CN1989128A - 新的4-苯亚甲基-哌啶衍生物 - Google Patents
新的4-苯亚甲基-哌啶衍生物 Download PDFInfo
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- CN1989128A CN1989128A CNA2005800243746A CN200580024374A CN1989128A CN 1989128 A CN1989128 A CN 1989128A CN A2005800243746 A CNA2005800243746 A CN A2005800243746A CN 200580024374 A CN200580024374 A CN 200580024374A CN 1989128 A CN1989128 A CN 1989128A
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- oxo
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- ben yajiaji
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- piperidines
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Abstract
本发明涉及用作NMDA拮抗剂,特别是含有NR2B亚单位的受体拮抗剂和镇痛剂的式(I)的新4-苯亚甲基-哌啶衍生物。
Description
本发明涉及为具有改善的体内特征的NR2B选择性NMDA受体拮抗剂或为制备NMDA受体拮抗剂的中间体的新4-苯亚甲基-哌啶衍生物。
发明背景
N-甲基-D-天冬氨酸(NMDA)受体是在中枢神经系统广泛表达的配体门控的阳离子通道。NMDA受体与神经元的发育和可塑性变化有关。由谷氨酸,NMDA受体的天然配体过度活化NMDA受体可以引起细胞的钙超载。这触发了改变细胞功能并最终可导致神经元的死亡的细胞内级联事件。NMDA受体拮抗剂可用于治疗许多伴随谷氨酸过度释放或任意原因引起的NMDA受体过度活化的疾病。[Curr Opin InvestigDrugs.2003 4:826-32]。
NMDA受体是由至少一个NR1亚单位与一种或多种四NR2亚单位(NR2A-D)构成的异聚体。由不同的NR2亚单位构成的NMDA受体在CNS中的空间分布和药理学敏感性是不同的。由于其限制性分布(在前脑和脊髓的胶状质中密度最高)这些亚单位中特别令人感兴趣的是NR2B亚单位[Neuropharmacology,
38,611-623(1999)]。这种亚型的选择性化合物是可得的并且已经证明在中风[stroke,
28,2244-2251(1997)]、创伤性脑损伤[Brain Res.,
792,291-298(1998)]、帕金森病[Exp.Neurol.,
163,239-243(2000)]、神经性和炎性疼痛[Neuropharmacology,
38,611-623(1999)]的动物模型中是有效的。
而且,NMDA受体的NR2B亚型选择性拮抗剂提供了优于NMDA受体非选择性拮抗剂的治疗优势。通道阻滞剂类型的非选择性NMDA拮抗剂苯环利定和氯胺酮诱发人体的致幻觉反应、幻觉、烦躁不安、紧张和健忘。这些严重的副反应妨碍了它们作为潜在性药物在临床上的应用。属于此类的化合物也导致了动物行为异常,例如刺激运动活动,诱发健忘症和损害运动协调。动物中这些反应的严重程度被认为可预知临床副反应的强度。预期NR2B亚型选择性拮抗剂不具有这些副反应的大多数。据报道在动物行为研究中一些NR2B选择性化合物[Ro 63-1908in J.Pharmacol.Exp.Ther.,302(2002)940-948and Ro 25-6981in Behav.Pharmacol.,14(2003)477-487]增加了自发活动,而对于另一种NR2B选择性拮抗,CP-101,606,以及属于其他类的Ro 256981没有观察到这样的副作用[Neuropharmcology,38,611-623(1999)]。其他人证实了直到56mg/kg s.c.和100mg/kgi.p.CP-101,606也缺乏运动刺激作用[Soc.Neurosc.Abstr.21,439.9.1995.]。因此,根据我们最全的知识,CP-101,606是唯一的一贯被报道缺乏运动刺激作用的NR2B选择性拮抗剂。由于CP-101,606口服效力弱并且根据公开的信息仅发现其通过静脉途径施用于人类,而且它具有多晶形CYP 2D6介导的代谢[Drug Metabolism and Disposition 31:76-87],因此仍十分需要副作用低(高治疗指数)、口服效力良好(生物利用度)和具有良好发展的用于治疗目的,特别是口服治疗的新NR2B拮抗剂。
本发明化合物的饱和类似物在专利第WO2003010159号中描述为NR2B亚型选择性NMDA拮抗剂。然而,式(I)的4-苯亚甲基-哌啶衍生物的相近结构的类似物在文献中是未知的。
发明概述
发现本发明式(I)的新4-苯亚甲基-哌啶衍生物是对含有NR2B亚单位的受体具有选择性的功能活性的NMDA拮抗剂。我们还发现苯亚甲基-哌啶类在体内具有与其饱和的苯甲基-哌啶类似物相似的止痛效能。令人惊讶地,虽然后者分子以其最大有效止痛剂量或稍微超过其最大有效止痛剂量会引起运动刺激,但本发明的测试化合物直到40-60倍的止痛剂量也没有运动刺激作用。该特征可提供优于具有较低治疗指数的NR2B选择性NMDA拮抗剂的治疗优势。令人惊讶地,后者分子在稍微超过其止痛剂量范围时产生了运动刺激作用,而本发明的化合物直至40-60倍于止痛剂的剂量前无运动刺激作用。该特征可以提供优于具有较低治疗指数的NR2B选择性NMDA拮抗剂的治疗作用。
发明详述
因此本发明首先涉及式(I)的新4-苯亚甲基-哌啶衍生物
-其中含义为
