CN1391570A - 具有抑制tnf活性的苯基-和吡啶基-四氢吡啶 - Google Patents
具有抑制tnf活性的苯基-和吡啶基-四氢吡啶 Download PDFInfo
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- CN1391570A CN1391570A CN00816075A CN00816075A CN1391570A CN 1391570 A CN1391570 A CN 1391570A CN 00816075 A CN00816075 A CN 00816075A CN 00816075 A CN00816075 A CN 00816075A CN 1391570 A CN1391570 A CN 1391570A
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- Prior art keywords
- compound
- represent hydrogen
- structural formula
- alkyl
- base
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- B29D35/00—Producing footwear
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- B29D35/061—Producing footwear having soles or heels formed and joined on to preformed uppers using a moulding technique, e.g. by injection moulding, pressing and vulcanising by injection moulding
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Abstract
本发明涉及式(I)化合物、其盐和溶剂化物,含有这些化合物的药物组合物、制备它们的方法及中间体,其中X代表N或CH;R1代表氢或卤素原子或CF3基;R2和R3独立地代表氢原子或甲基;n是0或1;A代表结构式(a)或(b)的基团,其中R4代表氢或卤素原子、(C1-C4)烷基、CF3基、氨基、单(C1-C4)烷基氨基或二(C1-C4)烷基氨基;R5代表氢或卤素原子、(C1-C4)烷氧基、(C1-C4)烷基或CF3基;R6代表氢原子、(C1-C4)烷基或(C1-C4)烷氧基。
Description
本发明涉及新的苯基-和吡啶基-四氢吡啶、含有它们的药物组合物、制备它们的方法以及在该方法中的合成中间体。
US 5 118 691和US 5 620 988公开了喹啉基-3-烷基取代的四氢吡啶,它们显示出多巴胺能的活性。
现在已经发现某些喹啉基烷基或异喹啉基烷基取代的四氢吡啶对于调控TNF-α(肿瘤坏死因子)具有强有力的活性。
作为免疫、炎症、细胞繁殖、纤维化等的介质,TNF-α是一种最近已引起注意的细胞因子(cytokine)。这种介质在发炎的分泌滑液的组织中大量存在,并在自身免疫性发病中发挥重要的作用(Annu.Rep.Med.Chem.,1997,
32:241-250)。
因此,根据本发明的一个方面,本发明涉及结构式(I)的四氢吡啶、其盐或溶剂化物:其中
X代表N或CH;
R1代表氢或卤素原子或CF3基;
R2和R3独立地代表氢原子或甲基;
n是0或1;
R4代表氢或卤素原子、(C1-C4)烷基、CF3基、氨基、单(C1-C4)烷基氨基或二(C1-C4)烷基氨基;
R5代表氢或卤素原子、(C1-C4)烷氧基、(C1-C4)烷基或CF3基;
R6代表氢原子、(C1-C4)烷基或(C1-C4)烷氧基。
在本说明书中,术语“(C1-C4)烷基”表示一价饱和的直链或支链的(C1-C4)烃基。
在本说明书中,术语“卤素”表示一种选自氯、溴、碘和氟的原子。
优选的化合物是那些其中n为0的化合物。
另外优选的化合物是那些其中R2和R3为氢的化合物。
另外优选的化合物是那些其中R1为CF3基的化合物。
另外优选的化合物是那些其中R1为氟原子的化合物。
另外优选的化合物是那些其中X为CH和R1位于苯的2位或3位的化合物。
另外优选的化合物是那些其中X为CH和R1为CF3基的化合物。
另外优选的化合物是那些其中X为氮原子和吡啶在2位和6位被取代的化合物。
根据本发明,结构式(I)的化合物可以以N-氧化物衍生物的形式存在。如上面结构式所示,结构式(I)的化合物尤其可以在四氢吡啶上或在基团A的喹啉或异喹啉上具有N-氧化基团,或另一方面两个N-氧化基团可能同时存在。
本发明结构式(I)化合物的盐既包括含有药物上可接受的无机酸或有机酸的加成盐,例如盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、磷酸二氢盐、柠檬酸盐、马来酸盐、酒石酸盐、富马酸盐、葡糖酸盐、甲磺酸盐、2-萘磺酸盐等,也包括使结构式(I)化合物能适当分离或结晶的加成盐,例如苦味酸盐或草酸盐,或包括含有旋光性酸的加成盐,旋光性酸例如樟脑磺酸和扁桃酸或取代的扁桃酸。
当R2或者R3之一为甲基且另一个为氢时,由于不对称碳之故,结构式(I)化合物的旋光性纯的立体异构体和任意比例的异构体的混合物构成了本发明的部分。
