New 1H-pyrazolo(3,4-b)pyridine compounds are guanylate cyclase stimulators useful for treating and/or preventing e.g. heart failure, angina pectoris, hypertonia, pulmonary hypertonia, ischemia, vascular disease, and fibrotic disorder

摘要

1H-Pyrazolo[3,4-b]pyridine compounds (I) or their N-oxides, salts, solvate, salts of N-oxide and solvates of N-oxides and salts, are new. 1H-Pyrazolo[3,4-b]pyridine compounds of formula (I) or their N-oxides, salts, solvate, salts of N-oxide and solvates of N-oxides and salts, are new. A : N or CR 3>; R 3> : H, D, F, CHF 2, CF 3, (1-4C)-alkyl, cyclopropyl or cyclobutyl; L : a-CR4AR4B-(CR5AR5B) p-b; a : connection point at carbonyl group; b : connection point to pyrimidine or triazine ring; p : 0-2; either R4A, R5A : H, F, (1-4C)-alkyl or OH; and R4B : H, F, (1-4C)-alkyl, CF 3, (1-4C)-alkoxy-carbonylamino or phenyl, where (1-4C)-alkyl is optionally substituted by 1 or 2 F, CF 3, OH, hydroxycarbonyl or (1-4C)-alkoxycarbonyl; and R5B : H, F, (1-4C)-alkyl or CF 3; or R4AR4BC : 3-6 membered carbocyclic ring, 4-6 membered heterocyclic ring (both optionally substituted by 1 or 2 F or (1-4C)-alkyl), an oxo group or (2-4C)-alkenyl; R 1> : H or F; and R 2> : benzyl substituted by 1-3 F. Independent claims are included for: (1) the preparation of (I); (2) a 3-(1H-pyrazolo[3,4-b]pyridin-3-yl)-[1,2,4]triazin-5-ylamine compound of formula (XV); (3) a 3-(1H-pyrazolo[3,4-b]pyridin-3-yl)-[1,2,4]triazin-5-ol compound of formula (XIII); and (4) a medicament comprising (I), inert and non-toxic auxiliary agent and a further active agent, which is an organic nitrate, nitiric 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; Thrombolytic; Antiarteriosclerotic; Antiarrhythmic; Antiparkinsonian; Antiinflammatory; Endocrine-Gen.; Antilipemic; Anorectic; Uropathic; Nephrotropic; Neuroprotective; Hypotensive; Respiratory-Gen.; CNS-Gen.; Nootropic; 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 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3d]pyrimidin-6-one exhibited a minimal effective concentration of 0.01 mu M.