New benzodioxane compounds

A compound of formula (I): ##STR1## in which: X represents oxygen or methylene, PA1 n represents 1, 2 or 3, PA1 R.sub.1 represents hydrogen, aminocarbonyl or hydroxymethyl, PA1 R.sub.2 represents: ##STR2## in which R.sub.3 and R.sub.4 are as defined in the description, the isomers thereof and the addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same are useful in the treatment of schizophrenia.

FIELD OF THE INVENTION 
The present invention relates to new benzodioxane compounds. 
DESCRIPTION OF THE PRIOR ART 
A certain number of 1,4-benzodioxane derivatives have been described in the 
literature. This is more particularly the case for the compounds described 
in Patents EP 307,970, EP 210,581 or FR 2,449,088, which exhibit a 
vasodilatory activity or alternatively for the compounds described in 
Patent EP 446,921, which possess anxiolytic properties. 
SUMMARY OF THE INVENTION 
Besides the fact that they are novel, the compounds of the present 
invention exhibit particularly advantageous pharmacological properties. 
Indeed, one of the challenges in psychopharmacology today is to find novel 
medicaments which allow better control of schizophrenia, the treatment of 
which is currently unsatisfactory. Conventional neuroleptic agents, such 
as haloperidol, provide quite good care for the productive symptoms (such 
as fabulation and hallucinations) but their effectiveness with regard to 
deficiency symptoms (such as social withdrawal) is very poor. Furthermore, 
they induce an extrapyramidal syndrome of Parkinson type, as has been 
indicated by A. Y. Deutch et al. (Schizophrenia Research, 4, 121-151, 
1991) and H. Y. Meltzer et al. (Pharmacol. Rev., 43,587-604, 1991). 
Unlike haloperidol, clozapine is more effective in treating the deficiency 
symptoms, and it is even effective in patients who are resistant to 
haloperidol. Moreover, it appears not to bring about an extrapyramidal 
syndrom, as has been indicated by Coward et at. (Psychopharmacology, 99, 
s6-s12, 1989). This difference is apparently due to the receptor profile 
of clozapine, which differs from that of haloperidol: for example, its low 
relative activity on the D.sub.2 receptors and its relatively high 
affinity for the adrenergic (.alpha..sub.1) and serotinergic (5-HT.sub.2A 
; 5-HT.sub.2C) receptors. These results have been indicated by H. Canton 
et al. (Eur. J. Pharmacol., 191, 93-96, 1990) as well as by A. Y. Deutch 
and H. Y. Meltzer, cited above. 
Moreover, unlike haloperidol, clozapine shows a certain affinity for the 
5-HT.sub.1A receptors, the activation of which is associated with 
anxiolytic, antidepressant and possibly even antipsychotic effects, as has 
been indicated by S. Ahlenius (Pharmacol. & Toxicol., 64, 3-5, 1989), J. 
E. Barrett et al. (in "5-HT.sub.1A agonists, 5-HT.sub.3 antagonists and 
benzodiazepines: their comparative behavioural pharmacology" Ed. R. J. 
Rogers and S. J. Cooper, Wiley & Sons Ltd., Chichester, pp. 59-105, 1991), 
M. J. Millan et al. (Drug News & Perspectives, 5, 397-466, 1992), J. M. A. 
Sitsen (Drug News & Perspectives, 4, 414-418, 1991). 
However, on account of its toxicity, clozapine cannot be envisaged in the 
general treatment of schizophrenic states. It was thus particularly 
advantageous to find products sharing the mechanism of clopazine but 
devoid of its toxic effects, which are directly associated with its 
specific chemical structure. 
The compounds described in this patent correspond to the desired profile. 
Indeed, they exhibit (in vitro and in vivo) a very similar biochemical and 
functional profile to that of clopazine and, in addition, have higher 
affinities for the 5-HT.sub.1A receptors. They thus possess an original 
profile which appears to be well suited to a better treatment of 
schizophrenia, in comparison with that which may currently be obtained 
with the products available. 
DETAILED DESCRIPTION OF THE INVENTION 
More specifically, the present invention relates to the compounds of 
formula (I): 
##STR3## 
in which: X represents an oxygen atom or a methylene group, 
n represents 1, 2 or 3, 
R.sub.1 represents a hydrogen atom, an aminocarbonyl group or a 
hydroxymethyl group, 
R.sub.2 represents a group: 
##STR4## 
in which: either R.sub.3 represents a hydrogen atom or a linear or 
branched (C.sub.1 -C.sub.6) alkyl group, and R.sub.4 represents: 
a linear or branched (C.sub.1 -C.sub.4) alkyl group 
which is unsubstituted or substituted with a phenyl group (which may or may 
not be substituted with one or more halogen atoms or linear or branched 
(C.sub.1 -C.sub.4) alkyl groups, linear or branched (C.sub.1 -C.sub.4) 
alkoxy groups, trihalomethyl groups or hydroxyl groups), on condition 
that, in these cases, R.sub.1 is other than a hydrogen atom, 
or which is substituted with a benzoylamino group (which may or may not be 
substituted on the phenyl ring with one or more halogen atoms or linear or 
branched (C.sub.1 -C.sub.4) alkyl groups, linear or branched (C.sub.1 
-C.sub.4) alkoxy groups, trihalomethyl groups or hydroxyl groups), 
or a benzoyl group (which may or may not be substituted with one or more 
halogen atoms or linear or branched (C.sub.1 -C.sub.4) alkyl groups, 
linear or branched (C.sub.1 -C.sub.4) alkoxy groups, trihalomethyl groups 
or hydroxyl groups). 
or R.sub.3 and R.sub.4 form, together with the nitrogen atom to which they 
are attached, a group: 
##STR5## 
in which: m represents 1, 2 or 3, 
R.sub.5 represents a benzoyl (which may or may not be substituted with one 
or more halogen atoms or linear or branched (C.sub.1 -C.sub.4) alkyl 
groups, linear or branched (C.sub.1 -C.sub.4) alkoxy groups, hydroxyl 
groups or trihalomethyl groups), 
benzoylmethyl (which may or may not be substituted on the phenyl ring with 
one or more halogen atoms or linear or branched (C.sub.1 -C.sub.4) alkyl 
groups, linear or branched (C.sub.1 -C.sub.4) alkoxy groups, hydroxyl 
groups or trihalomethyl groups), 
2-oxo-(3H)-benzimidazol-1-yl, 
1H-indazol-3-yl methyl (which may or may not be substituted on the phenyl 
ring with a halogen atom), 
or 1,2-benzisoxazol-3-yl methyl group (which may or may not be substituted 
on the phenyl ring with a halogen atom), 
the enantiomers, diastereoisomers and epimers thereof, and the addition 
salts thereof with a pharmaceutically acceptable acid or base. 