结构式(I)化合物可以下列方法合成,该方法包括:
(a)使结构式(II)的化合物与结构式(III)的酸的官能衍生物反应,
其中R2、R3、n和A定义如上;
(b)还原由此得到的结构式(IV)化合物的羰基;
(d)分离出因此得到的结构式(I)化合物,并任选将其转化为它的盐或溶剂化物或者转化为它的N-氧化物衍生物。
步骤(a)的反应可以适宜地在有机溶剂中、在-10℃与反应混合物回流温度之间的温度下进行。
当步骤(a)的反应是放热反应时,该反应可以优选在无需加热的情况下进行,例如在这种情况中,其中氯化物用作结构式(III)的酸的官能衍生物。
可以采用的合适的结构式(III)的酸的官能衍生物为可选择地活化了的游离酸(例如采用BOP=三(二甲基氨基)苯并三唑-1-氧基鏻六氟磷酸化物)(tris(dimethylamino)benzotriazol-1-yloxyphosphoniumhexafluorophosphate)、酸酐、酸酐混合物、活性酯或酰基卤,优选溴化物。在活性酯中,特别优选的是p-硝基苯基酯,但是甲氧苯基、三苯甲游基和二苯甲基酯等也合适。
反应溶剂优选采用卤化溶剂,如二氯甲烷、二氯乙烷、1,1,1-三氯乙烷、氯仿等,但与所用试剂相容的其它有机溶剂,例如二氧杂环己烷、四氢呋喃或如同己烷的烃,也可以采用。
该反应可以方便地在质子受体存在下完成,质子受体例如碱性碳酸盐或叔胺,例如三乙胺。
根据常规工艺,步骤(b)的还原反应采用合适的还原剂,如硼烷配合物例如甲硫醚/甲硼烷([CH3]2S-BH3)、氢化铝或氢化锂铝复合物,在惰性有机溶剂中,在0℃与反应混合物回流温度之间的温度下可以方便地进行。
“惰性有机溶剂”表示的意思是不干扰反应的溶剂,这样的溶剂如醚,例如乙醚、四氢呋喃(THF)、二氧杂环己烷或1,2-二甲氧基乙烷。
根据一种优选的工艺,该步骤采用相对起始化合物(II)过量的甲硫醚/硼烷,在回流温度下,可选择地在惰性气氛下进行。还原反应通常几小时后完成。
步骤(c)的脱水作用,如采用乙酸/硫酸混合物,在室温与所用溶剂的回流温度之间的温度下,易于实现。
根据一种优选的方法,步骤(c)的反应在体积比为3/1的乙酸/硫酸混合物中,通过加热至约100℃1-3小时而完成。
根据常规方法,所需化合物以游离碱或其盐的形式分离出来。游离碱在有机溶剂中可以通过简单的成盐作用转化为一种它的盐,有机溶剂如醇,优选乙醇或异丙醇;醚,如1,2-二甲氧基乙烷;乙酸乙酯;丙酮或烃,如己烷。
根据常规方法,所得到的结构式(I)化合物被分离出来,并可选择地将其转化为它的盐或溶剂化物或者转化为它的N-氧化物衍生物。
结构式(I)化合物也可以由结构式(VI)化合物出发,通过下列方式制备:用结构式(VII)的醛进行缩合/还原反应,其中X和R1定义如上,其中R2、R3、n和A定义如上,分离出结构式(I)化合物,并可选择地将其转化为它的盐或溶剂化物或者转化为它的N-氧化物衍生物。
根据常规方法,缩合/还原反应通过在有机溶剂中,如醇,例如甲醇,在酸性介质中,在还原剂如氰基硼氢化钠存在下,混合起始化合物(VI)和(VII)而完成。
结构式(II)、(III)和(VI)的起始化合物是已知的,或者可以以与已知化合物相类似的方法制备出。同样的产物,例如在WO 9701536;J.Am.Chem.Soc.,1948,
70:2843-2847;J.Med.Chem.,1997,
40(7):1049中有描述。
结构式(IV)、(V)和(VII)的化合物是新化合物,并构成本发明的另一方面。
根据通常的方法,结构式(VII)的化合物可以按下列方式制的:在钯催化剂和强碱如三乙胺存在下,将合适的羟基(异)喹啉的三氟甲基磺酰基衍生物(也称作三氟甲基磺酸化物“triflate”)与N,N-二烷基乙醇胺乙烯基醚一起加热,并使因此得到的中间物与浓硫酸反应。这种方法的实施例在实验部分有报导。另外,也可根据众所周知的方法,结构式(VII)的化合物可以通过还原结构式(III)相应的酸而制得。
在喹啉或异喹啉的氮原子上含有N-氧化基团的结构式(I)化合物,可以由结构式(III)或(VII)的化合物的N-氧化物衍生物制得。如此合成的实施例在实验部分给出。
在四氢吡啶的氮原子上含有N-氧化基团的结构式(I)化合物,可以通过氧化相应的结构式(I)化合物而制得。在这种情况下,由以上合成所得到的结构式(I)化合物根据常规方法,经过氧化反应,例如在合适的溶剂中与m-氯过苯甲酸反应,以及按照那些本领域技术人员所熟知的常规方法进行分离。
本发明的化合物有抑制TNF-α的有利的特性。
借助于实验可以证明这些特性,实验目的在于测定分子对Balb/c鼠体内用来自大肠杆菌(Escherichia Coli)的脂多糖(LPS)(055:B5,Sigma,St.Louis,Mo)诱导的TNF-α合成的影响。
这些实验产品对数组五只雌性7~8周大的Balb/c鼠(CharlesRiver,法国)经口服给入。一小时后,LPS经静脉给入(10μg/鼠)。LPS给入后1.5小时对每只动物进行采血。样品进行离心分离并回收血浆,将血浆在-80℃下冷冻。采用商业试剂盒(R & D,Abingdon,英国)测定TNF-α。
在该实验中,发现本发明的代表性化合物活性非常高,甚至以很低的剂量抑制TNF-α的合成。
