Patent DE-102012200356-A1 (DE)
Title: New substituted imidazopyrid(az)ine compounds are soluble guanylate cyclase stimulators, useful to treat e.g. heart disease, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disease or renal insufficiency
Inventor: FOLLMANN MARKUS
IPC: C07D487/04
Filed: 2012-01-11
Abstract: Substituted imidazopyrid(az)ine compounds (I) are new. Substituted imidazopyrid(az)ine compounds of formula (I) and their N-oxides, salts, solvates, salts of N-oxides and solvates of the N-oxides or their salts are new. A : N or CR3; R3 : 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, phenyl, 5- or 6-membered heteroaryl (all optionally substituted with 1-3 substituents comprising F, difluoromethyl, trifluoromethyl, 1-4C-alkyl, difluoromethoxy, trifluoromethoxy, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, cyclopropyl or cyclobutyl), H, D, halo, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl or hydroxy; L : a1-CR4AR4B-(CR5AR5B) p-a2; a1 : point of attachment to the carbonyl group; a2 : point of attachment to the pyrimidine or triazine ring; p, s : 0-2; either R4A : H, F, 1-4C-alkyl (optionally substituted with 1-3 substituents comprising F, amino, trifluoromethyl, hydroxy, hydroxycarbonyl or 1-4C-alkoxycarbonyl), hydroxy or amino; and R4B : H, F, difluoromethyl, trifluoromethyl, 1-6C-alkyl (optionally substituted with 1-3 substituents comprising F, cyano, trifluoromethyl, 1-7C-cycloalkyl, hydroxy, difluoromethoxy, trifluormethoxy, 1-4C-alkoxy, hydroxycarbonyl, 1-4C-alkoxycarbonyl or amino), 1-6C-alkoxycarbonylamino, cyano, 3-7C-cycloalkyl, difluoromethoxy, trifluoromethoxy, phenyl or -Q-R8; or R4A+C+R4B : 3-6 membered carbocycle or 4-6 membered heterocycle (both optionally substituted with 1 or 2 substituents comprising F or 1-4C-alkyl), oxo-group or 2-4C-alkenyl; Q : a bond or 1-4C-alkanediyl; R8 : -(C=O) r, -OR9, -(C=O) rNR9R10, -C(=S)-NR9R10, -NR9-(C=O)-R12, -NR9-(C=O)-NR10R11, -NR9-SO 2-NR10R11, -NR9-SO 2-R12, -S(O) s-R12, -SO 2-NR9R10, 4-7 membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl; r : 0 or 1; either R9-R11 : 4-7 membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl (all optionally substituted with 1-3 substituents comprising halo, cyano, difluoromethyl, trifluoromethyl, 1-6C-alkyl, 3-7C-cycloalkyl, hydroxy, oxo, thiooxo or 1-4C-alkoxy), H, 1-6C-alkyl or 3-8C-cycloalkyl; and R12 : 1-6C-alkyl or 3-7C-cycloalkyl; or R9+R10, R10+R11, R9+R12 : 4-7 membered heterocycle (optionally substituted with 1 or 2 substituents comprising cyano, trifluoromethyl, 1-6C-alkyl, hydroxy, oxo, 1-6C-alkoxy, trifluoromethoxy, 1-6C-alkoxycarbonyl, amino, mono-1-6C-alkylamino or di-1-6C-alkylamino), where the above 1-4C-alkyl-, 1-6C-alkyl-, 3-8C-cycloalkyl- and 4-7 membered heterocyclyl-groups are optionally further substituted with 1-3 substituents comprising F, difluoromethyl, trifluoromethyl, 1-6C-alkyl, 1-7C-cycloalkyl, hydroxy, difluoromethoxy, trifluoromethoxy, 1-4C-alkoxy, hydroxycarbonyl, 1-4C-alkoxycarbonyl, amino, phenyl, 4-7 membered heterocyclyl or 5- or 6-membered heteroaryl; R5A : H, F, 1-4C-alkyl, 1-4C-alkoxycarbonyl or hydroxy; R5B : H, F, 1-4C-alkyl or trifluoromethyl; M : CH or N; R1 : 1-6C-alkyl (substituted with difluoromethyl or trifluoromethyl, or optionally substituted with 1-3 substituents comprising F), 3-8C-cycloalkylmethyl (optionally substituted with 1 or 2 substituents comprising F, methyl or methoxy), or benzyl or 5- or 6-membered heteroarylmethyl (both optionally substituted with 1-3 F); R2, R6 : H, cyano, halo, difluoromethyl, trifluoromethyl, 1-4C-alkyl or 3-7C-cycloalkyl; and R7 : H, cyano, difluoromethyl, trifluoromethyl, 1-4C-alkyl or 3-7C-cycloalkyl. Independent claims are included for: (1) the preparation of (I); and (2) a drug comprising (I) in combination with further active agents comprising organic nitrates, nitric oxide donors, cyclic guanosine monophosphate-phosphodiesterase inhibitors, antithrombotic agents, blood pressure lowering agents or lipid modifying agents. [Image] ACTIVITY : Cardiant; Antianginal; Hypotensive; Respiratory-Gen.; Vasotropic; Nephrotropic; Thrombolytic; Antiinflammatory; Antiarteriosclerotic; Antiarrhythmic; Cardiovascular-Gen.; Antibacterial; Immunosuppressive; Antiallergic; Cerebroprotective; Endocrine-Gen.; Antidiabetic; Antilipemic; Hemostatic; Anorectic; Ophthalmological; Antiulcer; Antianemic; Antiasthmatic; CNS-Gen.; Nootropic; Vulnerary; Neuroprotective; Antiparkinsonian; Anticonvulsant; Neuroleptic; Tranquilizer; Antidepressant; Hypnotic; Antimigraine; Gastrointestinal-Gen.; Dermatological; Cytostatic. MECHANISM OF ACTION : Soluble guanylate cyclase stimulator. The soluble guanylate cyclase stimulating activity of (I) was tested in a recombinant guanylate cyclase reporter cell line using an in vitro assay. The results showed that 2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one exhibited a minimal effective concentration of 0.01 mu M.