CN1120038A - 一类取代的哌啶-1-乙醇的酯类、制备及其药用 - Google Patents

一类取代的哌啶-1-乙醇的酯类、制备及其药用 Download PDF

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CN1120038A
CN1120038A CN95108920A CN95108920A CN1120038A CN 1120038 A CN1120038 A CN 1120038A CN 95108920 A CN95108920 A CN 95108920A CN 95108920 A CN95108920 A CN 95108920A CN 1120038 A CN1120038 A CN 1120038A
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J·P·特恩奥特
J·福斯特
P·拉德努瓦
M·C·雷欧纳斯
A·威克
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Abstract

通式(I)的化合物及其在医药中的应用。
其中，R代表直链或支链和/或任选含一个烯键的(C1-C19)烷基、(C3-C6)环烷基、(C3-C6)环烷基甲基、任选被卤原子取代的苯基或任选被卤原子取代的苯基甲基。

Description

一类取代的哌啶-1-乙醇的酯类、制备及其药用
本发明涉及α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-1-乙醇的酯类，它们的制备及其在医药中的应用。
本发明的化合物对应于下述通式其中，R代表直链或支链和/或任选含一个烯键的(C1-C19)烷基、(C3-C6)环烷基、(C3-C6)环烷基甲基、任选被卤原子取代的苯基或任选被卤原子取代的苯基甲基。
在本发明化合物的结构中，其中一个碳原子是不对称的，因此，它们可以以纯的旋光对映体的形式或以对映体混合物的形式存在。另外，它们还可以以游离碱或加成盐的状态存在。
按照本发明，通式(I)的化合物可通过使式(II)的α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-1-乙醇与通式(RCO)2O的酸酐或通式RCOC1的酰氯在酯化反应领域公知的反应条件下反应制得，其中R如前述定义。
Figure A9510892000041
式(II)的化合物及其对映体可参见专利EP-0,109,317和FR-2,628,470。
通式RCOC1的酰氯可购得，或者也可以从对应的酸出发，按照已知方法进行制备，例如用亚硫酰氯进行作用。
下列实施例详细说明本发明一些化合物的制备。微量元素分析和IR谱、NMR谱证实所得化合物的结构。
各题目中括号内的化合物号数对应于后边表中的号数。实施例1(化合物1)(±)-α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-1-乙醇的乙酸酯的(E)-丁-2-烯二酸盐(1∶1)。
在250ml圆底烧瓶中加入3.47g(0.01mol)(±)-α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-2-乙醇和20ml乙酸酐，混合物在室温下搅拌过夜。蒸发过量酸酐，用100ml乙酸乙酯处理残余物，加入过量3N氨水，分出有机相，水相用乙酸乙酯萃取，合并有机相，用水洗涤，用硫酸钠干燥，减压蒸发溶剂，得到4.5g油状产物，用硅胶柱色谱纯化，用98/2的二氯甲烷/甲醇混合物洗出。将纯化的馏分溶于乙醇中，并且1当量富马酸制得富马酸盐。
用乙醇重结晶两次，用丙-2-醇重结晶一次，干燥后，得到0.89g化合物。
熔点：164-165℃实施例2(化合物2)
R-(-)-α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-2-乙醇的乙酸酯
在50ml圆底烧瓶中，加入2.62g(0.00753mol)R-(-)-α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-1-乙醇和15ml乙酐，混合物在室温下搅拌过夜。将混合物倾至冰水上，搅拌1小时，加入氨水。形成微白色油状物并全部凝固。分出该产物并用五氧化二磷干燥，得到2.77g固体。
用丙-2-醇重结晶并干燥后得到1.87g左旋产物。
熔点：73-74℃
[α]D 25＝-43.8(C＝1，CHCl3)。实施例3(化合物3)
S-(+)-α-[(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-1-乙醇的乙酸酯
用前述实施例的方法，从3.16g(0.0098mol)S-(+)-α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-1-乙醇出发，得到2.35g右旋化合物。
熔点：73-74℃
[α]D 25＝+42.0°(C＝1，CHCl3)实施例4(化合物5)
