Patent DE-10345648-A1 (DE)
Title: Production of new or known tetrahydropyranyl-pyridone compounds, for use as phosphatase inhibitors, e.g. for treating cancer, from pyridinone and pyranone compounds via several new intermediates
Inventor: FUERSTNER ALOIS
IPC: C07D405/04
Filed: 2003-10-01
Abstract: A multistage process is claimed for producing 3-(5-alkyl-tetrahydropyran-2-yl)-1H-pyridin-2-one compounds (I) from 4-hydroxy-pyridin-2-ones (II) and 6-oxy-6H-pyran-3-ones (III) via new tetrahydro-5,9-dioxa-3-azafluorene-4,7-dione and 3-(pyran-2-yl)-pyridin-2-one derivative intermediates (IV) - (VIII). Some of the products (I) are new compounds. Production of tetrahydropyranyl-pyridone compounds of formula (I) involves: (1) reacting a hydroxypyridone of formula (II) with a pyranone of formula (III) in presence of a catalyst based on palladium or nickel and suitable ligands to give a tricyclic compound of formula (IV); (2) introducing protecting groups in the 2- and 4-positions of the pyridone ring (or reacting with a compound providing protecting groups) to give a pyranonyl-pyridone compound of formula (V); (3) alkylating at the double bond of the pyranone ring by 1,4-addition (Michael addition) to the enone to give an oxo-tetrahydropyranyl-pyridone of formula (VI); (4) subjecting (VI) to olefinization reaction to give an alkylidene-tetrahydropyranyl-pyridone of formula (VII); (5) hydrogenating (VII) in presence of a transition metal catalyst to form an alkyl-tetrahydropyranyl-pyridone of formula (VIII); (6) cleaving the protecting groups R1>3> and R1>4> to give (I; R3>, R4> = H); (7) optionally protecting the 4-hydroxy group and N-atom of the pyridone ring to give (I; R3> and/or R4> other than H); and (8) optionally N-oxidizing (I; R3> = H) to give (I; R3> = OH) (or in a variant N-oxidizing (VIII) to introduce the N-hydroxy group before conversion to (I)). [Image] [Image] [Image] [Image] R1>, R2>H, alkyl, alkenyl, alkynyl, aryl, perfluoroalkyl, perfluoroaryl, halo, OH, SH, NO2, NH2, CN, CHO, COOH, COOLi, COONa, COOK, OR, SR, COOR, COSR, CONH2, CONHR, CONR2, CH(OR)2, COR, NHR, NR2, NHCOR, NHCOOR, OCONHR, OCOOR, SCOOR, SCONHR, SCOR, SOR, SO2R, SO3R, SO2NH2, SO2NHR, SO2NR2, SO3Na, SO3K, OSO2R, NHSO2R, NRSO2R or SiR3; R3>H, alkyl, aryl, OH or OR; R4>H, alkyl, aryl, COR, COOR or SiR3; R5>, R7>, R8>H, alkyl, alkenyl, alkynyl or aryl; R6>1-20C alkyl; R : H, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or perfluoroaryl; R1>0>H, alkyl, COR, P(O)(OR)2 or SO2R; R1>3>, R1>4>conventional protecting groups; R1>5>H, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or perfluoroaryl; alkyl moieties have 1-6C, alkenyl moieties 2-6C and alkynyl moieties 3-6C. Independent claims are included for: (1) (I) as new compounds, provided that R6> is other than 6-methyl-octyl; (2) the intermediates (IV) - (VIII) as new compounds; and (3) the preparation of 3-allyl-4-hydroxy-2-pyridone compounds of formula (XIII) by reacting (II) with an allyl alcohol derivative of formula R2>9>O-CR3>3>R3>4>-C(R3>0>)=CR3>1>R3>2> (XII) in presence of a transition metal catalyst. [Image] R2>9>as for R1>0>; R3>0> - R3>4>as for R1>, R2> (except that R is more broadly defined as 'a suitable residue'). ACTIVITY : Cytostatic; immunosuppressive; antiinflammatory; osteopathic; antidiabetic; anorectic; neuroprotective; antibacterial. MECHANISM OF ACTION : Phosphatase inhibitor. 1,4-Dihydroxy-3-(3-methyl-5-tetradecyl-tetrahydropyran-2-yl)-5-phenyl-1H-pyridin-2-one (Ia) had IC50 2.8 MicroM for inhibition of the phosphatase PTP1B.