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`therapeutic patents.
`-.pert opinion on
`9, no 5 (May 1999)
`snerai Collection
`•J 772 C9765
`?ceived: 06-22-2000
`
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`Ashley Publications
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`Vol. 9 No. 5
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`May 1999
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`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
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`IMBPCINE
`ESUlMSii •nateria
`NLM a
`-3'ubje.et UOOn^yi
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`ISSN 1354-3776
`
`MYLAN - EXHIBIT 1008
`
`

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`Senior Advisory Panel
`
`Abou-Gharbia M: Wyeth-Ayerst, USA
`Arnaud J-C: Servier, France
`Coombes 1: formerly Hoechst, UK
`Dalgleish A: St George's Hospital, UK
`de Clercq E: ffega Institut, Belgium
`Evans C: Chiroscience, UK
`Fitzgerald JD: Materia Medica, UK
`Floyd D: Bristol-Myers Squibb, USA
`Glennon RA: Virginia Commonwealth
`University, USA
`Hill CH: Roche, UK
`Jacobson KA: NIH, USA
`Krogsgaard-Larsen P: Danish School of
`Pharmacy Denmark
`Moos WH : Chiron Corp., USA
`Mullen A: Bayer AG, Germany
`Poste G: SmithKline Beecham, USA
`Rees D: Organon, UK
`Ross BC: Glaxo Wellcome, UK
`Steele PR: IP Consultant, UK
`Stevens RW: Pfizer, Japan
`Taylor JB: Rhdne-Poulenc Rorer, UK
`Terrett N: Pfizer, UK
`Timmermanns P: DuPont Merck, USA
`
`Section Editorial Board
`
`Pulmonary-Allergy, Derma tological,
`Gastrointestinal & Arthritis
`
`Djuric SW, Kaminski JJ, Landry Y, Lipani J,
`Murthy S, Norman P, Sircar JC, Summers JB,
`Talley JJ, Trivedi B, Whittaker M
`
`Anti-infectives
`
`Cooper RDG, Croft S, Furman P, Hector RF,
`Highfield P, Hunter PA, Kirst H, LeeVJ, Ridley
`R, Rodriguez M, Smith PW
`
`Biologicals, Immunologicals & Drug
`Delivery
`
`Amos M, Deonarain MP, Epenetos AA,
`George A, Graf H, Gregonardis G, Larner A
`
`Central 3 Peripheral Nervous Systems
`
`Baudy RB, Bousquet P, Christos T, Cliffe I,
`Costentin J, Franco R, Halazy S, Hoban C,
`Howard H, Johnson G, McElroy AB,
`Spence RR Williams M
`
`Cardiovascular & Renal
`
`Baldwin JJ, Chakravarty PK, Doherty AM,
`Grove R, MGIIer CE, Perone M, Spada AR
`Suckling KE, Trybulski E
`
`Oncologic, Endocrine & Metabolic
`
`Baldwin RW, Beeley NRA, Connors T, Dale I,
`Davis P, Dueholm KL, Ecker G, Fields G,
`Gallagher JT, Hindley RM, Hughes L,
`Martini I, Miller WR, Remuzzi G,
`Rosenberg S, Skibo E, Williams T
`
`Expert Opinion on Therapeutic Patents
`http://www.ashley-pub.com
`
`Commissioning Editor: Liz Williams
`Production Editor: Paula Rhodes
`Publisher: James Drake
`
`Aims and scope: Expert Opinion on Therapeutic Patents aims to provide an evaluated guide to
`developments in the recent patent literature. The journal is divided into six therapeutic sections.
`Each section is reviewed every six months, allowing systematic and comprehensive coverage of
`the most important topics:
`• Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis (January & July)
`• Anti-infectives (February & August)
`• Biologicals, Immunologicals & Drug Delivery (March & September)
`• Central & Peripheral Nervous Systems (April & October)
`• Cardiovascular & Renal (May & November)
`• Oncologic, Endocrine & Metabolic (June & December)
`Authors are encouraged to express their Expert Opinion of the status of the research under
`review, rather than to simply review the available data. Each issue of the journal contains
`annotated patent selections and short patent evaluations which highlight inventions and
`innovative ideas deemed by relevant experts to be of potential importance.
