CN1291984A - 甘氨酸传输抑制剂 - Google Patents

甘氨酸传输抑制剂 Download PDF

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CN1291984A
CN1291984A CN99803530A CN99803530A CN1291984A CN 1291984 A CN1291984 A CN 1291984A CN 99803530 A CN99803530 A CN 99803530A CN 99803530 A CN99803530 A CN 99803530A CN 1291984 A CN1291984 A CN 1291984A
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W·H·M·L·卢伊顿
F·E·贾森斯
L·E·J·肯尼斯
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract

本发明涉及抑制甘氨酸传输的α,α－二苯基－1－哌啶丁酰胺在制备治疗中枢神经和末梢神经***疾病的药物中的用途,尤其是在治疗精神病,疼痛,癫痫,神经变性疾病(阿尔茨海默病),中风,头部外伤,多发性硬化等疾病的药物中的用途。本发明还涉及新化合物,它们的制备方法以及它们的药物形式。

Description

甘氨酸传输抑制剂
本发明涉及抑制甘氨酸传输的α，α-二苯基-1-哌啶丁酰胺在制备治疗中枢神经和末梢神经***疾病的药物中的用途，尤其是在制备治疗精神病，疼痛，癫痫，神经变性疾病(阿尔茨海默病)，中风，头部外伤，多发性硬化等疾病的药物中的用途。本发明还涉及新化合物，它们的制备方法以及它们的药物形式。
N，N-二甲基-α，α-二苯基-1-哌啶丁酰胺，如4-(4-氯苯基)-4-羟基-N，N-二甲基-α，α-二苯基-1-哌啶丁酰胺(氯苯哌酰胺，ImodiumTM)是已知的抗腹泻药物。这些化合物，它们的活性以及它们的制备方法首先公开于美国专利3，714，159。
本发明涉及抑制甘氨酸传输的化合物在制备治疗中枢神经和末梢神经***疾病的药物中的用途，所说化合物具有式(I)结构，其N-氧化物、立体化学异构体形式和可药用加成盐，其中R1和R2分别代表氢或C1-4烷基；X代表下列基团：其中点划线代表任选的键；-R3代表下列基团：
Figure 9980353000081
其中R6和R7分别代表氢，或二者与它们相连的两个碳原子一
起构成苯环；
R8代表氢或卤素；
n是1或2；R4代表氢，羟基，C1-4烷氧基，C1-4烷氧基C1-4烷基，或芳基C1-4烷氧基；R5代表二芳基甲氧基C1-4烷基，或下列基团：
Figure 9980353000091
其中B1代表-CH2-，-CH(OH)-，-NH-，-CH2-NH-或直键；B2代表-NH-，-CH2-或直键；B3代表-NR12-，-CH2，-C(=O)-或直键；B7代表-C1-4烷二基-NH-或-NH-C1-4烷基-；B8代表-NR19-，-CH2或-CH(芳基)-；每个Y各代表O或S；-a1=a2-a3=a4-代表下列二价基团：-CH=CH-CH=CH-(b-1-a)或-N=CH-N=CH-(b-1-b)其中基团(b-1-a)中的氢原子可以被羟基取代；R9代表C1-4烷基，芳基取代的C1-4烷基，噻吩基，呋喃基，羟基C1-4烷基取代的呋喃基，或噻唑基；R10代表芳基，芳基氨基，C1-4烷基氨基，C1-4烷硫基；R11代表氢，C1-4烷基，卤素或三氟甲基；R12代表氢或C1-4烷基羰基；R13代表氢，C1-4烷基或芳基；R14代表氢或卤素；R15和R16各代表氢或芳基；R17代表氢或C1-4烷基；R18代表芳基，10，11-二氢-5H-二苯并[b，f]吖庚因-5-基或任意被一个或两个分别选自C3-7环烷基和芳基的取代基取代的C1-4烷基，；R19代表氢，C1-4烷基羰基或二芳基C1-4烷基；R20，R21，R22和R23分别代表氢，C1-4烷基或芳基；R24代表氢或三氟甲基；R25代表氢或卤素；及如果R5代表式(b-3)基团，则R4可以是苯基-C1-4烷基氨基羰基；及R4和R5可以一起形成下式螺环基：
Figure 9980353000101
其中R26和R27各代表氢，C1-4烷基，芳基或芳基C1-4烷基；芳基指苯基，或被1或2个下列取代基取代的苯基：C1-4烷基，卤素，三氟甲基，羟基或C1-4烷氧基。
