Benzodiazepines and Phenothiazines

1
STRUCTURE:-
BENZODIAZEPINE is a psychoactive drug whose core chemical
structure is the fusion of a benzene ring and a diazepine ring.

2
History:-
The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo
Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. The
pharmacological properties of the compounds prepared initially were disappointing, and
Sternbach abandoned the project. Two years later, in April 1957, co-worker Earl Reeder
noticed a "nicely crystalline" compound left over from the discontinued project while
spring cleaning in the lab.

Unexpectedly, the compound showed very strong sedative, anticonvulsant and

muscle relaxant effects. These impressive clinical findings led to its speedy introduction
throughout the world in 1960 under the brand name Librium.

Following chlordiazepoxide, diazepam was marketed by Hoffmann–La Roche

under the brand name Valium in 1963, and for a while the two were the most
commercially successful drugs.

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.[1]
3
CLASSIFICATION:-

Based on structure benzodiazepines are classified as :-

1. 1,4-Benzodiazepines.
Ex:-oxazepam, nitrazepam, diazepam

2. 1,5-Benzodiazepin-2,4-diones.
Ex:-clobazam, triflubazam

3 . [1,2,4]-Triazolo 1,4-Benzodiazepines.
Ex:-triazolam, estazolam, brotizolam

4. Imidazolo-1,4-Benzodiazepines.
Ex:-loprazolam

4
General synthesis :-
The 2- amino aryl ketone is condensed with a bifunctional, two carbon
fragment to give 1,4-benzodiazepin-2-ones.

R
R
O
NH
N
H2NCH2COOEt.HCl

O Glycine ethyl
R1 ester hydrochloride
R1 N

R2
R2

O
H2
XC C X

NH3 or (CH2)6N4
R
O
N

R1 O

R2

5
 H H
O
X CH2NH2
N N

CH2NH2 CrO3
O
R1 N N
R1 R1

R2
R2 R2

Alkylation of 1-unsubstituted molecules:-

H
R
O
O
N
N

1)NaH or CH3ONa
2)RX
R1 N
R1 N

R2
R2

6
DIAZEPAM:- Properties:-
Synthesis:- •white to yellow crystalline powder.
NH2 •sparingly soluble in water, freely soluble
O in chloroform and alcohol.
Cl
O
+ CH3CH2O C •M.P. 131-135oc.
CH2NH2.HCl

Glycine ethyl ester

Uses:-
2-Amino-5-chlorobenzophenone
•To control anxiety and tension states,
O
H
N the relief of muscle spasm.
Pyridine
•It is also helpful in combating
Cl N withdrawal symptoms in chronic
alcoholics.

Metabolism:-
(CH3)2SO4/C2H5ONa
metabolized to nordiazepam.
H3C Half life:-60hrs
O
N

Cl N

7
 NITRAZEPAM:-
7-Nitro 1,3-dihydro-5-phenyl-2H-1,4-Benzodiazepin-2-one.

O
Br Properties:-
O
BrCH2 C
H
N CH2 yellow, crystalline, powder with out
NH2
C odor or taste.
Br
O
It is insoluble in water and sparingly
O
O2N
O2N soluble in chloroform.
C6H5
m.p.238o
C6H5

2-Amino-5-nitrobenzophenone
Liq.NH3
Uses:-
Mainly used as sedative hypnotic
O and in the management of
H
N myoclonic seizures.

N
O2N Half life:-30hrs

8
FLUNITRAZEPAM:-
Cl O
NH2 C
NH2

F ZnCl2
+
O
Cl Cl C

NH2 O
H
N C

O CH2
H2/PdCl2/C BrCH2COBr
C
C O Br
F
F

NH3

H
H
H3C O
O
O N
N
N

N
O2N N
N KNO3
O2N
H2SO4
NaH/CH3I F
F
F

9
1,5-benzodiazepin-2,4-diones
NO2 NO2 COOC2H5

ClCOCH2CH3OOC2H5

R NH R N O
Clobazepam and Triflubazam have
Antianxiety property with mild side
effects.

