EP1001941A1

EP1001941A1 - Fused heterocyclic compounds and their use as kynurenine-3-hydroxylase inhibitors

Info

Publication number: EP1001941A1
Application number: EP98938689A
Authority: EP
Inventors: Paolo Pevarello; Mario Varasi; Franco Heidempergher; Felicita Greco; Carmela Speciale
Original assignee: Pharmacia and Upjohn SpA
Current assignee: Pfizer Italia SRL
Priority date: 1997-07-30
Filing date: 1998-07-02
Publication date: 2000-05-24
Also published as: WO1999006375A1; GB9716101D0; CA2296606A1; AU8731798A; JP2001512107A

Abstract

A compound which is a condensed heterocycle of formula (I) wherein a, b and c are all single bonds; or a, b and c are all double bonds; or a is a double bond and b and c are single bonds; m is zero or an integer of 1 to 6; W is -CONH-, -SO2- or -CO-; X is O, S or NR2, in which R2 is hydrogen, C1-C6 alkyl, benzyl, pyridyl, tetrahydropyranyl or a phenyl ring unsubstituted or substituted by one or two substituents which are the same or different and are chosen independently from halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, amino, hydroxy, formylamino, C2-C6 alkanoylamino trifluoromethyl and C1-C6 alkoxycarbonyl; each of R and R1 is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylamino or C1-C6 alkoxy-carbonyl; and Q is C1-C14 alkyl or a phenyl ring or an unsaturated pentatomic heteromonocyclic ring containing two or three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the phenyl ring and the heteromonocyclic ring are unsubstituted or substituted by one or two substituents which are the same or different and are chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkanoylamino, formylamino, and C1-C6 alkoxy-carbonyl, or a pharmaceutically acceptable salts thereof, is useful as a kynurenine-3-hydroxylase inhibitor.

Description

FUSED HETEROCYCLIC COMPOUNDS AND THEIR USE AS KYNURENINE-3-HYDROXYLASE INHIBITORS

The present invention relates to novel fused heterocyclic compounds, to a process for their preparation, to pharmaceutical compositions containing them and their use in therapy. The compounds of the invention act as inhibitors of kynurenine-3 -hydroxy lase (KYN- OH), an enzyme which forms part of the metabolic pathway of kynurenine. It is well known that through the kynurenine pathway, tryptophan metabolism gives rise to the formation of 3-hydroxykynurenine (3-OH-KYN) and quinolinic acid (QUIN). on the one side, and kynurenic acid (KYNA), on the other side, as shown in Figure 1. (The legend to Figure 1 is to be found on the last page of the experimental part of the specification).

KYNA is endowed with neuroprotective properties (J. Neurosci. 1990. 10. 2965-2973), whereas QUIN is a relatively potent neurotoxin which has been implicated in the pathogenesis of a variety of neurological disorders including Huntington^'s disease and epilepsy (Life Sci. 1984. 35, 19-32: Nature, 1986, 321. 168-171 ; Science, 1983. 219, 316- 318).

Increased concentrations of QUIN have also been indicated as responsible for neurological disorders accompanying many infections and inflammatory diseases including Aquired Immunodeficiency Syndrome (AIDS) (Ann. Neurol. 1991. 29, 202-209). One of the main strategies aimed at altering the KYNA/QUIN balance blocking 3-OH-KYN and QUIN^'s production and increasing KYNA production, entails inhibition of the key enzyme of the kynurenine (KYN) pathway, among which Kynurenιne-3 -hydroxy lase 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 a novel compound which is a condensed heterocycle of formula (I)

wherein 3, b and c are all single bonds; or a, b and c are all double bonds; or a is a double bond and b_ and c are single bonds; m is zero or an integer of 1 to 6;

W is -CONH-, -SO₂- or -CO-; X is O, S or NR₂, in which R is hydrogen, C,-C₆ alkyl. benzyl, pyridyl. tetrahydropyranyl or a phenyl ring unsubstituted or substituted by one or two substituents which are the same or different and are chosen independently from halogen, C,-C₆ alkyl, C,-C₆ alkoxy. nitro. amino. hydroxy, formylamino. C\-C₆ alkanoylamino trifluoromethyl and C,-C₆ alkoxycarbonyl; each of R and R|is independenth' hydrogen, halogen, hydroxy. triluoromethyl. nitro. amino. phenyl. benzyl. C_rC₍₁ alkyl. C,-C₆ alkoxy. C₂-C₆ alkanoylamino. formylamino or