Among the pharmaceutically acceptable acids which may be mentioned, without 
any limitation being implied, are hydrochloric acid, hydrobromic acid, 
sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic 
acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric 
acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, 
methanesulfonic acid, camphoric acid, etc. 
Among the pharmaceutically acceptable bases which may be mentioned, without 
any limitation being implied, are sodium hydroxide, potassium hydroxide, 
triethylamine, tert-butylamine, etc. 
The invention also covers the process for the preparation of the compounds 
of formula (I). 
The process for the preparation of the compounds of formula (I), such that 
X represents an oxygen atom and R.sub.1 represents a hydrogen atom, 
comprises a compound of formula (II) being used as starting material: 
##STR6## 
which compound is reacted with 1,2-dibromoethane in the presence of 
potassium carbonate and copper powder in an alcoholic medium, to give the 
compound of formula (III): 
##STR7## 
which compound is converted, in an acidic medium, into the compound of 
formula (IV): 
##STR8## 
which compound of formula (IV) is condensed: either with a compound of 
formula (V), after reacting with sodium ethoxide: 
EQU Br--(CH.sub.2).sub.n --Cl (V) 
in which n has the same meaning as in the formula (I), to give the compound 
of formula (VI): 
##STR9## 
in which n has the same meaning as in the formula (I), which compound is 
then reacted with an amine of formula (VII), the isomers of which have 
optionally been separated: 
##STR10## 
in which R'.sub.4 has the same meaning as R.sub.4 except for the case 
where R.sub.4 represents a substituted or unsubstituted benzoyl group, to 
give the compound of formula (I/a), a specific case of the compounds of 
formula (I): 
##STR11## 
in which n, R.sub.3 and R'.sub.4 have the same meaning as above, or with a 
nitrile of formula (VIII), in a basic medium, 
EQU Br--(CH.sub.2).sub.n-1 --CN (VIII) 
in which n has the same meaning as in the formula (I), to give the compound 
of formula (IX): 
##STR12## 
in which n has the same meaning as in the formula (I), which compound is 
reduced using lithium aluminum hydride, to give the compound of formula 
(X): 
##STR13## 
in which n has the same meaning as in the formula (I), which compound is 
reacted with an acid chloride of formula (XI): 
EQU Cl--CO--R".sub.4 (XI) 
in which R".sub.4 represents a phenyl group (which may or may not be 
substituted with one or more halogen atoms or linear or branched (C.sub.1 
-C.sub.4) alkyl groups, linear or branched (C.sub.1 -C.sub.4) alkoxy 
groups, trihalomethyl groups or hydroxyl groups), to give the compound of 
formula (I/b), a specific case of the compounds of formula (I): 
##STR14## 
in which n and R".sub.4 have the same meaning as above, which compound of 
formula (I/b) may, if so desired, undergo a reduction in the presence of 
tetrabutylammonium borohydride, to give the compound of formula (I/c), a 
specific case of the compounds of formula (I): 
##STR15## 
in which n and R".sub.4 have the same meaning as above, which compound of 
formula (I/a), (I/b) or (I/c): 
may be purified, if required, according to a standard purification 
technique, and 
the isomers of which are, if required, separated according to a standard 
separation technique, and 
which is converted, if so desired, into the addition salts thereof with a 
pharmaceutically acceptable base. 
The process for the preparation of the compounds of formula (I), such that 
X represents an oxygen atom and R.sub.1 represents an aminocarbonyl or 
hydroxymethyl group, comprises a compound of formula (XII) being used as 
starting material: 
##STR16## 
which compound is reacted with ethyl 2,3-dibromopropionate, in a basic 
medium, to give the compound of formula (XIII): 
##STR17## 
which compound is reacted, if so desired, in an ammoniacal solution, to 
give the compound of formula (XIV): 
##STR18## 
which compound of formula (XIII) or (XIV) is condensed: either with a 
compound of formula (V): 
EQU Br--(CH.sub.2).sub.n --Cl (V) 
in which n has the same meaning as in the formula (I), to give the 
compounds of formula (XV) or (XVI) respectively: 
##STR19## 
in which n has the same meaning as in the formula (I), which compounds are 
reacted respectively with an amine of formula (VII), the isomers of which 
have optionally been separated: 
##STR20## 
in which R'.sub.4 has the same meaning as R.sub.4, except for the case 
where R.sub.4 represents a substituted or unsubstituted benzoyl group, to 
give the compounds of formula (XVII) or (I/d), a specific case of the 
compounds of formula (I): 
##STR21## 
in which n, R.sub.3 and R'.sub.4 have the same meaning as above, which 
compound of formula (XVII) is reduced in the presence of lithium aluminum 
hydride, to give the compound of formula (I/e), a specific case of the 
compounds of formula (I): 
##STR22## 
in which n, R.sub.3 and R'.sub.4 have the same meaning as in the formula 
(I), or with a nitrile of formula (VIII), in a basic medium, 
EQU Br--(CH.sub.2).sub.n-1 --CN (VIII) 
in which n has the same meaning as in the formula (I), to give the 
compounds of formula (XVIII) or (XIX) respectively: 
##STR23## 
in which n has the same meaning as in the formula (I), which compounds are 
reduced using lithium aluminum hydride, to give the compounds of formula 
(XX) or (XXI) respectively: 
##STR24## 
in which n has the same meaning as in the formula (I), which compounds are 
reacted, respectively, with an acid chloride of formula (XI): 
EQU Cl--CO--R".sub.4 (XI) 
in which R".sub.4 represents a phenyl group (which may or may not be 
substituted with one or more halogen atoms or linear or branched (C.sub.1 
-C.sub.4) alkyl groups, linear or branched (C.sub.1 -C.sub.4) alkoxy 
groups, trihalomethyl groups or hydroxyl groups), to give the compounds of 
formula (I/f) or (I/g) respectively, specific cases of the compounds of 
formula (I): 
##STR25## 
in which n and R".sub.4 have the same meaning as above, which compounds of 
formula (I/f) or (I/g) may, if so desired, undergo a reduction in the 
presence of tetrabutylammonium borohydride, to give the compounds of 
formula (I/h) or (I/i) respectively, specific cases of the compounds of 
formula (I): 
##STR26## 
in which n and R".sub.4 have the same meaning as above, which compound of 
formula (I/d), (I/e), (I/f), (I/g), (I/h) or (I/i): 
may be purified, if required, according to a standard purification 
technique, and 
the isomers of which are, if required, separated according to a standard 
separation technique, and 
which is converted, if so desired, into the salts thereof with a 
pharmaceutically acceptable base. 
