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

Abstract

Acylhydrazone derivatives of the formula (I) are SGK inhibitors and can be used for the treatment of SGK-induced diseases and conditions, such as diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertonia, cardiovascular diseases and renal diseases, generally in any type of fibrosis and inflammatory process. In which R 1 , R 5 each, independently of one another, H, OH, OA, OAc or methyl, R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 each, independently of one another, H, OH, OA, OAc, OCF 3 , Hal, NO 2 , CF 3 , A, CN, OSO 2 CH 3 , SO 2 CH 3 , NH 2 or COOH, R 11 H or CH 3 , A alkyl having 1, 2, 3 or 4 C atoms, X CH 2 , CH 2 CH 2 , OCH 2 or —CH(OH)—, Hal F, Cl, Br or I.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 5  each, independently of one another, denote H, OH, OA, OAc or methyl, 
         R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10  each, independently of one another, denote H, OH, OA, OAc, OCF 3 , Hal, NO 2 , CF 3 , A, CN, OSO 2 CH 3 , SO 2 CH 3 , NH 2  or COOH, 
         R 11  denotes H or CH 3 , 
         A denotes alkyl having 1, 2, 3 or 4 C atoms, 
         X denotes CH 2 , CH 2 CH 2 , OCH 2  or —CH(OH)—, 
         Hal denotes F, Cl, Br or I, 
       
       or a pharmaceutically acceptable prodrug, salt, solvate or stereoisomer thereof or a mixture thereof in all ratios. 
     
     
         2 . A compound according to  claim 1  wherein
 R 1  denotes H, methyl, OA, OAc or OH,   R 5  denotes H, methyl or OA,   R 2  denotes H, NO 2 , Hal OA, A or COOH,   R 4  denotes H, Hal, A, CF 3 , NO 2  or OA   R 3  denotes OH, OAc, SO 2 CH 3 , Hal, CF 3 , OCF 3 , COOH, OA, H, A or NO 2 ,   R 6  denotes H, A or OA,   R 7  denotes OA, H, Hal, OH, CF 3 , NO 2  or NH 2 ,   R 8  denotes H, OH, OA or Hal,   R 9  denotes H, A, Hal, OSO 2 CH 3  or OH,   R 10  denotes H, A, OA or Hal,   R 11  denotes H or CH 3 ,   A denotes alkyl having 1, 2, 3 or 4 C atoms,   X denotes CH 2 , CH 2 CH 2 , OCH 2  or —CH(OH)—,   Hal denotes F, Cl, Br or I,   
       or a pharmaceutically acceptable prodrug, salt, solvate or stereoisomer thereof or a mixture thereof in all ratios. 
     
     
         3 . A compound according to  claim 1  wherein
 R 1  denotes methyl, OA or OH,   R 5  denotes H or methyl,   R 2  denotes H, NO 2  or Hal,   R 4  denotes H or Hal,   R 3  denotes OH or OAc,   R 6  denotes H,   R 7  denotes OA, H, Hal, OH, CF 3  or NO 2 ,   R 8  denotes H, OH or Hal,   R 9  denotes H, A, Hal, OSO 2 CH 3  or OH,   R 10  denotes H, A or Hal,   R 11  denotes H or CH 3 ,   A denotes alkyl having 1, 2, 3 or 4 C atoms,   X denotes CH 2 , CH 2 CH 2 , OCH 2  or —CH(OH)—,   Hal denotes F, Cl, Br or I,   
       or a pharmaceutically acceptable prodrug, salt, solvate or stereoisomer thereof or a mixture thereof in all ratios. 
     
     
         4 . Compounds A compound according to  claim 1  wherein
 R 1  denotes OH, OCH 3  or methyl,   R 5  denotes H,   R 2  denotes H,   R 4  denotes H,   R 3  denotes OH,   R 6  denotes H,   R 7  denotes OH,   R 8  denotes H, OH or Hal,   R 9  denotes H, A, Hal, OSO 2 CH 3  or OH,   R 10  denotes H, A or Hal,   R 11  denotes H or CH 3 ,   A denotes alkyl having 1, 2, 3 or 4 C atoms,   X denotes CH 2 , CH 2 CH 2 , OCH 2  or —CH(OH)—,   Hal denotes F, Cl, Br or I,   
       or a pharmaceutically acceptable prodrug, salt, solvate or stereoisomer thereof or a mixture thereof in all ratios. 
     
     
         5 . 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, 
       and the or a pharmaceutically acceptable prodrug, salt, solvate or stereoisomer thereof or a mixture thereof in all ratios. 
     
     
         6 . (canceled) 
     
     
         7 . A method for the treatment and/or prophylaxis of a disease in which the inhibition, regulation and/or modulation of signal transduction by a kinase plays a role, comprising administering to a subject in need thereof at least one compound of Formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 5  are each, independently of one another, H, OH, OA, OAc or methyl, 
         R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10  are each, independently of one another H, OH, OA, OAc, OCF 3  Hal, NO 2 , CF 3 , A, CN, OSO 2 CH 3 , SO 2 CH 3 , NH 2  or COOH, 
         R 11  is H or CH 3 , 
         A is alkyl having 1, 2, 3 or 4 C atoms, 
         X is CH 2 , CH 2 CH 2 , OCH 2  or —CH(OH)—, 
         Hal is F, Cl, Br or L, 
       
       or a pharmaceutically usable derivative, salt, solvate or a stereoisomer thereof or a mixture thereof in all ratios. 
     
     
         8 . The method according to  claim 7 , wherein the kinase is serum and glucocorticoid dependent kinase (SGK). 
     
     
         9 . The method according to  claim 8  comprising inhibiting the activity of said SGK. 
     
     
         10 . A method for the treatment or prevention of diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertonia, cardiovascular disease, renal disease, fibrosis or inflammatory process, cancer, tumour, tumour metastases, coagulopathy, neuronal excitability, glaucoma, cataract, bacterial infection, or a method for antiinfection therapy, or increasing learning ability and attention comprising administering to a subject in need thereof a compound of  claim 1 . 
     
     
         11 . The method according to  claim 10 , wherein the diabetes is diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy or microangiopathy. 
     
     
         12 . The method according to  claim 10 , wherein the cardiovascular disease is cardial fibroses after myocardial infarction, cardiac hypertrophy, cardiac insufficiency or arteriosclerosis. 
     
     
         13 . The method according to  claim 10 , wherein the renal disease is glomerulosclerosis, nephrosclerosis, nephritis, nephropathy or electrolyte excretion disorder. 
     
     
         14 . The method according to  claim 10 , wherein the fibrosis or inflammatory process comprises liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthrosis, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis, scarring or Alzheimer's disease. 
     
     
         15 . (canceled) 
     
     
         16 . A kit comprising
 (a) a first package comprising a compound according to  claim 1  or a pharmaceutical composition thereof, and   (b) a second package comprising an effective amount of a further pharmacological active ingredient.   
     
     
         17 . A process for the synthesis of a compound of  claim 1  comprising hydrazonation. 
     
     
         18 . The method of  claim 8  wherein said SGK is sgk-1. 
     
     
         19 . A method of inhibiting tumor growth and/or metastasis in a subject comprising administering to said subject an effective amount of at least one compound of  claim 1 . 
     
     
         20 . The method of  claim 19  wherein said tumor is sensitive to SGK inhibition.