WO2003064428A1 - Furano- et thienopyrimidines en tant qu'inhibiteurs de la neurokinase - Google Patents

Furano- et thienopyrimidines en tant qu'inhibiteurs de la neurokinase Download PDF

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Publication number
WO2003064428A1
WO2003064428A1 PCT/DK2003/000054 DK0300054W WO03064428A1 WO 2003064428 A1 WO2003064428 A1 WO 2003064428A1 DK 0300054 W DK0300054 W DK 0300054W WO 03064428 A1 WO03064428 A1 WO 03064428A1
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Prior art keywords
alk
pyrimidin
hydrazine
thieno
ylmethylene
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PCT/DK2003/000054
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English (en)
Inventor
Mario Rottländer
Samms Anette Graven
Jakob Felding
Jan Torleif Pedersen
Kim Andersen
Ejner Knud Moltzen
KRISTENSEN Jesper LANGGÅRD
Thomas Balle
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H. Lundbeck A/S
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Publication of WO2003064428A1 publication Critical patent/WO2003064428A1/fr

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    • 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
    • C07D491/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • R 6 represents C ⁇ _ 6 -alk(en/yn)yl, C 3-8 -cycloalk(en/yn)yl, C -8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl or Ar 1 ;
  • R 6 represents indolyl, hydroxy-C 1-6 -alk(en/yn)yl-thiophenyl, C i -6 -alk(en/yn)yloxy-C i -6 -alk(en/yn)yl-thiophenyl, benzo [1,3] dioxolyl, pyrrolyl, C 1-6 -alk(en/yn)ylphenyl or hydroxyphenyl all of which may be substituted one or more times by halogen, cyano, nitro, C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 1-6 -alk(en yn)yloxy-C 1-6 -alk(en/yn)yl,
  • Ar 1 and Ar 2 are independently selected from the group represented by aryl, a heterocycle or a carbocycle all of which may be substituted one or more times by halogen, cyano, nitro, C 1-6 -alk(en/yn)yl, C 1 _ 6 -alk(en yn)yloxy, C 1-6 -alk(en/yn)yloxy- C i -6 -alk(en yn)yl, aryloxy-, a yl- -e-alk en yhJyloxy, halo- -e-all n/ynJyloxy, C 1-6 -alk(en/yn)yl- sulfanyl, hydroxy, hy ⁇ oxy-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, cyano- C ⁇ -6 -alk(en/yn)y
  • R 7 and R 8 are independently selected from the group represented by hydrogen and C 1-6 -alk(en/yn)yl which may be further substituted by hydroxy, halogen, C 1-6 -alkoxy, cyano, nitro, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl or a heterocycle; or R 7 and R 8 together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one or more further heteroatoms and may optionally be substituted by halogen, C 1-6 -alk(en/yn)yl, hydroxy, hydroxy- C 1-6 -alk(en/yn)yl or acyl; the aryls may be further substituted by halogen, cyano, nitro, C 1-6 -alk(en/yn)yl, C ⁇ -6 -alk(en
  • R 6 is not an optionally substituted hydroxyphenyl
  • the invention provides, in yet another embodiment, a compound as above as a medicament.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula I as defined above or a pharmaceutically acceptable acid addition salt thereof or prodrug thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.
  • A is S.
  • W is NH.
  • R 4 and R 5 are both hydrogen.
  • R 3 is C 1 _ 6 -alk(en yn)yl, or R 9 -Ar 2 .
  • R 9 is C 1-6 -alkyl optionally substituted by OH.
  • R 3 is methyl, ethyl, isopropyl or an optionally substituted benzyl, 1-phenethyl or pyridylmethyl.
  • R 3 is an optionally substituted benzyl, 1-phenethyl or pyridylmethyl.
  • benzyl, 1-phenethyl or pyridylmethyl are unsubstituted or substituted by -CONR 7 R 8 .
  • R 3 is C 1-6 -alkyl.
  • R 3 is C ⁇ -6 -alkyl wherein the carbon adjacent to the heterocyclic ring is a primary, secondary or tertiary carbon.
