Patent JP-5300729-B2 (JP)
IPC: A61P29/00
Filed: 2007-10-17
Granted: 2013-09-25
Abstract: Substituted dihydropyrazolone derivatives (I) are new. Substituted dihydropyrazolone derivatives of formula (I) are new. R 1>heteroaryl compounds of formula (a) or (b); A : C-R 4> or N, where maximum two ring members of A are simultaneously N; E : C-R 5> or N, where maximum two ring members of E are simultaneously N; R 2>nitrogen containing heteroaryl-group of formula (c)-(o); a1, a2 : point of attachment with the dihydropyrazolthione ring; G : C-R 6> or N, where maximum two ring members of G are simultaneously N; J : O, S or N-R 7>; L : C-R 8> or N, where maximum two ring members of L are simultaneously N; M : C-R 9> or N, where maximum two ring members of M are simultaneously N; R 4>, R 6>, R 8>, R 9>H, halo, cyano, NO 2, (1-6C)-alkyl (substituted with 1-3 of T), (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl (where the (hetero)cycloalkyl, phenyl and heteroaryl are substituted with 1-3 of T 1>), -C(=O)-R 1> 0>, -C(=O)-OR 1> 1>, -C(=O)-NR 1> 2>R 1> 3>, -O-C(=O)-R 1> 4>, -O-C(=O)-NR 1> 5>R 1> 6>, -NR 1> 7>-C(=O)-R 1> 8>, -NR 1> 9>-C(=O)-OR 2> 0>, -NR 2> 1>-C(=O)-NR 2> 2>R 2> 3>, -NR 2> 4>-SO 2-R 2> 5>, -SO 2-R 2> 6>, -SO 2-NR 2> 7>R 2> 8>, -OR 2> 9>, -SR 3> 0> or -NR 3> 1>R 3> 2>; T : halo, CN, oxo, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C(=O)-R 1>0, -C(=O)-OR 1> 1>, -C(=O)-NR 1> 2>R 1> 3>, -O-C(=O)-R 1> 4>, -O-C(=O)-NR 1> 5>R 1> 6>, -NR 1> 7>-C(=O)-R 1> 8>, -NR 1> 9>-C(=O)-OR 2> 0>, -NR 2> 1>-C(=O)-NR 2> 2>R 2> 3>, -NR 2> 4>-SO 2-R 2> 5>, -SO 2-R 2> 6>, -SO 2-NR 2> 7>R 2> 8>, -OR 2> 9>, -SR 3> 0> or -NR 3> 1>R 3> 2>, where the cycloalkyl-, heterocycloalkyl-, phenyl- and heteroaryl are substituted by 1-3 of halo, CN, (1-4C)-alkyl, trifluoromethyl, OH, (1-4C)-alkoxy, trifluoromethoxy, oxo, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, hydroxycarbonyl and/or (1-4C)-alkoxycarbonyl; T 1>(1-6C)-alkyl, halo, CN, oxo, -C(=O)-R 1> 0>, -C(=O)-OR 1> 1>, -C(=O)-NR 1> 2>R 1> 3>, -O-C(=O)-R 1> 4>, -O-C(=O)-NR 1> 5>R 1> 6>, -NR 1> 7>-C(=O)-R 1> 8>, -NR 1> 9>-C(=O)-OR 2> 0>, -NR 2> 1>-C(=O)-NR 2> 2>R 2> 3>, -NR 2> 4>-SO 2-R 2> 5>, -SO 2-R 2> 6>, -SO 2-NR 2> 7>R 2> 8>, -OR 2> 9>, -SR 3> 0> or -NR 3> 1>R 3> 2>, where the alkyl is substituted with 1-3 of halo, CN, OH, trifluoromethoxy, (1-4C)-alkoxy, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, hydroxycarbonyl, (1-4C)-alkoxycarbonyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5- or 6-membered heteroaryl; either R 1> 0>-R 1> 2>, R 1> 4>, R 1> 5>, R 1> 8>, R 2> 0>, R 2> 2>, R 2> 5>-R 2> 7>, R 2> 9>-R 3> 1>H, (1-6C)-alkyl (substituted with 1-3 of halo, cyano, OH, trifluoromethoxy, (1-4C)-alkoxy, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, hydroxycarbonyl, (1-4C)-alkoxycarbonyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5- or 6-membered heteroaryl), (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5- or 6-membered heteroaryl (where the (hetero)cycloalkyl, phenyl and heteroaryl are substituted with 1-3 of halo, cyano, (1-4C)-alkyl, trifluoromethyl, OH, (1-4C)-alkoxy, trifluoromethoxy, oxo, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, hydroxycarbonyl or (1-4C)-alkoxycarbonyl); and R 1> 3>, R 1> 6>, R 1> 7>, R 1> 9>, R 2> 1>, R 2> 3>, R 2> 4>, R 2> 8>, R 3> 2>H or (1-6C)-alkyl, which is optionally substituted with halo, CN, OH, trifluoromethoxy, (1-4C)-alkoxy, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, hydroxycarbonyl or (1-4C)-alkoxycarbonyl; or R 1> 2>R 1> 3>, R 1> 5>R 1> 6>, R 1> 7>R 1> 8>, R 1> 9>R 2> 0>, R 2> 1>R 2> 2>, R 2> 2>R 2> 3>, R 2> 4>R 2> 5>, R 2> 7>R 2> 8>, R 3> 1>R 3> 2>5- or 6-membered heterocycloalkyl ring; R 5>H, halo, CN, nitro, (1-6C)-alkyl, trifluoromethyl, OH, (1-6C)-alkoxy, trifluoromethoxy, amino, mono-(1-6C)-alkylamino, di-(1-6C)-alkylamino, hydroxycarbonyl or (1-6C)-alkoxycarbonyl; R 7>H, (1-6C)-alkyl (substituted with 1-3 of T) , (3-7C)-cycloalkyl, 4-7 membered (hetero)cycloalkyl, phenyl, or 5- or 6-membered heteroaryl (where the (hetero)cycloalkyl, phenyl and heteroaryl are substituted with 1-3 of T 1>); and R 3>H, (1-6C)-alkyl or (3-7C)-cycloalkyl. Independent claims are included for: (1) the preparations of (I); and (2) a medicament comprising (I) and an inert, non-toxic auxiliary material. [Image] [Image] [Image] [Image] [Image] - ACTIVITY : Cardiovascular-Gen; Cardiant; Antianemic; Nephrotropic; Antianginal; Cerebroprotective; Vasotropic; Antiarteriosclerotic; Hypotensive; Respiratory-Gen; Antiarthritic; Antirheumatic; Ophthalmological; Antiparkinsonian; Neuroprotective; Nootropic; Analgesic; Vulnerary; Anabolic; Endocrine-Gen; Antidiabetic; Antimicrobial; Antiinflammatory. - MECHANISM OF ACTION : Hypoxia-inducible transcription factor (HIF)-prolyl-4-hydroxylase inhibitor. The ability of (I) to inhibit the activity of HIF-prolyl-4-hydroxylase was tested in in-vitro using the method described in Oehme F., Jonghaus W., Narouz-Ott L., Huetter J., Flamme I., Anal. Biochem. 330 (1), 74-80 (2004). The results showed that (I) exhibited an IC 5 0 value of = 30 mu M.