CONDENSED BENZOTHIOPYRANIC COMPOUNDS

Abstract: The use of a compound of formula (I) wherein W is a -CONH-, -SO2- or -CO-; X is -O- or -NR2- in which R2 is C1-C6 alkyl, benzyl, pyridyl or a phenyl ring, the phenyl ring being 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 R and R1 is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylanino or C1-C6 alkoxy-carbonyl; m is zero or an integer of 1 to 6 and Q is C1-C14 alkyl; or m is zero, 1 or 2 and Q is a phenyl ring or an unsaturated pentatomic heteromonocyclic ring containing two or three heteroatoms chosen independently 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, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylamino and C1-C6 alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as kynurenine-3-hydroxylase inhibitor is disclosed.

Description: CONDENSED BENZOTHIOPYRANIC COMPOUNDS The present invention relates to condensed benzothiopyranic compounds, 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, triptophan 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 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. EP-B-0274443 describes condensed pyrazole compounds active as immunomodulating agents. A selected class of compounds falling within the general formula of such document have been found to be also active as inhibitors of KYN-OH. Accordingly the present invention as a first object provides the use of a compound of formula (I) wherein W is a -CONH-, -SO 2 - or -CO-; X is -O- or -NR,- in which R : is C,-C 6 alkyl. benzyl, pyridyl or a phenyl ring, the phenyl ring being 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 r C 6 alkanoylamino and C,-C 6 alkoxy-carbonyl; each of R and R, is independently hydrogen, halogen, hydroxy. trifluoromethyl. nitro, amino, phenyl. benzyl, C,-C 6 alkyl. C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino or C,-C 6 alkoxy-carbonyl; m is zero or an integer of 1 to 6 and Q is C,-C M alkyl; or m is zero, 1 or 2 and Q is a phenyl ring or an unsaturated pentatomic heteromonocyclic ring containing two or three heteroatoms chosen independently 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, hydroxy. trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C : -C 6 alkanoylamino, formylamino and C r C 6 alkoxy-carbonyl; or a pharmaceuticalh acceptable salt thereof, in the manufacture of a medicament for use as kynurenine-3- hydroxylase inhibitor. It has to be noticed that in the compounds of formula (I) and in the other compounds of the invention herein disclosed the -CO-CH(CN)- W- chain may be represented also by a tautomeric structure, namely the following enol structure -C(OH)=C(CN)-W-. 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, calcium and aluminium hydroxydes, or with organic bases such as 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, 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. Preferred salts of the compounds of formula (I) are the sodium and the potassium salts thereof. 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 formula 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 -(CH 2 ) m - chain or C,-C 14 alkyl may be a branched or straight chain. A C,-C| 4 alkyl group is preferably a C,-C 6 alkyl group. A C,-C 6 alkyl group is preferably a C,-C 4 alkyl group. Representative examples of C,-C 4 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec-, and tert-butyl. A C,-C 6 alkoxy group is preferably a C,-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,-C 6 alkoxy-carbonyl group is preferably a C,-C 4 alkoxy-carbonyl group typically a C,-C 2 alkoxy-carbonyl one. 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 is fluorine, bromine, chlorine or iodine, in particular chlorine, bromine or fluorine. Preferred compounds of formula (I) are those wherein W is as defined above; X is O or NR 2 . wherein R 2 represents C,-C 4 alkyl, benzyl, pyridyl or phenyl, the phenyl 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 and R, is independently hydrogen, halogen, hydroxy. trifluoromethyl, amino, C | -C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino, or C,-C 4 alkoxy-carbonyl; m is zero or 1 ; Q is C,-C 4 alkyl or a phenyl. oxazole, isoxazole, thiazole, pyrazole. imidazole. 1.2,3- triazole, 1,2,4-triazole. 