EP1001940A1 - Composes heterocycliques condenses - Google Patents

Composes heterocycliques condenses

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Publication number
EP1001940A1
EP1001940A1 EP98939623A EP98939623A EP1001940A1 EP 1001940 A1 EP1001940 A1 EP 1001940A1 EP 98939623 A EP98939623 A EP 98939623A EP 98939623 A EP98939623 A EP 98939623A EP 1001940 A1 EP1001940 A1 EP 1001940A1
Authority
EP
European Patent Office
Prior art keywords
oxo
phenyl
methyl
cyano
pyrazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98939623A
Other languages
German (de)
English (en)
Inventor
Mario Varasi
Paolo Pevarello
Franco Heidempergher
Salvatore Toma
Carmela Speciale
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Italia SRL
Original Assignee
Pharmacia and Upjohn SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia and Upjohn SpA filed Critical Pharmacia and Upjohn SpA
Publication of EP1001940A1 publication Critical patent/EP1001940A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems

Definitions

  • the present invention relates to condensed pyrazole 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-hydroxylase (KYN- OH), an enzyme which forms part of the metabolic pathway of kynurenine. It is well known that through the kynurenine pathway, triptophan metabolism gives rise to the formation of 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QULN), 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).
  • the present invention provides the use of a compound which is a condensed pyrazole derivative of formula (I)
  • W is -CONH-, -S0 2 - or -CO-;
  • X is -O- or -NR 4 - in which R 4 is hydrogen, C,-C 6 alkyl, benzyl, pyridyl, tetrahydropyranyl or a phenyl ring, the phenyl ring being unsubstituted or substituted by one or two substituents which are the same or different and are chosen independently from halogen, trifluoromethyl, C,-C 6 alkyl, C,-C 6 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 6 alkanoylamino and C,-C 6 alkoxy-carbonyl; each of R, R restroom and R 2 , which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino or C
  • the present invention includes within its scope all the possible isomers, stereoisomers, optical isomers and their mixtures and the metabolites and the metabolic precursors (or bioprecursors) of the compounds of formula (I).
  • Examples of pharmaceutically acceptable salts of the compounds of the invention are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases such as lysine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N- ethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine, ⁇ -phenethylamine, N- benzyl- ⁇ -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.
  • 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.
  • 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 to formula (I) but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
  • pharmaceutically acceptable bioprecursors otherwise known as pro-drugs
  • alkyl, alkoxy, alkanoylamino and alkoxy-carbonyl groups may be branched or straight chain groups.
  • a C 2 -C 6 alkylene, -(CH 2 ) m -, -(CH 2 ) n - chain or C,-C I4 alkyl may be a branched or straight chain.
  • a C,-C l4 alkyl group is preferably a C,-C 6 alkyl group.
  • a C,-C 6 alkyl group is preferably a C r C 4 alkyl group.
  • Representative examples of C,-C 4 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec-, and tert-butyl.
  • a C,-C 6 alkoxy group is preferably a C,-C 4 alkoxy group.
  • Representative examples of C,- C 4 alkoxy groups include methoxy, and ethoxy.
  • a C 2 -C 6 alkanoylamino group is preferably an acetylamino or propionylamino group.
  • a C,-C 6 alkoxy-carbonyl group is preferably a C,-C 4 alkoxy-carbonyl group typically a C,-C 2 one.
  • 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 for use in the invention are those wherein, in formula (I), W is as defined above;
  • X is O or NR 4 , wherein R 4 is hydrogen, C r C 4 alkyl, benzyl, pyridyl, tetrahydropyranyl or phenyl, the phenyl ring being unsubstituted or substituted by one or two substituents which are the same or different and are chosen independently from halogen, trifluoromethyl, C,-C 4 alkyl, C,-C 4 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 4 alkanoylamino and C,-C 4 alkoxy-carbonyl; each of R, R, and R 2 , which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, amino, C,-C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino, or C,- C 4 alkoxy-carbonyl; and R 3 is hydrogen; or R 2 and R 3 taken together
  • Q is C,-C 4 alkyl or a phenyl, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3- triazole, 1,2,4-triazole, 1,2,4-oxadiazole or 1,3,4-thiadiazole ring unsubstituted or substituted by one or two substituents, which are the same or different and are selected independently from halogen, hydroxy, trifluoromethyl, nitro, amino, C,-C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino and C,-C 4 alkoxy-carbonyl; and the pharmaceutically acceptable salt thereof.
  • Examples of preferred compounds for use in the invention are the following: 2-Cyano-N-phenyl-3-(7-methyl-2,3,7,9b-tetrahydro-lH-acenaphtho[l,2-c]pyrazol-9-yl)- 3-oxo-propanamide; 2-Cyano-N-(4-methoxy-phenyl)-3-(7-methyl-2,3,7,9b-tetrahydro-lH-acenaphtho[l,2- c]pyrazol-9-yl)-3-oxo-propanamide;
  • the present invention further provides a novel compound which is a condensed pyrazole derivative of formula (IA)
  • W is -CONH-, -SO 2 - or -CO-;
  • X is -O- , or -NR 4 - in which R 4 is hydrogen, C,-C 6 alkyl, benzyl, pyridyl, tetrahydropyranyl or a phenyl ring, the phenyl ring being unsubstituted or substituted by one or two substituents, which are the same or different and are chosen independently from halogen, trifluoromethyl, C,-C 6 alkyl, C,-C 6 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 6 alkanoylamino and C,-C 6 alkoxy-carbonyl; each of R, R restroom and R 2 , which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamin
  • Q is C,-C, 4 alkyl, a phenyl ring or an unsaturated pentatomic heteromono-cyclic ring containing two or three heteroatoms which are the same or different and are chosen from independently 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,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C,-C 6 alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof; and wherein, when at the same time X is -NR 4 in which R 4 is C,- C 6 alkyl, pyridyl or a phenyl ring unsubstituted or substituted by
  • R and R are hydrogen, hydroxy, halogen, trifluoromethyl, nitro, amino, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino or C,-C 6 alkoxy-carbonyl;
  • R 2 and R 3 are hydrogen;
  • m is zero or an integer of 1 to 6 and Q is C,-C 14 alkyl or a phenyl ring optionally substituted by one or two substituents which are the same or different and are chosen from halogen, hydroxy, trifluoromethyl, nitro, amino, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C,-C 6 alkoxy-carbonyl; then W is other than -CONH-;
  • Preferred compounds of the invention are those wherein, in formula (IA) and subject to the above provisos,
  • W is -CONH-, -SO 2 - or -CO-;
  • X is O or NR 4 , wherein R 4 represents hydrogen, C,-C 4 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 C 4 alkyl, C,-C 4 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 4 alkanoylamino and C,-C 4 alkoxy-carbonyl; each of R, R, and R 2 , which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, amino, C,-C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino or C,-C 4 alkoxy carbonyl; and R 3 is hydrogen; or R 2 and R 3 taken together form a C
