Publication Classification
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`(200601)
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`(2006.01)
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`(52) U.S. Cl. .............. .. 514l217.07; 514/212.08; 514K218
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`Int C!
`A613. 31/55
`A6111" 31/551
`A6]P 31/04
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`I|l|||llllllllllllllll|l||l|ll|||||||ll||||||||l||l| |l||||||||||||||||l|||||l||Il|||l|l||
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`US 2009008233'7A1
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`(19) United States
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`(12) Patent Application Publication (10) Pub. No.: US 2009/0082337 A1
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`(43) Pub. Date:
`Venkastesh et al.
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`Mar. 26, 2009
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`(76)
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`(54) COMPOSITIONS COMPRISING QUINOLONE
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`AND METHODS FOR TREATING OR
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`CONTROLLING Il\FECTIONS
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`Srini Venkastesh, Pittsford, NY
`Inventors:
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`(US); Hnngna Wang, Fall‘pOI‘I, NY
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`(US); Erning Xia, Penfield, NY
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`(US); Matthew S. Jonasse,
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`Webster, NY (US)
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`Correspondence Address:
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`Bauscl.1'& Lamb Incorporated
`One Bausch & Lomb Place
`Rochester, NY 14604-2701 (US)
`_
`APPL N0"
`Filed:
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`121205946
`Sep. 8, 2008
`Related US. Application Data
`Provisional application No. 60/974,141, filed on Sep.
`21, 2007.
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`(57)
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`ABSTRACT
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`Compositions for treating or controlling infections comprise
`a fluoroquinolone having Formulae 1-VIII and have a pie] in
`the range from about 3.5 to about 5.5 or from about 10.5 to
`about 12. Methocis for treating or controlling such infection
`use such compositions. Such compositions and methods can
`deliver a higher amount ofthe fiuoroquinolone to the affected
`site.
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`SENJU-MITSUBISHI 2089
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`

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`Patent Application Publication
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`Mar. 26, 2009
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`US 2009l0082337 A1
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`FIG.1
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`C3)
`2
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`C)
`H
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`—t
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`1--1
`«=3
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`0.01
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`(10113!!!) Kuuqnlos
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`

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`US 2009/0082337 A1
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`Mar. 26, 2009
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`COMPOSITIONS COINIPRISING QUINOLONE.
`AND METHODS FOR TREATING OR
`CONTROLLING INFECTIONS
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`CROSS-REFERENCE
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`[0001] This application claims the benefit of Provisional
`Patent Application No. 60/974,141 filed Sep. 21, 2007 which
`is incorporated by reference herein.
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`BACKGROUND OF THE INVENTION
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`[0007] Quinolones comprise a family of newer antibacte-
`rial agents, some of which have been used for the foregoing
`conditions. However, quinolones typically l1ave low solubil-
`ity, and thus, extra measures have been used to increase their
`availability at the target sites.
`[0008] An additional challenge in the treatment of infec-
`tions is the emergence of bacterial resistance to antibiotics.
`Such resistance may be attributed to prior widespread, and
`largely effective, therapeutic and prophylactic use of antibi-
`otics, which, unfortunately, over time has also selected for
`resistant strains ofvarious bacterial pathogens. Ofparticular
`concern to the public health have been the emergence and
`proliferation of bacterial strains that are resistant to multiple
`antibiotics in the current arsenal of antimicrobial agents.
`Therefore, a condition may not respond to an initially pre-
`scribed therapy, and, in such a case, another medicament must
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`be given, resulting in delayed control ofthe pathogen.
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`[0009] Therefore, there is a continued need to develop
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`improved pharmaceutical compositions for combating infec-
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`tions. It is also very desirable to provide pharmaceutical com-
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`positions that can overcome at least some ofthe shortcomings
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`of prior-art antimicrobial agents.
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`SUMMARY OF THE INVENTION
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`[0010]
`In general, the present invention provides pharma-
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`ceutical compositions and methods using such compositions
`for the treatment or control of infections.
`[0011]
`In one aspect, the present invention provides phar-
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`maceutical compositions and methods using such composi-
`tions for the treatment or control of infections of an eye, an
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`ear, a portion of a respiratory system, or a combination
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`thereof.
