OA10669A

OA10669A - Zwitterionic forms of trovafloxacin

Info

Publication number: OA10669A
Application number: OA9800026A
Authority: OA
Inventors: Douglas John Meldrum Allen; David Bruning Joseph; Timothy Norris
Original assignee: Pfizer
Priority date: 1995-08-29
Filing date: 1998-02-27
Publication date: 2000-11-06
Also published as: JP3188476B2; HRP960395A2; CA2229786C; CO4480739A1; IL122651A; ZA967282B; NZ312199A; BR9609998A; AU6367696A; KR100343909B1; CN1190889A; DZ2087A1; IL122651A0; MX9801664A; CZ56698A3; SK23898A3; HUP9900170A2; TNSN96109A1; HRP960395B1; HUP9900170A3

Abstract

A zwitterionic form of trovafloxacin having formula (I) selected from the group consisting of its crystalline hygroscopic and non-hygroscopic polymorphs and pentahydrate and methods for their preparation. The invention further relates to methods of using, and pharmaceutical compositions comprising, the compounds of the invention for treatment of bacterial infections in mammals.

Description

-1- 010669

ZWITTERIONIC FORMS OF TROVAFLOXACIN

Background of the Invention

This invention relates to the naphthyridone antibiotic trovafloxacin. Moreparticularly, it relates to polymorphe and the pentahydrate of the zwitterionic form ofthereof having the formula I, below, and methods for their préparation. The inventionfurther relates to methods of using, and pharmaceutical compositions comprising, thecompounds of the invention for treatment of bacterial infections in mammals.

The antibacterial activity of the aforementioned naphthyridone antibiotic isdescribed in United States Patent No. 5,164,402 [the '402 patent] and 5,229,396 issued11/17/92 and 7/20/93, respectively, the disclosures of which are hereby incorporatedherein by référencé in their entirety. The foregoing patents are assigned in commonwith the présent application.

The zwitterionic forms of trovafloxacin are useful for the administration of thedrug as a suspension.

Summarv of the Invention

According to afirst embodiment of the invention there is provided a trovafloxacinzwitterionic crystal form having the formula

which is selected from the group consisting of a) a non hygroscopic first polymorph PI exhibiting the following characteristic X-ray powder diffraction pattern 010669 -2-

Peak no. 1 2 5 4 S 6 z 5 9i I 2 0(°) Cu 6.9 9.8 11.3 12.0 13.9 16.1 16.6 17.1 17.4 I | d space 12.7 9.0 7.9 7.4 6.4 5.5 5.4 5.2 5.1 I Peak no. 10 u 12 15 14 15 16 12 2_0_(°) Cu 19.7 22.9 23.6 24.9 25.4 25.9 27.7 29.5 d space 4.5 3.9 3.8 3.6 3.5 3.4 3.2 3.0 10 b) a hygroscopic second polymorph PII exhibiting the characteristic X-ray powder diffraction pattern 1 Peak no. 1 2 5 4 5 5 2 8 | I 2 0(°) Cu 8.4 9.5 10.2 14.7 16.8 17.9 22.6 26.1 1 d space 10.6 9.3 8.7 6.0 5.3 5.0 3.9 3.4 c) a pentahydrate, trovafloxacin zwitterion pentahydrate, exhibiting the characteristic X-ray powder diffraction pattern

Peak — 1 2 3 4 5 6 7 8 9 2_0_(°) Cu 6.6 8.6 12.7 13.3 15.9 18.6 19.2 20.1 21.0 d space 13.3 10.3 7.0 6.6 5.5 4.8 4.6 4.4 4.2 fl fi Peak 1 no» 15 n 12 15 14 15 15 12 2_0_(°) Cu 22.5 22.9 23.6 24.9 25.4 25.9 27.7 29.5 d space 4.0 3.9 3.8 3.6 3.5 3.4 3.2 3.0 010669 -3- A second embodiment of the invention relates to a process for preparing azwitterion, of trovafloxacin, of the formula I which is selected from the group consistingof a non hygroscopic polymorph PI, a hygroscopic polymorph PII and a pentahydratethereof, as described above, comprising

A. the steps of treating an aqueous suspension of a metastable form of thecompound of the formula I 1) with a nonpolar solvent followed bv azectroplc removaî ofresidual water and vacuum drying to form sald hygroscopic polymorph PII whichexhibits the characteristic X-ray powder diffraction pattern described in oiaim 1 ; 2) with a polar solvent followed by azeotropic removai of residualwater and vacuum drying; or 3) with water and air drying the residue at an elevated température,removing the mother liquor and air drying the residue at room température to constantweight to form the pentahydrate; or B) treating the hygroscopic second polymorph PII with a refluxing polarsolvent to form the non-hygroscopic first polymorph PI.

