MXPA98001664A - Zwitterionic forms of trovafloxacin, procedure for its preparation, compositions that contain them and use of the mis - Google Patents

Abstract

A zwitterionic form of trovafloxacin of form(I): selected from the group consisting of its crystalline polymorphs and hygroscopic polymorphs and methods for their preparation, the invention further relates to methods of use, and pharmaceutical compositions comprising them, the compounds of the invention for the treatment of bacterial infections in mammals

Description

ZWITTERIONIC FORMS OF TROVAFLOXACIN. PROCEDURE FOR PREPARATION. COMPOSITIONS THAT CONTAIN AND USE THEMSELVES BACKGROUND OF THE INVENTION This invention relates to the naf iridone antibiotic trovafloxacin. More specifically it refers to the polymorphs and the pentahydrate of the itterionic form thereof having formula I, below, and the methods for their preparation. The invention further relates to the methods of use, and the pharmaceutical compositions including them, the compounds of the invention for the treatment of bacterial infections in mammals. The antibacterial activity of the antibiotic naphthyridone mentioned above is described in U.S. Patent No. 5,164,402 [the '402 patent and 5,229,396 issued on November 17, 1992 and July 20, 1993, respectively, the descriptions of which are incorporated herein by reference in their entirety. The foregoing patents are assigned in common with the present application. The zwitterionic forms of trovafloxacin are useful for the administration of the drug in suspension.

BRIEF DESCRIPTION OF THE INVENTION According to a first embodiment of the invention, a zwitterionic crystalline form of trovafloxacin of formula which is selected from the group consisting of a) a first non-hygroscopic polymorph Pl having the following characteristic powder X-ray diffraction pattern. b) a second hygroscopic polymorph PII having the characteristic powder X-ray diffraction pattern. and c) a pentahydrate, zwitterion pentahydrate of trovafloxacin, which has the characteristic powder X-ray diffraction pattern.

A second embodiment of the invention relates to a method of preparation of a troge of trovafloxacin of formula I selected from the group consisting of a non-hygroscopic polymorph Pl, a hygroscopic polymorph PII and a pentahydrate thereof, such as described above, comprising A. the steps of treating an aqueous suspension of a metastable form of the compound of formula I 1) with a non-polar solvent followed by azeotropic removal of the residual water and drying under vacuum to form said hygroscopic polymorph PII showing the characteristic powder X-ray diffraction pattern described in claim 1; 2) with a polar solvent followed by azeotropic removal of the residual water and drying under vacuum; 3) with water and drying the residue with air at an elevated temperature, removing the mother liquor and drying the residue with air at room temperature until constant weight to form the pentahydrate; or B. treating the second hygroscopic polymorph PII with a refluxing polar solvent to form the first non-hygroscopic polymorph Pl. According to a third embodiment of the invention, a method for preparing the metastable form of the zwitterion, trovafloxacin, of formula I, is provided by a) treatment of an acid salt of rovafloxacin with a base to raise the pH of the mixture to between 7.5 and 8.5 at an elevated temperature, removal of the mother liquor, washing of the crystals with water and drying of the crystals in vacuo at about 35 to about 40 ° C; or b) treatment of a compound of formula wherein A is hydrogen or an amino protecting group such as t-butyloxycarbonyl, benzyloxycarbonyl, alkylcarbonyl (Ci-Ce) and benzyl; and B is hydrogen or a protecting group of the carboxylic acid selected from benzyl, t-butyl and alkyl (Ci-Ce); with an amino deprotecting agent and / or carboxylic acid, respectively. An embodiment of the invention provides a method of treating bacterial infections in a mammal comprising administering to said mammal an effective amount in the treatment of a bacterial infection of a compound of formula I as described above. According to a fifth embodiment of the invention there is provided a composition for treating bacterial infections in a mammal comprising an effective amount in the treatment of a bacterial infection of a compound of formula I and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound comprising a stable itterionic form of the trovafloxacin antibiotic of formula More specifically, it relates to a compound of formula I which is selected from a) a first non-hygroscopic polymorph Pl having the characteristic powder X-ray diffraction pattern described above; b) a second hygroscopic polymorph PII having the characteristic powder X-ray diffraction pattern described above; and c) a pentahydrate, zwitterion pentahydrate of trovafloxacin, which has the characteristic powder X-ray diffraction pattern described above. The invention also relates to methods of preparing the compounds of formula I as illustrated in the following schemes.

