WO1999028309A1

WO1999028309A1 - 1,3,4-thiadiazoles derivatives as kyn-oh inhibitors

Info

Publication number: WO1999028309A1
Application number: PCT/EP1998/006995
Authority: WO
Inventors: Paolo Pevarello; Raffaella Amici; Manuela Villa; Salvatore Toma; Mario Varasi
Original assignee: Pharmacia & Upjohn S.P.A.
Priority date: 1997-11-26
Filing date: 1998-10-27
Publication date: 1999-06-10
Also published as: GB9725055D0; JP2001524547A; AU1487599A; EP1054876A1; CA2310008A1

Abstract

Compounds of formula (I) wherein m is zero or 1; Q represents a C6-C14 aromatic ring system or an optionally substituted, saturated or unsaturated, heteromonocyclic or heterobicyclic ring containing one or two heteroatoms chosen from oxygen, sulfur and nitrogen X is oxygen or sulfur; Y is oxygen, sulfur or NH; p is 0 or 1; R is CC13, CF3, a N(R7R8) group, in which each of R7 and R8 is independently hydrogen or C1-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 an optionally substituted phenyl or naphthyl ring; R1 is hydrogen, CH2OPO3H2, a -(CH2)n-N(R9R10) group in which n is an integer of 1 to 4 and each of R9 and R10 is independently hydrogen, C1-C6 alkyl or phenyl, or R9 and R10, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C5-C7 heterocyclic ring; or R1 is a group of formula (A) wherein X, Y, p and R are independently as defined above; and the pharmaticeutically acceptable salts thereof have kynurenine-3-hydroxylase enzyme inhibitory activity.

Description

1,3,4-THIADIAZOLES DERIVATIVES AS KYN-OH INHIBITORS

The present invention relates to novel 1,3,4-thiadiazoles 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-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 compounds able of inhibiting this enzyme. The compounds of the present invention fulfill such a need. Accordingly, the present invention provides the use of a 1 ,3,4-thiadiazole compound of formula (I)

(I) wherein m is zero or 1 ; Q represents a C₆-C₎₄ aromatic ring system or a saturated or unsaturated heteromonocychc 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_rC₆ alkyl, hydroxy, C,-C₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a SO₂N(R₂R₃) group, in which each of R₂ and R₃ is independently hydrogen, C,-C₆ alkyl or phenyl, and a

N(R₄R₅) group, in which each of R₄ and R₅ is independently hydrogen, C|-C₆ alkyl or SO₂R₆, in which R^ is C,-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; p is 0 or 1 ;

R is CC1₃, CF₃, a N(R₇R_g) group, in which each of R₇ and R₈ is independently hydrogen or C 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, C C₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a S0₂N(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;

Ri is hydrogen, CH₂OPO₃H , a -(CH₂)_n-N(R₉R₁₀) group in which n is an integer of 1 to 4 and each of R₉ and R₁₀ is independently hydrogen, C C₆ alkyl or phenyl, or R₉ and R₁₀, 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:

Λ ^2^R 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),

X

(I) wherein m is zero or 1 ;

Q represents a C₆-C₁₄ aromatic ring system or a saturated or unsaturated heteromonocychc 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_rC₆ alkyl, hydroxy, C,-C₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a S0₂N(R₂R₃) group, in which each of R₂ and R₃ is independently hydrogen, C_rC₆ alkyl or phenyl, and a N(R₄R₅) group, in which each of R₄ and R₅ is independently hydrogen, C C₆ alkyl or SO₂R₆, in which R₆ is C_rC₆ 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; p is 0 or 1 ;

R is CC1₃, CF₃, a N(R₇R₈) group, in which each of R₇ and R₈ is independently hydrogen or C,-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_rC₆ alkyl, hydroxy, C,-C₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a S0₂N(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(R₉Rι₀) group in which n is an integer of 1 to 4 and each of R₉ and R₁₀ is independently hydrogen, C_rC₆ alkyl or phenyl, or R₉ and R₁₀, 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:

Λ_γ^ ^R 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 (I)

^X (I) wherein m is zero or 1 ;

Q represents a C₆-C₁₄ 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, C_rC₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a S0₂N(R₂R₃) group, in which each of R₂ and R₃ is independently hydrogen, C,-C₆ alkyl or phenyl, and a N(R R₅) group, in which each of R and R₅ is independently hydrogen,

C,-C₆ alkyl or SO R₆, in which R₆ is C_rC₆ 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; p is 0 or 1 ;

R is CC1₃, CF₃, a N(R₇R₈) group, in which each of R₇ and R₈ is independently hydrogen or C_rC₆ 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, C,-C₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a S0₂N(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 1 to 4 and each of R₉ and R₁₀ is independently hydrogen, C,-C₆ alkyl or phenyl, or R₉ and R₁₀, 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.