(±)-α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-1-乙醇的十一烷酸酯的(E)-丁-2-烯二酸盐(1∶1)
在圆底烧瓶中加入4.65g(0.025mol)十一烷酸，加入3.5g(0.03mol)亚硫酰氯，混合物在60℃油浴中加热2小时。
减压蒸发过量亚硫酰氯，用甲苯夹带法除去其残余，用冰浴冷却残留物，滴入7g(0.02mol)(±)-α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-1-乙醇于50ml吡啶中的溶液，搅拌该鲜黄色混合物30分钟，在室温下静置过夜。
减压蒸发溶剂，残留物用硅胶柱色谱纯化，用乙酸乙酯洗出。
得到4g粘稠油状物，将它溶于25ml乙醇中，加入1g富马酸，冷却该溶液2天。
向结晶物中加入50ml石油醚，混合物搅拌15分钟，过滤分出白色沉淀。用丙-2-醇重结晶后，得到0.86g化合物。
熔点：144-145℃实施例5(化合物9)
(±)-α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-2-乙醇的环戊烷乙酸酯的(E)-丁-2-烯二酸盐(1∶1)
在备有氯化钙管的250ml圆底烧瓶中，加入3.8g(0.03mol)环戊烷乙酸和12g(0.1mol)亚硫酰氯，加入1滴N，N-二甲基甲酰胺，用60℃油浴加热混合物3小时。
混合物在室温下搅拌过夜，蒸发、再用甲苯夹带除去过量亚硫酰氯。
得到透明油状物，用5ml甲苯稀释，将甲苯逐滴倾至含有3.47g(0.01mol)(±)-α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-1-乙醇在15ml吡啶中的溶液的圆底烧瓶中，混合物在室温下搅拌过夜。
减至蒸发溶剂，用水夹带除去残余的吡啶，用水和乙酸乙酯处理残留物，分出有机相，水相用乙酸乙酯萃取两次，合并有机相，用硫酸钠干燥，减压蒸发溶剂。
得到7.9g油状物，先用冷异丙醚萃取，再用沸腾的异丙醚充分萃取，合并有机相，用滤纸过滤除去混浊，减压蒸发异丙醚，残留物用硅胶柱色谱纯化，用异丙醚洗出。
得到3.14g油状物，由它用1当量富马酸在乙醇中制得富马酸盐。
用25ml丙-2-醇重结晶并干燥后，得到1.94g富马酸盐。
熔点：146-147℃
下表说明本发明几种化合物的化学结构和物理性质。在“R”-栏中，“cC5H9-”表示环戊基，“4-F-C6H4-”表示4-氟苯基。在“盐”一栏中，“-”表示碱状态的化合物，“fum.”表示(E)-丁-2-烯二酸盐(1∶1)(富马酸盐)，“HCl”表示盐酸盐(1∶1)，“ox”表示乙二酸盐(1∶1)(草酸盐)。
                                              表
    N°     R    异构体   盐   F(℃)     [α]D 20(c＝1)
    12345678     CH3-CH3-CH3-CHH3-(CH2)3-CH3-(CH2)9-(CH3)2CH-(CH3)3C-cC5H9-     (±)R(-)S(+)(±)(±)(±)(±)(±)   fum.--fum.fum.fum.fum.fum.   164-16573-7473-74159-160144-145173-174181-182169-170 -43,8°(CHCl3)+42,0°(CHCl3)-----
    N°     R   异构体   盐   F(℃)     [α]D 20(c＝1)
    91011121314151617     cC5H9-CH2-4-F-C6H4-4-F-C6H4-CH2-CH3(CH2)16-CH3(CH2)16-CH3(CH2)16-cis-CH3(CH3)7CH＝CH(CH2)7-cis-CH3(CH2)7CH＝CH(CH2)7-cis-CH3(CH2)7CH＝CH(CH2)7-     (±)(±)(±)(±)R(-)S(+)(±)R(-)S(+)   fum.fum.HClfum.fum.fum.ox.ox.ox.   146-147197-198195-196115-116116-118116-118119-12099-10099-100      -----28,9°(CH3OH)+26,7°(CH3OH)--27,5°(CH3OH)+26,5°(CH3OH)
对本发明的化合物进行实验，显示了它们的神经保护和趋神经性活性。
为此，按照Schoemaker和Coll.Eur.J.Pharmacol.(1990)176 249-250中所述方案，试验本发明的化合物在大鼠大脑皮层膜中抑制[3H]艾芬地尔与对NMDA受体络合物的聚胺敏感的调节位点的结合的情况。将150-230g的雄性Sprague-Dawley大鼠杀死，将大脑皮层在20体积的冰冷的50mM Tris-HCl缓冲液(0℃时pH＝7.4)中用Ultra-TuraxTM(Ikawerk)或PolytronTM(Kinematica)仪器均质化。均质化物以45,000×g 10分钟离心法洗洗两次，沉淀物再悬浮于新鲜缓冲液中。最后的沉淀物用20体积的同一缓冲液处理。
