-胺;
二甲基-{3-[2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-2-基)-乙氧基]-丙基}-胺;
二甲基-[2-(2-苯乙基-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-[3-(2-苯乙基-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
二甲基-[2-(2-苯乙基-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-[3-(2-苯乙基-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
二甲基-{2-[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-乙基}-胺;
二甲基-[2-(1H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-[2-(2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-{3-[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-丙基}-胺;
二甲基-[3-(1H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
二甲基-[3-(2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
二甲基-{2-[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-乙基}-胺;
二甲基-[2-(1H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-[2-(2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-{3-[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-丙基}-胺;
二甲基-[3-(1H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
二甲基-[3-(2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
{2-[11-氯-2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-乙基}-二甲基-胺;
[2-(11-氯-1H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-二甲基-胺;
[2-(11-氯-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-二甲基-胺;
{3-[11-氯-2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-丙基}-二甲基-胺;
[3-(11-氯-1H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-二甲基-胺;和
[3-(11-氯-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-二甲基-胺。
一般而言,由式I代表的1,2-二氮杂-二苯并[e,h]薁类化合物、它们药学上可接受的盐和溶剂化物可以借助我们的早期国际公报WO03/099822所述方法加以制备,全文结合在此作为参考,并且如随27.08.2004的信的修改。
本发明化合物在治疗这样的疾病和障碍中是尤其有效的,其中生物胺、例如5-羟色胺、去甲肾上腺素和多巴胺的神经化学平衡是紊乱的,并且可能是由某些神经递质的合成失衡(过大或过小)、贮存、释放、代谢和/或再吸收的不规则所导致的。
已经发现,本发明化合物对5-羟色胺受体、尤其5-HT2A和5-HT2C以及σ1受体表现显著的结合亲和性,并具有高度的选择性。
在本发明的一个实施方式中,式I化合物或者其盐或溶剂化物对5-HT2A和5-HT2C5-羟色胺受体显示结合亲和性,浓度以IC50值表示小于1μM,并且Ki值小于1μM。
在本发明的另一个实施方式中,式I化合物或者其盐或溶剂化物对5-HT2A5-羟色胺受体显示结合亲和性,浓度以IC50值表示小于约200nM,Ki值小于约100nM。
在本发明的另一个实施方式中,式I化合物或者其盐或溶剂化物对5-HT2C5-羟色胺受体显示结合亲和性,浓度以IC50值表示小于约200nM,并且Ki值小于约100nM。
已经发现,本发明化合物对σ1受体表现显著的结合亲和性。
在本发明的一个实施方式中,式I化合物或者其盐或溶剂化物对σ1受体显示结合亲和性,浓度以IC50值表示小于1μM,并且Ki值小于1μM。
在本发明的另一个实施方式中,式I化合物或者其盐或溶剂化物对σ1受体显示结合亲和性,浓度以IC50值表示小于约200nM,并且Ki值小于约100nM。
由于5-羟色胺受体是一系列CNS障碍的病理生理学的关键(直接或间接参与一些其它神经递质的活化,例如多巴胺和/或受体),本发明化合物可以用于制备治疗和预防其中生物胺和它们的受体扮演重要角色的疾病、损伤和障碍的药物制剂。
