MXPA97008875A - Use of pyrrolidine derivatives in the preparation of medicines intended for the alcohol treatment - Google Patents

Abstract

The invention relates to the use of the pyrrolidone derivatives of the general formula: (I), wherein the treatment of chronic alcoholism to the states due to alcohol abuse

Description

USE OF PYROLROLIDINE DERIVATIVES IN THE PREPARATION OF MEDICINES INTENDED FOR THE TREATMENT OF ALCOHOLISM DESCRIPTION OF THE INVENTION The present invention relates to the use of derivatives of the formula: its racemic and enantiomers when it contains one or several asymmetric centers and their salts in the treatment of chronic alcoholism or states due to alcohol abuse and the application of these derivatives in the preparation of drugs for the treatment of chronic alcoholism or the states due to alcohol abuse.

In the formula (I), REF: 25898 Either R represents a methylene radical, ethylene, SO, S02, CHOH or a sulfur atom, Ri represents a pyridyl radical optionally substituted by one or more alkyl radicals, furyl optionally substituted by one or more alkyl radicals, thienyl optionally substituted by one or more alkyl, quinolyl radicals optionally substituted by one or more alkyl radicals, naphthyl optionally substituted by one or more alkyl radicals, indolyl optionally substituted by one or more alkyl or phenyl radicals optionally substituted by one or more substituents chosen from the atoms of halogen and the radicals alkyl, alkoxy, hydroxy, nitro, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, -C0-NR7Rβ / -NH-CO-CH3, trifluoromethyl or trifluoromethoxy and R5 represents a hydrogen atom, or R represents a methylene radical , R_ represents a hydrogen atom and R5 represents a phenyl radical, or R represents a CHR6 radical, Ri and R5 each represent a hydrogen atom, R2 represents an alkoxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, -CONR9R10 radical or phenyl optionally substituted by one or more substituents chosen from the alkyl, alkoxy or hydroxy radicals. R3 represents a phenyl radical (optionally substituted by one or more substituents selected from halogen atoms and alkyl, alkoxy and alkylthio radicals), naphthyl, indolyl, quinolyl or phenylamino whose phenyl nucleus is optionally substituted by one or more substituents selected from the group consisting of halogen atoms and the alkyl, alkoxy, alkylthio, trifluoromethyl, carboxy, alkoxycarbonyl, hydroxy, nitro, amino, acyl, cyano, sulfamoyl, carbamoyl, hydroxyiminoalkyl, alkoxyiminoalkyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, 5-tetrazolyl, 5-tetrazolyl alkyl, trifluoromethylsulfonamido radicals , alkylsulfinyl, mono or polyhydroxyalkyl, sulfo, -alq-O-CO-alk, -alk-COOX, -alq-O -alk, -alk'-COOX, -O-alq-COOX, -CH = CH-COOX, -CO-COOX, -alq-S03H in the form of salt, -CH = CH-alq ', -C (= NOH) -COOX, -S-alko-COOX, -0-CH2-alq' -COOX, - CX = N-0-alk-COOX, -alk-N (OH) -CO-alk or 2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl, -R represents a hydrogen atom or a radica alkyl, -Re represents a phenyl radical, -R7 represents a hydrogen atom or an alkyl, phenylalkyl or phenyl radical optionally substituted by one or more substituents selected from the halogen atoms and the alkyl, alkoxy and alkylthio radicals. -R8 represents an alkyl, phenylalkyl or phenyl radical optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio radicals, or R7 and Rβ form with the nitrogen atom to which they are attached saturated or unsaturated polycyclic or monocyclic heterocycle containing 4 to 9 carbon atoms and one or more heteroatoms (O, N) and optionally substituted by one or more alkyl radicals, -R9 represents a hydrogen atom or an alkyl, cycloalkylalkyl, cycloalkyl radical , phenylalkyl or phenyl optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio radicals, -Rio represents an alkyl, cycloalkylalkyl, cycloalkyl, phenylalkyl or phenyl radical optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl radicals, alkoxy and alkylthio, or Rg and Rio form together with the nitrogen atom to which they are attached a saturated or unsaturated monocyclic or polycyclic heterocycle containing 4 to 9 carbon atoms and one or more heteroatoms (0, N, S ) and optionally substituted by one or more alkyl radicals, - X represents a hydrogen atom, an alkyl or phenylalkyl radical, alk represents an alkyl or alkylene radical, - alk represents a hydroxyalkyl, hydroxyalkylene, alkoxyalkyl or alkoxyalkylene radical. In the foregoing definitions and which will be cited below, unless otherwise mentioned, the alkyl, alkylene and alkoxy radicals and the alkyl, alkylene and alkoxy portions containing 1 to 4 straight or branched chain carbon atoms, the radicals or acyl portions containing 2 to 4 carbon atoms and the radicals and cycloalkyl portions containing 3 to 6 carbon atoms. When R-? and Rß form with the nitrogen atom to which they are attached a heterocycle, this is preferably a piperidino ring optionally substituted by one or more alkyl radicals or a 1,2,3,4-tetrahydroquinoline cycle.