Object of the present invention is also to provide a new 1 ,3,4-thiadiazole compound of formula (I)

X

(I) wherein m is zero or 1 ;

Q represents a C₆-C₁₄ aromatic ring system or a saturated or unsaturated heteromonocychc 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_rC₆ alkyl, hydroxy, C,-C₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a SO₂N(R₂R₃) group, in which each of R₂ and R₃ is independently hydrogen, C_rC₆ alkyl or phenyl, and a N(R₄R₅) group, in which each of R₄ and R₅ is independently hydrogen, C_rC₆ alkyl or SO₂R₆, in which R₆ is C,-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; p is 0 or 1;

R is CC1₃, CF₃, a N(R₇R_g) group, in which each of R₇ and R₈ is independently hydrogen or C,-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_rC₆ alkyl, hydroxy, C_rC₆ 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(R₉Rι₀) group in which n is an integer of 1 to 4 and each of Re, and R₁₀ is independently hydrogen, C_rC₆ alkyl or phenyl, or R₉ and R₁₀, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C -C₇ heterocyclic ring; or R_! is a group of formula:

Λ_γΛl2^R 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 compounds of the invention.

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

Representative examples of C_|-C₆ alkyl groups include C,-C₄ alkyl groups such as methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl.

Representative examples of C_rC₆ alkoxy groups include C,-C₄ alkoxy groups such as methoxy or ethoxy.

Representative examples of C₂-C₈ alkanoylamino include C₂-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-C₁₄ aromatic ring system, it is preferably phenyl or naphthyl; when Q is a saturated or unsaturated heteromonocychc 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 [l,3,4]thiadiazole(alkyl) moiety through either a carbon or a nitrogen atom, as known in the art.

When R₄ and R₅ or R₇ and R₈ or Re, and R_i0, respectively, taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C₅-C₇ 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 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-phenethyiamine, N-benzyl-β- 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 compounds 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, C,-C alkyl, C,-C₄ alkoxy, nitro, a SO₂N(R₂R₃) group, in which each of R₂ and R₃ is independently hydrogen or C,-C₄ alkyl, and a N(R₄R₅) group in which each of R₄ and R₅ is independently hydrogen, C,-C alkyl or SO₂R₆, in which R₆ is C_rC 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; R is CC1₃, CF₃, a N(R₇R₈) group, in which each of R₇ and R₈ is independently hydrogen or C_rC₄ 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, C_rC₄ alkyl, C_rC₄ alkoxy, nitro, a SO₂N(R₂R₃) group, in which each of R₂ and R₃ is as defined above, and a N(R R₅) group, in which each of R₄ and R₅ is as defined above;

R, is hydrogen, CH₂OPO₃H₂, a -(CH₂)_n-N(R₉R,₀) group in which n is an integer of 2 to 4 and each of R₉ and R₁₀ is independently hydrogen, C,-C₄ alkyl or phenyl or R₉ and R₁₀, 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 compounds of formula (I) are the following: 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 4-fluorophenyl)-[l ,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5-ι 3,4-difluorophenyl)-[ 1 ,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5- 3-pyridyl)-[l ,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5- 4-pyridyl)-[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5- 2-pyridyl)-[l ,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5- mo holin-l-yl)-[l ,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5- 4-methyl-piperazin-l -yl)-

[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5-_' pyrrolidin- 1 -yl)-[ 1 ,3 ,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5- 4-(pyrrolidin- 1 -yl)-phenyl]-

[l ,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 -amino]-5- 4-methanesulfonylamino-phenyl)-

[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5- imidazol-l-ylmethyl)-[l ,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl ^■amino]-5- imidazol-l-yl)-[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 3-aza-bicyclo[3.2.2]non-3-yl)-

[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(lH-imidazol-4-yl)-[l ,3,4]thiadiazole;

2-[N-hydroxymethyl-N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl-

[l,3,4]thiadiazole, phosphate;

2-[N-(phenyloxycarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole;

2-[N-(benzyloxycarbonyl)-amino]-5-phenyl-[l ,3,4]thiadiazole;

2-[N-(4-pyridyloxycarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole;

2-[N-(phenyloxythiocarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole;

2-[N-(benzyloxythiocarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole;

