Oxindole hydrazide modulators of protein tyrosine phosphatases (ptps)

Abstract

The present invention is related to the use of oxindole hydrazide derivatives of formula (I) for the treatment and/or prevention of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising diabetes type I and/or II, inadequate glucose tolerance, insulin resistance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, polycystic ovary syndrome (PCOS). In particular, the present invention is related to the use of oxindole hydrazide derivatives of formula (I) to modulate, notably to inhibit the activity of PTPs, in particular of PTP1B, TC-PTP, SHP and GLEPP-1. The present invention is furthermore related to novel oxindole hydrazide derivatives and method of preparation thereof.

1 . 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 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 
       R 1  is halogen or —(C═O)N—(C 6 -C 18 )-alkyl, d is 1 to 4; 
       R 2  is H, —CO—NH—R or —(CH 2 ) u —CO—OR, wherein u is an integer from 1 to 7 and R is H or (C 1 -C 6 )-alkyl; 
       R 3  is H or C 1 -C 6 -alkyl; 
       R 4 , R 5 , R 6  and R 7  are each independently from each other selected from the group consisting of H, halogen, —NO 2 , —OH, (C 1 -C 6 )-alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl which may contain 1-2 further heteroatoms selected from O, N or S, (C 1 -C 6 )-alkyl-heterocycloalkyl wherein said heterocyclolalkyl may contain 1-2 further heteroatoms selected from O, N or S, aryl, (C 1 -C 6 )-alkyl-aryl, heteroaryl, (C 1 -C 6 )-alkyl-heteroaryl; 
       R 8  is selected from the group comprising or consisting of H, halogen, hydroxy, acyl, amino, carboxy, cyano, nitro, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyl, C 1 -C 6 -alkyl alkoxycarbonyl, carbonylamino, hydrazinocarbonyl, aminocarbonyl, C 1 -C 6 -alkyl aminocarbonyl, C 1 -C 6 -alkyl acyloxy, acylamino, C 1 -C 6 -alkyl acylamino, ureido, C 1 -C 6 -alkyl ureido, C 1 -C 6 -alkyl carbamate, C 1 -C 6 -alkyl amino, C 1 -C 6  alkoxy, C 1 -C 6 -alkyl alkoxy, sulfanyl, C 1 -C 6 -alkyl sulfanyl, sulfinyl, C 1 -C 6 -alkyl sulfinyl, sulfonyl, sulfonylamino, C 1 -C 6 -alkyl sulfonyl, C 1 -C 6 -alkyl sulfonylaminoaryl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl or heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 2 -C 6 -alkenyl-aryl or -heteroaryl, C 2 -C 6 -alkynyl aryl or -heteroaryl 
       A is selected from the group consisting of a bond, —O—, —S—, —SO—, —SO 2 —, 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; 
       wherein said metabolic disorders mediated by insulin resistance or hyperglycemia is at least one disorder selected from the group consisting of diabetes type I diabetes type II, diabetes type I and III, inadequate glucose tolerance, insulin resistance, hyperlipi-demia, hypertriglyceridemia, hypercholesterolemia, obesity, and polycystic ovary syndrome (PCOS). 
     
   
   
       2 . A method according to  claim 1 , wherein R 8  of the oxindole hydrazide is selected from the group consisting of H, halogen, cyano, (C 1 -C 6 )alkyl, aryl, heteroaryl, —SO—R 9 , —SO 2 —R 9 , (C 1 -C 6 )alkyl-SO 2 —R 9 , —NO 2 , —N(R 9 ) 2 , (C 1 -C 6 )-alkyl-O—R 9 , —SR 9 , —SO 2 —R 9 , —(C═O)O—R 9 , —(C═O)—R 9 , —(C═O)N(R 9 ) 2 , —(C═O)NH—R 9 , —(C═O)NR 9 —N(R 9 ) 2 , —NR 9 —(C═O)—N(R 9 ) 2 , —NR 9 —(SO 2 —R 9 ) —NH—(C═O)—R 9 , (C 1 -C 6 )-alkyl-NH—(C═O)—R 9 , —NR 9 —(C═O)—R 9  wherein R 9  is selected from the group consisting of H, C 3 -C 8  cycloalkyl, 3-8 membered heterocycloalkyl which may contain 1-2 further heteroatoms selected from O, N or S, (C 1 -C 6 )-alkyl-heterocycloalkyl wherein said heterocycloalkyl may contain 1-2 further heteroatoms selected from O, N or S, aryl, (C 1 -C 6 )-alkyl-aryl, (C 1 -C 6 )-alkoxy-aryl, heteroaryl, (C 1 -C 6 )-alkyl-heteroaryl or (C 1 -C 6 )-alkoxy-heteroaryl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-COOR 10  wherein R 10  is H or (C 1 -C 6 )alkyl or —NH 2 , 
   
   
       3 . A method according to  claim 1 , wherein said metabolic disorder is diabetes type II. 
   
