Tremextrexate derivatives and pharmaceutical compositions comprising the same

Abstract

The present invention provides for thermally stable forms of 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline, or trimetrexate. A crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate, or trimetrexate monohydrate, belonging to the space group P{overscore (1)} (#2) and having a triclinic cell with dimensions of about a=7.699 Å, b=9.606 Å and c=13.012 Å is disclosed. A novel Schiff base compound, 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyphenylimino)-methinyl]quinazoline, is also disclosed. The present invention further provides novel methods of producing stable trimetrexate free base compounds, including crystalline trimetrexate monohydrate. The crystalline monohydrate form provides increased stability over the anhydrous form.

What is claimed is:  
     
         1 . Thermally stable 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline, wherein said compound is not a salt.  
     
     
         2 . The thermally stable 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline of  claim 1 , wherein said compound is a hydrate.  
     
     
         3 . 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate.  
     
     
         4 . Crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate.  
     
     
         5 . The crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate according to  claim 4  having an x-ray powder diffraction pattern essentially the same as FIG. 1.  
     
     
         6 . The crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate according to  claim 4  having an x-ray powder diffraction pattern essentially the same as Table 1.  
     
     
         7 . Crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate belonging to the space group P{overscore (1)}(#2) and having a triclinic cell with dimensions of a=7.699 Å, b=9.606 Å and c=13.012 Å.  
     
     
         8 . A thermally stable compound of  claim 1 ,  2  or  3 , wherein said compound is sterile.  
     
     
         9 . A crystalline 2,4-diamino-5-methyl-6-[(3 ,4,5-trimethoxyanilino)methyl] quinazoline monohydrate of  claim 4 ,  5 ,  6  or  7 , wherein said compound is sterile.  
     
     
         10 . A method of producing 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate comprising: 
 a. preparing a crude trimetrexate base from trimetrexate acetate hydrate;    b. recrystallizing the crude trimetrexate base with dimethyl formamide (DMF) to produce a pure trimetrexate-DMF adduct;    c. converting the trimetrexate-DMF adduct to trimetrexate hydrochloride; and    d. converting trimetrexate hydrochloride to pure, crystalline trimetrexate monohydrate.    
     
     
         11 . The method of  claim 10  wherein step (a) is carried out in water, aliphatic C 2  to C 4  alcohols, or a mixture thereof.  
     
     
         12 . The method of  claim 11  wherein the solvent is a mixture of n-butanol and water.  
     
     
         13 . The method of  claim 12  wherein the n-butanol and water are in a ratio of from 1:1 to 10:1.  
     
     
         14 . The method of  claim 10  wherein step (a) comprises preparing a solution of trimetrexate acetate in a basic mixture of n-butanol and water; heating said solution in the presence of a catalytic amount of sodium metabisulfite; filtering the solution; further heating the solution to a temperature of about 50 to 90° C.; and adding aqueous ammonia to crystallize crude trimetrexate base.  
     
     
         15 . The method of  claim 14  wherein the filtering is carried out at a pressure of about 1 bar.  
     
     
         16 . The method of  claim 14  which further comprises cooling the solution to room temperature after the crude trimetrexate base crystallizes, filtering the crude trimetrexate base, and washing the crude trimetrexate base.  
     
     
         17 . The method of  claim 16  wherein the crude trimetrexate base is washed with ethanol, water or a mixture thereof.  
     
     
         18 . The method of  claim 10  wherein step (b) comprises dissolving the crude trimetrexate base in a solvent comprising dimethyl formamide; heating the DMF solution; adding a C 2  to C 4  alcohol; and cooling the DMF solution to a temperature at which the trimetrexate-DMF adduct crystallizes.  
     
     
         19 . The method of  claim 18  which further comprises filtering the trimetrexate-DMF adduct.  
     
     
         20 . The method of  claim 19  which further comprises washing the filtered trimetrexate-DMF adduct with a C 2  to C 4  alcohol.  
     
     
         21 . The method of  claim 10  wherein in step (c), the trimetrexate-DMF adduct is converted into trimetrexate hydrochloride via a trimetrexate gluconate intermediate.  
     
     
         22 . The method of  claim 21  wherein said trimetrexate gluconate intermediate is produced by contacting the trimetrexate-DMF adduct with a source of gluconate.  
     
     
         23 . The method of  claim 21  wherein the trimetrexate gluconate intermediate is converted into trimetrexate hydrochloride using acetic acid and an aqueous sodium chloride solution to crystallize trimetrexate hydrochloride.  
     
     
         24 . The method of  claim 23  which further comprises heating the trimetrexate gluconate solution.  
     
     
         25 . The method of  claim 23  which further comprises filtering the trimetrexate hydrochloride.  
     
     
         26 . The method of  claim 25  which further comprises washing the filtered trimetrexate hydrochloride with water, a C 2  to C 4  alcohol, or a mixture thereof.  
     
     
         27 . The method of  claim 10  wherein step (d) comprises heating trimetrexate hydrochloride in a mixture of water and C 2  to C 4  alcohol and raising the pH of the suspension to precipitate trimetrexate monohydrate.  
     
     
         28 . The method of  claim 27  which further comprises filtering, washing, and drying under vacuum the trimetrexate monohydrate.  
     
     
         29 . The method of  claim 10  which further comprises sieving and optionally blending the trimetrexate monohydrate.  
     
     
         30 . A method of producing 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate comprising: 
 a. converting quinazoline aldehyde formate or quinazoline aldehyde diformate to 2,4-diamino-5-methyl-6-quinazoline carboxaldehyde hydrate;    b. coupling the 2,4-diamino-5-methyl-6-quinazoline carboxaldehyde hydrate with trimethoxyaniline to produce 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyphenylimino)methyl] quinazoline;    c. reducing 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyphenylimino)methyl] quinazoline to trimetrexate acetate hydrate; and    d. preparing pure trimetrexate monohydrate by treating trimetrexate acetate hydrate with ammonia and purifying the trimetrexate monohydrate product.