Thiazolidine-2,4-dione derivatives, in the form of racemates or optically active isomers, corresponding to the formula (I) ##STR1## in which n=2 or 3, R.sub.1 =H, alkyl, benzoyl, acetyl or optionally substituted benzyl, R.sub.2 =H or alkyl, R.sub.3 =phenyl, which is optionally substituted by halogen, alkyl, alkoxy, NO.sub.2, CF.sub.3 or CF.sub.3 S, or naphthyl, and R.sub.4 =H, alkyl, phenyl, benzoyl or allyl, and acid addition salts thereof. These compounds are useful in therapy as anti-convulsants or anti-depressants.

DESCRIPTION 
The present invention relates to thiazolidine-2,4-dione derivatives in the 
form of racemates or enantiomers, their addition salts with 
pharmaceutically acceptable acids, their preparation and their application 
in therapy. 
The derivatives of the invention correspond to the formula (I) 
##STR2## 
in which n is 2 or 3, R.sub.1 is a hydrogen atom, an alkyl radical having 
1 to 4 carbon atoms, the benzoyl radical, the acetyl radical, or the 
benzyl radical which may or may not carry a substituent chosen from 
amongst methyl or methoxy radicals and halogen atoms, R.sub.2 is a 
hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, R.sub.3 is 
either a phenyl radical, which may or may not carry one or more 
substituents chosen from the group comprising halogen atoms, alkyl and 
alkoxy radicals having 1 to 4 carbon atoms, and the radicals NO.sub.2, 
CF.sub.3 and CF.sub.3 S, or a naphthyl radical, and R.sub.4 is a hydrogen 
atom, an alkyl radical having 1 to 4 carbon atoms, the phenyl radical, the 
benzyl radical or the allyl radical, except for the compounds in which 
R.sub.3 is C.sub.6 H.sub.5 and R.sub.4 is H when R.sub.1 and R.sub.2 are 
CH.sub.3 and n is 2 or 3. 
The addition salts of the compounds (I) with pharmaceutically acceptable 
acids form part of the invention. 
The compounds of the invention contain an asymmetric carbon and can 
therefore give rise to two optically active isomers. 
These isomers can be separated by any suitable method or prepared by 
stereospecific synthesis, and they form part of the invention. 
The preferred compounds of the invention are those in which n is 2, and 
these include a particular group comprising the compounds in which R.sub.1 
and R.sub.2 are H. 
The alkyl and alkoxy radicals are preferably methyl and methoxy radicals. 
According to the invention, the compounds are prepared in accordance with 
the following reaction scheme: 
##STR3## 
The condensation of the compounds (II) and (III) is preferably carried out 
in acid at a temperature of 60.degree. to 80.degree. C. 
When R.sub.4 is H, the process of the invention consists in reacting the 
compound (II) with the compound (III)' 
##STR4## 
and then subjecting the resulting compound (IV)' 
##STR5## 
to diverse conversion reactions leading to the various compounds (I): see 
reaction scheme below. 
1. Hydrolysis leading to (I) in which R.sub.1 =R.sub.2 =R.sub.4 =H, which 
can be alkylated to give the compound (I) in which R.sub.1 and R.sub.2 can 
be different from H; 
2.1 substitution in the 2-position of the imidazo[2,1-b]thiazole ring by 
R.sub.4, followed by hydrolysis leading to (I) in which R.sub.1 =R.sub.2 
=H; 
2.2 substitution in the 2-position of the imidazo[2,1-b]thiazole ring by 
R.sub.4, followed by substitution on the nitrogen by R.sub.1 and 
hydrolysis leading to (I) in which R.sub.2 =H; and 
3. substitution on the nitrogen by R.sub.1, followed by hydrolysis leading 
to (I) in which R.sub.2 =R.sub.4 =H. 
The starting products (III)' are known. 
The intermediates (IV) are new except for those in which R.sub.4 is H, n=2 
and R.sub.3 is C.sub.6 H.sub.5, 2--Cl--C.sub.6 H.sub.4, 
2,4-di--Cl--C.sub.6 H.sub.3 and 3,4-di--Cl--C.sub.6 H.sub.3. 
##STR6##

The following examples illustrate the invention. 
The analyses and IR and NMR spectra confirm the structure of the compounds. 
