CN1356984A - 神经营养蛋白作用增强剂 - Google Patents
神经营养蛋白作用增强剂 Download PDFInfo
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- CN1356984A CN1356984A CN00809192A CN00809192A CN1356984A CN 1356984 A CN1356984 A CN 1356984A CN 00809192 A CN00809192 A CN 00809192A CN 00809192 A CN00809192 A CN 00809192A CN 1356984 A CN1356984 A CN 1356984A
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- neurotrophin
- compound
- protentiators
- amino
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Abstract
含有具有通式(I)代表的6(5H)-菲啶酮衍生物或其药理上可接受的盐的神经营养蛋白作用增强剂,其作为神经变性疾病的预防药或治疗药是有用的。式中,R1,R1’,R2和R2’可相同或不同,代表氢原子或卤原子,R3和R3’之一代表氨基,且另一个代表氢原子。条件是,当R1,R1’之一代表卤原子,则另一个代表氢原子;且当R2,R2’之一代表卤原子,则另一个代表氢原子。
Description
发明所属技术领域
本发明涉及含有6(5H)-菲啶酮衍生物或其药学上可接受的盐的神经营养蛋白作用增强剂,含有该神经营养蛋白作用增强剂的神经变性疾病的预防剂或治疗剂,或6(5H)-菲啶酮衍生物或其药学上可接受的盐在制造神经变性疾病的预防或治疗的组合物中的应用。
背景技术
神经变性疾病是神经细胞的变性、细胞死亡为原因引起的疾病,包括阿耳茨海默氏类型的痴呆症、帕金森氏病、肌萎缩性脊髓侧索硬化症、杭廷顿氏舞蹈病、某些末梢感觉神经障碍等。例如,在阿尔海默氏类型的痴呆症中,确认了前脑基底的胆碱能神经细胞或海马、大脑皮质的锥体细胞的变性、脱落,并认为这就是痴呆症状表现的原因。另外,在帕金森氏病中,认为中脑多巴胺能神经细胞选择性变性、脱落是运动障碍的原因。另外,在肌萎缩性脊髓侧索硬化症中的运动神经变性,在杭廷顿氏舞蹈病中的纹状体神经细胞的变性,在糖尿病患者或接受制癌剂治疗的患者中可看到的末稍感觉神经障碍中的脊髓感觉神经细胞变性,分别被认为是这些疾病的原因。但是,到目前为止,由于没有抑制神经细胞变性、细胞死亡的手段,因此没有从根本上治疗这些神经变性疾病的药物,现状是只能进行暂缓症状的代替疗法。
特别是,阿尔海默氏类型的痴呆症患者的增加,正成为近年来很大的社会问题,但是作为治疗药只是使用乙酰胆碱酯酶抑制剂。该药物只是暂时缓和病症不能延迟疾病的进行,因此,只是对于初期患者短时间内有效。另外,由于该药物对末稍神经系统也有作用,恐怕会发生严重的副作用,因此作为必须长期给药的痴呆症治疗剂不能说是令人满意的。另外,WO98/27975中,记载了6(5H)-菲啶酮和2-硝基-6(5H)-菲啶酮等,具有聚(ADP-核糖)聚合酶抑制活性,在延长细胞寿命的同时有提高增殖活性的效果,在阿尔海默氏类型的痴呆症中是有用的。但是,没有记载对于本来不增殖的神经细胞细胞的效果或对其他神经系统的作用,因此,是基于什么样的理由对阿尔海默氏类型的痴呆症有用并不清楚。另外,在帕金森氏病的治疗中,已知通过L-DOPA的多巴胺补充疗法显示显著效果,但是,长时间使用已知会出现不随意运动或精神症状等各种副作用。对于肌萎缩性脊髓侧索硬化症、杭廷顿氏舞蹈病、末梢感觉神经障碍等,到目前为止还没有有效的治疗手段。
在这样的状况下,作为新的神经变性疾病治疗药的可能性很大的神经营养因子正受到关注[Annu.Rev.Pharmacol.Toxicol.,37,239(1997)]。神经营养因子是存在于生物体内在表达神经系统功能时起重要角色的蛋白质群,而且它是可恢复变性神经功能的物质。其中,特别是在被称为神经营养蛋白的神经营养因子中,包括神经生长因子(nerve growth factor,以下简称为NGF),脑由来的神经营养因子(brain-derived neurotrophic factor,以下简称为BDNF),神经营养蛋白-3(neurotrophin-3,以下简称为NT-3),神经营养蛋白-4/5(neurotrophin-4/5,以下简称为NT-4/5)等,这些在神经细胞的生存或神经系统的功能维持中起重要作用。
NGF在末梢神经系统中,对脊髓后根神经节的感觉神经细胞或交感神经细胞作用,在中枢神经系统中,对前脑基底和纹状体的胆碱能神经细胞作用。BDNF对于脊髓后根神经节的感觉神经细胞,脊髓运动神经细胞,前脑基底的胆碱能和GABA能神经细胞,中脑的多巴胺能神经细胞,脊核的5-羟色胺能神经细胞,海马、大脑皮质的锥体细胞,小脑颗粒细胞,视网膜神经细胞等大范围的神经细胞作用。NT-3对感觉神经细胞、运动神经细胞、海马、大脑皮质的锥体细胞等作用。另外,NT-4/5对交感神经细胞或脊髓后根神经节感觉神经细胞作用。
实际上,由于神经营养蛋白在神经变性疾病的动物模型中,抑制神经细胞的变性,各种试验体系中显示恢复神经系统功能的作用,因此认为它作为上述伴随神经细胞变性的神经变性疾病的治疗药是有用的。例如,由于NGF抑制受阻碍的胆碱能神经细胞或老龄动物的胆碱能神经细胞的变性,可恢复动物的记忆学习功能[J.Neurosci.14,4815(1994)],因此,认为它作为阿尔海默氏类型的痴呆症和脑血管性痴呆症的治疗药是有用的。另外,BDNF具有可恢复受障碍动物的胆碱能神经的作用[J.neurosci.,12,4391(1992)],恢复多巴胺能神经作用[Proc.Natl.Acad.Sci.USA,89,11347(1992)],恢复变性的运动神经作用[Nature,360,753(1992),]除此之外,由于还与被认为是记忆的基础过程的在海马、大脑皮质的突触长期增强现象相关[Proc.Natl.Acad.Sci.USA,92,8856(1995)],因此可认为它作为痴呆症,帕金森氏病,脊髓运动神经障碍,肌萎缩性脊髓侧索硬化症等的治疗药是有用的。另外,对于NGF和NT-3,由于可确认具有可抑制末梢感觉神经的变性,恢复功能的作用[Ann.Neurol.,29,87(1991),出处同上38,30(1995)],因此可认为它作为糖尿病患者或制癌剂给药时看到的末梢感觉神经障碍的治疗药是有用的。
