Patent DE-102007061766-A1 (DE)
Title: New 4-(4-cyano-2-thioaryl)-dihydro-pyrimidinone compounds are human neutrophil elastase inhibitor, useful for the treatment or prevention of e.g. pulmonary arterial hypertonia, acute lung injury and diseases of the cardiovascular system
Inventor: NUSSBAUM FRANZ
IPC: A61P11/00
Filed: 2007-12-20
Abstract: 4-(4-Cyano-2-thioaryl)-dihydro-pyrimidinone compounds (I) and their salts, solvates and solvates of the salts, are new. 4-(4-Cyano-2-thioaryl)-dihydro-pyrimidinone compounds of formula (I) and their salts, solvates and solvates of the salts, are new. A, E : C-R 7>or N; R 7>H, F or Cl; Z : O or S; n : 0-2; R 1>1-6C-alkyl (substituted with OH, 1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, hydroxycarbonyl, aminocarbonyl, 3-6C-cycloalkyl or phenyl), 3-6C-cycloalkyl (substituted up to two times with 1-4C-alkyl, OH and/or 1-4C-alkoxy), phenyl (substituted up to two times with F, Cl, CN, 1-4C-alkyl, difluoromethyl, trifluoromethyl, 1-4C-alkoxy, difluoromethoxy and/or trifluoromethoxy) or 2-6C-alkenyl; R 2>H, F or Cl; R 3>CN or a group of formula -C(=O)-R 8>, -C(=O)-O-R 8>, -C(=O)-NH 2or -C(=O)-NH-R 8>; R 8>1-6C-alkyl or 3-6C-cycloalkyl (both up to two times substituted with OH, 1-4C-alkoxy, hydroxycarbonyl, 1-4C-alkoxycarbonyl, amino, mono- and/or di-1-4C-alkylamino, where CH 2group in 1-6C-alkyl and 3-6C-cycloalkyl forms a chemically stable compound and can be exchanged by O atom) or 3-6C-alkenyl; either R 4>methyl or ethyl; or R 3>R 4>annelated amine group of formula (a-C(=O)-N(R 9>)-CH 2-aa); a : a bond formed at the 5th position of the dihydropyrimidine ring; aa : a bond formed at the 6th position of the dihydropyrimidine ring; R 9>H, 1-6C-alkyl (substituted with OH, 1-4C-alkoxy, aminocarbonyl, 1-4C-acyl amino or 3-6C-cycloalkyl) or 3-6C-cycloalkyl; R 5>phenyl, pyridyl or pyrimidinyl (all up to two times substituted with F, Cl, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy and/or trifluoromethoxy), H, 1-6C-alkyl (substituted up to three times with F), -C(=O)-O-R 1> 0>, -L 1>-C(=O)-O-R 1> 1>, -L 2>-C(=O)-NR 1> 2>R 1> 3>, -L 2>-SO 2-NR 1> 2>R 1> 3>, -L 2>-C(=O)-NR 1> 4>-NR 1> 2>R 1> 3>or -L 2>-SO 2-R 1> 5>; L 1>1-6C-alkanediyl; L 2>a bond or 1-6C-alkanediyl; R 1> 0>1-6C-alkyl; R 1> 1>H or 1-6C-alkyl; either R 1> 2>, R 1> 3>1-6C-alkyl, 3-6C-cycloalkyl or 4 to 6 membered heterocyclyl (all substituted up to two times with F, OH, 1-4C-alkoxy, oxo, amino, mono- or di-(1-4C)-alkyl amino, hydroxycarbonyl, 1-4C-alkoxycarbonyl and/or aminocarbonyl, where CH 2group in 1-6C-alkyl forms a chemically stable compound and can be exchanged by O-atom) or H; or NR 1> 2>R 1> 3>4- to 6-membered heterocyclic compound, which contains a further ring heteroatom from N, O, S, SO or SO 2and is substituted up to two times with 1-4C-alkyl (further substituted with OH or 1-4C-alkoxy), OH, 1-4C-alkoxy, oxo, amino, mono- and/or di-1-4C-alkyl amino; R 1> 4>H or 1-4C-alkyl; R 1> 5>phenyl or 5- or 6 membered heteroaryl (both up to two times substituted with F, Cl, CN, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy and/or trifluoromethoxy), 1-6C-alkyl (substituted with F, Cl, OH, 1-4C-alkoxy, mono- or di-1-4C-alkyl amino) or 3-6C-cycloalkyl; and R 6>H, F or Cl. Where one of the two ring member A and E is N and other is C-R 7>. Independent claims are included for: (1) the preparation of (I); and (2) a medicament comprising (I) in combination with one or more inert, non-toxic auxiliary materials. [Image] ACTIVITY : Respiratory-Gen.; Muscular-Gen.; Hypotensive; Cardiant; Metabolic; CNS-Gen.; Cardiovascular-Gen.; Vasotropic; Antibacterial; Immunosuppressive; Antiarteriosclerotic; Antiinflammatory; Gastrointestinal-Gen.; Cytostatic; Antiarthritic; Antirheumatic; Anticoagulant; Nephrotropic; Cerebroprotective; Antidiabetic; Anorectic; Neuroprotective; Nootropic; Antiparkinsonian; Anticonvulsant; Antidepressant; Antiallergic; Antithyroid; Dermatological; Antipsoriatic; Antiseborrheic; Virucide; Anti-HIV; Ophthalmological; Anabolic; Osteopathic; Vulnerary. MECHANISM OF ACTION : Human neutrophil elastase inhibitor. The ability of (I) to inhibit human neutrophil elastase was tested by using an in-vitro inhibition test (in which the signal intensity of the fluorescent light i.e. directly proportional to the enzyme activity, resulting from human neutrophil elastase mediated amidolytic cleavage of a suitable peptide substrate, was measured). The result showed that (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N-(2-hydroxyethyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide (I) exhibited an IC 5 0value of less than 0.3.