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WO2006134431A1 - Sel de formiate de la gemifloxacine - Google Patents

Sel de formiate de la gemifloxacine Download PDF

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Publication number
WO2006134431A1
WO2006134431A1 PCT/IB2006/001061 IB2006001061W WO2006134431A1 WO 2006134431 A1 WO2006134431 A1 WO 2006134431A1 IB 2006001061 W IB2006001061 W IB 2006001061W WO 2006134431 A1 WO2006134431 A1 WO 2006134431A1
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WO
WIPO (PCT)
Prior art keywords
gemifloxacin
formate salt
hydrate
water
formate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2006/001061
Other languages
English (en)
Inventor
Neera Tiwari
Hashim Nizar Poovanathil Nagoor Meeran
Vinod George
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2006134431A1 publication Critical patent/WO2006134431A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel formate salt of gemifloxacin or its hydrate, processes for its preparation, pharmaceutical composition incorporating the salt, and methods of treatment comprising administrating the formate salt of gemifloxacin or its hydrate.
  • Gemifloxacin which is chemically 7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)-l- pyrrolidinyl]-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-l, S-naphthyridme-S-carboxylic acid, is represented by Formula I
  • the formate salt of gemifloxacin or its hydrate shows a potent antibacterial activity against broad pathogenic strains, including both gram-positive and gram-negative strains, with comparable solubility in water so as to exhibit a good antibacterial activity in the biological systems.
  • Several processes for the preparation of gemifloxacin have been described in the literature, such as in U.S. 5,633,262, WO 01/18002, U.S. 6307059, Journal of Medicinal Chemistry (1997), 40 (22), 3584, which are herein incorporated by reference. While U.S.
  • naphthyridine carboxylic acid derivatives including gemifloxacin can form salts with inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, etc. as well as organic acid such as acetic acid, succinic acid, benzoic acid, sulphonic acids, etc., it is believed that no such salt has been prepared.
  • inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, etc.
  • organic acid such as acetic acid, succinic acid, benzoic acid, sulphonic acids, etc.
  • U.S. 6,723,734 discloses methane sulphonic acid salt of gemifloxacin along with its process of preparation.
  • WO 00/17199 and WO 01/18002 disclose improved processes for the preparation of methane sulphonate salt of gemifloxacin and its hydrates.
  • WO 03/087100 discloses a process for the preparation of acid salts of gemifloxacin, which does not include the formate salt.
  • the application mentions in the specification that the process disclosed is applicable for different acid salts of gemifloxacin such as salts with hydrochloric acid, methane sulphonic acid, sulphuric acid, and acetic acid, only the methane sulphonic acid salt is specifically prepared.
  • a first aspect of the present invention provides a novel formate salt of gemifloxacin of Formula II
  • a second aspect of the present invention provides a process for preparing the formate salt of gemifloxacin or its hydrate.
  • the process includes contacting gemifloxacin with formic acid in one or more suitable solvents and isolating the formate salt of gemifloxacin or its hydrate.
  • a third aspect of the present invention provides a method of treating bacterial infections comprising administering the formate salt of gemifloxacin or its hydrate.
  • a fourth aspect of the present invention provides a pharmaceutical composition comprising formate salt of gemifloxacin or its hydrate along with one or more pharmaceutically acceptable excipients.
  • FIG. 1 is a powder X-ray powder diffraction (XRD) pattern of gemifloxacin formate hydrate. - A -
  • FIG. 2 is a DSC graph of gemifloxacin formate hydrate.
  • FIG. 3 is a TGA graph of gemifloxacin formate hydrate Detailed Description of the Invention
  • Gemifloxacin formate or its hydrate is a crystalline solid.
  • Crystalline gemifloxacin formate hydrate may be characterized by strong X-ray peaks at about 26.96, 24.52, 23.10, 9.80, 7.62 ⁇ 0.2 degrees two-theta and weak peaks at about 25.30, 25.18, 23.72, 21.36, 14.80, 8.04, 4.88 ⁇ 0.2 degrees two-theta.
  • Crystalline gemifloxacin formate may also be characterized by its DSC and TGA graphs. Gemifloxacin formate obtained by the present invention has an endotherm at about 160°C in the DSC thermogram.
  • the gemifloxacin free base to be used for the preparation of the formate salt can be obtained by any of the methods known in the art including those described in U.S. 5,633,262, WO 01/18002, U.S. 6,307,059, Journal of Medicinal Chemistry (1997), 40 (22), 3584 which are herein incorporated by reference.
  • the starting gemifloxacin free base may be obtained as a solution directly from a reaction mixture in which gemifloxacin is formed and used as such without isolation.
  • Suitable solvents for preparing the formate salt of gemifloxacin or its hydrate are the customary inert solvents that do not change under the reaction conditions.
  • suitable solvents for carrying out the process include water, water-miscible solvents and mixtures thereof.
  • water-miscible solvents as used herein, is meant to include solvents which do not form a two-phase system with water under the given reaction conditions.
  • water-miscible solvents include alcohols, ketones, nitriles, ethers, dipolar aprotic solvents and mixtures thereof.
  • Examples of alcohols include straight and branched-chain lower alcohols such as methanol, ethanol, isopropanol and mixtures thereof.
  • Examples of ketones include acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof.
  • Examples of ethers include tetrahydofuran.
  • Examples of dipolar aprotic solvents include nitriles, dimethylformamide, dimethyl sulphoxide and mixtures thereof.
  • mixture of water and alcohol may be used.
  • water and isopropanol may be used in some particular embodiments.
  • the ratio of water and isopropanol maybe from 1:1 to 1:5, preferably 1:2.
  • Formic acid used for the preparation of gemifloxacin formate may be in the range of about 0.8 to about 2.5 equivalents.
  • the term "contacting" includes dissolving, slurrying, stirring or a combination thereof.
  • the mixture of gemifloxacin free base, formic acid and solvent may be heated from room temperature to 60°C to obtain a clear solution for a time period sufficient to complete the reaction, preferably for about 5 to 15 minutes.
  • the solution of gemifloxacin free base, formic acid and solvent may be treated with a decolorizing agent such as activated charcoal before precipitation.
  • a decolorizing agent such as activated charcoal
  • the formate salt of gemifloxacin or its hydrate may be precipitated out of the solution or the reaction mixture.
  • the precipitation may be spontaneous depending upon the solvent used and reaction conditions.
  • the precipitation may also be facilitated by adding seeds of the formate salt of gemifloxacin or its hydrate.
  • the seeds of gemifloxacin formate may be added at a temperature range of about 25 0 C to 35°C.
  • the precipitation may also be induced by reducing the temperature.
  • Isolation of the formate salt of gemifloxacin may be accomplished by concentration, precipitation, cooling, filtration or centrifugation or a combination thereof followed by drying.
  • the precipitated formate salt of gemifloxacin or its hydrate may be isolated in a solid state by conventional methods such as filtration or centrifugation, optionally followed by washing and/or drying and may be purified by crystallization.
  • the formate salt of gemifloxacin of the present invention has a better solubility and stability as compared to the methane sulphonic acid salt of gemifloxacin reported earlier.
  • the gemifloxacin formate salt of the present invention has a solubility of at least 1 gm in 15 ml water at room temperature.
  • the formate salt of gemifloxacin or its hydrate has a broad antibacterial activity in comparison with the early stage antibacterial compounds, and therefore, has been widely and practically used for treatment of diseases in clinical fields such as acute bacterial exacerbation of chronic bronchitis and community acquired pneumonia.
  • the salt is usually administered as part of a pharmaceutical composition which comprises the formate salt of gemifloxacin or its hydrate, and one or more pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients.
  • the salt may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed, for example, peroral or parental.
  • Any suitable route of administration may be employed, for example, peroral or parental.
  • the filtrate was allowed to cool to 35 0 C and seed crystal of formate salt (0.5 g) was added.
  • the suspension was cooled to 25 0 C and stirred at 20-25°C for 6-8 hours. It was further cooled to 5°C for 1 hour and then filtered.
  • the precipitate was washed with an isopropanol:water (2:1) mixture (200 ml) and then with isopropanol (200 ml).
  • the wet material was dried at 50-55 0 C to give the formate salt of gemifloxacin.
  • Example 2 To a suspension of (R,S)-7-(3 -aminomethyl-4-synmethoxyiminopyrrolidin- 1 -yl)- 1 - cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylic acid (100 g) in a mixture of ethanol (800 ml) and water (400 ml) was added formic acid (11.8 g) at 45-50 0 C and stirred for 10 minutes. To the resulting solution was added activated charcoal (20 g) and the solution was again stirred for 30 minutes at 45-50 0 C and then filtered.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a trait à un nouveau sel de formiate de la gémifloxacine ou son hydrate, à des procédés pour sa préparation, à des compositions pharmaceutiques comportant le sel de formiate, et à des procédés de traitement comprenant l'administration du sel de formiate de la gémifloxacine.
PCT/IB2006/001061 2005-05-03 2006-04-28 Sel de formiate de la gemifloxacine Ceased WO2006134431A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1100/DEL/2005 2005-05-03
IN1100DE2005 2005-05-03

