This topic covers drugs of Sedative & Hypnotic especially from Benzodiazepine class including drugs such as Diazepam , Nitrazepam, Lorazepam, Oxazepam etc also deals with drugs of alcohol class. reference should be take from Med Chem by Algarswamy , Organic Chemistry by Robert Neilson Boyd and Robert Thornton Morrison or any other suitable reference book.

1. MEDICINAL CHEMISTRY
GUIDED BY –
RESPECTED PRADNYA GONDANE MAAM

2. SEDATIVES AND HYPNOTICS
• GROUP NAME: DIAZEPAM DUDES
• GROUP MEMBERS :
• ROUNAK LEDWANI
• MOHIT DONGARWAR
• KARTIK KANUGO
• JATIN JANI

3. INTRODUCTION :
 Sedatives are central nervous system (CNS) depressant drugs that reduce
excitement, tension, and produce relaxation.
 Hypnotics are drugs that depress the CNS and produce sleep similar to
that of natural sleep.
 Both sedative and hypnotic action may reside in the same drug.
 At lower dose, the drug may act as sedative, while at a higher dose the
same drug may act as hypnotic.

4. Sedatives and hypnotics are also
used as the following:
 antianxiety agents
 anticonvulsants
 muscle relaxants
 general anaesthetics
 preanaesthetic medication
 antipsychiatrics
 to potentiate analgesic drugs
 adjuvant to anaesthesia
 a co-drug in the treatment of hypertension

5. Sedatives and hypnotics are classified on the
basis of their chemical structure, as follows:
 1. Barbiturates
 2. Benzodiazepines
 3. Acyclic hypnotics containing nitrogen
 4. Cyclic hypnotics containing nitrogen
 5. Alcohols and aldehydes
 6. Acetylene derivatives

6. BENZODIAZEPINES
 The benzodiazepines continue to be widely used for the management of
anxiety states. Since anxiety symptoms may be relieved by many
benzodiazepines, it is not easy to demonstrate the superiority of one
individual drug over another.
 Benzodiazepines can cause a dose-dependent decrease in both rapid
eyeball movement and non rapid eyeball movement and slowly cause
sleep, although to a lesser extent than barbiturates.

7.  Mode of action: Benzodiazepine receptors are present in the brain
and they form a part of GABA𝑨 receptor’s chloride ion channel
macromolecular complex. Binding of benzodiazepines to these receptors
produces activation of GABA𝑨 receptor and increases chloride
conductance by increasing the frequency of opening chloride ion
These in turn inhibit neuronal activity by hyper-polarization and de-
polarization block.
 Metabolism of Benzodiazepines: Compounds without the hydroxyl
group are nonpolar, and undergoes hepatic oxidation. Compounds with
hydroxyl groups have more polarity and are readily converted into the
glucuronide conjugates and excreted easily. These compounds are also
metabolized by 3-hydroxylation of benzodiazepine ring.

8. Benzodiazepine

9. 1. Diazepam(Calmpose, Diazep,
Valium)
IUPAC: 7-Chloro-1-methyl-5-phenyl-1,4-benzodidiazepin-2-one
Benzodiazepine Diazepam
R1 -CH3
R2 =O
R3 –H
R7 -Cl
R2’ -H

10. Synthesis of Diazepam

11. Properties and uses
 It is white or almost white crystalline powder.
 It is soluble in ethanol and slightly soluble in water.
 It is used as skeletal muscle relaxant, anti-convulsant and anti-anxiety
agent.
 It take longer time to achieve sedative and hypnotic effect.
 Patient should avoid driving until a few days after the drug is discontinued.

12. Assay, storage, dose and dosage forms
 Assay: dissolve the sample in acetic anhydride and titrate with 0.1 M
perchloric acid and determine the endpoint using potentiometer.
 Storage: store in well closed airtight container and protect from light.
 Dose: for short term management of anxiety- 2 mg 3 time a day.
for insomnia- 5-15 mg at bedtime
 Dosage form: Diazepam tablet IP BP
Diazepam injection IP BP
Diazepam Capsule IP
Diazepam oral solution BP

13. 2. Nitrazepam(Nipam, Dormin,
Nitrosun)
Nitrazepam
IUPAC: 7-Nitro-5-phenyl-1,4-benzodiazepine-2-one

14. Properties and Uses
 It is yellow crystalline powder.
 It is slightly soluble in alcohol and insoluble in water.
 It used as sedative and hypnotic.
 It is used in management of myoclonic siezures.

