Chapter 6 Central ervous System Drugs part 2 Sedative-hypnotics and Antiepileptics
6.3 Sedative-hypnotics ( 镇静 - 催眠药 ) 6.3.1 Introduction Anxiety disordersare characterized by an abnormal or inappropriate wariness. As many as 25% of adults suffering from some form of clinical anxiety at some point in their life. 20 million American, 30 million European and japanese suffering from insomnia yearly. Anxiety was subdivided into: Dyssomnias involves: insomnia( 失眠 ), hypersomnia( 嗜睡 ) excessive daytime sleepiness (EDS) social anxiety disorder (SAD, 社交焦虑症 ) posttraumatic stress disorder (PTSD, 创伤后焦虑 ) obsessive compulsive disorder (CD, 强迫症 ) generalized anxiety disorder (GAD, 泛焦虑症 )
6.3.2 assification of Sedative-hypnotics Barbitals(phenobarbital) Benzodiazepines(Diazapam) thers (zolpidem ) R 1 R 2 R 3 R 1 R 2 R 3 R 4 3 C 3 C C3 C 3 Antihistamines (1-antagonists), diphenhydramine ( 苯海拉明 ) GABA A benzodiazepine receptor (ω1) antagonists, Diazapam( 地西泮 ) zolpidem( 唑吡坦 ) Melatonin receptor agonists, ramelteon ( 雷美替胺 ) GABA A receptor agonists/modulators, Gaboxadol ( 加波沙朵 ) Selective GABA reuptake inhibitors, Tiagabine ( 噻加宾 ) Smalldose Middle dose igh dose verdose (Sedative) (hypnotics) (anesthesia) (kill beself)
6.3.3 Benzodiazepines R 2 1) Structures R 1 R 4 R 3 R1 R2 R3 R4 drugs C3 2 2 (C 2 ) 2 (C 2 5 ) 2 F C3 F diazepam oxazepam temazepam lorazepam nitrazepam clonazepam flurazepam fludiazepam
2) Stucture-activity Relationship of Benzodiazepines 1 Pharmacophore The 7-membered ring maintains the key features in an optimal 3D arrangement. Two moieties that were initially presumed to determine the activity of chlordiazepoxide, the methyl amine and -oxide, could be removed without loss of biological activity. This SAR work led to the identification of the more potent BZ, diazepam. R 1 A R 2 B R 4 R 3 7 1 2 5 4 Chlordiazepoxide( 氯氮卓 )
2Position 1,2 Biological activity may be increased when lactam carbonyl has been incorporated into a 1,2,4-triazolyl heterocycle as seen in alprazolam and triazolam. Complete removal of the lactam carbonyl results in a significant loss of biological activity. 8 S 1 6 2 3 4 Alprazolam ( 阿普唑仑 ) Triazolam( 三唑仑 )
3Position 3 hydroxylation Polar hydroxyl at the 3-position, present in oxazepam as a metabolite of diazepam, increase biological activity 去甲地西泮 temazepam lorazepam 奥沙西泮 葡萄糖醛酸结合物 葡萄糖醛酸结合物
4 7 or 2 -position of aryl group Electron withdrawing groups(, 2 )on the aryl group are generally observed, for example nitrozepam, clonazepam. 7 1 2 5 4 2' 2 2 itrozepam( 硝西泮 ) clonazepam( 氯硝西泮 )
Diazepam 地西泮 3 C 1 5 2 4 1 2 5 4 3 2-1,4- 二氮杂卓 -2- 酮 1,3- 二氢 -2-1,4- 二氮杂卓 -2- 酮 Chemical ame 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2-1,4-benzodiazepin-2-one 7- 氯 -1,3- 二氢 -1- 甲基 -5- 苯基 -2-1,4- 苯并二氮杂 -2- 酮
Synthesis route (C 3 ) 2 S 4 C 3 C 6 5. C 3 S 4 Fe, C 2 5 C 2 C C 6 12 (C 2 ) 6 4. C 3 用途 : 常用的镇静 催眠药, 用于一般性失眠和抗癫痫
Zolpedem, 唑吡坦 3 C C 3 3 C C3 Chemical ame Chemical ame,-dimethyl-2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide, - 二甲基 -2-(6- 甲基 -2- 对甲苯基咪唑并 [1,2-a] 吡啶 -3- 基 ) 乙酰胺
Synthesis route 3 C 3 C C 3 C3 C 3 3 C C 3 Br / Br 2 2 C 3 C 2 2 Br C 3 C 3 C 3 C 2 Br C 3 3 C C 3 C 3 C 3 Action Zopiclone, a type of imidazopyridine, is a non-bzs interacting at the ω1 binding site. This drug has the efficacy without the major liabilities of the classical BZs.
