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WO2009040754A2 - Polymorphes de sel de lysine et de l'acide s-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypipéridin-1-yl)-5-méthyl-1-oxo-1h,5h-benzo[i,j]quinolizine-2-carboxylique - Google Patents

Polymorphes de sel de lysine et de l'acide s-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypipéridin-1-yl)-5-méthyl-1-oxo-1h,5h-benzo[i,j]quinolizine-2-carboxylique Download PDF

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Publication number
WO2009040754A2
WO2009040754A2 PCT/IB2008/053903 IB2008053903W WO2009040754A2 WO 2009040754 A2 WO2009040754 A2 WO 2009040754A2 IB 2008053903 W IB2008053903 W IB 2008053903W WO 2009040754 A2 WO2009040754 A2 WO 2009040754A2
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WIPO (PCT)
Prior art keywords
oxo
fluoro
quinolizine
methyl
dihydro
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Ceased
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PCT/IB2008/053903
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WO2009040754A3 (fr
Inventor
Prasad Deshpande
Rajesh Kale
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Wockhardt Research Centre
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Wockhardt Research Centre
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to polymorphic forms of L-lysine salt of S-
  • compositions that include the polymorphic forms of L-lysine salt of S-
  • the fluoroquinolone class of compounds forms an important armamentarium as an antibacterial agent due to their broad spectrum and excellent pharmacokinetics.
  • Several compounds from this class of antibacterials are in clinical use, for example nalidixic acid, norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin.
  • nadifloxacin 9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin- l-yl)-5-methyl- 1-oxo- IH, 5H-benzo[i,j]quinolizine-2-carboxylic acid referred to as nadifloxacin, is reported in U.S. Patent No. 4,399,134.
  • the Japanese patent applications JP 63,192,753A and JP 05,339,238 A disclose racemic nadifloxacin and S-(-)-nadifloxacin.
  • (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl- 1-oxo- 1H,5H benzo[i,j]quinolizine-2-carboxylic acid may have the X-ray diffraction pattern of FIG. 1, infrared spectrum of FIG. 2 and differential scanning calorimetry thermogram of FIG. 5.
  • (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H benzo[i,j]quinolizine-2-carboxylic acid may have the X-ray diffraction pattern of FIG. 3 and infrared spectrum of FIG. 4.
  • compositions that include the crystalline or amorphous polymorphs of L-lysine salt of S- (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j ]quinolizine-2-carboxylic acid; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the methods include providing pharmaceutical compositions that include the crystalline or amorphous polymorphs of L-lysine salt of S- (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j ]quinolizine-2-carboxylic acid and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • FIG. 1 is an X-ray powder diffraction pattern of crystalline S-
  • FIG. 2 is an infrared spectrum in KBr of crystalline S-
  • FIG. 3 is an X-ray powder diffraction pattern of amorphous S-
  • FIG. 4 is an infrared spectrum of amorphous S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxy piperidine-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid lysine salt.
  • FIG. 5 is Differential scanning calorimetry thermogram of crystalline S-
  • the crystalline polymorph is characterized by its X-ray powder diffraction pattern, infrared spectrum and differential scanning calorimetry thermogram as shown in FIGS. 1, 2, and 5, respectively.
  • the amorphous form is characterized by its X-ray powder diffraction pattern and infrared spectrum as shown in FIGS. 3 and 4, respectively.
  • a first aspect of the invention provides a crystalline polymorph of L-lysine salt of S-
  • a second aspect of the invention provides an amorphous polymorph of L-lysine salt of S-
  • a third aspect of the invention provides a process for the preparation of crystalline polymorph of L-lysine salt of S-
  • suitable solvents' includes any solvent or solvent mixture in which S-
  • (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j ]quinolizine-2-carboxylic acid can be solubilized, including, for example, water, alcohols, ketones, nitriles, cyclic ethers, and mixtures thereof.
  • solvents include acetone, acetonitrile, dioxane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, and the like.
  • (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j ]quinolizine-2-carboxylic acid includes one or more of distillation, distillation under vacuum, crystallization, precipitation, cooling, filtration, filtration under vacuum, de- cantation and centrifugation.
  • (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j ]quinolizine-2-carboxylic acid may be dissolved in organic solvent: water mixture by heating to about 60 0 C to about 8O 0 C.
  • L-lysine monohydrate may be added as a solid.
  • the reaction mixture may be stirred for about 1-2 hours at about 7O 0 C to about 8O 0 C where upon a suspension may be obtained.
  • the suspension may be cooled from about 3O 0 C to about 35 0 C and may be filtered under suction to obtain a crystalline solid.
  • a fourth aspect of the invention provides a process for the preparation of amorphous form of L-lysine salt of S-