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`

`
`Expert Opinion on Therapeutic Patents
`
`Recent developments with oxazolidinone
`antibiotics
`
`Bernd Riedl & Rainer Endermann
`Bayer AG, Pharma Research Centre, D-42096 Wuppertal, Germany
`
`The emerging problems with multiple antibiotic-resistant Gram-positive
`cocci led to the re-evaluation of an antibacterial class of compounds, the
`oxazolidinones. During the 1990s, many companies such as Upjohn, Bayer,
`Zeneca, Roussel Uclaf, Marion Merrell Dow and Glaxo published their
`work on antibacterial active oxazolidinones. The primary work in this area
`started in the 1980s atDuPont. The efforts of these scientists led to N-phenyl
`and N-heteroaryl oxazolidinones with strong antibacterial activity in vitro
`and in vivo. The most advanced oxazolidinone, linezolid, discovered by
`scientists at Upjohn, is currently undergoing Phase III clinical trials.
`Keywords: antibiotic, DuP-721, enterococci, eperezolid, Gram-positive,
`linezolid, methicillin-resistant Staphylococcus aureus, methicillin-resistant
`Streptococcus epidermidis, monoamine oxidase inhibitors, mycobacteria,
`N-phenyl oxazolidinone, N-pyridyl oxazolidinone, N-thienyl oxazolidinone,
`oxazolidinone, penicillin-resistant Streptococcus pneumoniae, staphylococci,
`vancomycin-resistant enterococci
`
`Exp. Opin. Ther. Patents (1999) 9(5):625-633
`
`1. Introduction
`
`http ://www.ashley-pub.com
`
`Review
`Introduction
`1.
`2. N-Phenyl oxazolidinones
`3. N-Heteroaryl
`oxazolidinones
`4. Acyl group variations
`5. Oxazolidinone core unit
`modifications
`6. Non anti-infective
`activities
`7. Expert opinion
`Bibliography
`Patents
`
`The evolution and spread of resistance to currently available antimicrobial
`agents in important pathogens is a serious medical problem [1-3]. In
`particular, infections caused by multiresistant Gram-positive cocci are a
`threat in antibacterial therapy. Therefore, the primary focus of the
`worldwide antibiotic discovery programs is the identification of newr
`compound classes with novel mechanisms of action.
`The oxazolidinones represent a relatively new class of orally active,
`synthetic antimicrobial agents with a Gram-positive spectrum of activity.
`They inhibit an early event in the bacterial protein biosynthesis [4-6]. After
`sequencing the ribosomalRNAgenes of oxazolidinone-resistant strains and
`comparing it to sensitive parental strains, mutations were found in the
`peptidyl transferase domain of the 23S rRNA [7]. This supports earlier results
`that demonstrated oxazolidinone binding to the SOS subunit of the
`ribosome [8-10]. A recent publication [11] describes the target for oxazolidi­
`nones in more detail. Drug binding sites were found on both ribosomal
`subunits. The 16S and the 23S rRNAs are directly involved in oxazolidinone
`binding. Furthermore, the inhibition of tRNA translocation is discussed as
`mechanism of action.
`as
`such
`activity
`antibacterial
`Oxazolidinones with
`S-^-acetamidomethyW- aryl-2-oxazolidinones were first described in the
`1980s by scientists from DuPont [12-14]. In 1987 at the 27th IG\AC, DuPont
`presented two candidate compounds DuP-721 [15-17] and DuP-105 [15,16],
`625
`1999© Ashley Publications Ltd. ISSN 1354-3776
`
`

`
`626 Recent developments with oxazolidinone antibiotics
`
`O
`
`o
`\ 1
`W^-N O
`
`HO
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`
`demonstrating high in vitro and in vivo activity vs.
`Gram-positive pathogens and Mycobacterium
`tuberculosis [18].
`
`The increasing clinical problems with multiresistant
`pathogens along with the attractive properties of the
`oxazolidinones encouraged workers at Upjohn to
`start a discovery program [19]. These efforts led to two
`clinical candidates, eperezolid (2, U-100592) and
`linezolid (1, U-l00766) [20,21], Both compounds
`exhibited potent in vitro activity against
`Gram-positive bacteria, including multiresistant
`strains [22,23]. In various experimental infections,
`these oxazolidinones demonstrated excellent
`therapeutic efficacy [24]. Toxicological studies of the
`candidates in rats and dogs showed a fevourable
`safety profile. In Phase I studies using either p.o. or iv.