When Rg and Rio form with the nitrogen atom to which they are attached a heterocycle, this is preferably a piperidino, 1-perhydroazepinyl, 1, 2, 3, 6-tetrahydro-1-pyridyl, 1, 2, 3 cycle. 4-tetrahydro-1-quinolyl, 1-pyrrolidinyl, 1, 2, 3, 4-tetrahydro-2-isoquinolyl, thiomorpholino or 1-indolyl, these rings may optionally be substituted by at least one alkyl radical. The compounds of the formula (I) comprising one or more asymmetric centers have isomeric forms. The racemates and the enantiomers of these compounds also form part of the invention. The compounds of the formula (I) may optionally exist in the form of addition salts with a mineral or organic acid. The compounds of the formula (I) which comprise a carboxy, sulfo or alk-S03H residue can also exist in the form of metal salts or addition salts with the pharmaceutically acceptable nitrogenous bases. As examples of pharmaceutically acceptable salts, the addition salts with the mineral or organic acids (such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophylline acetate, salicylate, methylene bis) can be cited. ß-oxinaftoato, hydrochloride, sulfate, nitrate and phosphate), the salts with the alkali metals (sodium, potassium, lithium) or with the alkaline earth metals (calcium, magnesium), the ammonium salt, the salts of nitrogenous bases (ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl-β-phenethylamine, choline, arginine, leucine, lysine, N-methyl glucamine). The products of the formula (I) and their salts can be prepared under the conditions described in the PCT international application WO 93/01167. In accordance with PCT International Application WO 93/01167, the compounds of formula (I) exhibit interesting pharmacological properties. These compounds possess a strong affinity for the cholecystokinin (CCK) and gastrin receptors and are thus useful in the treatment and prevention of disorders linked to CCK and gastrin at the level of the nervous system and the gastrointestinal tract. Thus, according to PCT international application WO 93/01167, the compounds can be used for the treatment or prevention of psychosis, anxiety problems, Parkinson's disease, tardive dyskinesia, irritable bowel syndrome, acute pancreatitis, ulcers, intestinal motility disorders, certain tumors sensitive to CCK and as appetite regulator. These compounds, which also have a potentiating effect on the analgesic activity of narcotic and non-narcotic drugs, may have an analgesic effect of their own. On the other hand, compounds that have a strong affinity for CCK receptors modify memory capacities, can be effective in memory disorders. It has now been found that the compounds of the formula (I), their racemic and enantiomers when they contain at least one asymmetric center and its salts are particularly useful for the treatment of chronic alcoholism or the conditions resulting from alcohol abuse. . Based on the work of H.H. Samson and R.A. Harris, Trends Pharmacol. Sci., 33, 206-211 (1992) and performing the tests on rats trained for heavy alcohol consumption, the efficacy of the compounds according to the invention can be demonstrated by noting the behavior of the rats according to alcohol consumption. . Carrying out the repeated treatments with the products according to the invention at doses between 5 and 25 mg / kg i.p. per day for 14 days the alcohol consumption of the treated animals decreases by 2/3. In the rat provided with alcohol, made alcohol-dependent, the compounds allow a decrease in alcohol consumption that can achieve more than 40% when the compounds according to the invention are administered at doses between 5 and 50 mg / kg by intraperitoneal route . The activity of the products can also be evidenced in the monkeys that live in the Caribbean islands (Cercopithecus aethiops), of which some voluntarily consume alcoholic beverages. When the compounds according to the invention are administered at doses comprising between 4 and 50 mg / kg orally for 2 weeks to the monkeys accustomed to consuming more than 5 g of ethanol per day, the consumption decreases by 40% the first week and 30% the second. On the other hand, the products according to the invention have no influence on the food consumption since the average weight remains constant as well as in the consumption of water. Of particular interest are the compounds of the formula (I) for which R represents a methylene radical, a sulfur atom or an SO radical, Ri represents a substituted phenyl radical optionally substituted, R2 represents a phenyl or alkoxycarbonyl radical, R4 and R5 represent a hydrogen atom, R3 represents a phenylamino radical of which the phenyl nucleus is substituted by a carboxy radical, -alk-COOH, -S-alko-COOH, hydroxyalkyl, alko '-COOH or alqS03H, hydroxyiminoalkyl. More particularly interesting are the products of the formula (I) in which Rx and R2 are in the cis