Pyridazine derivatives having a psychotropic action and compositions

This invention relates to pyridazine derivatives substituted in the 4-position by a cyano group having psychotropic activity. It also relates to a process for the preparation of these products and their application as medicaments. ##STR1##

Pyridazine derivatives have been proposed as medicaments for many years. In 
a large number of cases, these are substances which are active on the 
cardiovascular system and which have, in particular, a hypotensive or 
vasodilatory effect. More rarely, pyridazine derivatives have been 
mentioned as having an antiinflammatory and analgesic action. Finally, 
French Pat. No. 2,141,697 describes a family of products corresponding to 
the general formula: 
##STR2## 
in which: R.sub.1 represents hydrogen or a lower alkyl group; 
Ar represents an aromatic radical; and 
R.sub.2 denotes a group: 
##STR3## 
in which n=2 or 3 and Y and Z represent a lower alkyl group, or 
alternatively 
##STR4## 
constitutes a heterocyclic radical. 
These compounds are characterised by a psychotropic activity of the 
psychotonic type. 
It has now been found that the introduction of the cyano group into the 
4-position of pyridazine substantially improves the therapeutic properties 
of these products compared with the properties described for the same 
family of pyridazines unsubstituted in the 4-position or substituted in 
the same position by a methyl group, the best-known example of which is 
minaprine (DCI) (Ar=C.sub.6 H.sub.5, R.sub.1 =CH.sub.3, R.sub.2 
=.beta.-morpholinoethyl). 
Thus, according to one of its features, the present invention relates to 
4-cyanopyridazines having the following formula: 
##STR5## 
in which: one of the substituents R.sub.1 and R.sub.2 represents hydrogen 
or a lower alkyl group and the other represents hydrogen; a C.sub.1 
-C.sub.6 alkyl group; a C.sub.3 -C.sub.7 cycloalkyl group; a phenyl group; 
a phenyl group monosubstituted by a halogen atom, a nitro group, a 
trifluoromethyl group, a hydroxyl group, a C.sub.1 -C.sub.6 alkoxy group, 
a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkanoyloxy group, a 
cyano group, a C.sub.1 -C.sub.6 alkylthio group, a C.sub.1 -C.sub.6 
alkylsulphinyl group, a C.sub.1 -C.sub.6 alkylsulphonyl group or a 
sulphamyl group; a phenyl group disubstituted by one of the abovementioned 
substituents on the one hand and a chlorine or fluorine atom or a methoxy 
group on the other; a naphth-1-yl group; a naphth-2-yl group; a thien-2-yl 
group; a thien-3-yl group; or an indol-3-yl group; 
Alk represents an ethylene group, a 1,2-propylene group or a 1,3-propylene 
group; 
X denotes hydrogen; and 
Y represents hydrogen or a .beta.-hydroxyethyl group, or alteratively 
The group 
##STR6## 
represents a morpholin-4-yl or 3-oxomorpholin-4-yl group, and also their 
pharmaceutically acceptable salts. 
Comparison of the products of the invention with minaprine in several 
pharmacological tests, demonstrating their psychotropic activity, showed 
that the products according to the invention have a median effective dose 
which is comparable to or less than that of minaprine, while their 
toxicity is considerably lower. Thus, the compounds according to the 
invention have a very much higher therapeutic index than minaprine. 
According to another feature, the present invention relates to a process 
for the preparation of the compounds of the formula I in which R.sub.1, 
R.sub.2, Alk, X and Y are as defined above, which is represented by the 
following scheme: 
##STR7## 
The process of the present invention is characterised in that the following 
reactions are carried out: 
(a) an appropriately substituted 4-ethoxycarbonylpyridazone (II) is treated 
with aqueous ammonia to give the corresponding pyridazone-4-carboxamide 
(III); 
(b) the pyridazone-4-carboxamide is treated with phosphorus oxychloride to 
give the 3-chloro-4-cyanopyridazine (IV); and 
(c) by reaction with the amine 
##STR8## 
the pyridazine is substituted in the 3-position to give the compound (I). 
In the first step, excess concentrated aqueous ammonia solution is used and 
the reaction is carried out at ambient temperature for 10 to 15 hours. 
