WO1999016753A2 - Composes 3-oxo-propanenitrile tricycliques - Google Patents

Composes 3-oxo-propanenitrile tricycliques Download PDF

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Publication number
WO1999016753A2
WO1999016753A2 PCT/EP1998/006051 EP9806051W WO9916753A2 WO 1999016753 A2 WO1999016753 A2 WO 1999016753A2 EP 9806051 W EP9806051 W EP 9806051W WO 9916753 A2 WO9916753 A2 WO 9916753A2
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Prior art keywords
oxo
methyl
propionitrile
phenyl
cyano
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PCT/EP1998/006051
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English (en)
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WO1999016753A3 (fr
Inventor
Paolo Pevarello
Mario Varasi
Raffaella Amici
Salvatore Toma
Carmela Speciale
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Pharmacia & Upjohn S.P.A.
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Priority to EP98956836A priority Critical patent/EP1019380A2/fr
Priority to AU13343/99A priority patent/AU1334399A/en
Priority to JP2000513839A priority patent/JP2001518469A/ja
Priority to CA002302025A priority patent/CA2302025A1/fr
Publication of WO1999016753A2 publication Critical patent/WO1999016753A2/fr
Publication of WO1999016753A3 publication Critical patent/WO1999016753A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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

Definitions

  • the present invention relates to novel tri cyclic 3-oxo-propanenitrile 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 -hydro xylase (KYN-
  • 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 ;
  • 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.
  • the compounds of the present invention fulfill such a need.
  • the present invention provides novel tricyclic 3-oxo-propanenitrile compounds of formula (I)
  • Y represents a nitrogen atom or a CH or N-oxide group
  • X represents an oxygen atom or NR 2 wherein R 2 represents C,-C 6 alkyl, benzyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C C 6 alkyl, C r C 6 alkoxy, nitro, amino, formylamino and C 2 -C 8 alkanoylamino; each of R and R, is independently hydrogen, halogen, CF 3 , C r C 6 alkyl, hydroxy, C r C 6 alkoxy, C 3 -C 4 alkenyloxy, nitro, amino, formylamino, C 2 -C 8 alkanoylamino or C 2 -C 8 alkanoyloxy; m is zero or an integer of 1 to 6; Q is C1-C1 4 alkyl, phenyl or unsaturated pentatomic heteromonocyclic ring containing two or
  • the present invention also includes within its scope the pharmaceutically acceptable salts, and all possible isomers, stereoisomers and opti al 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.
  • X, Y, R, R b m, Q .and W are as defined above.
  • alkyl, alkanoyloxy, alkoxy and alkanoylamino groups may be branched or straight chain groups.
  • a CpC 1 alkyl group is preferably a C,-C 6 alkyl group.
  • C,-C 6 alkyl groups include C.-C alkyl groups such as methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl.
  • C C 6 alkoxy groups include C.-C 4 alkoxy groups such as methoxy or ethoxy.
  • C 2 -C 8 alkanoylamino include C 2 -C 4 alkanoyl groups such as acetylamino or propionylamino.
  • Representative examples of C 2 -C 8 alkanoyloxy include C 2 -C alkanoyl groups such as acetoxy or propionyloxy.
  • a C 3 -C 4 alkenyloxy group is preferably allyloxy.
  • 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 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, ⁇ -phenethylamine,
  • inorganic bases e.g. sodium, potassium, calcium and aluminium hydroxydes
  • organic bases e.g. lysine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N- ethylpiperidine, N,N-diethylaminoethylamine,
  • N-benzyl- ⁇ -phenethylamine N-benzyl-N,N-dimethylamine and the other acceptable organic amines.
  • Preferred compounds of the invention are the compounds of formula (I) wherein: Y represents a nitrogen atom or a CH group;
  • X is oxygen or NR 2 wherein R 2 represents C,-C 4 alkyl or phenyl unsubstituted or substituted by one or two substituents selected independently from halogen, trifiuoromethyl, C r C alkyl, C,-C 4 alkoxy and nitro; each of R and R, independently is hydrogen, nitro, halogen, trifiuoromethyl, C,-C 4 alkyl or C r C 4 alkoxy; m is zero or 1 ;
  • Q is C r C 4 alkyl or a phenyl ring unsubstituted or substituted by one or two substituents selected from halogen, trifiuoromethyl, nitro, C,-C 4 alkyl and C r C 4 alkoxy;
  • W is a -CONH-, -SO 2 - or -CO- group; and the pharmaceutically acceptable salts thereof.
  • a further object of the present invention is also to provide a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance, in particular as kynurenine-3-hydroxylase enzyme inhibitor.
  • Object of the present invention is also the use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use 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 -hydroxy lase inhibitor, such method comprising adminstering thereto a therapeutically effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention and the salts thereof can be obtained, for instance, by a process comprising: a) reacting a compound of formula (II)
