TRICYCLIC 3-OXO-PROPANENITRILE COMPOUNDS

Abstract: Tricyclic 3-oxo-propanenitrile compounds of formula (I), wherein Y represents a nitrogen atom or a CH or N-oxide group; X represents an oxygen atom or NR2 wherein R2 represents C1-C6 alkyl, benzyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, nitro, amino, formylamino and C2-C8 alkanoylamino; each of R and R1 is independently hydrogen, halogen, CF3, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C3-C4 alkenyloxy, nitro, amino, formylamino, C2-C8 alkanoylamino or C2-C8 alkanoyloxy; m is zero or an integer of 1 to 6; Q is C1-C14 alkyl, phenyl or unsaturated pentatomic heteromonocylic ring containing two or three heteroatoms chosen from oxygen, sulphur and nitrogen, wherein the phenyl ring and the heteromonocylic ring are unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, nitro, amino, formylamino, C2-C8 alkanoylamino or C2-C8 alkanoyloxy; and W represents a -CONH- or -SO2- or -CO- group; and pharmaceutically acceptable salt thereof having kynurenine-3-hydroxylase enzyme inhibitor activity are provided.

Description: TRICYCLIC 3-OXO-PROPANENITRILE COMPOUNDS The present invention relates to novel tri cyclic 3-oxo-propanenitrile compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use in therapy. The compounds of the invention act as inhibitors of Kynurenine-3 -hydro xylase (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 potent neurotoxin which has been implicated in the pathogenesis of a variety of neurological disorders (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 key enzymes of the kynurenine (KYN) pathway, among which Kynurenine-3- hydroxylase (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 novel tricyclic 3-oxo-propanenitrile compounds of formula (I) wherein Y represents a nitrogen atom or a CH or N-oxide group; X represents an oxygen atom or NR 2 wherein R 2 represents C,-C 6 alkyl, benzyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C C 6 alkyl, C r C 6 alkoxy, nitro, amino, formylamino and C 2 -C 8 alkanoylamino; each of R and R, is independently hydrogen, halogen, CF 3 , C r C 6 alkyl, hydroxy, C r C 6 alkoxy, C 3 -C 4 alkenyloxy, nitro, amino, formylamino, C 2 -C 8 alkanoylamino or C 2 -C 8 alkanoyloxy; m is zero or an integer of 1 to 6; Q is C1-C1 4 alkyl, phenyl or unsaturated pentatomic heteromonocyclic ring containing two or three heteroatoms chosen from oxygen, sulphur and nitrogen, wherein the phenyl ring and the heteromonocyclic ring are unsubstituted or substituted by one or two substituents chosen independently from halogen, CF 3 , C C 6 alkyl, hydroxy, C r C 6 alkoxy, nitro, .amino, formylamino, C 2 -C 8 alkanoylamino or C 2 -C 8 alkanoyloxy; and W represents a -CONH-, -SO 2 - or -CO- group. The present invention also includes within its scope the pharmaceutically acceptable salts, and all possible isomers, stereoisomers and opti al isomers and their mixtures, and both the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of the invention. It has to be noticed that the compounds of formula (I) may be represented also by a tautomeric structure, namely the enol structure of formula (la) wherein X, Y, R, R b m, Q .and W are as defined above. However, the compounds of formula (la), which fall within the scope of the present invention too, are described in the present specification either as compounds of formula (I) or of formula (la) as more convenient or appropriate in the art. The alkyl, alkanoyloxy, alkoxy and alkanoylamino groups may be branched or straight chain groups. A CpC 1 alkyl group is preferably a C,-C 6 alkyl group. Representative examples of C,-C 6 alkyl groups include C.-C alkyl groups such as methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl. Representative examples of C C 6 alkoxy groups include C.-C 4 alkoxy groups such as methoxy or ethoxy. Representative examples of C 2 -C 8 alkanoylamino include C 2 -C 4 alkanoyl groups such as acetylamino or propionylamino. Representative examples of C 2 -C 8 alkanoyloxy include C 2 -C alkanoyl groups such as acetoxy or propionyloxy. A C 3 -C 4 alkenyloxy group is preferably allyloxy. When Q is a heteromonocyclic ring as defined above it is preferably chosen from oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4- oxadiazole and 1,3,4-thiadiazole. A halogen atom is fluorine, bromine, chlorine or iodine; in particular chlorine or fluorine. Pharmaceutically acceptable salts of the compounds of the invention include base addition salts with inorganic bases, e.g. sodium, potassium, calcium and aluminium hydroxydes or with organic bases, e.g. lysine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N- ethylpiperidine, N,N-diethylaminoethylamine, N-ethyl-morpholine, β-phenethylamine, N-benzyl-β-phenethylamine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines. Preferred compounds of the invention are the compounds of formula (I) wherein: Y represents a nitrogen atom or a CH group; X is oxygen or NR 2 wherein R 2 represents C,-C 4 alkyl or phenyl unsubstituted or substituted by one or two substituents selected independently from halogen, trifiuoromethyl, C r C alkyl, C,-C 4 alkoxy and nitro; each of R and R, independently is hydrogen, nitro, halogen, trifiuoromethyl, C,-C 4 alkyl or C r C 4 alkoxy; m is zero or 1 ; Q is C r C 4 alkyl or a phenyl ring unsubstituted or substituted by one or two substituents selected from halogen, trifiuoromethyl, nitro, C,-C 4 alkyl and C r C 4 alkoxy; W is a -CONH-, -SO 2 - or -CO- group; and the pharmaceutically acceptable salts thereof. Examples of preferred compounds of the invention are the following: 2-ciano-3-hydroxy-3-(l-methyl-lH-benzo[g]indazol-3-yl)-N-phenyl-acrylamide: 2-cyano-3-(8-fluoro-l -methyl- lH-benzo!g)indazol-3-yl)-3-oxo-N-phenyl-propionamide: 2-cyano-3-(9-chloro-l-methyl-lH-benzolg]indazol-3-yl)-3-oxo-N-phenyl-propionamide: 2-cyano-3-(9-methoxy-l -methyl- lH-benzo[gJindazol-3-yl)-3-oxo-N-phenyl- propionamide; 2-cyano-N-(4-methoxy-phenyl)-3 -( 1 -methyl- 1 H-benzo[g]indazol-3 -y l)-3 -oxo- propionamide; 2-cyano-N-(4-fluoro-phenyl)-3-(l-methyl-lH-benzo[glindazol-3-yl)-3-oxo- propionamide; 2-cyano-N-(3 -nitro-phenyl)-3 -( 1 -methyl- 1 H-benzo[g]indazol-3 -y l)-3 -oxo-propionamide ; 2-cyano-N-(3-trifluoromethyl-phenyl)-3-(l-methyl-lH-benzo[g]indazol-3-yl)-3-oxo- propion-amide; 2-cyano-N-(3-methyl-phenyl)-3-(l-methyl-lH-benzo[g]ind.azol-3-yl)-3-oxo- propionamide; 2-cyano-N-(3-chloro-phenyl)-3-(l-methyl-lH-benzofgjindazol-3-yl)-3-oxo- propionamide; N-butyl-2-cyano-3-(l-methyl-lH-benzofgJindazol-3-yl)-3-oxo-propionamide; N-benzyl-2-cyano-3-(l-methyl-lH-benzo[g]indazol-3-yl)-3-oxo-propionamide; 2-cyano-3-hydroxy-3-(l-phenyl-lH-benzolg]indazol-3-yl)-N-phenyl-acrylamide; 2-cyano-3-(l-methyl-lH-pyrazolof4,3-c]quinolin-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(l-phenyl-lH-pyrazolo[4,3-cJquinolin-3-yl)-3-oxo-N-phenyl-propion.amide; 2-cyano-3-hydroxy-3-(isoxazolo[2,l-a]naphthalen-3-yl)-N-phenyl-acrylamide, 2-cyano-3-(8-fluoro-isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(9-chloro-isox.azolo[2,l-a]naphthalen-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(9-methoxy-isoxazolof2,l-alnaphthalen-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-N-(4-methoxy-phenyl)-3 -(isoxazolo[2, 1 -aJnaphthalen-3 -y l)-3 -oxo- propionamide; 2-cyano-N-(4-fluoro-phenyl)-3-(isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionamide; 2-cyano-N-(3-nitro-phenyl)-3-(isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo-propionamide; 2-cyano-N-(3-trifluoromethyl-phenyl)-3-(isoxazolof2,l-alnaphthalen-3-yl)-3-oxo- propionamide; 2-cyano-N-(3-methyl-phenyl)-3-(isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo-propionamide; 