`dosing, eperezolid (2) and linezolid (1) achieved
`plasma concentrations above the MIC values of
`relevant pathogens [25]. Both oxazolidinones are
`well-tolerated in humans at clinically relevant doses
`[26]. For a given dose, linezolid (1) produced higher
`plasma levels than eperezolid (2). Due to its advanta­
`geous pharmacokinetic profile, Upjohn continued the
`clinical development program with linezolid (1).
`During Phase II clinical trials, linezolid (1) was studied
`© Ashley Publications Ltd. All rights reserved.
`
`in a dose range of750 - 1000 mg/day for up to 21 days.
`The oxazolidinone showed good efficacy and
`excellent tolerability. Phase HI clinical trials are
`underway.
`
`Bayer has also taken interest in this compound class
`and new N-heteroaryl oxazolidinones with improved
`antimicrobial activity have been prepared. Modifica­
`tions of the oxazolidinone core unit have been
`reported by Zeneca, Marion Merrell Dow [27], Roussel
`Uclaf [28], Glaxo [29] and Pharmacia & Upjohn.
`
`In addition to the antimicrobial activity, other pharma­
`cological activities of the oxazolidinones have been
`reported.
`
`A comprehensive review from Brickner [19] discussed
`the structure-activity relationship (SAR) findings of
`DuPont and Upjohn and described in detail the
`oxazolidinones that entered clinical trials. Our review
`will focus on the recent activity selected from
`the
`patent literature since 1996.
`
`2. N-Phenyl oxazolidinones
`
`The N-phenyl oxazolidinones are the most advanced
`series of antibacterial oxazolidinones, first described
`by DuPont in the 1980s.
`
`DuPont presented compounds bearing a
`^-S-acetamidomethyl side-chain, DuP-721 and
`DuP-105. Both oxazolidinones demonstrated good in
`vitro and in vivo activity against Gram-positive
`pathogens. These parentally and orally active
`candidates entered Phase I clinical trials, but the
`development was later discontinued for tolerability
`reasons.
`
`Scientists at Upjohn focused on fluorine substituted
`N-phenyl oxazolidinones [30].
`
`The most promising representative of the 3-fluoro-N-
`phenyl-oxazolidinone series
`is
`linezolid
`(('5j-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-
`-5-oxazolidin-yl]methyl]-acetamide) (1) [116], which
`was identified in the early 1990s. It possesses good in
`vitro and in vivo potency vs. Gram-positive bacteria
`such as staphylococci [31], pneumococci [32] and
`enterococci [33,34], including resistant strains
`(methicillin-resistant Staphylococcus aureus [MRSA],
`methicillin-resistant Streptococcus epidermidis
`[MRSE], penicillin-re sistant Strep to coccus pneumoniae
`[PRSP], vancomycin-resistant enterococci [VRE]).
`linezolid (1) is currendy in clinical development
`Exp. Opin. Ther. Patents (1999) 9(5)
`
`

`
`(Phase III) for
`severe hospital infections. The
`3-fluoro-N-phenyl subclass seems to have both good
`in vivo potency and low toxicity.
`Antibacterial therapy of intensive care unit (ICU)
`patients requires iv.-treatment Most of the antibacte­
`rial oxazolidinones are insoluble in water and are
`therefore causing difficulties in finding a suitable iv.
`formulation. Upjohn described the water solubility
`and antibacterial activity of N-oxides [117] including
`the N-oxide of linezolid (1). This N-oxide retained
`most of linezolid's antibacterial activity (MIC = 4
`(Xg/ml vs. S. aureus UC 9213) and had good water
`solubility (N-oxide 348 mg/ml, linezolid 3.7 mg/ml).
`This prodrug approach should help in finding suitable
`iv. formulations for oxazolidinones. This is not
`necessary for linezolid (1) since there is an
`appropriate iv. formulation already in use.