C_rC₆ alkoxy-carbonyl; and

Q is C|-C|₄ alkyl or a phenyl ring or or an unsaturated pentatomic heteromonocyclic ring containing two or three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the phenyl ring and the heteromonocyclic ring are unsubstituted or substituted by one or two substituents which are the same or different and are chosen independently from halogen, hydroxy. trifluoromethyl, nitro, amino, phenyl, benzyl, C_rC₆ alkyl, C_rC₆ alkoxy, C -C₆ alkanoylamino, formylamino and C,-C₆ alkoxy-carbonyl; or a pharmaceutically acceptable salts thereof. It has to be noticed that in the compounds of formula (I) the group

wherein W, m and Q are as defined above, may be represented also by a tautomeric structure, namely the enol structure of formula (a)

(a) The present invention includes within its scope the pharmaceutically acceptable salts and also all the possible isomers. Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxydes, or with organic bases such as lysine. triethylamine. triethanolamine. dibenzylamine, methylbenzylamine. di-(2-ethyl- hexyl)-amine, piperidine. N-ethylpiperidine, N.N-diethylaminoethylamine, N- ethylmorpholine. β-phenethylamine. N-benzyl-β-phenethylamine. N-benzyl-N,N- dimethylamine and the other acceptable organic amines, as well as the salts with inorganic, e.g. hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric. maleic. malic, fumaric. methanesulfonic and ethanesulfonic acids. Preferred salts of the compounds of formula (I) are the sodium and the potassium salts thereof. As stated above, the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different structure from formula (I) but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I). A -(CH₂)_m- chain or an alkyl or alkoxy chain may be a branched or straight chain. A C_rC_M alkyl group is preferably a C,-C₆ alkyl group.

A C,-C₆ alkyl group is preferably a C_rC₄ alkyl group. Representative examples of C,-C₄ alkyl groups include methyl, ethyl, n- and iso-propyl. n-. iso-. sec-, and tert-butyl. A C,-C_ft alkoxy group is preferably a C,-C alkoxy group. Representative examples of C,- C₄ alkoxy groups include methoxy, and ethoxy.

A C₂-C₆ alkanoylamino group is preferably an acetylamino or propionylamino group.

A C,-C₆ alkoxy-carbonyl group is preferably a C_rC₄ alkoxy-carbonyl group typically a

C_|-C₂ one.

When Q is a heteromonocyclic ring as defined above it is preferably chosen from oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3-triazole. 1.2,4-triazole, 1,2,4-oxadiazole and 1,3,4-thiadiazole. A halogen is fluorine, bromine, chlorine or iodine, in particular chlorine, bromine or fluorine.

Preferred compounds of the invention as defined above are those wherein W is as defined above: X is 0. S or NR₂, wherein R₂ is hydrogen, C_rC alkyl, benzyl, pyridyl, tetrahydropyranyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents which are the same or different and are chosen independently from halogen, trifluoromethyl, C,-C₄ alkyl, C C₄ alkoxy, nitro, amino, hydroxy, formylamino, C₂-C₄ alkanoylamino and C_rC₄ alkoxy-carbonyl; each of R and R[ which are the same or different is independently hydrogen, halogen, hydroxy, trifluoromethyl, amino, C,-C₄ alkyl, C C₄ alkoxy, C -C₄ alkanoylamino, or C_rC₄ alkoxy-carbonyl; m is zero or 1 ; and

Q is C C₄ alkyl or a phenyl, oxazole, isoxazole. thiazole, pyrazole. imidazole. 1.2,3- triazole. 1 ,2,4-triazole. 1.2,4-oxadiazole or 1,3,4-thiadiazole ring unsubstituted or substituted by one or two substituents which are the same or different and are selected independently from halogen, hydroxy. trifluoromethyl, nitro, amino, C_rC₄ alkyl, C_rC₄ alkoxy. C₂-C₄ alkanoylamino and C , -C₄ alkoxy-carbonyl;

Examples of preferred compounds of the invention are the following: 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-Cyano-3-(5-fluoro- 1 -methyl- 1 H-indazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-Cyano-3-(5,6-difluoro- 1 -methyl- 1 H-indazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-Cyano-3-(5-methoxy-l -methyl- lH-indazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(4-methoxy-phenyl)-propanamide; 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(4-fluoro-phenyl)-propanamide: 2-Cyano-3-( l -methyl- lH-indazol-3-yl)-3-oxo-N-(3-nitro-phenyl)-propanamide;

2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(3-chloro-phenyl)-propanamide: 2-Cyano-3-( l -methyl- lH-indazol-3-yl)-3-oxo-N-(3-trifluoromethyl-phenyl)-propanamide: 2-Cyano-3-(l-methyl-lH-indazol-3-yl)-3-oxo-N-(3-methyl-phenyl)-propanamide; 2-Benzoyl-3-( 1 -methyl- 1 H-indazol-3-yl)-3-oxo-propanenitrile; 2-Benenesulfonyl-3-( 1 -methyl- lH-indazol-3-yl)-3-oxo- propanenitrile; 3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-phenyl-propanamide; 3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-phenyl-propanamide; 2-Cyano-3 -( 1 -methyl- 1 H-indazol-3 -yl)-3 -oxo-N-benzyl-propanamide; 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-butyl-propanamide; 3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-benzyl-propanamide;

3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-butyl-propanamide; 3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-benzyl-propanamide; and 3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-butyl-propanamide; and the pharmaceutically acceptable salts thereof.