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`In another aspect, a pharmaceutical composition
`[0012]
`comprises a high concentration of a quinolonc soluble in a
`pharmaceutically acceptable vehicle.
`[0013]
`In still another aspect, the pharmaceutical composi-
`tion comprises an aqueous solution.
`[0014]
`In yet another aspect, the pharmaceutical composi-
`tion is effective against at least a bacterium that is resistant to
`at least a prior-art antibacterial agent.
`[0015]
`In a further aspect, such quinolone comprises at
`least one member of a family of fluoroquinolones that have
`Fonnula I or salts thereof,
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`O
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`(I)
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`OR‘
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`N
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`2
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`wherein R‘ is selected from the group consi sting ofhydrogen,
`unsubstituted lower alkyl groups, substituted lower alkyl
`groups, cycloalhyl groups, unsubstituted C5-C24 aryl groups,
`substituted C5-C24 aryl groups, unsubstituted C5-C2,, het-
`eroaryl groups, substituted C5-C24 heteroaryl groups, and
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`[0002] The present invention relates to compositions and
`methods for treating or controlling infections. In particular,
`the present invention relates to such compositions comprising
`a quinolonc carboxylic acid or a derivative thereof, and to
`rnethods of using such compositions.
`[0003] Pathogens continue to pose a serious threat to public
`health as indicated by a worldwide resurgence of diseases
`caused by bacteria, fungi, and/or viruses. Infections by pat11o-
`genie microorganisms afi'cct a large number ofpatients every
`year. Common infections include those of the eye, ear, and
`respiratory system. An experienced medical practitioner
`often can determine the etiology of an infection and, there-
`fore, prescribe an effective treatment. However, infections are
`ofien caused by mixed types ofmicroorganisms that may not
`be immediately obvious on presentation. Consequently, an
`initial treatment regimen may not be immediately effective
`and must be replaced with another. In cases where the patients
`are especially vulnerable, such as those with a compromised
`immune system, a delayed onset of a beneficial effect of the
`treatment may lead to increased risk ofmore serious compli-
`cations.
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`[0004] Otitis media, an infection of the middle ear, is a
`majorworldwide infection in children. By the age of 2 years,
`seventy percent of children have experienced at least one
`episode of acute otitis media (“AOM”). T. Heikkinen et a1.,
`Cliiz. Microbial. REM, Vol. 16, No.2, 230 (2003). Otitis media
`can also occur in adults. AOM is generally considered a
`bacterial infection that is treated with antibiotics. The three
`most common bacteria isolated from the middle ear fluid
`(“MEI-"") are Streptococcuspneumoniac, Haenrophflrrs influ-
`enzae, and Moraxelia catarrlralis. See; e.g., J. T. Kirchener,
`American Family Plrysician, Apr. 15, 1999. In cases of otitis
`externa, the most conunon bacteria are Pseudomonas aerrrgi-
`nose and Staphylococcus aureus. Fungi have also been found
`to a lesser extent in cases of otic in.fections.
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`Infections of the upper respiratory system are also
`[0005]
`common. The common cold is mostly ofviral etiology. How-
`ever, bacteria and fungi have also often caused other infec-
`tions of the upper respiratory system. Bacteria are the most
`common infectious agents in sinusitis. Streptococcus pneu-
`moniae, Haemoplzilus frrfirrenzae, and Moraxella cafarrizalis
`have been found in most of cases of sinusitis. Other possible
`bacterial culprits include other streptococcal strains and Sta-
`plzylococcus arrrerrs.
