WO1997028800A1 - Use of thiazolidine derivatives to prepare drugs for treating drugs abuse - Google Patents

Abstract

The use of thiazolidine derivatives of general formula (I), isomers thereof and salts thereof, to prepare drugs for treating drug or substance abuse leading to pharmacomania or excess consumption, is disclosed.

Description

APPLICATION OF THIAZOLIDINE DERIVATIVES IN THE PREPARATION OF DRUGS FOR THE TREATMENT OF DRUG ABUSE

Nowadays, drug dependence, drug addiction and, more generally, the abuse of licit or illicit substances is a major problem in the world and products making it possible to reduce or eliminate these behaviors have become necessary.

10 It has now been found, and this is the subject of the present application, compounds for treating the abuse of drugs or substances giving rise to drug addiction or excessive use, that is to say -to say compounds which decrease or suppress the intake of these products. Among these drugs and substances giving rise to drug addiction or use

H excessive, there may be mentioned nicotine, benzodiazepines, caffeine, narcotic drugs such as amphetamines, cocaine, cannabinoids, morphine and derivatives and opiates, hallucinogens such as LSD, ecstasy, mescaline, psyiocibine and, in general, all the compounds whose abuse poses a public health problem.

The present invention relates to the use of derivatives of formula:

leurs isomères et leurs sels au traitement de l'abus de drogues ou de substances donnant lieu a des pharmacomanies ou a un usage excessif.

their isomers and their salts for the treatment of drug or substance abuse resulting in drug abuse or excessive use.

The present invention also relates to the use of these compounds in the preparation of a medicament intended for the treatment of the abuse of drugs or substances giving rise to drug addiction or excessive use. In formula (I),

R1 represents a radical - (CH2) _n -C00Ra or - (CH2) _n -C0NRbRc,

R2 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, hydroxy, nitro, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, trifluoromethyl and trifiuoromethoxy radicals,

R3 represents a radical -COORd or -CONReRf,

R4 represents a hydrogen atom or an alkyl radical,

R5 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, trifluoromethyl, carboxy, alkoxycarbonyl, hydroxy, nitro, amino, acyl, cyano, sulfamoyl, carbamoyl, hydroxyiminoalkyl, alkoxyiminoalkyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, tetrazolyl-5, tetrazolyl-5 alkyl, trifluoromethylsulfonamido, alkylsulfinyl, mono or polyhydroxyalkyl, suifo, -alk-O-CO-alk, -alk-COOX, -alk-O-alk,

-alk'-COOX, -O-alk-COOX, -CH = CH-COOX, -CO-COOX, -alk-S03H (in salt form), -CH = CH-alk \ -C (= NOH) - COOX, -S-alk-COOX, -SO-alk-COOX,

-Sθ2-alk-COOX, -0-CH2-alk'-COOX, -CX = N-0-alk-COOX,

-alk-N (OH) -CO-alk, -aik-S02H, -Sθ2-NH-CO-Rg, -Sθ2-NH-Sθ2-Rg, -CO-NH-CO-Rg, -CO-NH-Sθ2 -Rg, -B (OH) 2, -C (NH ₂ ) = NOH, -Sθ2-NH-Rh,

-CO-NH-Rh,

or 2,2-dimethyl-4,6-dioxane-1, 3-yl-5,

Ra represents a hydrogen atom or an alkyl radical,

Rb represents a hydrogen atom or an alkyl radical,

Rc represents an alkyl, tetrazolyl-5, phenylalkyl radical in which the phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio or phenyl radicals optionally substituted by one or more substituents chosen from halogen atoms and the alkyl, alkoxy and alkylthio radicals,

or Rb and Rc form, with the nitrogen atom to which they are attached, a saturated or unsaturated mono or polycyclic heterocycle containing 4 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulfur and optionally substituted by one or more alkyl radicals,

Rd represents an alkyl radical,

Re represents a hydrogen atom or an alkyl radical,

Rf represents an alkyl, cycloalkyl or cycloalkylalkyl radical,

or Re and Rf form with the nitrogen atom to which they are attached a mono or polycyclic heterocycle saturated or unsaturated containing 4 to 9 atoms carbon and one or more heteroatoms chosen from oxygen, nitrogen or sulfur and optionally substituted by one or more alkyl radicals,

Rg represents an alkyl, cycloalkyl, trifluoromethyl, phenyl radical optionally substituted by one or more substituents chosen from cyano, alkoxy, nitro, amino and halogen atoms,

Rh represents a tetrazolyl-5 radical,

Ri represents C = O or S = O,

Rj represents O or C = O,

n is 0 or 1

X represents a hydrogen atom or an alkyl or phenylalkyl radical,

alk represents an alkyl or alkylene radical,

alk 'represents a hydroxyalkyl, hydroxyalkylene, alkoxyalkyl or alkoxyalkyiene radical.

