Patent FR-2949466-A1 (FR)
Title: New 2-pyridin-2-yl-pyrazol-3(2H)-one compounds are hypoxia inducible factor activators useful to treat e.g. lower limb ischemia, angina pectoris, myocardial infarction, atherosclerosis, pulmonary hypertension, glaucoma and kidney diseases
Inventor: ALTENBURGER JEAN MICHEL
IPC: A61K31/4439
Filed: 2009-08-28
Abstract: 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. R : -SO 2-NR3R4, H, halo, halo-1-5C alkyl, CO 2R5 or -SO 2-R4; R1 : -W1-(3-6C) cycloalkyl, heterocycloalkyl group not containing nitrogen atom or -W1-aryl, -W1-heteroaryl, -W1-heterocycloalkyl, -W1-COOR5-, or -W1-CONR5R6- (where the aryl, heteroaryl and heterocycloalkyl are optionally substituted on a carbon atom by one or more substituents of halo, (1-5C)alkyl, -(1-5C)alkylene-O-(1-5C)alkyl, (1-5C)alkoxy, hydroxy, halo(1-5C)alkyl, CN, -O(1-5C)alkylene-O-(1-5C)alkyl, -O-(1-5C)alkyl-NR5R6, -SO 2-(1-5C)-alkyl, NR5R6 or -CO 2R5), when R1 is heterocycloalkyl comprising N, then it optionally bearing a substituent comprising 1-5C alkyl; R2 : H, 1-5C alkyl, -(1-5C)alkylene-O-(1-5C)alkyl, halo(1-5C)alkyl, -W1-COOR5, -W1-CONHR5, or -W1-CO-NR5R6; n : 0-2; W1 : 1-5C alkylene (optionally substituted by -(CH 2) n-CO 2-R5 or -(CH 2) n-CO-NR5R6) or 3-6C cycloalkylene; either R3, R4 : H, (1-5C)alkyl, 3-6C cycloalkyl, -(1-5C)alkylene-O-(1-5C)alkyl, aryl, -CH 2-aryl, heteroaryl, heterocycloalkyl, -W1-OH, -W1-CHOH-CH 2OH, -W1-CO 2-R5, -W1-R5R6 or -W1-O-(CH 2) n-aryl, where the cycloalkyl and heterocycloalkyl are optionally substituted on at least one carbon atom by (1-5C)alkyl, (1-5C)alkoxy, OH, -W1-R5R6 or -W1-CO 2-R5 and on at least one heteroatom comprising N optionally substituted by at least one 1-5C alkyl in heterocycloalkyl group, provided that when R3 and R4 are same, they cannot be a hydrogen atom; or NR3R4 : heterocycloalkyl optionally substituted on at least one carbon atom and/or, where appropriate, on at least one heteroatom by at least one (1-5C) alkyl and -CH 2-aryl; R5, R6 : H, 1-5C alkyl, or halo-1-5C alkyl; either R3, R4 : H, (1-5C)alkyl, (3-6C) cycloalkyl, -(1-5C)alkyl-(1-5C) alkoxy, aryl, -CH 2-aryl or heteroaryl; or NR3R4 : heterocycloalkyl optionally substituted on C or heteroatom by one or more substituents of 1-5C alkyl or -CH 2-aryl; and R5, R6 : H or (1-5C)alkyl. Provided that (I) excludes: 4-benzyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(2,4-dichlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(4-methoxybenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(4-bromobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 2-(pyridin-2-yl)-4-[2-(trifluoromethyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one, 4-(4-chlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4- (1,3-benzodioxol-5-ylmethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(3-methylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(2-chlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(4-methylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(3-chlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(4-tert-butylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-benzyl-5-methyl-2-(pyridin-2-yl)-1, 2-dihydro-3H-pyrazol-3-one, 5-methyl-4-(1-phenylethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-benzyl-2-(6-chloropyridin-2-yl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one, and 4-{1-[4-(diethylamino)phenyl]ethyl}-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one. Independent claims are included for: (1) the preparation of (I); (2) a combination of (I) with one or other active compounds useful in the treatment of hypertension, heart failure, diabetes and anemia; and (3) 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, after treatment of cells by one of the compounds to be tested, 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; (e) incubating in the dark before reading and measuring the luminescence which is depending on the activity of beta galactosidase. [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 6-(4-(3-[2-(dimethylamino)ethoxy]benzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N- phenylpyridine-3-sulfonamide hydrochloride exhibited EC 5 0 value of 2E-06 M.