鉴于上文解释的本发明化合物的可取生物性质,治疗有效量式I化合物的给药提供了与更少副作用有关的CNS疾病和障碍的有效治疗方法,因为它们对于σ1受体和5-HT2A和5-HT2C5-羟色胺受体的选择性有所改善。
一般而言,本发明化合物可以用于制备用作抗抑郁剂、抗焦虑剂、抗精神病剂或治疗偏头痛药的药物制剂。
进而,本发明化合物可以用于制备治疗和预防这样的疾病和障碍的药物制剂,所述的疾病和障碍是中枢神经系统神经化学平衡紊乱的结果,例如抑郁与中度抑郁、焦虑、两极性精神障碍、睡眠障碍、性障碍、精神病、边缘性精神病、精神分裂症、偏头痛、人格障碍和强迫观念与行为障碍、社会恐怖或恐慌发作、儿童器质性精神障碍、攻击、老年人记忆障碍和人格障碍、成瘾、肥胖、食欲过盛和相似障碍、打鼾、经前期烦恼。
同样,这些化合物可以用于治疗和/或预防由创伤、脑中风、神经变性疾病、心血管障碍(例如高血压、血栓形成、梗塞和相似疾病)以及胃肠障碍所导致的CNS损伤。
本发明活性物质及其药学上可接受的盐或溶剂化物的有效剂量依赖于通式I化合物的功效、CNS疾病和障碍的属性和严重性以及所治疗患者的体重,并且可以从0.001-10mg/kg体重。在任何情况下,平均体重70kg的成人的单位剂量被理解为0.07-1000mg通式I化合物或者其药学上可接受的盐或溶剂化物。单位剂量可以每天给予一次或若干次,例如每天2、3或4次,最常见为每天1至3次。
本发明更具体涉及有效剂量的化合物,它们结合5-羟色胺、σ、肾上腺素能、多巴胺或毒蕈碱受体和/或充当一种或多种生物胺(5-羟色胺、多巴胺、去甲肾上腺素)再吸收的抑制剂。
术语“盐”可以包括游离碱的酸加成盐或加成盐。可以用于生成药学上可接受的酸加成盐的酸的实例包括但不限于从无毒的无机酸衍生的盐,例如硝酸、磷酸、硫酸、氢溴酸、氢碘酸、氢氟酸、亚磷酸,以及从无毒的有机酸衍生的盐,例如脂族一元和二元羧酸、苯基-取代的链烷酸、羟基链烷酸、链烷二酸、芳族酸、脂族和芳族磺酸,和乙酸、马来酸、琥珀酸或柠檬酸。这类盐的非限制性实例包括萘二磺酸盐(napadisylate)、苯磺酸盐、硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、三氟乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、邻苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐等。也涵盖氨基酸的盐,例如精氨酸盐等和葡萄糖酸盐、半乳糖醛酸盐(例如参见Berge S.M.et al.“PharmaceuticalSalts,”J.of Pharma.Sci.,1977;66:1)。
所述碱性化合物的酸加成盐是这样制备的,按常规方式使游离碱形式与足量所需酸接触,生成盐。按常规方式使盐形式与碱接触,再分离游离碱,可以再生游离碱形式。游离碱形式多少不同于它们各自的盐形式之处在于某些物理性质,例如在极性溶剂中的溶解度,但是出于本发明的目的,盐等价于它们各自的游离碱。
药学上可接受的碱加成盐是与金属或胺生成的,例如碱金属和碱土金属或有机胺。用作阳离子的金属的实例有钠、钾、镁、钙等。适合的胺的实例有N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、二环己胺、乙二胺、N-甲基葡糖胺和普鲁卡因。
所述酸性化合物的碱加成盐是这样制备的,按常规方式使游离酸形式与足量所需碱接触,生成盐。按常规方式使盐形式与酸接触,再分离游离酸,可以再生游离酸形式。
按照本发明,优选的药学上可接受的盐涉及氢溴酸、盐酸、高氯酸、硫酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、苯磺酸、草酸、对-甲苯磺酸、2-萘磺酸和磷酸的盐。
由式I代表的化合物或它们的盐所生成的药学上可接受的溶剂化物涉及水合物、乙醇化物等(最常见为水合物)。
用于本发明组合物的措辞“药学上可接受的”是指这类组合物的分子实体和其他成分,它们是生理学上可耐受的,并且在对哺乳动物(例如人)给药时通常不产生不期望的反应。优选地,本文所用的术语“药学上可接受的”表示获得联邦或州政府管理机构批准的,或者列在美国药典或其他公认的用于哺乳动物、更确切为人类的药典中的。
进而,本发明涉及药物制剂,其含有有效无毒剂量的本发明化合物以及药学上可接受的载体或溶剂。
用于本发明药物组合物的术语“载体”是指稀释剂、赋形剂或载体,它们与活性化合物一起给药。这类药物载体可以是无菌液体,例如水、盐水溶液、葡萄糖水溶液、甘油水溶液,和油类,包括石油、动物、植物或合成来源的那些,例如花生油、大豆油、矿物油、芝麻油等。不过,由于memantine是高度可溶的,水溶液是优选的。适合的药物载体参见“Remington’s Pharmaceutical Sciences”by E.W.Martin,18th Edition。本发明特别优选的是适合于即时释放的载体,也就是在短时间内例如60分钟或以下释放大多数或全部活性成分,使迅速的药物吸收成为可能。
“药学上可接受的赋形剂”表示可用于制备药物组合物的赋形剂,它一般是安全、无毒的,在生物学或其他方面不是不可取的,包括兽医用途以及人类药物用途的可接受的赋形剂。用在本申请中的“药学上可接受的赋形剂”包括一种和一种以上这类赋形剂。
药物制剂是这样得到的,将治疗活性量作为活性成分的某种物质与药学上可接受的载体掺合,根据所需的给药途径可能具有不同的剂型。这些药物制剂尤其涉及口服、舌下、直肠、经皮或肠胃外给药途径。