`[0006] Keratitis and conjunctivitis, two common ocular
`infections, are caused mostly by bacteria, fungi, andfor
`viruses. Among these microorganisms, numerous cocci (Sta-
`phylococcus, Streptococcus, and Neisseria species) and
`bacilli (Corgvnebacterium, Propionobacrerirrnr, Clostridizrrrr,
`Pseudomonas, Klebsiella, Henropbilrrs, Moraxelia, Proteus,
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`

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`Mar. 26, 2009
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`US 2009/0082337 A1
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`group, and amino groups substituted with one or two lower
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`alkyl groups; R3 is selected from the group consisting of
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`hydrogen, unsubstituted lower alkyl groups, substituted
`lower alley] groups. cycloalkyl groups, unsubstituted lower
`alkoxy groups, substituted lower alkoxy groups, unsubsti-
`tuted C5-C24 aryl groups, substituted C5-C24 aryl groups,
`unsubstituted C5-C24 heteroaryl groups, substituted C5-C24
`heteroaryl groups, unsubstituted C5-C24ary1oxy groups, sub-
`stituted C5-C34 aryloxy groups, tuisubstituted C5-C24 l1et-
`eroaryloxy groups, substituted C5-C24 heteroaryloxy groups,
`a11d groups that can be hydrolyzed in living bodies; X is
`selected from the group consisting of halogen atoms; Y is
`selected from the roup consisting ofCH3, 0, S, SO, S02, and
`NR‘, wherein R is selected from the group consisting of
`hydrogen, unsubstituted lower allcyl groups, substituted
`lower alkyl groups, and cycloalhyl groups; and Z is selected
`from the group consisting of oxygen and two hydrogen
`__atoms; and wherein the compositions are capable of inhibit-
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`ing a growth or survival of mixed types of microorganisms
`causing said infections.
`‘
`[0016]
`In still another aspect, said quinolone comprises a
`member of a family offluoroquinoloneshaving Formula II or
`salts thereof,
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`(11)
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`[0023] As used herein, the term “lower allryl” or “lower
`alkyl group" means a C,-C, 5 linear- or branched-chain satu-
`rated aliphatic hydrocarbonmonovalent group, which may be
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`unsubstituted or substituted. The group may be partially or
`completely substituted with halogen atoms (F, Cl, Br, or I).
`Non-limiting examples of lower alkyl groups include methyl,
`ethyl, n-propyl, l-methylethyl (or isopropyl), n-butyl, n—pen-
`tyl, 1,1-dinrelhylethyl (or t-butyi), and the like. It may be
`abbreviated as “Alk”.
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`[0024] As used herein, the term “lower alkoxy” or “lower
`alkoxy group” means a C ,-C, 5
`linear- or branched-chain
`saturated aliphatic alkoxy monovalent group, which may be
`unsubstituted or substituted. The group may be partially or
`completely substituted with halogen atoms (F, Cl, Br, or I).
`Non-limiting examples oflower alkoxy groups include 1neth-
`oxy, ethoxy, n-propoxy, 1-metlryletlioxy (isopropoxy), n-bu-
`toxy, n-pentoxy, t-butoxy, and the like.
`[0025] The term “cycloalkyl” or “cycloalkyl group” means
`a stable aliphatic saturated 3- to 15-membered monocyclic or
`polycyclic monovalent radical consisting solely of carbon
`and hydrogen atoms which may comprise one or more fused
`orbridged ring(s), preferably a 3- to 7-uiembered monocyclic
`rings. Other exemplary embodiments of cycloall-zyl groups
`include 7- to 10-rnembered bicyclic rings. Unless otherwise
`specified, the eyeloallcyl ring may be attached at any carbon
`atom which results in a stable structure and, if substituted,
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`may be substituted at any suitable carbon atom which results
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`in a stable structure. Exemplary cycloalky] groups include
`cyclopropyl, cyclobutyl, cyelopcntyl, cyclohexyl, cyclohep-
`tyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adaman-
`tyl, tetrahydronaphthyl (tetralin), 1-decalinyl, bicyclo[2.2.2]
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`l-mcthylcyclopropyl,
`octanyl,
`2-methylcyclopcntyl,
`2-methylcyclooctyl, and the like.
`[0026] As used herein, the term “aryl" or “aryl group"
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`means an aromatic carbocyclic monovalent or divalent radi-
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`cal. In some embodiments, the aryl group has a number of
`wherein R‘, R3, X, Y, and Z have the meanings as disclosed
`carbon atoms from 5 to 24 and has a single ring (c.g., phcnyl
`above; and wherein the composition is capable of inhibiting a
`or phenylene), multiple condensed rings (e.g., naphthyl or
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`growth or survival ofmixed types ofmicroorgatiisrns causing
`anthranyl), or multiple bridged rings (e.g., biphenyl). Unless
`an infection.
