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Sedative and Hypnotics 75
(iii) Carbamol: 2-chloro-2-ethyl-butyryl urea
HC —C—C—NH—C—NH
52 2
CH
25
Br
CH
3
O
O
Fig. 5.5
(iv) Petrichloral: Pentacrythritol Hemiacetal with chloral
C(CH OCH(OH)CCl )
234
Fig. 5.6
5.3.4 Heterocyclic Sedative and Hypnotics
(i) Glutethimide: 3-ethyl-3-phenyl-2,6-piperidinedinone
N
H
CH
65
CH
25
O
O
Fig. 5.7
(ii) Clomethazole: 5-(2-chloroethyl)-4-methylthiazole
S
CH
3
CH · CH Cl
22
N
Fig. 5.8
(iii) Zopiclone: 4-methyl-1-piperazine carboxylic acid ester of 6-(5-chloro-2-pyridyl)-6, 7-dihydro-
7-hydroxy-5-H-pyrrolo-(3, 4, b) pyrazine-5-one
N
N
N
Cl
N—CH
3
O—C—N
O
N
Fig. 5.9
76 A Textbook of Medicinal Chemistry
5.3.5 Miscellaneous Sedative and Hypnotics
(i) Valnoctamide: 2-ethyl-3-methyl valeramide
CH —CH—CH—C—NH
25 2
O
CH
25
CH
3
Fig. 5.10
(ii) Propofol: 2,6-Bis(1-methylethyl) phenol
HO
OH
CH
3
OHCH
3
Fig. 5.11
(iii) Melatonine: N-[2-(5-methoxy-1H-Indol-3yl)ethyl] metamide.
O
H
H
C
CH
3
N
H
Fig. 5.12
5.4 MECHANISM OF ACTION
Both barbiturates and benzodiazepines bind to allosteric site of GABA
A
receptors followed by
activating the receptors and alter the transmission of ions by opening the receptors and increase the
affinity of GABA for its receptors by altering the structure. Receptors activation increases the
membrane permeability to chloride ions, after binding of GABA to its receptors, thereby produces
hyper polarization in the cell body. This, in turn, inhibits neuronal activity. However, benzodiazepines
A
receptors. α subunits contain a histidin
amino acid residue. However, benzodiazepines bind to the receptor followed by increasing the
frequency of opening of the associated chloride ion channels, which causes hyperpolarization which
potentiates inhibitory action of GABA leading to sedative and anxiolytic effect. On the other hand
barbiturates binding site is believed to be different from benzodiazepines, that occurs at picrotoxin
binding site on chloride ion channels.
Sedative and Hypnotics 77
5.5 BARBITURATES
Chemically barbiturates are the derivatives of barbituric acid and are synthesized from the
condensation of malonic acid derivatives and urea derivatives. Barbiturates exert their pharmacological
action on CNS, expressed in patient behaviour to the obvious effects like sedation, sleep or general
anaesthesia depending on the administered dosage. Barbiturates are further classified on the physical
presence into the cell membrane and exhibit drug-receptor interaction. Barbiturates are used for a
period of time for the treatment of insomnia, controlling several convulsant condition and for the
treatment of various forms of epilepsy. They are also used for pre- and post-operational sedation,
for relieving patient from anxiety, nervousness and tension. Barbiturates are considered lethal at
about 10 times the hypnotic dose that is believed to be 6–10 gm of phenobarbital or 2–3 gm of
secobarbital, pentobarbital or amobarbital.
5.5.1 General Synthetic Approach of Sedative and Hypnotics
C
H
COOet
H
COOet
C
R
COOet
H
COOet
R—X
C H ONa
25
Monoalkyl
diethyl malonate
Diethyl malonate
R—X
1
C H ONa
25
C
R
COOet
R
1
COOet
N—C
H
R
2
NH
2
O
N
N
H
O
C
O
O
R
1
R
R
2
5, 5-Dialkyl barbiturates
X = Halogen
Urea derivative
C H ONa
25
Note: This synthetic approach is meant for all barbiturates except hexobarbital and phenobarbital.
Fig. 5.13
1. Phenobarbital (Luminal)
®
: 5-ethyl-5-phenyl barbituric acid or 5-ethyl-5-
phenylhexahydropyrimidine 2, 4, 6-trione phenobarbital is suggested in the treatment of epilepsy,
cholera, spastic paralysis, etc.
