BENZENESULFONAMIDE COMPOUNDS

Abstract: Compounds of formula (I) wherein X is O or S; at least one of R, R1, R2, R3, and R4, which are the same or different, is an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylamino and C1-C6 alkoxy-carbonyl or two adjacents of R-R4 taken together form a benzene ring; and the remaining ones are hydrogen; R5 is hydrogen, C1-C6 alkyl, a benzyl or a phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, nitro, amino, hydroxy, formylamino, C2-C6 alkanoylamino and C1-C6 alkoxy-carbonyl; each of R6 and R7, which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylamino and C1-C6 alkoxy-carbonyl; or R6 and R7 taken together form a C6-C14 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylamino and C1-C6 alkoxy-carbonyl and the pharmaceutically acceptable salts thereof have kynurenine-3-hydroxylase enzyme inhibitory activity.

Description: BENZENESULFONAMIDE COMPOUNDS The present invention relates to novel benzenesulfonamides, to a process for their preparation, to pharmaceutical compositions containing them and their use in therapy. The compounds of the invention act as inhibitors of kynurenine-3 -hydroxy lase (KYN- OH), an enzyme which forms part of the metabolic pathway of kynurenine. It is well known that through the kynurenine pathway, tryptophan metabolism gives rise to the formation of 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN), on the one side, and kynurenic acid (KYNA), on the other side, as shown in Figure 1. (The legend to Figure 1 is to be found on the last page of the experimental part of the specification). KYNA is endowed with neuroprotective properties (J. Neurosci. 1990, 10, 2965-2973), whereas QUIN is a relatively potent neurotoxin which has been implicated in the pathogenesis of a variety of neurological disorders including Huntington's disease and epilepsy (Life Sci. 1984, 35, 19-32; Nature, 1986, 321, 168-171 ; Science, 1983, 219, 316- 318). Increased concentrations of QUIN have also been indicated as responsible for neurological disorders accompanying many infections and inflammatory diseases including Acquired Immunodeficiency Syndrome (AIDS) (Ann. Neurol. 1991, 29, 202- 209). One of the main strategies aimed at altering the KYNA/QUIN balance blocking 3- OH-KYN and QUIN's production and increasing KYNA production, entails inhibition of the key enzyme of the kynurenine (KYN) pathway, among which KYN-OH is of primary importance. Consequently, there is a need in therapy of compounds able of inhibiting this enzyme. The compounds of the present invention fulfill such a need. Accordingly, the present invention provides the use of a benzenesulfonamide compound of formula (I) wherein X is O or S; at least one of R, R,, R 2 , R 3 , and R 4 , which are the same or different, is an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C,-C 6 alkoxy-carbonyl. or two adjacents of R-R 4 taken together form a benzene ring; and the remaining ones are hydrogen; R 5 is hydrogen, C r C 6 alkyl, a benzyl or a phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 6 alkyl, C r C 6 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 6 alkanoylamino and C r C 6 alkoxy-carbonyl; each of R 6 and R 7 , which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C C 6 alkoxy-carbonyl; or R 6 and R 7 taken together form a C 6 -Cι 4 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as kynurenine-3 -hydroxy lase enzyme inhibitor. The present invention also provides a benzenesulfonamide compound of formula (I) wherein X is O or S; at least one of R, R., R 2 , R 3 , and R 4 , which are the same or different, is an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl. or two adjacents of R-R taken together form a benzene ring; and the remaining ones are hydrogen; R 5 is hydrogen, C r C 6 alkyl, a benzyl or a phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 6 alkyl, C r C 6 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 6 alkanoylamino and C r C 6 alkoxy-carbonyl; each of Rή and R 7 , which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl; or R 6 and R 7 taken together form a C 6 -C 1 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C C 6 alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular as kynurenine-3-hydroxylase enzyme inhibitor. The present invention also provides a method of treating a mammal, including humans, in need of a kynurenine-3-hydroxylase enzyme inhibitor, the method comprising administering thereto a therapeutically effective amount of a benzenesulfonamide compound of formula (I) wherein X is O or S; at least one of R, R b R 2 , R 3 , and R 4 , which are the same or different, is an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl. or two adjacents of R-R 4 taken together