SCHEME 1 metastable form of zwitterion polymorph PII polymorph Pl pentahydrate Stable forms of zwitterion As shown in Scheme 1, a salt 1 of trovafloxacin is converted, wherein X is an anion selected from those formed from mineral acids such as hydrochloric, sulfuric, nitric and phosphoric; organic acids such as sulfonic acids, e.g. benzenesulfonic (benzyl), p-toluenesulfonic (PTSA, tosyl), methanesulfonic (MSA, mesyl) and trifluoro-ethanesulfonic (triflic), and carboxylic acids, eg, acetic, propionic, benzoic, citric, tartaric, maleic, fumaric, succinic and malic , in a metastable zwitterionic form 2 by raising the pH of a suspension including compound 1 to a pH of about 7.5 and 8.5 at a temperature in the range of about 45 to about 55 ° C using a basic aqueous solution. A preferred salt is the mesylate. Useful bases in the practice of this aspect of the invention include inorganic bases such as alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates and organic bases such as trialkylamines (C -Cß), pyridine and morpholine. A preferred aqueous base is saturated sodium bicarbonate. The saturated sodium product is then dried. The wet product is then dried to constant weight, under vacuum, at a temperature of from about 35 to about 40 ° C. Alternatively, as shown in scheme 2, compound 2 could be prepared directly from protected precursors 6, from trovafloxacin salts 1 wherein A is hydrogen or an amino protecting group such as t-butyloxycarbonyl, benzyloxycarbonyl, alkylcarbonyl (Ci-Ce) and benzyl; and B is hydrogen or a protective group of the carboxylic acid selected from benzyl, t-butyl and alkyl (Ci-Cß); with an amino deprotecting agent and / or carboxylic acid, respectively. A preferred compound 6, wherein A is hydrogen and B is ethyl, is converted to compound 2 by treatment with a solution of NaOH in a polar solvent at an elevated temperature. A preferred solvent is methanol and the temperature is the reflux temperature of the solvent. The pH of the solution was then adjusted to between about 6.5 and 8.0 with dilute HCl and then saturated aqueous NaHCO3 was added to adjust the pH to between about 7.5 and 8.5. The product was then recovered as indicated above. The metastable zwitterion 2 of trovafloxacin is converted to the hygroscopic polymorph PII, 4, by treatment with an apolar solvent such as a hydrocarbon. A preferred hydrocarbon is hexanes. The residual water was azeotropically removed and the product dried at about 35 to about 40 * C in vacuo. Solvents useful for the azeotropic removal of traces of water include aliphatic to polar hydrocarbons, such as hexanes and octanes, and aromatic hydrocarbons such as benzene and toluene. Aliphatic hydrocarbons are preferred solvents, more preferably hexanes. The non-hygroscopic polymorph Pl, 3, can be prepared from compound 2 by treatment with a polar solvent followed by azeotropic removal of the water and vacuum drying at about 30 to about 40 ° C. Useful polar solvents for this conversion include alkyl esters (Ci-Cß) of alkylcarboxylic acids (C2-Cß) and alkanols (Ci-Cß). A preferred solvent is ethyl acetate. Alternatively, compound 3 can be prepared from compound 4 by treating compound 4 with a polar refluxing solvent, as described above. A preferred solvent is ethyl acetate. Compound 5, the pentahydrate of the compound of formula I, is prepared by air-drying the wet crystals of compound 1, at room temperature, until a constant weight is reached. Alternatively, compound 5 could be prepared from compound 4 by treatment with water until a constant uptake of water has been obtained. Compound 3 is not converted to compound 5 by exposure to water. The antibacterial compounds of the invention, ie, the polymorph Pl, the polymorph PII and the pentahydrate (hereinafter "the active compounds") are useful in the treatment of animals and humans that have a broad appearance of bacterial infections. They are especially useful in the treatment of Gram-positive bacterial strains. The active compounds may be administered alone, but will generally be administered in a mixture with a pharmaceutical carrier selected in accordance with the intended administration route and conventional pharmaceutical practice. For example, they can be administered orally or in the form of tablets containing excipients such as starch or lactose, or in capsules either alone or mixed with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. In the case of animals, they are advantageously included in an animal feed or in the drinking water at a concentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm. They can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example salt or glucose sufficient to make the solution isotonic. In the case of animals, the compounds of formula I can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to about 50 mg / kg / day, advantageously about 0.2 to about 10 / mg / kg / day given in a single daily dose or in up to three divided doses.

