MXPA98001665A - Polymorphoses of profarmaco of 6-n- (l-ala-l-ala) -trovafloxacin, procedure for its preparation and use of mis - Google Patents

Abstract

A prodrug of trovafloxacin having the formula (I): which is selected from its polymorph PII and the monohydrate PII.M and the pseudomorph PIII.PS thereof and methods for its preparation, the polymorph PII and the monohydrate PII.M are described. and psudomorph PIII.PS thereof, the invention further relates to the use thereof in the preparation of pharmaceutical compositions comprising the compounds of the invention, for the treatment of bacterial infections in mammals, and the compositions containing them.

Description

POLIMORPHOS OF PROFRRMRCO OF 6-N- (L-fiLR-L-RLR) -TROvRFLOXRCINfl. PROCEDURE PRRR YOUR PREPRESSION AND USE OF THEMSELVES BACKGROUND OF THE INVENTION This invention relates to a Loxacin trova prodrug which has the formula selected from the group formed by polymorph PII and monohydrate PII.M and pseudomorph PII.PS thereof and to procedures for their preparation. The invention further relates to methods of use, and to pharmaceutical compositions comprising The compounds of the invention for the treatment of bacterial infections in mammals. The antibacterial activity of trovafLoxacin is described in U.S. Patent No. 5,164,402 (The '402 patent) and in U.S. Patent 5,229,396 < The '396 patent) granted on November 17, 1992 and July 20, 1993, respectively, The descriptions of which are hereby added as background in their entirety. The above patents were assigned in common with the present application. In the aforementioned patents, a polymorph Pl of the compound of formula I and methods for its preparation are also described.

BRIEF DESCRIPTION OF THE INVENTION In a first embodiment, the present invention relates to a prodrug of trovafloxacin having the formula C H3SO3H said prodrug being selected from the group consisting of a) a polymorph PII having the following X-ray powder diffraction pattern fl = 2T (S) Cu B = separation d b) a monohydrate PII.M presenting the following X-ray powder diffraction pattern fl = 2T (Q> CU B = separation d and c> a pseudomorph PII.PS having the following X-ray powder diffraction pattern fl = 2T (9) Cu B = separation d According to a second embodiment of the invention, there is provided a process for preparing the prodrug PII, as described above, which comprises treating the prodrug Pl, of the formula I, with the dry ethanoL, which has the following X-ray powder diffraction pattern, fl = 2T (Q) Cu B = separation d According to another aspect of the previous embodiment, the invention provides a process for preparing a monohydrate, PII.M, as described above, of the polymorph PII, which comprises a) treating the polymorph PII with an aqueous solvent; b) treat the PII polymorph with water; or c) treating a pseudomorph PII.M, PII.PS, with water. Still another aspect of the above embodiment of the invention provides a method for preparing a pseudomorph, PII.PS, as described above, of the PII.M monohydrate, which comprises vacuum drying the PII.M monohydrate. The invention also provides pharmaceutical compositions comprising an effective antibacterial amount of a compound of the formula I, as described above, together with a pharmaceutically acceptable diluent or carrier. In another embodiment, the invention provides a method for treating a bacterial infection in a mammal comprising administering to said mammal an amount effective to treat bacterial infection of a compound of formula I, as described above. A third embodiment of the invention provides a prodrug of trovafLoxacin consisting of polymorph PII, characterized by the X-ray diffraction pattern described above, which is prepared by treating the polymorph Pl, characterized by the X-ray diffraction pattern described above, with dry ethanol. According to another aspect of the foregoing embodiment, a prodrug of trovafLoxacin is provided which comprises the monohydrate PII.M of polymorph PII, characterized by the X-ray diffraction pattern described above, which is prepared: a) by treating the poly Plorph, characterized by the X-ray diffraction pattern described above, with an organic solvent containing water; b) treating the PII polymorph with water; or c) treating the PII.PS pseudomorph of PII.M, with water. Yet another aspect of the foregoing embodiment provides a prodrug of trovafloxacin comprising its pseudomorph PII.Ps, characterized by the X-ray diffraction pattern described above, which is prepared by vacuum drying the monohydrate PII.M.

