The present invention relates to new heterocycle-substituted piperazines, to a process for preparing these and to pharmaceutical compositions containing them.

Some piperazinyl alkyl benzothiazolinonyl compounds have already been disclosed in the European Patent Application EP 0281309. The pharmacological results of these compounds have been recently published in J. Med. Chem., 1991, 34, 6, 1860-1866 and it appears that such compounds are potential atypical antipsychotic agents. This activity seems due to a high affinity to both serotoninergic and dopaminergic receptors. However it is well known that exist various subclasses of serotoninergic receptors, the most well known being 5HT1A, 5HT1B, 5HT2, 5HT3. It also exists various subclasses of dopaminergic receptors D1, D2 etc.

The pharmacological results of compound of European Patent 0281309 published in J. Med. Chem. 1991, 34, 4, 1860-1866 mainly indicate the binding to 5HT.sub.1 A, 5HT.sub.2 and D.sub.2 receptors. It is well known elsewhere that the pharmacological effects obtained when stimulation these two 5HT.sub.1 A and 5HT.sub.2 receptors are mainly the opposite ones. So, according to the publication J. Med. Chem. 1991, 34, 6, 1860-1866, it is suitable to obtain the stimulation of the 5HT.sub.1 A receptors (agonism) without the stimulation of 5HT.sub.2 receptors (antagonism), but the publication does not indicate if the compounds are agonists or antagonists of 5HT.sub.2 receptors.

Another way of obtaining compounds without such an inconvenient is to obtain compounds binding to 5HT.sub.1 A receptors without binding to 5HT.sub.2 receptors.

Surprisingly our compounds bind both to 5HT.sub.1 A and D.sub.2 receptors with an affinity which is a little better than compounds of European Patent Application EP 0281309 but, overall with a much greater selectivity concerning 5HT2 receptors. The selectivity of binding to 5HT.sub.1 A receptors in comparison with 5HT.sub.2 receptors is about for our compounds from 10 to 30 fold greater than for compounds of European Patent Applications EP 0281309.

The very high affinity and selectivity of the compounds of the invention for 5HT.sub.1 A serotoninergic receptors render them usable in the treatment of diseases of the serotoninergic system, and more especially depression, stress, anxiety and schizophrenia, at lower doses than the compounds of the prior art. This feature, combined with their low toxicity, renders the compounds of the invention usable with much greater safety than the compounds of the prior art, which is especially advantageous in view of the frailty of the populations at which this type of treatment is aimed.

More specifically, the present invention relates to the compounds of general formula (I): ##STR2## in which:

R.sub.1 represents hydrogen or lower alkyl,

n represents 1 or 2,

X represents CH.sub.2 or a single bond,

R.sub.2 and R.sub.3 together with the nitrogen atom which carries them, form a mono- or bicyclic heterocyclic system, each ring being five- or six-membered and optionally including in its carbon skeleton one or two hetero atoms selected from nitrogen, oxygen and sulfur, said ring being unsubstituted or substituted on a nitrogen atom present with a lower alkyl, phenyl, phenyl (lower alkyl), pyridyl, or pyrimidinyl group, or a phenyl group substituted with one or more lower alkyl, trifluoromethyl, or lower alkoxy groups or halogen atoms, or phenyl (lower alkyl) group substituted on the phenyl ring with one or more lower alkyl, trifluoromethyl or lower alkoxy groups or halogen atoms, or a pyridyl group substituted with one or more lower alkyl, trifluoromethyl or lower alkoxy groups or halogen atoms, their enantiomers, diastereoisomers and epimers as well as their addition salts with a pharmaceutically acceptable acid or a pharmaceutically acceptable base when R.sub.1 =H.

Among pharmaceutically acceptable acids, hydrochloric, sulfuric, tartaric, maleic, fumaric, oxalic, methanesulfonic, camphoric, ethanesulfonic and citric acids, and the like, may be mentioned without implied limitation. Among pharmaceutically acceptable bases, sodium, potassium and calcium hydroxides, as well as sodium, potassium and calcium carbonates, and the like, may be mentioned without implied limitation.