  • R 3 is methyl, ethyl or isopropyl.
  • R 6 represents C 1--6 -alk(en/yn)yl or Ar 1 wherein Ar 1 is an optionally substituted thiophenyl, indolyl, phenyl, pyrrolyl, quinolinyl, benzo[l,3]dioxolyl or thiazolyl.
  • Ar 1 is an optionally substituted indolyl, hydroxy-C ⁇ -6 -alk(en/yn)yl-thiophenyl, C ⁇ -6 -alk(en/yn)yloxy-C ⁇ -6 -alk(en yn)yl- thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C 1-6 -alk(en yn)ylphenyl or hydroxyphenyl.
  • Ar 1 is an optionally substituted indolyl, hydroxy-C ⁇ -6 -alk(en/yn)yl-thiophenyl, C 1-6 -alk(en/yn)yloxy-C ⁇ -6 -alk(en/yn)yl- thiophenyl.
  • indolyl is indol-3-yl and/or thiophenyl is thiophen-2-yl.
  • Ar 1 is unsubstituted or substituted one or more times by C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, hydroxy, nitro, halogen, R 7 R 8 NCO-C 1-6 -alk(en/yn)yl; -NR 7 R 8 , C 1-6 -alk(en/yn)yl-CON-, cyano, C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yloxycarbonyl or aryl.
  • A is S
  • W is NH
  • R 4 and R 5 are both hydrogen
  • R 3 is an optionally substituted benzyl, 1-phenethyl, pyridylmethyl, methyl, ethyl or isopropyl
  • R 6 is C 1-6 -alk(en yn)yl, or Ar 1 wherein Ar 1 is optionally substituted thiophenyl, phenyl, indolyl, pyrrolyl, quinolinyl, thiazolyl or benzo[l,3]dioxolyl.
  • R 3 is an optionally substituted benzyl, 1-phenethyl or pyridylmethyl.
  • Ar 1 is unsubstituted or substituted one or more times by C 1-6 -alk(en yn)yl, C 1-6 -alk(en/yn)yloxy, hydroxy, nitro, halogen, R 7 R 8 NCO-C 1-6 -alk(en/yn)yl; -NR 7 R 8 , C ⁇ -6 -alk(en/yn)yl-CON-, cyano,
  • R 3 is methyl, ethyl or isopropyl, 1-phenethyl or benzyl, which may be substituted by -CONR 7 R 8 .
  • the invention is related to a compound of formula I wherein
  • R 3 represents a group ofthe formula
  • R 9 represents O, NH, NR 1' , S, -CONR 1' -, -CO-, C 1-6 -alkyl or C 2-6 -alkenyl, wherein said C 1-6 -alkyl or C -6 -alkenyl optionally is substituted by OH, halogen, C 1-6 -alkoxy or C 3-8 -cycloalkyl;
  • R 6 represents C 1 - 6 -alk(en/yn)yl, C 3-8 -cycloalk(en yn)yl, C 3-8 -cycloalk(en)yl- C 1-6 -alk(en/yn)yl or Ar 1 ;
  • R 3 represents halogen, C 1 _ 6 -alk(en/yn)yl, C 3-8 -cycloalk(en/yn)yl, aryl, a heterocycle, hydroxy, C ⁇ -aU n/ynJyloxy, C 1-6 -alk(en yn)yloxy-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en/yn)oxy, C 1-6 -alk(en yn)yl sulfanyl, acyl, R 7 R 8 N-C ⁇ _ 6 -alk(en/yn)yl or -NR 7 R 8 ;
  • R 6 is not optionally substituted hydroxyphenyl
  • the compound is not N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)- N'-(thiophen-2-ylmethylene)-hydrazine.
  • R 3 represents a group of the formula
  • R 9 represents O, NH, NR 1' , S, -CONR 1' -, -CO-, C 1-6 -alkyl or C 2-6 -alkenyl, wherein said C 1-6 -alkyl or C 2-6 -alkenyl optionally is substituted by OH, halogen, C 1-6 -alkoxy or C 3-8 -cycloalkyl;
  • R 6 represents C 1 _ 6 -alk(en/yn)yl, C 3-8 -cycloalk(en yn)yl, C 3-8 -cycloalk(en)yl- C ⁇ -6 -alk(en/yn)yl or Ar 1 .
