This presentation will help you understand the concise summary of Benzodiazepines from the Medicinal Chemistry point of view. it is a brief and concise summary so if there is any mistake, you can point out it to me or make corrections yourself. thanks Amjad Anwar

1. By;
AMJAD ANWAR
Department of Pharmacy, UOM

2.  A large number of drugs that have primary Sedative and Hypnotic
affects are the derivatives of 1, 4-Benzodiazepines
 The first pharmacologically active member of this class of drugs was
chordiazepines, which was synthesized by Sternbach in 1959.

3.  It was discovered accidently, when 6-Chloro-2-Chloromethyl-4-
Phenylquinazoline-3-Oxide was treated with Methyl amine, Instead
of obtaining the expected 6-Chloro-2-methylaminomethyl-4-
Phenyl quinazoline-3-Oxide, It was observed that ring enlargement
occurred and the resultant compound form was Chlordiazepoxide.

4.  When it was discovered that Chlordiazepoxide is
rapidly metabolized to a series of active
compounds, Nordazepam and Oxazepam, it gave
great attention towards the synthesis and testing
of these compounds.
General Structure of 1, 4-Benzodiazepine

5. Drug Name R1 R2 R3 R4 R5
Diazepam CH3 =O H Cl H
Oxazepam H =O OH Cl H
Chlorazepate H =O COOH Cl H
Prazepam -CH2-….. =O H Cl H
Lorazepam H =O OH Cl Cl
Halozepam -CH2CF3 =O H Cl H
Temzepam CH3 =O OH Cl H
Flurazepam -CH2CH2N(C2H5)2 =O H Cl F
Chlorzepam H =O H Cl NO2

6.  Drugs to be discussed
◦ Diazepam
◦ Chlordiazepoxide
◦ Oxazepam
◦ Lorazepam

7.  Molecular Formula
◦ C16H13ClN2O
 Chemical Structure
 Chemical Name
◦ Chemically it is 7-Chloro-1, 3-dihydro-1-methyl-5-
Phenyl-3H-1, 4-Benzodiazepine-2-one.

8. Description
◦ It is off-white to yellow practically odorless
crystalline powder
◦ It is stable in air
◦ It melts at about 133oC
Solubility
 1 gm of it soluble in;
◦ 2 ml of Chloroform
◦ 16 ml of Alcohol
◦ 333 ml of water

9. Molecular Formula
◦ C16H14ClN3O
Chemical Structure
Chemical Name
◦ 7-Chloro-2(Methylamino)-5-Phenyl-3H-1, 4-
Benzodiazepine-4-Oxide

10. Description
 It is yellow practically odorless crystalline powder,
sensitive to sunlight
 It melts at about 242oC
 Its PKa value is 4.6
Solubility
 1 gm of it is soluble in;
◦ 50 ml alcohol
◦ 130 ml Ether
◦ > 1000 ml of Water

11.  Molecular Formula
◦ C15H11ClN2O2
 Chemical Structure
Chemical Name
 Chemically it is 7-Chloro-1, 3-dihydro-3-Hydroxy-5-Phenyl-3H-1,
4-Benzodiazepine-2-one

12. Description
 It is creamy white to pale yellow powder
 It is odorless and bitter in taste, stable in light and
more Hygroscopic
 PH of a suspension (1 in 50 ml) is from 4.8 to 7.0
 Melting point = Indefinite
Solubility
 1 gm of it soluble in;
◦ 220 ml of Alcohol
◦ 270 ml of Chloroform
◦ >1000 ml of Water
 Generally it is;
◦ Practically insoluble in water and
◦ Slightly soluble in Alcohol and Chloroform

13. Molecular Formula
◦ C15H10ClN2O2
Chemical Structure
Chemical Name
◦ Chemically it is 7-Chloro-5-(2-chlorophenyl)-1,3-
bihydro-3-Hydroxy-1, 4- Benzodiazepine-2- one

16. 1) The presence of an electron attracting
substituent, like Chlorine, at position # 7 is
required for activity. The more electron attracting
it is, greater is the activity.
2) A Phenyl group at Position # 5 is also essential
for activity.

17. 3) If the Phenyl group at position # 5 is the Ortho (2’) or
Diortho (2’, 6’) substituted with electron attracting substituents
like Cl, F, the activity increases. Para-substitution on the other
hand greatly decreases the activity.
 E.g. Lorazepam is more active than Diazepam
 Sedative dose of Lorazepam = 1-2 mg twice daily
 Sedative dose of Diazepam = 5 mg twice daily.

18. 4) Alkyl substitution at position No. 1 (N1)
increases the activity.
 E.g. Diazepam is more active than Oxazepam
(Without N1 methyl group).
◦ Sedative dose of Diazepam = 50 mg twice a day
◦ Sedative dose of Oxazepam = 15-30 mg twice a day
5) Alkyl substitution at position # 3 decreases the
activity, whereas OH group at the same position
has no such effect on the activity.
 The presence or absence of OH group at position
# 3 is important pharmacokinetically.
 Compounds without the OH group are not polar
and are readily converted to their Glucoronide
Conjugates.

19.  Additional research yielded compounds with a fused
triazole ring as in Alphrazolam. These compounds are
more active than other Benzodiazepines (Diazepam etc.)
 These compounds are mainly metabolized by Hydroxylation of the
methyl substituent on the Triazole ring. These are also metabolized
by the (3) Hydroxylation of the 1, 4-Benzodiazepine ring.

20. ◦ It is very interesting to be noted that the presence
of an electron attracting group at Position # 7 is not
required for the activity among these compounds.
6) Saturation of the 4-5 double bond or its
shift to 3-4 position decreases the activity.
7) Any substitution at position # 6, 8 & 9 also
decreases the activity.

21.  Diazepam and all other Benzodiazepines enhance
the increased Chloride ions conductance induced
by the interaction of GABA with its receptors, due
to increased frequency of Chloride Ion channels
opening.
 This effect occurs at post-synaptic receptors at all
level of Neuroaxis, including Cerebral cortex,
Cerebellar cortex, Substantia Nigra, Hypothalamus,
Hippocampus and Spinal cord.

22.  Anxiety
 Hypnosis
 For sedation, amnesia before medical and surgical
procedures
 Epileptic disorders
 Anesthetic pre-Medication
 For control of ethanol or other sedative-hypnotic
withdrawal states
 For skeletal muscles relaxation in specific
neuromuscular disorders
 Night terrors
 As a diagnostic aids
 For the treatment of Psychiatry