除了作为上述神经变性疾病治疗药的有用性以外,NGF或BDNF在试验脑梗塞模型中,由于可减轻神经细胞的障碍[J.Neurosci.11,2914(1991)]、[Neurosurgery,34,323(1994)],因此可认为其作为脑梗塞等脑缺血后的神经细胞死亡防止药、后遗症治疗药是有用的。
但是,神经营养蛋白是蛋白质,为了对中枢神经系统作用,因此必须脑室内直接给药,由于这些原因等其使用受到限制。另外,由于神经营养蛋白是活性非常高的物质,全身给药时存在作用于在生物体内本来应该没有大量存在的部位的可性能,可能会发生副作用。例如,有报告显示在使用NGF脑室内给药的患者中,由于对疼痛过敏的副作用停止给药的例子,这可能是由于在非目标作用部位的脊髓中对感觉神经过度刺激造成的。
另一方面,作为解决如上所述的适应上的问题的方法,有报告说已知例如对NGF的合成·分泌有诱导作用的甾族化合物类、儿茶酚类、聚烯类化合物等,在动物模型中显示改善学习的效果。但是,这些NGF产生促进剂的主要目标是非神经细胞,对神经系统以外的组织带来恶劣影响的可能性很高。另外,这些物质中,对NGF产生诱导的浓度与显示细胞毒性的浓度不一定能分开的很多,不能充分满足实用性。
另外,在对生物体给药时,由于即使在本来应该不存在NGF的部位也诱导NGF的产生,存在表现与使用NGF给药同样的副作用的危险性。
发明的公开
本发明者等,以开发新的抗神经变性疾病剂为目的,对各种6(5H)-菲啶酮衍生物的药理活性进行了长期认真的研究,结果发现,具有特殊结构的6(5H)-菲啶酮衍生物具有优秀的神经营养蛋白作用增强活性,作为抗神经变性疾病剂[阿尔海默氏类型的痴呆症、帕金森氏病、肌萎缩性脊髓侧索硬化症、杭廷顿氏舞蹈病、或末梢感觉神经障碍(特别是阿尔海默氏类型的痴呆症)是预防药或治疗药(特别是治疗药),或脑缺血后的神经细胞死亡防止药或后遗症治疗药]是有用的,并因此完成了本发明。
本发明的神经营养蛋白作用增强剂,对于神经营养蛋白的目标神经细胞作用,具有增强神经营养蛋白作用的新的作用机理。使用本发明的神经营养蛋白作用增强剂对生物体给药时,通过增强生物体内存在的神经营养蛋白的作用,可发挥治疗上述神经变性疾病或抑制脑缺血后的神经细胞死亡的效果。这样的增强剂,由于只对生物体内神经营养蛋白实际发挥功能的部位作用,没有在NGF或NGF合成促进剂中看到的副作用。另外,本发明的神经营养蛋白作用增强剂,通过与不表现副作用程度的少量神经营养蛋白或神经营养蛋白产生促进剂同时对生物体给药,可发挥只增强目标作用的治疗效果。
本发明提供了含有6(5H)-菲啶酮衍生物或其药理上可接受的盐的神经蛋白作用增强剂,含有该神经营养蛋白作用增强剂的为预防或治疗神经变性疾病的组合物,或6(5H)-菲啶酮衍生物或其药理上可接受的盐在制造预防或治疗神经变性疾病中的应用。
上式中,R1和R2可相同或不同,表示氢原子或卤原子,R3表示氨基。
在上述R1和R2的定义中,“卤原子”是指,例如氟原子、氯原子、溴原子或碘原子,优选氟原子、氯原子或溴原子,更优选氯原子或溴原子,特别优选氯原子。
作为本发明神经营养蛋白作用增强剂有效成分的具有前述通式(I)的化合物,可通过酸处理容易地转化为药理上可接受的盐。作为这些盐,可列举例如盐酸盐、硫酸盐、硝酸盐、磷酸盐等无机盐,乙酸盐、丙酸盐、丁酸盐、苯甲酸盐、草酸盐、丙二酸盐、丁二酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐等有机酸盐,但是优选盐酸盐、硫酸盐、硝酸盐、草酸盐、丁二酸盐、富马酸盐或甲磺酸盐,特别优选盐酸盐。
作为本发明神经营养蛋白作用增强剂有效成分的具有前述通式(I)的化合物或其药理上可接受的盐,有可能通过在大气中放置,或重结晶,吸收水分,或带着吸附水,形成水合物,含有这样的水的化合物盐形成的神经营养蛋白作用增强剂也包括在本发明中。
更优选,可列举含有具有下面通式的化合物或其药理上可接受的盐的神经营养蛋白作用增强剂,
在本发明中优选可列举,通式(I)中,
(1)含有R1和R2可相同或不同,是氢原子、氯原子或溴原子的化合物或其药理上可接受的盐的神经营养蛋白作用增强剂;
(2)含有R1和R2是氯原子或溴原子的化合物或其药理上可接受的盐的神经营养蛋白作用增强剂;
(3)含有R1和R2是氯原子的化合物或其药理上可接受的盐的神经营养蛋白作用增强剂;在上述中,以(1)~(3)的顺序,优选按顺序上升的次序。
在含有本发明前述通式(I)的化合物或其药理上可接受的盐的神经营养蛋白作用增强剂中,作为优选的有效成分,例如可列举下表中记载的化合物,但是本发明并不限于含有这些化合物或其药理上可接受的盐的神经营养蛋白作用增强剂。【表1】
化合物号 | R1 | R2 | R3 |
1 | H | H | 1-NH2 |
2 | H | H | 2-NH2 |
3 | H | H | 3-NH2 |
4 | H | H | 4-NH2 |
5 | H | H | 7-NH2 |
6 | H | H | 8-NH2 |
7 | H | H | 9-NH2 |
8 | H | H | 10-NH2 |
9 | 2-Cl | H | 1-NH2 |
10 | 2-Br | H | 1-NH2 |
11 | 3-F | H | 1-NH2 |
12 | 3-Cl | H | 1-NH2 |
13 | 3-Br | H | 1-NH2 |
14 | 3-I | H | 1-NH2 |