The present invention also provides a compound as defined above for use in a method of treatment of the human or animal body by therapy. In particular the compound thus defined is for use as a kynurenine-3-hydroxylase inhibitor.

The present invention also provides the use of a compound which is a condensed heterocycle of formula (I) as defined above, or a pharmaceutically acceptable salt thereof. in the manufacture of a medicament for use as a kynurenine-3 -hydroxy lase enzyme inhibitor.

The present invention also provides a method of treating a mammal, including a human, in need of a kynurenine-3 -hydroxy lase inhibitor: which method comprises administering thereto a therapeutically effective amount of a compound as defined above.

The compounds of the invention can be obtained, for instance, by a process comprising:

A) reacting a compound of formula (II)

R

(ID wherein a,b,c, R and R, are as defined above and X is ϋ or S or NR₂ wherein R₂ is as defined above except hydrogen and Z is a derivative of a carboxy group, with a compound of formula (III)

. CN

CH

(III) W- (CH₂)_m-Q wherein m, Q, and W are as defined above, thus obtaining a compound of formula (I) in which R₂ is as defined above except hydrogen; or

B) reacting a compound of formula (IV)

wherein a,b,c, R and R_\ are as defined above and X is O, S, and NR wherein R₂ is as defined above except hydrogen, with a compound of formula (V) or (VI)

Z-(CH,)_m-Q (V)

OCN-(CH₂)_m-Q (VI)

wherein m, Q and Z are as defined above, so obtaining a a compound of formula (I) wherein W is a -CO- or a -CONH- group respectively and R₂ is as defined above except hydrogen: or

A) hydrolysing a compound oi formula (I) in which X is NR wherein R₂ is tetrahydropyranyl. so to obtain a compound of formula (I) in which R₂ is hydrogen: and

B) if desired, converting a compound of formula (I) into another compound 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 if desired, separating a mixture of isomers of a compound of formula (I) into the single isomers

A compound of formula (I) may be converted into another compound of formula (I) by known methods. For example, in a compound of formula (I) a nitro group may be converted into an amino group b> treatment, for example, with stannous chloride in concentrated hydrochloric acid using, an organic cosolvent such as dioxane, tetrahydofuran at a temperature varying between room temperature and about 100 °C. Furthermore, for example, an amino group may be converted into a formylamino or a C₂-

C₄ alkanoylamino group, for example by reacting with formic acid or with a suitable C₂- C₄ alkanoyl anhydride without any solvent or in a organic solvent such as dioxane, dimethylformamide, tetrahydofuran, usually in the presence of a base such as triethylamine, at a temperature varying between 0 °C and about 100 °C. The above process-variant A) and B) are analogy process which can be carried out according to well known methods in the art When Z is a derivative of a carboxy group it is preferably a reactive derivative thereof, for example, a halocarbonyl group, preferably a chlorocarbonyl group, or a C₂-C₇ alkoxycarbonyl, preferably a C₂-C₃ alkoxycarbonyl group.

The reaction between a compound of formula (II) wherein Z is a reactive derivative of a carboxy group and a compound of formula (III) can be carried out,for example, in the presence of a strong base such as sodium hydride, potassium t-butoxide. in a inert solvent such as 1,2-dimethoxyethane, dioxane, dimethylformamide. at a temperature ranging from about 0 °C to 100 °C. The reaction between a compound of formula (IV) and a compound of formula (V) or (VI) can be carried out. for example, in the presence of a base such as triethylamine. in a inert solvent such as toluene, dioxane. tetrahydofuran. dimethylformamide, dichloromethane at a temperature varying between 0 °C and about 100 °C.

The above process C) can be carried out according to well known methods in the art. For example, the hydrolysis can be performed in a aqueous solution of a halohydric acid. typically HCl, in a suitable solvent, e.g. dioxane or tetrahydrofuran at a temperature varying from room temperature to about 40 °C.

The compounds of formula (IV) wherein R, R,, and X are as defined above, which are new chemical entities and are a further object of this invention, may be obtained, for example, reacting a compound of formula (II) wherein X is O or S or NR₂ wherein R₂ is as defined above except hydrogen with acetonitrile in dioxane in the presence of NaH at 60 °C according to known procedures.