According to a third embodiment of the invention there is provided a processfor preparing the metastable form of the zwitterion, of trovafloxacin, of the formula I,by a) treating an acid sait of trovafloxacin with a base to raise the pH of themixture to between 7.5 and 8.5 at an elevated température, removai of the motherliquor, washing the crystals with water and drying the crystals under vacuum at about35 to about 40 °C; or b) treating a compound of the formula 010669 -4-

wherein A is hydrogen or an amine protecting group such as t-butyloxycarbonyl,benzyloxycarbonyl, (C^CgJalkylcarbonyl and benzyi; and 6 is hydrogen or a carboxylic acid protecting group selected from benzyi, t-butyland (C,-Ce) alkyl ; with an amine and/or carboxylic acid deprotecting agent, respectively. A fourth embodiment of the invention provides a method of treating bacterialinfections in a mammal which comprises administering to said mammal a bacterialinfection treating effective amount of a compound of formula I as described above.

According to a fifth embodiment of the invention there is provided a compositionfor treating bacterial infections in a mammal which comprises a bacterial infectiontreating effective amount of a compound of formula I and a pharmaceutically acceptablecarrier.

Detailed Description of the Invention

The présent invention relates to a compound comprising a stable zwitterionicform of the antibiotic trovafloxacin of the formula 010669 -5-

More particularly, it is related to a compound of the formula I which is selected from a) a non hygroscopic first polymorph PI exhibiting the characteristic X-ray powder diffraction pattern described above; 15 b) a hygroscopic second polymorph PII exhibiting the characteristic X-ray powder diffraction pattern described above; and c) a pentahydrate, trovafloxacin zwitterion pentahydrate, exhibiting the characteristic X-ray powder diffraction pattern described above.

The invention also relates to processes for the préparation of the compounds20 of the formula I as illustrated in the following schemes. 010669 -6- SCHEME 1

«etastable form of zuitterion

polymorph pi I polymorph PI pentahydrate 010669 -7- SCHEME 2

metastable forms of zwitterion 010669 -8-

As shown in Scheme 1 a trovafloxacin sait 1, wherein X is an anion selectedfrom those formed from minerai acids such as hydrochloric, sutfuric, nitric andphosphoric; organic acids such as sulfonic acids, e. g. benzenesulfonic (besylic), p-toluenesulfonic (PTSA, tosylic), methanesulfonic (MSA, mesylic) andtrifluoromethanesuifonic (triflic); and carboxylic acids e.g., acetic, proprionic, benzoic,citric, tartane, maleic, fumaric, succinic and malic, is converted to a metastablezwitterionic form 2 by raising the pH of a siurry comprising compound 1 to a pH ofbetween about 7.5 and 3.5 at a température in the range of about 45 to about 55°Cusing an aqueous basic solution. A preferred sait is the mesylate. The bases usefulin the practice of this aspect of the invention include inorganic bases such as aikaii oraikaline earth hydroxides, carbonates and bicarbonates and organic bases such astri(C1-Cs)aikyl amines, pyridine and morpholine. A preferred aqueous base is saturatedsodium bicarbonate. The wet product is then dried to constant weight, in vacuo, at atempérature from about 35 to about 40 °C. AJternatively, as shown in scheme 2, compound 2 may be prepared directly fromprotected precursors 6, of the trovafloxacin saits 1, of the formula

wherein A is hydrogen or an amine protecting group such as t-butyloxycarbonyl, benzyloxycarbonyl, (C,-Ce)alkylcarbonyl and benzyl; and B is hydrogen or a carboxylic acid protecting group selected from benzyl, t-butyl and (C,-Ce) alkyl; with an amine and/or carboxylic acid deprotecting agent, respectively. -9- 010669 A preferred compound 6, wherein A is hydrogen and B is ethyl, is converted tocompound 2 by treatment with a solution of NaOH in a polar solvent at an elevatedtempérature. A preferred solvent is methanol and the température is the refluxtempérature of the solvent. The pH of the solution was thon adjusted to between about6.5 and 8.0 with dilute HCl and saturated aqueous NaHCO, was then added to adjustthe pH to between about 7.5 and 8.5. The product was recovered as indicated above.

