NOUVEAUX DERIVES DE (5-HALO-6-OXO-1,6-DIHYDRO-PYRIMIDIN-2-YL)-AMIDE, LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE COMME INHIBITEURS DE PHOSPHORYLATION D'AKT(PKB)

• Main Authors: CERTAL VICTOR, EL AHMAD YOUSSEF, DOERFLINGER, GILLEST BREVETS, DIDIER, ERIC, HALLEY FRANK, KARLSSON KARL ANDREAS, BROLLO MAURICE, CARRY, JEANRISTOPHEMENT BREVETS
• Format: Patent
• Language: French
• Published: 08.02.2013
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

Pyrimidinone compounds (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases, are new. Pyrimidinone compounds of formula (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases, are new. R : H or alkyl; R1 : H or methyl; R2 : H or F; R3 : H or halo; R4 : H, halo or hydroxyl, alkyl (optionally substituted by halo or OH), or alkoxy (optionally substituted by one or more halo); R5, R5a : H or alkyl group; R6 : H, alkyl (optionally substituted by halo or OH); and R7 : halo. Independent claims are included for: (1) the preparations of (I); and (2) intermediates comprising 2,3-dihydro-1H-indole compounds of formula (Q) (preferably 4-fluoro-2-methyl-2,3-dihydro-1H-indole, 4-fluoro-2-methyl-2,3-dihydro-1H-indole,5,6-difluoro-2-methyl-2,3-dihydro-1H-indole and 4-chloro-5-fluoro-2-methyl-2,3-dihydro-1H-indole), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester compound of formula (G) or (L), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid metal salt of formula (M) and [2-(4-morpholino-6-oxo-1H-pyrimidin-2-yl)acetyl]oxysodium of formula (H). Y0 : Na, Li or K. [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Akt phosphorylation inhibitor. The ability of (I) to inhibit akt phosphorylation was tested in human prostate carcinoma (PC3) cell line using multi- spot biomarker detection of meso scale technique. The result showed that 5-fluoro-2-[2-(4-chloro-5-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one exhibited an IC 5 0value of 2 nM.