15 | 4-Cl | H | 1-NH2 |
16 | 4-Br | H | 1-NH2 |
17 | 7-Cl | H | 1-NH2 |
18 | 7-Br | H | 1-NH2 |
19 | 8-F | H | 1-NH2 |
20 | 8-Cl | H | 1-NH2 |
21 | 8-Br | H | 1-NH2 |
22 | 8-I | H | 1-NH2 |
23 | 9-Cl | H | 1-NH2 |
24 | 9-Br | H | 1-NH2 |
25 | 10-Cl | H | 1-NH2 |
26 | 10-Br | H | 1-NH2 |
27 | 1-Cl | H | 2-NH2 |
28 | 1-Br | H | 2-NH2 |
29 | 3-F | H | 2-NH2 |
30 | 3-Cl | H | 2-NH2 |
31 | 3-Br | H | 2-NH2 |
32 | 3-I | H | 2-NH2 |
33 | 4-Cl | H | 2-NH2 |
34 | 4-Br | H | 2-NH2 |
35 | 7-Cl | H | 2-NH2 |
36 | 7-Br | H | 2-NH2 |
37 | 8-F | H | 2-NH2 |
38 | 8-Cl | H | 2-NH2 |
39 | 8-Br | H | 2-NH2 |
40 | 8-I | H | 2-NH2 |
41 | 9-Cl | H | 2-NH2 |
42 | 9-Br | H | 2-NH2 |
43 | 10-Cl | H | 2-NH2 |
44 | 10-Br | H | 2-NH2 |
45 | 1-Cl | H | 3-NH2 |
46 | 1-Br | H | 3-NH2 |
47 | 2-F | H | 3-NH2 |
48 | 2-Cl | H | 3-NH2 |
49 | 2-Br | H | 3-NH2 |
50 | 2-I | H | 3-NH2 |
51 | 4-Cl | H | 3-NH2 |
52 | 4-Br | H | 3-NH2 |
53 | 7-Cl | H | 3-NH2 |
54 | 7-Br | H | 3-NH2 |
55 | 8-F | H | 3-NH2 |
56 | 8-Cl | H | 3-NH2 |
57 | 8-Br | H | 3-NH2 |
58 | 8-I | H | 3-NH2 |
59 | 9-Cl | H | 3-NH2 |
60 | 9-Br | H | 3-NH2 |
61 | 10-Cl | H | 3-NH2 |
62 | 10-Br | H | 3-NH2 |
63 | 1-Cl | H | 4-NH2 |
64 | 1-Br | H | 4-NH2 |
65 | 2-Cl | H | 4-NH2 |
66 | 2-Br | H | 4-NH2 |
67 | 3-F | H | 4-NH2 |
68 | 3-Cl | H | 4-NH2 |
69 | 3-Br | H | 4-NH2 |
70 | 3-I | H | 4-NH2 |
71 | 7-Cl | H | 4-NH2 |
72 | 7-Br | H | 4-NH2 |
73 | 8-F | H | 4-NH2 |
74 | 8-Cl | H | 4-NH2 |
75 | 8-Br | H | 4-NH2 |
76 | 8-I | H | 4-NH2 |
77 | 9-Cl | H | 4-NH2 |
78 | 9-Br | H | 4-NH2 |
79 | 10-Cl | H | 4-NH2 |
80 | 10-Br | H | 4-NH2 |
81 | 1-Cl | H | 7-NH2 |
82 | 1-Br | H | 7-NH2 |
83 | 2-Cl | H | 7-NH2 |
84 | 2-Br | H | 7-NH2 |
85 | 3-F | H | 7-NH2 |
86 | 3-Cl | H | 7-NH2 |
87 | 3-Br | H | 7-NH2 |
88 | 3-I | H | 7-NH2 |
89 | 4-Cl | H | 7-NH2 |
90 | 4-Br | H | 7-NH2 |
91 | 8-F | H | 7-NH2 |
92 | 8-Cl | H | 7-NH2 |
93 | 8-Br | H | 7-NH2 |
94 | 8-I | H | 7-NH2 |
95 | 9-Cl | H | 7-NH2 |
96 | 9-Br | H | 7-NH2 |
97 | 10-Cl | H | 7-NH2 |
98 | 10-Br | H | 7-NH2 |
99 | 1-F | H | 8-NH2 |
100 | 1-Cl | H | 8-NH2 |
101 | 1-Br | H | 8-NH2 |
102 | 1-I | H | 8-NH2 |
103 | 2-Cl | H | 8-NH2 |
104 | 2-Br | H | 8-NH2 |
105 | 3-F | H | 8-NH2 |
106 | 3-Cl | H | 8-NH2 |
107 | 3-Br | H | 8-NH2 |
108 | 3-I | H | 8-NH2 |
109 | 4-Cl | H | 8-NH2 |
110 | 4-Br | H | 8-NH2 |
111 | 7-Cl | H | 8-NH2 |
112 | 7-Br | H | 8-NH2 |
113 | 9-Cl | H | 8-NH2 |
114 | 9-Br | H | 8-NH2 |
115 | 10-Cl | H | 8-NH2 |
116 | 10-Br | H | 8-NH2 |
117 | 1-Cl | H | 9-NH2 |
118 | 1-Br | H | 9-NH2 |
119 | 2-Cl | H | 9-NH2 |
120 | 2-Br | H | 9-NH2 |
121 | 3-F | H | 9-NH2 |