H2/Ni

H
O
N NH2
C2H5ONa COOC2H5

R N O
R N
O

CH3I
H3C
NaH O
R=Cl Clobazepam
N =CF3 Triflubazam

R N
O

10
[1,2,4]-triazolo-1,4-benzodiazepines:-
• compounds in this series have exhibited potent biological activity greater than
1,4-benzodiazepine-2-ones.

•Alprazolam is an anxiolytic which has been found to cause significantly less drowsiness
than diazepam and which may also be useful for treating Panic disorders and depression.

• It is primarily metabolized by hydroxylation either on the C-1 methyl group or at the 4-

position of the ring system.
R N NAME R R1
N Triazolam CH3 Cl
N Estazolam H H
Alprazolam CH3 H
Adinazolam CH2N(CH3)2 H
Cl N

R1

11
TRIAZOLAM:-
8-Chloro-6(o-chloro phenyl)-1methyl-4H-5-triazolo[4,3-a]-1,4-benzodiazepine
NH2 H

H2N CH2 N

Cl
O
+ COOC2H5.HCl
Pyridine Properties:-
Cl N
Sparingly soluble in
Cl
water and alcohol
Cl
M.P-235OC
2-Amino-2,5-dichloro benzophenone

O
P4S10
H3C C
NH
H H
NH S
N N
H3C CONHNH2

BUTANOL
N Cl N
Cl

Cl Cl

2500C

H3C N
C
N
N

Cl N

Cl

12
Imidazolo-1,4-benzodiazepines:-
Loprazolam:-
H
H
O
S
N
N
1.HNO3/H2SO4

2. P2S5
N
O2N N

Cl
Cl

1.H2NCH2COOH/Na2CO3
HC N(CH3)2
2. N C N
O
O
N
N N
N

(CH3)2N CH(OC2H5)2

O2N N
O2N N

Cl
Cl
HC N N CH3

O
NH N CH3

N
N

O2N N

Cl

13
Based on duration of action:

1. Short acting drugs (t1/2=6hrs):

eg: triazolam,
midazolam,
brotizolam

2.Medium acting drugs (t1/2=6-12hrs):

Eg: temazepam,
lometazepam,
loprazolam

3.Long acting drugs (t1/2=more than12hrs):

Eg: nitrazepam,
flurazepam,
flunitrazepam
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 A B
SAR:-
C

1. In ring A an electron withdrawing group such as Cl, Br, No2,or CF3,CN at position 7.

2. A methyl group is attached to the nitrogen atom in 1 position in ring B. however

substituents at position 1that are metabolically removed are still clinically useful.
ex:-flurazepam,prazepam.

3. Replacement of the carbonyl function with two hydrogens in the second positiion
gives medazepam less potent than diazepam. Replacement of one of the hydrogen
with a OH on third position lowers activity on the one hand and aids elimination on
the other.

4. Introduction of a carboxyl function in the third position increases the duration of

action (clorazepate) and also favours formation of a water soluble salts.

15
5. A phenyl substituent at the fifth position α-pyridyl derivative and cyclo
alkyl substituents at fifth position give potent compounds.

6.Electro negative substituents such as Cl or F at the ortho position and

disubstitution in both ortho positions in ring C
7. Derivatives with additional rings joining the diazepine nucleus at the 1 and
2 positions Are generally more active than the corresponding 1-
methylbenzodiazepines.
8. The positioning of a trizole ring on the α-face of the 1,4-benzodiazepine
nucleus, in place of the amide moiety of the benzodiazepinones, enhances
its biological activity.
9. Replacement of the benzene ring by heteroaromatic (e.g: pyrozole) ring
resulted In compounds with interesting anxiolytic properties.(ripazepam)
10.Saturation of the 4,5-double bond reduces potency, as does a shift of the
unsaturation into the 3,4-position.