The invention also encompasses the process for preparing the compounds of general formula (I), wherein a derivative of formula (II): ##STR3## with Hal representing a halogen atom and R.sub.1 and X having the same definition as in the formula (I), and n' represents 1 or 3, is used as a starting material, which compound is treated with a trialkylsilane in an acid medium to yield a compound of formula (III): ##STR4## with X, R.sub.1, n and Hal as defined above, which is condensed with an amine of formula: ##STR5## with R.sub.2 and R.sub.3 having the same definition as above, to yield a compound of formula (I): ##STR6## with R.sub.1, X, n, R.sub.2 and R.sub.3 having the same definition as above, the isomers of which are separated, where appropriate, and purified if necessary by chromatography or crystallization, which compound of formula (I) may be, if so desired, salified with a pharmaceutically acceptable acid.

The compounds of formula (I) possess advantageous pharmacological properties.

Binding tests showed that the compounds of the invention behave as very potent ligands of 5-HT.sub.1 A receptors. This affinity is accompanied by a very great selectivity with respect to other receptors, in particular 5HT.sub.2, in contrast to the behavior observed with the compounds of the prior art.

The compounds of the invention are of low toxicity, and possess good activity in the pigeon conflict test, confirming the activity detected by binding.

The compounds of the invention hence find their application in the treatment of distress, anxiety, depression, schizophrenia, psychoses, dementia, senile dementia, aggressiveness, agitation and disorders.

The subject of the present invention is also pharmaceutical compositions containing as active principle at least one compound of general formula (I) or one of its addition salts with a pharmaceutically acceptable acid or, where appropriate, with a pharmaceutically acceptable base, alone or in combination with one or more non-toxic, inert excipients or vehicles.

Among the pharmaceutical compositions according to the invention, there may be mentioned, more especially, those which are suitable for oral, parenteral or nasal administration, simple or sugar-coated tablets, sublingual tablets, sachets, packets, hard gelatin capsules, sublingual preparations, troches, suppositories, creams, ointments, skin gels, and the like.

The dosage varies according to the patient's age and weight and the nature and severity of the condition, as well as the administration route. The latter may be oral, nasal, rectal or parenteral.

Generally speaking, single doses range between 0.05 and 30 mg for conditions affecting mental behavior and between 1 mg and 500 mg for the treatment of pain and of arterial hypertension, that is to say, taken in one to three doses per 24 hours.

The examples which follow illustrate the invention and in no way limit the latter.

The 1H nuclear magnetic resonance spectra were recorded using TMS (tetramethylsilane) as an internal reference. The chemical shifts are expressed in parts per million (ppm). The infrared spectra were run in the form of a potassium bromide disk containing approximately 1% of the product to be analyzed.

The preparations do not form part of the invention, but are useful for carrying out the synthesis of the compounds of the invention.

PREPARATION 1

6-(Bromoacetyl)Benzothiazolinone

210 g (1.60 mol) of aluminum chloride are introduced into a 500-cm.sup.3 ground-necked flask surmounted by a condenser, and 43 cm.sup.3 of dimethylformamide are then added dropwise and with magnetic stirring via a dropping funnel. 30.2 g (0.2 mol) of benzothiazolinone are then added and, while the reaction medium homogenizes, the temperature is stabilized at 70.degree. C. using an oil bath. 19.8 cm.sup.3 (0.24 mol) of bromoacetyl chloride are then introduced gradually. After the addition, the mixture is left stirring for one hour at a temperature of 70.degree. C. The reaction medium is hydrolyzed by pouring it onto crushed ice and the precipitate obtained is drained, washed copiously with water and dried. The product is recrystallized in dioxane.

Yield: 65%.

Melting point: 235.degree. C. with decomposition.

