Novel heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases

Abstract

The present invention relates to novel antidiabetic compounds, their tautomeric forms, their derivatives, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. This invention particularly relates to novel azolidinedione derivatives of the general formula (I), and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.

1 - 25 . (cancel).  
     
     
         26 . A compound of formula (1)  
       
         
           
           
               
               
           
         
       
       its pharmaceutically acceptable salts  
       where one of the X, Y or Z represent C═O or C═S and the remaining of X, Y, and Z represent a group C═ or C═C to form a six membered ring; R 1 , R 2  and R 3  are substituents either on X, Y or Z or on a nitrogen atom and may be the same or different and represent hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, amino, alkylamino, acylamino, arylamino or carboxylic acid and its derivatives, with the provision that when R 1 , R 1  or R 3  is on a nitrogen atom its does not represent hydrogen; or any two of R 1 , R 1  and R 3  along with the adjacent atoms to which they are attached may form a substituted or unsubstituted cyclic structure of 4 to 7 atoms with one or more double bonds which may be carbocyclic or may contain one or more heteroatoms selected from oxygen, nitrogen and sulfur; the linking group represented by (CH 2 ) n —O— may be attached either through nitrogen atom or through X, Y or Z, where n is an integer ranging from 1-4; Ar represents an optionally substituted divalent aromatic or heterocyclic group; R 4  represents hydrogen or lower alkyl group or forms a bond together with the adjacent group A; A represents CR 5 , where R 5  represents hydrogen or R 5  forms a bond together with R 4 .  
     
     
         27 . The compound as claimed in  claim 26 , wherein X is a C═O, Y is C═C and Z is C═.  
     
     
         28 . The compound as claimed in  claim 26 , wherein Y is a C═O, X is C═C and Z is C═.  
     
     
         29 . The compound as claimed in  claim 26 , wherein R 1 , R 2  and R 3  represent hydrogen, halogen, alkyl, cycloalkyl, aryl or aralkyl.  
     
     
         30 . The compound as claimed in  claim 26 , wherein:  
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound as claimed in  claim 26 , wherein the optional substituents on R 1 , R 2  and R 3  are selected from halogen, hydroxyl or alkyl.  
     
     
         32 . The compound as claimed in  claim 26 , wherein the cyclic structure formed by any two of R 1 , R 2  and R 3  are selected from optionally substituted phenyl, naphthyl, thienyl, furyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, azacyclobutenyl, isoxazolyl, azepinyl, pyridyl, pyridazyl, pyrimidinyl, dihydrofuryl, dihydrothienyl, tetrahydropyridyl, tetrahydrophenyl or tetrahydronaphthyl.  
     
     
         33 . The compound as claimed in  claim 32 , wherein the cyclic structure formed by any two of R 1 , R 2  and R 3  are selected from optionally substituted phenyl, thienyl or pyridyl.  
     
     
         34 . The compound as claimed in  claim 32 , wherein the cyclic structure formed by any two of R 1 , R 2  and R 3  is optionally substituted phenyl.  
     
     
         35 . The compound as claimed in  claim 26 , wherein the optional substituents on the cyclic structure formed by any two of R 1 , R 2  and R 3  are selected from lower alkyl or alkoxy group.  
     
     
         36 . The compound as claimed in  claim 26 , wherein Ar represents divalent phenylene.  
     
     
         37 . The compound as claimed in  claim 26 , wherein R 4  represents hydrogen, lower alkyl or forms a bond with A.  
     
     
         38 . The compound as claimed in  claim 37 , wherein R 4  represents hydrogen or forms a bond with A.  
     
     
         39 . The compound as claimed in  claim 26 , wherein A represents CR 5 , R 5  represents hydrogen or forms a bond with R 4 .  
     
     
         40 . The compound as claimed in  claim 26 , where in B represents O.  
     
     
         41 . The compound as claimed in  claim 26 , wherein the ring structure comprising A and B is 2,4-dioxothiazolidin-5-yl.  
     