   
       4 . A method according to  claim 1 , wherein B in the oxindole hydrazide is independently selected from the group consisting of phenyl, naphthyl, phenantrenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, [1,3]thiazolo[3,2-b][1,2,4]triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, benzo(2,1,3)oxadiazolyl, benzo(1,2,3)oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridazinyl, pyrimidyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, xanthenyl, benzoquinolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxolanyl, pyrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 1,2,4-oxadiazolidinyl, 1,2,5-oxadiazolidinyl, 1,3,4-oxadiazolidinyl, isoxazolidinyl or morpholinyl. 
   
   
       5 . A method according to  claim 4 , wherein B of the oxindole hydrazide is selected from the group consisting of phenyl, biphenyl, benzo(1,2,5)-oxadiazolyl, furyl, thiadiazolyl, thienyl, thiazolyl, indolyl, piperidinyl, pyridyl, 1,2,3-triazolyl, 1,2,4-triazolyl and tetrazolyl. 
   
   
       6 . A method according to  claim 1 , wherein R 4 , R 5 , R 6  and R 7  of the oxindole hydrazide are each independently from each other selected from the group consisting of H and (C 1 -C 6 )-alkyl. 
   
   
       7 . A method according to  claim 1 , wherein in the oxindole hydrazide R 1  is Br or I and d is 1. 
   
   
       8 . A method according to  claim 7 , wherein in the oxindole hydrazide n and m are each 0, A is a bond or O, B is phenyl, p is 1 and R 8  is —NH—CO—(C 1 -C 6 -alkyl)-Ar 1 , or —O—Ar 1  wherein Ar 1  is a phenyl group. 
   
   
       9 . A method according to  claim 1 , wherein the oxindole hydrazide is represented by formula (Ia)
 wherein m′ is 0 or 1 R 8  is selected from the group consisting of H, halogen, cyano, (C 1 -C 6 )alkyl, aryl, heteroaryl, —SR 9 , —SO—R 9 , —SO 2 —R 9 , (C 1 -C 6 )alkyl-SO 2 —R 9 , —NO 2 , —N(R 9 ) 2 , —OR 9 , (C 1 -C 6 )-alkyl-O—R 9 , —(C═O)O—R 9 , —(C═O)—R 9 , —(C═O)N(R 9 ) 2 , —(C═O)NH—R 9 , —(C═O)NR 9 —N(R 9 ) 2 , —NR 9 —(C═O)—N(R 9 ) 2 , —NR 9 —(SO 2 —R 9 ), —NH—(C═O)—R 9 , (C 1 -C 6 )-alkyl-NH—(C═O)—R 9 , —NR 9 —(C═O)—R 9  wherein R 9  is selected from the group consisting of H, C 3 -C 8  cycloalkyl, 3-8 membered heterocycloalkyl which may contain 1-2 further heteroatoms selected from O, N or S, (C 1 -C 6 )-alkyl-heterocycloalkyl wherein said heterocycloalkyl may contain 1-2 further heteroatoms selected from O, N or S, aryl, (C 1 -C 6 )-alkyl-aryl, (C 1 -C 1 )-alkoxy-aryl, heteroaryl, (C 1 -C 6 )-alkyl-heteroaryl or (C 1 -C 6 )-alkoxy-heteroaryl, (C 1 -C 6 ) alkyl, C 1 -C 6 )-alkyl-COOR 10  wherein R 10  is H or (C 1 -C 6 )alkyl or —NH 2 .   
   
   
       10 . A method according to  claim 9 , wherein in the oxindole hydrazide R 8  is —NO 2 , —NH—(C═O)—R 9  or —COOR 9 . 
     
       
         
         
             
             
         
       
     
   
   
       11 - 19 . (canceled) 
   
   
       20 . 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; 
       R 8  is selected in the group consisting of H, halogen, cyano, (C 1 -C 6 )alkyl, aryl, heteroaryl, —SO—R 9 , —SO 2 —R 9 , (C 1 -C 6 )alkyl-SO 2 —R 9 , —NO 2 , —N(R 9 ) 2 , (C 1 -C 6 )-alkyl-O—R 9 , —SR 9 , —SO 2 —R 9 , —(C═O)O—R 9 , —(C═O)—R 9 , —(C═O)N(R 9 ) 2 , —(C═O)NH—R 9 , —(C═O)NR 9 —N(R 9 ) 2 , —NR 9 —(C═O)—N(R 9 ) 2 , —NR 9 —(SO 2 —R 9 ), —NH—(C═O)—R 9 , (C 1 -C 6 )-alkyl-NH—(C═O)—R 9 , —NR 9 —(C═O)—R 9  wherein R 9  is selected from the group consisting of H, C 3 -C 8  cycloalkyl, 3-8 membered heterocycloalkyl which may contain 1-2 further heteroatoms selected from O, N or S, (C 1 -C 6 )-alkyl-heterocycloalkyl wherein said heterocycloalkyl may contain 1-2 further heteroatoms selected from O, N or S, aryl, (C 1 -C 6 )-alkyl-aryl, (C 1 -C 6 )-alkoxy-aryl, heteroaryl, (C 1 -C 6 )-alkyl-heteroaryl or (C 1 -C 6 )-alkoxy-heteroaryl, C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-COOR 10  wherein R 10  is H or (C 1 -C 6 )alkyl or —NH 2 ; 
       m′ is 0 or 1; 
       p is an integer from 1 to 3; 
       for use as a medicament. 
     