Metastabletrovafioxaein zwitterion £ >s converted to hygroscopic polymorph PII,4, by treatment with a non polar solvent such as a hydrocarbon. A preferredhydrocarbon is hexanes. Résiduel water is removed azeotropically and the productdried at about 35 to about 40°C under vacuum. Solvents useful for the azeotropicremoval of water traces include non-polar aliphatic hydrocarbons, such as hexanes andoctanes, and aromatic hydrocarbons such as benzene and toluene. Preferred solventsare the aliphatic hydrocarbons, most preferably hexanes.

Non hygroscopic polymorph PI 3, can be prepared from compound 2 bytreatment with a polar solvent followed by azeotropic removal of water and vacuumdrying at about 30 to about 40°C. Polar solvents useful for this conversion include(C,-Ce)aikyl esters of (C2-Ce)alkylcarboxylic acids and (C,-Ce)alkanols. A preferredsolvent is ethyl acetate.

Altematively, compound 3 can be prepared from compound 4 by treatingcompound 4 with a refluxing polar solvent, as described above. A preferred solvent isis ethyl acetate.

Compound 5, the pentahydrate of the compound of formula I, is prepared byair drying the wet crystals of compound i, at room température, until constant weightis achieved. Altematively, compound 5 may be prepared from compound 4 bytreatment with water until a constant water uptake has been obtained. Compound 3is not converted to compound § by exposure to water.

The antibacterial compounds of the invention, i.e., polymorph PI, polymorph PIIand the pentahydrate (hereafter "the active compounds") are useful in the treatment ofanimais and humans having a broad spectrum of bacterial infections. They areparticularly useful in treating gram-positive bacterial strains.

The active compounds may be administered alone, but will generally be administered in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered oraliy or in the form of tablets containing such excipients as 010669 -10- starch or lactose, or in capsules either alone or in admixture with excipients, or In theform of élixirs or suspensions containing flavoring or coloring agents. In the case ofanimais, they are advantageously contained in an animal feed or drinking water in aconcentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm.They can be injected parenterally, for example, intramuscularly, intravenously orsubcutaneously, For parentéral administration, they are best used in the form of astérile aqueous solution which can contain other solutés, for exampie, enough sait orglucose to make the solution isotonie. In the case of animais, the compounds offormula I can be administered intramuscularly or subcutaneously at dosage levels ofabout 0.1 to about 50 mg/kg/day, advantageously about 0.2 to about 10 mg/kg/daygiven in a single daily dose or up to 3 divided doses.

The active compounds can be administered to humans, for the treatment ofbacterial diseases by either oral or parentéral routes. They may be administered orailyat dosage levels of about 0.1 to 500 mg/kg/day, advantageously 0.5-50 mg/kg/daygiven in a single dosage or up to 3 divided dosages. For intramuscular or intravenousadministration, dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50mg/kg/day. While intramuscular administration may be a single dose or up to 3 divideddoses, intravenous administration can include a continuous drip. Variations willnecessarily occur depending on the weight and condition of the subject being treatedand the particular route of administration chosen as will be known to those skilled inthe art.

The active compounds may be administered alone, but will generally beadministered in a mixture with a pharmaceutical carrier selected with regard to theintended route of administration and standard pharmaceutical practice. For example,they can be administered oraily or in the form of tablets containing such excipients asstarch or lactose, or in capsules either alone or in admixture with excipients, or in theform of élixirs or suspensions containing flavoring or coloring agents. In the case ofanimais, they are advantageously contained in an animal feed or drinking water in aconcentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm.They can be injected parenterally, for example, intramuscularly, intravenously orsubcutaneously, For parentéral administration, they are best used in the form of astérile aqueous solution which can contain other solutés, for example, enough sait orglucose to make the solution isotonie. In the case of animais, the compounds offormula I can be administered intramuscularly or subcutaneously at dosage levels of 010669 -11- about 0.1 to about 50 mg/kg/day, advantageously about 0.2 to about 10 mg/kg/daygiven in a single daily dose or up to 3 divided doses. The active compounds can beadministered to humans by either oral or parentéral routes, and may be administeredorally at dosage levels of about 0.1 to 500 mg/kg/day, advantageously 0.5-50mg/kg/day given in a single dosage or up to 3 divided dosages. For intramuscular orintravenous administration, dosage levels are about 0.1-200 mg/kg/day, advantageously0.5-50 mg/kg/day, While intramuscular administration may be a single dose or up to3 divided doses, intravenous administration can indude a continuous drip, Variationswill necessarily occur depending on the weight and condition of the subject beingtreated and the particuiar route of administration chosen as will be known to thoseskilled in the art.

