New ring-fused 4-aminopyrimidine compounds are guanylate cyclase stimulators useful to treat and/or prevent e.g. heart failure, angina pectoris, hypertonia, pulmonary hypertonia, ischemia, vascular disease and renal insufficiency

摘要

Ring-fused 4-aminopyrimidine compounds (I) and their N-oxides, salts, solvates, salts of N-oxides or solvates of N-oxides and salts, are new. Ring-fused 4-aminopyrimidine compounds of formula (I) and their N-oxides, salts, solvates, salts of N-oxides or solvates of N-oxides and salts, are new. A : 1-3C-alkandiyl (optionally substituted by 1 or 2 F, CF 3, OH, amino or 1-4C-alkyl (optionally substituted by 1-3 F, CF 3or OH)) or a cyclic group of formula (AA); a : connection point with pyrimidine ring; b : connection point with the carbonyl group; R 1 : H or F; R 2 : 1-6C-alkyl (substituted by CF 3or optionally substituted by 1-3 F) or benzyl substituted by 1-3 F; and ring Q : 4-6 membered heterocyclic ring. Independent claims are included for: (1) the preparation of (I); and (2) a medicament comprising (I) in combination with an inert, non-toxic auxiliary agent and a further active agent comprising organic nitrate, nitric oxide donors, cGMP-phosphodiesterase inhibitors, anti-thrombotic active agents, blood pressure lowering agents and/or fat metabolism modifying agent. [Image] ACTIVITY : Cardiant; Antianginal; Muscular-Gen.; Vasotropic; Nephrotropic; Thrombolytic; Antiarteriosclerotic; Antiarrhythmic; Antiparkinsonian; Antiinflammatory; Endocrine-Gen.; Antilipemic; Anorectic; Uropathic; Hypotensive; Respiratory-Gen.; CNS-Gen.; Nootropic; Neuroprotective; Cerebroprotective; Anticonvulsant; Antidepressant; Antibacterial; Immunosuppressive; Gastrointestinal-Gen.; Antiarthritic; Antirheumatic; Vulnerary; Hepatotropic; Virucide; Osteopathic; Ophthalmological. MECHANISM OF ACTION : Guanylate cyclase stimulator. The ability of (I) to stimulate guanylate cyclase was tested using recombinant guanylate cyclase reporter cell line. The results showed that 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one exhibited a minimal effective concentration of 0.001 mu M.