CN1167762A - 四氢异喹啉衍生物及其用途 - Google Patents

四氢异喹啉衍生物及其用途 Download PDF

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CN1167762A
CN1167762A CN97102918A CN97102918A CN1167762A CN 1167762 A CN1167762 A CN 1167762A CN 97102918 A CN97102918 A CN 97102918A CN 97102918 A CN97102918 A CN 97102918A CN 1167762 A CN1167762 A CN 1167762A
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isophthalic acid
methyl isophthalic
tetrahydroisoquinoline
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dimethoxy
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A·阿兰因
A·布尔森
B·巴特尔曼
G·费希尔
M-P·海茨·内德哈特
V·马特尔
E·皮纳德
S·罗弗
G·特鲁伯
R·怀勒
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F Hoffmann La Roche AG
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Abstract

本发明涉及通式I的四氢异喹啉衍生物及其药用可接受盐用于制备控制或治疗疾病的药物的用途，该疾病表现为NMDA受体亚型特异性阻滞剂治疗的病症，其中A是芳基，R1是氢、羟基、低级烷基、低级烷氧基、R-CO-或R-COO-，其中R是低级烷基；R2是氢、低级烷基或环烷基；R3-R7是氢、低级烷基、低级烷氧基、羟基或R3和R4在一起为-(CH2)n-或R6和R7在一起为-OCH2O-和n是3或4。

Description

四氢异喹啉衍生物及其用途
本发明涉及通式I的化合物或其药用可接受盐，
Figure A9710291800041
其中A是芳基，R1是氢、羟基、低级烷基、低级烷氧基、R-CO-或R-COO-，其中R是低级烷基；R2是氢、低级烷基或环烷基；R3-R7是氢、低级烷基、低级烷氧基、羟基或R3和R4在一起为-(CH2)n-或R6和R7在一起为-OCH2O-和n是3或4。
上述异喹啉衍生物及其盐中大多数是已知化合物。在US3238212、US3067203和US3217007中这些化合物被描述为具有止痛、解痉、止咳的活性。Mol.Pharmacol.(1976)，12(5)，854-61描述了四氢异喹啉类对多巴胺及β-腺苷酸环化酶体系的激动和拮抗活性的试验。
现已惊奇地发现本发明化合物是NMDA-R亚型的选择性阻滞剂。
NMDA受体具有调控神经元活性和可塑性的关键功能，这使它们在作为改善CNS和建立学习和记忆的基础的传递过程中成为关键参与者。在神经退化的急性和慢性形式的病理条件下，NMDA受体的过度活化对于引发神经细胞死亡起关键作用。
NMDA受体由源于不同基因的称为NR-1(8个不同的联结(splice)变体)和NR-2(A至D)的两个亚单位族组成。来自这两个亚单位族的成员在不同的脑区表现出截然不同的分布。NR-1成员与不同的NR-2亚单位的异侧的结合使NMDA受体表现不同的药理学性质。
NMDA受体亚型特异性阻滞剂可能治疗的病症包括例如由打击和脑外伤导致的急性神经退化和诸如早老性痴呆、帕金森症、杭廷顿氏症、ALS(肌萎缩性侧索硬化症)的慢性神经退化，以及由细菌或病毒感染引起的神经退化，另外，治疗的病症还有诸如精神分裂症、焦虑症和抑郁症。
因此本发明的化合物用于治疗例如由打击和脑外伤导致的急性神经退化和诸如早老性痴呆、帕金森症、杭廷顿氏症、ALS(肌萎缩性侧索硬化症)的慢性神经退化，以及由细菌或病毒感染引起的神经退化，另外，治疗的病症还有诸如精神分裂症、焦虑症和抑郁症。
