FR2717806A1 - 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

! The present invention relates to novel aminoalkyls.

benzothiazolinones, their

  process for their preparation and the pharmaceutical compositions containing them.

  Patent application EP 478 446 describes (aminoalkyl) benzothiazolinone derivatives

  as antipsychotic, analgesic and anxyolitic agents.

  The Applicant has now discovered new aminoalkyl benzothiazolinones which surprisingly have an affinity for receptors

  sigma (c) much more intense than the derivatives of application EP 478 446.

  The very high affinity of the derivatives of the invention for the sigma A receptors, 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, cerebral circulatory insufficiency, memory disorders and Alzheimer's disease, inflammatory diseases of the immune type such as

  as arthritis, 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 job security.

  More particularly, the present invention relates to the derivatives of formula (I): R1 N o = c S v '(CH2) - N, R3 in which: - R1 represents a hydrogen atom or a lower alkyl group, the said group being unsubstituted or substituted, - R2 and R3 independently represent one of the other a hydrogen atom, an alkyl, cycloalkyl, alkenyl, alkynyl group, or a group - (CH2) n aryl in which n represents 1, 2, 3 or 4, the aryl group possibly being unsubstituted or substituted, or R2 and R3 together forming a heterocycle of 5 to 9 vertices rheterocycle being saturated and being able to contain other heteroatoms such as oxygen, or sulfur and being able to be unsubstituted or substituted ,

  it being understood that during the description of formula (I),

  - the substituted term associated with the aryl radical means that the substitution can be made by one or more radicals chosen from halogen, lower alkyl, lower alkoxy or trifluoromethyl, - the substituted term associated with the heterocycle formed by NR2R3 means that the substitution can be make with one or more radicals chosen from lower alkyl, - the terms' alkyl ',' alkenyl ',' alkoxy 'and' alkynyl designate linear or branched groups containing from 1 to 6 carbon atoms, the term aryl means phenyl or naphthyl , their optical isomers, where appropriate in pure form or as a mixture, and their addition salts with a pharmaceutically acceptable acid or when R1 represents a

  hydrogen their addition salts with a pharmaceutically acceptable base.

  Preferably, the invention relates to benzothiazolinone derivatives in

  which R2 and R3 together form a morpholino, piperidino and pyrrolidino ring.

  Preferably, the invention relates to the following compounds: 6-43-morpholinopropyl) benzothiazolinone, - 3-methyl 6- (3morpholinopropyl) benzothiazolinone, The invention also extends to the process for preparing the compounds of the invention, in which is introduced into a suitable solution a compound of formula (II) u Ri (11) NO = c I (l S (CH2) - Hal R23 in which R1 is as defined in formula (I) and Hal is an atom halogen, which is condensed with a compound of formula (II): iR2

H-N (III)

'$ (CH2) 3 N.

  R3 in which R2 and R3 are as defined in formula (1), to obtain a compound of formula (1): Ri N 0 t R2

S (CH2) - N

  R3 in which R1, R2 and R3 are as defined above, compounds of formula (1) which are, if desired, separated, where appropriate, into their different optical isomers in pure form or as a mixture, or salified with a pharmaceutically acceptable acid, or if R1 represents a hydrogen atom salified by a

pharmaceutically acceptable base.

  The raw materials used in the process described above are either commercial or 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 430 800.

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

  The very high affinity of the derivatives of the invention for 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,;. S 151 ), tardive dyskinesia (Lindstrom, LH: Acta Psychiatr. Scand. 1988, 77. 1122), psychotic disorders (Chouinard, F., Annable, L. Psychopharmacology 1984, 84, 282), and disorders such as damage linked to ischemia, cerebral circulatory insufficiency, memory disorders, Alzheimer's disease and shock states (Pontecorvo, MJ, Brain Res. Bull. 1991, 2, 461), regulation of immune phenomena ( Carroll, Fl, Med. Chem. Res. 1992, 2, 3), cocaine addiction treatment (Abou - Gharbia, M., Academic. Press. Inc. Bristol. J. Ed. Publisher. 1993, a 1 ), the diagonstic and the localization of the tumors (Hudzik, TJ, Psychopharmacology. 1992, 108. 115; Abou - Gharbia, M., Academic. Press Inc. Bristol. J. Ed. Publisher 1993, 2.1) and vomiting (Hudzik, T.J., Eur. J. Pharmacol. 1993, 236. 279), inflammatory diseases of immune origin as well

  that bowel motility disorders.