DESCRIPTION DETRLLRDR OF LR INVENTION This invention relates to a prodrug of trovafLoxacin, which has the formula selected from the group consisting of a polymorph PII and the monohydrate PII.M and the pseudomorph PII.PS thereof and to pharmaceutical compositions comprising PII, PII.M and PII.PS and to methods of using them. The invention also relates to processes for preparing PII, PII.M and PII.PS as illustrated in the following reaction scheme. eSQUEHP 1 CH3S 03H POLIMORFO I (Pl) / \ POLIMORFO II (PU)? POLYMORFO II MONOHYDRATE (PIT M) POLIMORFO II PSEUDOMORFO (PII PS) With reference to Scheme I, the polymorph Pl becomes the polymorph PII by treatment with dry ethanoL. The conversion is carried out conveniently at about room temperature. The polymorph Pl can be prepared according to the procedure of Example 49 of the '402 patent or the co-pending United States patent application together with the present invention with the filing number PC91T6, the descriptions of which are appended here as background in its entirety. The application PC9186 is assigned in common together with the present application. The polymorph PII can then be converted to the PII.M monohydrate by treating with water. The water can be in liquid or vapor form. Alternatively, the PII.M monidrate can be prepared by treatment of PlLimorph Pl with organic solvents, such as C?-C 4 alkyl esters of CA-CA alkanoic acids and C ^-C alca alkanols, which contain water at a temperature from about room temperature to the reflux temperature of the solvent. A preferred solvent is ethyl acetate containing about 0.1% of water and the conversion is carried out at about 40-50 ° C, preferably at about 45 ° C. The excess water is extracted from the product by azeotropic distillation to the reflux temperature of the solvent. Another preferred solvent is ethanol containing about 5% water or a minor amount. The conversion is carried out by treating PII with the solvent at its reflux temperature (approximately 7T ° C) and the product is recovered, as crystals, to cool the solution. The resulting crystals are dried to a water content of about 2.7% to provide the desired product. The PII.M monohydrate can be converted to a PII pseudomorph. PS by vacuum drying. The pseudomorph can be converted to the monohydrate by treatment with liquid water as indicated above with respect to the conversion of PII into PII.M. The antibacterial compounds of formula I, ie, the polymorph PII, the monohydrate PII.M and the pseudomorph PII.PS (hereinafter the "active compounds") which can be synthesized using the methods and intermediates of this invention are useful in the treatment of animals and humans that have a broad spectrum of bacterial infections. These are particularly useful in the treatment of gram-positive bacterial strains. The active compounds can be administered as lozenges, although they are usually administered in admixture with a selected pharmaceutical carrier with respect to the chosen administration route and conventional pharmaceutical practice. For example, these can be administered orally or in the form of tablets containing excipients such as aldimon 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 contained in an animal feed or in the drinking water in a concentration of about 5 to about 5,000 ppm, preferably about 25 to about 500 ppm. These can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, these are best used in the form of a sterile aqueous solution that may contain other solutes, for example, enough salt or glucose to make the isotonic solution. In the case of animals, the compounds of formula I can be administered intramuscularly or subcutaneously at dosage levels of from about 0.1 to about 50 mg / kg / day, advantageously from about 0.2 to about 10 mg / kg / day administered in a single dose per day or up to 3 divided doses. The active compounds can be administered to humans, for the treatment of bacterial diseases by oral or parenteral routes. These can be administered orally at dosage levels of about 0.1 to 500 mg / kg / day, advantageously 0.5 to 50 mg / kg / day administered in a single dose or up to 3 divided doses. For intramuscular or intravenous administration, dosage levels vary from about 0.1 to 200 mg / kg / day, advantageously from 0.5 to 50 mg / kg / day. While intramuscular administration may be a single dose or up to 3 divided doses, intravenous administration may include a continuous drip. Necessarily, variations will be presented depending on the weight and disorder of the patient in question and the particular route of administration chosen, as will be known by experts in the technique. The antibacterial activity of the compounds of the invention are shown by assaying according to the Steer replicator technique which is a standard in vitro bacterial assay procedure described by E. Steers et al., Flntibiotics and Chemotherapy, 9, 307 (1959). The following examples illustrate the methods and compounds of the present invention. It will be understood, however, that the invention is not limited to the specific details. 53EMPIP 1 L-flLaniL-Nf (1ot.5tt.6a) -3-t6-carboxy-ß- (2,4-difluoro-phenyl) -3- fLuoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-iL ] -3- azabicilcLoC3.1.03hex-6-iL > -N'-tert-butyloxycarbonyl-L-alaninamide The bipolar ion of trovafLoxacin (prepared as described in the application with filing number PC9186 together with The present) (3 g) was stirred with dichloromethane (45 ml) at about 25 ° C to form a white suspension. N-tert-butyloxycarbonyl-L-alanyl-L-alanine (2.19 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.95 g) were added to the suspension and the resulting reaction mixture was stirred for 4 hours. hours at approximately 25 ° C. The reaction mixture was cooled to about 5 ° C for 1 hour and the title product was isolated as white crystals by filtration. The crystals were washed with dichloromethane (approximately 15 ml) and dried in vacuo. Yield, 4.7 g, 80%.

