BZD类和THIQ类非竞争性AMPA受体拮抗剂的合成及修饰
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摘要
抑郁症是一种神经系统疾病,与谷氨酸能系统异常有关。谷氨酸能神经信号传递活动是通过两种不同受体参与的,它们是:离子(转移)型谷氨酸受体(iGluRs)和代谢型谷氨酸受体(mGluRs),其中起主要作用的是iGluRs。根据iGluRs对不同激动剂的亲和性不同又可以细分为三个不同亚级受体:N-甲基-D-天冬氨酸(NMDA)受体,卡英酸(KA)受体以及α-氨基-3-羟基-5-甲基-4-异唑丙酸(AMPA)受体。NMDA受体是最早被用于抑郁症治疗研究的受体,但是由于NMDA受体拮抗剂对机体产生不可逆的损伤,目前已经被最新发现的具有更好活性,更安全的AMPA受体拮抗剂代替。2,3-苯并二氮类化合物(2,3-BZD)和四氢异喹啉类化合物(THIQ)是两种具有代表性的AMPA受体拮抗剂,它们对神经系统疾病的广泛活性使它们成为AMPA受体拮抗剂的研究热点。本文针对2,3-BZD类化合物和THIQ类化合物的研究主要包含以下几方面:
1.选择Friedel-Crafts酰基化反应作为BZD衍生物合成路线的关键步骤;分别以羧酸,酸酐,酰氯为酰化剂,对Lewis酸和质子酸,溶剂,温度,当量做条件筛选;确定优化酰基化条件,合成得到重要中间体1-[2-(4-溴苯甲酰基)-4,5-二甲氧基苯基]-丙酮K-3;K-3在浓硫酸的催化下与水合肼环合得到1-(4-溴苯基)-7,8-二甲氧基-4-甲基-5H-苯并二氮K-Br-BZD。
2.将卤代芳烃在Pd催化下胺的偶联反应应用于卤代BZD类化合物的结构修饰,得到[4-(7,8-二甲氧基-4-甲基-5H-苯并二氮)-1-苯基]- 4-甲氧基苯胺K-347和[4-(7,8-二甲氧基-4-甲基-5H-苯并二氮)-1-苯基]- 4-硝基苯胺K-353两个衍生物(未见有文献报道)。
3.本文以芳醛和芳基乙腈为原料合成了不同R1-4,R7取代的苯基酮,以酯为原料与水合肼反应生成不同R5取代的酰肼;以苯基酮与酰肼为原料反应生成芳酰腙,还原得到中间体酰肼;经过条件筛选,确定合环反应条件,以中间体酰肼为底物,TMSCl/NaI催化,通过Pictet-Spengler反应合成了65个THIQ类化合物(包括6个分离得到的异构体),这些化合物均未见有文献报道。
4.本文通过对化合物A-2的X-ray衍射数据,及化合物B-13 3JHH偶合常数分析,确定化合物trans和cis两种异构体构型。并设计一系列反应考查R1-4,R5,R6,R7不同位置不同结构的取代基对THIQ类化合物空间结构的影响。其中R1-4对合环和构型都有影响;R6,R7对立体选择性有显著的影响;R5(除对甲苯磺酰基)没有明显的立体选择性差异,但是当R5为对甲苯磺酰基时,却表现了专一的立体选择性。
5.本文得到的BZD衍生物与THIQ衍生物结构与四特征药效团模型吻合,有做抗抑郁或抗惊厥活性筛选的价值。
Depression is one of the most common neurological problems resulted from the disorder of Glutamatergic neurotransmission which is mediated by ionotropic receptors (iGluRs) and metabotropic receptors (mGluRs). The iGluRs are ligand gated ion channels which are further subdivided into three classes based on their affinity for specific agonists: the N-methyl-D-aspartic acid (NMDA), the kainic acid (KA), andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subtpypes. NMDA receptor antagonists are the first one being applied for the antidepression therapy, while because of being considered relation with some irreversible damage, they are now replaced by AMPA receptor antagonists, which are found with more active neuromodulating effects and less adverse effects. 2, 3-Benzodiazepine (2, 3-BZD) and tetra- hydroisoquinolines (THIQs) are two representative AMPAR antagonists, and they have received considerable attention due to their diverse activity to neuromodulating effects. This paper focuses on 2, 3-BZDs and THIQs giving following discussion:
1. The Friedel-Crafts acylation is chosen as the key step during sythesis of BZD derivatives. The synthetic method is considered by trying a series of reaction conditions including screening acylating reagent, catalyst, solvent, reaction temperature and equivalent of the substrates. The key intermediate 1-[2-(4-Bromo-benzoyl)-4, 5-dimethoxy-phenyl]–propan-2-one K-3 which is prepared by applying the optimized condition, then is dehydrated with hydrazine hydrate in the presence of concentrated sulfuric acid to give 1-(4-Bromo-phenyl)-7, 8- dimethoxy-4-methyl-5H-benzodiazepine K-Br-BZD.
2. The modification of BZD is proceeded by applying the palladium catalyzed amide coupling reaction and provide two BZD derivatives: 7, 8–dimethoxy-1-(4-methoxy-phenyl)-4-methyl-5H-benzodiazepine K- 347 and 7, 8-dimethoxy-1-(4-nitro-phenyl)-4-methyl-5H-benzo- diazepine K-353.
3. Different R1-4 and R7 substituted phenyl acetones are prepared from benzaldehyde and phenyl cyanide; different hydrazine are prepared from different acid esters; different hydrazones was prepared from the obtained phenyl acetones and hydrazines then undergoing reductive reaction to provide the key intermediate hydrazide, which via Pictet-Spengler reaction give 65 new THIQs.
