CN115974849A - 一种吲哚氧乙酰胺类衍生物、包含其的药物组合物及其应用 - Google Patents
一种吲哚氧乙酰胺类衍生物、包含其的药物组合物及其应用 Download PDFInfo
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- CN115974849A CN115974849A CN202211695746.XA CN202211695746A CN115974849A CN 115974849 A CN115974849 A CN 115974849A CN 202211695746 A CN202211695746 A CN 202211695746A CN 115974849 A CN115974849 A CN 115974849A
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- chloro
- methylphenyl
- oxopyrrolidin
- indol
- amino
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Abstract
本发明提供一种吲哚氧乙酰胺类衍生物、包含其的药物组合物及其应用,吲哚氧乙酰胺类衍生物具有如式(Ⅰ)所示的化合物、其药学上可接受的盐或其溶剂化物,
Description
技术领域
本发明属于药物化学领域,具体涉及一种吲哚氧乙酰胺类衍生物、包含其的药物组合物及其应用
背景技术
肝癌是全球第七大常见癌症也是导致全世界癌症相关死亡的第二大主要原因,肝癌目前的治疗方法主要是手术治疗和靶向药物治疗。目前肝癌治疗的一线药物主要包括索拉非尼,瑞伐非尼,5-FU等,虽然取得了有益的治疗效果,但随着给药时间的延长会使癌细胞会产生耐药性,从而无效,并且患者会出现严重的副反应,因此目前尚无完善的肝癌全身化疗方案。
β-1,3-葡萄糖醛酸转移酶I(beta-1,3-glucuronyltransferase 3,B3GAT3,)是参与硫酸乙酰肝素和硫酸软骨素生物合成的必需酶,是负责硫酸化糖胺聚糖生物合成的第一个克隆的糖基转移酶,包括肝素/硫酸乙酰肝素、硫酸软骨素和硫酸皮肤素,在己糖醛酸-糖胺聚糖链的整体合成中起着门控作用。蛋白聚糖(PG)是一种结构多样的多聚阴离子分子,分布广泛在细胞表面和组织中的细胞外基质上,可以直接影响细胞周期。在参与肿瘤细胞功能的众多大分子中,PG对肿瘤组织新生血管的形成和恶性细胞的增殖起着重要作用。B3GAT3作为一种糖基转移酶,在蛋白聚糖(PG)生物合成中扮演重要角色。研究表明,B3GAT3在肝癌中过度表达且不利于病后恢复,在敲除了HepG2细胞中的B3GAT3后,肝癌细胞增殖、迁移和侵袭都受到了抑制,并逆转了上皮细胞-间充质转化(EMT)过程。开发新型具有抑制B3GAT3作用的药物不仅能够为肝癌治疗提出新思路,而且也有望克服已上市相关药物的副作用,具有广阔的应用前景和实用价值。
发明内容
本发明的目的在于提供一种能够抑制B3GAT3的化合物,还提供包含其的药物组合物及其应用。
为了实现上述目的,本发明所采用的技术方案为:
一种吲哚氧乙酰胺类衍生物,它包括如式(Ⅰ)所示的化合物、其药学上可接受的盐或其溶剂化物,
R3是氢原子或C1-6烷基。
所述药学上可接受的盐包括与下列酸形成的盐:盐酸、硫酸、磷酸、氢溴酸、醋酸、三氟乙酸、丙酮酸、柠檬酸、酒石酸、乳酸、马来酸、苯磺酸或琥珀酸。
作为技术方案的进一步改进,它为式(Ⅱ)所示的化合物、其药学上可接受的盐或其溶剂化物,
式(Ⅱ)中,
R2是氢原子、甲酸甲酯基或甲酸基;
R3是氢原子或甲基。
本发明化合物的制备方法,包括如下步骤:
其中,
步骤A:化合物Int1与二碳酸二叔丁酯在碱性二氯甲烷反应得到得到化合物Int2;
步骤B:化合物Int2在三甲基铝的二氯甲烷中与2-氯-4-甲基苯胺反应得到化合物Int3;
步骤C:化合物Int3与三苯基膦和偶氮二甲酸二异丙酯作用下转化为Int4;
步骤D;化合物Int4在三氟乙酸作用下脱去Boc基团得到化合物Int5;
步骤E:取代吲哚在乙醚中与草酰氯作用得到化合物Int6;
步骤F:化合物Int6与Int5在N,N-二甲基甲酰胺中反应得到通式(I)部分化合物;
步骤G:5-硝基吲哚经过还原反应得到化合物Int7;
步骤H:化合物Int7与二碳酸二叔丁酯在碱性二氯甲烷反应得到得到化合Int8。
步骤I:化合物In8在乙醚中与草酰氯作用得到化合物Int9;
步骤J:化合物Int9与Int5在N,N-二甲基甲酰胺中反应得到化合物Int10;
步骤K:化合物Int10在三氟乙酸作用下脱去Boc基团得到化合物Int11;
步骤L:化合物Int11与不同的取代羧基经酸胺缩合得到通式(I)部分化合物。
作为技术方案的进一步改进,所述卤素为氟原子或溴原子。
作为技术方案的进一步改进,它选自以下任一种化合物,
(2R)-N-(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)双环[2.2.1]庚-5-烯-2-甲酰胺;
叔丁基(2S,4R)-2-((3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)氨基甲酰基)-4-羟基吡咯烷-1-甲酸酯;
2S,4R)-N-(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)-4-羟基吡咯烷-2-甲酰胺;
2-(5-(2-((1r,3R,5S)-金刚烷-1-基)乙酰胺)-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺;