`otherwise specified, the aryl ring may be attached at any
`[0017]
`In still another aspect, the present invention pro-
`suitable carbon atom which results in a stable structure and, if
`vides a method for treating or controlling an infection of an
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`substituted, may be substituted at any suitable carbon atom
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`eye, an car, a portion ofa respiratory system, or a combination
`which results in a stable structure. Non-limiting examples of
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`thereof. The method comprises adrnjni stering a composition
`aryl groups include phenyl, naphthyl, anthryl, phenanthryl,
`comprising a fiuoroquinolone having Formula I or II soluble
`indanyl, indenyl, biphenyl, andthe like. It may be abbreviated
`as “Ar".
`therein at a high concentration to a site of infection to treat or
`control said infection.
`[0018]
`In one embodiment, the method comprises topically
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`administering such a composition. In another embodiment,
`the method comprises orally administering such a composi-
`tron.
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`[0027] The term “heteroaryl" or “heteroaryl group" means
`a stable aromatic monocyclic or polycyclic monovalent or
`divalent radical, which may comprise one or more fused or
`bridged r-ing(s). In some embodiments, the heteroaryl group
`has S-24 members, preferably a 5- to 7-membered monocy-
`clic or 7- to 10-membered bicyclie radical. The heteroaryl
`group can have from one to four heteroatoms in the ring(s)
`independently selected from nitrogen, oxygen. and sulfur,
`wherein any sulfiir heteroatoms may optionally be oxidized
`and any nitrogen lreteroatonl may optionally be oxidized or be
`quaternized. Unless otherwise specified, the heteroaryl ring
`may be attached at any suitable heteroatom or carbon atom
`which results in a stable structure and, if substituted, may be
`substituted at any suitable heteroatom or carbon atom winch
`results in a stable structure. Non-limiting examples of hot-
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`FIG. 1 shows the solubility ofthe compound having
`[0021]
`Formula IV in USP water.
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`[0019]
`In yet another aspect, said infection comprises
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`infections of an eye, an ear, a portion of an upper respiratory
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`system, or a combination thereof.
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`[0020] Other features and advantages of the present inven-
`tion will become apparent from the following detailed
`description and claims and the appended figures.
`BRIEF DESCRIPTION OF THE FIGURE
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`N
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`2.
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`Na,
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`Mar. 26, 2009 _
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`US 2009/0082337 Al
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`indolizinyl,
`triazinyl,
`pyridaziuyl, pyrimidiiiyl, pyrazinyl,
`groups, cycloalkyl groups, unsubstituted C5-C24 aryl groups,
`azaindolizinyl, indolyl, azaindolyl, diazaindolyl, dihydroin-
`substituted C5-C24 aryl groups, unsubstituted C5-C24 het-
`
`
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`dolyl, diltydroazaindoyl,
`isoindolyl, azaisoindolyl, benze-
`
`
`eroaryl groups, substituted C5-C24 heteroaryl groups, and
`furanyl, furanopyridinyl, furanopyrimidinyl, furanopyrazi-
`
`groups that can be hydrolyzed in living bodies; R2 is selected
`dihydrobenzofuranyi,
`nyl,
`furanopyridazinyl,
`from the group consisting ofhydrogen, unsubstituted amino
`dihydrofuranopyridinyl,
`diliydrofuranopyrimidinyl,
`ben-
`group, and amino groups substituted with one or two lower
`zotliienyl, thienopyri dinyl, tliienopyriniidinyl, thienopyrazi-
`allcyl groups; R3 is selected from the group consisting of