The active compounds can be administered to humans, for the treatment of bacterial diseases either orally or parenterally. They could be administered orally at dosage levels of about 0.1 to 500 mg / kg / day, advantageously 0.5-50 mg / kg / day given in a single dose or in up to three divided doses. For intramuscular or intravenous administration, the dosage levels are approximately 0.1-200 mg / kg / day, advantageously 0.5-500 mg / kg / day. While intramuscular administration may be a single dose or up to three divided doses, intravenous administration may include a continuous drip. As is known to those skilled in the art, variations will necessarily occur depending on the weight and condition of the subject to be treated and the specific route of administration. The active compounds may be administered alone, but will generally be administered in a mixture with a pharmaceutical carrier selected in accordance with the intended administration route and conventional pharmaceutical practice. For example, they can be administered orally or in the form of tablets containing excipients such as starch or lactose, or in capsules either alone or mixed with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. In the case of animals, they are advantageously included in an animal feed or in the drinking water at a concentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm. They can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example salt or glucose sufficient to make the solution isotonic. In the case of animals, the compounds of formula I can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to about 50 mg / kg / day, advantageously about 0.2 to about 10 mg / kg / day given in a single daily dose or in up to three divided doses. For intramuscular or intravenous administration, the dosage levels are about 0.1-200 mg / kg / day, advantageously, 0.5-50 mg / kg / day. While the intramuscular administration may be a single dose or up to three divided doses, intravenous administration may include a continuous drip. The variations will necessarily be given depending on the weight and condition of the individual under treatment and the particular route of administration chosen as is known to those initiated in the art. The antibacterial activity of the compounds of the invention is shown by analysis according to the Steer replication technique which is a conventional method of bacterial analysis in vivo described by E. Steers et al., Antibiotics and Che otherapy, 9, 307 (1959).

The following examples illustrate the processes and compounds of the present invention. It should be understood, however, that the invention is not limited to the specific examples.

EXAMPLE 1 Zwitterion of trovafloxacin. metastable form A. Trovafloxacin mesylate (prepared according to Example 13B of the '402 patent) (20 g) was stirred with demineralised water (100 ml). The crystal suspension was heated to about 50 ° C and the pH of the suspension was adjusted to about 8.0 by the addition of saturated sodium bicarbonate solution. The suspension was maintained at about 50 ° C for 30 minutes, allowed to cool to about 25 ° C and stirred at this temperature for 30 minutes. The crystals were isolated by filtration and washed with demineralized water (27 ml). The wet crystals were suspended in demineralized water (100 ml) and stirred for about 1 hour at about 50 ° C, then cooled to about 20 ° C and stirred at this temperature for about 1 hour. The crystals were filtered from the mother liquors, washed with demineralized water (about 27 ml) and dried at constant weight under vacuum at 40 ° C to give the title product containing 2.5% residual water by analysis. Yield 16.25 g, 97%.

B. The ethyl ester of trovafloxacin (prepared according to the procedure of the co-pending United States patent application together with the present serial number 08/490827, filed on June 15, 1995, the description of which is it is incorporated herein by reference in its entirety The foregoing application is assigned in common with the present application) (10 g) was stirred with methanol (75 ml), water (25 ml) and sodium hydroxide in lentils (1.8 g). The resulting mixture was heated to reflux at about 72 ° C to form a solution. The solution was cooled to approximately 25 ° C and the pH adjusted to approximately 7.5, by the addition of 6 N hydrochloric acid, to form a suspension, saturated sodium bicarbonate solution (50 ml) was added and the suspension was stirred for 30 minutes. at about 25 ° C. The title product was isolated and washed with water (20 ml) and dried under vacuum at about 45 ° C. Yield 7.72 g, 82.5%.

