The compound of the invention act as inhibitors of Kynurenine-3-hydroxylase (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 compound able of inhibiting this enzyme.

The compound of the present invention fulfill such a need.

Accordingly, the present invention provides the use of a 1,3, 4-thiadiazole compound of formula (I) wherein m is zero or 1; Q represents a C6-C, 4 aromatic ring system or a saturated or unsaturated heteromonocyclic or heterobicyclic ring containing one or two heteroatoms chosen from oxygen, sulfur and nitrogen, wherein said aromatic or heterocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, Cl-C6 alkyl, hydroxy, C1-C6 alkoxy, nitro, formylamino, C2-Cg alkanoylamino, C2-C8 alkanoyloxy, a SO2N(R2R3) group, in which each of R2 and R3 is independently hydrogen, C1-C6 alkyl or phenyl, and a N (R4R5) group, in which each of R4 and R5 is independently hydrogen, Cl-C6 alkyl or SO2R6, in which R6 is C,-C6 alkyl or phenyl, or R4and R5, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring; X is oxygen or sulfur; Y is oxygen, sulfur or NH; p is 0 or I; R is CC13, CF3, a N (R7R8) group, in which each of R7 and R8 is independently hydrogen or

Cl-C6 alkyl or R7 and Rg taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring or R is a phenyl or naphthyl ring, wherein such heterocyclic, phenyl or naphthyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, C,-C6 alkyl, hydroxy, Cl-C6 alkoxy, nitro, formylamino, C2-C8 alkanoylamino, C2-C8 alkanoyloxy, a SO2N(R2R3) group, in which each of R2 and R3 is as defined above, and a N (R4R5) group, in which each of R4 and R5 is as defined above; R, is hydrogen, CH2OPO3H2, a -(CH2)n-N(R9R10) group in which n is an integer of l to 4 and each of Rg and Rlo is independently hydrogen, Cl-C6 alkyl or phenyl, or R9 and Rlo, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring; or R, is a group of formula: wherein X, Y, p and R are independently as defined above; or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use as kynurenine-3-hydroxylase enzyme inhibitor.

A further object of the present invention is also to provide a 1,3,4-thiadiazole compound of formula (I), wherein in is zero or 1; Q represents a C6-C, 4 aromatic ring system or a saturated or unsaturated heteromonocyclic or heterobicyclic ring containing one or two heteroatoms chosen from oxygen. sulfur and nitrogen, wherein said aromatic or heterocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, C-C6 alkyl, hydroxy, Cl-C6 alkoxy, nitro, formylamino, C2-C8 alkanoylamino, C2-C8 alkanoyloxy, a SO2N (R2R3) group, in which each of R2 and R3 is independently hydrogen, Cl-C6 alkyl or phenyl, and a N (R4R5) group, in which each of R4 and Rs is independently hydrogen, Cl-C6 alkyl or SO2R6, in which R6 is Cl-C6 alkyl or phenyl, or R4 and R5, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated Ci-C7 heterocyclic ring; X is oxygen or sulfur; Y is oxygen, sulfur or NH; pisOor 1; R is CC13, CF3, a N (R7R8) group, in which each of R7 and R8 is independently hydrogen or Cl-C6 alkyl or R7 and R8 taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring or R is a phenyl or naphthyl ring, wherein such heterocyclic, phenyl or naphthyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, C,-C6 alkyl, hydroxy, Cl-C6 alkoxy, nitro, formylamino, C2-C8 alkanoylamino, C2-C8 alkanoyloxy, a SO2N (R2R3)

group, in which each of R2 and R3 is as defined above, and a N (R4R5) group, in which each of R4 and Rosis as defined above; R, is hydrogen, CH2OPO3H2, a -(CH2)n-N(R9R10) group in which n is an integer of I to 4 and each of R9 and Riz vis independently hydrogen, Cl-C6 alkyl or phenyl, or R9 and R, o, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring; or R, is a group of formula: wherein X, Y, p and R are independently as defined above; or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance, in particular 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-hydroxylase inhibitor, such method comprising administering thereto a therapeutically effective amount of a 1,3,4-thiadiazole compound of formula (1) wherein m is zero or 1; Q represents a C6-C, 4 aromatic ring system or a saturated or unsaturated heteromonocyclic or heterobicyclic ring containing one or two heteroatoms chosen from oxygen, sulfur and nitrogen, wherein said aromatic or heterocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, Cl-C6 alkyl, hydroxy, C1-C6 alkoxy, nitro, formylamino, C2-C8 alkanoylamino, C2-C8 alkanoyloxy, a SO2N(R2R3) group, in which each of R2 and R3 is independently hydrogen, Cl-C6 alkyl or phenyl, and a N (R4R5) group, in which each of R4 and R5is independently hydrogen, Cl-C6 alkyl or SO2R6, in which R6 is C I-C6 alkyl or phenyl, or R4 and R5, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring; X is oxygen or sulfur; Y is oxygen, sulfur or NH; pisOor l; R is CC13, CF3, a N (R7R8) group, in which each of R7 and R8 is independently hydrogen or Cl-C6 alkyl or R7 and R8 taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring or R is a phenyl or naphthyl ring, wherein such heterocyclic, phenyl or naphthyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, C,-C6 alkyl, hydroxy, Cl-C6 alkoxy, nitro, formylamino, C2-C8 alkanoylamino, C2-C8 alkanoyloxy, a SO2N(R2R3) group, in which each of R2 and R3 is as defined above, and a N (R4R5) group, in which each of R4 and Rosis as defined above; R, is hydrogen, CH2OPO3H2, a -(CH2)n-N(R9R10) group in which n is an integer of I to 4 and each of R9 and Rio is independently hydrogen, Cl-C6 alkyl or phenyl, or R9 and R, o,

taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring; or Rl is a group of formula: wherein X, Y, p and R are independently as defined above; or a pharmaceutically acceptable salt thereof.

Object of the present invention is also to provide a new 1,3,4-thiadiazole compound of formula (I) wherein m is zero or 1; Q represents a C6-CI4 aromatic ring system or a saturated or unsaturated heteromonocyclic or heterobicyclic ring containing one or two heteroatoms chosen from oxygen, sulfur and nitrogen, wherein said aromatic or heterocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, Cl-C6 alkyl, hydroxy, Cl-C6 alkoxy, nitro, formylamino, C2-C8 alkanoylamino, C2-C8 alkanoyloxy, a SO2N(R2R3) group, in which each of R2 and R3 is independently hydrogen, Cl-C6 alkyl or phenyl, and a N (R4R5) group, in which each of R4 and R_i is independently hydrogen, Cl-C6 alkyl or SO2R6, in which R6 is Ci-C6 alkyl or phenyl, or R4 and R5, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring; X is oxygen or sulfur; Y is oxygen, sulfur or NH; pisOor 1; R is CC13, CF3, a N (R7R8) group, in which each of R7 and R8 is independently hydrogen or Cl-C6 alkyl or R7 and Rg taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring or R is a phenyl or naphthyl ring, wherein such heterocyclic, phenyl or naphthyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, Cl-C6 alkyl, hydroxy, Cl-C6 alkoxy, nitro, formylamino, C2-C8 alkanoylamino, C2-C8 alkanoyloxy, a SO2N(R2R3) group, in which each of R2 and R3 is as defined above, and a N (R4R) group, in which each of R4 and R5 is as defined above; Rl is hydrogen, CH2OPO3H2, a- (CH2) n-N (R9Rlo) group in which n is an integer of 1 to 4 and each of R9 and R, o is independently hydrogen, Cl-C6 alkyl or phenyl, or R9 and R, o, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring; or R, is a group of formula: wherein X, Y, p and R are independently as defined above; or a pharmaceutically acceptable salt

thereof The present invention also include within its scope all possible isomers, stereoisomers and optical isomers and their mixtures, and both the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compound of the invention.

The alkyl, alkanoyloxy, alkoxy and alkanoylamino groups may be branche or straight chain groups.

Representative examples Of C,-C6 alkyl groups include Cl-C4 alkyl groups such as methyl, ethyl, n-and iso-propyl, n-, iso-, sec-rand tert-butyl.

Representative examples of Cl-C6 alkoxy groups include Cl-C4 alkoxy groups such as methoxy or ethoxy.

Representative examples of CZ-Cg alkanoylamino include CZ-C4 alkanoyl groups such as acetylamino or propionylamino.

Representative examples of C2-C8 alkanoyloxy include C2-C4 alkanoyl groups such as acetoxy or propionyloxy.

When Q is a C6-C^4 aromatic ring system, it is preferably phenyl or naphthyl; when Q is a saturated or unsaturated heteromonocyclic or heterobicyclic ring as defined above, it is preferably chosen from pyridine, imidazole, pyrrolidine, morpholine, piperidine, piperazine, 3-azabicyclo [3.2.2] nonane, cycloheptylamine and 1,2,5,6-tetrahydropyridine and it is linked to the [1,3,4] thiadiazole (alkyl) moiety through either a carbon or a nitrogen atom, as known in the art.

When R4 and Rs or R7 and R8 or Rg and Rlo respectively, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated CS-C heterocyclic ring, said ring is preferably chosen from pyridine, imidazole, pyrrolidine, morpholine, piperidine, piperazine, cycloheptylamine and 1,2,5,6-tetrahydropyridine.

