Patent EP-2029552-B1 (EP)
Inventor: LUECKING ULRICH
IPC: A61P35/00
Filed: 2007-05-16
Granted: 2010-09-22
Abstract: Sulfimide compounds (I) and their salts, diastereomers and enantiomers, are new. Sulfimide compounds of formula (I) and their salts, diastereomers and enantiomers, are new. R 1>1-6C alkyl, 2-6C alkenyl, 1-6C alkoxy, 2-6C alkynyl (all optionally substituted by OH, -NR 8>R 9>, -NR 7>-C(O)-R 12>, -NR 7>-C(O)-OR 12>, -NR 7>-C(O)-NR 8>R 9>, -NR 7>-SO 2-R 12>, CN, halo, 1-6C alkoxy, -CF 3 or -OCF 3), phenyl, monocyclic heteroaryl ring (both optionally substituted by OH, -NR 8>R 9>, NR 7>-C(O)-R 12>, NR 7>-C(O)-OR 12>, NR 7>-C(O)-NR 8>R 9>, NR 7>-SO 2-R 12>, CN, halo, CF 3, 1-6C alkoxy, OCF 3 or 1-6C alkyl), H, halo, CN, nitro, NR 8>R 9>, -NR 7>-C(O)-R 12>, -NR 7>-C(O)-OR 12>, -NR 7>-C(O)-NR 8>R 9>, -NR 7>-SO 2-R 12>, -CF 3 or -OCF 3; R 2>1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, 3-7C cycloalkyl, phenyl, naphthyl ring, 3-8 heterocyclyl, mono- or bicyclic heteroaryl ring (all optionally substituted by halo, OH, -NR 8>R 9>, -NR 7>-C(O)-R 12>, -NR 7>-C(O)-OR 12>, NR 7>-C(O)-NR 8>R 9>, NR 7>-SO 2-R 12>, CN, -C(O)R 6>, -O(CO)-R 12>, -SO 2NR 8>R 9>, -SO 2-R 12>, -S(O)(NR 8>)R 12>, -(N)S(O)R 13>R 14>, CF 3, OCF 3, -N[(CO)-(1-6C alkyl)] 2, 1-6C alkoxy, 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 3-8C cycloalkyl, phenyl, naphthyl, 3-8C heterocyclyl or monocyclic or bicyclic heteroaryl (optionally substituted by halo, OH, 1-6C alkyl, 1-6C alkoxy, -NR 8>R 9>, -C(O)OR 15>, -SO 2NR 8>R 9>, -CF 3 or -OCF 3)) or H; either R 3>1-6C alkyl, 1-6C alkoxy (both optionally substituted by halo, OH, 1-6C alkoxy, CF 3, OCF 3 or NR 8>R 9>), 3-7C cycloalkyl (optionally substituted by halo, OH, 1-8C alkoxy, CF 3, OCF 3, NR 8>R 9> or 1-6C alkyl), OH, halo, CN, nitro, CF 3, OCF 3, C(O)NR 8>R 9>, C(S)NR 8>R 9>, NR 8>R 9>, NR 7>-C(O)-R 12>, NR 7>-C(O)-OR 12>, NR 7>-C(O)-NR 8>R 9> or NR 7>-SO 2-R 12>; and R 4>1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 3-7C cycloalkyl-, phenyl, 3-8 heterocyclyl or monocyclic heteroaryl (all optionally substituted by OH, -NR 8>R 9>, CN, halo, CF 3, 1-6C alkoxy, OCF 3 or 1-6C alkyl); and Q : phenyl ring; or R 3>R 4>+Q : 5-7-membered ring (optionally substituted by OH, 1-6C alkyl, 1-6C alkoxy, halo or NR 8>R 9>), when the ring is 5-membered, then Q further contains a double bond in addition to the double bond; either R 5>SO 2-(CH 2) n-R 12>, C(O)R 12>, C(O)OR 12>, C(O)NR 8>R 9>, C(S)OR 12>, C(S)NR 8>R 9> or R 12>; or R 4>R 5>5-7 membered heterocyclic ring of formula (a) or (b); W 1>, Y 1>CH 2 group (optionally substituted by OH, 1-6C alkyl, 1-6C alkoxy or NR 8>R 9>), 1-6C alkyl, 1-6C alkoxy (both optionally substituted by OH, 1-6C alkoxy or NR 8>R 9>) or optionally imide-double bonds (containing 1 or 2 double bonds); either