药物制剂可以利用常规药物助剂和制备途径加以制备。口服给药剂型可以是糖浆剂、胶囊剂、片剂等剂型,其中常用固体载体是惰性物质,例如乳糖、淀粉、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、甘露糖醇等,常用液体口服助剂包括乙醇、甘油、水等。利用常规方法,所有助剂可以任选地掺合有崩解剂、稀释剂、造粒剂、湿润剂、粘合剂等。肠胃外剂型可以使用水或一些其他无菌载体制备。在使用一些普通的液体载体制备口服制剂时,例如水、二醇、油类、醇类等,制剂可以是糖浆剂、乳剂、软明胶胶囊剂或无菌可注射液体的剂型,例如安瓿,或者非水性液体悬浮液。为了制备口服制剂,使用固体载体例如淀粉、糖、高岭土、湿润剂、粘合剂、崩解剂等,制剂可以是粉末剂、胶囊剂、片剂、硬明胶胶囊剂或可以在胶囊中给药的颗粒剂的剂型,固体载体的量可以各不相同(最常见为1mg至1g)。由于容易使用,片剂和胶囊剂是最方便的口服制剂,其中使用固体载体。就肠胃外制剂而言,载体多半是无菌的水,不过为了提高溶解度,其中也可以含有其他成分。就可注射溶液的制备而言,使用氯化钠溶液、葡萄糖溶液或其混合物。可注射溶液也可以含有延迟活性组分释放的组分。可以用于这种目的的适宜油类例如有花生油、芝麻油、棉籽油、玉米油、大豆油、长链脂肪酸的合成甘油酯或者一些所述油的混合物。可注射悬浮液可以按这样一种方式制备,以便所用适合的液体载体掺合有悬浮剂。在适宜于经皮给药的制剂中,作为载体有改善活性物质渗透性的物质和/或适合的湿润剂,它们可以合并有任何来源的适合的添加剂,这些添加剂不会对皮肤导致有害影响。所述添加剂可以促进皮肤给药和/或可以用于制备所需制剂,它们可以以各种方式应用,例如透皮、点涂或者以软膏剂的方式。
为了提高本发明化合物的溶解度和/或稳定性,在药理制剂中可以使用α-、β-或γ-环糊精或其衍生物,尤其是羟基烷基取代的环糊精,即2-羟丙基-β-环糊精。助溶剂、例如醇类也可以改善本发明化合物在各种药物制剂中的溶解度和/或稳定性。
“治疗”一种状态、障碍或病症包括:
(1)在可能患有该状态、障碍或病症或者有此倾向、但是尚未经历或显示该状态、障碍或病症的临床或亚临床症状的哺乳动物中,防止或延迟正在形成的该状态、障碍或病症的临床症状的出现,
(2)抑制该状态、障碍或病症,也就是阻止或减少该疾病或其至少一种临床或亚临床症状的发展,或者
(3)缓解该疾病,也就是导致该状态、障碍或病症或者至少一种其临床或亚临床症状的消退。
对受治疗者的益处是统计学上显著的或者至少是患者或医师可察觉的。
“治疗有效量”意味着化合物在对哺乳动物给药治疗一种状态、障碍或病症时足以实现这类治疗的量。“治疗有效量”将因化合物、疾病及其严重性和受治疗哺乳动物的年龄、体重、身体条件与反应性而变化。
剂量和给药方案可以根据受治疗患者或哺乳动物的年龄、性别、身体条件以及通过应用本发明化合物所达到的益处和副作用以及医师的判断加以调节,正如本领域技术人员所领会的。
本文所用的术语需要的宿主或受治疗者表示哺乳动物,优选人。
本发明化合物对神经化学稳态的影响是这样测定的,借助体外研究,例如用于5-HT2A的放射性核素-标记的放射性配体结合测定法,(Bonhaus D.W.Br.J.Pharmacol.1995,115:622;Saucier C.J.Neurochem.1997,68:1998)和用于5-HT2C受体(Wolf W.A.J.Neurochem.1997,69:1449),用于σ1受体的体外结合测定法(ThomsonW.and Donn R.Arthritis Res.2002,4:302-306),和借助体内研究,例如悬尾试验(Vogel H.G.and Vogel W.H.Drug Discovery andEvaluation Pharmacological Assays,Springer 1997,304)、苯丙胺-诱导的小鼠运动过多(Millan M.J.et al,1998 J Pharmacol.Exp.Ther.287:167-186)、小鼠被迫游泳试验(Porsolt R.D.et al.Arch.Int.Pharmacodyn.1977,229:327-336)、大鼠间-氯苯基哌嗪(m-CPP)试验(Drug Dev.Res.1989,18:119-144)和大鼠阿朴吗啡-色胺-去甲肾上腺素(ATN)试验(Arch.Int.Pharmacodyn.1977,227:238-253)。
测定5-HT2A和5-HT2C受体结合亲和性的体外方法
将小浓度具有巨大受体结合亲和性的放射性配体与富集某种受体的组织样品(1-5mg组织)温育在缓冲培养基(0.2-5mL)中。在CHO-K1或COS-7细胞中表达重组人HT2A和HT2C受体,并且也用于竞争性结合。在温育期间,放射性配体与受体结合。当达到结合平衡时,分离与放射性配体结合的受体和那些没有与所述配体结合的受体,测量受体/放射性配体复合物的放射性。在竞争性结合实验中测试供试化合物与受体的相互作用。向含有富集相应受体和放射性配体的所制备组织的温育混合物中加入各种浓度的供试化合物。供试化合物抑制放射性配体结合,其与某种化合物对受体的亲和性和该化合物的浓度成比例。
用于5-HT2A受体结合测定的放射性配体是[3H]-酮色林,所用组织是人皮质或者在CHO-K1中表达的重组5-HT2A受体。
用于5-HT2c受体结合测定的放射性配体是[3H]-美舒麦角,所用组织是脉络丛或者在CHO-K1细胞中表达的重组5-HT2c受体。
