CN103130790B - 一种3-苯并异噁唑-4-吲哚马来酰亚胺衍生物及其用途 - Google Patents
一种3-苯并异噁唑-4-吲哚马来酰亚胺衍生物及其用途 Download PDFInfo
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Abstract
本发明提供一类具有新型结构的3-苯并异噁唑-4-吲哚马来酰亚胺衍生物,该类化合物具有高效选择性的GSK-3β抑制活性,可用于治疗GSK-3β介导疾病如糖尿病、双向精神障碍、阿尔茨海默病、癌症、炎性疾病、抑郁症、神经保护和精神分裂症。本发明设计合理,制备方法简单实用。本发明结构通式如下:。
Description
(一)技术领域
本发涉及一种3-苯并异噁唑-4-吲哚马来酰亚胺衍生物及其用途。
(二)背景技术
糖原合成酶激酶-3 (glycogen synthas kinase-3,GSK-3) 于1980年被鉴定出来。它是一种多功能的丝氨酸/苏氨酸类蛋白激酶,在所有真核生物中都有分布。在哺乳动物中主要有2种亚型:GSK-3α和GSK-3β。其中GSK-3β通过参与胰岛素、Wnt/β-连环蛋白、Hedgehog以及 Notch等信号传导通路,在调控细胞的分化、代谢、凋亡及基因表达等方面都起着重要作用。这些信号传导途径的失调与2型糖尿病、阿尔茨海默病、癌症等疾病密切相关。例如在2型糖尿病中,过度表达的GSK-3β可以通过磷酸化糖原合成酶(GS)而抑制其活性,降低细胞外葡萄糖向糖原转化的能力;另外过度表达的GSK-3β也会使胰岛素受体底物-1(IRS-1)中多个丝氨酸残基磷酸化,消弱胰岛素信号的传导,导致靶组织对胰岛素的反应性降低,主要表现为脂肪和肌肉组织对葡萄糖的摄取减少。上述原因均会导致血糖浓度的上升。在阿尔茨海默尔氏病中,过表达的GSK-3β会导致Tau蛋白过度磷酸化,引起神经元纤维缠结,并会导致神经元死亡。因此,GSK-3β抑制剂可用于预防和治疗糖尿病和阿尔茨海默尔氏病等疾病。开发具有高活性和选择性的GSK-3β抑制剂已成为当前新药开发的热点。
迄今为止,已发现了多种类型的GSK-3β抑制剂,以小分子抑制剂居多,如 paullones类化合物、靛玉红类化合物、氨基嘧啶类化合物、Li离子和TDZD等。其中Li离子、TDZD为非ATP竞争型抑制剂,其余为ATP竞争型抑制剂。这些小分子抑制剂与ATP竞争活性口袋的作用方式大多为与催化区的 Asp133和Val135形成2至3个氢键,另外结构水也可作为水桥连接蛋白残基和小分子形成氢键。然而目前已开发的GSK-3β的抑制剂在抑制活性和选择性方面有待于进一步提高,开发具有新型结构的高效特异性GSK-3β抑制剂已成为当务之急。
(三)发明内容
本发明的目的是提供一类3-苯并异噁唑-4-吲哚马来酰亚胺类化合物,可用于治疗GSK-3β介导的疾病如糖尿病、双向精神障碍、阿尔茨海默病、癌症、炎性疾病、抑郁症、神经保护和精神分裂症等,化合物的结构通式如下:
其中:
R1,R3为一和二取代基,取代基独立的选自:氢,碳原子数为1-3的直链、支链和环烷基; 碳原子数为1-3的直链、支链和环烷氧基;卤素。
R2为氢, 碳原子数为1-5的直链、支链和环烷基; (CH2)nR4,其中n=1-5, R4为吡咯、咪唑、三氮唑、吗啉、四氢吡咯、哌啶,二甲氨基。
3-苯并异噁唑-4-吲哚马来酰亚胺类化合物可以由吲哚草酸酯衍生物(3)与1,2-苯并异噁唑-3-乙酰胺类衍生物(9)在叔丁醇钾的作用下缩合制得,反应式如下:
其中关键中间体吲哚草酸酯衍生物(3)可以各种取代吲哚为原料,经酰化、醇解和烷基化得到,反应式如下:
部分含氨基或取代氨基侧链的吲哚草酸酯衍生物还可以吲哚衍生物为原料,首先与二溴化物发生烷基化反应,接着经氨解、成盐和酰化反应制得,反应式如下:
另一个关键中间体1,2-苯并异噁唑-3-乙酰胺类衍生物可以各种取代的邻羟基苯乙酮为原料经环合、重排和氨解反应制得,反应式如下:
本发明设计合成的3-苯并异噁唑-4-吲哚马来酰亚胺类化合物是一类高效特异性GSK-3β抑制剂,适合于以GSK-3β为靶点的药物的开发。
(四)附图说明
图1为GSK-3β抑制剂对tau蛋白396位丝氨酸磷酸化的影响图
(五)具体实施方式
本发明结合实施例作进一步的说明。以下的实施例是说明本发明的,而不是以任何方式限制本发明。
.中间体及目标化合物的制备:
实施例1:2-(1H-吲哚-3-基)-2-氧代乙酸甲酯(2a)的制备
在三口烧瓶中加入3.0 g(0.026 mol)吲哚,30 mL无水乙醚,搅拌溶解,控制温度0-5 0C,缓慢滴加3.4 g(0.026 mol)草酰氯的乙醚(5 mL)溶液,滴完后保温反应1h, 然后降温至-25 0C左右,滴加16.3 g甲醇钠的甲醇溶液(17.5%,0.052 mol),滴完后搅拌30 min,然后将反应液倒入100 mL冰水中,过滤,水洗(3 × 10 mL),二氯甲烷洗(2 × 10 mL),干燥后得到4.5g淡黄色固体2a,收率:86.3%,mp: 208-210 0C。1H NMR (500 MHz, DMSO) δ 12.48 (brs, 1H), 8.46 (d, J = 3.5 Hz, 1H), 8.16 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 7.0 Hz, 1H), 7.32-7.26 (m, 2H), 3.90 (s, 3H).
