WO1999006375A1 - Composes heterocycliques fondus et utilisation de ces composes comme inhibiteurs de la kynurenine-3-hydroxylase - Google Patents

Composes heterocycliques fondus et utilisation de ces composes comme inhibiteurs de la kynurenine-3-hydroxylase Download PDF

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Publication number
WO1999006375A1
WO1999006375A1 PCT/EP1998/004218 EP9804218W WO9906375A1 WO 1999006375 A1 WO1999006375 A1 WO 1999006375A1 EP 9804218 W EP9804218 W EP 9804218W WO 9906375 A1 WO9906375 A1 WO 9906375A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
oxo
cyano
propanamide
compound
Prior art date
Application number
PCT/EP1998/004218
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English (en)
Inventor
Paolo Pevarello
Mario Varasi
Franco Heidempergher
Felicita Greco
Carmela Speciale
Original Assignee
Pharmacia & Upjohn S.P.A.
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 & Upjohn S.P.A. filed Critical Pharmacia & Upjohn S.P.A.
Priority to CA002296606A priority Critical patent/CA2296606A1/fr
Priority to AU87317/98A priority patent/AU8731798A/en
Priority to JP2000505134A priority patent/JP2001512107A/ja
Priority to EP98938689A priority patent/EP1001941A1/fr
Publication of WO1999006375A1 publication Critical patent/WO1999006375A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole 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
    • 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 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).
  • 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-, -SO 2 - or -CO-;
  • X is O, S or NR 2 , in which R is hydrogen, C,-C 6 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,-C 6 alkyl, C,-C 6 alkoxy. nitro. amino. hydroxy, formylamino. C ⁇ -C 6 alkanoylamino trifluoromethyl and C,-C 6 alkoxycarbonyl; each of R and R
  • Q is C
  • W, m and Q are as defined above, may be represented also by a tautomeric structure, namely the enol structure of formula (a)
  • the present invention includes within its scope the pharmaceutically acceptable salts and also all the possible isomers.
  • pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxydes, or with organic bases such as lysine.
  • 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.
  • the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e.
  • a -(CH 2 ) m - chain or an alkyl or alkoxy chain may be a branched or straight chain.
  • a C r C M 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 ft alkoxy group is preferably a C,-C 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 r C 4 alkoxy-carbonyl group typically a
  • 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 NR 2 , wherein R 2 is hydrogen, C r C 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,-C 4 alkyl, C C 4 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 4 alkanoylamino and C r C 4 alkoxy-carbonyl; each of R and R[ which are the same or different is independently hydrogen, halogen, hydroxy, trifluoromethyl, amino, C,-C 4 alkyl, C C 4 alkoxy, C -C 4 alkanoylamino, or C r C 4 alkoxy-carbonyl; m is zero or 1
  • 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 r C 4 alkyl, C r C 4 alkoxy. C 2 -C 4 alkanoylamino and C , -C 4 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-
  • 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.
  • 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 compound of formula (I) may be converted into another compound of formula (I) by known methods.
  • 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.
  • 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.
  • 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, preferably a C 2 -C 3 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.
  • 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.
  • a halohydric acid typically HCl
  • a suitable solvent e.g. dioxane or tetrahydrofuran at a temperature varying from room temperature to about 40 °C.
  • 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 NR 2 wherein R 2 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 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.
  • 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.
  • 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.
  • AIDS Acquired Immunodeficiency Syndrome
  • 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 lOO ⁇ l was constituted of 44 ⁇ g 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 ⁇ 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 cent ⁇ fuged for 7 min
  • 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 representat ⁇ 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
  • 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.
  • 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
  • the reaction mixture was allowed to react at room temperature for 40' then acidified to pH
  • Capsule each weighing 0.23 g and containing 50 mg of the active substance can be prepared as follow:
  • composition for 500 capsules is 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-
  • IDO Indolamineoxigenase
  • KYN-OH Kynurenine-3-hydroxylase
  • KYNA Kynurenic acid
  • 3-OHAA 3-Hydroxy anthranilic acid
  • KYNase Kynureninase
  • 3-HAO 3-Hydroxy anthranilic acid deoxygenase
  • KAT Kynurenine amino transferase
  • 3-OH-KYN 3-Hydroxy-kynurenine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne un composé qui est un hétérocycle condensé selon la formule (I). Dans cette formule, a, b et c sont tous des simples liaisons; ou a, b et c sont tous des doubles liaisons, ou a est un double liaison et b et c sont tous des doubles liaisons, ou a est une double liaison et b et c sont des simples liaisons. m est égal à zéro ou un nombre entier compris entre 1 et 6; W représente -CONH-, -SO2- ou -CO-; X représente O, S ou NR2 dans lequel R2 est hydrogène, alkyle C1-C6, benzyle, pyridyle, tétrahydropyranyle ou une chaîne phényle non substituée ou substituée par un ou plusieurs substituants qui sont semblables ou différents et sont choisis indépendamment parmi halogène, alkyle C1-C6; R et R1 sont indépendamment hydrogène, halogène, hydroxy, trifluorométhyle, nitro, amino, phényle, benzyle, alkyle C1-C6, alcoxy C1-C6; et Q représente alkyle C1-C14 ou une chaîne phényle ou une chaîne hétéromonocyclique pényle ou une chaîne hétéromonocyclique pentatomique non saturée contenant deux ou trois hétéroatomes choisis indépendamment parmi de l'oxygène, soufre et azote, où la chaîne phényle et la chaîne hétéromonocyclique ne sont pas substituées ou sont substituées ou sont substituées par un ou deux substituants qui sont les mêmes ou différents et sont choisis indépendamment parmi halogène, hydroxy, trifluorométhyle, nitro, amino, phényle, benzyle, alkyle C1-C6, alcoxy C1-C6, alcanoylamino C2-C6, formylamino et alcoxy-carbonyl C1-C6, alcoxy C1-C6 ou des sels pharmaceutiquement acceptables de ces derniers. Ce composé présente une grande utilité comme inhibiteur de la kynurénine-3-hydroxylase.
PCT/EP1998/004218 1997-07-30 1998-07-02 Composes heterocycliques fondus et utilisation de ces composes comme inhibiteurs de la kynurenine-3-hydroxylase WO1999006375A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002296606A CA2296606A1 (fr) 1997-07-30 1998-07-02 Composes heterocycliques fondus et utilisation de ces composes comme inhibiteurs de la kynurenine-3-hydroxylase
AU87317/98A AU8731798A (en) 1997-07-30 1998-07-02 Fused heterocyclic compounds and their use as kynurenine-3-hydroxylase inhibitors
JP2000505134A JP2001512107A (ja) 1997-07-30 1998-07-02 融合ヘテロ環式化合物及びそのキヌレニン−３−ヒドロキシラーゼ阻害剤としての使用
EP98938689A EP1001941A1 (fr) 1997-07-30 1998-07-02 Composes heterocycliques fondus et utilisation de ces composes comme inhibiteurs de la kynurenine-3-hydroxylase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9716101.2A GB9716101D0 (en) 1997-07-30 1997-07-30 Fused heterocyclic compounds
GB9716101.2 1997-07-30