2-[N-(4-pyridyloxythiocarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole; l-Phenyl-3-(5-phenyl-[l,3,4]thiadiazol-2-yl)-urea;

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

The compounds 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 (III)

wherein p, X, Y and R are as defined above and W is a leaving group thus obtaining a compound of formula (I) wherein R_\ is either hydrogen or a group of formula

_Ύ ^R 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

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 m 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

Ri is hydrogen; or d) hydrogenolising a compound of formula (VI)

(VI) wherein m, Q, X, Y, p and R are as defined above thus obtaining a compound of formula

(I), wherein R, is CH₂OPO₃H₂; or e) reacting a compound of formula (I), wherein Rj is hydrogen, with a compound of formula (VII)

wherein n, R₉ and R₁₀ are as defined above, and Z is a leaving group, thus obtaining a compound of formula (I) wherein Rj is -(CH₂)_n-N(R₉R₁₀); 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), 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 OCCl

The reaction between a compound of formula (II) and a compound of formula (III) can be carried out, for example, in the presence of a base such as triethylamine, 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 reaction conditions lead to a compound of formula (I) in which R, is either hydrogen or a - CX-Y-(CH₂)_p-R group.

The reaction 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 reaction 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 reaction 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-C₈ 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 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 intermediate compounds of formula (II), (III), (IV), (V) and (VII) are known compounds or can be obtained according to known methods. For example a compound of formula (II), wherein m is zero and Q is a heteromonocychc or a heterobicyclic ring, linked to the [1.3,4]thiadiazole moiety through a nitrogen atom, can be obtained, for example, by reacting a compound of formula (VIII)

with a heteromonocychc 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 m is zero or 1 and Q is phenyl, pyridyl, naphthyl, or imidazolyl can be obtained by a process comprising: f) reacting a compound of formula (IX)

Q-(CH₂) — CH = NNHCSNH₂ ^m (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)—CONHNHCSNH, ^m (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)

Q-(CH₂) — COOH

^{2 m} (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)

(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)

^X (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 compounds 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 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 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 -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 30 μl was constituted of 44 μg of suspended extract, 100 mM Tris /Cl^" buffer pH 8.1, 10 mM EDTA, 100 mM KC1, 0.8 mM NADPH, 0.025 mM L-Kynurenine, 0.3 μCi L-(3,5-³H)Kynurenine (10 Ci/mmol) and 3 μl of different concentration of inhibitor solutions. After the incubation, the reaction was terminated by the addition of 300 μl of 7.5 (W/v) activated charcoal, and centrifuged for 7 min..

A 75 μl aliquot of supernatant was transferred to optiplate and 200 μl of liquid scintillation added. The optiplates were vortexed and the radioactivity counted in a scintillation counter. The obtained results, which have been reported in the following Table 1 , demonstrate the efficacy of a representative compound of the invention 2-[N-(2,2,2- trichloroethyloxycarbonyl)-amino]-5-phenyl-[l ,3,4]thiadiazole(internal code PNU- 153833).

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 153833 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 2-amino-5-phenyl-[1.3,4]thiadiazole.

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 inert atmosphere. The reaction 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)-[l,3,4]thiadiazole: m.p. 229-231°C; 2-amino-5-(lH-imidazol-4-yl)-[l,3,4]thiadiazole; and 2-amino-5-(3,4-difluorophenyl)-[l,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 reaction mixture was refluxed for 6h. The solvent was evaporated under reduced pressure, the residue was dissolved in concentrated HC1 (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)-[l,3,4]thiadiazole; 2-amino-5-(2-pyridyl)-[l,3,4]thiadiazole: m.p. 216-221 °C; 2-amino-5-(4-methanesulfonylamino)-[l ,3,4]thiadiazole; 2-amino-5-[4-(pirrolidin-l-yl)-phenyl]-[l ,3,4]thiadiazole: m.p. >250°C; 2-amino-5-[4-(l ,2,5,6-tetrahydro-pyridin-l-yl)-phenyl]-[l,3,4]thiadiazole; 2-amino-5-[4-methanesulfonylamino-phenyl]-[l ,3,4]thiadiazole; and 2-amino-5-(imidazol-l-ylmethyl)-[l,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-[l ,3,4]thiadiazole (9.0 g; 40 mmol) in absolute ethanol (150 ml), under magnetic stirring at room temperature. The reaction 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), suspended in IN NaOH (31 ml) while cooling and neutralized to pH 7 with IN HC1. 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-(morpholin-l-yl)-[l,3,4]thiadiazole; and 2-amino-5-(pirrolidin-l-yl)-[l ,3,4]thiadiazole.