l22 | 3-Cl | H | 9-NH2 |
123 | 3-Br | H | 9-NH2 |
124 | 3-I | H | 9-NH2 |
125 | 4-Cl | H | 9-NH2 |
126 | 4-Br | H | 9-NH2 |
127 | 7-Cl | H | 9-NH2 |
128 | 7-Br | H | 9-NH2 |
129 | 8-F | H | 9-NH2 |
130 | 8-Cl | H | 9-NH2 |
131 | 8-Br | H | 9-NH2 |
132 | 8-I | H | 9-NH2 |
133 | 10-Cl | H | 9-NH2 |
134 | 10-Br | H | 9-NH2 |
135 | 1-Cl | H | 10-NH2 |
136 | 1-Br | H | 10-NH2 |
137 | 2-Cl | H | 10-NH2 |
138 | 2-Br | H | 10-NH2 |
139 | 3-F | H | 10-NH2 |
140 | 3-Cl | H | 10-NH2 |
141 | 3-Br | H | 10-NH2 |
142 | 3-I | H | 10-NH2 |
143 | 4-Cl | H | 10-NH2 |
144 | 4-Br | H | 10-NH2 |
145 | 7-Cl | H | 10-NH2 |
146 | 7-Br | H | 10-NH2 |
147 | 8-F | H | 10-NH2 |
148 | 8-Cl | H | 10-NH2 |
149 | 8-Br | H | 10-NH2 |
150 | 8-I | H | 10-NH2 |
151 | 9-Cl | H | 10-NH2 |
152 | 9-Br | H | 10-NH2 |
153 | 2-Cl | 3-Cl | 1-NH2 |
154 | 2-Cl | 4-Cl | 1-NH2 |
155 | 2-Cl | 7-Cl | 1-NH2 |
156 | 2-Cl | 8-Cl | 1-NH2 |
157 | 2-Cl | 9-Cl | 1-NH2 |
158 | 2-Cl | 10-Cl | 1-NH2 |
159 | 3-Cl | 4-Cl | 1-NH2 |
160 | 3-Cl | 7-Cl | 1-NH2 |
161 | 3-F | 8-F | 1-NH2 |
162 | 3-F | 8-Cl | 1-NH2 |
163 | 3-F | 8-Br | 1-NH2 |
164 | 3-F | 8-1 | 1-NH2 |
165 | 3-Cl | 8-F | 1-NH2 |
166 | 3-Cl | 8-Cl | 1-NH2 |
167 | 3-Cl | 8-Br | 1-NH2 |
168 | 3-Cl | 8-I | 1-NH2 |
169 | 3-Br | 8-F | 1-NH2 |
170 | 3-Br | 8-Cl | 1-NH2 |
171 | 3-Br | 8-Br | 1-NH2 |
172 | 3-Br | 8-I | 1-NH2 |
173 | 3-I | 8-F | 1-NH2 |
174 | 3-I | 8-Cl | 1-NH2 |
175 | 3-I | 8-Br | 1-NH2 |
176 | 3-I | 8-I | 1-NH2 |
177 | 3-Cl | 9-Cl | 1-NH2 |
178 | 3-Cl | 10-Cl | 1-NH2 |
179 | 4-Cl | 7-Cl | 1-NH2 |
180 | 4-Cl | 8-Cl | 1-NH2 |
181 | 4-Cl | 9-Cl | 1-NH2 |
182 | 4-Cl | 10-Cl | 1-NH2 |
183 | 7-Cl | 8-Cl | 1-NH2 |
184 | 7-Cl | 9-Cl | 1-NH2 |
185 | 7-Cl | 10-Cl | 1-NH2 |
186 | 8-Cl | 9-Cl | 1-NH2 |
187 | 8-Cl | 10-Cl | 1-NH2 |
188 | 9-Cl | 10-Cl | 1-NH2 |
189 | 1-Cl | 3-Cl | 2-NH2 |
190 | 1-Cl | 4-Cl | 2-NH2 |
191 | 1-Cl | 7-Cl | 2-NH2 |
192 | 1-Cl | 8-Cl | 2-NH2 |
193 | 1-Cl | 9-Cl | 2-NH2 |
194 | 1-Cl | 10-Cl | 2-NH2 |
195 | 3-Cl | 4-Cl | 2-NH2 |
196 | 3-Cl | 7-Cl | 2-NH2 |
197 | 3-F | 8-F | 2-NH2 |
198 | 3-F | 8-Cl | 2-NH2 |
199 | 3-F | 8-Br | 2-NH2 |
200 | 3-F | 8-I | 2-NH2 |
201 | 3-Cl | 8-F | 2-NH2 |
202 | 3-Cl | 8-Cl | 2-NH2 |
203 | 3-Cl | 8-Br | 2-NH2 |
204 | 3-Cl | 8-I | 2-NH2 |
205 | 3-Br | 8-F | 2-NH2 |
206 | 3-Br | 8-Cl | 2-NH2 |
207 | 3-Br | 8-Br | 2-NH2 |
208 | 3-Br | 8-I | 2-NH2 |
209 | 3-I | 8-F | 2-NH2 |
210 | 3-I | 8-Cl | 2-NH2 |
211 | 3-I | 8-Br | 2-NH2 |
212 | 3-I | 8-I | 2-NH2 |
213 | 3-Cl | 9-Cl | 2-NH2 |
214 | 3-Cl | 10-Cl | 2-NH2 |
215 | 4-Cl | 7-Cl | 2-NH2 |
216 | 4-Cl | 8-Cl | 2-NH2 |