EXAMPLE 2 Polymorph Pl of the zwitterion of trovafloxacin (non-hygroscopic form) Trovafloxacin mesylate (75 g) was stirred with demineralised water (375 ml). The crystal suspension was heated to about 50 ° C and the pH of the suspension was adjusted to about 8.0 by the addition of saturated sodium bicarbonate solution. The suspension was maintained at about 50 ° C for 30 minutes, allowed to cool to about 25 ° C and stirred at this temperature for 30 minutes. The crystals were isolated by filtration and washed with demineralized water (100 ml). The wet crystals were suspended in demineralised water (375 ml) and stirred for 1 hour at about 50 ° C, then cooled to about 20 ° C and stirred at this temperature for about 1 hour. The crystalline product was filtered from the mother liquor and washed with demineralized water (about 100 ml). The wet crystals were stirred with ethyl acetate (1125 ml) and the resulting suspension was heated to reflux and the water was removed azeotropically. The substantially anhydrous suspension was cooled to about 25 ° C, the crystals were isolated by filtration and dried under vacuum at 40 ° C until all the solvent had been removed to give the title product. Yield 60.9 g, 94%. The product is characterized by the powder X-ray diffraction pattern described above.

EXAMPLE 3 Polymorph PII hygroscopic zwitterion of trovafloxacin The title product of Example 1, paragraph A, (5 g) was mixed with hexanes (150 ml) to form a suspension.

The suspension was heated to reflux and traces of waste water were removed azeotropically. After refluxing for 4 hours, the crystal suspension was cooled to about 25 ° C, isolated by filtration and dried at constant weight in vacuo at about 40 ° C. Yield 4.7 g, 94% The title product was characterized by the powder X-ray diffraction pattern described above.

EXAMPLE 4 Zwitterion pentahydrate of rovafloxacin Trovafloxacin mesylate (50 g) was stirred with demineralised water (250 ml). The crystal suspension was heated to 50 ° C and the pH of the suspension was adjusted to about 8.0 by the addition of saturated sodium bicarbonate solution. The suspension was maintained at about 50 ° C for 30 minutes, allowed to cool to about 25 ° C and stirred at this temperature for 30 minutes. The crystals were isolated by filtration and washed with demineralized water (70 ml). The wet crystals were suspended in demineralized water (250 ml) and stirred for 1 hour at about 50 ° C, then cooled to about 20 ° C and stirred at this temperature for about 1 hour. The crystalline product was filtered from the mother liquors and washed with demineralized water (about 70 ml). The wet crystals were air-dried at constant weight at room temperature to give the title product which by analysis contained 17.6% water.

Yield 48.4 g, 84%. The title product was characterized by the powder X-ray diffraction pattern described above.

Claims (20)

NOVELTY OF THE INVENTION CLAIMS

1. - A zwitterionic crystalline form of trovafloxacin of formula which is selected from the group consisting of a) a first non-hygroscopic polymorph Pl having the following characteristic powder X-ray diffraction pattern: for peak No. 1, the value of 2T (Q) Cu is 6.9 and the of space d is 12.7; for No. 2, 9.8 and 9.0; for No. 3, 11.3 and 7.9; for No. 4, 12.0 and 7.4; for No. 5, 13.9 and 6.4; for No. 6, 16.1 and 5.5; for No. 7, 16.6 and 5.4; for No. 8, 17.1 and 5.2, for No. 9, 17.4 and 5.1; for No. 10, 19.7 and 4.5; for No. 11, 20.3 and 4.4; for No. 12, 21.2 and 4.2; for No. 13, 22.8 and 3.9; for No. 14, 23.8 and 3.7, and for No. 15, 26.3 and 3.4, respectively; b) a second hygroscopic polymorph PII having the characteristic powder X-ray diffraction pattern: for peak No. 1, the value of 2T (Q) Cu is 8.4 and that of space d is 10.6; for No. 2, 9.5 and 9.3; for No. 3, 10.2 and 8.7; for No. 4, 14.7 and 6.0; for No. 5, 16.8 and 5.3; for No. 6, 17.9 and 5.0; for No. 7, 22.6 and 3.9; and for No. 8, 26.1 and 3.4, respectively; and c) a pentahydrate, zwitterionic pentahydrate of trovafloxacin, having the characteristic powder X-ray diffraction pattern: for peak No. 1, the value of 2T (S) Cu is 6.6 and that of space d is 13.3; for No. 2, 8.6 and 10.3; for No. 3, 12.7 and 7.0; for No. 4, 13.3 and 6.6; for No. 5, 15.9 and 5.5; for No. 6, 18.6 and 4.8; for No. 7, 19.2 and 4.6; for No. 8, 20.1 and 4.4, for No. 9, 21.0 and 4.2; for No. 10, 22.6 and -; for No. 11, 22.9 and 3.9; for No. 12, 23.6 and 3.8; for No. 13, 24.9 and 3.6; for No. 14, 25.4 and 3.5, and for No. 15, 25.9 and 3.4, for No. 16, 27.7 and 3.2; and for No. 17, 29.5 and 3.0, respectively.