The antibacterial activity of the compounds of the invention is shown by testingaccording to the Steer's replicator technique which is a standard in vitro bacterial testingmethod described by E. Steers et al., Antibiotics and Chemotherapy, 9, 307 (1959).

The following examples illustrate the methods and compounds of the présentinvention. It will be understood, however, that the invention is not limited to the spécifieexamples.

Example 1

Trovafloxacin zwitterion, metastable form A. Trovafloxacin mesylate (prepared according to Example 13B of the *402patent) (20 g) was stirred with demineralized water (100 mL). The crystal slurry washeated to about 50 °C and the slurry adjusted to a pH of about 8.0 by addition ofsaturated sodium bicarbonate solution. The slurry was held at about 50 °C for 30minutes, allowed to cool to about 25 °C and stined at this température 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 about1 hour at about 50 °C, then cooled to about 20°C and stirred at this température forabout 1 hour. The crystals were fittered from the mother liquor, washed withdemineralized water (about 27 mL) and dried to constant weight under vacuum at about40 °C to yield the title product which contained 2.5 % résiduel water by analysis. Yield16 .25 g, 97%. B. The ethyi ester of trovafloxacin (prepared according to the method of co-pending United States patent application serial number 08/490827, filed June 15,1995, 0 î 0669 -12- the disclosures of which are hereby incorporated herein by reference in its entirety. Theforegoing application is assigned in common with the présent application. (10 g) was stirred with methanol (75 mL), water (25 mL) and sodium hydroxide pellets(1.8 g). The résultant mixture was heated to reflux at about 72 °C to form a solution.The solution was cooled to about 25 °C and the pH adjusted to about 7.5, by additionof 6N hydrochloric acid, to form a slurry. Saturated sodium bicarbonate solution (50mL) was added and the slurry stined for 30 minutes at about 25 °C, The titie productwas isolated and washed with water (20 mL) and dried under vacuum about 45 °C.Yield 7.72 g, 82.5 %.

Example 2

Trovafloxacin zwitterion polvmorph PI (non hyqroscopic form)Trovafloxacin mesylate, (75 g) was stirred with demineralised water (375 mL).

The crystal slurry was heated to about 50 °C and the slurry adjusted to a pH of about8.0 by addition of saturated sodium bicarbonate solution. The slurry was held at about50 °C for 30 minutes, allowed to cool to about 25 °C and stirred at this températurefor 30 minutes. Crystals were isolated by filtration and washed with demineralised water(100 mL). The wet crystals were suspended in demineralised water (375 mL) andstirred for 1 hour at about 50 °C, then cooled to about 20 °C and stirred at thistempérature for about 1 hour. The crystalline product was filtered from the motherliquor and washed with demineralised water (about 100 mL). The wet crystals werestirred with ethyl acetate (1125 mL) and the résultant slurry heated to reflux and thewater azeotropically removed. The essentially anhydrous slurry was cooled to about25 °C, the crystals were isolated by filtration and dried under vacuum at 40 °C until ailthe solvent had been removed to provide the titie product. Yield 60 .9 g, 94 %.

The product is characterized by the X-ray powder diffraction pattern described above.

Example 3

Trovafloxacin zwitterion hygroscopic polvmorph PIIThe titie product of Example 1, paragraph A, (5 g) was mixed with hexanes (150 mL) to form a slurry. The slurry was heated to reflux and traces of résiduel water were removed azeotropically. After 4 hours at reflux the crystal slurry was cooled to about 25 °C, isolated bÿ filtration and dried to constant weight under vacuum at about 40 °C.

Yield 4.7 g, 94 %. The titie product was characterized by the X-ray powder diffraction pattern described above. -13- 010669 10

Example 4

Trovafloxacin zwitterion pentahvdrate

Trovafloxacin mesylate (50 g) was stirred with demineraiised water (250 mL).The crystal slurry was heated to 50 °C and the slurry adjusted to a pH of about 8.0by addition of saturated sodium bicarbonate solution. The slurry was held at about 50° C for 30 minutes, allowed to cool to about 25 °C and stirred at this température for30 minutes. The crystals were isoiaied by filtration and washed with demineraiisedwater (70 mL). The wet crystals were suspended in demineraiised water (250 mL) andstirred for 1 hour at about 50 °C, then cooled to about 20°C and stirred at thistempérature for about 1 hour. The crystalline product was filtered from the motherliquor, washed with demineraiised water (about 70 mL). The wet crystals were air driedto constatnt weight at room température to yield the title product which contained 17.6% water by analysis. Yield 48.4 g, 84 %

