1. Compound, optionally in the form of a pure optical isomer or a mixture of such isomers, corresponding to the general formula (I) in which R1 represents a hydrogen atom or a (C1-C4) alkyl or cyclo(C3-C7) alkylmethyl group, X1 represents a hydrogen or halogen atom or a (C1-C4)alkoxy group, or alternatively OR1 and X1 together represent a group of formula -OCH20-, -0(CH2)2-, -0(CH2)3-, -0(CH2)20- or -0(CH2)30-, X2 represents a hydrogen atom, an amino group or a group of general formula -NHC02R in which R represents a (C1-C4)alkyl or phenyl(C1-C2)alkyl group, X3 represents a hydrogen or halogen atom, and R2 represents a hydrogen atom or a (C1-C6)alkyl group, which is optionally substituted, or a phenyl(C1-C4) alkyl or [(4-dimethylamino)piperid-l-ylcarbonyl] (C2-C4)alkyl group, in the form of a base or an addition salt with an acid.

2. Process for the preparation of compounds according to Claim 1, characterized in that an ester of general formula (II) in which R1; X1, X2 and X3 are as defined in Claim 1 and R3 represents a methyl or ethyl group, is reacted with hydrazine hydrate, in order to obtain a hydrazide of general formula (III) which is cyclized into an oxadiazole of general formula (IV) either using phosgene, in an aprotic solvent, or using phenyl chloroformate, in an aprotic solvent, after which the oxadiazole of general formula (IV) is reacted with an alcohol of general formula (V) in which Boc represents a (1,1-dimethylethoxy)carbonyl group, in the presence of triphenylphosphine and ethyl azodicarboxylate, in an aprotic solvent, in order to obtain a compound of general formula (I) in which R2 represents a hydrogen atom, and, finally, the latter compound is subjected to an alkylation using a derivative of general formula R2-X, in which X represents a leaving group, and R2 is as defined in Claim 1, but is other than a hydrogen atom.

3. Medicinal product, characterized in that it consists of a compound according to Claim 1.

4. Pharmaceutical composition, character- ized in that it contains a compound according to Claim 1, combined with an excipient.

5. A compound of general formula (I), as defined herein, substantially as herein described, particularly with reference to the foregoing examples.

6. A process for the preparation of compounds of general formula (I), as defined herein, substantially as herein described, particularly with reference to the foregoing examples.

7. Medical product, substantially as herein described, particularly with reference to the foregoing examples.

8. A pharmaceutical composition, substantially as herein described, particularly with reference to the foregoing examples.

9. A process for preparing a pharmaceutical composition, substantially as herein described, particularly with reference to the foregoing examples. 3-(Pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3h)-one derivatives, their preparation and their therapeutic application Compounds corresponding to the general formula (I) in which R1 represents hydrogen or an alkyl or cycloalkylmethyl group, X1 represents hydrogen or a halogen or an alkoxy group, or alternatively OR1 and X1 together represent a group of formula -OCH2O-, -O(CH2)2-, -O(CH2)3-, -O(CH2)2O- or -O(CH2)3O-, X2 represents hydrogen, an amino group or a group of general formula -NHCO2R in which R represents an alkyl or phenylalkyl group, X3 represents hydrogen or a halogen, and R2 represents hydrogen or an alkyl, phenylalkyl or [(4-dimethylamino)piperid- 1-ylcarbonyl]alkyl group. Therapeutic application.

The present invention relates to compounds of the
general formula (I)

in which
R-L represents a hydrogen atom or a (C1-C4)alkyl or
cyclo(C3-C7) alkylmethy1 group,
X1 represents a hydrogen atom or a (C1-C4) alkoxy group,
or alternatively
OR1 and X1 together represent a group of formula
-OCH20-, -0(CH2)2-, -0(CH2)3-, -0(CH2)20- or -0(CH2)30-,
X2 represents a hydrogen atom, an amino group or a
group of general formula -NHC02R in which R represents
a (C1-C4)alkyl or phenyl(C1-C2)alkyl group,
X3 represents a hydrogen or halogen atom, and
R2 represents a hydrogen atom or a (C1-C6)alkyl group,
which is optionally substituted, or a phenyl(C1-C4) alkyl
or [(4-dimethylamino)piperid-1-ylcarbonyl] (C2-C4)alkyl
group.

