AU761586B2 - New aminotriazole compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

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AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT too.

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Application Number: Lodged: Invention Title: NEW AMINOTRIAZOLE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING

THEM

The following statement is a full description of this invention, including the best method of performing it known to us The present invention relates to new aminotriazole compounds, to a process for their preparation and to pharmaceutical compositions containing them.

The compounds of the present invention have a novel structure characterised by the combination of an aminotriazole group, a hydrazide structure and an aromatic-type spacer.

The compounds are used in the treatment of pathologies associated with the neuropeptide Y (NPY).

The Neuropeptide Y (NPY) is a peptide of 36 amino acids, related to the peptide YY (PYY) and to pancreatic polypeptides Originally isolated from pig brain (Proc. Natl.

Acad. Sci., 1982, 79, 5485), NPY is widely distributed in mammals at the level of the :10 central and peripheral nervous systems. This neurotransmitter is present in high concentrations in nerve fibres of the brain, but also of the heart, the sympathetic ganglia, blood vessels and smooth muscles of the vas deferens and of the gastrointestinal tract. It is responsible for various physiological effects which are exerted via the intermediary of specific receptors The latter form a heterogeneous group, 6 sub-types of which have been identified to date Y 1 to Y 6 (Pharmacological Reviews, 1998, 50, 143). NPY is involved in eating behaviour by strongly stimulating food intake (Proc. Natl. Acad. Sci..

1985, 82, 3940), or by exerting a regulatory role on the HPA (hypothalamic-pituitaryadrenal) axis of Neuroendocrinol., 1995, 7, 273). It also exhibits anxiolytic and sedative properties (Neuropsychopharmacology, 1993, 8, 357), a strong vasoconstrictive ability 20 (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).

Various NPY receptor ligands have been described recently. By way of example, there may be mentioned cyclic peptide compounds (WO 9400486), amino acid compounds of arginine (WO 9417035) or non-peptide compounds (WO 9827063).

In addition to the fact that the compounds of the invention are new, they have demonstrated an in vivo inhibitory action on food intake and weight gain. That effect is exerted via the intermediary of binding to the NPY receptors. It will thus be possible to use the compounds of the invention in the treatment of pathologies in which an NPY receptor ligand is necessary, especially in the treatment of pathologies associated with eating behaviour disorders or energy balance disorders, such as diabetes, obesity, bulimia, anorexia nervosa, and also in the treatment of arterial hypertension, anxiety, depression, epilepsy, sexual dysfunctions and sleep disorders.

The present invention relates especially to compounds of formula

NH-A-CO-NH-(NH)-W-Z

Y -N wherein: nisor 1, W represents a -CO- group or an S(0)q group wherein q is 0, 1 or 2, the grouping

X.

Y -Z 4 represents a group selected from N-i

R

N-,

N'N

H

N-N

R

N

N-N

H R

R

G4 Z represents an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group, A represents a grouping selected from -A 2

-A

1

-A

2

-A

2 -Ai- and -A 1

-A

2

-A

1 wherein A 1 is an alkylene group and A 2 represents an optionally substituted phenylene, optionally substituted naphthylene, cycloalkylene, or optionally substituted heteroarylene group, R represents a hydrogen atom, or an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group,

R

1 represents an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base, wherein the term "alkyl" denotes a linear or branched group having from 1 to 6 carbon atoms, the term "alkylene" denotes a linear or branched bivalent radical containing from 1 to 6 carbon atoms, the term alkenyl denotes a linear or branched group having from 2 to 6 carbon atoms and from 1 to 3 double bond, the term alkynyl denotes a linear or branched group having from 2 to 6 carbon atoms and from 1 to 3 triple bond, the term "aryl" denotes a phenyl, naphthyl, biphenyl, dihydronaphthyl or tetrahydronaphthyl group, the term "heteroaryl" denotes an unsaturated or partially unsaturated mono- or bi-cyclic group having from 5 to 11 ring members, containing from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulphur, the terms "phenylene" and "naphthylene" denote bivalent phenyl and naphthyl radicals, respectively, the term cycloalkylene denotes a bivalent saturated cyclic radical having from 3 to 8 carbon atoms, the term "heteroarylene" denotes a bivalent heteroaryl radical as defined hereinbefore, the expression "optionally substituted" applied to the terms "aryl", "arylalkyl", "heteroaryl" or "heteroarylalkyl" means that those groups are substituted on their cyclic moiety by from 1 to 5 identical or different substituents selected from linear or branched (Ci-C 6 )alkyl, linear or branched (Ci-C 6 )alkoxy, halogen, hydroxy, linear or branched perhalo-(Ci-C 6 )alkyl, nitro, amino (optionally substituted by one or two linear or branched S(Ci-C 6 )alkyl groups), linear or branched (Ci-C 6 )acyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two linear or branched (Ci-C 6 )alkyl groups), linear or branched (Ci-C 6 )acylamino, linear or branched (Ci-C 6 )alkoxycarbonyl, formyl, carboxy, S". sulpho, nitrile, linear or branched (Ci-C 6 )aminoalkyl (optionally substituted on the nitrogen atom by one or two linear or branched (Ci-C 6 )alkyl group), linear or branched (C 1

C

6 )thioalkyl (optionally substituted on the sulfur atom by a linear or branched (Ci-C 6 )alkyl group), or linear or branched (Ci-C 6 )hydroxyalkyl (optionally substituted on the oxygen atom by a linear or branched (C -C 6 )alkyl group), the expression "optionally substituted" applied to the terms "phenylene", "naphthylene" or "heteroarylene" means that those groups are substituted by from one to three identical or different groups selected from linear or branched (Ci-C 6 )alkyl, linear or branched (CI-C 6 alkoxy, halogen, hydroxy, linear or branched perhalo-(Ci-C 6 )alkyl, nitro, amino (optionally substituted by one or two linear or branched (Ci-C 6 )alkyl groups), linear or branched (Ci-C 6 )acyl, formyl, carboxy, linear or branched (Ci-C 6 )alkoxycarbonyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two linear or branched (Ci-C 6 )alkyl groups), linear or branched (C 1

-C

6 )acylamino and nitrile.

Among the heteroaryl groups preference is given to the pyridyl, furyl, thienyl and indolyl groups.

Among the heteroarylene groups preference is given to the pyridinylene and pyrazinylene groups.

Among the pharmaceutically acceptable acids there may be mentioned by way of nonlimiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methane- sulphonic acid, camphoric acid, etc..

Among the pharmaceutically acceptable bases there may be mentioned by way of nonlimiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, 10 etc..

An advantageous aspect of the invention relates to compounds of formula wherein n is 1.

Another advantageous aspect of the invention relates to compounds of formula wherein nis0.

15 Preferred compounds of the invention are those wherein W represents an SO 2 group.

.Preferred compounds of the invention are those wherein the grouping XG N represents a group selected from: Y N R N N R N N R 1 R

R

GI G2 Other preferred compounds of the invention are those wherein the grouping X N 20 represents a group selected from: N represents a group selected from Y "R

H

O N O

N

N-N N-N H R R G3 G4 In preferred compounds of formula A represents a grouping A 2

A

2 being more especially a phenylene, pyridinylene or pyrazinylene group.

In other preferred compounds of formula A represents a grouping -A 1

-A

2 or -A 2 -Al-,

A

2 being more especially a phenylene, pyridinylene or pyrazinylene group.