本发明还涉及治疗温血动物中枢神经和末梢神经***疾病的方法，尤其是治疗精神病，疼痛，癫痫，神经变性疾病(阿尔茨海默病)，中风，头部外伤，多发性硬化等疾病的方法。所说方法包括给患者使用与可药用载体混合的治疗有效量的式(I)化合物或其N-氧化物形式，可药用酸或碱加成盐或立体化学异构体形式。
在上文和下文定义中，卤素通常是指氟，氯，溴和碘；C3-7环烷基通常是指环丙基，环丁基，环戊基，环己基和环庚基；C1-4烷基定义为有1-4个碳原子的直链和支链的饱和烃，如甲基，乙基，丙基，丁基，1-甲基乙基，2-甲基丙基，2，2-二甲基乙基等；C1-4烷二基定义为有1-4个碳原子的直链和支链的二价饱和烃，如1，1-甲二基，1，2-乙二基，1，3-丙二基，1，4-丁二基，1，2-丙二基，2，3-丁二基等。
上述可药用加成盐是指由式(I)化合物构成有治疗活性的无毒碱或酸加成盐。式(I)化合物本身是游离碱的酸加成盐形式可以通过用适当酸处理该游离碱得到，所说的酸包括，例如无机酸，比如氢卤酸如盐酸或氢溴酸，硫酸，硝酸，磷酸等；或有机酸，比如乙酸，羟基乙酸，丙酸，乳酸，丙酮酸，草酸，丙二酸，琥珀酸，马来酸，富马酸，苹果酸，酒石酸，柠檬酸，甲磺酸，乙磺酸，苯磺酸，对甲苯磺酸，环己氨磺酸，水杨酸，对氨基水杨酸，扑酸等。
含有酸性质子的式(I)化合物可以通过用适当有机碱或无机碱处理转化成它们的有治疗活性的无毒碱，如金属或胺加成盐形式。相应的碱盐形式包括，例如，铵盐，碱金属和碱土金属盐如锂盐，钠盐，钾盐，镁盐，钙盐等；与有机碱形成的盐，如苄星青霉素G，N-甲基-D-葡糖胺，hydrabamine盐，以及与氨基酸形成的盐，如与精氨酸，赖氨酸等。
相反，所说盐也可以通过用适当碱或酸处理转化成游离形式。
这里所用术语加成盐还包括式(I)化合物的溶剂化物及其盐。这些溶剂化物有，例如，水合物，醇化物等。
式(I)化合物的N-氧化物形式是指其中哌啶的氮原子被氧化成N-氧化物的式(I)化合物。
这里所用术语“立体化学异构体形式”被定义为式(I)化合物所有可能的立体异构体形式。除非另有说明，化合物的化学命名也表示所有可能的立体化学异构体形式的混合物，特别是外消旋混合物，所说混合物包括基本分子结构的所有非对映体和对映体。显然，式(I)化合物的立体化学异构体形式及其混合物都属于式(I)范围。
尤其是式(I)化合物及它们的一些中间体在它们的结构中至少有一个立体结构(stereogenic)中心。该立体结构中心可以是R或S构型，所用符号R和S符合《纯应用化学》(Pure Appl．Chem．)，45：11-30(1976)所述法则。
有些式(I)化合物可以它们的互变异构体形式存在。尽管这些形式在上面结构式中没有明确指出，但也属于本发明范围。
无论在本文中何处使用，术语式(I)化合物都包括其N-氧化物形式，可药用加成盐和所有立体异构体形式。
式(I)化合物的确是新化合物，但要满足以下条件：如果R4是氢，R5是其中B1是-CH2-的式(b-1)基团，及R9是4-氟苄基，则-a1=a2-a3=a4-不能是-CH=CH-CH=CH-；及如果R4是氢，R5是其中B1是-NH-r的式(b-1)基团，及R9是4-甲氧基苄基，则-a1=a2-a3=a4-不能是-CH=N-CH=N-。本发明还涉及将所说新的式(I)化合物用作药物。
最好R5是二芳基甲氧基C1-4烷基或式(b-2)，(b-3)，(b-4)，(b-5)，(b-6)，(b-7)，(b-8)，(b-9)，(b-10)，(b-11)，(b-12)或(b-13)基团；或者R5与R4一起形成式(b-14)螺环基。
令人感兴趣的化合物是其中R1和R2是甲基的式(I)化合物。
具体的化合物是其中X代表式(a)基团的式(I)化合物，更具体地，X代表其中R6和R7与它们相连的两个碳原子一起构成一个苯环的式(a)基团。
其它具体的化合物是其中X代表式(b)基团的式(I)化合物，其中R5是式(b-1)基团，优选R9代表被芳基取代的C1-4烷基，更优选地，R9是4-氟苄基。
另一些具体的化合物是其中X代表式(b)基团的式(I)化合物，其中R5是式(b-2)基团，优选Y是S。
优选化合物是
4-(11，12-二氢-6H-苯并咪唑并[2，1-b][3]苯并吖庚因-6-基)-N，N-二甲基-α，α-二苯基-1-哌啶丁酰胺；
4-[[1-[(4-氟苯基)甲基]-1H-苯并咪唑-2-基]羟甲基]-N，N-二甲基-α，α-二苯基-1-哌啶丁酰胺；
及其N-氧化物，立体异构体形式和可药用加成盐。
通常，式(I)化合物可以根据US3，714，159，US4，695，575和US5，008，268所述反应方法进行制备，更具体地，通过其中W是适当反荷离子如卤素的式(II)中间体或其官能团衍生物与式(III)中间体反应来制备。
