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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5484_Библиотеки_им_академика_М_И_Перельмана.pdf
Antipsychotic Drugs 155
(ii) Methylperidol
OH
N
CH
3
(iii) Trifluperidol
OH
N
CF
3
(iv) Peridol
OH
N
(v ) Haleperidide
C—N
N
Cl
O
(vi) Spiperone
C
N
O
N
NH
4. Benzamides
(i) Metoclopramide
HN
2
Cl
O
NH
N
CH
25
CH
25
OCH
3
(ii) Sulpiride
H NSO
22
O
N
H
N
OCH
3
CH
25
156 A Textbook of Medicinal Chemistry
(iii) Ramoxipride
O
NH — CH
2
N
OCH
3
CH
25
OHC
3
Br
Fig. 10.5
5. Dihydroindolone Derivatives
(i) Molindone (moban
®
)
N
O—HC
2
O
CH
3
CH
25
N
H
Fig. 10.6
6. Diphenyl Butyl Piperidine Derivatives:
(1) Pimozide (Orar
®
)
F
CH — (CH ) — N
23
N—H
O
F
N
(2) Fluspirilene (Imap
®
)
F
CH — (CH ) — N
23
F
N
N
O
(3) Penfluridol (semap
®
)
F
CH — (CH ) — N
23
F
OH
CF
3
Cl
Fig. 10.7
Antipsychotic Drugs 157
(7) Miscellaneous Class
(i) Resperidone (Resperdal
®
)
H
N
CH
3
N
N
O
O
F
(ii) Butaclamol
R = t-butyl Dexclamol R = isopropyl
N
OH
R
Fig. 10.8
10.5 TRICYCLIC NEUROLEPTICS/PHENOTHIAZINES
1. Tricyclic Neuroleptics/Phenothiazines
Phenothiazines are the class of neuroleptics. These are non-selective, competitive D
1
and D
2
receptors
antagonists which falls to block the action of dopamine in addition to their action exerts by blocking
α-adrenoceptors, serotonine, cholinergic, nicotinic and muscarinic receptors. Phenothiazines act
on CNS hence causing moderate sedative and antiemetic effects. They also affect thermoregulatory
system, skeletal muscles and endocrine system as well as action of analgesia.
10.5.1 Phenothiazines Structure and Structure Activity Relationship
1. Tricyclic neuroleptics may be observed into three substructures one is amine functional group
site (site A), second is intervening alkyl chain (site B) and third is diarylheterocyclic ring (site C). All
these sites affect the pharmacological action further.
N
R
1
S
1
2
3
4
5
6
7
8
9
R
2
(Position 2)
Favoured substitution
(Position 10)
Favoured substitution
Fig. 10.9: Basic structure.
158 A Textbook of Medicinal Chemistry
Z
XY
N
R
2
R
3
R
1
Site A Site B
Site C
(Amine
function)
Alkyl
chain
Diaryl
heterocyclic
ring
Fig. 10.10: Substructure of tricyclic neuroleptics.
2. Alkyl Chain Effects (Site B)
(i) The distance between site A and site C is always critical for pharmacological activity. Length
of carbon atom is 3 for tolerable instances and for optimal activity.
(ii) While shortening the carbon chain (two carbon atoms) leads to amplifying the anticholinergic
and antihistaminic activity, e.g., diethazine for Parkinson’s disease. Promethazine acts as
antihistamine
N
HC—CH—N
2
S
CH
25
CH
25
N
HC—CH
2
S
CH
3
CH
3
CH
3
N
Diethazine
Promethazine
Fig. 10.11
3. Effects on Aromatic substitution
(i) Introduction of aromatic substitution makes the effective tricyclic antipsychotic compounds
and influences the activity.
(ii) Substitution at position No. 2 of aromatic ring provides the compounds with enhanced
potency. Small alkyl substitution at position 2 would be tolerable while larger substitution
(R = phenyl) will make restriction in the free rotation therefore decreases the activity.
(ii) Electron withdrawing groups such as chloro and trifluoromethyl (CF
3
) show greater response
to antipsychotic activity rather than alkyl or alkoxy derivatives.
4. Nature of Amino Group (Site – A)
(i) Tertiary amine group always shows optimal activity rather than mono or desmethyl
chlorpromazine respectively.
(ii) In many cases larger N-alkyl group leads to decrease in the neuroleptic activity.
Antipsychotic Drugs 159
(iii) Groups of diethyl, pyrrolidinyl, morpholine and thiomorpholine of chlorpromazine show
lack of activity.
