Note: Descriptions are shown in the official language in which they were submitted.
4~3~
This invention relates to new 2,6-dialkoxybenzamide intermediate
compounds of the formula
Cl OR
~ COOH
Br OR
wherein Rl is an alkyl group with 1-3 carbon atoms.
This application is divided from copending Canadian Application
Serial No. 322l555 which is directed to a compound of the formula
R3
~$ CONHCH~
R2 ORl C2 5
or a pharmaceutically acceptable salt thereof, in which formula Rl represents
an alkyl group with 1-3 carbon atoms, R2 and R3 are the same or different and
each represents a hydrogen, chlorine or bromine atom and their therapeutic
use as antipsychotic agents.
Sulpiride, (United States patent 3,342,826) with the formula
H2NSO
~ CONHCH2 ~ J
OCH3 C2H5
is a recently marketed antipsychotic agent. Sulpiride produces weak extra-
pyramidal side effects in humans and weak catalepsy in experimental animals.
Although sulpiride has valuable properties we have found compounds
1~ 41~
which are still better. The superiority of these compounds over sulpiride
after oral administration is remarkable.
These antipsychoic compounds are characterized by the general
formula
R3 ,ORl
2 ~ CoNHcH2 - ~ J
R OR C2H5
wherein R represents an alkyl group with 1-3 carbon atoms, R and R are
the same or different and each represents a hydrogen, chlorine or bromine
atom.
Pharmaceutically acceptable salts of the compounds of the formula
I are also useful antipsychotic agents.
Alkyl groups with 1-3 carbon atoms are methyl, ethyl, n-propyl and
isopropyl.
The new compounds may be used therapeutically as the racemic mix-
tures of (~)- and ~-)-forms, which are obtained by synthesis. They may also
be resolved into the corresponding enantiomers which, likewise, may be used
in therapy. The (~)- and (-)-forms may also be obtained by reaction of an
optical active salt of 2-(aminomethyl)-1-ethylpyrrolidine with the dialkoxy-
benzamide moiety.
Compounds which structurally deviate from the formula I after ad-
ministration to a living organism may be transformed therein to a compoundof the formula I and in this structural form exerting their effects.
The compounds of formula I may be administered in the form of free
bases or their salts with non-toxic acids. Some typical examples of these
salts are the hydrobromide, hydrochloride, phosphate, sulphate, citrate, and
tartrate.
34
According to the present invention there are provided compounds use-
ful as intermediates for the preparation of therapeutically valuable 2,6-di-
alkoxybenzamides, which intermediates are characterized by the general formula
Cl ORl
~ COOH
Br~ ~ ORl
wherein Rl is an alkyl group with 1-3 carbon atoms. These compounds are valu-
able intermediates for the preparation of compounds of formula I.
In clinical practice the compounds of formula I will normally be
administered orally, rectally or by injection in the form of pharmaceutical
preparations comprising the active ingredient either as a free base or as a
pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydro-
chloride, hydrobromide, lactate, acetate, sulphate, sulphamate and the like
in association with a pharmaceutically acceptable carrier. Accordingly,
terms relating to the compounds of formula I whether generically or specifi-
cally are intended to include both the free amine base and the acid addition
salts of the free base, unless the context in which such terms are used, e.g.
in the specific examples would be inconsistent with the broad concept.
The carrier may be a solid, semisolid or liquid diluent or capsule.
Usually the active substance will constitute between 0.1 and 99% by weight of
the preparation, more specifically between 0.5 and 20% by weight for prepara-
tion intended for injection and between 2 and 50% by weight for preparationssuitable for oral administration.
To produce pharmaceutical preparations containing a compound of
formula I in the form of dosage units for oral application, the selected
compound may be mixed with a solid pulverulent carrier, e.g. lactose,
:,
,,
: ,
.