The compounds of formula (III). (V). (VI) are commercially available or may be prepared by well known procedures. The compounds of formula (II) wherein R, and Ri are as defined above, X is NR₂ wherein R₂ is as defined above and Z is a derivative of a carboxy group can be prepared following the procedure described in J.A.C.S. 74, 1952, p. 2009. The compounds of formula (II) wherein R, and R_j are as defined above, X is O and Z is a derivative of a carboxy group or can be prepared following the procedure described in Ber. Dtsch. Ges. 86, 1953, p 1096. The compounds of formula (II) wherein R, and R_t are as defined above, X is S and Z is a reactive derivative of a carboxy group can be prepared following the procedure described in il Farmaco 29 (2), 1974, p 109.

When in the compounds of the invention and the intermediate thereof groups are present which may interfere with the reaction they may be protected before the reaction takes place and then deprotected at the end of the reaction. For instance, hydroxy, amino and/or carboxy groups may be protected and then deprotected according to the common techniques known from the peptide chemistry.

Pharmacology

The compounds of the invention are active as kynurenine-3 -hydroxy lase enzyme inhibitors and therefore are useful in the prevention and/or treatment of neuropathological processes, related to a deranged production of quinolinic acid and/or 3 -hydroxy kynurenine due to excessive activation of neuro-transmission mediated by excitatory amino acid receptors and/or oxidative stress. Examples of such neuropathological processes are neurodegenerative pathologies including, e.g. Huntington^'s chorea, Alzheimer^'s disease. Parkinson^'s disease, olivoponto cerebellar atrophy, non-Alzheimer^'s dementias, including the dementia like syndrome caused by Acquired Immunodeficiency Syndrome (AIDS). multi-infarctual dementia, cerebral amyotrophic lateral sclerosis, cerebral ischemia. cerebral hypoxia, spinal and head trauma, and epilepsy.

A human or animal in need of a kynurenine-3 -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 lOOμl was constituted of 44 μg of suspended extract, 100 mM Tris/Cl^" buffer pH 8.1, 10 mM EDTA, 100 tnM KC1, 0.8 mM NADPH, 0.025 mM L-Kynurenine, 0.5 μCi L-(3,5-³H)Kynurenine (10 Ci/mmol) and 10 μl of different concentration of inhibitor solutions. After the incubation, the reaction was terminated by the addition of 1 ml of 7 5% (W/v) activated charcoal, vortexed and centπfuged for 7 min

A 500 μl aliquot of supernatant was counted by scintillation, spectroscopy in 5 ml of liquid scintillation

The obtained results, which have been reported in the following Table 1. demonstrate the efficacy of representative compounds of the invention

2-Cyano-3-hydroxy-3-(l -methyl- l H-ιndazol-3-yl)-N-phenvl-acrylamιde. sodium salt hydrate (internal code PNU 168704A),

2-Cyano-3-hydroxy-3-(l -methyl- lH-ιndazol-3-yl)-N-benzyl-acrylamιde sodium salt hydrate (internal code PNU 190349A) Table 1

The dosage level, suitable for administration to a mammal e 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 a representatι\ e compound of the invention PNU 168704 may range from about 10 to about 500 mg pro dose, from 1 to 5 times daih 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, parenterallv, 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-Cyano-3-(l -methyl-1 H-indazol-3-yiy3-oxo-N-phenyl-propanamide

1 -Methyl- lH-indazole-3-carboxylic acid (1.46 g; 0.0083 moles) was reacted with thionyl chloride (1.97 g; 0.0166 moles) in anhydrous dioxane at the reflux temperature for 2 h.

After cooling the solution was evaporated to dryness and the crude 1 -Methyl- lH-indazole- 3-carbonyl chloride was dissolved in anhydrous dioxane (50 mL). this solution was added under stirring at room temperature under inert atmasphere to the suspension of the carbanion obtained by treatment of phenylcarbamoylacetonitrile (1.47 g; 0.0091 moles) with 50% sodium hydride (0.6 g; 0.0125 moles) in anhydrous dioxane (130 mL). The reaction mixture was allowed to react at room temperature for 2 h, then acidified to pH 2 with 2N HCl and diluted with ice water. The precipitate was collected by filtration, washed with water until neutral and then dried. Crystallization from methanol gave 1.1 g of the desired product as a beige solid (m.p. 227.5-230 °C). C₁₈H₁₄N₄0 : required:

C= 67.92; H= 4.43; N= 17.60; found: C= 68.07; H= 4.48; N= 17.71.

