FR2717807A1 - New amino-alkyl benzo-thiazoline-ones bind to sigma receptors - Google Patents

Abstract

Aminoalkyl benzothiazolinones of formula (I), their optical isomers, and their acid and base addn. salts, are new. R1 = H or opt. substd. alkyl; R2 = -(CH2)3-N(R3)R4 (gp.R21), or a gp. of formula (R22); R3, R4 = H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl or -(CH2)m-aryl (opt. substd. on aryl by one or more halo, hydroxy, alkyl (opt. substd. by one or more halo) or lower alkoxy); m = 0-4; or NR3R4 = a 5-9 atom heterocyclic gp., opt. contg. further heteroatoms (O or S) (opt. substd. by one or more alkyl), or form a 4-(methoxyphenyl)-piperazin-1-yl gp.; n = 2-4; R5, R6 = H or halo; alkyl and alkoxy are 1-6C; alkenyl and alkynyl are 2-6C; aryl = phenyl or naphthyl; cycloalkyl is 3-8C.

Description

I

  The present invention relates to novel 6 - [(4-arylalkyl- 1-

  piperazino) alkyl] benzothiazolinones, process for their preparation and compositions

  pharmaceuticals that contain them.

  Patent application EP 478 446 describes 6- [(4-aryl-1-

  piperazino) alkyl] benzothiazolinones as well as 6- [4- (2,3,4trimethoxybenzyl) -1-

  piperazinoalkyl) benzothiazolinones of interest as antipsychotics.

  The Applicant has now discovered that new 6 - [(4arylalkyl-1-

  piperazino) alkyl] benzothiazolinones had an affinity on average 100 times higher

  for the sigma receptors to that of the derivatives of application EP 478 446.

  The very high affinity of the derivatives of the invention for the sigma receptors a, clearly greater than that obtained with the derivatives of application EP 478 446 makes them usable in the prevention and treatment of diseases linked to this type of receptors, namely psychiatric diseases, such as anxiety psychosis, depression, neuronal protection, memory impairment, cerebral circulatory failure in the elderly, Alzheimer's disease, inflammatory immune-type diseases such as arthritis and

  intestinal peristalsis disorders.

  Furthermore, the high selectivity of the derivatives of the present invention for sigma receptors, in particular their lack of affinity for D2 receptors, allows their use in therapy with increased safety. In particular, the side effects of the extrapyramidal type which are encountered during treatment with products with a high D2 component, to which these effects are attributed, are not found with the products of the invention which are on average 100 to 1000 times less affinity for D2 receptors than the derivatives of application EP 478 446. On the balance sheet, the products of the present invention have a selectivity ratio (sigma receptor affinity): (D2 receptor affinity) from 000 to 100,000 times greater than that obtained with the derivatives of application EP 478 446 which is completely unexpected given the slight structural differences existing between the derivatives of the invention and those of application EP 478 446 which considerably improves their safety in use. More particularly the present invention relates to the derivatives of formula (I): CH3

N R

O = C,

S 3 (CH2-CH2) n-N N-CH-

N R1

  n is 1 or 2, identical R1 and R2 represent a hydrogen or chlorine atom

  and their addition salts with a pharmaceutically acceptable acid.

  The invention also extends to the process for the preparation of the compounds of formula (I) in which a derivative of formula (II) is condensed CH3 NO = C s (10 S (CH2-CH2) n-Hail has the same meaning as in formula (I) and Hal represents a halogen atom, with a derivative of formula (111): R,

H-N N- CH2 -R2

H 2R

  o R1 and R2 have the same meaning as in formula (I) to obtain a derivative of

  formula (I) which is salified if desired with a pharmaceutically acceptable acid.