EXAMPLE 1 
3-(2-Aminoethyl)-5-methyl-5-(4-fluorophenyl)thiazolidine-2,4-dione hydrobr 
omide. 
[R.sub.1 =R.sub.2 =H; R.sub.3 =4--F--C.sub.6 H.sub.4 ; R.sub.4 =CH.sub.3 ] 
1.1 2-(p-Fluorophenyl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazol[2H]-3-one. 
18.9 g (0.185 mol) of ethylene-thiourea and 45.8 g (0.185 mol) of 
.alpha.-bromo-.alpha.-methyl-(p-fluorophenyl)-acetic acid in 110 cm.sup.3 
of acetic acid are introduced into a 1 liter round-bottomed flask. 
The mixture is heated at 65.degree.-75.degree. C. for 4 hours until a clear 
solution is obtained. The solution is allowed to cool and is concentrated. 
An orange oil is recovered and taken up in acetone. This yields a solid 
which is filtered off, washed with acetone, rinsed and dried. 
After recrystallisation from ethanol, a white solid is obtained. 
Melting point=227.degree.-229.degree. C. 
1.2 3-(2-Aminoethyl)-5-methyl-5-(4-fluorophenyl)-thiazolidine-2,4-dione 
hydrobromide. 
9.6 g of the hydrobromide obtained above, 40 ml of water and 4 ml of 
concentrated hydrobromic acid are introduced into a 250 ml round-bottomed 
flask. 
The mixture is heated under reflux for 6 hours. This yields a very light 
yellow, clear solution. The water is driven off in vacuo and a white solid 
is recovered. 
Melting point=227.degree.-228.5.degree. C. 
EXAMPLE 2 3-(2-Aminoethyl)-5-phenylthiazolidine-2,4-dione hydrobromide. 
[R.sub.1 =R.sub.2 =H; R.sub.3 =C.sub.6 H.sub.5 ; R.sub.4 =H] 
1. 2-Phenyl-5,6-dihydroimidazo[2,1-b]thiazol[2H]-3-one hydrobromide. 
10 g (0.098 mol) of ethylene-thiourea and 21.05 g (0.098 mol) of 
.alpha.-bromo-phenylacetic acid in 50 cm.sup.3 of acetic acid are 
introduced into a 250 cm.sup.3 round-bottomed flask. 
The mixture is heated at 65.degree.-75.degree. C. for 4 hours. It is 
allowed to cool. The precipitate is filtered off and dried and then 
recrystallised from methanol. 
The white solid obtained melts at 245.degree.-247.degree. C. with 
decomposition. 
2. 3-(2-Aminoethyl)-5-phenylthiazolidine-2,4-dione hydrobromide. 
15 g of the above hydrobromide, 20 cm.sup.3 of water and 4 cm.sup.3 of 
concentrated hydrobromic acid are introduced into a 100 cm.sup.3 
round-bottomed flask. The mixture is heated under reflux for 4 hours and 
the water is then driven off under reduced pressure. This yields a white 
solid which is washed and recrystallised from ethanol. 
Melting point=220.degree.-222.degree. C. 
EXAMPLE 3 3-(2-Acetylaminoethyl)-5-phenylthiazolidine-2,4-dione. 
[R.sub.1 =CH.sub.3 CO; R.sub.2 =H; R.sub.3 =C.sub.6 H.sub.5 ; R.sub.4 =H] 
3-(2-Aminoethyl)-5-phenylthiazolidine-2,4-dione is obtained from its 
hydrobromide (Example 2.2). It is a white solid which melts at 
139.5.degree.-140.5.degree. C. 
8.9 g (0.038 mol) of this base and 300 cm.sup.3 of dry pyridine are 
intoduced into a round-bottomed flask. The mixture is stirred for 30 
minutes and 3.14 g (0.04 mol) of acetyl chloride are then added slowly, 
under argon. 
After stirring for 2 hours, the pyridine is driven off. A yellow oil is 
recovered and taken up in chloroform. After washing and concentration, a 
light yellow oil is obtained, which crystallises immediately in ether. 
After recrystallisation from toluene, the white solid obtained melts at 
136.degree.-137.degree. C. 