实施例2:2-(5-甲氧基-1H-吲哚-3-基)-2-氧代乙酸甲酯(2b)的制备
合成方法同实施1,只是用5-甲氧基吲哚替换吲哚,得到淡黄色固体2b, 收率:71.0%,mp: 221-223 0C。1H NMR (500 MHz, DMSO) δ 12.34 (brs, 1H), 8.37 (d, J = 3.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 6.93 (dd, J = 9.0, 2.0 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H).
实施例3:2-(5-溴-1H-吲哚-3-基)-2-氧代乙酸甲酯(2c)的制备
合成方法同实施1,只是用5-溴吲哚替换吲哚,得到淡黄色固体2c,收率:55.3%,mp: 215-217 0C。1H NMR (500 MHz, DMSO) δ 12.59 (brs, 1H), 8.52 (d, J = 3.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (dd, J =8.5, 2.0 Hz, 1H), 3.90 (s, 3H).
实施例4:2-(6-溴-1H-吲哚-3-基)-2-氧代乙酸甲酯(2d)的制备
合成方法同实施1,只是用6-溴吲哚替换吲哚,得到淡黄色固体2d,收率:58.9%,mp: 207-209 0C。1H NMR (500 MHz, DMSO) δ 12.50 (brs, 1H), 8.50 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.43 (dd, J =8.5, 2.0 Hz, 1H), 3.90 (s, 3H).
实施例5:2-(6-氯-1H-吲哚-3-基)- 2-氧代乙酸甲酯(2e)的制备
合成方法同实施1,只是用6-氯吲哚替换吲哚,得到淡黄色固体4e,收率:62.8%,mp: 246-248 0C。1H NMR (500 MHz, DMSO) δ 12.52 (brs, 1H), 8.51 (d, J = 3.5 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.31 (dd, J =8.5, 2.0 Hz, 1H), 3.90 (s, 3H).
实施例6:2-(6-氟-1H-吲哚-3-基)-2-氧代乙酸甲酯(2f)的制备
合成方法同实施1,只是用6-氟吲哚替换吲哚,得到淡黄色固体4f,收率:60.3%,mp:182-184 0C。1H NMR (500 MHz, DMSO) δ 12.48 (brs, 1H), 8.48 (s, 1H), 8.15 (dd, J = 8.5, 5.5 Hz, 1H), 7.36 (dd, J = 9.5, 2.0 Hz, 1H), 7.15 (td, J = 9.5, 2.0 Hz,1H), 3.90 (s, 3H)
实施例7:3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a)的制备
在三口瓶中加入2.0 g(9.8 mmol)2a和100 mL无水四氢呋喃,搅拌溶解,加入2.7 g(12.3 mmol)Boc酸酐和0.01 g DMAP,室温反应3h。反应结束后将反应液减压浓缩,残留物用石油醚/乙酸乙酯重结晶,得到2.0 g白色固体3a,收率:67.1%, mp: 132-133 0C。1H NMR (500 MHz, CDCl3) δ 8.81 (s, 1H), 8.40 (dd, J = 6.5, 2.0 Hz, 1H), 8.17 (dd, 1H,J = 6.5, 1.5 Hz, 1H), 7.41-7.38 (m, 2H), 3.98 (s, 3H), 1.71 (s, 9H).
实施例8:2-(5-甲氧基-1-(3-吗啉丙基)-1H-吲哚-3-基)- 2-氧代乙酸甲酯(3b)的制备
在三口烧瓶中加入3.0 g(14.8 mmol)2b,30 ml无水DMF,搅拌溶解,将反应液降温至0 0C左右,分批加入0.51 g (14.8 mmol) 70%的NaH,加完后升至室温反应30 min,加入3.14 g(19.2 mmol)4-(3-氯丙基)吗啉,60 0C左右反应过夜,冷却后将反应液倒入150 mL中水中,乙酸乙酯萃取(3 × 100 mL),合并有机相,饱和食盐水洗(3 × 300 mL),无水硫酸钠干燥,减压浓缩,残余物用硅胶柱层析(乙酸乙酯:甲醇 = 50:1)提纯得2.8 g淡黄色固体3b,收率:64.7%, mp: 67-68 0C。1H NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 6.97 (dd, J = 9.0, 2.5 Hz, 1H), 4.28 (t, J =7.0 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.77-3.70 (m, 4H), 2.42-2.38 (m, 4H), 2.27 (t, J = 6.5 Hz, 2H), 2.06-2.01 (m, 2H).
实施例9:2-(5-溴-1-(3-吗啉丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3c)的制备
合成方法同实施例8,用2c替换2b,得到淡黄色固体3c,收率:56.6 %,mp: 112-113 0C。1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.5, 2.0 Hz, 1H), 4.29 (t, J = 7.0 Hz, 2H), 3.95 (s, 3H), 3.81-3.75 (m, 4H), 2.43-2.39 (m,4H), 2.25 (t, J = 6.5 Hz, 2H), 2.05-2.01 (m, 2H).
实施例10:2-(6-溴-1-(3-吗啉丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3d)的制备
合成方法同实施例8,用2d替换2b,得到淡黄色固体3d, 收率:54.9 %, mp: 102-103 0C。1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.67 (d, J =1.5 Hz, 1H), 7.45 (dd, J = 8.5, 1.5 Hz, 1H), 4.29 (t, J = 6.5 Hz, 2H), 3.95 (s, 3H), 3.86-3.69 (m, 4H), 2.43-2.39 (m, 4H), 2.25 (t, J = 6.5 Hz, 2H), 2.05-2.01 (m, 2H).
实施例11:2-(6-氯-1-(3-吗啉丙基)-1H-吲哚-3-基)- 2-氧代乙酸甲酯(3e)的制备
合成方法同实施例8,用2e替换2b,得到淡黄色固体3e, 收率:59.1 %,mp: 115-116 0C。1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 1.5 Hz, 1H), 7.30 (dd, J = 8.5, 1.5 Hz, 1H), 4.28 (t, J = 6.5 Hz, 2H), 3.94 (s, 3H), 3.80-3.70 (m, 4H), 2.43-2.37 (m, 4H), 2.24 (t, J = 6.5 Hz, 2H), 2.04-2.00 (m, 2H).