X和Y独立地为氢或卤素原子,羟基,氰基,硝基,氨基,任选由一个卤素原子或多个卤素原子取代的C1-C4烷氨基,任选由一个卤素原子或多个卤素原子取代的芳氨基,任选由一个卤素原子或多个卤素原子取代的芳烷基氨基,任选由一个卤素原子或多个卤素原子取代的C1-C4烷基磺酰胺基,任选由一个卤素原子或多个卤素原子取代的C1-C4烷酰基酰胺基,芳基磺酰胺基,C1-C4烷基磺酰氧基,羧基,三氟甲基,三氟甲氧基,C1-C4烷基-SO2-NH-CH2-,NH2-(CH2) 1-4-SO2-NH-,NH2-(CH2)1-4-(CO)-NH-,氨磺酰基[NH2-SO2-],甲酰基[-CHO],氨基-甲基[-CH2-NH2],羟甲基,C1-C4烷基,C1-C4烷氧甲基,卤代甲基,四唑基,或C1-C4烷氧基,任选由氨基取代的C1-C4烷氧羰基,C1-C6烷酰氧基,苯基或C1-C4烷氧基,或
在特定的情况下,相邻的X和Y基团与一个或多个相同或不同的另外的杂原子和-CH=和/或-CH2-基形成任选取代的4-7元的同环-或杂环,优选吗啉,吡咯,吡咯烷,氧代-或硫代-吡咯烷,吡唑,吡唑烷,咪唑,咪唑烷,氧代-或硫代-咪唑或咪唑烷,1,4-噁嗪,噁唑,噁唑烷,氧代-或硫代-噁唑烷,氧代-或硫代-噻唑烷,或3-氧代-1,4-噁嗪环,
Z是氢或卤素原子,硝基,氨基,C1-C4烷基,C1-C4烷氧基,氰基,三氟甲基,三氟甲氧基-
及其旋光对映体,外消旋化合物及盐。
而且,本发明的目的是含有式(I)的新4-苯亚甲基-哌啶衍生物或其旋光对映体或外消旋化合物或盐作为活性成分的药物组合物。
本发明的进一步的目的是生产式(I)新4-苯亚甲基-哌啶衍生物和制造含这些化合物的药剂的方法,以及使用这些化合物治疗的方法,即给治疗的哺乳动物-包括人-施用有效量的本发明式(I)的新苯亚甲基-哌啶衍生物本身或药剂形式。
根据本发明,式(I)的羧酸酰胺化合物可通过以下方法制备。
为了生产式(I)的化合物,其中X,Y和Z如式(I)所定义,使式(II)的仲胺
-其中Z具有与式(I)同样的含义-在碱存在下在适宜的溶剂中与乙基草酰氯反应
将得到式(III)的酯化合物
-其中Z具有与式(I)同样的含义-使用氢氧化碱进行皂化并将得到的式(IV)的草酰胺酸(oxalamid acid)
-其中Z的含义如上文式(I)所述-或其反应性衍生物与式(V)的苯胺反应
-其中X和Y的含义如前文式(I)所给出-,
然后在特定的情况下将所得的式(I)的4-苯亚甲基-哌啶衍生物-其中X,Y,Z如式(I)所定义-通过已知的方法通过引入新的取代基和/或修饰或除去存在的基团,和/或通过成盐和/或通过将化合物从盐中游离,和/或通过使用光学活性的酸或碱将所得的外消旋化合物拆分而转变成另外的式(I)化合物。
式(II)的羧酸和式(V)的苯胺反应,即形成酰胺键优选通过由式(II)的羧酸制备活性衍生物并且优选在碱存在下与式(V)的苯胺反应来进行。
在溶剂(例如二甲基甲酰胺,乙腈,氯代烃或烃)中在形成酰胺键期间羧酸转换成活性衍生物优选在原位进行。活性的衍生物可以是酰基氯(例如由羧酸与亚硫酰氯制备),混合酸酐(例如在碱,例如三乙胺存在下由羧酸与氯甲酸异丁酯制备),活性酯(例如在碱,如三乙胺存在下由羧酸和羟基苯并三唑和二环己基-碳二亚胺或六氟磷酸O-苯并三唑-1-基-N,N,N′,N′-四甲基脲(HBTU)制备)。活性衍生物在室温和0℃之间制备。必需的反应时间是6-20h。反应混合物通过柱色谱法使用Kieselgel 60(Merck)作为吸附剂和适当的洗脱剂对其进行纯化。将适当的级分浓缩得到纯化产物。产物的性质和量通过HPLC-MS法进行测定。
式(V)的苯胺可以商购获得或通过不同的已知方法来合成。在实施例中描述了某些无法商购获得的式(V)苯胺和式(IV)羧酸的合成。
如上所述,本发明式(I)的新4-苯亚甲基-哌啶衍生物是高效和选择性的NMDA受体拮抗剂,并且大部分化合物是NMDA受体NR2B亚型的选择性拮抗剂。为了表征化合物的NR2B选择性NMDA拮抗剂效能,我们使用了主要表达含有NR2B亚单位的NMDA受体的培养的皮层神经元。为了证明其选择性,使用由NR1/NR2A亚单位组合转染的HEK-293细胞。我们分别使用小鼠福尔马林和运动活性试验来测定有效的NR2B选择性拮抗剂的体内止痛效能和副作用倾向。。
试验方案
重组NMDA受体的表达
为了证明化合物的NR2B选择性,即研究它们对含有NR2A的NMDA受体的作用,我们在稳定表达具有NR1/NR2A亚单位组成的重组NMDA受体的细胞株上对最有效的化合物进行测试。使用阳离子脂质介导的转染方法将亚克隆至可诱导的哺乳动物表达载体的人NR1和NR2A亚单位的cDNAs引入缺乏NMDA受体的HEK293细胞中[Biotechniques,22,982-987.(1997);Neurochemistry International,43,19-29.(2003)]。使用对新霉素和潮霉素的耐药性来筛选具有载体和单克隆细胞株的克隆,由对NMDA暴露产生最高应答的克隆来建立。在荧光钙测量中测试了化合物对NMDA诱发的细胞溶质钙升高的抑制作用。在诱导过程中还存在氯胺酮(500μM)以防止细胞毒性。
使用荧光平板读数器通过测量大鼠皮层细胞培养物的细胞内钙浓
度来评价NMDA拮抗剂的体外效能
细胞内钙的测量在源于17天大的Charles River大鼠胚胎的原代新生皮层细胞培养物上进行(新生皮层细胞培养物的制备详见Johnson,M.I.;Bunge,R.P.(1992):Primary cell cultures ofperipheral and central neurons and glia.In:Protocols for NeuralCell Culture,eds:Fedoroff,S.,Richardson A.,The Humana PressInc.,51-75)。分离后,将细胞加到标准的96-孔微量培养板上,在37℃95%空气-5%CO2气氛中保持培养直到进行钙测量。
3-7天后将该培养物用于体外的细胞内的钙测量。这里认为细胞的体外成熟(age)主要表达含有NR2B的NMDA受体[MbI.Pharmacol.
