CN1368882A - 神经元死亡抑制剂 - Google Patents
神经元死亡抑制剂 Download PDFInfo
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Abstract
一种含有通式(1)的化合物或其酸加成盐作为活性组分的神经元死亡抑制剂,其中R1是氢或羟基;R2是氢或甲基;且R3是带有可以彼此相同或不同的1-3个取代基的吡啶基或苯基。
Description
技术领域
本发明涉及神经元死亡抑制剂、特别涉及针对与编程性细胞死亡相关的神经元死亡的抑制剂和抗脑神经元死亡的抑制剂。
在1972年,Kerr、Wyllie和Currie提出了基于超微结构分析的编程性细胞死亡的概念(细胞膜起泡、核碎裂等),从而将生理性细胞死亡与坏死区别开来。从此以后,已经揭示出就反复进行细胞分裂的真核细胞、特别是就其生长期中的那些真核细胞而言,编程性细胞死亡是维持正常组织内环境稳定的相当常规的途径。
尽管同样的情况对未分化的神经元细胞并不一定同样正确,但是据推定神经元细胞编程性细胞死亡的增加是诸如早老性痴呆、帕金森病和亨廷顿舞蹈病这样的中枢神经变性疾病的致病因素且编程性细胞死亡参与因局部缺血导致的大脑疾病中和大脑出血后脑部障碍中神经元死亡的加速现象。本发明者由此认识到开发神经元死亡抑制剂、特别是针对与编程性细胞死亡相关的神经元死亡的抑制剂且尤其是抗大脑区域中神经元死亡的抑制剂的必要性。
因此,本发明的一个目的是提供用于预防或治疗各种神经系统疾病的神经元死亡抑制剂、特别是针对与编程性细胞死亡相关的神经元死亡的抑制剂且尤其是抗大脑神经元死亡的抑制剂。
本发明的公开内容
本发明者已经对抗神经元死亡的各种化合物的抑制作用进行了广泛的研究。结果是已经发现由下述通式(1)代表的2-氧代-1-吡咯烷基烷基羧酸酰胺类对神经元死亡具有极强的抑制作用,从而完成了本发明。
[其中,R1代表氢原子或羟基;
R2代表氢原子或甲基;且
R3代表带有1-3个相同或不同取代基的吡啶基或苯基,所述苯基上的所述取代基选自:
卤原子;
三氟甲基;
硝基;
乙酰基;
C1-4烷基;
C1-4烷氧基;
C1-7烷硫基;
取代的烷硫基各自由下列通式代表:-S-(CH2)n-CH(R4)(R5)[其中,n代表1或2;R4代表氢原子或甲基,且R5代表羟基或由下列通式代表的氨基:-N(R9)(R10)(其中,R9代表氢原子或甲基且R10代表甲基、苄基或取代的苄基;或R9和R10可以与相邻的氮原子一起偶合成取代的吡咯烷环)];
取代的磺酰基各自由下列通式代表:-SO2R6(其中,R6代表氨基或C1-3烷基);和
取代的氨基乙氧基羰基各自由下列通式代表:-COO(CH2)n-N(R7)(R8)(其中,R7和R8各自独立地代表氢原子、甲基或乙基)]。
本发明还提供了上述通式(1)的化合物在制备神经元死亡抑制剂中的用途。本发明进一步提供了一种用于抑制神经元死亡的方法,该方法包括给予上述通式(1)的化合物的步骤。
附图简述
附图1显示了在给予奈非西坦后1天EL小鼠大脑中DNA的断裂情况;且附图2显示了在给予奈非西坦后5天EL小鼠大脑中DNA的断裂情况。
本发明的最佳实施方式