     
         42 . The compound as claimed in  claim 26 , wherein the pharmaceutically acceptable salts are selected from sodium, potassium or calcium.  
     
     
         43 . The compound as claimed in  claim 26 , wherein the —CH 2 ) n —O— group is linked either through nitrogen or Z, when Z represents C═.  
     
     
         44 . The compound as claimed in  claim 26 , where: 
 X is a C═O, Y is C═C and Z is C═; which is represented as a cyclic ring                          R 1 , R 2  and R 3  represent hydrogen or optionally substituted groups selected from alkyl, aryl, aralkyl with the provision that when R 1 , R 2  or R 3  is on a nitrogen atom, it does not represent hydrogen; or any two of R 1 , R 2  and R 3  along with the adjacent atoms to which they are attached may form a substituted or unsubstituted cyclic structure selected from phenyl, thienyl or pyridyl;    the linking group represented by (CH 2 ) n —O— may be attached either through nitrogen atom or through X, Y or Z, where n is an integer ranging from 1-2;    Ar represents divalent phenylene;    R 4  represents hydrogen or forms a bond together with the adjacent group A;    A represents CR 5 , where R 5  represents hydrogen or R 5  forms a bond together with R 4 ; its pharmaceutically acceptable salts.    
     
     
         45 . The compound as claimed in  claim 26 , where: 
 X is a C═O, Y is C═C and Z is C═; which is represented as a cyclic ring                          R 1 , R 2  and R 3  represent hydrogen or optionally substituted groups selected from alkyl, cycloalyl, aryl or aralkyl with the provision that when R 1 , R 2  or R 3  is on a nitrogen atom, it does not represent hydrogen; or any two of R 1 , R 2  and R 3  along with the adjacent atoms to which they are attached may form a substituted or unsubstituted phenyl;    the linking group represented by —(CH 2 ) n —O— is attached either through nitrogen atom or Z, where n is an integer ranging from 1-2;    Ar represents divalent phenylene;    R 4  represents hydrogen or forms a bond together with the adjacent group A;    A represents CR 5 , where R 5  represents hydrogen or R 5  forms a bond together with R 4 ; its pharmaceutically acceptable salts.    
     
     
         46 . The compound as claimed in  claim 45 , wherein the pharmaceutically acceptable salt is selected from sodium, potassium or calcium.  
     
     
         47 . The compound as claimed in  claim 46 , wherein the pharmaceutically acceptable salt is potassium.  
     
     
         48 . The compound as claimed in  claim 26 , which is selected from the group consisting of the following compounds: 
 5-[4-[2-[4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[2-Benzyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[2,5-Diethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[4-Oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethylene]thiazolidine-2,4-dione,    5-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[[3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[[1-Methyl-4-oxo-1,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[3-Methoxy-4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[4-Acetylamino-2-oxo-1,2-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[4-methyl-2-Propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,    5-4-[2-[2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,    5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,    5-[4-[2-[2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,    5-[4-[2-[2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,    5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione and its polymorphs,    5-[4-[[3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione,    5-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,    2-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl-1,2,4-oxadiazolidine-3,5-dione,    5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]oxazolidine-2,4-dione,    5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]oxazolidine-2,4-dione,    5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione sodium salt and its polymorphs,    5-[4-[2-[2,5,6-Trimethyl-4-oxo-3,4-dihydro-thieno-[2,3-d]-pyrimidin-3-yl]et hoxy]phenyl methylene]thiazolidine-2,4-dione,    5-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione, sodium salt,    5-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione, sodium salt,    5-[4-[2-[4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione, sodium salt,    5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione, sodium salt,    5-[4-[2-[2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,    5-[4-[2-[2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,    5-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,    5[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione sodium salt,    5-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione sodium salt,    5-[4-[[6,7-Dimethoxy-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione,    5-[4-[[6,7-Dimethoxy-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione sodium salt,    5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione potassium salt,    5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione calcium salt,    5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione sodium salt.    
     
