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Benzodiazepines and Phenothiazines
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.
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
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
Metabolism:-
(CH3)2SO4/C2H5ONa
metabolized to nordiazepam.
H3C
O
Half life:-60hrs
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
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.
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
Cl N
Sparingly soluble in
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. In ring A an electron withdrawing group such as Cl, Br, No2,or CF3,CN at position 7.
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.
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
•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
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
20
Pharmacological Effects of Benzodiazepines are
Concentration-Dependent.
• Nanomolar Concentrations
– Anxiolytic sedation – via 2 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
METABOLISM-
H3C
H3C
O
O
N
N
Cl N
Cl N
HO
H3C
O
O
N H
N
Cl N
Cl N
O
H
N
OH
Cl N
23
pharmacology of anxiolytic/sedative-hypnotics
.
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) O Cl F
H 2 H2
Prazepam
2
H2 C
O Cl H
C C
H
CH2 H2
Lorazepam O Cl Cl
OH
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
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
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
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:-
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
1.NaH
(CH2)3Cl It is more potent than
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)3 N 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:-
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
(A)Propyl H (CH2)3N(CH3)2.HCl
dialkylaminosidechain:
i)Promazine .HCl
II)Chlorpromazine (CH2)3N(CH3)2.
iii)Triflupromazine (CH2)3N(CH3)2.
(B)Alkyl piperidyl side H3C
Cl
chain: N
CF3
i)Thioridazine (CH2)2
H3C
SCH3
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 ).
45
Therapeutic uses
• (1) treatment of psychotic disorders: schizophrenia,
mania, paranoid states, alcoholic hallucinosis.
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.
48
thanq
49