O
C
N
|
H
HN
CH
25
OO
Fig. 5.14
78 A Textbook of Medicinal Chemistry
Synthesis:
CH — C N
2
CH — COOC H
252
Benzylcyanide
CHOH|H
+
25
COOC H
25
COOC H
25
Diethyl
oxalate
COOC H
25
CO
CH
COOC H
25
COOC H
25
CH
COOC H
25
COOC H
25
C—CH
25
COOC H
25
CH
25
O
O
H—N
N
|
H
HN—C—NH
22
Urea
O
1. C H ONa
2. C H Br
25
25
Phenobarbital
Fig. 5.15
2. Hexobarbital (Sombulex)
®
: 5-(1-cyclohexen-1-yl) 1, 5-dimethyl barbituric acid
Synthesis:
O+
COOMe
CH
2
CN
Cyclohexanone
Methyl
cyanoacetate
COOMe
CH
CN
(CH ) SO
32 4
C H ONa
25
COOMe
C—CN
CH
3
HN—C—NH
22
C H ONa
25
NH
HN
O
CH
3
NH
N
H
H
N
O
O
CH
3
O
N
H
N
2. H SO
24
(i) (CH ) SO | N-methylation
32 4
Hexobarbital
CH
3
H
Fig. 5.16
Hexabarbital is a short acting barbiturate which undergoes within 15 minutes and hypnotic action
remains for 1 to 2 hrs. It is used in the treatment of insomnia and pre-operative medication.
Sedative and Hypnotics 79
3. Mephobarbital (Mebaral)
®
: 5-ethyl-1-methyl-5-phenylbarbituric acid. Mephobarbital is used as
a sedative for relieving anxiety and tension. It is also used in the treatment of major or minor
epilepsy.
CO
O
CH
25
C
O
C
CH
3
Mephobarbital
H—N
N
Fig. 5.17
4. Amobarbital (Amytal)
®
: 5-ethyl-5-isoamyl barbituric acid. Amobarbital is suggested as a sporific
drug in various forms of insomnia and used as a sedative and an anticonvulsant drug.
O
CH — CH — CH — CH
22 3
O
H
H—N
CH
25
O
CH
3
N
Fig. 5.18
5. Pentobarbital (Nembutal)
®
: 5-Ethyl-5-(2-amil)barbituric acid. It is a isomer of amobarbital. It is
clinically useful as a relaxant and used for short-term insomnia.
CH
25
O
H—N
CH — C H
37
O
CH
3
N
H
O
Fig. 5.19
80 A Textbook of Medicinal Chemistry
5.6 SAR OF (BARBITURATES) SEDATIVE AND HYPNOTICS
H—N
1
2
3
4
5
6
N—H
RR
5
OO
O
Fig. 5.20
1. PKa Aspects of Barbiturates/Structural Features
(i) After several studies of synthetic approaches of barbiturates in 1951, scientist Sandberg
postulated the fundamental point for exhibiting better hypnotic activity. Barbituric acid must
be a weak acid and must have a lipid/water partition coefficient to a certain limit. This is only
the reason that 5, 5-disubstituted barbituric acid, 1, 5, 5-trisubstituted thiobarbituric acid and
1, 5, 5-trisubstituted barbituric acid exhibit remarkable hypnotics, anticonvulsant and
anaesthetic activities.
(ii) There are possible three lactam groups that can undergo pH dependent lactim-lactam
tautomerization—di-oxotautomaric form in alkaline media while trioxo tautomaric form in
acid media. The study revealed that the acidity of barbiturates in acqueous solution depends
on the number of substituents attached to it. Tautomerization is shown below.
HN
NH
RR
OO
O
N
NH
RR
OO
O
PKa 7.1–8.1
N
N
RR
ONa
+
O
O
PKa 11.7–12.7
–
–
Na
+
–
Barbituric acid
(Trioxo form)
(Dioxo form) (Mono oxoform)
Na
+
Fig. 5.21
2. 5, 5, Disubstitution
(i) Introduction of homologue series of carbon atom at fifth position of carbon resulting, increases
the lipophilic character of substituted barbituric acid.
Sedative and Hypnotics 81
(ii) Replacement of branching groups, unsaturation, alicyclic or aromatic substitution for alkyl
substituents, as well as introducion of halogen derivatives, increase the lipid solubility of
barbituric acid, subsequently easy penetration into blood brain barrier.
(iii) Introduction of polar group into alkyl substituents decrease the lipid solubility below the
desirable expect.
3. Substitution on Nitrogen Group
(i) Introduction of imide hydrogen by alkyl groups leads to increase in lipid solubility, quick
onset of action and shortening of duration of action.
(ii) Increase the size of alkyl substituent at nitrogen, further increase (C
1
–C
3
) is responsible for
decrease hydrophilic character, further increase alkyl substituents, imparts convulsant
character to barbiturates.
(iii) Alkyl substituents at both N
1
and N
3
render the drug non-acidic which make the inactive
compound.