The process for the preparation of the compounds of formula (I), such that 
X represents a methylene group, comprises a compound of formula (XXII) 
(obtained from 2,3-dihydroxybenzaldehyde according to the process 
described in J. Med. Chem., 26, 193, 1989) being used as starting 
material: 
##STR27## 
in which n has the same meaning as in the formula (I), which undergoes a 
catalytic hydrogenation to give the compound of formula (XXIII): 
##STR28## 
in which n has the same meaning as in the formula (I), which compound is 
reduced in the presence of lithium aluminum hydride, to give the compound 
of formula (XXIV): 
##STR29## 
in which n has the same meaning as in the formula (I), which compound is 
reacted with 1,2-dibromoethane or with ethyl 2,3-dibromopropionate, 
depending on the derivative of formula (I) which it is desired to obtain, 
to give the compound of formula (XXV): 
##STR30## 
in which R'.sub.1 represents a hydrogen atom or an ethoxycarbonyl group, 
which compound of formula (XXV) (which, when R'.sub.1 represents an 
ethoxycarbonyl group, may, if so desired, be subjected to the action of an 
ammoniacal solution, to give the corresponding amide), is then reacted 
with carbon tetrabromide in the presence of triphenylphosphine, to give 
the compound of formula (XXVI), 
##STR31## 
in which n has the same meaning as in the formula (I), and R".sub.1 
represents a hydrogen atom or an ethoxycarbonyl or aminocarbonyl group, 
which compound is then reacted with an amine of formula (VII), the isomers 
of which have optionally been separated: 
##STR32## 
in which R'.sub.4 has the same meaning as R.sub.4, except for the case 
where R.sub.4 represents a substituted or unsubstituted benzoyl group, to 
give the compound of formula (I/j), a specific case of the compounds of 
formula (I) (after conversion, in the presence of lithium aluminum 
hydride, of the group R".sub.1, when it represents an ethoxycarbonyl 
group, into a hydroxymethyl group): 
##STR33## 
in which R.sub.1, n, R.sub.3 and R'.sub.4 have the same meaning as above, 
which compound of formula (I/j): 
may, if required, be purified according to a standard purification 
technique, and 
the isomers of which are separated, if required, according to a standard 
separation technique, and 
which is converted, if so desired, into the addition salts thereof with a 
pharmaceutically acceptable base. 
The subject of the present invention is also the pharmaceutical 
compositions containing, as active principle, at least one compound of 
formula (I), alone or in combination with one or more inert, non-toxic 
vehicles or excipients. 
Among the pharmaceutical compositions according to the invention, there may 
more particularly be mentioned those which are suitable for oral, 
parenteral or nasal administration, simple or coated tablets, sublingual 
tablets, gelatin capsules, lozenges, suppositories, creams, ointments, 
dermal gels, etc. 
The useful dosage varies depending on the age and weight of the patient, 
the nature and severity of the complaint, and the route of administration. 
The latter may be oral, nasal, rectal or parenteral. Generally speaking, 
the unit dosage ranges between 20 .mu.g and 2 mg for a treatment dose 
taken 1 to 3 times per 24 hours.

The examples which follow illustrate the invention and in no way imply a 
limitation thereof. 
The starting materials used are known products or are prepared according to 
known procedures. 
Preparations A, B and C do not lead to the compounds of the invention, but 
to synthesis intermediates which are useful in the preparation of the 
compounds of formula (I). 
Preparation A: N-Propyl-N-[2-(4-fluorobenzoylamino)ethyl]amine 
Stage A: N-(2-Bromoethyl)-4-fluorobenzamide 
To a suspension containing 0.23 mol of-bromoethylamine hydrobromide in 200 
ml of chloroform, stirred at 5.degree. C., is added dropwise a solution 
containing 0.21 mol of 4-fluorobenzoyl chloride in 50 ml of chloroform, 
followed by a solution containing 0.46 mol of triethylamine in 100 ml of 
chloroform. The mixture is then stirred at room temperature for 1 hour and 
then at reflux for 4 hours. After cooling and evaporation of the solvent, 
the residue is taken up in 200 ml of ether. After filtration of the salts 
and concentration of the solvent, the expected product is obtained by 
purification of the residue by chromatography on a column of silica, using 
a dichloromethane/acetone (98/2) mixture as eluent. 
Stage B: N-Propyl-N-[2-(4-fluorobenzoylamino)ethyl]amine 
The product obtained in the preceding stage, dissolved in 40 ml of 
propylamine, is maintained at reflux for 4 hours. After cooling and 
distillation of the excess propylamine, the expected product is obtained 
after purification by chromatography on a column of silica, using a 
dichloromethane/methanol/aqueous ammonia (90/10/1) mixture as eluent. 