2. The compound according to claim 1 formed by said first polymorph Pl non-hygroscopic.

3. The compound according to claim 1 formed by said second polymorph PII hygroscopic.

4. The compound according to claim 1 formed by said pentahydrate.

5. The compound according to claim 1 formed by said metastable form.

6. - A process for the preparation of a compound of formula which is selected from the group consisting of a non-hygroscopic polymorph Pl, a hygroscopic polymorph PII and a pentahydrate thereof, comprising: A) the steps of treating an aqueous suspension of a metastable form of the compound of formula I; 1) with a non-polar solvent followed by azeotropic removal of the residual water and drying under vacuum to form said hygroscopic polymorph PII showing the characteristic powder X-ray diffraction pattern described in claim 1; 2) with a polar solvent followed by azeotropic removal of the residual water and drying under vacuum; or 3) with water and drying the residue with air at an elevated temperature, removing the mother liquor and drying the residue with air at room temperature to constant weight to form the pentahydrate; or B) treating the second hygroscopic polymorph PII with a refluxing polar solvent to form the first non-hygroscopic polymorph Pl.

7. The process of claim 6 wherein the metastable form of the compound of formula I is prepared by a) treating an acid salt of trovafloxacin with a base to raise the pH of the mixture to between 7.5 and 8.5 at a temperature elevated or b) treatment of a compound of formula wherein A is hydrogen or an amino protecting group such as t-butyloxycarbonyl, benzyloxycarbonyl, alkylcarbonyl (Ci-Cß) and benzyl; and B is hydrogen or a protecting group of the carboxylic acid selected from benzyl, t-butyl and alkyl (Ci-Cß); with an amino deprotecting agent and / or carboxylic acid, respectively.

8. The process of claim 6 step a) wherein the non-polar solvent is hexanes.

9. The process of claim 6 step b) wherein the polar solvent is ethyl acetate.

10. The use of the compound of claim 1, in the preparation of compositions for treating a bacterial infection in a mammal comprising administering to said mammal.

11. The use of claim 10 wherein said compound is a first polymorph Pl non-hygroscopic.

12. The use of claim 10 wherein said compound is a second hygroscopic polymorph PII.

13. The use of claim 10 wherein said compound is the zwitterion pentahydrate of trovafloxacin.

14. A composition for treating bacterial infections in a mammal comprising administering to said mammal an effective amount in the treatment of a bacterial infection of the compound of claim 1 and a pharmaceutically acceptable carrier.

15. The composition of claim 14 wherein said compound is the first non-hygroscopic polymorph Pl.

16. The composition of claim 14 wherein said compound is the second non-hygroscopic polymorph PII.

17. The composition of claim 14 wherein said compound is the zwitterion pentahydrate of rovafloxacin.

18. The composition of claim 14 wherein said composition is a suspension.

19. The process of claim 7 wherein A is hydrogen or an amino protecting group such as t-butyloxycarbonyl, benzyloxycarbonyl, alkylcarbonyl (Ci-Cß) and benzyl.

20. The process of claim 7 wherein said compound B is hydrogen and A is selected from benzyl, t-butyl and alkyl (Ci-Cß).