84
saccharose, sorbitol, mannitol, starches such as potato starch, corn starch
or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as
magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like,
and then compressed to form tablets. If coated tablets are required, the
cores, prepared as described above, may be coated with a concentrated sugar
solution which may contain, e.g. gum arabic, gelatine, talcum, titanium dio-
xide, and the like. Alternatively, the tablet can be coated with a lacquer
dissolved in a readily volatile organic solvent or mixture of organic sol-
vents. Dyestuffs may be added to these coatings in order to readily dis-
tinguish between tablets containing different active substances or differentamounts of the active compound.
For the preparation of soft gelatine capsules (pearl-shaped closed
capsules) consisting of gelatine and for example, glycerol or similar closed
capsules, the active substance may be admixed with a vegetable oil. Hard
gelatine capsules may contain granulates of the active substance in combina-
tion with solid, pulverulent carriers such as lactose, saccharose, sorbitol,
mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellu-
lose derivatives or gelatine.
Dosage units for rectal application can be prepared in the form of
suppositories comprising the active substance in admixture with a neutral
fatty base, or gelatine rectal capsules comprising the active substance in
admixture with vegetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of
syrups or suspensions for example, solutions containing from about 0.2% to
about 20% by weight of the active substance herein described, the balance
being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol.
Optionally such liquid preparations may contain colouring agents, flavouring
agents, saccharine and carboxymethyl-cellulose as a thickening agent.
--4--
4~4
Solutions for parentcral applications by injection can be prepared
in an aqueous solution of a water-soluble pharmaceutically acceptable salt
of the active substance preferably in a concentration of from about 0.5% to
about 10% by weight. These solutions may also contain stabilizing agents
and/or buffering agents and may conveniently be provided in various dosage
unit ampoules. Suitable peroral daily doses of the compounds of the inven-
tion are 100-500 mg, preferably 200-300 mg.
The preferred antipsychotic compounds of formula I have the follow-
ing formulas
Br OCH
~ ~ 3 1
// \ ~ CONHCH2 ~ N
~ I
Br / \OCH3 C2H5
Br OCH3
I
CONHCH2 1~ J
H OCH3 C2H5
Particularily the ~-)-forms of the above compounds are preferred.
The compounds of the formula I can be prepared by reaction of a
derivative a of 2,6-dialkoxybenzoic acid according to the present invention
of the formula
R3 ORl
</ \ ~ CO-Z II
R2/\~<oRl
wherein Rl represents an alkyl group with 1-3 carbon atoms, R2 and R3 are
the same or different and each represents a hydrogen, chlorine or bromine
--5--
4~34
atom and -CO-Z represents a reactive group capable of reacting with an amino
group under formation of an amide moiety, with 2-(aminomethyl)-1-ethylpyrroli-
dine of the formula
N-CH2 rN J
C2H5
The reaction is carried out in a suitable solvent, such as diethyl
ether, acetone or methyl ethyl ketone. The resulting amine hydrochloride
salt is readily recovered e.g. by filtration. Alternatively the obtained
salt is dissolved in water and converted to the free base using conventional
techniques, such as the addition of sodium hydroxide solution.
The acylating group -C0-Z in formula II may be an acid chloride
group, or a group functioning in the same way, e.g. an acid bromide, an acid
azid, an anhydride, a mixed anhydride formed with an inorganic acid or an
organic acid such as an alkyl carbonic acid, a carbonic acid. Alternatively,
the acid derivate (pref. an acid chloride) is reacted with the amine in the
presence of a base e.g. triethylamine. The group -CO-Z may also be an ester
group, e.g. alkyl ester such as methyl ester.
Intermediates
The free carboxylic acid intermediate of the present invention which
corresponds to the derivative of formula II is prepared by the halogenation
of a 2,6-dialkoxybenzoic acid with an appropriate halogenating agent, e.g.
free halogen or sulphuryl chloride. The preparation routes are illustrated
below.
