Patent DE-102006031224-A1 (DE)
Title: New sulfoximine-substituted pyrimidines useful for treating e.g. diseases caused by inflammatory, allergic or proliferative processes, oncological diseases, cancer, eye, autoimmune and neurodegerative diseases
Inventor: KRUEGER MARTIN
IPC: C07D409/14
Filed: 2006-06-30
Abstract: Sulfoximine-substituted pyrimidines are new. Sulfoximine-substituted pyrimidines of formula (I) are new. R 1optionally partly or fully saturated, mono/bi-cyclic (hetero)aryl (optionally substituted); R 2e.g. H or 2-10C alkenyl (all optionally substituted); n : 0 - 6; o : 1 -4; R 3e.g. -NR 8R 9, or 1-6C alkoxy (all optionally substituted); R 4e.g. H, -C(O)O-R 10, -C(O)-R 10, -Si(R 15R 16R 17), -R 18-Si(R 15R 16R 17), -SO 2-R 18- or 3-10C cycloalkyl (all optionally substituted); R 3 + R 55 - 7-membered ring and contain 1 - 2 double bonds (optionally substituted); R 4 + R 55 - 8-membered ring of the formula (Ia); V', W' and Y' : -CH 2 (optionally substituted) and the ring optionally contains -C(O)- and/or double bonds); R 51-6C alkyl, 2-6C alkenyl, 2-6C alkynyl or 3-7C cycloalkyl or (hetero)aryl (all optionally substituted); X : O, S or -NR 8-; X + R 23 - 8-membered ring, which contains at least hetero atom (optionally substituted); Q : 6-10C arylene or heteroarylene with 5 - 10 ring atoms; m : 0 - 4; R 6e.g. H, NR 8R 9, 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 6-10C-aryl or heteroaryl with 5 or 6 ring atoms (all optionally substituted); R 7H or 1-6C alkyl; R 8 and R 9e.g. H, 1-6C alkoxy, (CH 2) n-NR 11R 12, NR 11R 12, -(CO)-(C1- C6)alkyl, -(CH 2) n-(6-10C)aryl or heteroaryl with 5 or 6 ring atoms (all optionally substituted ); R 8 + R 95 - 7-membered ring (optionally substituted); R 101-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 3-7C cycloalkyl, 3-10C heterocyclyl, heteroaryl with 5 or 6 ring atoms or aryl group (all optionally substituted); R 11 and R 12e.g. H, 1-6C alkyl, hydroxy(1-6C) alkyl, (CO)-(1-6C) alkyl, (CO)-phenyl or benzyl (all optionally substituted); NR 11R 125 - 7-membered ring in which up to two methylene groups is replaced by -O-, -NR 7- or -C(=O)-; R 15 - R 171-6C alkyl and/or phenyl; and R 181-3C alkylene. Provided that when X is -NR 8-, then X + R 2 is 3 - 8-membered ring, which contains at least hetero atom and is optionally substituted. R 3 and the sulfoximine residue bound at neighboring positions of Q. Full Definitions are given in the DEFINITIONS (Full Definitions) section. An independent claim is included for preparation of pyrimidine (I). [Image] [Image] ACTIVITY : Antiinflammatory; Antiallergic; Cytostatic; Antiarthritic; Ophthalmological; Immunosuppressive; Endocrine-Gen.; Gynecological; Cardiovascular-Gen.; Antimicrobial; Protozoacide; Antimalarial; Nephrotropic; Neuroprotective; Virucide; Vasotropic; Dermatological; Antipsoriatic; Antiarteriosclerotic; Antiparasitic; Fungicide; Anticonvulsant; Nootropic; Antiparkinsonian; Anti-HIV; Hepatotropic; Respiratory-Gen.; Antipyretic; Antirheumatic; Muscular-Gen.; Vulnerary; Antiulcer; Gastrointestinal-Gen.; Auditory; Cerebroprotective; Antibacterial; CNS-Gen.; Hemostatic; Antithyroid; Antidiabetic. No biological data given. MECHANISM OF ACTION : Kinase (CDK, Aurora A, Aurora B, Aurora C, Tie-2, ITK and Tyk-2) inhibitor. ITK kinase inhibitory activity of (RS)-S-{2-bromo-4-[(4-{[(R)-1-(hydroxymethyl)propyl]amino}-5-(2-thienyl)pyrimidine-2-yl)amino]phenyl}-N-(ethoxycarbonyl)-S-methylsulfoximide (IA) was tested employing the ITK HTRF assay. N-terminal 6 His-tagged recombinant kinase domain of the human ITK (amino acids 352-617) expressed in baculovirus infected SF21 cells was incubated for 15 min at 22[deg]C in the presence compound (IA) in assay buffer (containing 8 mM 3-N-morpholino propane sulfonic acid/sodium hydroxide (NaOH) pH 7.0, 10 mM magnesium acetate, 0.2 mM ethylene diamine tetraacetic acid (EDTA), 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 10 mu M adenosine-tri-phosphate (ATP), 0.5 mu M biotinylated phosphorylated substrate, Tween20 (RTM: surfactant) (0.07 vol./vol.%), dimethylsulfoxide (1 vol./vol.%) (5 mu l). The mixture was further incubated for 1 h at 22[deg]C with a solution of HTRF detection reagents (40 nM streptavidine-XLent and 2.4 nM PT66-Eu-Chelate (RTM: europium-chelate labeled anti-phospho-tyrosine antibody) (5 mu l) in an aqueous EDTA-solution (100mM EDTA, bovine serum albumin (0.2 wt./vol%) in 50 mM 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid/NaOH pH 7.0). The binding of the biotinylated phosphorylated substrate to the streptavidine-XLent and the PT66-Eu-Chelate was determined by measurement of the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm, and IC 5 0 value was calculated. The compound (IA) showed IC 5 0 value of 0.4 mu M.