Patent DE-102007048447-A1 (DE)
Title: New substituted dihydropyrazole-3-thione compounds are hypoxia inducible factor-prolyl-4-hydroxylase inhibitor, useful for preparing medicament to treat and/or prevent e.g. cardiovascular diseases, wound healing and anemia
Inventor: JESKE MARIO
IPC: C07D401/14
Filed: 2007-10-10
Abstract: Substituted 1,2-dihydro-pyrazole-3-thione compounds (I), and their salts, solvates or solvates of the salts, where (I) excludes 3-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyridin-2-yl-1H-pyrazol-5-thiol, are new. Substituted 1,2-dihydro-pyrazole-3-thione compounds of formula (I) and their salts, solvates or solvates of the salts, where (I) excludes 3-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyridin-2-yl-1H-pyrazol-5-thiol, are new. R 1>a heteroaryl-group of formula (a), (b), (c), (d), (e) or (f); A : CR 4>or N, where at most two A are N; D 1>O, S or NR 5>; E : CR 6>or N, where at most two E are N; R 2>heteroaryl of formula (i)-(xiii); G : CR 7>or N, where at most two G are N; J : O, S or NR 8>; L : CR 9>or N, where at most two L are N; R 4>, R 7>, R 9>H, halo, CN, NO 2, (1-6C)-alkyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl or L 1>; R 5>, R 8>H, (1-6C)-alkyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl (where in R 4>, R 5>, R 7>-R 9>: (1-6C)-alkyl is 1-3 times substituted by halo, CN, oxo, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, or L 1>, where cycloalkyl-, heterocycloalkyl-, phenyl- or heteroaryl 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 (1-6C)-alkyl, halo, CN, oxo or L 1>where the alkyl is 1-3 times substituted by L 3>); R 10>, R 11>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>; R 12>, R 14>, R 15>, R 18>, R 20>, R 22>, R 25>-R 27>, R 29>-R 31>R 10>; and R 13>, R 16>, R 17>, R 19>, R 21>, R 23>, R 24>, R 28>, R 32>H or (1-6C)-alkyl 1-3 times substituted by halo, CN, OH, CF 3, (1-4C)-alkoxy, NH 2, (1-4C)-alkylamino, di-(1-4C)-alkylamino, COOH and/or (1-4C)-alkoxycarbonyl; or R 12>R 13>, R 15>R 16>, R 17>R 18>, R 19>R 20>, R 21>R 22>, R 22>R 23>, R 24>R 25>, R 27>R 28>, R 31>R 32>5-6-membered heterocycloalkyl ring (1-3 times substituted by L 2>); L 1>C(O)R 10>, C(O)OR 11>, C(O)NR 12>R 13>, OC(O)R 14>, OC(O)NR 15>R 16>, NR 17>C(O)R 18>, NR 19>C(O)OR 20>, NR 21>C(O)NR 22>R 23>, NR 24>SO 2R 25>, SO 2R 26>, SO 2NR 27>R 28>,-OR 29>, SR 30>or NR 31>R 32>; L 2>halo, CN, (1-4C)-alkyl, CF 3, OH, (1-4C)-alkoxy, CF 3O, oxo, NH 2, (1-4C)-alkylamino, di-(1-4C)alkylamino, COOH and/or (1-4C)-alkoxycarbonyl; L 3>halo, CN, OH, CF 3O, (1-4C)-alkoxy, NH 2, (1-4C)-alkylamino, di-(1-4C)-alkylamino, COOH, (1-4C)-alkoxycarbonyl, (3-7C)-cycloalkyl, 4-7-memebred heterocycloalkyl, phenyl and/or 5-6-membered heteroaryl; R 6>H, halo, CN, NO 2, (1-6C)-alkyl, CF 3, OH, (1-6C)-alkoxy, CF 3O, NH 2, (1-6C)-alkylamino, di-(1-6C)alkylamino, COOH or (1-6C)-alkoxycarbonyl; and R 3>H, 1-6C alkyl or (3-7C)-cycloalkyl. Independent claims are included for: (1) preparations of (I); and (2) a medicament comprising (I) in combination with an inert, non-toxic, auxiliary material and one or more active substances from angiotensin-converting enzyme or phosphodiesterase inhibitor, angiotensin II-receptor antagonist, beta-blocker, calcium-antagonist, 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 50value = 30.