2-cyano-N-(3-chloro-phenyl)-3-(isoxazolo[2,l-a)naphthalen-3-yl)-3-oxo-propionamide; N-benzyl-2-cyano-3-(isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionamide; N-butyl-2-cyano-3-(isox.azolo!2,l-a)naphthalen-3-yl)-3-oxo-propionamide; 2-benzoyl-3-(l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-(l -methyl- lH-benzo[g]indazol-3-yl)-3-oxo-propionitrile; 2-(4-fluoro-benzoyl)-3-(l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo-propionitrile: 2-(3-nitro-benzoyl)-3-(l-methyl-lH-benzo[gjindazol-3-yl)-3-oxo-propionitrile: 2-(3-trifluoromethyl-benzoyl)-3-(l-methyl-lH-benzolglindazol-3-yl)-3-oxo- propionitrile; 2-(3-methyl-benzoyl)-3-(l -methyl- lH-benzo[glindazol-3-yl)-3-oxo-propionitrile; 2-(3-chloro-benzoyl)-3-(l-methyl-lH-benzo(gIindazol-3-yl)-3-oxo-propionitrile: 2-benzoyl-3-(8-fluoro-l -methyl- lH-benzofg]indazol-3-yl)-3-oxo-propionitrile: 2-benzoyl-3-(9-chloro-l -methyl- lH-benzofgIindazol-3-yl)-3-oxo-propionitrile: 2-benzoyl-3-(9-methoxy-l -methyl- lH-benzo[gjindazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(isoxazolol2,l-aInaphthalen-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-(isoxazolof2.1-aJnaphthalen-3-yl)-3-oxo-propionitrile: 2-(4-fluoro-benzoyl)-3-(isoxazolo[2,l-alnaphthalen-3-yl)-3-oxo-propionitrile: 2-(3-nitro-benzoyl)-3-(isoxazolo[2,l -aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-trifluoromethyl-benzoyl)-3-(isoxazolof2,l-a]naphthalen-3-yl)-3-oxo-propionitrile; 2-(3-methyl-benzoyl)-3-(isoxazolo[2,l-ainaphthalen-3-yl)-3-oxo-propionitrile: 2-(3-chloro-benzoyl)-3-(isoxazolo(2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(8-fluoro-isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(9-chloro-isoxazolof2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(9-methoxy-isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile: 2-benzenesulfonyl-3-(l -methyl- lH-benzo[gjindazol-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l -methyl- lH-benzolglindazol-3-yl)-3-oxo- propionitrile; 2-(4-fluoro-benzenesulfonyl)-3-(l-methyl-lH-benzo(glindazol-3-yl)-3-oxo- propionitrile; 2-(3-nitro-benzenesulfonyl)-3-(l-methyl-lH-benzolglindazol-3-yl)-3-oxo-propionitrile: 2-(3-trifluoromethyl-benzenesulfonyl)-3-(l-methyl-lH-benzo[giindazol-3-yl)-3-oxo- propionitrile; 2-(3-methyl-benzenesulfonyl)-3-(l-methyl-lH-benzolg]indazol-3-yl)-3-oxo- propionitrile; 2-(3-chloro-benzenesulfonyl)-3-(l-methyl-lH-benzo[g)indazol-3-yl)-3-oxo- propionitrile; 2-benzenesulfonyl-3-(8-fluoro-l-methyl-lH-benzo[g]indazol-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(9-chloro-l -methyl- lH-benzoIgjindazol-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(9-methoxy-l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(isoxazolof2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-(4-fluoro-benzenesulfonyl)-3-(isoxazolo!2,l-aInaphthalen-3-yl)-3-oxo-propionitrile; 2-(3 -nitro-benzenesulfony l)-3 -(isoxazolo[2, 1 -aJnaphthalen-3 -yl)-3 -oxo-propionitrile ; 2-(3-trifluoromethyl-benzenesulfonyl)-3-(isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo- propionitrile; 2-(3-methyl-benzenesulfonyl)-3-(isoxazoloI2,l-a]naphthalen-3-yl)-3-oxo-propionitrile; 2-(3-chloro-benzenesulfonyl)-3-(isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(8-fluoro-isoxazolof2,l-ainaphthalen-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(9-chloro-isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(9-methoxy-isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; and 2-benzenesulfonyl-3-(isoxazolo[2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; and the pharmaceutically acceptable salts thereof. A further object of the present invention is also to provide a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance, in particular as kynurenine-3-hydroxylase enzyme inhibitor. Object of the present invention is also the use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as kynurenine-3-hydroxylase enzyme inhibitor. The present invention also provides a method of treating a mammal, including human, in need of a kynurenine-3 -hydroxy lase inhibitor, such method comprising adminstering thereto a therapeutically effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof. The compounds of the invention and the salts thereof can be obtained, for instance, by a process comprising: a) reacting a compound of formula (II) wherein X, R and R, are as defined above, Y represents a nitrogen atom or a CH group and Z is a derivative of a carboxy group,with a compound of formula (III) wherein m, Q .and W are as defined above, thus obtaining a compound of formula (I) in which Y represents a nitrogen atom or a CH group; or b) reacting a compound of formula (IV) wherein X, R and R, are as defined above and Y represents a nitrogen atom or a CH group, with a compound of formula (V) or (VI) Q-(CH 2 ) Z Q-(CH 2 )-N=C=O (V) (VI) wherein Q, m .and Z are as defined above, so obtaining a compound of formula (I) wherein W is a -CO- or a -CONH- group respectively and Y represents a nitrogen atom or a CH group; or c) oxidizing a compound of formula (I) wherein Y is a nitrogen atom into the corresponding compound of formula (I) in which Y is a N-oxide group; and, 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. The above process-variants a), b) and c) are analogy processes which can be carried out according to well known methods in the art. When Z is a derivative of a carboxy group, it is preferably a reactive derivative thereof, for example a halocarbonyl group, preferably a chlorocarbonyl group, or a C 2 -C 7 alkoxycarbonyl group, preferably a C 2 -C 3 alkoxycarbonyl group. The reaction between a compound of formula (II) wherein Z is a reactive derivative of a carboxy group and a compound of formula (III) can be carried out, for example, in the presence of a strong base such as sodium hydride, potassium t-butoxide, thallous ethoxide, in an inert solvent such as 1 ,2-dimethoxyethane, dioxane, dimethylformamide, at a temperature ranging from about 0°C to about 100°C. The reaction between a compound of formula (IV) and a compound of formula (V) or (VI) can be carried out, for example, in the presence of a base such as sodium hydride or triethylamine, in an inert solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide, dichloromethane, at a temperature varying between about 0°C and about 100°C. The conversion of a compound of formula (I) wherein Y is a nitrogen atom into the corresponding compound of formula (I) in which Y is a N-oxide group may be performed by treatment, for example, with m-chloroperbenzoic acid or perbenzoic acid in a solvent such as dichloromethane or with H 2 O 2 in acetic acid. Also the optional conversion of a compound of formula (I) into another compound of formula (I) can be carried out according to 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, if necessary, an organic cosolvent such as acetic acid, 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 8 alkanoylamino group, for example by reacting with formic acid or with the suitable C 2 -C 8 alkanoylanhydride without any solvent or in an organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as pyridine or triethylamine, at a temperature varyng between about 0°C and about 100°C. The optional salification of a compound of formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods. The compounds of formula (II) as herein defined are novel compounds and are a further object of the present invention. A compound of formula (II), wherein Z is a C 2 -C 7 alkoxycarbonyl group, can be otbained for instance by aromatization of a compound of formula (VII) wherein R, R. and X are as defined above and A is a NH or CH 2 group. Aromatization reaction may be accomplished using quinones such as, e.g. chloroanil (2.3,5,6-tetrachloro-l,4- benzoquinone) or DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone), in