实施例12:2-(6-氟-1-(3-吗啉丙基)-1H-吲哚-3-基)- 2-氧代乙酸甲酯(3f)的制备
合成方法同实施例8,用2f替换2b,得到淡黄色固体3f, 收率:64.8 %,mp: 116-117 0C。1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 8.38 (dd, J = 8.5, 5.5 Hz, 1H), 7.16 (dd, J = 9.0, 2.0 Hz, 1H), 7.13–7.06 (m, 1H), 4.27 (t, J = 6.5 Hz, 2H), 3.95 (s, 3H), 3.79-3.70 (m, 4H), 2.43-2.39 (m, 4H), 2.27 (t, J = 6.5 Hz, 2H), 2.06-2.00 (m, 2H).
实施例13:2-(1-(2-吗啉乙基)-1H-吲哚-3-基)- 2-氧代乙酸甲酯(3g)的制备
合成方法同实施例8,用2a替换2b,4-(2-氯乙基)吗啉替换4-(3-氯丙基)吗啉,得到淡黄色固体3g, 收率:52.4 %,mp:116-117 0C。1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H), 8.49-8.44 (m, 1H), 7.43-7.39 (m, 1H), 7.38-7.35 (m, 2H), 4.29 (t, J = 6.5 Hz, 2H), 3.97 (s, 3H), 3.75-3.69 (m, 4H), 2.81 (t, J = 6.5 Hz, 2H), 2.54-2.47 (m, 4H).
实施例14:2-(1-(3-吗啉丙基)-1H-吲哚-3-基)- 2-氧代乙酸甲酯(3h)的制备
合成方法同实施例8,用2a替换2b,得到淡黄色固体3h, 收率:67.5%, mp:103-104 0C。1H NMR (500 MHz, CDCl3) δ 8.47-8.43 (m, 2H), 7.46 -7.41 (m, 1H), 7.38 -7.32 (m, 2H), 4.32 (t, J = 6.5 Hz, 2H), 3.95 (s, 3H), 3.78-3.72 (m, 4H), 2.44-2.38 (m, 4H), 2.28 (t, J = 6.5 Hz, 2H), 2.08-2.02 (m, 2H).
实施例15:1-(4-溴丁基)-1H-吲哚(4a)的制备
在三口烧瓶中加入5.0 g(43.0 mmol)吲哚和50 mL无水DMF,搅拌溶解,降温至0 0C 左右,分批加入1.8 g(51.6 mmol)70%的NaH,加完后升至室温反应30 min,将此反应液缓慢滴入46.4 g(215.0 mmol)1,4-二溴丁烷和10 mL无水DMF组成的溶液中,滴完后室温反应过夜, 反应完后将反应液倒入300 mL冰水中,乙酸乙酯萃取(3 × 100mL),合并有机相,饱和食盐水洗(3 × 300mL),无水硫酸钠干燥,减压浓缩,残余物用硅胶柱层析(石油醚:乙酸乙酯 = 80:1)提纯得到7.6 g无色油状液体4a, 收率:71.2%,1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.14-7.11 (m, 2H), 6.53 (d, J = 3.0 Hz, 1H), 4.19 (t, J = 7.0 Hz, 2H), 3.40 (t, J = 6.5 Hz, 2H), 2.07-2.00 (m, 2H), 1.90-1.85 (m, 2H).
实施例16:4-(4-(1-H吲哚-1-基)丁基)吗啉(5a)的制备
在三口瓶中加入2.0 g(7.9 mmol) 1-(4-溴丁基)-1H-吲哚 (4a), 6.9 g(79.0 mmol)吗啡啉、1.9 g(13.8 mmol)无水碳酸钾和30 mL无水DMF,50 0C反应6h,冷至室温后将反应液倒入200 mL水中,乙酸乙酯萃取(3 × 100mL),合并有机相,饱和食盐水洗(3 × 300mL),无水硫酸钠干燥,减压浓缩,残余物用硅胶柱层析(石油醚:乙酸乙酯:三乙胺=20:100:1)提纯得1.6 g无色油状液体5a, 收率:80.1%,1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24-7.21 (m, 1H), 7.14-7.11 (m, 2H), 6.51 (d, J = 3.0 Hz, 1H), 4.17 (t, J = 7.0 Hz, 2H), 3.71-3.70 (m, 4H), 2.39 -2.33 (m, 6H), 1.93-1.87 (m, 2H), 1.57-1.50(m, 2H).
实施例17:2-(1-(4-吗啉丁基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3i)的制备
在三口瓶加入1.3 g (5.0 mmol)4-(4-(1-H吲哚-1-基)丁基)吗啉(5a), 30 ml无水乙腈和30 ml无水乙醚,搅拌溶解后在室温下慢慢滴加5.5 ml (5.5 mmol) 1M HCl的1,4-二氧六环溶液,加完后室温下搅拌30 min,然后控制温度0-5 0C,滴加0.76 g(6.0mmol) 草酰氯和5 ml 无水乙醚组成的溶液,加完后保温反应2h左右, 然后在0-5 ℃滴加10 ml无水甲醇,加完后升至室温反应2h,然后将反应液倒入冰的碳酸氢钠溶液中,乙酸乙酯萃取(3 × 50 mL),合并有机相,饱和食盐水洗(150 mL),无水硫酸钠干燥,减压浓缩,残余物用硅胶柱层析(乙酸乙酯:甲醇 = 50:1)提纯得0.94 g淡黄色固体3i,收率:54.6%, mp:84-85 0C。1H NMR (500 MHz, CDCl3) δ 8.48-8.44(m, 1H), 8.40 (s, 1H), 7.44-7.38 (m, 1H), 7.39-7.34 (m, 2H), 4.23 (t, J = 7.5 Hz, 2H), 3.97 (s, 3H), 3.73-3.65 (m, 4H), 2.39-2.34 (m, 6H), 2.02 -1.92 (m, 2H), 1.59-1.51(m, 2H).