EXAMPLE 4 3-(2-Aminoethyl)-5-methyl-5-phenylthiazolidine-2,4-dione 
hydrochloride. 
[R.sub.1 =R.sub.2 =H; R.sub.3 =CH.sub.3 ; R.sub.4 =C.sub.6 H.sub.5 ] 
4.1 2-Phenyl-2-methyl-5,6-dihydroimidazo[2,1-b]thiazol[2H]-3-one. 
A solution in dry DMF (400 ml) of the compound obtained under 2.1, in the 
form of the free base (32.7 g, 0.15 mol), is added to sodium hydride which 
has been washed with pentane beforehand, whilst cooling in an ice bath. 
The addition is carried out in the course of 30 minutes under a nitrogen 
atmosphere. The suspension is stirred for 1 hour at ambient temperature 
and cooled in an ice bath and methyl iodide (21.3 g, 0.15 mol) is added 
dropwise in the course of 5 minutes. 
The reaction mixture is stirred for 3 hours and the light red solution is 
poured into water. Extraction is carried out with ethyl acetate until the 
extracts are colourless; the extracts are washed with water and dried over 
MgSO.sub.4. The mixture is filtered and evaporated and a yellow solid is 
obtained. After recrystallisation from a mixture of isopropyl ether and 
ethyl acetate, the solid melts at 102.degree.-103.5.degree. C. 
4.2. 3-(2-Aminoethyl)-5-methyl-5-phenylthiazolidine-2,4-dione 
hydrochloride. 
A suspension, in 80 ml of water, of the free base obtained above (see 4.1) 
(9.2 g, 0.04 mol) is acidified to pH 1-2 with 2 N hydrochloric acid. 
The colourless solution is heated under reflux for 6 hours. The reaction 
medium is concentrated under reduced pressure. This yields a white solid 
which is recrystallised from ethanol. 
Melting point=223.degree.-224.5.degree. C. 
EXAMPLE 5 3-(2-Dimethylaminoethyl)-5-methyl-5-phenylthiazolidine-2,4-dione 
hydrochloride. 
[R.sub.1 =R.sub.2 =CH.sub.3 ; R.sub.3 =C.sub.6 H.sub.5 ; R.sub.4 =CH.sub.3 
] 
A mixture of the compound obtained under 4.2 (12.6 g, 0.044 mol), formic 
acid (10.13 g, 0.22 mol) and formaldehyde (8.6 ml of a 35% strength 
solution, 0.01 mol) is heated at 100.degree. C. for 12 hours. 
The colourless solution is cooled and diluted with water and the mixture is 
washed with CHCl.sub.3. It is rendered alkaline with Na.sub.2 CO.sub.3 and 
extracted with CHCl.sub.3. 
The extracts are washed, dried over MgSO.sub.4 and evaporated. 
This yields an oil which is taken up and treated with Et.sub.2 O/HCl. 
The white precipitate is filtered off and recrystallised from a mixture of 
EtOH and petroleum ether and then from methyl ethyl ketone. 
Melting point=178.5.degree.-179.5.degree. C. 
EXAMPLE 6 3-(2-Benzylaminoethyl)-5-methyl-5-phenylthiazolidine-2,4-dione 
hydrobromide. 
[R.sub.1 =C.sub.6 H.sub.5 CH.sub.2 ; R.sub.2 =H; R.sub.3 =C.sub.6 H.sub.5 ; 
R.sub.4 =CH.sub.3 ] 
Benzyl bromide (5.13 g, 0.013 mol) is added to a solution in EtOAc (250 ml) 
of the compound obtained under 4.1 (6.96 g, 0.03 mol). 
The mixture is heated under reflux for 5 days and the precipitate (A) of 
the formula 
##STR7## 
is filtered off. 
A further amount of the compound A can be obtained by heating the filtrate 
for 5 days with 0.03 mol of benzyl bromide. 
The compound A (9.3 g) is taken up in a mixture of ethanol and water (25/25 
ml) and the mixture is heated under reflux for 4 hours. The light red 
solution is cooled, treated with charcoal and evaporated. 
The white solid obtained by trituration is recrystallised from a mixture of 
ethanol and petroleum ether and then from a mixture of isopropanol and 
ethanol. 
Melting point=169.degree.-170.5.degree. C. 