Preparation B: 3-[(6-Fluoro-1,2-benzisoxazol-3-yl)methyl]pyrrolidine 
Stage A: 1-Benzyl-3-[2-(2,4-difluorophenyl)-2-hydroxyethyl]pyrrolidine 
A solution containing 0.38 mol of 1-benzyl-3-chloromethylpyrrolidine in 200 
ml of tetrahydrofuran (THF) is added, at 65.degree. C., to a suspension 
containing 9.3 g of magnesium in 100 ml of THF. The mixture is maintained 
at reflux and, after disappearance of the metal, followed by cooling, this 
solution is added to a solution containing 0.38 mol of 
2,4-difluorobenzaldehyde in 300 ml of THF. The mixture is maintained at 
room temperature for 12 hours and is then hydrolyzed with 220 ml of 
saturated ammonium chloride solution. After extraction with 
dichloromethane and then evaporation, the residual oil is purified by 
chromatography on a column of silica, using a 
dichloromethane/methanol/aqueous ammonia (98/2/0.2) mixture as eluent, and 
gives the expected product. 
Stage B: 1-Benzyl-3-(2,4-difluorobenzoylmethyl)pyrrolidine 
67 g of chromium trioxide are added, with stirring and at 0.degree. C., to 
700 ml of pyridine, followed, 15 minutes later, by 0.214 mol of the 
compound described in the preceding stage, dissolved in 150 ml of 
pyridine. The mixture is maintained at room temperature for 12 hours, 
evaporated and the residue is taken up in 500 ml of water and 500 ml of 
dichloromethane. The precipitate formed is filtered off and washed with 
dichloromethane. The organic phases are combined, washed with 1N sodium 
hydroxide, with saturated sodium chloride solution and then dried and 
evaporated. The residual oil is purified by chromatography on a column of 
silica, using a dichloromethane/methanol/aqueous ammonia (98/2/0.2) 
mixture as eluent, and gives the expected product. 
Stage C: 1-Benzyl-3-[6-fluoro-1,2-benzisoxazol-3-yl)methyl]pyrrolidine 
0.19 tool of the product obtained in the preceding stage and 0.95 mol of 
hydroxylamine hydrochloride in 600 ml of pyridine are maintained at reflux 
for 24 hours. After concentration of the solvent, the residue is taken up 
in dichloromethane. The organic phase is then washed with water and 
evaporated. The residue is taken up in 100 ml of dimethylformamide (DMF) 
and is added to a suspension containing 4.3 g of sodium hydride in 50 ml 
of DMF. After stirring for one hour, the reaction mixture is hydrolyzed 
and then extracted with dichloromethane. After washing the organic phase 
with water and evaporation of the solvent, the residual oil is purified by 
chromatography on a column of silica, using a dichloromethane/methanol 
(97/3) mixture as eluent, and gives the expected product. 
Stage D: 
1-Ethoxycarbonyl-3-[6-fluoro-1,2-benzisoxazol-3-yl)methyl]pyrrolidine 
A mixture containing 80 mmol of the compound obtained in the preceding 
stage and 160 mmol of ethyl chloroformate in 350 ml of toluene is 
maintained at reflux for 24 hours. After cooling, washing of the toluene 
phase with 1N hydrochloric acid, then with 1N sodium hydroxide and 
evaporation, the expected product is obtained. 
Stage E: 3-[(6-Fluoro-1,2-benzisoxazol-3-yl)methyl]pyrrolidine 
58 mmol of the compound obtained in the preceding stage and 250 ml of 48% 
hydrobromic acid are heated at 90.degree. C. for 1 hour. After 
concentration, the expected product is obtained by release from the 
residue using 5N sodium hydroxide. 
Preparation C: 3-[(6-Fluoro-1H-indazol-3-yl)methyl]pyrrolidine 
Stage A: 1-Benzyl-[(6-Fluoro-1H-indazol-3-yl)methyl]pyrrolidine 
64 mmol of the compound obtained in Stage B of Preparation B and 64 mmol of 
hydrazine hydrate in 200 ml of 1-butanol are maintained at reflux for 72 
hours. After cooling and evaporation, the residue is taken up in 
dichloromethane. The organic phase is washed with water and evaporated. 
The residual oil is purified by chromatography on a column of silica, 
using a dichloromethane/methanol/aqueous ammonia (96/4/0.4) mixture as 
eluent. 
Stage B: 3-[(6-Fluoro-1H-indazol-3-yl)methyl]pyrrolidine 
The product obtained in the preceding stage undergoes a catalytic 
debenzylation in ethanol, at 45.degree. C., using 10% palladium on 
charcoal as catalyst. 
EXAMPLE 1 
5-{2-[4-(4-Fluorobenzoyl)piperidino]ethoxy}-1,4-benzodioxane hydrochloride 
Stage A: 5-Methoxy-1,4-benzodioxane 
A heterogeneous mixture containing 1.42 mol of 3-methoxycatechol, 1.57 mol 
of 1,2-dibromoethane, 1.42 mol of potassium carbonate and 4 g of copper 
powder in 150 ml of glycerol is heated at 110.degree. C. for 15 hours. 
After cooling, the mixture is poured into 1 l of water. The aqueous phase 
is extracted with ethyl ether. The ether phases are then washed with 1N 
sodium hydroxide, dried and evaporated, and give the expected product. 
Stage B: 5-Hydroxy-1,4-benzodioxane 
The compound obtained in the preceding stage is maintained at reflux in 500 
ml of 48% hydrobromic acid and 800 ml of glacial acetic acid. After 
cooling and concentration, the residue is taken up in 1 l of water and the 
aqueous phase is extracted with ethyl ether. The ether phases are combined 
and evaporated. The expected product is obtained after purification by 
chromatography on a column of silica, using dichloromethane as eluent. 
Stage C: 5-(2-Chloroethoxy)-1,4-benzodioxane 
To 500 ml of 1N sodium ethoxide solution is added dropwise a solution 
containing 500 mmol of the compound obtained in the preceding stage in 150 
ml of ethanol. The mixture is stirred for 1 hour, and a solution 
containing 500 mmol of 1-bromo-2-chloroethane in 150 ml of ethanol is 
added to the above mixture. The mixture is then maintained at reflux for 
24 hours. After cooling, filtration of the salts and evaporation, the 
residue is taken up in isopropyl ether and the expected product which 
precipitates is filtered off. Melting point: 73.degree. C. 