form a benzene ring; and the remaining ones are hydrogen; R 5 is hydrogen, C,-C 6 alkyl, a benzyl or a phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C,-C 6 alkyl, C,-C 6 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 6 alkanoylamino and C r C 6 alkoxy-carbonyl; each of R 6 and R 7 , which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl; or R 6 and R 7 taken together form a C 6 -C, 4 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof. The present invention also provides novel benzenesulfonamide compounds of formula (I) wherein X is O or S; at least one of R, R,, R 2 , R 3 , .and R 4 , which .are the same or different, is an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy. C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl. or two adjacents of R-R 4 taken together form a benzene ring; and the remaining ones are hydrogen; R 5 is hydrogen, C r C 6 alkyl, a benzyl or a phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 6 alkyl, C r C 6 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 6 alkanoylamino and C,-C 6 alkoxy-carbonyl; each of R 6 and R 7 , which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl; or R 6 and R 7 taken together form a C 6 -C )4 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 6 alkyl, Cι-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C,-C 6 alkoxy-carbonyl; and the pharmaceutically acceptable salts thereof. The present invention includes within its scope all the possible isomers, stereoisomers, optical isomers and their mixtures and the metabolites and the metabolic precursors (or bioprecursors) of the compounds of formula (I). Examples of pharmaceutically acceptable salts of the compounds of the invention are either those with inorganic bases, such as sodium, potassium hydroxydes as well as the salts with inorganic, e.g. hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulfonic and ethanesulfonic acids. As stated above, the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different to formula (I) but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I). The alkyl, alkoxy, alkanoylamino and alkoxy-carbonyl groups may be branched or straight chain groups. A C,-C 6 alkyl group is preferably a C,-C 4 alkyl group. Representative examples of C r C 4 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec-, and tert-butyl. A C r C 6 alkoxy group is preferably a C r C 4 alkoxy group. Representative examples of C r C 4 alkoxy groups include methoxy, and ethoxy. A C 2 -C 6 alkanoylamino group is preferably an acetylamino or propionylamino group. A C r C 6 alkoxy-carbonyl group is preferably a C C 4 alkoxy-carbonyl group typically a C r C 2 one. A halogen is fluorine, bromine, chlorine or iodine, in particular chlorine, bromine or fluorine. When one or more of R-R 4 is a heteromonocyclic ring, said ring is linked to the phenyl moiety through a C-C bond and is preferably chosen from the group including pyrrole. furane, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-thiadiazoIe, benzoxazole and benzothiazole. When R 6 and R 7 taken together for a C 6 -C, 4 aromatic ring system it is preferably phenyl or naphthyl. Preferred compounds of formula (I) are those wherein: X is O or S; at least one of R-R 4 is a heterocyclic ring selected independently from pyrrole, furane, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1 ,2,4- oxadiazole, 1,3,4-thiadiazole, benzoxazole and benzothiazole in which said ring is optionally substituted by one or two substituents independently chosen from halogen, C,-C alkyl and phenyl; the remining ones being hydrogen; R 5 is hydrogen, C,-C 4 alkyl, benzyl, or a phenyl ring, the phenyl ring being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 4 alkyl, C,-C 4 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 4 alkanoylamino and C,-C 4 alkoxy-carbonyl; each of R 6 and R 7 which are the same or different, is independently hydrogen or phenyl wherein the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C<- C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino, formyulamino and C,-C 4 alkoxy-carbonyl; or R 6 and R 7 taken together form a C 6 -C, 4 aromatic ring system unsubstituted or substituted by one or two substitutents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 4 alkyl, C r C 4 alkoxy, C 2 -C 4 alkanoylamino, formylamino and C r C 4 alkoxy-carbonyl; and the pharmaceutically acceptable salt thereof. Examples of preferred compounds of formula (I) are the following: N-(5-Chloro-benzoxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide: N-(5-Chloro-benzoxazol-2-yl)-3-isoxazol-3-yl-benzenesulfonamide: N-Oxazol-2-yl-4-isoxazol-3-yl-benzenesulfonamide; N-Thiazol-2-yl-4-isoxazol-3-yl-benzenesulfonamide; N-(4-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(4-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(5-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(5-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-[4-(3-Nitro-phenyl)-oxazol-2-yl]-4-isoxazol-benzenesulfonamide; N-[4-(3-Nitro-phenyl)-thiazol-2-yl]-4-isoxazol-benzenesulfonamide N-(5-Chloro-benzoxazol-2-yl)-4-oxazol-2-yl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-3-oxazol-2-yl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-3-isoxazol-3-yl-benzenesulfonamide; N-Oxazol-2-yl-4-oxazol-2-yl-benzenesulfonamide; N-Thiazol-2-yl-4-oxazol-2-yl-benzenesulfonamide; N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-isoxazol-3-yl- benzenesulfonamide; N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-oxazol-2-yl]-4-isoxazol-3-yl- benzenesulfonamide; N-Oxazol-2-yl-4-thiazol-2-yl-benzenesulfonamide; N-Thiazol-2-yl-4-thiazol-2-yl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-Benzyl-N-(5-Chloro-benzoxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; 4-Benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide; 4-Benzoxazol-2-yl-N-(5-chloro-benzothiazol-2-yl)-benzenesulfonamide; 4-Benzothiazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide; 4-Benzothiazol-2-yl-N-(5-chloro-benzothiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-thiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-thiazol-2-yl)-benzenesulfonamide; 4-Benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-N-phenyl-benzenesulfonamide; N-Benzyl-4-benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide; and the pharmaceutically acceptable salts thereof. The compounds of formula (I) and the salts thereof can be obtained, for instance, by a process comprising: A) reacting a compound of formula (II) wherein R, R,, R 2 , R 3 , and R 4 , are as defined above and Y is a leaving group, with a compound of formula (III) (III) wherein X, R 5 , R 6 , and R 7 are as indicated above; or B) converting a compound of formula (I) in which R 5 is hydrogen in another compound of formula (I) wherein R 5 is as defined above except hydrogen; or, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of formula (I) into a salt thereof, and/or, if desired converting a salt of a compound of formula (I) into a free compound of formula (I), and/or if desired, separating a mixture of isomers of a compound of formula (I) into the single isomers. A compound of formula (I) may be converted into another compound of formula(I) by known methods. For example, in a compound of formula (I) a nitro group may be converted into an amino group by treatment, for example, with stannous chloride in concentrated hydrochloric acid using, an organic cosolvent such as dioxane, tetrahydrofuran at a temperature varying between room temperature and about 100 °C. Furthermore, for example, an amino group may be converted into a formylamino or a C 2 - C 4 alkanoylamino group, for example by reacting with formic acid or with a suitable C 2 - C 4 alkanoyl anhydride without any solvent or in a organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as triethylamine, at a temperature varying between 0 °C and about 100 °C. In a compound of formula (II) Y as leaving group is a good leaving group, for example a halogen atom, typically chlorine, iodine, or bromine, in particular chlorine. The reaction between a compound of formula (II) and a compound of formula (III) can be carried out, for example, in the presence of a base such as triethylamine or pyridine, in a inert solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide, dichloromethane at a temperature varying between 0 °C and about 100 °C. The reaction can be also carried out without base and solvent at a temperature varying between 100 °C and about 200 °C. The conversion of a compound of formula (I) wherein R is hydrogen in another compound of formula (I) wherein R 5 is as defined above except hydrogen can be carried out, for example, in the presence of a base such as sodium hydride, potassium t-butoxide, potassium carbonate in a solvent such as 1 ,2-dimethoxyethane, dioxane, dimethylformamide, acetone and in the presence of a phase-transfer catalyst such as tetra- n-butylammonium iodide at a temperature ranging from about 0 °C to 100 °C, or in the presence of copper bronze and a base such as potassium carbonate at a temperature varying between 100 °C and about 200 °C. The intermediates of formula (II) are either described in Phosphorus, Sulfur, Silicon Relat. Elem. 92, 1-4, 1994, 65-76 or may be prepared analogously. The intermediates of formula (III) are either commercially available or or can be obtained by known methods. Pharmacology The compounds of the invention are active as kynurenine-3-hydroxylase enzyme inhibitors and