Since the carbon atom via which the
pyrrolidine ring is attached to the rest of the
molecule is asymmetric, the compounds of the invention
can exist in the form of pure enantiomers or mixtures
of enantiomers.
They can also exist in the form of bases or
addition salts with acids.
The compounds of general formula (I) can be
prepared according to a process illustrated by the
scheme which follows.

An ester of general formula (II), in which
R1# X1# X2 and X3 are as defined above and R3 represents
a methyl or ethyl group, is reacted with hydrazine
hydrate, in the absence of solvent or in a polar protic
solvent, for example ethanol, in order to obtain a
hydrazide of general formula (III), which is cyclized
into an oxadiazole of general formula (IV) either using
phosgene, in an aprotic solvent, for example dioxane,
or using phenyl chloroformate, in an aprotic solvent,
for example toluene.
When, in the general formula (II), X2
represents an amino group, the latter reacts with the
phosgene and the product obtained is esterified with an
alcohol of general formula ROH, in which R is defined
as above, the amino group thus being protected by a
group -C02R. The oxadiazole of general formula (IV) is
then reacted with an alcohol of general formula (V), in
which Boc represents a (1,1-dimethylethoxy)carbonyl
group, in the presence of triphenylphosphine and ethyl
azodicarboxylate, in an aprotic solvent, for example
tetrahydrofuran, after which the (1,1-dimethylethoxy)_
carbonyl protecting group is removed using
trifluoroacetic acid. A compound of general formula (I)
in which R2 represents a hydrogen atom is thus
obtained.
If so desired, the latter compound can then
be subjected to an alkylation using a derivative of
general formula R2-X, in which X represents a leaving

group, for example a halogen atom or a methane-
sulphonate or para-toluenesulphonate group, and R2 is
as defined above, but other than a hydrogen atom, in
the presence of triethylamine, in an aprotic solvent,
for example acetonitrile. Finally, when X2 is a group
-NHC02R, the protecting group can, if so desired, be
removed in acidic medium.
The starting esters of general formula (II)
and/or the corresponding acids are described in
particular in patent applications EP-0 , 231, 139,
EP-0,234,872, WO-84/03281, WO-93/16072 and WO-94/19344.
The alcohols of general formula (V) are known
or can be prepared according to any known method;
(R/S)-1-[(1,1-dimethylethoxy)carbonyl]pyrrolidin-3-ol
is described in J. Am. Chem. Soc. (1982) 104 5852-
5853, and the (R) enantiomer is described in
Tetrahedron (1988) 44 (17) 5479-5486.
The examples which follow illustrate in
detail the preparation of a number of compounds
according to the invention. The elemental microanalyses
and the IR and NMR spectra confirm the structures of
the compounds obtained. The compound numbers indicated
in parentheses in the titles correspond to those in the
table given later. In the compound names, the hyphen
"-" forms part of the name, and the line "_" serves
merely to indicate the line break; it should be removed
in the absence of a line break and should not be
replaced either by a normal hyphen or by a space.

Example 1 (Compound No. 9)
Phenylmethyl [2-chloro-4-(5-oxo-4-(pyrrolidin-3-yl)-
4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-methoxyphenyl]_
carbamate
1.1. 4-Amino-5-chloro-2-methoxybenzoic acid
hydrazide
51.5 g (0.239 mol) of methyl 4-amino-5-chloro-
2-methoxybenzoate suspended in 460 ml of ethanol are
introduced into all reactor. 119 g (2.39 mol) of
hydrazine hydrate are added over 15 min and the mixture
is refluxed for 15 h.
The mixture is cooled using a bath of ice and
the precipitate is collected by filtration, rinsed with
ethanol and dried under reduced pressure at 80°C for
2 h 30. 47.5 g of product are thus obtained.
Melting point: 211°C.
1.2. Phenylmethyl [2-chloro-5-methoxy-4-(5-oxo-4,5-
dihydro-1,3,4-oxadiazol-2-yl)phenyl]carbamate
461 ml (0.875 mol) of a 1.93M solution of phosgene in
toluene is added dropwise, over one hour, at room
temperature and with stirring, to a suspension of
37.7 g (0.175 mol) of 4-amino-5-chloro-2-methoxybenzoic
acid hydrazide in 1200 ml of dioxane in a 3 1 reactor.
The mixture is stirred at room temperature
overnight and is then heated at 80°C for 1 h. The
excess phosgene is stripped off by passing a stream of