Stage D: 5-{2-[4-(4-Fluorobenzoyl)piperidino]ethoxy}-1,4-benzodioxane 
hydrochloride 
A mixture containing 21 mmol of the product obtained in the preceding 
stage, 17 mmol of 4-(4-fluorobenzyl)piperidine, 21 mmol of potassium 
carbonate and a few mg of potassium iodide in 50 ml of 
4-methyl-2-pentanone is maintained at reflux for 18 hours. After cooling, 
50 ml of water are added to the reaction medium and the aqueous phase is 
extracted with dichloromethane. The organic phases are combined, washed, 
dried and evaporated. The expected product, in the form of the base, is 
obtained after purification of the residue by chromatography on a column 
of silica, using a dichloromethane/ethanol (98/2) mixture as eluent. It is 
converted into the corresponding hydrochloride by dilution in ethyl ether 
and dropwise addition of the stoichiometric amount of 10N hydrochloric 
ethanol. The hydrochloride is then filtered off, washed with ether and 
dried. Melting point: 152.degree. C. 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 62.63 5.97 3.32 8.40 
found 62.49 5.95 3.18 8.47 
______________________________________ 
The products of Examples 2 to 8 were prepared according to the process 
described in Example 1, using the corresponding starting materials. 
EXAMPLE 2 
5-{2-[3-(4-Fluorobenzoylmethyl)pyrrolidin-1-yl}-1,4-benzodioxane 
hydrochloride 
Stages A, B, C: identical to Stages A, B and C of Example 1. 
Stage D: Replace 4-(4-fluorobenzoyl)piperidine with 
3-(4-fluorobenzylmethyl)pyrrolidine. 
Melting point: 134.degree. C. 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 62.63 5.97 3.32 8.40 
found 62.64 6.06 3.16 8.52 
______________________________________ 
EXAMPLE 3 
5-{2-[4-(2-Oxo-(3H)-benzimidazol-1-yl)piperidino ]ethoxy}-1,4-benzodioxane 
hydrochloride 
Stages A, B, C: identical to Stages A, B and C of Example 1. 
Stage D: Replace 4-(4-fluorobenzoyl)piperidine with 
1-(piperidin-4-yl)-2-(3H) -benzimidazolone. 
Melting point: 155.degree. C. 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 61.18 6.07 9.73 8.21 
found 61.07 6.1 9.71 8.14 
______________________________________ 
EXAMPLE 4 
5-{2-[N-propyl-N-[2-(4-Fluorobenzoylamino)ethyl]amino]ethoxy}-1,4-benzodiox 
ane hydrochloride 
Stages A, B, C: identical to stages A, B and C of Example 1. 
Stage D: Replace 4-(4-fluorobenzoyl)piperidine with the amine described in 
Preparation A. 
Melting point: 147.degree. C. 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 60.20 6.43 6.38 8.08 
found 59.71 6.53 6.33 8.27 
______________________________________ 
EXAMPLE 5 
5-{2-[3-(4-Fluorobenzoylmethyl)pyrrolidin-1-yl]ethoxy}-1,4-benzodioxane 
hydrochloride, (+) isomer 
Stages A, B, C: identical to Stages A, B and C of Example 1. 
Stage D: Replace 4-(4-fluorobenzoyl)piperidine with the (+) isomer of 
3-(4-fluorobenzoylmethyl)pyrrolidine obtained according to the process 
described in Patent EP 389,352. 
The hydrochloride is obtained by salification of the base in an 
acetone/ethyl ether (50/50) mixture with one equivalent of hydrochloric 
acid in ethanol. Melting point: 120.degree.-122.degree. C. Optical 
rotation: [.alpha.].sub.D.sup.21 =+4.15.degree. (c=1%, methanol) 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 62.63 5.97 3.32 8.40 
found 62.65 5.89 3.31 8.41 
______________________________________ 
EXAMPLE 6 
5-{2-[3-(4-Fluorobenzoylmethyl)pyrrolidin-1-yl]ethoxy}-1,4-benzodioxane 
hydrochloride, (-) isomer 
Stages A, B, C: identical to Stages A, B and C of Example 1. 
Stage D: Replace 4-(4-fluorobenzoyl)piperidine with the (-) isomer of 
3-(4-fluorobenzoylmethyl)pyrrolidine obtained according to the process 
described in Patent EP 389,352. 
The hydrochloride is obtained as described in Example 5. Melting point: 
120.degree.-122.degree. C. Optical rotation: [.alpha.].sub.D.sup.21 
=-4.75.degree. (c=1%, methanol) 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 62.63 5.97 3.32 8.40 
found 62.59 5.86 3.37 8.28 
______________________________________ 
EXAMPLE 7 
5-{2-[3-[(6-Fluoro-1H-indazol-3-yl)methyl]pyrrolidin-1-yl]ethoxy}-1,4-benzo 
dioxane hydrochloride 
Stages A, B, C: identical to Stages A, B and C of Example 1. 
Stage D: Replace 4-(4-fluorobenzoyl)piperidine with 
3-[(6-fluoro-1H-indazol-3-yl)methyl]pyrrolidine described in Preparation 
C. 
Purification of the expected product, in base form, is performed by 
chromatography on a column of silica, using a 
dichloromethane/methanol/aqueous ammonia (95/5/0.5) mixture as eluent. 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 61.26 5.78 9.75 7.40 
found 61.33 6.05 9.14 7.35 
______________________________________ 
EXAMPLE 8 
5-{2-[3-[(6-Fluoro-1,2-benzisoxazol-3-yl)methyl]pyrrolidin-1-yl]ethoxy}-1,4 
-benzodioxane hydrochloride 
Stages A, B, C: identical to Stages A, B and C of Example 1. 
Stage D: Replace 4-(4-fluorobenzoyl)piperidine with 
3-[(6-fluoro-1,2-benzisoxazol-3-yl)methyl]pyrrolidine described in 
Preparation B. 
Purification of the product obtained, in base form, is performed by 
chromatography on a column of silica, using a dichloromethane/methanol 
(97/3) mixture as eluent. 