  Among the pharmaceutically acceptable acids which can be used to form an addition salt with the compounds of the invention, there may be mentioned by way of example and without limitation, hydrochloric, sulfuric, phosphoric, tartaric acids, malic, maleic, fumaric, oxalic, methanesulfonic, ethanesulfonic, camphoric and citric. Preferably, the invention relates to the following derivatives: - 3-methyl 6- [2- (4-benzylpiperazin-1-yl) ethyl] benzothiazolinone - 3-methyl 6- [2- (4- (2,4-dichlorobenzyl ) piperazin-1-yl) ethyl] benzothiazolinone - 3-methyl 6 [2- (4- (3,4-dichlorobenzyl) piperazin-1-yl) ethyl] benzothiazolinone - 3methyl 6- [4- (4-benzylpiperazin-1 -yl) butyl] benzothiazolinone - 3- methyl 6- {4- [4- (2,4-dichlorobenzyl) piperazin-1 - yl] butyl} benzothiazolinone 3-methyl 6- {4- [4- (3,4dichlorobenzyl) piperazin-1-yl] butyl} benzothiazolinone

  as well as their addition salts with a pharmaceutically acceptable acid.

  The raw materials used in the process described above are easily accessible to those skilled in the art according to processes well known in the literature. Reference will be made more particularly, for the compounds of formula (II), to the

  description of patent application EP 478 446.

  The compounds of formula (I) have interesting pharmacological properties.

  The very high affinity of the derivatives of the invention for the receptors o makes them usable in the treatment of motor disorders such as dystonia (Walker, JM: Drug specificity of pharmacology dystonia, Pharmacol. Biochem. Bechem. 1990, 3 151), tardive dyskinesia (Lindstrom, LH: Acta Psychiatr. Scand. 1988, 77. 1122), psychiatric disorders (Chouinard, F., Annable, L. Psychopharmacology 1984, 84, 282), and disorders such as damage related to ischemia and shock (Pontecorvo, MJ, Brain Res. Bull. 1991, 26, 461), cerebral circulatory failure, Alzheimer's disease, memory impairment, vomiting, regulation of phenomena immune systems (Carroll, Fl, Med. Chem. Res. 1992, 2, 3), treatment for cocaine addiction (Abou-Gharbia, M., Academic. Press. Inc. Bristol. J. Ed. Publisher. 1993, 28, 1), diagnosis and localization of tumors (Hudzik, TJ, Psychopharmacology. 1992, 10, 115 Abou Ghar bia, M., Academic, Press. Inc. Bristol. J. Ed. Publisher 1993, 2. 1). (Hudzik, T.J., Eur. J. Pharmacol. 1993, 236, 279)), inflammatory diseases of immune origin,

  as well as intestinal motility disorders.

  The present invention also relates to pharmaceutical compositions containing the compounds of formula (I) or, where appropriate, one of their addition salts with a

  pharmaceutically acceptable acid in combination with one or more excipients.

  Among the pharmaceutical compositions according to the invention, there may be mentioned, more particularly those which are suitable for oral, parenteral, nasal, per or transcutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets , sachets, packages, capsules, lollipops, tablets, suppositories, creams, ointments, dermal gels,

  and oral or injectable ampoules.

  The dosage varies according to the age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges from 0.01 mg to 100 mg per 24 hours in 1 or 2 doses, more specifically 0.1 to 10 mg,

  The following examples illustrate the invention and do not limit it in any way.

  The 1H nuclear magnetic resonance spectra were performed using TMS (tetramethylsilane) as an internal reference. Chemical shifts are expressed in parts per million (p.p.m.). The infrared spectra were performed in the form

  of potassium bromide tablet containing approximately 1% of the product to be analyzed.

  EXAMPLE 1 3-METHYL-6- [2- (4- BENZYLPIPERAZIN-1- DICHLORHYDRATE)

YL) ETHYL] BENZOTHIAZOLINONE

  Reagents: 3-methyl 6- (2-bromoethyl) benzothiazolinone: 0.0074 mole (2 g) 4-benzylpiperazine: 0.0074 mole (1.30 cm3) Potassium carbonate: 0.029 mole (4 g) Anhydrous dimethylformamide: 50 cm3 Procedure: In a 250 cm3 necked flask fitted with a condenser and containing 30 cm3 of anhydrous dimethytformamide, introduce 0.0074 mole of 4-benzylpiperazine and 0.029 mole of potassium carbonate. Heat at reflux for thirty minutes, then add 0.0074 mole of 3-methyl-6- (2-bromoethyl) benzothiazolinone in solution in 20

cm3 of dimethylformamide.