A halogen atom is fluorine, bromine, chlorine or iodine; in particular chlorine or fluorine.

Pharmaceutically acceptable salts of the compound 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, N-benzyl-ß- phenethylamine, N-benzyl-N, N-dimethylamine and the other acceptable organic amines, as well as the salts with inorganic, e. g. hydrochloride, hydrobromic and sulphuric acids and with organic acids, e. g. citric, tartaric, maleic, malic, fumaric, methanesulphonic, ethanesulphonic and isethionic acids.

Preferred compound of formula (I) are those wherein; m is zero or 1; X, Y and p are as defined above; Q represents a phenyl, naphthyl, pyridyl, imidazolyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, 3-azabicyclo [3. 2.2] nonyl, cycloheptylamino or 1,2,5,6- tetrahydropyridyl ring, wherein said ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, Cl-C4 alkyl, Cl-C4 alkoxy, nitro, a SO2N (R2R3) group, in which each of RZ and R3 is independently hydrogen or C-C4 alkyl, and a N (R4Rs) group in which each of R4 and RS is independently hydrogen, Cl-C4 alkyl or SO2R6, in which R6 is Cl-C4 alkyl or phenyl, or R4and R5, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated Cs-C7 heterocyclic ring;

R is CCI3, CF3, a N (R7R8) group, in which each of R7 and R8 is independently hydrogen or C,-C4 alkyl or, R7 and R8, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring, or R is a phenyl or naphthyl ring wherein said heterocyclic, phenyl or naphthyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3, Cl-C4 alkyl, C,-C4 alkoxy, nitro, a SO2N(R2R3) group, in which each of R2 and R3 is as defined above, and a N (R4R5) group, in which each of R4 and R5 is as defined above; R, is hydrogen, CH2OPO3H2, a -(CH2)n-N(R9R10) group in which n is an integer of 2 to 4 and each of R9 and R, o is independently hydrogen, Cl-C4 alkyl or phenyl or R9 and Rlo, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring; or R, is a group of formula: wherein X, Y, R and p are as defined above; and the pharmaceutically acceptable salts thereof.

Examples of preferred compound of formula (I) are the following: 2- [N- (2,2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl- [ 1,3,4]thiadiazole; 2- [N- (2,2, 2-trichloroethyloxycarbonyl)-amino]-5-(4-fluorophenyl)-[1,3, 4]thiadiazole ; 2- [N- (2,2, 2-trichloroethyloxycarbonyl)-amino]-5-(3,4-difluorophenyl)-[ 1,3, 4] thiadiazole; 2- [N- (2,2,2-trichloroethyloxycarbonyl)-amino]-5- (3-pyridyl)- [ 1,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-pyridyl)- [1,3,4]thiadiazole; 2- [N- (2,2, 2-trichloroethyloxycarbonyl)-amino]-5-(2-pyridyl)-[1,3, 4] thiadiazole; 2- [N- (2,2, 2-trichloroethyloxycarbonyl)-amino]-5-(morpholin-1-yl)-[1,3, 4] thiadiazole; 2-[N- (2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-methyl-piperaz in-1-yl)- [1,3,4] thiadiazole; 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5- (pyrrolidin-1-yl)-[l, 3,4] thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-[4-(pyrrolid in-1-yl)-phenyl]- [1,3,4] thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-[4-(1,2,5,6- tetrahydro-pyridin-1-yl)- phenyl]- [1,3,4]thiadiazole; 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5- (4-sulfamoyl-phenyl)- [ 1,3,4] thiadiazole; 2- [N- (2,2,2-trichloroethyloxycarbonyl)-aminoj-5- (4-methanesulfonylamino-phenyl)- [1,3,4] thiadiazole; 2- [N- (2,2,2-trichloroethyloxycarbonyl)-amino]-5-(imidazol-1-ylmet hyl)- [1,3,4]thiadiazole; 2- [N- (2,2,2-trichloroethyloxyvarbonyl)-amino]-5-(imidazol-1-yl)- [1,3,4]thiadiazole; 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5- (3-aza-bicyclo [3.2.2] non-3-yl)- [1,3,4] thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(1H-imidazol -4-yl)-[1,3,4]thiadiazole; 2- [N-hydroxymethyl-N- (2,2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl- [1,3,4] thiadiazole, phosphate; 2-[N-(phenyloxycarbonyl)-amino]-5-phenyl-[1, 3,4] thiadiazole; 2-[N-(benzyloxycarbonyl)-amino]-5-phenyl-[1, 3,4] thiadiazole; 2- [N- (4-pyridyloxycarbonyl)-amino]-5-phenyl- [ 1,3,4]thiadiazole; 2- [N- (phenyloxythiocarbonyl)-aminol-5-phenyl- [ 1,3,4]thiadiazole; 2- [N- (benzyloxythlocarbonyl)-amino]-5-phenyl- [ 1,3,4]thiadiazole; 2-[N-(4-pyridyloxythiocarbonyl)-amino]-5-phenyl-[1,3,4]thiad iazole;