2-(5-(2-(苯并[d][1,3]二氧代醇-5-基)乙酰胺)-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺;
叔丁基(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)氨基甲酸酯;
2-(5-氨基-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺;
N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-(5-氰基-1H-吲哚-3-基)2-氧代乙酰胺;
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-羧酸甲酯;
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-羧酸;
2-(5-溴-1-甲基-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺;
N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-(5-氟-1H-吲哚-3-基)2-氧代乙酰胺;
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-6-甲酸甲酯;
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-6-甲酸;或,
2-(5-溴-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺。
本发明公开一种药物组合物,它包含所述含取代吲哚氧乙酰胺类衍生物及一种或多种药学上可接受的辅料或载体。药学上可接受的辅料系指生产药品和调配处方时使用的赋形剂和附加剂,包括溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂等。药学上可接受的载体,是指能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系,包括微囊与微球、纳米粒、脂质体等。当药物组合物用于实体瘤肿瘤疾病时,优选组合物形式为有效成分+载体。
作为技术方案的进一步改进,所述药物组合物的剂型为片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂或注射液。
本发明公开一种所述吲哚氧乙酰胺类衍生物的应用,因所述吲哚氧乙酰胺类衍生物具有B3GAT3抑制作用,它用于制备预防和/或治疗B3GAT3介导的疾病的药物。
作为技术方案的进一步改进,所述的B3GAT3介导的疾病包括不成比例的身材矮小、骨骼发育不良、面部畸形、铲状远端指骨和关节挛缩、关节过度活动与脱位和骨骼脆弱性、严重多处骨折综合征、皮肤松弛样综合征、先天性心脏缺陷和恶性肿瘤。
作为技术方案的进一步改进,所述的B3GAT3介导的疾病为肝癌。
一种所述吲哚氧乙酰胺类衍生物的应用,因所述吲哚氧乙酰胺类衍生物具有B3GAT3抑制作用,它用于制备B3GAT3抑制剂。
本发明相对现有技术具有突出的实质性特点和显著的进步,具体的说,本发明的吲哚氧乙酰胺类衍生物具有B3GAT3抑制作用,为肝癌治疗提供了新思路。进一步说,本发明在不同肝癌的细胞系中表现出了高活性的B3GAT3抑制作用,具有重要的应用价值。再一步说,本发明的化合物制备方法简单,具有可实施性。
具体实施方式
下面通过具体实施方式,对本发明的技术方案做进一步的详细描述。
以下实施例中,“室温”是指大约10℃至大约35℃。混合溶剂表示的比例是体混合比例,除非另作说明,否则%是指wt%。
在砫胶柱色谱中,碱性砫胶是指使用氨基丙基硅烷结合的硅胶。在高效液相色谱(HPLC)中,C18是指使用十八烷基结合的硅胶。洗脱溶剂的比例是体积混合比例,除非另作说明。
在下面实施例和实验实施例中,使用下列缩写。
THF:四氢呋喃,
EA:乙酸乙酯,
PE:石油醚,
DCM:二氯甲烷,
DMSO:二甲基亚砜,
DIEA:N,N-二异丙基乙胺,
HATU:2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
M:摩尔浓度。
利用Fourier变换类型NMR,测定1H-NMR(质子核磁共振波谱)。对于分析,使用ACD/SpecManager等。不描述活性氢(例如羟基、氨基等等)的峰。
利用LC/MS(液相色谱质谱仪)测定MS(质谱)。作为电离法,使用ESI(电喷射离子化)方法等。数据表示那些实测值。通常,观察分子离子峰。在盐的情况下,通常观察到游离形式的分子离子峰或碎片离子峰。
实施例1
N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-(5-氰基-1H-吲哚-3-基)2-氧代乙酰胺
步骤(A)-叔丁基(2-氧代四氢呋喃-3-基)氨基甲酸酯
将高丝氨酸内脂盐酸盐(4.5g.32.8mmol),N,N-二异丙基乙胺(8mL,50mmol),DCM30mL加入在100mL反应瓶中,然后加入(Boc)2O(12mL,50mmol),在氮气条件下反应12h,TLC检测反应完成后,蒸发溶剂,分别用40mL DCM萃取3次,合并有机层,减压浓缩得到产物6123mg,收率为96.7%。1H NMR(300MHz,Chloroform-d)δ5.12(s,1H),4.53–4.11(m,3H),2.76(q,J=9.0,6.1Hz,1H),2.42–2.08(m,1H),1.53(s,9H).
