Claims for Patent: 6,017,922

Summary for Patent: 6,017,922

Title:	Thermally stable trimetrexates and processes for producing 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 P1(#2) and having a triclinic cell with dimensions of about a=7.699 .ANG., b=9.606 .ANG. and c=13.012 .ANG. 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.
Inventor(s):	Stogniew; Martin (Blue Bell, PA), Grafe; Ingomar (Nurnberg, DE), Morsdorf; Johann (Langenzenn, DE)
Assignee:	U.S. Bioscience, Inc. (Conshohocken, PA)
Application Number:	09/080,290
Patent Claims:	1. A thermally stable non-salt 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline. 2. A thermally stable non-salt 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline solvate. 3. The thermally stable non-salt of claim 2 wherein said solvate is a hydrate. 4. The thermally stable non-salt of claim 3 wherein said hydrate is a monohydrate. 5. The thermally stable non-salt of claim 2 wherein said thermally stable non-salt is crystalline. 6. The thermally stable non-salt of claim 2 wherein said thermally stable non-salt is substantially pure. 7. The thermally stable non-salt of claim 2 wherein said thermally stable non-salt is sterile. 8. A thermally stable crystalline non-salt hydrate of 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline. 9. The thermally stable crystalline non-salt hydrate of claim 8 wherein said hydrate is a monohydrate. 10. 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate. 11. Crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate. 12. The crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate according to claim 11 having an X-ray powder diffraction pattern essentially the same as FIG. 1. 13. The crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate according to claim 11 having atomic coordinates as determined from an X-ray powder diffraction pattern, wherein said atomic coordinates are essentially the same as those provided by Table 2. 14. The crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate according to claim 11 wherein said compound is substantially pure. 15. Crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate belonging to the space group PT(#2) and having a triclinic cell with dimensions of a=7.699 .ANG., b=9.606 .ANG. and c=13.012 .ANG.. 16. The crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate according to claim 15 wherein said compound is substantially pure. 17. A pharmaceutical composition comprising a thermally stable non-salt 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline and a pharmaceutically acceptable carrier. 18. A pharmaceutical composition comprising crystalline 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline monohydrate and a pharmaceutically acceptable carrier. 19. The pharmaceutical composition of claim 17 or 18 wherein said thermally stable non-salt is crystalline.