  Heat the reaction mixture for 12 hours. Leave to cool and wring out the mineral precipitate. Pour the filtrate into 30 cm3 of distilled water and acidify. Let shake

  during 30 minutes. Extract with ethyl acetate to remove the residual raw material.

  The aqueous phase is immediately alkalized.

  Extract the organic phase with ethyl acetate. Combine the organic fractions and

  dry the whole, filter then evaporate in a water bath under reduced pressure.

  Take up the residue with 50 cm3 of absolute alcohol, bubbling acid

  hydrochloric gas, drain the precipitate formed and recrystallize it.

  Molecular mass: 440.36 g mole-1 for C21 H27CI2N3OS Yield 45% Melting point (hydrochloride):> 270 C Recrystallization solvent: Absolute alcohol Elemental analysis:

% C% H% N

  Calculated: 57.27 6.18 9.54 Found: 57.31 6.15 9.50 Infrared spectrometry: 2900 cm-1 v CH (alkyls) 2340 cm-1 v NH + (hydrochloride) 1690 cm -1 v CO (NCOS) 1600 cm-1 v C = C (aromatics) Nuclear magnetic resonance spectrometry (80MHz; DMSO, d6): 3 = 2.80-3.14 ppm (solid, 12H) ethyl and piperazine 3 = 3.40 ppm (singlet, 3H) NCH3 ô = 4.10 ppm (singlet, 2H) CH_2-C6H5 3 = 7.20-7.70 ppm (solid, 8H) Aromatic H = 11.00 ppm (signal, 2H) 2NH + exchangeable in D20

  EXAMPLE 2 DICHLORHYDRATE 3-METHYL-6- [4- (4-BENZYLPIPERAZIN-1-YL) BUTYL]

BENZOTHIAZOLINONE

  Reagents: 3-methyl-6- (4-bromobutyl) benzothiazolinone: 0.01 mole (3 g) 4benzylpiperazine: 0.01 mole (1.80 cm3) potassium carbonate: 0.04 mole (5.5 g) Dimethylformamide anhydrous: 45 cm3 Procedure: it is identical to that used in Example 1 as a replacement, ant 3-methyl

  6- (2-bromoethyl) benzothiazolinone with 3-methyl 6- (4bromobutyl) benzothiazolinone.

  Molecular mass: 468.42 g.mole-1 for C23H31 CI2N30S Yield 55% Melting point (hydrochloride):> 250 C Recrystallization solvent: Absolute alcohol Elemental analysis:

% C% H% N

  Calculated: 58.97 6.67 8.97 Found: 58.59 6.72 8.96 Infrared spectrometry: 3400-2320 cm-1 v NH + (hydrochloride) 3040-2840 cm'1 v CH ( alkyles) 1670 cm-1 v CO (NCOS) 1600 cm-1 v C = C (aromatic) Nuclear magnetic resonance spectrometry (80MHz; DMSO, d6): = 1.70 ppm (solid, 4H) CH2- H2: - H2-CH2 = 2.00-2.75 ppm (solid, 4H) H 2-CH2-CH2-CH2 = 3.20-3.70 ppm (solid, 11H) NCH3 and piperazine ô = 6.90-7 , 40 ppm (solid, 8H) Aromatic H

  EXAMPLE 3: 3-METHYL-6- DICHLORHYDRATE {2- [4-2,4-DICHLOROBENZYL)

  PIPERAZIN-1-YL) ETHYL] BENZOTHIAZOUNONE

  Reagents: 3-methyl 6- (2-bromoethyl) benzothiazolinone: 0.0073 mole (2 g)

  2,4-dichlorobenzyl dihydrochloride

  piperazine: 0.0073 mole (2.3 g) Triethylamine: 0.0150 mole (2 cm3) Anhydrous acetone: 70 cm3

  Procedure: it is identical to that used in Example 1 instead, erasing the 1-

  benzylpiperazine with 1- (2,4-dichlorobenzyl) piperazine Molecular mass: 509.26 g.mole-1 for C21H25Cl4N3OS Yield: 60% Melting point (hydrochloride):> 250 C Recrystallization solvent: Absolute alcohol Elemental analysis:

% C% H% N

  Calculated: 49.52 4.94 8.25 Found: 49.37 5.05 8.27 Infrared spectrometry: 2940 cm'1 v CH (alkyls) 2620-2180 cm'1 v NH + (hydrochloride) 1700 cm-1 v CO (NCOS) 1580 cm'1 v C = C (aromatic) Nuclear magnetic resonance spectrometry (300MHz; DMSO, d6): 6 = 3.60 ppm (multiplet, 2H) CH -C6 H3-Cl2 6 = 3.70 ppm (singlet, 3H) NCH3 a = 7.20-7.70 ppm (solid, 6H) H aromatic ô = 8.70 ppm (signal, 1H) NH + exchangeable in D20 = 10.85 ppm (signal, 1 H) NH + exchangeable in D20

  EXAMPLE 4 3-METHYL-6- DICHLORHYDRATE {4- [4- (2,4-DICHLOROBENZYL)

  PIPERAZIN-1-YL) BUTYL] BENZOTHIAZOUNONE

  Reagents: 3-methyl 6- (4-bromobutyl) benzothiazolinone: 0.0066 mole (2 g)

  2,4-dichlorobenzyl dihydrochloride

  piperazine: 0.0066 mole (2.1 g) Triethylamine: 0.0132 mole (1.80 cm3) Anhydrous acetone: 50cm3

  Procedure: it is identical to that used in Example 2, replacing 1-

  benzylpiperazine with 1- (2,4-dichlorobenzyl) piperazine Molecular mass: 537.31 g.mole-1 for C23H29CI4N3OS Yield: 42% Melting point (hydrochloride): 257-259 C Recrystallization solvent: Absolute alcohol Elemental analysis:

% C% H% N

  Calculated: 51.41 5.44 7.82 Found: 51.27 5.36 7.78 Infrared spectrometry: 3400-2360 cm'1 v NH + (hydrochloride) 3040-2840 cm-1 v CH ( alkyles) 1680 cm-1 v CO (NCOS) 1580 cm-1 v C = C (aromatic) Nuclear magnetic resonance spectrometry (80MHz; DMSO, d6): = 4.25 ppm (singlet, 2H) H.2-C6 H3-C12 = 7.00-8.00 ppm (solid, 6H) Aromatic H, = 11.50 ppm (signal, 2H) 2NH + 6 changeable in D20

  EXAMPLE 5: 3-METHYL-6- {2- [4- (3,4-DICHLOROBENZYL) PIPERAZIN-1-YL)

ETHYL] BENZOTHIAZOLINONE

  Reagents: 3-methyl 6- (2-bromoethyl) benzothiazolinone: 0.0073 mole (2 g)

  3,4-dichlorobenzyl dihydrochloride

  piperazine: 0.0073 mole (2.1 g) Potassium carbonate: 0.029 mole (4 g) Anhydrous acetone: 50 cm3

  Procedure: it is identical to that used in Example 2 instead, erasing the 1-

  benzylpiperazine with 1- (3,4-dichlorobenzyl) piperazine Molecular mass: 509.26 g.mole-1 for C21H25CI4N3OS Yield: 56% Melting point (hydrochloride):> 250 C Recrystallization solvent: Absolute alcohol Elemental analysis:

% C% H% N

  Calculated: 49.52 4.94 8.25 Found: 49.37 5.05 8.27 Infrared spectrometry: 2900 cm-1 v CH (alkyls) 2300 cm-1 v NH + (hydrochloride) 1700 cm -1 v CO (NCOS) 1590-1570 cm-1 v C = C (aromatic) Nuclear magnetic resonance spectrometry (80MHz; DMSO, d6): = 2.80-3.15 ppm (solid, 12H) ethylpiperazine = 3 , 40 ppm (singlet, 3H) NCH3 = 4.10 ppm (singlet, 2H) CH2-C6 H3-CI2 8 = 7.20-7.70 ppm (solid, 6H) Aromatic H, 5 = 11.00 ppm ( signal, 2H) 2NH + exchangeable in D20

  EXAMPLE 6 3-METHYL-6- DICHLORHYDRATE {4- [4- (3,4-DICHLORO-

  BENZYL) PIPERAZ! N-1-YL) BUTYL] BENZOTHIAZOUNONE

  Reagents: 3-methyl 6- (4-bromobutyl) benzothiazolinone: 0.0033 mole (1 g)