  • X, R and R are as defined above, Y represents a nitrogen atom or a CH group and Z is a derivative of a carboxy group,with a compound of formula (III)
  • 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 C 2 -C 7 alkoxycarbonyl group, preferably a C 2 -C 3 alkoxycarbonyl 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, thallous ethoxide, in an inert solvent such as 1 ,2-dimethoxyethane, dioxane, dimethylformamide, at a temperature ranging from about 0°C to about 100°C.
  • a strong base such as sodium hydride, potassium t-butoxide, thallous ethoxide
  • an inert solvent such as 1 ,2-dimethoxyethane, dioxane, dimethylformamide
  • 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 sodium hydride or triethylamine, in an inert solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide, dichloromethane, at a temperature varying between about 0°C and about 100°C.
  • a base such as sodium hydride or triethylamine
  • an inert solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide, dichloromethane
  • the conversion of a compound of formula (I) wherein Y is a nitrogen atom into the corresponding compound of formula (I) in which Y is a N-oxide group may be performed by treatment, for example, with m-chloroperbenzoic acid or perbenzoic acid in a solvent such as dichloromethane or with H 2 O 2 in acetic acid.
  • a compound of formula (I) into another compound of formula (I) can be carried out according to known methods.
  • 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.
  • an amino group may be converted into a formylamino or a C 2 -C 8 alkanoylamino group, for example by reacting with formic acid or with the suitable C 2 -C 8 alkanoylanhydride without any solvent or in an organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as pyridine or triethylamine, at a temperature varyng between about 0°C and about 100°C.
  • a compound of formula (II), wherein Z is a C 2 -C 7 alkoxycarbonyl group, can be otbained for instance by aromatization of a compound of formula (VII)
  • Aromatization reaction may be accomplished using quinones such as, e.g. chloroanil (2.3,5,6-tetrachloro-l,4- benzoquinone) or DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone), in a solvent such as toluene, dioxane, at a temperature varying between about room temperature and about 120°C.
  • Aromatization reaction, wherein Y is a nitrogen atom can be simply performed warming a compound of formula (VII) in an organic solvent such as dimethylformamide.
  • a compound of formula (VII) may be prepared, for example, by reacting a compound of formula (VIII)
  • R, Ri and A are as defined above and R 3 is a lower alkyl, e.g. C,-C 6 alkyl, preferably C r C 2 alkyl, with a compound of formula (IX)
  • reaction between a compound of formula (VIII) and a compound of formula (IX) may be carried out, for example, in an organic solvent such as C,-C 6 alkyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, acetic acid, at a temperature varying between about 0°C and about 150°C, in the presence or in the absence of a suitable acid, e.g. methanesulfonic acid.
  • organic solvent such as C,-C 6 alkyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, acetic acid
  • a compound of formula (II), wherein Z is halocarbonyl, preferably chlorocarbonyl, may be prepared, for example, by reacting the corresponding compound of formula (II), wherein Z is carboxy, with the suitable acid halide, for example oxalyl chloride, thionyl chloride, PC1 3 , PBr 3 , in an inert solvent such as ether, benzene, dichloromethane, dioxane or without any solvent, at a temperature varying between about 0°C and about 100°C.
  • the suitable acid halide for example oxalyl chloride, thionyl chloride, PC1 3 , PBr 3
  • an inert solvent such as ether, benzene, dichloromethane, dioxane or without any solvent
  • the compounds of formula (II), wherein Z is carboxy may be prepared, for example, by hydrolysis of the corresponding compounds of formula (II) wherein Z is C 2 -C 7 alkoxycarbonyl, according to standard methods well known in the art, for example, by basic hydrolysis, carried out e.g. by treatment with sodium or potassium hydroxide in a solvent such as water, C 2 -C 6 alkyl alcohol, dioxane, dimethylformamide and their mixtures, at a temperature varying between about 0°C and about 50°C.
  • Compounds of formula (III) are, in some cases, commercially available products, or may be prepared by methods well known in the art.
  • a compound of formula (IV) as herein defined are novel compounds and are a further object of this invention.