a solvent such as toluene, dioxane, at a temperature varying between about room temperature and about 120°C. Aromatization reaction, wherein Y is a nitrogen atom, can be simply performed warming a compound of formula (VII) in an organic solvent such as dimethylformamide. A compound of formula (VII) may be prepared, for example, by reacting a compound of formula (VIII) wherein R, Ri and A are as defined above and R 3 is a lower alkyl, e.g. C,-C 6 alkyl, preferably C r C 2 alkyl, with a compound of formula (IX) H-X-NH 2 (IX) wherein X is oxygen or NR 2 wherein R 2 is as defined above. The reaction between a compound of formula (VIII) and a compound of formula (IX) may be carried out, for example, in an organic solvent such as C,-C 6 alkyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, acetic acid, at a temperature varying between about 0°C and about 150°C, in the presence or in the absence of a suitable acid, e.g. methanesulfonic acid. A compound of formula (II), wherein Z is halocarbonyl, preferably chlorocarbonyl, may be prepared, for example, by reacting the corresponding compound of formula (II), wherein Z is carboxy, with the suitable acid halide, for example oxalyl chloride, thionyl chloride, PC1 3 , PBr 3 , in an inert solvent such as ether, benzene, dichloromethane, dioxane or without any solvent, at a temperature varying between about 0°C and about 100°C. The compounds of formula (II), wherein Z is carboxy may be prepared, for example, by hydrolysis of the corresponding compounds of formula (II) wherein Z is C 2 -C 7 alkoxycarbonyl, according to standard methods well known in the art, for example, by basic hydrolysis, carried out e.g. by treatment with sodium or potassium hydroxide in a solvent such as water, C 2 -C 6 alkyl alcohol, dioxane, dimethylformamide and their mixtures, at a temperature varying between about 0°C and about 50°C. Compounds of formula (III) are, in some cases, commercially available products, or may be prepared by methods well known in the art. Also the compounds of formula (IV) as herein defined are novel compounds and are a further object of this invention. A compound of formula (IV) can be obtained by process a) above, for example, by reacting a compound of formula (II), wherein Z is C 2 -C 7 alkoxycarbonyl, with acetonitrile, in the presence of a strong base e.g. sodium hydride, potassium tert- butoxide, in an inert organic solvent such as benzene, dioxane, tetrahydrofuran, at a temperature varying between about 0°C and about 100°C. A compound of formula (VIII) may be prepared, for example, by reacting a compound of formula (X) wherein R, Ri and A are as defined above, with a compound of formula (XI) COOR. COOR 5 ( χι ) wherein each of R 4 and R 5 , being the same or different, is C,-C 6 alkyl, preferably methyl or ethyl. The reaction between a compound of formula (X) and a compound of formula (XI) may be carried out, for example, in the presence of a strong base such as sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide, in an organic solvent such as C,-C 6 alkyl alcohol, benzene, dioxane, dimethylformamide, at a temperature varying between about 0°C and about 100°C. When in the compounds of formula (X) Y represents a nitrogen atom, it needs to be protected before submitting these compounds to the hereabove illustrated reaction. This group may be protected before being reacted and then deprotected according to methods well known in organic chemistry, for example, by reacting with p-toluensulfonylchloride in pyridine at a temperature varying between 0°C and about 120°C and then by treatment with methanesulfonic acid and anisole at a temperature ranging from about 0°C to about 60°C. The compounds of formula (V), (VI), (X) and (XI) are known compounds and may be prepared by conventional methods: in some cases they are commercially available products. When in the compounds of the invention and the intermediate products thereof, groups are present which may interfere with the hereabove illustrated reactions, they may be protected before the reactions take place and then deprotected at the end of the reactions, according to well known methods in organic chemistry. 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 neuropatho logical processes, related to a deranged production of QUIN and/or 3-OH- KYN 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, olivoponto cerebellar atrophy, non-Alzheimer's dementias, including the dementia like syndrome caused by Acquired Immunodeficiency Syndrom (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-hydroxylase 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 mitochondrial extract was used as enzymatic preparation for this assay. The assay for kynurenine 3-hydroxylase activity was carried out at 37°C for a time of 30 min. The reaction mixture of a total volume of 100 ml was constituted of 44 mg of suspended extract, 100 μM Tris/Cl " buffer pH 8.1, 10 μM EDTA, 100 μM KC1, 0.8 μM NADPH, 0.025 μM L-Kynurenine, 0.5 μCi L-(3,5- 3 H)Kynurenine (10 Ci/μmol) and 10 μl of different concentration of inhibitor solutions. After the incubation, the reaction was terminated by the addition of 1 μl of 7.5% (W/v) activated charcoal, vortexed and centrifuged for 7 min.. A 500 μl aliquot of supernatant was counted by scintillation, spectroscopy in 5 μl of liquid scintillation. The obtained results, which have been reported in the following Table 1 , demonstrate the efficacy of the representative compound of the invention 2-cyano-3-hydroxy-3-(l - methyl-l-H-benzo[g]indazol-3-yl)-N-phenyl-acrylamide sodium salt (internal code PNU- 168754 A). Table 1 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 dosage adopted for oral administration e.g. for the representative compound of the invention PNU 168754 may range from about 10 to about 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. intramuscolarly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion. The invention includes also pharmaceutical compositions comprising a compound of formula (I) 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; disaggregating 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 Preparation of hydroxy-(l-oxo-3.4-dihydro-lH-naphthalen-2-ylidene)-acetic acid, ethyl ester To a solution of sodium ethoxide (4.49 g; 0.066 mol) in anhydrous ethanol (50 ml) cooled at about 10°C, α- tetralone (8.77 g; 0.06 mol), dissolved in anhydrous ethanol (10 ml), was added under stirring under inert atmosphere. After a few minutes diethyl oxalate (8.76 g; 0.06 mol) was added and the reaction mixture was kept under stirring for 2h 30 min at about 40°C. After cooling the suspension thus obtained was diluted with ice water and then acified to pH 4 with 0.1 N HC1. The product was extracted with ethyl acetate and the organic solutions collected, washed with water until neutral and then dried over anhydrous sodium sulfate. Evaporation of the solvent to dryness in vacuo gave 14 g (95 %) of crude hydroxy-(l-oxo-3,4-dihydro-lH-naphthalen-2- ylidene)-acetic acid, ethyl ester, a brown oil, which was used without further purification. N.M.R. (CDC1 3 ) δ ppm: 1.4 (t, 3H, -CO 2 CH 2 CH 2 ), 3.0 (s, 4H, -CH 2 CH 2 -), 4.4 (q, 2H, -CO 2 CH 2 CH 3 ), 7.2-8.1 (m, 4H, phenyl protons). Analogously, the following products can be prepared: (7-fluoro-l-oxo-3,4-dihydro-lH-naphthalen-2-ylidene)-hydroxy-acetic acid, ethyl ester; (8-chloro-l-oxo-3,4-dihydro-lH-naphthalen-2-ylidene)-hydroxy-acetic acid, ethyl ester; and (8-methoxy- 1 -oxo-3 ,4-dihydro- 1 H-naphthalen-2-ylidene)-hydroxy-acetic acid, ethyl ester. Example 2 Preparation of l-methyl-4.5-dihydro-lH-benzofglindazole-3-carboxylic acid, ethyl ester Methylhydrazine (3.6 ml; 0.068 mol) was added under stirring