JEHP Q 2 MetasuL-L-RLaniL-NC (1a.5o..6ot) -3- [6-carboxy-8- (2,4-dlfluoropheniL) -3-fLuoro-5,8-dihydro-5-oxo-1,8-na tiridin-2-yl] - 3-azabicyclo [3.1.Q] hex-6-iL > -L-alananamide The title compound of Example 1 (10 g) and tetrahydrofuran (60 ml) were stirred to form a suspension at about 25 ° C. Methanesulfonic acid (2.9 g) was added to the suspension and the resulting reaction mixture was heated to reflux (about 66 ° C) for about 6 hours. The reaction mixture was cooled to about 5 ° C and the crystals of the title product were isolated by filtration, washed with cold tetrahydrofuran (ca. 15 ml) and dried in vacuo at 40 ° C. Yield 9.4 g, 94%.

EJ? MP Q 3 MetasuL-L-RLaniL-N-C (1ot.5ot.6a) -3-C6-carboxy-8- (2,4-difluoro-phenyl) -3-f-L-5-dihydro-5-oxo-1.8 -naphyridin-2-yl] -3-azabicicLoC3.1.Q] hex-6-iL > -L-alananamide The title compound of Example 1 (10 g), acetone (80 mL) and water (1.8 mL) were stirred to form a suspension at a temperature of about 20 ° C. Methanesulfonic acid (4.4 g) was added to the suspension and the resulting reaction mixture was heated to reflux (about 56 ° C) for about 4 hours. Additional acetone (40 ml) was added to the reaction mixture during the reflux period. The reaction mixture was cooled to about 5 ° C and the resulting crystals of the title product were isolated by filtration, washed with cold acetone (about 25 mL) and dried under vacuum at about 35 ° C. Yield 9.9 g, 93%.

E3EMPL0 4 L-RLaniL-N- < : (1tt.Sa.6a) -3- [6-carboxy-8- (2,4-difluoro-enyl) -3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl] -3-azabicho [ 3.1.Q] hex-6-iL-N / -tetra-butyloxycarbonyl-L-alaninamide Methanesulfate of 7- (Cla, 5a, 6a] -] 6-amino-3-naphthyridin-2-it] -3-azabicyclo [3.1.03hex-3-yl] -6-fluoro-1- (2 , 4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (40 g) with dichloromethane (600 ml) at about 20 ° C to form a white suspension. Triethylamine (7.9 g), N-tert-butyloxycarbonyl-L-aLaniL-L-alanine (23.76 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (21.24 g) were added to the suspension and the resulting reaction mixture for about 16 hours at about 25 ° C. The reaction mixture was cooled to about 5 ° C for 1 hour and the title product was isolated as white crystals by filtration. The crystals were washed with dichloromethane (approximately 80 mL) and dried in vacuo. Yield 42.6 g, 83%.

E3EMPUQ 5 Poleimorph PII of L-flLa-N ~ C MetanosuLfate (1o-.5c..6o -) - 3- [6-carboxy-8- (2,4-dl LuorofeniL) -3-fLuoro-5,8-dihydro-5 -oxo-1.8- naphthyridin-2-iL] -3-azabicic [3.1.03hex-6-iL > -L-alananamide The title product of Example 2 or 3 was stirred in dry ethanol (water content less than about 0.1%) (2.9 mL) for 48 hours at about 25 ° C. The title product was isolated by filtration. The product is characterized by the X-ray powder diffraction pattern described above.

EXAMPLE 6 Polymorph II Monohydrate (Pil.M) fl. The title product of Example 2 or 3 (4 g) was heated to reflux (about 78 ° C) in ethanoL containing water (less than 5%) (40 mL) for about 1 hour. An additional amount of ethanol (8 ml) was added during the reflux period to obtain a solution. The reaction mixture was cooled to about 25 ° C to obtain a crystal suspension. The crystals were isolated by filtration and dried to a water content of 2.7% to obtain the title product. Performance 90%. B. The product of the title of Example 2 was heated or 3 (20 g) at about 45 ° C in ethyl acetate (300 mt).

Water (21 mL) was then added slowly to form a suspension. The suspension was heated to reflux and the water (approximately 19 ml) azeotropically removed. The solution was cooled to approximately 25 ° C to obtain a crystal suspension. The crystals were isolated by filtration and dried to a water content of about 31 2.7% to obtain the title product. Performance 99%. The title product is characterized by the X-ray powder diffraction pattern described above.

EXAMPLE 7 Pseudomorph PII.PS of PoLimorph II Monohydrate The title product of Example 6 was dried in vacuo until all the water was removed to provide the title product. The product of the title is characterized by the X-ray powder diffraction pattern described above.