实施例18:2-(1-(2-(1H-咪唑-1-基)乙基)-1H-吲哚-3-基)- 2-氧代乙酸甲酯(3j)的制备
合成方法同实施例8,用2a替换2b,1-(2-氯乙基)-1H-咪唑替换4-(3-氯丙基)吗啉,得到淡黄色固体3j, 收率:48.6%, mp:120-121 0C。1H NMR (500 MHz, CDCl3) δ 8.49 -8.43 (m, 1H), 8.01 (s, 1H), 7.41-33 (m, 2H), 7.25-7.23 (m, 1H), 7.22 (s, 1H), 7.04 (s, 1H), 6.65 (s, 1H), 4.52 (t, J = 6.0 Hz, 2H), 4.42 (t, J = 6.0 Hz, 2H), 3.93 (s, 3H).
实施例19:2-(1-(3-(1H-咪唑-1-基)丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3k)的制备
合成方法同实施例8,用2a替换2b,1-(3-氯丙基)-1H-咪唑替换4-(3-氯丙基)吗啉,得到淡黄色固体3k, 收率:52.8%,mp: 72-73 0C。 1H NMR (500 MHz, CDCl3) δ 8.51-8.46 (m, 1H), 8.36 (s, 1H), 7.53 (s, 1H), 7.42-7.34 (m, 2H), 7.30-7.27 (m, 1H), 7.17 (s, 1H), 6.96 (s, 1H), 4.20 (t, J = 7.0 Hz, 2H), 4.00 (t, J = 7.0 Hz, 2H), 3.98 (s, 3H), 2.48-2.40 (m, 2H).
实施例20:2-(1-(4-(1H-咪唑-1-基)丁基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3l)的制备
合成方法同实施例8,用2a替换2b,1-(4-氯丁基)-1H-咪唑替换4-(3-氯丙基)吗啉,得到淡黄色粘稠状液体, 收率:41.6%。1H NMR (500 MHz, CDCl3) δ 8.50-8.42 (m, 1H), 8.35 (s, 1H), 7.44 (s, 1H), 7.38 -7.32 (m, 3H), 7.06 (s, 1H), 6.85 (s, 1H), 4.19 (t, J = 7.0 Hz, 2H), 3.96 (s, 3H), 3.93 (t, J = 7.0 Hz, 2H), 1.95-1.86 (m, 2H), 1.87-1.77 (m, 2H).
实施例21:2-(1-(3-(1H-1,2,4-三氮唑-1-基)丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3m)的制备
合成方法同实施例8,用2a替换2b,1-(3-氯丙基)-1H-1,2,4-三氮唑替换4-(3-氯丙基)吗啉,得到淡黄色固体3m,收率:64.5%,mp: 98-99 0C。1H NMR (500 MHz, CDCl3) δ 8.49-8.45 (m, 1H), 8.44 (s, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.40-7.36 (m, 2H), 7.35- 7.32 (m, 1H), 4.31 (t, J = 7.0 Hz, 2H), 4.18 (t, J = 7.0 Hz, 2H), 3.97 (s, 3H), 2.59-2.49 (m, 2H).
实施例22:2-(1-(3-(哌啶-1-基)丙基)-1H-吲哚-3-基-2-氧代乙酸甲酯(3n)的制备
合成方法同实施例8,用2a替换2b,1-(3-氯丙基)哌啶替换4-(3-氯丙基)吗啉,得到淡黄色固体3n,收率: 52.4%,mp:66-67 0C。1H NMR (500 MHz, DMSO) δ 8.47 (s, 1H), 8.20 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.39-7.27 (m, 2H), 4.34 (t, J = 7.0 Hz, 2H), 3.90 (s, 3H), 2.29-2.18 (m, 4H), 2.13 (t, J = 6.5 Hz, 2H), 1.96-1.90 (m, 2H), 1.55- 1.41 (m, 4H), 1.40-1.30 (m, 2H).
实施例23:2-(1-(3-(四氢吡咯-1-基)丙基-1H-吲哚-3-基)-2-氧代乙酸甲酯(3o)的制备
合成方法同实施例8,用2a替换2b,1-(3-氯丙基)四氢吡咯替换4-(3-氯丙基)吗啉,得到淡黄色固体3o,收率:48.5%,mp: 56-58 0C。1H NMR (500 MHz, DMSO) δ 8.50 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.39 -7.27 (m, 2H), 4.37 (t, J = 7.0 Hz, 2H), 3.90 (s, 3H), 2.42-2.39 (m, 4H), 2.35 (t, J = 6.5 Hz, 2H), 2.00-1.92 (m, 2H), 1.72-167 (m, 4H).
实施例24:2-(1-甲基-1H-吲哚-3-基)-2-氧代乙酸甲酯(3p)的制备
在三口烧瓶中加入1.0 g(4.9 mmol)2a和10 mL无水DMF,降温至0 0C,加入0.17 g(4.9 mmol)70%的NaH,加完后升至室温反应30 min,然后降温至0 0C左右,滴加0.83g(5.9 mmol)CH3I,滴完后升至室温反应1h,反应结束后,将反应液倒入100 mL冰水中,乙酸乙酯萃取(3 × 50mL),合并有机相,饱和食盐水洗(3 × 150mL),无水硫酸钠干燥,减压浓缩,残余物用硅胶柱层析(石油醚:乙酸乙酯=3:1)提纯得0.81g白色固体3p,收率:76.4%,mp: 73-74 0C。1H NMR (500 MHz, CDCl3 ) δ 8.51-8.42 (m, 1H), 8.35 (s, 1H), 7.39- 7.36 (m, 3H), 3.96 (s, 3H), 3.88 (s, 3H).
实施例25:2-(1-丁基-1H-吲哚-3-基)-2-氧代乙酸甲酯(3q)的制备
合成方法同实施例24,用溴丁烷替换碘甲烷,得到白色固体5q, 收率:80.5%,mp: 81-82 0C。1H NMR (500 MHz, CDCl3) δ 8.48-8.44 (m, 1H), 8.39 (s, 1H), 7.45-7.38 (m, 1H), 7.37 -7.32 (m, 2H), 4.20 (t, J = 7.5 Hz, 2H), 3.96 (s, 3H), 1.86-1.82 (m, 2H), 1.42-1.38 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H).
