New heteroaryl-substituted piperidine compounds are protease-activated receptor antagonists useful for the treatment and/or prophylaxis of e.g. cardiovascular diseases, thromboembolic diseases, tumors, stroke, hypertension and asthma

摘要

Heteroaryl-substituted piperidine compounds (I) and their salts, solvates or solvate of the salts, are new. Heteroaryl-substituted piperidine compounds of formula (I) and their salts, solvates or solvate of the salts, are new. A : [1,2,4]oxadiazole group of formula (a), thiazole group of formula (b) or (e), [1,3,4]oxadiazole group of formula (c), isoxazole group of formula (d), [1,3,4]thiadiazole group of formula (g) or oxazole group of formula (h); aa : connection with piperidine ring; aaa : connection with R 2>; R 1>phenyl substituted with 1-3 substituents of monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, methylsulfonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or 3-6C-cycloalkyl (where 2-4C-alkoxy is substituted by CH 3O or C 2H 5O and the cycloalkyl is substituted by 1-3 substituents of halo or 1-4C-alkyl); R 2>4-6-membered heterocycle, phenyl, 5- or 6-membered heteroaryl (all substituted by 1-3 substituents of halo, CN, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 1-4C-alkyl, 1-4C-alkoxy, 1-6C-alkylamino, 1-4C-alkoxycarbonylamino, 3-6C-cycloalkyl, 4-6 membered heterocycle, phenyl or 5-6 membered heteroaryl, where: alkyl amino is substituted by 1-4C-alkoxy or 1-6C-alkyl amino, 1-4C-alkyl is substituted by halo, OH, amino, aminocarbonyl, 1-4C-alkoxy, 1-6C-alkylamino, 1-4C-alkylthio, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylsulfonyl, 1-4C-alkoxycarbonyl, 1-4C-alkoxycarbonylamino, 3-6C-cycloalkyl, 3-6C-cycloalkylamino, 4-6-membered heterocyclyl, phenyl, phenoxy, 5- or 6-membered heteroaryl or 5- or 6-membered heteroarylthio, and the cycloalkyl, heterocycle, phenyl, phenoxy, heteroaryl or heteroarylthio is substituted by 1-3 substituents of halo, CN, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 1-4C-alkyl, 1-4C-alkoxy, 3-6C-cycloalkyl, 4-6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl); and R 3>1-6C-alkyl, 1-6C-alkoxy, 1-6C-alkylamino, 3-7C-cycloalkyl, 4-6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl (where: the alkyl, 2-6C-alkoxy and alkylamino is substituted by OH, amino, CN or 1-4C-alkoxy, and the cycloalkyl, heterocycle, phenol or heteroaryl is substituted by 1-3 substituents of halo, CN, NO 2, oxo, OH, amino, aminomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, hydroxy carbonyl, amino carbonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-6C-alkyl amino, 1-4C-alkoxy carbonyl or 1-4C-alkyl aminocarbonyl), H, trifluoromethyl, aminomethyl, 1-6C-alkyl, 2-6C-alkenyl, 1-4C-alkoxycarbonyl, 3-6C-cycloalkyl, cyclopentenyl, 1,3-benzodioxolyl or pyridylaminocarbonyl. An independent claim is included for the preparations of (I). [Image] [Image] [Image] ACTIVITY : Cardiovascular-Gen.; Thrombolytic; Cytostatic; Anticoagulant; Hemostatic; Cardiant; Antianginal; Vasotropic; Cerebroprotective; Antiarrhythmic; Muscular-Gen.; Osteopathic; Hypotensive; Antiasthmatic; Nephrotropic; Neuroprotective; Nootropic; Immunosuppressive; Antiinflammatory; Gastrointestinal-Gen.; Antiulcer; Ophthalmological; Antiarthritic; Antirheumatic; Respiratory-Gen.; Antiarteriosclerotic; Antibacterial; Antipyretic; Fungicide; Virucide; Antimicrobial; Uropathic; Vulnerary. MECHANISM OF ACTION : Protease-activated receptor antagonist. The antagonistic activity of (I) was tested in recombinant cell line. The results showed that (I), preferably {3-[3-(2-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5-[3-methyl-4-(trifluoromethoxy)phenyl]piperidin-1-yl}(morpholin-4-yl)methanone exhibited an IC 5 0value of 3.01 nM.