In the above definitions or those which will be cited below, unless otherwise stated, the radicals and alkyl, alkylene and alkoxy portions contain 1 to 4 carbon atoms in a straight or branched chain and the cycloalkyl radicals or portions contain 3 to 6 atoms of carbon.

The compounds of formula (I) have isomeric forms. These isomers are also part of the invention.

When Rb and Rc or Re and Rf form with the nitrogen atom to which they are attached a mono or polycyclic heterocycle saturated or unsaturated containing 4 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulfur and optionally substituted by one or more alkyl radicals, this is preferably a morpholinyl, thiomorphohnyl, piperidyl residue optionally substituted by one or more alkyl, pyrrolidmyl, tetrahydro-1, 2,3,4 qumolyie or N-alkyl radicals piperazinyl The compounds of formula (I) comprising a basic residue can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, a ether or a chlorinated solvent.

The compounds of formula (I) comprising an acid residue can optionally be converted into metal salts or into addition salts with nitrogenous bases according to methods known per se. These salts can be obtained by the action of a metal base (alkaline or alkaline-earth, for example), ammonia, an amine or a salt of an amme on a compound of formula (I) , in a solvent. The salt formed is separated by the usual methods.

These salts are also part of the invention.

As examples of pharmaceutically acceptable salts, mention may be made of addition salts with mineral or organic acids (such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylene-bis- b-oxynaphtoate, hydrochloride, sulphate, nitrate and phosphate), salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium), ammonium salt, salts of nitrogenous bases (ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl-b-phenethylamiπe, chohπe, arginine, leukme, lysine, N-methyl glucamine).

The products of formula (I) and their salts can be prepared under the conditions described in international application WO95 / 35314.

According to international application WO95 / 35314, the compounds of formula (I) have interesting pharmacological properties. These compounds have a strong affinity for the receptors of cholecystokinme (CCK) and gastric and are thus useful in the treatment and the prevention of disorders related to CCK and gastric in the nervous system and the gastrointestinal tract. .

Thus, according to international PCT application W095 / 35314, these compounds can be used for the treatment or prevention of psychoses, anxiety disorders, depression, neurodegeneration, panic attacks, Parkinson's disease, tardive diskynesia, irritable bowel syndrome, acute pancreatitis, ulcers, intestinal motility disorders , certain tumors sensitive to CCK, as an appetite regulator, in withdrawal from chronic treatment and abuse of alcohol or drugs and as a constrictor of the pupil of the eye. These compounds also have a potentiating effect on the analgesic activity of narcotic and non-narcotic drugs. In addition, they can have their own analgesic effect. In addition, these compounds can be effective in memory disorders.

The effect of the compounds of formula (I) for the treatment of drug or substance abuse giving rise to drug addiction or excessive use was evaluated in the test for drug self-administration in mice according to the protocol described by A. KUZMIN et al., Pharmacol. Biochem. Behav., 41, 497-500 (1992) for morphine and cocaine. In this test, the compounds of formula (I), at doses equal to or less than 100 mg / kg, oppose the self-administration of drugs or substances giving rise to drug addiction or excessive use (amphetamine , cocaine, morphine, diazepam, mescaline).