Analogously the following products can be prepared:

2-Cyano-3-(5-fluoro- 1 -methyl- 1 H-indazol-3-yl)-3-oxo-N-phenyl-propanamide:

2-Cyano-3-(5,6-difluoro-l -methyl- lH-indazol-3-yl)-3-oxo-N-phenyl-propanamide: 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-phenyl-propanamide: 2-Cyano-3-(5-methoxy-l -methyl- lH-indazol-3-yl)-3-oxo-N-phenyl-propanamide: 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(4-methoxy-phenyl)-propanamide: 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(4-fluoro-phenyl)-propanamide: 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(3-nitro-phenyl)-propanamide; 2-Cyano-3-(l-methyl-lH-indazol-3-yl)-3-oxo-N-(3-chioro-phenyl)-propanamide: 2-Cyano-3-(l -methyl-lH-indazol-3-yl)-3-oxo-N-(3-trifluoromethyl-phenyl)-propanamide; 2-Cyano-3 -( 1 -methyl- 1 H-indazol-3 -yl)-3-oxo-N-(3 -methyl-phenyl)-propanamide: 2-Benzoyl-3-(l -methyl- lH-indazol-3-yl)-3-oxo- propanenitrile;

2-Benenesulfonyl-3-(l -methyl- lH-indazol-3-yl)-3-oxo- propanenitrile; 3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-phenyl-propanamide; 3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-phenyl-propanamide; 2-Cyano-3-[l-(tetrahydro-pyran-2-yl)-lH-indazol-3-yI]-3-oxo-N-phenyl-propanamide; 2-Cyano-3-(l-methyl-3a,4,5,6,7,7a-hexahydro-lH-indazol-3-yl)-3-oxo-N-phenyl- propanamide;

2-Cyano-3 -( 1 -methyl- 1 H-indazol-3 -yl)-3 -oxo-N-benzyl-propanamide ; 2-Cyano-3-(l-methyl-lH-indazol-3-yl)-3-oxo-N-butyl-propanamide; 3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-benzyl-propanamide; 3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-butyl-propanamide;

3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-benzyl-propanamide; 3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-butyl-propanamide; Example 2

Preparation of 3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-phenyl-propanamide: triethylamine (2.6 mL: 0.0186 moles) and phenylisocyanate (1.9 mL: 0.0177 moles) dissolved in dimethylformamide (20 mL) were added to a solution of 3-Benzo[d]isoxazol- 3-yl-3-oxo-propionitrile (3.15: 0.0169 moles) in anhydrous dimethylformamide (90 mL).

The reaction mixture was allowed to react at room temperature for 40' then acidified to pH

2 with 2 N HCl and diluted with ice water. The precipitate was collected by filtration. washed with water until neutral and then dried. Crystallization from methanol gave 4.48 g of the desired product as a beige solid. C_{| 7}H_nN₃O₃; required: C= 66.88: H= 3.63; N= 13.76; found: C= 67.08: H= 3.58: N= 13.40.

Analogously the following products can be prepared:

2-Cyano-3-(l -methyl- l H-indazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-Cyano-3-(5-fluoro- 1 -methyl- l H-indazol-3-yl)-3-oxo-N-phenyl-propanamide: 2-Cyano-3-(5,6-difluoro-l -methyl- l H-indazol-3-yl)-3-oxo-N-phenyl-propanamide: 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-phenyl-propanamide: 2-Cyano-3-(5-methoxy-l -methyl- l H-indazol-3-yl)-3-oxo-N-phenyl-propanamide: 2-Cyano-3-(l-methyl-lH-indazol-3-yl)-3-oxo-N-(4-methoxy-phenyl)-propanamide: 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(4-fluoro-phenyl)-propanamide: 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(3-nitro-phenyl)-propanamide: 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(3-chloro-phenyl)-propanamide: 2-Cyano-3-(l -methyl-lH-indazol-3-yl)-3-oxo-N-(3-trifluoromethyl-phenyl)-propanamide: 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(3-methyl-phenyl)-propanamide: 2-Benzoyl-3-(l-methyl-lH-indazol-3-yl)-3-oxo- propanenitrile; 3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-phenyl-propanamide;

2-Cyano-3-[l-(tetrahydro-pyran-2-yl)-lH-indazol-3-yl]-3-oxo-N-phenyl-propanamide; 2-Cyano-3-(l-methyl-3a,4,5,6,7,7a-hexahydro-lH-indazol-3-yl)-3-oxo-N-phenyl- propanamide; 2-Cyano-3-(l-methyl-lH-indazol-3-yl)-3-oxo-N-benzyl-propanamide; 2-Cyano-3-( 1 -methyl- 1 H-indazol-3-yl)-3-oxo-N-butyl-propanamide;

3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-benzyl-propanamide;

3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-butyl-propanamide;

3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-benzyl-propanamide; 3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-butyl-propanamide;