The title product was characterized by the X-ray powder diffraction patterndescribed above. 15

Claims

010669 -14- CLAIMS

1. A trovafloxacin zwitterionic crystal form having the formula

selected from the group consisting of a) a non hygroscopic first polymorph PI exhibiting the characteristic X-raypowder diffraction pattern Peak no. 1 2 3 4 5 6 7 8 9 I 2_0_(°) Cu 6.9 9.8 11.3 12.0 13.9 16.1 16.6 17.1 174 I d space 12.7 9.0 7.9 7.4 6.4 5.5 5.4 5.2 5.1 | Peak no. 10 H 12 13 14 15 2_0_(°) Cu 19.7 20.3 21.2 22.8 23.8 26.3 d space 4.5 4.4 4.2 3.9 3.7 3.4 b) a hygroscopic second polymorph PII exhibiting the characteristic X-raypowder diffraction pattern Peak no. 1 2 3 4 5 6 7 8 2_0_(°) Cu 8.4 9.5 10.2 14.7 16.8 17.9 22.6 26.1 d space 10.6 9.3 8.7 6.0 5.3 5.0 3.9 3.4 010669 -15- and c) a pentahydrate, trovafloxacin zwitterion pentahydrate, exhib'rting the characteristic X-ray powder diffraction pattern Peak no. 1 2 2 4 § 6 7 5 9 2_0_(°) Cu ..... 6.6 8.6 12.7 13.3 15.9 18.6 19.2 20.1 21.0 d space 13.3 10.3 7.0 6.6 5.5 4.8 4.6 4.4 4.2 Peak no. 10 11 12 15 14 15 15 17 2JU°) Cu 22.6 22.9 23.6 24.9 25.4 25.9 27.7 29.6 d space 3.9 3.8 3.6 3.5 3.4 3.2 3.0
2. The compound according to claim 1 consisting of said non hygroscopicfirst polymorph PI.
3. The compound according to claim 1 consisting of said hygroscopic second polymorph PH.
4. The compound according to claim 1 consisting of said pentahydrate.
5. The compound according to ciaim 1 consisting of said metastable form.
6. A process for preparing a compound of the formula 20 -16- 010669

selected from the group consisting of a non hygroscopic polymorph PI, a hygroscopicpolymorph PII and a pentahydrate thereof comprising A. the steps of treating an aqueous suspension of a metastable form of thecompound of the formula I 1) with a nonpolar solvent followed by azeotropic removal ofrésiduel water and vacuum drying to form said hygroscopic polymorph PII whichexhibits the characteristic X-ray powder diffraction pattern described in daim 1 ; 2) with a polar solvent followed by azeotropic removal of residualwater and vacuum drying; or 3) with water and air drying the residue at an elevated température,removing the mother liquor and air drying the residue at room température to constantweight to form the pentahydrate; or B. by treating the hygroscopic second polymorph PII with a refluxing polarsolvent to form the non-hygroscopic first polymorph PI,
7. The process of daim 6 wherein the metastable form, of the compoundof formula I, is prepared by a) treating an add sait of trovafloxacin with a base to raise the pHof the mixture to between 7.5 and 8.5 at an elevated température; or b) by treating a compound of the formula 17 10

010669 15 wherein A is hydrogen or an amine protecting group such as t-butyloxycarbonyl,benzyloxycarbonyl. (Cj-Cgialkylcarbonyl and benzyl: and B is hydrogen or a carboxylicacid protecting group selected from benzyl, t-butyl and (Cj-Cg) alkyl; with an amine and/or carboxylic acid deprotecting agent, respectively. 20 25
8. The process of claim 6 step a) wherein the non solvent is hexanes.
9. The process of claim 6 step b) wherein the polar solvent is ethyl acetate.
10. A composition for treating bacterial infections in a mammal whichcomprises a bacterial infection treating effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.
11. The composition of claim 10 wherein said compound is the non hygroscopicfirst polymorph PI.
12. The composition of claim 10 wherein said compound is the hygroscopicsecond polymorph PII.
13. The composition of claim 10 wherein said compound is trovafloxacinzwitterion pentahydrate.
14. The composition of claim 10 wherein said composition is a suspension.
15. The method of claim 7 wherein A is hydrogen or an amine protecting groupsuch as t-butvloxycarbonyl. benzyloxycarbonyl. (C|-Cg)alkylcarbonyl and benzyl.
16. The method of claim 7 wherein said compound is B is hydrogen and A isselected from benzyl, t-butyl and (Ci-Cg)alkyl. 50