Of particular interest are the compounds of formula (I) for which R- | represents a radical - (CH2) n * COORa or - (CH2) rrCONRbRc, R2 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, hydroxy, alkoxycarbonyl, trifluoromethyl and tπfluoromethoxy radicals , R3 represents a radical -COORd or -CONReRf, R4 represents a hydrogen atom or an alkyl radical (1 or 2C), R5 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and radicals alkyl, alkoxy, alkylthio, trifluoromethyl, carboxy, alkoxycarbonyl, hydroxy, nitro, amino, acyl, cyano, sulfamoyl, carbamoyy, hydroxyimmoalkyl, aicoxyimmoalkyl, hydroxyaminocarbonyl, alkoxyammocarbonyl, tetrazolyl-5, tetrazolyl-5-alkylmylalkylmyl alkylsulfuryl . suifo, -alk-O-CO-alk, -alk-COOX, -alk-O-alk, -alk'-COOX, -O-alk-COOX, -CH = CH-COOX -CO-COOX, -alk- S03H (as salt), -CH = CH-alk \ -C (= NOH) -COOX, -S-alk-COOX, -SO-alk-COOX, -Sθ2-alk-COOX, -0-CH ₂ -alk'-COOX, -CX = N-0-alk- COOX, -alk-N (OH) -CO-alk, -alk-S02H, Ra represents a hydrogen atom or an alkyl radical, Rb represents a hydrogen atom or an alkyl radical, Rc represents an alkyl radical, tetrazolyl -5, phenylalkyl in which the phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals or phenyl optionally substituted by one or more substituents chosen from halogen atoms and radicals alkyl, alkoxy and alkylthio, or else Rb and Rc form, with the nitrogen atom to which they are attached, a saturated or unsaturated mono or polycyclic heterocycle containing 4 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, l nitrogen or sulfur and optionally substituted by one or more alkyl radicals, Rd represents an alkyl radical, Re represents an atom of hydrogen or an alkyl radical, Rf represents an alkyl, cycloalkyl or cycloalkylalkyl radical, or else Re and Rf form, with the nitrogen atom to which they are attached, a saturated or unsaturated mono or polycyclic heterocycle containing 4 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulfur and optionally substituted by one or more alkyl radicals, n is equal to 0 or 1, X represents a hydrogen atom or an alkyl or phenylalkyl radical, alk represents an alkyl or alkylene radical, alk ′ represents a hydroxyalkyl, hydroxyalkylene, alkoxyalkyl or alkoxyalkylene radical, their isomers and their salts.

Among these compounds the preferred ones are the following:

methoxycarbonyl-5 {[(methyl-3 phenyl) -3 ureιdo] -2 acetyl} -3 phenyl-4 thιazolιdιnecarboxylate-2-tert-butyl- (2S, 4S, 5R),

phenylacetic acid {[(tert-butoxycarbonyl-2 carboxy-5 phenyl-4 thιazolιdιnyl-3- (2S, 4S.5R)) - 2 oxo-ethyl] -3 ureιdo} -3,

acid {{[(tert-butoxycarbonyl-2 carboxy-5 phenyl-4 thιazolιdιnyl-3- (2S, 4S, 5R)) - 2 oxo-2 ethyl] -3 ureιdo} -3 phenyl} -2 propιonιque- (S) ,

tert-buty methoxycarbonyl-5 {[(methyl-3 phenyl) -3 ureιdo] -2 acetyl} -3 (fluoro-2 phenyl) -4 thιazolιdιnιarecarboxylate-2! e- (2S, 4S, 5R), tert-butoxycarbonyl-2 acid {[(methyl-3 phenyl) -3 ureιdo] -2 acetyl} -3 (fluoro-2 phenyl) -4 thιazohdιnecarboxylιque-5- (2S, 4S, 5R),

and their salts.

The medicaments according to the invention are constituted by a compound of formula (I) in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or in the form of a compound. tion in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, saccharose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, it is possible to use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or 'paraffin oil. These compositions can include substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers.

The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, there may be employed water, ^¬ pylèneglycol, polyethylene glycol, vegetable oils, especially ^olive oil, injectable organic esters, for example ethyl oleate or other solvents d organic suitable:,. These compositions can also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by sanitizing filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

In human therapy, the medicaments according to the invention are particularly useful in the treatment of drug abuse.

The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 0.05 g and 1 g per day orally for an adult with unit doses ranging from 10 mg to 500 mg of active substance.

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.