由于这种活性以及它们的低毒性,结构式(I)化合物和其盐或其溶剂化物可以用于治疗与免疫和炎症病症相关的疾病或用作镇痛药。特别是,结构式(I)化合物可以用于治疗动脉粥样硬化、自身免疫性疾病、引起神经细胞脱髓鞘作用的疾病(如多样硬化)、哮喘、风湿性关节炎、纤维化疾病、肺原发纤维化、膀胱纤维化、glumerulonephritis、风湿性脊椎炎、骨关节炎、痛风、骨和软骨再吸收(resorbtion)、骨质疏松、佩吉特氏病、多种骨髓瘤、uveoretinitis、脓毒性休克、败血病、内毒素性休克、移植物对宿主的反应、移植排斥、成人呼吸窘迫综合征、矽肺、石棉沉着病、肺肉质变、克罗恩氏病、溃疡性结肠炎、夏科氏综合征、早老性痴呆、帕金森病、播散性红斑狼疮、血液动力休克、局部贫血病理(心肌梗塞、心肌局部缺血、冠状动脉痉挛、心绞痛、心功能不全、心脏病发作)、局部贫血后再输入疾病发作、疟疾、分枝杆菌感染、脑膜炎、麻风病、病毒感染(爱滋病病毒、细胞肥大病毒、疱疹病毒)、与爱滋病有关的机会感染、肺结核、牛皮癣、特异性皮炎和接触性皮炎、糖尿病、恶病质、癌和辐射引致的损害。
结构式(I)化合物和药物上可接受的其盐和其溶剂化物优选口服给药。
在本发明的口服药物组合物中,活性成分可以单位给药形态给药,以含有常规药物载体的混合物形式给入动物和人体,用于治疗上述疾病。合适的单位给药形态包括,例如,能易分裂的片剂、凝胶胶囊、粉末、颗粒和口服溶液或悬浊液。
当制备片剂状的固体组合物时,主要活性成分与如明胶、淀粉、乳糖、硬脂酸镁、滑石粉、阿拉伯树胶等药物赋形剂混合。该片剂可以用蔗糖或其它适合的材料涂层,或者作为选择可以对它们进行处理以便它们具有持续或延迟的活性,以及以便它们连续地释放预定量的活性成分。
凝胶胶囊状的制剂,通过将活性成分与稀释剂混合,所得到的混合物注入软或硬凝胶胶囊中而制得。
糖浆或酏剂状的制剂可包括活性成分,同时包括甜味剂,甜味剂优选为没有热量的甜味剂,对羟基苯甲酸甲酯和对羟基苯甲酸丙酯可含在其中作为防腐剂,以及还可含有香料和适合的着色剂。
水分散性粉末或颗粒包括活性成分与分散剂或润湿剂,或如聚乙烯吡咯烷酮的悬浮剂,以及与甜味剂或香味增强剂的混合物。
活性成分也可以可选择地与一种或多种载体或添加剂配制成微胶囊状。
根据本发明,在药物组合物中,活性成分也可以呈在环糊精或其醚或其酯中的包合配合物(inclusion complex)形态。
活性成分的给药量按照常例依疾病的进展程度以及病人的年龄和体重。不过,单位剂量一般包括0.001mg~100mg的活性成分,更好的是0.01mg~50mg,优选0.1mg~20mg,有利的是0.5mg~10mg的活性成分。
根据本发明的另一方面,本发明涉及包括结构式(I)化合物或药物上可接受的盐或溶剂化物和至少一种化合物的组合物,所述至少一种化合物选自免疫抑制剂,例如干扰素β-1b、促肾上腺皮质激素、糖皮质激素(例如强的松或甲基强的松龙)、白细胞间介素-1抑制剂。
更特别的是,本发明涉及包括结构式(I)化合物或药物上可接受的盐或溶剂化物和至少一种化合物的组合物,所述至少一种化合物选自罗喹美克(roquinimex)(1,2-二氢-4-羟基-N,1-二甲基-2-氧代-3-喹啉甲酰苯胺(1,2-dihydro-4-hydroxy-N,1-dimethyl-2-oxo-3-quinolinecarboxanilide)、咪咯蓝(myloran)(Autoimmune公司的包含牛的髓磷脂的产品)、安特灵(antegren)(Elan/AthenaNeurosciences公司的单克隆人的抗体)和重组体干扰素β-1b。
其它可能的组合物是那些由结构式(I)化合物或药物上可接受的其盐或溶剂化物和钾-通道阻断剂(例如fampridine即4-氨基吡啶)组成的组合物。
根据本发明的另一方面,本发明涉及一种治疗与免疫和炎症病症相关的疾病以及治疗疼痛的方法,特别是,动脉粥样硬化、自身免疫性疾病、引起神经细胞脱髓鞘作用的疾病(如多样硬化)、哮喘、风湿性关节炎、纤维化疾病、肺原发纤维化、膀胱纤维化、glumerulonephritis、风湿性脊椎炎、骨关节炎、痛风、骨和软骨再吸收(resorbtion)、骨质疏松、佩吉特氏病、多种骨髓瘤、uveoretinitis、脓毒性休克、败血病、内毒素性休克、移植物对宿主的反应、移植排斥、成人呼吸窘迫综合征、矽肺、石棉沉着病、肺肉质变、克罗恩氏病、溃疡性结肠炎、夏科氏综合征、早老性痴呆、帕金森病、播散性红斑狼疮、血液动力休克、局部贫血病理(心肌梗塞、心肌局部缺血、冠状动脉痉挛、心绞痛、心功能不全、心脏病发作)、局部贫血后再输入疾病发作、疟疾、分枝杆菌感染、脑膜炎、麻风病、病毒感染(爱滋病病毒、细胞肥大病毒、疱疹病毒)、与爱滋病有关的机会感染、肺结核、牛皮癣、特异性皮炎和接触性皮炎、糖尿病、恶病质、癌和辐射引致的损害,该方法包括将结构式(I)化合物或药物上可接受的其盐或其溶剂化物单独给药或与其它活性成分组合给药。
以下实施例举例说明本发明。制备17-异喹啉基乙醛