In the compounds of formula RI preferably represents an optionally substituted aryl group.

In the compounds of formula R will advantageously be selected from hydrogen, and an optionally substituted aryl group (more especially phenyl), and an optionally substituted 10 heteroaryl group (more especially pyridinyl, furyl or thienyl).

An advantageous aspect of the invention relates to compounds of formula wherein Z represents a group selected from alkyl, optionally substituted aryl and optionally substituted heteroaryl group.

The present invention relates especially advantageously to compounds of formula (I) wherein n is 1, W represents an SO 2 group, A represents a group selected from phenylene, pyridinylene and pyrazinylene, Ri represents an optionally substituted aryl group, R is selected from a hydrogen atom, an optionally substituted aryl group and an optionally substituted heteroaryl group, and Z represents an alkyl, an optionally substituted aryl group or an optionally substituted heteroaryl group.

The preferred aryl group of the invention is the phenyl group.

The invention relates most especially to the following compounds N'-[4-(1{5-phenyl-1- [3 -(trifluoromethyl)phenyl] -JH- 1,2,4-triazol-3 -yl }amino)benzoyl] benzenesulphonohydrazide 4-methoxy-N'-[4-(({5-phenyl-1- [3-trifluoromethyl)phenyl] -JH- 1,2,4-triazol-3-yl amino)benzoyl]benzenesulphonohydrazide {4-[(5-phenyl- 1H-i ,2,4-triazol-3-yl)amino]benzoyl }benzenesulphonohydrazide [5 -phenyl- 1 -(2-pyridyl)- 1 H-i ,2,4-triazol-3 -yl] amino)} benzoyl)benzenesulphonohydrazide [4-(1{5-oxo- 1 -(trifluoromethyl)phenyl]-4,5-dihydro-JH- 1 ,2,4-triazol-3 -yl amino)benzoyl }benzenesulphonohydrazide [5-oxo- 1 -(2-pyridyl)-4,5-dihydro-JH- 1 ,2,4-triazol-3 -yl] amino)} benzoyl)benzenesulphonohydrazide 5 [-oxo- 1 -(2-pyridinyl)-4,5 -dihydro- 1 H-i ,2,4-triazol-3 -yl] amino) -3-pyridinyl)carbonyl]benzenesulphonohydrazide.

The present invention relates also to a process for the preparation of compounds of formula characterised in that there is used as starting material a compound of formula (II) P-NH-A-C-OH (I 0 wherein A is as defined for formula and P represents a protecting group for the amine function, which is reacted in the presence of a coupling agent with a compound of formula (III): wherein n, W and Z are as defined for formula to yield, after deprotection of the amine function by removal of the P group, a compound of formula (IV): H2N-A-C-NH-(NH)-W-Z

(IV)

II

0 wherein n, A, W and Z are as defined hereinbefore, which compound (IV) is then condensed in a basic medium with an isothiocyanate of formula C-N=C=S

(V)

II

0 wherein R' 1 is as defined for R 1 in formula or represents a linear or branched

(C

1

-C

6 )alkoxy group, :10 to yield a compound of formula (VI): R'i-C- NH-ANH-C-NH-A-C-NH-(NH)W-Z (VI) II II O S O wherein n, R'I, A, W and Z are as defined hereinbefore, which compound of formula (VI) is either, when R'I represents a linear or branched (Ci-C 6 )alkoxy group, condensed in the presence of a coupling agent with a hydrazine of formula R-NH-NH 2 wherein R is as defined for formula to yield a compound of formula (VII/a) R'-C-N--NH-C-NH-A-C-NH-(NH)-W-Z (VII/a) O N O

NH

R

wherein R, A, n, W and Z are as defined hereinbefore, and R'i represents a linear or branched (Ci-C 6 )alkoxy group, which compound (VII/a) cyclises, spontaneously or after treatment in an acid medium, depending upon the nature of the R group, to yield a mixture of the two compounds of formulae and NH-A-C-NH-(NH)n-W-Z H II N-0 (I/a)

/N

R

NH-A-C-NH-(NH)-W-Z

II

R (I/b)

H

particular cases of the compounds of formula wherein R, A, n, W and Z are as defined hereinbefore, which compounds and may be separated according to conventional separation techniques, 10 or, when R'I represents an Ri group as defined for formula condensed in the presence of a coupling agent with a hydrazine of formula R-NH-NH 2 wherein R is as defined for formula to yield a compound of formula (VII/b) p R--C-NH-C-NH-A-C-NH-(NH)-W-Z (VII/b) O N O

NH

R

wherein R 1 R, A, n, W and Z are as defined hereinbefore, which compound (VII/b) is subjected to a cyclisation reaction followed by dehydration, spontaneously or after treatment in an acid medium, depending upon the nature of the R group, to yield a mixture of the two compounds of formulae and N NH-A-C-NH-(NH)n-W-Z

II

R 0 (I/c)

N

R

N _NH-A-C-NH-(NH)-W-Z RI (I/d) N

R

particular cases of the compounds of formula wherein RI, R, A, n, W and Z are as defined hereinbefore, which compounds and may be separated according to conventional separation techniques, which compounds and constitute the totality of the compounds of formula are separated, where appropriate, into their enantiomers and/or diastereoisomers 10 according to a conventional separation technique, are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.

The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula on its own or in combination with one or *15 more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal or transdermal administration, tablets or drag6es, sublingual tablets, gelatin capsules, lozenges, 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 disorder and the route of administration, which may be oral, nasal, rectal or parenteral. The unit dose generally ranges from 0.05 to 500 mg for a treatment in from 1 to 3 administrations per 24 hours.

11 The following Examples illustrate the invention and do not limit it in any way. The structures of the compounds described were confirmed by the usual spectroscopic techniques.

The starting materials used are known products or are prepared according to known procedures.

EXAMPLE 1: N'-[4-({5-Phenyl-l-[3-(trifluoromethyl)phenyl]-lH-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide Step a Tert-butyl 4-{[2-(phenylsulphonyl)hydrazino]carbonyl}phenylcarbamate 12.1 mmol (1.65 g) of l-hydroxy-7-azabenzotriazole and 18 mmol (3.45 g) of EDCI are 10 added in succession to a solution of 12 mmol (2.85 g) of 4-[(tert-butoxycarbonyl)amino]benzoic acid in 20 ml of dimethylformamide. The reaction mixture is stirred at room temperature for one hour, and 18 mmol (3.1 g) of benzenesulphonohydrazide are added. After stirring for eight hours at room temperature, the reaction mixture is poured into 100 ml of a 10% hydrochloric acid solution and 15 extracted four times with 50 ml of ethyl acetate. The organic phase is washed twice with 50 ml of water and then three times with an aqueous saturated sodium hydrogen carbonate solution and once with 50 ml of an aqueous saturated sodium chloride solution. After drying over magnesium sulphate, filtration and concentration, the expected product is obtained.

Step b N'-(4-(Aminobenzoyl)benzenesulphonohydrazide hydrochloride The compound described in the preceding Step is dissolved in 40 ml of 4M hydrochloric acid in dioxane. After stirring overnight at room temperature, the solvent is removed by evaporation at room temperature. The residue is suspended in 300 ml of ether and filtered.

The resulting solid is washed 4 times with 30 ml of ether and then dried under reduced pressure to yield the expected product.