Figure 9980353000131
所说反应可以在对反应惰性的溶剂，如在甲基异丁酮，N，N-二甲基乙酰胺或N，N-二甲基甲酰胺中，在适当碱如碳酸钠，碳酸氢钠或三乙胺存在下，以及任选在碘化钾存在下进行。
在本反应和下述制备过程中，可以根据本领域普通技术人员已知的方法从反应介质中分离出来反应产物，如果需要，再进一步纯化，这些方法包括，例如，萃取法，结晶法，蒸馏法，研磨法和色谱法。
还可以采用本领域已知的官能团转换方法对式(I)化合物进行彼此间的相互转化。
可以采用本领域已知的将三价氮转化成其N-氧化物形式的方法将式(I)化合物转化成相应的N-氧化物形式。所说N-氧化反应一般是通过式(I)起始原料与3-苯基-2-(苯基磺酰基)氧杂环乙亚胺(oxaziridine)或与适当有机或无机过氧化物反应进行。适当的无机过氧化物包括，例如，过氧化氢，碱金属或碱土金属过氧化物，如过氧化钠，过氧化钾；适当的有机过氧化物可以包括过氧酸(peroxyacid)，如苯甲过氧酸(benzenecarboperoxoic acid)或卤素取代的苯甲过氧酸，例如，3-氯苯甲过氧酸，过氧烷基酸如过氧乙酸，烷基过氧化氢如叔丁基过氧化氢。合适的溶剂有，例如，水，低级链烷醇如乙醇等，烃如甲苯，酮如2-丁酮，卤化烃如二氯甲烷，以及这些溶剂的混合物。
本发明一些式(I)化合物和一些中间体可能含有一个不对称碳原子。所说化合物和所说中间体的纯立体化学异构体形式可以用现有技术中的已知方法制得。例如，非对映体可以用物理方法如选择性结晶法或色谱技术，例如反流分布，液相色谱等方法分离。对映体可以用以下方法从外消旋混合物得到：首先，用适当的溶解剂如手性酸将外消旋混合物转化成非对映体盐或化合物的混合物；然后，用物理方法如选择性结晶法或色谱技术，例如，液相色谱等方法分离，将所说非对映体盐或化合物的混合物分离；最后，将所说分离的非对映体盐或化合物转化为对应的对映体。纯立体化学异构体形式也可以从相应的中间体和起始原料的纯立体化学异构体形式制得，条件是介入的反应都是立体有择性的。
分离式(I)化合物和中间体的对映体形式的另一种方法涉及到液相色谱，尤其是采用手性固定相的液相色谱。
一些中间体和起始原料是已知化合物，而且可以购得或根据现有技术中的已知方法制备。
甘氨酸是中枢神经和末梢神经***中抑制性和刺激性神经突触的氨基酸神经传递质。甘氨酸这些显著的功能是由两类受体介导，它们分别与不同类型的甘氨酸传输体有关。甘氨酸的抑制性行为由对生物碱马钱子碱惊厥剂敏感的甘氨酸受体介导，并因此称为“马钱子碱敏感的”。马钱子碱敏感的甘氨酸受体主要是在脊髓和脑干中发现的。
通过调节谷氨酸酯-神经***中主要的刺激性神经传递质-的行为使甘氨酸在刺激性传输中发挥作用(Johnson和Ascher，《自然》(Nature)，325：529-531(1987)；Fletcher等人，《甘氨酸传输》(Glycine Transmission)，Otterson和Storm-Mathisen编辑，pp．193-219(1990))。明确地说，甘氨酸是被称为N-甲基-D-天冬氨酸酯(NMDA)一类谷氨酸酯的约束性共促效剂。NMDA受体范围很宽地分布于整个脑中，尤其是在大脑皮质和海马形成位置具有高密度。
传输体从突触中吸收神经传递质，进而调整突触中神经传递质的浓度和范围，二者一起决定突触传输的数量。通过防止神经传递质向相邻的突触扩散传输体维护了突触传输的逼真程度。最后，通过将释放的传递质重新摄取到前突触端，传输体准许传递质重新被利用。神经传递质的传输取决于细胞外的钠和膜两边的电压差。在特殊条件下，例如在捕获期间，传输体可以相反的方式作用，即以不依赖钙的非细胞外的方式释放神经传递质(Attwell等人，《神经元》(Neuron)，11：401-407(1993))。因此，神经传递质传输体的调整提供了一种改变突触活性的方法，即提供了治疗中枢神经和末梢神经***紊乱有用的治疗方法。
分子克隆技术揭示了两种称为GlyT-1和GlyT-2的甘氨酸传输体的存在。GlyT-1主要是在前脑中发现的，其分布对应于谷氨酸能途径和NMDA受体的分布(Smith等人，《神经元》(Neuron)，8：927-935(1992))。至少有3种GlyT-1接合变体是已知的，分别称为GlyT-1a，GlyT-1b和GlyT-1c(Kim等人，《分子药理学》(MolecularPharmacology)，45：608-617(1994))，它们中的每一个在脑及周边组织中都表现出唯一的分布。而GlyT-2主要是在脑干和脊髓中发现的，其分布紧紧对应于马钱子碱敏感的甘氨酸受体的分布(Liu等人，《生物化学杂志》(J．Biological Chemistry)，268：22802-8(1993)；Jursky和Nelson，《神经化学》(Neurochemistry)，64：1026-33(1995))。因此，人们期望，通过调节甘氨酸的突触水平，GlyT-1和GlyT-2可以分别选择性地调整NMDA受体和马钱子碱敏感的甘氨酸受体的活性。
