New 2-pyridin-2-yl-pyrazol-3(2H)-one compounds are hypoxia inducible factor activators, useful for the treatment of hypertension, heart failure, diabetes, anemia, angina pectoris or myocardial infarction and pulmonary hypertension

摘要

2-Pyridin-2-yl-pyrazol-3(2H)-one compounds (I) and their base or acid addition salts are new. 2-Pyridin-2-yl-pyrazol-3(2H)-one compounds of formula (I) and their base or acid addition salts are new. n : 1-4; m : 0-2; o = 0 or 1; X : -CHR1a-, -CHR1a-, NR1a or heteroatom comprising O or S; R1a : 1-5C alkyl, 1-5C alkoxy, -CH 2-aryl, -COR 5 or -COOR 5; R 1 : oxo, -COOR 5, -W 1-OH or -W 1-NR 5R 6; R 2 : H, 1-5C alkyl, 1-5C alkoxy, -COOR 5, NR 5R 6, CONR 5R 6, SO 2NR 3R 4, heteroaryl (optionally substituted by 1-5C alkyl), -W 1-aryl, -W 1-heteroaryl, -O-W 1-aryl, -O-W 1-heteroaryl or -O-W 1-NR 5R 6, preferably R 2 is located in gamma-position of pyridine; either R 3, R 4 : H, 1-5C alkyl, 3-6C cycloalkyl, (hetero)aryl, -CH 2-heteroaryl, -1-5C alkyl-NR 5R 6, -W 1-OH or -W 1-NR 5R 6; or NR 3R 4 : heterocycloalkyl optionally substituted by 1-5C alkyl or -CH 2-aryl; W 1 : 1-5C alkylene optionally substituted by one or more OH; and R 5, R 6 : H, 1-5C alkyl or 3-6C cycloalkyl. Independent claims are included for: (1) the preparation of (I); (2) phenyl-hydrazine ester compounds of formula (IVa) or (IVb); (3) combination of (I) with one or other active compounds useful in the treatment of hypertension, heart failure, diabetes and anemia; and (4) process of homogeneous test for direct measurement by beta-galactosidase complementation of the amount of hypoxia-inducible factor-1 (HIF1) alpha protein in the cell nucleus, preferably human embryonic kidney (HEK) cells, comprising: (a) inoculating, the cells in a suitable culture medium; (b) adding compounds to be tested to an appropriate concentration in an appropriate solvent to cells previously inoculated in culture medium; (c) incubating cells thus prepared in an incubator at 37[deg] C, preferably for 6 hours; (d) lysing the cells with a lysis buffer containing a chemiluminescent substrate of the beta-galactosidase; and (e) incubating in the dark before reading and measuring the luminescence which is depending on the activity of beta galactosidase. [Image] [Image] ACTIVITY : Cardiovascular-Gen.; Vasotropic; Cardiant; Antianginal; Antiarteriosclerotic; Cerebroprotective; Hypotensive; Respiratory-Gen.; Ophthalmological; Nephrotropic; Neuroprotective; Antianemic; CNS-Gen.; Muscular-Gen.; Antidiabetic. MECHANISM OF ACTION : Hypoxia inducible factor (HIF) activator. The ability of (I) to activate the HIF was tested using erythropoietin kit. The results showed that 2-[5-[ethyl(phenyl)sulfonyl]pyridin-2-yl]-3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridine-5-tert-butyl carboxylate EC 5 0 value of 1E-06 M.