Zabofloxacin

UNII-LV66BA6V2G, DW-224a

Molecular Formula: C₁₉H₂₀FN₅O₄

 Molecular Weight: 401.391603

DONG WHA PHARMA SOUTH KOREA in phase 3

1-Cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3.4]oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

poster…..http://www.jmilabs.com/data/posters/ICID2008%5C22008.pdf

Zabofloxacin is being developed as a new fluoroquinolone antibiotic that is a potent and selective inhibitor of the essential bacterial type II topoisomerases and topoisomerase IV. Zabofloxacin is indicated for community-acquired respiratory infections due to Gram-positive bacteria. The aim of this study was to compare the pharmacokinetics (PK) of the zabofloxacin hydrochloride 400 mg capsule (DW224a, 366.7 mg aszabofloxacin) with the PK of the zabofloxacin aspartate 488 mg tablet (DW224aa, 366.5 mg as zabofloxacin) in healthy Korean male volunteers to assess the bioequivalence between the two drug formulations

Zabofloxacin hydrochloride is a fluoroquinolone antibiotic with enhanced in vitro activity against Streptococcus pneumoniae, including strains resistant to other antibiotics. The spectrum of activity of zabofloxacin includes bacterial strains that are responsible for most community-acquired respiratory infections. Phase III clinical studies are currently ongoing at Dong-Wha for the treatment of patients with acute bacterial exacerbation of chronic obstructive pulmonary disease. Phase II trials had been ongoing at IASO; however no recent developments have been reported.The product candidate was originated by Dong Wha. In 2007, Dong Wha granted PB BioSciences worldwide exclusive development and marketing rights, except in Japan, Korea, China, Taiwan, Singapore, Indonesia, India, Thailand, Malaysia, Vietnam, Hong Kong, Australia and New Zealand.

Zabofloxacin was separated using an isocratic elution on a Capcell Pak C18 column using an acetonitrile–methanol–phosphate buffer (1 g of KH₂PO₄ and 1 g of heptane sulfonic acid sodium salt in 720 mL of purified water) and a 1 M tetrabutylammonium dihydrogenphosphate solution (18.5:8.5:72:1, by volume) as a mobile phase at a flow rate of 0.25 mL/min with UV detection at 275 nm. The lower limit of quantification (LLOQ) and the upper limit of quantification (ULOQ) were 100 ng/mL and 20000 ng/mL, respectively, with acceptable linearity in the range from 100 to 20000 ng/mL (R > 0.999). The intra- and inter-day accuracy (RE) ranged from −8.2% to 1.8% and the intra- and inter-day precision (CV) ranged from 3.8% to 10.6% for zabofloxacin. In addition, stock solution stability, recovery, freeze–thaw effects, and short-term and long-term stability met the acceptance criteria.

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Example 1. l-Cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-4- oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid methanesulfonate

30 350mg of

7-[2-(t-buthoxycarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3.4]oct-6-yl]-l- cyclopropyl-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid was dissolved in 5ml of dichloromethane and thereto 0.6ml of trifluoroacetic acid was dropped. The mixture was stirred for 5 hours at room temperature and thereto 10ml (if ethylether was added. It was stirred additionally for 1 hour and thus precipitated solid was filtered, dissolved in 5ml of diluted NaOH and neutralized with diluted hydrochloric acid. The precipitate thus obtained was filtered and dried. The resulting solid was added to 5ml of lN-methanesulfonic acid in ethanol and stirred for 1 hour. Thus obtained precipitate was filtered and dried to give 185g of the titled compound(yield : 47.8%). m.p. : 228- 229 ^°C

1H-NMR(DMSO-dG+CF₃COOD, ppm): 0.97(s, 2H), 1.14(d, 2H), 2.48(s, 3H), 3.57(bs, IH), 3.88(s, 3H), 4.06-4.17(m, 411), 4.40(s, 2H), 4.49(s, 2H), 7.88(d, Hi, J=12.67Hz), 8.49(s, IH).

 

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US20100184795

aspartate of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid comprises a step of reacting 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid with aspartic acid in a solvent. The method can be represented by Scheme 1.