1 ,2,4-oxadiazole or 1,3,4-thiadiazole ring unsubstituted or substituted by one or two substituents selected independently from halogen, hydroxy, trifluoromethyl, nitro, amino. C,-C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino and C,-C 4 alkoxy-carbonyl; and the pharmaceutically acceptable salt thereof. Examples of preferred compounds of formula (I) are the following: 2-cyano-3-( 1.4-dihydro- 1 -methyl-[ 1 ]-benzothiopyrano[4.3-c]pyrazol-3-yl)-3-oxo-N- phenyl-propanamide; 2-cyano-3-(1.4-dihydro-l-phenyl-[l ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N- phenyl-propanamide; 2-cyano-3-(l ,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo-N-phenyl- propanamide; 2-benzenesulfonyl-3-(l,4-dihydro-l-methyl-[l]-benzothiopyrano[4.3-c]pyrazol-3-yl)-3- oxo -propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l,4-dihydro-l-methyl-[l]-benzothiopyrano[4,3- c]pyrazol-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(l,4-dihydro-8-fluoro-l-methyl-[l ]-benzothiopyrano[4.3-c]pyrazol- 3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-( 1 ,4-dihydro-8-fluoro- 1 -methyl-[ 1 ]- benzothiopyrano [4,3 -c]pyrazol-3 -y l)-3 -oxo-propionitrile ; 2-benzenesulfonyl-3-( 1 ,4-dihydro- 1 -phenyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo-propionitrile; 2-benzenesulfonyl-3-(l,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)- 3 -oxo-propionitrile; 2-benzenesulfonyl-3-(l,4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-( 1 ,4-dihydro-8-fluoro-[ 1 ]-benzothiopyrano[4,3- c]isoxazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(l,4-dihydro-l-methyl-[l]-benzothiopyrano[4,3-c]pyrazoI-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-l-methyl-[l]-benzothiopyrano[4,3-c]pyrazol-3- yl)-3-oxo-propionitrile; 2-benzoyl-3-(l,4-dihydro-8-fluoro-l-methyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo-propionitrile 2-(4-methoxy-benzoyl)-3-( 1.4-dihydro-8-fluoro- 1 -methyl-[ 1 ]-benzothiopyrano[4.3- c]pyrazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-( 1.4-dihydro- 1 -phenyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo- propionitrile; 2-benzoyl-3-( 1 ,4-dihydro-[ 1 ]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo-propionitrile: 2-(4-methoxy-benzoyl)-3-( l,4-dihydro-[l ]-benzothiopyrano[4.3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-benzoyl-3-(1.4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3-c]isoxazol-3- yl)-3-oxo-propionitrile; and the pharmaceutically acceptable salts thereof. A further object of the present invention is a novel compound of formula (I A) wherein W is -CONH-, -SO 2 - or -CO-; X is -0- , or -NR,- in which R 2 is C,-C 6 alkyl, benzyl, pyridyl or a phenyl ring, the phenyl ring being unsubstituted or substituted by one or two substituents chosen independent!},' 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 and R, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino or C,-C 6 alkoxy-carbonyl; m is zero or an integer of 1 to 6 and Q is C,-C l4 alkyl; or m is zero, 1 or 2 and Q is a phenyl ring or an unsaturated pentatomic heteromono-cyclic ring containing two or three heteroatoms independently 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, 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; and wherein, when at the same time X is -NR 2 in which R 2 is C,- C 6 alkyl, benzyl, pyridyl or a phenyl ring unsubstituted or substituted by one or two substituents chosen from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, nitro, amino, formylamino, C,-C 6 alkanoylamino and trifluoromethyl; R and R, are hydrogen, hydroxy. halogen, nitro, amino, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino or formylamino; m is zero or an integer of 1 to 6 and Q is C,-C I4 alkyl or m is zero, 1 or 2 and Q is a phenyl ring optionally substituted by one or two substituents chosen from halogen, hydroxy, trifluoromethyl, nitro, amino, C,-C 6 alkyl, C,-C 6 alkoxy. C 2 -C 6 alkanoylamino and formylamino; then W is other than -CONH-. The preferred features exemplified above as to a compound of formula (I) apply also to a compound of formula (IA) . Preferred compounds of formula (IA) are those wherein, subject to the above proviso: W is a -CONH-, -SO 2 - or -CO- group; X is O or NR 2 , wherein R 2 represents C,-C 4 alkyl, benzyl, pyridyl or phenyl, the phenyl 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 or C,-C 4 alkoxy-carbonyl; each of R and R, is independently hydrogen, halogen, hydroxy, trifluoromethyl, amino. C,-C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino or C,-C 4 alkoxy carbonyl; m is zero or 1 ; Q is C,-C 4 alkyl or a phenyl, oxazole. isoxazole, thiazole, pyrazole, imidazole, 1 ,2,3- triazole. 