`
`nyl,
`lhieuopyridazinyl,
`dihydrobenzothienyl,
`dihy-
`hydrogen, unsubstituted lower allcyl groups, substituted
`
`drothienopyridinyl, dihydrothienopyriniidinyl,
`indazolyl,
`lower alltyl groups, cycloallryl groups, unsubstituted lower
`azaindazolyl, diazaindazolyl, benzimidazolyl,
`i1nidazopy-
`alkoxy groups, substituted lower alkoxy groups, unsubsti-
`ridinyl, benztlliazolyl, thiazolopyridinyl, thiazolopyrimidi-
`tuted C5-C24 aryl groups, substituted C5-C24 aryl groups,
`nyl, beuzoxazolyl, benzoxazinyl, benzoxazinonyl, oxazol-
`unsubstituted C5-C2,, heteroaryl groups, substituted C5-C24
`opyridiiiyl, oxazolopyrimidinyl, bcnzisoxazolyl, purinyl,
`heteroaryl groups, unsubstituted C5-C2,, aryloxy groups, sub-
`cliromanyl, azacliroinanyl, quinolizinyl, quiuolinyl, dihydro-
`stituted C5-C24 aryloxy groups, unsubstituted C5-C24 het-
`quinolinyl, tetraliydroquinolinyl, isoquinolinyl, dihydroiso-
`eroaryloxy groups, substituted C5-C24 hctcroaryloxy groups,
`
`
`
`quinolinyl, tetrahydroisoquinolinyl, cinnolinyl, azacinnoli-
`and groups that can be hydrolyzed in living bodies; X is
`nyl,
`phthalazinyl,
`azaphthalazinyl,
`quinazolinyl,
`selected from the group consisting of halogen atoms; Y is
`azaquinazolinyl, quinoxalinyl, azaquinoxalinyl, naphthyridi-
`selected from the group consisting ofCH3, 0, S, S0, S02, and
`nyl, dihydronaphtliyridiriyl,
`tetrahydronaphtliyridinyl, pte-
`NR4, wherein R4 is selected from the group consisting of
`
`ridinyl, carbazolyl, acridinyl, plienazinyl, phenotliiazzinyl,
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`hydrogen, unsubstituted lower alkyl groups, substituted
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`and phenoxazinyl, and the like.
`lower all-:yl groups, and cycloalkyl groups; and Z is selected
`[0028]
`In general, the present invention provides a pharma-
`from the group consisting of oxygen and two hydrogen
`ceutical coiiiposition and a method for treating or controlling
`atoms; and wherein the compositions are capable of inhibit-
`an infection.
`ing a growth or survival of mixed types of microorganisms
`causing said infections.
`[0036]
`In another aspect, said infection is caused by mixed
`types of bacteria.
`[0037]
`In one aspect, said infection is selected from the
`group consisting ofotitis, sinusitis, nasophrayngitis, orophia-
`yngitis, cpiglottitis, laryngotrachcitis, bronchitis, bronchioli-
`tis,
`pneumonia,
`keratitis,
`conjunctivitis,
`blepharitis,
`
`hordeolum, phlyctenulosis, endophtlialmitis, preseptal and
`orbital cellulites, dacryocystitis, and combinations thereof.
`[0033]
`In one aspect, R1 is selected from the group consist-
`ing of hydrogen, C,-C5 (or alternatively, C,-C3) substituted
`and unsubstituted alkyl groups, C3-Cm (or alternatively,
`
`C3-C5)cycloa1kyl groups, C5-C1,, (or zdtematively, C5-C14, or
`C5-Cm, or C5-Cm) substituted and unsubstituted aryl groups,
`C5-C14 (or alteniatively, C6-C14, or C5-Cm, or C6-Cw) sub-
`stituted and unsubstituted heteroaryl groups, and groups that
`can be hydrolyzed in living bodies. In one embodiment, R‘ is
`selected from the group consisting ofC,-C5 (or alternatively,
`C,-C3) substituted and unsubstituted alkyl groups.
`[0039]
`In another aspect, R2 is selected from the group
`consisting of ‘unsubstituted amino group and aniino groups
`s~iil‘p;§1tuted with one or two C,-C5 (or alternatively, C,-C3)
`a
`groups.
`[0040]
`In still another aspect, R3 is selected from the group
`consisting of hydrogen, C,-C5 (or alternatively, C,-C3) sub-
`stituted and unsubstituted alkyl groups, C3-Cm (or alterna-
`tively, C3-C_.=) cycloalkyl groups, C,-C,
`(or alternatively,
`E31-C13) substitpteclcanél umubétitgted alkExyCgro)upsl,)C5-C613
`or a ternative y,
`-
`, or
`-
`, or
`-
`su stitut
`and unsubstituted 6aryIl4 groulfs, 85-C14 6(ormalternatively,
`C6-CM, or C5-C,9, or C5-Cw) substituted and unsubstituted
`heteroaryl groups, and C5-C14 (or alternatively, C5-CH, or
`C5-Cm, or C5-Cm) substitutecl and unsubstituted aryloxy
`groups, In one embodiment, R isselected from the group
`consisting of C3-C“, (or alternatively, C3-C5) cycloalkyl
`groups.