  • R 3 represents halogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en yn)yl, aryl, a heterocycle, hydroxy, hydroxy- C 1-6 -alk(en yn)yl, C 1-6 -alk(en/yn)yloxy, C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en yn)yl, C 3-8 -cycloalk(en yn)oxy, C 1-6 -alk(en yn)yl sulfanyl, acyl, or -NR 7 R 8 ;
  • R 6 represents indolyl, hydroxy-C 1-6 -alk(en/yn)yl-thiophenyl,
  • A is S
  • W is NH and R 4 and R 5 are both hydrogen
  • R 3 is an optionally substituted benzyl, 1-phenethyl, pyridylmethyl, methyl, ethyl or isopropyl
  • R 6 is optionally substituted indolyl, hydroxy-C 1-6 -alk(en yn)yl-thiophenyl, C 1-6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl- thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C 1-6 -alk(en/yn)ylphenyl or hydroxyphenyl.
  • R is methyl, ethyl or isopropyl
  • R 6 is an optionally substituted.
  • Ar 1 is an optionally substituted indolyl, hydroxy-C 1-6 -alk(en/yn)yl-thiophenyl, C i -6 -alk(en yn)yloxy-C ⁇ -6 -alk(en/yn)yl-thiophenyl.
  • Particular compounds ofthe invention are compounds la-69a ofthe examples.
  • Halogen means fluoro, chloro, bromo or iodo.
  • C 1-6 -alk(en yn)yl means a C 1-6 -alkyl, C 2-6 -alkenyl or a C 2-6 -alkynyl group.
  • C 3-8 -cycloalk(en)yl means a C 3-8 -cycloalkyl- or cycloalkenyl group.
  • C 1-6 -alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-mefhyl-2-propyl and 2-methyl-l -propyl.
  • C 2-6 alkenyl and C 2-6 alkynyl designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
  • C 3-8 -cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.
  • C 3-8 -cycloalkenyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and including one double bond.
  • C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl and C 1-6 -alk(en/yn)yl are as defined above.
  • C 1-6 -alk(en yn)yloxy C 1 _ 6 -alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, C ⁇ -6 -alk(en/yn)ylsulfanyl, hydroxy-C 1-6 -alk(en/yn)yl, halo- C 1-6 -alk(en/yn)yloxy, C 1-6 -alk(en/yn)ylsulfonyl, cyano-C 1-6 -alk(en/yn)yl, hydroxy- C 1-6 -alk(en/yn)yl, NR x R y - C 1-6 -alk(en/yn)yl, NR r CO- C ⁇ -al (en/yn)yl etc.
  • C 1-6 -alk(en/yn)yloxycarbonyl refers to groups ofthe formula -COO-C ⁇ -6 -alk(en/yn)yl, wherein C 1-6 -alk(en yn)yl are as defined above.
  • acyl refers to formyl, C 1-6 -alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C 1-6 -alk(en/yn)ylcarbonyl, C 3-8 -cycloalk(en)ylcarbonyl or a C -8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl-carbonyl group.
  • heterocycle designates rings such as 5-membered monocyclic rings such as 3H-l,2,3-oxathiazole, 1,3,2-oxathiazole, 1,3,2-dioxazole, 3H-l,2,3-dithiazole, 1,3,2-dithiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, lH-l,2,3-triazole, isoxazole, oxazole, isothiazole, thiazole, lH-imidazole, lH-pyrazole, lH-pyrrole, furan or thiophene and 6-membered monocyclic rings such as 1,2,3-oxathiazine, 1,2,4-oxathiazine, 1,2,5-oxathiazine, 1,4,2-oxathiazine, 1,4,3-oxafhiazine, 1,2,3-dioxazine, 1,2,4-di
  • bicyclic compounds wherein the above rings are fused to a benzene ring such as indole, benzofuran, isobenzofuran, benzothiophen, benzimidazol, quinoline, isoquinoline, dihydroquinoline,
  • rings such as morpholin, piperidin, azepin, piperazin, homopiperazin, and ring systems fused to a benzene ring, such as benzodioxan, benzodithiodioxan, benzo[l,3]dioxol, dihydroindol, dihydrobenzofuran or dihydrobenzothiophen.