因此，人们期望抑制或活化甘氨酸传输体的化合物能够改变受体功能，从而利于多种疾病的治疗。因此，通过增加甘氨酸的突触水平抑制GlyT-2特性被用来消除马钱子碱敏感的甘氨酸受体的神经元活性，进而消除疼痛相关信息(即伤害感受)在脊髓中的传输，该信息显然是由这些受体介导的(Yaksh，《疼痛》(Pain)，37：111-123(1989))。另外，提高抑制性甘氨酸能通过马钱子碱敏感的甘氨酸受体在脊髓中的传输可被用来降低肌肉的机能亢进，这一点对治疗与肌肉收缩增加如痉挛状态，肌阵挛和癫痫有关的疾病或症状很有用(Truong等人，《运动疾病》(Movement Disorder)，3：77-87(1988)；Becker，FASEB J，4：2767-74(1990))。通过调节甘氨酸受体可以治疗的痉挛状态与癫痫，中风，脑外伤，多发性硬化，脊髓损伤，张力障碍和其它神经***病症和损伤有关。
NMDA受体涉及到记忆力和学习能力(Rison和Stanton，《神经学生物行为评论》(Neurosci．Biobehav．Rev．)，19：533-552(1995)；Danysz等人，《行为药理学》(Behavioral Pharmacol．)，6：455-474(1995))；而且，NMDA介导的神经元传输功能的降低显然对精神***症有贡献(Olney和Farber，《普通神经病学档案》(Archives General Psychiatry)，52：998-1007(1996))。因此，抑制GlyT-1从而增加NMDA受体甘氨酸活化能力的药剂可以被用作新型抗精神病药和抗痴呆药，以及用来治疗其它认知过程减弱的疾病，如注意力缺陷症和有机脑综合征。相反，NMDA受体过分活化已经蕴含在大量疾病状态中，特别是在与下列疾病有关的神经元死亡中：中风，脑外伤和可能的神经变性疾病如阿尔茨海默病，多发性梗塞痴呆，AIDS痴呆，亨廷顿病，帕金森病，肌萎缩性侧索硬化或发生神经元细胞死亡的其它症状(Coyle＆Puttfarcken，《科学》(Science)，262：689-695(1993)；Lipton和Rosenberg，《新英格兰医学杂志》(New Engl．J．of Medicine)，330：613-622(1993)；Choi，《神经元》(Neuron)，1：623-634(1988))。因此，增加GlyT-1活性的药剂将使NMDA受体甘氨酸活化能力降低，这些药剂被用于治疗上述疾病和相关疾病。类似地，那些直接阻断位于NMDA受体上的甘氨酸的药物可用于治疗上述疾病和相关疾病。
为了给药，本化合物可以制成含有可药用载体和作为活性成分的治疗有效量的式(I)新化合物的各种药物组合物。为了制备本发明药物组合物，作为活性成分的有效量的具体化合物以加成盐或游离酸或碱的形式与可药用载体以紧密混合的方式结合，这些组合物可以有很多种形式，这取决于给药所需的制剂形式。这些药物组合物优选采用适于口服给药，皮下或胃肠外注射的理想的单一剂量形式。例如，在制备口服剂型的组合物时任何常用的药物介质都可以使用，例如，在制备口服液体制剂如悬浮剂，糖浆，酏剂和溶液时可以使用水，二元醇类，油类，醇类等；而在制备粉剂，丸剂，胶囊剂和片剂时可使用淀粉，糖类，高岭土，润滑剂，粘结剂，崩解剂等固体载体。由于片剂和胶囊剂易于给药，因此，它们是最有效的口服单剂，这种情况显然用的是固体药用载体。对于胃肠外组合物，虽然可以含有其它成分如助溶剂，但载体通常还是无菌水，至少大部分是无菌水。注射液可以制成，例如，载体为盐水溶液，葡萄糖溶液，或盐水溶液和葡萄糖溶液的混合物的制剂。含有式(I)化合物的注射液也可以在油中配制以延长活性。用于此目的的合适的油包括，例如，花生油，芝麻油，棉籽油，玉米油，豆油，长链脂肪酸的合成甘油酯，以及它们的混合物和与其它油类的混合物。注射悬浮液可以用适当的液体载体，悬浮剂等制备。在适于皮下给药的组合物中载体任选含有渗透性提高剂和／或适宜的润湿剂，任选与极少量任何合适的天然添加剂结合，所说添加剂对皮肤没有任何明显的有害作用。所说添加剂可以用于给皮肤给药和／或帮助制备所要的组合物。这些组合物可以多种方式给药，例如，制成透皮贴剂，贴剂(spot-on)或软膏。由于式(I)的加成盐的水溶性超过其游离碱或游离酸形式，因此它显然更适于水性组合物的制备。