1-Phenyl-3-(5-phenyl-[1, 3,4] thiadiazol-2-yl)-urea; 2- [N, N-bis (2-naphthyloxythiocarbonyl)-amino]-5- (4-fluoro-phenyl)- [ 1,3,4] thiadiazole; 1-Phenyl-3-(5-pyridin-3-yl-[1, 3,4] thiadiazol-2-yl)-urea; 1-(5-Phenyl-[1, 3,4] thiadiazol-2-yl)-3- (2,2,2-trichloroethyl)-urea; 2- [N- (2,2,2-trifluoroethyloxycarbonyl)-amino]-5-phenyl-[1,3,4]thi adiazole; and the pharmaceutically acceptable salts thereof.

The compound of the present invention and the salts thereof can be obtained, for instance, by a process comprising: a) reacting a compound of formula (II) wherein Q and m are as defined above, with a compound of formula (ICI) wherein p, X, Y and R are as defined above and W is a leaving group thus obtaining a compound of formula (I) wherein Rl is either hydrogen or a group of formula wherein p, X, Y and R are as defined above ; or b) reacting a compound of formula (I) wherein m and Q are as defined above, with a compound of formula (IV) HY- (CH2)-R<BR> p (IV) wherein p, Y and R are as defined above, thus obtaining a compound of formula (I) wherein X is oxygen and R, is hydrogen; or c) reacting a compound of formula (V) wherein in and Q are as defined above, with a compound of formula (IV), wherein p, Y and R are as defined above, thus obtaining a compound of formula (I) wherein X is oxygen and Rl is hydrogen; or d) hydrogenolising a compound of formula (VI)

wherein m, Q, X, Y, p and R are as defined above thus obtaining a compound of formula R1isCH2OPO3H2;or(I),wherein e) reacting a compound of formula (I), wherein R, is hydrogen, with a compound of formula (VII) Z-(CH2)n-N(R9R10)(VII) wherein n, R9 and R, o are as defined above, and Z is a leaving group, thus obtaining a compound of formula (I) wherein R, is- (CH2),,-N (RgRio)-l 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 sin (Jle isomers.

The above process-variants a), b), c) d) and e) are analogy processes which can be carried out according to well known methods in the art.

The leaving W group is a common leaving group, typically Cl or OCCl3.

The rection between a compound of formula (II) and a compound of formula (III) can be carried out, for example, in the presence of a base such as triethylamine, potassium carbonate, in a suitable solvent such as dichloromethane, acetone, dioxane, acetonitrile, toluene, at a temperature ranging from about-20°C to reflux. As known in the art, different rection conditions lead to a compound of formula (I) in which R, is either hydrogen or a- CX-Y-(CH2) p-R(CH2) p-R group.

The rection between a compound of formula (I) as defined under process b) and a compound of formula (IV) can be carried out, for example, in a suitable solvent such as toluene or dichloromethane, at a temperature ranging from about-20°C to reflux.

The rection between a compound of formula (V) and a compound of formula (IV) can be carried out, for example, in a suitable solvent such as toluene. dichloromethane, chloroform, diethyl ether, at a temperature ranging from about-20°C to reflux.

The hydrogenolysis of a compound of formula (VI) can be carried out for example, in the presence of a catalytic amount of Pd/C (5 or 10%) and cyclohexene, 1,4-cyclohexadiene or formic acid, without a solvent or in an organic solvent, such as methanol, at a temperature ranging from about room temperature to reflux.

The leaving group Z is a common leaving group, typically halogen or a mesyl or tosyl group.

The rection between a compound of formula (I), wherein R, is hydrogen, and a compound of formula (VII) can be carried out, for example, in the presence of a base such as sodium hydride, potassium carbonate, potassium or sodium hydroxyde, in a suitable solvent such as N, N-dimethylformamide, tetrahydrofurane, dioxane, acetonitrile, toluene, at a temperature ranging from about-20°C to reflux.

