6.3 Sedative-hypnotics ( 镇静 - 催眠药 ) Introduction Anxiety disordersare characterized by an abnormal or inappropriate wariness. As many as 25% of

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1 Chapter 6 Central ervous System Drugs part 2 Sedative-hypnotics and Antiepileptics

2 6.3 Sedative-hypnotics ( 镇静 - 催眠药 ) 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 )

3 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)

4 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

5 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 Chlordiazepoxide( 氯氮卓 )

6 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 Alprazolam ( 阿普唑仑 ) Triazolam( 三唑仑 )

7 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

8 4 7 or 2 -position of aryl group Electron withdrawing groups(, 2 )on the aryl group are generally observed, for example nitrozepam, clonazepam ' 2 2 itrozepam( 硝西泮 ) clonazepam( 氯硝西泮 )

9 Diazepam 地西泮 3 C ,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

10 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

11 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

12 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.

13 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 ).

14 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 )

15 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

16 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

17 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

18 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

19 Synthesis route ac 3 p 7-8 Benzoin condensation ( 2 ) 2 C 2 2 a,c a a a Pinacol rearangement

20 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

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