IC50和Ki低于1μM的化合物被视为有活性。
化合物:[2-(11-氯-1H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-二甲基-胺、二甲基-[3-(1H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺和二甲基-[3-(2-苯乙基-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺对5-HT2A和5-HT2C5-羟色胺受体显示结合亲和性,以IC50值表示小于200nM,并且Ki值小于100nM。
预计本发明其它化合物将观察到相似的结果。
测定σ1受体结合亲和性的体外方法
使Jurkat细胞生长在补充有10%胎牛血清、100U/ml青霉素和100μg/ml链霉素的RPMI培养基中,收集并均质化它们的悬液。离心后,分离膜级分,再悬浮在磷酸盐缓冲液(pH=7.5)中,以小的等分试样贮存在液氮中直至使用。
如先前所述测量不同放射性标记配体与Jurkat细胞膜的结合(Ramamoorthy et al.,1995)。为了鉴别Jurkat细胞系中的σ结合部位,首先使用[3H]氟哌啶醇作为配体。氟哌啶醇是1型和2型σ受体的高亲和性配体。使用Jurkat细胞膜进行结合测定,在单独[3H]氟哌啶醇(10nM)的存在下测定总结合,在[3H]氟哌啶醇(10nM)和未标记的氟哌啶醇(10μM)的存在下测定非特异性结合。
在室温下,将膜与配体在磷酸盐缓冲液中温育3小时。洗涤滤器后,借助液体闪烁分光术测定与滤器有关的放射性。
IC50和Ki低于1μM的化合物被视为有活性。
预计本发明其它化合物将观察到相似的结果。
小鼠被迫游泳试验
使用体重20-25g的雄性CD1小鼠进行实验。每组10只动物,通过在测试之前30min经口管饲,用供试化合物、丙咪嗪(阳性对照)或载体(阴性对照)处理,以测定功效。在实验当天,将动物置于玻璃圆柱体中(高18.2cm,直径13.3cm),灌入温热至22℃的水至10cm高度。不动性被定义为动物挣扎结束和漂浮开始,其中活动减少至动物为保持其头部在水面以上所不可缺少的那些,2分钟后开始记录,然后监测4分钟。
计算显示被动行为的动物百分比,并与用载体处理的对照组比较。
在10mg/kg的剂量下减少动物的不动性达30%且高于对照组的化合物被视为有活性。
预计本发明其它化合物将观察到相似的结果。
小鼠悬尾试验
使用体重20-25g的雄性Balb/cJ小鼠进行实验。每组9只动物,通过在测试之前30min腹膜内注射、皮下注射或经口管饲,用供试化合物、丙咪嗪(阳性对照)或载体(阴性对照)处理,以测量潜在的抗抑郁活性。在约90cm的高度悬挂小鼠的尾巴,观察5分钟。在观察期内小鼠悬挂完全不动达1分钟被定义为抑郁。在用具有抗抑郁作用的物质处理的动物中,不动期缩短了。
计算显示被动行为的动物百分比,与用载体处理的对照组比较。利用Fischer精确检验分析结果的显著性。
在10mg/kg的剂量下减少动物的不动性达40%且高于对照组的化合物被视为有活性。
预计本发明其它化合物将观察到相似的结果。
苯丙胺-诱导的小鼠运动过多
在运动过多诱导之前30分钟,将体重30-35g的雄性瑞士OFA小鼠用载体(盐水)或供试化合物处理。腹膜内给予硫酸右苯丙胺,剂量2mg/kg。30分钟后,将动物置于80×80cm的木箱中,其中的光照强度较低(100lux),进行运动活性记录。利用视频图象分析仪在30min内测定运动活性。测量总运动持续时间、运动的次数和总旅行距离。在0.25mg/kg的剂量下测试氟哌啶醇(在0.5%甲基纤维素中制备,充当参照物质)。
如果在10mg/kg的剂量下减少苯丙胺-诱导的实验动物运动过多达30%且高于载体处理的对照组,那么化合物被视为有活性。
预计本发明其它化合物将观察到相似的结果。
大鼠间-氯苯基哌嗪(m-CPP)试验
在试验前1小时对大鼠经口给予供试物质,在试验前15分钟静脉内给予1mg/kg剂量的m-CPP。在实验开始时,对大鼠进行开放场所试验(Drug Dev.Res.1989,18,119-144):仪器由开放的箱子组成,尺寸为80×65×35cm,在一壁上有直径10cm的开口,通过它连接尺寸为25×21×21cm的无照明室,并且开口用光源照明(IR光源或Kleverlux;12V/20W),距离为66cm;给予供试物质后一小时,将动物置于黑暗(无照明)室内,以便它们的头背离照明的出口,并且测量动物从黑暗室到达明亮室的穿行情况共10分钟。
物质的活性剂量被定义为由m-CPP诱导的效应减少40%和以上的剂量。
预计本发明其它化合物将观察到相似的结果。
大鼠阿朴吗啡-色胺-去甲肾上腺素(ATN)试验
在实验开始时(t=0),向动物静脉内注射1.25mg/kg阿朴吗啡,然后是40mg/kg色胺(t=60min)和1.25mg/kg去甲肾上腺素(t=90min)。
在60分钟内观察到有异常激越和正常行为的状态(苯丙胺试验),然后在色胺试验中观察到后爪(腿)的双侧(两侧)阵挛性惊厥和机体的全身震颤(观察期5分钟),在去甲肾上腺素试验中在注射后120分钟内死亡。
计算显示被动行为的动物百分比,与用载体处理的对照组比较。
在10mg/kg的剂量下比对照组减少所观察效应(可动性)持续时间达40%的化合物被视为在体内试验中有活性。
预计本发明其它化合物将观察到相似的结果。
