New substituted morpholinyl-3H-pyrimidin-4-one compounds are akt phosphorylation inhibitors useful for treating gastric cancer, ovarian cancer, glioblastomas, melanoma, sarcomas, brain cancer, bone cancer and hamartomas

摘要

Substituted morpholinyl-3H-pyrimidin-4-one compounds (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. Substituted morpholinyl-3H-pyrimidin-4-one compounds of formula (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. X : O or S; Y1 : S; R : H; 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, or alkyl (optionally substituted by halo or OH); and R7 : H. Independent claims are included for: (1) the preparation of (I); and (2) intermediates comprising (4-morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester compound of formula (C) and (4-morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid metal salt of formula (D). 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 2-[2-((S)-2-methyl-2,3-dihydro-indol-1-yl)-2-thioxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-thione exhibited an IC 5 0value of 4 nM.