  • suitable solvents' includes any solvent or solvent mixture in which S-
  • (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j ]quinolizine-2-carboxylic acid can be solubilized, including, for example, water, alcohols, ketones, nitriles, and mixtures thereof.
  • solvents include acetone, acetonitrile, methanol, ethanol, propanol, isopropanol, and the like.
  • (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j ]quinolizine-2-carboxylic acid includes one or more of distillation, distillation under vacuum, crystallization, precipitation, cooling, filtration, filtration under vacuum, de- cantation and centrifugation.
  • Examples of anti- solvents that may be added to precipitate the amorphous form of L- lysine salt of S- (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j ]quinolizine-2-carboxylic acid include hydrocarbons such as hexane, cyclohexane, toluene, heptane, pentane and octane; lower alkyl ethers such as diethylether, diiso- propylether, and mixtures thereof.
  • (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j ]quinolizine-2-carboxylic acid may be dissolved in a suitable solvent including, for example, alcohols such as methanol, ethanol, propanol, isopropanol, and the like.
  • L- lysine and water may be added to this solution and the reaction mixture may be heated.
  • the reaction mixture which may be turbid initially, may turn to a clear solution when heated at about 65 0 C to about 7O 0 C.
  • the reaction mixture may be stirred for about 15-30 minutes at a temperature from about 65 0 C to about 7O 0 C.
  • the reaction mixture may be cooled to room temperature and the solvent may be evaporated under vacuum at a temperature below 25 0 C to obtain an oily residue.
  • the oily residue may be stirred with an anti-solvent such as diethyl ether, dioxane, hexane, heptane, or pentane where upon a solid may be precipitated.
  • the solid so obtained may be filtered and dried under vacuum at a temperature from about 25 0 C to about 30 0 C to get a free flowing amorphous solid.
  • a fifth aspect of the invention provides pharmaceutical compositions containing crystalline or amorphous polymorphs of L-lysine salt of S-
  • compositions may be prepared by combining the polymorphs of this invention with a suitable carrier, diluent, solvent or excipient.
  • suitable carrier diluent, solvent or excipient.
  • the compositions may be prepared as solid, liquid, parenteral or topical dosage forms.
  • the pharmaceutical compositions of the polymorphs of invention may be prepared as oral solid dosage forms.
  • the dosage forms can be prepared by mixing the polymorphs of the invention with other ingredients.
  • the other ingredients utilized to formulate solid oral dosage forms may include inert ingredients such as microcrystalline cellulose, methyl cellulose, and the like, suitable sweetening and/or flavouring agents, and preservatives.
  • Such solid oral dosage forms or dry formulations suitable for preparation of suspensions may be formulated such that they may contain an effective dose of the compound of the invention. In general, the solid dosage forms containing 100 mg-2000 mg of the compound of the invention are contemplated.
  • the preparations suitable for oral suspension may also contain a similar dosage.
  • the pharmaceutical formulations can be formulated together with auxiliaries and additives usually employed in pharmacy, such as tablet binders, fillers, preservatives, tablet disintegrating agents, flow regulating, agents, plasticizers, wetting agents, dispersing agents, emulsifiers, solvents, pH altering additives, flavorings, and the like.
  • auxiliaries and additives usually employed in pharmacy, such as tablet binders, fillers, preservatives, tablet disintegrating agents, flow regulating, agents, plasticizers, wetting agents, dispersing agents, emulsifiers, solvents, pH altering additives, flavorings, and the like.
  • compositions of the polymorphs of the invention may be prepared as compositions for parenteral administration such as for intramuscular, intravenous or subcutaneous administration.
  • parenteral administration such as for intramuscular, intravenous or subcutaneous administration.
  • suitable diluents which may be used include water, ethyl alcohol, polypropylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters.
  • suitable diluents which may be used include water, ethyl alcohol, polypropylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters.
  • Sodium chloride, glucose or glycerol may also be incorporated.
  • (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j ]quinolizine-2-carboxylic acid in the injectable preparation may be present in the range of 0.1 mg/ml to 100 mg/ml.
  • compositions of the polymorphs of invention may be prepared as compositions for topical administration.
  • compositions for topical administration for example, creams, ointments, sprays, shampoos, lotions, gels, dusting powders, and the like.
  • an effective amount of the polymorphs according to the invention in a topical form may be from about 0.1% to about 10% by weight of the total composition.
  • these may be used as non-sprayable forms, viscous to semisolid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water.
  • Suitable formulations include, but are not limited to, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g. preservatives, antioxidants, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc.