`
`In one aspect, the present invention provides phar-
`[0029]
`maceutical compositions and methods using such composi-
`tions for the treatment or control of infections of an eye. an
`car, a portion of a respiratory system, or a combination
`thereof.
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`In another aspect, a pharmaceutical composition
`[0030]
`comprises a high concentration of a quiuolone soluble in a
`
`pharmaceutically acceptable vehicle.
`[0031]
`In a still another aspect, said concentration is greater
`than about 0.05 percent by weight (or, alternatively, greater
`than about 0. 1, or 1 percent by weight) of the total compo-
`sition.
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`[0032]
`In still another aspect, said concentration is in the
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`range from about 0.05 percent to about 2 percent by weight
`(or, alternatively, from about 0.05 percent to about I percent
`by weight) of the total composition.
`[0033]
`In yet another aspect, the pharmaceutical composi-
`tion comprises an aqueous solution.
`[0034]
`In yet another aspect, the pharmaceutical composi-
`tion is eflective against at least a bacterium that is resistant to
`at least a prior-art antibacterial agent.
`[0035]
`In a fiirther aspect, such quinolone comprises at
`least one member of a family of fluoroquinolones that have
`Formula I or salts thereof,
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`o
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`(1)
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`on‘
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`l
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`N
`I
`R3
`
`X
`
`r
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`F”\
`Y
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`2
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`R2
`
`[0041]
`
`In yet another aspect, X is selected from the group
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`US 2009/0082337 A1
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`Mar. 26, 2009
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`“"3
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`0
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`O
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`OH
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`|
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`N
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`%
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`0
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`O
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`‘V’
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`F
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`N
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`C]
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`In a further aspect, Y is CH: and Z conipiises two
`{0042]
`hydrogen atoms.
`[0043]
`In still a1iotheraspect,Y is NH, 7. is o, and X is (:1.
`[0044]
`Some non-limiting ineiiibers of the family of com-
`pounds having Formula I are shown in Table 1. Other com-
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`pounds oftlie family not listed in Table 1 are also suitable in
`
`Selected situations.
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`TABLE 1
`
`
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`
`
`Some Selected Pluoroquuiolones
`
`
`
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`
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`
`
`
`
`NH;
`
`
`Compound R‘
`R2
`I
`R’
`x Y
`z
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`
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`F
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`1
`2
`3
`4
`
`H
`H
`H
`H
`
`11
`NH2
`NH;
`NI-I(CH_,)
`
`Cl CH,
`CH,
`
`
`Cl CH2
`CH,
`cyclopropyl Cl CH;
`cycloprcpyl Cl CH2
`
`
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`
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`
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`
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`
`
`2H
`2H
`2H
`2}!
`
`
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`_
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`|
`
`N
`
`OH
`
`Cl
`
`N
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`
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`NH;
`
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`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`
`18
`19
`20
`31
`22
`33
`24
`
`25
`
`Cl CH2
`cyclopropyl
`CH3 NH(CI-I3)
`Cl CH2
`cyclopropyl
`CH3 N(CH3)2
`Cl CH2
`cyclopropyl
`CHJ NH(C2H5)
`Cl CH2
`cyclopmpyl
`CH3 NH(C3H7)
`C1 CH2
`CH3 N(CH3)(C2H5] Wclopmpyl
`cl NH
`H
`NH:
`cyclopmpyl
`CH; N'H(CH3)
`cyclopropyl Cl NH
`
`0
`0
`0
`0
`0
`0
`O
`
`O
`
`_
`_
`_
`In still other einbodinieiits, the fiuoroquinolone car-
`E0047]
`boxylic acid included in a composition of the present inven-
`tion has Formula VII or VIII.
