CN1989127A - 作为nr2b受体拮抗剂的犬尿烯酸酰胺衍生物 - Google Patents
作为nr2b受体拮抗剂的犬尿烯酸酰胺衍生物 Download PDFInfo
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- CN1989127A CN1989127A CNA2005800247588A CN200580024758A CN1989127A CN 1989127 A CN1989127 A CN 1989127A CN A2005800247588 A CNA2005800247588 A CN A2005800247588A CN 200580024758 A CN200580024758 A CN 200580024758A CN 1989127 A CN1989127 A CN 1989127A
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- quinoline
- piperidines
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Abstract
式(I)的新的犬尿烯酸酰胺衍生物,及其旋光对映体,外消旋物及盐为高效的和选择性的NMDA受体拮抗剂,而且大部分化合物是选择性的NMDA受体NR2B亚型的拮抗剂。
Description
本发明涉及为NMDA受体拮抗剂或制备NMDA受体拮抗剂中间体的新犬尿烯酸酰胺衍生物。
发明背景
N-甲基-D-天冬氨酸(NMDA)受体是嵌入在神经元细胞膜上的配体门控的阳离子通道。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死亡的级联细胞内事件[TINS,
10,299-302(1987)]。NMDA受体拮抗剂可用于治疗许多伴随中枢神经系统内的主要兴奋神经递质谷氨酸过度释放的疾病。
NMDA受体是由至少7种已知的亚单位基因构成的异数集群。NR1亚单位是功能性NMDA受体通道的必需部分。有四种基因编码NR2亚单位(NR2A-D)。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。近来,报道了NR3A和NR3B。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的NR2B亚单位。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[BrainRes.,
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,预期NMDA受体的NR2B亚型选择性拮抗剂几乎不具有或不具有通常由非选择性NMDA受体拮抗剂所引起的不利副反应,即拟精神病作用例如眩晕,头痛,幻觉,烦躁不安和认知和运动功能障碍。
NR2B亚型的选择性NMDA拮抗作用可以使用特异性结合并且作用于含有NR2B亚单位受体的变构调节部位的化合物来实现。可以通过使用特定的放射性配体例如[125I]-艾芬地尔[J.Neurochem.,
61,120-126(1993)]或[3H]-Ro25,6981[J.Neurochem.,
70,2147-2155(1998)]进行置换(结合)研究来描述此结合部位的特性。虽然不是很特异,但由于艾芬地尔是该受体第一个已知的配体,它仍被称为艾芬地尔结合部位。
式(I)的羧酸酰胺衍生物的相近结构的类似物根据文献是未知的。
发明概述
令人惊奇的是,发现本发明式(I)的新的犬尿烯酸酰胺衍生物是含有NR2B亚单位的NMDA受体的功能性拮抗剂,同时其对含有NR2A亚单位的NMDA受体无效。因此,它们被认为是NR2B亚型的特异性NMDA拮抗剂。某些化合物口服施用后在小鼠体内疼痛模型中证明是有效的。
发明详述
因此本发明首先涉及式(I)的新的犬尿烯酸酰胺衍生物
-其中含义为
X和Y独立地为氢原子,羟基,氨基,任选由一个卤素原子或多个卤素原子取代的C1-C4烷基亚磺酰氨基,任选由一个卤素原子或多个卤素原子取代的C1-C4烷酰基酰氨基,C1-C4烷氧基,C1-C4烷氧羰基或
在特定的情况下,相邻的X和Y基团可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元的同素环-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,或3-氧代-1,4-噁嗪环,
W是氧原子,以及C1-C4亚烷基,C2-C4亚烯基,氨羰基,-NH-,-N(烷基)-,-CH2O-,-CH2S-,-CH(OH)-,-OCH2-基,-其中烷基的含义是C1-C4烷基-,
另外的C-C双键并且在这种情况下V表示参与双键的电子对,
Z是氢原子或卤素原子,C1-C4烷基,C1-C4烷氧基,三氟甲基,羟基或羧基,
以及其旋光对映体,外消旋物及盐。