therefore are useful in the prevention and/or treatment of neuropathological processes, related to a deranged production of quinolinic acid and/or 3- hydroxykynurenine due to excessive activation of neuro transmission mediated by excitatory amino acid receptors and/or oxidative stress. Examples of such neuropathological processes are neurodegenerative pathologies including, e.g. Huntington's chorea, Alzheimer's disease, Parkinson's disease, olivopontocerebellar atrophy, non- Alzheimer's dementias, including the dementia like syndrome caused by Acquired Immunodeficiency Syndrome (AIDS), multi-infarctual ' dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal and head trauma, and epilepsy. A human or animal in need of a kynurenine-3 -hydroxy lase enzyme inhibitor can thus be treated by a method which comprises the administration thereto of a therapeutically effective amount of a compound of the invention or a salt thereof. The condition of the human or animal can thereby be improved. The efficacy of the compounds of the invention in the inhibition of the enzyme kynurenine-3 -hydroxy lase was evaluated e.g., in rat liver mitochondrial extract following the method reported below, according to the procedure described in "Analytical Biochem. (1992), 205, 257-262", with minor modifications. The assay for kynurenine 3-hydroxylase is based on the enzymatic synthesis of tritiated water during the hydroxylation reaction. Radiolabeled water was quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal. Rat liver mitochonidrial extract was used as enzymatic preparation for this assay. The assay for kynurenine 3 -hydroxy lase activity was carired out at 37°C for a time of 30 min. The reaction mixture of a total volume of 30 μl was constituted of 44 μg of suspended extract, 100 mM Tris/Cl " buffer pH 8.1 , 10 mM EDTA, 100 mM KC1, 0.8 mM NADPH, 0.025 mM L-Kynurenine, 0.3 μCi L-(3,5- 3 H)Kynurenine (10 Ci/mmol) and 3 μl of different concentration of inhibitor solutions. After the incubation, the reaction was terminated by the addition of 300 μl of 7.5% (W/v) activated charcoal, and centrifuged for 7 min.. A 75 μl aliquot of supernatant was transferred to optiplate and 200 μl of liquid scintillation added. The optiplates were vortexed and the radioactivity counted in a scintillation counter. The dosage level, suitable for administration to a mammal, e.g.: to humans, depends on the age, weight, conditions of the patient and on the administration route. For example the oral dosage in adult humans for the compound 4-Benzoxazol-2-yl-N-(5- chloro-benzoxazol-2-yl)-benzenesulfonamide may range from about 10 to 500 mg pro dose from 1 to 5 times daily. The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion. The invention includes also pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent). The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example, the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gum, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; desegregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscolar injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, acqueous, isotonic saline solutions or they may contain as a carrier propylene glycol. The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate but do not limit the invention. Example 1 4-Benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesυlfonamide: 4-Benzoxazol-2-yl-benzenesulfonyl chloride (0.59 g; 0.0020 mol) was added to a solution of 2- Amino-5-chlorobenzoxazole (0.34 g; 0.0020 mol) and triethylamine (0.34 mL; 0.0024 mol) in toluene (15 mL) at 0 °C. The reaction was stirred at room temperature for 24 h then diluted with toluene, washed with brine, dried over anhydrous sodium sulphate and evaporated after filtration. The crude product was purified by silica gel column chromatography (ethyl acetate: cyclohexane 1 :3 as eluant), to give 0.34 g of the desired product as a white solid C 2 oH 12 ClN 3 θ 4 S; required: C= 56.41 ; H= 2.84; N= 9.87; found: C= 56.06; H= 2.98; N= 9.65. Analogously the following products can be prepared: N-(5-Chloro-benzoxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-3-isoxazol-3-yl-benzenesulfonamide; N-Oxazol-2-yl-4-isoxazol-3-yl-benzenesulfonamide; N-Thiazol-2-yl-4-isoxazol-3-yl-benzenesulfonamide; N-(4-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(4-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(5-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(5-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-[4-(3-Nitro-phenyl)-oxazol-2-yl]-4-isoxazol-benzenesulfonamide; N-[4-(3-Nitro-phenyl)-thiazol-2-yl]-4-isoxazol-benzenesulfonamide