12- Step c N-Benzoyl-N'-(4-{[2-phenylsulphonyl)hydrazino]carbonyl}phenyl)thiourea 11.1 mmol (0.66 ml) of diisopropylethylamine are added to a suspension of 11.1 mmol (3.65 g) of the compound described in the preceding Step in 20 ml of acetonitrile. After dissolution, 13.9 mmol (1.86 ml) of benzoyl isothiocyanate are added. The reaction mixture is stirred for 8 hours at room temperature. The precipitate that forms is filtered off and washed twice with 5 ml of acetonitrile and 4 times with 25 ml of ether to yield, after drying, the expected product.

Step d: N'-[4-({5-Phenyl-l-[3-(trifluoromethyl)phenyl]-lH-, 2, 4-triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide 3.4 mmol (0.528 ml) of 3-(trifluoromethyl)phenylhydrazine and 6.16 mmol (1.41 g) of oo..

EDCI are added to a solution of 3.08 mmol (1.4 g) of the compound described in the preceding Step in 5 ml of dimethylformamide. The reaction mixture is stirred at room temperature overnight. The mixture is poured into 10 ml of aqueous 10% HCI and then 15 extracted 3 times with 100 ml of ethyl acetate. The organic phases are combined and washed once with 20 ml of water, twice with 20 ml of an aqueous saturated sodium hydrogen carbonate solution and once with an aqueous saturated sodium chloride solution.

The organic phase is dried over magnesium sulphate, filtered and evaporated.

The resulting product is purified by chromatography over silica gel using a 20 dichloromethane/ethyl acetate mixture, 75/25, as eluant to yield the title product.

Mass spectrum ESI-MS MH 579 The compounds of Examples 2 to 25 are obtained according to the process described in Example 1, using the appropriate sulphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d, respectively.

EXAMPLE 2 N'-[4-({5-[2-Chlorophenyl]-1-[3-(trifluoromethyl)phenyl]-lH-1,2,4triazol-3-yl}amino)benzoyl]benzenesulphonohydrazide Mass spectrum ESI-MS MH 613 13 EXAMPLE 3: [2-Chlorophenylj- 1 -phenyl-JH- 1,2,4-triazol-3-yI) amino)benzoylj benzenesulphonohydrazide Mass sectrum: ESI-MS:MH 545 EXAMPLE 4: EXAMPLE 5: EXAMPLE 6: {4-t(1 ,5-Diphenyl-JH-1 ,2,4-triazol-3-yl)amino] benzoyl}-4methoxybenzenesulphonohydrazide N'-(4-{I1-(4-Fluorophenyl)-5-phenyl-JH-1 ,2,4-triazol-3-yI amino)benzoyl)-4-methoxybenzenesulphonohydrazide 4-Methoxy-N'-[4-({5-phenyl-1-[3-trifluoromethyl)phenylJ-1H-1,2,4triazol-3-yl~amino)benzoyl] benzenesulphonohydrazide .*0 000 0 10 se s00 to 0. o Mass spectrum ESI-MS :MH+ 609

S

S

EXAMPLE 7: EXAMPLE 8: N'-(4-{[1-(4-Fluorophenyl)-5-phenyl-JH-1 ,2,4-triazol-3-ylI amino)benzoyl)-4-methoxybenzenesulphonohydrazide ,5-Diphenyl-JH-1,2,4-triazol-3-yl)aminoj benzoyl}benzenesulphonohydrazide N'-14-({5-I4-ChlorophenyI1-1-13-(trifluoromethyl)phenylI-1H-1 ,2,4triazol-3-yl~amino)benzoylj benzenesulphonohydrazide N'-(4-15-(4-Chlorophenyl)-1-phenyl-JH-1 ,2,4-triazol-3-yl] amino)benzoyl)benzenesulphonohydrazide EXAMPLE 9: EXAMPLE 10: Mass spectrum ESI-MS :MH+ 546 14 EXAMPLE 11 [5-(4-Chlorophenyl)-1-(4-fluorophenyl)-JH-1,2,4-triazol-3-yl amino) benzoyl)benzenesulphonohydrazide Mass spectrum. ESI-MS:MH 564 EXAMPLE 12: N'-[4-({5-[4-Methoxyphenyl] -1-[3-(trifluoromethyl)phenyl]-JH-1 ,2,4triazol-3-yl~amino)benzoyljbenzenesulphonohydrazide Mass spectrum.: ESI-MS M= 609 ;:::EXAMPLE 13: N'-(4-{[5-(4-Methoxyphenyl)-1 -phenyl-JH-1 ,2,4-triazol-3-ylJ amino)benzoyl)benzenesulphonohydrazide Mass spectrum.: ESI-MS :MH+ 541 EXAMPLE 14: {I1-(4-Fluorophenyl)-5-(4-methoxyphenyl)-JH-1,2,4-triazol-3ylj amino) benzoyl)benzenesulphonobydrazide ~Mass spectrum. ESI-MS:MH 559 EXAMPLE 15: N'-{4-I(1-Benzyl-5-phenyl-JH-1 ,2,4-triazol-3-yI)aminolbenzoyl}benzenesulphonohydrazide Mass sectrum: ESI-MS:MH 525 EXAMPLE 16 {4-t(5-Phenyl-JH-1,2,4-triazol-3-yl)aminol benzoyllbenzenesulphonohydrazide Mass sectrum: ESI-MS:MH+ 435 EXAMPLE 17: N'-(4-{15-PhenyI-1 -(2-pyridyl)-JH-1,2,4-triazol-3-ylJ amino) benzoyl)benzenesulphonohydrazide Mass spectrum: ESI-MS :MH+ 512 EXAMPLE 18: N'-I4-({5-Pheny--I4-(trifluoromethyl)pheny]-1H-1 ,2,4-triazol-3-y} amino)benzoyllbenzenesulphonohydrazide Mass sectrum. ESI-MS:MH+=579 EXAMPLE 19 N'-[4-({5-PhenyIl-I2-(trifluoromethy)pheny1-1H-1,2,4-triazol-3-yI amino)benzoyl] benzenesulphonohydrazide EXAMPLE 20: 4-MethyI-N'-I4-({5-phenyl-l-I3-(trifluoromethy)phenfl]1H-1,2,4triazol-3-yl~amino)benzoyl] benzenesulphonohydrazide Mass spectrum. ESI-MS:MH+=593 EXAMPLE 21 N'-[4-({5-Phenyl-1-13-(trifluoromethyl)phenly]H-1 ,2,4-triazol-3-yI I1 amino)benzoylj methanesuiphonohydrazide Mass spectrum: ESI-MS :MH+ 517 EXAMPLE 22 2,4,6-Trichloro-N'-t4-({5-phenyl-1-I3-(trifluoromfethy)phel-1H- 1 ,2,4-triazol-3-yI~amino)benzoylJ benzenesulphonohydrazide EXAMPLE 23 2,4,6-Trinmethyl-N'-4-(5-phel--3-(trifluoromethy1)phelJ-JH- 1 ,2,4-triazol-3-yI~amino)benzoylj beuzenesuiphonohydrazide Mass spectrum: ESI-MS :MH+ 621 16- EXAMPLE 24: 5-(Dimethylamino)-N'- {5-phenyl- [3-(trifluoromethyl)phenylj JH-1 ,2,4-triazol-3-yl} amino)benzoyll-1 -naphthalenesulphonohydrazide Mass spectrum: ESI-MS :MH+ 672 EXAMPLE 25: {4-[(1-Benzyl-5-phenyl-JH-1 ,2,4-triazol-3-yI)aminoj benzoyl}-4methoxysulphonohydrazide Mass sectrum. ESI-MS:MH 555 EXAMPLE 26: N-14-({5-Phenyl-l-3-(trifluoromethyl)phenyll-JH-1,2,4-triazol-3-yl) :**:amino)benzoyl] beuzenesuiphonamide The expected product is obtained by using the process described in Example 1, in Step a replacing benzenesulphonohydrazide by benzenesulphonamide.