`The main focus of the discovery program at Upjohn
`was the evaluation of the SAR around the 3-fluoro-N-
`phenyl oxazolidinones. The common feature of these
`3-fluoro-N-phenyl oxazolidinones is a nitrogen
`containing heterocycle attached to the 4-position of
`the phenyl ring.
`heterocycles were
`Small four- and five-membered
`described in 1996 [101], and exhibited reasonable in
`vitro potency (3, MIC vs. S. aureus or Streptococcus
`pneumonia ~ 1 - 4 |ig/ml).
`N-Fluorophenyl oxazolidinones substituted with
`bicyclic nitrogen containing heterocycles were
`described [102,107] and exhibited good efficacy after
`oral dosing (ED50 ~ 5 mgAg) in murine infections
`caused by £ aureus.
`Aromatic five-membered nitrogen containing hetero-
`cycles in the 4-position of the N-phenyl
`oxazolidinones increased the in vitro potency 2- to
`4-fold compared to the corresponding non-aromatic
`analogues. These compounds were described by
`scientists from Upjohn [103] and Zeneca [104]. Formyl
`groups as substituents in the distal ring (4) increased
`the activity. The same effect was observed by Bayer
`scientists [105] in the N-heteroaryl oxazolidinone
`series. These formyl compounds cannot translate their
`excellent in vitro potency into in vivo efficacy (due to
`pharmacokinetic and metabolic problems).
`the
`in
`The most promising compounds
`N-(3-fluorophenyl)oxazolidinone series, substituted
`with a five-membered
`aromatic heterocycle, are the
`thiazole substituted compounds [35].
`(3-Fluoro-4-(2-(5-cyanothiazolyl))phenyl-2-oxo-5-
`© Ashley Publications Ltd. All rights reserved.
`
`Riedl & Endermann 627
`
`0
`
`k A 0
`
`NHCOCHj
`
`5
`
`6
`
`NHCOCH3
`
`v
`
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`H. NHCOCH3
`
`NC
`
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`
`8 R =
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`
`CHj
`
`0 "
`• +
`
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`o-N TX^0"-
`
`oxazolidinyl)methyl)acetamide (5) exhibited very
`strong antibacterial in vitro activity against
`Gram-positive cocci (MIC vs. S. aureus <0.125 (ig/ml)
`as well as against fastidious Gram-negative organisms
`(MIC vs. Haemophilus influenzae 30063 ~2 (Ag/ml).
`The left side of the molecule allows for many
`variations. Besides the above mentioned small four-
`and five-membered
`heterocycles, large tricyclic
`systems connected to the oxazolidinone still showed
`reasonable in vitro potency [106] (6, MIC vs. S. aureus
`~2 - 4 Hg/ml).
`Another field of intense research within the area of
`N-phenyl-oxazolidinones are the piperazine deriva­
`tives exemplified by ('i'y)-N-(3-(3-fluoro-4-(4-(4-
`pyrimidinyl) - l-piperazinyl)phenyl-2-oxo-5-
`oxazolidinyl)methyl)acetamide (7). Scientists from
`Upjohn [108] and Zeneca [109,110] reported
`compounds with good MIC values and reasonable in
`vivo potency (7, ED50 =4.4 mgAg, S- aureus infection
`in mice). The heterocycles in 4-position of the pipera­
`zine unit are mainly pyrimidine, pyridine and other
`nitrogen containing five- and six-membered heterocy­
`cles [36]. Even large substituents like 2-(6-nitro-
`benzothiazole) on the piperazine unit [111] exhibited
`strong potency vs. Gram-positive bacteria (8, MIC vs.
`Exp. Opin. Ther. Patents (1999) 9(5)
`
`

`
`628 Recent developments with oxazolidinone antibiotics
`
`H3C~N^\
`
`F\
`
`O
`A
`
`x^\ 3
`
`9
`
`o
`L A
`
`NHCOCHj
`
`NHCOCHj
`
`10 R = S
`11 R = SO2
`
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`
`HO
`
`\
`
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`
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`= ^ / N O
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`
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`NHCOCH3
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`15 X = S
`16 X = SO
`17 X = S02
`
`NHCOCHj
`
`NHCOCHJ
`
`J-, aureus =0.5 (ig/ml). This is another indication that
`there are few space limitations on the left side of the
`molecule.