实施例26:2-(1-(3-(叔丁基二甲基硅基)氧)丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3r)的制备
合成方法同实施例8,用2a替换2b,3-溴丙基叔丁基二甲基硅烷替换4-(3-氯丙基)吗啉,得到淡黄色固体5r,收率:62.5 %,mp: 69-71 0C。1H NMR (500 MHz, CDCl3) δ 8.40-8.36 (m, 1H), 8.31 (s, 1H), 7.39-7.34 (m, 1H), 7.31-7.24 (m, 2H), 4.27 (t, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.52 (t, J = 5.5 Hz, 2H), 2.06-1.92 (m, 2H), 0.87 (s, 9H), 0.01 (s, 6H).
实施例27:4-羟基香豆素(7a)的制备
在三口瓶中加入2.1 g (60 mmol)70%的NaH和34 mL无水甲苯,室温下缓慢滴加1.63 g(12.0 mmol)邻羟基苯乙酮,加完后室温搅拌1h,然后滴加2 mL碳酸二乙酯和7 mL无水甲苯组成的溶液,滴完后加热回流5h,冷却,反应液减压浓缩,残余物用20 mL冰水溶解,2NHCl酸化,抽滤,滤饼用水洗涤(3 × 10mL),干燥得粗品,用少量无水乙醇重结晶,得1.74g白色固体7a,收率:91.5%, mp: 212-213 0C(Lit. 213-215 0C)。
实施例28:2-(苯并[d]异噁唑-3-基)乙酸(8a)的制备
在三口瓶中加入20 mL无水甲醇和0.99 g(42.9mmol)金属钠,待钠和甲醇反应完全后加入2.98 g(42.9 mmol)盐酸羟胺,搅拌15min,然后加入2.0 g(12.3 mmol) 4-羟基香豆素7a,加热回流12h,反应完后减压浓缩,残留物中加入50 mL水溶解,水溶液用NaHCO3碱化,乙醚萃取 (3 × 20 mL),水层用2NHCl酸化,析出固体,过滤,干燥得0.87g 白色固体8a,收率:39.9%,mp: 125-126 0C(Lit. 122-124 0C)。
实施例29:2-(苯并[d]异噁唑-3-基)乙酰胺(9a)的制备
在三口瓶中加入化合物1.5 g(8.5 mmol)8a、60 mL无水DCM、19.2 mL DMF、1.4 g(9.3 mmol)1-羟基苯并三唑(HOB)和3.8 g(18.6 mmol)二环己基碳二亚胺,室温反应1h,然后加入36.1 g(33.9 mmol)氨的1,4-二氧六环溶液,室温反应过夜。过滤,滤液倒入100 mL水中,水层用二氯甲烷萃取(3 × 30 mL),合并有机层,有机相用饱和食盐水洗(3 × 100 mL),无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用硅胶柱层析(乙酸乙酯:甲醇=100:1)提纯,得到0.8 g白色固体9a,收率:53.7%,mp:148-149 0C(Lit.147-149 0C)。
实施例30:3-(苯并[d]异噁唑-3-基)-4-(1H-吲哚-3-基)-1H-吡咯-2,5-酮(10a)的制备
在三口瓶中加入49 mg (0.28 mmol) 1,2-苯并异噁唑-3-乙酰胺(9a)、109 mg (0.36 mmol) 3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a)和10 mL无水THF,搅拌溶解,控制温度-10 0C左右, 缓慢滴入94.0 mg (0.84 mmol)叔丁醇钾和10 mL无水THF组成的溶液,滴完后升至室温反应2h, 然后加入5mL浓盐酸, 搅拌30 min,再将反应液倒入50 mL冰水中,用碳酸氢钠中和至碱性,乙酸乙酯萃取(3 × 30 mL),合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物用硅胶柱层析(二氯甲烷:甲醇=50:1)提纯,得到40 mg红色固体10a,收率:44.4%, 熔点:227-228 0C。1H NMR (500 MHz, DMSO) δ 12.14 (brs,1H), 11.44 (brs, 1H), 8.23 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.69-7.58 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.08-7.04 (m, 1H), 6.72 (t, J = 8.0 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H). ESI-MS: m/z [M+H]+ 330. Anal. Calcd for C19H11N3O3: C, 69.30; H, 3.37; N, 12.76. Found: C, 69.06; H, 3.45; N, 12.64.
实施例31:3-(苯并[d]异噁唑-3-基)-4-(5-甲氧基-1-(3-吗啉丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10b)的制备
操作过程同实施例30,用2-(5-甲氧基-1-(3-吗啉丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3b)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯 (3a),得到红色固体10b,收率:11.6%, 熔点:191-193 0C。1H NMR (500 MHz, CDCl3) δ 8.27 (s, 1H), 7.97 (brs, 1H), 7.66-7.62 (m, 2H), 7.57 (td, J = 8.0, 1.5 Hz, 1H), 7.25-7.23 (m, 2H), 6.76 (dd, J = 9.0, 2.5 Hz, 1H), 5.94 (d, J = 2.5 Hz, 1H), 4.29 (t, J = 6.5 Hz, 2H), 3.77 (t, J = 4.5 Hz, 4H), 3.11 (s, 3H), 2.48-2.42 (m, 4H), 2.32 (t, J = 6.5 Hz, 2H), 2.06-2.01(m, 2H). ESI-MS: m/z [M+H]+ 487. Anal. Calcd for C27H26N4O5: C, 66.65; H, 5.39; N, 11.52. Found: C, 66.76; H, 5.47; N, 11.62.
实施例32:3-(苯并[d]异噁唑-3-基)-4-(5-溴-1-(3-吗啉丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10c)的制备
操作过程同实施例30,用2-(5-溴-1-(3-吗啉丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3c)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a), 得到红色固体10c,收率:21.3%, 熔点:180-182 0C。1H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 7.97(brs, 1H), 7.68 (t, J = 8.5 Hz, 2H), 7.61 (td, J = 8.5, 1.5 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.26-7.25 (m, 2H), 6.81 (s, 1H), 4.29 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 4.5 Hz , 4H), 2.42-2.39 (m, 4H), 2.30 (t, J = 6.6 Hz, 2H), 2.03-2.01 (m, 2H). ESI-MS: m/z [M+H]+ 535. Anal. Calcd for C26H23N4O4Br: C, 58.33; H, 4.33; N, 10.46. Found: C, 58.21; H, 4.49; N, 10.53.
