PHC 801 - Tranquilizers (Anxiolytics) - Prof. T. O. Idowu.ppt

Advance chemistry of Tranquilizers (Anxiolytics) for undergraduate and postgraduate students

1. Professor Thomas O. Idowu
Department of Pharmaceutical Chemistry,
Faculty of Pharmacy,
Obafemi Awolowo University, Nigeria
PHC 801: Tranquilizers (Anxiolytics)
1

2. 2
Anxiolytics (Tranquilizers)
Many illnesses are accompanied by anxiety, a worried state during
which a syndrome characterized by feelings of helplessness,
despair, dark premonitions, and asthenia begins to develop.
It can be accompanied by headaches, increased perspiration,
nausea, tachycardia, dry mouth, etc.
The primary use of tranquilizers is alleviation of emotional symptoms
associated with psychoneurotic or psychosomatic disturbances, such
as
excitement, anxiety, worry, muscle tension, and elevated motor
activity. Used independently, they are not acceptable for rapid relief of
severe psychotic conditions, and are used in such cases in
combination with antipsychotic drugs.

3. 3
Anxiolytics that are presently used in medicine are divided into two
groups. They are:
(i). Benzodiazepines represented by:
diazepam, chlordiazepoxide, chlorazepate, galazepam, lorazepam,
midazolam, alprazolam, oxazepam, prazepam; and
(ii). other anxiolytics, or nonbenzodiazepine structures which are
represented by meprobamate, buspirone, chlormezanone, and
hydroxyzine.

4. 4
BENZODIAZEPINES
Benzodiazepines turned out to be extremely effective drugs for treating neurotic
conditions.
The primary effects of benzodiazepines on the central nervous system (CNS) are:
relief of anxiety, and worry, sedative effect, relaxation of skeletal muscle, and
soporific action.
From the chemical point of view, benzodiazepines are formally divided
into two main groups:
(i). simple 1,4-benzodiazepines (chlordiazepoxide, diazepam,
lorazepam); and
(ii). Heterocyclic 1,4-benzodiazepines (alprazolam, medzolam, and
others).

5. 5
Chlordiazepoxide (Librium)
Alprazolam (Xamax)
N
N
Cl
NHCH
3
O
1
4
6
7
8
Diazepam (Valium)
N
N
Cl
O
CH
3
Oxazepam (Serax)
N
H
N
Cl
O
OH
Nitrazepam (Mogadon)
N
H
N
Cl
O
Flurazepam (Dalmane)
N
N
Cl
O
CH
2CH
2N
C
2H
5
C
2H
5
F
Flunitrazepam (Rohypnol)
N
N
O
2N
O
CH
3
Midazolam (Versed)
Triazolam (Halcion)
N
N
Cl
N
H
3C
F
N
N
Cl
N
H
3C
Cl
N
N
Cl
N
N
H
3C
N
H
N
Cl
O
OH
Cl
Lorazepam (Ativan)
EXAMPLES OF BENZODIAZEPINES

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Structural features for good antianxiety potency
A condition necessary for the expression of anxiolytic activity of
benzodiazepines is the presence of
(i). A methyl group attached to the nitrogen atom at 1-position
(ii). an electronegative group such as halogen, NO
2
, CF
3
and CN on C
7

of the benzodiazepine system.
(iii). a phenyl group (or a phenyl group with an electronegative
substituents such as F in the o-position) on C
5 of the system which
increases the pharmacological activity of these compounds.

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Methabolism
Most benzodiazepines are completely absorbed after oral administration and
are rapidly distributed to the brain and other perfused organs
They are metabolized by hydrolysis, hydroxylation, dealkylation, reduction, and
conjugation to active or inactive compounds
Assay:
By non-aqueous titration using 0.1M perchloric acid as titrant and by UV
spectrophotometry

8. 8
2-amino-5-chlorobenzophenone.
O
NH
2
Cl
NOH
NH
2
Cl
NH
2OH
ClCH
2COCl
R = CH
3, Chlordiazepoxide (Librium)
(results from unexpected ring
expansion reaction)
N
N
Cl
NHR
O
1
4
6
7
8
Cl
CH
2Cl
O
N
N
CH
3NH
2
2-amino-5-chlorobenzophenone
oxide
methylamine
chloroacetic acid
chloride in acetic acid
easily cyclizes to 6-
chloro-2-chloromethyl-4-
phenylquinazolin-3-oxide
hydroxylamine
6-chloro-2-chloromethyl-4-
phenylquinazolin-3-oxide
SYNTHESIS OF CHLORDIAZEPOXIDE

9. 9
NH
2
A
+
ClOC
O
NH
2
Cl
NOH
NH
2
Cl
ZnCl
2 NH
2OH
ClCH
2COCl
NOH
NHCOCH
2Cl
Cl
Cyclization
Cl
CH
2Cl
O
6 - Chloro -2 -chloromethyl -4 phenylquinazoline -3 -oxide
N
N
Cl
N
NCH
2NH
2
R = CH
3, Chlordiazepoxide (Librium)
(results from unexpected ring
expansion reaction)
N
N
Cl
NHR
O
1
4
6
7
8
Epected product
R
2NH
RNH
2 (Rearrangement)
SYNTHESIS OF CHLORDIAZEPOXIDE

10. 10
SARS OF BENZODIAZEPINES
(I) Ring A substitution
(i). Optimum position for substitution is C-7
(ii). Only electron withdrawing groups lead to increase in functional anxiolytic
activity e.g Cl, Br, CF
3 NO
2
(iii). Any substitution on positions 6, 8, 9 leads to decrease in anxiolytic activity
B
4'
5
3
9
C
N
H
N
Cl
O
1
4
6
7
8
A

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(II) Ring B substitution
(i). N
1
- substitution lead to increased activity by N – alkyl, haloalkyl, alkynyl and
aminoalkyl groups
(ii). Substitution on position C-3 by hydroxylation leads to less duration of action
and less potency due to rapid conjugation, but still clinically useful e. g
oxazepam, lorazepam
(iii). Proton accepting group (e. g. ketone moiety) in position C-2 appears to be
necessary.
(iv). 4-5 double bond or 4 – position nitrogen in ring B is not required for in vivo
anxiolytic activity.
(v). Annelating the 1, 2 – bond of ring B with an additional “electron-rich”(i.e.
proton acceptor), e. g. s-triazole or imidazole results in pharmacologically active
benzodiazine derivatives with high affinity for the benzodiazepine receptor e. g.
alprazolam, triazolam and estrazolam – clinically effective, anxiolytic agents

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(II) Ring C substitution
(i). Electron withdrawing group e.g. Cl, F at C-2’ leads to increase in activity
(ii). Any substitution at C-4’ leads to dramatic decrease in activity
(iii). C-ring can be heteroaromatic, even cycloalkenyl

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ANXIOLYTIC OF NONBENZODIAZEPINE STRUCTURES
Meprobamate (Meprobamate, 2-methyl-2-propyl-1,3-propandiol dicarbamate)
This was proposed before the introduction of benzodiazepines into medical
practice.
The exact mechanism of action of this drug is not known; however, its effects on
the CNS are more similar to the effects barbiturates than to benzodiazepines, but
with shorter lasting action. After the introduction of benzodiazepines into
practice, the use of this drug became significantly less.
Meprobamate is used primarily as a daytime anxiolytic in treating
conditions of anxiety associated with everyday, usual, and common stress.

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Synthesis of Meprobamate

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