EP1001941A1 - 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

Info

Publication number
EP1001941A1
EP1001941A1 EP98938689A EP98938689A EP1001941A1 EP 1001941 A1 EP1001941 A1 EP 1001941A1 EP 98938689 A EP98938689 A EP 98938689A EP 98938689 A EP98938689 A EP 98938689A EP 1001941 A1 EP1001941 A1 EP 1001941A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
oxo
cyano
propanamide
compound
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Withdrawn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
EP98938689A
Other languages
German (de)
English (en)
Inventor
Paolo Pevarello
Mario Varasi
Franco Heidempergher
Felicita Greco
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 EP1001941A1 publication Critical patent/EP1001941A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

  • 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
  • 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.
  • 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.
  • 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 -
  • 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 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.
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the reaction mixture was allowed to react at room temperature for 40' then acidified to pH
  • 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-
  • KYN-OH Kynurenine-3-hydroxylase
  • 3-OHAA 3-Hydroxy anthranilic acid
  • KYNase Kynureninase

Landscapes

  • 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.
EP98938689A 1997-07-30 1998-07-02 Composes heterocycliques fondus et utilisation de ces composes comme inhibiteurs de la kynurenine-3-hydroxylase Withdrawn EP1001941A1 (fr)

Applications Claiming Priority (3)

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

Publications (1)

Publication Number Publication Date
EP1001941A1 true EP1001941A1 (fr) 2000-05-24

Family

ID=10816708

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98938689A Withdrawn EP1001941A1 (fr) 1997-07-30 1998-07-02 Composes heterocycliques fondus et utilisation de ces composes comme inhibiteurs de la kynurenine-3-hydroxylase

Country Status (6)

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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1648448A4 (fr) * 2003-07-29 2009-04-01 Smithkline Beecham Corp Composes chimiques
BR112016024455B1 (pt) 2014-04-23 2023-02-07 Mitsubishi Tanabe Pharma Corporation Composto heterocíclico bicíclico ou tricíclico

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5143923B1 (en) * 1991-04-29 1993-11-02 Hoechst-Roussel Pharmaceuticals Incorporated Benzoisothiazole-and benzisoxazole-3-carboxamides
GB9521486D0 (en) * 1995-10-20 1995-12-20 Pharmacia Spa Fluoro-substituted benzoylpropionic acid derivatives
GB9522617D0 (en) * 1995-11-03 1996-01-03 Pharmacia Spa 4-Phenyl-4-oxo-butenoic acid derivatives with kynurenine-3-hydroxylase inhibiting activity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9906375A1 *

Also Published As

Publication number Publication date
WO1999006375A1 (fr) 1999-02-11
JP2001512107A (ja) 2001-08-21
GB9716101D0 (en) 1997-10-01
AU8731798A (en) 1999-02-22
CA2296606A1 (fr) 1999-02-11

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