实施例33:3-(苯并[d]异噁唑-3-基)-4-(6-溴-1-(3-吗啉丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10d)的制备
操作过程同实施例30,用2-(6-溴-1-(3-吗啉丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3d)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10d,收率:12.7%, 熔点:226-228 0C。1H NMR (500 MHz, CDCl3) δ 8.27 (s, 1H), 7.97(brs, 1H), 7.68-7.64 (m, 2H), 7.62(d, J =2.0 Hz, 1H), 7.59(td, J = 7.0, 1.0 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 6.99 (dd, J = 8.0, 2.0Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.29 (t, J = 6.5 Hz, 2H), 3.79 (t, J = 4.5 Hz, 4H), 2.47-2.40 (m, 4H), 2.29 (t, J = 6.5Hz, 2H), 2.05-2.02 (m, 2H). ESI-MS: m/z [M+H]+ 535. Anal. Calcd for C26H23N4O4Br: C, 58.33; H, 4.33; N, 10.46. Found: C, 58.39; H, 4.51; N, 10.42.
实施例34:3-(苯并[d]异噁唑-3-基)-4-(6-氯-1-(3-吗啉丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10e)的制备
操作过程同实施例30,用2-(6-氯-1-(3-吗啉丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3e)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10e,收率:11.5%, 熔点:216-218 0C。1H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 7.97 (brs, 1H), 7.65 (t, J = 7.5 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 6.85 (dd, J = 8.5, 1.5 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 4.29 (t, J = 6.5 Hz, 2H), 3.78 (t, J = 4.5 Hz, 4H), 2.45-2.41 (m, 4H), 2.29 (t, J = 6.5 Hz, 2H), 2.06-2.02 (m, 2H). ESI-MS: m/z [M+H]+ 491. Anal. Calcd for C26H23N4O4Cl: C, 63.61; H, 4.72; N, 11.41. Found: C, 63.52; H, 4.64; N, 11.51.
实施例35:3-(苯并[d]异噁唑-3-基)-4-(6-氟-1-(3-吗啉丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10f)的制备
操作过程同实施例30,用2-(6-氟-1-(3-吗啉丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3f)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10f,收率:29.9%,熔点:219-221 0C。1H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 8.06 (brs, 1H), 7.66-7.66 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 9.5 Hz, 1H), 6.68-6.62 (m, 2H), 4.27 (t, J = 6.5 Hz, 2H), 3.77 (t, J = 4.5 Hz, 4H), 2.46-2.41 (m, 4H), 2.31 (t, J = 6.5 Hz, 2H), 2.06-2.03 (m, 2H). ESI-MS: m/z [M+H]+ 475. Anal. Calcd for C26H23N4O4F: C, 65.81; H, 4.89; N, 11.81. Found: C, 65.99; H, 4.75; N, 11.87.
实施例36:3-(苯并[d]异噁唑-3-基)-4-(1-(2-吗啉乙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10g)的制备
操作过程同实施例30,只是用2-(1-(2-吗啉乙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3g)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10g,收率:24.0%, 熔点:205-207 0C。1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 7.79 (brs, 1H), 7.57(t, J = 7.5 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.31 (t, J = 6.5Hz, 2H), 3.73 (t, J = 7.5 Hz , 4H), 2.82 (t, J = 6.5 Hz, 2H), 2.56-2.42 (m, 4H). ESI-MS: m/z [M+H]+ 443. Anal. C25H22N4O4: C, 67.86; H, 5.01; N, 12.66. Found: C, 67.96; H, 5.11; N, 12.85.
实施例37:3-(苯并[d]异噁唑-3-基)-4-(1-(3-吗啉丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10h)的制备
操作过程同实施例30,只是用2-(1-(3-吗啉丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3h)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10h,收率:38.1%, 熔点:197-198 0C。1H NMR (500 MHz, CDCl3) δ 8.89(brs, 1H), 8.33 (s, 1H), 7.66-7.60 (m, 2H), 7.55 (td, J = 7.0, 1.0 Hz 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.86 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 4.32 (t, J = 6.5 Hz, 2H), 3.79 (t, J = 4.5 Hz, 4H), 2.52-2.42 (m, 4H), 2.37 (t, J = 7.0 Hz, 2H), 2.13-2.05 (m, 2H). ESI-MS: m/z [M+H]+ 457. Anal. C26H24N4O4: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.69; H, 5.25; N, 12.41.
实施例38: 3-(苯并[d]异噁唑-3-基)-4-(1-(4-吗啉丁基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10i)的制备
操作过程同实施例30,用2-(1-(4-吗啉丁基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3i)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10i,收率:22.6%, 熔点:89-91 0C。1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 8.25(brs, 1H), 7.66-7.62 (m, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.18 (t, J = 7.0 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.23 (t, J = 6.5 Hz, 2H), 3.71 (t, J = 4.5 Hz, 4H), 2.45-2.35 (m, 6H), 2.01-1.90 (m, 2H), 1.62-1.55 (m, 2H). ESI-MS: m/z [M+H]+ 471. Anal. C27H26N4O4: C, 68.92; H, 5.57; N, 11.91. Found: C, 68.75; H, 5.62; N, 11.82.
实施例39:3-(苯并[d]异噁唑-3-基)-4-(1-(2-(1H-咪唑-1-基)乙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10j)的制备
操作过程同实施例30,用2-(1-(2-(1H-咪唑-1-基)乙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3j)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10j,收率:16.7%, 熔点:234-235 0C。1H NMR (500 MHz, DMSO) δ11.43(brs, 1H), 8.05 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.62 (td, J =8.5, 1.0 Hz, 1H), 7.50 (d, J = 8.0Hz, 1H), 7.46 (d, J = 8.0Hz, 1H),7.35 (s, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.10 (s, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.83 (s, 1H), 6.72 (t, J = 7.5 Hz, 1H), 6.46 (d, J = 8.0 Hz, 1H), 4.69 (t, J = 6.0 Hz, 2H), 4.42 (t, J = 6.0 Hz, 2H). ESI-MS: m/z [M+H]+ 424. Anal. C24H17N5O3: C, 68.08; H, 4.05; N, 16.54. Found: C, 68.22; H, 4.01; N, 16.72.