Publications (1)

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WO1999006375A1 true WO1999006375A1 (fr) 1999-02-11

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PCT/EP1998/004218 WO1999006375A1 (fr) 1997-07-30 1998-07-02 Composes heterocycliques fondus et utilisation de ces composes comme inhibiteurs de la kynurenine-3-hydroxylase

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EP (1) EP1001941A1 (fr)
JP (1) JP2001512107A (fr)
AU (1) AU8731798A (fr)
CA (1) CA2296606A1 (fr)
GB (1) GB9716101D0 (fr)
WO (1) WO1999006375A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011681A1 (fr) * 2003-07-29 2005-02-10 Smithkline Beecham Corporation Composes chimiques
EP3135674A4 (fr) * 2014-04-23 2017-12-20 Mitsubishi Tanabe Pharma Corporation Nouveau composé hétérocyclique bicyclique ou tricyclique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5143923A (en) * 1991-04-29 1992-09-01 Hoechst-Roussel Pharmaceuticals Inc. Benzoisothiazole- and benziosoxazole-3-carboxamides
WO1997015550A1 (fr) * 1995-10-20 1997-05-01 Pharmacia & Upjohn S.P.A. Derives de l'acide benzoylpropionique substitues par fluoro
WO1997017316A1 (fr) * 1995-11-03 1997-05-15 Pharmacia & Upjohn S.P.A. Derives de l'acide 4-phenyl-4-oxo-2-butenoique possedant une activite inhibitrice de la kynurenine-3-hydroxylase

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5143923A (en) * 1991-04-29 1992-09-01 Hoechst-Roussel Pharmaceuticals Inc. Benzoisothiazole- and benziosoxazole-3-carboxamides
US5143923B1 (en) * 1991-04-29 1993-11-02 Hoechst-Roussel Pharmaceuticals Incorporated Benzoisothiazole-and benzisoxazole-3-carboxamides
WO1997015550A1 (fr) * 1995-10-20 1997-05-01 Pharmacia & Upjohn S.P.A. Derives de l'acide benzoylpropionique substitues par fluoro
WO1997017316A1 (fr) * 1995-11-03 1997-05-15 Pharmacia & Upjohn S.P.A. Derives de l'acide 4-phenyl-4-oxo-2-butenoique possedant une activite inhibitrice de la kynurenine-3-hydroxylase

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011681A1 (fr) * 2003-07-29 2005-02-10 Smithkline Beecham Corporation Composes chimiques
EP3135674A4 (fr) * 2014-04-23 2017-12-20 Mitsubishi Tanabe Pharma Corporation Nouveau composé hétérocyclique bicyclique ou tricyclique
US10065972B2 (en) 2014-04-23 2018-09-04 Mitsubishi Tanabe Pharma Corporation Bicyclic or tricyclic heterocyclic compound
RU2702113C2 (ru) * 2014-04-23 2019-10-04 Мицубиси Танабе Фарма Корпорейшн Новое бициклическое или трициклическое гетероциклическое соединение
EP3683222A1 (fr) * 2014-04-23 2020-07-22 Mitsubishi Tanabe Pharma Corporation Nouveau composé hétérocyclique bicyclique ou tricyclique

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JP2001512107A (ja) 2001-08-21
EP1001941A1 (fr) 2000-05-24
CA2296606A1 (fr) 1999-02-11
GB9716101D0 (en) 1997-10-01
AU8731798A (en) 1999-02-22

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