to a solution of hydroxy- (l-oxo-3,4-dihydro-lH-naphthalen-2-ylidene)-acetic acid, ethyl ester (15.0 g; 0.061 mol) in acetic acid (100 ml) at room temperature (exotermic reaction). The reaction mixture was stirred without cooling for 7 h and was then diluted with ice water (200 ml). The products (both isomers) were extracted with ethyl acetate (300 ml), the organic solution was dried over anhydrous sodium sulfate and the solvent was evaporated. The desired isomer (R f <) was separated by flash chromatography on silica gel with a gradient of 20-50% AcOEt in hexane as eluent. Evaporation of the purified fractions gave 8.3 g (53%) of l-methyl-4,5-dihydro-lH-benzo[gJindazole-3-carboxylic acid, ethyl ester, m.p. 1 15-1 16°C. N.M.R. (CDC1 3 ) δ ppm: 1.4 (t, 3H, -C0 2 CH 2 CH 3 ), 2.9-3.1 (m, 4H, -CH 2 CH 2 -), 4.2 (s, 3H, -N-CH 3 ), 4.4 (q, 2H, -C0 2 CH 2 CH 3 ), 7.2-7.6 (m, 4H, phenyl protons). Analogously, the following products can be prepared: 8-fluoro-l-methyl-4,5-dihydro-lH-benzofgJindazole-3-carboxylic acid, ethyl ester; 9-chloro-l-methyl-4,5-dihydro-lH-benzo[glindazole-3-carboxylic acid, ethyl ester; 9-methoxy-l-methyl-4,5-dihydro-lH-benzo[glindazole-3-carboxylic acid, ethyl ester; and l-phenyl-4,5-dihydro-lH-benzolglindazole-3-carboxylic acid, ethyl ester: m.p. 156- 159°C. Example 3 Preparation of 1 -methyl- lH-benzo[glindazole-3-carboxylic acid, ethyl ester. l-Methyl-4,5-dihydro-lH-benzo[g]indazole-3-carboxylic acid, ethyl ester (6.0 g; 0.023 mol) and 10.63 g (0.046 mol) of DDQ in 100 ml of dioxane was refluxed for 7h, cooled, filtered, and the solvent evaporated. The residue was dissolved in benzene, washed twice with 10% NaOH, three times with water, dried (sodium sulfate) and the solvent evaporated to give 4.94 g (83%) of 1 -methyl- lH-benzo(glindazole-3-carboxylic acid, ethyl ester, m.p. 122-123°C. N.M.R. (CDCI 3 ) δ ppm: 1.5 (t, 3H, -CO 2 CH 2 CH. 3 ), 4.55 (q, 2H, -CO 2 CH 2 CH 3 ), 4.65 (s, 3H, -N-CH 3 ), 7.6-8.5 (m, 6H, aromatic protons). Analogously, the following products can be prepared: 8-fluoro-l -methyl- lH-benzo[gJindazole-3-carboxylic acid, ethyl ester; 9-chloro-l -methyl- lH-benzo[gJindazole-3-carboxylic acid, ethyl ester; 9-methoxy-l -methyl- 1 H-benzo[gIindazole-3 -carboxy lie acid, ethyl ester; and 1 -phenyl- lH-benzo[g]indazole-3-carboxylic acid, ethyl ester: m.p. 143-145°C. Example 4 Preparation of N-(p-toluensulfonyl)-4-oxo-l.2.3.4-tetrahydro-quinoline. p-Toluensulfonyl chloride (12.83 g, 0.067 mol) was added portionwise to a solution of 4-oxo-l,2,3,4-tetrahydro-quinoline (9.00 g, 0.061 mol) in pyridine (87 ml) maintained under magnetic stirring at room temperature. The reaction mixture was refluxed for about 8 hours, cooled at room temperature, and poured into water (300 ml); the resulting solid was filtered, washed with water and dried in vacuum at 60°C. The title compound was obtained as a beige solid (13.5 g, 75%), m.p. 138-141°C. Example 5 Preparation of hydroxy-[4-oxo-l-(p-toluensulfonyl>2.4-dihydro-lH-quinolin-3- ylidenej-acetic acid, ethyl ester. Diethyl oxalate (12.76 ml, 0.094 mol) was added dropwise to a solution of sodium ethylate (8.16 g, 0.120 mol) in dry benzene (150 ml) maintained under nitrogen atmosphere; the mixture was heated to reflux for about 10 minutes. After cooling at 0- 3°C with an ice-water bath, a solution of N-p-toluensulfonyl-4-oxo- 1,2,3, 4-tetrahydro- quinoline (13.5 g, 0.045 mmol) in THF (300 ml) was added dropwise. The reaction mixture was allowed to warm at room temperature and stirred for about 4 hours. It was then diluted with water (300 ml), acidified to pH 5-6 with N HCl and extracted with ethyl acetate (4X200 ml); the organic layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate and concentrated under vacuum to yield the title compound as an orange solid (17 g, 94%), m.p. 1 15-120°C. N.M.R. (CDC1 3 ) δ ppm: 7.8 (m, 2H); 7.65 (m, 1H); 7.4 (m, 1H); 7.23 (d, 2H); 7.08 (d, 2H); 5 (s, 2H, N£H 2 ); 4.45 (q, 2H, OCH 2 CH 3 ); 2.31 (s, 3H, CH 3 ); 1.46 (t, 3H, OCH 2 CH 3 ). Example 6 Preparation of 5-(p-toluensulfonyl)- 1 -methyl-4.5-dihydro- 1 H-pyrazolo[4.3-c]quinoline- 3-carboxylic acid, ethyl ester. Methylhydrazine (4.51 ml, 0.0848 mol) was added dropwise to a solution of hydroxy- [4-oxo-l-(p-toluensulfonyl)-2,4-dihydro-lH-quinolin-3-ylidene]-acetic acid, ethyl ester (17 g, 0.0424 mol) in glacial acetic acid (180 ml) at room temperature; the reaction mixture was heated at 50°C for about 10 hours, cooled at room temperature, diluted with water (200 ml) and extracted with ethyl acetate (3X200 ml). The organic layers were combined, washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was flash chromatographed on silica gel using cyclohexane/ethyl acetate 20÷40 as eluent to separate the two regioisomers (about 1 : 1 ratio): the title compound was obtained as a light yellow solid (7.5 g, 43%), m.p. 165- 168°C. N.M.R. (CDCI 3 ) δ ppm: 7.87 (m, 1H); 7.45 (m, 3H); 7.12 (d, 2H); 6.89 (d, 2H); 5.05 (s, 2H, NCH 2 ); 4.47 (q, 2H, OCH 2 CH 3 ); 3.8 (s, 3H, NCH 2 ); 2.25 (s, 3H, CH 3 ); 1.47 (t, 3H, OCH 2 CH 3 ). Example 7 Preparation of l-methyl-4.5-dihydro-lH-pyrazolo[4.3-c]quinoline-3-carboxylic acid. ethyl ester. A solution of 5-(p-toluensulfonyl)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline- 3-carboxylic acid, ethyl ester (7 g, 0.0170 mol), methanesulphonic acid (27.7 ml) and anisole (5.55 ml, 0.0511 mol) was maintained under magnetic stirring at 50°C for about 5 hours; it was then diluted with ice-water (100 ml) and basified with N NaOH: the aqueous mixture was extracted with ethyl acetate (3X150 ml). The organic layers were combined, washed with water until neutral, with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was slurried with methanol, filtered and dried in vacuum at 45 °C to give a light yellow solid (4.7 g) which was used in the next step without any further purification, m.p. 206-210°C. N.M.R. (CDC1 3 ) δ ppm: 7.5 (m, 1H); 7 (m, 1H); 6.6 (m, 2H); 6.1 (broad s, 1H, NH); 4.55 (d, 2H, NCH 2 ); 4.27 (q, 2H, OCH 2 CH 3 ); 4.1 (s, 3H, NCH 3 ); 1.3 (t, 3H, OCH 2 CH 2 ). Example 8 Preparation of 1 -methyl- lH-pyrazolo[4.3-c]quinoline-3-carboxylic acid, ethyl ester. l-Methyl-4,5-dihydro-lH-pyrazolo[4,3-c]quinoline-3-carboxylic acid, ethyl ester (4.7g. 0.0170 mol) was dissolved in DMF (130 ml) and heated to 100°C for about 32 hours. The reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate (3X200 ml); the aqueous layer was added with NaCl and extracted with ethyl acetate (2X100 ml). The organic layers were combined, washed with water (300 ml), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was slurried with diethyl ether and filtered to yield the title compound as a colorless solid (2.5 g, 58%), m.p. 123-125°C. N.M.R. (CDCI 3 ) δ ppm: 9.67 (s, 1H, NCH); 8.38 (m, 2H); 7.8 (m, 2H); 4.61 (s, 3H, NCH 3 ); 4.58 (q, 2H, O£H 2 CH 3 ); 1.52 (t, 3H, OCH J CHJ). Example 9 Preparation of 3-(l-methyl-lH-benzolglindazol-3-yl)-3-oxo-propionitrile. To a suspension of 55% sodium hydride (1.03 g; 0.024 mol) in anhydrous dioxane (20 ml), 1 -methyl- lH-benzolg]indazole-3-carboxylic acid, ethyl ester (3.0 g; 0.012 mol) and then anhydrous acetonitrile (20 ml) were added under stirring at room temperature, in inert atmophere. The reaction mixture was heated to about 55°C, under stirring, and then kept at that temperature for 30 min. After cooling, the suspension was diluted with ice water obtaining a solution that was acidified to pH 4 with 2N HCl. The precipitate was filtered, washed with water until neutral and then dried in vacuo at 50°C. Crystallization from dichloromethane/isopropyl ether gave 2.18 g (74%) of 3-(l -methyl- lH-benzo[gjindazol-3-yl)-3-oxo-propionitrile, m.p. >220°C. N.M.R. (DMSO) δ ppm: 4.6 (s, 3H, -N-CH 3 ), 4.7 (s, 