15. Assay, Storage, dose and dosage form
 Assay: Dissolve the sample in acetic anhydride. Titrate the solution with 0.1
M perchloric acid and determine the endpoint potentiometrically.
 Storage: it is stored in well-closed airtight container ad protect from light.
 Adult Dose: for short term insomnia management- 5mg at night.
 Elderly and debilitated patient requires less than normal adult dose.
 Dosage form: Nitrazepam tablets IP BP
Nitrazepam oral suspension BP

16. 3. Oxazepam (Serepax)
7-Chloro-3-hydroxy-5-phenyl-1,4-benzodiazepin-2-one

17. Oxazepam (Serepax)
Properties and uses: It is a white or almost white crystalline powder slightly soluble in
ethanol and insoluble in water. It is useful for the control of acute tremulousness,
inebriation, or anxiety associated with alcohol withdrawal.
Side effects : rashes, nausea, lethargy, oedema, slurred speech, tremor, and altered libido.
More severe reactions include leucopenia and jaundice.
Assay: Dissolve the sample in anhydrous acetic acid and acetic anhydride. Titrate with 0.1
M perchloric acid and determine the endpoint potentiometrically.
Storage: It should be stored in well-closed airtight containers and protected from light.
Dose: For anxiety, alcohol withdrawal syndrome—Adult: 15–30 mg 3 or 4 times/day. For
insomnia associated with anxiety: Adult: 15–25 mg given 1 h before bedtime. Up to 50 mg
may be occasionally required.
Dosage forms: Oxazepam tablets B.P.

18. 4. Lorazepam (Larposa, Lorvan)
 7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,4-benzodiazepin-2-one

19.  Properties and uses: It is a white or almost white crystalline powder, which is insoluble
in water
 sparingly soluble in ethanol
 sparingly soluble in methylene chloride.
 It shows polymorphism. It is used as sedative and hypnotic.
 It has much more polarity than diazepam, for example, metabolism is relatively
uncomplicated, and the duration of action is short.
 Assay: Dissolve the sample in dimethylformamide. Titrate with 0.1 M
tetrabutylammonium hydroxide and determine the endpoint potentiometrically.
 Dose: For Anxiety—Adult: Usual dose 1–6 mg daily in 2 or 3 divided doses. Largest
dose taken at night. Up to 10 mg daily has been used. For insomnia associated with
anxiety; Adult: 1–4 mg as a single dose given at bedtime. Dosage forms: Lorazepam
injection B.P
., Lorazepam tablets B.P

20. Alprazolam (Niravam, Xanax)
IUPAC: 8-Chloro-1-methyl-6-phenyl-4H-1,2,4- -triazolo(4,3-a) (1,4)benzodiazepine

21. Properties & uses, Assay and storage.
 It is white crystalline powder.
 Practically insoluble in water, free soluble in methylene chloride, sparingly
soluble in alcohol.
 It shows polymorphism.
 Use in short term management of insomnia characterized by difficult in
falling sleep, frequent nocturnal awakening and early morning awakening.
 Its duration is short and the drug is highly potent anxiolytic in doses of mg.
 Assay: dissolve sample in 3 vol. of anhydrous acetic acid and 2 vol. of acetic
anhydride. Titrate with 0.1 M perchloric acid determine the end point using
potentiometer. Titrate to second point of inflexion.

22. Clorazepate(Tranxene, Tranxilium,
Novo-Clopate)
Uses- it is used as sedative and hypnotic

23. Chlordiazepoxide (IBS-10, librium)
IUPAC- 7-chloro-2-methylamino-5-phenyl-3H-1,4-
benzodiazepine-4-oxide
Uses- It belongs to benzodiazepine class.
It is a sedative and hypnotic.
It is a CNS depressant and helps to control symptom of
alcohol withdrawal.
It helps in reliving anxiety and hence helps in sleep.

24. SAR of Benzodiazepines
 • The presence of electron attracting substituents (Cl, F, Br, NO2 )
at position C-7 is required for the activity, and the more electron
attracting substituents leads to potent activity.
 • Position 6, 8, and 9 should be unsubstituted for the activity.
 • Phenyl (or) pyridyl at the C-5 position promotes activity. If the
phenyl ring substituted with electron attracting groups at 2’ or 2’ ,
6’ position, then the activity is increased.
 • On the other hand, substituents at 3’ , 4’ , and 5’ positions
decreases activity greatly.
 • Saturation of 4, 5 double bond or shift of it to the 3, 4 position
decreases the activity.

25.  • Alkyl substitution at position 3 decreases the activity, but the presence or
absence of hydroxyl group is essential. Compounds without 3-hydroxyl
group are nonpolar and usually have long half-life. Compounds with the 3-
hydroxyl group have short half-life because of rapid conjugation with
glucuronic acid.
 • Substitution at N1 by alkyl, halo alkyl, and amino alkyl group increases
the activity.
 • Reduction of carbonyl function at C-2 position to CH2 yields less potent
compound.
 • Triazolo benzodiazepine (Alprazolam) is found to be more potent, they
do not require any substitution at 7th position.

26. Ethchlorvynol (Placidyl)
IUPAC: 1-Chloro-3-ethyl1-penten-4-yn-3-ol

27. Properties & uses and dose.
 It is CNS depressant.
 It also possess muscle relaxant and anticonvulsant properties.
 Adverse effects include suppression of REM sleep, ataxia and hypotension.
 Dose: 500-1000 mg hypnotic.
100-200 mg sedative.

28. Zolpidem
It is a new drug.
It is white crystalline powder. Hygroscopic in nature.
It is slightly soluble in water, sparingly soluble in methanol, insoluble
in methylene chloride.
It is used for the management of insomnia.
IUPAC- N,N-Dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-
yl]acetamide hemitartrate

29. Thank you