TH103191A - Pharmacy acceptable salt of thymodypressin And methods for producing these things - Google Patents

Abstract

DC60 (10/09/52) This invention relates to the pharmaceutically acceptable crystalline and amorphous salts of D-isoglutamyl-D-tryptophan and to the methods for their production, the pharmaceutical compounds containing them, and their use in the preparation of pharmaceutical compounds for the treatment of various conditions and/or diseases. In particular, this invention relates to the potassium salt of D-isoglutamyl-D-tryptophan (1:1), the lithium salt of D-isoglutamyl-D-tryptophan (1:1), the calcium salt of D-isoglutamyl-D-tryptophan (2:1), the magnesium salt of D-isoglutamyl-D-tryptophan (2:1). D-isoglutamyl-D-tryptophan (2;1), and the organic ammonium salts of D-isoglutamyl-D-tryptophan (1;1). This invention relates to the pharmaceutically acceptable crystalline and amorphous salts of D-isoglutamyl-D-tryptophan and to the methods for their production, the pharmaceutical compounds containing them, and their use in the preparation of pharmaceutical compounds for the treatment of various conditions and/or diseases. In particular, this invention relates to the potassium salt of D-isoglutamyl-D-tryptophan (1;1), the lithium salt of D-isoglutamyl-D-tryptophan (1;1), the calcium salt of D-isoglutamyl-D-tryptophan (2;1), the magnesium salt of D-isoglutamyl-D-tryptophan (2;1). D-isoglutamil-D-tryptophan (2;1), and the organic ammonium salt of D-isoglutamil-D-tryptophan (1;1).

Claims (34)