(iv) In contrast to other groups like N-methylpiperazine leads to enhance potency as well.
5. Alteration within Tricyclic Topology
(i) Deviation of sulphur group with other element produce the corresponding phenoxazine and
phenoselenazine derivatives.
(ii) Phenoxazine exhibits as less active compounds than phenothiazines.
(iii) Replacement of nitrogen atom within the phenothiazine ring system with methane carbon
made another series of neuroleptics.
(iv) Introduction of double bond within propylamino chain provides the compounds geometric
isomers.
10.5.2 Specific Derivatives
1. Promazine (Sparine®): 10-(3-dimethylamine propyl) phenothiazine.
Promazine is a potent antipsychotic agent. Its one milligram of dose is sufficient to counteract
psychoses condition. Promazine is used in the treatment of psychomotor excitement in schizophrenics
and manic depressive conditions.
Synthesis:
N
S
H
Phenothiazine
Alkylation
+ Cl — CH — CH — CH — N
222
CH
3
CH
3
3-Dimethylamino
-propyl chloride
CH — CH — CH — N
222
CH
3
CH
3
Promazine
N
S
NaNH
2
(Sodium Amide)
Fig. 10.12
2. Chlorpromazine (Megaphen
®
): 2-chloro-10-(3-dime thylaminopropyl)-phenothiazine
Chlorpromazine is active in the salt with HCl. It was the first phenothiazine compound introduced in
the therapeutic manner. Chlorpromazine is used in various psychomotor conditions like schizophrenia,
chronic paranoid condition, alcohol psychosis, neurosis, etc.
160 A Textbook of Medicinal Chemistry
N
H
S
HCS
3
+
CH
3
CHCl
25
N
CH — CH —
22
S
HCS
3
Alkylation
NaNH
2
2-methylthiophenothiazine
2-(2-chloroethyl)-1-
methylpi peridine
Thioridazine
N
CH
3
N
Fig. 10.15
N
S
CH — CH — CH — N
222
CH
25
CH
25
Cl
Fig. 10.13: Chlorpromazine.
3. Triflupromazine (Vesprin
®
): 2-fluoromethyl-10-(3-dimethyl amino propyl)-Phenothiazine.
Triflupromazine is an active antipsychotic drug. Its few milligram of dose is sufficient for
antipsychotic action. It is used in the treatment of various psychomotor excitements in patients
with psyzophrenia for paranoid and manic-depressive conditions.
Synthesis:
N
S
H
2-Trifluromethyl
phenothiazine
+ Cl — CH — CH — CH — N
222
CH
3
CH
3
3-Dimethylaminopropyl chloride
CH — CH — CH — N
222
CH
3
CH
3
FC
3
N
S
FC
3
Fig. 10.14
4. Thioridazine (Conapax®): 10-[2-(1-methyl-2-piperidyl)-ethyl]-2-(methyl thio)-phenothiazine.
Thioridazine is the congener of piperidine nucleus containing phenothiazine. Thioridazine also have
the character of higher anticholinergic action. It produces lower EPS than others. It shows sedative
and hypotensive activity. It is mainly effective in the mental and emotional disorders accompanied
by fear, stress and excitement conditions.
Synthesis:
Antipsychotic Drugs 161
5. Mesoridazine (Serentil®): 10-[2-(1-methyl-2-piperidyl)-ethyl]-2-(methyl sulfinyl) phenothiazine.
Mesoridazine also contains piperidine nucleus in phenothiazine. Mesoridazine is used in the
treatment of schizophrenia-psychoneurotic problems, in severe and chronic alcoholism.
Synthesis:
CO
Acylation
(CO)
CH
32
2-methylthiophenothiazine
CH
3
CO
CH
3
HO
22
H
KCO/CHOH
23 3
(Deacylation)
CH
3
CH CH Cl
22
N
2-(2-chloroethyl)-1-methyl piperidine
NaNH
2
CH — CH
22
HCSO
3
N
(Oxidation)
Alkylation
Mesoridazine
H
HCS
3
N
S
HCS
3
N
S
N
S
HCOS
3
N
S
HCSO
3
N
S
CH
3
Fig. 10.16
10.6 THIOXANTHENE DERIVATIVES
Thioxanthenes are structurally different from phenothiazene in respect of the nitrogen atom of the
centrally ring situated of the tricyclic system replaced by carbon which is joined to the side chain
with double bond. Pharmacological concerns are similar to that of phenothiazines.
