Oxindole hydrazide modulators of protein tyrosine phosphatases (ptps)

A medicant which comprises, a pharmaceutically acceptable medium and an oxindole hydrazide of formula (II)

• wherein:
• A is O or a bond;
• B is independently selected from the group consisting of arylene, heteroarylene, heterocycloalkylene or cycloalkylene;
• R8 is selected in the group consisting of H, halogen, cyano, (C1-C6)alkyl, aryl, heteroaryl, —SO—R9, —SO2—R9, (C1-C6)alkyl-SO2—R9, —NO2, —N(R9)2, (C1-C6)-alkyl-O—R9, —SR9, —SO2—R9, —(C═O)O—R9, —(C═O)—R9, —(C═O)N(R9)2, —(C═O)NH—R9, —(C═O)NR9—N(R9)2, —NR9—(C═O)—N(R9)2, —NR9—(SO2—R9), —NH—(C═O)—R9, (C1-C6)-alkyl-NH—(C═O)—R9, —NR9—(C═O)—R9 wherein R9 is selected from the group consisting of H, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl which may contain 1-2 further heteroatoms selected from O, N or S, (C1-C6)-alkyl-heterocycloalkyl wherein said heterocycloalkyl may contain 1-2 further heteroatoms selected from O, N or S, aryl, (C1-C6)-alkyl-aryl, (C1-C6)-alkoxy-aryl, heteroaryl, (C1-C6)-alkyl-heteroaryl or (C1-C6)-alkoxy-heteroaryl, C1-C6)-alkyl, (C1-C6)-alkyl-COOR10 wherein R10 is H or (C1-C6)alkyl or —NH2;
• m′ is 0 or 1;
• p is an integer from 1 to 3;
• for use as a medicament.

A method for treating and/or preventing at least one metabolic disorder mediated by insulin resistance or hyperglycemia, which comprises:

• administering to a mammal in need thereof a pharmaceutically acceptable composition comprising an oxindole hydrazide of formula (II)
• wherein:
• A is O or a bond;
• B is independently selected from the group consisting of arylene, heteroarylene, heterocycloalkylene or cycloalkylene;
• R8 is selected in the group consisting of H, halogen, cyano, (C1-C6)alkyl, aryl, heteroaryl, —SO—R9, —SO2—R9, (C1-C6)alkyl-SO2—R9, —NO2, —N(R9)2, (C1-C6)-alkyl-O—R9, —SR9, —SO2—R9, —(C═O)O—R9, —(C═O)—R9, —(C═O)N(R9)2, —(C═O)NH—R9, —(C═O)NR9—N(R9)2, —NR9—(C═O)—N(R9)2, —NR9—(SO2—R9), —NH—(C═O)—R9, (C1-C6)-alkyl-NH—(C═O)—R9, —NR9—(C═O)—R9 wherein R9 is selected from the group consisting of H, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl which may contain 1-2 further heteroatoms selected from O, N or S, (C1-C6)alkyl-heterocycloalkyl wherein said heterocycloalkyl may contain 1-2 further heteroatoms selected from O, N or S, aryl, (C1-C6)-alkyl-aryl, (C1-C6)-alkoxy-aryl, heteroaryl, (C1-C6)-alkyl-heteroaryl or (C1-C6)-alkoxy-heteroaryl, (C1-C6)-alkyl, (C1-C6)-alkyl-COOR10 wherein R10 is H or (C1-C6)alkyl or —NH2;
• m′ is 0 or 1;
• p is an integer from 1 to 3,
• wherein at least one metabolic disorders mediated by insulin resistance or hyperglycemia is selected from the group consisting of diabetes type I, diabetes type II, inadequate glucose tolerance, insulin resistance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, and polycystic ovary syndrome (PCOS).

A compound of formula (B) selected from the group consisting of:

• N-[4-(Hydrazinocarbonyl)phenyl]-3-phenylpropanamide;
• Phenylmethyl-4-[(N-aminocarbamoyl)methoxy]benzoate;
• N-[4-(Hydrazinocarbonyl)phenyl]-2-furamide;
• N-[4-(Hydrazinocarbonyl)phenyl]hexanamide;
• 4-Cyano-N-[4-(hydrazinocarbonyl)phenyl]benzamide;
• 4-(Hexyloxy)-N-[4-(hydrazinocarbonyl)phenyl]benzamide;
• 4-Heptyl-N-[4-(hydrazinocarbonyl)phenyl]benzamide;
• 4-(2-Hydrazino-2-oxoethoxy)benzoic acid;
• 4-Cyano-N-[3-(hydrazinocarbonyl)phenyl]benzamide;
• 4-(Hydrazinocarbonyl-N-(3-[(trifluoromethyl)sulfonyl]phenyl)benzamide;
• 4-Chloro-N-[4-(hydrazinocarbonyl)benzyl]benzamide;
• 1-Benzoyl-4-piperidinecarbohydrazide;
• N-[4-(Hydrazinocarbonyl)phenyl]-2-phenoxyacetamide;
• N-[4-(Hydrazinocarbonyl)benzyl]-3-nitrobenzamide;
• N-[4-(Hydrazinocarbonyl)phenyl][1,1′-biphenyl]-4-carboxamide;
• 3-(1,3-Benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide;
• 4-{[4-(Hydrazinocarbonyl)benzoyl]amino}benzoic acid;
• 3-(3,4-Dihydroxyphenyl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide;
• N-[4-(Hydrazinocarbonyl)phenyl]-3-phenylpropanamide;
• N-[4-(Hydrazinocarbonyl)phenyl]-2-phenoxyacetamide;
• N-[4-(Hydrazinocarbonyl)benzyl]-3-nitrobenzamide;
• Methyl-3-(2-hydrazino-2-oxoethoxy)benzoate;
• 2-[4-(1H-Tetrazol-5-yl)phenoxy]acetohydrazide;
• 4-(Hydrazinocarbonyl)-N-phenylbenzamide;
• 4-[4-(Morpholinylmethyl)phenoxy]benzohydrazide;
• 4-(2-Hydrazinocarbonyl-ethyl)-benzoic acid methyl ester;
• 2-[4-(1H-Tetrazol-5-yl)phenoxy]acetohydrazide;
• 2-(4-Cyanophenoxy)acetohydrazide;
• Methyl-4-[methyl(3-phenylpropanoyl)amino]benzoate;
• N-[4-(hydrazinocarbonyl)phenyl]-N-methyl-3-phenylpropanamide;
• Methyl-(5-iodo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate;
• Methyl-4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate;
• tert-Butyl 2-{4-[(4-methoxy-4-oxobutanoyl)amino]benzoyl}hydrazinecarboxylate;
• tert-Butyl 2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl}hydrazinecarboxylate;
• tert-Butyl 2-(4-{[4-(methoxycarbonyl)benzoyl]amino}benzoyl)hydrazinecarboxylate;
• tert-Butyl 2-{4-[(9-methoxy-9-oxononanoyl)amino]benzoyl}hydrazinecarboxylate;
• tert-Butyl 2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl}hydrazinecarboxylate;
• 4-({[4-(Methoxycarbonyl)benzoyl]amino}methyl)benzoic acid;
• tert-Butyl 2-[4-({[4-(methoxycarbonyl)benzoyl]amino}methyl)benzoyl]hydrazine-carboxylate;
• tert-Butyl 2-(4-hydroxybenzoyl)hydrazinecarboxylate;
• tert-Butyl 2-{4-[(1S)-1-benzyl-2-(benzyloxy)-2-oxoethoxy]benzoyl}hydrazinecarboxylate;
• Methyl-4-(5-iodo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)butanoate;
• and
• tert-Butyl 2-[4-({[4-(3-methoxy-3-oxopropyl)phenyl]sulfonyl}amino)benzoyl]hydrazine-carboxylate.

A method for modulating the activity of a protein tyrosine phosphatase (PTP), which comprises:

• contacting at least one PTP with an oxindole hydrazide derivative according to formula (I)
• as well as its tautomers, geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein
• R1 is halogen or —(C═O)N—(C6-C18)-alkyl, d is 1 to 4;
• R2 is H, —CO—NH—R or —(CH2)u—CO—OR, wherein u is an integer from 1 to 7 and R is H or (C1-C6)-alkyl;
• R3 is H or C1-C6-alkyl;
• R4, R5, R6 and R7 are each independently from each other selected from the group consisting of H, halogen, —NO2, —OH, (C1-C6)-alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl which may contain 1-2 further heteroatoms selected from O, N or S, (C1-C6)-alkyl-heterocycloalkyl wherein said heterocyclolalkyl may contain 1-2 further heteroatoms selected from O, N or S, aryl, (C1-C6)-alkyl-aryl, heteroaryl, (C1-C6)-alkyl-heteroaryl;
• R8 is selected from the group comprising or consisting of H, halogen, hydroxy, acyl, amino, carboxy, cyano, nitro, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkyl carboxy, C1-C6-alkyl acyl, C1-C6-alkyl alkoxycarbonyl, carbonylamino, hydrazinocarbonyl, aminocarbonyl, C1-C6-alkyl aminocarbonyl, C1-C6-alkyl acyloxy, acylamino, C1-C6-alkyl acylamino, ureido, C1-C6-alkyl ureido, C1-C6-alkyl carbamate, C1-C6-alkyl amino, C1-C6 alkoxy, C1-C6-alkyl alkoxy, sulfanyl, C1-C6-alkyl sulfanyl, sulfinyl, C1-C6-alkyl sulfinyl, sulfonyl, sulfonylamino, C1-C6-alkyl sulfonyl, C1-C6-alkyl sulfonylaminoaryl, aryl, heteroaryl, C3-C8-cycloalkyl or heterocycloalkyl, C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C2-C6-alkenyl-aryl or -heteroaryl, C2-C6-alkynyl aryl or -heteroaryl
• A is selected from the group consisting of a bond, —O—, —S—, —SO—, —SO2—, amino, urea, sulfonylamino or acylamino;
• B is arylene, heteroarylene, heterocycloalkylene or cycloalkylene;
• X is C, S or SO;
• m, n and p are each independently from each other an integer from 0 to 6;
• m is also 0, 1 or 2, while n is 0 or 1, and p is 1 or 2.