1. A process for the preparation of gemifloxacin of the formula I:
or a pharmaceutically acceptable salt thereof:
which comprises:
a) reacting 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid of the formula II:
with boric acid of the formula III:
in the presence of acetic anhydride and acetic acid to give a borane compound of the formula IV:
b) reacting the borane compound of the formula IV with 4-aminomethyl-3-methoxyimino-pyrrolidine of the formula V:
to give the compound of formula VI:
c) and treating the compound of formula VI with an alkaline metal hydroxide, carbonate or bicarbonate to obtain gemifloxacin of the formula I and optionally converting the gemifloxacin formed into a pharmaceutically acceptable acid addition salt of gemifloxacin.
2. The process according to claim 1, wherein the reaction in step (a) is carried out at about 30\xb0 C. to the reflux temperature.
3. The process according to claim 2, wherein the reaction is carried out at about 80\xb0 C. to the reflux temperature.
4. The process according to claim 3, wherein the reaction is carried out at the reflux temperature.
5. The process according to claim 1, wherein the reaction in step (b) is carried out in a solvent selected from hydrocarbon solvents, chlorinated hydrocarbon solvents, acetonitrile, tetrahydrofuran, 1,4-dioxane and a mixture thereof.
6. The process according to claim 5, wherein the solvent is n-hexane, cyclohexane, n-heptane, methylene chloride or 1,4-dioxane.
7. The process according to claim 6, wherein the solvent is acetonitrile.
8. The process according to claim 1, wherein the reaction in step (b) is carried out at about 15-100\xb0 C.
9. The process according to claim 8, wherein the reaction in step (b) is carried out at about 30-80\xb0 C.
10. The process according to claim 9, wherein the reaction in step (b) is carried out at about 50-60\xb0 C.
11. The process according to claim 1, wherein the alkaline metal hydroxide is sodium hydroxide or potassium hydroxide, the alkaline metal carbonate is sodium carbonate or potassium carbonate, and the alkaline metal bicarbonate is sodium bicarbonate or potassium bicarbonate.
12. The process according to claim 11, wherein the alkaline metal hydroxide is sodium hydroxide.
13. A process for the preparation of amorphous gemifloxacin, which comprises:
a) preparing a solution of gemifloxacin in dimethylformamide or methylene chloride; and
b) isolating amorphous gemifloxacin from the solution.
14. The process according to claim 13, wherein the isolation of amorphous gemifloxacin is performed by techniques such as cooling, seeding, partial removal of the solvent from the solution, addition of a precipitating solvent or a combination thereof.
15. The process according to claim 14, wherein the isolation is performed by cooling.
16. The process according to claim 14, wherein the isolation is performed by using a precipitating solvent.
17. The process according to claim 16, wherein the precipitating solvent is diisopropyl ether.
18. A compound of the formula IV:
19. A compound of the formula VI:
20. Gemifloxacin hemihydrate.
21. A process for the preparation of gemifloxacin hemihydrate of claim 20, which comprises drying wet gemifloxacin at 40-100\xb0 C. until the water content is reduced to 1.8-2.4% by weight.
22. The process according to claim 21, wherein the drying is carried out at 50-70\xb0 C.
23. Gemifloxacin monohydrate.
24. A process for the preparation of the gemifloxacin monohydrate of claim 23, which comprises drying wet gemifloxacin at 40-100\xb0 C. until the water content is reduced to 4.0-5.0% by weight.
25. The process according to claim 24, wherein the drying is carried out at 50-70\xb0 C.
26. Gemifloxacin sesquihydrate.
27. A process for the preparation of the gemifloxacin sesquihydrate of claim 26, which comprises drying wet gemifloxacin at 40-100\xb0 C. till the water content is reduced to 5.8-6.5% by weight.
28. The process according to claim 27, wherein the drying is carried out at 50-70\xb0 C.
29. A crystalline gemifloxacin lactate, characterized by an X-ray powder diffraction spectrum having peaks expressed as 2\u03b8 at about 7.4, 7.7, 8.2, 9.1, 12.4, 18.5, 19.8, 23.6, 25.7 and 26.8 degrees.
30. A process for the preparation of the crystalline gemifloxacin lactate of claim 29, which comprises contacting gemifloxacin with lactic acid in a solvent medium and crystallizing the gemifloxacin lactate from the solution.
31. The process according to claim 30, wherein the solvent is selected from a chlorinated hydrocarbon solvent, alcoholic solvent and a mixture thereof.
32. The process according to claim 31, wherein the chlorinated hydrocarbon solvents are methylene chloride, ethylene chloride, chloroform and a mixture thereof.
33. The process according to claim 32, wherein the chlorinated hydrocarbon solvent is methylene chloride.
34. The process according to claim 31, wherein the alcoholic solvent is methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and a mixture thereof.
35. The process according to claim 34, wherein the alcoholic solvent is ethanol.
36. Crystalline gemifloxacin formate.
37. A process for the preparation of the crystalline gemifloxacin formate of claim 36, which comprises contacting gemifloxacin with formic acid in a solvent medium and crystallizing the gemifloxacin formate from the solution.