Also the optional conversion of a compound of formula (I) into another compound of formula (I) can be carried out according to known methods; processes b) and e) are examples of such conversions. Moreover, 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 C2-C8 alkanoylamino group, for example by reacting with formic acid or with the suitable C2-Cs alkanoylanhydride without any solvent or in an organic solvent such as dioxane, N, N-dimethylformamide, tetrahydrofuran, usually in the presence of a base such as pyridine or triethylamine, at a temperature varying between 0°C and about 1 OO°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 intermediate compound of formula (II), (III), (IV), (V) and (VII) are known compound or can be obtained according to known methods. For example a compound of formula (II), wherein in is zero and Q is a heteromonocyclic or a heterobicyclic ring, linked to the [1. 3,4thiadiazole moiety through a nitrogen atom, can be obtained, for example. by reacting a compound of formula (VIII) with a heteromonocyclic or a heterobicyclic amine, in the presence of a base, such as potassium carbonate, triethylamine, sodium hydride, in a suitable solvent, such as ethanol, DMSO, tetrahydrofuran at a temperature varying between about 0°C and about 100°C.

A compound of formula (II), wherein in is zero or I and Q is phenyl, pyridyl, naphthyl, or imidazolyl can be obtained by a process comprising: f) reacting a compound of formula (IX) Q (CH2) m CH NNHCSNH2 (IX) with ferric chloride hexahydrate, in a suitable solvent, such as ethanol, water or methanol and their mixture, at a temperature ranging from about 0°C to about 100°C ; or g) cyclizing a compound of formula (X) Q-(CH2)m-CONHNHCSNH2(X) in the presence of an acid, such as sulphuric acid, poliphosphoric acid, methanesulphonic acid, without any solvent or in an organic solvent, such as toluene, at a temperature ranging from room temperature to about 150°C, or h) reacting a compound of formula (XI) <BR> <BR> <BR> Q- (CH2) m COOH (l)<BR> <BR> <BR> (XI) with thiosemicarbazide, in the presence of an acid, such as sulphuric acid, poliphosphoric acid, methanesulphonic acid, without any solvent, at a temperature ranging from room temperature to about 150°C.

A compound of formula (I) as defined in process b) can be obtained by reacting a compound of formula (II) with trichloromethyl carbonate or trichloromethylchloroformate, in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, toluene, at a temperature ranging from about -20°C to reflux.

A compound of formula (V) can be prepared by reacting a compound of formula (II) with trichloromethylcarbonate or trichloromethylchloroformate, in a suitable solvent, such as. dichloromethane, toluene, at a temperature ranging from about-20°C to reflux.

A compound of formula (VI) can be prepared, for example, by reacting a compound of formula(XII)

wherein Q, m, X, Y, p and R are as defined above, with sodium or silver dibenzylphosphate, in a suitable solvent, such as benzene or toluene, at a temperature ranging from room temperature to reflux.

A compound of formula (XII) can be prepared, for example, by reacting a compound of formula (XIII) wherein Q, m, X, Y, p and R are as defined above, with thionyl chloride or phosphorous trichloride, in a suitable solvent, such as dichloromethane, toluene, at a temperature ranging from about 0°C to reflux.

A compound of formula (XIII) can be obtained, for example, by reacting a compound of formula (I), wherein R, is hydrogen, with formaldehyde, in the presence of a base such as potassium or cesium carbonate, in a suitable solvent, such as tetrahydrofurane or water, at a temperature ranging from room temperature to reflux.

The compound of formula (VIII), (IX), (X) and (XI), are, in some cases, commercially available products, or may be prepared by methods well known in the art.

When in the compound of the invention and the intermediate products thereof, groups are present which may interfere with the hereabove illustrated rections, they may be protected before the rections take place and then deprotected at the end of the rections, according to well known methods in organic chemistry.

Pharmacology The compound of the invention are active as kynurenine-3-hydroxylase enzyme inhibitors and therefore are useful in the prevention and/or treatment of neuropathological processes, related to a deranged production of QUIN and/or 3-OH-KYN due to excessive activation of neurotransmission 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-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 compound of the invention in the inhibition of the enzyme kynurenine-3-hydroxylase was evaluated e. g., in rat liver mitochondrial extract following the method reporte 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 rection. Radiolabeled water was quantifie 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 rection mixture of a total volume of 30 tl was constituted of 44 zig of suspende extract, 100 mM Tris/Cl-buffer pH 8.1,10 mM EDTA, 100 mM KCl, 0.8 mM NADPH, 0.025 mM L-Kynurenine, 0.3 µCi L-(3,5-3H) Kynurenine (10 Ci/mmol) and 3 tl of different concentration of inhibitor solutions. After the incubation, the rection was terminated by the addition of 300 il of 7.5 (W/v) activated charcoal, and centrifuged for 7 min..

A 75 il aliquot of supernatant was transferred to optiplate and 200 1ll of liquid scintillation added. The optiplates were vortexed and the radioactivity counted in a scintillation conter.

The obtained results, which have been reporte in the following Table 1, demonstrate the efficacy of a representative compound of the invention 2- [N- (2,2,2- trichloroethyloxycarbonyl)-amino]-5-phenyl- [1,3,4] thiadiazole (internal code PNU- 153833).