步骤(B)-叔丁基(1-((2-氯-4-甲基苯基)氨基)-4-羟基-1-氧代丁烷-2-基)氨基甲酸酯
在室温和氮气条件下,向100mL反应瓶中加入2-氯-4-甲基苯胺(2000mg,14.2mmol)和无水DCM(10mL),之后滴加三甲基铝的正己烷溶液(8mL,16mmol)。将所得混合物搅拌15分钟,然后将溶于无水DCM(5mL)的叔丁基(2-氧代四氢呋喃-3-基)氨基甲酸酯(3216mg,16mmol)缓慢加入在上述溶液中,并在环境温度下继续搅拌18h。TLC监测反应完成后用10%柠檬酸水溶液(10mL)小心淬灭反应,泡腾停止后,分别用40mL DCM萃取3次,合并有机层。有机层用无水Na2SO4干燥,过滤并真空浓缩。Biotage柱层析得到产品,展开剂石油醚乙酸乙酯(V/V)=3:1冲出产物,减压浓缩干燥得到白色油状液体4000mg,收率为82%。1HNMR(300MHz,Chloroform-d)δ8.42(s,1H),8.12(d,J=8.3Hz,1H),7.18(d,J=2.0Hz,1H),7.06(dd,J=8.4,2.0Hz,1H),5.72(d,J=7.3Hz,1H),4.52(s,1H),3.81(dd,J=6.9,4.0Hz,2H),2.29(s,3H),2.20–2.06(m,1H),2.04(s,1H),1.95(s,1H),1.46(s,9H).
步骤(C)-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
在室温和氮气氛围下,向偶氮二甲酸二叔丁酯(690.78mg,3mmol)的无水THF(2mL)溶液中加入三丁基膦(786mg,3mmol),并将该溶液搅拌五分钟。然后滴加入冷却至0℃的叔丁基(1-((2-氯-4-甲基苯基)氨基)-4-羟基-1-氧代丁烷-2-基)氨基甲酸酯(800mg,2.33mmol)的无水THF(5mL)中,0℃下反应1h,之后使反应混合物缓慢升温至室温并搅拌18h。点板检测反应完成后,蒸发溶剂,分别用40mL乙酸乙酯萃取3次,合并有机层,依次用水(2×50mL),饱和食盐水(1×50mL)洗涤有机层,并经无水硫酸钠干燥,并在减压下浓缩得到粗化合物。Biotage柱层析分离粗产品,展开剂石油醚乙酸乙酯(V/V)=51得到产物,减压浓缩干燥得到白色液体454mg,收率60%。1H NMR(300MHz,Chloroform-d)δ7.21(t,J=1.1Hz,1H),7.08(d,J=1.9Hz,2H),5.20(d,J=7.0Hz,1H),4.00(dt,J=6.8,3.2Hz,1H),3.80(ddd,J=12.4,7.5,5.7Hz,1H),3.70(ddd,J=12.5,7.5,5.7Hz,1H),2.44(dddd,J=12.3,7.5,5.7,3.2Hz,1H),2.36(s,3H),2.19(dddd,J=12.3,7.5,5.8,3.3Hz,1H),1.42(s,9H).
步骤(D)-3-氨基-1-(2-氯-4-甲基苯基)吡咯烷-2-酮
在室温下,将(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯(400mg,1.23mmol)溶于10mL无水DCM中,加入1mL三氟乙酸,在氮气保护下反应2h,TLC检测反应完成后加入饱和碳酸氢钠溶液,调节溶液pH值为碱性,分别用20mL DCM萃取3次,合并有机层。有机层用无水Na2SO4干燥,过滤并真空浓缩得到白色油状液体233mg,收率为84.5%。1H NMR(300MHz,Chloroform-d)δ7.21(t,J=1.0Hz,1H),7.08(d,J=1.9Hz,2H),3.80(ddd,J=12.7,7.3,5.5Hz,1H),3.70(ddd,J=12.6,7.3,5.5Hz,1H),3.36(tt,J=5.2,2.7Hz,1H),2.44(dddd,J=12.7,7.3,5.5,2.7Hz,1H),2.36(s,3H),2.19(dddd,J=12.6,7.3,5.5,2.7Hz,1H),1.68(d,J=5.1Hz,2H).
步骤(E)-2-(5-氰基-1H-吲哚-3-基)-2-氧代乙酰氯
在50mL单口瓶中加入5-氰基氟吲哚(1396g,6mmol)和10m L无水乙醚,0℃下缓慢滴加草酰氯(0.77mL,9mmol),滴加完毕后,继续在0℃下反应约1.5小时。TLC监控反应进程,反应完全后,直接抽滤,用冰的无水乙醚洗涤,得黄色粉末1.21g,即标题化合物。无需进一步纯化,直接用于下一步反应。
步骤(F)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-(5-氰基-1H-吲哚-3-基)2-氧代乙酰胺
在0℃条件下,将3-氨基-1-(2-氯-4-甲基苯基)吡咯烷-2-酮(224mg,1mmol),碳酸钾(276mg,2mmol),加入到10mL无水DCM中,随后缓慢滴加(5-氰基-1H-吲哚-3-基)-2-氧代乙酰氯(278.4mg,1.2mmol),反应2h。点板检测反应完成后,分别用20mL DCM萃取3次,合并有机层。有机层用无水Na2SO4干燥,过滤并真空浓缩。Biotage柱层析得到产品,展开剂石油醚乙酸乙酯(V/V)=1:1冲出产物,减压浓缩干燥得到白色固体160mg,收率为38.0%。1HNMR(400MHz,DMSO-d6)δ12.70(d,J=3.2Hz,1H),9.29(d,J=8.7Hz,1H),8.96(d,J=3.1Hz,1H),8.60(d,J=1.6Hz,1H),7.75(d,J=8.4Hz,1H),7.68(dd,J=8.4,1.7Hz,1H),7.41(d,J=1.9Hz,1H),7.34(d,J=8.0Hz,1H),7.24(dd,J=8.2,1.9Hz,1H),4.79(dt,J=10.5,8.7Hz,1H),3.73(td,J=9.3,6.7Hz,1H),3.64(td,J=9.1,1.8Hz,1H),2.50–2.40(m,1H),2.34(s,4H).