217 | 4-Cl | 9-Cl | 2-NH2 |
218 | 4-Cl | 10-Cl | 2-NH2 |
219 | 7-Cl | 8-Cl | 2-NH2 |
220 | 7-Cl | 9-Cl | 2-NH2 |
221 | 7-Cl | 10-Cl | 2-NH2 |
222 | 8-Cl | 9-Cl | 2-NH2 |
223 | 8-Cl | 10-Cl | 2-NH2 |
224 | 9-Cl | 10-Cl | 2-NH2 |
225 | 3-a | 8-Cl | 4-NH2 |
226 | 3-Cl | 8-Br | 4-NH2 |
227 | 3-Br | 8-Cl | 4-NH2 |
228 | 3-Br | 8-Br | 4-NH2 |
229 | 3-Cl | 8-Cl | 7-NH2 |
230 | 3-a | 8-Br | 7-NH2 |
231 | 3-Br | 8-Cl | 7-NH2 |
232 | 3-Br | 8-Br | 7-NH2 |
233 | 3-Cl | 8-Cl | 9-NH2 |
234 | 3-Cl | 8-Br | 9-NH2 |
235 | 3-Br | 8-Cl | 9-NH2 |
236 | 3-Br | 8-Br | 9-NH2 |
237 | 3-Cl | 8-Cl | 10-NH2 |
238 | 3-Cl | 8-Br | 10-NH2 |
239 | 3-Br | 8-Cl | 10-NH2 |
240 | 3-Br | 8-Br | 10-NH2 |
在上述表中,优选的例示化合物序号可列举1、2、3、4、5、6、7、8、33、34、37、38、39、55、56、57、61、62、65、66、161、162、163、165、166、167、169、170、171、197、198、199、201、202、203、205、206或207。
更优选的例示化合物序号可列举1、2、3、4、6、7、8、34、38、56、57、61、65、66、166、171、202或207。
特别优选可列举:
例示化合物序号166:1-氨基-3,8-二氯-6(5H)-菲啶酮,
例示化合物序号171:1-氨基-3,8-二溴-6(5H)-菲啶酮,
例示化合物序号202:2-氨基-3,8-二氯-6(5H)-菲啶酮,
例示化合物序号207:2-氨基-3,8-二溴-6(5H)-菲啶酮。
本发明的神经营养蛋白作用增强剂的有效成分,具有前述通式(I)的化合物,是公知的或可按照公知方法容易地制备。{例如,WO96/19458、WO98/27975、US5,589,483,[J.Heterocyclic Chem.,7,313,(1970),出处同上,7,597(1970),],[Aust.J.Chem.,20,2037(1967)],[J.Med.Chem.,12,822(1969),出处同上37,2085(1994)],[Teteahedron Lett.,(36),3911(1968).],[Chem.Abstr.,119,48881(1993),出处同上,118,6533(1993),出处同上,112,181384(1990),出处同上,112,168840(1990),出处同上,112.97946(1990),出处同上,111,23003(1989),出处同上,107,123664(1987),出处同上,95,42866(1981),出处同上,95,42867(1981), 出处同上,85,46352(1976),出处同上,72,121337(1970),出处同上,68,59420(1968),出处同上,83,96982(1975), 出处同上,73,35200(1970),出处同上,71,91236(1969)]等}。
上式中,R1、R2和R3定义同前,R4表示硝基,R5表示羧基。
A方法是制备化合物(I)的方法。
步骤A1,是制备具有通式(III)化合物的步骤,可通过将具有通式(II)的化合物在乙酸中与硝酸反应得到。
反应温度可根据原料化合物变化,通常为-10℃~150℃,优选0℃~100℃。
反应时间可根据原料化合物、反应温度变化,通常为5分钟至12小时,优选10分钟至3小时。
反应完成后,各反应目的化合物可按照常规方法从反应混合物中收集。反应完成后,目的化合物析出时,或通过蒸除溶剂析出目的化合物时,可通过将其适当过滤,或,通过在反应完成后,向反应液中加水,加入与水不混溶的溶剂(例如,苯,乙醚,或乙酸乙酯等)萃取出目的化合物后,将萃取出的有机层用水洗涤,用无水硫酸镁等干燥后,蒸除溶剂得到目的化合物。所得目的化合物,如果需要,可通过重结晶、再沉淀、色谱法等进行进一步的纯化。
步骤A2是制备化合物(I)的步骤,可通过将化合物(III)
(1)在惰性溶剂中,在甲酸存在下,使用钯炭进行还原,
(2)在惰性溶剂中,浓盐酸存在下,用氯化锡还原,或
(3)在惰性溶剂中,在肼存在下(优选水合肼存在下),使用阮内镍或钯炭(优选钯炭)进行还原得到。
在步骤A2(1)、A2(2)、A2(3)中使用的溶剂,只要是对反应没有阻碍,可在某种程度上溶解起始物的物质都可以,对此没有特别的限制,例如,在步骤A2(1)和A2(2)中,可使用甲醇、乙醇、丙醇、异丙醇、丁醇或异丁醇等醇类,优选甲醇或乙醇。另一方面,在步骤A2(3)可使用例如己烷、环己烷、庚烷、轻石油或石油醚等脂肪烃类;苯、甲苯或二甲苯等芳香烃类;二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、氯苯或二氯苯等卤代烃类;乙醚、异丙醚、四氢呋喃、二噁烷、二甲氧乙烷或二乙二醇二甲醚等醚类;甲醇、乙醇、丙醇、异丙醇、丁醇或异丁醇等醇类;或上述有机溶剂的混合溶剂,优选芳香烃类、醇类、或芳香烃类和醇类的混合溶剂,更优选醇类(特别是乙醇)。
反应温度可根据原料化合物、试剂、溶剂的种类变化,在步骤A2(1)中,通常为-20℃~100℃(优选20℃~80℃),在A2(2)步骤中,通常为0℃~150℃(优选50℃~100℃),在步骤A2(3)中,通常为-20℃~150℃(优选20℃~50℃)。