PREPARATION 2

6-(2-Bromoethyl)Benzothiazolinone

In a 500-cm.sup.3 ground-necked flask surmounted by a condenser, and placed in an oil bath, 40.8 g (0.15 mol) of 6-(bromoacetyl)benzothiazolinone are dissolved in 90 cm.sup.3 of trifluoroacetic acid with magnetic stirring and while the temperature is stabilized at 60.degree. C. 52.7 cm.sup.3 (0.33 mol) of triethylsilane are introduced dropwise via a dropping funnel. After the addition, the heating is stopped and the mixture is then left stirring vigorously for 30 hours. The reaction medium is hydrolyzed by pouring it into ice-cold water, and the precipitate obtained is drained and washed with water until the filtrate is neutral and then with hexane. The product is dried and recrystallized in absolute ethanol.

Yield: 80%.

Melting point: 179.degree.-180.degree. C.

PREPARATION 3

3-Methylbenzothiazolinone

In a 2-liter flask, 75.6 g (0.5 mol) of benzothiazolinone are dissolved in a solution containing 20 g of sodium hydroxide (0.5 mol) in approximately 800 cm.sup.3 of water. The solution is filtered. With magnetic stirring, 47.5 cm.sup.3 of methylsulfate (0.5 mol) are introduced drop-wise with a dropping funnel. After the addition, the mixture is left stirring for 20 hours at room temperature. The medium is alkalinized with a slight excess of sodium hydroxide and left stirring for one hour. The precipitate obtained is drained and washed with water until the filtrate is neutral. The product is dried. It is recrystallized in propanol.

Yield: 88%.

Melting point: 72.degree.-74.degree. C.

PREPARATION 4

3-Methyl-6-(Bromoacetyl)Benzothiazolinone

210 g (1.60 mol) of aluminum chloride are introduced into a 500-cm.sup.3 ground-necked flask surmounted by a condenser, and 43 cm.sup.3 of dimethylformamide are then added dropwise and with magnetic stirring via a dropping funnel. 33 g (0.20 mol) of 3-methylbenzothiazolinone are then added and, while the reaction medium homogenizes, the temperature is stabilized at 70.degree. C. using an oil bath. 19.8 cm.sup.3 (0.24 mol) of bromoacetyl chloride are then added gradually. After the addition, the mixture is left stirring for one hour at a temperature of 70.degree. C. The reaction medium is hydrolyzed by pouring it onto crushed ice and the precipitate obtained is drained, washed with water until the filtrate is neutral and dried. The product is recrystallized in 95.degree. strength alcohol.

Yield: 66%.

Melting point: 164.degree.-165.degree. C.

PREPARATION 5

3-Methyl-6-(2-Bromoethyl)Benzothiazolinone

In a 500-cm.sup.3 ground-necked flask surmounted by a condenser and placed in an oil bath, 42.9 g (0.15 mol) of 3-methyl-6-(bromoacetyl)benzothiazolinone are dissolved in 77 cm3 of trifluoroacetic acid with magnetic stirring and while the temperature is stabilized at 60.degree. C. 52.7 cm.sup.3 (0.33 mol) of triethylsilane are introduced dropwise via a dropping funnel. After the addition, the heating is stopped and the mixture is left stirring vigorously for 30 hours. The reaction medium is hydrolyzed by pouring it into ice-cold water, and the precipitate obtained is drained and washed with water until the filtrate is neutral and then with hexane. The product is dried and recrystallized in cyclohexane.

Yield: 86%.

Melting point: 97.degree.-98.degree. C.

PREPARATION 6

7-(Bromoacetyl)Benzothiazinone

0.01 mol of 7-acetylbenzothiazinone, described in Am. Chem. Rome, is dissolved in 100 cm.sup.3 of methylene chloride. 0.011 mol of bromine is added dropwise and with stirring via a dropping funnel, and stirring is maintained for 13 hours. The mixture is filtered and evaporated to dryness and the residue is recrystallized.

