Patent DE-102007049157-A1 (DE)
Title: New substituted 2,3-dihydro-(1,2,3)triazol-4-one compounds are hypoxia inducible factor-prolyl-4-hydroxylase inhibitor, useful for preparing medicament to treat and/or prevent e.g. cardiovascular diseases, inflammatory disease and anemia
Inventor: JESKE MARIO
IPC: C07D401/14
Filed: 2007-10-13
Abstract: Substituted 2,3-dihydro-[1,2,3]triazol-4-one compounds (I), and their salts, solvates or solvates of the salts, are new. Substituted 2,3-dihydro-[1,2,3]triazol-4-one compounds of formula (I), and their salts, solvates or solvates of the salts, are new. R 1>a heteroaryl-group of formula (a), (b), (c), (d), (e) or (f); A : C-R 3>or N, where maximum two ring members of A represents N; D 1>O, S or N-R 4>; E : C-R 5>or N, where maximum two ring members of E represents N; R 2>a heteroaryl group of formula (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii) or (xiii); G : C-R 7>or N, where maximum two ring members of G represents N; J : O, S or N-R 7>; L : C-R 8>or N, where maximum two ring members of L represents N; R 3>, R 6>, R 8>H or a substituent of the series of halo, CN, NO 2, (1-6C)-alkyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl or L 1>; R 4>, R 7>H or a substituent of series of (1-6C)-alkyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl (where in R 3>, R 4>, R 6>-R 8>: (1-6C)-alkyl is 1-3 times substituted by series of halo, CN, oxo, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, or L 1>, where cycloalkyl-, heterocycloalkyl-, phenyl- or heteroaryl-remainders are 1-3 times substituted by L 2>, and (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl are 1-3 times substituted by a series of (1-6C)-alkyl, halo, CN, oxo or L 1>, where the alkyl group is 1-3 times substituted by L 3>); R 9>, R 1> 0>H, (1-6C)-alkyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl, where (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl are 1-3 times substituted by L 2>, and (1-6C)-alkyl is 1-3 times substituted by L 3>; either R 1> 1>, R 1> 3>, R 1> 4>, R 1> 6>, R 1> 9>, R 2> 1>, R 2> 4>-R 2> 6>, R 2> 8>-R 3> 0>R 9>; and R 1> 2>, R 1> 5>, R 1> 6>, R 1> 8>, R 2> 0>, R 2> 2>, R 2> 3>, R 2> 7>, R 3> 1>H or (1-6C)-alkyl, where (1-6C)-alkyl is 1-3 times substituted by halo, CN, OH, CF 3, (1-4C)-alkoxy, NH 2, mono-(1-4C)-alkylamino, di-(1-4C)-alkyl amino, hydroxycarbonyl and/or (1-4C)-alkoxycarbonyl; or R 1> 1>R 1> 2>, R 1> 4>R 1> 5>, R 1> 6>R 1> 7>, R 1> 8>R 1> 9>, R 2> 0>R 2> 1>, R 2> 1>R 2> 2>, R 2> 3>R 2> 4>, R 2> 6>R 2> 7>, R 3> 0>R 3> 1>5-6-membered heterocycloalkyl ring (1-3 times substituted by L 2>); L 1>-C(=O)-R 9>, -C(=O)-OR 1> 0>, -C(=O)-NR 1> 1>R 1> 1>, -O-C(=O)-R 1> 3>, -O-C(=O)-NR 1> 4>R 1> 5>, -NR 1> 7>-C(=O)-R 1> 7>, -NR 1> 8>-C(=O)-OR 1> 9>, -NR 2> 0>-C(=O)-NR 2> 1>R 2> 2>, -NR 2> 3>-SO 2-R 2> 4>, -SO 2-R 2> 5>, -SO 2-NR 2> 6>R 2> 7>, -OR 2> 8>, -SR 2> 9>OR -NR 3> 0>R 3> 1>; L 2>halo, CN, (1-4C)-alkyl, CF 3, OH, (1-4C)-alkoxy, CF 3O, oxo, NH 2, mono-(1-4C)-alkyl amino, di-(1-4C)-alkyl amino, hydroxycarbonyl and/or (1-4C)-alkoxycarbonyl; L 3>halo, CN, OH, CF 3O, (1-4C)-alkoxy, NH 2, mono-(1-4C)-alkyl amino, di-(1-4C)-alkyl amino, hydroxycarbonyl, (1-4C)-alkoxycarbonyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl and/or 5-6-membered heteroaryl; and R 5>H or a substituents of series of halo, CN, NO 2, (1-6C)-alkyl, CF 3, OH, (1-6C)-alkoxy, CF 3O, NH 2, mono-(1-6C)-alkylamino, di-(1-6C)-alkyl amino, hydroxycarbonyl or (1-6C)-alkoxycarbonyl. Independent claims are included for: (1) the preparation of (I); and (2) a medicament comprising (I), in combination with an inert, non-toxic, auxiliary material and one or more further active substances of angiotensin-converting enzyme-inhibitor, angiotensin II-receptor antagonist, beta-receptor-blocker, calcium-antagonist, phosphodiesterase-inhibitor, mineralocorticoid-receptor-antagonist, diuretics, aspirin, iron-supplements, vitamin B12- and folic acid-supplements, statin, digitalis (digoxin)-derivative, tumor-chemotherapeutics or antibiotics. [Image] [Image] [Image] [Image] [Image] ACTIVITY : Cardiovascular-Gen.; Cardiant; Antianemic; Nephrotropic; Vulnerary; Antimicrobial; Anti-HIV; Antiinflammatory; Antiarthritic; Antirheumatic; Metabolic; Cytostatic; Ophthalmological; Cerebroprotective; Antiparkinsonian; Neuroprotective; Nootropic; Analgesic; Endocrine-Gen.; Antidiabetic; Vasotropic; Antianginal; Antiarteriosclerotic. MECHANISM OF ACTION : Hypoxia inducible factor-prolyl-4-hydroxylase inhibitor. The ability of (I) to inhibit hypoxia inducible factor-prolyl-4-hydroxylase was tested using in-vitro test by inhibiting prolylhydroxylase containing cell lysate with (I) for 60 minutes. The results showed that 2-pyridin-2-yl-4-pyridin-3-yl-1,2-dihydro-3H-pyrazol-3-thion-hydrochloride exhibited an IC 5 0value of = 30.