The following examples illustrate medicaments according to the invention:

EXAMPLE A

Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:

- Compound of formula (I) 50 mg

- Cellulose 18 mg

- Lactose 55 mg - Colloidal silica 1 mg

- Carboxymethyl starch sodium 10 mg

- Talc 10 mg

- Magnesium stearate 1 mg

EXAMPLE B

Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:

- Compound of formula (I) 50 mg

- Lactose 104 mg - Cellulose 40 mg

- Polyvidone 10 mg

- Carboxymethyl starch sodium 22 mg

- Talc 10 mg

- Magnesium stearate 2 mg - Colloidal silica 2 mg

- Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3,5-24,5) q.s.p. 1 film-coated tablet finished at 245 mg

EXAMPLE C

A solution for injection containing 10 mg of active product having the following composition is prepared:

- Compound of formula (I) 10 mg

- Benzoic acid 80 mg

- Benzyl alcohol 0.06 cm ³

- Sodium benzoate 80 mg - 95% ethanol 0.4 cm ³

- Sodium hydroxide 24 mg

- Propylene glycol 1.6 cm ³

- Water q.s.p. 4 cm3

Claims

1 - Application of the compounds of formula:

in what R- | represents a radical - (CH2) _n -COORa or - (CH2) _n -CONRbRc, R2 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, hydroxy, nitro, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, trifluoromethyl and trifluoromethoxy radicals, R3 represents a radical -COORd or -CONReRf, R4 represents a hydrogen atom or an alkyl radical, R5 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, trifluoromethyle, carboxy, alkoxycarbonyl, hydroxy, nitro, amino, acyl, cyano, sulfamoyie, carbamoyie, hydroxyiminoalkyle, alkoxyimmoalkyle, hydroxyaminocarbonyle, alkoxyammocarbonyle, tetrazolyl-5, tétrazolyl-5 alkyl, tπfluorométhylsulfonamido, alkylsulfinyle, mono or polyhydroxyalkyle, suifo, -alk-O-CO-alk, -alk-COOX, -alk-O-alk'alk COOX, -O-alk-COOX, -CH = CH-COOX, -CO-COOX, -alk-S03H (as salt), -CH = CH-alk \ -C (= NOH) -COOX, -S -alk-COOX, -SO-alk-COOX, -Sθ2-alk-COOX, -0-CH2-alk'-COOX, -CX = N-0-alk-COOX, -alk-N (OH) -CO-alk, -alk-S02H, -Sθ2-NH-CO-Rg, -Sθ2-NH-Sθ2-Rg, -CO-NH-CO-Rg, -CO-NH-Sθ2 -Rg, -B (OH) ₂ , -C (NH ₂ ) = NOH, -S0 ₂ -NH-Rh, -CO-NH-Rh,