     
         49 . The compound as claimed in  claim 26 , which is selected from the group consisting of the following compounds: 
 5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl    methyl]thiazolidine-2,4-dione,    5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione,    5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione, sodium salt,    5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione, sodium salt,    5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione and its polymorphs,    5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione sodium salt and its polymorphs,    5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione, potassium salt,    5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione, sodium salt.    
     
     
         50 . The compound as claimed in  claim 26 , which is selected from the group consisting of the following compounds: 
 5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione sodium salt,    5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]thiazolidine-2,4-dione sodium salt,    5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione potassium salt,    5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione sodium salt.    
     
     
         51 . The compound as claimed in  claim 26 , which is selected from the group consisting of the following compounds: 
 5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione potassium salt,    5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene]thiazolidine-2,4-dione sodium salt.    
     
     
         52 . The compound as claimed in  claim 26  is 
 5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione potassium salt    
     
     
         53 . A pharmaceutical composition which comprises a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       as defined in  claim 26  and pharmaceutically acceptable carriers, diluents, excipients or solvates.  
     
     
         54 . The pharmaceutical composition as claimed in  claim 53 , in the form of a tablet, capsule, powder, syrup, solution or suspension.  
     
     
         55 . The compound of formula (I) as claimed in  claim 52 , is selected from 
 5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione,    5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione sodium salt,    5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione potassium salt.    
     
     
         56 . The compound of formula (I) as claimed in  claim 52 , is 
 5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione potassium salt.    
     
     
         57 . A method of reducing blood glucose, triglycerides or hyperlipidaermia in a subject in need thereof comprising administering an effective amount of a compound of formula (I) as claimed in  claim 26 .  
     
     
         58 . A method of reducing blood glucose, triglycerides or hyperlipidaemia in a subject in need thereof comprising administering an effective amount of a compound of formula (I) as claimed in  claim 48 .  
     
     
         59 . A method of reducing blood glucose, triglycerides or hyperlipidaemia in a subject in need thereof comprising administering an effective amount of a compound 5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione potassium salt as claimed in  claim 56 .  
     
     
         60 . A method of treating diabetes caused by insulin resistance or impaired glucose tolerance or complications of diabetes said diabetes caused by insulin resistance or impaired glucose tolerance comprising administering a therapeutically effective amount of a compound of formula (I) as claimed in  claim 26 .  
     
     
         61 . The method according to  claim 60 , wherein the complication is dyslipidaemia, hypertension, coronary heart disease, cardiovascular disorders, atherosclerosis, obesity, psoriasis, polycystic ovarian syndrome (PCOS), diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease, microalbuminuria or an eating disorder.  
     
     
         62 . A method of treating diabetes caused by insulin resistance or impaired glucose tolerance or complications of diabetes said diabetes caused by insulin resistance or impaired glucose tolerance comprising administering a therapeutically effective amount of a compound of formula (I) as claimed in  claim 48 .  
     
     
         63 . A method of treating diabetes caused by insulin resistance or impaired glucose tolerance or complications of diabetes said diabetes caused by insulin resistance or impaired glucose tolerance comprising administering a therapeutically effective amount of a compound 5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione potassium salt as claimed in  claim 56 .  
     
     
         64 . The method according to  claim 62 , wherein the complication is dyslipidaemia, hypertension, coronary heart disease, cardiovascular disorders, atherosclerosis, obesity, psoriasis, polycystic ovarian syndrome (PCOS), diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease, microalbuminuria or an eating disorder.  
     
     
         65 . The method according to  claim 63 , wherein the complication is dyslipidaemia, hypertension, coronary heart disease, cardiovascular disorders, atherosclerosis, obesity, psoriasis, polycystic ovarian syndrome (PCOS), diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease, microalbuminuria or an eating disorder.