1,2,4-triazole. 1,2,4-oxadiazole or 1,3,4-thiadiazole ring unsubstituted or substituted by one or two substituents selected from halogen, hydroxy. trifluoromethyl, nitro. amino. C,-C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino and C,-C 4 alkoxy-carbonyl; and the pharmaceutically acceptable salts thereof. A preferred class of compounds of formula (IA) are those wherein X is NR 2 in which R : is as defined above, W is -CONH-, Q is a heteromonocyclic ring, containing two or three heteroatoms chosen from oxygen and nitrogen, optionally substituted by one or two substituents independently chosen from halogen, hydroxy, trifluoromethyl, nitro. amino. phenyl. benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C : -C 6 alkanoylamino. formylamino and C r C, alkoxy-carbonyl; and m, R and R, are as defined above; and the pharmaceutically acceptable salts thereof. A preferred class of compounds of formula (IA) are also those wherein W is -S0 2 - or - CO-, X is -O- or -NR 2 in which R 2 is as defined above, and m. R and R,. Q are as defined above; and the pharmaceutically acceptable salts thereof. Examples of preferred compounds of formula (IA) are the following: 2-cyano-3-(l ,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo-N-phenyl- propanamide; 2-benzenesulfonyl-3-( 1 ,4-dihydro- 1 -methyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-( 1 ,4-dihydro- 1 -methyl-[ 1 ]-benzothiopyrano[4,3- c]pyrazol-3-yl)-3-oxo-propionitrile: 2-benzenesulfonyl-3-(l,4-dihydro-8-fluoro-l-methyl-[l]-benzothiopyrano[4,3-c]pyrazol- 3 -yl)-3 -oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-( 1 ,4-dihydro-8-fluoro- 1 -methyl-[ 1 ]- benzothiopyrano [4,3 -c]pyrazol-3 -y l)-3 -oxo-propionitrile ; 2-benzenesulfonyl-3-( 1 ,4-dihydro- 1 -phenyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo-propionitrile; 2-benzenesulfonyl-3-(l,4-dihydro-[l ]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-( 1 ,4-dihydro-[ 1 ]-benzothiopyrano[4.3-c]isoxazol-3-yl)- 3-oxo-propionitrile; 2-benzenesulfonyl-3-(l,4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(1.4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3- c]isoxazo!-3-yl)-3-oxo-propionitrile: 2-benzoyl-3-( 1 ,4-dihydro- 1 -methy l-[ 1 ]-benzothiopyrano[4.3-c]pyrazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzoyl)-3-( 1.4-dihydro- 1 -methyl-[l ]-benzothiopyrano[4.3-c]pyrazol-3- yl)-3-oxo-propionitrile; 2-benzoyl-3-(l ,4-dihydro-8-fluoro- l -methyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-( 1.4-dihydro-8-fluoro- 1 -methyl-[ 1 ]-benzothiopyrano[4.3- c]pyrazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(l,4-dihydro-l-phenyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo- propionitrile; 2-benzoyl-3-(l,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-[l ]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-benzoyl-3-(l,4-dihydro-8-fluoro-[l]-benzothiopyrano[4.3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzoyl)-3-( 1 ,4-dihydro-8-fluoro-[l ]-benzothiopyrano[4,3-c]isoxazol-3- yl)-3-oxo-propionitrile; and the pharmaceutically acceptable salts thereof. A pharmaceutically acceptable salt of a compound of formula (IA) is for instance a pharmaceutically acceptable salt as defined as to a compound of formula (I). Object of the present invention is also a compound of formula (IA) or a pharmaceutically acceptable salt thereof for use as a medicament, in particular as kynurenine-3 -hydroxy lase enzyme inhibitor. The compounds of formula (I) and (IA) are herein defined also the "compounds of the invention". The present invention also provides a method of treating a mammal, including human, in need of a kynurenine-3-hydroxylase inhibitor; such method comprising administering thereto a therapeutically effective amount of a compound of the invention, as defined above, or a pharmaceutically acceptable salt thereof. The compounds of the invention and the salts thereof can be obtained by an analogy process as disclosed for instance in EP-B-0274443. In particular a novel compound of formula (IA) or a pharmaceutically acceptable salt thereof can be obtained by a process comprising: a) reacting a compound of formula (II) wherein R and R, are as defined above and X is O or NR. wherein R 2 is as defined above and Z is a derivative of a carboxy group, with a compound of formula (III) NC-CH 2 -W-(CH 2 ) m -Q (HI) wherein m, Q and W are as defined above, thus obtaining a compound of formula (IA); or b) reacting a compound of formula (IV) wherein R and R, are as defined above and X is O or NR, wherein R 2 is as defined above, with a compound of formula (V) or (VI) Z-(CH 2 ) m -Q (V) OCN-(CH 2 )_-Q (VI) wherein Q, m and Z are as defined above, so obtaining a compound of formula (IA) wherein W is a -CO- or a -CONH- group respectively; and if desired, converting a compound of formula (IA) into another compound of formula (IA), and/or. if desired, converting a compound of formula (IA) into a salt thereof, and/or, if desired converting a salt of a compound of formula (IA) into a free compound of formula (IA), and if desired, separating a mixture of isomers of a compound of formula (IA) into the single isomers. A compound of formula (IA) may be converted into another compound of formula(I A) by known methods. For example, in a compound of formula (IA) 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 dioxane, tetrahydofuran 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 : - C 4 alkanoyl anhydride without any solvent or in a organic solvent such as dioxane. dimethylformamide, tetrahydofuran, usually in the presence of a base such as triethylamine, at a temperature varying between about 0 °C and about 100 °C. When Z is a derivative of a carboxy group it is for example a reactive derivative thereof, i.e., a halocarbonyl group, preferably a chlorocarbonyl group, or a C,-C 7 alkoxy-carbonyl. preferably a C,-C 3 alkoxy-carbonyl 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. 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 triethylamine, in an inert solvent such as toluene, dioxane. tetrahydofuran, dimethylformamide, dichloromethane at a temperature varying between about 0° C and about 100° C. The intermediate compounds (II) and (VI) are either novel or known compounds or can be obtained by known methods from known compounds. For instance the compounds of formula (II) wherein R, R, and Z are as defined above and X is O are novel and are a further object of this invention, they may be obtained, for example, by reacting a compound of formula (VII) wherein R and R, are as defined above and R 3 is C,-C 6 alkyl, preferably C,-C 2 alkyl with hydroxylamine hydrochloride. This reaction may be carried out, for example, in acetic acid at a temperature varying between room temperature and about 70 °C. The compounds of formula (IV) wherein R and R, are as defined above and X is O are novel and are a further object of this invention, they may be obtained, for example, by reacting a compound of formula (II) wherein R, R, and Z are as defined above and X is 0 with acetonitrile in dioxane in the presence of NaH at about 60° C following the procedure described in EP-B- 0274443. The compounds of formula (II) wherein R and R, are as defined above, X is NR 2 wherein R 2 is as defined above and Z is a reactive derivative of a carboxy group are described in EP-B-0274443. The compounds of formula (IV) wherein R and R, are as defined above and X is NR 2 wherein R 2 is as defined above are described in EP-B-0274443. The compounds of formula (VII) are described in EP-B-0274443. The compounds of formula (III), (V). (VI) are commercially available or may be prepared by well known procedures. When in the compounds of the invention and the intermediate thereof groups are present which may interfere with the reaction they may be protected before the reaction takes place and then deprotected at the end of the reaction. For instance, hydroxy, amino and/or carboxy groups may be protected and then deprotected according to the common techniques known from the peptide chemistry. Pharmacology The compounds of the invention are active as kynurenine-3 -hydroxy lase 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, olivoponto cerebellar 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-hydroxylase 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 -hydro xylase 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 -hydroxy lase 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 -hydroxy lase activity was carried out at 37°C for a time of 30 min. The reaction mixture of a total volume of 100 μl was constituted of 44 μg 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 representative compounds of the invention: 2-cyano-3-(l,4-dihydro-l-methyl- [l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (internal code PNU- 151338); 2-cyano-3-( 1 ,4-dihydro- 1 -phenyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3- yl)-3-oxo-N-phenyl-propanamide (internal code PNU-152221 ); 2-benzenesulfonyl-3-(l ,4- dihydro-l-phenyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propionitrile (internal code PNU- 152017); 2-benzoyl-3-( 1 ,4-dihydro- 1 -phenyl-[ 1 ]-benzothiopyrano[4,3- c]pyrazol-3-yl)-3 -oxo-propionitrile (internal code PNU- 152030) 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 151338 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. 