Mass sectrum.* ESI-MS:MH 564 The compounds of Examples 27 and 28 are obtained in the same manner as for Example 26, using the appropriate isothiocyanate and hydrazine in Steps c and d, respectively.

EXAMPLE 27: N-{4-I(1,5-Diphenyl-JH-1 ,2,4-triazol-3-yl)aminoj benzoyl}benzenesulphonamide Mass spectrum ESI-MS :MH+ 496 EXAMPLE 28 fi1-(4-Fluorophenyl)-5-phenyl-JH-1 ,2,4-triazol-3-yI amino)benzoyl)benzenesulphonamide EXAMPLE 29 14-({5-Oxo-1-3-(trifluoromethyl)phelyl -4,5-dihydro-JH-1 ,2,4triazol-3-yllamino)benzoyl~benzenesulphonohydrazide 17- Step Ethyl (4-([2-(phenylsulphonyl)hydrazinojcarbonyl~anilino)carbothioylcarbamate The expected product is obtained according to the process described in Example 1, Step c, replacing benzoyl isothiocyanate by ethyl thioxocarbamnate.

Step b -[3-(trifluoromethyl)phenylj-4, 5-dihydro-JH-J, 2, 4-triazol- 3-yl~amino)benzoyl~benzenesulphonohydrazide 1.065 mmol (0.139 ml) of 3-(trifluoromethyl)phenylhydrazine and 1.42 mmol (0.272 g) of EDCI are added to a solution of 0.71 mmol (0.3 g) of the compound described in the preceding Step in 3 ml of dimethylformamide. The reaction mixture is stirred at room temperature overnight. The mixture is poured into 5 ml of aqueous 10% HCl and then extracted 3 times with 5 ml of ethyl acetate. The organic phases are combined and washed once with 5 ml of water. The organic phase is dried over magnesium sulphate, filtered and evaporated. The residue is taken up in a 10% trifluoroacetic acid solution in dioxane and heated at 50'C overnight. The reaction mixture is evaporated and the precipitate that forms in the course of the evaporation is washed with 2 ml of acetonitrile and twice with 5 ml of ether and then dried in vacuc to yield the title product.

Mass spectrum: ESI-MS :MH+ 519 The compounds of Examples 30 to 39 are obtained according to the process described in Example 29 using the appropriate sulphonohydrazides and hydrazines.

EXAMPLE 30: [(5-Oxo-1-phenyl-4,5-dihydro-JH-1 ,2,4-triazol-3-yI)aminoI benzoyllbenzenesulphonohydrazide Mass sectrum. ESI-MS:MH+=451 EXAMPLE 31 -(4-Fluorophenyl)-5-oxo-4,5-dihydro-JH-1 ,2,4-triazol-3-yIJ amino) benzoyl)benzenesulphonohydrazide Mass spectrum: ESI-MS :MH+ 469 EXAMPLE 32: N'-(4-{15-Oxo-1 -(2-pyridyl)-4,5-dihydro-JH-1,2,4-triazol-3-yl] amino) benzoyl)benzenesulphonohydrazide Mass spectrum: ESI-MS:MH 452 EXAMPLE 33: {4-I(1 -Benzyl-5-oxo-4,5-dihydro-JH-1 ,2,4-triazol-3-yl)aminolbenzoyl~benzenesulphonohydrazide EXAMPLE 34 4-Methyl-N'-t4-({5-oxo-1- [3-(trifluoromethyl)phenyl] JH-1,2,4-triazol-3-yl~amino)benzoyl] benzenesulphonohydrazide Mass sectrum:. ESI-MS:MHr= 533 *.:EXAMPLE 35: 4-Methoxy-N'-14-({5-oxo-l-13-(trifluoroniethyl)phenyll-4,5-dihydro- JH-1,2,4-triazol-3-yI~amino)benzoyl] beuzenesuiphonohydrazide Mass sectrum* ESI-MS:MW 549 EXAMPLE 36: 4-Methoxy-N'- {4-I(5-oxo--phenyl-4,5-dihydro-JH-1,2,4-triazol-3-yl) amino] benzoyl~benzenesulphonohydrazide EXAMPLE 37: N'-(4-{I1-(4-Fluorophenyl)-5-oxo-4,5-dihydro-JH-1 ,2,4-triazol-3-yI]amino) benzoyl)-4-methoxybenzenesulphonohydrazide EXAMPLE 38 N'-{4-[(1-Benzyl-5-oxo-4,5-dihydro-JH-1 ,2,4-triazol-3-yl)aminolbenzoyl}-4-methoxybenzenesulphonohydrazide EXAMPLE 39 N'-Benzoyl-4-({5-phenyl-1-13-(trifluoromethyl)phenyll-JH-1 ,2,4triazol-3-yl} amino)benzohydrazide 19- The expected product is obtained according to the process described in Example 1, in Step a replacing benzenesulphonohydrazide by benzohydrazide.

Mass sectrum. ESI-MS:MH 543 The compounds of Examples 40 to 45 are obtained in the same manner as for Example 39, replacing suiphonohydrazide by the corresponding hydrazide and using the appropriate isothiocyanates and hydrazines.

EXAMPLE 40: N'-Benzoyl-4-[(1 ,5-diphenyl-JH-1 ,2,4-triazol-3-yl)aminojbenzohydrazide Mass sectrum. ESI-MS:MH 475 EXAMPLE 41: N'-Benzoyl-4- {[1-(4-fluorophenyl)-5-phenyl-JH-1,2,4-triazol-3-ylJ amino) benzohydrazide *Mass spectrum. ESI-MS :MH+ 493 EXAMPLE 42 N'-Benzoyl-4-15-phenyl-1-(2-pyridyl)-JH-1,2,4-triazol-3-yll amino)benzohydrazide j 5 Mass sectrum. ESI-MS:MH 476 EXAMPLE 43: N'-Benzoyl-4-( [3,5-bis(trifluoromethyl)phenyl]-5-phenyl-JH-1 ,2,4triazol-3-yI~amino)benzobydrazide Mass spectrum* ESI-MS:MH 611 EXAMPLE 44: 4-1(1 ,5-Diphenyl-JH-1 ,2,4-triazol-3-yI)aminoj-N'-(l-naphthoyl)benzohydrazide Mass spectrum* ESI-MS:MH 525 20 EXAMPLE 45: 4- flu-(4-Fluorophenyl)-5-phenyl-JH-1 ,2,4-triazol-3-ylJ amino}-N'-(1 naphthoyl)benzohydrazide Mass spectrum. ESI-MS:MH 543 The compounds of Examples 46 to 48 are obtained according to the process described in Example 1, using the appropriate suiphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d, respectively.