实施例2
叔丁基(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)氨基甲酸酯
步骤(G)-5-氨基吲哚
于100mL单口瓶中加入5-硝基吲哚(1296mg,8mmol),Pd/C(195mg),甲醇10mL,接入氢气气球置换空气,在室温下进行氢化反应5h,TLC监控反应进程,反应完全后,直接抽滤,将滤液浓缩得到粗品产物5-胺基吲哚。
步骤(H)-5-N-Boc-氨基吲哚
常温下,将粗品5-胺基吲哚溶于EA溶液中,加入(Boc)2O4mL,反应6h,TLC监控反应进程,反应完成后减压浓缩,分别用20mL乙酸乙酯萃取3次,合并有机层,饱和食盐水洗涤,分离有机相加入无水Na2SO4干燥,减压浓缩得到粗品,Biotage柱层析得到产品,展开剂石油醚乙酸乙酯(V/V)=101得到产物,减压浓缩干燥得到白色固体1299mg,收率70%。1H NMR(300MHz,Chloroform-d)δ8.22(s,1H),7.67(s,1H),7.32–7.19(m,1H),7.14(t,J=2.8Hz,1H),7.09(dd,J=8.7,2.1Hz,1H),6.58–
6.25(m,2H),1.53(s,9H).
步骤(I)-叔丁基(3-(2-氯-2-氧代乙酰基)-1H-吲哚-5-基)氨基甲酸酯
利用与实施例1,步骤(E)中一样的方法,由5-N-Boc-氨基吲哚与草酰氯反应获得标题化合物。
步骤(J)-叔丁基(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)氨基甲酸酯
用叔丁基(3-(2-氯-2-氧代乙酰基)-1H-吲哚-5-基)氨基甲酸酯(387mg,1.2mmol)替换掉实施例1步骤(F)中的(5-氰基-1H-吲哚-3-基)-2-氧代乙酰氯,其它步骤参照实施例1中的制备方法,制得黄色固体化合物214mg,收率42.0%。1H NMR(300MHz,Chloroform-d)δ10.71(d,J=3.4Hz,1H),8.53(d,J=3.3Hz,1H),8.21(d,J=8.0Hz,1H),7.95(d,J=2.1Hz,1H),7.35–7.26(m,1H),7.21–7.13(m,2H),7.04(q,J=4.2,3.1Hz,2H),4.88(q,J=9.1Hz,1H),3.87–3.61(m,2H),2.64(dt,J=14.8,7.7Hz,1H),2.35(dd,J=18.2,7.0Hz,1H),2.28(s,3H),2.05(s,1H),1.51(s,9H).
实施例3
步骤(K)-2-(5-氨基-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺
用叔丁基(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)氨基甲酸酯(510.mg,1mmol)替换掉实施例1步骤(D)中的(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯,其它步骤参照实施例1步骤(D)中的制备方法,制得黄色固体化合物336mg,收率82.0%。1H NMR(300MHz,Chloroform-d)δ10.43(s,1H),8.62(d,J=3.1Hz,1H),8.25(d,J=8.0Hz,1H),7.45(d,J=2.2Hz,1H),7.20(d,J=1.8Hz,1H),7.12(d,J=8.0Hz,1H),7.05–6.93(m,2H),6.51(dd,J=8.6,2.2Hz,1H),4.83(q,J=9.1Hz,1H),3.68(dt,J=30.6,9.0Hz,2H),3.34(s,3H),2.62(s,1H),2.25(s,4H).
实施例4
步骤(L)-(2R)-N-(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)双环[2.2.1]庚-5-烯-2-甲酰胺
在氮气氛围下,将双环[2.2.1]庚-5-烯-2-羧酸(138mg,1mmol),HATU(456mg,1.2mmol),DIPEA(0.35mL,2mmol)溶于无水DCM(6mL)中室温下反应30min,之后加入2-(5-氨基-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺(410mg,1mmol)继续反应6h,TLC点板监测反应完成后,蒸发溶剂,分别用20mLDCM萃取3次,合并有机层,依次用水(2×50mL),饱和食盐水(1×50mL)洗涤有机层,并经无水硫酸钠干燥,并在减压下浓缩得到粗化合物。Biotage柱层析分离粗产品,展开剂石油醚乙酸乙酯(V/V)=11得到产物,减压浓缩干燥得到白色液体225mg,收率42.6%。1H NMR(300MHz,DMSO-d6)δ12.18(d,J=3.3Hz,1H),9.78(s,1H),9.13(dd,J=8.7,3.2Hz,1H),8.73–8.67(m,1H),8.44(d,J=2.0Hz,1H),7.57(dd,J=8.8,2.1Hz,1H),7.50–7.38(m,3H),7.33(d,J=8.0Hz,1H),7.24(dd,J=8.3,1.9Hz,1H),6.19(dq,J=5.6,3.0,2.4Hz,2H),5.89(dd,J=5.6,2.8Hz,1H),4.77(dt,J=12.4,8.9Hz,1H),4.03(q,J=7.1Hz,1H),3.80–3.58(m,3H),3.36(d,J=7.1Hz,3H),3.32(s,1H),3.06(dt,J=8.7,4.0Hz,1H),2.88(s,1H),2.46(d,J=5.6Hz,1H),2.33(s,5H),1.99(s,1H),1.90–1.70(m,1H),1.44(ddd,J=11.5,4.3,1.9Hz,1H),1.36–1.30(m,2H),1.20(dt,J=14.2,6.3Hz,1H).