`
`(VII)
`
`(V111)
`
`O
`
`O
`
`OH
`
`OH
`
`0
`
`N
`
`O
`
`\’
`i
`
`K
`
`|
`
`F
`
`N
`
`51'
`’NH;
`
`F
`
`O
`
`/“‘N
`
`HN
`
`0
`
`'-,
`
`Cl
`
`Cl
`
`
`
`In one embodiment, the fluoroquinolone carboxylic
`[0045]
`acid included in a composition of the present invention has
`Formula II].
`
`CH1}
`
`1-}
`
`2H
`
`cyelopropyl Cl NH
`
`O
`
`
`
`
`
`
`
`
`
`
`N(CH3)2
`H
`NH-L,
`CH3
`C2H5 NH2
`H
`NH;
`H
`NH;
`H
`NT-I(C2H5)
`H
`N1-I(C2H5]
`H
`NH2
`H
`NH2
`H
`NH2
`H
`NH;
`H
`NI-I2
`CH, NH2
`
`
`
`
`
`
`
`
`
`
`
`
`
`2H
`C] CH;
`cyclopropyl
`2H
`cyclopropyl Cl CH2
`21-!
`cyclcpropyl Cl CH;
`2H
`cyclopi-opyl
`F
`CH2
`2H
`cyclopropyl Br CH;
`2H
`cyclopmpyl Cl
`CH-_,
`2H
`cyclopropyl
`F
`CH2
`2H
`cyclupcntyl Ci CH2
`
`0
`cyclopropyl
`Cl CH2
`0
`cyclopropyl
`F
`CH2
`0
`cyclopropyl Br CH2
`cyclopropyl
`Cl CH(C_;H5) O
`cyclopropyl
`Cl CH2
`0
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`

`
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`Mar. 26, 2009
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`US 2009/0082337 A1
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`cillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, ben-
`In still another aspect, a composition of the present
`[0048]
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`invention comprises an enantiomer of one of the compounds
`zylpenicillinic acid, benzylpenicillin sodium, carbenicillin.
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`having Formula I, II, or III.
`carindacillin, clometocillin, cloxacillin, cyclacillin, diclox-
`
`[0049]
`In still another aspect, a composition of the present
`acillin, epicillin, fenbenicillin, fioxacillin, hetacillin, lena-
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`invention comprises a mixture of enantiomers of one of the
`mpicillin, metampicillin, methicillin sodium, nrezlocillin,
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`compounds having Formula I, II, or III.
`nafcillin sodium, oxacillin, penamecillin, penethamate
`[0050]
`In yet another aspect, a composition of the present
`hydriodide, penicillin G benethamine, penicillin G benza-
`invention has apl-I inthe range from about 3.5 to about 5.5 (or.
`tl1i.ne, penicillin G benzhydrylamine, penicillin G calcium,
`alternatively, from about 3.5 to 5, orfrom about 4 to 5, or from
`penicillin G hydrabamine, penicillin G potassium, penicillin
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`about 4 to 5.5), or from about 10.5 to about 12 (or, alterna-
`
`G procaine, penicillin N, penicillin O, penicillinV, penicillin
`
`tively, from about 10.5 to 11, or from about 11 to 12).
`V henzathine, penicillin V hydrabatnine, penimepicycline,
`
`[0051]
`In a further aspect, a composition of tl1e present
`phenethicillin potassium, piperacillin, pivampicillin, propi-
`
`
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`invention further comprises an additional anti-infective medi-
`
`cillin, quinacillin, sulbenicillin, sultamicillin, talampicillin,
`
`cament that is selected from the group consisting of an anti-
`temocillin, ticarcillin), ritipenem, lincosamides (e.g., clinda-
`
`bacterial agent other than the quinoloues having Formulae I,
`mycin, lincomycin), niacrolidcs (e.g., azithromycin, carbo-
`
`
`II, III, IV, V, VI ,VII, and VIII; an antifungal agent; an antiviral
`mycin, clarithromyciu, dirithromycin, erytltromyciu, eryth-
`
`agent; an antiprotozoal agent; and combinations thereof.
`romycin acistrate, erythromycin estolate, erylhromycin
`[0052]
`In another aspect, the additional antibacterial agent
`glucoheptonate, erythromycin lactobionate, erythromycin
`otherthan the quinolones having Formulae I, II, III, IV, V, VI,
`propionate, erythromycin stearate, josamycin, leucomycins,
`
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`VII, and VIII comprises another quinolone.