argon through at this temperature for 2 h. 72 ml
(0.7 mol) of benzyl alcohol are then added and the
heating is continued for 1 h at 100°C. The mixture is
cooled and concentrated under reduced pressure and the
residue is triturated from isopropyl ether. The solid
obtained is filtered off and dried. 60.3 g of product
are thus obtained.
Melting point: 214°C.
1.3. Phenylmethyl [2-chloro-4-[3-[1-(1,l-dimethyl_
ethoxy)carbonyl]pyrrolidin-3-yl]-5-oxo-4,5-
dihydro-1,3,4-oxadiazol-2-yl]-5-methoxyphenyl]_
carbamate
9.8 g (26.1 mmol) of phenylmethyl [2-chloro-5-methoxy-
4-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl]_
carbamate dissolved in 100 ml of tetrahydrofuran,
11.6 g (44.3 mmol) of triphenylphosphine and 4.9 g
(26.1 mmol) of 1-[(1,1-dimethylethoxy)carbonyl]_
pyrrolidin-3-ol are introduced into a 500 ml three-
necked round-bottomed flask. While stirring the mixture
at 0°C, a solution of 5.9 g (33.9 mmol) of ethyl
azodicarboxylate in 6 ml of tetrahydrofuran is added
dropwise and the stirring is continued at room
temperature for 24 h.
The solvent is evaporated off under reduced
pressure and the residue is purified by chromatography
on silica gel, eluting with 65/35, 60/40 and finally
30/70 mixtures of heptane and ethyl acetate. 10.1 g of

product are obtained.
Melting point: 138°C.
1.4. Phenylmethyl [2-chloro-4-(5-oxo-4-(pyrrolidin-
3-yl)-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-methoxy_
phenyl]carbamate
10.1 g (18.5 mmol) of phenylmethyl [2-chloro-
4-[3-[1-(1,1-dimethylethoxy)carbonyl]pyrrolidin-3-yl]-
5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl]-5-methoxy_
phenyl]carbamate dissolved in 100 ml of dichloromethane
are introduced into a 500 ml three-necked round-
bottomed flask. The solution is cooled to 0°C, 14.3 ml
(185 mmol) of trifluoroacetic acid are added dropwise
and the mixture is stirred at room temperature for
17 h.
The solvent is evaporated off under reduced
pressure, the residue is dissolved in 1500 ml of
ethanol and the solution is acidified by addition of
4.5 ml of a solution of hydrochloric acid in ethanol. A
white solid is obtained, which is taken up in 80 ml of
water and 80 ml of chloroform, aqueous ammonia is added
and the mixture is extracted with chloroform. The
solvent is evaporated off under reduced pressure in
order to obtain 4.7 g of product in the form of a white
solid.
Melting point: 131°C.

Example 2 (Compound No. 10)
Phenylmethyl [2-chloro-5-methoxy-4-[5-oxo-4-(l-butyl_
pyrrolidin-3-yl)-4,5-dihydro-l,3,4-oxadiazol-2-yl]_
phenyl]carbamate
1.5 g (3.37 mmol) of phenylmethyl [2-chloro-4-(5-oxo-
4-(pyrrolidin-3-yl)-4,5-dihydro-l,3,4-oxadiazol-2-yl)-
5-methoxyphenyl]carbamate dissolved in 26 ml of
acetonitrile, and 1.41 ml (10.1 mmol) of triethylamine
are placed in a 100 ml three-necked round-bottomed
flask. A solution of 0.6 g (4.38 mmol) of 1-bromobutane
in 4 ml of acetonitrile is added and the mixture is
heated at 60°C for 15 h.
The solvent is evaporated off under reduced pressure
and the residue is purified by chromatography on silica
gel, eluting with a 99/1/0.1, 98/2/0.2 and finally
95/5/0.5 mixture of chloroform, methanol and aqueous
ammonia. 1.3 5 g of product are thus obtained in the
form of a white solid.
Melting point: 114°C.
Example 3 (Compound No. 8)
5-(4-Amino-5-chloro-2-methoxyphenyl)-3-[3-(1-butyl-
pyrrolidin-3-yl)]-1,3,4-oxadiazol-2(3H)-one
hydrobromide
1.29 g (2.58 mmol) of phenylmethyl [2-chloro-5-methoxy-
4-[5-OXO-4-(l-butylpyrrolidin-3-yl)-4,5-dihydro-l,3,4-