在上述测定法中测试的一些本发明化合物在至少两项所述试验中显示作用,不过这些结果仅代表化合物生物作用的说明,不以任何方式限制本发明。
Claims (15)
1.通式I化合物和它们药学上可接受的盐和溶剂化物用于制备药物制剂的用途,
其中
X表示CH2或者选自O、S、S(=O)、S(=O)2和NRa的杂原子,其中Ra是氢或者选自C1-C3-烷基、C1-C3-烷酰基、C1-C7-烷氧基羰基、C7-C10-芳基烷氧基羰基、C7-C10-芳酰基、C7-C10-芳基烷基、C3-C7-烷基甲硅烷基和C5-C10-烷基甲硅烷基烷氧基烷基的取代基;
Y和Z彼此独立地表示一个或多个相同或不同的连接于任意可用碳原子的取代基,选自氢、卤素、C1-C4-烷基、C2-C4-烯基、C2-C4-炔基、卤代-C1-C4-烷基、羟基、C1-C4-烷氧基、三氟甲氧基、C1-C4-烷酰基、氨基、氨基-C1-C4-烷基、N-(C1-C4-烷基)氨基、N,N-二(C1-C4-烷基)氨基、巯基、C1-C4-烷硫基、磺酰基、C1-C4-烷基磺酰基、亚磺酰基、C1-C4-烷基亚磺酰基、羧基、C1-C4-烷氧基羰基、氰基和硝基;
R1表示CHO、CH2OH或式II取代基:
其中
R3和R4同时或彼此独立地具有下列含义:氢;C1-C4-烷基;具有芳族环以及稠合芳族环含义的芳基,含有一个具有至少6个碳原子的环或两个具有总计10个碳原子的环,并且在碳原子之间具有交替的双键;或者与N一起具有杂环或杂芳基的含义,其中杂环涉及五元或六元完全饱和或部分不饱和的杂环基团,含有至少一个选自O、S和N的杂原子,并且其中所述杂环可以任选地被一个或两个取代基取代,所述取代基选自卤素、C1-C4烷基、氰基、硝基、羟基、C1-C4烷氧基、巯基、C1-C4烷硫基、氨基、N-(C1-C4)烷基氨基、N,N-二(C1-C4-烷基)-氨基、磺酰基、C1-C4烷基磺酰基、亚磺酰基、C1-C4烷基亚磺酰基;其中杂芳基涉及单环或双环的芳族和部分芳族基团,具有4至12个碳原子并且它们中的至少一个是选自O、S和N的杂原子,并且其中所述杂芳基可以任选地被一个或两个取代基取代,所述取代基选自卤素、C1-C4烷基、氰基、硝基、羟基、C1-C4烷氧基、巯基、C1-C4烷硫基、氨基、N-(C1-C4)烷基氨基、N,N-二(C1-C4-烷基)-氨基、磺酰基、C1-C4烷基磺酰基、亚磺酰基、C1-C4烷基亚磺酰基;
m代表整数1至3;
n代表整数0至3;
Q1和Q2彼此独立地具有氧、硫或下列基团的含义:
其中取代基
y1和y2彼此独立地具有下列含义:氢;卤素;C1-C4-烷基,任选地被一个、两个、三个或更多个取代基取代,所述取代基选自卤原子、羟基、C1-C4烷氧基、巯基、C1-C4烷硫基、氨基、N-(C1-C4)烷基氨基、N,N-二(C1-C4-烷基)-氨基、磺酰基、C1-C4烷基磺酰基、亚磺酰基和C1-C4烷基亚磺酰基;芳基,其任选地被一个、两个、三个或更多个取代基取代,所述取代基选自卤原子、羟基、C1-C4烷氧基、巯基、C1-C4烷硫基、氨基、N-(C1-C4)烷基氨基、N,N-二(C1-C4-烷基)-氨基、磺酰基、C1-C4烷基磺酰基、亚磺酰基和C1-C4烷基亚磺酰基,其中芳基具有如上所定义的含义;羟基;C1-C4-烷氧基;C1-C4-烷酰基;巯基;C1-C4-烷硫基;磺酰基;C1-C4-烷基磺酰基;亚磺酰基;C1-C4-烷基亚磺酰基;氰基;硝基;或者一起构成羰基或亚氨基;或者
R1具有氢的含义,条件是R2同时具有CH2OCH2CH2Si(CH3)3、CH2CH2C6H5、CH2CH2OH或式II取代基的含义;
R2表示氢、CH2OCH2CH2Si(CH3)3、CH2CH2C6H5、CH2CH2OH或式II取代基,其中式II具有如上所定义的含义;
该药物制剂用于治疗和预防由生物胺或其它神经递质神经化学平衡紊乱所导致的中枢神经系统疾病、损伤和障碍。
2.根据权利要求1的用途,其中所选择的生物胺是5-羟色胺、去甲肾上腺素和多巴胺。
3.根据权利要求1的用途,其中神经递质是谷氨酸。
4.根据权利要求1、2或3的用途,其中通式I化合物通过调节生物胺或神经递质的合成、贮存、释放、代谢和/或再吸收和与它们受体的结合而作用于神经化学平衡。
5.根据权利要求4的用途,其中通式I化合物对一种或多种生物胺的受体显示结合亲和性。
6.根据权利要求5的用途,其中通式I化合物对5-羟色胺5-HT2A和5-HT2C受体显示显著的结合亲和性。
7.根据权利要求6的用途,其中通式I化合物对所选择的5-羟色胺受体显示结合亲和性,IC50<1μM。
8.根据权利要求1的用途,其中通式I化合物通过调控中枢神经递质系统而充当σ1受体配体,IC50<1μM。
9.根据权利要求1、6或8的用途,其中通式I化合物对σ1受体和至少一种选自5-HT2A和5-HT2C的5-羟色胺受体显示双重结合亲和性。
10.根据权利要求1的用途,其中中枢神经系统的疾病和障碍选自焦虑、抑郁与中度抑郁、两极性精神障碍、睡眠障碍、性障碍、精神病、边缘性精神病、精神分裂症、偏头痛、人格障碍和强迫观念与行为障碍、社会恐怖或恐慌发作、儿童器质性精神障碍、攻击、老年人记忆障碍和人格障碍、成瘾、肥胖、食欲过盛和相似障碍、打鼾、经前期烦恼。
11.根据权利要求1的用途,其中中枢神经系统损伤是由创伤、脑中风、神经变性疾病、心血管障碍(例如高血压、血栓形成、梗塞)以及胃肠障碍所导致的。
12.根据权利要求1的用途,其中X代表O、S或NRa,其中Ra是氢或者选自C1-C3-烷基、C1-C3-烷酰基、C7-C10-芳酰基和C7-C10-芳基烷基的取代基。