1.5g(0.0103mol)的7-羟基异喹啉和5.3ml的吡啶冷却到0℃。将1.86ml的三氟甲基磺酸酐(triflic anhydride)滴加进去。该混合物在0℃下搅拌1小时,然后在室温下搅拌2小时。所得到的混合物倾入冰水混合物中并用乙酸乙酯萃取,干燥有机相并减压蒸去溶剂。粗产物采用硅胶柱层析法进行纯化,用7/3的环己烷/乙酸乙酯混合物进行洗脱。得到油状的7-羟基异喹啉三氟甲烷磺酸酯。在氩气下,1.65g的该产物与27.5ml的无水二甲基甲酰胺、41mg的乙酸钯、1.65ml的无水三乙胺和1.38g的N,N-二乙基乙醇胺乙烯基醚混合。该混合物在80℃下加热36小时。所得到的混合物倾入水/乙酸乙酯混合物中,分离两相,采用水洗涤有机相并进行干燥,减压蒸去溶剂。剩余物采用硅胶柱层析法进行纯化,用9/1的乙酸乙酯/甲醇混合物进行洗脱。得到2-[2-(7-异喹啉基(乙烯基)氧)]-N,N-二乙基-1-乙胺。1.5g的该产物用130ml水和13ml 96%的硫酸进行处理。该混合物在60℃下加热4.5小时并倾入冰中,将饱和NaHCO3水溶液加入进去并用乙酸乙酯萃取混合物。干燥有机相,减压蒸去溶剂。得到标题化合物。制备26-异喹啉基乙醛
如制备1所述进行实验,但是采用6-羟基异喹啉,得到标题化合物。制备37-异喹啉基乙醛N-氧化物
14ml水、3.5ml 96%的硫酸和400mg在制备1中作为中间产物得到的2-[2-(7-异喹啉基(乙烯基)氧)]-N,N-二乙基-1-乙胺混合在一起。将24ml的甲醇加入进去,该混合物在65℃下加热5.5小时。所得到的混合物倾入冰中,将饱和NaHCO3水溶液加入进去并用乙酸乙酯萃取混合物。干燥有机相,减压蒸去溶剂。产物采用硅胶柱层析法进行纯化,用1/1的环己烷/乙酸乙酯混合物进行洗脱,得到7-(2,2-二甲氧基乙基)异喹啉。100mg的该产物溶解在15ml二氯甲烷中并将135mg的m-氯过苯甲酸(MCPBA)加入进去,接着在室温下搅拌3小时。该混合物用二氯甲烷稀释,加入碳酸氢钠水溶液至中性pH,所得到的混合物用二氯甲烷进行萃取,有机萃取液通过硫酸钠干燥并过滤,减压蒸去溶剂,得到7-(2,2-二甲氧基乙基)异喹啉N-氧化物。在0℃温度下,105mg的该产物溶解在0.2ml二氯甲烷中并将0.4ml的1/1三氟乙酸/水混合物加入进去。该混合物在0℃下搅拌2小时,然后在室温下搅拌过夜。加入二氯甲烷,该混合物用碳酸氢钠溶液洗至稍稍碱性pH,有机相经硫酸钠干燥并过滤,减压蒸去溶剂,得到标题产物。实施例16-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)喹啉和其盐酸盐1a)1-(4-羟基-4-(3-三氟甲基苯基)-1-哌啶基)-2-(6-喹啉基)-1-乙酮(ethanone)
在60ml二氯甲烷中,2.8g(0.015mol)6-喹啉基乙酸、4.2g(0.0015mol)4-羟基-4-(3-三氟甲基苯基)哌啶、6.63g(0.015mol)BOP和5.3ml三乙胺的混合物搅拌过夜。将100ml的乙酸乙酯加入进去,并用水和1N氢氧化钠溶液洗涤该混合物,经硫酸钠干燥,蒸去溶剂。得到5.9g的标题化合物。1b)6-(2-(4-羟基-4-(3-三氟甲基苯基)-1-哌啶基)乙基)喹啉
实施例1a得到的产物溶解在70ml无水THF中,将其加热至回流,并将50ml THF中的4.05ml(0.0427mol)的甲硫醚/甲硼烷加入进去。该混合物在室温下搅拌15分钟,然后回流搅拌30分钟。蒸去溶剂,剩余物溶解在乙酸乙酯/稀NH4OH混合物中,分离两相,有机相用水洗涤。有机相经硫酸钠干燥,减压蒸去溶剂。粗产物采用硅胶柱层析法进行纯化,用9/1的乙酸乙酯/甲醇混合物进行洗脱。得到1.95g的标题化合物。熔点=140~142℃。1c)6-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)喹啉和其盐酸盐
1.1g上一步的产物溶解在12ml的乙酸中,将3.0ml的浓硫酸加入进去,该混合物在100℃下加热2小时。所得到的混合物倾入冰中,加入稀NH4OH,用乙酸乙酯萃取该混合物。有机萃取液用水洗涤,干燥并在减压下进行蒸发。
粗产物用层析法进行纯化,用乙酸乙酯洗脱。得到标题化合物。其盐酸盐采用用盐酸饱和的异丙醇溶液制备出。熔点(盐酸盐)=220~222℃。
实施例27-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)喹啉和其二盐酸盐二水合物
如实施例1所述进行实验,但是采用7-喹啉基乙酸取代6-喹啉基乙酸,得到标题化合物。熔点(二盐酸盐二水合物)=216~218℃。
实施例37-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉和其二盐酸盐二水合物
1.75g(0.0077mol)的4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶、30ml甲醇、1.15ml的冰乙酸和0.73g无水乙酸乙酯混合在一起。该混合物冷却至0~5℃,并将1.14g 7-异喹啉基乙醛(由制备1得到)加入进去,接着小心加入1.1g(0.0175mol)的氰基硼氢钠。该混合物在0~5℃下搅拌1.5小时,再在室温下搅拌过夜。将7ml的浓盐酸加入进去,所得到的混合物搅拌10分钟,减压下蒸去溶剂,剩余物溶解在乙酸乙酯/稀NH4OH混合物中。有机相通过硫酸钠干燥并过滤,蒸去溶剂。剩余物在硅胶柱上进行纯化,用9/1乙酸乙酯/甲醇混合物洗脱。得到标题混合物。其盐酸盐采用用盐酸饱和的异丙醇溶液制备出。得到1.1g的产物。熔点(二盐酸盐二水合物)=230~233℃。