`
`Researchers at Zeneca described lactam analogues
`[112] of the above mentioned piperazines, exempli­
`fied
`by N-('i'/)-[3-(3-fluoro-4-[4-methyl-3-
`oxopiperazin-1 -yl]phenyl) -2-oxooxazolidin-5-
`ylmethyl]acetamide (9). This compound showed
`similar MIC values (9, MIC vs. Gram-positive cocci =
`© Ashley Publications Ltd. All rights reserved.
`
`0.5 - 2 (ig/ml) compared to the corresponding
`piperazines.
`Another subclass in this area is the thiomorpholino
`derivatives [113] such as ^-N-[[3-[3-fluoro-4-(4-
`thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]
`methyljacetamide (U-100480) (10) and the
`corresponding sulfone (U-101244) (11). Both showed
`strong activity against mycobacteria [37] such as
`Afycobacterium tuberculosis (10, MIC =0.5 (Xg/ml, 11,
`MIC =0.5 (ig/ml) and My cobacte riu m avium (10, MIC
`= 1 (ig/ml, 11, MIC =2 (ig/ml). This particular patent
`[113] includes in vivo data for a tuberculosis model.
`The last subclass of nitrogen containing heterocycles
`are the 4-piperidines and 4-tetrahydropyridines,
`exemplified by ^i1>)-(-)-N-[[3-[4-[l-(hydroxya-
`cetyl)-3,6-dihydro-2H-pyridin-4-yl]-3-fluorophenyl]-2
`-oxo-5-oxazolidinyl]methyl]acetamide (12). Scientists
`from Upjohn [114] and Zeneca [115] are working in
`this area. The in vivo activities in this class look
`promising (12, S. aureus infection in mice, ED50 = 1
`mg/kg).
`
`3. N-Heteroaryl oxazolidinones
`Scientists at Bayer started to look at N-heteroaryl
`oxazolidinones. Bioisosteres for the phenyl
`substituenton the oxazolidinones, such as thiophenes
`[105] and pyridines were investigated as well as benzo
`annellated five- and six-membered heterocycles.
`The most active compounds in vitro in the N-thienyl
`oxazolidinone series [105] have a phenyl substituent
`in the 5-position of the thiophene unit, which is
`further substituted with formyl groups in the 3- and
`4-position. These compounds exhibited strong in
`vitro activity (MIC -0.25 |ig/ml) but no in vivo activity
`(due to metabolic and pharmacokinetic problems).
`Replacement of the phenyl substituent on the thienyl
`unit with a 3-pyridyl (13), or a 4-pyridyl unit, led to
`compounds with strong in vitro and in vivo potency
`[38,39].
`The N-pyridyl oxazolidinones [40] exhibited similar
`SAR. The compound with the best in vivo activity
`within this series is the bispyridyl oxazolidinone (14)
`[39]. This compound exhibited high serum levels in
`mice after oral dosing and therefore, showing similar
`to superior in vivo potency compared to linezolid (1)
`in experimental infections.
`Another focus at Bayer is the oxazolidinones with
`benzo anellated five- and six-membered heterocycles
`Exp. Opin. Ther. Patents (1999) 9(5)
`
`

`
`connected to the oxazolidinone nitrogen [118-120].
`The 6-N-oxazolidinyl benzothiazoles [118] exhibited
`good in vitro antibacterial potency (16, MIC vs.
`Gram-positive cocci 0.25 - 2 ng/ml). The best substitu-
`ents on the benzothiazole (2-position) seems to be
`thiomethyl (15), the corresponding sulfoxide (16)
`and sulfone (17). The non-aromatic benzo anellated
`five-membered heterocycle series demonstrated even
`better antibacterial potency in vitro (18 [41,120] MIC
`vs. Gram-positive cocci 0.06 - 0.25 |ig/ml). In addition,
`they possessed comparable or even better in vivo
`efficacy than linezolid (1). Compound 19 reportedly
`[42] exhibited strong activity in murine 5. aureus
`sepsis models (ED100 = 25 mg/kg).
