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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
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
N COCH2CH3
(CH2)3 N N CH2CH2OH
Carphenazine
d) Bridged piperidine derivatives :retains nueroleptic property
N Cl
(CH2)3 N
N Cl
(CH2)3 N OH
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
N N
(CH2)3 N(CH3)2
1-Azophenothiazine
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
Treatment of appropriate diphenylamine with a mixture of sulfur and iodine
S
I2
N
H N
H
DIPHENYLAMINE
PHENOTHIAZINE
Promethazine:-
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
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
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.
Thioridazine:- Synthesis:-
1.LiPh 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
Properties:-
Uses:-
it is effevtive for relif of symptoms of neurotic depressive reactions
Metabolism :-
It is metabolised to active drug mesoridazine
generic name R2 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
6 5 4
S
7 3
H3C
N 8 10
2
ii)Mesoridazine O SCH3 (CH2)2
9 N 1 R2
R1
• Other side-effects:
• (dry mouth, constipation, blurred vision,
hypotension, etc.) are due to block of other
receptors, particularly α–adrenoceptors and
muscarinic ACh receptors.
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.