EXAMPLE 7 3-(2-Methylaminoethyl)-5-phenylthiazolidine-2,4-dione 
hydrochloride. 
[R.sub.1 =CH.sub.3 ; R.sub.2 =H; R.sub.3 =C.sub.6 H.sub.5 ; R.sub.4 =H] 
Dimethyl sulphate (6.3 g, 0.05 mol) is added to a suspension in ethyl 
acetate (250 ml) of the compound obtained under 2.1 (10.9 g, 0.05 mol) and 
the mixture is heated under reflux. 
The reaction mixture is cooled after 6 hours and filtered. 
The methylsulphate melts at 161.degree.-4.degree. C. 
The white crystalline product is dissolved in water (50 ml) and the 
solution is heated under reflux for 6 hours. The light yellow solution is 
brought to pH 2-3 and extracted with chloroform. The extracts are dried 
over MgSO.sub.4 and evaporated and the oil is taken up in acetone. It is 
converted into the hydrochloride. 
After recrystallisation from isopropanol and then from a mixture of ethanol 
and petroleum ether, a white solid is obtained. 
Melting point=226.5.degree.-228.5.degree. C. 
EXAMPLE 8 3-(2-Aminoethyl)-5-(naphth-1-yl)-thiazolidine-2,4-dione 
hydrobromide. 
1.1 2-(Naphth-1-yl)-5,6-dihydroimidazo[2,1-b]thiazol[2H]-3-one 
hydrobromide. 
42.4 g (0.415 mol) of ethylene-thiourea and 110 g (0.415 mol) of 
.alpha.-bromo-(naphth-1-yl)-acetic acid are introduced into a 1 liter 
round-bottomed flask. 
The mixture is heated at 65.degree.-75.degree. C. for 4 hours. The solid 
obtained is filtered off and recrystallised from a mixture of methanol and 
water. 
Melting point=304.degree.-306.degree. C. 
1.2 3-(2-Aminoethyl)-5-naphth-1-yl)-thiazolidine-2,4-dione hydrobromide. 
12 g of the hydrobromide obtained under 1.1, 80 ml of water and 8 ml of HBr 
are introduced into a 250 ml round-bottomed flask. The mixture is heated 
under reflux for 6 hours. The solution obtained is concentrated in vacuo. 
The solid obtained is recrystallised from isopropyl alcohol. 
Melting point=142.degree.-144.degree. C. 
EXAMPLE 9 3-(2-Aminoethyl)-5-(3,4-dichlorophenyl)thiazolidine-2,4-dione 
hydrobromide. 
[R.sub.1 =R.sub.2 =H; R.sub.3 =3,4--Cl.sub.2 --C.sub.6 H.sub.3 ; R.sub.4 
=H] 
1.1 2-(3,4-Dichlorophenyl)-5,6-dihydroimidazo[2,1-b]thiazol[2H]-3-one 
hydrobromide. 
2.0 g (0.02 mol) of ethylene-thiourea and 6.5 g (0.023 mol) of 
.alpha.-bromo-3,4-dichlorophenylacetic acid in 15 cm.sup.3 of acetic acid 
are introduced into a 250 cm.sup.3 round-bottomed flask. The mixture is 
heated at 65.degree.-75.degree. C. for 4 hours. After 1/2 hour, the 
solution becomes clear and then solidifies. A solid is recovered and 
rinsed with acetone. 
Melting point=265.degree.-267.degree. C. (decomposition). 
1.2 3-(2-Aminoethyl)-5-(3,4-dichlorophenyl)-thiazolidine-2,4-dione 
hydrobromide. 
6.2 g (0.0168 mol) of the hydrobromide, 60 cm.sup.3 of water and 3 cm.sup.3 
of concentrated hydrobromic acid are introduced into a 250 cm.sup.3 
round-bottomed flask. The mixture is heated at the reflux temperature for 
6 hours until a clear colourless solution is obtained. It is concentrated 
in vacuo at 90.degree. C. This yields a white solid. It is rinsed with hot 
ethyl acetate and filtered off. The white solid obtained is recrystallised 
from a mixture of acetone and ethanol (2/1) and then once again from 
ethanol. 
Melting point=226.degree.-228.degree. C. 
The compounds of the invention, prepared by way of examples, are summarised 
in Table I which follows. 