1. Thiothixene (Navane
®
): N, N-dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidine]-
thioxanthane-2-sulfonamide. Thiothixene displays a fundamental chemical and pharmacological
162 A Textbook of Medicinal Chemistry
similarities to the piperazine derivatives of phenothiazines. Due to presence of carbon atom and side
chain double bond, the possible Z and E isomers are produced. Thiothixene is used in the treatment
of psychotic disorders.
Synthesis:
9H-thioxanthane
ClSO H
3
Chlorosulphonic
acid
+
SO H
3
(1) SOCl
2
(2) (CH ) NH
32
Thionyl
chloride
9H-thiozanthane
SO N
2
(i) HCHO
(ii) (CH ) NH
32
Aminomethylation
CO
CH
3
SO N
2
CH
3
CH
3
(ii) CH COOCH
33
Methyl acetate
(1) C H Li (butyllithium)
49
SO N
2
CO
CH — CH — N
22
SO N
2
CH
3
CH
3
N-Methylpiperazine
CH
3
CH
3
CH
3
CH
3
CO
CH —CH —N N—CH
22 3
[H] Reduction
SO N
2
CH
3
CH
3
CH OH
CH —CH —N N—CH
22 3
POCl
3
(Dehydration)
SO N
2
CH
3
CH
3
CH
CH —CH —N N—CH
22 3
Thiothixene
S
S
S
S
S
S
S
CH
3
CH
3
Alkylation
N
N
H
CH
3
S
Fig. 10.17
Antipsychotic Drugs 163
2. Chlorproxithene (Clothixene
®
): 2-chloro-9 (1-dimethyl-amino)-3-propyliden]-thioxanthene.
Chlorproxithene is a potent antipsychotic agent and possesses sedative like action. It is supposed to
be an antiemetic agent. Chloroproxithene is used in the treatment of distinguished psychoses
conditions, psyzophrenia, reactive and neurotic depression, in the condition of excitement concerning
with fear and stress.
S
Cl
CH
3
CH
3
HC — CH — CH — N
22
Synthesis:
O
CH — CH — N
22
N — (CH ) — MgBr
23
HC
3
HC
3
(Tertiary alcohol)
CH
3
CH
3
CH — CH — CH — N
2
2
CH
3
CH
3
CH COCl
3
(Acylation)
2-Chlorothioxanthone
(A) -3-dimethyl amino
propylmagnesium bromide
Chlorproxithene
Cl
S
CH
2
HO
Cl
S
Cl
S
A
Fig. 10.18
10.7 DIBENZOXAZEPINE AND DIBENZDIAZEPINE DERIVATIVES
Dibenzoxazepine and dibenzdiazepine derivatives are structurally different from other derivatives.
However, their mode of action, uses and side effects are analogue to phenothiazine derivatives.
1. Loxapine (Loxapac
®
): -2-chloro-11-[4-methyl-1-piperazinyl]-dibenz-[b, f] [1, 4] exazepine.
Loxapine is the derivative of dibenzoxazepine series. It is a potent psychotic agent rather than
chlorpromazine. It shows less sedation than chlorpromazine. Loxapine is suggested in the treatment
of psychotic conditions particularly in the case of chronic and severe schizophrenia.
Chlorproxithene
164 A Textbook of Medicinal Chemistry
Synthesis:
O
Cl
NH
2
+
Cl-COOC H
25
Ethylchloro formate
O
Cl
NH
2
COOC H
25
CH — N N —H
3
2-(-4-chlorophnoxy) aniline
O
Cl
N
N
N
CH
3
O
NH
2
N
N
CH
3
CO
POCl
3
(Cyclization)
Fig. 10.19
2. Clozapine (Leponex
®
): -8-chloro-11-[4-methyl-1-piperazinyl-5H-dibenzo] [b, e][1, 4]-diazepine.
Clozapine is the derivative of dibenzdiazepine ring series. Clozapine is an antipsychotic drug with
sedative properties. On the other hand clozapine does not show depression and extrapyraimidal
disorders. Clozapine is used in the treatment of severe and chronic schizophrenic conditions, in the
condition of psychomotor excitement also.
Synthesis:
NO
2
Cl
NH
2
Cl
C
OCH
3
O
+
H C — N N —H
3
Cu
4-chloro-2-nitro-aniline
O-chloro
benzoic acid
methylesters
N
NO
2
C O
OCH
3
Cl
H
Fig. 10.20 (Contd.)
N-methyl-piperzine