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Definitions

• the present invention relates to new aminotriazolone compounds, their preparation process and the pharmaceutical compositions containing them.
• the compounds of the present invention have an original structure and find their use in the treatment of pathologies linked to neuropeptide Y (NPY).
• Neuropeptide Y is a peptide of 36 amino acids, close to peptide YY (PYY) and pancreatic polypeptides (PP). Originally isolated from the pig brain (Proc. Natl. Acad. Sci., 1982, 79, 5485), NPY is widely distributed in mammals in the central and peripheral nervous system. This neurotransmitter is present in high concentrations in the nerve fibers of the brain, but also of the heart, sympathetic ganglia, blood vessels and smooth muscles of the vas deferens and the gastrointestinal tract. It is responsible for various physiological effects which are exerted via specific receptors (Y).
• Y specific receptors
• NPY neuropeptide-N-phenylcholine
• NPY neuropeptide-N-phenylcholine
• HPA axis Hide-Pituitary - Adrenal
• It also has anxiolytic and sedative properties (Neuropsychopharmacology, 1993, 8, 357), a strong vasoconstrictor power (Eur. J. PharmacoL, 1984, 85, 519) which induces an increase in blood pressure, and also has an effect on the circadian rhythm (Neuroscience and Biobehavioral Reviews, 1995, 19, 349).
• NPY receptor ligands have been described recently.
• the compounds of the invention apart from the fact that they are new, have shown an inhibitory action in vivo on food gain and weight gain. This effect is exerted via a bond with NPY receptors.
• the compounds of the invention may therefore be used in the treatment of pathologies requiring a ligand for NPY receptors, in particular in the treatment of pathologies linked to eating behavior or energy balance disorders, such as diabetes, obesity, bulimia, anorexia nervosa, but also in the treatment of high blood pressure, anxiety, depression, epilepsy, sexual dysfunctions and sleep disorders.
• the present invention relates more particularly to the compounds of formula (I):
• R 1 and R 2 independently of one another, represent a hydrogen atom or an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, heteroaryl unsubstituted or substituted, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, it being understood that at least one of the groups R 1 and R 2 is different from a hydrogen atom,
• R 3 represents a hydrogen atom or an unsubstituted or substituted alkyl group, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl or unsubstituted heterocycloalkyl substituted or substituted, • i represents a group of formula (II):
• W represents a bond or an alkylene chain containing from 1 to 6 carbon atoms
• B represents a mono or polycyclic group, aromatic or not, containing 3 to 10 vertices, which can contain from 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, and containing at least one oxo substituent, -COR (in which R represents a hydrogen atom or an alkyl, alkoxy, amino, alkylamino, dialkylamino) or hydroxy group, and which may contain one or more unsaturations as well as a or several substituents (in addition to the oxo, COR or hydroxy group defined above) chosen from alkyl, alkoxy, aryl, arylalkyl, and halogen atoms,
• R 5 represents a hydrogen atom or an alkyl group
• A represents a group chosen from -A 2 -, -A ⁇ -A 2 -, -A 2 -A ⁇ - or -A ⁇ -A 2 -Ai- in which Ai is an alkylene, alkenylene or alkynylene group, and A 2 represents an unsubstituted or substituted phenylene group, unsubstituted or substituted naphthylene, unsubstituted or substituted cycloalkylene, unsubstituted or substituted heteroarylene or unsubstituted or substituted heterocycloalkylene,
• alkyl designates a linear or branched group of 1 to 6 carbon atoms
• alkylene denotes a bivalent linear or branched radical containing from 1 to 6 carbon atoms
• alkenyl denotes a linear or branched group containing from 2 to 6 carbon atoms and from 1 to 3 double bonds
• alkenylene designates a bivalent radical, linear or branched, containing from 2 to 6 carbon atoms and 1 to 3 double bonds
• alkynyl designates a linear or branched group containing from 2 to 6 carbon atoms and from 1 to 3 triple bonds
• alkynylene designates a linear or branched bivalent radical containing from 2 to 6 carbon atoms and from 1 to 3 triple bonds
• aryl denotes a phenyl, naphthyl, biphenyl, dihydronapthyl or tetrahydronapthyl group