13.根据权利要求1或12的用途,其中Y和Z彼此独立地表示一个或多个相同或不同的连接于任意可用碳原子的取代基,选自氢、氟、氯、溴、C1-C4-烷基、卤代-C1-C4-烷基、羟基、C1-C4-烷氧基、三氟甲氧基、C1-C4-烷酰基、氨基、氨基-C1-C4-烷基、C1-C4-烷基氨基、N-(C1-C4-烷基)氨基、N,N-二(C1-C4-烷基)氨基、巯基、C1-C4-烷硫基、氰基和硝基。
14.根据权利要求1、12或13的用途,其中R1具有CHO、CH2OH或式II取代基的含义:
其中
R3和R4同时或彼此独立地具有下列含义:氢;C1-C4-烷基;芳基,其中的芳基具有如上所定义的含义;或者与N一起具有杂环或杂芳基的含义,选自吗啉-4-基、哌啶-1-基、吡咯烷-1-基、咪唑-1-基和哌嗪-1-基;
m代表整数1至3;
n代表整数0至3;
Q1和Q2彼此独立地具有氧或CH2基团的含义;或者
R1具有氢的含义,条件是R2同时具有CH2OCH2CH2Si(CH3)3、CH2CH2C6H5、CH2CH2OH或式II取代基的含义。
15.根据权利要求1的用途,其中通式I化合物、其药学上可接受的盐和溶剂化物选自下组:
2-(8-氧杂-1,2-二氮杂-二苯并[e,h]薁-1-基)-乙醇;
2-(8-氧杂-1,2-二氮杂-二苯并[e,h]薁-2-基)-乙醇;
2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-1-基)-乙醇;
2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-2-基)-乙醇;
(2-苯乙基-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基)-甲醇;
(2-苯乙基-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基)-甲醇;
[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基]-甲醇;
[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基]-甲醇;
[11-氧-2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基]-甲醇;
二甲基-{2-[2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-1-基)-乙氧基]-乙基}-胺;
二甲基-{3-[2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-1-基)-乙氧基]-丙基}-胺;
二甲基-{2-[2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-2-基)-乙氧基]-乙基}-胺;
二甲基-{3-[2-(8-硫杂-1,2-二氮杂-二苯并[e,h]薁-2-基)-乙氧基]-丙基}-胺;
二甲基-[2-(2-苯乙基-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-[3-(2-苯乙基-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
二甲基-[2-(2-苯乙基-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-[3-(2-苯乙基-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
二甲基-{2-[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-乙基}-胺;
二甲基-[2-(1H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-[2-(2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-{3-[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-丙基}-胺;
二甲基-[3-(1H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
二甲基-[3-(2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
二甲基-{2-[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-乙基}-胺;
二甲基-[2-(1H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-[2-(2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-胺;
二甲基-{3-[2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-丙基}-胺;
二甲基-[3-(1H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
二甲基-[3-(2H-8-硫杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-胺;