position with respect to each other. Of particular interest are the following compounds: (2RS, 5SR) -1-. { 2- [3- (3- ((RS) -1-hydroxy-ethyl) phenyl) -ureido] acetyl} 5-phenylprolinate of tert-butyl, 2- acid. { 3-. { 3- [2- ((2S, 5R) -2-tert-butoxycarbonyl-5-pheny1-1-pyrrolidinyl) -2-oxo-ethyl] ureido} phenyl } -propionic, - acid (2RS, 5SR) -. { 3-. { 3- [2- (2-tert-butoxycarbonyl-5-pheny1-1-pyrrolidinyl) -2-oxo-ethyl] ureido} phenylthio} -acetic, - acid (2R, 4R) -3-. { 3- [2- (4-tert-butoxycarbonyl-2-fluoro-3-thiazolidinyl) -2-oxo-ethyl] ureido} phenylacetic, - acid 2-. { 3-. { 3- [2- ((2R, 4R) -4-tert-butoxycarbonyl-2- (2-fluoro-phenyl) -3-thiazolidinyl) -2-oxo-ethyl] ureido} phenyl } -propionic, - (RS) -l-. { 3-. { 3- [2- ((2R, 4R) -4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl) -2-oxo-ethyl] ureido} phenyl } etansul-fonato de potasio, - (RS) -l-. { 3-. { 3- [2- ((2S, 5R) -2-tert-butoxycarbonyl-5-pheny1-1-pyrrolidinyl) -2-oxo-ethyl] ureido} phenyl Jetansul-fonato potassium, - (2S, 5R) -3-. { 3- [2- (2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) -2-oxo-ethyl] ureido} Potassium-1-phenyl-methanesulfonate, - (2S, 5R) -3- acid. { 3- [2- (2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) -2-oxo-ethyl] ureido} benzoic, - acid (2RS, 5SR) -3-. { 3-. { 2- [2-tert-butoxycarbonyl-5- (2-fluoro-phenyl) -1-pyrrolidinyl] -2-oxo-ethyl} ureido} -benzoic, - (cis) -3- acid. { 3- [2- (2,5-diphenyl-l-pyrrolidinyl) -2-oxo-ethyl] ureido} benzoic, - acid (2RS, 5SR) -3-. { 2- [2- (2-hydroxy-phenyl) -5-phenyl-1-pyrrolidinyl] -2-oxo-ureido} phenylacetic, - (2R, 4R) -3- acid. { 3- [2- (4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl) -2-oxo-ethyl] ureido} phenylacetic, - (2R, 4R) -3- acid. { 3- [2- (4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl) -2-oxo-ethyl] ureido} benzoic, - 2- acid. { 3-. { -3- [2- ((1RS, 2R, 4R) -4-tert-butoxycarbonyl-2- (2-fluoro-phenyl) -l-oxido-3-thiazolidinyl) -2-oxo-ethyl} ureido} phenyl } propionic, - (2R, 4R) -3- acid. { 3- [2- (4-tert-butoxycarbonyl-2- (2,3-difluoro-phenyl) -3-thiazolidinyl) -2-oxo-ethyl] ureido} -phenylacetic, - (2RS, 5SR) -l-. { 2-. { 3- [3- ((E) -1-hydroxyimino-ethyl) -phenyl] ureido} -5-phenyl-tert-butyl proline, and its salts. The medicaments according to the invention are constituted by a compound of the formula (I) under the 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 composition in the which itself 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, lozenges) or granules can be used. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions may 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 or layer. As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil can be used. These compositions may comprise substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers. Sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, may be employed. These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. The sterilization can be done in several ways, for example by aseptic 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. 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 therapeutics, the medicaments according to the invention are particularly useful in the treatment of chronic alcoholism and states due to alcohol abuse. Doses depend on the effect sought, the duration of treatment and the route of administration used; they are generally comprised 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 according to age, weight and all other factors appropriate to the subject to be treated. The following examples illustrate the medicaments according to the invention: EXAMPLE A The capsules dosed at 50 mg of active compound having the following composition are prepared according to the usual technique: - Compound of the formula (I) 50 mg - Cellulose 18 mg - Lactose 55 mg - Colloidal silica 1 mg - Carboxymethylstarch sodium 10 mg - Talc 10 mg - Magnesium stearate 1 mg EXAMPLE B Tablets dosed at 50 mg of active compound having the following composition are prepared according to the usual technique: - Compound of the formula (I) 50 mg - Lactose 104 mg - Cellulose 40 mg - Polividone 10 mg - Carboxymethylstarch sodium 22 mg - Talc 10 mg - Magnesium stearate 2 mg - Colloidal silica 2 mg - Mixture of hydroxymethyl cellulose, glycerin, titanium oxide (72-3.5-24.5) csp 1 film-coated or finished tablet at 245 mg EXAMPLE C An injectable solution containing 10 mg of active compound having the following composition is prepared: - Compound of the formula (I) 10 mg - Benzoic acid 80 mg - Benzyl alcohol 0.06 cm3 - Sodium Benzoate 80 mg - 95% Ethanol 0.4 cm3 - Sodium Hydroxide 24 mg - Propylene Glycol 1.6 cm3 - Water c.s. 4 cm3 It is noted that in relation to this date, the best known method, by the applicant to carry out the aforementioned invention, is that which refers to the manufacture of the objects to which it refers.

