New tetrahydro-pyrimido(1,2-a)pyrimidin-6-one derivatives are akt phosphorylation inhibitors useful for treating e.g. liver cancers, glioblastoma, thyroid cancers, bladder cancers, breast cancers, melanoma, Pompe disease and malaria

摘要

Tetrahydro-pyrimido(1,2-a)pyrimidin-6-one derivatives (I) and their all possible isomeric forms, racemates, enantiomers, diastereoisomers, or addition salts with mineral and organic acids or bases are new. Tetrahydro-pyrimido(1,2-a)pyrimidin-6-one derivatives of formula (I) and their all possible isomeric forms, racemates, enantiomers, diastereoisomers, or addition salts with mineral and organic acids or bases, are new. R 1 : -L-aryl or -L-heteroaryl group (both optionally substituted by one or more groups of alkoxy, phenoxy, alkylthio, alkyl or heterocycloalkyl (all optionally substituted by one or more halo or NR1vR1w), halo, OH, CN, nitro, -COOH, cycloalkyl, -COOalk, NR1xR1y-, -CONR1xR1y, NR1xCOR1y-, -NR1xCO2R1z, or -COR1y, where the heterocycloalkyl and heteroaryl optionally contains one or more oxo); L : single, bond, 1-6C alkyl (optionally substituted by OH), CO, COalk or L1a-X; L1a : 1-6C alkyl; X : O or S; R 2 : H or alkyl; R 3 : alkyl optionally substituted by one or more halo; R 4 : H or halo; either R1x : H or alkyl; and R1y : H, cycloalkyl or alkyl (optionally substituted by one or more OH, alkoxy, NR1vR1w or heterocycloalkyl); or NR1xR1y : 3-10 membered cyclic group (optionally containing heteroatoms of O, S, NH or N-alkyl and optionally substituted by one or more halo, alkyl, hydroxyl, oxo, alkoxy, NH 2, NHalk or N(alk) 2), preferably morpholino group; either R1v : H or alkyl; and R1w : H, cycloalkyl or alkyl (optionally substituted by one or more OH, alkoxy, or heterocycloalkyl); or NR1vR1w : 3-10 membered cyclic group optionally containing heteroatoms of O, S, NH or N-alkyl and optionally substituted by one or more halo, alkyl, hydroxyl, oxo, alkoxy, NH 2, NHalk or N(alk) 2; alk : alkyl; and R1z : cycloalkyl or alkyl (optionally substituted by one or more OH, alkoxy, NR1vR1w or heterocycloalkyl), where all the alkyl (alk), alkoxy and alkylthio are linear or branched 1-6C alkyl, 1-6C alkoxy and 1-6C alkylthio. Independent claims are included for: (1) the preparations of (I); and (2) intermediates comprising substituted 2-hydroxy-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one compound of formula (C), 2-chloro-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one compound of formula (D), 2-morpholin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one compound of formula (E), and 2-chloro-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one compound of formula (J). [Image] [Image] ACTIVITY : Cytostatic; Metabolic; Antimalarial; Hypnotic; Protozoacide; Antiparasitic. MECHANISM OF ACTION : Akt phosphorylation inhibitor; Protein kinase B (PKB) inhibitor. The ability of (I) to inhibit Akt phosphorylation was tested in human prostate carcinoma cells using western blotting technique. The result showed that (S)-9-[2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one exhibited an IC 5 0value of 15 nM.