  • a compound of formula (IV) can be obtained by process a) above, for example, by reacting a compound of formula (II), wherein Z is C 2 -C 7 alkoxycarbonyl, with acetonitrile, in the presence of a strong base e.g. sodium hydride, potassium tert- butoxide, in an inert organic solvent such as benzene, dioxane, tetrahydrofuran, at a temperature varying between about 0°C and about 100°C.
  • a compound of formula (VIII) may be prepared, for example, by reacting a compound of formula (X)
  • each of R 4 and R 5 being the same or different, is C,-C 6 alkyl, preferably methyl or ethyl.
  • the reaction between a compound of formula (X) and a compound of formula (XI) may be carried out, for example, in the presence of a strong base such as sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide, in an organic solvent such as C,-C 6 alkyl alcohol, benzene, dioxane, dimethylformamide, at a temperature varying between about 0°C and about 100°C.
  • a strong base such as sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide
  • organic solvent such as C,-C 6 alkyl alcohol, benzene, dioxane, dimethylformamide
  • This group may be protected before being reacted and then deprotected according to methods well known in organic chemistry, for example, by reacting with p-toluensulfonylchloride in pyridine at a temperature varying between 0°C and about 120°C and then by treatment with methanesulfonic acid and anisole at a temperature ranging from about 0°C to about 60°C.
  • the compounds of formula (V), (VI), (X) and (XI) are known compounds and may be prepared by conventional methods: in some cases they are commercially available products. 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.
  • the compounds of the invention are active as kynurenine-3-hydroxylase enzyme inhibitors and therefore are useful in the prevention and/or treatment of neuropatho logical processes, related to a deranged production of QUIN and/or 3-OH- KYN 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. 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.
  • AIDS Acquired Immunodeficiency Syndrom
  • 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 100 ml was constituted of 44 mg of suspended extract, 100 ⁇ M Tris/Cl " buffer pH 8.1, 10 ⁇ M EDTA, 100 ⁇ M KC1, 0.8 ⁇ M NADPH, 0.025 ⁇ M L-Kynurenine, 0.5 ⁇ Ci L-(3,5- 3 H)Kynurenine (10 Ci/ ⁇ mol) and 10 ⁇ l of different concentration of inhibitor solutions.
  • the reaction was terminated by the addition of 1 ⁇ l of 7.5% (W/v) activated charcoal, vortexed and centrifuged for 7 min..
  • 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 168754 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.
  • 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).
  • 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; disaggregating 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 polyviny
  • 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.
  • 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.
  • 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.
  • a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • Methylhydrazine (3.6 ml; 0.068 mol) was added under stirring to a solution of hydroxy- (l-oxo-3,4-dihydro-lH-naphthalen-2-ylidene)-acetic acid, ethyl ester (15.0 g; 0.061 mol) in acetic acid (100 ml) at room temperature (exotermic reaction).
  • the reaction mixture was stirred without cooling for 7 h and was then diluted with ice water (200 ml).
  • the products (both isomers) were extracted with ethyl acetate (300 ml), the organic solution was dried over anhydrous sodium sulfate and the solvent was evaporated.
  • Example 3 Preparation of 1 -methyl- lH-benzo[glindazole-3-carboxylic acid, ethyl ester.
  • Methylhydrazine (4.51 ml, 0.0848 mol) was added dropwise to a solution of hydroxy- [4-oxo-l-(p-toluensulfonyl)-2,4-dihydro-lH-quinolin-3-ylidene]-acetic acid, ethyl ester (17 g, 0.0424 mol) in glacial acetic acid (180 ml) at room temperature; the reaction mixture was heated at 50°C for about 10 hours, cooled at room temperature, diluted with water (200 ml) and extracted with ethyl acetate (3X200 ml).
  • the following products can be prepared: 8-fluoro-isoxazolo[2,l-a]naphthalene-3-carboxylic acid, ethyl ester; 9-chloro-isoxazolo[2, 1 -a]naphthalene-3-carboxylic acid, ethyl ester; and 9-methoxy-isoxazolo[2,l-a]naphthalene-3-carboxylic acid, ethyl ester.
  • the following products can be prepared: 3-(8-fluoro-isoxazolo[2,l-a)naphthalen-3-yl)-3-oxo-propionitrile; 3-(9-chloro-isoxazolof2, 1 -aJnaphthalen-3-yl)-3-oxo-propionitrile; .and 3-(9-methoxy-isoxazolo[2,l-aJnaphthalen-3-yl)-3-oxo-propionitrile.
  • Capsule each weighting 0.23 g and containing 50 mg of the active substance can be prepared as follows: Composition for 500 capsules:
  • This formulation can be incapsulated in two hard gelatin capsules of two pieces, each with each capsule weighing 0.23 g.
  • a pharmaceutical injectable composition can be manifactured dissolving 50 g 2-cyano-
  • IDO Indolamineoxigenase
  • KYN-OH Kynurenine-3 -hydroxy lase
  • KAT kynurenine amino transferase

