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1. 发明专利

DE102005062742A1 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 未知
公开(公告)号：DE102005062742A1
公开(公告)日：2007-06-28
申请号：DE102005062742
申请日：2005-12-22
申请人： BAYER SCHERING PHARMA AG
发明人： LUECKING ULRICH , NGUYEN DUY , BONIN ARNE VON , AHSEN OLIVER VON , KRUEGER MARTIN , BRIEM HANS , KETTSCHAU HANS , PRIEN OLAF
IPC分类号： C07D409/04 , A61K31/505 , A61K31/506 , A61P29/00 , A61P35/00 , C07D239/42 , C07D403/04
摘要： 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.

2. 发明专利

DE102006031224A1 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 未知
公开(公告)号：DE102006031224A1
公开(公告)日：2008-01-17
申请号：DE102006031224
申请日：2006-06-30
申请人： BAYER SCHERING PHARMA AG
发明人： KRUEGER MARTIN , MENGEL ANNE , LUECKING ULRICH , BRIEM HANS , KROLIKIEWICZ KONRAD , BONIN ARNE VON , BOEMER ULF , BOTHE ULRICH
IPC分类号： C07D409/04 , A61K31/505 , A61K31/506 , A61P29/00 , A61P35/00 , C07D239/28 , C07D403/04 , C07D409/14 , C07D413/04 , C07D417/04
摘要： 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.

3. 发明专利

DE102006027156A1 New sulfimide compounds are protein kinase inhibitors useful to treat e.g. cancer, Hodgkin's lymphoma, Kaposi's sarcoma, cardiovascular disease, Crohn's disease, endometriosis and hemangioma 未知
公开(公告)号：DE102006027156A1
公开(公告)日：2007-12-13
申请号：DE102006027156
申请日：2006-06-08
申请人： BAYER SCHERING PHARMA AG
发明人： LUECKING ULRICH , NGUYEN DUY , BONIN ARNE VON , AHSEN OLIVER VON , SIEMEISTER GERHARD , JAUTELAT ROLF , DOECKE WOLF-DIETRICH
IPC分类号： C07D239/48 , A61K31/505 , A61K31/506 , A61P35/00 , C07D401/12
摘要： 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.

4. 发明专利

DE102006029447A1 未知
公开(公告)号：DE102006029447A1
公开(公告)日：2007-12-27
申请号：DE102006029447
申请日：2006-06-21
申请人： BAYER SCHERING PHARMA AG
发明人： PRIEN OLAF , EIS KNUT , BONIN ARNE VON , BADER BENJAMIN , GUENTHER JUDITH
IPC分类号： C07D487/04 , A61K31/5025 , A61P29/00 , A61P35/00 , A61P37/00

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