   
   
       21 . 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; 
       R 8  is selected in the group consisting of H, halogen, cyano, (C 1 -C 6 )alkyl, aryl, heteroaryl, —SO—R 9 , —SO 2 —R 9 , (C 1 -C 6 )alkyl-SO 2 —R 9 , —NO 2 , —N(R 9 ) 2 , (C 1 -C 6 )-alkyl-O—R 9 , —SR 9 , —SO 2 —R 9 , —(C═O)O—R 9 , —(C═O)—R 9 , —(C═O)N(R 9 ) 2 , —(C═O)NH—R 9 , —(C═O)NR 9 —N(R 9 ) 2 , —NR 9 —(C═O)—N(R 9 ) 2 , —NR 9 —(SO 2 —R 9 ), —NH—(C═O)—R 9 , (C 1 -C 6 )-alkyl-NH—(C═O)—R 9 , —NR 9 —(C═O)—R 9  wherein R 9  is selected from the group consisting of H, C 3 -C 8  cycloalkyl, 3-8 membered heterocycloalkyl which may contain 1-2 further heteroatoms selected from O, N or S, (C 1 -C 6 )alkyl-heterocycloalkyl wherein said heterocycloalkyl may contain 1-2 further heteroatoms selected from O, N or S, aryl, (C 1 -C 6 )-alkyl-aryl, (C 1 -C 6 )-alkoxy-aryl, heteroaryl, (C 1 -C 6 )-alkyl-heteroaryl or (C 1 -C 6 )-alkoxy-heteroaryl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-COOR 10  wherein R 10  is H or (C 1 -C 6 )alkyl or —NH 2 ; 
       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). 
     
   
   
       22 - 24 . (canceled) 
   
   
       25 . 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.   
   
   
       26 . 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 
       R 1  is halogen or —(C═O)N—(C 6 -C 18 )-alkyl, d is 1 to 4; 
       R 2  is H, —CO—NH—R or —(CH 2 ) u —CO—OR, wherein u is an integer from 1 to 7 and R is H or (C 1 -C 6 )-alkyl; 
       R 3  is H or C 1 -C 6 -alkyl; 
       R 4 , R 5 , R 6  and R 7  are each independently from each other selected from the group consisting of H, halogen, —NO 2 , —OH, (C 1 -C 6 )-alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl which may contain 1-2 further heteroatoms selected from O, N or S, (C 1 -C 6 )-alkyl-heterocycloalkyl wherein said heterocyclolalkyl may contain 1-2 further heteroatoms selected from O, N or S, aryl, (C 1 -C 6 )-alkyl-aryl, heteroaryl, (C 1 -C 6 )-alkyl-heteroaryl; 
       R 8  is selected from the group comprising or consisting of H, halogen, hydroxy, acyl, amino, carboxy, cyano, nitro, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyl, C 1 -C 6 -alkyl alkoxycarbonyl, carbonylamino, hydrazinocarbonyl, aminocarbonyl, C 1 -C 6 -alkyl aminocarbonyl, C 1 -C 6 -alkyl acyloxy, acylamino, C 1 -C 6 -alkyl acylamino, ureido, C 1 -C 6 -alkyl ureido, C 1 -C 6 -alkyl carbamate, C 1 -C 6 -alkyl amino, C 1 -C 6  alkoxy, C 1 -C 6 -alkyl alkoxy, sulfanyl, C 1 -C 6 -alkyl sulfanyl, sulfinyl, C 1 -C 6 -alkyl sulfinyl, sulfonyl, sulfonylamino, C 1 -C 6 -alkyl sulfonyl, C 1 -C 6 -alkyl sulfonylaminoaryl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl or heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 2 -C 6 -alkenyl-aryl or -heteroaryl, C 2 -C 6 -alkynyl aryl or -heteroaryl 
       A is selected from the group consisting of a bond, —O—, —S—, —SO—, —SO 2 —, 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. 
     
   
   
       27 . A method according to  claim 26 , wherein at least one PTP is selected from the group consisting of PTP1B, TC-PTP, SHP, and GLEPP-1. 
   
   
       28 . A method according to  claim 26 , wherein at least one PTP is PTP1B. 
   
   
       29 . A method according to  claim 27 , wherein said modulating occurs by reducing the activity of PTP1B. 
   
   
       30 . A method according to  claim 26 , wherein said contacting occurs in a patient in need of treating or preventing a disorder mediated by PTP1B.