实施例40:3-(苯并[d]异噁唑-3-基)-4-(1-(3-(1H-咪唑-1-基)丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10k)的制备
操作过程同实施例30,用2-(1-(3-(1H-咪唑-1-基)丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3k)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10k,收率:16.1%, 熔点:208-210 0C。1H NMR (500 MHz, CDCl3) δ8.32 (brs, 1H), 8.24 (s, 1H), 7.67 (d, J = 8.5 Hz,1H), 7.85 (d, J = 8.5 Hz,1H), 7.61-7.53 (m, 2H), 7.29 (t, J = 7.0 Hz, 1H), 7.24-7.18 (m, 2H), 7.17 (s, 1H), 6.98 (s, 1H), 6.94 (td, J = 7.0, 1.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.20 (t, J = 6.5 Hz, 2H), 3.99 (t, J = 6.5 Hz, 2H), 2.47-2.40 (m, 2H). ESI-MS: m/z [M+H]+ 438. Anal. C25H19N5O3: C, 68.64; H, 4.38; N, 16.01. Found: C, 68.81; H, 4.35; N, 16.26.
实施例41:3-(苯并[d]异噁唑-3-基)-4-(1-(4-(1H-咪唑-1-基)丁基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10l)的制备
操作过程同实施例30,用2-(1-(4-(1H-咪唑-1-基)丁基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3l)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10l,收率:15.6%, 熔点:203-205 0C。1H NMR (500 MHz, CDCl3) δ 8.35(brs, 1H), 8.24 (s, 1H), 7.69-7.63 (m, 2H), 7.57 (td, J = 7.0, 1.5Hz, 1H), 7.47 (s, 1H), 7.29 (d, J = 6.0 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.08 (s, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.87 (s, 1H), 6.78(d, J = 8.0 Hz, 1H), 4.21 (t, J = 6.5 Hz, 2H), 3.92 (t, J = 6.5 Hz, 2H), 1.95-1.87 (m, 2H), 1.86 -1.80 (m, 2H). ESI-MS: m/z [M+H]+ 452. Anal. C26H21N5O3: C, 69.17; H, 4.69; N, 15.51. Found: C, 68.96; H, 4.65; N, 15.73.
实施例42:3-(苯并[d]异噁唑-3-基)-4-(1-(3-(1H-1,2,4-三氮唑-1-基)丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10m)的制备
操作过程同实施例30,只是用2-(1-(3-(1H-1,2,4-三氮唑-1-基)丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3m)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10m,收率:21.3%, 熔点:214-216 0C。 1H NMR (500 MHz, DMSO) δ 11.46 (brs, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.66-7.61(m, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.79 (t, J = 8.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.36 (t, J = 6.5 Hz, 2H), 4.20 (t, J = 6.5 Hz, 2H), 2.36-2.28 (m, 2H). ESI-MS: m/z [M+H]+ 439. Anal. C24H18N6O3: C, 65.75; H, 4.14; N, 19.17. Found: C, 65.58; H, 4.12; N, 19.34.
实施例43:3-(苯并[d]异噁唑-3-基)-4-(1-(3-(哌啶-1-基)丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10n)的制备
操作过程同实施例30,只是用2-(1-(3-(哌啶-1-基)丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3n)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10n,收率:15.6%, 熔点:73-75 0C。1H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.55 (td, J = 8.0, 1.0 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.85 (t, J = 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 4.31 (t, J = 7.0 Hz, 2H), 2.55-2.35 (m, 6H), 2.17-2.10 (m, 2H), 1.73-1.61 (m, 4H), 1.52-1.47 (m, 2H). ESI-MS: m/z [M+H]+ 455. Anal. C27H26N4O3: C, 71.35; H, 5.77; N, 12.33. Found: C, 71.13; H, 5.63; N, 12.46.
实施例44:3-(苯并[d]异噁唑-3-基)-4-(1-(3-(四氢吡咯-1-基)丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10o)的制备
操作过程同实施例30,只是用2-(1-(3-(四氢吡咯-1-基)丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3o)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10o,收率:20.8%, 熔点:171-173 0C。1H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 7.63 (d, J = 8.5, 1H), 7.59 (d, J = 8.5, 1H), 7.54 (td, J = 8.5, 1H, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 4.32 (t, J = 7.0Hz, 2H), 2.65-2.55 (m, 6H), 2.25-2.15 (m, 2H), 1.89-1.83 (m, 4H). ESI-MS: m/z [M+H]+ 441. Anal. C26H24N4O3: C, 70.89; H, 5.49; N, 12.72. Found: C, 70.68; H, 5.34; N, 12.97.
实施例45:3-(苯并[d]异噁唑-3-基)-4-(1-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10p)的制备
操作过程同同实施例30,只是用2-(1-甲基-1H-吲哚-3-基)-2-氧代乙酸甲酯(3p)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10p,收率:27.8%, 熔点:221-222 0C。1H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H),7.81 (brs,1H), 7.65 (d, J = 9.5 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H). ESI-MS: m/z [M+H]+ 344. Anal. C20H13N3O3: C, 69.96; H, 3.82; N, 12.24. Found: C, 70.11; H, 3.77; N, 12.05.
实施例46:3-(苯并[d]异噁唑-3-基)-4-(1-丁基-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10q)的制备
操作过程同实施例30,用2-(1-丁基-1H-吲哚-3-基)-2-氧代乙酸甲酯(3q)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a), 得到红色固体10q,收率:35.2%, 熔点:180-182 0C。1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.82 (brs,1H), 7.65 (d, J =8.5, 1H), 7.61 (d, J =8.5, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.75 (d, J =7.5 Hz, 1H), 4.22 (t, J = 7.5, 2H), 1.95-1.83 (m, 2H), 1.42-1.37 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H). ESI-MS: m/z [M+H]+ 386. Anal. C23H19N3O3: C, 71.67; H, 4.97; N, 10.90. Found: C, 71.55; H,4.84; N, 11.03.