Table 1 KYN-3-OH inhibition Compound IC ; o PNU-153833 0.8 zip 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 153833 may range from about 10 to about 500 mg pro dose, from I to 5 times daily.

The compound of the invention can be administered in a variety of dosage forms, e. g. orally, in the form of tables, capsules, sugar or film coated tables, 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 inclues 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 compound 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, mulsions 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 mulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcool.

The suspension or solutions for intramuscolar injections may contais 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-amino-5-phen [1. 3y41thiadiazole.

To a suspension of benzoic acid (10.0 g; 82 mmol) in 96% sulphuric acid (25 ml) cooled at about 0°C, thiosemicarbazide (7.4 g; 82 mmol) was added under stirring and insert atmosphere. The rection mixture was then kept under stirring for 8h at about 100°C. After cooling the suspension thus obtained was diluted with ice water and then basified to pH 10 with 30% ammonia solution. The solid isolated by filtration was washed with water until neutral and air-dried to give the title compound as a ligth yellow solid (6 g, 43%): m. p. 216- 218°C.

Analogously, the following products can be prepared: 2-amino-5- (4-fluorophenyl)- [1,3,4] thiadiazole: m. p. 229-231°C; 2-amino-5-(1H-imidazol-4-yl)-[1, 3,4] thiadiazole; and 2-amino-5- (3, 4-difluorophenyl)- [1,3,4] thiadiazole: m. p. 167-170°C; Example 2 Preparation of 2-amino-5-(4-pyridyl)-[1,3,4]thiadiazole, Ferric chloride hexahydrate (4.5 g; 17 mmol) was added under stirring to a suspension of pyridine-4-carboxaldehyde-thiosemicarbazone (1.0 g; 5 mmol) in ethanol (75 ml) at room temperature. The rection mixture was refluxed for 6h. The solvent was evaporated under reduced pressure, the residue was dissolve in concentrated HCI (20 ml) and water was

added (80 ml); the mixture was then filtered through a Celite pad and the filtrate was basified to pH 10 with 30% ammonia solution. The solid isolated by filtration was washed with water and air-dried to give the title compound as a yellow solid (0. 55g; 55%): m. p.

236-238°C.

Analogously, the following products can be prepared: 2-amino-5- (3-pyridyl)- [1,3,4]thiadiazole; 2-amino-5-(2-pyridyl)-[1, 3,4] thiadiazole: m. p. 216-221°C ; 2-amino-5- (4-methanesulfonylamino)- [1,3,4]thiadiazole; 2-amino-5- [4- (pirrolidin-1-yl)-phenyl]- [1,3,4thiadiazole: m. p. >250°C ; 2-amino-5-[4-(1, 2,5,6-tetrahydro-pyridin-1-yl)-phenyl]- [1,3,4] thiadiazole; 2-amino-5-[4-methanesulfonylamino-phenyl]- [1,3,4] thiadiazole; and 2-amino-5-(imidazol-1-ylmethyl)- [1,(imidazol-1-ylmethyl)- [1, 3,4] thiadiazole; Example 3 Preparation of 2-amino-5-(3-azabicyclo[3.2.2]non-3-yl)-[1,3,4]thiadiazole.

3-azabicyclo [3.2.2] nonane (5.5 g; 44 mmol) and triethylamine (5.62 g 44 mmol) were added to a suspension of 2-amino-5-bromo- [1,3, 4]thiadiazole (9.0 g; 40 mmol) in absolut ethanol (150 ml), under magnetic stirring at room temperature. The rection mixture was refluxed for about 6h, concentrated to a small volume (50 ml) and filtered; the residue was washed with ethanol, ice-cooled water (2X5 ml), suspende in 1N NaOH (31 ml) while cooling and neutralized to pH 7 with IN HCI. The resulting solid was filtered, washed with water and dried in vacuo at 80°C to yield the title compound as a beige solid (5.0 g; 47%): m. p. 204-206°C Analogously, the following products can be prepared: 2-amino-5-(4-methyl-piperidin-1-yl)-[1, 3,4] thiadiazole; 2-amino-5-(morpholi-1-yl)-[1, 3,4] thiadiazole; and 2-amino-5-(pirrolidin-1-yl)-[1, 3,4] thiadiazole.

Example 4 2-amino-5-(imidazol-1-yl)-[1,3,4]thiadiazole.Preparationof Sodium hydride (0.16 g, 50% w/w disperse in oil, 3.33 mmol) was added portionwise to a suspension of imidazole (0.21 g, 3.06 mmol) in dry dimethylformamide (5 ml) maintained under magnetic stirring at 5°C. After stirring at room temperature for about lh, a solution of 2-amino-5-bromo-[1, 3, 4] thiadiazole (0.5 g; 2.78 mmol) in DMF (10 ml) was added dropwise. The rection mixture was heated at 80°C for about 4 hours, cooled at 5°C and poured into ice/water (30 ml); the resulting. solid was filtered, washed with water and dried in vacuum to yield the title compound which was used without any further purification.