or 2,2-methyl-1,oxo-4,6 dιoxanne-1, 3-yl-5, Ra represents a hydrogen atom or an alkyl radical, Rb represents a hydrogen atom or an alkyl radical, Rc represents an alkyl, tetrazolyl-5, phenylalkyl radical in which the phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio or phenyl radicals optionally substituted by one or more substituents chosen from halogen atoms and the alkyl, alkoxy and alkylthio radicals, or else Rb and Rc form, with the nitrogen atom to which they are attached, a saturated or unsaturated mono or polycyclic heterocycle containing 4 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulfur and optionally substituted by one or more alkyl radicals, Rd represents an alkyl radical, Re represents a hydrogen atom or an alkyl radical, Rf represents an alkyl, cycloalkyl or cycloalkylalkyl radical, or Re and Rf form with the nitrogen atom to which they are attached a mono or polycyclic heterocycle saturated or unsaturated containing 4 to 9 atoms carbon and one or more heteroatoms chosen from oxygen, nitrogen or sulfur and optionally substituted by one or more alkyl radicals, Rg represents an alkyl, cycloalkyl, trifluoromethyl, phenyl radical optionally substituted by one or more substituents chosen from cyano, alkoxy, nitro, amino and halogen atoms, Rh represents a tetrazolyl-5 radical, Ri represents C = O or S≈O, Rj represents O or C = O, n is 0 or 1 X represents a hydrogen atom or an alkyl or phenylalkyl radical, alk represents an alkyl or alkylene radical, alk ′ represents a hydroxyalkyl, hydroxyalkylene, alkoxyalkyl or alkoxyalkylene radical, it being understood that the alkyl, alkylene and alkoxy radicals and portions contain 1 to 4 carbon atoms in straight or branched chain and the radicals or cycloalkyl portions contain 3 to 6 carbon atoms, their isomers and their salts, in the preparation of a medicament intended for the treatment of drug abuse or substances giving rise to drug addiction or excessive use 2 - Application of a compound of formula (I) according to claim 1 for which R- | represents a radical - (CH2) _n -COORa or - (CH2) _n -CONRbRc, R2 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, hydroxy, alkoxycarbonyl, trifluoromethyl radicals and tπfluoromethoxy, R3 represents a radical -COORd or -CONReRf, R4 represents a hydrogen atom or an alkyl radical (1 or 2C), R5 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, trifluoromethyl, carboxy, alkoxycarbonyl, hydroxy, nitro, amino, acyl, cyano, sulfamoyie, carbamoyie, hydroxyiminoalkyle, alkoxyiminoalkyle, hydroxyaminocarbonyle, radicals alkoxyaminocarbonyl, tetrazolyl-5, tetrazolyl-5 alkyl, trifluoromethylsulfonamido, alkylsulfinyl, mono or polyhydroxyalkyl, suifo, -alk-O-CO-alk, -alk-COOX, -alk-O-alk, -alk'-COOX, -O -alk-COOX, -CH = CH-COOX, -CO-COOX, -alk-S03H (in salt form), -CH = CH-alk \ -C (= NOH) -COOX, -S-alk-COOX , -SO-alk-COOX, -Sθ2-alk-COOX, -0-CH2-alk'-COOX, -CX≈NO-alk-COOX, -aik-N (OH) -CO-alk, -alk-S02H , Ra represents a hydrogen atom or an alkyl radical, Rb represents a hydrogen atom or an alkyl radical, Rc represents an alkyl, tetrazolyl-5, phenylalkyl radical in which the phenyl nucleus is optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio or phenyl radicals optionally substituted with one or more substituents chosen from halogen atoms and the alkyl, alkoxy and alkylthio radicals, or else Rb and Rc form with the atom nitrogen to which they are attached a mono or polycyc heterocycle saturated or unsaturated liquefied containing 4 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulfur and optionally substituted by one or more alkyl radicals, Rd represents an alkyl radical, Re represents an atom of hydrogen or an alkyl radical, Rf represents an alkyl, cycloalkyl or cycloalkylalkyl radical, or else Re and Rf form, with the nitrogen atom to which they are attached, a saturated or unsaturated mono or polycyclic heterocycle containing 4 to 9 carbon atoms and a or several heteroatoms chosen from oxygen, nitrogen or sulfur and optionally substituted by one or more alkyl radicals, n is equal to 0 or 1, X represents a hydrogen atom or an alkyl or phenylalkyl radical, alk represents a alkyl or alkylene radical, alk ′ represents a hydroxyalkyl, hydroxyalkylene, alkoxyalkyl or alkoxyalkylene radical, their isomers and their salts, for the preparation of a medicament intended for u treatment of drug or substance abuse resulting in drug abuse or excessive use. 3 - Application of a compound of formula (I) according to claim 1 chosen from the following compounds: methoxycarbonyl-5 {[(methyl-3 phenyl) -3 ureido] -2 acetyl} -3 phenyl-4 thιazolidinecarbo ^χ tert-butyl vlate-2- (2S, 4S, 5R), phenylacetic acid {[(tert-butoxycarbonyl-2 carboxy-5 phenyl-4 thiazolidinyl-3- (2S, 4S, 5R)) - 2 oxo-2 ethyl] -3 ureido} -3, {{[(tert-butoxycarbonyl-2 carboxy-5 phenyl-4 thiazolidinyl-3- (2S, 4S, 5R)) - 2 oxo-2 ethyl] -3 ureido} -3 phenyl} -2 propionic acid- (S) , methoxycarbonyl-5 {[(3-methylphenyl) -3 ureido] -2 acetyl} -3 (2-fluoro phenyl) -4 thiazolidinecarboxylate-2-tert-butyl- (2S, 4S, 5R), tert-butoxycarbonyl-2 {[(3-methylphenyl) -3 ureido] -2 acetyl} -3 (2-fluoro-phenyl) -4 thiazolidinecarboxylic-5- (2S, 4S, 5R) acid, and their salts, in the preparation of a medicament intended for the treatment of drug abuse or of substances giving rise to drug addiction or excessive use. 4 - Application according to one of claims 1 to 3 for which the drug or the substance giving rise to drug addiction or excessive use is nicotine, caffeine, a benzodiazepine, a narcotic or a hallucinogen. 5 - Application according to claim 4 for which the narcotic is an amphetamine, cocaine, a cannabinoid, morphine or a derivative thereof or an opioid. 6 - Application according to claim 4 for which the hallucinogen is LSD, ecstasy, mescaline or psylocibine.