  • aryl refers to carbocyclic, aromatic systems such as phenyl, naphtyl, anthracene and phenantrene.
  • aryloxy and refer to aryl as defined and C 1-6 -alk(en/yn)yloxy as defined above.
  • carbocyclic refers to partly or completely saturated systems such as cyclohexen, indan or flurene.
  • heteroatom refers to atoms different from carbon and hydrogen, such as nitrogen, oxygen and sulphur.
  • organic acid addition salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline.
  • Exemplary of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
  • the acid addition salts ofthe invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, hi general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • Some of the compounds of the present invention contain chiral centres and such compounds exist in the fonn of isomers (e.g. enantiomers).
  • the invention includes all such isomers and any mixtures thereof including racemic mixtures.
  • Racemic forms can be resolved into the optical antipodes by known methods, for example, by chromatography on an optically active matrix.
  • the compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
  • Optically active compounds can also be prepared from optically active starting materials.
  • thienopyrimidinones are converted to the corresponding 4-chloro-thienopyrimidines by standard procedures known to chemists skilled in the art, such as reaction with POCl 3 in DMF, with or without an aprotic solvent such as 1,2-dichloroethane at a suitable temperature.
  • compounds of the general formula II, wherein R 3 is hydrogen are deprotonated ort/7.0 to sulfur by the application of strong bases like butyllithium or lithium diisopropylamide (LDA), in aprotic solvents, such as THF or ether, at a suitable temperature.
  • LDA lithium diisopropylamide
  • aprotic solvents such as THF or ether
  • electrophiles including aldehydes, ketones, acid halides, chloro formates, isocyanates, and alkyl halides, reactions well known to the chemist skilled in the art.
  • the obtained 4-chloro-thienopyrimidines are converted to a properly substituted hydrazine compound by reaction at a suitable temperature with a suitable hydrazine derivative in the absence or presence of a (non-nucleophilic) solvent such as THF.
  • R 4 , R 5 , R 7 and R 8 are as defined above, and R' is a suitable alkyl such as methyl or ethyl.
  • esters ofthe general structure N are then saponified to the corresponding acids by methods known to chemists skilled in the art, this includes reaction with aqueous KOH.
  • the resulting acids are then chlorinated by standard procedures known to chemists skilled in the art, such as reaction with POCl 3 in DMF, with or without an aprotic solvent such as 1,2-dichloroethane at a suitable temperature.
  • the resulting acid-chloride substituted 4-chloro-thienopyrimidines are hydrolysed partially or fully under aqueous workup conditions and are re-converted into the acid chloride substituted 4-chloro-thienopyrimidines by the treatment with chlorinating agent, such as thionyl chloride, which then can be converted into amides of the general structure NI by standard methods known to the chemists skilled in the art, such as reaction with primary or secondary amines with or without base with or without a suitable non- nucleophilic solvent, such as e.g. THF or DMF, at a suitable temperature.
  • chlorinating agent such as thionyl chloride
  • the resulting acid-chloride substituted 4-chloro-tliienopyrimidines can directly be converted to compounds of the general formula N by in-situ reaction with with primary or secondary amines.
  • Chlorides of the general structure NI are then converted to hydrazine compounds of the general formula III by the reaction with a properly substituted hydrazine derivative in the absence or presence of a non-nucleophilic solvent, such as THF, at a suitable temperature.
  • Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with an IonSpray source and a Shimadzu LC-8A/SLC-10A LC system.
  • Ethyl-4-(3-oxopropyl)-benzoate, ethyl-3-(3-oxopropyl)-benzoate and m ⁇ thyl- 2-(3-oxopropyl)-benzoate were prepared by Sonogashira reaction and subsequent reduction and oxidation reactions according to the procedure described for ethyl- 3-(3-oxopropyl)-benzoate by C.-P. Chuang et al. J. Org. Chem. 1988, 53, 3210.