4. The configuration of the trans and cis isomers are confirmed by analysis of the X-ray of A-2 and the coupling constant 3JHH of B-13.
5. Detailed discussion about the effects resulted from R1-4, R5, R6, R7 on the configuration of the THIQs are involved in the paper. R1-4 effect on both coupling reaction and configuration of the products. R6, R7 have distinct effects on the steteoselectivity. R5 does not show clear effects on the products configuration, while when R5 is p-tosyl group, it appears highly stereoselective character.
6. The structure of the desired BZD derivatives and THIQ derivatives are comparable to the 4-feature pharmacophore model, and they could be valuable for following bioactivity test on antidepression or anticonvulsant.
1.选择Friedel-Crafts酰基化反应作为BZD衍生物合成路线的关键步骤;分别以羧酸,酸酐,酰氯为酰化剂,对Lewis酸和质子酸,溶剂,温度,当量做条件筛选;确定优化酰基化条件,合成得到重要中间体1-[2-(4-溴苯甲酰基)-4,5-二甲氧基苯基]-丙酮K-3;K-3在浓硫酸的催化下与水合肼环合得到1-(4-溴苯基)-7,8-二甲氧基-4-甲基-5H-苯并二氮K-Br-BZD。
2.将卤代芳烃在Pd催化下胺的偶联反应应用于卤代BZD类化合物的结构修饰,得到[4-(7,8-二甲氧基-4-甲基-5H-苯并二氮)-1-苯基]- 4-甲氧基苯胺K-347和[4-(7,8-二甲氧基-4-甲基-5H-苯并二氮)-1-苯基]- 4-硝基苯胺K-353两个衍生物(未见有文献报道)。
3.本文以芳醛和芳基乙腈为原料合成了不同R1-4,R7取代的苯基酮,以酯为原料与水合肼反应生成不同R5取代的酰肼;以苯基酮与酰肼为原料反应生成芳酰腙,还原得到中间体酰肼;经过条件筛选,确定合环反应条件,以中间体酰肼为底物,TMSCl/NaI催化,通过Pictet-Spengler反应合成了65个THIQ类化合物(包括6个分离得到的异构体),这些化合物均未见有文献报道。
4.本文通过对化合物A-2的X-ray衍射数据,及化合物B-13 3JHH偶合常数分析,确定化合物trans和cis两种异构体构型。并设计一系列反应考查R1-4,R5,R6,R7不同位置不同结构的取代基对THIQ类化合物空间结构的影响。其中R1-4对合环和构型都有影响;R6,R7对立体选择性有显著的影响;R5(除对甲苯磺酰基)没有明显的立体选择性差异,但是当R5为对甲苯磺酰基时,却表现了专一的立体选择性。
5.本文得到的BZD衍生物与THIQ衍生物结构与四特征药效团模型吻合,有做抗抑郁或抗惊厥活性筛选的价值。
Depression is one of the most common neurological problems resulted from the disorder of Glutamatergic neurotransmission which is mediated by ionotropic receptors (iGluRs) and metabotropic receptors (mGluRs). The iGluRs are ligand gated ion channels which are further subdivided into three classes based on their affinity for specific agonists: the N-methyl-D-aspartic acid (NMDA), the kainic acid (KA), andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subtpypes. NMDA receptor antagonists are the first one being applied for the antidepression therapy, while because of being considered relation with some irreversible damage, they are now replaced by AMPA receptor antagonists, which are found with more active neuromodulating effects and less adverse effects. 2, 3-Benzodiazepine (2, 3-BZD) and tetra- hydroisoquinolines (THIQs) are two representative AMPAR antagonists, and they have received considerable attention due to their diverse activity to neuromodulating effects. This paper focuses on 2, 3-BZDs and THIQs giving following discussion:
1. The Friedel-Crafts acylation is chosen as the key step during sythesis of BZD derivatives. The synthetic method is considered by trying a series of reaction conditions including screening acylating reagent, catalyst, solvent, reaction temperature and equivalent of the substrates. The key intermediate 1-[2-(4-Bromo-benzoyl)-4, 5-dimethoxy-phenyl]–propan-2-one K-3 which is prepared by applying the optimized condition, then is dehydrated with hydrazine hydrate in the presence of concentrated sulfuric acid to give 1-(4-Bromo-phenyl)-7, 8- dimethoxy-4-methyl-5H-benzodiazepine K-Br-BZD.
2. The modification of BZD is proceeded by applying the palladium catalyzed amide coupling reaction and provide two BZD derivatives: 7, 8–dimethoxy-1-(4-methoxy-phenyl)-4-methyl-5H-benzodiazepine K- 347 and 7, 8-dimethoxy-1-(4-nitro-phenyl)-4-methyl-5H-benzo- diazepine K-353.
3. Different R1-4 and R7 substituted phenyl acetones are prepared from benzaldehyde and phenyl cyanide; different hydrazine are prepared from different acid esters; different hydrazones was prepared from the obtained phenyl acetones and hydrazines then undergoing reductive reaction to provide the key intermediate hydrazide, which via Pictet-Spengler reaction give 65 new THIQs.
4. The configuration of the trans and cis isomers are confirmed by analysis of the X-ray of A-2 and the coupling constant 3JHH of B-13.
5. Detailed discussion about the effects resulted from R1-4, R5, R6, R7 on the configuration of the THIQs are involved in the paper. R1-4 effect on both coupling reaction and configuration of the products. R6, R7 have distinct effects on the steteoselectivity. R5 does not show clear effects on the products configuration, while when R5 is p-tosyl group, it appears highly stereoselective character.
6. The structure of the desired BZD derivatives and THIQ derivatives are comparable to the 4-feature pharmacophore model, and they could be valuable for following bioactivity test on antidepression or anticonvulsant.
引文
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