4. Modification of Oxygen Atom
(i) Replacement of oxygen at carbon 2 position by sulphur atom leads to increase lipid soluble
character and increase onset of action, e.g., thiopental is used as intravenous anaesthetics.
5.7 BENZODIAZEPINES
All benzodiazepines show sedative effect on low doses. Even in higher doses they induce sleep and
further coma. The sedative effect caused by benzodiazepines impaires motor skills, memory and
judgement. Benzodiazepines have advantages over barbiturates. They exert multiple pharmacological
effects on CNS including sedation, hypnosis, decrease anxiety, muscle relaxation and anticonvulsant
activity. Benzodiazepines enhance GABAergic transmission in all CNS structures. The major
advantages of benzodiazepines that they show less tolerance and dependency than other classical
sedative and hypnotics (barbiturates) and are safer at larger dose.
(i) Diazepam (Valium)
®
: 7-chloro-1, 3-dihydro-1-methyl-5-phenyl-1, 4-benzodiazepine-2-one.
Diazepam is used for the several anxiety states and is useful in the treatment of convulsants, as
premedication in anaesthesiology.
O
Cl
N
N
CH
3
Fig. 5.22
82 A Textbook of Medicinal Chemistry
Synthesis:
Cl
NH
2
+
Cl
ZnCl
2
Friedal-Crafts
Acylation
Cl
NH
2
C=O
O
Cl
N
H
N
Cl
N—C
H
C=O
CH — Cl
2
O
NH
3
Cyclization
O
Cl
N
N
CH
3
CH I / DMF
3
Diazepam
Non-diazepam
4-chloroaniline Benzoyl
chloride
COCl
ClCH — C — Cl
2
O
Chlorocetyl
chloride
Fig. 5.23
2. Triazolobenzodiazepines
Triazolobenzodiazepines is the class of benzodiazepines. This category of drugs contains triazole
ring in association of N
1
and its adjacent carbon atom. This class of sedative and hypnotics show
remarkable activity. Presence of methyl group undergoes oxidative metabolism to methyl alcohol
followed by conjugation. Therefore, it shows short duration of action:
Sedative and Hypnotics 83
Synthesis:
Cl
NH
2
C=O
R
+ H N — CH — COOC H
2252
O
Cl
N
N
R
Pyridine
Glycine ethyl
ester
H
Cl
N
R
N—H
C
CH
3
H
N
Cl
N
R
S
N
H
PS
52
N
O
Cl
N
R
N
N
R¢
N
CH — C — NHNH
32
O
(Acetylhydrazide)
O-amino benzophenones
R = H, R = H Estazolam
R = CH , R = Cl Triazolam
R = CH , R = CH Alp azolam
¢
¢
¢
3
33
r
Fig. 5.24
Alprazoam (Xanax)
®
: 8-chloro-1-methyl-6-phenyl-4H,S. triazolo [4, 3-a] [1, 4] Benzodiazepine
Triazelam: 8-chloro-6-(2-chlorophenyl)-1-methyl-4 H,S-[4, 3-a] [1, 4] Benzodiazepine
3. Oxazepam (Serax)
®
: 7-chloro-1, 3-dihydro-3-hydroxy-5-phenyl-2H-1, 4-Benzodiazepine-2-one
Cl
N
H
N
CHOH
C=O
Fig. 5.25
84 A Textbook of Medicinal Chemistry
Oxazepam is used as sedative and hypnotics. Its duration of action is short.
4. Chlordiazepoxide: 7-chloro-2-(methylamino)-5-phenyl-3H-1, 4-benzodiazepine-4-oxide
H
N—CH
3
Cl
N
N
7
6
5
4
3
2
1
9
8
O
Fig. 5.26
Chlordiazepoxide possesses alkylamine group at position number 2 that would undergo N-
demethylation and hydrolysis resultant producing demoxepam as a major metabolite. Principally, it
is converted into nordazepam followed by oxepam.
Synthesis:
Cl
C=O
NH
2
Cl
C=N—OH
NH
2
NH OH
2
Hydroxyl
amine
NHCH
3
Cl
N
N
CH NH
32
Rearrangement
O
CH Cl
2
Cl
N
N
O
Cl — CH — C — Cl
2
Chloroacetyl
chloride
O
Aminophenone
Chlordiazepoxide
Fig. 5.27
1. Non-Benzodiazepines Derivatives
Non-benzodiazepines are used as short-acting hypnotics in U.S. and Europe. It is believed that these
derivatives act on GABA
A
receptor with higher affinity than benzodiazepines. There are two drug
examples, i.e., zolpidem and zopiclone, that belong to non-benzodiazepines class.