• heteroaryl designates an unsaturated or partially unsaturated mono or bicyclic group containing from 5 to 11 links, containing from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur,
• phenylene and naphthylene respectively denote bivalent phenyl and naphthyl radicals
• heteroarylene denotes a bivalent heteroaryl radical as defined above
• heterocycloalkyl designates a saturated mono or bicyclic group containing from 4 to 11 links, containing from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur,
• heterocycloalkylene denotes a bivalent mono or bicyclic saturated radical containing from 4 to 11 links, containing from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur,
• cycloalkyl designates a saturated cyclic group containing from 3 to 8 carbon atoms
• cycloalkylene designates a saturated cyclic bivalent group containing from 3 to 8 carbon atoms
• substituted assigned to the terms aryl, or heteroaryl, means that these groups are substituted on their cyclic part by 1 to 5 substituents, identical or different, chosen from linear or branched (-) alkyl, alkoxy (C ⁇ -C 6 ) linear or branched, halogen, hydroxy, perhaloalkyl (C ⁇ -C 6 ) linear or branched, nitro, amino (unsubstituted or substituted by one or two groups chosen from alkyl (C ⁇ -C 6 ) linear or branched, aryl and heteroaryl) , linear or branched acyl (C ⁇ -C 6 ), aminocarbonyl (optionally substituted on the nitrogen atom by one or two groups alkyl (Ci-C 6) linear or branched), acylamino (Ci-C 6) linear or branched alkoxycarbonyl (C ⁇ -C6) linear or branched, formyl, carboxy, sulpho, sulphin
• substituted assigned to the terms alkyl, alkenyl or alkynyl means that these groups may be substituted by one or more chosen groups hydroxy, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted heterocycloalkyl or substituted or halogen atoms,
• substituted assigned to the terms phenylene, naphthylene or heteroarylene means that these groups are substituted by one to three identical or different groups, chosen from linear or branched (C ⁇ -C 6 ) alkyl, alkoxy (C ! -C 6 ) linear or branched, halogen, hydroxy, perhaloalkyl (-C ⁇ ) linear or branched, nitro, amino
• the invention relates to the compounds of formula (I) for which A represents a phenylene group and more particularly an unsubstituted phenylene group.
• R 1 and R are the hydrogen atom and the aryl group, for example pyridyl or phenyl, these groups being unsubstituted or substituted.
• the invention relates more particularly to the compounds of formula (I) for which R 3 and R 5 represent a hydrogen atom.
• the preferred R groups are the groups of formula (H '):
• n 0, 1, 2 or 3
• X represents an oxygen or sulfur atom and in this case Y represents a CH 2 group, or X represents an NH group and in this case Y represents a CH 2 group or an oxygen atom.
• R 4 groups are the groups of formula (II "):
• n 0, 1 or 2
• Z represents a hydroxy or amino group
• C represents a 6-membered aromatic ring, optionally substituted and possibly containing from 1 to 3 nitrogen atoms.
• the invention relates to the compounds of formula (I) for which V represents a CO or CH group.
• the invention relates to the compounds of formula (I) which are: N - [(3R) -2-oxotetrahydro-3-furanyl] -4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl ] -4,5- dihydro-1H-1,2,4-triazol-3-yl ⁇ amino) benzamide / 4- ⁇ [1 - (3-Methylphenyl) -5-oxo-4,5-dihydro- 1H- 1,2,4-triazol-3-yl] amino ⁇ -N - [(3R) -2- oxotetrahydro-3-furanyljbenzamide / 4 - ⁇ [1- (3-Methylphenyl) -5-oxo-4,5- dihydro-1H-1,2,4-triazol-3-yl] amino ⁇ -N - [(3R) -2- oxotetrahydro-3-thi
• the present invention also relates to the process for preparing the compounds of formula (I) characterized in that the compound of formula (III) is used as starting material:
• R a represents a linear or branched alkoxy group (C ⁇ -C 6 ),
• the present invention also relates to pharmaceutical compositions containing as active principle at least one compound of formula (I), alone or in combination with one or more inert non-toxic, pharmaceutically acceptable excipients or vehicles.
• compositions according to the invention there may be mentioned more particularly those which are suitable for oral, parenteral, nasal, transdermal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments , dermal gels, etc.
• the useful dosage varies according to the age and weight of the patient, the nature and severity of the condition and the route of administration. This can be oral, nasal, rectal or parenteral. In general, the unit dosage ranges from 0.05 to 500 mg for a treatment in 1 to 3 doses per 24 hours.
