Hypnotics and Sedatives Chapter 2 수면진정제 Hypnotics and Sedatives

Hypnotics and sedatives 1869: Chloral hydrate가 수면제로 도입(Liebreich). 1882: M. Conrad와 M. Guthzeit가 barbital 합성. 1904: E. Fischer와 A. Dilthey가 효율적합성방법 확립. Bayer에서 Veronal®도입. Schering사에서 Na염 Medinal® 개발 Structural class: - Barbiturate: Barbital, Phenobarbital, Pentobarbital - Benzodiazepine: Triazolam, Flurazepam, - Pyrazolpyrimidine: Zaleplon - Piperidinediones: Glutethimide, Thalidomide - Antihistamine, Anticholinergics etc.

Classification of Hypnotics Bezodiazepines GABA receptor Mild supression of REM Estrazolam, Flurazepam, temazepam etc. Barbiturate GABA inhibitory action(Cl-Channel) Phenobarital, thiopental Piperidinediones GABA Inhibitory action Supress REM Glutethimde, Thalidomide Nonbezodiazepine GABA agonist GABA receptor agonist Zolpidem, Zopiclone Antihistamines Antihistamine(penetration of BBB) Piphenhydramine, Doxylamine

Barbitals act as similar mode of allosteric effect GABA receptor and BZD Barbitals act as similar mode of allosteric effect

Clinical Evaluation of Hypnotics

Sleeping Cycle NREM(90 min) : Physical recovery REM(20 min): Memory Consolidation

EEG Pattern of sleeping

Circadian Rhythm

Melatonin

Biosynthesis of melatonin How about drinking Milk before sleeping ?

산조인

Barbital* 5,5-Diethylpyrimidine-2,4,6(1H,3H,5H)-trione 5,5-Diethylbarbituric Acid Veronal®(Bayer) 현재 국내에서는 사용되지 않음

SAR of Barbitals N sub: lipophilic, short acting N, N-disub: non ionization, inactive Long Chain: Lipophilic, short acting S: lipophilic, short acting

Duration time and Metabolism of Barbitals

Barbital Retrosynthesis C-alkylation

Barbital Synthesis

Phenobarbital* 5-Ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione 5-Ethyl-5-phenylbarbituric Acid 제품명 : 페노바르비탈 정(하나), 바이넥스 페노바르비탈 정(바이넥스), 페노바르비탈 주(제일), Luminal®(Bayer) E. Fischer와 A. Dilthey에 의하여 합성(1903년). Epilepsy 환자에게 수면 목적으로 투여. 항경련 목적으로도 사용됨.

Phenobarbital Retrosynthesis I

Phenobarbital Synthesis I

Phenobarbital Retrosynthesis II

Phenobarbital Synthesis II

Pentobarbital Sodium** Sodium 5-Ethyl(1-methylbutyl)barbiturate 엔토발 주(한림), Nembutal Sodium®(Lundbeck) Barbital 합성법과 유사

Pentobarbital Sodium Synthesis

Triazolam 8-Chloro-5-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4] benzodiazepine 할시온 정(한국화이자), 트리탐 정(환인), 졸민 정(명인), Halcion®(Pharmacia and Upjohn)

Triazolam Retrosynthesis Triazole synthesis

Triazolam Synthesis Triazole synthesis

Triazole synthesis

Melatonin and Bzd

Flurazepam 7-Chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H -1,4-benzodiazepin-2-one 달마돔 정 (고려), Dalmane®(Valeant Pharm)

Flurazepam Retrosynthesis

Flurazepam Synthesis I

Flurazepam Synthesis I Gabriel synthesis

Flurazepam Synthesis II

Zolpidem N,N,6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide 스틸녹스 정(사노피), 졸피람 정(환인), 졸피아트 정(대웅), 졸피움 정(고려), Ambien®(Sanofi-Aventis)

Clinical Application

Zolpidem Retrosynthesis

Zolpidem Synthesis I A

Synthesis of Pyrrole(A)

Zolpidem Synthesis II B Mannich reaction

Mannich Reaction Iminium salt

Synthesis of B(Mannich Rx)

Hydroxyzine HCl** (RS)-2-(2-{4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl}ethoxy)ethanol 로진 정(한국파마), 르잔 정(대림), 유시락스 정/시럽(유한), 하이진 정(대우), 히드록신정(헤파가드), Atarax(Pfizer)

Hydroxyzine HCl Retrosynthesis

Hydroxyzine HCl Synthesis

Ramelteon** Melatonin receptor agonist (-)-(S)-N-[2-(2,6,7,8-Tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethyl] propionamide, N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e][1]benzoxol -8-yl]ethyl]propanamide Rizerem(Takeda) Melatonin receptor agonist

Ramelteon

Circadian Rhythm

Melantonin

Milk and Sleeping ?

Ramelteon Retrosynthesis Why? *

Ramelteon Synthesis Modified Wittig reaction

Wittig Reaction

Demethylation by BBr3

Ramelteon Synthesis

[3, 3] sigmatropic rearrangement