本发明的目的是式I化合物在治疗或预防由相应的NMDA受体亚单位的过度活化导致的疾病中的应用——诸如例如由打击和脑外伤导致的急性神经退化和诸如早老性痴呆、帕金森症、杭廷顿氏症、ALS(肌萎缩性侧索硬化症)的慢性神经退化，以及由细菌或病毒感染引起的神经退化，另外，治疗的病症还有诸如精神分裂症、焦虑症和抑郁症，这些化合物在相应药物的制备中的应用，以及含有这些化合物的药物。本发明的目的还有式Ia的新化合物
Figure A9710291800051
其中A、R1、R2和R5-R7如上所述，m是1或2。
另一方面，本发明涉及降低急性或慢性神经退化的方法，其包括供给病人治疗有效量的式I化合物。
下列在本叙述中使用的一般术语的定义的应用不考虑所述术语是否单独或联合出现。
作为在此使用的术语，“低级烷基”指含1-4个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基等。术语“芳基”指芳香烃残基，尤其是苯基，可以是未取代的或被一个或多个(最多3个)取代基取代的，取代基选自羟基低级烷基、卤素、低级烷氧基或硝基。
术语“卤素”指氯、碘、氟或溴。术语“低级烷氧基”指一个如前文定义的烷基通过一个氧原子结合。术语“环烷基”指饱和的含3-6个碳原子的环烷烃残基。
式I的四氢异喹啉化合物有两个不对称碳原子。因此，可能有两种立体异构的外消旋物。本发明包含所有可能的外消旋物和它们的旋光对映体。
典型的优选化合物为2-(6，7-二甲氧基-2-甲基-1，2，3，4-四氢异喹啉-1-基)-1-对甲苯基乙醇；1-[2-(4-氯苯基)-乙基]-6-甲氧基-2-甲基-1，2，3，4-四氢异喹啉-7-醇；1-(4-氯苯基)-2-(6，7-二甲氧基-2-甲基-1，2，3，4-四氢异喹啉-1-基)-乙醇；1-[2-(4-氯苯基)-乙基]-2-甲基-1，2，3，4-四氢异喹啉-6，7-二醇；6，7-二甲氧基-2-甲基-1-(2-对甲苯基乙基)-1，2，3，4-四氢异喹啉；6-[2-(4-氯苯基)-乙基]-8，9-二甲氧基-5-甲基-1，2，3，4，4a，5，6，10b-八氢菲啶；2-(6，7-二甲氧基-2-甲基-1，2，3，4-四氢异喹啉-1-基)-1-(4-硝基苯基)-乙醇；和6-[2-(4-氯苯基)-乙基]-8，9-二甲氧基-1，2，3，4，4a，5，6，10b-八氢菲啶。
本发明的式I化合物及其药学上可接受的盐可以用在上述参考中描述的方法制备，例如在US3238212或US3217007中描述了一种方法，包括将通式II的二氢异喹啉鎓化合物
Figure A9710291800061
其中R2和R5-R7如上所述，与式CH3COA的酮在碱性缩合剂存在下反应，其中A如上所述。
在本发明实践中，氧代基还原为羟基是用本身已知的方法进行的。然而，使用碱金属-金属氢化物，诸如氢化锂铝或特别是硼氢化钠、硼氢化钾等完成起始物还原是合适的。优选的方法包括用硼氢化钠在一种溶剂存在下进行还原，此溶剂在还原剂存在下是稳定的。适合的溶剂包括例如甲醇、乙醇或二甲基甲酰胺。在进行完还原反应后，任何芳烷氧基，尤其是苄氧基可以通过氢解被迅速解离而得到游离的羟基。
这种脱苄基采用催化进行是有利的，例如在贵金属催化剂存在下，诸如铂。在另外的工艺步骤中，化合物可被酯化。酯可通过与惯用的酰化试剂反应来制备。
式I化合物及其药学可接受盐也可在一种酸——优选POCl3——存在下环化式III酰胺
Figure A9710291800071
其中A、R1、R2和R5-R7如上所述，得到相应的1-苯基-乙基-3，4-二氢异喹啉衍生物，后者接着用适合的还原剂——诸如碱金属-金属氢化物，例如硼氢化钠——还原。
新的式IA化合物可在一种酸——优选POCl3——存在下环化式IV酰胺来制备，如上述用于环化式III酰胺的方法。
如上所述，式I的四氢异喹啉有两个不对称碳原子，可能形成两种立体异构的外消旋物。如果这些外消旋物同时生成，它们可用本身上已知的方法分离，例如用色谱法或用分级结晶法。如果需要，外消旋物本身可通过本身上已知的方法拆分成它们的旋光对映体，例如用分级结晶法处理其与旋光活性酸形成的盐，诸如α-酒石酸、二苯甲酰基-α-酒石酸或α-樟脑磺酸。
式I化合物可被转化为药学可接受酸的加成盐。这些盐可根据本身已知的、本领域任何技术人员熟悉的方法制备。
式I化合物的活性可用下列方法论证：3H-MK801(Dizocilpine)在体外结合