• Example 1 4 - [(1-cyclohexyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) amino] -N - [(3S) -2-oxotetrahydro trifluoroacetate -3-furanyl] benzamide
• the procedure is as in Example 43, replacing in Step B 3- (trifluoromethyl) - phenylhydrazine with cyclohexylhydrazine.
• Mass spectrum: ESI-MS: MH + 386
• Example 3 4 - [(1-Cyclohexyl-5-oxo-4,5-dihydro-1H-1,2,4-triazoI-3-yl) ammo] -N- ⁇ [(1R *, 2R *) - 2-hydroxycyclohexyl] methyl ⁇ benzamide
• Example 8 N - [(1R, 2S) -2-hydroxy-2,3-dihydro-lfi-indèn-1-yl] -4 - [(5-oxo-1-phenyl-4,5-dihydro-1H -l, 2,4-triazol-3-yl) amino] benzamide
• Example 10 N - [(1S, 2R) -2-hydroxy-2,3-dihydro-III? -Inden-1-yl] -3 - [(5-oxo-1-phenyl-4,5-dihydro- lH-l, 2,4-triazol-3-yl) amino] benzamide
• the procedure is as in Example 9, replacing in stage D the (1R, 2S) -1-amino-2,3-dihydro-1H-inden-2-ol with the (1S, 2R) -l-amino-2 , 3-dihydro-lH-inden-2-ol
• Example 18 4 - ⁇ [1- (3-Methylphenyl) -5-oxo-4,5-dihydro-lfl-1,2,4-triazol-3-yl] amino ⁇ - N - [(3R) -2 -oxotétrahydro-3-furanyl] benzamide
• Example 19 4 - ⁇ [1- (3-Methylphenyl) -5-oxo-4,5-dihydro-li ⁇ -1,2,4-triazol-3-yl] amino ⁇ - N - [(3R) -2 -oxotétrahydro-3-thienyl] benzamide
• Example 21 4 - ⁇ [1- (3-Methylphenyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl] amino ⁇ - N- (2-oxo-3 -azépanyl) benzamide
• Example 23 4 - ⁇ [1- (3,5-Dimethylphenyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl] amino ⁇ -N - [(1R, 2S) -2-hydroxy-2,3-dihydro-ljh-inden-l-yl] benzamide
• Example 25 4 - ⁇ [1- (4-Methoxyphenyl) -5-oxo-4,5-dihydro-1JEr-1,2,4-triazol-3-yl] amino ⁇ -N - [(3R) -2 -oxotétrahydro-3-furanyl] benzamide
• Example 43 The procedure is as in Example 43, replacing 3- (trifluoromethyl) - phenylhydrazine in stage B with 1- (4-methoxyphenyl) hydrazine.
• Example 26 4 - ⁇ [1- (4-Methoxyphenyl) -5-oxo-4,5-dihydro-li ⁇ -1,2,4-triazol-3-yl] amino ⁇ -N- (2-oxo-3 -azépanyl) benzamide
• Example 43 The procedure is as in Example 43, replacing 3- (trifluoromethyl) - phenylhydrazine in stage B with l- (3-methoxyphenyl) hydrazine, and replacing R (+) - ⁇ -amino-butyrolactone in stage D (1R, 2S) -1 amino-2,3-dihydro-1H-inden-2-ol.
• Example 43 The procedure is as in Example 43, replacing 3- (trifluoromethyl) - phenylhydrazine in stage B with 1- (4-fluorophenyl) hydrazine, and replacing R (+) - ⁇ -amino-butyrolactone in stage D (1R, 2S) -1 amino-2,3-dihydro-1H-inden-2-ol.
• Example 30 4 - ⁇ [1- (3-Chlorophenyl) -5-oxo-4,5-dihydro-1H r -l, 2,4-triazol-3-yl] amino ⁇ - N - [(3R) - 2-oxotetrahydro-3-furanyl] benzamide
• Example 32 4 - ⁇ [1- (3-Chlorophenyl) -5-oxo-4,5-dihydro-1 J Hl, 2,4-triazol-3-yl] amino ⁇ - N- (2-oxo-3 -azépanyl) benzamide
• the procedure is as in Example 29, replacing in stage D the (3R) -3-aminodihydro- 2 (3H) -thiophenone with 3-amino-2-azepanone.