16
Pharmacological uses:-
•Anxiolytic

•Sedative and hypnotic

•Anticonvulsant

•Muscle relaxant

•Alcohol withdrawal

17
Mechanism of action:-
Benzodiazepines bind with high affinity to a distinct population of
Binding sites in the brain.
Benzodiazepines do not open the chloride channels by themselves but they act
allosterically to increase the affinity of the receptors for GABA

This increased conductance raises the membrane potential of

the neuron resulting in inhibition of neuronal firing.
-
Binding also requires that alpha subunits contain a histidine amino
acid residue, (i.e., α1, α2, α3 and α5 containing GABAA receptors).
For this reason, benzodiazepines show no affinity for GABAA
receptors containing α4 and α6 subunits with an arginine instead of a
histidine residue.[1

18
Schematic diagram of the (α1)2(β2)2(γ2) GABAA
receptor complex that depicts the five-protein subunits
that form the receptor, the chloride (Cl-) ion channel
pore at the center, the two GABA active binding sites
at the α1 and β2 interfaces and the benzodiazepine
(BZD) allosteric binding site at the α1 and γ2 interfac
19
 Properties continued
Anticonvulsant
activity and amnesic
properties are thought
to be mediated by α1
receptors2

• Benzodiazepines and
barbiturates bind more
strongly when GABA is also
bound to the receptor

20
Pharmacological Effects of Benzodiazepines are
Concentration-Dependent.
• Nanomolar Concentrations
– Anxiolytic sedation – via a2 subunit.
– Action effectively blocked by flumazenil.

• Micromolar Concentrations
– Anesthesia – diazepam, midazolam, lorazepam.
– Activity due to binding of benzodiazepines to low-affinity
site on GABA-A receptor.

21
Pharmacokinetics:

• Absorption

• Distribution

• Metabolism

• Toxicity

22
 H3C

METABOLISM-
H3C
O O
N
N

N Cl N
Cl

HO

H3C
O
O
N H
N

Cl N
Cl N

O
H
N

OH

Cl N

23
 pharmacology of anxiolytic/sedative-hypnotics

Adverse Effects: Benzodiazepines

• Sedation and impairment of performance
Psychomotor skills: driving; engaging in dangerous
physical activities; using hazardous machinery,
especially during initial phase of treatment
• Memory impairment
Anterograde amnesia (desired before surgery, other
procedures).
Dose-related, and tolerance may not develop.
Most likely with triazolam

.
24
 R1
R2
N

R3

R7 N

R'2

NAME R1 R2 R3 R7 R’2
Diazepam CH3 O H2 Cl H
Oxazepam H O OH Cl H
Nitrazepam H O H2 NO2 H
Medazepam CH3 H2 H2 Cl H
Flurazepam (CH2)2N(C2H5)2 O H2 Cl F
H2
Prazepam H2 C O H2 Cl H
C C CH2
H

Lorazepam O OH Cl Cl
H

25
26
Phenothiazine is an organic compound that occurs in various antipsychotic and
antihistaminic drugs.
It has the formula S(C6H4)2NH.
This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The
compound is related to the thiazine-class of heterocyclic compounds.
Derivatives of the parent compound find wide use as drugs.

STRUCTURE:-

27
 Numbering:-

6 5 4
S
7 3

8 10
2
9 N 1

History:-
•During second world war, a number of phenothiazine derivatives were
Prepared in the laboratories of the French pharmaceutical
manufacturer,‘RHONE POULENC’ in Paris
•Promazine possess strong anti-histaminic activity.
•Synthesis of chlorpromazine, a very large number of phenothiazine
derivatives.
•Possessing pharmacological actions like sedative and hypnotic
potent antihistaminic, tranqulizer, analgesic , urinary antiseptic

28
Modifications of the alkyl side chain:-
1) Maximum potency is retained when there is a three carbon spacing
between the basic amino group and the nitrogen of the phenothiazines
nucleus.
2) Substitution on the propylene chain of 10-(3-aminopropyl) phenothiazine
may also influence antipsychotic potency.