实施例46-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉和其二盐酸盐二水合物
如实施例3所述进行实验,但是采用6-异喹啉基乙醛(由制备2得到)取代7-异喹啉基乙醛,得到标题化合物。熔点(二盐酸盐二水合物)=222~224℃。
实施例56-(2-(4-(3-氟苯基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉和其二盐酸盐
如实施例3所述进行实验,但是采用6-异喹啉基乙醛(由制备2得到)取代7-异喹啉基乙醛,以及4-(3-氟苯基)-1,2,3,6-四氢吡啶取代4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶,得到标题化合物。熔点(二盐酸盐)=242~244℃。实施例67-(2-(4-(3-氟苯基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉和其二盐酸盐
如实施例3所述进行实验,但是采用4-(3-氟苯基)-1,2,3,6-四氢吡啶取代4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶,得到标题化合物。熔点(二盐酸盐)=227~229℃。
实施例77-(2-(4-苯基-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉和其二盐酸盐
如实施例3所述进行实验,但是采用4-苯基-1,2,3,6-四氢吡啶取代4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶,得到标题化合物。熔点(二盐酸盐)=259~261℃。
实施例86-(2-(4-(3-氟苯基)-1,2,3,6-四氢吡啶-1-基)乙基)喹啉和其二盐酸盐
如实施例1所述进行实验,但是采用4-羟基-4-(3-氟苯基)哌啶取代4-羟基-4-(3-三氟甲基苯基)哌啶,得到标题化合物。熔点(二盐酸盐)=216~218℃。
实施例97-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-氧桥(oxido)-1-基)乙基)喹啉和其盐酸盐
在0~5℃的温度下,将0.086g的m-氯过苯甲酸加入到0.19g(0.5mmol)的7-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉在25ml二氯甲烷中的溶液中。该混合物在0~5℃下搅拌2小时,用饱和碳酸氢钠水溶液进行洗涤,并分离两相。有机相通过硫酸钠干燥,过滤并减压下蒸发。产物采用快速层析法进行纯化,用1/1的甲醇/乙酸乙酯混合物进行洗脱,得到标题化合物。其盐酸盐采用用盐酸饱和的异丙醇溶液制备出。熔点(盐酸盐)=166~168℃。实施例107-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉-N-氧化物和其盐酸盐
如实施例3所述进行实验,但是7-异喹啉基乙醛N-氧化物(由制备3得到)取代7-异喹啉基乙醛,得到标题化合物。熔点(盐酸盐)=198~201℃。
实施例117-(2-(4-(6-三氟甲基吡啶-2-基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉和其二盐酸盐二水合物
在16ml的甲醇中,0.650g(0.0028mol)4-(6-三氟甲基-2-吡啶基)-1,2,3,6-四氢吡啶、16ml甲醇、0.693g乙酸钠、1.6ml乙酸和根据制备所得到的1.05g 7-异喹啉基乙醛(由制备1得到)混合在一起。该混合物冷却至0~5℃,10分钟后,小心加入1.06g的氰基硼氢钠。所得到的混合物在0~5℃下搅拌30分钟,再在室温下搅拌过夜。将7ml的浓盐酸加入进去,该混合物搅拌30分钟,减压下蒸去溶剂,剩余物溶解在乙酸乙酯/稀NH4OH混合物中至碱性pH。有机相通过硫酸钠干燥并过滤,蒸去溶剂。剩余物采用硅胶柱快速层析法进行纯化,用9/1乙酸乙酯/甲醇混合物洗脱。得到油状标题化合物(碱)。其盐酸盐采用用盐酸饱和的异丙醇溶液制备出。标题化合物以其二盐酸盐二水合物盐的形态得到。熔点(二盐酸盐二水合物)=203~206℃。
实施例126-(2-(4-(6-三氟甲基吡啶-2-基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉和其二盐酸盐
如实施例11所述进行实验,但是采用6-异喹啉基乙醛取代7-异喹啉基乙醛,得到标题化合物。熔点(二盐酸盐)=190~195℃。
实施例137-(2-(4-(6-氯吡啶-2-基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉和其二盐酸盐
如实施例11所述进行实验,但是采用4-(6-氯吡啶-2-基)-1,2,3,6-四氢吡啶取代4-(6-三氟甲基-2-吡啶基)-1,2,3,6-四氢吡啶,得到标题化合物。熔点(二盐酸盐)=110~112℃。
实施例147-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)-1,3-二甲基异喹啉和其二盐酸盐
如实施例3所述进行实验,但是采用1,3-二甲基-7-异喹啉基乙醛,得到标题化合物。熔点(二盐酸盐)=209℃。