X : O, S or NR 15>; and R 15>C(O)-(1-6C)-alkyl, C(O)-phenyl, C(O)-benzyl (all optionally substituted by OH, NR 10>R 11>, CN, halo, CF 3, 1-6C alkoxy or OCF 3), H, 1-6C alkyl, 3-8C cycloalkyl-, phenyl, heterocyclyl ring with 3-8 ring atoms or monocyclic heteroaryl; or X+R 15>+R 2>3-8 membered ring (optionally containing N atom in addition to heteroatoms and substituted with OH, 1-6C alkyl, 1-6C alkoxy, -C(O)R 12>, -SO 2R 12>, halo or -NR 8>R 9>, optionally contains 1-3 double bonds and interrupted by one or more -C(O)-groups); R 6>1-6C alkyl, 3-6 alkenyl, 3-6C alkynyl, 1-6C alkoxy, 3-7C cycloalkyl-, phenyl, 3-8 heterocyclyl or monocyclic heteroaryl (all optionally substituted by OH, NR 8>R 9>, CN, halo, CF 3, 1-6C alkoxy or OCF 3), H or OH; R 7>H or 1-6C alkyl; either R 8>, R 9>1-6C-alkyl, 2-6C alkenyl, 3-8C cycloalkyl, phenyl, heterocyclyl with 3-8 ring atoms, monocyclic heteroaryl (all optionally substituted by OH, NR 10>R 11>, CN, halo, CF 3, 1-6C alkoxy or OCF 3) or H; or NR 8>R 9>5-7 membered ring (optionally containing 1 or 2 heteroatoms in addition to N atom and optionally substituted with OH, -NR 10>R 11>, CN, halo, -CF 3, 1-6C-alkoxy or -OCF 3); R 10>, R 11>H or 1-6C alkyl (optionally substituted by OH, CN, halo, CF 3, 1-6C alkoxy or OCF 3); R 12>, R 13>, R 14>1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 3-7C cycloalkyl-, phenyl, heterocyclyl with 3-8 ring atoms, monocyclic heteroaryl (all optionally substituted by OH, nitro, NR 8>R 9>, NH-C(O)-1-6C alkyl, CN, halo, CF 3, 1-6C alkyl, 1-6C-alkoxy or OCF 3) or CF 3; R 16>1-6C alkyl, 3-6C alkenyl, 3-6C alkynyl, 3-7C cycloalkyl, phenyl, heterocyclyl with 3-8 ring atoms, monocyclic heteroaryl (all optionally substituted by OH, NR 8>R 9>, CN, halo, CF 3, 1-6C alkoxy or OCF 3) or H; m : 0-4; o : 1-3; and n : 0-1. Independent claims are included for: (1) the preparation of (I); (2) the preparation of a 2-chloro-pyrimidine compound of formula (IV) comprising reaction of 2,4-dichloro-pyrimidine compound of formula (VI) with a nucleophilic compound of formula (H-X-R 2>); (3) compound of formula (IV); (4) the preparation of a nucleophilic compound of formula (VII) comprising imination of a thioether compound of formula (IX) to give a sulfimide compound of formula (VIII) and reduction of the nitro-group of (VIII); and (5)ccompound of formula (VII). [Image] [Image] ACTIVITY : Cytostatic; Cardiovascular-Gen; Vasotropic; Antiarteriosclerotic; Antiinflammatory; Gastrointestinal-Gen; Gynecological. MECHANISM OF ACTION : Protein kinase inhibitor. The ability of (I) to inhibit protein kinase was tested using cyclin-dependent kinase-2 assay. The results showed that (RS)-S-{4-[(5-bromo-4-{[(R)-2-hydroxy-1,2-dimethylpropyl]amino}pyrimidin-2-yl)amino]phenyl}-N-mesyl-S-methylsulfimide exhibited an IC 5 0 value of 6 nM.