本发明的进一步的目的是生产式(I)犬尿烯酸酰胺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,即给要治疗的哺乳动物-包括人-施用有效量的本发明式(I)的犬尿烯酸酰胺衍生物本身或药剂。
本发明的式(I)的新犬尿烯酸酰胺衍生物是高效的和选择性的NMDA受体拮抗剂,而且大部分化合物是NMDA受体NR2B亚型的选择性的拮抗剂。
根据本发明式(I)的新犬尿烯酸酰胺衍生物可由式(II)的羧酸:
-其中X和Y的含义如前式(I)所述-或其活性衍生物与式(III)的胺
然后在特定的情况下,将获得的式(I)的犬尿烯酸酰胺衍生物-其中X,Y,W,Z和虚线键
如式(I)所述-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/或成盐和/或通过将化合物从盐中游离,和/或使用光学活性的酸或碱将所得的外消旋物拆分而转变成另外的式(I)化合物。
式(II)的羧酸和式(III)的胺反应,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(III)的胺反应来进行。
在适当溶剂(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O-苯并三唑-1-基-N,N,N′,N′-四甲基六氟磷酸脲(HBTU)制备)。活性衍生物在室温和0℃之间制备。将式(III)适当的胺作为碱或与无机酸形成的盐加至所得的溶液或混悬液中以便使胺释放所需的碱,例如三乙胺,被单独加至反应混合物中。随后将浓缩的反应物通过薄层色谱法。必需的反应时间是6-20h。反应混合物的后处理可以通过不同的方法进行。
当反应混合物是混悬液时,滤出沉淀并在适宜的溶剂中重结晶得到纯化产物。如果结晶不能得到纯化产物,则可使用柱色谱法进行纯化。使用Kieselgel 60作为吸附剂和不同的溶剂系统,例如甲苯/甲醇,氯仿/甲醇或甲苯/丙酮作为洗脱剂进行柱色谱法。如果反应混合物在酰化末期是溶液,则将其浓缩,然后将残留物结晶或通过如上所述的柱色谱法进行纯化。产物的结构通过IR,NMR和质谱测定。
在特定情况下,将获得的式(I)的犬尿烯酸酰胺衍生物-与制备方法无关-通过引入另外的取代基和/或修饰或除去存在的基团,和/或与酸成盐和/或通过使用碱进行处理而由获得的酸加成盐释放式(I)的羧酸酰胺衍生物和/或通过使用碱处理将游离的式(I)的犬尿烯酸酰胺衍生物转化为盐而转变成另外的式(I)的犬尿烯酸酰胺衍生物。
例如使甲基和苯甲基从代表X,Y和Z的甲氧基和苯甲氧基基团裂解,可得到苯酚衍生物。苯甲基的除去例如可以在乙酸溶液中通过催化氢化或使用溴化氢来进行,甲基的裂解可以在二氯甲烷溶液中使用三溴化硼来进行。可以使用不同的酰化剂将含有游离酚羟基的式(I)的犬尿烯酸酰胺衍生物转化为酰氧基。该反应在碱(例如三乙胺或碳酸钠)存在的情况下使用酰基氯或酸酐作为酰化剂在室温下在氯化烃中进行。可以使用关于酰化酚羟基所述的不同的酰化或磺酰化剂将含有氨基的式(I)的犬尿烯酸酰胺衍生物转变为酰氨基或磺酰氨基衍生物。在碱存在的情况下可通过酸酐或酸卤将游离的羟基酯化。
式(II)的羧酸和式(III)的仲胺是可商购获得的或可以通过已知的不同方法合成。在实施例中描述了某些无法商购获得的式(II)羧酸和式(III)仲胺的合成。
试验方案
重组NMDA受体的表达
为了证明我们化合物的NR2B选择性,我们在稳定表达具有NR1/NR2A或NR1/NR2B亚单位组成的重组NMDA受体的细胞系上对它们进行测试。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NR1-3和NR2A或大鼠NR1a和NR2B亚单位的cDNAs引入缺乏NMDA受体的HEK293细胞中[Biotechniques,1997 May;22(5),982-7;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系的克隆,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诱发的细胞溶质钙浓度升高的抑制作用。在加入诱导剂后48-72h进行研究。在诱导过程中还存在氯胺酮(500μM)以防止细胞毒性。
基于使用荧光计平板读数器测量细胞内钙浓度,评价化合物对表
达重组NMDA受体的HEK293细胞的功能性NMDA拮抗剂效力。
由于已知兴奋时NMDA受体对于钙离子是可渗透的,因此在将激动剂(NMDA)施于细胞后通过测量细胞内钙浓度的升高可表征NMDA受体的活化程度,以及被功能性拮抗剂抑制的程度。由于大鼠和人体NMDA受体具有很高的序列同源性(对于NR1,NR2A,和NR2B亚单位,分别为99,95,97%),因此人们相信它们的药理学敏感性即使有差异也会很小。因此,由大鼠NMDA受体(克隆的或原生的)获得的结果可很好地外推至人NMDA受体。
细胞内钙的测量在表达NR1a和NR2B或NR2A NMDA受体亚单位的HEK293细胞上进行。将细胞加到标准的96-孔微量培养板上,在37℃95%空气-5%CO2气氛中保持培养物直到进行测试。