• Mass spectrum: ESI-MS: M ⁇ + 441
• Example 33 4 - ⁇ [1- (3-Chlorophenyl) -5-oxo-4,5-dihydro-l Tl, 2,4-triazol-3-yl] amino ⁇ - N ⁇ [(1R, 25) - l-hydroxy-2,3-dihydro-l -inden-2-yl] benzamide
• Example 34 4 - ⁇ [1- (4-Chlorophenyl) -5-oxo-4,5-dihydro-lfi-1,2,4-triazol-3-yl] amino ⁇ - N - [(3R) -2 -oxotétrahydro-3-furanyl] benzamide
• Example 35 4 - ⁇ [1- (4-Chlorophenyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl] amino ⁇ - N- ⁇ [(1S *, 2R *) - 2-hydroxycyclohexyl] methyl ⁇ benzamide
• Example 36 4 - ⁇ [1- (4-Chlorophenyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl] amino ⁇ - N - ⁇ [(1R *, 2R *) - 2-hydroxycyclohexyl] methyl ⁇ benzamide
• Example 38 (1R *, 2S *) - 2 - [(4 - ⁇ [1- (4-chlorophenyl) -5-oxo-4,5-dihydro-1H-1,2,4- triazol ⁇ 3-yl ] amino ⁇ benzoyl) amino] ethyl cyclohexanecarboxylate
• Example 39 4 - ( ⁇ [1- (3-ChlorophenyI) -5-oxo-4,5-dihydro-li ⁇ -1,2,4-triazol-3-yI] amino ⁇ methyl) -N - [(1R 5 2S) -2-hydroxy-2,3-dihydro-1 J H-inden-1-yl] benzamide
• Example 43 The procedure is as in Example 43, replacing ethyl 4-aminobenzoate in stage A with ethyl 4- (aminomethyl) benzoate, replacing 3- (trifluoromethyl) -phenylhydrazine in stage B with l- ( 3-chlorophenyl) hydrazine, and replacing in stage D the R (+) - ⁇ -amino-butyrolactone by the (1R, 2S) -l-amino-2,3-dihydro-1H-inden-
• Example 40 4 - ( ⁇ [1- (3-Chlorophenyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl] amino ⁇ methyl) -N - [(15 , 2R) -2-hydroxy-2,3-dihydro-lH-inden-l-yl] benzamide
• Example 41 4 - ⁇ [1- (3,5-Dichlorophenyl) -5-oxo-4,5-dihydro-1 J Hl, 2,4-triazol ⁇ 3-yl] amino ⁇ -N - [(1R, 2S) -2-hydroxy-2,3-dihydro-1 J H-inden-1-yl] benzamide
• the procedure is as in Example 43, replacing 3- (trifluoromethyl) - phenylhydrazine in stage B with l- (3,5-dichlorophenyl) hydrazine, and replacing R (+) - ⁇ -amino- in stage D butyrolactone with (1R, 2S) -1-amino-2,3-dihydro-1H-inden-2-ol.
• Stage B 4 - ( ⁇ 5-Oxo-l- [3- (trifluoromethyl) phenyl] -4,5-dihydro-l ⁇ .-1,2,4-triazol-3-yljamino) ethyl benzoate
• the product obtained is dissolved in a solution of trifluoroacetic acid at 10% in dioxane and heated at 50 ° C overnight.
• the sentence organic is concentrated and the solid obtained is filtered and washed with ethyl ether (3 times) then dried under vacuum to yield the title product.
• Stage C 4 - ( ⁇ 5-oxo-l- [3- (trtfluoromethyl) phenyl] -4,5-dihydro-l * ⁇ -1,2,4-triazol -3-yl ⁇ amino) benzoic acid
• Example 48 N - [(4R) -3-oxoisoxazolidinyl] -4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl] -
• Example 50 N ⁇ (2-oxo-3-azepanyl) -4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl] ⁇ 4,5 ⁇ dihydro-1H-1,2,4-triazol- 3-yl ⁇ amino) benzamide
• Example 43 The procedure is as in Example 43, replacing the R (+) - ⁇ -aminobutyrolactone in stage D with 3-amino-2-azepanone.
• Example 52 N - [(lS, 2R) -2-hydroxy-2,3-dihydro-l ⁇ -indèn-l-yl] -4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl] -4,5-dihydro-1 / M, 2,4-triazol-3-yl ⁇ amino) benzamide
• Example 54 N- (5-chloro-2-hydroxyphenyl) -4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl] - 4,5-dihydro-l-1,2,4-triazol- 3-yl ⁇ amino) benzamide
• the procedure is as in Example 43, replacing R (+) - ⁇ -aminobutyrolactone in stage D with 2-amino-4-chlorophenol.