  3,4-dichlorobenzyl dihydrochloride

  piperazine: 0.0033 mole (1 g) Potassium carbonate: 0.0132 mole (1.8 g) Anhydrous acetone: 40 cm3

  Procedure: it is identical to that used in Example 2, replacing 1-

  benzylpiperazine with 1- (3,4-dichlorobenzyl) piperazine Molecular mass: 537.31 g.mole-1 for C23H29C14N30S Yield: 45% Melting point (hydrochloride):> 250 C Recrystallization solvent: Absolute alcohol o10 Elemental analysis:

% C% H% N

  Calculated 51.41 5.44 7.82 Found 51, 30 5.43 7.75 Infrared spectrometry: 3400-2360 cm-1 v NH + (hydrochloride) 3040-2960 cm-1 v CH (alkyls) 1670 cm-1 v CO (NCOS) 1600 cm-1 v C = C (aromatic) Nuclear magnetic resonance spectrometry (80MHz; DMSO, d6): = 1.40-1.80 ppm (solid, 4H) CH2-C H2- CH2 ô = 4.20 ppm (singlet, 2H) H-C6 H3-C12 ô = 7.00-8.00 ppm (solid, 6H) Aromatic H ô = 11.25 ppm (signal, 2H) 2NH + exchangeable in D20

  PHARMACOLOGICAL STUDY OF THE DERIVATIVES OF THE INVENTION

  EXAMPLE A: STUDY OF ACUTE TOXICITY

  Acute toxicity was assessed after oral administration to groups of 8 mice (26 + 2 grams) with a dose of 100 mg.kg'1 of the compounds of the invention. The animals were observed at regular intervals during the first day and daily during

  two weeks after treatment.

  It appears that the compounds of the invention are completely non-toxic. They do not cause any death after administration at a dose of 100 mg. kg-1 and there are no disturbances

  after administration of this dose.

  EXAMPLE B: IN VITRO AFFINITY RECEPTOR REPORT

  The products are tested on each receptor at 5 different concentrations (10-5M, -6M, 10-7M, 10-8M, 10-9M) in triplicate. When the binding coefficient IC50 is less than a concentration of 10-6M, the Ki is measured using 12 concentrations of the product. 1v The table below groups together the receptors for which the affinity of the compounds of the invention has been determined, the tissue chosen, the concentration used to determine the

  non-specific and the radioligand used to mark the receptor.

  Radioligand receptor Non-tissue or specific site -HT1A 8- OH DPAT 105M Hippocampus Buspirone -HT1 B [3H] 10-5M Rat brain Cyanopindolol Cold serotonin -HT1 C N-methyl 10-5M Front cortex mesulergin Mianserin Hippocampus -HT2 [3H ] 10-5M Ketanserin frontal cortex Spiperone -HT3 [3H] 10-5M Rat ileum Quipazine Zacopride Paoi [3H] 105M Rat brain Prazosine Phentolamine a2 [3H] 10-5M Rat brain Rauwolscine Yohimbine D1 [3H] 10M Striatum de rat SCH 23390 Butaclamol D2 [3H] 10-6M Striatum of rat Raclopride Haloperidol Ml [3H] 10-5M Cortex Telenzepine Atropine H1 [3H] 10M Cortex of calf Pyrilamine Chlorpheniramine [3H] DTG 10-6M 3-PPP Calf hippocampus Test results have shown that the compounds of the invention are powerful and selective a receptor ligands. By way of comparison, the derivatives of the present invention have an affinity 100 to 1000 times more powerful than the derivatives of application EP 478 446 for the sigma receptor, and more particularly examples 28 to 32 and 172 of

  this application structurally closest to those of the present invention.

  Furthermore, the derivatives of the present invention are also much more selective than the derivatives of application EP 478 446. In particular, they are 100 to 1000 times

  less affinity for D2 receptors than the derivatives of application EP 478 446.

  EXAMPLE C ANTAGONISM OF HYPERMOTILITY INDUCED BY

AMPHETAMINE

  Groups of 10 NMRI-CERJ mice are injected intraperitoneally (IP) with 4 mg kg-1 of d-amphetamine immediately after the IP injection of the test compound, and the

  mouse in an actimeter for 30 minutes.