在测试前使细胞装载荧光Ca2+-敏感染料,Fluo-4/AM(2-2.5μM)。还可通过用在测量过程中使用的溶液(140mM NaCl,5mM KC1,2mMCaCl2,5mM HEPES[4-(2-羟乙基)-1-哌嗪乙烷-磺酸],5mM HEPES-Na,20mM葡萄糖,10μM甘氨酸,pH=7.4]洗涤两次来停止装载。然后加入溶解在上述溶液(90μl/孔)中的测试化合物。使用平板读数器荧光计进行细胞内钙的测量。通过施用200μM NMDA诱导了反映细胞内钙浓度的Fluo-4-荧光的升高。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力。
化合物在单一浓度点的抑制效力表示为对照NMDA反应的抑制百分数。对于表达NR1a/NR2B的细胞制备了浓度-抑制曲线。S形的浓度-抑制曲线与数据相吻合,将IC50值定义为产生使用化合物能够获得的半数最大抑制作用的浓度。平均IC50值由至少三个独立的试验获得。对于表达NR1-3/NR2A的细胞,分别在10和15微摩浓度测试了本发明化合物和参照化合物对NMDA诱导的细胞内钙浓度的升高的拮抗作用。
化合物的生物活性
表1中列出了所选择的实施例的本发明化合物在NR1a/NR2B转染细胞中测定的IC50值和在NR1a/NR2A转染细胞中15μM浓度时的抑制百分数。为了进行比较,还测定了最有效的已知参考化合物的数据并在表2中列出。
在NR1-3/NR2A转染细胞的功能性NMDA拮抗作用试验中本发明的化合物所显示的IC50值小于15μM,并且在此浓度对NR1/NR1A转染细胞是无活性的。因此本发明的化合物和药物组合物是NR2B亚型特异性的NMDA拮抗剂。与已知的参考化合物相比一些化合物具有更高的效力(见表1)。
表1
通过荧光法在表达NR1a/NR2B或NR1-3/NR2A亚单位的细胞上
测定的化合物的NMDA拮抗剂活性
实施例的化合物 | NR1a/NR2B | NR1-3/NR2A | ||
IC50[nM] | n | 在15μM的抑制% | n | |
2 | 3.7 | 3 | 7.0 | 1 |
1 | 4.0 | 2 | -0.9 | 1 |
3 | 3.8 | 2 | -2.4 | 1 |
5 | 21.5 | 2 | 5.7 | 1 |
6 | 8.9 | 2 | 14.0 | 1 |
4 | 1.9 | 2 | -5.1 | 1 |
7 | 5.1 | 2 | 5.1 | 1 |
8 | 3.3 | 2 | -3.5 | 1 |
9 | 5.6 | 2 | -2.1 | 1 |
10 | 28.0 | 2 | 0.2 | 1 |
表2
通过荧光法在表达NR1a/NR2B或NR1-3/NR2A亚单位的细胞上
测定的参照化合物的NMDA拮抗剂活性
NR1a/NR2B | NR1-3/NR2A | |||
参照化合物编码 | IC50[nM] | n | 在10μM的抑制% | n |
CI-1041 | 8.4 | 4 | 21.0 | 1 |
Co-101244 | 4.8 | 3 | -8.7 | 1 |
EMD 95885 | 48 | 1 | 0.1 | 1 |
CP 101,606 | 30 | 3 | 2.5 | 1 |
Ro 25.6981 | 57 | 4 | 1.0 | 1 |
艾芬地尔 | 459 | 5 | -2.7 | 1 |
MK-801 | 43 | 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,
Co-111103:1-[2-(4-羟苯氧基)乙基]-4-(4-氟苯甲基)哌啶,
Ro 256981:R-(R*,S*)-1-(4-羟苯基)-2-甲基-3-[4-(苯甲基)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。
测定体内效能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。已知NMDA受体参与对福尔马林注射反应的第二阶段并且这种行为反应对于NMDA受体的阻断敏感[Dickenson,A.and BessonJ.-M.(Editors):Chapter 1,pp.6-7:Animal models of Analgesia;and Chapter 8,pp.180-183:Mechanism of Central Hypersensitivity:Excitatory Amino Acid Mechanisms and Their Control-InPharmacology of pain.Springer-Verlag(Berlin)1997.]因此,我们使用福尔马林试验的第二阶段来表征化合物的体内效能。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[Hunskaar,S.,等:formalin test in mice,a Useful Technique forEvaluating Mild Analgesics,Journal of Neuroscience Methods,14(1985)69-76.]