4B4
Br OR ~ Rl
COOH ~ COOH
Br OR Br
'1 Br2/HAC
. ¦ _ I /Br2/Dioxan ~)~C12
=~ORI B~ ~OR
, \
S2C12 ~ 2Cl2 Equivalent
excess \ ~ / Br2/HAc
COOH ~ COOH
Rl ORl
The free carboxylic acid is then converted by conventional means '!
to the corresponding derivative of the formula II.
Preparation of starting materials
Example 1. 3-Bromo-2,6-dimethoxybenzoic acid
A solution of 15 ml of bromine ~0.3 mol) in 50 ml of chloroform
is added dropwise while stirring and cooling in ice to 54.9 g~0.3 mol) of
2,6-dimethoxybenzoic acid in 150 ml of dioxan. ~he solution is left at room
~, -7-
84
temperature overnight. The solvent is evapc~rated and the residue recrystal-
lized from a4ueous ethanol. Yield: 59.3 g, m.p. 144-45C.
Example 2. 3-Chloro-2,6-dimethoxybenzoic acid
A solution of 16.2 ml (0.2 mol) of sulphuryl chloride in 100 ml of
chloroform is added dropwise while stirring to a solution of 36.4 g (0.2 mol)
of 2,6-dimethoxybenzoic acid in 300 ml of chloroform. The mixture is heated
for 0.5 h at 50C and left overnight at room temperature. The solvent is
evaporated and the residue recrystallized from isopropyl ether - light petro-
leum. Yield: 35.4 g, m.p. 132-33C.
Example 3. 3,5-Dibromo-2,6-dimethoxybenzoic acid
A solution of 12 ml (0.23 mol) of bromine in 50 ml of acetic acid
is added dropwise while stirring to a mixture of 18.2 g (0.1 mol) of 2,6-
dimethoxybenzoic acid and 21 g (0.25 mol) of dry sodium acetate in 150 ml of
acetic acid. The mixture is stirred over night at room temperature and is
then poured into 1 litre of ice water. The precipitate is filtered off,
washed with water and dried. The crude compound is purified by recrystalliza-
tion from light petroleum. Yield: 14.1 g, m.p. 108-10C.
Example 4. 3,5-Dichloro-2,6-dimethoxybenzoic acid
A solution of 20 ml (0.25 mol) of sulphuryl chloride in 50 ml of
chloroform is added dropwise to a solution of 15.0 g (0.08 mol) 2,6-dimethoxy-
benzoic acid in 100 ml of chloroform. The solution is left over night at
room temperature and is then refluxed for 0.5 h. The solvent is evaporated
and the residue recrystallized twice from light petroleum. Yield: 17.0 g,
m.p. 98-100C (first recrystallization). Yield: 12.0 g, m.p. 102-103C
(second recrystallization).
4~4
Preparation of Intermediate
Example 5. 3-Bromo-5-chloro-2,6-dimethoxybenzoic acid
A. From 3-chloro-2,6-dimethoxybenzoic acid
A solution of 1.5 ml (0.03 mol) of bromine in acetic acid is added
to a mixture of 2.7 g (0.01 mol) of 3-chloro-2,6-dimethoxybenzoic acid and
3.0 g of anhydrous sodium acetate in 50 ml of acetic acid. The mixture is
left at room temperature over night and is then poured into 300 ml of ice
water. The precipitate is filtered off, washed with water, dried and recry-
stallized from isopropyl ether - light petroleum. Yield: 0.5 g, m.p. 99-
100C.
Analysis, calculated for CgH8BrC104: C 36.58, H 2.73, Br 27.04,
Cl 12.00, 0 21.65.
Found: C 36.6, H 2.51, Cl 11.8.