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; 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 suspensions 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 2-Cyano-3-(l,4-dihydro-l-phenyl-[ " ll-benzothiopyrano[4.3-c1pyrazol-3- yl)-3-oxo-N-phenyl-propanamide Thiochroman-4-one (5 g) is reacted with diethyl oxalate (4.44 g) in anhydrous ethanol (25 ml) in the presence of sodium ethoxide (2.07 g) under stirring for 1 h at about 10°C and then for 3 h at 25°C. The precipitate is filtered and washed with cold ethanol then dissolved in water. Acidification with citric acid gives an oil precipitate which is extracted with ethyl acetate. Evaporation of the solvent in vacuo to dryness gives 3-ethoxalyl- thiochroman-4-one, oil (5.65 g), which is reacted with phenylhydrazine (2.54 g) in acetic acid (35 ml) at a temperature varying between 25°C and about 40°C for 30 minutes. The reaction mixture is diluted with ice water and then neutralized with 30%o ammonium hydroxide. The precipitate is filtered, dissolved in ethyl acetate and washed with water. After evaporation of the solvent in vacuo the residue is crystallized from dichloromethane/isopropyl ether to give 1.4-dihydro-l-phenyl-[l]-benzothiopyrano[4,3- c]pyrazole-3-carboxylic acid, ethyl ester, m.p. 139-141°C (4.2 g), which is reacted with acetonitrile (16.5 g) in dioxane (25 ml) in the presence of 50% sodium hydride (1.2 g) under stirring at 60°C for 30 minutes. After cooling the reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered and washed with water and purified over SiO 2 column using hexane/ethyl acetate 80:20 as eluent. Crystallization from dichloromethane/isopropyl ether gives 3-(l,4-dihydro-l-phenyl-[l ]- benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanenitrile, m.p. 151-153°C (3.45 g), which is reacted with phenyl isocyanate (1.3 g) in the presence of triethylamine (1.15 g) in dimethylformamide (30 ml) under stirring at 25-30°C for 30 minutes. The reaction mixture is diluted with ice water and the precipitate is filtered and washed with water. Crystallization from dichloromethane/methanol gives 4 g of 2-cyano-3-(l ,4-dihydro-l - phenyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide. m.p. 228- 230°C. By proceeding analogously, using methylhydrazine or hydroxylamine hydrochloride, the following products can be prepared: 2-cyano-3-( 1 ,4-dihydro- 1 -methyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N- phenyl-propanamide, m.p. 240-242°C; 2-cyano-3-(l,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo-N-phenyl- propanamide. Example 2 Preparation of 2-Benzenesulfonyl-3-( 1 ,4-dihydro- 1 -phenyl-[ 11-benzothiopyrano[4,3- c1pyrazol-3-yl)-3-oxo-propionitrile l,4-Dihydro-l-phenyl-[l]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid, ethyl ester (3.36 g) suspended in dioxane (60 ml) is treated with N/l NaOH (30 ml) under stirring at room temperature for 5 h. The reaction mixture is diluted with ice water and acidified to pH 3 with 37%o HCl. The precipitate is filtered, washed with water and dried in vacuo at 50°C to give l,4-dihydro-l-phenyl-[l]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid (2.8 g) which is reacted with oxalyl chloride (17 g) under stirring, at room temperature for 8h. The reaction mixture is evaporated to dryness in vacuo and the residue 1.4-dihydro-l - phenyl-[l ]-benzothiopyrano[4.3-c]pyrazole-3-carbonyl chloride (2.9 g), is dissolved in anhydrous dioxane (30 ml) and added under stirring to a suspension obtained by treatment of (phenylsulfonyl)acetonitrile (1.81 g) with 50% sodium hydride (0.65 g) in anhydrous dioxane (50 ml). The reaction mixture is kept at room temperature for 1 h and is then acidified to pH 2 with 2N HCl and diluted with ice water. The product is extracted with ethyl acetate and the organic solutions are collected, washed with water, dried