N-(5-Chloro-benzoxazol-2-yl)-4-oxazol-2-yl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-3-oxazol-2-yl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-3-isoxazol-3-yl-benzenesulfonamide; N-Oxazol-2-yl-4-oxazol-2-yl-benzenesulfonamide; N-Thiazol-2-yl-4-oxazol-2-yl-benzenesulfonamide; N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-isoxazol-3-yl- benzenesulfonamide; N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-oxazol-2-yl]-4-isoxazol-3-yl- benzenesulfonamide; N-Oxazol-2-yl-4-thiazol-2-yl-benzenesulfonamide; N-Thiazol-2-yl-4-thiazol-2-yl-benzenesulfonamide; 4-Benzoxazol-2-yl-N-(5-chloro-benzothiazol-2-yl)-benzenesulfonamide; 4-Benzothiazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide; 4-Benzothiazol-2-yl-N-(5-chloro-benzothiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-thiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-thiazol-2-yl)-benzenesulfonamide; Example 2 4-Benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-N-phenyl-benzenesulfonamide: Bromobenzene (0.72 g; 0.0046 mol), and 4-Benzoxazol-2-yl-N-(5-chloro-benzoxazol-2- yl)-benzenesulfonamide; (1.23 g; 0.0029 mol), copper bronze (0.45 g) and potassium carbonate (0J5 g) were heated at reflux for 10 h. To the cooled mixture water was added and the excess of bromobenzene was removed by steam distillation. The cooled residue was ground with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness after filtration. The crude product was purified by silica gel column chromatagraphy (ethyl acetate: cyclohexane 1 :4 as eluant), to give 0.55 g of the desired product as a white solid. C 26 H 16 C1N 3 0 4 S; required: C= 62.22; H= 3.21 ; N= 8.37; found: C= 61.98; H= 3.35; N= 8.1 1. Analogously the following products can be prepared: N-Oxazol-2-yl-4-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-Thiazol-2-yl-4-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-(4-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-(4-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-(5-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-(5-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-[4-(3-Nitro-phenyl)-oxazol-2-yl]-4-isoxazol-N-phenyl-benzenesulfonamide; N-[4-(3-Nitro-phenyl)-thiazol-2-yl]-4-isoxazol-N-phenyl-benzenesulfonamide N-(5-Chloro-benzoxazol-2-yl)-4-oxazol-2-yl-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-3-oxazol-2-yl-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-3-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-Oxazol-2-yl-4-oxazol-2-yl-N-phenyl-benzenesulfonamide; N-Thiazol-2-yl-4-oxazol-2-yl-N-phenyl-benzenesulfonamide; N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-isoxazol-3-yl-N-phenyl- benzenesulfonamide ; N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-oxazol-2-yl]-4-isoxazol-3-yl-N-phenyl- benzenesulfonamide; N-Oxazol-2-yl-4-thiazol-2-yl-N-phenyl-benzenesulfonamide; N-Thiazol-2-yl-4-thiazol-2-yl-N-phenyl-benzenesulfonamide; 4-Benzoxazol-2-yl-N-(5-chloro-benzothiazol-2-yl)-N-phenyl-benzenesulfonamide; 4-Benzothiazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-N-phenyl-benzenesulfonamide; 4-Benzothiazol-2-yl-N-(5-chloro-benzothiazol-2-yl)-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-thiazol-2-yl)-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-oxazol-2-yl)-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-oxazol-2-yl)-N-phenyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-thiazol-2-yl)-N-phenyl-benzenesulfonamide. Example 3 N-Benzyl-4-benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide: To a solution of 4-Benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide (2.47 g; 0.0058 mol) in 20 ml of acetone, potassium carbonate (2.49 g; 0.018 mol), catalytic tetra-n-butylammonium iodide and benzyl bromide (1.2 g; 0.007 mol) were added. The mixture was stirred under nitrogen at 25 °C for 24 h. The mixture was diluted with 200 ml of ethyl acetate . washed with brine, dried over anhydrous sodium sulphate and evaporated to dryness after filtration. The crude product was purified by silica gel column chromatography (ethyl acetate: cyclohexane 1 :3 as eluant) to give 1.9 g of the desired product as a grey solid. C 27 H 18 C1N,0 4 S; required: C= 62.85; H= 3.52; N= 8.14; found: C= 62.58; H= 3.79; N= 7.89. Analogously the following products can be prepared: N-Benzyl-N-(5-Chloro-benzoxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Benzyl-N-(5-Chloro-benzoxazol-2-yl)-3-isoxazol-3-yl-benzenesulfonamide; N-Benzyl-N-Oxazol-2-yl-4-isoxazol-3-yl-benzenesulfonamide; N-Benzyl-N-Thiazol-2-yl-4-isoxazol-3-yl-benzenesulfonamide; N-Benzyl-N-(4-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Benzyl-N-(4-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Benzyl-N-(5-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Benzyl-N-(5-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Benzyl-N-[4-(3-Nitro-phenyl)-oxazol-2-yl]-4-isoxazol-benzenesulfonamide; N-Benzyl-N-[4-(3-Nitro-phenyl)-thiazol-2-yl]-4-isoxazol-benzenesulfonamide