上述通式(1)的化合物例如是描述在日本未审公开专利申请(kokai)号sho 56-2960、日本未审公开专利申请(kokai)号sho61-280470、日本未审公开专利申请(kokai)号Hei 4-160496和日本专利申请号Hei 3-46466中的已知化合物。作为其作用,已知它们具有改善大脑功能的作用(日本专利公开号Sho 62-5404)、缓解早老性痴呆的作用(日本未审公开申请(kokai)号Hei 5-163144)缓解脑血管性痴呆的作用(日本未审公开专利申请(kokai)号Hei5-163145)和在EL小鼠体内的镇痉作用(Nakamoto等,笫17届日本神经病学协会会议年报再版纲要和摘要(Program and AbstractReprints of the 17th Annual Meeting of Japanese Society ofNeurology)(1993年12月7-9日,在Nayoya)”,18页,No.P1A20)以及使线粒体膜保持稳定的作用(日本专利申请号Hei 8-260649)。然而,这些化合物对抗神经元死亡的作用完全没有得到认识。
下面将描述由存在于通式(1)中苯基上的R3所代表的取代基。卤原子包括氯原子和氟原子。C1-4烷基包括直链或支链烷基,诸如甲基、乙基、正丙基、仲丁基和正丁基。C1-4烷氧基包括直链或支链烷氧基,诸如甲氧基、乙氧基和异丙氧基。C1-7烷硫基包括直链或支链烷硫基,诸如甲硫基、正丙硫基、异丙硫基、仲丁硫基和正庚硫基。
由R10代表的取代苄基的实例包括:被1-3个诸如二甲氧基苄基这样的C1-4烷氧基取代的苄基;被1-3个诸如二甲基苄基这样的C1-4烷基取代的苄基;和被诸如甲基-甲氧基苄基这样的至少一个C1-4烷基和至少一个C1-4烷氧基、但总计不超过3个取代的苄基。由R9和R10与相邻氮原子一起形成的取代的吡咯烷环的实例包括2-氧代吡咯烷环、3-氧代吡咯烷环和2,5-二氧代吡咯烷环。
由-S-(CH2)n-CH(R4)(R5)代表的取代烷硫基的实例包括2-羟基丙硫基、2-(N,N-二甲氨基)丙硫基、2-(N-甲基-N-苄基氨基)乙硫基、2-N-甲基-N-(3,4-二甲氧基苄基氨基)乙硫基和2-(2-氧代-1-吡咯烷基)乙硫基。
由R6代表的C1-3烷基包括直链或支链烷基,诸如甲基、乙基和异丙基。由-SO2R6代表的取代的磺酰基包括氨基磺酰基和甲基磺酰基。
各自由-COO(CH2)n-N(R7)(R8)代表的取代的氨基乙氧基羰基包括2-(N,N-二乙氨基)乙氧基羰基。
由R3代表的吡啶基的实例包括3-吡啶基和4-吡啶基。
优选作为本发明药剂的活性组分的化合物的特殊实例包括:
(1)2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;
(2)4-羟基-2-氧代-1-吡咯烷基乙酸2,6-二乙基N-酰苯胺;
(3)4-羟基-2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;
(4)2-(2-氧代-吡咯烷基)丙酸N-3-吡啶酰胺;
(5)2-氧代-1-吡咯烷基乙酸4-异丙基N-硫代酰苯胺;
(6)2-(2-氧代-1-吡咯烷基)-1-丙酸4-(2-丁硫基)N-酰苯胺;
(7)2-(2-氧代-1-吡咯烷基)丙酸4-异丙基N-酰苯胺;
(8)2-(2-氧代-1-吡咯烷基)丙酸2,4-二甲基N-酰苯胺;
(9)2-(2-氧代-1-吡咯烷基)丙酸2,4,6-三甲基N-酰苯胺;
(10)2-(2-氧代-1-吡咯烷基)丙酸2-甲氧基-5-甲基N-酰苯胺;
(11)2-(2-氧代-1-吡咯烷基)丙酸2,6-二氯N-酰苯胺;
(12)2-吡咯烷酮乙酰胺;
(13)1-茴香酰-2-吡咯烷酮(pyrrolidinone);和
(14)4-羟基-2-氧代-1-吡咯烷乙酰胺。
此外,优选的是日本专利公开号Hei 3-46466第1019页上的表3中公开的化合物。