将上述药物组合物制成易于给药的剂量单位形式或单剂是非常有益的。本说明书和所附权利要求书中所用的剂量单位形式指适合单剂的物理上离散的单元，每个单元含有经过计算能产生所要治疗效果的预定量的活性成分，并含有所要求的药物载体。这种剂量单位形式的实例有：片剂(包括带刻痕或包衣的片剂)，胶囊剂，丸剂，粉包，干胶片，注射液或悬浮液，一茶匙，一汤匙等，以及它们的分开的多倍包装。
下列实施例用以说明本发明。
实施例部分
实施例A．1
将按照US3，714，159所述方法制备的二甲基(四氢-3，3-二苯基-2-呋喃亚基)溴化铵(0．01mol)，(±)-4-(11，12-二氢-6H-苯并咪唑并[2，1-b][3]苯并吖庚因-6-基)哌啶(0．01mol)，Na2CO3(0．01mol)和KI(10mg)的甲基异丁基酮(200ml)混合物搅拌及回流过夜。蒸发溶剂，将剩余物溶入H2O／CH2Cl2。分离出有机相，水相再次用CH2Cl2萃取。干燥合并的有机相，过滤并蒸发溶剂。剩余物在硅胶上方用玻璃滤纸进行纯化(洗脱剂：CH2Cl2／CH3OH 95／5至90／10)。收集纯化部分并蒸发，剩余物从CH3CN结晶，得到0．88g(15％)(±)-4-(11，12-二氢-6H-苯并咪唑并[2，1-b][3]苯并吖庚因-6-基)-N，N-二甲基-α，α-二苯基-1-哌啶丁酰胺(化合物1；m．p．255．3℃)。
实施例A．2
在70℃向搅拌的4-(3-溴-2-氧丙基)-N，N-二甲基-α，α-二苯基-1-哌啶丁酰胺一氢溴化物(13g)的甲醇(80ml)混合物中加入(2，6-二甲基苯基)硫脲(4．1g)。在回流温度继续搅拌1小时。蒸发溶剂，将剩余物溶入水。加入碳酸钾，直到pH达到约9。用乙酸乙酯萃取混合物。通过酸碱萃取纯化有机相，干燥，过滤并蒸发溶剂。剩余物从甲醇结晶。滤出沉淀，洗涤并干燥，得到6．7g(52％)4-[[2-[(2，6-二甲基苯基)氨基]-4-噻唑基]甲基]-N，N-二甲基-α，α-二苯基-1-哌啶丁酰胺(化合物47；m．p．210．5℃)。
用类似方法制备
4-[[2-[(2，6-二氯苯基)氨基]-4-噻唑基]甲基]-N，N-二甲基-α，α-二苯基-1-哌啶丁酰胺(化合物48；m．p．207．0℃)；及
N，N-二甲基-4-[[2-(甲基氨基)-4-噻唑基]甲基]-α，α-二苯基-1-哌啶丁酰胺(化合物49；m．p．188．3℃)。
实施例A．3
向搅拌的NaH(78％的分散液；0．55g)的1，4-二噁烷(50ml)混合物中加入1-(4-氟苯基)-N，N-二甲基-4-氧-α，α-二苯基-1，3，8-三氮杂螺[4，5]癸烷-8-丁酰胺(7．7g)。在室温搅拌1小时后将混合物加热到60℃，加入2．3g(氯甲基)苯。在60℃持续搅拌过夜。将反应混合物倒在水上，用CHCl3萃取。萃取液用水洗涤，干燥，过滤并蒸发溶剂。剩余物在硅胶上用柱色谱纯化，用氨气饱和的CHCl3和3％甲醇混合物作洗脱剂。收集纯化部分并蒸发溶剂，剩余物在正己烷中研磨。滤出沉淀，然后干燥，得到2g1-(4-氟苯基)-N，N-二甲基-4-氧-α，α-二苯基-3-苯基甲基-1，3，8-三氮杂螺[4，5]癸烷-8-丁酰胺(化合物50；m．p．139．8℃)。
表1和2列出了根据实施例A．1方法制备的化合物。一些化合物的制备采用了不同于实施例A．1中所用的碱和／或溶剂。另外，一些化合物的制备没有用KI。表1和2中“反应条件”一栏提到了反应条件，该栏中的MIK表示甲基异丁基酮，DMA表示N，N-二甲基乙酰胺，及DMF表示N，N-二甲基甲酰胺。
表1
Figure 9980353000192
Figure 9980353000201
表2
Figure 9980353000233
还可根据实施例A．1所述方法，但不用KI，制备1-(5-氯-2-甲基苯基)-N，N-二甲基-4-氧-α，α-二苯基-1，3，8-三氮杂螺[4，5]癸烷-8-丁酰胺(化合物46；m．p．175．7℃)。药理学实施例实施例B．1：通过GlyT-1传输体传输的测定
将Subconfluent HEK 293-GlyT1细胞(即稳定表达人甘氨酸传输体1的细胞系)以每孔50，000个细胞的密度接种到有100μL DMEM培养基(Dulbecco’s Modified Eagle Medium，其中有10％胎牛血清，1mM丙酮酸钠，2mM谷氨酸，100U青霉素／ml和0．1mg／ml链霉素)的Cytostar-T板上。将细胞在37℃，5％CO2及95％相对湿度条件下培养48小时。