oxadiazol-2-yl]phenyl]carbamate dissolved in 13 ml of
acetic acid are introduced into a 50 ml three-necked
round-bottomed flask, 3.2 ml of a 33% solution of
hydrobromic acid in acetic acid are added and the
mixture is stirred at room temperature for 46 h.
The solvent is evaporated off under reduced
pressure and the solid obtained is washed with ether
and then with ethanol and recrystallized from ethanol
in order to obtain 0.53 g of pure product in the form
of a white solid.
Melting point: 197°C.
Example 4 (Compound No. 11)
Phenylmethyl (S)-[6-chloro-8-[(4-pyrrolidin-3-yl)-
5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl]-2,3-dihydro-
1,4-benzodioxin-5-yl)carbamate
4.1. Ethyl 8-amino-2,3-dihydro-l,4-benzodioxine-
5-carboxylate
23.5 g (0.198 mol) of thionyl chloride are introduced
slowly into a 2 1 three-necked round-bottomed flask
containing 772 ml of ethanol cooled to -40°C, with
stirring, the stirring is continued at this temperature
for 1 h, 38.6 g (0.198 mol) of 8-amino-2,3-dihydro-l,4-
benzodioxine-5-carboxylic acid dissolved in 100 ml of
ethanol are added slowly, over 15 min, and the mixture
is allowed to warm to room temperature overnight.
The mixture is refluxed for 4 h, the solvent

is evaporated off under reduced pressure, the residue
is taken up in water and sodium carbonate and the
resulting mixture is extracted with chloroform. After
washing, drying and evaporation of the organic phase,
34.06 g of ester are obtained in the form of a white
solid.
Melting point: 112°C.
4.2. Ethyl 8-amino-7-chloro-2,3-dihydro-l,4-
benzodioxine-5-carboxylate
37 g (0.165 mol) of ethyl 8-amino-2,3-dihydro-l,4-
benzodioxine-5-carboxylate dissolved in 370 ml of
dioxane are introduced into all round-bottomed flask,
23.2 g (0.174 mol) of N-chlorosuccinimide are added, at
room temperature and with magnetic stirring, and the
mixture is stirred overnight. It is diluted with water,
extracted with ethyl acetate and, after the usual
processing of the organic phase, 42 g of compound are
obtained, which product is recrystallized from a
mixture of diethyl ether and diisopropyl ether.
Melting point: 105-106°C.
4.3. 8-Amino-7-chloro-2,3-dihydro-l,4-benzodioxine-
5-carboxylic acid hydrazide
38.4 g (0.149 mol) of ethyl 8-amino-7-chloro-2,3-
dihydro-1,4-benzodioxine-5-carboxylate suspended in
150 ml of ethanol are introduced into all reactor,
149 g (2.98 mol) of hydrazine hydrate are added, over

15 min, and the mixture is refluxed for 1 h.
The mixture is cooled using a bath of ice and
the precipitate is collected by filtration, washed with
ethanol and dried under reduced pressure.
33 g of compound are obtained.
Melting point: 227-231°C.
4.4. Phenylmethyl [6-chloro-8-(5-oxo-4,5-dihydro-l,3,4-
oxadiazol-2-yl)-2,3-dihydro-l,4-benzodioxin-
5-yl]carbamate
32.6 g of 8-amino-7-chloro-2,3-dihydro-l-benzodioxine-
5-carboxylic acid hydrazide and 330 ml of dioxane are
introduced into all reactor, at room temperature and
with magnetic stirring, 310 ml (0.4 mol) of a 0.193M
solution of phosgene in toluene are added dropwise to
this suspension over one and a half hours and the
mixture is stirred at room temperature overnight and
heated at reflux for 5 h.
The excess phosgene is stripped off at this
temperature by passing a stream of argon through for
2 h, the mixture is cooled and concentrated under
reduced pressure, the residue is taken up in 200 ml of
benzyl alcohol and heated to 100°C overnight, the
mixture is cooled and concentrated under reduced
pressure and the residue is triturated from diisopropyl
ether. After filtration and drying, 52.6 g of compound
are obtained.
Melting point: 230°C.