CH2CH2CH2 N(CH3)2
1 2 3

a) Methyl group at 1 position

a
b) Cyclopropane ring at 1 position
c) Oxygen introduced at 1-position

29
Modification of basic amino group:-
a) effect of 3o amino group
b) alkylation of basic amino group
c) replacement of dimethylamino group of chloropromazine
i) with pyrrolidine, morpholinyl
ii) with piperidyl, piperazine
eg:-
S

N COCH2CH3

(CH2)3 N N CH2CH2OH

Carphenazine

30
d) Bridged piperidine derivatives :retains nueroleptic property

N Cl

(CH2)3 N

Bridged piperidine derivative

e) Introduction of hydroxyl, methyl, groups at 4 position:-increases potency

N Cl

(CH2)3 N OH

31
 f) Esterified with long chain fatty acids to produce slowly absobed, long acting,
Lipophilic prodrugs
S
Ex:-

N CF3

(CH2)3 N N CH2CH2OCO(CH2)8CH3

Fluphenazine decanoate

Phenothiazine ring substitution:-

a) Substitution at 2 position is optimal for neuroleptic potency.
potency increases in the following order of position of ring substitution:-
1<4<3<2
b) 2-substitution of the phenothiazine nucleus increases the neuroleptic potency
in the following order:-
OH<H<CN<CH3<Cl<CF3
c) Oxidation of the 5 sulfur of antipsychotic phenothiazines decreases activity

32
d) Aza-phenothiazines are more effective agents.

N N

(CH2)3 N(CH3)2
1-Azophenothiazine

33
Phenothiazines synthesis:-

(CH2)2N(CH3)2
O CH2N(CH3)2 O

benzodioxanes ethaniolamines

H CH3
N CH2CH2N
CH3
N CH2CH3
CH2CH2N(CH3)2 ethylenediamines
diethazine

S
S

N
N Cl
CH2CHN(CH3)2
(CH2)3N(CH3)2
CH3
Chlorpromazine
promethazine 34
Treatment of appropriate diphenylamine with a mixture of sulfur and iodine

S
I2
N
H N
H
DIPHENYLAMINE
PHENOTHIAZINE

35
Promethazine:-

Chemically, promethazine hydrochloride appears as a white to faint yellow crystlline

powder that is practically odorless.

Promethazine as the hydrochloride salt is freely soluble in water and somewhat

soluble in alcohol. Promethazine is a chiral compound, occurring as a mixture of
enantiomers

36
Chlorpromazine:-
First synthesized on December 11, 1950, chlorpromazine was the first
drug developed with specific antipsychotic action, and would serve as
the prototype for the phenothiazine class of drugs, which later grew to
comprise several other agents.
S
S/I2

N Cl
N Cl

H H
3-chlorodiphenylamine 2-chlorophenathiazine
1.NaNH2
2.Cl(CH2)3N(CH3)2

N Cl

(CH2)3N(CH3)2

Chloropromazine

37
Mechanism of action:-
It is a dopamine inhibitor, increases dopamine turnover in the brain, and
stimulates prolatin release. The increased brain turnover of dopamine
may be related to its therapeutic effects; it achieves a higher
concentration in the brain that in the blood stream.
Metabolism:-
The cytochrome P450 isoenzymes 1A2 and 2D6 are needed for
metabolism of chlorpromazine. CYP 2D6 is the main enzyme catalyzing
7-hydroxylation of chlorpromazine, the reaction being partially catalyzed
by CYP 1A2.
Excretion:-.
Less than 1% of the unchanged drug is excreted via the kidneys in the
urine. In which 20-70% is excreted as conjugated or unconjugated
metabolites, whereas 5-6% is excreted in feces

38
Piperazine derivatives:-
Synthesis of prochlorperazine and trifluperazine:-

S
Properties:-
S
1.NaH Pale yellow crystalline powder,
2.Br(CH2)3Cl with slightly bitter taste
N X
H N X m.p:198-2030c
X=Cl,CF3,CO(CH2)2CH3
(CH2)3Cl It is more potent than
1.NaH
2.Cl(CH2)3N NCH3
chlorpromazine
HN NCH3
It has high prvelance of extra
pyramidal effects and therfore
S S mainly used as antiemitic.