实施例5
N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-(5-氟-1H-吲哚-3-基)2-氧代乙酰胺
用(5-氟-1H-吲哚-3-基)-2-氧代乙酰氯(270mg,1.2mmol)替换掉实施例1步骤(F)中的5-(氰基-1H-吲哚-3-基)-2-氧代乙酰氯,其它步骤参照实施例1步骤(F)中制备方法,制得白色固体化合物187mg,收率45.2%。1H NMR(400MHz,DMSO-d6)δ12.82(d,J=4.2Hz,1H),8.84(d,J=7.3Hz,1H),7.92(d,J=7.5Hz,1H),7.50(dd,J=7.1,5.1Hz,1H),7.30(dd,J=7.9,2.7Hz,1H),7.21(d,J=2.2Hz,1H),7.08(d,J=1.8Hz,2H),6.80(ddd,J=7.9,7.1,2.7Hz,1H),4.79(dt,J=10.5,8.7Hz,1H),3.73(td,J=9.3,6.7Hz,1H),3.64(td,J=9.1,1.8Hz,1H),2.50–2.40(m,1H),2.34(s,4H).
实施例6
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-羧酸甲酯
用3-(2-氯-2-氧代乙酰基)-1H-吲哚-5-羧酸甲酯(318mg,1.2mmol)替换掉实施例8步骤中的5-(氰基-1H-吲哚-3-基)-2-氧代乙酰氯,其它步骤参照实施例8中的制备方法,制得白色固体化合物196mg,收率43.4%。1H NMR(300MHz,DMSO-d6)δ12.87(s,1H),9.26(d,J=8.7Hz,1H),8.97–8.87(m,2H),7.97–7.88(m,1H),7.69(d,J=8.6Hz,1H),7.53–7.04(m,3H),4.81(q,J=9.3Hz,1H),3.91(s,3H),3.81–3.60(m,2H),2.46(d,J=8.1Hz,1H),2.34(s,4H).
实施例7
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-6-甲酸甲酯
用3-(2-氯-2-氧代乙酰基)-1H-吲哚-6-甲酸甲酯(318mg,1.2mmol)替换掉实施例8步骤中的5-(氰基-1H-吲哚-3-基)-2-氧代乙酰氯,其它步骤参照实施例8中的制备方法,制得白色固体化合物172mg,收率37.9%。1H NMR(400MHz,Chloroform-d)δ11.11(dd,J=7.5,3.4Hz,1H),9.06(d,J=3.2Hz,1H),8.17–8.02(m,2H),8.01–7.97(m,1H),7.85(dd,J=8.4,1.5Hz,1H),7.27–7.17(m,2H),7.05(dt,J=8.3,2.3Hz,1H),4.92(dq,J=10.6,8.5Hz,1H),3.91(s,4H),3.76(t,J=9.4Hz,1H),2.77–2.65(m,1H),2.44(tq,J=16.6,6.5,4.8Hz,1H),2.27(s,3H).
实施例8
2-(5-溴-1-甲基-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺
用2-(5-溴-1-甲基-1H-吲哚-3-基)-2-氧代乙酰氯(358mg,1.2mmol)替换掉实施例8步骤中的5-(氰基-1H-吲哚-3-基)-2-氧代乙酰氯,其它步骤参照实施例8中的制备方法,制得白色固体化合物163mg,收率33.4%。1H NMR(300MHz,DMSO-d6)δ9.21(d,J=8.7Hz,1H),8.86(s,1H),8.38(d,J=1.9Hz,1H),7.62(d,J=8.7Hz,1H),7.50(dt,J=8.6,2.1Hz,1H),7.42(d,J=1.9Hz,1H),7.33(d,J=8.1Hz,1H),7.24(dd,J=8.4,1.9Hz,1H),4.76(dt,J=10.4,8.7Hz,1H),3.93(s,3H),3.80–3.57(m,2H),2.44(s,1H),2.33(s,4H).
实施例9
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-羧酸
将3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-羧酸甲酯(150mg,0.33mmol),10mL甲醇加于100mL反应瓶中,之后加入2N NaOH溶液3mL,80℃条件下回流2h,TLC监测反应完成后,加入2N HCl,调节pH值约为2-3,静置析出固体。过滤固体,用饱和食盐水洗涤2-3次,干燥得到白色固体130mg,收率是90%。1H NMR(300MHz,DMSO-d6)δ12.54(d,J=3.2Hz,1H),9.23(d,J=8.7Hz,1H),8.89(dd,J=11.0,2.3Hz,2H),7.90(dd,J=8.5,1.7Hz,1H),7.63(d,J=8.5Hz,1H),7.42(d,J=1.8Hz,1H),7.34(d,J=8.0Hz,1H),7.24(dd,J=8.2,1.9Hz,1H),4.86–4.71(m,1H),3.80–3.58(m,2H),2.49–2.37(m,1H),2.34(s,4H).