在冰上切割没有小脑和延髓的取自150-200g雄性大鼠的全脑。然后该组织在4℃在50体积的冷Tris HCl 50mM、EDTA二钠10mM，pH＝7.4的缓冲液(温重/v)中以Ultra-Turrax最大速度在30秒内均化。均浆在48’000Xg(20’000rpm，SS34，Sorvall RC5C)离心10分钟。颗粒用相同体积的缓冲液再均化，均浆在37℃孵化10分钟。如上述方法离心后，颗粒用相同体积的缓冲液再均化，在-80℃将35ml馏分  冷冻至少16小时但不超过2周。
对于结合试验，如上述方法离心均浆，颗粒通过在25体积的冷Tris HCl5mM，pH＝7.4的缓冲液中均化(Ultra-Turrax，最大速度，30秒)洗涤三次，如上述方法离心。最终的颗粒在25体积的缓冲液(最初的湿重)里再均化并如此用于分析。在分析中最终膜的浓度为20mg/ml。
孵化在1nM谷氨酸、甘氨酸和亚精胺存在下进行。MK-801，(+)-[3-3H(N)]，NEN(NET-972)20Ci/mmol以5nM最终浓度使用。在100mMTCP存在下没有测到特定的结合。在室温孵化2小时后，过滤悬浮液(WhatmannGF/B，渗入0.1％聚氮丙啶2小时)并用3ml冷Tris HCl 5mM，pH＝7.4的缓冲液洗涤五次。空气干燥的滤纸在Tri-Carb 2500TR闪烁计数器里与10mlUltimagold(Packard)搅动后计数。
DPM被换算为特定结合百分数，这些值用非线性回归统计程序(BINDING，H.Affolter，瑞士)处理，得到低和高亲和结合位点的IC50值(＝在各个位点产生一半最大抑制的浓度)。每个试验至少重复三次，最终IC50值以各个试验的平均+/-标准偏差核算。
参考：R.W.Ransom和N.L.Stec.Journal of Neurochemisty 51，830-836，1988。重组NMDA受体的电生理学用于NMDA受体的亚单位NMDAR1C和NMDAR2A的cDNA克隆编码(参见Hollmann和Heinemann，1994，Annu.Rev.Neurosci.17：31，NMDA受体亚单位的命名法)被从大鼠脑λgtllcDNA库中象在别处公开的(Sigel等人，1994，J.Biol.Chem.269：8204)那样分离出来。用于大鼠脑NMDA受体的亚单位NMDAR2B的克隆从S.Nakanishi(Kyoto，日本)获得。用以前描述的方法(Malherbe等人，1990，Mol.Brain Res.8：199)将cDNA转录、覆盖(capped)及poly(A+)-tailed。南非蛙(Xenopus laevis)的卵母细胞被用来表示NMDAR1C和NMDAR2A亚单位的结合或NMDAR1C和NMDAR2B亚单位的结合。将大约3fmol的1∶1的各个mRNA碎片混合物注入每个卵母细胞。4-5天后用电压夹实验(参见Methfessel等人，1986，Pflügers Arch.407：577，卵母细胞试验的方法和电压夹)测量通过NMDA受体通道的离子流。膜电位固定在-80mV，受体用施加改进的含激动L-天冬氨酸(Asp)和甘氨酸(Gly)的Ringer溶液激活。对每个亚单位结合选择不同的激动剂浓度以计算出两种类型受体对激动剂不同的敏感性(70μM Asp+2.5μM Gly用于NMDAR1C-NMDAR2A，15μM Asp+0.2μM Gly用于NMDAR1C-NMDAR2B)。通过卵母细胞的快速超融合将激动剂每2.5分钟间隔15秒加入。在一系列初始控制后，刺激增加浓度的被测拮抗物加入到基础的Ringer和含激动剂的溶液里。为了数据分析，激动剂诱导作用(y)对拮抗剂的浓度(x)作图，对数方程y＝A/[1+(x/IC50)H]适于计算50％抑制浓度(IC50)数据。对每个拮抗物测试3-6个卵母细胞，如果可能，至少对每个卵母细胞至少包括3个IC50浓度。但是，即使IC50还没有达到100μM.高于100μM的浓度也从不使用，对于两种化合物，因为有限的溶解度，最大浓度甚至较低(20-30μM)。在这些情况下，一个用于IC50的较低限(例如“＞100μM”)在表“试验结果”里给出。在另两种情况下，0.1μM的浓度产生缓慢增长的阻滞，30分钟后超过50％。由于阻滞开始得缓慢，甚至在较低浓度也无法测试，替代的用于IC50的上限(“＜0.1μM”)在表“试验结果”里给出。所有其它情况的IC50值是通过对数曲线对映确定的各个IC50的数学平均值。受试的式I化合物受试的式I化合物