{2-[11-氯-2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-乙基}-二甲基-胺;
[2-(11-氯-1H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-二甲基-胺;
[2-(11-氯-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-乙基]-二甲基-胺;
{3-[11-氯-2-(2-三甲基甲硅烷基-乙氧基甲基)-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基]-丙基}-二甲基-胺;
[3-(11-氯-1H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-二甲基-胺;和
[3-(11-氯-2H-8-氧杂-1,2-二氮杂-二苯并[e,h]薁-3-基甲氧基)-丙基]-二甲基-胺。
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HRP20030956A | 2003-11-21 | ||
HR20030956A HRP20030956A2 (en) | 2003-11-21 | 2003-11-21 | USE OF 1,2-DIAZA-DIBENZO[e,h]AZULENES FOR THE MANU |
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CN1901904A true CN1901904A (zh) | 2007-01-24 |
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US (1) | US20070173492A1 (zh) |
EP (1) | EP1686989B1 (zh) |
JP (1) | JP2007512307A (zh) |
CN (1) | CN1901904A (zh) |
AT (1) | ATE420637T1 (zh) |
CA (1) | CA2546590A1 (zh) |
DE (1) | DE602004019133D1 (zh) |
ES (1) | ES2320229T3 (zh) |
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WO (1) | WO2005049015A1 (zh) |
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CH532038A (de) * | 1970-05-25 | 1972-12-31 | Ciba Geigy Ag | Verfahren zur Herstellung von neuen Cycloheptenderivaten |
US3859439A (en) * | 1970-05-26 | 1975-01-07 | Ciba Geigy Corp | 2,3-dihydro-5 -trifluoromethyl-1h-dibenzo(2,3:6,7) thiepino (4,5-c) pyrroles as cns-depressants |
US3711489A (en) * | 1971-03-31 | 1973-01-16 | Pfizer | Certain 8,9-dihydro(3,4,7,8)cycloocta(1,2-d)imidazoles |
US4112110A (en) * | 1974-02-22 | 1978-09-05 | Ciba-Geigy Corporation | Oxygenated azatetracyclic compounds |
US4271179A (en) * | 1976-05-24 | 1981-06-02 | Akzona Incorporated | 1,2,3,3a,8,12b-Hexahydro-dibenzo[1,2;5,6]cyclohepta[3,4-C]pyrroles and pharmaceutical use thereof |
NL7605526A (nl) * | 1976-05-24 | 1977-11-28 | Akzo Nv | Nieuwe tetracyclische derivaten. |
US4198421A (en) * | 1978-11-30 | 1980-04-15 | E. I. Du Pont De Nemours And Company | Antiinflammatory 2-substituted-dibenzo[2,3:6,7]oxepino[4,5-d]imidazoles |
US4267184A (en) * | 1979-02-08 | 1981-05-12 | E. I. Du Pont De Nemours And Company | Antiinflammatory 4,5-diaryl-2-(substituted-thio)pyrroles and their corresponding sulfoxides and sulfones |
