US 7,405,239 B2 · Acylhydrazone derivatives and the use thereof in the inhibition, regulation and/or modulation of kinase signal transduction

Abstract

The invention relates to acylhydrazone derivatives of formula (I), which are SGK inhibitors and can be used for the treatment of diseases and afflictions associated with SGK, such as diabetes, obesity, metabolic syndrome (dyslipidaemia), systematic and pulmonary hypertension, cardiovascular diseases and kidney diseases and in general for all types of fibroses and inflammatory processes. In said formula: R1 and R5 independently of one another represent H, OH, OA, OAc or methyl; R2, R3, R4, R6, R7, R8, R9 and R10 independently of one another represent H, OH, OA, OAc, OCF3, Hal, NO2, CF3, A, CN, OSO2CH3, SO2CH3, NH2, or COOH; R11 represents H or CH3; A represents an alkyl comprising 1, 2, 3, or 4 C atoms; X represents CH2, CH2CH2, OCH2 or —CH(OH)— and Hal represents F, Cl, Br or I.

A compound which is

N-(4-hydroxy-2-methoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-[1-(4-hydroxy-2-methoxyphenyl)ethylidene]-(3-hydroxyphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3-methoxyphenyl)acetohydrazide,
N-(3-fluoro-4-hydroxybenzylidene)phenylacetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(4-hydroxyphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3,4-dichlorophenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-m-tolylacetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-o-tolylacetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(2-chlorophenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3-chlorophenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(4-fluorophenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(2-chloro-4-fluorophenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3-fluorophenyl)acetohydrazide,
N-(4-hydroxybenzylidene)-(3-methoxyphenyl)acetohydrazide,
N-(4-hydroxy-2,6-dimethylbenzylidene)-(3-methoxyphenyl)acetohydrazide,
N-(3-fluoro-4-hydroxybenzylidene)-(3-methoxyphenyl)acetohydrazide,
N-[1-(4-hydroxy-2-methoxyphenyl)ethylidene]-(3-methoxyphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3-methylsulfonyloxyphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3,5-dihydroxyphenyl)acetohydrazide,
N-(3-fluoro-4-hydroxybenzylidene)-(3-fluorophenyl)acetohydrazide,
N-(4-acetoxy-2-methoxybenzylidene)-(3-methoxyphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3-trifluoromethylphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-3-(3-methoxyphenyl)propiohydrazide,
N-(2,4-dihydroxybenzylidene)-(3-methoxyphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3-methoxyphenoxy)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3-nitrophenyl)acetohydrazide,
N-(5-chloro-2-hydroxybenzylidene)-(3-methoxyphenyl)acetohydrazide,
N-(2-hydroxy-5-nitrobenzylidene)-(3-methoxyphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-2-hydroxy-2-phenylacetohydrazide,
N-(2-ethoxy-4-hydroxybenzylidene)-(3-methoxyphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3-bromophenyl)acetohydrazide,
N-[1-(4-hydroxyphenyl)ethylidene]-(3-methoxyphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3,5-difluorophenyl)acetohydrazide,
N-(4-hydroxy-2-methylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-ethoxy-4-hydroxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-methoxy-4-hydroxy-6-methylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-methoxy-4-hydroxybenzylidene)-(2-fluorophenyl)acetohydrazide,
N-(2,4-dihydroxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-5-chlorobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(4-methylsulfonylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2,6-dimethyl-4-hydroxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-methoxy-4-hydroxybenzylidene)-(3-hydroxy-4-methoxyphenyl)acetohydrazide,
N-(2-methoxy-4-hydroxybenzylidene)-(2,3-dimethoxyphenyl)acetohydrazide,
N-(2-methoxy-4-hydroxybenzylidene)-(3-aminophenyl)acetohydrazide,
N-(2,4-dihydroxy-6-methylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-methoxy-4-hydroxybenzylidene)-(2-methyl-3-methoxyphenyl)acetohydrazide,
N-(4-bromobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(4-iodobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-bromo-5-chlorobenzylidene) -(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-5-tert-butylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-5-bromobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-5-trifluoromethoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-methoxy-5-nitrobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(4-hydroxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(4-hydroxy-2-methoxybenzylidene)-(3-ethoxyphenyl)acetohydrazide,
N-(2-hydroxy-3,5-dichlorobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-5-iodobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-methyl-5-chlorobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-5-fluorobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-6-methylbenzylidene)-(3,5-difluorophenyl)acetohydrazide,
N-(2-hydroxy-6-methylbenzylidene)-(3-fluorophenyl)acetohydrazide,
N-(2-hydroxy-6-methylbenzylidene)phenyl acetohydrazide,
N-[1-(4-hydroxyphenyl)ethylidene]-(3-hydroxyphenyl)acetohydrazide,
N-[1-(2,4-dihydroxyphenyl)ethylidene]-(3-hydroxyphenyl)acetohydrazide,
N-(2,4-dihydroxy-6-methylbenzylidene)-(3-methyl-5-methoxyphenyl)acetohydrazide,
N-(2,4-dihydroxy-6-methylbenzylidene)-(3,5-dihydroxyphenyl)acetohydrazide,
N-(2-hydroxy-4-carboxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2,3-dimethyl-4-hydroxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(3,5-di-tert-butyl-4-hydroxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(3,5-dimethyl-4-hydroxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-acetoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-methoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-5-methoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-5-nitrobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-methylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-nitrobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-6-methoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-5-methylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(3-bromobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-tert-butylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-4-methylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-nitro-5-bromobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-4-methyl-5-chlorobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2,6-dimethoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-fluorobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-bromo-5-nitrobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-6-methylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-4-methoxy-6-methylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-4-acetoxy-6-methylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-4-bromobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(3-chloro-4-hydroxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-bromo-5-methoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2,4,6-trimethylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(3,5-dibromo-4-hydroxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2,4,5-trimethoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-methoxy-5-bromobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(4-hydroxy-3-ethoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-methoxy-4-nitrobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(-(4-hydroxy-3-carboxybenzylidene)-3-hydroxyphenyl)acetohydrazide,
N-(2-hydroxy-3-methoxy-5-bromobenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(4-carboxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2,4-dimethylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2-methylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(4-trifluoromethylbenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(4-trifluoromethoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
N-(2,4-dihydroxy-6-methylbenzylidene)-(3-hydroxy-5-methylphenyl)acetohydrazide,
N-(2,4-dihydroxy-6-methylbenzylidene)-(3-hydroxy-2-methylphenyl)acetohydrazide, or
N-(2-hydroxy-4,6-dimethoxybenzylidene)-(3-hydroxyphenyl)acetohydrazide,
or a pharmaceutically acceptable prodrug, salt, or stereoisomer thereof or a mixture thereof in all ratios.

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Acylhydrazone derivatives and the use thereof in the inhibition, regulation and/or modulation of kinase signal transduction

Life of this patent

Acylhydrazone derivatives and the use thereof in the inhibition, regulation and/or modulation of kinase signal transduction

Life of this patent

Abstract

Claims5