over anhydrous sodium sulfate and then evaporated. The residue is crystallized from dichloromethane/methanol to give 2.9 g of 2-benzenesulfonyl-3-(l,4-dihydro-l-phenyl- [ 1 ]-benzothiopyrano[4.3-c]pyrazol-3-yl)-3-oxo-propionitrile. m.p. 195- 198°C. By proceeding analogously, using the suitable esters, the following products can be prepared: 2-benzenesulfonyl-3-(l ,4-dihydro-l-methyl-[l]-benzothiopyrano[4.3-c]pyrazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-( 1 ,4-dihydro- 1 -methyl-[ 1 ]-benzothiopyrano[4.3- c]pyrazol-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(l,4-dihydro-8-fluoro-l-methyl-[l]-benzothiopyrano[4,3-c]pyrazol- 3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l,4-dihydro-8-fluoro-l-methyl-[l]- benzothiopyrano [4,3 -c]pyrazol-3 -yl)-3 -oxo-propionitrile; 2-benzenesulfonyl-3-(l ,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l ,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)- 3 -oxo-propionitrile ; 2-benzenesulfonyl-3-(1.4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l ,4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3- c]isoxazol-3-yl)-3-oxo-propionitrile. Example 3 Preparation of 2-Benzoyl-3-( 1.4-dihydro-l-phenyl-[11-benzothiopyrano[4,3-c]pyrazol-3- yl)-3-oxo-propιonitrile To a solution of 3-(l ,4-dihydro-l -phenyl-[l ]-benzothiopyrano[4.3-c]pyrazol-3-yl)-3-oxo- propanenitrile (0.50 g) in dichloromethane (20 ml), triethylamine (0.23 ml) is added under stirring, at room temperature. Benzoyl chloride (0.18 ml) is added and the reaction mixture is allowed to react at room temperature for lh. The solution is washed with water, dried over anhydrous sodium sulfate and then evaporated. The residue is purified by flash chromatography on silica gel using dichloromethane/ AcOEt 98:2 as eluent. The purified fractions are collected and evaporated to dryness. The residue is triturated in MeOH to give 0.33 g of 2-benzoyl-3-(l ,4-dihydro-l-phenyl-[l]-benzothiopyrano[4,3-c]pyrazol-3- yl)-3 -oxo-propionitrile. m.p. 199-200°C. By proceeding analogously, using the suitable 3-oxo-propanenitriles, the following products can be prepared: 2-benzoyl-3-( 1 ,4-dihydro- 1 -methyl-[ 1 ]-benzothiopyrano[4.3-c]pyrazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-l-methyl-[l]-benzothiopyrano[4,3-c]pyrazol-3- yl)-3-oxo-propionitrile; 2-benzoyl-3-( 1.4-dihydro-8-fluoro- 1 -methyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-( 1 ,4-dihydro-8-fluoro- 1 -methyl-[ 1 ]-benzothiopyrano[4,3- c]pyrazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(1.4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-(l,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-benzoyl-3-(l,4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzoyl)-3-(l,4-dihydro-8-fluoro-[l]-benzothiopyrano[4.3-c]isoxazol-3" yl)-3 -oxo-propionitrile. 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: 2-cyano-3-( 1 ,4-dihydro- 1 -methyl-[l ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N- phenyl-propanamide 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 2- cyano-3-(l,4-dihydro-l-methyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl- propanamide 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 1. Use of a compound of formula (I) wherein W is a -CONH-, -SO,- or -CO-; X is -O- or -NR 2 - in which R 2 is C,-C 6 alkyl. benzyl, pyridyl or a phenyl ring, the phenyl ring being 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 and R, is independently hydrogen, halogen, hydroxy, trifluoromethyl. nitro. amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino. formylamino or C i -C 6 alkoxy-carbonyl; m is zero or an integer of 1 to 6 and Q is C r C alkyl; or m is zero, 1 or 2 and Q is a phenyl ring or an unsaturated pentatomic heteromonocyclic ring containing two or three heteroatoms chosen independently 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, 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, in the manufacture of a medicament for use as kynurenine-3- hydroxylase inhibitor. 2. Use according to claim 1, wherein in formula (I), W is as defined in claim 1 ; X is O or NR 2 , wherein R 2 represents C,-C 4 alkyl, benzyl, pyridyl or phenyl, the phenyl 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 and R, is independently hydrogen, halogen, hydroxy, trifluoromethyl, amino. C,-C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino, or C,-C 4 alkoxy-carbonyl; m is zero or 1 ; Q is C,-C 4 alkyl or a phenyl, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3- triazole. 