Example 4

Preparation of 2-amino-5-(imidazol-l-yl)-[l ,3.4]thiadiazole.

Sodium hydride (0.16 g, 50% w/w dispersed 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-[l,3,4]thiadiazole (0.5 g; 2.78 mmol) in DMF (10 ml) was added dropwise. The reaction 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

Preparation 2-[N-(2.2.2-trichloroethyloxycarbonyl)-amino]-5-phenyl-[1.3.4]thiadiazole. To a suspension of 2-amino-5-phenyl-[l ,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 reaction mixture was allowed to warm to room temperature and stirring was continued 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) δ ppm: 13 (s, broad, IH, NHCOO); 7.85-7.45 (m. 5H, Ph); 5.07 (s, 2H, CH₂CC1₃).

Analogously, the following products can be prepared

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 4-fluorophenyl)-[l,3,4]thiadiazole: m.p.

>230°C;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 3,4-difluorophenyl)-[l,3,4]thiadiazole:

296-298°C;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 3-pyridyl)-[l,3,4]thiadiazole:

250-260°C;

2-[N-(2,2,2-trichloroethyloxycarbonyl •amino]-5 4-pyridyl)-[l ,3,4]thiadiazole:

294-297°C;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]- 2-pyridyl)-[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]- morpholin-1 -yl)-[l ,3.4]thiadiazole:

206-209°C;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 4-methyl-piperazin- 1 -yl)-

[l,3,4]thiadiazole: 195-200°C;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 pyrrolidin-l-yl)-[l,3.4]thiadiazole:

239-242°C;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 4-(pyrrolidin- 1 -yl)-phenyl]-

[l ,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 4-( 1 ,2,5,6-tetrahydro-pyridin- 1 -yl)- phenyl]-[l ,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-methanesulfonylamino-phenyl)-

[l ,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 imidazol-l-ylmethyl)-[l ,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 imidazol-l-yl)-[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl -amino]-5 3-aza-bicyclo[3.2.2]non-3-yl)-

[l,3,4]thiadiazole; and 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(lH-imidazol-4-yl)-[l,3,4]thiadiazole.

Example 6

Preparation of 2-[N-(phenyloxycarbonyl)-amino]-5-phenyl-[1.3.4]thiadiazole.

To a suspension of 0.5 g (2.8 mmol) of 2-amino-5-phenyl-[l,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 chloro formate in 7 ml of dichloromethane dropwise while the temperature was mantained at -10°C. After the addition the reaction mixture was stirred at -10°C for 2 h. The dichloromethane solution so obtained was washed with 50 ml of 0.5 N HC1, 50 ml of NaHCO₃ 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 purified 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) δ ppm: 12.9 (s, IH, NHCO); 7.2-8.0 (m, 10H, aromatic protons).

By proceeding analogously, using the suitable chloroformates or chlorothionoformate, the following products can be prepared:

2-[N-(benzyloxycarbonyl)-amino]-5-phenyl-[l ,3,4]thiadiazole: m.p. 210-214°C; 2-[N-(phenyloxythiocarbonyl)-amino]-5-phenyl-[l ,3,4]thiadiazole; 2-[N-( 1,1,1 -trichloromethyloxycarbonyl)-amino]-5-phenyl-[ 1 ,3,4]thiadiazole; 2-[N-(benzyloxythiocarbonyl)-amino]-5-phenyl-[l ,3,4]thiadiazole;

2-[N-(4-pyridyloxythiocarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole; and 2-[N,N-bis(2-naphthyloxythiocarbonyl)-amino]-5-(4-fluorophenyl)-[l,3,4]thiadiazole.

Example 7 Preparation of l -(5-phenyl-[1.3.4]thiadiazol-2-yl -3-(2.2.2-trichloroethyl)-urea.

A mixture of 2-[N-(l ,l ,l-trichloromethyloxycarbonyl)-amino]-5-phenyl-[l ,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 alcohols, the following products can be prepared: l-phenyl-3-(5-pyridin-3-yl-[l,3,4]thiadiazol-2-yl)-urea; 2-[N-(2,2,2-trifluoroethyloxycarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole; l-phenyl-3-(5-phenyl-[l,3,4]thiadiazol-2-yl)-urea; and

2-[N-(4-pyridyloxycarbonyl)-amino]-5-phenyl-[l ,3,4]thiadiazole.

