Patent DE-102008057343-A1 (DE)
Title: New phenyl or pyridyl 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: A61K31/4439
Filed: 2008-11-14
Abstract: Phenyl or pyridyl ring containing compounds (I) and their solvates, salts or solvate of the salts are new. Phenyl or pyridyl ring containing compounds of formula (I) and their solvates, salts or solvate of the salts are new. Ring A : phenyl or pyridyl 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; ring N : saturated 4-10-membered aza-heterocycle containing at least one N-atom as ring member, and further containing one or two hetero-ring member of N, O, S and/or S(O) 2; X : a bond, b-(CH 2) q-N(R 6>)-bb, b-N(R 6>)-(CH 2) q-bb, -O-, -S-, -C(=O)-, -S(=O) 2-, b-C(=O)-N(R 6>)-bb or b-N(R 6>)-C(=O)-bb; b : connection point with ring N; bb : connection point with ring A; q : 0-2; R 6>(1-6C)-alkyl or (3-6C)-cycloalkyl (both optionally substituted by OH or (1-4C)-alkoxy), or H; R 1>F, (1-6C)-alkyl, OH, (1-6C)-alkoxy, oxo, amino, mono-(1-6C)-alkylamino, di-(1-6C)-alkylamino or (3-6C)-cycloalkyl, where (1-6C)-alkyl is optionally 2 or 3 times substituted with F and twice substituted with OH, (1-4C)-alkoxy, amino, mono-(1-4C)-alkylamino or di-(1-4C)-alkylamino, (3-6C)-cycloalkyl is optionally 2 or 3 times substituted with F, (1-4C)-alkyl, OH, (1-4C)-alkoxy, amino, mono-(1-4C)-alkylamino or di-(1-4C)-alkylamino; m : 0-4; R 2>(1-6C)-alkyl, (1-6C)-alkylcarbonyl, (1-6C)-alkoxycarbonyl, (1-6C)-alkylsulfonyl or (3-6C)-cycloalkyl, where the alkyl group in (1-6C)-alkyl, (1-6C)-alkylcarbonyl, (1-6C)-alkoxycarbonyl or (1-6C)-alkylsulfonyl is optionally 2 or 3 times substituted with F and twice substituted with OH, (1-4C)-alkoxy, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, (3-6C)-cycloalkyl or 4-6-membered heterocycle, and the (3-6C)-cycloalkyl is optionally 2 or 3 times substituted with F, (1-4C)-alkyl, OH, (1-4C)-alkoxy, amino, mono-(1-4C)-alkylamino or di-(1-4C)-alkylamino; n : 0 or 1, and when aza-heterocycle contains further N atoms as a ring member, then n is 2; R 3>CH 3, C 2H 5or CF 3; R 4>H, halo, CN, pentafluorothio, (1-6C)-alkyl, tri-(1-4C)-alkylsilyl, -OR 7>, -NR 7>R 8>, -N(R 7>)-C(=O)-R 8>, -N(R 7>)-C(=O)-OR 8>, -N(R 7>)-S(=O) 2-R 8>, -C(=O)-OR 7>, -C(=O)-NR 7>R 8>, -SR 7>, -S(=O)-R 7>, -S(=O) 2-R 7>, -S(=O) 2-NR 7>R 8>, (3-6C)-cycloalkyl, 4-6-membered heterocycle or 5-6-membered heteroaryl, where (1-6C)-alkyl is optionally 2 or 3 times substituted with F, -OR 7>, -NR 7>R 8>, -N(R 7>)-C(=O)-R 8>, -N(R 7>)-C(=O)-OR 8>, -C(=O)-OR 7>, -C(=O)-NR 7>R 8>, (3-6C)-cycloalkyl, 4-6-membered heterocycle or 5-6-membered heteroaryl, the cycloalkyl- and heterocycle groups are 2 or 3 times substituted with 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 or 3 times substituted with F, Cl, CN, (1-4C)-alkyl, CF 3, (1-4C)-alkoxy or CF 3O; either R 7>, R 8>H, (1-6C)-alkyl, (3-6C)-cycloalkyl or 4-6-membered heterocycle, where (1-6C)-alkyl is optionally 2 or 3 times substituted with F and twice substituted with 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, where the cycloalkyl- and heterocycle are optionally 2 or 3 times substituted with 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 7>R 8>N : a 4-6-membered heterocycle containing further ring heteroatom of N, O, S or S(O) 2and optionally 2 or 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 p : 0-2. An independent claim is included for a medicament comprising (I) in combination with one or more inert, non-toxic auxiliary agent. [Image] [Image] [Image] [Image] [Image] 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 (4-cyclopropyl-piperazin-1-yl)-(3-{5-methyl-3-[3-(4-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-pyrazol-1-ylmethyl}-phenyl)-methanone exhibited an IC 50value of 2 nmole/l.