The second step is carried out with excess phosphorus oxychloride at a 
temperature of about 80.degree. C. for several hours. 
Finally, the last step is carried out by heating the two reactants in a 
suitable solvent such as n-butanol. 
Most of the starting materials are known. Those which are not can easily be 
prepared, for example by reacting an .alpha.-halogenoketone of the 
formula: 
##STR9## 
in which Hal is a chlorine or bromine atom, with ethyl malonate to form 
the substituted malonate: 
##STR10## 
This is treated with hydrazine to give the product of the formula: 
##STR11## 
which, on dehydrogenation, for example with bromine in acetic acid, yields 
the desired product II. 
The key intermediates in the process of the present invention, which have 
the formulae III and IV above, are new products if at least one of the 
substituents R.sub.1 and R.sub.2 is other than hydrogen or the methyl 
group. 
According to another feature, the present invention also relates to these 
compounds of the formulae III and IV as new products which can be used as 
intermediates. 
Finally, according to yet another feature, the present invention relates to 
pharmaceutical compositions containing, as active products, the compounds 
of the formula I above or their pharmaceutically acceptable salts. 
In the pharmaceutical compositions of the present invention for oral, 
sublingual, subcutaneous, intramuscular, intravenous, transdermal or 
rectal administration, the active ingredients of the formula I above can 
be administered to mammals, including humans, in unit forms of 
administration, as a mixture with conventional pharmaceutical carriers, 
for the treatment of various neurological and psychiatric complaints: mood 
and behaviour disorders, neurological and endogenous depressions, memory 
disorders, infantile hyperkinesis, antism, and sexual insufficiencies of 
psychogenic origin. 
Suitable unit forms of administration which must be mentioned include forms 
for oral administration, such as tablets, gelatine capsules, powders, 
granules and solutions or suspensions to be taken orally, and forms of 
sublingual and buccal administration, and also forms of parenteral 
administration which can be used for subcutaneous, intramuscular or 
intravenous administration. 
To obtain the desired therapeutic effect, the dose of active principle can 
vary between 0.1 and 50 mg per kg of body weight per day. 
Each unit dose can contain from 1 to 500 mg of active ingredient in 
combination with a suitable pharmaceutical carrier. It can be administered 
from 1 to 4 times per day. 
The examples which follow illustrate the invention without however limiting 
it. 
PREATION 1 
(a) Ethyl phenacylmalonate 
240.25 g of ethyl malonate, 138 g of potassium carbonate, 5 g of potassium 
iodide and 154 g of phenacyl chloride in 2 liters of anhydrous acetone are 
heated under reflux overnight. 
After the inorganic salts have been filtered off, the filtrate is 
evaporated to dryness and the excess ethyl malonate is then distilled off 
under reduced pressure (pressure: 0.5 mbar; temperature: about 60.degree. 
C.). The distillation residue is chromatographed on a silica column using 
a cyclohexane/ethyl acetate mixture (9/1) as the eluent. The expected 
ketoester is in the form of a red oil. Yield: 80.3%. 
(b) 4-Ethoxycarbonyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one 
40.5 g of the previously obtained product are dissolved in 70 ml of 
absolute ethanol, and 7.25 g of hydrazine hydrate are added dropwise to 
the reaction medium at a temperature of the order of 0.degree. C., with 
stirring. When the reaction medium has returned to ambient temperature, it 
is stirred for 24 hours and the beige precipitate obtained, which 
corresonds to the expected pyridazinone, is then filtered off. 
The filtrate is treated with 3.62 g of hydrazine hydrate. After stirring 
for 24 hours, an additional quantity of pyridazinone can be filtered off. 
The same operation is repeated once more on the filtrate. 
After purification by passage through a silica column using a 
cyclohexane/ethyl acetate mixture (volume volume: 1/1) as the eluent, the 
expected compound is obtained with a yield of 37%. 