在上述化合物中,特别优选的是2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺[N-(2,6-二甲基苯基)-2-(2-氧代-1-吡咯烷基)-乙酰胺,常用名称为:奈非西坦]、2-吡咯烷酮乙酰胺、1-茴香酰-2-吡咯烷酮(pyrrolidinone)和4-羟基-2-氧代-1-吡咯烷乙酰胺。
作为上述化合物(1),任意一种游离形式或药物上可接受的酸加成盐的形式均是可用的。本发明还包括所述化合物的任意水合物或溶剂合物。药物上可接受的酸加成盐包括诸如盐酸、氢溴酸、氢碘酸、硫酸、硝酸和磷酸这样无机酸的盐和诸如乙酸、马来酸、富马酸、柠檬酸、草酸、琥珀酸、酒石酸、苹果酸、扁桃酸、甲磺酸、对甲苯磺酸和10-樟脑-磺酸这样有机酸的盐。
当上述化合物(1)带有不对称碳原子时,不对称碳原子的空间构型并不受到特别限制。可以使用所需的旋光活性物质、所需的其旋光异构体混合物和外消旋混合物中的任意一种。还可以使用带有至少两个不对称碳原子的所需非对映异构体的混合物。
上述化合物(1)或其酸加成盐用作神经元死亡抑制剂,可明显抑制由小鼠大脑中神经元死亡导致的DNA断裂,对其稍后进行描述。因此,上述化合物(1)或其酸加成盐用作与神经元死亡增加相关的疾病、特别是与涉及编程性细胞死亡的神经元死亡增加相关的疾病、更具体地说是与大脑神经元死亡增加相关的疾病的预防药或药物,所述的与大脑神经元死亡增加相关的疾病例如有:诸如早老性痴呆、帕金森病和亨廷顿舞蹈病这样的中枢神经变性疾病和因局部缺血导致的大脑疾病和大脑出血后脑部障碍。
对本发明药剂的给药途径没有特定的限制且可以通过口服方式或非肠道方式给予本发明的药剂。作为本发明的药物,可以给予用作其活性组分的上述化合物(1)或其盐,但优选将它制成含有化合物(1)和药物上可接受的添加剂的药物组合物。作为药物上可接受的添加剂,使用的有赋形剂、崩解剂、崩解助剂、粘合剂、润滑剂、包衣剂、着色剂、稀释剂、基质、加溶剂、加溶助剂、等渗剂、pH调节剂、稳定剂、推进剂和压敏粘合剂。适合于口服给药的制剂包括片剂、胶囊、粉剂、微粒(fine subtilaes)、颗粒剂、液体和糖浆剂。适合于非肠道给药的制剂包括注射剂、滴剂、栓剂、吸入剂和硬膏剂。在本发明的药剂中,可以混入一种或多种活性组分。
对本发明药剂的剂量没有特别限制且可以根据诸如治疗或预防目的、疾病类型、患者的年龄或症状以及给药途径这样的不同情况的需要对其进行选择。通常的每日剂量约为每位成年患者19mg-1000mg、优选约60-900mg。已经证实本发明中特别优选的2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺[常用名称:奈非西坦]是一种显示出2,005mg/kg急性毒性的高度安全的化合物(雄性大鼠,口服)(日本未审公开专利申请(kokai)号Hei 5-163144)。
实施例
下文通过实施例来具体地描述本发明。不过,应考虑到本发明并不限于这些实施例或受到它们的限制。
实施例1
使用3组各自由6只30周龄小鼠构成的组,所述的小鼠即每周给予一次致癫痫刺激且由此具有低阈值的EL小鼠(EL[s])、至少在观察过程中不给予致癫痫刺激且无癫痫发作的EL小鼠(EL[ns])和DDY小鼠用作对照组。将各组与由40-50周龄小鼠组成的组进行比较以便忽略衰老的影响。在恒冷箱中将10μm厚切片固定在明胶包被的载玻片上,随后在4℃下用0.1%柠檬酸钠和0.1%Triton-X-100渗透5分钟。通过将荧光素标记的核苷酸与使用末端转移酶(TdT)裂解的DNA 3’-OH末端聚合来检测DNA的断裂情况。与共轭了过氧化物酶(PD)或碱性磷酸酶(AP)的抗荧光素抗体的反应显色,由此能够通过光学显微镜进行检测。作为阴性对照的是TdT(-),而作为阳性对照,使用以DNAaseI处理的样品。对试验组(30周龄,EL[s])每日口服给予一次奈非西坦(10mg/kg)。当由此控制了癫痫发作的发生时,观察奈非西坦给药期限(1、3、5和7天)与DNA断裂出现的频率之间的关系。