6.4 Antiepileptics( 抗癫痫药 ) 1) Introduction Epilepsy is the most common neurological disorder in humans, affecting 1 2% of the global population. According to World ealth rganization data, approximately 50 million people worldwide, suffer from epilepsy. Epilepsy is a chronic neurological disorder that is manifested in the form of recurrent, spontaneous seizure episodes( 发作 )or convulsions( 惊厥 ).
2) Type of epilepsy Generalized seizures ( 全身性发作 ) Partial seizures ( 部分性发作 ) 1 Generalized tonic-clonic seizure ( 全身强直 阵挛性发作, 大发作 ) 2Absenceseizure( 失神发作, 小发作 ) 1Simplepartialseizure partial ( 单纯部分性发作 ) 2 自主神经性发作 3 Complex partial seizures( 复杂部分性发作 )
3) assification Barbitals(phenobarbital, 苯巴比妥 ) Benzodiazepines (oxazepam 奥沙西泮 ) ydantoin (Phenytoin, 苯妥英 ) Succinimide(ethosuximide, 乙琥胺 ) ther Agents (Carbamazepine 卡马西平 Sodium Valproate 丙戊酸钠 ) 3 C 3 C C 3 phenobarbital oxazepam phenytoin ethosuximide C 2 Carbamazepine 3 C 2 C 2 C CCa 3 C 2 C 2 C Sodium Valproate
3 C 4) homotypical drugs of Barbiturates C=/C2 R 1 R 2 氢化嘧啶二酮类 phenobarbital 扑米酮 R 1 =C 2 5 R 2 =C 6 5 R 1 R 2 - C= C/ R 1 R 2 R 1 R 2 R 3 R 3 乙内酰脲类 噁唑酮 苯妥因 R 1 =C 6 5 R 2 =C 6 5 R 3 = 三甲双酮 R 1 =C 3 R 2 =C 3 R 3 =C 3 C/C2 R 1 R 2 R 3 丁二酰亚胺类 苯琥胺 R 1 = R 2 =C 6 5 R 3 =C 3
5) Stucture-activity Relationship on homotypical drugs of Barbiturates Several major groups of drugs have the common structure similar to Barbiturates An overall pattern in the foregoing is that R and R should both be hydrocarbon substituents. If both R and R are lower alkyls, the tendency is to be active against absence seizures( 小发作 )and not active against tonic-clonic seizure( 大发作 ). If one of the hydrocarbon substituents is an aryl group, activity tends to be directed toward tonic-clonic seizures. R R' R'' C C C R'' = -C-- Barbiturates = -- ydantoins = -C 2 - Succinimides
Phenotoin Sodium 苯妥英钠 a 5 1 P Chemical ame 5,5-Diphenylimidazolidine-2,4-dione sodium salt 5,5- 二苯基咪唑 -2,4- 二酮钠盐 fosphenytoin Action Phenytoin is not a CS depressant and produces its effects primarily via interactions with voltage-sensitive sodium (av) channels. It is available as a prodrug, fosphenytoin( 磷苯妥英 ),which can be infused more rapidly than phenytoin. 用途 : 用于癫痫的大发作和部分发作首选, 对癫痫小发作无效
Synthesis route ac 3 p 7-8 Benzoin condensation ( 2 ) 2 C 2 2 a,c 2 5 2 a a 5 1 2 a Pinacol rearangement
本节重点内容 : 1. 镇静催眠药主要结构类型有苯并二氮卓类 ( 如地西泮 三唑仑等 ) 和非苯并二氮卓类 ( 如唑吡坦等 ) 2. 掌握苯二氮卓类药物的基本结构 代表性药物代表性药物 构效关系构效关系 3. 抗癫痫药的结构类型有巴比妥类类 ( 如苯巴比妥 ) 乙内酰脲类 ( 如苯妥英钠 ) 和其他类 ( 如卡马西平 ) 4. 掌握代表性药物地西泮 唑吡坦唑吡坦 苯妥英钠的结构苯妥英钠的结构 化学名化学名 合成方法及用途