100μl的该悬浮液液体在0℃用1nm[3H]艾芬地尔(比活性：30-50Ci/mmol)在3μM GBR 12909(ResearchBiochemicals Inc.，Natik，MA，USA)存在下，在有或没有竞争物存在下培养120分钟，最终体积为1,000μl。
培养后，用5ml冰冷的50mM(0℃时pH＝7.4)Tris-HCl缓冲液稀释混合物，用Whatman GF/BTM滤器过滤回收膜(滤器用0.05％聚亚乙基亚胺预处理)，然后用5ml冰冷的缓冲液洗涤两次。
用10μM艾芬地尔确定非特异性结合性，按常规方法分析数据，计算CI50浓度，也就是抑制[3H]艾芬地尔结合性50％的浓度。
在本实验中最具活性的化合物的CI50值为0.4μM。
还评价了本发明化合物对[3H]艾芬地尔结合位点的亲和性，其中[3H]艾芬地尔结合位点与NMDA受体不关连并且与σ位点相仪。
将体重为150-230g的雄性Sprague-Dawley大鼠杀死，将其大脑皮层在4℃于20体积的冰冷的pH＝7.4的50mMTris-HCl缓冲液中用Ultra-TuraxTM(lkawerk)或PolytronTM(Kinematica)仪器均质化。于45000×g离心10分钟后，弃去上清液，在同样条件下再洗涤沉淀一次，然后再悬浮于起始体积的缓冲液中。
100ml的膜悬浮液在1ml含有待实验化合物和0.5nM[3H]艾芬地尔的缓冲液中于37℃培养30分钟。在10μM艾芬地尔存在下确定非特异性结合性。结合的放射性通过Whatman GF/BTM滤器过滤分离，滤器预先用0.05％聚亚乙基亚胺处理，然后用5ml冰冷缓冲液洗涤两次。用常用方法分析结果，并计算抑制[3H]艾芬地尔结合性50％的浓度。
在本实验中最具活性的化合物的CI50为0.04-0.4μM。
最后本发明的化合还进行小鼠大脑局部缺血实验。局部缺血由心跳停止引起，而心跳停止经静脉快速注射氯化镁而引起。在本实验中，测定“存活时间”，也就是每只小鼠在注射氯化镁的时刻至可观察到的最后一次呼吸运动的时间间隔。最后一次运动看作是中枢神经系统功能终止的标志。
对照小鼠一般在注射氯化镁后19秒出现呼吸停止。
雄性小鼠(Charles River CD1)每10只一组进行实验。实验前随意进食和饮水。在经腹膜内施用本发明化合物10分钟后测试存活时间。计算接受了本发明的待实验化合物的一组10只小鼠和只接受了液体载体的一组10只小鼠之间的存活时间之差。
存活时间的延长随化合物剂量变化的情况按半对数曲线作图。
用该曲线可计算“3秒有效剂量”(DE3″)，也就是使得与未经处理的对照小鼠相比存活时间增加3秒的剂量。
存活时间增加3秒具有统计意义并可重复。
在本实验中最具活性化合物的(DE3″)，经腹膜内是3mg/Kg左右。
所进行实验的结果表明本发明的化合物具有神经保护活性和趋神经性活性。
该活性可用于神经障碍疾病的治疗和防止，例如由局部缺血发作、心跳或呼吸停止、脑栓形成或脑栓塞形成、颅外伤或背髓创伤引发的神经疾病。本发明的化合物还可用于治疗脑衰老、多种梗塞引发的痴呆、脉管性痴呆、多发性硬化，用于治疗橄榄体-脑桥小脑萎缩及其他神经疾病，例如阿尔茨海默症、匹克病、享廷顿舞蹈病等。
它们还可用于治疗创伤型、局部缺血型、代谢型、传染型、酒精型、医原型或遗传型周围神经疾病，用于治疗影响运动神经元的疾病，例如侧肌萎缩硬化或萎缩硬化。
对于青光眼患者，它们可用于防止视神经或视网膜的变性。
最后还可预计它们将用于治疗抽搐、偏头痛和/或嗜毒症，例如用作防吐剂。
本发明的化合物可单独使用，或者也可与其他药物结合使用，例如和重组的组织血浆酶原活化剂等抗血栓形成剂一起使用，用于治疗血栓-栓塞型大脑梗塞，或者与降眼内血压剂一起使用，用于治疗青光眼，还可以和抗癌剂一起使用，以降低后者的副作用(神经病等)。
为此，它们可以与适宜的赋形剂结合在一起以各种适于经肠或非经肠给药的形式提供，例如下列形式：片剂、糖衣剂、胶囊剂、囊剂、栓剂、贴剂、可口服或可注射的溶液剂或悬浮液剂，剂量为可使得活性物质的日剂量为1-1000mg。

Claims (4)

1.游离碱或加成盐状态的、纯旋光对映体或对映体混合物形式的下列通式(I)化合物：其中，R代表直链或支链和/或任选含一个烯键的(C1-C19)烷基、(C3-C6)环烷基、(C3-C6)环烷基甲基、任选被卤原子取代的苯基或任选被卤原子取代的苯基甲基。
2.制备权利要求1的化合物的方法，其特征在于使α-(4-氯苯基)-4-[(4-氟苯基)甲基]哌啶-1-乙醇与通式(RCO)2O的酸酐或通式RCOC1的酰氯反应，其中R如权利要求1定义。
3.药品，其特征在于它由权利要求1的化合物构成。
4.药物组合物，其特征在于它包含与赋形剂结合的权利要求1的化合物。
CN95108920A 1994-07-13 1995-07-12 一类取代的哌啶-1-乙醇的酯类、制备及其药用 Pending CN1120038A (zh)

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