  • auxiliary agents e.g. preservatives, antioxidants, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc.
  • other suitable preparations include sprayable aerosols, wherein the active ingredient is preferably in combination with a solid or liquid inert carrier material.
  • the compounds of the invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123 and 4,008,719; the disclosures of which are hereby incorporated by reference.
  • the total daily dose range is generally from about 200 mg to about 1500 mg of the Lysine salt form. However, the dose may be higher or lower depending on the needs and conditions of the patient.
  • a sixth aspect the invention provides methods of treating bacterial infections using crystalline or amorphous polymorphs of L-lysine salt of S-
  • the polymorphic forms of the invention may be useful in the treatment of humans and animals in need of prophylaxis and/or therapy for systemic or topical bacterial infections especially, resistant gram-positive organism infections, gram-negative organism infections, mycobacterial infections and nosocomial pathogen infections, which composition comprises an amount of the compound of the invention substantially sufficient to eradicate said infections, but not to cause any undue side effects.
  • the compound and compositions of this invention can be administered for prevention of bacterial infections to humans and animals that are at risk of being infected, for example a compound or composition of this invention can be administered to a patient prior to and/or after surgery, health care workers or others who are at risk of being infected.
  • the bacterial infections which can be treated by using the compound and composition comprising the compound of invention are infections such as impetigo, pneumonia, bronchitis, skin and soft tissue infections, respiratory tract infections, pharyngitis, endocarditis, urinary tract infections, gastro-intestinal infections and bacteremias caused by Staphylococcus aureus, coagulase negative staphylococci, me- thicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase negative staphylococci, enterococci, beta-haemolytic streptococci, viridans group of streptococci, mycobacterial infections due to multi-drug resistant M.
  • infections such as impetigo, pneumonia, bronchitis, skin and soft tissue infections, respiratory tract infections, pharyngitis, endocarditis, urinary tract infections, gastro-intestinal infections and bacteremias caused by Staphylococcus aureus, coagulase negative staphylococci
  • tuberculosis and other atypical mycobacteria such as M. intracellulare and M. avium
  • Gram-negative pathogens such as Chryseobacterium meningosepticum, Chryseobacterium indologense and other Gram-negative pathogens such as E. coli, Klebsiella, Proteus, Serratia, Citrobacter, and Pseudomonas.
  • the invention encompasses administering the compound of invention to a human or other animal subject.
  • the compound and compositions to be used in the invention must, accordingly, be pharmaceutically acceptable.
  • a 'pharmaceutically acceptable' component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • the invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
  • the suspension was cooled to 30 0 C to 35 0 C and was filtered under suction to get a crystalline solid.
  • the polymorph was characterized by the following analytical data.
  • DSC Differential Scanning Colorimetry
  • Example-2 Preparation of amorphous S-
  • X-ray Powder Diffraction Analysis 300 mg each of the test sample prepared as above were thinly spread on a sample holder. X-ray powder diffraction analyses (40kv x 40 mA Rigaku D/max 2200) were performed under the conditions listed below:
  • FIG. 5 is a diagrammatic representation of FIG. 5.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des formes polymorphes de sel de L-lysine de l'acide S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypipéridin-1-yl)-5-méthyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylique et sur des procédés de préparation de formes polymorphiques. L'invention porte également sur des compositions pharmaceutiques qui comprennent les formes polymorphiques de sel de L-lysine et de l'acide S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypipéridin-1-yl)-5-méthyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylique et sur l'utilisation des compositions pour le traitement d'infections bactériennes.
PCT/IB2008/053903 2007-09-27 2008-09-25 Polymorphes de sel de lysine et de l'acide s-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypipéridin-1-yl)-5-méthyl-1-oxo-1h,5h-benzo[i,j]quinolizine-2-carboxylique Ceased WO2009040754A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1911MU2007 2007-09-27
IN1911/MUM/2007 2007-09-27

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WO2009040754A2 true WO2009040754A2 (fr) 2009-04-02
WO2009040754A3 WO2009040754A3 (fr) 2009-09-03

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PCT/IB2008/053903 Ceased WO2009040754A2 (fr) 2007-09-27 2008-09-25 Polymorphes de sel de lysine et de l'acide s-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypipéridin-1-yl)-5-méthyl-1-oxo-1h,5h-benzo[i,j]quinolizine-2-carboxylique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2030620A1 (fr) * 1999-05-07 2009-03-04 Wockhardt Limited Acides carboxyliques (s)-benzoquinolizines et leur utilisation en tant qu'agents antibactériens

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