45,846-853.(1994)]。在测试前使细胞装载荧光Ca2+-敏感染料,Fluo-4/AM(2μM)。通过用于测量的溶液(140mM NaCl,5mM KCl,2mM CaCl2,5mM HEPES,5mM HEPES-Na,20mM葡萄糖,10μM甘氨酸,pH=7.4)洗涤细胞两次来停止装载。洗涤后将测试化合物加入在上述溶液的细胞中(90μl/孔)。使用荧光平板读数器进行细胞内钙的测量:Fluo-4-荧光的升高,因此细胞内钙浓度是由应用40μM NMDA所诱导的。在不同浓度的化合物存在下通过测量钙升高的减少来评价测试化合物的抑制效能。
使用由至少三个独立实验获得的数据计算剂量-反应曲线和IC50值。化合物在单一浓度点的抑制效能表示为NMDA反应的抑制百分数。S形的浓度-抑制曲线与数据相吻合并且IC50值确定为产生由该化合物引起的半数最大抑制作用的浓度。
在表1中,列出了该试验所测定的本发明最有效的化合物的NR2B拮抗剂效能。表2给出了几种已知的选择性NR2B拮抗剂参照化合物和非选择性NMDA受体拮抗剂MK-801的结果。
表1
通过荧光法在皮层细胞(NR2B活性)或转染的HEK293细胞(NR2A
活性)上测定的化合物的NMDA拮抗剂活性
表5的化合物 | 大鼠皮层细胞(NR2B) | HEK293细胞(NR2A) |
appr.IC50 | 15μM的抑制作用 | |
3 | ++ | - |
5 | +++ | N.E. |
6 | ++ | - |
7 | + | - |
10 | ++ | - |
11 | +++ | - |
12 | +++ | - |
13 | ++ | - |
14 | ++ | - |
15 | +++ | - |
16 | ++ | - |
17 | + | - |
20 | ++ | - |
22 | +++ | N.E. |
23 | ++ | - |
25 | +++ | - |
26 | ++ | - |
27 | ++ | - |
30 | ++ | - |
32 | +++ | N.E. |
33 | ++ | - |
35 | +++ | - |
40 | +++ | N.E. |
41 | +++ | N.E. |
42 | + | - |
1 | +++ | N.E. |
+:IC50在500和1000nM之间
++:IC50在50和500nM之间
+++:IC50小于50nM
-:没有测试
N.E.:无效,即抑制作用小于30%
表2
通过荧光法在皮层细胞(NR2B活性)或转染的HEK293细胞(NR2A
活性)上测定的参照化合物的NMDA拮抗剂活性
大鼠皮层细胞 | NR1-3/NR2A | |||
参照化合物编码 | IC50[nM] | n | 在10μM的抑制% | n |
CI-1041 | 6.6 | 4 | 21.0 | 1 |
Co-101244 | 23 | 3 | -8.7 | 1 |
EMD 95885 | 35 | 1 | 0.1 | 1 |
CP-101,606 | 41 | 3 | 2.5 | 1 |
Ro 25.6981 | 159 | 4 | 1.0 | 1 |
赤-艾芬地尔 | 483 | 5 | -2.7 | 1 |
MK-801 | 37 | 3 | IC50=386nM | 2 |
参照化合物如下:
CI-1041:6-(2-[4-(4-氟-苯甲基)-哌啶-1-基]-乙烷亚磺酰基}-3H-苯并噁唑-2-酮
Co 101244:1-[2-(4-羟苯氧基)乙基]-4-羟基-4-(4-甲基苯甲基)哌啶
EMD 95885:6-[3-(4-氟苯甲基)哌啶-1基]丙酰]-2,3-二氢-苯并噁唑-2-酮
CP-101,606:(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇
Ro 256981:R-(R*,S*)-1-(4-羟苯基)-2-甲基-3-[4-(苯基甲基)哌啶-1-基]-1-丙醇。
艾芬地尔:赤-2-(4-苯甲基哌啶子基)-1-(4-羟苯基)-1-丙醇
MK-801:(+)-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺
测定体内效力的小鼠福尔马林试验
已知将稀释的福尔马林注射入大鼠或小鼠的后爪可引起两阶段的用舔/咬其损伤爪所用的时间测量的疼痛相关行为。第二阶段通常定义为福尔马林注射后在15-60min时间间隔内检测出的疼痛相关事件,峰活性在大约30min。已知NMDA受体参与福尔马林注射的第二阶段的反应并且这种行为反应对于NMDA受体的阻断敏感[Dickenson,A.andBesson J.-M.(Editors):Chapter 1,pp.6-7:Animal models ofAnalgesia;and Chapter 8,pp.180-183:Mechanism of CentralHypersensitivity:Excitatory Amino Acid Mechanisms and TheirControl-In Pharmacology of Pain.Springer-Verlag (Berlin)1997.]。因此,我们使用福尔马林试验的第二阶段的来表征化合物的体内效力,认为抑制第二阶段的反应表明了抵抗化学诱导的持续性疼痛的止痛作用[Hunker,S.,等:Formalin test in mice,a UsefulTechnique for Evaluating Mild Analgesics,Journal ofNeuroscience Methods,14(1985)69-76.]。