结果,从30周龄(成年)和用作阴性对照的40周龄(有衰老的影响)的DDY小鼠中均没有检测到DNA的断裂。在具有癫痫发作的EL小鼠(EL[s])中,无论是30周龄的小鼠还是40周龄的小鼠均从其海马和顶骨皮质中确定了DNA断裂。在没有癫痫发作的EL小鼠(EL[ns])中,无论是30周龄的小鼠还是40周龄的小鼠均以比(EL[s])低的频率仅在较窄的区域内确定了DNA断裂。在其海马中,没有观察到DNA断裂。
EL小鼠用作区域特异性继发性全身性癫痫的模型。尽管没有严重的组织损伤,但是已知它们可在构成部分复杂的发作的海马和顶骨皮质中加速了自由基的产生、在获得致癫痫过程中NO升高和立即早期基因(c-fos,zif)的位点特异性表达。在海马和顶骨皮质中DNA断裂的定位明显提示神经元细胞在小鼠海马和顶骨皮质中的编程性细胞死亡过程得到了发展。
通过单一给予奈非西坦确定海马和顶骨皮质中的DNA断裂情况(附图1)。
在给予奈非西坦后5天,在顶骨皮质中没有观察到改变,而在海马中DNA断裂消失(附图2)。由此认识到奈非西坦抑制了神经元细胞的编程性细胞死亡。
工业实用性
化合物(1)或其酸加成盐选择性地抑制了神经元死亡、特别是编程性细胞死亡且由此用作诸如早老性痴呆、帕金森病和亨廷顿舞蹈病这样的中枢神经变性疾病和与局部缺血相关的大脑疾病和大脑出血后脑部障碍的预防药或治疗药。
Claims (18)
[其中,R1代表氢原子或羟基;
R2代表氢原子或甲基;且
R3代表带有1-3个相同或不同取代基的吡啶基或苯基,所述苯基上的所述取代基选自:
卤原子;
三氟甲基;
硝基;
乙酰基;
C1-4烷基;
C1-4烷氧基;
C1-7烷硫基;
取代的烷硫基各自由下列通式代表:-S-(CH2)n-CH(R4)(R5)[其中,n代表1或2;R4代表氢原子或甲基,且R5代表羟基或由下列通式代表的氨基:-N(R9)(R10)(其中,R9代表氢原子或甲基且R10代表甲基、苄基或取代的苄基;或R9和R10可以与相邻的氮原子一起偶合成取代的吡咯烷环)];
取代的磺酰基各自由下列通式代表:-SO2R6(其中,R6代表氨基或C1-3烷基);和
取代的氨基乙氧基羰基各自由下列通式代表:-COO(CH2)n-N(R7)(R8)(其中,R7和R8各自独立地代表氢原子、甲基或乙基)]。
2.一种根据权利要求1的神经元死亡抑制剂,其中所述的活性组分是一种选自下列化合物组成的组的化合物:
(1)2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;
(2)4-羟基-2-氧代-1-吡咯烷基乙酸2,6-二乙基N-酰苯胺;
(3)4-羟基-2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;
(4)2-(2-氧代-吡咯烷基)丙酸N-3-吡啶酰胺;
(5)2-氧代-1-吡咯烷基乙酸4-异丙基N-硫代酰苯胺;
(6)2-(2-氧代-1-吡咯烷基)-1-丙酸4-(2-丁硫基)N-酰苯胺;
(7)2-(2-氧代-1-吡咯烷基)丙酸4-异丙基N-酰苯胺;
(8)2-(2-氧代-1-吡咯烷基)丙酸2,4-二甲基N-酰苯胺;
(9)2-(2-氧代-1-吡咯烷基)丙酸2,4,6-三甲基N-酰苯胺;
