Thiazolidinedione derivative and its use as antidiabetic

Abstract

A polymorphic form of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (the “Polymorph”) characterised in that it provides: (i) an infra red spectrum containing peaks at 1752, 1546, 1154, 621, and 602 cm −1 ; and/or (ii) a Raman spectrum containing peaks at 1751, 1243 and 602 cm −1 ; and/or (iii) a solid-state nuclear magnetic resonance spectrum containing peaks at 111.9, 114.8, 119.6, 129.2, 134.0, 138.0, 144.7, 153.2, 157.1, 170.7, 172.0, and 175.0 ppm; and/or (iv) an X-ray powder diffraction (XRPD) pattern which gives calculated lattice spacings of 6.46, 5.39, 4.83, 4.68, 3.71, 3.63, 3.58, and 3.48 Angstroms; a process for preparing such a compound, a pharmaceutical composition containing such a compound and the use of such a compound in medicine.

1 - 14 . (Cancelled).  
     
     
         15 . A compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, wherein said compound provides at least one of: 
 (i) an infra red spectrum containing peaks at 1752, 1546, 1154, 621, and 602 cm −1 ;    (ii) a Raman spectrum containing peaks at 1751, 1243 and 602 cm −1 ;    (iii) a solid-state  13 C nuclear magnetic resonance spectrum containing peaks at 111.9, 114.8, 119.6, 129.2, 134.0, 138.0, 144.7, 153.2, 157.1, 170.7, 170.7, 172.0 and 175.0 ppm; and    (iv) an X-ray powder diffraction pattern which gives calculated lattice spacings of 6.46, 5.39, 4.83, 4.68, 3.71, 3.63, 3.58, and 3.48 Angstroms.    
     
     
         16 . A compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, wherein said compound provides each of: 
 (i) an infra red spectrum containing peaks at 1752, 1546, 1154, 621, and 602 cm −1 ;    (ii) a Raman spectrum containing peaks at 1751, 1243 and 602 cm −1 ;    (iii) a solid-state 13C nuclear magnetic resonance spectrum containing peaks at 111.9, 114.8, 119.6, 129.2, 134.0, 138.0, 144.7, 153.2, 157.1, 170.7, 170.7, 172.0 and 175.0 ppm; and    (iv) an X-ray powder diffraction pattern which gives calculated lattice spacings of 6.46, 5.39, 4.83, 4.68, 3.71, 3.63, 3.58, and 3.48 Angstroms.    
     
     
         17 . A compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, wherein said compound, in a mineral oil dispersion, provides an infra red spectrum substantially in accordance with FIG. 1.  
     
     
         18 . A compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, wherein said compound provides a Raman spectrum substantially in accordance with FIG. 2.  
     
     
         19 . A compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, wherein said compound provides a solid-state  13 C nuclear magnetic resonance spectrum substantially in accordance with FIG. 3.  
     
     
         20 . A compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, wherein said compound provides a solid-state  13 C nuclear magnetic resonance spectrum substantially in accordance with Table I.  
     
     
         21 . A compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, wherein said compound provides an X-ray powder diffraction pattern substantially in accordance with FIG. 4.  
     
     
         22 . A compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, wherein said compound provides an X-ray powder diffraction pattern substantially in accordance with Table II.  
     
     
         23 . A compound according to  claim 15 , in isolated form.  
     
     
         24 . A process for preparing the compound according to  claim 15 , comprising: 
 cooling a solution of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt in denatured ethanol from an elevated temperature to crystallize said 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, and recovering said compound.    
     
     
         25 . A method for the treatment of diabetes mellitus, conditions associated with diabetes mellitus and complications thereof, in a human or non-human mammal which comprises administering an effective, non-toxic, amount of the compound according to any one of claims  15 - 23  to a human or non-human mammal in need thereof.  
     
     
         26 . A method for the treatment of Type II diabetes in a human or non-human mammal which comprises administering an effective, non-toxic, amount of the compound according to any one of claims  15 - 23  to a human or non-human mammal in need thereof.  
     