N CO(CH2)2CH3 N X

(CH)3Cl (CH2)3

N N

N N

CH3 CH3
X=Cl;prochlorperazine
Butaperazine =CF3:Trifluperazine

39
Hydroxyethyl piperazine derivatives:-
O
O
O H2C CH2
C N N CH2CH2OH
C N NH
C2H5O
C2H5O

H2O
HN N CH2CH2OH

S
S
HN N CH2CH2OH

N X
N X
(CH2)3N N CH2CH2OH
(CH2)3Cl

X=Cl,CF3,CH3CO,C2H5CO
Fluphenazine hydrochloride:-
Properties:-
•It is a white crystalline powder.
•It is soluble in water and alcohol and practically insoluble in ether.
•The drug is more potent, exhibits a more prolonged duration of action,
is less sedative.
40
Thioridazine:-
1.LiPh
Synthesis:- CH3I
2.HCHO
N CH3 N CH2CH2OH N CH2CH2OH
PICOLINE
CH3

Cat/H2 SOCl2

N CH2CH2Cl
N CH2CH2OH
CH3
CH3
2-(--Methyl-1-piperidyl)
ethyl chloride
S
S
CH3SNa

N Cl
N SCH3
H
H
S

N CH2CH2Cl
CH3 N SCH3

CH2CH2

Thioridazine N

H3C 41
Properties:-

It is a slight yellow powder with a bitter taste.

It is freely soluble in water, chloroform and alcohol and insoluble in ether.

Uses:-
it is effevtive for relif of symptoms of neurotic depressive reactions

Metabolism :-
It is metabolised to active drug mesoridazine

42
 6 5 4
S
7 3

8 10
2
9 N 1 R2

generic name R2 R1 R1
H
(A)Propyl (CH2)3N(CH3)2.HCl
dialkylaminosidechain:
i)Promazine .HCl
II)Chlorpromazine Cl (CH2)3N(CH3)2.
iii)Triflupromazine CF3 (CH2)3N(CH3)2.
(B)Alkyl piperidyl side H3C

chain: N

i)Thioridazine SCH3 (CH2)2

H3C

N
ii)Mesoridazine O SCH3 (CH2)2

©Propyl piperizine side

chain
(CH2)3N NCH3
i)Prochlorperazine Cl

ii)fluphenazine CF3 (CH2)3N N CH2CH2OH

43
 Phenothiazines
Pharmacologic effects and mechanism:
(1) CNS:
a. neuroleptic effect--- D1, D5---D1-like receprtors
D2-4------D2-like receptors
Antipsychotic drugs probably owe their therapeutic effects
mainly to blockade of D2-receptors (lies in midbrain-cortex
and midbrain-limbic system ).

b. antiemetic effect--- inhibit chemoreceptor trigger zone or

directly depress the medullary vomiting center.
c. temperature-regulating effect--- produce hypothermia
44
(2) Autonomic nervous system:
Block α-adrenergic and M-Cholinergic receptors
and result in hypotension, dry mouth, constipation
and blurred vision.
(3) Endocrine system:
Increase the release of prolactin and decrease
corticotropin release and secretion of pituitary
growth hormone.

45
 Therapeutic uses
• (1) treatment of psychotic disorders: schizophrenia,
mania, paranoid states, alcoholic hallucinosis.

• (2) treatment of nausea and vomiting of certain

causes.

• (3) anesthesia in hypothermia and artificial

hibernation (used with pethidine and promethazine).

46
Adverse Effects:
• Extrapyramidal motor disturbances:
(1) Parkinson-like symptoms;
(2) akathisia;
(3) acute dystonias.
Treatment: anticholinergic

• Other side-effects:
• (dry mouth, constipation, blurred vision, hypotension, etc.) are
due to block of other receptors, particularly α–adrenoceptors
and muscarinic ACh receptors.

Contact dermatitis, blood dyscrasias, obstructive jaundice

sometimes occurs with phenothiazines.
47
 Adverse Effects

• Tardive dyskinesia :
Comprises mainly involuntary movements of face and tongue, but also
of trunk and limbs, appearing after months or years of antipsychotic
treatment. It may be associated with proliferation of dopamine
receptors (possibly presynaptic) in corpus striatum. Treatment is
generally unsuccessful.

Cardiac toxicity and endocrine effects.

48
thanq

49