38. The process according to claim 37, wherein the solvent is selected from a chlorinated hydrocarbon solvent, alcoholic solvent and a mixture thereof.
39. The process according to claim 38, wherein the chlorinated hydrocarbon solvent is methylene chloride, ethylene chloride, chloroform and a mixture thereof.
40. The process according to claim 39, wherein the chlorinated hydrocarbon solvent is methylene chloride.
41. The process according to claim 38, wherein the alcoholic solvent is methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and a mixture thereof.
42. The process according to claim 41, wherein the alcoholic solvent is ethanol.
43. A pharmaceutical composition comprising gemifloxacin hemihydrate and a pharmaceutically acceptable excipient.
44. A pharmaceutical composition comprising gemifloxacin monohydrate and a pharmaceutically acceptable excipient.
45. A pharmaceutical composition comprising gemifloxacin sesquihydrate and a pharmaceutically acceptable excipient.
46. A pharmaceutical composition comprising crystalline gemifloxacin lactate and a pharmaceutically acceptable excipient.
47. A pharmaceutical composition comprising crystalline gemifloxacin formate and a pharmaceutically acceptable excipient.
48. An aqueous infusion solution comprising 0.015 to 0.5 gm of gemifloxacin per 100 ml of aqueous solution and an amount of at least one physiologically tolerated acid which suffices to dissolve the gemifloxacin, wherein there are about 1.33 to 2.2 moles per mole of gemifloxacin, of the physiologically tolerated acid.
49. An infusion solution according to claim 48, wherein the physiologically tolerated acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, propionic acid, succinic acid, glutaric acid, citric acid, fumaric acid, maleic acid, tartaric acid, glutamic acid, gluconic acid, glucuronic acid, galacturonic acid, ascorbic acid, phosphoric acid, nitric acid, acetic acid, maleic acid, L-aspartic acid, lactic acid and a mixture thereof.
50. An infusion solution according to claim 49, wherein the physiologically tolerated acid is lactic acid, hydrochloric acid or a mixture thereof.
51. An infusion solution according to claim 50, wherein the physiologically tolerated acid is lactic acid.
52. An infusion solution according to claim 51, wherein the lactic acid is present in about 1.33 to 1.50 moles per mole of gemifloxacin.
53. An infusion solution according to claim 48, having a pH from 3.0 to 5.2.
54. An infusion solution according to claim 53, having a pH from 3.6 to 4.7.
55. An infusion solution according to claim 54, having a pH from 3.9 to 4.5.
56. An infusion solution according to claim 55, having a pH from 4.1 to 4.3.
57. An infusion solution according to claim 48, which is substantially isotonic.
58. An infusion solution according to claim 48, containing 1.33 to 2.2 moles of lactic acid and 0.0 to 0.80 moles of hydrochloric acid per mole of gemifloxacin, and relative to 100 ml of solution, 0.6 to 2.2 gm of NaCl.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method for producing objects, volumic elements, modules and furniture made from modules composed of individual structural elements comprising the steps of:
providing a flat composite material of uniform thickness having a plurality of layers,
cutting from the flat material a blank for the structural element,
applying desired fold lines to the blank including angular end portions for forming an angled connecting site,
cutting into the fold lines,
folding the blank along the cut-in fold lines, thereby realizing outer edges,
joining outer edges of the blank to form a closed folded thin-walled shell of a structural element having weight bearing capacity, and
connecting two or more structural elements via a fixing nodal element, at the angled connecting site for joining two or more structural elements via the fixing nodal element, whereby the angled sites of each of the elements are meeting at a single point to form a corner, and wherein the nodal element has legs angularly oriented for inserting into the corresponding shell of the structural element such that the angled sites of each element are joined to form a single point and the inserted fixing nodal element is thus no longer visible.
2. The method of claim 1, further comprising the step of joining the fixing nodal element at a 90 degree angle to each of the structural elements to form a connection wherein the fixing nodal element has a cross-section fitting into a cross section of the structural element to be connected to a single point.
3. The method of claim 1, wherein the composite material is composed of plastic malleable outer layers and a middle layer made of a hard, non-malleable material.
4. The method of claim 3, wherein the malleable material of the outer layers are selected from the group consisting a material; which is a metal-, plastic-, paper-, textile-, fiber- or leather-based material.
5. The method of claims 4, wherein the metal is aluminum.
6. The method of claim 3, wherein the non-malleable material utilized for the middle layer is selected from the group consisting of plywood, foam, glass, stone, cement or ceramic.
7. The method of claim 1, wherein the outer ends of the folded, blank are joined by gluing, reshaping, retro-shaping, pressing, force-fitting, soldering, welding or textile joining.
8. The method of claim 7, wherein the joining of the outer ends is carried out gluing with a chemically reactive adhesive.
9. The method of claim 8, wherein the adhesive is polyurethane.
10. The method of claim 1, wherein the folded, thin-walled shell of the structural element is constructed with a polygonal, triangular or rectangular, cross-section.