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Ozenoxacin in phase 3……topical formulation in the treatment of impetigo

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1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1 ,4-dihydro-3- quinolinecarboxylic acid

1-cyclopropyl-8-methyl-7-{5-methyl-6-[(methylamino)methyl]-3-pyridyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid.

Ferrer Internacional (Spain), phase 3 Gram-positive

Ferrer Internacional has completed one Phase III clinical trial to evaluate the topical formulation of ozenoxacin in the treatment of impetigo [

Ozenoxacin 
CAS Number: 245765-41-7Molecular Formula: C21H21N3O3 
Molecular Weight: 363.41 g.mol-1

poster……http://landing.quotientbioresearch.com/blog/bid/50380/Ozenoxacin-Activity-against-Atypical-Bacteria

Ozenoxacin is active against a great number of pathogens, such as Propionibacterium acnes, Staphylococcus aureus, methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) including ciprofloxacin-resistant strains, methicillin-susceptible Staphylococcus epidermidis (MSSE), methicillin-resistant Staphylococcus epidermidis (MRSE), Streptococcus pyogenes, Group G Streptococci, penicillin-resistant Streptococcus pneumoniae, Beta-lactamase positive Haemophilus influenzae, non-typeable strains of Haemophilus influenzae, Beta-lactamase positive Moraxella catarrhalis, Neisseria meningitides, Legionella pneumophila, Mycoplasma pneumoniae, Legionella pneumophila, Mycobacterium tuberculosis, Streptococcus agalactiae group B, Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum Helicobacter pylori, Bacteroides fragilis, Clostridium perfringens, Escherichia coli, quinolone-resistant Escherichia coli, Salmonella spp., Shigella spp., ciprofloxacin-susceptible Pseudomonas aeruginosa, Clostridium difficile, and Listeria monocytogenes.

Ozenoxacin is a novel non-fluorinated quinolone antibacterial agent. It is currently in late stage phase 3 trials for the topical treatment of impetigo. The bacterial action of ozenoxacin is through the dual inhibition of DNA gyrase and topoisomerase IV. Excellent in vitro and in vivo antibacterial activity has been demonstrated in pre-clinical and clinical studies against a broad range of bacterial organisms. This includes organisms with emerging resistance to quinolones. Phase I and II clinical trials have also shown that ozenoxacin is a safe and effective antibacterial agent. No evidence of adverse effects as linked to topically formulated halogenated quinolones has been shown.

Ozenoxacin (I) was firstly disclosed in US6335447, and equivalent patents. Its chemical name is 1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1 ,4-dihydro-3- quinolinecarboxylic acid. Its chemical formula is: H

Figure imgf000003_0001

Ozenoxacin (I)

Topical application of antimicrobial agents is a useful tool for therapy of skin and skin structures infections, sexually transmitted diseases and genital tract infections and some systemic infections susceptible to topical treatment. Topical antimicrobial therapy has several potential advantages compared with systemic therapy.

Firstly, it can avoid an unnecessary exposure of the gut flora which may exert selection for resistance. Secondly, it is expected that the high local drug concentration in topical application and the negligible systemic absorption should overwhelm many mutational resistances. Thirdly, topical applications are less likely than systemic therapy to cause side effects. Accordingly, some topical compositions comprising ozenoxacin have been reported in the art.

JP2002356426A discloses ointments and gels for skin. An ointment comprising ozenoxacin 1%, N-methyl-2-pyrrolidone 8%, propylene glycol 14.9%, oleic acid 0.9%, diisopropanolamine 2.3%, polyethylene glycol 400 20.2%, polyethylene glycol 4000 50.2%, and water 3.2% is reported in Example 2.

JP2003226643A discloses aqueous solutions comprising ozenoxacin, cyclodextrin, and a viscous agent.

EP1731138A1 discloses fine particle dispersion liquid comprising ozenoxacin to be used in the manufacture of pharmaceutical compositions.

WO2007015453A1 discloses lotions comprising ozenoxacin.

JP2007119456A discloses aqueous suspensions containing nanoparticles and solution granules of ozenoxacin to be used in the manufacture of pharmaceutical compositions. Ophthalmic solutions are mentioned preferably. A combined use of ozenoxacin, magnesium ions, and hydroxypropyl-β-cyclodextrin specially for ophthalmic use is disclosed in Yamakawa, T. et al., Journal of Controlled Release (2003), 86(1 ), 101-103.

Semisolid topical compositions are useful alternatives to liquid compositions, because of their better manipulation and consequent patient preferences. However, in spite of the great diversity of components present in the semisolid compositions disclosed in the art, no quantitative stability studies are available for them.

Thus, there is a need of proved stable semisolid topical compositions comprising ozenoxacin as active ingredient, wherein microbiological and therapeutic activities are warranted because of demonstrated durable and prolonged pharmaceutical stability.

Synthesis

US6335447

http://www.google.co.in/patents/US6335447

EXAMPLE 5

To a solution of 0.80 g of 7-[6-({[(benzyloxy)-carbonyl] (methyl)amino}methyl)-5-methyl-3-pyrdyl]-1-cyclo-propyl-8-methyl-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid in 16 ml of acetic acid was added 0.20 g of 5% (w/w) palladium-carbon and the mixture was stirred at ambient temperature and atmospheric pressure for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in a mixed solvent consisting of 3.8 ml of ethanol and 3.8 ml of water. After adding 3.8 ml of an aqueous 1 mol/l sodium hydroxide solution thereto and adjusting the solution to pH 5.5with 1 mol/l hydrochloric acid, 10 ml of chloroform was added thereto. An organic layer was separated and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. Addition of diethyl ether to the obtained residue and filtration of crystals afforded 0.25 g of colorless crystals of 1-cyclopropyl-8-methyl-7-{5-methyl-6-[(methylamino)methyl]-3-pyridyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid.

IR (KBr) cm−1: 3322, 1721; NMR(d1-TFA) δ: 1.2-1.9 (4H, m), 2.94 (3H, s), 3.05 (3H, s), 3.29 (3H, s), 4.6-5.0 (1H, m), 5.12 (2H, s), 7.91 (1H, d, J=8.5 Hz), 8.6-9.0 (2H, m), 9.0-9.3 (1H, brs), 9.75 (1H, s). Melting point: 199° C.

 

  1. Ferrer Group. Key development projects. Available online: http://www.ferrergrupo.com/Innovation_Innovacion-Pipeline-de-proyectos-ENG (accessed on 15 April 2013).
  2. Yamakawa, T.; Mitsuyama, J.; Hayashi, K. In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone. J. Antimicrob. Chemother. 200249, 455–465, doi:10.1093/jac/49.3.455.
  3. Ferrer Internacional. Efficacy and safety of ozenoxacin 1% cream versus placebo in the treatment of patients with impetigo. Available online: http://clinicaltrials.gov/ct2/show/NCT01397461 (accessed on 13 April 2013).
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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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