PYRIDOPYRAZINE DERIVATIVES AND USE THEREOF AS MODULATORS OF THE SIGNAL TRANSDUCTION PATHS

• Main Authors: SEIPELT, IRENE, SCHUSTER, TILMANN, CZECH, MICHAEL, CLAUS, ECKHARD, POLYMEROPOULOS, EMMANUEL, GÜNTHER, ECKHARD
• Format: Patent
• Language: English; Polish
• Published: 30.10.2015
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

Treatment and prevention of physiological and pathophysiological state mediated by signal transduction pathway selected from rat sarcoma-rapid accelerated fibrosarcoma-mitogen activated protein kinase-extracellualr signal-regulated kinase signal transduction pathway, phosphoinositol 3-kinase-Akt signal transduction pathway and stress-activated protein kinase signal transduction pathway comprises administering a pyridopyrazine derivative (I). Treatment or prevention of physiological and/or pathophysiological state mediated by at least one signal transduction pathway selected from rat sarcoma-rapid accelerated fibrosarcoma-mitogen activated protein kinase-extracellualr signal-regulated kinase signal transduction pathway, the phosphoinositol 3-kinase-Akt signal transduction pathway and the stress-activated protein kinase signal transduction pathway comprises administering a pyridopyrazine derivatives of formula (I). R 1and R 2 : e.g. aryl (optionally substituted by T 1) or heteroaryl (optionally substituted by T 2); T 1 : e.g. F or heteroaryl; T 2 : e.g. F or NH-alkyl-NH 2; R 3and R 4 : H or NR 9R 10; R 9 : e.g. alkyl or alkyl-heteroaryl (all optionally substituted) or H; R 10 : -C(Y 1)NR 11R 1) 2; Y 1 : O or S; R 11and R 12 : alkyl (optionally substituted by e.g. T 3or SO 2O-alkyl-aryl), cycloalkyl (optionally substituted by e.g. F or aryl), heterocyclyl (optionally substituted by e.g. OH or aryl), aryl (optionally substituted by T 1or S-heterocyclyl), heteroaryl (optionally substituted by T 2) or H, and T 3 : e.g. CO 2H or heteroaryl. Full Definitions are given in the DEFINITIONS (Full Definitions) section. Independent claims are also included for: (1) new pyridopyrazine derivatives (I') selected from 232 compounds as given in the specification e.g. 1-ethyl-3-[3-(3-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea; (2) a pharmaceutical composition (C1) comprising compounds (I'), and (3) a kit comprising compounds (I') and active substance. [Image] ACTIVITY : Cytostatic; Antiinflammatory; Analgesic; Antirheumatic; Antiarthritic; Anti-HIV; Neuroprotective; Nootropic; Antipsoriatic; Gynecological; Vulnerary; Immunosuppressive; Vasotropic; Antidiabetic; Nephrotropic; Anticoagulant; Thrombolytic; Ophthalmological; Antiasthmatic; Antiallergic; Respiratory-Gen.; Gastrointestinal-Gen.; Antiarteriosclerotic; Cardiant; Cardiovascular-Gen.; Antithyroid; Cerebroprotective; Anorectic; Antianginal; Hypotensive; Angiogenesis inhibitor. The efficacy of 1-ethyl-3-[3-p-tolylamino-pyrido[2,3-b]pyrazin-6-yl]-urea (Ia) was evaluated for cytostatic activity using sodium 3'-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonic acid (XTT) assay. The tumor cell lines were injected into 96-well microtitre plates and then incubated overnight in an incubator at 37[deg]C, 5% carbon dioxide (CO 2) and 95% air humidity. (Ia) (0.28 mu M) was added to the cells in quarter-logarithmically graded dilutions. The cell plates were then incubated for 45 hours in an incubator at 37[deg]C, 5% CO 2and 95% air humidity and EC 50value measured. (Ia) Showed an EC 50value of 0.9 mu M. MECHANISM OF ACTION : Extracellular signal-regulated kinase inhibitor; Phosphoinositol 3-kinase inhibitor; Stress-activated protein kinase inhibitor. The efficacy of 1-ethyl-3-[3-(3-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea (Ib) was evaluated for extracellular signal-regulated kinase inhibitory activity using extracellular signal-regulated kinase assay. 1-Ethyl-3-[3-(3-hydroxyphenyl)-pyrido[2,3-b]pyrazin-6-yl]urea (Ib), extracellular signal-regulated kinase (0.625 ng), adenosine triphosphate (10 mu M)and myelin basic protein (MBP) substrate (15 nM) were incubated on a 384-well Optiplate in a volume of 15 mu l for 1 hour in Tris (25 mM), magnesium dichloride (10 mM), Tween 20(RTM: Polysorbate 20) (0.1%), NaVO 4(100 mu M), DTT (2 mM) at pH 7.5. The kinase reaction was then stopped by adding the bead mixes (10 mu l) pre-incubated with anti-phospho MBP antibody (320 pM), in Tris (25 mM), sodium chloride (200 mM), ethylenediaminetetraacetic acid (110 nM) and bovine serum albumin (0.3%) and IC 50value measured. (Ib) Showed IC 50of 0.104 mu M.