  The number of photocell interruptions is counted, as is the

stereotypical behavior.

  The activity of the compounds tested is expressed as a percentage of the antagonism of hyperactivity induced by amphetamine. The compounds of the invention are powerful antagonists of amphitamine-induced hypermotility, which makes it possible to conclude that

  activity in central nervous system disorders for the products of the invention.

  EXAMPLE D: SEARCH FOR CATALEPSIGENIC EFFECT

  The catalepsigenic effect is sought in rats by the intraperitoneal route. This test is predictive of the existence of side effects of the extrapyramidal type. 6 groups of Wistar rats received an injection of the compounds of the invention and are then tested for their

  catalepsigenic activity 30 minutes apart. Haloperidol is used as a reference.

  The results show that the compounds of the invention have a very low catalepsigenic power compared to haloperidol which produces, at a dose of 2 mg.kg'1, a catalepsigenic effect of 95% under the same study conditions. This result confirms the absence of side effects of the extrapyramidal type of the products of the invention which could be

  expected following the results of bindings (example B).

  EXAMPLE E: STUDY OF THE ANTIDEPRESSIVE ACTIVITY OF THE COMPOUNDS

THE INVENTION

PRINCIPLE:

  The study of the products is carried out on the model of learned renunciation which consists in inducing in animals, by a series of uncontrollable aversive events, a deficit during

  subsequent avoidance tasks.

PROTOCOL:

  This test was developed by Sherman A.D., Sacquitne J.L., and Petty F. (Pharmacol.

  Biochem. Behav., 1982, 16, 449-454). We use male Wistar rats weighing between 180 and 200 grams. The animals are kept in the pet store one week before the test, in plastic boxes, in groups of 10, at room temperature

  from 21 C + 1 0 C, with free access to water and food.

  The animals are then isolated in small boxes and are subjected to 60 inevitable electric shocks (0.8 mA every minute + 15 seconds). A group of rats

  witnesses does not receive electric shocks.

  0 The animals' ability to perform avoidance training (passage from one compartment to another, in order to avoid electric shock) is assessed 48 hours after and for 3 consecutive days. During the training sessions, the animals undergo 2 tests per minute for 15 minutes. The number of escape failures is noted for each rat. The animals are treated (i.e. 0.5 cm 3/100 g) on an empty stomach 6 hours after the inevitable shocks and 4 days in a row, in the morning 30 minutes before the training session and in the evening between 6 and 7 p.m.

  The products studied are dissolved in distilled water.

  The products studied are administered at doses of 0.05 mg.kgl / day.

RESULTS:

  The test proves that the products of the invention significantly reduce the number of escape failures, which translates, for certain products of the invention, a strong

antidepressant type activity.

  EXAMPLE F: STUDY OF ANXIOLYTIC ACTIVITY - TESTING OF CAGES

CLEAR / DARK MOUSE

PRINCIPLE:

  We propose to study the anxiolytic effects of the compounds of the invention,

  using the light / dark cage test in mice.

PROTOCOL:

  This test was developed by Crawley et al. (1981, Pharmacol. Biochem. Behav.),

  then modified and behaviorally validated.

  These are two cages of equal size (20 X 20 X 14 cm) in PVC. One is strongly lit by a 100 W lamp ('cold "light), the other is dimmed. The two cages are separated from each other by means of a small opaque tunnel (5 X 7 cm The mice are individually introduced into the dark cage, the time spent by the animals in the cell is recorded by means of keyboards connected to a computer.

  lit cage as well as the number of transitions between the obscure cage and the lit cage.

  Each experimental group includes at least 15 animals.

RESULTS:

  The administration, by the intraperitoneal route of certain products of the invention leads to an increase in the time spent by the mice in the lit cage and in the number of

  transitions between the dark cage and the lit cage.

  This significant increase in the two parameters studied shows the

  remarkable anxiolytic activity of certain compounds of the invention.

  EXAMPLE G: SEARCH FOR AN ANTIARTHRMIC TYPE ACTIVITY IN

THE RAT

  Groups of 5 male or female Lewis rats weighing 130 to 150 g are used.