2H,-COCH 2 CN), 7.6-8.6 (m, 6H, aromatic protons). Analogously, the following products can be prepared: 3-(l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)-3-oxo-propionitrile; 3-(l-phenyl-lH-pyrazolo[4,3-c]quinolin-3-yl)-3-oxo-propionitrile; 3-(8-fluoro-l-methyl-lH-benzo[glindazol-3-yl)-3-oxo-propionitrile; 3-(9-chloro-l-methyl-lH-benzo[g]indazol-3-yl)-3-oxo-propionitrile; 3-(9-methoxy-l-methyl-lH-benzo[glindazol-3-yl)-3-oxo-propionitrile; and 3-(l-phenyl-lH-benzolg]indazol-3-yl)-3-oxo-propionitrile: m.p. 151-156°C. Example 10 Preparation of 2-cyano-3-hydroxy-3-(l -methyl- lH-benzofglindazol-3-ylVN-phenyl- acrylamide. To a suspension of 3-(l -methyl- lH-benzolglindazol-3-yl)-3-oxo-propionitrile (2.80 g; 0.01 1 mol) in dimethylformamide (60 ml), triethylamine (1.7 ml; 0.012 mol) was added under stirring, at room temperature obtaining a solution. Phenylisocyanate (1.3 ml; 0.012 mol) diluted with dimethylformamide (2 ml) was added and the rection mixture was allowed to react at room temperature for 30 min. The solution was acidified to pH 2 with 2N HCl and diluted with ice water. The precipitate was filtered, washed with water until neutral and then dried in vacuo at 50°C. Trituration in MeOH (40 ml) gave 3.10 g (75%) of 2-cyano-3-hydroxy-3-(l -methyl- lH-benzo[gjindazol-3-yl)-N-phenyl- acrylamide, m.p. 263°C (dec). N.M.R. (DMSO) δ ppm: 4.6 (s, 3H, -N-CH 3 ), 7-8.6 (m, 1 1H, aromatic protons). 1 1.1 (s, 1H, -CO-NH-Ph). Analogously, the following products can be prepared: 2-cyano-3-(8-fluoro-l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(9-chloro-l -methyl- lH-benzolgIindazol-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(9-methoxy-l -methyl- lH-benzo!gjindazol-3-yl)-3-oxo-N-phenyl- propionamide; 2-cyano-N-(4-methoxy-phenyl)-3-(l-methyl-lH-benzo!gJindazol-3-yl)-3-oxo- propionamide; 2-cyano-N-(4-fluoro-phenyl)-3 -( 1 -methyl- 1 H-benzo(gJ indazol-3 -yl)-3 -oxo- propionamide; 2-cyano-N-(3-nitro-phenyl)-3-(l-methyl-lH-benzo|gJindazol-3-yl)-3-oxo-propionamide; 2-cyano-N-(3-trifluoromethyl-phenyl)-3-(l -methyl- lH-benzo[g]indazol-3-yl)-3-oxo- propionamide; 2-cyano-N-(3-methyl-phenyl)-3-(l -methyl- lH-benzo[gIindazol-3-yl)-3-oxo- propionamide; 2-cyano-N-(3-chloro-phenyl)-3-(l -methyl- lH-benzo!glindazol-3-yl)-3-oxo- propionamide; 2-cyano-3-(l-methyl-lH-pyrazolof4,3-clquinolin-3-yl)-3-oxo-N-phenyl-propionamide: m.p. 250°C (dec); 2-cyano-3 -( 1 -phenyl- 1 H-pyrazolo[4,3 -clquinolin-3 -yl)-3 -oxo-N-pheny 1-propionamide : m.p. 260-263°C; N-butyl-2-cyano-3-(l -methyl- lH-benzo[g]indazol-3-yl)-3-oxo-propionamide; N-berιzyl-2-cyano-3-(l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo-propionamide; and 2-cyano-3-hydroxy-3-(l-phenyl-lH-benzo[glindazol-3-yl)-N-phenyl-acrylamide; m.p. 252°C (dec). Example 11 Preparation of 4.5-dihydro-isoxazolo[2.1-a]naphthalene-3-carboxylic acid, ethyl ester. Hydroxylamine hydrochloride (2.48 g; 0.036 mol) was added under stirring to a solution of hydroxy-(l-oxo-3,4-dihydro-lH-naphthalen-2-ylidene)-acetic acid, ethyl ester (8.0 g; 0.032 mol) in acetic acid (50 ml) at room temperature. The reaction mixture was stirred at about 60°C for 8 h and, after cooling, was then diluted with ice water (250 ml). The precipitate was filtered, washed with water and then dried in vacuo at 30°C to give 5.2 g (66%>) of 4,5-dihydro-isoxazolo[2,l-a]naphthalene-3-carboxylic acid, ethyl ester, m.p. 84-87°C. N.M.R. (CDCI 3 ) δ ppm: 1.4 (t, 3H, -CO 2 CH 2 CH 3 ), 2.9-3.2 (m, 4H, -CH 2 CH 2 -), 4.5 (q, 2H, -CO 2 CH 2 CH 3 ), 7.2-7.8 (m, 4H, phenyl protons). Analogously, the following products can be prepared: 8-fluoro-4,5-dihydro-isoxazolo[2,l-a]naphthalene-3-carboxylic acid, ethyl ester; 9-chloro-4,5-dihydro-isoxazolo[2,l-a]naphthalene-3-carboxylic acid, ethyl ester; and 9-methoxy-4,5-dihydro-isoxazolo[2,l-a]naphthalene-3-carboxylic acid, ethyl ester. Example 12 Preparation of isoxazolo[2.1-a]naphthalene-3-carboxylic acid, ethyl ester. 4,5-Dihydro-isoxazolo[2,l-a]naphthalene-3-carboxylic acid, ethyl ester (3.0 g; 0.012 mol) and 5.6 g (0.024 mol) of DDQ in 50 ml of dioxane was refluxed for 12 h, cooled, filtered, and the solvent evaporated. The residue was dissolved in benzene, washed twice with 10% NaOH, three times with water, dried (sodium sulfate) and the solvent evaporated. The residue was triturated in MeOH to give 1.44 g (48%) of isoxazolo[2,l- a]naphthalene-3 -carboxy lie acid, ethyl ester, m.p. 95-97°C. N.M.R. (CDCI 3 ) δ ppm: 1.5 (t, 3H, -CO 2 CH 2 CH 3 ), 4.6 (q, 2H, -C0 2 CH 2 CH 3 ), 7.7-8.5 (m. 6H. aromatic protons). Analogously, the following products can be prepared: 8-fluoro-isoxazolo[2,l-a]naphthalene-3-carboxylic acid, ethyl ester; 9-chloro-isoxazolo[2, 1 -a]naphthalene-3-carboxylic acid, ethyl ester; and 9-methoxy-isoxazolo[2,l-a]naphthalene-3-carboxylic acid, ethyl ester. Example 13 Preparation of 3-(isoxazolof2.1-alnaphthalen-3-yl)-3-oxo-propionitrile. To a suspension of 55% sodium hydride (0.51 g; 0.012 mol) in anhydrous dioxane (10 ml), isoxazolo[2,l-a]naphthalene-3-carboxylic acid, ethyl ester (1.40 g; 0.006 mol) and then anhydrous acetonitrile (10 ml) were added under stirring at room temperature, in inert atmophere. The reaction mixture was heated to about 55°C, under stirring, and then kept at that temperature for 30 min. After cooling, the suspension was diluted with ice water obtaining a solution that was acidified to pH 4 with 2N HCl. The precipitate was filtered, washed with water until neutral and then dried in vacuo at 30°C. The product was purified by flash chromatography on silica gel with dichloromethane as eluent to give 0.78 g (57%) of 3-(isoxazoloI2,l-alnaphthalen-3-yl)-3-oxo-propionitrile, m.p. 183-184°C. N.M.R. (DMSO) δ ppm: 4.4 (s, 2H,-COCH 2 CN), 7.7-8.5 (m, 6H, aromatic protons). Analogously, the following products can be prepared: 3-(8-fluoro-isoxazolo[2,l-a)naphthalen-3-yl)-3-oxo-propionitrile; 3-(9-chloro-isoxazolof2, 1 -aJnaphthalen-3-yl)-3-oxo-propionitrile; .and 3-(9-methoxy-isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile. Example 14 Preparation of 2-cyano-3-hydroxy-3-(isoxazolof2.1 -alnaphthalen-3-ylVN-phenyl- acrylamide. To a solution of 3-(isoxazolo[2,l-a|naphthalen-3-yl)-3-oxo-propionitrile (0.75 g; 0.003 mol) in dimethylformamide (8 ml), triethylamine (0.49 ml; 0.003 mol) was added under stirring, at room temperature. Phenylisocyanate (0.36 ml; 0.003 mol) diluted with dimethylfomamide (0.5 ml) was added and the rection mixture was allowed to react at room temperature for lh 30 min. The solution was acidified to pH 2 with 2N HCl and diluted with ice water. The precipitate was filtered, washed with water until neutral and then dried in vacuo at 30°C. Trituration in MeOH (20 ml) gave 0.93 g (82%) of 2- cy.ano-3-hydroxy-3-(isox.azolo[2, 1 -a|naphthalen-3-yl)-N-phenyl-acrylamide, m.p. 231 - 233°C (dec). N.M.R. (DMSO) δ ppm: 6.9-8.5 (m, 1 IH, aromatic protons), 1 1.9 (s, IH, -CO-NH-Ph). Analogously, the following products can be prepared: 2-cyano-3-(8-fluoro-isoxazolo[2,l-a)naphthalen-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(9-chloro-isoxazolof2,l-a]naphthalen-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(9-methoxy-isoxazolo[2,l-alnaphthalen-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-N-(4-methoxy-phenyl)-3-(isoxazolo[2,l -alnaphthalen-3-yl)-3 -oxo- propionamide; 2-cyano-N-(4-fluoro-phenyl)-3-(isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionamide; 2-cyano-N-(3-nitro-phenyl)-3-(isoxazolof2,l-alnaphthalen-3-yl)-3-oxo-propionamide: 2-cyano-N-(3-trifluoromethyl-phenyl)-3-(isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo- propionamide; 2-cyano-N-(3-methyl-phenyl)-3-(isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo-propionamide; 