`The switch from
`the benzo anellated to the pyrido
`anellated series caused a loss in activity by a fector of 4
`- 8 [121],
`
`4. Acyl group variations
`
`The SAR of the methylamino acyl group in the
`5-position of the oxazolidinone seemed to be
`narrowed down to acetyl amino methyl in this
`position. Most of the companies, which are active in
`the field of oxazolidinone s with antibacterial activity,
`use this substituent preferentially.
`
`There are three patents from Bayer [122-124] and one
`from Pharmacia & Upjohn [138] describing different
`acyl groups and amide replacements in the 5-position
`of the oxazolidinone. All of these groups are unpolar
`and rather small. The thioacetyl aminomethyl group
`(20) instead of the acetyl aminomethyl substituent in
`the 5-position of the oxazolidinone [123] led to very
`potent compounds (20, MtCyj. Gram-positive cocci <
`0.125 ng/ml).
`
`Other small groups are also tolerated [43]. Methylcar-
`bamate analogues of the 5-aminomethyl
`oxazolidinones as well as trifiuoropropionate [124]
`derivatives (21) are described with reasonable in vitro
`potency. The N-bispyridyl oxazolidinone carbamate
`(22) [42] exhibited, despite its only moderate in vitro
`vivo efficacy (ED100 = 25 mg/kg
`activity, excellent
`systemic infection in mice with 5. aureus 48N), which
`is due to an improved pharmacokinetic profile. All of
`these modifications led to slightly less active
`compounds, compared to their acetyl aminomethyl
`analogues, but improved the pharmacokinetic
`profiles in rodents (longer lasting serum levels due to
`improved stability).
`© Ashley Publications Ltd. All rights reserved.
`
`Riedl & Endermann 629
`
`\
`
`/
`
`H3C
`
`w
`
`rCMo
`
`NHR
`
`18 R=COCH3
`19 R=COCH2CH3
`20 R=CSCH3
`
`O
`
`7 \\ A o q
`
`M
`
`\_N
`H
`
`CF3
`
`21
`
`V
`
`Nsa,
`
`O
`N O O P",
`
`\
`
`N«a,
`
`o
`
`H3C
`
`\
`
`H
`
`NHCOCH3
`
`22
`o
`t ?
`
`23
`
`N'I
`
`\
`
`.M. t o
`
`24
`5. Oxazolidinone core unit modifications
`
`NHCOCH3
`
`The first oxazolidinone core unit modifications date
`back to 1994. Scientists from Roussel Uclaf [28]
`published their work in the area of replacements of
`the central oxazolidinone moiety. The corresponding
`butenolide (23), pyrrolidinone and pyrrolidine to
`DuP-721 have been prepared. The only replacement
`tolerated was the butenolide (24) where similar in
`vitro activity to DuP-721 was observed. Similar results
`were described by Glaxo [29] in 1996.
`
`Researchers at Marion Merrell Dow [27] explored the
`oxazolidinone core unit in a very systematic
`approach, incorporating open chain analogues of
`DuP-721 as well as imidazolidin-2-ones, thiazolidin-
`2-ones, oxazolidine-2-thiones, 1,2,3-oxathiazolidin-
`2-ones or 2,2-diones, and 1,3,2-oxazaphospholidin-
`Exp. Opin. Ther. Patents (1999) 9(5)
`
`

`
`630 Recent developments with oxazolidinone antibiotics
`
`2-ones. These modifications led to compounds
`without any antibacterial activity.
`Researchers at Pharmacia Upjohn [125] replaced the
`oxazolidinone core unit with an isoxazoline unit and
`retained most of the in vitro antibacterial activity (loss
`of a factor 2-4 compared to the corresponding
`oxazolidinone). fRj-N-^S-Dihydro-S-tHl^S^-
`te trahydro-1-(hydroxy acetyl)-4-pyridinyl]phenyl]-5-
`isoxazolyl]methyl] acetamide (24) showed good in
`vitro antibacterial activity (MIC vs. Gram-positive
`cocci: 0.5 - 4 |ig/ml) and reasonable in vivo activity
`(ED50 = 6 mg/kg in murine i1. aureus sepsis model).