第3天，在设计用来清洗微滴定板上所有96个孔的同时带有摄取缓冲液(25mM Hepes，5．4mM葡萄糖酸钾，1．8mM葡萄糖酸钙，0．8mM MgSO4，140mM NaCl，5mM葡萄糖，5mM丙氨酸，用2M Tris调整到pH7．5)的Tecan PW96微处理器控制的清洗机上洗涤细胞。将Tecan PW96编程洗涤细胞5次，并每孔留下75μL。将试验化合物溶解于不同毫摩尔浓度的DMSO。将1μL试验溶液滴加到每个孔中，然后将细胞在室温下培养5-10分钟。加入用摄取缓冲液稀释的25μL 30μM[U14C]甘氨酸。将细胞在室温下培养1小时。将滴定板密封，在Packard微滴定板闪烁计数器(TopCount)上测定[U14C]甘氨酸摄取。根据从各种浓度的每种试验药物得到的结果计算抑制50％甘氨酸摄取的浓度(IC50)。本发明试验化合物的计算数据以pIC50值(IC50的负对数值)示于表3。
还试验了公开于US4，695，575的化合物51 4-[[1-[(4-氟苯基)甲基]-1H-苯并咪唑-2-基]甲基]-N，N-二甲基-α，α-二苯基-1-哌啶丁酰胺和公开于US5，008，268的化合物52 4-[[9-[(4-甲氧基苯基)甲基]-9H-嘌呤-8-基]氨基]-N，N-二甲基-α，α-二苯基-1-哌啶丁酰胺(E)-2-丁烯二酸盐(2∶5)。
表3
Figure 9980353000251
化合物号 PIC50
282930313233343536373839 6．566．106．636．176．126．216．357．226．256．906．046．23
化合物号 PIC50
131415161718192021222324252627 6．286．036．046．126．136．036．296．396．086．036．036．086．366．106．26
化合物号 PIC50
404142434445464748495051525354 6．366．526．126．126．706．006．276．796．546．126．606．916．476．396．61
组合物实施例
下面的制剂列举了根据本发明适于的动物和人患者全身给药的典型的药物组合物。“活性成分”(A．I．)指式(I)化合物或其可药用加成盐。
实施例C．1：包膜片剂片芯的制备
将100g A．I．，570g乳糖和200g淀粉的混合物充分混合，加入5g月桂基硫酸钠和10g聚乙烯吡咯烷酮的约200ml水溶液润湿混合物。将湿粉混合物过筛，干燥，再过筛。加入100g微晶纤维素和15g氢化植物油，然后整个混合均匀并压制成片，得到10，000片每片含有10mg活性成分的片剂。包衣
在10g甲基纤维素的75ml变性酒精溶液中加入5g乙基纤维素的150ml二氯甲烷溶液，然后加入75ml二氯甲烷和2．5ml 1，2，3-丙三醇。将10g聚乙二醇融化，然后将其溶解于75ml二氯甲烷。将第二种溶液加到第一种溶液中，并加入2．5g硬脂酸镁，5g聚乙烯吡咯烷酮和30ml浓色素悬浮液，然后整个混合均匀。在包衣设备中用所得混合物将片芯包衣。

Claims (10)

1．抑制甘氨酸传输的化合物在制备治疗中枢神经和末梢神经***疾病的药物中的用途，所说化合物具有式(I)结构，其N-氧化物、立体化学异构体形式和可药用加成盐，其中R1和R2分别代表氢或C1-4烷基；X代表下列基团：
Figure 9980353000022
其中点划线代表任选的键；-R3代表下列基团：其中R6和R7分别代表氢，或二者与它们相连的两个碳原子一起构成苯环；R8代表氢或卤素；n是1或2；R4代表氢，羟基，C1-4烷氧基，C1-4烷氧基C1-4烷基，或芳基C1-4烷氧基；R5代表二芳基甲氧基C1-4烷基，或下列基团：
其中B1代表-CH2-，-CH(OH)-，-NH-，-CH2-NH-或直键；
B2代表-NH-，-CH2-或直键；
B3代表-NR12-，-CH2-，-C(=O)-或直键；
B7代表-C1-4烷二基-NH-或-NH-C1-4烷基-；
B8代表-NR19-，-CH2-或-CH(芳基)-；
每个Y各代表O或S；
-a1=a2-a3=a4-代表下列二价基团：
-CH=CH-CH=CH-(b-1-a)
或-N=CH-N=CH-(b-1-b)
其中基团(b-1-a)中的氢原子可以被羟基取代；
R9代表C1-4烷基，芳基取代的C1-4烷基，噻吩基，呋喃基，羟基C1-4烷基取代的呋喃基，或噻唑基；
R10代表芳基，芳基氨基，C1-4烷基氨基，C1-4烷硫基；
R11代表氢，C1-4烷基，卤素或三氟甲基；
R12代表氢或C1-4烷基羰基；
R13代表氢，C1-4烷基或芳基；
R14代表氢或卤素；
R15和R16各代表氢或芳基；