 

Example 1 Preparation of the D-Aspartic Acid Salt of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid

1-Cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (5.0 g) was added to 50% ethanol (80 mL), and then the mixture was stirred at 50° C. for 10 minutes. D-Aspartic acid (2.0 g) was added and then the mixture was stirred at 50° C. for 1 hour. The mixture was cooled to room temperature, and then the resulting solid was collected by filtration. Ethanol (100 mL) was added to the filtrate, and then the mixture was stirred for 30 minutes. The resulting solid was collected by filtration to obtain a total of 5.55 g of the target compound (yield: 83%). Melting point: 200-201° C. ¹H NMR (D₂O): δ 0.97 (bs, 2H), 1.27 (d, 2H), 2.00 (dd, 1H, J=8.8, 17.6 Hz), 2.77 (dd, 1H, J=3.3, 17.0 Hz), 3.53 (bs, 1H), 3.84 (dd, 1H, J=3.3, 8.78 Hz), 4.01 (s, 3H), 4.31-4.45 (m, 8H), 7.46 (d, 1H, J=12.2 Hz), 8.42 (s, 1H).

Example 2 Preparation of L-Aspartic Acid Salt of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid

1-Cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (500 mg) was added to 50% ethanol (20 mL), and then the mixture was stirred at 50° C. for 10 minutes. L-Aspartic acid (174 mg) was added and then the mixture was stirred at 50° C. for 1 hour. The mixture was cooled to room temperature. Ethanol (20 mL) was added to the reaction mixture, and then the mixture was stirred for 30 minutes. The resulting solid was collected by filtration to obtain 550 mg of the target compound (yield: 82%). Melting point: 205-206° C. ¹H NMR (d₆-DMSO): δ 0.93 (d, 2H, J=3.5 Hz), 1.20 (d, 2H, J=6.8 Hz), 2.42 (dd, 1H, J=9.2, 17.3 Hz), 2.59 (dd, 1H, J=3.3, 17.2 Hz), 3.50 (m, 1H), 3.59 (1H, dd, J=3.1, 9.1 Hz), 3.91 (s, 3H), 4.24 (m, 6H), 4.41 (br, 2H), 7.59 (d, 1H, J=12.4 Hz), 8.41 (s, 1H).

Example 3 Preparation of Hydrochloric Acid Salt, Phosphate Salt, and Formate Salt of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid

3-1 Hydrochloric Acid Salt

Ethanol (3 mL) was cooled to 0° C. and acetyl chloride (1.13 mL) was added, and then the mixture was stirred for 30 minutes. 1-Cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (800 mg) was added to the reaction mixture, and then stirred at 0° C. for 30 minutes. Tetrahydrofuran (4 mL) was added, and then the mixture was stirred for 30 minutes. The resulting solid was collected by filtration and dried to obtain 776 mg of the target compound (yield: 89%). Melting point: 244-245° C. ¹H NMR (d₆-DMSO): δ 1.07 (d, 2H, J=4.7 Hz), 1.21 (d, 2H, J=6.8 Hz), 3.68 (m, 1H), 3.94 (s, 3H), 4.17 (m, 2H), 4.40 (s, 2H), 4.53 (s, 2H), 8.03 (d, 1H, J=12.5 Hz), 8.59 (s, 1H).

ref

Subacute toxicity and toxicokinetics of a new antibiotic, DW-224a, after single and 4-week repeated oral administration in dogs.

US4957922 *	Mar 29, 1989	Sep 18, 1990	Bayer Aktiengesellschaft	Infusion solutions of 1-cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid
US5563149 *	Aug 8, 1994	Oct 8, 1996	Cheil Foods & Chemicals, Inc.	Aqueous solutions of pyridone carboxylic acids
US6552196 *	Sep 6, 2001	Apr 22, 2003	Dong Wha Pharmaceutical Industrial Co., Ltd.	Quinolone carboxylic acid derivatives

US2010184795

7-23-2010

ASPARTATE OF 1-CYCLOPROPYL-6-FLUORO-7-(8-METHOXYIMINO-2,6-DIAZA-SPIRO[3.4]OCT-6-YL)-4-OXO-1,4-DIHYDRO-[1,8]NAPHTHYRIDINE-3-CARBOXYLIC ACID, METHOD FOR PREPARING THE SAME, AND ANTIMICROBIAL PHARMACEUTICAL COMPOSITION COMPRISING THE SAME