Medicinal Chemistry of Benzodiazepines with reference to Diazepam

1. BENZODIAZEPINE
(INTRO, MOA, SAR)
(Diazepam synthesis)
Department of pharmacy
University of Peshawar

2. INTRODUCTION
 Benzodiazepines (BZD), sometimes called
"benzos", are a class of psychoactive
drugs whose core chemical structure is the
fusion of a benzene ring and a diazepine ring.
 Diazepine is a heterocycle with
two nitrogen atoms, five carbon atom and the
maximum possible number of
cumulative double bonds. The "benzo" prefix
indicates the benzene ring fused onto the
diazepine ring.
 Different benzodiazepines have been
developed through chemical substitutions at
two major positions on the benzodiazepine
structure , Therefore, all benzodiazepines are
simply variations on the same core chemical
structure.

3. BENZODIAZEPINE EXAMPLES
DRUG R1 R2 R3 R4
DIAZEPAM Cl CH3 H H
NITRAZEPAM NO2 H H H
CLONAZEPAM NO2 H H Cl

4. HISTORY
 The first benzodiazepine, chlordiazepoxide (Librium), was synthesized
in 1955 by Leo Sternbach.
 Following chlordiazepoxide, Diazepam was synthesized in 1959 and
marketed by Hoffmann–La Roche under the brand name Valium in
1963.
 The introduction of benzodiazepines led to a decrease in the
prescription of barbiturates, and by the 1970s they had largely replaced
the older drugs for sedative and hypnotic uses.

5. CLASSIFICATION
 SHORT ACTING (5-20 HRS):
 Lorazepam (Ativan)
 Alprazolam (Xanax)
 INTERMEDIATE ACTING (10-30 HRS):
 Diazepam (Valium)
 Bromazepam (Lexotanil)
 LONG ACTING (30-100 HRS):
 Clonazepam (Rivotril)
 Clorazepate (Tranxene)
 ULTRA LONG ACTING (40-200 HRS):
 Flurazepam (Dalmane)
 Flunitrazepam (Rohypnol)

6. ADVANTAGES OF BDZ
 BDZ’s have high therapeutic index. Ingestion of even 20 hypnotic doses does
not usually endanger life.
 Hypnotic does not affect respiration or cardiovascular functions. Higher doses
produce mild respiration & hypotension which is problematic only in patients
with respiratory insufficiency & cardiac abnormality.
 BZDs have practically no action on other body system
 BZDs cause little distortion of sleep pattern
 BZDs do not alter disposition of other drug by microsomal enzyme induction.
 They have lower abuse liability: tolerance is mild, psychological & physical
dependence & withdrawal syndrome are less marked.
 A specific BZDs antagonist flumazenil is available which can be used in case of
poisoning.

7. MECHANISM OF ACTION
 Benzodiazepines work by increasing the efficiency of a natural brain
chemical, GABA, to decrease the excitability of neurons. This reduces the
communication between neurons and, therefore, has a calming effect on many
of the functions of the brain.
 GABA controls the excitability of neurons by binding to
the GABAa receptor. GABAa receptors contain an ion channel that
conducts chloride ions across neuronal cell membranes. GABAa receptor
complexes also contain a single binding site for benzodiazepines.
 Binding of benzodiazepines to this receptor complex promotes binding of
GABA, which in turn increases the conduction of chloride ions across the
neuronal cell membrane. This increased conductance raises the membrane
potential of the neuron, resulting in inhibition of neuronal firing.

8. MECHANISM OF ACTION

9. SAR
DIAZEPINE RING (B):
1. Diazepine ring (B) is essential for
activity.
2. Carbonyl group at P-2 is essential for
activity.
3. Double bond between P-4, P-5 is
essential for optimum activity.
4. Shifting double bond to P-3, P-4
deceases activity.
5. Phenyl group at P-5 increases
activity.

10. SAR
DIAZEPINE RING (B):
6. Substitution at P-3 decreases activity
except hydroxyl group which
increases polarity and metabolism.
7. Addition of electron rich ring at P-
1,2 forms derivatives having
increased affinity e.g Alprazolam,
Midazolam.

11. SAR
BENZENE RING (A):
1. Electronegative substitution (NO2,
X) at P-7 is essential for activity,
Higher electronegativity; increases
activity.
2. For optimum activity P-6, 8, 9 must
remain un-substituted.

12. SAR
PHENYL RING (C):
1. Electropositive substitution at P-2’
or P-6’ or both increases activity.
2. Substitution at P-4’ decreases
activity.

13. DIAZEPAM SYNTHESIS
 STEP 1:
5-Chloroaniline upon reaction with Nitrous acid forms Diazonium salt.

14. DIAZEPAM SYNTHESIS
 STEP 2:
Azocoupling of Diazonium salt with Ethyl a-benzylacetoacetic ester in an
alkaline solution gives 4-Chlorophenyl hydrazone of ethyl ester of phenyl
pyruvic acid.

15. DIAZEPAM SYNTHESIS
 STEP 3:
4-Chlorophenyl hydrazone of ethyl ester of phenyl pyruvic acid in presence
of Hydrochloric acid undergoes Fischer indole synthesis reaction and form
Ethyl ester of 5-chloro-3-phenylindolyl-2-carboxylic acid

16. DIAZEPAM SYNTHESIS
 STEP 4:
5-chloro-3-phenylindolyl-2-carboxylic acid when alkylated with dimethyl
sulfate gives 1-methyl-5-chloro-3-phenyl-indolyl-2-carbocylic acid ethyl
ester.

17. DIAZEPAM SYNTHESIS
 STEP 5:
1-methyl-5-chloro-3-phenyl-indolyl-2-carbocylic acid ethyl ester when
reacted with ammonia gives 1-methyl-5-chloro-3-phenyl-indolyl-2-amide.

18. DIAZEPAM SYNTHESIS
 STEP 6:
1-methyl-5-chloro-3-phenyl-indolyl-2-amide is reduced by lithium
aluminum hydride gives 1-methyl-3-phenyl-5-chloro-2-
aminomethylindole.

19. DIAZEPAM SYNTHESIS
 STEP 7:
1-methyl-3-phenyl-5-chloro-2-aminomethylindole is treated with
chromium oxide to open the indole ring to form 1-methyl-3-phenyl-5-
chloro-2-aminobenzophenone.

20. DIAZEPAM SYNTHESIS
 STEP 8:
1-methyl-3-phenyl-5-chloro-2-aminobenzophenone under the reaction
conditions cyclizes into Diazepam.

21. INDICATIONS
 Alcohol withdrawal (Diazepam)
 Anxiety (Lorazepam, Diazepam)
 Bipolar disorder (Clonazepam)
 Insomnia (Lorazepam)
 Muscle spasm (Diazepam)
 Nausea and vomiting (Lorazepam)
 Status epilepticus (Diazepam, Lorazepam)
 Tetanus (Diazepam)

22. THANK YOU!