  The present invention also relates to pharmaceutical compositions containing the compounds of formula (I) or one of their addition salts with an acid or, where appropriate, with a pharmaceutically acceptable base, 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 0.1 mg to 1 g per 24 hours in 1 or 2 intakes, more specifically 1 to 100 mg, per

example 1 to 10 mg.

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

  The 1H nuclear magnetic resonance spectra were performed using TMS (tetramethylsilane) as an internal reference. The 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.

  The preparations are not part of the invention but are useful for carrying out the

  synthesis of the derivatives of the invention.

  PREPARATION 1: 6- (3-CHLOROPROPIONYL) BENZOTHIAZOUNONE

  Reagents: Benzothiazolinone 0.05 mole (7.55 g) 3-Chloropropionyl chloride 0.05 mole (4.77 cm3) Aluminum chloride 0.40 mole (52.50 g) Dimethylformamide 0.12 mole (9, 20 cm3) Procedure: In a flask with a ground neck surmounted by a water cooler, introduce 0.40 mole of aluminum chloride then, drop by drop and with magnetic stirring, 0.12 mole of

anhydrous dimethylformamide.

  Add 0.05 mole of benzothiazolinone and stabilize the temperature at 70 "C.

  homogenize the medium and slowly add 0.05 mole of 3chloropropionyl chloride.

  After addition, leave for one hour with stirring at 70 C. Pour the medium onto crushed ice, wring out the precipitate formed, wash it with water until the washings are neutral,

dry it and then recrystallize it.

  Molecular mass 241.69 g.mole-1 for C10H8CINO2S Melting point 174-177 C (decomposition) Yield 55% Recrystallization solvent Absolute ethanol

  PREPARATION 2: 6- (3-CHLOROPROPYL) BENZOTHIAZOUNONE

  Reagents: 6- (3-chloropropionyl) benzothiazolinone: 0.10 mole (24.16 g) Trifluoroacetic acid: 0.80 mole (61.60 cm3) Triethylsilane: 0.20 mole (32.00 cm3) Procedure:

  In a 250 cm3 neck-necked flask dissolve 0.1 mole of 6- (3-

  chloropropionyl) benzothiazolinone in 0.8 moles of trifluoroacetic acid. Using a dropping funnel, add 0.2 mol of triethylsilane dropwise and with magnetic stirring. Adapt a guard of calcium chloride and maintain agitation at temperature

  room for the time required.

  Pour the reaction mixture into 500 cm3 of ice water.

  Wring out the precipitate obtained, wash it with water until the washings are neutral,

dry and then recrystallize it.

  Reaction time: 50 hours Molecular mass: 227.71 g.mole-1 for C10H10CINOS Melting point: 131-133 C Yield: 86% Recrystallization solvent Toluene

  PREPARATION 3: 3-METHYL 6- (3-CHLOROPROPIONYL) BENZOTHIAZOLINONE

  Reagents: 3-Methylbenzothiazolinone 0.05 mole (8.25 g) 3-Chloropropionyl chloride 0.06 mole (5.72 cm3) Aluminum chloride 0.40 mole (52.50 g) Dimethylformamide 0.20 mole ( 9.20 cm3)

  Procedure: it is identical to that used to obtain the 6- (3-

  chloropropionyl) benzothiazolinone by replacing benzothiazolinone

with 3-methyl benzothiazolinone.