Claims (1)

1. NOVELTY OF LR INVENTION CLAIMS A prodrug of trovafloxacin that has the formula CH3S03H wherein said prodrug is a) a polyhydride monohydrate PII.M, which presents the following X-ray powder diffraction pattern: for peak No. 1, the value of 2T (9) Cu is 3.6 and that of space d is 24.2; for No. 2, 7.3 and 12.2; for No. 3, 13.7 and 6.5; for No. 4, 14.5 and 6.1; for No. 5, 17.1 and 5.2; for No. 6, 21.0 and 4.2; for No. 7, 23.6 and 3.8; and for No. 8, 26.7 and 3.3, respectively; or b) a PII.PS pseudomorph, which has the following X-ray powder diffraction pattern: for peak No. 1, the value of 2T (9) Cu is 3.7 and that of space d is 24.2; for No. 2, 7.3 and 12.2; for No. 3, 13.6 and 6.5; for No. 4, 14.5 and 6.1; for No. 5, 17.1 and 5.2; for No. 6, 21.0 and 4.2; for No. 7, 22.0 and 4.0; for No. 8, 22.4 and 4.0; for No. 9, 23.6 and 3.8; for No. 10, 24.2 and 3.7; for No. 11, 25.6 and 3.5; for No. 12, 26.7 and 3.3; for No. 13, 28.4 and 3.1; and for No. 14, 29.4 and 3.0, respectively. 2.- The compound in accordance with the claim 1, which comprises the monohydrate PII.M. 3. The compound according to claim 1, comprising the pseudomorph PII.PS. 4. A process for preparing the prodrug monohydrate PII.M, of trovafLoxacin, of formula I, comprising a) preparing the polymorph PII presenting the X-ray diffraction pattern: for peak No. 1, eL value of 2T (9) Cu is 3.4 and that of space d is 26.0; for No. 2, 6.8 and 13.1; for No. 3, 13.5 and 6.6; for No. 4, 16.8 and 5.3; for No. 5, 19.6 and 4.5; for No. 6, 20.3 and 4.4; for No. 7, 23.1 and 3.8; for No. 8, 25.7 and 3.5; for No. 9, 27.8 and 3.2, respectively; treating the polymer prodrug Pl which presents the X-ray powder diffraction pattern: for the peak No. 1, the value of 2T (9) Cu is 6.1 and the space D is 14.5; for No. 2, 7.3 and 12.1; for No. 3, 7.9 and 11.2; for No. 4, 9.5 and 9.3; for No. 5, 11.7 and 7.6; for No. 6, 14.2 and 6.2; for No. 7, 14.9 and 6.0; for No. 8, 15.8 and 5.6; for No. 9, 16.8 and 5.3, for No. 10, 20.1 and 4.4; for No. 11, 21.4 and 4.2; for No. 12, 22.7 and 3.9; for No. 13, 24.9 and 3.6; and for No. 14, 26.0 and 3.4, respectively, with dry ethanol; or an organic solvent containing water; and b) treating the PII polymorph with water, or treating a PII.M, PII.PS pseudomorph, with water. 5. The method according to claim 4, step (a) wherein said organic solvent is selected from the group consisting of alkyl esters of Ci-CA of alkanoic acids of dC,., And alcandés of CA-C * . 6. The process according to claim 5, step (a) wherein said solvent is ethyl acetate. 7. The method according to claim 4, steps (a) and (b), further comprising drying under vacuum of the PII.M monohydrate to form the pseudomorph, PII.PS, thereof. 8. The use of the prodrug according to claim 1 in the preparation of compositions for treating a bacterial infection in a mammal. 9. The use according to claim 8, further characterized in that said prodrug is PII.M. monohydrate. 10. The use according to claim 8, further characterized in that said prodrug is pseudomorph of PII.S. 11. A pharmaceutical composition for treating a bacterial infection in a mammal comprising an amount effective to treat bacterial infection, the prodrug in accordance with claim 1 and a pharmaceutically acceptable carrier. 12. The composition according to claim 11, wherein said prodrug is the monohydrate PII.M. 13. The composition according to claim 11, wherein said prodrug is the pseudomorph PII.PS. 14. The compound according to claim 2, which has a water content of about 2.7%. 15. A prodrug of trovafLoxacin comprising the polymorph monohydrate PII.M, characterized by the powder diffraction pattern of X-rays, described above, which is prepared a) by treating the Pl Plimorph, characterized by the X-ray diffraction pattern. described above, with dry ethanol or an organic solvent containing water to form the polymorph PII, characterized by the X-ray pattern described above; and b) treating the polymorph PII with water; or treating the PII.PS pseudomorph of PII.M with water. 16. The prodrug according to claim 15, comprising its pseudomorph PII.PS, characterized by the X-ray diffraction pattern described above, which is prepared by vacuum drying the monohydrate PII.M.