     
         27 . A pharmaceutical composition comprising an effective, non-toxic amount of the compound according to any one of claims  15 - 23  and a pharmaceutically acceptable carrier therefor, wherein the compound is in crystalline form.  
     
     
         28 . A pharmaceutical composition consisting essentially of an effective, non-toxic amount of the compound according to any one of claims  15 - 23  and a pharmaceutically acceptable carrier therefor, wherein the compound is in crystalline form.  
     
     
         29 . A pharmaceutical composition according to  claim 27 , wherein said composition is adapted for oral administration.  
     
     
         30 . A pharmaceutical composition according to  claim 29 , wherein said composition is in the form of a tablet or a capsule.  
     
     
         31 . A pharmaceutical composition according to  claim 28 , wherein said composition is adapted for oral administration.  
     
     
         32 . A pharmaceutical composition according to  claim 31 , wherein said composition is in the form of a tablet or a capsule.  
     
     
         33 . A process for converting the compound according to  claim 15  into a polymorph of said compound, comprising: 
 (a) seeding a solution of the compound according to  claim 15  in a solvent with the polymorph of said compound;  
 (b) recovering the polymorph of the compound according to  claim 15 .  
 
     
     
         34 . A process according to  claim 33 , wherein said solvent is acetone or ethanol.  
     
     
         35 . A process according to  claim 33 , further comprising filtering the solution formed in step (a).  
     
     
         36 . A process according to  claim 35 , further comprising heating or concentrating said filtered solution.  
     
     
         37 . A process according to  claim 36 , further comprising cooling the heated the solution at a rate of about 1° C./min.  
     
     
         38 . A process according to  claim 33 , wherein the solution is seeded at a temperature of 50° C.  
     
     
         39 . A process for the preparation of a pharmaceutical composition comprising admixing an effective, non-toxic amount of the compound according to any one of claims  15 - 23  with a pharmaceutically acceptable carrier therefor.  
     
     
         40 . A pharmaceutical composition comprising: 
 an effective, non-toxic amount of a compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt;    at least one other antidiabetic agent selected from the group consisting of a sulphonylurea and a biguanide;    and a pharmaceutically acceptable carrier therefor;    wherein said compound is in a crystalline form that provides at least one of:    (i) an infra red spectrum containing peaks at 1752, 1546, 1154, 621, and 602 cm −1 ;    (ii) a Raman spectrum containing peaks at 1751, 1243 and 602 cm −1 ;    (iii) a solid-state 13C nuclear magnetic resonance spectrum containing peaks at 111.9, 114.8, 119.6, 129.2, 134.0, 138.0, 144.7, 153.2, 157.1, 170.7, 170.7, 172.0 and 175.0 ppm; and    (iv) an X-ray powder diffraction pattern which gives calculated lattice spacings of 6.46, 5.39, 4.83, 4.68, 3.71, 3.63, 3.58, and 3.48 Angstroms.    
     
     
         41 . A pharmaceutical composition comprising: 
 an effective, non-toxic amount of a compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt;    at least one other antidiabetic agent selected from the group consisting of a sulphonylurea and a biguanide;    and a pharmaceutically acceptable carrier therefor;    wherein said compound is in a crystalline form that provides each of:    (i) an infra red spectrum containing peaks at 1752, 1546, 1154, 621, and 602 cm −1 ;    (ii) a Raman spectrum containing peaks at 1751, 1243 and 602 cm −1 ;    (iii) a solid-state 13C nuclear magnetic resonance spectrum containing peaks at 111.9, 114.8, 119.6, 129.2, 134.0, 138.0, 144.7, 153.2, 157.1, 170.7, 170.7, 172.0 and 175.0 ppm; and    (iv) an X-ray powder diffraction pattern which gives calculated lattice spacings of 6.46, 5.39, 4.83, 4.68, 3.71, 3.63, 3.58, and 3.48 Angstroms.    
     
