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zabofloxacin, 219680-11-2

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
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.
…………………………

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).

 

………………………………..

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.

 

Figure US20100184795A1-20100722-C00005

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.

Han J, Kim JC, Chung MK, Kim B, Choi DR.

Biol Pharm Bull. 2003 Jun;26(6):832-9

Determination of zabofloxacin in rat plasma by liquid chromatography with mass spectrometry and its application to pharmacokinetic study.

Jin HE, Lee KR, Kang IH, Chung SJ, Shim CK.

J Pharm Biomed Anal. 2011 Mar 25;54(4):873-7. doi: 10.1016/j.jpba.2010.11.001. Epub 2010 Nov 9.

Kosowska-Shick, K.; Credito, K.; Pankuch, G.A.; Lin, G.; Bozdogan, B.; McGhee, P.; Dewasse, B.;
Choi, D.-R.; Ryu, J.M.; Appelbaum, P.C. Antipneumococcal activity of DW-224a, a new
quinolone, compared to those of eight other agents. Antimicrob. Agents Chemother. 2006, 50,
2064–2071.

Park, H.-S.; Kim, H.-J.; Seol, M.-J.; Choi, D.-R.; Choi, E.-C.; Kwak, J.-H. In vitro and in vivo
antibacterial activities of DW-224a, a new fluoronaphthyridone. Antimicrob. Agents Chemother.
2006, 50, 2261–2264.

Dong Wha Pharmaceutical Co. Ltd. A study to evaluate efficacy and safety profile of
Zabofloxacin tablet 400 mg and moxifloxacin tablet 400 mg. Available online:
http://www.clinicaltrials.gov/ct2/show/NCT01658020 (accessed on 15 July 2013).

 Dong Wha Pharmaceutical Co. Ltd. A new quinolone antibiotic. Available online:
http://www.dong-wha.co.kr/english/rnd/rnd02_03.asp (accessed on 15 April 2013).

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
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
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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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