反应时间可根据原料化合物、试剂、溶剂的种类、反应温度等变化,在A2(1)步骤中,通常为10分钟至24小时(优选30分钟至6小时),在步骤A2(2)中,通常为10分钟至24小时(优选30分钟至6小时),在步骤A2(3)中,通常为10分钟至24小时(优选30分钟至6小时)。
反应完成后,本步骤的目的化合物可按照常规方法从反应混合物中收集。例如,反应完成后,存在不溶物时,可通过适当过滤后,将滤液浓缩,或,通过向浓缩滤液得到的残渣中加入水后,将pH调至碱性,加入与水不混溶的溶剂(例如,苯,乙醚,或乙酸乙酯等)萃取出目的化合物后,将萃取有机层用水洗涤,用无水硫酸镁等干燥后,蒸除溶剂得到目的化合物。所得目的化合物,如果需要,可通过重结晶、再沉淀、色谱法等进行进一步的纯化。
B法是另一个制备化合物(I)的方法。
步骤B1是制备通式(V)化合物的步骤,可通过将通式(IV)化合物在碳酸钠水溶液中(优选10%碳酸钠水溶液中),在氢存在下与阮内镍反应得到。
反应温度可根据原料化合物、试剂等变化,通常为-10℃~100℃,优选10℃~50℃。
反应时间可根据原料化合物、试剂、反应温度等变化,通常为10分钟至10小时,优选30分钟至5小时。
反应完成后,本步骤的目的化合物可按照常规方法从反应混合物中收集。例如,反应完成后,过滤催化剂,蒸除溶剂,向所得残渣中加入水后,将水层调至酸性,过滤析出物,或反应完成后,过滤催化剂,用酸(优选盐酸)将反应液的pH调至酸性,加入与水不混溶的溶剂(例如,苯,乙醚,或乙酸乙酯等)萃取出目的化合物后,将萃取有机层用水洗涤,用无水硫酸镁等干燥后,蒸除溶剂得到目的化合物。所得目的化合物,如果需要,可通过重结晶、再沉淀、色谱法等进行进一步的纯化。
步骤B2是制备化合物(I)的步骤,可通过将通式(V)化合物在硫酸中,与叠氮化钠反应得到。
反应温度可根据原料化合物变化,通常为0℃~150℃,优选50℃~100℃。
反应时间可根据原料化合物、反应温度变化,通常为5分钟至6小时,优选10分钟至1小时。
反应完成后,本步骤的目的化合物可按照常规方法从反应混合物中收集。例如,在反应完成后,向反应液中加入水,过滤析出物,通过用碱水溶液处理(优选用氢氧化钾水溶液处理)可得到目的化合物。所得目的化合物,如果需要,可通过重结晶、再沉淀、色谱法等进行进一步的纯化。
C方法是制备化合物(III)的另一方法。
步骤C1是制备化合物(III)的步骤,可通过将通式(VI)化合物与多磷酸反应得到。
反应温度可根据原料化合物变化,通常为0℃~150℃,优选50℃~100℃。
反应时间可根据原料化合物、反应温度变化,通常为5分钟至6小时,优选10分钟至1小时。
反应完成后,本步骤的反应目的化合物可按照常规方法从反应混合物中收集。例如,反应完成后,目的化合物析出的情况或通过蒸除溶剂将目的化合物析出的情况下,可通过适当过滤收集,或反应完成后,向反应液中加入水,加入与水不混溶的溶剂(例如,苯,乙醚,或乙酸乙酯等)萃取出目的化合物后,将萃取有机层用水洗涤,用无水硫酸镁等干燥后,蒸除溶剂得到目的化合物。所得目的化合物,如果需要,可通过重结晶、再沉淀、色谱法等进行进一步的纯化。
D方法是制备化合物(III)的另一方法。
步骤D1是制备通式(VIII)的步骤,可将通式(VII)化合物在乙酸中与硝酸反应得到,可在与A1步骤相同的反应条件下进行。
步骤D2是制备化合物(III)的步骤,可通过将化合物(VIII)在硫酸中与叠氮化钠反应得到,可在与步骤B2相同的反应条件下进行。
原料化合物(II)、(IV)、和(VII)等是公知的或可按照公知方法容易地制备。[例如,[Svnthesis,4,192(1972)]、WO96/19458、WO98/27975、US5,589,483,[J.Heterocyclic Chem.,7,313,(1970),出处同上,7,597(1970),],[Aust.J.Chem.,20,2037(1967)],[J.Med.Chem.,7,31,(1964),出处同上12,822(1969),出处同上37,2085(1994)],[Teteahedron Lett.,(36),3911(1968).],发明实施的最佳方案
下面显示实施例和制剂例,对本发明进行更详细地说明,但本发明并不限于这些实施例。
实施例1
在大鼠肾上腺髓质由来的褐色肿瘤细胞株(PC12细胞)中的分化诱导
将PC12细胞悬浮于含有10%马血清和5%牛血清的DMEM培养基中,放入预先用骨胶原涂层的24孔板中。24小时后,交换培养基,添加如表1所示浓度的神经营养蛋白[人重组NGF或NT-3(AustralBiologicals)]和按照[J.Heterocyclic Chem.,7,597(1970)]中记载的方法合成的1-氨基-3,8-二氯-6(5H)-菲啶酮(例示化合物序号166),培养72小时。除去培养基,将细胞用2%戊二醛固定,在显微镜下观察细胞,计算具有比细胞体长的凸起的细胞的比例。结果如表2所示。表2具有突起的PC12细胞的比例(%)
(用各3例同一处理试验的平均值±标准误差表示)
神经营养蛋白(ng/ml) | 不添加化合物 | 例示化合物序号166(3μM) | 例示化合物序号:166(30μM) |
NGF(5) | 8±0.9 | 12±1.3 | 29±2.6 |
NGF(20) | 27±2.8 | 51±6.5 | 72±2.0 |
NGF(50) | 57±3.6 | 79±3.0 | 88±0.7 |
NT-3(100) | 2±0.6 | 62±0.2 | 73±3.6 |
通过添加NGF,PC12细胞的分化被诱导,具有神经突起的细胞比例增加,1-氨基-3,8-二氯-6(5H)-菲啶酮可进一步增加该比例,并增强NGF引起的PC12细胞的分化诱导。另外,NT-3在单独使用时不显示充分的分化诱导能力,但是,1-氨基-3,8-二氯-6(5H)-菲啶酮可显著增加其作用,可诱导PC12细胞的分化。该结果显示,1-氨基-3,8-二氯-6(5H)-菲啶酮具有显著的神经营养蛋白增强作用。