Example 8

Preparation of 2-[N-hydroxymethyl N-(2.2.2-trichloroethyloxycarbonyl)-amino]-5-phenyl- [1.3.4]thiadiazole.

A suspension of 1.0 g of 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl- [l ,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-chloromethyl-N-(2.2.2-trichloroethyloxycarbonyπ-amino]-5-phenyl- [1.3.4]thiadiazole.

A solution of 2-[N-hydroxymethyl-N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl- [l ,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 ml 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- [1.3.4]thiadiazole dibenzyl phosphate 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-[l ,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 1 1

Preparation of 2-[N-hydroxymethyl-N-(2.2.2-trichloroethyloxycarbonyπ-amino]-5-phenyl-

[1.3.4]thiadiazole phosphate

A mixture of 2-[N-hydroxymethyl-N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl-

[l,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-[l,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

Claims

The use of a compound which is a 1,3,4-thiadiazole of formula (I)

X

(I) wherein m is zero or 1 ;

Q represents a C₆-C₁₄ aromatic ring system or a saturated or unsaturated heteromonocychc 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, C_rC₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C -C₈ alkanoyloxy, a SO₂N(R₂R₃) group, in which each of R₂ and R₃ is independently hydrogen, C C₆ alkyl or phenyl, and a N(R₄R₅) group, in which each of R₄ and R₅ is independently hydrogen, C,-C₆ alkyl or SO₂R₆, in which R₆ is C_rC₆ 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; p is O or 1 ;

R is CC1₃, CF₃, a N(R₇R₈) group, in which each of R₇ and R₈ is independently hydrogen or C,-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, CF , C_rC₆ alkyl, hydroxy, C,-C₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a S0₂N(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 1 to 4 and each of R₉ and R₁₀ is independently hydrogen, C_rC₆ alkyl or phenyl, or Rg and R₁₀, 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: _╬│╬¢ ^R 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 a kynurenine-3-hydroxylase enzyme inhibitor.

2. Use according to claim 1 wherein the medicament is for use in the prevention and/or treatment of a neurodegenerative pathology.

3. Use according to claim 2 wherein the neurodegenerative pathology is selected from Huntington's chorea, Alzheimer's disease, Parkinson's disease, olivoponto cerebellar atrophy, non- Alzheimer's dementia, multi-infarctual dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia, cerebral hypoxia, spinal or head trauma and epilepsy.

4. A compound which is a 1 ,3,4-thiadiazole of formula (I),

X

(I) wherein m is zero or 1 ;

Q represents a C₆-C,₄ aromatic ring system or a saturated or unsaturated heteromonocychc 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_rC₆ alkyl, hydroxy, C_rC₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a S0₂N(R₂R₃) group, in which each of R₂ and R₃ is independently hydrogen, C_rC₆ alkyl or phenyl, and a N(R₄R₅) group, in which each of R₄ and R₅ is independently hydrogen, C,-C₆ alkyl or SO₂R₆, in which R₆ is C_rC₆ 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; p is 0 or 1 ;

R is CC1₃, CF₃, a N(R₇R₈) group, in which each of R₇ and R₈ is independently hydrogen or C|-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_rC₆ alkyl, hydroxy, C_rC₆ 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 1 to 4 and each of R₉ and R₁₀ is independently hydrogen, C_rC₆ alkyl or phenyl, or R₉ and R_l0, 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:

╬¢_╬│╬¢%-^R wherein

X, Y, p and R are independently as defined above, or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance.

5. A compound as claimed in claim 4 for use as a kynurenine-3 -hydroxy lase enzyme inhibitor.

6. 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 which is a 1,3,4-thiadiazole of formula (I)

(I)

wherein m is zero or 1 ; Q represents a C₆-C₁₄ aromatic ring system or a saturated or unsaturated heteromonocychc 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_rC₆ alkyl, hydroxy, C,-C₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a SO₂N(R₂R₃) group, in which each of R₂ and R₃ is independently hydrogen, C,-C₆ alkyl or phenyl, and a N(R₄R₅) group, in which each of R₄ and R₅ is independently hydrogen, C C₆ alkyl or SO₂R₆, in which R^ is C,-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 NFI; p is 0 or 1 ;

R is CC1₃, CF₃, a N(R₇R₈) group, in which each of R₇ and R₈ is independently hydrogen or

C_rC₆ 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_rC₆ alkyl, hydroxy, C,-C₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a SO₂N(R R₃) group, in which each of R₂ and R₃ is as defined above, and a N(R₄R₅) group, in which each of R and R₅ is as defined above;

Ri is hydrogen, CH₂OPO₃H₂, a -(CH₂)_n-N(R₉R₁₀) group in which n is an integer of 1 to 4 and each of Rg and R_|0 is independently hydrogen, C_rC₆ alkyl or phenyl, or R₉ and R╬╣₀, 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.

