Patent DE-102008057364-A1 (DE)
Title: New pyridyl or phenyl ring containing compounds are hypoxia-inducible factor regulation pathway modulators, useful to treat and/or prevent e.g. cancer or tumor diseases, heart attack, arrhythmia, stroke, psoriasis and diabetic retinopathy
Inventor: HAERTER MICHAEL
IPC: A61P13/12
Filed: 2008-11-14
Abstract: Pyridyl or phenyl ring containing compounds (I) and their solvates, salts or solvate of the salts are new. Pyridyl or phenyl ring containing compounds of formula (I) and their solvates, salts or solvate of the salts are new. Ring A : pyridyl or phenyl ring; ring B : 1H-pyrazole group of formula (a1) or (b1), 1H-imidazole group of formula (c1), 1H-pyrrole group of formula (d1), or 2H-pyrrole group of formula (e1); a : connection point with the adjacent CH 2-group; aa : connection point with the ring (D); ring D : [1,2,4]oxadiazole group of formula (f1) or (g1), [1,3,4]oxadiazole group of formula (h1), oxazole group of formula (i1)-(l1), isoxazole group of formula (m1) or (n1), or 1H-imidazole group of formula (o1); aaa : connection point with the ring B; aaaa : connection point with the ring (E); ring E : phenyl or pyridyl ring; R 1>H, halo, CN, (1-6C)-alkyl, (2-6C)-alkenyl, (2-6C)-alkynyl, (3-6C)-cycloalkyl, -OR 6>, -SR 6>, -S(=O)-R 6>, -S(=O) 2-R 6>, -C(=O)-OR 6>, -C(=O)-NR 6>R 7>, -S(=O) 2-NR 6>R 7>, -NR 6>R 8>, -N(R 6>)-C(=O)-R 7>or -N(R 6>)-S(=O) 2-R 7>, where (1-6C)-alkyl, (2-6C)-alkenyl or (2-6C)-alkynyl is optionally 2-3 times substituted by F, OH, (1-4C)-alkoxy, CF 3O, tri-(1-4C)-alkylsilyl, (1-4C)-alkoxycarbonyl or (3-6C)-cycloalkyl, and the cycloalkyl is optionally 2-3 times substituted by F, (1-4C)-alkyl, CF 3, OH, (1-4C)-alkoxy, CF 3O or (1-4C)-alkoxycarbonyl; R 6>, R 7>H, (1-6C)-alkyl or (3-6C)-cycloalkyl, where the (1-6C)-alkyl is optionally 2-3 times substituted by F, OH, (1-4C)-alkoxy, CF 3O, (1-4C)-alkoxycarbonyl or (3-6C)-cycloalkyl, the cycloalkyl is optionally 2-3 times substituted by F, (1-4C)-alkyl, CF 3, OH, (1-4C)-alkoxy, CF 3O or (1-4C)-alkoxycarbonyl; R 8>H, (1-6C)-alkyl, (3-6C)-cycloalkyl or 5- or 6-membered heteroaryl, where (1-6C)-alkyl is optionally 2-3 times substituted by F, OH, (1-4C)-alkoxy, CF 3O, (1-4C)-alkoxycarbonyl, (3-6C)-cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 5- or 6-membered heteroaryl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and cycloalkyl group is optionally 2-3 times substituted by F, (1-4C)-alkyl, CF 3, OH, (1-4C)-alkoxy or (1-4C)-alkoxycarbonyl, and the heteroaryl is 2-3 times substituted by F, Cl, CN, (1-4C)-alkyl, CF 3, (1-4C)-alkoxy or CF 3O; R 2>H, F, Cl, CN, CH 3, CF 3, OH, CH 3O or CF 3O; R 3>CH 3, C 2H 4or CF 3; R 4>H, halo, CN, pentafluorothio, (1-6C)-alkyl, tri-(1-4C)-alkylsilyl, -OR 9>, -NR 9>R 1>0>, -N(R 9>)-C(=O)-R 1>0>, -N(R 9>)-C(=O)-OR 1>0>, -N(R 9>)-S(=O) 2-R 1>0>, -C(=O)-OR 9>, -C(=O)-NR 9>R 1>0>, -SR 9>, -S(=O)-R 9>, -S(=O) 2-R 9>, -S(=O) 2-NR 9>R 1>0>, (3-6C)-cycloalkyl, 4-6-membered heterocycle or 5- or 6-membered heteroaryl, where (1-6C)-alkyl for is optionally 2-3 times substituted by F, -OR 9>, -NR 9>R 1>0>, -N(R 9>)-C(=O)-R 1>0>, -N(R 9>)-C(=O)-OR 1>0>, -C(=O)-OR 9>, -C(=O)-NR 9>R 1>0>, (3-6C)-cycloalkyl, 4-6-membered heterocycle or 5- or 6-membered heteroaryl, the cycloalkyl- and heterocycle are 2-3 times substituted by F, (1-4C)-alkyl, CF 3, OH, (1-4C)-alkoxy, CF 3O, oxo, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, (1-4C)-alkylcarbonylamino, (1-4C)-alkoxycarbonylamino, (1-4C)-alkylcarbonyl or (1-4C)-alkoxycarbonyl, and the heteroaryl is optionally 2-3 times substituted by F, Cl, CN, (1-4C)-alkyl, CF 3, (1-4C)-alkoxy or CF 3O; either R 9>, R 1>0>H, (1-6C)-alkyl, (3-6C)-cycloalkyl or 4-6-membered heterocycle, where the (1-6C)-alkyl is 2-3 times substituted F, OH, (1-4C)-alkoxy, CF 3O, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, (1-4C)-alkoxycarbonyl, (3-6C)-cycloalkyl or 4-6-membered heterocycle, and the cycloalkyl and heterocycle are optionally 2-3 times substituted by F, (1-4C)-alkyl, CF 3, OH, (1-4C)-alkoxy, CF 3O, oxo, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, (1-4C)-alkylcarbonyl or (1-4C)-alkoxycarbonyl; or R 9>R 1>0>N : a 4-6-membered heterocycle further containing a heteroatom of N, O, S or S(O) 2and 2-3 times substituted by F, (1-4C)-alkyl, CF 3, OH, (1-4C)-alkoxy, oxo, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, (1-4C)-alkylcarbonyl or (1-4C)-alkoxycarbonyl; R 5>F, Cl, CN, CH 3, CF 3or OH; and n : 0-2. An independent claim is included for a medicament comprising (I) in combination with one or more inert, non-toxic auxiliary agent. ACTIVITY : Cytostatic; Cardiant; Vasotropic; Antiarrhythmic; Cerebroprotective; Antipsoriatic; Ophthalmological; Antiinflammatory; Antiarthritic; Antirheumatic; Hemostatic; Vulnerary. MECHANISM OF ACTION : Hypoxia-inducible factor regulation pathway modulator. The ability of (I) to modulate hypoxia-inducible factor regulation pathway was tested in HCT 116 cells using hypoxia-inducible factor luciferase assay. The results showed that N-methyl-5-[(5-methyl-3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)methyl]pyridin-2-amine exhibited an IC 50value of 2 nmole/l.