______________________________________ 
Elemental microanalysis: 
C % H % N % 
______________________________________ 
calculated 60.76 5.56 6.44 
found 61.21 5.54 6.49 
______________________________________ 
EXAMPLE 9 
5-{2-(4-(4-Fluorobenzoyl)piperidino]ethoxy}-1,4-benzodioxane-2-carboxamide 
hydrochloride 
Stage A: Ethyl ester of 5-hydroxy-1,4-benzodioxane-2-carboxylic acid 
To a solution containing 0.8 mol of pyrogallol in 1 l of acetate are added 
2.4 mol of potassium carbonate, followed by dropwise addition of 2.4 mol 
of ethyl 2,3-dibromopropionate. The mixture is then maintained at reflux 
for 15 hours. After cooling, filtration of the precipitate and washing of 
the latter with acetone, the filtrate is recovered and concentrated. The 
residue is taken up in ether and, after filtration of the ether phase, the 
latter is evaporated and gives the expected product. 
Stage B: 5-Hydroxy-1,4-benzodioxane-2-carboxamide 
A mixture containing 350 mmol of the product obtained in the preceding 
stage in 1.3 l of a 28% ammoniacal solution is stirred at room temperature 
for 18 hours. After concentration of the reaction medium, the residue is 
taken up in 300 ml of ether. The expected product is obtained after 
filtration of the precipitate formed and is dried. 
Stage C: 5-(2-Chloroethoxy)-1,4-benzodioxane-2-carboxamide 
The expected product is obtained according to the process described in 
Stage C of Example 1, from the compound obtained in the above stage. 
Stage D: 
5-{2-(4-(4-Fluorobenzoyl)piperidino]ethoxy}-1,4-benzodioxane-2-carboxamide 
hydrochloride 
The expected product is obtained according to the process described in 
Stage D of Example 1, from the compound described in the above stage. 
Melting point: 215.degree. C. 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 59.42 5.64 6.03 7.63 
found 59.39 5.80 5.83 7.59 
______________________________________ 
EXAMPLE 10 
2-Hydroxymethyl-5-[2-(N,N-dipropylamino)ethoxy]-1,4-benzodioxane oxalate 
Stage A: Ethyl ester of 5-(2-chloroethyl)-1,4-benzodioxane-2-carboxylic 
acid 
The expected product is obtained from the compound described in Stage A of 
Example 9, according to the process described in Stage C of Example 1. 
Stage B: Ethyl ester of 
5-[2-(N,N-dipropylaminoethoxy]-1,4-benzodioxane-2-carboxylic acid 
50 mmol of the compound obtained in the preceding stage in 50 ml of 
dipropylamine are maintained at 150.degree. C. for 10 hours. After 
cooling, the medium is concentrated under vacuum and the expected product 
is obtained after purification of the residue by chromatography on a 
column of silica, using a dichloromethane/ethanol/aqueous ammonia 
(90/10/1) mixture as eluent. 
Stage C: 2-Hydroxymethyl-5-[2-(N,N-dipropylamino)ethoxy]-1,4-benzodioxane 
oxalate 
To a suspension containing 13.7 mmol of lithium aluminum hydride in 100 ml 
of ether, stirred at room temperature under a nitrogen atmosphere, is 
added dropwise a solution containing 12 mmol of the product obtained in 
the above stage in 50 ml of ether. The mixture is kept stirring for 1 hour 
and is hydrolyzed with saturated ammonium chloride solution. The organic 
phase is recovered, washed with water, dried and evaporated, and gives the 
expected product in the form of the base. To the latter, diluted in 50 ml 
of ethanol, is added 1 equivalent of oxalic acid, followed, after stirring 
for 5 minutes, by 50 ml of isopropyl ether. The oxalate is obtained by 
filtration and is dried. Melting point: 148.degree. C. 
EXAMPLE 11 
5-[2-(2,3,4-Trimethoxybenzoylamino)ethoxy]-1,4-benzodioxane 
Stage A: 5-Cyanomethoxy-1,4-benzodioxane 
To a stirred suspension containing 0.38 mol of the compound obtained in 
Stage B of Example 1 and 1.14 mol of potassium carbonate in 500 ml of 
acetone is added dropwise a solution containing 0.76 mol of 
bromoacetonitrile in 100 ml of acetone. The medium is then kept stirring 
for 18 hours. After filtration of the salts and evaporation, the expected 
product is obtained. 
Stage B: 5-(2-Aminoethoxy)-1,4-benzodioxane 
The expected product is obtained according to the process described in 
Stage C of Example 10, from the product described in the above stage. 
Stage C: 5-[2-(2,3,4-Trimethoxybenzoylamino)ethoxy]-1,4-benzodioxane 
To a stirred solution, at room temperature, containing 4.7 mmol of the 
product obtained in the preceding stage in 20 ml of dichloromethane is 
added dropwise a solution containing 10.5 mmol of 3,4,5-trimethoxybenzoyl 
chloride in 20 ml of dichloromethane, followed by 10.5 mmol of 
triethylamine in 20 ml of dichloromethane. The mixture is then stirred at 
room temperature for 2 hours. After filtration of the salts and washing of 
the medium with water, the organic phase is dried and evaporated. The 
residue is taken up in ether and gives the expected product which 
precipitates and which is recrystallized in ethanol. Melting point: 
128.degree. C. 
______________________________________ 
Elemental microanalysis: 
C % H % N % 
______________________________________ 
calculated 61.69 5.95 3.60 
found 61.26 5.89 3.70 
______________________________________ 
EXAMPLE 12 
2-Hydroxymethyl-5-[2-(4-fluorobenzoylamino)ethoxy]-1,4-benzodioxane 
Stage A: Ethyl ester of 5-cyanomethyl-1,4-benzodioxane-2-carboxylic acid 
The expected product was obtained according to the process described in 
Stage A of Example 11, from the compound described in Stage A of Example 9 
and bromoacetonitrile. 
Stage B: 2-Hydroxymethyl-5-(2-aminoethoxy)-1,4-benzodioxane 
The expected product was obtained according to the process described in 
Stage C of Example 10, from the compound described in the above stage, 
using 2 equivalents of lithium aluminum hydride. 