4.5. Phenylmethyl (S)-[6-chloro-8-[4-[1-[(1,1-
dimethylethoxy)carbonyl]pyrrolidin-3-yl]-5-oxo-
4,5-dihydro-l,3,4-oxadiazol-2-yl]-2,3-dihydro-l,4-
benzodioxin-5-yl]carbamate
10.8 g (26.7 mraol) of phenylmethyl [6-chloro-8-(5-oxo-
4,5-dihydro-l,3,4-oxadiazol-2-yl)-2,3-dihydro-l,4-
benzodioxin-5-yl]carbamate dissolved in 110 ml of
tetrahydrofuran, and 11.9 g (45.4 mmol) of triphenyl_
phosphine are placed in a 500 ml three-necked round-
bottomed flask. A solution of 5.0 g (26.7 mmol) of
(R)-1-[(1,1-dimethylethoxy)carbonyl]pyrrolidin-3-ol in
50 ml of tetrahydrofuran is added and the solution is
cooled to 0°C. A solution of 5.5 ml (34.7 mmol) of
ethyl azodicarboxylate in 6 ml of tetrahydrofuran is
then added dropwise and stirring is continued for 2 0 h.
The solvent is evaporated off under reduced
pressure and the residue is purified by chromatography
on silica gel, eluting with a 99/1 mixture of
chloroform and methanol. Fractions containing the
product are recovered and are repurified by
chromatography on silica gel, eluting with chloroform.
4.8 g of pure product are thus obtained in the form of
a white solid.
Melting point: 157°C [a]£° = +36.8° (c = l, CHC13).
4.6. Phenylmethyl (S)-[6-chloro-8-[(4-pyrrolidin-3-yl)-
5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl]-2,3-
dihydro-1,4-benzodioxin-5-yl)carbamate

4.7 g (8.2 mmol) of phenylmethyl (S)-[6-chloro-
8-[4-[1-[(1,1-dimethylethoxy)carbonyl]pyrrolidin-3-yl]-
5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl]-2,3-dihydro-
1,4-benzodioxin-5-yl)carbamate dissolved in 47 ml of
dichloromethane are introduced into a 2 50 ml three-
necked round-bottomed flask. The solution is cooled to
0°C, 6.3 ml (82.0 mmol) of trifluoroacetic acid are
added and the mixture is stirred at room temperature
for 4 h.
The solvent is evaporated off under reduced
pressure and 40 ml of water and 40 ml of chloroform are
added. The solution is basified by addition of 4 ml of
concentrated aqueous ammonia, it is extracted with
dichloromethane and the organic phase is evaporated off
under reduced pressure. The residue is purified by
chromatography on silica gel, eluting with a 95/5/0.5
mixture of chloroform, methanol and aqueous ammonia, in
order to obtain 3.5 g of product in the form of a white
solid.
Melting point: 126°C [a]£° = 3,0° (c=l, CHC13).
Example 5 (Compound No. 3).
(S)-5-(8-amino-7-chloro-2,3-dihydro-l,4-benzodioxin-
5-yl)-3-[1-[5-[4-(dimethylamino)piperidin-1-yl]-
5-oxopentyl]pyrrolidin-3-yl]-1,3,4-oxadiazol-2-(3H)-one
5.1. Methyl (S)-3-[5-[7-chloro-8-[[(phenylmethoxy)_
carbonyl]amino]-2,3-dihydro-l,4-benzodioxin-

