New 6-morpholin-4-yl-pyrimidin-4-(3H)-one derivatives are protein kinase B inhibitors useful for treating e.g. gastric cancers, glioblastoma, thyroid cancers, bladder cancers, breast cancers, melanoma, sarcomas and larynx cancer

摘要

6-Morpholin-4-yl-pyrimidin-4-(3H)-one derivatives (I) and their all possible isomeric and racemic forms, enantiomers, diastereoisomers, or addition salts with mineral and organic acids or bases are new. 6-Morpholin-4-yl-pyrimidin-4-(3H)-one derivatives of formula (I) and their all possible isomeric and racemic forms, enantiomers, diastereoisomers, or addition salts with mineral and organic acids or bases are new. Z : Nalk or N-phenyl (both optionally substituted by one or more halo, alkyl, alkoxy, hydroxyl, cyano or phenyl optionally substituted by one or more halo, OH, alkoxy or alkyl), -O-,-NH, or Ncycloalkyl; n : 0-4; R 1 : alkyl or alkoxy (both optionally substituted by NR1xR1y or one or more halo), H, halo or OH, provided that R 1fused with phenyl to form a naphthyl group; R 2, R 3 : H, halo, alkyl optionally substituted by one or more halo; R 4 : H; alk : alkyl; either R1x : H or alkyl; and R1y : H or alkyl; 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, where all the alkyl and alkoxy is 1-6C alkyl and 1-6C alkoxy. 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 ethyl ester (C), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-sodium acetate (D1), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-lithium acetate (D2), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-potassium acetate (D3), 2-(4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-N-phenyl-acetamide compound of formula (F), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester compound of formula (J), and substituted 2-(4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-N-phenyl-acetamide compound of formula (K) (where Z is NH or O). [Image] [Image] ACTIVITY : Cytostatic. 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 sandwich immunoassay. The result showed that 2-[(6-methyl-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one exhibited an IC 5 0value of 8 nM.