`Butenolides and isoxazolines are the only oxazolidi­
`none replacements that have retained some
`antibacterial activity. There has been no reported
`improvement in properties such as the pharmacoki­
`netic profile or tolerability.
`
`6. Non anti-infective activities
`Oxazolidinone s without anti-infective activity have
`been known for a long time. By inhibition of the
`monoamine oxidase (MAO) [44], oxazolidinones
`increase central nervous system (CNS) levels of
`biogenic amines and are used for the treatment of
`depression. Synthelabo described novel oxazolidi­
`nones [126] with MAO inhibitor activity. (^-5-
`Methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-l,2-
`benzisoxazol-3-yl]oxazolidin-2-one is specifically
`claimed. In 1997, Synthelabo filed
`three additional
`patents [127-129] on oxazolidin-2-ones which may be
`used for the treatment of depression or neurodegen­
`erative disease.
`Tanabe Seiyaku [130] reported the antireserpine
`activity of ('R)-3-[6-(cyclopropyl-methoxy)
`naphthalen-2-yl]-5-methoxymethyloxazolidin-2-one
`in a rat ischaemic brain model. The compound was
`claimed for the treatment of cerebrovascular disease
`and depression.
`Oxazolidinones described by Tanabe Seiyaku [131]
`increase the levels of dopamine in the rat striatum.
`These derivatives are stated to be efficacious when
`co-administered with L-DOPA for the treatment of
`Parkinson's disease.
`piperidinyl-
`identified
`Merck GmbH
`methyloxazolidin-2-one [132] derivatives as
`CNS-active compounds. These agents may be used for
`the treatment of sleeping disorders as well as for the
`treatment of depression.
`© Ashley Publications Ltd. All rights reserved.
`
`Novel oxazolidinone derivatives which inhibit platelet
`aggregation are claimed by Boehringer Mannheim
`[133] and Merck GmbH [134-136]. The compounds act
`as fibrinogen antagonists [45] and may be useful in the
`treatment of thrombosis and myocardial infarction.
`
`3-Phenyl-5-(3-indolylpiperidinylmethyl) oxazolidin-
`2-ones, acting as 5-HT2A antagonists and inhibiting
`5-HT reabsorption, were claimed by Merck GmbH
`[137]. These compounds may be useful for treatment
`in neurodegeneration and central nervous disorders.
`
`7. Expert opinion
`
`The oxazolidinone s demonstrate excellent activity
`against Gram-positive pathogens, especially against
`staphylococcus and streptococcus species. In view of
`increasing resistance problems in clinical settings, the
`potency of this class of compounds against multiple
`antibiotic resistant organisms is very important Their
`spectrum of activity also includes M tuberculosis. The
`oral bioavailability of these compounds is an
`additional benefit, as it allows for sequential therapy.
`These attractive properties resulted in the clinical
`development of Pharmacia & Upjohn's linezolid for
`the treatment of infections due to susceptible and
`resistant Gram-positive bacteria. In Phase HI clinical
`trials, linezolid appears to be highly efficacious and
`well-tolerated.
`
`Further research in the field of oxazolidinones should
`broaden the spectrum of activity to include clinically
`relevant Gram-negative pathogens. The activity of
`thiazole substituted compounds from the
`N-(3-fluorophenyl)oxazolidinone series against the
`fastidious Gram-negative organism Haem ophilu s
`influenzae indicates that this goal can be reached by
`oxazolidinone derivatisation programs. The optimisa­
`tion of the structure-toxicity relationship will be an
`important prerequisite for the entry into the general
`practitioner market.
`
`With these characteristics the oxazolidinones
`represent a valuable class of fully synthetic antibacte­
`rial agents.
`
`The urgent medical need for entirely new classes of
`antibiotics, for the treatment of infections caused by
`resistant organisms makes future efforts in the area of
`oxazolidinones necessary.
`Exp. Opin. Ther. Patents (1999) 9(5)
`
`

`
`Bibliography
`
`Papers of special note have been highlighted as:
`•
`of interest
`• •
`of considerable interest
`
`TOMASZ A: Multiple-antibiotic-resistant pathogenic
`bacteria. New Engl. J. Med. (1994) 17:1247-1251.