实施例10
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-6-甲酸
将3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-6-甲酸甲酯(150mg,0.33mmol),10mL甲醇加于100mL反应瓶中,之后加入2N NaOH溶液3mL,80℃条件下回流2h,TLC监测反应完成后,加入2N HCl,调节pH值约为2-3,静置析出固体。过滤固体,用饱和食盐水洗涤2-3次,干燥得到白色固体123mg,收率是85.2%。1H NMR(400MHz,DMSO-d6)δ12.96(d,J=3.3Hz,1H),9.22(d,J=8.7Hz,1H),8.89(d,J=3.3Hz,1H),8.29(d,J=8.3Hz,1H),8.18(d,J=1.4Hz,1H),7.86(dd,J=8.4,1.5Hz,1H),7.41(d,J=1.8Hz,1H),7.33(d,J=8.0Hz,1H),7.24(dd,J=8.2,1.9Hz,1H),4.77(dt,J=10.5,8.8Hz,1H),3.72(td,J=9.3,6.7Hz,2H),2.47–2.41(m,1H),2.33(s,4H).
实施例11
叔丁基(2S,4R)-2-((3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)氨基甲酰基)-4-羟基吡咯烷-1-甲酸酯
用(2S,4R)-1-(叔丁氧基羰基)-4-羟基吡咯烷-2-羧酸(231.5.mg,1mmol)替换掉实施例17步骤中的双环[2.2.1]庚-5-烯-2-羧酸,其它步骤参照实施例17步骤中的制备方法,制得白色固体化合物155mg,收率25.1%。1H NMR(400MHz,Chloroform-d)δ9.10(d,J=7.6Hz,1H),8.84(d,J=7.3Hz,1H),8.27(s,1H),7.92(d,J=7.5Hz,1H),7.80(d,J=2.6Hz,1H),7.62(d,J=7.3Hz,1H),7.30(dd,J=7.3,2.2Hz,1H),7.23–7.19(m,1H),7.08(d,J=1.9Hz,2H),4.57(ddd,J=7.1,5.1,0.7Hz,1H),4.30–4.22(m,1H),4.00(dt,J=7.5,3.5Hz,1H),3.87(dd,J=12.4,2.4Hz,1H),3.83–3.78(m,1H),3.77(d,J=5.7Hz,1H),3.70(ddd,J=12.4,7.5,5.7Hz,1H),3.61(dd,J=12.4,4.3Hz,1H),2.48–2.37(m,3H),2.36(s,3H),2.22–2.11(m,3H),1.45(s,9H).
实施例12
(2S,4R)-N-(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)-4-羟基吡咯烷-2-甲酰胺
用叔丁基(2S,4R)-2-((3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)氨基甲酰基)-4-羟基吡咯烷-1-甲酸酯(150.mg,0.24mmol)替换掉实施例7步骤(D)中的(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯,其它步骤参照实施例7步骤(D)中的制备方法,制得黄色固体化合物91.9mg,收率73.2%。1H NMR(400MHz,Chloroform-d)δ9.10(d,J=7.6Hz,1H),8.84(d,J=7.3Hz,1H),8.27(s,1H),7.92(d,J=7.5Hz,1H),7.80(d,J=2.5Hz,1H),7.62(d,J=7.3Hz,1H),7.30(dd,J=7.3,2.2Hz,1H),7.21(t,J=1.0Hz,1H),7.08(d,J=1.9Hz,2H),4.17(dtdd,J=8.3,4.5,2.0,0.8Hz,1H),4.00(dt,J=7.5,3.5Hz,1H),3.96(tdd,J=5.4,3.7,0.7Hz,1H),3.80(ddd,J=12.5,7.5,5.7Hz,1H),3.70(ddd,J=12.5,7.5,5.7Hz,1H),3.59(d,J=4.9Hz,1H),3.23(ddd,J=12.1,4.3,1.6Hz,1H),2.90(ddd,J=12.5,4.2,3.5Hz,1H),2.44(dddd,J=12.3,7.4,5.7,3.4Hz,1H),2.36(s,3H),2.25–2.14(m,4H),1.96(ddd,J=12.5,6.4,3.7Hz,1H).
实施例13
2-(5-(2-((1r,3R,5S)-金刚烷-1-基)乙酰胺)-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺
用2-((1r,3R,5S)-金刚烷-1-基)乙酸(194.mg,1mmol)替换掉实施例17步骤中的双环[2.2.1]庚-5-烯-2-羧酸,其它步骤参照实施例17步骤中的制备方法,制得白色固体化合物212mg,收率36.3%。1H NMR(400MHz,Chloroform-d)δ9.10(d,J=7.6Hz,1H),8.84(d,J=7.3Hz,1H),7.92(d,J=7.5Hz,1H),7.86(s,1H),7.80(d,J=2.6Hz,1H),7.62(d,J=7.3Hz,1H),7.30(dd,J=7.3,2.2Hz,1H),7.23–7.19(m,1H),7.08(d,J=2.0Hz,2H),4.00(dt,J=7.5,3.5Hz,1H),3.80(ddd,J=12.5,7.5,5.7Hz,1H),3.70(ddd,J=12.5,7.5,5.7Hz,1H),2.44(dddd,J=12.2,7.4,5.7,3.4Hz,1H),2.36(d,J=5.1Hz,6H),2.19(dddd,J=12.4,7.7,5.8,3.5Hz,1H),2.02–1.92(m,4H),1.56–1.51(m,15H).