实施例2
在大鼠脊髓神经后根神经节感觉神经细胞的生存维持中的效果
从确定妊娠17天的SD大鼠(日本SLC)取出胎儿,在实体显微镜下摘出脊髓后根神经节。将其在磷酸缓冲生理盐水中用1mg/ml胶原酶、2mg/ml胰蛋白酶、2mg/mlDNase I处理后,分散于含有10%胎牛血清的MEM培养基中。将这样得到的感觉神经细胞悬浮液放入预先用昆布氨酸、聚D赖氨酸涂层的12孔板中(Becton DickinsonLabware)立即加入神经营养蛋白(NGF或NT-3)和1-氨基-3,8-二氯-6(5H)-菲啶酮(例示化合物序号:166)或6(5H)-菲啶酮(化合物A)。在第二天将培养基交换一半时,加入阿糖胞苷使之浓度达到10μM,将神经细胞以外的细胞灭死。此时加入神经营养蛋白和被检化合物,追加使其达到最初的浓度。再连续培养两天后,在显微镜下拍摄细胞照片,计算生存神经细胞的个数。其结果如表3和表4所示。表3生存的脊髓后根神经节的感觉神经细胞数(每mm2)
(用各3例同一处理试验的平均值±标准误差表示)表4生存的脊髓后根神经节的感觉神经细胞数(每mm2)
[用各3例同一处理试验的平均值±标准误差表示化合物A:6(5H)-菲啶酮]
神经营养蛋白(ng/ml) | 不添加化合物 | 例示化合物序号:166(3μM) |
不添加 | 5±1.2 | 24±1.6 |
NGF(1ng/ml) | 44±5.5 | 71±1.7 |
NT-3(100ng/ml) | 19±5.0 | 168±21.1 |
神经营养蛋白(ng/ml) | 不添加化合物 | 例示化合物序号:166(1μM) | 化合物A(1μM) |
不添加 | 3±0.4 | 11±4.0 | 6±0.8 |
NT-3(100ng/ml) | 33±4.9 | 133±1 3.1 | 37±3.6 |
1-氨基-3,8-二氯-6(5H)-菲啶酮可显著增强由于添加NGF和NT-3促进的脊髓后根神经节的感觉神经细胞的生存,但是在6(5H)-菲啶酮中完全看不到这样的作用。该结果显示,1-氨基-3,8-二氯-6(5H)-菲啶酮对末梢感觉神经有生存促进效果。
实施例3
在成熟大鼠海马、纹状体组织切片中神经营养蛋白应答的增强作用
将雄性SD大鼠(日本SLC)在麻醉下断头,摘出海马和纹状体。使用“Mcllwain组织切碎机”(Mickle Laboratory EngineeringCompany)将组织切为0.2×0.2mm的切片,在DMEM培养基中悬浮后,加入神经营养蛋白(NGF或NT-3)和1-氨基-3,8-二氯-6(5H)-菲啶酮,在37℃保温20分钟。将组织用冰冷却的Tris缓冲生理盐水(TBS)洗净后,在含有1%Triton X100、10μg/ml亮抑蛋白酶肽、10μg/ml抑蛋白酶肽、1mM的苯基甲基磺酰氟、1mM钒酸钠的TBS中,剧烈搅拌溶解。在14000g离心15分钟除去不溶物,使用蛋白分析试剂盒(Bio-Rad Laboratories,Ltd.)测定可溶化的组织萃取液中含有的蛋白质量。向配制的含有等量的蛋白质的萃取液中,加入作为神经营养蛋白受体的Trk特异性结合的抗Trk抗体C-14(SantaCruz Biotechnology Inc),在4℃混合16小时。这样形成组织液中含有的Trk受体与抗体的免疫复合体,将该复合体用蛋白A琼脂糖凝胶珠(Amersham Pharmacia Biotech)沉淀。用十二烷基硫酸钠-聚丙烯酰胺凝胶电泳法将收集的Trk蛋白质与其它蛋白质分离,Western污点分析法将其移至硝基纤维素膜上。该膜与识别磷酸化酪氨酸的抗体4G10(Upstate Biotechnology Inc)反应,在膜上固定化的Trk蛋白质的磷酸化酪氨酸的量通过增感化学发光试剂盒(Amersham Pharmacia Biotech)在膜上成为可视化。将该薄膜用数码相机拍照,用数字图像分析软件(Eastman Kodak Company)定量结合浓度。其结果如表5所示。表5在成熟大鼠脑组织中活化的神经营养蛋白受体Trk的量
(在纹状体中由于NGF引起活化的量作为100时的相对值)
组织 | NT-3(100ng/ml) | NT-3(100ng/ml)+例示化合物序号166(30μM) |
纹状体 | 12 | 68 |
海马 | 27 | 58 |
表5所示结果证明,1-氨基-3,8-二氯-6(5H)-菲啶酮,即使在实际成为神经变性疾病治疗对象的成体脑神经系统中,也具有神经营养蛋白增强作用。制剂例1硬胶囊
将50mg粉末状实施例7(d)的化合物、128.7mg的乳糖、70mg纤维素和1.3mg硬脂酸镁混合,通过60目的筛网后,将该粉末250mg加入3号明胶胶囊,制成胶囊剂。制剂例2片剂
将50mg粉末状实施例7(d)的化合物、124mg的乳糖、25mg纤维素和1mg硬脂酸镁混合,通过打片机打片,形成每片200mg的片剂。该片剂可根据需要进行糖衣。产业上的可利用性
含有本发明前述通式(I)的6(5H)-菲啶酮衍生物或其药理上可接受的盐的神经营养蛋白作用增强剂,由于具有优秀的神经营养蛋白作用增强活性,毒性弱,因此作为神经变性疾病的预防药或治疗药[阿尔海默氏类型的痴呆症、帕金森氏病、肌萎缩性脊髓侧索硬化症、杭廷顿氏舞蹈病或末梢感觉神经障碍(特别是阿尔海默氏类型的痴呆症)的预防药或治疗药(特别是治疗药),或脑缺血后的神经细胞死亡防止药或后遗症治疗药]是有用的。
将本发明的神经营养蛋白作用增强剂用作上述疾病的预防药或治疗药使用时,将具有前述通式(I)的6(5H)-菲啶酮衍生物或其药理上可接受的盐类本身或与适当的药理上可接受的赋形剂、稀释剂等混合,可通过片剂、胶囊剂、颗粒剂、散剂或糖浆剂口服或注射或栓剂等非口服给药。