(c) 4-Ethoxycarbonyl-6-phenyl-2H-pyridazin-3-one 
(II) R.sub.1 =C.sub.6 H.sub.5 ; R.sub.2 =H 
9 g of the compound obtained under (b) are dissolved in 200 ml of acetic 
acid, and 11.18 g of bromine are then added to the solution, with 
stirring. Decolouration of the medium occurs after 5 minutes. After 2 
hours at ambient temperature, and with stirring, the medium is poured into 
200 ml of water, the mixture is then extracted with methylene chloride and 
the organic phase is evaporated to dryness. 
The residue is taken up three times with cyclohexane. The beige powder 
obtained is chromatographed on a silica column using a cyclohexane/ethyl 
acetate mixture (volume/volume: 1/1) as the eluent. The expected 
pyridazinone is obtained with a yield of 51%. Melting point 150.degree. C. 
PREATION 2 to 8 
The products (II) described in Table 1 are obtained, following the 
procedure described in Preparation 1, starting from: 
para-chlorophenyl chloromethyl ketone, 
para-fluorophenyl chloromethyl ketone, 
.alpha.-naphthyl bromomethyl ketone, 
cyclohexyl chloromethyl ketone, 
2,4-dichlorophenyl chloromethyl ketone, 
indol-3-yl chloromethyl ketone, 
thien-3-yl chloromethyl ketone, 
by reaction with ethyl malonate, condensation with hydrazine hydrate and 
dehydrogenation with bromine in acetic acid. 
TABLE 1 
______________________________________ 
Compounds II 
Preparation No. R1 R2 
______________________________________ 
##STR12## H 
3 
##STR13## H 
4 
##STR14## H 
5 
##STR15## H 
6 
##STR16## H 
7 
##STR17## H 
8 
##STR18## H 
______________________________________ 
PREATIONS 9 TO 18 
The products described in Table 2 are obtained, following the procedure 
described in Preparation 1, starting from: 
4-methoxyphenyl chloromethyl ketone, 
4-hydroxyphenyl chloromethyl ketone, 
3,4-dimethoxyphenyl chloromethyl ketone, 
4-nitrophenyl chloromethyl ketone, 
3-methylphenyl chloromethyl ketone, 
cyclopentyl chloromethyl ketone, 
3-trifluoromethylphenyl chloromethyl ketone, 
phenyl 1-chloroethyl ketone, 
methyl .alpha.-chlorobenzyl ketone, 
.alpha.-chlorophenylacetaldehyde, 
by reaction with ethyl malonate, condensation with hydrazine hydrate and 
dehydrogenation with bromine in acetic acid. 
TABLE 2 
______________________________________ 
Preparation Compounds II 
No. R1 R2 
______________________________________ 
9 
##STR19## H 
10 
##STR20## H 
11 
##STR21## H 
12 
##STR22## H 
13 
##STR23## H 
14 
##STR24## H 
15 
##STR25## H 
16 
##STR26## CH.sub.3 
17 CH.sub.3 
##STR27## 
18 H 
##STR28## 
______________________________________ 
PREATIONS 19 TO 36 
The products mentioned in Table 3 are obtained in the same way, starting 
from: 
4-methylthiophenyl chloromethyl ketone, 
4-methylsulphinylphenyl chloromethyl ketone, 
4-methylsulphonylphenyl chloromethyl ketone, 
naphth-2-yl chloromethyl ketone, 
thien-2-yl chloromethyl ketone, 
2-chlorophenyl chloromethyl ketone, 
3-chlorophenyl chloromethyl ketone, 
3,4-dichlorophenyl chloromethyl ketone, 
cyclopropyl chloromethyl ketone, 
4-methylphenyl chloromethyl ketone, 
2-methylphenyl chloromethyl ketone, 
4-trifluoromethylphenyl chloromethyl ketone, 
cyclooctyl chloromethyl ketone, 
4-cyanophenyl chloromethyl ketone, 
4-sulphamoylphenyl chloromethyl ketone, 
3,4-dihydroxyphenyl chloromethyl ketone, 
4-acetoxyphenyl chloromethyl ketone, 
.alpha.-bromodeoxybenzoin. 