实施例157-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)-1,3-二乙基异喹啉和其二盐酸盐
如实施例3所述进行实验,但是采用1,3-二乙基-7-异喹啉基乙醛,得到标题化合物。熔点(二盐酸盐)=192℃。
实施例167-(2-(4-(4-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉和其草酸氢盐(dioxolate)
如实施例3所述进行实验,但是采用4-(4-三氟甲基苯基)-1,2,3,6-四氢吡啶取代4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶,得到标题化合物。熔点(草酸氢盐)=138~140℃。
实施例177-(2-(4-(2-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉和其二盐酸盐
如实施例3所述进行实验,但是采用4-(2-三氟甲基苯基)-1,2,3,6-四氢吡啶取代4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶,得到标题化合物。熔点(二盐酸盐)=158~160℃。
实施例187-(2-(4-(3-氟苯基)-1,2,3,6-四氢吡啶-1-基)乙基)喹啉和其盐酸盐
如实施例1所述进行实验,但是采用4-(3-氟苯基)-1,2,3,6-四氢吡啶取代4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶,以及7-喹啉基乙酸取代6-喹啉基乙酸,得到标题化合物。熔点(盐酸盐)=132℃。
实施例197-(2-(4-(6-三氟甲基吡啶-2-基)-1,2,3,6-四氢吡啶-1-基)乙基)喹啉和其二盐酸盐
如实施例3所述进行实验,但是采用4-(6-三氟甲基吡啶-2-基)-1,2,3,6-四氢吡啶取代4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶,以及7-喹啉基乙醛取代7-异喹啉基乙醛,得到标题化合物。熔点(二盐酸盐)=135~136℃。
实施例207-(2-(4-(6-三氟甲基吡啶-2-基)-1,2,3,6-四氢吡啶-1-基)乙基)喹啉N-氧化物
如实施例3所述进行实验,但是采用4-(6-三氟甲基吡啶-2-基)-1,2,3,6-四氢吡啶取代4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶,以及7-异喹啉基乙醛N-氧化物(由制备3制得)取代7-异喹啉基乙醛,得到标题化合物。
实施例21~26
如以上实施例所述进行实验,制备下列化合物:
7-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)-3-甲基异喹啉;
7-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)-1-甲基异喹啉;
7-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)-3-乙基异喹啉,熔点(二盐酸盐)=230℃;
7-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)-1-乙基异喹啉;
7-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)-3-甲氧基异喹啉;
7-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)-2-甲基喹啉,熔点(二盐酸盐)=221℃。
Claims (18)
2.根据权利要求1所述的化合物,其中n为0。
3.根据权利要求1或2所述的化合物,其中R2和R3为氢。
4.根据权利要求1-3所述的化合物,其中R1为CF3基。
5.根据权利要求1-3所述的化合物,其中R1为氟原子。
6.根据权利要求1-3所述的化合物,其中X为CH和R1位于苯的3位上。
7.根据权利要求1-3所述的化合物,其中X为CH和R1位于苯的2位上。
8.根据权利要求1-3所述的化合物,其中X为氮原子和吡啶在2位和6位被取代。
9.根据权利要求1-8所述的化合物,该化合物选自其单-N-氧化物和双-N-氧化物衍生物。
10.根据权利要求1所述的化合物,该化合物选自7-(2-(4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶-1-基)乙基)异喹啉,及其单-N-氧化物和双-N-氧化物衍生物、盐和溶剂化物。
11.一种制备权利要求1所述化合物的方法,其特征是,使结构式(VI)化合物与结构式(VII)的醛进行缩合/还原反应,其中X和R1如权利要求1中定义,其中R2、R3、n和A如权利要求1中定义,分离出结构式(I)化合物,并任选地将其转化为它的盐或溶剂化物或者转化为它的N-氧化物。
13.一种结构式(V)的化合物、其盐或溶剂化物,其中
X代表N或CH;
R1代表氢或卤素原子或CF3基;
R2和R3独立地代表氢原子或甲基;
n是0或1;
A代表结构式(a)或(b)的基团:其中
R4代表氢或卤素原子、(C1-C4)烷基、CF3基、氨基、单(C1-C4)烷基氨基或二(C1-C4)烷基氨基;