实施例14
2-(5-(2-(苯并[d][1,3]二氧代醇-5-基)乙酰胺)-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺
用2-(苯并[d][1,3]二氧代醇-5-基)乙酸(180mg,1mmol)替换掉实施例17步骤中的双环[2.2.1]庚-5-烯-2-羧酸,其它步骤参照实施例17步骤中的制备方法,制得白色固体化合物125mg,收率22.1%。1H NMR(400MHz,Chloroform-d)δ9.10(d,J=7.6Hz,1H),8.84(d,J=7.3Hz,1H),7.97–7.89(m,2H),7.80(d,J=2.5Hz,1H),7.62(d,J=7.3Hz,1H),7.30(dd,J=7.3,2.2Hz,1H),7.21(t,J=1.0Hz,1H),7.08(d,J=2.0Hz,2H),6.81(q,J=1.1Hz,1H),6.77–6.74(m,2H),5.91(s,2H),4.00(dt,J=7.5,3.5Hz,1H),3.87(t,J=0.9Hz,2H),3.80(ddd,J=12.5,7.5,5.7Hz,1H),3.70(ddd,J=12.5,7.5,5.7Hz,1H),2.44(dddd,J=12.3,7.4,5.7,3.4Hz,1H),2.36(s,3H),2.19(dddd,J=12.5,7.7,5.8,3.5Hz,1H).
实施例15
2-(5-溴-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺
用2-(5-溴-1H-吲哚-3-基)-2-氧代乙酰氯(343.8mg,1.2mmol)替换掉实施例8步骤中的5-(氰基-1H-吲哚-3-基)-2-氧代乙酰氯,其它步骤参照实施例8中的制备方法,制得白色固体化合物164mg,收率34.6%。1H NMR(300MHz,DMSO-d6)δppm12.43(s,1H),9.26(d,J=8.7Hz,1H),8.86(s,1H),8.41(d,J=1.5Hz,1H),7.56(d,J=8.6Hz,1Н),7.48-7.37(m,2H),7.34(d,J=8.0Hz,1H),7.24(d,J=8.0Hz,1H),4.81(q,J=9.1Hz,1H),3.93-3.44(m,2H),2.50-2.40(m,1H),2.64-2.33(m,4H).
实施例16
CCK-8法测定肿瘤细胞的存活率
实验原理:B3GAT3抑制剂可以抑制肝癌细胞中B3GAT3的表达,从使肝癌细胞死亡。因此,我们可以通过高转移人肝癌细胞(MHCC-97H)和人肝癌细胞(Huh7)的细胞毒活性实验,间接反映B3GAT3抑制剂的抑制能力,B3GAT3抑制剂抑制能力越强,人肝癌细胞存活率越低,对应的IC50值越小。
实验材料与仪器
(1)细胞:人肝癌MHCC-97H细胞和人肝癌Huh7细胞均购自中国科学院典型培养物保藏中心。
(2)实验耗材见表1
表1实验耗材表
试剂配制和测定
(A)MHCC-97H细胞系的测定
MHCC-97H细胞培养基的配制:MHCC-97H细胞使用含有10%胎牛血清(FBS)和1%双抗的DMEM培养基进行细胞培养,具体配制过程如下:无菌条件下精确吸取55mL FBS,5.5mLP双抗,加入500mL瓶装DMEM培养基中混匀置于4℃冰箱备用。
受试化合物的配制:依据受试化合物的分子量,采用DMSO配制成20mM的母液储备于-80℃冰箱。
实验方法:(1).取处于对数生长期的MHCC-97H细胞,弃培养液,经含EDTA的0.25%Trypsin消化细胞,制成单细胞悬液。
(2).用DMEM培养基(含10%(V/V))FBS,1% Pen Strep)调整细胞密度为30000/mL,接种至96孔板,100μL/孔,每孔细胞数量约为3000个,置37℃,5% CO2细胞培养箱中培养24h直至贴壁。
(3).含药培养基的配制:将受试化合物进行100倍稀释使其终浓度为200μM,并依次等比稀释,使其终浓度为200μM,100μM,50μM,25μM。
(4)溶剂组加入含1%DMSO的DMEM培养基10μL,使DMSO终浓度为0.01%;给药组加入步骤(3)的不同浓度的受试化合物10μL使终浓度为20μM,10μM,5μM,2.5μM。
(5)72h后,在每个孔中加入10μL的CCK-8溶液,继续置37℃,5% CO2细胞培养箱中孵育2h。孵育结束后使用酶标仪在450nm的波长下测定其吸光度(OD)值。同时,利用Graphpad prism统计软件,计算受试化合物的IC50值。
(B)Huh7细胞系的测定
将实施例16步骤(A)的MHCC-97H细胞系替换为Huh7细胞系,其他实验操作一致,最终计算受试化合物在Huh7细胞系的IC50值。
细胞活力(%)=[A(加药)-A(空白)]/[A(0加药)-A(空白)]×100
A(加药):具有细胞、CCK-8溶液和药物溶液的孔的OD值
A(0加药):具有细胞、CCK-8溶液而没有药物溶液的孔的OD值
A(空白):没有细胞的孔的OD值。
细胞活力:细胞增殖活力或细胞毒性活力结果展示于表2中。
表2不同物质对细胞的细胞活力结果
注:表2中“ND”表示空白对照组抑制率为0;“--”表示未检测相关数据。
表2的测试结果表明,实施例3,5,8,10和15对MHCC-97H细胞系和Huh7细胞系均显示出较高的细胞活性,其中以实施例3,5,15效果最好,说明了部分本发明化合物在抑制肝癌细胞的增殖方面表现出有益的效果。
实施例17
本发明部分化合物对B3GAT3的靶点结合验证
在pH值为4.0的10mM醋酸胺缓冲液中进行B3GAT3蛋白偶联,约20000个响应单位(RU)的B3GAT3蛋白共价偶联在CM5传感器芯片上。在25℃下进行动力学亲和力测定。在结合试验中,使用补充有5%DMSO的流动缓冲液PBS-P对化合物进行梯度稀释。运行缓冲液用于空白进样,并使用溶剂校正法校正样品中的参考误差。将化合物以30μL/min的流速注入偶联有B3GAT3的CM5芯片90s,并使其离解90s。使用Biacore T2000计算稳态KD值,结果展示于表3中。KD值约小,则化合物对蛋白的亲和力越高。