Figure A9710291800112
试验结果
化合物ABCDEFGHOJKLMNOPQRSTUVWXYZAA           3H-MK801/IC50(μM)高                       低                               电生理学/IC50(μM)卵母细胞NMDAR1C&2A                               NMDAR1C&2B
    0.040.090.120.290.340.40.460.50.590.60.911.371.391.591.61.71.762.12.182.312.712.93.63.873.94.14.62     223541911161293158758914610761319895370101951611471235687110129223393135185     ＞10015＞2019＞3021     ≤0.10.490.0430.28＜0.11.2
通过筛选式I化合物，化合物的这个化学组可被确定为NMDA受体亚型选择性阻滞剂，并且对于选中的化合物，对NMDAR-2B亚单位的优选可通过用在卵母细胞进行的克隆的NMDA受体亚型的电生理特征证明。
在此描述的式I化合物及其盐可以被结合到标准的药用剂型里，例如与常用的药用辅助剂材料——例如有机或无机惰性载体材料，诸如水、明胶、乳糖、淀粉、硬脂酸镁、滑石、植物油、树胶、聚烷基二醇等——用于口服或肠胃外给药。药用制剂可以采用固体形式，例如片剂、栓剂、胶囊，或用液体形式，例如溶液、悬浮液或乳剂。可加入药用辅助剂材料，包括防腐剂、稳定剂、润湿剂、乳化剂、改变渗透压或作为缓冲剂的盐类。药用制剂也可含有其它治疗活性成分。
式I化合物每日给药的剂量随使用的个别化合物、选择的给药途径和接受者而变化。式I化合物给药的典型方法是口服和肠胃外形式给药途径。式I化合物的口服配方优选成人每天在150-1.5mg范围。式I化合物的肠胃外形式配方优选成人每天在5-500mg范围。
本发明进一步用下列实施例详细说明。
  实施例1
                               片剂(湿法成粒)
成分                              mg/片
                           5mg  25mg  100mg  500mg1.2-(6，7-二甲氧基-2-甲基-1，2，3，4-四氢异喹啉-1-基)-   5    25    100    5001-对甲苯基乙醇2.无水乳糖  TG                 125  105   30     1503.Sta-Rx 1500                  6    6     6      304.微晶纤维素                   30   30    30     1505.硬脂酸镁                     1    1     1      1
                总量       167  167   167    831制备方法：1.混合成分1、2、3和4并用纯化水成粒。2.在50℃干燥颗粒。3.使颗粒通过合适的研磨设备。4.加入成分5并混合三分钟；在合适的压床上压片。
        实施例2
                                   胶囊剂
成分                              mg/胶囊
                           5mg    25mg  100mg  500mg1.2-(6，7-二甲氧基-2-甲基-1，2，3，4-四氢异喹啉-1-基)-   5      25    100    5001-对甲苯基乙醇2.含水乳糖                     159    123   148    …3.玉米淀粉                     25     35    40     704.滑石                         10     15    10     255.硬脂酸镁                     1      2     2      5