1 ,2,4-triazole, 1,2,4-oxadiazole or 1,3,4-thiadiazole ring unsubstituted or substituted by one or two substituents selected independently from halogen, hydroxy, trifluoromethyl, nitro. amino. C,-C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino and C,-C 4 alkoxy-carbonyl. 3. Use according to claim 1. wherein the compound of formula (I) is selected from 2-cyano-3-( 1 ,4-dihydro- 1 -methyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N- phenyl-propanamide; 2-cyano-3-(l ,4-dihydro-l-phenyl-[l ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N- phenyl-propanamide; 2-cyano-3-(l,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo-N-phenyl- propanamide; 2-benzenesulfonyl-3-(l ,4-dihydro-l -methyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo -propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l ,4-dihydro-l-methyl-[l ]-benzothiopyrano[4.3- c]pyrazol-3-yl)-3-oxo-propionitrile: 2-benzenesulfonyl-3-(1.4-dihydro-8-fluoro-l -methyl-[l ]-benzothiopyrano[4,3-c]pyrazol- 3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-( 1.4-dihydro-8-fluoro-l-methyl-[l]- benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(l,4-dihydro-l-phenyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo-propionitrile; 2-benzenesulfonyl-3-(l,4-dihydro-[l ]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(1.4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)- 3 -oxo-propionitrile; 2-benzenesulfonyl-3-(l,4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l,4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3- c]isoxazol-3-yl)-3-oxo-propionitrile; 2-benzoy l-3-( 1 ,4-dihydro- 1 -methy 1- [ 1 ]-benzothiopyrano [4,3 -c]pyrazol-3 -yl)-3 -oxo- propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-l-methyl-[l]-benzothiopyrano[4.3-c]pyrazol-3- yl)-3-oxo-propionitrile; 2-benzoyl-3-( 1 ,4-dihydro-8-fluoro- 1 -methyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-8-fluoro-l-methyl-[l]-benzothiopyrano[4.3- c]pyrazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-( 1 ,4-dihydro- 1 -phenyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo- propionitrile; 2-benzoyl-3-(l ,4-dihydro-[l ]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-[l ]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-benzoyl-3-(l ,4-dihydro-8-fluoro-[l ]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-8-fluoro-[l ]-benzothiopyrano[4.3-c]isoxazol-3- yl)-3-oxo-propionitrile: or a pharmaceutically acceptable salt thereof. 4. A method of treating a mammal, including humans, in need of a kynurenine-3- hydroxylase inhibitor, such method comprising administering thereto a therapeutically effective amount of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt tehreof. 5. A compound of formula (I A) wherein W is -CONH-, -SO 2 - or -CO-; X is -O- , or -NR 2 - in which R 2 is C,-C 6 alkyl, benzyl, pyridyl or a phenyl ring, the phenyl ring being 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 and R, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C ή alkyl. C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino or C,-C 6 alkoxy-carbonyl; m is zero or an integer of 1 to 6 and Q is C,-C l4 alkyl; or m is zero, 1 or 2 and Q is a phenyl ring or an unsaturated pentatomic heteromono-cyclic ring containing two or three heteroatoms independently 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, 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 a pharmaceutically acceptable salt thereof; and wherein, when at the same time X is -NR 2 in which R 2 is C,- C 6 alkyl, benzyl, pyridyl or a phenyl ring unsubstituted or substituted by one or two substituents chosen from halogen. C,-C 6 alkyl, C,-C 6 alkoxy, nitro, amino, formylamino. C 2 -C 6 alkanoylamino and trifluoromethyl; R and R, are hydrogen, hydroxy. halogen, nitro. amino. C,-C 5 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino or formylamino: m I s zero or an integer of 1 to 6 and Q is C,-C alkyl or m is zero, 1 or 2 and Q is a phenyl ring optionally substituted by one or two substituents chosen from halogen, hydroxy. trifluoromethyl, nitro. amino, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino and formylaminol; then W is other than -CONH-. 