使用雄性NMRI小鼠(20-25g)。试验前禁食任何固体食物大约16小时但动物可自由摄入20%的葡萄糖溶液。使动物在玻璃圆筒中适应1个小时(cc.直径15cm),然后移至后部有镜子的相同圆筒中以便于观察。试验物质混悬于5%的tween-80中(每kg体重10ml)。在注射福尔马林15min前通过管饲法口服施用(将在0.9%盐水中的20μ11%甲醛通过皮下注入右后爪的背侧面)。在福尔马林注射后,测量从20至25分钟舔和咬注射的爪子的时间。为确定ED50值,将不同剂量(至少五个剂量)的试验物质给予5只小鼠的组并将结果表示为同一天相对于载体对照组观察的舔所花费时间的抑制百分数。通过Boltzman′s S形曲线拟合计算ED50值(即,产生50%抑制作用的剂量)。
小鼠自发运动活性的测定
在试验中使用重20-22g的雄性NMRI小鼠。
在四通道活性监视器测定自发运动活性。该装置由沿着盒子所有底轴(bottom axis)装配的2×16对光电池的丙烯酸盒(43cm×43cm×32cm)组成。为了检测竖立反应(rearing response)沿着盒子两个对边在10cm高处放置另外列的光电池(16对)。
实验组由10只动物组成。在口服施用测试化合物或载体(tween-80)三十分钟后,分别将动物放入四个盒子中的一个,时间为一小时。以15min间隔以一个小时内使光束中断的次数来测定水平和垂直运动。
计算每组水平活动数据的平均值±SE,然后测定与对照组(载体-处理)相比的百分率变化。当化合物的作用使光束中断增加超过50%时认为其产生运动刺激作用。因此,定义为无刺激作用的剂量(LMAfree)产生小于50%的增加。
表3表示本发明所选择的某些化合物(表格上部)和它们相近的苯甲基-哌啶类似物(表格下部)在止痛和运动活性试验中获得的结果。[A=2-(4-苯甲基-哌啶-1-基)-2-氧代-N-(2-氧代-2,3-二氢-苯并噁唑-6-基)-乙酰胺和B=2-[4-[4-甲基-苯甲基]-哌啶-1-基-2-氧代-N-(2-氧代-2,3-二氢-1H-吲哚-5-基)-乙酰胺]。因此,对1-A和24-B的不同之处仅在于双键的存在而不是单键。
表3
两种类型的NR2B拮抗剂在福尔马林试验和运动活性(LMA)试验中
的表征。计算治疗指数(TI)
苯亚甲基-哌啶 | ||||
福尔马林 | LMA | TI | ||
表5的化合物 | ED50mg/kg | 剂量mg/kg | %增加 | LMAfree/ED50 |
1 | 1.3 | 60 | 35* | 46 |
120 | 69 | |||
24 | 0.94 | 60 | 13* | >64 |
苯甲基-哌啶 | ||||
福尔马林 | LMA | TI | ||
参照化合物 | ED50mg/kg | 剂量mg/kg | %增加量 | LMAfree/ED50 |
A | 0.85 | 1 | 34* | <1.2 |
3 | 62 | |||
B | 0.48 | 3.75 | 72 | <8 |
7.5 | 141 |
*小于50%认为无副反应
非选择性NMDA受体拮抗剂MK-801和选择性NR2B拮抗剂CI-1041(Soc Neurosci Abst 2000,26(Part 2):Abst 527.4.),CP-101,606和Ro-256981的止痛和运动活性数据在表4中给出。
表4
NMDA拮抗剂参照化合物在福尔马林试验和运动活性(LMA)试验中
的表征。计算治疗指数(TI)
参照化合物 | ||||
福尔马林 | LMA | TI | ||
参照化合物编码 | ED50mg/kg | 剂量mg/kg | %增加量 | LMAfree/ED50 |
MK-801 | 0.15 | 0.1 | 114 | <1 |
0.3 | 217 | |||
CI-1041 | 2.4 | 10 | 137 | <4 |
Ro 25-6981 | >20* | |||
CP-101,606 | >20* |
*CP-101,606和Ro-256981在20mg/kg时产生的福尔马林反应抑制作用分别仅为38%和12%。
可见NMDA受体的非选择性拮抗剂,MK-801在药理学活性剂量范围内增加了运动活性。LMA的刺激作用是不利的副作用。某些选择性NR2B拮抗剂化合物如在专利申请WO 2003010159中描述的参照分子CI-1041或苯甲基-哌啶化合物[A=2-(4-苯甲基-哌啶-1-基)-2-氧代-N-(2-氧代-2,3-二氢-苯并噁唑-6-基)-乙酰胺和B=2-[4-[4-甲基-苯甲基]-哌啶-1-基]-2-氧代-N-(2-氧代-2,3-二氢-1H-吲哚-5-基)-乙酰胺]所表现出的产生镇痛的剂量与刺激运动活性的剂量之间也几乎没有区别。令人惊讶地,后者分子的苯亚甲基-哌啶的变型,即,本发明的化合物在直到很高的剂量也没有引起活动过度(表3)。当具有体内高效能的试验苯甲基哌啶的TIs范围为1至8时,它们苯亚甲基哌啶对应物的TIs在相当高的范围内,在46和64之间或更高。在表面上进行微小的结构修正后显著不同的曲线是没有预料到的。