表3不同物质对B3GAT3的KD值
实施例 | Max.conc.(μM) | <![CDATA[K<sub>D</sub>(μM)]]> |
3 | 50 | 9.915 |
5 | 25 | 238.5 |
15 | 50 | 112.8 |
表3的测试结果表明,实施例3,5,15对B3GAT3均有较高的亲和力,说明本发明部分化合物具有与B3GAT3结合的能力。
以上药理学数据显示:本发明化合物通过作用于B3GAT3靶点从而抑制肝癌细胞的增殖与恶性发展,展现出了较强的抑制恶性肿瘤的作用。
最后应当说明的是:以上实施例仅用以说明本发明的技术方案而非对其限制;尽管参照较佳实施例对本发明进行了详细的说明,所属领域的普通技术人员应当理解,依然可以对本发明的具体实施方式进行修改或者对部分技术特征进行等同替换;而不脱离本发明技术方案的精神,其均应涵盖在本发明请求保护的技术方案范围当中。
Claims (10)
3.根据权利要求2所述的吲哚氧乙酰胺类衍生物,其特征在于,所述卤素为氟原子或溴原子。
4.根据权利要求1-3任一项所述的含取代吲哚氧乙酰胺类衍生物,其特征在于,它选自以下任一种化合物,
(2R)-N-(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)双环[2.2.1]庚-5-烯-2-甲酰胺;
叔丁基(2S,4R)-2-((3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)氨基甲酰基)-4-羟基吡咯烷-1-甲酸酯;
2S,4R)-N-(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)-4-羟基吡咯烷-2-甲酰胺;
2-(5-(2-((1r,3R,5S)-金刚烷-1-基)乙酰胺)-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺;
2-(5-(2-(苯并[d][1,3]二氧代醇-5-基)乙酰胺)-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺;
叔丁基(3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-基)氨基甲酸酯;
2-(5-氨基-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺;
N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-(5-氰基-1H-吲哚-3-基)2-氧代乙酰胺;
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-羧酸甲酯;
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-5-羧酸;
2-(5-溴-1-甲基-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺;
N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-(5-氟-1H-吲哚-3-基)2-氧代乙酰胺;
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-6-甲酸甲酯;
3-(2-((1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)氨基)-2-氧乙酰基)-1H-吲哚-6-甲酸;或,
2-(5-溴-1H-吲哚-3-基)-N-(1-(2-氯-4-甲基苯基)-2-氧代吡咯烷-3-基)-2-氧代乙酰胺。
5.一种药物组合物,其特征在于,它包含权利要求1-4任一项所述吲哚氧乙酰胺类衍生物及一种或多种药学上可接受的辅料或载体。
6.根据权利要求5所述的药物组合物,其特征在于,所述药物组合物的剂型为片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂或注射液。
7.一种根据权利要求1-4任一项所述吲哚氧乙酰胺类衍生物的应用,其特征在于,它用于制备预防和/或治疗B3GAT3介导疾病的药物。
8.根据权利要求7所述的应用,其特征在于,所述的B3GAT3介导的疾病包括骨骼发育不良、面部畸形、铲状远端指骨和关节挛缩、关节过度活动与脱位和骨骼脆弱性、严重多处骨折综合征、皮肤松弛样综合征、先天性心脏缺陷和恶性肿瘤。
9.根据权利要求8所述的应用,其特征在于,所述的B3GAT3介导的疾病为肝癌。
10.一种根据权利要求1-4任一项所述吲哚氧乙酰胺类衍生物的应用,其特征在于,它用于制备B3GAT3抑制剂。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004022553A1 (de) * | 2002-08-17 | 2004-03-18 | Aventis Pharma Deutschland Gmbh | INDOL-ODER BENZIMIDAZOLDERIVATE ZUR MODULATION DER IλB-KINASE |
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CN114213310A (zh) * | 2021-12-31 | 2022-03-22 | 中国药科大学 | 吲哚啉化合物及其衍生物、制备方法、药物组合物和应用 |
CN114456150A (zh) * | 2022-01-12 | 2022-05-10 | 中国药科大学 | Nr2b受体拮抗剂或其可药用的盐、制备方法及用途 |
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