7. A compound which is a 1,3,4-thiadiazole of formula (I)

X

(I) wherein m is zero or 1 ; Q represents a C₆-C_l4 aromatic ring system or a saturated or unsaturated heteromonocychc 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_rC₆ alkyl, hydroxy, C,-C₆ alkoxy, nitro, formylamino, C -C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a SO₂N(R₂R₃) group, in which each of R₂ and R₃ is independently hydrogen, C,-C₆ alkyl or phenyl, and a N(R₄R₅) group, in which each of R₄ and R₅ is independently hydrogen, C,-C₆ alkyl or SO₂R₆, in which R₆ is C_rC₆ 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; p is 0 or 1 ;

R is CC1₃, CF₃, a N(R₇R_g) group, in which each of R₇ and R_g is independently hydrogen or

C,-C₆ alkyl or R₇ and R_g 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, C,-C₆ alkoxy, nitro, formylamino, C₂-C₈ alkanoylamino, C₂-C₈ alkanoyloxy, a S0₂N(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(R₉R,₀) group in which n is an integer of 1 to 4 and each of R₉ and R,₀ is independently hydrogen, C,-C₆ alkyl or phenyl, or R₉ and R , 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

8. A compound according to claim 7 wherein, in formula (I), 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, C_rC₄ alkyl, C,-C₄ alkoxy, nitro, a S0₂N(R₂R₃) group, in which each of R₂ and R₃ is independently hydrogen or C,-C₄ alkyl, and a N(R R₅) group in which each of R₄ and R₅ is independently hydrogen, C_rC₄ alkyl or SO₂R₆, in which R₆ is C,-C₄ 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; R is CC1₃, CF₃, a N(R₇R₈) group, in which each of R₇ and R₈ is independently hydrogen or C_rC₄ 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, C,-C₄ alkyl, C,-C₄ alkoxy, nitro, 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;

R_t is hydrogen, CH₂OPO₃H₂, a -(CH₂)_n-N(R₉R╬╣₀) group in which n is an integer of 2 to 4 and each of R₉ and R₁₀ is independently hydrogen, C,-C₄ alkyl or phenyl or R₉ and R,₀. taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated C-C₇ heterocyclic ring; or R, is a group of formula:

╬¢_╬Ä╬¢72^R wherein

X, Y, R and p are as defined above.

9. A compound selected from:

2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-fluorophenyl)-[l ,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)-[l ,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-pyridyl)-[l ,3,4]thiadiazole:

2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(2-pyridyl)-[l ,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(morpholin-l -yl)-[l ,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-methyl-piperazin-l-yl)- [l,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(pyrrolidin-l-yl)-[l ,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-[4-(pyrrolidin-l-yl)-phenyl]-

[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-[4-( 1 ,2,5, 6-tetrahydro-pyridin- 1 -yl)- phenyl]-[l,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-sulfamoyl-phenyl)-[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(4-methanesulfonylamino-phenyl)- [l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(imidazol-l-ylmethyl)-[l,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(imidazol-l-yl)-[l ,3,4]thiadiazole; 2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(3-aza-bicyclo[3.2.2]non-3-yl)-

[l,3,4]thiadiazole;

2-[N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-(lH-imidazol-4-yl)-[l ,3,4]thiadiazole; 2-[N-hydroxymethyl-N-(2,2,2-trichloroethyloxycarbonyl)-amino]-5-phenyl- [l,3,4]thiadiazole phosphate; 2-[N-(phenyloxycarbonyl)-amino]-5-phenyl-[l ,3,4]thiadiazole; 2-[N-(benzyloxycarbonyl)-amino]-5-phenyl-[l ,3,4]thiadiazole; 2-[N-(4-pyridyloxycarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole; 2-[N-(phenyloxythiocarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole; 2-[N-(benzyloxythiocarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole; 2-[N-(4-pyridyloxythiocarbonyl)-amino]-5-phenyl-[l,3,4]thiadiazole; l-Phenyl-3-(5-phenyl-[l,3,4]thiadiazol-2-yl)-urea;

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

10 . A pharmaceutical composition comprising a compound as defined in claim 7, and a pharmaceutically acceptable carrier and/or diluent.