• Mass spectrum: ESI-MS: MH + 490
• Example 55 4- ⁇ Methyl [1- (3-methylphenyl) -5-oxo-4,5-dmydro-l # -l, 2,4-triazol-3-yl] amino ⁇ -N- [(3R) -2-oxotetrahydro-3-furanyl] benzamide
• Example 43 The procedure is as in Example 43, replacing 3- (trifluoromethyl) - phenylhydrazine in stage B with l- (3-nitrophenyl) hydrazine, and replacing R (+) - ⁇ - aminobutyrolactone in stage D with ( lR, 2S) -l-amino-2,3-dihydro-lH-inden-2-ol.
• Example 57 4 - ( ⁇ l- [4- (AminosuIfonyI) phenyI] -5-oxo-4,5-dihydro-1 / M, 2,4-triazoI-3- yl ⁇ amino) -N - [(1R , 2S) -2-hydroxy-2,3-dihydro-lfl-inden-l-yl] benzamide
• EXAMPLE 58 Acid of 4- ⁇ 3- [4 - ( ⁇ [(1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] amino ⁇ carbonyI) anilino] -5-oxo -4,5-dihydro-lJ7-l, 2,4-triazol-l-yl ⁇ benzenesulfonic
• the procedure is as in Example 43, replacing 3- (trifluoromethyl) - phenylhydrazine in stage B with 4-hydrazinobenzenesulfonic acid, and replacing R (+) - ⁇ -aminobutyrolactone in stage D with (1R, 2S ) -l-amino-2,3-dihydro-lH-inden-2-ol.
• Example 60 N - [(1R, 2S) -2-hydroxy-2,3-dihydro-1 J fiT-inden-1-yl] -4 - ⁇ [1- (2-naphthyl) -5- oxo-4 , 5-dihydro-lH-l, 2,4-triazol-3-yl] amino ⁇ benzamide
• Example 43 The procedure is as in Example 43, replacing 3- (trifluoromethyl) - phenylhydrazine in stage B with l- (2-naphthyl) hydrazine, and replacing R (+) - ⁇ - aminobutyrolactone in stage D with ( lR, 2S) -l-amino-2,3-dihydro-lH-inden-2-ol.
• Example 43 The procedure is as in Example 43, replacing 3- (trifluoromethyl) - phenylhydrazine in stage B with 2-hydrazinoquinoline, and replacing R (+) - ⁇ - aminobutyrolactone in stage D with (1R, 2S) - 1-2,3-amino-dihydro-1H-inden-2-ol.
• Example 62 4 - ⁇ [1- (1,3-Benzothiazol-2-yl) -5-oxo-4,5-dihydro-1 J Hl, 2,4-triazol-3-yl] amino ⁇ -N- [(1R, 2-hydroxy-2,3-dihydro-liI-mdèn-l-yI] benzamide
• the procedure is as in Example 43, replacing 3- (trifluoromethyl) - phenylhydrazine in stage B with 2-hydrazino-1,3-benzothiazole, and replacing in R stage D (+) - -aminobutyrolactone with ( lR, 2S) -l-amino-2,3-dihydro-lH-inden-2-ol.
• Mass spectrum: ESI-MS: M- ⁇ 483
• Example 63 5- [4 - ( ⁇ [(lS, 2R) -2 ⁇ hydroxy-2,3-dihydro-lIMndèn-l-yl] amino ⁇ methyl) anilino] -2-phenyl-2,4-dihydro- 3fl-l, 2,4-triazol-3-one
• Example 76 The procedure is as in Example 76, replacing in step A the acid 4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl] -4,5-dihydro- IH- 1,2,4-triazol -3-yl ⁇ amino) benzoic acid (obtained in stage C of Example 43) with 4 - [(5-oxo-1-phenyl-4,5-dihydro-1H-1,2,4-) acid triazol-3-yl) amino] benzoic (obtained in stage C of Example 4) and by replacing in stage C the
• Example 64 5- [4 - ( ⁇ [(1R, 2S) -2-hydroxy-2,3-dihydro-1 T-inden-1-yl] amino ⁇ methyl) anilino] -2-phenyl-2 trifluoroacetate , 4-dihydro-3H-l, 2,4-triazoI-3-one
• Example 65 Trifluoroacetate of (1R *, 2S *) - 2 - [(4 - ⁇ [1- (3-methylphenyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-3 -yl] amino ⁇ benzyI) amino] cyclopentanecarboxamide
• Example 76 The procedure is as in Example 76, replacing in step A the acid 4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl] -4,5-dihydro-1H-1,2,4-triazol -3-yl ⁇ amino) benzoic acid (obtained in stage C of Example 43) with 4 - ⁇ [1- (3-methylphenyl) -5-oxo-4,5-dihydro-1H-1 acid, 2,4-triazol-3-yl] amino ⁇ benzoic (obtained in Stage C of Example 18) and replacing in Stage C the R (+) - -aminobutyrolactone with (1R *, 2S *) - 2 - aminocyclopentanecarboxamide.