2-cyano-N-(3-chloro-phenyl)-3-(isoxazolo[2,l-alnaphthalen-3-yl)-3-oxo-propionamide; N-benzyl-2-cyano-3-(isoxazolo[2,l-alnaphthalen-3-yl)-3-oxo-propionamide; and N-butyl-2-cyano-3-(isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionamide. Example 15 Preparation of 2-benzoyl-3-(l-methyl-lH-benzofglindazol-3-yl)-3-oxo-propionitrile. To a solution of 3-(l-methyl-lH-benzo[glindazol-3-yl)-3-oxo-propionitrile (0.50 g; 0.002 mol) in dichloromethane (20 ml), triethylamine (0.31 ml; 0.002 mol) was added under stirring, at room temperature. Benzoyl chloride (0.23 ml; 0.002 mol) was added and the reaction mixture was allowed to react at room temperature for lh. The solution was washed with water, dried over anhydrous sodium sulfate and then evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/ AcOEt 98:2 as eluent. The purified fractions were collected and evaporated to dryness. The residue was triturated in MeOH (6 ml)to give 0.35 g (50%) of 2-benzoyl-3-(l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo-propionitrile. Analogously, the following products can be prepared: 2-(4-methoxy-benzoyl)-3 -( 1 -methyl- 1 H-benzo[gJindazol-3 -y l)-3 -oxo-propionitrile; 2-(4-fluoro-benzoyl)-3 -( 1 -methyl- 1 H-benzo[gJindazol-3-yl)-3 -oxo-propionitrile ; 2-(3-nitro-benzoyl)-3-(l-methyl-lH-benzo[giindazol-3-yl)-3-oxo-propionitrile; 2-(3-trifluoromethyl-benzoyl)-3-(l-methyl-lH-benzo[glindazol-3-yl)-3-oxo- propionitrile; 2-(3-methyl-benzoyl)-3-(l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo-propionitrile; 2-(3 -chloro-benzoyl)-3 -( 1 -methyl- 1 H-benzo[gϋndazol-3 -yl)-3 -oxo-propionitrile; 2-benzoyl-3-(8-fluoro-l-methyl-lH-benzofg]indazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(9-chloro- 1 -methyl- 1 H-benzo[gJind.azol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(9-methoxy- 1 -methyl- 1 H-benzofgJind.azol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(isoxazolof2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzoyl)-3 -(isoxazolo[2, 1 -aJnaphthalen-3-yl)-3 -oxo-propionitrile ; 2-(4-fluoro-benzoyl)-3-(isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo-propionitrile; 2-(3-nitro-benzoyl)-3-(isoxazolo[2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-trifluoromethyl-benzoyl)-3-(isoxazoloI2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-methyl-benzoyl)-3-(isox^olo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-chloro-benzoyl)-3-(isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(8-fluoro-isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(9-chloro-isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; and 2-benzoyl-3-(9-methoxy-isoxazolof2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile. Example 16 Preparation of 1 -methyl- lH-benzofglindazole-3-carboxylic acid. 1 -Methyl- lH-benzo[gIindazole-3-carboxylic acid, ethyl ester (1.50 g; 0.006 mol) was heated at the reflux temperature for 4h 30 min with a 0.1 N KOH solution in 95% methanol (70 ml; 0.007 mol). After cooling the precipitate was collected by filtration, washed with 95% ethanol and dissolved in water. The solution was acidified to pH 3 with 2N HCl and the precipitate was filtered, washed with water until neutral and then dried in vacuo at 50°C to give 1.19 g (89%) of 1 -methyl- lH-benzofglindazole-3- carboxylic acid. Analogously the following products can be prepared: 8-fluoro- 1 -methyl- 1 H-benzo[gJindazole-3 -carboxy lie acid; 9-chloro- 1 -methyl- 1 H-benzo[gjindazole-3-carboxylic acid; 9-methoxy- 1 -methyl- 1 H-benzo[glindazole-3-carboxylic acid; 8-fluoro-isoxazolo[2, 1 -a]naphthalene-3-carboxylic acid; 9-chloro-isoxazolo[2, 1 -a]naphthalene-3-carboxylic acid; 9-methoxy-isoxazolo[2,l-a]naphthalene-3-carboxylic acid; and isoxazolo[2,l-a]naphthalene-3-carboxylic acid. Example 17 Preparation of 2-benzenesulfonyl-3-(l-methyl-lH-benzolglindazol-3-yD-3-oxo- propionitrile. 1 -Methyl- lH-benzoIgJindazole-3-carboxylic acid (0.40 g; 0.002 mol) was reacted with thionyl chloride (0.42 g; 0.004 mol) in anhydrous dioxane (6 ml) at the reflux temperature for 1.5 hours. After cooling the solution was evaporated to dryness in vacuo .and the crude 1 -methyl- lH-benzo[gJindazole-3-carbonyl chloride was dissolved in anhydrous dioxane (15 ml). This solution was added under stirring at room temperature under inert atmosphere to the suspension of the carbanion obtained by treatment of (phenylsulfonyl)acetonitrile (0.35 g; 0.002 mol) with 55% sodium hydride (0.12 g; 0.003 mol) in anhydrous dioxane (25 ml); the reaction mixture was allowed to react at room temperature for 1.5 hours and was then acidified to pH 2 with 2N HCl and diluted with ice water. The product was extracted with ethyl acetate and the organic solutions collected, washed with water, dried over anhydrous sodium sulfate and then evaporated. The residue was dissolved in ethyl acetate (50 ml) and extracted twice with 0.1 N NaOH (20 ml). The alkaline solutions were collected, acidified to pH 3 with 2N HCl and then extracted three times with ethyl acetate. The organic solutions were collected, washed with water and then dried over anhydrous sodium sulfate. Evaporation of the solvent to dryness gave 0.31 g (45%) of 2-benzenesulfonyl-3-(l -methyl- lH-benzoJg]indazol-3-yl)- 3-oxo-propionitrile. Analogously the following products can be prepared: 2-(4-methoxy-benzenesulfonyl)-3-(l -methyl- lH-benzo[g)indazol-3-yl)-3-oxo- propionitrile; 2-(4-fluoro-benzenesulfonyl)-3-(l -methyl- lH-benzolglindazol-3-yl)-3-oxo- propionitrile; 2-(3-nitro-benzenesulfonyl)-3-(l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo-propionitrile; 2-(3-trifluoromethyl-benzenesulfonyl)-3-(l-methyl-lH-benzo(gJind^ol-3-yl)-3-oxo- propionitrile; 2-(3-methyl-benzenesulfonyl)-3-(l -methyl- lH-benzo[g!indazol-3-yl)-3-oxo- propionitrile; 2-(3-chloro-benzenesulfonyl)-3-(l -methyl- lH-benzofglindazol-3-yl)-3-oxo- propionitrile; 2-benzenesulfonyl-3-(8-fluoro- 1 -methyl- 1 H-benzof g]indazol-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(9-chloro-l -methyl- lH-benzolglindazol-3-yl)-3-oxo-propionitrile 2-benzenesulfonyl-3-(9-methoxy-l -methyl- lH-benzo!gJindazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(isoxazolof2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-(4-fluoro-benzenesulfonyl)-3-(isox.azolo[2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-nitro-benzenesulfonyl)-3-(isoxazolof2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-trifluoromethyl-benzenesulfonyl)-3-(isoxazolof2,l-alnaphthalen-3-yl)-3-oxo- propionitrile; 2-(3-methyl-benzenesulfonyl)-3-(isoxazolo[2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-chloro-benzenesulfonyl)-3-(isoxazolo[2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(8-fluoro-methoxy-isoxazolof2,l-a)naphthalen-3-yl)-3-oxo- propionitrile; 2-benzenesulfonyl-3-(9-chloro-isoxazolo[2,l-aInaphthalen-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(9-methoxy-isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo-propionitrile; and 2-benzenesulfonyl-3-(isoxazolof2,l-ajnaphthalen-3-yl)-3-oxo-propionitrile. Example 18 Preparation of 2-cyano-3-hydroxy-3-(l -methyl- lH-benzofglindazol-3-yl -N-phenyl- acrylamide. sodium salt. 2-Cyano-3-hydroxy-3-(l -methyl- lH-benzofgjindazol-3-yl)-N-phenyl-acrylamide (2.75 g; 0.0075 mol) was suspended in ethanol (180 mL) and 0.1 N NaOH (75 mL; 0.0075 mol) was added. The solution so obtained was evaporated to dryness to afford the desired compound, m.p. 31 1°C (dec). C 22 H 15 N 4 NaO 2 ; required: C= 67.69; H= 3.87; N= 14.35; found: C=67.45; H=3.90; NX4.28. Analogously the following derivatived can be prepared: 2-cyano-3-hydroxy-3-(8-fluoro-l-methyl-lH-benzolgJindazol-3-yl)-N-phenyl- acrylamide, sodium salt; 2-cyano-3-hydroxy-3-(9-chloro-l-methyl-lH-benzo(g]indazol-3-yl)-N-phenyl- acrylamide, sodium salt; 2-cyano-3-hydroxy-3-(9-methoxy- 1 -methyl- 1 