INTERMEDIATE PRODUCTS FOR THE PREPARATION OF PYRIDAZINONE ALDOSE REDUCTASE INHIBITORS.

摘要

Pyridazinone derivatives (I) are new. Pyridazinone derivatives of formula (I) and their prodrugs and salts are new. [Image] A : S, SO or SO 2; R 1, R 2H or Me; R 3Het 1, CHR 4Het 1 or NR 6R 7; R 4H or 1-3C alkyl; R 61-6C alkyl, aryl or Het 2; R 7Het 3; Het 1pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolinyl, naphthyridinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisothiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazolopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazolopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl (all optionally substituted by 1-4 halo, formyl, 1-6C alkoxycarbonyl, 1-6C alkenyloxycarbonyl, 1-4C alkoxy-(1-4C alkyl), C(OH)R 12R 13, 1-4C alkylcarbonylamido, 3-7C cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, T, T 1, 1-4C alkylsulfenyl, 1-4C alkylsulfonyl, 3-7C cycloalkyl, 1-6C alkyl (optionally substituted by 1-3 F) or 1-4C alkoxy (optionally substituted by 1-5 F) and in which benzyl, T and T 1 are optionally substituted by 1-3 OH, halo, 1-4C hydroxyalkyl, 1-4C alkoxy-(1-4C alkyl), 1-6C alkylsulfenyl, 1-6C alkylsulfinyl, 1-6C alkylsulfonyl, 1-6C alkyl (optionally substituted by 1-5 F) or 1-4C alkoxy (optionally substituted by 1-5 of F) and in which T 1 is optionally substituted by 1 or 2 OH, halo, 1-4C alkyl, 1-4C hydroxyalkyl, 1-4C alkoxy-(1-4C alkyl), 1-4C alkylphenyl (optionally substituted by Cl, Br, OMe, Me or SO 2-phenyl (optionally substituted by Cl, Br, OMe, Me, 1-4C alkyl (optionally substituted by 1-5 F) or 1-4C alkoxy (optionally substituted by 1-3 F))); T : phenyl, naphthyl, pyridyl, triazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy; T 1imidazolyl, oxazolyl, isoxazolyl, thiazolyl or pyrazolyl; R 12, R 13H or 1-4C alkyl; Het 2, Het 3T 1, pyridyl, triazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy or thiophenoxy (all optionally substituted by 1-4 halo, formyl, 1-6C alkoxycarbonyl, 1-6C alkenyloxycarbonyl, 1-4C alkoxy-(1-4C alkyl), C(OH)R 18R 19, 1-4C alkylcarbonylamido, 3-7C cycloalkylcarbonylamido, phenylcarbonylamido, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, 1-4C alkylsulfenyl, 1-4C alkylsulfonyl, 3-7C cycloalkyl, 1-4C alkyl (optionally substituted by up to 3 of F) or 1-4C alkoxy (optionally substituted by up to 5 of F) and in which T and T 1 are optionally substituted by 1-3 OH, halo, 1-4C hydroxyalkyl, 1-4C alkoxy-(1-4C alkyl), 1-4C alkyl (optionally substituted by 1-51 F) or 1-4C alkoxy (optionally substituted by 1-5 F) and in which T 1 is optionally substituted by 1 or 2 OH, halo, 1-4C hydroxyalkyl, 1-4C alkoxy-(1-4C alkyl), 1-4C alkyl (optionally substituted by 1-5 F) or 1-4C alkoxy (optionally substituted by 1-3 F), and R 18, R 19H or 1-4C alkyl, provided that when R 3 = NR 6R 7, then A = SO 2. Independent claims are also included for the following: (1) a composition comprising (I) and a compound (III) comprising a sorbitol dehydrogenase inhibitor (SDI), glycogen phosphorylase inhibitor (GPI), selective serotonin reuptake inhibitor (SSRI), 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (a vastatin), a thiazolidinedione antidiabetic agent (a glitazone), a gamma -aminobutyric acid (GABA) agonist, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-II (A-II) receptor antagonist or a phosphodiesterase type 5 (PDE-5) inhibitor; (2) a kit comprising a unit dose of (I) and a second unit dose comprising (III); (3) new pyridazine derivatives of formula (II), and (4) 5-chloro-2-mercapto-3-methylbenzofuran. [Image] Z : 1-6C alkyl or phenyl or benzyl (both optionally substituted by 1 or 2 Cl or Me), and R 3a.Het 1 or CHR 4Het 1. ACTIVITY : Vasotropic; Antidiabetic; Neuroprotective; Nephrotropic; Ophthalmological; Antiulcer. Tests are described but no results are given. MECHANISM OF ACTION : Aldose reductase inhibition.