B. From 3-Bromo-2,6-dimethoxybenzoic acid
A solution of 40 ml (0.5 mol) of sulphuryl chloride in 100 ml of
chloroform is added dropwise to a solution of 26.1 g ~0.1 mol) of 3-bromo-
2,6-dimethoxybenzoic acid in 150 ml of chloroform. After a night at room
temperature the solution is refluxed for 45 minutes. The solvent is evapor-
ated and the residue recrystallized from isopropyl ether - light petroleum.
Yield: 23.5 g, m.p. 98.5-100C.
Preparation of antipsychotic-agents of formula I
Example 6. N-Ethyl-2-~2,6-dimethoxybenzamidomethyl) pyrrolidine hydrochloride
30 ml of thionyl chloride is added to 18.2 g ~0.1 mol) of 2,6-di-
methoxybenzoic acid. The mixture is heated on a steam bath for 30 minutes.
To the solution is added 50 ml of toluene. The solvent and excess thionyl
chloride is evaporated at reduced pressure. The residue is dissolved in 50
ml of dry methyl ethyl ketone. The solution is added dropwise while stirring
_g _
,, .
8~
to 12.8 g (0.1 mol) of 2-(aminomethyl)-1-ethyl-pyrrolidine in 50 ml methyl-
ethyl ketone. After the addition the mixture is stirred for 30 minutes at
room temperature. ~e obtained precipitate is filtered off, washed with ether
and recrystallized from ethanol - isopropyl ether. Yield: 26.7 g, m.p. 182-
84C.
Example 7. N-Ethyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)pyrrolidine
hydrocXloride
30 ml of thionyl chloride is added to 17.6 g (0.067 mol) of 3-
bromo-2,6-dimethoxybenzoic acid. The mixture is heated on a steam bath for
30 minutes. To the solution is added 50 ml of toluene. The solvent and ex-
cess thionyl chloride is evaporated at reduced pressure. The residue is dis-
solved in 50 ml of dry methyl ethyl ketone. The solution is added dropwise
while stirring to 9.23 g ~0.072 mol) of 2-~aminomethyl)-1-ethylpyrrilidine
in 50 ml of methyl ethyl ketone. After stirring for 30 minutes at room tem-
perature 150 ml of ethyl ether is added. The obtained precipitate is filtered
off, washed with ether and recrystallized twice from ethanol-isopropyl ether.
Yield: 21.0 g, m.p. 182-84C ~first recrystallization). m.p. 184-85C (se-
cond recrystallization).
Example 8. N-Ethyl-2-(3-chloro-2,6-dimethoxybenzamidomethyl)pyrrolidine
hydrochloride
30 ml of thionyl chloride is added to 17.0 g (0.078 mol) of 3-
chloro-2,6-dimethoxybenzoic acid. The mixture is heated on a steam bath for
30 minutes. To the solution is added 50 ml of toluene. The solvent and ex-
cess thionyl chloride is evaporated at reduced pressure. The residue is dis-
solved in 50 ml of dry methyl ethyl ketone. The solution is added dropwise
while stirring to 10.0 g (0.078 mol) of 2-(aminomethyl)-1-ethylpyrrolidine
in 50 ml of methyl ethyl ketone. After stirring for 30 minutes at room
-10-
?484
temperature 150 ml of ether is added. The obtained precipitate is filtered
off, washed with ether and recrystallized twice from ethanol - isopropyl
ether Yield: 21.3 g, m.p. 175-77C (first recrystallization). m.p. 179-
80C (second recrystallization).
Example 9. N-Ethyl-2-(3,5-dibromo-2,6-dimethoxybenzamidomethyl) pyrrolidine
hydrochloride
Using the same method as for compound of Example 8 this compound is
prepared from 20.4 g (0.06 mol) of 3,5-dibromo-2,6-dimethoxybenzoic acid, 50
ml of thionyl chloride and 7.7 g (0.06 mol) of 2-(aminomethyl)-1-ethylpyrro-
lidine. The obtained product is recrystalliæed from ethanol-ethyl ether.