TABLE 3 
______________________________________ 
Preparation Compounds II 
No R1 R2 
______________________________________ 
19 
##STR29## H 
20 
##STR30## H 
21 
##STR31## H 
22 
##STR32## H 
23 
##STR33## H 
24 
##STR34## H 
25 
##STR35## H 
26 
##STR36## H 
27 
##STR37## H 
28 
##STR38## H 
29 
##STR39## H 
30 
##STR40## H 
31 
##STR41## H 
32 
##STR42## H 
33 
##STR43## H 
34 
##STR44## H 
35 
##STR45## H 
36 
##STR46## 
##STR47## 
______________________________________

EXAMPLE 1 
6-Phenyl-3-oxo-2H-pyridazine-4-carboxamide 
(III) R.sub.1 =C.sub.6 H.sub.5 ; R.sub.2 =H 
2 g of the product obtained in Preparation 1 are added to 40 ml of 
concentrated ammonia solution and the mixture is stirred overnight at 
ambient temperature. The solid is filtered off and dried to give the 
expected product. 
Yield 86%; melting point&gt;300.degree. C. 
EXAMPLES 2 TO 17 
The compounds III described in Table 4 are obtained, following the 
procedure of Example 1, starting from the corresponding ethoxycarbonyl 
derivatives. 
TABLE 4 
______________________________________ 
Example Compounds III 
No R1 R2 
______________________________________ 
##STR48## H 
3 
##STR49## H 
4 
##STR50## H 
5 
##STR51## H 
6 
##STR52## H 
7 
##STR53## H 
8 
##STR54## H 
9 
##STR55## H 
10 
##STR56## H 
11 
##STR57## H 
12 
##STR58## H 
13 
##STR59## H 
14 
##STR60## H 
15 
##STR61## H 
16 
##STR62## 
##STR63## 
17 
##STR64## H 
______________________________________ 
EXAMPLE 18 
3-Chloro-4-cyano-6-phenylpyridazine 
(IV) R.sub.1 =C.sub.6 H.sub.5 ; R.sub.2 =H 
1.5 g of the product obtained in Example 1 are dissolved in 20 ml of 
phosphorus oxychloride and the solution is then heated at 80.degree. C. 
for 5 hours. The mixture is poured into 50 ml of water. A precipitate 
appears, which is filtered off and dried. 
Yield: 58.3%; melting point 206.degree. C. 
EXAMPLES 19 TO 34 
The 3-chloro-4-cyanopyridazines of the formula IV described in Table 5 are 
obtained, following the procedure of Example 18, starting from the 
corresponding amides of the formula III. 
TABLE 5 
______________________________________ 
Ex- 
am- 
ple Compounds IV 
No. R.sub.1 R.sub.2 Melting point or Rf 
______________________________________ 
19 
##STR65## H Chromatography 
20 
##STR66## H Melting point: 170.degree. C. 
21 
##STR67## H Chromatography 
22 
##STR68## H Rf: 0.9 (hexane - ethyl acetate) 
23 
##STR69## H Melting point: 152-154.degree. C. 
24 
##STR70## H Rf: 0.4 (hexane - ethyl acetate 2/1) 
25 
##STR71## H Melting point: 152.degree. C. 
26 
##STR72## H Melting point 196-198.degree. C. 
27 
##STR73## H Melting point 204-206.degree. C. 
28 
##STR74## H Melting point: 231-232.degree. C. 
29 
##STR75## H Rf: 0.8 (hexane - ethyl acetate 2/1) 
30 
##STR76## H Melting point 191.degree. C. 
31 
##STR77## H Rf: 0.7 (hexane - ethyl acetate 2/1) 
32 
##STR78## H Rf: 0.8 (hexane - ethyl acetate 1/1) 
33 
##STR79## 
##STR80## 
-- 
34 
##STR81## H Rf: 0.9 (hexane - ethyl acetate 
______________________________________ 
1/1, vol/vol) 
EXAMPLE 35 
3-(2-Morpholinoethylamino)-4-cyano-6-phenylpyridazine dihydrochloride. SR 
95 191. 