使用雄性albino 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(cc.直径15cm)中适应1个小时,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%的吐温-80中(每kg体重10ml)。在注射福尔马林前15min通过管饲法口服施用(将在0.9%盐水中的20μl1%福尔马林通过皮下注入右后爪的背侧面)。测量从注射福尔马林后20至25分舔和咬注射的爪子所用的时间。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观察的相对于载体对照组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)。
表3
选定化合物在小鼠福尔马林试验中的ED50值
实施例的化合物 | ED50(mg/kg p.o.) |
2 | >20 |
1 | 9.5 |
3 | 8.9* |
4 | >20 |
6 | 0.46 |
7 | >20 |
8 | 8.2 |
9 | >20 |
参照化合物编码 | - |
CI-1041 | 2.4mg/kg |
Co-101,244 | p.o.无活性,5.9mg/kg i.p. |
EMD 95885 | 3.7mg/kg |
CP-101,606 | >20mg/kg(s.c.和p.o.) |
Co-111103 | >20mg/kg |
Ro-25,6981 | p.o.无活性,5.1mg/kg i.p. |
*:具有60%最大效果的部分抑制
可以使用在NR2B部位作用的NMDA拮抗剂有利地治疗的疾病,如Loftis最近综述的[Pharmacology & Therapeutics 2003,97:55-85],包括精神分裂症,帕金森氏病,亨廷顿舞蹈病,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.2001,429:71-78]。
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拮抗剂可以有效的疾病,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[Drug and Alcohol depend.,
59,1-15(2000)],肌痉挛[Neurosci.Lett.,
73,143-148(1987)],不同起因的痴呆[Expert Opin.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WO00/00197国际专利申请]。
因此,有效量的本发明的化合物可有利地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,耐受性的发展,滥用潜力的减少和滥用药物例如乙醇,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,例如阿尔茨海默氏病,帕金森氏病,亨廷顿舞蹈病,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其本身或适宜以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。
在每个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,施用途径和每天治疗次数。活性成分的实际使用剂量可以由熟悉治疗的患者的本领域中熟练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在一个剂量单元通常包含0.01至100mg的活性成分,当然在一些组合物中活性成分的量可以超过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、润滑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、氧化铁颜料等涂敷。在胶囊剂情况中,将活性成分和适当的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(吐温20,吐温60,吐温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。
以下实施例说明本发明但不以任何方式限制本发明。
实施例1
2-[4-(4-氟-苯甲基)-哌啶-1-羰基]-6-羟基-1H-喹啉-4-酮
0.5g(2.4mmol)6-羟基-4-氧代-1,4-二氢-喹啉-2-羧酸[J.Med.Chem.,
17,685-690.(1974)],0.75ml(5.4mmol)三乙胺,0.6g(2.6mmol)4-(4-氟-苯甲基)-哌啶盐酸盐[J.Med.Chem.,
35,4903.(1992)],1.0g(2.6mmol)HBTU[0-苯并三唑-1-基-N,N,N′,N′-四甲基脲六氟磷酸酯(Advanced Chem.Tech.)和15ml二甲基甲酰胺的混合物在室温下搅拌24h。将反应混合物浓缩并通过柱色谱法使用Kieselge160作为吸附剂(Merck)和甲苯∶甲醇=4∶1作为洗脱剂对残留物进行纯化得到0.18g(19%)的标题化合物。Mp.:190℃(乙醚)。
实施例2
2-(4-苯甲基-哌啶-1-羰基)-6-羟基-1H-喹啉-4-酮
本标题化合物按照实施例1所述方法由6-羟基-4-氧代-1,4-二氢-喹啉-2-羧酸和4-苯甲基-哌啶制备。Mp.:127℃(乙醚)。
实施例3
6-羟基-2-[4-(4-甲基-苯甲基)-哌啶-1-羰基]-1H-喹啉-4-酮
本标题化合物按照实施例1所述方法由6-羟基-4-氧代-1,4-二氢-喹啉-2-羧酸和4-(4-甲基苯甲基)-哌啶[JOrg.Chem.,
64,3763.(1999)]制备。Mp.:152(乙醚)。
实施例4
2-[4-(4-氯-苯甲基)-哌啶-1-羰基]-6-羟基-1H-喹啉-4-酮
本标题化合物按照实施例1所述方法由6-羟基-4-氧代-1,4-二氢-喹啉-2-羧酸和4-(4-氯-苯甲基)-哌啶制备(C.A.