Having described the invention as above, the content of the following is claimed as property

Claims (7)

1. The application of the compounds of the formula: characterized in that - whether R represents a methylene radical, ethylene, SO, S02, CHOH or a sulfur atom, Ri represents a pyridyl radical optionally substituted by one or more alkyl radicals, furyl optionally substituted by one or more alkyl radicals, thienyl optionally substituted by one or more alkyl, quinolyl radicals optionally substituted by one or more alkyl radicals, naphthyl optionally substituted by one or more alkyl radicals, indolyl optionally substituted by one or more alkyl or phenyl radicals optionally substituted by one or more substituents chosen from the atoms of halogen and the radicals alkyl, alkoxy, hydroxy, nitro, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, -CO-NR7Rβ, -NH-CO-CH 3, trifluoromethyl or trifluoromethoxy and R 5 represents a hydrogen atom. - or R represents a methylene radical, Ri represents a hydrogen atom and R5 represents a phenyl radical, - or R represents a radical CHR6, Ri and R5 each represent a hydrogen atom, -R2 represents an alkoxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl radical , -CONRgRIO or phenyl optionally substituted by one or more substituents chosen from the alkyl, alkoxy or hydroxy radicals, -R3 represents a phenyl radical (optionally substituted by one or more substituents selected from the halogen atoms and the alkyl, alkoxy and alkylthio radicals) ), naphthyl, indolyl, quinolyl or phenylamino whose phenyl nucleus is optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy, alkylthio, trifluoromethyl, carboxy, alkoxycarbonyl, hydroxy, nitro, amino, acyl, cyano radicals , sulfamoyl, carbamoyl, hydroxyiminoalkyl, alkoxyiminoalkyl, hydroxyaminocarbonyl, alkoxyaminocar bonyl, 5-tetrazolyl, 5-tetrazolyl-alkyl, trifluoromethylsulfonamido, alkylsulfinyl, mono- or polyhydroxyalkyl, sulfo, -alk-O-CO-alk, -alk-COOX, -alk-O -alk, -alk '-COOX, -O -alk-COOX, -CH = CH-COOX, -CO-COOX, -alq-S03H in the form of salt, -CH = CH-alq ', -C (= NOH) -COOX, -S-alq-COOX , -0-CH2-alq '-COOX, -CX = N-0 -alk-COOX, -alk- (OH) -CO-alk or 2,2-dimethyl-4,6-dioxo-1,3-dioxan-5 -yl, -R4 represents a hydrogen atom or an alkyl radical, -R6 represents a phenyl radical, -R7 represents a hydrogen atom or an alkyl, phenylalkyl or phenyl radical optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio radicals. -R8 represents an alkyl, phenylalkyl or phenyl radical optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio radicals, or R7 and R8 form with the nitrogen atom to which they are attached, a saturated or unsaturated monocyclic or polycyclic heterocycle contain4 to 9 carbon atoms and one or more heteroatoms (0, N) and optionally substituted by one or more alkyl radicals, -Rg represents a hydrogen atom or an alkyl radical, cycloalkylalkyl, cycloalkyl, phenylalkyl or phenyl optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio radicals, -Rio represents an alkyl, cycloalkylalkyl, cycloalkyl, phenylalkyl or phenyl radical optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio radicals, either R9 and Rio form together n the nitrogen atom to which they are attached a saturated or unsaturated monocyclic or polycyclic heterocycle contain4 to 9 carbon atoms and one or more heteroatoms (O, N, S) and optionally substituted by one or more alkyl radicals, X represents a hydrogen atom, an alkyl or phenylalkyl radical, - alk represents an alkyl or alkylene radical, alk represents a hydroxyalkyl, hydroxyalkylene, alkoxyalkyl or alkoxyalkylene radical, it is understood that the alkyl, alkylene and alkoxy radicals and the alkyl, alkylene moieties , and alkoxy contain 1 to 4 straight or branched chain carbon atoms, the radicals and acyl portions contain 2 to 4 carbon atoms and the radicals and cycloalkyl portions contain 3 to 6 carbon atoms, as well as their salts and their racemates and enantiomers when the same they comprise at least one asymmetric center, to the preparation of a medicament destined to the treatment of the chronic alcoholism or the states due to the alcohol abuse.