  Molecular mass: 237.27 g.mole'1 for C11H10CINO2S Melting point: 174-1770C Yield: 60% Recrystallization solvent: Absolute ethanol

  PREPARATION 4: 3-METHYL 6- (3-CHLOROPROPYL) BENZOTHIAZOLINONE

  Reagents: 3-Methyl 6- (3-chloropropionyl) benzothiazolinone 0.1 mole (23.72 g) Trifluoroacetic acid 0.8 mole (61.60 cm3) Triethylsilane 0.2 mole (32.00 cm3)

  Procedure: it is identical to that used to obtain the 6- (3-

  chloropropyl) benzothiazolinone by replacing 6- (3-chloropropionyl) benzothiazolinone with 3-methyl 6- (3-chloropropionyl) benzothiazolinone. Reaction time: 72 hours Molecular mass: 241.73 g.mole-1 for C11 H12CINOS Melting point: 41-43 C Yield: 84% Recrystallization solvent: Cyclohexane

  EXAMPLE 1: 6- (3-MORPHOLINOPROPYL) BENZOTHIAZOLINONE

  Introduce 0.02 mole (4.55 g) of 6- (3chloropropyl) benzothiazolinone, 0.03 mole into a 250 cm3 necked flask fitted with a condenser and containing 80 cm3 of absolute alcohol

  mole (2.60 cm3) of morpholine and 0.03 mole (4.20 cm3) of triethylamine.

  Heat the mixture at reflux for thirty hours. Wring out the precipitate

  triethylamine hydrochloride then evaporate the filtrate in a water bath under reduced pressure.

  Take up the residue in a 1N aqueous hydrochloric acid solution and extract with ether. The aqueous phase is made alkaline with a 10% sodium hydroxide solution. Extract twice with ether, combine the ethereal phases, dry them over calcium chloride, filter and

evaporate under reduced pressure.

  Take up the residue with anhydrous ether, bubbled gaseous hydrochloric acid, drain the precipitate formed and recrystallize it. We obtain the title compound under

form of hydrochloride.

  Molecular mass: 314.83 g mol-1 for C14H19CIN202S Yield: 62% Melting point: 239-241 C Recrystallization solvent: Absolute alcohol Elemental analysis:

% C% H% N

  Calculated: 54.40 6.08 8.89 Found: 54.33 5.86 8.72 Infrared spectrometry: 2920 cm-1 v CH (alkyls) 2660-2450 cm-1 v NH + (hydrochloride) 1690 cm-1 v CO (NCOS) 1600 cm-1 v C = C (aromatic) Nuclear magnetic resonance spectrometry (80MHz; DMSO, d6): S = 2.20 ppm (solid, 2H) CH2-CH2-CH2 ô = 2.70 ppm (triplet, 2H) Benzothiazolinone-CH2 = 7.00 ppm (singlet, 2H) H4.5 (benzothiazolinone) 6 = 7.40 ppm (singlet, 1H) H7 (benzothiazolinone) 8 = 11.80 ppm (signal, 2H) NH, NH + exchangeable in D20

  EXAMPLE 2: 3-METHYL 6- (3-MORPHOLINOPROPYL) BENZOTHIAZOUNONE

  Reagents: 3-methyl 6- (3-chloropropyl) benzothiazolinone 0.02 mole (4.83 g) Morpholine: 0.03 mole (2.60 cm3) Triethylamine: 0.03 mole (4.20 cm3) Anhydrous acetone: 60 cm3

  Procedure: it is identical to that used in Example 1, replacing the 6- (3-

  chloropropyl) benzothiazolinone with 3-methyl 6- (3chloropropyl) benzothiazolinone.

  Molecular mass: 328.86 g.mole-1 for C15H21CIN202S Yield: 67% Melting point (hydrochloride): 210-212 C Recrystallization solvent: Absolute alcohol Elemental analysis:

% C% H% N

  Calculated: 54.78 6.43 8.52 Found: 54.76 6.70 8.70 Infrared spectrometry: 2900 cm-1 v CH (alkyls) 2660-2450 cm'1 v NH + (hydrochloride) 1670 cm-1 v CO (NCOS) 1600 cm-1 v C = C (aromatic) Nuclear magnetic resonance spectrometry (80MHz; DMSO, d6): 6 = 2.10 ppm (multipiet, 2H) CH2-H2j-CH2 5 = 2.75 ppm (triplet, 2H) Benzothiazolinone-CH2 ô = 3.40 ppm (singlet, 3H) NCH3 = 3.90 ppm (multiplet, 4H); H2-O-CH2 6 = 7.35 ppm (multiplet, 3H) H4.5.7 (benzothiazolinone) = 11.20 ppm (signal, 1H) NH + exchangeable in D20

  EXAMPLE 3: 6- [3- (3,5-DIMETHYL) MORPHOLINOPROPYL] BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine with 3,5-dimethylmorpholine, the title compound is obtained.