(0.2 g, 43%) Example 5 Preparation2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-p henyl-[1,3,4]thiadiazole, To a suspension of 2-amino-5-phenyl- [1,3,4] thiadiazole (6.0 g, 34 mmol) in acetone (200 ml), maintained under magnetic stirring and inert atmosphere, triethylamine (5.65 ml, 44 mmol) and 2,2,2-trichloroethylchloroformate (5. 59ml, 41 mmol) were added, while cooling at about -5°C. The rection mixture was allowed to warm to room temperature and stirring

was continue for about 6h. After filtering, acetone was removed under vacuum and the residue was chromatographed on silica gel, using cyclohexane/ethyl acetate 80/20 as eluent. The title compound was obtained, after crystallization from ethanol, as a colorless solid (5.0 g, 47%), m. p. 245-246°C.

N. M. R. (DMSO-d6) # ppm : 13 (s, broad, IH, NHCOO); 7.85-7.45 (m, 5H, Ph); 5. 07 (s, 2H, CH2CCl3).

Analogously, the following products can be prepared: 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5- (4-fluorophenyl)- [1,3,4] thiadiazole: m. p.

>230°C; 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5- (3, 4-difluorophenyl)- [ 1,3,4] thiadiazole: 296-298°C; 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5- (3-pyridyl)- [ 1,3,4] thiadiazole: 250-260°C; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-pyridyl)- [1,3,4]thiadiazole: 294-297°C; 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5- (2-pyridyl)- [ 1,3,4] thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(morpholin-1 -yl)-[1,3, 4] thiadiazole: 206-209°C; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-methyl-pi perazin-1-yl)- [1,3,4] thiadiazole: 195-200°C; 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5- (pyrrolidin-1-yl)- [1,3.4] thiadiazole: 239-242°C; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-[4-(pyrrolid in-1-yl)-phenyl]- [1,3,4thiadiazole; 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5- [4- ( I, 2,5,6-tetrahydro-pyridin-1-yl)- phenyl]- [1,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-sulfamoyl -phenyl)-[1,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-methanesu lfonylamino-phenyl)- [1,3,4] thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(imidazol-1- ylmethyl)-[1,3,4]thiadiazole; 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5- (imidazol- I-yl)- [1,3,4] thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(3-aza-bicyc lo[3.2.2]non-3-yl)- [1,3,4] thiadiazole; and 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(1H-imidazol -4-yl)-[1,3,4]thiadiazole.

Example 6 2-[N-(phenyloxycarbonyl)-amino]-5-phenyl-[1,3,4]thiadiazole. Preparationof To a suspension of 0.5 g (2.8 mmol) of 2-amino-5-phenyl- [1,3,4] thiadiazole in 50 ml of dichloromethane was added 0.6 ml (4.3 mmol) of triethylamine. To this mixture was added a solution of 0.46 ml (3.6 mmol) of phenyl chloroformate in 7 ml of dichloromethane dropwise while the temperature was mantained at -10°C. After the addition the rection mixture was stirred at -10°C for 2 h. The dichloromethane solution so obtained was washed with 50 ml of 0.5 N HCI, 50 ml of NaHC03 aq., 50 ml of brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure in a rotary evaporator and the residue was purifie by flash chromatography on silica gel using

cyclohexane/ethyl acetate 40~60 as eluent to give 0.55 g (66%) of the title compound: m. p.

218°C(dec.).

N. M. R. (DMSO) 6 ppm: 12.9 (s, 1H, NHCO); 7.2-8.0 (m, l OH, aromatic protons).

By proceeding analogously, using the suitable chloroformates or chlorothionoformate, the following products can be prepared: 2- [N- (benzyloxycarbonyl)-amino]-5-phenyl- [1,3,4] thiadiazole: m. p. 210-214°C; 2-[N-(phenyloxythiocarbonyl)-amino]-5-phenyl-[1, 3,4] thiadiazole; 2-[N-(1,1,1-trichloromethyloxycarbonyl)-amino]-5-phenyl-[1, 3,4] thiadiazole; 2- [N- (benzyloxythiocarbonyl)-amino]-5-phenyl- [ 1,3,4]thiadiazole; 2- [N- (4-pyridyloxythiocarbonyl)-amino]-5-phenyl- [1,3,4] thiadiazole; and 2-[N,N-bis(2-naphthyloxythiocarbonyl)-amino]-5-(4-fluorophen yl)-[1,3,4]thiadiazole.