Yield: 20.2 g, m.p. 164-65C. The free base is precipitated from the water
solution of the hydrochloric salt by the addition of sodium hydroxide, m.p.
133-134C.
Example 10. N-Ethyl-2-(3,5-dichloro-2,6-dimethoxybenzamidomethyl) pyrrolidine
20 ml of thionyl chloride is added to 11.9 g ~0.047 mol) of 3,5- ~.
dichloro-2,6-dimethoxybenzoic acid. The mixture is heated on a steam bath
for 30 minutes. To the solution is added 50 ml of toluene. The solvent and
excess thionyl chloride is evaporated at reduced pressure. The residue is
dissolved in 50 ml of dry ethyl ether. To the obtained solution is added
dropwise while stirring 6.0 g ~0.047 mol) of 2-(aminomethyl)-1-ethylpyrroli-
dine in 50 ml of ethyl ether. After 30 minutes at room temperature 300 ml
of water is added while stirring. The water layer is separated and alkalized
with sodium hydroxide solution which is added dropwise while stirring and
cooling in ice. The precipitate is collected and washed with water. Yield:
9.0 g, m.p. 120-21C.
Example 11. N-Ethyl-2-(3-bromo-5-chloro-2,6-dimethoxybenzamidomethyl) pyrro-
lidine
20 ml of thionyl chloride is added to 11.82 g (0.04 mol) of 3-bromo-
8~
5-chloro-2,6-dimethoxybenzoic acid. The mixture is heated on a steam bath
for 1 hour. To the solution is added 50 ml of toluene. The solvent and ex-
cess thionyl chloride is evaporated at reduced pressure. The residue is
dissolved in 50 ml of dry methyl ethyl ketone. The solution is added dropwise
while stirring to 5.13 g (0.04 mol) 2-(aminomethyl)-1-ethylpyrrolidine in 50
ml methyl ethyl ketone. After stirring for 30 minutes at room temperature
300 ml of ether is added. The obtained semisolid product is separated and
dissolved in 300 ml of water. Sodium hydroxide solution is added while stir-
ring and cooling in ice. The precipitate is collected and washed with water.
Yield: 12.0 g, m.p. 124-25C.
Example 12. N-Ethyl-2-(3,5-dibromo-2,6-dimethoxybenzamidomethyl) pyrrolidine
20 ml of thionyl chloride is added to 12.2 g ~0.036 mol) of 3,5-
dibromo-2,6-dimethoxybenzoic acid. The mixture is heated on a steam bath
for 30 minutes. To the solution is added toluene and the solvent and excess
thionyl chloride is evaporated at reduced pressure. To the residue is added
dropwise while stirring a chloroform extract prepared as follows: 75 ml of
30% sodium hydroxide is added to 10.0 g ~0.036 mol) of ~+)-2-~aminomethyl)-
l-ethyl-pyrrolidine d-tartrate. The mixture is extracted with 100 ml of
chlorOform and the extract is dried with magnesium sulphate.
After the addition of the chloroform extract the obtained solution
is heated on a steam bath for 10 minutes. The solvent is evaporated and the
residue is dissolved in 150 ml of water, acidified with hydrochloric acid,
and extracted with ether. The water layer is alkalized with sodium hydroxide
solution and the obtained precipitate is collected and washed with water.
Yield: 7.0 g, m.p. 161-62C, [~]D0 =+53.4o ~1% in acetone)
Example 13. N-Ethyl-2-~3,5-dibromo-2,6-dimethoxybenzamidomethyl) pyrrolidine
hydrochloride
Using the same method as for compound in Example 12 this compound
-12-
4i~/4
is prepared from 19.8 g (0.056 mol) of 3,5-dibromo-2,6-dimethoxybenzoic acid,
30 ml of thionyl chloride and 15.58 g (0.056 mol) of (-)-2-(aminomethyl)-1-
ethylpyrrolidine l-tartrate. Yield: 14.3 g, m.p. 161-62, [a]D =-56.4
~0.4% in acetone). The free amine is converted to the hydrochloride by
treating 13.0 g of the base in 50 ml of acetone with hydrogen chloride in
ether. Yield: 13.5 g, m.p. 159-60C.