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne des composés 3-oxo-propanenitrile tricycliques correspondant à la formule (I), ainsi qu'un sel de ceux-ci, acceptable sur le plan pharmacologique. Dans cette formule Y représente un atome d'azote ou un groupe CH ou N-oxyde, X représente un atome d'oxygène ou NR2 dans lequel R2 représente alkyle C1-C6, benzyle, pyridyle ou phényle, phényle n'étant pas substitué ou l'étant par un ou deux substituants choisis indépendamment dans le groupe constitué par halogène, trifluorométhyle, alkyle C1-C6, alcoxy C1-C6, nitro, amino, formylamino et alcanoylamino C2-C8, R et R1 représentent chacun indépendamment hydrogène, halogène, CF3, alkyle C1-C6, hydroxy, alcoxy C1-C6, alcényloxy C3-C4, nitro, amino, formylamino, alcanoylamino C2-C8, ou alcanoyloxy C2-C8, m vaut zéro ou est un nombre entier compris entre 1 et 6, Q représente alkyle C1-C14, un noyau phényle ou un noyau hétéromonocyclique pentatomique insaturé contenant deux ou trois hétéroatomes choisis parmi oxygène, soufre et azote, le noyau phényle et le noyau hétéromonocyclique n'étant pas substitués ou l'étant pas un ou deux substituants choisis indépendamment dans le groupe constitué par halogène, CF3, alkyle C1-C6, hydroxy, alcoxy C1-C6, nitro, amino, formylamino, alcanoylamino C2-C8 ou alcanoyloxy C2- C8, et W représente un groupe -CONH- ou -SO2- ou -CO-. Ces composés et leur sel possèdent une activité inhibitrice de l'enzyme kynurénine-3-hydroxylase.
PCT/EP1998/006051 1997-10-01 1998-09-23 Composes 3-oxo-propanenitrile tricycliques WO1999016753A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98956836A EP1019380A2 (fr) 1997-10-01 1998-09-23 Composes 3-oxo-propanenitrile tricycliques
AU13343/99A AU1334399A (en) 1997-10-01 1998-09-23 Tricyclic 3-oxo-propanenitrile compounds
JP2000513839A JP2001518469A (ja) 1997-10-01 1998-09-23 三環式３−オキソ−プロパンニトリル化合物
CA002302025A CA2302025A1 (fr) 1997-10-01 1998-09-23 Composes 3-oxo-propanenitrile tricycliques