2. Application of a compound of the formula (I) according to claim 1 for which R represents a methylene radical, a sulfur atom or an SO radical, Ri represents an optionally substituted phenyl radical, R 2 represents a phenyl or alkoxycarbonyl radical, R and Rs represent a hydrogen atom and R3 represents a phenylamino radical of which the phenyl nucleus is substituted by a carboxy radical, -alk-COOH, -S-alko-COOH, hydroxyalkyl, alko-COOH or alq-S03H under the form of salt, in the preparation of a drug intended for the treatment of chronic alcoholism or states due to alcohol abuse.

3. The application of a compound of the formula (I) according to claim 1 chosen from the following compounds: (2RS, 5SR) -l-. { 2- [3- (3- ((RS) -1-hydroxy-ethyl) phenyl) -ureido] acetyl} -5-phenyl tert-butyl proline, 2- acid. { 3-. { 3- [2- ((2S, 5R) -2-tert-butoxycarbonyl-5-pheny1-1-pyrrolidinyl) -2-oxo-ethyl] ureido} phenyl } -propionic, acid (2RS, 5SR) -. { 3-. { 3- [2- (2-tert-butoxycarbonyl-5-pheny1-1-pyrrolidinyl) -2-oxo-ethyl] ureido} phenylthio} -acetic, acid (2R, 4R) -3-. { 3- [2- (4-tert-butoxycarbonyl-2-fluoro-3-thiazolidinyl) -2-oxo-ethyl] ureido} phenylacetic, 2- acid. { 3-. { 3- [2- ((2R, 4R) -4-tert-butoxycarbonyl-2- (2-fluoro-phenyl) -3-thiazolidinyl) -2-oxo-ethyl] ureido} -phenyl} propionic, (RS) -l-. { 3-. { 3- [2- ((2R, 4R) -4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl) -2-oxo-ethyl] ureido} phenyl } etansul-fonato de potasio, - (RS) -l-. { 3-. { 3- [2- ((2S, 5R) -2-tert-butoxycarbonyl-5-pheny1-1-pyrrolidinyl) -2-oxo-ethyl] ureido} feni1 } potassium etansul-fonate, (2S, 5R) -3-. { 3- [2- (2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) -2-oxo-ethyl] ureido} potassium pheni1-methanesulfonate, (2S, 5R) -3- acid. { 3- [2- (2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) -2-oxo-ethyl] ureido} benzoic, acid (2RS, 5SR) -3-. { 3-. { 2- [2-tert-butoxycarbonyl-5- (2-fluoro-phenyl) -1-pyrrolidinyl] -2-oxo-ethyl} ureido} -benzoic acid (cis) -3-. { 3- [2- (2, 5-diphenyl-1-pyrrolidinyl) -2-oxo-ethyl] ureido} benzoic, acid (2RS, 5SR) -3-. { 2- [2- (2-hydroxy-phenyl) -5-phenyl-1-pyrrolidinyl] -2-oxo-ureido} phenylacetic, - (2R, 4R) -3- acid. { 3- [2- (4-tert-butoxycarbonyl-2-pheny1-3-thiazolidinyl) -2-oxo-ethyl] ureido} phenylacetic acid (2R, 4R) -3-. { 3- [2- (4-tert-butoxycarbonyl-2-pheny1-3-thiazolidinyl) -2-oxo ethyl] ureido} benzoic.