Publications (1)

Publication Number Publication Date
WO2006134431A1 true WO2006134431A1 (fr) 2006-12-21

Family

ID=36933416

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/001061 Ceased WO2006134431A1 (fr) 2005-05-03 2006-04-28 Sel de formiate de la gemifloxacine

Country Status (1)

Country Link
WO (1) WO2006134431A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0688772A1 (fr) * 1994-06-16 1995-12-27 LG Chemical Limited Dérivés de l'acide quinolinecarboxylique ayant des substituants 7-(4-amino-méthyl-3-oxime)-pyrrolidine et procédé pour leur préparation
WO2001018002A1 (fr) * 1999-09-03 2001-03-15 Sb Pharmco Puerto Rico Inc Production de derives d'acide naphtyridine-3-carboxylique
WO2001045679A2 (fr) * 1999-12-22 2001-06-28 Schulz Hans Herrmann Utilisation d'agents chimiotherapeutiques
US20030050321A1 (en) * 1997-03-21 2003-03-13 Lg Chemical Ltd. Salt of naphthyridine carboxylic acid derivative
WO2003087100A1 (fr) * 2002-04-08 2003-10-23 Lg Life Sciences Ltd. Procede de preparation de sels acides de gemifloxacine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0688772A1 (fr) * 1994-06-16 1995-12-27 LG Chemical Limited Dérivés de l'acide quinolinecarboxylique ayant des substituants 7-(4-amino-méthyl-3-oxime)-pyrrolidine et procédé pour leur préparation
US20030050321A1 (en) * 1997-03-21 2003-03-13 Lg Chemical Ltd. Salt of naphthyridine carboxylic acid derivative
WO2001018002A1 (fr) * 1999-09-03 2001-03-15 Sb Pharmco Puerto Rico Inc Production de derives d'acide naphtyridine-3-carboxylique
WO2001045679A2 (fr) * 1999-12-22 2001-06-28 Schulz Hans Herrmann Utilisation d'agents chimiotherapeutiques
WO2003087100A1 (fr) * 2002-04-08 2003-10-23 Lg Life Sciences Ltd. Procede de preparation de sels acides de gemifloxacine

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