(I) R.sub.1 =C.sub.6 H.sub.5 ; R.sub.2 =H; Alk=(CH.sub.2).sub.2 ; 
##STR82## 
7.3 g of the chlorine compound of Example 18 are dissolved in 60 ml of 
normal butanol, and 8 g of N-(2-aminoethyl)-morpholine are added. The 
mixture is heated under reflux for 3 hours and then poured into 1000 ml of 
water. The organic phase is extracted with ether and the ether solution is 
then extracted with a 1N solution of sulphuric acid. The aqueous phase is 
separated off, rendered alkaline with sodium hydroxide and extracted with 
ether. The ether phase is dried over magnesium sulphate and the solvent is 
then evaporated off to dryness in vacuo. This gives a yellow solid. Yield 
81.3%; melting point 138.degree. C. 
6.8 g of the product obtained above are dissolved in 100 ml of dry 
methanol, and a stream of hydrogen chloride is bubbled into the solution. 
The solvent is evaporated off to dryness in vacuo and the residue is taken 
up with anhydrous ether. 
A precipitate of 3-(2-morpholinoethylamino)-4-cyano-6-phenylpyridazine 
dihydrochloride forms, which is recrystallised twice from isopropanol. 
Melting point 144.degree. C. (decomposition). 
Starting from the base, the following salts of the same compound can be 
prepared in the same manner: 
______________________________________ 
Monocitrate Melting point 181.degree. C. 
(aqueous ethanol) 
Diglutamate Melting point above 260.degree. C. 
(aqueous ethanol) 
Monohydrochloride 
Melting point 230.degree. C. 
Monofumarate Melting point 204.degree. C. 
(acetone) 
Monomaleate Melting point 168.degree. C. 
(acetone) 
______________________________________ 
EXAMPLES 36 TO 51 
The compounds (I) described in Table 6 are obtained, following the 
procedure described above, by reacting the corresponding chlorinated 
derivative of the formula (IV) with N-(2-aminoethyl)-morpholine. 
TABLE 6 
______________________________________ 
##STR83## 
SR 
Pro- 
Ex- duct Salt or base 
am- Code Melting point 
ple No. R.sub.1 R.sub.2 
(.degree.C.) (solvent) 
______________________________________ 
36 95276 A 
##STR84## H Dihydrochloride 135-140 (decomposition) 
37 95306 
##STR85## H Base 208 
38 95294 A 
##STR86## H Dihydrochloride 130-140 (decomposition 
isopropanol) 
39 95331 A 
##STR87## H Dihydrochloride 168 (decomposition) 
40 42632 A 
##STR88## H Fumarate (2/3) 183-185 (acetone) with 
0.5 H.sub.2 O 
41 95324 A 
##STR89## H Dihydrochloride 228 (isopropanol) 
42 95274 A 
##STR90## H Dihydrochloride 170 (methanol) 
43 42595 A 
##STR91## H Fumarate (1/1) 240-242 (acetone) 
44 42638 A 
##STR92## H Maleate (1/1) 240-242 (acetone) 
45 42692 
##STR93## H Base 184-186 (isopropanol) 
46 95323 A 
##STR94## H Dihydrochloride 260 (decomposition) 
47 42639 
##STR95## H Base 150-151 (isopropanol) 
48 95330 A 
##STR96## H Dihydrochloride 278 Base 159 
49 95328 
##STR97## H Base 129 
50 95071 A 
##STR98## 
##STR99## 
Monohydrochloride 210 (decomposition) 
51 95329 
##STR100## H Base 205 (methanol) 
______________________________________ 
EXAMPLES 52 TO 56 
The compounds (I) collated in Table 7 are obtained from various 
3-chloropyridazines following the procedure of Example 35, but varying the 
amine compound used. 
TABLE 7 
__________________________________________________________________________ 
Example No 
SR Code No. 