Stage C: 
2-Hydroxymethyl-5-[2-(4-fluorobenzoylamino)ethoxy]-1,4-benzodioxane 
The expected product was obtained according to the process described in 
Stage C of Example 11, from the compound described in the above stage and 
4-fluorobenzoyl chloride. Melting point: 124.degree. C. 
______________________________________ 
Elemental microanalysis: 
C % H % N % 
______________________________________ 
calculated 62.24 5.22 4.03 
found 62.13 5.30 3.88 
______________________________________ 
EXAMPLE 13 
5-[2-(3,4,5-Trimethoxybenzylamino)ethoxy-1,4-benzodioxane hydrochloride 
6.3 mmol of the compound obtained in Stage C of Example 11 and 19 mmol of 
tetrabutylammonium borohydride are maintained at reflux in 100 ml of 
dichloromethane for 24 hours. After evaporation of the solvent, the 
reaction medium is hydrolyzed with 50 ml of 10% hydrochloric acid at room 
temperature. The mixture is then maintained at reflux for one hour. After 
extraction with dichloromethane, the organic phase is washed with sodium 
hydroxide, dried and concentrated under vacuum. The expected product, in 
the form of the base, is then obtained after purification of the residue 
by chromatography on a column of silica, using a dichloromethane/methanol 
(97/3) mixture as eluent. After dilution in ether and stoichiometric 
addition of 6N hydrochloric ether, the corresponding hydrochloride is 
obtained. Melting point: 149.degree. C. 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 58.32 6.36 3.40 8.61 
found 58.02 6.35 3.45 8.44 
______________________________________ 
EXAMPLE 14 
5-{3-[3-(4-Fluorobenzoylmethyl)pyrrolidin-1-yl]propyl}-1,4-benzodioxane 
hydrochloride 
Stage A: Methyl ester of 3-(2,3-dihydroxyphenyl)propionic acid 
The expected product is obtained by catalytic hydrogenation in methanol, at 
room temperature and pressure, in the presence of 10% palladium on 
charcoal as catalyst, of the methyl ester of 
(2,3-dihydroxy-phenyl)cinnamic acid (obtained from 
2,3-dihydroxybenzaldehyde according to the procedure described in J. Het. 
Chem., 26, 193, 1989). 
Stage B: 3-(2,3-Dihydroxyphenyl)propanol 
The expected product is obtained according to the process described in 
Stage C of Example 10, from the compound obtained in the above stage. 
Stage C: 5-(3-Hydroxypropyl)-1,4-benzodioxane 
The expected product is obtained according to the process described in 
Stage A of Example 1, from the compound obtained in the above stage. 
Stage D: 5-(3-Bromopropyl)-1,4-benzodioxane 
To a stirred solution, at 8.degree. C., containing 36 mmol of the compound 
obtained in the preceding stage and 58.4 mmol of carbon tetrabromide in 
150 ml of dimethylformamide are added portionwise 58.4 mmol of 
triphenylphosphine. The mixture is stirred at 8.degree. C. for 2 hours and 
is then poured into 300 ml of ice-water. The medium is extracted with 
ether and the ether phase is dried and evaporated. The expected product is 
then obtained by purification of the residue by chromatography on a column 
of silica, using dichloromethane as eluent. 
Stage E: 
5-{3-[3-(4-Fluorobenzoylmethyl)pyrrolidin-1-yl]propyl}-1,4-benzodioxane 
hydrochloride 
The expected product is obtained according to the process described in 
Stage D of Example 1, from the compound obtained in the above stage and 
3-(4-fluorobenzoylmethyl)pyrrolidine. 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 65.79 6.48 3.34 8.44 
found 65.11 6.11 4.03 8.32 
______________________________________ 
EXAMPLE 15 
5-{2-[4-(4-Fluorobenzoyl)perhydroazepin-1-yl]ethoxy}-1,4-benzodioxane 
hydrochloride 
A mixture of 5 g of 5-(2-chloroethoxy)-1,4-benzodioxane, 7.8 g of 
4-(4-fluorobenzoyl)perhydroazepine hydrobromide (described in Patent EP 
389,352), 1 g of potassium iodide and 6.5 g of potassium carbonate in 100 
ml of diethyl ketone is maintained at 100 C. for 24 hours. The inorganic 
salts are then filtered off and the filtrate is concentrated under vacuum. 
The residue is purified by chromatography on a column of silica, with a 
dichloromethane/methanol/aqueous ammonia (97/3/0.3) eluent mixture. The 
base obtained is salified with hydrochloric methanol in an acetone/ether 
mixture. Melting point: 106.degree.-107.degree. C. 
______________________________________ 
Elemental microanalysis: 
C % H % N % Cl % 
______________________________________ 
calculated 63.37 6.24 3.21 8.13 
found 63.01 6.13 2.98 7.94 
______________________________________ 
Pharmacological Study of the Compounds of the Invention 
EXAMPLE 16 
Receptor profile of the compounds of the invention 
The interaction of these compounds with various receptors was determined 
using standard binding studies as described by M. J. Millan et al. (J. 
Pharmacol. Exp. Ther., 268, 337-352, 1994 and Drug News & Perspectives, 5, 
397-406, 1992). The receptor profile of the compounds of the invention is 
presented in the table below. The affinities of the compounds are 
expressed as pKi. 
______________________________________ 
Receptor Profile (pKi) 
Examples D.sub.1 
D.sub.2 5-HT.sub.1A 
5-HT.sub.2A 
5-HT.sub.2C 
.alpha..sub.1 
______________________________________ 
ex. 2 6.60 7.36 8.31 8.40 8.10 8.61 
ex. 5 6.56 7.33 8.32 8.48 8.03 8.19 
ex. 6 6.69 7.27 8.44 8.62 8.18 8.93 
ex. 7 NT 7.27 8.77 7.66 7.03 NT 
ex. 8 NT 6.59 8.41 7.88 7.02 NT 
Haloperidol 
7.39 8.73 5.55 7.08 5.24 8.01 
Clozapine 
6.74 6.65 6.53 7.63 8.06 8.22 
______________________________________ 
NT = not tested 
EXAMPLE 17 
Antipsychotic properties 
Two well-established tests were used in order to determine the 
antipsychotic properties of the compounds of the invention, in which tests 
all of the antipsychotic agents are clinically active, as has been shown 
by A. Y. Deutch et al. (Schizophrenia Research, 4, 121-156, 1991) and A. 