Applications Claiming Priority (2)

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GB9720899.5 1997-10-01
GBGB9720899.5A GB9720899D0 (en) 1997-10-01 1997-10-01 Condensed heterocyclic compounds

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WO1999016753A3 WO1999016753A3 (fr) 1999-05-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7049271B2 (en) 2000-05-08 2006-05-23 Bayer Aktiengesellschaft Phenyl-substituted 2-enamino-ketonitriles
WO2007143523A2 (fr) 2006-06-02 2007-12-13 Elan Pharmaceuticals, Inc. Sulfonamides tricycliques condensés inhibiteurs de gamma-secrétase

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3842099A (en) * 1969-10-06 1974-10-15 Teikoku Hormune Mfg Co Ltd Naphtho(2,1-d)isoxazole derivatives
EP0021207A1 (fr) * 1979-06-11 1981-01-07 Ciba-Geigy Ag Alphacarbamoyle-pyrrolpropionitriles, procédé pour leur préparation et compositions pharmaceutiques les contenant
US4435407A (en) * 1982-01-07 1984-03-06 Ciba-Geigy Corporation Certain substituted β-oxo-α-carbamoylpyrrolepropionitriles
EP0156091A1 (fr) * 1982-09-28 1985-10-02 Ciba-Geigy Ag Bêta-oxo-alpha-carbamoyl-pyrrolpropionitriles, procédés de leur préparation, composés les contenant et leur utilisation thérapeutique
EP0274443A1 (fr) * 1987-01-09 1988-07-13 FARMITALIA CARLO ERBA S.r.l. Dérivés d'hétéroaryl oxo-3 propanenitrile et procédé pour leur préparation
WO1989012638A1 (fr) * 1988-06-20 1989-12-28 Farmitalia Carlo Erba S.R.L. Derives de 3-oxo-propane-nitrile tricycliques et procede servant a leur preparation
EP0372470A2 (fr) * 1988-12-08 1990-06-13 Ciba-Geigy Ag Cyano-alpha-oxo-bêta-propionamides
DE3940074A1 (de) * 1989-02-06 1990-08-09 Erba Carlo Spa Kondensierte 3-oxo-propannitrilderivate und verfahren zu ihrer herstellung
WO1991001309A1 (fr) * 1989-07-17 1991-02-07 Farmitalia Carlo Erba S.R.L. Derives d'heteroaryl-3-oxo-propanenitrile utiles a la stimulation de la myelopoïese
EP0620489A1 (fr) * 1993-04-12 1994-10-19 Konica Corporation Procédé de formation d'image photographique cyan

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3542826B2 (ja) * 1994-07-11 2004-07-14 帝国臓器製薬株式会社 新規な二環式化合物縮合［２，１−ｄ］イソキサゾール−３−カルボン酸誘導体

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3842099A (en) * 1969-10-06 1974-10-15 Teikoku Hormune Mfg Co Ltd Naphtho(2,1-d)isoxazole derivatives
EP0021207A1 (fr) * 1979-06-11 1981-01-07 Ciba-Geigy Ag Alphacarbamoyle-pyrrolpropionitriles, procédé pour leur préparation et compositions pharmaceutiques les contenant
US4435407A (en) * 1982-01-07 1984-03-06 Ciba-Geigy Corporation Certain substituted β-oxo-α-carbamoylpyrrolepropionitriles
EP0156091A1 (fr) * 1982-09-28 1985-10-02 Ciba-Geigy Ag Bêta-oxo-alpha-carbamoyl-pyrrolpropionitriles, procédés de leur préparation, composés les contenant et leur utilisation thérapeutique
EP0274443A1 (fr) * 1987-01-09 1988-07-13 FARMITALIA CARLO ERBA S.r.l. Dérivés d'hétéroaryl oxo-3 propanenitrile et procédé pour leur préparation
WO1989012638A1 (fr) * 1988-06-20 1989-12-28 Farmitalia Carlo Erba S.R.L. Derives de 3-oxo-propane-nitrile tricycliques et procede servant a leur preparation
EP0372470A2 (fr) * 1988-12-08 1990-06-13 Ciba-Geigy Ag Cyano-alpha-oxo-bêta-propionamides
DE3940074A1 (de) * 1989-02-06 1990-08-09 Erba Carlo Spa Kondensierte 3-oxo-propannitrilderivate und verfahren zu ihrer herstellung
WO1991001309A1 (fr) * 1989-07-17 1991-02-07 Farmitalia Carlo Erba S.R.L. Derives d'heteroaryl-3-oxo-propanenitrile utiles a la stimulation de la myelopoïese
EP0620489A1 (fr) * 1993-04-12 1994-10-19 Konica Corporation Procédé de formation d'image photographique cyan

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 96, no. 5, 31 May 1996 & JP 08 027131 A (TEIKOKU HORMONE MPG CO LTD), 30 January 1996 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7049271B2 (en) 2000-05-08 2006-05-23 Bayer Aktiengesellschaft Phenyl-substituted 2-enamino-ketonitriles
WO2007143523A2 (fr) 2006-06-02 2007-12-13 Elan Pharmaceuticals, Inc. Sulfonamides tricycliques condensés inhibiteurs de gamma-secrétase

Also Published As

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GB9720899D0 (en) 1997-12-03
EP1019380A2 (fr) 2000-07-19
JP2001518469A (ja) 2001-10-16
WO1999016753A3 (fr) 1999-05-20
CA2302025A1 (fr) 1999-04-08
AU1334399A (en) 1999-04-23

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