. The application of the compounds of the formula: F characterized in that - whether R represents a methylene radical, ethylene, SO, S02, CHOH or a sulfur atom, Rx represents a pyridyl radical optionally substituted by one or several alkyl radicals, furyl optionally substituted by one or more alkyl radicals, thienyl optionally substituted by one or more alkyl, quinolyl radicals optionally substituted by one or more alkyl radicals, naphthyl optionally substituted by one or more alkyl radicals, indolyl optionally substituted by one or more alkyl or phenyl radicals optionally substituted by one or more substituents chosen from the atoms of halogen and the alkyl, alkoxy, hydroxy, nitro, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, -CO-NR7R8, -NH-CO-CH3f trifluoromethyl or trifluoromethoxy radicals and R5 represents a hydrogen atom, - or R represents a methylene radical , Ri represents a hydrogen atom and R5 represents a phenyl radical, - or R represents a radical CHR6, Ri and R5 each represent a hydrogen atom, -R2 represents an alkoxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, -CONRgRio radical or phenyl optionally substituted by one or more substituents chosen from the alkyl radicals, alkoxy or hydroxy, -R3 represents a phenyl radical (optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio radicals), naphthyl, indolyl, quinolyl or phenylamino of which the phenyl nucleus is optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy, alkylthio, trifluoromethyl, carboxy, alkoxycarbonyl, hydroxy, nitro, amino, acyl, cyano, sulfamoyl, carbamoyl, hydroxyiminoalkyl, alkoxyiminoalkyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, -tetrazolyl, 5-tetrazolyl-alkyl, trifluoromethylsulfonamido, alkylsulfinyl, mono- or polyhydroxyalkyl, sulfo, -alk-0-CO-alk, -alk-COOX, -alk-O -alk, -alk '-COOX, -0-alkyl- COOX, -CH = CH-COOX, -CO-COOX, -alq-S03H in the form of salt, -CH = CH-alq ', -C (= NOH) -COOX, -S-alq-COOX, -0 -CH2-alq '-COOX, -CX = N-0-alq-COOX, -alk-N (OH) -CO-alk or 2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl , -R4 represents a hydrogen atom or an alkyl radical, -Re represents a phenyl radical, -R7 represents a hydrogen atom or an alkyl, phenylalkyl or phenyl radical optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy radicals and alkylthio, -R8 represents an alkyl, phenylalkyl or phenyl radical optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio radicals, or R and R8 form with the nitrogen atom to which they are the same a saturated or unsaturated monocyclic or polycyclic heterocycle containing 4 to 9 carbon atoms and one or more heteroatoms (0, N) and optionally substituted by one or more alkyl radicals, -Rg represents a hydrogen atom or an alkyl radical, cycloalkylalkyl, cycloalkyl, phenylalkyl or phenyl optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio radicals, -Rio represents an alkyl, cycloalkylalkyl, cycloalkyl, phenylalkyl or phenyl radical optionally substituted by one or more substituents chosen from the halogen atoms and the alkyl, alkoxy and alkylthio radicals, or R9 and Rio form together with the nitrogen atom to which they are attached a saturated or unsaturated monocyclic or polycyclic heterocycle containing 4 to 9 carbon atoms and one or more heteroatoms (0, N, S) and optionally substituted by one or more alkyl radicals, - X represents a hydrogen atom, an alkyl or phenylalkyl radical, -alk represents an alkyl or alkylene radical, alk represents a hydroxyalkyl, hydroxyalkylene, alkoxyalkyl or alkoxyalkylene radical, it is understood that the alkyl, alkylene and alkoxy radicals and the alkyl portions, Alkylene and alkoxy contain 1 to 4 straight or branched chain carbon atoms, the radicals and acyl portions contain 2 to 4 carbon atoms and the radicals and cycloalkyl portions contain 3 to 6 carbon atoms, as well as their salts and their racemic and enantiomers when they comprise at least one asymmetric center, in the preparation of a medicament that allows the patient to reduce by himself your alcohol consumption