  • reaction mixture cooled to room temperature and poured onto ice (150 mL) and transferred to a separation funnel with aqueous NaHCO 3 (sat.) (150 mL) and ethyl acetate (350 mL). The phases were separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The organics were combined, washed with water (2 x 150 mL) and brine (150 mL), dried over Na 2 SO 4 , filtered and evaporated in vacuo. Yield: 3.8 g, (100%).
  • the kinase domain of human mixed lineage kinase 1 (MLKIKD) was prepared with an ⁇ -terminal glutathione-S-transferase (GST) fusion partner by expression in baculovirus and purification via glutathione affinity chromatography.
  • GST glutathione-S-transferase
  • the activity assay for MLK1 was performed in 96-well Millipore Multiscreen plates.
  • Each 50 ⁇ L assay mixture contained 50 mM HEPES (pH 7.0), 1 mM EGTA, 10 mM MgCl 2 , 1 mM DTT, 25 mM ⁇ -glycerophosphate, 60 ⁇ M ATP, 1 ⁇ Ci [ ⁇ - 32 P]ATP, 0.1% BSA, 500 ⁇ g/mL myelin basic protein, 2% DMSO, 1 uM test compound, and 1 ⁇ g/mL of baculoviral GST-MLKI KD - Samples were incubated for 15 min at 37 °C. The reaction was stopped by adding ice-cold 50% TCA, and the proteins were allowed to precipitate for 30 min at 4 °C.
  • the plates were then washed four times with 200 ⁇ L of ice-cold 25% TCA. Supermix scintillation cocktail was added, and the plates were allowed to equilibrate for 1-2 hours prior to counting in the Wallac MicroBeta 1450 Plus scintillation counter.
  • the pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
  • Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine.
  • adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.

Abstract

Dans un mode de réalisation, l'invention concerne l'utilisation d'un composé représenté par la formule générale (I) dans laquelle les groupes variables sont tels que définis dans les revendications, ou d'un sel d'addition acide pharmaceutiquement acceptable de ce composé, pour la préparation d'un médicament destiné au traitement de la maladie de Parkinson, la démence telle que la démence liée à l'âge, la démence associée au VIH-1, le syndrome cognitif et moteur associé au VIH-1, l'encéphalopathie liée au VIH et la démence sénile du type Alzheimer, ainsi que de troubles de la mémoire, des ischémies cérébrales et des ischémies de la moelle épinière, des ischémies faisant suite à un accident vasculaire cérébrale ou à des lésions traumatique du cerveau ou de la moelle épinière, la chorée de Huntington, la sclérose en plaques, le glaucome, la promotion de la survie de cellules transplantées, une maladie neuronale motrice/ASL, un traumatisme neuronal ou la dégénérescence maculaire liée à l'âge. Dans un autre mode de réalisation, l'invention concerne de nouveaux composés représentés par la formule générale (I). Dans un autre mode de réalisation encore, l'invention concerne une composition pharmaceutique contenant un composé représenté par la formule générale (I). Les composés de cette invention sont des inhibiteurs de la neurokinase.