Example 14. N-Ethyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl) pyrrolidine
hydrochloride
23.8 g (0.09 mol) of 3-bromo-2,6-dimethoxybenzoic acid is heated
with 35 ml of thionyl chloride on a steam bath for 30 minutes. After the
addition of toluene the excess thionyl chloride is evaporated at reduced
pressure. To the residue is added dropwise while stirring a mixture of 12.6
g ~0.09 mol) of triethylamine and a chloroform extract prepared as follows:
100 ml of 30% sodium hydroxide solution is added to 25.0 g ~0.09 mol) of ~-)-
2-(aminomethyl)-1-ethylpyrrolidine l-tartrate. The mixture is extracted with
150 ml of chloroform and the extract is dried with magnesium sulphate. After
the addition of the chloroform extract the obtained solution is heated on a
steam bath for 10 minutes. The solvent is evaporated and the residue is dis-
solved in water, acidified with hydrochloric acid, and extracted with ether.
The water layer is alkalized with sodium hydroxide and extracted with chloro-
form. The extract is dried with magnesium sulphate and the solvent is eva-
porated. The residual oil is dissolved in ether and acidified with hydrogen
chloride. The obtained precipitate is collected by filtration. Yield: 20.3
g m.p. 166-68, [a]D =-11.1 (0.5% in water).
Example 15. N-Ethyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl) pyrrolidine
hydrochloride
Using the same method as for compound in Example 14, except of the
-13-
11C1~484
addition of triethylamine, this compound was prepared from 8.4 g (0.032 mol)of 3-bromo-Z,6-dimethoxybenzoic acid, 20 ml of thionyl chloride and 9.0 g
(0.032 mol) of ~+)-2-(aminomethyl)-1-ethylpyrrolidine d-tartrate. Yield:
7.5 g m.p. 166-68C, [~]D0 + 10.7 ~0.5% in water).
In table 1 are summarized physicaL data for the compounds prepared
according to the descriptions in Examples 6-15.
-14-
8~
~ ,~ UO~ ~
h ~`I r I 11i u i
~ `I
+
_l a~ o~
~ ~ _~
r~ O N ~D
o\ I .. ..
~ a- o 1~ ~
C~ _l
. oo
~ I` 00 ~ ~
v, ~ ~ a. a~ oo CO
Q~ ~
~ 'O
0 1~: 1~ _~ ~ oo ~) ~ ~D
_I ~ ~ ~1 ~ C~7 ~ C~ ~) ~ t~) ~ ~ O O
X o
~ ..
_~ U~ ~ ~, ~ N O
_l V~ z
,C U) ¢ 00 00 ~ ~
O ~ ~; ~D N ~ ~ I N ~ ~D 0~
z ~ t" o
I 00 00 1~ ~ N N a~ N N
~/ O $ ~ O u~ ~ N N
.
~ ~\ S 4 N ~ ~ N ~ --
N ~ N~
~ x :r
.S
Ul ~CY:
z
N~ ~ h ~I h _I h h
~ a~ a~ a~ a~ a~ a~ a~ .
h_I ~
~P a~ ~ h h h h h h `--
O h ~ X ~ ~ 00 al o ~ N
rl !11 ~1 _I ~1
-15 -
4~4
~ U~ o ~ o ,~
o\ ~ ~ ~ I~ 00 1~ 1`
t~ r~ I` oo o~ oo co
H ~ 00 00 00 00 1`
~_ ~ Z U~
¢ ~ ~ ~0
O I~ t~ O~ ~ ~ O
3 ~ ~
:'
o~ a~ ~ I` ~ .