H-benzo[gJindazol-3-yl)-N-phenyl- acrylamide, sodium salt; N-(4-methoxy-phenyl)-2-cyano-3-hydroxy-3-(l-methyl-lH-benzo[g|indazol-3-yl)- acrylamide, sodium salt; N-(4-fluoro-phenyl)-2-cyano-3-hydroxy-3-(l -methyl- lH-benzolglindazol-3-yl)- acrylamide, sodium salt; N-(3-nitro-phenyl)-2-cyano-3-hydroxy-3-(l -methyl- lH-benzofgJindazol-3-yl)- acrylamide, sodium salt; N-(3-trifluoromethyl-phenyl)-2-cyano-3-hydroxy-3-(l-methyl-lH-benzo{gJindazol-3- yl)-acrylamide, sodium salt; N-(3-methyl-phenyl)-2-cyano-3-hydroxy-3-(l -methyl- lH-benzo[gJindazol-3-yl)- acrylamide, sodium salt; N-(3 -chloro-phenyl)-2-cyano-3 -hydroxy-3 -( 1 -methyl- 1 H-benzo(gJ indazol-3-y 1)- acrylamide, sodium salt; N-butyl-2-cyano-3-hydroxy-3-(l-methyl-lH-benzo(glindazol-3-yl)-acrylamide, sodium salt; N-benzyl-2-cyano-3-hydroxy-3-(l -methyl- lH-benzo[glindazol-3-yl)-acrylamide. sodium salt; 2-cyano-3-hydroxy-3-(l-phenyl-lH-benzofgJindazol-3-yl)-N-phenyl-acrylamide. sodium salt: m.p. 220°C (dec); 2-cyano-3-hydroxy-3-(l -methyl- lH-pyrazolo[4,3-cIquinolin-3-yl)-N-phenyl-acrylamide, sodium salt: m.p. 210°C (dec); 2-cyano-3-hydroxy-3-(l -phenyl- lH-pyrazolo[4,3-cJquinolin-3-yl)-N-phenyl-acr 'lamide. sodium salt; 2-cyano-3-hydroxy-3-(isoxazolo(2,l-a]naphthalen-3-yl)-N-phenyl-acrylamide, sodium salt: m.p. 195°C (dec); 2-cyano-3-hydroxy-3-(8-fluoro-isoxazoloI2,l-aJnaphthalen-3-yl)-N-phenyl-acrylamide. sodium salt; 2-cyano-3-hydroxy-3-(9-chloro-isoxazolo[2,l-alnaphthalen-3-yl)-N-phenyl-acrylamide, sodium salt; 2-cyano-3-hydroxy-3-(9-methoxy-isoxazolo[2,l-ajnaphthalen-3-yl)-N-phenyl- acrylamide, sodium salt; N-(4-methoxy-phenyl)-2-cyano-3-hydroxy-3-(isoxazolo[2,l-alnaphthalen-3-yl)- acrylamide, sodium salt; N-(4-fluoro-phenyl)-2-cyano-3-hydroxy-3-(isoxazolo[2,l -aJnaphthalen-3-yl)- acrylamide, sodium salt; N-(3-nitro-phenyl)-2-cyano-3-hydroxy-3-(isoxazolo[2,l-a)naphthalen-3-yl)-acrylamide, sodium salt; N-(3-trifluoromethyl-phenyl)-2-cyano-3-hydroxy-3-(isoxazolo[2,l-alnaphthalen-3-yl)- acrylamide, sodium salt; N-(3-methyl-phenyl)-2-cyano-3-hydroxy-3-(isoxazolo(2,l-alnaphthalen-3-yl)- acrylamide, sodium salt; N-(3 -chloro-phenyl)-2-cyano-3 -hydroxy-3 -(isoxazoloβ, 1 -ajnaphthalen-3 -yl)- acrylamide, sodium salt; N-benzyl-2-cyano-3-hydroxy-3-(isoxazolo[2,l-alnaphthalen-3-yl)-acrylamide, sodium salt; N-butyl-2-cyano-3-hydroxy-3-(isoxazolo[2, 1 -a]naphthalen-3-yl)-acrylamide, sodium salt; 2-benzenesulfonyl-3-hydroxy-3-(l-methyl-lH-benzo[gJindazol-3-yl)-acrylonitrile, sodium salt; 2-(4-methoxy-benzenesulfonyl)-3-hydroxy-3-(l-methyl-lH-benzolg]indazol-3-yl)- acrylonitrile, sodium salt; 2-(4-fluoro-benzenesulfonyl)-3-hydroxy-3-(l-methyl-lH-benzolg]indazol-3-yl)- acrylonitrile, sodium salt; 2-(3-nitro-benzenesulfonyl)-3-hydroxy-3-(l -methyl-lH-benzolgiindazol-3-yl)- acrylonitrile, sodium salt; 2-(3-trifluoromethyl-benzenesulfonyl)-3-hydroxy-3-( 1 -methyl- 1 H-benzo[gJindazol-3- yl)-acrylonitrile, sodium salt; 2-(3-methyl-benzenesulfonyl)-3-hydroxy-3-(l -methyl- lH-benzolgl indazol-3-yl)- acrylonitrile, sodium salt; 2-(3-chloro-benzenesulfonyl)-3-hydroxy-3-(l-methyl-lH-benzo[g]indazol-3-yl)- acrylonitrile, sodium salt; 2-benzenesulfonyl-3-hydroxy-3-(8-fluoro-l-methyl-lH-benzofgJindazol-3-yl)- acrylonitrile, sodium salt; 2-benzenesulfonyl-3-hydroxy-3-(9-chloro-l -methyl- lH-benzo[gJindazol-3-yl)- acrylonitrile, sodium salt; 2-benzenesulfonyl-3-hydroxy-3-(9-methoxy- 1 -methyl- 1 H-benzofgJindazol-3-yl)- acrylonitrile, sodium salt; 2-(4-methoxy-benzenesulfonyl)-3 -hydroxy-3 -(isoxazolo[2 , 1 -alnaphthalen-3 -y 1 )- acrylonitrile, sodium salt; 2-(4-fluoro-benzenesulfonyl)-3-hydroxy-3-(isoxazolo[2,l-alnaphthalen-3-yl)- acrylonitrile, sodium salt; 2-(3-nitro-benzenesulfonyl)-3-hydroxy-3-(isoxazolo[2,l-a)naphthalen-3-yl)- acrylonitrile, sodium salt; 2-(3-trifluoromethyl-benzenesulfonyl)-3-hydroxy-3-(isoxazolol2,l-alnaphthalen-3-yl)- acrylonitrile, sodium salt; 2-(3-methyl-benzenesulfonyl)-3-hydroxy-3-(isoxazolo[2,l-aJnaphthalen-3-yl)- acrylonitrile, sodium salt; 2-(3-chloro-benzenesulfonyl)-3-hydroxy-3-(isoxazolo[2,l-a)naphthalen-3-yl)- acrylonitrile, sodium salt; 2-benzenesulfonyl-3-hydroxy-3-(8-fluoro-isoxazolo[2,l-a]naphthalen-3-yl)-acrylonitrile, sodium salt; 2-benzenesulfonyl-3-hydroxy-3-(9-chloro-isoxazolo[2, 1 -alnaphthalen-3-yl)- acrylonitrile, sodium salt; 2-benzenesulfonyl-3-hydroxy-3-(9-methoxy-isoxazolo(2,l-a]naphthalen-3-yl)- acrylonitrile, sodium salt; and 2-benzenesulfonyl-3-hydroxy-3-(isoxazolo[2, 1 -a!naphthalen-3-yl)-acrylonitrile. sodium salt. Example 19 Capsule, each weighting 0.23 g and containing 50 mg of the active substance can be prepared as follows: Composition for 500 capsules: 2-cyano-3-hydroxy-3-(l -methyl- l-H-benzo[g]indazol-3-yl)-N-phenyl-acrylamide sodium salt 25 g Lactose 80 g Corn starch 5 g Magnesium stearate 5 g This formulation can be incapsulated in two hard gelatin capsules of two pieces, each with each capsule weighing 0.23 g. Example 20 Intramuscular injection of 50 mg/ml A pharmaceutical injectable composition can be manifactured dissolving 50 g 2-cyano- 3-hydroxy-3-(l -methyl- l-H-benzo[g]indazol-3-yl)-N-phenyl-acrylamide sodium salt in sterile propyleneglycol (1000 ml) and sealed in 1-5 ml ampoules. Legend to Figure 1 IDO = Indolamineoxigenase KYN = Kynurenine KYN-OH = Kynurenine-3 -hydroxy lase 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 A compound which is a tricyclic-3-oxo-propanenitrile of formula (I) wherein Y represents a nitrogen atom or a CH or N-oxide group; X represents an oxygen atom or NR 2 wherein R 2 represents C,-C 6 alkyl, benzyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifiuoromethyl, C r C 6 alkyl, C,-C 6 alkoxy. nitro, amino. formylamino and C 2 -C 8 alkanoylamino; each of R and R, is independently hydrogen, halogen, CF 3 , C.-C 6 alkyl, hydroxy. C,-C 6 alkoxy, C 3 -C 4 alkenyloxy, nitro, amino, formylamino, C 2 -C 8 alkanoylamino or C 2 -C 8 alkanoyloxy; m is zero or an integer of 1 to 6; Q is C,-C 1 alkyl, phenyl or unsaturated pentatomic heteromonocyclic ring containing two or three heteroatoms chosen from oxygen, sulphur and nitrogen, wherein the phenyl ring and the heteromonocyclic ring are unsubstituted or substituted by one or two substituents chosen independently from halogen, CF 3 , C r C 6 alkyl, hydroxy. C,-C 6 alkoxy, nitro, amino, formylamino, C 2 -C 8 alkanoylamino or C 2 -C 8 alkanoyloxy: and W represents a -CONH-, -SO 2 - or -CO- group; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein Y represents a nitrogen atom or a CH group; X is oxygen or NR 2 wherein R 2 represents C C 4 alkyl or phenyl unsubstituted or substituted by one or two substituents selected independently from halogen, trifiuoromethyl, C C 4 alkyl, C C 4 alkoxy and nitro; each of R and R { independently is hydrogen, nitro, halogen, trifiuoromethyl, C C 4 alkyl or C r C 4 alkoxy; m is zero or 1 ; Q is C r C 4 alkyl or a phenyl ring unsubstituted or substituted by one or two substituents selected from halogen, trifiuoromethyl, nitro, C,-C 4 alkyl and C r C 4 alkoxy; and W is a -CONH-, -SO 2 - or -CO- group. A compound selected from 2-ciano-3 -hydroxy-3-( 1 -methyl- 1 H-benzofgJindazol-3-yl)-N-phenyl-acrylamide; 2-cyano-3-(8-fluoro- 1 -methyl- 1 H-benzo[g]indazol-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(9-chloro-l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(9-methoxy-l-methyl-lH-benzofgJindazol-3-yl)-3-oxo-N-phenyl- propion-amide; 2-cyano-N-(4-methoxy-phenyl)-3-(l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo- propionamide; 2-cyano-N-(4-fluoro-phenyl)-3-(l -methyl- lH-benzo[gjindazol-3-yl)-3-oxo- propionamide; 2-cyano-N-(3 -nitro-pheny l)-3 -( 1 -methyl- 1 H-benzolg] indazol-3 -yl)-3 -oxo-propionamide; 2-cyano-N-(3-trifluoromethyl-phenyl)-3-(l -methyl- lH-benzo[giindazol-3-yl)-3 -oxo- propionamide; 2-cyano-N-(3-methyl-phenyl)-3-( 1 -methyl- 1 H-benzolglindazol-3-yl)-3-oxo- propionamide; 2-cyano-N-(3-chloro-phenyl)-3-(l -methyl- lH-benzofglindazol-3-yl)-3-oxo- propionamide; N-butyl-2-cyano-3-(l -methyl- lH-benzolglindazol-3-yl)-3-oxo-propionamide; N-benzyl-2-cyano-3-(l-methyl-lH-benzo[gIindazol-3-yl)-3-oxo-propionamide; 2-cyano-3-hydroxy-3-(l-phenyl-lH-benzo[glindazol-3-yl)-N-phenyl-acrylamide; 2-cyano-3-(l-methyl-lH-pyrazolof4,3-c)quinolin-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(l -phenyl- lH-pyrazolo[4,3-cjquinolin-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-hydroxy-3-(isoxazolo[2,l-a)naphthalen-3-yl)-N-phenyl-acrylamide; 2-cyano-3-(8-fluoro-isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(9-chloro-isoxazolof2,l-a]naphthalen-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-3-(9-methoxy-isoxazolof2,l-aInaphthalen-3-yl)-3-oxo-N-phenyl-propionamide; 2-cyano-N-(4-methoxy-phenyl)-3-(isoxazolo[2, 1 -alnaphthalen-3-yl)-3 -oxo- propionamide; 2-cyano-N-(4-fluoro-phenyl)-3-(isoxazoloI2,l-aJnaphthalen-3-yl)-3-oxo-propionamide; 2-cyano-N-(3-nitro-phenyl)-3-(isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionamide; 2-cyano-N-(3-trifluoromethyl-phenyl)-3-(isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo- propionamide; 2-cyano-N-(3-methyl-phenyl)-3-(isoxazolo[2,l-ainaphthalen-3-yl)-3-oxo-propionamide; 2-cyano-N-(3-chloro-phenyl)-3-(isoxazolof2,l-a]naphthalen-3-yl)-3-oxo-propionamide; N-benzyl-2-cyano-3 -(isoxazolof2, 1 -aJnaphthalen-3 -yl)-3 -oxo-propionamide ; N-butyl-2-cyano-3-(isoxazolof2,l-aJnaphthalen-3-yl)-3-oxo-propionamide; 2-benzoyl-3-(l-methyl-lH-benzo[glindazol-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-(l -methyl- lH-benzolg]indazol-3-yl)-3-oxo-propionitrile; 2-(4-fluoro-benzoyl)-3-(l -methyl- 1 H-benzo(gIindazol-3-yl)-3-oxo-propionitrile; 2-(3-nitro-benzoyl)-3-(l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo-propionitrile; 2-(3-trifluoromethyl-benzoyl)-3-(l-methyl-lH-benzolglindazol-3-yl)-3-oxo- propionitrile; 2-(3-methyl-benzoyl)-3-( 1 -methyl- 1 H-benzoIglindazol-3-yl)-3-oxo-propionitrile; 2-(3-chloro-benzoyl)-3-(l-methyl-lH-benzo[g]ind^ol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(8-fluoro-l-methyl-lH-benzo[gJindazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(9-chloro-l-methyl-lH-benzo[glindazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(9-methoxy-l -methyl- lH-benzo[gJindazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(isoxazolof2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-(isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-(4-fluoro-benzoyl)-3-(isoxazolo[2,l-a]naphthalen-3-yl)-3-oxo-propionitrile; 2-(3-nitro-benzoyl)-3-(isoxazolof2,l-a]naphthalen-3-yl)-3-oxo-propionitrile; 2-(3-trifluoromethyl-benzoyl)-3-(isoxazolof2, 1 -aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-methyl-benzoyl)-3-(isoxazolof2,l-ajnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-chloro-benzoyl)-3-(isoxazolof2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(8-fluoro-isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile- 2-benzoyl-3-(9-chloro-isoxazolof2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(9-methoxy-isoxazolof2,l-ajnaphthalen-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(l -methyl- lH-benzo(g]indazol-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l -methyl- lH-benzo(gJ indazol-3-yl)-3-oxo- propionitrile; 2-(4-fluoro-benzenesulfonyl)-3-(l -methyl- lH-benzo[g]indazol-3-yl)-3-oxo- propionitrile; 2-(3-nitro-benzenesulfonyl)-3-(l-methyl-lH-benzo[glindazol-3-yl)-3-oxo-propionitrile; 2-(3-trifluoromethyl-benzenesulfonyl)-3-(l -methyl- lH-benzo[glindazol-3-yl)-3-oxo- propionitrile; 2-(3-methyl-benzenesulfonyl)-3-(l -methyl- lH-benzo[gJind.azol-3-yl)-3-oxo- propionitrile; 2-(3-chloro-benzenesulfonyl)-3-(l -methyl- lH-benzo[glindazol-3-yl)-3-oxo- propionitrile; 2-benzenesulfonyl-3-(8-fluoro-l -methyl- lH-benzolg]indazol-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(9-chloro- 1 -methyl- 1 H-benzolg]indazol-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(9-methoxy-l-methyl-lH-benzo(gJindazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(isoxazolo[2,l-ainaphthalen-3-yl)-3-oxo-propionitrile; 2-(4-fluoro-benzenesulfonyl)-3-(isoxazolo[2, 1 -aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-nitro-benzenesulfonyl)-3-(isoxazolo!2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3-trifluoromethyl-benzenesulfonyl)-3-(isoxazolof2,l-a)naphthalen-3-yl)-3-oxo- propionitrile; 2-(3-methyl-benzenesulfonyl)-3-(isoxazoloI2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-(3 -chloro-benzenesulfony l)-3 -(isoxazolo[2, 1 -a|naphthalen-3 -y l)-3 -oxo-propionitrile ; 2-benzenesulfonyl-3-(8-fluoro-isoxazolo[2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(9-chloro-isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(9-methoxy-isoxazolof2,l-a)naphthalen-3-yl)-3-oxo-propionitrile; and 2-benzenesulfonyl-3-(isoxazolo[2,l-alnaphthalen-3-yl)-3-oxo-propionitrile; .and the pharmaceutically acceptable salts thereof. 4. A compound as defined in claim 1 for use as an active therapeutic substance. 5. A compound as claimed in claim 4 for use as a kynurenine-3-hydroxylase enzyme inhibitor. 6. A compound as claimed in claim 4 for use in the prevention or treatment of a neuropathological process. 7. Use of a compound as defined in claim 1 in the manufacture of a medicament for use as a kynurenine-3-hydroxylase enzyme inhibitor. 8. A method of treating a mammal in need of a kynurenine-3 -hydroxy lase inhibitor, the method comprising administering thereto a therapeutically effective amount of a compound as defined in claim 1. 9. A pharmaceutical composition comprising a compound as defined in claim , and a pharmaceutically acceptable carrier or diluent. 10. A compound of formula (II) wherein X, R and Rj are defined in claim 1, Y is a nitrogen atom or a CH group and Z is a derivative of a carboxy group. 1 1. A compound of formula (IV) wherein X, R and R, are as defined in claim 1 and Y is a nitrogen atom or a CH group. 12. A process for the preparation of a compound of formula (I) as defined in claim 1 or a salt thereof, the process comprising a) reacting a compound of formula (II) wherein X, R and R { are as defined in claim 1, Y represents a nitrogen atom or a CH group and Z is a derivative of a carboxy group, with a compound of formula (III) wherein m, Q and W are as defined in claim 1 , thus obtaining a compound of formula (I) in which Y represents a nitrogen atom or a CH group; or b) reacting a compound of formula (IV) wherein X, R and R { are as defined in claim 1 and Y represents a nitrogen atom or a CH group, with a compound of formula (V) or (VI) Q-(CH 2 ) m -Z Q Q--((CCHH 92 ))--NN = = C=O (V) (VI) wherein Q and m are as defined in claim 1 and Z is a derivative of a carboxy group, so obtaining a compound of formula (I) wherein W is a -CO- or a -CONH- group respectively and Y represents a nitrogen atom or a CH group; or c) oxidizing a compound of formula (I) wherein Y is a nitrogen atom into the corresponding compound of formula (I) in which Y is a N-oxide group; and. 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.

Inventors: AMICI RAFFAELLA, PEVARELLO PAOLO, SPECIALE CARMELA, TOMA SALVATORE, VARASI MARIO, AMICI, RAFFAELLA, PEVARELLO, PAOLO, SPECIALE, CARMELA, TOMA, SALVATORE, VARASI, MARIO
Applicants: AMICI RAFFAELLA, PEVARELLO PAOLO, PHARMACIA & UPJOHN SPA, SPECIALE CARMELA, TOMA SALVATORE, VARASI MARIO, AMICI, RAFFAELLA, PEVARELLO, PAOLO, PHARMACIA & UPJOHN S.P.A., SPECIALE, CARMELA, TOMA, SALVATORE, VARASI, MARIO
Application year: 1998
Main classification: C07D231
IPC codes: A61K31, A61P9, A61P25, A61P31, A61P43, C07D231, C07D261, C07D471, C07D498