  EXAMPLE 4: 3-METHYL 6- [3- (3,5-DIMETHYL) MORPHOULINOPROPYL] BENZOTHIAZO-

LINONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine with 3,5-dimethylmorpholine, the title compound is obtained.

  EXAMPLE 5: 6- (3-PIPERIDIN-1-YL-PROPYL) BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine with piperidine, the title compound is obtained.

  EXAMPLE 6: 3-METHYL 6- (3-PIPERIDIN-1-YL-PROPYL) BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine with piperidine, the title compound is obtained.

  EXAMPLE 7: 6- (3-PYRROLIDIN-1-YL-PROPYL) BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine with pyrrolidine, the title compound is obtained.

  EXAMPLE 8: 3-METHYL 6- (3-PYRROLIDIN-1-YL-PROPYL) BENZOTHIAZOUNONE

  o10 By proceeding in the same way as in Example 2, but by replacing the

  morpholine with pyrrolidine, the title compound is obtained.

  EXAMPLE 9: 6- (3-N, N-DIPROPYLAMINOPROPYL) BENZOTHIAZOUNONE

  By proceeding in the same manner as in Example 1, but replacing the morpholine with N, N-dipropylamine, the product of the filter is obtained.

  EXAMPLE 10: 3-METHYL 6- (3-N, N-DIPROPYLAMINOPROPYL) BENZOTHIA-

ZOLINONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine with N, N-dipropylamine, the title product is obtained.

  EXAMPLE 11: 6- (3-N-CYCLOHEXYLAMINOPROPYL) BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine by cyclohexylamine, the title product is obtained.

  EXAMPLE 12: 3-METHYL 6- (3-N-CYCLOHEXYLAMINOPROPYL) BENZOTHIAZO-

LINONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine by cyclohexylamine, the title product is obtained.

  EXAMPLE 13: 6- (3-BENZYLAMINOPROPYL) BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine with benzylamine, the title product is obtained.

  EXAMPLE 14: 3-METHYL 6- (3-BENZYLAMINOPROPYL) BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine with benzylamine, the title product is obtained.

  EXAMPLE 15: 6- [3- (4-METHOXYBENZYL) AMINOPROPYL) BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine with 4-methoxybenzylamine, the title product is obtained.

  EXAMPLE 16: 3-METHYL 6- [3- (4-METHOXYBENZYL) AMINOPROPYL) BENZO-

THIAZOLINONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine with 4-methoxybenzylamine, the title product is obtained.

  EXAMPLE 17: 6- {3- [1- (NAPHT-1-YL) ETHYLAMINO] PROPYL} BENZOTHIA-

ZOLINONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine with 1- (1-naphthyl) ethylamine, the title product is obtained.

  EXAMPLE 18: 3-METHYL 6- {3- [1- (NAPHT-1-YL) ETHYLAMINO] PROPYL} BENZO-

THIAZOLINONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine with 1- (1-naphthyl) ethylamine, the title product is obtained.

  EXAMPLE 19: 6- [3- (4-METHYLBENZYL) AMINOPROPYL] BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine with 4-methylbenzylamine, the title product is obtained.

  EXAMPLE 20: 3-METHYL 6- [3- (4-METHYLBENZYL) AMINOPROPYL] BENZO-

THIAZOLINONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine with 4-methylbenzylamine, the title product is obtained.