R.sub.1 R.sub.2 
Alk 
##STR101## 
Melting point .degree.C.Base 
or salt 
__________________________________________________________________________ 
52 95290 A 
##STR102## 
H (CH.sub.2).sub.2 
NH.sub.2 Dihydrochloride 130-140 
53 95291 A 
" H " NHCH.sub.2 CH.sub.2 OH 
Dihydrochloride 110-110 
(hygroscopic) 
54 95332 A 
##STR103## 
H " " Dihydrochloride 
124 (decomposition) 
55 95292 A 
##STR104## 
H 
##STR105## 
##STR106## 
Dihydrochloride 135-140 
(decomposition) 
56 42633 
##STR107## 
H (CH.sub.2).sub.2 
NH.sub.2 Base 200-202 (ethanol) 
__________________________________________________________________________ 
EXAMPLE 57 
3-[2-(3-Oxomorpholino)-ethylamino]-4-cyano-6-phenylpyridazine 
hydrochloride. SR 95327 A 
R.sub.1 =C.sub.6 H.sub.5 ; R.sub.2 =H; Alk=(CH.sub.2).sub.2 ; 
##STR108## 
(a) A solution of 4.2 g of sodium hydroxide in 54 ml of water is added to a 
solution of 3 g of compound 95291 A (Example 53) in 54 ml of methylene 
chloride and the mixture is then cooled to -5.degree. C., -10.degree. C., 
with stirring. 1.17 g of chloroacetyl chloride are added slowly, the 
temperature is then allowed to rise to 20.degree. C. and the mixture is 
left for 15 hours at this temperature, with stirring. The organic phase is 
separated off and evaporated to dryness in vacuo. 
This gives a yellow solid, which is used as such for the following step: 
(b) The product obtained above is dissolved in 27 ml of anhydrous methanol, 
and a solution of sodium methylate, obtained by reacting 0.24 g of sodium 
with 27 ml of anhydrous methanol, is added. The mixture is heated under 
reflux for 6 hours and evaporated to dryness. The residue is taken up in 
water and extracted with ethyl acetate. The organic layer is separated 
off, dried over sodium sulphate and evaporated to dryness. The product is 
purified by chromatography on a silica column using an ethyl 
acetate/methanol mixture, 8/2 vol/vol, as the 
This gives a pale yellow oil (1.5 g). This is dissolved in methanol and dry 
hydrogen chloride is bubbled into the solution. The mixture is evaporated 
to dryness and the residue is taken up in the minimum quantity of 
methanol. Anhydrous ether is added and the precipitate of hydrochloride is 
filtered off; melting point 128.degree. C. 
EXAMPLE 58 
Galenical preparation 
The gelatine capsules containing the following ingredients may be indicated 
as an example of a galenical preparation: 
______________________________________ 
Active principle 50 mg 
Aerosil 0.5 mg 
Magnesium stearate 1.5 mg 
STA RX 1500 starch 48 mg 
100 mg 
______________________________________ 
The psychotropic activity of a compound representative of the invention, 
namely compound SR 95191 (Example 37), was measured in three 
pharmacological tests and compared with minaprine and iminaprine, which is 
a very widely used antidepressant. Likewise, the toxicity of the product 
was compared with that of the reference products. 
DESPAIR BEHAVIOUR 
This test was carried out on CD1 (Charles River) female mice, weighing 18 
to 23 g, by the method described by PORSOLT (Archives Internationales de 
Pharmacodynamie, 1977, 327-336). 
The principle of this test is as follows: when a mouse is placed in a 
narrow vessel filled with water, it struggles and then, after 2 to 4 
minutes, it becomes immobile and floats on its abdomen, with its back 
hunched and its back paws tucked under the body, and it only makes the few 
movements necessary to keep its head above the water. This is the 
so-called despair reaction. 
Certain psychotropic drugs, in particular antidepressants, lengthen the 
time for which the mouse struggles. 
The following protocol was selected: 
The products to be studied were administered intraperitoneally 1 hour 
before the test. For the test, the animals are placed in a narrow vessel 
(10.times.10.times.10 cm) filled with water to a height of 6 cm, the 
temperature being 24.degree. C. plus or minus 2.degree. C. The animals are 
left in the water for 6 minutes and the time for which the animal remains 
immobile between the 2nd and 6th minutes is measured. The activity of the 
substance is the greater, the shorter this time. 
Each substance was studied on a batch of 10 mice. The results are the 
average of at least two experiments. 