实施例47:3-(苯并[d]异噁唑-3-基)-4-(1-(3-羟丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮(10r)的制备
操作过程同实施例30,用2-(1-(3-羟丙基)-1H-吲哚-3-基)-2-氧代乙酸甲酯(3r)代替3-(2-甲氧基-2-乙酰羰基)-1H-吲哚-1-叔丁基羧酸酯(3a),得到红色固体10r,收率:10.0%。熔点:219-220 0C。1H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 7.64 (t, J = 8.0 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.24 (t, J =8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 4.39 (t, J =7.0 Hz, 2H), 3.67 (t, J = 7.0 Hz, 2H), 2.17-2.10 (m, 2H). ESI-MS: m/z [M+H]+ 388. Anal. C22H17N3O4: C, 68.21; H, 4.42; N, 10.85. Found: C, 68.07; H, 4.51; N, 11.09.
2.目标化合物对GSK-3β活性及选择性测试:
(1)酶水平的GSK-3β抑制活性测定:
通过大肠杆菌表达系统表达C端6×His融合GSK-3β蛋白,并经过Ni2+亲和纯化方法纯化,激酶活性检测采用10L反应体系的Invitrogen的Z-LYTE激酶试剂盒,每个样品3复孔。利用酶标仪Envision多标记微孔板检测仪 (PerkinElmer公司产品)检测400 nm激发下 445 nm以及 520 nm处的荧光强度,利用试剂盒提供的公式计算得到样品孔的底物磷酸化率,以此反应激酶活性高低。抑制率大于50%的用GraphPad Prism 软件拟合得出IC50值, 实验中采用的阳性化合物为staurosporine,部分测试结果见下表1:
表1目标化合物对GSK-3β的抑制活性
(2) 目标化合物对GSK-3β的选择性
我们选择性了部分代表性的化合物, 在0.8 ug的浓度下检测了它们对PKCE,JAK2, BRAF, IKK2等激酶的抑制率,对于抑制率大于50%的化合物进一步测定了其IC50,实验中采用的阳性化合物为staurosporine, 测试结果见下表2:
表2 目标化合物对GSK-3β的选择性
结果表明,虽然Staurosporine对GSK-3β具有很强的抑制活性(IC50=0.20 μm),但其对受试的其它酶如PKCE, JAK2, BRAF, IKK2 和DraK2同样具有很强的抑制活性, 缺少选择性。本发明设计合成的化合物10c, 10j, 10k和10p对GSK-3β具有很强的抑制活性,对受试的其它酶几乎没有抑制活性,显示了很好的选择性。
细胞水平的GSK-3β抑制活性的测定
老年痴呆症患者的神经元细胞,能够分泌较多的A-beta淀粉样蛋白。该蛋白诱发神经元tau蛋白的过度磷酸化,从而引起神经元纤维缠结现象,神经元纤维缠结是老年痴呆症的主要症状。GSK-3β是磷酸化tau蛋白的主要激酶,该激酶对tau蛋白396位丝氨酸等一系列残基进行磷酸化。因此GSK-3β激酶的特异性抑制剂对减弱tau蛋白磷酸化,减轻老年痴呆症症状,具有一定的药效作用。本模型针对人神经肿瘤细胞SH-SY5Y,用A-beta淀粉样蛋白诱导tau蛋白过度磷酸化,检测GSK-3β抑制剂对tau蛋白396位丝氨酸磷酸化的影响,从而评价这些抑制剂在细胞水平的活性, 我们选择了部分化合物进行了细胞水平的GSK-3β抑制活性的测定,具体方法为: SH-SY5Y细胞用含有10%胎牛血清,1%青霉素和1%链霉素的DMEM/F12(1:1)培养基在5% CO2环境的37℃培养箱中培养。培养基每两天换一次。在12孔板中接每孔25万的SH-SY5Y细胞,培养过夜,饥饿12h后,加入浓度为1M化合物,1h后再加入20M Aβ25-35,继续处理6小时。6小时后,用冰冷的PBS洗两次后,用1×SDS buffer收样。样品10%SDS聚丙烯酰胺凝胶跑电泳,将蛋白转于PVDF膜上。膜用5%牛奶封闭1h,一抗(EPIT MICS公司的Tau Phospho(ser396))孵育过夜,二抗为兔抗,孵育1h,用ECL曝光显影, 部分测试结果见附图1。
如附图1所示,化合物10c,10j-10m,10p-10r能够显著减少A-beta淀粉样蛋白诱发的神经元tau蛋白的过度磷酸化,在细胞水平显示了GSK-3β的抑制活性。
综上所述,3-苯并异噁唑-4-吲哚马来酰亚胺衍生物是一类高效特异性GSK-3β抑制剂,在GSK-3β介导疾病如糖尿病、双向精神障碍、阿尔茨海默病、癌症、炎性疾病、抑郁症、神经保护和精神分裂症中具有很好的应用前景。
Claims (4)
1.一种3-苯并异噁唑-4-吲哚马来酰亚胺衍生物,其特征在于,具体为:
3-(苯并[d]异噁唑-3-基)-4-(1-(2-(1H-咪唑-1-基)乙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮,或
3-(苯并[d]异噁唑-3-基)-4-(1-(3-(1H-咪唑-1-基)丙基)-1H-吲哚-3-基)-1H-吡咯-2,5-酮。
2.根据权利要求1所述的3-苯并异噁唑-4-吲哚马来酰亚胺类化合物及其药学上可接受的盐在制备GSK-3β介导疾病治疗药物中的应用。
3.根据权利要求1所述的3-苯并异噁唑-4-吲哚马来酰亚胺类化合物及其药学上可接受的盐在制备治疗糖尿病、双向精神障碍、阿尔茨海默病、癌症、炎性疾病、抑郁症和精神分裂症药物中的应用。
4.根据权利要求1所述的3-苯并异噁唑-4-吲哚马来酰亚胺类化合物及其药学上可接受的盐在制备神经保护药物中的应用。
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