Patent FR-2969609-A1 (FR)
Title: New dihydro-6-oxo-pyrimidine compounds are akt phosphorylation inhibitors useful for treating e.g. gastric cancer, glioblastomas, thyroid cancer, bladder cancer, breast cancer, melanoma, myeloid hematopoietic tumors, and sarcomas
Inventor: BROLLO MAURICE
IPC: A61K31/513
Filed: 2010-12-28
Abstract: Dihydro-6-oxo-pyrimidine compounds (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. Dihydro-6-oxo-pyrimidine compounds of formula (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. A : pyridyl group (optionally substituted by a halogen atom or an alkyl or alkoxy), or morpholine group (optionally substituted by one or more deuterium atom or alkyl optionally substituted by one or more halo and hydroxyl group), provided that two adjacent substituents of morpholine may together form cyclic group with the carbon atoms to which they are attached; R1 : (hetero)aryl (optionally substituted by one or more halo, hydroxyl, CN, nitro, -COOH, -COOalk, -NR1xR1y, CONR1xR1y-, -NR1xCOR1y, -COR1y, -NR1xCO 2R1z, alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, cycloalkyl, O-cycloalkyl, heterocycloalkyl, aryl or heteroaryl), where the alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by halo, OH, alkoxy or NR1vR1w, the aryl and heteroaryl are optionally substituted by one or more alkyl and alkoxy group, optionally substituted by one or more halo, and the heterocycloalkyl and heteroaryl group optionally contain one or more oxo; either R : H, alkyl or alkoxy; or RR1 : saturated or partially saturated or fully unsaturated 5- or 6-membered ring fused to an aryl or heteroaryl and optionally containing one or more other heteroatoms of O, S, N, NH or Nalk, where the bicyclic group is optionally substituted by one or more halo or OH; R1a, R1b : H, halo or alkyl group optionally substituted by one or more halogen atoms; R1c : H or alkyl group optionally substituted by one or more halogen atoms; either R1x : H or alkyl group; and R1y : H, cycloalkyl group, or alkyl optionally substituted by one or more OH, alkoxy, NR1vR1w or heterocycloalkyl; or NR1xR1y : 3-10 membered cyclic group (optionally one or more other heteroatoms of O, S, NH or N-alkyl group), where the cyclic group is optionally substituted by halo, OH, oxo, alkyl, alkoxy, NH 2, NHalk, or N(alk) 2; either R1v : H or alkyl group; and R1w : H, cycloalkyl group or alkyl optionally substituted by one or more OH, alkoxy, or heterocycloalkyl; or NR1vR1w : 3-10 membered cyclic group (optionally one or more other heteroatoms of O, S, NH or N-alkyl group), where the cyclic group is optionally substituted by one or more halo, OH, oxo, alkyl, alkoxy, NH 2, NHalk, or N(alk) 2; and R1z : cycloalkyl group, 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 and contains 1-6C. Independent claims are included for: (1) the preparations of (I); and (2) intermediates comprising (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid metal salt (KN), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester compound of formula (JM) and 2,3-dihydro-1H-indole compound of formula (P). Y0 : Na, Li or K. R2 : H or F; R3 : H or halo; R4 : H, halo, OH, alkoxy (optionally substituted by at least 1 halo) or alkyl (optionally substituted by at least 1 halo or OH); R5, R5a : H or alkyl, and R6 : H or alkyl (optionally substituted by at least 1 halo (preferably F), OH or alkoxy). [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 (-)-2-[2-(2-methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-(2,2,6,6-morpholin-D4)-4-yl-3H-pyrimidin-4-one exhibited an IC 5 0value of 5 nM.