Example 7 Preparation of 1-(5-phenyl-[1,3, 4] thiadiazol-2-yl)-3- (2, 2, 2-trichloroethyl)-urea.

A mixture of 2- [N- (1, 1, 1-trichloromethyloxycarbonyl)-amino]-5-phenyl- [1,3,4] thiadiazole (2.5 g, 7.4 mmoles) and 2,2,2-trichloro-ethylamine (1.43 g, 9.6 mmoles) in dry dichloromethane (50 ml) was stirred at room temperature for 1 h, washed with water, dried over sodium sulfate and then concentrated. The residue was slurried with methanol, filtered and dried in vacuum at 45°C to give 1.0 g (40 %) of the title compound.

By proceeding analogously, using the suitable amines or alcools, the following products can be prepared: 1-phenyl-3-(5-pyridin-3-yl-[1,3, 4] thiadiazol-2-yl)-urea; 2-[N-(2,2,2-trifluoroethyloxycarbonyl)-amino]-5-phenyl-[1,3, 4]thiadiazole; 1-phenyl-3-(5-phenyl-[1, 3,4] thiadiazol-2-yl)-urea; and 2- [N- (4-pyridyloxycarbonyl)-amino]-5-phenyl- [1,3,4]thiadiazole.

Example 8 Preparation of 2-[N-hydroxymethyl-N-(2,2,2-trichloroethyloxycarbonyl)-amino ]-5-phenyl- 1 3. 41thiadiazole.

A suspension of 1.0 g of 2-[N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl- [1,3,4] thiadiazole (2.8 mmol), 4.3 ml of formalin (60 mmol, 37% formaldehyde in water), 0.034 g of potassium carbonate (0. 252 mmol) in water (25 ml), was stirred at room temperature for about 1 h and at reflux for about 8 h. The mixture was filtered and the resulting solid was washed with 3% aqueous formaldehyde, air dried for about 24 h to give 0.7 g (65%) of the title compound which was used in the next step without any further purification.

Example 9 Preparation of 2- [N-chloromethl-N- (2, 2 2-trichloroethyloxvcarbonvll-aminol-5-phenyl- 1. 3. 4) thiadiazole.

A solution of 2-[N-hydroxymethyl-N-(2, 2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl- [1,3,4] thiadiazole (0.7 g, 1.82 mmol) and 0.16 ml of phosphorous trichloride in 5 ml of dichloromethane was stirred at room temperature for 24 h, diluted with a further 3 mi of dichloromethane and extracted once with water (5 ml) and with 5% w/v aqueous sodium carbonate solution (2X15 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under vacuum to give 0.44 g (60%) of the title compound which was used in the next step without any further purification.

Example 10 Preparation of 2-[N-hydroxymethyl-N-(2,2,2-trichloroethyloxycarbonyl)-amino ]-5-phenyl- [1. 3, 41tniadiazole dibenzvl phoshate ester.

A suspension of silver dibenzyl phosphate (0.43 g, 1.12 mmol) and 2- [N-chloromethyl-N- (2,2, 2-trichloroethyloxycarbonyl)-amino]-5-phenyl-[1, 3,4] thiadiazole (0.44 g, 1.09 mmol) in toluene (10 ml) was refluxed for about 2 h, hot filtered under reduced pressure, extracted with 5% aqueous potassium carbonate solution (8 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue (0.35 g) was used in the next step without any further purification.

Example I I Preparation of 2-[N-hydroxymethyl-N-(2,2,2-trichloroethyloxycarbonyl)-amino ]-5-phenyl- [1,3,4]thiadiazolehosphate A mixture of 2- [N-hydroxymethyl-N- (2,2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl- [1,3,4] thiadiazole dibenzyl phosphate ester (0.35 g, 0.55 mmol), 10% Pd/C (0.17 mg), cyclohexene (8 ml) and ethanol (16 ml) was refluxed with stirring for about 2.5 h, filtered and the filtrate was evaporated under reduced pressure. The residue was slurried with ethanol, filtered and dried in vacuum at 40°C to give the title compound as a colorless solid (0.16 g, 65%).

Example 12 Capsule, each weighing 0.23 g and containing 50 mg of the active substance can be prepared as follows: Composition for 500 capsules: 2- [N- (2,2, 2-trichloroethyloxycarbonyl)-amino]-5-phenyl-[1,3,4] thiadiazole 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 13 Intramuscular injection of 50 mg/ml A pharmaceutical injectable composition can be manifactured dissolving 50 g 2- [N- (2,2,2- trichloroethyloxycarbonyl)-amino]-5-phenyl- [1,3,4] thiadiazole in sterile propyleneglycol (1000 ml) and sealed in 1-5 ml ampoules.

Legend to Figure 1 IDO = Indolamineoxygenase 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-OHKYN = 3-Hydroxy-kynurenine