  • Q is C,-C 4 alkyl or a phenyl, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3- triazole, 1,2,4-triazole, 1,2,4-oxadiazole or 1,3,4-thiadiazole ring unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, hydroxy, trifluoromethyl, nitro, amino, C,-C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino and C,-C 4 alkoxy-carbonyl.
  • a preferred class of compounds are those wherein, in formula (IA), X is NR 4 in which R 4 is as defined above, W is -CONH-, Q is a heteromonocyclic ring, containing two or three heteroatoms chosen from oxygen and nitrogen, optionally substituted by one or two substituents which are the same or different and are independently chosen from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C,-C 6 alkoxy-carbonyl; and m, R, R,, R 2 and R 3 are as defined above
  • a preferred class of compounds of the invention are those wherein, in formula (IA), W is -S0 2 - or -CO-, X is -O- or -NR 4 - in which R 4 is as defined above, and m, R, R,, R 2 , R 3 and Q are as defined above; and the pharmaceutically acceptable salts thereof.
  • Examples of preferred compounds of the invention are the following condensed pyrazole derivatives of formula (IA):
  • the present invention further provides the following compounds and the pharmaceutically acceptable salts thereof, which fall within the scope of EP-B-0278603 and EP-B-0347773, cited above, but are not specifically mentioned therein:
  • a pharmaceutically acceptable salt of a compound of formula (IA) or of a new chemical entity, cited above, is for instance a pharmaceutically acceptable salt as defined as to a compound of formula (I).
  • the present invention also provides a compound which is a condensed pyrazole derivative of formula (IA), or a novel chemical entity as defined above, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
  • the compound thus defined is for use as a kynurenine-3- hydroxylase 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; such method comprising administering thereto a therapeutically effective amount of a compound of the invention, as defined above.
  • the compounds of the invention can be obtained by an analogy process as disclosed for instance in EP-B-0278603 and in EP-B-0347773.
  • a novel condensed pyrazole derivative of formula (IA) or a pharmaceutically acceptable salt thereof can be obtained by a process comprising: a) reacting a compound of formula (II)
  • R, R,, R 2 , and R 3 are as defined above and X is O or NR 4 wherein R 4 is as defined above except hydrogen and Z is a derivative of a carboxy group, with a compound of formula (III)
  • R, R,, R 2 , and R 3 are as defined above and X is O or NR 4 wherein R 4 is as defined above except hydrogen, with a compound of formula (V) or (VI)
  • a compound of formula (I A) may be converted into another compound of formula(IA) by known methods.
  • a nitro group may be converted into an amino group by 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.
  • an amino group may be converted into a formylamino or a C 2 - C 4 alkanoylamino group, for example by reacting with formic acid or with a suitable C 2 - C 4 alkanoyl anhydride without any solvent or in a organic solvent such as dioxane, dimethylformamide, tetrahydofuran, usually in the presence of a base such as triethylamine, at a temperature varying between 0 °C and about 100 °C.
  • a base such as triethylamine
  • Z is a derivative of a carboxy group it is for example a reactive derivative thereof, i.e., a halocarbonyl group, preferably a chlorocarbonyl group, or a C,-C 7 alkoxy-carbonyl, preferably a C,-C 3 alkoxy-carbonyl group.
  • 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.
  • a strong base such as sodium hydride, potassium t-butoxide
  • a inert solvent such as 1 ,2-dimethoxyethane, dioxane, dimethylformamide
  • 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.
  • a base such as triethylamine
  • 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.
  • the hydrolysis can be performed in a aqueous solution of a halohydric acid, typically HC1, in a suitable solvent, e.g. dioxane or t
  • the intermediate compounds (II) and (VI) are either novel or known compounds or can be obtained by known methods from known compounds.
  • the remaining compounds of formula (II) wherein R, R,, R 2 , R 3 and Z are as defined above and X is O are new and are a further object of this invention. They may be obtained, for example, by reacting a compound of formula (VII)
  • 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 quinolinic acid and/or 3- hydroxykynurenine due to excessive activation of neuro-transmission mediated by excitatory amino acid receptors and/or oxidative stress.
  • neuropathological processes are neurodegenerative pathologies including, e.g.
  • a human or animal in need of a kynurenine-3-hydroxylase enzyme inhibitor can thus be treated by a method which comprises the administration thereto of a therapeutically effective amount of a compound of the invention or a salt thereof. The condition of the human or animal can thereby be improved.
  • the assay for kynurenine 3-hydroxylase is based on the enzymatic synthesis of tritiated water during the hydroxylation reaction. Radiolabeled water was quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal. Rat liver mitochondrial extract was used as enzymatic preparation for this assay. The assay for kynurenine 3-hydroxylase activity was carried out at 37°C for a time of 30 min.
  • the reaction mixture of a total volume of 100 ⁇ l was constituted of 44 ⁇ g 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, 0.5 ⁇ Ci L-(3,5- 3 H)Kynurenine (10 Ci/mmol) and 10 ⁇ l of different concentration of inhibitor solutions.
  • the reaction was terminated by the addition of 1 ml of 7.5% (W/v) activated charcoal, vortexed and centrifuged for 7 min.. A 500 ⁇ l aliquot of supernatant was counted by scintillation, spectroscopy in 5 ml of liquid scintillation.
  • 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 one representative compound of the invention PNU 155154A may range from about 10 to about 500 mg pro dose, from 1 to 5 times daily.
  • the compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.
  • the invention includes also pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent).
  • 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.
  • 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; desegregating agents, e.g.
  • 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 polyvin
  • 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.
  • 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.
  • a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • 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-(l-Methyl-l,4- dihydro-indeno-[l,2-c]pyrazol-3-yl)-3-oxo-propanenitrile (4 g; 0.0169 moles) in anhydrous dimethylformamide (100 mL).
  • the reaction mixture was allowed to react at room temperature for 30' 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.
  • Capsule each weighing 0.23 g and containing 50 mg of the active substance can be prepared as follow: Composition for 500 capsules:
  • This formulation can be encapsulated in two hard gelatin capsules of two pieces, each with each capsule weighing 0.23 g.
  • a pharmaceutical injectable composition can be manufactured dissolving 50 g of 2- Cyano-3-hydroxy-N-phenyl-3-(7-methyl-2,3,7,9b-tetrahydro-l H-acenaphtho[l ,2- c]pyrazol-9-yl)-acrylamide, sodium salt in sterile propylenglycol (1000 mL) and sealed in 1-5 ampoules.
  • IDO Indolamineoxigenase
  • KYN Kynurenine
  • KYN-OH Kynurenine-3-hydroxylase
  • KYNA Kynurenic acid
  • 3-OHAA 3-Hydroxy anthranilic acid
  • KAT Kynurenine amino transferase