EXAMPLE 46: 4-ehlN-4[5-hnl-H124trao -laibenzoyl}beuzenesulphonohydrazide Mass spectrum ESI-MS :MH+ 449 EXAMPLE 47 {4-[(5-Phenyl)-1H-1 ,2,4-triazol-3-yl)aminoj benzoyl}methanesulphonohydrazide Mass sectrum. ESI-MS:MH 373 EXAMPLE 48 4-Methoxy-N'-{4-I(5-phenyl-JH-1 ,2,4-triazol-3-yl)aminoJ benzoyl}benzenesuiphonohydrazide The compounds of Examples 49 to 60 are obtained according to the process described in Example 1, using the appropriate suiphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d, respectively, and in Step a replacing 4-[tert-butoxycarbonyl) amino]benzoic acid by 3-[(tert-butoxycarbonyl)amino]benzoic acid.

EXAMPLE 49 {5-Phenyl-1-[3-(trifluoromethyl)phenyll-1H-1 ,2,4-triazol-3-yI}amino)benzoyljbenzenesulpholohydrazide Mass spectrum. ESI-MS:MH 579 -21- EXAMPLE 50: ,5-Diphenyl-1H-1 ,2,4-triazol-3-yI)aminoj benzoyl}benzenesulphonohydrazide Mass sectrum: B SI-MS:MI-+= 511 EXAMPLE 51 N'-(3-{[5-Phenyl-1-(2-pyridinyl)-1H-1 ,2,4-triazol-3-yI amino)benzoyl)benzenesulphonohydrazide Mass sectrum. ESI-MS:MH 512 :0....EXAMPLE 52 N'-(3-15-(2-Chlorophenyl)-1-phenyl-1H-1 ,2,4-triazol-3-ylJ amino)benzoyl)benzenesulphonohydrazide .:Mass spectrum ESI-MS :MH+ 546 :::)oEXAMPLE 53: {[-(2-Chlorophenyl)-1 -(2-pyridinyl)-1H-1,2,4-triazol-3-yJ amino) benzoyl)benzenesulphonohydrazide Mass spectrum ESI-MS :MH+ 547 EXAMPLE 54 4-Methoxy-N'-[3-({5-phenyl-1-13-(trifluoromethyl)phenylJ-lH-1 ,2,4triazol-3-yl~amino)benzoylj beuzenesuiphonohydrazide Mass sectrum: ESI-MS:MH 609 EXAMPLE 55: ,5-Diphenyl-lH-1,2,4-triazol-3-yI)aminoJ benzoyl}-4methoxybenzenesulphonohydrazide Mass spectrum: ESI-MS :MH+ 541 22 EXAMPLE 56: 4-Methoxy-N'-(3- {[5-phenyl-1-(2-pyridinyl)-1H-1,2,4-triazol-3-ylJamino) benzoyl)benzenesulphonohydrazide Mass spectrum.: ESI-MS :MH+ 542 EXAMPLE 57: N'-[3-({5-(2-Chlorophenyl)-1-[3-(trifluoromethyl)phenyll-1H-1 ,2,4triazol-3-yl}amino)benzoyl1-4-methoxybenzelesulphoflohydrazide Mass spec trum.: ESI-MS :MH+ 644 EXAMPLE 58 {[5-(2-Chlorophenyl)-1-phenyl-1H-1 ,2,4-triazol-3-ylI amino)benzoyl)-4-methoxybenzenesulphonohydrazide .:Mass spectrum. ESI-MS :MW =576 EXAMPLE 59: [5-(2-Chlorophenyl)-1-(2-pyridinyl)-1H-1,2,4-triazol-3-yI amino) benzoyl)-4-methoxybenzenesulphonohydrazide Mass sectrum. ESI-MS:MH 577 EXAMPLE 60 N'[-1-2Clrphnl--3(rfuroehlpey l-,2,4triazol-3-yl~amino)benzoyllbenzenesulpholohydrazide Mass spectrum ESI-MS :MH+ 614 The compounds of Examples 61 to 63 are obtained according to the process described in Example 1, using the appropriate suiphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d, respectively, and in Step a replacing 4-[tert-butoxycarbonyl)amino]benzoic acid by 4- {[(tert-butoxycarbonyl)amino]methyl }benzoic acid.

23 EXAMPLE 61: 4-Methoxy-N'-{4-1( {5-phenyl-1 3-(trifluoromethyl)pheny]-1H-1 ,2,4triazol-3-yl} amino)methylj benzoyl) beuzenesuiphonohydrazide Mass spec trum. ESI-MS:MH 737 EXAMPLE 62 N'-(4-{I(1,5-Diphenyl-lH-1 ,2,4-triazol-3-yI)amino] methyl) benzoyl)benzenesulphonohydrazide Mass sec frum. ESI-MS:MH 639 EXAMPLE 63 [5-Phenyl-l-(2-pyridinyl)-1H-1,2,4-triazol-3-yI amino)methyl)benzoyljbenzenesulphonohydrazide :**Goo 0 0 Mass spectrum ESI-MS: MH+ 754 ~1O The compounds of Examples 64 to 66 are obtained according to the process described in Example 1, using the appropriate suiphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d, respectively, and in Step a replacing 4-[(tert-butoxycarbonyl)ease amino]benzoic acid by {4-[(tert-butoxycarbonyl)amino]phenyl acetic acid.

EXAMPLE 64: 4-Methoxy-N'-{[4-({5-phenyl-l-[3-(trifluoromethyl)phenyl]-1H- 1,2,4- 00 triazol-3-yl~amino)phenylj acetyl~benzenesulphonohydrazide Mass spectrum* ESI-MS:MH 623 EXAMPLE 65: ,5-Diphenyl-1H-1 ,2,4-triazol-3-yl)aminoj phenyl~acetyl)-4methoxybenzenesulphonohydrazide Mass spectrum. ESI-MS:MH 555 24 EXAMPLE 66: 4-Methoxy-N'-1(4-{ [5-phenyl-1 -(2-pyridinyl)-1H-1 ,2,4-triazol-3-ylJ amino) phenyl)acetyl] beuzenesuiphonohydrazide Mass spectrum. ESI-MS:MH 556 The compounds of Examples 67 to 72 are obtained according to the process described in Example 1 using the appropriate suiphonohydrazides, isothiocyanates and hydrazines in Steps a, c and d, respectively, and in Step a replacing 4-[tert-butoxycarbonyl)amino]benzoic acid by 6-[(tert-butoxycarbonyl)amino]-3-pyridazinecarboxylic acid.