77,34266w)。Mp.:194℃(乙醚)。
实施例5
2-(4-苯甲氧基-哌啶-1-羰基)-6-羟基-1H-喹啉-4-酮
本标题化合物按照实施例1所述方法由6-羟基-4-氧代-1,4-二氢-喹啉-2-羧酸和4-苯甲氧基-哌啶制备[TetrahedronLett.,
36,3465.(1995)]。Mp.:103℃(乙醚)。
实施例6
6-羟基-2-(4-苯氧甲基-哌啶-1-羰基)-1H-喹啉-4-酮
本标题化合物按照实施例1所述方法由6-羟基-4-氧代-1,4-二氢-喹啉-2-羧酸和4-苯氧基-甲基-哌啶制备[DE 254 999(1977)]。Mp.:130℃(乙醚)。
实施例7
2-[4-(4-氯-苯氧基)-哌啶-1-羰基]-6-羟基-1H-喹啉-4-酮
a)4-(4-氯-苯氧基)-哌啶-1-羧酸叔丁酯
在氩气下,将3.0g(60%,75mmol)的氢化钠加至搅拌的10.0g(49.7mmol)4-羟基-哌啶-1-羧酸叔丁基酯[Bioorg.Med.Chem.Lett.
10,2815.(2000)]在80ml二甲基甲酰胺的溶液中。反应混合物在40℃搅拌1h,然后在20℃逐滴加入在20ml二甲基甲酰胺中的5.3ml(49.7mmol)1-氯-4-氟-苯(Aldrich)的溶液。反应混合物在80℃搅拌4h,冷却至20℃,逐滴加入1ml乙醇,倾入100ml水并使用乙酸乙酯进行萃取。有机层经过硫酸钠干燥并浓缩。残留物通过柱色谱法使用Kieselgel 60(Merck)作为吸附剂和乙酸乙酯作为洗脱剂进行纯化得到11.07g(75.5%)的标题化合物。Mp.:油。
b)4-(4-氯-苯氧基)-哌啶盐酸盐
将11.07g(37.5mmol)的4-(4-氯-苯氧基)-哌啶-1-羧酸叔丁基酯加入150ml2.5M盐酸的乙酸乙酯溶液中。反应混合物在20℃搅拌3h,然后浓缩至50ml。滤出沉淀的结晶,使用乙酸乙酯洗涤得到7.0g(75.2%)的标题化合物。Mp.:194-196℃。
c)2-[4-(4-氯-苯氧基)-哌啶-1-羰基]-6-羟基-1H-喹啉-4-酮
(45
本标题化合物按照实施例1所述方法由6-羟基-4-氧代-1,4-二氢-喹啉-2-羧酸和4-(4-氯-苯氧基)-哌啶制备。Mp.:91℃(乙醚)。
实施例8
6-羟基-2-(4-对-甲苯氧基-哌啶-1-羰基)-1H-喹啉-4-酮
本标题化合物按照实施例1所述方法由6-羟基-4-氧代-1,4-二氢-喹啉-2-羧酸和4-对-甲苯氧基-哌啶制备[JMed.Chem.,
21,309.(1978)]。Mp.:258-260℃(乙醚)。
实施例9
6-(4-苯甲基-哌啶-1-羰基)-1,5-二氢-噁唑并[4.5-g]喹啉
-2,8-二酮
a)2-(2-氧代-2,3-二氢-苯并噁唑-6-基氨基)-丁-2-烯二酸二甲
酯
1.0g(6.66mmol)6-氨基-3H-苯并噁唑-2-酮[US2806853],0.9ml(7.3mmol)乙炔二羧酸二甲酯(Aldrich)和15ml甲醇的混合物回流2h。反应混合物冷却至20℃,滤出沉淀的结晶,使用甲醇洗涤得到1.7g(87%)的标题化合物。Mp.:172℃。
b)2,8-二氧代-1,2,5,8-四氢-噁唑并[4,5-g]喹啉-6-羧酸甲酯
将1.7g(5.8mmol)2-(2-氧代-2,3-二氢-苯并噁唑-6-基氨基)-丁-2-烯二酸二甲酯按小分加入10ml煮沸的Dowtherm(Fluka)的搅拌溶液中。加入完成后将反应混合物回流10min,然后冷却至室温,滤出沉淀产物并使用己烷洗涤得到1.16g(76%)的标题化合物。Mp.:297℃。
c)2,8-二氧代-1,2,5,8-四氢-噁唑并[4,5-g]喹啉-6-羧酸
1.16g(4.4mmol)2,8-二氧代-1,2,5,8-四氢-噁唑并[4,5-g]喹啉-6-羧酸甲酯,40ml甲醇,10ml水和1.25g(31.2mmol)氢氧化钠的混合物在20℃搅拌1h。将甲醇减压蒸馏。使用2M的盐酸将反应混合物酸化并滤出沉淀的结晶,使用水洗涤得到0.9g(82%)的标题化合物。Mp.>300℃。