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  • Biomedical Technology (AREA)
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  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne un composé qui est un dérivé de pyrazole condensé présentant la formule (I). Dans cette dernière, W représente -CONH-, -SO2- ou -CO-; X représente -O- ou -NR4- où R4 représente hydrogène, alkyle C1-C6, benzyle, pyridyle, tétrahydropyranyle ou un cycle phénylique qui est substitué ou non par un ou deux substituants similaires ou différents qui sont choisis indépendamment parmi halogène, trifluorométhyle, alkyle C1-C6, alcoxy C1-C6, nitro, amino, hydroxy, formylamino, alcanoylamino C2-C6 et carbonyle-alcoxy C1-C6. Chacun de R, R1 et R2, qui sont identiques ou différents, représente indépendamment hydrogène, halogène, hydroxy, trifluorométhyle, nitro, amino, phényle, benzyle, alkyle C1-C6, alcoxy C1-C6, alcanoylamino C2-C6, formylamino ou carbonyle-alcoxy C1-C6; et R3 représente hydrogène; ou R2 et R3 pris ensemble forment une chaîne alkylène C2-C6, -CH=CH-CH= ou -O-(CH2)n dans laquelle n représente 1, 2 ou 3; m représente zéro ou un nombre entier de 1 à 6; et Q représente alkyle C1-C14, un cycle phénylique ou une chaîne hétéromono-cyclique pentatomique non saturée, contenant deux ou trois hétéroatomes qui sont identiques ou différents et sont choisis indépendamment parmi de l'oxygène, du soufre et de l'azote, et où le cycle phénylique et la chaîne hétéromonocyclique ne sont pas substituées ou sont substituées par un ou deux substituants qui sont similaires ou différents et sont choisis indépendamment parmi halogène, hydroxy, trifluorométhyle, nitro, amino, phényle, benzyle, alkyle C1-C6, alcoxy C1-C6, alkanoylamino C2-C6, formylamino et carbonyle-alcoxy C1-C6. L'invention concerne également un sel pharmaceutiquement acceptable de ce composé. Ce dernier présente une grande utilité dans la fabrication d'un médicament prévu pour être utilisé comme inhibiteur de la kynurénine-3-hydroxylase.
EP98939623A 1997-07-30 1998-07-02 Composes heterocycliques condenses Withdrawn EP1001940A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9716103.8A GB9716103D0 (en) 1997-07-30 1997-07-30 Condensed heterocyclic compounds
GB9716103 1997-07-30
PCT/EP1998/004217 WO1999006374A1 (fr) 1997-07-30 1998-07-02 Composes heterocycliques condenses