5-yl]2-OXO-2,3-dihydro-l,3,4-oxadiazol-3-yl]_
pyrrolidine-1-pentanoate
3.46 g (7.32 mmol) of phenylmethyl (S)-[6-chloro-
8-[(4-pyrrolidin-3-yl)-5-oxo-4,5-dihydro-l,3,4-
oxadiazol-2-yl]-2,3-dihydro-l,4-benzodioxin-
5-yl)carbamate dissolved in 62 ml of acetonitrile, and
6.2 g (44 mmol) of triethylamine are introduced into a
250 ml three-necked round-bottomed flask. 2.74 g
(19 mmol) of methyl 5-chloropentanoate dissolved in
7 ml of acetonitrile are added at room temperature and
the reaction medium is refluxed for 120 h. The solvent
is evaporated off under reduced pressure, the residue
is taken up in 70 ml of water and 70 ml of chloroform,
the organic phase is separated out, the solvent is
evaporated off under reduced pressure and the liquid
residue is purified by chromatography on silica gel,
eluting with a 98/2/0.2 mixture of chloroform, methanol
and aqueous ammonia. 0.54 g of product is thus obtained
in the form of a sticky paste.
[a]l° = +29.2° (c=l, CHC13).
5.2. (S)-3-[5-[8-amino-7-chloro-2,3-dihydro-l,4-
benzodioxin-5-yl]2-oxo-2,3-dihydro-l,3,4-
oxadiazol-3-yl]pyrrolidine-1-pentanoic acid
0.50 g (0.85 mmol) of methyl (S)-3-[5-[7-chloro-
8-[[(phenylmethoxy)carbonyl]amino]-2,3-dihydro-l,4-
benzodioxin-5-yl]2-oxo-2,3-dihydro-l,3,4-oxadiazol-
3-yl]pyrrolidine-l-pentanoate dissolved in 5 ml of

concentrated aqueous hydrochloric acid is placed in a
25 ml round-bottomed flask and the reaction medium is
refluxed for 22 h.
The aqueous hydrochloric acid is evaporated
off under reduced pressure, in order to obtain 0.25 g
of crude product which is used without further
purification in the following step.
5.3. (S)-5-(8-amino-7-chloro-2,3-dihydro-l,4-
benzodioxin-5-yl)-3-[l-[5-[4-(dimethy1_
amino)piperidin-1-yl]-5-oxopentyl]pyrrolidin-
3-yl]-1,3,4-oxadiazol-2-(3H)-one
0.24 g (0.51 mmol) of (S)-3-[5-[7-chloro-8-amino-2,3-
dihydro-1,4-benzodioxin-5-yl]2-oxo-2,3-dihydro-l,3,4-
oxadiazol-3-yl]pyrrolidine-l-pentanoic acid dissolved
in 2.5 ml of dimethylformamide, and 0.14 ml (1.01 mmol)
of triethylamine are introduced into a 25 ml three-
necked round-bottomed flask. A solution of 0.16 g
(1.01 mmol) of 1,1'-carbonylbis-lH-imidazole in 1.1 ml
of dimethylformamide is added dropwise and the mixture
is stirred at room temperature for 2 h 30 min. A
solution of 0.76 mmol of 4-(dimethylamino)piperidine in
1.8 ml of dimethylformamide (prepared beforehand by
heating a suspension of 0.16 g (0.76 mmol) of
4-(dimethylamino)piperidine dihydrochloride in 1.8 ml
of dimethylformamide and 0.28 ml (2.02 mmol) of
triethylamine at 6 0°C for 2 h) is added and the mixture
is stirred at room temperature for 18 h.

The reaction medium is poured into 3 0 ml of
water and extracted with chloroform. The product is
purified by chromatography on silica gel, eluting with
a 95/5/0.5 and then 80/20/2 mixture of chloroform,
methanol and aqueous ammonia. 0.08 g of product is thus
obtained in the form of a sticky paste.
[cc]g° = +26° (c = 0.4, CHC13).
The table which follows illustrates the chemical
structures and the physical properties of a number of
compounds of the invention.

The compounds of the invention underwent tests which
revealed their value as therapeutically active
substances.
Thus, the compounds of the invention were
studied as regards their affinity towards the 5-HT4
receptors in guinea pig striatum according to the
method described by Grossman et al. in Br. J.
Pharmacol. (1993) 109 618-624.
Guinea pigs (Hartley, Charles River, France)
weighing 300 to 400 g are sacrificed, the brains are
removed and the striata are excised and frozen at
-80°C.
On the day of the experiment, the tissue is
thawed to +4°C in 3 3 volumes of Hepes-NaOH buffer
(50 mM, pH = 7.4 at 20°C), the mixture is homogenized
using a Polytron™ grinder, the homogenate is
centrifuged at 48,000 x g for 10 min, the pellet is
recovered, resuspended and recentrifuged under the same
conditions and the final pellet is suspended in Hepes-
NaOH buffer, in a proportion of 30 mg of tissue per ml.
100 JJ.1 of this membrane suspension is incubated at 0°C
for 120 min in the presence of [3H]GR113808 (ligand
described in the article cited, specific activity 80-85
Ci/mmol) in a final volume of 1 ml of Hepes-NaOH buffer
(50 mM, pH = 7.4), in the presence or absence of test
compound. The incubation is stopped by filtration
through a Whatman GF/B filter pretreated with 0.1%
polyethyleneimine, each tube is rinsed with 4 ml of