  EXAMPLE 21: 6- [3- (4-TRIFLUOROMETHYLBENZYL) AMINOPROPYL] BENZO-

THIAZOLINONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine with 4-trifluoromethylbenzylamine, the title product is obtained.

  EXAMPLE 22: 3-METHYL 6- [3- (4-TRIFLUOROMETHYLBENZYL) AMINOPROPYL]

BENZOTHIAZOLINONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine with 4-trifluoromethylbenzylamine, the title product is obtained.

  EXAMPLE 23: 6- [3- (3,4-DICHLOROBENZYL) AMINOPROPYL] BENZOTHIAZO-

LINONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine with 3,4-dichlorobenzylamine, the title product is obtained.

  EXAMPLE 24: 3-METHYL 6- [3- (3,4-DICHLOROBENZYL) AMINOPROPYL] BENZO-

THIAZOLINONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine with 3,4-dichlorobenzylamine, the title product is obtained.

  EXAMPLE 25: 6- (3-THIOMORPHOLINOPROPYL) BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 1, but by replacing the

  morpholine by thiomorpholine, we obtain the title product.

  EXAMPLE 26: 3-METHYL 6- (3-THIOMORPHOLINOPROPYL) BENZOTHIAZOLI-

  NONE By proceeding in the same way as in Example 2, but by replacing the

  morpholine by thiomorpholine, we obtain the title product.

  EXAMPLE 27: 3-METHYL 6- (3-ALLYLAMINOPROPYL) BENZOTHIAZOUNONE

  By proceeding in the same way as in Example 2, but by replacing the

  morpholine by allylamine, the title product is obtained.

  PHARMACOLOGICAL STUDY OF THE DERIVATIVES OF THE INVENTION

  EXAMPLE A: STUDY OF ACUTE TOXICITY

  The acute toxicity was assessed after oral administration to batches 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. 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 fraction and the radioligand used to label the receptor.

  Radioligand receptor Non-tissue fraction or specific site -HT1 A 8- OH DPAT 10-5M Hippocampus Buspirone -HT1 B [3H] 10-5M Rat brain Cyanopindolol Cold serotonin -HT1 C N-methyl 10-5M Mesulergin frontal cortex Mianserin Hippocampus - HT2 [3H] 10-5M Ketanserin frontal cortex Spiperone -HT3 [3H] 10-5M rat ileum Quipazine Zacopride a1 [3H] 10-5M Rat brain Prazosine Phentolamine aO2 [3H] 10-5M Rat brain Rauwolscine Yohimbine D1 [ 3H] 106M Rat striatum SCH 23390 Butaclamor D2 [3H] 106M Rat striatum Raclopride Haloperidol M1 [3H] 10-5M Cortex Telenzepine Atropine H1 [3H] 10'6M Calf cortex Pyrilamine Chlorpheniramine [3H] DTG 1 0- 6M 3 -PPP Calf hippocampus The test results showed that the compounds of the invention are powerful and selective ligands for c receptors. By way of comparison, the derivatives of the present invention have an affinity 100 times more powerful than the derivatives of application EP 478 446 for the sigma receptor. 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 with 4 mg kg'1 of d-amphetamine just after the test compound (injects IP), and the mice are placed

  in an actimeter for 30 minutes.

  The number of photocell interruptions is counted, as well as the

stereotypical behavior.

  The activity of the compounds tested is expressed as a percentage of the antagonism of

  amphetamine-induced hyperactivity.

  The test results show that the inventon compounds are potent antagonists of amphetamine-induced hypermotility. This allows us to conclude that

  activity in central nervous system disorders for inventon products.

2717806

  EXAMPLE D: SEARCH FOR CATALEPSIGENIC EFFECT

  The catalepsigenic effect is sought in rats by the intraperitoneal route. 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 of this test reveal that the compounds of the invention have a very weak catalepsigenic effect in comparison with haloperidol under the same test 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 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.

  The animals' ability to carry out an avoidance training (passage from one compartment to another, in order to avoid electric shocks) 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.kg / day.