US4267190A (en) * | 1980-04-18 | 1981-05-12 | E. I. Du Pont De Nemours And Company | Antiinflammatory 4,5-diaryl-α,α-bis(polyfluoromethyl)-1H-pyrrole-2-methanethiols |
FR2504140A1 (fr) * | 1981-04-16 | 1982-10-22 | Centre Nat Rech Scient | Nouveaux derives tetracycliques de la dibenzazepine, leur procede de preparation et les compositions pharmaceutiques en renfermant |
IE62754B1 (en) * | 1988-08-26 | 1995-02-22 | Akzo Nv | Tetracyclic antidepressants |
TR199801164T2 (xx) * | 1996-04-12 | 1998-10-21 | Janssen Pharmaceutica N.V. | S�bstit�e edilmi� tetrasiklik tetrahidrofuran t�revleri. |
UA52778C2 (uk) * | 1997-10-10 | 2003-01-15 | Янссен Фармацевтика Н.В. | Галогенозаміщені тетрациклічні похідні тетрагідрофурану, спосіб їх отримання та композиція на їх основі |
HRP20020305A8 (en) * | 2002-04-10 | 2009-03-31 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | 2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
HRP20020440B1 (en) * | 2002-05-21 | 2008-02-29 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | 1-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof |
HRP20020452A2 (en) * | 2002-05-23 | 2004-02-29 | Pliva D D | 1,2-diaza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof |
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2003
- 2003-11-21 HR HR20030956A patent/HRP20030956A2/xx not_active Application Discontinuation
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2004
- 2004-11-19 US US10/595,934 patent/US20070173492A1/en not_active Abandoned
- 2004-11-19 ES ES04798732T patent/ES2320229T3/es active Active
- 2004-11-19 CA CA002546590A patent/CA2546590A1/en not_active Abandoned
- 2004-11-19 JP JP2006540630A patent/JP2007512307A/ja active Pending
- 2004-11-19 WO PCT/HR2004/000053 patent/WO2005049015A1/en active Application Filing
- 2004-11-19 CN CNA2004800385511A patent/CN1901904A/zh active Pending
- 2004-11-19 EP EP04798732A patent/EP1686989B1/en active Active
- 2004-11-19 DE DE602004019133T patent/DE602004019133D1/de active Active
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CA2546590A1 (en) | 2005-06-02 |
JP2007512307A (ja) | 2007-05-17 |
US20070173492A1 (en) | 2007-07-26 |
DE602004019133D1 (de) | 2009-03-05 |
WO2005049015A1 (en) | 2005-06-02 |
EP1686989A1 (en) | 2006-08-09 |
ES2320229T3 (es) | 2009-05-20 |
ATE420637T1 (de) | 2009-01-15 |
HRP20030956A2 (en) | 2005-08-31 |
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