N-Benzyl-N-(5-Chloro-benzoxazol-2-yl)-4-oxazol-2-yl-benzenesulfonamide; N-Benzyl-N-(5-Chloro-benzoxazol-2-yl)-3-oxazol-2-yl-benzenesulfonamide; N-Benzyl-N-(5-Chloro-benzothiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Benzyl-N-(5-Chloro-benzothiazol-2-yl)-3-isoxazol-3-yl-benzenesulfonamide; N-Benzyl-N-Oxazol-2-yl-4-oxazol-2-yl-benzenesulfoaamide; N-Benzyl-N-Thiazol-2-yl-4-oxazol-2-yl-benzenesulfonamide; N-Benzyl-N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-isoxazol-3-yl- benzenesulfonamide; N-Benzyl-N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-oxazol-2-yl]-4-isoxazol-3-yl- benzenesulfonamide; N-Benzyl-N-Oxazol-2-yl-4-thiazol-2-yl-benzenesulfonamide; N-Benzyl-N-Thiazol-2-yl-4-thiazol-2-yl-benzenesulfonamide; N-Ethyl-N-(5-Chloro-benzoxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Ethyl-N-(5-Chloro-benzoxazol-2-yl)-3-isoxazol-3-yl-benzenesulfonamide; N-Ethyl-N-Oxazol-2-yl-4-isoxazol-3-yl-benzenesulfonamide; N-Ethyl-N-Thiazol-2-yl-4-isoxazol-3-yl-benzenesulfonamide; N-Ethyl-N-(4-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Ethyl-N-(4-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Ethyl-N-(5-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Ethyl-N-(5-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Ethyl-N-[4-(3-Nitro-phenyl)-oxazol-2-yl]-4-isoxazol-benzenesulfonamide; N-Ethyl-N-[4-(3-Nitro-phenyl)-thiazol-2-yl]-4-isoxazol-benzenesulfonamide N-Ethyl-N-(5-Chloro-benzoxazol-2-yl)-4-oxazol-2-yl-benzenesulfonamide; N-Ethyl-N-(5-Chloro-benzoxazol-2-yl)-3-oxazol-2-yl-benzenesulfonamide; N-Ethyl-N-(5-Chloro-benzothiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-Ethyl-N-(5-Chloro-benzothiazol-2-yl)-3-isoxazol-3-yl-benzenesulfonamide; N-Ethyl-N-Oxazol-2-yl-4-oxazol-2-yl-benzenesulfonamide; N-Ethyl-N-Thiazol-2-yl-4-oxazol-2-yl-benzenesulfonamide; N-Ethyl-N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-isoxazol-3-yl- benzenesulfonamide; N-Ethyl-N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-oxazol-2-yl]-4-isoxazol-3-yl- benzenesulfonamide; N-Ethyl-N-Oxazol-2-yl-4-thiazol-2-yl-benzenesulfonamide; N-Ethyl-N-Thiazol-2-yl-4-thiazol-2-yl-benzenesulfonamide; N-Benzyl-4-benzoxazol-N-(5-chloro-benzothiazol-2-yl)-benzenesulfonamide; N-Benzyl-4-benzoxazol-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide; N-Benzyl-4-benzoxazol-N-(5-chloro-benzothiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-N-benzyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-N-benzyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-N-benzyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-N-benzyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-thiazol-2-yl)-N-benzyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-oxazol-2-yl)-N-benzyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-oxazol-2-yl)-N-benzyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-thiazol-2-yl)-N-benzyl-benzenesulfonamide; N-Ethyl-4-benzoxazol-N-(5-chloro-benzothiazol-2-yl)-benzenesulfonamide; N- Ethyl-4-benzoxazol-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide; N- Ethyl-4-benzoxazol-N-(5-chloro-benzothiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-N-ethyl-l-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-N-ethyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-N-ethyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-N-ethyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-thiazol-2-yl)-N-ethyl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-oxazol-2-yl)-N-ethyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-oxazol-2-yl)-N-ethyl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-thiazol-2-yl)-N-benzyl-benzenesulfonamide. Example 4 Capsule, each weighing 0.23 g and containing 50 mg of the active substance can be prepared as follow: Composition for 500 capsules: 4-Benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide 25 g Lactose 80 g Corn starch 5 g Magnesium stearate 5 g This formulation can be encapsulated in two hard gelatin capsules of two pieces, each with each capsule weighing 0.23 g. Example 5 Intramuscular injection of 50 mg/mL A pharmaceutical injectable composition can be manufactured dissolving 50 g of 4- Benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide in sterile propylenglycol (1000 mL) and sealed in 1-5 ampoules. Legend to Figure 1 IDO = Indolamineoxigenase; KYN = Kynurenine; KYN-OH = Kynurenine-3-hydroxylase; KYNA = Kynurenic acid; 3-OHAA = 3-Hydroxy anthranilic acid; KYNase = Kynureninase; QUIN = Quinolinic acid; 3-HAO = 3-Hydroxy anthranilic acid deoxygenase; KAT = Kynurenine amino transferase; 3-OH-KYN = 3-Hydroxy-kynurenine.