     
         42 . A pharmaceutical composition comprising: 
 an effective, non-toxic amount of a compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt;    at least one other antidiabetic agent selected from the group consisting of a sulphonylurea and a biguanide;    and a pharmaceutically acceptable carrier therefor;    wherein said compound is in a crystalline form that, in a mineral oil dispersion, provides an infra red spectrum substantially in accordance with FIG. 1.    
     
     
         43 . A pharmaceutical composition comprising: 
 an effective, non-toxic amount of a compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt;    at least one other antidiabetic agent selected from the group consisting of a sulphonylurea and a biguanide;    and a pharmaceutically acceptable carrier therefor;    wherein said compound is in a crystalline form that provides a Raman spectrum substantially in accordance with FIG. 2.    
     
     
         44 . A pharmaceutical composition comprising: 
 an effective, non-toxic amount of a compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt;    at least one other antidiabetic agent selected from the group consisting of a sulphonylurea and a biguanide;    and a pharmaceutically acceptable carrier therefor;    wherein said compound is in a crystalline form that provides a solid-state  13 C nuclear magnetic resonance spectrum substantially in accordance with FIG. 3.    
     
     
         45 . A pharmaceutical composition comprising: 
 an effective, non-toxic amount of a compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt;    at least one other antidiabetic agent selected from the group consisting of a sulphonylurea and a biguanide;    and a pharmaceutically acceptable carrier therefor;    wherein said compound is in a crystalline form that provides a solid-state  13 C nuclear magnetic resonance spectrum substantially in accordance with Table I.    
     
     
         46 . A pharmaceutical composition comprising: 
 an effective, non-toxic amount of a compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt;    at least one other antidiabetic agent selected from the group consisting of a sulphonylurea and a biguanide;    and a pharmaceutically acceptable carrier therefor;    wherein said compound is in a crystalline form that provides an X-ray powder diffraction pattern substantially in accordance with FIG. 4.    
     
     
         47 . A pharmaceutical composition comprising: 
 an effective, non-toxic amount of a compound, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt;    at least one other antidiabetic agent selected from the group consisting of a sulphonylurea and a biguanide;    and a pharmaceutically acceptable carrier therefor;    wherein said compound is in a crystalline form that provides an X-ray powder diffraction pattern substantially in accordance with Table II.    
     
     
         48 . The pharmaceutical composition according to any one of claims  40 - 47 , wherein the at least one other antidiabetic agent is a sulphonylurea.  
     
     
         49 . The pharmaceutical composition according to any one of claims  40 - 47 , wherein the at least one other antidiabetic agent is a biguanide.  
     
     
         50 . The pharmaceutical composition according to any one of claims  40 - 47 , wherein said composition contains both a sulphonylurea and a biguanide.  
     
     
         51 . The pharmaceutical composition according to  claim 49 , wherein the biguanide is metformin.  
     
     
         52 . The pharmaceutical composition according to  claim 50 , wherein the biguanide is metformin.  
     
     
         53 . The pharmaceutical composition according to any one of claims  40 - 47 , wherein the composition is adapted for oral administration.  
     
     
         54 . The pharmaceutical composition according to any one of claims  40 - 47 , wherein the composition is in the form of a tablet or a capsule.  
     
     
         55 . A method for the treatment or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and complications thereof, in a human or non-human mammal which comprises administering an effective, non-toxic, amount of the composition according to any one of claims  40 - 47  to a human or non-human mammal in need thereof.  
     
     
         56 . A method for the treatment or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and complications thereof, in a human or non-human mammal which comprises administering an effective, non-toxic, amount of the composition according to any one of claims  40 - 47  to a human or non-human mammal in need thereof.  
     
     
         57 . A method for the treatment of Type II diabetes in a human or non-human mammal which comprises administering an effective, non-toxic, amount of the composition according to any one of claims  40 - 47  to a human or non-human mammal in need thereof.  
     
     
         58 . A method for the treatment of Type II diabetes in a human or non-human mammal which comprises administering an effective, non-toxic, amount of the composition according to any one of claims  40 - 47  to a human or non-human mammal in need thereof.