buffer at 0°C, the filtration is repeated and the
radioactivity retained on the filter is measured by-
liquid scintigraphy.
The non-specific binding is determined in the
presence of 3 0 |IM serotonin. The specific binding
represents 90% of the total radioactivity recovered on
the filter.
For each concentration of test compound, the
percentage of inhibition of the specific binding of
[3H]GR113808, and then the IC50, the concentration of
test compound which inhibits the specific binding by
50%, are determined.
The IC50 values for the most active compounds
are between 0.7 and 15 mM.
The compounds of the invention were also
studied as regards their agonist or antagonist effects
with respect to the 5-HT4 receptors in rat oesophagus
according to the method described by Baxter et al. in
Naunyn Schmied. Arch. Pharmacol. (1991) 343 439.
Male Sprague-Dawley rats weighing 3 00 to
450 g are used. A fragment of about 1.5 cm of the
terminal part of the oesophagus is removed rapidly, the
muscle layer is removed, the internal muscular mucous
tunic is opened longitudinally, it is mounted in an
isolated-organ tank containing Krebs-Henseleit solution
at 32°C oxygenated by a stream of carbogen (95% 02 and
5% C02), and is connected to an isometric transducer
under a basal tension of 0.5 g. A contraction of the

tissue is induced by the addition of 0.5 |J.M carbachol
and, after waiting for the contraction to stabilize (15
min), the preparation is then exposed to serotonin
(1 HM) in order to quantify the maximum relaxation. The
tissue is washed and, after 20 min, a fresh 0.5 |im
carbachol is added, and the preparation is exposed to
the test compound at cumulative concentrations
increasing from 0.1 to 1 |J.M. The compounds which induce
a relaxation are considered as 5-HT4 agonists.
For the compounds which do not induce
relaxation, the preparation is exposed to serotonin at
cumulative concentrations increasing from 0.1 nM to a
concentration which induces a maximum relaxation, and
the curve of relaxation due to serotonin, in the
presence of the test compound, is then compared with a
standard curve established in the absence of the said
compound. If its presence induces a displacement of the
curve towards the right, the test compound is then
considered as a 5-HT4 antagonist.
The results of these two biological tests
show that the compounds of the invention are powerful
ligands for the 5-HT4-type serotoninergic receptors,
and that they act on these receptors either as agonists
or as antagonists.
The compounds can thus be used for the
treatment and prevention of disorders in which the
5-HT4 receptors are involved, whether this is at the
level of the central nervous system, the

gastrointestinal system, the cardiovascular system or
the urinary system.
On the central nervous system, these
disorders and complaints comprise, in particular,
neurological and psychiatric disorders such as
cognitive disorders, psychosis, compulsive and
obsessive behaviour, depressive states and states of
anxiety. The cognitive disorders comprise, for example,
memory and attention deficiencies, dementia states
(senile dementias such as Alzheimer's disease or age-
related dementias), cerebrovascular deficiencies and
Parkinson's disease. The psychoses comprise, for
example, paranoia, schizophrenia, mania and autism. The
compulsive and obsessive behaviour comprises, for
example, eating disorders such as bulimia or loss of
appetite. The depressive states and states of anxiety
comprise, for example, anticipational-type anxiety
(before a surgical operation, before dental treatment,
etc.), anxiety caused by the dependence on or
withdrawal from alcohol or drugs, mania, seasonally-
induced disorders, migraine and nausea.
On the gastrointestinal system, these
disorders and complaints comprise, in particular,
vomiting induced by a medical treatment, direct or
indirect disorders of gastromotility of the oesophagus,
of the stomach or of the intestine, specific diseases
such as dyspepsia, ulcers, gastro-oesophageal reflux,
flatulence, irritable bowel syndrome, intestinal