`midecamycins, miokamycin, oleandomycin, primycin, rooki-
`
`
`In still another aspect, said another quinolone is
`[0053]
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`tamycin, rosaramicin, roxithromyciu, spiramycin, t.roleando-
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`mycin), polypeptides (e.g., amphomycin, bacitracin, capreo-
`selected from the group consisting of cinoxaciu, ciprofioxa-
`cin, Clinafloxacin, dilloxacin, enoxacin, lleroxacin, gatill0xa-
`mycin,
`colistin,
`enduracidin, enviomycin,
`fusafungine,
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`cin, grepafioxacin,
`levofloxacin,
`lomefloxacin, miloxacin,
`gramicidin s, grarm'cidin(s), mikamycin, polymyxin, pristi-
`namycin, ristocetin, teicoplanin,
`thiostrepton, tuberactino-
`moxifloxacin, nadifioxacin, norfioxacin, ofioxacin, pazu-
`lloxacin, pelloxacin, sitafloxacin, sparlloxacin, temalloxacin,
`rnycin, tyrocidine, tyrothricin, vancomycin, viomycin, vir-
`tosufloxacin, trovafloxacin, mixtures thereof, and combina-
`giniamycin, zinc bacitracin), tetracyclines (e.g., apicycline,
`
`
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`tions thereof.
`
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`chlortetracycline, clomocycline, demeclocycline, doxycy-
`
`
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`cline, guamecycline, lymecycline, meclocycline, methacy-
`[0054]
`In yet another aspect, said another quinolone has a
`
`cline, minocycline, oxytetracycline, peninrepicycline, pipa-
`lVflC9,, value fora Gram-negative bacterium that is lower than
`cycline,
`rolitetracycline,
`sancycline,
`tetracycline),
`that ofthe fiuoroquiuolone having Formula I, II, III, IV, V, VI,
`cycloserine, mupirocin, and tuberin.
`VII, or VIII for the same bacterium, said fluoroquinolone
`being included in the composition. MICE“, is the minimum
`[0056] Non-limiting examples of synthetic antibacterial
`concentration of the active compound required to inhibit
`agents include 2,4-diarninopyrimidines (e.g., brodimoprim,
`
`ninety percent ofthe growth ofa specified pathogen, in ug/ml.
`tetroxoprim, trimethoprim), nitrofiirans (e.g., furaltadone,
`[0055] Non-limiting examples ofantibacterial agents other
`fiirazolium chloride, nifuradene, nifitratel, nifurfoline,
`
`than the quinolones having antibacterial agent other than the
`nifurpirinol, nifurprazine, uifurtoinol, nitrofuirantoin), qui-
`
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`
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`quinolones; having Formulae 1, II, III, IV, V, VI,VIl, and VIII
`nolones and analogs (e.g., cinoxacin, ciprofloxacin, cIina-
`
`
`include biologically-derived antibacterial agents such as ami-
`floxacin, difloxacin, enoxacin, fleroxacin, flumequine, gati-
`
`
`
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`noglycosides (e.g., arnikacin, aprarnycin, arbekacin, bamber~
`lloxacin,
`grepalloxacin,
`levolloxacin,
`lomelloxacin.
`
`
`miloxacin, moxifloxacin, nadifioxacin, nalidixic acid, nor-
`mycins, butirosiu, dibekacin, dihydrostreptomycin, forti1ni-
`cin(s), gentamicin, isepamicin, kanamycin, micronomiciu,
`floxacin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin,
`neornycin, neomycin undecylenate, netilmicin, paromomy-
`pipemidic acid, piromidic acid, rosoxacin, rufloxacin, spar-
`cin, ribostamycin, sisomicin, spectinomycin, streptomycin,
`floxacin, temafloxacin, tosufloxaciu, trovafloxacin, sulfona—
`
`
`tobramycin,
`trospcctomycin), amphenicols (e.g., azidam-
`mides (e.g., acotyl sulfamethoxypyrazinc, benzylsulfamidc,
`
`fenicol, chlorampheni