具有高TI的NR2B拮抗剂特别地有利于可用NR2B拮抗剂治疗的疾病的药物治疗。在苯亚甲基哌啶中存在对持续疼痛模型具有高效力和高治疗指数的化合物。本发明的化合物具有比先前的专利化合物更加有利的关于可能的治疗用途的曲线。
有利地可以使用在NR2B部位作用的NMDA拮抗剂治疗的疾病,如Loftis最近的综述[Pharmacology Therapeutics,
97 55-85(2003)],包括精神分裂症,帕金森病,亨廷顿病,由缺氧和局部缺血引起的兴奋性中毒,癫痫发作,药物滥用,和疼痛,特别是任何原因的神经性,炎性和内脏的疼痛[Eur.J.Pharmacol,
429,71-78(2001)]。
由于与非选择性NMDA拮抗剂相比它们具有减少副作用的倾向,NR2B选择性拮抗剂可用于NMDA拮抗剂有效的疾病,例如肌萎缩性侧索硬化[Neurol.Res.,
21 309-12(1999)],例如酒精,阿片样物质或可卡因戒断综合征[Drag and alcohol depend.,
59,1-15(2000)],肌痉挛[Neurosci.Lett.,
73,143-148(1987)],不同起因的痴呆[ExpertOpin.Investig.Drugs,
9,1397-406(2000)],焦虑,抑郁,偏头疼,低血糖,视网膜的变性疾病(例如CMV视网膜炎),青光眼,哮喘,耳鸣,听力损失[Drug News Perspect,
11,523-569(1998)和WO.00/00197国际专利申请]。
因此,有利地有效量的本发明的化合物可用于治疗大脑或脊髓的创伤性损伤,阿片类物质治疗疼痛的耐受和/或依赖,滥用药物例如乙醇,阿片样物质或可卡因的戒断综合征,局部缺血性CNS疾病,慢性神经变性疾病,例如阿尔茨海默病,帕金森病,亨廷顿病,疼痛和慢性疼痛状态,例如神经性疼痛。
本发明的化合物以及它们药学上可接受的盐可以以此或适宜的药物组合物形式使用。这些组合物(药物)可以是固体,液体或半液体形式并且可加入实践中通常使用的药物助剂和辅助材料,例如载体,赋形剂,稀释剂,稳定剂,润湿剂或乳化剂,pH-和渗透压-调节剂,调味剂,或芳香剂,以及增进制剂或供应制剂的添加剂。
在特定情形下起到治疗作用所需要的剂量可以在大范围内改变并满足个体需要,这取决于疾病的阶段,所治疗患者的状况和体重,以及患者对活性成分的敏感性,施用途径和治疗天数。活性成分的实际使用剂量可以由熟悉患者所接受治疗的知识领域的主治医生来安全地确定。
包含根据本发明活性成分的药物组合物的一个剂量单元通常包含0.01至100mg的活性成分,当然可能在一些组合物中活性成分的量超过了上文定义的上限或下限。
药物组合物的固体形式可以是例如片剂,糖衣片,胶囊,丸剂或用于注射剂制备的冻干粉末安瓿剂。液体组合物是可注射和可输注的组合物,液体药物,充填液和滴剂。半液体组合物可以是软膏,香脂,乳膏,振摇混合物和栓剂。
为了施用简单,如果药物组合物所包括的剂量单元含施用一次或几次或施用其二分之一或三分之一或四分之一的量的活性成分,是适合的。这样的剂量单元是例如片剂,该片剂能够用其促进对分或四分的凹槽来粉碎以利于准确施用需要量的活性成分。
片剂可以用酸溶层包衣以确保在离开胃之后释放活性成分内容物。这样的片剂包肠溶衣。通过将活性成分装入胶囊也能得到类似的效果。
口服施用的药物组合物可以包括例如作为赋形剂的乳糖或淀粉,作为粘合剂或粒化剂的羧甲基纤维素钠,甲基纤维素,聚乙烯吡咯烷酮或淀粉糊。加入作为崩解剂的马铃薯淀粉或微晶纤维素,但也可使用超支链淀粉或甲醛酪蛋白。滑石、胶体硅酸、硬脂精、硬脂酸钙或硬脂酸镁可用作抗粘着剂或滑润剂。
片剂可以例如通过湿法制粒后压制来制备。在适当的设备中用粘合剂水溶液、醇溶液或醇水溶液将混合的活性成分和赋形剂以及在特定情况下部分崩解剂制粒,然后将颗粒干燥。将其他崩解剂、滑润剂和抗粘着剂加入在干燥的颗粒中,并将混合物压制成片剂。在特定情况下,制备的片剂具有等分槽以便于施用。
片剂可由活性成分和适当的助剂的混合物通过压制直接制备。在特定情况下,片剂可用通常在制药实践中使用的添加剂例如稳定剂、调味剂、着色剂,例如糖、纤维素衍生物(甲基纤维素或乙基纤维素、羧甲基纤维素钠等)、聚乙烯吡咯烷酮、磷酸钙、碳酸钙、食用着色剂、食用酒精(food lace)、芳香剂、氧化铁颜料等包衣。在胶囊剂情况中,将活性成分和助剂的混合物装在胶囊中。
液体口服组合物,例如悬浮液、糖浆剂、酏剂,可通过用水、二醇、油、醇、着色剂和调味剂进行制备。
为直肠施用,将组合物配制成栓剂或灌肠剂。栓剂除活性成分外可含称为前栓动物脂的载体。载体可以是植物油,例如氢化植物油、C12-C18脂肪酸甘油三酯(优选商品名为Witepsol的载体)。将活性成分与熔化的前栓动物脂均匀混合并模制成栓剂。