ANTAGONISM OF RESERPINE-INDUCED PTOSIS 
This test, which is described by GOURET (Journal de pharmacologie Paris 
1973, 4 (1), 105-128), was carried out on CD1 (Charles River) female mice 
weighing 20 g plus or minus 1 g. Reserpine causes ptosis 1 hour after its 
intravenous administration; certain antidepressants oppose this ptosis. 
The following protocol was selected: 
The substances to be studied were administered intraperitoneally. The 
reserpine is administered intravenously at the same time, at a dose of 2 
mg/kg. 1 hour after the administration of reserpine, the number of animals 
which do not exhibit ptosis are noted. 
This test was carried out on batches of 10 mice; the results are expressed 
as a percentage of animals which do not exhibit ptosis and are the average 
of at least two experiments. 
ROTATIONAL BEHAVIOUR 
This test is described by PROTAIS et al. in Journal de pharmacologie, 1976, 
7, 251-255. 
CD1 Charles River female mice weighing from 20 to 24 g first undergo 
unilateral lesion of the striatum by the stereotaxic injection of 
6-hydroxydopamine at a dose of 8 .mu.g per animal. One week after this 
operation, the product is administered intraperitoneally to groups of 7 
mice. The number of rotations is evaluated over 2 minutes, 1 hour after 
the administration of the product. Rotations on the same side as the 
lesion are counted as positive and those on the opposite side are counted 
as negative. The algebraic sum of the rotations for a group of treated 
animals is compared with that for the group of control animals, which have 
only received the vehicle (physiological serum). 
ACUTE TOXICITY 
The products to be studied were administered intraperitoneally in 
increasing doses to batches of 10 mice. The mortality caused by the 
products studied was noted for 24 hours following the administration of 
the product. 
The 50% lethal dose, that is to say the dose causing the depth of 50% of 
the animals studied, is determined from the results obtained for each of 
the products studied. 
The results obtained are shown in Table 8. 
TABLE 8 
__________________________________________________________________________ 
Toxicity, 
Reserpine- 
intraperi- 
induced ptosis, 
toneal ad- 
intraperitoneal 
Despair behaviour, 
Rotational behaviour, 
ministration 
administration 
intraperitoneal 
intraperitoneal admini- 
Compound 
LD.sup.50 
ED.sup.50 
administration 
stration 
__________________________________________________________________________ 
SR 95191 
250 mg/kg 
3.9 mg/kg 
5 mg/kg: -26%++ 
0.1 mg/kg: 
-60%++ 
2 mg/kg: 
-107%++ 
63 mg/kg 
5 mg/kg 
5 mg/kg: -31%++ 
0.125 mg/kg: 
-53%++ 
2 mg/kg: 
-82%++ 
89 mg/kg 
2.4 mg/kg 
10 mg/kg: -38%++ 
3 mg/kg: 
-6% n.s. 
__________________________________________________________________________ 
++: p 0.1 Student test 
n.s.: not significant 
In the same manner, the psychotropic activity of two other compounds 
representative of the invention, namely compounds SR 95274 A (Example 42) 
and SR 95294 A (Example 38), was determined in two of the above 
pharmacological tests: rotational behaviour and antagonism of 
reserpine-induced ptosis. The results obtained are indicated in Table 9 
below, together with the toxicity of these products administered 
intraperitoneally under the conditions indicated above. 
TABLE 9 
______________________________________ 
Test for the 
antagonism of 
reserpine- 
Toxicity, induced ptosis, 
Rotational behav- 
intraperi- intraperi- iour of mice (intra- 
toneal toneal peritoneal 
Products administration 
administration 
administration) 
______________________________________ 
SR 95 274 A 
LD.sub.50 ED.sub.50 = 
0.5 mg/kg - 
60%* 
&gt;300 mg/kg 2.6 mg/kg 2 mg/kg - 
82%* 
SR 95 294 A ED.sub.50 = 
0.5 mg/kg - 
74%* 
10 mg/kg 2 mg/kg - 
92%* 
Minaprine 
LD.sub.50 = 
ED.sub.50 = 
2 mg/kg - 
82%* 
63 mg/kg 5 mg/kg 
______________________________________ 
*p &lt; 0.01, Student test