(10)2-(2-氧代-1-吡咯烷基)丙酸2-甲氧基-5-甲基N-酰苯胺;
(11)2-(2-氧代-1-吡咯烷基)丙酸2,6-二氯N-酰苯胺;
(12)2-吡咯烷酮乙酰胺;
(13)1-茴香酰-2-吡咯烷酮;和
(14)4-羟基-2-氧代-1-吡咯烷乙酰胺。
3.一种根据权利要求1的神经元死亡抑制剂,其中所述的活性组分是一种选自下列化合物组成的组的化合物:2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;2-吡咯烷酮乙酰胺;1-茴香酰-2-吡咯烷酮;和4-羟基-2-氧代-1-吡咯烷乙酰胺。
4.一种根据权利要求1的神经元死亡抑制剂,其中所述的活性组分是2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺。
5.一种根据权利要求1的神经元死亡抑制剂,其中所述的神经元死亡是由编程性细胞死亡导致的细胞死亡。
6.一种根据权利要求1的神经元死亡抑制剂,其中神经元死亡是脑神经元死亡。
[其中,R1代表氢原子或羟基;
R2代表氢原子或甲基;且
R3代表带有1-3个相同或不同取代基的吡啶基或苯基,所述苯基上的所述取代基选自:
卤原子;
三氟甲基;
硝基;
乙酰基;
C1-4烷基;
C1-4烷氧基;
C1-7烷硫基;
取代的烷硫基各自由下列通式代表:-S-(CH2)n-CH(R4)(R5)[其中,n代表1或2;R4代表氢原子或甲基,且R5代表羟基或由下列通式代表的氨基:-N(R9)(R10)(其中,R9代表氢原子或甲基且R10代表甲基、苄基或取代的苄基;或R9和R10可以与相邻的氮原子一起偶合成取代的吡咯烷环)];
取代的磺酰基各自由下列通式代表:-SO2R6(其中,R6代表氨基或C1-3烷基);和
取代的氨基乙氧基羰基各自由下列通式代表:-COO(CH2)n-N(R7)(R8)(其中,R7和R8各自独立地代表氢原子、甲基或乙基)。
8.根据权利要求7的用途,其中由通式(1)代表的化合物是一种选自下列化合物组成的组的化合物:
(1)2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;
(2)4-羟基-2-氧代-1-吡咯烷基乙酸2,6-二乙基N-酰苯胺;
(3)4-羟基-2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;
(4)2-(2-氧代-吡咯烷基)丙酸N-3-吡啶酰胺;
(5)2-氧代-1-吡咯烷基乙酸4-异丙基N-硫代酰苯胺;
(6)2-(2-氧代-1-吡咯烷基)-1-丙酸4-(2-丁硫基)N-酰苯胺;
(7)2-(2-氧代-1-吡咯烷基)丙酸4-异丙基N-酰苯胺;
(8)2-(2-氧代-1-吡咯烷基)丙酸2,4-二甲基N-酰苯胺;
(9)2-(2-氧代-1-吡咯烷基)丙酸2,4,6-三甲基N-酰苯胺;
(10)2-(2-氧代-1-吡咯烷基)丙酸2-甲氧基-5-甲基N-酰苯胺;
(11)2-(2-氧代-1-吡咯烷基)丙酸2,6-二氯N-酰苯胺;
(12)2-吡咯烷酮乙酰胺;
(13)1-茴香酰-2-吡咯烷酮(pyrrolidinone);和
(14)4-羟基-2-氧代-1-吡咯烷乙酰胺。
9.根据权利要求7的用途,其中由通式(1)代表的化合物是一种选自下列化合物组成的组的化合物:2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;2-吡咯烷酮乙酰胺;1-茴香酰-2-吡咯烷酮(pyrrolidinone);和4-羟基-2-氧代-1-吡咯烷乙酰胺。