TABLE I 
__________________________________________________________________________ 
Com- Melting 
pound point 
No. R.sub.1 R.sub.2 
R.sub.3 R.sub.4 n Salt (.degree.C.) 
__________________________________________________________________________ 
1 H H C.sub.6 H.sub.5 
H 2 HBr 220-222 
2 C.sub.6 H.sub.5 CO 
H C.sub.6 H.sub.5 
H 2 -- 156-7 
3 CH.sub.3 CO 
H C.sub.6 H.sub.5 
H 2 -- 136-7 
4 H H C.sub.6 H.sub.5 
H 3 HBr 194-195.5 
5 H H C.sub.6 H.sub.5 
C.sub.6 H.sub.5 CH.sub.2 
2 (CO.sub.2 H).sub.2.1H.sub.2 O 
149-150 
6 H H C.sub.6 H.sub.5 
CH.sub.3 
2 HCl 223-224.5 
7 H H C.sub.6 H.sub.5 
C.sub.6 H.sub.5 
2 HCl 205-206.5 
8 H H 4-Cl--C.sub.6 H.sub.4 
H 2 HBr 184-185.5 
9 H H 4-MeO--C.sub.6 H.sub.4 
H 2 HBr 176-177.5 
10 H H 4-Cl--C.sub.6 H.sub.4 
H 3 HBr 183-5 
11 H H 4-MeO--C.sub. 6 H.sub.4 
H 3 HBr 217-218.5 
12 C.sub.6 H.sub.5 CH.sub.2 
H C.sub.6 H.sub.5 
H 2 (CO.sub.2 H).sub.2 
227-228 
13 CH.sub.3 H C.sub.6 H.sub.5 
H 2 HCl 226.5-228.5 
14 CH.sub.3 H C.sub.6 H.sub.5 
CH.sub.3 
2 HCl 162-163.5 
15 C.sub.6 H.sub.5 CH.sub.2 
H C.sub.6 H.sub.5 
CH.sub.3 
2 HBr 169-170.5 
16 H H 4-F--C.sub.6 H.sub.4 
H 2 HBr 200-201.5 
17 H H 4-Br--C.sub.6 H.sub.4 
H 2 HBr 213-214.5 
18 CH.sub.3 CH.sub.3 
C.sub.6 H.sub.5 
CH.sub.3 
2 HCl 178-179.5 
19 H H 4-Cl--C.sub.6 H.sub.4 
CH.sub.3 
2 HCl 204-5 
20 H H 4-Cl--C.sub.6 H.sub.4 
C.sub.2 H.sub.5 
2 HCl 248.5-250 
21 H H 4-Cl--C.sub.6 H.sub.4 
n-C.sub.3 H.sub.7 
2 HCl 250-2 
22 H H 4-Cl--C.sub.6 H.sub.4 
H.sub.2 C.dbd.CHCH.sub.2 
2 HCl 228-9 
23 H H 4-F--C.sub.6 H.sub.4 
CH.sub.3 
2 HBr 227-228.5 
24 H H Naphth-1-yl 
H 2 HBr 142-4 
25 H H 2-Cl--C.sub.6 H.sub.4 
H 2 HBr 226-227.5 
26 H H 4-CH.sub.3 --C.sub.6 H.sub.4 
H 2 HCl.1/2H.sub.2 O 
190-192.5 
27 H H 3-CF.sub.3 --C.sub.6 H.sub.4 
H 2 HCl 185-186.5 
28 H H 3-MeO--C.sub.6 H.sub.4 
H 2 HCl 218.5-220 
29 H H 3-NO.sub.2 --C.sub.6 H.sub.4 
H 2 HCl 216-217.5 
30 H H C.sub.6 H.sub.5 
C.sub.2 H.sub.5 
2 HCl 202-203.5 
31 H H C.sub.6 H.sub.5 
Iso-C.sub.3 H.sub.7 
2 HCl.1/2H.sub.2 O 
144-145.5 
32 H H C.sub.6 H.sub.5 
n-C.sub.3 H.sub.7 
2 HCl 217-218.5 
33 CH.sub.3 CH.sub.3 
Naphth-1-yl 
H 2 HCl.1/4H.sub.2 O 
213-215 
34 H H Naphth-1-yl 
CH.sub.3 
2 HCl.1/2H.sub.2 O 
167.5-169 
35 C.sub.6 H.sub.5 CH.sub.2 
H Naphth-1-yl 
H 2 HBr.1/4H.sub.2 O 
190-1 
36 H H 3-Cl--C.sub.6 H.sub.4 
H 2 HBr 189-190.5 
37 C.sub.6 H.sub.5 CH.sub.2 
H 3-CF.sub.3 --C.sub.6 H.sub.4 
H 2 HBr 136-8 
38 H H 2,4-Cl.sub.2 --C.sub.6 H.sub.3 
H 2 HBr 216.5-218 
39 H H 3,4-Cl.sub.2 --C.sub.6 H.sub.3 
H 2 HBr 226-8 
40 H H 3-CF.sub.3 S--C.sub.6 H.sub.4 
H 2 HBr 162-3.5 
41 2-CH.sub.3 --C.sub.6 H.sub.4 CH.sub.2 
H 3-CH.sub.3 O--C.sub.6 H.sub.4 
H 2 HBr 145.5-147 
42 H H 4-F-3-CF.sub.3 --C.sub.6 H.sub.3 
H 2 HBr 122-4 
43 CH.sub.3 H 3,4-Cl.sub.2 --C.sub.6 H.sub.3 
H 2 HCl 249-251 
44 CH.sub.3 H 3-CF.sub.3 --C.sub.6 H.sub.4 