Claims: CLAIMS The use of a compound which is a benzenesulfonamide of formula (I) wherein X is O or S; at least one of R, R,, R 2 , R 3 , and R 4 , which are the same or different, is an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C.-C 6 alkoxy-carbonyl. or two adjacents of R-R 4 taken together form a benzene ring; and the remaining ones are hydrogen; R 5 is hydrogen, C,-C 6 alkyl, a benzyl or a phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 6 alkyl, C,-C 6 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 6 alkanoylamino and C.-C 6 alkoxy-carbonyl; each of R 6 and R 7 , which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C,-C 6 alkoxy-carbonyl; or R 6 and R 7 taken together form a C 6 -C 1 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C Γ C 6 alkoxy-carbonyl, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as a kynurenine-3-hydroxylase enzyme inhibitor. 2. Use according to claim 1 wherein the medicament is for use in the prevention and/or treatment of a neurodegenerative pathology. 3. Use according to claim 2 wherein the neurodegenerative pathology is selected from Huntington's chorea, Alzheimer's disease, Parkinson's disease, olivoponto cerebellar atrophy, non- Alzheimer's dementia, multi-infarctual dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal or head trauma and epilepsy. 4. A compound which is a benzenesulfonamide of formula (I) wherein X is O or S; at least one of R, R b R 2 , R 3 , and R , which are the same or different, is an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C.-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C.-C 6 alkoxy-carbonyl, or two adjacents of R-R 4 taken together form a benzene ring; and the remaining ones are hydrogen; R 5 is hydrogen, C r C 6 alkyl, a benzyl or a phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 6 alkyl, C,-C 6 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 6 alkanoylamino and C,-C 6 alkoxy-carbonyl; each of R 6 and R 7 , which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl; or R 6 and R 7 taken together form a C 6 -C 14 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance.. 5. A compound accordiing to claim 4 for use as a kynurenine-3 -hydroxy lase enzyme inhibitor. A compound which is a benzenesulfonamide of formula (I) wherein X is O or S; at least one of R, R b R 2 , R 3 , and R 4 , which are the same or different, is an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C C 6 alkoxy-carbonyl. or two adjacents of R-R 4 taken together form a benzene ring; and the remaining ones are hydrogen; R 5 is hydrogen, C,-C 6 alkyl, a benzyl or a phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C,-C 6 alkyl, C r C 6 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 6 alkanoylamino and C r C 6 alkoxy-carbonyl; each of R 6 and R 7 , which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C.-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl; or R 6 and R 7 taken together form a C 6 -C 14 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C i -C 6 alkoxy-carbonyl. or a pharmaceutically acceptable salt thereof. 7. A compound, according to claim 6 wherein, in formula (I), X is O or S; at least one of R-R 4 is a heterocyclic ring selected independently from pyrrole, furane, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3-triazole, 1 ,2,4-triazole, 1 ,2,4- oxadiazole, 1 ,3,4-thiadiazole, benzoxazole and benzothiazole in which said ring is optionally substituted by one or two substituents independently chosen from halogen, C|-C 4 alkyl and phenyl: the remaining ones being hydrogen; R 5 is hydrogen, C,-C 4 alkyl, benzyl, or a phenyl ring, the phenyl ring being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C,-C 4 alkyl, C.-C 4 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 4 alkanoylamino and C,-C 4 alkoxy-carbonyl; each of R 6 and R 7 which are the same or different, is independently hydrogen or phenyl wherein the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,- C 4 alkyl, C r C 4 alkoxy, C 2 -C 4 alkanoylamino, formyulamino and C C 4 alkoxy-carbonyl; or R^ and R 7 taken together form a C 6 -C 14 aromatic ring system unsubstituted or substituted by one or two substitutents chosen independently from halogen, hydroxy, triluoromethyl, nitro, amino, phenyl, benzyl, C r C alkyl, C r C 4 alkoxy. C 2 -C 4 alkanoylamino, formylamino and C r C 4 alkoxy-carbonyl. 