secretion disorders and diarrhoeas, for example those
induced by cholera or by carcinoid syndrome.
On the cardiovascular system, these disorders
and complaints comprise, in particular, pathologies
associated, directly or indirectly, with cardiac
arrhythmia.
On the urinary system, these disorders and
complaints comprise, in particular, incontinence of any
kind, as well as their causes or consequences, for
example kidney damage, kidney stones or kidney
infections.
The compounds of the invention can be in any
composition form which is suitable for enteral or
parenteral administration, such as tablets, coated
tablets, gelatin capsules, wafer capsules, drinkable or
injectable suspensions or solutions, such as syrups or
vials, transdermal patches, suppositories, etc.,
combined with suitable excipients, and dosed to allow a
daily administration of from 0.001 to 20 mg/kg.

WE CLAIM:
1. Compound, optionally in the form of a
pure optical isomer or a mixture of such isomers,
corresponding to the general formula (I)

in which
R1 represents a hydrogen atom or a (C1-C4) alkyl or
cyclo(C3-C7) alkylmethyl group,
X1 represents a hydrogen or halogen atom or a
(C1-C4)alkoxy group, or alternatively
OR1 and X1 together represent a group of formula
-OCH20-, -0(CH2)2-, -0(CH2)3-, -0(CH2)20- or -0(CH2)30-,
X2 represents a hydrogen atom, an amino group or a
group of general formula -NHC02R in which R represents
a (C1-C4)alkyl or phenyl(C1-C2)alkyl group,
X3 represents a hydrogen or halogen atom, and
R2 represents a hydrogen atom or a (C1-C6)alkyl group,
which is optionally substituted, or a phenyl(C1-C4) alkyl
or [(4-dimethylamino)piperid-l-ylcarbonyl] (C2-C4)alkyl
group,
in the form of a base or an addition salt with an acid.

2. Process for the preparation of compounds
according to Claim 1, characterized in that an ester of
general formula (II)

in which R1; X1, X2 and X3 are as defined in Claim 1 and
R3 represents a methyl or ethyl group, is reacted with
hydrazine hydrate, in order to obtain a hydrazide of
general formula (III)

which is cyclized into an oxadiazole of general formula
(IV)

either using phosgene, in an aprotic solvent, or using
phenyl chloroformate, in an aprotic solvent, after
which the oxadiazole of general formula (IV) is reacted
with an alcohol of general formula (V)


in which Boc represents a (1,1-dimethylethoxy)carbonyl
group, in the presence of triphenylphosphine and ethyl
azodicarboxylate, in an aprotic solvent, in order to
obtain a compound of general formula (I) in which R2
represents a hydrogen atom, and, finally, the latter
compound is subjected to an alkylation using a
derivative of general formula R2-X, in which X
represents a leaving group, and R2 is as defined in
Claim 1, but is other than a hydrogen atom.
3. Medicinal product, characterized in that
it consists of a compound according to Claim 1.
4. Pharmaceutical composition, character-
ized in that it contains a compound according to Claim
1, combined with an excipient.

5. A compound of general formula (I), as defined herein,
substantially as herein described, particularly with
reference to the foregoing examples.
6. A process for the preparation of compounds of general
formula (I), as defined herein, substantially as herein
described, particularly with reference to the foregoing
examples.
7. Medical product, substantially as herein described,
particularly with reference to the foregoing examples.
8. A pharmaceutical composition, substantially as herein
described, particularly with reference to the foregoing
examples.
9. A process for preparing a pharmaceutical composition,
substantially as herein described, particularly with
reference to the foregoing examples.

3-(Pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3h)-one
derivatives, their preparation and
their therapeutic application
Compounds corresponding to the general formula (I)

in which R1 represents hydrogen or an alkyl or
cycloalkylmethyl group, X1 represents hydrogen or a
halogen or an alkoxy group, or alternatively OR1 and X1
together represent a group of formula -OCH2O-,
-O(CH2)2-, -O(CH2)3-, -O(CH2)2O- or -O(CH2)3O-, X2
represents hydrogen, an amino group or a group of
general formula -NHCO2R in which R represents an alkyl
or phenylalkyl group, X3 represents hydrogen or a
halogen, and R2 represents hydrogen or an alkyl,
phenylalkyl or [(4-dimethylamino)piperid-
1-ylcarbonyl]alkyl group.
Therapeutic application.