A. Mengens et al. (J. Pharmacol. Exp. Ther., 260, 160-167, 1992): 
verticalization inhibition induced by a dopaminergic agonist: apomorphine 
(according to the procedure described by P. Protais et al., 
Psychopharmacol., 50, 1-6, 1976), 
motor activity inhibition induced by amphetamine (which increases the 
release of catecholamines) according to the procedure described by A. A. 
Mengens, cited above. 
An activity in these tests appears to reflect blocking of the mesolimbic 
dopaminergic pathways, which are believed to be hyperactive in 
schizophrenics, as described by P. C. Waldmeier et al. (Eur. J. 
Pharmacol., 55, 363-373, 1979) and A. Y. Deutch, cited above. The 
activities of the compounds of the invention were compared with those of 
haloperidol and of clozapine. 
Verticalization Test using Apomorphine in Mice 
The experiment was performed on male CF (Charles River) mice of average 
weight 25 g. thirty minutes before the start of the test, each mouse was 
placed in a cylindrical cage (O12 cm 14 cm), with vertical metal bars and 
a smooth plastic lid, after having received a subcutaneous injection of 
solvent or of product. At T.sub.0, a solution of apomorphine (0.75 mg/kg) 
or of physiological saline was administered subcutaneously to the animal, 
which was returned to the barred cage. At T.sub.10 (10 minutes) and at 
T.sub.20 (20 minutes), a score was attributed to each animal after 
observation for approximately one minute: 
score 0 (4 feet on the floor); 
score 1 (animal raised on hind legs, forefeet on the vertical bars); 
score 2 (animal gripping on to the bars with all 4 feet). 
The total score of the 2 measurements then represents the verticalization 
value of the animal, which is used for the statistical analysis. 
Test of the Motor Activity Induced by Amphetamine 
Male Wistar rats (200-220 g) were placed in transparent polycarbonate 
individual cages the night before the test. The locomotor activity was 
recorded using photoelectric cells (Systeme Lablinc, Coulbourn) connected 
via an interface to a microcomputer. There are two transverse banks of 
photoelectric cells per cage. The test takes place under artificial light, 
starting from 1.00 p.m., during daylight hours. The product or solvent was 
administered to the animal subcutaneously, 30 minutes before the start of 
the test. At T.sub.0, the animal received an intraperitoneal injection of 
physiological saline or of D-amphetamine (2.5 mg/kg): the motor activity 
of the animal (small and large movements) was recorded continuously for 1 
hour, from T.sub.0 to T.sub.60. 
The results of these two tests are presented in the table below: 
______________________________________ 
Verticalization 
Locomotion 
(Apomorphine) (Amphetamine) 
DI.sub.50 
(95% L.C.) DI.sub.50 
(95% L.C.) 
Examples (mg/kg) (mg/kg) (mg/kg) 
(mg/kg) 
______________________________________ 
Ex. 2 0.28 (0.17-0.47) 
2.17 (1.44-3.28) 
Ex. 5 0.26 (0.12-0.57) 
2.80 (1.51-5.18) 
Ex. 6 0.25 (0.15-0.41) 
1.94 (1.05-3.60) 
Ex. 7 0.41 (0.04-3.99) 
NT 
Ex. 8 (*) 
.apprxeq.0.63 NT 
Haloperidol 
0.013 (0.008-0.022) 
0.043 (0.03-0.06) 
Clozapine 
2.22 (1.70-2.90) 
12.85 (9.25-17.86) 
______________________________________ 
ID.sub.50 (95% C.L.) = Inhibitory Dose.sub.50 (95% Confidence Limits) 
NT = not tested 
(*) The precise value could not be determined 
EXAMPLE 18 
Catalepsy in rats 
In order to determine the potential of the compounds of the invention to 
generate a syndrome of extrapyramidal type, the capacity to induce a 
catalepsy in rats was examined. This phenomenon is due to an antagonism of 
the nigrostriatal dopaminergic transmission. The activities of the 
compounds were compared with those of haloperidol and clozapine. 
Procedure 
Male Wistar rats (220-240 g) were placed in individual cages and food was 
witheld the night before the test. The test used to evaluate the 
cataleptogenic properties of a product consists in placing each of the 
animal's hind feet on the forefoot located on the same side and in 
measuring the time in seconds for which the animal kept this "crossed 
feet" position, up to 30 seconds, as described by P. C. Waldmeier et al. 
(Eur. J. Pharmacol., 55,363-373, 1979). Each animal underwent three tests, 
at intervals of one minute; the average value of the three tests then 
represents the catalepsy time of the animal, which is used for the 
statistical analysis. The product to be tested was administered to the 
animal subcutaneously, 30 minutes before the test. 
The results of the induction of catalepsy in rats are presented in the 
table below. 
The effective cataleptogenic dose ED.sub.5.sbsb.0 is that which induces 
catalepsy for an average duration of 15 seconds, that is to say for 50% of 
the maximum duration of the test (30 seconds). 
______________________________________ 
Induction of the catalepsy 
Examples DE.sub.50 (mg/kg) 
(95% C.L.) (mg/kg) 
______________________________________ 
Ex. 2 &gt;40.0 
Ex. 5 &gt;40.0 
Ex. 6 &gt;40.0 
Haloperidol 0.156 (0.05-0.38) 
Clozapine &gt;40.0 
______________________________________ 
ED.sub.50 (95% L.C.) = Effective Dose.sub.50 (95% Confidence Limits) 
EXAMPLE 19 
Pharmaceutical composition 
Preparation formula for 1000 tablets containing a 0.1 mg dose 
______________________________________ 
Compound of Example 2 100 mg 
Hydroxypropylcellulose 2 g 
Wheat starch 10 g 
Lactose 100 g 
Magnesium stearate 3 g 
Talc 3 g 
______________________________________