~ ~ _~0 ~0
¢ CJ~ Ci~ ~ I~ I~ ~
E~ c~
~7 ~
~ a~
~ L~
X ~ X :~
t~ h
~ C~ X :C
~1~ h h h
t~
_~
:~ h ~ r~ ,~ ,_
~ I ~_ +
-16-
P484
The following examples illustrate how the compound of the present
invention may be included in pharmaceutical preparations.
Example 16. Preparation of soft gela~nc caps _
500 g of active substance were mixed with 500 g of corn oil, where-
upon the mixture was filled in soft gelatine capsules, each capsule containing -
100 mg of the mixture ~i.e. 50 mg of active substance).
Example 17. Preparation of soft gelatirls capsules
500 g of active substance were mixed with 750 g of pea nut oil,
whereupon the mixture was filled in soft gelatine capsules, each capsule con-
taining 125 mg of the mixture (i.e. 50 mg of active substance).
Example 18. Preparation of tablets
50 kg of active substance were mixed with 20 kg of silicic acid of
the trade mark Aerosil. 45 kg of potato starch and 50 kg of lactose were
mixed therewith and the mixture was moistened with a starch paste prepared
from 5 kg of potato starch and distilled water, whereupon the mixture was
granulated through a sieve. The granulate was dried and sieved, whereupon
2 kg of magnesium stearate was mixed into it. Finally the mixture was pres-
sed into tablets each welghing 172 mg.
Example 19. Preparation of effervescing tablets
100 g of active substance, 140 g of finely divided citric acid,
100 g of finely divided sodium hydrogen carbonate, 3.5 g of magnesium stear-
ate and flavouring agents (q.s.) were mixed and the mixture was pressed into
tablets each containing 100 mg of active substance.
Example 20. Preparation of a sustained release tablet
200 g of active substance were melted together with 50 g of stearic
acid and 50 g of carnauba wax. The mixture thus obtained was cooled and
ground to a particle size of at most 1 mm in diameter. The mixture thus
-17-
84
obtained was mixed with 5 g of magnesium stearate and pressed into tablets
each weighing 305 mg. Each tablet thus contains 200 mg of active substance.
Pharmacology
Introduction
An abundance of studies suggest that the antipsychotic action of
neuroleptics is in some way related to the decrease in catecholamine trans-
mission in the brain caused by these drugs and more specifically due to
central dopamine (DA) receptor blockade as originally suggested by Carlsson
(Acta Pharmacol. 20, 140-144, 1963; J. Neur. Transmission, 34, 125-132, 1973).
Most compounds with an antipsychotic action appear to affect sev-
eral DA systems in the brain. It has been hypothetized that the antipsycho-
tic action may be linked to blockade of DA receptors in the subcortical and
cortical limbic structures (J. Pharm. Pharmacol. 25, 346, 1973; Lancet, nov. 6,
1027, 1976) or to blockade of DA receptors in the nigroneostriatal DA system
(Intern. J. Neurol. 6, 27-45, 1967).
There are several techniques available to study DA receptor block-
ade in the brain. One method is based on the ability of anti-psychotics to
block the behavioural effects induced by the DA agonist apomorphine. Apo-
morphine produces in rats and other species a characteristic syndrome consist-
ing of repetitive movements (stereo-typies) and hyperactivity which appear to
be due to activation of postsynaptic DA receptors in the brain (J. Pharm.
Pharmacol. 19, 627, 1967; J. Neurol. Transm. 40, 97-113, 1977). The stereo-
typies (chewing, licking, biting) appear mainly to reflect action on DA
receptors of the neostriatal system (J. Psychiat. Res., 11, 1, 1974) whereas
the increased locomotion (hyperactivity) mainly appears to be due to activa-
tion of DA receptors in mesolimbic structures (nucleus olfactorium, nucleus
accumbens), (J. Pharm. Pharmacol. 25, 1003, 1973).