EXAMPLE 67: 4-Methoxy-N'-{16-({5-phenyl-1-[3-(trifluoromethyl)phenyll-1H-1,2,4triazol-3-yI~amino)-3-pyridazinyllcarbonyl~benzenesulphonohydrazide Mass spectrum: ESI-MS:MH 611 EXAMPLE 68: ,5-Diphenyl-1H-1 ,2,4-triazol-3-yl)aminoj-3-pyridazinyl)carbonyl)-4-methoxybenzenesulphonohydrazide sectrum* ESI-MS:MH+=543 EXAMPLE 69: 4-Methoxy-N- 1(6-15-phenyI-1-(2-pyridinyl)-1H-1 ,2,4-triazol-3-yl] amino}-3-pyridazinyl)carbonyll benzenesulphonohydrazide Mass sectrum* ESI-MS:MH 544 EXAMPLE 70 N'-{16-({5-Phenyl-1 -13-(trifluoromethyl)phenyll-1H-1 ,2,4-triazol-3yl)amino)-3-pyridazinyllcarbonyl)benzenesulphonohydrazide .Mass spec trum: ESI-MS:MH 581 EXAMPLE 71 1(1 ,5-Diphenyl-1H-1 ,2,4-triazol-3-yl)aminoj-3-pyridazinyl}carbonyl)benzenesulphonohydrazide Mass spectrum: ESI-MS:MH 513 EXAMPLE 72 N'-[(6-{[5-Phenyl-l-(2-pyridinyl)-1H-1 ,2,4-triazol-3-yJ amino}-3pyridazinyl)carbonyllbenzenesulphonohydrazide Mass sectrum. ESI-MS:MH 514 The compounds of Examples 73 to 75 are obtained according to the process described in Example 1 using the appropriate suiphonohydrazides, isothiocyanates and hydrazines in 00 Steps a, c and d, respectively, and in Step a replacing 4-[tert-butoxycarbonyl)amnino]benzoic acid by 6-[(tert-butoxycarbonyl)amino]nicotinic acid.

EXAMPLE 73 [6-({5-Phenyl-1 -13-(trifluoromethyl)phenyl-lH-1 ,2,4-triazol-3yIlamino)-3-pyridinylj carbonyl~benzenesulphonohydrazide Mass spectrum. ESI-MS:MH 580 EXAMPLE 74 N'-({6-[(1,5-Diphenyl-lH-1,2,4-triazol-3-yI)amino]-3-pyridinyl}carbonyl)benzenesulphonohydrazide Mass spectrum ESI-MS :MH+ 512 EXAMPLE 75: N'-I(6-{15-Phenyl-1 -(2-pyridinyl)-1H-1 ,2,4-triazol-3-yI] amino}-3pyridinyl)carbonylj benzenesulphonohydrazide Mass sectrum ESI-MS:MH+ =513 26 The compounds of Examples 76 to 78 are obtained according to the process described in Example 1 using the appropriate suiphonohydrazides and hydrazines.

EXAMPLE 76: 4-Methyl-N'- 14-( {5-oxo-1- [3-(trifluoromethyl)phenyl] 1H-1,2,4-triazol-3-yllamino)benzoyl] benzenesulphonohydrazide Mass sectrum: ESI-MS:MH 533 EXAMPLE 77: 2,4,6-Trimethyl-N'-14-({5-oxo-1-13-(trifluoromethyl)phenyl dihydro-1H-1 ,2,4-triazol-3-yl~amino)benzoyll benzene- *io.suiphonohydrazide Mass spectrum.: ESI-MS: MH+ 561 EXAMPLE 78 14-({5-Oxo-1 -13-(trifluoromethyl)phenyl]-4,5-dihydro-1H-1 ,2,4triazol-3-yl~amino)benzoylj methanesuiphonohydrazide Mass spectrun: ESI-MS:MH+=457 EXAMPLE 79 N'-[(6-{[5-Oxo-1-(2-pyridinyl)-4,5-dihydro-lH-1,2,4-triazol-3-ylJ- 0: amino}-3-pyridinyl)carbonylj benzenesulphonohydrazide 26 The expected product is obtained according to the process described in Example 1, Steps a.

b and c, in Step a replacing 4-[(tert-butoxycarbonyl)amino]benzoic acid by 6-[tertbutoxycarbonyl)amino] nicotinic acid, in Step c replacing benzoyl isothiocyanate by ethyl thioxocarbamate, and, according to the process described in Example 2 1, Step b, replacing 3-(trifluoromethyl)phenylhydrazine by 2-hydrazinopyridine.

Mass szectrum: ESI-MS:MH 453 The products of Examples 80 to 96 are obtained according to the process described in Example 1, in Step a replacing the suiphonohydrazides by the appropriate hydrazides, and using the appropriate isothiocyanates and hydrazines in Steps c and d, respectively.

EXAMPLE 80: 4-1(1 ,5-Diphenyl-1H-1,2,4-triazol-3-yl)aminol-N'-(3-nitrobenzoyl)benzohydrazide Mass spec trum: ESI-MS:MH+=520 EXAMPLE 81: 4-1(1 ,5-Diphenyl-1H-1,2,4-triazol-3-yl)aminoj-N'-[4- (trifluoromethyl)benzoyljbenzohydrazide Mass spec trum ESI-MS :MW+ 543 EXAMPLE 82: 4-1(1 ,5-Diphenyl-1H-1,2,4-triazol-3-yl)aminoj-N'-(3,4,5trimethoxybenzoyl)benzohydrazide Mass sec frum: ESI-MS:MH 565 EXAMPLE 83: 4-1(1 ,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino] -N'-(3-methoxybenzoyl)benzohydrazide Mass sectrum* ESI-MS:MH 505 EXAMPLE 84: ,5-Diphenyl-1H-1,2,4-triazol-3-y)amino] -N'-(4-methoxybenzoyl)benzohydrazide Mass spectrum. ESI-MS:MH 505 EXAMPLE 85: ,5-Diphenyl-1H-1 ,2,4-triazol-3-yl)amino] -N'-(3-furoyl)benzohydrazide Mass spectrum: ESI-MS :MH+ 465 -28- EXAMPLE 86: ,5-Diphenyl-1H-1 ,2,4-triazol-3-yl)aminoJ-N'-isonicotinoylbenzohydrazide Mass spec trum: ESI-MS :MHW 476 EXAMPLE 87: ,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N'-(1-naphthoyl)benzohydrazide Mass sectrum. ESI-MS:MH 539 EXAMPLE 88 N'-(3,4-Dimethoxybenzoyl)-4-[(1,5-diphenyl-lH-1,2,4-triazol-3-yl)amino] benzohydrazide Mass spectrum: ESI-MS:MW 535 0 EXAMPLE 89: 4-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N'-(2-naphthoyl)benzohydrazide Mass spectrum.: ESI-MS :MH+ 525 EXAMPLE 90 N'-(3-Chlorobenzoyl)-4-[(1,5-diphenyl-H-1,2,4-triazol-3-y)amilbenzohydrazide Mass sectrum. ESI-MS:MH+ 509 EXAMPLE 91 N'-[3,5-Bis(trifluoromethyl)benzoyll-4-K1 ,5-diphenyl-lH-1,2,4triazol-3-yI)amino] benzohydrazide Mass spectrum. ESI-MS:MH 611 29 EXAMPLE 92: 4-1(1 ,5-Diphenyl-1H-1 ,2,4-triazol-3-yl)amino]-N'-(2-thienylcarbonyl)benzohydrazide Mass sectrum. ESI-MS:MH+ =481 EXAMPLE 93 N'-(4-Chlorobenzoyl)-4- 1(1,5-diphenyl-1H-1 ,2,4-triazol-3-yl)amino] benzohydrazide Mass sec frum. ESI-MS:MH 509 EXAMPLE 94: N'-(2-Chlorobenzoyl)-4-[(1,5-diphenyl-lH-1,2,4-triazol-3-yl)aminojbenzohydrazide Mass sec frum: ESI-MS:MH 509 EXAMPLE 95 4-1(1 ,5-Diphenyl-1H-1,2,4-triazol-3-yl)amino]-N'-(3-hydroxybenzoyl)benzohydrazide Mass spectrum ESI-MS :MH+ 491 EXAMPLE 96: 4-[(1,5-Diphenyl-1H-1,2,4-triazol-3-yl)aminoj-N'-(3,4,5-trihydroxybenzoyl)benzohydrazide Mass spec trum.: ESI-MS :MH+ 523 EXAMPLE 97: -Benzyl-3-phenyl-lH-1 ,2,4-triazol-5-yl)aminojbenzoyl} benzenesulfonohydrazide The title product is isolated during the purification of the compound described in example 30 EXAMPLE 98: I(1-BenzyI-3-rhenyl-1H-1 ,2,4-triazol-5-yl)aminoj benzoyl}-4m~thoxybenzenesulfonohydrazide The title product is isolated during the purification of the compound described in example -31 PHARMACOLOGICAL STUDY EXAMPLE A Measurement of the effect on food intake and weight development in the obese mouse The compounds of the invention were administered in vivo to the obese ob/ob mouse in order to evaluate their influence on food intake and weight development. The animals used are 13- to 18-week-old female ob/ob C57B1/6J mice. They are divided into groups each comprising 4 animals per cage, the cages being fitted with a grating floor, and the mice having free access to food.