R5代表氢或卤素原子、(C1-C4)烷氧基、(C1-C4)烷基或CF3基;
R6代表氢原子、(C1-C4)烷基或(C1-C4)烷氧基。
14.一种结构式(IV)的化合物、其盐或溶剂化物其中
X代表N或CH;
R1代表氢或卤素原子或CF3基;
R2和R3独立地代表氢原子或甲基;
n是0或1;
A代表结构式(a)或(b)的基团其中
R4代表氢或卤素原子、(C1-C4)烷基、CF3基、氨基、单(C1-C4)烷基氨基或二(C1-C4)烷基氨基;
R5代表氢或卤素原子、(C1-C4)烷氧基、(C1-C4)烷基或CF3基;
R6代表氢原子、(C1-C4)烷基或(C1-C4)烷氧基。
16.一种含有权利要求1~10所述的结构式(I)化合物或药物上可接受的盐或溶剂化物作为活性成分的药物组合物。
17.根据权利要求16所述的组合物,其特征是,该组合物含有0.001mg~100mg的活性成分。
18.权利要求1~10所述的结构式(I)化合物或药物上可接受的盐或溶剂化物的应用,用于制备镇痛药,和/或用于制备治疗与免疫和炎症病症相关的疾病的药物。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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FR9913206A FR2800071B1 (fr) | 1999-10-22 | 1999-10-22 | Tetrahydropyridines, procede pour leur preparation et compositions pharmaceutiques les contenant |
FR99/13206 | 1999-10-22 | ||
FR0008328A FR2810984B1 (fr) | 2000-06-28 | 2000-06-28 | Pyridyl-tetrahydropyridines, procede pour leur preparation et compositions pharmaceutiques les contenant |
FR00/08328 | 2000-06-28 |
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CN1391570A true CN1391570A (zh) | 2003-01-15 |
CN1158276C CN1158276C (zh) | 2004-07-21 |
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CNB008160759A Expired - Fee Related CN1158276C (zh) | 1999-10-22 | 2000-10-19 | 具有抑制tnf活性的苯基-和吡啶基-四氢吡啶 |
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US (1) | US6509351B1 (zh) |
EP (1) | EP1226137B8 (zh) |
JP (1) | JP4831908B2 (zh) |
KR (1) | KR100755115B1 (zh) |
CN (1) | CN1158276C (zh) |
AR (1) | AR026188A1 (zh) |
AT (1) | ATE271554T1 (zh) |
AU (1) | AU778306B2 (zh) |
BG (1) | BG65564B1 (zh) |
BR (1) | BR0014871A (zh) |
CA (1) | CA2386417C (zh) |
CZ (1) | CZ301566B6 (zh) |
DE (1) | DE60012355T2 (zh) |
DK (1) | DK1226137T3 (zh) |
EA (1) | EA004508B1 (zh) |
EE (1) | EE05055B1 (zh) |
ES (1) | ES2223594T3 (zh) |
HK (1) | HK1046532B (zh) |
HR (1) | HRP20020347B1 (zh) |
HU (1) | HUP0204444A3 (zh) |
IL (2) | IL149250A0 (zh) |
IS (1) | IS2308B (zh) |
ME (1) | MEP25108A (zh) |
MX (1) | MXPA02003979A (zh) |
NO (1) | NO322596B1 (zh) |
NZ (1) | NZ518112A (zh) |
PL (1) | PL198421B1 (zh) |
PT (1) | PT1226137E (zh) |
RS (1) | RS50399B (zh) |
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FR2823748B1 (fr) * | 2001-04-20 | 2004-02-20 | Sanofi Synthelabo | Tetrahydropyridyl-alkyl-benzodiazines, procede pour leur preparation et compositions pharmaceutiques les contenant |
