1. Hypnotics and Sedatives
Chapter 2
수면진정제
Hypnotics and Sedatives

2. 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.

3. 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

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

5. Clinical Evaluation
of Hypnotics

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

8. EEG Pattern of sleeping

9. Circadian Rhythm

10. Melatonin

11. Biosynthesis of melatonin
How about drinking Milk before sleeping ?

12. 산조인

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

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

15. Duration time and Metabolism of Barbitals

16. Barbital
Retrosynthesis
C-alkylation

17. Barbital
Synthesis

18. 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.

19. Phenobarbital
Retrosynthesis I

20. Phenobarbital
Synthesis I

21. Phenobarbital
Retrosynthesis II

22. Phenobarbital
Synthesis II

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

24. Pentobarbital Sodium
Synthesis

25. 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)

26. Triazolam
Retrosynthesis
Triazole synthesis

27. Triazolam
Synthesis
Triazole synthesis

28. Triazole synthesis

29. Melatonin and Bzd

30. 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)

31. Flurazepam
Retrosynthesis

32. Flurazepam
Synthesis I

33. Flurazepam
Synthesis I
Gabriel synthesis

34. Flurazepam
Synthesis II

35. 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)

36. Clinical Application

37. Zolpidem
Retrosynthesis

38. Zolpidem
Synthesis I A

39. Synthesis of Pyrrole(A)

40. Zolpidem
Synthesis II B
Mannich reaction

41. Mannich Reaction
Iminium salt

42. Synthesis of B(Mannich Rx)

43. 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)

44. Hydroxyzine HCl
Retrosynthesis

45. Hydroxyzine HCl
Synthesis

46. 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

47. Ramelteon

48. Circadian Rhythm

49. Melantonin

50. Milk and Sleeping ?

51. Ramelteon
Retrosynthesis
Why? *

52. Ramelteon
Synthesis
Modified Wittig reaction

53. Wittig Reaction

54. Demethylation by BBr3

55. Ramelteon
Synthesis

56. [3, 3] sigmatropic rearrangement