スルホキシイミン置換ピリミジン、それらの調製及び医薬としての使用

Japanese Patent JP5344564

B2

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.

JPS59206364	1-PYRIMIDINYLOXY-3-HETEROARYLALKYLAMINO-2-PROPANOL, MANUFACTURE AND USE
WO/2010/113834	PYRIMIDINE COMPOUND
WO/2013/170421	RILPIVIRINE HYDROCHLORIDE ALCOHOLATE POLYMORPH AND PREPARATION METHOD THEREOF

Rükink, Ulrich
Nguyen, Doi
Von Bonin, Arne
Von azen, olifer
Kruger, Martin
Bream, hans
Ketchau, Georg
Prien, Olaf
Mengel, Anne
Choriki Bits, Konrad
Bemer, wolf
Beaute, Ulrich
Hartunk, Ingo

JP2008546291A

November 20, 2013

December 19, 2006

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Bayer Intellectual Property GmbH

C07D239/48; A61K31/505; A61K31/506; A61K31/5377; A61K31/55; A61P1/04; A61P13/12; A61P17/06; A61P17/14; A61P19/02; A61P25/00; A61P25/28; A61P27/02; A61P29/00; A61P31/12; A61P35/00; A61P35/04; A61P37/06; A61P37/08; A61P43/00; C07D401/04; C07D401/12; C07D403/04; C07D405/04; C07D409/04; C07D409/14; C07D413/04; C07D417/04

JP2002533446A

WO2005113548A1
WO2006099974A1
WO2006034872A1
WO2004048343A1
WO2005037800A1

Atsushi Aoki
Takashi Ishida
Fukumoto product
Tetsuji Koga
Kazuhiro Nakamura
Yoichi Watanabe
Masaru Nakajima

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