FR2831166B1 (fr) * | 2001-10-18 | 2004-02-27 | Sanofi Synthelabo | Aralkyl-tetrahydro-pyridines, leur preparation et compositions pharmaceutiques les contenant |
FR2832405B1 (fr) | 2001-11-19 | 2004-12-10 | Sanofi Synthelabo | Tetrahydropyridyl-alkyl-heterocycles azotes, procede pour leur preparation et compositions pharmaceutiques les contenant |
FR2840896B1 (fr) * | 2002-06-18 | 2005-04-08 | Sanofi Synthelabo | Phenyl-et pyridyl-piperazines, procede pour leur preparation et compositions pharmaceutiques les contenant |
JP4866610B2 (ja) | 2003-08-18 | 2012-02-01 | 富士フイルムファインケミカルズ株式会社 | ピリジルテトラヒドロピリジン類およびピリジルピペリジン類 |
FR2883285B1 (fr) * | 2005-03-17 | 2007-05-18 | Sanofi Aventis Sa | Sel besylate de la 7-(2-(4-(3-trifluoromethyl-phenyl) -1,2,3,6-tetrahudro-pyrid-1-yl)ethyl) isoquinoleine, sa preparation et son utilisation en therapeutique |
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US3991061A (en) * | 1975-07-16 | 1976-11-09 | G. D. Searle & Co. | Azanaphthaleneacetic acid derivatives |
US4704390A (en) * | 1986-02-13 | 1987-11-03 | Warner-Lambert Company | Phenyl and heterocyclic tetrahydropyridyl alkoxy-benzheterocyclic compounds as antipsychotic agents |
US5045550A (en) * | 1990-09-20 | 1991-09-03 | Warner-Lambert Co. | Substituted tetrahydropyridines as central nervous system agents |
US5118691A (en) * | 1990-09-20 | 1992-06-02 | Warner-Lambert Co. | Substituted tetrahydropyridines as central nervous system agents |
US5273977A (en) * | 1990-11-05 | 1993-12-28 | Warner-Lambert Company | Substituted tetrahydropyridines and hydroxypiperidines as central nervous system agents |
AU2521597A (en) * | 1996-04-12 | 1997-11-07 | Sumitomo Pharmaceuticals Company, Limited | Piperidinylpyramidine derivatives |
US5776939A (en) * | 1997-06-12 | 1998-07-07 | Eli Lilly And Company | Drug resistance and multidrug resistance modulators |
US6281216B1 (en) * | 1998-02-09 | 2001-08-28 | Duphar International Research B.V. | 2-aminoquinoline derivatives having d4-agonistic activity |
FR2803593B1 (fr) * | 2000-01-06 | 2002-02-15 | Sanofi Synthelabo | Nouvelles tetrahydropyridines, procede pour leur preparation et compositions pharmaceutiques les contenant |
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