1. The pharmaceutically acceptable salt of D-isoglutamyl-D-tryptophan of the formula (chemical formula) l, where M is chosen from the potassium and lithium-containing groups. 2. A pharmaceutically acceptable salt pursuant to claim 1, where M is potassium and the salt is in an amorphous form. 3. A pharmaceutically acceptable salt pursuant to claim 1, where M is potassium and the salt is in crystalline form. 4. The potassium salt D-isoglutamil-D-tryptophan, as per claim 3, was characterized by X-ray powder diffraction peaks with the following 2-theta values: 9.91, 14.84, 15.81, 18.97, 19.76, 24.04, 24.36, 24.82, 25.48, 27.49, 27.94, 28.42, 30.82, 31.28, 31.69, 32.17, 34.35, 35.81, and 36.96°. 5. The potassium salt D-isoglutamyl-D-tryptophan, as per claim 3, was characterized by peaks in the X-ray diffraction pattern prepared in Figure 1A. 6. A pharmaceutically acceptable salt pursuant to claim 1, where M is lithium and the salt is in an amorphous form. 7. A pharmaceutically acceptable salt pursuant to claim 1, where M is lithium and the salt is in crystalline form. 8. The lithium salt of D-isoglutamil-D-tryptophan under claim 7 was studied, characterized by the following 2-theta refractive index peaks: 13.57, 15.53, 18.71, 20.11, 23.34, 24.1, 25.09, 27.31, 27.72, 28.39, 29.31, 30.19, 31.21, 32.03, 33.05, 33.62, and 37.41°. 9. The potassium salt D-isoglutamil-D-tryptophan, as per claim 7, was studied. Its characterization is shown by the X-ray powder refraction peaks prepared in Figure 2A. 10. Pharmaceutically acceptable salts of D-isoglutamyl-D-tryptophan of formula (chemical formula) II, where B is selected from the calcium and magnesium-containing groups. 11. A pharmaceutically acceptable salt pursuant to claim 10, where B is magnesium and the salt is in crystalline form. 12. The crystalline magnesium salts of D-isoglutamyl-D-tryptophan (1;2) according to claim 11 were characterized by the following 2-theta powder refractive index peaks: 12.2, 13.74, 14.84, 16.16, 17.96, 18.52, 18.49, 19.49, 21.05, 21.56, 22.56, 23.36, 24.12, 26.27, 27.65, 28.42, 19.14, 30.55, 31.77, 32.62, 33.26, 35.05, 36.34, 37.22, and 38.05. 13. The crystalline magnesium salts of D-isoglutamyl-D-tryptophan (1;2) according to claim 11 were studied in the X-ray powder refraction model prepared in Figure 3A, 14. A pharmaceutically acceptable salt pursuant to claim clause 10, where B is calcium and where the salt has a degree of crystallinity of less than approximately 67% by weight. 15. Calcium salt of D-isoglutamil-D-tryptophan according to claim 14 with a degree of crystallinity of less than approximately 50%. 16. Calcium salt of D-isoglutamil-D-tryptophan according to claim 14 with a degree of crystallinity of less than approximately 25%. 17. Pharmaceutically acceptable salts of D-isoglutamyl-D-tryptophan of formula III (chemical formula) III, where A is chosen from groups consisting of terit-butylammonium, tris(hydroxymethyl)methylammonium and N-methyl-D-glucosylammonium. 18. Pharmaceutically acceptable salts of D-isoglutamyl-D-tryptophan pursuant to claim 17, where A is terit-butylammonium and its salts have the formula (chemical formula) and where the salts are in amorphous form. 19. Pharmaceutically acceptable salts of D-isoglutamyl-D-tryptophan pursuant to claim 17, where A is tris(hydroxymethyl)methylammonium and the salt has the formula (chemical formula) and where the salt exists in the amorphous form. 20. Pharmaceutically acceptable salts of D-isoglutamyl-D-tryptophan pursuant to claim 17, where A is methyl-(2,3,4,5,6-pentahydroxy-hexyl)-ammonium and salts with the formula (chemical formula) and where the salts are in amorphous form. 21. The procedure for the preparation of metal salts of D-isoglutamyl-D-tryptophan of formula l (chemical formula) l, where M is chosen from the lithium and potassium groups, consists of: (a) reaction of D-isoglutamyl-D-tryptophan in water with lithium or potassium hydroxide; and (b) saturation of the solution into an oil and addition of isopropanol with stirring to induce precipitation of the salt; reuse of these precipitates; and vacuum drying of the product to obtain the metal salts of formula l. 22. The procedure for the preparation of the metal salts of D-isoglutamyl-D-tryptophan of formula II (chemical formula) II, where B is calcium, consists of: (a) the reaction of D-isoglutamyl-D-tryptophan in water with calcium hydroxide; and (b) the concentration of the solution by stirring to induce precipitation of the salts; the reuse of these precipitates; and vacuum drying of the product to obtain the metal salts of formula II. 23. The procedure for the preparation of the metal salts of D-isoglutamyl-D-tryptophan of formula II, (chemical formula) II, where B is magnesium, consists of: (a) reaction of D-isoglutamyl-D-tryptophan with magnesium ethoxide in isopropanol; and (b) concentration of the solution to obtain a solid; aqueous mixing of the solution; filtration of the insoluble fraction; dilution of the filtrated fraction with water while stirring to precipitate the product; reuse of the precipitates; and vacuum drying of the metal salts of formula II. 24. Procedure for the preparation of organic amine salts of D-isoglutamyl-D-tryptophan of formula III (chemical formula) III, where A is selected from groups consisting of terit-butylammonium or trit(hydroxymethyl)methylammonium, and methyl-(2,3,4,5,6-pentahydroxyhexyl)-ammonium, the procedure consists of; (a) reaction of D-isoglutamyl-D-tryptophan in aqueous with aqueous organic amines where the organic amine is selected from groups consisting of terit-butylamine, N-methylglucamine, and tromethamine; and (b) concentration of the solution by co-evaporation with isopropanol; addition of acetone to precipitate the salt; reuse of the precipitates; and vacuum drying of the product to obtain the ammonium salts. Organic formula III 25. The procedure for the preparation of D-isoglutamyl-D-tryptophan of formula lV (chemical formula) lV, where M is sodium, consists of: (a) the reaction of D-isoglutamyl-D-tryptophan in aqueous solution with sodium hydroxide; and (b) the saturation of the solution into an oil and the addition of isopropanol with stirring to induce precipitation of the salt; the reuse of these precipitates; and vacuum drying of the product to obtain the metal salt of formula lV. 26. The method of salt exchange for the pharmaceutically acceptable salt of D-isoglutamyl-D-tryptophan, denoted by the general formula l, (chemical formula) l, where M is chosen from the lithium and potassium-containing groups, consists of; (a) the reaction of the ammonium salt, denoted by the formula Vll (chemical formula) Vll, in an aqueous solution with approximately one equivalent of the hydroxide of the metal denoted by MOH, where M is as defined above; and (b) the evaporation of the solvent to obtain a solid which is then mixed with water and isopropanol to obtain a compound of the formula l. 27. The method of salt exchange for the pharmaceutically acceptable salt of D-isoglutamyl-D-tryptophan, denoted by the general formula ll, (chemical formula) ll, where B is chosen from the calcium and magnesium-containing groups, consists of: (a) the reaction of the ammonium salt, denoted by the formula (chemical formula) Vll, in an aqueous solution with approximately 0.5 equivalents of the metal hydroxide B(OH)2, where B is as defined above; and (b) the evaporation of the solvent to obtain a solid which is then mixed with water and isopropanol to obtain a compound of the formula ll. 28. Method according to claim 26, where M is potassium, MOH is potassium hydroxide, and the compound is represented by the following formula; (chemical formula) 29. Method according to claim 26, where M is lithium, MOH is lithium hydroxide, and the compound is represented by the following formula; (chemical formula) 30. Method according to claim 27, where M is magnesium, B(OH)2 is magnesium hydroxide, and the compounds are represented by the following formulas; (chemical formulas) 31. Method according to claim 27, where B is calcium, B(OH)2 is calcium hydroxide, and the compounds are represented by the following formulas; (chemical formulas) 32. The pharmaceutical compound contains a salt that is pharmaceutically acceptable under claims 1, 10, 17, 18, or 19. 33. A procedure for the manufacture of pharmaceutical components in which such procedure involves the combination of pharmaceutically acceptable salts of claims 1, 10, 17, 18 or 19 with at least one pharmaceutically acceptable carrier. 34. The use of pharmaceutically acceptable salts of claims 1, 10, 17, 18, or 19 without chromatographic purification in pharmaceutical compositions.