Example 3

Preparation of 2-Cyano-3-( 1 H-indazol-3-ylV3-oxo-N-phenyl-propanamide 2 N HCl (30 mL) was added to a solution of 2-Cyano-3-[l-(tetrahydro-pyran-2-yl)-lH- indazol-3-yl]-3-oxo-N-phenyl-propanamide (2.49 g; 0.0064 moles) and the solution was stirred 10 h at 40 °C. The mixture was poured into ice water and extracted with ethyl acetate then the organic layer washed with water.dried over anhydrous sodium sulfate and evaporated to dryness.The crude product was ground with diisopropyl ether to give 2.3 g of the desired compound. C_{l 7}H₁₂N₄0₂: required: C= 67.10; H= 3.97; N= 18.41 : found: C= 67.26: H= 4.09; N= 18.19. Analogously the following products can be prepared:

2-Cyano-3-( 1 H-indazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-Cyano-3-(lH-indazol-3-yl)-3-oxo-N-(4-fluoro-phenyl-phenyl-propanamide; 2-Benzoyl-3-( 1 H-indazol-3-yl)-3-oxo-propanenitrile; 2-Benenesulfonyl-3-(lH-indazol-3-yl)-3-oxo- propanenitrile; 2-Cyano-3-(2,3-dihydro-lH-indazol-3-yl)-3-oxo-N-phenyl-propanamide.

Example 4

Preparation of 3-H -Methyl- l H-indazol-3-yl .-3-oxo-propanenitrile

To the suspension of 55% NaH (0.51 g; 0.01 17 moles) in anhydrous dioxane (10 mL) 1- Methyl-lH-indazole-3-carboxylic acid ethyl ester ( 1.25 g: 0.0061 moles) and acetonitrile (10 mL) were added under stirring at room temperature under nitrogen atmosphere. The mixture was heated at 50 °C for 40' then poured into ice water. The solution was acidified to pH 3.5 with 2 N HCl and the precipitate was collected by filtration, washed with water until neutral and dried. Crystallization fron methanol afforded 1.0 g of the desired product as a beige solid. C_πH₉N₃0: required: C= 66.32; H= 4.55; N= 21.09; found: 66.06; H= 4.58; N= 21.03. Analogously the following product can be prepared:

3-Benzo[d]isothiazol-3-yl-3-oxo- propanenitrile;

3-Benzo[d]isoxazol-3-yl-3-oxo- propanenitrile;

3-(l-Methyl-3a,4, 5,6,7, 7a-hexahydro-lH-indazol-3-yl)-3-oxo-propanenitrile. Example 5

Preparation of 2-Cyano-3-hydroxy-3-(l -methyl- lH-indazol-3-yl>N-phenyl-acrylamide. sodium salt hydrate 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-phenyl-propanamide (0.404 g; 0.00127 moles) was dissolved in ethanol (40 mL) and 0.1 N NaOH (12.7 mL; 0.00127 moles) was added. The solution was evaporated to dryness to obtain the desired compound (m.p. 250 °C dec.).C₁₈H₁₃N₄NaO₂.H₂O; required: C= 63.52; H= 3.85; N= 16.46: Na= 6.76; found: C=66.15; H=3.96; N=16.32; Na= 6.56. Analogously the following products can be prepared:

2-Cyano-3-hydroxy-3-(5-fluoro-l -methyl-lH-indazol-3-yl)-N-phenyl-acrylamide. sodium salt;

2-Cyano-3-hydroxy-3-(5,6-difluoro- l -methyl- lH-indazol-3-yl)-N-phenyl-acrylamide. sodium salt;

2-Cyano-3-hydroxy-3-(5-methoxy-l -methyl- lH-indazol-3-yl)-N-phenyl-acrylamide, sodium salt;

2-Cyano-3-hydroxy-3-( 1 -methyl- 1 H-indazol-3-yl)-N-phenyl-acrylamide, sodium salt;

2-Cyano-3-hydroxy-3-( 1 -methyl- 1 H-indazol-3-yl)-N-(4-fluoro-phenyl)-acrylamide, sodium salt;

2-Cyano-3-hydroxy-3-( 1 -methyl- 1 H-indazol-3-yl)-N-(3-nitro-phenyl)-acrylamide, sodium salt;

2-Cyano-3 -hydroxy-3 -( 1 -methyl- 1 H-indazol-3 -yl)-N-(3 -chloro-pheny l)-acry lamide, sodium salt; 2-Cyano-3-hydroxy-3-( 1 -methyl- 1 H-indazol-3-yl)-N-(3-trifiuoromethyl-phenyl)- acrylamide, sodium salt;

2-Cyano-3-hydroxy-3-(l -methyl- lH-indazol-3-yl)-N-(3-methyl-phenyl)-acrylamide, sodium salt; 2-Benenesulfonyl-3-hydroxy-3-(l-methyl-lH-indazol-3-yl)-acrylonitrile, sodium salt; 3-Benzo[d]isoxazol-3-yl-2-cyano-3-hydroxy-N-phenyl-acrylamide, sodium salt;