为胃肠外施用,将组合物配制成注射液。为制备注射液,将活性成分溶解在蒸馏水和/或不同的有机溶剂中,例如乙二醇醚,在特定条件下,存在增溶剂例如聚氧乙烯山梨糖醇酐单月桂酸酯、单油酸酯或单硬脂酸酯(Tween 20,Tween 60,Tween 80)。注射液还可包括不同的助剂,例如保存剂例如乙二胺四乙酸盐,以及pH调节剂和缓冲液和特定条件下的局部麻醉药如利多卡因。在装入安瓿前将含本发明活性成分的注射液过滤,在装入后将其灭菌。
如果活性成分吸湿,那么通过冻干可使其稳定。
表征方法
通过与质量选择性检测器相连的高效液相色谱使用具有Microplate Sampler的HP1100二元梯度色谱系统(Agilent,Waldbronn),由Chemstation软件控制来对本发明的化合物进行表征。使用HP二极管阵列检测器在225和240nm获得UV光谱。所有的试验使用装备有电喷射离子化源的HP MSD(Agilent,Waldbronn)单一四极光谱仪来确定结构。
合成产物溶解于1ml DMSO中(Aldrich,德国)。使用DMSO将100μl的各种溶液稀释至1000μl体积。在由Supelco(Bellefonte,Pennsylvania)获得的Discovery RP C-16 Amide,5cm×4.6mm×5μm柱上使用1ml/分钟的流速进行分析色谱试验以进行鉴别。获得的化合物由它们K′值(纯度,容量因子)表征。K′因子由下式进行计算:
k′=(tR-t0)/t0
其中k′=容量因子,tR=保留时间和t0=洗脱液保留时间
洗脱液A是包含0.1%水的三氟乙酸(TFA)(Sigma,德国),洗脱液B是包含0.1%TFA和5%洗脱液A的95%乙腈(Merck,德国)。使用梯度洗脱,由100%的洗脱液A开始在5分钟内变化到100%的洗脱液B。
下列实施例举例说明本发明,对本发明无任何限制。
实施例1
2-(4-苯亚甲基-哌啶-1-基)-2-氧代-N-(2-氧代-2,3-二氢-苯并
噁唑-6-基)-乙酰胺
1a)1-苯甲基-4-苯亚甲基-哌啶
在氩气下,在0℃向搅拌的在1350ml二甲基甲酰胺中的133.2g(704mmol)的N-苯甲基-4-哌啶酮(Aldrich)和161g(705mmol)苯甲基-磷酸二乙酯(Aldrich)的溶液中加入40.5g(60%,37.5mmol)的氢化钠。将反应混合物在20℃搅拌2h,逐滴加入100ml乙醇,倾入1500ml水并使用乙醚萃取。有机层经过硫酸钠干燥并浓缩。粗制品在下一步中使用。Mp.:油。
1b)4-苯亚甲基-哌啶盐酸盐
在0℃下向搅拌的在21二氯乙烷中的先前得到的粗制1-苯甲基-4-苯亚甲基-哌啶(~704mmol)的溶液中逐滴加入80ml(741mmol)的1-氯乙基-氯甲酸酯。将反应混合物在0℃搅拌1h和回流1h,然后浓缩并将残留物溶解于11甲醇中,回流1h。浓缩反应混合物并使用丙酮对残留物进行结晶得到103.25g(70.1%)的标题化合物。Mp.:186℃(丙酮)。
1c)(4-苯亚甲基-哌啶-1-基)-氧代-乙酸乙酯
在10℃以下向搅拌的在11氯仿中的103.25g(0.492mol)的4-苯亚甲基-哌啶盐酸盐和144.55ml(1.039mol)的三乙胺溶液中逐滴加入55.75ml(0.499mol)的乙基草酰氯,将反应混合物在室温搅拌1h。然后将200ml水和200ml 8%的碳酸氢钠溶液加入混合物中,分离有机层,经过硫酸钠干燥并浓缩。粗品在下步中使用。Mp.:油。
1d)(4-苯亚甲基-哌啶-1-基)-氧代-乙酸
向搅拌的在200ml乙醇中的先前得到的粗制(4-苯亚甲基-哌啶-1-基)-氧代-乙酸乙酯(~0.492mol)溶液中加入在300ml水和500ml乙醇中的27.6g(0.69mol)氢氧化钠的溶液。将反应混合物在室温搅拌1h后冷却并使用盐酸酸化。收集固体沉淀,用水洗涤得到107.32g(88.9%)的标题化合物。Mp.:125℃(乙醇-水)。
1e)2-(4-苯亚甲基-哌啶-1-基)-2-氧代-N-(2-氧代-2,3-二氢-
苯并噁唑-6-基)-乙酰胺
49mg(0.2mmol)(4-苯亚甲基-哌啶-1-基)-氧代-乙酸,33μl(0.24mmol)三乙胺,30mg(0.2mmol)6-氨基-3H-苯并噁唑-2-酮[J.Chem.Soc,321.(1938)]79.6mg(0.21mmol)HBTU[六氟磷酸O-苯并三唑-1-基-N,N,N′,N′-四甲基脲(Advanced Chem.Tech.)]和1ml二甲基甲酰胺的混合物在室温下搅拌24h。通过柱色谱法使用Kieselgel60(Merck)作为吸附剂和甲苯∶甲醇=4∶1为洗脱剂对反应混合物进行纯化。产物的性质和量通过如上所述的HPLC-MS法测定。K′=9.66。我们使用上述方法制备以下式(I)的化合物:
表5
实施例2
药物组合物的制备;
a)片剂:
将0.01-50%的式(I)的活性成分,15-50%的乳糖,15-50%的马铃薯淀粉,5-15%的聚乙烯吡咯烷酮,1-5%的滑石粉,0.01-3%的硬脂酸镁,1-3%的胶体二氧化硅和2-7%的过支链淀粉混合,然后通过湿法制粒并压制成片剂。
b)糖衣片,薄膜包衣片:
将按照上述方法制备的片剂用由肠或胃溶薄膜组成的,或由糖或滑石粉组成的层包衣。糖衣片用蜂蜡和carnuba腊的混合物抛光。
c)胶囊:
将0.01-50%的式(I)活性成分,1-5%的十二烷基硫酸钠,15-50%的淀粉,15-50%的乳糖,1-3%的胶体二氧化硅和0.01-3%的硬脂酸镁充分混合,将混合物过筛并填充至硬明胶胶囊中。
d)混悬液:
成分:0.01-15%的式(I)活性成分,0.1-2%的氢氧化钠,0.1-3%的柠檬酸,0.05-0.2%的尼泊金(4-羟基苯甲酸甲酯钠),0.005-0.02%的对羟基苯甲酸丙酯,0.01-0.5%的卡波普(聚丙烯酸),0.1-5%的96%乙醇,0.1-1%的矫味剂,20-70%的山梨醇(70%水溶液)和30-50%的蒸馏水。
在剧烈搅拌下,按小份将卡波普加至在20ml蒸馏水中的尼泊金和枸橼酸溶液中,并将溶液放置10-12h。然后在搅拌下加入在1ml蒸馏水中的氢氧化钠,山梨醇水溶液并最终加入乙醇覆盆子香精。往载体中按小份加入活性成分并使用浸渍匀浆机悬浮。最后用蒸馏水将该悬浮剂加至所需最终体积,且将该悬浮糖浆过胶体研磨设备。
e)栓剂:
对每种栓剂,将0.01-15%的式(I)活性成分和1-20%的乳糖充分混合,然后将50-95%的栓剂前动物脂肪(例如Witepsol 4)熔化并冷却至35℃,用匀化器将活性成分和乳糖的混合物在其中混合。将所得混合物冷却塑模。
f)冻干粉安瓿组合物:
以注射用双蒸水制成5%的甘露醇或乳糖溶液,将该溶液过滤以获得灭菌溶液。0.01-5%式(I)活性成分的水溶液也以注射用双蒸水制成,并将此溶液过滤以获得灭菌溶液。在无菌条件下将这两种溶液混合,在安瓿中装入1ml,将安瓿内容物冻干,且将安瓿在氮气下密封。在施用前,将安瓿内容物溶解在灭菌水或0.9%(生理的)灭菌氯化钠水溶液中。
Claims (9)
1、式(I)新的4-苯亚甲基-哌啶衍生物
-其中含义为
X和Y独立地为氢或卤素原子,羟基,氰基,硝基,氨基,任选由一个卤素原子或多个卤素原子取代的C1-C4烷氨基,任选由一个卤素原子或多个卤素原子取代的芳氨基,任选由一个卤素原子或多个卤素原子取代的芳烷基氨基,任选由一个卤素原子或多个卤素原子取代的C1-C4烷基磺酰胺基,任选由一个卤素原子或多个卤素原子取代的C1-C4烷酰基酰胺基,芳基磺酰胺基,C1-C4烷基磺酰氧基,羧基,三氟甲基,三氟甲氧基,C1-C4烷基-SO2-NH-CH2-,NH2-(CH2)1-4-SO2-NH-,NH2-(CH2)1-4-(CO)-NH-,氨磺酰基[NH2-SO2-],甲酰基[-CHO],氨基-甲基[-CH2-NH2],羟甲基,C1-C4烷基,C1-C4烷氧甲基,卤代甲基,四唑基,或C1-C4烷氧基,C1-C4烷氧羰基,C1-C6烷酰氧基,苯基或C1-C4烷氧基,任选由氨基取代,或
在特定的情况下,相邻的X和Y基团与一个或多个相同或不同的另外的杂原子和-CH=和/或-CH2-基形成任选取代的4-7元的同环-或杂环,优选吗啉,吡咯,吡咯烷,氧代-或硫代-吡咯烷,吡唑,吡唑烷,咪唑,咪唑烷,氧代-或硫代-咪唑或咪唑烷,1,4-噁嗪,噁唑,噁唑烷,氧代-或硫代-噁唑烷,氧代-或硫代-噻唑烷,或3-氧代-1,4-噁嗪环,
Z是氢或卤素原子,硝基,氨基,C1-C4烷基,C1-C4烷氧基,氰基,三氟甲基,三氟甲氧基-
及其旋光对映体,外消旋化合物及盐。
2、属于权利要求1的范围的下组的4-苯亚甲基-哌啶衍生物的化合物
2-(4-苯亚甲基-哌啶-1-基)-2-氧代-N-(2-氧代-2,3-二氢-苯并噁唑-6-基)乙酰胺
2-(4-苯亚甲基-哌啶-1-基)-2-氧代-N-(2-氧代-2,3-二氢-苯并噻唑-6-基)乙酰胺
2-[4-(4-氯-苯亚甲基)-哌啶-1-基]-2-氧代-N-(2-氧代-2,3-二氢-苯并噁唑-6-基)乙酰胺
2-[4-(4-氯-苯亚甲基)-哌啶-1-基]-2-氧代-N-(2-氧代-2,3-二氢-苯并咪唑-5-基)乙酰胺
2-[4-(4-氯-苯亚甲基)-哌啶-1-基]-2-氧代-N-(2-氧代-2,3-二氢-苯并噻唑-6-基)乙酰胺
2-[4-(4-甲基-苯亚甲基)-哌啶-1-基]-2-氧代-N-(2-氧代-2,3-二氢-苯并咪唑-5-基)乙酰胺
2-[4-(4-甲基-苯亚甲基)-哌啶-1-基]-2-氧代-N-(2-氧代-2,3-二氢-苯并噻唑-6-基)乙酰胺
2-[4-(4-甲氧基-苯亚甲基)-哌啶-1-基]-2-氧代-N-(2-氧代-2,3-二氢-苯并咪唑-5-基)乙酰胺
2-[4-(4-甲氧基-苯亚甲基)-哌啶-1-基]-2-氧代-N-(2-氧代-2,3-二氢-苯并噻唑-5-基)乙酰胺
N-(4-甲磺酰氨基-苯基)-2-[4-(4-甲氧基-苯亚甲基)-哌啶-1-基]-2-氧代-乙酰胺
2-[4-(4-氟-苯亚甲基)-哌啶-1-基]-2-氧代-N-(2-氧代-2,3-二氢-苯并噻唑-6-基)乙酰胺
及其旋光对映体,外消旋化合物及盐。
3、含有有效量的式(I)的4-苯亚甲基-哌啶衍生物-其中X,Y,Z含义如权利要求1-或其盐作为活性成分和实践中通常使用的辅助材料,例如载体,赋形剂,稀释剂,稳定剂,润湿剂或乳化剂,pH-和渗透压-调节剂,调味剂或芳香剂,以及增进制剂或供应制剂的添加剂的药物组合物。
4、制备式(I)的4-苯亚甲基-哌啶衍生物的方法,-其中X,Y,Z的含义如权利要求1,其特征在于:使式(II)的仲胺