PCT/DK2003/000054 2002-01-29 2003-01-28 Furano- et thienopyrimidines en tant qu'inhibiteurs de la neurokinase WO2003064428A1 (fr)

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WO2005007144A2 (fr) * 2003-07-14 2005-01-27 Decode Genetics Ehf Methodes de diagnostic et de traitement de l'asthme et d'autres maladies respiratoires reposant sur une association d'haplotypes
WO2006081555A2 (fr) * 2005-01-26 2006-08-03 Decode Genetics Ehf. Methodes de diagnostique et de traitement de l'asthme, de la rhinite allergique et d'autres maladies respiratoires mettant en oeuvre une association d'haplotypes
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
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US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999024440A1 (fr) * 1997-11-11 1999-05-20 Pfizer Products Inc. Derives de thienopyrimidine et thienopyridine utiles comme agents anticancereux
WO2002051849A1 (fr) * 2000-12-26 2002-07-04 Daiichi Pharmaceutical Co., Ltd. Inhibiteurs cdk4
WO2002057271A2 (fr) * 2000-10-23 2002-07-25 Board Of Regents, The University Of Texas System Inhibiteurs de la famille src a base de thienopyrimidine
WO2002089809A1 (fr) * 2001-05-04 2002-11-14 The Procter & Gamble Company Utilisations medicales d'hydrazones et d'hydrazines

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999024440A1 (fr) * 1997-11-11 1999-05-20 Pfizer Products Inc. Derives de thienopyrimidine et thienopyridine utiles comme agents anticancereux
WO2002057271A2 (fr) * 2000-10-23 2002-07-25 Board Of Regents, The University Of Texas System Inhibiteurs de la famille src a base de thienopyrimidine
WO2002051849A1 (fr) * 2000-12-26 2002-07-04 Daiichi Pharmaceutical Co., Ltd. Inhibiteurs cdk4
WO2002089809A1 (fr) * 2001-05-04 2002-11-14 The Procter & Gamble Company Utilisations medicales d'hydrazones et d'hydrazines

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMCATS [online] 17 January 2002 (2002-01-17), "Benzaldehyde, 2-hydroxy-5-methyl-, (5,6-dimethylhieno(2,3-d)pyrimidin-4-yl)hydrazone", XP002966610, accession no. STN Database accession no. 2002:1379996 *
DATABASE CHEMCATS [online] 2 January 2002 (2002-01-02), "Benzaldehyde, 2-hydroxy-, (6-ethylthieno)2,3-d)pyrimidin-4-yl)hydrazone", XP002966611, accession no. STN Database accession no. 2002:1418002 *
DATABASE CHEMCATS [online] 2 January 2002 (2002-01-02), "Benzaldehyde, 2-hydroxy-5-nitro-, (6-ethylthieno(2,3-d)pyrimidin-4-yl)hydrazone", XP002966613, accession no. STN Database accession no. 2002:1417403 *
DATABASE CHEMCATS [online] 2 January 2002 (2002-01-02), "Benzaldehyde, 3,5-dibromo-2-hydroxy-, (6-ethylthieno(2,3-d)pyrimidin-4-yl)hydrazone", XP002966612, accession no. STN Database accession no. 2002:1417402 *
DATABASE REGISTRY XP002966614 *
DATABASE REGISTRY XP002966615 *
DATABASE REGISTRY XP002966616 *
DATABASE REGISTRY XP002966617 *
DATABASE REGISTRY XP002966618 *
DATABASE REGISTRY XP002966619 *
DATABASE REGISTRY XP002966620 *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007144A3 (fr) * 2003-07-14 2005-06-16 Decode Genetics Ehf Methodes de diagnostic et de traitement de l'asthme et d'autres maladies respiratoires reposant sur une association d'haplotypes
WO2005007144A2 (fr) * 2003-07-14 2005-01-27 Decode Genetics Ehf Methodes de diagnostic et de traitement de l'asthme et d'autres maladies respiratoires reposant sur une association d'haplotypes
WO2006081555A2 (fr) * 2005-01-26 2006-08-03 Decode Genetics Ehf. Methodes de diagnostique et de traitement de l'asthme, de la rhinite allergique et d'autres maladies respiratoires mettant en oeuvre une association d'haplotypes
WO2006081555A3 (fr) * 2005-01-26 2007-08-09 Decode Genetics Ehf Methodes de diagnostique et de traitement de l'asthme, de la rhinite allergique et d'autres maladies respiratoires mettant en oeuvre une association d'haplotypes
US9266834B2 (en) 2006-03-15 2016-02-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US9132122B2 (en) 2007-09-14 2015-09-15 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US9226930B2 (en) 2009-05-12 2016-01-05 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-a] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US10071095B2 (en) 2009-05-12 2018-09-11 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10584129B2 (en) 2013-06-04 2020-03-10 Janssen Pharmaceuticals Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
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