PREPARATION 7

7-(2-Bromoethyl)-3-Oxo-2,3-Dihydro-1,4-Benzothiazine

This product is advantageously obtained either by catalytic hydrogenation of 7-(bromoacetyl)-3-oxo-2,3-dihydro-1,4-benzothiazine, in an acetic acid medium in the presence of palladinized charcoal, or by the action of trialkylsilane on this compound in a trifluoroacetic acid medium.

PREPARATION 8

6-(4-Bromobutyl)Benzothiazolinone

Using the procedure described in Preparation 2, but replacing 6-(bromoacetyl)benzothiazolinone by 6-(4-bromobutyryl)benzothiazolinone, the product of the title is obtained.

PREPARATION 9

3-Methyl-6-(4-Bromobutyl)Benzothiazolinone

Using the procedure described in Preparation 5, but replacing 6-(bromoacetyl)-3-methylbenzothiazolinone by 3-methyl-6-(4-bromobutyryl)benzothiazolinone, the product of the title is obtained.

EXAMPLE 1

3-Methyl-6-{2-[4-(2,3,4-Trimethoxybenzyl)-1-Piperazinyl])-Ethyl}Benzothiazo linone Dihydrochloride

5.4 g (0.02 mol) of 3-methyl-6-(2-bromoethyl)benzothiazolinone, dissolved beforehand in 150 cm.sup.3 of dioxane, followed by 5.9 g (0.022 mol) of trimetazidine and 1 g of triethylamine (0.01 mol), are introduced into a 250-cm.sup.3 ground-necked flask equipped with a reflux condenser. The mixture is heated to reflux with magnetic stirring for 96 hours. After cooling, the reaction mixture is drained and the filtrate is then evaporated on a water bath under vacuum. The residue is taken up with 5% HCl solution. The acidic aqueous phase is washed with ethyl acetate and then alkalinized with 10% sodium hydroxide solution. It is extracted with ether and the organic phase is washed with distilled water and then dried over calcium chloride. The organic phase is filtered and evaported to dryness on a water bath under vacuum. The residue is taken up in absolute ethanol, a stream of gaseous HCl is bubbled through and the product is drained and then dried. It is recrystallized in methanol.

Yield: 52%.

Melting point: 242.degree. C.

Molecular weight: 530.52 g/mol.

    ______________________________________
    Percentage composition:
    ______________________________________
    Calculated C 54.34 H 6.27     N 7.92
                                        Cl 13.37
    Found      C 53.80 H 6.20     N 7.79
                                        Cl 13.35
    ______________________________________

    ______________________________________
    Percentage composition:
    ______________________________________
    Calculated C 55.08 H 5.06     N 9.18
                                        Cl 7.74
    Found      C 54.98 H 5.12     N 9.03
                                        Cl 7.81
    ______________________________________

    ______________________________________
    Percentage composition:
    ______________________________________
    Calculated C 60.06 H 6.24     N 10.01
                                         Cl 8.44
    Found      C 60.15 H 6.24     N 09.88
                                         Cl 8.68
    ______________________________________

    ______________________________________
    Percentage composition:
    ______________________________________
    Calculated C 54.05 H 5.44     N 9.45
                                        Cl 15.96
    Found      C 54.11 H 5.45     N 9.48
                                        Cl 15.81
    ______________________________________

    ______________________________________
    Percentage composition:
    ______________________________________
    Calculated
              C 58.95      H 4.95  N 10.31
    Found     C 59.02      H 4.76  N 10.28
    ______________________________________

    ______________________________________
    Preparation formula for 1,000 tablets
    ______________________________________
    3-Methyl-6-{2-[4-(3-trifluoromethylphenyl)-1-
                                 2,5 g
    piperazinyl]ethyl}benzothiazolinone hydrochloride
    Wheat starch                 15 g
    Corn starch                  15 g
    Lactose                      65 g
    Magnesium stearate           2 g
    Silica                       1 g
    Hydroxypropylcellulose       2 g
    ______________________________________