3-Benzo[d]isothiazol-3-yl-2-cyano-3-hydroxy-N-phenyl-acrylamide, sodium salt; 2-Cyano-3-hydroxy-3-(l-methyl-3a,4,5,6,7,7a-hexahydro-lH-indazol-3-yl)-N-phenyl- acrylamide, sodium salt;

2-Cyano-3-hydroxy-3-( 1 -methyl- 1 H-indazol-3-yl)-N-benzyl-acrylamide, sodium salt hydrate;

2-Cyano-3-hydroxy-3-( 1 -methyl- 1 H-indazol-3-yl)-N-butyl-acrylamide, sodium salt; 3-Benzo[d]isoxazol-3-yl-2-cyano-3-hydroxy-N-benzyl-acrylamide, sodium salt; 3-Benzo[d]isoxazol-3-yl-2-cyano-3-hydroxy-N-butyl-acrylarnide, sodium salt; 3-Benzo[d]isothiazol-3-yl-2-cyano-3-hydroxy-N-benzyl-acrylamide, sodium salt; 3-Benzo[d]isothiazol-3-yl-2-cyano-3-hydroxy-N-butyl-acrylamide, sodium salt.

Example 6

Capsule, each weighing 0.23 g and containing 50 mg of the active substance can be prepared as follow:

Composition for 500 capsules:

2-Cyano-3 -hydroxy-3 -( 1 -methyl- 1 H-indazol-3 -y l)-N-pheny 1-acrylamide. sodium salt hydrate 25 g

Lactose 80 g Corn starch 5 g

Magnesium stearate 5 g

This formulation can be encapsulated in two hard gelatin capsules of two pieces, each with each capsule weighing 0.23 g.

Example 7

Intramuscular injection of 50 mg/mL

A pharmaceutical injectable composition can be manufactured dissolving 50 g of 2-

Cyano-3-hydroxy-3-(l-methyl-lH-indazol-3-yl)-N-phenyl-acrylamide, sodium salt hydrate in sterile propylenglycol (1000 mL) and sealed in 1-5 ampoules.

Legend to Figure 1

IDO = Indolamineoxigenase;

KYN = Kynurenine;

KYN-OH = Kynurenine-3-hydroxylase;

KYNA = Kynurenic acid;

3-OHAA = 3-Hydroxy anthranilic acid; KYNase = Kynureninase;

QUIN = Quinolinic acid;

3-HAO = 3-Hydroxy anthranilic acid deoxygenase; KAT = Kynurenine amino transferase; 3-OH-KYN = 3-Hydroxy-kynurenine.

Claims

1. A compound which is a condensed heterocycle of formula (I)

wherein a, b and c are all single bonds; or a, b and c are all double bonds: or a is a double bond and b and c are single bonds: m is zero or an integer of 1 to 6; W is -CONH-, -SO₂- or -CO-:

X is O. S or NR₂, in which R₂ is hydrogen, C,-C₆ alkyl, benzyl, pyridyl. tetrahydropyranyl or a phenyl ring unsubstituted or substituted by one or two substituents which are the same or different and are chosen independently from halogen, C_rC₆ alkyl, C_rC₆ alkoxy, nitro, amino, hydroxy, formylamino, C₂-C₆ alkanoylamino trifluoromethyl and C,-C₆ alkoxycarbonyl; each of R and R╬╝s independently hydrogen, halogen, hydroxy, triluoromethyl, nitro, amino, phenyl, benzyl. C_rC₆ alkyl. C_rC₆ alkoxy, C₂-C₆ alkanoylamino, formylamino or C|-C₆ alkoxy-carbonyl; and Q is C,-C₁₄ alkyl or a phenyl ring or or an unsaturated pentatomic heteromonocyclic ring containing two or three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the phenyl ring and the heteromonocyclic ring are unsubstituted or substituted by one or two substituents which are the same or different and are chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C C₆ alkyl, C C₆ alkoxy, C₂-C₆ alkanoylamino, formylamino and C_rC₆ alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof.