R17代表氢或C1-4烷基；
R18代表芳基，10，11-二氢-5H-二苯并[b，f]吖庚因-5-基或任意被一个或两个分别选自C3-7环烷基和芳基的取代基取代的C1-4烷基，；
R19代表氢，C1-4烷基羰基或二芳基C1-4烷基；
R20，R21，R22和R23分别代表氢，C1-4烷基或芳基；
R24代表氢或三氟甲基；
R25代表氢或卤素；及
如果R5代表式(b-3)基团，则R4可以是苯基C1-4烷基氨基羰基；及
R4和R5可以一起形成下式螺环基：
其中R26和R27各代表氢，C1-4烷基，芳基或芳基C1-4烷基；
芳基指苯基，或被1或2个下列取代基取代的苯基：C1-4烷基，卤素，三氟甲基，羟基或C1-4烷氧基。
2．根据权利要求1的用途，其中R1和R2是甲基。
3．根据权利要求1或2的用途，其中X是式(a)或(b)基团。
4．根据权利要求1的用途，其中疾病是精神病，疼痛，癫痫，神经变性疾病，中风，头部外伤或多发性硬化。
5．权利要求1-3之一定义的式(I)化合物，条件是：如果R4是氢，R5是其中B1是-CH2-的式(b-1)基团，及R9是4-氟苄基，则-a1=a2-a3=a4-不能是-CH=CH-CH=CH-；及如果R4是氢，R5是其中B1是-NH-的式(b-1)基团，及R9是4-甲氧基苄基，则-a1=a2-a3=a4-不能是-CH=N-CH=N-。
6．权利要求5要求的化合物，其中R5是二芳基甲氧基C1-4烷基或式(b-2)，(b-3)，(b-4)，(b-5)，(b-6)，(b-7)，(b-8)，(b-9)，(b-10)，(b-11)，(b-12)或(b-13)基团；或者R5与R4一起形成式(b-14)螺环基。
7．一种药物组合物，其中含有可药用载体和作为活性成分的治疗有效量的权利要求5或6所说的化合物。
8．制备权利要求7所要求的药物组合物的方法，特征在于：治疗有效量的权利要求5或6所说的化合物与药物载体紧密混合。
9．权利要求5或6所说的化合物用作药物。
10．制备权利要求5所要求的化合物的方法，特征在于：将其中W是适当反荷离子的式(II)中间体或其官能团衍生物与式(III)中间体，在对反应惰性的溶剂中，在适当碱存在下，以及任选在碘化钾存在下进行反应，
Figure 9980353000061
而且，如果需要，通过用酸处理，将式(I)化合物转化为酸加成盐，或者用碱处理，将式(I)化合物转化为碱加成盐，或者相反，通过用碱处理，将酸加成盐转化为游离碱，或者用酸处理，将碱加成盐转化为游离酸；以及，如果需要，制成其N-氧化物和／或立体化学异构体形式。
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100372838C (zh) * 2003-02-17 2008-03-05 弗·哈夫曼-拉罗切有限公司 哌啶-苯磺酰胺衍生物
CN102256975A (zh) * 2008-12-04 2011-11-23 赛诺菲 氮杂二环-三氟甲基苯甲酰胺衍生物的新的多晶型形式
CN102766080A (zh) * 2011-05-06 2012-11-07 上海医药工业研究院 一类吡咯烷衍生物、其制备方法及应用

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA73749C2 (en) * 1999-11-01 2005-09-15 Diarylenines
WO2002019967A2 (en) 2000-09-08 2002-03-14 Gliatech, Inc. Substituted hydrazine derivatives
US6946474B2 (en) 2000-09-14 2005-09-20 Merck & Co., Inc. Nitrogen-containing compounds and their use as glycine transport inhibitors
EP1325912A4 (en) * 2000-10-12 2004-05-12 Ssp Co Ltd 2,2-DIPHENYLBUTANAMIDE DERIVATIVES AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS
AR032653A1 (es) 2001-02-09 2003-11-19 Telik Inc Inhibidores heterociclicos del trasportador de glicina 2 composiciones farmaceuticas, uso y metodos.