• Example 70 5- [4 - ( ⁇ [(1R, 25) -2-hydroxy-2,3-dihydro-lfl-inden-1-yl] amino ⁇ methyl) anilino] -2- (3-methylphenyl) trifluoroacetate ) -2,4-dihydro-3H-1,2,4-triazol-3-one
• the procedure is as in Example 65, replacing in stage C the (1R *, 2S *) - 2-aminocyclopentanecarboxamide with the (1R, 2S) -l-amino-2,3-dihydro-1H-inden-2-ol .
• Mass spectrum: ESI-MS: M ⁇ + 428
• Example 76 The procedure is as in Example 76, replacing in step A the acid 4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl] -4,5-dihydro-1H-1,2,4-triazol -3-yl ⁇ amino) benzoic acid (obtained in stage C of Example 43) with 4 - ⁇ [1- (3-chlorophenyl) -5-oxo-4,5-dihydro-1H- 1 acid, 2,4-triazol-3-yl] amino ⁇ benzoic (obtained in stage C of Example 29) and replacing in stage C the R (+) - ⁇ -aminobutyrolactone by 3-amino-2-azepanone.
• Example 72 2- (3-Chlorophenyl) -5- [4 - ( ⁇ [(1S, 2R) -2-hydroxy-2,3-dihydro-lif-inden-1-yI] amino ⁇ methyl) aniino trifluoroacetate ] -2,4-dihydro-3H-1,2,4-triazol-3-one
• Example 73 2- (3-Chlorophenyl) -5- [4 - ( ⁇ [(1R, 25) -2-hydroxy-2,3-dihydro-li ⁇ -inden-1-yl] amino ⁇ methyl) anilino trifluoroacetate ] -2,4-dihydro-3H-1,2,4-triazol-3-one
• Example 74 2- (4-Chlorophenyl) -5- ⁇ 4 - [(2-hydroxyanilino) methyl] anilino ⁇ -2,4-dihydro-3J2-1,2,4-triazol-3-one trifluoroacetate
• the procedure is as in Example 76, replacing in step A the acid 4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl] -4,5-dihydro-1H-1,2,4-triazol -3-yl ⁇ amino) benzoic acid (obtained in stage C of Example 43) with 4 - ⁇ [1- (4-chlorophenyl) -5-oxo-4,5-dihydro-1H- 1 acid, 2,4-triazol-3-yl] amino ⁇ benzoic (obtained in stage C of Example 34) and replacing in stage C the R (+) - ⁇ -aminobutyrolactone with 2-aminophenol.
• Example 75 5- [4 - ( ⁇ benzyI [(lS *, 2S *) - 2-hydroxycyclohexyl] amino ⁇ methyl) anilino] -2- (4-chlorophenyl) -2,4-dihydro-3H-1 trifluoroacetate , 2,4-triazol- 3-one
• Example 76 5- [4 - ( ⁇ [(3R) -2-oxotetrahydro-3-furanyl] amino ⁇ methyl) anilino] hydrochloride -2- [3- (trifluoromethyl) phenyl] -2,4-dihydro-3H -1,4,4-triazol-3- one
• Stage B 4 ⁇ ( ⁇ 5-Oxo-l- [3- (trifluoromethyl) phenyl] -4,5-dihydro-1H-1,2,4-triazol-3-yl ⁇ amino) benzaldehyde
• IM lithium aluminum hydride
• tetrahydrofuran 50 ml
• a solution in tetrahydrofuran 100 ml of the compound obtained in stage A under an inert atmosphere and at - 40 ° C.
• reaction medium After one hour of stirring at -40 ° C, the reaction medium is brought to 0 ° C until complete disappearance of the starting product, then cooled to -10 ° C and the excess of reducing agent is destroyed by slow addition d 'water.