Publications (1)

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EP1001940A1 true EP1001940A1 (fr) 2000-05-24

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EP98939623A Withdrawn EP1001940A1 (fr) 1997-07-30 1998-07-02 Composes heterocycliques condenses

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EP (1) EP1001940A1 (fr)
JP (1) JP2001512106A (fr)
AU (1) AU8806698A (fr)
CA (1) CA2297096A1 (fr)
GB (1) GB9716103D0 (fr)
WO (1) WO1999006374A1 (fr)

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IT1393930B1 (it) * 2009-02-25 2012-05-17 Neuroscienze Pharmaness S C A R L Composti farmaceutici

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NZ223204A (en) * 1987-01-21 1989-12-21 Erba Farmitalia Pyrazole derivatives and pharmaceutical compositions
GB8814587D0 (en) * 1988-06-20 1988-07-27 Erba Carlo Spa Condensed pyrazole 3-oxo-propanenitrile derivatives & process for their preparation
IT1265101B1 (it) * 1993-07-23 1996-10-30 Erba Carlo Spa Derivati dell'acido 2-ammino-4-fenil-4-osso butirrico
GB2316072B (en) * 1996-08-05 2000-05-10 Pharmacia Spa Pyrrolo[3,2-c]quinoline derivatives

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See references of WO9906374A1 *

Also Published As

Publication number Publication date
GB9716103D0 (en) 1997-10-01
AU8806698A (en) 1999-02-22
CA2297096A1 (fr) 1999-02-11
WO1999006374A1 (fr) 1999-02-11
JP2001512106A (ja) 2001-08-21

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