o0 Before the experiments, the animals are conditioned for a period ranging from 2 to 3 weeks *o.0 until their food consumption has stabilised. The experiments may be summarised as follows:

O**

15 D-14 to D-7 conditioning SD-7 to D-3 :measurement of the basal food intake DO to D+3 :animals treated twice daily, the control groups being given the carrier SDO to D+4 :daily measurement of food intake and body weight.

The test compounds are dissolved, immediately before use, in water, 0.9% sodium chloride, propylene glycol or dimethyl sulphoxide, depending upon their solubility, and are administered intraperitoneally in a volume of 2.5 ml/kg.

The parameters measured are the food intake and the body weight.

-32- The results are expressed as percentage variation in food intake under treatment compared with the basal food intake; percentage variation in body weight between the first and last day of treatment.

By way of example, the results obtained with the compounds of Examples 1 and 6 are as follows Food intake Body weight Product Dose (mg/kg) variation (Dl) variation Control Treated (D4/DO) Example 1 1 -34 -45 -6.4 Example 6 5 -23 -34 -11.2 EXAMPLE B Meaurement of the in vitro affinity for NPY receptors The capacity of the compounds of the invention to bind to NPY receptors was measured on various cell lines, each expressing one of the receptor sub-types studied. Competition binding experiments were carried out using the peptide 25 I]-PYY as radioligand at concentrations ranging from 15 to 65 pM. The non-specific fraction is measured in the presence of a concentration of 1 iM NPY. The cells are incubated for a period ranging from 1 to 2 hours depending upon the lines, and the radioactivity is collected after filtration over a GF/C filter treated with 0.1% PEI, before being measured.

Results: The results are expressed as IC 50 The compounds of the invention appear to be capable of significantly displacing the reference ligand the IC 50 values vary from a few nanomoles to some hundreds of nanomoles.

By way of example, the compounds of Examples 1 and 6 have an IC50 value of nM and 7 nM, respectively, for the Y 5 receptor.

EXAMPLE C Acute toxicity study Acute toxicity was evaluated after oral administration of increasing doses of the test compound to groups each comprising 8 mice (26 6 grams). The animals were observed at regular intervals over the course of the first day and daily for the two weeks following treatment.

The compounds of the invention appear to be not very toxic at all.

EXAMPLE D: Pharmaceutical composition Formulation for the preparation of 1000 tablets each comprising a dose of 10 mg Compound of Example 1 10 g Hydroxypropyl 2 g 20 W heat starch 10 g Lactose 100 g M agnesium stearate 3 g T a 3 g Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

oo

Claims (21)

1. Compounds of formula NH-A-CO-NH-(NH)-W-Z /GX (I) Y N R S wherein: Snisor 1, W represents a -CO- group or an S(O)q group wherein q is 0, 1 or 2, I C the grouping Ni~ represents a group selected from RN- R H N-N R O.Ny N-N H R G4 Z represents an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group, A represents a grouping selected from -A 2 -Ai-A 2 -A 2 -Al- and -AI-A 2 -A 1 wherein A 1 is an alkylene group and A 2 represents an optionally substituted phenylene, optionally substituted naphthylene, cycloalkylene, or optionally substituted heteroarylene group, R represents a hydrogen atom, or an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted hetero-arylalkyl group, R, represents an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base, wherein: the term "alkyl" denotes a linear or branched group having from 1 to 6 carbon atoms, the term "alkylene" denotes a linear or branched bivalent radical containing from 1 to 6 carbon atoms, the term alkenyl denotes a linear or branched group having from 2 to 6 carbon atoms and from 1 to 3 double bond, the term alkynyl denotes a linear or branched group having from 2 to 6 carbon atoms and from 1 to 3 triple bond, the term "aryl" denotes a phenyl, naphthyl, biphenyl, dihydronaphthyl or tetrahydronaphthyl group, the term "heteroaryl" denotes an unsaturated or partially unsaturated mono- or bi-cyclic group having from 5 to 11 ring members, containing from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulphur, the terms "phenylene" and "naphthylene" denote bivalent phenyl and naphthyl radicals, respectively, the term cycloalkylene denotes a bivalent saturated cyclic radical having from 3 to 8 carbon atoms, the term "heteroarylene" denotes a bivalent heteroaryl radical as defined hereinbefore, the expression "optionally substituted" applied to the terms "aryl", "arylalkyl", "heteroaryl" or "heteroarylalkyl" means that those groups are substituted on their cyclic moiety by from 1 to 5 identical or different substituents selected from linear or branched (Ci-C 6 )alkyl, linear or branched (CI-C6)alkoxy, halogen, hydroxy, linear or branched perhalo-(Ci-C 6 )alkyl, nitro, amino (optionally substituted by one or two linear or branched (Ci-C 6 )alkyl groups), linear or branched (C 1 -C 6 )acyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two linear or branched (Ci-C 6 )alkyl groups), linear or branched (Ci-C 6 )acylamino, linear or branched (Ci-C 6 )alkoxycarbonyl, formyl, carboxy, sulpho, nitrile, linear or branched (Ci-C 6 )aminoalkyl (optionally substituted on the nitrogen o0 atom by one or two linear or branched (CI-C 6 )alkyl group), linear or branched (Cl- C 6 )thioalkyl (optionally substituted on the sulfur atom by a linear or branched (Ci-C 6 )alkyl group), or linear or branched (Ci-C 6 )hydroxyalkyl (optionally substituted on the oxygen atom by a linear or branched (Ci-C 6 )alkyl group), the expression "optionally substituted" applied to the terms "phenylene", "naphthylene" or "heteroarylene" means that those groups are substituted by from one to three identical or different groups selected from linear or branched (Ci-C 6 )alkyl, linear or branched (CI-C 6 alkoxy, halogen, hydroxy, linear or branched perhalo-(Ci-C 6 )alkyl, nitro, amino (optionally substituted by one or two linear or branched (Ci-C 6 )alkyl groups), linear or branched (Ci-C 6 )acyl, formyl, carboxy, linear or branched (Ci-C 6 )alkoxycarbonyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two linear or branched (Ci-C 6 )alkyl groups), linear or branched (Ci-C 6 )acylamino and nitrile.