• the expected product is extracted with ethyl acetate. The organic phase is washed with water, then washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title product.
• Stage C 5- [4 - ( ⁇ [(3R) -2-Oxotetrahydro-3-furanyl] amino ⁇ methyl) anilino] hydrochloride -2- [3- (trifluoromethyl) phenyl] -2,4-dihydro-3H -1,4,4-triazol-3-one
• Example 77 5- [4 - ( ⁇ [(4R) -3-oxoisoxazolidinyl] amino ⁇ methyl) anilino] -2- [3- (trifluoromethyl) phenyl] -2,4-dihydro-3H-1,2 hydrochloride , 4-triazol-3-one
• Example 79 Trifluoroacetate of (lR *, 2S *) - 2 - ⁇ [4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl) -4,5-dihydro-lfl-1,2,4- triazol-3-yl ⁇ amino) benzyl] amino ⁇ cyclopentanecarboxamide
• Example 80 5- [4 - ( ⁇ [(1R *, 2R *) - 2-hydroxycyclohexyl] amino ⁇ methyl) anilino] -2- [3- (trifluoromethyl) phenyl] -2,4-dihydro-3fl trifluoroacetate -1,4,4-triazoI-3-one
• Example 81 Trifluoroacetate of (1R * 2S *) - 2 - ⁇ [4 - ( ⁇ 5-oxo-l- [3- (trifluoromethyl) phenyl) -4,5-dihydro-lfl-1,2,4-triazol -3-yl ⁇ amino) benzyl] amino ⁇ cyclohexanecarboxamide
• Example 82 Trifluoroacetate of 5- (4 - ⁇ [(3 ⁇ hydroxy-2-pyridinyl) ammo] methyl ⁇ anilino) -2- [3- (trifluoromethyl) phenyl] -2,4-dihydro-3 J - ⁇ - l, 2,4-triazol-3- one
• Example 83 5- [4 - ( ⁇ [(1R, 25) -2-hydroxy-2,3-dihydro-lfl-inden-1-yl] amino ⁇ methyl) anilino] trifluoroacetate] -2- [3- ( trifluoromethyl) phenyl] -2,4-dihydro-3J ⁇ -1, 2,4-triazol-3-one
• Example 84 5- [4 - ( ⁇ benzyl [(15 , *, 2S *) - 2-hydroxycyclohexyl] amino ⁇ methyl) anilino] -2- [3- (trifluoromethyl) phenyl] -2,4-dihydro trifluoroacetate -3fl- l, 2,4-triazol-3-one
• the products of the invention were treated in vivo in the Wistar rat subjected to a food restriction of 24 hours, in order to evaluate their influence on food intake.
• the animals used are male Wistar rats (275-300 g).
• Rats are distributed individually in cages with mesh floors and free access to food and drink. The animals are kept at the pet store under controlled temperature, humidity and light conditions for a period of 6 days before carrying out the treatments.
• the synopsis of the experiments is as follows:
• the tested products are dissolved immediately in 10% DMSO + Solutol HS 15 at 10%), depending on their solubility, and are administered intraperitoneally (IP), at a dose of 5 or 7.5 mg / kg and at a volume of 2.0 ml / kg.
• IP intraperitoneally
• the compounds of the invention show a very good percentage of inhibition of food intake: the percentage of inhibition of food intake of the batch treated relative to the Food intake vehicle control is calculated for each time (2, 3, 4, 5 or 7 hours after treatment) and analyzed with a single factor ANONA test (treatment factor).
• the capacity of the compounds of the invention to bind to ⁇ PY receptors was measured on different cell lines each expressing one of the receptor subtypes studied.
• Competitive binding experiments were carried out using the peptide [IJ-PYY as radioligand at concentrations varying from 15 to 65 pM.
• the non-specific fraction is measured in the presence of a concentration of 1 ⁇ M of ⁇ PY.
• the cells are incubated for a period varying from 1 to 2 hours depending on the lines, and the radioactivity is collected after filtration on a GF / C filter treated with 0.1% PEI, before being measured.
• IC 50 The results are expressed in IC 50 . It appears that the compounds of the invention are capable of displacing the reference ligand significantly: the IC 50 vary from a few nanomoles to a few hundred nanomoles.
• the acute toxicity was assessed after oral administration to groups of 8 mice (26 ⁇ 6 grams) of increasing doses of product to be studied. The animals were observed at regular intervals during the first day and daily during the two weeks following the treatment.

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