  A suspension of 0.3 mg of Mycobacterium tuberculorsis killed in 0.1 ml of mineral oil (complete Freund's adjuvant, CFA) is administered in the subplant of the right hind paw on Day 1. The volumes of the hind paws are measured by displacement of water on Days 0, 1, 5, 14 and 18. The rats are weighed on days 0 and 18. The products to be tested are placed in suspension in carboxymethyl cellulose and

  administered orally for 5 consecutive days from days 1 to 5.

  In parallel, a control group is used in order to eliminate the artifacts resulting from the handling of the animals. A group treated with a reference product allows validation

of the test.

  The products of the invention at a dose of 10 mg / kg-1 allow inhibition of the increase in the volume of the paw in the delayed phase of the inflammation (Days 14 to

18).

  EXAMPLE H PHARMACEUTICAL COMPOSITION FOR TREATMENT

  DISORDERS OF THE CENTRAL NERVOUS SYSTEM

  Tablets containing 0.1 mg of 3-methyl 6- [2- (4-benzylpiperazin-1- yl) ethyl] benzothiazolinone Formula for 10,000 tablets: 3-methyl 6- [2- (4-benzylpiperazin-1-yl ) ethyl] benzothiazolinone ....... 1 g Wheat starch .................................. .................................

  .......... 75 g Corn starch ................................... ........ DTD: ................................. 75 g Lactose .... ....................... DTD: ......................... .................................... 325 g Magnesium stearate ......... ............................................ .DTD: ... ........ 10 g Silica ....................................... ............ DTD: .................................... ....... 5 g Hydroxypropyl cellulose ....................................... ......................... .10 g..DTD:

Claims (10)

  1. Compounds of formula (I): CH3 1R O CN S L (CH2-CH2) n-N \ / NCH2 R2 v-J o n is 1 or 2, identical R1 and R2 represent a hydrogen or chlorine atom   and their addition salts with a pharmaceutically acceptable acid.   2. Compound according to claim 1 which is 3-methyl 6- [2- (4benzylpiperazin-1-   yl) ethyl] benzothiazolinone, as well as its addition salts with a pharmaceutically acid acceptable.   3. Compound according to claim 1 which is 3-methyl 6- {2- [4- (2,4-   dichlorobenzyl) piperazin-1-yl) ethyl] benzothiazolinone, as well as its addition salts with a   pharmaceutically acceptable acid.   4. Compound according to claim 1 which is 3-methyl 6- {2- [4- (3,4-   dichlorobenzyl) piperazin-1-yl) ethyl] benzothiazolinone, as well as its addition salts with a pharmaceutically acceptable acid.   5. A compound according to claim 1 which is 3-methyl 6- [4- (4benzylpiperazin-1-   yl) butyl] benzothiazolinone, as well as its addition salts with a pharmaceutically acid acceptable.   6. Compound according to claim 1 which is 3-methyl 6- {4- [4- (2,4-   dichlorobenzyl) piperazin-1-yl) butyl] benzothiazolinone, as well as its addition salts with a   pharmaceutically acceptable acid.   7. A compound according to claim 1 which is 3-methyl 6- {4- [4- (3,4-   dichlorobenzyl) piperazin-1-yl) butyl] benzothiazolinone, as well as its addition salts with a   pharmaceutically acceptable acid.   8. A process for the preparation of the compounds of formula I according to claim 1, in which a derivative of formula (II) CH NO = c: N '(10 S (CH2-CH2) n-Hai or has the same meaning as in formula (I) and Hal represents a halogen atom with a derivative of formula (111): R1 H-N N-CH 2S1   o R1 and R2 have the same meaning as in formula (I) to obtain a derivative of   formula (I) which is salified if desired with a pharmaceutically acceptable acid.   9. Pharmaceutical composition containing as active ingredient at least one compound   according to one of claims 1 to 7 in combination with one or more excipients or   inert, non-toxic, pharmaceutically acceptable vehicles.   10. Pharmaceutical composition according to claim 9 containing an active ingredient   according to one of claims 1 to 7 usable in the treatment of psychiatric illnesses   such as psychosis, anxiety depression, neuronal protection, memory impairment, cerebral circulatory failure in the elderly, Alzheimer's disease, diseases   immune-type inflammatory, arthritis, and intestinal peristalsis disorders.