5. The application of a compound of the formula (I) according to claim 4, for which R represents a methylene radical, a sulfur atom or an SO radical, Ri represents an optionally substituted phenyl radical, R 2 represents a phenyl radical or alkoxycarbonyl, R and Rs represent a hydrogen atom and R3 represents a phenylamino radical of which the phenyl nucleus is substituted by a carboxy radical, -alk-COOH, -S-alq-COOH, hydroxyalkyl, alko- COOH or alq-S03H in the form of salt, for the preparation of a medication that allows the patient to reduce his alcohol consumption by himself.

6. The application of a compound of the formula (I) according to claim 5, chosen from the following compounds: - (2RS, 5SR) -l-. { 2- [3- (3- ((RS) -1-hydroxyethyl) phenyl) -ureido] acetyl} -5-phenyl tert-butyl proline, 2- acid. { 3-. { 3- [2- ((2S, 5R) -2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) -2-oxo-ethyl] ureido} phenyl } -propionic, - acid (2RS, 5SR) -. { 3-. { 3- [2- (2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) -2-oxo-ethyl] ureido} phenylthio} -acetic, acid (2R, 4R) -3-. { 3- [2- (4-tert-butoxycarbonyl-2-fluoro-3-thiazolidinyl) -2-oxo-ethyl] ureido} phenylacetic, - 2- acid. { 3-. { 3- [2- ((2R, R) -4-tert-butoxycarbonyl-2- (2-fluoro-phenyl) -3-thiazolidinyl) -2-oxo-ethyl] ureido} -phenyl} propionic, (RS) -l-. { 3-. { 3- [2- ((2R, 4R) -4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl) -2-oxo-ethyl] ureido} phenyl } etansul-fonato potassium, (RS) -l-. { 3-. { 3- [2- ((2S, 5R) -2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) -2-oxo-ethyl] ureido} Phenyl potassium hydrogensulfonate, (2S, 5R) -3-. { 3- [2- (2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) -2-oxo-ethyl] ureido} phenyl } potassium methanesulfonate, (2S, 5R) -3- acid. { 3- [2- (2-tert-butoxycarbonyl-5-pheny1-1-pyrrolidinyl) -2-oxo-ethyl] ureido} benzoic, acid (2RS, 5SR) -3-. { 3-. { 2- [2-tert-butoxycarbonyl-5- (2-fluoro-phenyl) -1-pyrrolidinyl] -2-oxo-ethyl} ureido} -benzoic acid (cis) -3-. { 3- [2- (2, 5-diphenyl-1-pyrrolidinyl) -2-oxo-ethyl] ureido} benzoic, acid (2RS, 5SR) -3-. { 2- [2- (2-hydroxy-phenyl) -5-phenyl-1-pyrrolidinyl] -2-oxo-ureido} phenylacetic acid (2R, 4R) -3-. { 3- [2- (4-tert-butoxycarbonyl-2-pheny1-3-thiazolidinyl) -2-oxo-ethyl] ureido} phenylacetic, - (2R, 4R) -3- acid. { 3- [2-. { 4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl) -2-oxo-ethyl] ureido} enzoic, acid 2-. { 3-. { 3- [2- ((1RS, 2R, 4R) -4-tert-butoxy-carbo-nil-2- (2-fluoro-phenyl) -l-oxide-3-thiazolidinyl) -2-oxo-ethyl] ureide } phenyl } propionic, - (2R, 4R) -3- acid. { 3- [2- (4-tert-butoxycarbonyl-2- (2,3-difluoro-phenyl) -3-thiazolidinyl) -2-oxo-ethyl] ureido} phenylacetic, (2RS, 5SR) -l-. { 2-. { 3- [(E) -3- (1-hydroxyimino-ethyl) -phenyl] ureido} acetyl } -5-phenylprolinate of tert-butyl, its racemic and enantiomers which contain at least one asymmetric carbon and its salts, in the preparation of a medicament that allows the patient to reduce himself alcohol consumption.

7. The application of acid 2-. { 3-. { 3- [2- ((2R, 4R) -4-tert-butoxycarbonyl-2- (2-fluoro-phenyl) -3-thiazolidinyl) -2-oxo-ethyl] ureido} phenyl } propionic in the preparation of a medication that allows the patient to reduce his alcohol consumption by himself.