d)6-(4-苯甲基-哌啶-1-羰基)-1,5-二氢-噁唑并[4,5-g]喹啉
-2,8-二酮
本标题化合物按照实施例1所述方法由2,8-二氧代-1,2,5,8-四氢-噁唑并[4,5-g]喹啉-6-羧酸和4-苯甲基-哌啶制备。Mp.:215℃(乙醚)。
实施例10
6-羟基-2-(4-苯氧基-哌啶-1-羰基)-1H-喹啉-4-酮
本标题化合物按照实施例1所述方法由6-羟基-4-氧代-1,4-二氢-喹啉-2-羧酸和4-苯氧基-哌啶[J Med.Chem.,
17,1000-1003.(1974)]制备。Mp.:270℃(乙醚)。
实施例11
2-(4-苯甲基-4-羟基-哌啶-1-羰基)-6-羟基-1H-喹啉-4-酮
本标题化合物按照实施例1所述方法由6-羟基-4-氧代-1,4-二氢-喹啉-2-羧酸和4-苯甲基-哌啶-4-醇制备[JMed.Chem.,
42,2087-2104.(1999)]。Mp.:178℃(乙醚)。
实施例12
2-(4-苯甲基-4-羟基-哌啶-1-羰基)-7-羟基-IH-喹啉-4-酮
a)2-(4-苯甲基-哌啶-1-羰基)-7-苯甲氧基-1H-喹啉-4-酮
本标题化合物按照实施例1所述方法由7-苯甲氧基-4-氧代-1,4-二氢-喹啉-2-羧酸[J Med.Chem.,
34,1243-1252.(1991)]和4-苯甲基-哌啶制备。Mp.:228℃(异丙醇)。
b)2-(4-苯甲基-4-羟基-哌啶-1-羰基)-7-羟基-1H-喹啉-4-酮
将0.5g(1.1mmol)2-(4-苯甲基-哌啶-1-羰基)-7-苯甲氧基-1H-喹啉-4-酮,20ml四氢呋喃,20ml甲醇,0.2g 10%Pd/C催化剂的混合物氢化2h。滤出催化剂,使用四氢呋喃洗涤并浓缩滤液。残留物通过柱色谱法使用Kieselgel 60作为吸收剂(Merck)和甲苯∶甲醇=4∶1作为洗脱剂进行纯化得到0.32g(80.7%)的标题化合物。Mp.:174℃(乙醚)。
实施例13
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,或由糖和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%的甘露醇或乳糖水溶液,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 (10)
1、式(I)新的犬尿烯酸酰胺衍生物
-其中含义为
X和Y立地为氢原子,羟基,氨基,任选由一个卤素原子或多个卤素原子取代的C1-C4烷基亚磺酰氨基,任选由一个卤素原子或多个卤素原子取代的C1-C4烷酰基酰氨基,C1-C4烷氧基,C1-C4烷氧羰基,或
在特定的情况下,相邻的X和Y基团可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元的同素环-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,或3-氧代-1,4-噁嗪环,
W是氧原子,以及C1-C4亚烷基,C2-C4亚烯基,氨羰基,-NH-,-N(烷基)-,-CH2O-,-CH2S-,-CH(OH)-,-OCH2-基,-其中烷基的含义是C1-C4烷基-,
当W是C1-C4亚烷基或C3-C4亚烯基时,虚线键
之一可以表示另外的C-C双键并且在这种情况下V表示参与双键的电子对,
Z是氢原子或卤素原子,C1-C4烷基,C1-C4烷氧基,三氟甲基,羟基或羧基,
以及其旋光对映体,外消旋物及盐。
2、如权利要求1所定义的式(I)的化合物,-其中含义为:
X为氢原子,
Y为羟基或苯甲氧基或相邻的X和Y基团形成-NH-CO-O-链,
W是氧原子以及C1-C4亚烷基、-CH2O-,或-OCH2-基,
V是羟基或氢原子,
Z是氢或卤素原子、或C1-C4烷基,并且虚线键
表示C-C单键。
3、属于权利要求1的范围的下组的犬尿烯酸酰胺衍生物的一种化合物:
2-[4-(4-氟-苯甲基)-哌啶-1-羰基]-6-羟基-1H-喹啉-4-酮,
2-(4-苯甲基-哌啶-1-羰基)-6-羟基-1H-喹啉-4-酮,
6-羟基-2-[4-(4-甲基-苯甲基)-哌啶-1-羰基]-1H-喹啉-4-酮,
2-[4-(4-氯-苯甲基)-哌啶-1-羰基]-6-羟基-1H-喹啉-4-酮,
2-(4-苯甲氧基-哌啶-1-羰基)-6-羟基-1H-喹啉-4-酮,
6-羟基-2-(4-苯氧基甲基-哌啶-1-羰基)-1H-喹啉-4-酮,
2-[4-(4-氯-苯氧基)-哌啶-1-羰基]-6-羟基-1H-喹啉-4-酮,
6-羟基-2-(4-对-甲苯氧基-哌啶-1-羰基)-1H-喹啉-4-酮,
6-(4-苯甲基-哌啶-1-羰基)-1,5-二氢-噁唑并[4,5-g]-喹啉-2,8-二酮,
6-羟基-2-(4-苯氧基-哌啶-1-羰基)-1H-喹啉-4-酮,
2-(4-苯甲基-4-羟基-哌啶-1-羰基)-6-羟基-1H-喹啉-4-酮,和
2-(4-苯甲基-4-羟基-哌啶-1-羰基)-7-羟基-1H-喹啉-4-酮。
6、如权利要求5的方法,其特征在于优选在碱存在的情况下使式(II)的羧酸的活性衍生物-其中X和Y的含义如权利要求1所给出-和式(III)的胺-其中Z,V,W和虚线键
的含义如权利要求1所给出-反应。
7、如权利要求5的方法,其特征在于使式(II)的羧酸-其中X和Y的含义如权利要求1所给出-和式(III)的胺-其中Z,V,W和虚线键的含义如权利要求1所给出-在二甲基甲酰胺中在三乙胺和O-苯并三唑-1-基-N,N,N′,N′-四甲基六氟磷酸脲(HBTU)存在的情况下反应。
8、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)的犬尿烯酸酰胺衍生物-其中X,Y,W,V,Z和虚线键
含义如权利要求1所给出-或其旋光对映体或外消旋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。
9、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,例如阿尔茨海默氏病,帕金森氏病,亨廷顿舞蹈病,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,其特征在于给要治疗的哺乳动物施用有效量的式(I)的犬尿烯酸酰胺衍生物-其中X,Y,W,V,Z和虚线键
含义如权利要求1所给出-或其旋光对映体或外消旋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。
10、式(I)的犬尿烯酸酰胺衍生物-其中X,Y,W,V,Z和虚线键含义如权利要求1所给出-或其旋光对映体或外消旋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,例如阿尔茨海默氏病,帕金森氏病,亨廷顿舞蹈病,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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WO2006010967A1 (en) | 2006-02-02 |
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AP2006003842A0 (en) | 2006-12-31 |
EA011636B1 (ru) | 2009-04-28 |
IL179487A0 (en) | 2007-05-15 |
NO20071111L (no) | 2007-02-27 |
TNSN07015A1 (en) | 2008-06-02 |
BRPI0513912A (pt) | 2008-05-20 |
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