-18-
??484
A number of studies have demonstrated that neuroleptics block apo-
morphine stereotypies and that this blockade is well related to blockade of
DA transmission measured by other techniques. Thus, the antiapomorphine
effect correlates with changes in DA turnover (Eur. J. Pharmacol., 11, 303,
1970), DA receptor binding studies (Life Science, 17, 993-1002, 1976) and
most important with antipsychotic efficacy (Nature, 263, 388-341, 1976).
Methods
Male Spraque-Dawley rats weighing 225-275 g were used. The rats
were observed in perspex cages (40 (L) x 25(w) x 30 (h) cm) and the behaviour
10 was scored 5, 20, 40, and 60 minutes after apomorphine. The compounds were
injected 60 minutes prior to apomorphine hydrochloride (1 mg/kg) which was
injected subcutaneously into the neck. This dose and form of administration
was found to produce a very consistent response and very low variation in
response strength. Further more, apomorphine given s.c. also produced a very
consistent hyperactivity.
Directly after injection, the animals were placed in the cages, one
in each cage. Scoring of the stereotypies were performed by two separate
methods. The first scoring system was a modified version of the system in-
troduced by Costall and Naylor (1973). The strength of the stereotypy was
20 scored on a 0-3 scale as follows:
Score Description of stereotyped behaviour
0 No change in behaviour compared to saline
controls or sedated.
1 Discontinuous sniffing.
2 Continuous sniffing.
3 Continuous sniffing. Chewing, biting and
licking.
-19--
,,
4~4
In the second system the number of animals displaying hyperactivity
caused by apomorphine were scored. Each group consisted of 6-8 animals. Sa-
line controls were always run simultaneously. ED50's are in the first scoring
system (0-3 scale), the doses which reduce the strength of the stereotypies
by 50% over the observation period of 60 minutes. ED50's of the second scor-
ing system are the doses which reduce tlle number of animals showing hyperac-
tivity by 50% over the observation period of 60 minutes. The ED50's were
calculated from log dose-response curves by the method of least squares from
4-6 dose levels with 6-8 animals per dose level.
Results
The results are presented in Table 2. The compounds of the inven-
tion were compared with the antipsychotic sulpiride (Life Science, 17, 1551-
1556, 1975). The tabulated results indicate that the compounds of the present
invention are potent inhibitors of DA receptors in the brain. Due to their
ability to antagonize both apomorphine stereotypies and hyperactivity they
probably block DA receptors in both striatal and limbic areas (see Introduc-
tion) Furthermore they are considerably more active than the antipsychotic
drug sulpiride. Since there is a highly significant correlation between the
blockade of apomorphine and clinical antipsychotic efficacy (Nature, 263,
388-341, 1976), it is very likely that the compounds of the present invention
will show a highly potent antipsychotic action in man.
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4~4
TABLE 2
The ability to block apomorphine induced stereotypies and hyperactivity
. .
Compound according Stereotypies Hyperactivity
to Example No. ED5~ ~mol/kg i.p. ED50 umol/kg i-p-
6 122 70
7 23 11
8 ~7 30
9 5.3 1.8
5.8 3.0
11 6.2 3.9
12 >178 ~11
13 3.3 0.33
14 5.6 0.83
>196 ~123
Sulpiride 293 50
The compounds of the invention were also compared to sulpiride in
the same test system after oral administration. The results are tabulated
below.
TABLE 3
Compound acc. to Stereotypies Hyperactivity
Example No. ED50 ~mol/kg P- ED50 ~mol/kg p.-
7 47 ~19 mg/kg) 17 (7 mg/kg)
9 8.2 ~4.0 mg/kg) 5.5 (2.7 mg/kg)
Sulpiride >586 (>200 mg/kg) >586 (> 200 mg/kg)
48~.~
As can be seen sulpiride has lost all activity. This is in contrast
to the tested compounds of formula I which are still effective after oral ad-
ministration.
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