2. Compounds of formula according to claim 1 wherein n is 1, their enantiomers. diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

3. Compounds of formula according to claim 1 wherein n is 0, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. -37-

4. Compounds of formula according to claim 1 wherein W represents an SO 2 group, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. Compounds of formula according to claim 1 wherein the grouping X. jGN Y *g represents a group selected from N-( N R-,N I N R N R ijNR their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

6. Compounds of formula according to claim 1 wherein the grouping -K G N N R~ represents a group selected from O(N N-N R O N N-N H R R G4 their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

7. Compounds of formula according to claim 1 wherein A represents a grouping A 2 their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. -38-

8. Compounds of formula according to claim 1 wherein A represents a grouping -AI-A 2 or -A 2 their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

9. Compounds of formula according to claim 1 wherein Ri represents an optionally substituted aryl group, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. Compounds of formula according to claim 1 wherein R is selected from a hydrogen atom, an optionally substituted aryl group and an optionally substituted heteroaryl group, their enantiomers, diastereoisomers and addition salts thereof with "r0 a pharmaceutically acceptable acid or base.

11. Compounds of formula according to claim 1 wherein Z represents a group selected from alkyl, optionally substituted aryl, and optionally substituted heteroaryl, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

12. Compounds of formula according to claim 1 wherein n is 1, W represents an SO 2 group, A represents a group selected from phenylene, pyridinylene and pyrazinylene, RI represents an optionally substituted aryl group, R is selected from a hydrogen atom, an optionally substituted aryl group and an optionally substituted heteroaryl group, and Z represents an alkyl, optionally substituted aryl or optionally substituted heteroaryl group, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

13. Compound of formula according to claim 1 which is N'-[4-({5-phenyl-l-[3- (trifluoromethyl)phenyl]-IH-1,2,4-triazol-3-yl}amino)benzoyl]benzenesulphono- hydrazide. 39

14. Compound of formula according to claim 1 which is N'-{4-[5-phenyl-1H-1,2,4- triazol-3 -yl)amnino]benzoyl }benzenesulphonohydrazide. Compound of formula according to claim 1 which is N'-(4-{[5-phenyl-1-(2- pyridyl)- 1 H-i ,2,4-triazol-3 -yl] amino)} benzoyl)benzenesulphonohydrazide.

16. Compound of formula according to claim 1 which is 1 ,2,4-triazol-3-yl amino)benzoyl benzene- suiphonohydrazide.

17. Compound of formula according to claim 1 which is [5-oxo-1-(2-pyridyl)- -dihydro-JIH- 1 ,2,4-triazol-3 -yl] amino)} benzoyl)benzenesulphonohydrazide. ~o 18. Compound of formula according to claim 1 which is pyridinyl)-4,5 -dihydro- 1 H-i ,2,4-triazol-3 -yl]amino -3 -pyridinyl)carbonyl] benzene- suiphonohydrazide.

19. Process for the preparation of compounds of formula according to claim 1, characterised in that there is used as starting material a compound of formula (11) see* P-NH-A-C-OH (II) 0 wherein A is as defined for formula and P represents a protecting group for the amine fuinction, which is reacted in the presence of a coupling agent with a compound of formula (111): wherein n, W and Z are as defined for formula d' to yield, after deprotection of the amine function by removal of the P group, a compound of formula (IV): H2N-A-C-NH-(NH)-W-Z (IV) II O wherein n, A, W and Z are as defined hereinbefore, which compound (IV) is then condensed in a basic medium with an isothiocyanate of formula (V) II O 0 wherein R'i is as defined for Ri in formula or represents a linear or branched (Ci-C 6 )alkoxy group, O to yield a compound of formula (VI): R'-C-NH-C-NH-A-C-NH-(NH),W-Z (VI) 0 S 0 wherein n, R'I, A, W and Z are as defined hereinbefore, which compound of formula (VI) is either, when R'I represents a linear or branched (Ci-C 6 )alkoxy group, condensed in the presence of a coupling agent with a hydrazine of formula R-NH-NH 2 wherein R is as defined for formula to yield a compound of formula (VII/a) R'-C-NH-C-NH-A-C-NH-(NH)-W-Z (VII/a) O N O NH R wherein R, A, n, W and Z are as defined hereinbefore, and R'I represents a linear or branched (C -C 6 )alkoxy group, -41- which compound (VII/a) cyclises, spontaneously or after treatment in an acid medium, depending upon the nature of the R group, to yield a mixture of the two compounds of formulae and NH-A-C-NH-(NH)-W-Z H II S0 (I/a) N OlN R NH-A-C-NH-(NH)-W-Z II N 0 (I/b) O N 'R .5 H :5 particular cases of the compounds of formula wherein R, A, n, W and Z are as defined hereinbefore, which compounds and may be separated according to conventional separation techniques, i10 or, when R' 1 represents an RI group as defined for formula condensed in the presence of a coupling agent with a hydrazine of formula R-NH-NH 2 wherein R is as defined for formula to yield a compound of formula (VII/b): R-C-NH-C-NH-A-C-NH-(NH)-W-Z (VII/b) 0 N 0 NH R wherein RI, R, A, n, W and Z are as defined hereinbefore, which compound (VII/b) is subjected to a cyclisation reaction followed by dehydration, spontaneously or after treatment in an acid medium, depending upon the nature of the R group, to yield a mixture of the two compounds of formulae and N NH-A-C-NH-(NH)-W-Z R 1 (I/c) N R N NH-A-C-NH-(NH)-W-Z R N 0 (I/d) N "R particular cases of the compounds of formula wherein R 1 R, A, n, W and Z are as defined hereinbefore, which compounds and may be separated according to conventional separation techniques, which compounds and constitute the totality of the compounds of formula are separated, where appropriate, into their enantiomers and/or diastereoisomers according to a conventional separation technique, are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.

20. Pharmaceutical compositions comprising as active ingredient at least one compound according to any one of claims 1 to 18, on its own or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

21. Pharmaceutical compositions according to claim 20 comprising at least one active ingredient according to any one of claims 1 to 18 for use as Neuropeptide Y receptor ligand in the treatment of pathologies associated with eating behaviour disorders or energy balance disorders, such as diabetes, obesity, bulimia, anorexia nervosa, or in the treatment of arterial hypertension, anxiety, depression, epilepsy, sexual dysfunctions and sleep disorders.

22. The use of at least one compound according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment of pathologies associated with eating behaviour disorders or energy balance disorders, or arterial hypertension, anxiety, depression, epilepsy, sexual dysfunction or sleep disorders.

23. A method of treating pathologies associated with eating behaviour disorders or energy balance disorders, or arterial hypertension, anxiety, depression, epilepsy, sexual dysfunction or sleep disorders, the method comprising administering to a patient a therapeutically effective amount of at least one compound according to any one of claims 1 to 18.

24. A compound according to claim 1 substantially as hereinbefore described with reference to Examples 1 to 98. A process according to claim 19 substantially as hereinbefore described with reference to the preparative examples.

26. A pharmaceutical composition according to claim 20 substantially as hereinbefore described with reference to Example D. :00.0 DATED this 1st day of April 2003 LES LABORATOIRES SERVIER WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P17234AU00 CJHIKJSIJPFNRH .o •o.oo Doge