2. A compound as defined in claim 1 wherein, in formula (I),

X is O, S or NR₂, wherein R₂ is hydrogen, C_rC alkyl, benzyl, pyridyl, tetrahydropyranyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents which are the same or different and are chosen independently from halogen, trifluoromethyl, C_r

C₄ alkyl, C_rC₄ alkoxy, nitro, amino, hydroxy, formylamino, C₂-C₄ alkanoylamino and C_r

C₄ alkoxy-carbonyl; each of R and R_! which are the same or different is independently hydrogen, halogen, hydroxy, trifluoromethyl, amino, C,-C₄ alkyl, C,-C₄ alkoxy, C₂-C₄ alkanoylamino, or C

C₄ alkoxy-carbonyl; m is zero or 1 ; and

Q is C_rC₄ alkyl or a phenyl, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3- triazole, 1,2,4-triazole, 1 ,2,4-oxadiazole or 1,3,4-thiadiazole ring unsubstituted or substituted by one or two substituents which are the same or different and are each selected independently from halogen, hydroxy, trifluoromethyl, nitro, amino, C_rC₄ alkyl, C,-C₄ alkoxy, C₂-C₄ alkanoylamino and C_rC₄ alkoxy-carbonyl.

3. A compound selected from

2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-Cyano-3-(5-fluoro- 1 -methyl- 1 H-indazol-3-yl)-3-oxo-N-phenyl-propanamide;

2-Cyano-3-(5,6-difluoro- 1 -methyl- 1 H-indazol-3-yl)-3-oxo-N-phenyl-propanamide;

2-Cyano-3-( 1 -methyl- 1 H-indazol-3-yl)-3-oxo-N-phenyl-propanamide;

2-Cyano-3-(5-methoxy- 1 -methyl- 1 H-indazol-3-yl)-3-oxo-N-phenyl-propanamide;

2-Cyano-3-(l-methyl-lH-indazol-3-yl)-3-oxo-N-(4-methoxy-phenyl)-propanamide; 2-Cyano-3 -( 1 -methyl- 1 H-indazol-3 -y l)-3-oxo-N-(4-fluoro-phenyl)-propanamide;

2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(3-nitro-phenyl)-propanamide:

2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-(3-chloro-phenyl)-propanamide;

2-Cyano-3-(l-methyl-lH-indazol-3-yl)-3-oxo-N-(3-trifluoromethyl-phenyl)-propanamide;

2-Cyano-3-(l-methyl-lH-indazol-3-yl)-3-oxo-N-(3-methyl-phenyl)-propanamide; 2-Benzoyl-3-( 1 -methyl- 1 H-indazol-3-yl)-3-oxo-propanenitrile;

2-Benenesulfonyl-3-(l -methyl- lH-indazol-3-yl)-3-oxo- propanenitrile;

3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-phenyl-propanamide;

3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-phenyl-propanamide;

2-Cyano-3-( 1 -methyl- 1 H-indazol-3-yl)-3-oxo-N-benzyl-propanamide; 2-Cyano-3-(l -methyl- lH-indazol-3-yl)-3-oxo-N-butyl-propanamide;

3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-benzyl-propanamide; 3-Benzo-[d]isoxazol-3-yl-2-cyano-3-oxo-N-butyl-propanamide; 3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-benzyl-propanamide; and 3-Benzo-[d]isothiazol-3-yl-2-cyano-3-oxo-N-butyl-propanamide; and the pharmaceutically acceptable salts thereof.

4. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and /or diluent and, as an active principle, a compound as defined in claim 1.

5. A compound as defined in claim 1 for use in a method of treatment of the human or animal body by therapy.

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

7. A method of treating a mammal, including a human, in need of a kynurenine-3- hydroxylase inhibitor, which method com╧åises administering thereto a therapeutically effective amount of a compound as defined in claim 1.

8. A compound of formula (IV)

wherein a, b. c. R and R, are as defined in claim 1 and X is O. S or NR₂ wherein R₂ is as defined in claim 1 except hydrogen.

9. A process for the production of a compound as defined in claim 1 , which process comprises:

a) reacting a compound of formula (II)

wherein a,b,c, R and Rj are as defined in claim 1 and X is O or S or NR₂ wherein R₂ is as defined in claim 1 except hydrogen and Z is a derivative of a carboxy group, with a compound of formula (III)

.CN

?^H (III)

W-(CH₂)_m-Q wherein m, Q, and W are as defined in claim 1 , thus obtaining a compound of formula (I) in which R₂ is as defined above except hydrogen; or B) reacting a compound of formula (IV)

wherein a,b,c, R and R, are as defined above and X is O, S, and NR₂ wherein R₂ is as defined above except hydrogen, with a compound of formula (V) or (VI)

Z-(CH₂)_m-Q (V)

OCN-(CH₂)_m-Q (VI)

wherein m. Q and Z are as defined above, so obtaining a a compound of formula (I) wherein W is a -CO- or a -CONH- group respectively and R is as defined above except hydrogen; or

C) hydrolysing a compound of formula (I) in which X is NR₂ wherein R₂ is tetrahydropyranyl, so to obtain a compound of formula (I) in which R₂ is hydrogen; 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 if desired, separating a mixture of isomers of a compound of formula (I) into the single isomers.