8. A compound selected from: N-(5-Chloro-benzoxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-3-isoxazol-3-yl-benzenesulfonamide; N-Oxazol-2-yl-4-isoxazol-3-yl-benzenesulfonamide; N-Thiazol-2-yl-4-isoxazol-3-yl-benzenesulfonamide; N-(4-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(4-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(5-Phenyl-oxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-(5-Phenyl-thiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; N-[4-(3-Nitro-phenyl)-oxazol-2-yl]-4-isoxazol-benzenesulfonamide; N-[4-(3-Nitro-phenyl)-thiazol-2-yl]-4-isoxazol-benzenesulfonamide N-(5-Chloro-benzoxazol-2-yl)-4-oxazol-2-yl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-3-oxazol-2-yl-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide: N-(5-Chloro-benzothiazol-2-yl)-3-isoxazol-3-yl-benzenesulfonamide; N-Oxazol-2-yl-4-oxazol-2-yl-benzenesulfonamide; N-Thiazol-2-yl-4-oxazol-2-yl-benzenesulfonamide; N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-isoxazol-3-yl- benzenesulfonamide; N-[4-(2-Fluoro-5-trifluoromethyl-phenyl)-oxazol-2-yl]-4-isoxazol-3-yl- benzenesulfonamide; N-Oxazol-2-yl-4-thiazol-2-yl-benzenesulfonamide; N-Thiazol-2-yl-4-thiazol-2-yl-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-isoxazol-3-yl-N-phenyl-benzenesulfonamide; N-Benzyl-N-(5-Chloro-benzoxazol-2-yl)-4-isoxazol-3-yl-benzenesulfonamide; 4-Benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide; 4-Benzoxazol-2-yl-N-(5-chloro-benzothiazol-2-yl)-benzenesulfonamide; 4-Benzothiazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide; 4-Benzothiazol-2-yl-N-(5-chloro-benzothiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-phenyl-thiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-thiazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzoxazol-2-yl)-4-(5-methyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-oxazol-2-yl)-benzenesulfonamide; N-(5-Chloro-benzothiazol-2-yl)-4-(5-methyl-thiazol-2-yl)-benzenesulfonamide; 4-Benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-N-phenyl-benzenesulfonamide; N-Benzyl-4-benzoxazol-2-yl-N-(5-chloro-benzoxazol-2-yl)-benzenesulfonamide; and the pharmaceutically acceptable salts thereof. 9. A pharmaceutical composition comprising a compound as defined in claim 6, and a pharmaceutically acceptable carrier and/or diluent. 10. A method of treating a mammal, including a human, in need of a kynurenine-3- hydroxy lase enzyme inhibitor, the method comprising administering thereto a therapeutically effective amount of a compound which is a benzenesulfonamide of formula (I) wherein X is O or S; at least one of R, R R 2 , R 3 , and R , which are the same or different, is an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 6 alkyl, C.-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl. or two adjacents of R-R 4 taken together form a benzene ring; and the remaining ones are hydrogen; R 5 is hydrogen, C--C 6 alkyl, a benzyl or a phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C,-C 6 alkyl, C,-C 6 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 6 alkanoylamino and C,-C 6 alkoxy-carbonyl; each of R 6 and R 7 , which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C alkyl. C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C,-C 6 alkoxy-carbonyl; or R 6 and R 7 taken together form a C 6 -C 14 aromatic ring system unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl. nitro, amino, phenyl, benzyl, C.-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C,-C 6 alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof.

Inventors: GRECO FELICITA, HEIDEMPERGHER FRANCO, PEVARELLO PAOLO, SPECIALE CARMELA, VARASI MARIO, GRECO, FELICITA, HEIDEMPERGHER, FRANCO, PEVARELLO, PAOLO, SPECIALE, CARMELA, VARASI, MARIO
Applicants: GRECO FELICITA, HEIDEMPERGHER FRANCO, PEVARELLO PAOLO, PHARMACIA & UPJOHN SPA, SPECIALE CARMELA, VARASI MARIO, GRECO, FELICITA, HEIDEMPERGHER, FRANCO, PEVARELLO, PAOLO, PHARMACIA & UPJOHN S.P.A., SPECIALE, CARMELA, VARASI, MARIO
Application year: 1998
Main classification: C07D263
IPC codes: A61K31, A61P25, A61P43, C07D263, C07D277, C07D413, C07D417