10.根据权利要求7的用途,其中由通式(1)代表的化合物是2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺。
11.根据权利要求7的用途,其中所述的神经元死亡是由编程性细胞死亡导致的细胞死亡。
12.根据权利要求7的用途,其中神经元死亡是脑神经元死亡。
13.一种用于抑制神经元死亡的治疗方法,该方法包括给予由下列通式(1)代表的2-氧代-1-吡咯烷基烷基羧酸酰胺或其药物上可接受的酸加成盐的步骤:
[其中,R1代表氢原子或羟基;
R2代表氢原子或甲基;且
R3代表带有1-3个相同或不同取代基的吡啶基或苯基,所述苯基上的所述取代基选自:
卤原子;
三氟甲基;
硝基;
乙酰基;
C1-4烷基;
C1-4烷氧基;
C1-7烷硫基;
取代的烷硫基各自由下列通式代表:-S-(CH2)n-CH(R4)(R5)[其中,n代表1或2;R4代表氢原子或甲基,且R5代表羟基或由下列通式代表的氨基:-N(R9)(R10)(其中,R9代表氢原子或甲基且R10代表甲基、苄基或取代的苄基;或R9和R10可以与相邻的氮原子一起偶合成取代的吡咯烷环)];
取代的磺酰基各自由下列通式代表:-SO2R6(其中,R6代表氨基或C1-3烷基);和
取代的氨基乙氧基羰基各自由下列通式代表:-COO(CH2)n-N(R7)(R8)(其中,R7和R8各自独立地代表氢原子、甲基或乙基)]。
14.一种根据权利要求13的方法,其中所述的化合物是一种选自下列化合物组成的组的化合物:
(1)2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;
(2)4-羟基-2-氧代-1-吡咯烷基乙酸2,6-二乙基N-酰苯胺;
(3)4-羟基-2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;
(4)2-(2-氧代-吡咯烷基)丙酸N-3-吡啶酰胺;
(5)2-氧代-1-吡咯烷基乙酸4-异丙基N-硫代酰苯胺;
(6)2-(2-氧代-1-吡咯烷基)-1-丙酸4-(2-丁硫基)N-酰苯胺;
(7)2-(2-氧代-1-吡咯烷基)丙酸4-异丙基N-酰苯胺;
(8)2-(2-氧代-1-吡咯烷基)丙酸2,4-二甲基N-酰苯胺;
(9)2-(2-氧代-1-吡咯烷基)丙酸2,4,6-三甲基N-酰苯胺;
(10)2-(2-氧代-1-吡咯烷基)丙酸2-甲氧基-5-甲基N-酰苯胺;
(11)2-(2-氧代-1-吡咯烷基)丙酸2,6-二氯N-酰苯胺;
(12)2-吡咯烷酮乙酰胺;
(13)1-茴香酰-2-吡咯烷酮(pyrrolidinone);和
(14)4-羟基-2-氧代-1-吡咯烷乙酰胺。
15.一种根据权利要求13的方法,其中由通式(1)代表的化合物是一种选自下列化合物组成的组的化合物:2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺;2-吡咯烷酮乙酰胺;1-茴香酰-2-吡咯烷酮(pyrrolidinone);和4-羟基-2-氧代-1-吡咯烷乙酰胺。
16.一种根据权利要求13的方法,其中由通式(1)代表的化合物是2-氧代-1-吡咯烷基乙酸2,6-二甲基N-酰苯胺。
17.一种根据权利要求13的方法,其中所述的神经元死亡是由编程性细胞死亡导致的细胞死亡。
18.一种根据权利要求13的方法,其中神经元死亡是脑神经元死亡。
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