                总量       200    200   300    600制备方法：1.在合适的混合器里混合成分1、2和3三十分钟。2.加入成分4和5并混合三分钟。3.装如胶囊。
        实施例3
                                 片剂(湿法成粒)
成分                                  mg/片
                              5mg    25mg  100mg  500mg1.2-(6，7-二甲氧基-2-甲基-1，2，3，4-四氢异喹啉-1-基)-      5      25    100    5001-对甲苯基乙醇2.无水乳糖                        125    105   30     1503.Sta-Rx1500                      6      6     6      304.微晶纤维素                      30     30    30     1505.硬脂酸镁                        1      2     2      5
                  总量        167    168   168    835制备方法：1.混合成分1、2、3和4并用纯化水成粒。2.在50℃干燥颗粒。3.使颗粒通过合适的研磨设备。4.加入成分5并混合三分钟；在合适的压床上压片。

Claims (6)

1.通式I的四氢异喹啉衍生物及其药用可接受盐用于制备控制或治疗疾病的药物的用途，该疾病表现NMDA受体亚型特异性阻滞剂治疗的病症，
Figure A9710291800021
其中A是芳基，R1是氢、羟基、低级烷基、低级烷氧基、R-CO-或R-COO-，其中R是低级烷基；R2是氢、低级烷基或环烷基；R3-R7是氢、低级烷基、低级烷氧基、羟基或R3和R4在一起为-(CH2)n-或R6和R7在一起为-OCH2O-和n是3或4。
2.根据权利要求1式I化合物的用途，其中治疗的病症包括例如由打击和脑外伤导致的急性神经退化和诸如早老性痴呆、帕金森症、杭廷顿氏症、ALS(肌萎缩性侧索硬化症)的慢性神经退化，以及由细菌或病毒感染引起的神经退化，另外，治疗的病症还有诸如精神分裂症、焦虑症和抑郁症。
3.根据权利要求1或2的用途，其中式I化合物为：2-(6，7-二甲氧基-2-甲基-1，2，3，4-四氢异喹啉-1-基)-1-对甲苯基乙醇；1-[2-(4-氯苯基)-乙基]-6-甲氧基-2-甲基-1，2，3，4-四氢异喹啉-7-醇；1-(4-氯苯基)-2-(6，7-二甲氧基-2-甲基-1，2，3，4-四氢异喹啉-1-基)-乙醇；1-[2-(4-氯苯基)-乙基]-2-甲基-1，2，3，4-四氢异喹啉-6，7-二醇；6，7-二甲氧基-2-甲基-1-(2-对甲苯基乙基)-1，2，3，4-四氢异喹啉；6-[2-(4-氯苯基)-乙基]-8，9-二甲氧基-5-甲基-1，2，3，4，4a，5，6，10b-八氢菲啶；2-(6，7-二甲氧基-2-甲基-1，2，3，4-四氢异喹啉-1-基)-1-(4-硝基苯基)-乙醇；和6-[2-(4-氯苯基)-乙基]-8，9-二甲氧基-1，2，3，4，4a，5，6，10b-八氢菲啶。
4.式Ia化合物
Figure A9710291800031
其中A、R1、R2和R5-R7如权利要求1或2所述，m是1或2。
5.含有一种或多种根据权利要求1的式I化合物的药物，其用来治疗例如由打击和脑外伤导致的急性神经退化疾病和诸如早老性痴呆、帕金森症、杭廷顿氏症、ALS(肌萎缩性侧索硬化症)的慢性神经退化疾病，以及由细菌或病毒感染引起的神经退化，另外，治疗的病症还有诸如精神分裂症、焦虑症和抑郁症。
6.一种治疗或预防疾病的方法，该疾病表现NMDA受体亚型特异性阻滞剂治疗的病症，诸如例如由打击和脑外伤导致的急性神经退化疾病和诸如早老性痴呆、帕金森症、杭廷顿氏症、ALS(肌萎缩性侧索硬化症)的慢性神经退化疾病，以及由细菌或病毒感染引起的神经退化，另外，治疗的病症还有诸如精神分裂症、焦虑症和抑郁症，其包括给需要这种治疗或预防的病人施加有效量的根据权利要求1的式I化合物。
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