H 2 HCl 181-3 
45 H H 2-Br-4,5-di- 
H 2 HCl 216-8 
CH.sub.3 O--C.sub.6 H.sub.2 
46 C.sub.2 H.sub.5 
H 3-CF.sub.3 --C.sub.6 H.sub.4 
H 2 HCl 147.5-9 
__________________________________________________________________________ 
The compounds of the invention were subjected to pharmacological 
experiments which showed an anticonvulsive activity and, in certain cases, 
an antidepressive activity. 
The acute toxicity was determined intraperitoneally on mice. It varies from 
200 to 1,000 mg/kg. 
The anticonvulsive activity was determined by the test for the antagonism 
towards the convulsions induced by bicuculline in mice (M. Perez de la 
Mora and R. Tapia, Biochem. Pharmacol., 22, 2,635-2,639 (1973)). 
The products to be studied are injected intraperitoneally, 30 minutes 
before the bicuculline (0.9 mg/kg, administered intravenously). The 
criterion adopted for this test is lethality and the percentage mortality 
is noted for each batch, 2 hours after administration of the bicuculline 
(control batch: 100% mortality). 
For each product, the 50% active dose (AD 50 or the dose which protects 50% 
of animals from the lethal effects of the bicuculline) is determined 
graphically. 
The AD 50 of the compounds of the invention, administered 
intraperitoneally, varies between 20 and 60 mg/kg. 
The antidepressive activity was determined in accordance with the test for 
the antagonism towards the ptosis induced by reserpine (C. Gouret et al., 
J. Pharmacol. (Paris), 8, 333-350 (1977)). 
The mice (male, CDl Charles River, France, 18-22 g) simultaneously receive 
the products to be studied or the solvent (administered intraperitoneally) 
and the reserpine (4 mg/kg, administered subcutaneously). 
Sixty minutes later, the degree of palpebral ptosis is estimated, for each 
mouse, by means of a rating scale (0 to 4). 
The mean rating and the % variation relative to the control batch are 
calculated for each dose. 
The AD 50, or the dose which reduces the mean ptosis score by 50%, relative 
to the controls, is determined graphically for each product. 
The AD of the compounds of the invention ranges from 1.5 to 10 mg/kg. The 
results of the tests show that the compounds of the invention are 
anticonvulsive agents which are useful for treating various types of 
epilepsy, and antidepressants which are useful for treating depression. 
The compounds of the invention can be presented in any form which is 
suitable for oral, parenteral or endorectal administration, for example in 
the form of tablets, dragees, sugar-coated pills, solutions which can be 
taken orally or injected, and the like, toether with any suitable 
excipient. 
The daily dosage can range from 200 to 1,500 mg/kg for the anticonvulsive 
agents and from 5 to 200 mg for the antidepressants.