JPWO2003082819A1 (ja) * 2002-04-01 2005-08-04 日本ケミファ株式会社 Ｎ−フェニル−ｎ−（４−ピペリジニル）アミド誘導体
FR2838739B1 (fr) * 2002-04-19 2004-05-28 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl)benzamide, leur preparation et leur application en therapeutique
US6995168B2 (en) * 2002-05-31 2006-02-07 Euro-Celtique S.A. Triazaspiro compounds useful for treating or preventing pain
FR2842804B1 (fr) * 2002-07-29 2004-09-03 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
FR2842805A1 (fr) * 2002-07-29 2004-01-30 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide,leur preparation et leur application et therapeutique
US7202259B2 (en) 2002-11-18 2007-04-10 Euro-Celtique S.A. Therapeutic agents useful for treating pain
MXPA06001665A (es) * 2003-08-11 2006-04-28 Hoffmann La Roche Piperazina con grupo fenilo sustituido -or y su uso como inhibidores del transportador de glicina 1 (glyt-1).
FR2861070B1 (fr) 2003-10-17 2006-01-06 Sanofi Synthelabo Derives de n-[phenyl(pyrrolidin-2-yl)methyl]benzamide et n-[(azepan-2-yl)phenylmethyl]benzamide, leur preparation et leur application en therapeutique
FR2861076B1 (fr) * 2003-10-17 2006-01-06 Sanofi Synthelabo Derives de n-heterocyclymethylbenzamide, leur preparation et leur application en therapeutique
FR2861071B1 (fr) 2003-10-17 2006-01-06 Sanofi Synthelabo Derives de n-[phenyl(alkylpiperidin-2-yl) methyl]benzamide, leur prepartation et leur application en therapeutique
WO2005058317A1 (en) * 2003-12-18 2005-06-30 Glaxo Group Limited Glycine transporter-1 inhibirors
AU2005210496B2 (en) 2004-01-30 2009-04-23 Euro-Celtique S.A. Methods for making 4-Tetrazolyl-4-Phenylpiperidine compounds
GB0408774D0 (en) * 2004-04-20 2004-05-26 Glaxo Group Ltd Compounds
DE602005014274D1 (de) 2004-12-09 2009-06-10 Hoffmann La Roche Phenylpiperazin-methanon-derivate
ES2338139T3 (es) 2004-12-15 2010-05-04 F. Hoffmann-La Roche Ag Fenil-metanonas bi- y triciclicas sustituidas como inhibidores del transportador de la glicina i (glyt-1) para el tratamiento de la enfermedad de alzheimer.
US7485637B2 (en) 2005-01-04 2009-02-03 Hoffmann-La Roche Inc. Benzoyl-tetrahydropiperidine derivatives
DE602005022113D1 (de) 2005-01-07 2010-08-12 Hoffmann La Roche Phenyl)methanon-derivate als glycin-transporter 1 (glyt-1) hemmer zur behandlung von neurologischen und neuropsychiatrischen erkrankungen
DE602006007682D1 (de) 2005-01-18 2009-08-20 Hoffmann La Roche 2,5-disubstituierte phenylmethanonderivative als glycintransporter-1-inhibitoren (glyt-1) zur behandlung von neurologischen und neuropsychiatrischen störungen
KR100915472B1 (ko) 2005-01-26 2009-09-03 에프. 호프만-라 로슈 아게 페닐 메탄온 유도체 및 그의 글라이신 트랜스포터 1억제제로서의 용도
ES2334578T3 (es) 2005-02-07 2010-03-12 F. Hoffmann-La Roche Ag Fenil-metanonas sustituidas por heterociclo como inhibidores del transportador 1 de la glicina.
JP4193949B2 (ja) 2005-04-08 2008-12-10 ファイザー・プロダクツ・インク Ｉ型グリシン輸送阻害剤としての二環式［３．１．０］ヘテロアリールアミド
WO2009010479A2 (en) * 2007-07-13 2009-01-22 Euroscreen S.A. Heterocyclic methylene piperidine derivatives and their use
EP2727473A4 (en) * 2011-06-28 2015-05-06 Vivozon Inc COMBINATION OF EFFICIENT SUBSTANCES WITH SYNERGISTIC EFFECTS OF MULTIPLE TARGETING AND USE THEREOF

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3714159A (en) * 1971-03-30 1973-01-30 Janssen Pharmaceutica Nv 2,2-diaryl-4-(4'-aryl-4'-hydroxy-piper-idino)-butyramides
US4695575A (en) * 1984-11-13 1987-09-22 Janssen Pharmaceutica, N.V. 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines
GB8515934D0 (en) * 1985-06-24 1985-07-24 Janssen Pharmaceutica Nv (4-piperidinomethyl and-hetero)purines
CA1332236C (en) * 1985-10-11 1994-10-04 Lourens Wals –,-–-diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, n-oxides
CA2255727A1 (en) * 1996-05-31 1997-12-04 Trophix Pharmaceuticals, Inc. Pharmaceutical for treating of neurological and neuropsychiatric disorders

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100372838C (zh) * 2003-02-17 2008-03-05 弗·哈夫曼-拉罗切有限公司 哌啶-苯磺酰胺衍生物
CN102256975A (zh) * 2008-12-04 2011-11-23 赛诺菲 氮杂二环-三氟甲基苯甲酰胺衍生物的新的多晶型形式
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