6. A compound as defined in claim 5 wherein, in formula (IA), W is a -CONH-, -SO 2 - or -CO- group; X is O or NR 2 , wherein R 2 represents C,-C 4 alkyl, benzyl, pyridyl or phenyl, the phenyl 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 or C,-C 4 alkoxy-carbonyl; each of R and R, is independently hydrogen, halogen, hydroxy, trifluoromethyl, amino, C,-C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino or C,-C 4 alkoxycarbonyl; m is zero or 1 ; Q is C,-C 4 alkyl or a phenyl, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3- triazole, 1,2,4-triazole, 1 ,2,4-oxadiazole or 1,3,4-thiadiazole ring unsubstituted or substituted by one or two substituents selected from halogen, hydroxy, trifluoromethyl, nitro. amino, C,-C 4 alkyl. C,-C 4 alkoxy, C 2 -C 4 alkanoylamino and C,-C 4 alkoxy-carbonyl. 7. A compound as defined in claim 5 wherein, in formula (I A), X is NR 2 in which R 2 is as defined in claim 5; W is -CONH-; Q is a heteromonocyclic ring, containing two or three heteroatoms chosen from oxygen and nitrogen, optionally substituted by one or two substituents independently chosen 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; and m. R and R, are as defined in claim 5. 8. A compound as defined in claim 5 wherein, in formula (IA), W is -S0 2 - or -CO-; X is -O- or -NR 2 - in which R 2 is as defined in claim 5. and m, R and R Q are as defined in claim 5. 9. A compound selected from 2-cyano-3-(l,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo-N-phenyl- propanamide; 2-benzenesulfonyl-3-( 1 ,4-dihydro- 1 -methyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo -propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-( 1 ,4-dihydro- 1 -methyl-[l ]-benzothiopyrano[4,3- c]pyrazol-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-( 1 ,4-dihydro-8-fluoro- 1 -methyl-[ 1 ]-benzothiopyrano[4,3-c]pyrazol- 3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-( 1 ,4-dihydro-8-fluoro- 1 -methyl-[ 1 ]- benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propionitrile; 2-benzenesulfonyl-3-(l,4-dihydro-l-phenyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo-propionitrile; 2-benzenesulfony 1-3 -( 1 ,4-dihydro- [ 1 ] -benzothiopyrano [4,3 -c]isoxazol-3 -y l)-3 -oxo- propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)- 3-oxo-propionitrile; 2-benzenesulfonyl-3-( 1 ,4-dihydro-8-fluoro-[ 1 ]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzenesulfonyl)-3-(l,4-dihydro-8-fluoro-[l ]-benzothiopyrano[4,3- c]isoxazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-(l,4-dihydro-l-methyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-l-methyl-[l]-benzothiopyrano[4,3-c]pyrazol-3- yl)-3-oxo-propionitrile; 2-benzoyl-3-(l ,4-dihydro-8-fluoro-l-methyl-[l]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3- oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-( 1 ,4-dihydro-8-fluoro- 1 -methyl-[ 1 ]-benzothiopyrano[4,3- c]pyrazol-3-yl)-3-oxo-propionitrile; 2-benzoyl-3-( 1 ,4-dihydro- 1 -phenyl-[l ]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo- propionitrile; 2-benzoyl-3-(l,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo-propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-benzoyl-3-(l ,4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3-c]isoxazol-3-yl)-3-oxo- propionitrile; 2-(4-methoxy-benzoyl)-3-(l ,4-dihydro-8-fluoro-[l]-benzothiopyrano[4,3-c]isoxazol-3- yl)-3 -oxo-propionitrile; or a pharmaceutically acceptable salt thereof. 10. A compound as defined in claim 5 or a pharmaceutically acceptable salt tehreof for use as a medicament. 11. A compound as defined in claim 5 or a pharmaceutically acceptable salt thereof for use as kynurenine-3 -hydroxy lase inhibitor. 12. A pharmaceutically composition which comprises, as an active principle a compound of formula (IA), as defined in claim 5 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier and/or diluent. 13. A compound of formula (II) wherein X is O and R and R, are as defined as in claim 1 and Z is a derivative of a carboxy group. 14. A compound of formula (IV) wherein X is O and R and R, are as defined in claim 1.

Inventors: AMICI RAFFAELLA, GRECO FELICITA, PEVARELLO PAOLO, SPECIALE CARMELA, VARASI MARIO, AMICI, RAFFAELLA, GRECO, FELICITA, PEVARELLO, PAOLO, SPECIALE, CARMELA, VARASI, MARIO
Applicants: AMICI RAFFAELLA, GRECO FELICITA, PEVARELLO PAOLO, PHARMACIA & UPJOHN SPA, SPECIALE CARMELA, VARASI MARIO, AMICI, RAFFAELLA, GRECO, FELICITA, PEVARELLO, PAOLO, PHARMACIA & UPJOHN S.P.A., SPECIALE, CARMELA, VARASI, MARIO
Application year: 1998
Main classification: C07D495
IPC codes: A61K31, A61P25, A61P43, C07D495, C07D498