`
`SERVICE RF: Antibiotics that resist resistance. Science
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`LEVY SB: The challenge of antibiotic resistance. Set. Am.
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`EUSUCE DC, EELDMAN PA, ZAJAC I, SLEE AM: Mecha-
`nism of action of DuP-721: inhibition of an early event
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`DALY JS, EUOPOULOS GM, REISZNER E, MOELLERING
`RC: Activity and mechanism of action ofDuP-105 and
`DuP-721, new oxazolidinone compounds. J. Antimi-
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`
`EUSUCE DC, EELDMAN PA, SLEEAM: The mechanism of
`action of DuP-721, a new antibacterial agent: effects on
`macromolecular synthesis. Biochem. Biophjs. Sex. Com-
`mun. (1988) 150:965-971.
`
`SWANEY SM, SHEMABARGER DL, SCHAADTRD, BOCKJH,
`SLIGHTOMJL, ZURENKO GE Oxazolidinone resistance
`is associated with a mutation in the peptidyl transfe-
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`nia (1998). Abstract C-104.
`
`UN AH, MURRAY RW, VIDMARTJ, MAROTTKR: The oxa-
`zolidinone eperezolid binds to the SOS ribosomal
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`Recent discussion of the oxazolidinone binding side.
`
`SWANEY SM, AOKI H, GANOZA MC, SHINABARGER DL
`The oxazolidinone linezolid inhibits initiation of pro­
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`Recent discussion of the mode of action.
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`BURGHARDT H, SCHIMZ KL, MULLER M On the target of
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`FEBSUtt. (1998) 425:40-44.
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`11. MATASSOVANB, RODNEMAMV, ENDERMANNRetal.: Ri-
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`12.
`
`13.
`
`GREGORY WA, BRnTELLI DR, WANG C-IJ etal: Antibac-
`terials. synthesis and structure-activity studies of 3-
`aryl-2-oxazolidinones. 1. The 'B' group./. Med. Cbem.
`(1989) 32:1673-1681.
`Good example of SAR.
`
`GREGORY WA, BRITTELLI DR, WANG C-IJ etal: Antibac-
`terials. synthesis and structure-activity studies of 3-
`aryl-2-oxazolidinones. 2. The 'A' group./. Med. Cbem.
`(1990) 33:2569-2578.
`Good example of SAR.
`
`Riedl & Endermann 631
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`PARKC-H, BRrrTEUI DR, WANG C-IJ etal.-. Antibacteri-
`als. Synthesis and structure-activity studies of 3-aryl-
`2-oxazolidinones. 4. Multiply-substituted aryl deriva-
`lives. J. Med. Cbem. (1992) 35:1156-1165.
`Good example of SAR.
`
`SLEE AM, WUONOLA MA, MCRIPIEY RJ et«/.: Oxazolidi-
`nones, a new class of synthetic antibacterial agents: in
`vitro andlfl vivo activities ofDuP-105 andDuP-721 .^4z-
`timicrob. Agents Chemother. (1987) 31:1791-1797.
`Early example of antibacterial active oxazolidinones.
`
`BRUMFTTT W, HAMtLTON-MUIFK JMT: In vitro micro-
`biological activities of DuP-105 and DuP-721, novel
`synthetic oxazolidinones. J. Antimicrob. Chem other.
`(1988) 21:711-720.
`
`17. WANG C-IJ, GREGORY WA, WUONOLA MA: Chiral syn­
`thesis of DuP-721, a new antibacterial agent. Tetrahe-
`dron (1989) 45:1323-1326.
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`ASHTEKAR DR, COSTA-PERIERA R, SHRIMVASAN T,
`lYYER R, VISHAVANATHAN N, RITTEL W: Oxazolidi­
`nones, a new class of synthetic antituberculosis agent.
`in vitro and in vivo activities of DuP-721 against Myco­
`bacterium tuberculosis. Diagn. Microbiol. Infect. Dis.
`(1991) 14:465-471.
`
`BRICKNERSJ: Oxazolidinone antibacterial agents. Curr.
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`Recent overview of the field of antibacterial oxazolidinones.
`
`Linezolid, U-100766. Drugs Future (1996) 21:1116-1123.
`Summary of the clinically most advanced oxaz