RESULTS

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

  strong antidepressant 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 space 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: SEARCHING FOR ANTIARTRACTIC ACTIVITY AT

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 tuberculosis 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 O, 1, 5, 14 and 18. The rats are weighed on days 0 and 18. The test products are placed in suspension in carboxymethyl cellulose and administered orally

  for 5 consecutive days from days 1 to 5.

  EXAMPLE H: PHARMACEUTICAL COMPOSITION

  Tablets containing 0.1 mg of 6- (3-morpholinopropyl) benzothiazolinone.

  Formula for 10,000 tablets: - 6- (3morpholinopropyl) benzothiazolinone ..................................... 1 g - Wheat starch ........................................... ..........

  ........................ 75 g - Corn starch ................... DTD : ................................................. ........ 75 g Lactose ....................................... ............................ .DTD: ................... 325 g - Magnesium stearate ...................... DTD: ................... ....................... 10 g - Silica ................. DTD: .... .................................................. ................... DTD: .... 5g - Hydroxypropyl cellulose ..................... .................. DTD: ......................... 10 g..DTD : 18 2717806

Claims (7)

  1. Compound of formula (I): I1 N o = C I1I R2 () S (CH2) -N   R3 in which: - R1 represents a hydrogen atom or a lower alkyl group, the said group being unsubstituted or substituted, - R2 and R3 independently represent one of r'autre a hydrogen atom, an alkyl group, cycloalkyl, alkenyl, alkynyl, or a group - (CH2) n aryl in which n represents 1, 2, 3 or 4, the aryl group possibly being unsubstituted or substituted, or R2 and R3 together form a heterocydcle of 5 to 9 vertices rheterocycle being saturated and being able to contain other heteroatoms such as oxygen, or sulfur and being able to be unsubstituted or substituted,   it being understood that during the description of formula (I),   - the substituted term associated with the aryl radical means that the substitution can be made by one or more radicals chosen from halogen, lower alkyl, lower alkoxy or trifluoromethyl, - the substituted term associated with the heterocycle formed by NR2R3 means that the substitution can be make with one or more radicals chosen from lower alkyl, - the terms 'alkyl', 'alkenyl', 'alkoxy and' alkynyl denote linear or branched groups containing from 1 to 6 carbon atoms, the term aryl means phenyl or naphthyl, their optical isomers, where appropriate in pure form or as a mixture, and their addition salts with a pharmaceutically acceptable acid or when R1 represents a   hydrogen their addition salts with a pharmaceutically acceptable base.   2. Compound according to claim 1 which is 6-3-morpholinopropyl) benzothiazolinone, its optical isomers as well as its addition salts with an acid pharmaceutically acceptable.   3. Compound according to claim 1 which is 3-methyl 6- (3morpholinopropyl) benzothiazolinone, its optical isomers as well as its addition salts with an acid pharmaceutically acceptable.   4. Method for preparing the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II) is introduced into an appropriate solution: R1 N \ XN   O = c! S (CH2) 3- Hai in which R1 is as defined in formula (I) and Hal is a halogen atom, which is condensed with a compound of formula (111): / R2 H-N (I11)   R3 in which R2 and R3 are as defined in formula (I), to obtain a compound of formula (I): S (CH2) a Ns R3 in which R1, R2 and R3 are as defined above, the compounds of formula (I) which are, if desired, separated into their different optical isomers in pure form or as a mixture, or salified with a pharmaceutically acceptable acid or if R1 represents a hydrogen atom salified by a pharmaceutically acceptable base.   5. Pharmaceutical composition containing as active principle at least one of the compounds according to claim 1 or one of its addition salts with an acid if appropriate or   a pharmaceutically acceptable base, in combination with one or more excipients.   6. Pharmaceutical composition according to claim 5 useful in the prevention and   treatment of receptor-related disorders a.   7. Pharmaceutical composition according to claim 5 useful in the prevention and treatment of motor disorders, psychotic disorders, damage related to ischemia and shock, Alzheimer's disease, cerebral circulatory failure, disorders of memory, in the regulation of immune phenomena, in the   treatment for cocaine addiction and diagnosis and location of tumors.