这些制剂可使用赋形剂(可列举例如,乳糖、白糖、葡萄糖、甘露糖醇、山梨糖醇等糖衍生物;玉米淀粉、马铃薯淀粉、α淀粉和糊精等淀粉衍生物;结晶纤维素等纤维素衍生物;阿拉伯胶;葡聚糖和茁霉多糖等有机赋形剂;和轻质硅酸酐,合成硅酸铝、硅酸钙、偏硅酸铝酸镁等硅酸盐衍生物;磷酸氢钙等磷酸盐;碳酸钙等碳酸盐;硫酸钙等硫酸盐等无机赋形剂。)、润滑剂(可列举例如,硬脂酸、硬脂酸钙、硬脂酸镁等硬脂酸金属盐;滑石;胶体二氧化硅;蜂蜡,鲸蜡等蜡类;硼酸;己二酸;硫酸钠等硫酸盐;乙二醇;富马酸;苯甲酸钠;DL亮氨酸;十二烷基硫酸钠,十二烷基硫酸镁等十二烷基硫酸盐;硅酸酐,硅酸水合物等硅酸类;以及上述淀粉衍生物。)、粘合剂(可列举例如,羟丙基纤维素,羟丙基甲基纤维素,聚乙烯基吡咯烷酮,聚乙二醇,以及与前述赋形剂一样的化合物。)、崩解剂(可列举例如,低取代的羟丙基纤维素,羧甲基纤维素,羧甲基纤维素钙,内部交联的羧甲基纤维素钠等纤维素衍生物;羧甲基淀粉,羧甲基淀粉钠,交联的聚乙烯基吡咯烷酮等化学修饰的淀粉·纤维素类。)、乳化剂(可列举例如,膨润土,蜂胶等胶体粘土;氢氧化镁,氢氧化铝等金属氢氧化物;十二烷基硫酸钠,硬脂酸钙等阴离子表面活性剂;氯苄烷铵等阴离子表面活性剂;聚氧乙烯烷基醚,聚氧乙烯脱水山梨醇脂肪酸酯,蔗糖脂肪酸酯等非离子表面活性剂。)、稳定剂(可列举对羟基苯甲酸甲酯,对羟基苯甲酸丙等对羟基苯甲酸酯类;氯丁醇,苄醇,苯乙醇等醇类;氯苄烷铵;苯酚;甲酚等酚类;硫汞撒;脱氢醋酸;以及山梨酸等。)、矫味矫臭剂(可列举例如,通常使用的甜味剂,酸味剂,香料等。)、稀释剂等添加剂用公知的方法制造。
其使用量可根据症状、年龄等变化,对于成人在口服给药时,每次下限是1mg(优选10mg)、上限是1000mg(优选500mg),静脉内给药时,每次下限是0.5mg(优选5mg),上限是500mg(优选250mg),最好根据症状每天给药1至6次。
Claims (7)
2.在权利要求1中的神经营养蛋白作用增强剂,含有R1和R2可相同或不同,表示氢原子、氯原子或溴原子的化合物或其药理上可接受的盐。
3.在权利要求1中的神经营养蛋白作用增强剂,含有R1和R2是氯原子或溴原子的化合物或其药理上可接受的盐。
4.在权利要求1中的神经营养蛋白作用增强剂,含有
1-氨基-3,8-二氯-6(5H)-菲啶酮
1-氨基-3,8-二溴-6(5H)-菲啶酮
2-氨基-3,8-二氯-6(5H)-菲啶酮,或
2-氨基-3,8-二溴-6(5H)-菲啶酮或其药理上可接受的盐。
5.含有选自权利要求1-4任一项中记载的神经营养蛋白作用增强剂的神经变性疾病的预防药或治疗药。
6.权利要求5中记载的预防药或治疗药,其中,神经变性疾病是阿耳茨海默氏类型的痴呆症、帕金森氏病、肌萎缩性脊髓侧索硬化症、杭廷顿氏舞蹈病或末梢感觉神经障碍。
7.权利要求5中记载的脑缺血后的神经细胞死亡防止药或后遗症治疗药,其中,神经变性疾病是脑缺血后的神经细胞死亡或后遗症。
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CN102944674A (zh) * | 2012-11-05 | 2013-02-27 | 武汉远征世纪制药有限公司 | 一种检测TrkB受体pan-Tyr位点活性的ELISA试剂盒及其使用方法 |
CN107082761A (zh) * | 2017-04-17 | 2017-08-22 | 上海大学 | 菲啶酮或苯并菲啶酮衍生物及其合成方法 |
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US20020022636A1 (en) * | 1997-09-03 | 2002-02-21 | Jia-He Li | Oxo-substituted compounds, process of making, and compositions and methods for inhibiting parp activity |
WO1999011644A1 (en) * | 1997-09-03 | 1999-03-11 | Guilford Pharmaceuticals Inc. | Di-n-heterocyclic compounds, methods, and compositions for inhibiting parp activity |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN102944674A (zh) * | 2012-11-05 | 2013-02-27 | 武汉远征世纪制药有限公司 | 一种检测TrkB受体pan-Tyr位点活性的ELISA试剂盒及其使用方法 |
CN102944674B (zh) * | 2012-11-05 | 2014-10-22 | 武汉远征世纪制药有限公司 | 一种检测TrkB受体pan-Tyr位点活性的ELISA试剂盒及其使用方法 |
CN107082761A (zh) * | 2017-04-17 | 2017-08-22 | 上海大学 | 菲啶酮或苯并菲啶酮衍生物及其合成方法 |
CN107082761B (zh) * | 2017-04-17 | 2020-04-03 | 上海大学 | 菲啶酮或苯并菲啶酮衍生物及其合成方法 |
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KR20010112441A (ko) | 2001-12-20 |
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US20020119993A1 (en) | 2002-08-29 |
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AU3839200A (en) | 2000-11-02 |
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IL145867A0 (en) | 2002-07-25 |
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