-其中Z具有与式(I)同样的含义-在碱存在下在适宜的溶剂中与乙基草酰氯反应
将得到式(III)的酯化合物
-其中Z具有与式(I)同样的含义-使用氢氧化碱进行皂化并将得到的式(IV)的草酰胺酸
-其中Z的含义如上文式(I)所述-或其反应性衍生物与式(V)的苯胺反应
-其中X和Y的含义如前文式(I)所给出-在二氯甲烷中,
然后任选将所得式(I)的4-苯亚甲基-哌啶衍生物-其中X,Y,Z的含义如权利要求1所列出-通过已知的方法通过引入新的取代基和/或修饰或除去存在的基团,和/或通过成盐和/或将化合物从盐中游离而转变成另外的式(I)化合物。
5、如权利要求4的方法,其特征在于在碱存在的情况下使式(IV)的羧酸的活性衍生物-其中Z含义如权利要求1所列出-和式(V)的苯胺-其中X和Y含义如权利要求1所列出-在碱的存在下反应。
6、如权利要求4的方法,其特征在于使式(IV)的羧酸的活性衍生物-其中Z含义如权利要求1所列出-和式(V)的苯胺-其中X和Y含义如权利要求1所列出-在二甲基甲酰胺中在三乙胺和六氟磷酸O-苯并三唑-1-基-N,N,N′,N′-四甲基脲(HBTU)存在的情况下反应。
7、制备具有NR2B选择性NMDA受体拮抗剂作用的药物组合物的方法,其特征在于将式(I)的4-苯亚甲基-哌啶衍生物-其中X,Y,Z的含义如权利要求1所列出-或其旋光对映体或外消旋化合物或药学上可接受的盐作为活性成分和实践中通常使用的辅助材料,例如载体,赋形剂,稀释剂,稳定剂,润湿剂或乳化剂,pH-和渗透压-调节剂,调味剂,或芳香剂,以及增进制剂或供应制剂的添加剂混合。
8、治疗和缓解哺乳动物-包括人-的以下疾病-大脑或脊髓的创伤性损伤,与人免疫缺陷病毒(HIV)相关的神经元损伤,肌萎缩性侧索硬化,阿片类物质治疗疼痛的耐受和/或依赖,滥用药物例如乙醇、阿片样物质或可卡因的戒断综合征,局部缺血性CNS疾病,慢性神经变性疾病,例如阿尔茨海默病、帕金森病、亨廷顿病,疼痛和慢性疼痛状态,例如神经性疼痛或癌症相关疼痛,癫痫,焦虑,抑郁,偏头疼,精神病,肌肉痉挛,不同原因的痴呆,低血糖,视网膜的变性疾病,青光眼,哮喘,耳鸣,氨基糖苷抗生素诱发的听力损失的症状的方法,其特征在于如此给所治疗的哺乳动物施用有效量/数量的式(I)的4-苯亚甲基-哌啶衍生物-其中X,Y,Z的含义如权利要求1所列出-或其旋光对映体或外消旋化合物或药学上可接受的盐或将其与在药学上通常应用的载体、填充剂等组合使用。
9、式(I)的4-苯亚甲基-哌啶衍生物-其中X,Y,Z的含义如权利要求1所列出-或其旋光对映体或外消旋化合物或药学上可接受的盐制备用于治疗和缓解哺乳动物,包括人的以下疾病症状的药物的用途,疾病包括大脑或脊髓的创伤性损伤,与人免疫缺陷病毒(HIV)相关的神经元损伤,肌萎缩性侧索硬化,阿片类物质治疗疼痛的耐受和/或依赖,滥用药物例如乙醇、阿片样物质或可卡因的戒断综合征,局部缺血性CNS疾病,慢性神经变性疾病,例如阿尔茨海默病、帕金森病、亨廷顿病,疼痛和慢性疼痛状态,例如神经性疼痛或癌症相关疼痛,癫痫,焦虑,抑郁,偏头疼,精神病,肌肉痉挛,不同原因的痴呆,低血糖,视网膜的变性疾病,青光眼,哮喘,耳鸣,氨基糖苷抗生素诱发的听力损失。
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EP2024355B1 (en) * | 2006-06-08 | 2010-07-14 | Bristol-Myers Squibb Company | Alkene piperidine derivatives as antiviral agents |
WO2010006020A1 (en) * | 2008-07-08 | 2010-01-14 | Forest Laboratories Holdings Limited | Novel crystalline form of 2-[4(4-fluoro-benzyl)-piperidine-1-yl]-2-oxo-n-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-acetamide |
CN102762554A (zh) | 2010-02-16 | 2012-10-31 | 辉瑞大药厂 | 5-ht4受体的部分激动剂(r)-4-((4-((4-(四氢呋喃-3-基氧基)苯并[d]异*唑-3-基氧基)甲基)哌啶-1-基)甲基)四氢-2h-吡喃-4-醇 |
AU2011299904A1 (en) | 2010-09-07 | 2013-05-02 | Taiho Pharmaceutical Co., Ltd. | Prostaglandin D synthase inhibitory piperidine compounds |
US20120322824A1 (en) * | 2011-01-04 | 2012-12-20 | Surratt Christopher K | Cocaine Antagonist/Antidepressant Pharmaceutical Preparations |
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